PMID- 23432603 TI - Local redundancy governs infants' spontaneous orienting to visual-temporal sequences. AB - Two experiments demonstrate that 5-month-olds are sensitive to local redundancy in visual-temporal sequences. In Experiment 1, 20 infants saw 2 separate sequences of looming colored shapes that possessed the same elements but contrasting transitional probabilities. One sequence was random whereas the other was based on bigrams. Without any prior exposure, infants looked longer at the random sequence. In Experiment 2, 17 infants looked equally long at bigram- and trigram-based sequences. However, an analysis of local redundancy revealed that in both experiments disengagement from the sequences was governed by local repetitions rather than by global sequence statistics. This finding suggests that a spontaneous sensitivity to stimulus complexity helps orient infants to sequences they can learn from. PMID- 23432604 TI - Preliminary reliability and validity testing of a self-efficacy questionnaire for Chinese family caregivers. AB - OBJECTIVES: To develop and test preliminary reliability and validity of a Self Efficacy Questionnaire for Chinese Family Caregivers (SEQCFC). METHODS: A cross sectional survey of 196 family caregivers (CGs) of people with dementia (CGs) was conducted to determine the factor structure of a SEQCFC of people with dementia. Following factor analyses, preliminary testing was performed, including internal consistency, 4-week test-retest reliability, and construct and convergent validity. RESULTS: Factor analyses with direct oblimin rotation were performed. Eight items were removed and five subscales (self-efficacy for gathering information about treatment, symptoms and health care; obtaining support; responding to behaviour disturbances; managing household, personal and medical care; and managing distress associated with caregiving) were identified. The Cronbach's alpha coefficients for the whole scale and for each subscale were all over 0.80. The 4-week test-retest reliabilities for the whole scale and for each subscale ranged from 0.64 to 0.85. The convergent validity was acceptable. CONCLUSIONS: Evidence for the preliminary testing of the SEQCFC was encouraging. A future follow-up study using confirmatory factor analysis with a new sample from different recruitment centres in Shanghai will be conducted. Future psychometric property testings of the questionnaire will be required for CGs from other regions of mainland China. PMID- 23432605 TI - Ex vivo comparison of bursting strength of ventral median and right ventral paramedian celiotomies in horses. AB - OBJECTIVE: To compare bursting strength and failure mode between ventral median (VM) and right ventral paramedian (RVP) celiotomies closed with 1 section of USP 7 braided polydioxanone (7PD). STUDY DESIGN: Ex vivo experimental. ANIMALS: Equine cadavers (n = 12). METHODS: A 25 cm VM or RVP (positioned 5 cm lateral to the linea alba) celiotomy was created in fresh equine cadavers. A 200 L polyurethane bladder was inserted into the abdomen. Celiotomies were closed in a simple continuous pattern with 1 section of 7PD. The bladder was inflated with compressed air until construct failure. Horse signalment, body weight, celiotomy type, failure mode (suture or abdominal wall), failure location (adjacent or remote from the celiotomy), and bursting strength (mmHg) were recorded. Interactions between independent and dependent variables were assessed with statistical tests including linear regression. RESULTS: Increasing age (P = .002) and Quarter horse-type breed (P = .01) had a negative effect on bursting strength. When age and breed were controlled, RVP celiotomies had a lower bursting strength compared with VM celiotomies (P = .039). None of the celiotomies failed at the suture. CONCLUSION: VM celiotomies have a greater bursting strength than RVP celiotomies when age and breed are controlled. Celiotomy bursting strength decreases with increasing age and is lower in Quarter horse-type breeds compared with non-Quarter horse-type breeds. PMID- 23432606 TI - A life-course perspective on economic stress and tobacco smoking: a population based study. AB - AIMS: To investigate the associations between economic stress in childhood and adulthood and tobacco smoking, with reference to the accumulation, critical period and social mobility hypotheses from life-course epidemiology. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: The 2008 public health survey in Skane, Sweden is a cross-sectional postal questionnaire study based on a random sample which yielded 28 198 participants aged 18-80 years (55% participation). Logistic regression models were used to investigate associations between economic stress in childhood and adulthood and tobacco smoking. FINDINGS: A 17.4% prevalence of men and 19.1% of women reported tobacco smoking. Tobacco smoking was more prevalent among middle-aged men and young women, among those born outside Sweden, with low occupational status, low social support, low trust, economic stress in childhood and adulthood. The accumulation hypothesis was confirmed because combined childhood and adulthood exposures to economic stress were associated (P < 0.001) with tobacco smoking in a graded manner. The critical period hypothesis was not supported because the associations between economic stress in childhood as well as adulthood, respectively, and tobacco smoking were significant (P = 0.004 and P < 0.001) throughout the analyses. The social mobility hypothesis was confirmed because upward social mobility was associated significantly (P < 0.001) with lower odds of smoking, while downward social mobility was associated significantly (P < 0.001) with higher odds of smoking. CONCLUSIONS: Downward social mobility and economic stress in both childhood and adulthood should be considered as risk factors for tobacco smoking over the life-course. PMID- 23432608 TI - Surface-state engineering for interconnects on H-passivated Si(100). AB - Surface-state engineering strategies for atomic-size interconnects on H passivated Si(100) surfaces are explored. The well-known simple interconnect formed by removing H-atoms from one of the Si atoms per dimer of a dimer row along the Si(100) surface is poorly conducting. This is because one-dimensional like instabilities open electronic gaps. Here, we explore two strategies to reduce the instabilities: spacing the dangling bonds with H atoms and changing the geometry by increasing the lateral size of the wires. The resulting wires are evaluated using density functional theory. Surprisingly, zigzag dangling-bond wires attain atomically confined conduction properties comparable with the conduction of free-standing metallic monatomic wires. These results hint at band engineering strategies for the development of electronically driven nanocircuits. PMID- 23432607 TI - The role of angiogenin in pT1-T2 tongue carcinoma neo-angiogenesis and cell proliferation: an exploratory study. AB - BACKGROUND: Angiogenin (ANG) is a member of the ribonuclease superfamily and of medical interest largely because it supports the growth of primary and metastatic malignancies. This study is the first to investigate the potential role of ANG in tongue carcinoma neo-angiogenesis and cancer cell proliferation. METHODS: Angiogenin expression (in carcinoma cells and endothelial intratumor vessel cells), CD105-assessed micro-vessel density (MVD), and MIB-1 expression were correlated with prognostic parameters in 28 primarily consecutively operated pT1 T2 tongue carcinomas (squamous cell carcinoma [SCC]). Whenever feasible, a computer-based image analysis system was used for the immunohistochemical reaction analysis. RESULTS: No significant correlations emerged between ANG expression in the tongue carcinoma cells or endothelial intratumor vessel cells and tongue SCC recurrence rate or disease-free survival (DFS). ANG expression was also unrelated to CD105-assessed MVD or MIB-1 expression. Conversely, CD105 assessed MVD correlated directly with recurrence rate (P = 0.02) and DFS was significantly shorter in cases with CD105-assessed MVD >167 micro-vessels/mm(2) than in those with CD105-assessed MVD <=167 micro-vessels/mm(2) (P = 0.042). CONCLUSIONS: Our results support the hypothesis that CD105-assessed MVD would be a valuable parameter for predicting which patients with tongue SCC are at greatest risk of disease recurrence. Despite our study results, the role of ANG in tongue carcinoma warrants further investigation in larger series. PMID- 23432609 TI - Characteristics of fever, etiologic factors, antibiotic use and prognosis in febrile dermatology inpatients. AB - BACKGROUND: Generally, fever is observed in >30% of hospitalized patients. However, little is known about fever in dermatology inpatients. OBJECTIVES: The aim of this study was to investigate and document the incidence, characteristics, and etiologic factors of fever in febrile dermatology inpatients and to describe the practice of antibiotic use and prognosis in the same group. METHODS: The medical records for 928 inpatients were retrospectively analyzed. RESULTS: The incidence of fever was found to be 16.2%. Mean length of hospital stay was found to be longer in febrile patients. Of the 176 febrile episodes, 79 (44.9%) occurred in patients without infections, 43 (24.4%) in patients with community acquired infections, 25 (14.2%) in patients with healthcare-associated infections, 18 (10.2%) in patients classified with fever of non infectious/infectious causes, and 11 (6.3%) in a group for whom the etiologic factors of fever were undetermined. Antibiotic treatment was started in 36.2% of febrile inpatients. The overall mortality rate was 0.6%. CONCLUSIONS: This is the first study to investigate febrile episodes in dermatology inpatients. Fever is a frequently encountered symptom in dermatology inpatients. Febrile episodes resulted from mostly non-infectious entities, mainly consisting of inflammatory dermatologic disorders. Antibiotics were ordered in a higher percentage of patients in the febrile group. Dermatologists started prophylactic or empiric antibiotic therapy in febrile patients with non-infectious or inflammatory diagnoses on the assumption that these patients had an increased risk for infection as a result of impaired skin integrity and use of immunosuppressive drug therapy. The overall mortality rate was very low in the study group of dermatology inpatients. PMID- 23432611 TI - Blatchford score is a useful tool for predicting the need for intervention in cancer patients with upper gastrointestinal bleeding. AB - BACKGROUND AND AIM: The Blatchford score is based on clinical and laboratory variables to predict the need for clinical interventions in upper gastrointestinal bleeding (UGIB). The primary object was to evaluate the Blatchford score with clinical and full Rockall scores in patients with active cancer presenting to the emergency department with UGIB. The secondary object was to assess the accuracy of the Blatchford score at different source of UGIB; cancer bleeding versus non-malignant lesions. METHODS: We reviewed and extracted data from electronic medical record on patients with active cancer presenting to the emergency department from January 2009 to December 2011. Clinical interventions included blood transfusion, therapeutic endoscopy, angiographic intervention, and surgery. RESULTS: Of the 225 patients included, 197 (87.6%) received interventions. Comparing the area under receiver-operator curves, the Blatchford score (0.86, 95% confidence interval [CI] 0.77-0.95) was superior to clinical Rockall (0.67, 95% CI 0.55-0.79) and full Rockall score (0.72, 95% CI 0.61-0.83) in predicting interventions. When the score of 2 or less is counted as negative, sensitivity of 0.99 and specificity of 0.54 were calculated. When the patients were separated according to the source of UGIB, sensitivity and specificity were not changed. CONCLUSIONS: The Blatchford score outperformed both Rockall scoring system in predicting intervention in patients with active cancer. The source of bleeding was not important factor in the score performance. The Blatchford score has a very good sensitivity. However, suboptimal specificity limits its role as sole means of decision making in cancer patient with UGIB. PMID- 23432610 TI - Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin. AB - AIMS: Rifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults. METHODS: An integrated population pharmacokinetic model developed in nonmem 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, who were established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy. RESULTS: The bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children, respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared with those in adults. CONCLUSIONS: The model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug-drug interactions should be evaluated in paediatric patient populations. PMID- 23432612 TI - Cytotoxicity and topoisomerase I/II inhibition activity of novel 4-aryl/alkyl-1 (piperidin-4-yl)-carbonylthiosemicarbazides and 4-benzoylthiosemicarbazides. AB - A series of eight thiosemicarbazide derivatives was examined for cytotoxicity in breast cancer cell cultures. Among them, 4-benzoylthiosemicarbazides proved to be only slightly less potent than chlorambucil in both MDA-MB-231 and MCF-7 lines. In contrast, 4-aryl/alkylthiosemicarbazides revealed significantly lower cytotoxicity effect. Subsequently, all titled compounds were tested as potential human topoisomerase I and II (topo I and topo II) inhibitors. Mechanistic studies revealed that tested thiosemicarbazides act as both topoisomerase I and topoisomerase II inhibitors. Among them, the best inhibitory activity was found for 4-benzoylthiosemicarbazides (1 and 2) with IC50 at 50 uM against topo II. PMID- 23432613 TI - Avoiding bladder catheterisation in total knee arthroplasty: patient selection criteria and low-dose spinal anaesthesia. AB - BACKGROUND: Bladder catheterisation may be inconvenient for patients, delay mobilisation and risk complications. We hypothesised that by excluding pre operatively patients at high risk of post-operative urinary retention, the majority of patients could avoid perioperative catheterisation during low-dose spinal anaesthesia. METHODS: Patients undergoing total knee arthroplasty were assigned if fit for spinal anaesthesia and without severe symptoms of lower urinary tract obstruction, gross incontinence, mobilisation difficulties hindering micturition and > 200 ml residual urine volume. Bladder volume was monitored by ultrasound and temporary catheterisation advised if > 400 ml. RESULTS: Fifty-two patients (men 54%, age 65 +/- 9 years, body mass index 31 +/- 5, 30% with history of urinary tract problems) were included. Intrathecal hyperbaric bupivacaine given was 7.8 +/- 1.08 mg and always 7.5 MUg sufentanil providing sufficient anaesthesia in all cases. Crystalloid given during surgery was 8.5 +/- 4.0 ml/kg. Voluntary micturition was reached by 46 patients (88%, confidence interval (CI) 79-97%), but six (12%, CI 3-21%) needed temporary catheterisation once (four men/two women). Larger bladder volumes were found in those catheterised than those with voluntary micturition on the pre-operative (131 +/- 76 ml vs. 68 +/- 57 ml, P = 0.03) and first post-operative bladder scan (445 +/- 169 ml vs. 271 +/- 129 ml, P = 0.004). All but two patients (96%) could be mobilised the same day. No patient suffered bladder dysfunction. CONCLUSION: Low-dose spinal anaesthesia combined with simple selection criteria allowed for early mobilisation (96%) and avoidance of bladder catheterisation in the vast majority (88%) of patients undergoing total knee arthroplasty, and the rest (12%) only needed a single temporary catheterisation. PMID- 23432614 TI - Editorial: Intraoperative magnetic resonance spectroscopy and gliomas. PMID- 23432615 TI - An unusual cause of syncope: diaphragmatic hernia. PMID- 23432616 TI - Mammary ductal elongation and myoepithelial migration are regulated by the composition of the extracellular matrix. AB - Mammary branching morphogenesis occurs over a period of weeks deep inside an adipocyte-rich stroma. The adipocytes contain light-scattering lipid droplets that limit the depth of penetration of visible light. Organotypic culture methods were developed to enable high-resolution optical monitoring of branching morphogenesis ex vivo. A challenge has been to identify the best culture conditions to model specific developmental events. We recently demonstrated that collagen I induces protrusive invasion in both normal and neoplastic mammary epithelium. In this study, we observed that the abundance of collagen I fibrils correlated strongly with invasive behaviour, even when the collagen I concentration was identical. We found that the extent of fibril assembly was experimentally manipulable by varying the incubation time at 4 degrees C following pH neutralization. We next tested the capacity of collagen I fibrils to induce invasive behaviour when presented in combination with basement membrane proteins (Matrigel). We found that epithelial organoids in mixed gels of collagen I and basement membrane proteins exhibited more extensive branching morphogenesis but did not initiate protrusions into the matrix. Organoids in pure Matrigel produced many small epithelial buds that were bare of myoepithelial cells. Surprisingly, organoids in mixed gels of collagen I and Matrigel produced fewer epithelial buds, the buds elongated further, and the elongating buds remained covered by myoepithelial cells. Our mixed gels therefore provide a more physiologically accurate model of mammary branching morphogenesis. Our results also suggest that changes in the composition of the extracellular matrix could induce migration of epithelial cells past myoepithelial coverage. PMID- 23432617 TI - Thalidomide in systemic mastocytosis: results from an open-label, multicentre, phase II study. AB - Mastocytosis can lead to organ failure as well as systemic symptoms that can be disabling, with considerable deterioration in quality of life. Beside symptomatic treatments, interferon-alpha and purine analogues have been shown to be effective but complete or long-term remission is rarely obtained with these drugs. We conducted a phase II, multicentre, study to investigate thalidomide in severely symptomatic indolent and aggressive systemic mastocytosis. Twenty patients were enrolled of whom 16 were analysed for response. The overall response rate was 56%. Responses were observed in the skin in 61% of patients with a significant decrease in the pruritus score. Mast cell mediator-related symptoms responded in 71% of cases and 25% of aggressive systemic mastocytosis patients had a response in terms of B/C findings (borderline/cytoreduction needed). Bone marrow mast cell infiltration decreased in five of the eight evaluable patients. There was no significant improvement in the AFIRMM (Association Francaise pour les Initiatives de Recherche sur le Mastocyte et Les Mastocytoses), Quality of Life or Hamilton scores. Grade 3-4 toxicities consisted of peripheral neuropathy (11%) and myelosuppression (neutropenia: 5%; thrombocytopenia: 11%). In conclusion, thalidomide might be useful in mastocytosis and in the treatment of mast cell related symptoms. It might be considered in selected patients, taking into account the benefit/risk balance and the individual patient evaluation. PMID- 23432618 TI - A novel method of CD34+ cell separation from umbilical cord blood. AB - BACKGROUND: Umbilical cord blood (UCB) is rich in the heavily glycosylated CD34 antigen-bearing hematopoietic stem cells that are valuable for transplantation therapy of malignant and nonmalignant disease. CD34+ cell yields (0.13%-0.25% 0.3%) of mononuclear cells (UCMCs) isolated by anti-CD34 monoclonal antibody (MoAb) on immunomagnetic particles (e.g., Miltenyi particles) are insufficient to treat adults. STUDY DESIGN AND METHODS: We fractionated UCMCs by physicochemical charge-based methods. Avoiding Miltenyi particles and HESPAN yielded 30 x 10(6) to 54 x 10(6) UCMCs/20 mL UCB by Ficoll-Isopaque for serial depletion fractionation, using nylon wool column (NWC) or direct rosetting with sheep red blood cells (SRBCs) without incubation in the cold. RESULTS: CD34+ cell yields (approx. 5.12%) were 39 times greater than 0.13% (Korean study, 11,098 UCB units) and 10 to 20 times greater than 0.25% to 0.3% harvested by anti-CD34 Miltenyi particles. SRBC depletion of most high-specific-gravity T cells achieved considerable enrichment of CD34+ and BY55+ cells. Using NWC achieved 2.5-fold enrichment of CD34+ cells and twofold enrichment of BY55+ cells. Direct SRBC rosetting provided better or higher enrichment of CD34+ cells. Overall CD34+ cell yield in low-density fraction was more than twice after direct rosetting (38% vs. 16%) in contrast to separation by NWC followed by SRBC rosetting. CD3+ cell yields (by three CD markers) were approximately 8.83%, far below approximately 30 x 10(7) /kg considered acceptable to avoid graft-versus-host disease. Natural killer cell yields (CD16+/CD56+ and BY55+/ CD160+) are in perfect agreement. CONCLUSIONS: Achieving approximately 5% CD34+ cell yields from single UCB donations, a major advance, holds great promise for CD34+ cell therapy of adults and larger children, and cheaper cultured RBC manufacture. PMID- 23432619 TI - Castor oil and mineral oil nanoemulsion: development and compatibility with a soft contact lens. AB - CONTEXT: The non-invasive ophthalmic therapy has a drawback: low residence time in the eye socket. Nanoparticles and contact lenses have been studied as promising ocular drug delivery systems. OBJECTIVE: To develop a nanoemulsion and evaluate its compatibility with a soft contact lens as a potential strategy for ocular delivery. MATERIALS AND METHODS: The formulations were developed by spontaneous emulsification and fully characterized. Two drops of nanoemulsion were instilled on the surface of a commercial contact lens and its transparency was measured using a UV-Vis spectrophotometer. Before and after the instillation of the drops, the morphology (scanning electron microscopy - SEM) and ion permeability of the lenses were analyzed. RESULTS: The formulations had a mean particle size of 234 nm, polydispersity below 0.16, zeta potential of -8.56 +/- 3.49 mV, slightly acid pH, viscosity ~1.2 mPa s(-1) and spherical-shaped particles. Nanoemulsion was non-irritant (hen's egg test-chorioallantoic membrane), which was confirmed by the cytotoxicity studies in the SIRC cell cultures. After instillation, SEM analysis showed nanodroplets inside and on the surface of the lenses, although their transparency remained near 100%. No significant differences were found between lens ion permeability coefficients before and after instillation. CONCLUSIONS: Formulations presented appropriate physicochemical characteristics and suitability for ocular application. The contact lens remained transparent and ion-permeable after association with the formulation. PMID- 23432620 TI - What is your diagnosis? Impression smears of a cerebral mass from a dog. PMID- 23432621 TI - Fragment-based drug discovery using a multidomain, parallel MD-MM/PBSA screening protocol. AB - We have developed a rigorous computational screening protocol to identify novel fragment-like inhibitors of N(5)-CAIR mutase (PurE), a key enzyme involved in de novo purine synthesis that represents a novel target for the design of antibacterial agents. This computational screening protocol utilizes molecular docking, graphics processing unit (GPU)-accelerated molecular dynamics, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) free energy estimations to investigate the binding modes and energies of fragments in the active sites of PurE. PurE is a functional octamer comprised of identical subunits. The octameric structure, with its eight active sites, provided a distinct advantage in these studies because, for a given simulation length, we were able to place eight separate fragment compounds in the active sites to increase the throughput of the MM/PBSA analysis. To validate this protocol, we have screened an in-house fragment library consisting of 352 compounds. The theoretical results were then compared with the results of two experimental fragment screens, Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) binding analyses. In these validation studies, the protocol was able to effectively identify the competitive binders that had been independently identified by experimental testing, suggesting the potential utility of this method for the identification of novel fragments for future development as PurE inhibitors. PMID- 23432622 TI - Mind-mindedness and theory of mind: mediating roles of language and perspectival symbolic play. AB - Relations among indices of maternal mind-mindedness (appropriate and nonattuned mind-related comments) and children's: (a) internal state vocabulary and perspectival symbolic play at 26 months (N = 206), and (b) theory of mind (ToM) at 51 months (n = 161) were investigated. Appropriate comments were positively associated with ToM, but were unrelated to internal state language and perspectival symbolic play. Nonattuned comments were negatively correlated with internal state language and perspectival symbolic play, but were unrelated to ToM. Path analyses indicated that the best fit model assumed: (a) indirect links between nonattuned comments and ToM via children's perspectival symbolic play, (b) a direct link between appropriate comments and ToM, and (c) an indirect link between appropriate comments and ToM via children's concurrent receptive verbal ability. PMID- 23432623 TI - Factors that hinder organ donation: religio-cultural or lack of information and trust. AB - OBJECTIVES: This paper examines factors that influence Malaysian persons with a tertiary level of education on their willingness to donate organs. MATERIALS AND METHODS: A survey was done in the Klang Valley (Kuala Lumpur and its suburbs) at several designated locations. A total of 1420 people were approached, and we focused the sample of 688 respondents with a tertiary level of education. Respondents were given 2 sets of answers: (1) a religio-cultural category and (2) a structural category. They were allowed to choose more than 1 reason. RESULTS: Our findings revealed that only 47.5 percent of respondents declined becoming organ donors. The highest frequency recorded was "I am not convinced that my body part will be used beneficially " (30.1%), followed by "I do not have enough access to information " (29.2%), "I want my body to remain intact after death " (16.9%), and "It is against my religion " (9.9%). CONCLUSIONS: Our study revealed that religio-cultural factors are not a prime explanation for the lack of organ donation in the Malaysian case. This study suggests that better procurement methods used by dedicated agencies, as well as better education, could reduce the shortage between organ supply and demand. PMID- 23432624 TI - Immunohistochemical analysis of the monoclonal antibody 4B5 in breast tissue expressing human epidermal growth factor receptor 4 (HER4). AB - AIMS: A recent study examining the specificity of human epidermal growth factor receptor (HER) 2 pharmacodiagnostic antibodies demonstrated that CB11 and 4B5 stain both HER2-transfected and HER4-transfected cell lines. However, there has been no evidence showing that 4B5 has affinity for HER4 in clinically obtained tissues, and, if so, whether this has any impact on the assessment of HER2. We therefore sought to determine the expression of membrane-bound HER4 in clinical breast carcinomas, and evaluate its impact on the clinical utility of 4B5 in determining HER2 status. METHODS AND RESULTS: Breast carcinomas were assessed by immunohistochemistry (IHC) for membrane-bound HER4 using anti-HER4 clone E200. HER2 expression in these cases was then assessed using anti-HER2 clone 4B5, and a reference clone, SP3. In all 117 membrane HER4-positive cases (out of 241), 4B5 scored equal to or less than the reference anti-HER2 clone SP3. Eighteen cases were positive for membrane-bound HER4 by E200 and negative by 4B5, including a membrane HER4 level 3+ case. CONCLUSIONS: No cross-reactivity of 4B5 with membrane-bound HER4 was identified in the clinical IHC analysis of formalin-fixed paraffin-embedded breast carcinoma cases as evidenced by the HER4 antibody clone E200. PMID- 23432625 TI - Trametinib (GSK1120212) in the treatment of melanoma. AB - INTRODUCTION: The discovery of somatic mutations in melanoma has advanced our knowledge of the biology of the disease. The mutations, such as those in NRAS, BRAF, GNAQ and GNA11, promote the growth of melanoma cells in most part through the mitogen-activated protein kinase (MAPK) pathway. Understanding the molecular pathways of some of these mutations has resulted in the successful development of selective BRAF inhibitors. Yet, a cure for advanced melanoma is far from reality. Targeting MAPK/ERK kinase (MEK), an essential intermediary kinase protein within the MAPK pathway, may be a promising way to treat patients with BRAF or other genomic mutation. AREAS COVERED: The authors discuss the MAPK pathway in melanoma and review the preclinical and clinical studies of the MEK inhibitor, trametinib , in melanoma. They also discuss the potential of using trametinib in the targeted therapy of advanced melanoma. EXPERT OPINION: Studies have demonstrated the activity of trametinib in BRAF-mutant melanoma, suggesting that it could be a very reasonable alternative to BRAF inhibitors for these patients. Current clinical investigations have shown great promise with the combination of trametinib and dabrafenib in patients with BRAF-mutant melanoma; a number of clinical trials of trametinib in combination with other targeted drugs are underway. PMID- 23432627 TI - The experience of caregiving: the influence of coping strategies on behavioral and psychological symptoms in patients with Alzheimer's disease. AB - OBJECTIVES: To determine whether caregiver coping strategies are independently associated with behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) after accounting for patient characteristics. METHODS: Cross sectional data analysis of 80 patients with AD and their primary caregivers. The presence of BPS was recorded using the Neuropsychiatric Inventory (NPI). The relationship between caregiver characteristics and BPS was assessed through one way analysis of variance, two-tailed student t-tests or correlation coefficients. Multivariate linear regression was used to determine the combined effect of all caregiver factors that were significant on bivariate analysis regarding coping and BPS controlling for patient characteristics. RESULTS: Caregivers were on average 62 years old, 77% female, and most were the children or the spouse of the patient. Over 50% had significant depression or anxiety. Patients were on average 77 years old and 62% were female, and most had moderate to severe dementia. After adjusting for patient characteristics, patients cared for by more depressed, more burdened, or those using more disengagement coping strategies showed higher NPI mean composite scores. CONCLUSION: Coping strategies are associated with BPS regardeless of patient characteristics. Interventions to reduce BPS should focus on which psychological coping strategies caregivers use. Understanding how coping strategies influence BPS may help tailor specific interventions for caregivers. PMID- 23432628 TI - Targeting cytokines: production and characterization of anti-TNF-alpha scFvs by phage display technology. AB - The antibody display technology (ADT) such as phage display (PD) has substantially improved the production of monoclonal antibodies (mAbs) and Ab fragments through bypassing several limitations associated with the traditional approach of hybridoma technology. In the current study, we capitalized on the PD technology to produce high affinity single chain variable fragment (scFv) against tumor necrosis factor-alpha (TNF- alpha), which is a potent pro-inflammatory cytokine and plays important role in various inflammatory diseases and malignancies. To pursue production of scFv antibody fragments against human TNF- alpha, we performed five rounds of biopanning using stepwise decreased amount of TNF-alpha (1 to 0.1 MU g), a semi-synthetic phage antibody library (Tomlinson I + J) and TG1 cells. Antibody clones were isolated and selected through enzyme linked immunosorbent assay (ELISA) screening. The selected scFv antibody fragments were further characterized by means of ELISA, PCR, restriction fragment length polymorphism (RFLP) and Western blot analyses as well as fluorescence microscopy and flow cytometry. Based upon binding affinity to TNF-alpha , 15 clones were selected out of 50 positive clones enriched from PD in vitro selection. The selected scFvs displayed high specificity and binding affinity with Kd values at nm range to human TNF-alpha . The immunofluorescence analysis revealed significant binding of the selected scFv antibody fragments to the Raji B lymphoblasts. The effectiveness of the selected scFv fragments was further validated by flow cytometry analysis in the lipopolysaccharide (LPS) treated mouse fibroblast L929 cells. Based upon these findings, we propose the selected fully human anti-TNF-alpha scFv antibody fragments as potential immunotherapy agents that may be translated into preclinical/clinical applications. PMID- 23432626 TI - Characterizing the longitudinal patterns of substance use among individuals diagnosed with serious mental illness after psychiatric hospitalization. AB - AIM: To characterize longitudinal patterns of substance use across a large sample of psychiatric patients discharged from inpatient admission, followed for 1-year post-hospitalization. DESIGN: Prospective cohort study. SETTING: Kansas City, MO, USA; Pittsburgh, PA, USA; Worcester, MA, USA. PARTICIPANTS: Eight hundred and one schizophrenia-spectrum (n = 204), bipolar (n = 137) and depressive disorder (n = 460) patients from the MacArthur Violence Risk Assessment Study. MEASUREMENTS: Symptoms, functioning, drug/alcohol use assessed by the Brief Psychiatric Rating Scale, the Global Assessment of Functioning, and substance use interviews. FINDINGS: Patients used alcohol (67.0%; n = 540) and cannabis (30.0%; n = 237) more frequently than other substances up to 30 days before admission, and those with depressive and schizophrenia-spectrum used heroin more than individuals with bipolar (P = 0.023). Post-hospitalization, patients using alcohol (B = -0.15, P < 0.001) and cannabis (B = -0.27, P < 0.001) decreased, but patterns varied across diagnosis and genders. Patients using cannabis decreased at greater rates in depressive and schizophrenia-spectrum compared with bipolar (all P < 0.05), and more men used alcohol (B = 0.76, P < 0.001) and cannabis (B = 1.56, P < 0.001) than women. Cannabis (B = 1.65, P < 0.001) and alcohol (B = 1.04, P = 0.002) were associated with higher symptomatology; cannabis (B = -2.33, P < 0.001) and alcohol (B = -1.45, P = 0.012) were associated with lower functioning. CONCLUSIONS: Substance use is frequent and associated with poor recovery in patients with serious mental illness recently discharged from psychiatric hospitalization. Addiction treatments personalized by diagnosis and gender may be effective for improving outcomes in people with serious mental illness. PMID- 23432630 TI - Photoluminescent SiC tetrapods. AB - Recently, significant research efforts have been made to develop complex nanostructures to provide more sophisticated control over the optical and electronic properties of nanomaterials. However, there are only a handful of semiconductors that allow control over their geometry via simple chemical processes. Herein, we present a molecularly seeded synthesis of a complex nanostructure, SiC tetrapods, and report on their structural and optical properties. The SiC tetrapods exhibit narrow line width photoluminescence at wavelengths spanning the visible to near-infrared spectral range. Synthesized from low-toxicity, earth abundant elements, these tetrapods are a compelling replacement for technologically important quantum optical materials that frequently require toxic metals such as Cd and Se. This previously unknown geometry of SiC nanostructures is a compelling platform for biolabeling, sensing, spintronics, and optoelectronics. PMID- 23432631 TI - Prevalence and characteristics of nodular gastritis in Japanese elderly. AB - BACKGROUND AND AIM: Nodular gastritis (NG) is defined as antral gastritis with endoscopic findings usually characterized by a miliary pattern resembling "goose flesh." There is a possible association between NG and gastric cancer. The aim of our study is to investigate whether there are some differences between young and elderly people in incidence and characteristics of NG and estimate potential risk factors for gastric cancer in adults with NG. METHODS: Patients underwent upper gastrointestinal endoscopy for abdominal symptoms or cancer screening. Incidence rates and relationship between an elderly group (40 years or older) and young group (< 40 years) were assessed by endoscopic grade of NG, atrophic grade, concomitant diseases, and serum pepsinogen (PG). RESULTS: NG was found in 62 cases (0.94%) out of 6623 patients who underwent endoscopy, with a mean age of 47.3 +/- 13.3 years. Female patients were present at a significantly higher rate in the elderly group (P < 0.001). The grade of neutrophil infiltration in the greater curvature of the upper gastric body was recognized at a significantly higher rate in the elderly group (P < 0.05). PG II was present at a higher rate and PG I/II at a lower rate in the elderly group (P < 0.05). The odds ratio for the risk of gastric cancer in patients with NG was 2.1 (95% confidence interval 0.3-15.3) in the elderly group. CONCLUSION: NG in the elderly was also suggested to be a risk factor for gastric cancer as well as in the young. PMID- 23432632 TI - Implant survival and marginal bone loss at turned and oxidized implants in periodontitis-susceptible smokers and never-smokers: a retrospective, clinical, radiographic case-control study. AB - BACKGROUND: Little is known about the long-term outcome of oxidized surface oral implants, especially in periodontitis-susceptible smokers. The aim of this study is to determine implant survival and marginal bone loss at turned and oxidized implants in smokers and never-smokers with periodontitis. METHODS: Forty smokers and 40 never-smokers with experience of advanced periodontal disease, treated with implants 5 years previously, are included in this study. Groups were matched for sex, oral hygiene, and implant distribution, and patients were subgrouped by implant surface type (turned or oxidized). RESULTS: The overall implant survival rate was 96.9% in never-smokers and 89.6% in smokers. Compared with oxidized implants, turned implants failed more frequently in smokers. In smokers, mean (standard error of the mean) marginal bone loss at 5 years was 1.54 (0.21) mm at turned and 1.16 (0.24) mm at oxidized implants. In never-smokers, significantly greater bone loss was found at oxidized implants, 1.26 (0.15) mm, than at turned implants, 0.84 (0.14) mm. Oxidized implants demonstrated similar bone loss for both groups. Turned implants lost significantly more bone in smokers. Compared with never-smokers, the smokers' likelihood ratio for implant failure was 4.68, 6.40 for turned and 0.00 for oxidized implants. CONCLUSIONS: The results of the study underscore the need for prevention and cessation of smoking. Turned implants failed more frequently and lost more marginal bone in smokers. In contrast, oxidized implants showed similar failure rates and bone loss in smokers and never-smokers. Turned implants displayed less bone loss than oxidized implants in never-smokers. Oxidized surface implants are more suitable for patients susceptible to periodontitis who smoke. PMID- 23432633 TI - Evaluation of progesterone permeability from supercritical fluid processed dispersion systems. AB - The aim of this study was to investigate the permeability of unique dispersion systems prepared by supercritical fluid (SCF) processing, to deliver bioidentical progesterone (PGN) across mouse skin. Semisolid dispersions of PGN were made up of either polyethylene glycol (PEG) 400/4000, Gelucire 44/14, d-alpha-tocopheryl PEG 1000 succinate (TPGS), tanscutol P or myritol 318. SCF dispersion systems were compared with various control formulations; a market cream, aqueous suspension, and three conventionally prepared dispersions ? comelted, cosolvent and physically mixed systems. The permeability coefficient in the absence or presence of a permeation enhancer was evaluated using ex vivo mouse skin. The permeation study results for the TPGS/myritol/transcutol P dispersion system prepared using supercritical carbon dioxide (SC-CO2) had a two-fold improvement in transdermal permeation over 24 h compared to the control formulation, 245.7 and 126 ug cm(-2), respectively (p value < 0.05). In this study, the skin integrity and morphology was also investigated for changes due to the formulation constituents using histological examination and Fourier transform infrared spectroscopy. The particles from the gas-saturated suspension method and SC-CO2 together with TPGS/myritol/transcutol P may offer potential advantages over the available cream on the market based on the vastly improved lag time and flux of PGN across the skin. PMID- 23432634 TI - In memoriam: Amal K. Kurban, MD, 1928-2011. PMID- 23432635 TI - Utilizing redox-mediated Bergman cyclization toward the development of dual action metalloenediyne therapeutics. AB - Reaction of 2 equiv of 1,2-bis((diphenylphosphino)ethynyl)benzene (dppeb, 1) with Pt(cod)Cl2 followed by treatment with N2H4 yields the reduced Pt(0) metalloenediyne, Pt(dppeb)2, 2. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of 2 with 1 equiv of I2 in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near quantitatively generates the cis-Bergman-cyclized, diiodo product 3 ((31)P: delta = 41 ppm, J(Pt-P) = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate ((31)P: delta = -33 ppm). In contrast, addition of 2 equiv of I2 in the absence of additional radical trap instantaneously forms a metastable Pt(dppeb)2(2+) intermediate species, 4, that is characterized by delta = 51 ppm in the (31)P NMR (J(Pt-P) = 3171 Hz) and nu(C=C) = 2169 cm(-1) in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, 4 undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt(dppnap-I2)I2 (dppnap-I2 = (1,4-diiodonaphthalene-2,3 diyl)bis(diphenylphosphine)), 5, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate 4: one where the phosphine core has migrated to a trans-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two cis-chelating phosphine ligands (41 degrees dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt-P bond lengths (>2.4 A), indicating that nucleophilic ligand substitution by I(-) is on the reaction trajectory to the cyclized product 5. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics. PMID- 23432636 TI - Surgery for high-grade gliomas in the aging. AB - OBJECTIVE: High-grade glioma (HGG) is the commonest primary brain tumor in adults. We prospectively assessed outcome following surgery and adjuvant treatment for HGG in older patients. MATERIALS AND METHODS: Patients >= 60 years undergoing craniotomies for gliomas WHO grade 3 and 4 at Oslo and Haukeland University Hospitals 2008-2009 were included (n = 80). Outcome was assessed at six months, and overall mortality evaluated at two years. RESULTS: Forty-two males and 38 females of median age 68.5 (60-83) years were included, 35% attended a follow-up appointment at six months. Surgical mortality was 1.3%. Surgical morbidity included neurological sequela (10%), post-operative hematomas (3.8%) and hydrocephalus (1.3%). Median overall survival was 8.4 months and significantly increased by adjuvant radiochemotherapy. In univariate survival analyses, age >= 80 years, subtotal resection, American Society of Anesthesiology (ASA) scores 3-4, Karnofsky performance scale (KPS) < 70, and mini-mental state examination (MMSE) score < 25 significantly reduced survival. CONCLUSIONS: Surgical treatment of HGG carries low mortality and acceptable morbidity in patients aged >= 60 years. There is improved survival following bimodal adjuvant treatment. Maximum tumor resection should be attempted. Treatment might be less beneficial in patients aged >= 80 years and in those with poor pre-operative function. PMID- 23432637 TI - Characterizing the bacterial associates of three Caribbean sponges along a gradient from shallow to mesophotic depths. AB - Bacteriosponges have been shown to support relatively stable microbial communities across both distance and time, but little is known about the effect of depth on the composition of the associated community. To address this question, we examined the bacterial communities associated with three common Caribbean bacteriosponges collected at the same location over a depth gradient from approximately 10-100 m. The 16S rRNA genes of the associated communities were assessed using terminal restriction fragment length polymorphism and clone library analyses. Our results indicated that the stability and specificity of the associated bacterial communities varied with the host sponge but that each sponge supported a distinct community. Analyses of similarity suggested differences in community composition with depth, but examination of in silico predicted terminal restriction fragments failed to identify bacteria that occurred specifically at particular depths. Plakortis angulospiculatus, Agelas conifera, and Xestospongia muta supported diverse Chloroflexi species, while X. muta appeared to be the only sponge that hosted a cyanobacterial community. Regardless of host sponge, each species maintained a 'core' group of bacterial associates across a depth range with the composition of the remaining community presumably influenced by both biotic and abiotic factors. PMID- 23432638 TI - Effect of insulin on the soluble receptor for advanced glycation end products (RAGE). AB - AIMS: The receptor for advanced glycation end products (RAGE) plays an important role in the pathogenesis of diabetic complications. RAGE transcript splicing generates a number of isoforms, including a full-length membrane-bound receptor and a soluble isoform, endogenous secretory RAGE (esRAGE). Soluble forms of the receptor (sRAGE) can also be formed by ectodomain shedding of the membrane associated receptor. We have evaluated serum levels of sRAGE and esRAGE in Chinese patients with Type 1 diabetes and investigated the effect of insulin on the generation of esRAGE and sRAGE in vitro. METHODS: Serum sRAGE and esRAGE were measured by ELISA. The in vitro effect of insulin was investigated by incubating THP-1 macrophages with insulin and RAGE isoforms in cell lysate and conditioned media determined. RESULTS: In patients with diabetes, both serum esRAGE and sRAGE were significantly higher than in age-matched healthy subjects without diabetes. In vitro, insulin increased esRAGE and total RAGE isoform expression in cell lysate on a western blot, and reverse transcription-polymerase chain reaction showed an increase in esRAGE and full-length RAGE mRNA. This was accompanied by an increase in esRAGE and sRAGE in cell conditioned media. Pretreatment of THP-1 cells with a general metalloproteinase inhibitor GM6001 significantly reduced the production of sRAGE, suggesting that insulin also increased the cleavage of full length cell surface RAGE to form sRAGE. CONCLUSIONS: Chinese patients with Type 1 diabetes have higher serum levels of esRAGE and sRAGE. In vitro, insulin not only increases both full-length RAGE and esRAGE expression, but can also stimulate the shedding of sRAGE from the membrane-bound receptor. PMID- 23432639 TI - Medical treatment improves social behavior in a primate endometriosis model (Callithrix jacchus). AB - BACKGROUND: As endometriosis is known to be very painful in humans, therapeutic studies should consider pain-related aspects in experimental animals too. In a previous study, we found that common marmosets suffering from endometriosis show remarkable deviations in social behavior and cognitive tasks. METHODS: Female marmosets with endometriosis undergoing medical treatment were tested vs. two control groups (healthy and endometriosis monkeys without treatment) concerning behavioral aspects, cognitive skills, and mobility. RESULTS: The treated monkeys performed significant more social and self-grooming, comfort behavior and were more active than the untreated endometriosis monkeys. The treated marmosets even returned to equal levels as their healthy conspecifics. Cognitive and mobility tests revealed no significant differences. CONCLUSIONS: A beneficial effect of the applied endometriosis medication on behavioral impairments could be obtained. Including such measurements in therapeutic research contributes to aspects of animal welfare and pain-relieving potential of the tested compound. PMID- 23432640 TI - A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. AB - Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had >= 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including >= grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity. PMID- 23432641 TI - Evaluation of epicardial fat tissue thickness in patients with Hashimoto thyroiditis. AB - OBJECTIVE: Hypothyroidism, whether overt or subclinical, has multiple effects on the cardiovascular system. Epicardial fat tissue (EFT) is closely related to cardiovascular disorders and atherosclerosis. Our study aimed to assess EFT thickness and carotid artery intima-media thickness (CIMT) in patients with Hashimoto's thyroiditis (HT) displaying overt and subclinical hypothyroidism (SCH). DESIGN AND PATIENTS: The study included 33 patients with SCH and 24 patients with overt hypothyroidism (OH) with HT as well as 32 healthy controls. EFT thickness, CIMT, thyroid hormone levels and lipid parameters were measured in all subjects. Correlation analysis and linear regression analysis were performed for EFT thickness. RESULTS: Mean EFT thickness was 2.89 +/- 0.38, 3.53 +/- 0.92 and 4.56 +/- 1.61 mm in control, SCH and OH groups, respectively (P < 0.001). EFT thickness of OH patients was high compared with SCH and control subjects (P < 0.01 and <0.001, respectively). CIMT of OH patients was high compared with SCH and control subjects (P < 0.01 and <0.001, respectively). In addition, EFT was significantly thicker in SCH patients than in controls (P < 0.05). Correlation analysis showed that EFT thickness was significantly positively correlated with CIMT, age, body mass index, systolic blood pressure, thyroid-stimulating hormone, total and LDL cholesterol and triglyceride and negatively correlated with free T4. In the regression analysis, EFT thickness retained its independent and positive association with CIMT, patient group (particularly OH) and systolic blood pressure. CONCLUSIONS: Epicardial fat tissue thickness may be a useful indicator of early atherosclerosis in SCH and OH patients with HT. PMID- 23432642 TI - Effect of glycine powder air-polishing as an adjunct in the treatment of peri implant mucositis: a pilot clinical trial. AB - BACKGROUND: Glycine powder air-polishing (GPAP) has the potential to effectively erase biofilms and may improve the treatment efficacy of peri-implant mucositis. This pilot clinical trial evaluated the effect of GPAP as an adjunct in treating peri-implant mucositis. MATERIALS AND METHODS: Twenty-four subjects having at least one implant with peri-implant mucositis were randomly assigned to test (12 subjects with 17 implants) and control (12 subjects with 16 implants) groups. Following baseline assessment, all subjects received oral hygiene instruction and non-surgical debridement. In the test group, the sites with probing depth (PD) >=4 mm were additionally treated by GPAP for 5 sec. Clinical parameters were measured at 1-week, 1-month, and 3-month recall visits. RESULTS: At the 3-month visit, the mean reductions in PD at site level were 0.93 +/- 0.93 mm and 0.91 +/- 0.98 mm in the test and control groups, respectively (P < 0.05), and no significant difference existed between two groups. Mean bleeding score was also significantly reduced in both groups after the intervention. No complications or discomfort were reported during the study. CONCLUSIONS: This pilot clinical trial suggests that non-surgical mechanical debridement may effectively control peri implant mucositis, and adjunctive GPAP treatment seems to have a limited beneficial effect as compared with mechanical debridement alone. However, further clinical trials with a large sample size are needed to confirm this preliminary observation. PMID- 23432643 TI - Introduction. PMID- 23432644 TI - The role of chromatin remodeling in medulloblastoma. AB - The unexpectedly high frequency and universality of alterations to the chromatin machinery is one of the most striking themes emerging from the current deluge of cancer genomics data. Medulloblastoma (MB), a malignant pediatric brain tumor, is no exception to this trend, with a wealth of recent studies indicating multiple alterations at all levels of chromatin processing. MB is typically now regarded as being composed of four major molecular entities (WNT, SHH, Group 3 and Group 4), which vary in their clinical and biological characteristics. Similarities and differences across these subgroups are also reflected in the specific chromatin modifiers that are found to be altered in each group, and each new cancer genome sequence or microarray profile is adding to this important knowledge base. These data are fundamentally changing our understanding of tumor developmental pathways, not just for MB but also for cancer as a whole. They also provide a new class of targets for the development of rational, personalized therapeutic approaches. The mechanisms by which these chromatin remodelers are dysregulated in MB, and the consequences both for future basic research and for translation to the clinic, will be examined here. PMID- 23432645 TI - Rhabdoid tumors: an initial clue to the role of chromatin remodeling in cancer. AB - The discovery of biallelic, inactivating SMARCB1 mutations in rhabdoid tumors (RTs) over a decade ago represented the first recognized link between chromatin remodeling and tumor suppression. SMARCB1 is a core subunit of the SWI/SNF chromatin remodeling complex, and the recent emergence of frequent mutations in genes that encode subunits of this complex across a wide variety of cancers suggests that perturbation of this chromatin remodeling complex constitutes a key driver of cancer formation. Despite the highly aggressive nature of RTs, they are genetically simple cancers that appear to lack chromosomal instability and contain very few mutations. Indeed, the mutation rate in RTs is among the lowest of all cancers sequenced, with loss of SMARCB1 as essentially the sole recurrent event. Given the genetic simplicity of this disease, understanding the chromatin dysregulation caused by SMARCB1 loss may provide more general insight into how epigenetic alterations can contribute to oncogenic transformation and may reveal opportunities for targeted therapy not only of RT but also the variety of other SWI/SNF mutant cancers. PMID- 23432646 TI - Emerging insights into the ependymoma epigenome. AB - Ependymoma is the third most common pediatric brain tumor, yet because of the paucity of effective therapeutic interventions, 45% of patients remain incurable. Recent transcriptional and copy number profiling of the disease has identified few driver genes and in fact points to a balanced genomic profile. Candidate gene approaches looking at hypermethylated promoters and genome-wide epigenetic arrays suggest that DNA methylation may be critical to ependymoma pathogenesis. This review attempts to highlight existing and emerging evidence implicating the ependymoma epigenome as a key player and that epigenetic modifiers may offer new targeted therapeutic avenues for patients. PMID- 23432647 TI - Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail. AB - Primary brain tumors occur in 8 out of 100 000 people and are the leading cause of cancer-related death in children. Among brain tumors, high-grade astrocytomas (HGAs) including glioblastoma multiforme (GBM) are aggressive and are lethal human cancers. Despite decades of concerted therapeutic efforts, HGAs remain essentially incurable in adults and children. Recent discoveries have revolutionized our understanding of these tumors in children and young adults. Recurrent somatic driver mutations in the tail of histone 3 variant 3 (H3.3), leading to amino acid substitutions at key residues, namely lysine (K) 27 (K27M) and glycine 34 (G34R/G34V), were identified as a new molecular mechanism in pediatric GBM. These mutations represent the pediatric counterpart of the recurrent mutations in isocitrate dehydrogenases (IDH) identified in young adult gliomas and provide a much-needed new pathway that can be targeted for therapeutic development. This review will provide an overview of the potential role of these mutations in altering chromatin structure and affecting specific molecular pathways ultimately leading to gliomagenesis. The distinct changes in chromatin structure and the specific downstream events induced by each mutation need characterizing independently if progress is to be made in tackling this devastating cancer. PMID- 23432649 TI - 47-year-old man with left leg numbness. AB - A 47-year-old white male with a history of uveitis, hypercalcemia and nephrolithiasis presented with acute onset partial seizure. On exam he had decreased sensation to light touch on his left lower extremity. A Brain MRI revealed a right frontal mass, which was initially thought to be a metastatic lesion or a primary brain tumor. However, biopsy of the lesion revealed it to be a non-caseating granulomatous lesion consistent with neurosarcoidosis. PMID- 23432648 TI - Metabolic modulation of epigenetics in gliomas. AB - Cancer metabolism and epigenetics are two relatively new areas of cancer research. Recent years have seen an explosion of studies implicating either altered tumor metabolism or epigenetic mechanisms in the pathogenesis or maintenance of brain tumors. A new paradigm is emerging in cancer biology that represents a convergence of these themes, the metabolic regulation of epigenetics. We discuss this interrelationship in the context of two metabolic enzymes that can influence the pathogenesis of gliomas by altering the epigenetic state. The first of these enzymes is isocitrate dehydrogenase 1 (IDH1), which is mutated in secondary glioblastomas and ~70% of grade II/III astrocytomas and oligodendrogliomas. Mutant IDH1 results in the production of a metabolite 2 hydroxyglutarate (2-HG) that can inhibit DNA and histone demethylating enzymes resulting in the glioma-CpG island phenotype (G-CIMP) and increased histone methylation marks. Pyruvate kinase M2 (PKM2), an enzyme that plays a critical role in the glycolytic pathway, is a second example of a metabolic enzyme that can affect histone modifications. In epidermal growth factor receptor (EGFR) driven glioblastoma, PKM2 translocates to the nucleus and phosphorylates histone 3 at threonine 11 (H3-T11). This causes dissociation of HDAC3 from the CCND1 (Cyclin D1) and c-MYC promoters and subsequent histone acetylation, leading to transcription of Cyclin-D1 and c-MYC, and subsequent cell proliferation. Modification of the epigenetic state by alterations in metabolic enzymes is a novel phenomenon that contributes to the pathogenesis of gliomas and may help in the identification of new therapeutic targets. PMID- 23432650 TI - A 63 year old woman with white matter lesions and pachymeningeal inflammation. AB - We describe the case of a 63-year-old woman with CNS Rosai-Dorfman disease, presenting with diffuse dural infiltration, mimicking idiopathic hypertrophic pachymeningitis, and right vertebral artery dissection. Her symptoms included a progressive 11-month history of vertigo, gait ataxia, and right thalamic stroke. A diagnosis of CNS Rosai-Dorfman disease was made following open dural biopsy, and later confirmed on autopsy studies. The autopsy demonstrated widespread dural infiltration by inflammatory cells, principally large histiocytes, many of which exhibited emperipolesis, a characteristic finding in Rosai-Dorfman disease. A second pathological finding on autopsy was the presence of multiple demyelinating plaques (with preservation of axons), located in the corpus callosum, periventricular white matter, and multiple brainstem segments. These were consistent with a diagnosis of multiple sclerosis. This case description serves to remind clinicians that CNS Rosai-Dorfman disease-although uncommon-may present as a focal, dural-based, hemispheric mass lesion, or as diffuse pachymeningeal inflammation. Our case was also unusual due to the co-existence of CNS Rosai Dorfman disease, multiple sclerosis, and polycythemia vera (all rare diseases) in a single patient. Although the overlap of disorders may have been co-incidental, one could raise the question whether all three disorders were triggered by the same underlying dysimmune state. PMID- 23432651 TI - A 30 year old man with an acute presentation of a cerebellopontine angle lesion. AB - Schwannomas are slow-growing tumors with symptoms manifesting progressively. We report the case of a patient who manifested a sudden loss of consciousness as clinical presentation of an intracranial schwannoma with no acute hemorrhage or hydrocephalus. A 30-year-old male presented comatose and posturing. Cerebral CT revealed an extra-axial lesion with a heterogeneous enhancement and a cystic component located on the right cerebellopontine angle (CPA), displacing the brain stem. No acute hemorrhage or hydrocephalus was documented. Through a retrosigmoid suboccipital craniotomy, an extended subtotal tumor resection was performed. The patient experienced no functional hearing impairment and resumed his daily-life activities 3 months after surgery. Histopathological examination was compatible with a benign schwannoma. An exuberant lymphoplasmacytic infiltrate was found in many areas, signing the presence of an unusual inflammatory reaction with adjacent important intratumoral edema. We propose that the exuberant inflammatory infiltrate and the associated intratumoral edema acted as determining elements in the increase of mass effect and sudden clinical deterioration. PMID- 23432652 TI - 48-year-old woman with a cerebellopontine angle mass. AB - Intracranial chondromas are rare benign neoplasms with an estimated incidence rate of 0.2-0.3%. They usually occur at the skull base, or arise from the dura and leptomeninges. Rarely, they have been reported at the cerebellopontine (CP) angle. Here we describe an interesting case of CP angle chondroma which was clinically and radiologically diagnosed as schwannoma and meningioma. PMID- 23432653 TI - Gratitude for a job well done! PMID- 23432654 TI - NYC4, the rice ortholog of Arabidopsis THF1, is involved in the degradation of chlorophyll - protein complexes during leaf senescence. AB - Yellowing/chlorophyll breakdown is a prominent phenomenon in leaf senescence, and is associated with the degradation of chlorophyll - protein complexes. From a rice mutant population generated by ionizing radiation, we isolated nyc4-1, a stay-green mutant with a defect in chlorophyll breakdown during leaf senescence. Using gene mapping, nyc4-1 was found to be linked to two chromosomal regions. We extracted Os07g0558500 as a candidate for NYC4 via gene expression microarray analysis, and concluded from further evidence that disruption of the gene by a translocation-related event causes the nyc4 phenotype. Os07g0558500 is thought to be the ortholog of THF1 in Arabidopsis thaliana. The thf1 mutant leaves show variegation in a light intensity-dependent manner. Surprisingly, the Fv /Fm value remained high in nyc4-1 during the dark incubation, suggesting that photosystem II retained its function. Western blot analysis revealed that, in nyc4-1, the PSII core subunits D1 and D2 were significantly retained during leaf senescence in comparison with wild-type and other non-functional stay-green mutants, including sgr-2, a mutant of the key regulator of chlorophyll degradation SGR. The role of NYC4 in degradation of chlorophyll and chlorophyll - protein complexes during leaf senescence is discussed. PMID- 23432656 TI - Behavioural recovery on simple and complex tasks by means of cell replacement therapy in unilateral 6-hydroxydopamine-lesioned mice. AB - Before cell replacement therapies can enter the clinic, it is imperative to test the therapeutic benefits in well-described animal models. In the present study, we aimed to investigate the effects of 6-hydroxydopamine lesions to the medial forebrain bundle and subsequent grafting of embryonic day (E)12.5 ventral mesencephalon into the denervated striatum in C57/Bl6 mice on a battery of simple motor tests (drug-induced rotation, rotarod, and corridor) and the lateralised choice reaction time task conducted in the mouse nine-hole box. Histological analysis confirmed effective lesions and good graft survival. The lesion induced marked deficits in the choice reaction time task, the rotarod test, and corridor test, and these deficits were partially but significantly alleviated in the grafted mice. Although the lesions induced significant rotation following injections of amphetamine and apomorphine, respectively, the grafts did not, suprisingly, alleviate the rotation deficit. This study shows the ability of ventral mesencephalic tissue to ameliorate some of the lesion-induced deficits, and the power of operant testing in detecting small but significant improvements. The behavioural tests presented are useful drug-free approaches for evaluating cell-based therapies. PMID- 23432657 TI - Coronally advanced flap alone or with connective tissue graft in the treatment of single gingival recession defects: a long-term randomized clinical trial. AB - BACKGROUND: Numerous surgical approaches for the treatment of single gingival recession (GR) defects are documented in the literature. The aim of this 5-year, split mouth-design, randomized clinical trial was to evaluate the effectiveness of coronally advanced flap (CAF) alone versus CAF with connective tissue graft (CAF+CTG) in the treatment of single Miller Class I and II GR defects. METHODS: Thirty-seven patients with 114 bilateral, single Miller Class I and II GR defects were treated with CAF on one side of the mouth and CAF+CTG on the other side. Clinical measurements (GR length [REC], keratinized tissue width [KT], complete root coverage [CRC], and percentage of root coverage [PRC]) were evaluated before surgery and after 6, 12, 24, and 60 months. RESULTS: There was a significant reduction of REC and increase of KT after surgery in both groups. CAF+CTG showed significantly better results for all evaluated clinical parameters in all observed follow-up periods. Miller Class I defects showed better results in terms of REC, CRC, and PRC, whereas Miller Class II showed better results in KT, both in favor of CAF+CTG. Miller Class I defects showed better results than Miller Class II GR defects regardless of the surgical procedure used. CONCLUSIONS: Both surgical procedures were effective in the treatment of single Miller Class I and II GR defects. The CAF+CTG procedure provided better long-term outcomes (60 months postoperatively) than CAF alone. Long-term stability of the gingival margin is less predictable for Miller Class II GR defects compared to those of Class I. PMID- 23432658 TI - Patterns of skin metastases: a review of 25 years' experience at a single cancer center. AB - BACKGROUND: Skin metastases can be defined as the spread of a tumor from its site of primary origin to the skin. Skin metastasis may be the first sign of advanced cancer or an indicator of cancer recurrence. OBJECTIVES: To review patient data of 401 skin metastases available from our institution and compare this information to previously published studies. METHODS: Patient data from the Cancer Registry at RPCI database was reviewed for skin metastasis using vendor software. We included all cases of carcinoma, melanoma, sarcomas, and hematologic malignancies entered during a 25-year period from January 4, 1985, to March 1, 2010. Data identifying the relationship of tumor incidence, morphology, and skin metastasis was reviewed. A total of 401 patients who had skin metastases at the time of cancer diagnosis or had skin metastases as a recurrent site were included in this study. Extensive literature review was conducted using PubMed for articles relating to skin metastases and its clinical presentation and histological features. RESULTS: Breast cancer was the most common cancer to metastasize to the skin (32.7% of all skin metastases seen) followed by bronchus and lung (13.2%), skin (melanoma; 9.5%), lymph nodes (7.5%), oral cavity/pharynx/larynx (6.2%), blood and bone marrow (5.5%), and colorectal (4.2%). The most common histological types of tumors were identified as adenocarcinoma (infiltrating ductal carcinoma [22.7%]), lobular carcinoma (4.7%), and non-adenocarcinoma (squamous cell carcinoma [12.2%] and malignant melanoma [5.2%]). CONCLUSIONS: This is the largest review of skin metastases in the United States in the past 25 years. We found the primary cancers that metastasize to the skin have changed in frequency from previous studies. Our data are helpful in indicating which cancers have the strongest predilection for skin metastasis. Identification of these cancers can help both the clinician and patient detect early signs of metastases, which may allow for earlier diagnosis, implementation of therapy, and possible prolonged survival. PMID- 23432659 TI - Using reinforcement learning to examine dynamic attention allocation during reading. AB - A fundamental question in reading research concerns whether attention is allocated strictly serially, supporting lexical processing of one word at a time, or in parallel, supporting concurrent lexical processing of two or more words (Reichle, Liversedge, Pollatsek, & Rayner, 2009). The origins of this debate are reviewed. We then report three simulations to address this question using artificial reading agents (Liu & Reichle, 2010; Reichle & Laurent, 2006) that learn to dynamically allocate attention to 1-4 words to "read" as efficiently as possible. These simulation results indicate that the agents strongly preferred serial word processing, although they occasionally attended to more than one word concurrently. The reason for this preference is discussed, along with implications for the debate about how humans allocate attention during reading. PMID- 23432660 TI - Noninvasive evaluation of hepatic fibrosis in hepatitis C virus-infected patients using ethoxybenzyl-magnetic resonance imaging. AB - BACKGROUND AND AIMS: Liver biopsy is the gold standard test to determine the grade of fibrosis, but there are associated problems. Because gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid is secreted partially in hepatocytes and bile, it is possible that ethoxybenzyl-magnetic resonance imaging (EOB-MRI) correlates with liver function and liver fibrosis. The aim of this study was to compare the fibrosis seen in liver biopsy samples to the signal intensity of the hepatobiliary phase measured on EOB-MRI in hepatitis C virus (HCV)-infected patients. METHODS: Two hundred twenty-four (estimation 149, validation 75) HCV-infected patients with histologically proven liver tissue who underwent EOB-MRI were studied. Overall, fibrosis staging was 15/24/19/46/45 for F0/F1/F2/F3/F4, respectively. A 1.5-Tesla magnetic resonance system was used, and the regions of interest of the liver were measured. Four methods were used: (i) relative enhancement: (post-enhanced signal intensity [SI] - pre-enhanced intensity)/pre-enhanced intensity; (ii) liver-to-intervertebral disk ratio (LI): post-enhanced (liver SI/interdisc SI)/pre-enhanced (liver SI/inter disc SI); (iii) liver-to-muscle ratio: post-enhanced (liver SI/muscle SI)/pre-enhanced (liver SI/muscle SI); and (iv) liver-to-spleen ratio: post-enhanced (liver SI/spleen SI)/pre-enhanced (liver SI/spleen SI). RESULTS: To discriminate F0-1 versus F2-4 or F0-2 versus F3-4 or F0-3 versus F4, LI at 25 min (LI25) had the highest area under receiver operating characteristic (0.88, 0.87, and 0.87, respectively) in these four methods and also in the validation set. CONCLUSION: LI at 25 min seems to be a useful method to determine the staging of fibrosis as a non-invasive method in HCV-infected hepatitis or cirrhosis patients. PMID- 23432661 TI - Sleep and cognition in preschool years: specific links to executive functioning. AB - This study investigated the prospective links between sleep in infancy and preschoolers' cognitive performance. Mothers of 65 infants completed a sleep diary when infants were aged 1 year, and children completed two subscales of the Wechsler Preschool and Primary Scale of Intelligence at 4 years, indexing general cognitive ability and complex executive functioning. Consistent with hypotheses, children getting higher proportions of their sleep at night as infants were found to perform better on executive functions, but did not show better general cognition. Relations held after controlling for family socioeconomic status and prior cognitive functioning. These findings suggest that the special importance of sleep for higher order cognition, documented among adults, may appear very early in life. PMID- 23432662 TI - Discovery of a novel selective PPARgamma ligand with partial agonist binding properties by integrated in silico/in vitro work flow. AB - Full agonists to the peroxisome proliferator-activated receptor (PPAR)gamma, such as Rosiglitazone, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPARgamma is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In an effort to identify novel PPARgamma ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties. Toward this end we applied an integrated in silico/in vitro workflow, based on pharmacophore- and structure-based virtual screening of the ZINC library, coupled with competitive binding and transactivation assays, and adipocyte differentiation and gene expression studies. Hit compound 9 was identified as the most potent ligand (IC50 = 0.3 MUM) and a relatively poor inducer of adipocyte differentiation. The binding mode of compound 9 was confirmed by molecular dynamics simulation, and the calculated free energy of binding was -8.4 kcal/mol. A novel functional group, the carbonitrile group, was identified to be a key substituent in the ligand-protein interactions. Further studies on the transcriptional regulation properties of compound 9 revealed a gene regulatory profile that was to a large extent unique, however functionally closer to that of a partial agonist. PMID- 23432663 TI - Elevated homocysteine levels in levodopa-treated idiopathic Parkinson's disease: a meta-analysis. AB - To assess the association between the elevation of plasma homocysteine (Hcy) level and long-term levodopa (L-dopa) therapy in idiopathic Parkinson's disease (PD). We performed a systematic literature review to recruit original studies published up to May 14, 2012. Studies enrolled should be controlled, with specific information of long-term L-dopa application and plasma Hcy in patients with PD. Effects were summarized using standardized mean differences (SMDs) or weighted mean differences (WMDs). Our search enrolled 22 eligible studies. Plasma Hcy levels were significantly higher in L-dopa-treated patients than those in healthy controls [SMD 0.97; 95% confidence interval (CI) 0.80-1.14, P < 0.001], L dopa-naive patients with PD (SMD 0.99; 95% CI 0.54-1.44, P < 0.001), and untreated patients (SMD 0.52; 95% CI 0.18-0.86, P < 0.01). However, its levels in untreated patients with PD were not significantly higher than in healthy controls (SMD 0.24; 95% CI -0.03 to 0.51, P > 0.05). Patients with PD treated with L-dopa plus catechol-O-methyltransferase inhibitor (COMT-I) showed lower plasma Hcy concentrations compared with L-dopa-treated patients (WMD 4.62; 95% CI 2.89-6.35, P < 0.001). L-dopa treatment is associated with the increase in plasma Hcy level in patients with PD. COMT-I may attenuate L-dopa-induced elevation of Hcy level. PMID- 23432664 TI - The role of pregnancy-specific glycoprotein 1a (PSG1a) in regulating the innate and adaptive immune response. AB - Among several explanations for the acceptance of the fetus, the one that suggests that the maternal immune system is suppressed or modified has been the subject of many studies. Thus, it has been proposed that the cells of innate immune system might be able to distinguish the pregnant from the non-pregnant state producing a signal, the so-called signal P. We have previously proposed that pregnancy specific glycoprotein 1a (PSG1a), a representative member of the main glycoprotein family secreted by placental trophoblast, may modulate the activation of antigen-presenting cells promoting the T-cell shift of the maternal cell immunity toward a less harmful phenotype. In this review, we summarize current knowledge concerning the contribution of pregnancy-specific glycoprotein 1a (PSG1a) to modulate the maternal innate and adaptive immune response in order to assure a successful pregnancy. PMID- 23432665 TI - Evaluating safety and efficacy of rabbit antithymocyte globulin induction in elderly kidney transplant recipients. AB - OBJECTIVES: The optimal immunosuppression regimen for elderly kidney transplant recipients is poorly defined. We sought to evaluate the short-term efficacy and safety of thymoglobulin in geriatric recipients of deceased-donor kidneys. MATERIALS AND METHODS: A single-center, retrospective analysis was undertaken between elderly (>= 65 years) (n=137) and nonelderly (n=276) kidney transplant recipients who received rabbit antithymocyte globulin induction and calcineurin inhibitor, mycophenolic acid, and prednisone maintenance. RESULTS: The mean age was 70 versus 52 years. Fewer elderly patients had an earlier transplant or panel reactive antibodies > 20%, but had more machine perfused, older, and extended criteria donor kidneys. Elderly patients received lower rabbit antithymocyte globulin (5.4 vs 5.6 mg/kg; P = .04) and initial mycophenolic acid doses (1620 vs 1774 mg; P = .002), and experienced less delayed graft function (31.1% vs 50.0%; P < .001). Death-censored graft survival and graft function at 3 years and biopsy proven acute rejection at 1 year were comparable; however, there was lower 3-year patient survival in elderly patients. Donor age was the only factor associated with reduced patient survival. Rates of malignancy, infection, or thrombocytopenia were similar; however, leukopenia occurred less frequently in elderly patients (11.7% vs 19.9%; P = .038). CONCLUSIONS: Elderly kidney transplant recipients receiving rabbit antithymocyte globulin did not experience different short-term graft survival, graft function or rates of infection, malignancy or hematologic adverse reactions than did nonelderly patients; they experienced fewer episodes of delayed graft function, but had lower 3-year patient survival. PMID- 23432666 TI - A randomized controlled clinical multicenter trial comparing the clinical and histological performance of a new, modified polylactide-co-glycolide acid membrane to an expanded polytetrafluorethylene membrane in guided bone regeneration procedures. AB - OBJECTIVES: To compare the clinical and histological outcomes of a resorbable modified polylactide/polyglycolide acid (PLGA) test membrane and a titanium reinforced expanded polytetrafluorethylene (ePTFE) control membrane used for guided bone regeneration (GBR) around dental implants. MATERIALS AND METHODS: A total of 40 patients with peri-implant dehiscence-type defects were randomly allocated to a GBR procedure using either a modified PLGA test or an ePTFE control membrane. Soft tissue condition, implant integration, adverse events and quality of life were recorded during the 6-month healing period. At re-entry peri implant bone defect dimensions were measured and compared with values recorded at implant/GBR surgery. A biopsy was retrieved for qualitative and quantitative histological analyses. A comparison between the groups was conducted using non parametric statistical tests. RESULTS: Soft tissue complications were observed in five test patients and two control patients. Except for soft tissue complications and incomplete regeneration, no procedure- or device-related adverse events were observed. The vertical bone defect component was, in mean, reduced by-5.1 mm (95% CI -6.8, -3.3) in the test group and -6.9 mm (95% CI -8.2, -5.5 mm) in the control group. The mean residual vertical defect height measured 1.2 +/- 2.4 mm in the test group and 0.3 +/- 1.1 mm in the control group meaning a mean defect resolution of 81% in the test group and 96% in the control group (P = 0.161). The horizontal bone thickness at implant shoulder level decreased from a mean of 3.2 mm to 1.4 mm (-56%, mean -1.7 mm, 95% CI -2.3, -1.1) in the test group and from 3.3 mm to 2.5 mm (-24%, mean -0.8 mm, 95% CI -1.3, -0.3) in the control group (P = 0.022). Qualitative and quantitative histological analyses did not show significant differences in the tissue composition between groups. CONCLUSION: Peri-implant GBR was successfully performed using either of the membranes. The control membrane was able to better maintain the horizontal thickness of regenerated bone and revealed less soft tissue complications. No statistically valid evidence about the superiority of one membrane was found in any other parameters. Soft tissue dehiscences occur with both types of membranes and can impair the amount of regenerated bone. PMID- 23432667 TI - Low-temperature plasmas at atmospheric pressure: toward new pharmaceutical treatments in medicine. AB - This article concerns a new field covered by low-temperature plasmas at atmospheric pressure for medical treatments. This is based on the very attractive possibility to tune and design plasmas as possible pharmaceutical products using selectively some active species (charged particles, radicals, atomic and molecular agents, UV radiations) and even electric fields self-generated by the plasma. The delivery of active species occurs at the gaseous level. This means that there is no need for a carrier medium, and the treatment of living tissue or surface is optimal because plasmas can penetrate small pores, spread over rough surfaces, and reach both prokaryotic and eukaryotic cells. The present article gives first a review on the main low-temperature plasma setups potentially usable for medical treatments with an emphasis on the setups as, for instance, plasma jets developed in our laboratory. Then, the present article gives a review of the current state of the art of such plasmas as pharmaceutical products or therapeutic tools in medicine with a light on a selection of forefront researches particularly in the field of chronic wounds, blood coagulation, and cancer treatment. PMID- 23432668 TI - Cardiovascular and systemic risk in nonalcoholic fatty liver disease - atherosclerosis as a major player in the natural course of NAFLD. AB - Non-alcoholic fatty liver disease (NAFLD) encompasses pure steatosis through nonalcoholic steatohepatitis (NASH) and is the most common cause of chronic liver disease in Western countries. NASH is a progressive liver disease that increases the risk of cirrhosis and end-stage liver disease. Interestingly, the global health risk of NAFLD is not confined to the liver. Compared with those without NAFLD, patients with NAFLD exhibit not only increased liver-related complications and liver-related mortality but also increased risk of developing type 2 diabetes, cardiovascular disease (CVD) and chronic kidney disease, increased risk of post-operative complications after major liver surgery, and increased risk of developing certain malignancies, including primary liver cancer and colorectal cancer. In this review, we discuss the current evidence linking NAFLD with the risk of CVD in the setting of the more complex scenario of other hepatic and extra-hepatic complications that may occur during the natural course of NAFLD. Moreover, we provide a brief description of the putative biological mechanisms underlying such complications, particular emphasis being given to CVD. We conclude that NAFLD is a complex health problem with implications far beyond the liver. Hence, it may cause a significant global health burden and the assistance of patients with NAFLD impacts on the work of physicians from many different medical specialties. PMID- 23432669 TI - Gut-liver axis and microbiota in NAFLD: insight pathophysiology for novel therapeutic target. AB - There is increasing evidence for a correlation between intestinal microbiota, bacterial translocation and hepatic steatosis. Intestinal microbiota affects nutrient absorption and energy homeostasis. Altered intestinal permeability may favor the passage of bacteriaderived compounds into systemic circulation, causing a systemic inflammatory state, characteristic of the metabolic syndrome. The interaction between intestinal permeability and luminal bacteria is involved in the pathogenesis and evolution of non-alcoholic liver disease. Microbiota pharmacological modulation could be a promising tool for a new therapeutical approach to non-alcoholic fatty liver disease. PMID- 23432670 TI - Regulation of angiogenesis and bone regeneration with natural and synthetic small molecules. AB - Regeneration of bone requires the coordinated processes of angiogenesis and osteogenesis. These repair mechanisms are closely linked through both direct cell cell contact and indirect paracrine signaling among osteoblasts, endothelial cells, and other cell types. The vasculature provides a source of nutrients, oxygen, metabolic substrates, and access for circulating cells that help to support new bone formation. The complexity of the endogenous signaling axis that promotes angiogenesis provides numerous opportunities for therapeutic intervention ranging from progenitor cell mobilization to endothelial proliferation and sprouting. Small molecules are particularly appealing for regenerative medicine applications because many exhibit extended in vivo stability, low cost, and scalable production. Innovative techniques for developing small molecules such as high throughput functional assays and broad spectrum database analysis techniques have led to the development of new compounds and the identification of novel applications of existing drugs. In addition, rapid advances in biomaterials design and synthesis provide platforms to deliver therapeutic small molecules to sites of bone injury. This review presents an overview of current strategies for harnessing endogenous healing mechanisms using small molecules by targeting angiogenesis, osteogenesis, or both. PMID- 23432671 TI - Strategies to direct angiogenesis within scaffolds for bone tissue engineering. AB - There is a profound need for orthopaedic grafting strategies due to various trauma and musculoskeletal diseases. Tissue engineering offers a promising avenue to develop viable grafts for bone repair. The transfer of bone tissue engineering strategies to clinical applications is limited by the failure to adequately vascularize scaffolds after implantation. This review focuses on the natural processes for bone and vessel formation as well as the microenvironmental cues and microscale fabrication techniques to properly coordinate these events towards successful vascularization of tissue engineered scaffolds. PMID- 23432672 TI - Osteogenic peptides in bone regeneration. AB - Due to their short half-life and diffusion away from the site of regeneration, osteogenic proteins, used in regenerative medicine, require high doses leading to undesirable side effects. An exciting approach is to utilize peptides derived from the active domains of soluble and insoluble components of the bone extracellular matrix (ECM) to initiate the cascade of osteogenesis, vasculogenesis, mineralization, and bone formation. Osteogenic peptides derived from bone morphogenetic proteins, integrin-binding and heparin-binding peptides, collagen-derived peptides, peptides derived from bone sialoprotein and enamel matrix proteins, vasoconstrictive peptides, peptides derived from the histone proteins involved in the structure of chromatin and those derived from receptor binding domain of human thrombin, peptides that abolish the expression of tumor necrosis factor-alpha, and neuropeptides have been discovered. In this work, anabolic effects of osteogenic peptides in particular with respect to cell adhesion, differentiation, and mineralization are discussed. These peptides show significantly higher biological activity in vitro and in vivo, in small animal models, when immobilized in a matrix by conjugation or grafting, most likely due to the peptide mobility and its diffusion away from the site of regeneration. Combination of osteogenic and integrin- binding peptides synergistically enhances cell adhesion and mineralization. Functionalization of orthopedic implants with osteogenic peptides can improve cell adhesion, mineralization, and overall integration of the implant with the surrounding tissue, which in turn reduces implant loosening and failure. The use of osteogenic peptides as an alternative growth factor in orthopedic applications rests on future in vivo studies that evaluate these peptides in primates and humans. PMID- 23432673 TI - The role of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in orthopaedic bone repair and regeneration. AB - Recombinant human PDGF BB homodimer (rhPDGF-BB) is a potent recruiter of, and strong mitogenic factor for, cells crucial to musculoskeletal tissue repair, including mesenchymal stem cells (MSCs), osteogenic cells and tenocytes. rhPDGF BB also upregulates angiogenesis. These properties allow rhPDGF-BB to trigger the cascade of bone and adjoining soft tissue repair and regeneration. This mechanism of action has been established in numerous preclinical and clinical studies. Demonstration of the safety and efficacy of rhPDGF-BB in the healing of chronic foot ulcers in diabetic patients and regeneration of alveolar (jaw) bone lost due to chronic infection from periodontal disease has resulted in two FDA-approved products based on this molecule. A third product is in late stages of clinical development, with pilot and pivotal clinical studies of rhPDGF-BB mixed with an osteoconductive bone matrix (Augment((r)) Bone Graft) in foot and ankle fusions demonstrating that this product is at least as effective as bone autograft, and has an improved safety profile. Additional combinations of rhPDGF-BB with tissue specific matrices are also being studied clinically in additional musculoskeletal indications. PMID- 23432674 TI - Gene therapy for bone regeneration. AB - Nonunions and delayed unions are among the more challenging clinical and surgical entities an orthopaedic surgeon must manage. Effective strategies that address these complex problems are in need and gene therapy represents a potential therapeutic option. Among the many properties that bone morphogenetic proteins (BMPs) possess, their potent osteoinductive effects make them attractive growth factors for use in gene therapy to address large bony defects. Gene therapy enables a sustained production of BMP to be achieved at specific sites of interest and represents a significant advantage over protein-delivery based systems. Viruses are effective vectors for delivering BMP cDNA because they are designed to efficiently infect cells and transmit genetic material. However, safety concerns such as immune system activation and insertional mutagenesis represent drawbacks that may limit their clinical efficacy. Nonviral vectors are emerging as attractive candidates for gene delivery since they avoid many of the safety issues seen with viral vectors but have lower genetic transfer efficiency. A wide variety or preclinical studies of bone regeneration using BMPs have demonstrated the efficacy of both in vivo and ex vivo gene therapy techniques and these will be explored in this review article. PMID- 23432675 TI - Osteoinductive biomaterial geometries for bone regenerative engineering. AB - Worldwide, more than 2.2 million patients undergo bone graft procedures annually. In each of these procedures an interface is formed between the host tissue and the graft material. Synthetic implants exhibit an interface with the host tissue and the formation of a homogenous interface consisting of bone and void of intervening soft tissue is desired (osseointegration); recent developments have highlighted the benefit of incorporating nanostructures at that interface. Autograft and allograft bone are frequently used for bone loss, nonunion fractures, and spinal fusions; however, both are plagued with complications either due to supply or inadequate graft properties. In contrast to bone tissue engineering, which uses a top-down approach to repair bone defects, bone regenerative engineering uses a bottom-up approach focused on strategies incorporating stem cells, biomaterials, and growth factors alone or in combination to generate or regenerate bone tissue. Early constructs developed for bone regenerative engineering utilized polymeric microstructures, presenting surface features with characteristic dimensions similar to that of a cell (1um - 1000um). These microstructures were typically biodegradable and demonstrated an excellent ability to match the mechanics of native bone tissue. They were also osteoconductive-capable of promoting osteoblast growth. On the other hand, the osteoinductive abilities of these microstructures were lacking. Osteoinduction, or the ability to promote the progression of a preosteoblastic cell to a mature osteoblast, historically was achieved in two ways: via the addition of nanoscale ceramics to the microstructures or via an external stimulus such as the addition of bone morphogenetic proteins (BMPs). More recent developments in bone regenerative engineering have utilized polymeric nanostructures (less than 1um) with characteristic dimensions an order of magnitude or more less than that of a cell to stimulate and drive an osteoinductive response in the absence of growth factors. Despite strong literature evidence supporting the nanostructures' ability to be both osteoconductive and osteoinductive, there is still disparity regarding how nanostructures regulate the progression towards an osteoblastic phenotype. This review will explore unique micro- and nano-architectures, how they initiate osteoinductive signals through pathways similar to BMPs, and how these unique geometries can be translated to the clinic. PMID- 23432676 TI - Fibroblast growth factor-2, bone homeostasis and fracture repair. AB - There remains a great need to develop therapeutic agents to treat critical size defects and non-union fractures and one of the potential agents is recombinant human fibroblast growth factor 2 (FGF-2). We discuss the function of FGF-2 in bone formation, bone resorption, and downstream signaling pathways and review the role of exogenous FGF-2 in fracture healing. The importance of endogenous FGF-2 in bone formation and its potential importance in fracture healing in response to parathyroid hormone (PTH) and bone morphogenetic protein 2 (BMP2) is described. In addition we will review, FGF-2 signaling crosstalk with Wnt signaling and PTH signaling in bone formation and repair. Finally, we discuss the outstanding unresolved issues in the application of FGF-2 as therapeutic agent for bone regeneration. PMID- 23432677 TI - Combined angiogenic and osteogenic factor delivery for bone regenerative engineering. AB - Both osteogenesis and angiogenesis are integrated parts of bone growth and regeneration. Combined delivery of osteogenic and angiogenic factors is a novel approach in bone regenerative engineering. Exogenous addition of mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) together with an osteoconductive scaffold is a very promising method to enhance bone repair. This concept has been incorporated into the development of new strategies for bone tissue engineering and significant advancements have been made in last 10 years. In contrary to previous belief that VEGF modulates bone repair only by enhancing angiogenesis in the proximity of bone injury, recent evidence also suggests that cross-talk between VEGF and BMP signaling pathways in MSCs promotes osteoblastic differentiation of MSCs which aids in fracture repair. Future studies should focus on cross-talk between angiogenesis and osteogenesis, optimization of VEGF/BMP ratios, selection of the most potent BMPs, and optimization of delivery methods for VEGF and BMP. Recent discoveries from basic research including effective delivery of growth factors and cells to the area of interest will help bring VEGF plus BMP for bone healing from the bench to the patient's bedside. PMID- 23432678 TI - Osteoinductive small molecules: growth factor alternatives for bone tissue engineering. AB - Tissue engineering aims to repair, restore, and regenerate lost or damaged tissues by using biomaterials, cells, mechanical forces and factors (chemical and biological) alone or in combination. Growth factors are routinely used in the tissue engineering approach to expedite the process of regeneration. The growth factor approach has been hampered by several complications including high dose requirements, lower half-life, protein instability, higher costs and undesired side effects. Recently a variety of alternative small molecules of both natural and synthetic origin have been explored as alternatives to growth factors for tissue regeneration applications. Small molecules are simple biochemical components that elicit certain cellular responses through signaling cascades. Small molecules present a viable alternative to biological factors. Small molecule strategies can reduce various side effects, maintain bioactivity in a biological environment and minimize cost issues associated with complex biological growth factors. This manuscript focuses on three-osteoinductive small molecules, namely melatonin, resveratrol (from natural sources) and purmorphamine (synthetically designed) as inducers of bone formation and osteogenic differentiation of stem cells. Efforts have been made to summarize possible biological pathways involved in the action of each of these drugs. Melatonin is known to affect Mitogen Activated Protein (MAP) kinase, Bone morphogenic protein (BMP) and canonical wnt signaling. Resveratrol is known to activate cascades involving Wnt and NAD-dependent deacetylase sirtuin-1 (Sirt1). Purmorphamine is a Hedgehog (Hh) pathway agonist as it acts on Smoothened (Smo) receptors. These mechanisms and the way they are affected by the respective small molecules will also be discussed in the manuscript. PMID- 23432680 TI - Growth differentiation factor 5 regulation in bone regeneration. AB - Growth differentiation factor 5 (GDF5) is a member of the bone morphogenic protein (BMP) family and plays critical roles in organ development processes including bone, cartilage, ligament, and joint formation. GDF5 is expressed in the cartilage primordium in the early limb development, and in the interzone of joint formation sites. GDF5 is also observed in adult tissue and cell lines. This spatialtemporal expression pattern of GDF5 proves its essential role in the formation of bone and cartilage. Similar to other members of BMPs, the signaling cascade of GDF5 is originated through binding to type I and type II receptors and thus regulating the downstream intracellular biochemical processes. Mutations of GDF5 are associated with several human and animal diseases that are characterized by skeletal deformity such as short digits and short limbs. In vitro and in vivo studies demonstrated that overexpression of GDF5 or administration of recombinant protein promotes chondrogenesis and osteogenesis. Moreover, a promising feature of GDF5 is osteoinduction, which is used in tissue engineering for bone repair with or without a carrier in animal platforms and in human preclinical settings. The exciting results signify that GDF5 is a compelling candidate for bone tissue engineering by enhancing osteogenesis and angiogenesis. In this review, we will focus the discussion on the basic structure, signaling pathways, function in cartilage and bone formation, and potential clinical application of GDF5 in bone tissue regeneration. PMID- 23432681 TI - Bone morphogenetic proteins for bone regeneration and their alternatives. PMID- 23432682 TI - Too exhausted to remember: ego depletion undermines subsequent event-based prospective memory. AB - Past research has consistently found that people are likely to do worse on high level cognitive tasks after exerting self-control on previous actions. However, little has been unraveled about to what extent ego depletion affects subsequent prospective memory. Drawing upon the self-control strength model and the relationship between self-control resources and executive control, this study proposes that the initial actions of self-control may undermine subsequent event based prospective memory (EBPM). Ego depletion was manipulated through watching a video requiring visual attention (Experiment 1) or completing an incongruent Stroop task (Experiment 2). Participants were then tested on EBPM embedded in an ongoing task. As predicted, the results showed that after ruling out possible intervening variables (e.g. mood, focal and nonfocal cues, and characteristics of ongoing task and ego depletion task), participants in the high-depletion condition performed significantly worse on EBPM than those in the low-depletion condition. The results suggested that the effect of ego depletion on EBPM was mainly due to an impaired prospective component rather than to a retrospective component. PMID- 23432683 TI - Interlayer breathing and shear modes in few-trilayer MoS2 and WSe2. AB - Two-dimensional (2D) layered transition metal dichalcogenides (TMDs) have recently attracted tremendous interest as potential valleytronic and nanoelectronic materials, in addition to being well-known as excellent lubricants in the bulk. The interlayer van der Waals (vdW) coupling and low-frequency phonon modes and how they evolve with the number of layers are important for both the mechanical and the electrical properties of 2D TMDs. Here we uncover the ultralow frequency interlayer breathing and shear modes in few-layer MoS2 and WSe2, prototypical layered TMDs, using both Raman spectroscopy and first principles calculations. Remarkably, the frequencies of these modes can be perfectly described using a simple linear chain model with only nearest-neighbor interactions. We show that the derived in-plane (shear) and out-of-plane (breathing) force constants from experiment remain the same from two-layer 2D crystals to the bulk materials, suggesting that the nanoscale interlayer frictional characteristics of these excellent lubricants should be independent of the number of layers. PMID- 23432679 TI - Stem cell-based tissue engineering approaches for musculoskeletal regeneration. AB - The field of regenerative medicine and tissue engineering is an ever evolving field that holds promise in treating numerous musculoskeletal diseases and injuries. An important impetus in the development of the field was the discovery and implementation of stem cells. The utilization of mesenchymal stem cells, and later embryonic and induced pluripotent stem cells, opens new arenas for tissue engineering and presents the potential of developing stem cell-based therapies for disease treatment. Multipotent and pluripotent stem cells can produce various lineage tissues, and allow for derivation of a tissue that may be comprised of multiple cell types. As the field grows, the combination of biomaterial scaffolds and bioreactors provides methods to create an environment for stem cells that better represent their microenvironment for new tissue formation. As technologies for the fabrication of biomaterial scaffolds advance, the ability of scaffolds to modulate stem cell behavior advances as well. The composition of scaffolds could be of natural or synthetic materials and could be tailored to enhance cell self renewal and/or direct cell fates. In addition to biomaterial scaffolds, studies of tissue development and cellular microenvironments have determined other factors, such as growth factors and oxygen tension, that are crucial to the regulation of stem cell activity. The overarching goal of stem cell-based tissue engineering research is to precisely control differentiation of stem cells in culture. In this article, we review current developments in tissue engineering, focusing on several stem cell sources, induction factors including growth factors, oxygen tension, biomaterials, and mechanical stimulation, and the internal and external regulatory mechanisms that govern proliferation and differentiation. PMID- 23432685 TI - Refining the predictors of risk for central nervous system involvement in patients with mantle cell lymphoma. PMID- 23432684 TI - The effect of secondary prophylaxis versus episodic treatment on the range of motion of target joints in patients with haemophilia. AB - This study prospectively compared the effect of secondary prophylaxis to episodic treatment on target joint (TJ) range of motion (ROM), number of joint haemorrhages and new TJ development in patients with moderate or severe haemophilia. Two-hundred and eighty-six males, 17% in prophylaxis, 83% in episodic treatment group, participating in the Centers for Disease Control and Prevention's Universal Data Collection project, fulfilled inclusion criteria: age >2 years at enrollment, free of TJs at enrollment, developed at least one TJ after enrollment, and received either prophylaxis or episodic treatment continuously for two follow-up visits after TJ development. The outcomes of interest - percentage change in TJ ROM, number of joint haemorrhages and new TJ development, were modelled using multivariate linear, Poisson and logistic regression techniques respectively. Individuals who received secondary prophylaxis in comparison to episodic treatment were younger at TJ development (P < 0.01); there was no difference in the decrease in TJ ROM between the two groups (P = 0.9). Factors significantly associated with a higher rate of haemarthroses included episodic treatment, severe haemophilia, age >5 years at TJ development, obesity and inhibitor negative status. Secondary prophylaxis significantly decreased haemarthroses but was not associated with a significant improvement in TJ ROM or with new TJ development. PMID- 23432686 TI - Bridging the gap between epidemiology and clinical research in lymphoma. PMID- 23432687 TI - Cyclosporine modulation of multidrug resistance in combination with pravastatin, mitoxantrone and etoposide for adult patients with relapsed/refractory acute myeloid leukemia: a phase 1/2 study. PMID- 23432688 TI - Prognostic role of tumor-associated macrophages and angiogenesis in classical Hodgkin lymphoma. AB - We studied by immunohistochemistry CD68 + tumor-associated macrophages (TAMs) and angiogenesis in 121 consecutive cases of uniformly treated classical Hodgkin lymphoma (cHL). High TAM count showed a significant correlation with age >= 45, mixed cellularity subtype and high beta2-microglobulin level. Vessel density (VD) was unrelated to clinicopathological features, while a significant correlation was found between TAM count and VD. Patients with high TAMs showed a trend toward reduced progression-free survival and significantly shorter overall survival (OS). No correlation was found between VD and survival. At multivariate analysis, bulky disease was an independent predictor of reduced progression-free survival, while independent adverse prognostic factors for OS were male sex, age >= 45, advanced stage and bulky disease. High TAM count results in an adverse overall outcome in cHL and is significantly correlated to VD. Since VD has no prognostic relevance, the adverse effect of TAMs is presumably unrelated to angiogenesis. PMID- 23432689 TI - A BCR-JAK2 fusion gene from ins(22;9)(q11;p13p24) in a patient with atypical chronic myeloid leukemia. PMID- 23432690 TI - Decreased 5-hydroxymethylcytosine levels are associated with TET2 mutation and unfavorable overall survival in myelodysplastic syndromes. AB - The clinical significance and mechanisms of TET2 are not well defined in myeloid malignancies. We detected TET2 mutations and assayed its catalyzing conversion product 5-hydroxymethylcytosine (5-hmC) in 61 Chinese patients with MDS. Ten patients were identified to have TET2 mutations (16.4%). 5-hmC levels in patients with MDS with TET2 mutations were significantly lower than in those without mutations, and CD34+ cells of patients with MDS exhibited a lower 5-hmC content than that of controls. TET2 expression and 5-hmC in patients with MDS with P15 methylation were both significantly lower than in those without P15 methylation. We did not observe a correlation between TET2 mutations and overall survival (OS) in MDS. Interestingly, we found that patients with MDS with higher 5-hmC levels or in lower risk groups of the Revised International Prognostic Scoring System (IPSS-R) had a longer overall survival, suggesting that 5-hmC levels may be a new molecular marker for prognostic assessment of MDS and that revised IPSS criteria are also applicable to the risk categories of Chinese patients with MDS. PMID- 23432692 TI - Frequency and expression of inhibitory markers of CD4(+) CD25(+) FOXP3(+) regulatory T cells in patients with common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is the most symptomatic primary antibody deficiency associated with recurrent infections and chronic inflammatory diseases as well as autoimmunity. CD4(+) CD25(+) FOXP3(+) regulatory T cells (Tregs) are critical T cell subsets for maintaining self-tolerance and regulation of immune response to antigens thus play a pivotal role in preventing autoimmunity. Thirty seven CVID patients and 18 age-/sex-matched controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were obtained from both groups, and the percentage of Tregs was calculated using flow cytometry method. The mRNA expression of Tregs' surface markers cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and glucocorticoid-induced tumour necrosis factor receptor (GITR), which are associated with Tregs' inhibitory function, was compared between patients and controls by quantitative real-time PCR TaqMan method. The results revealed that the frequency of Tregs was significantly lower in CVID patients than normal individuals (P < 0.001). In addition, CVID patients with autoimmunity were found to have markedly reduced proportion of Tregs compared to those cases without autoimmune diseases (P = 0.023). A significant difference was seen in factor forkhead box P3 (FOXP3) expression between CVID patients and controls (P < 0.001). The mRNAs of CTLA-4 and GITR genes were expressed at lower levels in CVID patients compared to control group (P = 0.005 and <0.001, respectively). Our findings showed reduced proportion of Tregs in CVID patients together with downregulation of FOXP3 protein and diminished expression of inhibitory Tregs' markers. It could be concluded that all of these changes may be responsible for cellular immune dysregulation observed in these patients especially those with autoimmune manifestation. PMID- 23432693 TI - Risk indicators associated with dental erosion among Jordanian school children aged 12-14 years of age. AB - AIM: To identify potential risk indicators of dental erosion (DE) among 12- to 14 year-old Jordanian school children. DESIGN: A random cross-sectional sample was selected from Amman, Irbid, and Al-Karak governorates. A weighted multistage random sampling system was used to yield 3812, 12- to 14-year-old school children from 81 schools. The study utilized a self-reported questionnaire of factors reported in the literature and thought to be associated with DE. Full mouth recording using the tooth wear index modified by Millward et al. (1994) was performed by a single calibrated examiner. RESULTS: Logistic regression analysis defined the risk indicators that were simultaneously associated with DE with geographical location, medical condition including frequent mouth dryness, and having frequent bouts of vomiting or using a cortisol inhaler, dietary habits including consumption of carbonated beverages, lemon, sour candies, and sports drinks, keeping soft drinks in the mouth for a long time, brushing teeth following soft beverages or drinking lemon juice at bed time. CONCLUSIONS: Dental erosion is a multifactorial condition in which mouth dryness, vomiting, cortisol inhaler use, keeping soft drinks in the mouth, drinking beverages at bed time, consumption of lemon, sour candies, and having confectionary as snacks are risk indicators, and area of residence are all potential factors. PMID- 23432691 TI - Macrophages in multiple myeloma: emerging concepts and therapeutic implications. AB - Multiple myeloma, a clonal plasma cell malignancy, has long provided a prototypic model to study regulatory interactions between malignant cells and their microenvironment. Myeloma-associated macrophages have historically received limited scrutiny, but recent work points to central and non-redundant roles in myeloma niche homeostasis. The evidence supports a paradigm of complex, dynamic and often mutable interactions between macrophages and other cellular constituents of the niche. We and others have shown that macrophages support myeloma cell growth, viability and drug resistance through both contact-mediated and non-contact-mediated mechanisms. These tumor-beneficial roles have evolved in opposition to, or in parallel with, intrinsic pro-inflammatory and tumoricidal properties. Thus, simple blockade of protective "don't eat me" signals on the surface of myeloma cells leads to macrophage-mediated myeloma cell killing. Macrophages also enhance the tumor-supportive role of mesenchymal stem/stromal cells (MSCs) in the niche: importantly, this interaction is bidirectional, producing a distinct state of macrophage polarization that we termed "MSC educated macrophages." The intriguing pattern of cross-talk between macrophages, MSCs and tumor cells highlights the myeloma niche as a dynamic multi-cellular structure. Targeted reprogramming of these interactions harbors significant untapped therapeutic potential, particularly in the setting of minimal residual disease, the main obstacle toward a cure. PMID- 23432695 TI - Acute and severe acne in a patient treated with bevacizumab. AB - BACKGROUND: Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that inhibits angiogenesis. Bevacizumab is typically well tolerated; its major side effects include hypertension, proteinuria, bleeding, gastrointestinal perforation, and arterial thrombotic events, among others. Cutaneous side effects associated with the use of bevacizumab are rare and involve mainly itching and exfoliative dermatitis. Nonspecific skin rash and acneiform eruptions have recently been described in patients following infusion of bevacizumab. METHODS: Findings in a 52-year-old patient with stage IV lung cancer with brain metastasis, who developed severe, acute, and persistent acne after intravenous (IV) infusion of bevacizumab, are examined. RESULTS: The cutaneous eruption was classified as true acne rather than as an acneiform eruption because all cutaneous lesions of acne, namely comedones, inflammatory papules, and pustules, were present. CONCLUSIONS: To the authors' knowledge, this is the first report of an association between acne and IV administration of bevacizumab. PMID- 23432694 TI - Prevalence of viruses in stool of premature neonates at a neonatal intensive care unit. AB - AIM: Premature neonates represent a population highly vulnerable to infection. This study aims to profile viral colonisation of gut and the associated clinical manifestations among premature neonates admitted to a neonatal intensive care unit (NICU) in Australia. METHODS: In a cohort of 75 premature neonates born at less than 32 weeks gestation, who were followed for 4 weeks following admission to a NICU in Sydney, Australia, multiplex polymerase chain reaction assays were used to determine viral presence in stool, and clinical data were examined. RESULTS: Overall, viral RNA or DNA was detected in 24/419 (5.7%) of specimens, including norovirus genogroup 2 (1.9%), enterovirus (1.2%), herpes simplex virus 2 (1.2%), cytomegalovirus (0.7%), Epstein-Barr virus (0.5%) and rotavirus (0.2%). Viral infection was detected in 13/75 (17%) of premature neonates at some time point, including five (7%) neonates shedding more than one type of virus in stool. A higher rate of infection was observed among premature neonates with intrauterine growth restriction (56%) compared with those infants born appropriate for gestational age (12%. P = 0.006). CONCLUSION: The overall viral detection rate in stool of 5.7% (affecting 17% of neonates) indicates viral infections are an important health risk for premature infants in NICU. PMID- 23432696 TI - Relaxin-3 innervation of the intergeniculate leaflet of the rat thalamus - neuronal tract-tracing and in vitro electrophysiological studies. AB - Behavioural state is controlled by a range of neural systems that are sensitive to internal and external stimuli. The relaxin-3 and relaxin family peptide receptor 3 (RXFP3) system has emerged as a putative ascending arousal network with putative involvement in regulation of stress responses, neuroendocrine control, feeding and metabolism, circadian activity and cognition. Relaxin 3/gamma-aminobutyric acid neuron populations have been identified in the nucleus incertus, pontine raphe nucleus, periaqueductal grey (PAG) and an area dorsal to the substantia nigra. Relaxin-3-positive fibres/terminals densely innervate arousal-related structures in the brainstem, hypothalamus and limbic forebrain, but the functional significance of the heterogeneous relaxin-3 neuron distribution and its inputs to specific brain areas are unclear. Therefore, in this study, we used neuronal tract-tracing and immunofluorescence staining to explore the source of the dense relaxin-3 innervation of the intergeniculate leaflet (IGL) of the thalamus, a component of the neural circadian timing system. Confocal microscopy analysis revealed that relaxin-3-positive neurons retrogradely labelled from the IGL were predominantly present in the PAG and these neurons expressed corticotropin-releasing factor receptor-like immunoreactivity. Subsequently, whole-cell patch-clamp recordings revealed heterogeneous effects of RXFP3 activation in the IGL by the RXFP3 agonist, relaxin-3 B-chain/insulin-like peptide-5 A-chain (R3/I5). Identified, neuropeptide Y-positive IGL neurons, known to influence suprachiasmatic nucleus activity, were excited by R3/I5, whereas neurons of unidentified neurotransmitter content were either depolarized or displayed a decrease in action potential firing and/or membrane potential hyperpolarization. Our data identify a PAG to IGL relaxin-3/RXFP3 pathway that might convey stress-related information to key elements of the circadian system and influence behavioural state rhythmicity. PMID- 23432697 TI - Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation. AB - BACKGROUND AND AIM: Currently, hepatitis B virus (HBV) re-infection after liver transplantation (LT) can be almost completely suppressed by the administration of HBV reverse transcriptase inhibitors and hepatitis B immunoglobulins. However, after transplantation, there is no indicator of HBV replication because tests for the serum hepatitis B surface antigen and HBV-DNA are both negative. Therefore, the criteria for reducing and discontinuing these precautions are unclear. In this study, we examined the serum HBV core-related antigen (HBcrAg) and intrahepatic covalently closed circular DNA (cccDNA) in order to determine if these could be useful markers for HBV re-infection. METHODS: Thirty-one patients underwent LT for HBV-related liver disease at Nagasaki University Hospital from 2001 to 2010. Of these, 20 cases were followed up for more than 1 year (median follow-up period, 903 days). We measured serum HBcrAg and intrahepatic cccDNA levels in liver tissue. In addition, in nine cases, we assessed the serial changes of HBcrAg and intrahepatic cccDNA levels from preoperative periods to stable periods. RESULTS: We examined serum HBcrAg and intrahepatic cccDNA levels in 20 patients (35 samples). HBcrAg and cccDNA levels were significantly correlated with each other (r = 0.616, P < 0.001). From a clinical aspect, the fibrosis stage was significantly lower in both HBcrAg- and cccDNA-negative patients than in HBcrAg- or cccDNA-positive patients. CONCLUSIONS: HBcrAg and cccDNA were useful as HBV re-infection markers after LT. Keeping patients' HBcrAg and cccDNA negative after LT might contribute to long-term graft survival. PMID- 23432698 TI - The evolving role of VEGF-targeted therapies in the treatment of metastatic colorectal cancer. AB - Therapies that target angiogenesis and the VEGF pathway are a component of treatment for patients with metastatic colorectal cancer (mCRC). Bevacizumab is a humanized monoclonal antibody that binds to VEGFA. Chemotherapy plus bevacizumab has led to improved outcomes for mCRC patients. Despite these benefits, progressive disease invariably ensues. Multiple members of the VEGF family can potentially contribute to tumor angiogenesis and/or evasion of antiangiogenic therapy if one pathway should be inhibited. Aflibercept, a new biological agent, is a multiple angiogenic factor trap that prevents not only VEGFA, but also VEGFB and PlGF from activating their native receptors. Key clinical data for bevacizumab and aflibercept for treatment of mCRC, clinical evidence for use of these agents beyond progression, and the search for angiogenic biomarkers to better define patients most likely to benefit from these interventions will be reviewed. PMID- 23432699 TI - In situ visualization of self-assembly of charged gold nanoparticles. AB - Self-assembly of Au nanoparticles (NPs) coated with positively charged cetyltrimethylammonium ions (CTA(+)) and negatively charged citrate ions in aqueous liquid cell was investigated by in situ transmission electron microscopy (TEM). Under electron illumination in TEM, the hydrated electrons will reduce the overall positive charges of the CTA(+) covered Au NPs and decrease the repulsive electrostatic forces among NPs, leading to assembly of individual NPs into one dimensional structures. On the contrary, the negatively charged Au NPs coated with citrate ions are steady in liquid cell regardless of electron beam intensity. PMID- 23432700 TI - Touching up mental rotation: effects of manual experience on 6-month-old infants' mental object rotation. AB - In this study, 6-month-olds' ability to mentally rotate objects was investigated using the violation-of-expectation paradigm. Forty infants watched an asymmetric object being moved straight down behind an occluder. When the occluder was lowered, it revealed the original object (possible) or its mirror image (impossible) in one of five orientations. Whereas half of the infants were allowed to manually explore the object prior to testing, the other half was only allowed to observe the object. Results showed that infants with prior hands-on experience looked significantly longer at the mirror image, while infants with observational experience did not discriminate between test events. These findings demonstrate that 6-month-olds' mental rotations benefit from manual exploration, highlighting the importance of motor experience for cognitive performance. PMID- 23432701 TI - Uncoupling protein-2 gene polymorphisms are associated with obesity in Hungarian children. AB - AIM: To determine the frequency of common polymorphisms of genes associated with energy metabolism among normal weight and overweight/obese children to look for effects on childhood obesity. METHODS: Among 709 overweight/obese and 637 normal weight children (age 6-17 years), anthropometric measurements were carried out and genotyping for the following gene polymorphisms: beta3 -adrenoreceptor Trp64Arg, uncoupling protein (UCP) -1 -3826 A/G, UCP-2 -866 G/A and exon 8 del/ins, UCP-3 -55 C/T and peroxisome proliferator-activated receptor-gamma Pro12Ala. RESULTS: On multivariate regression analysis adjusted for age and gender heterozygosity and homozygosity for the UCP-2 -866 A variant was associated with an odds ratio (OR) for obesity of 0.69 (95% CI: 0.52-0.92; p = 0.013) and 0.50 (95% CI: 0.32-0.79; p = 0.003), respectively, compared with G/G homozygotes. Heterozygotes and homozygotes for the UCP-2 exon 8 ins allele had an OR for obesity of 1.66 (95% CI: 1.24-2.23; p = 0.001) and 2.12 (95% CI: 1.23 3.63; p = 0.006), respectively, compared with del/del homozygotes. There were no significant differences in obesity risk in association with the other examined gene polymorphisms. CONCLUSION: Common polymorphisms of the UCP-2 gene might influence the propensity to overweight/obesity in Hungarian children. PMID- 23432702 TI - Investigation of trace elements in pterygium tissue. AB - PURPOSE: In this study, we compare the concentrations of the essential trace elements chromium (Cr), copper (Cu), selenium (Se), manganese (Mn), boron (B) and zinc (Zn) in both pterygium and normal conjunctiva and investigate the role they play in the development of pterygium. METHODS: Included in the study were 38 patients with pterygium and 38 control patients in matching age groups who had been operated on for strabismus or cataracts and in whom conjunctiva samples were collected from the nasal limbus area. All conjunctiva samples were kept at -80 degrees C until the performance of the biochemical investigations. The B, Cr, Mn, Cu, Zn and Se levels in the samples were then measured. The levels of all tissue trace elements were determined by using Agilent 7500a Inductively Coupled Plasma Mass Spectrometer (Agilent Technologies, Santa Clara, CA). RESULTS: Cr, Mn, Zn and Se levels are significantly lower in the study group as compared to those of the control group (p < 0.001 for all four values). Regarding the level of B, there was no significant difference between the groups. The Cu levels of almost all subjects in the control group and all subjects in the pterygium group were under the detection limit. CONCLUSIONS: These findings indicate that remarkable differences in Mn, Zn, Se and Cr levels exist in pterygium tissues. Further investigation of electrolyte composition of the conjunctiva is needed to understand the genesis and developmental mechanism of pterygium. PMID- 23432703 TI - Reosseointegration of mechanically disintegrated implants in dogs: mechanical and histometric analyses. AB - OBJECTIVES: This study evaluated the reosseointegration of implants that had been reinserted following the mechanical disintegration of immature osseointegration in dogs. MATERIALS AND METHODS: Rotationally mobile implants were installed into an oversized drill space in five canine mandibles. After a healing period of 4 weeks, the immature osseointegration of the implant was intentionally disintegrated by the application of a mechanical countertorque and then reinserted at the same site (experimental group); in the control group, the mobile implant remained submerged without any surgical intervention. The animals were euthanized 4 weeks after the disruption of osseointegration. Changes in the implant stability quotient (ISQ) and Periotest value (PTV) were analyzed, and the bone-implant contact (%) was measured histometrically. RESULTS: All experimental and control sites showed successful mechanical stability at 8-week healing period. The mean ISQ was significantly higher in the experimental group than in the control group at 8 weeks (P < 0.01). In histology, immature woven-bone that bridged between the parent bone and the pre-existing residual bone on implant surface could be observed in experimental sites. The mean bone-implant contact was significantly higher in the experimental group than in the control group (P < 0.05). CONCLUSION: Within the limitation of the small sample used in this study, it is concluded that following the mechanical disruption of osseointegration, an implant can be successfully reosseointegrated with unloaded and submerged healing for a certain period. PMID- 23432704 TI - Direct determination of danofloxacin and flumequine in milk by use of fluorescence spectrometry in combination with partial least-squares calibration. AB - A new method for the simultaneous determination of danofloxacin and flumequine in milk samples was developed by using the nonlinear variable-angle synchronous fluorescence technique to acquire data and a partial least-squares chemometric algorithm to process them. A calibration set of standard samples was designed by combination of a factorial design with two levels per factor and a central star design. Whey was used as the third component of the calibration matrix. In order to assess the goodness of the proposed method, a prediction set of 11 synthetic samples was analyzed, obtaining recovery percentages between 96.1% and 104.0%. Limits of detection, calculated by means of a new criterion, were 0.90 and 12.4 ng mL(-1) for danofloxacin and flumequine, respectively. Finally, the simultaneous determination of both fluoroquinoles in milk samples containing the analytes was successfully carried out, obtaining an average recovery percentage of 99.3 +/- 4.4 for danofloxacin and 100.7 +/- 4.4. PMID- 23432705 TI - High-throughput and sensitive quantitation of plasma catecholamines by ultraperformance liquid chromatography-tandem mass spectrometry using a solid phase microwell extraction plate. AB - Plasma catecholamines provide a reliable biomarker of sympathetic activity. The low circulating concentrations of catecholamines and analytical interferences require tedious sample preparation and long chromatographic runs to ensure their accurate quantification by HPLC with electrochemical detection. Published or commercially available methods relying on solid phase extraction technology lack sensitivity or require derivatization of catecholamine by hazardous reagents prior to tandem mass spectrometry (MS) analysis. Here, we manufactured a novel 96 well microplate device specifically designed to extract plasma catecholamines prior to their quantification by a new and highly sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Processing time, which included sample purification on activated aluminum oxide and elution, is less than 1 h per 96-well microplate. The UPLC-MS/MS analysis run time is 2.0 min per sample. This UPLC-MS/MS method does not require a derivatization step, reduces the turnaround time by 10-fold compared to conventional methods used for routine application, and allows catecholamine quantification in reduced plasma sample volumes (50-250 MUL, e.g., from children and mice). PMID- 23432706 TI - Clinical consequences of aspirin and clopidogrel resistance: an overview. AB - The aim of this review is to introduce the concept of personalized medicine in secondary stroke prevention with antiplatelet medication. In the last years, many studies have been conducted regarding aspirin resistance and genotyping of clopidogrel metabolism. A review of the currently published data on this issue emphasizes the importance of focusing on the individualizing approach in antiplatelet therapy to achieve maximal therapeutic beneficial effect. However, many authors suggest that, before new information from ongoing trials become available, good clinical practice should dictate the use of low dose of aspirin that was shown to be effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, because higher doses do not have significantly better efficacy than lower doses in secondary stroke prevention, but lower-dose aspirin is associated with less side effects. On the other hand, many factors are associated with clopidogrel resistance, and recent genetic studies showed that the CYP2C19*2 genotype (loss-of-function allele) is related to poor metabolism of clopidogrel, but larger studies are needed to definitively confirm or rule out the clinical significance of this genetic effect. The aim of personalized approach in secondary stroke prevention is to take the most appropriate medicine in the right dose in accordance with the clinical condition of the patient and associated risk factors. PMID- 23432708 TI - Ab initio MRCI+Q study on low-lying states of CS including spin-orbit coupling. AB - Carbon monosulfide (CS), which plays an important role in a variety of research fields, has long received considerable interest. Due to its transient nature and large state density, the electronic states of CS have not been well understood, especially the interactions between different states. In this paper, we performed a detail ab initio study on the low-lying electronic states of CS by means of the internally contracted multireference configuration interaction method (including Davidson correction) with scalar relativistic correction using the Douglas-Kroll Hess Hamiltonian. We focused on the spin-orbit coupling of the states via the state interaction method with the full Breit-Pauli Hamiltonian. The potential energy curves (PECs) of 18 Lambda-S states correlated with the lowest dissociation limit of the CS molecule were calculated, as well as those of 50 Omega states generated from the Lambda-S states. The spectroscopic constants of the bound states were obtained, which are in good agreement with previous available experimental and theoretical results. The state perturbations of the a(3)Pi and A(1)Pi states with other low-lying electronic states are discussed in detail, based on the calculated spin-orbit matrix as well as the PECs of the Omega states. Avoided crossing in the states of CS was indicated when spin-orbit coupling was taken into account. Finally, the allowed transition dipole moments as well as the lifetimes of the five lowest vibrational states of the A(1)Pi1, A'(1)Sigma(+)0(+) and a(3)Pii states were obtained. PMID- 23432707 TI - CD8+ effector T cells at the fetal-maternal interface, balancing fetal tolerance and antiviral immunity. AB - During pregnancy CD8+ effector T cells need optimal immune regulation to prevent a detrimental response to allogeneic fetal cells while providing immune protection to infections. A significant proportion of (prospective) mothers carry naive or memory CD8+ T cells with a TCR that can directly bind to paternal MHC molecules. In addition, a high percentage of pregnant women develop specific T cell responses to fetal minor histocompatibility antigens (mHags). Under normal conditions, fetal-maternal MHC and mHag mismatches lead to elevated lymphocyte activation but do not induce pregnancy failure. Furthermore, viral infections alter the maternal CD8+ T cell response by changing the CD8+ T cell repertoire and increasing the influx of CD8+ T cells to decidual tissue. The normally high T cell activation threshold at the fetal-maternal interface may prevent efficient clearance of viral infections. Conversely, the increased inflammatory response due to viral infections may break fetal-maternal tolerance and lead to pregnancy complications. The aim of this review is to discuss the recent studies of CD8+ T cells in pregnancy, identify potential mechanisms for antigen-specific immune recognition of fetal extravillous trophoblast (EVT) cells by CD8+ T cells, and discuss the impact of viral infections and virus-specific CD8+ T cells during pregnancy. PMID- 23432709 TI - Contact investigations for outbreaks of Mycobacterium tuberculosis: advances through whole genome sequencing. AB - The control of tuberculosis depends on the identification and treatment of infectious patients and their contacts, who are currently identified through a combined approach of genotyping and epidemiological investigation. However, epidemiological data are often challenging to obtain, and genotyping data are difficult to interpret without them. Whole genome sequencing (WGS) technology is increasingly affordable, and offers the prospect of identifying plausible transmission events between patients without prior recourse to epidemiological data. We discuss the current approaches to tuberculosis control, and how WGS might advance public health efforts in the future. PMID- 23432710 TI - Dissecting glycosylation steps in lobophorin biosynthesis implies an iterative glycosyltransferase. AB - The identification of a lobophorin biosynthetic gene cluster from the deep-sea derived Streptomyces sp. SCSIO 01127 reveals a paradigm of three glycosyltransferases (GTs) LobG1-LobG3 being responsible for appending four sugars. Characterization of five differentially glycosylated metabolites from three GT gene-inactivation mutants allowed the assignment of GT functions and the implication of LobG3 as an iterative GT to attach two digitoxoses. PMID- 23432711 TI - Identifying endogenous neural stem cells in the adult brain in vitro and in vivo: novel approaches. AB - In the 1960s, Joseph Altman reported that the adult mammalian brain is capable of generating new neurons. Today it is understood that some of these neurons are derived from uncommitted cells in the subventricular zone lining the lateral ventricles, and the dentate gyrus of the hippocampus. The first area generates new neuroblasts which migrate to the olfactory bulb, whereas hippocampal neurogenesis seems to play roles in particular types of learning and memory. A part of these uncommitted (immature) cells is able to divide and their progeny can generate all three major cell types of the nervous system: neurons, astrocytes, and oligodendrocytes; these properties define such cells as neural stem cells. Although the roles of these cells are not yet clear, it is accepted that they affect functions including olfaction and learning/memory. Experiments with insults to the central nervous system also show that neural stem cells are quickly mobilized due to injury and in various disorders by proliferating, and migrating to injury sites. This suggests a role of endogenous neural stem cells in disease. New pools of stem cells are being discovered, suggesting an even more important role for these cells. To understand these cells and to coax them to contribute to tissue repair it would be very useful to be able to image them in the living organism. Here we discuss advances in imaging approaches as well as new concepts that emerge from stem cell biology with emphasis on the interface between imaging and stem cells. PMID- 23432712 TI - Endophenotypes and biological markers of schizophrenia: from biological signs of illness to novel treatment targets. AB - Schizophrenia is a chronic, often disabling mental illness with a lifetime prevalence of ~1% worldwide, and 2-to-3 times higher mortality rates are reported in schizophrenia patients compared to the general population. Although research has been increasingly focusing on identifying novel diagnostic and treatment resources for this illness, the diagnosis of schizophrenia is still based on clinical criteria, which are subjectively assessed and tend to vary across the course of the illness. Endophenotypes are commonly described as molecular, neuropsychological, neuro-imaging, and electrophysiological parameters that are closely associated to the genetic underpinnings of a specific disorder. Putative endophenotypes for psychiatric disorders should: 1) be associated with a specific illness in the population, 2) be heritable, 3) be present regardless of the patients clinical status, 4) co-segregate with the illness within families, and 5) be detected in non-affected family members of psychiatric patients at higher rates than in the general population. Whenever a genetic association is not present, or has not been investigated, the term biomarker is usually preferred. Endophenotypes and biomarkers are stable over time and are largely symptom independent, thus enabling an objective diagnosis of schizophrenia. Furthermore, these measures could be utilized to assess the risk of developing this disorder, and to identify novel pharmacological targets for its treatment. In this article I will present some of the most promising endophenotypes and biological markers of schizophrenia. For each of them, I will briefly describe abnormal findings in schizophrenia patients and, whenever available, in their first-degree relatives. I will then review the ability of each of these measures to identify individuals with schizophrenia (diagnostic value) and to assess the risk for schizophrenia (predictive value). Finally, I will discuss how some of these endophenotypes and biological markers could be utilized to develop novel treatment targets for schizophrenia, as well as to further the current understanding of the neurobiology of this disorder. PMID- 23432713 TI - Focusing on the interactions between the GABAergic system and neurosteroids in neurodevelopmental disorders. AB - Neurosteroids play essential roles in the control of central nervous system functions during physiological and pathological conditions. Increasing evidences show gender differences in the pathogenesis and clinical manifestations of several neurodevelopmental conditions, including Autism Spectrum Disorders (ASD), possibly due to the action of sex hormones during critical periods of brain development. Furthermore, it is known that neuroactive steroids contribute to neuroprotection, spinogenesis, synaptogenesis, as well as to modulation of neuronal excitability via their interaction with GABA receptors. Dysfunctions of GABAergic signaling early in development lead to a severe excitation-inhibition unbalance in neuronal circuits, which may contribute to the pathophysiology of autism. In this review, we summarize recent data concerning the functional role of neurosteroids and their relationship with the GABAergic system, focusing on GABA-mediated neurotrasmission alterations characterizing some neurodevelopmental disorders. PMID- 23432714 TI - Diffusion tensor imaging to determine effects of antidementive treatment on cerebral structural connectivity in Alzheimer's disease. AB - Introduction of diffusion tensor imaging (DTI) in 1980 and its advancement in the last three decades offered the possibility to visualize and quantify changes in white matter. DTI allows the evaluation of the structural integrity in complex neurodegenerative diseases, such as Alzheimer's disease (AD). Progressive disintegration of functional and structural neural network coordination contributes to the cognitive dysfunction in AD. Therefore, detection of loss of cortico-cortical projections may support an early diagnosis at prodromal stages of disease which may prove essential for future preventive AD treatment trials. Moreover, structural integrity measured by DTI may help to distinguish between symptomatic and disease modifying effects of pharmacological interventions. This review gives a concise account on the physical basis of DTI acquisition and processing. We summarize DTI findings in normal aging and AD and regarding the effects of cognitive intervention and antidementive treatment on structural neural connectivity. Finally, we evaluate the promising future potential of DTI to become a surrogate endpoint in clinical AD trials. PMID- 23432715 TI - Synaptic plasticity as a therapeutic target in the treatment of autism-related single-gene disorders. AB - The term "Autism Spectrum" is often used to describe disorders that are currently classified as Pervasive Developmental Disorders. These disorders are typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviors and/or cognitive delays or mental retardation; sometimes they present high comorbidity rates with epilepsy. Although these diagnoses share some common features, individuals with these disorders are thought to be "on the spectrum" because of differences in severity across these domains. Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. Of particular interest are transgenic technologies that allowed the engineering of several mouse models mimicking different kinds of monogenic heritable forms of ASDs. These transgenic models provide excellent opportunities to explore in detail cellular and molecular mechanisms underlying disease pathology and to identify novel targets for therapeutic intervention. Increasing evidence suggests that the pathophysiological core of the murine model is primarily due to changes in normal synaptic transmission and plasticity. Here, we will extensively review the synaptic alterations across different animal models of ASDs and recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. We describe how pharmacological modulation of mGlu5 receptor, through the use of positive or negative allosteric modulators (depending on the specific disorder), may represent a promising therapeutic strategy for ASDs treatment. PMID- 23432716 TI - Clinical neurophysiology of brain plasticity in aging brain. AB - The pathophysiological mechanisms underlying normal aging and neurodegenerative disorders represent the focus of a bulk of recent research. Physiological brain aging is characterized by a progressive dysfunction and loss of synaptic contacts and neuronal abnormal apoptosis. Neural and synaptic redundancy as well as functional and structural plastic remodeling of brain networking promote maintenance of brain activity in healthy elderly for everyday life but are not sufficient to face the pathologic scenario of excessive synaptic/ neuronal loss as in dementias. It is, then, important to implement techniques that are able to measure changes in normal aging brain and to discriminate the threshold from neurodegenerative processes. Rhythmic electromagnetic brain oscillatory activity is a hallmark of neuronal function and it contains relevant traces of neuronal assemblies cooperation across different brain functions; an integrated approach utilizing modern neurophysiological techniques, including electroencephalography (EEG), event-related potentials (ERPs), and transcranial magnetic stimulation (TMS), together with biological markers and structural and functional imaging is promising for largescale, affordable, and non-invasive intercept of at-risk populations both at a group and probably also at a single-subject level. This approach might also guarantee the possibility of studying drug-induced changes in the electrical properties of the human cortex, developing and testing models of brain connectivity and treating neuropsychiatric diseases. In this paper some neurophysiological cutting-edge techniques will be presented that provide innovative information and deal with the broad issue of the role of neurophysiology for the assessment of patho-physiological aging and dementia also providing new insight to the actions of central nervous system drugs at the cortical level. PMID- 23432717 TI - Imaging epigenetics in Alzheimer's disease. AB - Sporadic Alzheimer's disease (AD) is a prevalent, complex and chronically progressive brain disease. Its course is non-linear, dynamic, adaptive to maladaptive, and compensatory to decompensatory, affecting large-scale neural networks through a plethora of mechanistic and signaling pathway alterations that converge into regional and cell type-specific neurodegeneration and, finally, into clinically overt cognitive and behavioral decline. This decline includes reductions in the activities of daily living, quality of life, independence, and life expectancy. Evolving lines of research suggest that epigenetic mechanisms may play a crucial role during AD development and progression. Epigenetics designates molecular mechanisms that alter gene expression without modifications of the genetic code. This topic includes modifications on DNA and histone proteins, the primary elements of chromatin structure. Accumulating evidence has revealed the relevant processes that mediate epigenetic modifications and has begun to elucidate how these processes are apparently dysregulated in AD. This evidence has led to the clarification of the roles of specific classes of therapeutic compounds that affect epigenetic pathways and characteristics of the epigenome. This insight is accompanied by the development of new methods for studying the global patterns of DNA methylation and chromatin alterations. In particular, high-throughput sequencing approaches, such as next-generation DNA sequencing techniques, are beginning to drive the field into the next stage of development. In parallel, genetic imaging is beginning to answer additional questions through its ability to uncover genetic variants, with or without genome wide significance, that are related to brain structure, function and metabolism, which impact disease risk and fundamental network-based cognitive processes. Neuroimaging measures can further be used to define AD systems and endophenotypes. The integration of genetic neuroimaging methods with epigenetic markers in humans appears promising. This evolving development may lead to a new research discipline - imaging epigenetics - that will provide deeper insight into the causative pathogenetic and pathophysiological pathways through which genes and environment interrelate during life and impact human brain development, physiology, aging and disease. This knowledge may open doors for the development of novel biomarkers and preventive and disease-modifying treatments. PMID- 23432718 TI - Key role of mitochondria in Alzheimer's disease synaptic dysfunction. AB - Neuronal transmission and functional synapses require mitochondria, which are mainly involved in the generation of energy (ATP and NAD(+)), regulation of cell signaling and calcium homeostasis. Particularly intriguing is emerging data suggesting the relationship between mitochondria and neurotrophic factors that can act at the synaptic level promoting neuronal transmission and plasticity. On the other hand, disturbances in mitochondrial functions might contribute to impaired synaptic transmission and neuronal degeneration in Alzheimer's Disease and other chronic and acute neurodegenerative disorders. Here, we review the molecular mediators controling mitochondrial function and their impact on synaptic dysfunction associated with the pathogenesis of Alzheimer's Disease. PMID- 23432719 TI - Schizophrenia: causes and treatments. AB - Schizophrenia is a major mental illness that is characterized by psychosis, apathy, social withdrawal and cognitive impairment. These abnormalities in patients results in impaired functioning in work, school, parenting, self-care, independent living, interpersonal relationships, and leisure. Although the search for the biological correlates of schizophrenia has met with limited success, new advances in genetics and pharmacology are promising. Here, we describe the symptoms, causes, diagnosis, strategies for treatment, and clinical impact of the currently available medications. PMID- 23432720 TI - Editorial: targeting synaptic dysfunction and neural connectivity in neurological and psychiatric disorders. PMID- 23432721 TI - Cytarabine, aclarubicin and granulocyte colony-stimulating factor regimen represents an effective and safe salvage regimen for patients with acute myeloid leukemia refractory to first course of induction chemotherapy. AB - There is no consensus regarding the optimal second induction course regimen for patients with acute myeloid leukemia (AML) refractory to an initial course of front-line induction. The CAG regimen (cytarabine, aclarubicin and granulocyte colony-stimulating factor) has shown promise for relapsed/refractory AML. We retrospectively compared the efficacy and toxicity of the CAG regimen (n = 44) with a non-CAG regimen (n = 31) in 75 patients with AML refractory to an initial induction chemotherapy. The complete remission (CR) rate was higher for the CAG than the non-CAG regimen (63.5% vs. 38.7%, p = 0.038), and this was more pronounced in the subgroup of patients with a lower white blood cell (WBC) count before first/second induction, better- and intermediate-risk patients, and non AML-M4/5 (p = 0.019). Although the CAG group demonstrated a higher disease-free survival than the non-CAG group among the intermediate- and poor-risk patients (p = 0.019), no differences in overall survival were observed. The CAG regimen produced hematological and non-hematological side effects similar to those of the non-CAG regimen. The most frequent CAG regimen side effects were infection (45.5%), fever (50%) and elevated transaminase levels (31.8%). No patients died within 4 weeks after initiating the second induction course in the CAG regimen. Thus, CAG represents a highly effective and safe salvage regimen for patients with AML who are refractory to the first induction chemotherapy. This regimen may be of specific benefit for CR in patients with low WBC count, better- and intermediate-risk, and non-M4/5 disease. PMID- 23432722 TI - Combination of albumin-bound paclitaxel and pegylated liposomal doxorubicin is effective in treatment of heavily treated relapsed/refractory diffuse large B cell lymphoma: a case report. PMID- 23432723 TI - Frequencies of immature CD34 + CD38 - and CD34 + CD38-CD19 + blasts correlate with minimal residual disease level in pediatric B-cell precursor acute lymphoblastic leukemia. PMID- 23432724 TI - Lenalidomide in International Prognostic Scoring System Low and Intermediate-1 risk myelodysplastic syndromes with del(5q): an Italian phase II trial of health related quality of life, safety and efficacy. AB - In lower-risk myelodysplastic syndromes (MDS) with del(5q), lenalidomide induces erythroid responses associated with better survival. In a phase II, single-arm trial, 45 patients with anemia and lower-risk del(5q) MDS received lenalidomide 10 mg/day to evaluate quality of life (QoL) changes, measured by QOL-E, safety, responses and survival. Lenalidomide was well tolerated, with 80% completing >= 24 weeks of treatment. Earlier study discontinuation was related to disease progression (n = 5), death (n = 1) and withdrawal of consent (n = 3). Within 24 weeks, 82% obtained erythroid responses, durable in 69% at 52 weeks. Cytogenetic responses occurred in 29 patients (64%), with 10 patients achieving a complete cytogenetic response. QoL-E scores correlated with hemoglobin levels and improved in erythroid responders. Erythroid responders had an 86% reduced risk of disease progression and an 80% reduction in mortality risk compared with non-responders. These findings corroborate earlier studies and give further support to the use of lenalidomide in lower-risk MDS and del(5q). PMID- 23432725 TI - Frequency and extent of CD30 expression in diffuse large B-cell lymphoma and its relation to clinical and biologic factors: a retrospective study of 167 cases. AB - Previous studies have suggested that CD30 may be expressed in diffuse large B cell lymphomas (DLBCLs). However, the prevalence of CD30 + DLBCLs and extent of CD30 expression within an individual tumor have not been fully evaluated. The aim of this study was to determine the frequency and extent of CD30 expression in DLBCLs, and explore possible relationships between CD30 expression and clinical and biologic variables. We retrospectively identified and analyzed 167 cases of CD30 + DLBCLs from our pathology archive. Twenty-one percent (95% confidence interval [CI]: 14.8-27.1%) of these cases expressed CD30, and in 52% of them CD30 was positive in > 80% of tumor cells. CD30 expression was more frequent in DLBCLs with non-germinal center origin phenotype, BCL2 + DLBCLs and in patients <= 47 years old. There was significant interaction of BCL2 expression with age and subtype of DLBCL. A multivariate analysis performed in BCL2 + DLBCLs showed a higher frequency of CD30 + cases in non-germinal center DLBCLs (odds ratio [OR]: 6.5, 95% CI: 1.1-36.5) and in patients <= 47 years old (OR: 6.9, 95% CI: 1.5 29.5). These associations could suggest a common biologic pathogenesis. The effectiveness of anti-CD30 drugs in other lymphomas opens the possibility for their use in patients with CD30 + DLBCLs. PMID- 23432726 TI - Chk1-mediated phosphorylation of receptor-associated late transducer at serine 250 increases its stability by stimulating its interaction with 14-3-3. AB - Receptor-associated late transducer (RALT) acts as a negative feedback inhibitor of ErbB receptor signaling via physical interaction with ErbB. Although RALT contains a 14-3-3 binding motif (247-RSHSGP-252), little is known about the molecular basis and significance of binding to 14-3-3. Here, we report that 14-3 3 interacts with RALT in H9c2 and COS-7 cells in a Ser-250 phosphorylation dependent manner. An in vitro kinase assay showed that RALT is a substrate for checkpoint kinase 1 (Chk1). Interaction between ectopically expressed RALT and endogenous 14-3-3 was partially suppressed by pretreatment with the Chk1 inhibitor, UCN-01. In addition, expression of constitutively active Chk1 (Chk11 365 ) resulted in increased phosphorylation of the RALT 14-3-3 binding motif and enhanced the interaction between RALT and 14-3-3theta. Furthermore, fluorescence microscopy revealed that rapid trafficking of RALT to endosome-like vesicle structures was decelerated by coexpression of Chk11-365 , whereas this coexpression had no significant impact on trafficking of the RALT S250A mutant. Finally, a cycloheximide chase assay indicated that coexpression of Chk11-365 decelerated the degradation of ectopically expressed RALT, but not that of the S250A mutant. Collectively, these results suggest that Chk1 plays a role in regulating RALT protein stability by facilitating the interaction between 14-3-3 and RALT. PMID- 23432727 TI - Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. AB - Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2.5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR. PMID- 23432728 TI - A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma. AB - INTRODUCTION: Expression of fusion oncoproteins generated by recurrent chromosomal translocations represents a major tumorigenic mechanism characteristic of multiple cancers, including one-third of all sarcomas. Oncogenic fusion genes provide novel targets for therapeutic intervention. The PAX3-FOXO1 oncoprotein in alveolar rhabdomyosarcoma (ARMS) is presented as a paradigm to examine therapeutic strategies for targeting sarcoma-associated fusion genes. AREAS COVERED: This review discusses the role of PAX3-FOXO1 in ARMS tumors. Besides evaluating various approaches to molecularly target PAX3-FOXO1 itself, this review highlights therapeutically attractive downstream genes activated by PAX3-FOXO1. EXPERT OPINION: Oncogenic fusion proteins represent desirable therapeutic targets because their expression is specific to tumor cells, but these fusions generally characterize rare malignancies. Full development and testing of potential drugs targeted to these fusions are complicated by the small numbers of patients in these disease categories. Although efforts to develop targeted therapies against fusion proteins should continue, molecular targets that are applicable to a broader tumor landscape should be pursued. A shift of the traditional paradigm to view therapeutic intervention as target-specific rather than tumor-specific will help to circumvent the challenges posed by rare tumors and maximize the possibility of developing successful new treatments for patients with these rare translocation associated sarcomas. PMID- 23432729 TI - Pityriasis versicolor: a case of resistance to treatment. PMID- 23432730 TI - Brinzolamide-timolol fixed combination for the prevention of intraocular pressure elevation after phacoemulsification. AB - BACKGROUND: To evaluate the efficacy of brinzolamide-timolol fixed combination in intraocular pressure during the first 24 h after uneventful phacoemulsification cataract surgery using Viscoat and Provisc. DESIGN: Prospective randomized comparative case series. PARTICIPANTS: Ninety-two eyes of equal patients scheduled for phacoemulsification cataract surgery. METHODS: Treatment group (52 eyes) received a drop of brinzolamide-timolol fixed combination immediately after surgery. Control group (40 eyes) received no treatment. MAIN OUTCOME MEASURES: Intraocular pressure preoperatively and at 6, 12 and 24 h postoperatively. RESULTS: Six hours after surgery the mean intraocular pressure decreased by 0.3 +/- 2.95 mmHg (P > 0.05) in the treatment group and increased by 6.8 +/- 2.78 mmHg (P < 0.001) in the control group. Twelve hours postoperatively, the mean intraocular pressure increased by 0.23 +/- 3.49 mmHg (P > 0.05) in the treatment group and by 5.3 +/- 3.26 mmHg (P < 0.001) in the control group. Twenty-four hours after surgery, the mean intraocular pressure decreased by 1.76 +/- 2.83 mmHg (P < 0.01) in the treatment group and in the control group increased by 1.4 +/- 2.46 mmHg (P > 0.05). The intraocular pressure in the treatment group was statistically significantly lower compared with the control group at 6, 12 and 24 h postoperatively. None of the eyes in the treatment group had postoperative intraocular pressure elevation >=10 mmHg; such an increase was recorded in 20% and 10% of control eyes at 6 and 12 h after surgery, respectively. CONCLUSION: A single dose of brinzolamide-timolol fixed combination after phacoemulsification cataract surgery prevented a significant intraocular pressure increase during the first 24 h postoperatively. PMID- 23432731 TI - Retrospective study of the effect of enhanced systematic sexually transmitted infection screening, facilitated by the use of electronic patient records, in an HIV-infected cohort. AB - OBJECTIVES: The aim of the study was to assess the impact of electronic checklists in enhancing sexually transmitted infection (STI) screening in routine HIV care. METHODS: This was a retrospective cohort study. In two HIV clinics, new STIs were recorded for three consecutive 12-month periods between 2009 and 2012 in a cohort of 882 HIV-infected patients. These three years coincided with the introduction of enhanced STI screening based on prompts within the electronic patient record (EPR) system. RESULTS: The number of diagnoses and the incidence of STIs more than doubled between 2010-2011 and 2011-2012 in both men who have sex with men (MSM) [from 18 of 115 (15%) to 42 of 132 (32%), a rise in STI incidence from 15.6 to 31.8/100 person-years; P < 0.001] and heterosexual patients [from six of 716 (0.8%) to 19 of 749 (2.5%), a rise in STI incidence from 0.8 to 2.5/100 person-years; P < 0.005]. The rise was significant in MSM for infections with chlamydia [from seven of 115 (6%) to 14 of 132 (11%), a rise in incidence from 6.0 to 10.6/100 person-years; P < 0.05], gonorrhoea [from five of 115 (4%) to 12 of 132 (9%), a rise in STI incidence from 4.3 to 9.1/100 person years; P < 0.05] and early syphilis [from four of 115 (3%) to 13 of 132 (10%), a rise in incidence from 3.5 to 9.8/100 person-years; P < 0.001], but not for hepatitis C virus (HCV) and Lymphogranuloma venereum (LGV) infections. The rise was significant in heterosexual patients for infection with chlamydia [from four of 716 (0.6%) to 13 of 749 (1.7%), a rise in incidence from 0.6 to 1.7/100 person years; P < 0.0001] but not for gonorrhoea, syphilis or Trichomonas vaginalis (TV). CONCLUSIONS: These data show that implementing systematic, frequent and routine STI screening led to a large increase in detected STIs in this HIV infected cohort. This process is greatly enhanced by the use EPRs. PMID- 23432733 TI - Neonatal length inaccuracies in clinical practice and related percentile discrepancies detected by a simple length-board. AB - AIM: The study aims to assess accuracy of standard practice measurement of neonatal length compared with a gold-standard length-board technique. METHODS: Data were obtained from a population-based, cross-sectional study of 602 term babies at Royal Prince Alfred Hospital, Sydney, Australia, in 2010. Neonatal length was measured by standard clinical practice and by a length-board (gold standard) and measurements compared. Standard growth curve percentiles were used to plot length measurements. The Bland and Altman method was used to assess agreement, and acceptable levels of agreement were set at <=1 cm and <=0.5 cm. RESULTS: The limits of agreement were between -3.06 cm (95% CI -3.08 to -3.04) and 2.67 cm (95% CI 2.65 to 2.69). Neonates whose standard-practice length fell within 0.5 cm of the gold standard totalled 41% (241 neonates), while 59% (342) were >0.5 cm. The change in length resulted in a change in the percentile range of 53% (309) on a standard growth curve percentile. When examining neonates whose length was plotted at the extremes of percentile regions, the positive predictive value results of the standard practice compared with the gold standard were poor, with positive predictive values of 37.5%, 57.1% and 31.3% for neonates who were measured as <3rd, <10th and >=90th percentile, respectively. CONCLUSIONS: In current clinical practice, measures of neonatal length are often inaccurate, which has implications for potentially erroneous clinical care. Health-care providers should be educated on the importance of length and trained in how to measure length with the correct technique using a length-board. PMID- 23432734 TI - Online lexical competition during spoken word recognition and word learning in children and adults. AB - Lexical competition that occurs as speech unfolds is a hallmark of adult oral language comprehension crucial to rapid incremental speech processing. This study used pause detection to examine whether lexical competition operates similarly at 7-8 years and tested variables that influence "online" lexical activity in adults. Children (n = 20) and adults (n = 17) were slower to detect pauses in familiar words with later uniqueness points. Faster latencies were obtained for words with late uniqueness points in constraining compared with neutral sentences; no such effect was observed for early unique words. Following exposure to novel competitors ("biscal"), children (n = 18) and adults (n = 18) showed competition for existing words with early uniqueness points ("biscuit") after 24 hr. Thus, online lexical competition effects are remarkably similar across development. PMID- 23432732 TI - gamma-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Abeta. AB - Deposition of beta -amyloid (Abeta) peptides, cleavage products of beta-amyloid precursor protein (APP) by beta-secretase-1 (BACE1) and gamma-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). gamma-Secretase inhibition is a therapeutical anti-Abeta approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Abeta peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Abeta efficacy. The present study compared active gamma-secretase binding sites with Abeta deposition in aged and AD human cerebrum, and explored the possibility of Abeta production and secretion by the choroid plexus (CP). The specific binding density of [(3) H] L-685,458, a radiolabeled high-affinity gamma-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and beta-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Abeta40 and Abeta42 into the medium. Overall, our results suggest that gamma-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Abeta, probably at reduced levels in AD. PMID- 23432735 TI - Comparison of abdominal ultrasound and magnetic resonance imaging for detection of abdominal lymphadenopathy in dogs with metastatic apocrine gland adenocarcinoma of the anal sac. AB - Imaging studies in humans with anal and rectal cancer indicate that magnetic resonance imaging (MRI) is a more sensitive technique than abdominal ultrasound (AUS) for the detection of abdominal lymphadenopathy. The purpose of this retrospective study was to directly compare the efficacy of these two techniques in detecting abdominal lymphadenopathy in dogs with apocrine gland adenocarcinoma of the anal sac (AGAAS). Six dogs with histologically confirmed AGAAS and histopathologic confirmation of metastasis to abdominal lymph nodes (LNs) had AUS and abdominal MRI. AUS identified lymphadenopathy in two of six dogs, whereas MRI identified lymphadenopathy in all the six dogs. Lymphadenopathy was predominantly sacral in location, with involvement of the medial iliac and hypogastric LNs in only two cases. These data suggest that MRI is more sensitive than AUS for detecting sacral abdominal lymphadenopathy in dogs with AGAAS. As such, MRI could be considered in any patient with AGAAS for initial staging of this disease. PMID- 23432736 TI - Assessing, teaching and defining: issues in obstetrics and gynecology. PMID- 23432737 TI - Congestive heart failure with diffuse neonatal hemangiomatosis--case report and literature review. AB - BACKGROUND: Vascular hemangiomas are considered to be a common finding among neonates and infants. The presence of five or more cutaneous hemangiomas may carry a higher incidence of multiple organ involvement MATERIALS & METHODS: An eleven week old female infant with high cardiac output heart failure and multiple cutaneous hemangiomas was referred to our clinic. Soon after birth she failed to gain weight and developed breathlessness. There was partial response to Captopril and Frusemide therapy, with development of a progressive cough. Echocardiogram and liver and brain ultrasound scans revealed heart chamber enlargement, multiple liver hemangiomas and an isolated cerebellar arterio-venous malformation (AVM). Supportive treatment for congestive heart failure combined with propranolol therapy resulted in rapid clinical response and recovery. DISCUSSION: The diagnosis of Diffuse Neonatal Hemangiomatosis in infants with failure to thrive and symptoms of heart failure raises the possibility of internal organ involvement. Augmentation of propranolol in such cases may cause regression of Hemangiomatosis with patient clinical improvement. CONCLUSION: We report our experience with a single patient of Hemangiomatosis induced heart failure which responded to propranolol combined with medication to control heart failure and failure to thrive prevention. This treatment should be further evaluated with special attention to potential adverse effects, tolerance and compliance. PMID- 23432738 TI - 8th world kidney day. PMID- 23432739 TI - Perspectives on death, dying and advance care planning from patients receiving haemodialysis. AB - BACKGROUND: The illness trajectory of End Stage Kidney Disease (ESKD) is not linear therefore it can be difficult for practitioners to know when end-of-life care begins. Advance care planning (ACP) allows patients to take part in decision making, however much of the research conducted stems from North America and Canada where individuals have experience of ACP. The aim of the study was to determine the views of Irish patients receiving haemodialysis, on death, dying and ACP. METHODS: A quantitative, descriptive design was used with a convenience sample of 50 patients. Data were collected by means of a researcher administered questionnaire and analysed using descriptive statistics. FINDINGS: The majority of participants were comfortable talking about death, but not necessarily among family, with most desiring medical interventions to prolong life. The control of pain and other symptoms, being physically comfortable and being at peace spiritually were the most important issues at end of life. CONCLUSION: This study provides an insight into what is important to patients in relation to death, dying and advance care planning. PMID- 23432740 TI - The impact of nurse-led education on haemodialysis patients' phosphate binder medication adherence. AB - BACKGROUND: Phosphate binder medication adherence is required to maintain optimal phosphate levels and minimise bone disease in people with end stage kidney disease. OBJECTIVES: To examine the impact of a nurse-led education intervention on bone disorder markers, adherence to phosphate binder medication and medication knowledge. DESIGN: Descriptive study with a paired pre-post intervention survey. PARTICIPANTS: Adults receiving haemodialysis. METHODS: Twelve-week intervention where patients self-administered their phosphate binder medication at each dialysis treatment. Nurses provided individualised education. Patients completed a pre- and post-intervention survey designed to explore their knowledge of phosphate binders. RESULTS: There were no statistically significant changes in clinical markers but a significant improvement in the proportion of patients who took their phosphate binder correctly, increasing from 44 to 72% (p = 0.016). There were moderate to large effect size changes for improved knowledge. CONCLUSIONS: A nurse-led intervention education programme can increase patients' phosphate binder adherence. However, this does not necessarily manifest into improved serum phosphate levels. PMID- 23432741 TI - Effect of nutritional intervention on malnutrition indicators in patients on haemodialysis. AB - OBJECTIVE: To formulate a nutrient supplement using low cost, commonly available food ingredients and test its efficacy on various nutritional parameters in haemodialysis (HD) subjects. DESIGN: Prospective intervention study. SUBJECTS: 15 subjects who did not have diabetes were recruited for the study. The subjects served as self controls. APPROACH: The subjects received a multi-nutrient formulation for a period of 3 months. Somatic status [weight, mid upper arm circumference (MUAC), mid upper arm muscle circumference (MUAMC), waist and hip measurements], biochemical parameters [blood urea nitrogen (BUN), total iron binding capacity (TIBC),serum levels of creatinine, albumin, triglycerides, sodium, potassium, calcium, phosphorus and high sensitive C-reactive protein(HsCRP)], dietary intake and malnutrition inflammation score (MIS) were assessed. RESULTS: Significant increments (P <= 0.01) in anthropometric measurements. Significant increases (P <= 0.01) in Hb, BUN, serum creatinine, albumin and total protein and a significant decrease (P <= 0.01) in HsCRP and MIS were observed at the end of the study. An increase in baseline food/nutrient intake was also observed. CONCLUSION: Nutritional supplementation designed for haemodialysis, improved their nutritional status in the short term study. PMID- 23432742 TI - A literature review of end-stage renal disease and cachexia: understanding experience to inform evidence-based healthcare. AB - INTRODUCTION: Cachexia is a major cause of morbidity and mortality in people who have end-stage renal disease (ESRD). The majority of research into cachexia in ESRD has focused on the biological aspects of the syndrome and potential treatment modalities. While this research is necessary, it predominately focuses on the physical impact of cachexia in ESRD. The multi-dimensional psychosocial ramifications of this syndrome have been highlighted in other end-stage illness trajectories, but have not been systematically explored in persons who have ESRD. AIM: This paper discusses why this research is necessary, alongside further studies to help define the pathophysiology of this syndrome. CONCLUSION: The rich insightful data gained from understanding the patients' illness experience will positively contribute to the limited knowledge base available and inform future holistic patient-centred care delivery which recognises and responds to not only the biological but also the psychosocial impact of cachexia. PMID- 23432743 TI - 7th annual scientific meeting of the uk cardiorenal forum. PMID- 23432747 TI - Report on the first Asia-Pacific Kidney Development Workshop. PMID- 23432746 TI - Reconciling a Salmonella enterica metabolic model with experimental data confirms that overexpression of the glyoxylate shunt can rescue a lethal ppc deletion mutant. AB - The in silico reconstruction of metabolic networks has become an effective and useful systems biology approach to predict and explain many different cellular phenotypes. When simulation outputs do not match experimental data, the source of the inconsistency can often be traced to incomplete biological information that is consequently not captured in the model. To address this problem, general approaches continue to be needed that can suggest experimentally testable hypotheses to reconcile inconsistencies between simulation and experimental data. Here, we present such an approach that focuses specifically on correcting cases in which experimental data show a particular gene to be essential but model simulations do not. We use metabolic models to predict efficient compensatory pathways, after which cloning and overexpression of these pathways are performed to investigate whether they restore growth and to help determine why these compensatory pathways are not active in mutant cells. We demonstrate this technique for a ppc knockout of Salmonella enterica serovar Typhimurium; the inability of cells to route flux through the glyoxylate shunt when ppc is removed was correctly identified by our approach as the cause of the discrepancy. These results demonstrate the feasibility of our approach to drive biological discovery while simultaneously refining metabolic network reconstructions. PMID- 23432748 TI - Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. PMID- 23432749 TI - Antiviral medications for preventing cytomegalovirus disease (CMV) in solid organ transplant recipients. PMID- 23432750 TI - Transient Brugada electrocardiogram pattern associated with Tenchkoff catheter exit site infection. PMID- 23432751 TI - Transient massive proteinuria after gelatin-derived plasma expander (Gelofusine(r)) administration. PMID- 23432752 TI - Acute oxalate nephropathy secondary to orlistat-induced enteric hyperoxaluria. PMID- 23432753 TI - Comprehensive insights into the structural and chemical changes in mixed-anion FeOF electrodes by using operando PDF and NMR spectroscopy. AB - In-depth analysis of operando X-ray pair distribution function (PDF) data is combined with Li NMR spectroscopy to gain comprehensive insights into the electrochemical reaction mechanism of high-performance iron oxyfluoride electrodes. While the full discharge capacity could be recovered upon charge, implying reversibility of the electrochemical reaction, the atomic structure of the electrode formed after cycling (discharge-charge) differs from the pristine uncycled electrode material. Instead, the "active" electrode that forms upon cycling is a nanocomposite of an amorphous rutile phase and a nanoscale rock salt phase. Bond valence sum analysis, based on the precise structural parameters (bond lengths and coordination number) extracted from the in situ PDF data, suggests that anion partitioning occurs during the electrochemical reaction, with the rutile phase being F-rich and the rock salt phase being O-rich. The F- and O rich phases react sequentially; Fe in a F-rich environment reacts preferentially during both discharge and charge. PMID- 23432754 TI - Transcriptome analyses reveal protein and domain families that delineate stage related development in the economically important parasitic nematodes, Ostertagia ostertagi and Cooperia oncophora. AB - BACKGROUND: Cooperia oncophora and Ostertagia ostertagi are among the most important gastrointestinal nematodes of cattle worldwide. The economic losses caused by these parasites are on the order of hundreds of millions of dollars per year. Conventional treatment of these parasites is through anthelmintic drugs; however, as resistance to anthelmintics increases, overall effectiveness has begun decreasing. New methods of control and alternative drug targets are necessary. In-depth analysis of transcriptomic data can help provide these targets. RESULTS: The assembly of 8.7 million and 11 million sequences from C. oncophora and O. ostertagi, respectively, resulted in 29,900 and 34,792 transcripts. Among these, 69% and 73% of the predicted peptides encoded by C. oncophora and O. ostertagi had homologues in other nematodes. Approximately 21% and 24% were constitutively expressed in both species, respectively; however, the numbers of transcripts that were stage specific were much smaller (~1% of the transcripts expressed in a stage). Approximately 21% of the transcripts in C. oncophora and 22% in O. ostertagi were up-regulated in a particular stage. Functional molecular signatures were detected for 46% and 35% of the transcripts in C. oncophora and O. ostertagi, respectively. More in-depth examinations of the most prevalent domains led to knowledge of gene expression changes between the free-living (egg, L1, L2 and L3 sheathed) and parasitic (L3 exsheathed, L4, and adult) stages. Domains previously implicated in growth and development such as chromo domains and the MADF domain tended to dominate in the free-living stages. In contrast, domains potentially involved in feeding such as the zinc finger and CAP domains dominated in the parasitic stages. Pathway analyses showed significant associations between life-cycle stages and peptides involved in energy metabolism in O. ostertagi whereas metabolism of cofactors and vitamins were specifically up-regulated in the parasitic stages of C. oncophora. Substantial differences were observed also between Gene Ontology terms associated with free-living and parasitic stages. CONCLUSIONS: This study characterized transcriptomes from multiple life stages from both C. oncophora and O. ostertagi. These data represent an important resource for studying these parasites. The results of this study show distinct differences in the genes involved in the free living and parasitic life cycle stages. The data produced will enable better annotation of the upcoming genome sequences and will allow future comparative analyses of the biology, evolution and adaptation to parasitism in nematodes. PMID- 23432755 TI - Prospective randomized trial of maintenance immunosuppression with rapid discontinuation of prednisone in adult kidney transplantation. AB - Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10 year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 MUg/L) and low-level sirolimus (SIR, 3-7 MUg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 MUg/L) and high-level SIR (8-12 MUg/L) (TACL/SIR(H) , n=140). Median follow-up was ~7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP. PMID- 23432756 TI - Which types of regulatory T cells play important roles in implantation and pregnancy maintenance? AB - Regulatory T cells (Treg) play essential roles in implantation and allogeneic pregnancy maintenance in mice and humans. Recent data have shown the heterogeneity of Treg, such as thymic (naturally occurring) Treg, extrathymic (inducible or peripheral) Treg, naive Treg, effector Treg, resting (non proliferating) Treg and activated (proliferating) Treg. Importantly, Foxp3, which was believed to be a specific marker for Treg, is transiently expressed in T cells when conventional T cells are activated and proliferating in humans showing that Foxp3 is not a specific marker for Treg. Therefore, we should evaluate the true Treg level and clarify which types of Treg cells play important roles in implantation and pregnancy maintenance in mice and humans. PMID- 23432757 TI - Comparative proteomic analysis of the effect of temperature and fertilizer on gliadin and glutenin accumulation in the developing endosperm and flour from Triticum aestivum L. cv. Butte 86. AB - BACKGROUND: Flour quality is largely determined by the gluten proteins, a complex mixture of proteins consisting of high molecular weight-glutenin subunits (HMW GS), low molecular weight-glutenin subunits (LMW-GS), and alpha-, gamma-, and omega-gliadins. Detailed proteomic analyses of the effects of fertilizer and high temperature on individual gliadin and glutenin protein levels are needed to determine how these environmental factors influence flour quality. RESULTS: Wheat plants (Triticum aestivum L. cv. Butte 86) were grown in greenhouses under moderate and high temperature regimens with and without post-anthesis fertilizer. Quantitative two-dimensional gel electrophoresis was used to construct accumulation profiles in developing endosperm for the entire complement of gluten proteins identified previously by tandem mass spectrometry. Amounts of individual gliadins and glutenins were also determined in flour produced under each of the regimens. Under all environmental regimens, most HMW-GS, LMW-GS, gamma- and omega gliadins accumulated rapidly during early stages of grain development and leveled off during middle stages of development. A subset of LMW-GS showed a second distinct profile, accumulating throughout development, while alpha-gliadins showed a variety of accumulation profiles. In flour, fourteen distinct gluten proteins responded similarly to fertilizer, high temperature, and high temperature plus fertilizer. The majority of HMW-GS and omega-gliadins and some alpha-gliadins increased while two LMW-GS and a minor gamma-gliadin decreased. Fertilizer did not influence gluten protein accumulation under high temperature conditions. Additionally, the effects of fertilizer and high temperature were not additive; very few changes were observed when plants that received fertilizer were subjected to high temperature. CONCLUSIONS: Although post-anthesis temperature and fertilizer have very different effects on grain development and yield, the two treatments elicit surprisingly similar effects on the accumulation of gluten proteins. The similarity of the responses to the different treatments is likely due to source-sink activities of nitrogen reserves in the wheat plant. Because each protein that showed a response in this study is linked to a gene sequence, the work sets the stage for transgenic studies that will better elucidate the roles of specific proteins in flour quality and in the response to the environment. PMID- 23432758 TI - Response of circulating heat shock protein 70 and anti-heat shock protein 70 antibodies to catheter ablation of atrial fibrillation. AB - BACKGROUND: This pilot study investigated the association between heat shock protein 70 (HSP70) and anti-HSP70 antibodies as well as their changes and rhythm outcome after atrial fibrillation (AF) catheter ablation. METHODS: We studied 67 patients with AF (59+/-11 years, 66% male, 66% lone AF) undergoing catheter ablation. Circulating HSP70 and anti-HSP70 antibody levels were quantified using commercially available assays before and 6 months after catheter ablation. Serial 7-day Holter ECGs were used to detect AF recurrences. RESULTS: At baseline, HSP70 was detectable in 14 patients (21%), but there was no correlation between clinical or echocardiographic variables and the presence or the level of HSP70. In contrast, patients with paroxysmal AF (n=39) showed lower anti-HSP70 antibodies (median [IQR] of 43 [28 - 62] MUg/ml) than patients with persistent AF (n=28; 53 [41 - 85] MUg/ml, p=0.035). Using multivariable regression analysis, AF type was the only variable associated with anti-HSP70 antibodies (Beta=0.342, p=0.008). At 6 months, HSP70 was present in 27 patients (41%, p<0.001 vs. baseline). Similarly, there was an increase of anti-HSP70 antibodies (48 [36 - 72] vs. 57 [43 - 87] MUg/ml, p<0.001). AF recurrence rates were higher in patients with HSP70 increase >=0.025 ng/ml (32 vs. 11%, p=0.038) or anti-HSP70 increase >=2.5 MUg/ml (26 vs. 4%, p=0.033). CONCLUSIONS: HSP70 and anti-HSP70 antibodies may - at least in part - be associated in the progression of AF and AF recurrence after catheter ablation. PMID- 23432759 TI - The development of language constancy: attention to native versus nonnative accents. AB - The time frame for infants' acquisition of language constancy was probed, using the phonetic variation in a rarely heard accent (South African English) or a frequently heard accent (American English). A total of 156 Australian infants were tested. Six-month-olds looked longer to Australian English than less commonly heard South African accent, but at 9 months, showed similar looking times. With the more frequently heard American accent, 3-month-olds looked longer to Australian and American English, whereas 6-month-olds looked equally. Together these results imply that in the 1st year, differential attention to native versus nonnative accents decreases as infants develop a sense of language constancy for the common native language. However, experience with the nonnative accent can expedite this process. PMID- 23432760 TI - Combination of albendazole and 2-methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice. AB - BACKGROUND: Albendazole (ABZ) is a microtubule-targeting anthelmintic with a remarkable activity against a variety of human cancer cells. In this study, we examined if the antitumor activity of ABZ could be enhanced by its combination with other microtubule-binding agents. METHODS: The interactions between ABZ and microtubule-binding agents, paclitaxel, vinblastine, colchicine, and 2 methoxyestradiol were characterized using median effect analysis method in HCT 116 colorectal cancer cells and DU145 prostate cancer cell line. The mechanism underlying the synergistic interaction related to tubulin polymerization and apoptosis was then investigated. Finally, the effect of the combination therapy on the survival of HCT-116 tumor-bearing nude mice was evaluated. RESULTS: Among the tested drugs, a synergistic anti-proliferative effect was observed with the combination of low concentrations of ABZ plus colchicine and ABZ plus 2 methoxyestradiol (2ME). Exploring the mechanism of the interaction between ABZ and 2ME revealed that the combination therapy synergistically activated the extrinsic pathway of apoptosis. Consistent with in vitro results, the combination of low concentration of ABZ with 2ME prolonged the survival of mice-bearing HCT 116 tumors. High concentration of ABZ in combination with 2ME, however, proved to be less effective than ABZ alone. CONCLUSIONS: The combination of low doses of ABZ and 2ME has shown promising results in our pre-clinical model. Additionally, the finding that the combination of two microtubule-binding agents that share the same binding site can act synergistically may lead to the development of new therapeutic strategies in cancer treatment. PMID- 23432762 TI - Association between pterygium and plica semilunaris morphology. PMID- 23432761 TI - Determinants of alveolar ridge preservation differ by anatomic location. AB - AIM: To investigate and compare outcomes following alveolar ridge preservation (ARP) in posterior maxilla and mandible. METHODS: Twenty-four patients (54 +/- 3 years) with single posterior tooth extraction were included. ARP was performed with freeze-dried bone allograft and collagen membrane. Clinical parameters were recorded at extraction and re-entry. Harvested bone cores were analysed by microcomputed tomography (micro-CT), histomorphometry and immunohistochemistry. RESULTS: In both jaws, ARP prevented ridge height loss, but ridge width was significantly reduced by approximately 2.5 mm. Healing time, initial clinical attachment loss and amount of keratinized tissue at extraction site were identified as determinants of ridge height outcome. Buccal plate thickness and tooth root length were identified as determinants of ridge width outcome. In addition, initial ridge width was positively correlated with ridge width loss. Micro-CT revealed greater mineralization per unit volume in new bone compared with existing bone in mandible (p < 0.001). Distributions of residual graft, new cellular bone and immature tissue were similar in both jaws. CONCLUSION: Within the limitations of this study, the results indicate that in different anatomic locations different factors may determine ARP outcomes. Further studies are needed to better understand determinants of ARP outcomes. PMID- 23432763 TI - Phosphate handling by end-stage kidneys and benefits of residual renal function on phosphate removal in patients on haemodialysis. AB - AIM: We investigated the handling of phosphate by end-stage kidneys and the contribution of residual renal function (RRF) to phosphate homeostasis in haemodialysis patients. METHODS: Blood and 24 h urinary specimens were obtained from 79 consecutive chronic haemodialysis patients with a urinary output greater than 100 mL/day. Thirty-five patients with a glomerular filtration rate (GFR) >= 3.0 mL/min were included as group A, and 44 patients with GFR < 3.0 mL/min as group B. Additionally, the whole dialysed fluids during a session of haemodialysis were collected from another nine patients. Concentrations of phosphate, creatinine, urea nitrogen, intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF-23) were measured. RESULTS: Twenty-four hour urinary phosphate excretion (UPE) was 283 +/- 115 and 139 +/- 57 mg/day (9.1 +/- 3.5 and 4.5 +/- 1.8 mmol/day) in groups A and B, respectively. Tubular reabsorption of phosphate (TRP) was 39.2 +/- 13.3 and 31.7 +/- 13.6% in groups A and B, respectively (P = 0.02). UPE significantly correlated with GFR (r = 0.85, P < 0.001) and PTH (r = 0.44, P < 0.001), but not with FGF-23, in the entire patient population. The correlation between UPE and intact PTH levels was absent in group B. Weekly UPE in group A was significantly greater (P < 0.001), while that in group B was similar to the amount of phosphate removed by a haemodialysis session. CONCLUSIONS: Urinary phosphate excretion by end-stage kidneys depends more on GFR than diminishing TRP. The action of PTH on the kidneys remains until GFR decreases to as low as 3 mL/min. Residual renal function plays a significant role in phosphate elimination, and it is possible that FGF-23 no longer acts effectively to excrete phosphate in the urine in these patients. PMID- 23432765 TI - Protecting group-free concise synthesis of (RS)/(S)-lubeluzole. AB - Three new, concise, and protecting group-free synthetic routes for (RS)- and (S) lubeluzole are reported in higher (46-62%) overall yields compared to the reported procedures (6-35%). The key steps involve C-N bond formation via epoxide aminolysis and nucleophilic substitution of 2-chlorobenzothiazole with suitably designed precursor amines and are performed in aqueous medium. Water offers an advantage in promoting the reactions compared to organic solvents and its role is envisaged as hydrogen-bond mediated electrophile-nucleophile dual activation. PMID- 23432764 TI - Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update. AB - BACKGROUND: The management of minimal, mild and moderate head injuries is still controversial. In 2000, the Scandinavian Neurotrauma Committee (SNC) presented evidence-based guidelines for initial management of these injuries. Since then, considerable new evidence has emerged. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Systematic evidence-based review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, based upon relevant clinical questions with respect to patient-important outcomes, including Quality Assessment of Diagnostic Accuracy Studies (QUADAS) and Centre of Evidence Based Medicine (CEBM) quality ratings. Based upon the results, GRADE recommendations, guidelines and discharge instructions were drafted. A modified Delphi approach was used for consensus and relevant clinical stakeholders were consulted. CONCLUSIONS: We present the updated SNC guidelines for initial management of minimal, mild and moderate head injury in adults including criteria for computed tomography (CT) scan selection, admission and discharge with suggestions for monitoring routines and discharge advice for patients. The guidelines are designed to primarily detect neurosurgical intervention with traumatic CT findings as a secondary goal. For elements lacking good evidence, such as in-hospital monitoring, routines were largely based on consensus. We suggest external validation of the guidelines before widespread clinical use is recommended. PMID- 23432766 TI - Influence of a nanoporous zirconia implant surface of on cell viability of human osteoblasts. AB - PURPOSE: The dense nonretentive surface of zirconia implants was modified into a nanoporous surface using selective infiltration etching surface treatment. The aim of this study was to investigate the influence of such a nanoporous modified zirconia surface on the attachment of human osteoblasts. MATERIALS AND METHODS: Human osteoblasts were cultured for 21 days on (i) selective infiltration etched zirconia (nanoporous surface), (ii) polished zirconia, (iii) polished titanium, or (iv) airborne particle abraded acid etched (SLA) titanium disks. After the culture period the following parameters were assessed: number of cells, the morphology of the cells, the attachment of the cells, alkaline phosphatase activity, and the level of total protein (alpha= 0.05). RESULTS: Statistical analysis revealed a significantly higher cell count on the third (F = 17.4, p < 0.001) and eighth day (F = 163, p < 0.001) for nanoporous zirconia and SLA titanium surfaces compared to polished specimens. The number of cells (nanoporous zirconia 160 +/- 20/mm(2) , SLA titanium 133 +/- 15/mm(2) ) and cell size (nanoporous zirconia 50.7 +/- 3 MUm, SLA titanium 42.5 +/- 4 MUm) were significantly higher than polished specimens. Nanoporous zirconia specimens demonstrated comparable alkaline phosphatase activity (0.0036 +/- 0.0035 ng/MUl) and intracellular protein content (72.7 +/- 0.9 ng/MUl) compared to other tested groups. Scanning electron microscopy revealed that cells attached on the polished surface using finger-like processes, whereas on the nanoporous surface, finger like processes were not observed, as the cell membrane appeared to be in close proximity to the underlying surface. CONCLUSION: The findings of this study suggest that a nanoporous zirconia surface favors cell growth and attachment compared to a polished surface. It was proposed that a nanoporous zirconia surface may improve clinical performance of zirconia implants. PMID- 23432767 TI - A comparison of bone density and bone morphology between patients presenting with hip fractures, spinal fractures or a combination of the two. AB - BACKGROUND: Currently it is uncertain how to define osteoporosis and who to treat after a hip fracture. There is little to support the universal treatment of all such patients but how to select those most in need of treatment is not clear. In this study we have compared cortical and trabecular bone status between patients with spinal fractures and those with hip fracture with or without spinal fracture with the aim to begin to identify, by a simple clinical method (spine x-ray), a group of hip fracture patients likely to be more responsive to treatment with current antiresorptive agents. METHODS: Comparison of convenience samples of three groups of 50 patients, one with spinal fractures, one with a hip fracture, and one with both. Measurements consist of bone mineral density at the lumbar spine, at the four standard hip sites, number, distribution and severity of spinal fractures by the method of Genant, cortical bone thickness at the infero medial femoral neck site, femoral neck and axis length and femoral neck width. RESULTS: Patients with spinal fractures alone have the most deficient bones at both trabecular and cortical sites: those with hip fracture and no spinal fractures the best at trabecular bone and most cortical bone sites: and those with both hip and spinal fractures intermediate in most measurements. Hip axis length and neck width did not differ between groups. CONCLUSION: The presence of the spinal fracture indicates poor trabecular bone status in hip fracture patients. Hip fracture patients without spinal fractures have a bone mass similar to the reference range for their age and gender. Poor trabecular bone in hip fracture patients may point to a category of patient more likely to benefit from therapy and may be indicated by the presence of spinal fractures. PMID- 23432768 TI - FTIR spectroscopy of three fundamental bands of H2F+. AB - The nu1, nu2, and nu3 bands of H2F(+) were observed with a Fourier transform absorption spectroscopic technique in the 3 and 7 MUm regions. The ion was produced with a hollow cathode discharge in a F2, He, and H2 gas mixture. A simultaneous analysis of FT data combined with laser spectroscopic data was carried out using the Watson's A-reduced Hamiltonian to determine molecular constants in vibrationally excited states. The effect of the vibration-rotation interaction between the nu1 and nu3 states was found to be small compared with the case of H2O. The vibration-rotation transitions of the nu2 band were first identified and analyzed to obtain molecular constants in the nu2 state, and the band origin was determined to be 1370.5236 (7) cm(-1) with one standard deviation in parentheses. Determined molecular constants can be used to derive the re structure of H2F(+) as re(H-F) = 0.9608(6) A, ?e(H-F-H) = 112.2(2) degrees with the error corresponding to the uncertainty of the assumed vibration rotation constant gamma2(a) and the range of the values derived from three pairs of rotational constants. PMID- 23432769 TI - Orphan papers and ghostwriting: the case against the ICMJE criterion of authorship. AB - Although popular, I argue that the International Committee of Medical Journal Editors (ICMJE) account of authorship is flawed. It inadvertently allows for practices that it was designed to prevent. In addition, it creates a new category of authorless papers--orphan papers. The original World Association of Medical Editors (WAME) criterion is preferable. PMID- 23432770 TI - The epistemic integrity of NASA practices in the Space Shuttle Program. AB - This article presents an account of epistemic integrity and uses it to demonstrate that the epistemic integrity of different kinds of practices in NASA's Space Shuttle Program was limited. We focus on the following kinds of practices: (1) research by working engineers, (2) review by middle-level managers, and (3) communication with the public. We argue that the epistemic integrity of these practices was undermined by production pressure at NASA, i.e., the pressure to launch an unreasonable amount of flights per year. Finally, our findings are used to develop some potential strategies to protect epistemic integrity in aerospace science. PMID- 23432771 TI - Implications of a single highly cited article on a journal and its citation indexes: a tale of two journals. AB - Citation indexes such as journal impact factor are increasingly used to evaluate the quality of a scholarly work and/or assess one's scientific contributions. However, this simplistic approach has increasingly been refuted with publication gaming and incorrect applications to rank one's academic significance. These indexes are being game not only by researchers but also subtly by journal editors. Although the attention drawn from the public pertaining to such misbehaviors from editors is limited, the associated implications cannot be undermined. In this article, the focus will be on the motivations, impacts, and lessons learnt from how single highly cited article can have on the reactions from and the reputation of two academic journals: Folia Phoniatrica et Logopaedica and Acta Crystallographica Section A. For the former, it adopted an unconventional approach to improve its prominence in the field while the latter reiterates the correct and the original intent of citation indexes, as well as the importance of good editorial governance. From these incidents, few considerations are proposed to assist in minimising the recurrence of possible publication gaming in the editorial process. However, the inherent ethical values of an individual should still take precedence of any preventive measure. PMID- 23432772 TI - Spinning a stem cell ethics web. AB - The goal of this study was to provide an ethics education resource for trainees and researchers in the Canadian Stem Cell Network that would address the multiple ethical challenges in stem cell research including accountability in and for research across its multiple dimensions. The website was built using a bottom-up type approach based on an ethics needs assessment in combination with a top-down expert-driven component. There have been 3,615 visitors to the website since it was launched in July, 2011. The ongoing rate of returning visitors (20%) indicates that the website is becoming a valuable tool used multiple times. PMID- 23432773 TI - The cycle of bias in health research: a framework and toolbox for critical appraisal training. AB - Recognizing bias in health research is crucial for evidence-based decision making. We worked with eight community groups to develop materials for nine modular, individualized critical appraisal workshops we conducted with 102 consumers (four workshops), 43 healthcare providers (three workshops), and 33 journalists (two workshops) in California. We presented workshops using a "cycle of bias" framework, and developed a toolbox of presentations, problem-based small group sessions, and skill-building materials to improve participants' ability to evaluate research for financial and other conflicts of interest, bias, validity, and applicability. Participant feedback indicated that the adaptability of the toolbox and our focus on bias were critical elements in the success of our workshops. PMID- 23432774 TI - Impact of joint contractures on functioning and social participation in older individuals--development of a standard set (JointConFunctionSet): study protocol. AB - BACKGROUND: Joint contractures are frequent in older individuals in geriatric care settings. Even though they are used as indicator of quality of care, there is neither a common standard to describe functioning and disability in patients nor an established standardized assessment to describe and quantify the impact of joint contractures on patients' functioning. Thus, the aim of our study is (1) to develop a standard set for the assessment of the impact of joint contractures on functioning and social participation in older individuals and (2) to develop and validate a standardized assessment instrument for describing and quantifying the impact of joint contractures on the individuals' functioning. METHODS: The standard set for joint contractures integrate the perspectives of all potentially relevant user groups, from the affected individuals to clinicians and researchers. The development of this set follows the methodology to develop an International Classification of Functioning Disability and Health (ICF) Core Set and involves a formal decision-making and consensus process. Evidence from four preparatory studies will be integrated including qualitative interviews with patients, a systematic review of the literature, a survey with health professionals, and a cross sectional study with patients affected by joint contractures. The assessment instrument will be developed using item-response theory models. The instrument will be validated. DISCUSSION: The standard set for joint contractures will provide a list of aspects of functioning and health most relevant for older individuals in geriatric care settings with joint contractures. This list will describe body functions, body structures, activities and participation and related environmental factors. This standard set will define what aspects of functioning should be assessed in individuals with joint contractures and will be the basis of the new assessment instrument to evaluate the impact of joint contractures on functioning and social participation. PMID- 23432775 TI - Duodenal bulb biopsy in children for the diagnosis of coeliac disease: experience from Perth, Australia. AB - AIM: The study aims to assess the usefulness of duodenal bulb biopsy in the diagnosis of coeliac disease (CD) in a paediatric population. METHODS: Since February 2009, in our institution, we have routinely included duodenal bulb biopsy in addition to distal duodenal biopsies in children undergoing diagnostic upper gastrointestinal endoscopy. All children diagnosed with CD between February 2009 and May 2011 were identified, and those children who had biopsy finding of CD limited to duodenal bulb were reviewed with regard to clinical, serological and histopathological parameters. Duodenal bulb biopsy reports of those children who did not have CD were also reviewed as control group. RESULTS: A total of 101 children were diagnosed with CD during the study period. The mean age was 8.21 years (+/-3.63), 33 males and 68 females. There were 8 out of 101 (7.92%) who had histological changes consistent with CD exclusively in the duodenal bulb, with normal histology in the distal duodenum. None of duodenal bulb biopsy was abnormal in the control group. CONCLUSIONS: In some children, diagnostic CD changes may be limited to the duodenal bulb only and hence we recommend that duodenal bulb biopsies be included routinely in children suspected with CD to improve the diagnostic yield. PMID- 23432776 TI - Restless legs syndrome in combined hormonal contraception users. AB - The goal of the study was to estimate the prevalence of restless legs syndrome (RLS) among women of childbearing age taking combined hormonal or combined oral contraception (CHC). A survey that included demographic information, contraceptive use history, the four criteria necessary for RLS diagnosis and an International RLS study group severity scale was distributed to 145 women taking CHC and 169 matched control women not on CHC. A high prevalence of moderate to severe RLS of 20.7% was found. A significant correlation between CHC use and RLS was not found (p = 0.53). RLS severity was not significantly associated with CHC use either (p = 0.2127). Women with RLS were significantly heavier compared with those without RLS (p = 0.0015). RLS severity weakly correlated with body mass index (R = 0.26, p = 0.044). Hormonal contraceptive therapy does not increase the risk of developing RLS symptoms. PMID- 23432777 TI - Polylactic acid vs. polyacrylamide hydrogel for treatment of facial lipoatrophy: a randomized controlled trial [Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS) 132 SMILE]. AB - OBJECTIVES: The aim of the study was to demonstrate the noninferiority of polyacrylamide hydrogel (PH) vs. polylactic acid (PLA) for the treatment of facial lipoatrophy in HIV-infected adults. METHODS: A randomized, blinded, multicentre, noninferiority 96-week study was carried out. Patients with facial lipoatrophy were randomly assigned to receive intradermal injections with PH or PLA, and were blinded to the filler. The primary efficacy endpoint was patient satisfaction at week 48 assessed using a visual analogue scale score (VAS). Secondary efficacy end-points included cheek thickness and skin-fold, lipoatrophy grading and quality of life. Safety was assessed by the reporting of adverse events. RESULTS: A total of 148 patients were included in the study; 93% were men, the median age was 47 years, the median CD4 count was 528 cells/MUL, and the median duration of antiretroviral therapy was 12 years. Mean VAS increased from 2.8 at baseline to 7.1 and 7.5 in the PLA and PH arms, respectively, at week 48 (P=0.0002 for noninferiority) and was sustained at week 96 (6.7 and 7.9 in the PLA and PH arms, respectively; P=0.003 for noninferiority). Cheek thickness and skin-fold increases and lipoatrophy improvement were similar in the two arms. Quality of life remained unchanged or improved depending on the questionnaire used. In injected patients, subcutaneous nodules emerged in 28 (41%) and 26 (37%) patients in the PLA and PH arms, respectively (P=0.73). Four patients in the PH arm developed severe inflammatory nodules, a median of 17 months after the last injection. CONCLUSIONS: PH and PLA have similar efficacies in the treatment of facial lipoatrophy, but PH may be associated with more delayed inflammatory nodules. PMID- 23432778 TI - Oxidative stress and anti-oxidative defence in patients with age-related macular degeneration. AB - PURPOSE: To evaluate the oxidative stress status and anti-oxidative defence in patients with age-related macular degeneration (AMD). METHODS: A total of 22 patients diagnosed with AMD and 23 age-matched healthy controls were included in the present study. Serum levels of total oxidant status (TOS), total antioxidant status (TAS), total thiol status (TTS) and paraoxonase 1 (PON1) activity were investigated from samples. RESULTS: Significant increase in TOS levels were observed in sera of AMD patients (25.3 +/- 12.8) compared to controls (15.0 +/- 4.4). TTS (404.3 +/- 55.3) and serum PON1 enzyme activities (163.0 +/- 65.5) were significantly lower in AMD patients (594.0 +/- 64.2) relative to control groups (252.8 +/- 132.7). CONCLUSION: The results of the present study show that there is a significant increase in oxidative stress in AMD patients and significant decrease in antioxidant defence, in the total thiol level and in PON1 activity in AMD patients compared with controls. The increased oxidative stress and decreased antioxidant levels may have a synergistic role in AMD development. PMID- 23432779 TI - Dressing wear time after breast reconstruction: study protocol for a randomized controlled trial. AB - BACKGROUND: One of the major risk variables for surgical site infection is wound management. Understanding infection risk factors for breast operations is essential in order to develop infection-prevention strategies and improve surgical outcomes. The aim of this trial is to assess the influence of dressing wear time on surgical site infection rates and skin colonization. Patients' perception at self-assessment will also be analyzed. METHODS/DESIGN: This is a two-arm randomized controlled trial. Two hundred breast cancer patients undergoing immediate or delayed breast reconstruction will be prospectively enrolled. Patients will be randomly allocated to group I (dressing removed on postoperative day one) or group II (dressing removed on postoperative day six). Surgical site infections will be defined by standard criteria from the Centers for Disease Control and Prevention (CDC). Skin colonization will be assessed by culture of samples collected at predefined time points. Patients will score dressing wear time with regard to safety, comfort and convenience. DISCUSSION: The evidence to support dressing standards for breast surgery wounds is empiric and scarce. CDC recommends protecting, with a sterile dressing for 24 to 48 hours postoperatively, a primarily closed incision, but there is no recommendation to cover this kind of incision beyond 48 hours, or on the appropriate time to shower or bathe with an uncovered incision. The results of the ongoing trial may support standard recommendations regarding dressing wear time after breast reconstruction. TRIAL REGISTRATION: ClinicalTrials.gov identifier: http://NCT01148823. PMID- 23432780 TI - Exploring potential chemical markers by metabolomics method for studying the processing mechanism of traditional Chinese medicine using RPLC-Q-TOF/MS: a case study of Radix Aconiti. AB - BACKGROUND: Pao zhi is a common traditional approach that usually occurs before most herbs are prescribed whereby during processing, secondary plant metabolites are transformed, thus helping to increase potency, reduce toxicity and altering their effects. Using Radix Aconiti (Chuan Wu, CW) as a model herb, suitable chemical markers are crucial for studying the processing mechanisms of these herbs. RESULTS: In this study, the comprehensive metabolomic characters of CW and Prepared CW (ZCW) by RPLC-Q-TOF/MS were investigated to guarantee clinical safety. Multivariate analyses successfully identified specific metabolite changes between CW and ZCW. In addition, 22 key biomarkers responsible for the detoxifying actions of pao zhi were discovered. The processing mechanism of CW were discussed according to the identified metabolites. This method is efficient, providing more accurate characterisations of traditional pao zhi detoxification. CONCLUSIONS: The proposed strategy proves that RPLC-Q-TOF/MS-based metabolomic analysis does not only explore chemical markers but can also provide a comprehensive understanding of the transformation mechanisms underlying pao zhi. PMID- 23432781 TI - Non-centrosomal microtubules regulate F-actin organization through the suppression of GEF-H1 activity. AB - Animal cells contain two populations of microtubules: one radiating from the centrosome and the other growing from non-centrosomal sites. Whether or not they have differing roles in cellular architecture and function remains not fully understood. The cytoplasmic protein Nezha (also known as CAMSAP3) stabilizes non centrosomal microtubules by attaching to their minus ends. Here, we found that depletion of CAMSAP3 in HeLa cells resulted in a relative increase in centrosomal microtubules, and this change was accompanied by accelerated actin stress fiber formation. In these cells, RhoA activity was upregulated, and the soluble fraction of GEF-H1, a RhoGEF whose activity is inhibited by binding to microtubules, increased, explaining why stress fiber formation was promoted. We further found that CAMSAP3 depletion led to an increase in detyrosinated microtubules, and these microtubules did not interact with GEF-H1. These findings suggest that CAMSAP3-anchored non-centrosomal microtubules capture GEF-H1 more efficiently than other microtubules do and that a balance between these microtubules is important to maintain proper actin organization. PMID- 23432782 TI - Utility of transient elastography in the non-invasive evaluation of cystic fibrosis liver disease. AB - BACKGROUND: Liver disease frequently complicates cystic fibrosis (CF), with CF liver disease (CFLD) a leading cause of death. Liver biopsy is rarely performed because of the patchy nature of the disease. Transient elastography can reliably stage liver fibrosis via liver stiffness measurement (LSM). AIMS: To evaluate LSM as a diagnostic tool in adults with CFLD. METHODS: Fifty adult patients with CF were prospectively studied: 25 with CFLD and 25 without CFLD. The presence of CFLD and portal hypertension (PHT) was assessed according to strict established criteria based on serial biochemistry and imaging. All patients underwent LSM; APRI, Hepascore((r)) and Forns score were calculated. RESULTS: Median LSM was higher in those with CFLD [8.1 kPa (IQR 6.8-9.5) vs. 5.0 kPa (IQR 4.1-5.6); P < 0.001]. On multivariate analysis, LSM was the only variable associated with CFLD (OR 2.74, 95% CI 1.53-4.89; P = 0.001). AUROC for LSM predicting CFLD was 0.87 (95% CI 0.77-0.98) and an LSM >= 6.8 kPa predicted CFLD with 76.0% sensitivity and 92.0% specificity. Median LSM was higher in those with PHT [15.7 kPa (IQR 9.2 17.2) vs. 5.4 kPa (IQR 4.3-6.8); P < 0.001]. The AUROC for LSM predicting the presence of PHT was 0.96 (95% CI 0.92-1.00). An LSM cut-off of >= 8.9 kPa predicted the presence of PHT with 87.5% sensitivity, 90.5% specificity, 63.6% positive predictive value and 92.9% negative predictive value. CONCLUSIONS: LSM is an accurate and reliable non-invasive tool in assessing CFLD and PHT. An LSM >= 6.8 kPa is highly suggestive of CFLD and an LSM <8.9 kPa reliably excludes PHT. PMID- 23432783 TI - The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis. AB - The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1 year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL. PMID- 23432784 TI - TNF-alpha upregulates Fgl2 expression in rat myocardial ischemia/reperfusion injury. AB - OBJECTIVE: Proinflammatory cytokine TNF-alpha during MI/R injury has been studied extensively. However, how TNF-alpha induces microvascular dysfunction in MI/R is still unclear. This study investigates whether TNF-alpha regulates fibrinogen like protein 2 (fgl2) expression, a procoagulant resulting in the formation of fibrin-rich microthrombus in MI/R injury. METHODS AND RESULTS: Microthrombosis, TNF-alpha and fgl2 expression were assessed in rats with MI/R injury. The effect of TNF-alpha on fgl2 expression and fgl2 prothrombinase activity was investigated in CMECs, then CMECs were pretreated with selective inhibitors of NF-kappaB and p38 MAPK pathways. TNF-alpha and fgl2 expression were both upregulated in MI/R group. When neutralization of TNF-alpha, fgl2 expression was decreased in vivo. Fgl2 expression was upregulated in CMECs exposed to TNF-alpha. Accordingly, the ability of thrombin generation was increased in CMECs. Besides, TNF-alpha-induced fgl2 expression in the cells was suppressed by NF-kappaB inhibitor PDTC and/or p38 MAPK inhibitor SB203580. CONCLUSION: TNF-alpha upregulates fgl2 expression via activation of NF-kB and p38 MAPK in CMECs. TNF-alpha-induced flg2 in CMECs mediates the formation of fibrin-rich microthrombus, which may be one of the mechanisms of microvascular dysfunction or obstruction due to MI/R injury. PMID- 23432785 TI - New guidelines for the initial management of head injury. AB - The majority of patients presenting with mild head trauma will have no intracranial pathology and can be safely discharged home. It is estimated that 10% to 15% of these patients will have clinically significant findings on computed tomography imaging and up to 1% may require neurosurgical intervention. The revised Scandinavian Head Trauma Guidelines provide an evidence- and consensus-based algorithm to assist physicians in determining which patients presenting with minimal, mild or moderate blunt head injury are at higher risk for intracranial pathology and thus require neuroimaging and hospital admission. Striking a balance between health care costs and risk of morbidity remains an ongoing challenge and we will present our concerns with this useful, but conservative management algorithm. PMID- 23432786 TI - Effects of sitagliptin beyond glycemic control: focus on quality of life. AB - BACKGROUND: Recently, incretin hormones, including glucagon-like peptide-1 (GLP 1) analogue and dipeptidyl peptidase-4 (DPP-4) inhibitor, have been found to regulate glucose metabolism. The aim of this study was to elucidate the efficacy and safety of the clinical usage of DPP-4 inhibitors in Japan. METHODS: This study was designed as a prospective, open-label, multi-center trial. Patients with diabetes mellitus type 2 (T2DM) with poor glycemic profiles (HbA1c >= 6.2%) in spite of receiving a medical diet, therapeutic exercise, and/or medications were eligible for this study. The participants received 50 to 100 mg of the DPP-4 inhibitor sitagliptin once daily for 12 months. RESULTS: One hundred and eighty eight subjects were enrolled. After 12 months of sitagliptin treatment, HbA1c levels decreased (7.65% +/- 1.32% to 7.05% +/- 1.10%, p < 0.001) as well as fasting plasma glucose (FPG) (145 +/- 52 mg/dl to 129 +/- 43 mg/dl, p = 0.005). The rate of glycemic control achieved (in accordance with the guidelines of the Japanese Diabetes Society) significantly increased. Blood pressure and serum levels of triglycerides and total cholesterol decreased significantly. Furthermore, the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Symptomatic Scores improved significantly. Adverse events such as hypoglycemia and loss of consciousness occurred in twenty three subjects (11%). CONCLUSIONS: These results suggest that the actions of DPP-4 inhibitors improve not only glycemic control, but also blood pressure, lipid profiles, and quality of life (QOL). Sitagliptin is a sound agent for use in the comprehensive treatment of patients with T2DM. PMID- 23432787 TI - Immunogenic properties of amyloid beta oligomers. AB - BACKGROUND: The central molecule in the pathogenesis of Alzheimer's disease (AD) is believed to be a small-sized polypeptide - beta amyloid (Abeta) which has an ability to assemble spontaneously into oligomers. Various studies concerning therapeutic and prophylactic approaches for AD are based on the immunotherapy using antibodies against Abeta. It has been suggested that either active immunization with Abeta or passive immunization with anti-Abeta antibodies might help to prevent or reduce the symptoms of the disease. However, knowledge on the mechanisms of Abeta-induced immune response is rather limited. Previous research on Abeta1-42 oligomers in rat brain cultures showed that the neurotoxicity of these oligomers considerably depends on their size. In the current study, we evaluated the dependence of immunogenicity of Abeta1-42 oligomers on the size of oligomeric particles and identified the immunodominant epitopes of the oligomers. RESULTS: Mice were immunized with various Abeta1-42 oligomers. The analysis of serum antibodies revealed that small Abeta1-42 oligomers (1-2 nm in size) are highly immunogenic. They induced predominantly IgG2b and IgG2a responses. In contrast, larger Abeta1-42 oligomers and monomers induced weaker IgG response in immunized mice. The monoclonal antibody against 1-2 nm Abeta1-42 oligomers was generated and used for antigenic characterization of Abeta1-42 oligomers. Epitope mapping of both monoclonal and polyclonal antibodies demonstrated that the main immunodominant region of the 1-2 nm Abeta1-42 oligomers is located at the amino terminus (N-terminus) of the peptide, between amino acids 1 and 19. CONCLUSIONS: Small Abeta1-42 oligomers of size 1-2 nm induce the strongest immune response in mice. The N-terminus of Abeta1-42 oligomers represents an immunodominant region which indicates its surface localization and accessibility to the B cells. The results of the current study may be important for further development of Abeta based vaccination and immunotherapy strategies. PMID- 23432788 TI - MITEs in the promoters of effector genes allow prediction of novel virulence genes in Fusarium oxysporum. AB - BACKGROUND: The plant-pathogenic fungus Fusarium oxysporum f.sp.lycopersici (Fol) has accessory, lineage-specific (LS) chromosomes that can be transferred horizontally between strains. A single LS chromosome in the Fol4287 reference strain harbors all known Fol effector genes. Transfer of this pathogenicity chromosome confers virulence to a previously non-pathogenic recipient strain. We hypothesize that expression and evolution of effector genes is influenced by their genomic context. RESULTS: To gain a better understanding of the genomic context of the effector genes, we manually curated the annotated genes on the pathogenicity chromosome and identified and classified transposable elements. Both retro- and DNA transposons are present with no particular overrepresented class. Retrotransposons appear evenly distributed over the chromosome, while DNA transposons tend to concentrate in large chromosomal subregions. In general, genes on the pathogenicity chromosome are dispersed within the repeat landscape. Effector genes are present within subregions enriched for DNA transposons. A miniature Impala (mimp) is always present in their promoters. Although promoter deletion studies of two effector gene loci did not reveal a direct function of the mimp for gene expression, we were able to use proximity to a mimp as a criterion to identify new effector gene candidates. Through xylem sap proteomics we confirmed that several of these candidates encode proteins secreted during plant infection. CONCLUSIONS: Effector genes in Fol reside in characteristic subregions on a pathogenicity chromosome. Their genomic context allowed us to develop a method for the successful identification of novel effector genes. Since our approach is not based on effector gene similarity, but on unique genomic features, it can easily be extended to identify effector genes in Fo strains with different host specificities. PMID- 23432790 TI - Psychotropic drug initiation or increased dosage and the acute risk of falls: a prospective cohort study of nursing home residents. AB - BACKGROUND: Previous studies suggest that psychotropic drug changes may signal an acute period of time whereby a person is highly vulnerable to fall. It is unknown whether certain classes of psychotropic agents are less safe with respect to the acute risk of falls. Our purpose was to compare fall rates in the 7 days following a change of an antidepressant, antipsychotic, or benzodiazepine. We also identified specific times when residents are at high risk for falls with respect to a psychotropic drug change. METHODS: Residents in our one-year study included 851 long term care residents from two nursing home facilities in Boston, MA, U.S.A. (May 2010 - May 2011). Drug changes (i.e., new prescriptions or increased dose of a previously used drug) were ascertained using the computerized provider order entry system, whereas falls were ascertained by incident reports. Negative binomial regression was used to compare the rate of falls following a drug change between medication classes. Further, we calculated the rate of falls for each of the 7 days before and 7 days after a psychotropic drug change. RESULTS: Forty-eight percent of residents were prescribed a new prescription or increased dose of a psychotropic drug during the study. The rate of falls was similar in the 7 days following a change to a SSRI versus non-SSRI antidepressant (11.9 versus 14.4 falls/1,000 person years; p = 0.58), a typical versus an atypical antipsychotic (25.4 versus 17.1 falls/1,000 person years; p = 0.10), or a short versus long acting benzodiazepine (15.2 versus 13.9 falls/1,000 person years; p = 0.23). Fall risk was highest on day 4 before the drug change (19.0 falls/1,000 person days), on the day of the drug change through 2 days after the drug change (17.6-20.3 falls/1,000 person days), and 5-6 days after the drug change (17.6-19.0 falls/1,000 person days). CONCLUSIONS: In the nursing home, risk of falls was similar following a psychotropic drug change of any class. We observed higher fall risk in the days before, but mostly after the drug change. We recommend that nursing home residents be closely monitored following a psychotropic drug change in an effort to reduce falls. PMID- 23432789 TI - Factors related with symptom duration until diagnosis and treatment of symptomatic colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) survival depends mostly on stage at the time of diagnosis. However, symptom duration at diagnosis or treatment have also been considered as predictors of stage and survival. This study was designed to: 1) establish the distinct time-symptom duration intervals; 2) identify factors associated with symptom duration until diagnosis and treatment. METHODS: This is a cross-sectional study of all incident cases of symptomatic CRC during 2006-2009 (795 incident cases) in 5 Spanish regions. Data were obtained from patients' interviews and reviews of primary care and hospital clinical records. MEASUREMENTS: CRC symptoms, symptom perception, trust in the general practitioner (GP), primary care and hospital examinations/visits before diagnosis, type of referral and tumor characteristics at diagnosis. Symptom Diagnosis Interval (SDI) was calculated as time from first CRC symptoms to date of diagnosis. Symptom Treatment Interval (STI) was defined as time from first CRC symptoms until start of treatment. Nonparametric tests were used to compare SDI and STI according to different variables. RESULTS: Symptom to diagnosis interval for CRC was 128 days and symptom treatment interval was 155. No statistically significant differences were observed between colon and rectum cancers. Women experienced longer intervals than men. Symptom presentation such as vomiting or abdominal pain and the presence of obstruction led to shorter diagnostic or treatment intervals. Time elapsed was also shorter in those patients that perceived their first symptom/s as serious, disclosed it to their acquaintances, contacted emergencies services or had trust in their GPs. Primary care and hospital doctor examinations and investigations appeared to be related to time elapsed to diagnosis or treatment. CONCLUSIONS: Results show that gender, symptom perception and help seeking behaviour are the main patient factors related to interval duration. Health service performance also has a very important role in symptom to diagnosis and treatment interval. If time to diagnosis is to be reduced, interventions and guidelines must be developed to ensure appropriate examination and diagnosis during both primary and hospital care. PMID- 23432791 TI - A glow of HLA typing in organ transplantation. AB - The transplant of organs and tissues is one of the greatest curative achievements of this century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the main goal of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. Cell surface molecules that induce an antigenic stimulus cause the rejection immune response to grafted tissue or organ. A wide variety of transplantation antigens have been described, including the major histocompatibility molecules, minor histocompatibility antigens, ABO blood group antigens and endothelial cell antigens. The sensitization to MHC antigens may be caused by transfusions, pregnancy, or failed previous grafts leading to development of anti-human leukocyte antigen (HLA) antibodies that are important factor responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complication Anti-HLA Abs may be present in healthy individuals. Methods for HLA typing are described, including serological methods, molecular techniques of sequence-specific priming (SSP), sequence-specific oligonucleotide probing (SSOP), Sequence based typing (SBT) and reference strand based conformation analysis (RSCA) method. Problems with organ transplantation are reservoir of organs and immune suppressive treatments that used to decrease rate of rejection with less side effect and complications. PMID- 23432792 TI - Renal tubular dysfunction in children with sickle cell haemoglobinopathy. AB - AIM: Children with sickle cell disease (SCD) are remarkably more prone than others to renal dysfunction. The kidneys, as one of the systemic long-term hazards in SCD, may be affected by both the haemodynamic changes of chronic anaemia as well as by the consequences of vaso-occlusion. The aim of this study was to evaluate the proximal tubular function in a group of Saudi children with established SCD. METHODS: This study was conducted in Al-Khafji Joint Operations (KJO) Hospital, in Saudi Arabia during the period from June 2011 to August 2012. Thirty-four children: Group I (18 males and 16 females) with SCD (HBSS) and 27 children: Group II (17 males and 10 females) with sickle cell trait (HBAS) were evaluated for urinary excretion of retinol binding protein (RBP) and - Beta 2 microglobulin (beta2 MG). RESULTS: Group I patients showed a significantly impaired urinary concentrating ability compared to that of Group II (417 +/- 94 mOsm/kg vs 581 +/- 165 mOsm/kg). The urinary excretions of RBP and beta2 microglobulin were significantly higher in Group I than in Group II. The values were 762.01 +/- 124.20 MUg/L and 841.84 +/- 389.02 MUg/L versus 198.12 +/- 42.24 MUg/L and 298.3 +/- 38.11 MUg/L, respectively. CONCLUSION: Significant proximal tubular dysfunction was a feature in the SCD group, indicated by high urinary RBP and beta2-microglobulin excretion. Assessing the urinary excretion of these low molecular weight proteins in children with sickle cell disease at different points of diagnosis may add key clinical information to the follow up of renal tubular function in patients with SCD. PMID- 23432793 TI - Endogenous panophthalmitis with orbital cellulitis secondary to Escherichia coli. PMID- 23432794 TI - Desmoid tumor of posterior cruciate ligament of the knee: a case report. AB - BACKGROUND: Desmoid tumor is a rare type of cancer that develops in the tissues that form tendons and ligaments. These tumors, also called aggressive fibromatosis, are considered benign with no metastatic potential. They may invade nearby tissues and organs, however, and can be difficult to control. Desmoid tumor in the posterior cruciate ligament (PCL) of the knee has never been described in the literature. CASE PRESENTATION: A 49-year-old man presented with a 2-month history of posteromedial knee dull pain and decreased range of motion of the knee. He was diagnosed desmoid tumor of posterior cruciate ligament of the knee by intraoperative biopsy, and underwent successful PCL resection and reconstruction by Four-strand semitendinosus and gracilis tendon autograft arthroscopically, and fortunately five years after operation, there were no clues as to recurrence of the tumor examined by Magnetic Resonance Imaging (MRI). CONCLUSION: Desmoid tumor is characterized by infiltrative growth and a tendency towards recurrence,as this tumor entity is rare, data giving evidence based recommendations for the optimal treatment algorithm for this disease is lacking. At present there is no definite and effective method of treatment. However, early detection of the tumor play an important role, MRI is now the most important method for the detection of tumor extent, which facilitates the treatment choice as well as the prediction of prognosis. In our case, we followed-up the patient five years postoperatively by MRI and got a good result. PMID- 23432795 TI - Periodontitis and chronic kidney disease: a systematic review of the association of diseases and the effect of periodontal treatment on estimated glomerular filtration rate. AB - AIM: The aim of this systematic review (SR) was to evaluate the association between periodontitis and chronic kidney disease (CKD) and the effect of periodontal treatment (PT) on the estimated glomerular filtration rate (eGFR). METHODS: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched up to and including September 30, 2012 to observational (S1) and interventional (S2) studies on the association of periodontitis with CKD. Studies were considered eligible for inclusion if they reported the eGFR. Search was conducted by two independent reviewers. The methodological quality of the observational studies was assessed using the Newcastle-Ottawa Scale (NOS) adapted for this review, and the Cochrane's Collaboration risk of bias assessment tool. A random-effects odds-ratio meta analysis was conducted to estimate the degree of association between periodontitis and CKD. RESULTS: Search strategy identified 2456 potentially eligible articles, of which four cross-sectional, one retrospective, and three interventional studies were included. Four S1, 80.0% reported some degree of association between periodontitis and CKD. Similarly, such an outcome was supported by pooled estimates (OR: 1.65, 95% Confidence Interval: 1.35, 2.01, p < 0.00001, chi(2) = 1.70, I(2 ) = 0%). All interventional studies found positive outcomes related to treatment. CONCLUSION: There is quite consistent evidence to support the positive association between periodontitis and CKD, as well as the positive effect of PT on eGFR. PMID- 23432796 TI - Muscle strength, physical fitness and well-being in children and adolescents with juvenile idiopathic arthritis and the effect of an exercise programme: a randomized controlled trial. AB - BACKGROUND: Decreased muscle strength, fitness and well-being are common in children and adolescents with juvenile idiopathic arthritis (JIA) compared to healthy peers. Biological drugs have improved health in children with JIA, but despite this pain is still a major symptom and bone health is reported as decreased in the group. The improvement made by the biological drugs makes it possible to more demanding exercises. To jump is an exercise that can improve bone heath, fitness and muscle strength. The aim of the study was to see if an exercise programme with jumps had an effect on muscle strength, physical fitness and well-being and how it was tolerated. METHODS: Muscle strength and well-being were studied before and after a 12-week exercise programme in 54 children and adolescents with JIA, 9-21 years old. The participants were randomized into an exercise and a control group. Muscle strength, fitness and well-being were documented before and after the training period and at follow-up after 6 months. Physical activity in leisure time was documented in diaries. The fitness/exercise programme was performed at home three times a week and included rope skipping and muscle strength training exercises.Assessment included measurement of muscle strength with a handheld device, and with Grip-it, step-test for fitness with documentation of heart rate and pain perception and two questionnaires (CHAQ, CHQ) on well-being. RESULTS: There were no differences between exercise and control group regarding muscle strength, grip strength, fitness or well-being at base line. Muscle weakness was present in hip extensors, hip abductors and handgrip. For the exercise group muscle strength in hip and knee extensors increased after the 12-week exercise programme and was maintained in knee extensors at follow-up. There was no change in fitness tested with the individually adapted step-test. The CHQ questionnaire showed that pain was common in the exercise group and in the control group. There were only small changes in the CHAQ and CHQ after the training period. The fitness/exercise programme was well tolerated and pain did not increase during the study. CONCLUSIONS: A weight bearing exercise programme, with muscle strength training with free weights and rope skipping was well tolerated without negative consequences on pain. It also improved muscle strength in the legs and can be recommended for children and adolescents with JIA. PMID- 23432797 TI - The effects of an increasing gradient of maternal obesity on pregnancy outcomes. AB - BACKGROUND: Maternal obesity is becoming more prevalent in obstetrics and has been linked with pregnancy complications and perinatal outcomes. The gradient of association of increasing maternal obesity and pregnancy outcome is less well studied. AIMS: To determine the influence of an increasing gradient of obesity, categorised by the body mass index (BMI), on pregnancy outcomes and to determine the BMI thresholds at which pregnancy complications occur. MATERIALS AND METHODS: Secondary analysis of an observational study on pregnancy and obesity. The BMI at the first prenatal visit was grouped into BMI categories (<18.5, 18.5-24.9, 25 29.9, 30-34.9, 35-39.9, 40-44.9, and >=45) and compared with the normal category (BMI 18.5-25) for pregnancy outcomes and adjusted for known cofounders. RESULTS: A total of 4,490 women were stratified into the pre-pregnancy BMI categories: <18.5 (n = 276), 18.5-24.9 (n = 1965), 25-29.9 (n = 1072), 30-34.9 (n = 551), 35 39.9 (n = 317), 40-44.9 (n = 167), and >=45 (n = 142). The maternal demographics were significantly different between BMI groups (P < 0.001). Compared to women with a normal BMI, different BMI thresholds convey an increased risk for specific pregnancy complications: BMI>=25 for gestational diabetes (P < 0.001), induction of labour (P < 0.001), caesarean delivery (P < 0.001) and large for gestational age neonate (P < 0.001); BMI>=30 for pre-eclampsia (P < 0.001), wound infection (P = 0.001), shoulder dystocia (P < 0.001) and meconium (P = 0.006); BMI>=35 for urinary tract infection (P < 0.001) and postpartum haemorrhage (P < 0.001); BMI>=40 for endometritis (P < 0.001). CONCLUSIONS: Body mass index thresholds exist at which pregnancy complications significantly increase and they vary depending on outcome ranging from BMI >=25 to a BMI >=40. PMID- 23432798 TI - Tumefactive perivascular spaces mimicking cerebral edema in a patient with diabetic hyperglycemic hyperosmolar syndrome: a case report. AB - INTRODUCTION: Acute cerebral edema is a significant cause of death in patients treated for diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. CASE PRESENTATION: We present the case of a 44-year-old African American woman admitted with acute severe headache and diagnosed with diabetic hyperglycemic hyperosmolar syndrome. Computed tomography of the head showed diffuse leukoencephalopathy, but sparing of the cortex. We were concerned for acute cerebral edema secondary to hyperglycemic hyperosmolar syndrome. Magnetic resonance imaging of the brain showed numerous collections of cystic spaces in the white matter of both hemispheres representing tumefactive perivascular spaces. Her headache improved with correction of the hyperglycemic hyperosmolar state. CONCLUSION: Although the clinical presentation and head computed tomography were concerning for cerebral edema, the distinctive features on brain magnetic resonance imaging helped to clarify the diagnosis and differentiate it from other processes. PMID- 23432800 TI - Waterborne human pathogenic viruses of public health concern. AB - In recent years, the impending impact of waterborne pathogens on human health has become a growing concern. Drinking water and recreational exposure to polluted water have shown to be linked to viral infections, since viruses are shed in extremely high numbers in the faeces and vomit of infected individuals and are routinely introduced into the water environment. All of the identified pathogenic viruses that pose a significant public health threat in the water environment are transmitted via the faecal-oral route. This group, are collectively known as enteric viruses, and their possible health effects include gastroenteritis, paralysis, meningitis, hepatitis, respiratory illness and diarrhoea. This review addresses both past and recent investigations into viral contamination of surface waters, with emphasis on six types of potential waterborne human pathogenic viruses. In addition, the viral associated illnesses are outlined with reference to their pathogenesis and routes of transmission. PMID- 23432799 TI - Development of the adult PedsQLTM neurofibromatosis type 1 module: initial feasibility, reliability and validity. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder with significant impact on health-related quality of life (HRQOL). Research in understanding the pathogenetic mechanisms of neurofibroma development has led to the use of new clinical trials for the treatment of NF1. One of the most important outcomes of a trial is improvement in quality of life, however, no condition specific HRQOL instrument for NF1 exists. The objective of this study was to develop an NF1 HRQOL instrument as a module of PedsQLTM and to test for its initial feasibility, internal consistency reliability and validity in adults with NF1. METHODS: The NF1 specific HRQOL instrument was developed using a standard method of PedsQLTM module development - literature review, focus group/semi-structured interviews, cognitive interviews and experts' review of initial draft, pilot testing and field testing. Field testing involved 134 adults with NF1. Feasibility was measured by the percentage of missing responses, internal consistency reliability was measured with Cronbach's alpha and validity was measured by the known-groups method. RESULTS: Feasibility, measured by the percentage of missing responses was 4.8% for all subscales on the adult version of the NF1-specific instrument. Internal consistency reliability for the Total Score (alpha =0.97) and subscale reliabilities ranging from 0.72 to 0.96 were acceptable for group comparisons. The PedsQLTM NF1 module distinguished between NF1 adults with excellent to very good, good, and fair to poor health status. CONCLUSIONS: The results demonstrate the initial feasibility, reliability and validity of the PedsQLTM NF1 module in adult patients. The PedsQLTM NF1 Module can be used to understand the multidimensional nature of NF1 on the HRQOL patients with this disorder. PMID- 23432801 TI - The effect of antenatal monthly sulphadoxine-pyrimethamine, alone or with azithromycin, on foetal and neonatal growth faltering in Malawi: a randomised controlled trial. AB - OBJECTIVE: To examine the potential to reduce foetal and neonatal growth faltering through intermittent preventive treatment in pregnancy (IPTp) of malaria and reproductive tract infections with monthly sulphadoxine-pyrimethamine (SP), alone or with two doses of azithromycin. METHODS: We enrolled 1320 women with uncomplicated second trimester pregnancies into a randomised, partially placebo controlled, outcome assessor-blinded clinical trial in Malawi. The participants received either two doses of SP (control), SP monthly (monthly SP) or SP monthly and azithromycin (1 g) twice (AZI-SP). Newborn size was measured within two days of birth and infant growth at four weeks of age. RESULTS: Babies in the AZI-SP group were on average (95% CI) 140 g (70-200) heavier at birth and 0.6 cm (0.2-0.9) longer at four weeks of age than control group babies. Corresponding differences between the monthly SP and control groups were 80 g (20 140) and 0.3 cm (-0.0 to 0.6). Compared with controls, babies in the AZI-SP group had a relative risk of 0.61 (0.40-0.93) for low birthweight, 0.60 (0.44-0.81) for stunting and 0.48 (0.29-0.79) for underweight at four weeks of age. Corresponding differences were similar but smaller between the monthly SP and control groups. CONCLUSIONS: An IPTp regimen with monthly SP given to all pregnant women is likely to increase mean birthweight and length at four weeks of age in malaria holoendemic areas. Adding azithromycin to the regimen appears to offer further benefits in reducing foetal and neonatal growth faltering. PMID- 23432804 TI - Contrast-Enhanced Ultrasound for the differentiation of benign and malignant focal liver lesions: a meta-analysis. AB - BACKGROUND: International guidelines of Ultrasound recommend the performance of contrast-enhanced ultrasound (CEUS) as the first method of choice after conventional ultrasound for the diagnostic work-up of focal liver lesions. However, these recommendations are based on the results of multiple single studies and only few large multicentre studies. AIMS: The rationale of the present systematic review and meta-analysis was to assess the overall sensitivity and specificity of CEUS for the diagnosis of malignant liver lesions. METHODS: Literature databases were searched up to March 2012. Inclusion criteria were evaluation of CEUS, assessment of sensitivity and specificity of CEUS for the diagnosis of malignant liver lesions. The meta-analysis was performed using the random-effects model based on the DerSimonian Laird method. Quality analyses were carried out to assess sources of heterogeneity. RESULTS: A total of 45 studies with 8147 focal liver lesions were included in the analysis. Overall sensitivity and specificity of CEUS for the diagnosis of malignant liver lesions was 93% (95% CI: 91-95%) and 90% (95%-CI: 88-92%) respectively. Significant heterogeneity was found between studies. However, subanalysis revealed no significant difference when evaluating studies using histology for all liver lesions, when comparing high-quality and low-quality studies, and blinded vs non-blinded studies. CONCLUSION: The results of this meta-analysis support the international recommendations on CEUS for the diagnostic work-up of focal liver lesions selecting patients who need further diagnostics. PMID- 23432803 TI - Immunohistochemical detection of Hsp90 and Ki-67 in pterygium. AB - BACKGROUND: To examine the immunohistochemical expression of heat shock protein 90 (Hsp90) and Ki-67 protein in human pterygium. MATERIALS AND METHODS: Tissues obtained during pterygium surgery of 15 patients who underwent the bare-sclera procedure and 10 normal conjunctivae were studied. All of these pterygia were primary ones. Recurrent pterygia were excluded. Normal bulbar conjunctivas (2 x 2 mm) were obtained from the nasal region close to the limbus from patients during their cataract and retina surgeries. Immunohistochemical detection of Hsp90 and Ki67 was done using the streptavidin-biotin method in paraffin embedded tissue sections. RESULTS: The percentage of cells stained for Hsp90 was greater for pterygium epithelium (76 +/- 10.8) than for normal conjunctiva (1.4 +/- 0.8). In each pterygium sample more than 60% of cells were positive. The differences in positive cells between normal and pterygium epithelium were highly significant for Hsp90 (P < 0,001).Pterygium epithelium also showed a higher percentage of cells that stained for Ki67 (10.1 +/- 9.5) than for normal conjunctiva (2.1 +/- 1.9). The differences in positive cells were also statistically significant for Ki67 (P < 0.01). Although there were significant differences in the majority of samples observed. It was noted that in some samples there was no difference between normal and pterygium epithelium for Ki67. CONCLUSION: Our results indicate an abnormal expression of Hsp90 and ki-67 in pterygium samples when compared to normal conjunctiva.The finding of abnormal expression of levels of Hsp90 in pterygium samples can stimulate new research into pterygium and its recurrence. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1128478792898812. PMID- 23432805 TI - Neuropsychological tests for assessment of healthy ethnic minority elderly population. PMID- 23432802 TI - Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease. AB - The developing fetus must actively learn to tolerate benign antigens or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in the periphery. Fetal CD4(+) T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of fetal T cells and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis. PMID- 23432806 TI - Weight status and dietary intake determine serum leptin concentrations in pregnant and lactating women and their infants. AB - Leptin regulates energy homeostasis and immune and metabolic functions. Highly elevated leptin concentrations during pregnancy may be associated with aberrations in maternal metabolism and long-term health consequences both in women and children. The objective of the present study was to evaluate whether dietary counselling, probiotic supplementation, maternal characteristics or dietary intake during pregnancy has an impact on serum leptin concentrations in women, cord blood or in children. A total of 256 pregnant women were randomised to a control group (n 85) or to receive dietary counselling with probiotics (n 85) or placebo (n 86). Dietary counselling aimed at affecting the type of fat used and to increase the amount of fibre in the women's diet. Women's dietary intake and serum leptin concentrations were analysed at the first and third trimesters of pregnancy and at 1 month postpartum. Furthermore, leptin concentrations were measured from the cord blood and from children's serum at 1 and 6 months of age. Weight status and dietary composition were the key determinants of leptin concentrations. Specifically, high dietary fibre and low SFA intakes were related to low serum leptin concentrations in women. Female sex and birth weight were associated with higher infant leptin, whereas cord blood leptin was additionally affected by maternal leptin concentration and protein intake. Probiotics or dietary counselling did not affect leptin concentrations. Weight control to recommended levels and modification of diet towards higher fibre and lower SFA intakes during pregnancy may through leptin concentrations provide health benefits to both women and children. PMID- 23432807 TI - An autoinflammatory neurological disease due to interleukin 6 hypersecretion. AB - Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI. He also suffered from chronic recurrent osteomyelitis of the mandible. The hypothesis of an autoinflammatory disease prompted us to test for the presence of mutations in interleukin-1 pathway genes and to investigate the function of this pathway in the mononuclear cells obtained from the patient. Search for mutations in genes associated with interleukin-1-pathway demonstrated a novel NLRP3 (CIAS1) mutation (p.I288M) and a previously described MEFV mutation (p.R761H), but their combination was found to be non-pathogenic. On the other hand, we uncovered a selective interleukin-6 hypersecretion within the central nervous system as the likely pathogenic mechanism. This is also supported by the response to the anti-interleukin-6 receptor monoclonal antibody tocilizumab, but not to the recombinant interleukin 1-receptor antagonist anakinra. Exome sequencing failed to identify mutations in other genes known to be involved in autoinflammatory diseases. We propose that the disease described in this patient might be a prototype of a novel category of autoinflammatory diseases characterized by prominent neurological involvement. PMID- 23432808 TI - Angiotensin-converting enzyme inhibition and food restriction restore delayed preconditioning in diabetic mice. AB - BACKGROUND: Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential. METHODS: Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student's t-test or one-way ANOVA followed by a Fisher's LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher's LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant. RESULTS: Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob. CONCLUSION: Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome. PMID- 23432809 TI - High-density SNP-based genetic map development and linkage disequilibrium assessment in Brassica napus L. AB - BACKGROUND: High density genetic maps built with SNP markers that are polymorphic in various genetic backgrounds are very useful for studying the genetics of agronomical traits as well as genome organization and evolution. Simultaneous dense SNP genotyping of segregating populations and variety collections was applied to oilseed rape (Brassica napus L.) to obtain a high density genetic map for this species and to study the linkage disequilibrium pattern. RESULTS: We developed an integrated genetic map for oilseed rape by high throughput SNP genotyping of four segregating doubled haploid populations. A very high level of collinearity was observed between the four individual maps and a large number of markers (>59%) was common to more than two maps. The precise integrated map comprises 5764 SNP and 1603 PCR markers. With a total genetic length of 2250 cM, the integrated map contains a density of 3.27 markers (2.56 SNP) per cM. Genotyping of these mapped SNP markers in oilseed rape collections allowed polymorphism level and linkage disequilibrium (LD) to be studied across the different collections (winter vs spring, different seed quality types) and along the linkage groups. Overall, polymorphism level was higher and LD decayed faster in spring than in "00" winter oilseed rape types but this was shown to vary greatly along the linkage groups. CONCLUSIONS: Our study provides a valuable resource for further genetic studies using linkage or association mapping, for marker assisted breeding and for Brassica napus sequence assembly and genome organization analyses. PMID- 23432810 TI - Honokiol blocks store operated calcium entry in CHO cells expressing the M3 muscarinic receptor: honokiol and muscarinic signaling. AB - BACKGROUND: Honokiol, a cell-permeable phenolic compound derived from the bark of magnolia trees and present in Asian herbal teas, has a unique array of pharmacological actions, including the inhibition of multiple autonomic responses. We determined the effects of honokiol on calcium signaling underlying transmission mediated by human M3 muscarinic receptors expressed in Chinese hamster ovary (CHO) cells. Receptor binding was determined in radiolabelled ligand binding assays; changes in intracellular calcium concentrations were determined using a fura-2 ratiometric imaging protocol; cytotoxicity was determined using a dye reduction assay. RESULTS: Honokiol had a potent (EC50 ~ 5 MUmol/l) inhibitory effect on store operated calcium entry (SOCE) that was induced by activation of the M3 receptors. This effect was specific, rapid and partially reversible, and was seen at concentrations not associated with cytotoxicity, inhibition of IP3 receptor-mediated calcium release, depletion of ER calcium stores, or disruption of M3 receptor binding. CONCLUSIONS: It is likely that an inhibition of SOCE contributes to honokiol disruption of parasympathetic motor functions, as well as many of its beneficial pharmacological properties. PMID- 23432811 TI - Safety and tolerability of a focused ultrasound device for treatment of adipose tissue in subjects undergoing abdominoplasty: a placebo-control pilot study. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) lipolysis is a noninvasive alternative to existing surgical body-sculpting methods. OBJECTIVE: To evaluate the safety, tolerability, and histologic outcome of HIFU lipolysis using a novel device in human subjects. METHODS AND MATERIALS: In a single-blind pilot study, six healthy subjects scheduled to undergo abdominoplasty within 4 weeks received HIFU lipolysis on one side of the umbilicus. An identical placebo treatment was given to the contralateral side. Patient evaluation of complications, blood tests, and urine analysis were performed 1, 3, 7, 14, and 28 days after treatment. Excised tissue from the treated areas was sent for histologic review. RESULTS: Treatment was well tolerated. Average visual analogue pain scale scores were 3.5 +/- 2.3 (range 1-7) and 0.17 +/- 0.41 (range 0-1). No major adverse events were documented, and laboratory analysis after HIFU lipolysis was normal. Fat necrosis with infiltration of lymphocytes and macrophages without adjacent tissue damage was documented on histology 2 to 4 weeks after HIFU lipolysis. Damage extent correlated with size of the area treated. No pathologic findings were found on the control side. CONCLUSIONS: High-intensity focused ultrasound treatment was well tolerated and safe. Focal damage to target tissue was documented, with adjacent tissues remaining intact. PMID- 23432812 TI - Safety and reactogenicity of primary vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in Vietnamese infants: a randomised, controlled trial. AB - BACKGROUND: Pneumococcal infections are major causes of child mortality and morbidity worldwide and antibiotic resistance of Streptococcus pneumoniae is a major concern, especially in Asian countries. The present study was designed to evaluate the reactogenicity and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when co-administered with the licensed diphtheria, tetanus, acellular pertussis, hepatitis B virus, inactivated poliovirus and H. influenzae type b vaccine (DTPa-HBV-IPV/Hib) in a 3 dose primary vaccination course in Vietnamese infants. METHODS: This phase III, open, randomised study was conducted in one centre in Ho Chi Minh City between February and July 2011. Healthy infants (N=300) were randomised (2:1) to receive either PHiD-CV co-administered with DTPa-HBV-IPV/Hib (PHiD-CV group) or DTPa-HBV IPV/Hib alone (Control group) at 2, 3, and 4 months of age. RESULTS: Within 31 days post-vaccination, 8.2% of overall doses in the PHiD-CV group and 3.0% of overall doses in the Control group were followed by at least one solicited and/or unsolicited, local and/or general adverse event of grade 3 intensity. Pain at injection site was the most common grade 3 solicited symptom, which was reported following 6.5% and 1.0% of overall doses in the PHiD-CV and Control groups, respectively. Within 4 days post-vaccination, the most common solicited local and general symptoms reported with any intensity were pain (48.9% and 31.0% of doses in the PHiD-CV and Control groups) and irritability (58.0% and 40.4% of doses in the PHiD-CV and Control groups). Within 31 days post-vaccination, the incidence of unsolicited symptoms was comparable in both groups (following 12.3% and 14.8% of doses in the PHiD-CV and Control groups, respectively). Throughout the study, 13 serious adverse events (SAEs) were reported in 9 infants in the PHiD-CV group and 11 SAEs in 6 infants in the Control group. None of them were fatal or considered causally related to vaccination. CONCLUSIONS: PHiD-CV had a clinically acceptable safety profile when co-administered with DTPa-HBV-IPV/Hib in Vietnamese infants. The reactogenicity of PHiD-CV was comparable to that observed in other South-East Asian populations. PMID- 23432813 TI - Different biokinetics of nanomedicines linking to their toxicity; an overview. AB - In spite of the extreme rise to the knowledge of nanotechnology in pharmaceutical sciences, there are currently limited experimental works studying the interactions between nanoparticles (NPs) and the biological system. Adjustment of size and surface area plays the main role in the reaction between NPs and cells leading to their increased entrance into cells through skin, gastrointestinal and respiratory system. Moreover, change in physicochemical reactivity of NPs causes them to interact with circulatory and cellular proteins differentially leading to the altered parameters of their biokinetics, including adsorption, distribution, translocation, transformation, and elimination. A direct relationship between the surface area, reactive oxygen species generating capability, and proinflammatory effects of NPs have been found in respiratory tract toxicity. Additionally, complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanodrugs have been well defined. Inhalation studies of some NPs have confirmed the translocation of inhaled materials to extra pulmonary organs such as central nervous system (CNS) via olfactory neurons and induction of inflammatory response. Injectable uncoated NPs have a tendency to remain on the injection site while the poly ethanol glycol (PEG)-coated NPs can be notably drained from the injection site to get as far as the lymph nodes where they accumulate. This confirms the existence of channels within the extracellular matrix for NPs to move along. Furthermore, induction of DNA strand breaks and formation of micronuclei have been recorded for exposure to some NPs such as single-walled carbon nanotubes.In the recent years, most of the studies have simply outlined better efficacy of nanodrugs, but few discussed their possible toxic reactions specially if used chronically. Therefore, we emphasize that this part of the nanoscience must not be undermined and toxicologists must be sensitive to set up suitable in vivo or in vitro toxicity models. A system for collecting data about the relationships between NPs' structure-size-efficacy-toxicity (SSET) should be specified with special regard to portal of entry and target organ. PMID- 23432815 TI - Spiritual coping, religiosity and quality of life: a study on Muslim patients undergoing haemodialysis. AB - AIM: The number of haemodialysis patients globally is increasing and spiritual resources may help overcome adjustment problems among such patients. This study examined the relationships between spiritual/religious, demographic and clinical variables and quality of life among Iranian Muslims undergoing haemodialysis. METHODS: Using a cross-sectional design, 362 haemodialysis patients were surveyed from three general hospitals located in Tehran, Iran. Spiritual coping strategies, Duke University Religion Index, EQ-5D 3L and a demographic questionnaire were administered. Hierarchical regression was used to identify predictors of quality of life and health status. RESULTS: The distribution of reported problems across dimensions of quality of life was: mobility (59.4%), usual activities (30.4%), self-care (21.3%), pain/discomfort (47.8%) and anxiety/depression (29.3%). Univariate analysis showed that factors such as age, sex, marital status, location, number of children, body mass index, serum albumin, having diabetes mellitus or other comorbidity, as well as spiritual/religious factors that were related to quality of life, health status or both. Regression models revealed that demographics, clinical variables and especially spiritual/religious factors explained about 40% of variance of quality of life and nearly 25% of the variance in health status. CONCLUSION: Spiritual resources may contribute to better quality of life and health status among haemodialysis patients. Further longitudinal studies are needed to determine whether these associations are causal and the direction of effect. PMID- 23432814 TI - E-cadherin gene re-expression in chronic lymphocytic leukemia cells by HDAC inhibitors. AB - BACKGROUND: The tumor suppressor gene E-cadherin gene is frequently silenced in chronic lymphocytic leukemia (CLL) cells and results in wnt-pathway activation. We analyzed the role of histone epigenetic modifications in E-cadherin gene silencing. METHODS: CLL specimens were treated with histone deacetylase inhibitor (HDACi) MS-275 and analyzed for E-cadherin expression with western blot and RT PCR analysis. The downstream effects of HDACi treated leukemic cells were studied by analyzing the effect on wnt-pathway signaling. HDACi induced alterations in E cadherin splicing were investigated by transcript specific real time PCR analysis. RESULTS: Treatment of CLL specimens with histone deacetylase inhibitors (HDACi) treatment resulted in an increase of the E-cadherin RNA transcript (5 to 119 fold increase, n=10) in eight out of ten CLL specimens indicating that this gene is down regulated by histone hypoacetylation in a majority of CLL specimens. The E-cadherin re-expression in CLL specimens was noted by western blot analysis as well. Besides epigenetic silencing another mechanism of E-cadherin inactivation is aberrant exon 11 splicing resulting in an alternatively spliced transcript that lacks exon 11 and is degraded by the non-sense mediated decay (NMD) pathway. Our chromatin immunoprecipitation experiments show that HDACi increased the acetylation of histones H3 and H4 in the E-cadherin promoter region. This also affected the E-cadherin exon 11 splicing pattern as HDACi treated CLL specimens preferentially expressed the correctly spliced transcript and not the exon 11 skipped aberrant transcript. The re-expressed E- cadherin binds to beta-catenin with inhibition of the active wnt-beta-catenin pathway in these cells. This resulted in a down regulation of two wnt target genes, LEF and cyclinD1 and the wnt pathway reporter. CONCLUSION: The E-cadherin gene is epigenetically modified and hypoacetylated in CLL leukemic cells. Treatment of CLL specimens with HDACi MS-275 activates transcription from this silent gene with expression of more correctly spliced E-cadherin transcripts as compared to the aberrant exon11 skipped transcripts that in turn inhibits the wnt signaling pathway. The data highlights the role of epigenetic modifications in altering gene splicing patterns. PMID- 23432816 TI - Quercetin relaxes rat tail main artery partly via a PKG-mediated stimulation of KCa 1.1 channels. AB - AIM: Protein kinases, activated by vasodilator substances, affect vascular function by regulating large conductance Ca(2+) -activated K(+) (KCa 1.1) channels. Thus, the aim of the present investigation was to address the hypothesis that quercetin-induced vasorelaxation is caused by a PKG-mediated stimulation of KCa 1.1 currents. METHODS: Single freshly isolated myocytes and endothelium-denuded rings of the rat tail main artery were employed for electrophysiological and contractility measurements respectively. RESULTS: Quercetin relaxed vessels and increased KCa 1.1 currents in a concentration dependent manner: both effects were antagonized by the specific KCa 1.1 channel blocker iberiotoxin. Stimulation of KCa 1.1 currents was fully reversible upon drug washout, markedly reduced by Rp-8-Br-PET-cGMPs, a PKG-inhibitor, but not affected by catalase. Quercetin shifted by 34.3 mV the voltage dependence of KCa 1.1 channel activation towards more negative membrane potentials without affecting its slope. Under conditions of tight functional coupling between sarcoplasmic reticulum Ca(2+) release sites and KCa 1.1 channels, quercetin decreased both the frequency and the amplitude of KCa 1.1 transient currents in a ryanodine-like manner. CONCLUSION: The natural flavonoid quercetin relaxes the rat tail main artery partly via a PKG-mediated stimulation of smooth muscle KC a 1.1 channels. PMID- 23432817 TI - Hypogonadotropic hypogonadism presenting with arhinia: a case report. AB - INTRODUCTION: Arhinia, congenital absence of the nose, is a rare malformation. We present the third reported case of arhinia accompanied by hypogonadism and demonstrate that this is due to gonadotropin deficiency. CASE PRESENTATION: A 13 year-old Caucasian boy with congenital arhinia presented for evaluation of delayed puberty and micropenis. We examined genes known to be associated with hypogonadotropic hypogonadism for mutations and performed a chromosomal microarray to assess copy number variation. CONCLUSION: No mutations in KAL1, FGFR1, PROK2, PROKR2, FGF8, CHD7 and GnRHR were identified in our patient and there were no copy number variations observed that would explain the phenotype. Though studies are limited in such patients, we suggest that hypogonadotropic hypogonadism is associated with arhinia and that the two entities likely result from a common genetic cause that affects early nasal development and gonadotropin releasing hormone neuron formation or migration. PMID- 23432818 TI - Multiple deliveries: the reduced impact of in vitro fertilisation in Australia. AB - BACKGROUND: The number of twins born in Australia steadily increased from 2420 sets in 1983 to 4458 sets in 2010. At one stage, almost 25% of all twin deliveries in Australia were a consequence of assisted reproductive technologies. AIMS: To determine the influence of a policy of single embryo transfer (SET) on the rate of multiple deliveries in Australia. METHODS: We used population data to compare the prevalence of twin and higher order multiple births in women giving birth in Australia before and after the implementation of the RTAC COP 2001 and 2005 revisions for ART units. RESULTS: There was a steady fall in the twin delivery rate for assisted reproductive technologies from 210.4 per 1000 deliveries in 2001 to 84.3 per 1000 deliveries in 2009. In 2009, assisted reproductive technologies accounted for approximately 16% of all twin births from 3% of all conceptions, substantially less than the 24.5% in 2002. CONCLUSIONS: The decline in multiple births is multifactorial. However, the fall in the proportion of ART multiple births has paralleled adoption of a voluntary policy of SET within a setting of largely public funding of ART. PMID- 23432819 TI - Effect of folic acid supplementation on homocysteine concentration and association with training in handball players. AB - BACKGROUND: Strenuous physical activity can alter the status of folic acid, a vitamin directly associated with homocysteine (Hcy); alterations in this nutrient are a risk factor for cardiovascular disease. Handball players are a population at risk for nutrient deficiency because of poor dietary habits. OBJECTIVE: The aims of this study were to evaluate nutritional status for macronutrients and folic acid in members of a high-performance handball team, and determine the effect of a nutritional intervention with folic acid supplementation and education. DESIGN: A total of 14 high-performance handball players were monitored by recording training time, training intensity (according to three levels of residual heart rate (RHR): <60%, 60%-80% and >80%), and subjective perceived exertion (RPE) during a 4-month training period. Nutritional, laboratory and physical activity variables were recorded at baseline (Week 0), after 2 months of dietary supplementation with 200 MUg folic acid (50% of the recommended daily allowance) (Week 8) and after 2 months without supplementation (Week 16). We compared training load and analyzed changes in plasma concentrations of Hcy before and after the intervention. RESULTS: Bivariate analysis showed a significant negative correlation (P < 0.01) between Hcy and folic acid concentrations (r = -0.84) at Week 8, reflecting a significant change in Hcy concentration (P < 0.05) as a result of hyperhomocysteinemia following the accumulation of high training loads. At Week 16 we observed a significant negative correlation (P < 0.01) between Hcy concentration and training time with an RHR <60%, indicating that aerobic exercise avoided abrupt changes in Hcy and may thus reduce the risk of cardiovascular accidents in high-performance athletes. CONCLUSION: Integral monitoring and education are needed for practitioners of handball sports to record their folic acid status, a factor that directly affects Hcy metabolism. Folic acid supplementation may protect athletes against alterations that can lead to cardiovascular events related to exertion during competition. PMID- 23432820 TI - Modified distally based sural adipofascial flap for reconstructing of leg and ankle. AB - BACKGROUND: While free flaps can be used in many cases to cover soft tissue defects in the distal leg and ankle in a single stage, factors such as diabetes and advanced age can interfere with success of vascular anastomoses. METHODS: Twenty-five patients with deep tissue exposure of the distal leg and ankle underwent reconstruction with a modified reverse sural adipofascial flap. Seventeen cases were due to trauma (13 due to high velocity trauma). All 17 had anterior tibial soft tissue defects without significant rear calf soft tissue injury. Eight patients had iatrogenic soft tissue defects due to orthopaedic surgeries for fractures. The flap is raised through two small incisions (3-5 cm) in the posterior aspect of the leg and the subcutaneous fat is split such that some is preserved with the skin. Once the flap is in place, it is covered by a full-thickness skin graft and the donor site is closed primarily. RESULTS: Twenty one flaps survived. Four had partial loss of the skin graft on the flap, which healed spontaneously without secondary resurfacing. Anatomic contour was obtained in the recipient sites of all 25 patients. All donor sites healed primarily with the preservation of protective sensation in the calf and acceptable aesthetic appearance. Numbness in the lateral dorsal foot improved gradually and only minor residual numbness was noted at 1 year postoperatively. CONCLUSIONS: The modified reverse sural adipofascial flap preserved the sensation of the donor site and the anatomic contour of both recipient and donor sites. PMID- 23432821 TI - Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. AB - BACKGROUND: This study sought to estimate the severity, etiology, and clinical importance of treatment-related lymphopenia in patients with stage III non-small cell lung cancer. METHODS: Serial lymphocyte counts and survival were analyzed retrospectively in 47 patients accounting for known prognostic factors. RESULTS: Total lymphocyte counts (TLCs) were normal before therapy and did not change following neoadjuvant chemotherapy. Following radiation, TLC fell by 67% (median 500 cells/mm(3), p <.00001). Multivariate analysis revealed an association between severe TLC and survival (HR 1.70, 95% CI: 0.8-3.6). CONCLUSIONS: Rapid and severe lymphopenia occurred in 50% of patients following radiation which was associated with reduced survival. PMID- 23432822 TI - Peri-implant soft tissues around implants with a modified neck surface. Part 1. Clinical and histometric outcomes: a pilot study in minipigs. AB - AIM: The goal of this study was to investigate the effect of a modified transgingival implant collar surface (acid-etched structure and hydrophilic properties) comparatively to a machined collar surface on the clinical and soft tissue integration to pure titanium implants (Ti) and titanium implants alloyed with zirconium (TiZr). MATERIAL AND METHODS: Twenty-seven implants belonging to the following groups (9 of each group): Ti modSLA with machined collar (Ti-M), Ti modSLA with machined, acid-etched surface collar (Ti-modMA) and TiZr modSLA with machined, acid-etched surface collar (TiZr-modMA) were placed in the mandible of 6 minipigs. After 8 weeks of healing, clinical measurements were taken and the sample sites were dissected and processed for histological evaluation. RESULTS: Eight weeks after implantation, the mucosa was generally located above the implant shoulder for all implant types. Histomorphometric evaluation revealed that the sulcular epithelium, junctional epithelium and the connective tissue contact were similar in the three groups. Adjusted comparisons showed that the first bone-to-implant contact was statistically more coronal for the Ti-modMA in comparison with the machined. CONCLUSION: The soft tissue dimensions around all implant prototypes were similar and not affected by the implant surface modification. PMID- 23432823 TI - An intermediate care unit for older people with both physical and psychiatric disorders: naturalistic outcome study. AB - BACKGROUND: An intermediate care unit opened in 2008 aiming to relieve pressure on beds in the local general hospital. Its goal was to provide rehabilitation for people recovering from physical illness who had coexisting psychiatric symptoms, including from delirium, but for whom assessment suggested that discharge home might be achieved. As an experimental unit, it warranted evaluation. We aimed to identify clinical factors associated with higher rates of discharge of the patients to their own homes. METHODS: A naturalistic retrospective exploratory cohort study of 100 consecutive admissions to the intermediate care unit. A backward logistic regression analysis was performed. RESULTS: Discharge home was associated with better scores on the Barthel Index of Activities of Daily Living at the time of discharge, a shorter duration of stay, and a psychiatric diagnosis other than delirium. CONCLUSIONS: At the time of pre-admission assessment, clinical factors which were likely to predict discharge home were unclear, suggesting a need for further studies to determine who might best benefit from this sort of intermediate care placement. PMID- 23432824 TI - Comparative transcriptomics reveals different strategies of Trichoderma mycoparasitism. AB - BACKGROUND: Trichoderma is a genus of mycotrophic filamentous fungi (teleomorph Hypocrea) which possess a bright variety of biotrophic and saprotrophic lifestyles. The ability to parasitize and/or kill other fungi (mycoparasitism) is used in plant protection against soil-borne fungal diseases (biological control, or biocontrol). To investigate mechanisms of mycoparasitism, we compared the transcriptional responses of cosmopolitan opportunistic species and powerful biocontrol agents Trichoderma atroviride and T. virens with tropical ecologically restricted species T. reesei during confrontations with a plant pathogenic fungus Rhizoctonia solani. RESULTS: The three Trichoderma spp. exhibited a strikingly different transcriptomic response already before physical contact with alien hyphae. T. atroviride expressed an array of genes involved in production of secondary metabolites, GH16 beta-glucanases, various proteases and small secreted cysteine rich proteins. T. virens, on the other hand, expressed mainly the genes for biosynthesis of gliotoxin, respective precursors and also glutathione, which is necessary for gliotoxin biosynthesis. In contrast, T. reesei increased the expression of genes encoding cellulases and hemicellulases, and of the genes involved in solute transport. The majority of differentially regulated genes were orthologues present in all three species or both in T. atroviride and T. virens, indicating that the regulation of expression of these genes is different in the three Trichoderma spp. The genes expressed in all three fungi exhibited a nonrandom genomic distribution, indicating a possibility for their regulation via chromatin modification. CONCLUSION: This genome-wide expression study demonstrates that the initial Trichoderma mycotrophy has differentiated into several alternative ecological strategies ranging from parasitism to predation and saprotrophy. It provides first insights into the mechanisms of interactions between Trichoderma and other fungi that may be exploited for further development of biofungicides. PMID- 23432825 TI - IMGT/Collier-de-Perles: a two-dimensional visualization tool for amino acid domain sequences. AB - IMGT/Collier-de-Perles is a tool that allows the user to analyze and draw two dimensional graphical representations (or IMGT Collier de Perles) of protein domains (e.g., hydropathy plots). The IMGT/Collier-de-Perles specializes in the area of immunoglobulins (IG) or antibodies, T cell receptors (TR) and major histocompatibility (MH) of human and other vertebrate species as well as other proteins of the immunoglobulin superfamily (IgSF) and of the major histocompatibility superfamily (MhSF) and related proteins of the immune system of vertebrates and invertebrates. PMID- 23432826 TI - Probabilistic cue combination: less is more. AB - Learning about the structure of the world requires learning probabilistic relationships: rules in which cues do not predict outcomes with certainty. However, in some cases, the ability to track probabilistic relationships is a handicap, leading adults to perform non-normatively in prediction tasks. For example, in the dilution effect, predictions made from the combination of two cues of different strengths are less accurate than those made from the stronger cue alone. Here we show that dilution is an adult problem; 11-month-old infants combine strong and weak predictors normatively. These results extend and add support for the less is more hypothesis: limited cognitive resources can lead children to represent probabilistic information differently from adults, and this difference in representation can have important downstream consequences for prediction. PMID- 23432827 TI - Developmental trends in auditory processing can provide early predictions of language acquisition in young infants. AB - Auditory processing capabilities at the subcortical level have been hypothesized to impact an individual's development of both language and reading abilities. The present study examined whether auditory processing capabilities relate to language development in healthy 9-month-old infants. Participants were 71 infants (31 boys and 40 girls) with both Auditory Brainstem Response (ABR) and language assessments. At 6 weeks and/or 9 months of age, the infants underwent ABR testing using both a standard hearing screening protocol with 30 dB clicks and a second protocol using click pairs separated by 8, 16, and 64-ms intervals presented at 80 dB. We evaluated the effects of interval duration on ABR latency and amplitude elicited by the second click. At 9 months, language development was assessed via parent report on the Chinese Communicative Development Inventory - Putonghua version (CCDI-P). Wave V latency z-scores of the 64-ms condition at 6 weeks showed strong direct relationships with Wave V latency in the same condition at 9 months. More importantly, shorter Wave V latencies at 9 months showed strong relationships with the CCDI-P composite consisting of phrases understood, gestures, and words produced. Likewise, infants who had greater decreases in Wave V latencies from 6 weeks to 9 months had higher CCDI-P composite scores. Females had higher language development scores and shorter Wave V latencies at both ages than males. Interestingly, when the ABR Wave V latencies at both ages were taken into account, the direct effects of gender on language disappeared. In conclusion, these results support the importance of low-level auditory processing capabilities for early language acquisition in a population of typically developing young infants. Moreover, the auditory brainstem response in this paradigm shows promise as an electrophysiological marker to predict individual differences in language development in young children. PMID- 23432828 TI - Infants' mu suppression during the observation of real and mimicked goal-directed actions. AB - Since their discovery in the early 1990s, mirror neurons have been proposed to be related to many social-communicative abilities, such as imitation. However, research into the early manifestations of the putative neural mirroring system and its role in early social development is still inconclusive. In the current EEG study, mu suppression, generally thought to reflect activity in neural mirroring systems was investigated in 18- to 30-month-olds during the observation of object manipulations as well as mimicked actions. EEG power data recorded from frontal, central, and parietal electrodes were analysed. As predicted, based on previous research, mu wave suppression was found over central electrodes during action observation and execution. In addition, a similar suppression was found during the observation of intransitive, mimicked hand movements. To a lesser extent, the results also showed mu suppression at parietal electrode sites, over all three conditions. Mu wave suppression during the observation of hand movements and during the execution of actions was significantly correlated with quality of imitation, but not with age or language level. PMID- 23432829 TI - Frontolimbic neural circuitry at 6 months predicts individual differences in joint attention at 9 months. AB - Elucidating the neural basis of joint attention in infancy promises to yield important insights into the development of language and social cognition, and directly informs developmental models of autism. We describe a new method for evaluating responding to joint attention performance in infancy that highlights the 9- to 10-month period as a time interval of maximal individual differences. We then demonstrate that fractional anisotropy in the right uncinate fasciculus, a white matter fiber bundle connecting the amygdala to the ventral-medial prefrontal cortex and anterior temporal pole, measured in 6-month-olds predicts individual differences in responding to joint attention at 9 months of age. The white matter microstructure of the right uncinate was not related to receptive language ability at 9 months. These findings suggest that the development of core nonverbal social communication skills in infancy is largely supported by preceding developments within right lateralized frontotemporal brain systems. PMID- 23432830 TI - East-West cultural differences in context-sensitivity are evident in early childhood. AB - Accumulating evidence suggests that North Americans tend to focus on central objects whereas East Asians tend to pay more attention to contextual information in a visual scene. Although it is generally believed that such culturally divergent attention tendencies develop through socialization, existing evidence largely depends on adult samples. Moreover, no past research has investigated the relation between context-sensitivity and other domains of cognitive development. The present study examined children in the United States and Japan (N = 175, age 4-9 years) to investigate the developmental pattern in context-sensitivity and its relation to executive function. The study found that context-sensitivity increased with age across cultures. Nevertheless, Japanese children showed significantly greater context-sensitivity than American children. Also, context sensitivity fully mediated the cultural difference in a set-shifting executive function task, which might help explain past findings that East Asian children outperformed their American counterparts on executive function. PMID- 23432831 TI - The mentalistic basis of core social cognition: experiments in preverbal infants and a computational model. AB - Evaluating individuals based on their pro- and anti-social behaviors is fundamental to successful human interaction. Recent research suggests that even preverbal infants engage in social evaluation; however, it remains an open question whether infants' judgments are driven uniquely by an analysis of the mental states that motivate others' helpful and unhelpful actions, or whether non mentalistic inferences are at play. Here we present evidence from 10-month-olds, motivated and supported by a Bayesian computational model, for mentalistic social evaluation in the first year of life.A video abstract of this article can be viewed at http://youtu.be/rD_Ry5oqCYE. PMID- 23432832 TI - Perception of the motion trajectory of objects from moving cast shadows in infant Japanese macaques (Macaca fuscata). AB - The shadows cast by moving objects enable human adults and infants to infer the motion trajectories of objects. Nonhuman animals must also be able to discriminate between objects and their shadows and infer the spatial layout of objects from cast shadows. However, the evolutionary and comparative developmental origins of sensitivity to cast shadows have not been investigated. In this study, we used a familiarity/novelty preferential looking procedure to assess the ability of infant macaques, aged 7-24 weeks, to discriminate between a 'depth' display containing a ball and cast shadow moving diagonally and an 'up' display containing a ball with a diagonal trajectory and a shadow with a horizontal trajectory. The infant macaques could discriminate the trajectories of the balls based on the moving shadows. These findings suggest that the ability to perceive the motion trajectory of an object from the moving shadow is common to both humans and macaques. PMID- 23432833 TI - SES differences in language processing skill and vocabulary are evident at 18 months. AB - This research revealed both similarities and striking differences in early language proficiency among infants from a broad range of advantaged and disadvantaged families. English-learning infants (n = 48) were followed longitudinally from 18 to 24 months, using real-time measures of spoken language processing. The first goal was to track developmental changes in processing efficiency in relation to vocabulary learning in this diverse sample. The second goal was to examine differences in these crucial aspects of early language development in relation to family socioeconomic status (SES). The most important findings were that significant disparities in vocabulary and language processing efficiency were already evident at 18 months between infants from higher- and lower-SES families, and by 24 months there was a 6-month gap between SES groups in processing skills critical to language development. PMID- 23432834 TI - Bidirectional influences between maternal parenting and children's peer problems: a longitudinal monozygotic twin difference study. AB - This twin study examined the bidirectional relationship between maternal parenting behaviors and children's peer problems that were not confounded by genetic and family environmental factors. Mothers of 259 monozygotic twin pairs reported parenting behaviors and peer problems when twins were 42 and 48 months. Path analyses on monozygotic twin difference scores revealed that authoritative parenting (the presence of consistent discipline and lack of harsh parenting) and peer problems simultaneously influenced each other. Authoritative parenting reduced peer problems, and peer problems increased authoritative parenting. Neither consistent discipline nor harsh parenting alone was associated with peer problems. These results suggest that maternal authoritative parenting works protectively in regard to children's peer problems, and peer problems can evoke such effective parenting. PMID- 23432835 TI - Generalist genes and cognitive abilities in Chinese twins. AB - This study considered how far nonverbal cognitive, language and reading abilities are affected by common genetic influences in a sample of 312 typically developing Chinese twin pairs aged from 3 to 11 years. Children were individually given tasks of Chinese word reading, receptive vocabulary, phonological memory, tone awareness, syllable and rhyme awareness, rapid automatized naming, morphological awareness and orthographic skills, and Raven's Colored Progressive Matrices. Factor analyses on the verbal tasks adjusted for age indicated two factors: Language as the first factor and Reading as the second factor. Univariate genetic analyses indicated that genetic influences were substantial for nonverbal cognitive ability and moderate for language and reading. Multivariate genetic analyses showed that nonverbal cognitive ability, language and reading were influenced by shared genetic origins, although there were specific genetic influences on verbal skills that were distinct from those on nonverbal cognitive ability. This study extends the Generalist Genes Hypothesis to Chinese language and reading skills, suggesting that the general effects of genes could be universal across languages. PMID- 23432836 TI - Speed isn't everything: complex processing speed measures mask individual differences and developmental changes in executive control. AB - The rate at which people process information appears to influence many aspects of cognition across the lifespan. However, many commonly accepted measures of 'processing speed' may require goal maintenance, manipulation of information in working memory, and decision-making, blurring the distinction between processing speed and executive control and resulting in overestimation of processing speed contributions to cognition. This concern may apply particularly to studies of developmental change, as even seemingly simple processing speed measures may require executive processes to keep children and older adults on task. We report two new studies and a re-analysis of a published study, testing predictions about how different processing speed measures influence conclusions about executive control across the lifespan. We find that the choice of processing speed measure affects the relationship observed between processing speed and executive control, in a manner that changes with age, and that choice of processing speed measure affects conclusions about development and the relationship among executive control measures. Implications for understanding processing speed, executive control, and their development are discussed. PMID- 23432837 TI - Auditory habituation in the fetus and neonate: an fMEG study. AB - Habituation--the most basic form of learning--is used to evaluate central nervous system (CNS) maturation and to detect abnormalities in fetal brain development. In the current study, habituation, stimulus specificity and dishabituation of auditory evoked responses were measured in fetuses and newborns using fetal magnetoencephalography (fMEG). An auditory habituation paradigm consisting of 100 trains of five 500 Hz tones, one 750 Hz tone (dishabituator) and two more 500 Hz tones, respectively, were presented to 41 fetuses (gestational age 30-39 weeks) and 22 newborns or babies (age 6-89 days). A response decrement between the first and fifth tones (habituation), an increment between the fifth tone and the dishabituator (stimulus specificity) and an increment between the fifth (last tone before the dishabituator) and seventh tones (first tone after the dishabituator) (dishabituation) were expected. Fetuses showed weak responses to the first tone. However, a significant response decrement between the second and fifth tones (habituation) and a significant increment between the fifth tone and the dishabituator (stimulus specificity) were found. No significant difference was found for dishabituation nor was a developmental trend found at the group level. From the neonatal data, significant values for stimulus specificity were found. Sensory fatigue or adaptation was ruled out as a reason for the response decrement due to the strong reactions to the dishabituator. Taken together, the current study used fMEG to directly show fetal habituation and provides evidence of fetal learning in the last trimester of pregnancy. PMID- 23432838 TI - Target article with commentaries: developmental niche construction. AB - Niche construction is the modification of components of the environment through an organism's activities. Humans modify their environments mainly through ontogenetic and cultural processes, and it is this reliance on learning, plasticity and culture that lends human niche construction a special potency. In this paper we aim to facilitate discussion between researchers interested in niche construction and those interested in human cognitive development by highlighting some of the related processes. We discuss the transmission of culturally relevant information, how the human mind is a symbol-generating and artefact-devising system, and how these processes are bi-directional, with infants and children both being directed, and directing, their own development. We reflect on these in the light of four approaches: natural pedagogy, activity theory, distributed cognition and situated learning. Throughout, we highlight pertinent examples in non-humans that parallel or further explicate the processes discussed. Finally we offer three future directions; two involving the use of new techniques in the realms of neuroscience and modelling, and the third suggesting exploration of changes in the effects of niche construction across the lifespan. PMID- 23432839 TI - On hermit crabs and humans. PMID- 23432840 TI - Lifespan development of neuromodulation of adaptive control and motivation as an ontogenetic mechanism for developmental niche construction. PMID- 23432841 TI - NCT and developmental psychology: a welcome rapprochement. PMID- 23432842 TI - NCT and culture-conscious developmental science: the Laboratory of Comparative Human Cognition. PMID- 23432843 TI - GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. AB - BACKGROUND & AIMS: Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK). METHODS: ApoE KO and adiponectin (Acrp30) knockdown mice fed a high fat diet (HFD) were treated with liraglutide (1 mg/kg, twice daily) for 8 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis. RESULTS: The results showed that the combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-alpha and NF-kappaB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS). These changes were accompanied by elevated plasma of Acrp30, increased Acrp30 mRNA, AMP Kinase phosphorylation, and decreased mitogen activated protein kinase 4 (MKK4) mRNA expression and JNK phosphorylation. CONCLUSIONS: Our study also showed potent inhibitory effects of liraglutide on MKK4/JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia. PMID- 23432844 TI - Postural influences on the mechanical and neural components of the cardiovagal baroreflex. AB - AIM: The ability to maintain arterial blood pressure when faced with a postural challenge has implications for the occurrence of syncope and falls. It has been suggested that posture-induced declines in the mechanical component of the baroreflex response drive reductions in cardiovagal baroreflex sensitivity associated with postural stress. However, these conclusions are largely based upon spontaneous methods of baroreflex assessment, the accuracy of which has been questioned. Therefore, the aim was to engage a partially open-loop approach to explore the influence of posture on the mechanical and neural components of the baroreflex. METHODS: In nine healthy participants, we measured continuous blood pressure, heart rate, RR interval and carotid artery diameter during supine and standing postures. The modified Oxford method was used to quantify baroreflex sensitivity. RESULTS: In response to falling pressures, baroreflex sensitivity was similar between postures (P = 0.798). In response to rising pressures, there was an attenuated (P = 0.042) baroreflex sensitivity (mean +/- SE) in the standing position (-0.70 +/- 0.11 beats min(-1) mmHg(-1)) compared with supine ( 0.83 +/- 0.06 beats min(-1) mmHg(-1)). This was explained by a diminished (P = 0.016) neural component whilst standing (-30.17 +/- 4.16 beats min(-1) mm(-1)) compared with supine (-38.23 +/- 3.31 beats min(-1) mm(-1)). These effects were consistent when baroreflex sensitivity was determined using RR interval. CONCLUSION: Cardiovagal baroreflex sensitivity in response to rising pressures is reduced in young individuals during postural stress. Our data suggest that the mechanical component is unaffected by standing, and the reduction in baroreflex sensitivity is driven by the neural component. PMID- 23432845 TI - Driving patterns in older adults with glaucoma. AB - BACKGROUND: The ability to drive is important for ensuring quality of life for many older adults. Glaucoma is prevalent in this age group and may affect driving. The purpose of this study is to determine if glaucoma and glaucomatous visual field (VF) loss are associated with driving cessation, limitations, and deference to another driver in older adults. METHODS: Cross-sectional study. Eighty-one glaucoma subjects and 58 glaucoma suspect controls between age 60 and 80 reported if they had ceased driving, limited their driving in various ways, or preferred another to drive. RESULTS: Twenty-three percent of glaucoma subjects and 6.9% of suspects had ceased driving (p = 0.01). Glaucoma subjects also had more driving limitations than suspects (2.0 vs. 1.1, p = 0.007). In multivariable models, driving cessation was more likely for glaucoma subjects as compared to suspects (OR = 4.0; 95% CI = 1.1-14.7; p = 0.03). The odds of driving cessation doubled with each 5 decibel (dB) decrement in the better-eye VF mean deviation (MD) (OR = 2.0; 95% CI = 1.4-2.9; p < 0.001). Glaucoma subjects were also more likely than suspects to report a greater number of driving limitations (OR = 4.7; 95% CI = 1.3-16.8; p = 0.02). The likelihood of reporting more limitations increased with the VF loss severity (OR = 1.6 per 5 dB decrement in the better eye VF MD; 95% CI = 1.1-2.4; p = 0.02). Neither glaucoma nor VF MD was associated with other driver preference (p > 0.1 for both). CONCLUSIONS: Glaucoma and glaucomatous VF loss are associated with greater likelihood of driving cessation and greater limitation of driving in the elderly. Further prospective study is merited to assess when and why people with glaucoma change their driving habits, and to determine if their observed self-regulation of driving is adequate to ensure safety. PMID- 23432846 TI - Correlation between chemosensitivity to anticancer drugs and telomerase reverse transcriptase mRNA expression in gastric cancer. AB - BACKGROUND: The determination of sensitive chemotherapy drugs for gastric cancer (GC) is one of the greatest challenges of adjuvant therapy. Here we evaluated the chemosensitivity of GC to anticancer drugs and the telomerase reverse transcriptase (hTERT) mRNA expression, and investigated the relationship of them. METHODS: The GC cells which were collected from 68 patients with primary GC were primary cultured. The chemosensitivity of GC cells to anticancer drugs was evaluated successfully using the MTT assay for 60 cases of GC cells, and the hTERT mRNA expression was examined in 60 cases of GC tissues and corresponding normal gastric mucosa and 6 cases of chronic superficial gastritis mucosa by in situ hybridization. RESULTS: Taxol, cisplatin and 5-fluorouracil were in general more effective than adriamycin and mitomycin for GC cells, and the chemosensitivity to anticancer drugs was associated with tumor histological types and a worse tumor grade. Compared to normal gastric mucosa tissues, hTERT mRNA expression was significantly increased in GC (P<0.05), which was related with a worse differentiation and drug-resistance to 5-fluorouracil or adriamycin in GC. CONCLUSIONS: These data demonstrate for the first time that examinations of hTERT mRNA expression as an important factor could be used to select the chemotherapeutic drugs for GC patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793217009875483. PMID- 23432847 TI - Routine data from prevention of mother-to-child transmission (PMTCT) HIV testing not yet ready for HIV surveillance in Mozambique: a retrospective analysis of matched test results. AB - BACKGROUND: Opt-out HIV testing is offered at 70% of antenatal care (ANC) clinics in Mozambique through the prevention of mother-to-child transmission (PMTCT) program. If routine data from this program were of sufficient quality, their heightened coverage and continuous availability could complement or even replace biannual sentinel serosurveys that currently serve as the primary HIV surveillance system in Mozambique. METHODS: We assessed the efficacy of routine HIV testing data from prevention of mother-to-child transmission programs for estimating the prevalence of HIV infection among pregnant women. The PMTCT program uses sequential point-of-care rapid tests conducted on site while ANC surveillance surveys use dried blood spots tested sequentially for HIV-1/2 antibodies at a central laboratory. We compared matched routine PMTCT and ANC surveillance test results collected during 2007 and 2009 ANC surveillance surveys from 36 sentinel sites. RESULTS: After excluding 659 women without PMTCT data, including 83 who refused rapid testing, test results from a total of 20,563 women were available. Pooling the data from both years indicated HIV prevalence from routine PMTCT testing was 14.4% versus 15.2% from surveillance testing (relative difference -5.1%; absolute difference -0.78%). Positive percent agreement (PPA) of PMTCT versus surveillance tests was 88.5% (95% Confidence Interval [CI]: 85.7 91.3%), with 19 sites having PPA below 90%; Negative percent agreement (NPA) was 98.9% (CI: 98.5-99.2%). No significant difference was found among three regions (North, Center and South), however both PPA and NPA were significantly higher in 2009 than 2007 (p < 0.05). CONCLUSIONS: We found low PPA of PMTCT test results compared to surveillance data which is indicative either of testing errors or data reporting problems. Nonetheless, PPA improved significantly from 2007 to 2009, a possible positive trend that should be investigated further. Although use of PMTCT test results would not dramatically change HIV prevalence estimates among pregnant women, the impact of site-level differences on surveillance models should be evaluated before these data are used to replace or complement ANC surveillance surveys. PMID- 23432848 TI - Gastrointestinal well-being in subjects reporting mild gastrointestinal discomfort: characteristics and properties of a global assessment measure. AB - There is a lack of recognised markers for measuring gastrointestinal (GI) well being and digestive symptoms in the general population. The aim of the present study was to demonstrate construct validity of a global assessment tool of GI well-being. In this randomised double-blind study, 197 adult women consumed either a probiotic fermented milk or a control dairy product daily during 4 weeks. GI well-being was assessed weekly using a single question and subjects indicated whether their GI well-being remained the same, improved or worsened compared with the baseline period. Responders for GI well-being were subjects reporting improvement for at least 2 weeks of the 4 weeks of intervention. Frequency of individual digestive symptoms was assessed weekly. Health-related quality of life (HRQoL) was measured at baseline and at the end of the study. Subjects reporting improvement of their GI well-being had a significantly (P<0.05) lower frequency of combined digestive symptoms than individuals with no change, whereas subjects with worsened GI well-being had a significantly (P<0.05) higher digestive symptom frequency. Number of weeks with reported GI well-being improvement was significantly (P<0.05) correlated with the decrease in digestive symptoms (r 0.58) and the HRQoL digestive comfort dimension (r 0.47). When compared with non-responders, responders had significantly (P<0.0001) fewer average digestive symptoms and higher scores on digestive comfort of the HRQoL questionnaire. The data provide construct validity for a single-item questionnaire as a measure of GI well-being improvement. These data support the use of this questionnaire as an end point for nutritional intervention in the general population. PMID- 23432849 TI - Transcriptional analysis of the effect of exogenous decanoic acid stress on Streptomyces roseosporus. AB - BACKGROUND: Daptomycin is an important antibiotic against infections caused by drug-resistant pathogens. Its production critically depends on the addition of decanoic acid during fermentation. Unfortunately, decanoic acid (>2.5 mM) is toxic to daptomycin producer, Streptomyces roseosporus. RESULTS: To understand the mechanism underlying decanoic tolerance or toxicity, the responses of S. roseosporus was determined by a combination of phospholipid fatty acid analysis, reactive oxygen species (ROS) measurement and RNA sequencing. Assays using fluorescent dyes indicated a sharp increase in reactive oxygen species during decanoic acid stress; fatty acid analysis revealed a marked increase in the composition of branched-chain fatty acids by approximately 10%, with a corresponding decrease in straight-chain fatty acids; functional analysis indicated decanoic acid stress has components common to other stress response, including perturbation of respiratory functions (nuo and cyd operons), oxidative stress, and heat shock. Interestingly, our transcriptomic analysis revealed that genes coding for components of proteasome and related to treholase synthesis were up-regulated in the decanoic acid -treated cells. CONCLUSION: These findings represent an important first step in understanding mechanism of decanoic acid toxicity and provide a basis for engineering microbial tolerance. PMID- 23432850 TI - Low-dose rituximab for the treatment of acute thrombotic thrombocytopenic purpura: report of four cases. AB - OBJECTIVE AND IMPORTANCE: Thrombotic thrombocytopenic purpura (TTP) is a life threatening disorder that needs prompt diagnosis and treatment. Front-line therapy consists of plasma exchange (PEx) and steroids, but, in some instances, this is not enough to achieve a complete and sustained response. CLINICAL PRESENTATION: We report four cases of TTP treated with low-dose rituximab, PEx, and a short course of steroids with an excellent outcome. Three of the patients had primary TTP and another presented an underlying human immunodeficiency virus infection. INTERVENTION: Rituximab, 100 mg intravenously, was initiated on days 2 8 from the start of PEx as first-line therapy in three cases and as salvage therapy for relapsing disease in one. The number of PEx needed ranged from 5 to 12 sessions. All patients achieved complete remission and are currently asymptomatic, with complete response duration of 8-22 months. CONCLUSION: Treatment of TTP with low-dose rituximab, along with PEx and steroids, seems to be as effective as the standard dose of monoclonal antibody. PMID- 23432851 TI - Management of adult attention deficit hyperactivity disorder in UK primary care: a survey of general practitioners. AB - BACKGROUND: Compared to existing literature on childhood attention deficit hyperactivity disorder (ADHD), little published adult data are available, particularly outside of the United States. Using General Practitioner (GP) questionnaires from the United Kingdom, this study aimed to examine a number of issues related to ADHD in adults, across three cohorts of patients, adults who received ADHD drug treatment in childhood/adolescence but stopped prior to adulthood; adults who received ADHD drug treatment in childhood/adolescence and continued treatment into adulthood and adults who started ADHD drug treatment in adulthood. METHODS: Patients with a diagnosis of ADHD and prescribed methylphenidate, dexamfetamine or atomoxetine were identified using data from The Health Improvement Network (THIN). Dates when these drugs started and stopped were used to classify patients into the three cohorts. From each cohort, 50 patients were randomly selected and questionnaires were sent via THIN to their GPs.GPs returned completed questionnaires to THIN who forwarded anonymised copies to the researchers. Datasets were analysed using descriptive statistics. RESULTS: Overall response rate was 89% (133/150). GPs stated that in 19 cases, the patient did not meet the criteria of that group; the number of valid questionnaires returned was 114 (76%). The following broad trends were observed: 1) GPs were not aware of the reason for treatment cessation in 43% of cases, 2) patient choice was the most common reason for discontinuation (56%), 3) 7% of patients who stopped pharmacological treatment subsequently reported experiencing ADHD symptoms, 4) 58% of patients who started pharmacological treatment for ADHD in adulthood received pharmacological treatment for other mental health conditions prior to the ADHD being diagnosed. CONCLUSION: This study presents some key findings relating to ADHD; GPs were often not aware of the reason for patients stopping ADHD treatment in childhood or adolescence. Patient choice was identified as the most common reason for treatment cessation. For patients who started pharmacological treatment in adulthood, many patients received pharmacological treatment for comorbidities before a diagnosis of ADHD was made. PMID- 23432853 TI - Turnover superficial temporal fascia flap: a galeopericranial-based random flap for coverage of vertex defects on the scalp. PMID- 23432852 TI - The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. AB - Despite enormous advances in CNS research, CNS disorders remain the world's leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies.Following dosing, not only the chemical properties of the drug and blood-brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra individual variation, often encountered in CNS drug therapy.For effective therapy, drugs should access the CNS "at the right place, at the right time, and at the right concentration". To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs.In this review the term "Mastermind approach" is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be translated to the human situation. On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the "Mastermind approach" has a high potential for the prediction of human CNS drug effects. PMID- 23432854 TI - Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. AB - BACKGROUND: Vitamin D has effects on the innate and adaptive immune system. In asthmatic children low vitamin D levels are associated with poor asthma control, reduced lung function, increased medication intake, and exacerbations. Little is known about vitamin D in adult asthma patients or its association with asthma severity and control. METHODS: Clinical parameters of asthma control and 25 hydroxyvitamin D (25(OH)D) serum concentrations were evaluated in 280 adult asthma patients (mean +/- SD: 45.0 +/- 13.8 yrs., 40% male, FEV1 74.9 +/- 23.4%, 55% severe, 51% uncontrolled). RESULTS: 25(OH)D concentrations in adult asthmatics were low (25.6 +/-11.8 ng/ml) and vitamin D insufficiency or deficiency (vitamin D <30 ng/ml) was common (67%). 25(OH)D levels were related to asthma severity (intermittent: 31.1 +/- 13.0 ng/ml, mild: 27.3 +/- 11.9 ng/ml, moderate: 26.5 +/- 12.0 ng/ml, severe: 24.0 +/- 11.8 ng/ml, p = 0.046) and control (controlled: 29.5 +/- 12.5 ng/ml, partly controlled 25.9 +/- 10.8 ng/ml, uncontrolled: 24.2 +/- 11.8 ng/ml, p = 0.030). The frequency of vitamin D insufficiency or deficiency was significantly higher in patients with severe or uncontrolled asthma and was associated with a lower FEV1 (vitamin D <30 vs. >=30 ng/ml 2.3 +/- 0.9 L vs. 2.7 +/- 1.0 L, p = 0.006), higher levels of exhaled NO (45 +/- 46 ppb vs. 31 +/- 37 ppb, p = 0.023), a higher BMI (28.3 +/- 6.2 vs. 25.1 +/- 3.9, p < 0.001), and sputum eosinophilia (5.1 +/- 11.8% vs. 0.5 +/- 1.0%, p = 0.005). The use of oral corticosteroids or sputum eosinophilia was associated with a 20% or 40% higher risk of vitamin D insufficiency or deficiency. CONCLUSIONS: 25(OH)D levels below 30 ng/ml are common in adult asthma and most pronounced in patients with severe and/or uncontrolled asthma, supporting the hypothesis that improving suboptimal vitamin D status might be effective in prevention and treatment of asthma. PMID- 23432855 TI - Changes in hydration status of elite Olympic class sailors in different climates and the effects of different fluid replacement beverages. AB - BACKGROUND: Olympic class sailing poses physiological challenges similar to other endurance sports such as cycling or running, with sport specific challenges of limited access to nutrition and hydration during competition. As changes in hydration status can impair sports performance, examining fluid consumption patterns and fluid/electrolyte requirements of Olympic class sailors is necessary to develop specific recommendations for these elite athletes. The purpose of this study was to examine if Olympic class sailors could maintain hydration status with self-regulated fluid consumption in cold conditions and the effect of fixed fluid intake on hydration status in warm conditions. METHODS: In our cold condition study (CCS), 11 elite Olympic class sailors were provided ad libitum access to three different drinks. Crystal Light (control, C); Gatorade (experimental control, G); and customized sailing-specific Infinit (experimental, IN) (1.0:0.22 CHO:PRO), were provided on three separate training days in cold 7.1 degrees C [4.2 - 11.3]. Our warm condition study (WCS) examined the effect of fixed fluid intake (11.5 mL.kg.-1.h-1) of C, G and heat-specific experimental Infinit (INW)(1.0:0.074 CHO:PRO) on the hydration status of eight elite Olympic Laser class sailors in 19.5 degrees C [17.0 - 23.3]. Both studies used a completely random design. RESULTS: In CCS, participants consumed 802 +/- 91, 924 +/- 137 and 707 +/- 152 mL of fluid in each group respectively. This did not change urine specific gravity, but did lead to a main effect for time for body mass (p < 0.001), blood sodium, potassium and chloride with all groups lower post training (p < 0.05). In WCS, fixed fluid intake increased participant's body mass post-training in all groups (p < 0.01) and decreased urine specific gravity post training (p < 0.01). There was a main effect for time for blood sodium, potassium and chloride concentration, with lower values observed post-training (p < 0.05). C blood sodium concentrations were lower than the INW group post-training (p = 0.031) with a trend towards significance in the G group (p = 0.069). CONCLUSION: Ad libitum fluid consumption in cold conditions was insufficient in preventing a decrease in body mass and blood electrolyte concentration post-training. However, when a fixed volume of 11.5 mL.kg.-1.h-1 was consumed during warm condition training, hydration status was maintained by preventing changes in body mass and urine specific gravity. PMID- 23432856 TI - Combining malaria vector control interventions: some trial design issues. PMID- 23432857 TI - Tuberculosis diagnosed in a rural setting in Angola. Accuracy of follow-up sputum smears to predict outcome. AB - OBJECTIVE: To analyze treatment outcome and the accuracy of positive sputum smear at 2 months to predict treatment failure in a cohort of patients with tuberculosis (TB) in a rural setting in Angola. DESIGN: Observational study of patients with TB from January 2009 to August 2010 in Hospital Nossa Senhora da Paz in Angola. A multivariate analysis was performed to identify variables associated with treatment failure and death. Sensitivity, specificity, positive and negative predictive values and likelihood ratios to define the accuracy of a positive sputum smear at 2 months to predict treatment failure were calculated. RESULTS: One thousand four hundred and twenty-five patients were diagnosed with TB. Overall, 526 patients were cured from TB and 419 had treatment completed, so 945 (66.3%) patients achieved treatment success. The outcomes of the remaining patients were: 91 (6.4%) had treatment failure, 100 (7%) died, 49 (3.4%) interrupted treatment, and 240 (16.8%) were transferred out. Variables associated with a higher risk of treatment failure were previously treated patients (odds ratio, 2.36; 95% confidence interval, 1.32-4.2) and positive sputum smear at 2 months (odds ratio, 9.81; 95% confidence interval, 5.88-16.36). Among the group of 551 patients with sputum smear confirmed at diagnosis and specimens taken at 2 and 5 months, the positive predictive value (31%) and the positive likelihood ratio (3.21) of a positive sputum smear taken at 2 months to predict treatment failure were low. CONCLUSIONS: Patients with positive sputum smear at 2 months have a higher risk of treatment failure. However, this by itself is a poor predictor of treatment failure. PMID- 23432858 TI - Systematic teaching method to enhance the effectiveness of training for paragonimiasis. AB - The clinical symptoms of human paragonimiasis are complex and variable, and patients can easily be misdiagnosed. Pagumogonimus skrjabini is the species causing this disease found only in China. A 2002 epidemiological survey showed that the rate of paragonimiasis was 21.96% in the migration areas of the Three Gorge Reservoir, Chongqing, China. Therefore, there is a need to train medical workers to treat individuals in these areas. The Third Military Medical University (TMMU) in Chongqing built a comprehensive and systematic teaching method, which included teaching students about the basic biology of the organism, guiding students to use appropriate diagnostic tests and participate in scientific research to develop diagnostic kits, and visiting endemic areas to provide on-site teaching. The use of on-site teaching is an innovative approach for training undergraduate medical students in human parasitology. Three improvements were implemented during the on-site teaching component of the program: (1) systematizing the learning process; (2) integrating formal knowledge with clinical experience; and (3) enhancing students' knowledge of medical ethics. Based on a survey, 95% of students believed that this systematic teaching system gave them a more comprehensive grasp of knowledge on P. skrjabini, and graduate students were able to provide early diagnosis of P. skrjabini cases in this remote region. Students also participated in the research and development of a P. skrjabini diagnostic kit, for which a patent has been applied, and during the on-site teaching process, data were collected for the government and health sector to assist in public-health planning and decision-making for this disease. PMID- 23432859 TI - Epidemiologic pattern of meningococcal meningitis in northern Cameroon in 2007 2010: contribution of PCR-enhanced surveillance. AB - OBJECTIVES: Monitoring acute bacterial meningitis in northern Cameroon. METHODS: Health professionals collected cerebrospinal fluid (CSF) specimens from patients presenting with clinical symptoms of meningitis. Specimens were tested using gram stain, latex agglutination test, and culture. A PCR assay completed the diagnostic testing. Multilocus sequence typing (MLST) was performed on some Neisseria meningitidis (Nm) isolates. RESULTS: From 2007 through 2010, of the 1429 CSF specimens tested, 292 (20.4%) were positive, either for Nm (205), Streptococcus pneumoniae (Sp) (57), or Haemophilus influenzae (Hi) (30). From 2007 through 2009, the serogroup W135 represented 98.8% of 164 case isolates. Until 2008, most serogroup W135 isolates presented the sequence-type ST-2881 usually associated with sporadic cases. Since 2009, the ST-11 (an epidemic associated clone) became predominant, although no epidemic occurred. Serogroup A ST-7 was observed in 2010 and caused a localized epidemic. Using the detection PCR on turbid CSF, a 2.7-fold increase in cases with etiologic diagnosis was obtained, compared to culture. All tested meningococcal isolates (42) were susceptible to ampicillin, chloramphenicol, and cefotaxim. CONCLUSIONS: Resurgence of serogroup A and recent increase in ST-11 among serogroup W135 isolates were worrying when considered with the epidemic wave of serogroup A meningitis, which affected neighboring countries and the serogroup W135 epidemic in Niger in 2009-2010. PMID- 23432861 TI - An analysis of the prevalence of malaria in Turkey over the last 85 years. AB - BACKGROUND: Affecting 106 countries, malaria is a major global burden. Though intensive antimalaria efforts in Turkey have been successful in bringing down the number of cases, historically malaria was a serious public health concern. METHODS: This paper reviews the prevalence rates of malaria in Turkey over the last 85 years (1925-2010). The time series of malaria prevalence was evaluated for possible structural changes by using Chow breakpoint tests and regression models using dummy variables, with autocorrelated errors and generalized autoregressive conditional heteroscedasticity models to assess the impact of volatility in prevalence. RESULTS: Seventy-eight cases of malaria were diagnosed in Turkey in 2010. Malaria prevalence rates in the country show a statistically significant volatility, which underlines the fragility of efforts to control the disease. CONCLUSIONS: It is necessary to analyse the national malaria control programme to evaluate to what extent its programmatic capacity, financial resources, and political commitment are sufficient to avoid eroding the gains that have already been made and, ultimately, eradicate malaria. It is essential that there should be no lessening in the long-standing efforts to reduce malaria. PMID- 23432860 TI - Association of high plasma TNF-alpha levels and TNF-alpha/IL-10 ratios with TNF2 allele in severe P. falciparum malaria patients in Sri Lanka. AB - Plasma levels of pro- and anti-inflammatory cytokines of Plasmodium falciparum infected patients with severe malaria (SM; n = 62) and uncomplicated malaria (UM; n = 69) from Sri Lanka were assessed. SM patients had significantly higher levels of TNF-alpha (P < 0.01), IL-6 (P < 0.01), and IL-10 (P < 0.05) compared to the UM patients. Plasma IL-2 levels of these patients were undetectable. TNF-alpha levels of a third group of patients with uncomplicated P. falciparum malaria, who were recruited during their fever episodes (UMF; n = 14) were significantly higher than those of the UM patients (P < 0.001) and comparable to SM patients. Plasma IFN-gamma levels of SM patients were higher compared to UM patients, but was not statistically significant. Body temperature in both SM and UMF groups were significantly higher compared to UM group, whereas percentages of parasitemia in all three groups were comparable. Analysis of plasma TNF-alpha levels and the ratio of TNF-alpha/IL-10 in UM (n = 34) and SM (n = 34) patients carrying TNF1 and TNF2 allelic types showed that SM patients carrying TNF2 had significantly higher TNF-alpha levels as well as TNF-alpha/IL-10 ratio compared to UM patients carrying TNF1, UM patients carrying TNF2 and SM patients carrying TNF1 (P < 0.05). These results suggest that the high circulating TNF-alpha levels and the inadequate IL-10 response in the SM patients carrying TNF2 allele could have contributed to the development of severe falciparum malarial disease. PMID- 23432862 TI - Isolated tuberculous liver abscess in immunocompetent children - report of two cases. AB - Isolated tuberculous liver abscess (TLA) without active pulmonary or miliary tuberculosis, or other clinical evidence of tuberculosis, is distinctly rare and only few cases have been reported in the literature. We report two cases of isolated TLA in immunocompetent children, treated successfully by percutaneous aspiration followed by systemic antituberculous drugs. PMID- 23432863 TI - Co-infection with Cyclospora cayetanensis and Salmonella typhi in a patient with HIV infection and chronic diarrhoea. AB - A 45-year-old-Haitian male patient with fever, abdominal cramping, chronic diarrhoea and weight loss of about 3 kg was investigated. Stool examination revealed Salmonella typhi and Cyclospora cayetanensis. The HIV test was positive with a CD4 count of 130 cells/mm(3). We provided the first report of co infection Cyclospora cayetanensis and Salmonella typhi in a HIV patient with chronic diarrhoea. The patient was treated with oral ciprofloxacin, 500 mg, twice daily for two weeks, with a good clinical outcome. PMID- 23432864 TI - Pleuropulmonary paragonimiasis: mimicker of tuberculosis. AB - Infection caused by the lung fluke is endemic in north eastern parts of India. Paragonimus westermani and Paragonimus heterotremus are known to be endemic in eastern Indian states of Manipur and Nagaland. The infection is related to eating habits of the locals and is acquired by ingestion of raw, inadequately cooked crabs or crayfish containing encysted metacercariae which act as second intermediate hosts during the life cycle of the lung fluke. Diagnosis is generally delayed due to lack of suspicion and presentation similar to tuberculosis which is endemic in the population. We report pleuropulmonary paragonimiasis in a soldier from eastern India who presented with chest pain, haemoptysis, and eosinophilia. He gave history of consumption of raw crabs while on leave at his native village in Nagaland. Ova morphologically resembling Paragonimus heterotremus were detected in sputum and bronchoalveolar lavage specimen. Symptoms resolved with praziquantel treatment. PMID- 23432865 TI - Predictors of outcome following endoscopic thoracic sympathectomy. AB - BACKGROUND: Endoscopic thoracic sympathectomy (ETS) provides definitive management for primary focal hyperhidrosis and facial blushing. These conditions are debilitating and not uncommon, but many clinicians avoid ETS due to the risk of complications, particularly compensatory sweating (CS). This retrospective cohort study aimed to evaluate the degree of symptom resolution, patient satisfaction and adverse reactions after ETS and to identify subgroups of patients more likely to achieve a satisfactory outcome. METHODS: From 2004 to 2010, 210 patients underwent ETS performed by a single surgeon. These patients responded to a questionnaire regarding levels of satisfaction, symptom resolution and complications encountered, particularly CS. RESULTS: Palmar hyperhidrosis (97%) and scalp/facial hyperhidrosis (93%) demonstrated greater degrees of symptom resolution than axillary hyperhidrosis (71%) and facial blushing (71%) (P < 0.001). Rates of severe CS were lowest in patients with palmar hyperhidrosis (8%) and highest in patients with axillary (26%) and scalp/facial (44.5%) hyperhidrosis (P = 0.0003). The probability of experiencing no CS was highest at young ages and decreased with age (P = 0.0006). Satisfaction rates also fell as age increased (P = 0.004). Satisfaction rates were highest in patients with palmar (90%) and lowest in patients with scalp/facial (52%) hyperhidrosis (P < 0.02). DISCUSSION: Patient satisfaction following ETS is highest among younger patients and those undergoing the procedure for palmar hyperhidrosis. Dissatisfaction arises from failure to achieve the desired aim as well as the development of severe CS, which is more common in older patients and those undergoing ETS for axillary and scalp/facial hyperhidrosis. PMID- 23432866 TI - Reproductive immunology: piece by piece. PMID- 23432867 TI - Natural killer cells in human pregnancy. AB - While conventional NK cells play an important role in early defenses against pathogens thanks to their cytolytic activity and production of pro-inflammatory chemokines and cytokines, those present in decidua (dNK cells), during early pregnancy, are primarily involved in tissue building and remodeling and in the formation of new blood vessels. This occurs mainly via the release of IL-8, VEGF, SDF-1 and IP-10. In addition, we show that by interacting with particular myelomonocytic cells (dCD14(+)) they contribute to the induction of regulatory T cells (Tregs). In turn, Tregs are thought to play a pivotal role in immunosuppression and induction of tolerance toward the fetal allograft. We recently demonstrated that CD34(+) hematopoietic precursors (dCD34(+)) are present in decidual tissues, thus suggesting that dNK cells might derive from such precursors. Indeed, this was confined by in vitro experiments in which dCD34(+) cells differentiated into dNK cells upon culture with appropriate cytokine combinations or even in co-culture with decidua-derived stromal cells (dSC). It is possible to speculate that inappropriate cellular interactions in the decidual microenvironment or defects of dNK (or dCD14(+)) cell generation might negatively influence pregnancy success. PMID- 23432868 TI - Immune aspects of embryo-maternal cross-talk in the bovine uterus. AB - This mini-review summarizes the results of recent transcriptome studies of bovine endometrium during the estrous cycle and during the pre-implantation phase, with a focus on immune response genes. Gene expression changes in the bovine endometrium during the estrous cycle were compared to a similar study in equine endometrium. The results indicate species-specific expression patterns, particularly for genes with immune functions. These are presumably the consequence of adaptations to differences in the physiology of reproduction in each species, including development of the conceptus, hormone profiles during the estrous cycle, and insemination. The results from a number of transcriptome studies during the pre-implantation phase, as well as comparison to the effects of human interferon alpha on bovine endometrial gene expression, suggest that during pregnancy there is no general suppression of the maternal immune system, but rather a fine-tuned regulation of immune cells. This presumably facilitates tolerance to the immunologically 'foreign' conceptus and at the same time activation of the immune system to defend against microbial and viral infections. Furthermore, comparison of differentially expressed genes in bovine endometrium to similar studies in human endometrial samples reveals a number of similar changes, indicating the existence of shared mechanisms in preparation for embryo implantation. PMID- 23432869 TI - Pregnancy-acquired fetal progenitor cells. AB - The transfer and persistence of fetal progenitor cells into the mother throughout pregnancy has sparked considerable interest as a trafficking stem cell and immunological phenomenon. Indeed, the intriguing longevity of semi-allogeneic fetal microchimeric cells (FMC) in parous women raises questions over their potential clinical implications. FMC have been associated with both immune modulatory roles and participation in maternal tissue repair. Although their influence on maternal health is as yet unresolved, FMC selectively home to damaged maternal tissues and often integrate, adopting site-appropriate phenotypes. FMC features, such as plasticity and persistence in their maternal host, suggest that they likely include pluripotent, or various multipotent and committed stem and progenitor cells. Recent efforts to determine what cell types are involved have established that FMC include cells of ectodermal, endodermal, mesodermal, and perhaps trophectodermal lineages. This review details FMC phenotypes and discusses how FMC themselves may be considered a naturally occurring stem cell therapy. PMID- 23432870 TI - Immune balance at the foeto-maternal interface as the fulcrum of reproductive success. AB - Viviparity has many evolutionary advantages but brings with it the problem of the semi-allogeneic foetus having to coexist with the mother for the duration of pregnancy. In species with haemochorial placentation this problem is particularly evident as foetal trophoblast cells are extensively intermingled with maternal tissue and are directly exposed to maternal blood. Fascinating adaptations on both the foetal and maternal side have allowed for this interaction to be re directed away from an immune rejection response not only towards immunotolerance, but in fact towards actively supporting reproductive success. Recent data have shown that some of these remarkable adaptations are conserved between mice and humans. Thus, a subset of trophoblast cells that is directly exposed to the maternal uterine environment shares the feature of expressing an unusual antigen repertoire on their surface. Paternal antigens can be recognized by maternal immune cells, in particular uterine natural killer cells that express cognate receptors, to regulate the extensive remodelling events that take place at the implantation site. Detailed genetic dissection experiments in the mouse have further demonstrated the direct impact of antigenic dissimilarity on foetal growth. With the availability of inbred strains, in vitro culture systems of trophoblast stem cells, and in-depth genetic, genomic and epigenomic data the mouse will be a valuable model system to study the intricate immune crosstalk at the foeto-maternal boundary. These insights will pave the way towards unravelling the mutual and synergistic interactions between trophoblast and its surrounding maternal environment, and in doing so help understand pregnancy pathologies. PMID- 23432871 TI - The role of progesterone in implantation and trophoblast invasion. AB - With its genomic and non-genomic actions, progesterone plays a role in preparing the endometrium for implantation and also in regulating trophoblast invasion and migration. The genomic actions of progesterone are mediated by the classical nuclear progesterone receptors, PR-A and PR-B. In addition to their genomic actions, nuclear progesterone receptors may also trigger rapid cytoplasmic signalling events. Membrane-bound progesterone receptors have been implicated in the rapid non-genomic actions of progesterone. Both genomic and extra-nuclear actions of progesterone are crucial for adequate decidualisation and implantation. Progesterone plays a role in establishing uterine receptivity by blocking the proliferative effect of oestrogen, by inducing genes that allow the endometrium to permit embryo attachment, and also acts as a negative regulator of trophoblast invasion by controlling matrix metalloproteinase (MMP) activity. PMID- 23432872 TI - Pregnancy-associated miRNA-clusters. AB - MicroRNAs (miRNAs) are expressed in the placenta and can be detected in maternal plasma. An increasing number of studies have been published on the cellular origin, distribution and function of miRNAs in pregnancy. Specific miRNA profiles have been described for the placenta, maternal plasma and several pregnancy disorders. It has been observed that numerous miRNAs, which are predominantly or exclusively expressed during pregnancy, are clustered in chromosomal regions, may be controlled by the same promoters, may have similar seed regions and targets, and work synergistically. The three most eminent clusters are the chromosome 19 miRNA cluster (C19MC), C14MC and miR-371-3 cluster, which is also localized on chromosome 19. MiRNA members of these clusters are not only detected in the placenta, but also in other compartments, e.g. in serum where they have the potential to become novel biomarkers of pregnancy disorders. Additionally, some members are also expressed in a variety of tumors. Antagonism of selected miRNAs or their targets may lead to novel strategies for the development of new drug classes in pregnancy disorders or other diseases. This review summarizes current knowledge on the pregnancy-related miRNA clusters - the C19MC, C14MC and miR-371 3 cluster - in regard to pregnancy and also other, mostly pathological circumstances. PMID- 23432873 TI - From mice to women: the conundrum of immunity to infection during pregnancy. AB - Resistance to infection is the ability of the host to evoke a strong immune response sufficient to eliminate the infectious agent. In contrast, maternal tolerance to the fetus necessitates careful regulation of immune responses. Successful pregnancy requires the maternal host to effectively balance the opposing processes of maternal immune reactivity and tolerance to the fetus. However, this balance can be perturbed by infections which are recognized as the major cause of adverse pregnancy outcome including pre-term labor. Select pathogens also pose a serious threat of severe maternal illness. These include intracellular and chronic pathogens that have evolved immune evasive strategies. Murine models of intracellular bacteria and parasites that mimic pathogenesis of infection in humans have been developed. While human epidemiological studies provide insight into maternal immunity to infection, experimental infection in pregnant mice is a vital tool to unravel the complex molecular mechanisms of placental infection, congenital transmission and maternal illness. We will provide a comprehensive review of the pathogenesis of several infection models in pregnant mice and their clinical relevance. These models have revealed the immunological function of the placenta in responding to, and resisting infection. Murine feto-placental infection provides an effective way to evaluate new intervention strategies for managing infections during pregnancy, adverse fetal outcome and long-term effects on the offspring and mother. PMID- 23432875 TI - Animal models for anti-angiogenic therapy in endometriosis. AB - Endometriosis is a gynecological disease characterized by the growth of endometrium outside of the uterine cavity. It is often associated with dysmenorrhea, dyspareunia, pelvic pain and infertility. One of the key requirements for endometriotic lesions to survive is development of a blood supply to support their growth. Indeed, dense vascularization is characteristic feature of endometriotic lesions. This has led to the idea that suppression of blood vessel growth (anti-angiogenic therapy) may be a successful therapeutic approach for endometriosis. Potential effectiveness of anti-angiogenic therapies has been assessed in some animal models but there are no reports of human clinical trials. Without understanding the specific mechanism by which endometriosis lesions establish a new blood supply, short-term animal experiments will have limited value for translation into human medicine. Further, it is crucial to use appropriate animal models to assess efficacy of anti-angiogenic compounds. Syngeneic and autologous rodent models, where endometrial fragments are auto-transplanted into the peritoneal cavity are commonly used in anti angiogenic therapy studies. Another approach is xenograft models where human endometrium is engrafted into immunodeficient mice. Here we review the animal models and experimental techniques used to evaluate anti-angiogenic therapies for endometriosis. We also review our own work on the role of stromal cell derived factor-1 in the recruitment of endothelial progenitor cells in endometriotic lesion angiogenesis, and the effects of the anti-angiogenic peptide ABT-898, a thrombospondin-1 mimetic, on endometriotic lesion growth and vascular development. PMID- 23432876 TI - Inducers of G-protein coupled estrogen receptor (GPER) in endometriosis: potential implications for macrophages and follicle maturation. AB - Endometriosis is an estrogen dependent chronic inflammation and thus a condition of stress. Though the G-protein coupled estrogen receptor (GPER) has been shown to be up-regulated in ovarian endometriosis, insights involved in inducing this receptor expression are largely elusive. Therefore, this study investigated whether stress-related factors (ACTH, prednisolone) or inflammatory factors (IL 1beta, TNFalpha, and PGE(2)) factors may affect GPER. To further link GPER to endometriosis pathophysiology it was tracked in macrophages and follicles of endometriotic ovaries. This study found GPER expression to be modulated by stress related hormones as well as inflammation and to be up-regulated in endometriosis associated macrophages. At the same time, follicles of ovaries affected by endometriosis presented significantly reduced GPER positivity when compared to controls, suggesting a possible way by which endometriosis may affect folliculogenesis. The multiple roles of GPER as presented herein make it a promising future candidate for targeted molecular endometriosis treatment. PMID- 23432874 TI - Innate and adaptive anti-HIV immune responses in the female reproductive tract. AB - The mucosal surface of the female reproductive tract (FRT) is the primary site of transmission for a plethora of sexually transmitted infections, including human immunodeficiency virus (HIV), that represent a significant burden upon womens' health worldwide. However, fundamental aspects of innate and adaptive immune protection against HIV infection in the FRT are poorly understood. The FRT immune system is regulated by the cyclical changes of the sex hormones estradiol and progesterone across the menstrual cycle, which as we have hypothesized, leads to the creation of a window of vulnerability during the secretory stage of the menstrual cycle, when the risk of HIV transmission is increased. The goal of this review is to summarize the multiple levels of protection against HIV infection in the FRT, the contribution of different cell types including epithelial cells, macrophages, T cells, and dendritic cells to this, and their regulation by estradiol and progesterone. Understanding the unique immune environment in the FRT will allow for the potential development of novel therapeutic interventions such as vaccines and microbicides that may reduce or prevent HIV transmission in women. PMID- 23432877 TI - Characterization of regulatory T cells in decidua of miscarriage cases with abnormal or normal fetal chromosomal content. AB - Decreased regulatory T (Treg) cells have been reported in cases of recurrent pregnancy loss. To understand the role of Treg cells in human pregnancy, we have studied the frequency, localization and characterization of Treg cells in the decidua. The frequency of Foxp3(+) cells among CD3(+)CD8(-) cells at the decidua basalis in cases of miscarriage with a normal embryo karyotype (n=10) was significantly lower than in normally progressing pregnancies (n=10). However, those frequencies in miscarriage with an abnormal embryo karyotype were similar to normally progressing pregnancies. Next, we used flow cytometry to study Treg cell expression of the proliferation marker Ki67 and functional Treg marker CCR5. The frequency of Foxp3(+)CD4(+) T cells in miscarriage with a normal embryo (n=10) was significantly lower than those in normally progressing pregnancies (n=15) and in miscarriage with an abnormal embryo (n=14). In miscarriage with a normal embryo, the population of Ki67(-)Foxp3(+)CD4(+) T cells was significantly smaller than in normal pregnancy. However, the frequencies of Ki67(+)Foxp3(+)CD4(+) cells and CCR5(+)Foxp3(+)CD4(+) cells were not different between the three groups. These data suggest that increased Ki67(-) Treg cells in the decidua basalis may play an important role in the induction of immune tolerance, and that immune-medicated pregnancy loss may be caused by decreased Ki67(-) Treg cells in the implantation site. PMID- 23432878 TI - Resistin concentration and gestational diabetes: a systematic review of the literature. AB - Gestational diabetes (GD) exposes mothers and infants to the risk of immediate and later adverse outcomes. Increased insulin resistance is a common feature of GD and obesity. Because of its critical role in regulating insulin sensitivity, resistin has been implicated in the physiopathology of GD. The aim of this study was to review the existing literature on the relationship between circulating maternal resistin levels and GD. Three electronic databases (MEDLINE, EMBASE, and LILACS) were searched for pertinent studies published from 2001 to 2012, without language restrictions. Eleven studies, with a total of 639 participants between 23 and 41 weeks of gestation, were included. The number of GD patients per study ranged from 11 to 81, with varying degrees of disease severity and several different GD diagnostic criteria. Mean concentrations of resistin varied widely both in control women (0.05-22.21 ng/ml) and in GD patients (0.05-62.38 ng/ml). We performed a meta-analysis including a total of 10 studies, and also subgroup analyses according to gestational age at sample collection (up to 32 and >33 weeks). The pooled absolute mean difference (WMD) in resistin levels was slightly lower in GD patients than in controls, but this did not reach statistical significance (WMD=-0.02, 95% CI -0.07 to 0.04). According to the data from the 11 studies analyzed, there was no association between circulating resistin levels and GD. However, this result should be interpreted with caution owing to the large heterogeneity amongst the existing published studies. PMID- 23432879 TI - Acetaminophen and pregnancy: short- and long-term consequences for mother and child. AB - Counter-intuitively, over-the-counter medication is commonly taken by pregnant women. In this context, acetaminophen (APAP, e.g. Paracetamol, Tylenol) is generally recommended by physicians to treat fever and pain during pregnancy. Thus, APAP ranks at the top of the list of medications taken prenatally. Insights on an increased risk for pregnancy complications such as miscarriage, stillbirth, preterm birth or fetal malformations upon APAP exposure are rather ambiguous. However, emerging evidence arising from human trials clearly reveals a significant correlation between APAP use during pregnancy and an increased risk for the development of asthma in children later in life. Pathways through which APAP increases this risk are still elusive. APAP can be liver toxic and since APAP appears to freely cross the placenta, therapeutic and certainly toxic doses could not only affect maternal, but also fetal hepatocytes. It is noteworthy that during fetal development, the liver transiently functions as the main hematopoietic organ. We here review the effect of APAP on metabolic and immunological parameters in pregnant women and on fetal development and immune ontogeny in order to delineate novel, putative and to date underrated pathways through which APAP use during pregnancy can impair maternal, fetal and long term children's health. We conclude that future studies are urgently needed to reconsider the safety and dosage of APAP during pregnancy and - based on the advances made in the field of reproduction as well as APAP metabolism - we propose pathways, which should be addressed in future research and clinical endeavors. PMID- 23432880 TI - Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system of presumed autoimmune origin. Intriguingly, pregnancy in female MS patients is associated with a substantial decrease in relapse rate. However, post-partum the relapse rate increases in a rebounding fashion above the rate seen before pregnancy. Wide gaps remain in our understanding of the biological mechanisms underlying these pregnancy-related effects in MS patients. To date, most attempts to explain MS disease amelioration during pregnancy have focused on levels of circulating hormones with immunomodulatory properties such as estrogens and global shifts in systemic maternal immune cell composition. However, recent advances in our understanding of feto-maternal tolerance have provided evidence that fetal antigens directly interact with the maternal immune system. This results in specific immunomodulation such as fetal-antigen-dependent induction of regulatory T cells. Thus, the "shaping" of maternal immune responses by fetal antigens may represent an endogenous pathway by which antigen-specific immunomodulation might also contribute to reinstalling tolerance to autoantigens in MS. Reproductive immunology therefore has great potential to provide insights into MS immunopathogenesis and highlight novel avenues for treatment of MS and other autoimmune diseases. PMID- 23432881 TI - Alcohol, hospital admissions, and falls in older adults: a longitudinal evaluation. AB - BACKGROUND: There are limited data on the impacts of alcohol use in older adults. We aimed to evaluate self-reported hospital admissions and falls against current Australian alcohol consumption guidelines. METHODS: We conducted a longitudinal analysis of data from five Australian cohort studies. The study comprised 16,785 people aged 65 years or older at baseline. Alcohol consumption was categorized using Australian guidelines in standard (10 g) drinks per day as "abstinent," "low-risk" (>0 <=2), "long-term risk" (>2 <=4), or "short-term risk" (>4). Separate generalized estimating equations for men and women, controlling for key demographic, and health variables (depression, diabetes, circulatory and musculoskeletal conditions) were used to examine the relationship of alcohol consumption with hospitalization and falls against a reference category of low risk consumption. RESULTS: Most participants were in the low (10,369, 62%) or abstinent (5,488, 33%) categories. Among women, all alcohol groups had greater odds of admission than low-risk users; among men, only the abstinent group had increased odds. For both genders, depression, diabetes, circulatory and musculoskeletal conditions all increased the odds of admission. For both genders, the unadjusted model showed that abstainers had increased odds of falling, with depression, diabetes, and for women, musculoskeletal conditions also associated with falls in the adjusted model. CONCLUSION: These outcomes suggest that older women in particular could benefit from targeted alcohol consumption messages or interventions. In relation to falls, other health conditions appear better targets for intervention than alcohol use. PMID- 23432882 TI - Spontaneous vaginal delivery or caesarean section? What do Turkish women think? AB - The aim of this study was to describe women's feelings, attitudes and beliefs about different modes of childbirth. A descriptive cross-sectional study was conducted at the obstetrics clinics of Ege University and Dr Ekrem Hayri Ustundag Obstetrics and Gynaecology Hospital in Izmir, Turkey. Three-hundred forty-two women who had given birth via spontaneous vaginal delivery (SVD) or caesarean section (C/S) between June and December 2009 voluntarily agreed to participate. Fifty-seven per cent of participants were aged 20-24. Sixty per cent of the women (n = 205) had undergone C/S during their last delivery; among these women, the birth method of 90% (n = 185) was decided by their doctors, whereas the remaining 10% (n = 20) made the decision themselves or with their partners. Sixty-three per cent (n = 250) of women who underwent C/S said that if they gave birth again, they would prefer to deliver via SVD. Eighty-eight per cent (n = 300) of women wanted the legal right to choose their birth method. Although the rate of C/S was high, most women stated that if given the choice, they would prefer a SVD if they had another child. PMID- 23432883 TI - Paediatric nurses' experience with death: the effect of empathic tendency on their anxiety levels. AB - The purpose of this descriptive and analytic study is to investigate the effect on anxiety levels of nurses' empathic tendency after experiencing death of patients in the paediatric intensive care unit. No sampling method was used in this study, and all 58 nurses working in the paediatric intensive care unit that agreed to participate in the study were included. The score mean of Empathic Tendency Scale for nurses was 77.43 +/- 4.55, their score mean of trait anxiety inventory was 39.82 +/- 5.53 and their score mean of state anxiety inventory was 48.03 +/- 6.80. This study concluded that nurses had a mild trait anxiety level under normal conditions and experienced moderate anxiety levels when faced with death. This study concluded that the empathic tendency of nurses working in the paediatric intensive care unit had no effect on their anxiety levels when faced with death; however, the anxiety level of nurses decreased as their empathic trends increased. PMID- 23432884 TI - Effect of anxiety and depression on self-care agency and quality of life in hospitalized patients with chronic obstructive pulmonary disease: a questionnaire survey. AB - Chronic obstructive pulmonary disease (COPD) affects the lives of individuals in a number of ways; it causes an increase in the need for help and support and a decline in self-care agency and quality of life. This research has been conducted in patients with COPD hospitalized in the Pulmonary Department of Erzincan State Hospital in the eastern Turkey to examine the effect of anxiety and depression on self-care agency and quality of life (n = 135). The results showed that 69.6% and 85.6% of the patients were at risk for anxiety and depression, respectively, and that the mean scores of self-care agency and quality of life decreased as the mean scores of anxiety and depression increased. It was also established that the mean score of the quality of life increased as the mean score of self-care agency went up. It could be concluded that the majority of the patients are at risk for anxiety and depression and that presence of anxiety or depression has a negative effect on the self-care agency and the quality of life. The recognition and treatment of depression and anxiety in patients with COPD provide significant improvements in self-care agency and quality of life of patients. PMID- 23432885 TI - An exploration of graduate nurses' perceptions of their preparedness for practice after undertaking the final year of their bachelor of nursing degree in a university-based clinical school of nursing. AB - The nursing literature continues to give ongoing attention to university-educated nurses' preparedness for practice in the first year following graduation. This interpretive descriptive study explored the impact of a university-based clinical school of nursing experience on graduate nurses' perceptions of their preparedness for practice. Ten registered nurses who undertook their graduate year programme in the same hospital where they attended the university-based clinical school of nursing were interviewed. The interviews were audio-recorded, transcribed verbatim, and analysed to reveal themes and categories. Thematic data analysis revealed three themes: 'being situated in a clinical school within a hospital', 'the university away from the university' and 'engagement with practice'. The outcome of the experience of being situated in a university-based clinical school of nursing contributed to the participants' sense of being prepared for practice as a graduate nurse. PMID- 23432886 TI - Factors affecting health status in patients with chronic obstructive pulmonary disease. AB - The aim of this study is to determine the correlation between the quality of life (QOL) and subjective dyspnoea, subjective fatigue, sleep quality, and the forced expiratory volume in first second (FEV(1)) % predicted value and collective contribution of these variables on QOL. The study was conducted with 102 patients. Pulmonary function tests (FEV(1) % predicted value, FEV(1) /forced vital capacity), subjective dyspnoea, subjective fatigue, sleep quality were assessed. There were negative correlations between QOL total score and pulmonary function tests, positive correlations between QOL total score and subjective dyspnoea score, subjective fatigue and sleep quality total scores. In addition, subjective dyspnoea, subjective fatigue and sleep quality total scores and FEV(1) % predicted value accounted for 68.1% of the variance on QOL. As a conclusion of these findings, it has been recommended that these variables should be considered when planning an approach towards improving the QOL in chronic obstructive pulmonary disease patients. PMID- 23432887 TI - The relational model of spiritual engagement depicted by palliative care clients and caregivers. AB - This paper aims to explicate the essence of spiritual engagement from the perspective of palliative care clients and their caregivers. Van Manen's hermeneutic phenomenological approach guided this study. In-depth interviews of 14 rural Australian participants with experience of a life-limiting condition provided rich discourse of the lived experience of spiritual engagement. This research highlights spiritual engagement represented in a relational model developed from a creative synthesis of the emerging themes. Spiritual engagement is associated with 'personal transformation', 'human values of love, compassion and altruism', 'maintaining relationships', 'participating in religious practices' and 'culture'. The findings of this research are supported by Mayes' observations on spirituality, that is, the 'pursuit of a trans-personal and trans temporal reality that serves as the ontological ground for an ethic of compassion and service'. PMID- 23432888 TI - Knowledge about anti-tuberculosis treatment among nurses at tuberculosis clinics. AB - Nurses are primary responsible for Direct Observation Therapy Strategy and administration of anti-tuberculosis (TB) medications. Lack of knowledge might result with medication errors and ineffective TB control. The purpose of this study was to assess knowledge of nurses about anti-TB treatment. A descriptive cross-sectional study was conducted in Turkey with 208 nurses employed at TB and lung disease clinics of health-care settings in Ankara. Data were collected through a questionnaire, which included questions about demographics and a knowledge test with true-false questions related to TB treatment. Overall scores were high with a mean score of 18.5 out of 24, but there was knowledge deficiency in effects and side-effects of anti-TB drugs. Knowledge is foundational for any practice and for TB control. Clinical experience and continuing education after graduation influence the level of knowledge. PMID- 23432889 TI - The feasibility, acceptability and sustainability of nurse-led chronic disease management in Australian general practice: the perspectives of key stakeholders. AB - This was the first Australian study investigating the acceptability, feasibility and sustainability of a nurse-led model of chronic disease management in general practice. A concurrent mixed-methods design was used within a 12-month intervention of nurse-led care in three general practices. Adult patients with type 2 diabetes, hypertension and/or stable ischaemic heart disease were randomized into nurse-led or standard care. Semi-structured interviews explored perceptions of key stakeholders towards this model including patients in the nurse-led arm, and all practice staff pre- and posttrial. The data were thematically analysed and the emergent themes were: importance of time; collaborative relationships; nurse job satisfaction, confidence and competence; patient self-management and choice. Our findings showed that nurses provided chronic disease management that was acceptable, feasible and sustainable. The collaborative involvement of doctors was intrinsic to patient acceptability of nurse-led care that facilitated job satisfaction, and therefore retention and growth within this nursing speciality. PMID- 23432890 TI - Venous thromboembolism (VTE) risk assessment: rural nurses' knowledge and use in a rural acute care hospital. AB - It is estimated that about 2000 people die as a result of venous thromboembolism (VTE) each year, with a further 30,000 being hospitalized. Prophylaxis significantly reduces VTE morbidity and mortality, and thus represents a real long-term health-care benefit. The aim of this study was twofold: (i) to assess the current level of compliance to VTE risk assessment and prophylaxis best practice guidelines within an Australian rural hospital; and (ii) to determine the effectiveness of nurse education on that compliance. VTE compliance information was obtained from auditing patient notes for a 3-month period prior to nurse education and was repeated after the education. Nurse knowledge of VTE risk assessment and prophylaxis use was also measured. Both compliance with and knowledge of best practice VTE risk assessment and prophylaxis increased following nurse education. Although the sample size was relatively small, this study has shown nurse education to be effective at increasing VTE compliance and awareness within an Australian rural hospital. This relatively inexpensive and simple intervention bears consideration and could lead to reductions in the morbidity and mortality associated with VTE, as well as reduction in associated health-care costs. PMID- 23432891 TI - Determination of the use of traditional practices to ease labour among Turkish women. AB - The purpose of this study was to determine the use of traditional practices to ease labour among Turkish women. Face-to-face interviews were conducted with 809 women by using an investigator-designed questionnaire. The mean age of the women was 28.9 +/- 8.33 years (min = 15, max = 74), 49.4% were between 20-29 years of age and more than half (56.2%) of the women had had one to two pregnancies. The results showed that traditional practices were known and applied mostly by the women who were at an advanced age, less educated and who lived in rural areas. In addition, the knowledge and application status of traditional practices related to religious beliefs were found to be very high compared with superstitious practices. It was suggested that nurses provide culturally competent care that requires a commitment by the individual nurse to develop, refine and use specific skills in the care of women. PMID- 23432892 TI - Burden experienced by community health volunteers in Taiwan: a qualitative study. AB - In Taiwan, volunteers of each Community Health Promotion Development Centres help to diffuse healthy lifestyle education and complement the paid workforce, especially community nurses. An interpretive, descriptive qualitative design, using focus groups, was conducted to explore the burden experienced by community health volunteers in Taiwan. The data were analyzed inductively, and emergent themes were explored. The majority of participants were female between 50 and 59 years old with an average of 4.5 years experience as a volunteer. Thematic analysis resulted in four themes: preparation and scope of practice, lack of support for the role, work overload and expectations of the role. Volunteers in Taiwan do not always have the necessary skills to care for their clientele because of an inadequate programme of orientation, lack of continuing education and support for the role, role overload and expectations placed upon them by the clients and others. PMID- 23432893 TI - Evaluation of nursing documentation on patient hygienic care. AB - This study was conducted to evaluate nursing documentation on patient hygienic care and to analyze the consistency between actual care given by nurses and that of documented in nursing record. Data were collected from 85 nurses employed at critical care units, on whom 255 sets of observations were performed through a structured participant observation form, which could be used to record the observation episodes and to audit nursing records. Results indicated that the most frequent performed hygienic care was oral care, perianal care, hand washing and bed bathing. The consistency between actual patient hygienic care and its documentation was 77.6%. The quality of nursing records was poor and inadequate to reflect individualized nursing care. Results suggest that more emphasis is needed in nursing practice and nursing education on the quality of record keeping in nursing to increase its evidential value. PMID- 23432894 TI - Intervention for ineffective airway clearance in asthmatic children: a controlled and randomized clinical trial. AB - This study aimed to analyse the effectiveness of an intervention for the nursing diagnosis of ineffective airway clearance in asthmatic children. A blinded, randomized and controlled clinical trial was developed in a paediatric hospital located on northeast of Brazil with 42 asthmatic children aged <= 36 months. The children were randomly divided into two groups (intervention and control) by means of a simple drawing. The applied intervention included actions related to change of positioning and stimulation of cough. The main findings of this study show that before the intervention, no significant difference was observed in the health status of the children. After the intervention, the indicators of choking (16.83 vs. 26.17, P = 0.007) and adventitious breath sounds (16.4 vs. 26.6, P = 0.005) were higher, on average, in the intervention group. It was observed an improvement in obstructive symptoms in children who received the intervention proposed. PMID- 23432895 TI - Improving the safety of continuously infused fluids in the emergency department. AB - When an unexpected crisis happens to patients with multiple continuous infusion fluids in the emergency department (ED), nurses need to recognize specific medication promptly and accurately for appropriate action. This study aims to evaluate the efficiency of colour-coded label system in ED fluids during an uneventful crisis simulation event. Promptness and accuracy of finding the correct fluid between the pre- and postintervention in each three groups (emergency nurses, intensive care unit nurses and nursing students) for three different scenarios (potassium, heparin and normal saline scenario) were assessed. Time improvement for all three groups from pre- to postintervention for all three scenarios were statistically significant (P < 0.001). There were no incorrect fluids indicated by all three groups of participants at postintervention analysis. Colour-coded labelling system in a simulated environment significantly improved the promptness and accuracy of finding the correct fluid from multiple infused continuous fluids. PMID- 23432896 TI - Developing scale for colleague solidarity among nurses in Turkey. AB - There is a need for an appropriate instrument to measure colleague solidarity among nurses. This study was carried out to develop a Colleague Solidarity of Nurses' Scale (CSNS). This study was planned to be descriptive and methodological. The CSNS examined content validity, construct validity, test retest reliability and internal consistency reliability. The trial form of the CSNS, which was composed of 44 items, was given to 200 nurses, followed by validity and reliability analyses. Following the analyses, 21 items were excluded from the scale, leaving an attitude scale made up of 23 items. Factor analysis of the data showed that the scale has a three sub-factor structure: emotional solidarity, academic solidarity and negative opinions about solidarity. The Cronbach's alpha reliability of the whole scale was 0.80. This study provides evidence that the CSNS possesses robust solidarity among nurses. PMID- 23432897 TI - Comparative genomics using teleost fish helps to systematically identify target gene bodies of functionally defined human enhancers. AB - BACKGROUND: Human genome is enriched with thousands of conserved non-coding elements (CNEs). Recently, a medium throughput strategy was employed to analyze the ability of human CNEs to drive tissue specific expression during mouse embryogenesis. These data led to the establishment of publicly available genome wide catalog of functionally defined human enhancers. Scattering of enhancers over larger regions in vertebrate genomes seriously impede attempts to pinpoint their precise target genes. Such associations are prerequisite to explore the significance of this in vivo characterized catalog of human enhancers in development, disease and evolution. RESULTS: This study is an attempt to systematically identify the target gene-bodies for functionally defined human CNE enhancers. For the purpose we adopted the orthology/paralogy mapping approach and compared the CNE induced reporter expression with reported endogenous expression pattern of neighboring genes. This procedure pinpointed specific target gene bodies for the total of 192 human CNE-enhancers. This enables us to gauge the maximum genomic search space for enhancer hunting: 4 Mb of genomic sequence around the gene of interest (2 Mb on either side). Furthermore, we used human rodent comparison for a set of 159 orthologous enhancer pairs to infer that the central nervous system (CNS) specific gene expression is closely associated with the cooperative interaction among at least eight distinct transcription factors: SOX5, HFH, SOX17, HNF3beta, c-FOS, Tal1beta-E47S, MEF and FREAC. CONCLUSIONS: In conclusion, the systematic wiring of cis-acting sites and their target gene bodies is an important step to unravel the role of in vivo characterized catalog of human enhancers in development, physiology and medicine. PMID- 23432898 TI - Prognostic factors for corneal graft recovery after severe corneal graft rejection following penetrating keratoplasty. AB - BACKGROUND: To investigate the outcome and prognostic factors for corneal graft recovery after severe corneal graft rejection following penetrating keratoplasty (PKP) treated with topical and systemic steroids. METHODS: Fifty-eight eyes in 58 patients with severe corneal graft rejection following PKP were treated with topical and systemic steroids. Factors affecting the reversibility and maintenance of graft transparency were analyzed. RESULTS: Graft transparency was restored in 37 of 58 eyes (63.8%). Clarity of the graft was maintained in 25 of 37 eyes after transparency was restored, while corneal decompensation developed at a mean of 6.0 +/- 4.3 months in the remainder. The interval between rejection and treatment with systemic steroids was shorter in cases that recovered graft transparency (OR, 0.88, 95% CI. 0.80-0.97, P = 0.0093). Corneal decompensation after the recovery of corneal transparency tend to occur in cases of regraft (OR, 0.09, 95% CI. 0.01-0.54, P = 0.0091). CONCLUSIONS: Severe corneal graft rejection after PKP was reversible in approximately two-thirds of the cases, with graft transparency being maintained in two-thirds of them when treated with both topical and systemic steroids. Early treatment confers a benefit in terms of the recovery of graft transparency. PMID- 23432900 TI - CDC and USPSTF 2012 recommendations for screening for hepatitis C virus infection: overview and take-home messages. PMID- 23432901 TI - The road ahead: what if gastroenterologists were accountable for preventing colorectal cancer? PMID- 23432899 TI - DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition. AB - BACKGROUND: The prevention of persistent human immunodeficiency virus type 1 (HIV 1) infection requires the clarification of the mode of viral transduction into resting macrophages. Recently, DNA double-strand breaks (DSBs) were shown to enhance infection by D64A virus, which has a defective integrase catalytic activity (IN-CA). However, the mechanism by which DSBs upregulate viral transduction was unclear. Here we analyzed the roles of DSBs during IN-CA independent viral transduction into macrophages. RESULTS: We used cellular systems with rare-cutting endonucleases and found that D64A virus integrated efficiently into the sites of artificially induced DSBs. This IN-CA-independent viral transduction was blocked by an inhibitor of ataxia telangiectasia mutated protein (ATM) but was resistant to raltegravir (RAL), an inhibitor of integrase activity during strand transfer. Moreover, Vpr, an accessory gene product of HIV 1, induced DSBs in resting macrophages and significantly enhanced the rate of IN CA-independent viral transduction into macrophages with concomitant production of secondary viruses. CONCLUSION: DSBs contribute to the IN-CA-independent viral infection of macrophages, which is resistant to RAL. Thus, the ATM-dependent cellular pathway and Vpr-induced DNA damage are novel targets for preventing persistent HIV-1 infection. PMID- 23432902 TI - MuRF-1 and p-GSK3beta expression in muscle atrophy of cirrhosis. AB - BACKGROUND: Chronic diseases, including cirrhosis, are often accompanied by protein-energy malnutrition and muscle loss, which in turn negatively affect quality of life, morbidity and mortality. Unlike other chronic conditions, few data are available on the molecular mechanisms underlying muscle wasting in this clinical setting. AIMS: To assess mechanisms of muscle atrophy in patients with cirrhosis. METHODS: Nutritional [subjective global assessment (SGA) and anthropometry] and metabolic assessment was performed in 30 cirrhotic patients awaiting liver transplantation. Rectus abdominis biopsies were obtained intraoperatively in 22 cirrhotic patients and in 10 well-nourished subjects undergoing elective surgery for non-neoplastic disease, as a control group. Total RNA was extracted and mRNA for atrogenes (MuRF-1, Atrogin-1/MAFbx), myostatin (MSTN), GSK3beta and IGF-1 was assayed. RESULTS: A total of 50% of cirrhotic patients were malnourished based on SGA, while 53% were muscle-depleted according to mid-arm muscle area (MAMA<5th percentile). MuRF-1 RNA expression was significantly increased in malnourished cirrhotic patients (SGA-B/C) vs. well nourished patients (SGA-A) (P = 0.01). The phosphorylation of GSK3beta was up regulated in cirrhotic patients with hepatocellular carcinoma (HCC) vs. patients without tumour (P < 0.05). CONCLUSIONS: Muscle loss is frequently found in end stage liver disease patients. Molecular factors pertaining to signalling pathways known to be involved in the regulation of muscle mass are altered during cirrhosis and HCC. PMID- 23432903 TI - Postnatal development of the renal medulla; role of the renin-angiotensin system. AB - Adverse events during foetal development can predispose the individual for cardiovascular disease later in life, a correlation known as foetal programming of adult hypertension. The 'programming' events have been associated with the kidneys due to the significant role in extracellular volume control and long-term blood pressure regulation. Previously, nephron endowment and functional consequences of a low nephron number have been extensively investigated without achieving a full explanation of the underlying pathophysiological mechanisms. In this review, we will focus on mechanisms of postnatal development in the renal medulla with regard to the programming effects. The renin-angiotensin system is critically involved in mammalian kidney development and impaired signalling gives rise to developmental renal lesions that have been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given. PMID- 23432904 TI - Genome-scale reconstruction and in silico analysis of Klebsiella oxytoca for 2,3 butanediol production. AB - BACKGROUND: Klebsiella oxytoca, a Gram-negative, rod-shaped, and facultative anaerobic bacterium, is one of the most promising 2,3-butanediol (2,3-BD) producers. In order to improve the metabolic performance of K. oxytoca as an efficient biofactory, it is necessary to assess its metabolic characteristics with a system-wide scope, and to optimize the metabolic pathways at a systems level. Provision of the complete genome sequence of K. oxytoca enabled the construction of genome-scale metabolic model of K. oxytoca and its in silico analyses. RESULTS: The genome-scale metabolic model of K. oxytoca was constructed using the annotated genome with biochemical and physiological information. The stoichiometric model, KoxGSC1457, is composed of 1,457 reactions and 1,099 metabolites. The model was further refined by applying biomass composition equations and comparing in silico results with experimental data based on constraints-based flux analyses. Then, the model was applied to in silico analyses to understand the properties of K. oxytoca and also to improve its capabilities for 2,3-BD production according to genetic and environmental perturbations. Firstly, in silico analysis, which tested the effect of augmenting the metabolic flux pool of 2,3-BD precursors, elucidated that increasing the pyruvate pool is primarily important for 2,3-BD synthesis. Secondly, we performed in silico single gene knockout simulation for 2,3-BD overproduction, and investigated the changes of the in silico flux solution space of a ldhA gene knockout mutant in comparison with that of the wild-type strain. Finally, the KoxGSC1457 model was used to optimize the oxygen levels during fermentation for 2,3-BD production. CONCLUSIONS: The genome-scale metabolic model, KoxGSC1457, constructed in this study successfully investigated metabolic characteristics of K. oxytoca at systems level. The KoxGSC1457 model could be employed as an useful tool to analyze its metabolic capabilities, to predict its physiological responses according to environmental and genetic perturbations, and to design metabolic engineering strategies to improve its metabolic performance. PMID- 23432905 TI - International recommendations for outpatient palliative care and prehospital palliative emergencies - a prospective questionnaire-based investigation. AB - BACKGROUND: To determine the international recommendations and current practices for the treatment and prevention of palliative emergencies. The primary goal of the study was to gather information from experts on their nationally practised concepts. METHODS: One hundred and fifty self-report surveys were distributed by email to selected leading experts (palliative and emergency medical care) in Europe, North and South America, Africa, Asia, and Australia. An expert in this context was defined as an author of an article that was ranked by three reviewers as relevant to outpatient palliative and emergency medical . RESULTS: The total response rate was 61% (n = 92 experts). Survey responses were obtained from 35 different countries. The following standards in the treatment of palliative emergencies were recommended: (1) early integration of "Palliative Care Teams" (PCTs) and basic outpatient palliative care systems, (2) end-of-life discussions, (3) defined emergency medical documents, drug boxes, and "Do not attempt resuscitation" orders and (4) emergency medical training (physicians and paramedics). CONCLUSIONS: This study detected structurally and nationally differences in outpatient palliative care regarding the treatment of palliative emergencies. Accordingly, these differences should be discussed and adapted to the respective specifications of individual single countries. A single established outpatient palliative emergency medical care concept may be the basis for an overall out-of-hospital palliative care system. PMID- 23432907 TI - Short-form Mini-Nutritional Assessment with either BMI or calf circumference is effective in rating the nutritional status of elderly Taiwanese -- results of a national cohort study. AB - The present study was aimed to validate two normalised short-form (SF) Mini Nutritional Assessments (MNA) that contained either BMI (Taiwan version 1, T1) or calf circumference (CC; Taiwan version 2, T2) for rating the nutritional status of elderly Taiwanese. Both versions adopted Taiwanese anthropometric cut-offs, but T2 further had the BMI item replaced by CC. We compared the ability of the two SF in rating the nutritional status of 2674 elderly Taiwanese in the 1999 'Taiwan Longitudinal Survey on Aging' with their respective full versions. We evaluated the agreement between the SF and full scales with weighted kappa and performed Cox regression analysis for the follow-up 4-year mortality according to nutritional status rated at baseline. The results showed that the agreements between the respective SF and the full MNA were good (weighted kappa: 0.679 for T1 and 0.667 for T2). Both SF performed well in predicting follow-up 4-year mortality relative to the full MNA. In conclusion, MNA-T1-SF and -T2-SF have good consistency with the full MNA and have quite comparable abilities in rating the nutritional status of elderly Taiwanese. Both SF versions appear appropriate for functioning as stand-alone units for rating the nutritional status of the elderly in community-living settings or the general population. PMID- 23432906 TI - Acute lower respiratory infections in >= 5 year -old hospitalized patients in Cambodia, a low-income tropical country: clinical characteristics and pathogenic etiology. AB - BACKGROUND: Few data exist on viral and bacterial etiology of acute lower respiratory infections (ALRI) in >= 5 year -old persons in the tropics. METHODS: We conducted active surveillance of community-acquired ALRI in two hospitals in Cambodia, a low-income tropical country. Patients were tested for acid-fast bacilli (AFB) by direct sputum examination, other bacteria by blood and/or sputum cultures, and respiratory viruses using molecular techniques on nasopharyngeal/throat swabs. Pulmonologists reviewed clinical/laboratory data and interpreted chest X-rays (CXR) to confirm ALRI. RESULTS: Between April 2007 - December 2009, 1,904 patients aged >=5 years were admitted with acute pneumonia (50.4%), lung sequelae-associated ALRI (24.3%), isolated pleural effusions (8.9%) or normal CXR-related ALRI (17.1%); 61 (3.2%) died during hospitalization. The two former diagnoses were predominantly due to bacterial etiologies while viral detection was more frequent in the two latter diagnoses. AFB-positive accounted for 25.6% of acute pneumonia. Of the positive cultures (16.8%), abscess-prone Gram-negative bacteria (39.6%) and Haemophilus influenzae (38.0%) were most frequent, followed by Streptococcus pneumoniae (17.7%). Of the identified viruses, the three most common viruses included rhinoviruses (49.5%), respiratory syncytial virus (17.7%) and influenza viruses (12.1%) regardless of the diagnostic groups. Wheezing was associated with viral identification (31.9% vs. 13.8%, p < 0.001) independent of age and time-to-admission. CONCLUSIONS: High frequency of H. influenzae and S. pneumoniae infections support the need for introduction of the respective vaccines in the national immunization program. Tuberculosis was frequent in patients with acute pneumonia, requiring further investigation. The relationship between respiratory viruses and wheezing merits further studies. PMID- 23432908 TI - The characterization and certification of a quantitative reference material for Legionella detection and quantification by qPCR. AB - AIMS: The characterization and certification of a Legionella DNA quantitative reference material as a primary measurement standard for Legionella qPCR. METHODS AND RESULTS: Twelve laboratories participated in a collaborative certification campaign. A candidate reference DNA material was analysed through PCR-based limiting dilution assays (LDAs). The validated data were used to statistically assign both a reference value and an associated uncertainty to the reference material. CONCLUSIONS: This LDA method allowed for the direct quantification of the amount of Legionella DNA per tube in genomic units (GU) and the determination of the associated uncertainties. This method could be used for the certification of all types of microbiological standards for qPCR. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of this primary standard will improve the accuracy of Legionella qPCR measurements and the overall consistency of these measurements among different laboratories. The extensive use of this certified reference material (CRM) has been integrated in the French standard NF T90-471 (April 2010) and in the ISO Technical Specification 12 869 (Anon 2012 International Standardisation Organisation) for validating qPCR methods and ensuring the reliability of these methods. PMID- 23432909 TI - Gastric non-secreting neuroendocrine tumor and hypochlorhydria-related hypergastrinemia: a case report. AB - INTRODUCTION: Zollinger-Ellison syndrome is characterized by recurrent peptic ulcers and diarrhea that result from gastrin-secreting neuroendocrine tumors of the gastrointestinal tract; nevertheless, severe hypergastrinemia may also have alternative pathogenetic explanations. CASE PRESENTATION: A 61-year-old woman of Caucasian origin presented with a history of epigastric pain and early satiety, severe hypergastrinemia (approximately 2000 pg/mL) and a neuroendocrine polyp in the corpus of her stomach. Chronic atrophic gastritis and intestinal metaplasia was present, but she denied use of acid suppressant drugs and the results of tests for Helicobacter pylori as well as gastric parietal cell and intrinsic factor antibodies were negative. She underwent a radical gastric tangential resection. Six months later, serum gastrin was still elevated despite lack of recurrence of tumor. CONCLUSION: The clinical picture was suggestive for a hypochlorhydria-related hypergastrinemia with subsequent development of a non secreting carcinoid. We suggest a periodic endoscopic follow-up in patients with severe hypochlorhydria-related hypergastrinemia in order to earlier detect neuroendocrine polyps. PMID- 23432910 TI - The effect of alkaline phosphatase and intrahepatic metastases in large hepatocellular carcinoma. AB - BACKGROUND: Hepatectomy is the standard treatment for HCC. However, large HCC poses a difficult challenge because of the technical complexity of surgical resection and the fear of postoperative hepatic decompensation. We analyzed the outcome and prognostic factors in patients with large hepatocellular carcinoma (HCC >=10 cm) after surgery. METHODS: We retrospectively investigated the medical records of 91 patients who had undergone hepatectomy between January 2006 and June 2010. A survival analysis was performed utilizing the Kaplan-Meier method and prognostic factors were evaluated using Cox regression analysis. RESULTS: Of the 91 patients evaluated, most tumors were associated with hepatitis B virus (HBV). The median tumor size was 12.3 cm (range, 10 to 21 cm), with microvascular invasion present in most patients. The postoperative mortality rate was 2.2%. The median disease-free survival and overall survival were six months and 41 months. The one-year, two-year, and three-year disease-free survival rates were 33.5%, 29.3%, and 18.8%, respectively. The one-year, two-year, and three-year overall survival rates were 73.9%, 63.7%, and 54.8%, respectively. Of the 89 surviving patients, 69 patients (77.5%) developed HCC recurrence during the mean follow-up period of 23.4 +/- 15.9 months. On multivariate analysis, the statistically significant factors that predicted HCC recurrence were ALP >= 80 IU/mL (P = 0.009) and intrahepatic metastases (P = 0.013). CONCLUSIONS: Our study suggests that preoperative ALP levels (>= 80 IU/L) and intrahepatic metastases could be utilized to monitor and predict recurrence in HCC patients. PMID- 23432911 TI - Optimal specimen collection and transport methods for the detection of avian influenza virus and Newcastle disease virus. AB - BACKGROUND: Active and passive surveillance for avian influenza virus (AIV) and Newcastle disease virus (NDV) is widespread in commercial poultry worldwide, therefore optimization of sample collection and transport would be valuable to achieve the best sensitivity and specificity possible, and to develop the most accurate and efficient testing programs. A H7N2 low pathogenicity (LP) AIV strain was selected and used as an indicator virus because it is present in lower concentrations in swabbings and thus requires greater sensitivity for detection compared to highly pathogenic (HP) AIV. For similar reasons a mesogenic strain of NDV was selected. Using oro-pharyngeal and cloacal swabs collected from chickens experimentally exposed to the viruses we evaluated the effects of numerous aspects of sample collection and transport: 1) swab construction material (flocked nylon, non-flocked Dacron, or urethane foam), 2) transport media (brain heart infusion broth [BHI] or phosphate buffered saline [PBS]), 3) media volume (2 ml or 3.5 ml), 4) transporting the swab wet in the vial or removing the swab prior to transport, or transporting the swab dry with no media, and 5) single swabs versus pooling 5 or 11 swabs per vial. RESULTS: Using real-time RT-PCR (rRT PCR), virus isolation (VI) and commercial antigen detection immunoassays for AIV we observed statistically significant differences and consistent trends with some elements of sample collection and transport; media, dry transport and swab construction. Conversely, the number of swabs pooled (1, 5 or 11) and whether the swab was removed prior to transport did not impact virus detection. Similarly, with NDV detection by both VI and rRT-PCR was not affected by the numbers of swabs collected in a single vial (1, 5 or 11). CONCLUSIONS: We observed that flocked and foam swabs were superior to non-flocked swabs, BHI media was better than PBS, and transporting swabs wet was better for virus recovery and detection than transporting them dry. There was no observable difference in detection whether the swab was removed prior to transport or left in the vial. Also, with both AIV and NDV, there was no observed difference in virus detection between pools of 1, 5 or 11 swabs. PMID- 23432912 TI - Structural and mechanistic principles of intramembrane proteolysis--lessons from rhomboids. AB - Intramembrane proteases cleave membrane proteins in their transmembrane helices to regulate a wide range of biological processes. They catalyse hydrolytic reactions within the hydrophobic environment of lipid membranes where water is normally excluded. How? Do the different classes of intramembrane proteases share any mechanistic principles? In this review these questions will be discussed in view of the crystal structures of prokaryotic members of the three known catalytic types of intramembrane proteases published over the past 7 years. Rhomboids, the intramembrane serine proteases that are the best understood family, will be the initial area of focus, and the principles that have arisen from a number of structural and biochemical studies will be considered. The site 2 metalloprotease and GXGD-type aspartyl protease structures will then be discussed, with parallels drawn and differences highlighted between these enzymes and the rhomboids. Despite the significant advances achieved so far, to obtain a detailed understanding of the mechanism of any intramembrane protease, high resolution structural information on the substrate-enzyme complex is required. This remains a major challenge for the field. PMID- 23432913 TI - Exploring factors influencing asthma control and asthma-specific health-related quality of life among children. AB - BACKGROUND: Little is known about factors contributing to children's asthma control status and health-related quality of life (HRQoL). The study objectives were to assess the relationship between asthma control and asthma-specific HRQoL in asthmatic children, and to examine the extent to which parental health literacy, perceived self-efficacy with patient-physician interaction, and satisfaction with shared decision-making (SDM) contribute to children's asthma control and asthma-specific HRQoL. METHODS: This cross-sectional study utilized data collected from a sample of asthmatic children (n = 160) aged 8-17 years and their parents (n = 160) who visited a university medical center. Asthma-specific HRQoL was self-reported by children using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Asthma Impact Scale. Satisfaction with SDM, perceived self-efficacy with patient physician interaction, parental health literacy, and asthma control were reported by parents using standardized measures. Structural equation modeling (SEM) was performed to test the hypothesized pathways. RESULTS: Path analysis revealed that children with better asthma control reported higher asthma-specific HRQoL (beta = 0.4, P < 0.001). Parents with higher health literacy and greater perceived self efficacy with patient-physician interactions were associated with higher satisfaction with SDM (beta = 0.38, P < 0.05; beta = 0.58, P < 0.001, respectively). Greater satisfaction with SDM was in turn associated with better asthma control (beta = -0.26, P < 0.01). CONCLUSION: Children's asthma control status influenced their asthma-specific HRQoL. However, parental factors such as perceived self-efficacy with patient-physician interaction and satisfaction with shared decision-making indirectly influenced children's asthma control status and asthma-specific HRQoL. PMID- 23432915 TI - Longitudinal analysis of ear infection and hearing impairment: findings from 6 year prospective cohorts of Australian children. AB - BACKGROUND: Middle ear infection is common in childhood. Despite its prevalence, there is little longitudinal evidence about the impact of ear infection, particularly its association to hearing loss. By using 6-year prospective data, we investigate the onset and impact over time of ear infection in Australian children. METHODS: We analyse 4 waves of the Longitudinal Study of Australian Children (LSAC) survey collected in 2004, 2006, 2008, and 2010. There are two age cohorts in this study (B cohort aged 0/1 to 6/7 years N=4242 and K cohort aged 4/5 to 10/11 years N=4169). Exposure was parent-reported ear infection and outcome was parent-reported hearing problems. We modelled ear infection onset and subsequent impact on hearing using multivariate logistic regressions, reporting Adjusted Odds Ratios (AOR) and Confidence Intervals (95% CI). Separate analyses were reported for indigenous and non-indigenous children. RESULTS: Associations of ear infections between waves were found to be very strong both among both indigenous and non-indigenous children in the two cohorts. Reported ear infections at earlier wave were also associated with hearing problems in subsequent wave. For example, reported ear infections at age 4/5 years among the K cohort were found to be predictors of hearing problems at age 8/9 years (AOR 4.0, 95% CI 2.2-7.3 among non-indigenous children and AOR 7.7 95% CI 1.0-59.4 among indigenous children). Number of repeated ear infections during the 6-year follow-up revealed strong dose-response relationships with subsequent hearing problems among non-indigenous children (AORs ranged from 4.4 to 31.7 in the B cohort and 4.4 to 51.0 in the K cohort) but not statistically significant among indigenous children partly due to small sample. CONCLUSIONS: This study revealed the longitudinal impact of ear infections on hearing problems in both indigenous and non-indigenous children. These findings highlight the need for special attention and follow-up on children with repeated ear infections. PMID- 23432914 TI - Comparative transcriptomics of early dipteran development. AB - BACKGROUND: Modern sequencing technologies have massively increased the amount of data available for comparative genomics. Whole-transcriptome shotgun sequencing (RNA-seq) provides a powerful basis for comparative studies. In particular, this approach holds great promise for emerging model species in fields such as evolutionary developmental biology (evo-devo). RESULTS: We have sequenced early embryonic transcriptomes of two non-drosophilid dipteran species: the moth midge Clogmia albipunctata, and the scuttle fly Megaselia abdita. Our analysis includes a third, published, transcriptome for the hoverfly Episyrphus balteatus. These emerging models for comparative developmental studies close an important phylogenetic gap between Drosophila melanogaster and other insect model systems. In this paper, we provide a comparative analysis of early embryonic transcriptomes across species, and use our data for a phylogenomic re-evaluation of dipteran phylogenetic relationships. CONCLUSIONS: We show how comparative transcriptomics can be used to create useful resources for evo-devo, and to investigate phylogenetic relationships. Our results demonstrate that de novo assembly of short (Illumina) reads yields high-quality, high-coverage transcriptomic data sets. We use these data to investigate deep dipteran phylogenetic relationships. Our results, based on a concatenation of 160 orthologous genes, provide support for the traditional view of Clogmia being the sister group of Brachycera (Megaselia, Episyrphus, Drosophila), rather than that of Culicomorpha (which includes mosquitoes and blackflies). PMID- 23432916 TI - Reconstruction of the inner canthus region using combined V-Y island pedicle flaps. PMID- 23432917 TI - Blood-brain barrier transport of amyloid beta peptides in efflux pump knock-out animals evaluated by in vivo optical imaging. AB - BACKGROUND: Abeta transport (flux) across the blood-brain barrier (BBB) is thought to contribute to the pathogenesis of Alzheimer's disease as well as to elimination of toxic amyloid from the brain by immunotherapy. Several BBB transporters have been implicated in Abeta exchange between brain parenchyma and the circulation, including efflux transporters P-glycoprotein/ABCB1 and BCRP/ABCG2. Here we describe an application of in vivo optical imaging methods to study Abeta transport across the BBB in wild-type or animals deficient in specific efflux transporters. METHODS/DESIGN: Synthetic human Abeta1-40 or scrambled Abeta40-1 peptides were labeled with the near-infrared fluorescent tracer, Cy5.5. The free tracer or Cy5.5-labeled peptides were injected intravenously into Abcb1-KO or Abcg2-KO mice or their corresponding wild-type controls. The animals were imaged prospectively at different time points over a period of 8 hours using eXplore Optix small animal imager. At the end of the observation, animals were sacrificed by perfusion, their brains were imaged ex vivo and sectioned for immunofluorescence analyses. DISCUSSION: After appropriate circulation time, the fluorescence concentration in the head ROI measured in vivo was close to background values in both wild-type and Abcb1-KO or Abcg2-KO mice injected with either free dye or scrambled Abeta40-1-Cy5.5. In animals injected with Abeta1-40-Cy5.5, the deficiency in either Abcb1 or Abcg2 resulted in significant increases in fluorescence concentration in the head ROIs 2 hours after injection compared to wild-type animals. Fluorescence decay (elimination rate) over 2-8 hours after injection was similar between wild-type (t1/2 = 1.97 h) and Abcg2-KO (t1/2 = 2.34 h) and was slightly faster (t1/2 = 1.38 h) in Abcb1 KO mice. In vivo time-domain imaging method allows prospective, dynamic analyses of brain uptake/elimination of fluorescently-labeled compounds, including Abeta. Deficiency of either of the two major efflux pumps, Abcb1 and Abcg2, implicated in Abeta trafficking across the BBB, resulted in increased accumulation of peripherally-injected Abeta1-40 in the brain. PMID- 23432918 TI - Acute pancreas allograft rejection is associated with increased risk of graft failure in pancreas transplantation. AB - The effect of acute allograft rejection (AR) on long-term pancreas allograft function is unclear. We retrospectively studied 227 consecutive pancreas transplants performed at our institution between January 1, 998 and December 31, 2009 including: 56 simultaneous pancreas and kidney (SPK), 69 pancreas transplantation alone (PTA); and 102 pancreas after kidney (PAK) transplants. With a median follow-up of 6.1 (IQR 3-9) years, 57 patients developed 79 episodes of AR, and 19 experienced more than one episode. The cumulative incidence for AR was 14.7%, 19.7%, 26.6% and 29.1% at 1, 2, 5 and 10 years. PTA transplant (hazards ratio [HR]=2.28, p=0.001) and donor age (per 10 years) (HR=1.34, p=0.006) were associated with higher risk for AR. The first AR episode after 3 months post PT was associated with increased risk for complete loss (CL) (HR 3.79, p<0.001), and the first AR episode occurring during 3- to 12-month and 12- to 24-month periods after PT were associated with significantly increased risk for at least partial loss (PL) (HR 2.84, p=0.014; and HR 6.25, p<0.001, respectively). We conclude that AR is associated with increased risk for CL and at least PL. The time that the first AR is observed may influence subsequent graft failure. PMID- 23432919 TI - Single-wall carbon nanohorns inhibited activation of microglia induced by lipopolysaccharide through blocking of Sirt3. AB - Single-wall carbon nanohorns (SWNHs) have been demonstrated to accumulate in cytotoxic levels within organs of various animal models and cell types, which emerge as a wide range of promising biomedical imaging. Septic encephalopathy (SE) is an early sign of sepsis and associated with an increased rate of morbidity and mortality. Microglia activation plays an important role in neuroinflammation, which contributes to neuronal damage. Inhibition of microglia activation may have therapeutic benefits, which can alleviate the progression of neurodegeneration. Therefore, we investigated the functional changes of mice microglia cell lines pre-treated with or without lipopolysaccharide (LPS) induced by SWNHs. To address this question, the research about direct role of SWNHs on the growth, proliferation, and apoptosis of microglia cell lines in mice (N9 and BV2) pre-treated with or without LPS had been performed. Our results indicate that the particle diameter of SWNHs in water is between 342 to 712 nm. The images in scanning electron microscope showed that SWNHs on polystyrene surface are individual particles. LPS induced activation of mice microglia, promoted its growth and proliferation, and inhibited its apoptosis. SWNHs inhibited proliferation, delayed mitotic entry, and promoted apoptosis of mice microglia cells. The effects followed gradually increasing cultured time and concentrations of SWNHs, especially in cells pre-treated with LPS. SWNHs induced a significantly increase in G1 phase and inhibition of S phase of mice microglia cells in a dose manner dependent of SWNHs, especially in cells pre-treated with LPS. The transmission electron microscope images showed that individual spherical SWNH particles smaller than 100 nm in diameters were localized inside lysosomes of mice microglia cells. SWNHs inhibited mitotic entry, growth and proliferation of mice microglia cells, and promoted its apoptosis, especially in cells pre-treated with LPS. SWNHs inhibited expression of Sirt3 and energy metabolism related with Sirt3 in mice microglia cells in a dose-dependent manner, especially in cells pre treated with LPS. The role of SWNHs on mice microglia was implicating Sirt3 and energy metabolism associated with it. PMID- 23432920 TI - Prevention of acute GVHD in mice by treatment with Tripterygium hypoglaucum Hutch combined with cyclosporin A. AB - OBJECTIVE: To elucidate the protective roles and the underlying mechanism of Tripterygium hypoglaucum Hutch (THH) in mice graft-versus-host disease (GVHD). METHODS: BALB/c (H-2k(d)) mice were firstly treated with total body irradiation and infused with a mixture of bone marrow and spleen cells from C57BL/6. Then the severity of acute GVHD (aGVHD), chimeras of donor cells, inflammatory cytokines (IFN-gamma, IL-4, and IL-10) of plasma, and regulatory T cells were evaluated to elucidate the different drug combinations and concentrations of cyclosporin A (CsA) and THH in preventing aGVHD. RESULTS: The control group treated with phosphate buffer solution displayed more obvious ruffled hair, hunched posture, diarrhea, reduced weight and more lymphocytes infiltration into the spleen and intestine than these treated with CsA, THH or low-dosed CsA combined with THH, especially those treated with low-dosed CsA combined with THH. No significant differences were observed in the chimeras of donor cells and survival rate among the CsA, THH, or CsA combined with THH-treated groups. Further studies implied that THH might reduce the aGVHD by increasing IL-10, decreasing IL-4, activating Treg cell, and maintaining a relatively high Foxp3 mRNA level. CONCLUSION: THH decreased the occurrence of mouse aGVHD and prolonged the survival time by increasing the levels of CD(4)(+)/CD(25)(+) T cells, regulating the cytokine secretion and promoting the expression of Foxp3. PMID- 23432921 TI - Very low food security in the USA is linked with exposure to violence. AB - OBJECTIVE: To investigate characteristics of exposure to violence in relation to food security status among female-headed households. DESIGN: Ongoing mixed-method participatory action study. Questions addressed food insecurity, public assistance, and maternal and child health. Grounded theory analysis of qualitative themes related to violence was performed. These themes were then categorized by food security status. SETTING: Homes of low-income families in Philadelphia, PA, USA. SUBJECTS: Forty-four mothers of children under 3 years of age participating in public assistance programmes. RESULTS: Forty women described exposure to violence ranging from fear of violence to personal experiences with rape. Exposure to violence affected mental health, ability to continue school and obtain work with living wages, and subsequently the ability to afford food. Exposure to violence during childhood and being a perpetrator of violence were both linked to very low food security status and depressive symptoms. Ten of seventeen (59%) participants reporting very low food security described life changing violence, compared with three of fifteen (20%) participants reporting low food security and four of twelve (33%) reporting food security. Examples of violent experiences among the very low food secure group included exposure to child abuse, neglect and rape that suggest exposure to violence is an important factor in the experience of very low food security. CONCLUSIONS: Descriptions of childhood trauma and life-changing violence are linked with severe food security. Policy makers and clinicians should incorporate violence prevention efforts when addressing hunger. PMID- 23432922 TI - Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. AB - BACKGROUND: Clinical studies have shown that integrase strand transfer inhibitors can be used to treat HIV-1 infection. Although the first-generation integrase inhibitors are susceptible to the emergence of resistance mutations that impair their efficacy in therapy, such resistance has not been identified to date in drug-naive patients who have been treated with the second-generation inhibitor dolutegravir. During previous in vitro selection study, we identified a R263K mutation as the most common substitution to arise in the presence of dolutegravir with H51Y arising as a secondary mutation. Additional experiments reported here provide a plausible explanation for the absence of reported dolutegravir resistance among integrase inhibitor-naive patients to date. RESULTS: We now show that H51Y in combination with R263K increases resistance to dolutegravir but is accompanied by dramatic decreases in both enzymatic activity and viral replication. CONCLUSIONS: Since H51Y and R263K may define a unique resistance pathway to dolutegravir, our results are consistent with the absence of resistance mutations in antiretroviral drug-naive patients treated with this drug. PMID- 23432923 TI - Nutritional support and functional capacity in chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - Currently, there is confusion about the value of using nutritional support to treat malnutrition and improve functional outcomes in chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis of randomized, controlled trials (RCT) aimed to clarify the effectiveness of nutritional support in improving functional outcomes in COPD. A systematic review identified 12 RCT (n = 448) in stable COPD patients investigating the effects of nutritional support (dietary advice (1 RCT), oral nutritional supplements (10 RCT), enteral tube feeding (1 RCT)) versus control on functional outcomes. Meta-analysis of the changes induced by intervention found that while respiratory function (forced expiratory volume in 1 s, lung capacity, blood gases) was unresponsive to nutritional support, both inspiratory and expiratory muscle strength (maximal inspiratory mouth pressure +3.86 standard error (SE) 1.89 cm H2 O, P = 0.041; maximal expiratory mouth pressure +11.85 SE 5.54 cm H2 O, P = 0.032) and handgrip strength (+1.35 SE 0.69 kg, P = 0.05) were significantly improved and associated with weight gains of >=2 kg. Nutritional support produced significant improvements in quality of life in some trials, although meta-analysis was not possible. It also led to improved exercise performance and enhancement of exercise rehabilitation programmes. This systematic review and meta-analysis demonstrates that nutritional support in COPD results in significant improvements in a number of clinically relevant functional outcomes, complementing a previous review showing improvements in nutritional intake and weight. PMID- 23432924 TI - Novel signalling mechanisms and targets in renal ischaemia and reperfusion injury. AB - Acute kidney injury (AKI) induced by ischaemia and reperfusion (I/R) injury is a common and severe clinical problem. Vascular dysfunction, immune system activation and tubular epithelial cell injury contribute to functional and structural deterioration. The search for novel therapeutic interventions for I/R induced AKI is a dynamic area of experimental research. Pharmacological targeting of injury mediators and corresponding intracellular signalling in endothelial cells, inflammatory cells and the injured tubular epithelium could provide new opportunities yet may also pose great translational challenge. Here, we focus on signalling mediators, their receptors and intracellular signalling pathways which bear potential to abrogate cellular processes involved in the pathogenesis of I/R induced AKI. Sphingosine 1 phosphate (S1P) and its respective receptors, cytochrome P450 (CYP450)-dependent vasoactive eicosanoids, NF-kappaB- and protein kinase-C (PKC)-related pathways are representatives of such 'druggable' pleiotropic targets. For example, pharmacological agents targeting S1P and PKC isoforms are already in clinical use for treatment for autoimmune diseases and were previously subject of clinical trials in kidney transplantation where I/R induced AKI occurs as a common complication. We summarize recent in vitro and in vivo experimental studies using pharmacological and genomic targeting and highlight some of the challenges to clinical application of these advances. PMID- 23432925 TI - Implanted intrathecal drug delivery systems and radiation treatment. AB - PURPOSE: Radiotherapy affects the functioning of pacemakers. Guidelines based on dosimetric data exist regarding tolerable doses to pacemakers. Little is known about the effects of radiation on implantable drug delivery systems (IDDS). The objective of our study is to evaluate the safety of radiation treatment delivered to patients with IDDS. METHODS AND MATERIALS: We evaluated patients who received external beam radiation therapy in our department after implantation of an IDDS between January 1, 2000 and November 30, 2011. Information was collected on IDDS function, treatment goals, treatment fields, prescribed doses, treatment energies, and cumulative radiation doses to the pump and the catheter. RESULTS: A total of 39 patients received 60 separate courses of radiation therapy, of which 12 patients received radiation with either the pump or the catheter in the field. The remaining patients received scatter radiation only. The goal of radiation was palliative in all but one of the patients. Cumulative pump doses ranged from 5 to 36 Gy, and catheter doses ranged from 15 to 45 Gy. Beam energies ranged from 6 to 18 MV photons. All devices were checked after the completion of radiotherapy with a median follow-up of 4.5 months, and all were found to be in good working condition. CONCLUSIONS: IDDS failures related to external beam radiation therapy seem to represent a rare occurrence. While we do not see reason to limit radiotherapy in patients with IDDS, we recommend device check after the completion of radiotherapy as well as if the patient has an increase in pain or analgesic requirement. PMID- 23432926 TI - Antioxidant capacity of chewing stick miswak Salvadora persica. AB - BACKGROUND: Chewing stick (miswak Salvadora persica L.) is an effective tool for oral hygiene. It possessed various biological properties including significant antibacterial and anti-fungal effects. In the present study, we evaluated the antioxidant compounds in miswak. METHOD: Miswak root was extracted with 80% methanol. Methanol extract as antioxidant was evaluated by using DPPH, ABTS and phosphomolybdenum complex assays and analysis by GC-MS. Peroxidase, catalase and polyphenoloxidase assays were performed for crude extract of miswak root. RESULTS: The methanol extract of miswak contained the highest amount of crude extract among the various solvent extracts. The methanol extract showed a concentration dependent scavenging of DPPH and ABTS radicals with IC50 values 4.8 and 1.6 MUg crude extract, respectively. The total antioxidant activities, based on the reduction of molybdenum (VI) to molybdenum (V), increased with increasing crude extract content. The correlation coefficients (R2) between total crude extract and DPPH, ABTS scavenging activities and the formation of phosphomolybdenum complex were 0.97, 0.99 and 0.95, respectively. The GC-MS analysis showed that the methanol extract doesn't contain phenolic and flavonoid compounds or under detected limit. After silylation of methanol extract, three compounds namely 2-furancarboxaldehyde-5-(hydroxymethyl), furan-2-carboxylic acid 3-methyl- trimethylsilyl ester and D-erythro-pentofuranose-2-deoxy-1,3,5-tris-O (trimethylsilyl) were identified by GC-MS analysis. These furan derivatives as they contain hydroxyl groups could be possessed antioxidant activities. The antioxidant enzymes were also detected in the miswak extract with high level of peroxidase and low level of catalase and polyphenoloxidase. CONCLUSIONS: The synergistic actions of antioxidant compounds and antioxidant enzymes make miswak is a good chewing stick for oral hygiene and food purposes. PMID- 23432927 TI - Health care workers causing large nosocomial outbreaks: a systematic review. AB - BACKGROUNDS: Staff in the hospital itself may be the source of a nosocomial outbreak (NO). But the role of undetected carriers as an outbreak source is yet unknown. METHODS: A systematic review was conducted to evaluate outbreaks caused by health care workers (HCW). The Worldwide Outbreak Database and PubMed served as primary sources of data. Articles in English, German or French were included. Other reviews were excluded. There were no restrictions with respect to the date of publication.Data on setting, pathogens, route of transmission, and characteristics of the HCW was retrieved. Data from large outbreaks were compared to smaller outbreaks. RESULTS: 152 outbreaks were included, mainly from surgery, neonatology, and gynecology departments. Most frequent corresponding infections were surgical site infections, infection by hepatitis B virus, and septicemia. Hepatitis B virus (27 NO), S. aureus (49 NO) and S. pyogenes (19 NO) were the predominant pathogens involved. 59 outbreaks (41.5%) derived from physicians and 56 outbreaks (39.4%) derived from nurses. Transmission mainly occurred via direct contact. Surgical and pediatric departments were significantly associated with smaller outbreaks, and gynecology with larger outbreaks. Awareness of carrier status significantly decreased the risk of causing large outbreaks. CONCLUSIONS: As NO caused by HCW represent a rare event, screening of personnel should not be performed regularly. However, if certain species of microorganisms are involved, the possibility of a carrier should be taken into account. PMID- 23432928 TI - Viscous methyl cellulose solution thickens gastric mucosa and increases the number of gland mucous cells in mice. AB - We have observed a stiffening of the gastric wall in mice following oral administration of viscous methyl cellulose (MC) solution as a vehicle for food chemicals, an effect which has not previously been reported. To further investigate this effect, young male ICR mice(n 48) were divided into four groups (one control and three experimental groups) of twelve mice each. Experimental groups I, II and III were administered 0.2 ml of 0.5% (w/v) MC viscous solution/d via a stomach tube for 2, 3 and 4 weeks, respectively. Stomachs were collected following 12 h fasting. The weight of the stomach and mucosa of seven mice per group was measured, and the mucosa was used for the measurement of 8-oxo-20 deoxyguanosine (8-oxodG). Stomach tissue slices from the remaining five mice per group were stained with haematoxylin and eosin to measure mucosal thickness, and were immunostained with an HIK1083 antibody to determine the number of gastric gland mucous cells. The mucosal thickness of the groups administered the MC solution for 3 and 4 weeks, and the size of the HIK1083-immunostained area of the groups administered the MC solution for 2, 3 and 4 weeks were significantly increased(P,0.01) compared with those of the control group. The amount of 8-oxodG was not significantly affected. These results indicate that oral administration of viscous MC solution leads to the thickening of the gastric mucosa, which may be related to an increase in the number of gland mucous cells. PMID- 23432930 TI - Correction: MiRNA-26b inhibits proliferation by targeting PTGS2 in breast cancer. PMID- 23432929 TI - Resource factors for mental health resilience in early childhood: An analysis with multiple methodologies. AB - BACKGROUND: Given that relatively little is known about the development of resilience in early childhood, this longitudinal study aimed to identify preschool resource factors associated with young children's mental health resilience to family adversity. METHODS: A community sample of 474 young Australian children was assessed in preschool (mean age 4.59 years, 49% male), and again two years later after their transition into formal schooling. At each assessment, standard questionnaires were used to obtain ratings from both parents and teachers about the quality of children's relationships with parents and teachers, children's self-concept and self-control, mental health (Strengths and Difficulties Questionnaire), and family adversities (including stressful life events and socioeconomic disadvantage). RESULTS: Greater exposure to cumulative family adversities was associated with both greater teacher- and parent-reported child mental health difficulties two years later. Multiple methodologies for operationalizing resilience were used to identify resources associated with resilient mental health outcomes. Higher quality child-parent and child-teacher relationships, and greater child self-concept and self-control were associated with resilient mental health outcomes. With the exception of child-teacher relationships, these resources were also prospective antecedents of subsequent resilient mental health outcomes in children with no pre-existing mental health difficulties. Child-parent relationships and child self-concept generally had promotive effects, being equally beneficial for children facing both low- and high-adversity. Child self-control demonstrated a small protective effect on teacher-reported outcomes, with greater self-control conferring greater protection to children under conditions of high-adversity. CONCLUSIONS: Findings suggest that early intervention and prevention strategies that focus on fostering child-adult relationship quality, self-concept, and self-control in young children may help build children's mental health and their resilience to family adversities. PMID- 23432931 TI - Assessing knowledge and attitudes towards screening among users of Faecal Immunochemical Test (FIT). AB - BACKGROUND: Informed decision making is recognized as important in screening. Invitees should be provided with relevant information, enabling them to make an informed decision. This may be more difficult in ethnic minority and low socio economic status groups. We aimed to assess the proportion of informed decisions to participate in a faecal immunochemical test (FIT)-based colorectal cancer (CRC) screening pilot and to explore differences in knowledge and attitude across various subgroups. METHODS: Asymptomatic persons aged 50-74 were invited to a second round of a Dutch FIT-based pilot screening programme for CRC. An information leaflet containing all information relevant to enable informed decision making accompanied the invitation. Informed choice was assessed by a mailed questionnaire. Knowledge was elicited through 18 items and attitude towards screening through four items. Main outcome measure was the proportion of informed decision makers among participants. Differences between subgroups were evaluated using logistic regression. RESULTS: Of 5367 screening participants, 2774 (52%) completed the questionnaire. Knowledge was adequate in 2554 (92%); 2736 (99%) showed a positive attitude towards screening. A total of 2525 persons had made an informed choice (91%); male gender, low education level, non-Dutch ethnicity and not speaking Dutch at home were negatively associated with having adequate knowledge in multivariable analysis. CONCLUSION: In FIT-based screening for CRC, the majority of responders made an informed decision to participate. However, we did not succeed in equally providing all population subgroups with sufficient information. Future initiatives should be aimed at reaching these groups to further enable informed decision making. PMID- 23432932 TI - Postoperative preferences in cutaneous surgery: a patient-centered investigation from an academic dermatologic surgery practice. AB - BACKGROUND: Little is known about postoperative preferences regarding dermatologic surgery. OBJECTIVE: To determine patient preferences for postoperative follow-up after dermatologic surgery, desired follow-up interval, reasons for desired follow-up or lack thereof, and factors that may be associated with these preferences. MATERIALS AND METHODS: Patients who underwent Mohs micrographic surgery or excision within 24 months of Mohs micrographic surgery or excision were retrospectively surveyed regarding their postoperative follow-up preferences. Procedure, tumor attributes, complications, and medications were recorded. RESULTS: Eighty-nine percent of patients considered postoperative follow-up important, with 55% opting for follow-up within 4 weeks and an additional 29.1% within 2 to 3 months. After multivariate analyses, there were no significantly associated covariates of interest regarding preference for follow up. Reasons for desiring follow-up included to ensure the wound healed well (50%), to ensure the cancer had not returned (27.9%), and to examine the rest of the skin (18.6%). CONCLUSION: A majority of patients desired postoperative follow up visits for a variety of reasons. Anticipation of postoperative concerns should be included in dermatologic surgery planning. PMID- 23432933 TI - The ATP-binding cassette transporter subfamily C member 2 in Bombyx mori larvae is a functional receptor for Cry toxins from Bacillus thuringiensis. AB - Bacillus thuringiensis is the most widely used biopesticide, and its Cry toxin genes are essential transgenes for the generation of insect-resistant transgenic crops. Recent reports have suggested that ATP-binding cassette transporter subfamily C2 (ABCC2) proteins are implicated in Cry intoxication, and that a single amino acid insertion results in high levels of resistance to Cry1 toxins. However, there is currently no available direct evidence of functional interactions between ABCC2 and Cry toxins. To address this important knowledge gap, we investigated the role of Bombyx mori ABCC2 (BmABCC2) or its mutant from a Cry1Ab-resistant B. mori strain on Cry1A toxin action. When we expressed BmABCC2 ectopically on Sf9 cells, it served as a functional receptor, and the single amino acid insertion found in BmABCC2 from Cry1Ab-resistant larvae resulted in lack of susceptibility to Cry1Ab and Cry1Ac. Using the same expression system, we found that Bo. mori cadherin-like receptor (BtR175) conferred susceptibility to Cry1A toxins, albeit to a lower degree than BmABCC2. Coexpression of BtR175 and BmABCC2 resulted in the highest cell susceptibility to Cry1A, Cry1F, and even the phylogenetically distant Cry8Ca toxin, when compared with expression of either receptor alone. The susceptibility observed in the coexpressing cells and that in Bo. mori larvae are likely to be correlated, suggesting that BtR175 and BmABCC2 are important factors determining larval susceptibility. Our study demonstrates, for the first time, Cry toxin receptor functionality for ABCC2, and highlights the crucial role of this protein and cadherin in the mechanism of action of Cry toxin. PMID- 23432935 TI - Don't turn your back on the symptoms of psychosis: a proof-of-principle, quasi experimental public health trial to reduce the duration of untreated psychosis in Birmingham, UK. AB - BACKGROUND: Reducing the duration of untreated psychosis (DUP) is an aspiration of international guidelines for first episode psychosis; however, public health initiatives have met with mixed results. Systematic reviews suggest that greater focus on the sources of delay within care pathways, (which will vary between healthcare settings) is needed to achieve sustainable reductions in DUP (BJP 198: 256-263; 2011). METHODS/DESIGN: A quasi-experimental trial, comparing a targeted intervention area with a 'detection as usual' area in the same city. A proof-of principle trial, no a priori assumptions are made regarding effect size; key outcome will be an estimate of the potential effect size for a definitive trial. DUP and number of new cases will be collected over an 18-month period in target and control areas and compared; historical data on DUP collected in both areas over the previous three years, will serve as a benchmark. The intervention will focus on reducing two significant DUP component delays within the overall care pathway: delays within the mental health service and help-seeking delay. DISCUSSION: This pragmatic trial will be the first to target known delays within the care pathway for those with a first episode of psychosis. If successful, this will provide a generalizable methodology that can be implemented in a variety of healthcare contexts with differing sources of delay. PMID- 23432934 TI - Active subnetwork recovery with a mechanism-dependent scoring function; with application to angiogenesis and organogenesis studies. AB - BACKGROUND: The learning active subnetworks problem involves finding subnetworks of a bio-molecular network that are active in a particular condition. Many approaches integrate observation data (e.g., gene expression) with the network topology to find candidate subnetworks. Increasingly, pathway databases contain additional annotation information that can be mined to improve prediction accuracy, e.g., interaction mechanism (e.g., transcription, microRNA, cleavage) annotations. We introduce a mechanism-based approach to active subnetwork recovery which exploits such annotations. We suggest that neighboring interactions in a network tend to be co-activated in a way that depends on the "correlation" of their mechanism annotations. e.g., neighboring phosphorylation and de-phosphorylation interactions may be more likely to be co-activated than neighboring phosphorylation and covalent bonding interactions. RESULTS: Our method iteratively learns the mechanism correlations and finds the most likely active subnetwork. We use a probabilistic graphical model with a Markov Random Field component which creates dependencies between the states (active or non active) of neighboring interactions, that incorporates a mechanism-based component to the function. We apply a heuristic-based EM-based algorithm suitable for the problem. We validated our method's performance using simulated data in networks downloaded from GeneGO against the same approach without the mechanism based component, and two other existing methods. We validated our methods performance in correctly recovering (1) the true interaction states, and (2) global network properties of the original network against these other methods. We applied our method to networks generated from time-course gene expression studies in angiogenesis and lung organogenesis and validated the findings from a biological perspective against current literature. CONCLUSIONS: The advantage of our mechanism-based approach is best seen in networks composed of connected regions with a large number of interactions annotated with a subset of mechanisms, e.g., a regulatory region of transcription interactions, or a cleavage cascade region. When applied to real datasets, our method recovered novel and biologically meaningful putative interactions, e.g., interactions from an integrin signaling pathway using the angiogenesis dataset, and a group of regulatory microRNA interactions in an organogenesis network. PMID- 23432937 TI - Antidiuretic effect of antimuscarinic agents in rat model depends on C-fibre afferent nerves in the bladder. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Antichollnergic agents are anticipated to diminish storage symptoms, as well as nocturia. Nevertheless, the effect of this treatment on polyuria related to nocturia is not clear. By subgroup analysis of the data set from a phase III clinical trial of antimuscarinic agent for OAB patients in Japan, imidafenacin was found to improve nocturia with a reduction in nocturnal polyuria. This study adds the effects and underlying mechanism of antimuscarinic agents decreasing urine production through inhibition of C-fibre in the bladder of water-leaded rats. OBJECTIVE: To evaluate the effects and underlying mechanisms of antimuscarinic agents used to decrease in urine production in water-loaded rats. SUBJECTS AND METHODS: Urine production was measured using a cystostomy catheter in female Sprague-Dawley rats every 2 h. The effect of the antimuscarinic agents atropine, tolterodine and imidafenacin on urine production was investigated under water-loaded conditions, which were induced by i.p. injection of 15 mL saline. Blood samples were collected to determine the levels of antidiuretic hormone (ADH), aldosterone (ALD), atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) before, and 2 and 8 h after, antimuscarinic agent administration. To induce desensitization of C fibre afferent nerves, resiniferatoxin (RTX)was injected s.c. or intravesically 2 days before experiments. RESULTS: Urine production increased and reached its maximum 2 h after 15 mL saline injection. Imidafenacin and tolterodine decreased urine production in water-loaded rats, but ADH, ALD, ANP and BNP levels were not different between imidafenacin-treated and vehicle-treated rats. The inhibitory effect on urine production was not found in RTX-treated rats. Atropine did not reduce urine production. CONCLUSION: These results suggest that antimuscarinic agents decrease urine volume through C-fibres in the bladder; thus, antimuscarinics with inhibitory effects on C-fibres could be beneficial for nocturia with nocturnal polyuria. PMID- 23432936 TI - A serine/threonine phosphatase encoded by MG_207 of Mycoplasma genitalium is critical for its virulence. AB - BACKGROUND: Bacterial signal transduction systems like two component system (TCS) and Serine/Threonine kinase (STK) and Serine/Threonine phosphatase (STP) play important roles in the virulence and pathogenesis of bacterial pathogens. Mycoplasma genitalium, a mollicute that causes the urogenital diseases urethritis and cervicitis in men and women, respectively, is a pathogen which lacks TCS but possesses STK/STP. In this study, we investigated the biochemical and virulence properties of an STP protein encoded by the gene MG_207 of this species. RESULTS: We overexpressed MG207 in Escherichia coli overexpression system as a recombinant His10MG207 protein and purified it with affinity chromatography. This recombinant protein readily hydrolyzed the substrate p-nitrophenyl phosphate (pNPP) in a dose dependent manner. Additional studies using synthetic peptides as substrates revealed that the recombinant protein was able to hydrolyze the threonine phosphate. Further, a transposon insertion mutant strain of M. genitalium (TIM207) that lacks the protein MG207 showed differentially phosphorylated proteins when compared to the wild type G37 strain. Mass spectrometry revealed that some of the key proteins differentially phosphorylated in TIM207 strain were putative cytoskeletal protein encoded by the gene MG_328 and pyruvate dehydrogenase E1 alpha chain encoded by the gene MG_274. In addition, TIM207 was noticed to be less cytotoxic to HeLa cells and this correlated with the production of less hydrogen peroxide by this strain. This strain was also less efficient in inducing the differentiation of THP-1 cell line as compared to wild type M. genitalium. CONCLUSIONS: The results of the study suggest that MG207 is an important signaling protein of M. genitalium and its presence may be crucial for the virulence of this species. PMID- 23432938 TI - Lateral supraorbital approach applied to sellar tumors in 23 consecutive patients: the Suzhou experience from China. AB - BACKGROUND: Pituitary adenoma, craniopharyngioma and meningioma are common sellar lesions, accounting for more than 90% of sellar tumors. The aim of this study is to assess the reliability and safety of the lateral supraorbital (LSO) approach to remove sellar tumors. METHODS: Between June 2011 and December 2011, 23 patients with neoplastic lesions underwent surgery by the corresponding author (ZW) via the LSO approach. The clinical presentations, neuroradiological findings, microsurgical techniques, and outcome at discharge of these patients were analyzed. In addition, the clinical series in the available literature written in English were also extensively reviewed. Eleven (48%) patients were treated for pituitary adenoma; six (26%) patients for tuberculum sellae meningioma; and six (26%) patients for craniopharyngioma. RESULTS: Seemingly complete tumor removal was achieved in 21 patients (91%); surgical mortality was one patient (4.3%). Postoperatively, no patient had developed cerebrospinal fluid leakage or new visual deficits. One (4%) patient had intracranial infection, and one (4%) had a postoperative hematoma. The median Karnofsky score at discharge was 87.4 (range, 0 to 100). The Glasgow outcome scale at discharge was 4.6 (range, 1 to 5). Of all, 21 (91.3%) patients achieved favorable outcomes. CONCLUSION: Sellar tumors can be removed via the LSO approach with relatively low morbidity and mortality. Surgical results with this fast and simple approach are similar to those obtained with more extensive, complex, and time-consuming approaches. PMID- 23432939 TI - What are the clinical criteria justifying spinal manipulative therapy for neck pain?- a systematic review of randomized controlled trials. AB - OBJECTIVE: Manipulation and mobilization are used to treat neck pain. However, little is known about the diagnostic criteria used to determine the need for manipulation in cases of neck pain. The primary aim of this study was to determine what diagnostic criteria are used to identify which neck pain sufferers should receive spinal manipulation or mobilization. DESIGN: We systematically reviewed randomized controlled trials (RCT) involving mobilization or manipulation for neck pain. A data extraction pro forma was developed and trialled before two independent assessors extracted data sets from each RCT. A descriptive analysis was undertaken. RESULTS: Thirty RCTs met the inclusion criteria. Acute and chronic "Mechanical" neck pain was the most common (43%) diagnosis at recruitment to the RCTs but some (10%) included patients with cervicogenic headache. Clinical criteria were used to determine the need for neck manipulation in over half (63%) of the RCTs. This usually involved exclusion of serious conditions, manual examination for tenderness on palpation, and/or altered vertebral motion in the neck or upper thoracic region which are known to lack validity. The remainder of the RCTs did not report a diagnostic strategy. All RCTs lacked detail descriptions of diagnostic criteria or interventions used. CONCLUSIONS: This systematic review highlights the absence of reliable and valid diagnostic protocols to determine the need for spinal manipulation in persons presenting with non-serious, idiopathic, or whiplash-associated (grade II) neck pain. Guidelines requiring the reporting of valid diagnostic criteria are needed to improve the quality of RCTs concerning manual therapy. PMID- 23432940 TI - Epidemiology of uveitis in children over a 10-year period. AB - OBJECTIVES: The aim of the present study is to investigate the demographics, aetiologies, complications, treatments and visual outcomes in paediatric uveitis patients in the French-speaking part of Switzerland. METHODS: Chart review of all patients diagnosed with uveitis before the age of 16 years, presenting to two tertiary referral centres (uveitis and paediatric rheumatology clinics) in Lausanne, Switzerland, between 2000 and 2009. RESULTS: Seventy-nine children (37 girls) were identified, 62 living in Switzerland, 15 in Europe and 2 in North Africa. Median age at first symptoms was 9.0 years (range 1.5-15.8 years), with a median follow-up time of 1.8 years (0-8 years). Both eyes were involved in 51 patients (64.6%). The course was acute in 30.4%, chronic in 60.8% and recurrent in 8.9%. Anterior uveitis occurred in 39.2%, intermediate in 32.9%, posterior in 22.8% and panuveitis in 5.1%. The three main diagnoses were idiopathic uveitis (34.2%), JIA-related uveitis (22.8%) and toxoplasmic retinochoroiditis (15.2%). During the last follow-up visit, the visual acuity (VA) was >=8/10 in 72% of all eyes with a measurable VA. Cataract (8%), ocular hypertension/glaucoma (8%) and macular fibrosis (4%) were the three most common severe complications. Systemic steroids were given to 56% and biological agents to 24% of patients with inflammatory uveitis. CONCLUSIONS: Uveitis in children can be a devastating disease. A strict classification of aetiologies and a tight collaboration between paediatric rheumatologists and ophthalmologists are important to ensure early control of ocular inflammation and improve long-term visual prognosis. PMID- 23432941 TI - Percutaneous transhepatic variceal embolization combined with endoscopic ligation for the prevention of variceal rebleeding. AB - OBJECTIVE: To compare the efficiency of percutaneous transhepatic variceal embolization (PTVE) plus endoscopic variceal ligation (EVL) with EVL alone in the treatment of esophageal variceal bleeding. METHODS: Cirrhotic patients with recent esophageal variceal bleeding from January 2007 to December 2011 were collected and assigned to PTVE + EVL (N = 41) or EVL (N = 47) groups. We performed chart reviews and prospective follow-up to determine variceal rebleeding, recurrence of varices and survival. RESULTS: During the follow-up period, recurrence of esophageal varices (EV) occurred in 8 patients (19.5%) in the PTVE + EVL group and 23 (48.9%) in the EVL group (P = 0.004). The time to recurrence of EV was 9.2 +/- 2.7 months and 4.9 +/- 2.1 months, respectively. Three patients (7.3%) in the PTVE + EVL group and 12 (25.5%) in the EVL group experienced rebleeding from all sources (P = 0.023). One patient (2.4%) in the PTVE + EVL group and 7 (14.9%) in the EVL group experienced rebleeding from EV (P = 0.024). Multivariate Cox analysis indicated that the treatment method was the only predictor of rebleeding. There was no significant difference in the survival rate between the two groups. CONCLUSION: With adequate and permanent obliteration of EV and their feeding veins, the combination of PTVE with cyanoacrylate and EVL is more effective than EVL alone in the prevention and treatment of EV recurrence and rebleeding. PMID- 23432942 TI - Effect of both protective and reducing agents in the synthesis of multicolor silver nanoparticles. AB - In this paper, the influence of variable molar ratios between reducing and loading agents (1:100, 1:50, 1:20, 1:10, 1:5, 1:2, 1:1, 2:1) and between protective and loading agents (0.3:1, 0.75:1, 1.5:1, 3:1, 7.5:1, 30:1, 75:1) in the synthesis of silver nanoparticles by chemical reduction has been evaluated to obtain multicolor nanoparticles with a high stability in time. The protective agent poly(acrylic acid, sodium salt) (PAA) and reducing agent dimethylaminoborane (DMAB) play a key role in the formation of the resultant color. Evolution of the optical absorption bands of the silver nanoparticles as a function of PAA and DMAB molar ratios made it possible to confirm the presence of silver nanoparticles or clusters with a specific shape. The results reveal that a wide range of colors (violet, blue, green, brown, yellow, red, orange), sizes (from nanometer to micrometer), and shapes (cubic, rod, triangle, hexagonal, spherical) can be perfectly tuned by means of a fine control of the PAA and DMAB molar concentrations. PMID- 23432944 TI - A population based survey in Ethiopia using questionnaire as proxy to estimate obstetric fistula prevalence: results from demographic and health survey. AB - BACKGROUND: Obstetric Fistula (OF) remains a major public health problem in areas where unattended obstructed labor is common and maternal mortality is high. Obstetric Fistula was able to be prevented, treated and eradicated in high-income countries; however, it still affects many women in low-income countries. To our knowledge, only few studies have described the prevalence and factors associated with Obstetric Fistula in Ethiopia in population-based surveys. OBJECTIVE: The aim of this study is to describe the prevalence and factors associated with Obstetric Fistula in Ethiopia. METHODS: The study used women's dataset from the 2005 Ethiopian Demographic and Health Survey. The survey sample was designed to provide national, urban/rural, and regional representative estimates of key health and demographic indicators. The sample was selected using a two-stage stratified sampling process. OF was measured using questionnaire. The data is analyzed using descriptive and multivariate statistical methods to determine factors associated with Obstetric Fistula. RESULTS: A total of 14,070 women of reproductive age group were included in the survey. Of which 23.2% ever heard of obstetric fistula. Among women who ever given birth (9,713), some 103 (1.06%, 95% CI; 0.89%-1.31%) experienced obstetric fistula in their lifetime, which means 10.6 per 1000 women who ever gave birth. It is estimated that in Ethiopia nearly 142,387 (95% CI: 115,080-169,694) of obstetric fistula patients exist. Those women who are circumcised had higher odds of reporting the condition (Chi square = 4.41, p-value = 0.036). In the logistic regression model women from rural areas were less likely to report obstetric fistula than their urban counterparts (OR = 0.21, 95% CI: 0.06-0.69). Women who gave birth 10 or more had higher odds of developing obstetric fistula than women with 1-4 child (OR = 4.34; 95% CI; 1.29 14.55). CONCLUSIONS: Obstetric fistula is a major public and reproductive health concern in Ethiopia. This calls for increased access to emergency obstetric care, expansion of fistula repair service and active finding of women with OF with campaigns of ending fistula is recommended. PMID- 23432943 TI - Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury. AB - Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 antibodies of potential importance in regulating allograft vascular injury. We performed a case-control study in which we compared anti-LG3 IgG titers in kidney transplant recipients with AVR (n=15) versus those with acute tubulo-interstitial rejection (ATIR) (n=15) or stable graft function (n=30). Patients who experienced AVR had elevated anti-LG3 titers pre and posttransplantation compared to subjects with ATIR or stable graft function (p<0.05 for both mediators). Elevated pretransplant anti-LG3 titers (OR: 4.62, 95% CI: 1.08-19.72) and pretransplant donor-specific antibodies (DSA) (OR 4.79, 95% CI: 1.03-22.19) were both independently associated with AVR. To address the functional role of anti-LG3 antibodies in AVR, we turned to passive transfer of anti-LG3 antibodies in an animal model of vascular rejection based on orthotopic aortic transplantation between fully MHC-mismatched mice. Neointima formation, C4d deposition and allograft inflammation were significantly increased in recipients of an ischemic aortic allograft passively transferred with anti-LG3 antibodies. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling. PMID- 23432945 TI - Intrastriatal gene delivery of GDNF persistently attenuates methamphetamine self administration and relapse in mice. AB - Relapse of drug abuse after abstinence is a major challenge to the treatment of addicts. In our well-established mouse models of methamphetamine (Meth) self administration and reinstatement, bilateral microinjection of adeno-associated virus vectors expressing GDNF (AAV-Gdnf) into the striatum significantly reduced Meth self-administration, without affecting locomotor activity. Moreover, the intrastriatal AAV-Gdnf attenuated cue-induced reinstatement of Meth-seeking behaviour in a sustainable manner. In addition, this manipulation showed that Meth-primed reinstatement of Meth-seeking behaviour was reduced. These findings suggest that the AAV vector-mediated Gdnf gene transfer into the striatum is an effective and sustainable approach to attenuate Meth self-administration and Meth associated cue-induced relapsing behaviour and that the AAV-mediated Gdnf gene transfer in the brain may be a valuable gene therapy against drug dependence and protracted relapse in clinical settings. PMID- 23432946 TI - High-level expression and characterization of a chimeric lipase from Rhizopus oryzae for biodiesel production. AB - BACKGROUND: Production of biodiesel from non-edible oils is receiving increasing attention. Tung oil, called "China wood oil" is one kind of promising non-edible biodiesel oil in China. To our knowledge, tung oil has not been used to produce biodiesel by enzymatic method. The enzymatic production of biodiesel has been investigated extensively by using Rhizopus oryzae lipase as catalyst. However, the high cost of R. oryzae lipase remains a barrier for its industrial applications. Through different heterologous expression strategies and fermentation techniques, the highest expression level of the lipase from R. oryzae reached 1334 U/mL in Pichia pastoris, which is still not optimistic for industry applications. RESULTS: The prosequence of lipases from Rhizopus sp. is very important for the folding and secretion of an active lipase. A chimeric lipase from R. oryzae was constructed by replacing the prosequence with that from the R. chinensis lipase and expressed in P. pastoris. The maximum activity of the chimera reached 4050 U/mL, which was 11 fold higher than that of the parent. The properties of the chimera were studied. The immobilized chimera was used successfully for biodiesel production from tung oil, which achieved higher FAME yield compared with the free chimeric lipase, non-chimeric lipase and mature lipase. By response surface methodology, three variables, water content, methanol to tung oil molar ratio and enzyme dosage were proved to be crucial parameters for biosynthesis of FAME and the FAME yield reached 91.9+/-2.5% at the optimized conditions by adding 5.66 wt.% of the initial water based on oil weight, 3.88 of methanol to tung oil molar ratio and 13.24 wt.% of enzyme concentration based on oil weight at 40 degrees C. CONCLUSIONS: This is the first report on improving the expression level of the lipase from R. oryzae by replacing prosequences. The immobilized chimera was used successfully for biodiesel production from tung oil. Using tung oil as non-edible raw material and a chimeric lipase from R. oryzae as an economic catalyst make this study a promising one for biodiesel applications. PMID- 23432948 TI - Sociodemographic, lifestyle and dietary correlates of dietary supplement use in a large sample of French adults: results from the NutriNet-Sante cohort study. AB - Information on the determinants of dietary supplement (DS) use in France is largely lacking, especially in population subgroups such as smokers. Also, little is known about the role of health professionals in DS purchases. The aim of the present study was to describe DS use along with its sociodemographic, lifestyle and dietary correlates in a large sample of French adults (age 18+years) participating in the NutriNet-Sante cohort study. Data were collected by self administered Internet questionnaires. Food intakes were assessed by 24 h dietary records. Data on DS use were available for 79,786 participants. Supplement users were compared with non-users by logistic regression. Current DS use at least three times/week was reported by 14.6% of men and 28.1% of women. Mg, and vitamins B6 and C were the most frequently consumed nutrients. DS were prescribed or recommended by a physician in 54.9% of the cases. DS use was positively associated with knowledge of nutritional recommendations and organic product consumption, following a healthier diet and lifestyle (non-smoker, moderate leisure-time physical activity). Current smokers used less DS than did non smokers, but their DS consumption was substantial (19.0%) and they were more likely to self-medicate. The present study provides updated and detailed information on DS use determinants in a large French cohort, including a focus on smokers, for whom the long-term effects of DS use are poorly documented and could represent a risk. These findings pave the way for future aetiological studies. PMID- 23432947 TI - Induction of selective cytotoxicity and apoptosis in human T4-lymphoblastoid cell line (CEMss) by boesenbergin a isolated from boesenbergia rotunda rhizomes involves mitochondrial pathway, activation of caspase 3 and G2/M phase cell cycle arrest. AB - BACKGROUND: Boesenbergia rotunda (Roxb.) Schlecht (family zingiberaceae) is a rhizomatous herb that is distributed from north-eastern India to south-east Asia, especially in Indonesia, Thailand and Malaysia. Previous research has shown that the crude extract of this plant has cytotoxic properties. The current study examines the cytotoxic properties of boesenbergin A isolated from Boesenbergia rotunda. METHODS: MTT assay was used to check the cytotoxicity of boesenbergin A. The morphological assessment of apoptosis was monitored using normal and fluorescence microscopy. The early and late phase of apoptosis was investigated using annexin V and DNA laddering assays, respectively. The mitochondrial membrane potential (MMP) was assessed by fluorescence microscopy. Human apoptosis proteome profiler assays were performed to investigate the mechanism of cell death. In addition, the protein levels of Bax, Bcl2 and HSP 70 were also analyzed using western blot. Assays of caspase =-3/7, -8 and =-9 were carried out in order to test for induction during treatment. Lastly, cell cycle progression was analyzed using flow cytometry. RESULTS: Boesenbergin A was found to have the highest toxicity towards CEMss cancer cells (IC50 = 8 MUg/ml). The morphology of CEMss cells after treatment showed evidence of apoptosis that included blebbing and chromatin condensation. The annexin V assay revealed that early apoptosis is induced after treatment. The DNA laddering assay confirmed that DNA fragmentation had occurred during late apoptosis. The cell cycle analysis indicated that boesenbergin A was able to induce G2/M phase arrest in CEMss cells. The activity of caspases -3/7, -8 and -9 was increased after treatment which indicates both intrinsic and extrinsic pathways are induced during apoptosis. The involvement of mitochondria was established by increased mitochondrial membrane potential and up and down regulation of Bcl2 and Bax proteins as well as HSP70. CONCLUSION: In conclusion, the results demonstrated that boesenbergin A induced apoptosis of CEMss cells through Bcl2/Bax signaling pathways with the involvement of caspases and G2/M phase cell cycle arrest. The current findings warrant further research on boesenbergin A as a novel chemotherapeutic agent for leukemia intervention including studies in animal models. PMID- 23432949 TI - Concurrent rearrangements of BCL2, BCL3, and BCL11A genes in atypical chronic lymphocytic leukemia. AB - The most frequent chromosomal aberrations with the well established prognostic meaning in chronic lymphocytic leukemia (CLL) are +12, del(11q), del(13q), and del(17p). Less common translocations lead to deregulation of genes primarily due to juxtaposition with IGH gene. We present a case of CLL patient with atypical morphology and an aggressive course of disease. In spite of aggressive treatment including allogeneic hematopoietic stem cell transplantation disease progressed into a rare cutaneous Richter's syndrome. Trisomy 12 was found as a sole chromosomal change at initial cytogenetic analysis of lymphoma cells. At progression, besides trisomy 12 three concomitant balanced translocations t(2;14)(p13;q32), t(14;19)(q32;q13), and t(18;22)(q21;q11) were found. The same karyotype was confirmed in cells aspirated from skin infiltrates at Richter transformation. Atypical cytological features, trisomy 12, and a progressive course of disease observed in our case are typical for CLL with each of particular Ig translocations that were concomitantly found in CLL for the first time. Similar to "double hit" lymphoma concurrent rearrangements may be relevant also in CLL. PMID- 23432950 TI - Do patients have a voice? The social stratification of health center governing boards. AB - CONTEXT: To ensure community responsiveness, federally qualified health centres (FQHCs) in the United States are required to be governed by a patient majority. However, to the extent that these patient trustees resemble the typical low income patients served by FQHCs, status generalization theory suggests that they will be passed over for leadership positions within the board in favour of more prestigious individuals. METHODS: Using 4 years of data on health centre governing boards obtained from the Health Resources and Services Administration via a Freedom of Information Act Request, the likelihood of holding executive committee office is modelled as a function of trustee characteristics using Chamberlain's conditional logistic regressions. RESULTS: The results indicate that representative patient trustees are significantly less likely than other trustees to hold a position on the executive committee or serve as board chair. CONCLUSIONS: Given the power of the board leadership to set the agenda, the reduced likelihood of representative patient trustees serving in leadership positions may ultimately limit the representative voice given to patients, making FQHCs potentially less responsive to their communities. These findings also have important implications for other settings where engaging and empowering patients is sought. PMID- 23432951 TI - Ambulatory models of care for obstructive sleep apnoea: Diagnosis and management. AB - The high prevalence of obstructive sleep apnoea (OSA) and increasing awareness of its potential health consequences has placed significant pressure on laboratory based sleep services leading to growing waiting lists and delays in diagnosis and treatment. Consequently, there has been increasing interest in the use of simplified, ambulatory models of care involving clinical prediction tools, portable sleep monitoring and home autotitrating continuous positive airway pressure. Researchers are also exploring the potential role for a wider range of health-care providers, including trained nurses and general practitioners, in the primary management of OSA. Recent randomized, controlled studies evaluating the clinical effectiveness of ambulatory management strategies versus traditional laboratory-based care for patients with OSA have consistently demonstrated that comparable patient outcomes can be achieved. The cost-effectiveness of these strategies is currently being debated, and further research examining the long term economic implications of ambulatory models of care is needed. PMID- 23432952 TI - Successful removal of a henna tattoo using 2,940-nm ablative laser resurfacing. PMID- 23432953 TI - Babesia microti: an unusual travel-related disease. AB - BACKGROUND: Human babesiosis is a rare tick-borne infectious disease. The clinical presentation ranges from an asymptomatic form to a life threatening infection with severe hemolysis. Human babesiosis due to Babesia microti is the most common and is endemic in North America. CASE PRESENTATION: We report a European patient with severe pancytopenia and reactive hemophagocytosis related to a Babesia microti infection. Babesia infection was acquired during a travel in the USA. CONCLUSION: Babesiosis should be considered in patients who traveled in endemic areas, especially North America for the most common agent Babesia microti. PMID- 23432954 TI - Impact of quality improvement strategies on the quality of life and well-being of individuals with spinal cord injury: a systematic review protocol. AB - BACKGROUND: After a spinal cord injury, quality of life, as well as the determinants of quality of life, has been widely assessed. However, to date, there have been no systematic reviews on the impact of quality improvement strategies, including self-management strategies, on the quality of life and well being of individuals with a spinal cord injury. The current protocol outlines a strategy for a systematic review that aims to identify, assess, and synthesize evidence on the impact of quality improvement strategies on the quality of life and physical and psychological well-being of individuals with spinal cord injury. METHODS/DESIGN: All study designs, except qualitative studies will be included. Studies reporting on quality improvement including audit and feedback, case management, team changes, electronic patient registries, clinician education, clinical reminders, facilitated relay of clinical information to clinicians, patient education, (promotion of) self-management, patient reminder systems, and continuous quality improvement among individuals with spinal cord injury will be included. The primary outcome is quality of life. The secondary outcomes are physical and psychological well-being. Studies will be included regardless of publication status, year of dissemination, or language of dissemination. Potentially relevant articles not written in English will be translated. We will search Medline, CINAHL, EMBASE, and PsycINFO. The use of these databases will be supplemented by other data sources, including unpublished data. Two independent reviewers will conduct all levels of screening, data abstraction, and quality appraisal. Results will be grouped according to the target group of the varying quality improvement strategies (that is, health system, health-care professionals, or patients) and/or by any other noteworthy grouping variable, such as etiology of spinal cord condition or by sex. If deemed appropriate, a meta-analysis will be conducted. DISCUSSION: This systematic review will identify those quality improvement strategies aimed at the health system, health-care professionals, and patients that impact the quality of life and well-being of individuals with spinal cord injury. Knowledge and application of such quality improvement strategies may reduce inappropriate health-care utilization costs, such as acute care inpatient readmission in the years post injury. Prospero registry number: CRD42012003058. PMID- 23432956 TI - On the future of mass-spectrometry-based lipidomics. AB - Lipids have highly diverse functions that go beyond cellular membrane structure and energy storage. One of the great challenges in lipid research will be to understand how the enormous complexity of lipid homeostasis is maintained. Genetic approaches combined with mass spectrometry-based lipidomics will help to elucidate how cells create and maintain their nonrandom lipid distribution within tissues, cells, organelles and lipid bilayers. Lipid homeostasis is crucial for many cellular processes and we are currently only beginning to understand the specific functions of lipids and the local environment that they create. PMID- 23432957 TI - Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer. AB - BACKGROUND: The loss of tumor suppressor gene expression is involved in the carcinogenesis of gastric cancer (GC). Klotho is a recently identified tumor suppressor gene that epigenetically inactivated in gastric cancer. However, the signaling pathways involved in the suppressive role of klotho have rarely been reported in gastric cancer. In this study, we investigated the involvement of klotho in gastric cancer cell proliferation, apoptosis, and autophagy as well as the associated signaling. METHODS: Methylation of klotho gene promoter in GC 7901, MNK-45 and AGS gastric cancer cells as well as GES-1 normal gastric epithelial cells was detected by bisulfate-based PCR. Restoration of klotho gene expression was established by applying a demethylating agent and delivering aklotho gene expression vector into GC-7901 cells. Cell viability was measured by CCK-8 assay. Cell apoptosis and cycling were analyzed by flow cytometry. Autophagy was measured by detecting LC3-I and LC3-II expression. Protein levels and phosphorylation were measured by Western blot assay. RESULTS: Methylation of klotho gene promoter and expression of the klotho gene were detected in GC cells. Restoration of klotho gene expression significantly inhibited cell proliferation, induced cell apoptosis, and increased LC3-I/LC3-II expression in GC cells. Restoration of klotho gene expression downregulated the phosphorylation levels of IGF-1 receptor, IRS-1, PI3K, Akt, and mTOR proteins. Both apoptosis and autophagy inhibitors blocked klotho-induced apoptosis and autophagy. CONCLUSION: Klotho is a tumor suppressor in gastric cancer, which regulates IGF-1R phosphorylation and the subsequent activation of IRS-1/PI3K/Akt/mTOR signaling, tumor cell proliferation, apoptosis, and autophagy. PMID- 23432955 TI - Transcriptional cross-activation between toxin-antitoxin systems of Escherichia coli. AB - BACKGROUND: Bacterial toxin-antitoxin (TA) systems are formed by potent regulatory or suicide factors (toxins) and their short-lived inhibitors (antitoxins). Antitoxins are DNA-binding proteins and auto-repress transcription of TA operons. Transcription of multiple TA operons is activated in temporarily non-growing persister cells that can resist killing by antibiotics. Consequently, the antitoxin levels of persisters must have been dropped and toxins are released of inhibition. RESULTS: Here, we describe transcriptional cross-activation between different TA systems of Escherichia coli. We find that the chromosomal relBEF operon is activated in response to production of the toxins MazF, MqsR, HicA, and HipA. Expression of the RelE toxin in turn induces transcription of several TA operons. We show that induction of mazEF during amino acid starvation depends on relBE and does not occur in a relBEF deletion mutant. Induction of TA operons has been previously shown to depend on Lon protease which is activated by polyphospate accumulation. We show that transcriptional cross-activation occurs also in strains deficient for Lon, ClpP, and HslV proteases and polyphosphate kinase. Furthermore, we find that toxins cleave the TA mRNA in vivo, which is followed by degradation of the antitoxin-encoding fragments and selective accumulation of the toxin-encoding regions. We show that these accumulating fragments can be translated to produce more toxin. CONCLUSION: Transcriptional activation followed by cleavage of the mRNA and disproportionate production of the toxin constitutes a possible positive feedback loop, which can fire other TA systems and cause bistable growth heterogeneity. Cross-interacting TA systems have a potential to form a complex network of mutually activating regulators in bacteria. PMID- 23432958 TI - Health care utilization among veterans with pain and posttraumatic stress symptoms. AB - OBJECTIVE: To examine health care utilization among veterans with both chronic pain and posttraumatic stress symptoms. METHODS: Retrospective cohort study of 40,716 veterans in a VA regional network from January 1, 2002 to January 1, 2007. Veterans were categorized into pain-only, posttraumatic stress disorder symptoms (PTSD)-only, and pain plus PTSD (pain+PTSD) comparison groups. Negative binomial models were used to compare adjusted rates of primary care, mental health, and specialty pain service use, as well as opioids, benzodiazepines, nonopioid analgesics, and antidepressant prescriptions. Rates of clinic visits were calculated by days per year, and rates of medication use were calculated by prescription months per year. Participants were followed for a mean duration of 47 months. RESULTS: Participants were 94.7% men and had a mean age of 58.9 years. Nearly all used primary care (99.2%), 37.1% used pain-related specialty care, and 33.8% used mental health services. Nonopioid and opioid analgesics were the most commonly used medications (63.7% and 53.8%, respectively). Except for mental health visits, which did not differ between PTSD-only and pain+PTSD groups, the pain+PTSD group used significantly more of all categories of health care services than the pain-only and PTSD-only groups. For example, the pain+PTSD group had 7% more primary care visits (rate ratio [RR]=1.07; 95% confidence interval [CI]: 1.05, 1.09) than the pain-only group and 46% more primary care visits than the PTSD-only group (RR=1.46; 95% CI: 1.40, 1.52). Adjusted rates of opioid, benzodiazepine, nonopioid analgesic, and antidepressant prescriptions were higher for the pain+PTSD group than either of the comparison groups. CONCLUSIONS: Our findings support our expectation that veterans with both pain and PTSD symptoms use more health care services than those with pain or PTSD symptoms alone. Research is needed to assess the health care costs associated with increases in health care utilization among these veterans. PMID- 23432959 TI - Video Endoscopic Inguinal Lymphadenectomy (VEIL)--a prospective critical perioperative assessment of feasibility and morbidity with points of technique in penile carcinoma. AB - BACKGROUND: Inguinal lymph node involvement is an important prognostic factor in penile cancer. Inguinal lymph node dissection allows staging and treatment of inguinal nodal disease. However, it causes morbidity and is associated with complications, such as lymphocele, skin loss and infection. Video Endoscopic Inguinal Lymphadenectomy (VEIL) is an endoscopic procedure, and it seems to be a new and attractive approach duplicating the standard open procedure with less morbidity. We present here a critical perioperative assessment with points of technique. METHODS: Ten patients with moderate to high grade penile carcinoma with clinically negative inguinal lymph nodes were subjected to elective VEIL. VEIL was done in standard surgical steps. Perioperative parameters were assessed that is - duration of the surgery, lymph-related complications, time until drain removal, lymph node yield, surgical emphysema and histopathological positivity of lymph nodes. RESULTS: Operative time for VEIL was 120 to 180 minutes. Lymph node yield was 7 to 12 lymph nodes. No skin related complications were seen with VEIL. Lymph related complications, that is, lymphocele, were seen in only two patients. The suction drain was removed after four to eight days (mean 5.1). Overall morbidity was 20% with VEIL. CONCLUSION: In our early experience, VEIL was a safe and feasible technique in patients with penile carcinoma with non palpable inguinal lymph nodes. It allows the removal of inguinal lymph nodes within the same limits as in conventional surgical dissection and potentially reduces surgical morbidity. PMID- 23432960 TI - Does obesity affect the accuracy of prostate-specific antigen (PSA) for predicting prostate cancer among men undergoing prostate biopsy. AB - What's known on the subject? and what does the study add?: As most urologist known, obesity significantly lowers serum PSA levels. So there is some concern about delayed diagnosis of prostate cancer in obese men. In the present study, we found that the accuracy level of PSA for detecting prostate cancer was not significantly different between different obesity levels. A well-designed study adjusting for several factors, e.g. diet, exercise, medication and comorbidity, which may possibly compensate for the associated effects on PSA levels, is needed for confirmation of the present findings. OBJECTIVE: To investigate prostate specific antigen (PSA) accuracy in detecting prostate cancer according to body mass index (BMI) in Asian men with a PSA level of <30 ng/mL using contemporary multicore (>= 12) prostate biopsy. PATIENTS AND METHODS: We reviewed the records of 3471 patients, whose initial PSA levels were <30 ng/mL, who underwent multicore (>= 12) transrectal ultrasound-guided prostate biopsy between January 2004 and May 2011. BMI was categorised as performed previously for the Asian population: <23, 23-24.9, 25-29.9, and >= 30 kg/m(2) . PSA accuracy for detecting prostate cancer in each BMI group was assessed based on the receiver operating characteristics-derived area under the curve. RESULTS: The mean age and median PSA level were inversely associated with BMI; the median PSA level in each BMI category was 7.84, 7.75, 7.33 and 5.79 ng/mL, respectively (P < 0.001). In all, prostate cancer was detected from biopsy in 1102 (31.7%) patients. The PSA accuracy for predicting prostate cancer in all patients was estimated to be 0.607, and PSA accuracies in each BMI category were 0.638, 0.572, 0.613 and 0.544, respectively; there was no significant difference among the groups in terms of PSA accuracy. CONCLUSIONS: The accuracy of PSA in predicting prostate cancer did not change regardless of BMI category in Asian men. However, as patients with higher BMIs had lower PSA levels than those with lower BMIs, it can therefore be suggested that the PSA threshold should be lower in obese men to discriminate between prostate cancer and benign conditions in the real clinical situation. PMID- 23432961 TI - Ulcerogenic risk assessment of diets for pigs in relation to gastric lesion prevalence. AB - BACKGROUND: Gastric ulcers in fattening pigs from intensive pork production can cause sudden deaths on farm and the grinding intensity of the diet appears to be among the risk factors. The objective of this work is to adopt the latest laboratory tests and thresholds for the ulcerogenic risk assessment of diets from experimental reports and verify the class of risk in relation to gastric lesion prevalence in reared finishers. RESULTS: Specificity and accuracy of feed safety tests based on the ulcerogenic risk of feed associated with the particle size distribution of diets were calculated on the occurrence of gastric lesions observed at a slaughterhouse: 41 lard-type hogs, fed with two diets [pelleted (n = 21 pigs) vs. mixed meal (n = 20 pigs)], analyzed at the laboratory of our Institute, were involved. Gross inspection at the abattoir allowed the identification of the development of macroscopic gastric lesions in the pigs (13/21) fed with a pelleted complete diet, ranked in Class 1 (high ulcerogenic risk) on laboratory assessment. Breakdown of gastric lesion severity: hyperkeratosis (13/13), mucosal erosions (11/13) and bleeding ulcers (2/13). This occurrence was compared to the morphology of stomach mucosa from 20 finishers fed with a mixed meal diet, ranked in Class 3 (low ulcerogenic risk), in which no gastric lesions were observed. Very fine particle (VFP) mass (<0.4 mm) according to cut off thresholds (>36%) for the safety ranking of diets, showed: 100% positive predictive value (PPV); 100% specificity; 88.1% accuracy; 72.2% sensitivity. CONCLUSIONS: Three factors emerged: the elevated mass (42.6%) of <0.4 mm particles in the pelleted complete diet confirmed the associated risk rank in Class 1 assessed by laboratory procedures, as gastric lesions were selectively observed in 61.9% of finishers fed with the high risk diet; in these animals, macroscopic gastric lesions occurred within four weeks and showed a sub clinical course, independently of severity; proper sieving analysis is necessary to define the VFP proportion in feedstuffs with certainty, as an adequate measure to assess the ulcerogenic risk class of the diet. PMID- 23432962 TI - Genome sequence-based species delimitation with confidence intervals and improved distance functions. AB - BACKGROUND: For the last 25 years species delimitation in prokaryotes (Archaea and Bacteria) was to a large extent based on DNA-DNA hybridization (DDH), a tedious lab procedure designed in the early 1970s that served its purpose astonishingly well in the absence of deciphered genome sequences. With the rapid progress in genome sequencing time has come to directly use the now available and easy to generate genome sequences for delimitation of species. GBDP (Genome Blast Distance Phylogeny) infers genome-to-genome distances between pairs of entirely or partially sequenced genomes, a digital, highly reliable estimator for the relatedness of genomes. Its application as an in-silico replacement for DDH was recently introduced. The main challenge in the implementation of such an application is to produce digital DDH values that must mimic the wet-lab DDH values as close as possible to ensure consistency in the Prokaryotic species concept. RESULTS: Correlation and regression analyses were used to determine the best-performing methods and the most influential parameters. GBDP was further enriched with a set of new features such as confidence intervals for intergenomic distances obtained via resampling or via the statistical models for DDH prediction and an additional family of distance functions. As in previous analyses, GBDP obtained the highest agreement with wet-lab DDH among all tested methods, but improved models led to a further increase in the accuracy of DDH prediction. Confidence intervals yielded stable results when inferred from the statistical models, whereas those obtained via resampling showed marked differences between the underlying distance functions. CONCLUSIONS: Despite the high accuracy of GBDP-based DDH prediction, inferences from limited empirical data are always associated with a certain degree of uncertainty. It is thus crucial to enrich in-silico DDH replacements with confidence-interval estimation, enabling the user to statistically evaluate the outcomes. Such methodological advancements, easily accessible through the web service at http://ggdc.dsmz.de, are crucial steps towards a consistent and truly genome sequence-based classification of microorganisms. PMID- 23432963 TI - BK virus genotype variance and discordant BK viremia PCR assay results. PMID- 23432965 TI - Resveratrol and quercetin-induced apoptosis of human 232B4 chronic lymphocytic leukemia cells by activation of caspase-3 and cell cycle arrest. AB - Chronic lymphocytic leukemia (CLL), defined by accumulation of pathogenic B cells, has a very complex biology due to various factors such as inherited, host, and environmental factors. Recently, finding new therapeutic agents or development of novel treatment strategies have been paid attention. Resveratrol and quercetin, important phytoalexins found in many plants, have been reported to have cytotoxic effects on various types of cancer. In this study, we examined cytotoxic, cytostatic, and apoptotic effects of these two important phenolic compounds on 232B4 human CLL cells. Cytotoxic effects of resveratrol and quercetin were determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using caspase-3 colorimetric assay. Annexin V FITC/PI double staining was performed to measure apoptotic cell population. Effects of resveratrol and quercetin on cell cycle profiles of CLL cells were investigated by flow cytometry. Treatment of CLL cells with resveratrol and quercetin caused dose dependent inhibition of cell proliferation and increased apoptotic cell population through induction of caspase-3 activity. Cell cycle analysis displayed cell cycle arrest mainly in G0/G1 for both polyphenols. Our data, in total, showed for the first time that resveratrol and quercetin might block CLL growth through inducing apoptosis and cell cycle arrest. PMID- 23432964 TI - High prevalence of obesity among women who enrolled in HIV prevention trials in KwaZulu-Natal, South Africa: healthy diet and life style messages should be integrated into HIV prevention programs. AB - BACKGROUND: In South Africa, poverty and the dual epidemics of HIV and tuberculosis underscore the need for prevention efforts for obesity. The aim of this study was to describe the prevalence of obesity in a cohort of South African women and discuss the implications for public health practices. METHODS: A total of 5,495 HIV-negative women from KwaZulu-Natal, South Africa enrolled in three microbicide trials during the period of 2002-2008 were categorised as normal weight (body mass index (BMI: 18.6-<25), overweight (BMI: 25-<30) or obese (BMI: 30+). Incidence of HIV and other sexually transmitted infections such as Chlamydia and gonorrhoea were also estimated and compared by BMI groups. Combined data was analysed using STATA 10.0. RESULTS: Approximately 70% of the sample population was classified as being overweight or obese. Older age and lack of education were determined to be significant predictors of obesity. Women who were 35 years or older were more than three times as likely to be overweight and more than 12 times as likely to be obese compared to the youngest group. The highest HIV and STI incidence rates were observed among those with BMI <25 kg/m(2) (normal weight) compared to women with BMI more than 25 kg/m2 (8.1 and 19.8 per 100 person-year respectively, P<0.001, both). CONCLUSION: Effective obesity prevention strategies are needed to re-formulate HIV prevention programmes by incorporating healthy diet and life style messages to target those who are at highest risk not just for HIV infection but also for non-communicable diseases. PMID- 23432966 TI - A study comparing the efficacy and risk of adverse events using two techniques of electrocautery for the treatment of seborrheic keratoses. PMID- 23432967 TI - Cost comparison of adding pregabalin or gabapentin for the first time to the therapy of patients with painful axial radiculopathy treated in Spain. AB - OBJECTIVES: This paper aims to compare the costs of initiating pregabalin or gabapentin in the therapeutic management of patients with painful axial radiculopathy in routine medical practice. METHODS: A retrospective claim database analysis was carried-out using medical records of patients of both gender aged >18 years with axial painful radiculopathy (ICD-9-CM codes: 353.0 [cervical], 353.3 [thoracic] or 353.1 [lumbar]) who initiated pregabalin or gabapentin therapy between 2006 and 2008. The economic evaluation included healthcare resource utilisation and corresponding costs from a third-payer perspective during 12 months post index date. Estimates of indirect costs due to sick leave were also computed. RESULTS: A total of 571 records were eligible for analysis: 375 (66%) treated with pregabalin and 193 (34%) gabapentin. Time since diagnosis, duration of treatment, prevalence of most co-morbidities and previous use of analgesics were comparable. However, concomitant use of analgesics was higher in the gabapentin cohort; 3.1 (1.7) vs. 2.8 (1.8); p<0.05, mainly due to greater use of opioids (31.1% vs. 21.2%; p<0.05) and non-narcotic drugs (63.7% vs. 52.1%; p<0.01). Adjusted total costs per patient were significantly lower in the pregabalin group; ?2.472 (2.101-2.836) vs. ?3.346 (2.866-3.825); p=0.005, due to lower absenteeism costs; ?1.012 (658-1.365) vs. ?1.595 (1.129-2.062); p=0.042, and lower adjusted healthcare costs; ?1.460 (1.360-1.560) vs. ?1.750 (1.618 1.882); p=0.001. CONCLUSIONS: In a population setting, pregabalin-treated patients with painful radiculopathies were considerably less costly for the healthcare payer than those treated with gabapentin in routine clinical practice. Patients treated with pregabalin had significantly fewer days of sick leave than gabapentin-treated patients. PMID- 23432968 TI - Citrus aurantium L. essential oil exhibits anxiolytic-like activity mediated by 5 HT(1A)-receptors and reduces cholesterol after repeated oral treatment. AB - BACKGROUND: The current treatments for anxiety disorders and depression have multiple adverse effects in addition to a delayed onset of action, which has prompted efforts to find new substances with potential activity in these disorders. Citrus aurantium was chosen based on ethnopharmacological data because traditional medicine refers to the Citrus genus as useful in diminishing the symptoms of anxiety or insomnia, and C. aurantium has more recently been proposed as an adjuvant for antidepressants. In the present work, we investigated the biological activity underlying the anxiolytic and antidepressant effects of C. aurantium essential oil (EO), the putative mechanism of the anxiolytic-like effect, and the neurochemical changes in specific brain structures of mice after acute treatment. We also monitored the mice for possible signs of toxicity after a 14-day treatment. METHODS: The anxiolytic-like activity of the EO was investigated in a light/dark box, and the antidepressant activity was investigated in a forced swim test. Flumazenil, a competitive antagonist of benzodiazepine binding, and the selective 5-HT(1A) receptor antagonist WAY100635 were used in the experimental procedures to determine the mechanism of action of the EO. To exclude false positive results due to motor impairment, the mice were submitted to the rotarod test. RESULTS: The data suggest that the anxiolytic-like activity observed in the light/dark box procedure after acute (5 mg/kg) or 14-day repeated (1 mg/kg/day) dosing was mediated by the serotonergic system (5-HT(1A) receptors). Acute treatment with the EO showed no activity in the forced swim test, which is sensitive to antidepressants. A neurochemical evaluation showed no alterations in neurotransmitter levels in the cortex, the striatum, the pons, and the hypothalamus. Furthermore, no locomotor impairment or signs of toxicity or biochemical changes, except a reduction in cholesterol levels, were observed after treatment with the EO. CONCLUSION: This work contributes to a better understanding of the biological activity of C. aurantium EO by characterizing the mechanism of action underlying its anxiolytic-like activity. PMID- 23432969 TI - Safety and efficacy of calcium and magnesium infusions in the chemoprevention of oxaliplatin-induced sensory neuropathy in gastrointestinal cancers. AB - OBJECTIVE: To derive a more precise estimation on the safety and efficacy of calcium and magnesium (Ca and Mg) infusions in the prevention of oxaliplatin induced sensory neuropathy. METHODS: A total of 16 studies including 1765 individuals were involved in this meta-analysis. Odds ratio (OR) and its 95% confidence interval (CI) were calculated. RESULTS: The difference in the incidence of oxaliplatin-induced neuropathy grade >= 1 was statistically significant between the Ca and Mg infusions treatment group and the untreated group (National Cancer Institute common toxicity criteria [NCI CTC]: OR 0.44, 95% CI 0.31-0.62, P = 0.000; oxaliplatin-specific scale [OSS]: OR 0.30, 95% CI 0.20 0.45, P = 0.000). Similar results were found in the incidences of oxaliplatin induced neuropathy grade >= 2 (NCI CTC: OR 0.60, 95% CI 0.46-0.77, P = 0.000; OSS: OR 0.45, 95% CI 0.30-0.67, P = 0.000). However, we did not detect a trend of fewer oxaliplatin-induced neuropathy grade >= 3 incidences in the Ca and Mg infusions treatment group than the untreated group (NCI CTC: OR 0.67, 95% CI 0.44 1.01, P = 0.054; OSS: OR 0.66, 95% CI 0.34-1.29, P = 0.224). There was no difference in the response rate between the Ca and Mg treated group and the untreated group (OR 0.89, 95% CI 0.67-1.17, P = 0.391). CONCLUSION: Ca and Mg infusions do not alter the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers, which may be reasonable to add them to lessen the incidence of neuropathy. PMID- 23432970 TI - Monocyte chemoattractant protein-1 promoter polymorphism and plasma levels in alzheimer's disease. AB - BACKGROUND: Neurodegenerative disorders such Alzheimer's disease (AD) are often characterized by senile plaques and neurofibrillary tangle. In addition, reactive astrogliosis, microglia activation and a chronic inflammation are found in AD brain. Activated microglia has been reported to express a large number of beta chemokines including monocyte chemoattractant protein-1 (MCP-1). The potential role of MCP-1 in AD pathogenesis is supported by the over expression of MCP-1 associated with an increase of amyloid deposition in transgenic mice. MCP-1 protein may be regulated by a single nucleotide polymorphism (SNP) occurring at position -2518 of the MCP-1 gene promoter. In this paper we correlated the A 2518G MCP-1 SNP distribution in three different populations: AD, control and MCI (mild cognitive impairment) population to evaluate whether this SNP might be a risk factor for AD or for MCI-AD conversion. MCP-1 plasma levels were also measured and correlated to the cognitive impairment (CIND) and AD risk. RESULTS: No differences in genotype distribution and allele frequencies of A-2518G MCP-1 SNP among AD patients, MCI subjects and controls were observed even after APOEe4 variation adjustment with logistic regression. However in MCI subjects, followed up for two years, this SNP appears to influence the progression of the disease; being the G allele slightly more frequent in MCI patients that developed AD. MCP 1 plasma levels were different among CIND (cognitive impairment but no dementia), AD and controls. The MCP-1 A-2518G promoter polymorphism did not affect MCP-1 plasma levels within the three populations. CONCLUSIONS: MCP-1 G allele did not affect the risk of AD, but slightly influenced MCI conversion to AD and MCP-1 plasma levels were increased in subjects with preclinical AD. PMID- 23432972 TI - Liposome: classification, preparation, and applications. AB - Liposomes, sphere-shaped vesicles consisting of one or more phospholipid bilayers, were first described in the mid-60s. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Since then, liposomes have made their way to the market. Among several talented new drug delivery systems, liposomes characterize an advanced technology to deliver active molecules to the site of action, and at present, several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles to 'second-generation liposomes', in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability and regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents. PMID- 23432973 TI - Pneumatisation of turbinates and paranasal sinuses in children: case report. AB - OBJECTIVE: To describe a rare case of multiple anatomical variations in the sinonasal skeleton of an adolescent with chronic rhinosinusitis, together with its successful surgical management. CASE REPORT: A 15-year-old male adolescent was referred with a 3-year history of nasal blockage and hyposmia. His symptoms did not improve on maximal medical therapy. A pre-operative computed tomography scan revealed numerous anatomical variations in his nose and paranasal sinuses. He underwent neuronavigation-assisted endoscopic sinus surgery without complication, and with subsequent resolution of his symptoms at 10 months. CONCLUSION: Chronic rhinosinusitis in children offers its own set of unique surgical challenges. The effectiveness and safety of sinus surgery in this population can be improved through the knowledge of anatomical variants, and is aided by the use of image guidance systems. PMID- 23432971 TI - Polyamines and cancer: implications for chemotherapy and chemoprevention. AB - Polyamines are small organic cations that are essential for normal cell growth and development in eukaryotes. Under normal physiological conditions, intracellular polyamine concentrations are tightly regulated through a dynamic network of biosynthetic and catabolic enzymes, and a poorly characterised transport system. This precise regulation ensures that the intracellular concentration of polyamines is maintained within strictly controlled limits. It has frequently been observed that the metabolism of, and the requirement for, polyamines in tumours is frequently dysregulated. Elevated levels of polyamines have been associated with breast, colon, lung, prostate and skin cancers, and altered levels of rate-limiting enzymes in both biosynthesis and catabolism have been observed. Based on these observations and the absolute requirement for polyamines in tumour growth, the polyamine pathway is a rational target for chemoprevention and chemotherapeutics. Here we describe the recent advances made in the polyamine field and focus on the roles of polyamines and polyamine metabolism in neoplasia through a discussion of the current animal models for the polyamine pathway, chemotherapeutic strategies that target the polyamine pathway, chemotherapeutic clinical trials for polyamine pathway-specific drugs and ongoing clinical trials targeting polyamine biosynthesis. PMID- 23432974 TI - Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. AB - BACKGROUND: The epidemiology of invasive mold infections (IMI) in transplant recipients differs based on geography, hosts, preventative strategies, and methods of diagnosis. METHODS: We conducted a retrospective observational study to evaluate the epidemiology of proven and probable IMI, using prior definitions, among all adult hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients in the era of "classic" culture-based diagnostics (2000-2009). Epidemiology was evaluated before and after an initiative was begun to increase bronchoscopy in HSCT recipients after 2005. RESULTS: In total, 106 patients with one IMI were identified. Invasive aspergillosis (IA) was the most common IMI (69; 65.1%), followed by mucormycosis (9; 8.5%). The overall rate of IMI (and IA) was 3.5% (2.5%) in allogeneic HSCT recipients. The overall incidence for IMI among lung, kidney, liver, and heart transplant recipients was 49, 2, 11, and 10 per 1000 person-years, respectively. The observed rate of IMI among human leukocyte antigen-matched unrelated and haploidentical HSCT recipients increased from 0.6% annually to 3.0% after bronchoscopy initiation (P < 0.05). The 12-week mortality among allogeneic HSCT, liver, kidney, heart, and lung recipients with IMI was 52.4%, 47.1%, 27.8%, 16.7%, and 9.5%, respectively. Among allogeneic HSCT (odds ratio [OR]: 0.07, P = 0.007) and SOT (OR: 0.22, P = 0.05) recipients with IA, normal platelet count was associated with improved survival. Male gender (OR: 14.4, P = 0.007) and elevated bilirubin (OR: 5.7, P = 0.04) were significant predictors of mortality for allogeneic HSCT and SOT recipients with IA, respectively. CONCLUSIONS: During the era of culture-based diagnostics, observed rates of IMI were low among all transplants except lung transplant recipients, with relatively higher mortality rates. Diagnostic aggressiveness and host variables impact the reported incidence and outcome of IMI and likely account for institutional variability in multicenter studies. Definitions to standardize diagnoses among SOT recipients are needed. PMID- 23432975 TI - Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome, GH deficiency, Arnold Chiari malformation and pituitary hypoplasia. AB - BACKGROUND: Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder (prevalence 1:125,000) characterised by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa and short stature. The known genetic causes are point mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) (5%). CASE PRESENTATION: We describe, for the first time in literature, a RTS Caucasian girl, 14-year-old, with growth hormone (GH) deficiency, pituitary hypoplasia, Arnold Chiari malformation type 1, double syringomyelic cavity and a novel CREBBP mutation (c.3546insCC). CONCLUSION: We hypothesize that CREBBP mutation we have identified in this patient could be responsible also for RTS atypical features as GH deficiency and pituitary hypoplasia. PMID- 23432976 TI - A case of dominant dystrophic epidermolysis bullosa with diabetes mellitus presenting as progressive recalcitrant blisters and erosions. PMID- 23432977 TI - Prevalence of diabetic nephropathy complicating non-diabetic renal disease among Chinese patients with type 2 diabetes mellitus. AB - BACKGROUND: The incidence of diabetes mellitus (DM) and diabetic nephropathy (DN) have risen rapidly in the past few decades and have become an economic burden to the healthcare system in China. DN is a major complication of DM and is a leading cause of end-stage renal disease (ESRD). The occurrence of non-diabetic renal disease (NDRD) in diabetic patients has been increasingly recognized in recent years. It is generally believed that it is difficult to reverse DN, whereas some cases of NDRD are readily treatable and remittable. However, DN is known to co exist with NDRD in a poorly defined population of patients with type 2 diabetes mellitus (T2DM). This study estimated the prevalence of co-existing DN and NDRD in Chinese patients. METHODS: Data were retrospectively analyzed from 244 patients with T2DM who had undergone a renal biopsy between January 2003 and December 2011 at the Nephrology Department, China-Japan Friendship Hospital, China. Male patients numbered 151 (61.9%) of the study population. The biopsies were performed because urinary abnormalities or renal function were atypical of a diagnosis of DN. Biopsy samples were examined using light, immunofluorescence (IF) and electron microscopy (EM). Clinical parameters were recorded for each patient at the time of biopsy. RESULTS: Nineteen of 244 diabetic patients (7.8%) had co-existing DN and NDRD. These patients showed clinical features and pathologic characteristics of DN, including a high prevalence of diabetic retinopathy (89.5%), a long duration of diabetes, increased thickness of the glomerular basement membrane (GBM) and mesangial expansion. However, they also presented with clinical findings which were inconsistent with DN, such as hematuria, rapidly progressive renal failure and marked proteinuria. Immunoglobulin A (IgA) nephropathy was apparent in 10 out of the 19 patients (52.6%), tubulointerstitial lesions were found in four patients (21.1%), membrano proliferative glomerulonephritis (MPGN) in three patients (15.8%) and membranous nephropathy (MN) in two patients (10.5%). CONCLUSION: Retrospective analysis of biopsy data suggests that approximately 8% of Chinese patients with T2DM may have co-existing DN and NDRD. The most common histological diagnosis in our small series was IgA nephropathy. PMID- 23432978 TI - Case report: Breast cancer associated with contralateral tuberculosis of axillary lymph nodes. AB - BACKGROUND: Breast cancer coexisting with tuberculous axillary lymph nodes is rare. CASE REPORT: We report a 69 years old Yemeni patient with a left breast invasive ductal carcinoma associated with contralateral tuberculous axillary lymph nodes containing microcalcifications mimicking malignancy. The patient had to be investigated for the possibility of bilateral breast cancer since she had no history of previous exposure to tuberculosis. CONCLUSION: Tuberculosis involving lymph nodes can create a diagnostic dilemma in the presence of a malignant process. The presence of calcifications in lymph nodes should raise the possibility of tuberculosis even in the absence of contact history with tuberculosis. PMID- 23432979 TI - Leukotriene C4 aggravates bleomycin-induced pulmonary fibrosis in mice. AB - BACKGROUND AND OBJECTIVE: Synthesis of cysteinyl leukotrienes (cys-LT) is thought to cause inflammatory disorders such as bronchial asthma and allergic rhinitis. Recent reports have suggested that leukotriene C4 (LTC4 ) is an important regulator of pulmonary fibrosis. This study examined the effect of LTC4 in LTC4 synthase-overexpressed transgenic mice with bleomycin-induced pulmonary fibrosis. The function of lung-derived fibroblasts from transgenic mice was also investigated. METHODS: Bleomycin was administrated to transgenic mice and wild type (WT) mice by intratracheal instillation. Concentrations of interleukin (IL) 4 and -13, interferon-gamma, and transforming growth factor (TGF)-beta1 in bronchoalveolar lavage fluid were measured 1, 3, 7 and 14 days after the administration of bleomycin. Lung tissue was examined histopathologically on day 14. In addition, lung-derived fibroblasts from transgenic and WT mice were cultured for 7 days. Expression of TGF-beta1 mRNA was measured by real-time polymerase chain reaction. RESULTS: Both the pathological scores for pulmonary fibrosis (3.8 +/- 0.4 vs 2.0 +/- 0.1, P < 0.05) and the levels of IL-4 (12.1 +/- 2.3 vs <7.8 pg/mL, P < 0.05), IL-13 (26.5 +/- 5.2 vs <7.8 pg/mL, P < 0.01) and TGF-beta1 (211.1 +/- 30.2 vs 21.3 +/- 1.2 pg/mL, P < 0.01) on day 14 were significantly greater in transgenic than in WT mice. Furthermore, the reduction of LTC4 by pranlukast hydrate, a cys-LT1 receptor antagonist, in fibroblasts from transgenic significantly (P < 0.05) decreased the expression of TGF-beta1 mRNA (by ~50%) compared with those from WT mice. CONCLUSIONS: Overexpression of LTC4 , amplifies bleomycin-induced pulmonary fibrosis in mice. Our findings suggest a role for LTC4 in lung fibrosis. PMID- 23432980 TI - ETHNOPRED: a novel machine learning method for accurate continental and sub continental ancestry identification and population stratification correction. AB - BACKGROUND: Population stratification is a systematic difference in allele frequencies between subpopulations. This can lead to spurious association findings in the case-control genome wide association studies (GWASs) used to identify single nucleotide polymorphisms (SNPs) associated with disease-linked phenotypes. Methods such as self-declared ancestry, ancestry informative markers, genomic control, structured association, and principal component analysis are used to assess and correct population stratification but each has limitations. We provide an alternative technique to address population stratification. RESULTS: We propose a novel machine learning method, ETHNOPRED, which uses the genotype and ethnicity data from the HapMap project to learn ensembles of disjoint decision trees, capable of accurately predicting an individual's continental and sub-continental ancestry. To predict an individual's continental ancestry, ETHNOPRED produced an ensemble of 3 decision trees involving a total of 10 SNPs, with 10-fold cross validation accuracy of 100% using HapMap II dataset. We extended this model to involve 29 disjoint decision trees over 149 SNPs, and showed that this ensemble has an accuracy of >= 99.9%, even if some of those 149 SNP values were missing. On an independent dataset, predominantly of Caucasian origin, our continental classifier showed 96.8% accuracy and improved genomic control's lambda from 1.22 to 1.11. We next used the HapMap III dataset to learn classifiers to distinguish European subpopulations (North-Western vs. Southern), East Asian subpopulations (Chinese vs. Japanese), African subpopulations (Eastern vs. Western), North American subpopulations (European vs. Chinese vs. African vs. Mexican vs. Indian), and Kenyan subpopulations (Luhya vs. Maasai). In these cases, ETHNOPRED produced ensembles of 3, 39, 21, 11, and 25 disjoint decision trees, respectively involving 31, 502, 526, 242 and 271 SNPs, with 10-fold cross validation accuracy of 86.5% +/- 2.4%, 95.6% +/- 3.9%, 95.6% +/- 2.1%, 98.3% +/- 2.0%, and 95.9% +/- 1.5%. However, ETHNOPRED was unable to produce a classifier that can accurately distinguish Chinese in Beijing vs. Chinese in Denver. CONCLUSIONS: ETHNOPRED is a novel technique for producing classifiers that can identify an individual's continental and sub-continental heritage, based on a small number of SNPs. We show that its learned classifiers are simple, cost efficient, accurate, transparent, flexible, fast, applicable to large scale GWASs, and robust to missing values. PMID- 23432981 TI - Phylogenetic analysis of erythritol catabolic loci within the Rhizobiales and proteobacteria. AB - BACKGROUND: The ability to use erythritol as a sole carbon source is not universal among the Rhizobiaceae. Based on the relatedness to the catabolic genes in Brucella it has been suggested that the eryABCD operon may have been horizontally transferred into Rhizobium. During work characterizing a locus necessary for the transport and catabolism of erythritol, adonitol and L-arabitol in Sinorhizobium meliloti, we became interested in the differences between the erythritol loci of S. meliloti and R. leguminosarum. Utilizing the Ortholog Neighborhood Viewer from the DOE Joint Genome Institute database it appeared that loci for erythritol and polyol utilization had distinct arrangements that suggested these loci may have undergone genetic rearrangements. RESULTS: A data set was established of genetic loci containing erythritol/polyol orthologs for 19 different proteobacterial species. These loci were analyzed for genetic content and arrangement of genes associated with erythritol, adonitol and L-arabitol catabolism. Phylogenetic trees were constructed for core erythritol catabolic genes and contrasted with the species phylogeny. Additionally, phylogenetic trees were constructed for genes that showed differences in arrangement among the putative erythritol loci in these species. CONCLUSIONS: Three distinct erythritol/polyol loci arrangements have been identified that reflect metabolic need or specialization. Comparison of the phylogenetic trees of core erythritol catabolic genes with species phylogeny provides evidence that is consistent with these loci having been horizontally transferred from the alpha-proteobacteria into both the beta and gamma-proteobacteria. ABC transporters within these loci adopt 2 unique genetic arrangements, and although biological data suggests they are functional erythritol transporters, phylogenetic analysis suggests they may not be orthologs and probably should be considered analogs. Finally, evidence for the presence of paralogs, and xenologs of erythritol catabolic genes in some of the genomes included in the analysis is provided. PMID- 23432982 TI - Relationship between non-alcoholic fatty liver disease and kidney function: a communication between two organs that needs further exploration. AB - Non-alcoholic fatty liver disease (NAFLD) is now regarded as hepatic component of the metabolic syndrome. In addition, NAFLD has emerged as a growing public health problem worldwide and an important challenge for health authorities. NAFLD is associated with insulin resistance and hyperlipidaemia and this appears as the potential pathogenic role of NAFLD in the development and progression of chronic kidney disease (CKD). Interestingly, NAFLD and CKD may share common pathogenic mechanisms like obesity, abdominal obesity, insulin resistance, hyperlipidaemia, hypertension and inflammation. Importantly, the association between NAFLD and CKD is also being shown to be independent of obesity, hypertension, and other potentially confounding features of the metabolic syndrome, and it occurs both in patients without diabetes and in those with diabetes. How the liver communicates with kidney in individuals with NAFLD is not well known and indeed an urgent research is needed to further elucidate the complex and intertwined mechanisms that link NAFLD and CKD. One potential pathway for future exploration may be inflammatory mediators in NAFLD that may lead to deterioration in renal function. In addition, large clinical studies are needed to study the impact of NAFLD on the progression of CKD and in particular during dialysis and transplant and importantly how treatment of NAFLD and weight loss will have reversible potential benefit in improving renal function. PMID- 23432983 TI - Infection with Helicobacter pylori strains carrying babA2 and cagA is associated with an increased risk of peptic ulcer disease development in Iraq. AB - BACKGROUND AND STUDY AIM: Several genes of Helicobacter pylori, such as vacA, cagA, iceA and babA, have been reported to significantly increase the risk of gastrointestinal diseases. The aim of this study was to study the relationship between H. pylori virulence factors and clinical outcomes and identify the independent markers of peptic ulcer disease in Iraq. PATIENTS AND METHODS: DNA was extracted from specimens taken from 154 unselected H. Pylori positive Iraqi patients. Genotyping was performed by the polymerase chain reaction (PCR), using specific primers for cagA, vacA (s, m), iceA and babA2 genes. RESULTS: A total of 56 (82%) peptic ulcer disease (PUD) patients carried cagA+ strains, significantly more than the 56 (65%) non-ulcer disease (NUD) patients (p=0.017). The difference in the prevalence of babA2 positivity was significant between patients with NUD (33.7%) and PUD (58.8%) (p=0.002). In addition, babA2 was associated as an independent factor, with PUD (p=0.005; odds ratio (OR)=0.4; confidence interval (CI)=0.18-0.68) followed by cagA (p=0.05; OR=0.4; CI=0.18-0.85). Forty-five isolates (29%) were typed as 'triple positive' strains, and their presence was significantly associated with PUD (p=0.001). CONCLUSION: The cagA and babA2 genotypes might be considered as useful markers for PUD patients. However, iceA1 and iceA2 seem not to be good markers for the disease. The presence of H. pylori strains with triple-positive status is of high clinical relevance to H. pylori associated diseases. PMID- 23432984 TI - The potential role of APOBEC3G in limiting replication of hepatitis B virus. AB - BACKGROUND AND STUDY AIMS: Recent findings introduced APOBEC3G (A3G) as a host factor that blocks viral replication. It induces G to A hypermutations in viral DNA at the step of reverse transcription and in response to interferon. This study aimed to investigate the expression of liver A3G protein in association with both replication of hepatitis B virus (HBV) and frequency of G to A mutations in BCP (basal core promoter)-PC (pre-core) region. PATIENTS AND METHODS: Fifty-one liver biopsies of naive chronic hepatitis B (CHB) patients enrolled for the expression of A3G were done by immunohistochemistry (IHC) standard method. The presence of HBV DNA and sequences of BCP-PC region at the time of liver biopsy was investigated in all patients. RESULTS: Among 34 patients with detectable HBV DNA, 31 carried 1-5 G to A mutations in the BCP-PC region. IHC results showed that the expression level of A3G in CHB patients' liver was very low. Of all patients, A3G is expressed in three undetectable HBV DNA subjects and a patient with 2.24*10(4) copies ml(-1) of HBV DNA. G to A mutated residues were indicated at positions 1727, 1757 and 1896 of the HBV genome of this patient. CONCLUSION: This study indicates that despite very low levels of both A3G in liver and the number of positive subjects, A3G has a potential role to restrict the in vivo replication of HBV. PMID- 23432985 TI - Predominance of females with oesophageal cancer in Gezira, Central Sudan. AB - BACKGROUND: The majority of oesophageal cancer cases occur in developing countries. Globally males predominate. OBJECTIVE: This study aims to review the clinical aspects of oesophageal carcinoma in Sudanese patients referred to endoscopy in Gezira, Central Sudan. PATIENTS & METHOD: Data were collected from patients who underwent endoscopy during the period from 2005 to 2007 at The Gezira Centre for Gastroenterology Endoscopies and Laparoscopic Surgery. Demographic and clinical data including; sex, age, locality of residence, clinical presentation, tumour site and morphology were collected and analysed. RESULTS: Seven hundred and two patients were consecutively referred to our centre for endoscopy. Seventy-three out of 702 patients (9.6%) referred for endoscopy proved to have oesophageal cancer. Fifty-five out of 73 patients (75.3%) were females generating a male to female ratio of 1:3.3. The mean age of females was 52.75+/-11.66years and that of males was 66.11+/-9.52. Sixteen (21.9%) patients came from the Managil; 14 (19.2%) from Hasaheesa and Rufaa; 14 (19.2%) from Blue Nile; 10 (13.7%) from Wadmedani (Central Sudan) and 19 (26%) from Elfaw and Kassala. In most cases (75.3%), the tumours were located in the middle third of the oesophagus. 79.5% of the tumours were squamous cell type. CONCLUSION: Patients referred for endoscopy to The Gezira Centre for Gastroenterology, Endoscopies and Laparoscopic Surgery in Gezira revealed a greater proportion of women than of men diagnosed with the disease (1:3.3). More studies are needed to investigate the epidemiology of this disease and to identify the reason for the apparent gender uneven manifestation. PMID- 23432986 TI - Complications in paediatric liver transplant from Kuwait when transplanted abroad. AB - BACKGROUND AND STUDY AIMS: Since the introduction of liver transplantation (LTx) in children suffering from liver failure in 1963, many centres around the world have offered this service to children that have no other alternative. The aim of this retrospective study is to analyse the results of paediatric liver transplant in Kuwait over the last decade. PATIENTS AND METHODS: A retrospective chart review was done involving paediatric patients during the time period of 1995 2004. The information collected included patient demographics, indications for liver transplantation, survival of both patient and allograft, and complications. RESULTS: A total of 16 cases were found and analysed. The mean age was 3.6years (ranged 5months-17years). There were nine boys and seven girls. The most common indications for LTx were biliary atresia and metabolic liver disease. All the liver transplants were done abroad. There were totally nine deceased donor and seven living related cases. The complications were acute cellular rejection in five, hypertension in two, biliary complications in four, cytomegalovirus (CMV) infection in three and post lymphoproliferative disease in two cases. All but one patient are presently alive. CONCLUSION: The above information demonstrates that LTx in Kuwati children is safe and improves the quality of life for those that would otherwise have no other alternative. PMID- 23432987 TI - Effects of Ramadan fasting on peptic ulcer disease as diagnosed by upper gastrointestinal endoscopy. AB - BACKGROUND AND STUDY AIMS: The diagnostic methods such as upper gastrointestinal endoscopy (UGE) have played an important role in the evaluation of peptic ulcer (PU). Every year, millions of Muslims fast in Ramadan month. The aim of this study was to evaluate the effect of fasting on PU via UGE. PATIENTS AND METHODS: A total of 321 patients in the period from 2009 to 2011, who underwent UGE as a diagnostic work-up mainly for epigastric pain, were analysed. Patients were divided into three groups: Patients who have been evaluated by UGE, in the month just before Ramadan (group I, n=69), in Ramadan month (group II, n=132) and in the month just after Ramadan (group III, n=120). Continuous data were expressed as the mean+/-SD, and were compared with one-way analysis of variance (ANOVA) test amongst groups. Categorical data were given as percentages and were compared with the chi-squared test. RESULTS: Epigastric pain was the most common indication for referral in each group. Interestingly, the indication 'bleeding' was found to be the least in group II, but was far from statistical significance. The highest prevalence of duodenal ulcers and duodenitis was found in group II; the differences to the other groups were statistically significant. CONCLUSION: Duodenal ulcers and duodenitis were found more during Ramadan month. We recommend that, the patients with epigastric pain may fast by taking their medications. PMID- 23432988 TI - Acute pancreatitis complicating acute hepatitis A virus infection. AB - Acute pancreatitis complicating acute hepatitis A is very rare especially in children. We report here an 11 year old female patient with picture of acute hepatitis proved to be caused by hepatitis A. One week later patient's condition worsened, she was jaundiced, with persistent vomiting and looked acutely ill and uncomfortable with severe steady abdominal pain mainly in the epigastrium and upper quadrants. Acute pancreatitis was suspected and proved by a clinical picture associated with elevated serum amylase and serum lipase and by MRCP. The patient was managed conservatively with gradual clinical and laboratory improvement, and she was discharged after one week in a good clinical condition. PMID- 23432989 TI - An infrequent cause of colonic stenosis. AB - We present the case of a young woman with intestinal endometriosis, in which colonic stenosis unusually represents the clinical onset; diagnostic workup allows to highlight the role of gastrointestinal ultrasounds that suggest the nature of the stenosis. PMID- 23432990 TI - Abdominal cocoon--a rare case of intestinal obstruction. A report of two cases. AB - We present the imaging findings in 2 adolescent girls with abdominal cocoon formation, a rare cause of intestinal obstruction. It may be primary/idiopathic or secondary in nature and is characterized by small bowel encapsulation. Familiarity with the imaging findings and a high index of suspicion helps in reaching the diagnosis pre-operatively in this rare condition and hence planning surgical management. PMID- 23432993 TI - The expression and significance of miR-17-92 cluster miRs in CD4+ T cells from patients with systemic lupus erythematosus. PMID- 23432992 TI - A thematic analysis of quality of life in lung transplant: the existing evidence and implications for future directions. AB - Health-related quality of life (HRQL) has been assessed in various lung transplantation (LT) investigations but never analyzed systematically across multiple studies. We addressed this knowledge gap through a systematic literature review. We searched the PubMed, CINAHL and PsychInfo databases for publications from January 1, 1983 to December 31, 2011. We performed a thematic analysis of published studies of HRQL in LT. Using a comparative, consensus-based approach, we identified themes that consistently emerged from the data, classifying each study according to primary and secondary thematic categories as well as by study design. Of 749 publications initially identified, 73 remained after exclusions. Seven core themes emerged: (1) Determinants of HRQL; (2) Psychosocial factors in HRQL; (3) Pre- and posttransplant HRQL comparisons; (4) Long-term longitudinal HRQL studies; (5) HRQL effects of therapies and interventions; (6) HRQL instrument validation and methodology; (7) HRQL prediction of clinical outcomes. Overall, LT significantly and substantially improves HRQL, predominantly in domains related to physical health and functioning. The existing literature demonstrates substantial heterogeneity in methodology and approach; relatively few studies assessed HRQL longitudinally within the same persons. Opportunity for future study lies in validating existing and potential novel HRQL instruments and further elucidating the determinants of HRQL through longitudinal multidimensional investigation. PMID- 23432994 TI - An investigation of the effects of the antioxidants, ebselen or N-acetyl cysteine on human peripheral blood mononuclear cells and T cells. AB - BACKGROUND: The research literature has documented age-related increases in genetic damage, including oxidative DNA damage, in human T lymphocytes, in vitro and ex vivo. Such damage has the potential to interfere with the ability of the T cells to proliferate at times when they need to, such as when antigen challenged. The consequence of this could be a sub-optimal immune response in vivo. CONTEXT AND PURPOSE: The purpose of the research reported in this paper was to investigate the impact of two antioxidants, which can be administered in vivo, Ebselen and N-acetyl L-cysteine, on the age-related increase in genetic damage, and on T cell proliferation and lifespan. In vitro human T cell clones, ex vivo peripheral blood mononuclear cells or T cells were supplemented with different concentrations of antioxidants, under standard conditions and for different periods of time. A range of assays were then applied in order to determine any impact of the antioxidants. RESULTS: 30 MUM ebselen or 7.5 mM N-acetyl L-cysteine supplementation resulted in a significantly higher intracellular GSH: GSSG ratio. This increased ratio was accompanied by reduced levels of oxidative DNA damage in established CD4+ human T cell clones, from a young or a middle-aged donor. Additionally, cultures of primary human peripheral blood mononuclear cells and CD4+ T cells from donors aged 25-30 or 55-60 years were also supplemented with these agents. Cells from all sources exhibited increased proliferation, and in the case of the T cell clones, an increase in cumulative population doublings. Neither ebselen nor N-acetyl L-cysteine had such effects on clones supplemented from the midpoint of their in vitro lifespan. CONCLUSIONS: Ebselen and N-acetyl L cysteine, under certain conditions, may have anti-immunosenescent potential in T cells in in vitro clonal and ex vivo polyclonal culture models. PMID- 23432995 TI - EGCG induces human mesothelioma cell death by inducing reactive oxygen species and autophagy. AB - Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. We studied whether a green tea polyphenol, epigallocathechin-3-gallate (EGCG), could induce cell death in five human mesothelioma cell lines. We found that EGCG induced apoptosis in all five mesothelioma cell lines in a dose dependent manner. We further clarified the cell killing mechanism. EGCG induced reactive oxygen species (ROS), and impaired the mitochondrial membrane potential. As treatment with ROS scavengers, catalase and tempol, significantly inhibited the EGCG-induced apoptosis, ROS is considered to be responsible for the EGCG induced apoptosis. Further, we found that EGCG induced autophagy, and that when autophagy was suppressed by chloroquine, the EGCG-induced cell death was enhanced. Taken together, these results suggest that EGCG has a great potential for the treatment of mesothelioma by inducing apoptosis and autophagy. PMID- 23432997 TI - Pulsed and conventional radiofrequency treatment: which is effective for dental procedure-related symptomatic trigeminal neuralgia? AB - OBJECTIVES: Many patients develop dental treatment-related symptomatic trigeminal neuralgia. However, the effectiveness of pulsed radiofrequency (PRF) treatment and conventional radiofrequency thermocoagulation (RFTC) for treatment of this disorder has not been determined. This retrospective study was conducted to compare the effectiveness and complications of PRF and RFTC in these patients. METHODS: Fifty-four patients who experienced the onset of symptomatic trigeminal neuralgia after a dental treatment were managed by PRF or RFTC. Data were collected by reviewing their medical records and conducting a questionnaire. Patients' characteristics, the dental procedures that caused the trigeminal neuralgia, the baseline and posttreatment pain intensities, duration of pain relief, complications, and satisfactions to the treatment were evaluated. RESULTS: Pain intensities were lower at 1 week (3.0/10 vs 6.4/10), at 1 month (2.5/10 vs 5.9/10), 3 months (2.6/10 vs 5.5/10), 6 months (3.1/10 vs 7.1/10) and 1 year (4.8/10 vs 7.2/10) in the RFTC group (28 patients) than in the PRF group (26 patients) (P < 0.05). The duration of pain relief without medication in the RFTC group (10.8 months) was longer than that in the PRF group (0 months). The incidence of complications in the RFTC group (46.4%) was higher than that in the PRF group (3.8%) (P < 0.05). The RFTC group reported higher satisfaction ratings (3.86/5) than the PRF group (2.19/5) (P < 0.05). CONCLUSIONS: Although the RFTC group had more complications than the PRF group, most were minor and transient, and the patient satisfaction rate with RFTC was very high. Therefore, RFTC is an effective tool for the treatment of dental procedure-induced trigeminal neuralgia. PMID- 23432996 TI - Feasibility of community-based screening for cardiovascular disease risk in an ethnic community: the South Asian Cardiovascular Health Assessment and Management Program (SA-CHAMP). AB - BACKGROUND: South Asian Canadians experience disproportionately high rates of cardiovascular disease (CVD). The goal of this qualitative study was to determine the feasibility of implementing a sustainable, culturally adapted, community based CVD risk factor screening program for this population. METHODS: South Asians (>= 45 years) in Calgary, Alberta underwent opportunistic cardiovascular risk factor screening by lay trained volunteers at local religious facilities. Those with elevated blood pressure (BP) or >= 1 risk factor underwent point of care cholesterol testing, 10-year CVD risk calculation, counseling, and referral to family physicians and local culturally tailored chronic disease management (CDM) programs. Participants were invited for re-screening and were surveyed about health system follow-up, satisfaction with the program and suggestions for improvement. Changes in risk factors from baseline were estimated using McNemar's test (proportions) and paired t-tests (continuous measures). RESULTS: Baseline assessment was completed for 238 participants (median age 64 years, 51% female). Mean TC, HDL and TC/HDL were 5.41 mmol/L, 1.12 mmol/L and 4.7, respectively. Mean systolic and diastolic blood pressures (mmHg) were 129 and 75 respectively. Blood pressure and TC/HDL ratios exceeded recommended targets in 36% and 58%, respectively, and 76% were at high risk for CVD. Ninety-nine participants (47% female) attended re-screening. 82% had accessed health care providers, 22% reported medication changes and 3.5% had attended the CDM programs. While BP remained unchanged, TC and TC/HDL decreased and HDL increased significantly (mean differences: -0.52 mmol/L, -1.04 and +0.07 mmol/L, respectively). Participants were very satisfied (80%) or satisfied (20%) with the project. Participants suggested screening sessions and CDM programs be more accessible by: delivering evening or weekends programs at more sites, providing transportation, offering multilingual programs/translation assistance, reducing screening wait times and increasing numbers of project staff. CONCLUSIONS: SA-CHAMP demonstrated the feasibility and value of implementing a lay volunteer-led, culturally adapted, sustainable community-based CVD risk factor screening program in South Asian places of worship in Calgary, Alberta, Canada. Subsequent screening and CDM programs were refined based on the learnings from this study. Further research is needed to determine physician and patient factors associated with uptake of and adherence to risk reduction strategies. PMID- 23432999 TI - Induced pH-dependent shift by local surface plasmon resonance in functionalized gold nanorods. AB - Localized surface plasmon resonance (LSPR) spectroscopy of metallic nanoparticles is a powerful tool for chemical and biological sensing experiments. In this study, we observed LSPR shifts of 11-mercaptoundecanoic acid modified gold nanorods (GNR-MUA) for the pH range of 6.41 to 8.88. We proposed a mechanism involving changes of the dipole moment after protonation/deprotonation carboxylic groups of 11-mercaptoundecanoic acid (MUA) which plays an important role by modulating LSPR around the functionalized GNR. Such a stable and easily prepared GNR-MUA has potential to become one of the most efficient and promising pH nanosensors to study intra- or extra-cellular pH in a wide range of chemical or biological systems. PMID- 23433000 TI - Type I tympanoplasty with island chondro-perichondral tragal graft: the preferred technique? AB - OBJECTIVE: This retrospective, comparative study aimed to assess anatomical and functional results in a group of adults undergoing type I tympanoplasty for subtotal tympanic membrane perforation, using two different types of graft. SUBJECTS AND METHODS: The study included 106 patients affected by chronic otitis media, who underwent underlay type I tympanoplasty, 53 using an autologous chondro-perichondral tragal graft and 53 using temporalis fascia. Anatomical and functional outcomes were evaluated over time. RESULTS: Audiometric results comparing the cartilage and fascia groups at six months and one year after surgery showed no statistically significant differences. Assessment of anatomical outcomes indicated a greater number of complications in the fascia group. CONCLUSION: Functional results indicate the validity of the cartilage tympanoplasty, while anatomical results indicate a slightly better outcome in terms of graft re-perforation and retraction, compared with temporalis fascia at one-year follow up. These results suggest that the cartilage technique is preferable for type I tympanoplasty. PMID- 23432998 TI - SHIFT: server for hidden stops analysis in frame-shifted translation. AB - BACKGROUND: Frameshift is one of the three classes of recoding. Frame-shifts lead to waste of energy, resources and activity of the biosynthetic machinery. In addition, some peptides synthesized after frame-shifts are probably cytotoxic which serve as plausible cause for innumerable number of diseases and disorders such as muscular dystrophies, lysosomal storage disorders, and cancer. Hidden stop codons occur naturally in coding sequences among all organisms. These codons are associated with the early termination of translation for incorrect reading frame selection and help to reduce the metabolic cost related to the frameshift events. Researchers have identified several consequences of hidden stop codons and their association with myriad disorders. However the wealth of information available is speckled and not effortlessly acquiescent to data-mining. To reduce this gap, this work describes an algorithmic web based tool to study hidden stops in frameshifted translation for all the lineages through respective genetic code systems. FINDINGS: This paper describes SHIFT, an algorithmic web application tool that provides a user-friendly interface for identifying and analyzing hidden stops in frameshifted translation of genomic sequences for all available genetic code systems. We have calculated the correlation between codon usage frequencies and the plausible contribution of codons towards hidden stops in an off-frame context. Markovian chains of various order have been used to model hidden stops in frameshifted peptides and their evolutionary association with naturally occurring hidden stops. In order to obtain reliable and persuasive estimates for the naturally occurring and predicted hidden stops statistical measures have been implemented. CONCLUSIONS: This paper presented SHIFT, an algorithmic tool that allows user-friendly exploration, analysis, and visualization of hidden stop codons in frameshifted translations. It is expected that this web based tool would serve as a useful complement for analyzing hidden stop codons in all available genetic code systems. SHIFT is freely available for academic and research purpose at http://www.nuccore.org/shift/. PMID- 23433001 TI - Short-term culture of ovarian cortex pieces to assess the cryopreservation outcome in wild felids for genome conservation. AB - BACKGROUND: Cryopreservation of ovarian tissue has the potential to preserve female germ cells of endangered mammals. In the present study, a freezing protocol successfully used for human tissue, was adapted for preserving ovarian tissue of domestic and non-domestic felids. Ovaries from non-domestic felid species were obtained from seven freshly euthanized and two recently deceased wild felids kept in different European Zoos. In addition, ovaries from domestic cats were obtained after ovariectomy from local veterinary clinics for methological adaptations.Ovarian cortex was dissected and uniform sized pieces of 2 mm diameter were obtained. Using a slow freezing protocol (-0.3 degrees C per min) in 1.5 mol/L ethylene glycol, 0.1 mol/L sucrose, the pieces were cultured for up to 14 days both before and after cryopreservation. The integrity of primordial follicles was assessed by histology, and the impact of different protein sources (FCS or BSA) and Vitamin C was determined during two weeks of culture. RESULTS AND CONCLUSION: During culture the number of primordial follicles decreased within the ovarian pieces (p < 0.05). This effect was less pronounced when FCS was used as the protein source instead of BSA. Supplementation with Vitamin C had a detrimental effect on follicle survival. Since the procedure of cryopreservation had no effect on the follicle survival after one week of culture we conclude that the freezing protocol was suitable for felids. This is the first report of preserving a huge amount of follicles within ovarian tissue by slow freezing performed in several wild feline species. PMID- 23433002 TI - A gasless laparoscopic technique of wide excision for gastric gastrointestinal stromal tumor versus open method. AB - BACKGROUND: Traditional open surgery for gastrointestinal stromal tumors (GIST) requires a long incision. Moreover, the gas-filling laparoscopic technique used in GIST surgery still has its limitations. Therefore, we developed a gasless laparoscopic (GL) surgery for GIST and compared it with traditional open surgery. METHODS: Between October 2007 and September 2009, 62 GIST patients in the National Taiwan University Hospital received wide excisions. Of these 62 patients, 30 underwent the new procedure (GL group) and 32 had open surgery (OS group). Preoperative and postoperative clinicopathologic characteristics were compared between the groups. RESULTS: There were no significant differences in preoperative characteristics or blood loss. However, the days to first flatus, postoperative hospital stay, wound length, white blood cell count at postoperative day one, and peak daily body temperature were all significantly improved in the GL group. Usage of postoperative analgesia on postoperative days one to five was also significantly lower in the GL group. CONCLUSIONS: Wide excision laparoscopy for gastric GIST can be performed more safely, more effectively, and with faster postoperative recovery using the gasless technique as compared with the open method. We, therefore, recommend this new surgical technique, which hybridizes the advantages of both the traditional open method and pure laparoscopic surgery. PMID- 23433003 TI - Chicken lines divergent for low or high abdominal fat deposition: a relevant model to study the regulation of energy metabolism. AB - Divergent selection of chickens for low or high abdominal fat (AF) but similar BW at 63 days of age was undertaken in 1977. The selection programme was conducted over seven successive generations. The difference between lines was then maintained constant at about twice the AF in the fat line as in the lean line. The aims of the first studies on these divergent chicken lines were to describe the growth, body composition and reproductive performance in young and adult birds. The lines were then used to improve the understanding of the relationship between fatness and energy and protein metabolism in the liver, muscle and adipose tissues, as well as the regulation of such metabolism at hormonal, gene and hypothalamic levels. The effects on muscle energy metabolism in relation to meat quality parameters were also described. This paper reviews the main results obtained with these lines. PMID- 23433004 TI - ClusCo: clustering and comparison of protein models. AB - BACKGROUND: The development, optimization and validation of protein modeling methods require efficient tools for structural comparison. Frequently, a large number of models need to be compared with the target native structure. The main reason for the development of Clusco software was to create a high-throughput tool for all-versus-all comparison, because calculating similarity matrix is the one of the bottlenecks in the protein modeling pipeline. RESULTS: Clusco is fast and easy-to-use software for high-throughput comparison of protein models with different similarity measures (cRMSD, dRMSD, GDT_TS, TM-Score, MaxSub, Contact Map Overlap) and clustering of the comparison results with standard methods: K means Clustering or Hierarchical Agglomerative Clustering. CONCLUSIONS: The application was highly optimized and written in C/C++, including the code for parallel execution on CPU and GPU, which resulted in a significant speedup over similar clustering and scoring computation programs. PMID- 23433005 TI - Type I Arnold-Chiari malformation with bronchiectasis, respiratory failure, and sleep disordered breathing: a case report. AB - Arnold Chiari Malformation (ACM) is defined as a condition where part of the cerebellar tissue herniates into the cervical canal toward the medulla and spinal cord resulting in a number of clinical manifestations. Type I ACM consists of variable displacement of the medulla throughout the formamen magnum into the cervical canal, with prominent cerebellar herniation.Type I ACM is characterized by symptoms related to the compression of craniovertebral junction, including ataxia, dysphagia, nistagmus, headache, dizziness, and sleep disordered breathing. We report a case of a life-long non-smoker, 54 years old woman who presented these symptoms associated with bronchiectasis secondary to recurrent inhalation pneumonia, hypercapnic respiratory failure, and central sleep apnea (CSA).CSA was first unsuccessfully treated with nocturnal c-PAP. The subsequent treatment with low flow oxygen led to breathing pattern stabilization with resolution of CSA and related clinical symptoms during sleep. We suggest that in patients with type I ACM the presence of pulmonary manifestations aggravating other respiratory disturbances including sleep disordered breathing (SDB) should be actively investigated. The early diagnosis is desirable in order to avoid serious and/or poorly reversible damages. PMID- 23433006 TI - Deaths of tuberculosis patients in urban China: a retrospective cohort study. AB - BACKGROUND: The case-fatality rate for tuberculosis (TB) remains high in China, whereas risk factors for deaths among TB cases are still unclear. DESIGN: This was a retrospective cohort study of all pulmonary TB patients registered in four districts of Shanghai from 2004 to 2008. Data were derived from the China National TB Surveillance System. A total of 4271 patients were followed up in communities. Data were analysed using Cox regression. RESULTS: The percentage of all-cause deaths in the study population was 15% 2-6 years after the most recent TB diagnosis. TB was responsible for only 17% of all deaths; male sex was significantly associated with all-cause deaths. After adjustment for sex, age and treatment history, four factors were significantly and independently associated with increased risk of death: psychopathy, chronic bronchitis, cancer and the presence of multiple diseases. TB was responsible for 7.2 potential years of life lost (PYLL); PYLL was higher in females (8.2) than males (5.3). CONCLUSIONS: TB remains a significant problem in urban China. Implementation of improved clinical management, prevention strategies and other public health programmes should target TB patients with chronic conditions, particularly those with multiple diseases. PMID- 23433007 TI - Bacterial isolates from infected wounds and their antibiotic susceptibility pattern: some remarks about wound infection. AB - Wound infection plays an important role in the development of chronicity, delaying wound healing. This study aimed to identify the bacterial pathogens present in infected wounds and characterise their resistance profile to the most common antibiotics used in therapy. Three hundred and twelve wound swab samples were collected from 213 patients and analysed for the identification of microorganisms and for the determination of their antibiotic susceptibility. Patients with diverse type of wounds were included in this retrospective study, carried out from March to September 2012. A total of 28 species were isolated from 217 infected wounds. The most common bacterial species detected was Staphylococcus aureus (37%), followed by Pseudomonas aeruginosa (17%), Proteus mirabilis (10%), Escherichia coli (6%) and Corynebacterium spp. (5%). Polymicrobial infection was found in 59 (27.1%) of the samples and was mainly constituted with two species. The most common association was S. aureus/P. aeruginosa. All Gram-positives were susceptible to vancomycin and linezolid. Gram negatives showed quite high resistance to the majority of antibiotics, being amikacin the most active against these bacteria. This study is mostly oriented to health care practitioners who deal with wound management, making them aware about the importance of wound infection and helping them to choose the adequate treatment options to control microbial infection in wounds. PMID- 23433008 TI - Hepatitis B inactive carriers: clinical course and outcomes. AB - OBJECTIVE: Hepatitis B virus (HBV) inactive carriers are HBV e antigen (HBeAg) negative patients with normal alanine aminotransferase (ALT) levels and HBV DNA of <= 10000 copies/mL. We aimed to determine the clinical impact of ALT and HBV DNA elevations during the course of HBV infection. METHODS: From January 1989 to January 2012, 146 inactive carriers were prospectively followed every 6-12 months with ALT and HBV DNA measurements and with hepatocellular carcinoma (HCC) surveillance. RESULTS: During the follow-up of 8 +/- 6.3 years, 56 of the 146 patients maintained ALT <= 40 U/L and HBV DNA <= 10000 copies/mL. However, 39 had rises of ALT > 40-80 U/L and 4 had ALT > 80 U/L; all except one reverted to baseline values. Also, during follow up, 69 (47.3%) inactive carriers had increases in HBV DNA of > 10000-999999 copies/mL; 38 of these patients' HBV DNA returned to baseline levels, while the remaining 31 patients maintained elevated HBV DNA values but had corresponding ALT of <= 40 U/L. There were four liver related outcomes: 129 (88.4%) remained "inactive carriers", 13 (8.9%) had loss of hepatitis B surface antigen (HBsAg), one (0.7%) had a spontaneous reactivation to HBeAg-negative chronic hepatitis, and two (1.4%) developed HCC. CONCLUSIONS: Although the prognosis of inactive carrier is favorable, transient ALT and HBV DNA elevations may be observed but have minimal clinical significance. Moreover, continuous HCC surveillance remains necessary since the risk of development still exists. PMID- 23433009 TI - Physicochemical and antioxidant properties of Malaysian honeys produced by Apis cerana, Apis dorsata and Apis mellifera. AB - BACKGROUND: The aim of the present study was to evaluate the physicochemical and antioxidant properties of Malaysian monofloral honey samples-acacia, pineapple and borneo honey-and compare them with tualang honey. Acacia and pineapple honey are produced by Apis mellifera bees while borneo and tualang honey are produced by Apis cerana and Apis dorsata bees, respectively. METHODS: The physical parameters of honey, such as pH, moisture content, electrical conductivity (EC), total dissolved solids (TDS), color intensity, total sugar and apparent sucrose content, were measured. Hydroxymethylfurfural (HMF) was measured using high performance liquid chromatography, and a number of biochemical and antioxidant tests were performed to determine the antioxidant properties of the honey samples. RESULTS: Acacia honey was the most acidic (pH 3.53), whereas pineapple honey had the lowest moisture content (14.86%), indicating that both types of honey can resist microbial spoilage more effectively when compared to tualang honey (pH 3.80 and 17.53% moisture content). Acacia honey contained the highest EC (0.76 mS/cm), whereas borneo honey had the highest (377 ppm) TDS. The mean HMF content in Malaysian honey was 35.98 mg/kg. Tualang honey, which is amber color, had the highest color intensity (544.33 mAU). Acacia honey is the sweetest, and contained the highest concentration of total sugar, reducing sugar and apparent sucrose. Tualang honey had the highest concentration of phenolic compounds (352.73 +/- 0.81 mg galic acid/kg), flavonoids (65.65 +/- 0.74 mg catechin/kg), DPPH (59.89%), FRAP values (576.91 +/- 0.64 MUM Fe (II)/100 g) and protein content (4.83 +/- 0.02 g/kg) as well as the lowest AEAC values (244.10 +/- 5.24 mg/kg), indicating its strong antioxidant properties. Proline, an important amino acid that is present in honey was also measured in the present study and it was found at the highest concentration in pineapple honey. Several strong correlations were found among the biochemical and antioxidant parameters of all the Malaysian honeys. CONCLUSION: Although Malaysian honeys are of good quality, tualang honey contains the strongest antioxidant properties by far. PMID- 23433010 TI - Use of porcine xenografts on partial-thickness vermilion border and mucosal lower lip Mohs defects. PMID- 23433012 TI - Refractory chronic pelvic pain syndrome in men: can transcutaneous electrical nerve stimulation help? AB - OBJECTIVE: To evaluate the effect of transcutaneous electrical nerve stimulation (TENS) for treating men with refractory chronic pelvic pain syndrome (CPPS). PATIENTS AND METHODS: A consecutive series of 60 men treated with TENS for refractory CPPS was evaluated prospectively at an academic tertiary referral centre. The effects of treatment were evaluated by a pain diary and by the quality of life item of the National Institutes of Health Chronic Prostatitis Symptom Index at baseline, after 12 weeks of TENS treatment, and at last known follow-up. Adverse events related to TENS were also assessed. RESULTS: The mean (95% confidence interval, CI; range) age of the 60 men was 46.9 (43.5-50.3; 21 82) years. TENS was successful after 12 weeks of treatment in 29 (48%) patients and a positive effect was sustained during a mean (95%, CI; range) follow-up of 43.6 (33.2-56; 6-88) months in 21 patients. After 12 weeks of TENS treatment, mean (95% CI) pain visual analogue scale decreased significantly (P < 0.001) from 6.6 (6.3-6.9) to 3.9 (3.2-4.6). Patients' quality of life changed significantly after TENS treatment (P < 0.001). Before TENS, all 60 patients felt mostly dissatisfied (n = 17; 28%), unhappy (n = 28; 47%) or terrible (n = 15; 25%). After 12 weeks of TENS treatment, 29 (48%) patients felt mostly satisfied (n = 5), pleased (n = 18) or delighted (n = 6). No adverse events related to TENS were noted. CONCLUSION: TENS may be an effective and safe treatment for refractory CPPS in men, warranting randomized, placebo-controlled trials. PMID- 23433011 TI - Commensal bacteria-dependent select expression of CXCL2 contributes to periodontal tissue homeostasis. AB - The oral and intestinal host tissues both carry a heavy microbial burden. Although commensal bacteria contribute to healthy intestinal tissue structure and function, their contribution to oral health is poorly understood. A crucial component of periodontal health is the recruitment of neutrophils to periodontal tissue. To elucidate this process, gingival tissues of specific-pathogen-free and germ-free wild-type mice and CXCR2KO and MyD88KO mice were examined for quantitative analysis of neutrophils and CXCR2 chemoattractants (CXCL1, CXCL2). We show that the recruitment of neutrophils to the gingival tissue does not require commensal bacterial colonization but is entirely dependent on CXCR2 expression. Strikingly, however, commensal bacteria selectively upregulate the expression of CXCL2, but not CXCL1, in a MyD88-dependent way that correlates with increased neutrophil recruitment as compared with germ-free conditions. This is the first evidence that the selective use of chemokine receptor ligands contributes to neutrophil homing to healthy periodontal tissue. PMID- 23433013 TI - High pulse pressure and metabolic syndrome are associated with proteinuria in young adult women. AB - BACKGROUND: Obesity and metabolic syndrome play causative roles in the increasing prevalence of proteinuria in the general population. However, in young adult women the clinical significance of incidentally discovered proteinuria and its association with metabolic syndrome are unclear. We investigated the prevalence and risk factors for proteinuria in this population. METHODS: A total of 10,385 women aged 20 to 39 years who underwent health screenings were surveyed. Each patient was tested for proteinuria with a dipstick (-, +/-, 1+, 2+, or 3+), and proteinuria was defined as 1+ or greater. Persistent proteinuria was established by confirming proteinuria in a subsequent test. Metabolic syndrome was defined in accordance with the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asia. RESULTS: The mean age was 28.9+/-5.5 years, and the prevalence of persistent proteinuria was 1.0%. Among these subjects with persistent proteinuria, obesity and metabolic syndrome were found in 10.4% and 5.2%, respectively. Metabolic syndrome, as well as its components of hypertension, hyperglycemia, central obesity, low high-density lipoprotein levels, and high triglyceride levels, was closely related to the presence of proteinuria. In addition, a wide pulse pressure of >=40 mmHg was another independent risk factor for proteinuria [odds ratio (OR) 3.29, 95% confidence interval (CI) 1.03-11.91)]. This had an additive effect on metabolic syndrome in terms of predicting proteinuria. Even in subjects without metabolic syndrome, the influence of an increased pulse pressure was consistent (OR 2.75, 95% CI 1.03 8.61). CONCLUSIONS: Specific attention to proteinuria may be necessary in asymptomatic young women aged 20 to 39 years if they have metabolic syndrome or a wide pulse pressure. PMID- 23433014 TI - 18-FDG-PET in assessing disease activity in Takayasu arteritis: a meta-analysis. AB - OBJECTIVES: To assess the diagnosis value of 18-FDG-PET in estimating disease activity in Takayasu arteritis. METHODS: A complete search of PubMed, EMBASE and The Cochrane Library was finished to July 25, 2012. Sensitivity and specificity as well as pooled estimates of positive and negative likelihood ratios (PLR and NLR) were calculated by Meta-Disc. We also calculated the area under the sROC curve (AUC) and the Q* index. RESULTS: The meta-analysis was finished with 6 study retrieved from the database search. The pooled sensitivity, and specificity with 95% confidence interval were 70.1% (95% CI, 58.6-80.0) and 77.2% (95% CI, 64.2-87.3). The PLR and NLR were 2.313 (95% CI 1.108-4.829) and 0.341 (95% CI 0.142-0.824). The AUC was 0.805(+/-0.084) and Q* index was 0.7402 (+/-0.0739). CONCLUSIONS: 18-FDG-PET had moderate diagnosis value in assessing TA activity. It may add additional value to the current diagnosis methods. PMID- 23433015 TI - Bilateral transfemoral lower extremity transplantation: result at 1 year. AB - Upper limb transplantation has become a treatment option for upper limb amputees with good midterm results. Lower extremity transplantation has never been considered for fear of poor results. The authors present a bilateral transfemoral transplantation of lower extremities performed to a 22-year patient at 12 months of follow-up. The donor was a full HLA-mismatched female multiorgan donor. CMV status was D-/R-. A primary CMV infection coincident with an acute rejection occurred at 3 months and responded to treatment. At 1 year, the Tinel's sign is at malleolar level, there is active knee extension and active plantar flexion of the foot. The patient is walking between parallel bars. Further substantial improvements are expected with longer rehabilitation and follow-up. PMID- 23433016 TI - Man with facial pain. Ludwig's angina. PMID- 23433017 TI - How does one learn critical care procedures in a pediatric emergency department? PMID- 23433018 TI - Continuing care for patients choosing the emergency department as a site for primary care: feasibility, benefits, and EMTALA considerations. PMID- 23433019 TI - Update on emerging infections: news from the Centers for Disease Control and Prevention. Commentary. PMID- 23433020 TI - Change of shift. Balad's final dispo. PMID- 23433021 TI - Young man with fever and cough. Scrub typhus pneumonitis. PMID- 23433022 TI - Failure to develop sensitization despite repeated administration of ovine fab snake antivenom: update of a single-patient, multicenter case series. PMID- 23433023 TI - Are we ready for palliative medicine? PMID- 23433024 TI - Triage systems: outcome measures to validate. PMID- 23433025 TI - Oligo-evidence for oligoanalgesia: a non sequitur? PMID- 23433026 TI - In reply. PMID- 23433027 TI - Emergency physician contractual relationships. Policy statement. PMID- 23433028 TI - Sensory small fiber function differentially assessed with diode laser (DL) quantitative sensory testing (QST) in painful neuropathy (PN). AB - Sensory function of small peripheral nerve fiber was assessed by means of quantitative sensory testing (QST) during which sensory stimulation was provided using diode laser (DL) in patients suffering from painful neuropathy (PN) and compared with symptom-free healthy controls (HC). Based on previous research work using DL stimulation, parameters that demonstrated safe and specific activation of A-delta, which were distinct from stimulation parameters for the activation of C-fibers, were utilized in this study. Results of this study demonstrated that this differential activation pointed to the impaired function of A-delta fibers while C-fiber function was unaffected. Stimulation of HC reproduced previously published results, and stimulation during this study was safe also without any dermal effect in patients with PN and in HC. Parameters used in this study were demonstrated in previous preclinical rodent study identical differential effect on activation of A-delta and C-fibers, and as such, DL is an ideal tool for translational pain research where specific activation of A-delta or C-fibers, or both, is required. PMID- 23433029 TI - Geographic and urban-rural disparities in the total prevalence of neural tube defects and their subtypes during 2006-2008 in China: a study using the hospital based birth defects surveillance system. AB - BACKGROUND: Previous reports on the prevalence of neural tube defects (NTDs) in China did not include cases of NTDs that were less than 28 weeks of gestational age (GA) and hence did not accurately reflect the total prevalence of NTDs or the geographic and urban-rural disparities in their prevalence. This article includes cases of NTDs that were less than 28 weeks of GA. METHODS: Data used in this study were collected from 2006 to 2008 using a nationwide hospital-based registry, the Chinese Birth Defects Monitoring Network. The total prevalence ratio (PR) of NTDs and their subtypes, the ratios of PR (PRR), and 95% confidence intervals (CI) were used to analyse geographic disparities at both the regional (north, south) and provincial levels and to analyse disparities between rural and urban areas. RESULTS: Overall, the total PR of NTDs was 14.0 per 10,000 births. The PRR of NTDs of rural women between the north and south region was 2.26 (95% CI: 2.04-2.52), which was much higher than that of urban women (PRR: 1.56, 95% CI: 1.41-1.72). The three subtypes of NTDs had different geographic distribution at the level of province. The urban-rural PRR of NTDs was 2.14 (95% CI: 1.94 2.34) in the north but only 1.47 (95% CI: 1.31-1.66) in the south. CONCLUSIONS: There is a high total prevalence of NTDs, which remains one of the major public health concerns in China. Eliminating the geographic and urban-rural disparities in the disease burden is a priority for future intervention. PMID- 23433030 TI - Selective defoliation affects plant growth, fruit transcriptional ripening program and flavonoid metabolism in grapevine. AB - BACKGROUND: The selective removal of grapevine leaves around berry clusters can improve the quality of ripening fruits by influencing parameters such as the berry sugar and anthocyanin content at harvest. The outcome depends strongly on the timing of defoliation, which influences the source-sink balance and the modified microclimate surrounding the berries. We removed the basal leaves from Vitis vinifera L. cv Sangiovese shoots at the pre-bloom and veraison stages, and investigated responses such as shoot growth, fruit morphology and composition compared to untreated controls. Moreover, we performed a genome-wide expression analysis to explore the impact of these defoliation treatments on berry transcriptome. RESULTS: We found that pre-bloom defoliation improved berry quality traits such as sugar and anthocyanin content, whereas defoliation at veraison had a detrimental effect, e.g. less anthocyanin and higher incidence of sunburn damage. Genome-wide expression analysis during berry ripening revealed that defoliation at either stage resulted in major transcriptome reprogramming, which slightly delayed the onset of ripening. However, a closer investigation of individual gene expression profiles identified genes that were specifically modulated by defoliation at each stage, reflecting the uncoupling of metabolic processes such as flavonoid biosynthesis, cell wall and stress metabolism, from the general ripening program. CONCLUSIONS: The specific transcriptional modifications we observed following defoliation at different time points allow the identification of the developmental or metabolic processes affected in berries thus deepening the knowledge of the mechanisms by which these agronomical practices impact the final berry ripening traits. PMID- 23433031 TI - Familial resemblance in religiousness in a secular society: a twin study. AB - It is well known that human behavior and individual psychological traits are moderately to substantially heritable. Over the past decade, an increasing number of studies have explored the genetic and environmental influence on religiousness. These studies originate predominantly from countries generally considered more religious than the very secular northern European countries. Comparisons of the results are complicated by diverse definitions of religiousness, but several studies indicate that the influence of the family environment is most predominant in early life, whereas genetic influences increase with age. We performed a population-based twin study of religiousness in a secular society using data from a Web-based survey sent to 6,707 Danish twins born 1970-1989, who were identified in the Danish Twin Registry. We applied Fishman's three conceptual dimensions of religiousness: cognition, practice, and importance. In all polygenic models and biometric analyses, we controlled for gender and age. The study sample comprised 2,237 same sex twins, a response rate of 45%. We found high correlations within both monozygotic and dizygotic twin pairs in most items of religiousness, indicating a large influence from shared environmental factors. Personal religiousness such as praying to God, believing in God, and finding strength and comfort in religion were more influenced by genetic factors than were social forms of religiousness such as church attendance. We found a small tendency for increasing genetic influence with increasing age for some religious items, but not for all. PMID- 23433032 TI - Double-ligand modulation for engineering magnetic nanoclusters. AB - Magnetic nanoclusters (MNCs) are agglomerated individual magnetic nanoparticles (MNPs) that show great promise in increasing magnetic resonance imaging (MRI) sensitivity. Here, we report an effective strategy to engineer MNCs based on double-ligand modulation to enhance MRI sensitivity. The oleic acid-coated individual MNPs self-assembled and then were enveloped by polysorbate 80, using a nanoemulsion method to prepare MNCs. By modulating the amounts of the two ligands, and thus the size and magnetic content of the resultant MNCs, we were able to enormously improve MRI sensitivity. PMID- 23433033 TI - Life-history and hormonal control of aggression in black redstarts: Blocking testosterone does not decrease territorial aggression, but changes the emphasis of vocal behaviours during simulated territorial intrusions. AB - INTRODUCTION: Many studies in behavioural endocrinology attempt to link territorial aggression with testosterone, but the exact relationship between testosterone and territorial behaviour is still unclear and may depend on the ecology of a species. The degree to which testosterone facilitates territorial behaviour is particularly little understood in species that defend territories during breeding and outside the breeding season, when plasma levels of testosterone are low. Here we suggest that species that defend territories in contexts other than reproduction may have lost the direct regulation of territorial behaviour by androgens even during the breeding season. In such species, only those components of breeding territoriality that function simultaneously as sexually selected signals may be under control of sex steroids. RESULTS: We investigated black redstarts (Phoenicurus ochruros), a species that shows periods of territoriality within and outside of the breeding season. We treated territorial males with an anti-androgen and an aromatase inhibitor during the breeding season to block both the direct and indirect effects of testosterone. Three and ten days after the treatment, implanted males were challenged with a simulated territorial intrusion. The treatment did not reduce the overall territorial response, but it changed the emphasis of territoriality: experimental males invested more in behaviours addressed directly towards the intruder, whereas placebo-treated males put most effort into their vocal response, a component of territoriality that may be primarily directed towards their mating partner rather than the male opponent. CONCLUSIONS: In combination with previous findings, these data suggest that overall territoriality may be decoupled from testosterone in male black redstarts. However, high levels of testosterone during breeding may facilitate-context dependent changes in song. PMID- 23433034 TI - Application of platelet-rich gel to enhance healing of transmetatarsal amputations in diabetic dysvascular patients. AB - Transmetatarsal amputation (TMA) represents an effective surgical procedure used to treat several clinical conditions such as forefoot infection, gangrene and chronic ulceration in diabetic patients. TMA permits walking without the need for prosthesis, but nevertheless is burdened with a high complications rate. The aim of this study was to evaluate the possibility to use platelet gel (PG) as an adjuvant therapy when performing TMA procedure in diabetic patients. In a 6-year period, 26 diabetic patients had undergone TMA procedure followed by autologous PG applications (group A) and 32 patients had undergone TMA as sole procedure (group B). After TMA procedure, the treatment is based on outpatient management and consists of a weekly platelet-rich plasma gel application on the surgical wound for 1 month in group A and on clinical evaluation only for group B. For group A, healing rate was of 96.15% and one patient (3.84%) presented wound dehiscence, and no postoperative wound infections occurred. For group B, healing rate was of 59.37%; severe infection of the stump prompted to the proximal amputations in 40.62% of patients during the follow-up period. PG application may be an effective adjuvant treatment to improve wound healing in diabetic dysvascular patients. PMID- 23433035 TI - Should trainee doctors use the developing world to gain clinical experience? The annual Varsity Medical Debate - London, Friday 20th January, 2012. AB - The 2012 Varsity Medical Debate between Oxford University and Cambridge University provided a stage for representatives from these famous institutions to debate the motion "This house believes that trainee doctors should be able to use the developing world to gain clinical experience." This article brings together many of the arguments put forward during the debate, centring around three major points of contention: the potential intrinsic wrong of 'using' patients in developing countries; the effects on the elective participant; and the effects on the host community. The article goes on to critically appraise overseas elective programmes, offering a number of solutions that would help optimise their effectiveness in the developing world. PMID- 23433036 TI - In vivo gene expression of Pseudomonas putida KT2440 in the rhizosphere of different plants. AB - Pseudomonas putida KT2440 has the ability to colonize the rhizosphere of a wide range of plants and can reach cell densities in the range of 10(5) -10(6) cfu g soil(-1) . Using the IVET technology we investigated which KT2440 genes were expressed in the rhizosphere of four different plants: pine, cypress, evergreen oak and rosemary. We identified 39 different transcriptional fusions containing the promoters of annotated genes that were preferentially expressed in the rhizosphere. Six of them were expressed in the rhizosphere of all the plant types tested, 11 were expressed in more than one plant and the remaining 22 fusions were found to be expressed in only one type of plant. Another 40 fusions were found to correspond to likely promoters that encode antisense RNAs of unknown function, some of which were isolated as fusions from the bacteria recovered in the rhizosphere from all of the plants, while others were specific to one or several of the plants. The results obtained in this study suggest that plant specific signals are sensed by KT2440 in the rhizosphere and that the signals and consequent gene expression are related to the bacteria's successful establishment in this niche. PMID- 23433037 TI - Lung stem cells: do they exist? AB - Recognition of the potential of stem cell-based therapies for alleviating intractable lung diseases has provided the impetus for research aimed at identifying regenerative cells in the adult lung, understanding how they are organized and regulated, and how they could be harnessed in lung regenerative medicine. In this review, we describe the attributes of adult stem and progenitor cells in adult organs and how they are regulated by the permissive or restrictive microenvironment in which they reside. We describe the power and limitations of experimental models, cell separative strategies and functional assays used to model the organization and regulation of adult airway and alveolar stem cells in the adult lung. The review summarizes recent progress and obstacles in defining endogenous lung epithelial stem and progenitor cells in mouse models and in translational studies. PMID- 23433038 TI - Silencing of mammalian Sar1 isoforms reveals COPII-independent protein sorting and transport. AB - The Sar1 GTPase coordinates the assembly of coat protein complex-II (COPII) at specific sites of the endoplasmic reticulum (ER). COPII is required for ER-to Golgi transport, as it provides a structural and functional framework to ship out protein cargoes produced in the ER. To investigate the requirement of COPII mediated transport in mammalian cells, we used small interfering RNA (siRNA) mediated depletion of Sar1A and Sar1B. We report that depletion of these two mammalian forms of Sar1 disrupts COPII assembly and the cells fail to organize transitional elements that coordinate classical ER-to-Golgi protein transfer. Under these conditions, minimal Golgi stacks are seen in proximity to juxtanuclear ER membranes that contain elements of the intermediate compartment, and from which these stacks coordinate biosynthetic transport of protein cargo, such as the vesicular stomatitis virus G protein and albumin. Here, transport of procollagen-I is inhibited. These data provide proof-of-principle for the contribution of alternative mechanisms that support biosynthetic trafficking in mammalian cells, providing evidence of a functional boundary associated with a bypass of COPII. PMID- 23433039 TI - Vector-borne helminths of dogs and humans - focus on central and eastern parts of Europe. AB - Comments on the article "Vector-borne helminths of dogs and humans in Europe" published in Parasites and Vectors 2013, 6:16. PMID- 23433040 TI - Morphometric analysis of the placenta in the New World mouse Necromys lasiurus (Rodentia, Cricetidae): a comparison of placental development in cricetids and murids. AB - BACKGROUND: Stereology is an established method to extrapolate three-dimensional quantities from two-dimensional images. It was applied to placentation in the mouse, but not yet for other rodents. Herein, we provide the first study on quantitative placental development in a sigmodontine rodent species with relatively similar gestational time. Placental structure was also compared to the mouse, in order to evaluate similarities and differences in developmental patterns at the end of gestation. METHODS: Fetal and placental tissues of Necromys lasiurus were collected and weighed at 3 different stages of gestation (early, mid and late gestation) for placental stereology. The total and relative volumes of placenta and of its main layers were investigated. Volume fractions of labyrinth components were quantified by the One Stop method in 31 placentae collected from different individuals, using the Mercator software. Data generated at the end of gestation from N. lasiurus placentae were compared to those of Mus musculus domesticus obtained at the same stage. RESULTS: A significant increase in the total absolute volumes of the placenta and its main layers occurred from early to mid-gestation, followed by a reduction near term, with the labyrinth layer becoming the most prominent area. Moreover, at the end of gestation, the total volume of the mouse placenta was significantly increased compared to that of N. lasiurus although the proportions of the labyrinth layer and junctional zones were similar. Analysis of the volume fractions of the components in the labyrinth indicated a significant increase in fetal vessels and sinusoidal giant cells, a decrease in labyrinthine trophoblast whereas the proportion of maternal blood space remained stable in the course of gestation. On the other hand, in the mouse, volume fractions of fetal vessels and sinusoidal giant cells decreased whereas the volume fraction of labyrinthine trophoblast increased compared to N. lasiurus placenta. CONCLUSIONS: Placental development differed between N. lasiurus and M. musculus domesticus. In particular, the low placental efficiency in N. lasiurus seemed to induce morphological optimization of fetomaternal exchanges. In conclusion, despite similar structural aspects of placentation in these species, the quantitative dynamics showed important differences. PMID- 23433041 TI - Preliminary experience with intraoperative near-infrared fluorescence imaging in percutaneous sclerotherapy of soft-tissue venous malformations. AB - BACKGROUND: It has recently been demonstrated that near-infrared (NIR) fluorescence imaging can be used to visualize the blood vasculature. Although sclerotherapy has been successfully used in treating venous malformations, the spread of sclerosant is difficult to monitor during sclerotherapy. OBJECTIVE: To evaluate the safety and efficacy of NIR fluorescence imaging in percutaneous sclerotherapy of soft-tissue venous malformations. METHODS AND MATERIALS: The use of NIR fluorescence imaging after administration of indocyanine green (ICG) was evaluated in duplex-guided sclerotherapy performed on 15 patients with venous malformations. The lower extremities were involved in seven, the upper extremities in four, and the face in four. RESULTS: In 13 of the 15 procedures, spotty fluorescence images were obtained, and in eight procedures, linear fluorescence images were obtained. In two patients with intramuscular venous malformations in the lower extremities, no fluorescence images were obtained. Observational depth seemed to be <1 cm below the skin surface with an ICG concentration of 0.01 mg/mL. No complications associated with ICG were observed. Adjacent tissue ulceration occurred in one patient. CONCLUSION: NIR fluorescence imaging with ICG can be a useful additional monitor for percutaneous sclerotherapy of venous malformations, especially in the face and hands, enabling noninvasive assessment of real-time spread of sclerosant. PMID- 23433043 TI - Evaluation of the depth of sedation in an intensive care unit based on the photo motor reflex variations measured by video pupillometry. AB - BACKGROUND: Evaluating depth of sedation in the intensive care unit (ICU) is crucial for the management of mechanically ventilated patients but can be challenging in some situations. Because the depth of hypnosis is correlated with the decrease in photomotor reflex (PMR), we suggest using pupillometric video as an automated, noninvasive, simple, and reproducible technique to evaluate the depth of sedation in ICU patients. We compare the effectiveness of this procedure to the bispectral index (BIS). METHODS: Thirty-one patients requiring sedation and ventilation were included in this monocentric, observational study. The posology of hypnotics and morphinics were based on the Richmond Agitation and Sedation Scale (RASS). PMR was measured by the Neurolight(r) (IDMED) system and BIS value by BIS Vista(r) (Anandic Medical Systems). RASS, PMR, and BIS were measured three times daily in all patients. Data acquired by pupillometric video included variation in pupillary diameter (DeltaPD), latency time (LT), and maximal speed of pupillary constriction (Vmax). These parameters were analyzed after having classified BIS values in three groups (<40 heavy sedation; 40 <= BIS <= 60 acceptable sedation; >60 light sedation). Exclusion criteria were neurological or ophthalmologic pathologies that could interfere with PMR. RESULTS: There was a significant difference in Vmax and DeltaPD between the BIS < 40 group and 40 <= BIS <= 60 groups (p < 0.0001 for each) and between the BIS < 40 and BIS > 60 groups (p < 0.0001 for each). There were no significant differences in Vmax and DeltaPD between the 40 <= BIS <= 60 and BIS > 60 groups. There was no correlation between any of the BIS groups and LT. CONCLUSIONS: Vmax and DeltaPD seem to be relevant criteria compared with the BIS and the RASS. Pupillometric video monitoring of depth of sedation could be beneficial in ICU patients, especially for those under myorelaxant drugs, where no clinical evaluation of sedation is possible. PMID- 23433042 TI - The investigation of a traditional Chinese medicine, Guizhi Fuling Wan (GFW) as an intravesical therapeutic agent for urothelial carcinoma of the bladder. AB - BACKGROUND: The high risk of recurrence faced by patients with bladder cancer has necessitated the administration of supplemental intravesical chemotherapy; however, such treatments often result in severe side effects. As a result, novel intravesical agents with enhanced efficacy and minimal toxicity are urgently required for the treatment of bladder cancer. METHODS: Guizhi Fuling Wan (GFW) is a traditional Chinese medicine shown to inhibit the growth of hepatocellular carcinoma. This study evaluated the growth inhibition of GFW using normal human urothelial cells and bladder cancer cells; the efficacy of GFW treatment was further compared with mitomycin C, epirubicin, and cisplatin. We also examined the progression of cell cycle and apoptosis in bladder cancer cells in response to GFW treatment. CCK-8 was employed to analyze cell viability and flow cytometry was used to study the cell cycle and apoptosis. The mechanisms underlying GFW induced cell cycle arrest were determined by Western blot analysis. RESULTS: Our data demonstrate the potent inhibitory effect of GFW in the proliferation of bladder cancer cell lines, BFTC 905 and TSGH 8301. GFW presented relatively high selectivity with regard to cancer cells and minimal toxicity to normal urothelial cells. Our results also demonstrate that GFW interferes with cell cycle progression through the activation of CHK2 and P21 and induces apoptosis in these bladder cancer cells. CONCLUSIONS: Our results provide experimental evidence to support GFW as a strong candidate for intravesicle chemotherapy against bladder cancer. PMID- 23433044 TI - Lack of predictive correlation between peripheral arterial tone and colour flow Doppler parameters in men with erectile dysfunction. AB - OBJECTIVE: To evaluate whether peripheral arterial tone (PAT) can predict the results of penile colour flow Doppler in the evaluation of erectile dysfunction (ED). PATIENTS AND METHODS: Fifty men presenting to an ED clinic were tested with an Endo-PAT2000 machine (Itamar Medical, Caesarea, Israel), which assessed augmentation index (AI), a measure of arterial stiffness, and reactive hyperaemia index (RHI), a measure of endothelial vasodilatation. Penile haemodynamics were measured and used to identify both arterial insufficiency (abnormal peak systolic velocity [PSV]) and veno-occlusive disease (abnormal end diastolic velocity [EDV]) after pharmacological erection with prostaglandin E1 using colour flow Doppler. Between-group comparisons were carried out using a Wilcoxon rank-sum test for continuous variables and a chi-squared test for categorical variables. Simple and multivariable logistic regression analyses were used to analyse the correlation between outcome measures. RESULTS: Using Doppler analysis, 58% of patients were found to have arterial insufficiency (abnormal PSV) and 48% had veno-occlussive disease (abnormal EDV). Using the Endo-PAT machine, 44% of patients were found to have increased arterial stiffness (abnormal AI) and 54% had decreased endothelial relaxation (abnormal RHI). Neither AI nor RHI were correlated with PSV or EDV. The closest association was between high AI and low PSV, with a sensitivity of 0.55 and specificity of 0.71. CONCLUSIONS: In our patient cohort, PAT did not reliably predict the results of penile Doppler. The two tests appear to measure different although potentially complementary aspects of the local and systemic vasculature. PMID- 23433045 TI - Protein structure based prediction of catalytic residues. AB - BACKGROUND: Worldwide structural genomics projects continue to release new protein structures at an unprecedented pace, so far nearly 6000, but only about 60% of these proteins have any sort of functional annotation. RESULTS: We explored a range of features that can be used for the prediction of functional residues given a known three-dimensional structure. These features include various centrality measures of nodes in graphs of interacting residues: closeness, betweenness and page-rank centrality. We also analyzed the distance of functional amino acids to the general center of mass (GCM) of the structure, relative solvent accessibility (RSA), and the use of relative entropy as a measure of sequence conservation. From the selected features, neural networks were trained to identify catalytic residues. We found that using distance to the GCM together with amino acid type provide a good discriminant function, when combined independently with sequence conservation. Using an independent test set of 29 annotated protein structures, the method returned 411 of the initial 9262 residues as the most likely to be involved in function. The output 411 residues contain 70 of the annotated 111 catalytic residues. This represents an approximately 14-fold enrichment of catalytic residues on the entire input set (corresponding to a sensitivity of 63% and a precision of 17%), a performance competitive with that of other state-of-the-art methods. CONCLUSIONS: We found that several of the graph based measures utilize the same underlying feature of protein structures, which can be simply and more effectively captured with the distance to GCM definition. This also has the added the advantage of simplicity and easy implementation. Meanwhile sequence conservation remains by far the most influential feature in identifying functional residues. We also found that due the rapid changes in size and composition of sequence databases, conservation calculations must be recalibrated for specific reference databases. PMID- 23433047 TI - Renal transplantation after ex vivo normothermic perfusion: the first clinical study. AB - Ex vivo normothermic perfusion (EVNP) is a novel method of preservation that restores circulation and allows an organ to regain function prior to transplantation. The aim of this study was to assess the effects of EVNP in kidneys from marginal donors. Eighteen kidneys from extended criteria donors (ECD) underwent a period of EVNP immediately before transplantation. Kidneys were perfused with a plasma free red-cell based solution at a mean temperature of 34.6 degrees C. The outcome of these kidneys was compared to a control group of 47 ECD kidneys that underwent static cold storage (CS). The mean donor age was 61 +/- 1 years in the EVNP and 62 +/- 6 years in the CS group (p = 0.520). EVNP kidneys were perfused for an average of 63 +/- 16 min and all were transplanted successfully. The delayed graft function rate (DGF), defined as the requirement for dialysis within the first 7 days was 1/18 patients (5.6%) in the EVNP group versus 17/47 (36.2%) in the CS group (p = 0.014). There was no difference in graft or patient survival at 12 months (p = 0.510, 1.000). This first series of EVNP in renal transplantation demonstrates that this technique is both feasible and safe. Our preliminary data suggests that EVNP offers promise as a new technique of kidney preservation. PMID- 23433046 TI - Prevalence of chronic kidney disease in patients with type 2 diabetes in Spain: PERCEDIME2 study. AB - BACKGROUND: The objective of this study was to determinate the prevalence of chronic kidney disease (CKD) and the different stages of CKD in patients with type 2 diabetes mellitus (DM2) treated in primary care consults in Spain. METHODS: A national cross-sectional study was performed in primary care consults. The following data were collected: demographic and anthropometric information; list of present cardiovascular risk factors (CVRF); previous macrovascular and microvascular disease history; physical examination and analytical data from the previous 12 months, including the urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) to evaluate renal function. RESULTS: With regard to the patients, 27.9% presented some degree of CKD as follows: 3.5% with stage 1; 6.4% with stage 2; 16.8% with stage 3 (11.6% with stage 3A and 5.2% with stage 3B); and 1.2% with stages 4 and 5. The prevalence of patients with UACR >= 30 mg/g was 15.4% (13% microalbuminuria and 2.4% macroalbuminuria). Renal impairment (RI) was found in 206 patients (18%) of whom 133 patients (64.6%) was stage 3A, 60 patients (29.1%) was stage 3B and 13 patients (6.3%) stages 4 and 5. Among patients with RI, 143 patients (69.4%) had normoalbuminuria. The following variables were significantly associated with CKD: age; sex (women); systolic arterial blood pressure (SABP) >= 150 mmHg; and a previous history of cardiovascular disease. CONCLUSIONS: The results showed that the prevalence for any type of CKD was 27.9%. A systematic determination of UACR and eGFR may contribute to an early diagnosis, thus allowing intervention during the initial stages of the disease when treatment is more efficient. PMID- 23433048 TI - Medicinal plants for the treatment of uterus inflammation: implications from Iranian folk medicine. PMID- 23433049 TI - Chinese herbs for memory disorders: a review and systematic analysis of classical herbal literature. AB - Text mining and other literature-based investigations can assist in identifying natural products for experimental and clinical research. This article details a method for systematically analyzing data derived from the classical Chinese medical literature. We present the results of electronic searches of Zhong Hua Yi Dian ("Encyclopaedia of Traditional Chinese Medicine"), a CD of 1000 premodern (before 1950) medical books, for single herbs, and other natural products used for dementia, memory disorders, and memory improvement. This review explores how the terminology for these disorders has changed over time and which herbs have been used more or less frequently, and compares the results from the premodern literature with the herbs indexed for memory disorders in a modern pharmacopoeia. The searches located 731 citations deriving from 127 different books written between ca. 188 ad and ca. 1920. Of the 110 different natural products identified, those most frequently cited for forgetfulness were yuan zhi (Polygala tenuifolia), fu shen (Poria cocos), and chang pu (Acorus spp.), all of which have been cited repeatedly over the past 1800 years and appear among the 31 herbs indexed in a modern pharmacopoeia. By providing a complete, hierarchically organized list of herbs for a specific disorder, this approach can assist researchers in selecting herbs for research. PMID- 23433050 TI - Anticonvulsant effect of Berberis integerrima L. root extracts in mice. AB - Berberis integerrima is a member of Berberidaceae family. Berberine is one of the main constituents of this plant, having neuroprotective effect on central nervous system diseases. In this study, the anticonvulsant activity of methanolic extract, and hydromethanolic fraction, and chloroform fraction of B integerrima was assessed. The anticonvulsant effect of B integerrima was investigated using both pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizure models. The LD50 value of the methanolic extract was 302.676 mg/kg. In the PTZ test, methanolic extract (140 and 200 mg/kg, i.p., p<0.01), hydromethanolic fraction (200 mg/kg, p<0.01), and chloroform fraction (200 mg/kg, p<0.01) increased the onset time of hind limb tonic extensions (HLTEs). The protective effect against mortality (convulsion survivors/animals tested) was 2/8 in methanolic extract, and 3/8 in hydromethanolic fraction at a dose of 200 mg/kg and in chloroform fraction at a dose of 140 mg/kg. In the MES test, this plant did not display any significant effect in reducing HLTE duration. According to phytochemical screening, methanolic extract contained alkaloids and tannins. The present study, conducted in mice, indicated that B integerrima has anticonvulsant activity in PTZ-induced seizures. It is concluded that B integerrima may be useful in petit mal epilepsy. PMID- 23433051 TI - Effect of aqueous and ethanolic extracts of Nigella sativa seeds on milk production in rats. AB - Nigella sativa L. is used as a galactagogue in traditional medicine. Hence, the effects of aqueous and ethanolic extracts of N. sativa seeds on milk production in rats were evaluated. The measurement of milk production was by measuring pup weight during suckling period. The intraperitoneal LD(50) values of aqueous and ethanolic extracts of N. sativa were 4.23 and 4.9 g/kg, respectively. The aqueous (0.5 g/kg) and ethanolic extracts (1 g/kg) increased milk production significantly (p < 0.001), producing about 31.3% and 37.6% more milk than control, respectively. During the study period, the pups gained weight with the aqueous (0.5 g/kg, p < 0.01) and ethanolic extracts (1 g/kg, p < 0.05). It is concluded that aqueous and ethanolic extracts of N. sativa can stimulate milk production in rats. PMID- 23433052 TI - alpha-Glucosidase and alpha-amylase inhibitory activity of Senna surattensis. AB - In this study, we investigated the inhibitory effects of ethanolic extract of the leaves of Senna surattensis (EESS) on alpha-glucosidase and alpha-amylase. We also studied the in vitro antidiabetic activity of S. surattensis using the glucose uptake by isolated rat hemidiaphragm model. In vitro studies using mammalian alpha-glucosidase extracted from the small intestine homogenate of mouse showed that the extract was found to be more effective in inhibiting the activities of maltase [half maximal inhibitory concentration (IC(50)): 209.15 MUg/mL] and sucrase (IC(50): 366.44 MUg/mL) when compared with the control group (acarbose). The extract of S. surattensis were further quantified with respect to porcine pancreatic alpha-amylase inhibition using the chromogenic 3,5 dinitrosalicylic acid method. Interestingly, S. surattensis was also found to exhibit alpha-amylase (IC(50): 123.95 MUg/mL) inhibitory activity. The glucose uptake in the rat hemidiaphragm was significantly (p < 0.01) increased by EESS (220.95 +/- 5.4 mg/g/30 minute) when compared with the control group. The total polyphenolic content of EESS was found to be 98 MUg pyrocatechol/mg of the extract. These results suggest that EESS inhibited carbohydrate digestive enzymes and increased the peripheral uptake of glucose. This study endorses the use of this plant for further studies to determine their potential for managing type II diabetes. PMID- 23433053 TI - Antidiabetic properties and mechanism of action of Orthosiphon stamineus Benth bioactive sub-fraction in streptozotocin-induced diabetic rats. AB - Orthosiphon stamineus is a popular folk medicine widely used to treat many diseases including diabetes. Previous studies have shown that the sub-fraction of chloroform extract was able to inhibit the rise of blood glucose levels in a glucose tolerance test. This study was carried out to evaluate the chronic effect and possible mechanism of action of the bioactive chloroform sub-fraction of O. stamineus using streptozotocin-induced diabetic rats and in vitro methods. Administration of the chloroform extract sub-fraction 2 (Cf2-b) at a dose of 1 g/kg twice daily on diabetic rats for 14 days showed a significant lowering (p < 0.05) of the final blood glucose level compared to the pretreatment level. However, there were no significant differences in the plasma insulin levels post treatment compared to the pretreatment levels for all doses of Cf2-b. Conversely, Cf2-b at a concentration of 2 mg/mL significantly increased (p < 0.001) the glucose uptake by the rat diaphragm muscle. The increase in glucose uptake was also shown when the muscle was incubated in a solution containing 1 IU/mL of insulin or 1 mg/mL of metformin. Furthermore, the effect of this sub-fraction on glucose absorption in the everted rat jejunum showed that Cf2-b at concentrations of 0.5 mg/mL, 1 mg/mL and, 2 mg/mL significantly reduced the glucose absorption of the jejunum (p < 0.05-0.001). Similarly, the absorption of glucose was also inhibited by 1 mg/mL and 2 mg/mL of metformin (p < 0.001). These results suggest that the effect of Cf2-b may be due to extra-pancreatic mechanisms. There was no evidence that the plant extract stimulated the release of insulin in order to lower the blood glucose level. PMID- 23433054 TI - Evaluation of the safety of Sanyak (Dioscoreae rhizoma) pharmacopuncture according to the extraction method: a double-blind randomized controlled trial. AB - The study was conducted to evaluate the safety of Sanyak (Dioscoreae rhizoma) pharmacopuncture by injecting to healthy participants. Among the subjective symptoms, pain after the injection was statistically significant in the group injected with alcohol extract of Sanyak. The mean platelet volume and blood in the urinalysis after the injections were statistically significant between groups. After injections, the total protein level in liver function tests and hematocrit changed significantly. However, all of these changes were within normal limits, and Sanyak pharmacopuncture did not cause any severe physical responses or subjective symptoms and may, therefore, be considered safe. PMID- 23433055 TI - Hepatoprotective activity of methanol extract of Melastoma malabathricum leaf in rats. AB - The present study aimed to determine the hepatoprotective activity of a methanol extract of Melastoma malabathricum leaves (MEMM) using two established rat models. Ten groups of rats (n=6) were given a once-daily administration of 10% dimethyl sulfoxide (negative control), 200 mg/kg silymarin (positive control), or MEMM (50, 250, or 500 mg/kg) for 7 days followed by induction of hepatotoxicity either using paracetamol or carbon tetrachloride. Blood samples and livers were collected for biochemical and microscopic analysis. Based on the results obtained, MEMM exhibited a significant (p<0.05) hepatoprotective activity against both inducers, as indicated by an improvement in the liver function test. These observations were supported by the histologic findings. In conclusion, M. malabathricum leaves possessed hepatoprotective activity, which could be linked to their phytochemical constituents and antioxidant activity; this therefore requires further in-depth studies. PMID- 23433056 TI - Acupuncture for management of balance impairment in a patient with bipolar disorder. AB - A case is reported of unexplained unilateral thigh muscle atrophy and frequent falling with poor response to conventional conservative treatments in a patient with bipolar disorder who self-selected acupuncture treatment as a last resort. The patient experienced gradual improvements in lower extremity weakness and fewer falls during the 8-month treatment. No adverse event or aggravation of the bipolar disorder was observed. These outcomes suggest that acupuncture may be a feasible adjunct for reducing falling and restoring postural balances in patients with bipolar disorder. PMID- 23433057 TI - Factors affecting hearing improvement following successful repair of the tympanic membrane. AB - BACKGROUND: The main aim of tympanic membrane repair is the elimination of chronic or intermittent aural discharge. Hearing improvement may or may not occur following a technically successful operation. METHOD: This study entailed a retrospective analysis of prospectively collected data from 203 operations that resulted in an intact tympanic membrane 6 months after surgery. RESULTS: Complete hearing data were available for 169 operations on 160 patients. Of these, 53 per cent resulted in closure of the air-bone gap to within 10 dB, and 54 per cent of cases had post-operative hearing thresholds of at least 30 dB. The mean hearing change after surgery was +8.3 dB. Multiple regression analysis indicated that hearing improvement was more likely in large compared with small perforations. Smaller hearing gains occurred in ears with erosion of the stapes arch and/or fixation of the stapes, as well as in those with active discharge at the time of surgery and in revision cases. CONCLUSION: Greater hearing improvement can be expected following successful repair of perforations involving more than 50 per cent of the drum area. Poorer results are likely to occur in ears with additional middle-ear pathology and in revision cases. PMID- 23433058 TI - 3D CT-guided pulsed radiofrequency treatment for trigeminal neuralgia. AB - Trigeminal neuralgia (TN) is a pain syndrome characterized by pain in the trigeminal area often accompanied by a brief facial spasm or tic. The purpose of our study was to investigate the efficacy and clinical utility of CT-guided pulsed radiofrequency (PRF) for treatment of TN. Patients who were diagnosed with severe TN between September 2010 and October 2010 at Beijing Tiantan Hospital were included. Pulsed radiofrequency treatment (PRFT) was employed to treat TN. To verify the accurate needle position, a thin-section cranial CT scan was performed by using a multidetector CT scanner. Three-dimensional reconstruction was performed to visualize the location of the needle and the foramen ovale. A total of 20 patients were included in the study. Seven patients (35%) had favorable outcome 1 year after the PRFT. The numeric rating scale in the 7 patients with good outcome was significantly lower than the 13 patients with bad outcome at 1 day, 1 week, and 2 weeks after the treatment. The remaining 13 patients had residual pain 2 weeks after the PRFT and had to receive radiofrequency thermocoagulation (RFTC). In conclusion, the results of our study demonstrate that CT-guided PRFT is not an effective method of pain treatment for idiopathic TN as compared with conventional RFTC. However, CT-guided PRFT is associated with less complication than RFTC. PMID- 23433059 TI - The 'ubiquitous' reality of vector immunology. AB - Ubiquitination (ubiquitylation) is a common protein modification that regulates a multitude of processes within the cell. This modification is typically accomplished through the covalent binding of ubiquitin to a lysine residue onto a target protein and is catalysed by the presence of three enzymes: an activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). In recent years, ubiquitination has risen as a major signalling regulator of immunity and microbial pathogenesis in the mammalian system. Still, little is known about how ubiquitin relates specifically to vector immunology. Here, we provide a brief overview of ubiquitin biochemistry and describe how ubiquitination regulates immune responses in arthropods of medical relevance. We also discuss scientific gaps in the literature and suggest that, similar to mammals, ubiquitin is a major regulator of immunity in medically important arthropods. PMID- 23433060 TI - The story of artesunate-mefloquine (ASMQ), innovative partnerships in drug development: case study. AB - BACKGROUND: The Drugs for Neglected Diseases initiative (DNDi) is a not-for profit organization committed to providing affordable medicines and access to treatments in resource-poor settings. Traditionally drug development has happened "in house" within pharmaceutical companies, with research and development costs ultimately recuperated through drug sales. The development of drugs for the treatment of neglected tropical diseases requires a completely different model that goes beyond the scope of market-driven research and development. Artesunate and mefloquine are well-established drugs for the treatment of uncomplicated malaria, with a strong safety record based on many years of field-based studies and use. The administration of such artemisinin-based combination therapy in a fixed-dose combination is expected to improve patient compliance and to reduce the risk of emerging drug resistance. CASE DESCRIPTION: DNDi developed an innovative approach to drug development, reliant on strong collaborations with a wide range of partners from the commercial world, academia, government institutions and NGOs, each of which had a specific role to play in the development of a fixed dose combination of artesunate and mefloquine. DISCUSSION AND EVALUATION: DNDi undertook the development of a fixed-dose combination of artesunate with mefloquine. Partnerships were formed across five continents, addressing formulation, control and production through to clinical trials and product registration, resulting in a safe and efficacious fixed dose combination treatment which is now available to treat patients in resource-poor settings. The south-south technology transfer of production from Farmanguinhos/Fiocruz in Brazil to Cipla Ltd in India was the first of its kind. Of additional benefit was the increased capacity within the knowledge base and infrastructure in developing countries. CONCLUSIONS: This collaborative approach to drug development involving international partnerships and independent funding mechanisms is a powerful new way to develop drugs for tropical diseases. PMID- 23433061 TI - A randomized control trial: training program of university students as health promoters. AB - BACKGROUND: Several studies have reported the following as determining factors for the adoption of healthy lifestyles among undergraduate students: gender, socioeconomic level, prior lifestyles, environment, parental lifestyles and health status, career choice, and healthy support networks. However, these factors are influenced by students' knowledge about healthy lifestyles. METHODS/DESIGN: We will carry out a randomized trial in a sample of 280 new undergraduate students at the National Autonomous University of Mexico's Faculty of Higher Studies-Zaragoza (FES-Zaragoza, UNAM). There will be an experimental group (n = 140), comprising 20 students from each of the seven university departments (careers); these students will receive training as university student health promoters through an e-learning course. This course will allow the topics necessary for such promoters to be reviewed. There will be a control group (n = 140), comprising 20 students from each of the seven departments (careers); these students will not undergo the training. Later, the students who comply satisfactorily with the e-learning course will replicate the course to 10 of their classmates. A healthy-lifestyle questionnaire will be given to all the participants, and the parameters established in the self-care card will be recorded before and after the training. The study variables are as follows: (i) independent variable-compliance with the e-learning course; (ii) dependent variables-lifestyles changes prior to the educative intervention (including healthy eating, physical activity, and addiction prevention) and parameters related to health status established in self-care (including weight, body mass index, waist circumference, and hip circumference). Data will be analyzed using Student's t test and logistic regression analysis odds ratios with 95% confidence intervals. The analysis of the open answers will be carried out with ATLAS. ti 5.5 software. DISCUSSION: Health promotion among university students should incorporate options that are feasible for and attractive to students. Thus, as proposed in the present protocol, e-learning courses offer excellent possibilities because they allow students to program their learning in their available time without affecting their academic studies. TRIAL REGISTRATION: http://ISRCTN77787889. PMID- 23433063 TI - Ovarian reserve and anti-Mullerian hormone (AMH) in mothers of dizygotic twins. AB - This study aimed to explore if natural dizygotic (DZ) twinning is associated with earlier menopause and lower anti-Mullerian hormone (AMH) values. We investigated if advanced biological reproductive aging, which can be responsible for the multiple follicle growth in familial twinning, is similar to mechanisms that occur in normal ovarian aging, reflected by earlier menopause in mothers of DZ twins and lower levels of AMH. A total of 16 mothers of DZ twins enrolled with the Netherlands Twin Register (average age at first assessment: 35.9 +/- 3.0 years) and 14 control mothers (35.1 +/- 3 years) took part in a prospective study. Fifteen years after entry into the study, which included follicle stimulating hormone (FSH) assessment, AMH was measured in stored serum samples and menopause status was evaluated. Average AMH levels were not significantly different between DZ twin mothers and controls (2.1 +/- 2.4 MUg/L vs. 1.9 +/- 1.9 MUg/L). Among the 16 mothers of twins, 7 had an elevated (FSH) value over 10 U/L at first assessment. Their AMH levels were lower than the nine twin mothers with normal FSH values: 0.6 +/- 0.4 versus 3.4 +/- 2.6 MUg/L (p = .01). Of the mothers of twins, eight mothers had entered menopause at the second assessment compared with only one control mother (p = .07). Thus, slightly more DZ mothers were in menopause than the control mothers, although this difference was not significant. The subgroup of DZ twin mothers who had an increased FSH concentration 15 years ago had a limited ovarian reserve as reflected by lower AMH levels. These data indicate that advanced ovarian aging can be a feature in familial DZ twinning, particularly with elevated early follicular phase FSH. PMID- 23433062 TI - Oil palm phenolics confer neuroprotective effects involving cognitive and motor functions in mice. AB - OBJECTIVES: Phenolics are important phytochemicals which have positive effects on chronic diseases, including neurodegenerative ailments. The oil palm (Elaeis guineensis) is a rich source of water-soluble phenolics. This study was carried out to discover the effects of administering oil palm phenolics (OPP) to mice, with the aim of identifying whether these compounds possess significant neuroprotective properties. METHODS: OPP was given to BALB/c mice on a normal diet as fluids for 6 weeks while the controls were given distilled water. These animals were tested in a water maze and on a rotarod weekly to assess the effects of OPP on cognitive and motor functions, respectively. Using Illumina microarrays, we further explored the brain gene expression changes caused by OPP in order to determine the molecular mechanisms involved. Real-time quantitative reverse transcription-polymerase chain reaction experiments were then carried out to validate the microarray data. RESULTS: We found that mice given OPP showed better cognitive function and spatial learning when tested in a water maze, and their performance also improved when tested on a rotarod, possibly due to better motor function and balance. Microarray gene expression analysis showed that these compounds up-regulated genes involved in brain development and activity, such as those under the regulation of the brain-derived neurotrophic factor. OPP also down-regulated genes involved in inflammation. DISCUSSION: These results suggest that the improvement of mouse cognitive and motor functions by OPP is caused by the neuroprotective and anti-inflammatory effects of the extract. PMID- 23433064 TI - Goal-directed fluid therapy- a survey of anaesthetists in the UK, USA, Australia and New Zealand. AB - BACKGROUND: Goal-directed fluid therapy (GDFT) has been shown to reduce complications and hospital length of stay following major surgery. However, there has been no assessment regarding its use in clinical practice. METHODS: An electronic survey was administered to randomly selected anaesthetists from the United Kingdom (UK, n = 2000) and the United States of America (USA, n = 2000), and 500 anaesthetists from Australia/New Zealand (AUS/NZ). Preferences, clinical use and attitudes towards GDFT were investigated. Results were collated to examine regional differences. RESULTS: The response rates from the UK (n = 708) and AUS/NZ (n = 180) were 35%, and 36% respectively. The response rate from the USA was very low (n = 178; 9%). GDFT use was significantly more common in the UK than in AUS/NZ (p < 0.01). The Oesophageal Doppler Monitor was the most preferred instrument in the UK (n = 362; h76%) with no clear preferences in other regions. GDFT was most commonly utilised in major abdominal surgery and for patients with significant comorbidities. The commonest reasons stated for not using GDFT were either lack of availability of monitoring tools (AUS/NZ: 57 (70%); UK: 94 (64%)) or a lack of experience with instruments (AUS/NZ: 43 (53%); UK: 51 (35%)). A subset of respondents (AUS/NZ: 22(27%); UK: 45 (30%)) felt GDFT provided no perceived benefit. Enthusiasm towards the use of GDFT in the absence of existing barriers was high. CONCLUSION: Several hypotheses were generated regarding important differences in the use of GDFT between anaesthetists from the UK and AUS/NZ. There is significant interest in utilising GDFT in clinical practice and existing barriers should be addressed. PMID- 23433065 TI - Habitat productivity constrains the distribution of social spiders across continents - case study of the genus Stegodyphus. AB - INTRODUCTION: Sociality has evolved independently multiple times across the spider phylogeny, and despite wide taxonomic and geographical breadth the social species are characterized by a common geographical constrain to tropical and subtropical areas. Here we investigate the environmental factors that drive macro ecological patterns in social and solitary species in a genus that shows a Mediterranean-Afro-Oriental distribution (Stegodyphus). Both selected drivers (productivity and seasonality) may affect the abundance of potential prey insects, but seasonality may further directly affect survival due to mortality caused by extreme climatic events. Based on a comprehensive dataset including information about the distribution of three independently derived social species and 13 solitary congeners we tested the hypotheses that the distribution of social Stegodyphus species relative to solitary congeners is: (1) restricted to habitats of high vegetation productivity and (2) constrained to areas with a stable climate (low precipitation seasonality). RESULTS: Using spatial logistic regression modelling and information-theoretic model selection, we show that social species occur at higher vegetation productivity than solitary, while precipitation seasonality received limited support as a predictor of social spider occurrence. An analysis of insect biomass data across the Stegodyphus distribution range confirmed that vegetation productivity is positively correlated to potential insect prey biomass. CONCLUSIONS: Habitat productivity constrains the distribution of social spiders across continents compared to their solitary congeners, with group-living in spiders being restricted to areas with relatively high vegetation productivity and insect prey biomass. As known for other taxa, permanent sociality likely evolves in response to high predation pressure and imposes within-group competition for resources. Our results suggest that group living is contingent upon productive environmental conditions where elevated prey abundance meet the increased demand for food of social groups. PMID- 23433066 TI - Coexistence of Guillain-Barre syndrome and Behcet's disease. AB - Behcet's disease (BD) is a multisystemic, recurrent and inflammatory disorder. Neurological involvement is rare and affects mainly the central nervous system (CNS) in the form of brainstem meningoencephalitis or dural sinus thrombosis. Peripheral neuropathy is usually not observed during the course of BD but some reports have shown electrophysiologic evidence of subclinical neuropathy, mononeuritis multiplex and cranial neuropathy in BD patients. The co-occurrence of Guillain-Barre syndrome (GBS), an acute inflammatory demyelinating neuropathy, with other autoimmune or systemic diseases is rare. We present a case of BD with clinical and electrophysiological diagnosis of GBS. The findings of the patient were discussed with reference to literature. PMID- 23433067 TI - Four-year prospective evaluation of the relationship between meaning in life and smoking status. AB - BACKGROUND: To date, all investigations on the relationship between smoking and perceived level of meaning in life have used cross-sectional designs. Therefore, the purpose of the present prospective study, conducted with a four-year time lag, was to test the predictive power of the life meaning construct concerning changes in smoking status. METHODS: The data of 4,294 respondents (40.3% male, M(age) = 54.7 +/- 16.5 yrs) from the Hungarian Epidemiological Panel Survey were analyzed using the Kruskal-Wallis and Mann-Whitney U-test and structural equation modeling (SEM) with a nominal outcome variable. Gender, age, and educational level were included in the study as covariates. RESULTS: On the bivariate level, results showed that both baseline and follow-up meaning in life scores were higher in stable non-smokers when compared to stable smokers. However, quitters and starters differed from stable non-smokers in their baseline but not in follow up life meaning scores. The other relationships (stable smokers vs. quitters; stable smokers vs. starters, starters vs. quitters) were non-significant in both time points. According to the SEM-analysis, a higher sense of meaning in life measured at baseline and follow-up is associated with a lower likelihood (OR = 0.54, z = 2.80, p = 0.005; OR = 0.64, z = 2.88, p = 0.004, respectively) of being a stable smoker compared to being a stable non-smoker, confirming the expected relationship between smoking and decreased level of meaning in life. However, neither baseline nor follow-up life meaning scores predicted significantly quitting and uptake of smoking. CONCLUSIONS: If future research from other cultures verifies the protective role of a higher level of meaning in life against smoking, then smoking prevention and cessation programs will also have to include such components that help individuals experience more meaning in their lives. PMID- 23433068 TI - Cheek interpolation flap and composite graft repair of a nasal tip and full thickness soft triangle defect. PMID- 23433069 TI - Analysis of androgen receptor and anti-Mullerian hormone pathways in human granulosa cells under luteinizing hormone treatment. AB - BACKGROUND: The objective of this study was to determine the gene expression profiles of the androgen/androgen receptor (AR) and anti-Mullerian hormone (AMH)/ Sry-related high-mobility group box 9 (SOX9) pathways in granulosa-luteal cells from patients undergoing standard in vitro fertilization (IVF) with or without recombinant luteinizing hormone (rLH) therapy. METHODS: Levels of reproductive hormones in the pre-ovulatory follicular fluid and the expression levels of LHR (luteinizing hormone receptor), AR, SOX9, AMH, AR-associated protein 54(ARA54)and ARA70 were determined in granulosa-luteal cells by real-time reverse transcription PCR. The effects of androgen and rLH treatments on AR and AMH expression levels were also tested in vitro using HO23 cells. RESULTS: We collected 35 an 70 granulosa cell samples from patients cycled with and without rLH supplementation, respectively. The clinical outcomes were similar in patients who received rLH therapy and those who did not, though the pre-ovulatory follicular fluid levels of androstenedione, testosterone, and estradiol were significantly higher and progesterone was lower in the rLH supplementation group. Moreover, granulosa-luteal cell mRNA levels of LHR, AR, AMH, and SOX9 were significantly higher in the rLH supplementation group relative to the group that did not receive rLH supplementation. In addition, we observed significant correlations between LHR and AR mRNA expression and among AR, AMH, and SOX9 mRNA expression in granulosa-luteal cells from patients undergoing standard IVF treatment. CONCLUSIONS: Increased expression of LHR, AR, AMH, and SOX9 is characteristic of granulosa-luteal cells from IVF/ intracytoplasmic sperm injection (ICSI) patients receiving rLH supplementation. PMID- 23433071 TI - New one-pot synthesis of Au and Ag nanoparticles using green rust reactive particle as a micro-reactor. AB - A new, simple, and fast one-pot synthesis of supported Au or Ag nanoparticles is implemented, for which a reactive Fe(II)-bearing green rust inorganic particle is used as an individual micro-reactor acting as both the reducing agent and support for the resulting metal nanoparticles. The mechanism involves both the solid state oxidation of the green rust support (sulfate or carbonate) and the reduction-precipitation of soluble metal precursor. The resulting nanohybrids have a platy inorganic part supporting about one to ten nanoparticles with sizes in the 20 to 120 nm range. PMID- 23433070 TI - Saturation mutagenesis of selected residues of the alpha-peptide of the lantibiotic lacticin 3147 yields a derivative with enhanced antimicrobial activity. AB - The lantibiotic lacticin 3147 consists of two ribosomally synthesized and post translationally modified antimicrobial peptides, Ltnalpha and Ltnbeta, which act synergistically against a wide range of Gram-positive microorganisms. We performed saturation mutagenesis of specific residues of Ltnalpha to determine their functional importance. The results establish that Ltnalpha is more tolerant to change than previously suggested by alanine scanning mutagenesis. One substitution, LtnalphaH23S, was identified which improved the specific activity of lacticin 3147 against one pathogenic strain, Staphylococcus aureus NCDO1499. This represents the first occasion upon which the activity of a two peptide lantibiotic has been enhanced through bioengineering. PMID- 23433072 TI - Morus alba and active compound oxyresveratrol exert anti-inflammatory activity via inhibition of leukocyte migration involving MEK/ERK signaling. AB - BACKGROUND: Morus alba has long been used in traditional Chinese medicine to treat inflammatory diseases; however, the scientific basis for such usage and the mechanism of action are not well understood. This study investigated the action of M. alba on leukocyte migration, one key step in inflammation. METHODS: Gas chromatography-mass spectrometry (GC-MS) and cluster analyses of supercritical CO2 extracts of three Morus species were performed for chemotaxonomy-aided plant authentication. Phytochemistry and CXCR4-mediated chemotaxis assays were used to characterize the chemical and biological properties of M. alba and its active compound, oxyresveratrol. fluorescence-activated cell sorting (FACS) and Western blot analyses were conducted to determine the mode of action of oxyresveratrol. RESULTS: Chemotaxonomy was used to help authenticate M. alba. Chemotaxis-based isolation identified oxyresveratrol as an active component in M. alba. Phytochemical and chemotaxis assays showed that the crude extract, ethyl acetate fraction and oxyresveratrol from M. alba suppressed cell migration of Jurkat T cells in response to SDF-1. Mechanistic study indicated that oxyresveratrol diminished CXCR4-mediated T-cell migration via inhibition of the MEK/ERK signaling cascade. CONCLUSIONS: A combination of GC-MS and cluster analysis techniques are applicable for authentication of the Morus species. Anti inflammatory benefits of M. alba and its active compound, oxyresveratrol, may involve the inhibition of CXCR-4-mediated chemotaxis and MEK/ERK pathway in T and other immune cells. PMID- 23433074 TI - A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a frequent cause of end stage renal disease. Renal transplantation in patients with FSGS is often complicated by disease recurrence, which is associated with poor outcome. There are no tests that reliably predict recurrence of FSGS after transplantation. The aim of this study was to evaluate if clinical criteria can identify patients at high risk for recurrent disease. METHODS: We retrospectively studied 94 patients who received a first renal transplant at a median age of 37 years (range 5-69 years). Patients were assigned to one of three groups: familial or genetic FSGS (group I; n=18), secondary FSGS (group II; n=10) and idiopathic FSGS (group III; n=66). Pretransplant clinical characteristics were analyzed to determine predictors of a recurrence after transplantation. RESULTS: FSGS only recurred in patients with idiopathic FSGS (group III; 42%). Patients with a recurrence had a significantly lower serum albumin, higher 24-hour proteinuria and higher estimated glomerular filtration rate at diagnosis. Serum albumin at diagnosis was the only independent predictor of a recurrence in patients with idiopathic FSGS. Patients with recurrent FSGS had more acute rejection episodes (54% vs. 27%, P =0.02) and lower five year graft survival compared to patients without a recurrence (50 vs. 82%, P <0.01). CONCLUSIONS: Clinical criteria allow identification of patients at high risk of recurrent FSGS after renal transplantation. This information can be used in the counseling and management of patients with FSGS. PMID- 23433073 TI - Ancient complexity, opisthokont plasticity, and discovery of the 11th subfamily of Arf GAP proteins. AB - The organelle paralogy hypothesis is one model for the acquisition of nonendosymbiotic organelles, generated from molecular evolutionary analyses of proteins encoding specificity in the membrane traffic system. GTPase activating proteins (GAPs) for the ADP-ribosylation factor (Arfs) GTPases are additional regulators of the kinetics and fidelity of membrane traffic. Here we describe molecular evolutionary analyses of the Arf GAP protein family. Of the 10 subfamilies previously defined in humans, we find that 5 were likely present in the last eukaryotic common ancestor. Of the 3 most recently derived subfamilies, 1 was likely present in the ancestor of opisthokonts (animals and fungi) and apusomonads (flagellates classified as the sister lineage to opisthokonts), while 2 arose in the holozoan lineage. We also propose to have identified a novel ancient subfamily (ArfGAPC2), present in diverse eukaryotes but which is lost frequently, including in the opisthokonts. Surprisingly few ancient domains accompanying the ArfGAP domain were identified, in marked contrast to the extensively decorated human Arf GAPs. Phylogenetic analyses of the subfamilies reveal patterns of single and multiple gene duplications specific to the Holozoa, to some degree mirroring evolution of Arf GAP targets, the Arfs. Conservation, and lack thereof, of various residues in the ArfGAP structure provide contextualization of previously identified functional amino acids and their application to Arf GAP biology in general. Overall, our results yield insights into current Arf GAP biology, reveal complexity in the ancient eukaryotic ancestor and integrate the Arf GAP family into a proposed mechanism for the evolution of nonendosymbiotic organelles. PMID- 23433075 TI - An Ecofriendly synthesis of silver nano-bioconjugates by Penicillium citrinum (MTCC9999) and its antimicrobial effect. AB - This report provides for the first time a novel environment friendly extracellular synthesis of stable silver nano-bioconjugates (SNBCs) at room temperature at pH 5.0 using Penicillium citrinum MTCC 9999 biomass. The UV Visible spectral scan of dispersed SNBCs solution showed absorption in the region 340-450 nm due to surface plasma resonance (SPR). Typical Transmission Electron Microscopic (TEM) images showed that although two populations were present but most of them were in 20-30 nm range. Average zeta potential of SNBCs was -21 mV suggesting some biomolecules capped the nanoparticles imparting a net negative charge over it. FTIR analysis also showed that biomolecules were involved in stabilization. SNBCs showed strong antibacterial activity against both Gram positive (Bacillus subtilis) and Gram negative bacteria (Escherichia coli). SNBCs also showed strong antifungal activity as assessed against Schizosaccharomyces pombe. In the case of E. coli the minimum inhibitory concentrations (MIC) of SNBCs was 4 MUg/ml while in B. subtilis it was 8 MUg/ml. In the case of E. coli the minimum bactericidal concentrations (MBC) of SNBCs was 8 MUg/ml while in B. subtilis it was 32 MUg/ml. The SNBCs exerted its antibacterial and antifungal activity through generation of reactive oxygen species (ROS) inside the cell. PMID- 23433076 TI - Do patients with allergic rhinitis have a particular personality trait? AB - OBJECTIVES: This study investigated the personality traits of patients with allergic rhinitis. It also examined the association between personality type and the type of allergic rhinitis, and compared this with the general population. METHODS: A descriptive observational pilot study was carried out on 50 consecutive cases of allergic rhinitis who presented to the allergy clinic between June and October 2010. These patients were compared with a control group comprising 50 individuals from the general population that had no symptoms of allergic rhinitis. Both groups completed the International Personality Disorder Examination questionnaire for the assessment of personality traits. RESULTS: Persons falling into cluster C personality type showed a positive correlation with the type and severity of allergic rhinitis. The majority of control group individuals fell into cluster A. This indicated a correlation between allergic rhinitis and a dominant anxious trait compared with the control group. CONCLUSION: In psycho-allergological research, the potential relevance of personality factors in the maintenance and exacerbation of atopic symptoms is still a matter of debate. More attention should be paid to the psychological status of allergic rhinitis patients, and appropriate treatment should be provided to improve their symptoms and quality of life. PMID- 23433077 TI - Networking the host immune response in Plasmodium vivax malaria. AB - BACKGROUND: Plasmodium vivax malaria clinical outcomes are a consequence of the interaction of multiple parasite, environmental and host factors. The host molecular and genetic determinants driving susceptibility to disease severity in this infection are largely unknown. Here, a network analysis of large-scale data from a significant number of individuals with different clinical presentations of P. vivax malaria was performed in an attempt to identify patterns of association between various candidate biomarkers and the clinical outcomes. METHODS: A retrospective analysis of 530 individuals from the Brazilian Amazon, including P. vivax-infected individuals who developed different clinical outcomes (148 asymptomatic malaria, 187 symptomatic malaria, 13 severe non-lethal malaria, and six severe lethal malaria) as well as 176 non-infected controls, was performed. Plasma levels of liver transaminases, bilirubins, creatinine, fibrinogen, C reactive protein, superoxide dismutase (SOD)-1, haem oxygenase (HO)-1 and a panel composed by multiple cytokines and chemokines were measured and compared between the different clinical groups using network analysis. RESULTS: Non-infected individuals displayed several statistically significant interactions in the networks, including associations between the levels of IL-10 and IL-4 with the chemokine CXCL9. Individuals with asymptomatic malaria displayed multiple significant interactions involving IL-4. Subjects with mild or severe non-lethal malaria displayed substantial loss of interactions in the networks and TNF had significant associations more frequently with other parameters. Cases of lethal P. vivax malaria infection were associated with significant interactions between TNF ALT, HO-1 and SOD-1. CONCLUSIONS: The findings imply that clinical immunity to P. vivax malaria is associated with multiple significant interactions in the network, mostly involving IL-4, while lethality is linked to a systematic reduction of complexity of these interactions and to an increase in connections between markers linked to haemolysis-induced damage. PMID- 23433078 TI - Can malaria vector control accelerate the interruption of lymphatic filariasis transmission in Africa; capturing a window of opportunity? AB - BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000, and nearly all endemic countries in the Americas, Eastern Mediterranean and Asia-Pacific regions have now initiated the WHO recommended mass drug administration (MDA) campaign to interrupt transmission of the parasite. However, nearly 50% of the LF endemic countries in Africa are yet to implement the GPELF MDA strategy, which does not include vector control. Nevertheless, the recent scale up in insecticide treated /long lasting nets (ITNs/LLINs) and indoor residual spraying (IRS) for malaria control in Africa may significantly impact LF transmission because the parasite is transmitted mainly by Anopheles mosquitoes. This study examined the magnitude, geographical extent and potential impact of vector control in the 17 African countries that are yet to or have only recently started MDA. METHODS: National data on mosquito bed nets, ITNs/LLINs and IRS were obtained from published literature, national reports, surveys and datasets from public sources such as Demographic Health Surveys, Malaria Indicator Surveys, Multiple Indicator Cluster Surveys, Malaria Report, Roll Back Malaria and President's Malaria Initiative websites. The type, number and distribution of interventions were summarised and mapped at sub national level. and compared with known or potential LF distributions, and those which may be co-endemic with Loa loa and MDA is contraindicated. RESULTS: Analyses found that vector control activities had increased significantly since 2005, with a three-fold increase in ITN ownership and IRS coverage. However, coverage varied dramatically across the 17 countries; some regions reported >70% ITNs ownership and regular IRS activity, while others had no coverage in remote rural populations where the risk of LF was potentially high and co-endemic with high risk L.loa. CONCLUSIONS: Despite many African countries being slow to initiate MDA for LF, the continued commitment and global financial support for NTDs, and the concurrent expansion of vector control activities for malaria, is promising. It is not beyond the capacity of GPELF to reach its target of global LF elimination by 2020, but monitoring and evaluating the impact of these activities over the next decade will be critical to its success. PMID- 23433080 TI - Immunosuppressive effects of the traditional Chinese herb Qu Mai on human alloreactive T cells. AB - Current therapies for transplant rejection are suboptimally effective. In an effort to discover novel immunosuppressants we used cytokine ELISPOT and ELISAs to screen extracts from 53 traditional Chinese herbs for their ability to suppress human alloreactive T cells. We identified a dichloromethane-soluble fraction (Qu Mai fraction AD [QMAD]) of Qu Mai (Dianthus superbus) as a candidate. High-performance liquid chromatography (HPLC) analysis of QMAD revealed three dominant peaks, each with a MW ~600 Daltons and distinct from cyclosporine and rapamycin. When we added QMAD to human mixed lymphocyte cultures, we observed dose-dependent inhibition of proliferation and IFNgamma production, by naive and memory alloreactive T cells, and observed an increased frequency of Foxp3(+) CD4(+) T cells. To address whether QMAD induces regulatory T cells we added QMAD to anti-CD3/CD28-stimulated naive CD4 T cells and observed a dose-dependent upregulation of Foxp3 associated with new suppressive capacity. Mechanistically, QMAD did not induce T cell IL-10 or TGFbeta but blocked T cell AKT phosphorylation, a key signaling nexus required for T cell proliferation and expansion, that simultaneously prevents Foxp3 transcription. Our findings provide novel insight into the antiinflammatory effects of one traditional Chinese herb, and support the need for continued isolation, characterization and testing of QMAD-derived components as immune suppressants for transplant rejection. PMID- 23433083 TI - Fatal haemorrhagic varicella in a patient with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. PMID- 23433081 TI - Educational differences in self-rated physical fitness among Finns. AB - BACKGROUND: The high educated live longer and healthier lives when compared to the low educated. Physical fitness as a health indicator reflects the level of physical activity along with other health-influencing factors such as obesity, smoking, chronic diseases and individual training effects. Studies support that self-rated physical fitness correlates with objectively measured physical fitness well. However, the educational differences in self-rated physical fitness are not known. METHODS: Our aim was to study educational differences in self-rated physical fitness in Finnish population. The data were collected in 2007 for a cross-sectional population based National FINRISK Study. The analyzed data included 2722 men and 3108 women aged 25 to 74 years. Statistical method was ordinal logistic regression. RESULTS: Longer educational career was associated with better self-rated physical fitness. The educational differences in self rated physical fitness were largely explained by health behavior. Leisure-time physical activity explained fully and body mass index partly the educational differences in self-rated physical fitness among men. The combination of body mass index, history of chronic diseases and smoking explained the differences fully among men and partly among women. Leisure-time, occupational and commuting physical activities, body mass index, history of chronic diseases and smoking together explained all educational differences in self-rated physical fitness among both genders. CONCLUSIONS: Although educational differences in self-rated physical fitness were found, they were explained by health behavior related factors. Leisure-time physical activity offered the strongest single explanation for the educational differences in self-rated physical fitness. Thus, possibilities for leisure-time physical activity should be increased especially among the low educated. PMID- 23433082 TI - Understanding the Canadian adult CT head rule trial: use of the theoretical domains framework for process evaluation. AB - BACKGROUND: The Canadian CT Head Rule was prospectively derived and validated to assist clinicians with diagnostic decision-making regarding the use of computed tomography (CT) in adult patients with minor head injury. A recent intervention trial failed to demonstrate a decrease in the rate of head CTs following implementation of the rule in Canadian emergency departments. Yet, the same intervention, which included a one-hour educational session and reminders at the point of requisition, was successful in reducing cervical spine imaging rates in the same emergency departments. The reason for the varied effect of the intervention across these two behaviours is unclear. There is an increasing appreciation for the use of theory to conduct process evaluations to better understand how strategies are linked with outcomes in implementation trials. The Theoretical Domains Framework (TDF) has been used to explore health professional behaviour and to design behaviour change interventions but, to date, has not been used to guide a theory-based process evaluation. In this proof of concept study, we explored whether the TDF could be used to guide a retrospective process evaluation to better understand emergency physicians' responses to the interventions employed in the Canadian CT Head Rule trial. METHODS: A semi structured interview guide, based on the 12 domains from the TDF, was used to conduct telephone interviews with project leads and physician participants from the intervention sites in the Canadian CT Head Rule trial. Two reviewers independently coded the anonymised interview transcripts using the TDF as a coding framework. Relevant domains were identified by: the presence of conflicting beliefs within a domain; the frequency of beliefs; and the likely strength of the impact of a belief on the behaviour. RESULTS: Eight physicians from four of the intervention sites in the Canadian CT Head Rule trial participated in the interviews. Barriers likely to assist with understanding physicians' responses to the intervention in the trial were identified in six of the theoretical domains: beliefs about consequences; beliefs about capabilities; behavioural regulation; memory, attention and decision processes; environmental context and resources; and social influences. Despite knowledge that the Canadian CT Head Rule was highly sensitive and reliable for identifying clinically important brain injuries and strong beliefs about the benefits for using the rule, a number of barriers were identified that may have prevented physicians from consistently applying the rule. CONCLUSION: This proof of concept study demonstrates the use of the TDF as a guiding framework to design a retrospective theory-based process evaluation. There is a need for further development and testing of methods for using the TDF to guide theory-based process evaluations running alongside behaviour change intervention trials. PMID- 23433084 TI - Improved shrunken centroid classifiers for high-dimensional class-imbalanced data. AB - BACKGROUND: PAM, a nearest shrunken centroid method (NSC), is a popular classification method for high-dimensional data. ALP and AHP are NSC algorithms that were proposed to improve upon PAM. The NSC methods base their classification rules on shrunken centroids; in practice the amount of shrinkage is estimated minimizing the overall cross-validated (CV) error rate. RESULTS: We show that when data are class-imbalanced the three NSC classifiers are biased towards the majority class. The bias is larger when the number of variables or class imbalance is larger and/or the differences between classes are smaller. To diminish the class-imbalance problem of the NSC classifiers we propose to estimate the amount of shrinkage by maximizing the CV geometric mean of the class specific predictive accuracies (g-means). CONCLUSIONS: The results obtained on simulated and real high-dimensional class-imbalanced data show that our approach outperforms the currently used strategy based on the minimization of the overall error rate when NSC classifiers are biased towards the majority class. The number of variables included in the NSC classifiers when using our approach is much smaller than with the original approach. This result is supported by experiments on simulated and real high-dimensional class-imbalanced data. PMID- 23433086 TI - Hypercaloric high-lipid diet and brain development: effects on cortical spreading depression in adult rats. AB - Nutritional conditions early in life constitute one of the environmental factors that can influence brain electrophysiology, as evaluated through the phenomenon denominated as cortical spreading depression (CSD). OBJECTIVE: To evaluate the effects of hypercaloric diet intake in different phases of life on CSD features in adult rats. METHODS: Newborn Wistar rats were suckled by dams fed a high-lipid (cafeteria) hypercaloric diet during the lactation period. After suckling, part of the pups remained in the high-lipid diet until the end of the experiment in adulthood (group 'full-life' FL), and the other part received the control (lab chow) diet (group L). A third group received the hypercaloric diet only at adulthood (group Ad). When the animals reached 90-93 days of life, CSD was recorded. RESULTS: CSD propagation velocities (in mm/minute) and CSD amplitudes (in mV) were reduced (P < 0.05) in the groups L (2.77 +/- 0.07 and 7.1 +/- 2.0 for velocity and amplitude, respectively) and FL (3.05 +/- 0.17 and 8.5 +/- 1.9), but not in the group Ad (3.36 +/- 0.11 and 10.7 +/- 2.0), in comparison with a control group (C), fed the lab chow diet during the entire life (3.52 +/- 0.18 and 10.8 +/- 2.2). DISCUSSION: CSD velocity changes observed in adulthood were associated with the hypercaloric dietary treatment during brain development, constituting evidence in favor of permanent or at least long-lasting electrophysiological effects related to the prevailing nutritional status during the period of brain growth spurt. PMID- 23433085 TI - Gender differences in the association of visceral and subcutaneous adiposity with adiponectin in African Americans: the Jackson Heart Study. AB - BACKGROUND: Adiponectin, paradoxically reduced in obesity and with lower levels in African Americans (AA), modulates several cardiometabolic risk factors. Because abdominal visceral adipose tissue (VAT), known to be reduced in AA, and subcutaneous adipose tissue (SAT) compartments may confer differential metabolic risk profiles, we investigated the associations of VAT and SAT with serum adiponectin, separately by gender, with the hypothesis that VAT is more strongly inversely associated with adiponectin than SAT. METHODS: Participants from the Jackson Heart Study, an ongoing cohort of AA (n = 2,799; 64% women; mean age, 55 +/- 11 years) underwent computer tomography assessment of SAT and VAT volumes, and had stored serum specimens analyzed for adiponectin levels. These levels were examined by gender in relation to increments of VAT and SAT. RESULTS: Compared to women, men had significantly lower mean levels of adiponectin (3.9 +/- 3.0 MUg/mL vs. 6.0 +/- 4.4 MUg/mL; p < 0.01) and mean volume of SAT (1,721 +/- 803 cm(3) vs. 2,668 +/- 968 cm(3); p < 0.01) but significantly higher mean volume of VAT (884 +/- 416 cm(3) vs. 801 +/- 363 cm(3); p < 0.01). Among women, a one standard deviation increment in VAT was inversely associated with adiponectin (beta = - 0.13; p < 0.0001) after controlling for age, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, education, pack-years of smoking and daily intake of alcohol. The statistically significant inverse association of VAT and adiponectin persisted after additionally adjusting for SAT, body mass index (BMI) and waist circumference (WC), suggesting that VAT provides significant information above and beyond BMI and WC. Among men, after the same multivariable adjustment, there was a direct association of SAT and adiponectin (beta = 0.18; p = 0.002) that persisted when controlling for BMI and WC, supporting a beneficial effect of SAT. Insulin resistance mediated the association of SAT with adiponectin in women. CONCLUSION: In African Americans, abdominal visceral adipose tissue had an inverse association with serum adiponectin concentrations only among women. Abdominal subcutaneous adipose tissue appeared as a protective fat depot in men. PMID- 23433087 TI - Obligatory duetting behaviour in the Chrysoperla carnea-group of cryptic species (Neuroptera: Chrysopidae): its role in shaping evolutionary history. AB - An unusual system of communication has evolved in green lacewings of the Chrysoperla carnea-group, triggering rapid proliferation of numerous cryptic species across all of the Northern Hemisphere and large portions of Africa. The system is based on sexually monomorphic, substrate-borne vibrational signals, produced by abdominal oscillation. These low-frequency signals are exchanged between courting individuals in a precise duetting format. The song of each of the more than 20 described species exhibits a unique acoustical phenotype that reproductively isolates the taxon from all other species with which it might come into contact. Here, we review what is known about duetting behaviour in the carnea-group, emphasizing the dominant role that duetting has played in the evolution, ecology, and speciation of the complex. Included are descriptions and discussions of song diversity and its impact on reproductive isolation among species, the genetic basis of interspecific song differences, partitioning of acoustic space among sympatric species, parallel song evolution in allopatric species pairs, and modes of speciation within the complex. We also emphasize the importance of correctly identifying by song all species of the carnea-group that are to be used either in experimental studies or programs of biological control, while acknowledging the continuing relevance of morphology to carnea-group systematics. PMID- 23433089 TI - Effect on signal-to-noise ratio of splitting the continuous contacts of cuff electrodes into smaller recording areas. AB - BACKGROUND: Cuff electrodes have been widely used chronically in different clinical applications. This neural interface has been dominantly used for nerve stimulation while interfering noise is the major issue when employed for recording purposes. Advancements have been made in rejecting extra-neural interference by using continuous ring contacts in tripolar topologies. Ring contacts provide an average of the neural activity, and thus reduce the information retrieved. Splitting these contacts into smaller recording areas could potentially increase the information content. In this study, we investigate the impact of such discretization on the Signal-to-Noise Ratio (SNR). The effect of contacts positioning and an additional short circuited pair of electrodes were also addressed. METHODS: Different recording configurations using ring, dot, and a mixed of both contacts were studied in vitro in a frog model. An interfering signal was induced in the medium to simulate myoelectric noise. The experimental setup was design in such a way that the only difference between recordings was the configuration used. The inter-session experimental differences were taken care of by a common configuration that allowed normalization between electrode designs. RESULTS: It was found that splitting all contacts into small recording areas had negative effects on noise rejection. However, if this is only applied to the central contact creating a mixed tripole configuration, a considerable and statistically significant improvement was observed. Moreover, the signal to noise ratio was equal or larger than what can be achieved with the best known configuration, namely the short circuited tripole. This suggests that for recording purposes, any tripole topology would benefit from splitting the central contact into one or more discrete contacts. CONCLUSIONS: Our results showed that a mixed tripole configuration performs better than the configuration including only ring contacts. Therefore, splitting the central ring contact of a cuff electrode into a number of dot contacts not only provides additional information but also an improved SNR. In addition, the effect of an additional pair of short circuited electrodes and the "end effect" observed with the presented method are in line with previous findings by other authors. PMID- 23433088 TI - Phytopathogen type III effectors as probes of biological systems. AB - Bacterial phytopathogens utilize a myriad of virulence factors to modulate their plant hosts in order to promote successful pathogenesis. One potent virulence strategy is to inject these virulence proteins into plant cells via the type III secretion system. Characterizing the host targets and the molecular mechanisms of type III secreted proteins, known as effectors, has illuminated our understanding of eukaryotic cell biology. As a result, these effectors can serve as molecular probes to aid in our understanding of plant cellular processes, such as immune signalling, vesicle trafficking, cytoskeleton stability and transcriptional regulation. Furthermore, given that effectors directly and specifically interact with their targets within plant cells, these virulence proteins have enormous biotechnological potential for manipulating eukaryotic systems. PMID- 23433090 TI - Comparison of the killing effects between nitrogen-doped and pure TiO2 on HeLa cells with visible light irradiation. AB - The killing effect of nitrogen-doped titanium dioxide (N-TiO2) nanoparticles on human cervical carcinoma (HeLa) cells by visible light photodynamic therapy (PDT) was higher than that of TiO2 nanoparticles. To study the mechanism of the killing effect, the reactive oxygen species produced by the visible-light-activated N TiO2 and pure-TiO2 were evaluated and compared. The changes of the cellular parameters, such as the mitochondrial membrane potential (MMP), intracellular Ca2+, and nitrogen monoxide (NO) concentrations after PDT were measured and compared for N-TiO2- and TiO2-treated HeLa cells. The N-TiO2 resulted in more loss of MMP and higher increase of Ca2+ and NO in HeLa cells than pure TiO2. The cell morphology changes with time were also examined by a confocal microscope. The cells incubated with N-TiO2 exhibited serious distortion and membrane breakage at 60 min after the PDT. PMID- 23433091 TI - Risk of venous thrombosis in patients with chronic kidney disease: identification of high-risk groups. AB - BACKGROUND: Although an association between venous thrombosis and chronic kidney disease has recently been established, it is unknown which patients with chronic kidney disease are most likely to benefit from thromboprophylaxis. OBJECTIVE: The aim of this study was to assess the association between venous thrombosis and chronic kidney disease in combination with arterial thrombosis, malignancy, surgery and thrombophilia to identify high-risk groups as a basis for personalized prevention. METHODS: This study included 2473 consecutive patients with first venous thrombosis and 2936 controls from a case-control study (the MEGA study). RESULTS: Moderately decreased kidney function (eGFR 30-60 mL min(-1) ) was associated with a 2.5-fold (95% CI, 1.9-3.4) increased risk and severely decreased kidney function (eGFR < 30 mL min(-1) ) was associated with a 5.5-fold (95% CI 1.8-16.7) increased risk of venous thrombosis, compared with those with normal kidney function (eGFR > 90 mL min(-1) ). The risk of venous thrombosis was additionally increased for moderately and severely reduced kidney function in combination with arterial thrombosis (odds ratio, 4.9; 95% CI, 2.2-10.9), malignancy (5.8; 95% CI, 2.8-12.1), surgery (14.0; 95%, CI 5.0-39.4), immobilization (17.1; 95% CI, 6.8-43.0) or thrombophilia (odds ratios, 4.3-9.5), with particularly high risks when three or more risk factors were present (odds ratio, 56.3; 95% CI, 7.6-419.3). CONCLUSION: Decreased kidney function is associated with an increased risk of venous thrombosis. The risk increased substantially in the presence of one or more other risk factors for thrombosis. PMID- 23433092 TI - BXSB/MpJ-Yaa mice develop autoimmune dacryoadenitis with the appearance of inflammatory cell marker messenger RNAs in the lacrimal fluid. AB - BACKGROUND: Dacryoadenitis is characteristic of an autoimmune exocrinopathy, e.g. Sjogren syndrome. We pathologically examined the lacrimal glands of autoimmune prone BXSB/MpJ-Yaa mice for the appearance of pathological signs of dacryoadenitis progression in autoimmune dacryoadenitis models, particularly focusing on messenger RNAs in the lacrimal fluid. METHODS: The lacrimal glands of the BXSB/MpJ-Yaa and C57BL/6 mice were histopathologically analyzed in parallel with the evaluation of lacrimation and messenger RNA expression of water channels (Aqp3, Aqp4 and Aqp5). In addition, autoimmune model mice (MRL/MpJ-lpr/lpr and NZB/NZWF1) were used for evaluating cell infiltration and detecting inflammatory cell marker messenger RNAs (Cd68, Ptprc and Cd3e) in the lacrimal fluids by polymerase chain reaction-based methods. RESULTS: B-cell predominant lymphocytic infiltrations and the destruction of acini were observed in the lacrimal glands of BXSB/MpJ-Yaa mice. There was no significant difference in the quantity of lacrimal fluid between the BXSB/MpJ-Yaa and C57BL/6 mice. In the BXSB/MpJ-Yaa mice, Aqp3 expression increased significantly with the cell infiltration score, whereas expression of Aqp4 and Aqp5 tended to decrease. Aqp3 expression increased significantly with the cell infiltration score in BXSB/MpJ-Yaa mice. Among inflammatory cell markers, Cd68 was more frequently detected in the lacrimal fluid of the BXSB/MpJ-Yaa, MRL/MpJ-lpr/lpr and NZB/NZWF1 mice than in that of the C57BL/6 mice. CONCLUSION: BXSB/MpJ-Yaa mice clearly developed autoimmune dacryoadenitis. The altered expression of water channels in lacrimal glands might be associated with the preservation of lacrimal fluid excretion in BXSB/MpJ-Yaa mice. The detection of inflammatory cell markers in lacrimal fluid could be used as a diagnostic marker for autoimmune dacryoadenitis. PMID- 23433093 TI - Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells. AB - BACKGROUND: Capsaicin, a pungent phytochemical in a variety of red peppers of the genus Capsicum, has shown an anti-proliferative effect on various human cancer cell lines. In contrast, capsaicin has also been considered to promote the growth of cancer cells. Thus, the effects of capsaicin on various cell types need to be explored. The anti-proliferative effects of capsaicin on human KB cancer cells are still unknown. Therefore, we examined the viability, cell cycle progression, and factors associated with apoptosis in KB cells treated with capsaicin. METHODS: The cell proliferation/viability and cytotoxicity of KB cells exposed to capsaicin were determined by a sulforhodamine B colorimetric assay and trypan blue exclusion. Apoptosis was detected by Hoechst staining and confirmed by western blot analysis of poly-(ADP-ribose) polymerase cleavage. Cell cycle distribution and changes of the mitochondrial membrane potential were analyzed by flow cytometry. Furthermore, the expression of caspase 3, 8 and 9 was evaluated by immunoblotting. RESULTS: We found that treatment of KB cells with capsaicin significantly reduced cell proliferation/viability and induced cell death in a dose-dependent manner compared with that in the untreated control. Cell cycle analysis indicated that exposure of KB cells to capsaicin resulted in cell cycle arrest at G2/M phase. Capsaicin-induced growth inhibition of KB cells appeared to be associated with induction of apoptosis. Moreover, capsaicin induced disruption of the mitochondrial membrane potential as well as activation of caspase 9, 3 and poly-(ADP-ribose) polymerase in KB cells. CONCLUSIONS: Our data demonstrate that capsaicin modulates cell cycle progression and induces apoptosis in human KB cancer cells through mitochondrial membrane permeabilization and caspase activation. These observations suggest an anti-cancer activity of capsaicin. PMID- 23433094 TI - The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis. AB - BACKGROUND: Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). METHODS: To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. RESULTS: Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the "high hepcidin" 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02). CONCLUSIONS: The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management. PMID- 23433095 TI - Can cycle day 7 FSH concentration during controlled ovarian stimulation be used to guide FSH dosing for in vitro fertilization? AB - BACKGROUND: When stimulating a patient with poor ovarian response for IVF, the maximal dose of gonadotropins injected is often determined by arbitrary standards rather than a measured response. The purpose of this study was to determine if serum FSH concentration during an IVF stimulation cycle reflects follicular utilization of FSH and whether serum FSH values may inform dose adjustments of exogenous FSH. METHODS: In this retrospective cross sectional study we studied 155 consecutive IVF cycles stimulated only with recombinant human FSH. We only included long GnRH agonist protocols in which endogenous FSH levels were suppressed. We correlated the serum concentration of cycle day (CD) 7 FSH with the number of oocytes retrieved, cleaving embryos and pregnancy rate. RESULTS: We found that a CD7 FSH concentration above 22 IU/L was associated with poor response regardless of the daily dose of FSH injected and a lower pregnancy rate. CONCLUSIONS: We concluded that CD7 FSH concentration during stimulation could be used to guide FSH dosing in poor responders. If the CD7 FSH concentration is above 22 IU/L increasing the dose of FSH in an attempt to recruit more growing follicles is unlikely to be successful. PMID- 23433096 TI - Difficult airway in a child with severe dystonia. AB - OBJECTIVE: To describe the management of a 15-year-old girl with repeated life threatening complications of her tracheostomy secondary to muscle dystonia and thoracolumbocervical lordosis. METHOD: This paper reports a retrospective case review. RESULTS: Regular microlaryngoscopy and bronchoscopy, treatment with systemic steroids and a soft tracheostomy tube, in addition to better control of the dystonia, resulted in control of the patient's airway. This minimised tracheal inflammation and granulation tissue formation. CONCLUSION: The need for a tracheostomy in patients with thoracolumbocervical lordosis and severe dystonia should be considered only after all other options of airway management have been explored. Every attempt should be made to minimise tracheal trauma caused by excessive movement of a tracheostomy tube. PMID- 23433097 TI - Effects of donepezil 23 mg on Severe Impairment Battery domains in patients with moderate to severe Alzheimer's disease: evaluating the impact of baseline severity. AB - INTRODUCTION: The US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer's disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose. Results from this study indicated that after 24 weeks, donepezil 23 mg/day provided significant cognitive benefits over donepezil 10 mg/day, measured using the Severe Impairment Battery (SIB). In the analyses reported herein, we further characterize the range of cognitive domains impacted by treatment with donepezil 23 mg/day. METHODS: A post hoc analysis was conducted using data from a 24-week, randomized, double-blind trial comparing donepezil 23 mg/day versus 10 mg/day in 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20). Changes from baseline to week 24 in the nine SIB domain scores were analyzed in the intent-to-treat (ITT) population (baseline MMSE 0 to 20), in patients with more severe baseline AD (MMSE 0 to 16), and in severity strata based on baseline MMSE scores (0 to 5, 6 to 10, 11 to 15, 16 to 20). RESULTS: In the ITT population, changes in six of the nine SIB domains favored donepezil 23 mg/day over donepezil 10 mg/day. LS mean treatment differences were significant for the language, visuospatial ability, and construction domains. In the more advanced cohort of patients (MMSE 0 to 16 at baseline), LS mean treatment differences were statistically significant favoring donepezil 23 mg/day in five of the nine domains: language, memory, visuospatial ability, attention, and construction. Descriptive analysis of LS mean changes in SIB domain scores in the four baseline severity strata showed variable patterns of response; overall, cognitive benefits of donepezil 23 mg/day were greatest in patients with MMSE scores of 0 to 15. CONCLUSIONS: These results suggest that donepezil 23 mg/day provides benefits over 10 mg/day across a range of cognitive domains. The magnitude of benefit and domains impacted varied depending on the stage of AD; significant benefits with higher dose donepezil were most apparent at more advanced stages of AD and were most prominent in the language domain. PMID- 23433098 TI - Parent smoker role conflict and planning to quit smoking: a cross-sectional study. AB - BACKGROUND: Role conflict can motivate behavior change. No prior studies have explored the association between parent/smoker role conflict and readiness to quit. The objective of the study is to assess the association of a measure of parent/smoker role conflict with other parent and child characteristics and to test the hypothesis that parent/smoker role conflict is associated with a parent's intention to quit smoking in the next 30 days. As part of a cluster randomized controlled trial to address parental smoking (Clinical Effort Against Secondhand Smoke Exposure-CEASE), research assistants completed exit interviews with 1980 parents whose children had been seen in 20 Pediatric Research in Office Settings (PROS) practices and asked a novel identity-conflict question about "how strongly you agree or disagree" with the statement, "My being a smoker gets in the way of my being a parent." Response choices were dichotomized as "Strongly Agree" or "Agree" versus "Disagree" or "Strongly Disagree" for the analysis. Parents were also asked whether they were "seriously planning to quit smoking in 30 days." Chi-square and logistic regression were performed to assess the association between role conflict and other parent/children characteristics. A similar strategy was used to determine whether role conflict was independently associated with intention to quit in the next 30 days. METHODS: As part of a RTC in 20 pediatric practices, exit interviews were held with smoking parents after their child's exam. Parents who smoked were asked questions about smoking behavior, smoke-free home and car rules, and role conflict. Role conflict was assessed with the question, "Please tell me how strongly you agree or disagree with the statement: 'My being a smoker gets in the way of my being a parent.' (Answer choices were: "Strongly agree, Agree, Disagree, Strongly Disagree.") RESULTS: Of 1980 eligible smokers identified, 1935 (97%) responded to the role conflict question, and of those, 563 (29%) reported experiencing conflict. Factors that were significantly associated with parent/smoker role conflict in the multivariable model included: being non-Hispanic white, allowing home smoking, the child being seen that day for a sick visit, parents receiving any assistance for their smoking, and planning to quit in the next 30 days. In a separate multivariable logistic regression model, parent/smoker role conflict was independently associated with intention to quit in the next 30 days [AOR 2.25 (95% CI 1.80-2.18)]. CONCLUSION: This study demonstrated an association between parent/smoker role conflict and readiness to quit. Interventions that increase parent/smoker role conflict might act to increase readiness to quit among parents who smoke. PMID- 23433099 TI - Blastocystis infection in Malaysia: evidence of waterborne and human-to-human transmissions among the Proto-Malay, Negrito and Senoi tribes of Orang Asli. AB - BACKGROUND: Blastocystis has been described as the most common intestinal parasite in humans and has an increased impact on public health. However, the transmission of this parasite has not been conclusively determined. METHODS: To contribute to a better comprehension of the epidemiology of this infection, a cross-sectional survey aimed at providing the first documented data on the prevalence and risk factors associated with Blastocystis infection was carried out among three Orang Asli tribes (Proto-Malay, Negrito and Senoi) in selected villages at Negeri Sembilan, Perak and Pahang, Peninsular Malaysia. Faecal samples were examined by formalin-ether sedimentation and trichrome staining techniques. RESULTS: Of 500 individuals, 20.4% (102) were detected positive for Blastocystis; 13.3% (20/150) of Proto-Malays, 21.6% (30/139) of Negritos and 24.7% (52/211) of Senois were positive for Blastocystis, respectively. The positive cases showed a decrease with increasing age and most of the positive cases were observed in individuals less than 15 years old. Multivariate analysis confirmed that drinking untreated water and the presence of other family members infected with Blastocystis were significant risk factors of infection among the three tribes and overall population studied. CONCLUSION: Essentially, the findings highlighted that Blastocystis infection is prevalent among Orang Asli communities in Malaysia. Further studies using molecular approaches to distinguish the subtype of Blastocystis is needed. The present study also revealed that this infection may be transmitted through waterborne and human-to human contact. Therefore, interventions with the provision of clean water supply for the communities and health education especially to the parents are urgently required. PMID- 23433100 TI - Abbreviations for device names: a proposed methodology with specific examples. AB - BACKGROUND: Many devices used in dermatology lack generic names. If investigators use commercial device names, they risk the appearance of bias. Alternatively, reliance on ad-hoc names and abbreviations may confuse readers who do not recognize these. OBJECTIVE: To develop a system for assigning abbreviations to denote devices commonly used in dermatology. Secondarily, to use this system to create abbreviations for FDA-approved neurotoxins and prepackaged injectable soft tissue augmentation materials. METHODS: The American Society for Dermatologic Surgery convened a Lexicon Task Force in March 2012. One charge of this Task Force was to develop criteria for assigning abbreviations to medical devices. A modified consensus process was used. RESULTS: Abbreviations to denote devices were to be: based on a standardized approach; transparent to the casual reader; markedly brief; and in all cases, different than the commercial names. Three letter all caps abbreviations, some with subscripts, were assigned to denote each of the approved neurotoxins and fillers. CONCLUSION: A common system of abbreviations for medical devices in dermatology may avoid the appearance of bias while ensuring effective communication. The proposed system may be expanded to name other devices, and the ensuing abbreviations may be suitable for journal articles, continuing medical education lectures, or other academic or clinical purposes. PMID- 23433101 TI - Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. AB - In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids +/- induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients. PMID- 23433102 TI - Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. AB - BACKGROUND: Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. METHODS: Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials. RESULTS: The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments. CONCLUSIONS: Pyronaridine artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931. PMID- 23433103 TI - Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3beta/Snail signaling in renal cell carcinoma. AB - Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than that of patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition and cellular migration and invasion in RCC. Also, no alteration of alpha-2,6-sialidase activity was found after Klotho overexpression in RCC. The molecular signals for this phenomenon involved the Klotho-mediated inhibition of PI3K/Akt/GSK3beta/Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho acts as a tumor suppressor by inhibiting PI3K/Akt/GSK3beta/Snail signaling, thus suppressing epithelial mesenchymal transition and tumor migration and invasion during RCC progression. As a result, Klotho might be used as a potential therapy for advanced RCC. PMID- 23433104 TI - Cranial radiotherapy predisposes to abdominal adiposity in survivors of childhood acute lymphocytic leukemia. AB - BACKGROUND: Advances in treatment of acute lymphocytic leukemia increased the likelihood of developing late treatment-associated effects, such as abdominal adiposity, increasing the risk of cardiovascular disease in this population. Cranial radiotherapy is one of the factors that might be involved in this process. The aim of this study was to determine the effect of cranial radiotherapy on adiposity indexes in survivors of acute lymphocytic leukemia. METHODS: A comparative cross-sectional study of 56 acute lymphocytic leukemia survivors, chronological age between 15 and 24 years, assigned into two groups according to the exposure to cranial radiotherapy (25 irradiated and 31 non irradiated), assessed according to body fat (dual energy X-ray absorptiometry), computed tomography scan-derived abdominal adipose tissue, lipid profile, and insulin resistance. RESULTS: Cranial radiotherapy increased body fat and abdominal adipose tissue and altered lipid panel. Yet, lipids showed no clinical relevance so far. There were significantly more obese patients among those who received cranial radiotherapy (52% irradiated versus 22.6% non-irradiated), based on dual energy X-ray absorptiometry body fat measurements. Nonetheless, no association was observed between cranial radiotherapy and body mass index, waist circumference, waist-to-height ratio or insulin resistance. CONCLUSIONS: Adolescent and young adult survivors of childhood acute lymphocytic leukemia showed an increase in body fat and an alteration of fat distribution, which were related to cranial radiotherapy. Fat compartment modifications possibly indicate a disease of adipose tissue, and cranial radiotherapy imports in this process. PMID- 23433105 TI - Dealing with missing data in the Center for Epidemiologic Studies Depression self report scale: a study based on the French E3N cohort. AB - BACKGROUND: The Center for Epidemiologic Studies - Depression scale (CES-D) is a validated tool commonly used to screen depressive symptoms. As with any self administered questionnaire, missing data are frequently observed and can strongly bias any inference. The objective of this study was to investigate the best approach for handling missing data in the CES-D scale. METHODS: Among the 71,412 women from the French E3N prospective cohort (Etude Epidemiologique aupres des femmes de la Mutuelle Generale de l'Education Nationale) who returned the questionnaire comprising the CES-D scale in 2005, 45% had missing values in the scale. The reasons for failure to complete certain items were investigated by semi-directive interviews on a random sample of 204 participants. The prevalence of high depressive symptoms (score >= 16, hDS) was estimated after applying various methods for ignorable missing data including multiple imputation using imputation models with CES-D items with or without covariates. The accuracy of imputation models was investigated. Various scenarios of nonignorable missing data mechanisms were investigated by a sensitivity analysis based on the mixture modelling approach. RESULTS: The interviews showed that participants were not reluctant to answer the CES-D scale. Possible reasons for nonresponse were identified. The prevalence of hDS among complete responders was 26.1%. After multiple imputation, the prevalence was 28.6%, 29.8% and 31.7% for women presenting up to 4, 10 and 20 missing values, respectively. The estimates were robust to the various imputation models investigated and to the scenarios of nonignorable missing data. CONCLUSIONS: The CES-D scale can easily be used in large cohorts even in the presence of missing data. Based on the results from both a qualitative study and a sensitivity analysis under various scenarios of missing data mechanism in a population of women, missing data mechanism does not appear to be nonignorable and estimates are robust to departures from ignorability. Multiple imputation is recommended to reliably handle missing data in the CES-D scale. PMID- 23433106 TI - DNA barcoding for conservation, seed banking and ecological restoration of Acacia in the Midwest of Western Australia. AB - We used DNA barcoding to address an important conservation issue in the Midwest of Western Australia, working on Australia's largest genus of flowering plant. We tested whether or not currently recommended plant DNA barcoding regions (matK and rbcL) were able to discriminate Acacia taxa of varying phylogenetic distances, and ultimately identify an ambiguously labelled seed collection from a mine-site restoration project. Although matK successfully identified the unknown seed as the rare and conservation priority listed A. karina, and was able to resolve six of the eleven study species, this region was difficult to amplify and sequence. In contrast, rbcL was straightforward to recover and align, but could not determine the origin of the seed and only resolved 3 of the 11 species. Other chloroplast regions (rpl32-trnL, psbA-trnH, trnL-F and trnK) had mixed success resolving the studied taxa. In general, species were better resolved in multilocus data sets compared to single-locus data sets. We recommend using the formal barcoding regions supplemented with data from other plastid regions, particularly rpl32-trnL, for barcoding in Acacia. Our study demonstrates the novel use of DNA barcoding for seed identification and illustrates the practical potential of DNA barcoding for the growing discipline of restoration ecology. PMID- 23433107 TI - Single-molecule fluorescence in situ hybridization: quantitative imaging of single RNA molecules. AB - In situ detection of RNAs is becoming increasingly important for analysis of gene expression within and between intact cells in tissues. International genomics efforts are now cataloging patterns of RNA transcription that play roles in cell function, differentiation, and disease formation, and they are demonstrating the importance of coding and noncoding RNA transcripts in these processes. However, these techniques typically provide ensemble averages of transcription across many cells. In situ hybridization-based analysis methods complement these studies by providing information about how expression levels change between cells within normal and diseased tissues, and they provide information about the localization of transcripts within cells, which is important in understanding mechanisms of gene regulation. Multi-color, single-molecule fluorescence in situ hybridization (smFISH) is particularly useful since it enables analysis of several different transcripts simultaneously. Combining smFISH with immunofluorescent protein detection provides additional information about the association between transcription level, cellular localization, and protein expression in individual cells. PMID- 23433108 TI - Mouse models of polycystic kidney disease induced by defects of ciliary proteins. AB - Polycystic kidney disease (PKD) is a common hereditary disorder which is characterized by fluid-filled cysts in the kidney. Mutation in either PKD1, encoding polycystin-1 (PC1), or PKD2, encoding polycystin-2 (PC2), are causative genes of PKD. Recent studies indicate that renal cilia, known as mechanosensors, detecting flow stimulation through renal tubules, have a critical function in maintaining homeostasis of renal epithelial cells. Because most proteins related to PKD are localized to renal cilia or have a function in ciliogenesis. PC1/PC2 heterodimer is localized to the cilia, playing a role in calcium channels. Also, disruptions of ciliary proteins, except for PC1 and PC2, could be involved in the induction of polycystic kidney disease. Based on these findings, various PKD mice models were produced to understand the roles of primary cilia defects in renal cyst formation. In this review, we will describe the general role of cilia in renal epithelial cells, and the relationship between ciliary defects and PKD. We also discuss mouse models of PKD related to ciliary defects based on recent studies. PMID- 23433109 TI - Altered expression of adrenocorticotropic hormone in the epileptic gerbil hippocampus following spontaneous seizure. AB - We investigated the temporal alterations of adrenocorticotropic hormone (ACTH) immunoreactivity in the hippocampus after seizure onset. Expression of ACTH was observed within interneurons in the pre-seizure group of seizure sensitive gerbils, whereas its immunoreactivities were rarely detected in seizure resistant gerbil. Three hr after the seizure, ACTH immunoreactivity was significantly increased in interneurons within all hippocampal regions. On the basis of their localization and morphology through immunofluorescence staining, these cells were identified as GABAA alpha1-containing interneurons. At the 12 hr postictal period, ACTH expression in these regions was down-regulated, in a similar manner to the pre-seizure group of gerbils. These findings support the increase in ACTH synthesis that contributes to a reduction of corticotrophin-releasing factor via the negative feedback system which in turn provides an opportunity to enhance the excitability of GABAergic interneurons. Therefore, ACTH may play an important role in the reduction of excitotoxicity in all hippocampal regions. PMID- 23433110 TI - Tetrahydropteridines possess antioxidant roles to guard against glucose-induced oxidative stress in Dictyostelium discoideum. AB - Glucose effects on the vegetative growth of Dictyostelium discoideum Ax2 were studied by examining oxidative stress and tetrahydropteridine synthesis in cells cultured with different concentrations (0.5X, 7.7 g L(-1); 1X, 15.4 g L(-1); 2X, 30.8 g L(-1)) of glucose. The growth rate was optimal in 1X cells (cells grown in 1X glucose) but was impaired drastically in 2X cells, below the level of 0.5X cells. There were glucose-dependent increases in reactive oxygen species (ROS) levels and mitochondrial dysfunction in parallel with the mRNA copy numbers of the enzymes catalyzing tetrahydropteridine synthesis and regeneration. On the other hand, both the specific activities of the enzymes and tetrahydropteridine levels in 2X cells were lower than those in 1X cells, but were higher than those in 0.5X cells. Given the antioxidant function of tetrahydropteridines and both the beneficial and harmful effects of ROS, the results suggest glucose-induced oxidative stress in Dictyostelium, a process that might originate from aerobic glycolysis, as well as a protective role of tetrahydropteridines against this stress. PMID- 23433111 TI - Egr-1 regulates the transcription of the BRCA1 gene by etoposide. AB - The breast cancer susceptibility gene BRCA1 encodes a nuclear protein, which functions as a tumor suppressor and is involved in gene transcription and DNA repair processes. Many families with inherited breast and ovarian cancers have mutations in the BRCA1 gene. However, only a few studies have reported on the mechanism underlying the regulation of BRCA1 expression in humans. In this study, we investigated the transcriptional regulation of BRCA1 in HeLa cells treated with etoposide. We found that three Egr-1-binding sequences (EBSs) were located at -1031, -1005, and -385 within the enhancer region of the BRCA1 gene. Forced expression of Egr-1 stimulated the BRCA1 promoter activity. EMSA data showed that Egr-1 bound directly to the EBS within the BRCA1 gene. Knockdown of Egr-1 through the expression of a small hairpin RNA (shRNA) attenuated etoposide-induced BRCA1 promoter activity. We conclude that Egr-1 targets the BRCA1 gene in HeLa cells exposed to etoposide. PMID- 23433112 TI - Somatic mutation patterns and compound response in cancers. AB - The use of various cancer cell lines can recapitulate known tumor-associated mutations and genetically define cancer subsets. This approach also enables comparative surveys of associations between cancer mutations and drug responses. Here, we analyzed the effects of ~40,000 compounds on cancer cell lines that showed diverse mutation-dependent sensitivity profiles. Over 1,000 compounds exhibited unique sensitivity on cell lines with specific mutational genotypes, and these compounds were clustered into six different classes of mutation oriented sensitivity. The present analysis provides new insights into the relationship between somatic mutations and selectivity response of chemicals, and these results should have applications related to predicting and optimizing therapeutic windows for anti-cancer agents. PMID- 23433113 TI - Elevated RalA activity in the hippocampus of PI3Kgamma knock-out mice lacking NMDAR-dependent long-term depression. AB - Phosphoinositide 3-kinases (PI3Ks) play key roles in synaptic plasticity and cognitive functions in the brain. We recently found that genetic deletion of PI3Kgamma, the only known member of class IB PI3Ks, results in impaired N-methyl D-aspartate receptor-dependent long-term depression (NMDAR-LTD) in the hippocampus. The activity of RalA, a small GTP-binding protein, increases following NMDAR-LTD inducing stimuli, and this increase in RalA activity is essential for inducing NMDAR-LTD. We found that RalA activity increased significantly in PI3Kgamma knockout mice. Furthermore, NMDAR-LTD-inducing stimuli did not increase RalA activity in PI3Kgamma knockout mice. These results suggest that constitutively increased RalA activity occludes further increases in RalA activity during induction of LTD, causing impaired NMDAR-LTD. We propose that PI3Kgamma regulates the activity of RalA, which is one of the molecular mechanisms inducing NMDAR dependent LTD. PMID- 23433114 TI - Analysis and characterization of the functional TGFbeta receptors required for BMP6-induced osteogenic differentiation of mesenchymal progenitor cells. AB - Although BMP6 is highly capable of inducing osteogenic differentiation of mesenchymal progenitor cells (MPCs), the molecular mechanism involved remains to be fully elucidated. Using dominant negative (dn) mutant form of type I and type II TGFbeta receptors, we demonstrated that three dn-type I receptors (dnALK2, dnALK3, dnALK6), and three dn-type II receptors (dnBMPRII, dnActRII, dnActRIIB), effectively diminished BMP6- induced osteogenic differentiation of MPCs. These findings suggested that ALK2, ALK3, ALK6, BMPRII, ActRII and ActRIIB are essential for BMP6-induced osteogenic differentiation of MPCs. However, MPCs in this study do not express ActRIIB. Moreover, RNA interference of ALK2, ALK3, ALK6, BMPRII and ActRII inhibited BMP6-induced osteogenic differentiation in MPCs. Our results strongly suggested that BMP6-induced osteogenic differentiation of MPCs is mediated by its functional TGFbeta receptors including ALK2, ALK3, ALK6, BMPRII, and ActRII. PMID- 23433115 TI - Overexpression of TTRAP inhibits cell growth and induces apoptosis in osteosarcoma cells. AB - TTRAP is a multi-functional protein that is involved in multiple aspects of cellular functions including cell proliferation, apoptosis and the repair of DNA damage. Here, we demonstrated that the lentivirus-mediated overexpression of TTRAP significantly inhibited cell growth and induced apoptosis in osteosarcoma cells. The ectopic TTRAP suppressed the growth and colony formation capacity of two osteosarcoma cell lines, U2OS and Saos-2. Cell apoptosis was induced in U2OS cells and the cell cycle was arrested at G2/M phase in Saos-2 cells. Exogenous expression of TTRAP in serum-starved U2OS and Saos-2 cells induced an increase in caspase-3/-7 activity and a decrease in cyclin B1 expression. In comparison with wild-type TTRAP, mutations in the 5'-tyrosyl-DNA phosphodiesterase activity of TTRAP, in particular TTRAP(E152A), showed decreased inhibitory activity on cell growth. These results may aid in clarifying the physiological functions of TTRAP, especially its roles in the regulation of cell growth and tumorigenesis. PMID- 23433116 TI - Salsolinol, a catechol neurotoxin, induces oxidative modification of cytochrome c. AB - Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), an endogenous neurotoxin, is known to perform a role in the pathogenesis of Parkinson's disease (PD). In this study, we evaluated oxidative modification of cytochrome c occurring after incubation with salsolinol. When cytochrome c was incubated with salsolinol, protein aggregation increased in a dosedependent manner. The formation of carbonyl compounds and the release of iron were obtained in salsolinol- treated cytochrome c. Salsolinol also led to the release of iron from cytochrome c. Reactive oxygen species (ROS) scavengers and iron specific chelator inhibited the salsolinol-mediated cytochrome c modification and carbonyl compound formation. It is suggested that oxidative damage of cytochrome c by salsolinol might induce the increase of iron content in cells, subsequently leading to the deleterious condition which was observed. This mechanism may, in part, provide an explanation for the deterioration of organs under neurodegenerative disorders such as PD. PMID- 23433117 TI - Transduced PEP-1-FK506BP ameliorates corneal injury in Botulinum toxin A-induced dry eye mouse model. AB - FK506 binding protein 12 (FK506BP) belongs to a family of immunophilins, and is involved in multiple biological processes. However, the function of FK506BP in corneal disease remains unclear. In this study, we examined the protective effects on dry eye disease in a Botulinum toxin A (BTX-A) induced mouse model, using a cell-permeable PEP-1-FK506BP protein. PEP-1-FK506BP efficiently transduced into human corneal epithelial cells in a time- and dose-dependent manner, and remained stable in the cells for 48 h. In addition, we demonstrated that topical application of PEP-1-FK506BP was transduced into mouse cornea and conjunctiva by immunohistochemistry. Furthermore, topical application of PEP-1 FK506BP to BTX-A-induced mouse model markedly inhibited expression levels of pro inflammatory cytokines such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and macrophage inhibitory factor (MIF) in corneal and conjunctival epithelium. These results suggest PEP-1-FK506BP as a potential therapeutic agent for dry eye diseases. PMID- 23433118 TI - H-RN, a peptide derived from hepatocyte growth factor, inhibits corneal neovascularization by inducing endothelial apoptosis and arresting the cell cycle. AB - BACKGROUND: The goal of this study was to investigate the anti-angiogenic activity of a novel peptide H-RN, derived from the hepatocyte growth factor kringle 1 domain (HGF K1), in a mouse model of corneal neovascularization. The anti-angiogenic effect of H-RN on vascular endothelial growth factor (VEGF) stimulated cell proliferation, cell migration and endothelial cell tube formation was assessed in vitro using Human Umbilical Vein Endothelial Cells (HUVECs) and in vivo using a mouse cornea micropocket assay. Apoptosis and cell cycle arrest were assessed by flow cytometry. A scrambled peptide was used as a negative control. RESULTS: H-RN effectively inhibited VEGF-stimulated HUVEC proliferation, migration and tube formation on Matrigel, while a scrambled peptide exerted no effect. In the mouse model of corneal angiogenesis, VEGF-stimulated angiogenesis was significantly inhibited by H-RN compared to a scrambled peptide that had no such activity. VEGF protected HUVECs from apoptosis, while H-RN inhibited this protective effect of VEGF. VEGF significantly increased the proportion of cells in the S phase compared to control treated cells (p<0.05). Treatment with H-RN (1.5 mM) induced the accumulation of cells in G0/G1 phase, while the proportion of cells in the S phase and G2/M phase decreased significantly compared to control group (p<0.05). CONCLUSIONS: H-RN has anti-angiogenic activity in HUVECs and in a mouse model of VEGF-induced corneal neovascularization. The anti angiogenic activity of H-RN was related to apoptosis and cell cycle arrest, indicating a potential strategy for anti-angiogenic treatment in the cornea. PMID- 23433119 TI - Dietary patterns in stroke patients in Northwest India. AB - OBJECTIVES: Little is known about the dietary patterns among stroke patients in India. We explored the dietary patterns in stroke patients and attempted to correlate the dietary patterns with stroke characteristics. METHODS: This hospital-based study was carried out in a tertiary referral centre in Northwest India from March 2008 to September 2009. All first ever stroke (ischaemic and hemorrhagic) patients were interviewed by the dietician using an oral diet questionnaire. The demographic information and risk factors were noted and outcome was assessed after 30 days using modified Rankin scale (<=2 = good outcome). RESULTS: A total of 210 stroke patients were enrolled. The mean age was 60 +/- 14 years and 126 (60%) patients were men. Hypertension (167 (79.5%)) was the major risk factor. All patients consumed cereals and beverages. Consumption of other food items in the diet were as follows: milk and milk products (203 (96.7%)), saturated fats (butter, butter oil, cream) (133 (63.3%)), bakery items (139 (66.2%)), fried snacks (116 (55.2%)), fruits (96 (45.7%)), and juices (20 (9.5%)). Large proportion of the patients (112 (53.6%)) consumed more food calories than recommended. Use of fried snacks was significant in patients who consumed alcohol (P = 0.03) and patients who had diabetes mellitus were more likely to use saturated fats (P = 0.01). DISCUSSION: Majority of the patients consumed milk and milk products. Fruits and juices were consumed by a small proportion of patients. Our results provide opportunities for stroke prevention by diet modification. PMID- 23433120 TI - The effects of decreased body temperature on the onset, duration and action of medetomidine and its antagonist atipamezole in juvenile farmed estuarine crocodiles (Crocodylus porosus). AB - OBJECTIVE: To determine the efficacy of medetomidine for immobilisation of captive juvenile crocodiles over a range of temperatures, and its reversibility with atipamezole. STUDY DESIGN: Prospective experimental study. ANIMALS: Forty male estuarine crocodiles (body weight 2.0 to 4.8 kg). METHODS: Each crocodile was randomly assigned to one of four temperature groups: Group 1:32 degrees C; Group 2:27 degrees C; Group 3:22 degrees C; and Group 4:17 degrees C (n = 10 for each group). Medetomidine (0.5 mg kg(-1) ) was administered intramuscularly (IM) into the thoracic limb of all crocodiles. After 50 minutes, all animals from each group received 2.5 mg kg(-1) atipamezole IM in the opposite thoracic limb and time to recovery was documented. Heart and respiratory rates and the degree of immobilisation were monitored every 5 minutes until recovery, and behaviour monitored for 7 subsequent days. RESULTS: Onset of immobilisation occurred at 15 +/- 10 minutes in Group 1, and at 30 +/- 10 minutes in Groups 2 and 3. In Group 4, animals were not immobilised. Recovery following atipamezole was 10 +/- 5 minutes at all temperatures. One-way analysis of variance (anova) demonstrated a significant difference in induction times between groups (p < 0.01) but not in recovery times following atipamezole administration (p < 0.25). Heart and respiratory rates decreased markedly following medetomidine administration and increased markedly following atipamezole reversal. CONCLUSIONS AND CLINICAL RELEVANCE: Medetomidine administered in the thoracic limb of juvenile captive estuarine crocodiles provides profound sedation or immobilisation at temperatures of 22 degrees C and above. Atipamezole administered in the contralateral thoracic limb results in consistent reversal of the effects of medetomidine and a return to normal behaviour within 15-20 minutes regardless of temperature. Even though immobilisation is not induced at 17 degrees C, profound reversible sedation does occur reliably and repeatably. PMID- 23433121 TI - Direct-write, highly aligned chitosan-poly(ethylene oxide) nanofiber patterns for cell morphology and spreading control. AB - Near-field electrospinning has been demonstrated to be able to achieve direct write and highly aligned chitosan nanofibers (CNF) with prescribed positioning density. Cell spreading in preferential direction could be observed on parallel aligned nanofibers, and the CNF patterns were capable of guiding cell extension when the distances between them are 20 and 100 MUm, respectively. Alignment of the cells was characterized according to their elongation and orientation using the fast Fourier transform data and binary image analysis. Parallel CNF indicates that the alignment values sequentially increased as a function of positioning density such that incrementally more aligned cells were closely related to the increasing CNF positioning density. These maskless, low-cost, and direct-write patterns can be facily fabricated and will be a promising tool to study cell based research such as cell adhesion, spreading, and tissue architecture. PMID- 23433122 TI - Absence of clinical correlates of diabetic retinopathy in the Ins2Akita retina. AB - BACKGROUND: The Ins2(Akita) mouse has been reported to display retinal pathology degeneration associated with advanced diabetic retinopathy. In the present study, we monitored retinal changes in these mice to establish if this model displays clinical features associated with advanced diabetic retinopathy in human patients. METHODS: Ins2(Akita) mice (n = 55) on a C57Bl/6J background were monitored clinically from 9 to 25 weeks of age using a combination of scanning laser ophthalmoscopy, fluorescein angiography and optical coherence tomography. After clinical imaging, eyes were processed for immunostaining to examine microglial, astroglial and Muller glial responses to hyperglycaemia. To complement our optical coherence tomography imaging, retinal morphology and thicknesses were examined in high-quality semi-thin sections. RESULTS: No retinal thinning or disruption of retinal architecture was observed by optical coherence tomography or resin histology in Ins2(Akita) mice up to 6 months of age. In addition, no vascular changes were detected by fluorescein angiography or by scanning laser ophthalmoscopy. With the exception of microglial activation, reduced glial fibrillary acid protein expression in astrocytes and an increase in glial fibrillary acid protein expression by Muller cells, no other changes were observed in the Ins2(Akita) retina. CONCLUSIONS: Our results indicate that the classical clinical correlates of human diabetic retinopathy are absent in Ins2(Akita) mice up to 6 months of age suggesting that either the histopathological processes underlying the development of diabetic retinopathy in this model require longer than 5 months of hyperglycaemia to result in disruption of retinal architecture or that advanced diabetic retinopathy is not a feature of the Ins2(Akita) diabetic mouse. PMID- 23433123 TI - Claudin-7 increases chemosensitivity to cisplatin through the upregulation of caspase pathway in human NCI-H522 lung cancer cells. AB - Claudins are a family of tight junction (TJ) integral membrane proteins that play a crucial role in maintaining cell polarity, adhesion, and paracellular permeability. Changes in expression levels of claudin proteins have been associated with human lung cancer. Previously, we have reported that claudin-7 expression is significantly downregulated in human lung carcinomas. To investigate the role of claudin-7 in lung cancer cells after anti-cancer drug treatments, we transfected claudin-7 cDNA into human NCI-H522 lung cancer cells, which have no detectable expression of claudin-7 protein. Flow cytometry analysis demonstrated that cells transfected with claudin-7 had a significantly higher percentage of cell apoptosis when compared to that of vector transfected cell population. The cell viability assayed by MTT and Annexin V was significantly decreased and cell apoptosis was dramatically increased in claudin-7 transfected cells compared to that of vector transfected cells after cisplatin treatment. Cisplatin is an anti-cancer drug clinically used to treat tumors in several tissues including lung tumors. Most importantly, after cisplatin treatment, the expression levels of cleaved caspase-3, -8, and poly adenosine 5'-diphosphate ribose polymerase (PARP) were much higher in claudin-7 transfected cells than in control cells. Furthermore, using the site-directed mutagenesis approach, we identified that claudin-7 was phosphorylated at serine 204 by protein kinase C. Non-phosphorylated claudin-7 mutant showed increased cell viability, suggesting that phosphorylation increases chemosensitivity to cisplatin treatment. We concluded that claudin-7 expression in H522 lung cancer cells increases chemosensitivity to cisplatin through the increased activation of caspase pathway. PMID- 23433124 TI - Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids. AB - BACKGROUND: Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. METHODS: In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 - 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. RESULTS: Hybrids 1 - 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os. CONCLUSIONS: These compounds provide a new class of desperately needed anti malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated. PMID- 23433125 TI - Microvascular damage in type 1 diabetic patients is reversed in the first year after simultaneous pancreas-kidney transplantation. AB - Simultaneous pancreas-kidney transplantation (SPK) is an advanced treatment option for type 1 diabetes mellitus (DM) patients with microvascular disease including nephropathy. Sidestreamdarkfield (SDF) imaging has emerged as a noninvasive tool to visualize the human microcirculation. This study assessed the effect of SPK in diabetic nephropathy (DN) patients on microvascular alterations using SDF and correlated this with markers for endothelial dysfunction. Microvascular morphology was visualized using SDF of the oral mucosa in DN (n = 26) and SPK patients (n = 38), healthy controls (n = 20), DM1 patients (n = 15, DM >= 40 mL/min) and DN patients with a kidney transplant (KTx, n = 15). Furthermore, 21 DN patients were studied longitudinally up to 12 months after SPK. Circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and soluble thrombomodulin (sTM) were measured using ELISA. Capillary tortuosity in the DN (1.83 +/- 0.42) and DM >= 40 mL/min (1.55 +/- 0.1) group was increased and showed reversal after SPK (1.31 +/- 0.3, p < 0.001), but not after KTx (1.64 +/- 0.1). sTM levels were increased in DN patients and reduced in SPK and KTx recipients (p < 0.05), while the Ang-2/Ang-1 ratio was normalized after SPK and not after KTx alone (from 0.16 +/- 0.04 to 0.08 +/- 0.02, p < 0.05). Interestingly, in the longitudinal study, reversal of capillary tortuosity and decrease in Ang-2/Ang-1 ratio and sTM was observed within 12 months after SPK. SPK is effective in reversing the systemic microvascular structural abnormalities in DN patients in the first year after transplantation. PMID- 23433126 TI - CAUTI and readmission penalties: urologists beware. PMID- 23433127 TI - Legends in urology. PMID- 23433128 TI - The influence of PSA-RNA yield on the analysis of expressed prostatic secretions (EPS) for prostate cancer diagnosis. AB - INTRODUCTION: In patients with prostate cancer, luminal prostate-specific antigen (PSA) enters the circulation because the basement membrane and glandular epithelium are damaged. Given that excess mobilization of prostate cells during prostatic massage can influence normalization in diagnostic testing, we studied PSA mRNA levels in expressed prostatic secretions (EPS) from patients undergoing biopsy for prostate cancer to determine if prostate cells are preferentially mobilized from patients with prostate cancer during prostatic massage. MATERIALS AND METHODS: Quantitative Reverse-Transcription PCR (qRT-PCR) was used to measure the RNA levels of GAPDH, PSA, TMPRSS2:ERG and PCA3 in EPS specimens obtained from patients undergoing biopsy for prostate cancer. RESULTS: The level of PSA mRNA is significantly elevated in EPS specimens obtained from patients with a subsequent diagnosis of prostate cancer. This correlation influenced diagnostic testing results from EPS in two ways. First, when used as an exclusion parameter it appears to improve the diagnostic performance of TMPRSS2:ERG in EPS. Second, when used as a normalization parameter it appears to decrease the performance of these same tests. CONCLUSION: When comparing the results of mRNA based prostate cancer diagnostics in EPS it will be essential to consider PSA mRNA as a prostate specific gene and not a housekeeping gene. PMID- 23433129 TI - High pressure vaginography to diagnose vaginal ureteral ectopia in patients with continuous urinary incontinence. AB - INTRODUCTION: Continuous urinary incontinence in female patients can be a diagnostic dilemma if traditional imaging fails to identify a source. Vaginography has been used to diagnose vaginal ectopic ureters in the past with mixed results. MATERIALS AND METHODS: Institutional review board approval was obtained for a retrospective review. Five teenage females with continuous incontinence and prior negative imaging work ups underwent high pressure vaginography. Their findings and treatment outcomes are reviewed. RESULTS: A vaginal ectopic ureter was diagnosed in each of the five patients at a mean age 15.8 years. Each had undergone prior magnetic resonance urography that was non diagnostic. Four of the five were managed surgically with resolution of their incontinence. One was lost to follow up. CONCLUSION: High pressure vaginogram should be considered during the work up of female patients with continuous urinary incontinence, especially when other imaging modalities fail to identify an etiology. PMID- 23433130 TI - Lactobacillus for preventing recurrent urinary tract infections in women: meta analysis. AB - INTRODUCTION: Urinary tract infections (UTIs) are the most common infections affecting women, and often recur. Lactobacillus probiotics could potentially replace low dose, long term antibiotics as a safer prophylactic for recurrent UTI (rUTI). This systematic review and meta-analysis was performed to compile the results of existing randomized clinical trials (RCTs) to determine the efficacy of probiotic Lactobacillus species in preventing rUTI. MATERIALS AND METHODS: MEDLINE and EMBASE were searched from inception to July 2012 for RCTs using a Lactobacillus prophylactic against rUTI in premenopausal adult women. A random effects model meta-analysis was performed using a pooled risk ratio, comparing incidence of rUTI in patients receiving Lactobacillus to control. RESULTS: Data from 294 patients across five studies were included. There was no statistically significant difference in the risk for rUTI in patients receiving Lactobacillus versus controls, as indicated by the pooled risk ratio of 0.85 (95% confidence interval of 0.58-1.25, p = 0.41). A sensitivity analysis was performed, excluding studies using ineffective strains and studies testing for safety. Data from 127 patients in two studies were included. A statistically significant decrease in rUTI was found in patients given Lactobacillus, denoted by the pooled risk ratio of 0.51 (95% confidence interval 0.26-0.99, p = 0.05) with no statistical heterogeneity (I2 = 0%). CONCLUSION: Probiotic strains of Lactobacillus are safe and effective in preventing rUTI in adult women. However, more RCTs are required before a definitive recommendation can be made since the patient population contributing data to this meta-analysis was small. PMID- 23433131 TI - Is cystoscopy indicated for incidentally identified bladder wall thickening? AB - INTRODUCTION: The purpose of this study was to evaluate the yield of cystoscopy in detecting bladder malignancy following incidentally identified bladder wall thickening observed on computed tomography (CT) scans. METHODS AND MATERIALS: Data from 3000 consecutive patients who underwent diagnostic cystoscopy at a single institution from 2006-2009 were collected retrospectively. All prior CT scan reports were reviewed, and patients whose sole indication for cystoscopy was incidentally detected bladder wall thickening were identified. Patients were categorized as diffuse thickening, focal thickening, or focal bladder mass based on the radiologist's report. Collected data included patient age, gender, race, smoking history, history of hematuria, medications for benign prostate hypertrophy or overactive bladder as well as cystoscopy results, pathology results, and follow up. RESULTS: Twenty-two patients (0.7% of cystoscopies) underwent cystoscopy for incidentally identified bladder wall thickening including 11 (50%) with focal bladder wall thickening, 8 (36.4%) with diffuse bladder wall thickening, and 3 (13.6%) with focal bladder mass lesions. Five patients (22.7%) had suspicious lesions on cystoscopy requiring endoscopic surgery with biopsy. Two patients with focal bladder mass lesions were found to have low grade, superficial bladder cancer (66.7% of patients with focal bladder mass lesions and 9.1% of all patients with incidental bladder wall thickening). No patients with diffuse or focal bladder wall thickening had malignancy. CONCLUSIONS: Incidental findings of diffuse and focal bladder wall thickening on CT scan were found to have a low yield for the detection of urinary tract malignancy. Incidentally detected focal bladder mass lesions are more likely to have malignant pathology. PMID- 23433132 TI - Prostate cancer detection rate at repeat saturation biopsy: PCPT risk calculator versus PCA3 score versus case-finding protocol. AB - INTRODUCTION: To evaluate Prostate Cancer Prevention Trial (PCPT) risk calculator versus prostate cancer gene 3 (PCA3) score versus case-finding protocol accuracy in prostate cancer diagnosis in patients with prostate-specific antigen (PSA) below 10 ng/mL submitted to repeat saturation biopsy (SPBx). MATERIALS AND METHODS: From December 2010 to December 2011, 100 patients (median 66 years) underwent a SPBx (median 30 cores); the indications for repeat biopsy were those of a case-finding protocol: PSA values between 4.1 ng/mL-10 ng/mL or 2.6 ng/mL-4 ng/mL with F/T PSA <= 25% and <= 20%, respectively. All patients had negative digital rectal examination (DRE) and median PSA was 7.9 ng/mL. The performance of PCPT risk calculator (alone, combined with PSA free/total ( F/T) or PCA3 score) and PCA3 score in comparison with the case-finding protocol results (alone or combined with PCA3 score) was retrospectively evaluated in terms of detection rate for cancer and number of avoided biopsies. RESULTS: Prostate cancer was found in 28 (28%) patients; in the presence and absence of prostate cancer median PCA3 score was 57 versus 35 (p < 0.05). Using PCPT risk calculator (cut off probability of 25%) combined with PCA3 score no prostate cancer would be missed avoiding 8% of unnecessary biopsies. PCA3 score > 20 missed 7.2% of cancer; the case-finding protocol combined with PCA3 score > 35 would save 22% of avoidable biopsies, missing no cancer if all patients with PSA F/T <= 15% would undergo prostate biopsy irrespective of PCA3 values. CONCLUSIONS: PCA3 score improves PCPT risk calculator accuracy in prostate cancer diagnosis; moreover, PCA3 score combined with PSA F/T reduce number of unnecessary biopsies (about 20%). PMID- 23433133 TI - Biomarkers to improve PSA-cancer screening. PMID- 23433134 TI - Association between urinary diversion and quality of life after radical cystectomy. AB - INTRODUCTION: We examined the association between type of urinary diversion and quality of life (QoL) in patients who underwent radical cystectomy for primary bladder cancer using a validated, disease-specific instrument. MATERIALS AND METHODS: A cohort of 314 consecutive patients treated with radical cystectomy and urinary diversion for primary bladder cancer between January 2000 and December 2006 was analyzed. Participants were mailed the validated Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index (FACT-VCI) questionnaire. Univariable and multivariable linear regression analyses were used to examine the association between type of urinary diversion (ileal conduit versus orthotopic neobladder) and QoL. RESULTS: Eighty-four out of 168 (50% response rate) evaluable patients completed the FACT-VCI questionnaire. The median follow up duration was 5.6 years (range, 2.1 to 9.3 years). ANOVA showed statistically significant differences favoring orthotopic neobladder urinary diversion with more favorable QoL scores on the FACT-VCI (mean difference 5.6 points, p = .03) and radical cystectomy-specific domain (mean difference 2.9 points, p = .05). However, multivariable linear regression analyses showed no statistically significant association between the type of urinary diversion and QoL (FACT-VCI: beta = 4.1 points, p = .177; radical cystectomy-specific: beta = 1.5 points, p = .390). CONCLUSIONS: Type of urinary diversion was not associated with QoL after radical cystectomy. Randomized controlled trials comparing types of urinary diversion using validated, disease-specific QoL instruments are needed. PMID- 23433135 TI - Is simpler better? Quality of life based on type of urinary diversion. PMID- 23433136 TI - Short term outcomes of GreenLight vapor incision technique (VIT) of the prostate: comparison of outcomes to standard GreenLight 120W HPS vaporization in prostate volumes greater than 80 cc. AB - INTRODUCTION: To evaluate a hybrid technique involving GreenLight 120W HPS vapor incision tissue removal in prostate glands > 80 cc. MATERIALS AND METHODS: Vapor incision technique (VIT) was performed in 25 consecutive men with a prostate > 80 cc by a single surgeon from May 2010 until September 2010. VIT involved adenoma incisions at 5 and 7-o'clock positions followed by 3, 9 and 12 o'clock down to the surgical capsule. Side-fire vaporization along the capsule excised transurethral resection of the prostate (TURP) like tissue strips for later retrieval. Functional evaluations were performed at 1 and 3 months. Outcomes and complications were compared retrospectively to baseline and a size matched- cohort of 25 men who previously underwent standard vaporization-only photoselective vaporization prostatectomy (PVP). RESULTS: The VIT and control subgroups were comparable. Mean laser time, operative time and energy usage were reduced in the VIT group compared to controls (35 min versus 48 min; 63 min versus 80 min; and 227 k versus 325 kJ respectively; all p < 0.05). At 3 months the VIT subgroup demonstrated improved Qmax and post void residual (PVR) (197% versus 173%, 88% versus 72%; all p < 0.05) compared to control. VIT showed a 68% reduction in mean preoperative PSA at 3 months compared to 50% for the control group (p<0.01). Hospital stay, catheterization time and complication rates were comparable. CONCLUSIONS: Our data demonstrates that VIT provides superior short term outcomes to standard HPS-PVP in men with prostate volumes > 80 cc. VIT appears to be more time-efficient, consumes less energy and obtains tissue for pathological evaluation. Further follow up is required to assess the durability of GreenLight HPS-VIT to PVP vaporization-only for large prostate glands. PMID- 23433137 TI - Adult granulosa cell tumor of the testicle. AB - We report a rare case of adult granulosa cell tumor of the testis in a 68-year old man. A case and literature review of the associated clinical features, histopathological characteristics and immunochemistry are presented. The tumor is typically slow growing but has a higher risk of malignancy when > 5 cm. Our patient was disease-free 18 months following a right radical orchiectomy. PMID- 23433138 TI - Epithelioid PEComa (epithelioid angiomyolipoma) of the kidney: a rare tumor subtype for patients presenting with an enhancing renal mass. AB - Epithelioid angiomyolipomas, or perivascular epithelioid cell tumors (epithelioid PEComas) of the kidney, are histologically related to renal angiomyolipomas (AMLs). However, in contrast to typical AMLs, this rare tumor can exhibit an aggressive clinical course with approximately 50% of reported cases demonstrating disease progression. In this report, we present a case of a 24-year-old female with a history of stone disease who was incidentally found to have a 9.0 cm right renal mass that was difficult to characterize radiographically preoperatively. The patient underwent a right radical nephrectomy, and pathology revealed a renal epithelioid PEComa. PMID- 23433139 TI - Combined partial cystectomy and cesarean delivery in a pregnant female with bladder pheochromocytoma. AB - We report the first known case of concurrent partial cystectomy and cesarean delivery in a pregnant female with bladder pheochromocytoma. A 28-year-old G4P2 female presented at 28 weeks gestation with labile blood pressures requiring three antihypertensive medications. Urinary catecholamines were elevated, and a subsequent MRI showed a 2.6 cm x 3.2 cm bladder wall mass. She underwent combined cesarian section and partial cystectomy at 37 weeks. Fluid resuscitation and vasopressors were required in the immediate postoperative period. While bladder pheochromocytoma with pregnancy is a rare occurrence, concurrent delivery and removal of the bladder tumor can be performed safely. PMID- 23433140 TI - Intradetrusor onabotulinumtoxinA injection: how I do it. AB - Overactive bladder is a highly prevalent condition that may have significant impact on quality of life. This condition may be idiopathic or may have a neurogenic etiology. Antimuscarinics have long been the preferred agents for the treatment of this condition. OnabotulinumtoxinA, an injectible agent that prevents presynaptic release of acetylcholine at the neuromuscular junction, has emerged as an important option in the management of patients with urinary incontinence caused by refractory detrusor overactivity. This manuscript describes our technique for performing utilizing this therapy, describes key equipment needed and provides technical tips for avoiding common pitfalls. PMID- 23433141 TI - Mid term outcome of robotic mesh sacrocolpopexy. AB - INTRODUCTION: Use of robotic mesh sacrocolpopexy (RMS) has increased for management of pelvic organ prolapse (POP). We present our experience with mid term follow up. MATERIALS AND METHODS: A retrospective chart review of consecutive patients who had RMS was performed. Patients underwent history and physical exam including POP-Q classification. In cases of bladder involvement a standing voiding cystourethrogram and urodynamics with vaginal pack reduction of the prolapse were done. Indication for RMS was patient preference, BMI < 30, no prior major abdominal surgery, and age < 80. We utilized Marlex mesh and absorbable polyglactin sutures to anchor the mesh to the vaginal wall and apex. Follow up was at 6 weeks, 6 and 12 months and yearly thereafter. The Urogenital Distress Inventory (UDI-6), Incontinence Impact Questionnaire (IIQ-7) and a quality of life (QoL) questionnaire (range 0 excellent to 10 terrible) were obtained pre and postoperatively. RESULTS: Thirty-five patients underwent RMS from January 2008 to July 2011 with at least 6 months follow up. Thirty-four patients (97%) had previous hysterectomy. Twenty-eight (80%) patients had previous surgery for pelvic organ prolapse (POP) and/or stress incontinence. Mean age and median follow up were 65 years (37-79) and 28 months (7-50) respectively. Mean preoperative C-point was -1.1 (+1 to -4) compared to -9.7 ( 12 to -10) postoperatively (p < .0.001). Five intraoperative vaginotomies were repaired primarily. No patients required conversion to open. No patient had recurrent vault prolapse. Three patients had secondary POP procedures. One patient developed a mesh erosion requiring surgical repair. Functional outcome improvement was noted with score reduction for QoL of 4.1 to 1.3 (p < 0.001), UDI 6 of 27.3 to 16.1 (p = 0.002), and IIQ-7 of 18.3 to 3.9 (p = 0.031). CONCLUSIONS: RMS performed reliably to correct symptomatic POP. The use of absorbable sutures to secure the mesh to the vaginal walls resulted in satisfactory anatomic outcomes and did not increase the risk of mesh erosion. PMID- 23433142 TI - Comparison of clamping technique in robotic partial nephrectomy: does unclamped partial nephrectomy improve perioperative outcomes and renal function? AB - INTRODUCTION: Partial nephrectomy without renal vascular occlusion has been introduced to improve outcomes in patients undergoing robotic partial nephrectomy (RPN). We prospectively evaluated unclamped RPN at our institution and compared this to other clamping techniques in a non-randomized fashion. MATERIALS AND METHODS: Ninety-five consecutive patients who successfully completed RPN between June 2010 and October 2011 are included in this analysis. All RPNs were performed by a single surgeon. Clamping technique was artery and vein (AV), artery alone (AO) or unclamped (U) without hypotensive anesthesia. Clamping decision was based on surgeon preference and feasibility of minimizing ischemia. All patients had bilateral functional renal units. RESULTS: Eighteen (19%), 58 (61%) and 19 (20%) patients had AV, AO and U technique respectively. Preoperative characteristics including age (p = 0.43), body mass index (p = 0.40) and RENAL nephromety distribution (p = 0.10) were similar. In AV and AO, mean warm ischemia time were 19 and 17 minutes and similar between the two cohorts (p = 0.39). Mean glomerular filtration rate (GFR) and overall percentage decrease in GFR at time of at last follow up were (64, 69, 81, p = 0.12) and (6%, 6%,and 2%,p = 0.79) for AV, AO and U respectively. Median follow up for last serum creatinine was 113 days and was similar between all cohorts (p = 0.37). Complication rate (p = 0.37), positive margin rate (p = 0.84), and change in hemoglobin concentration postoperatively (p = 0.94) were similar between cohorts. CONCLUSIONS: Unclamped partial nephrectomy is possible in patients undergoing RPN. In this study, it does not significantly alter perioperative or postoperative renal function or change rate of complications. Minimal ischemia, irrespective of clamping technique, in patients with bilateral renal units does not appear to adversely effect intermediate term renal function in these patients. PMID- 23433143 TI - A systematic review of intervention effects on potential mediators of children's physical activity. AB - BACKGROUND: Many interventions aiming to increase children's physical activity have been developed and implemented in a variety of settings, and these interventions have previously been reviewed; however the focus of these reviews tends to be on the intervention effects on physical activity outcomes without consideration of the reasons and pathways leading to intervention success or otherwise.To systematically review the efficacy of physical activity interventions targeting 5-12 year old children on potential mediators and, where possible, to calculate the size of the intervention effect on the potential mediator. METHODS: A systematic search identified intervention studies that reported outcomes on potential mediators of physical activity among 5-12 year old children. Original research articles published between 1985 and April 2012 were reviewed. RESULTS: Eighteen potential mediators were identified from 31 studies. Positive effects on cognitive/psychological potential mediators were reported in 15 out of 31 studies. Positive effects on social environmental potential mediators were reported in three out of seven studies, and no effects on the physical environment were reported. Although no studies were identified that performed a mediating analysis, 33 positive intervention effects were found on targeted potential mediators (with effect sizes ranging from small to large) and 73% of the time a positive effect on the physical activity outcome was reported. CONCLUSIONS: Many studies have reported null intervention effects on potential mediators of children's physical activity; however, it is important that intervention studies statistically examine the mediating effects of interventions so the most effective strategies can be implemented in future programs. PMID- 23433145 TI - Why should I prepare? A mixed method study exploring the motives of medical undergraduate students to prepare for clinical skills training sessions. AB - BACKGROUND: Although preparation for educational activities is considered beneficial for student learning, many students do not perform preparatory assignments. This phenomenon has received little attention in the literature although it might provide medical educators with the opportunity to enhance student learning. Therefore, we explored why students prepare or not prepare. METHODS: An explorative mixed methods study was performed. In a qualitative study, 24 short group interviews with medical undergraduate students (n=209) were conducted on why they prepared for skills training sessions. In a subsequent quantitative study the resulting themes were used to construct a questionnaire. The questionnaire was presented to all undergraduate medical students at Maastricht University and 847 students completed it. Scales were constructed by a combination of exploratory factor analysis, reliability analysis, and content analysis. Between-class differences in the scale scores were investigated using ANOVA. RESULTS: The qualitative study showed that students' opinions on preparation are influenced by both personal factors, categorized as 'personal learning style', 'attitudes and beliefs', and 'planning and organization', as well as external factors, including 'preparatory advice', 'pressure, consequence, and checking of preparation', 'teacher-related motivations', and 'contents and schedule of the training sessions'. The quantitative study showed that 'the objective structured clinical examination' and 'facilitation of both understanding and memorizing the learning material', were the two most motivating items. The two most demotivating aspects were 'other students saying that preparation was not useful' and 'indistinct preparatory advices'. Factor analyses yielded three scales: 'urge to learn', 'expected difficulties', and 'lack of motivation'. Between group differences were found between the three classes on the first two scales. CONCLUSIONS: Students make an active and complex choice whether to prepare or not, based on multiple factors. Practical implications for educational practice are discussed. PMID- 23433144 TI - Dengue induces platelet activation, mitochondrial dysfunction and cell death through mechanisms that involve DC-SIGN and caspases. AB - BACKGROUND: Worldwide, dengue is the most prevalent human arbovirus disease. Dengue infection may cause a range of clinical manifestations from self-limiting febrile illness through to a life-threatening syndrome accompanied by both bleeding and shock. Thrombocytopenia is frequently observed in mild and severe disease; however, the mechanisms involved in DENV-induced platelet activation and thrombocytopenia are incompletely understood. PATIENTS AND METHODS: Freshly isolated platelets from patients with dengue were evaluated for markers of activation, mitochondrial alteration and activation of cell death pathways. In parallel, we examined direct DENV-induced activation and apoptosis of platelets obtained from healthy subjects. RESULTS: We found that platelets from DENV infected patients exhibited increased activation by comparison to control subjects. Moreover, platelets from DENV-infected patients exhibited classic signs of the intrinsic pathway of apoptosis that include increased surface phosphatidylserine exposure, mitochondrial depolarization and activation of caspase-9 and -3. Indeed, thrombocytopenia was shown to strongly associate with enhanced platelet activation and cell death in DENV-infected patients. Platelet activation, mitochondrial dysfunction and caspase-dependent phosphatidylserine exposure on platelets were also observed when platelets from healthy subjects were directly exposed to DENV in vitro. DENV-induced platelet activation was shown to occur through mechanisms largely dependent on DC-SIGN. CONCLUSIONS: Together our results demonstrate that platelets from patients with dengue present signs of activation, mitochondrial dysfunction and activation of the apoptosis caspase cascade, which may contribute to the development of thrombocytopenia in patients with dengue. Our results also suggest the involvement of DC-SIGN as a critical receptor in DENV-dependent platelet activation. PMID- 23433146 TI - An evaluation of three sampling methods to monitor a digenetic trematode Centrocestus formosanus in a spring-fed ecosystem. AB - Centrocestus formosanus is a digenetic trematode from Asia that parasitizes multiple hosts and is a concern in the Comal River, Texas, USA, because of its negative effects on the endangered fountain darter Etheostoma fonticola. To determine a practical sampling method to monitor C. formosanus in the Comal River, we evaluated three sampling methods using wild-caught fish, caged fish reared in the laboratory, and cercariometry. Cercariometry detected significant spatial and temporal patterns of cercarial density in river water that were similar with metacercarial intensity in caged fish, but inconsistent with metacercarial intensity in wild-caught fish. Our results also showed a positive correlation between cercarial density in river water and metacercarial intensity in caged fish. Conversely, the relationship was not significant between cercarial density and metacercarial intensity in wild-caught fish. Because cercariometry predicted similar trends with the caged fountain darter sampling method, cercariometry was useful in predicting C. formosanus gill infections, infection rate, and longevity in infected fountain darters. Although trends from cercariometry and caged fish sampling methods were similar, we recommend cercariometry because it was less expensive to use given the amount of sampling effort required and provides trends that can be used to make pro-active management decisions in C. formosanus-infested aquatic ecosystems. PMID- 23433148 TI - Identification of the contribution of the ankle and hip joints to multi-segmental balance control. AB - BACKGROUND: Human stance involves multiple segments, including the legs and trunk, and requires coordinated actions of both. A novel method was developed that reliably estimates the contribution of the left and right leg (i.e., the ankle and hip joints) to the balance control of individual subjects. METHODS: The method was evaluated using simulations of a double-inverted pendulum model and the applicability was demonstrated with an experiment with seven healthy and one Parkinsonian participant. Model simulations indicated that two perturbations are required to reliably estimate the dynamics of a double-inverted pendulum balance control system. In the experiment, two multisine perturbation signals were applied simultaneously. The balance control system dynamic behaviour of the participants was estimated by Frequency Response Functions (FRFs), which relate ankle and hip joint angles to joint torques, using a multivariate closed-loop system identification technique. RESULTS: In the model simulations, the FRFs were reliably estimated, also in the presence of realistic levels of noise. In the experiment, the participants responded consistently to the perturbations, indicated by low noise-to-signal ratios of the ankle angle (0.24), hip angle (0.28), ankle torque (0.07), and hip torque (0.33). The developed method could detect that the Parkinson patient controlled his balance asymmetrically, that is, the right ankle and hip joints produced more corrective torque. CONCLUSION: The method allows for a reliable estimate of the multisegmental feedback mechanism that stabilizes stance, of individual participants and of separate legs. PMID- 23433149 TI - [Intervention of pyrrolidine dithiocarbamate on expressions of connective tissue growth factor, type I collagen, and type III collage in acute paraquat poisoned rats]. AB - OBJECTIVE: To observe the changes in the expression of connective tissue growth factor (CTGF), type I collagen (Col I), and type III collagen (Col III) among the rats with acute paraquat (PQ) poisoning and the intervention effect of pyrrolidine dithiocarbamate (PDTC) on their expression, and to investigate the mechanism of PQ-induced pulmonary fibrosis and the intervention effect of PDTC on the disease. METHODS: Sprague-Dawley rats were randomly divided into control group (n = 6), PQ group (n = 36), and PQ + PDTC group (n = 36). The PQ group and PQ + PDTC group were given a single dose of saline-diluted PQ (80 mg/kg) by gavage; 2 h later, the PQ + PDTC group was intraperitoneally injected with a single dose of PDTC (100 mg/kg), and the PQ group was intraperitoneally injected with the same amount of saline. The control group was given saline (1 ml/kg) by gavage and was intraperitoneally injected with the same amount of saline 2h later. At 1, 3, 7, 14, 25, and 56 days after operation, the protein expression of CTGF was evaluated by Western blot; the mRNA expression of CTGF, Col I, and Col III was analyzed by real-time quantitative PCR; the content of hydroxyproline in lung tissue was measured, and the pathological changes of lung tissue of the poisoned rats were observed. RESULTS: The protein expression of CTGF in the PQ group increased as the time went on, slowly from the 3rd to the 14th day and rapidly from the 28th to the 56th day, significantly higher than that in the control group at each time point (P < 0.05 or P < 0.01). The mRNA expression of CTGF in the PQ group began to rise markedly on the 1st day, increased rapidly from the 3rd to the 14th day, and remained at a relatively high level from the 28th to the 56th day, significantly higher than that in the control group at each time point (P < 0.01). The mRNA expression of Col I in the PQ group changed little on the 1st and 3rd day, increased slightly on the 7th day, and increased greatly from the 14th to the 56th day, significantly higher than that in the control group from the 7th to the 56th day (P < 0.05 or P < 0.01). The mRNA expression of Col III in the PQ group began to rise on the 1st day, reached the peak level on the 7th day, and then declined, significantly higher than that in the control group at each time point (P < 0.05 or P < 0.01). Masson staining showed that fibroblasts proliferated from the 14th to the 28th day, and collagen fibers increased gradually. Compared with the PQ group, the PQ + PDTC group showed significantly decreased protein expression of CTGF as well as mRNA expression of CTGF, Col I, and Col III (P < 0.05 or P < 0.01). CONCLUSION: In PQ induced pulmonary fibrosis, the expression of CTGF keeps rising, and the collagen secretion and matrix synthesis are increased probably by upregulating the transcriptional levels of Col I and Col III; CTGF plays an important role in PQ induced pulmonary fibrosis. PDTC can inhibit the expression of CTGF, thus reducing the lung injury in rats with PQ poisoning. PMID- 23433150 TI - [Hypoxia-inducible factor-1alpha expression in renal tissue of rats with paraquat poisoning]. AB - OBJECTIVE: To observe the pathological changes of renal tissue in the rats with paraquat (PQ) poisoning as well as the serum creatinine (SCr) levels and expression levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and transforming growth factor-beta (TGF-bgr;) in renal tissue at different time points after PQ poisoning, and to investigate the association of HIF-1alpha with renal injury after PQ poisoning. METHODS: Forty-eight healthy male Sprague-Dawley rats were randomly divided into control group (n = 6) and PQ group (n = 42). The control group was given a single dose of 1 ml saline by gavage; the PQ group was given a single dose of 1 ml PQ (50 mg/kg), which was prepared by diluting 20% raw liquid of PQ with saline, by gavage. The PQ group was further divided into 2, 6, 12, 24, 48, 72 and 120 h PQ subgroups (n = 6 for each subgroup) to be examined at 2, 6, 12, 24, 48, 72, or 120 h after gavage. Their arterial blood was collected for blood gas analysis as well as blood lactic acid (BLA) and SCr measurement; renal sections were subjected to HE staining; the protein expression of HIF 1alpha and TGF-beta in renal tissue was measured by Western blot. RESULTS: The BLA level and SCr level began to rise at 6h after poisoning. Compared with the control group, the 6, 12, 24, 48, 72 and 120 h PQ subgroups had significantly increased BLA and SCr levels (P < 0.05); the 72 and 120 h PQ subgroup showed hypoxemia (P < 0.05). The protein expression of HIF-1alpha in PQ group increased significantly at 6h and reached the peak level at 72 h, with a significant difference from that in the control group at 6, 12, 24, 48, 72, and 120 h (P < 0.05). The protein expression of TGF-beta in PQ group began to rise at 24 h, reached the peak level at 72 h, and declined at 120 h, with a significant difference from that in the control group at 24, 48, and 72 h (P < 0.05). The protein expression of HIF-1alpha was positively correlated with SCr level (r = 0.9308, P = 0.0008), uncorrelated with arterial partial pressure of oxygen (r = 0.6996, P = 0.0534), and positively correlated with BLA level (r = 0.9483, P = 0.0003). The pathological changes of renal tissue mainly included the degeneration and necrosis of renal tubular epithelial cells, which worsened as the time went on and appeared less severe at 120 h. CONCLUSION: The HIF-1alpha expression in renal tissue increases significantly in the early stage of PQ poisoning, which is associated with increased BLA and SCr levels and causes upregulated expression of TGF-beta that promotes renal fibrosis. PMID- 23433151 TI - [The effects of benzene poisoning on expression of multidrug resistance 1 gene and P-glycoprotein in bone marrow mononuclear cells of C57BL/6 mice]. AB - OBJECTIVE: To investigate the effects of benzene poisoning on the expression of multidrug resistance 1 (MDR1) gene and P-glycoprotein (P-gp) in the bone marrow mononuclear cells (BMMNCs) of C57BL/6 mice. METHODS: C57BL/6 mice were randomly divided into control group (n = 24), low-dose group (n = 24), medium-dose group (n = 24), and high-dose group (n = 24) to receive corn oil, 25 mg/kg benzene, 50 mg/kg benzene, or 100 mg/kg benzene by gavage, once daily, 5 days/weeks, for 4 weeks. The mice were sacrificed on day 12, 26, or 29 of poisoning. Peripheral blood routine test was performed; real-time quantitative PCR was used to measure the MDR1 gene expression in BMMNCs; Western blot was used to measure the P-gp expression in BMMNCs. RESULTS: On day 12, the red blood cell count and hemoglobin level in the high-dose group were significantly lower than those in the control group, low-dose group, and medium-dose group (P < 0.01 or P < 0.05). On day 26, the white blood cell count in the high-dose group was significantly lower than those in the control group, low-dose group, and medium-dose group (P < 0.01 or P < 0.05). At each time point, the mRNA expression of MDR1 gene in the low-dose group, medium-dose group, and high-dose group was significantly lower than that in the control group (P < 0.01). On day 26, the P-gp expression in the high-dose group was significantly lower than those in the control group, low-dose group, and medium-dose group, and the P-gp expression in the medium-dose group was significantly lower than that in the low-dose group (P < 0.01 or P < 0.05). On day 29, the P-gp expression in the low-dose group, medium-dose group, and high dose group was significantly lower than that in the control group (P < 0.05). CONCLUSION: Benzene poisoning can affect the expression of MDR1 gene and P-gp, which may be one of the mechanisms of benzene hematotoxicity. PMID- 23433152 TI - [One case of delirium with 2,4-D butylate poisoning]. PMID- 23433153 TI - [Comprehensive analysis of asbestos-induced occupational lung cancer and mesothelioma]. AB - OBJECTIVE: To revise diagnosis criteria of asbestos-induced occupational lung cancer. METHODS: All literatures which met the criteria of cohort studies with results of lung cancer incidence or mortality among workers exposed to asbestos would incorporate into the systematic review. Meanwhile, the information about diagnosis criteria on asbestos-induced lung cancer in other countries was collected. Meta analysis was used to calculate meta-SMR and its 95% confidence interval. RESULTS: 21 asbestos-exposed cohorts were summarized. The percentage of all deaths due to mesothelioma was 0 to 36.36%. The main kind of asbestos-exposed raw material was chrysotile which accounted for 47.6%, and 7 cohorts (33.3%) didn't provide the information. There were 13 cohorts in 15 which concluded that the lung cancer risk of workers with asbestos exposure had increased (lung cancer SMR = 1.6 ~ 6.52, P < 0.05). Meta-SMR of 10 included cohorts is 2.09, with 95%CI 1.73 to 2.52 by using Meta analysis. When cumulative asbestos exposure years were less than one year, the risk of lung cancer had increased (lung cancer SMR = 1.6 ~ 1.82, P < 0.05). When latent period of lung cancer was more than 15 years, the risk of lung cancer had increased (lung cancer SMR = 2.08 ~ 3.75, P < 0.05). There were three studies, which had analyzed the relation between cumulative asbestos exposure years and the risk of mesothelioma, showing that when cumulative asbestos exposure years were less than one year, the risk of mesothelioma had increased (mesothelioma SMR = 18.0 ~ 20.0, P < 0.05). When latent period of mesothelioma was more than 15 years, the risk of mesothelioma had increased. CONCLUSION: The emphasis of the new version of asbestos-induced lung cancer and mesothelioma diagnosis criteria should focus on cumulative asbestos exposure years and latent period. PMID- 23433154 TI - [Study of estimation method for incidence of new cases of coal workers' pneumoconiosis in China]. AB - OBJECTIVE: To estimate the coverage level of case reporting for coal workers' pneumoconiosis (CWP) and the incidence of CWP in China according to the data from CWP reporting database in China as well as the data on annual raw coal output, coal workers, etc. from relevant year books, and to provide scientific data for CWP control measures. METHODS: The data on the numbers of coal workers and annual raw coal outputs of national top 100 enterprises in coal sector (Top 100 in coal sector) were acquired from China Coal Industry Yearbook; the annual per capita output of raw coal in each enterprise was calculated. The numbers of coal workers in the enterprises other than the Top 100 were estimated based on the annual per capita output of raw coal in the Top 100 and the annual raw coal outputs of the enterprises other than the Top 100. The numbers of coal workers in the enterprises that reported CWP cases were estimated based on the distribution of these enterprises in China, and the coverage rates of case reporting in the Top 100 and other enterprises were calculated accordingly. The total number of CWP cases and the number of CWP cases due to per million tons of raw coal output were estimated according to the coverage rates of case reporting and the total numbers of reported CWP cases in China. RESULTS: The mean coverage rates of case reporting in the Top 100 and other enterprises were 55.34% and 5.18%, respectively. The estimated mean numbers of new CWP cases in the Top 100 and other enterprises were 3088 and 98205, respectively; the estimated total number of new CWP cases nationwide was 101293. The estimated mean numbers of new CWP cases due to per million tons of raw coal output were 2.05 in the Top 100 and 7341 in other enterprises. The number of reported CWP cases accounted for 6.7% of the estimated number of CWP cases (6796/101293). CONCLUSION: It is urgent to enhance occupational disease control in coal sector, and the estimation results for CWP should be spread and applied. The system of occupational disease control should be further improved. PMID- 23433155 TI - [Relationship between high incidence of lung cancer among non-smoking women and silica in C1 bituminous coal in Xuanwei, Yunnan Province, China]. AB - OBJECTIVE: To measure the content of silica in C1 bituminous coal and its combustion products in the high-incidence area of lung cancer in Xuanwei, Yunnan Province, China and to investigate the relationship between high incidence of lung cancer among non-smoking women and silica produced naturally in C1 bituminous coal in Xuan Wei. METHODS: The C1 bituminous coal widely used in the high-incidence area of lung cancer in Xuanwei was selected as experiment group, while the C2+1, K7, and M30 bituminous coal that was mined and used in the low incidence area of lung cancer in Xuanwei for more than 10 years were selected as control group. Fourteen paraffin-embedded cancer tissue samples from the non smoking women with non-small cell lung cancer who were born in Xuanwei and were at least the 3rd generation of the family living there were collected from the department of pathology, the third affiliated hospital of kunming medical university (tumor hospital of yunnan province). Titrimetric potassium silicofluoride method was used to measure the content of silica in raw coal and its bottom ashes in 20 samples from the experimental group and control group. Scanning electron microscopy (SEM) was used to observe the morphology of silica particles in C1 bituminous coal and its bottom ashes, and scanning electron microscopy coupled with energy dispersive X-ray analyzer (SEM-EDX) was used to analyze the microscopic composition. Transmission electron microscope (TEM) was used to observe the morphology of silica particles in the bottom ashes and coal soot of C1 bituminous coal as well as the lung cancer tissue from the non-smoking women in Xuanwei, and transmission electron microscope coupled with energy dispersive X-ray analyzer (TEM-EDX) was used to analyze the microscopic composition. The silica particles were separated from the coal soot and bottom ashes and characterized by physical method. RESULTS: The silica content in C1 bituminous coal and its bottom ashes was significantly higher than that in C2+1, K7, and M30 bituminous coal (P < 0.05). The bottom ashes of C1 bituminous coal contained a large quantity of silica particles, mostly with microscale sizes. Silica particles were found in the soot of C1 bituminous coal and the lung cancer tissue from non-smoking women in Xuanwei. The silica particles in the bottom ashes were mostly 120 ~ 500 nm in diameter, had various shapes, and contained such elements as iron, aluminium, calcium, and potassium; the silica particles in the coal soot were mostly nanoscale, ranging from 37 nm to 80 nm in diameter, had various shapes, with some in fibrous form, had non smooth surfaces, and contained such elements as iron, potassium, calcium, aluminium, and sulfur. CONCLUSION: In Xuanwei, the incidence of lung cancer among non-smoking women is high in the area where silica-rich C1 bituminous coal is produced. There are silica particles enriched in both the combustion products (coal soot and bottom ashes) of C1 bituminous coal and the cancer tissue from the non-smoking women with non-small cell lung cancer, with similar morphology and microscopic composition. We hypothesize that the silica particles from combusted C1 bituminous coal in Xuanwei are mixed with indoor air and inhaled along with other suspended particles. PMID- 23433156 TI - [Investigation of work-related acute pesticide poisoning among farmers in Jiangsu Province and the risk factors]. AB - OBJECTIVE: To determine the incidence of work-related acute pesticide poisoning among farmers in Jiangsu Province and to identify the risk factors. METHODS: Multi-stage stratified sampling and cluster sampling methods were used to randomly select 1490 farmers from the south (Z village), centre (Y village) and north (X village) of Jiangsu Province. The database was established by EpiData 3.1. SPSS 17.0 and SAS 9.13 were used to do chi-square test, trend chi-square test, single factor and multi-factor logistic regression analysis. RESULTS: Among 1490 farmers, 121 people had work-related acute pesticide poisoning in the past year. The incidence rate in Jiangsu Province was 8.1%. 118 farmers (97.5%) were mild pesticide poisoning.3 farmers (2.5%) were moderate pesticide poisoning. The incidence rate of Work-related acute pesticide poisoning in X village of North Jiangsu Province (13.5%, 68/505) is obviously higher than that in Y village of Central Jiangsu Province (4.8%, 19/399) and Z village of South Jiangsu Province (5.8%, 34/586), and the difference is statistically significant (chi(2) = 29.60, P < 0.01). The incidence rate of Work-related acute pesticide poisoning in female (10.4%, 58/557) is obviously higher than that in male (6.8%, 63/933), and the difference is statistically significant (chi(2) = 6.26, P < 0.05). There are lack of safety guidance, unsafety application methods (without alternate row spraying, without backward application, without down-wind application) and risk behaviors in the spraying (without read labels, preparing pesticides without gloves, wiping sweat with hand (s), equipment leakage, body pollution by pesticide, working when feeling sick, without bath after work). If farmers have risk behaviors above, the incidence rate of Work-related acute pesticide poisoning will be obviously higher than farmers who receive safety guidance and have no such dangerous behaviors, and all the differences are statistically significant (P < 0.05). The group of 24 ~ 34 years old has the highest risk of work-related acute pesticide poisoning (OR = 7.15). CONCLUSION: The incidence rate of work-related acute pesticide poisoning among farmers in Jiangsu Province was higher. Effective measures are needed to prevent and reduce the occurrence of work-related acute pesticide poisoning. We can teach the farmers who spray pesticides about safety guidance, safety application methods and avoiding risky behaviors. PMID- 23433157 TI - [Analysis of needlestick and sharps injuries among medical staff in upper first class hospital]. AB - OBJECTIVE: To investigate the incidence of needlestick and sharps injuries among the medical staff in an upper first-class hospital and its risk factors and to provide a basis for the infection control department of hospital and health administration department to establish the policies for safe injection. METHODS: A questionnaire survey was conducted in 800 healthcare professionals in an upper first-class hospital in Nanjing, China to investigate the incidence of needlestick and sharps injuries in the past year. A total of 641 persons completed the questionnaire, including 239 doctors, 348 nurses, and 54 other healthcare workers. The obtained data were subjected to chi-square test and logistic analysis. RESULTS: Needlestick and sharps injuries occurred in 373 of 641 healthcare professionals, with an incidence rate of 58.19%. There were significant differences in the incidence of needlestick and sharps injuries among the medical staff of different types or in different departments (P < 0.01). The syringe needles, glass, scalp infusion needles, and suture needles were the major medical apparatus that caused needlestick and sharps injuries; the incidence rate of injury caused by suture needles in doctors (48.21%) was significantly higher than that in nurses (6.72%) (P < 0.01), and the incidence rates of injuries caused by syringe needles, scalp infusion needles, and glass in nurses (71.15%, 59.68%, and 49.04%) were significantly higher than those in doctors (46.43%, 6.25%, and 16.96%) (P < 0.01); compared with nurses, the doctors had higher incidence rates of injuries due to body fluid or tissue sample collection, wound flushing, suture, and cutting (P < 0.05); compared with doctors, the nurses had higher incidence rates of injuries due to injection, intravenous infusion, heparin cap sealing, intravenous infusion line connection, and venous or arterial blood collection (P < 0.05). CONCLUSION: Needlestick and sharps injuries are common in medical staff. The results of the study on risk factors provide a basis for the infection control department of hospital and health administration department to establish the policies for safe injection. PMID- 23433158 TI - [Health survey of plant workers for an occupational exposure to ammonium perchlorate]. AB - OBJECTIVE: To understand the occupational hazards of ammonium perchlorate dust on operating workers and to provide the basis preventive measures for protecting the workers' health. METHODS: 36 workers exposed to ammonium perchlorate dust and 48 unexposed workers from one factory were selected as the exposure and control groups. Investigations on the general condition, sampling of dust in the workplaces and a special medical examination were conducted for two groups, including occupational history, clinical manifestations, blood routine test, hepatic and renal functions, indexes of thyroid hormone, spirometric test and chest X-ray. RESULTS: The total dust concentration of AP in the batch plant reached to 51.63 +/- 43.27 mg/m(3), exceeding the U.S. Occupational Safety and Health Administration (OSHA) permission exposure limits. The systolic blood pressure in the exposure group was higher than that of the control group (146.14 +/- 21.03 VS 134.67 +/- 18.58), and the difference was statistically significant (P < 0.05). The detection rates of the cumulative total symptoms, short of breath and skin itch symptoms in the exposure group were significantly higher than those in the control group (86.11% VS 66.67%; 30.56% VS 12.50%) (P < 0.05), respectively. FT(3) level in the exposure group significantly lowered than the control group, and the difference was statistically significant (P < 0.01); The pulmonary function result showed that FEV1/FVC% in the exposure group was lower than that in the control group (106.50 +/- 28.99 VS 111.70 +/- 19.72), but the difference was not significant. X-ray examination revealed one case of pulmonary X-ray abnormalities in the exposure group, diagnosis of pneumoconiosis, and one case with about 1.0 * 1.0 small nodules detected on the left of lung door area in the control group. CONCLUSIONS: The systolic blood pressure of workers in the exposure group was significantly higher, which could not exclude related to the exposure to AP dust; The T(3) levels in the exposure workers were lower than those in the control group, which may due to AP exposure, suggesting that long term chronic exposure to AP dust may affect thyroid function. PMID- 23433159 TI - [Study of mechanical irritation effects in workers exposed to rock wool]. AB - OBJECTIVE: To explore the effects of mechanical irritation to the skin, eyes, and upper respiratory tract in workers exposed to rock wool. METHODS: The gravimetric concentration of total dust and number concentration of fibre in the air of the rock wool workplace were determined . 109 rock wool manufacturing and processing workers were taken as the exposed group, 104 workers from an air separation plant, a papermaking plant and cover making plant were served as control group. All subjects accepted the questionnaire interview and clinical examination of the skin, eyes, nose and the pharynx. RESULTS: 10.1% of the exposed group had the irritant contact dermatitis, which showed linear trend with the current gravimetric concentration of total dust (P < 0.05) but no association with the exposure age (P > 0.05), and the detection rate of conjunctivitis of the exposed group (12.8%) was significantly higher than the control group (2.8%) (P < 0.05). The percentages of shin and eye itching symptoms of the exposed group (54.1% and 42.9%) were significantly higher than the control group (11.5% and 26.5%) (P < 0.05), but the differences among/between the exposed subgroups with different exposure level and different exposure age were not statistically significant (P > 0.05). The differences of the detection rate of chronic rhinitis and chronic pharyngitis and the percentages of the symptoms of nose and pharynx between the exposed group and control group were not statistically significant (P > 0.05), except the rhinorrhea symptom. CONCLUSIONS: Occupational exposure to rock wool had some degree of the mechanical irritation effects on the skin and eyes. The current exposure level of total dust should be emphatically controlled. PMID- 23433160 TI - [Analysis of new pneumoconiosis cases during 2006 to 2011 in Tianjin]. PMID- 23433161 TI - [Coal tar pitch smoke extract-induced pyroptosis in human bronchial epithelial cells]. AB - OBJECTIVE: To explore whether coal tar pitch smoke extract (CTP) induced pyroptosis in human bronchial epithelial cells (BEAS-2B). METHODS: BEAS-2B cells were treated with different concentrations of CTP (1, 3 ug/ml) for 8h and 24 h, respectively. Lactic dehydrogenase (LDH) activity and interleukin-1 beta (IL 1beta) levels in the supernatants of cell culture media were measured with LDH activity or human IL-1beta ELISA kit, respectively. The activity of Caspase-1 was measured with Caspase-1 colorimetric assay kit. RESULTS: The activity of caspase 1 in 1 and 3 ug/ml CTP groups were (9.29 +/- 0.30) and (8.67 +/- 0.59) umol/ml respectively which were both significantly increased compared to that (7.42 +/- 0.59) umol/ml in the control group (P < 0.05) after 8 h exposure, but there was no significant difference in the activity of LDH and levels of IL-1beta in the cell culture media among the CTP and control groups. 24 h after exposure, the activity of LDH in the CTP (1, 3 ug/ml) groups were (1323.03 +/- 28.53) and (1148.45 +/- 16.42) U/dl respectively which were significantly higher than that (1091.93 +/- 26.64) U/dl in the control group (P < 0.05), and the levels of IL 1beta in the CTP (1 and 3 ug/ml) groups were (125.37 +/- 25.00) pg/ml and (92.04 +/- 19.09) pg/ml respectively which were significantly higher than that (46.20 +/ 14.43) pg/ml in the control group (P < 0.05), but there was no significant difference in the activity of Caspase-1 among CTP and control groups (P < 0.05). CONCLUSION: CTP treatment induced early increase in caspase-1 activity followed by the increase in LDH activity and IL-1 levels, indicative of pyroptosis in human bronchial epithelial cells. PMID- 23433162 TI - [One case report on malignant pleural mesothelioma by crocidolite]. PMID- 23433163 TI - [Serum myeloperoxidase activity and serum paraoxonase-1 activity in patients with silicosis and observation subjects and their clinical significance]. AB - OBJECTIVE: To investigate the serum myeloperoxidase (MPO) activity and serum paraoxonase-1 (PON-1) activity in patients with silicosis and observation subjects and their clinical significance. METHODS: Seventy-two patients with silicosis (stage I: 30 cases, stage II: 22 cases, stage III: 20 cases) and 37 observation subjects were selected as a case group, and 110 healthy men were selected as a control group. Serum MPO activity was measured by double-antibody sandwich enzyme-linked immunosorbent assay, and serum PON-1 activity was measured by chemical spectrophotometry. RESULTS: Serum MPO activity was significantly higher in the case group than in the control group [(102.1 +/- 15.7) U/L vs. (62.4 +/- 11.4) U/L, P < 0.01], but serum PON-1 activity was significantly lower in the case group than in the control group [(85.4 +/- 15.7) U/ml vs. (125.4 +/- 13.7) U/ml, P < 0.01]. Serum MPO activity was significantly lower in patients with stages I, II, and III silicosis than in the observation subjects [(91.3 +/- 13.5) U/L, (85.7 +/- 14.4) U/L, and (88.6 +/- 14.5) U/L vs. (128.4 +/- 16.4) U/L, P < 0.01]. Serum PON-1 activity declined as the stage of silicosis increased; serum PON-1 activity was significantly lower in the patients with stages II and III silicosis than in the observation subjects and the patients with stage I silicosis [(70.4 +/- 11.4) U/ml and (67.6 +/- 13.7) U/ml vs. (101.5 +/- 14.0) U/ml and (89.1 +/- 10.1) U/ml, P < 0.01]. CONCLUSION: Serum MPO activity and serum PON-1 activity are valuable for early diagnosis of silicosis and evaluation of patient's condition. PMID- 23433164 TI - [Nassariidete poisoning 21 cases clinical treatment]. PMID- 23433165 TI - [Prevention of the diver acute otitis externa in the large vertical extent saturation diving]. PMID- 23433166 TI - [The control and management of occupational benzene poisoning in United States]. PMID- 23433167 TI - [Determination of alachlor in serum by gas chromatography]. PMID- 23433168 TI - [Method for determining concentration of dichlorvos in serum by gas chromatography]. AB - OBJECTIVE: To develop a method for determining the concentration of dichlorvos in serum by gas chromatography and to provide a basis for clinical diagnosis and monitoring of dichlorvos poisoning. METHODS: The serum (0.5 ml)collected from patients with dichlorvos poisoning was mixed with ethyl acetate (2.0 ml) and underwent shaking/extraction; the obtained liquid was subjected to standing (5 min) and centrifuging (4000 rpm); the obtained supernatant was collected and blow dried with nitrogen and was then dissolved in ethanol (50 ul); 1.0 ul of the obtained liquid was collected and loaded into a glass-packed column; gas chromatography was performed using a nitrogen-phosphorus detector. RESULTS: A linear relationship was found when the concentration of dichlorvos in serum was 5.0 ~ 50.0 ug/ml, with a regression equation of y = 804.13x-691.8 (r = 0.9992). The minimum detectable concentration was 2.0 ug/ml, the recovery rate was 86.8% ~ 94.5%, the relative standard deviation (RSD) was 4.6% ~ 5.5%, with an intra-day RSD of 4.52% ~ 5.21% and an inter-day RSD of 3.56% ~ 5.52%. CONCLUSION: This determination method is easy to operate, efficient, and accurate, and can be used for quickly diagnosing dichlorvos poisoning and quantitatively evaluating treatment outcome. PMID- 23433169 TI - [Involvement of microRNA in pulmonary inflammation and fibrosis]. PMID- 23433170 TI - [Renal injure and metabolic acidosis associated with toluene]. PMID- 23433171 TI - [The role of calcium activated neutral protease in organophosphate-induced delayed neuropathy]. PMID- 23433173 TI - Intra-oral lymphangioma successfully treated using fractional carbon dioxide laser. PMID- 23433172 TI - How effective are the components of active management of the third stage of labor? AB - BACKGROUND: Active management of the third stage of labor is recommended for the prevention of post-partum hemorrhage and commonly entails prophylactic administration of a uterotonic agent, controlled cord traction, and uterine massage. While oxytocin is the first-choice uterotonic, it is not known whether its effectiveness varies by route of administration. There is also insufficient evidence regarding the value of controlled cord traction or uterine massage. This analysis assessed the independent and combined effectiveness of all three interventions, and the effect of route of oxytocin administration on post-partum blood loss. METHODS: Secondary data were analyzed from 39202 hospital-based births in four countries and two clinical regimens: one in which oxytocin was administered following delivery of the baby; the other in which it was not. We used logistic regression to examine associations between clinical and demographic variables and post-partum blood loss >= 700 mL. RESULTS: Among those with no oxytocin prophylaxis, provision of controlled cord traction reduced hemorrhage risk by nearly 50% as compared with expectant management (P < 0.001). Among those with oxytocin prophylaxis, provision of controlled cord traction reduced hemorrhage risk by 66% when oxytocin was intramuscular (P < 0.001), but conferred no benefit when oxytocin was intravenous. Route of administration was important when oxytocin was the only intervention provided: intravenous administration reduced hemorrhage risk by 76% as compared with intramuscular administration (P < 0.001); when combined with other interventions, route of administration had no effect. In both clinical regimens, uterine massage was associated with increased hemorrhage risk. CONCLUSIONS: Recommendations for active management of the third stage of labor should account for setting-related differences such as the availability of oxytocin and its route of administration. The optimal combination of interventions will vary accordingly. PMID- 23433174 TI - Postpartum deep vein thrombosis and pulmonary embolism in twin pregnancy: undertaking of clinical symptoms leading to massive complications. AB - BACKGROUND: Deep Vein Thrombosis (DVT) is an important cause of morbidity and is the first cause of maternal death after delivery in Western Nations. The risk of venous thromboembolism is present throughout the pregnancy and is maximal during postpartum, especially after twin delivery. Many of the signs and symptoms of DVT overlap those of a normal pregnancy causing difficulty for diagnosis. CASE REPORT: We report the case of a 33 year-old woman transferred to our Department one week after caesarean section for twin delivery. She presented with severe abdominal pain, fever, abdominal distension and shortness of breath. She had no personal or family history of thromboembolism. Computerized Tomography Scan revealed right ovarian vein thrombosis, left renal vein thrombosis extending up to the Inferior Vena Cava and pulmonary embolism with bilateral pleural effusion. Caval filter was positioned and anticoagulation therapy associated with antibiotics was instituted. Pancreatitis showed up two days after and was promptly treated. Three months after discharge the caval filter was removed and oral anticoagulation was stopped. During a 12-months follow-up, she remained stable and symptom free. RESULTS: Ovarian vein thrombosis is rare but recognition of signs and symptoms is fundamental to start adequate therapy and avoid potential serious sequelae. The risk for maternal postpartum ovarian vein thrombosis is increased by caesarean section delivery of twins. Such patients should be closely monitored. We illustrated how an underestimated condition can lead to massive complications. PMID- 23433175 TI - Are family practice trainers and their host practices any better? Comparing practice trainers and non-trainers and their practices. AB - BACKGROUND: Family Physician (FP) trainees are expected to be provided with high quality training in well organized practice settings. This study examines differences between FP trainers and non-trainers and their practices to see whether there are differences in trainers and non-trainers and in how their practices are organized and their services are delivered. METHOD: 203 practices (88 non-training and 115 training) with 512 FPs (335 non-trainers and 177 trainers) were assessed using the "Visit Instrument Practice organization (VIP)" on 369 items (142 FP-level; 227 Practice level). Analyses (ANOVA, ANCOVA) were conducted for each level by calculating differences between FP trainees and non trainees and their host practices. RESULTS: Trainers scored higher on all but one of the items, and significantly higher on 47 items, of which 13 remained significant after correcting for covariates. Training practices scored higher on all items and significantly higher on 61 items, of which 23 remained significant after correcting for covariates. Trainers (and training practices) provided more diagnostic and therapeutic services, made better use of team skills and scored higher on practice organization, chronic care services and quality management than non-training practices. Trainers reported more job satisfaction and commitment and less job stress than non-trainers. DISCUSSION: There are positive differences between FP trainers and non-trainers in both the level and the quality of services provided by their host practices. Training institutions can use this information to promote the advantages of becoming a FP trainer and training practice as well as to improve the quality of training settings for FPs. PMID- 23433176 TI - Multiple insecticide resistance mechanisms in Anopheles gambiae s.l. populations from Cameroon, Central Africa. AB - BACKGROUND: Increasing incidence of DDT and pyrethroid resistance in Anopheles mosquitoes is seen as a limiting factor for malaria vector control. The current study aimed at an in-depth characterization of An. gambiae s.l. resistance to insecticides in Cameroon, in order to guide malaria vector control interventions. METHODS: Anopheles gambiae s.l. mosquitoes were collected as larvae and pupae from six localities spread throughout the four main biogeographical domains of Cameroon and reared to adults in insectaries. Standard WHO insecticide susceptibility tests were carried out with 4% DDT, 0.75% permethrin and 0.05% deltamethrin. Mortality rates and knockdown times (kdt50 and kdt95) were determined and the effect of pre-exposure to the synergists DEF, DEM and PBO was assessed. Tested mosquitoes were identified to species and molecular forms (M or S) using PCR-RFLP. The hot ligation method was used to depict kdr mutations and biochemical assays were conducted to assess detoxifying enzyme activities. RESULTS: The An. arabiensis population from Pitoa was fully susceptible to DDT and permethrin (mortality rates>98%) and showed reduced susceptibility to deltamethrin. Resistance to DDT was widespread in An. gambiae s.s. populations and heterogeneous levels of susceptibility to permethrin and deltamethrin were observed. In many cases, prior exposure to synergists partially restored insecticide knockdown effect and increased mortality rates, suggesting a role of detoxifying enzymes in increasing mosquito survival upon challenge by pyrethroids and, to a lower extent DDT. The distribution of kdr alleles suggested a major role of kdr-based resistance in the S form of An. gambiae. In biochemical tests, all but one mosquito population overexpressed P450 activity, whereas baseline GST activity was low and similar in all field mosquito populations and in the control. CONCLUSION: In Cameroon, multiple resistance mechanisms segregate in the S form of An. gambiae resulting in heterogeneous resistance profiles, whereas in the M form and An. arabiensis insecticide tolerance seems to be essentially mediated by enzyme-based detoxification. Synergists partially restored susceptibility to pyrethroid insecticides, and might help mitigate the impact of vector resistance in the field. However, additional vector control tools are needed to further impact on malaria transmission in such settings. PMID- 23433177 TI - Feeding a DHA-enriched diet increases skeletal muscle protein synthesis in growing pigs: association with increased skeletal muscle insulin action and local mRNA expression of insulin-like growth factor 1. AB - Dietary n-3 PUFA have been demonstrated to promote muscle growth in growing animals. In the present study, fractional protein synthesis rates (FSR) in the skeletal muscle of growing pigs fed a DHA-enriched (DE) diet (DE treatment) or a soyabean oil (SO) diet (SO treatment) were evaluated in the fed and feed-deprived states. Feeding-induced increases in muscle FSR, as well as the activation of the mammalian target of rapamycin and protein kinase B, were higher in the DE treatment as indicated by the positive interaction between diet and feeding. In the fed state, the activation of eIF4E-binding protein 1 in the skeletal muscle of pigs on the DE diet was higher than that in pigs on the SO diet (P<0.05). Feeding the DE diet increased muscle insulin-like growth factor 1 (IGF-1) expression (P<0.05) and insulin action (as demonstrated by increased insulin receptor (IR) phosphorylation, P<0.05), resulting in increased IR substrate 1 activation in the fed state. However, no difference in plasma IGF-1 concentration or hepatic IGF-1 expression between the two treatments was associated. The increased IGF-1 expression in the DE treatment was associated with increased mRNA expression of the signal transducer and activator of transcription 5A and decreased mRNA expression of protein tyrosine phosphatase, non-receptor type 3 in skeletal muscle. Moreover, mRNA expression of protein tyrosine phosphatase, non receptor type 1 (PTPN1), the activation of PTPN1 and the activation of NF-kappaB in muscle were significantly lower in the DE treatment (P<0.05). The results of the present study suggest that feeding a DE diet increased feeding-induced muscle protein synthesis in growing pigs, and muscle IGF-1 expression and insulin action were involved in this action. PMID- 23433178 TI - Configurable pattern-based evolutionary biclustering of gene expression data. AB - BACKGROUND: Biclustering algorithms for microarray data aim at discovering functionally related gene sets under different subsets of experimental conditions. Due to the problem complexity and the characteristics of microarray datasets, heuristic searches are usually used instead of exhaustive algorithms. Also, the comparison among different techniques is still a challenge. The obtained results vary in relevant features such as the number of genes or conditions, which makes it difficult to carry out a fair comparison. Moreover, existing approaches do not allow the user to specify any preferences on these properties. RESULTS: Here, we present the first biclustering algorithm in which it is possible to particularize several biclusters features in terms of different objectives. This can be done by tuning the specified features in the algorithm or also by incorporating new objectives into the search. Furthermore, our approach bases the bicluster evaluation in the use of expression patterns, being able to recognize both shifting and scaling patterns either simultaneously or not. Evolutionary computation has been chosen as the search strategy, naming thus our proposal Evo-Bexpa (Evolutionary Biclustering based in Expression Patterns). CONCLUSIONS: We have conducted experiments on both synthetic and real datasets demonstrating Evo-Bexpa abilities to obtain meaningful biclusters. Synthetic experiments have been designed in order to compare Evo-Bexpa performance with other approaches when looking for perfect patterns. Experiments with four different real datasets also confirm the proper performing of our algorithm, whose results have been biologically validated through Gene Ontology. PMID- 23433180 TI - Tramadol plus metamizole combined or not with anti-inflammatory drugs is clinically effective for moderate to severe chronic pain treatment in cancer patients. AB - OBJECTIVE: To test the effectiveness and safety of tramadol plus metamizole combined or not with a non-steroidal anti-inflammatory drug (NSAID) for treating moderate to severe chronic neoplastic pain in dogs, and its impact on quality of life (QL). STUDY DESIGN: Prospective, uncontrolled, open-label, clinical study. ANIMALS: Sixty nine client-owned dogs with multiple forms of cancer and visual analog scale (VAS) pain score >= 40 after receiving NSAIDs for at least 7 days. METHODS: The MN group received metamizole + NSAID, MNT group received metamizole + NSAID + tramadol and MT group received metamizole + tramadol. Pain was scored by the 0 to 100 mm VAS (0 = no pain, 100 = worst pain) and analgesic therapy was considered effective if 25 mm differences in VAS scores were observed between day 0 and the follow ups. The QL was evaluated according to a 0 to 36 scoring method for dogs (0 = worst, 36 = best) and side effects were recorded. Data were registered at day 0 (baseline) and at the first and second follow ups (7 and 14 days after day 0, respectively). RESULTS: The MN group had less analgesia at day 7 (25%) and day 14 (42%) than MNT (59%, p = 0.0274; 76%, p = 0.0251, respectively) and MT groups (69%, p = 0.0151; 81%, p = 0.0341, respectively). The QL scores were lower in the MN group at the first (score 23) and second follow up (score 26) than in MNT (27, p = 0.0847; 30, p = 0.0002) and MT (28, p = 0.0384; 31, p = 0.0001) groups. Side effects were more commonly observed in the MN group (87%) than in MNT (24%, p < 0.0001) and MT groups (25%, p = 0.0003) at the first follow up. CONCLUSIONS AND CLINICAL RELEVANCE: Tramadol plus metamizole combined or not with NSAID were well tolerated and clinically effective to treat moderate to severe pain in dogs with cancer and improved QL. PMID- 23433179 TI - CD154: the atherosclerotic risk factor in rheumatoid arthritis? AB - Atherosclerosis, now regarded as a chronic inflammatory disease of the arterial wall, and its clinical manifestations have increasingly been associated with rheumatoid arthritis (RA), supporting the notion that autoimmune diseases and vascular disorders share common etiological features. Indeed, evidence pertaining to this matter indicates that inflammation and its multiple components are the driving force behind the pathogenesis of these disorders. Interestingly, CD154 and its receptors have emerged as major players in the development of RA and atherosclerosis, which raises the possibility that this axis may represent an important biological link between both complications. Indeed, CD154 signaling elicits critical inflammatory responses that are common to the pathogenesis of both diseases. Here, we provide an overview of the traditional and disease related interrelations between RA and vascular abnormalities, while focusing on CD154 as a potential mediator in the development of atherosclerotic events in RA patients. PMID- 23433181 TI - Antenatal taurine supplementation improves cerebral neurogenesis in fetal rats with intrauterine growth restriction through the PKA-CREB signal pathway. AB - OBJECTIVE: This study seeks to explore whether antenatal supplement of taurine may improve the brain development of fetal rats with intrauterine growth restriction (IUGR) via the protein kinase A-cyclic adenosine monophosphate (cAMP) response element protein (PKA-CREB) pathway. METHODS: Fifteen pregnant rats were randomly divided into control group, IUGR model, and IUGR with antenatal taurine supplement group. Brain tissues were obtained immediately after rats were born. PKA-CREB signal pathway activity and glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels were measured by reverse transcription polymerase chain reaction and immunohistochemistry stains, whereas immunoreactive cells of neuron-specific enolase (NSE) and proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry stains. RESULTS: The results showed that: (1) In the IUGR group, a greater number of PCNA and NSE immunoreactive cells were found in brain tissues compared with controls, and prenatal taurine supplementation led to a further increase. (2) Expression of PKA, CREB, and GDNF were increased in mRNA and protein levels due to taurine supplementation. DISCUSSION: Antenatal taurine supplementation shows effects of promotion of cell proliferation and activation of neurotrophic factors on fetal rat brain in a model of IUGR by activating the PKA-CREB signal pathway, increasing expression of neurotrophic factors, and promoting cell proliferation to counteract neuron loss caused by IUGR. PMID- 23433182 TI - Histone modifications in the male germ line of Drosophila. AB - BACKGROUND: In the male germ line of Drosophila chromatin remains decondensed and highly transcribed during meiotic prophase until it is rapidly compacted. A large proportion of the cell cycle-regulated histone H3.1 is replaced by H3.3, a histone variant encoded outside the histone repeat cluster and not subject to cell cycle controlled expression. RESULTS: We investigated histone modification patterns in testes of D. melanogaster and D. hydei. In somatic cells of the testis envelope and in germ cells these modification patterns differ from those typically seen in eu- and heterochromatin of other somatic cells. During the meiotic prophase some modifications expected in active chromatin are not found or are found at low level. The absence of H4K16ac suggests that dosage compensation does not take place. Certain histone modifications correspond to either the cell cycle-regulated histone H3.1 or to the testis-specific variant H3.3. In spermatogonia we found H3K9 methylation in cytoplasmic histones, most likely corresponding to the H3.3 histone variant. Most histone modifications persist throughout the meiotic divisions. The majority of modifications persist until the early spermatid nuclei, and only a minority further persist until the final chromatin compaction stages before individualization of the spermatozoa. CONCLUSION: Histone modification patterns in the male germ line differ from expected patterns. They are consistent with an absence of dosage compensation of the X chromosome during the male meiotic prophase. The cell cycle-regulated histone variant H3.1 and H3.3, expressed throughout the cell cycle, also vary in their modification patterns. Postmeiotically, we observed a highly complex pattern of the histone modifications until late spermatid nuclear elongation stages. This may be in part due to postmeiotic transcription and in part to differential histone replacement during chromatin condensation. PMID- 23433183 TI - Bevacizumab eye drops delay corneal epithelial wound healing and increase the stromal response to epithelial injury in rats. AB - BACKGROUND: To evaluate the effects of bevacizumab eye drops on corneal epithelial wound healing and the stromal response after epithelial injury in rats. METHODS: We divided 160 Sprague-Dawley male rats into two groups and de epithelized corneas with a microblade. Five percent bevacizumab (Avastin) and antibiotic (Cravit) eyedrops were treated four times daily in the bevacizumab group and antibiotic eye drops only in the control group. Wound area evaluation, enzyme-linked immunosorbent assay, immunofluorescent staining, and real-time polymerase chain reaction were performed with rat corneas. RESULTS: The percentage of wound healing in the bevacizumab group was lower than in the control group at 24, 48 and 72 hours after epithelial debridement (P = 0.02, 0.01 and 0.01). Corneal matrix metalloproteinase-2 (P = 0.02, 0.01 and 0.02), matrix metalloproteinase-9 (P = 0.03, 0.01 and 0.01) and transforming growth factor-beta (P = 0.02, 0.02 and 0.01) proteins in the bevacizumab group were higher than control group at 24, 48, and 72 hours. Matrix metalloproteinase-2, matrix metalloproteinase-9, transforming growth factor-b and a-smooth muscle actin were strongly stained in the bevacizumab corneas compared with control corneas in immunofluorescent staining. Matrix metalloproteinase-2 (P = 0.04, 0.03 and 0.04), matrix metalloproteinase- 9 (P = 0.03, 0.01 and 0.02), transforming growth factor b (P = 0.03, 0.03 and 0.03) and a-smooth muscle actin (P = 0.04, 0.01 and 0.04) messenger RNA levels in the bevacizumab group were also highly expressed compared with the control group at 24, 48, and 72 hours. CONCLUSIONS: The bevacizumab eye drops delay the wound healing and increase stromal response after corneal epithelial injury in rats. PMID- 23433186 TI - Persistent foci of falciparum malaria among tribes over two decades in Koraput district of Odisha State, India. AB - BACKGROUND: Koraput, a predominantly tribe-inhabited and one of the highly endemic districts of Odisha State that contributes a substantial number of malaria cases to the India's total. Control of malaria in such districts would contribute to change the national scenario on malaria situation. Hence, a study was carried out to measure the magnitude of malaria prevalence in the district to strengthen the malaria control activities. METHODS: Prevalence of malaria was assessed through a sample blood survey (SBS) in seven randomly selected community health centres (CHCs). Individuals of all age groups in the villages selected (one in each subcentre) were screened for malaria infection. Both thick and thin smears were prepared from blood samples collected by finger prick, stained and examined for malaria parasites searching 100 fields in each smear. The results of a blood survey (n = 10,733) carried out, as a part of another study, during 1986 87 covering a population of 17,722 spread in 37 villages of Koraput district were compared with the current survey results. Software SPSS version 16.0 was used for data analysis. RESULT: During the current study, blood survey was done in 135 villages screening 12,045 individuals (16.1% of the total population) and among them, 1,983 (16.5%) were found positive for malaria parasites. Plasmodium falciparum was the major malaria parasite species accounted for 89.1% (1,767) of the total positives; Plasmodium vivax and Plasmodium malariae accounted for 9.3% (184) and 0.2% (5), respectively. Gametocytes were found in 7.7% (n = 152) of the positive cases. The majority of parasite carriers (78.9%) were afebrile. The 1986 87 blood survey showed that of 10,733 people screened, 833 (7.8%) were positive for malaria parasites, 714 (85.7%) with P. falciparum, 86 (10.3%) with P. vivax, 12 (1.4%) with P. malariae and 21 (2.5%) with mixed infections. CONCLUSION: The results of the current study indicated a rising trend in transmission of malaria in Koraput district compared to the situation during 1986-87 and indicated the necessity for a focused and reinforced approach for the control of the disease by improving people's access to diagnosis and treatment and ensuring implementation of the intervention measures with adequate coverage and compliance. PMID- 23433184 TI - Transcriptome analysis of Inbred Long Sleep and Inbred Short Sleep mice. AB - Many studies have utilized the Inbred Long Sleep and Inbred Short Sleep mouse strains to model the genetic influence on initial sensitivity to ethanol. The mechanisms underlying this divergent phenotype are still not completely understood. In this study, we attempt to identify genes that are differentially expressed between these two strains and to identify baseline networks of co expressed genes, which may provide insight regarding their phenotypic differences. We examined the whole brain and striatal transcriptomes of both strains, using next generation RNA sequencing techniques. Many genes were differentially expressed between strains, including several in chromosomal regions previously shown to influence initial sensitivity to ethanol. These results are in concordance with a similar sample of striatal transcriptomes measured using microarrays. In addition to the higher dynamic range, RNA-Seq is not hindered by high background noise or polymorphisms in probesets as with microarray technology, and we are able to analyze exome sequence of abundant genes. Furthermore, utilizing Weighted Gene Co-expression Network Analysis, we identified several modules of co-expressed genes corresponding to strain differences. Several candidate genes were identified, including protein phosphatase 1 regulatory unit 1b (Ppp1r1b), prodynorphin (Pdyn), proenkephalin (Penk), ras association (RalGDS/AF-6) domain family member 2 (Rassf2), myosin 1d (Myo1d) and transthyretin (Ttr). In addition, we propose a role for potassium channel activity as well as map kinase signaling in the observed phenotypic differences between the two strains. PMID- 23433187 TI - CartograTree: connecting tree genomes, phenotypes and environment. AB - Today, researchers spend a tremendous amount of time gathering, formatting, filtering and visualizing data collected from disparate sources. Under the umbrella of forest tree biology, we seek to provide a platform and leverage modern technologies to connect biotic and abiotic data. Our goal is to provide an integrated web-based workspace that connects environmental, genomic and phenotypic data via geo-referenced coordinates. Here, we connect the genomic query web-based workspace, DiversiTree and a novel geographical interface called CartograTree to data housed on the TreeGenes database. To accomplish this goal, we implemented Simple Semantic Web Architecture and Protocol to enable the primary genomics database, TreeGenes, to communicate with semantic web services regardless of platform or back-end technologies. The novelty of CartograTree lies in the interactive workspace that allows for geographical visualization and engagement of high performance computing (HPC) resources. The application provides a unique tool set to facilitate research on the ecology, physiology and evolution of forest tree species. CartograTree can be accessed at: http://dendrome.ucdavis.edu/cartogratree. PMID- 23433188 TI - Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome. AB - OBJECTIVE: Acute respiratory distress syndrome (ARDS) frequently complicates critical illness. We hypothesized that an infusion of recombinant human activated protein C (rh-APC), a natural anticoagulant, would attenuate pulmonary coagulopathy and injury. METHODS: In this sub study of a multicenter open-label randomized controlled trial of patients with ARDS, we compared an intravenous (i.v.) infusion of rh-APC (24 mcg kg(-1) h(-1) for 96 h) with placebo. Patients with sepsis or septic shock were excluded. RESULTS: In 27 patients serial non directed bronchoalveolar lavage fluid (NBLF) samples were obtained: 16 patients were treated with rh-APC and 11 patients with placebo. The rh-APC infusion was associated with higher APC levels in plasma during the infusion period of 4 days (P = 0.001), as well as higher APC levels in NBLF up to day 5 after the start of the infusion (P = 0.028). An infusion of rh-APC was associated with lower levels of thrombin-antithrombin complexes (P = 0.009) and soluble tissue factor (P = 0.011) in NBLF, compared with treatment with placebo. An infusion of rh-APC affected fibrinolysis, as plasminogen activator activity levels in NBLF were higher in the patients treated with rh-APC (P = 0.01), presumably as a result of lower NBLF levels of plasminogen activator inhibitor 1, (P = 0.01). The rh-APC infusion decreased the lung injury score (P = 0.005) and simplified the acute physiology score (P = 0.013) on day 5, when compared with baseline. The rh-APC infusion was not associated with bleeding complications. CONCLUSION: An infusion of rh-APC in patients with ARDS attenuates pulmonary coagulopathy and injury. PMID- 23433189 TI - On the origin of emission and thermal quenching of SRSO:Er3+ films grown by ECR PECVD. AB - Silicon nanocrystals embedded in a silicon-rich silicon oxide matrix doped with Er3+ ions have been fabricated by electron cyclotron resonance plasma-enhanced chemical vapor deposition. Indirect excitation of erbium photoluminescence via silicon nanocrystals has been investigated. Temperature quenching of the photoluminescence originating from the silicon nanocrystals and the erbium ions has been observed. Activation energies of the thermally activated quenching process were estimated for different excitation wavelengths. The temperature quenching mechanism of the emission is discussed. Also, the origin of visible emission and kinetic properties of Er-related emission have been discussed in details. PMID- 23433190 TI - The WINROP algorithm and other innovations in the screening for retinopathy of prematurity. PMID- 23433191 TI - Comparison of central corneal thickness measured with anterior segment optical coherence tomography versus ultrasonic pachymetry. AB - PURPOSE: To compare central corneal thickness measured with anterior segment optical coherence tomography (AS-OCT) and ultrasonic pachymetry (UP). METHOD: A prospective, observational and cross-sectional study was performed. The central corneal thickness was measured in 112 eyes of 112 consecutive patients with AS OCT and UP. All examinations were performed by the same examiner. The measurements obtained between the 2 instruments were compared to assess the level of agreement. RESULTS: The average corneal thickness value obtained by AS-OCT was 531.47 +/- 26.23 MUm, while that measured by UP was 532.51 +/- 26.04 MUm. The intraclass correlation coefficient was 0.957 (P <.001). The Student's t-test did not show a statistically significant difference (1.04 +/- 7.70 MUm, P =.158). Finally, the Bland-Altman analysis showed a high level of agreement between 2 methods of measurement. CONCLUSIONS: In the context of normal corneas, there was good agreement between the measurement of central corneal thickness with AS-OCT and UP, although there was a slight overestimation of the measurement using UP (1.04 MUm). PMID- 23433192 TI - Fundus autofluorescence: applications and perspectives. AB - PURPOSE: To describe the findings of the study of autofluorescence of the different retinal diseases included in the study. To determine in which diseases autofluorescence may be more, or just as, useful as fluorescein angiography (FAG) in terms of diagnostic information. MATERIAL AND METHODS: We studied the retinal autofluorescence of 123 eyes of 93 patients, including various diseases of the eye fundus. In all cases we explored the fundus, retinal autofluorescence, and, if indicated, FAG was performed. Analysis of the autofluorescence was performed using the Heidelberg Retina angiography Angiograph 2 (HRA2) Heidelberg Engineering (Germany). RESULTS: The autofluorescence information provided was equal or better (than FAG) in: 68.18% of cases of macular edema, 50% of pigment epithelium detachments, 100% of pigment epithelium atrophies, 100% of central serous chorioretinopathy; 55.55% of choroidal neovascularization, 100% of retinal dystrophies with deposition of lipofuscin, 100% of hard exudates and pre-retinal hemorrhages. CONCLUSIONS: Autofluorescence is a quick and non-invasive examination method, comfortable for both patient and examiner, and with a very short learning curve. It provides diagnostic information about many eye fundus diseases. While more studies and more experience with its use are needed, its interest lies in the possibility of avoiding the performing of angiography in patients with these diseases, and in the additional information autofluorescence provides about the functional situation of cells and retinal pigments. PMID- 23433193 TI - Post-surgical visual outcome and complications in Boston type 1 keratoprosthesis. AB - OBJECTIVE: To describe the visual outcome of patients who underwent Boston type 1 keratoprosthesis (KPro1) implantation, and describe serious sight-threatening post-operative complications. METHODS: We performed an analysis of the clinical records of all patients who underwent Boston keratoprosthesis implantation (BKI)in our institution from May 2006 to February 2011. RESULTS: A total of 41 eyes of 37 patients were included in the final analysis, of whom 22 (59.45%) were male and 15 were (40.54%) female. The mean age was 56.44 years (range 2-90). The most frequent diagnoses were bullous keratopathy, autoimmune diseases, such as Stevens-Johnson syndrome (SJS)/Lyell syndrome (LS), and aniridic keratopathy. The mean number of previous keratoplasties (PK) was 2.36 (range 0-8), the mean number of previous non-PK surgeries was 1.58 (range 0-9). The mean follow-up time was 22.17 months (range 3-46). The mean best corrected visual acuity (BCVA) logMAR before surgery was 2.05 (range 1.10-2.52), and the mean best corrected visual acuity achieved after surgery was 1.16 (range 0.08- 2.70). The most frequent complication was the formation of retroprosthetic membrane (RPM) which appeared in 22 (53.65%) eyes. Of these, 6 (27.27%) appeared after another surgery. Fourteen (63.63%) RPM required treatment, an average of 1.71 (range 1-4) laser YAG applications were performed, and surgical membranectomy was performed in 3 patients. Eleven (26.82%) eyes showed chorioretinal adhesion problems, 6 (14.63%) of which occurred after follow-up of BKI surgery. Infectious complications occurred in 7 (17.07%) cases; 2 (4.87%) patients had infectious keratitis and 5 (12.19%) endophthalmitis. CONCLUSIONS: Visual function improved in most patients. Those with prior multiple ocular surgeries and alterations of systemic immunity such as SJS, LS, and diabetes mellitus are at increased risk for serious sight threatening complications, such as RPM, chorioretinal detachment and infection. Nevertheless, we consider KPro as an effective alternative in patients with multiple ocular pathology and imminent risk of rejection of a new KP. PMID- 23433194 TI - Intraoperative floppy-iris syndrome. AB - OBJECTIVE: Intraoperative-floppy iris syndrome (IFIS) has been recently described. It has been demonstrated that this new syndrome complicates cataract surgery. In this paper we have reviewed the syndrome, and offer practical information specially related to the origin and management of this syndrome and we offer practical information. MATERIAL AND METHODS: A review of the related medical literature using PubMed and Cochrane databases. Combining the search terms tamsulosin, cataract, IFIS and intraoperative floppy iris syndrome, more than 200 articles were found. Eighty-two of them were obtained and analysed. In the remaining only the abstract could be studied. RESULTS: The aetiological association between IFIS and tamsulosin (and to a lesser degree between IFIS and other alpha-antagonists) is well established. Other aetiological associations are doubtful. Most of the literature is centred on cataract surgery. However, a similar syndrome has been described during trabeculectomy. A possible association between these drugs and choroidal detachments has also been described. Undoubtedly tamsulosin treatment makes cataract surgery more difficult and increases the probability of intraoperative complications. Protocols to manage the syndrome have not yet been developed. Intracameral injection of alpha adrenergic agonists seems to be useful. However there is no evidence of the usefulness of discontinuing the drug or using preoperative mydriatics. CONCLUSION: The aetiological and clinic features of the syndrome are well established. More studies are needed to provide scientific evidence on the most appropriate way to cope with this syndrome. PMID- 23433195 TI - Pigmented paravenous retinochoroidal atrophy with macular involvement. AB - CASE REPORT: A 65-year-old female, with poor visual acuity in right eye since childhood, was referred to our hospital. Funduscopic examination revealed bone spicule pigmentation and choroidal and retinal pigment epithelium atrophy along the vascular arcades, with macular involvement in right eye. The patient was diagnosed with pigmented paravenous retinochoroidal atrophy (PPRCA). DISCUSSION: PPRCA is a rare disease, of unknown origin, characterised by retinochoroidal atrophy and retinal pigmentation along retinal veins, generally without macular involvement. Latest publications show a slow progression. No effective treatment is available. PMID- 23433196 TI - Eyelid ectropion caused by glasses. Mechanical centurion syndrome. AB - CASE REPORT: A 73 year-old woman with epiphora and ocular irritation resistant to medical treatment. The lacrimal pathway was permeable and there was no eyelid malposition. On examining the patient with her glasses on, both lower eyelids presented an inner third ectropion. Once the diagnosis was established and the mechanical factor resolved, the clinical symptoms improved within a few days. DISCUSSION: The diagnosis of the eyelid ectropion can be more complex when the ectropion is secondary to wearing glasses. The presence of the epicanthic fold shows the importance of the mechanical factor. In our patient the characteristics of the ectropion were similar to the so-called centurion syndrome. PMID- 23433197 TI - Discrimination of topiramate induced angle closure glaucoma from primary angle closure glaucoma: the triple of age, pattern of clinical presentation and drug history. PMID- 23433198 TI - [Peter Falk, Lieutenant Columbo]. PMID- 23433199 TI - [Eye pathology in the paintings by Piero della Francesca. Segismundo Pandolfo Malatesta's ptosis]. PMID- 23433200 TI - The effects of multistrain probiotic compound on bismuth-containing quadruple therapy for Helicobacter pylori infection: a randomized placebo-controlled triple blind study. AB - BACKGROUND: Evidence has shown benefits of single-strain probiotics for Helicobacter pylori eradication. We investigated the effects of adding a multistrain probiotic compound on bismuth-containing quadruple therapy for H. pylori infection. MATERIALS AND METHODS: Adult patients with peptic ulcer disease and confirmed H. pylori infection (n = 180) were randomized to receive bismuth containing quadruple therapy (omeprazole, bismuth subcitrate, amoxicillin, and clarithromycin) plus a probiotic compound or placebo for 2 weeks. The probiotic compound contained seven bacterial species including Lactobacillus and Bifidobacterium strains and Streptococcus thermophiles. Eradication of H. pylori was assessed 4 weeks after medication by (13) C urea breath test. Other outcomes were dyspepsia symptoms, therapy-related adverse effects, and patient's tolerance. RESULTS: Eighty-four patients in the probiotic and 86 in the placebo group completed the trial. With per-protocol (intention to treat) analysis, H. pylori was eradicated in 82.1% (76.6%) of the probiotic and 84.8% (81.1%) of the placebo group, p = .392 (0.292). Symptoms were significantly improved with similar trends in both groups. Regarding the adverse effects, diarrhea was less frequent (2.2 vs 11.1%, p = .016), while abdominal pain was more frequent (10 vs 2.2%, p = .029) in the probiotic group. The two groups were similar in treatment tolerance (p = .851). CONCLUSIONS: In overall, our studied multistrain probiotic compound has not beneficial effects in the treatment of H. pylori infection. It might be related to the low dosage of our probiotic regimen and/or high frequency of upper gastrointestinal adverse effects which in turn could decrease the eradication efficacy. PMID- 23433201 TI - Mutation Reporter Tool: an online tool to interrogate loci of interest, with its utility demonstrated using hepatitis B virus. AB - BACKGROUND: An online tool, which extracts and summarises nucleotide or amino acid sequence data at specified loci of interest, was developed and tested using the basic core promoter/precore (BCP/PC) region of the hepatitis B virus (HBV). The tool is aimed at researchers without specialist computer skills. METHODS: The tool consists of a web-based front-end, with a CGI script, which runs Python code to generate an output web-page. The Python code searches the input sequence data for a specified anchor motif, after which it generates summary tables and graphs of residue and motif distributions. RESULTS: After the user provides an input file in FASTA format containing aligned sequence data (nucleotides or amino acids) and specifies an anchor motif at a known coordinate, the tool summarizes the nucleotides or amino acids at the specified loci, their frequency and analyzes motif patterns of the loci.The tool can output a graph that displays the frequency of mutations relative to a reference sequence. The tool was used to analyze the BCP/PC region of HBV belonging to subgenotypes A1, A2 and subgenotype D and to serotype HBV. The "Discovery Mode" ignores conserved loci and assists in identifying potential loci of interest. CONCLUSIONS: Although HBV was used to demonstrate the utility of the Mutation Reporter Tool, the tool has wide application as it is genome-agnostic: nucleotide or amino acid sequence data from any organism can be processed. Rapid characterisation of many sequences can be achieved easily when the loci of interest are known. The tool is available online, without charge, at http://hvdr.bioinf.wits.ac.za/tools. PMID- 23433202 TI - Learning the facts in medical school is not enough: which factors predict successful application of procedural knowledge in a laboratory setting? AB - BACKGROUND: Medical knowledge encompasses both conceptual (facts or "what" information) and procedural knowledge ("how" and "why" information). Conceptual knowledge is known to be an essential prerequisite for clinical problem solving. Primarily, medical students learn from textbooks and often struggle with the process of applying their conceptual knowledge to clinical problems. Recent studies address the question of how to foster the acquisition of procedural knowledge and its application in medical education. However, little is known about the factors which predict performance in procedural knowledge tasks. Which additional factors of the learner predict performance in procedural knowledge? METHODS: Domain specific conceptual knowledge (facts) in clinical nephrology was provided to 80 medical students (3rd to 5th year) using electronic flashcards in a laboratory setting. Learner characteristics were obtained by questionnaires. Procedural knowledge in clinical nephrology was assessed by key feature problems (KFP) and problem solving tasks (PST) reflecting strategic and conditional knowledge, respectively. RESULTS: Results in procedural knowledge tests (KFP and PST) correlated significantly with each other. In univariate analysis, performance in procedural knowledge (sum of KFP+PST) was significantly correlated with the results in (1) the conceptual knowledge test (CKT), (2) the intended future career as hospital based doctor, (3) the duration of clinical clerkships, and (4) the results in the written German National Medical Examination Part I on preclinical subjects (NME-I). After multiple regression analysis only clinical clerkship experience and NME-I performance remained independent influencing factors. CONCLUSIONS: Performance in procedural knowledge tests seems independent from the degree of domain specific conceptual knowledge above a certain level. Procedural knowledge may be fostered by clinical experience. More attention should be paid to the interplay of individual clinical clerkship experiences and structured teaching of procedural knowledge and its assessment in medical education curricula. PMID- 23433203 TI - The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. AB - BACKGROUND: Alterations of intestinal microbiota and hypersensitivity to colonic distension are two features of the irritable bowel syndrome (IBS). However, the role of intestinal microbiota in visceral hypersensitivity of IBS patients is far to be established. The aim of our study was to determine whether the intestinal microbiota is involved in the visceral hypersensitivity in IBS. METHODS: The painful response to colorectal distension and colonic mucosal parameters were assessed in gnotobiotic rats. Germfree (GF) rats were inoculated with the fecal microbiota from IBS patients characterized by hypersensitivity to colorectal distension (IBS HMA rats) or from non-hypersensitive healthy volunteers (Healthy HMA rats). Conventional rats were studied as normosensitivity control. Fecal microbial analyses were carried out in human and HMA rats fecal samples using cultural and molecular approaches. KEY RESULTS: The microbial dysbiosis of the IBS gut microbiota (more sulfate-reducing bacteria and Enterobacteriaceae and less bifidobacteria) could be maintained in gnotobiotic rats. The number of abdominal contractions in response to colorectal distensions was significantly higher in IBS HMA rats than in healthy HMA rats. No difference was observed between healthy HMA and conventional rats. Colorectal compliance, epithelial paracellular permeability, and density of colonic mucosal mast cells were similar in the three groups of rats. CONCLUSIONS & INFERENCES: We herein showed that sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota. Mucosal alterations associated with microbiota transfer are not involved in this hypersensitivity. The altered IBS microbiota may have important role in the hypersensitivity characterizing IBS patients through specific bacterial metabolites. PMID- 23433204 TI - A new surveillance indicator identifying optimal timeliness and accuracy: application to the Korean National Notifiable Disease Surveillance System for 2001-2007. AB - Although immediate notification of a case is crucial for epidemic control, clinicians may delay notification due to uncertainties in diagnosis, reflecting a trade-off between timeliness and the accuracy of surveillance. We assessed this trade-off for four epidemic-prone diseases that require immediate notification of suspected cases: shigellosis, typhoid fever, paratyphoid fever, and cholera in the Korean National Notifiable Disease Surveillance System data for 2001-2007. Timeliness was measured as the time to registration (T R), being the time interval from symptom onset to notification by the clinician to the local public health centre. We introduced a new index, 'time-accuracy trade-off ratio' to indicate time saved by clinical vs. laboratory-based notifications. Clinical notifications comprised 34.4% of total notifications, and these showed a shorter median T R than laboratory-based notifications (1-4 days). The trade-off ratio was greatest for shigellosis (3.3 days), and smallest for typhoid fever (0.6 days). A higher trade-off ratio provides stronger evidence for clinical notification without waiting for laboratory confirmation. PMID- 23433205 TI - [Effects of dibutyl phthalate and monobutyl phthalate on testosterone secretion and insulin-like factor 3 expression of Leydig tumor cells in mice]. AB - OBJECTIVE: To observe the effects of dibutyl phthalate (DBP) and monobutyl phthalate (MBP) on the mRNA and protein expression of insulin-like factor 3 (INSL3) in the Leydig tumor cells (MA-10) of mice and the level of testosterone secreted from MA-10 cells. METHODS: The MA-10 cells of mice, used as a cellular model, were exposed to DBP and MBP. The content of testosterone in the supernatant medium was measured by enzyme-linked immunosorbent assay; the mRNA and protein expression levels of INSL3 in MA-10 cells were measured by quantitative PCR and Western Blot. RESULTS: Compared with the control group, MA 10 cells showed increased synthesis of testosterone when exposed to low concentrations of DBP and MBP (10(-9) ~ 10(-6) mol/L) and inhibited synthesis of testosterone when exposed to high concentrations of DBP and MBP (10(-3) mol/L), and the typical two-way effects became more significant as the time went one and the concentrations increased (P < 0.05). Compared with the control group, MA-10 cells showed significantly lower mRNA and protein expression levels of INSL3 when exposed to 10(-6) and 10(-4) mol/L DBP (P < 0.05); MA-10 cells showed increased protein expression of INSL3 when exposed to 10(-7) mol/L MBP, and the mRNA and protein expression levels of INSL3 decreased as the concentration of MBP increased. CONCLUSION: DBP and MBP can inhibit the secretion of testosterone from MA-10 cells at high concentrations, but stimulate the secretion of testosterone at low concentrations. Both DBP and MBP have inhibitory effects on the mRNA and protein expression of INSL3 in MA-10 cells. PMID- 23433206 TI - [Effects of carbon disulfide exposure during peri-implantation on estrogen receptor-alpha expression in uterus and serum level of estrogen in pregnant mice]. AB - OBJECTIVE: To evaluate the effects of carbon disulfide (CS(2)) exposure during peri-implantation on the estrogen receptor-alpha (ER-alpha) expression in the uterus and serum level of estradiol (E(2)) in pregnant mice, and to explore the mechanism of embryotoxicity of CS(2). METHODS: Healthy female mice were exposed to a single dose of CS(2) (631.4 mg/kg) or olive oil (solvent control) on gestational day (GD)3, GD4, GD5, or GD6. At different time points after exposure, the serum E(2) levels of the pregnant mice were measured by enzyme-linked immunosorbent assay, and the expression levels of ER-alpha in the uterus were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot. RESULTS: Compared with the control group, the GD3, GD4, GD5, and GD6 exposure groups showed significantly decreased serum E(2) levels on day 7 of gestation (P < 0.05); the GD3 and GD5 exposure groups showed significantly decreased serum E(2) levels on day 6 of gestation (P < 0.05). The expression level of ER-alpha in the GD 4 exposure group was 23.6% lower than that in the control group on day 5 of gestation, and the expression level of ER-alpha in the GD 5 exposure group was 72.9% lower than that in the control group on day 6 of gestation (P < 0.05); the GD 3 and GD 6 exposure groups showed lower expression levels of ER-alpha than the control group at any time point, but no significant difference was found (P > 0.05). CONCLUSION: CS(2) exposure during peri implantation can reduce the ER-alpha expression in the uterus and the serum level of E(2) in pregnant mice, which may be one of the mechanisms of embryotoxicity of CS(2). PMID- 23433207 TI - [Effects of bromopropane exposure on expression of DNA methyltransferases and level of histone acetylation in testis of male rats]. AB - OBJECTIVE: To investigate the changes in the expression of DNA methyltransferases (DNMTs) and activities of histone acetyltransferase (HAT) and histone deacetylase (HDAC) in the testis of male rats exposed to bromopropanes (BPs). METHODS: Twenty seven male rats were randomly divided into three groups to be intraperitoneally injected with 1-BP,2-BP, or corn oil (as a control) for two weeks. The sperm count and morphology in the epididymis were evaluated. The mRNA expression of DNMT1, DNMT3a, and DNMT3b and activities of HAT and HDAC in the testis were measured by quantitative real-time PCR and ELISA. RESULTS: Compared with the control group, the BP exposure groups showed significant decreased absolute and relative sperm counts; the proportion of tailless sperm increased in the 1-BP exposure group, while the proportion of sperm with abnormal heads increased in the 2-BP exposure group. The 2-BP exposure group had significantly lower mRNA expression of DNMT1, DNMT3a, and DNMT3b than the control group (P < 0.05). There were no significant differences in the activities of HAT and HDAC between the control group and 1-BP exposure group; the 2-BP exposure group showed significantly higher HAT activity than the control group (P < 0.05), but no significant difference was found in HDAC activity between them. CONCLUSION: Exposure to 2-BP might induce abnormal DNA methylation and histone acetylation, and epigenetic regulation might play an important role in the reproductive toxicity of 2-BP. PMID- 23433208 TI - [Relationship between occupational stress and type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate the association of occupational stress and related factors with type 2 diabetes mellitus (T2MD). METHODS: In case-control study, a questionnaire survey was conducted in 201 T2MD patients and 201 controls, who were selected from the staff members of organizations, enterprises, and institutions in Ningxia Hui Autonomous Region, China according to inclusion and exclusion criteria, to acquire the information on general condition and occupational stress. These subjects also underwent physical examinations and blood biochemical analyses. RESULTS: The T2MD group had significantly higher total occupational stress score, as well as the scores on such factors as workload, interpersonal relationship, and home/work balance than the control group (P < 0.01). After adjustment for age, gender, education level, smoking, and drinking, the odds ratios for T2MD were 2.538 and 3.075 in the people with moderate and severe stress, respectively, compared to those with mild stress. The risk factors for T2MD included drinking, family history of diabetes, waist circumference, triglyceride level, and total occupational stress score, while the protective factors included educational level and high-density lipoprotein level. CONCLUSION: Occupational stress is associated with the incidence of T2MD; the higher the degree of stress, the greater the risk of T2MD. Relevant measures should be taken to reduce the occupational stress or improve the ability of workers to cope with the stress, thus decreasing the incidence of T2MD among occupational population. PMID- 23433209 TI - [Effect of aluminum trichloride on abnormal phosphorylation of tau protein in SH SY5Y cells]. AB - OBJECTIVE: To investigate the effect of aluminum trichloride on the abnormal phosphorylation of tau protein in SH-SY5Y cells. METHODS: SH-SY5Y cells were assigned to control group and aluminum trichloride exposure groups (200, 400, and 800 umol/L Al(3+)). The cell morphology was observed after 48 hours of exposure; the cell viability was measured by CCK-8 assay; total protein was extracted from the cells, and the expression of phospho-tau (p-tau) 181, 231, 262, and 396 and tau 5 was measured by Western blot. RESULTS: As the Al(3+) concentration rose, the number of living SH-SY5Y cells decreased, and the synapses of the cells retracted. The viability of cells exposed to 800 umol/L Al(3+) was significantly lower than that of the control group (P < 0.05). The 200, 400, and 800 umol/L Al(3+) exposure groups showed significantly higher expression of p-tau 181, 231, and 396 and tau5 than the control group (P < 0.05), and the 800 umol/L Al(3+) exposure group showed significantly higher expression of p-tau 262 than the control group (P < 0.05). CONCLUSION: Under the present experimental conditions, aluminum trichloride has toxic effect on SH-SY5Y cells and can lead to abnormal expression of p-tau 181, 231, and 396 and tau 5 at low Al(3+) concentration. PMID- 23433210 TI - [Changes in Ca(2+)concentration and caspase-3 expression and their relationship in Raji cells exposed to electromagnetic radiation]. AB - OBJECTIVE: To study the effects of electromagnetic pulse (EMP), S-band high power microwave (S-HPM), and X-band high power microwave (X-HPM) on the Ca(2+) concentration and caspase-3 expression in Raji cells and the relationship between Ca(2+) concentration and caspase-3 expression, and to investigate the regulatory mechanism of electromagnetic radiation damage. METHODS: Raji cells were cultured conventionally. Some cells were irradiated by EMP, S-HPM, and X-HPM in the logarithmic growth phase for 6 hours and then collected; others received sham irradiation as a control. The Ca(2+) concentration in the cells was measured by laser scanning confocal microscope; the caspase-3 expression in the cells was evaluated by Western blot. RESULTS: Compared with the control group (Ca(2+) fluorescence intensity = 43.08 +/- 2.08; caspase-3 expression level = 0.444 +/- 0.13), the EMP,S-HPM, and X-HPM groups had significantly increased Ca(2+) concentrations, with Ca(2+) fluorescence intensities of 69.56 +/- 1.71, 50.06 +/- 1.89, and 70.68 +/- 1.59, respectively (P < 0.01), and had upregulated caspase-3 expression, with expression levels of 0.964 +/- 0.12, 0.586 +/- 0.16, and 0.970 +/- 0.07, respectively (P < 0.01). Each of the EMP and X-HPM groups had significantly higher Ca(2+) fluorescence intensity and caspase-3 expression level than the S-HPM group (P < 0.01), but there were no significant differences between the EMP and X-HPM groups. The linear regression analysis showed that the caspase-3 expression was upregulated as the Ca(2+) concentration increased, with a positive correlation between them (P < 0.01). CONCLUSION: EMP, S-HPM, and X-HPM cause damage probably by increasing the Ca(2+) concentration in cells and in turn inducing caspase-3 overexpression. PMID- 23433211 TI - [Effects of subchronic benzo[a]pyrene exposure on hippocampal cholinergic system in rats]. AB - OBJECTIVE: To observe the effects of subchronic benzo[a]pyrene (B[a]P) exposure on the neurobehavior and hippocampal acetylcholine (Ach) level, acetylcholinesterase (AChE) activity, and mRNA and protein expression of nicotinic acetylcholine receptor alpha7 subtype (nAChR alpha7) in rats, and to investigate the neurotoxic mechanism of B[a]P. METHODS: Sixty healthy male SD rats were randomly divided into blank control group, solvent control group, and B [a]P exposure groups. Each rat in the exposure groups was intraperitoneally injected with B[a]P at 1.0, 2.5, or 6.25 mg/kg once every other day for 90 days. The learning and memory ability of the rats was examined by Morris water maze test and step-down test; the hippocampal Ach level was measured by alkaline hydroxylamine method; the AChE activity was measured by DNTB method; the mRNA and protein expression levels of hippocampal nAChR alpha7 were measured by quantitative PCR and Western blot. RESULTS: The 2.5 and 6.25 mg/kg B[a]P exposure groups showed significantly lower learning and memory abilities than the blank control group and solvent control group (P < 0.05); also, the two groups had significantly lower hippocampal Ach levels than the blank control group, solvent control group, and 1.0 mg/kg B[a]P exposure group (P < 0.05). The 6.25 mg/kg B[a]P exposure group showed significantly lower hippocampal AChE activity than the blank control group, solvent control group, and 1.0 mg/kg B[a]P exposure group (P < 0.05). There were no significant differences in the mRNA and protein expression levels of nAChR alpha7 among all groups (P > 0.05). The hippocampal Ach level was negatively correlated with the mean escape latency period and total distance travelled (r = -0.567, P < 0.01; r = -0.503, P < 0.01) but positively correlated with the time in platform quadrant (r = 0.800, P < 0.01). CONCLUSION: Subchronic B[a]P exposure may impair the learning and memory ability in rats, which is related to the downregulation of hippocampal Ach level. PMID- 23433212 TI - [Effect of aluminum exposure on cognitive function in electrolytic workers and its influential factors]. AB - OBJECTIVE: To clarify the effect of aluminum exposure on the cognitive function in electrolytic workers and the prevalence of mild cognitive impairment (MCI) among them by prevalence survey, and to investigate its influential factors. METHODS: Sixty-six retired workers from the electrolysis workshop of an electrolytic aluminum plant were selected as an aluminum exposure group, while 70 retired workers from a flour mill in the same region were selected as a control group. MCI patients were screened out by Mini-Mental State Examination (MMSE); the blood aluminum level was measured by inductively coupled plasma-mass spectrometry; multivariate statistical analysis was used to investigate the influential factors for MMSE scores and the correlation between blood aluminum level and MCI prevalence. RESULTS: The aluminum exposure group showed a significantly higher blood aluminum level than the control group (25.18 +/- 2.65 ug/L vs 9.97 +/- 2.83 ug/L, P < 0.01). The total MMSE score of the aluminum exposure group (26.13 +/- 2.57) was significantly lower than that of the control group (27.89 +/- 1.91) (P < 0.05), particularly the scores on time and place orientation, short-term memory, calculation ability, and language skill (P < 0.05). The detection rate of MCI was significantly higher in the aluminum exposure group (18.2%) than in the control group (5.7%) (P < 0.01). The main influential factors for MMSE scores were gender, age, education level, and blood aluminum level. The logistic regression analysis indicated that the MCI prevalence was significantly correlated with blood aluminum level in the study population (OR = 1.168, P < 0.01). CONCLUSION: Long-term exposure to aluminum can cause cognitive disorders in electrolytic workers and may be one of the risk factors for MCI. Advanced age, male, low education level, and high blood aluminum level may be high-risk factors for cognitive impairment. PMID- 23433213 TI - [Inductive effect of zinc oxide nanoparticles on interleukin 8 gene expression in human bronchial epithelial cells and its regulatory mechanism]. AB - OBJECTIVE: To clarify the effect of zinc oxide nanoparticles (ZnO-NPs) (30 nm in diameter) on the interleukin 8 (IL-8) gene expression in human bronchial epithelial cells (BEAS-2B) and its regulatory mechanism. METHODS: BEAS-2B cells were used in the study. The MTT assay was employed to evaluate the damage to BEAS 2B cells by ZnO-NPs. RT-PCR and ELISA were used to measure the mRNA and protein expression levels of IL-8 in the BEAS-2B cells exposed to ZnO-NPs. The IL-8 mRNA decay assay was used to determine the effect of ZnO-NPs on IL-8 mRNA stability. RESULTS: Exposure to ZnO-NPs significantly increased the level of IL-8 mRNA in BEAS-2B cells and the level of IL-8 protein in supernatant medium. The transcription inhibitor significantly reduced the mRNA expression of IL-8 induced by ZnO-NPs. ZnO-NPs significantly delayed IL-8 mRNA degradation in the BEAS-2B cells that were pretreated with actinomycin D for terminating IL-8 mRNA synthesis. CONCLUSION: ZnO-NPs can increase the mRNA and protein expression levels of IL-8 and IL-8 mRNA stability in BEAS-2B cells. PMID- 23433214 TI - [Association of vitamin D receptor gene haplotypes and genotype combinations with susceptibility to occupational elevated blood lead]. AB - OBJECTIVE: To investigate the association of the haplotypes and genotype combinations of vitamin D receptor (VDR) BsmI (rs1544410), Tru9I (rs757343), ApaI (rs7975232), and TaqI (rs731236) with the susceptibility to elevated blood lead in Chinese Han population. METHODS: According to Diagnostic Criteria of Occupational Chronic Lead Poisoning (GBZ 37-2002) and Occupational Exposure Limits for Hazardous Agents in the Workplace Part 1: Chemical Hazardous Agents (GBZ 2.1-2007), the workers were divided into high-exposure group (lead dust >= 0.05 mg/m(3), lead fume >= 0.03 mg/m(3)) and low-exposure group based on the concentrations of lead fume and lead dust in the workplace. The high-exposure group was further divided into normal-blood lead subgroup and high-blood lead subgroup. Fasting peripheral venous blood (5 ml) was collected using a heparin tube; genomic DNA was extracted from the peripheral blood cells with a Qiagen kit; single nucleotide polymorphisms were detected by allelic discrimination assay using TaqMan probes (carrying fluorescent dyes); haplotypes were analyzed and compared by Haploview. RESULTS: VDR BsmI, Tru9I, ApaI, and TaqI were in Hardy Weinberg equilibrium between the normal-blood lead subgroup and high-blood lead subgroup (P > 0.05). Compared with haplotype CCCA which had the highest distribution frequency, haplotypes CCAA and CTCA were the high-risk factors for elevated blood lead (OR = 1.814, 95%CI = 1.055 ~ 3.119; OR = 1.919, 95%CI = 1.040 ~ 3.540). Compared with genotype combination CC + CC + CC + AA which had the highest distribution frequency, genotype combination CC + CC + AC + AA was the high-risk factor for elevated blood lead (OR = 2.800, 95%CI = 1.282 ~ 6.116). CONCLUSION: As for VDR BsmI, Tru9I, ApaI, and TaqI, haplotypes CCAA and CTCA and genotype combination CC + CC + AC + AA are associated with the susceptibility to elevated blood lead. PMID- 23433215 TI - Measurement of respiratory system compliance and respiratory system resistance in healthy dogs undergoing general anaesthesia for elective orthopaedic procedures. AB - OBJECTIVE: The aim of this study was to investigate normal values for the dynamic compliance of the respiratory system (Crs) and respiratory system resistance (Rrs) in mechanically ventilated anaesthetized dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: Forty healthy dogs undergoing elective orthopaedic surgery. Body weight was (mean +/- SD) 26.8 +/- 10.7 kg (range: 1.9-45.0 kg), age 4.7 +/- 2.9 years (range: 0.1-10.6 years). METHODS: Dogs were premedicated with acepromazine and methadone administered intramuscularly and anaesthesia induced with propofol intravenously. After endotracheal intubation the dog's lungs were connected to an appropriate breathing system depending on body weight and isoflurane in oxygen administered for maintenance of anaesthesia. The lungs were ventilated mechanically with variables set to maintain normocapnia (end-tidal carbon dioxide concentration 4.7-6.0 kPa). Peak inspiratory pressure, Crs, Rrs, tidal volume, respiratory rate and positive end-expiratory pressure were recorded at 5, 30, 60, 90 and 120 minutes after start of mechanical ventilation. Cardiovascular variables were recorded at time of collection of respiratory data. RESULTS: General additive modeling revealed the following relationships: Crs =[0.895 * body weight (kg)] + 8.845 and Rrs=[-0.0966 * body weight (kg)] + 6.965. Body weight and endotracheal tube diameter were associated with Crs (p<0.001 and p=0.002 respectively) and Rrs (p=0.017 and p=0.002 respectively), body weight being linearly related to Crs and inversely to Rrs. CONCLUSION AND CLINICAL RELEVANCE: Body weight was linearly related to Crs while Rrs has an inverse linear relationship with body weight in mechanically ventilated dogs. The derived values of Crs and Rrs may be used for monitoring of lung function and ventilation in healthy dogs under anaesthesia. PMID- 23433216 TI - Perspectives about and approaches to weight gain in pregnancy: a qualitative study of physicians and nurse midwives. AB - BACKGROUND: Over one third of reproductive age women in the US are obese. Pregnancy is a strong risk factor for obesity, with excess weight gain as the greatest predictor of long term obesity. The majority of pregnant women gain more weight than recommended by the Institute of Medicine guidelines. The objective of this study was to understand prenatal care providers' perspectives on weight gain during pregnancy. METHODS: Semi-structured qualitative interviews of 10 prenatal care providers (three family physicians, three obstetricians, and four nurse midwives) at a University Hospital in the Midwest, that included the ranking of important prenatal issues, and open-ended questions addressing: 1) general perceptions; 2) approach with patients; and 3) clinical care challenges. RESULTS: Providers felt that appropriate weight gain during pregnancy was not a high priority. Many providers waited until patients had gained excess weight before addressing the issue, were not familiar with established guidelines, and lacked resources for patients. Providers also believed that their counseling had low impact on patients, avoided counseling due to sensitivity of the topic, and believed that patients were more influenced by other factors, such as their family, habits, and culture. CONCLUSIONS: Both providers and patients may benefit from increased awareness of the morbidity of excess weight gain during pregnancy. Practice-level policies that support the monitoring and management of weight gain during pregnancy could also improve care. Research that further investigates the barriers to appropriate weight gain is warranted. PMID- 23433217 TI - Early community-based family practice elective positively influences medical students' career considerations--a pre-post-comparison. AB - BACKGROUND: Demographic change and recruitment problems in family practice are increasingly threatening an adequate primary care workforce in many countries. Thus, it is important to attract young physicians to the field. The purpose of the present study was to examine the effect of an early community-based 28-h family practice elective with one-to-one mentoring on medical students' consideration of family practice as a career option, their interest in working office-based, and several perceptions with regard to specific aspects of a family physician's work. METHODS: First- and second-year medical students completed questionnaires before and after a short community-based family practice elective, consisting of a preparatory course and a community-based practical experience with one-to-one mentoring by trained family physicians. RESULTS: We found a significantly higher rate of students favoring family practice as a career option after the elective (32.7% vs. 26.0%, p = 0.039). Furthermore, the ranking of family practice among other considered career options improved (p = 0.002). Considerations to work office-based in the future did not change significantly. Perceptions regarding a family physician's job changed positively with regard to the possibility of long-term doctor-patient relationships and treatment of complex disease patterns. The majority of the students described identification with the respective family physician tutor as a professional role model and an increased interest in the specialty. CONCLUSIONS: Our results indicate that a short community-based family practice elective early in medical education may positively influence medical students' considerations of a career in family practice. Furthermore, perceptions regarding the specialty with significant impact on its attractiveness may be positively adjusted. Further research is needed to evaluate the influence of different components of a family practice curriculum on the de facto career decisions of young physicians after graduation. PMID- 23433218 TI - A preliminary study of the psychological differences in infertile couples and their relation to the coping styles. AB - BACKGROUND: Studies from Western countries have observed that couples undergoing infertility treatment suffer various physical and psychological difficulties at a higher frequency than the comparable general population. These relate to treatment challenges and other psychosocial stressors, often influenced by coping style, personality factors and available support systems. There is paucity of studies in non-Western populations. OBJECTIVE: The aim of this pilot investigation was to evaluate characteristics and gender differences in perceived psychological difficulties reported by infertile Malaysian couples. In particular, depression, anxiety and stress, along with correlated coping styles, were examined between spouses. METHODS: Demographic information, including age, ethnicity and duration and causes of infertility, were collected from participants treated within a fertility clinic. The Depression, Anxiety and Stress Scale (DASS) and Coping Inventory for Stressful Situation (CISS) were completed to measure psychological distress and coping styles. RESULTS: Depression, anxiety and stress-related difficulties were reported at significantly higher frequency by wives than husbands (p<0.05). There were no significant differences in coping styles between wives and husbands. However, emotional-oriented coping style was associated with significantly higher levels of depression, anxiety and stress (p<0.05) within the overall sample with odds ratios of 2.5, 3.0 and 1.5, respectively. CONCLUSION: The study confirms that, as with Western subjects, Malaysian infertile couples demonstrate the vulnerability to psychological distress that occurs more frequently among wives than husbands. As anticipated, emotional coping style was associated with greater distress in both genders. PMID- 23433219 TI - The risk and associated factors of methamphetamine psychosis in methamphetamine dependent patients in Malaysia. AB - OBJECTIVE: The objective of this study was to determine the risk of lifetime and current methamphetamine-induced psychosis in patients with methamphetamine dependence. The association between psychiatric co-morbidity and methamphetamine induced psychosis was also studied. METHODS: This was a cross-sectional study conducted concurrently at a teaching hospital and a drug rehabilitation center in Malaysia. Patients with the diagnosis of methamphetamine based on DSM-IV were interviewed using the Mini International Neuropsychiatric Interview (M.I.N.I.) for methamphetamine-induced psychosis and other Axis I psychiatric disorders. The information on sociodemographic background and drug use history was obtained from interview or medical records. RESULTS: Of 292 subjects, 47.9% of the subjects had a past history of psychotic symptoms and 13.0% of the patients were having current psychotic symptoms. Co-morbid major depressive disorder (OR=7.18, 95 CI=2.612-19.708), bipolar disorder (OR=13.807, 95 CI=5.194-36.706), antisocial personality disorder (OR=12.619, 95 CI=6.702-23.759) and heavy methamphetamine uses were significantly associated with lifetime methamphetamine-induced psychosis after adjusted for other factors. Major depressive disorder (OR=2.870, CI=1.154-7.142) and antisocial personality disorder (OR=3.299, 95 CI=1.375-7.914) were the only factors associated with current psychosis. CONCLUSION: There was a high risk of psychosis in patients with methamphetamine dependence. It was associated with co-morbid affective disorder, antisocial personality, and heavy methamphetamine use. It is recommended that all cases of methamphetamine dependence should be screened for psychotic symptoms. PMID- 23433220 TI - Suicide ideation and intent in Malaysia: a review of the literature. AB - The aim of this paper was to review the literature on suicide ideation and intent in Malaysia. PsyINFO, PubMed, Medline databases from 1845 to 2012 and detailed manual search of local official reports from Ministry of Health, Malaysian Psychiatric Association and unpublished dissertations from 3 local universities providing postgraduate psychiatric training, were included in the current review. A total of 13 studies on suicide ideation and intent in Malaysia were found and reviewed. The review showed that research on suicide ideation and intent in Malaysia was fragmented and limited, at best. Approximately 50% of existing research on suicide ideation and intent simply focused on sociodemographic data. Fifty-four percent of the data were obtained from hospitals. No study has been conducted on treatment and interventions for suicide ideation and intent. None of the studies used validated suicide scales. The impact of culture was rarely considered. It was clear from the review that for researchers, clinicians and public health policy makers to gain a better understanding of suicide behavior especially suicide ideation and intent in Malaysia, more systematic and empirically stringent methodologies and research frameworks need to be used. PMID- 23433221 TI - Risk of hypertension in patients with bipolar disorder in Taiwan: a population based study. AB - OBJECTIVE: To examine the prevalence, incidence, and risk factors of hypertension in patients with bipolar disorder in Taiwan. METHOD: The National Health Research Institute provided a database of 1,000,000 random subjects for study in Taiwan. Study subjects >= 18 years or older had at least one service claim during 2005 for either outpatient or inpatient care, with a primary or secondary diagnosis of hypertension combined with antihypertensive drug treatment were identified. We also compared the incidence of hypertension in patients with bipolar disorder and the general population from 2006 through 2010. RESULTS: The 1-year prevalence of hypertension in patients with bipolar disorder was higher than the general population (18.13% vs. 13.22%, odds ratio, 1.43; 95% confidence interval, 1.25 1.64) in Taiwan. Compared with the general population, patients with bipolar disorder had a higher prevalence of hypertension among 18- to 39-year-olds and 40 to 59-year-olds, in both sexes, and in the group with lower socioeconomic status. The average annual incidence of hypertension in patients with bipolar disorder from 2006 to 2010 was higher than the general population (2.83% vs. 1.99%, risk ratio, 1.40; 95% confidence interval, 1.20-1.62). Patients with bipolar disorder had a higher incidence of hypertension among 18- to 39-year-olds and 40- to 59-year-olds and in both sexes compared with the general population. CONCLUSIONS: Patients with bipolar disorder had a higher prevalence and a higher incidence of hypertension than those in the general population. Prevention, early detection, and comprehensive treatment of hypertension are important issues for patients with bipolar disorder. PMID- 23433222 TI - Psychometric properties of the Chinese version of Strength and Difficulties Questionnaire. AB - This study aimed to establish the norms and to examine the psychometric properties of the Chinese version of the Strengths and Difficulties Questionnaire (SDQ). Sample included a representative sample of 3534 students (grades 1 to 8) from one city and one suburb each in Northern and Southern Taiwan by using a multistage sampling method and 211 psychiatric outpatients diagnosed with attention-deficit hyperactivity disorder (ADHD), aged 6 to 15, consecutively recruited from a medical center in Taipei. All the parents and teachers and participants with grade 4 or higher completed the SDQ. Parents and teachers also completed the Child Behavior Checklist and the measures about inattention, hyperactivity, and oppositional symptoms. Similar to Western studies, principal component analyses confirmed the five psychological dimensions of the SDQ for the parent, teacher, and student forms. The three forms of the Chinese SDQ showed satisfactory test-retest reliability, internal consistency, concurrent validity, and discriminant validity. All the subscales of the three forms of the Chinese SDQ clearly distinguished clinical participants with ADHD from school-based participants. Like Western studies, our findings indicate that the Chinese SDQ demonstrates a reliable and valid instrument for measuring internalizing, externalizing, and prosocial behaviors in Taiwanese child and adolescent population. PMID- 23433223 TI - Sex differences in verbal fluency during adolescence: a functional magnetic resonance imaging study in gender dysphoric and control boys and girls. AB - INTRODUCTION: In the literature, verbal fluency (VF) is generally described as a female-favoring task. Although it is conceivable that this sex difference only evolves during adolescence or adulthood under influence of sex steroids, this has never been investigated in young adolescents. AIM: First, to assess sex differences in VF performance and regional brain activation in adolescents. Second, to determine if untreated transsexual adolescents differ from their sex of birth with regard to VF performance and regional brain activation. METHOD: Twenty-five boys, 26 girls, 8 Male-to-Female transsexual adolescents (MtFs), and 14 Female-to-Male transsexual adolescents (FtMs) were tested in a cross-sectional study, while performing a phonetic and semantic VF task within an MRI scanner. MAIN OUTCOME MEASURES: Functional MRI response during VF task. RESULTS: Boys and girls produced similar amounts of words, but the group MtFs produced significantly more words in the phonetic condition compared to control boys, girls, and FtMs. During the semantic condition, no differences were found. With regard to brain activity, control boys showed more activation in the right Rolandic operculum, a small area adjacent to Broca's area, compared to girls. No significant differences in brain activity were found comparing transsexual adolescents, although sub-threshold activation was found in the right Rolandic operculum indicating a trendwise increase in activation from control girls to FtMs to MtFs to control boys. CONCLUSIONS: The better performance of MtFs is consistent with our expectation that MtFs perform better on female-favoring tasks. Moreover, they produced more words than girls and FtMs. Even though a trendwise linear increase in brain activity between the four groups only approached significance, it may indicate differences in individuals with gender identity disorder compared to their birth sex. Although our findings should thus be interpreted with caution, they suggest a biological basis for both transgender groups performing in-between the two sexes. PMID- 23433224 TI - Development of an in vitro drug sensitivity assay for Trichuris muris first-stage larvae. AB - BACKGROUND: Trichuriasis represents a major public health problem in the developing world and is regarded as a neglected disease. Albendazole and mebendazole, the two drugs of choice against trichuriasis display only moderate cure rates, hence alternative drugs are needed. To identify candidate compounds, in vitro drug sensitivity testing currently relies on the adult Trichuris muris motility assay. The objective of the present study was to develop a simple and cost-effective drug sensitivity assay using Trichuris muris first-stage larvae (L1). METHODS: Several potential triggers that induce hatching of T. muris were studied, including gastrointestinal enzymes, acidic environment and intestinal microflora. Next, optimal culture conditions for T. muris L1 were determined assessing a wide range of culture media. T. muris L1 were incubated in the presence of mebendazole, ivermectin, nitazoxanide, levamisole or oxantel pamoate at 37 degrees C. The viability of the parasites was evaluated microscopically after 24 hours. The usefulness of fluorescent markers (resazurin, calcein AM, ethidium homodimer-1 or fluorescein-conjugated albumin) in drug sensitivity testing was also assessed. RESULTS: The established L1 motility assay provided accurate and reproducible drug effect data in vitro. IC50 values for oxantel pamoate, levamisole and nitazoxanide were 0.05, 1.75 and 4.43 MUg/mL, respectively. Mebendazole and ivermectin failed to show any trichuricidal effect on L1. No correlation was found between data from the four fluorescent markers and the comparative motility assay. CONCLUSIONS: The motility assay based on L1 was found suitable for drug sensitivity screening. It is rather simple, cost effective, time-saving and sustains medium-throughput testing. Furthermore, it greatly reduces the need for the animal host and is therefore more ethical. None of the viability markers assessed in this study were found to be satisfactory. PMID- 23433225 TI - Convergent evolution of heat-inducibility during subfunctionalization of the Hsp70 gene family. AB - BACKGROUND: Heat-shock proteins of the 70 kDa family (Hsp70s) are essential chaperones required for key cellular functions. In eukaryotes, four subfamilies can be distinguished according to their function and localisation in different cellular compartments: cytosol, endoplasmic reticulum, mitochondria and chloroplasts. Generally, multiple cytosol-type Hsp70s can be found in metazoans that show either constitutive expression and/or stress-inducibility, arguing for the evolution of different tasks and functions. Information about the hsp70 copy number and diversity in microbial eukaryotes is, however, scarce, and detailed knowledge about the differential gene expression in most protists is lacking. Therefore, we have characterised the Hsp70 gene family of Paramecium caudatum to gain insight into the evolution and differential heat stress response of the distinct family members in protists and to investigate the diversification of eukaryotic hsp70s focusing on the evolution of heat-inducibility. RESULTS: Eleven putative hsp70 genes could be detected in P. caudatum comprising homologs of three major Hsp70-subfamilies. Phylogenetic analyses revealed five evolutionarily distinct Hsp70-groups, each with a closer relationship to orthologous sequences of Paramecium tetraurelia than to another P. caudatum Hsp70-group. These highly diverse, paralogous groups resulted from duplications preceding Paramecium speciation, underwent divergent evolution and were subject to purifying selection. Heat-shock treatments were performed to test for differential expression patterns among the five Hsp70-groups as well as for a functional conservation within Paramecium. These treatments induced exceptionally high mRNA up-regulations in one cytosolic group with a low basal expression, indicative for the major heat inducible hsp70s. All other groups showed comparatively high basal expression levels and moderate heat-inducibility, signifying constitutively expressed genes. Comparative EST analyses for P. tetraurelia hsp70s unveiled a corresponding expression pattern, which supports a functionally conserved evolution of the Hsp70 gene family in Paramecium. CONCLUSIONS: Our analyses suggest an independent evolution of the heat-inducible cytosol-type hsp70s in Paramecium and in its close relative Tetrahymena, as well as within higher eukaryotes. This result indicates convergent evolution during hsp70 subfunctionalization and implies that heat-inducibility evolved several times during the course of eukaryotic evolution. PMID- 23433226 TI - Measuring health workers' motivation in rural health facilities: baseline results from three study districts in Zambia. AB - INTRODUCTION: Health worker motivation can potentially affect the provision of health services. Low morale among the workforce can undermine the quality of service provision and drive workers away from the profession. While the presence of high-quality, motivated staff is a key aspect of health system performance, it is also one of the most difficult factors to measure. METHODS: We assessed health worker motivation as part of the baseline assessment for a health system strengthening intervention in three rural districts in Zambia. The intervention (Better Health Outcomes Through Mentoring and Assessment (BHOMA)) aims to increase health worker motivation through training, mentoring and support. We assessed motivation by examining underlying issues grouped around relevant outcome constructs such as job satisfaction, general motivation, burnout, organization commitment, conscientiousness and timeliness that collectively measure overall levels of motivation. The tools and the concepts have been used in high-income countries and they were recently applied in African settings to measure health worker motivation. RESULTS: Female participants had the highest motivation scores (female: mean 78.5 (SD 7.8) vs male: mean (SD 7.0)). By type of worker, nurses had the highest scores while environmental health technicians had the lowest score (77.4 (SD 7.8 vs 73.2 (SD 9.3)). Health workers who had been in post longer also had higher scores (>7 months). Health workers who had received some form of training in the preceding 12 months were more likely to have a higher score; this was also true for those older than 40 years when compared to those less than 40 years of age. The highest score values were noted in conscientiousness and timeliness, with all districts scoring above 80. CONCLUSIONS: This study evaluated motivation among rural health workers using a simple adapted tool to measure the concept of motivation. Results showed variation in motivation score by sex, type of health worker, training and time in post. Further research is needed to establish why these health worker attributes were associated with motivation and whether health system interventions targeting health workers, such as the current intervention, could influence health worker motivation. PMID- 23433227 TI - Periodic knee injections of collagen tripeptide delay cartilage degeneration in rabbit experimental osteoarthritis. AB - INTRODUCTION: Collagen peptides have been reported to possess various biological activities for various cell types. The purposes of this study were, first, to examine the therapeutic effects of collagen tripeptide (Ctp) in rabbit osteoarthritis and, second, to explore a synergetic effect with hyaluronan (HA). METHODS: Osteoarthritis was induced by anterior cruciate ligament transection of the right knee in 72 Japanese white rabbits and they were divided into four groups (control, Ctp, HA and Ctp/HA). Each material was injected weekly into the knee, and knee joint samples were collected 5, 10 and 15 weeks after surgery. Macroscopic and histomorphological analyses of cartilage were conducted. Expression of type II collagen and matrix metalloproteinase-13 was also analyzed immunohistochemically. A Tukey's honestly significant difference test was used to evaluate the statistical significance of difference in the macroscopic, histological and immnohistochemical results. RESULTS: All treatment groups exhibited slightly higher resistance to the progression of osteoarthritis than the control group macroscopically 15 weeks after surgery. Histologically, intra articular injection of Ctp significantly reduced cartilage degradation 10 weeks after surgery, and Ctp/HA significantly reduced it 5 weeks after surgery in comparison with the control. Immunohistochemically, both Ctp-treated and Ctp/HA treated groups had significantly increased type II collagen-positive chondrocytes at the fifth week after the surgery, although the numbers of matrix metalloproteinase-13-positive chondrocytes were not affected. CONCLUSION: Periodical injections of Ctp and Ctp/HA delayed progression of cartilage degeneration of early osteoarthritis induced by anterior cruciate ligament transection in rabbits. This effect appears to be exerted by promotion of type II collagen synthesis predominantly. PMID- 23433228 TI - Prevalence and comorbidity of diabetes mellitus among non-institutionalized older adults in Germany - results of the national telephone health interview survey 'German Health Update (GEDA)' 2009. AB - BACKGROUND: Despite the major public health impact of diabetes, recent population based data regarding its prevalence and comorbidity are sparse. METHODS: The prevalence and comorbidity of diabetes mellitus were analyzed in a nationally representative sample (N = 9133) of the non-institutionalized German adult population aged 50 years and older. Information on physician-diagnosed diabetes and 20 other chronic health conditions was collected as part of the national telephone health interview survey 'German Health Update (GEDA)' 2009. Overall, 51.2% of contacted persons participated. Among persons with diabetes, diabetes severity was defined according to the type and number of diabetes-concordant conditions: no diabetes-concordant condition (grade 1); hypertension and/or hyperlipidemia only (grade 2); one comorbidity likely to represent diabetes related micro- or macrovascular end-organ damage (grade 3); several such comorbidities (grade 4). Determinants of diabetes severity were analyzed by multivariable ordinal regression. RESULTS: The 12-month prevalence of diabetes was 13.6% with no significant difference between men and women. Persons with diabetes had a significantly higher prevalence and average number of diabetes concordant as well as diabetes-discordant comorbidities than persons without diabetes. Among persons with diabetes, 10.2%, 46.8%, 35.6% and 7.4% were classified as having severity grade 1-4, respectively. Determinants of diabetes severity included age (cumulative odds ratio 1.05, 95% confidence interval 1.03 1.07, per year) and number of discordant comorbidities (1.40, 1.25-1.55). With respect to specific discordant comorbidities, diabetes severity was correlated to depression (2.15, 1.29-3.56), respiratory disease (2.75, 1.72-4.41), musculoskeletal disease (1.53, 1.06-2.21), and severe hearing impairment (3.00, 1.21-7.41). CONCLUSIONS: Diabetes is highly prevalent in the non institutionalized German adult population 50 years and older. Diabetes comorbidities including diabetes-concordant and diabetes-discordant conditions need to be considered in epidemiological studies, in order to monitor disease burden and quality of diabetes care. Definitional standards of diabetes severity need to be refined and consented. PMID- 23433229 TI - Mitochondrial optic neuropathies: our travels from bench to bedside and back again. AB - The standard scientific method requires that you make an interesting observation, generate a hypothesis and then design an experiment to test the hypothesis. In ophthalmology, as in most fields of medicine, the observations and hypotheses tend to have more degrees of freedom, and the interpretation of experiments is also more complicated and often indeterminate. But sometimes it works out, going back and forth from bench to bedside to bench, in reiterative cycles. A successful example of alternating bench and bedside studies was presented (AAS) at the 2012 Alper Memorial given at the Washington Hospital Medical Center, illustrating a series of questions and investigations that pertain to mitochondrial optic neuropathies, beginning two decades ago, before the concept of mitochondrial optic neuropathies had much meaning. Basic science questions are often best answered by that extraordinary experiment of nature that we call clinical disease, and clinical questions are often best tested in the laboratory. PMID- 23433230 TI - Performance of two rapid diagnostic tests for malaria diagnosis at the China Myanmar border area. AB - BACKGROUND: Rapid diagnostic tests (RDTs) have become an essential tool in the contemporary malaria control and management programmes in the world. This study aims to evaluate the performance of two commonly used RDTs for malaria diagnosis in the China-Myanmar border area. METHODS: A total 606 febrile patients in the China-Myanmar border were recruited to this study and were diagnosed for malaria infections by microscopy, two RDTs tests (Pf/Pan device, and Pv/Pf device) and nested PCR. RESULTS: Malaria parasites were found in 143 patients by microscopy, of which 51, 73, and 19 were Plasmodium falciparum, Plasmodium vivax and P. falciparum/P. vivax mixed infections, respectively. Compared to microscopy, the sensitivity of the Pf/Pan device was 88.6% for P. falciparum and 69.9% for P. vivax with the specificity of 90.4%. For a subset of 350 patients, the sensitivity of the Pf/Pan device and Pv/Pf device for detection of P. falciparum was 87.5% and 91.7%, respectively; and for detection of P. vivax was 72.0% and 73.8%, respectively. The specificity of the Pf/Pan device and Pv/Pf device was 94.3% and 96.5%, respectively. Nested PCR detected malaria parasites in 174 of 606 samples, of which 67, 79, two and 26 were P. falciparum, P. vivax, P. ovale and P. falciparum/P. vivax mixed infections, respectively. Compared to nested PCR, all other methods had sensitivity below 80%, suggesting that a significant number of cases were missed. CONCLUSIONS: Compared to PCR, both microscopy and RDTs had lower sensitivities. RDTs had similar performance to microscopy for P. falciparum diagnosis, but performed worse for P. vivax diagnosis. Other RDT products should be selected with higher sensitivity (and good specificity) for both P. falciparum and P. vivax diagnosis. PMID- 23433231 TI - Post-thrombotic syndrome: a clinical review. AB - Up to half of patients with proximal deep vein thrombosis (DVT) will develop post thrombotic syndrome (PTS) despite optimal anticoagulant therapy. PTS significantly impacts upon quality of life and has major health-economic implications. This narrative review describes the pathophysiology, risk factors, and diagnosis, prevention and treatment of PTS, to improve our understanding of the disease and guide treatment. Relevant articles were identified through systematic searches of the PubMed, EMBASE and Cochrane databases between 1966 and November 2011. Studies were included for detailed assessment if they met the following criteria: published in English, human study participants, study population aged > 18 years, and lower limb post-thrombotic syndrome. All non systematic reviews and single patient case reports were excluded. Recurrent thrombosis, thrombus location and obesity are major risk factors, whereas the importance of gender and age remain uncertain. The diagnosis of PTS is based on clinical findings in patients with a known history of DVT. Several clinical scales have been described, with the Villalta Score gaining increasing popularity. Adequate anticoagulation and use of elastic compression stockings (ECS) following DVT can reduce the incidence of PTS. Catheter-directed thrombolysis and mechanical thrombectomy of acute DVT may preserve valvular function. Studies to date of these techniques are encouraging, and have reported improved hemodynamics and a reduced incidence of PTS. The management of established PTS is challenging. Compression therapy, aimed at reducing the underling venous hypertension, remains the mainstay of treatment. This is despite a paucity of high-quality evidence to support its use. Pharmacologic and surgical treatments have also been described, with a number of studies citing symptomatic improvement. PMID- 23433235 TI - Relationships between dietary macronutrients and adult neurogenesis in the regulation of energy metabolism. AB - Of the environmental factors which have an impact on body weight, nutrients are most influential. Within normal limits, hypothalamic and related neuronal populations correct perturbations in energy metabolism, to return the body to its nutritional set-point, either through direct response to nutrients or indirectly via peripheral appetite signals. Excessive intake of certain macronutrients, such as simple carbohydrates and SFA, can lead to obesity and attendant metabolic dysfunction, also reflected in alterations in structural plasticity, and, intriguingly,neurogenesis, in some of these brain regions. Neurogenesis, previously thought to occur only in the embryo, is now known to take place in the adult brain, dependent on numerous stimulating and inhibiting factors, including dietary components. Because of classic associations between neurogenesis and the hippocampus, in learning and cognition, this brain region has also been the focus of attention in the study of links between diet and neurogenesis. Recently, however, a more complete picture of this relationship has been building: not only has the hypothalamus been shown to satisfy the criteria for a neurogenic niche, but appetite-related mediators, including circulating hormones, such as leptin and ghrelin, pro-inflammatory cytokines and the endocannabinoid intracellular messengers, are also being examined for their potential role in mediating neurogenic responses to macronutrients. The present review draws together these observations and investigates whether n-3 PUFA may exert their attenuating effects on body weight through the stimulation of adult neurogenesis. Exploration of the effects of nutraceuticals on neurogenic brain regions may encourage the development of new rational therapies in the fight against obesity. PMID- 23433232 TI - A preliminary study suggests that nicotine and prefrontal dopamine affect cortico striatal areas in smokers with performance feedback. AB - Nicotine and tonic dopamine (DA) levels [as inferred by catechol-O-methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine * COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine * COMT genotype interaction for BOLD signal during performance feedback in cortico-striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy. PMID- 23433236 TI - Blue light emission from the heterostructured ZnO/InGaN/GaN. AB - ZnO/InGaN/GaN heterostructured light-emitting diodes (LEDs) were fabricated by molecular beam epitaxy and atomic layer deposition. InGaN films consisted of an Mg-doped InGaN layer, an undoped InGaN layer, and a Si-doped InGaN layer. Current voltage characteristic of the heterojunction indicated a diode-like rectification behavior. The electroluminescence spectra under forward biases presented a blue emission accompanied by a broad peak centered at 600 nm. With appropriate emission intensity ratio, the heterostructured LEDs had potential application in white LEDs. Moreover, a UV emission and an emission peak centered at 560 nm were observed under reverse bias. PMID- 23433237 TI - Novel spinal cord stimulation parameters in patients with predominant back pain. AB - OBJECTIVES: To examine the feasibility of novel high-frequency spinal cord stimulation therapy in a cohort of patients with chronic predominant back pain during a four day, percutaneous trial. DESIGN: Prospective, multicenter open label pilot trial. SETTING AND PATIENTS: Twenty-four patients with back pain greater than leg pain who were candidates for spinal cord stimulation were trialed at five U.S. centers. INTERVENTIONS: Patients completed a percutaneous trial with a commercially available spinal cord stimulator. The implanted leads were then connected to the novel external stimulation device and patients were trialed for an additional four days. OUTCOME MEASURES: Pain intensity ratings, subjective descriptions, and patients' preference. RESULTS: There was significant improvement from baseline in overall pain scores (8.68 to 2.03, [p < 0.001]) and back pain scores (8.12 to 1.88, [p < 0.001]) with the investigational stimulation. The investigational stimulation was preferred to the commercially available systems in 21 of 24 patients (88%). CONCLUSIONS: Patients with predominant back pain reported a substantial reduction in overall pain and back pain when trialed with high-frequency spinal cord stimulation therapy. PMID- 23433238 TI - Improvement of quality of life and symptoms after gastric electrical stimulation in children with functional dyspepsia. AB - BACKGROUND: Our objective is to evaluate the effect of gastric electrical stimulation (GES) on symptoms and quality of life for pediatric patients with functional dyspepsia (FD). METHODS: Twenty-four patients (16 female, median 15 years) were treated with GES for FD after a median of 24 months of symptoms (3 months-14 years). At baseline, 46% required tube feeds and 25% parenteral nutrition. Sixty percent had gastroparesis. The PedsQL GI Module (PedsQL) was completed for 18/24 both pre-/post-GES after a median of 8 months. Patients also completed the Symptom Monitor Worksheet (SMW) pre-/post-GES after a median of 6 months. Pre-/post-GES global health was also assessed. KEY RESULTS: Significant improvements were seen in multiple areas of the PedsQL, including stomach pain/upset, food/drink limits, heartburn/reflux, gas/bloating, patient worry, medication tolerance, and constipation (P < 0.05). A decrease was found in combined symptom severity/frequency based on SMW (P < 0.01). Improvements were made in all categories, including vomiting, nausea, early satiety, bloating, fullness, epigastric pain, and burning (P < 0.01). Improvements in PedsQL/SMW scores remained when analysis was limited to normal or delayed gastric emptying (P < 0.05, P < 0.05). Thirteen percent needed tube feeds and 13% parenteral nutrition after GES. Sixty-five percent reported that their health was much improved after GES vs 15% the same or worse. Five patients experienced complications, primarily mild abdominal discomfort. CONCLUSIONS & INFERENCES: In the largest series to date of pediatric patients who have undergone GES for FD, we found significant improvements in upper gastrointestinal symptoms, quality of life, and perception of global health. Patients were less dependent on tube feeding or parenteral nutrition. PMID- 23433239 TI - A rare case of Candida parapsilosis endocarditis in a young healthy woman--case report. AB - Disseminated fungal infections are still rare conditions, mostly caused by Candida spp. during immunosuppression. Infection of immunocompetent individuals is uncommon. Endocarditis is a rare manifestation during candidaemia, mostly in patients with prosthetic valves. Affection of previously unaltered valves is uncommon. CASE PRESENTATION: We presented a case of a young, previously healthy female patient with endocarditis, caused by Candida parapsilosis. The initial symptom, fever, was present four months before hospital admittance. She was febrile without other symptoms and during observation in a local hospital. After her condition deteriorated, she was transferred to the Institute for infectious and tropical diseases, Belgrade. Clinical findings on admission include petechial skin rash and moderate hepatosplenomegaly. Newly developed systolic murmur was noted, and Candida parapsilosis was isolated in multiple blood cultures. Echocardiography revealed 15 * 14 mm vegetations on the right aortic vellum. She was treated with antifungal drugs (fluconasole, liposomal amphotericin B), and the affected valve was successfully replaced. The same strain of Candida parapsilosis was isolated from the intraoperative material of the valve. There were no markers of immunosuppression or other conditions which could affect the immune system. CONCLUSION: After a prolonged period of treatment she was successfully cured, and she received a long-term intermittent suppressive fluconasole therapy for the time being. PMID- 23433241 TI - Sex- and age-specific trends in antibiotic resistance patterns of Escherichia coli urinary isolates from outpatients. AB - BACKGROUND: Urinary tract infections (UTIs) are one of the most common infections treated in ambulatory care settings, however the epidemiology differs by age and sex. The incidence of UTI is far greater in females than males, and infection in pediatric patients is more often due to anatomical abnormalities. The purpose of this research was to describe age- and sex-specific trends in antibiotic susceptibility to common urinary anti-infectives among urinary isolates of Escherichia coli from ambulatory primary care patients in a regional health maintenance organization. METHODS: Clinical microbiology data were collected for all urine cultures from patients with visits to primary care clinics in a regional health maintenance organization between 2005 and 2010. The first positive culture for E. coli tested for antibiotic susceptibilities per patient per year was included in the analysis dataset. The frequency of susceptibility to ampicillin, amoxicillin-clavulanate, ciprofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole (TMP/SMX) was calculated for male and female patients. The Cochrane-Mantel-Haenzel test was used to test for differences in age-stratified susceptibility to each antibiotic between males and females. RESULTS: A total of 43,493 E. coli isolates from 34,539 unique patients were identified for study inclusion. After stratifying by age, E. coli susceptibility to ampicillin, amoxicillin-clavulanate, ciprofloxacin, and nitrofurantoin differed significantly between males and females. However, the magnitude of the differences was less than 10% for all strata except amoxicillin-clavulanate susceptibility in E. coli isolated from males age 18-64 compared to females of the same age. CONCLUSIONS: We did not observe clinically meaningful differences in antibiotic susceptibility to common urinary anti-infectives among E. coli isolated from males versus females. These data suggest that male sex alone should not be used as an indication for empiric use of second-line broad-spectrum antibiotic agents for the treatment of UTIs. PMID- 23433240 TI - DNA barcoding of freshwater rotifera in Mexico: evidence of cryptic speciation in common rotifers. AB - DNA barcodes are useful tools to identify and discover new species in a wide range of taxa. Here, we report the first barcode study of monogonont rotifers from fresh and brackish waters in Mexico, and discuss the taxonomic implications of this work. We used DNA barcodes based on the sequence of cytochrome oxidase I to examine patterns of divergence among 417 specimens that represented 63 morphological taxa of rotifers. The mean sequence divergence among conspecific rotifer individuals was 0.75%, whereas the mean sequence divergence among congeneric taxa was 20.8%. The barcodes could discriminate between all the morphospecies identified. Moreover, the barcoding data revealed the presence of possible cryptic species in Ascomorpha ovalis, Lecane bulla, L. cornuta, L. curvicornis, L. crepida, L. lunaris, L. hastata, Platyias quadricornis, Keratella cochlearis, Brachionus calyciflorus and Testudinella patina, as well as in some forms and varieties such as B. quadridentatus f. brevispinus, B. quadridentatus f. cluniorbicularis and Mytilina ventralis var. macracantha. Barcode analysis also enabled some forms and varieties of common species to be identified as separate species. The results obtained support recent taxonomic revisions, such as the recognition of the genus Plationus, and the presence of cryptic speciation in L. bulla. This work shows that DNA barcoding identifies species effectively, can aid taxonomists by identifying cryptic species, and is an important tool for resolving taxonomic controversies. PMID- 23433242 TI - Orthology Guided Assembly in highly heterozygous crops: creating a reference transcriptome to uncover genetic diversity in Lolium perenne. AB - Despite current advances in next-generation sequencing data analysis procedures, de novo assembly of a reference sequence required for SNP discovery and expression analysis is still a major challenge in genetically uncharacterized, highly heterozygous species. High levels of polymorphism inherent to outbreeding crop species hamper De Bruijn Graph-based de novo assembly algorithms, causing transcript fragmentation and the redundant assembly of allelic contigs. If multiple genotypes are sequenced to study genetic diversity, primary de novo assembly is best performed per genotype to limit the level of polymorphism and avoid transcript fragmentation. Here, we propose an Orthology Guided Assembly procedure that first uses sequence similarity (tBLASTn) to proteins of a model species to select allelic and fragmented contigs from all genotypes and then performs CAP3 clustering on a gene-by-gene basis. Thus, we simultaneously annotate putative orthologues for each protein of the model species, resolve allelic redundancy and fragmentation and create a de novo transcript sequence representing the consensus of all alleles present in the sequenced genotypes. We demonstrate the procedure using RNA-seq data from 14 genotypes of Lolium perenne to generate a reference transcriptome for gene discovery and translational research, to reveal the transcriptome-wide distribution and density of SNPs in an outbreeding crop and to illustrate the effect of polymorphisms on the assembly procedure. The results presented here illustrate that constructing a non redundant reference sequence is essential for comparative genomics, orthology based annotation and candidate gene selection but also for read mapping and subsequent polymorphism discovery and/or read count-based gene expression analysis. PMID- 23433245 TI - Differences in wage rates for males and females in the health sector: a consideration of unpaid overtime to decompose the gender wage gap. AB - BACKGROUND: In Australia a persistent and sizable gender wage gap exists. In recent years this gap has been steadily widening. The negative impact of gender wage differentials is the disincentive to work more hours. This implies a substantial cost on the Australian health sector. This study aimed to identify the magnitude of gender wage differentials within the health sector. The investigation accounts for unpaid overtime. Given the limited availability of information, little empirical evidence exists that accounts for unpaid overtime. METHODS: Information was collected from a sample of 10,066 Australian full-time employees within the health sector. Initially, ordinary least-squares regression was used to identify the gender wage gap when unpaid overtime was included and then excluded from the model. The sample was also stratified by gender and then by occupation to allow for comparisons. Later the Blinder-Oaxaca decomposition method was employed to identify and quantify the contribution of individual endowments to wage differentials between males and females. RESULTS: The analyses of data revealed a gender wage gap that varied across occupations. The inclusion of unpaid overtime in the analysis led to a slight reduction in the wage differential. The results showed an adjusted wage gap of 16.7%. CONCLUSIONS: Unpaid overtime made a significant but small contribution to wage differentials. Being female remained the major contributing factor to the wage gap. Given that wage differentials provide a disincentive to work more hours, serious attempts to deal with the skilled labour shortage in the health sector need to address the gender wage gap. PMID- 23433243 TI - Exaggerated object affordance and absent automatic inhibition in alien hand syndrome. AB - Patients with alien hand syndrome (AHS) experience making apparently deliberate and purposeful movements with their hand against their will. However, the mechanisms contributing to these involuntary actions remain poorly understood. Here, we describe two experimental investigations in a patient with corticobasal syndrome (CBS) with alien hand behaviour in her right hand. First, we show that responses with the alien hand are made significantly more quickly to images of objects which afford an action with that hand compared to objects which afford an action with the unaffected hand. This finding suggests that involuntary grasping behaviours in AHS might be due to exaggerated, automatic motor activation evoked by objects which afford actions with that limb. Second, using a backwards masked priming task, we found normal automatic inhibition of primed responses in the patient's unaffected hand, but importantly there was no evidence of such suppression in the alien limb. Taken together, these findings suggest that grasping behaviours in AHS may result from exaggerated object affordance effects, which might potentially arise from disrupted inhibition of automatically evoked responses. PMID- 23433244 TI - Evolution of Escherichia coli rifampicin resistance in an antibiotic-free environment during thermal stress. AB - BACKGROUND: Beneficial mutations play an essential role in bacterial adaptation, yet little is known about their fitness effects across genetic backgrounds and environments. One prominent example of bacterial adaptation is antibiotic resistance. Until recently, the paradigm has been that antibiotic resistance is selected by the presence of antibiotics because resistant mutations confer fitness costs in antibiotic free environments. In this study we show that it is not always the case, documenting the selection and fixation of resistant mutations in populations of Escherichia coli B that had never been exposed to antibiotics but instead evolved for 2000 generations at high temperature (42.2 degrees C). RESULTS: We found parallel mutations within the rpoB gene encoding the beta subunit of RNA polymerase. These amino acid substitutions conferred different levels of rifampicin resistance. The resistant mutations typically appeared, and were fixed, early in the evolution experiment. We confirmed the high advantage of these mutations at 42.2 degrees C in glucose-limited medium. However, the rpoB mutations had different fitness effects across three genetic backgrounds and six environments. CONCLUSIONS: We describe resistance mutations that are not necessarily costly in the absence of antibiotics or compensatory mutations but are highly beneficial at high temperature and low glucose. Their fitness effects depend on the environment and the genetic background, providing glimpses into the prevalence of epistasis and pleiotropy. PMID- 23433246 TI - Mining: South Africa's legacy and burden in the context of occupational respiratory diseases. PMID- 23433247 TI - Norovirus outbreaks: a systematic review of commonly implicated transmission routes and vehicles. AB - Causal mechanisms of norovirus outbreaks are often not revealed. Understanding the transmission route (e.g. foodborne, waterborne, or environmental) and vehicle (e.g. shellfish or recreational water) of a norovirus outbreak, however, is of great public health importance; this information can facilitate interventions for an ongoing outbreak and regulatory action to limit future outbreaks. Towards this goal, we conducted a systematic review to examine whether published outbreak information was associated with the implicated transmission route or vehicle. Genogroup distribution was associated with transmission route and food vehicle, but attack rate and the presence of GII.4 strain were not associated with transmission route, food vehicle, or water vehicle. Attack rate, genogroup distribution, and GII.4 strain distribution also varied by other outbreak characteristics (e.g. setting, season, hemisphere). These relationships suggest that different genogroups exploit different environmental conditions and thereby can be used to predict the likelihood of various transmission routes or vehicles. PMID- 23433249 TI - Optical imaging correlates with magnetic resonance imaging breast density and reveals composition changes during neoadjuvant chemotherapy. AB - INTRODUCTION: In addition to being a risk factor for breast cancer, breast density has been hypothesized to be a surrogate biomarker for predicting response to endocrine-based chemotherapies. The purpose of this study was to evaluate whether a noninvasive bedside scanner based on diffuse optical spectroscopic imaging (DOSI) provides quantitative metrics to measure and track changes in breast tissue composition and density. To access a broad range of densities in a limited patient population, we performed optical measurements on the contralateral normal breast of patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSI parameters, including tissue hemoglobin, water, and lipid concentrations, were obtained and correlated with magnetic resonance imaging (MRI)-measured fibroglandular tissue density. We evaluated how DOSI could be used to assess breast density while gaining new insight into the impact of chemotherapy on breast tissue. METHODS: This was a retrospective study of 28 volunteers undergoing NAC treatment for breast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtained from the contralateral normal breast before and during NAC. Longitudinal DOSI measurements were used to calculate breast tissue concentrations of oxygenated and deoxygenated hemoglobin, water, and lipid. These values were compared with MRI-measured fibroglandular density before and during therapy. RESULTS: Water (r = 0.843; P < 0.001), deoxyhemoglobin (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. Mean DOSI parameters differed significantly between pre- and postmenopausal subjects at baseline (water, P < 0.001; deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NAC treatment measured at about 90 days, significant reductions were observed in oxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline. Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012). CONCLUSIONS: DOSI functional measurements correlate with MRI fibroglandular density, both before therapy and during NAC. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of density based on hemoglobin and water that could be used at the bedside to assess response to therapy and evaluate disease risk. PMID- 23433248 TI - ZIPping to pain relief: the role (or not) of PKMzeta in chronic pain. AB - Chronic pain remains a significant clinical problem despite substantial advances in our understanding of how persistent nociceptor stimulation drives plasticity in the CNS. A major theme that has emerged in this area of work is the strong similarity between plasticity involved in learning and memory in CNS regions such as cortex and hippocampus with mechanisms underlying chronic pain development and maintenance in the spinal dorsal horn and other CNS areas such as anterior cingulate cortex (ACC). We, and others have recently implicated an atypical PKC (aPKC), called PKMzeta, in the maintenance of pain plasticity based on biochemical assays and the use of a peptide pseudosubstrate inhibitor called ZIP. These studies indicate remarkable parallels between the potential role of PKMzeta as a key molecule for the maintenance of long-term memory and long-term potentiation (LTP) and the maintenance of a chronic pain state. On the other hand, very recent studies have disputed the specificity of ZIP and called into question the role of PKMzeta as a memory maintenance molecule. Here we critically review the evidence that PKMzeta might represent a new target for the reversal of certain chronic pain states. Furthermore, we consider whether ZIP might have other aPKC or even non-aPKC targets and the significance of such off-target effects for evaluating maintenance mechanisms of chronic pain. We conclude that, current controversies aside, utilization of ZIP as a tool to interrogate maintenance mechanisms of chronic pain and further investigations into the potential role of PKMzeta, and other aPKCs, in pain plasticity are likely to lead to further insights with the potential to unravel the enigma that is the disease of chronic pain. PMID- 23433250 TI - Second-stage non-response in the Swiss health survey: determinants and bias in outcomes. AB - BACKGROUND: Unit non-response occurs in sample surveys when a target subject does not respond to a survey. Potential implications are decreased power, increased standard error, and non-response bias. The objective of this study was to assess the factors associated with participation in a written survey (MSHS) of subjects who had previously participated in the Swiss Health Survey (SHS) and to evaluate to what extent non-participation could impact the estimation of various MSHS health outcomes. METHODS: Multivariate logistic regression was used to assess the factors associated with MSHS participation (n=14,393) by eligible SHS participants (n=17,931). Crude participation rates and the adjusted odds ratios of participation (OR) were reported. In order to report potential bias in MSHS outcomes, the average age-standardized and sex-specific outcome values in non participants were predicted based on several different linear regression models which had been previously fitted on MSHS participants. RESULTS: Adjusting for all other variables, women (OR=1.63) as compared with men, subjects with a secondary (OR=1.48) or tertiary education (OR=1.76) as compared with those with primary education, white-collar workers (high level non-manual workers OR=1.29, medium and low level non-manual workers OR=1.26 and OR=1.25 respectively) as compared with unskilled manual workers, Swiss nationals (OR=1.60) as compared to non Swiss, and subjects with very good or good self-rated health (OR=1.35) were more likely to participate in the MSHS. People who work full-time were less likely to participate than those without paid work (OR=0.76). There were no statistically significant differences in the likelihood of participation between rural and urban areas, different geographic regions of Switzerland and household income quartiles.Except for myocardial infarction, all age-standardized and sex-specific average outcomes (influenza vaccination, arthrosis, osteoporosis, high blood pressure, depression, mastery, and sense of coherence) were significantly different between MSHS non-participants and participants. CONCLUSIONS: Subjects who participated in the MSHS had a higher socio-economic status, reported a better subjective health, and were more likely to be Swiss nationals. Small to moderate bias was found for most age-adjusted and sex-specific average outcomes. Consequently, these MSHS outcomes should be used and interpreted with care. PMID- 23433251 TI - Spatial abundance and clustering of Culicoides (Diptera: Ceratopogonidae) on a local scale. AB - BACKGROUND: Biting midges, Culicoides, of the Obsoletus group and the Pulicaris group have been involved in recent outbreaks of bluetongue virus and the former was also involved in the Schmallenberg virus outbreak in northern Europe. METHODS: For the first time, here we investigate the local abundance pattern of these two species groups in the field by intensive sampling with a grid of light traps on 16 catch nights. Neighboring trap catches can be spatially dependent on each other, hence we developed a conditional autoregressive (CAR) model framework to test a number of spatial and non-spatial covariates expected to affect Culicoides abundance. RESULTS: The distance to sheep penned in the corner of the study field significantly increased the abundance level up to 200 meters away from the sheep. Spatial clustering was found to be significant but could not be explained by any known factors, and cluster locations shifted between catch nights. No significant temporal autocorrelation was detected. CAR models for both species groups identified a significant positive impact of humidity and significant negative impacts of precipitation and wind turbulence. Temperature was also found to be significant with a peak at just below 16 degrees Celcius. Surprisingly, there was a significant positive impact of wind speed. The CAR model for the Pulicaris group also identified a significant attraction to the smaller groups of sheep placed in the field. Furthermore, a large number of spatial covariates which were incorrectly found to be significant in ordinary regression models were not significant in the CAR models. The 95% C.I. on the prediction estimates ranged from 20.4% to 304.8%, underlining the difficulties of predicting the abundance of Culicoides. CONCLUSIONS: We found that significant spatial clusters of Culicoides moved around in a dynamic pattern varying between catch nights. This conforms with the modeling but was not explained by any of the tested covariates. The mean abundance within these clusters was up to 11 times higher for the Obsoletus group and 4 times higher for the Pulicaris group compared to the rest of the field. PMID- 23433252 TI - Improved assay to detect Plasmodium falciparum using an uninterrupted, semi nested PCR and quantitative lateral flow analysis. AB - BACKGROUND: A rapid, non-invasive, and inexpensive point-of-care (POC) diagnostic for malaria followed by therapeutic intervention would improve the ability to control infection in endemic areas. METHODS: A semi-nested PCR amplification protocol is described for quantitative detection of Plasmodium falciparum and is compared to a traditional nested PCR. The approach uses primers that target the P. falciparum dihydrofolate reductase gene. RESULTS: This study demonstrates that it is possible to perform an uninterrupted, asymmetric, semi-nested PCR assay with reduced assay time to detect P. falciparum without compromising the sensitivity and specificity of the assay using saliva as a testing matrix. CONCLUSIONS: The development of this PCR allows nucleic acid amplification without the need to transfer amplicon from the first PCR step to a second reaction tube with nested primers, thus reducing both the chance of contamination and the time for analysis to < two hours. Analysis of the PCR amplicon yield was adapted to lateral flow detection using the quantitative up-converting phosphor (UCP) reporter technology. This approach provides a basis for migration of the assay to a POC microfluidic format. In addition the assay was successfully evaluated with oral samples. Oral fluid collection provides a simple non-invasive method to collect clinical samples. PMID- 23433253 TI - Head of household education level as a factor influencing whether delivery takes place in the presence of a skilled birth attendant in Busia, Uganda: a cross sectional household study. AB - BACKGROUND: Assistance during delivery by a skilled attendant is recommended as a means to reduce child and maternal mortality. Globally, higher levels of maternal education have been associated with better health behaviours at delivery. However, given that heads of households tend to be the decision makers regarding accessing healthcare, some educated mothers may find themselves prevented from accessing healthcare at the point of delivery. METHODS: We examined the association between head of household education level and health seeking behaviours at delivery across a sample of 392 households. Chi-squared analysis and odds ratios were calculated to measure the strength of the relationship between no, some primary, or some secondary or higher education attained by the head of household and the presence or absence of a skilled birth attendant at that child's birth, and whether the birth took place at a health facility. RESULTS: Heads of household (n = 392) were predominantly male (93.4% [(90.9%, 95.8%), a = 0.05]). We found a significant difference in skilled birth attendance between heads of households with some primary education and heads of household with some secondary education or higher (chi2 (1) = 6.231, p <0.05) whereby those with secondary or higher education were significantly more likely to seek a skilled birth attendant (OR = 1.5,[1.1,2.1]). The difference in health centre delivery between heads of household with a primary education and heads of household with a secondary or higher education was also significant (chi2 (1) = 7.519, p <0.05). Those with secondary or higher education were significantly more likely to deliver in a health facility (OR = 1.6,[1.2,2.1]). CONCLUSIONS: The results of our analysis, which identified the vast majority of heads of households as men, suggests that education, or rather limited or a lack of education for the head of household, may be a barrier to women's use of health care in Uganda and therefore reinforces the need to increase educational access among male heads of households. Improving the rates of health centre deliveries and utilization of services provided by skilled health workers might lie, in part, in increasing overall education levels of heads of households, specifically the education of male heads of households. PMID- 23433254 TI - Where do knee revisions for infection, fracture, and other revisions get treated? AB - Complicated knee revision procedures require specific expertise that may not be available across the healthcare network. Teaching hospitals appear to perform more knee revisions overall than urban or rural hospitals. We examined the location of care and payer status for all knee revisions including complex revisions (infection, periprosthetic fracture). Although only 39.7% of all primary total knee cases were performed in teaching hospitals, over half of all knee revisions were performed in teaching hospitals. Knee revision procedures, including treatment of periprosthetic infections and fractures are performed more often in teaching hospitals than in urban and rural settings combined. Reimbursement that does not match the cost of care for complex revision and infection cases may have a disproportionate impact on teaching hospitals. PMID- 23433255 TI - Posterior cruciate-retaining versus posterior-stabilized total knee arthroplasty: a meta-analysis. AB - The objective of this meta-analysis was to compare outcomes of posterior cruciate retaining and posterior stabilized prostheses. A computerized literature search was conducted to identify randomized controlled trials comparing the clinical outcomes of cruciate-retaining and posterior-stabilized designs. The table of contents of four major Orthopaedic journals and the references section of two arthroplasty text books were reviewed to identify other relevant studies. Ultimately, 1114 patients (1265 knees) were compared. Statistical analysis revealed a significant difference in flexion and range of motion in favor of posterior-stabilized knees, but no difference in complication rates. The clinical importance of this remains unknown. The decision to use one design versus the other should rest with the surgeon's preference and comfort with a particular design. PMID- 23433256 TI - Author reply: hip resurfacing arthroplasty in inflammatory arthritis. PMID- 23433257 TI - Ocular penetration of topical antibiotics: study on the penetration of chloramphenicol, tobramycin and netilmicin into the anterior chamber after topical administration. AB - BACKGROUND: To compare penetration in the aqueous humour of topically applied antibiotics. DESIGN: Randomized prospective study, Department of Ophthalmology, University of Perugia, Italy PARTICIPANTS: Patients undergoing cataract surgery. METHODS: One hundred twenty-two patients were included: 14 received one drop of chloramphenicol suspension; 12 one application of chloramphenicol gel; 11 one drop of netilmicin suspension; 13 one drop of tobramycin suspension; 37 repeated instillations of chloramphenicol suspension every 10 min for a total of four drops; and 35 repeated instillations of chloramphenicol gel every 10 min for a total of four drops. Samples were taken immediately before surgery from the anterior chamber in order to determine the antibiotic by means of high performance liquid chromatography. Samples were taken 45-190 min after the eye drops were instilled. MAIN OUTCOME MEASURES: Intraocular penetration of chloramphenicol, netilmicin and tobramicyn. RESULTS: After a single administration, netilmicin and tobramycin were undetectable, whereas the chloramphenicol suspension reached a mean concentration of 0.23 +/- 0.21 MUg/mL, and the chloramphenicol gel a mean concentration of 0.13 +/- 0.14 MUg/mL. After repeated administrations, the mean concentrations of the chloramphenicol suspension and gel were 0.60 +/- 0.26 MUg/mL and 0.58 +/- 0.18 MUg/mL, respectively. CONCLUSIONS: Tobramycin and netilmicin do not reach detectable concentrations, whereas chloramphenicol, after multiple administrations, reaches concentrations that are effective against Haemophilus influenzae and Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Neisseria meningitidis, Pasteurella multocida and Streptococcus pneumoniae. This means that chloramphenicol can be rationally used in the prophylaxis and treatment of infections supported by sensitive germs. PMID- 23433258 TI - Short- and long-term transfer of urethral catheterization skills from simulation training to performance on patients. AB - BACKGROUND: Inexperienced interns are responsible for most iatrogenic complications after urethral catheterization (UC). Although training on simulators is common, little is known about the transfer of learned skills to real clinical practice. This study aimed to evaluate the short- and long-term effects of UC simulated skills training on performance on real patients and to examine whether watching a video of the procedure immediately before assessment enhanced clinical performance. METHODS: This was an experimental study of the effect of a UC simulation-based skills course on medical students' short-term (after one week) and long-term (after six weeks) performance. The additional effect of video instruction before performance testing on real patients was studied in a randomized trial. Sixty-four students participated in the study, which was preceded by a pilot study investigating the validity aspects of a UC assessment form. RESULTS: The pilot study demonstrated sufficient inter-rater reliability, intra-class correlation coefficient 0.86, and a significant ability to discriminate between trainee performances when using the assessment form, p= 0.001. In the main study, more than 90% of students demonstrated an acceptable performance or better when tested on real patients. There was no significant difference in the total score between the one-week and the six-week groups when tested on real patients and no significant difference between the video and the control groups. CONCLUSIONS: Medical students demonstrated good transfer of UC skills learned in the skills lab to real clinical situations up to six weeks after training. Simulated UC training should be the standard for all medical school curricula to reduce avoidable complications. However, this study did not demonstrate that an instructional video, as a supplement to simulated skills training, improved clinical UC performance. TRIAL REGISTRATION: Current Controlled Trials ISRCTN:ISRCTN90745002. PMID- 23433259 TI - High-precision genetic mapping of behavioral traits in the diversity outbred mouse population. AB - Historically our ability to identify genetic variants underlying complex behavioral traits in mice has been limited by low mapping resolution of conventional mouse crosses. The newly developed Diversity Outbred (DO) population promises to deliver improved resolution that will circumvent costly fine-mapping studies. The DO is derived from the same founder strains as the Collaborative Cross (CC), including three wild-derived strains. Thus the DO provides more allelic diversity and greater potential for discovery compared to crosses involving standard mouse strains. We have characterized 283 male and female DO mice using open-field, light-dark box, tail-suspension and visual-cliff avoidance tests to generate 38 behavioral measures. We identified several quantitative trait loci (QTL) for these traits with support intervals ranging from 1 to 3 Mb in size. These intervals contain relatively few genes (ranging from 5 to 96). For a majority of QTL, using the founder allelic effects together with whole genome sequence data, we could further narrow the positional candidates. Several QTL replicate previously published loci. Novel loci were also identified for anxiety- and activity-related traits. Half of the QTLs are associated with wild-derived alleles, confirming the value to behavioral genetics of added genetic diversity in the DO. In the presence of wild-alleles we sometimes observe behaviors that are qualitatively different from the expected response. Our results demonstrate that high-precision mapping of behavioral traits can be achieved with moderate numbers of DO animals, representing a significant advance in our ability to leverage the mouse as a tool for behavioral genetics. PMID- 23433261 TI - Carbamazepine-related sexual disorders: beyond hormonal changes! PMID- 23433262 TI - Predicting the evolution of antibiotic resistance. AB - Mutations causing antibiotic resistance are often associated with a cost in the absence of antibiotics. Surprisingly, a new study found that bacteria adapting to increased temperature became resistant to rifampicin. By studying the consequences of the involved mutations in different conditions and genetic backgrounds, the authors illustrate how knowledge of two fundamental genetic properties, pleiotropy and epistasis, may help to predict the evolution of antibiotic resistance. PMID- 23433263 TI - High-resolution melting analysis for bird sexing: a successful approach to molecular sex identification using different biological samples. AB - High-resolution melting (HRM) analysis is a very attractive and flexible advanced post-PCR method with high sensitivity/specificity for simple, fast and cost effective genotyping based on the detection of specific melting profiles of PCR products. Next generation real-time PCR systems, along with improved saturating DNA-binding dyes, enable the direct acquisition of HRM data after quantitative PCR. Melting behaviour is particularly influenced by the length, nucleotide sequence and GC content of the amplicons. This method is expanding rapidly in several research areas such as human genetics, reproductive biology, microbiology and ecology/conservation of wild populations. Here we have developed a successful HRM protocol for avian sex identification based on the amplification of sex specific CHD1 fragments. The melting curve patterns allowed efficient sexual differentiation of 111 samples analysed (plucked feathers, muscle tissues, blood and oral cavity epithelial cells) of 14 bird species. In addition, we sequenced the amplified regions of the CHD1 gene and demonstrated the usefulness of this strategy for the genotype discrimination of various amplicons (CHD1Z and CHD1W), which have small size differences, ranging from 2 bp to 44 bp. The established methodology clearly revealed the advantages (e.g. closed-tube system, high sensitivity and rapidity) of a simple HRM assay for accurate sex differentiation of the species under study. The requirements, strengths and limitations of the method are addressed to provide a simple guide for its application in the field of molecular sexing of birds. The high sensitivity and resolution relative to previous real-time PCR methods makes HRM analysis an excellent approach for improving advanced molecular methods for bird sexing. PMID- 23433264 TI - Restoration of altered somatosensory cortical representation with spinal cord stimulation therapy in a patient with complex regional pain syndrome: a magnetoencephalography case study. AB - OBJECTIVES: Development of effective chronic pain treatment strategies has been hampered by the lack of an objective pain biomarker. Magnetoencephalography (MEG) has demonstrated cortical disorganization corresponding to the affected limb of complex regional pain syndrome (CRPS) patients and spinal cord stimulation (SCS) can acutely treat CRPS in a reversible and adjustable fashion. In order to better define a potential MEG-sensitive biomarker for chronic pain, our goal was to study the effects of therapeutic SCS on cortical disorganization in patients with unilateral limb CRPS. METHODS: Two patients treated with either thoracic or cervical SCS with leg or arm CRPS were studied with MEG. Baseline and tactile evoked responses were recorded with and without effective SCS therapy. RESULTS: All MEG recordings were obtained with minimal interference. In the patient with arm CRPS, with the stimulator off, first and fifth digit primary somatosensory (SI) cortical representations (D1/D5) were significantly disorganized and spatially inverted as compared with the opposite unaffected limb. Effective SCS therapy was then able to acutely normalize or restore hand cortical organization in the affected CRPS limb. This restoration of cortical organization was partially maintained with lingering pain relief when the stimulator was subsequently turned off. CONCLUSIONS: This is the first report of a MEG study showing D1/D5 cortical disorganization and its apparent reversal or restoration with cervical SCS therapy. Ours also is the first report of an apparent acute reversible interchange in the cortical representations of D1 and D5. Our limited data demonstrate that disorganization of SI cortex might be a neurophysiologic marker of chronic pain as shown with instantaneous normalization of SI disorganization or restoration of SI organization with therapeutic SCS. As a clinically proven tool for functional mapping, MEG might be shown to provide an objective measure of chronic pain. More data are required to further investigate this possibility. PMID- 23433260 TI - Neurogenesis in zebrafish - from embryo to adult. AB - Neurogenesis in the developing central nervous system consists of the induction and proliferation of neural progenitor cells and their subsequent differentiation into mature neurons. External as well as internal cues orchestrate neurogenesis in a precise temporal and spatial way. In the last 20 years, the zebrafish has proven to be an excellent model organism to study neurogenesis in the embryo. Recently, this vertebrate has also become a model for the investigation of adult neurogenesis and neural regeneration. Here, we summarize the contributions of zebrafish in neural development and adult neurogenesis. PMID- 23433265 TI - Special issue on the Accelerating Clinical Trials and Outcomes Research (ACTOR) Conference. PMID- 23433266 TI - Reciprocal access agreements between BJOT, AJOT, and CJOT: new resources for occupational therapists around the world. PMID- 23433267 TI - Opportunities for occupational therapy behavioral health: a call to action. PMID- 23433268 TI - Protocol development, treatment fidelity, adherence to treatment, and quality control. AB - Occupational therapy leaders have emphasized the importance of intervention effectiveness research. The CONSORT and TREND checklists have been suggested as useful tools for reporting the results of randomized and nonrandomized studies, respectively. Despite such recommendations, research protocols and reports continue to underutilize the available tools, a situation reflecting limited resources for and experience with the conduct of effectiveness research. To address this issue, and using the CONSORT statement to structure the analysis, this article discusses strategies for optimization of protocol development, treatment fidelity, adherence to treatment, and quality control. We recommend several approaches to increase the quality of research throughout these various processes. Examples of implementation from our laboratory provide evidence of the utility of these strategies. PMID- 23433269 TI - Recruitment, retention, and blinding in clinical trials. AB - The recruitment and retention of participants and the blinding of participants, health care providers, and data collectors present challenges for clinical trial investigators. This article reviews challenges and alternative strategies associated with these three important clinical trial activities. Common recruiting pitfalls, including low sample size, unfriendly study designs, suboptimal testing locations, and untimely recruitment are discussed together with strategies for overcoming these barriers. The use of active controls, technology-supported visit reminders, and up-front scheduling is recommended to prevent attrition and maximize retention of participants. Blinding is conceptualized as the process of concealing research design elements from key players in the research process. Strategies for blinding participants, health care providers, and data collectors are suggested. PMID- 23433270 TI - Making the best match: selecting outcome measures for clinical trials and outcome studies. AB - Selecting an appropriate outcome measure is a critical step in designing valid and useful clinical trials and outcome studies. This selection process needs to extend beyond examining basic psychometric properties to consider additional features of instruments that may affect their validity and utility for the study's purpose. This article discusses these additional factors and their potential impact on outcome measurement. Guidelines are proposed to help clinical researchers and consumers of clinical research literature evaluate the match between the study purpose, population, and instrument. PMID- 23433271 TI - Nuts and bolts of conducting feasibility studies. AB - Many factors can affect the successful implementation and validity of intervention studies. A primary purpose of feasibility and pilot studies is to assess the potential for successful implementation of the proposed main intervention studies and to reduce threats to the validity of these studies. This article describes a typology to guide the aims of feasibility and pilot studies designed to support the development of randomized controlled trials and provides an example of the studies underlying the development of one rehabilitation trial. The purpose of most feasibility and pilot studies should be to describe information and evidence related to the successful implementation and validity of a planned main trial. Null hypothesis significance testing is not appropriate for these studies unless the sample size is properly powered. The primary tests of the intervention effectiveness hypotheses should occur in the main study, not in the studies that are serving as feasibility or pilot studies. PMID- 23433272 TI - Introducing a new intervention: an overview of research phases and common challenges. AB - This article examines the challenges in and progress of behavioral intervention research, the trajectory followed for introducing new interventions, and key considerations in protocol development. Developing and testing health-related behavioral interventions involve an incremental and iterative process to build a robust body of evidence that initially supports feasibility and safety, then proves efficacy and effectiveness, and subsequently involves translation, implementation, and sustainability in a real-world context. This process occurs over close to two decades and yields less than 14% of the evidence being integrated into practice. New hybrid models that blend test phases and involve stakeholders and end users up front in developing and testing interventions may shorten this time frame and enhance adoption of a proven intervention. Knowledge of setting exigencies and implementation challenges may also inform intervention protocol development and facilitate rapid and efficient translation into practice. Although interventions needed to improve the public's health are complex and funding lags behind, introducing new interventions remains a critical and most worthy pursuit. PMID- 23433273 TI - Dissemination: bringing translational research to completion. AB - Despite the availability of innovative health care research, a gap exists between research-generated knowledge and the utilization of that knowledge in real-world practice settings. This article examines the transition from research to implementation in the context of the dissemination of A. Jean Ayres' sensory integration procedures and of the challenges currently facing the University of Southern California Well Elderly Studies research team. Drawing from the emerging field of implementation science, this article discusses how researchers can develop an implementation plan to more easily translate evidence into practice. Such plans should address the intervention's reach (i.e., its capacity to penetrate into the intended target population), the settings for which it is applicable, the leaders who will encourage practitioner uptake, stakeholder groups, and challenges to dissemination. By taking action to ensure the more effective dissemination of research-generated knowledge, researchers can increase the likelihood that their interventions will lead to improvements in practice and more effective care for consumers. PMID- 23433274 TI - Comprehensive behavioral intervention to improve occupational performance in children with Tourette disorder. AB - OBJECTIVE. We evaluated the efficacy of a comprehensive behavioral intervention for tics (CBIT) program to reduce tic severity and improve occupational performance in children with tic disorder using a one-group pretest-posttest design. METHOD. Thirty children with tic disorder completed an eight-session CBIT program. The program focused on habit reversal, relaxation training, and function based approaches to address how the environment and social situations (antecedents and consequences) sustain or influence tic severity. RESULTS. We observed significant reduction in the number of tics and improvement in scores on the Parent Tic Questionnaire, Subjective Units of Distress Scale, and Child Occupational Self Assessment after CBIT compared with scores at baseline. CONCLUSION. Findings provided support that CBIT reduced the number of tic expressions, tic severity, and level of distress associated with tic and improved these children's self-perception of their competence in and importance of performing everyday activities (i.e., occupational performance). PMID- 23433275 TI - Group constraint-induced movement therapy for children with hemiplegic cerebral palsy: a pilot study. AB - OBJECTIVE. We investigated the feasibility and effectiveness of group-based constraint-induced movement therapy (CIMT) for children with hemiplegic cerebral palsy in a clinical setting. METHOD. Seven children received CIMT together under the guidance of two occupational therapy practitioners, 2.5 hr/day, 5 days/wk for 4 wk. We used the Grasping and Visual-Motor Integration subtests of the Peabody Developmental Motor Scales to assess the primary outcome and the Functional Skills and Caregiver Assistance Scales of the Pediatric Evaluation Disability Inventory to assess the secondary outcome. Children were examined at preintervention, postintervention, and 1- and 3-mo follow-up. RESULTS. Children demonstrated significant improvement on all outcome measures after intervention (all ps < .05, effect sizes = .39-.84), and effects were maintained at 3-mo follow-up. CONCLUSION. This preliminary study revealed that group-based CIMT for children with hemiplegic cerebral palsy may be a feasible and effective alternative to individual CIMT in clinical practice. PMID- 23433276 TI - Children's assessment of participation and enjoyment/preference for activities of children: psychometric properties in a population with high-functioning autism. AB - The psychometric properties of assessments must be established for specific populations. The psychometric properties of the Children's Assessment of Participation and Enjoyment/Preference for Activities of Children have been studied only in a sample of children with physical disability. We conducted a study to determine the appropriateness of drawing inferences from this assessment for children with high-functioning autism (HFA). The content validity and test retest reliability (r > .7) were both found to be adequate for this population. Parents' agreement with most of their children's self-ratings on this assessment provided an estimate of interrater reliability. We also ascertained the feasibility of gathering recreational participation information from children with HFA and found that adaptations to facilitate the self-completion of the tool should be made available. The study findings support the use of this tool to assess recreational participation among children with HFA. PMID- 23433277 TI - Writing forces associated with four pencil grasp patterns in grade 4 children. AB - OBJECTIVE. We investigated differences in handwriting kinetics, speed, and legibility among four pencil grasps after a 10-min copy task. METHOD. Seventy four Grade 4 students completed a handwriting assessment before and after a copy task. Grip and axial forces were measured with an instrumented stylus and force sensitive tablet. We used multiple linear regression to analyze the relationship between grasp pattern and grip and axial forces. RESULTS. We found no kinetic differences among grasps, whether considered individually or grouped by the number of fingers on the barrel. However, when grasps were grouped according to the thumb position, the adducted grasps exhibited higher mean grip and axial forces. CONCLUSION. Grip forces were generally similar across the different grasps. Kinetic differences resulting from thumb position seemed to have no bearing on speed and legibility. Interventions for handwriting difficulties should focus more on speed and letter formation than on grasp pattern. PMID- 23433278 TI - Family-centered principles implemented in home-based, clinic-based, and school based pediatric settings. AB - OBJECTIVE: The goal of this study was to determine whether pediatric occupational therapy practitioners implemented family-centered principles in their practice. METHOD: Twenty-eight occupational therapy practitioners were interviewed in three practice settings: home based, clinic based, and school based. A grounded theory approach was used to analyze the results. Responses were compared across respondents and across practice settings. RESULTS: Responses varied among practitioners and, more significantly, practice settings. A continuum of family centered practice was demonstrated, with home-based practice as the most family centered, school-based practice as the least family centered, and clinic practice varying in between. CONCLUSION: Occupational therapy practitioners are familiar with most principles of family-centered practice. However, implementation of those principles differs significantly across practice settings. PMID- 23433279 TI - Effects of constraint-induced therapy combined with eye patching on functional outcomes and movement kinematics in poststroke neglect. AB - OBJECTIVE. We investigated the effect of constraint-induced therapy (CIT) plus eye patching (EP), CIT alone, and conventional treatment on functional performance, eye movement, and trunk-arm kinematics in stroke patients with neglect syndrome. METHOD. Twenty-four participants were recruited and randomly allocated to three intervention groups. All participants received intervention 2 hr/day, 5 days/wk, for 3 wk. Outcome measures included the Catherine Bergego Scale, eye movement, and trunk-arm kinematic analysis. RESULTS. The CIT + EP and CIT groups demonstrated larger improvements in functional performance than the control group. The CIT group showed better performance with left fixation points than the CIT+EP group and shorter reaction time than the control group. The CIT + EP group improved more in preplanned control and leftward trunk shift than the other two groups. CONCLUSION. CIT + EP and CIT were more effective interventions than conventional treatment of patients with neglect syndrome in daily functional performance. PMID- 23433280 TI - Psychometric Properties of the Practical Skills Test (PST). AB - The Practical Skills Test (PST) is a new assessment of individuals' knowledge of life skills. We evaluated the PST's reliability, validity, and sensitivity to change among a homeless population. Participants were 123 homeless persons in a longitudinal experimental study who were assessed before and after intervention with the PST, Allen Cognitive Level Screen-2000 (ACLS-2000), and Impact of Event Scale-Revised (IES-R). The PST showed generally good internal consistency, no floor effects, and limited ceiling effects (<20% on each test). Supportive evidence for the PST's convergent validity was seen in its moderate correlations with the ACLS-2000; we found no significant correlation with the IES-R. Paired t tests indicated that the PST is sensitive to changes in life skills after intervention, but effect sizes were small. The results suggest that the PST has generally good reliability and validity. However, ceiling effects suggest an area for further development. PMID- 23433282 TI - Philip King Brown and Arequipa Sanatorium: early occupational therapy as medical and social experiment. AB - Historical inquiry enriches occupational therapy practice by identifying enduring values and inspiring future excellence. This study presents for the first time the pioneering life and work of Philip King Brown, a San Francisco physician who used occupation to treat the physical, mental, and social effects of tuberculosis (TB) at Arequipa Sanatorium, the institution he founded in 1911. Through textual analysis of the Arequipa Sanatorium Records, this article evaluates and defends Brown's assertion that his institution was medically and socially experimental. The Arequipa Sanatorium promoted occupational therapy by demonstrating its viability in the treatment of TB, the era's most critical health threat. It also put into practice the ideals of holism, humanism, and occupational justice that resonate within the profession today. Finally, Arequipa provided an example of how an occupation program can change the public perception of disability. PMID- 23433283 TI - The evidence-based paradox. AB - Many occupational therapy practitioners consider evidence-based practice (EBP) to be the means by which occupational therapy can prove the validity of its services and thus support the legitimacy of our profession. The unquestioned acceptance of EBP as the way to establish credibility concerns me; unchallenged acceptance of any idea concerns me. Do practitioners accept EBP as the paradigm for guiding occupational therapy practice and research solely because it is presented as what we must do? I believe that practitioners must examine the implications for our profession of accepting EBP without question. In this article, I review EBP, present criticisms and concerns voiced by other professions and, finally, examine the implications of adopting an EBP perspective that replaces theory-directed practice. PMID- 23433284 TI - Upper limb arterial thromboembolism: a systematic review on incidence, risk factors, and prognosis, including a meta-analysis of risk-modifying drugs. AB - OBJECTIVES: The aim of this review is to focus on risk factors, risk-modifying drugs and prognosis for upper limb arterial thromboembolism, and the relationship between upper limb arterial thromboembolism and atrial fibrillation (AF). METHODS: We searched MEDLINE for studies on the epidemiology of upper limb thromboembolism from 1965 to June 2012. We also searched for contemporary, phase III randomized trial data on systemic (non-stroke) thromboembolism comparing warfarin with new oral anticoagulants (OACs) in patients with atrial fibrillation published after the year 1999. RESULTS: The incidence of upper limb thromboembolectomy was 3.3 per 100 000 person-years among men and 5.2 per 100 000 person-years among women; the risk of limb amputation, stroke and death after thromboembolectomy was increased. There was an increased risk of thromboembolectomy of the upper limb in patients with AF diagnosed with hypertension (hazard ratio [HR] 2.2-2.9), myocardial infarction (HR 2.9-3.9), heart failure (HR 1.6-1.9), and stroke (HR 2.2-3.8). For those diagnosed with diabetes mellitus, the risk was non-significantly increased by 1.2-1.4. Females had a 1.8-fold (95% confidence interval [CI] 1.5-2.3) fold increased risk of thromboembolectomy as compared with men. The risk reduction for systemic embolism with new OACs as compared with warfarin in patients with AF is similar to that seen with warfarin (odds ratio 0.79, 95% CI 0.38-1.64). CONCLUSIONS: Age, female sex, AF, hypertension, diabetes, myocardial infarction, heart failure and stroke are most common risk factors for thromboembolectomy of the upper limb. The availability of new OACs holds promise for reducing the risk of systemic thromboembolism, but specific data are still limited. PMID- 23433285 TI - Quality of life changes following inpatient and outpatient treatment in obsessive compulsive disorder: a study with 12 months follow-up. AB - BACKGROUND: Quality of life (QoL) is increasingly recognized as a critical outcome parameter in mental health studies. The aim of this study was to investigate different domains of the QoL in persons with obsessive-compulsive disorder (OCD) before and after a multimodal, disorder-specific in- and outpatient treatment. METHODS: Data of 73 persons with OCD treated in an inpatient setting followed by outpatient treatment were analyzed. The World Health Organization Quality of Life abbreviated (a multidimensional measure of the QoL) and the Beck Depression Inventory were administered prior to (baseline) and 12 months after the inpatient treatment (follow-up). RESULTS: At baseline, participants reported a significantly diminished psychological, social, physical, and global QoL compared to the German general population. Environmental QoL was not impaired in the present sample. The QoL was significantly improved at follow up, except for social QoL, but remained below norm values. The QoL improvement was predicted by improvements of depressive symptoms. CONCLUSIONS: The results indicate that persons with OCD suffer from a very low QoL. The QoL was significantly improved after 12 months of intensive state-of-the-art treatment. However, the QoL indices remained considerably lower than population norm values, indicating the need for additional research into novel treatment options for persons with OCD. PMID- 23433286 TI - Quebec and Canadian governments end their historic support of the asbestos industry. PMID- 23433288 TI - Time-to-tumor dose threshold analysis for intratracheal particle instillation induced lung tumors in a large carcinogenicity study. AB - BACKGROUND AND OBJECTIVES: A comprehensive time-to-tumor analysis of the 16 dose groups which received intratracheal instillations of "respirable granular bio durable particles without known significant specific toxicity" (GBP) in a large carcinogenicity study with rats should be conducted. METHODS: The primary lung tumors were mathematically treated as observed in an incidental context (non fatal occult tumors), based on biological observations and on the fact that lifetime was not considerably reduced even in groups with high tumor frequency. Maximum likelihood estimates of the parameters of time-to-tumor multistage Weibull models were calculated. RESULTS: Retained dust volume is a highly significantly better dose measure than instilled dust mass, where particle size is taken into account; there is no empirical support for a dose threshold from this study. CONCLUSIONS: Carcinogenicity studies with intratracheal instillation can lead to results that are relevant for the assessment of relative carcinogenic potencies of particles. A dose threshold for GBP is not supported. PMID- 23433287 TI - Sources and risk factors for lead exposure in indigenous children of the Peruvian Amazon, disentangling connections with oil activity. AB - INTRODUCTION: In the Corrientes river basin, Peruvian Amazon, lead exposure among indigenous communities was first reported in 2006. To address controversy regarding the main source of exposure, this study aimed to identify the sources and risk factors for lead exposure among children from the communities in question, and to clarify the potential relationship with oil activity. METHODS: This cross-sectional study was conducted in six communities. Participants were children aged 0-17 years and their mothers. Data collection included blood lead levels (BLLs) and hemoglobin determination, a questionnaire on risk factors and environmental sampling. We used age-stratified multivariate regression models, with generalized estimating equation to account for correlation within households. RESULTS: Twenty-seven percent of the children had BLLs >=10 MUg/dl. Mother's BLLs >=10 MUg/dl, playing and chewing lead scraps, fishing >=three times/week, and living in highly oil-exposed communities increased the risk of having BLLs >=10 MUg/dl. Lead concentrations in sediment, soil, dust, and fish samples were below reference values. CONCLUSIONS: Mother's BLLs >=10 MUg/dl, playing and chewing lead scraps to manufacture fishing sinkers were the most important risk factors for children's BLLs >=10 MUg/dl. The connection with oil activity appears to be through access to metal lead from the industry's wastes. PMID- 23433289 TI - Estimating work-related amputations in the Norwegian manufacturing sector: a 10 year retrospective study based on two-source capture-recapture method. AB - BACKGROUND: Work-related amputations are serious yet preventable injuries. Workers in the manufacturing sector in particular are vulnerable to amputation injuries compared to workers in other sectors. METHODS: In this study, we used a two-source capture recapture method to estimate the true number of annual work related amputations in the Norwegian manufacturing sector for a 10-year study period (1998-2007). The two-sources utilized in this study were the Norwegian Labor Inspection Authorities Registry of Work-Related Injuries (RWI) and the Association of Norwegian Private Insurance Companies registry for occupational injuries (ANPIC). RESULTS: We estimated an annual incidence rate that ranged from 21/100 000 to 62/100 000 workers during the study period. Our findings indicate an undercount of amputations reported to the Norwegian Labour Inspection Authority's registry ranging from 16% to 58% during the study period. CONCLUSIONS: Work-related amputations remain a challenge in the Norwegian manufacturing sector. This study underscores the need of robust epidemiological surveillance infrastructure and effective interventions to prevent amputations at work. PMID- 23433290 TI - Workplace injuries and risk reduction practices in Malaysia. AB - INTRODUCTION: This study on workplace injuries and risk reduction practices was part of the Malaysia National Health Morbidity Survey III (NHMS III) conducted in 2006. METHODS: This cross-sectional population-based survey was conducted to determine the incidence of workplaces injuries and assess the magnitude of some important risk reduction practices among workers. Data were gathered through face to-face household interviews using a pre-coded questionnaire. RESULTS: Of the 22 880 eligible respondents, 88.2% (20 180) responded. The incidence rate for injuries at the workplace was 4.9 per 100 (95% CI: 4.6-5.2). The overall proportion of workers who had received occupational safety and health (OSH) training before or within 1 month of starting work was 33.6%. Among respondents who perceived that personal protective equipment (PPE) was required at their workplace, only 38.9% (95% CI: 37.8-39.4) were provided with it by their employers. DISCUSSION: Further studies are urgently needed to identify reasons for and management of the low uptake of risk reduction practices. This issue needs to be addressed to ensure the safety and health of our working population. PMID- 23433292 TI - Provision of control measures for exposure of the hands to wet-working conditions in Australian workplaces. AB - OBJECTIVE: To analyze the occupational and demographic characteristics for workers participating in the Australian National Hazard Exposure Worker Surveillance (NHEWS) Survey, who reported the provision of various types of workplace control measures for exposure of the hands to wet-working conditions, and to identify the barriers for the provision of controls. METHODS: Computer assisted telephone interviews were conducted with 4500 workers in 2008. Workers were asked about the types of control measures provided to them in the workplace for exposure of the hands to liquids. RESULTS: Workplace size was the strongest predictor for the provision of control measures. Compared to workplaces with fewer than five employees, workers in workplaces with 200 or more employees were more likely to report provision of gloves, barrier creams and moisturizers, labeling and warning, and ongoing training and education about skin care. CONCLUSION: Smaller workplaces have poorer access to control measures to mitigate exposure to wet work. PMID- 23433291 TI - Healthcare worker safety: a vital component of surgical capacity development in low-resource settings. AB - INTRODUCTION: A disparate number of occupational exposures to bloodborne pathogens occur in low-income countries where disease prevalence is high and healthcare provider-per-population ratios are low. METHODS: In an effort to highlight the important role of healthcare worker safety in surgical capacity building in Rwanda, we measured self-reported presence of safety materials and compliance with personal protective equipment in the operating theatre as part of a nationwide survey to characterize emergency and essential surgical capacity in all government hospitals. RESULTS: We surveyed 44 hospitals. While staff report general availability of safe disposal of sharps and hazardous waste, presence of and compliance with eye protection was lacking. Staff were cognizant of prevention measures such as double-gloving and 'safe receptacles', as well as hospital policies for post-exposure prophylaxis for HIV following needlesticks, but there was little awareness of hepatitis exposure. CONCLUSIONS: Healthcare worker safety should be a key component of hospital-level surgical capacity. PMID- 23433293 TI - Personal protective equipment and work safety climate among Latino poultry processing workers in Western North Carolina, USA. AB - BACKGROUND: Job-appropriate personal protective equipment (PPE) is important for decreasing the high rates of occupational injury experienced by poultry processing workers. OBJECTIVES: This analysis describes the job-appropriate PPE provided to poultry processing workers by their employers and the PPE used by these workers, and it delineates the association of work safety climate with job appropriate PPE. METHODS: Data are from a cross-sectional study of 403 Latino poultry processing workers in North Carolina. RESULTS: Most poultry processing workers are not provided with nor use job-appropriate PPE; however, more workers use PPE than are provided. The provision and use of PPE differs by employer. Work safety climate was associated with use of job-appropriate PPE. CONCLUSIONS: Poultry processing workers should be provided with job-appropriate PPE. Workers' use of PPE is an indicator of safety climate. Further research about work safety climate and other work organization characteristics and job safety characteristics is needed. PMID- 23433294 TI - Assessing specific causation of mesothelioma following exposure to chrysotile asbestos-containing brake dust. AB - BACKGROUND: The question of whether chrysotile asbestos-containing brake dust can plausibly serve as a cause of mesothelioma in an exposed individual has become a matter of heated debate in the medical literature despite multiple international, federal, and state governmental agencies acknowledging a causal association. OBJECTIVES: We describe and provide an analysis of various industry and academic perspectives contributing to the debate. METHODS: A framework is presented for evaluating the general and specific causal relationship between brake dust exposure and mesothelioma utilizing the principles of forensic epidemiology, and by applying the Bradford-Hill criteria. RESULTS AND CONCLUSIONS: We conclude that there is a "net" of evidence favoring a causal relationship between brake dust associated chrysotile exposure and mesothelioma. The industry-sponsored position that there is insufficient evidence to support a contiguous "chain" of causation is specious from both a methodologic and evidentiary perspective. Finally, we suggest a semiquantitative approach for the evaluation of individual causation in putative cases of mesothelioma with a history of significant brake dust exposure. PMID- 23433295 TI - Mesothelioma associated with use of drywall joint compound: a case series and review of literature. AB - BACKGROUND: Drywall joint compound contained asbestos fibers, primarily chrysotile, in the 1950s through the 1970s. Workers in a variety of construction trades and homeowners were exposed to respirable asbestos from the use of these products, including during handling, mixing, sanding, and sweeping. Disturbance of in-place asbesto-containing joint compound continues to be a potential source of exposure during demolition or repair of wallboard. Studies from the 1970s and 1980s report air fiber measurements above current and historic regulatory limits during intended usage, and typical asbestos-related disease in drywall construction workers. OBJECTIVES: We present three cases of mesothelioma in which the only known exposure to asbestos was from joint compound and review the literature on exposure circumstances, dose and fiber types. CONCLUSIONS: Physicians treating mesothelioma patients should obtain a history of exposure to these products during work or home remodeling. PMID- 23433296 TI - Expanding control banding for workplace silica exposures throughout the Americas. AB - BACKGROUND: Silicosis, a lung disease caused by inhaling respirable crystalline silica dust, is an occupational illness affecting millions of workers worldwide. The National Institute for Occupational Safety and Health (NIOSH) has partnered with the World Health Organization, the International Labour Organization, and multiple agencies in the Americas to implement the program "The Elimination of Silicosis in the Americas". OBJECTIVES: One component of this program is control banding, a qualitative risk assessment and management strategy that allows non experts to use task-based hazard data and potential exposure information to determine appropriate controls. RESULTS: From 2005 to the present, NIOSH occupational health researchers have worked with experts in Chile, Peru, Colombia, and Brazil to assess, implement, and provide tools to evaluate the use of control banding methodology. PMID- 23433297 TI - The Mexican epidemic of obesity and the North American Free Trade Agreement. PMID- 23433299 TI - Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: extracellular signal-regulated kinase involvement. AB - Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells. PMID- 23433300 TI - The effect of infections on the mortality of cirrhotic patients with hepatic encephalopathy. AB - Cirrhotic patients are prone to having infections, which may aggravate hepatic encephalopathy (HE). However, the effect of infections on mortality in HE cirrhotic patients is not well described. The National Health Insurance Database, derived from the Taiwan National Health Insurance Programme, was used to identify 4150 adult HE cirrhotic patients hospitalized between 1 January 2004 and 31 December 2004. Nine hundred and eighty-five patients (23.7%) had one or more co existing infections during their hospitalization. After Cox proportional hazard regression modelling adjusted by the patients' gender, age, and medical comorbidity disorders, the hazard ratios (HRs) in HE patients with infections for 30-day, 30- to 90-day, and 90-day to 1-year mortalities were 1.66 [95% confidence interval (CI) 1.42-1.94], 1.51 (95% CI 1.23-1.85) and 1.34 (95% CI 1.13-1.58), respectively. Compared to the non-infection group, the HRs of pneumonia, spontaneous bacterial peritonitis, urinary tract infection, sepsis without specific focus (SWSF), cellulitis, and biliary tract infection were 2.11, 1.48, 1.06, 2.21, 1.06, and 0.78, respectively, for 30-day mortality; 1.82, 1.22, 0.93, 2.24, 0.31, and 2.82, respectively, for 30- to 90-day mortality; and 2.03, 0.82, 1.24, 1.64, 1.14, and 0.60, respectively, for 90-day to 1-year mortality for HE cirrhotic patients. We conclude that infections increase the mortality of HE cirrhotic patients, especially pneumonia and SWSF. PMID- 23433301 TI - A framework for scientific advice on health: EuSANH's principles and guidelines. AB - BACKGROUND: Society expects politicians to make sound decisions by bringing the best evidence to bear on the health problems in question. Performing this task requires access to independent sources of sound scientific advice. The European Science Advisory Network for Health (EuSANH) is a network of national science advisory bodies in Europe which are active in the field of health and provide independent scientific advice to their authorities. The EuSANH addressed this question in a European project. METHODS: Guidelines and principles for producing sound advice have been formulated after international comparative evaluations and extensive discussions among participants of the EuSANH-ISA project with input from international experts. RESULTS: A framework for scientific advice on health has been produced. CONCLUSIONS: This framework will ensure a uniform approach and thus opens possibilities for collaboration between science advisory bodies. PMID- 23433302 TI - Perception of malaria risk in a setting of reduced malaria transmission: a qualitative study in Zanzibar. AB - BACKGROUND: Malaria transmission has declined dramatically in Zanzibar in recent years. Continuing use of preventive measures such as long-lasting insecticidal treated nets (LLINs), and use of malaria rapid diagnostic tests (RDTs) are essential to prevent malaria resurgence. This study employed qualitative methods to explore community perceptions of malaria risk and adherence to prevention measures in two districts in Zanzibar. METHODS: Key informant interviews with 24 primary health care providers and 24 focus group discussions with local residents in Zanzibar districts Wete and Central were conducted during April and May 2012 focusing on perception of malaria risk, current preventive practices used, reasons for using preventive practices and effective strategies for malaria control. RESULTS: Health care providers and residents appear to be aware of the decreasing incidence of malaria. Both groups continue the use of malaria preventive practices in this low and seasonal transmission setting. The most important preventive measures identified were LLINs, indoor residual spraying (IRS), and education. Barriers to malaria prevention include: lack of staff at clinics, insufficient number of LLINs distributed, and inadequate malaria education. Reasons for continued use of preventive practices include: fear of malaria returning to high levels, presence of mosquitoes during rainy seasons, and concern about local cases from other villages or imported cases from mainland Tanzania. Mosques, clinics, schools and community meetings were listed as most important sources of education. However, residents express the desire for more education. CONCLUSION: Health care providers and residents generally reported consistent use of malaria preventive measures. However, maintaining and continuing to reduce malaria transmission will require ongoing education for both health care providers and residents to reinforce the importance of using preventive measures. Successful efforts to reduce malaria in Zanzibar will be jeopardized if residents believe that they are no longer at risk for malaria. In future studies, a year-round evaluation of the perception of malaria risk and use of preventive measures will inform the timing of education and prevention strategies for sustained malaria control. PMID- 23433303 TI - The ancestral activation promiscuity of ADP-glucose pyrophosphorylases from oxygenic photosynthetic organisms. AB - BACKGROUND: ADP-glucose pyrophosphorylase (ADP-Glc PPase) catalyzes the first committed step in the synthesis of glycogen in bacteria and starch in algae and plants. In oxygenic photosynthetic organisms, ADP-Glc PPase is mainly activated by 3-phosphoglycerate (3-PGA) and to a lesser extent by other metabolites. In this work, we analyzed the activation promiscuity of ADP-Glc PPase subunits from the cyanobacterium Anabaena PCC 7120, the green alga Ostreococcus tauri, and potato (Solanum tuberosum) tuber by comparing a specificity constant for 3-PGA, fructose-1,6-bisphosphate (FBP), fructose-6-phosphate, and glucose-6-phosphate. RESULTS: The 3-PGA specificity constant for the enzymes from Anabaena (homotetramer), O. tauri, and potato tuber was considerably higher than for other activators. O. tauri and potato tuber enzymes were heterotetramers comprising homologous small and large subunits. Conversely, the O. tauri small subunit (OtaS) homotetramer was more promiscuous because its FBP specificity constant was similar to that for 3-PGA. To explore the role of both OtaS and OtaL (O. tauri large subunit) in determining the specificity of the heterotetramer, we knocked out the catalytic activity of each subunit individually by site-directed mutagenesis. Interestingly, the mutants OtaSD148A/OtaL and OtaS/OtaLD171A had higher specificity constants for 3-PGA than for FBP. CONCLUSIONS: After gene duplication, OtaS seemed to have lost specificity for 3-PGA compared to FBP. This was physiologically and evolutionarily feasible because co-expression of both subunits restored the specificity for 3-PGA of the resulting heterotetrameric wild type enzyme. This widespread promiscuity seems to be ancestral and intrinsic to the enzyme family. Its presence could constitute an efficient evolutionary mechanism to accommodate the ADP-Glc PPase regulation to different metabolic needs. PMID- 23433304 TI - Predictors of perinatal mortality in rural population of Northwest Ethiopia: a prospective longitudinal study. AB - BACKGROUND: Perinatal mortality is one of the serious challenges in meeting maternal and child Millennium Development Goals in developing countries. Identifying its predictors is an important step to develop focused and appropriate health interventions for reducing perinatal deaths. This study therefore aims at identifying predictors of perinatal mortality in a rural setting in northwest Ethiopia. METHODS: A prospective longitudinal study was conducted at Dabat Health and Demographic Surveillance site, northwest Ethiopia, from November 2009 to August 2011. Data were collected by interviewing the mothers or guardians of eligible children. Multiple logistic regressions were employed to identify potential predictors. RESULTS: A total of 1752 eligible children were included in the study. Perinatal mortality rate in the study population was 50.22 per 1000 (95% CI: 39.99, 60.46) total births. In multiple logistic analysis, previous still birth [(AOR = 8.38, 95% CI: 3.94, 17.83)], twin birth [(AOR = 7.09, 95% CI: (3.22, 15.61)], not receiving tetanus toxoid vaccine during the index pregnancy [(AOR = 3.62, 95% CI: 1.57, 8.34)], short birth interval of less than 24 months [(AOR = 2.58, 95% CI: (1.61, 4.13)], maternal illiteracy [(AOR = 4.83, 95% CI: (1.45, 16.05)] and mothers' running own business [(AOR = 5.40, 95% CI: 1.40, 27.96)] were the main predictors associated with increased risk of perinatal death. CONCLUSIONS: Predictors of perinatal death in the study area are easily recognizable and potentially preventable with the existing maternal health programs. Efforts need to be intensified in expanding maternal and newborn health services to significantly reduce perinatal mortality in rural settings. PMID- 23433305 TI - Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. AB - AIMS: Aside from lowering blood glucose, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure-lowering effects of the GLP-1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes (T2DM) based on randomized controlled trials (RCTs) including data describing complete blood pressure (BP) changes from baseline. METHODS: We searched the major databases for published or unpublished RCTs that had been performed in patients with T2DM and compared the effects of exenatide and liraglutide to those of other common drugs used to treat T2DM. The RCTs that included data describing BP changes between the baseline and the end of the study were selected for further analysis. RESULTS: A total of 16 RCTs that enrolled 3443 patients in the GLP-1 RA treatment group and 2417 subjects in the control group were included in this meta-analysis. The GLP-1 RA exenatide reduced systolic blood pressure (SBP) when compared with both placebo and insulin glargine, with mean differences of -5.24 and -3.46 mmHg, respectively, and with 95% confidence intervals (CI) of -6.88 to -3.59, p < 0.00001 and -3.63 to -3.29, p < 0.00001, respectively. Meanwhile, in the exenatide-treated group, diastolic blood pressure (DBP) was reduced by -5.91 mmHg, with a 95% CI of -7.53 to -4.28, p < 0.00001 compared with the placebo group, and -0.99 mmHg with a 95% CI of 1.12 to -0.87, p < 0.00001 compared with the sitagliptin group. SBP changes in this meta-analysis were assessed in the groups treated with 1.2 or 1.8 mg liraglutide per day. In the 1.2 mg-treated group, liraglutide treatment reduced SBP compared with placebo and glimepiride treatment, with mean differences of 5.60 and -2.38 mmHg, and 95% CIs of -5.84 to -5.36, p < 0.00001 and -4.75 to 0.01, p = 0.05, respectively. In the 1.8-mg-treated group, liraglutide also reduced SBP compared with placebo and glimepiride treatment with mean differences of -4.49 and -2.62 mmHg, and a 95% CI of -4.73 to -4.26, p < 0.00001, and -2.91 to -2.33, p < 0.00001, respectively. CONCLUSION: Treatment with the GLP-1 RAs exenatide and liraglutide reduced SBP and DBP by 1 to 5 mmHg compared with some other anti-diabetic drugs including insulin, glimepiride and placebo for patients with T2DM. GLP-1 RAs may offer an alternative therapy for these patients and will help provide extra cardiovascular benefits. PMID- 23433306 TI - Blood meal origins and insecticide susceptibility of Anopheles arabiensis from Chano in South-West Ethiopia. AB - BACKGROUND: Anopheles arabiensis, the main malaria vector in Ethiopia, shows both anthropophilic and zoophilic behaviours. Insecticide resistance is increasing, and alternative methods of vector control are needed. The objectives of this study were to determine the blood meal origins and the susceptibility to insecticides of An. arabiensis from Chano village near Arba Minch in South-West Ethiopia. METHODS: Blood meal sources of anopheline mosquitoes collected using Centers for Disease Control and Prevention (CDC) light traps and pyrethrum spray catches (PSC) from human dwellings, and hand-held mouth aspirators from outdoor pit shelters were analysed using a direct enzyme-linked-immunosorbent assay (ELISA). The susceptibility of An. arabiensis to pyrethroid insecticides (alphacypermethrin, lambdacyhalothrin, deltamethrin, and cyfluthrin) and DDT was assessed using females reared from larval and pupal collections from natural breeding sites. RESULTS: The blood meal origins of 2967 freshly fed Anopheles mosquitoes were determined. An. arabiensis was the predominant species (75%), and it fed mainly on cattle. The densities of both freshly fed An. arabiensis and those fed on human blood followed similar seasonal patterns. The overall human blood index (HBI) of An. arabiensis, including mixed blood meals, was 44% and the bovine blood index (BBI) was 69%. The HBI of An. arabiensis from CDC light trap collections was 75% and this was higher than those for PSC (38%) and outdoor pit shelter collections (13%), while the BBI was 65% for PSC, 68% for outdoor pit shelters and 72% for CDC light traps. More freshly fed and human blood-fed An. arabiensis were sampled from houses close to the shore of Lake Abaya (the major breeding site).A high proportion of An. arabiensis was resistant to the pyrethroid insecticides, with a mortality rate of 56% for lambdacyhalothrin, 50% for cyfluthrin and alphacypermethrin, 47% for deltamethrin, and 10% for DDT. CONCLUSION: Anopheles arabiensis is the predominant species of anopheline mosquito in this region, and cattle are the main source of its blood meals. The greater tendency of this species to feed on cattle justifies the application of insecticides on cattle to control it. However, An. arabiensis has already developed resistance to the available pyrethroid insecticides, and alternative insecticides are needed for malaria vector control. PMID- 23433310 TI - Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies. AB - BACKGROUND: Inconsistent data on the association between prenatal alcohol exposure and a range of pregnancy outcomes, such as preterm birth (PTB) and small for gestational age (SGA) raise new questions. This study aimed to assess whether the association between low-moderate prenatal alcohol exposure and PTB and SGA differs according to maternal education, maternal mental distress or maternal smoking. METHODS: The Amsterdam Born Children and their Development (ABCD) Study (N = 5,238) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) (N = 16,301) are both large studies. Women provide information on alcohol intake in early pregnancy, 3 months postpartum and up to 17 years retrospectively. Multivariate logistic regression analyses and stratified regression analyses were performed to examine the association between prenatal alcohol exposure and PTB and SGA, respectively. RESULTS: No association was found between any level of prenatal alcohol exposure (non-daily, daily, non abstaining) and SGA. The offspring of daily drinkers and non-abstainers had a lower risk of PTB [ABCD: odds ratio (OR) 0.31, 95% confidence interval (CI) 0.13, 0.77; KiGGS: OR 0.75, 95% CI 0.57, 0.99]. Interactions with maternal education, maternal distress or maternal smoking were not significant. CONCLUSIONS: Although these results should be interpreted with caution, both studies showed no adverse effects of low-moderate prenatal alcohol exposure on PTB and SGA, not even in the offspring of women who were disadvantaged in terms of low education, high levels of distress, or smoking during pregnancy. PMID- 23433311 TI - A qualitative evaluation of New Zealand consumers perceptions of general practice nurses. AB - BACKGROUND: An important consideration in health service delivery is ensuring that services meet consumer needs and that consumers are satisfied with service delivery. Patient satisfaction can impact on compliance with suggested treatments and therefore impact on health outcomes. Comparatively few studies have explored consumer satisfaction with nurses in general practice. METHODS: A sub-group of 18 consumers from a larger quantitative evaluation of consumer satisfaction with New Zealand general practice nurses participated in semi-structured telephone interviews. Interview data was analysed using thematic analysis. RESULTS: Four major themes emerged from the data. These themes highlighted that, despite confusion experienced by some consumers regarding the practice nurse role, consumers were happy with the level of care provided by them. Consumers felt valued by Practice Nurses and considered them competent and highly knowledgeable. Findings also convey that consumers appreciate the accessibility and financial benefits of utilising the services of practice nurses. CONCLUSIONS: Consumers are highly satisfied with practice nurse service delivery and value their relationships with these health professionals. Consumers revealed that greater clarity around the practice nurse role and their scope of practice may enhance their utilisation. Spreading the message of practice nurses being the right person to deliver care, within their scope of practice, at the right time may have the potential to provide more timely care within the primary care setting. PMID- 23433312 TI - Should we maintain baby hatches in our society? AB - BACKGROUND: A baby hatch called the "Stork's Cradle" has been in place at Jikei Hospital in Kumamoto City, Japan, since May 10, 2007. Babyklappes were first established in Germany in 2000, and there are currently more than 90 locations. Attitudes regarding baby hatches are divided in Japan and neither opinions for nor against baby hatches have thus far been overwhelming. To consider the appropriateness of baby hatches, we present and examine the validity of each major objection to establishing baby hatches. DISCUSSION: There are various objections to baby hatches as follows: It violates a child's right to know the identity of his or her biological parents by allowing anonymous birth; it neglects fulfillment of the biological parents' basic obligation to raise their child and its very availability induces abandonment of infants; some people abuse it for very selfish reasons; it cannot save babies' lives; the rights of one parent can be ignored if the other surrenders a child without his or her consent; it puts a baby in medical jeopardy; and it has no clear legal basis. The authors would argue that there are many plausible refutations for each objection mainly based on priority of child's right to life, pregnant women's vulnerability and necessity of anonymity, social responsibility to protect and raise children, differences between dropping a child off at a baby hatch and child neglect, limited function of social childcare center, inevitability of abuse by a minority of people, necessary distinction between outcomes that occur only because baby hatches exist and those that occur regardless of their existence, important local direct and upmost measures for women in trouble, and difference between ambiguous legality and illegality. SUMMARY: We argue that a certain number of baby hatches should continue to be established as a last resort, in a form that can maintain anonymity if the parent dropping the child off so desires. It should be supported if it is initiated with good intentions; if the maximum possible effort is made at said facility to protect the interests, rights, and safety of the child; and if no clear evidence of harm exists. PMID- 23433313 TI - Incidence of hypotony and sympathetic ophthalmia following trans-scleral cyclophotocoagulation for glaucoma and a report of risk factors. AB - OBJECTIVE: To report the incidence and risk factors for hypotony and estimate the risk of sympathetic ophthalmia following diode laser trans-scleral cyclophotocoagulation (TSCPC). DESIGN: Retrospective study using data from a private tertiary glaucoma clinic and review of the literature. PARTICIPANTS: Seventy eyes of 70 patients with refractory glaucoma who received TSCPC treatment. METHODS: Review of the records of consecutive patients who underwent TSCPC by a single ophthalmic surgeon and review of the literature. MAIN OUTCOME MEASURES: Hypotony (including phthisis bulbi), sympathetic ophthalmia. RESULTS: Seven eyes (10%; CI 5-19%) developed hypotony and included 4 eyes that developed phthisis. Higher total energy delivered during TSCPC treatment was associated with an increased risk of hypotony: eyes that developed hypotony received a mean total energy of 192.5 +/- 73.2 joules, compared to a mean of 152.9 +/- 83.2 joules in hypotony-free cases. The risk of sympathetic ophthalmia estimated from a review of the published literature and current series was one in 1512, or 0.07% (CI 0.03%-0.17%). CONCLUSIONS: Total laser energy is one of several risk factors that act in a sufficient component cause-model to produce hypotony in an individual patient. The small sample size precluded inference for other individual putative risk factors but titrating laser energy may help decrease the occurrence of hypotony. The risk of sympathetic ophthalmia calculated from the literature is likely an overestimate caused by publication bias. PMID- 23433315 TI - Clostridium difficile outcomes difficult to generalize. PMID- 23433314 TI - Psychosocial risk factors, pre-motor symptoms and first-time hospitalization with Parkinson's disease: a prospective cohort study. AB - BACKGROUND AND PURPOSE: Experimental studies support a link between stress and development of parkinsonian symptoms, but prospective population studies are lacking. The aim of the current study is to determine the effects of several psychosocial factors on the risk of Parkinson's disease (PD), as well as to identify potential pre-motor symptoms for PD in a large prospective cohort study. METHODS: In 1991-1993, a total of 9955 women and men free of PD from the Copenhagen City Heart Study were asked about major life events, economic hardship, social network, impaired sleep and vital exhaustion. The participants were followed for first-time hospitalization with PD in nationwide registers until 2011. RESULTS: Vital exhaustion was associated with a higher risk of PD hospitalization in an exposure-dependent manner (P(trend) = 0.001), with high vs. low vital exhaustion being associated with a hazard ratio of 2.50 [95% confidence interval (CI): 1.28-4.89]. A slightly higher risk of PD hospitalization (hazard ratio = 1.49; 95% CI: 0.87-2.56) was suggested in participants with impaired sleep at baseline. No more than weak associations were observed for economic hardship, major life events or inadequate social network in the current study. CONCLUSIONS: Overall, the hypothesis that psychosocial risk factors affect the risk of PD is not supported. The results, however, suggest that vital exhaustion may be a pre-motor marker of the neurodegenerative process eventually leading to motor symptoms and clinical PD. Vital exhaustion may be useful for screening aimed at early detection and when considering disease-modifying therapies in people at high risk of clinical PD. PMID- 23433316 TI - Evolving friendships and shifting ethical dilemmas: fieldworkers' experiences in a short term community based study in Kenya. AB - Fieldworkers (FWs) are community members employed by research teams to support access to participants, address language barriers, and advise on culturally appropriate research conduct. The critical role that FWs play in studies, and the range of practical and ethical dilemmas associated with their involvement, is increasingly recognised. In this paper, we draw on qualitative observation and interview data collected alongside a six month basic science study which involved a team of FWs regularly visiting 47 participating households in their homes. The qualitative study documented how relationships between field workers and research participants were initiated, developed and evolved over the course of the study, the shifting dilemmas FWs faced and how they handled them. Even in this one case study, we see how the complex and evolving relationships between fieldworkers and study participants had important implications for consent processes, access to benefits and mutual understanding and trust. While the precise issues that FWs face are likely to depend on the type of research and the context in which that research is being conducted, we argue that appropriate support for field workers is a key requirement to strengthen ethical research practice and for the long term sustainability of research programmes. PMID- 23433317 TI - The Yin and Yang of pain: variability in formalin test nociception and morphine analgesia produced by the Yin Yang 1 transcription factor gene. AB - We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified. PMID- 23433319 TI - Hysterectomy and bilateral adnexectomy by laparoscopic single port access for female to male transsexualism. PMID- 23433320 TI - Advancing nematode barcoding: a primer cocktail for the cytochrome c oxidase subunit I gene from vertebrate parasitic nematodes. AB - Although nematodes are one of the most diverse metazoan phyla, species identification through morphology is difficult. Several genetic markers have been used for their identification, but most do not provide species-level resolution in all groups, and those that do lack primer sets effective across the phylum, precluding high-throughput processing. This study describes a cocktail of three novel primer pairs that overcome this limitation by recovering cytochrome c oxidase I (COI) barcodes from diverse nematode lineages parasitic on vertebrates, including members of three orders and eight families. Its effectiveness across a broad range of nematodes enables high-throughput processing. PMID- 23433318 TI - Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics. AB - BACKGROUND: The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. METHOD: The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. RESULTS: BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by > 75% after infection with oncolytic viruses. CONCLUSIONS: These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53 mutations. Although BIN-67 cells are resistant to standard chemotherapeutic agents, their sensitivity to oncolytic viruses suggests that their therapeutic use in SCCOHT should be considered. PMID- 23433321 TI - Calcineurin inhibitors and the IL12A locus influence risk of recurrent primary biliary cirrhosis after liver transplantation. PMID- 23433322 TI - Small Indian mongooses and masked palm civets serve as new reservoirs of Bartonella henselae and potential sources of infection for humans. AB - The prevalence and genetic properties of Bartonella species were investigated in small Indian mongooses and masked palm civets in Japan. Bartonella henselae, the causative agent of cat-scratch disease (CSD) was isolated from 15.9% (10/63) of the mongooses and 2.0% (1/50) of the masked palm civets, respectively. The bacteraemic level ranged from 3.0 * 10(1) to 8.9 * 10(3) CFU/mL in mongooses and was 7.0 * 10(3) CFU/mL in the masked palm civet. Multispacer typing (MST) analysis based on nine intergenic spacers resulted in the detection of five MST genotypes (MSTs 8, 14, 37, 58 and 59) for the isolates, which grouped in lineage 1 with MST genotypes of isolates from all CSD patients and most of the cats in Japan. It was also found that MST14 from the mongoose strains was the predominant genotype of cat and human strains. This is the first report on the isolation of B. henselae from small Indian mongooses and masked palm civets. The data obtained in the present study suggest that these animals serve as new reservoirs for B. henselae, and may play a role as potential sources of human infection. PMID- 23433323 TI - 17 OHPC for prevention of preterm birth in twins: back to the drawing board? PMID- 23433324 TI - Prevention of preterm delivery by 17 alpha-hydroxyprogesterone caproate in asymptomatic twin pregnancies with a short cervix: a randomized controlled trial. AB - OBJECTIVE: The objective of the study was to evaluate the use of 17 alpha hydroxyprogesterone caproate (17P) to reduce preterm delivery in women with a twin pregnancy and short cervix. STUDY DESIGN: This open-label, multicenter, randomized controlled trial included women with a twin pregnancy between 24(+0) and 31(+6) weeks of gestation who were asymptomatic and had a cervical length of 25 mm or less measured by routine transvaginal ultrasound. Women were randomized to receive (or not) 500 mg of intramuscular 17P, repeated twice weekly until 36 weeks or preterm delivery. The primary outcome was time from randomization to delivery. Analysis was performed according to the intent-to-treat principle. RESULTS: The 17P and control groups did not differ significantly for median [interquartile range] time to delivery: 45 (26-62) and 51 (36-66) days, respectively. However, treatment with 17P was associated with a significant increase in the rate of preterm delivery before 32 weeks. CONCLUSION: Twice weekly injections of 17P did not prolong pregnancy significantly in asymptomatic women with a twin pregnancy and short cervix. PMID- 23433325 TI - Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation induced offspring cerebral injury shown on magnetic resonance imaging. AB - OBJECTIVE: Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic N-acetyl cysteine (NAC). We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS)-induced neonatal brain injury using magnetic resonance imaging. STUDY DESIGN: Pregnant Sprague Dawley dams (n = 5-8) at embryonic day 18 received intraperitoneal injection of LPS or saline at time 0. Animals were randomized to receive 2 intravenous injections of NAC or saline (time -30 and 120 minutes). Pups were delivered spontaneously and allowed to mature until postnatal day 25. Female offspring were examined by magnetic resonance brain imaging and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess white matter injury and diffusion tensor imaging for apparent diffusion coefficient (ADC) to assess white and gray matter injury. RESULTS: Offspring of LPS-treated dams exhibited significantly increased T2 levels and increased ADC levels in white and gray matter (eg, hypothalamus, motor cortex, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of NAC-treated LPS dams demonstrated similar T2 and ADC levels as control in both white and gray matter. CONCLUSION: Maternal NAC treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. These studies suggest that maternal NAC therapy may be effective in human deliveries associated with maternal/fetal inflammation. PMID- 23433327 TI - Spinal cord injury facts and figures at a glance. PMID- 23433326 TI - Prevention of preterm birth by progestational agents: what are the molecular mechanisms? AB - OBJECTIVE: Clinically, vaginal progesterone (VP) and 17 alpha-hydroxyprogesterone caproate (17P) have been shown to prevent preterm birth (PTB) in high-risk populations. We hypothesize that treatment with these agents may prevent PTB by altering molecular pathways involved in uterine contractility or cervical remodeling. STUDY DESIGN: Using a mouse model, on embryonic day (E)14-E17 CD-1 pregnant mice were treated with: (1) 0.1 mL of 25 mg/mL of 17P subcutaneously; (2) 0.1 mL of castor oil subcutaneously; (3) 0.1 mL of 10 mg/mL of progesterone in a long-lasting Replens (Lil' Drug Store Products, Inc., Cedar Rapids, IA); or (4) 0.1 mL of the same Replens, with 4 dams per treatment group. Mice were sacrificed 6 hours after treatment on E17.5. Cervices and uteri were collected for molecular analysis. RESULTS: Exposure to VP significantly increased the expression of defensin 1 compared to Replens (P < .01) on E17.5. Neither VP nor 17P altered the expression of uterine contraction-associated proteins, progesterone-mediated regulators of uterine quiescence, microRNA involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune cell trafficking or collagen content in the cervix. CONCLUSION: Neither VP nor 17P had any effect on the studied pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP was noted to increase the expression of the antimicrobial protein defensin 1. Whether this molecular change from VP results in a functional effect and is a key mechanism by which VP prevents PTB requires further study. PMID- 23433328 TI - The Academy of SCI Professionals: multidisciplinary or interdisciplinary? PMID- 23433329 TI - Rehabilitation and treatment of spinal cord tumors. AB - CONTEXT: Due to advances in acute oncological treatment, patients with spinal cord tumors exhibit improved survival. However, these patients have not received the full benefits of rehabilitation services to address their neurological deficits and rehabilitation goals. OBJECTIVE: To evaluate the epidemiology and pathophysiology of spinal cord tumors, address methods of acute oncological management, review treatment for neurological sequelae, and understand the implications as they relate to rehabilitation. METHODS: An extensive literature review was performed regarding the epidemiology, pathophysiology, acute oncological management, neurological sequelae, and rehabilitation for patients with spinal cord tumors. Databases used included pubmed.gov and OVID, as well as individual journal and textbook articles. RESULTS: Access to treatment should be increased given improved survival and functional deficits for patients with spinal cord tumors. Individuals can benefit from inpatient rehabilitation programs, in spite of increased medical co-morbidity and neurological deficits. Specific areas of improvement include functionality, mood, quality of life, and survival. Adjustments to treatment plans must incorporate medical complications from cancer and its treatment, perceived quality of life, and prognosis. CONCLUSIONS: Patients with spinal cord tumors who participate in rehabilitation programs show general improvement in function, mood, quality of life, and survival. Adaptations to care plans should be made to accommodate medical co morbidities from cancer and its treatment, patient perceptions, and prognosis. PMID- 23433330 TI - One-year follow-up of Chinese people with spinal cord injury: a preliminary study. AB - BACKGROUND: A tertiary spinal cord injury (SCI) center was established in the northern region of Hong Kong, China and a multidisciplinary SCI rehabilitation program was developed to reintegrate patients into the community. OBJECTIVE: To investigate functional outcomes for Chinese people with SCI across a 1-year period. DESIGN: Longitudinal prospective design. METHODS: Thirty community dwelling participants with traumatic SCI were recruited. Functional status was measured using functional independence measure (FIM) on admission, upon discharge, 1-month, 3-month, 6-month, and 1-year post-discharge. Information on use of assistive devices and life role were also obtained. RESULTS: Twenty-three (76.67%) participants were men. Seventeen participants (10 with tetraplegia and 7 with paraplegia) were classified ASIA A, B, or C; 13 (7 with tetraplegia and 6 with paraplegia) were classified as ASIA D. Significant differences in FIM motor scores were only found between the tetraplegia group and three other diagnostic groups using Bonferroni post-hoc tests of repeated measure ANOVA (analysis of variance) (P < 0.05). Longitudinally, contrast tests of repeated measure ANOVA showed significant differences during the hospitalization period for all diagnostic groups. People in the ASIA D group showed significant functional improvement even after 1-year post-discharge (P < 0.05). At 1-year post discharge, only two participants were engaged in either remunerative employment or academic pursuit. CONCLUSION: Despite functional status improvement, few people with traumatic SCI were re-engaged in productive life role 1 year after discharge. Studies with longer follow-up would be beneficial. PMID- 23433331 TI - Conversational analysis of medical discourse in rehabilitation: a study in Korea. AB - OBJECTIVE: The purpose of this study is to conduct an analysis of actual communicative behaviors, including nonverbal ones, between physicians and patients in rehabilitation. DESIGN: Sixteen videotaped physician-patient interactions in a rehabilitation center in Korea were transcribed. And three coders placed utterances in transcripts into categories while watching the videotapes. RESULTS: Consistent with results of previous studies, patient active communicative behaviors varied considerably depending on individual patients. The findings revealed that, on average, patients' active communicative behaviors were less than 9% of patients' total utterances. In particular, almost half of the patients (N = 7) did not even ask one single question. The results also showed that physicians' empathic communicative acts averaged less than 3% of physicians' total utterances. In addition, among physicians' nonverbal behaviors, eye-contact showed significant correlation with physician empathic listening and supportive talks. CONCLUSIONS: The findings of this study indicated a considerable lack of empathic communicative behaviors of physicians in Korea. This might have led to infrequent use of active communicative behaviors by patients. In addition, the importance of physician's partnership for enhancement of active communicative behaviors of patients was demonstrated. To better serve patients, physicians who wish to improve their communication should first identify components of their empathic communicative behaviors that need improvement and then attempt to refine their skills. PMID- 23433332 TI - Posterior spinal artery syndrome showing marked swelling of the spinal cord: a clinico-pathological study. AB - OBJECTIVE: To describe a rare autopsy case of posterior spinal artery syndrome with marked swelling of the spinal cord, an unusually subacute onset and short clinical course. METHODS: Case report. FINDINGS: An 84-year-old Japanese woman presented with bilateral muscle weakness of the lower legs and sensory disturbance 1 week after head contusion. Neurological findings worsened gradually. She developed phrenic nerve paralysis and died of respiratory failure 6 weeks after the onset of neurological symptoms. On pathological examination, the spinal cord was markedly swollen in the cervical and upper thoracic segments. Microscopically, there was loss of myelin sheath in the bilateral posterior columns and neuronal loss of the posterior horns in all of the spinal segments. However, findings were unremarkable in the bilateral anterior columns and bilateral anterior horns in most of the spinal segments. Posterior spinal arteries had no stenosis, occlusion, or thrombosis. We considered that pathogenesis was infarction associated with head injury. CONCLUSION: To our knowledge, this is the first report of a case of posterior spinal artery syndrome with a markedly swollen spinal cord and poor prognosis. PMID- 23433333 TI - Adductor tenotomy and selective obturator neurectomy for the treatment of spasticity in a man with paraplegia. AB - CONTEXT: Excessive hip adductor spasticity in patients with spinal cord injury (SCI) can produce scissoring effect of the thighs which can interfere with various activities of daily living. If noninvasive measures do not produce desired results, surgical treatment may be considered. One surgical option for the management of adductor spasticity includes adductor tenotomy and selective obturator neurectomy. This procedure was performed in an individual with T11 paraplegia having severe adductor spasticity in both thighs. METHOD: Case report. FINDINGS: Adductor spasticity at hips was identified as the main barrier in functional activities and rehabilitation of our patient. After a trial of noninvasive treatment, a selective obturator neurectomy and adductor tenotomy were carried out, which completely relieved his adductor spasticity at both thighs without any complications. With comprehensive rehabilitation, the patient showed enhanced functional independence in various activities of daily living. This helped the patient to achieve functional indoor ambulation using orthosis in spite of complete paraplegia. Conclusion/clinical reference: Severe adductor spasticity can have debilitating effects and could be a major barrier in rehabilitation of patients with SCI. Surgical treatment for adductor spasticity can be considered when patients are unresponsive to noninvasive treatment. Relief from adductor spasticity can improve functional outcomes and decrease dependency. Although this procedure is commonly performed in patients with cerebral palsy, it remains a viable surgical alternative in carefully selected patients with SCI when other modes of treatment are contraindicated, failed, or not available. PMID- 23433334 TI - Granulocyte colony-stimulating factor reduced neuropathic pain associated with thoracic compression myelopathy: report of two cases. AB - CONTEXT: A clinical trial was conducted to evaluate the safety and efficacy of neuroprotective therapy using granulocyte colony-stimulating factor (G-CSF) for patients with worsening symptoms of compression myelopathy. During this trial, we found that neuropathic pain associated with thoracic myelopathy was dramatically reduced after G-CSF administration in two cases. FINDINGS: A 32-year-old man with compression of the spinal cord at levels T7-T10 complained of spastic gait associated with spontaneous severe pain from his back to his chest. G-CSF 10 ug/kg/day was administered for 5 consecutive days; his pain was reduced 1 day after the initial G-CSF administration. One month after administration, he underwent spinal fusion surgery for decompression of the spinal cord. Six months after G-CSF administration, he showed recovery from myelopathy and no recurrence of pain. A 68-year-old man with spastic gait and bilateral thigh pain caused by ossified ligamentum flavum at T11-T12 was treated with G-CSF 10 ug/kg/day for 5 days; his pain was reduced 1 day after initial administration. One month later, he underwent a T10-T12 laminectomy. Three months after G-CSF administration, his thigh pain began to attenuate. At 6 months after administration, he showed recovery from myelopathy, and his pain was still improved compared with that before administration. CONCLUSION: G-CSF may have a therapeutic effect on spinal neuropathic pain. PMID- 23433335 TI - Effectiveness of intense, activity-based physical therapy for individuals with spinal cord injury in promoting motor and sensory recovery: is olfactory mucosa autograft a factor? AB - BACKGROUND/OBJECTIVES: Rehabilitation for individuals with spinal cord injury (SCI) is expanding to include intense, activity-based, out-patient physical therapy (PT). The study's primary purposes were to (i) examine the effectiveness of intense PT in promoting motor and sensory recovery in individuals with SCI and (ii) compare recovery for individuals who had an olfactory mucosa autograft (OMA) with individuals who did not have the OMA while both groups participated in the intense PT program. METHODS: Prospective, non-randomized, non-blinded, intervention study. Using the American Spinal Injury Association examination, motor and sensory scores for 23 (7 OMA, 6 matched control and 10 other) participants were recorded. RESULTS: Mean therapy dosage was 137.3 total hours. The participants' total, upper and lower extremity motor scores improved significantly while sensory scores did not improve during the first 60 days and from initial to discharge examination. Incomplete SCI or paraplegia was associated with greater motor recovery. Five of 14 participants converted from motor-complete to motor-incomplete SCI. Individuals who had the OMA and participated in intense PT did not have greater sensory or greater magnitude or rate of motor recovery as compared with participants who had intense PT alone. CONCLUSION: This study provides encouraging evidence as to the effectiveness of intense PT for individuals with SCI. Future research is needed to identify the optimal therapy dosage and specific therapeutic activities required to generate clinically meaningful recovery for individuals with SCI including those who elect to undergo a neural recovery/regenerative surgical procedure and those that elect intense therapy alone. PMID- 23433336 TI - Motion is reduced in the unstable spine with the use of mechanical devices for bed transfers. AB - CONTEXT: Excessive spinal motion generated during multiple bed transfers of patients with unstable spine injuries may contribute to neurological deterioration. OBJECTIVE: To evaluate spinal motion in a cadaveric model of global spinal instability during hospital bed transfers using several commonly used techniques. DESIGN/PARTICIPANTS: A motion analysis and evaluation of hospital bed transfer techniques in a cadaveric model of C5-C6 and T12-L2 global spinal instability. Setting/outcome measures: Global instability at C5-C6 and T12 L2 was created. The motion in three planes was measured in both the cervical and lumbar spine during each bed transfer via electromagnetic motion detection devices. Comparisons between transfers performed using an air-assisted lateral transfer device, manual transfer, a rolling board, and a sliding board were made based on the maximum range of motion observed. RESULTS: Significantly less lateral bending at C5-C6 was observed in air-assisted device transfers when compared with the two other boards. Air-assisted device transfers produced significantly less axial rotation at T12-L2 than the rolling board, and manual transfers produced significantly less thoracolumbar rotation than both the rolling and sliding boards. No other significant differences were observed in cervical or lumbar motion. Motion versus time plots indicated that the log roll maneuvers performed during rolling board and sliding board transfers contributed most of the observed motion. CONCLUSIONS: Each transfer technique produced substantial motion. Transfer techniques that do not include the logroll maneuver can significantly decrease some components of cervical and lumbar motion. Thus, some spinal motion can be reduced through selection of transfer technique. PMID- 23433337 TI - Gene expression profiling of liver X receptor alpha and Bcl-2-associated X protein in experimental transection spinal cord-injured rats. AB - BACKGROUND: Study of molecular responses to central nervous system injury would be helpful for controlling the harmful pathways post-injury and triggering the useful pathways required for the treatment of injury. OBJECTIVE: To investigate the expression level of liver X receptor alpha (LXRalpha) which has anti inflammatory effects and pro-apoptotic Bcl-2-associated X protein (Bax) upon spinal cord injury (SCI). DESIGN: To induce SCI, transection was carried out at T9 level of male Wister rats. Approximately 8 mm of rostral, caudal, and epicenter tissues of injured sites in treated rats were chosen for quantitative real-time polymerase chain reaction at the 6, 24, and 72 hours, and 7 and 10 days post-surgery. RESULTS: Our results showed a complicated temporal and spatial pattern of alteration in LXRalpha and Bax mRNA expression levels after SCI. LXRalpha expression level followed a homologues pattern (additive and subtractive wave) with a difference in time at three areas of studied. Rostral, caudal, and epicenter expression patterns of Bax were dissimilar in these areas. Gradual increase in the expression of Bax without any decrease at the rostral area was observed, presumably indicating the active transcription process of this gene, regardless of its protein situation. CONCLUSION: A time lapse significant change in Bax expression level was observed only in the epicenter of injury, emphasizing that apoptotic responses are limited to this area. Furthermore, an increase in LXRalpha transcription level was observed first in rostral area and then extended to epicentral and caudal areas, implying that inflammation responses extended from rostral to caudal areas. PMID- 23433338 TI - Impact of vehicular strike on particulate matter air quality: results from a natural intervention study in Kathmandu valley. AB - In this natural intervention study, we evaluated the impact of vehicular shutdown during bandhas (general strikes) and meteorological parameters on ambient PM10 concentrations (particulate matter of aerodynamic diameter 10 MUm or less) in the Kathmandu Valley, Nepal. Publicly available PM10 data (January 2003-February 2008) collected at six monitoring stations were combined with meteorological and bandh data. Linear mixed effects regression models were used to examine the effects of bandhas on PM10 concentrations. Lower PM10 concentrations were observed during the monsoon season compared to the winter, across all monitoring stations, with the largest reduction observed for the urban high traffic area (mean +/- standard deviation: 290 +/- 71 vs 143 +/- 36 MUg/m(3)). In the high traffic area, there was 36 MUg/m(3) decrease in PM10 concentration during the bandh period compared to 2 days preceding the bandh, adjusting for season, rainfall, temperature, and windspeed. The improvements in air quality were short lived: PM10 concentration in the urban high traffic area increased by an average of 26 MUg/m(3) within the first 2 days after the bandh. Our results suggest that controlling vehicular traffic can have an immediate impact in improving particulate matter air quality even among the most polluted cities in the world. PMID- 23433339 TI - Policy development, implementation and evaluation by the AIDS control program in Uganda: a review of the processes. AB - BACKGROUND: The AIDS Control Program (ACP) in Uganda has spearheaded the national health sector HIV response for the last three decades. ACP has developed, revised and implemented various HIV prevention, care and treatment policies in order to keep interventions relevant to the changing dynamics of the HIV epidemic. However, the ACP team and partners remain concerned about the lengthy policy development processes. This study documented the policy development and revision processes to identify strengths and weaknesses in order to inform adjustments as Uganda embraces the move to 'zero' HIV infections. METHODS: Data was collected through a review of the relevant policy documents and key informant interviews with the five program officers involved in the recently developed Safe Male Circumcision (SMC) policy and the recently revised HIV Counseling and Testing (HCT) policy. Qualitative data was analyzed manually using pre-determined themes. RESULTS: Development and revision of the SMC and HCT policies followed similar processes that included a series of meetings between senior management and a selected technical working group. However, the gaps included: i) inadequate awareness of the existence of national policy development and management guidelines; ii) limited engagement of the policy analysis unit in the policy development/revision processes; iii) inadequate tracking and evaluation of the policies before revision or development of new related policies; iv) lack of specific protocols/standard operating procedures (SOPs); and, v) limited indigenous funding for the entire policy development processes which contributed to non-adherence to the anticipated timelines. CONCLUSIONS: Policy development and revision of the SMC and HCT policies followed similar processes. Gaps identified included lack of protocols/SOPs for the processes and limited indigenous funding to support adherence to anticipated timelines. We recommend active involvement of the policy analysis unit in all policy processes. Specific protocols/SOPs for development, analysis, revision, implementation, monitoring, evaluation and impact assessment processes should be developed prior to commencement of the activities. PMID- 23433340 TI - The emergence of wildlife species as a source of human rabies infection in Brazil. AB - Forty-five human rabies virus isolates from a wide geographical area of Brazil were characterized using an anti-nucleoprotein monoclonal antibody panel and by partial nucleotide sequencing analysis of the nucleoprotein gene. Three major antigenic groups related to the antigenic variants maintained in domestic dogs, vampire bats and marmosets were identified. Phylogenetic analyses revealed that the viruses from dog-related cases segregated into four sister clades: three associated with dog-endemic cycles in Brazil and one with the crab-eating fox cycle in the northeastern region of the country. The vampire bat- and marmoset related viruses formed two independent groups. The topology of these clades was conserved when these samples were compared to virus representatives of the currently reported rabies endemic cycles in the Americas. These results indicated the presence of multiple endemic transmission cycles maintained in four different reservoirs, domestic dogs, crab-eating foxes, vampire bats and marmosets, which are being transmitted directly to humans and should be considered as a high-risk for rabies infection. PMID- 23433341 TI - Qualitative research within trials: developing a standard operating procedure for a clinical trials unit. AB - BACKGROUND: Qualitative research methods are increasingly used within clinical trials to address broader research questions than can be addressed by quantitative methods alone. These methods enable health professionals, service users, and other stakeholders to contribute their views and experiences to evaluation of healthcare treatments, interventions, or policies, and influence the design of trials. Qualitative data often contribute information that is better able to reform policy or influence design. METHODS: Health services researchers, including trialists, clinicians, and qualitative researchers, worked collaboratively to develop a comprehensive portfolio of standard operating procedures (SOPs) for the West Wales Organisation for Rigorous Trials in Health (WWORTH), a clinical trials unit (CTU) at Swansea University, which has recently achieved registration with the UK Clinical Research Collaboration (UKCRC). Although the UKCRC requires a total of 25 SOPs from registered CTUs, WWORTH chose to add an additional qualitative-methods SOP (QM-SOP). RESULTS: The qualitative methods SOP (QM-SOP) defines good practice in designing and implementing qualitative components of trials, while allowing flexibility of approach and method. Its basic principles are that: qualitative researchers should be contributors from the start of trials with qualitative potential; the qualitative component should have clear aims; and the main study publication should report on the qualitative component. CONCLUSIONS: We recommend that CTUs consider developing a QM-SOP to enhance the conduct of quantitative trials by adding qualitative data and analysis. We judge that this improves the value of quantitative trials, and contributes to the future development of multi-method trials. PMID- 23433342 TI - A system-level, molecular evolutionary analysis of mammalian phototransduction. AB - BACKGROUND: Visual perception is initiated in the photoreceptor cells of the retina via the phototransduction system. This system has shown marked evolution during mammalian divergence in such complex attributes as activation time and recovery time. We have performed a molecular evolutionary analysis of proteins involved in mammalian phototransduction in order to unravel how the action of natural selection has been distributed throughout the system to evolve such traits. RESULTS: We found selective pressures to be non-randomly distributed according to both a simple protein classification scheme and a protein interaction network representation of the signaling pathway. Proteins which are topologically central in the signaling pathway, such as the G proteins, as well as retinoid cycle chaperones and proteins involved in photoreceptor cell-type determination, were found to be more constrained in their evolution. Proteins peripheral to the pathway, such as ion channels and exchangers, as well as the retinoid cycle enzymes, have experienced a relaxation of selective pressures. Furthermore, signals of positive selection were detected in two genes: the short wave (blue) opsin (OPN1SW) in hominids and the rod-specific Na+/ Ca2+, K+ ion exchanger (SLC24A1) in rodents. CONCLUSIONS: The functions of the proteins involved in phototransduction and the topology of the interactions between them have imposed non-random constraints on their evolution. Thus, in shaping or conserving system-level phototransduction traits, natural selection has targeted the underlying proteins in a concerted manner. PMID- 23433343 TI - Blacks and Whites in the Cuba have equal prevalence of hypertension: confirmation from a new population survey. AB - BACKGROUND: The excess burden of hypertension among blacks has been a prominent feature of the heath disparities literature, and many scientists presume it to be a stable and inevitable phenomenon. The underlying causes of this disparity can only be disentangled in a setting in which the population does not experience racial stratification of socioeconomic opportunities. While such conditions of racial equality remain uncommon, they may be approximated in Cuba, a country with a persistent policy of social inclusion over the last 5 decades. METHODS: We report on a 2010-2011 stratified probability sample of those aged 15-74 years from the urban population of Cienfuegos in central Cuba. A total of 1496 adults (880 women and 616 men) were recruited and assessed for blood pressure and anthropometrics according to standardized protocols, as well as medication use, educational attainment and observed skin tone (dichotomized into "black" and "white"). Weighted tabular and regression analyses were conducted to estimate adjusted prevalences of hypertension (> 140/90 mmHg) and adjusted prevalence odds ratios for contrasts between the two skin color groups. RESULTS: Mean pressures were higher for men than for women, but overall did not differ importantly between racial groups. About half of all diagnosed hypertensive men were on medication, a proportion that did not vary by racial group. For women, however, adjusted prevalence was somewhat higher among blacks, and treatment and control rates were also somewhat advantaged for white women. CONCLUSIONS: Overall, skin color was unrelated to mean blood pressure or hypertensive status in this population, although among women specifically some racial advantage appears evident in adjusted prevalence and control, and should be investigated further. The overall null result suggests that Cuba may exemplify the social conditions in which racial excess in hypertension, characteristic of much of the western world, is not a necessary reality. PMID- 23433344 TI - Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. AB - BACKGROUND: A recent study using a rat model found significant differences at the time of diabetes onset in the bacterial communities responsible for type 1 diabetes modulation. We hypothesized that type 1 diabetes in humans could also be linked to a specific gut microbiota. Our aim was to quantify and evaluate the difference in the composition of gut microbiota between children with type 1 diabetes and healthy children and to determine the possible relationship of the gut microbiota of children with type 1 diabetes with the glycemic level. METHODS: A case-control study was carried out with 16 children with type 1 diabetes and 16 healthy children. The fecal bacteria composition was investigated by polymerase chain reaction-denaturing gradient gel electrophoresis and real-time quantitative polymerase chain reaction. RESULTS: The mean similarity index was 47.39% for the healthy children and 37.56% for the children with diabetes, whereas the intergroup similarity index was 26.69%. In the children with diabetes, the bacterial number of Actinobacteria and Firmicutes, and the Firmicutes to Bacteroidetes ratio were all significantly decreased, with the quantity of Bacteroidetes significantly increased with respect to healthy children. At the genus level, we found a significant increase in the number of Clostridium, Bacteroides and Veillonella and a significant decrease in the number of Lactobacillus, Bifidobacterium, Blautia coccoides/Eubacterium rectale group and Prevotella in the children with diabetes. We also found that the number of Bifidobacterium and Lactobacillus, and the Firmicutes to Bacteroidetes ratio correlated negatively and significantly with the plasma glucose level while the quantity of Clostridium correlated positively and significantly with the plasma glucose level in the diabetes group. CONCLUSIONS: This is the first study showing that type 1 diabetes is associated with compositional changes in gut microbiota. The significant differences in the number of Bifidobacterium, Lactobacillus and Clostridium and in the Firmicutes to Bacteroidetes ratio observed between the two groups could be related to the glycemic level in the group with diabetes. Moreover, the quantity of bacteria essential to maintain gut integrity was significantly lower in the children with diabetes than the healthy children. These findings could be useful for developing strategies to control the development of type 1 diabetes by modifying the gut microbiota. PMID- 23433345 TI - Characterization of the complete mitochondrial genome of Spirocerca lupi: sequence, gene organization and phylogenetic implications. AB - BACKGROUND: Spirocerca lupi is a life-threating parasitic nematode of dogs that has a cosmopolitan distribution but is most prevalent in tropical and subtropical countries. Despite its veterinary importance in canids, the epidemiology, molecular ecology and population genetics of this parasite still remain unexplored. METHODS: The complete mitochondrial (mt) genome of S. lupi was amplified in four overlapping long fragments using primers designed based on partial cox1, rrnS, cox2 and nad2 sequences. Phylogenetic re-construction of 13 spirurid species (including S. lupi) was carried out using Bayesian inference (BI) based on concatenated amino acid sequence datasets. RESULTS: The complete mt genome sequence of S. lupi is 13,780 bp in length, including 12 protein-coding genes, 22 transfer RNA genes and two ribosomal RNA genes, but lacks the atp8 gene. The gene arrangement is identical to that of Thelazia callipaeda (Thelaziidae) and Setaria digitata (Onchocercidae), but distinct from that of Dracunculus medinensis (Dracunculidae) and Heliconema longissimum (Physalopteridae). All genes are transcribed in the same direction and have a nucleotide composition high in A and T. The content of A + T is 73.73% for S. lupi, in accordance with mt genomes of other spirurid nematodes sequenced to date. Phylogenetic analyses using concatenated amino acid sequences of the 12 protein-coding genes by BI showed that the S. lupi (Thelaziidae) is closely related to the families Setariidae and Onchocercidae. CONCLUSIONS: The present study determined the complete mt genome sequence of S. lupi. These new mt genome dataset should provide novel mtDNA markers for studying the molecular epidemiology and population genetics of this parasite, and should have implications for the molecular diagnosis, prevention and control of spirocercosis in dogs and other canids. PMID- 23433346 TI - Oral care perspectives of professionals in nursing homes for the elderly. AB - OBJECTIVES: Good oral health is an important aspect of quality of life. However, a number of studies have shown that oral care for the dependent elderly is unsatisfactory. The aim was to explore in nursing homes for the elderly what professionals with different responsibilities may consider as being important aspects of well-functioning daily oral care. METHODS: A total of 23 informants from three municipalities in the region of Varmland, Sweden, were interviewed. An interview guide was used, containing some demographic and open-ended questions about individual perceptions of issues according to the study aim. The interviews were tape-recorded and transcribed verbatim. RESULTS: In the manifest and latent analyses, six categories and three themes emerged. The categories were Key Processes, Communication, Priorities, Competence, Good Oral Health and Autonomy. The themes were Organization, Staff Approach and Staff's Views on Residents' Needs. An overall picture emerged that oral care, rather than occupying an integral position, played a peripheral role in nursing care. CONCLUSIONS: To improve oral care, there are opportunities to work with existing structures and clarify responsibilities and key processes. Oral care should be included in nursing work as a more highly prioritized task, and nurses' knowledge needs to be enhanced. A network of activities at all levels is needed to implement oral care in nursing care. PMID- 23433347 TI - Can community retail pharmacist and diabetes expert support facilitate insulin initiation by family physicians? Results of the AIM@GP randomized controlled trial. AB - BACKGROUND: Limited evidence exists on the effectiveness of external diabetes support provided by diabetes specialists and community retail pharmacists to facilitate insulin-prescribing in family practice. METHODS: A stratified, parallel group, randomized control study was conducted in 15 sites across Canada. Family physicians received insulin initiation/titration education, a physician specific 'report card' on the characteristics of their type 2 diabetes (T2DM) population, and a registry of insulin-eligible patients at a workshop. Intervention physicians in addition received: (1) diabetes specialist/educator consultation support (active diabetes specialist/educator consultation support for 2 months [the educator initiated contact every 2 weeks] and passive consultation support for 10 months [family physician initiated as needed]); and (2) community retail pharmacist support (option to refer patients to the pharmacist(s) for a 1-hour insulin-initiation session). The primary outcome was the insulin prescribing rate (IPR) per physician defined as the number of insulin starts of insulin-eligible patients during the 12-month strategy. RESULTS: Consenting, eligible physicians (n = 151) participated with 15 specialist sites and 107 community pharmacists providing the intervention. Most physicians were male (74%), and had an average of 81 patients with T2DM. Few (9%) routinely initiated patients on insulin. Physicians were randomly allocated to usual care (n = 78) or the intervention (n = 73). Intervention physicians had a mean (SE) IPR of 2.28 (0.27) compared to 2.29 (0.25) for control physicians, with an estimated adjusted RR (95% CI) of 0.99 (0.80 to 1.24), p = 0.96. CONCLUSIONS: An insulin support program utilizing diabetes experts and community retail pharmacists to enhance insulin prescribing in family practice was not successful. Too few physicians are appropriately intensifying diabetes management through insulin initiation, and aggressive therapeutic treatment is lacking. PMID- 23433348 TI - Blood meal sources and entomological inoculation rates of anophelines along a highland altitudinal transect in south-central Ethiopia. AB - BACKGROUND: The role of anophelines in transmitting malaria depends on their distribution, preference to feed on humans and also their susceptibility to Plasmodium gametocytes, all of which are affected by local environmental conditions. Blood meal source and entomological inoculation rate of anophelines was assessed along a highland altitudinal transect in south- central Ethiopia. METHODS: Monthly adult anopheline sampling was undertaken from July 2008 to June 2010 in Hobe (low altitude), Dirama (mid altitude) and Wurib (high altitude) villages located at average elevations of 1800 m, 2000 m and 2200 m, respectively. Anophelines were collected using CDC light trap, pyrethrum space spray catches (PSC) and artificial pit shelter methods. Upon collection, females were categorized according to their abdominal status and identified to species. Their human blood index, sporozoite rate and entomological inoculation rate was determined. RESULTS: A total of 4,558 female anophelines of which Anopheles arabiensis was the most prevalent (53.3%) followed by Anopheles demeilloni (26.3%), Anopheles christyi (8.9%), Anopheles pharoensis (7.9%) and Anopheles cinereus (3.6%) were caught and tested for blood meal source or sporozoite infection depending on their abdominal status. The proportions of human fed and bovine fed An. arabiensis were generally similar. In the low altitude village, there were 0.3% (1/300) and 0.2% (1/416) Plasmodium falciparum infected An. arabiensis among the CDC trap catches and PSC respectively. The percentage of Plasmodium vivax infected An. arabiensis were 3% (9/300) and 0.7(3/416) among the CDC and PSCs respectively in the village. In addition, there were 1.4% (1/71) and 50% (1/2) P. vivax infected An. pharoensis from the CDC light trap and PSCs, respectively. In the mid altitude village, 2.5% (1/40) and 1.7% (1/58) from among the CDC and PSCs of An. arabiensis respectively carried P. vivax sporozoites. Among the CDC light trap catches; there were 3.7 and 0 P. falciparum infective bites per year per household for An. arabiensis in the years July 2008 to June 2009 and July 2009 to June 2010 respectively in the low altitude village. The corresponding numbers for P. vivax infective bites for An. arabiensis were 33 and 14.5 in the same village. Space spray catches revealed 0.32 P. vivax infective bites per household for An. pharoensis during the first year in the low altitude village. CONCLUSION: Anopheles arabiensis was the most prevalent vector of P. vivax and P. falciparum malaria in the low and mid altitude villages followed by An. pharoensis. Annual entomological inoculation rates showed that vivax malaria transmission was higher than that of the falciparum and both decreased with increase in altitude. PMID- 23433349 TI - The effectiveness of medical assistant health coaching for low-income patients with uncontrolled diabetes, hypertension, and hyperlipidemia: protocol for a randomized controlled trial and baseline characteristics of the study population. AB - BACKGROUND: Many patients with chronic disease do not reach goals for management of their conditions. Self-management support provided by medical assistant health coaches within the clinical setting may help to improve clinical outcomes, but most studies to date lack statistical power or methodological rigor. Barriers to large scale implementation of the medical assistant coach model include lack of clinician buy-in and the absence of a business model that will make medical assistant health coaching sustainable. This study will add to the evidence base by determining the effectiveness of health coaching by medical assistants on clinical outcomes and patient self-management, by assessing the impact of health coaching on the clinician experience, and by examining the costs and potential savings of health coaching. METHODS/DESIGN: This randomized controlled trial will evaluate the effectiveness of clinic-based medical assistant health coaches to improve clinical outcomes and self-management skills among low-income patients with uncontrolled type 2 diabetes, hypertension, or hyperlipidemia. A total of 441 patients from two San Francisco primary care clinics have been enrolled and randomized to receive a health coach (n = 224) or usual care (n = 217). Patients participating in the health coaching group will receive coaching for 12 months from medical assistants trained as health coaches. The primary outcome is a change in hemoglobin A1c, systolic blood pressure, or LDL cholesterol among patients with uncontrolled diabetes, hypertension and hyperlipidemia, respectively. Self-management behaviors, perceptions of the health care team and clinician, BMI, and chronic disease self-efficacy will be measured at baseline and after 12 months. Clinician experience is being assessed through surveys and qualitative interviews. Cost and utilization data will be analyzed through cost predictive models. DISCUSSION: Medical assistants are an untapped resource to provide self-management support for patients with uncontrolled chronic disease. Having successfully completed recruitment, this study is uniquely poised to assess the effectiveness of the medical assistant health coaching model, to describe barriers and facilitators to implementation, and to develop a business case for sustainability. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT 01220336. PMID- 23433350 TI - Effects of antiproteolytic agents on corneal epithelial viability and matrix metalloproteinase-2 and metalloproteinase-9 activity in alkali-burned corneas of rats. AB - OBJECTIVE: To evaluate the effects of agents on corneal re-epithelization and metalloproteinase-2 and metalloproteinase-9 (MMP-2 and MMP-9) activities in corneas of rats submitted to ulceration. ANIMALS STUDIED: Ninety eight healthy rats. PROCEDURES: Corneal ulcers were created using 1N NaOH in their left eye. Eyes were treated every 6 h with 1% ethylenediaminetetraacetic acid (EDTA), 3% chondroitin sulfate (CS), 10% N-acetylcysteine NAc and saline (S) at 6-h intervals. Corneas were stained with fluorescein and photographed at the same time points. Following 20 h and 40-42 h of corneal injury, corneas were processed for scanning electron microscopy (SEM) to quantify microvilli density, and MMPs activities were analyzed using zymography. RESULTS: The percentage of wound area and the time in hours for corneal re-epithelization did not differ significantly among treatment groups (P > 0.05). In first and the second moments, latent MMP-2 was significantly elevated in the eyes treated with NAC and CS (P < 0.001). Active MMP-2 did not change significantly among treatment groups in the first moment (P > 0.05); significantly higher activity was observed in the second moment in the eyes treated with CS (P <0.001). In the second moment, latent MMP-9 decreased significantly in eyes treated with EDTA and S (P < 0.01). Microvilli corneal density did not change significantly between healthy subjects and treatment groups (P > 0.05). CONCLUSION: Any of the studied substances did not accelerate corneal re-epithelization and did not add protection to the corneal microvilli. Significant higher levels of active form of MMP-2 in 3% chondroitin sulfate-treated group may indicate that the agent acts as substrate for such enzyme. At the end of the experiment, 1% EDTA was the most efficient agent to inhibit significantly the latent form of MMP-9. However, any of the substances add benefit over saline on reducing the proteolytic activity in the cornea of rats after alkali injury. PMID- 23433351 TI - Relationship between macular ganglion cell complex thickness and macular outer retinal thickness: a spectral-domain optical coherence tomography study. AB - BACKGROUND: To assess the relationship between macular ganglion cell complex and macular outer retinal thicknesses. DESIGN: Case-control study. PARTICIPANTS: Forty-two normal eyes and 91 eyes with primary open-angle glaucoma were studied. METHODS: Spectral-domain optical coherence tomography (RTVue-100) was used to measure the macular ganglion cell complex and macular outer retinal thickness. Ganglion cell complex to outer retinal thickness ratio was also calculated. MAIN OUTCOME MEASURES: The relationships between the ganglion cell complex and outer retinal thicknesses and between the ganglion cell complex to outer retinal thickness ratio and outer retinal thickness were evaluated. RESULTS: There was a positive correlation between ganglion cell complex and outer retinal thicknesses in the normal group and the glaucoma group (r = 0.53, P < 0.001 and r = 0.42, P < 0.001, respectively). In that respect, there was no correlation between ganglion cell complex to outer retinal thickness ratio and outer retinal thickness in the both groups (r = -0.07, P = 0.657, and r = 0.04, P = 0.677, respectively). The ganglion cell complex to outer retinal thickness ratio was 55.65% in the normal group, 45.07% in the glaucoma group. This difference was statistically significant. CONCLUSIONS: The ganglion cell complex thickness may be affected by outer retinal thickness, and there is individual variation in the outer retinal thickness. Therefore, when determining the ganglion cell complex, it seems necessary to consider the outer retinal thickness as well. We propose the ratio as a suitable parameter to account for individual variations in outer retinal thickness. PMID- 23433352 TI - The relationship between depressive/anxiety symptoms during pregnancy/postpartum and sexual life decline after delivery. AB - INTRODUCTION: Several factors have been found to be independently associated with decline in sexual activity after delivery. However, the association between depression in pregnancy/postpartum and sexual problems is less clear. AIM: To prospectively evaluate the relationship between depressive/anxiety symptoms (DAS) during the perinatal period and sexual life in the postpartum period. METHODS: A prospective cohort study conducted between May 2005 and March 2007 included 831 pregnant women recruited from primary care clinics of the public sector in Sao Paulo, Brazil. Four groups with DAS during antenatal and postpartum periods were identified using the Self Report Questionnaire (SRQ-20): absence of both antenatal and postpartum DAS; presence of antenatal DAS only; presence of postpartum DAS only; and presence of both antenatal and postpartum DAS. The primary outcome was perception of sexual life decline (SLD) before and after pregnancy/delivery. Crude and adjusted risk ratios (RR), with 95% confidence intervals (95% CI), were calculated using Poisson regression to examine the associations between DAS and SLD. MAIN OUTCOME MEASURE: The main outcome measure of this study is the perception of SLD before and after pregnancy/delivery. RESULTS: SLD occurred in 21.1% of the cohort. In the multivariable analysis, the following variables were independently associated with SLD: DAS during both pregnancy and postpartum (RR: 3.17 [95% CI: 2.18-4.59]); DAS during only the postpartum period (RR: 3.45 [95% CI: 2.39-4.98]); a previous miscarriage (RR: 1.54 [95% CI: 1.06-2.23]); and maternal age (RR: 2.11 [95% CI: 1.22-3.65]). CONCLUSIONS: Postpartum women with DAS have an increased likelihood for SLD up to 18 months after delivery. Efforts to improve the rates of recognition and treatment of perinatal depression/anxiety in primary care settings have the potential to preserve sexual functioning for low-income mothers. PMID- 23433353 TI - The association of IL-6 and IL-6R gene polymorphisms with chronic periodontitis in a Chinese population. AB - OBJECTIVE: The aim of our investigation is to reveal the association of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) gene polymorphisms with chronic periodontitis in Northwestern Chinese Han Population. MATERIAL AND METHODS: A case-control study of 199 cases of chronic periodontitis patients and 216 healthy controls was performed. Genomic DNA was isolated from whole venous blood, and four single nucleotide polymorphisms (IL-6 -572 G/C and -1363 G/T, IL 6R -183 G/A and +48892 A/C) were analysed using polymerase chain reaction, followed by restriction fragment length polymorphism analysis and sequencing methods. RESULTS: Our SNP analyses showed that the distribution of the IL-6 -572 G/C and IL-6R -183 G/A polymorphisms did not differ between patients and controls. The frequency of the IL-6 -1363 G/T genotype GG was significantly increased chronic periodontitis cases (P = 0.023, odds ratio (OR) = 2.825 adjusted for gender and age.) The IL-6R +48892 A/C polymorphisms genotype CC was found to be protective against chronic periodontitis (P = 0.004, OR = 0.318 adjusted for gender and age.). In addition, compared with the other haplotypes, haplotype A(+48892) A(-183) was significantly associated with chronic periodontitis, with an odds ratio of 0.720 (P = 0.0235). CONCLUSION: Our results suggest that the IL-6 -1363 G/T and IL-6R +48892 A/C polymorphisms may contribute to genetic susceptibility to chronic periodontitis in Northwestern Chinese Han population. PMID- 23433354 TI - OCT4 increases BIRC5 and CCND1 expression and promotes cancer progression in hepatocellular carcinoma. AB - BACKGROUND: OCT4 and BIRC5 are preferentially expressed in human cancer cells and mediate cancer cell survival and tumor maintenance. However, the molecular mechanism that regulates OCT4 and BIRC5 expression is not well characterized. METHODS: By manipulating OCT4 and BIRC5 expression in hepatocellular carcinoma (HCC) cell lines, the regulatory mechanism of OCT4 on BIRC5 and CCND1 were investigated. RESULTS: Increasing or decreasing OCT4 expression could enhance or suppress BIRC5 expression, respectively, by regulating the activity of BIRC5 promoter. Because there is no binding site for OCT4 within BIRC5 promoter, the effect of OCT4 on BIRC5 promoter is indirect. An octamer motif for OCT4 in the CCND1 promoter has directly and partly participated in the regulation of CCND1 promoter activity, suggesting that OCT4 also could upregulated the expression of CCND1. Co-suppression of OCT4 and BIRC5 induced cancer cell apoptosis and cell cycle arrest, thereby efficiently inhibiting the proliferative activity of cancer cells and suppressing the growth of HCC xenogrfts in nude mice. CONCLUSION: OCT4 can upregulate BIRC5 and CCND1 expression by increasing their promoter activity. These factors collusively promotes HCC cell proliferation, and co-suppression of OCT4 and BIRC5 is potentially beneficial for HCC treatment. PMID- 23433355 TI - Feedback of research findings for vaccine trials: experiences from two malaria vaccine trials involving healthy children on the Kenyan Coast. AB - Internationally, calls for feedback of findings to be made an 'ethical imperative' or mandatory have been met with both strong support and opposition. Challenges include differences in issues by type of study and context, disentangling between aggregate and individual study results, and inadequate empirical evidence on which to draw. In this paper we present data from observations and interviews with key stakeholders involved in feeding back aggregate study findings for two Phase II malaria vaccine trials among children under the age of 5 years old on the Kenyan Coast. In our setting, feeding back of aggregate findings was an appreciated set of activities. The inclusion of individual results was important from the point of view of both participants and researchers, to reassure participants of trial safety, and to ensure that positive results were not over-interpreted and that individual level issues around blinding and control were clarified. Feedback sessions also offered an opportunity to re-evaluate and re-negotiate trial relationships and benefits, with potentially important implications for perceptions of and involvement in follow-up work for the trials and in future research. We found that feedback of findings is a complex but key step in a continuing set of social interactions between community members and research staff (particularly field staff who work at the interface with communities), and among community members themselves; a step which needs careful planning from the outset. We agree with others that individual and aggregate results need to be considered separately, and that for individual results, both the nature and value of the information, and the context, including social relationships, need to be taken into account. PMID- 23433356 TI - Class II alloantibody and mortality in simultaneous liver-kidney transplantation. AB - Hyperacute kidney rejection is unusual in crossmatch positive recipients of simultaneous liver-kidney transplants (SLKT). However, recent data suggest that these patients remain at risk for antibody-mediated kidney rejection. To further investigate the risk associated with donor-specific alloantibodies (DSA) in SLKT, we studied 86 consecutive SLKT patients with an available pre-SLKT serum sample. Serum samples were analyzed in a blinded fashion for HLA DSA using single antigen beads (median florescence intensity>=2,000=positive). Post-SLKT samples were analyzed when available (76%). Thirty patients had preformed DSA, and nine developed de novo DSA. Preformed class I DSA did not change the risk of rejection, patient or allograft survival. In contrast, preformed class II DSA was associated with a markedly increased risk of renal antibody mediated rejection (AMR) (p=0.006), liver allograft rejection (p=0.002), patient death (p=0.02), liver allograft loss (p=0.02) and renal allograft loss (p=0.045). Multivariable modeling showed class II DSA (preformed or de novo) to be an independent predictor of patient death (HR=2.2; p=0.043) and liver allograft loss (HR=2.2; p=0.044). These data warrant reconsideration of the approach to DSA in SLKT. PMID- 23433357 TI - Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines. AB - INTRODUCTION: Excessive sympathoadrenal activation in critical illness contributes directly to organ damage, and high concentrations of catecholamines damage the vascular endothelium. This study investigated associations between potential drivers of sympathoadrenal activation, circulating catecholamines and biomarkers of endothelial damage and outcome in ST segment elevation myocardial infarction (STEMI)-patients, hypothesizing that the catecholamine surge would reflect shock degree and correlate with biomarkers of endothelial damage. METHODS: This was a prospective study of 678 consecutive STEMI-patients admitted to a single high-volume invasive heart centre for primary percutaneous coronary intervention (pPCI) from September 2006 to July 2008. Blood samples were drawn immediately before pPCI. Plasma adrenaline, noradrenaline, syndecan-1 and thrombomodulin were measured retrospectively with complete data in 571 patients (84%). Median follow-up time was 28 (IQR 23 to 34) months. Follow-up was 99.7% complete. Outcomes were all-cause and cardiovascular mortality, re-myocardial infarction and admission due to heart failure. RESULTS: Circulating noradrenaline and adrenaline correlated weakly but independently with syndecan-1 (rho = 0.15 and rho = 0.13, both P <0.01) and thrombomodulin (rho = 0.11 and rho = 0.17, both P <0.01), biomarkers of glycocalyx and endothelial cell damage, respectively. Considering biomarkers, patients with shock pre-pPCI had higher adrenaline and syndecan-1 and patients admitted to ICU post-pPCI had higher syndecan-1 (all P <0.05), and in the patients with shock (n = 51) catecholamines correlated strongly with thrombomodulin and syndecan-1 (rho = 0.31 to 0.42, all P <0.05). During follow-up, 78 (14%) patients died (37 cardiovascular deaths) and 65 (11%) were admitted with heart failure. By multivariate Cox proportional hazards analyses, one quartile higher plasma adrenaline was weakly but independently associated with both 30-day and long term mortality and heart failure (30-day all cause mortality hazard ratio (95% CI) 1.39 (1.01 to 1.92), P = 0.046; 30-day heart failure 1.65 (1.17 to 2.34), P = 0.005; and long-term cardiovascular mortality 1.49 (1.08 to 2.04), P = 0.014). Furthermore, one quartile higher syndecan-1 was also weakly but independently associated with long-term all cause mortality (1.26 (1.02 to 1.57), P = 0.034). CONCLUSIONS: In STEMI patients treated with pPCI, catecholamines correlated weakly with biomarkers of endothelial damage, with the strongest correlations and highest adrenaline and syndecan-1 levels in patients with shock. Furthermore, adrenaline and syndecan-1 were weakly but independently associated with mortality and heart failure. Acute myocardial infarction appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines. PMID- 23433358 TI - Cellular and molecular mechanisms controlling the migration of melanocytes and melanoma cells. AB - During embryonic development in vertebrates, the neural crest-derived melanoblasts migrate along the dorsolateral axis and cross the basal membrane separating the dermis from the epidermis to reach their final location in the interfollicular epidermis and epidermal hair follicles. Neoplastic transformation converts melanocytes into highly invasive and metastatic melanoma cells. In vitro, these cells extend various types of protrusions and adopt two interconvertible modes of migration, mesenchymal and amoeboid, driven by different signalling molecules. In this review, we describe the major contributions of natural mouse mutants, mouse models generated by genetic engineering and in vitro culture systems, to identification of the genes, signalling pathways and mechanisms regulating the migration of normal and pathological cells of the melanocyte lineage, at both the cellular and molecular levels. PMID- 23433359 TI - A human neuronal model of Niemann Pick C disease developed from stem cells isolated from patient's skin. AB - BACKGROUND: Niemann Pick C (NPC) disease is a neurovisceral lysosomal storage disorder due to mutations in NPC1 or NPC2 genes, characterized by the accumulation of endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosomes/late endosomes. Even if the neurodegeneration is the main feature of the disease, the analysis of the molecular pathways linking the lipid accumulation and cellular damage in the brain has been challenging due to the limited availability of human neuronal models. OBJECTIVE: The aim of this study was to develop a human neuronal model of NPC disease by inducing neuronal differentiation of multipotent adult stem cells (MASC) isolated from NPC patients. METHODS: Stem cells were isolated from 3 NPC patients and 3 controls both from skin biopsies and previously established skin fibroblast cultures. Cells were induced to differentiate along a neuronal fate adapting methods previously described by Beltrami et al, 2007. The surface immunophenotype of stem cells was analyzed by FACS. Stem cell and neuronal markers expression were evaluated by immunofluorescence. Intracellular accumulation of cholesterol and gangliosides were assessed by filipin staining and immunofluorescence, respectively. A morphometric analysis was performed using a Neurite outgrowth image program. RESULTS: After 3 passages in selective medium, MASC isolated either from skin biopsies or previously established skin fibroblast cultures displayed an antigenic pattern characteristic of mesenchymal stem cells and expressed the stem cell markers Oct-4, Nanog, Sox-2 and nestin. A massive lysosomal accumulation of cholesterol was observed only in cells isolated from NPC patients. After the induction of neural differentiation, remarkable morphologic changes were observed and cells became positive to markers of the neuronal lineage NeuN and MAP2. Differentiated cells from NPC patients displayed characteristic features of NPC disease, they showed intracellular accumulation of unesterified cholesterol and GM2 ganglioside and presented morphological differences with respect to cells derived from healthy donors.In conclusion, we generated a human neuronal model of NPC disease through the induction of differentiation of stem cells obtained from patient's easily accessible sources. The strategy described here may be applied to easily generate human neuronal models of other neurodegenerative diseases. PMID- 23433360 TI - Concurrent outbreaks with co-infection of norovirus and Clostridium difficile in a long-term-care facility. AB - We describe an outbreak of simultaneous Clostridium difficile and norovirus infections in a long-term-care facility. Thirty patients experienced acute gastroenteritis, and four had co-infection with identical C. difficile 027 and genotype II.4 New Orleans norovirus strains. Co-occurring infection requires improved understanding of risk factors, clinical impact, and testing strategies. PMID- 23433361 TI - Protective effect of Tuscan black cabbage sprout extract against serum lipid increase and perturbations of liver antioxidant and detoxifying enzymes in rats fed a high-fat diet. AB - A diet rich in fat is considered a primary risk factor for CVD, cancer and failures in metabolism and endocrine functions. Hyperlipidaemia generates oxidative stress and weakens antioxidant defences as well as metabolic detoxification systems. Brassicaceae are vegetables rich in glucosinolates and isothiocyanates, affecting enzymatic antioxidant as well as phase II enzymes and conceivably counteracting high-fat diet (HFD)-associated pathologies. The protective role of Tuscan black cabbage (a variety of kale) sprout extract (TBCSE) intake against HFD alterations was here studied. The effects on rat hepatic antioxidant as well as detoxifying enzymes, and serum lipid- and body weightlowering properties of TBCSE, were investigated. Feeding the animals with a HFD for 21 d increased body as well as liver weights, and induced hyperlipidaemia, as confirmed by a higher serum lipid profile v. control diet. Daily intragastric administration of TBCSE to HFD-fed rats lowered serum total cholesterol, TAG and NEFA. Body and liver weight gains were also reduced. Antioxidant (catalase, NAD(P)H:quinone reductase, oxidised glutathione reductase and superoxide dismutase) and phase II (glutathione S-transferase and uridine diphosphate glucuronosyl transferase) enzymes were down-regulated by the HFD, while the extract restored normal levels in most groups. Generation of toxic intermediates, and membrane fatty acid composition changes by the HFD, might account for the altered hepatic antioxidant and detoxifying enzyme functions. The recovering effects of TBCSE could be attributed to high flavonoid, phenolic and organosulphur compound content, which possess free-radical-scavenging properties, enhance the antioxidant status and stimulate lipid catabolism. TBCSE intake emerges to be an effective alimentary strategy to counteract the perturbations associated with a diet rich in fat. PMID- 23433363 TI - Chromogenic agar medium for detection and isolation of Escherichia coli serogroups O26, O45, O103, O111, O121, and O145 from fresh beef and cattle feces. AB - Non-O157 Shiga toxin-producing Escherichia coli (STEC) strains are clinically important foodborne pathogens. Unlike E. coli O157:H7, these foodborne pathogens have no unique biochemical characteristics to readily distinguish them from other E. coli strains growing on plating media. In this study, a chromogenic agar medium was developed in order to differentiate among non-O157 STEC strains of serogroups O26, O45, O103, O111, O121, and O145 on a single agar medium. The ability of this chromogenic agar medium to select and distinguish among these pathogens is based on a combination of utilization of carbohydrates, b galactosidase activity, and resistance to selective agents. The agar medium in combination with immunomagnetic separation was evaluated and successfully allowed for the detection and isolation of these six serogroups from artificially contaminated fresh beef. The agar medium in combination with immunomagnetic separation also allowed successful detection and isolation of naturally occurring non-O157 STEC strains present in cattle feces. Thirty-five strains of the top six non-O157 STEC serogroups were isolated from 1,897 fecal samples collected from 271 feedlot cattle. This chromogenic agar medium could help significantly in routine screening for the top six non-O157 STEC serogroups from beef cattle and other food. PMID- 23433362 TI - Nucleoplasmic calcium signaling and cell proliferation: calcium signaling in the nucleus. AB - Calcium (Ca2+) is an essential signal transduction element involved in the regulation of several cellular activities and it is required at various key stages of the cell cycle. Intracellular Ca2+ is crucial for the orderly cell cycle progression and plays a vital role in the regulation of cell proliferation. Recently, it was demonstrated by in vitro and in vivo studies that nucleoplasmic Ca2+ regulates cell growth. Even though the mechanism by which nuclear Ca2+ regulates cell proliferation is not completely understood, there are reports demonstrating that activation of tyrosine kinase receptors (RTKs) leads to translocation of RTKs to the nucleus to generate localized nuclear Ca2+ signaling which are believed to modulate cell proliferation. Moreover, nuclear Ca2+ regulates the expression of genes involved in cell growth. This review will describe the nuclear Ca2+ signaling machinery and its role in cell proliferation. Additionally, the potential role of nuclear Ca2+ as a target in cancer therapy will be discussed. PMID- 23433365 TI - Reduction of Escherichia coli O157:H7 and Salmonella after application of various sanitizing treatments to harvesting knives. AB - Consumption of food contaminated with Escherichia coli O157:H7 and Salmonella can cause enteric disease in consumers. If not properly sanitized, knives used during animal harvest can spread these and other pathogens. This study evaluated the reduction of E. coli O157:H7 and Salmonella on harvesting knives after nonthermal sanitation. Knives were inoculated in cocktails of E. coli O157:H7 or Salmonella and treated by 30-s immersions in ambient-temperature solutions (unless temperature was specified) of 1.1 % sodium metasilicate (SMS), 200 ppm of quaternary ammonium compounds (QAC), 200 ppm of chlorine (Cl(2)), 5 % lactic acid (LA), 82.2 degrees C water, and 21 degrees C water. Initial and treated counts were determined by plating onto MacConkey and xylose lysine desoxycholate for E. coli O157:H7 and Salmonella, respectively. Initial counts were determined by sampling one side of the knife blade, while treated counts were sampled from the opposite side. Plates were incubated for 24 to 48 h at 37 degrees C. Mean attachment of E. coli O157:H7 and Salmonella was 4.51 and 5.09 log CFU/cm(2), respectively. Mean log reductions on knives inoculated with E. coli O157:H7 were 1.16, 3.51, 3.38, 1.38, 3.82, and 2 0.41 CFU/cm(2) after treatment in SMS, QAC, Cl(2), LA, 82.2 degrees C water, and 21 degrees C water, respectively (P <= 0.05). Knives inoculated with Salmonella showed reductions of 0.78, 3.42, 3.40, 2.91, 4.12, and 0.36 log CFU/cm(2) after treatment in SMS, QAC, Cl(2), LA, 82.2 degrees C water, and 21 degrees C water, respectively (P <= 0.05). Results indicate that some ambient-temperature sanitizing agents have the potential to significantly reduce E. coli O157:H7 and Salmonella populations on knives used during animal harvest. PMID- 23433366 TI - Inhibition and inactivation of Salmonella typhimurium biofilms from polystyrene and stainless steel surfaces by essential oils and phenolic constituent carvacrol. AB - Persistence of Salmonella biofilms within food processing environments is an important source of Salmonella contamination in the food chain. In this study, essential oils of thyme and oregano and their antimicrobial phenolic constituent carvacrol were evaluated for their ability to inhibit biofilm formation and inactivate preformed Salmonella biofilms. A crystal violet staining assay and CFU measurements were utilized to quantify biofilm cell mass, with evaluating factors such as strain variation, essential oil type, their concentrations, exposure time, as well as biofilm formation surface. Of the three Salmonella strains, Salmonella Typhimurium ATCC 23564 and Salmonella Typhimurium ATCC 19585 produced stronger biofilms than Salmonella Typhimurium ATCC 14028. Biofilm formation by different Salmonella strains was 1.5- to 2-fold higher at 22 degrees C than at 30 or 37 degrees C. The presence of nonbiocidal concentrations of thyme oil, oregano oil, and phenolic carvacrol at 0.006 to 0.012% suppressed Salmonella spp. biofilm formation 2- to 4-fold, but could not completely eliminate biofilm formation. There was high correlation in terms of biofilm inactivation, as determined by the crystal violet-stained optical density (at a 562-nm wavelength) readings and the viable CFU counts. Reduction of biofilm cell mass was dependent on antimicrobial concentration. A minimum concentration of 0.05 to 0.1% of these antimicrobial agents was needed to reduce a 7-log CFU biofilm mass to a nondetectable level on both polystyrene and stainless steel surfaces within 1 h of exposure time. PMID- 23433367 TI - Factors affecting thermal resistance of Salmonella enterica serovar enteritidis ODA 99-30581-13 in shell egg contents and use of heat-ozone combinations for egg pasteurization. AB - Infection of laying hens with Salmonella enterica serovar Enteritidis leads to deposition of the pathogen into the albumen or yolk of forming eggs. Heat treatment can inactivate internalized Salmonella Enteritidis in shell eggs, but factors such as the nature and location of contamination may influence the efficacy of thermal treatments. In the current research, natural contamination was mimicked by introducing small inocula of Salmonella Enteritidis into different locations of shell eggs and incubating inoculated eggs. These pathogen containing eggs were heated at 57 degrees C for 40 min, and temperature within eggs was monitored at the locations of inocula. Comparison of inactivation at equivalent internal temperatures revealed similar levels of lethality regardless of inoculum location. Refrigeration between incubation and heat treatment did not increase thermal resistance of cells in albumen but decreased cell inactivation in yolk. Sequential application of heat and gaseous ozone allows for the development of a process capable of decontaminating shell eggs with minimal thermal treatment and impact on egg quality. Inoculated eggs were subjected to (i) an immersion heating process similar to that used in commercial pasteurization or (ii) immersion heating, at reduced duration, followed by vacuum (50.8 kPa) and treatment with ozone gas (maximum 160 g/m(3)) under pressure (~187.5 kPa). All treatments tested produced greater than 5-log inactivation, which is required for "pasteurization" processes. Differences were observed in the visual quality of eggs depending on treatment parameters. Application of ozone subsequent to heating allows for a significant reduction in heating time without decreasing process lethality. PMID- 23433368 TI - Evaluating the predictive ability of a path-dependent thermal inactivation model for salmonella subjected to prior sublethal heating in ground turkey, beef, and pork. AB - Pathogen thermal inactivation models currently available to and used by industry consider only the present state of the product when predicting inactivation rates. However, bacteria subjected to sublethal thermal injury can develop partial protection against lethal temperatures. The objective of this study was to extend the capabilities of a previously published path-dependent Salmonella inactivation model by accounting for longer sublethal heating periods and different substrates and to test this new model against independent data. Ground samples of irradiated (> 10 kGy) turkey breast, beef round, and pork loin were inoculated with an eight-serovar Salmonella cocktail and subjected to 53 nonisothermal treatments (in triplicate) that combined a linear heating rate (1, 2, 3, 4, or 7 K/min), a variable length sublethal holding period (at 40, 45, or 50 degrees C), a lethal holding temperature (55, 58, 61, or 64 degrees C), and a nominal target kill (3- or 5-log reductions) (n = 159 for each meat species). When validated against nonisothermal data from similar treatments, traditional state-dependent model predictions resulted in root mean squared errors (RMSEs) of 2.9, 2.2, and 4.6 log CFU/g for turkey, beef, and pork, respectively. RMSEs for the new path-dependent model were 0.90, 0.81, and 0.82 log CFU/g for the same species, respectively, with reductions in error of 63 to 82 % relative to the state-dependent model. This new path-dependent model can significantly reduce error from the state-dependent model and could become a useful tool for assuring product safety, particularly relative to slow heating processes. PMID- 23433369 TI - A recurrent, multistate outbreak of salmonella serotype agona infections associated with dry, unsweetened cereal consumption, United States, 2008. AB - An outbreak of Salmonella enterica serotype Agona infections associated with nationwide distribution of cereal from Company X was identified in April 2008. This outbreak was detected using PulseNet, the national molecular subtyping network for foodborne disease surveillance, which coincided with Company X's voluntary recall of unsweetened puffed rice and wheat cereals after routine product sampling yielded Salmonella Agona. A case patient was defined as being infected with the outbreak strain of Salmonella Agona, with illness onset from 1 January through 1 July 2008. Case patients were interviewed using a standard questionnaire, and the proportion of ill persons who reported eating Company X puffed rice cereal was compared with Company X's market share data using binomial testing. The Minnesota Department of Agriculture inspected the cereal production facility and collected both product and environmental swab samples. Routine surveillance identified 33 case patients in 17 states. Of 32 patients interviewed, 24 (83%) reported eating Company X puffed rice cereal. Company X puffed rice cereal represented 0.063% of the total ready-to-eat dry cereal market share in the United States at the time of the investigation. Binomial testing suggested that the proportion of exposed case patients would not likely occur by chance (P < 0.0001). Of 17 cereal samples collected from case patient homes for laboratory testing, 2 (12%) yielded Salmonella Agona indistinguishable from the outbreak strain. Twelve environmental swabs and nine product samples from the cereal plant yielded the outbreak strain of Salmonella Agona. Company X cereal was implicated in a similar outbreak of Salmonella Agona infection in 1998 with the same outbreak strain linked to the same production facility. We hypothesize that a recent construction project at this facility created an open wall near the cereal production area allowing reintroduction of Salmonella Agona into the product, highlighting the resilience of Salmonella in dry food production environments. PMID- 23433371 TI - Influence of glucose concentrations on biofilm formation, motility, exoprotease production, and quorum sensing in Aeromonas hydrophila. AB - Aeromonas hydrophila recently has received increased attention because it is opportunistic and a primary human pathogen. A. hydrophila biofilm formation and its control are a major concern for food safety because biofilms are related to virulence. Therefore, we investigated biofilm formation, motility inhibition, quorum sensing, and exoprotease production of this opportunistic pathogen in response to various glucose concentrations from 0.05 to 2.5% (wt/vol). More than 0.05% glucose significantly impaired (P < 0.05) quorum sensing, biofilm formation, protease production, and swarming and swimming motility, whereas bacteria treated with 0.05% glucose had activity similar to that of the control (0% glucose). A stage shift biofilm assay revealed that the addition of glucose (2.5%) inhibited initial biofilm formation but not later stages. However, addition of quorum sensing molecules N-3-butanoyl-DL-homoserine lactone and N-3 hexanoyl homoserine lactone partially restored protease production, indicating that quorum sensing is controlled by glucose concentrations. Thus, glucose present in food or added as a preservative could regulate acyl-homoserine lactone quorum sensing molecules, which mediate biofilm formation and virulence in A. hydrophila. PMID- 23433370 TI - Microbiological quality and risk factors related to sandwiches served in bakeries, cafes, and sandwich bars in South Korea. AB - The objective of this study was to investigate the microbiological quality of sandwiches produced on site and served in bakeries, cafes, and sandwich bars in South Korea and to determine the major risk factors affecting the sanitation level in each store (n = 1,120). The microbiological quality of the sandwiches was analyzed, and the sanitation level of each store was evaluated as satisfactory or unsatisfactory based on sanitation guidelines. Total coliforms were detected in 906 samples (80.9%), but only 3 samples (0.3%) contained confirmed Escherichia coli contamination. The detection rate was highest for Bacillus cereus (10.0%), followed by Staphylococcus aureus (1.3%) and Salmonella (0.2%). Vibrio parahaemolyticus was not detected in any samples. The microbial contamination level was significantly lower in winter (P < 0.05) and in stores with a higher sanitation grade. Factors related to the microbiological quality of sandwiches were evaluated as the relative risk (RR) of coliform contamination, and the higher risk factors for sandwich contamination were improper holding temperature (RR = 8.75), cross-contamination (RR = 6.30), lack of proper ventilation systems (RR = 6.16), and the absence of clean and/or suitable outer garments (RR = 5.73). Most factors were related to the failure of food handlers to adhere to sanitation guidelines rather than to unsanitary environments. This study provides a comprehensive analysis of the relationship between the microbiological quality of sandwiches served on-site and various risk factors. These results will help researchers establish guidelines for the sanitary management of sandwich shops. PMID- 23433372 TI - Prevalence and characteristics of Listeria monocytogenes in bovine colostrum in Japan. AB - This study was conducted to determine the prevalence and characteristics of Listeria monocytogenes in bovine colostrum in Japan. We collected bovine colostrum samples from 210 dams from 21 dairy farms in Hokkaido prefecture (Japan) between March and June 2009. L. monocytogenes was detected in samples from 6 (28.6%) of the 21 farms. Of the 210 samples, 16 (7.6%) were positive for L. monocytogenes. We recovered 80 L. monocytogenes isolates; 44 (55%) isolates were classified as serotype 1/2b and 36 (45%) were classified as serotype 4b. The isolates were susceptible to penicillin, ampicillin, amoxicillin, gentamicin, kanamycin, streptomycin, erythromycin, vancomycin, tetracycline, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole. Pulsed-field gel electrophoresis (PFGE) characterization of the 80 isolates revealed six PFGE types. Two PFGE types corresponded to human listeriosis cases. Most L. monocytogenes isolates possessed virulence-associated genes (actA, hly, iap, inlA, inlC, mpl, plcA, plcB, opuCA, prfA, and clpC). One PFGE type isolate possessed an epidemic clone II marker. Our findings suggest that isolates from bovine colostrum have the potential to cause human and animal listeriosis. This is the first study on the prevalence and characteristics of L. monocytogenes isolated from bovine colostrum obtained from dairy farms. Our results have important implications for improving public health and elucidating the epidemiology of L. monocytogenes in bovine colostrum. PMID- 23433373 TI - Isolation and characterization of Clostridium difficile associated with beef cattle and commercially produced ground beef. AB - The incidence of Clostridium difficile infection has recently increased in North American and European countries. This pathogen has been isolated from retail pork, turkey, and beef products and reported associated with human illness. This increase in infections has been attributed to the emergence of a toxigenic strain designated North America pulsed-field gel electrophoresis type 1 (NAP1). The NAP1 strain has been isolated from calves as well as ground meat products, leading to speculation of illness from consumption of contaminated meat products. However, information on C. difficile associated with beef cattle during processing and commercially produced ground beef is limited. To address this data gap, samples from various steps during beef production were collected. Samples from hides (n = 525), preevisceration carcasses (n = 475), postintervention carcasses (n = 471), and 956 commercial ground beef samples were collected from across the United States. The prevalence of C. difficile spores on hides was 3.2%. C. difficile spores were not detected on preevisceration and postintervention carcasses or in commercially produced ground beef. Phenotypic and genetic characterizations were carried out for all 18 isolates collected from hide samples. Twenty-two percent of the isolates were nontoxigenic strains, while 78% of the isolates were toxigenic. Toxinotyping and PCR ribotyping patterns revealed that 6 and 33% of the isolates were identified as NAP1 and NAP7 strains, respectively. This article evidences that the prevalence of C. difficile, specifically pathogenic strains, in the U.S. beef production chain is low. PMID- 23433374 TI - Use of Lactobacillus acidophilus and Lactobacillus casei for a potential probiotic legume-based fermented product using pigeon pea (Cajanus cajan). AB - The aim of the present study was to evaluate the use of pigeon pea (Cajanus cajan) as an appropriate substrate in the production of a legume-based fermented product with Lactobacillus acidophilus ATCC 314 or Lactobacillus casei ATCC 393 and then to ascertain the effects of the addition of ingredients such as powdered milk and banana or strawberry sauce. The products were analyzed for viable cell counts, pH, and sensory attributes during product manufacture and throughout the refrigerated storage period at 3, 7, 14, 21, and 28 days. Nine types of products were produced. At the end of the storage period, the viability of L. acidophilus was above 7 log CFU/g in the presence of milk and 20% sucrose fruit sauce. For products with L. casei, the lack of ingredients such as milk caused no significant loss in viability; however, a high concentration of sucrose in the fruit sauce was an important factor in maintaining a high L. casei population. L. casei had high viability and good sensory attributes. Both strains could be considered suitable for a pigeon pea-based fermented potential probiotic product and a low-cost protein source. PMID- 23433375 TI - Tracking cross-contamination transfer dynamics at a mock retail deli market using GloGerm. AB - Ready-to-eat (RTE) deli meats are considered a food at high risk for causing foodborne illness. Deli meats are listed as the highest risk RTE food vehicle for Listeria monocytogenes. Cross-contamination in the retail deli market may contribute to spread of pathogens to deli meats. Understanding potential cross contamination pathways is essential for reducing the risk of contaminating various products. The objective of this study was to track cross-contamination pathways through a mock retail deli market using an abiotic surrogate, GloGerm, to visually represent how pathogens may spread through the deli environment via direct contact with food surfaces. Six contamination origination sites (slicer blade, meat chub, floor drain, preparation table, employee's glove, and employee's hands) were evaluated separately. Each site was inoculated with 20 ml of GloGerm, and a series of standard deli operations were completed (approximately 10 min of work). Photographs were then taken under UV illumination to visualize spread of GloGerm throughout the deli. A sensory panel evaluated the levels of contamination on the resulting contaminated surfaces. Five of the six contamination origination sites were associated with transfer of GloGerm to the deli case door handle, slicer blade, meat chub, preparation table, and the employee's gloves. Additional locations became contaminated (i.e., deli case shelf, prep table sink, and glove box), but this contamination was not consistent across all trials. Contamination did not spread from the floor drain to any food contact surfaces. The findings of this study reinforce the need for consistent equipment cleaning and food safety practices among deli workers to minimize cross-contamination. PMID- 23433376 TI - Food microbe tracker: a web-based tool for storage and comparison of food associated microbes. AB - Large amounts of molecular subtyping information are generated by the private sector, academia, and government agencies. However, use of subtype data is limited by a lack of effective data storage and sharing mechanisms that allow comparison of subtype data from multiple sources. Currently available subtype databases are generally limited in scope to a few data types (e.g., MLST. net) or are not publicly available (e.g., PulseNet). We describe the development and initial implementation of Food Microbe Tracker, a public Web-based database that allows archiving and exchange of a variety of molecular subtype data that can be cross-referenced with isolate source data, genetic data, and phenotypic characteristics. Data can be queried with a variety of search criteria, including DNA sequences and banding pattern data (e.g., ribotype or pulsed-field gel electrophoresis type). Food Microbe Tracker allows the deposition of data on any bacterial genus and species, bacteriophages, and other viruses. The bacterial genera and species that currently have the most entries in this database are Listeria monocytogenes, Salmonella, Streptococcus spp., Pseudomonas spp., Bacillus spp., and Paenibacillus spp., with over 40,000 isolates. The combination of pathogen and spoilage microorganism data in the database will facilitate source tracking and outbreak detection, improve discovery of emerging subtypes, and increase our understanding of transmission and ecology of these microbes. Continued addition of subtyping, genetic or phenotypic data for a variety of microbial species will broaden the database and facilitate large-scale studies on the diversity of food-associated microbes. PMID- 23433377 TI - Antibiotic-resistant bacteria associated with retail aquaculture products from Guangzhou, China. AB - This study examined the prevalence of antibiotic-resistant (ART) bacteria and representative antibiotic resistance (AR)-encoding genes associated with several aquaculture products from retail markets in Guangzhou, China. ART commensal bacteria were found in 100% of the products examined. Among 505 multidrug resistant isolates examined, close to one-fourth contained intI and sul1 genes: 15% contained sul2 and 5% contained tet (E). Incidences of beta-lactamase encoding genes bla(TEM), bla(CMY) and erythromycin resistance determinants ermB and ermC were 4.5, 1.7, 1.3, and 0.3%, respectively. Most of the ART isolates identified from the rinse water were Aeromonas spp.; those from intestines belonged to the Enterobacteriaceae. Plasmid-associated intI and AR-encoding genes were identified in several ART isolates by Southern hybridization. Three multidrug resistance-encoding plasmids were transferred into Escherichia coli DH5 a by chemical transformation and led to acquired AR in the transformants. In addition, the AR traits in many isolates were quite stable, even in the absence of selective pressure. Further studies are needed to reveal risk factors associated with the aquaculture production chain for targeted AR mitigation. PMID- 23433378 TI - A survey of food allergen control practices in the U.S. food industry. AB - Despite awareness of the importance of food allergy as a public health issue, recalls and adverse reactions linked to undeclared allergens in foods continue to occur with high frequency. To reduce the overall incidence of such problems and to ensure that food-allergic consumers have the information they need to prevent adverse reactions, it is important to understand which allergen control practices are currently used by the food industry. Therefore, the U.S. Food and Drug Administration carried out directed inspections of registered food facilities in 2010 to obtain a broader understanding of industry allergen control practices in the United States. The results of these inspections show that allergen awareness and the use of allergen controls have increased greatly in the last decade, but that small facilities lag in implementing allergen controls. PMID- 23433379 TI - Detection of Cyclospora, Cryptosporidium, and Giardia in ready-to-eat packaged leafy greens in Ontario, Canada. AB - Numerous foodborne outbreaks of diarrheal illness associated with the consumption of produce contaminated with protozoan parasites have been reported in North America in recent years. The present study reports on the presence of Cyclospora, Cryptosporidium, and Giardia in precut salads and leafy greens purchased at retail in Ontario, Canada. A total of 544 retail samples were collected between April 2009 and March 2010 and included a variety of salad blends and individual leafy greens. Most of these products were grown in the United States, with some from Canada and Mexico. Parasites were eluted and concentrated before detection by PCR and immunofluorescence microscopy. DNA sequences were aligned with reference sequences in GenBank. Cyclospora spp. were identified by PCR restriction fragment length polymorphism in nine (1.7 % ) samples and by DNA sequence analysis. Cryptosporidium spp. were identified in 32 (5.9%) samples; 29 were sequenced and aligned with the zoonotic species Cryptosporidium parvum. Giardia duodenalis was identified in 10 (1.8%) samples, and of the 9 samples successfully sequenced, 7 aligned with G. duodenalis assemblage B and 2 with assemblage A, both of which are also zoonotic. The presence of Cryptosporidium oocysts and Giardia cysts was confirmed in some of the PCR-positive samples using microscopy, while Cyclospora -like oocysts were observed in most of the Cyclospora PCR-positive samples. The relatively high prevalence of these parasites in packaged salads and leafy greens establishes a baseline for further studies and suggests a need for additional research with respect to the possible sources of contamination of these foods, the determination of parasite viability and virulence, and means to reduce foodborne transmission to humans. PMID- 23433380 TI - Evaluation of PCR detection of Salmonella in alfalfa sprouts and spent irrigation water collected during sprouting of naturally contaminated seed. AB - This study evaluated the efficacy of a PCR-based system (DuPont Qualicon BAX) for detection of Salmonella in sprouts and spent irrigation water collected during sprouting of seeds naturally contaminated with Salmonella. Alfalfa seeds were grown in Mason jars at 20 and 30 degrees C for 3 days. Levels of Salmonella present in the water and sprouts were determined by most-probable-number (MPN) analysis. Background microflora levels were also determined. Samples of spent irrigation water and sprouts were enriched overnight individually in tetrathionate broth and in buffered peptone water with novobiocin at 42 degrees C and then run in the BAX system. Samples were also enriched according to the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA BAM) method for Salmonella as a comparison. Salmonella levels were lower at 20 degrees C compared with 30 degrees C for some trials, and background microflora levels ranged from 10(7) to 10(8) CFU/g or ml at 20 degrees C and 10(8) to 10(9) CFU/g or ml at 30 degrees C. In trials with a Salmonella level >1.1 MPN/g or ml, both the BAX and FDA BAM methods were able to detect Salmonella in all samples. In trials with lower levels (0.21 MPN/g or ml or lower) of Salmonella, BAX was able to detect more positive samples than FDA BAM. For one trial with <0.003 MPN/g or ml of Salmonella, the presence of the pathogen was not indicated by either the BAX or the FDA BAM method. The results suggest that PCR detected low levels of Salmonella in sprouts or spent irrigation water collected from sprouting of naturally contaminated seeds. PMID- 23433381 TI - Inactivation of Escherichia coli O157:H7 on cattle hides by caprylic acid and beta-resorcylic acid. AB - Two naturally occurring, generally recognized as safe compounds, namely, caprylic acid (CA) (1%) and b -resorcylic acid (BR) (1%), and their combination, applied at 23 and 60 degrees C were evaluated for their antimicrobial effects against Escherichia coli O157:H7 on cattle hides in the presence and absence of bovine feces. Fresh cleaned cattle hides were cut into pieces (5 cm(2)), air dried, and inoculated with a five-strain mixture of nalidixic acid-resistant (50 MUg/ml) E. coli O157:H7 (~8.0 log CFU). The hide samples were air dried under a biosafety hood for 2 h and sprayed with 95% ethanol, 1% CA, 1% BR, or a mixture of 1% CA and 1% BR at 23 or 60 degrees C. The hide samples were kept at 23 degrees C, and E. coli O157:H7 populations were determined at 2 and 5 min after treatment. Both CA and BR were effective in decreasing E. coli O157:H7 populations on hides by 3 to 4 log CFU/cm(2) (P < 0.05). Sterile bovine feces had no effect on the decontaminating property of CA and BR on cattle hides (P > 0.05). Results of this study indicate that CA and BR could potentially be used to decontaminate cattle hides, but follow-up research under slaughterhouse conditions is warranted. PMID- 23433382 TI - Lineages and virulence gene content among extended-spectrum beta-lactamase producing Escherichia coli strains of food origin in Tunisia. AB - Nineteen extended-spectrum beta-lactamase (ESBL)-positive Escherichia coli strains recovered from food samples in Tunisia were characterized by multilocus sequence typing and phylogenetic typing, and the virulence gene and plasmid content were also determined. These strains presented unrelated pulsed-field gel electrophoresis patterns and contained genes coding for the following ESBLs (the number of strains is in parentheses): CTX-M-1 (15), CTX-M-14 (2), CTX-M-8 (1), and SHV-5 (1). Twelve different sequence types (STs) were identified among the 19 ESBL-positive strains, which included two new STs (ST2022 in 2 bla(CTX-M-14) containing strains and ST1970 in 2 bla(CTX-M-1)-containing strains). ST155 and ST602 were detected in four and three bla(CTX-M-1)-containing strains, respectively, and ST405 was detected in one bla(CTX-M-8)-producing strain. All ESBL-positive strains were ascribed to the phylogenetic groups A and B1. Most of the bla(CTX-M-1)-containing strains harbored an IncI1 plasmid, except for the four bla(CTX-M-1)-positive strains of beef origin and ST155, which harbored an IncN plasmid. The two bla(CTX-M-14)-containing strains contained an IncI1 plasmid. The virulence gene fimA was detected in all strains. Most strains also carried the aer gene, and six strains carried the eae gene. All strains were negative for the virulence genes sxt, papG-III, papC, hly, cnf1, and bfp. We conclude that ESBL-producing E. coli strains of food origin in Tunisia show high diversity and that plasmids harboring ESBL genes could be implicated in the dissemination of this resistance phenotype. PMID- 23433383 TI - Effect of the use of a neutralizing step after antimicrobial application on microbial counts during challenge studies for orange disinfection. AB - The effects of using a neutralizer after applying antimicrobial treatments and the effect of time lapse between treatment application and subsequent recovery and enumeration of Escherichia coli O157:H7 and Salmonella were investigated in Valencia oranges. Inoculated oranges surfaces were washed with distilled water for 15 s and then sprayed with a solution containing 200 mg/liter sodium hypochlorite (pH 6.5) for 15 s; they were then dipped in L-lactic acid (2.0% at 55 degrees C) for 1 min or in distilled water at 80 degrees C for 1 min. Posttreatment, oranges were divided into two groups. In the first group, oranges were dipped in neutralization treatment: 270 ml of buffered peptone water for 2 min for lactic acid-treated oranges, 270 ml of Dey-Engley broth for 2 min for chlorine-treated oranges, or 3.7 liters of tap water (25 degrees C) for 10 s for hot water-treated oranges. The second group of treated oranges was not subjected to any neutralizer. All oranges then were kept at room temperature (average 26.2 degrees C) and sampled at 0, 7.5, and 15 min for enumeration of surviving Salmonella and E. coli O157:H7. The orange surface (30 cm(2)) was excised for pathogen enumeration. The presence of free chlorine and changes in pH and temperature on the orange surface were determined in uninoculated, treated oranges. Free chlorine was detected on oranges after treatment; the change in temperature of orange surfaces was greater during treatment with hot water than with lactic acid. Nevertheless, pathogen enumeration did not show any impact of neutralizer use on the residual activity of antimicrobials or any impact of the time elapsed between antimicrobial treatment and recovery of bacterial pathogens from inoculated oranges (P >= 0.05). The results of this study indicate that the lack of a neutralizing step before enumeration of pathogens is not likely to affect the accuracy of results during challenge studies to test pathogen reduction strategies on oranges. PMID- 23433384 TI - Survival of Salmonella enterica serotype Tennessee during simulated gastric passage is improved by low water activity and high fat content. AB - The low water activity (a(w) 0.3) of peanut butter prohibits the growth of Salmonella in a product; however, illnesses are reported from peanut butter contaminated with very small doses, suggesting the food matrix itself influences the infectious dose of Salmonella, potentially by improving Salmonella's survival in the gastrointestinal tract. The purpose of our study was to quantify the survival of a peanut butter outbreak-associated strain of Salmonella enterica serotype Tennessee when inoculated into peanut butters with different fat contents and a(w) (high fat, high a(w); high fat, low a(w); low fat, high a(w); low fat, low a(w)) and then challenged with a simulated gastrointestinal system. Exposures to increased fat content and decreased a(w) both were associated with a protective effect on the survival of Salmonella Tennessee in the simulated gastric fluid compared with control cells. After a simulated intestinal phase, the populations of Salmonella Tennessee in the control and low-fat formulations were not significantly different; however, a 2-log CFU/g increase occurred in high-fat formulations. This study demonstrates that cross-protection from low a(w) stress and the presence of high fat results in improved survival in the low pH of the stomach. The potential for interaction of food matrix and stress adaptations could influence the virulence of Salmonella and should be considered for risk analysis. PMID- 23433385 TI - Effect of modified lysozyme on the microflora and sensory attributes of ground pork. AB - The effects of lysozyme monomer and thermochemically modified lysozyme on the microflora and sensory attributes of heated and unheated ground pork were investigated in this study. The dimer and trimer fractions of the modified lysozyme were 36.1 and 33.5%, respectively. The modified lysozyme exhibited higher hydrophobicity (40,600 U/mg of protein) and lower enzymatic activity (1,020 U/mg of protein) than the hydrophobicity (890 U/mg of protein) and activity (17,950 U/mg of protein) of the lysozyme monomer. Portions of ground pork (150 g) without lysozyme or supplemented with 5 mg/g lysozyme or modified lysozyme and either not heated or heated at 60 degrees C for 10 min were stored at 4 +/- 1 degrees C and sampled at various times between 1 and 144 h. Meat color was not affected by either additive. After storage for 72 h, the mean odor score for meat supplemented with modified lysozyme and heated decreased from 5.0 at 1 h to 4.1, while the scores for all the other preparations were <=3.2. After 144 h, the counts of Pseudomonas and Enterobacteriaceae in meat that was supplemented with modified lysozyme and not heated were, respectively, 1.1 and 0.9 log less than in the controls, and the numbers in such meat that was heated were, respectively, 1.2 and 2.4 log less than the numbers in the controls. The counts in meat supplemented with lysozyme and the controls were comparable. Heat treatment increased the bacteriostatic effect of modified lysozyme on gram negative bacteria. PMID- 23433386 TI - A probability model for enterotoxin production of Bacillus cereus as a function of pH and temperature. AB - Bacillus cereus is frequently isolated from a variety of foods, including vegetables, dairy products, meats, and other raw and processed foods. The bacterium is capable of producing an enterotoxin and emetic toxin that can cause severe nausea, vomiting, and diarrhea. The objectives of this study were to assess and model the probability of enterotoxin production of B. cereus in a broth model as affected by the broth pH and storage temperature. A three-strain mixture of B. cereus was inoculated in tryptic soy broth adjusted to pH 5.0, 6.0, 7.2, 8.0, and 8.5, and the samples were stored at 15, 20, 25, 30, and 35 degrees C for 24 h. A total of 25 combinations of pH and temperature, each with 10 samples, were tested. The presence of enterotoxin in broth was assayed using a commercial test kit. The probabilities of positive enterotoxin production in 25 treatments were fitted with a logistic regression to develop a probability model to describe the probability of toxin production as a function of pH and temperature. The resulting model showed that the probabilities of enterotoxin production of B. cereus in broth increased as the temperature increased and/or as the broth pH approached 7.0. The model described the experimental data satisfactorily and identified the boundary of pH and temperature for the production of enterotoxin. The model could provide information for assessing the food poisoning risk associated with enterotoxins of B. cereus and for the selection of product pH and storage temperature for foods to reduce the hazards associated with B. cereus. PMID- 23433387 TI - Isolation of a toxigenic and clinical genotype of clostridium difficile in retail meats in Costa Rica. AB - We isolated a regional toxigenic genotype of Clostridium difficile, previously found in human infection in 4 of 200 (2%) samples of retail meats for human consumption: 1 of 67 samples of beef, 2 of 66 of pork, and 1 of 67 of poultry meat. These four isolates were positive for the tcdA and tcdB genes but negative for deletion of the tcdC and cdtB genes. All strains induced cytopathic effects in HeLa cells. However, they were susceptible to some antibiotics to which clinical isolates are often resistant. All strains were susceptible to vancomycin, metronidazole, moxifloxacin, and rifampicin but resistant to clindamycin and ciprofloxacin. This first report of isolation of C. difficile in foodstuff from Latin America lends support to the notion that animal products serve as a reservoir for clinical strains of this pathogen in the community. PMID- 23433388 TI - Detection of quinolones in poultry meat obtained from retail centers in Santiago Province, the Dominican Republic. AB - In the Dominican Republic, poultry consumption per capita is greater than 34 kg of poultry meat per year. However, antibiotics, specifically the quinolone group, may be overused and can result in residues in the poultry meat. These residues are of concern because consumers may have allergies to antibiotics and antibiotic-resistant bacteria can develop from overuse of antibiotics in production. Little is known concerning this issue specifically for Santiago Province in the Dominican Republic. Thus, the main purpose of this research was to evaluate the incidence of residual quinolones in poultry meat and determine whether any residues detected were higher than the residue maximum limits (100 MUg/kg) established by food industry authorities, including the U.S. Food and Drug Administration and European Food Safety Authority. A total of 135 samples of chicken breast were taken from different retail meat centers in the nine municipalities of Santiago Province (Santiago, Tamboril, Sabana Iglesia, Villa Bisono, Punal, Villa Gonzalez, Licey, Janico, and San Jose De Las Matas) and were analyzed using the Equinox test (Immunotec, Swanton, VT). Of the 135 samples analyzed, 50% from Sabana Iglesia, 20% from Licey, 20% from San Jose De Las Matas, and 6.25% from Santiago contained residues of quinolones higher than the residue maximum limits. No quinolone residues were detected in samples obtained from Janico, Punal, Tamboril, Villa Bisono, or Villa Gonzalez. The results of this investigation suggest that some poultry meat sold for human consumption in Santiago Province of the Dominican Republic contains quinolone residues and may represent a health risk to some consumers. PMID- 23433389 TI - Heavy metals in canned tuna from Italian markets. AB - Fish is a good source of nutrients for humans but can pose a risk to human health because of the possible presence of some xenobiotics such as heavy metals and persistent organic contaminants. Constant monitoring is needed to minimize health risks and ensure product quality and consumer safety. The aim of the present study was to use atomic absorption spectrometry to determine the concentrations of some heavy metals (Hg, Pb, and Cd) in tuna packaged in different kinds of packages (cans or glass) in various countries (Italy and elsewhere). Concentrations of Cd and Hg were within the limits set by European Commission Regulation (EC) No 1881/2006 and in many samples were below the detection limit. Pb concentrations exceeded European limits in 9.8% of the analyzed samples. These results are reassuring in terms of food safety but highlighted the need to constantly monitor the concentrations of heavy metals in fish products that could endanger consumer health. PMID- 23433390 TI - Issues to consider when setting intervention targets with limited data for low moisture food commodities: a peanut case study. AB - Peanuts and peanut-containing products have been linked to at least seven salmonellosis outbreaks worldwide in the past two decades. In response, the Technical Committee on Food Microbiology of the North American Branch of the International Life Sciences Institute collaborated with the American Peanut Council to convene a workshop to develop a framework for managing risk in low moisture food commodities where large data sets are unavailable (using peanuts as the example). Workshop attendees were charged with answering questions regarding the appropriate statistical and scientific methods for setting log reduction targets with limited pathogen prevalence and concentration data, suitable quantities of data needed for determining appropriate log reduction targets, whether the requirement of a 5-log reduction in the absence of data to establish a target log reduction is appropriate, and what targeted log reduction would protect public health. This report concludes that the judgment about sufficient data is not solely scientific, but is instead a science-informed policy decision that must weigh additional societal issues. The participants noted that modeling efforts should proceed with sampling efforts, allowing one to compare various assumptions about prevalence and concentration and how they are combined. The discussions made clear that data and risk models developed for other low-moisture foods like almonds and pistachios may be applicable to peanuts. Workshop participants were comfortable with the use of a 5-log reduction for controlling risk in products like peanuts when the level of contamination of the raw ingredients is low (<1 CFU/g) and the process well controlled, even when limited data are available. The relevant stakeholders from the food safety community may eventually conclude that as additional data, assumptions, and models are developed, alternatives to a 5-log reduction might also result in the desired level of protection for peanuts and peanut products. PMID- 23433391 TI - Prevalence of obstructive sleep apnea in Asian adults: a systematic review of the literature. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common disease, affecting approximately 2% of women and 4% of men residing in Western communities. No systematically reviewed data are available about the prevalence of this disease in Asia, the most heavily populated continent. METHODS: PubMed/Medline, Scopus and Google Scholar were searched for articles published from 1993 to May 2012 that reported the prevalence of OSA diagnosed via sleep monitoring and the prevalence of patients at risk for OSA as assessed by symptomatology and/or sleep questionnaires. We have also searched abstract database of major pulmonary and sleep scientific societies for relevant abstracts presented from 2010 to 2012. The following inclusion criteria were used: articles published in English, age >= 18 years, >= 100 participants in studies using sleep monitoring for the diagnosis of OSA, >= 300 participants in studies using questionnaires to detect patients at high risk for OSA. EXCLUSION CRITERIA: duplicate publications, studies reporting the prevalence of central sleep apnea only, hospital based studies as well as studies assessing OSA prevalence among patients with resistant arterial hypertension, chronic kidney disease, heart failure and in patients with concomitant neurological disease. RESULTS: Twenty four articles were found to meet the inclusion criteria, covering 47,957 subjects (26,042 men and 21,915 women) and four relevant abstracts were noted. OSA prevalence ranged from 3.7% to 97.3%. Male gender, older age, a higher BMI and waist to hip ratio, greater neck circumference, arterial hypertension, smoking, snoring and daytime sleepiness were associated with OSA. Sample size, difference between the populations studied and the fact that some works included patients with a high pre-test probability of OSA explain the difference in prevalence rates. CONCLUSION: This systematic review highlights the lack of data regarding the prevalence of OSA in Asians. Only a few studies provide an approximate estimate of the OSA burden in some Asian communities. PMID- 23433392 TI - Smoking and dietary inadequacy among Inuvialuit women of child bearing age in the Northwest Territories, Canada. AB - OBJECTIVE: The prevalence of smoking in Aboriginal Canadians is higher than non Aboriginal Canadians, a behavior that also tends to alter dietary patterns. Compared with the general Canadian population, maternal smoking rates are almost twice as high. The aim of this study was to compare dietary adequacy of Inuvialuit women of childbearing age comparing smokers versus non-smokers. RESEARCH METHODS & PROCEDURES: A cross-sectional study, where participants completed a culturally specific quantitative food frequency questionnaire. Non parametric analysis was used to compare mean nutrient intake, dietary inadequacy and differences in nutrient density among smokers and non-smokers. Multiple logistic regression analyses were performed for key nutrients inadequacy and smoking status. Data was collected from three communities in the Beaufort Delta region of the Northwest Territories, Canada from randomly selected Inuvialuit women of childbearing age (19-44 years). RESULTS: Of 92 participants, 75% reported being smokers. There were no significant differences in age, BMI, marital status, education, number of people in household working and/or number of self employed, and physical activity between smokers and non-smokers. Non parametric analysis showed no differences in nutrient intake between smokers and non-smokers. Logistic regression however revealed there was a positive association between smoking and inadequacies of vitamin C (OR = 2.91, 95% CI, 1.17-5.25), iron (OR = 3.16, 95% CI, 1.27-5.90), and zinc (OR = 2.78, 95% CI, 1.12-4.94). A high percentage of women (>60%), regardless of smoking status, did not meet the dietary recommendations for fiber, vitamin D, E and potassium. CONCLUSIONS: This study provides evidence of inadequate dietary intake among Inuvialuit of childbearing age regardless of smoking behavior. PMID- 23433394 TI - Root caries: a survey of Queensland dentists. AB - BACKGROUND: Root caries stands to be a significant burden for Australia's ageing population. The objective of this study was to describe Queensland dental practitioners' perceptions of root caries prevalence, presentation and predisposing factors as well as diagnosis and recording practices. METHODS: Using the Queensland Dental Board register, all 2,515 dentists and dental specialists practising in Queensland were invited to participate in a questionnaire-based postal survey. RESULTS: Of the 660 responses received, 638 were included for final analysis. Use of diagnostic measures such as surface elasticity and contour were reported frequently. A majority of respondents (77%) reported not recording root caries in a way that could be distinguished from coronal caries. Dietary analysis was the most commonly reported adjunctive aid for risk assessment. Recommendations for use of remineralizing agents were frequently reported (home use 90%; in office use 71%). Salivary impairment was reported to be an important risk factor for root caries by 93% of respondents, but only 18% reported performing salivary analysis. A large proportion of respondents (32%) considered patients with diabetes to be of low or no risk of root caries. CONCLUSIONS: While the Queensland dental practitioners who participated in this survey demonstrated an awareness of root caries and its predisposing factors, clinical risk assessment particularly for patients with diabetes should be further examined. PMID- 23433393 TI - Comparative field evaluation of combinations of long-lasting insecticide treated nets and indoor residual spraying, relative to either method alone, for malaria prevention in an area where the main vector is Anopheles arabiensis. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are commonly used together in the same households to improve malaria control despite inconsistent evidence on whether such combinations actually offer better protection than nets alone or IRS alone. METHODS: Comparative tests were conducted using experimental huts fitted with LLINs, untreated nets, IRS plus untreated nets, or combinations of LLINs and IRS, in an area where Anopheles arabiensis is the predominant malaria vector species. Three LLIN types, Olyset(r), PermaNet 2.0(r) and Icon Life(r) nets and three IRS treatments, pirimiphos-methyl, DDT, and lambda cyhalothrin, were used singly or in combinations. We compared, number of mosquitoes entering huts, proportion and number killed, proportions prevented from blood-feeding, time when mosquitoes exited the huts, and proportions caught exiting. The tests were done for four months in dry season and another six months in wet season, each time using new intact nets. RESULTS: All the net types, used with or without IRS, prevented >99% of indoor mosquito bites. Adding PermaNet 2.0(r) and Icon Life(r), but not Olyset(r) nets into huts with any IRS increased mortality of malaria vectors relative to IRS alone. However, of all IRS treatments, only pirimiphos-methyl significantly increased vector mortality relative to LLINs alone, though this increase was modest. Overall, median mortality of An. arabiensis caught in huts with any of the treatments did not exceed 29%. No treatment reduced entry of the vectors into huts, except for marginal reductions due to PermaNet 2.0(r) nets and DDT. More than 95% of all mosquitoes were caught in exit traps rather than inside huts. CONCLUSIONS: Where the main malaria vector is An. arabiensis, adding IRS into houses with intact pyrethroid LLINs does not enhance house-hold level protection except where the IRS employs non-pyrethroid insecticides such as pirimiphos-methyl, which can confer modest enhancements. In contrast, adding intact bednets onto IRS enhances protection by preventing mosquito blood-feeding (even if the nets are non-insecticidal) and by slightly increasing mosquito mortality (in case of LLINs). The primary mode of action of intact LLINs against An. arabiensis is clearly bite prevention rather than insecticidal activity. Therefore, where resources are limited, priority should be to ensure that everyone at risk consistently uses LLINs and that the nets are regularly replaced before being excessively torn. Measures that maximize bite prevention (e.g. proper net sizes to effectively cover sleeping spaces, stronger net fibres that resist tears and burns and net use practices that preserve net longevity), should be emphasized. PMID- 23433395 TI - Improving community development by linking agriculture, nutrition and education: design of a randomised trial of "home-grown" school feeding in Mali. AB - BACKGROUND: Providing food through schools has well documented effects in terms of the education, health and nutrition of school children. However, there is limited evidence in terms of the benefits of providing a reliable market for small-holder farmers through "home-grown" school feeding approaches. This study aims to evaluate the impact of school feeding programmes sourced from small holder farmers on small-holder food security, as well as on school children's education, health and nutrition in Mali. In addition, this study will examine the links between social accountability and programme performance. DESIGN: This is a field experiment planned around the scale-up of the national school feeding programme, involving 116 primary schools in 58 communities in food insecure areas of Mali. The randomly assigned interventions are: 1) a school feeding programme group, including schools and villages where the standard government programme is implemented; 2) a "home-grown" school feeding and social accountability group, including schools and villages where the programme is implemented in addition to training of community based organisations and local government; and 3) the control group, including schools and household from villages where the intervention will be delayed by at least two years, preferably without informing schools and households. Primary outcomes include small-holder farmer income, school participation and learning, and community involvement in the programme. Other outcomes include nutritional status and diet-diversity. The evaluation will follow a mixed method approach, including household, school and village level surveys as well as focus group discussions with small-holder farmers, school children, parents and community members. The impact evaluation will be incorporated within the national monitoring and evaluation (M&E) system strengthening activities that are currently underway in Mali. Baselines surveys are planned for 2012. A monthly process monitoring visits, spot checks and quarterly reporting will be undertaken as part of the regular programme monitoring activities. Evaluation surveys are planned for 2014. DISCUSSION: National governments in sub-Saharan Africa have demonstrated strong leadership in the response to the recent food and financial crises by scaling-up school feeding programmes. "Home-grown" school feeding programmes have the potential to link the increased demand for school feeding goods and services to community-based stakeholders, including small-holder farmers and women's groups. Alongside assessing the more traditional benefits to school children, this evaluation will be the first to examine the impact of linking school food service provision to small-holder farmer income, as well as the link between community level engagement and programme performance. TRIAL REGISTRATION: ISRCTN76705891. PMID- 23433396 TI - Methods of tagSNP selection and other variables affecting imputation accuracy in swine. AB - BACKGROUND: Genotype imputation is a cost efficient alternative to use of high density genotypes for implementing genomic selection. The objective of this study was to investigate variables affecting imputation accuracy from low density tagSNP (average distance between tagSNP from 100kb to 1Mb) sets in swine, selected using LD information, physical location, or accuracy for genotype imputation. We compared results of imputation accuracy based on several sets of low density tagSNP of varying densities and selected using three different methods. In addition, we assessed the effect of varying size and composition of the reference panel of haplotypes used for imputation. RESULTS: TagSNP density of at least 1 tagSNP per 340kb (~7000 tagSNP) selected using pairwise LD information was necessary to achieve average imputation accuracy higher than 0.95. A commercial low density (9K) tagSNP set for swine was developed concurrent to this study and an average accuracy of imputation of 0.951 based on these tagSNP was estimated. Construction of a haplotype reference panel was most efficient when these haplotypes were obtained from randomly sampled individuals. Increasing the size of the original reference haplotype panel (128 haplotypes sampled from 32 sire/dam/offspring trios phased in a previous study) led to an overall increase in imputation accuracy (IA = 0.97 with 512 haplotypes), but was especially useful in increasing imputation accuracy of SNP with MAF below 0.1 and for SNP located in the chromosomal extremes (within 5% of chromosome end). CONCLUSION: The new commercially available 9K tagSNP set can be used to obtain imputed genotypes with high accuracy, even when imputation is based on a comparably small panel of reference haplotypes (128 haplotypes). Average imputation accuracy can be further increased by adding haplotypes to the reference panel. In addition, our results show that randomly sampling individuals to genotype for the construction of a reference haplotype panel is more cost efficient than specifically sampling older animals or trios with no observed loss in imputation accuracy. We expect that the use of imputed genotypes in swine breeding will yield highly accurate predictions of GEBV, based on the observed accuracy and reported results in dairy cattle, where genomic evaluation of some individuals is based on genotypes imputed with the same accuracy as our Yorkshire population. PMID- 23433397 TI - Validation of ICD-9-CM codes for identification of acetaminophen-related emergency department visits in a large pediatric hospital. AB - BACKGROUND: Acetaminophen overdose is a major concern among the pediatric population. Our objective was to assess the validity of International Classification of Disease (ICD-9-CM) codes for identification of pediatric emergency department (ED) visits resulting from acetaminophen exposure or overdose. METHODS: We conducted a retrospective medical record review of ED visits at Texas Children's Hospital in Houston, Texas, between January 1, 2005, and December 31, 2010. Visits coded with 1 or more ICD-9 codes for poisoning (965, 977, and their subcodes and supplemental E-codes E850, E858, E935, E947, and E950 and their subcodes) were identified from an administrative database, and further review of the medical records was conducted to identify true cases of acetaminophen exposure or overdose. We then examined the sensitivity, positive predictive value, and percentage of false positives identified by various codes and code combinations to establish which codes most accurately identified acetaminophen exposure or overdose. RESULTS: Of 1,215 ED visits documented with 1 or more of the selected codes, 316 (26.0%) were a result of acetaminophen exposure or overdose. Sensitivity was highest (87.0%) for the combination of codes 965.4 (poisoning by aromatic analgesics, not elsewhere classified) and E950.0 (suicide and self-inflicted poisoning by analgesics, antipyretics, and antirheumatics), with a positive predictive value of 86.2%. Code 965.4 alone yielded a sensitivity of 85.1%, with a positive predictive value of 92.8%. Code performance varied among age groups and depending on the type of exposure (intentional or unintentional). CONCLUSION: ICD-9 codes are useful for ascertaining which ED visits are a result of acetaminophen exposure or overdose within the pediatric population. However, because ICD-9 coding differs by age group and depending on the type of exposure, hypothesis-driven strategies must be utilized for each pediatric age group to avoid misclassification. PMID- 23433398 TI - Mast cells are present in the choroid of the normal eye in most vertebrate classes. AB - OBJECTIVE: Mast cells are bone marrow-derived tissue-homing leukocytes, which have traditionally been regarded as effector cells in allergic disorders, responses against parasites, and regulation of blood flow, but a broader perspective of their functional heterogeneity, such as immunomodulation, angiogenesis, tissue repair, and remodeling after injury, is now emerging. The persistence of mast cells in connective tissues throughout the evolution of vertebrates is evidence of strong selective pressure suggesting that these cells must have multiple beneficial and important roles in normal homeostasis. While mast cells are present within the uveal tract of eutherian mammals, there is little known about their presence in the choroid of other vertebrate classes. ANIMALS STUDIED: Eye tissues from a range of vertebrate species (fish, amphibian, reptiles, birds, marsupials, monotreme, and eutherian mammals) were investigated. Tissues were fixed in either 2% glutaraldehyde, 2% paraformaldehyde or a mixture of both and processed for resin embedding. Semi-thin sections of the retina and choroid were cut and stained with toluidine blue. RESULTS AND CONCLUSIONS: Mast cells were identified in the choroid of all classes of vertebrates investigated except sharks. Their morphology, location, and staining characteristics were remarkably similar from teleost fish through to eutherian mammals and bore close morphological resemblance to mammalian connective tissue mast cells. The similar morphology and distribution of mast cells in the choroid of all vertebrate classes studied suggest a basic physiological function that has been retained since the evolution of the vertebrate eye. PMID- 23433399 TI - Enhanced depth imaging optical coherence tomography of optic disc maculopathy without a visible optic pit. PMID- 23433400 TI - Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies. AB - BACKGROUND: Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2. METHODS: ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3 * anti-HER2/neu (HER2Bi) and/or anti-CD3 * anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines. RESULTS: EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50--80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133- and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets. CONCLUSION: High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens. PMID- 23433401 TI - Eicosapentaenoic acid suppresses palmitate-induced cytokine production by modulating long-chain acyl-CoA synthetase 1 expression in human THP-1 macrophages. AB - BACKGROUND: Chronic inflammation caused by macrophages may be associated with progression of arteriosclerosis or obesity, both risk factors for cardiovascular events. In the Japan EPA Lipid Intervention Study (JELIS), eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, was found to reduce the incidence of cardiovascular events. METHODS: The effect of EPA on the expression of inflammatory factors induced by palmitate, a saturated fatty acid, was investigated using human THP-1 macrophages. RESULTS: Palmitate induced expression of inflammatory cytokines and activated NF-kappaB, similar to lipopolysaccharide (LPS). EPA strongly suppressed palmitate-induced up-regulation of inflammatory factors while slightly suppressing LPS-induced factors. Both palmitate and LPS up regulated expression of long-chain acyl-CoA synthetase (ACSL) 1, while EPA preferentially suppressed palmitate-induced ACSL1 expression. Although an acyl CoA synthetase inhibitor and ACSL1 siRNA both suppressed palmitate-induced tumor necrosis factor (TNF)-alpha expression, the former had no effect on LPS-induced TNF-alpha expression. Palmitate may therefore stimulate cytokine production through a different mechanism than LPS mediated through Toll-like receptor 4, at least partly, and ACSL1 may play an important role in this mechanism. Finally, palmitate induced expression of sterol regulatory element-binding protein-1a and ACSL1, while EPA suppressed the expression of these genes. CONCLUSION: The suppressive effects of EPA on palmitate-induced cytokine production may be mediated by the suppression of ACSL1 expression, at least partly. This anti inflammatory effect of EPA may contribute to suppression of chronic inflammation caused by macrophages in atherosclerotic plaques. PMID- 23433402 TI - Tenascin-C deficiency in apo E-/- mouse increases eotaxin levels: implications for atherosclerosis. AB - AIM: To investigate the potential role of inflammatory cytokines in apo E-/- mouse in response to deletion of Tenascin-C (TNC) gene. METHODS AND RESULTS: We used antibody array and ELISA to compare the profile of circulating inflammatory cytokines in apo E-/- mice and apo E-/- TNC-/- double knockout mice. In addition, tissue culture studies were performed to investigate the activity of cells from each mouse genotype in vitro. Cytokine array analysis and subsequent ELISA showed that circulating eotaxin levels were selectively and markedly increased in response to TNC gene deletion in apo E-/- mice. In addition, considerable variation was noted in the circulating level of eotaxin among the control apo E-/ mouse group. Inbreeding of apo E-/- mice with high or low levels of plasma eotaxin showed that the level of eotaxin per se determines the extent of atherosclerosis in this mouse genotype. While endothelial cells from apo E-/- mice had low level of eotaxin expression, cells derived from apo E-/- TNC-/- mice expressed a high level of eotaxin. Transient transfection of eotaxin promoter reporter constructs revealed that eotaxin expression is regulated at the transcriptional level by TNC. Histochemical analysis of aortic sections revealed the massive accumulation of mast cells in the adventitia of double KO mice lesions whereas no such accumulation was detected in the control group. Plasma from the apo E-/- TNC-/- mice markedly stimulated mast cell migration whereas plasma from the apo E-/- mice had no such effect. CONCLUSION: These observations support the emerging hypothesis that TNC expression controls eotaxin level in apo E-/- mice and that this chemokine plays a key role in the development of atherosclerosis. PMID- 23433403 TI - Dose-dependent effects of short term atorvastatin treatment on arterial wall properties and on indices of left ventricular remodeling in ischemic heart failure. AB - OBJECTIVES: Statins, beyond their lipid lowering role, exert beneficial effect on endothelial function in patients with atherosclerosis. Aim of the present study was to examine the short term pleiotropic effects of different doses of atorvastatin treatment, on endothelial function, arterial stiffness and indices of left ventricular remodeling in heart failure (HF) patients. METHODS: We studied the effect of 4 weeks administration of atorvastatin in 22 patients with ischemic HF. The study was carried out on two separate arms, one with atorvastatin 40 mg/d and one with atorvastatin 10 mg/d (randomized, double-blind, cross-over design). Endothelial function was evaluated by flow mediated dilation (FMD) in the brachial artery and arterial stiffness by augmentation index (AIx). Serum levels of matrix metalloproteinase-9 (MMP-9) and intracellular adhesion molecule-1 (sICAM-1) were measured as biomarkers of left ventricular remodeling and endothelial function, respectively, while, b-type natriuretic peptide (BNP) was measured as a marker of left ventricular function. RESULTS: Compared to baseline, atorvastatin 40 mg/d significantly improved FMD values (3.18 +/- 3.03% vs. 5.98 +/- 2.49%, p = 0.001) and AIx values (25.98 +/- 8.55% vs. 23.09 +/- 8.87%, p = 0.046). In addition, compared to baseline measurements, treatment with atorvastatin 40 mg/d resulted in significantly decreased levels of serum logMMP-9 levels (2.47 +/- 0.23 ng/ml vs. 2.39 +/- 0.24 ng/ml, p = 0.04) and of logICAM-1 levels (2.46 +/- 0.13 ng/ml vs. 2.37 +/- 0.16 ng/ml, p < 0.001). No significant changes were found after treatment with atorvastatin 10 mg/d in the aforementioned parameters. CONCLUSIONS: Short term treatment with 40 mg/d of atorvastatin exerts beneficial impact on arterial wall properties and on indices of left ventricle remodeling in heart failure patients. PMID- 23433404 TI - Engaging communities to strengthen research ethics in low-income settings: selection and perceptions of members of a network of representatives in coastal Kenya. AB - There is wide agreement that community engagement is important for many research types and settings, often including interaction with 'representatives' of communities. There is relatively little published experience of community engagement in international research settings, with available information focusing on Community Advisory Boards or Groups (CAB/CAGs), or variants of these, where CAB/G members often advise researchers on behalf of the communities they represent. In this paper we describe a network of community members ('KEMRI Community Representatives', or 'KCRs') linked to a large multi-disciplinary research programme on the Kenyan Coast. Unlike many CAB/Gs, the intention with the KCR network has evolved to be for members to represent the geographical areas in which a diverse range of health studies are conducted through being typical of those communities. We draw on routine reports, self-administered questionnaires and interviews to: 1) document how typical KCR members are of the local communities in terms of basic characteristics, and 2) explore KCR's perceptions of their roles, and of the benefits and challenges of undertaking these roles. We conclude that this evolving network is a potentially valuable way of strengthening interactions between a research institution and a local geographic community, through contributing to meeting intrinsic ethical values such as showing respect, and instrumental values such as improving consent processes. However, there are numerous challenges involved. Other ways of interacting with members of local communities, including community leaders, and the most vulnerable groups least likely to be vocal in representative groups, have always been, and remain, essential. PMID- 23433405 TI - A single-nucleotide polymorphism of miR-196a-2 and vitiligo: an association study and functional analysis in a Han Chinese population. AB - Recent evidence indicates that oxidative stress and genetic factors play an important role in the pathogenesis of vitiligo. SNPs in miRNAs involved in oxidative stress could potentially influence the development of vitiligo. In this case-control study, we investigated the association of a functional SNP of rs11614913 in miR-196a-2 with risk of vitiligo. A significantly lower risk of vitiligo was associated with the rs11614913 miR-196a-2 CC genotype (adjusted OR, 0.77; CI, 0.60-0.98). In addition, TYRP1 gene expression was considerably down regulated by the rs11614913 C allele in miR-196a-2, which lowered the levels of intracellular reactive oxygen species (ROS) and reduced the proportion of early apoptosis in human melanocytes in response to H2 O2 treatment. Our data suggest that the rs11614913 C allele in miR-196a-2 confers potential protection against oxidative effects on human melanocytes through the modulation of the target gene, TYRP1, which may account for the decreased risk of vitiligo in this study population. PMID- 23433406 TI - Comparison of ranging behaviour in a multi-species complex of free-ranging hosts of bovine tuberculosis in relation to their use as disease sentinels. AB - Sentinel species are increasingly used by disease managers to detect and monitor the prevalence of zoonotic diseases in wildlife populations. Characterizing home range movements of sentinel hosts is thus important for developing improved disease surveillance methods, especially in systems where multiple host species co-exist. We studied ranging activity of major hosts of bovine tuberculosis (TB) in an upland habitat of New Zealand: we compared home-range coverage by ferrets (Mustela furo), wild deer (Cervus elaphus), feral pigs (Sus scrofa), brushtail possums (Trichosurus vulpecula) and free-ranging farmed cattle (Bos taurus). We also report in detail the proportional utilization of a seasonal (4-monthly) range area for the latter four species. Possums covered the smallest home range (<30 ha), ferrets covered ~100 ha, pigs ~4 km(2), deer and cattle both >30 km2. For any given weekly period, cattle, deer and pigs were shown to utilize 37-45% of their estimated 4-month range, while possums utilized 62% during any weekly period and 85% during any monthly period of their estimated 4-month range. We suggest that present means for estimating TB detection kernels, based on long term range size estimates for possums and sentinel species, probably overstate the true local surveillance coverage per individual. PMID- 23433407 TI - Reciprocal interaction between intestinal microbiota and mucosal lymphocyte in cynomolgus monkeys after alemtuzumab treatment. AB - It has been known that the gut microbiota plays a central role in shaping normal mucosal immunity, however, little information is available whether the variability of mucosal lymphocytes impacts the commensal flora. Here, we applied a cynomolgus monkey model to characterize the structure and composition of the gut microbiota in response to lymphocyte depletion and to determine their potential association. Molecular profiling of 16S rDNA showed that the intestinal microbiota composition was perturbed after the depletion of mucosal lymphocytes and were recovered following the repopulation. Some specific bacteria from the orders Lactobacillales, Enterobacteriales and Clostridiales, and the genus Prevotella and Faecalibacterium, were primarily responsible for the variations of the gut microbiota after lymphocyte depletion. Interestingly, the species richness of the ileal mucosal microbiota was associated the proportions of TCRalphabeta+ or TCRgammadelta+ T cells (p<0.01). We demonstrate for the first time the feature of intestinal microbiota composition after lymphocyte depletion and provide novel evidence that the perturbation of gut microbiota is associated with lymphocyte depletion. It may contribute to understand the relationship between gut commensal microbiota and mucosal immune system. Study results provide insight into biological activity of alemtuzumab in intestinal barrier in organ transplantation. PMID- 23433408 TI - Treatment modification of yttrium-90 radioembolization based on quantitative positron emission tomography/CT imaging. AB - Treatment activity for yttrium-90 ((90)Y) radioembolization when calculated by using the manufacturer-recommended technique is only partially patient-specific and may result in a subtumoricidal dose in some patients. The authors describe the use of quantitative (90)Y positron emission tomography/computed tomography as a tool to provide patient-specific optimization of treatment activity and evaluate this new method in a patient who previously received traditional (90)Y radioembolization. The modified treatment resulted in a 40-Gy increase in absorbed dose to tumor and complete resolution of disease in the treated area within 3 months. PMID- 23433411 TI - Percutaneous radiofrequency ablation with internally cooled versus internally cooled wet electrodes for small subphrenic hepatocellular carcinomas. AB - PURPOSE: To compare retrospectively technical effectiveness and complications after radiofrequency (RF) ablation with internally cooled wet (ICW) electrodes versus conventional internally cooled (IC) electrodes in patients with small (<=3 cm) subphrenic hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: From March 2008 to January 2012, 165 patients, each with a single small subphrenic HCC, were treated with RF ablation using IC (n = 81) or ICW (n = 84) electrodes. RESULTS: After initial RF ablation, technical success was achieved in 88% of patients treated with IC electrodes and 91% of patients treated with ICW electrodes (P = .623). At 1 month, technical effectiveness was achieved in 93% and 99% (P = .061). Mean ablation volume was significantly greater in patients treated with ICW electrodes compared with patients treated with IC electrodes, using 2-cm (14.5 cm(3) vs 6.2 cm(3); P = .001) and 3-cm (32.7 cm(3) vs 15.2 cm(3); P <.001) exposed tips. The 6-month and 1-, 2-, and 4-year local tumor progression rates were significantly lower after RF ablation with ICW electrodes (5%, 13%, 15%, and 26%) compared with IC electrodes (11%, 24%, 32%, and 35%; P = .044). Major complications occurred in 6% of patients treated with IC electrodes and 2% of patients treated with ICW electrodes. CONCLUSIONS: In the treatment of small subphrenic HCCs, percutaneous RF ablation using ICW electrodes results in larger ablation zones and lower rates of local tumor progression than RF ablation using conventional IC electrodes. PMID- 23433410 TI - Percutaneous computed tomography-guided renal mass radiofrequency ablation versus cryoablation: doses of sedation medication used. AB - PURPOSE: To compare the amount of sedation medication administered during radiofrequency (RF) ablation versus cryoablation of small renal masses. MATERIALS AND METHODS: Records were retrospectively reviewed in patients who underwent percutaneous computed tomography-guided RF ablation and cryoablation of small renal masses from January 2002 to June 2011 for patient and tumor characteristics, amount of medications used for moderate sedation, and complications. Sedation was performed by giving patients titrated doses of midazolam and fentanyl. Additional medications were given if the desired level of sedation was not achieved. RESULTS: There were 116 patients who underwent 136 ablation procedures; 71 patients underwent RF ablation, and 65 patients underwent cryoablation. RF ablation was associated with a significantly higher mean dose of fentanyl (mean dose for RF ablation, 236.43 MUg; mean dose for cryoablation, 172.27 MUg; P<.001). RF ablation was also associated with a higher mean dose of midazolam (mean dose for RF ablation, 4.5 mg; mean dose for cryoablation, 3.27 mg; P<.001). In the RF ablation group, two patients required additional sedation with droperidol. As a result of oversedation, two patients in the RF ablation cohort required sedation reversal with naloxone and flumazenil. None of the patients who underwent cryoablation required sedation reversal. No other sedation related complications occurred. CONCLUSIONS: Cryoablation of small renal masses was performed with less sedation medication than RF ablation. This finding suggests renal cryoablation is less painful than RF ablation; however, prospective studies with validated pain scales are needed to confirm these results. PMID- 23433412 TI - Frequency of external iliac artery branch injury in blunt trauma: improved detection with selective external iliac angiography. AB - PURPOSE: To assess the utility of selective external iliac artery (EIA) angiography and the frequency of injury to branches of the EIA in cases of blunt pelvic trauma. MATERIALS AND METHODS: A retrospective review of pelvic angiograms in 66 patients with blunt pelvic trauma was conducted over a 12-month period. Pelvic and femur fracture patterns were correlated to the presence of EIA injury. Pelvic arteriography was compared versus selective EIA angiography for the detection of arterial injury. RESULTS: Fifty-four of 66 patients (82%) exhibited pelvic arterial injury or elicited enough suspicion for injury to warrant embolization. Internal iliac artery embolization was performed in 50 of 66 (76%). EIA branch injury was identified in 11 of 66 patients (17%), and 10 were successfully embolized. EIA branch vessel injury was identified more frequently when there was ipsilateral intertrochanteric fracture (P = .07) or ipsilateral ilium fracture (P = .07). The sensitivity of nonselective pelvic angiography in the detection of EIA branch vessel injury was 45%. CONCLUSIONS: EIA branch injury occurs in a substantial fraction of patients with blunt pelvic trauma who undergo pelvic angiography. Selective EIA angiography should be considered in all patients undergoing pelvic angiography in this situation. PMID- 23433413 TI - Carotid revascularization in patients with ongoing oral anticoagulant therapy: the advantages of stent placement. AB - PURPOSE: To assess the influence of oral anticoagulant therapy conversion to heparin (OAT-CH) on carotid endarterectomy (CEA) outcomes and the influence of unmodified oral anticoagulant therapy (OAT) on carotid artery stenting (CAS) and to compare the outcomes of CEA in OAT-CH with CAS in ongoing OAT. MATERIALS AND METHODS: The 30-day results from all patients who underwent CEA and CAS in a 6 year period were analyzed for stroke, death, myocardial infarction (MI), and hematoma of the access site requiring surgical evacuation. We evaluated the influence of OAT-CH in CEA and the influence of OAT in CAS and compared CEA and CAS outcomes in patients receiving OAT-CH and OAT. RESULTS: Among 1,222 carotid revascularizations, there were 711 CEAs (58.1%) and 511 CAS procedures (41.9%). In the CEA group, 31 (4.4%) patients were treated with OAT-CH, and these patients had a significantly higher complication rate compared with patients not receiving OAT, including death (1 [3.2%] vs 4 [0.6%]; P = .04), stroke (4 [12.9%] vs 10 [1.4%]; P = .001), and hematoma (3 [9.6%] vs 11 [1.6%]; P = .02). In CAS, the results were similar in patients receiving OAT (30 [5.8%]) and patients not receiving OAT. Patients receiving OAT who underwent CAS had better outcomes than patients receiving OAT-CH who underwent CEA, including stroke, death, MI, and hematoma combined (0 [0.0%] vs 7 [22.5%]; P =.01). CONCLUSIONS: OAT management significantly influences the results of carotid revascularization. Because CAS with unmodified OAT had a significantly better outcome than CEA with OAT-CH, carotid revascularization strategies should favor CAS rather than CEA in this setting. PMID- 23433414 TI - Prospective comparison of cartesian acquisition with projection-like reconstruction magnetic resonance angiography with computed tomography angiography for evaluation of below-the-knee runoff. AB - PURPOSE: To compare prospectively the assessment of stenosis and radiologist confidence in the evaluation of below-the-knee lower extremity runoff vessels between computed tomography (CT) angiography and contrast-enhanced magnetic resonance (MR) angiography in a cohort of 19 clinical patients. MATERIALS AND METHODS: The study was compliant with the Health Insurance Portability and Accountability Act of 1996 and approved by the institutional review board. Imaging was performed in 19 consecutive patients with known or suspected peripheral arterial disease; both CT angiography and a more recently developed MR angiography technique were performed within 24 hours of each other and before any therapeutic intervention. Resulting images were randomized and interpreted in blinded fashion by four board-certified radiologists with expertise in CT angiography and MR angiography. Vasculature of the lower leg was apportioned into 22 segments, 11 for each leg. For each segment, degree of stenosis and confidence of diagnosis were determined using a 3-point scale. Differences between CT angiography and MR angiography were assessed for significance using pooled histograms that were analyzed using the Wilcoxon signed rank test. RESULTS: For assessment of stenosis, there was no difference in CT angiography compared with MR angiography for 20 of 22 segments. For confidence of diagnosis, assessment of popliteal arteries was superior on CT angiography compared with MR angiography (P<.05). Confidence in assessment of both tibioperoneal trunks and the left proximal anterior tibial artery was not significantly different between CT angiography and MR angiography. Confidence in assessment of all other 17 segments was superior with MR angiography compared with CT angiography (P<.02). CONCLUSIONS: MR angiography using the method described here is a promising technique for evaluating lower extremity arterial runoff. MR angiography had an overall superior performance in radiologist confidence compared with CT angiography for imaging runoff vessels below the knee. PMID- 23433415 TI - Recanalization of thrombosed arteriovenous fistulas for hemodialysis by minimal venotomy. AB - The present work describes the preliminary results of a new method of minimally invasive thrombectomy in the treatment of thrombosed arteriovenous fistula (AVF) with dilated aneurysm. Data from 25 patients who were treated with this minimal venotomy technique were retrospectively reviewed. The minimal venotomy was made on the dilated fistula, and thrombectomy was performed with forceps and Fogarty catheters through the venotomy site. Technical and clinical success was achieved in all 25 patients. There were two major and two minor complications (8% each). The two major complications consisted of bleeding at the venotomy site after early suture removal. PMID- 23433416 TI - T-shaped angioplasty with apex puncture of thrombosed looped hemodialysis grafts. AB - This study is a retrospective evaluation of an alternative technique for angioplasty of thrombosed loop hemodialysis grafts through a single vascular access. This technique can provide balloon angioplasty to the puncture site without any additional vascular accesses by using a T-shaped balloon catheter and can simplify thrombectomy procedures. PMID- 23433417 TI - Transcatheter arterial embolization with N-butyl cyanoacrylate for acute life threatening gastroduodenal bleeding uncontrolled by endoscopic hemostasis. AB - PURPOSE: To investigate the feasibility, efficacy, and safety of transcatheter arterial embolization with N-butyl cyanoacrylate (NBCA) for gastroduodenal nonvariceal bleeding uncontrolled by endoscopic hemostasis. MATERIALS AND METHODS: Between January 2006 and December 2011, a total of 317 patients underwent emergent endoscopic therapy for nonvariceal gastroduodenal bleeding, but hemostasis was not achieved in 20 cases. Emergent surgery was performed immediately following endoscopy in two patients. Arteriography was performed in the remaining 18 patients, and embolization with NBCA was performed in 15 patients (mean age, 71.3 y) in whom the bleeding site was detected on arteriography. For embolization, NBCA was mixed with iodized oil at a ratio of 1:1.5-1:4, and no other embolic material was used in the procedure. Technical and clinical success rates, recurrent bleeding, procedural time, complications, and clinical outcomes were determined for each procedure. RESULTS: Embolization with NBCA was technically and clinically successful in all procedures, without major complications. No patient receiving embolization with NBCA experienced recurrent bleeding or required further treatment after the one-session procedure. All patients were discharged after clinical improvement. The time between puncture of the femoral artery and completion of embolization ranged from 25 to 240 minutes (mean, 66 min), and the time between the microcatheter reaching the ultimate catheter location selected for embolization and hemostasis ranged from 142 to 550 seconds (mean, 322s). CONCLUSIONS: In this limited series, embolization with NBCA was found to be a safe, feasible, and effective treatment for gastroduodenal arterial bleeding when endoscopic hemostasis had failed. PMID- 23433418 TI - Geniculate artery embolization in the management of spontaneous recurrent hemarthrosis of the knee: case series. AB - Spontaneous recurrent hemarthrosis after knee arthroplasty is reported to occur in 0.3%-1% of patients, likely secondary to hypertrophic vascular synovium. Five patients who underwent previous arthroplasty presented with spontaneous hemarthrosis. Selective arterial embolization was performed with spherical embolic particles (diameter range, 100-700 MUm). Angiography demonstrated synovial hypervascularity with geniculate artery "tumor blush" appearance in all patients. Average time to resolution of effusion was 2.6 weeks, with no recurrences reported during follow-up (mean, 25.4 mo; range, 16-48 mo). Two patients experienced transient cutaneous ischemia. Selective geniculate artery embolization with spherical embolic particles is an effective treatment for spontaneous recurrent hemarthrosis of the knee. PMID- 23433419 TI - Interventional radiologists: a necessary evolution of leaded protective aprons design. PMID- 23433420 TI - A technique for chest wall port insertion to prevent air embolism using a hemostatic vascular sheath instead of a peel-away sheath. PMID- 23433421 TI - Percutaneous transhepatic sclerotherapy under balloon occlusion of the azygos vein for endoscopically unmanageable esophageal varices. PMID- 23433422 TI - Lumbar sacral plexopathy--a rare and late complication of endovascular aneurysm repair. PMID- 23433423 TI - Hybrid endografts are effective in distal and proximal fixation zones and in intermediate docking areas in endovascular aortic aneurysm repair. PMID- 23433424 TI - Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor. AB - BACKGROUND: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. METHODS: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3zeta, 1st gen) and 2nd generation (SCF-CD28 CD3zeta, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. RESULTS: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNgamma. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. CONCLUSIONS: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc. PMID- 23433425 TI - Ejaculation profiles of men following radiation therapy for prostate cancer. AB - OBJECTIVES: Radical prostatectomy (RP) is associated with anejaculation, which for some men is a source of bother and sexual dissatisfaction. Clinical experience has shown us some men after pelvic radiation therapy (RT) also experience anejaculation. This analysis was conducted to define the ejaculation profiles of men after RT for prostate cancer (PCa). METHODS: As a routine part of the sexual health evaluation for post-RT patients, men provided information regarding their ejaculatory function and orgasm. Analysis was conducted of a sexual medicine database reviewing demographic data, PCa factors, erectile, ejaculatory, and orgasmic function. Men with prior history of RP, cryotherapy, focal therapies, and androgen deprivation therapy (ADT) were excluded. Patients completed the International Index of Erectile Function (IIEF) questionnaire at follow-up visits commencing with the first posttreatment visit and specific attention was paid to the IIEF orgasm domain. RESULTS: Three hundred and sixty four consecutive patients were included. Two hundred and fifty-two patients had external beam, and 112 patients had brachytherapy (BT). Mean age was 64 +/- 11 (42-78) years and mean follow-up after RT was 6 +/- 4.5 years. Mean prostate size at time of RT was 42 +/- 21 g. Of the entire population, 72% lost the ability to ejaculate in an antegrade fashion after prostate RT by their last visit. The proportion experiencing anejaculation at 1, 3, and 5 years after RT was 16%, 69%, and 89%, respectively. For men with at least two IIEF questionnaires completed, the orgasm domain scores decreased dramatically over the follow-up period; orgasm domain scores (0-10): <12 months post-RT 7.4, 13-24 months 5.4, 25-36 months 3.2, >36 months 2.8 (P < 0.01). Multivariable analysis identified several factors predictive of failure to ejaculate: older age, ADT, RT dose > 100 Gy, and smaller prostates at the time of RT. CONCLUSIONS: The vast majority of men after prostate RT will experience anejaculation and should be counseled accordingly prior to undergoing therapy. We have identified predictive factors. PMID- 23433426 TI - Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators. AB - BACKGROUND: The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NP-C) is characterized by a broad clinical variability involving neurological, psychiatric and systemic signs. Diverse patterns of disease manifestation and progression considerably delay its diagnosis. Here we introduce the NP-C clinical database (NPC-cdb) to systematically obtain, store and analyze diagnostic and clinical findings in patients with NP-C. We apply NPC-cdb to study NP-C temporal expression in a large German-Swiss patient cohort. METHODS: Current and past medical history was systematically acquired from 42 patients using tailored questionnaires. Manifestation of 72 distinct neuropsychiatric signs was modeled over the course of disease. The sequence of disease progression was re constructed by a novel clinical outcome scale (NPC-cdb score). RESULTS: The efficiency of current clinical diagnostic standards negatively correlates with duration of disease (p<3.9x10(-4)), suggesting insufficient sensitivity in patients early in the disease process. Neurological signs considered as typical for NP-C were frequent (e.g., cognitive impairment 86%, ataxia 79%, vertical supranuclear gaze palsy 76%) and their presence co-occurred with accelerated diagnosis. However, less specific neuropsychiatric signs were reported to arise considerably more early in the disease process (e.g., clumsiness -4.9+/-1.1 y before diagnosis). Most patients showed a steady disease progression that correlated with age at neurological onset. However, a distinct subcohort (n=6) with initially steadily progressing disease later showed a 2.9-fold accelerated progression that was associated with the onset of seizures (p<7x10(-4)), suggesting seizures as predictive for a poor prognosis. CONCLUSIONS: Considering early, but less specific neuropsychiatric signs may accelerate the path to diagnosing NP-C in a patient. PMID- 23433427 TI - The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. AB - The immunomodulatory properties of mesenchymal stromal cells are the subject of increasing interest and of widening clinical applications, but the reproducibility of their effects is controversial and the underlying mechanisms have not been fully clarified. We investigated the transfer of membrane vesicles, a recently recognized pathway of intercellular communication, as possible mediator of the interaction between mesenchymal stromal cells and B lymphocytes. Mesenchymal stromal cells exhibited a strong dose-dependent inhibition of B-cell proliferation and differentiation in a CpG-stimulated peripheral blood mononuclear cell coculture system. We observed that these effects could be fully reproduced by membrane vesicles isolated from mesenchymal stromal cell culture supernatants in a dose-dependent fashion. Next, we evaluated the localization of fluorescently labeled membrane vesicles within specific cell subtypes both by flow cytometry and by confocal microscopy analysis. Membrane vesicles were found to be associated with stimulated B lymphocytes, but not with other cell phenotypes (T lymphocytes, dendritic cells, natural killer cells), in peripheral blood mononuclear cell culture. These results suggest that membrane vesicles derived from mesenchymal stromal cells are the conveyors of the immunosuppressive effect on B lymphocytes. These particles should be further evaluated as immunosuppressive agents in place of the parent cells, with possible advantages in term of standardization, safety, and feasibility. PMID- 23433429 TI - Low rate of recurrence of Helicobacter pylori infection in spite of high clarithromycin resistance in Pakistan. AB - BACKGROUND: The aim was to investigate the reinfection rate of H. pylori during a follow-up period of 12 months in adults who had undergone eradication therapy. METHODS: One hundred-twenty patients; 116 with gastritis, 3 with duodenal ulcer and 1 gastric ulcer, were studied. Their mean age was 41+/-13 years (range 18-77) and male: female ratio of 2:1. H. pylori were cultured and antibiotic sensitivity was determined by Epsilometer test (E-test) for clarithromycin (CLR) and amoxicillin (AMX). Primers of urease C gene of H. pylori and Sau-3 and Hha I restriction enzymes were used for polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). 14C urea breath test (14C-UBT) was performed 4 weeks after the eradication therapy. The successfully treated patients were observed for 12 months with 14C-UBT to assess H. pylori status. If 14C-UBT was negative, it was repeated after every 12 weeks. If 14C-UBT was positive, endoscopy was repeated with biopsies. RESULT: The eradication therapy was successful in 102(85%) patients. Out of forty-seven H. pylori isolates cultured, clarithromycin sensitivity was present in 30(64%) and amoxicillin in 45(98%), respectively. Follow-up 14C-urea breath tests of all 102 patients who eradicated H. pylori remained negative up to 9 months. However, in 6 patients, the 14C-UBT confirmed recurrence at 12 months. The recurrence rate was 6%. CONCLUSION: A low rate of recurrence of H. pylori infection was found in patients with dyspeptic symptoms. H. pylori isolates demonstrated a high invitro clarithromycin resistance. PMID- 23433430 TI - The impact of obesity-related SNP on appetite and energy intake. AB - An increasing number of studies have reported a heritable component for the regulation of energy intake and eating behaviour, although the individual polymorphisms and their 'effect size' are not fully elucidated. The aim of the present study was to examine the relationship between specific SNP and appetite responses and energy intake in overweight men. In a randomised cross-over trial, forty overweight men (age 32 (sd 09) years; BMI 27 (sd 2) kg/m2) attended four sessions 1 week apart and received three isoenergetic and isovolumetric servings of dairy snacks or water (control) in random order. Appetite ratings were determined using visual analogue scales and energy intake at an ad libitum lunch was assessed 90 min after the dairy snacks. Individuals were genotyped for SNP in the fat mass and obesity-associated (FTO), leptin (LEP), leptin receptor (LEPR) genes and a variant near the melanocortin-4 receptor (MC4R) locus. The postprandial fullness rating over the full experiment following intake of the different snacks was 17.2 % (P= 0.026) lower in A carriers compared with TT homozygotes for rs9939609 (FTO, dominant) and 18.6 % (P= 0.020) lower in G carriers compared with AA homozygotes for rs7799039 (LEP, dominant). These observations indicate that FTO and LEP polymorphisms are related to the variation in the feeling of fullness and may play a role in the regulation of food intake. Further studies are required to confirm these initial observations and investigate the 'penetrance' of these genotypes in additional population subgroups. PMID- 23433428 TI - Phylogeography of the neotropical Anopheles triannulatus complex (Diptera: Culicidae) supports deep structure and complex patterns. AB - BACKGROUND: The molecular phylogenetic relationships and population structure of the species of the Anopheles triannulatus complex: Anopheles triannulatus s.s., Anopheles halophylus and the putative species Anopheles triannulatus C were investigated. METHODS: The mitochondrial COI gene, the nuclear white gene and rDNA ITS2 of samples that include the known geographic distribution of these taxa were analyzed. Phylogenetic analyses were performed using Bayesian inference, Maximum parsimony and Maximum likelihood approaches. RESULTS: Each data set analyzed septely yielded a different topology but none provided evidence for the seption of An. halophylus and An. triannulatus C, consistent with the hypothesis that the two are undergoing incipient speciation. The phylogenetic analyses of the white gene found three main clades, whereas the statistical parsimony network detected only a single metapopulation of Anopheles triannulatus s.l. Seven COI lineages were detected by phylogenetic and network analysis. In contrast, the network, but not the phylogenetic analyses, strongly supported three ITS2 groups. Combined data analyses provided the best resolution of the trees, with two major clades, Amazonian (clade I) and trans-Andean + Amazon Delta (clade II). Clade I consists of multiple subclades: An. halophylus + An. triannulatus C; trans-Andean Venezuela; central Amazonia + central Bolivia; Atlantic coastal lowland; and Amazon delta. Clade II includes three subclades: Panama; cis-Andean Colombia; and cis-Venezuela. The Amazon delta specimens are in both clades, likely indicating local sympatry. Spatial and molecular variance analyses detected nine groups, corroborating some of subclades obtained in the combined data analysis. CONCLUSION: Combination of the three molecular markers provided the best resolution for differentiation within An. triannulatus s.s. and An. halophylus and C. The latest two species seem to be very closely related and the analyses performed were not conclusive regarding species differentiation. Further studies including new molecular markers would be desirable to solve this species status question. Besides, results of the study indicate a trans-Andean origin for An. triannulatus s.l. The potential implications for malaria epidemiology remain to be investigated. PMID- 23433431 TI - Efficacy and safety of fumaric acid esters in patients with psoriasis on medication for comorbid conditions - a retrospective evaluation (FACTS). AB - BACKGROUND: Safety and efficacy of fumaric acid esters (FAE) in patients with psoriasis requiring treated comorbidit condition were investigated. PATIENTS AND METHODS: Data collected from 7 dermatology centers were used for a retrospective analysis of patients treated continuously with FAE for at least 6 weeks who required at least one medication for a comorbid condition. The records were analyzed at baseline and after 1, 3, 6, 12 and 24 months of therapy. Safety parameters were monitored and the severity of skin symptoms was assessed by 'Physician's Global Assessment' (PGA). RESULTS: A total of 69 patients with moderate to severe psoriasis and a mean duration of 27.4 months of continuous treatment were included in the study. In less than 5% were interactions between FAE and co-medications observed. Changes of hepatic, renal or hematological laboratory parameters were usually insignificant and required a modification of FAE treatment in less than 12% of the cases. The percentage of patients documented as markedly improved or clear was 61% after 6 months, 77% after 12 months, and 75% after 24 months of therapy. CONCLUSIONS: In patients with moderate to severe psoriasis on co-medications, FAE were effective and safe without any noteworthy drug interactions. PMID- 23433432 TI - Combined impact of traditional and non-traditional health behaviors on mortality: a national prospective cohort study in Spanish older adults. AB - BACKGROUND: Data on the combined effect of lifestyles on mortality in older people have generally been collected from highly selected populations and have been limited to traditional health behaviors. In this study, we examined the combined impact of three traditional (smoking, physical activity and diet) and three non-traditional health behaviors (sleep duration, sedentary time and social interaction) on mortality among older adults. METHODS: A cohort of 3,465 individuals, representative of the Spanish population aged >=60 years, was established in 2000/2001 and followed-up prospectively through 2011. At baseline, the following positive behaviors were self-reported: never smoking or quitting tobacco >15 years, being very or moderately physically active, having a healthy diet score >= median in the cohort, sleeping 7 to 8 h/d, spending <8 h/d in sitting time, and seeing friends daily. Analyses were performed with Cox regression and adjusted for the main confounders. RESULTS: During an average nine year follow-up, 1,244 persons died. Hazard ratios (95% confidence interval) for all-cause mortality among participants with two, three, four, five and six compared to those with zero to one positive behaviors were, respectively, 0.63 (0.46 to 0.85), 0.41 (0.31 to 0.55), 0.32 (0.24 to 0.42), 0.26 (0.20 to 0.35) and 0.20 (0.15 to 0.28) (P for trend <0.001). The results were similar regardless of age, sex and health status at baseline. Those with six vs. zero to one positive health behaviors had an all-cause mortality risk equivalent to being 14 years younger. Adding the three non-traditional to the four traditional behaviors improved the model fit (likelihood ratio test, P <0.001) and the accuracy of mortality prediction (c-statistic: + 0.0031, P = 0.040). CONCLUSIONS: Adherence to some traditional and non-traditional health behaviors may substantially reduce mortality risk in older adults. PMID- 23433434 TI - No change in viral set point or CD4 cell decline among antiretroviral treatment naive, HIV-1-infected individuals enrolled in the Danish HIV Cohort Study in 1995 2010. AB - OBJECTIVES: Recent studies have reported faster progression of HIV infection than anticipated based on results from earlier studies. The aim of the present study was to examine if the virulence of HIV-1 infection changed in the period 1995 2010 among chronically HIV-infected individuals in Denmark. METHODS: We included all patients registered in the Danish HIV Cohort Study, who were diagnosed in 1995-2009, had a CD4 count > 100 cells/MUL at diagnosis and had at least two CD4 measurements prior to initiation of antiretroviral therapy (ART). Changes in viral set point and rate of CD4 cell decline from enrolment until the initiation of ART by calendar year of HIV diagnosis were analysed. Time to first CD4 count < 350 cells/MUL was compared among patients diagnosed in 1995-2000, 2001-2005 and 2006-2010. RESULTS: We followed 1469 HIV-infected patients for a total of 5783 person-years. The median viral set point was 4.27 log10 HIV-1 RNA copies/mL [interquartile range (IQR) 3.58-4.73 log10 copies/mL]. The median CD4 cell decline per year was 57 cells/MUL (IQR 10-139 cells/MUL). In analyses adjusted for age, gender, origin, route of transmission and CD4 count at diagnosis, there were no associations between year of diagnosis and viral set point or CD4 cell decline. Time to first CD4 count < 350 cells/MUL did not change in the study period [incidence rate ratio (IRR) 0.90 (95% confidence interval (CI) 0.76-1.06) for 2001-2005 and 1.09 (95% CI 0.79-1.34) for 2006-2010 compared with 1995-2000]. CONCLUSIONS: We found no evidence of changing trends in viral set point, CD4 cell decline or time to CD4 count < 350 cells/MUL during the period 1995-2010 in a cohort of chronically HIV-infected individuals. PMID- 23433433 TI - Modeling of electric field distribution in tissues during electroporation. AB - BACKGROUND: Electroporation based therapies and treatments (e.g. electrochemotherapy, gene electrotransfer for gene therapy and DNA vaccination, tissue ablation with irreversible electroporation and transdermal drug delivery) require a precise prediction of the therapy or treatment outcome by a personalized treatment planning procedure. Numerical modeling of local electric field distribution within electroporated tissues has become an important tool in treatment planning procedure in both clinical and experimental settings. Recent studies have reported that the uncertainties in electrical properties (i.e. electric conductivity of the treated tissues and the rate of increase in electric conductivity due to electroporation) predefined in numerical models have large effect on electroporation based therapy and treatment effectiveness. The aim of our study was to investigate whether the increase in electric conductivity of tissues needs to be taken into account when modeling tissue response to the electroporation pulses and how it affects the local electric distribution within electroporated tissues. METHODS: We built 3D numerical models for single tissue (one type of tissue, e.g. liver) and composite tissue (several types of tissues, e.g. subcutaneous tumor). Our computer simulations were performed by using three different modeling approaches that are based on finite element method: inverse analysis, nonlinear parametric and sequential analysis. We compared linear (i.e. tissue conductivity is constant) model and non-linear (i.e. tissue conductivity is electric field dependent) model. By calculating goodness of fit measure we compared the results of our numerical simulations to the results of in vivo measurements. RESULTS: The results of our study show that the nonlinear models (i.e. tissue conductivity is electric field dependent: sigma(E)) fit experimental data better than linear models (i.e. tissue conductivity is constant). This was found for both single tissue and composite tissue. Our results of electric field distribution modeling in linear model of composite tissue (i.e. in the subcutaneous tumor model that do not take into account the relationship sigma(E)) showed that a very high electric field (above irreversible threshold value) was concentrated only in the stratum corneum while the target tumor tissue was not successfully treated. Furthermore, the calculated volume of the target tumor tissue exposed to the electric field above reversible threshold in the subcutaneous model was zero assuming constant conductivities of each tissue.Our results also show that the inverse analysis allows for identification of both baseline tissue conductivity (i.e. conductivity of non-electroporated tissue) and tissue conductivity vs. electric field (sigma(E)) of electroporated tissue. CONCLUSION: Our results of modeling of electric field distribution in tissues during electroporation show that the changes in electrical conductivity due to electroporation need to be taken into account when an electroporation based treatment is planned or investigated. We concluded that the model of electric field distribution that takes into account the increase in electric conductivity due to electroporation yields more precise prediction of successfully electroporated target tissue volume. The findings of our study can significantly contribute to the current development of individualized patient-specific electroporation based treatment planning. PMID- 23433435 TI - Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer. AB - BACKGROUND: Failure of locoregional control is the main cause of recurrence in advanced head and neck cancer. This multi-center trial aims to improve outcome in two ways. Firstly, by redistribution of the radiation dose to the metabolically most FDG-PET avid part of the tumour. Hereby, a biologically more effective dose distribution might be achieved while simultaneously sparing normal tissues. Secondly, by improving patient selection. Both cisplatin and Epidermal Growth Factor Receptor (EGFR) antibodies like Cetuximab in combination with Radiotherapy (RT) are effective in enhancing tumour response. However, it is unknown which patients will benefit from either agent in combination with irradiation. We will analyze the predictive value of biological markers and (89)Zr-Cetuximab uptake for treatment outcome of chemoradiation with Cetuximab or cisplatin to improve patient selection. METHODS: ARTFORCE is a randomized phase II trial for 268 patients with a factorial 2 by 2 design: cisplatin versus Cetuximab and standard RT versus redistributed RT. Cisplatin is dosed weekly 40 mg/m(2) for 6 weeks. Cetuximab is dosed 250 mg/m(2) weekly (loading dose 400 mg/m(2)) for 6 weeks. The standard RT regimen consists of elective RT up to 54.25 Gy with a simultaneous integrated boost (SIB) to 70 Gy in 35 fractions in 6 weeks. Redistributed adaptive RT consists of elective RT up to 54.25 Gy with a SIB between 64-80 Gy in 35 fractions in 6 weeks with redistributed dose to the gross tumour volume (GTV) and clinical target volume (CTV), and adaptation of treatment for anatomical changes in the third week of treatment.Patients with locally advanced, biopsy confirmed squamous cell carcinoma of the oropharynx, oral cavity or hypopharynx are eligible.Primary endpoints are: locoregional recurrence free survival at 2 years, correlation of the median (89)Zr-cetuximab uptake and biological markers with treatment specific outcome, and toxicity. Secondary endpoints are quality of life, swallowing function preservation, progression free and overall survival. DISCUSSION: The objective of the ARTFORCE Head and Neck trial is to determine the predictive value of biological markers and (89)Zr-Cetuximab uptake, as it is unknown how to select patients for the appropriate concurrent agent. Also we will determine if adaptive RT and dose redistribution improve locoregional control without increasing toxicity.ClinicalTrials.gov Identifier: NCT01504815. PMID- 23433436 TI - Genotype - environment correlations in corals from the Great Barrier Reef. AB - BACKGROUND: Knowledge of genetic markers that are correlated to stress tolerance may improve spatial mapping of reef vulnerability and can inform restoration efforts, including the choice of genotypes for breeding and reseeding. In this manuscript we present two methods for screening transcriptome data for candidate genetic markers in two reef building corals, Acropora millepora and Pocillopora damicornis (types alpha and beta). In A. millepora, Single Nucleotide Polymorphisms (SNPs) were pre-selected by targeting genes believed to be involved in the coral thermal stress responses. In P. damicornis (type alpha and beta), SNPs showing varying allele frequencies between two populations from distinct environments were pre-selected. Allele frequencies at nine, five and eight of the pre-selected SNP loci were correlated against gradients of water clarity and temperature in a large number of populations along the Great Barrier Reef. RESULTS: A significant correlation between environmental category and SNP allele frequency was detected in up to 55% of the tested loci, which is an exceptional success rate for these types of tests. In P. damicornis, SNP allele frequencies of beta-hexosaminidase and Elongation factor 1-alpha were significantly correlated to temperature in type alpha and to temperature and/or water clarity respectively in type beta. Type alpha also showed a correlation between water clarity and SNP allele frequency in a gene of unknown function. In A. millepora, allele frequencies at five (beta-gamma crystallin, Galaxin, Ubiquitin, Ligand of Numb X2 and Thioredoxin) SNP loci showed significant correlations. CONCLUSIONS: After validation of these candidate loci through laboratory or field assessment of relative stress tolerance of colonies harbouring different alleles, it is anticipated that a proportion of these markers may represent the first coral candidate Quantitative Trait Loci for environmental stress tolerance and provide an important genetic tool that can be incorporated into spatial management decisions and restoration efforts of coral reefs. One pertinent example would be to combine spatial data of tolerant populations with genetic connectivity and thus identify high priority conservation reefs and implement targeted coral husbandry and active restoration efforts that use locally- and stress-adapted genotypes. PMID- 23433437 TI - Late-onset Leber hereditary optic neuropathy. AB - BACKGROUND: While Leber hereditary optic neuropathy typically causes bilateral visual loss in the second through fourth decades, we highlight visual loss from Leber hereditary optic neuropathy in older patients to characterize the clinical features of this cohort. DESIGN: Retrospective case series. PARTICIPANTS: Patients seen between January 2003 and July 2012 at Baylor College of Medicine and between April 2010 and July 2012 at The Methodist Hospital in Houston, Texas. METHODS: Patients with visual loss from genetically confirmed Leber hereditary optic neuropathy were identified via retrospective chart review. MAIN OUTCOME MEASURES: Clinical courses of patients. RESULTS: Five patients with visual loss from genetically confirmed Leber hereditary optic neuropathy were greater than 60 years of age at the time of visual loss (range 62-70 years, mean 66.4 +/- 3.0). CONCLUSION: This series reinforces the importance of including Leber hereditary optic neuropathy in the differential diagnosis of patients of any age with optic neuropathy. PMID- 23433438 TI - Plasma membrane-localized Al-transporter from blue hydrangea sepals is a member of the anion permease family. AB - In hydrangea sepals, an aluminum complex of delphinidin-3-O-glucoside is responsible for the development of the blue color, and co-existing copigments mediate the solubilization and stabilization of the blue Al-anthocyanin complex which is localized in the sepal vacuole. In addition, hydrangeas are Al hyperaccumulators and exhibit tolerance to acidic soils, in which the toxicity is due to soluble Al ion. Therefore, an Al-absorbing transport and storage system must exist in hydrangea. Recently, we cloned vacuolar and plasma membrane localized Al-transporters, HmVALT, and HmPALT1, which are both members of the aquaporin family. However, HmPALT1 was only expressed in the sepals, indicating that a different Al-transporter should exist for absorption and long-distance transportation in the hydrangea plant. Using genetic information and microarray analysis, we identified an additional aluminum transporter gene, HmPALT2, which belongs to a member of the anion permease. The transcript was expressed in all tissues of hydrangea plants, and a transient expression study indicated that the gene product is localized to the plasma membrane. The results of an aluminum tolerance assay using yeast cells showed that the HmPALT2 is also involved in the transport of other metal(loid)s. The over-expression of HmPALT2 in Arabidopsis resulted in aluminum-hypersensitivity, suggesting that HmPALT2 should work as an aluminum transporter into cells in planta. PMID- 23433439 TI - Carbapenems. AB - OBJECTIVE: To assess the relative strengths and weaknesses of carbapenems by considering their microbiological, clinical, pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) properties and defining optimal conditions of uses of the new generation of carbapenems. METHODS: Literature review. RESULTS: Except for ertapenem, the spectrum of activity is similar for all carbapenems, with little differences in activities of individual agents. The absence or reduced expression of two major porins in combination with various beta-lactamases and alteration of some penicillin binding proteins have been implicated in carbapenem resistance. All carbapenems are not alike, although they have very similar pharmacokinetic properties. The most important PK/PD parameter predicting bacteriological and clinical efficacy is T(>MIC). There is some circumstantial evidence, such as clinical data in severe critically ill septic patients, impaired renal function patients and neutropenic patients that imipenem has to exceed 66% of T(>MIC) to result in good clinical outcome. Continuous or extend infusion of carbapenems should result in at least equal efficacy to that of intermittent infusion in the treatment of infections with susceptible bacteria and appear highly appropriate for use in critically ill patients. CONCLUSIONS: Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring of carbapenems. PMID- 23433440 TI - In vitro activity (MICs and rate of kill) of AFN-1252, a novel FabI inhibitor, in the presence of serum and in combination with other antibiotics. AB - AFN-1252 is a novel inhibitor of FabI, an essential enzyme in fatty acid biosynthesis in Staphylococcus spp. AFN-1252 exhibits typical MIC(90) values of <=0.015 MUg/ml against diverse clinical isolates of S. aureus, oral absorption, long elimination half-live and efficacy in animal models. We now report high binding (~95%) to serum proteins of mouse, rat, dog and humans, associated with an eight-fold increase in minimal inhibitory concentration (MIC) and which may be responsible for the long elimination half-lives on pharmacokinetic studies. Unlike daptomycin, AFN-1252 activity is not reduced in the presence of lung surfactant. AFN-1252 exhibits a short post-antibiotic effect of 1.1 hours against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) following a 4-hour exposure period. The AFN-1252 unique spectrum of activity is not compromised by interactions with major antibiotic classes, but demonstrates synergy with low concentrations of gentamicin against MSSA and MRSA. These studies support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections. PMID- 23433441 TI - Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model. AB - AFN-1252, a new antimicrobial agent, specifically and potently inhibits fatty acid synthesis in Staphylococcus aureus. We characterized in vivo pharmacokinetic and pharmacodynamic profiles of AFN-1252 administered orally to neutropenic mice inoculated in thighs (~10(6) CFU) with methicillin-susceptible S. aureus (MSSA) ATCC 29213. Efficacy was also assessed in mice inoculated with MSSA, hospital acquired Methicillin-resistant Staphylococcus aureus (HA-MRSA) or community acquired (CA)-MRSA, and administered AFN-1252 or linezolid orally. Bacterial density was determined after 24 hours and efficacy defined as the change in CFU/thigh versus untreated controls at time 0. With MSSA, antibacterial reductions of >=1 log were observed at >=20 mg/kg doses, with fAUC/minimum inhibitory concentration (MIC) best describing the pharmacodynamic profile of AFN-1252. The 80, 50 and 5% maximum effects were observed with fAUC/MIC values of 22.3, 17.0, and 9.6, respectively. Similar values were obtained for CA-MRSA and HA-MRSA. AFN-1252 was 4-40 fold more effective than linezolid against CA-MRSA and HA-MRSA. These data demonstrate the excellent in vivo potency of AFN-1252 against phenotypically diverse S. aureus. PMID- 23433442 TI - Activity of AFN-1252, a novel FabI inhibitor, against Staphylococcus aureus in an in vitro pharmacodynamic model simulating human pharmacokinetics. AB - AFN-1252, a potent enoyl-ACP reductase (FabI) inhibitor, is under development for the treatment of Staphylococcus aureus infections. The activity of AFN-1252 against two isolates of S. aureus, MSSA 26213 and MRSA S186, was studied in an in vitro pharmacodynamic model simulating AFN-1252 pharmacokinetics in man. Reductions in bacterial viable count over the first 6 hours were generally 1-2 logs and maximal reductions in viable count were generally achieved at fAUC/MIC ratios of 100-200. Maximum reductions in viable count against MSSA 29213 and MRSA S186 were approximately 4 logs, achieved by 450 mg q12h (fAUC/MIC = 1875) dosing at 28 hours. Staphylococcal resistance to AFN-1252 did not develop throughout the 48-hour experiments. As multidrug resistance continues to increase, these studies support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections. PMID- 23433443 TI - Prevalence of plasmid-mediated quinolone resistance determinants in Enterobacteriaceae strains isolated in North-East Italy. AB - We investigated the prevalence of plasmid-mediated quinolone resistance genes in 756 clinical isolates of Enterobacteriaceae originating from Microbiology Diagnostic Laboratories of North-East Italy. Five point zero two percent of isolates carried a qnr determinant while the aac(6')-Ib-cr determinant was detected in 9.25% of isolates. We also investigated the association between the plasmid-mediated quinolone resistance and the beta-lactamase genes, and characterized the plasmids carrying these determinants of resistance. PMID- 23433444 TI - Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan. AB - From 1997 to 2003, 40 patients (all <40 years of age) with non-metastatic osteosarcoma of the extremities were treated with OOS-D and definitive surgery. Two cycles of doxorubicin 90 mg/m(2) plus cisplatin 120 mg/m(2) and ifosfamide 15 g/m(2) were given as neoadjuvant chemotherapy, and two cycles of doxorubicin/cisplatin and ifosfamide, and two cycles of high-dose methotrexate (10-12 g/m(2)) were given post-operatively. All patients underwent limb salvage surgeries, and 66% showed good response to neoadjuvant chemotherapy. With a median follow-up period of 117 months, 31 of the evaluable 40 patients were continuously disease-free, 7 were currently alive with no evidence of disease, and 2 died of disease. There was no local recurrence. The 5-year event-free and overall survival rates were 83 and 98%, respectively. The 10-year event-free and overall survival rates were 80 and 95%, respectively. The major form of toxicity was haematological one. PMID- 23433445 TI - A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group. AB - INTRODUCTION: Frequent administration of low doses of cytotoxic drugs (metronomic chemotherapy) has been suggested to suppress tumour growth possibly by inhibiting angiogenesis. We evaluated a metronomic regimen of oral vinorelbine in pre treated patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-six pre-treated NSCLC patients received oral vinorelbine at a fixed dose of 50 mg three times a week. RESULTS: Treatment was administered as second-line in 12 (26.1%) patients and as third- or further-line in 34 (73.9%). Grade 3-4 neutropenia was observed in 23.9% and febrile neutropenia in 10.9%. Grade 3 fatigue was the most common severe non-hematologic toxicity (10.9%). Response rate was 10.9%; 19.6% achieved disease stabilization. Median tumour progression (TTP) was 2.2 months, median overall survival 9.4 months and the 1-year survival rate was 30.1%. CONCLUSION: The administration of metronomic oral vinorelbine is feasible and results in acceptable clinical efficacy associated with manageable toxicity in a population consisting mostly of heavily pre-treated NSCLC patients. PMID- 23433446 TI - Safety analysis of weekly paclitaxel plus S-1 versus paclitaxel plus 5 fluorouracil/calcium folinate as first-line therapy in advanced gastric cancer: a multicenter open random phase II trial. AB - PURPOSE: To report the results of a safety analysis from a phase II trial comparing administration of weekly paclitaxel plus S-1 (TS) versus paclitaxel plus 5-fluorouracil (5-FU)/calcium folinate (LV) (TLF) as first-line therapy for advanced gastric cancer. METHODS: Patients (n = 240) with previously untreated advanced gastric cancer were randomly assigned to receive either TS or TLF in a 28-day cycle for six cycles. RESULTS: The clinical features of both sets of patients were similar, with the exception of the incidence of prior chemotherapy (P>0.05). Most treatment-related adverse events occurred at similar rates in both treatment arms. However, patients receiving TS experienced an increase in all grade especially grade 3/4 neutropenia, with an incidence of 43.7% in the TS arm and 16.3% in the TLF arm, respectively (P<0.05). Other severe adverse events were infrequent and not significantly different between the groups. CONCLUSION: The safety and tolerance of weekly paclitaxel plus S-1 or 5-FU/LV is well in untreated advanced gastric cancer patients. PMID- 23433447 TI - The ability of biofilm formation in clinical isolates of Acinetobacter baumannii belonging to two different European clones causing outbreaks in the Split University Hospital, Croatia. PMID- 23433448 TI - Participatory ergonomic intervention versus strength training on chronic pain and work disability in slaughterhouse workers: study protocol for a single-blind, randomized controlled trial. AB - BACKGROUND: The prevalence of musculoskeletal pain in the shoulder, arm and hand is high among slaughterhouse workers, allegedly due to the highly repetitive and forceful exposure of these body regions during work. Work disability is a common consequence of these pains. Lowering the physical exposure through ergonomics intervention is the traditional strategy to reduce the workload. An alternative strategy could be to increase physical capacity of the worker through strength training. This study investigates the effect of two contrasting interventions, participatory ergonomics versus strength training on pain and work disability in slaughterhouse workers with chronic pain. METHODS/DESIGN: 66 slaughterhouse workers were allocated to 10 weeks of (1) strength training of the shoulder, arm and hand muscles for 3 x 10 minutes per week, or (2) participatory ergonomics involving counseling on workstation adjustment and optimal use of work tools (~usual care control group). Inclusion criteria were (1) working at a slaughterhouse for at least 30 hours per week, (2) pain intensity in the shoulder, elbow/forearm, or hand/wrist of at least 3 on a 0-10 VAS scale during the last three months, (3) pain lasting for more than 3 months, (4) frequent pain (at least 3 days per week) (5) at least moderate work disability, (6) no strength training during the last year, (7) no ergonomics instruction during the last year.Perceived pain intensity (VAS scale 0-10) of the shoulder, elbow/forearm and hand/wrist (primary outcome) and Disability of the Arm, Shoulder and Hand (Work module, DASH questionnaire) were measured at baseline and 10-week follow-up. Further, total muscle tenderness score and muscle function were assessed during clinical examination at baseline and follow-up. DISCUSSION: This RCT study will provide experimental evidence of the effectiveness of contrasting work-site interventions aiming at reducing chronic pain and work disability among employees engaged in repetitive and forceful work. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01671267. PMID- 23433449 TI - Aorto-mesenteric and renal allograft transplant: a novel treatment for midaortic syndrome. AB - Midaortic syndrome (MAS) is a rare condition characterized by stenosis of the aorta and often involving renal and visceral arteries. Current therapies include medical management of associated hypertension, and interventional procedures such as angioplasty or surgical bypass. We report a 2-year-old female with severe MAS who was initially treated with angioplasty and stents in both her aorta and superior mesenteric artery (SMA). Due to the presence of long segment stenoses, her renal arteries were not amenable to surgical reconstruction and she rapidly progressed to Stage V chronic kidney disease. The patient underwent bilateral nephrectomy and renal transplantation using a donor thoracoabdominal aorta allograft to provide inflow for the kidney as well as to bypass the nearly occluded aorta. The donor SMA was used to bypass the native SMA stenosis. Postoperatively, the patient had normalization of four limb blood pressures. She weaned from five anti-hypertensive agents to monotherapy with excellent renal function. This is the first reported case of thoracoabdominal aortic bypass using allograft aorta to address MAS. This approach allowed for successful kidney transplantation with revascularization of the mesenteric, and distal aortic circulation using allograft conduit that will grow with the child, obviating the need for repeated interventional or surgical procedures. PMID- 23433450 TI - Classification of patients based on their evaluation of hospital outcomes: cluster analysis following a national survey in Norway. AB - BACKGROUND: A general trend towards positive patient-reported evaluations of hospitals could be taken as a sign that most patients form a homogeneous, reasonably pleased group, and consequently that there is little need for quality improvement. The objective of this study was to explore this assumption by identifying and statistically validating clusters of patients based on their evaluation of outcomes related to overall satisfaction, malpractice and benefit of treatment. METHODS: Data were collected using a national patient-experience survey of 61 hospitals in the 4 health regions in Norway during spring 2011. Postal questionnaires were mailed to 23,420 patients after their discharge from hospital. Cluster analysis was performed to identify response clusters of patients, based on their responses to single items about overall patient satisfaction, benefit of treatment and perception of malpractice. RESULTS: Cluster analysis identified six response groups, including one cluster with systematically poorer evaluation across outcomes (18.5% of patients) and one small outlier group (5.3%) with very poor scores across all outcomes. One-Way ANOVA with post-hoc tests showed that most differences between the six response groups on the three outcome items were significant. The response groups were significantly associated with nine patient-experience indicators (p < 0.001), and all groups were significantly different from each of the other groups on a majority of the patient-experience indicators. Clusters were significantly associated with age, education, self-perceived health, gender, and the degree to write open comments in the questionnaire. CONCLUSIONS: The study identified five response clusters with distinct patient-reported outcome scores, in addition to a heterogeneous outlier group with very poor scores across all outcomes. The outlier group and the cluster with systematically poorer evaluation across outcomes comprised almost one-quarter of all patients, clearly demonstrating the need to tailor quality initiatives and improve patient-perceived quality in hospitals. More research on patient clustering in patient evaluation is needed, as well as standardization of methodology to increase comparability across studies. PMID- 23433451 TI - Tramadol inhibits the contractility of isolated human myometrium. AB - This study was conducted to determine whether the atypical opioid analgesic tramadol inhibits the contractility of isolated non-pregnant human myometrium. Ten strips of non-pregnant human myometrium stimulated with 55 mm potassium chloride (KCl) were treated with three concentrations (30, 100 and 300 MUm) of tramadol to test for any inhibitory effect of tramadol. The effects of concurrent administration of the beta adrenoceptor antagonist propranolol (1 MUm), the guanylyl cyclase and nitric oxide synthase inhibitor methylene blue (20 MUm) and the opioid receptor antagonist naloxone (100 MUm) with tramadol were also studied. Tramadol caused a concentration-dependent inhibition of KCl-induced myometrial contractility, which was statistically significant at all three concentrations of tramadol used. Propranolol significantly reversed the inhibitory effect of 100 MUm tramadol on KCl-induced myometrial contractility but not that of 300 MUm tramadol. Neither methylene blue nor naloxone reversed the inhibitory effect of tramadol on KCl-induced myometrial contractility. These results suggest that tramadol inhibits KCl-induced contractility of isolated human myometrium. They also suggest that tramadol relaxes the myometrium due to stimulation of beta1 adrenoceptors. However, the concentrations of tramadol required to relax the myometrium were high and likely to be attained at toxic doses, rather than therapeutic doses, of tramadol. PMID- 23433452 TI - Modifiable diarrhoea risk factors in Egyptian children aged <5 years. AB - By conducting a case-control study in two university hospitals, we explored the association between modifiable risk behaviours and diarrhoea. Children aged <5 years attending outpatient clinics for diarrhoea were matched by age and sex with controls. Data were collected on family demographics, socioeconomic indicators, and risk behaviour practices. Two rectal swabs and a stool specimen were collected from cases and controls. Samples were cultured for bacterial pathogens using standard techniques and tested by ELISA to detect rotavirus and Cryptosporidium spp. Four hundred cases and controls were enrolled between 2007 and 2009. The strongest independent risk factors for diarrhoea were: presence of another household member with diarrhoea [matched odds ratio (mOR) 4.9, 95% CI 2.8 8.4] in the week preceding the survey, introduction to a new kind of food (mOR 3, 95% CI 1.7-5.4), and the child being cared for outside home (mOR 2.6, 95% CI 1.3 5.2). While these risk factors are not identifiable, in some age groups more easily modifiable risk factors were identified including: having no soap for handwashing (mOR 6.3, 95% CI 1.2-33.9) for children aged 7-12 months, and pacifier use (mOR 1.9, 95% CI 1.0-3.5) in children aged 0-6 months. In total, the findings of this study suggest that community-based interventions to improve practices related to sanitation and hygiene, handwashing and food could be utilized to reduce the burden of diarrhoea in Egyptian children aged <5 years. PMID- 23433453 TI - Highly conserved antigenic epitope regions of hemagglutinin and neuraminidase genes between 2009 H1N1 and seasonal H1N1 influenza: vaccine considerations. AB - An immunoinformatics study was conducted to determine the highly conserved antigenic epitope regions of hemagglutinin (HA) and neuraminidase (NA) genes in the humoral immunity and CD4+ and CD8+ T cellular immunity between 2009 pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. It was found that in sH1N1 viruses, 29 epitope regions of HA genes and 8 epitope regions of NA genes which had been experimentally identified, were highly conserved (97.1-100.0%) in the corresponding genes and predictive epitopes of the pH1N1 viruses. The results suggested that highly conserved antigenic epitope regions might act as the basis of common antigenic vaccines against pH1N1 and sH1N1 viruses. PMID- 23433454 TI - Redefining approaches to asthma: developing targeted biologic therapies. AB - Asthma is a chronic respiratory disorder canonically associated with type 2 airway inflammation as characterized by elevated levels of eosinophils, immunoglobulin E, and cytokines including interleukin (IL) 4, IL5, IL9, and IL13 and tumor necrosis factor (TNF) alpha. However, mounting evidence has shown that considerable heterogeneity exists in human asthma in terms of the nature and intensity of airway inflammation. While many asthma patients achieve acceptable control of symptoms with standard-of-care therapies such as beta2-adrenergic agonists and inhaled corticosteroids, a minority remains symptomatic despite maximal standard-of-care therapy and constitutes a significant unmet medical need. A growing number of investigational therapeutics under clinical development for asthma are biologic therapies that specifically target mediators of type 2 airway inflammation. In this chapter, we consider the biological functions of therapeutic targets in asthma and data from clinical trials of biologic agents directed against these targets. We discuss recent clinical trial results in terms of four key components of drug development: target selection, molecule selection, outcome selection, and patient selection, with particular attention paid to the emerging role of biomarkers in clinical development for asthma. PMID- 23433455 TI - Protein therapeutics targeted at the TNF superfamily. AB - Protein-based drugs with their unequivocal specificity achieved the long sought milestone of selectively disrupting cytokine pathways to alleviate ongoing inflammation. Tumor necrosis factor (TNF), a member of the superfamily of cytokines involved in regulating immune and inflammatory processes, provides an exemplary model of protein therapeutics. Antibody and receptor-based inhibitors of TNF modify inflammation leading to dramatic improvement in patients with certain autoimmune diseases. Collectively, the structure, specificity and valence of these protein-based drugs provide direct evidence that the essential mechanism of action is antagonism of the ligand-receptor interaction. Accumulating clinical knowledge regarding TNF inhibitors also provide insights into the mechanisms involved in different autoimmune diseases. Experience in the development of an arsenal of biologics directed at TNF has additionally contributed to knowledge toward overcoming the challenges of protein drugs, which include production, delivery, antigenicity and pharmacodynamics. Dramatic clinical outcomes with TNF inhibitors are driving investigation and development of biologics toward other members of the TNF superfamily to selectively alter functional properties of the immune system. PMID- 23433456 TI - Immunopharmacology of lipid A mimetics. AB - The structural core of bacterial lipopolysaccharide, lipid A, has played a role in medicine since the 1890s when William Coley sought to harness its immunostimulatory properties in the form of a crude bacterial extract. Recent decades have brought remarkable clarity to the structure of lipid A and the multicomponent endotoxin receptor system that evolved to detect it. A range of therapeutically useful versions of lipid A now exists, including preparations of detoxified lipid A, synthetic copies of naturally occurring biological intermediates such as lipid IVa, and synthetic mimetics. These agents are finding use as vaccine adjuvants, antagonists and immunostimulants whose structural features have been refined to potentiate efficacy while decreasing the risk of inflammatory side effects. PMID- 23433457 TI - The biology of thymic stromal lymphopoietin (TSLP). AB - Originally shown to promote the growth and activation of B cells, thymic stromal lymphopoietin (TSLP) is now known to have wide-ranging impacts on both hematopoietic and nonhematopoietic cell lineages, including dendritic cells, basophils, eosinophils, mast cells, CD4+, CD8+ and natural killer T cells, B cells and epithelial cells. While TSLP's role in the promotion of TH2 responses has been extensively studied in the context of lung- and skin-specific allergic disorders, it is becoming increasingly clear that TSLP may impact multiple disease states within multiple organ systems, including the blockade of TH1/TH17 responses and the promotion of cancer and autoimmunity. This chapter will highlight recent advances in the understanding of TSLP signal transduction, as well as the role of TSLP in allergy, autoimmunity and cancer. Importantly, these insights into TSLP's multifaceted roles could potentially allow for novel therapeutic manipulations of these disorders. PMID- 23433460 TI - Immunopharmacology. Preface. PMID- 23433461 TI - Efficacy and safety of 12 versus 48 months of dual antiplatelet therapy after implantation of a drug-eluting stent: the OPTImal DUAL antiplatelet therapy (OPTIDUAL) trial: study protocol for a randomized controlled trial. AB - BACKGROUND: Dual antiplatelet therapy with aspirin and thienopyridine is required after placement of coronary drug-eluting stents (DES) to prevent thrombotic complications. Current clinical guidelines recommend at least 6 to 12 months of treatment after a DES implantation, but it may be beneficial to apply dual antiplatelet therapy for a longer duration. METHODS/DESIGN: The optimal dual antiplatelet therapy (OPTIDUAL) study aims to compare the benefits and risks of dual antiplatelet therapy applied for either 12 or 48 months. We will examine the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention with DES for the treatment of coronary lesions. The OPTIDUAL study is an open-label multicenter, randomized, national trial that will include 1,966 patients treated with DES. All patients will be treated with dual antiplatelet therapy for 12 months (+/- 3). Then, patients with no MACCE or major bleeding will be randomized to receive either 36 additional months of clopidogrel plus aspirin or aspirin only. The primary end point is the combination of death from all causes, myocardial infarction, stroke and major bleeding. The secondary end points include the individual components of the primary end-point, stent thrombosis, repeat revascularization of the treated vessel and minor bleeding. DISCUSSION: This randomized trial is designed to assess the benefits and safety of 12 versus 48 months of dual antiplatelet therapy in patients that receive a DES. We aim to determine whether substantial prolongation of clopidogrel (a thienopyridine) after DES implantation offers an advantage over its discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00822536. PMID- 23433463 TI - Simulation of cellular packing in non-proliferative epithelia. AB - The physical laws governing the morphogenesis of biological tissues remain largely misunderstood. In particular, the role of the mechanical interactions occurring in this process needs to be better understood and studied. Inner follicular cells surrounding the oocytes of Ciona intestinalis form an epithelial monolayer resulting from an accretion process (without mitosis or apoptosis). This epithelium is elementary and useful for morphogenesis studies: the cells exhibit polygon packing with a specific but non-systematically repeatable topology (i.e. the distribution of pentagons, hexagons and heptagons changes). To understand the role of mechanical forces in tissue formation, we propose an innovative "2D spherical" model based on the physics of divided media. This approach simulates the cellular mechanical behavior and epithelium structuration by allowing cells to adopt a large variety of shapes and to self-organize in response to mechanical interactions. The numerical parameters considered in the model are derived from experimental data in order to perform pertinent and realistic simulations. The results obtained are compared to biological observations using the same counting method to characterize epithelium topology. Numerical and experimental data appear close enough to validate the model. It is then used for exploratory studies dealing with "Tissue Development Speed" variation, which is not easily attainable by experimentation. We show that the formation speed of the tissue influences its topology and hence its packing organization. PMID- 23433458 TI - Eicosanoids in metabolic syndrome. AB - Chronic persistent inflammation plays a significant role in disease pathology of cancer, cardiovascular disease, and metabolic syndrome (MetS). MetS is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. Nonalcoholic fatty liver disease (NAFLD) is associated with many of the MetS diseases. These metabolic derangements trigger a persistent inflammatory cascade, which includes production of lipid autacoids (eicosanoids) that recruit immune cells to the site of injury and subsequent expression of cytokines and chemokines that amplify the inflammatory response. In acute inflammation, the transcellular synthesis of antiinflammatory eicosanoids resolve inflammation, while persistent activation of the autacoid-cytokine-chemokine cascade in metabolic disease leads to chronic inflammation and accompanying tissue pathology. Many drugs targeting the eicosanoid pathways have been shown to be effective in the treatment of MetS, suggesting a common linkage between inflammation, MetS and drug metabolism. The cross-talk between inflammation and MetS seems apparent because of the growing evidence linking immune cell activation and metabolic disorders such as insulin resistance, dyslipidemia, and hypertriglyceridemia. Thus modulation of lipid metabolism through either dietary adjustment or selective drugs may become a new paradigm in the treatment of metabolic disorders. This review focuses on the mechanisms linking eicosanoid metabolism to persistent inflammation and altered lipid and carbohydrate metabolism in MetS. PMID- 23433462 TI - Evaluation of airway management associated hands-off time during cardiopulmonary resuscitation: a randomised manikin follow-up study. AB - INTRODUCTION: Airway management is an important component of cardiopulmonary resuscitation (CPR). Recent guidelines recommend keeping any interruptions of chest compressions as short as possible and not lasting more than 10 seconds. Endotracheal intubation seems to be the ideal method for establishing a secure airway by experienced providers, but emergency medical technicians (EMT) often lack training and practice. For the EMTs supraglottic devices might serve as alternatives. METHODS: 40 EMTs were trained in a 1-hour standardised audio-visual lesson to handle six different airway devices including endotracheal intubation, Combitube, EasyTube, I-Gel, Laryngeal Mask Airway and Laryngeal tube. EMTs performances were evaluated immediately after a brief practical demonstration, as well as after 1 and 3 months without any practice in between, in a randomised order. Hands-off time was pair-wise compared between airway devices using a repeated-measures mixed-effects model. RESULTS: Overall mean hands-off time was significantly (p<0.01) lower for Laryngeal tube (6.1s; confidence interval 5.2 6.9s), Combitube (7.9s; 95% CI 6.9-9.0s), EasyTube (8.8s; CI 7.3-10.3s), LMA (10.2s; CI 8.6-11.7s), and I-Gel (11.9s; CI 10.2-13.7s) compared to endotracheal intubation (39.4s; CI 34.0-44.9s). Hands-off time was within the recommended limit of 10s for Combitube, EasyTube and Laryngeal tube after 1 month and for all supraglottic devices after 3 months without any training, but far beyond recommended limits in all three evaluations for endotracheal intubation. CONCLUSION: Using supraglottic airway devices, EMTs achieved a hands-off time within the recommended time limit of 10s, even after three months without any training or practice. Supraglottic airway devices are recommended tools for EMTs with lack of experience in advanced airway management. PMID- 23433459 TI - The yin and yang of protein kinase C-theta (PKCtheta): a novel drug target for selective immunosuppression. AB - Protein kinase C-theta (PKCtheta) is a protein kinase C (PKC) family member expressed predominantly in T lymphocytes, and extensive studies addressing its function have been conducted. PKCtheta is the only T cell-expressed PKC that localizes selectively to the center of the immunological synapse (IS) following conventional T cell antigen stimulation, and this unique localization is essential for PKCtheta-mediated downstream signaling. While playing a minor role in T cell development, early in vitro studies relying, among others, on the use of PKCtheta-deficient (Prkcq(-/-)) T cells revealed that PKCtheta is required for the activation and proliferation of mature T cells, reflecting its importance in activating the transcription factors nuclear factor kappa B, activator protein-1, and nuclear factor of activated T cells, as well as for the survival of activated T cells. Upon subsequent analysis of in vivo immune responses in Prkcq(-/-) mice, it became clear that PKCtheta has a selective role in the immune system: it is required for experimental Th2- and Th17-mediated allergic and autoimmune diseases, respectively, and for alloimmune responses, but is dispensable for protective responses against pathogens and for graft-versus-leukemia responses. Surprisingly, PKCtheta was recently found to be excluded from the IS of regulatory T cells and to negatively regulate their suppressive function. These attributes of PKCtheta make it an attractive target for catalytic or allosteric inhibitors that are expected to selectively suppress harmful inflammatory and alloimmune responses without interfering with beneficial immunity to infections. Early progress in developing such drugs is being made, but additional studies on the role of PKCtheta in the human immune system are urgently needed. PMID- 23433464 TI - The effect of patient-specific annular motion on dynamic simulation of mitral valve function. AB - Most surgical procedures for patients with mitral regurgitation (MR) focus on optimization of annular dimension and shape utilizing ring annuloplasty to restore normal annular geometry, increase leaflet coaptation, and reduce regurgitation. Computational studies may provide insight on the effect of annular motion on mitral valve (MV) function through the incorporation of patient specific MV apparatus geometry from clinical imaging modalities such as echocardiography. In the present study, we have developed a novel algorithm for modeling patient-specific annular motion across the cardiac cycle to further improve our virtual MV modeling and simulation strategy. The MV apparatus including the leaflets, annulus, and location of papillary muscle tips was identified using patient 3D echocardiography data at end diastole and peak systole and converted to virtual MV model. Dynamic annular motion was modeled by incorporating the ECG-gated time-varying scaled annular displacement across the cardiac cycle. We performed dynamic finite element (FE) simulation of two sets of patient data with respect to the presence of MR. Annular morphology, stress distribution across the leaflets and annulus, and contact stress distribution were determined to assess the effect of annular motion on MV function and leaflet coaptation. The effect of dynamic annular motion clearly demonstrated reduced regions with large stress values and provided an improved accuracy in determining the location of improper leaflet coaptation. This strategy has the potential to better quantitate the extent of pathologic MV and better evaluate functional restoration following MV repair. PMID- 23433465 TI - Fat1 cadherin provides a novel minimal residual disease marker in acute lymphoblastic leukemia. AB - Measurement of minimal residual disease (MRD) maintains an important role in the clinical management of acute lymphoblastic leukemia (ALL). Recently, we identified Fat1 cadherin as a unique and independent prognostic factor for relapse-free and overall survival in pediatric pre-B-ALL. Here, we analyzed Fat1 mRNA for its potential as a novel marker of MRD in cases of pre-B- and T-ALL. Analyses of microarray data from 125 matched diagnosis/relapse samples across three independent datasets indicate that Fat1 mRNA is detectable in an average of 31.3% of diagnosed pre-B-ALL, of which 67.5% of cases remained positive at relapse. Furthermore, some 20% of cases with undetectable levels of Fat1 mRNA at diagnosis became positive upon relapse. T-ALL cases were 83.3% positive for Fat1 expression at diagnosis with 77.7% remaining positive at relapse. Towards proof of concept, we developed a quantitative polymerase chain reaction assay and demonstrate detection of Fat1 mRNA in leukemic cells mixed with normal peripheral blood cells at a sensitivity of 1 in 10 000 to 100 000 cells. Fat1 may therefore provide a new marker of MRD for patients with ALL lacking known genomic aberrations or within a multiplex approach to MRD detection. PMID- 23433466 TI - Complete resolution of calciphylaxis after kidney transplantation. AB - Calciphylaxis, a life-threatening and disabling complication in patients with end stage renal disease, occurs most frequently in those treated with maintenance dialysis, whether it be hemodialysis or peritoneal dialysis. The impact of kidney transplantation on calciphylaxis lesions is not clear. The general consensus is to treat calciphylaxis adequately prior to transplantation with either medical therapy or parathyroidectomy, as indicated. We describe the case of a patient on peritoneal dialysis therapy who had severe calciphylaxis lesions that failed to resolve upon pretransplantation medical treatment and that then resolved after kidney transplantation. PMID- 23433468 TI - Role of organic amendment application on greenhouse gas emission from soil. AB - Globally, substantial quantities of organic amendments (OAs) such as plant residues (3.8*10(9) Mg/yr), biosolids (10*10(7) Mg/yr), and animal manures (7*10(9) Mg/yr) are produced. Recycling these OAs in agriculture possesses several advantages such as improving plant growth, yield, soil carbon content, and microbial biomass and activity. Nevertheless, OA applications hold some disadvantages such as nutrient eutrophication and greenhouse gas (GHG) emission. Agriculture sector plays a vital role in GHG emission (carbon dioxide- CO2, methane- CH4, and nitrous oxide- N2O). Though CH4 and N2O are emitted in less quantity than CO2, they are 21 and 310 times more powerful in global warming potential, respectively. Although there have been reviews on the role of mineral fertilizer application on GHG emission, there has been no comprehensive review on the effect of OA application on GHG emission in agricultural soils. The review starts with the quantification of various OAs used in agriculture that include manures, biosolids, and crop residues along with their role in improving soil health. Then, it discusses four major OA induced-GHG emission processes (i.e., priming effect, methanogenesis, nitrification, and denitrification) by highlighting the impact of OA application on GHG emission from soil. For example, globally 10*10(7) Mg biosolids are produced annually which can result in the potential emission of 530 Gg of CH4 and 60 Gg of N2O. The article then aims to highlight the soil, climatic, and OA factors affecting OA induced-GHG emission and the management practices to mitigate the emission. This review emphasizes the future research needs in relation to nitrogen and carbon dynamics in soil to broaden the use of OAs in agriculture to maintain soil health with minimum impact on GHG emission from agriculture. PMID- 23433467 TI - Association of metabolic syndrome traits and severity of kidney stones: results from a nationwide survey on urolithiasis in Japan. AB - BACKGROUND: Although metabolic syndrome and its individual components have been associated with kidney stone disease, whether the clustering of metabolic syndrome traits increases the severity of kidney stone disease has not been examined in a large-scale study. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Data were obtained from 30,448 patients enrolled in the 6th Nationwide Survey on Urolithiasis in Japan conducted in 2005. Patients with lower urinary tract stones, struvite stones, cystine stones, or hyperparathyroidism and those younger than 15 years were excluded. PREDICTOR: Number of metabolic syndrome traits (obesity [body mass index >=25 kg/m(2)], diabetes, hypertension, and dyslipidemia). OUTCOMES: Severe form of kidney stone disease, defined as recurrent and/or multiple stones, and abnormalities in urine constituents (hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia). RESULTS: 11,555 patients were included in the final analyses. Proportions of patients with recurrent and/or multiple stones were 57.7%, 61.7%, 65.2%, 69.3%, and 73.3% with 0, 1, 2, 3, and 4 metabolic syndrome traits, respectively (P < 0.001). There was a significant and stepwise increase in the odds of recurrent and/or multiple stones after adjustment for age and sex. In patients with 4 metabolic syndrome traits, the odds was 1.8-fold greater compared with patients with 0 traits (OR, 1.78; 95% CI, 1.22-2.66). In addition, the presence of metabolic syndrome traits was associated with significantly increased odds of having hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia after adjustment for age and sex. LIMITATIONS: Cross-sectional design, absence of dietary data, ill-defined diagnostic criteria for metabolic syndrome traits, and missing data for the majority of participants. CONCLUSIONS: Metabolic syndrome trait clustering is associated with greater severity of kidney stone disease; increased urinary calcium, uric acid, and oxalate excretion; and decreased urinary citrate excretion. These results suggest that kidney stone disease should be regarded as a systemic disorder linked to metabolic syndrome. PMID- 23433469 TI - Evaluating the effect of measurement error when using one or two 24 h dietary recalls to assess eating out: a study in the context of the HECTOR project. AB - Eating out is often recorded through short-term measurements and the large within person variability in intakes may not be adequately captured. The present study aimed to understand the effect of measurement error when using eating-out data from one or two 24 h dietary recalls (24hDR), in order to describe intakes and assess associations between eating out and personal characteristics. In a sample of 366 adults from Potsdam, Germany, two 24hDR and a FFQ were collected. Out-of home intakes were estimated based on either one 24hDR or two 24hDR or the Multiple Source Method (MSM) combining the two 24hDR and the questionnaire. The distribution of out-of-home intakes of energy, macronutrients and selected foods was described. Multiple linear regression and partial correlation coefficients were estimated to assess associations between out-of-home energy intake and participants' characteristics. The mean daily out-of-home intakes estimated from the two 24hDR were similar to the usual intakes estimated through the MSM. The out-of-home energy intake, estimated through either one or two 24hDR, was positively associated with total energy intake, inversely with age and associations were stronger when using the two 24hDR. A marginally significant inverse association between out-of-home energy intake and physical activity at work was observed only on the basis of the two 24hDR. After applying the MSM, all significant associations remained and were more precise. Data on eating out collected through one or two 24hDR may not adequately describe intake distributions, but significant associations between eating out and participants' characteristics are highly unlikely to appear when in reality these do not exist. PMID- 23433470 TI - A specialized motion capture system for real-time analysis of mandibular movements using infrared cameras. AB - BACKGROUND: In the last years, several methods and devices have been proposed to record the human mandibular movements, since they provide quantitative parameters that support the diagnosis and treatment of temporomandibular disorders. The techniques currently employed suffer from a number of drawbacks including high price, unnatural to use, lack of support for real-time analysis and mandibular movements recording as a pure rotation. In this paper, we propose a specialized optical motion capture system, which causes a minimum obstruction and can support 3D mandibular movement analysis in real-time. METHODS: We used three infrared cameras together with nine reflective markers that were placed at key points of the face. Some classical techniques are suggested to conduct the camera calibration and three-dimensional reconstruction and we propose some specialized algorithms to automatically recognize our set of markers and track them along a motion capture session. RESULTS: To test the system, we developed a prototype software and performed a clinical experiment in a group of 22 subjects. They were instructed to execute several movements for the functional evaluation of the mandible while the system was employed to record them. The acquired parameters and the reconstructed trajectories were used to confirm the typical function of temporomandibular joint in some subjects and to highlight its abnormal behavior in others. CONCLUSIONS: The proposed system is an alternative to the existing optical, mechanical, electromagnetic and ultrasonic-based methods, and intends to address some drawbacks of currently available solutions. Its main goal is to assist specialists in diagnostic and treatment of temporomandibular disorders, since simple visual inspection may not be sufficient for a precise assessment of temporomandibular joint and associated muscles. PMID- 23433471 TI - Impact of geriatric consultation teams on clinical outcome in acute hospitals: a systematic review and meta-analysis. AB - BACKGROUND: Comprehensive geriatric assessment for older patients admitted to dedicated wards has proven to be beneficial, but the impact of comprehensive geriatric assessment delivered by mobile inpatient geriatric consultation teams remains unclear. This review and meta-analysis aims to determine the impact of inpatient geriatric consultation teams on clinical outcomes of interest in older adults. METHODS: An electronic search of Medline, CINAHL, EMBASE, Web of Science and Invert for English, French and Dutch articles was performed from inception to June 2012. Three independent reviewers selected prospective cohort studies assessing functional status, readmission rate, mortality or length of stay in adults aged 60 years or older. Twelve studies evaluating 4,546 participants in six countries were identified. Methodological quality of the included studies was assessed with the Methodological Index for Non-Randomized Studies. RESULTS: The individual studies show that an inpatient geriatric consultation team intervention has favorable effects on functional status, readmission and mortality rate. None of the studies found an effect on the length of the hospital stay. The meta-analysis found a beneficial effect of the intervention with regard to mortality rate at 6 months (relative risk 0.66; 95% confidence interval 0.52 to 0.85) and 8 months (relative risk 0.51; confidence interval 0.31 to 0.85) after hospital discharge. CONCLUSIONS: Inpatient geriatric consultation team interventions have a significant impact on mortality rate at 6 and 8 months postdischarge, but have no significant impact on functional status, readmission or length of stay. The reason for the lack of effect on these latter outcomes may be due to insufficient statistical power or the insensitivity of the measuring method for, for example, functional status. The questions of to whom IGCT intervention should be targeted and what can be achieved remain unanswered and require further research. TRIAL REGISTRATION: CRD42011001420 (http://www.crd.york.ac.uk/PROSPERO). PMID- 23433472 TI - Two-stage palatoplasty using a modified Furlow procedure. AB - A two-stage palatal repair using a modification of Furlow palatoplasty is presented. The authors investigate the speech outcome, fistula formation and maxillary growth. In a prospective, successive cohort study, 40 nonsyndromic patients with wide cleft palate were operated on between March 2001 and June 2006 by a single surgeon. 10 patients in the first cohort underwent a Furlow palatoplasty (control group). In 30 patients in the second cohort a unilateral myomucosal cheek flap was used in combination with a modified Furlow palatoplasty (study group). The hard palate was closed in both groups 9-12 months later. The Bzoch speech quality score was superior in the study group, and the hypernasality was significantly reduced in the study group. Overall fistula formation was 0%. At the time of hard palate reconstruction palatal cleft width was significantly reduced. Relative short-term follow up of maxillary growth was excellent. There were no postoperative haematomas, infections, or episodes of airway obstruction. This technique is particularly encouraging, because of better speech outcome, absence of raw surfaces on the soft palate, no fistula formation, and good maxillary growth. Further follow-up is necessary to determine the long-term effects on facial development. PMID- 23433473 TI - Buccal fat pad flap for the closure of oro-antral communication resulting from osteoradionecrosis. PMID- 23433474 TI - "You reap what you sow"--a case of heterotopic ossification within a fasciocutaneous radial forearm free flap reconstruction. AB - Heterotopic ossification is the formation of new bone outside of the skeleton. We describe a previously unreported case of heterotopic ossification occurring within a fasciocutaneous radial forearm free flap for reconstruction following tongue squamous cell carcinoma resection. Although this is a benign condition, it is important to consider and exclude a neoplastic recurrence. PMID- 23433475 TI - Surgical management of a giant cervical ganglioneuroma. AB - An 18-year-old patient presented with a major complaint of a mass in the right side of the neck. At the previous clinic, the patient underwent an open biopsy because the mass could not be diagnosed by fine needle aspiration. The patient was introduced to our institution after mass was diagnosed as ganglioneuroma by open biopsy. In our outpatient clinic, magnetic resonance imaging (MRI) and computed tomography (CT) were performed. Gradual growth of the mass was accompanied by sleep apnea syndrome. Ultimately, the patient was only able to sleep with nasal continuous positive airway pressure. Pathological examination confirmed the ganglioneuroma. MRI revealed expansion of the ganglioneuroma from the nasopharynx to the right upper mediastinum, occupying the surroundings of the contralateral carotid artery via the retropharyngeal space. CT revealed a tumor mass of 160mm*60mm*190mm in size. The mass was surgically resected without any postoperative neurological disorder including Horner syndrome. The clinical course was successful without recurrence. This is the first report of a successful treatment of a large ganglineuroma that had continuously expanded to the contralateral neck via the retropharyngeal space. PMID- 23433476 TI - Infantile inflammatory pseudotumor of the facial nerve as a complication of epidermal nevus syndrome with cholesteatoma. AB - The first reported case of facial paralysis due to an inflammatory pseudotumor (IPT) of the facial nerve as a complication of epidermal nevus syndrome (ENS) is herein presented. A 10-month-old female patient was diagnosed with ENS at 3 months of age. She was referred to us because of moderate left facial paralysis. Epidermal nevi of her left auricle extended deep into the external ear canal. Otoscopy revealed polypous nevi and cholesteatoma debris filling the left ear. Computed tomography showed a soft mass filling the ear canal, including the middle ear, and an enormously enlarged facial nerve. Surgical exploration revealed numerous polypous nevi, external ear cholesteatoma, and tumorous swelling of the facial nerve. The middle ear ossicles were completely lost. The facial paralysis was improved after decompression surgery, but recurred 5 months later. A second operation was conducted 10 months after the first. During this operation, facial nerve decompression was completed from the geniculate ganglion to near the stylomastoid foramen. Histological diagnosis of the facial nerve tumor was IPT probably caused by chronic external ear inflammation induced by epidermal nevi. The facial paralysis gradually improved to House-Blackmann grade III 5 years after the second operation. PMID- 23433477 TI - Peritraumatic distress but not dissociation predicts posttraumatic stress disorder in the elderly. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms include re-experiencing, avoidance, and hyperarousal after a particularly intense event. In view of the aging of the population, increased clinical knowledge is required for better understanding of PTSD in the elderly. Extending previous research in this field in adults and children, the aim of our study was to assess the utility of peri-traumatic dissociation and distress as a predictor of PTSD in the elderly. METHODS: A prospective longitudinal study was conducted in a consecutive cohort of subjects aged 65 years and over admitted to emergency departments after a physical assault or a road traffic accident. Peri traumatic responses of distress and of dissociation were measured. One, 6, and 12 months after trauma exposure, PTSD symptoms and diagnosis were assessed using both a dimensional and a semistructured interview. RESULTS: Thirty-nine male and female participants with an average age of 72.4 years were recruited. Mixed model regression analyses did not detect a significant effect of age, sex, nor time. Significant associations were detected between peri-traumatic distress and the self-report PTSD Checklist (p = 0.008), as well as the Clinician-administered PTSD scale (p = 0.03). No association was detected between peri-traumatic dissociation and PTSD. CONCLUSIONS: Peri-traumatic distress predicts PTSD symptoms and diagnosis in the elderly, thereby suggesting its systematic evaluation at the emergency department would be a worthwhile thing to do. PMID- 23433478 TI - Use of beta-blockers and mortality following ovarian cancer diagnosis: a population-based cohort study. AB - BACKGROUND: Experimental data suggest that catecholamine hormones are involved in stimulating the aggressiveness of ovarian cancer, but few population-based studies have examined this association. We therefore conducted a population-based cohort study to examine whether beta-blockers affect mortality following ovarian cancer diagnosis. METHODS: We used the Danish Cancer Registry to identify all patients diagnosed with ovarian cancer in northern Denmark between 1999 and 2010 (n=6,626). Data on medication use, comorbidity, and survival were obtained from medical databases. According to the last redeemed prescription before diagnosis, beta-blocker use was categorized as current (within <=90 days), previous (>90 days) or never. We used Cox proportional hazards regression to calculate hazard ratios (HRs) for all-cause mortality with 95% confidence intervals (CIs) adjusting for confounding factors. RESULTS: Among the ovarian cancer patients, 373 (5.6%) were current, 87 (1.3%) previous, and 6,166 (93.1%) were nonusers of beta-blockers. Median duration of use was 19.0 months among current users and 43.0 months among previous users. Median follow-up was 2.55 years (IQR: 0.81 9.23). Nonusers and current users of beta-blockers had similar comorbidity burden whereas previous users had moderate comorbidity more frequently. Compared with nonusers, the adjusted HR was 1.17 (95% CI: 1.02-1.34) for current users and 1.18 (95% CI: 0.90-1.55) for previous users. Secondary analyses stratifying by cancer stage and duration of beta-blocker use supported the overall results. CONCLUSIONS: We found no evidence that beta-blocker use was associated with decreased mortality following ovarian cancer diagnosis. PMID- 23433479 TI - Mothers' experiences and satisfactions with health extension program in Jimma zone, Ethiopia: a cross sectional study. AB - BACKGROUND: Although mothers are the fundamental unit of interventions in Health Extension Program in Ethiopia, their experiences and satisfactions with the service remain unstudied. Therefore, this study was aimed to assess mothers' experiences and satisfaction with health extension service. METHODS: A community based cross sectional study was conducted in Jimma Zone, Oromiya, Ethiopia. Three hundred Seventy-nine mothers were participated in the study. The study was conducted in four randomly selected rural villages. Systematic sampling technique was used to identify respondents. As part of the data collection process, four focus group discussions were conducted with mothers. SPSS 17.0 and ATLASti.4.1. Softwares were used for data analysis. RESULTS: One hundred Sixty nine (51.7%) of the respondents had an experience of interactions with health extension workers during one year prior to the survey, while 271 (71.5%) of them reported that they received visits from health extension workers during the same period. 298 (78.6%) of the respondents received information at least on one of the Health extension packages. In fact, they had better exposure to personal hygiene and environmental sanitation packages. Even though health extension program is being run by female workers alone, it was believed that the involvement of men is vital to the success of the program. Mothers thought that men are more courageous and professionally competent to deal with complex matters. They also tended to criticize health extension program for lacking curative services and health extension workers are less competent. The greater emphasis laid on outreach services was not supported. 286 (75.5%) of the respondents rated their relationship with health extension workers as positive. Similarly, higher satisfaction was reported though the program has problems. Age, perceived skill to diagnose community problems, perceived respect, involvement of husband and being recognized as a model family were significantly predicted satisfactions with health extension services. CONCLUSIONS: Most mothers had good relationship, were satisfied with and had positive attitude towards health extension program though the program was criticized for not including curative services and the less attention given to static services at health post. Stakeholders are required to reconsider these issues. PMID- 23433480 TI - Phylogenetic patterns of emergence of new genes support a model of frequent de novo evolution. AB - BACKGROUND: New gene emergence is so far assumed to be mostly driven by duplication and divergence of existing genes. The possibility that entirely new genes could emerge out of the non-coding genomic background was long thought to be almost negligible. With the increasing availability of fully sequenced genomes across broad scales of phylogeny, it has become possible to systematically study the origin of new genes over time and thus revisit this question. RESULTS: We have used phylostratigraphy to assess trends of gene evolution across successive phylogenetic phases, using mostly the well-annotated mouse genome as a reference. We find several significant general trends and confirm them for three other vertebrate genomes (humans, zebrafish and stickleback). Younger genes are shorter, both with respect to gene length, as well as to open reading frame length. They contain also fewer exons and have fewer recognizable domains. Average exon length, on the other hand, does not change much over time. Only the most recently evolved genes have longer exons and they are often associated with active promotor regions, i.e. are part of bidirectional promotors. We have also revisited the possibility that de novo evolution of genes could occur even within existing genes, by making use of an alternative reading frame (overprinting). We find several cases among the annotated Ensembl ORFs, where the new reading frame has emerged at a higher phylostratigraphic level than the original one. We discuss some of these overprinted genes, which include also the Hoxa9 gene where an alternative reading frame covering the homeobox has emerged within the lineage leading to rodents and primates (Euarchontoglires). CONCLUSIONS: We suggest that the overall trends of gene emergence are more compatible with a de novo evolution model for orphan genes than a general duplication-divergence model. Hence de novo evolution of genes appears to have occurred continuously throughout evolutionary time and should therefore be considered as a general mechanism for the emergence of new gene functions. PMID- 23433481 TI - Abattoir-based study on the epidemiology of caprine tuberculosis in Ethiopia using conventional and molecular tools. AB - BACKGROUND: Despite the important role of goats for meat and milk production in Ethiopia, little information is available on the epidemiology of caprine tuberculosis (TB). Caprine TB is important as milk is usually consumed raw particularly by Ethiopian pastoralists. The objectives of the present study were to estimate the prevalence of TB in goats at an abattoir, to evaluate associated risk factors and to characterize the causative mycobacteria. METHODS: A cross sectional study was conducted on 1990 randomly selected male goats that were slaughtered at Luna Export Abattoir of central Ethiopia. Postmortem examination, mycobacterial culturing and molecular typing techniques like genus typing, deletion typing and spoligotyping were used. RESULT: The overall prevalence of caprine TB-like lesions was 3.5%. The lesion prevalence increased significantly with increasing age. Mycobacteria were found by culture and seen as acid fast bacilli in 12% of the goats with TB-like lesions. Characterization of the eight isolates using multiplex polymerase chain reaction (PCR) indicated that five of them belonged to the genus Mycobacterium. Four of the latter were confirmed to be members of the M. tuberculosis complex. Further characterization of the three M. tuberculosis isolates by spoligotyping identified them as type SIT53 and two new spoligotypes. CONCLUSION: The isolation of M. tuberculosis from goats in this study indicates a potential risk of transmission of M. tuberculosis between humans and goats. PMID- 23433484 TI - Initial development and validation of a mitochondrial disease quality of life scale. AB - Mitochondrial diseases are a clinically diverse group of genetic disorders that often present to neurologists. Health related quality of life (HRQOL) is increasingly recognised as a fundamental patient based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess HRQOL across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop disease specific HRQOL measures that centre on symptoms characteristic of a specific disease or condition and their impact. This study presents the initial conceptualisation, development and preliminary psychometric assessment (validity and reliability) of a mitochondrial disease specific HRQOL measure (Newcastle Mitochondrial Quality of life measure (NMQ)). NMQ is a valuable assessment tool and consists of 63 items within 16 unidimensional domains, each demonstrating good internal reliability (Cronbach's alpha>=0.83) and construct validity. PMID- 23433485 TI - The redox-active, anti-cancer drug Dp44mT inhibits T-cell activation and CD25 through a copper-dependent mechanism. PMID- 23433483 TI - Consumption of coffee associated with reduced risk of liver cancer: a meta analysis. AB - BACKGROUND: Epidemiologic studies have reported inconsistent results regarding coffee consumption and the risk of liver cancer. We performed a meta-analysis of published case-control and cohort studies to investigate the association between coffee consumption and liver cancer. METHODS: We searched Medline, EMBASE, ISI Web of Science and the Cochrane library for studies published up to May 2012. We performed a meta-analysis of nine case-control studies and seven cohort studies. RESULTS: The summary odds ratio (OR) for high vs no/almost never drinkers was 0.50 (95% confidence interval (CI): 0.42-0.59), with no significant heterogeneity across studies (Q = 16.71; P = 0.337; I2 = 10.2%). The ORs were 0.50 (95% CI: 0.40-0.63) for case-control studies and 0.48 (95% CI: 0.38-0.62) for cohort studies. The OR was 0.38 (95% CI: 0.25-0.56) in males and 0.60 (95% CI: 0.33 1.10) in females. The OR was 0.45 (95% CI: 0.36-0.56) in Asian studies and 0.57 (95% CI: 0.44-0.75) in European studies. The OR was 0.39 (95% CI: 0.28-0.54) with no adjustment for a history of liver disease and 0.54 (95% CI: 0.46-0.66) after adjustment for a history of liver disease. CONCLUSIONS: The results of this meta analysis suggested an inverse association between coffee consumption and liver cancer. Because of the small number of studies, further prospective studies are needed. PMID- 23433482 TI - Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study. AB - OBJECTIVES: The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented. METHODS: HIV-infected subjects >= 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24 hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population. RESULTS: Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. CONCLUSIONS: This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients. PMID- 23433486 TI - Expansion of antibody secreting cells and modulation of neutralizing antibody activity in HIV infected individuals undergoing structured treatment interruptions. AB - BACKGROUND: HIV-1 infection generates numerous abnormalities in the B cell compartment which can be partly reversed by antiretroviral therapy. Our aim was to evaluate the effects that re-exposure to HIV antigens might have on the frequency and functionality of antibody secreting cells (ASC) in patients undergoing structured treatment interruptions (STI). As re-exposure to viral antigens may also boost the production of (neutralizing) antibodies, we also assessed the neutralizing activities during STI cycles. METHODS: Retrospective study of 10 patients undergoing 3 cycles of STI with 2 weeks on and 4 weeks off HAART. ASC frequencies were determined by flow cytometry in samples obtained at the beginning and the end of STI. Neutralization capacity, total IgG concentration and anti-gp120-IgG titres were evaluated. RESULTS: As expected, median viral loads were higher at the end of STI compared to on-HAART time points. The level of CD27 and CD38 expressing ACS followed the same pattern; with ASC being elevated up to 16 fold in some patients (median increase of 3.5% +/- 4.13). Eight out of 10 patients maintained stable total IgG levels during the study. After purifying IgG fractions from plasma, HIV-neutralizing activity was observed in the two subjects with highest anti-gp120 titers. In one of these patients the neutralizing activity remained constant while the other showed elevated neutralizing Ab after first STI and once treatment was reinitiated after the 2nd STI. CONCLUSIONS: Our data suggest that STI and its associated transient increases in viral load drive the frequencies of ASC in an antigen-specific manner. In some subjects, this re-exposure to autologous virus boosts the presence of neutralizing antibodies, similar to what is seen after influenza vaccination. STI may not boost clinically beneficial nAb levels but offers opportunities to isolate nAb producing cells at considerably higher levels than in subjects with completely suppressed viral replication. PMID- 23433487 TI - Acute retinal artery occlusion in systemic sclerosis: a rare manifestation of systemic sclerosis fibroproliferative vasculopathy. AB - OBJECTIVES: To describe three patients with systemic sclerosis (SSc) who developed acute unilateral blindness in the absence of any common etiologic factor for blindness. In one patient, the affected eye required enucleation and was examined histopathologically. METHODS: Following identification of the first patient with retinal artery occlusion at the Scleroderma Center of Thomas Jefferson University, every patient evaluated at the Center from May 2001 to December 2010 was prospectively assessed for the development of acute unilateral blindness. Two additional cases were identified. Here, we describe the clinical features, laboratory and ancillary examinations of the three patients with SSc who developed acute unilateral blindness and present the histopathological examination of one eye enucleated from one of the patients. RESULTS: Clinical and angiographic studies were consistent with acute retinal artery occlusion. The histopathological studies showed severe retinal ischemic atrophy and concentric narrowing and fibrosis of small retinal vessels. CONCLUSIONS: These findings suggest that acute retinal artery occlusion in these patients is a manifestation of the fibroproliferative vasculopathy characteristic of SSc. PMID- 23433488 TI - Evaluation of charged aerosol detector for purity assessment of protein. AB - Commercially available protein reference standard materials are widely used for the quantitation of intact proteins in biopharmaceuticals, food, and consumer products. However, the purity of protein reference standard materials are often assumed to be 100% or they may be assigned an inaccurate value because the methods used to determine protein purity often lack specificity and accuracy. In this study, a high performance liquid chromatography system equipped with a charged aerosol detector (HPLC-CAD) was used for universal response detection to provide a practical, specific, accurate, and robust method for the determination of the purity of protein reference standard materials. This work demonstrates the near uniform CAD responses for six proteins with different molecular weights and different structures. Flow injection analysis (FIA) was used to compare protein responses under various mobile phase and diluent compositions. Similar CAD responses for all six proteins were observed when the mobile phase composition included trifluoroacetic acid (TFA) and acetonitrile. These are typical conditions regularly applied to the separation of proteins by reversed phase (RP) chromatography. The universal response feature of the CAD was employed to determine the purity of Bowman-Birk inhibitor (BBI) reference standard material. This protein is an important ingredient in soybean products and has various therapy applications. Three major components were observed in the commercially available reference standard material by reversed phase gradient HPLC, BBI Native, BBI-Isoform 1, and BBI-Isoform 2 at relative compositions of 60.0%, 34.2%, and 5.8%, respectively. PMID- 23433489 TI - Residential proximity to industrial combustion facilities and risk of non-Hodgkin lymphoma: a case-control study. AB - BACKGROUND: Residence near municipal solid waste incinerators, a major historical source of dioxin emissions, has been associated with increased risk of non Hodgkin lymphoma (NHL) in European studies. The aim of our study was to evaluate residence near industrial combustion facilities and estimates of dioxin emissions in relation to NHL risk in the United States. METHODS: We conducted a population based case-control study of NHL (1998-2000) in four National Cancer Institute Surveillance Epidemiology and End Results centers (Detroit, Iowa, Los Angeles, Seattle). Residential histories 15 years before diagnosis (similar date for controls) were linked to an Environmental Protection Agency database of dioxin emitting facilities for 969 cases and 749 controls. We evaluated proximity (3 and 5 km) to 10 facility types that accounted for >85% of U.S. emissions and a distance-weighted average emission index (AEI [ng toxic equivalency quotient (TEQ)/year]). RESULTS: Proximity to any dioxin-emitting facility was not associated with NHL risk (3 km OR = 1.0, 95% CI 0.8-1.3). Risk was elevated for residence near cement kilns (5 km OR = 1.7, 95% CI 0.8-3.3; 3 km OR = 3.8, 95% CI 1.1-14.0) and reduced for residence near municipal solid waste incinerators (5 km OR = 0.5, 95% CI 0.3-0.9; 3 km OR = 0.3, 95% CI 0.1-1.4). The AEI was not associated with risk of NHL overall. Risk for marginal zone lymphoma was increased for the highest versus lowest quartile (5 km OR = 2.6, 95% CI 1.0-6.8; 3 km OR = 3.0, 95% CI 1.1-8.3). CONCLUSIONS: Overall, we found no association with residential exposure to dioxins and NHL risk. However, findings for high emissions and marginal zone lymphoma and for specific facility types and all NHL provide some evidence of an association and deserve future study. PMID- 23433490 TI - Immunomodulatory therapy versus surgery for Rasmussen syndrome in early childhood. AB - We examined seizure, cognitive, and motor outcomes in patients with Rasmussen syndrome or Rasmussen encephalitis (RS), after recent initiation of immunomodulatory therapies. Among 53 patients with a diagnosis of RS referred from all over Japan, 49 patients (male 22, female 27) with symptoms and findings characteristic of RS were evaluated. Regular intravenous immunoglobulin (IVIg) therapy was administered at a dose of 100mg/kg/day, etc. Regular steroid pulse therapy was conducted with methylprednisolone at a dose of 30mg/kg/day (children) or 1000mg/day (adults) for 3days. Tacrolimus was given at an initial dose of 0.1mg/kg/day (children). Mean onset age was 8.7+/-10.5years. Seizure-free rate was 71% after treatment by functional hemispherectomy (FH), and response rate for seizures was 81% by regular steroid pulse therapy, 42% by tacrolimus therapy, and 23% by regular IVIg therapy. Rate of patients with IQ higher than 80 (R80) was 50% by regular steroid pulse therapy, 43% by regular IVIg therapy, 29% by tacrolimus therapy, and 0% by FH. R80 after regular steroid pulse therapy was 100% in patients without MRI lesions, and 37% in those with advanced MRI lesions. Improvement of motor function (paresis) was observed only by immunomodulatory therapy. Motor function was aggravated in 100% of patients treated by FH, 62% by regular IVIg, and 10% by regular steroid pulse therapy. We suggest a new treatment strategy for RS using early immunomodulatory therapy: initiation of regular steroid pulse therapy after early diagnosis indicated by biomarkers, then switching to tacrolimus therapy after several months. PMID- 23433491 TI - Histological, biochemical, and genetic characterization of early-onset fulminating sialidosis type 2 in a Korean neonate with hydrops fetalis. AB - Non-immune hydrops fetalis is the most severe presenting feature of lysosomal storage disorders. However, it is difficult to identify the underlying condition because the different lysosomal storage diseases share many clinical features. A neonate with hydrops fetalis is described here. A lysosomal storage disorder was first suspected when the placental biopsy showed the presence of macrophages containing numerous cytoplasmic vacuoles. Subsequent comprehensive diagnostic processes and biochemical and molecular genetics characterization revealed a rare genetic cause, namely sialidosis type 2. Liquid chromatography-mass spectrometry revealed increased amounts of bound sialic acid in the urine. Pathogenic NEU1 mutations were detected. This is the first case with sialidosis type 2 ever known in the Korean population, exhibiting its most severe manifestation. PMID- 23433493 TI - Intact but not denatured ovine serum immunoglobulins positively modulate mucosal immune mediators in the growing rat challenged with Salmonella enteritidis. AB - Immunoglobulins are major glycoproteins that modulate the immune response of gut associated lymphoid tissue. In the present study, we sought to determine whether orally administered ovine serum immunoglobulins modulate selected indices of mucosal immune function and immune mediators in the growing rat challenged with Salmonella enteritidis. Rats were fed a casein-based basal control diet (BD; unchallenged). Three groups of rats were challenged orally with 1 x 10(7) viable S. enteritidis on day 15 of the study and were fed the BD, the BD containing freeze-dried ovine immunoglobulins (FDOI), or the BD containing autoclaved ovine immunoglobulins (AOI; negative control diet). The rats were randomly allocated to one of the four groups (n 15) and consumed their diet for 18 d. In all of the intestinal segments, the challenged rats fed either the BD or AOI diet produced higher (P<0.05) mucosal levels of interferon-g, TNFa, IgA and myeloperoxidase activity than the challenged rats fed the FDOI diet. In contrast, IL-4 and IL-10 levels were higher in the challenged FDOI-fed rats compared with the other challenged groups. The challenged FDOI-fed rats had higher (P<0.05) mucosal anti Salmonella IgA and IgG in all of the intestinal segments except the jejunum and ileum. Generally, the challenged rats receiving the FDOI diet had significantly (P<0.05) higher mucosal mucin protein content compared with challenged rats receiving either the BD or AOI diet. In conclusion, an ovine immunoglobulin fraction positively modulated some selected indices of mucosal immune function and its mediators in growing rats challenged with S. enteritidis. PMID- 23433492 TI - The effectiveness and cost-effectiveness of spinal cord stimulation for refractory angina (RASCAL study): study protocol for a pilot randomized controlled trial. AB - BACKGROUND: The RASCAL (Refractory Angina Spinal Cord stimulation and usuAL care) pilot study seeks to assess the feasibility of a definitive trial to assess if addition of spinal cord stimulation (SCS) to usual care is clinically superior and more cost-effective than usual care alone in patients with refractory angina. METHODS/DESIGN: This is an external pilot, patient-randomized controlled trial.The study will take place at three centers in the United Kingdom - South Tees Hospitals NHS Foundation Trust (The James Cook University Hospital), Dudley Group of Hospitals NHS Foundation Trust, and Basildon and Thurrock University Hospitals NHS Foundation Trust.The subjects will be 45 adults with refractory angina, that is, limiting angina despite optimal anti-angina therapy, Canadian Cardiovascular Society Functional Classification Class III and IV, angiographically documented coronary artery disease not suitable for revascularization, satisfactory multidisciplinary assessment and demonstrable ischemia on functional testing.The study will be stratified by center, age and Canadian Cardiovascular Society Functional Classification.Interventions will involve spinal cord stimulation plus usual care ('SCS group') or usual care alone ('UC group'). Usual care received by both groups will include consideration of an education session with a pain consultant, trial of a transcutaneous electrical neurostimulation, serial thoracic sympathectomy and oral/systemic analgesics.Expected outcomes will be recruitment and retention rates; reasons for agreeing/declining participation; variability in primary and secondary outcomes (to inform power calculations for a definitive trial); and completion rates of outcome measures. Trial patient-related outcomes include disease-specific and generic health-related quality of life, angina exercise capacity, intake of angina medications, frequency of angina attacks, complications and adverse events, and satisfaction. DISCUSSION: The RASCAL pilot trial seeks to determine the feasibility and design of a definitive randomized controlled trial comparing the addition of spinal cord stimulation to usual care versus usual care alone for patients with refractory angina.Fifteen patients have been recruited since recruitment opened in October 2011. The trial was originally scheduled to end in April 2013 but due to slow recruitment may have to be extended to late 2013. TRIAL REGISTRATION: ISRCTN65254102. PMID- 23433494 TI - How and why Toxoplasma makes us crazy. AB - For a long time, a latent toxoplasmosis, the lifelong presence of dormant stages of Toxoplasma in various tissues, including the brain, was considered harmless for immunocompetent persons. Within the past 10 years, however, many independent studies have shown that this parasitic disease, with a worldwide prevalence of about 30%, could be indirectly responsible for hundreds of thousands of deaths due to its effects on the rate of traffic and workplace accidents, and also suicides. Moreover, latent toxoplasmosis is probably one of the most important risk factors for schizophrenia. At least some of these effects, possibly mediated by increased dopamine and decreased tryptophan, are products of manipulation activity by Toxoplasma aiming to increase the probability of transmission from intermediate to definitive host through predation. PMID- 23433495 TI - Content of delusional thoughts in Alzheimer's disease and assessment of content specific brain dysfunctions with BEHAVE-AD-FW and SPECT. AB - BACKGROUND: A consensus on the brain dysfunction(s) underlying the delusions of Alzheimer's Dementia (AD) remains to be achieved. The aim of the present study was to test the hypothesis that content-based categorization of delusional ideas manifests as dysfunction of category-specific brain regions. METHODS: Fifty-nine consecutive first-visit AD outpatients underwent Single Photon Emission Computed Tomography (SPECT), Mini-Mental State Examination, and Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity scale (BEHAVE-AD-FW) to assess cerebral blood flow (CBF), cognitive function, and delusion, respectively. SPECT images were analyzed by SPM5. RESULTS: CBF decreased at the temporal poles and right inferior temporal gyrus in "delusion of theft," at the temporal poles in "suspiciousness/paranoia," at the right parahippocampal gyrus and insula in "abandonment," and at the right amygdala in "Residence is not home." CONCLUSIONS: Our findings offer a perspective on the discrete categories of the pathological thoughts of AD patients that have previously been lumped together as "delusions." Dysfunction of the temporal poles may be associated with a socioemotional deterioration that may include pathological suspiciousness. Delusion of theft may be a manifestation of socioemotional deterioration and poor insight. Emotional factors may be essential for delusions of abandonment and "not home." PMID- 23433496 TI - The optimal duration of compression therapy following varicose vein surgery: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: The optimal duration of compression therapy following varicose vein surgery of the great saphenous vein (GSV) remains controversial. Therefore, the aim of this study was to evaluate different durations of compression therapy after varicose vein surgery and their outcomes. DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Outcomes from short-duration (3-10 d) and long-duration (3-6 wk) compression therapy after GSV stripping and phlebectomies were evaluated. Pain was assessed post surgery using a visual analog scale. Secondary outcomes included leg volume, complications, and the duration of absenteeism from work. RESULTS: We identified 4 RCTs published between 1991 and 2009 that evaluated 686 patients. We observed non-significant differences in postoperative pain scores between the long-duration and short duration groups, with a weighted mean difference of -0.03 (95% confidence interval (CI): -0.53 to 0.47) at 4 weeks, and -0.01 (95% CI: -0.31 to 0.33) at 6 weeks, postoperatively. We also observed non-significant differences in the incidence of postoperative complications (risk ratio: 0.84, 95% CI: 0.60-1.18), and changes in leg volume, 4 weeks postoperatively (P = .18) between the groups. CONCLUSION: Our study results indicate that there are no benefits to long-term compression therapy after varicose vein surgery of the GSV regarding postoperative pain, leg volume, incidence of complications, and duration of absenteeism from work. PMID- 23433497 TI - Volume estimation of the aortic sac after EVAR using 3-D ultrasound - a novel, accurate and promising technique. AB - OBJECTIVES: Volume estimation is more sensitive than diameter measurement for detection of aneurysm growth after endovascular aneurysm repair (EVAR), but this has only been confirmed on three-dimensional, reconstructed computer tomography (3-D CT). The potential of 3-D ultrasound (3-D US) for volume estimation in EVAR surveillance is unknown. DESIGN: Prospective validation study comparing 3-D US with 3-D CT, using 3-D CT as the gold standard. MATERIALS AND METHODS: From August 2011 to March 2012, 93 consecutive EVAR patients were enrolled and examined with both 3-D US and CT angiography (CTA). Image data were analysed in a mutual blinded setup using a 3-D interactive segmentation technique. RESULTS: The technical success rate of 3D-US was 98% (91/93). In 91 EVAR patients (F/M; 10/81) eligible for further analysis, the mean maximum volume (SD) was 126 (58) ml using 3-D US and 128 (58) ml using 3-D CT. The mean difference was 1 ml (0.4%) and the limits of agreement were -14 to 16 ml (-11; 12%). CONCLUSION: Volume estimation of the aortic sac after EVAR using 3-D US is a feasible and accurate method using 3-D CT as the gold standard. PMID- 23433498 TI - Paraganglioma of the carotid body: treatment strategy and SDH-gene mutations. AB - OBJECTIVES: The aim of the present study was to review treatment results in patients with paraganglioma (PGL) of the neck presenting as carotid body tumour, long-term follow-up and relevance of genetic testing for succinate dehydrogenase (SDH)-gene mutations. DESIGN: Retrospective analysis of prospectively collected data and prospective genetic analysis. MATERIALS AND METHODS: Over a 25-year period (1987-2011) 50 patients were operated for 63 PGLs of the neck. Pre-, intra and postoperative findings were analysed. Sanger sequencing was performed for genetic testing of SDH-gene mutations (SDH B, SDHC and SDHD). RESULTS: Fifty patients underwent resection of 63 PGLs (62 benign, one malignant) without mortality. Eight patients underwent preoperative embolisation. Vascular surgical procedures were required in 15 operations (15/63 = 23.8%). Nerve lesions occurred after 13 operations (13/63 = 20.6%) and were associated with large tumours. A total of 44 patients are alive after a mean follow-up of 9.8 years. In 40 patients 17 SDH-gene mutations were detected (17/40 = 42.5%): 14 SDHD mutations, two SDHB mutations and one rare SDHC mutation. CONCLUSION: Surgery for PGL is recommended. All PGL patients should be screened for SDH mutations because it impacts the individual follow-up strategy. Whereas all PGL patients require annual ultrasound control, mutation carriers and family members with proven mutations should in addition be regularly examined by magnetic resonance imaging (MRI) of head, neck, thorax, abdomen and pelvis. PMID- 23433499 TI - Re. 'Is it right ASA scoring to be used in identification of nonoperated patients?'. PMID- 23433500 TI - The sticky platelet syndrome. AB - The sticky platelets syndrome (SPS) is a procoagulant condition based on either arterial, venous, or capillary thrombi caused by hyperesponsive and hyperaggregable platelets. This is a frequent disease, which often remains clinically inapparent, until stressful events or combination with other factors increase the risk of developing SPS. The condition is due to a congenital platelet defect with autosomal dominant characteristics, leading to the increased platelet aggregability when they are challenged with epinephrine and adenosine diphosphate. Nowadays classification of this disorder is based on platelet reactivity to both ADP and epinephrine (SPS type 1), epinephrine alone (SPS type 2), and ADP alone (SPS type 3). The diagnoses of the syndrome depend on the functional aggregometer assay. This condition should be taken into account whenever a patient with thrombophilia is considered. PMID- 23433501 TI - Economic efficiency of primary care for CVD prevention and treatment in Eastern European countries. AB - BACKGROUND: Cardiovascular disease (CVD) is the main cause of morbidity and mortality worldwide, but it also is highly preventable. The prevention rate mainly depends on the patients' readiness to follow recommendations and the state's capacity to support patients. Our study aims to show that proper primary care can decrease the CVD-related morbidity rate and increase the economic efficiency of the healthcare system. Since their admission to the European Union (EU), the Eastern European countries have been in a quest to achieve the Western European standards of living. As a representative Eastern European country, Romania implemented the same strategies as the rest of Eastern Europe, reflected in the health status and lifestyle of its inhabitants. Thus, a valid health policy implemented in Romania should be valid for the rest of the Eastern European countries. METHODS: Based on the data collected during the EUROASPIRE III Romania Follow Up study, the potential costs of healthcare were estimated for various cases over a 10-year time period. The total costs were split into patient supported costs and state-supported costs. The state-supported costs were used to deduce the rate of patients with severe CVD that can be treated yearly. A statistical model for the evolution of this rate was computed based on the readiness of the patients to comply with proper primary care treatment. RESULTS: We demonstrate that for patients ignoring the risks, a severe CVD has disadvantageous economic consequences, leading to increased healthcare expenses and even poverty. In contrast, performing appropriate prevention activities result in a decrease of the expenses allocated to a (eventual) CVD. In the long term, the number of patients with severe CVD that can be treated increases as the number of patients receiving proper primary care increases. CONCLUSIONS: Proper primary care can not only decrease the risk of major CVD but also decrease the healthcare costs and increase the number of patients that can be treated. Most importantly, the health standards of the EU can be achieved more rapidly when primary care is delivered appropriately. JEL: I18, H51. PMID- 23433502 TI - Delusions of body image in the prodrome. PMID- 23433503 TI - Early and late stages of visual processing in individuals in prodromal state and first episode schizophrenia: an ERP study. AB - BACKGROUND: P300 deficits in schizophrenia patients are well established, especially in the auditory modality. Several studies have also reported P300 abnormalities in schizophrenia in visual tasks, but these findings are inconsistent. Furthermore, reports on P300 in visual modality in prodromal subjects are very limited. While P300 indexes relatively late and complex cognitive functions such as context updating in working memory, sensory-evoked components such as the P1/N1 primarily index early stages of perceptual processing. Several previous studies suggest that P300 reduction in schizophrenia patients may be dissociable from these earlier components. Therefore, in this study, we measured the P300 component as well as the P1/N1 in a visual oddball paradigm in prodromal subjects and first episode schizophrenia patients, and compared them with those of healthy controls. METHOD: Visual P300 and P1/N1 were obtained from prodromal (PRO, n = 23), first episode schizophrenia patients (SZ, n = 17), and healthy control subjects (HC, n = 31), who silently counted infrequent target stimuli ("X") amid standard stimuli ("Y") presented on the screen while 64-channel EEG was recorded. RESULTS: Both PRO and SZ subjects showed reduced P300 amplitudes and delayed P300 peak latencies in comparison to control subjects. On the other hand, N1 amplitude was significantly reduced only in SZ but not in PRO. Increased severity of positive symptoms was significantly associated with smaller P300 amplitude in PRO. CONCLUSIONS: These results suggest that visual P300 is affected already at the prodromal stage and could be a marker of the prodromal phase of schizophrenia. PMID- 23433504 TI - Improving social perception in schizophrenia: the role of oxytocin. AB - Previous research has shown that patients with schizophrenia are impaired in a wide range of social cognitive abilities, including emotion recognition, empathy for others, and mental perspective-taking. Recent studies suggest that a dysfunction of the oxytocinergic system contributes to the social impairment in schizophrenia. Accordingly, the present study sought to examine whether patients with schizophrenia would improve in a social perception task after taking a single dose of oxytocin, as compared to a placebo. Thirty-five patients diagnosed with schizophrenia were compared with 46 psychologically healthy matched controls on their recognition of kinship and intimacy, using the Interpersonal Perception Task. All participants received a single intranasal dose of 24 IU oxytocin or placebo, one week apart. Overall, the participants were more accurate in judging intimacy and kinship following the administration of oxytocin, as opposed to a placebo. However, when comparing patients with controls, only the recognition of kinship improved significantly in the patient group, whereas no such effect was observed in the control group or in the recognition of intimacy in either group. This is one of the first studies to demonstrate that social perception in schizophrenia can be improved by the administration of oxytocin and that patients show a greater treatment effect than controls. PMID- 23433506 TI - Geriatric consultation services-are wards more effective than teams? AB - Geriatric consultation teams are one of the models for bringing comprehensive geriatric assessment to vulnerable and frail older people in the acute care hospital setting. While ward-based comprehensive geriatric assessment has been established as effective with reference to improving functional status and other outcomes, the team-based variant remains unproven for outcomes other than mortality in the medium term, as shown in a recent study published in BMC Medicine by Deschodt and colleagues. Further research might establish the effectiveness of the team-based model but, for current clinical practice, the emphasis should be on streaming older people with complex problems needing multidisciplinary assessment and treatment to ward-based models of comprehensive geriatric assessment. PMID- 23433505 TI - Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. AB - OBJECTIVE: Antipsychotic drugs are the mainstay of treatment for schizophrenia. However, a substantial proportion of patients are poorly responsive or resistant to first-line treatments, and clozapine treatment is often indicated. Therefore, we and others have used clozapine treatment as a proxy phenotype for antipsychotic treatment resistance in pharmacogenetic studies. In the present study, we utilized this phenotype to test previously-identified candidate genes for antipsychotic treatment response. METHOD: We assessed 89 Caucasian schizophrenia patients clinically assigned to clozapine treatment versus 190 Caucasian patients that were not selected for clozapine treatment. We conducted gene-based association tests on a set of 74 relevant candidate genes nominated in the CATIE pharmacogenetic study (Need et al., 2009), using the GATES procedure (Li et al., 2011). RESULTS: After correcting for multiple testing in the gene based association test, the gene for brain derived neurotrophic factor (BDNF) was significantly associated with treatment resistance. The top single nucleotide polymorphisms (SNPs) in BDNF included rs11030104 (OR = 2.57), rs10501087 (OR = 2.19) and rs6265 (Val66Met) (OR = 2.08). These SNPs appear to be in high linkage disequilibrium with each other. CONCLUSION: BDNF appears to have a strong association with antipsychotic treatment resistance. Future studies are needed to replicate this finding and further elucidate the biological pathways underlying the association between BDNF and antipsychotic drug response. PMID- 23433507 TI - An efficient de-convolution reconstruction method for spatiotemporal-encoding single-scan 2D MRI. AB - Spatiotemporal-encoding single-scan MRI method is relatively insensitive to field inhomogeneity compared to EPI method. Conjugate gradient (CG) method has been used to reconstruct super-resolved images from the original blurred ones based on coarse magnitude-calculation. In this article, a new de-convolution reconstruction method is proposed. Through removing the quadratic phase modulation from the signal acquired with spatiotemporal-encoding MRI, the signal can be described as a convolution of desired super-resolved image and a point spread function. The de-convolution method proposed herein not only is simpler than the CG method, but also provides super-resolved images with better quality. This new reconstruction method may make the spatiotemporal-encoding 2D MRI technique more valuable for clinic applications. PMID- 23433508 TI - Gastrointestinal function development and microbiota. AB - The intestinal microbiota plays an important role in the development of post natal gastrointestinal functions of the host. Recent advances in our capability to identify microbes and their function offer exciting opportunities to evaluate the complex cross talk between microbiota, intestinal barrier, immune system and the gut-brain axis. This review summarizes these interactions in the early colonization of gastrointestinal tract with a major focus on the role of intestinal microbiota in the pathogenesis of feeding intolerance in preterm newborn. The potential benefit of early probiotic supplementation opens new perspectives in case of altered intestinal colonization at birth as preventive and therapeutic agents. PMID- 23433509 TI - Precise generation of systems biology models from KEGG pathways. AB - BACKGROUND: The KEGG PATHWAY database provides a plethora of pathways for a diversity of organisms. All pathway components are directly linked to other KEGG databases, such as KEGG COMPOUND or KEGG REACTION. Therefore, the pathways can be extended with an enormous amount of information and provide a foundation for initial structural modeling approaches. As a drawback, KGML-formatted KEGG pathways are primarily designed for visualization purposes and often omit important details for the sake of a clear arrangement of its entries. Thus, a direct conversion into systems biology models would produce incomplete and erroneous models. RESULTS: Here, we present a precise method for processing and converting KEGG pathways into initial metabolic and signaling models encoded in the standardized community pathway formats SBML (Levels 2 and 3) and BioPAX (Levels 2 and 3). This method involves correcting invalid or incomplete KGML content, creating complete and valid stoichiometric reactions, translating relations to signaling models and augmenting the pathway content with various information, such as cross-references to Entrez Gene, OMIM, UniProt ChEBI, and many more.Finally, we compare several existing conversion tools for KEGG pathways and show that the conversion from KEGG to BioPAX does not involve a loss of information, whilst lossless translations to SBML can only be performed using SBML Level 3, including its recently proposed qualitative models and groups extension packages. CONCLUSIONS: Building correct BioPAX and SBML signaling models from the KEGG database is a unique characteristic of the proposed method. Further, there is no other approach that is able to appropriately construct metabolic models from KEGG pathways, including correct reactions with stoichiometry. The resulting initial models, which contain valid and comprehensive SBML or BioPAX code and a multitude of cross-references, lay the foundation to facilitate further modeling steps. PMID- 23433510 TI - [Superior vena cava syndrome induced by pacemaker probes, 12 years after introduction]. AB - Superior vena cava syndrome is a rare disease, most often found to result from a malignant process, which causes extrinsic compression of the superior vena cava. In recent years, there has been an increase of superior vena cava syndrome related to medical devices (implantable site, pacemaker [PM], central venous line for parenteral nutrition...). We report the case of a 37-year-old patient who developed a superior vena cava syndrome 12 years after implantation of a PM. The diagnosis was established on venography after two negative venous-CT focused on the superior vena cava. The superior vena cava syndrome improved immediately after angioplasty and stenting covering the PM probes at the superior vena cava/brachiocephalic venous trunk junction. PMID- 23433511 TI - [Giant aneurysm of the pulmonary artery: a case report]. AB - Pulmonary artery aneurysm is a rare condition accounting for less than 1% of all intra thoracic aneurysms. This paper reports a case of giant aneurysm of the trunk and branches of the pulmonary artery, which was discovered incidentally on a computed tomography angiogram in a 48-year-old man with a past history of pulmonary tuberculosis. Besides the aneurysm there was dilation of the pulmonary annulus with massive pulmonary regurgitation, a tight mitral stenosis and sequelae of pleural and pulmonary tuberculosis. The patient is being followed-up with medical treatment and has been stable clinically for the last ten months. PMID- 23433512 TI - Preface. Biomarkers in reproductive medicine. PMID- 23433513 TI - Uterine secretomics: a window on the maternal-embryo interface. AB - The analysis of endometrial secretions offers a window on human peri-implantation events that have hitherto been difficult to study noninvasively. Uterine secretomic analysis provides a sensitive means of interrogating the contents of secretions, which have been shown to play a key role in determining endometrial receptivity and embryo-endometrial signaling, and in providing a nourishing environment to the preimplantation embryo. Compared with other means of assessing the endometrium with genomics or proteomics, secretomics offers a nondisruptive approach, allowing analysis during conception cycles. It also provides information on the downstream molecular profile directly encountered by the embryo, offering an integrated review of the complete endometrial surface rather than information representative of only a discrete biopsy site. In this article, recent data derived from uterine secretomics are reviewed. In addition to in vivo studies, recent data from in vitro studies that are changing our understanding of the role of the endometrium in embryo selection are reviewed. Finally, the role of uterine secretions in nutrition and early development programming of the embryo is considered. PMID- 23433514 TI - Small glutamine-rich tetratricopeptide repeat-containing protein alpha is present in human ovaries but may not be differentially expressed in relation to polycystic ovary syndrome. AB - OBJECTIVE: To evaluate the expression and function of small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA), an androgen receptor (AR) molecular chaperone, in human ovarian tissues. DESIGN: Examine the effect of SGTA on AR subcellular localization in granulosa tumor cells (KGN) and SGTA expression in ovarian tissues. SETTING: University-based research laboratory. PATIENT(S): Archived tissues from premenopausal women and granulosa cells from infertile women receiving assisted reproduction. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): AR subcellular localization and SGTA protein or mRNA levels. RESULT(S): SGTA and AR proteins were expressed in the cytoplasm of KGN cells and exposure to androgen stimulated AR nuclear localization. SGTA protein knockdown increased AR nuclear localization at low (0-0.1 nmol/L) but not high (1-10 nmol/L) concentrations of androgen hormone. In ovarian tissues, SGTA was localized to the cytoplasm of granulosa cells at all stages of folliculogenesis and in thecal cells of antral follicles. SGTA protein levels were similar when comparing primordial and primary follicles within core biopsies (n = 40) from women with and without polycystic ovary syndrome (PCOS). Likewise, SGTA mRNA levels were not significantly different in granulosa cells from preovulatory follicles after hyperstimulation of women with and without PCOS. CONCLUSION(S): SGTA is present in human ovaries and has the potential to modulate AR signalling, but it may not be differentially expressed in PCOS. PMID- 23433515 TI - In vitro maturation of human immature oocytes for fertility preservation. AB - Cryopreservation of embryos, oocytes, or ovarian tissues is the main option for female fertility preservation. Oocyte cryopreservation has emerged as especially important: the dramatic increase in the number of infants born from vitrified oocytes indicates that it is becoming one of the most important intervention options. However, oocyte cryopreservation with standard controlled ovarian hyperstimulation may not be feasible for some cancer patients as there are serious concerns about the effect of ovarian stimulation with hormones on the risk of cancer recurrence. Also, urgent gonadotoxic cancer treatment may not allow sufficient time for a patient to undergo hormonal ovarian stimulation. Thus, immature oocyte retrieval from ovaries without ovarian stimulation followed by in vitro maturation and vitrification is a promising fertility preservation option for women who cannot undergo ovarian stimulation or cannot delay their gonadotoxic cancer treatment. Immature oocytes can be collected from the ovaries during both the follicular and luteal phases, which maximizes the possibility for fertility preservation. The combination of ovarian tissue cryopreservation with immature oocyte collection from the tissue followed by oocyte vitrification via in vitro maturation represents another promising approach of fertility preservation in young women with cancer. PMID- 23433516 TI - Tubo-ovarian dysplasia in relationship with ovulation induction in rats. AB - OBJECTIVE: To assess tubo-ovarian dysplasia via morphologic and immunohistochemical study of rats exposed to ovulation stimulation protocols. DESIGN: Animal experimental study. SETTING: Academic research hospital. ANIMAL(S): 72 female Wistar rats divided into three groups. INTERVENTION(S): Stimulation protocols using follicle-stimulating hormone (FSH) or clomiphene citrate for 3, 6, or 12 cycles, after which the animals were killed. MAIN OUTCOME MEASURE(S): Ovarian and tubal dysplasia score and immunohistochemical assessment using p53 and Ki67. RESULT(S): The ovarian dysplasia score was statistically significantly higher after 12 stimulation cycles in the groups receiving FSH (group B) or clomiphene citrate (group C) compared with control (group A). The tubal dysplasia score was statistically significantly increased after only three stimulation cycles in groups B and C. The Ki67 proliferation marker was statistically significantly expressed in the ovaries from group C, and in the fallopian tubes from groups B and C. P53 was constantly low in all three groups. CONCLUSION(S): Ovulation stimulation may induce tubal and ovarian histopathologic and immunohistochemical abnormalities with a dose effect. The role of the fallopian tubes and their interaction with the ovaries require further study. PMID- 23433517 TI - Oocyte in vitro maturation in normo-ovulatory women. AB - OBJECTIVE: To review the scientific literature concerning the application of oocyte in vitro maturation (IVM) as a treatment for normo-ovulatory women. DESIGN: Critical evaluation and comparison of the most relevant clinical studies. SETTING: Public IVF unit. PATIENT(S): Normo-ovulatory women. INTERVENTION(S): Oocyte IVM and cryopreservation. MAIN OUTCOME MEASURE(S): Maturation, fertilization, implantation, and pregnancy rates. RESULT(S): Maturation rates in vitro are suboptimal and influenced by several factors. IVM oocytes fertilize and undergo development in vitro with rates similar to in vivo matured control oocytes. In IVM cycles implantation and pregnancy rates are lower compared with controlled ovarian stimulation treatments, but accurate patient selection can improve IVM clinical outcome. CONCLUSION(S): In normal responders, IVM does not reach success rates similar to conventional ovarian stimulation regimens. However, it represents a milder approach to assisted reproduction treatment and an alternative intervention for specific conditions. PMID- 23433519 TI - Adsorption of lead ions from aqueous solution using porous carbon derived from rubber tires: experimental and computational study. AB - Effective activated porous carbon (AC) was prepared by thermal treatment of waste rubber tires and was further activated using oxidizing agents like nitric acid and hydrogen peroxide. The tire-derived porous carbon was characterized by means of FTIR and X-ray diffraction. Careful analysis of the IR spectra of the synthesized AC reveals a number of bands centered at about 3400, 2350, 1710, 1650, and 1300-1000cm(-1), proving the existence of hydroxyl and carboxylic groups on the surface of AC in addition to CC double bonds. The developed AC was tested and evaluated as a potential adsorbent for the removal of lead (II) ions. Experimental parameters, such as contact time, initial concentration, adsorbent dosage, and pH were optimized. AC was effective in a pH range between 4 and 7 with a highest uptake of lead ions at pH 5 and 6. For further understanding of the chemistry behind the process, density functional theory (DFT) calculations were performed at the B3LYP/6-31G(d) level adopting a functionalized pyrene molecule as a model. The binding energy of Pb(II) ion toward carboxylic acid, carbonyl, and hydroxyl groups was calculated. A binding energy in the range of 310-340kcal/mol, which is considered to be high and to be indicative of a chemisorptions process, was predicted. The adsorption of the lead ion toward the CO groups in relatively all cases shows more stable binding compared to the sorption toward the alcohol groups. PMID- 23433518 TI - Number of supernumerary vitrified blastocysts is positively correlated with implantation and live birth in single-blastocyst embryo transfers. AB - OBJECTIVE: To estimate whether live birth in single-blastocyst transfers is correlated with the number of sibling supernumerary vitrified blastocysts (embryos not transferred) generated from that same cycle. DESIGN: Retrospective cohort study. SETTING: A large academic assisted reproduction clinic. PATIENT(S): All single-blastocyst transfers in 2010 graded as "good" embryos by Society for Assisted Reproductive Technologies (SART) criteria. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation and live birth. RESULT(S): Of the 655 single blastocyst transfers that met inclusion criteria, implantation occurred in 65% and live birth in 54% of cycles. In chi-square analysis, patients with supernumerary vitrified blastocysts had a statistically higher implantation rate (65% versus 50%) and live-birth rate (56% versus 41%) when compared with patients without supernumerary blastocysts. Univariate logistic regression demonstrated an increase in implantation (OR 1.09; 95% CI, 1.03-1.15) and live birth (OR 1.06; 95% CI, 1.02-1.09) with increasing number of supernumerary blastocysts. Multivariate logistic regression analysis demonstrated that patient age and the number of supernumerary blastocysts were statistically significantly associated with implantation and live birth. CONCLUSION(S): The number of supernumerary vitrified blastocysts correlated positively with the odds of implantation and live birth in good quality single-blastocyst transfers. Patients with supernumerary blastocysts are good candidates for single-embryo transfer. PMID- 23433520 TI - Highly selective and sensitive analysis of dopamine by molecularly imprinted stir bar sorptive extraction technique coupled with complementary molecularly imprinted polymer sensor. AB - This paper reports a combination of molecularly imprinted stir bar sorptive extraction and complementary molecularly imprinted polymer-sensor for the analysis of dopamine as a biomarker of several neurodegenerative diseases occurred at ultra trace level. This exploited iniferter initiated polymerization via "surface grafting-from" approach onto magnetic stir bar (for sorptive extraction) and multiwalled carbon nanotubes-ceramic electrode (for detection). Such hyphenation helped dual pre-concentration of dopamine in aqueous, biological and pharmaceutical samples. This enabled high sensitivity to achieve the stringent limit [limit of detection: 4.9ngL(-1), RSD=2.4%, S/N=3, cerebrospinal fluid] of clinical detection, without any problems of non-specific contributions and cross-reactivity. PMID- 23433521 TI - Synergetic effect of carbon nanopore size and surface oxidation on CO2 capture from CO2/CH4 mixtures. AB - We have studied the synergetic effect of confinement (carbon nanopore size) and surface chemistry (the number of carbonyl groups) on CO2 capture from its mixtures with CH4 at typical operating conditions for industrial adsorptive separation (298 K and compressed CO2-CH4 mixtures). Although both confinement and surface oxidation have an impact on the efficiency of CO2/CH4 adsorptive separation at thermodynamics equilibrium, we show that surface functionalization is the most important factor in designing an efficient adsorbent for CO2 capture. Systematic Monte Carlo simulations revealed that adsorption of CH4 either pure or mixed with CO2 on oxidized nanoporous carbons is only slightly increased by the presence of functional groups (surface dipoles). In contrast, adsorption of CO2 is very sensitive to the number of carbonyl groups, which can be examined by a strong electric quadrupolar moment of CO2. Interestingly, the adsorbed amount of CH4 is strongly affected by the presence of the co-adsorbed CO2. In contrast, the CO2 uptake does not depend on the molar ratio of CH4 in the bulk mixture. The optimal carbonaceous porous adsorbent used for CO2 capture near ambient conditions should consist of narrow carbon nanopores with oxidized pore walls. Furthermore, the equilibrium separation factor was the greatest for CO2/CH4 mixtures with a low CO2 concentration. The maximum equilibrium separation factor of CO2 over CH4 of ~18-20 is theoretically predicted for strongly oxidized nanoporous carbons. Our findings call for a review of the standard uncharged model of carbonaceous materials used for the modeling of the adsorption separation processes of gas mixtures containing CO2 (and other molecules with strong electric quadrupolar moment or dipole moment). PMID- 23433522 TI - Surface hydrophobic co-modification of hollow silica nanoparticles toward large area transparent superhydrophobic coatings. AB - The present paper reports a novel, simple, and efficient approach to fabricate transparent superhydrophobic coatings on glass substrates by spray-coating stearic acid (STA) and 1H,1H,2H,2H-perflurooctyltriethoxysilane (POTS) co modified hollow silica nanoparticles (SPHSNs), the surfaces of which were hydrophobic. The surface wettability of coatings was dependent on the conditions of post-treatment: the water contact angle of coating increased and then leveled off with increase in either the drying temperature or the drying time. When the coating was treated at 150 degrees C for 5h, the water contact angle was as high as 160 degrees and the sliding angle was lower than 1 degrees , reaching excellent superhydrophobicity. They remained 159 degrees and <=1 degrees , respectively, even after 3months storage under indoor conditions (20 degrees C, 20%RH), demonstrating the long time stability of coating superhydrophobicity. The coating was robust both to the impact of water droplets (297 cm/s) and to acidic (pH=1) and basic (pH=14) droplets. It showed good transparency in the visible near infrared spectral range, and the maximum transmittance reached as high as 89%. Fourier transform infrared spectroscopy, transmission electron microscopy, differential scanning calorimetry, and thermogravimetric analysis were used to investigate the interactions among STA, POTS, and hollow silica nanoparticles (HSNs). Scanning electron microscopy and atomic force microscopy were used to observe and estimate the morphology and surface roughness of coatings. Optical properties were characterized by a UV-visible-near infrared spectrophotometer. Surface wettability was studied by a contact angle/interface system. The enhancement of hydrophobicity to superhydrophobicity by post-treatment was discussed based on the transition from the Wenzel state to the Cassie state. PMID- 23433523 TI - ["Vascular tufts"]. PMID- 23433524 TI - [Orbital mantle cell lymphoma]. AB - Ophthalmological involvement in mantle cell lymphoma is rare. An 84-year-old man presented with bilateral proptosis. Orbital biopsy established the diagnosis of mantle cell lymphoma. The diagnosis of mantle cell lymphoma is anatomopathological and immuno-histochemical. Orbital involvement is found most often in advanced stages of the disease, but may be the presenting sign as in the case of our patient. Treatment has improved with the use of rituximab, especially in elderly patients not eligible for autologous hematopoietic stem cell transplant. PMID- 23433525 TI - [Molteno implant and the vicryl tie technique: role of Visante anterior segment OCT]. PMID- 23433526 TI - [External ophthalmomyiasis (botfly larval infestation) in urban France]. PMID- 23433528 TI - Bilateral cochlear implantation in bilateral Langerhans cell histiocytosis. AB - BACKGROUND: Langerhans' cell histiocytosis (LCH) is a rare proliferative disorder that can have otologic manifestations in up to 30% of patients. Treatment of local and systemic disease may include medical, surgical, and radiation therapies. Involvement of the temporal bone can lead to conductive and, rarely, sensorineural hearing loss. Post-labyrinthectomy cochlear implantation can be an effective treatment option for sensorineural hearing loss in the setting of persistent LCH. METHODS: A retrospective case review at a tertiary academic medical center. Hearing in Noise Test (HINT) performed before and after bilateral cochlear implantation was examined. RESULTS: Following bilateral partial labyrinthectomy, post-operative testing showed a HINT in quiet of 17%. Left-sided cochlear implant followed by immunosuppressive therapy for persistent disease showed marked improvement with post-operative HINT in a quiet room of 80% and 63% at 1 and 2 years. Fifty-five months after left implantation, and 10 months after right cochlear implantation, binaural post-operative HINT in quiet was 81%. CONCLUSION: Surgical excision of LCH lesion remains a mainstay of treatment for temporal bone involvement. Bilateral cochlear implant with adjuvant immunosuppression in our patient demonstrated both immediate and delayed improvement in auditory function after staged cochlear implantation in the setting of persistent disease. PMID- 23433529 TI - Respiratory physiotherapy during an acute exacerbation--evidence versus practice. PMID- 23433530 TI - Cilostazol for primary prevention of stroke in peripheral artery disease: a population-based longitudinal study in Taiwan. AB - BACKGROUND: Clopidogrel, cilostazol, and aspirin were compared in terms of efficacy and safety for primary prevention of stroke in peripheral artery disease (PAD) patients. METHODS: This retrospective cohort study analyzed data contained in the Taiwan National Health Insurance Bureau database for patients treated for PAD but not for stroke during 2002-2008. Patients were stratified according to treatment with aspirin, clopidogrel, cilostazol, or combined therapy. The primary efficacy and safety endpoints were stroke and hemorrhage. RESULTS: Of the 931 patients enrolled in this study, 479 had received aspirin, 39 had received clopidogrel, 294 had received cilostazol alone, and 33 had received a cilostazol based combined therapy. Compared to patients treated with aspirin, the patients treated with cilostazol had significantly lower all-stroke risk not only in the overall group (HR=0.66, 95% CI=0.48-0.90, p=0.0086), but also in the subgroup of patients with diabetes (HR=0.64, 95% CI=0.42-0.98, p=0.0394) and in the subgroup of patients with high cardiovascular risk (HR=0.66, 95% CI=0.46-0.95, p=0.0254). Additionally, compared to patients treated with aspirin, those treated with cilostazol did not have significantly more hemorrhagic events in the overall group, in the diabetes subgroup, or in the high cardiovascular risk subgroup. Clopidogrel, cilostazol-based combined therapy and aspirin did not significantly differ in terms of efficacy and hemorrhagic events. CONCLUSION: Although this database study indicated that cilostazol therapy is an effective alternative treatment for primary prevention of stroke in PAD, further confirmation is needed in large, prospective, and randomized trials. PMID- 23433531 TI - Stem cell clonality -- theoretical concepts, experimental techniques, and clinical challenges. AB - Here we report highlights of discussions and results presented at an International Workshop on Concepts and Models of Stem Cell Organization held on July 16th and 17th, 2012 in Dresden, Germany. The goal of the workshop was to undertake a systematic survey of state-of-the-art methods and results of clonality studies of tissue regeneration and maintenance with a particular emphasis on the hematopoietic system. The meeting was the 6th in a series of similar conceptual workshops, termed StemCellMathLab,(2) all of which have had the general objective of using an interdisciplinary approach to discuss specific aspects of stem cell biology. The StemCellMathLab 2012, which was jointly organized by the Institute for Medical Informatics and Biometry, Medical Faculty Carl Gustav Carus, Dresden University of Technology and the Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, brought together 32 scientists from 8 countries, with scientific backgrounds in medicine, cell biology, virology, physics, computer sciences, bioinformatics and mathematics. The workshop focused on the following questions: (1) How heterogeneous are stem cells and their progeny? and (2) What are the characteristic differences in the clonal dynamics between physiological and pathophysiological situations? In discussing these questions, particular emphasis was placed on (a) the methods for quantifying clones and their dynamics in experimental and clinical settings and (b) general concepts and models for their description. In this workshop summary we start with an introduction to the current state of clonality research and a proposal for clearly defined terminology. Major topics of discussion include clonal heterogeneity in unperturbed tissues, clonal dynamics due to physiological and pathophysiological pressures and conceptual and technical issues of clone quantification. We conclude that an interactive cross-disciplinary approach to research in this field will continue to promote a conceptual understanding of tissue organization. PMID- 23433533 TI - Surveillance of dalbavancin potency and spectrum in the United States (2012). PMID- 23433532 TI - Absence of Pneumocystis dihydropteroate synthase mutants in Brittany, France. AB - Archival Pneumocystis jirovecii specimens from 84 patients monitored at Rennes University Hospital (Rennes, France) were assayed at the dihydropteroate synthase (DHPS) locus. No patient was infected with mutants. The results provide additional data showing that P. jirovecii infections involving DHPS mutants do not represent a public health issue in Brittany, western France. PMID- 23433534 TI - Extended culture of vitrified-warmed embryos in day-3 embryo transfer cycles: a randomized controlled pilot study. AB - Synchronization between embryonic stage and endometrium is vital to achieve a successful pregnancy. The objective of this study was to assess the implantation, clinical pregnancy and live birth rates of cryopreserved embryo transfer cycles using embryos after extended culture for 16h. A prospective randomized controlled pilot study was performed on women who underwent vitrified-warmed embryo transfer. Of the 540 women assessed for eligibility, 479 were randomly allocated to either extended culture for 16-18h (EC group, n=242) or conventional culture for 2h (control group, n=237). Endometrial preparation was the same in both groups. No significant differences were found between the extended culture and control groups respectively in clinical pregnancy rate per embryo transfer (42.48% versus 40.95%), implantation rate (21.79% versus 20.82%) or live birth rate per embryo transfer (37.61% versus 34.05%); however, the spontaneous reduction rate was lower in the extended culture group (10.04% versus 20.80%; P=0.032) In conclusion, extended culture of day-3 cleavage embryos for 16h would not influence the pregnancy outcome of day-3 cryopreserved embryo transfer cycles. Synchronization between embryonic stage and endometrium is vital to achieve a successful pregnancy and most implantation failures are possibly associated with inadequate endometrial receptivity or defects in the embryo endometrium crosstalk. In this paper, we regulated synchronization via extended post-warming culture using conventional day-3 endometrial preparation in vitrified-warmed embryo transfer cycles and observed the clinical outcomes, including implantation, clinical pregnancy and live birth rates. Extended post warming culture did not influence the clinical outcomes. This study implies that transfer of embryos at an advanced developmental stage may not affect implantation. This gives clinical doctors more flexibility in the performance of routine cryopreserved embryo transfer cycles. PMID- 23433535 TI - Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. AB - This study aimed to assess the von Willebrand factor (VWF) antigen levels and its proteolytic enzyme ADAMTS13 activity in preeclampsia. The study includes 10 non pregnant women, 50 normal pregnancy, and 110 preeclamptic (PE) women at the same period of pregnancy. For all studied groups plasma ADAMTS13 activities were determined with the FRETs-VWF 73 assay, while VWF antigen levels with an immunoturbometric assay. The plasma ADAMTS13 activity was significantly reduced in PE as compared with normal pregnancy and non-pregnant women (P < 0.01 for both). In contrast, plasma VWF antigen and VWF RCO were significantly elevated in PE, as compared with normal pregnancy group as well as non-pregnant women (P < 0.01 for both). In conclusion, reduction of plasma ADAMTS13 and elevation in VWF might have a role in the pathogenesis of PE. PMID- 23433537 TI - Association of child marriage with suicidal thoughts and attempts among adolescent girls in Ethiopia. AB - PURPOSE: Little information exists on the mental health implications of child marriage in Africa. This study examined the association between child marriage and suicidal ideation and suicide attempt among girls aged 10-17 years. METHODS: Data were drawn from a 2007 cross-sectional survey conducted in the Amhara region, Ethiopia. Multilevel logistic regression was used to analyze risk factors for suicidality. RESULTS: Approximately 5.2% of girls reported ever being married, 5.4% were promised in marriage, and 9.3% reported receiving marriage requests. Girls who were ever married (odds ratio [OR] = 1.81; 95% confidence interval [CI] = 1.03-3.18), were promised in marriage (OR = 2.35; 95% CI = 1.38 4.01) or had received marriage requests (OR = 2.29; 95% CI = 1.46-3.59) were significantly more likely than girls who were never in the marriage process to have had suicidal thoughts in the past 3 months. Residence in communities with high involvement in stopping child marriage was protective of suicidal ideation. The odds of suicide attempt were twice as high among girls with marriage requests as among those with none. CONCLUSIONS: Child marriage was associated with increased odds of suicidality. Findings call for stronger community engagement in child marriage prevention and mental health support for child brides. PMID- 23433536 TI - Silicon absorption and excretion is independent of age and sex in adults. AB - Host factors influencing the absorption and excretion of Si are poorly understood, although previous murine and human studies have suggested that age, sex and oestrogen status may affect Si metabolism and thus function. Here, serum and urine samples were collected from twenty-six healthy adults at baseline and over a 6 h period following ingestion of 17.4mg Si (orthosilicic acid) and analysed by inductively coupled plasma optical emission spectrometry. Fasting baseline serum and urinary Si concentrations were marginally higher in older adults (51-66 years old) compared with young adults (20-47 years old); however, there was no difference in the absorption of Si into serum (overall profile, rate of Si appearance, peak concentration and time to peak) between the different adult groups. The rate of elimination of Si from serum did not significantly differ with age or sex, although serum concentration at 6 h was higher in older adults and significantly correlated with age (r 0.5; P=0.01). There were, however, no significant differences in the excretion of Si into urine (a proxy for overall uptake) between the groups, averaging approximately 45 %. Oestradiol levels did not correlate with any of the above measures of Si. Thus, overall, host age and sex did not appear to markedly influence Si absorption or excretion in human adults and no correlations were found with serum oestradiol status. The marginally higher baseline and 6 h post-dose Si levels in older adults may reflect modestly impaired renal function and/or the loss of Si from connective tissues with ageing. PMID- 23433539 TI - Fulminant type 1 diabetes with robust recovery of insulin secretion: a case report. AB - In fulminant type 1 diabetes (FT1D), irreversible destruction of pancreatic beta cells occurs abruptly, leading to sudden diabetic ketoacidosis (DKA) in the absence of diabetes-related autoantibodies. This is the first case report of FT1D in which beta-cell was rescued with the commencement of insulin therapy during the evolution of FT1D. PMID- 23433538 TI - Prevalence of adolescents' self-weighing behaviors and associations with weight related behaviors and psychological well-being. AB - PURPOSE: To examine the relationships between self-weighing frequency, and weight related behaviors and psychological well-being in a population-based sample of adolescents. METHODS: This study compared weight-related behaviors between infrequent and frequent self-weighers, stratified by weight status and gender. Data were from Project EAT 2010 (Eating and Activity in Teens), a population based study of 2,778 adolescents. RESULTS: Approximately 14% of girls and boys weighed themselves frequently (weekly or more). In comparison to girls who were infrequent self-weighers, girls who were frequent self-weighers were more likely to diet, engage in unhealthy and extreme weight control behaviors, use unhealthy muscle-enhancing behaviors, and have lower self-esteem and greater body dissatisfaction. In comparison to boys who were infrequent self-weighers, boys who were frequent self-weighers were more likely to diet, engage in unhealthy and extreme weight control behaviors, use unhealthy muscle-enhancing behaviors, and report greater depressive symptoms. Among overweight adolescents, in addition to being associated with these harmful outcomes, frequent self-weighing was associated with the use of healthy weight control behaviors and with higher levels of moderate-to-vigorous activity. CONCLUSIONS: Findings indicate that adolescents who frequently self-weigh themselves are at increased risk for a number of problematic health behaviors and poorer psychological outcomes. For overweight adolescents, frequent self-weighing was additionally associated with a number of positive outcomes. Based upon these findings, any recommendations for weight monitoring should be made cautiously; all adolescents, including overweight adolescents, should be advised not to engage in frequent self-weighing behaviors. Furthermore, any adolescents engaging in frequent self-weighing behaviors should be monitored for problematic outcomes. PMID- 23433540 TI - Clinical features associated with a rapid decline in renal function among Japanese patients with type 2 diabetes mellitus: microscopic hematuria coexisting with diabetic retinopathy. AB - Four patients who exhibited the greatest decline in the estimated glomerular filtration rate [12.3-23.5 ml/min/1.73 m(2)/year] among 320 patients with type 2 diabetes and were followed for a median of 6.8 years had several clinical features in common, including marked albuminuria, microhematuria, retinopathy and poor medication adherence. PMID- 23433541 TI - A novel glucokinase deletion (p.Lys32del) and five previously described mutations co-segregate with the phenotype of mild familial hyperglycaemia (MODY2) in Brazilian families. AB - Six Brazilian families with mild familial hyperglycaemia have been screened for glucokinase (GCK) mutations. All had mutations that co-segregated with the phenotype. One of the mutations, the deletion 96_98delAAG (p.Lys32del), had not been previously described, reinforcing the worldwide prevalence of GCK MODY and widespread existence of undetected new mutations. PMID- 23433542 TI - Erdheim-Chester disease: a rare diagnosis with evocative imaging. PMID- 23433543 TI - Advantages of gadobenate dimeglumine-enhanced MR cholangiography in the diagnosis of post-liver transplant bile leakage. AB - OBJECTIVE: To assess the value of magnetic resonance cholangiography with gadobenate dimeglumine (Gd-BOPTA) where there is a suspicion of bile leakage in the post-liver transplant patient. PATIENTS AND METHODS: Eight patients who had undergone a liver transplant underwent 14 MR cholangiograms, five of whom presented bile leakage while the other three had no biliary system complications. The results were compared to conventional bile duct opacification (by endoscopy or t-tube cholangiogram). The analysis covered whether there was opacification of the common bile duct and intrahepatic bile ducts on T1-weighted sequences after an injection of Gd-BOPTA on delayed biliary excretion phase sequences that were carried out on average 74 min after the injection. Enhancing perihepatic collections were also taken into account. RESULTS: Opacification of the bile ducts on delayed-phase MR cholangiogram sequences was always seen in the absence of bile leakage, and was never found when leakage was present. Enhancing perihepatic collections pointed to bile leakage every time. CONCLUSION: Gd-BOPTA enhanced MR cholangiography is a simple and non-invasive technique for detecting bile leakage in the post-liver transplant patient. PMID- 23433544 TI - Institutional design and organizational practice for universal coverage in lesser developed countries: challenges facing the Lao PDR. AB - There is now widespread acceptance of the universal coverage approach, presented in the 2010 World Health Report. There are more and more voices for the benefit of creating a single national risk pool. Now, a body of literature is emerging on institutional design and organizational practice for universal coverage, related to management of the three health-financing functions: collection, pooling and purchasing. While all countries can move towards universal coverage, lower-income countries face particular challenges, including scarce resources and limited capacity. Recently, the Lao PDR has been preparing options for moving to a single national health insurance scheme. The aim is to combine four different social health protection schemes into a national health insurance authority (NHIA) with a single national fund- and risk-pool. This paper investigates the main institutional and organizational challenges related to the creation of the NHIA. The paper uses a qualitative approach, drawing on the World Health Organization's institutional and Organizational Assessment for Improving and Strengthening health financing (OASIS) conceptual framework for data analysis. Data were collected from a review of key health financing policy documents and from 17 semi structured key informant interviews. Policy makers and advisors are confronting issues related to institutional arrangements, funding sources for the authority and government support for subsidies to the demand-side health financing schemes. Compulsory membership is proposed, but the means for covering the informal sector have not been resolved. While unification of existing schemes may be the basis for creating a single risk pool, challenges related to administrative capacity and cross-subsidies remain. The example of Lao PDR illustrates the need to include consideration of national context, the sequencing of reforms and the time scale appropriate for achieving universal coverage. PMID- 23433545 TI - Does calf muscle spasticity contribute to postural imbalance? A study in persons with pure hereditary spastic paraparesis. AB - OBJECTIVES: The contribution of spasticity to postural imbalance in patients with upper motor neuron syndrome is still unclear. This study aimed to evaluate the responses to support-surface perturbations in patients with hereditary spastic paraparesis (HSP). These patients typically suffer from bilateral spasticity with relatively preserved muscle strength of the lower limbs. Particularly toes-up rotations were expected to be destabilizing due to insufficient suppression of calf muscle stretch reflexes. METHODS: Participants were seventeen symptomatic community-dwelling patients with autosomal dominant pure HSP and seventeen healthy controls. All patients had increased muscle tone of the triceps surae (TS) but no muscle contractures. Perturbations were applied by rotating or translating a platform with increasing intensity in four sagittal-plane directions. The primary outcome was maximum intensity ('limit of stability') sustained without stepping or grabbing in each type of perturbation. Leg muscle tone and strength were assessed with the Modified Ashworth Scale and Medical Research Council (MRC) scale, respectively. RESULTS: For toes-up perturbations, limits of stability in patients were substantially lower than in controls, which were related to TS muscle tone but not to tibialis anterior (TA) strength. Toes down rotations were indiscriminative. For backward perturbations, patients also had lower limits of stability, unrelated to TA strength or TS muscle tone. In forward perturbations, patients with TS strength MRC 4 were less stable than patients with normal TS strength and controls. CONCLUSION: Calf muscle spasticity and weakness differently contribute to postural imbalance in patients with HSP. This notion could have implications for the clinical management of spasticity. PMID- 23433546 TI - Clinical and biomechanical factors which predict timed up and down stairs test performance in hemiparetic patients. AB - BACKGROUND AND PURPOSE: The ability to ascend and descend a flight of stairs is considered as one of the best predictors of free-living activity and is correlated with domestic extrinsic activity in hemiparetic patients. However, the relationship between timed-stair performance and clinical and biomechanical parameters has never been studied this population. The aim of this study was to determine if performance on the Timed Up and Down Stairs (TUDS) test was related to clinical variables (maximal gait speed, strength and spasticity) and to biomechanical gait parameters (spatio-temporal, kinematic and kinetic gait parameters) in hemiparetic patients. METHODS: Sixty hemiparetic patients performed the TUDS test, underwent 3D gait-analysis and a clinical assessment. Pearson's correlations and two stepwise multiple linear regression analyses were carried out to identify the parameters which were the most highly correlated with TUDS test performance among the clinical variables and gait parameters on the paretic side. RESULTS: Maximal walking speed on the 10-m walk test and strength of the ankle dorsiflexors were the clinical variables that were the most related to TUDS test performance (63% of variance explained). The percentage of single support phase on the paretic side was the biomechanical gait parameter which was the most related to TUDS test performance (58% of variance explained). CONCLUSION: The results of this study identified three parameters which predicted the performance to ascend and descend a flight of stairs as fast as possible in hemiparetic patients. Rehabilitation programs which aim to improve stair performance and independence in daily life activities should focus on these three parameters. PMID- 23433547 TI - Compensatory-step training of healthy, mobile people with unilateral, transfemoral or knee disarticulation amputations: A potential intervention for trip-related falls. AB - The purpose of this study was to evaluate the effects of compensatory-step training of healthy, mobile, young-to-middle aged people with unilateral, transfemoral or knee disarticulation amputations. Outcomes of interest included recovery success, reliance on the prosthesis, and the kinematic variables relevant to trip recovery. Over the course of six training sessions, five subjects responded to postural disturbances that necessitated forward compensatory steps to avoid falling. Subjects improved their ability to recover from these postural disturbances without falling or hopping on the non-prosthetic limb. Subjects improved their compensatory stepping response by decreasing trunk flexion and increasing the sagittal plane distance between the body center of mass and the stepping foot. In response to more challenging disturbances, these training-related improvements were not observed for the initial step with the non prosthetic limb. Regardless of the stepping limb, step length and the change in pelvic height were not responsive to training. This study exhibits the potential benefits of a compensatory-step training program for amputees and informs future improvements to the protocol. PMID- 23433548 TI - Robust stability analysis of genetic regulatory network with time delays. AB - The robust asymptotic stability problem of genetic regulatory networks with time delays is investigated by Lyapunov functional approach and linear matrix inequality techniques (LMIs). Stability criteria for the delayed genetic regulatory networks are expressed as a set of LMIs, yielding much less conservative analytic results. New criteria with reduced conservatism are obtained and they involve less matrix parameters than the existing ones. Finally, three numerical examples are presented to illustrate effectiveness and less conservative results. PMID- 23433549 TI - UV-mediated downregulation of the endocytic collagen receptor, Endo180, contributes to accumulation of extracellular collagen fragments in photoaged skin. AB - BACKGROUND: Collagen is the most abundant protein in human skin and is responsible for its resilience. In particular during photoaging, collagen homeostasis is out of balance leading to a continuous loss of intact collagen and to the observed signs of aged skin such as diminished tensile strength and wrinkle development. The process of collagen turnover is very slow and the relevance of cellular uptake of damaged collagen, most likely mediated via Endo180 or integrin alpha2beta1, still remains a matter of investigation. OBJECTIVE: We investigated the role of different collagen receptors on dermal fibroblasts for collagen internalization and their impact on collagen homeostasis during photoaging. METHODS: TaqMan Real-Time PCR, flow cytometry, UV irradiation, knockdown experiments and immunostaining. RESULTS: We show that Endo180 and integrin alpha2 are regulated in photoaged skin and after acute UV stress in vivo and in vitro. Knockdown experiments revealed that Endo180 is essential for cellular uptake of collagen fragments by dermal fibroblasts, whereas integrin alpha2 is important for initial binding of collagen. UV irradiation decreases collagen endocytosis. This correlates with reduced Endo180 expression and pericellular accumulation of collagen fragments during photoaging. CONCLUSION: Our findings correlate for the first time impaired collagen uptake via Endo180 with the pericellular accumulation of collagen fragments during photoaging. We assume an altered pericellular niche of fibroblasts in photoaged skin that has an impact on collagen homeostasis. PMID- 23433550 TI - Tight junction dysfunction in the stratum granulosum leads to aberrant stratum corneum barrier function in claudin-1-deficient mice. AB - BACKGROUND: Tight junctions (TJs) contribute to the epithelial barrier function by preventing leakage of solutes through the intercellular space. In the skin, TJs occur in the stratum granulosum (SG), where claudin-1 and claudin-4 are expressed as adhesion molecules of TJs. Claudin-1-deficient (Cldn1(-/-)) mice die within one day of birth accompanied by excessive transepidermal water loss, indicating a critical role of TJs in the epidermal barrier function. However, it has been debated whether the impaired TJ function in the SG also affects the stratum corneum (SC) barrier function or whether it results in skin barrier defects despite a normal SC barrier. OBJECTIVE: To clarify whether the impaired TJ function affects the SC barrier function in Cldn1(-/-) mice. METHODS: The morphology, barrier function and biochemical characteristic of the SC were compared between Cldn1(-/-) and Cldn1(+/+) mice. RESULTS: Scanning electron microscopy demonstrated abnormally wrinkled and rough corneocytes in Cldn1(-/-) mice. Notably, the X-gal tracer easily permeated into the Cldn1(-/-) SC, and water evaporation through isolated Cldn1(-/-) SC sheets was significantly higher than that through Cldn1(+/+) SC sheets. Furthermore, the ceramide composition of the SC lipids and filaggrin processing were altered in Cldn1(-/-) mice. CONCLUSION: Cldn1(-/-) mice exhibited the abnormal SC formation and SC barrier defects. These findings demonstrate for the first time that TJs in the SG play crucial roles in the complete SC formation and SC barrier function. PMID- 23433551 TI - Neutrophil-derived tumor necrosis factor-alpha contributes to acute wound healing promoted by N-(3-oxododecanoyl)-L-homoserine lactone from Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is frequently isolated from chronic wounds and causes serious infection in immunocompromised hosts. N-(3-Oxododecanoyl)-L homoserine lactone (3-oxo-C12-HSL) is synthesized by an autoinducer synthase encoded by the bacterial lasI gene in P. aeruginosa, which regulates the production of virulence factors and biofilm formation in this bacterium. Recent studies have suggested that 3-oxo-C12-HSL contributes to the modulation of immune responses. However, the effect of this molecule on wound healing in P. aeruginosa infection remains to be elucidated. OBJECTIVE: We used an animal model to study the effect of 3-oxo-C12-HSL on wound healing in skin infected with P. aeruginosa. METHODS: Wounds were created on the backs of Sprague-Dawley (SD) rats and the P. aeruginosa strain PAO1 (PAO1) or its lasI deletion mutant (DeltalasI) was inoculated onto the wound surface. To examine the biological activity of 3-oxo C12-HSL, rats were injected intraperitoneally with anti-3-oxo-C12-HSL antiserum or administered 3-oxo-C12-HSL at the wound surface. The wound tissues were harvested for analysis of the healing process and inflammatory response. RESULTS: PAO1 inoculation significantly accelerated the wound healing and inflammatory response on day 3 post-wounding. These responses were reversed by inoculation with DeltalasI instead of PAO1 or treatment with anti-3-oxo-C12-HSL antiserum. In contrast, administration of 3-oxo-C12-HSL in the absence of PAO1 significantly promoted these responses, which were suppressed by the anti-TNF-alpha mAb. CONCLUSION: These results strongly suggest that 3-oxo-C12-HSL may be involved in healing wounds infected with P. aeruginosa through induction of inflammatory responses. PMID- 23433552 TI - Impaired inhibitory function of circulating CD4+CD25+ regulatory T cells in alopecia areata. PMID- 23433553 TI - Mercury biomagnification in a contaminated estuary food web: effects of age and trophic position using stable isotope analyses. AB - The main aim of this study was to ascertain the biomagnification processes in a mercury-contaminated estuary, by clarifying the trophic web structure through stable isotope ratios. For this purpose, primary producers (seagrasses and macroalgae), invertebrates (detritivores and benthic predators) and fish were analysed for total and organic mercury and for stable carbon and nitrogen isotopic signatures. Trophic structure was accurately described by delta(15)N, while delta(13)C reflected the carbon source for each species. An increase of mercury levels was observed with trophic level, particularly for organic mercury. Results confirm mercury biomagnification to occur in this estuarine food web, especially in the organic form, both in absolute concentrations and fraction of total mercury load. Age can be considered an important variable in mercury biomagnification studies, and data adjustments to account for the different exposure periods may be necessary for a correct assessment of trophic magnification rates and ecological risk. PMID- 23433554 TI - Spectrophotometric determination of sulfide based on peroxidase inhibition by detection of purpurogallin formation. AB - This paper presents a new method for spectrophotometirc detection of sulfide applying fungal peroxidase immobilized on sodium alginate. The sensing scheme was based on decrease of the absorbance of the orange compound, purpurogallin produced from pyrogallol and H2O2 as substrates, due to the inhibition of peroxidase by sulfide. Absorbance of purpurogallin was detected at 420nm by using a spectrophotometer. The proposed method could successfully detect the sulfide in the concentration range of 0.6-7.0MUM with a detection limit of 0.4MUM. The kinetic parameters of Michaelis-Menten with and without sulfide were also calculated. Possible inhibition mechanism of peroxidase by sulfide was deduced according to the variation of parameters and uncompetitive mechanism was observed with respect to hydrogen peroxide. The current method provides an easy to use method for sulfide detection in water samples. PMID- 23433555 TI - Moderate hypoxia is able to minimize the manganese-induced toxicity in tissues of silver catfish (Rhamdia quelen). AB - The aim of this study was to compare the effects of manganese (Mn) on silver catfish exposed to different levels of dissolved oxygen. Silver catfish (Rhamdia quelen) were exposed to increasing concentrations of Mn (4.2, 8.4 or 16.2mgL(-1)) under either normoxia (100 percent saturation) or moderate hypoxia (51.87 percent saturation) for 15 days. Under normoxia, Mn exposure increased lipid peroxidation (LP) in brain and kidney; it increased gluthatione (GSH) levels in brain and decreased catalase (CAT) activity in both tissues. Moderate hypoxia was able to prevent Mn-induced LP in brain and to reduce this oxidative parameter in kidney; GSH level was increased in brain, while CAT activity was reduced in both tissues. Activity of isolated mitochondria of liver and gills was reduced by Mn exposure under both levels of dissolved oxygen, but this effect was more prominent in normoxia. As expected, liver, kidney and gills showed an increase of Mn accumulation according to waterborne levels, and these parameters presented positive relationship. The highest waterborne Mn (8.4 and 16.2mgL(-1)) resulted in greater accumulation under normoxia, indicating that moderate hypoxia can stimulate mechanisms capable of reducing Mn accumulation in tissues (though not in blood). Moderate hypoxia can be considered a stress factor and Mn an aquatic anthropogenic contaminant. Therefore we hypothesized that these two conditions together are able to invoke defense mechanisms in juvenile silver catfish, acting in a compensatory form, which may be related to adaptation and/or hormesis. PMID- 23433556 TI - Ecophysiological tolerance of Lemna gibba L. exposed to cadmium. AB - In this study, an experiment was carried out to study the process of stress adaptation in Lemna gibba L. grown under cadmium stress (0-20mg Cd L(-1)). The level of photosynthetic pigments and soluble proteins decreased only upon exposure to high Cd concentrations (for pigments 5mg Cd L(-1); for soluble proteins 10mg Cd L(-1)). At the same time, the level of malondialdehyde (MDA) increased with increasing Cd concentration. These results suggested an alleviation of stress that was presumably the result of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione S-transferase (GST) as well as ascorbate peroxidase (APX), which increased linearly with increasing Cd levels. In addition, the proline content in L. gibba increased with increasing cadmium levels. These findings suggest that Lemna is equipped with an efficient antioxidant mechanism against Cd induced oxidative stress which protects the plant's photosynthetic machinery from damage.We also found that moderate Cd treatment (0.05-5mg L(-1) Cd) alleviated oxidative stress in plants, while the addition of higher amounts of Cd (10-20mg L(-1)) could cause an increasing generation of ROS, which was effectively scavenged by the antioxidative system. PMID- 23433557 TI - Colchicine after pulmonary vein isolation: is inflammation the new anti arrhythmic target. PMID- 23433558 TI - Elevated troponin and aortic valve disease. PMID- 23433559 TI - Detection of transvenous pacemaker and ICD lead vegetations: the ICE cold facts. PMID- 23433560 TI - Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf Recall Study. AB - OBJECTIVES: This study sought to determine whether epicardial fat volume predicts coronary events in the general population. BACKGROUND: Epicardial adipose tissue (EAT) is suggested to promote plaque development in the coronary artery tree. METHODS: We quantified EAT volume in participants from the prospective population based Heinz Nixdorf Recall cohort study free of cardiovascular disease. Incident coronary events were assessed during a follow-up period of 8.0 +/- 1.5 years. Multivariable association of EAT with cardiovascular risk factors, coronary artery calcification (CAC), and coronary events was assessed using regression analysis. RESULTS: From the overall 4,093 participants (age 59.4 years, 47% male), 130 subjects developed a fatal or nonfatal coronary event. Incidence of coronary events increased by quartile of EAT (0.9% vs. 4.7% for 1(st) and 4th quartile, respectively, p < 0.001). Doubling of EAT was associated with a 1.5 fold risk of coronary events when adjusting for cardiovascular risk factors (hazard ratio [HR] [95% confidence interval (CI)]: 1.54 [1.09 to 2.19]), which remained unaltered after further adjustment for CAC score (HR [95% CI]: 1.50 [1.07 to 2.11]). For discrimination of subjects with events from those without, we observed a trend for improvement of Harrell's C and explained variance by EAT over traditional cardiovascular risk factors, which, however, did not reach statistical significance (0.720 to 0.730 for risk factors alone and with EAT added, respectively, p = 0.10, R(2) = 2.73% to R(2) = 2.92%, time-dependent integrated discrimination improvement = 0.196%). CONCLUSIONS: Epicardial fat is associated with fatal and nonfatal coronary events in the general population independent of traditional cardiovascular risk factors and complements information from cardiac computed tomography above the CAC score. PMID- 23433561 TI - The fontan operation starts with the cavopulmonary shunt. PMID- 23433562 TI - Incremental cost-effectiveness of guideline-directed medical therapies for heart failure. AB - OBJECTIVES: This study sought to quantify the incremental cost-effectiveness ratios (ICER) of angiotensin-converting enzyme inhibitor (ACEI), beta-blocker (BB), and aldosterone antagonist (AldA) therapies for patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: There are evidence-based, guideline-directed medical therapies for patients with HFrEF, but the incremental cost-effectiveness of these therapies has not been well studied using contemporary data. METHODS: A Markov model with lifetime horizon and two states, dead or alive, was created. We compared HFrEF patients treated with diuretic agents alone to three treatment arms: 1) ACEI therapy alone; 2) ACEI+BB; and 3) ACEI+BB+AldA. Sequential therapy was also analyzed. HF hospitalizations and mortality rates were based on representative studies. Costs of medications and inpatient and outpatient care were accounted for. RESULTS: Treatment with ACEI and ACEI+BB strictly dominated treatment with diuretics only (cost-saving). The greatest gains in quality-adjusted life-years occurred when all 3 guideline directed medications were provided. The incremental cost-effectiveness ratio (ICER) of ACEI+BB+AldA versus ACEI+BB and ACEI+BB versus ACEI was <$1,500 per quality-adjusted life-year. The cost-savings in the ACEI and ACEI+BB cohorts compared to that with diuretics alone were $444 and $33, respectively. Assuming lower treatment costs and lower hospitalization rates in the ACEI+BB+AldA arm resulted in greater cost-savings. Even in the most unfavorable situations, the ICER was <$10,000 per life-year gained. CONCLUSIONS: Our analysis demonstrates that medical treatment of HFrEF is highly cost-effective and may even result in cost-savings. Greater efforts to ensure optimal adherence to guideline-directed medical therapy for HFrEF are warranted. PMID- 23433563 TI - Does flow during rest and relaxation suffice? PMID- 23433564 TI - Reply: To PMID 23040570. PMID- 23433565 TI - Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation. AB - OBJECTIVES: This study sought to collect data and evaluate the anecdotal use of transcatheter aortic valve implantation (TAVI) in pure native aortic valve regurgitation (NAVR) for patients who were deemed surgically inoperable BACKGROUND: Data and experience with TAVI in the treatment of patients with pure severe NAVR are limited. METHODS: Data on baseline patient characteristics, device and procedure parameters, echocardiographic parameters, and outcomes up to July 2012 were collected retrospectively from 14 centers that have performed TAVI for NAVR. RESULTS: A total of 43 patients underwent TAVI with the CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) at 14 centers (mean age, 75.3 +/- 8.8 years; 53% female; mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation), 26.9 +/- 17.9%; and mean Society of Thoracic Surgeons score, 10.2 +/- 5.3%). All patients had severe NAVR on echocardiography without aortic stenosis and 17 patients (39.5%) had the degree of aortic valvular calcification documented on CT or echocardiography. Vascular access was transfemoral (n = 35), subclavian (n = 4), direct aortic (n = 3), and carotid (n = 1). Implantation of a TAVI was performed in 42 patients (97.7%), and 8 patients (18.6%) required a second valve during the index procedure for residual aortic regurgitation. In all patients requiring second valves, valvular calcification was absent (p = 0.014). Post-procedure aortic regurgitation grade I or lower was present in 34 patients (79.1%). At 30 days, the major stroke incidence was 4.7%, and the all-cause mortality rate was 9.3%. At 12 months, the all-cause mortality rate was 21.4% (6 of 28 patients). CONCLUSIONS: This registry analysis demonstrates the feasibility and potential procedure difficulties when using TAVI for severe NAVR. Acceptable results may be achieved in carefully selected patients who are deemed too high risk for conventional surgery, but the possibility of requiring 2 valves and leaving residual aortic regurgitation remain important considerations. PMID- 23433566 TI - Thoracoscopic stand-alone left atrial appendectomy for thromboembolism prevention in nonvalvular atrial fibrillation. AB - OBJECTIVES: This study sought to evaluate thoracoscopic stand-alone left atrial appendectomy for thromboembolism prevention in nonvalvular atrial fibrillation (AF). BACKGROUND: Closing the left atrial appendage (LAA) is an efficacious alternative to oral anticoagulation as prevention against AF-induced thromboembolism, provided that the procedure is safe and complete. METHODS: Thirty patients (mean age, 74 +/- 5.0 years) who had had thromboembolisms were selected. A subgroup of 21 patients (mean age, 75 years; mean CHA2DS2 VASc score, 4.5) urgently needed an alternative treatment to anticoagulation: warfarin was contraindicated due to hemorrhagic side effects in 13, the international normalized ratio was uncontrollable in 7, and transient ischemic attacks had developed immediately after the warfarin dose was reduced for oncological treatment in 1. The LAA was thoracoscopically excised with an endoscopic cutter. RESULTS: Thoracoscopic appendectomy (mean operating time, 32 min, switched to mini-thoracotomy in 2 cases) led to no mortality and no major complications. Three-month post-operative 3-dimensional enhanced computed tomography, performed with patients' consent, confirmed the completeness of the appendectomy. Patients have been followed for 1 to 38 months (mean, 16 +/- 9.7 months [18 +/- 9.4 months for the subgroup]). One patient died of breast cancer 28 months after surgery. Despite discontinued anticoagulation, no patients have experienced recurrence of thromboembolism. CONCLUSIONS: Thoracoscopic stand-alone appendectomy is potentially safe and may allow surgeons to achieve relatively simple, complete LAA closure. Further experience may demonstrate this technique to be a viable option for thromboembolism prevention in nonvalvular AF. PMID- 23433567 TI - American College of Cardiology Foundation recommendations assume incorrectly that cardiac troponins T and I are equally cardiac specific. PMID- 23433568 TI - Reply: To PMID 22818071. PMID- 23433569 TI - Long-lasting airway inflammation associated with equid herpesvirus-2 in experimentally challenged horses. AB - The aim of this trial was to investigate the putative involvement of equid herpesvirus 2 (EHV-2) in airway inflammation of adult horses. Six horses received corticosteroid treatment, before either mock infection (n=2) or EHV-2 strain LK4 inoculation (n=4). These four horses were also submitted to immunosuppression 84 days post inoculation. EHV-2 was detected by quantitative PCR in respiratory samples up to respectively 21 days and 14 days. Nested PCR, cloning and sequencing allowed the detection of five different 'field' strains throughout the trial. Neutrophils proportions were transiently increased in respiratory fluids; neutrophilia being significantly associated with concomitant EHV-2 detection. The laboratory findings reproduced in this trial were compatible with sub-clinical lower airway inflammation and suggest that EHV-2 infection should be suspected when investigating poorly-performing horses. PMID- 23433570 TI - Salivary flow, testosterone, and femur bone mineral density in menopausal women with oral dryness feeling. AB - OBJECTIVES: We compared salivary flow, serum and saliva testosterone, and femur bone mineral density (BMD) of menopausal women with or without xerostomia. STUDY DESIGN: A case/control study was performed on 60 selected menopausal women with or without xerostomia. BMD and testosterone concentration were measured by a dual energy x-ray absorptiometry system and enzyme-linked immunosorbent assay method, respectively. RESULTS: Multinomial logistic regression demonstrated that low saliva flow rate (odds ratio [OR] = 22.8, 95% confidence interval [CI]: 5.4, 96.8), low femur BMD (OR = 6.0, CI: 1.8, 20.0), high stimulated saliva testosterone (OR = 5.2, CI: 2.0, 18.9), high unstimulated saliva testosterone (OR = 3.8, 95% CI: 1.6, 12.3), and high serum testosterone (OR = 2.7, CI: 1.1, 7.2) were associated with an increased risk of xerostomia in menopausal women. CONCLUSIONS: High serum and salivary testosterone and low femur BMD and saliva flow were associated with xerostomia. Of these factors, low salivary flow seems to be the most important element in the perception of dry mouth. PMID- 23433571 TI - Bilateral congenitally bicuspid aortic and pulmonic valves: a rare entity. AB - We present a case of a 70-year-old man who presented to hospital with autoimmune hemolytic anemia, who was found, incidentally, at postmortem, to have bilateral bicuspid aortic and pulmonic valves. PMID- 23433572 TI - Effects of nutrient and lime additions in mine site rehabilitation strategies on the accumulation of antimony and arsenic by native Australian plants. AB - The effects of nutrient and lime additions on antimony (Sb) and arsenic (As) accumulation by native Australian and naturalised plants growing in two contaminated mine site soils (2,735 mg kg(-1) and 4,517 mg kg(-1) Sb; 826 mg kg( 1) and 1606 As mgkg(-1)) was investigated using a glasshouse pot experiment. The results indicated an increase in soil solution concentrations with nutrient addition in both soils and also with nutrient+lime addition for Sb in one soil. Metalloid concentrations in plant roots were significantly greater than concentrations in above ground plant parts. The metalloid transfer to above ground plant parts from the roots and from the soil was, however, low (ratio of leaf concentration/soil concentration?1) for all species studied. Eucalyptus michaeliana was the most successful at colonisation with lowest metalloid transfer to above ground plant parts. Addition of nutrients and nutrients+lime to soils, in general, increased plant metalloid accumulation. Relative As accumulation was greater than that of Sb. All the plant species studied were suitable for consideration in the mine soil phytostabilisation strategies but lime additions should be limited and longer term trials also recommended. PMID- 23433574 TI - Polygenic familial hypercholesterolaemia: does it matter? PMID- 23433573 TI - Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. AB - BACKGROUND: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small effect LDL-C-raising alleles. METHODS: In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hopital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. FINDINGS: We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. INTERPRETATION: In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. FUNDING: British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry. PMID- 23433575 TI - Association of obesity with socio-economic factors and obesity-related chronic diseases in rural southwest China. AB - OBJECTIVES: This study examines how obesity is distributed across socio-economic gradients, and investigates the relationship between obesity and obesity-related chronic diseases in rural Yunnan province of China. STUDY DESIGN: The study design is a cross-sectional community survey. METHODS: A cross-sectional survey was conducted in three rural areas of Yunnan province between 2008 and 2010, among 10,007 consenting individuals aged >=18 years. Information on demographic characteristics, smoking and drinking habits, self-reported stroke and ischemic heart disease (IHD), and family history of obesity-related chronic diseases was obtained using a standard questionnaire. Fasting blood sugar level, blood pressure, height, weight, and waist and hip circumference measurements were recorded for each individual. RESULTS: The age-standardized prevalence of obesity and central obesity was 8.8% and 46.0% among the study populations, respectively. Obesity and central obesity were more common in females than in males. After adjusting for age, sex, and current smoking and drinking status, individuals who belonged to an ethnic minority group had a lower probability of being both obese and centrally obese. Educational level was found to be negatively associated with the prevalence of obesity, and yearly household income was found to be positively associated with prevalence of central obesity. The results of logistic regression analysis indicated that obese and centrally obese people were more likely to suffer from diabetes, hypertension, and stoke. A positive association of IHD was only found in centrally obese people. CONCLUSIONS: In order to reduce the obesity epidemic in rural southwest China, effective interventions must address socio economic factors. Reducing obesity has a profound impact on the reduction of morbidity associated with cardiovascular diseases and diabetes. PMID- 23433576 TI - Opportunities for protecting prisoner health: influenza vaccination as a case study. PMID- 23433577 TI - Public health management of Salmonella Typhi/Paratyphi case and contact screening: lessons from North London. AB - OBJECTIVES: To evaluate the public health management Salmonella enterica serovar Typhi (typhoid) and Salmonella enterica serovar Paratyphi (paratyphoid) cases and their contacts to assess the outcome of screening. STUDY DESIGN: Retrospective case note review. METHODS: 329 cases and 1153 contacts from North London over a four year period were reviewed. Structured questionnaires were developed to capture travel history, relationship between case/contact and the number, timing and documented results of faecal specimens. Evaluation of compliance with the clearance/screening schedule was examined and the positive yield of faecal samples for cases and contacts was calculated. RESULTS: 1% (3/329) of cases had a positive clearance sample; all were identified on their first faecal specimen. Of the 645 contacts who were screened, only 10 (1.5%), all of whom had travelled with the index case, were positive. Person-to-person transmission was only identified for two UK acquired cases, where possible carrier sources were identified outside the screening schedule. CONCLUSION: The lack of evidence of secondary transmission from acute cases, coupled with the low positive yield from clearance samples support the revision of the national guidance for the public health management of cases of enteric fever and their contacts. PMID- 23433578 TI - Erythrocyte membrane trans-fatty acid index is positively associated with a 10 year CHD risk probability. AB - Industry-generated trans-fatty acids (TFA) are detrimental to risk of CHD, but ruminant-originated TFA have been reported as neutral or equivocal. Therefore, the total TFA amount should not be the only factor considered when measuring the effects of TFA. In the present study, we addressed whether a version of the TFA index that unifies the effects of different TFA isomers into one equation could be used to reflect CHD risk probability (RP). The present cross-sectional study involved 2713 individuals divided into four groups that represented different pathological severities and potential risks of CHD: acute coronary syndrome (ACS, n 581); chronic coronary artery disease (CCAD, n 631); high-risk population (HRP, n 659); healthy volunteers (HV, n 842). A 10-year CHD RP was calculated. Meanwhile, the equation of the TFA index was derived using five TFA isomers (trans-16 : 1n-7, trans-16 : 1n-9, trans-18 : 1n-7, trans-18 : 1n-9 and trans-18 : 2n-6n-9), which were detected in the whole blood, serum and erythrocyte membranes of each subject. The TFA index and the 10-year CHD RP were compared by linear models. It was shown that only in the erythrocyte membrane, the TFA isomers were significantly different between the groups. In the ACS group, industry-generated TFA (trans-16 : 1n-9, trans-18 : 1n-9 and trans-18 : 2n-6n-9) were the highest, whereas ruminant-originated TFA (trans-16 : 1n-7 and trans-18 : 1n-7), which manifested an inverse relationship with CHD, were the lowest, and vice versa in the HV group. The TFA index decreased progressively from 7.12 to 5.06, 3.11 and 1.92 in the ACS, CCAD, HRP and HV groups, respectively. The erythrocyte membrane TFA index was positively associated with the 10-year CHD RP (R 2 0.9981) and manifested a strong linear correlation, which might reflect the true pathological severity of CHD. PMID- 23433579 TI - Mitochondrial DNA control region data reveal high prevalence of Native American lineages in Jujuy province, NW Argentina. AB - Mitochondrial control region (16024-576) sequences were generated from 180 individuals of four population nuclei from the province of Jujuy (NW Argentina), located at different altitudes above sea level. The frequency at which a randomly selected mtDNA profile would be expected to occur in the general population (random match probability) was estimated at 0.011, indicating a relatively high diversity. Analysis of the haplogroup distribution revealed that Native American lineages A2 (13.9%), B (56.7%), C1 (17.8%), D1 (8.9%) and D4h3a (1.1%) accounted for more than 98% of the total mtDNA haplogroup diversity in the sample examined. We detected a certain degree of genetic heterogeneity between two subpopulations located at different points along the altitudinal gradient (Valles and Puna), suggesting that altitude above sea level cannot be ruled out as a factor promoting divergences in mtDNA haplogroup frequencies, since altitude is closely associated with human living conditions, and consequently, with low demographic sizes and the occurrence of genetic drift processes in human communities. In all, mitochondrial DNA database obtained for Jujuy province strongly points to the need for creating local mtDNA databases, to avoid bias in forensic estimations caused by genetic substructuring of the populations. PMID- 23433580 TI - Extensive nosocomial transmission of tuberculosis in a low-incidence country. AB - BACKGROUND: This paper describes a nosocomial outbreak of tuberculosis in a hospital ward where the number of cases with active tuberculosis among contacts was unexpectedly high. The outbreak was not revealed until the Mycobacterium tuberculosis genotyping results from the first two secondary tuberculosis cases were available. AIM: To highlight the importance of correct infection control measures when tuberculosis is suspected. METHODS: A retrospective review of the contact investigations following the diagnosis of the index case admitted to the ward. FINDINGS: Seven contacts including three healthcare workers (HCWs) developed tuberculosis within 10 months after the death of a HIV positive patient from pulmonary tuberculosis. Six out of seven cases were verified by culture and all six M. tuberculosis isolates were confirmed by restriction fragment length polymorphism to cluster with the M. tuberculosis isolate from the index case. For the HCWs there was a correlation between number of working hours and risk of acquiring tuberculosis infection and disease. CONCLUSIONS: It is essential that infection control guidelines regarding tuberculosis are followed, and that HCWs should continuously be informed about current tuberculosis control measures. All staff members at clinics treating tuberculosis cases should be screened for latent tuberculosis infection in order to have a reference, in case of future contact-tracing after accidental exposure to tuberculosis. PMID- 23433581 TI - Glycerol significantly decreases the three hour efficacy of alcohol-based surgical hand rubs. AB - BACKGROUND: Glycerol in alcohol-based hand rubs has positive effects on skin condition and user acceptability, but, to the authors' knowledge, its effect on the bactericidal effect of alcohol-based pre-operative hand rubs has not been reported. AIM: To investigate the impact of glycerol on the reduction of resident hand flora by ethanol 80% (w/w), isopropanol 75% (w/w) and n-propanol 60% (V/V). METHODS: In three series of in-vivo laboratory tests on volunteers hands, the efficacy of each of three alcohol-based formulations was tested concurrently with and without added glycerol 1.45% (V/V) according to European Norm EN 12791 for testing pre-operative hand rubs. Formulations were allotted at random to 24 volunteers to rub on to their hands for 3 min. Viable counts from fingertip samples were compared with the respective pretreatment counts immediately after treatment and 3 h later. FINDINGS: The 3-h bactericidal effects of the three pure alcoholic formulations were significantly greater than those of formulations containing glycerol (P < 0.01). With ethanol, this was also true for the immediate effect. CONCLUSION: Glycerol 1.45% (V/V) inhibits the bactericidal efficacy of alcohol-based surgical hand rubs, especially sustained efficacy. PMID- 23433582 TI - [Endovascular occlusion of the vertical vein with an Amplatzer(r)Vascular Plug. Case report]. AB - The use of the Amplatzer(r)Vascular Plug has diversified and has been described successfully in different clinical settings. We describe another application for this device, presenting the case of a patient with a history of correction of total anomalous connection of pulmonary veins, who underwent occlusion of the unligated vertical vein with the Amplatzer(r)Vascular Plug. PMID- 23433585 TI - [Reflections on the draft of the Nursing in Medical-Surgical Care Speciality training program]. PMID- 23433583 TI - [Determination of molecular genetic markers in acute coronary syndromes and their relationship to cardiovascular adverse events]. AB - INTRODUCTION: The genes coding for proteins due to their activity in several metabolic pathways could be related with the onset of acute coronary syndromes. OBJECTIVE: Relationship among polymorphisms and adverse events in. METHODS: Prospective. In--hospital, one--year follow-up. Inclusion Acute coronary syndromes with ST elevation or depression secondary to atherothrombosis, clinical stability. In all, polymerase chain reaction and length polymorphism of restriction fragments. By standardizing chain reactions and genotyping,a preliminary analysis of distribution of genotypes was performed for each polymorphism and no deviations were observed in the law of Hardy-Weinberg equilibrium (P>.05). RESULTS: From 2003 to 2005, 150 subjects were enrolled. We analyzed 14 polymorphisms in 9 genes (fibrinogen, factor v, vii, ii, xiii, plasminogen activator and inhibitor-1, C-reactive protein). In acute coronary syndromes, fibrinogen>450 mg/dL and white blood count 8500 cells/mm(3) were markers of poor prognosis to one year. Regression analysis identified the -148 CT/TT and fibrinogen -717 AG/GG of C-reactive protein as a marker of recurrent ischemia and reinfarction 1691GA + AA. CONCLUSION: We are showing a relationship among polymorphisms involved in inflammation and hemostasis with adverse events in the acute phase and follow-up in acute coronary syndromes patients that could be considered as markers of ischemic heart disease. Larger sample is needed to confirm these results. PMID- 23433586 TI - [Efficiency of advanced practice nurses in elderly care centers]. PMID- 23433587 TI - The expression of AIB1 correlates with cellular proliferation in human prolactinomas. AB - Estrogens as well as certain growth factors strongly influence the development and growth of prolactinomas. However, the molecular mechanisms by which extracellular factors trigger prolactinomas are not well known. Amplified in breast cancer 1 (AIB1), also known as steroid receptor co-activator 3 (SRC-3), belongs to the p160/SRC family of nuclear receptor co-activators and is a major co-activator of the estrogen receptor. Here, we report that the estrogen receptor coactivator AIB1 is overexpressed in human prolactinomas and correlates with the detection of aromatase and estrogen receptor alpha (ERalpha). Of the 87 pituitary tumors evaluated in women, 56%, corresponding to hyperoprolactinemic women, contained an enriched population of prolactin-positive cells and hence were further classified as prolactinomas. All prolactinomas stained positive for both ERalpha and AIB1. Moreover, AIB1 sub-cellular distribution was indicative of the cell-cycle status of tumors; the nuclear expression of AIB1 was correlated with proliferative markers whereas the cytoplasmic localization of AIB1 coincided with active caspase-3. Thus, our results demonstrate for the first time that AIB1 is expressed in prolactinomas and suggest its participation in the regulation of proliferation and apoptosis of tumoral cells. Because aromatase expression is also enhanced in these prolactinomas and it is involved in the local production of estradiol, both mechanisms, ER-AIB1 and aromatase could be related. PMID- 23433588 TI - Anatomical study of the roots of cranial parasympathetic ganglia: a contribution to medical education. AB - A major key to increasing the safety of cranial surgery is a thorough understanding of anatomy. The anatomy of the head is of fundamental interest to dental and medical students early in their studies. Clinically, it is mostly relevant to surgeons who are performing interventions and reconstruction in the maxillofacial region, skull base, and the orbit. However, the level of appropriate anatomical knowledge necessary for general and special medical and surgical practice is still under discussion. This study maps the significant areas and structures of the head that are not normally accessible during dissection courses because of time and difficulties involved in the preparation. The detailed photodocumentation enriched by diagrams provides a view of structures until now only partially documented. Three parasympathetic ganglia are located in hardly accessible areas of the head - inside the orbit, infratemporal fossa, and in the pterygopalatine fossa. No detailed photographs have been found in current anatomical textbooks and atlases in relation to the morphology of fibers (roots) connected to the ciliary, otic, and pterygopalatine ganglia. Therefore, this study focused on the detailed display of sensory, sympathetic, and parasympathetic roots of ganglia to provide relevant photodocumentation and an improvement in human anatomy teaching. This study also confirms that cadaver dissection provides an excellent opportunity for the integration of anatomy and clinical medicine into the early clinical training of undergraduate dental and medical students. We believe this article, because of the details mentioned above, will be beneficial not only for the future anatomical undergraduate but also for postgraduate education. PMID- 23433589 TI - The male urethra: spatiotemporal distribution of molecular markers during early development. AB - The organogenesis of the male human urethra is still a subject of controversy. Although many studies have been conducted, the mechanisms of urethral development still need further investigation to clarify questions concerning the sequences in its development. Our aim has been to elucidate the spatiotemporal distribution of relevant immunohistochemical indicators during the development of the male urethral epithelium and its adjacent mesenchyme. Therefore, we analyzed male human embryos and foetuses between the 6th and 15th week after fertilization using histological and immunohistochemical methods. Monoclonal antibodies raised against cytokeratins (CKs) 7, 8, 13 and 17 as well as Ki67, E-Cadherin, p63, uroplakin III, smooth muscle actin (SMA) and vimentin were applied. Our results revealed that epithelial differentiation starts prior to the rupture of the cloacal membrane. At weeks (W) 8-9 the epithelium became transitional over the whole length of the elongating urethra. The urothelial staining pattern of uroplakin III receded continually, and, at the end of W 11, it had receded in proximal direction to the bladder neck comparable to the epithelial appearance in adults. The urogenital sinus epithelium provided the Wolffian duct with p63 positive cells, leading to the suggestion that the development of the male inner genitals requires a cellular stimulus by this very epithelium. CK 17-positive cells, which were described as epithelial stem cells, could be found in the extending urethral plate. This facilitates new insight into the pathogenesis and treatment of hypospadias, which is one of the most common malformations in newborn males. PMID- 23433590 TI - Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial. AB - BACKGROUND: In countries with a high incidence of HIV and tuberculosis co infection, nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs. We aimed to compare efficacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in co-infected patients. METHODS: We did a multicentre, open-label, randomised, non-inferiority trial at three health centres in Maputo, Mozambique. We enrolled adults (>=18 years) with tuberculosis and previously untreated HIV infection (CD4 cell counts <250 cells per MUL) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal. 4-6 weeks after the start of tuberculosis treatment, we randomly allocated patients (1:1) with central randomisation, block sizes of two to six, and stratified by site and CD4 cell count to nevirapine (200 mg twice daily) or efavirenz (600 mg once daily), plus lamivudine and stavudine. The primary endpoint was virological suppression at 48 weeks (HIV-1 RNA <50 copies per mL) in all patients who received at least one dose of study drug (intention-to-treat population); death and loss to follow-up were recorded as treatment failure. The non-inferiority margin for the difference of efficacy was 10%. We assessed efficacy in intention-to-treat and per-protocol populations and safety in all patients who received study drug. This study is registered with ClinicalTrials.gov, number NCT00495326. FINDINGS: Between October, 2007, and March, 2010, we enrolled 285 patients into each group. 242 (85%) patients in the nevirapine group and 233 (82%) patients in the efavirenz group completed follow up. In the intention-to-treat population, 184 patients (64.6%, 95% CI 58.7-70.1) allocated nevirapine achieved virological suppression at week 48, as did 199 patients (69.8%, 64.1-75.1) allocated efavirenz (one-sided 95% CI of the difference of efficacy 11.7%). In the per-protocol population, 170 (70.0%, 63.8 75.7) of 243 patients allocated nevirapine achieved virological suppression at week 48, as did 194 (78.9%, 73.2-83.8) of 246 patients allocated efavirenz (one sided 95% CI 15.4%). The median CD4 cell count at randomisation was 89 cells per MUL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine. 20 patients allocated nevirapine (7%) had grade 3-4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz (6%). Three patients had severe rash after receipt of nevirapine (1%) but no patients did after receipt of efavirenz. 18 patients in the nevirapine group died, as did 17 patients in the efavirenz group. INTERPRETATION: Although non-inferiority of the nevirapine-regimen was not shown, nevirapine at full dose could be a safe, acceptable alternative for patients unable to tolerate efavirenz. FUNDING: French Research Agency for HIV/AIDS and hepatitis (ANRS). PMID- 23433591 TI - ART and tuberculosis: the final nail in nevirapine's coffin? PMID- 23433593 TI - The lung cancer patient at the emergency department: a three-year retrospective study. AB - INTRODUCTION: Currently, there are limited data on the lung cancer patient at the emergency department. Our objective is to review the medical charts of those patients to determine the frequency and main causes of emergency consultations and the predicting factors for hospital admissions and deaths. METHODS: We conducted a retrospective study including all patients with lung cancer consulting at the emergency department of a cancer hospital. RESULTS: From January 1, 2008 to December 31, 2010, 269 patients with lung cancer presented at the emergency, corresponding to 548 consultations (8.3% of all 6575 visits). During the same period, 626 patients for lung cancer were treated in our institution meaning that 43% of them are consulting at least once the emergency department during the course of their disease. The main reasons for consultation were respiratory symptoms (22.3%) and fever (19.9%). Emergency visit leads to hospital admission in 63% of the cases. In multivariate analysis, the main independent predictor factor of hospitalisation is arrival by ambulance (odd ratio 12), which is also the principal predictor of death during hospitalisation (odd ratio 9.5). The presence of signs at physical examination is also an important factor. CONCLUSION: Our study shows that emergency visit is a frequent event for lung cancer patients and has identified simple factors predicting hospitalisation and deaths. PMID- 23433592 TI - Genetic polymorphisms of TERT and CLPTM1L and risk of lung cancer--a case-control study in a Chinese population. AB - BACKGROUND/OBJECTIVES: Genetic variants of telomerase reverse transcriptase (TERT) and cleft lip and palate trans-membrane 1 like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in TERT and CLPTM1L genes with lung cancer and explored their potential modifying effects on the relationship between environmental risk factors and lung cancer in a Chinese population. METHODS: We genotyped rs2736100 (TERT) and rs401681 (CLPTM1L) SNPs in a case-control study with 399 lung cancer cases and 466 controls form Taiyuan, China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. Potential confounders were controlled for in the adjusted models. RESULTS: We found that the GG genotype of TERT was positively associated with lung cancer (OR=1.47, 95% CI: 1.00-2.16). The association was stronger in participants older than 60years, exposed to low indoor air pollution and adenocarcinoma and squamous cell carcinoma (SCC) in recessive model analysis. The GA genotype of CLPTM1L was inversely associated with lung cancer (OR=0.72, 95% CI: 0.54-0.97). The association was stronger in participants 60 years old or younger, males, heavy smokers, exposed to low indoor air pollution and SCC in dominant model analysis. Individuals carrying both TERT and CLPTM1L risk genotypes had higher risk of lung cancer (OR=1.80, 95% CI: 1.15-2.82). Significant interaction was observed between CLPTM1L and indoor air pollution in association with lung cancer. CONCLUSIONS: Our results reiterate that genetic variants of TERT and CLPTM1L contribute to lung cancer susceptibility in Chinese population. These associations need to be verified in larger and different populations. PMID- 23433594 TI - Pediatric pancreatic EUS-guided trucut biopsy for evaluation of autoimmune pancreatitis. PMID- 23433595 TI - Clinical utility and interobserver agreement of autofluorescence imaging and magnification narrow-band imaging for the evaluation of Barrett's esophagus: a prospective tandem study. AB - BACKGROUND: New endoscopic imaging techniques, such as autofluorescence imaging (AFI) and narrow-band imaging (NBI), have been developed to improve the detection of neoplastic lesions in Barrett's esophagus (BE). OBJECTIVE: To evaluate the clinical utility of AFI and magnification NBI to detect high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) and the interobserver agreement. DESIGN: Prospective tandem study of eligible patients. SETTING: Single, academic tertiary care center. PATIENTS: Forty-two patients with a history of confirmed BE were prospectively enrolled. INTERVENTIONS: The BE segment was examined under high-definition white-light endoscopy, and the presence of visible lesions was recorded. Subsequently, AFI and magnification NBI were performed in tandem on areas of the BE segment away from visible lesions; images obtained by these 2 systems were graded according to the color of reflected light and surface patterns, respectively. Biopsy specimens were obtained at the end of the procedure. MAIN OUTCOME MEASUREMENTS: The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of the AFI and NBI patterns for the detection of HGD/EAC and interobserver agreement. RESULTS: Of the 42 patients enrolled, 14 (33%) had HGD/EAC. On patient-based analysis, AFI alone had a sensitivity, specificity, and NPV of 50%, 61%, and 71%, respectively, and the overall accuracy for the detection of HGD/EAC patients was 57%. By using magnification NBI in tandem fashion, the sensitivity and NPV improved to 71% and 76%, respectively, with a decrease in specificity to 46% and in overall accuracy to 55%. The 2 techniques had moderate interobserver agreement for both the patterns and prediction of histology. LIMITATIONS: Uncontrolled study performed at an academic center by expert endoscopists in a high-risk population. CONCLUSIONS: By using a multimodality endoscope, both AFI and magnification NBI had limited clinical accuracy and moderate overall interobserver agreement. AFI does not appear to be useful as a broad-based technique for the detection of neoplasia in patients with BE. PMID- 23433596 TI - High single-pass diagnostic yield of a new 25-gauge core biopsy needle for EUS guided FNA biopsy in solid pancreatic lesions. AB - BACKGROUND: Current limitations of EUS-guided FNA include the need for multiple passes and on-site cytology assessment and lack of core specimen. Recently, a new 25-gauge core biopsy needle (PC25) was developed to overcome these limitations. OBJECTIVE: To determine the diagnostic yield of EUS-guided FNA aspiration biopsy (FNAB) when using the PC25 needle among patients with solid pancreatic lesions. DESIGN: Retrospective analysis. SETTING: Academic tertiary referral center. PATIENTS: Fifty consecutive patients with a solid pancreatic lesion underwent EUS guided FNAB with PC25. INTERVENTIONS: EUS-guided FNAB with PC25. MAIN OUTCOME MEASUREMENTS: The primary outcome was the diagnostic yield in single and overall passes of EUS-guided FNAB when using the PC25 needle for pancreatic solid lesions. RESULTS: Cytologic analysis showed malignancy in 38 patients on the first pass, with a cumulative sensitivity of 83%, 91%, and 96% on passes 1, 2, and 3, respectively. Although visible core was reported in 46 patients (92%), histologic core was seen in 16 patients (32%). Histologic analysis showed malignancy in 29 patients on the first pass, with a cumulative sensitivity of 63% and 87% on pass 1 and passes 1 to 4, respectively. The sensitivity, specificity, and accuracy in combined cytologic and histologic results were 85%, 100%, and 86% for single pass and 96%, 100%, and 96% on multiple passes, respectively. No complications were seen. LIMITATIONS: A retrospective study design at a single center using a single arm. CONCLUSION: EUS-guided FNAB with the PC25 needle showed excellent single-pass and overall diagnostic yields. This needle appears to maintain a high cytologic yield, similar to standard 25-gauge FNA needles, while also providing some histologic core tissue. PMID- 23433597 TI - A gentle touch and a delicate pinch. PMID- 23433598 TI - Gastritis cystica profunda with a long stalk. PMID- 23433599 TI - Incidence of perforation in pediatric GI endoscopy and colonoscopy: an 11-year experience. PMID- 23433600 TI - Risk factors for post-traumatic pneumonia in patients with retained haemothorax: results of a prospective, observational AAST study. AB - INTRODUCTION: Retained haemothorax (RH) is a problematic sequela of thoracic trauma, reported in up to 20% of patients following chest injury. RH is associated with a higher severity of thoracic trauma and may portend the onset of other serious post-traumatic complications, including pneumonia. The development of pneumonia has previously been reported to be as high as 19.5% in the setting of traumatic RH. The purpose of this study was to identify risk factors for the development of pneumonia as a complication in RH. METHODS: We utilized the American Association for the Surgery of Trauma Post-Traumatic Retained Haemothorax database. Patients with post-traumatic RH were prospectively enrolled from 2009 to 2011. Inclusion criteria were placement of a thoracostomy tube within 24h of admission for the evacuation of pneumothorax or haemothorax and subsequent chest computed tomography scan chest showing RH. Patients treated with thoracotomy before placement of tube thoracostomy were excluded. For univariate analysis, the Chi-square test with Yates correction was used for comparison of categorical risk factors and the Student's t-test or the Mann-Whitney test for comparison of continuous risk factors. To identify independent risk factors for the development of pneumonia, variables from the univariate analysis significant at p<0.2 were entered into a forward logistic regression model. Adjusted odds ratio and 95% confidence intervals (CI) were derived. RESULTS: 328 patients with post-traumatic RH from 20 United States centres were enrolled. After stepwise regression analysis, ISS>25 (adjusted OR: 7.1; 95% CI: 3.1, 16.4; p<0.001), blunt mechanism of injury (adjusted OR: 3.5; 95% CI: 1.7, 7.2; p=0.001), and failure to administer peri-procedural antibiotics on the initial thoracostomy tube placement (adjusted OR: 2.6; 95% CI: 1.30, 5.4; p=0.01) were found to be independent predictors of the pneumonia in patients with post-traumatic RH. CONCLUSIONS: To our knowledge, our current study is the largest attempt to identify the independent predictors for pneumonia in this population. Our data show that elevated ISS, blunt thoracic trauma, and failure to administer peri-procedural antibiotics on tube thoracostomy placement are the statistically significant independent risk factors. PMID- 23433601 TI - Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes. AB - BACKGROUND: Combination therapy is required to provide adequate glycemic control in many patients with type 2 diabetes mellitus (T2DM). Because sodium-dependent glucose transporter (SGLT)-1 inhibition results in an increased release of glucagon-like peptide (GLP)-1, and because dipeptidyl peptidase (DPP)-4 inhibitors prevent its inactivation, the 2 mechanisms together provide an intriguing potential combination therapy. OBJECTIVES: This combination was explored in preclinical models and then tested in patients with T2DM to compare the effects of single-dose LX4211 400 mg and sitagliptin 100 mg, administered as monotherapy or in combination, on GLP-1, peptide tyrosine tyrosine (PYY), gastric inhibitory peptide (GIP), glucose, and insulin. METHODS: Preclinical: Obese male C57BL6J mice were assigned to 1 of 4 treatment groups: LX4211 60 mg/kg, sitagliptin 30 mg/kg, LX4211 + sitagliptin, or inactive vehicle. Clinical: This 3 treatment, 3-crossover, randomized, open-label study was conducted at a single center. Patients on metformin monotherapy were washed out from metformin and were randomly assigned to receive sequences of single-dose LX4211, sitagliptin, or the combination. In both studies, blood was collected for the analysis of pharmacodynamic variables (GLP-1, PYY, GIP, glucose, and insulin). In the clinical study, urine was collected to assess urinary glucose excretion. RESULTS: Preclinical: 120 mice were treated and assessed (5/time point/treatment group). With repeat daily dosing, the combination was associated with apparently synergistic increases in active GLP-1 relative to monotherapy with either agent; this finding was supported by findings from an additional 14-day repeated-dose experiment. Clinical: 18 patients were enrolled and treated (mean age, 49 years; 56% male; 89% white). The LX4211 + sitagliptin combination was associated with significantly increased active GLP-1, total GLP-1, and total PYY; with a significant reduction in total GIP; and with a significantly improved blood glucose level, with less insulin, compared with sitagliptin monotherapy. LX4211 was associated with a significant increase in total GLP-1 and PYY and a reduced total GIP, likely due to a reduction in SGLT1-mediated intestinal glucose absorption, whereas sitagliptin was associated with suppression of all 3 peptides relative to baseline. All treatments were well tolerated, with no evidence of diarrhea with LX4211 treatment. CONCLUSIONS: The findings from the preclinical studies suggest that the LX4211 + sitagliptin combination produced synergistic increases in active GLP-1 after a meal challenge containing glucose. These initial clinical results also suggest that a LX4211 + DPP-4 inhibitor combination may provide an option in patients with T2DM. The potential long-term clinical benefits of such combination treatment need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01441232. PMID- 23433602 TI - An anti-tumor protein produced by Trichinella spiralis induces apoptosis in human hepatoma H7402 cells. AB - Trichinella spiralis infection confers effective resistance to tumor cell expansion. In this study, a T7 phage cDNA display library was constructed to express genes encoded by T. spiralis. Organic phase multi-cell screening was used to sort through candidate proteins in a transfected human chronic myeloid leukemia cell line (K562) and a human hepatoma cell line (H7402) using the display library. The protein encoded by the A200711 gene was identified and analyzed using protein analysis software. To test the antitumor effects of A200711, variations in cell proliferation and apoptosis were monitored after recombinant pEGFP-N1-A200711 was transfected into H7402 cells. The results show that the expressed target gene successfully induced apoptosis in H7402 cells as measured by Hoechst-PI staining, MTT assay (p<0.05). This study warrants further investigation into the therapeutic use of A200711 for anti-hepatocellular carcinomas. PMID- 23433603 TI - Unique antigenic gene expression at different developmental stages of Trichinella pseudospiralis. AB - Parasite-induced and parasite-regulated larval capsule formation and host immunosuppression are two major characteristics that are unique in Trichinella spp. infections, but the molecule(s) and mechanism(s) that mediate these processes remain largely unknown. Trichinella pseudospiralis and Trichinella spiralis, are obviously different with respect to these two characteristics. A comparative study of these two species, in particular their antigen expression profiles at different developmental stages (the main molecules involved in the cross-talk or interaction between each parasite and its host), may help us better understand the parasite molecules and mechanisms involved. Here, we constructed cDNA libraries from T. pseudospiralis adults (Ad), newborn larvae (NBL) and muscle larvae (ML) mRNA and screened them with pig anti-T. pseudospiralis serum collected 26, 32 and 60 days post-infection (p.i.). The most abundant antigens were found to vary among life-cycle stages. Pyroglutamy peptidase 1-like and 6 phosphogluconolactonase-like genes predominated in the Ad stage and a serine protease (SS2-1-like gene) predominated in NBL similar to that observed in T. spiralis. Muscle larvae expressed proteasome activator complex subunit 3-like and 21 kDa excretory/secretory protein-like genes. This study indicated that parasites of two species may utilise different molecules and mechanisms for larvae capsule formation and host immunosuppression during their infections. Proteins of antigenic genes identified in this study may be also good candidates for diagnosis, treatment or vaccination for T. pseudospiralis infection, and also for the differential diagnosis of two species' infections. PMID- 23433604 TI - Modulation of inflammatory bowel disease in a mouse model following infection with Trichinella spiralis. AB - Infection of mice with Trichinella spiralis redirects the mucosal immune system from a Th1 to a protective Th2 response with a reduction in the severity of trinitrobenzesulfonic acid-induced colonic damage. T. spiralis infection induced IL-10 production in a dose-dependent manner in oxazolone (OXZ)-induced colitis. This phenomenon may be responsible for the lack of efficacy of T. spiralis in the treatment of OXZ-induced colitis. These results indicate that if the source of increased IL-10 production is identified and addressed, T. spiralis may alter the Th2 response. PMID- 23433605 TI - Differential immunological responses induced by infection with female muscle larvae and newborn larvae of Trichinella pseudospiralis. AB - Trichinella pseudospiralis infection can modulate the immunological response of autoimmune and allergic diseases leading to the amelioration of these diseases. The present study was undertaken to compare immunity induced by adult worms and muscle larvae. Higher eosinophilia was observed from newborn larva (NBL) infection than from adult females while higher levels of IgE were observed in adult female infections over those induced by NBL. The IgG1 response to ES antigen was more prominent in infections with adult females. The IgG2 responses to larval crude antigen were prominent against NBL. The Th2 cytokine, IL-4 cytokine was elevated in adult female infection following re-stimulation with adult crude antigen and ES. Both infections induced strong IFN-gamma responses. The present study demonstrates that adult female worms induced stronger Th2 responses (IgG1, IgE and IL-4 responses) than NBL. Further examination of the mechanisms involved in immune modulation may be helpful for identifying Trichinella-derived molecules responsible for regulating autoimmune and allergic diseases. PMID- 23433606 TI - Factors associated with effective reassessment of antibiotic therapy on day 3. AB - Reassessment of antibiotic therapy (RA) after 3 days is constitutive of French antibiotic stewardship. This delay is required because of the need for clinical reappraisal and for obtaining microbiological data. Our aim was to determine the factors associated with an effective RA. PATIENTS AND METHOD: A prospective study was made in a 350-bed general hospital in which all prescriptions are computerized and validated daily by prescribers. All curative antibiotic therapies were reassessed during 4 weeks. RA was defined as effective if the initial antibiotic treatment was modified. All clinical, biological, and radiological data having contributed to the initial prescription and to RA were recorded during bedside visit with the prescribers, two hospital physicians and one infectious diseases specialist. RESULTS: In one month, 148 antibiotic treatments were reassessed. Pulmonary, digestive, and urinary infections accounted for two thirds of the cases. An effective RA was recorded in 28 cases (19%) and associated with hospitalization in the ICU (P=0.001), imaging supporting the diagnosis (P=0.016), and persistence or aggravation of clinical signs (P=0.007). Microbiological findings were not contributive to an effective RA. CONCLUSION: RA was associated to hospitalization in the ICU, to an inflammatory syndrome, and to the clinical outcome after 3 days. These results should help to improve the implementation of infectious diseases advice. PMID- 23433607 TI - How to reduce antibiotic consumption for community-acquired pneumonia? AB - BACKGROUND: The difficulty to diagnose community-acquired pneumonia (CAP) and the lack of scientific data regarding the optimal duration of antibiotic therapy are responsible for overprescribing antibiotics. OBJECTIVE: The authors had for objective to perform a systematic review of the international medical literature on strategies aimed at reducing antibiotic consumption for CAP. METHODS: We performed a Pubmed search using the keywords CAP, antibiotic use, duration of antibiotic therapy, procalcitonin, short-course treatment, and biomarkers. We then made a critical review of the selected articles. RESULTS: Our review identified two strategies used to reduce antibiotic consumption for CAP. The first one was based on procalcitonin (PCT) use. This strategy, even though reducing the duration of antibiotic therapy, does not seem optimal since it is associated with longer antibiotic treatment than recommended by the Infectious Diseases Society of America. Moreover, this strategy is associated with an increased cost in biochemical tests. The other strategy is based on a 2-step clinical reassessment: 1) during the first 24 hours of hospitalization, to confirm the diagnosis of CAP and 2) during hospitalization, to shorten the duration of antibiotic therapy according to the patient's clinical status. CONCLUSION: Clinical reassessment, currently little studied compared to PCT guidance algorithm, seems to be promising to reduce antibiotic consumption for CAP. Especially since it was never compared to PCT guidance strategy in a randomized clinical trial. PMID- 23433608 TI - Alternatives to carbapenems in ESBL-producing Escherichia coli infections. AB - OBJECTIVES: The authors had for objective to assess the activity of a wide panel of antibiotics on extended-spectrum-beta-lactamase producing Escherichia coli isolates (ESBL-Ec), because of the sharp increase of their frequency, leading to an increased use of carbapenems. MATERIAL AND METHODS: We selected 100 ESBL-Ec in which ESBLs were identified by PCR and sequencing, between 2009 and 2010. We determined the MICs of amoxicillin-clavulanate, piperacillin-tazobactam, temocillin, mecillinam, cefoxitin, cefotaxime, ceftazidime, aztreonam, tigecycline, nitrofurantoin, and fosfomycin using reference methods. The susceptibility profiles were defined according to EUCAST 2012 recommendations. RESULTS: Fosfomycin, nitrofurantoin, and pivmecillinam were active against more than 90% of isolates and remain excellent choices for the oral treatment of urinary tract infections (UTIs). Temocillin and piperacillin-tazobactam are also good candidates for the treatment of pyelonephritis or bloodstream infections. Only 27, 23, and 8% of isolates were susceptible to ceftazidime, cefepime, and cefotaxime, respectively. CONCLUSION: Our study results prove that in many cases, there are non-carbapenem alternatives for the treatment of ESBL-Ec infections. PMID- 23433610 TI - Factors associated with adverse events resulting from medical errors in the emergency department: two work better than one. AB - BACKGROUND: The Emergency Department (ED) is an environment at risk for medical errors. OBJECTIVE: Our aim was to determine the factors associated with the adverse events resulting from medical errors in the ED among patients who were admitted. METHODS: This was a prospective observational study. For a 1-month period, we included all ED patients who were subsequently admitted to the medical ward. Detection of medical errors was made by the admitting physician and then validated by two experts who reviewed all available data and medical charts pertaining to the patient's hospital stay, including the first review from the ward physician. Related adverse events resulting from medical errors were then classified by type and severity. Adverse events were defined as medical errors that needed an intervention or caused harm to the patient. Univariate analysis examined relationships between characteristics of both patients and physicians and the risk of adverse events. RESULTS: From 197 analyzed patients, 130 errors were detected, of these, 34 were categorized as adverse events among 19 patients (10%). Seventy-six percent of these were categorized as proficiency errors. The only factors associated with a lower risk of adverse events were the transition of care involving a handoff within the ED (0% vs. 19%; p = 0.03) and the involvement of a resident (junior doctor) in addition to the senior physician (37% vs. 67%; p < 0.01). CONCLUSIONS: In our study, the involvement of more than one physician was associated with a lower risk of adverse events. PMID- 23433609 TI - A mathematical model of the unfolded protein stress response reveals the decision mechanism for recovery, adaptation and apoptosis. AB - BACKGROUND: The unfolded protein response (UPR) is a major signalling cascade acting in the quality control of protein folding in the endoplasmic reticulum (ER). The cascade is known to play an accessory role in a range of genetic and environmental disorders including neurodegenerative and cardiovascular diseases, diabetes and kidney diseases. The three major receptors of the ER stress involved with the UPR, i.e. IRE1 alpha, PERK and ATF6, signal through a complex web of pathways to convey an appropriate response. The emerging behaviour ranges from adaptive to maladaptive depending on the severity of unfolded protein accumulation in the ER; however, the decision mechanism for the switch and its timing have so far been poorly understood. RESULTS: Here, we propose a mechanism by which the UPR outcome switches between survival and death. We compose a mathematical model integrating the three signalling branches, and perform a comprehensive bifurcation analysis to investigate possible responses to stimuli. The analysis reveals three distinct states of behaviour, low, high and intermediate activity, associated with stress adaptation, tolerance, and the initiation of apoptosis. The decision to adapt or destruct can, therefore, be understood as a dynamic process where the balance between the stress and the folding capacity of the ER plays a pivotal role in managing the delivery of the most appropriate response. The model demonstrates for the first time that the UPR is capable of generating oscillations in translation attenuation and the apoptotic signals, and this is supplemented with a Bayesian sensitivity analysis identifying a set of parameters controlling this behaviour. CONCLUSIONS: This work contributes largely to the understanding of one of the most ubiquitous signalling pathways involved in protein folding quality control in the metazoan ER. The insights gained have direct consequences on the management of many UPR related diseases, revealing, in addition, an extended list of candidate disease modifiers. Demonstration of stress adaptation sheds light to how preconditioning might be beneficial in manifesting the UPR outcome to prevent untimely apoptosis, and paves the way to novel approaches for the treatment of many UPR-related conditions. PMID- 23433611 TI - Acute abdominal pain in the pediatric emergency department: a case of right lower quadrant wandering spleen that acutely torsed. PMID- 23433612 TI - Increasing zooplankton variance in the late 1990s unveils hydroclimate modifications in the Balearic Sea, Western Mediterranean. AB - We examined seasonal and interannual patterns of zooplankton functional groups in the Balearic Sea from 1994 to 2003 and revealed a conspicuous increase in zooplankton variance at community and population levels. The change occurred in 1999-2000, and paralleled modifications in the North Atlantic climate that cascaded down affecting the water column thermal gradient in the Balearic Sea. The observed modifications in both hydroclimate and ecological compartments raise the question of a potential ecological shift in the pelagic ecosystem of the Western Mediterranean in the late 1990s. PMID- 23433613 TI - Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis. AB - BACKGROUND AND AIM: Patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) are at increased risk of colon cancer. The aim of this study was to determine the natural history of LGD and its progression to high grade dysplasia (HGD)/colorectal cancer (CRC) in PSC-UC patients. METHODS: Ten PSC-UC patients with LGD who underwent surveillance colonoscopy from 1996 to 2011 were evaluated. Raised dysplasia was defined as a discrete raised lesion located in an area involved by either quiescent or active colitis that was endoscopically resected, while flat dysplasia was defined as the absence of documentation of a raised lesion. RESULTS: Of the 10 patients with LGD, 3 (30%) progressed to raised HGD over a mean follow-up of 13+/-11 months. Three of 10 patients had initial raised LGD while 7 had flat LGD. The location of HGD was in the proximal colon in all 3 patients. However all 3 patients who progressed to HGD had initial dysplasia located in the distal colon and had flat morphology. The incidence rate for detection of HGD/CRC was 9.4 cases per 100 person years at risk. Patients with LGD with flat morphology had an incidence rate of 17.8 cases per 100 person years at risk. HGD occurred more frequently within the first year of initial detection of LGD (23.5 per 100 patient years of follow-up). CONCLUSIONS: One third of patients with LGD progressed to HGD/CRC in PSC-UC. Most patients progress within the first year of diagnosis of LGD supporting early colectomy in PSC-UC patients with LGD. PMID- 23433614 TI - Association of erosion with dietary factors among 5-year-old children in India. AB - PURPOSE: The purpose of this study was to determine the association of dental erosion with dietary factors and oral hygiene practices among 5-year-old schoolchildren in Belgaum, Karnataka, India. METHODS: A random sample of 1,002 5 year-old children was drawn from Belgaum schools. Erosion was assessed using the modified Smith and Knight index. A self-designed questionnaire was used to probe into the details of the children's dietary practices. RESULTS: Frequency of consumption of beverages, canned juices, tamarind, and honey, a mixed diet, and frequency of teeth cleaning were significant predictors of dental erosion. Oral hygiene practices like timing of cleaning teeth and materials used did not show significant association with dental erosion. CONCLUSION: Certain dietary factors like canned juice, raw mango, gooseberry, tamarind, honey, buttermilk, and beverages showed significant correlation with dental erosion. Dietary counseling must take this into consideration. PMID- 23433615 TI - Behavior and progression of early carious lesions in early childhood: a 1-year follow-up study. AB - PURPOSE: The purpose of this 1-year follow-up study was to evaluate the behavior/progression of early carious lesions (active noncavitated carious lesions) by surface and type of tooth in early childhood. METHODS: A total of 179 3-and 4-year-old preschoolers took part in this study. Clinical examinations were conducted by a calibrated examiner using a mirror, ball-ended probe, gauze for cleaning and drying of teeth, and artificial light. The World Health Organization criteria, with an added measurement of early carious lesions (ECLs), were employed for the caries examinations. Descriptive statistics and logistic regression were used in the statistical analysis. RESULTS: After a 1-year follow up, the study population developed 1.60 +/- 1.64 new carious lesions. Children with caries activity at baseline showed much higher risks of developing new lesions than caries-free children (odds ratio=17.3 for ECL development, OR=24.5 for cavitations/fillings). Most ECLs remained active/unchanged after 1 year, whereas approximately 36% were arrested. Approximately 10% of the ECLs became cavitated, were filled, or were missing due to caries at follow-up. ECLs turned into cavities or fillings more frequently in the posterior region. CONCLUSION: This study's findings support the conservative management of ECLs since, after 1 year, the majority of lesions were active/unchanged or were arrested on the smooth surfaces of primary teeth. PMID- 23433616 TI - Determination of the dental arch form in the primary dentition using a polynomial equation model. AB - PURPOSE: Many geometric forms and mathematical functions have been proposed as models of the dental arch; however, no such information seems to be available for the primary dentition. The purpose of this study was to develop a model for dental arch form in the primary dentition. METHODS: The participants were 92 children (47 boys, 45 girls) in primary dentition. Dental casts were used to measure dental arch dimensions with digital calipers. The arch form was classified as round, long, and short. The values of A and B in the polynomial function formula Y=Ax(m) + Bx(n) were calculated so that the curve would pass through all teeth in the arch. Data were analyzed and compared with the independent t-test and multiple regression analysis. RESULTS: There was significant difference between boys and girls in dental arch widths (P=0.025) and depths at mandibular primary canines (P<0.001) but not significant at the maxillary primary canines (P>.05). The width and depth of the arches at the primary canines correlated significantly with the width and depth at the primary molars (P<0.001). CONCLUSIONS: The sixth-order polynomial function Y=Ax 6 +Bx 2 is a potentially accurate mathematical model of arch form for primary dentition. PMID- 23433617 TI - Dens invaginatus: review, relevance, and report of 3 cases. AB - Dens invaginatus is a rare developmental morphoanatomical variation resulting from the infolding of the dental papilla before biological mineralization that allows the invagination of inner dental epithelium. Permanent maxillary lateral incisors are most commonly affected, and the condition is frequently bilateral, but it may also prevail in permanent maxillary central incisors. The purpose of this paper was to provide an overview of the etiopathogenesis, frequency of occurrence, and clinical and radiographic features and to discuss 3 dens invaginatus cases. PMID- 23433618 TI - A community-based randomized trial of postcard mailings to increase dental utilization among low-income children. AB - PURPOSE: Increasing awareness about the importance of preventive dental care among low-income families has been considered to be key to overcoming nonfinancial access to care barriers for children. The purpose of this randomized, controlled trial was to measure the impact of postcard mailings on dental utilization by low-income children through a dental society program designed to increase access to dental care. METHODS: Five thousand eight hundred and seven low-income 2- to 4-year-olds were randomly assigned to 1 of 3 groups: (1) Group 1 (n=2,014) received postcards containing information on how to enroll in the Yakima County Access to Baby and Child Dentistry program; (2) Group 2 (n=2,014) received the enrollment information as well as additional information on the availability of fluoride varnish and the need to visit the dentist by the age of 1-year-old; and (3) Group 3 (n=1,779) did not receive postcards. RESULTS: Preventive services utilization rates were not different among the groups: 61% for Group 1, 62% for Group 2, and 60% for Group 3, although rates were high for a Medicaid population. CONCLUSIONS: Postcard mailings did not significantly increase utilization of preventive dental services. Other strategies to increase utilization of preventive oral health measures are needed. PMID- 23433619 TI - Impact of oral conditions on the quality of life of secondary schoolchildren in Nigeria. AB - PURPOSE: Oral health problems have been increasingly recognized as important factors causing a negative impact on daily performance and quality of life. The purpose of this study was to assess the impact of tooth extraction with no replacement, untreated fractured anterior teeth, malocclusion, dental restorations, and orthodontic braces on the quality of life in Nigerian schoolchildren. METHODS: A total of 197 9- to 17-year-old schoolchildren completed the Oral Health Impact Profile (OHIP) index/questionnaire. RESULTS: Students who had tooth extraction with no replacement and untreated fractured incisors had significantly higher mean OHIP scores for functional limitations, physical pain, psychological discomfort, physical, psychological, and social disabilities, and handicaps (P<.001) when compared to other groups and the control. The mean OHIP scores of students with features of malocclusion were significantly higher for functional limitations, psychological discomfort, and psychological disability compared to the control group (P<.001). CONCLUSIONS: Untreated dental problems had some negative impact on the quality of life on the 7 subscales of the OHIP. PMID- 23433620 TI - Dental needs and management of children with special health care needs according to type of disability. AB - PURPOSE: The purpose of this study was to investigate the dental needs and management of special health care needs children in Rio de Janeiro, Brazil, according to the type of disability. METHODS: Records of 428 0- to 19-year-old patients who received dental treatment at the Patients Special Care Needs Clinic (Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Universidade Federal do Rio de Janeiro) from 1996-2009 were analyzed. Information about the type of disability, use of medication, dental exam findings, management during treatment, dental treatment performed, and follow-up examinations were collected. Children were divided into 2 groups: those with medical conditions and those with intellectual disability. RESULTS: Patients with medical conditions used more medications and were older than those with intellectual disability. The most common dental treatments received were dental restorations (63%) and extractions (47%). There was no association between the type of disability and dental treatment needed. Children with intellectual disability were 3 times more likely to need general anesthesia and 7 times more likely to need physical restraint for dental care than the other group. CONCLUSIONS: Children with intellectual disability have a greater chance of requiring advanced management techniques during dental treatment. The development of effective oral health programs is recommended as well as a specific education program for their parents. PMID- 23433621 TI - Dental health in asthmatic children: a South Italy study. AB - PURPOSE: The purpose of this study was to examine the oral health status of children with mild intermittent or mild persistent asthma compared to healthy children. METHODS: A group of 124 asthmatic children was compared to 156 age matched healthy children. Bitewing radiographs were taken and clinical examinations were carried out to record caries prevalence, caries experience in both dentitions, periodontal health and dental enamel defects. RESULTS: Caries prevalence for asthmatic patients was 39% in the permanent dentition and 32% in the primary dentition. Healthy subjects presented 36% caries prevalence in the permanent dentition and 26% in the primary dentition. There was no statistically significant difference between the 2 groups in caries experience. The differences between asthmatic subjects and healthy subjects for periodontal health and enamel defects were not statistically significant either. CONCLUSIONS: Children affected by mild intermittent or mild persistent asthma do not seem to be more susceptible to oral diseases than healthy children. PMID- 23433622 TI - Dental Findings and Management in a Mucopolysaccharidosis Type IIIB Patient. AB - Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme a-N-acetylglucosaminidase. Affected subjects present developmental delay, attention deficit disorder, uncontrollable hyperactivity, and aggressive behavior, followed by progressive dementia and death in late adolescence. The purpose of this paper is to report the dental findings and treatment in a child with MPS IIIB. His primary molars and permanent mandibular incisors presented obliterated pulp chambers and root canals, which may be a clinical manifestation of this disorder. PMID- 23433623 TI - Torus palatinus in an infant: a case report. AB - The most significant exostoses of the human jaws are the torus palatinus and torus mandibularis. Torus palatinus has long been reported by various anthropological and anatomical studies. Even if it has no functional importance, it could interfere with oral functions. Although it has been the subject of numerous studies, torus palatinus is rarely reported in children. The purpose of this paper was to report a rare case of torus palatinus in a 11/2-year-old boy. PMID- 23433624 TI - Modified distal shoe appliance--fabrication and clinical performance. AB - When the primary second molar is prematurely lost, mesial movement and migration of the permanent first molar often occurs. This is one of the most difficult problems of the developing dentition confronted by pediatric dentists. Use of a space maintainer that will guide the permanent first molar into its normal position is indicated. In cases with bilateral premature loss of primary molars, the conventional design of distal shoe poses a variety of problems and, therefore, necessitates a customized design for the eruption guidance of permanent first molars. The purpose of this case report is to discuss an innovative design of a distal shoe appliance, which was used with good clinical results. PMID- 23433625 TI - A case report of green pigmentation in the permanent dentition. AB - Intrinsic green discoloration of teeth is an uncommon condition which mainly affects the primary dentition. Children can be teased about this, resulting in a loss of self-esteem and problems with social integration. The purpose of this paper was to present a case of green pigmentation in the permanent dentition caused by hyperbilirubinemia during infancy and an intermediate restorative approach to mask the esthetic deficiency arising from this. PMID- 23433626 TI - Esthetic and functional rehabilitation for oligodontia in the mixed dentition: case report. AB - Tooth agenesis can be considered the most common anomaly of craniofacial development in humans, with an estimated prevalence reaching up to 20% worldwide. Treatments for tooth agenesis include orthodontic space closure, use of fixed or removable dentures, and placement of dental implants. Some of these options may not be applicable to children in mixed dentition because they can prevent the normal development of facial bones. A multidisciplinary, staged approach considering the number, size, and development of the remaining teeth in the long term would be the most suitable treatment. The purpose of this paper is to describe a 5-year clinical follow-up of a case of oligodontia in a young female patient in mixed dentition. PMID- 23433627 TI - Macrodontia, shovel-shaped incisors, and multituberculism: probable Ekman Westborg-Julin trait. AB - Multiple macrodontia is a rare finding and is defined as a condition in which a tooth is significantly larger than normal. Macrodontia may occur as an isolated finding, part of a group of dental anomalies, or as a component of a syndrome with multiple oral and systemic manifestations. The purpose of this paper was to report a case of macrodontia affecting all permanent teeth and exhibiting shovel shaped maxillary and mandibular incisors and multituberculate molars and premolars. Some or all of this patient's characteristics have been reported in both males and females, with a ratio of 5:2. No inheritance pattern has been established, as these traits have generally occurred spontaneously. As more individuals are identified and as molecular techniques continue to advance, it is probable that a gene or genes responsible for macrodontia and the associated traits will be identified. PMID- 23433628 TI - 2012 index. PMID- 23433629 TI - Diabetes mellitus and incidence and mortality of kidney cancer: a meta-analysis. AB - BACKGROUND: Diabetes is associated with increased risk of a spectrum of cancers, but there are few meta-analyses on the association between diabetes and kidney cancer. We performed a meta-analysis of case-control studies and cohort studies to address the incidence and mortality of kidney cancer in diabetes. METHODS: Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: A total of 24 studies were included. We found that diabetes was significantly associated with increased risk of kidney cancer (RR=1.40, 95% CI=1.16 to 1.69), and the results were consistent between case-control and cohort studies. A slightly stronger positive relation was observed in women (RR=1.47, 95% CI=1.18 to 1.83) than in men (RR=1.28, 95% CI=1.10 to 1.48). Additional analyses indicated that the increased risk of kidney cancer was independent of alcohol consumption, body mass index (BMI)/obesity and smoking. However, there was no association between diabetes and mortality of kidney cancer (RR=1.12, 95% CI=0.99 to 1.20), without heterogeneity (P=0.419, I(2)=1.8%). CONCLUSIONS: Diabetes mellitus may increase the risk of kidney cancer in both women and men. PMID- 23433630 TI - [Ventricular perforation by pacemaker leads: diagnosis by computed tomography]. PMID- 23433631 TI - [Collateral transformation of the hepatic artery after liver transplantation]. PMID- 23433632 TI - Autochthonous strongyloidiasis, Bordeaux area, South-Western France. AB - Strongyloidiasis is a ubiquitous parasitic infection mostly endemic in tropical and subtropical regions, although sporadic autochthonous cases or sparse pockets have been reported in some areas of temperate regions. We report here the first, to our knowledge, autochthonous case diagnosed in the Arcachon basin in the coastal Aquitaine region of South-Western France. We failed to identify any recognized risk factor for transmission in this case of autochthonous infection occurring in a wealthy major tourist destination. PMID- 23433633 TI - Appropriate use of cardiovascular technology: 2013 ACCF appropriate use criteria methodology update: a report of the American College of Cardiology Foundation appropriate use criteria task force. PMID- 23433634 TI - Quantification of tackling demands in professional Australian football using integrated wearable athlete tracking technology. AB - OBJECTIVES: To describe and quantify the frequency, velocity and acceleration at impact during tackling in Australian football using a combination of video and athlete tracking technology. DESIGN: Quasi-experimental. METHODS: Data was collected from twenty professional Australian Football League players during four in-season matches. All tackles made by the player and those against the player were video-coded and time stamped at the point of contact and then subjectively categorised into low, medium and high intensity impact groups. Peak GPS and acceleration data were identified at the point of contact. Two-way analysis of variance was used to assess differences (p<0.05) between tackle type (made and against) and tackle intensity. RESULTS: A total of 173 tackles made and 179 tackles against were recorded. Significant differences were found between all tackle intensity groups. Peak velocity was significantly greater in high (19.5+/ 6.1 k mh(-1)) compared to medium (13.4+/-5.8 k mh(-1)) and low intensity (11.3+/ 5.0 k mh(-1)) tackles. Peak Player Load, a modified vector magnitude of tri-axial acceleration, was significantly greater in high (7.5+/-1.7 a.u.) compared to medium (4.9+/-1.5 a.u.) and low intensity (4.0+/-1.3 a.u.) tackles. CONCLUSIONS: High intensity tackles, although less frequent, are significantly greater in speed of movement immediately prior to contact and in the resultant impact acceleration compared to tackles of lower intensity. Differences in accelerometer data between tackles observed to be progressively greater in intensity suggest a level of ecological validity and provide preliminary support for the use of accelerometers to assess impact forces in contact invasion sports. PMID- 23433635 TI - Development and validation of the General Health Numeracy Test (GHNT). AB - OBJECTIVE: Because existing numeracy measures may not optimally assess 'health numeracy', we developed and validated the General Health Numeracy Test (GHNT). METHODS: An iterative pilot testing process produced 21 GHNT items that were administered to 205 patients along with validated measures of health literacy, objective numeracy, subjective numeracy, and medication understanding and medication adherence. We assessed the GHNT's internal consistency reliability, construct validity, and explored its predictive validity. RESULTS: On average, participants were 55.0 +/- 13.8 years old, 64.9% female, 29.8% non-White, and 51.7% had incomes <=$39K with 14.4 +/- 2.9 years of education. Psychometric testing produced a 6-item version (GHNT-6). The GHNT-21 and GHNT-6 had acceptable good internal consistency reliability (KR-20=0.87 vs. 0.77, respectively). Both versions were positively associated with income, education, health literacy, objective numeracy, and subjective numeracy (all p<.001). Furthermore, both versions were associated with participants' understanding of their medications and medication adherence in unadjusted analyses, but only the GHNT-21 was associated with medication understanding in adjusted analyses. CONCLUSIONS: The GHNT-21 and GHNT-6 are reliable and valid tools for assessing health numeracy. PRACTICE IMPLICATIONS: Brief, reliable, and valid assessments of health numeracy can assess a patient's numeracy status, and may ultimately help providers and educators tailor education to patients. PMID- 23433636 TI - Differentiating mTOR inhibitors in renal cell carcinoma. AB - PI3K/Akt/mTOR signalling is dysregulated in many cancers, including renal cell carcinoma (RCC), and activation of this pathway has been suggested to correlate with aggressive behavior and poor prognosis in RCC tumors. mTOR inhibition plays a principal role in the targeted treatment of many cancer types, including RCC. Although mTOR inhibitors share the same mechanism of action, differences in metabolism, formulation and dosing schedule underpin distinct PK/PD profiles such that they may be differentiated for use in a variety of treatment niches. Approved mTOR inhibitors temsirolimus and everolimus serve as important therapeutic options within the current RCC treatment paradigm, although their recommended applications differ in setting and patient population characteristics. Clinical practice guidelines recommend temsirolimus for use in treatment-naive patients with poor-prognosis metastatic RCC of any histology (predominant clear cell or non-clear cell histology). Everolimus provides a standard-of-care therapy for patients with metastatic RCC whose disease has progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. As therapeutic failure impacts the vast majority of patients with RCC, sequencing strategies of available agents or simultaneous targeting of multiple members of the PI3K/Akt/mTOR pathway may provide additional clinical benefit. Various classes of agents targeting the PI3K/Akt/mTOR pathway are currently being investigated, including mTORC1/mTORC2 kinase domain inhibitors, mTOR/PI3K dual inhibitors, PI3K-selective inhibitors, and programmed cell death 6 modulators. Clinical trials of mTOR inhibitors in a variety of tumor types are ongoing, and the role of mTOR inhibitors continues to evolve across the RCC treatment landscape. PMID- 23433637 TI - Robotic partial nephrectomy with selective parenchymal compression (Simon clamp). AB - OBJECTIVE: To present our initial experience using selective renal parenchymal ischemia, without hilar clamping, in robotic-assisted partial nephrectomy. MATERIAL AND METHODS: In four patients with T1a renal tumor we performed robotic assisted partial nephrectomy, using the Simon's clamp (Aesculap). It provides selective parenchymal compression without the need of vascular clamping. All patients had exofitic renal tumors in polar location. Renal parenchymal reconstruction was done as the standard technique. RESULTS: The median age was 49.6 years (42-59), 3 male and 1 female patient. Median operative time was 71,6 minutes (40-120). Mean stimated bleeding was 250 ml (50-400). Average tumor size was 3,25 cm (1,5-5,3). There were no complications and the average hospital stay was 3,5 days (1-7). The pathology was informed as renal cell carcinoma in three patients and one hemorrhagic cyst. The surgical margins were negative. CONCLUSION: Our preliminary results shows that selective renal parenchymal compression, with the Simon's clamp, provides an alternative to vascular control in selected patients with polar renal tumors. PMID- 23433638 TI - Nurturing the use of evolutionary diversity in nature conservation. PMID- 23433639 TI - Equipercentile linking of the BPRS and the PANSS. AB - The Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) are the most frequently used scales to rate the symptoms of schizophrenia. There are many situations in which it is important to know what a given total score or a percent reduction from baseline score of one scale means in terms of the other scale. We used the equipercentile linking method to identify corresponding scores of simultaneous BPRS and PANSS ratings in 3767 patients from antipsychotic drug trials. Data were collected at baseline and at weeks 1, 2, 4 and 6. BPRS total scores of 18, 30, 40 and 50 roughly corresponded to PANSS total scores of 31, 55, 73 and 90, respectively. An absolute BPRS improvement of 10, 20, 30, 40 points corresponded to a PANSS improvement of 15, 32, 50, and 67. A percentage improvement of the BPRS total score from baseline of 19%, 30%, 40% and 50% roughly corresponded to percentage PANSS improvement of 16%, 25%, 35%, and 44%. Thus a given PANSS percent improvement was always lower than the corresponding BPRS percent improvement, on the average by 4-5%. A reason may be the higher number of items used in the PANSS. These results are important for the comparison of trials that used these rating scales. We present a detailed conversion table in an online supplement. PMID- 23433640 TI - Gastrointestinal nematode infections in roe deer (Capreolus capreolus) from the NW of the Iberian Peninsula: assessment of some risk factors. AB - Intestinal contents of 218 roe deer hunted in the northwest (NW) of the Iberian Peninsula during the 2008-2009 hunting seasons were examined in order to provide information on the gastrointestinal (GI) nematode prevalence and intensity of infection and the possible influence of some environmental and intrinsic factors such as climatic conditions, age and sex. All the animals studied harboured GI nematodes, and a total of 20 different species belonging to ten genera were identified. Spiculopteragia spiculoptera/Spiculopteragia mathevossiani, Ostertagia leptospicularis/Ostertagia kolchida and Nematodirus filicollis were the most common. This is the first citation for Chabertia ovina, Cooperia pectinata, Cooperia punctata, Cooperia oncophora, Haemonchus contortus, Nematodirus spathiger, Oesophagostomum venulosum, Teladorsagia trifurcata, Trichostrongylus capricola, Trichostrongylus colubriformis, Trichostrongylus vitrinus and Trichuris capreoli in roe deer from the Iberian Peninsula. Prevalence and intensity were significantly higher in the abomasum, where infections with more than one GI nematode species were the most common; in the other intestinal segments infections with only one GI nematode species were the most prevalent. When considering the influence of the different risk factors on the prevalence of GI nematodes, the highest prevalence for most of the genera were observed in roe deer from coastal areas, where climatic conditions are more favourable for the development and survival of third stage larvae in the environment. Regarding the sex of the animals, the prevalence was, in general, higher in males than in females, probably due to behavioural and physiological sex-related differences. On the contrary, no differences were found in relation to the age of the animals. This study reveals that roe deer from the NW of the Iberian Peninsula are widely and intensely infected with gastrointestinal nematodes, which probably affect the health status of these ungulates. PMID- 23433641 TI - Proteomic analysis of the changed proteins of Trichinella spiralis infective larvae after co-culture in vitro with intestinal epithelial cells. AB - The purpose of this study was to determine the protein changes in Trichinella spiralis muscle larvae (ML) after in vitro co-culture with intestinal epithelial cells, and to analyze the changed proteins. Muscle larvae were incubated with HCT 8 cells for 18 h and the ML soluble proteins were analyzed by SDS-PAGE and Western blot. Results showed that seven additional protein bands (123, 77, 58, 36, 30, 28 and 21 kDa) were recognized by sera from infected mice after culture with HCT-8 cells. Three protein bands (97, 51 and 23 kDa) were not recognized by infection sera compared with proteins from ML incubated in RPMI-1640 medium only. Three bands (58, 36 and 21 kDa) were excised from gels, digested with trypsin, and identified by liquid chromatography and tandem mass spectrometry (LC-MS/MS) combined with bioinformatics. In total, 211 kinds of proteins were identified, and numerous enzymes (e.g. metallo- and serine proteases, cysteine proteinases) were found to be highly expressed. PMID- 23433642 TI - Extensively variable surface antigens of Sarcocystis spp. infecting Brazilian marsupials in the genus Didelphis occur in myriad allelic combinations, suggesting sexual recombination has aided their diversification. AB - Sarcocystis neurona and Sarcocystis falcatula are very similar species of Apicomplexan protozoa that use marsupials of the genus Didelphis as definitive hosts. These mammals can serve as definitive hosts not only for these two parasites, but for other Sarcocystis such as Sarcocystis speeri and Sarcocystis lindsayi. Sarcocystis shed by opossums (with the exception of S. neurona) can cause disease in a great variety of birds, being commonly associated with acute pulmonary sarcocystosis in zoos. S. neurona is the most commonly associated parasite with the equine protozoal myeloencephalitis in horses. Herein we assessed the variability of Sarcocystis spp. isolated from opossums of the state of Rio Grande do Sul, Brazil, by sequencing fragments of genes coding for glycosylphosphatidylinositol-anchored surface antigens (termed surface antigen or SAG), SAG2, SAG3 and SAG4. Two genetic groups were identified, one of them related to S. falcatula and the other related to S. neurona. Various allelic combinations of SAG2, SAG3 and SAG4 occur among S. falcatula related isolates and strong evidences suggest that such isolates may exchange high divergent alleles in possible sexual recombination processes. Regarding the group S. neurona-like (isolates G37 and G38), none of the individuals in this group share alleles with individuals of the other group. Comparing G37 and G38 strains and North American strains of S. neurona, four polymorphisms were identified at SAG-3, five at SAG-2 and three at SAG-4. Gene sequences of locus SAG-3 from isolates G37 and G38 differed from the other sequences by an insertion 81bp long. This insertion contains several dinucleotide repeats of AT, resembling a microsatellite locus and has already been detected in SAG3 sequences of S. neurona from North America. When aligned against North American strains of S. neurona, G37 and G38 isolates have a deletion of 8 nucleotides within this intron which indicate that S. neurona strains of South America are divergent from that of North America. From the results obtained so far, we have shown extensive variability in surface antigens coding sequences among Sarcocystis eliminated by mammals of the genus Didelphis spp. In addition, such divergent alleles may be exchanged in possible sexual recombination processes between different isolates of S. falcatula related isolate. The evolutionary relationships within S. falcatula related isolates will be best clarified after markers less subjected to selection pressures are analyzed in conjunction with surface antigen genes. These results may have a striking impact on the knowledge of the Sarcocystis species that infect opossums in Brazil and also in the epidemiology of the infections caused by these protozoans. PMID- 23433643 TI - Validation of a latex agglutination test for the detection of Trichinella infections in pigs. AB - An antigen detection kit (Trichin-L), based on latex agglutination and developed by the Bio-Rad company was validated at five European laboratories. The validation parameters included specificity, sensitivity, robustness and reproducibility. Specificity was evaluated by testing parasite antigens from five non-Trichinella parasites in addition to the Trichinella genus. To evaluate sensitivity, 10 pork samples spiked with 1, 3, 6 or 15 Trichinella larvae were tested in each laboratory. To evaluate the robustness of the test, the solubilized antigens were maintained at room temperature and tested at different times. Reproducibility was assessed in each laboratory using 40, 100g minced pork samples, each spiked with Trichinella spiralis. The use of larval homogenates obtained from the Trichin-L kit as a template for parasite identification at the species level by a multiplex PCR, was also evaluated. The results showed a high specificity and sensitivity where solubilized antigens maintained their stability and reactivity for up to three days. Reproducibility was high, as similar results were obtained in the five laboratories. The larval homogenates obtained using the Trichin-L kit were successfully used in multiplex PCRs to identify Trichinella species. PMID- 23433644 TI - Development of an ELISA to detect the humoral immune response to Trichinella zimbabwensis in Nile crocodiles (Crocodylus niloticus). AB - Crocodiles are known reservoir hosts of Trichinella papuae and Trichinella zimbabwensis, two zoonotic parasites that also infect mammals. Since commercial crocodile farming represents a key source of income in several countries, it is important to monitor this nematode infection in both farmed crocodiles and in breeding stocks which are frequently introduced from the wild. For this purpose, an indirect ELISA was developed to detect the anti-Trichinella immune response in crocodile sera. New Zealand rabbits were immunized with pooled sera from non infected farmed crocodiles in the presence of Freund's complete adjuvant. The anti-crocodile serum was then conjugated with horseradish peroxidase. Serum samples from four Nile crocodiles (Crocodylus niloticus) experimentally infected with T. zimbabwensis and from four uninfected crocodiles were used to set up the ELISA. The larval burden per gram of muscle tissue was determined by muscle biopsy. The test was performed on serum samples from an additional 15 experimentally infected crocodiles as well as eight wild Nile crocodiles. Among the 19 experimentally infected crocodiles, seroconversion was observed in 11 animals. The highest antibody response was observed six weeks post infection (p.i.), but in most of these animals, antibodies were not detectable after six weeks p.i. even though live larvae were present in the muscles up to six months p.i. PMID- 23433645 TI - Overwintering strategies of a population of anthelmintic-resistant Haemonchus contortus within a sheep flock from the United States Northern Great Plains. AB - Haemonchus contortus infections have been increasingly reported in ungulates from cold climates even though past studies have shown that the free-living juveniles from this species survive poorly under freezing conditions. Overwintering strategies of H. contortus have not been documented in the Unites States Northern Great Plains. A PCR survey identified H. contortus as vastly predominant trichostrongyle species present (in addition to occasional detections of Teladorsagia sp.) in a closed farm flock of sheep from Brookings County, SD. Benzimidazole (BZ) and avermectin (AV) anthelmintics had been used intensely for many years on this flock. During the autumn season, three fecal egg count reduction tests (doramectin, albendazole, and moxidectin) were performed over a 4 year span to assess drug effectiveness within the flock. Significant drug resistance was found in Haemonchus adults with doramectin (69% efficacy), marginal resistance was found with albendazole (90% efficacy) and no resistance was found in moxidectin (100% efficacy). The following spring, pre-lambing and post-lambing fecals were obtained from albendazole and moxidectin treatment years to assess the resistance of the tissue-dwelling fourth-stage juveniles (J4s) at those times. Albendazole treated pre-lambing fecals averaged only 4 EPG and treated post-lambing fecals increased to 454 EPG, indicating that many of the J4s were not killed during the autumn treatment. Moxidectin pre-lambing fecals averaged only 1 EPG, and post-lambing fecals only increased to 6 EPG in the treated moxidectin population and 1422 EPG in the untreated moxidectin population. In addition to evaluating the ability of H. contortus to overwinter as drug resistant tissue-dwelling J4s, this study also evaluated the overwintering ability of pasture-dwelling, free-living third-stage juveniles at this farm. In the summers of 2010 and 2011, naive tracer lambs were placed on a H. contortus contaminated pasture for 3 weeks to assess J3 winter survival. In 2010, tracer lambs only averaged 7 EPG whereas drylotted control lambs averaged 2 EPG; in 2011, tracer lambs averaged 2 EPG while the control lambs averaged 1 EPG. These results suggest that at this northern plains farm, yearly transmission of H. contortus is predominately through drug-resistant J4s. This is consistent with other cold-climate, overwintering studies involving H. contortus from Europe. PMID- 23433646 TI - Is Wolbachia participating in the bronchial reactivity of cats with heartworm associated respiratory disease? AB - Heartworm associated respiratory disease is a pulmonary syndrome in cats that results from the vascular and parenchymal inflammatory response associated with the arrival and death of Dirofilaria immitis worms into the distal pulmonary arteries. This parasite harbors intracellular Wolbachia, an endosymbiont bacteria. The association between the parasite and the bacteria is obligatory. Some studies suggest the involvement of Wolbachia in the development of the inflammatory reaction and in the polarization of the host immune response against the parasite. Barometric whole-body plethysmography is a non-invasive pulmonary function test that allows a dynamic study of breathing patterns and is useful to study airway disease and the response to different treatments. The aim of this prospective non-blinded study was to compare the influence of Wolbachia upon the respiratory function variables in a population of cats seropositive to D. immitis by use of Barometric whole-body plethysmography. Fourteen seropositive cats to Wolbachia and eight seronegative cats were put into the plethysmograph chamber and different respiratory variables were measured. The results were analyzed and compared between the two groups of animals. Significant differences were found for bronchoconstriction index variables PAU (pause) (P-value<0.05) and Penh (enhanced pause) (P-value<0.05). The results obtained in our study suggest that Wolbachia seems to produce a greater acute inflammatory response at bronchial, vascular and parenchymal level worsening the state of broncho-reactivity associated with the presence of seropositivity to D. immitis in cats. PMID- 23433647 TI - Prevalence of Tritrichomonas foetus infections in French catteries. AB - Recently, Tritrichomonas foetus, the known etiologic agent of bovine trichomonosis was identified in domestic cats in many countries around the world. In felids, this parasite would be a significant cause of large-bowel diarrhoea. Therefore the aim of the present study was to determine for the first time the prevalence of T. foetus infection in French catteries. In this epidemiological survey, rectal swabs from 140 cats participating in three international shows were tested for the presence of motile parasites by microscopy after culturing. The prevalence of T. foetus infection was 14.3% among cats (20/140) and 15.9% among catteries (18/117). These values were similar to those previously obtained in other European countries. Except for the age, no significant associations were found between the presence of T. foetus and various risk factors of infection such as the size of the cattery, the type of food, or the vicinity of a dog. Internal transcribed region of the ribosomal DNA unit was sequenced from the 20 T. foetus isolates identified in this study. They exhibited 100% identity and are homologous with other sequences of strains isolated from domestic cats in other countries. PMID- 23433648 TI - Protective immune response induced by co-immunization with the Trichinella spiralis recombinant Ts87 protein and a Ts87 DNA vaccine. AB - Ts87 is an immunodominant antigen that induces protective immunity against Trichinella spiralis larval challenge in mice. To determine if a combination of recombinant Ts87 protein and its coding DNA induces a stronger immune response in female C57BL/6 mice were immunized with 100 MUg of recombinant Ts87 protein plus its coding DNA cloned in vector pVAX1, or the same amount of recombinant protein or DNA only. Mouse subclass IgG responses showed that both co-immunized and single-immunized mice produced a balanced IgG2a/IgG1 (Th1/Th2) response. T-cell proliferation in co-immunized animals was significantly higher than in single immunized mice. Cytokine profiling in the co-immunization group showed a significant increase in the levels of IL-2, IL-4, IL-6 and IFN-gamma in the splenocytes of mice upon stimulation with the recombinant Ts87 protein; however, the expression of IL-17 was down-regulated. Challenge results showed that mice immunized with the recombinant Ts87 protein and its coding DNA produced reduced the muscle larval burden to a greater extent (43.8%) than the groups immunized with only the protein (39.7%) or the DNA (9.7%). A better Th1/Th2 immune response and consequent protection induced by co-immunization with the recombinant Ts87 protein and its coding DNA may result from an adjuvant effect of DNA and a specific persistent expression of Ts87. PMID- 23433649 TI - Surface associated antigens of Dirofilaria immitis adult worms activate the host fibrinolytic system. AB - Cardiopulmonary dirofilariosis (Dirofilaria immitis) is characterized by apparent contradictory events, like the long-term survival of adult worms in the circulatory system of the infected hosts and the development of life-threatening events like thromboembolisms and others. Thus parasite mechanisms, like the activation of fibrinolytic system, are key to the survival of both the worms and the host. The aim of this study was to investigate the interaction between D. immitis adult worms surface-associated antigens (DiSAA) and the fibrinolytic system of the host. We demonstrate that DiSAA extract is able to bind plasminogen and generate plasmin, with the latter occurring in a tissue plasminogen activator (t-PA) dependent manner. Additionally, 11 plasminogen-binding proteins from DiSAA extract were identified by proteomics and mass spectrometry (MS) (actin-5C, actin 1, enolase, fructose-bisphosphate aldolase, GAPDH, MSP domain protein, MSP 2, beta-galactosidase-binding-lectin, galectin, immunoglobulin I-set domain containing protein and cyclophilin Ovcyp-2). Because in a previous work we have shown the positive interaction between the excretory/secretory antigens of D. immitis (DiES) and the host fibrinolytic system and many of the molecules identified here are shared by both antigens, we hypothesize that DiSAA cooperate in host fibrinolytic system activation promoting the fibrin clot lysis. PMID- 23433650 TI - Protein changes in Trichinella spiralis muscle larvae in vitro induced by bovine bile. AB - The purpose of this study was to investigate bovine bile induced protein changes within Trichinella spiralis muscle larvae (ML) in vitro. The larvae were activated by 5% raw bovine bile diluted in saline and in serum-free RPMI-1640 medium at 37 degrees C in 5% CO2 for 2h and, respectively. The crude and excretory-secretory (ES) antigens from ML were analyzed by SDS-PAGE and Western blot. Following activation and comparison to blots of non-activated ML, blots of activated T. spiralis crude worm extract gave rise to three new protein bands (133, 125, and 26 kDa) when screened with mouse infection sera, and four new bands (125, 116, 80, and 29 kDa) when screened with sera from mice immunized with ES antigen. In the same screenings, a loss of two bands migrating at 106 and 25 kDa, and three bands migrating at 76, 58, and 16 kDa, respectively, was observed. When ES antigens from activated ML were blotted and compared to non-activated ML, four new bands (136, 39, 38, and 36 kDa) and seven new bands (136, 120, 100, 39, 36, 34, and 31 kDa) appeared when screened with infection sera and ES immune sera, respectively. In the same comparison, two bands migrating at 67 and 20 kDa, and ten bands migrating at 132, 112, 33, 32, 26, 23, 21, 19, 16, and 15 kDa, were no longer recognized by the ML infection sera and immune sera, respectively. The results showed that after the ML were activated by bile, their protein profiles changed. It is not yet clear if this change is related to the induction or loss of synthesized proteins, or to changes in the migration profiles of existing proteins as a result of post-translational modifications. PMID- 23433651 TI - Age-related changes in liver, kidney, and spleen stiffness in healthy children measured with acoustic radiation force impulse imaging. AB - OBJECTIVES: To evaluate the feasibility and age-related changes of shear wave velocity (SWV) in normal livers, kidneys, and spleens of children using acoustic radiation force impulse (ARFI) imaging. MATERIALS AND METHODS: Healthy pediatric volunteers prospectively underwent abdominal ultrasonography and ARFI. The subjects were divided into three groups according to age: group 1: <5 years old; group 2: 5-10 years old; and group 3: >10 years old. The SWV was measured using a 4-9 MHz linear probe for group 1 and a 1-4 MHz convex probe for groups 2 and 3. Three valid SWV measurements were acquired for each organ. RESULTS: Two hundred and two children (92 male, 110 female) with an average age of 8.1 years (+/- 4.7) were included in this study and had a successful measurement rate of 97% (196/202). The mean SWVs were 1.12 m/s for the liver, 2.19 m/s for the right kidney, 2.33 m/s for the left kidney, and 2.25 m/s for the spleen. The SWVs for the right and left kidneys, and the spleen showed age-related changes in all children (p<0.001). And the SWVs for the kidneys increased with age in group 1, and those for the liver changed with age in group 3. CONCLUSIONS: ARFI measurements are feasible for solid abdominal organs in children using high or low frequency probes. The mean ARFI SWV for the kidneys increased according to age in children less than 5 years of age and in the liver, it changed with age in children over 10. PMID- 23433652 TI - Is subcutaneous sumatriptan an effective treatment for adults presenting to the emergency department with acute migraine headache? PMID- 23433653 TI - Comparison of the unstructured clinician gestalt, the wells score, and the revised Geneva score to estimate pretest probability for suspected pulmonary embolism. AB - STUDY OBJECTIVE: The assessment of clinical probability (as low, moderate, or high) with clinical decision rules has become a cornerstone of diagnostic strategy for patients with suspected pulmonary embolism, but little is known about the use of physician gestalt assessment of clinical probability. We evaluate the performance of gestalt assessment for diagnosing pulmonary embolism. METHODS: We conducted a retrospective analysis of a prospective observational cohort of consecutive suspected pulmonary embolism patients in emergency departments. Accuracy of gestalt assessment was compared with the Wells score and the revised Geneva score by the area under the curve (AUC) of receiver operating characteristic curves. Agreement between the 3 methods was determined by kappa test. RESULTS: The study population was 1,038 patients, with a pulmonary embolism prevalence of 31.3%. AUC differed significantly between the 3 methods and was 0.81 (95% confidence interval [CI] 0.78 to 0.84) for gestalt assessment, 0.71 (95% CI 0.68 to 0.75) for Wells, and 0.66 (95% CI 0.63 to 0.70) for the revised Geneva score. The proportion of patients categorized as having low clinical probability was statistically higher with gestalt than with revised Geneva score (43% versus 26%; 95% CI for the difference of 17%=13% to 21%). Proportion of patients categorized as having high clinical probability was higher with gestalt than with Wells (24% versus 7%; 95% CI for the difference of 17%=14% to 20%) or revised Geneva score (24% versus 10%; 95% CI for the difference of 15%=13% to 21%). Pulmonary embolism prevalence was significantly lower with gestalt versus clinical decision rules in low clinical probability (7.6% for gestalt versus 13.0% for revised Geneva score and 12.6% for Wells score) and non-high clinical probability groups (18.3% for gestalt versus 29.3% for Wells and 27.4% for revised Geneva score) and was significantly higher with gestalt versus Wells score in high clinical probability groups (72.1% versus 58.1%). Agreement between the 3 methods was poor, with all kappa values below 0.3. CONCLUSION: In our retrospective study, gestalt assessment seems to perform better than clinical decision rules because of better selection of patients with low and high clinical probability. PMID- 23433654 TI - Diagnostic accuracy and use of nonmydriatic ocular fundus photography by emergency physicians: phase II of the FOTO-ED study. AB - STUDY OBJECTIVE: During the first phase of the Fundus Photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department study, 13% (44/350; 95% confidence interval [CI] 9% to 17%) of patients had an ocular fundus finding, such as papilledema, relevant to their emergency department (ED) management found by nonmydriatic ocular fundus photography reviewed by neuro-ophthalmologists. All of these findings were missed by emergency physicians, who examined only 14% of enrolled patients by direct ophthalmoscopy. In the present study, we evaluate the sensitivity of nonmydriatic ocular fundus photography, an alternative to direct ophthalmoscopy, for relevant findings when photographs are made available for use by emergency physicians during routine clinical care. METHODS: Three hundred fifty-four patients presenting to our ED with headache, focal neurologic deficit, visual change, or diastolic blood pressure greater than or equal to 120 mm Hg had nonmydriatic fundus photography obtained (Kowa nonmydriatic alpha-D). Photographs were placed on the electronic medical record for emergency physician review. Identification of relevant findings on photographs by emergency physicians was compared with a reference standard of neuro-ophthalmologist review. RESULTS: Emergency physicians reviewed photographs of 239 patients (68%). Thirty-five patients (10%; 95% CI 7% to 13%) had relevant findings identified by neuro ophthalmologist review (6 disc edema, 6 grade III/IV hypertensive retinopathy, 7 isolated hemorrhages, 15 optic disc pallor, and 1 retinal vascular occlusion). Emergency physicians identified 16 of 35 relevant findings (sensitivity 46%; 95% CI 29% to 63%) and also identified 289 of 319 normal findings (specificity 91%; 95% CI 87% to 94%). Emergency physicians reported that photographs were helpful for 125 patients (35%). CONCLUSION: Emergency physicians used nonmydriatic fundus photographs more frequently than they performed direct ophthalmoscopy, and their detection of relevant abnormalities improved. Ocular fundus photography often assisted ED care even when results were normal. Nonmydriatic ocular fundus photography offers a promising alternative to direct ophthalmoscopy. PMID- 23433655 TI - Effects of growth hormone treatment in adults with Prader-Willi syndrome. AB - OBJECTIVE: Since limited data exist on adults with Prader-Willi syndrome (PWS) and growth hormone (GH) treatment, we report our experience on the effects of treatment for one year on body composition, physical activity, strength and energy expenditure, diet, general chemistry and endocrine data with quality of life measures. DESIGN: We studied 11 adults with PWS (6F:5M; average age=32 yrs) over a 2 year period with GH treatment during the first year only. Electrolytes, IGF-I, glucose, thyroid, insulin, lipids, body composition, physical activity and strength, diet, energy expenditure and quality of life data were collected and analyzed statistically using linear modeling at baseline, at 12 months following GH therapy and at 24 months after treatment cessation for 12 months. RESULTS: Total lean muscle mass was significantly increased (p<0.05) during GH treatment along with moderate-vigorous physical activity and plasma IGF-I and HDL levels, but returned to near baseline after treatment. Percent body fat decreased during the 12 months of GH treatment but increased after treatment. CONCLUSIONS: Previously reported beneficial effects of GH treatment in children with PWS were found in our adults regarding body composition, physical activity and plasma HDL and IGF-I levels. Several beneficial effects diminished to near baseline after cessation of GH treatment for 12 months supporting the continuation of treatment in PWS into adulthood and possibly adults not previously treated during childhood. PMID- 23433656 TI - The effects of two weeks of recombinant growth hormone administration on the response of IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP) during a single bout of high resistance exercise in resistance trained young men. AB - OBJECTIVE: Recombinant human growth hormone (rhGH) is used by some athletes and body builders with the aim of enhancing performance, building muscle and improving physique. Detection of the misuse of rhGH has proved difficult for a number of reasons. One of these is the effect of preceding exercise. In this randomised, double blind placebo-controlled study, we determined the effects of rhGH administration in male amateur athletes on two candidate markers of rhGH abuse, IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP), following a bout of weightlifting exercise. DESIGN: Sixteen men entered a four week general weight training programme to homogenise their activity profile. They then undertook repeated bouts of standardised leg press weightlifting exercise (AHRET-acute heavy resistance exercise test). Blood samples were taken before and up to one hour after the AHRET. After the first laboratory visit (Test 1), the subjects were randomly assigned to receive daily injections of either rhGH (0.1 IU kg(-1) day(-1)) or placebo for two weeks. The AHRET was repeated after the two week dosing period (Test 2) and a further test was undertaken following a one week washout (Test 3). RESULTS: There was no effect of exercise on either IGF-I or P-III-NP in any test. Both markers were markedly elevated at Test 2 (p<0.001), with P-III-NP remaining elevated at Test 3 in the GH administration group (p<0.05). Application of the GH-2000 discriminant function positively identified GH administration in 17 of 40 blood samples taken at Test 2 from the rhGH group and none from the placebo group. CONCLUSION: The data show that rhGH results in elevated levels of IGF-I and P-III-NP in well-trained individuals and that leg press weightlifting exercise does not affect these markers. The GH-2000 discriminant function identified four of eight subjects taking rhGH with no false positive results. PMID- 23433657 TI - Lower than expected cytogenetic and molecular response to imatinib in Mexican patients with chronic myelogenous leukemia. AB - Imatinib has been considered as the gold standard for drug therapy of chronic myelogenous leukemia (CML) because it offers higher cytogenetic response and better quality of life than traditional drugs. In this study we applied the standard 400 mg dose of imatinib in 37 CML Ph (+) Mexican patients, monitoring their cytogenetic response using fluorescent in situ hybridization and carrying out molecular analyses using reverse transcription polymerase chain reaction. The study included 19 male and 18 female patients with a median age of 41 years. The median follow-up time from diagnosis was 56 months. Thirty-six patients (97%) achieved complete hematologic response in a median time of 29 days. Complete cytogenetic response and complete molecular remission was observed in only five (13%) and three (8.1%) patients, respectively, less than the expected rate (50 90%) reported in other studies. PMID- 23433658 TI - Percutaneous treatment of high-risk patients with intra-articular calcaneus fractures: a case series. AB - INTRODUCTION: Diabetics, smokers, patients with open fractures and drug addicts have shown to be at increased risk of having wound complications with traditional calcaneus fixation. The purpose of the study is to examine if high-risk patients with intra-articular calcaneus fractures can be managed safely using percutaneous reduction and fixation by examining a consecutive series of patients treated by the senior author. METHODS: The treatment group consisted of the senior author's first 17 percutaneously treated calcaneus fractures in high-risk patients. Risk factors included: open fracture, smoking, diabetes and cocaine, alcohol and solvent abuse. Reduction techniques included temporary external fixation, inflatable bone tamps, and arthroscopic assisted reduction manoeuvres. Fixation was accomplished with cannulated 4.5mm screws. Patients were followed up for 3 months minimum to look for wound complications and subsidence. RESULTS: Surgery was performed within 15 days from injury (average 6.7 days). Risk factors included: open fracture 1, smoking 16, diabetes 2, and substance abuse 9. Sanders' classification described: six type 2, nine type 3 and two type 4. Bohlers' angle increased from an average of -1.5 degrees (range -37 degrees to +30) to 25.8 degrees (range 7-36 degrees ). There were no wound issues or infections with the calcaneal fixation. Reduction was deemed excellent or good in 14, fair in 2 and poor in 1. Loss of Bohlers' angle of >4 degrees occurred in four cases; in three of these, the patients were non-compliant with weight bearing. CONCLUSION: High-risk patients with intra-articular calcaneus fractures that meet the criteria for surgical management can be managed with percutaneous surgical techniques with low risk of wound complications. PMID- 23433659 TI - Periarticular raft constructs and fracture stability in split-depression tibial plateau fractures. AB - OBJECTIVES: To evaluate relative fracture stability yielded by screws placed above a lateral plate, as well as locking and non-locking screws placed through a plate in a split depression tibia plateau fracture model. METHODS: Cadaver tibia specimens (mean age 74.1 years) were randomised across 3 groups: Groups 1: raft construct outside the plate, 2: non-locking raft screws through the plate, and 3: locking raft screws through the plate. Displacement of the depressed fragment was recorded with force values from 400N to 1600N in increasing 400N increments. The force required to elicit lateral plateau fragment displacement of 5mm, 10mm, and 15mm was also recorded. RESULTS: None of the mechanical testing results demonstrated statistical significance with p-values of <0.05. Cyclic testing of Groups 1, 2, and 3 at 400N revealed displacements of 0.54mm, 0.64mm, and 0.48mm, respectively. At 800N, displacements were 1.36mm, 1.4mm, and 1.4mm, respectively. At 1200N, displacements were 2.4mm, 1.9mm, and 2.1mm, respectively. At 1600N, displacements were 2.8mm, 2.5mm, and 2mm, respectively. Resistance to displacement data demonstrated the mean force required to displace the fracture 5mm in Groups 1, 2, and 3 were 250N, 330N, and 318N, respectively. For 10mm of displacement, forces required were 394N, 515N, and 556N, respectively. For 15mm of displacement, forces required were 681N, 853N, and 963N, respectively. Compared to combined groups using screws through the plate, Group 1 demonstrated lower displacement <=800N, but demonstrated greater displacement >800N. Group 2 demonstrated greatest resistance to plateau displacement of 5mm compared to Group 1 or 3, while Group 3 was most resistant to greater displacement. The combined group using screws through the plate (Groups 2+3) was consistently more resistant than Group 1 at all levels of displacement. CONCLUSIONS: Designs utilising screws through the plate trended towards statistically significant improved stability against plateau displacement relative to utilising screws outside the plate. Our study also suggests that there is no significant benefit of locking screws over non-locking screws in this unicondylar tibia plateau fracture model. PMID- 23433660 TI - Appendicular joint dislocations. AB - This study defines the incidence and epidemiology of joint dislocations and subluxations of the appendicular skeleton. All patients presenting acutely to hospital with a dislocation or subluxation of the appendicular skeleton from a defined population were included in the study. There were 974 dislocations or subluxations over one year between the 1st November 2008 and the 31st October 2009. There was an overall joint dislocation incidence of 157/10(5)/year (188/10(5)/year in males and 128/10(5)/year in females). Males demonstrated a bimodal distribution with a peak incidence of 446/10(5)/year at 15-24 years old and another of 349/10(5)/year in those over 90 years. Females demonstrate an increasing incidence from the seventh decade with a maximum incidence of 520/10(5)/year in those over 90 years. The most commonly affected joints are the glenohumeral (51.2/10(5)/year), the small joints of the hand (29.9/10(5)/year), the patellofemoral joint (21.6/10(5)/year), the prosthetic hip (19.0/10(5)/year), the ankle (11.5/10(5)/year), the acromioclavicular joint (8.9/10(5)/year) and the elbow (5.5/10(5)/year). Unlike fractures, dislocations are more common in the both the most affluent and the most socially deprived sections of the population. Joint disruptions are more common than previously estimated. PMID- 23433661 TI - The UK military experience of thoracic injury in the wars in Iraq and Afghanistan. AB - INTRODUCTION: Thoracic injury during warfare is associated with a high incidence of morbidity and mortality. This study examines the pattern and mortality of thoracic wounding in the counter-insurgency conflicts of Iraq and Afghanistan, and outlines the operative and decision making skills required by the modern military surgeon in the deployed hospital setting to manage these injuries. METHODS: The UK Joint Theatre Trauma Registry was searched between 2003 and 2011 to identify all patients who sustained battle-related thoracic injuries admitted to a UK Field Hospital (Role 3). All UK soldiers, coalition forces and local civilians were included. RESULTS: During the study period 7856 patients were admitted because of trauma, 826 (10.5%) of whom had thoracic injury. Thoracic injury-related mortality was 118/826 (14.3%). There were no differences in gender, age, coalition status and mechanism of injury between survivors and non survivors. Survivors had a significantly higher GCS, Revised Trauma Score and systolic blood pressure on admission to a Role 3 facility. Multivariable regression analysis identified admission systolic blood pressure less than 90, severe head or abdominal injury and cardiac arrest as independent predictors of mortality. CONCLUSIONS: Blast is the main mechanism of thoracic wounding in the recent conflicts in Iraq and Afghanistan. Thoracic trauma in association with severe head or abdominal injuries are predictors of mortality, rather than thoracic injury alone. Deploying surgeons require training in thoracic surgery in order to be able to manage patients appropriately at Role 3. PMID- 23433662 TI - A supplementary study from China: the use of pain medications after operative treatment of an ankle fracture. PMID- 23433663 TI - [Testicular torsion in children: Factors influencing delayed treatment and orchiectomy rate]. AB - INTRODUCTION: Acute scrotal pain is a true surgical emergency as patients presenting with acute scrotal pain may suffer from spermatic cord torsion and gonadal loss. We assessed whether the type of consultation (first consultation in our center or secondary transfer from a peripheral hospital or primary care practice), distance from home to hospital, and duration of pain had an impact on the orchiectomy rate. PATIENTS AND METHODS: We retrospectively reviewed the medical records of all patients under 15years of age suffering from acute scrotal pain who had surgical exploration between January 2007 and January 2010 in our center. Patient demographics, transfer status, time to consultation in our center, time to surgery, operative findings and clinical outcome were reviewed. RESULTS: Of the 76 patients with acute scrotal pain in whom surgical exploration was performed, 59 had acute spermatic cord torsion, 16 had torsion of the testicular appendage, and 1 had orchitis. In patients with acute spermatic cord torsion, the median age was 13 years (range: 0.18-14.97). In patients with acute spermatic cord torsion, 32 came straight to our center (direct admission group, 54.2%), and 27 (45.8%) came after a prior consultation out of side the center (transfer group). The median journey was 19km (range: 2.5-113) in the direct admission group and 44km (range: 2.5-393) in the transfer group (P=0.0072). The median time between pain onset and consultation at our center was 4.3h (range: 0.5-48) in the direct admission group, and 11h (range: 2-48) in the transfer group (P=0.6139). The median time between admission at our center and surgery was 2.5h, with no difference between the 2 groups (P=0.8789). The orchiectomy rate was 25% in the direct admission group and 14.8% in the transfer group (P=0.5177). In children who underwent orchiectomy, the duration of pain was consistently over 6h. The duration of pain was greater in patients with orchiectomy (12h [range: 1 72]) than in patients without orchiectomy (12h [range: 6-48]; P=0.0001). CONCLUSION: In this study, the orchiectomy rate depended on the duration of pain but not on transfer status. Acute scrotal pain must lead to surgical exploration as soon as possible, requiring close collaboration between peripheral hospitals, primary care physicians, and referral centers. PMID- 23433664 TI - [Adequation of thromboprophylaxis during former admission in patients attended in emergencies with thromboembolic disease]. PMID- 23433665 TI - Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors. AB - BACKGROUND AND OBJECTIVES: Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the response, and to analyze the effect of second-generation TKI on their outcome. PATIENTS AND METHODS: The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed. RESULTS: ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n=4), dasatinib (n=2), interferon (n=1) or hematopoietic stem cell transplantation (n=2). CONCLUSION: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients. PMID- 23433667 TI - Stereoselective synthesis of a new class of potent and selective inhibitors of human Delta8,7-sterol isomerase. AB - Starting from Grundmann's ketone a new chemotype of inhibitors of the post squalene part of cholesterol biosynthesis was developed. Stereoselective introduction of an angular methyl group at C-3a, followed by a plethora of functionalisations at C-4 and C-5 led to cis-configured amino alcohols as a new chemotype of inhibitors of cholesterol biosynthesis. In cell-based screening systems these compounds were identified to be selective inhibitors of human Delta8,7-sterol isomerase, inhibiting total cholesterol biosynthesis with IC50 values in the low nanomolar range. The most active compounds did not affect fungal Delta8,7-sterol isomerase (in ergosterol biosynthesis), neither showed noteworthy antimicrobial and cytotoxic effects. PMID- 23433666 TI - [The condition of the cardiovascular prevention in Spain]. AB - BACKGROUND AND OBJECTIVE: In Spain, where cardiovascular diseases are the leading cause of death, control of their risk factors is low. This study analyzes the implementation of cardiovascular risk (CVR) assessment in clinical practice and the existence of control objectives amongst quality care indicators and professional incentive systems. METHOD: Between 2010 and 2011, data from each autonomous community were collected, by means of a specific questionnaire concerning prevalence and control of major CVR factors, CVR assessment, and implementation of control objectives amongst quality care indicators and primary care incentive systems. RESULTS: Fifteen out of 17 autonomous communities filled in the questionnaire. CVR was calculated through SCORE in 9 autonomous communities, REGICOR in 3 and Framingham in 3, covering 3.4 to 77.6% of target population. The resulting control of the main CVR factors was low and variable: hypertension (22.7-61.3%), dyslipidemia (11-45.1%), diabetes (18.5-84%) and smoking (20-50.5%). Most autonomous communities did not consider CVR assessment and control amongst quality care indicators or incentive systems, highlighting the lack of initiatives on lifestyles. CONCLUSIONS: Variability exists in cardiovascular prevention policies among autonomous communities. It is necessary to implement a common agreed cardiovascular prevention guide, to encourage physicians to implement CVR in electronic clinical history, and to promote CVR assessment and control inclusion amongst quality care indicators and professional incentive systems, focusing on lifestyles management. PMID- 23433669 TI - Peripherally acting novel lipo-endomorphin-1 peptides in neuropathic pain without producing constipation. AB - We previously described two novel analogues of endomorphin-1 (Tyr-Pro-Trp-Phe NH2, 1), modified with an 8-carbon lipoamino acid (C8LAA) with or without replacement of Tyr(1) with 2,6-dimethyltyrosine (Dmt) at the N-terminus of the peptide (compounds 3 and 4, respectively). They were shown to be more stable and permeable, and acted as potent MU-opioid receptor agonists. In this study we report that the C8LAA modification resulted in successful systemic delivery of both analogues. They produced potent dose-dependent pain relief in a chronic constriction injury-rat model of neuropathic pain after intravenous administration with ED50 values obtained at 6.58 (+/-1.22) MUmol/kg for 3 and 6.18 (+/-1.17) MUmol/kg for 4. Using two different rat models of constipation that assess the effects of MU-opioid receptor agonists on stool hydration and gastro-intestinal motility, compound 3 produced insignificant constipation at 16 MUmol/kg, whereas morphine elicited significant constipation at 2 MUmol/kg. Compound 3 in contrast to morphine, did not attenuate the hypercapnic ventilatory response at 5 MUmol/kg, a dose that fully alleviated hindpaw sensitivity at the time of peak effect in CCI-rats. This finding revealed the lack of respiratory depression effect at antinociceptive dose. PMID- 23433668 TI - Novel inhibitors of bacterial virulence: development of 5,6 dihydrobenzo[h]quinazolin-4(3H)-ones for the inhibition of group A streptococcal streptokinase expression. AB - Resistance to antibiotics is an increasingly dire threat to human health that warrants the development of new modes of treating infection. We recently identified 1 (CCG-2979) as an inhibitor of the expression of streptokinase, a critical virulence factor in Group A Streptococcus that endows blood-borne bacteria with fibrinolytic capabilities. In this report, we describe the synthesis and biological evaluation of a series of novel 5,6 dihydrobenzo[h]quinazolin-4(3H)-one analogs of 1 undertaken with the goal of improving the modest potency of the lead. In addition to achieving an over 35 fold increase in potency, we identified structural modifications that improve the solubility and metabolic stability of the scaffold. The efficacy of two new compounds 12c (CCG-203592) and 12k (CCG-205363) against biofilm formation in Staphylococcus aureus represents a promising additional mode of action for this novel class of compounds. PMID- 23433671 TI - 3D co-culturing model of primary pancreatic islets and hepatocytes in hybrid spheroid to overcome pancreatic cell shortage. AB - Here, a spheroidal 3D co-culture model of primary (rat) pancreatic islets and hepatocytes with uniform size and shape was developed using hemispheric concave microwell arrays. We conducted morphological and functional analyses of hybrid spheroids versus mono-cultures of islets or hepatocytes (controls). For the establishment of a 3D hybrid model, a broad range of cell ratios - 1:1, 1:3, 1:5, 1:7, 3:1, 5:1 and 7:1 mixture - of hepatocytes and pancreatic islets were used. As control, each hepatocyte and pancreatic islet were mono-cultured forming 3D spheroids. The transient morphology of spheroid formation in 9 culture models was observed using optical microscopy. Cell viability under these culture environments was assessed, and the morphologies of the outer and inner porous cell-spheroid structures were investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and imaging of stained spheroid sections. The pancreatic islet-specific function of hybrid spheroids was evaluated by measuring insulin secretion and in vivo test by xenotransplantation of encapsulated spheroids in microfibers with a consistent maintenance of normal blood glucose levels over 4 weeks, while liver-specific functions were measured in terms of albumin secretion, urea secretion and cytochrome P450 activity. These diverse observations and evaluations validated the positive and bidirectional effects of co-cultured 3D spheroids. The proposed 3D co-culture model demonstrated that both cells appeared to support each other's functions strongly in spheroids, even though smaller proportions of each cell type was evaluated compared to mono-culture models, suggesting that the proposed model could help overcome the problem of cell shortages in clinical applications. PMID- 23433670 TI - Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. AB - Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia. PMID- 23433672 TI - Induced apoptosis of osteoblasts proliferating on polyhydroxyalkanoates. AB - The mechanism study on behaviors of cells influenced by biomaterial surface properties can provide profound guidances for functional tissue engineering scaffolds design. In this study, regulation of integrin-mediated cell-substrate interactions using rat osteoblasts incubated on PHA films was investigated. Compared with tissue culture plate (TCP), poly-3-hydroxybutyrate (PHB), copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) and copolymer of 3 hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx), osteoblasts inoculated on a terpolymer of 3-hydroxybutyrate, 3-hydroxyvalerate and 3-hydroxyhexanoate (PHBVHHx) were found to have higher apoptosis rates. Several integrin subunits in osteoblasts grown on PHBVHHx showed altered expressions. Simultaneously, extracellular matrics (ECM) were also remodeled on the material surface. Osteoblasts showed a higher expression of integrin subunit beta3 and alphav on PHBVHHx films compared with that on TCP. On the other hand, less vitronectin, osteopontin and fibronectin, the main ligands for integrin beta3 were expressed and deposited in ECM. The unligated integrin beta3 could recruit caspase-8 to the membrane and activate its downstream signaling which was proven by the caspase-8 activation assay. It was therefore concluded that the induced apoptosis of osteoblasts on PHBVHHx was regulated by recruitment of caspase-8 to the unligated integrin beta3. PMID- 23433673 TI - Bereaved parents' intentions and suggestions about research autopsies in children with lethal brain tumors. AB - OBJECTIVE: To determine bereaved parents' perceptions about participating in autopsy-related research and to elucidate their suggestions about how to improve the process. STUDY DESIGN: A prospective multicenter study was conducted to collect tumor tissue by autopsy of children with diffuse intrinsic pontine glioma. In the study, parents completed a questionnaire after their child's death to describe the purpose for, hopes (ie, desired outcomes of), and regrets about their participation in autopsy-related research. Parents also suggested ways to improve autopsy-related discussions. A semantic content analytic method was used to analyze responses and identify themes within and across parent responses. RESULTS: Responses from 33 parents indicated that the main reasons for participating in this study were to advance medical knowledge or find a cure, a desire to help others, and choosing as their child would want. Parents hoped that participation would help others or help find a cure as well as provide closure. Providing education/anticipatory guidance and having a trusted professional sensitively broach the topic of autopsy were suggestions to improve autopsy discussions. All parents felt that study participation was the right decision, and none regretted it; 91% agreed that they would make the choice again. CONCLUSION: Because autopsy can help advance scientific understanding of the disease itself and because parents reported having no regret and even cited benefits, researchers should be encouraged to continue autopsy-related research. Parental perceptions about such studies should be evaluated in other types of pediatric diseases. PMID- 23433674 TI - Perfusion-weighted cranial MR imaging findings in a patient with hemophagocytic lymphohistiocytosis. PMID- 23433675 TI - Dentate nuclei and Wernicke's encephalopathy. PMID- 23433676 TI - Anatomical variations of the anterior cerebral arterial circle visualized by multidetector computed tomography angiography: comparison with 3D rotational angiography. AB - OBJECTIVES: Multidetector computed tomography angiography (MD-CTA) has become the first-line screening technique for patients with subarachnoid hemorrhage not only for detecting aneurysms, but also for providing decisive angioarchitectural information. The anterior cerebral arterial circle (ACAC) is the most common location for anatomical variations and aneurysms. The aim of this study was to assess the diagnostic performance of 64-section MD-CTA in the detection and characterization of anatomical variations of the ACAC compared with three dimensional rotational angiography (3DRA). MATERIAL AND METHODS: In 104 patients, MD-CTA and 3DRA images of the internal carotid arteries were independently reviewed by two radiologists for variations, focusing on four arterial segments of the ACAC: the anterior communicating artery (ACoA); the A1 segments; the A2-A4 complexes; and the M1 segments. The percentages of variations detected by MD-CTA and 3DRA were compared using the chi-square test. Characterizations of the variations by MD-CTA compared with 3DRA were evaluated using the kappa statistic. RESULTS: A total of 114 variations in 624 segments (18.3%) were detected by MD CTA compared with 90 variations in 453 segments (19.9%) by 3DRA. The difference was not significant (P=0.56). In 453 selected segments analyzed with both techniques, 15 discordances in characterization were noted, mostly in the ACoA (10/15). However, the overall intertechnical kappa was excellent. Sensitivity, specificity, positive predictive values and negative predictive values were all greater than 90%. CONCLUSION: The overall diagnostic performance of MD-CTA in detecting anatomical variations of the ACAC was excellent compared with 3DRA. However, its lower spatial resolution led to misclassifications, especially in the ACoA. PMID- 23433677 TI - Combined Angio-SealTM and stenting rescue treatment in a case of iatrogenic common carotid artery dissection during direct puncture for ruptured intracranial aneurysm embolization: a technical note. AB - BACKGROUND AND IMPORTANCE: Direct puncture may offer an alternative access for embolization of intracranial aneurysms in patients presenting with tortuous vessels. Nevertheless, major complications such as compressive hematoma and arterial dissection can occur with this technique. CLINICAL PRESENTATION: A tight common carotid artery (CCA) dissection was seen secondary to direct puncture in a 72-year-old patient who presented with a ruptured anterior communicating artery (ACom) aneurysm. After regular coiling of the aneurysm and using a femoral approach, an Angio-SealTM device (St Jude Medical, Saint Paul, MN, USA) was placed and a carotid wallstent (Stryker Neurovascular, Fremont, CA, USA) successfully deployed at the dissected CCA, which was followed by good clinical and angiographic outcomes. CONCLUSION: A combined rescue technique combining Angio-Seal insertion and stent deployment was safe and effective for managing iatrogenic carotid artery dissection. PMID- 23433678 TI - Spina bifida manifesta: tethered cord syndrome with pilonidal sinus in a 4-month old baby. PMID- 23433679 TI - Synthesis, characterization and X-ray structural studies of four copper (II) complexes containing dinuclear paddle wheel structures. AB - BACKGROUND: Various dinuclear copper (II) complexes with octahedral geometry have been reported. The majority of these complexes contain N containing aromatic rings as axial ligands. There are also a few cases where the solvent used in the reaction occupies the axial position of the dinuclear copper (II) complex. This may occur by planned synthesis or some times by serendipity. Here we report some four copper (II) complexes containing solvent and or N containing heterocyclic ring as the axial ligand. RESULTS: Four compounds, each containing dinuclear Copper (II) units (with the most robust, frequently occurring paddle wheel structures) were synthesized and characterised by single crystal X-ray diffraction and by IR spectroscopy. The compounds 1 & 2 have the general formula Cu2(RCOO) 4(L)2 [(for (1) RCOO= 4-Chloro Benzoate, L= Isopropanol; for 2 RCOO= Benzoate, L= 2-Amino-4,6-dimethyl pyrimidine )] while 3 & 4 have the general formula, Cu2(RCOO) 4(S)2 Cu2(RCOO) 4(L)2 [RCOO=5-Chloro-thiophene-2-carboxylate L= 2-Amino-4,6-dimethyl pyrimidine, for 3 S= ethanol; for 4 S= methanol ]. A wide range of hydrogen bonds (of the O-H...O, N-H...O and N-H...N type) and pi-pi stacking interactions are present in the crystal structures. CONCLUSIONS: All compounds contain the dinuclear units, in which two Cu (II) ions are bridged by four syn, syn-eta1:eta1:MU carboxylates, showing a paddle-wheel cage type with a distorted octahedral geometry. The compounds 1 &2 contain a single dimeric unit while 3 &4 contain two dimeric units. The structures 3 and 4 are very interesting co-crystals of two paddle wheel molecules. Also it is interesting to note that the compounds 3 &4 are isostructural with similar cell parameters. Both the compounds 3 &4 differ in the solvent molecule coordinated to copper in one of the dimeric units. In all the four compounds, each of the copper dimers has an inversion centre. Every copper has a distorted octahedral centre, formed by four oxygen atoms (from different carboxylate) in the equatorial sites. The two axial positions are occupied by copper and the corresponding ligand. PMID- 23433680 TI - WHO recommendations for misoprostol use for obstetric and gynecologic indications. AB - BACKGROUND: Misoprostol, a prostaglandin E1 analog, stimulates uterine contractility and cervical ripening. A number of randomized trials and systematic reviews have evaluated its use in obstetric and gynecologic conditions. Misoprostol is inexpensive, stable at room temperature, and available in more than 80 countries, making it particularly useful in resource-poor settings. WHO recognizes the crucial role of misoprostol in reproductive health and has incorporated recommendations for its use into 4 reproductive health guidelines focused on induction of labor, prevention and treatment of postpartum hemorrhage, and management of spontaneous and induced abortion. METHODS AND RESULTS: All guidelines were prepared in accordance with the WHO Handbook for Guideline Development. The process included: identification of priority questions and critical outcomes; retrieval of evidence; assessment and synthesis of evidence; formulation of recommendations; and planning for dissemination, implementation, impact evaluation, and updating. The present report summarizes recommendations for misoprostol use in line with each guideline. CONCLUSION: The present comprehensive reference document was designed to enable clinicians and policy makers to quickly access and compare recommendations for the use of misoprostol in various reproductive health settings. PMID- 23433681 TI - Virulent feline calicivirus disease in a shelter in Italy: a case description. AB - Feline calicivirus (FCV) is a common pathogen of cats that is particularly widespread in multi-cat environments such as shelters and catteries. FCV infections are usually associated with acute, mild and self-limiting upper respiratory tract disease characterized by oral vesicles/ulcers. Recently, virulent systemic disease (VSD) associated with FCV infection has been reported in the USA and Europe. This paper describes a case of VSD affecting one adult, FIV infected cat ("Oscar") living in a shelter located in Northern Italy; the clinical, post-mortem and laboratory findings indicate that this is the first case of suspected FCV-VSD in this country. Similar to a previous report (Meyer et al., 2011), the disease affected only one cat, while others remained asymptomatic, despite their direct contact with "Oscar". Phylogenetic analysis identified unique features in the "Oscar" FCV isolate. The FIV infection of the patient might have favoured the generation of the virulent FCV strains in this cat. PMID- 23433682 TI - Chicken erythrocytes respond to Toll-like receptor ligands by up-regulating cytokine transcripts. AB - Avian erythrocytes are nucleated cells of myeloid origin that are able to actively transcribe and translate proteins. Although their role in gas exchange and transportation has been well described, it has recently been shown that chicken erythrocytes produce cytokines in response to Toll-like receptor (TLR) ligands, which raises the possibility that they also contribute to host immunity. To this end, the objective of the study was to gain some further insight into the immunological role of erythrocytes by identifying the repertoire of TLRs that they express and to elucidate their responses to the TLR3 and TLR21 ligands poly I:C and CpG oligodeoxynucleotide (ODN), respectively. The results suggest that erythrocytes constitutively express transcripts for TLRs 2, 3, 4, 5, and 21, as well as for many immunological genes including type I interferons (IFN) and interleukin (IL)-8. Moreover, it was found that treatment with both poly I:C and CpG ODN up-regulated transcripts for type I IFNs, while only poly I:C up regulated IL-8 transcripts and enhanced the production of nitrite. Future studies may be aimed at further characterizing the immunological role of erythrocytes. PMID- 23433683 TI - Expression patterns of porcine Toll-like receptors family set of genes (TLR1-10) in gut-associated lymphoid tissues alter with age. AB - The aim was to study the expression pattern of the porcine TLR family (TLR1-10) genes in gut-associated lymphoid tissues (GALT) of varying ages. A total of nine clinically healthy pigs of three ages group (1 day, 2 months and 5 months old) were selected for this experiment (three pigs in each group). Tissues from intestinal mucosa in stomach, duodenum, jejunum and ileum and mesenteric lymph node (MLN) were used. mRNA expression of TLRs (1-10) was detectable in all tissues and TLR3 showed the highest mRNA abundance among TLRs. TLR3 expression in stomach, and TLR1 and TLR6 expression in MLN were higher in adult than newborn pigs. The western blot results of TLR2, 3 and 9 in some cases, did not coincide with the mRNA expression results. The protein localization of TLR2, 3 and 9 showed that TLR expressing cells were abundant in the lamina propria, Peyer's patches in intestine, and around and within the lymphoid follicles in the MLN. This expressions study sheds the first light on the expression patterns of all TLR genes in GALT at different ages of pigs. PMID- 23433684 TI - Identification of a 43-kDa outer membrane protein of Fusobacterium necrophorum that exhibits similarity with pore-forming proteins of other Fusobacterium species. AB - A pair of primers was designed in an attempt to amplify outer membrane protein (OMP) gene of Fusobacterium necrophorum based on nucleotide sequence of the OMP of Fusobacterium nucleatum. Further analysis was performed to characterize its molecular properties and phylogeny in the genus Fusobacterium. We identified a predicated 43kDa outer membrane protein (43K OMP) in F. necrophorum, which showed the same properties as other pore-forming proteins of Gram-negative anaerobic bacteria according to analysis of signal peptide, AT-rich, membrane-spanning region and conserved motifs. The predicated 43K OMP exhibited 70.22%, 62.04%, 56.75%, 58.72%, 51.59%, 31.49% and 50.26% amino acid identity with the OMPs of F. nucleatum, Fusobacterium varium, Fusobacterium ucerans, Fusobacterium periodonticum, Fusobacterium mortiferum, Fusobacterium gonidiaformans and F. necrophorum (hypothetical protein), respectively. 11 common conserved domains and 10 common variable domains were found among the 45 aligned OMPs of Fusobacterium species. Distributions of the conserved and variable domains were highly associated with predicted membrane-spanning regions, cell surface exposed regions and B-cell epitope regions. Phylogenetic analysis revealed the predicated 43K OMP of F. necrophorum was closely related with the OMPs from F. nucleatum and F. periodonticum. These data will increase understanding of pathogenesis and genetic evolution of F. necrophorum. PMID- 23433685 TI - Modelling medical care usage under medical insurance scheme for urban non-working residents. AB - This research investigates and evaluates China's urban medical care usage for non working residents using microsimulation techniques. It focuses on modelling medical services usage and simulating medical expenses on hospitalization treatments as well as clinic services for serious illness in an urban area for the period of 2008-2010. A static microsimulation model was created to project the impact of the medical insurance scheme. Four kinds of achievements have been made. For three different scenarios, the model predicted the hospitalization services costs and payments, as well as the balance of the social pool fund and the medical burden on families. PMID- 23433686 TI - Quality control of elective surgery for drug-resistant epilepsy in a German reference centre--a long-term outcome study. AB - PURPOSE: Resective epilepsy surgery is the recommended treatment for a well defined group of patients with drug-resistant epilepsy. Long-term outcome studies are an appropriate quality control to assess the value of elective surgical procedures ethically and economically. This paper reports the long-term post surgical follow-up of adult patients of the Kork Epilepsy Centre. METHOD: Data collection was performed by means of a questionnaire to obtain updated information about postsurgical outcome, frequency and postsurgical seizure semiology in case of relapse, postsurgical use of antiepileptic drugs, social issues and satisfaction rates. We classified seizure outcome according to the ILAE surgery outcome scale (OC 1-OC 6). RESULTS: Outcome data of 340 adult patients were obtained. Mean post-operative follow-up was 6.7 years (range 1.0 21.6 years). Seizure remission was 67% if comprising patients with postoperative auras only (OC 1+OC 2). Sixty-two per cent of patients were completely seizure free. The majority of patients (78%) underwent temporal lobe resections. Sixty four per cent of these and 52% of the patients with extra-temporal resections became completely seizure-free (OC 1). Only 34% of the patients with negative MRI achieved complete seizure-freedom. CONCLUSION: In line with others our huge cohort sample that covers decades of experience with epilepsy surgery revealed satisfying long-term outcome results. Best results were obtained in lesional temporal lobe epilepsy, least favourable results in MRI-negative epilepsy. PMID- 23433687 TI - Comparison of two monitoring and treatment strategies for cows with acute puerperal metritis. AB - The objective of this study was to compare two strategies for screening and subsequent treatment of acute puerperal metritis (APM) in dairy cows. Therefore, we conducted a study on 79 cows with APM (cows with an enlarged uterus with fetid watery red-brown vaginal discharge and fever >39.5 degrees C) and 114 healthy control cows. Cows with APM were divided into two groups (treated, N = 67 cows; not treated, N = 12 cows). The treated animals were further subdivided into two groups (treated between Day 1 and 4 post partum, N =12 and treated between Day 5 and 10, N = 55). Serum haptoglobin concentrations, milk yield, cure rate, prevalence of endometritis, and cervical diameter on days in milk (DIM) 21 to 27 were compared between the groups. Cows were defined as cured when their rectal temperature was <39.5 degrees C 4 days after treatment and fever did not rebound over 39.4 degrees C until the end of the screening period which was DIM 10. The results of this study did not show any significant differences in cure rates, milk yield, or serum haptoglobin concentrations on DIM 2, 5, and 10 and subsequent uterine health (DIM 21-27). Considering this study as a proof of concept study, we conclude that there might not be a negative effect after a screening and treatment protocol beginning at DIM 5 and leaving early APM cows untreated. This hypothesis needs to be confirmed by a larger field study. Furthermore, antimicrobial therapy could be avoided in 12 of 55 cows (21.8%) in group 2 because of the protocol implementing treatments after DIM 5. These cows did not show signs of APM during the following 5 days. Therefore, these animals were considered as self-recovered leading to a cure rate of at least 21.8% (12 of 55 cows). PMID- 23433689 TI - Acanthamoeba keratitis: an emerging disease gathering importance worldwide? AB - Acanthamoeba keratitis (AK) is increasingly being recognized as a severe sight threatening ocular infection worldwide. Although contact lens wear is the leading risk factor for AK, Acanthamoeba parasites are also an important cause of keratitis in non-contact lens wearers. Diagnosis of AK is challenging, and the available treatments are lengthy and not fully effective against all strains. The pathogenesis of Acanthamoeba is still under study, and the identification of the key factors involved in this process should be useful for the development of fully effective therapies. This review focuses on recent developments on AK pathogenesis and diagnosis as well as novel strategies for the evaluation of anti amoebic agents that could be applied in the near future against these pathogens. PMID- 23433688 TI - Effects of docosahexaenoic acid supplementation during pregnancy on fetal heart rate and variability: a randomized clinical trial. AB - DHA (22:6n-3) supplementation during infancy has been associated with lower heart rate (HR) and improved neurobehavioral outcomes. We hypothesized that maternal DHA supplementation would improve fetal cardiac autonomic control and newborn neurobehavior. Pregnant women were randomized to 600 mg/day of DHA or placebo oil capsules at 14.4 (+/-4) weeks gestation. Fetal HR and HRV were calculated from magnetocardiograms (MCGs) at 24, 32 and 36 weeks gestational age (GA). Newborn neurobehavior was assessed using the Neonatal Behavioral Assessment Scale (NBAS). Post-partum maternal and infant red blood cell (RBC) DHA was significantly higher in the supplemented group as were metrics of fetal HRV and newborn neurobehavior in the autonomic and motor clusters. Higher HRV is associated with more responsive and flexible autonomic nervous system (ANS). Coupled with findings of improved autonomic and motor behavior, these data suggest that maternal DHA supplementation during pregnancy may impart an adaptive advantage to the fetus. PMID- 23433691 TI - Looking towards celebrating the 100(th) and beyond! PMID- 23433692 TI - Probiotics and oral health. PMID- 23433693 TI - Antiseptic mouth rinses: an update on comparative effectiveness, risks and recommendations. AB - PURPOSE: Antiseptic mouth rinses are widely recommended and marketed to improve oral health. This article summarizes current studies on the comparative effectiveness of selected antiseptic mouth rinses in controlling plaque and gingivitis, as well as risks associated with daily exposure, including salivary flow rate, oral cancer and wear of composite restorations. METHODS: Electronic database searches were conducted using Google Scholar and PubMed to identify articles comparing the effectiveness of 4 commercially marketed antiseptic mouth rinses differing in active ingredients (0.12% chlorhexidine gluconate, essential oils (menthol, thymol and eucalyptol) and methyl salicylate, 0.7% cetylpyridinium chloride and 20% aloe vera gel) for controlling plaque and gingivitis. Criteria for inclusion included controlled clinical trials and systematic reviews appearing in English language publications evaluating the comparative effectiveness of the mouth rinses in controlling plaque and gingivitis, as well as risks associated with daily usage. RESULTS: The majority of studies have shown mouth rinses containing chlorhexidine gluconate or essential oils and methyl salicylate provide clinically significant anti-gingivitis and anti-plaque benefits. Cetylpyridinium chloride has been found to provide only limited clinical benefits compared to inactive control mouth rinse. Inadequate evidence is available to evaluate the clinical effectiveness of aloe vera gel. Chlorhexidine, essential oils and cetylpyridinium have been found to be safe. However, limited data are available on the effects of the mouth rinse on wear patterns of dental restorations. Studies reviewed reported no significant difference in salivary flow rate related to alcohol based mouth rinse. CONCLUSION: Research supports the effectiveness of antiseptic mouth rinses in reducing plaque and gingivitis as an adjunct to home care. Insufficient evidence is available to support the claim that oral antiseptics can reduce the risk of developing periodontitis or the rate of progression of periodontitis. PMID- 23433694 TI - Chronic inflammatory gingival enlargement associated with orthodontic therapy--a case report. AB - PURPOSE: Gingival enlargement, also synonymous with the terms gingival hyperplasia or hypertrophy, is defined as an abnormal overgrowth of gingival tissues. A case of a 19-year-old male presenting with maxillary and mandibular chronic inflammatory gingival enlargement associated with prolonged orthodontic therapy is reported here. Surgical therapy was carried out to provide a good aesthetic outcome. No recurrence was reported at the end of 1 year. The importance of patient motivation and compliance during and after therapy as a critical factor in the success of treatment has also been highlighted through this case report. PMID- 23433695 TI - Dental hygienists' role in practice based research: PEARL Network evaluation. AB - PURPOSE: The goal of this paper is to evaluate the PEARL Network's satisfaction with training/support and assess the relationship between practice research coordinators (PRCs) involvement and study participation. METHODS: At the PEARL Network 2011 Annual Meeting, an evaluation form was completed by practitioner investigators and PRCs who attended the annual meeting. Results from the paper evaluation form were entered into an Excel database, and analyzed using the statistical analysis software SPSS. The bivariate correlation test, Pearson Correlation, was conducted, and results were considered significant if p<0.05. RESULTS: During a program evaluation among 84 network respondents, a positive correlation (p=0.004) was found between the number of PRCs and the number of studies in which a site participates. In addition, there was a positive correlation between satisfaction with the training, support and involvement of PRCs in organizing study activities (p=0.008). There was also positive correlation between satisfaction with training/support and the number of PRCs utilized by the office (p=0.039). CONCLUSION: Practice research coordinators are key members of the research team, and they are important to conducting clinical studies in everyday practice. PMID- 23433696 TI - Preliminary findings on the correlation of saliva pH, buffering capacity, flow, Consistency and Streptococcus mutans in relation to cigarette smoking. AB - PURPOSE: The purpose of this preliminary study was to examine the relationship of caries risk, salivary buffering capacity, salivary pH, salivary quality (flow, consistency) and levels of Streptococcus mutans in relation to cigarette smoking. METHODS: This clinical trial consisted of 53 volunteer patients receiving care in a university based dental hygiene clinic. Participants completed a questionnaire specific to their social history in regards to tobacco use, oral health and dietary history. Measurements of unstimulated saliva were collected followed by collection of stimulated saliva samples. These samples were used to measure salivary pH, buffering capacity and Streptococcus mutans levels. RESULTS: The subject's smoking status was significantly associated with caries risk (p= 0.001), with 25% of the variability of caries risk attributed to smoking. The smoking status was significantly associated with buffering capacity (p=0.025), with 9% of the variability of buffering status attributed to the smoking. Associations between smoking status and salivary pH were not statistically significant. The subject's caries risk was significantly associated with buffering capacity (p= 0.001), with 25% of the variability of caries risk attributed to the buffering capacity. The subject's caries risk was significantly associated with salivary pH (p= 0.031), with 9% of the variability of caries risk attributed to the salivary pH. The Streptococcus mutans test showed no statistical significance (p>0.05) possibly due to the number and low variance in the subjects. CONCLUSION: A relationship between caries risk and smoking, buffering capacity and smoking, and stimulated salivary pH and smoking were concluded. No significance difference (p>0.05) between caries risk and salivary pH, salivary quality and smoking, S. mutans and smoking were noted from the preliminary results. PMID- 23433697 TI - How do diet and body mass index impact dental caries in Hispanic elementary school children? AB - PURPOSE: The purpose of this observational study was to examine the association between body mass index and dental caries in Hispanic children. The research evaluated the influences of obesity, diet, parent education level, family acculturation, tooth brushing habits and gender as predictors of childhood caries. METHODS: One examiner visually screened 177 third grade students from 3 elementary schools located in southern California's Coachella Valley. The children were screened for number of decayed, missing and filled teeth (DMFT). Height, weight, age and gender determined their body mass index. Primary caregivers completed a 30-point questionnaire for each participant. Multivariate analyses accessed the association between childhood dental caries and weight status and the influences of the measured variables. RESULTS: Results indicate that those in the obese category had a statistically significant lower rate of DMFT than did children in the healthy weight category. Overweight children showed a higher DMFT than healthy weight children but the results were not statistically significant. Covariates that significantly influenced this association were diet and socioeconomic status. CONCLUSION: Results from this study provide oral health professionals with baseline data and literature to support development of preventive programs for this population that concurrently address both obesity and oral health issues in scope and design. PMID- 23433698 TI - An innovative HIV training program for dental hygiene students. AB - PURPOSE: Patients with HIV/AIDS deserve to be treated with compassion and receive comprehensive care by their dentist and dental hygienists. Previous studies have shown that many dental and dental hygiene students had negative attitudes towards treating such individuals. This article addresses the effectiveness of a program that trains dental hygiene students in the issues of treating this population. All pre-doctoral students at the Loma Linda University School of Dentistry are required to receive this training. Dental hygiene students complete a pre-session survey during their first year and a post-session survey as they complete the training during their second year. The survey questionnaire was administered during the period of 2003 to 2009, during which 197 students completed responses to the post-session survey. Five questions in the survey address self-evaluation of knowledge, attitudes, confidence in the efficacy of Universal Precautions and Post-Exposure Prophylaxis (PEP) following blood borne exposures. This study reports on 5 overlapping 2 year testing cycles and shows significant shifts in all 5 areas surveyed. The most significant gains were in "Familiarity with PEP" and "Confidence in the Efficacy of PEP." These data support the usefulness of an HIV program in preparing future dental hygienists to deliver appropriate care to persons living with HIV/AIDS. PMID- 23433699 TI - Pain from the inside: understanding the theoretical underpinning of person centered care delivered by pain teams. AB - Chronic back pain is globally acknowledged as a common reason why people seek help from health professionals. The complexity of persistent chronic pain can undermine the person's self-esteem and present a number of challenges to an individual's ability to manage their pain. Multi-professional person-centered care is advocated as a key strategy to support people with chronic back pain. However, the impact of these approaches on restoring the person's independence is unclear, and little is known about whether and how person-centered approaches restore autonomy and influence the person's ability to manage their pain. The aim of this grounded theory study was to generate understanding about person-centered care from the perspectives of people with chronic back pain and the multi professional teams who cared for them. Semi-structured interviews were used to collect data from 17 people with chronic back pain over one year. A constant comparative analytical approach identified five key categories: the skeptical professional, validation, becoming a person, regaining control, and restoring faith. These categories formed the "conditional partnership" as a theory to explain person-centered care, which related to the way in which the partnership developed between the patients and teams. The findings suggest that person centered care was influenced by the participants' need to be believed and the relationship developed with health care providers. Crucially, these findings suggest that legitimizing the pain experience through person-centered approaches to care can empower people with chronic back pain to regain control of their lives and their pain. PMID- 23433700 TI - Do barriers to pediatric pain management as perceived by nurses change over time? AB - For decades, nurses (RNs) have identified barriers to providing the optimal pain management that children deserve; yet no studies were found in the literature that assessed these barriers over time or across multiple pediatric hospitals. The purpose of this study was to reassess barriers that pediatric RNs perceive, and how they describe optimal pain management, 3 years after our initial assessment, collect quantitative data regarding barriers identified through comments during our initial assessment, and describe any changes over time. The Modified Barriers to Optimal Pain Management survey was used to measure barriers in both studies. RNs were invited via e-mail to complete an electronic survey. Descriptive and inferential statistics were used to compare results over time. Four hundred forty-two RNs responded, representing a 38% response rate. RNs continue to describe optimal pain management most often in terms of patient comfort and level of functioning. While small changes were seen for several of the barriers, the most significant barriers continued to involve delays in the availability of medications, insufficient physician medication orders, and insufficient orders and time allowed to pre-medicate patients before procedures. To our knowledge, this is the first study to reassess RNs' perceptions of barriers to pediatric pain management over time. While little change was seen in RNs' descriptions of optimal pain management or in RNs' perceptions of barriers, no single item was rated as more than a moderate barrier to pain management. The implications of these findings are discussed in the context of improvement strategies. PMID- 23433701 TI - Near-miss in focused lower-extremity ultrasound for deep venous thrombosis. AB - BACKGROUND: Focused, proximal compression ultrasound (FPCUS) is a commonly used point-of-care study in the Emergency Department (ED). Pelvic vein deep venous thrombosis (DVT) is a rare presentation, and Emergency Physicians need to be aware of the limitations and pitfalls of FPCUS. OBJECTIVE: A case of external iliac vein DVT diagnosed in the ED is presented, with a focus on subtle signs seen during FPCUS that led to the diagnosis and additional ultrasound techniques to aid in appropriate point-of-care diagnosis. CASE REPORT: We describe a patient who presented with lower-extremity pain and was subsequently diagnosed with external iliac DVT. A FPCUS study by Emergency Physicians was performed and demonstrated subtle findings that led to further investigation and appropriate diagnosis. CONCLUSION: Emergency physicians using FPCUS in the evaluation of lower-extremity pain or swelling need to be aware of the pitfalls, limitations, and advanced techniques to avoid misdiagnosis while evaluating for DVT. PMID- 23433702 TI - Acrochordon of the labia. PMID- 23433703 TI - [Integral approach to the patient with multiple chronic diseases in primary care: a trend in need of facts]. PMID- 23433704 TI - [The quality of diagnostic coding: a training need in primary care]. PMID- 23433705 TI - Aryl hydrocarbon receptor activation affects the dendritic cell phenotype and function during allergic sensitization. AB - Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses peanut sensitization by affecting T cell subsets. However, effects of AhR activation on dendritic cells (DC) in an allergic setting were not investigated yet. Therefore, we analysed the effects of AhR activation on DC phenotype in vivo, as well as their ex vivo potency to stimulate allergen specific splenic T cells and to induce CD4+CD25+Foxp3+ regulatory (T(reg)) cells. C3H/HeOuJ mice were treated with TCDD by gavage and subsequently sensitized to peanut extract (PE). After eight days, mice were sacrificed and DC in spleen and mesenteric lymph nodes (MLN) were characterized or cocultured with PE-specific CD4+ T cells. AhR activation almost doubled the absolute number of CD11c+CD103+ DC, while not affecting CD11b+ DC, the absolute number of DC, the expression of the activation makers MHCII, CD86, CD80, CD40, CD54 and CD8 on CD11c+ and the activation status of CD11c+CD103+ DC in the spleen. In the MLN, TCDD decreased the absolute number of DC and CD103+ DC, while not affecting CD11b+ DC and the expression of activation markers on DC. PE-pulsed splenic DC from TCDD-treated mice suppressed IL-5, IL-13 and IFN-gamma production by PE-specific T cells, but did not induce CD4+CD25+Foxp3+ T(reg) cells. This suppression of cytokine production was not mediated by the TCDD-induced increase in CD103+ DC in the spleen. Combined, these results indicate that AhR activation suppresses the initiation of food allergic responses by affecting DC and their interaction with effector T cells. PMID- 23433706 TI - A modified Vancouver Scar Scale linked with TBSA (mVSS-TBSA): Inter-rater reliability of an innovative burn scar assessment method. AB - BACKGROUND: Current scar assessment methods do not capture variation in scar outcome across the burn scar surface area. A new method (mVSS-TBSA) using a modified Vancouver Scar Scale (mVSS) linked with %TBSA was devised and inter rater reliability was assessed. METHOD: Three raters performed scar assessments on thirty patients with burn scars using the mVSS-TBSA. Scoring on pigmentation, vascularity, pliability and height was undertaken for the 'best' and 'worst' areas of each scar. Raters allocated the total body surface area of the scar (%TBSA) to three mVSS categories (<5, 5-10, >10). Intra-class correlation coefficient (ICC) and weighted kappa statistic (kw) were used to assess inter rater reliability. The data were also analysed for clinically relevant misclassifications between pairs of raters. RESULTS: Total mVSS scores showed 'fair to good' agreement (ICC 0.65-0.73) in the 'best' area of the scar while there was 'excellent' agreement in the 'worst' scar area (ICC 0.85-0.88). The kw of the individual mVSS components ranged from 0.44 to 0.84 and 0.02 to 0.86 for 'best' and 'worst' scar areas, respectively. Determination of scar %TBSA had 'excellent' reliability (ICC 0.91-0.96). Allocation of scar %TBSA to severity category <5 mVSS demonstrated 'good to excellent' reliability (ICC 0.63-0.80) and 'fair to good' reliability (ICC 0.42-0.74) for 5-10 mVSS category. However, misclassifications were observed for the total mVSS score in the 'worst' scar area and the allocation of scar %TBSA in the <5 mVSS category. CONCLUSION: Inter rater reliability of mVSS scores depends on the severity of the scar area being assessed. The mVSS-TBSA method of allocation of scar %TBSA to two broad mVSS categories, namely <5 and >=5 mVSS, has 'good to excellent' reliability. The mVSS TBSA has demonstrated utility for both clinical and research purposes; however, there is potential to misclassify scar outcome in some cases. PMID- 23433707 TI - Do anti-embolism stockings fit our legs? Leg survey and data analysis. AB - BACKGROUND: Anti-embolism stockings are commonly used worldwide to prevent the development of thrombosis in hospitalised patients. Patients are typically measured for, and fitted with, anti-embolism stockings during extended periods of non-ambulation. Anti-embolism stockings must critically fit the leg to achieve optimum blood flow and thus success of prophylaxis. Therefore, hospitals endeavour to maintain stock of anti-embolism stockings that fit the majority of their patients. OBJECTIVES: The objective of this study was to establish whether popular styles/brands of anti-embolism stockings "fitted" the legs of convenience sampled volunteers. DESIGN/METHODS: Volunteer's legs were measured at ankle, calf and thigh following guidance from British nurses and in accordance with brand instructions. Leg measurements were subsequently compared to the size charts of 10 anti-embolism stocking styles made by 4 different manufacturers. "Fit" is defined as a volunteer's leg measurements matching any stocking size in a range at all measurement points. SETTINGS: Volunteers were measured in different settings around Scotland, including private homes, work places and shopping centres. PARTICIPANTS: A convenience sample of 471 volunteers (283 female, 188 male) were recruited on the basis of willingness to participate and being over 16 years old. Volunteers ranged from 17 years to 82 years old with an average age of 35. RESULTS: The 10 different styles of anti-embolism stockings, made by 4 different brands, examined for this paper had a size match coefficient ranging from 0% to 100% for our volunteer's legs. The size match coefficient is strongly influenced by the Brand's sizing policy. CONCLUSIONS: The proportion of legs that "fit" a particular brand of anti-embolism stockings can be increased through: (1) the reduction of the number of leg measurement points that need to be matched to the size chart of the stockings; (2) the use of open-ended size ranges; (3) the use of increased size range width and (4) the use of increased overlap between sizes. However, all but the last of these measures can have a potentially deleterious impact on the ability of the stocking to deliver the optimum graduated pressure profile to all legs that "fit" the stocking, resulting in important implications to the efficacy of prophylaxis. PMID- 23433708 TI - Vision and proprioception in action monitoring by young and older adults. AB - Discrimination of proprioceptive and visual spatial information is a prerequisite for the learning of visuo-motor transformations. This study investigated the individual's capability to discriminate the directions of seen cursor motions and felt hand movements under a visuo-motor rotation paradigm and its age-related variation. Young and older participants performed 3-stroke arm movements on a digitizing tablet without seeing their arm. The visual feedback of the second stroke was rotated randomly by various angles ranging from -30 degrees to 30 degrees and displayed on a monitor. Older adults were poorer in discrimination than young adults. In both age groups, the felt hand direction was shifted toward the seen cursor direction (i.e., visual capture) by approximately 25% to 30% of the rotation of the visual feedback. Older adults also showed an enhanced visual capture. The results suggest that both the increased sensory noise and the increased assimilation of the bimodal information cause the reduction of discrimination capability in older adults. These findings provide underlying reasons for age-related changes in learning a new visuo-motor transformation. PMID- 23433709 TI - High glycemic and insulinemic responses to meals affect plasma growth hormone secretory characteristics in Quarter Horse weanlings. AB - Growth hormone is a key component of the somatotropic axis and is critical for the interplay between nutrition, regulation of metabolic functions, and subsequent processes of growth. The objective of this study was to investigate potential relations between meal feeding concentrates differing in the glycemic responses they elicit and GH secretory patterns in young growing horses. Twelve Quarter Horse weanlings (5.4 +/- 0.4 mo of age) were used in a crossover design, consisting of two 21-d periods and two treatments, a high-glycemic (HG) or low glycemic (LG) concentrate meal, fed twice daily. Horses were individually housed and fed hay ad libitum. On the final day of each period, quarter-hourly blood samples were drawn for 24 h to measure plasma glucose, insulin, non-esterified fatty acids, and GH. Growth hormone secretory characteristics were estimated with deconvolution analysis. After a meal, HG-fed horses exhibited a longer inhibition until the first pulse of GH secretion (P = 0.012). During late night hours (1:00 AM to 6:45 AM), HG horses secreted a greater amount of pulsatile GH than LG horses (P = 0.002). These differences highlight the potential relations between glycemic and insulinemic responses to meals and GH secretion. Dietary energy source and metabolic perturbations associated with feeding HG meals to young, growing horses have the potential to alter GH secretory patterns compared with LG meals. This may potentially affect the developmental pattern of various tissues in the young growing horse. PMID- 23433710 TI - Feeding 5-hydroxy-l-tryptophan during the transition from pregnancy to lactation increases calcium mobilization from bone in rats. AB - An increasing demand for calcium during pregnancy and lactation can result in both clinical and subclinical hypocalcemia during the early lactation period in several mammalian species, in particular the dairy cow. Serotonin (5-HT) was recently identified as a regulator of lactation and bone turnover. The purpose of this study was to determine whether supplementation of the maternal diet with a 5 HT precursor would increase maternal bone turnover and calcium mobilization to maintain appropriate circulating maternal concentrations of ionized calcium during lactation. Female Sprague-Dawley rats (n = 30) were fed either a control diet (n = 15) or a diet supplemented with the 5-HT precursor 5-hydroxytryptophan (5-HTP, 0.2%; n = 15) from day 13 of pregnancy through day 9 of lactation. Maternal serum and plasma (day 1 and day 9 of lactation), milk and pup weight (daily), mammary gland and bone tissue (day 9 of lactation) were collected for analysis. The 5-HTP diet elevated circulating maternal concentrations of 5-HT on day 1 and day 9 of lactation and parathyroid hormone related-protein (PTHrP) on day 9 of lactation (P < 0.033). In addition, 5-HTP supplementation increased total serum calcium concentrations on day 1 of lactation and total milk calcium concentration on day 9 of lactation (P < 0.032). Supplemental 5-HTP did not alter milk yield, maternal body weight, mammary gland structure, or pup litter weights (P > 0.05). Supplemental 5-HTP also resulted in increased concentrations of mammary 5-HT and PTHrP, as well as increased mRNA expression of rate-limiting enzyme in 5-HT synthesis, tryptophan hydroxylase 1, and Pthrp mRNA on day 9 of lactation (P < 0.028). In addition, supplementation of 5-HTP resulted in increased mRNA expression of maternal mammary calcium transporters and resorption of bone in the femur, indicated by increase osteoclast number and diameter as well as mRNA expression of classical markers of bone resorption on day 9 of lactation (P < 0.048). These results show that increasing 5-HT biosynthesis during the transition from pregnancy to lactation could be a potential therapeutic target to explore for prevention of subclinical and clinical hypocalcemia. PMID- 23433711 TI - Invariant natural killer T cells are phenotypically and functionally altered in Fabry disease. AB - Fabry disease is a lysosomal storage disease belonging to the group of sphingolipidoses. In Fabry disease there is accumulation of mainly globotriaosylceramide due to deficiency of the lysosomal enzyme alpha galactosidase A. The lysosome is an important compartment for the activity of invariant natural killer T (iNKT) cells. iNKT cells are lipid-specific T cells that were shown to be important in infection, autoimmunity and tumor surveillance. In several mouse models of lysosomal storage disorders there is a decrease in iNKT cell numbers. Furthermore, alterations on iNKT cell subsets have been recently described in the Fabry disease mouse model. Herein, we analyzed iNKT cells and their subsets in Fabry disease patients. Although there were no differences in the percentage of iNKT cells between Fabry disease patients and control subjects, Fabry disease patients presented a reduction in the iNKT CD4(+) cells accompanied by an increase in the iNKT DN cells. Since iNKT cell subsets produce different quantities of pro-inflammatory and anti-inflammatory cytokines, we analyzed IFN-gamma and IL-4 production by iNKT cells of Fabry disease patients and mice. We found a significant reduction in the production of IL-4 by mice splenic iNKT cells and human iNKT cell subsets, but no significant alterations in the production of IFN-gamma. Altogether, our results suggest a bias towards a pro inflammatory phenotype in Fabry disease iNKT cells. PMID- 23433712 TI - Mitochondrial aminoacyl-tRNA synthetases in human disease. AB - Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential in the process of transferring genetic information from mitochondrial DNA to the complexes of the oxidative phosphorylation system. These synthetases perform an integral step in the initiation of mitochondrial protein synthesis by charging tRNAs with their cognate amino acids. All mtARSs are encoded by nuclear genes, nine of which have recently been described as disease genes for mitochondrial disorders. Unexpectedly, the clinical presentations of these diseases are highly specific to the affected synthetase. Encephalopathy is the most common manifestation but again with gene-specific outcomes. Other clinical presentations include myopathy with anemia, cardiomyopathy, tubulopathy and hearing loss with female ovarian dysgenesis. Here we review the described mutation types and the associated patient phenotypes. The identified mutation spectrum suggests that only mutation types that allow some residual tRNA-charging activity can result in the described mtARS diseases but the molecular mechanisms behind the selective tissue involvement are not currently understood. PMID- 23433713 TI - Taenia saginata metacestode antigenic fractions obtained by ion-exchange chromatography: potential source of immunodominant markers applicable in the immunodiagnosis of human neurocysticercosis. AB - The aim of this study was to fractionate and partially characterize fractions obtained from the total saline extract (SE) of Taenia saginata metacestodes after ion-exchange procedure in carboxymethyl sepharose (CM) and diethylaminoethyl sepharose (DEAE) resins, as a source of antigenic markers applicable in the immunodiagnosis of neurocysticercosis (NCC). For IgG detection by enzyme-linked immunosorbent assay (ELISA) and immunoblotting, 140 serum samples were analyzed: 45 from patients with NCC (G1), 50 from patients with other parasitic infections (G2), and 45 from healthy individuals. Sensitivity (Se), specificity (Sp), area under curve (AUC), and likelihood ratios (LR) were calculated. CM S2 and DEAE S2 fractions provided high diagnostic values (Se 88.8% and 93.4%; Sp 93.7% and 92.6%; AUC 0.965 and 0.987; LR+ 14.07 and 12.67; LR- 0.11 and 0.07, respectively). In conclusion, CM S2 and DEAE S2 fractions are important sources of specific peptides, with high efficiency to diagnose NCC. PMID- 23433714 TI - Application of loop-mediated isothermal amplification assay for the sensitive and rapid diagnosis of visceral leishmaniasis and post-kala-azar dermal leishmaniasis. AB - Loop-mediated isothermal amplification (LAMP) is at the forefront in the search for innovative diagnostics for rapid and specific amplification of target DNA under isothermal conditions. We have applied LAMP assay using SYBR Green for clear-cut naked eye detection of Leishmania (Leishmania) donovani in 200 clinical samples of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). The assay was positive in 53/55 VL blood samples (sensitivity, 96.4%; 95% confidence interval [CI], 87.7-99%), 15/15 VL bone marrow aspirate samples (sensitivity, 100%; 95% CI, 79.6-100%), 60/62 PKDL tissue biopsy samples (sensitivity, 96.8%; 95% CI, 88.9-99.1%), and 1/68 control samples (specificity, 98.5%; 95% CI, 92.1-99.7%). The assay was specific for L. (L.) donovani, the causative species for VL and negative for L. (L.) infantum, L. (L.) tropica, and L. (L.) major. This is the first comprehensive clinical study demonstrating the applicability of the LAMP assay for a rapid and reliable molecular diagnosis of VL and PKDL. PMID- 23433715 TI - Chronic adherence to heat and moisture exchanger use in laryngectomized patients. AB - INTRODUCTION AND OBJECTIVE: Total laryngectomy leads to pulmonary problems such as excessive sputum production, forced expectoration and increased coughing. The use of a heat and moisture exchanger (Provox((r)) HME) reduces these symptoms. The aim of this study was to quantify chronic adherence to HME use in laryngectomized patients. METHODS: A prospective study of 115 patients laryngectomized at our centre during 2005-2011 was performed. RESULTS: Of the 115 patients, 90 (78.2%) used the HME consistently and 25 (21.8%) abandoned its use. The most common causes of desertion were adhesion problems due to mucus and skin irritation. Of the 30 patients with voice prostheses, 90% of them used the HME system regularly. Voice prosthesis use (P=.05) and early indication in postoperative laryngectomy (P=.001) were factors significantly associated with chronic HME use. CONCLUSIONS: There is high adherence (78.2%) to heat and moisture exchanger (Provox((r)) HME) use in laryngectomized patients. Chronic HME use was higher in patients with voice prosthesis and the ones with early indication in postoperative period. The major causes of abandonment were related to problems with the adhesive. PMID- 23433716 TI - [Nasal angiomyolipoma]. PMID- 23433717 TI - Probabilistic problem solving in biomedicine. PMID- 23433718 TI - CCL18 as an independent favorable prognostic biomarker in patients with colorectal cancer. AB - BACKGROUND: CCL18 has been shown to have an important role in the progression of gastric and breast cancers. However, the prognostic value of CCL18 in colorectal cancer (CRC) remains unknown. MATERIALS AND METHODS: We used immunohistochemistry to examine the expression of CCL18 in CRC patients. We applied both univariate and multivariate analysis to evaluate the prognostic value of CCL18 on CRC patients' survival. We used double staining to investigate the relationship between CCL18 and macrophages. RESULTS: A total 371 CRC patient samples were enrolled in immunohistochemical analysis. According to our criteria, 118 samples (31.8%) showed a high CCL18 expression level. Clinicopathologic analysis revealed an association between the expression level of CCL18 and the preoperative carcino embryonic antigen level (P = 0.001), and the preoperative carbohydrate antigen 19 9 level (P = 0.003). Survival analysis and multivariate analysis revealed that CCL18 was an independent favorable prognostic factor in patients with CRC (P = 0.033). Double staining implied that CCL18 was expressed by macrophages. CONCLUSIONS: A high CCL18 level might be an independent biomarker for predicting better survival of patients with CRC. PMID- 23433719 TI - Autologous platelet-poor plasma decreases the bronchial stump necrosis in rat. AB - BACKGROUND: Necrosis of the bronchial stump is a very important trigger for bronchopleural fistula. The administration of local autologous platelet-poor plasma (PPP) could protect the bronchial stump. MATERIALS AND METHODS: Left pneumonectomy was performed in 25 Sprague-Dawley rats. Animals were randomly assigned to a control group (n=13) and PPP group (n=12). PPP was locally administered on the bronchial stump after pneumonectomy. We analyzed histologic changes in the bronchial stump and messenger RNA expression changes of genes involved in wound repair at 10 and 20 d. RESULTS: Local PPP treatment produced a mass of fibrous tissue surrounding the bronchial stump and significantly decreased the presence of necrosis at 20 d. PPP increased the expression of insulin like growth factor 1 at 10 d although it did not reach statistical significance. CONCLUSIONS: Our findings indicate that local PPP treatment of the bronchial stump after pneumonectomy decreased necrosis and could have a protective effect on the bronchial stump. PMID- 23433720 TI - BMPR1A mutations in juvenile polyposis affect cellular localization. AB - BACKGROUND: Juvenile polyposis (JP) is characterized by the development of hamartomatous polyps of the gastrointestinal tract that collectively carry a significant risk of malignant transformation. Mutations in the bone morphogenetic protein receptor type 1A (BMPR1A) are known to predispose to JP. We set out to study the effect of such missense mutations on BMPR1A cellular localization. METHODS: We chose eight distinct mutations for analysis. We tagged a BMPR1A wild type (WT) expression plasmid with green fluorescent protein on its C-terminus. Site-directed mutagenesis was used to recreate JP patient mutations from the WT green fluorescent protein BMPR1A plasmid. We verified mutant expression vector sequences by direct sequencing. First, we transfected BMPR1A expression vectors into HEK-293T cells; then, we performed confocal microscopy to determine cellular localization. Four independent observers used a scoring system from 1 to 3 to categorize the degree of membrane versus cellular localization. RESULTS: Of the eight selected mutations, one was within the signaling peptide, four were within the extracellular domain, and three were within the intracellular domain. The WT BMPR1A vector had strong membrane staining, whereas all eight mutations had much less membrane and much more intracellular localization. Enzyme-linked immunosorbent assays for BMPR1A demonstrated no significant differences in protein quantities between constructs, except for one affecting the start codon. CONCLUSIONS: Bone morphogenetic protein receptor type 1A missense mutations occurring in patients with JP affected cellular localization in an in vitro model. These findings suggest a mechanism by which such mutations can lead to disease by altering downstream signaling through the bone morphogenetic protein pathway. PMID- 23433721 TI - Approval probabilities and regulatory review patterns for anticancer drugs in the European Union. AB - AIM: This article reviews outcomes of marketing authorization applications for anticancer drugs in the EU and outlines factors and hurdles of impact. METHODS: Procedures for initial approval of anticancer and non-cancer drugs were analyzed and compared to anticancer drug approvals in the USA and Japan for the same period. RESULTS: From 2006 to 2011, the regulatory review of 46 marketing authorization applications resulted in 29 new cancer drug approvals. The overall approval probability (63%) lagged behind the probability for non-cancer drugs (73%). Longer median active review times in line with additional clock-stop and EU Commission decision-making times as well as submission delays contribute to the 7.2 months median time-to-market delay [95% CI 4.7-15.0 months] compared to the USA; Japanese patients had to wait an additional 25.1 months [95% CI 6.2-34.1 months]. CONCLUSION: Marketing authorization applications for anticancer drugs in the EU are associated with modest approval success. Patients in the USA get access to new products earlier, fostered by the more frequent use of expedited review procedures. So far, both procedures were used in the EU for applications claiming a major public health interest, characterized by pivotal clinical trial hazard ratios below 0.70. PMID- 23433723 TI - The effectiveness of mutual support group intervention for Chinese families of people with schizophrenia: a randomised controlled trial with 24-month follow-up. AB - BACKGROUND: Positive effects on the relapse from illness and compliance with medication by patients have been observed from family intervention for schizophrenia. However, little attention has been paid to the effects on family members, particularly those in non-Western countries. Inconsistent and inconclusive findings were found on the family-related outcomes and longer-term effects of family intervention. OBJECTIVE: This study tested the effects of a nine-month family-led mutual support group for Chinese people with schizophrenia, compared with a psycho-education group and standard psychiatric care over a 24 month follow-up. DESIGN: A randomised controlled trial [registered with ClinicalTrials.gov (NCT00940394)] with repeated-measures, three-group design. SETTINGS: Two regional psychiatric outpatient clinics in Hong Kong. PARTICIPANTS: One hundred and thirty-five Chinese family caregivers and their patients with schizophrenia were randomly recruited, of whom 45 family dyads received family led mutual support group, a psycho-education group, or standard care. METHODS: After completing the pre-test questionnaire, the participants were randomly assigned into one of the three study groups. The mutual support and psycho education groups comprised 14 two-hour group sessions, with patients participating in at least 5 sessions. Those in standard care (and two treatment groups) received routine psychiatric care. Multiple patient and family-related psychosocial outcomes were compared at recruitment and at one week, 12 months, and 24 months following interventions. RESULTS: One hundred and twenty-six of 135 family dyads completed the three post-tests and 43 (95.6%) attended at least nine group sessions (60%) of the mutual support group programme. Mean ages of the family caregivers in the study ranged from 41.2 (SD=7.0) to 42.7 (SD=7.6) years. About two-thirds of the caregivers were male and patients' parent or spouse. The results of multivariate analysis of variance followed by Helmert contrasts tests indicated that the participants in the mutual support group indicated significantly greater improvement in family and patient functioning [F(2, 132)=5.40, p=0.005 and F(2, 132)=6.88, p=0.001, respectively] and social support for families [F(2, 131)=5.01, p=0.005], and in reducing patients' symptom severity [F(2, 132)=4.65, p=0.01] and length of re-hospitalisations [F(2, 132)=4.78, p=0.01] at 12- and 24-month follow-ups. CONCLUSIONS: Family-led mutual support group for schizophrenia produces longer-term benefits to both the patients' and families' functioning and relapse prevention for patients, compared with psycho-education and standard care. This group programme can be an effective family intervention for Chinese people with schizophrenia. PMID- 23433722 TI - Brain areas involved in the control of speed during a motor sequence of the foot: real movement versus mental imagery. AB - We investigated the cerebral networks involved in execution and mental imagery of sequential movements of the left foot, both performed at slow and fast speed. Twelve volunteers were scanned with a 3T MRI during execution and imagination of a sequence of ankle movements. Overt movement execution and motor imagery shared a common network including the premotor, parietal and cingulate cortices, the striatum and the cerebellum. Motor imagery recruited specifically the prefrontal cortex, whereas motor execution recruited specifically the sensorimotor cortex. We also found that slow movements specifically recruited frontopolar and right dorsomedian prefrontal areas bilaterally, during both execution and mental imagery, whereas fast movements strongly activated the sensorimotor cerebral cortex. Finally, we noted that anterior vermis, lobules VI/VII and VIII of the cerebellum were specifically activated during fast movements, both in imagination and execution. We show that the selection of the neural networks underlying voluntary movement of the foot is depending on the speed strategy and is sensitive to execution versus imagery. Moreover, to the light of surprising recent findings in monkeys showing that the vermis should no longer be considered as entirely isolated from the cerebral cortex (Coffman et al., 2011 [2]), we suggest that the anterior vermis contributes to computational aspects of fast commands, whereas more lateral cerebellar superior lobe and lobule VIII would regulate patterning and sequencing of submovements in conjunction with movement rate. We also suggest that execution of overt slow movements, which strongly involves prefrontal executive cortex as during motor mental imagery, is associated with conscious mental representation of the ongoing movements. PMID- 23433724 TI - The outcome of a rapid training program on nurses' attitudes regarding the prevention of aggression in emergency departments: a multi-site evaluation. AB - BACKGROUND: Patient aggression is a common source of occupational violence in emergency departments. Staff attitudes regarding the causes for aggression influence the way they manage it. The Management of Clinical Aggression - Rapid Emergency Department Intervention is a 45 min educational program that aims to promote the use of de-escalation techniques and effective communication skills to prevent patient aggression. OBJECTIVE: We sought to evaluate the impact of the program on staff attitudes regarding the prevention and early management of patient aggression. DESIGN: A mixed methods approach was used including a pre test post-test survey of training participants and individual interviews with key stakeholders. SETTING AND SAMPLE: The setting was public sector hospital emergency departments located in metropolitan and regional Victoria, Australia. A convenience sample of eighteen emergency departments was recruited via the Victorian Department of Health. PARTICIPANTS: Survey participants were nurses and midwives who were employed at the study sites. Interview participants were a purposive sample of nurse unit managers and trainers. METHODS: The Management of Aggression and Violence Attitude Scale was administered to training participants immediately before and 6-8 weeks after training. Semi-structured telephone interviews with trainers and managers occurred 8-10 weeks after the intervention. RESULTS: Four hundred and seventy one participants completed the pre-test and post-test. Statistically significant shifts were observed in 5/23 items (Wilcoxon Signed Ranks Test: p <= 0.01). Despite training, participants were undecided if it was possible to prevent patient aggression, and continued to be unsure about the use of physical restraint. Twenty-eight (82.3%) of managers' and trainers' eligible to be interviewed provided their perceptions of the impact of the program. Overall, these perceptions were consistent with the significant shifts observed in the survey items. CONCLUSION: There was limited evidence to demonstrate that the program significantly modified staff attitudes towards the prevention of patient aggression using the Management of Aggression and Violence Attitude Scale. Additional survey items that specifically measure staff attitudes about the use of restraint in emergency settings are needed to better understand decision making about restraining practices. Further work is indicated to quantify the impact of training in practice. PMID- 23433725 TI - Nurse exposure to physical and nonphysical violence, bullying, and sexual harassment: a quantitative review. AB - OBJECTIVES: This paper provides a quantitative review that estimates exposure rates by type of violence, setting, source, and world region. DESIGN: A quantitative review of the nursing violence literature was summarized. DATA SOURCES: A literature search was conducted using the CINAHL, Medline and PsycInfo data bases. Studies included had to report empirical results using a nursing sample, and include data on bullying, sexual harassment, and/or violence exposure rates. A total of 136 articles provided data on 151,347 nurses from 160 samples. PROCEDURE: Articles were identified through a database search and by consulting reference lists of review articles that were located. Relevant data were coded by the three authors. Categories depended on the availability of at least five studies. Exposure rates were coded as percentages of nurses in the sample who reported a given type of violence. Five types of violence were physical, nonphysical, bullying, sexual harassment, and combined (type of violence was not indicated). Setting, timeframe, country, and source of violence were coded. RESULTS: Overall violence exposure rates were 36.4% for physical violence, 66.9% for nonphysical violence, 39.7% for bullying, and 25% for sexual harassment, with 32.7% of nurses reporting having been physically injured in an assault. Rates of exposure varied by world region (Anglo, Asia, Europe and Middle East), with the highest rates for physical violence and sexual harassment in the Anglo region, and the highest rates of nonphysical violence and bullying in the Middle East. Regions also varied in the source of violence, with patients accounting for most of it in Anglo and European regions, whereas patents' families/friends were the most common source in the Middle East. CONCLUSIONS: About a third of nurses worldwide indicated exposure to physical violence and bullying, about a third reported injury, about a quarter experienced sexual harassment, and about two thirds indicated nonphysical violence. Physical violence was most prevalent in emergency departments, geriatric, and psychiatric facilities. Physical violence and sexual harassment were most prevalent in Anglo countries, and nonphysical violence and bullying were most prevalent in the Middle East. Patients accounted for most physical violence in the Anglo region and Europe, and patient family and friends accounted for the most in the Middle East. PMID- 23433726 TI - [Awake craniotomy. Considerations in special situations]. AB - Awake craniotomy was the earliest surgical procedure known, and it has become fashionable again. In the past it was used for the surgical management of intractable epilepsy, but nowadays, its indications are increasing, and it is a widely recognized technique for the resection of mass lesions involving the eloquent cortex, and for deep brain stimulation. The procedure is safe, provides excellent results, and saves money and resources. The anesthesiologist should know the principles underlying neuroanesthesia, the technique of scalp blockade, and the sedation protocols, as well as feeling comfortable with advanced airway management. The main anesthetic aim is to keep patients cooperating when required (analgesia-based anesthesia). This review attempts to summarize the most recent evidence from the clinical literature, a long as the number of patients undergoing craniotomies in the awake state are increasing, specifically in the pediatric population. PMID- 23433727 TI - [Necrotising fasciitis caused by Vibrio vulnificus]. PMID- 23433728 TI - [Prevention of adverse events for patient safety in chronic pain treatment units]. AB - OBJECTIVES: To identify preventive actions that minimise risk of patients safety in pain treatment units, and to cluster preventive actions into homogeneous groups. The current study is part of a project intended to improve patient safety in pain treatment units, and is aimed at identifying, prioritising and preventing patient safety risk. MATERIAL AND METHODS: A group of experts was selected from professionals with a specific clinical background and experience in pain treatment units. This group was provided with information on patient safety and on known adverse events, errors and related causes. Through a brainstorming method the participants were asked: What changes or improvements would need to be undertaken to absolutely prevent the occurrence of each adverse event? The participant's proposals were analysed and grouped according to their homogeneity. RESULTS: A total of 456 preventive actions were identified. The group that received the highest number of suggestions was the one including changes in the management of healthcare processes, followed by the group that considered improvements in clinical practice, training activities, protocols and policies, and patient communication. CONCLUSIONS: According to the consensus of the experts, management of healthcare processes and improvements in health care practices are the 2 interventions that are most likely to reduce patient safety risk in pain treatment units. PMID- 23433729 TI - Influence of prolonged immersion on the resistance of arthroscopy knots in biological media. AB - INTRODUCTION: Biomechanical studies of arthroscopic knots have been performed on sutures that were tied manually and tested immediately after tying. We performed this study to evaluate the knot and the suture during the healing phase, which was not evaluated in these previous studies. Our hypothesis was that the biomechanics features of arthroscopic knots may change in relation to the duration of incubation in biological media simulating synovial fluid. Thus our goal was to study the influence of incubation for 30 days in biological media simulating body fluid using a device to standardize knot tying and allow comparison of arthroscopic sutures. MATERIALS AND METHODS: Three Ultra-High Molecular Weight PolyEthylene (UHMPWE) sutures (Fiberwire, Orthocord and Maxbraid) were tested with a self-locking slip knot (SMC knot). Sixty identical knots were tied using a standardized device, and divided into two groups: the control group " D0 " and the group " D30 " where the knots were soaked in biological media simulating body fluid for 30 days. Cyclic loading tests were then performed on the knots in each group using a machine to define four variables: clinical failure, ultimate failure, knot slippage and the characteristics of failure. RESULTS: There was no significant difference between the two groups for knot resistance at clinical failure or ultimate failure, without regard to the suture, (P<0.05). After cyclic loading, the most slippage occurred in the Orthocord (~5.6mm) then the Maxbraid (~3.55mm) and the Fiberwire (~2.51mm). The only suture whose slippage was influenced by the duration of incubation was Orthocord. At clinical failure, the loop that slipped the most was the Orthocord suture (~5.45mm) then the Fiberwire (~4.8mm) and the Maxbraid (~4.1mm). In the Orthocord and Maxbraid sutures, knot slippage after clinical failure significantly increased with the duration of suture incubation (P<0.05). The reason for failure was breakage from tearing of suture fibers in all cases. CONCLUSION: Prolonged incubation of arthroscopic suture knots influences slippage, which could result in unsuccessful primary attachment of the tendon during the healing phase. LEVEL OF EVIDENCE: Level IV. Biomechanical study. PMID- 23433730 TI - A neurolaw perspective on psychiatric assessments of criminal responsibility: decision-making, mental disorder, and the brain. AB - In some criminal law cases, the defendant is assessed by a forensic psychiatrist or psychologist within the context of an insanity defense. In this article I argue that specific neuroscientific research can be helpful in improving the quality of such a forensic psychiatric evaluation. This will be clarified in two ways. Firstly, we shall adopt the approach of understanding these forensic assessments as evaluations of the influence of a mental disorder on a defendant's decision-making process. Secondly, I shall point to the fact that researchers in neuroscience have performed various studies over recent years on the influence of specific mental disorders on a patient's decision-making. I argue that such research, especially if modified to decision-making in criminal scenarios, could be very helpful to forensic psychiatric assessments. This kind of research aims to provide insights not merely into the presence of a mental disorder, but also into the actual impact of mental disorders on the decisions defendants have made in regard to their actions. PMID- 23433732 TI - Association of GSTT1 and GSTM1 polymorphisms with early pregnancy loss in an Indian population and a meta-analysis. AB - Glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase Mu 1 (GSTM1) enzymes of the glutathione detoxification pathway protect the embryo from oxidative stress. This study investigated GSTT1 and GSTM1 in relation to their role in conferring genetic susceptibility to pregnancy loss. In a case-control study, 174 early pregnancy loss (EPL) patients, of which 130 were recurrent pregnancy loss (RPL) patients, and 180 healthy controls were investigated. Null genotypes of GSTT1 and GSTM1 were identified in duplex PCR reaction systems. Age adjusted odds ratios (aOR) were calculated by logistic regression analysis. A meta-analysis was also conducted. The GSTT1 null genotype was significantly associated with EPL (aOR 4.47, P=0.004) and RPL (aOR 4.39, P=0.006). No significant association of the GSTM1 null genotype was found with RPL. In a meta analysis study, the presence of the GSTM1 null genotype was shown to be a risk for RPL. The GSTT1 null genotype was not found to be a risk factor for pregnancy loss in the pooled population but its association with RPL was found in the Indian population. This study suggests that women carriers of GSTT1 and GSTM1 null genotypes are more often at genetic risk of pregnancy loss. Glutathione S transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1), enzymes of detoxification pathway, protect the embryo from oxidative stress. In the present study we have investigated GSTT1 and GSTM1 in relation to their role in conferring genetic susceptibility for early pregnancy loss (EPL) and recurrent pregnancy loss (RPL). Meta-analysis on the polymorphisms was conducted to support our findings that the presence of mutant genotypes at this site increases the risk of pregnancy loss. The GSTT1 null genotype was significantly associated with both EPL and RPL. In the meta-analysis, the overall result showed that the association between GSTM1 null genotype and risk for RPL was statistically significant. On comparing the GSTT1 studies, great heterogeneity was found between studies. A subgroup analysis was performed based on ethnicity. Our results showed a significantly increased risk with the GSTT1 null genotype in the Indian population, but no risk was found in the pooled population. In conclusion, the data of the present study clearly suggest that GSTT1 and GSTM1 polymorphisms are genetic risk factors for pregnancy loss in the study population. PMID- 23433733 TI - Medication information seeking behavior of patients who use multiple medicines: how does it affect adherence? AB - OBJECTIVE: This article explores medication information seeking behavior (MISB). We aimed to develop a scale for measuring MISB and use it to explore the relationships between MISB, adherence and factors, which drive information seeking. METHODS: Patients (N=910) using multiple medicines completed questionnaires. Exploratory and confirmatory factor analyses were performed. Correlations and multivariate analyses were used to investigate the relationships between variables. RESULTS: Respondents sought medication information mainly from health professionals and written medicines information. The medication information seeking behavior scale (MISB) had acceptable reliability and validity. Information seeking was most intense among respondents who had recent changes in their medicine regimen and worries about their medicines. Those who sought medication information from autonomous sources were more likely to be non adherent than those who never did (OR=2.00 [1.48, 2.70]). Seeking information from health professionals had no influence on adherence. CONCLUSION: Health practitioners should carefully attend to patients' questions about medicines information. When patients mention that they are worried about their medicines and have sought medication information from television, magazines, brochures or family and friends, this could be a sign that they tend towards non-adherent behavior. PRACTICE IMPLICATIONS: The MISB scale could be used to learn more about patients' use of medication information. PMID- 23433734 TI - Development and psychometric validation of a scale to assess information needs in cardiac rehabilitation: the INCR Tool. AB - OBJECTIVE: To develop and psychometrically validate a tool to assess information needs in cardiac rehabilitation (CR) patients. METHODS: After a literature search, 60 information items divided into 11 areas of needs were identified. To establish content validity, they were reviewed by an expert panel (N=10). Refined items were pilot-tested in 34 patients on a 5-point Likert-scale from 1 "really not helpful" to 5 "very important". A final version was generated and psychometrically tested in 203 CR patients. Test-retest reliability was assessed via the intraclass correlation coefficient (ICC), the internal consistency using Cronbach's alpha, and criterion validity was assessed with regard to patient's education and duration in CR. RESULTS: Five items were excluded after ICC analysis as well as one area of needs. All 10 areas were considered internally consistent (Cronbach's alpha>0.7). Criterion validity was supported by significant differences in mean scores by educational level (p<0.05) and duration in CR (p<0.001). The mean total score was 4.08 +/- 0.53. Patients rated safety as their greatest information need. CONCLUSION: The INCR Tool was demonstrated to have good reliability and validity. PRACTICE IMPLICATIONS: This is an appropriate tool for application in clinical and research settings, assessing patients' needs during CR and as part of education programming. PMID- 23433735 TI - Web-based, self-management enhancing interventions with e-diaries and personalized feedback for persons with chronic illness: a tale of three studies. AB - OBJECTIVE: Chronic illness places high demands on patients. Interventions supporting self-management and providing personalized feedback might help patients to gain new perspectives and enhance use of constructive self-management strategies. We developed three comparable web-based CBT-grounded interventions including e-diaries and feedback delivered through PDAs/smartphones. The feasibility and efficacy of these interventions have been investigated for patients with irritable bowel syndrome (in an RCT), chronic widespread pain (RCT) and type 2 diabetes (feasibility study). METHODS: This is a descriptive study that summarizes the content, feasibility and efficacy of the interventions and discusses issues relevant for implementing this type of web-based therapeutic interventions in clinical practice. RESULTS: The web-based interventions appear feasible, acceptable and supportive. In a short and midterm time frame, the interventions promote self-management. CONCLUSION: Booster sessions may be needed for prolonged effects. Given the physical and mental symptoms of the patients under study and the nature of the intervention, providers who deliver the feedback need a health care background and training in this specific way of counseling. PRACTICE IMPLICATIONS: The results of the three studies suggest that personalized web-based interventions are effective and have the potential to support self-management in daily healthcare. Studies concerning clinical significance and implementation are needed. PMID- 23433736 TI - gamma irradiation with different dose rates induces different DNA damage responses in Petunia x hybrida cells. AB - In plants, there is evidence that different dose rate exposures to gamma (gamma) rays can cause different biological effects. The dynamics of DNA damage accumulation and molecular mechanisms that regulate recovery from radiation injury as a function of dose rate are poorly explored. To highlight dose-rate dependent differences in DNA damage, single cell gel electrophoresis was carried out on regenerating Petunia x hybrida leaf discs exposed to LDR (total dose 50 Gy, delivered at 0.33 Gy min(-1)) and HDR (total doses 50 and 100 Gy, delivered at 5.15 Gy min(-1)) gamma-ray in the 0-24h time period after treatments. Significant fluctuations of double strand breaks and different repair capacities were observed between treatments in the 0-4h time period following irradiation. Dose-rate-dependent changes in the expression of the PhMT2 and PhAPX genes encoding a type 2 metallothionein and the cytosolic isoform of ascorbate peroxidase, respectively, were detected by Quantitative RealTime-Polymerase Chain Reaction. The PhMT2 and PhAPX genes were significantly up-regulated (3.0- and 0.7 fold) in response to HDR. The results are discussed in light of the potential practical applications of LDR-based treatments in mutation breeding. PMID- 23433737 TI - The platelet-cancer loop. AB - The relationship between cancer and thrombosis has been established since 1865 when Armand Trousseau described superficial thrombophlebitis as forewarning sign of occult visceral malignancy. Platelets are the primary hemostatic tool and play a primordial role in cancer-induced thrombosis. Tumor-induced numerical and functional platelet abnormalities have been described in conjunction to changes in coagulation. Such changes are reported even in the absence of clinically detectable thrombosis and correlate with tumor progression and metastasis. Reciprocally, platelets seem to interplay with the tumors and the immune system, both directly and indirectly favoring tumor progressions, tethering and distant spread. A number of growth factors supporting tumor growth, angiogenesis and metastasis are released from the platelets. A reciprocating loop of tumor-induced platelet activation/platelet-induced tumor growth and dissemination is initiated, acting as a thrombosis trigger/tumor amplifier. Recent studies have demonstrated that the use of anti-platelet agents can break this loop resulting in a reduction of short-term risk for incident cancer, cancer mortality and metastasis. The beneficial effect in reduction in cancer-induced thrombosis remains to be established. The current review aims at shedding the light on the intimate reciprocal cross-talk between platelets and cancer and on exploring the potential beneficial effect of anti-platelet agents in breaking the deadly loop of tumor amplification. PMID- 23433738 TI - First-line treatment of indolent lymphoma: axing CHOP? PMID- 23433740 TI - Cholinergic markers in the cortex and hippocampus of some animal species and their correlation to Alzheimer's disease. AB - INTRODUCTION: The cholinergic system includes neurons located in the basal forebrain and their long axons that reach the cerebral cortex and the hippocampus. This system modulates cognitive function. In Alzheimer's disease (AD) and ageing, cognitive impairment is associated with progressive damage to cholinergic fibres, which leads us to the cholinergic hypothesis for AD. DEVELOPMENT: The AD produces alterations in the expression and activity of acetyltransferase (ChAT) and acetyl cholinesterase (AChE), enzymes specifically related to cholinergic system function. Both proteins play a role in cholinergic transmission, which is altered in both the cerebral cortex and the hippocampus due to ageing and AD. Dementia disorders are associated with the severe destruction and disorganisation of the cholinergic projections extending to both structures. Specific markers, such as anti-ChAT and anti-AChE antibodies, have been used in light immunohistochemistry and electron microscopy assays to study this system in adult members of certain animal species. CONCLUSIONS: This paper reviews the main immunomorphological studies of the cerebral cortex and hippocampus in some animal species with particular emphasis on the cholinergic system and its relationship with the AD. PMID- 23433741 TI - Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit. AB - Considerable evidence suggests that cannabinoids modulate the behavioral and physiological response to stressful events. We have recently shown that activating the cannabinoid system using the CB1/CB2 receptor agonist WIN55,212-2 (WIN) in proximity to exposure to single-prolonged stress (SPS), a rat model of emotional trauma, prevented the stress-induced enhancement of acoustic startle response, the impairment in avoidance extinction and the enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis (Ganon-Elazar and Akirav, 2012). Some of the effects were found to be mediated by CB1 receptors in the basolateral amygdala (BLA). Here we examined whether cannabinoid receptor activation in a putative brain circuit that includes the BLA, hippocampus and prefrontal cortex (PFC), could prevent the effects of traumatic stress on contextual fear extinction and alterations in glucocorticoid receptor (GR) protein levels. We found that: (i) SPS impaired contextual fear extinction tested one week after trauma exposure and that WIN prevented the stress-induced impairment of extinction when microinjected immediately after trauma exposure into the BLA or hippocampus (5 MUg), but not when microinjected into the PFC, (ii) the ameliorating effects of WIN on contextual extinction were prevented by blocking GRs in the BLA and hippocampus, and (iii) SPS up regulated GRs in the BLA, PFC and hippocampus and systemic WIN administration (0.5 mg/kg) after trauma exposure normalized GR levels in the BLA and hippocampus, but not in the PFC. Cannabinoid receptor activation in the aftermath of trauma exposure may regulate the emotional response to the trauma and prevent stress-induced impairment of extinction and GR up regulation through the mediation of CB1 receptors in the BLA and hippocampus. Taken together, the findings suggest that the interaction between the cannabinoid and glucocorticoid systems is crucial in the modulation of emotional trauma. PMID- 23433742 TI - Endometrial cancer: molecular and therapeutic aspects. AB - Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy. Although early-stage EC is effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. Chemotherapy has evolved into an important modality in high-risk early stage and advanced-stage disease, and in recurrent EC. Multi-institutional trials are in progress to better define optimal adjuvant treatment for subsets of patients, as well as the role of surgical staging in reducing both overuse and underuse of radiation therapy. Understanding and identifying the molecular biology and genetics of EC are central to the development of novel therapies. A number of molecular and genetic events have been observed in ECs, which have enabled us to have a better understanding of the biology and development of the disease. For example, the PTEN/AKT pathway and its downstream targets and the mTOR pathway have been shown to play an important role in EC pathogenesis. This review summarizes the background of the known molecular alterations, and the management of patients with EC. PMID- 23433743 TI - Placental expression of microRNA-17 and -19b is down-regulated in early pregnancy loss. AB - OBJECTIVE: First, to determine if microRNA-17 and -19b are expressed in villous samples at early stages of pregnancy. Second, to determine whether placental expressions of these microRNAs along with their main targets (PTEN, CREB-1, TGFbeta-1 and TGFbeta-RII) are altered in early pregnancy loss. STUDY DESIGN: Expression levels of microRNAs and mRNA targets in villous samples from early pregnancy loss (n=11) and matched normal cases (n=20) by gestational age were determined by RT-PCR. RESULTS: Both microRNA-17 and -19b were expressed in all cases of normal pregnancy. They were significantly down-regulated (relative ratios: 0.35 and 0.34 respectively) in early pregnancy loss. Their main target, PTEN mRNA, was significantly up-regulated in early pregnancy loss (relative ratio: 2.6, 95%CI: 0.2-29.8). TGF-beta1, CREB-1 and TGFbeta-RII were not significantly different between the two groups. CONCLUSION: microRNA-17 and -19b are expressed in early stages of pregnancy. They are down-regulated in villous samples from early pregnancy loss. We suggest that these main members of the microRNA-17-92 cluster might be involved in placental invasion and its dysregulation might also be related to other conditions characterized by defective placentation. PMID- 23433739 TI - Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. AB - BACKGROUND: Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle cell lymphomas. METHODS: We did a prospective, multicentre, randomised, open label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved >=3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024). INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects. FUNDING: Roche Pharma AG, Ribosepharm/Mundipharma GmbH. PMID- 23433744 TI - The serum protein alpha2-Heremans-Schmid glycoprotein/fetuin-a concentration and carotid intima-media thickness in women with polycystic ovary syndrome. AB - OBJECTIVE: To investigate fetuin-A concentrations and its association with metabolic and sonographic cardiovascular markers in women with polycystic ovary syndrome (PCOS) and healthy subjects. STUDY DESIGN: Thirty-five women with PCOS and 37 healthy control women were matched for body mass index (BMI) and age. Serum fetuin-A concentrations, and reproductive and adrenal hormones were measured, and insulin resistance and carotid intima media thickness (CIMT) were evaluated in both groups. The correlations between cardiovascular risk factors, CIMT and fetuin-A concentrations were tested. RESULTS: Mean fetuin-A concentrations were significantly elevated in the PCOS group compared with control subjects (101.2 ng/ml +/- 33.55 vs. 82.5 ng/ml +/- 32.65, P=0.019). CIMT was also higher in women with PCOS than in control subjects (0.51 +/- 0.05 mm vs. 0.44 +/- 0.05 mm, P<0.01). Serum lipid parameters were correlated to serum fetuin A concentrations in the PCOS group, but no correlation was found between fetuin-A and CIMT (rPCOS=0.244, pPCOS=0.158; rcontrol=-0.002, pcontrol=0.988). CONCLUSION: In this, the first study of fetuin-A concentrations in PCOS, the results showed that fetuin-A concentrations were increased in euglycemic patients with PCOS. PMID- 23433745 TI - Video endoscopic inguinal lymphadenectomy: surgical and oncological results. AB - INTRODUCTION: We evaluated the reproducibility of video endoscopic inguinal lymphadenectomy (VEIL) and we report our initial experience in the treatment of penile cancer with palpable inguinal lymph nodes. MATERIAL AND METHODS: From July 2006 to November 2010 were conducted 33 VEIL in 20 patients as complementary treatment for penile cancer in two referral hospitals in Latin America. We analyzed the epidemiological and clinical characteristics of patients and surgical and oncologic outcomes. RESULTS: Fifty-five percent of the patients included were clinical stage N0 and 45% were N +. Thirteen patients underwent bilateral VEIL and the remaining seven underwent VEIL unilateral and conventional open surgery in the contralateral limb. The average operative time for VEIL was 119 minutes and mean resected lymph nodes was 8 per lymphadenectomy. The overall complication rate was 33.2%. No patient had skin necrosis. The lymphatic complication rate was 27.2%. Of the 6 cases in which the saphenous vein was preserved (18.2%) there were no lymphatic complications (P=,2). The overall survival rate was 80% and cancer-specific survival was 90%. Mean follow-up was 20 months. CONCLUSIONS: VEIL in the adjunctive treatment of penile cancer is safe, reproducible and may be an alternative to conventional lymphadenectomy. Patients with palpable lymphadenopathy also may benefit from this technique. Oncological results seem to be adequate however require longer follow-up to be confirmed. PMID- 23433746 TI - An autopsy case of a homeless person with unilateral lower extremity edema. AB - We present an autopsy case of a homeless person showing remarkable unilateral lower extremity edema, which was strongly associated with the cause of death. A 55-year-old homeless man without any past medical history was found dead in a flophouse. External examination showed evidence of malnourishment and remarkable swelling of the right, lower extremity. Putrefactive discoloration in the same area was evident at the time of autopsy (approximately 30h post-mortem). The autopsy revealed focal pneumonia in the right lower lobe, dehydration and chronic pancreatitis. Dissection of the edematous extremity revealed massive abscess formation in the subcutaneous tissue and superficial fascia around the right knee joint. Histopathological findings were compatible with necrotizing fasciitis and blood chemistry results showed an elevation of HbA1c (6.3%). The cause of death is considered to be necrotizing fasciitis and secondary pneumonia/dehydration. This case suggests that necrotizing fasciitis should be differentiated during postmortem diagnosis, especially in cases showing lower extremity edema with early putrefactive changes. In addition, forensic pathologists should closely examine a lower extremity of such cases to detect a true cause of death, even if other pathological findings which can be a cause of death, such as pneumonia and dehydration, are observed in major internal organs. PMID- 23433748 TI - Prenatal maternal mood is associated with altered diurnal cortisol in adolescence. AB - BACKGROUND: Experimental animal work shows that prenatal stress has a persisting effect on the hypothalamic-pituitary-adrenal (HPA) axis of offspring. The implications of these findings for human health and development are not yet clear. METHODS: The data are based on the ALSPAC cohort, a prospective longitudinal study of a community sample that has followed mothers and children from pregnancy. When the children were aged 15 years, diurnal cortisol samples were collected at wake-up, 30 min post-awakening and at afternoon and evening times on up to three consecutive days on n=889 adolescents. Diurnal cortisol was predicted from prenatal anxiety and depression, obstetric, life-style, socio demographic, and postnatal covariates. RESULTS: Multilevel model analysis indicated that maternal prenatal anxiety was associated with a modest alteration of diurnal cortisol, indexed by a reduced cortisol awakening response and flatter diurnal slope. The effects were independent of psychosocial and obstetric covariates and measures of maternal postnatal anxiety; effects were similar for prenatal maternal depression. There was no association between adolescent cortisol and paternal prenatal anxiety. CONCLUSIONS: There are small but persisting associations between maternal prenatal mood and diurnal cortisol in the child that persist into adolescence and may constitute a programming effect. PMID- 23433749 TI - Blunted nocturnal cortisol rise is associated with higher carotid artery intima media thickness (CIMT) in overweight African American and Latino youth. AB - BACKGROUND: Blunted diurnal cortisol variation has been associated with overt cardiovascular disease in adults. The relationship between the diurnal cortisol variation and subclinical atherosclerosis in youth has yet to be investigated. The objectives of this study were to (1) determine the relationship between overnight cortisol measures and CIMT in overweight and obese, African-American and Latino children; (2) assess ethnic differences in these relationships; and (3) explore whether overnight cortisol and CIMT relationships were independent of inflammatory markers, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-? (TNF-?). METHODS: One hundred fifty-six overweight and obese African-American and Latino children (ages 8-17, 86 M/70 F, 55 African American/101 Latino) underwent measures of CIMT by B-mode ultrasound, nocturnal cortisol rise (NCR = salivary cortisol rise from 2200 h to awakening at 0530 h), cortisol awakening response (CAR = salivary cortisol from time of awakening to 30 min later), fasting serum cortisol and overnight urinary free cortisol. RESULTS: Using linear regression, salivary cortisol(0530 h) and NCR were negatively associated with CIMT (beta(standardized) = -0.215 and -0.220, p < 0.01) independent of age, height, percent body fat, ethnicity and systolic blood pressure. Nocturnal salivary cortisol(2200 h), morning serum cortisol, and overnight urinary free cortisol were not associated with CIMT. Using ANCOVA, participants with LOW NCR (NCR < 0.44 MUg/dL, n = 52) had significantly greater CIMT than those with HIGH NCR (NCR >= 0.91 MUg/dL, n = 52; 0.632 +/- 0.008 vs. 0.603 +/- 0.008 mm, p=0.01) after controlling for covariates. Ethnicity was independently associated with CIMT, whereby African-American children had greater CIMT than Latino children (-0.028 +/- 0.009, p=0.006). The relationships between cortisol measures and CIMT did not differ between the two ethnic groups (all p(interaction) = 0.28-0.97). CRP, IL-6 and TNF-? were not associated with CIMT (p > 0.05). IL-6 was inversely related to NCR (r = -0.186, p = 0.03), but it did not explain the relationship between NCR and CIMT. CONCLUSIONS: Salivary cortisol(0530 h) and NCR, but not CAR, nocturnal salivary cortisol(2200 h), morning serum cortisol or overnight urinary free cortisol were associated with CIMT, independent of relevant covariates, including inflammatory factors. A low awakening salivary cortisol or a blunted NCR may be related to increased atherosclerosis risk in overweight and obese minority youth. These findings support adult studies suggesting flattened daytime diurnal cortisol variation impacts cardiovascular disease risk. PMID- 23433750 TI - The effect of an electronic medicine dispenser on diversion of buprenorphine naloxone-experience from a medium-sized Finnish city. AB - Providing unobserved opioid substitution treatment (OST) safely is a major challenge. This study examined whether electronic medicine dispensers (EMDs) can reduce diversion of take-home buprenorphine-naloxone (BNX) in a medium-sized Finnish city. All BNX treated OST patients in Kuopio received their take-home BNX in EMDs for 4months. EMDs' effect on diversion was investigated using questionnaires completed by patients (n=37) and treatment staff (n=19), by survey at the local needle exchange service and by systematic review of drug screen data from the Kuopio University Hospital. The majority of patients (n=21, 68%) and treatment staff (n=11, 58%) preferred to use EMDs for the safe storage of tablets. Five patients (16%) declared that EMDs had prevented them from diverting BNX. However, EMDs had no detectable effect on the availability or origin of illegal BNX or on the hospital-treated buprenorphine-related health problems. EMDs may improve the safety of storage of take-home BNX, but their ability to prevent diversion needs further research. PMID- 23433751 TI - Management of chronic proximal fistulas after sleeve gastrectomy by laparoscopic Roux-limb placement. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an increasingly popular bariatric procedure. However, after LSG, leaks may occur that are difficult to treat and that can persist for months. Treatment is controversial and ranges from stent placement to total gastrectomy. We propose an alternative laparoscopic treatment. The aims of our study were to report on the incidence of chronic fistulas after LSG and the outcome of Roux-limb placement on these defects. The setting was a major teaching hospital in Belgium. METHODS: From January 1, 2002, to December 31, 2011, we performed LSG as a primary weight loss operation (PLSG) in 728 patients and as a corrective operation (CLSG) in 84 patients. A retrospective chart and database review was conducted. When a chronic leak persisted beyond 4 months, we performed a laparoscopic Roux-limb placement on the defect. RESULTS: Leaks occurred in 26 patients (3.6%) after PLSG and in 6 (7.1%) after CLSG. A leak persisted beyond 4 months in 7 patients (26.9%) after PLSG and in 2 patients (33.3%) after CLSG. Two patients with a chronic fistula after PLSG were referred to our hospital. In 11 patients, a Roux limb was laparoscopically sutured to the defect. The mean time for a chronic fistula to heal after Roux limb placement was 12.5+/-10.2 days, and the mean length of hospital stay was 19.6+/- 14.2. CONCLUSION: Proximal leaks after LSG are relatively rare. However, a significant number become chronic. Laparoscopic placement of a Roux-limb on the defect is a safe treatment with an eventual succes rate of 100%. PMID- 23433752 TI - Successful orthotopic liver transplantation after biliopancreatic diversion with duodenal switch. PMID- 23433753 TI - Biliary endoprosthesis in the management of gastric leak after sleeve gastrectomy. PMID- 23433754 TI - Diaphragmatic Richter's type of hernia involving the transverse colon after laparoscopic gastric bypass: an unusual complication. PMID- 23433755 TI - Non-surgical management of posterior positional plagiocephaly: orthotics versus repositioning. AB - OBJECTIVE: Evaluate from the literature, the evidence of comparative efficiency of non-surgical treatments (orthotics or head repositioning therapy) in posterior positional plagiocephaly. MATERIAL AND METHODS: Systematic review from scientific articles (original cohort studies and review of literature), published in French or in English, searched on five online literature data bases, comparing non chirurgical treatments (repositioning and orthotics therapy) for deformational plagiocephaly. A standardized method guidelines (Critical Review Form Quantitative Studies) has been used. RESULTS: Only 11 cohort studies met the inclusion criteria and six reviews of literature were analyzed. Many biases have been identified, most of the time, favoring the repositioning groups (older infants and plagiocephaly more severe). CONCLUSIONS: Several different orthotics seem to correct head deformities better and faster than repositioning protocols. Evaluation methods, treatment indications and long-term efficacy should be clarified. Studies about treatment risks are warranted. PMID- 23433756 TI - Joint CT/CBCT deformable registration and CBCT enhancement for cancer radiotherapy. AB - This paper details an algorithm to simultaneously perform registration of computed tomography (CT) and cone-beam computed (CBCT) images, and image enhancement of CBCT. The algorithm employs a viscous fluid model which naturally incorporates two components: a similarity measure for registration and an intensity correction term for image enhancement. Incorporating an intensity correction term improves the registration results. Furthermore, applying the image enhancement term to CBCT imagery leads to an intensity corrected CBCT with better image quality. To achieve minimal processing time, the algorithm is implemented on a graphic processing unit (GPU) platform. The advantage of the simultaneous optimization strategy is quantitatively validated and discussed using a synthetic example. The effectiveness of the proposed algorithm is then illustrated using six patient datasets, three head-and-neck datasets and three prostate datasets. PMID- 23433757 TI - Intravascular ultrasound predictors for edge restenosis after newer generation drug-eluting stent implantation. AB - The aim of the present study was to assess the intravascular ultrasound predictors for angiographic edge restenosis after newer generation drug-eluting stent implantation. A total of 820 patients (987 lesions) who underwent newer generation drug-eluting stent placement (236 Endeavor zotarolimus-eluting stents, 246 Resolute zotarolimus-eluting stents, and 505 everolimus-eluting stents) with 9 months of angiographic surveillance were enrolled. The post-stenting angiographic and intravascular ultrasound images of 1,668 reference segments (681 proximal and 987 distal) were analyzed. Overall, 37% of angiographically normal proximal reference segments and 21% of angiographically normal distal reference segments had plaque burden >50%. In the overall cohort of 1,668 reference segments, 47 (2.8%) had 9-month angiographic edge restenosis (diameter stenosis >50%). Edge restenosis was predicted by a post-stenting reference segment plaque burden >54.5% (sensitivity 81%, specificity 80%) and a reference segment minimum lumen area of 5.7 mm(2) (sensitivity 72%, specificity 59%). The edge restenosis rate was 2.1% in the Endeavor zotarolimus-eluting stents, 2.4% in the Resolute zotarolimus-eluting stents, and 3.4% in the everolimus-eluting stents lesions (p = 0.311). The predictive cutoff of the reference plaque burden was 56.3% for Endeavor zotarolimus-eluting stents, 57.3% for Resolute zotarolimus-eluting stents, and 54.2% for everolimus-eluting stents. The criteria for residual plaque burden were similar between proximal and distal reference segments (56.4% vs 51.9%, respectively), but the minimum lumen area criteria were quite different (<7.1 mm(2) for proximal vs <4.8 mm(2) for distal reference segments). In conclusion, after newer drug-eluting stent implantation, edge restenosis was predicted by post-stenting reference segment plaque burden >55%. PMID- 23433758 TI - A pilot study identifying statin nonadherence with visit-to-visit variability of low-density lipoprotein cholesterol. AB - Nonadherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication nonadherence. The visit-to-visit variability (VVV) of low-density lipoprotein (LDL) cholesterol might represent an opportunity to identify statin nonadherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center Health Plan, seen at either the Boston Medical Center or its affiliated community health centers, who were taking statins and had >=3 LDL cholesterol measurements from 2008 to 2011. The LDL cholesterol VVV (defined by the within-patient SD) was categorized into quintiles. Multivariate logistic regression models were generated with statin nonadherence (defined by the standard 80% pharmacy refill-based medication possession ratio threshold) as the dependent variable. The proportion of statin nonadherence increased across the quintiles of LDL cholesterol VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL cholesterol VVV had a strong positive association with statin nonadherence, with an adjusted odds ratio of 3.4 (95% confidence interval 1.7 to 7.1) in the highest versus lowest quintile of LDL cholesterol VVV. The age- and gender-adjusted model had poor discrimination (C statistic 0.62, 95% confidence interval 0.57 to 0.67), but the final adjusted model (age, gender, race, mean LDL cholesterol) demonstrated good discrimination (C-statistic 0.75, 95% confidence interval 0.71 to 0.79) between the adherent and nonadherent patients. In conclusion, the VVV of LDL cholesterol demonstrated a strong association with statin nonadherence in a clinic setting. Furthermore, a VVV of LDL cholesterol-based model had good discrimination characteristics for statin nonadherence. Research is needed to validate and generalize these findings to other populations and biomarkers. PMID- 23433759 TI - Effect of age, gender, and left ventricular diastolic function on left atrial volume index in adults without known cardiovascular disease or risk factors. AB - There are limited data on reference values of left atrial volume indexes (LAVIs) in adults without known cardiovascular disease or risk factors, as well as their stratification by age, gender, and diastolic stage. LAVIs were calculated using the biplane area-length method in accordance with guidelines in 966 consecutive patients (mean age 48.0 +/- 15.7 years) with no known cardiovascular disease or risk factors, with preserved left ventricular systolic function and normal or grade I diastolic dysfunction (DD). The mean LAVI was 23 +/- 8 ml/m(2). Using a conventional cut-off value of 34 ml/m(2) (mean + 2 SDs of the values derived from the guidelines) to define abnormal LAVI would label about 10% of patients as having dilated left atria and structural heart disease, whereas using the American Society of Echocardiography's recommended cutoff of the mean + 1 SD (i.e., 28 ml/m(2)) would do so for up to about 20%. The mean LAVI was similar between the genders (p = 0.10) and among different age groups (p = 0.60 for the trend across decades). Finally, when stratified by diastolic function, the mean LAVIs were 23.2 +/- 8.3 and 22.2 +/- 8.7 ml/m(2) for patients with normal (n = 653) and grade I DD (n = 313), respectively (p = 0.10). In conclusion, in this cohort of patients without known cardiovascular disease or risk factors, the cut off values for abnormal LAVI were greater than those adopted in the guidelines. There was no variation, however, by gender, age, or grade I DD, although subjects with long-standing grade I DD and/or high filling pressures were likely underrepresented. PMID- 23433760 TI - Prognostic value of depression, anxiety, and anger in hospitalized cardiovascular disease patients for predicting adverse cardiac outcomes. AB - Although attention has recently been focused on the role of psychosocial factors in patients with cardiovascular disease (CVD), the factors that have the greatest influence on prognosis have not yet been elucidated. The aim of this study was to evaluate the effects of depression, anxiety, and anger on the prognosis of patients with CVD. Four hundred fourteen consecutive patients hospitalized with CVD were prospectively enrolled. Depression was evaluated using the Patient Health Questionnaire, anxiety using the Generalized Anxiety Disorder Questionnaire, and anger using the Spielberger Trait Anger Scale. Cox proportional-hazards regression was used to examine the individual effects of depression, anxiety, and anger on a combined primary end point of cardiac death or cardiac hospitalization and on a combined secondary end point of all-cause death or hospitalization during follow-up (median 14.2 months). Multivariate analysis showed that depression was a significant risk factor for cardiovascular hospitalization or death after adjusting for cardiac risk factors and other psychosocial factors (hazard ratio 2.62, p = 0.02), whereas anxiety was not significantly associated with cardiovascular hospitalization or death after adjustment (hazard ratio 2.35, p = 0.10). Anger was associated with a low rate of cardiovascular hospitalization or death (hazard ratio 0.34, p <0.01). In conclusion, depression in hospitalized patients with CVD is a stronger independent risk factor for adverse cardiac events than either anxiety or anger. Anger may help prevent adverse outcomes. Routine screening for depression should therefore be performed in patients with CVD, and the potential effects of anger in clinical practice should be reconsidered. PMID- 23433761 TI - One- and twelve-month safety and efficacy outcomes of patients undergoing edge-to edge percutaneous mitral valve repair (from the GRASP Registry). AB - The aim of this study was to report on the 30-day and 1-year outcomes of percutaneous mitral valve repair with the MitraClip technique in patients with grade >=3+ mitral regurgitation (MR) at high risk for conventional surgical therapy enrolled in the prospective Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation (GRASP) registry. Acute device success was defined as residual MR <=2+ after clip implantation. The primary safety end point was the rate of major adverse events at 30 days. The primary efficacy end point was freedom from death, surgery for mitral valve dysfunction, or grade >=3+ MR at 30 days and 1 year. A total of 117 patients were treated. Eighty-nine patients (76%) presented with functional MR and 28 patients (24%) with organic MR. Acute device success was observed in all patients. Device implantation time significantly diminished with experience and varied significantly between cases with 1 versus >=2 clips. No procedural mortality was recorded. Major adverse events occurred in 4 patients at 30 days (4.3%). Deterioration to MR >=3+ was recorded in 25% of patients with degenerative MR and 7% of those with functional MR at 1 year. No surgery for mitral valve dysfunction occurred within 1 year. Freedom from death, surgery for mitral valve dysfunction, or grade >=3+ MR was 96.4% and 75.8% at 30 days and 1 year, respectively. No significant differences were noted in the primary efficacy end point between patients with degenerative MR and those with functional MR. In conclusion, percutaneous mitral valve repair with the MitraClip technique was shown to be safe and reasonably effective in 117 patients from a real-world setting. PMID- 23433762 TI - Transesophageal echocardiography for cardiac thromboembolic risk assessment in patients with severe, symptomatic aortic valve stenosis referred for potential transcatheter aortic valve implantation. AB - Stroke is a devastating complication after transcatheter aortic valve implantation (TAVI) and might partially be related to cardiac embolization. The aim of this single-center prospective study was to determine the incidence of intracardiac thrombi and left atrial spontaneous echo contrast (SEC), both known predictors of cardiac embolic stroke, in patients referred for potential TAVI. One hundred four consecutive patients with severe symptomatic aortic valve stenosis and at high or very high risk for surgery were included and underwent transesophageal echocardiography. In 11 patients (10.6%), intracardiac thrombi were detected, and 25 patients (24%) showed dense grade 2 SEC. Atrial fibrillation (p <0.0001), diastolic dysfunction (p = 0.0005), and atrial size (p = 0.0038) were related to the presence of intracardiac thrombus and/or dense SEC on multivariate analysis. In conclusion, the incidence of intracardiac thrombi and dense SEC in (very) high-risk patients with severe aortic valve stenosis referred for potential TAVI is high and can accurately be detected using transesophageal echocardiography. Systematic thromboembolic evaluation using transesophageal echocardiography is thus recommended in patients referred for TAVI. PMID- 23433763 TI - A 43- to 54-year follow-up of 1,000 patients with congenital heart disease. AB - From 1952 to 1963, 1,000 consecutive children with congenital heart disease were evaluated by 1 of us (R.C.A.). Current information for 994 patients with 36,086 patient-years is available. Of these, 362 have died, 130 as adults, of whom 67 died from a cardiac cause. Of the remaining 638 patients, 632 were living, and 6 were lost to follow-up. The survival curves for ventricular septal defect, atrial septal defect, patent ductus arteriosus, and pulmonary stenosis paralleled the normal curve. Cyanotic patients had a markedly reduced curve, with 19% alive at 50 years. Most patients were New York Heart Association class I, with only 3 in class IV, each from noncardiac causes. In conclusion, this experience should be helpful to physicians caring for adults with congenital heart disease and provide an optimistic outlook for the patients with less complex conditions. PMID- 23433764 TI - Long-term complications of implantable defibrillator therapy in Brugada syndrome. AB - Although the benefits of implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada syndrome (BrS) at risk of sudden cardiac arrest are well established, these relatively young patients can encounter complications in the long term. The objective of the present study was to determine the incidence of device complications in patients with BrS during long-term follow-up. The prevalence of device-related complications and the clinical outcome were determined in 41 consecutive patients with BrS (age 48 +/- 12 years; 38 men) who were treated with ICD implantation. During a median follow-up of 76 months (interquartile range 51 to 98), 15 patients (37%) experienced 21 adverse events, including 11 device-related complications in 8 (20%) and >=1 inappropriate shock in 10 (24%). Five patients (12%) received appropriate shocks for ventricular fibrillation. Excluding inappropriate shocks, 95.1%, 89.6%, 86.6%, and 73.3% of patients were free of device-related complications at 1, 3, 5, and 7 years, respectively. Also, 92.6%, 89.8%, 89.9%, and 86.1% were free of lethal arrhythmias at 1, 3, 5, and 7 years, respectively. Adverse effects related to ICD implantation are not uncommon, and their prevalence increases with the follow-up duration required for patients with BrS. In conclusion, because complications can be encountered even very late after device implantation, asymptomatic young patients should be carefully selected and educated about the long-term outcomes of ICD therapy. PMID- 23433765 TI - Relation between optimism and lipids in midlife. AB - The present research examined optimism's relation with total cholesterol, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. The hypothesis that optimism is associated with a healthier lipid profile was tested. The participants were 990 mostly white men and women from the Midlife in the United States study, who were, on average, 55.1 years old. Optimism was assessed by self-report using the Life Orientation Test. A fasting blood sample was used to assess the serum lipid levels. Linear and logistic regression models examined the cross-sectional association between optimism and lipid levels, accounting for covariates such as demographic characteristics (e.g., education) and health status (e.g., chronic medical conditions). After adjusting for covariates, the results suggested that greater optimism was associated with greater high-density lipoprotein cholesterol and lower triglycerides. Optimism was not associated with low-density lipoprotein or total cholesterol. The findings were robust to a variety of modeling strategies that considered the effect of treatment of cholesterol problems. The results also indicated that diet and body mass index might link optimism with lipids. In conclusion, this is the first study to suggest that optimism is associated with a healthy lipid profile; moreover, these associations can be explained, in part, by the presence of healthier behaviors and a lower body mass index. PMID- 23433766 TI - Comparison of electrocardiographic QTc duration in patients with supravalvar aortic stenosis with versus without Williams syndrome. AB - Cardiovascular abnormalities in Williams syndrome (WS) are largely attributable to elastin haploinsufficiency resulting from a large deletion of the elastin containing region on chromosome 7q11.23. The risk of sudden death in patients with WS is 25- to 100-fold greater than that in the general population. The corrected QT (QTc) interval is prolonged in 14% of patients with WS. Patients with nonsyndromic supravalvar aortic stenosis (NSVAS) have elastin mutations resulting in elastin haploinsufficiency and a vascular phenotype nearly identical to that of WS. No previous studies have evaluated the QTc duration in NSVAS. A retrospective review of all electrocardiograms (ECGs) performed on consecutive patients with NSVAS at Arkansas Children's Hospital from January 1, 1985 to January 1, 2012 was completed. ECGs with nonsinus rhythm or unmeasurable intervals were excluded. The ECGs were read by 1 reader who was unaware of previous readings. A QTc interval of >=460 ms was defined as prolonged. The NSVAS cohort was compared to previously published WS and control groups using the mixed model for continuous electrocardiographic variables and the generalized estimating equation for binary indicators for prolonged QTc. The generalized estimating equation used bootstrapping with 1,000 replicates. A total of 300 ECGs (median 6, range 1 to 27) from the 35 identified patients with NSVAS met the inclusion criteria. A total of 482 ECGs from patients with WS and 1,522 ECGs from controls were included. The mean age of the patients with NSVAS at ECG was 7.3 +/ 6.9 years; 64% were male. The mean QTc duration was 409 +/- 20 ms in the NSVAS group, 418 +/- 17 ms in the control group (p <0.001), and 436 +/- 27 ms in the WS group (p <0.001 compared to the control group). The prevalence of QTc prolongation was 0.3% in the NSVAS group, 2.0% in the control group (p <0.001), and 14.8% in the WS group (p <0.001 compared to controls). No patients with NSVAS died. In conclusion, cardiac repolarization is normal in patients with NSVAS. Elastin haploinsufficiency does not appear to be the etiology of QTc prolongation in patients with WS. The possible contribution of other genes on 7q11.23 to QTc prolongation in WS should be investigated. PMID- 23433767 TI - Meta-analysis of aerobic interval training on exercise capacity and systolic function in patients with heart failure and reduced ejection fractions. AB - It is unknown if vigorous to maximal aerobic interval training (INT) is more effective than traditionally prescribed moderate-intensity continuous aerobic training (MCT) for improving peak oxygen uptake (Vo2) and the left ventricular ejection fraction (LVEF) in patients with heart failure with reduced ejection fraction. MEDLINE, PubMed, Scopus, and the Web of Science were searched using the following keywords: "heart failure," high-intensity interval exercise," "high intensity interval training," "aerobic interval training," and "high-intensity aerobic interval training." Seven randomized trials were identified comparing the effects of INT and MCT on peak Vo2, 5 of which measured the LVEF at rest. The trials included clinically stable patients with heart failure with reduced ejection fraction with impaired left ventricular systolic function (mean LVEF 32%) who were relatively young (mean age 61 years) and predominantly men (82%). Weighted mean differences were calculated using a random-effects model. INT led to significantly higher increases in peak Vo2 compared with MCT (INT vs MCT, weighted mean difference 2.14 ml O2/kg/min, 95% confidence interval 0.66 to 3.63). Comparison of the effects of INT and MCT on the LVEF at rest was inconclusive (INT vs MCT, weighted mean difference 3.29%, 95% confidence interval -0.7% to 7.28%). In conclusion, in clinically stable patients with heart failure with reduced ejection fraction, INT is more effective than MCT for improving peak Vo2 but not the LVEF at rest. PMID- 23433768 TI - Comparison of effects of pitavastatin versus pravastatin on serum proprotein convertase subtilisin/kexin type 9 levels in statin-naive patients with coronary artery disease. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein cholesterol levels. Although statins increase serum PCSK9 levels, the effects of different types of statins on the serum PCSK9 levels have not been examined in detail. The purpose of the present study was to compare the effects of pitavastatin versus pravastatin on the serum PCSK9 levels. A total of 164 patients with coronary artery disease who were not receiving lipid-lowering therapy were randomly assigned to receive either 4 mg/day of pitavastatin (intensive lipid-lowering therapy) or 20 mg/day of pravastatin (moderate lipid lowering therapy). The serum PCSK9 levels were measured before statin treatment and 8 months after therapy. A significantly greater reduction in low-density lipoprotein cholesterol was observed in the pitavastatin group (-41% vs -28%, p = 0.0001). The serum levels of total PCSK9 and heterodimer PCSK9 significantly increased from 192 to 249 ng/ml (37%, p <0.0001) and 147 to 206 ng/ml (78%, p <0.0001) in the pitavastatin group and from 192 to 249 ng/ml (39%, p <0.0001) and 143 to 201 ng/ml (65%, p <0.0001) in the pravastatin group, respectively. The increase in total and heterodimer PSCK9 did not differ between the 2 groups. No significant correlations were found between the percentage of changes in heterodimer PCSK9 and changes in the various lipid parameters in either group. In conclusion, significant increases in the total and heterodimer PSCK9 levels were observed at 8 months after treatment with pitavastatin and pravastatin; however, these increases did not differ between the 2 statins. PMID- 23433769 TI - Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis. AB - Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest((r)) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis. REGISTRATION: NCT00769119. PMID- 23433770 TI - Functional and biological characteristics of asthma in cleaning workers. AB - OBJECTIVES: Cleaning workers have an increased risk of asthma but the underlying mechanisms are largely unknown. We studied functional and biological characteristics in asthmatic cleaners and compared these to healthy cleaners. METHODS: Forty-two cleaners with a history of asthma and/or recent respiratory symptoms and 53 symptom-free controls were identified. Fractional exhaled nitric oxide (FeNO) was measured and forced spirometry with reversibility testing was performed. Total IgE, pulmonary surfactant protein D and the 16 kDa Clara Cell secretory protein were measured in blood serum. Interleukins and other cytokines, growth factors, cys-leukotrienes and 8-isoprostane were measured in exhaled breath condensate. Information on occupational and domestic use of cleaning products was obtained in an interview. Associations between asthma status, specific characteristics and the use of cleaning products were evaluated using multivariable linear and logistic regression analyses. RESULTS: Asthma was associated with an 8% (95% confidence interval (CI) 1-15%) lower postbronchodilator FEV1, a higher prevalence of atopy (42% vs. 10%) and a 2.9 (CI 1.5-5.6) times higher level of total IgE. Asthma status was not associated with the other respiratory biomarkers. Most irritant products and sprays were more often used by asthmatic cleaners. The use of multiuse products, glass cleaners and polishes at work was associated with higher FeNO, particularly in controls. CONCLUSIONS: Asthma in cleaning workers is characterised by non-reversible lung function decrement and increased total IgE. Oxidative stress, altered lung permeability and eosinophilic inflammation are unlikely to play an important underlying role, although the latter may be affected by certain irritant cleaning exposures. PMID- 23433771 TI - [Inequalities in mortality between Andalusia and Spain from 1990 to 2010]. AB - OBJECTIVES: To describe inequalities in mortality between Andalusia and Spain as a whole by sex and age group between 1990 and 2010. METHODS: Deaths in Andalusia and Spain were obtained from the Andalusian Mortality Registry and the National Institute of Statistics, respectively. Population data, classified by sex and age group, were obtained from the National Institute of Statistics. Crude and age- and sex-adjusted standardized mortality rates were calculated. Additionally, standardized rate ratios between Andalusia and Spain were estimated, and joinpoint regression models were built to assess trends. RESULTS: In both sexes and in all the years studied, mortality was higher in Andalusia than in Spain as a whole. Rate ratios increased from 11% of men in Andalusia in 1990 to 14% in 2010 and from 9% of women in 1990 to 11% in 2010. By age group, mortality was higher than the Spanish average in Andalusian men and women, except in those aged less than 45 years in the first few years of the series. In both sexes and in all age groups, there were downward trends in Andalusia and Spain. CONCLUSION: Mortality in Andalusia is higher than the Spanish average with a tendency to decrease at a slightly slower rate than in Spain, indicating that inequalities have increased. If this tendency continues, mortality in Andalusia will not converge with the Spanish average in the near future. PMID- 23433772 TI - [Inequities in health among Latin American and Caribbean countries (2005-2010)]. AB - OBJECTIVE: To identify health inequalities among Latin American and Caribbean countries in recent years (2005-2010), based on the view that measurement of inequalities is the first step in identifying health inequities. METHOD: We performed an ecological study, whose units of analysis were 20 Latin American and Caribbean countries. These units were used to build the Inequalities in Health Index. This index summarizes, in a value ranging from 0 to 1, a set of socio economic and health indicators, developed by international organizations. These indicators are considered as proximal and contextual determinants of health. RESULTS: According to the index calculated, the five countries with the worst health status were Haiti, Guatemala, Bolivia, Venezuela and Honduras. In contrast, the five countries with the most favorable health status were Cuba, Argentina, Uruguay, Chile and Mexico. CONCLUSION: Even today, there are wide health inequalities in Latin America and the Caribbean. The country with the most favorable health indicators was Cuba and that with the least favorable was Haiti. We recommend systematic evaluation of health inequalities in Latin America and the Caribbean through the Inequalities in Health Index and other indices, in order to analyze actions, policies and programs to reduce inequities in this region. PMID- 23433773 TI - Influence of particle size and reactive oxygen species on cobalt chrome nanoparticle-mediated genotoxicity. AB - Patients with cobalt chrome (CoCr) metal-on-metal (MOM) implants may be exposed to a wide size range of metallic nanoparticles as a result of wear. In this study we have characterised the biological responses of human fibroblasts to two types of synthetically derived CoCr particles [(a) from a tribometer (30 nm) and (b) thermal plasma technology (20, 35, and 80 nm)] in vitro, testing their dependence on nanoparticle size or the generation of oxygen free radicals, or both. Metal ions were released from the surface of nanoparticles, particularly from larger (80 nm) particles generated by thermal plasma technology. Exposure of fibroblasts to these nanoparticles triggered rapid (2 h) generation of reactive oxygen species (ROS) that could be eliminated by inhibition of NADPH oxidase, suggesting that it was mediated by phagocytosis of the particles. The exposure also caused a more prolonged, MitoQ sensitive production of ROS (24 h), suggesting involvement of mitochondria. Consequently, we recorded elevated levels of aneuploidy, chromosome clumping, fragmentation of mitochondria and damage to the cytoskeleton particularly to the microtubule network. Exposure to the nanoparticles resulted in misshapen nuclei, disruption of mature lamin B1 and increased nucleoplasmic bridges, which could be prevented by MitoQ. In addition, increased numbers of micronuclei were observed and these were only partly prevented by MitoQ, and the incidence of micronuclei and ion release from the nanoparticles were positively correlated with nanoparticle size, although the cytogenetic changes, modifications in nuclear shape and the amount of ROS were not. These results suggest that cells exhibit diverse mitochondrial ROS-dependent and independent responses to CoCr particles, and that nanoparticle size and the amount of metal ion released are influential. PMID- 23433774 TI - Functionalized dendrimer-based delivery of angiotensin type 1 receptor siRNA for preserving cardiac function following infarction. AB - Cardiovascular disease (CVD) is the leading cause of death throughout the world and much pathology is associated with upregulation of inflammatory genes. Gene silencing using RNA interference is a powerful tool in regulating gene expression, but its application in CVDs has been prevented by the lack of efficient delivery systems. We report here the development of tadpole dendrimeric materials for siRNA delivery in a rat ischemia-reperfusion (IR) model. Angiotensin II (Ang II) type 1 receptor (AT1R), the major receptor that mediates most adverse effects of Ang II, was chosen to be the silencing targeting. Among the three tadpole dendrimers synthesized, the oligo-arginine conjugated dendrimer loaded with siRNA demonstrated effective down-regulation in AT1R expression in cardiomyocytes in vitro. When the dendrimeric material was applied in vivo, the siRNA delivery prevented the increase in AT1R levels and significantly improved cardiac function recovery compared to saline injection or empty dendrimer treated groups after IR injury. These experiments demonstrate a potential treatment for dysfunction caused by IR injury and may represent an alternative to AT1R blockade. PMID- 23433775 TI - The anti-tumor efficiency of poly(L-glutamic acid) dendrimers with polyhedral oligomeric silsesquioxane cores. AB - Peptide dendrimers represent superior drug carriers for their unique nanoarchitectures, excellent degradability and biocompatibility. In this research, poly(L-glutamic acid) dendrimers with polyhedral oligomeric silsesquioxane (POSS) as cores were synthesized. Tumor targeting moiety (biotin) and therapeutic drug doxorubicin (DOX) were immobilized on the dendrimers via pH sensitive hydrazone bonds. The size distribution and morphology of the drug dendrimer conjugates were characterized by DLS, AFM, and TEM. The drug release profiles, cellular uptake, in vitro and in vivo anti-tumor activities of the conjugates were investigated. The results revealed that the conjugates aggregated nanoparticles with the size around 100 nm. The drug-dendrimer conjugates could be internalized in mice breast cancer 4T1 cells efficiently. The IC50 of the conjugates was comparable to that of DOX.HCl. The in vivo experiments were carried out in mice xerograft breast cancer models, the results indicated that the inhibition efficiency of the DOX-dendrimer conjugates was much better than that of free DOX.HCl. PMID- 23433776 TI - SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused ultrasound enhanced brain-tumor drug delivery. AB - The blood-brain barrier (BBB) can be temporarily and locally opened by focused ultrasound (FUS) in the presence of circulating microbubbles (MBs). Currently, contrast-enhanced magnetic resonance imaging (CE-MRI) is used to monitor contrast agent leakage to verify BBB-opening and infer drug deposition. However, despite being administered concurrently, MBs, therapeutic agent, and contrast agent have distinct pharmacodynamic behaviors, thus complicating the quantification and optimization of BBB-opening and drug delivery. Here we propose multifunctional MBs loaded with therapeutic agent (doxorubicin; DOX) and conjugated with superparamagnetic iron oxide (SPIO) nanoparticles. These DOX-SPIO-MBs were designed to concurrently open the BBB and perform drug delivery upon FUS exposure, act as dual MRI and ultrasound contrast agent, and allow magnetic targeting (MT) to achieve enhanced drug delivery. We performed burst-tone FUS after injection of DOX-SPIO-MBs, followed by MT with an external magnet attached to the scalp in a rat glioma model. Animals were monitored by T2-weighted MRI and susceptibility weighted imaging and the concentration of SPIO particles was determined by spin-spin relaxivity. We found that DOX-SPIO-MBs were stable and provided significant superparamagnetic/acoustic properties for imaging. BBB opening and drug delivery were achieved concurrently during the FUS exposure. In addition, MT increased local SPIO deposition in tumor regions by 22.4%. Our findings suggest that DOX-SPIO-MBs with FUS could be an excellent theranostic tool for future image-guided drug delivery to brain tumors. PMID- 23433777 TI - Patient-reported use of collaborative goal setting and glycemic control among patients with diabetes. AB - OBJECTIVE: Little is known about how patient-clinician communication leads to better outcomes. Among patients with diabetes, we describe patient-reported use of collaborative goal setting and evaluate whether perceived competency and physician trust mediate the association between collaborative goal setting and glycemic control. METHODS: Data from a patient survey administered in 2008 to a cohort of insured patients aged 18+ years with diabetes who initiated oral mono therapy between 2000 and 2005 were joined with pharmaceutical claims data for the prior 12 months and laboratory data for the prior and subsequent 12 months (N=1065). A structural equation model (SEM) was used to test mediation models controlling for baseline HbA1c. RESULTS: The hypothesized mediation model was supported. Patient-reported use of more collaborative goal setting was associated with greater perceived self-management competency and increased level of trust in the physician (p<0.05). In turn, both greater perceived competence and increased trust were associated with increased control (p<0.05). CONCLUSIONS: Findings indicate that engaging patients in collaborative goal setting during clinical encounters has potential to foster a trusting patient-clinician relationship as well as enhance patient perceived competence, thereby improving clinical control. PRACTICE IMPLICATIONS: Fostering collaborative goal setting may yield payoffs in improved clinical outcomes among patients with diabetes. PMID- 23433778 TI - Developing and administering scripted video vignettes for experimental research of patient-provider communication. AB - OBJECTIVE: Scripted video-vignette studies enable experimental investigation of specific elements of patient-provider communication, separating cause and effect. However, scripted video vignettes are infrequently used to this end. Resultantly, few guidelines are available for their design, development and administration. We aim to suggest guidelines enabling more informed decisions when designing and conducting these studies. METHODS: Based on the available methodological literature, we discuss methodological considerations when developing and administering scripted video vignettes. RESULTS: Developing and using valid video vignettes requires: (I) deciding if using video vignettes is appropriate, (II) developing a valid script, (III) designing valid manipulations, (IV) converting the scripted consultation to video, and (V) administering the videos. We provide a first checklist of the methodological considerations in each phase. Advantages and pitfalls of possible approaches are discussed. CONCLUSIONS: No 'gold standard' exists for most methodological issues, as literature testing the consequences of different approaches is lacking. The best approach when developing and implementing video vignettes depends upon the aims and practical limitations of a particular study. PRACTICE IMPLICATIONS: Our checklist may serve as a starting point for further study of scripted video vignettes methodology. More detailed methodological reporting would yield new knowledge, thus allowing the research field to progress. PMID- 23433779 TI - Immune surveillance for ERAAP dysfunction. AB - The ER aminopeptidase associated with antigen processing, ERAAP (or ERAP1), is essential for trimming peptides that are presented by MHC class I molecules. ERAP1 is inhibited by human cytomegalovirus, and ERAP1 polymorphisms are associated with autoimmune diseases. How the immune system detects ERAAP dysfunction, however, is unknown. We have shown previously that ERAAP-deficient cells present an immunogenic pMHC I repertoire, that elicits CD8+ T cell response in WT mice. Additionally, we discovered that the WT CD8+ T cells recognized novel peptides presented by non-classical, or MHC class Ib, molecules on ERAAP deficient cells. The MHC Ib restricted WT CD8 T cells eliminated ERAAP-deficient cells in vitro and in vivo. We identified the FL9 peptide, presented by Qa-1(b), a MHC class Ib molecule exclusively on ERAAP-deficient cells. Remarkably, T cells specific for the FL9-Qa-1(b) complex were frequent in naive WT mice, and had an antigen-experienced phenotype. Thus, novel non-classical pQa-1(b) complexes direct cytotoxic T cells to target cells with defective peptide processing in the endoplasmic reticulum. Here, we discuss the implications of our findings, and the possible roles of pMHC Ib-specific T cells in immune surveillance for ERAAP dysfunction. PMID- 23433780 TI - [Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis on the use of anti-tumor necrosis factor drugs in inflammatory bowel disease]. PMID- 23433781 TI - Leukoaraiosis is associated with short- and long-term mortality in patients with intracerebral hemorrhage. AB - BACKGROUND: There are few recent European studies of mortality after intracerebral hemorrhage (ICH), particularly long-term follow-up studies. No previous European studies have included information on leukoaraiosis. METHODS: We studied all consecutive patients hospitalized with a first-ever intracerebral hemorrhage between 2005 and 2009 in a well-defined area and assessed the prognostic value of various baseline clinical and radiologic factors. Leukoaraiosis was scored on the baseline computed tomographic (CT) scan as described by van Swieten et al, with an overall score from 0 to 4. RESULTS: One hundred thirty-four patients were followed up for a median of 4.7 years (interquartile range 2.5-6.6). Overall mortality was 23% at 2 days, 30% at 7 days, 37% at 30 days, 46% at 1 year, and 53% at 2 years. Factors independently associated with increased 30-day mortality were warfarin use, leukoaraiosis score, intraventricular hemorrhage, and Glasgow Coma Scale (GCS) score. Factors independently associated with long-term mortality in the 85 patients who survived the first 30 days were leukoaraiosis score, coronary heart disease, and initial GCS score. Recurrent ICH occurred in 4.5% and was significantly more frequent after lobar ICH than after ICH in other locations (11.1% v 0%; P = .025). CONCLUSIONS: In unselected patients in Southern Norway with first-ever ICH, severe leukoaraiosis is independently associated with both 30-day and long-term mortality in 30-day survivors. Warfarin is independently associated with 30-day mortality and coronary heart disease with long-term mortality in 30-day survivors. Recurrent ICH is more frequent after lobar ICH than after ICH in other locations. PMID- 23433782 TI - Clinical deterioration following middle cerebral artery hemodynamic changes after intravenous thrombolysis for acute ischemic stroke. AB - BACKGROUND: Little information exists regarding what occurs in the affected artery in the days after acute ischemic stroke and its impact in the outcome. We sought to determine the hemodynamic evolution and correlated this evoution with clinical outcome in stroke patients treated with intravenous thrombolysis. METHODS: Using serial transcranial Doppler ultrasound (TCD) on days 1 (TCD1), 3 to 6 (TCD2), and 7 to 10 (TCD3) after stroke, we determined the hemodynamics in the affected artery by means of the thrombolysis in brain ischemia (TIBI) score and compared this with clinical outcome (National Institutes of Health Stroke Scale [NIHSS] score) and functional outcome (modified Rankin Scale score) at discharge and at 3 months. RESULTS: Thirty-four patients were studied. There were 24 men with a mean (+/- SD) age of 72.9 +/- 16.2 years. The mean time from stroke onset to the administration of intravenous tissue plasminogen activator was 181 +/- 54.4 minutes, and the mean NIHSS score at admission was 16.9 +/- 9. Hemodynamic changes were observed in 23 (68%) patients, including improvement in 17 (50%) patients and worsening in 6 (18%) patients within the first 10 days poststroke. Clinical deterioration (NIHSS >=4 points) was timely associated with hemodynamic deterioration in 3 cases. Patients achieving full recanalization at TCD3 had better mRS scores at 3 months (4 v 3; P = .02). CONCLUSIONS: Hemodynamic changes in the affected artery occurred in about two-thirds of patients within the first 10 days after receiving intravenous thrombolysis; 18% had hemodynamic deterioration, which was associated with clinical worsening in half of these cases. PMID- 23433783 TI - Preclusion of ischemic stroke patients from intravenous tissue plasminogen activator treatment for mild symptoms should not be based on low National Institutes of Health Stroke Scale Scores. AB - BACKGROUND: Intravenous tissue plasminogen activator (IV tPA) improves neurologic outcome after stroke, but is not recommended for patients with minor neurologic deficits commonly classified by a lower cutoff on the National Institutes of Health Stroke Scale (NIHSS). Because not all stroke signs are captured on the NIHSS, the use of a strict cutoff may exclude functionally impaired stroke patients from IV tPA treatment. METHODS: We described functional impairment, safety, and clinical outcome in patients derived from our hospital thrombolysis database who had stroke that was considered disabling despite a neurologic deficit that was considered mild. We used 2 cutoffs: NIHSS score <= 4 and <= 3. Functional impairment was assessed with the modified Rankin Scale (mRS). RESULTS: Between 2008 and 2011, a total of 670 acute ischemic stroke patients received IV tPA in our institution. 107 (16%) of these patients presented with a NIHSS score <= 4; 65 (10%) patients presented with a NIHSS score <= 3. All of these patients were considered functionally impaired (mRS score >= 2). The most frequent symptoms were language impairment (two-thirds), distal (hand) paresis (one third), and gait disorder in both groups. Symptomatic intracerebral hemorrhage occurred in 1 patient with a NIHSS score of 4 (1%). Despite IV tPA therapy, 26% had a nonfavorable outcome (mRS score 0-1) after 3 months, and 52% had persisting symptoms in both groups. CONCLUSIONS: Language impairment, distal (hand) paresis, and gait disorder are common disabling deficits in patients with low NIHSS scores. Judgment of whether a stroke is disabling should not be based on the NIHSS score but on the assessment of the individual neurologic deficits and their impact on functional impairment. PMID- 23433784 TI - Postoperative brain stroke after shoulder arthroscopy in the lateral decubitus position. AB - The beach chair position is used frequently for shoulder arthroscopy surgery. However, the beach chair position has been reported to be linked to postoperative cerebral stroke. The lateral decubitus position has been used as an alternative position to avoid such neurologic complications. We report a case of postoperative brain stroke in a 52-year-old man who underwent shoulder arthroscopy surgery in the lateral decubitus position. The patient experienced a brief period of intraoperative hypotension. Physicians should be aware of this potential complication that could be irrelevant to the position used. PMID- 23433785 TI - Management of acute contrast media reactions: assessing preparedness of a tertiary care veterans affairs medical center. PMID- 23433786 TI - Radiation oncology peer review: measuring quality. PMID- 23433788 TI - Cytokine effects on cell survival and death of A549 lung carcinoma cells. AB - PURPOSE: IL-13, TNF-alpha and IL-1beta have various effects on lung cancer growth and death, but the signaling pathways mediating these effects have not been extensively analyzed. Therefore, the effects of IL-13, TNF-alpha and IL-1beta alone, and in combination with Fas, on cell viability and death as well as major signaling pathways involved in these effects were investigated in A549 lung carcinoma cells. RESULTS: Using MTT and flow cytometry, IL-13, TNF-alpha and IL 1beta pretreatment decreased Fas-induced cell death. These anti-cell death effects were attenuated by pretreatment with inhibitors of Nuclear factor-kappaB [NF-kappaB], Phoshatidylinositole-3 kinase [PI3-K], JNK, p38 and ERK1/2 pathways. Using Western blot, IL-13, TNF-alpha and IL-1beta treated cells showed time dependent expression of p-ERK1/2, p-p38, p-JNK, p-Akt and p-IkappaBalpha proteins, decreased IkappaBalpha protein expression, no cleavage of Caspase-3 and PARP1 proteins and no notable alterations of Fas protein. IL-13 and TNF-alpha treated cells showed time-dependent increase of FLIPL expression. CONCLUSION: IL 13, TNF-alpha and IL-1beta attenuate the pro-cell death effects of Fas on A549 cells, at least partially, by pathways involving the NF-kappaB, PI3-K and MAP kinases, but not by alterations of Fas protein expression. The IL-13 and TNF alpha cell survival effects may also be due to increased expression of FLIPL protein. PMID- 23433787 TI - Activation profile of CXCL8-stimulated neutrophils and aging. AB - Neutrophils are pivotal effector cells of innate immunity representing the first line of defense against aggression. They are the first cells to arrive at the site of the aggression, where they can directly eliminate the invading microorganisms. Their activation and recruitment into peripheral tissues is indispensable for host defense. With aging, there are alterations of the receptor by driven functions of human neutrophils as a decrease in the functional changes in signaling elicited by specific receptors, as CXCR1. We investigated the activation of neutrophils from elderly after the cells were cultivated with CXCL8. Although, CXCL8 induced elastase (ELA) secretion, data showed neither myeloperoxidase (MPO) activity nor production of IL-6, IL-10, GM-CSF by neutrophils from elderly compared with young individuals. On the other hand, in the presence of only LPS or LPS associated with CXCL8 neutrophils from elderly individuals, there were significant levels of IL-6, IL-10, GM-CSF but not MPO. These results indicate that neutrophils from elderly do not respond to CXCL8 stimulus, but they are activated by LPS to produce cytokines. However, MPO activity from elderly individuals was not different in the presence or absence of LPS and CXCL8. PMID- 23433789 TI - Free IL-18 and IL-33 cytokines in chronic spontaneous urticaria. AB - Overproduction of IL-18 has been described in chronic urticaria. To evaluate free IL-18 and IL-33 in chronic spontaneous urticaria (CSU). IL-18, its inhibitor IL 18BP, IL-33 and its soluble receptor ST2 (sST2) were measured (ELISA) in the sera of 73 CSU patients. Free IL-18 was calculated (law of mass action). Autologous serum skin test (ASST) was performed in all patients. Total IL-18, IL-18BP and free IL-18 serum levels were significantly higher in CSU than in controls. IL-18 and IL-18BP increased significantly in both ASST-positive and negative subgroups. Free IL-18 resulted significantly higher in the ASST-negative, but not in the ASST-positive subgroup. No differences in IL-33/sST2 levels were detected between CSU and controls. Increased levels of free IL-18 and IL-18BP, but not IL-33, was detected in CSU. Whether IL-18 up-regulation is a consequence of inflammation or one of the causes of the pathology needs to be addressed. PMID- 23433790 TI - Peripheral autofluorescence and clinical findings in neovascular and non neovascular age-related macular degeneration. AB - PURPOSE: To characterize peripheral fundus autofluorescence (FAF) abnormalities in patients with age-related macular degeneration (AMD), correlate these with clinical findings, and identify risk factors associated with these FAF abnormalities. DESIGN: Clinic-based, cross-sectional study. PARTICIPANTS: A total of 119 consecutive patients: 100 patients with AMD (200 eyes) and 19 patients without AMD (38 eyes). METHODS: In a prospective study performed at the Doheny Eye Institute, University of Southern California, widefield 200-degree FAF and color images were obtained by the Optos 200Tx Ultra-Widefield device (Optos, Dunfermline, Scotland) using a standardized imaging protocol. The FAF images were captured centered on the fovea, and additional images were captured after steering the field of view inferiorly and superiorly. All FAF and color images were graded independently by 2 masked ophthalmologists with respect to the presence, location, extent, and type of peripheral (defined as outside the central 30 degrees) FAF abnormality. MAIN OUTCOME MEASURES: Presence and type of peripheral FAF abnormalities. RESULTS: Peripheral FAF abnormalities were evident in 164 eyes (68.9%), with several distinct FAF patterns identified: granular (46.2%), mottled (34.0%), and nummular (18.1%). A 90% concordance of FAF patterns was observed between both eyes. Abnormal FAF occurred more frequently in neovascular compared with non-neovascular AMD or normal eyes (86% vs. 72.8% vs. 18.4%, respectively, P<0.001). Significant risk factors for peripheral FAF abnormalities were AMD type (neovascular AMD odds ratio [OR], 12.7 and non neovascular AMD OR, 6.2 compared with normal eyes, P<0.001), older age (OR, 6.5; 95% confidence interval [CI], 2.4-17.8; P<0.001 for the oldest quartile compared with the youngest), and female sex (OR, 4.1; 95% CI, 1.9-8.9; P<0.001). Clinical features on color photography were detected in 174 eyes (73.1%): peripheral drusen (51.7%), retinal pigment epithelium (RPE) depigmentation (34.9%), RPE hyperpigmentation (branching reticular pigmentation) (22.7%), and atrophic patches (16.8%). There was a high correlation between specific FAF and clinical findings: granular FAF with peripheral drusen (P<0.001) and mottled FAF with RPE depigmentation (P<0.001). CONCLUSIONS: Several distinct patterns of peripheral FAF abnormalities were observed in 68.9% of patients, with AMD type, female sex, and age being independent risk factors. The peripheral FAF patterns correlate strongly with specific clinical features seen in eyes with AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23433791 TI - Sagittal alignment of the first metatarsophalangeal joint after arthrodesis for rheumatoid forefoot deformity. AB - The present study assessed the midterm results of reconstruction for rheumatoid forefoot deformity with arthrodesis of the first metatarsophalangeal (MTP) joint, scarf osteotomy, resection arthroplasty of the metatarsal head of the lesser toes, and surgical repair of hammertoe deformity (arthrodesis of the proximal interphalangeal joint). Special focus was placed on the sagittal alignment of the first metatarsophalangeal joint after arthrodesis. We retrospectively evaluated the postoperative clinical outcomes and radiographic findings for 16 consecutive female patients (20 feet) with symptomatic rheumatoid forefoot deformities. The mean duration of follow-up was 7.9 (range 4 to 13) years. All first MTP joints and first metatarsal bones were fused successfully. The mean value of the American Orthopaedic Foot and Ankle Society and Japanese Society for Foot Surgery clinical scores significantly improved overall, except for 2 patients (10%), who complained of first toe pain at the final follow-up visit owing to sagittal misalignment of the fused first MTP joint. Sagittal alignment of the first metatarsal varies greatly because of the rheumatoid midfoot and hindfoot deformities. Therefore, inclination of the first metatarsal should be considered when determining the first MTP joint sagittal fusion angle. PMID- 23433792 TI - Technical considerations for surgical intervention of Jones fractures. AB - Jones fractures are a common injury treated by foot and ankle surgeons. Surgical intervention is recommended because of the high rate of delayed union, nonunion, and repeat fracture, when treated conservatively. Percutaneous intramedullary screw fixation is commonly used in the treatment of these fractures. We present techniques that can increase the surgical efficiency and decrease the complications associated with percutaneous delivery of internal fixation. PMID- 23433793 TI - Management of pediatric spinal cord astrocytomas: outcomes with adjuvant radiation. AB - PURPOSE: Pediatric intramedullary spinal cord tumors are exceedingly rare; in the United States, 100 to 200 cases are recognized annually, of these, most are astrocytomas. The purpose of this study is to report the outcomes in pediatric patients with spinal cord astrocytomas treated at a tertiary care center. METHODS AND MATERIALS: An institutional review board-approved retrospective single institution study was performed for pediatric patients with spinal cord astrocytomas treated at our hospital from 1990 to 2010. The patients were evaluated on the extent of resection, progression-free survival (PFS), and development of radiation-related toxicities. Kaplan-Meier curves and multivariate regression model methods were used for analysis. RESULTS: Twenty-nine patients were included in the study, 24 with grade 1 or 2 (low-grade) tumors and 5 with grade 3 or 4 (high-grade) tumors. The median follow-up time was 55 months (range, 1-215 months) for patients with low-grade tumors and 17 months (range, 10-52 months) for those with high-grade tumors. Thirteen patients in the cohort received chemotherapy. All patients underwent at least 1 surgical resection. Twelve patients received radiation therapy to a median radiation dose of 47.5 Gy (range, 28.6-54.0 Gy). Fifteen patients with low-grade tumors and 1 patient with a high-grade tumor exhibited stable disease at the last follow-up visit. Acute toxicities of radiation therapy were low grade, whereas long-term sequelae were infrequent and manageable when they arose. All patients with low-grade tumors were alive at the last follow-up visit, compared with 1 patient with a high-grade tumor. CONCLUSION: Primary pediatric spinal cord astrocytomas vary widely in presentation and clinical course. Histopathologic grade remains a major prognostic factor. Patients with low-grade tumors tend to have excellent disease control and long-term survival compared to those with high-grade tumors. This experience suggests that radiation therapy may enhance tumor control with an acceptably low risk of long-term sequelae in this sensitive patient population. PMID- 23433794 TI - Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma. AB - PURPOSE: Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma. METHODS AND MATERIALS: Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at the University of Texas MD Anderson Cancer Center from 2003 to 2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4-103) for x-CSI patients and 26 months (range 11-63) for p-CSI. RESULTS: p-CSI patients lost less weight than x-CSI patients (1.2% vs 5.8%; P=.004), and less p-CSI patients had >5% weight loss compared with x-CSI (16% vs 64%; P=.004). p-CSI patients experienced less grade 2 nausea and vomiting compared with x-CSI (26% vs 71%; P=.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, P<.001). p-CSI patients had a smaller reduction in peripheral white blood cells, hemoglobin, and platelets compared with x-CSI (white blood cells 46% vs 55%, P=.04; hemoglobin 88% vs 97%, P=.009; platelets 48% vs 65%, P=.05). Mean vertebral doses were significantly associated with reductions in blood counts. CONCLUSIONS: This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including fewer acute gastrointestinal and hematologic toxicities. PMID- 23433796 TI - High LET radiation amplifies centrosome overduplication through a pathway of gamma-tubulin monoubiquitination. AB - PURPOSE: Radiation induces centrosome overduplication, leading to mitotic catastrophe and tumorigenesis. Because mitotic catastrophe is one of the major tumor cell killing factors in high linear energy transfer (LET) radiation therapy and long-term survivors from such treatment have a potential risk of secondary tumors, we investigated LET dependence of radiation-induced centrosome overduplication and the underlying mechanism. METHODS AND MATERIALS: Carbon and iron ion beams (13-200 keV/MUm) and gamma-rays (0.5 keV/MUm) were used as radiation sources. To count centrosomes after IR exposure, human U2OS and mouse NIH3T3 cells were immunostained with antibodies of gamma-tubulin and centrin 2. Similarly, Nbs1-, Brca1-, Ku70-, and DNA-PKcs-deficient mouse cells and their counterpart wild-type cells were used for measurement of centrosome overduplication. RESULTS: The number of excess centrosome-containing cells at interphase and the resulting multipolar spindle at mitosis were amplified with increased LET, reaching a maximum level of 100 keV/MUm, followed by sharp decrease in frequency. Interestingly, Ku70 and DNA-PKcs deficiencies marginally affected the induction of centrosome overduplication, whereas the cell killings were significantly enhanced. This was in contrast to observation that high LET radiation significantly enhanced frequencies of centrosome overduplication in Nbs1- and Brca1-deficient cells. Because NBS1/BRCA1 is implicated in monoubiquitination of gamma-tubulin, we subsequently tested whether it is affected by high LET radiation. As a result, monoubiquitination of gamma-tubulin was abolished in 48 to 72 hours after exposure to high LET radiation, although gamma-ray exposure slightly decreased it 48 hours postirradiation and was restored to a normal level at 72 hours. CONCLUSIONS: High LET radiation significantly reduces NBS1/BRCA1-mediated monoubiquitination of gamma-tubulin and amplifies centrosome overduplication with a peak at 100 keV/MUm. In contrast, Ku70 and DNA-PKcs deficiencies mitigate centrosome overduplication, although deficiencies of both NBS1/BRCA1 and Ku70/DNA-PKcs markedly enhance cell killing. PMID- 23433797 TI - Magnetic resonance imaging (MRI) markers for MRI-guided high-dose-rate brachytherapy: novel marker-flange for cervical cancer and marker catheters for prostate cancer. AB - PURPOSE: To present a novel marker-flange, addressing source-reconstruction uncertainties due to the artifacts of a titanium intracavitary applicator used for magnetic resonance imaging (MRI)-guided high-dose-rate (HDR) brachytherapy (BT); and to evaluate 7 different MRI marker agents used for interstitial prostate BT and intracavitary gynecologic HDR BT when treatment plans are guided by MRI. METHODS AND MATERIALS: Seven MRI marker agents were analyzed: saline solution, Conray-60, copper sulfate (CuSO4) (1.5 g/L), liquid vitamin E, fish oil, 1% agarose gel (1 g agarose powder per 100 mL distilled water), and a cobalt chloride complex contrast (C4) (CoCl2/glycine = 4:1). A plastic, ring-shaped marker-flange was designed and tested on both titanium and plastic applicators. Three separate phantoms were designed to test the marker-flange, interstitial catheters for prostate BT, and intracavitary catheters for gynecologic HDR BT. T1 and T2-weighted MRI were analyzed for all markers in each phantom and quantified as percentages compared with a 3% agarose gel background. The geometric accuracy of the MR signal for the marker-flange was measured using an MRI-CT fusion. RESULTS: The CuSO4 and C4 markers on T1-weighted MRI and saline on T2-weighted MRI showed the highest signals. The marker-flange showed hyper-signals of >500% with CuSO4 and C4 on T1-weighted MRI and of >400% with saline on T2-weighted MRI on titanium applicators. On T1-weighted MRI, the MRI signal inaccuracies of marker-flanges were measured <2 mm, regardless of marker agents, and that of CuSO4 was 0.42 +/- 0.14 mm. CONCLUSION: The use of interstitial/intracavitary markers for MRI-guided prostate/gynecologic BT was observed to be feasible, providing accurate source pathway reconstruction. The novel marker-flange can produce extremely intense, accurate signals, demonstrating its feasibility for gynecologic HDR BT. PMID- 23433795 TI - Detection and repair of ionizing radiation-induced DNA double strand breaks: new developments in nonhomologous end joining. AB - DNA damage can occur as a result of endogenous metabolic reactions and replication stress or from exogenous sources such as radiation therapy and chemotherapy. DNA double strand breaks are the most cytotoxic form of DNA damage, and defects in their repair can result in genome instability, a hallmark of cancer. The major pathway for the repair of ionizing radiation-induced DSBs in human cells is nonhomologous end joining. Here we review recent advances on the mechanism of nonhomologous end joining, as well as new findings on its component proteins and regulation. PMID- 23433798 TI - Contura Multi-Lumen Balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial. AB - PURPOSE: Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented. METHODS AND MATERIALS: Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: >= 95% of the prescribed dose (PD) covering >= 95% of the target volume (TV); maximum skin dose <= 125% of the PD; maximum rib dose <= 145% of the PD; and V150 <=50 cc and V200 <= 10 cc. RESULTS: Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P <=.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%. CONCLUSIONS: Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals. PMID- 23433799 TI - A population-based study of the fractionation of postlumpectomy breast radiation therapy. AB - PURPOSE: The optimal fractionation schedule of post lumpectomy radiation therapy remains controversial. The objective of this study was to describe the fractionation of post-lumpectomy radiation therapy (RT) in Ontario, before and after the seminal Ontario Clinical Oncology Group (OCOG) trial, which showed the equivalence of 16- and 25-fraction schedules. METHODS AND MATERIALS: This was a retrospective cohort study conducted by linking electronic treatment records to a population-based cancer registry. The study population included all patients who underwent lumpectomy for invasive breast cancer in Ontario, Canada, between 1984 and 2008. RESULTS: Over the study period, 41,747 breast cancer patients received post lumpectomy radiation therapy to the breast only. Both 16- and 25-fraction schedules were commonly used throughout the study period. In the early 1980s, shorter fractionation schedules were used in >80% of cases. Between 1985 and 1995, the proportion of patients treated with shorter fractionation decreased to 48%. After completion of the OCOG trial, shorter fractionation schemes were once again widely adopted across Ontario, and are currently used in about 71% of cases; however, large intercenter variations in fractionation persisted. CONCLUSIONS: The use of shorter schedules of post lumpectomy RT in Ontario increased after completion of the OCOG trial, but the trial had a less normative effect on practice than expected. PMID- 23433800 TI - Is stereotactic body radiation therapy an attractive option for unresectable liver metastases? A preliminary report from a phase 2 trial. AB - PURPOSE: To evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases. METHODS AND MATERIALS: Patients with 1 to 3 liver metastases, with maximum individual tumor diameters less than 6 cm and a Karnofsky Performance Status of at least 70, were enrolled and treated by SBRT on a phase 2 clinical trial. Dose prescription was 75 Gy on 3 consecutive days. SBRT was delivered using the volumetric modulated arc therapy by RapidArc (Varian, Palo Alto, CA) technique. The primary end-point was in-field local control. Secondary end-points were toxicity and survival. RESULTS: Between February 2010 and September 2011, a total of 61 patients with 76 lesions were treated. Among the patients, 21 (34.3%) had stable extrahepatic disease at study entry. The most frequent primary sites were colorectal (45.9%) and breast (18%). Of the patients, 78.7% had 1 lesion, 18.0% had 2 lesions, and 3.3% had 3 lesions. After a median of 12 months (range, 2-26 months), the in field local response rate was 94%. The median overall survival rate was 19 months, and actuarial survival at 12 months was 83.5%. None of the patients experienced grade 3 or higher acute toxicity. No radiation-induced liver disease was detected. One patient experienced G3 late toxicity at 6 months, resulting from chest wall pain. CONCLUSIONS: SBRT for unresectable liver metastases can be considered an effective, safe, and noninvasive therapeutic option, with excellent rates of local control and a low treatment-related toxicity. PMID- 23433802 TI - Virulence determinants for Vibrio parahaemolyticus infection. AB - Vibrio parahaemolyticus is a marine microorganism that causes acute gastroenteritis associated with the consumption of contaminated raw or under cooked seafood. During infection, the bacterium utilizes a wide variety of virulence factors, including adhesins, toxins and type III secretion systems, to cause both cytotoxicity in cultured cells and enterotoxicity in animal models. Herein, we describe recent discoveries on the regulation and characterization of the virulence factors from V. para. Determining how this bacterial pathogen uses virulence factors to mediate pathogenicity improves our understanding of V. para. infections and more generally, host-pathogen interactions. PMID- 23433801 TI - RNA polymerase and the ribosome: the close relationship. AB - In bacteria transcription and translation are linked in time and space. When coupled to RNA polymerase (RNAP), the translating ribosome ensures transcriptional processivity by preventing RNAP backtracking. Recent advances in the field have characterized important linker proteins that bridge the gap between transcription and translation: In particular, the NusE(S10):NusG complex and the NusG homolog, RfaH. The direct link between the moving ribosome and RNAP provides a basis for maintaining genomic integrity while enabling efficient transcription and timely translation of various genes within the bacterial cell. PMID- 23433803 TI - Cold-related mortality due to cardiovascular diseases, respiratory diseases and cancer: a case-crossover study. AB - OBJECTIVES: The aim of this study was to identify the relationship between low temperatures in winter and mortality due to cancer, cardiovascular diseases and respiratory diseases. STUDY DESIGN: Case-crossover study. METHODS: A case crossover study was performed in Cantabria (northern Spain) in the years 2004 2005; 3948 deaths were included. Odds ratios were estimated using conditional logistic regression, stratified by age, sex, and delay of exposure to low temperatures. RESULTS: There was an inverse dose-response relationship between temperature and mortality in the three causes of death studied; this result was consistent across genders and age groups. The higher OR for cancer mortality was seen on the first day of exposure (OR = 4.91; 95% CI: 1.65-13.07 in the whole population), and it decreased when exposure over several days in a row was considered; people aged 75 years or more were especially susceptible to cold temperatures (OR = 17.9; 95% CI: 2.38-134.8). Cardiovascular (OR = 2.63; 95% CI: 1.88-3.67) and respiratory mortality (OR = 2.72; 95% CI: 1.46-5.08) showed a weaker effect. CONCLUSION: There is a striking association between the extreme cold temperatures and mortality from cancer, not previously reported, which is more remarkable in the elderly. These results could be explained by a harvesting effect in which the cold acts as a trigger of death in terminally ill patients at high risk of dying a few days or weeks later. PMID- 23433804 TI - A review of nosocomial Salmonella outbreaks: infection control interventions found effective. AB - OBJECTIVE: To review nosocomial salmonellosis outbreaks to identify: mode of transmission; morbidity and mortality patterns; and recommendations for control and prevention. DESIGN: Documented nosocomial salmonellosis outbreaks in hospitals published from January 1995 to November 2011, written in the English language, were systematically reviewed. METHODS: The study methodology incorporated steps from the PRISMA statement for a high quality review process. Computer-aided searches of Scopus, CAB Global Health and CINAHL((r)), the Cumulative Index to Nursing and Allied Health Literature were completed to identify relevant outbreak reports written in English. To validate the electronic search methodology, bibliographies and reference lists of relevant review articles were hand-searched. Public health and government websites were searched for nosocomial salmonellosis. RESULTS: Fifty-two relevant reports were identified. The most frequently reported routes of transmission were food 31/52 (59.6%) and person-to-person transmission 7/52 (13.5%). Actions taken during the outbreak to control transmission included improvements to: 1) infection control practices (41.8% of actions); isolation or cohorting patients, hand hygiene practices, and enhancing cleaning and disinfection in patient care areas; and 2) food handling practices (24.4% of actions); reviewing food preparation practices, enhancing cleaning and sanitation of the kitchen, and controlling food temperatures. Investigators made recommendations retrospectively in outbreak reports to provide direction to health centees but these recommendations were not statistically evaluated for effectiveness. CONCLUSIONS: More emphasis should be placed on improving food handling practices, such as training food workers, monitoring food temperatures, and not using raw foods of animal origin, to prevent nosocomial salmonellosis outbreaks in hospitals because almost 60% of the outbreaks were foodborne. PMID- 23433805 TI - Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. AB - BACKGROUND: Androgen-deprivation therapy (ADT) has been suggested to increase the risk for cardiovascular diseases, including myocardial infarction (MI) and stroke, but data are inconsistent. OBJECTIVES: To investigate the association between ADT and risk for MI and stroke in Danish men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A national cohort study of all patients with incident prostate cancer registered in the Danish Cancer Registry from January 1, 2002, through 2010 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used Cox regression analysis to estimate hazard ratios (HR) of MI and stroke for ADT users versus nonusers, adjusting for age, prostate cancer stage, comorbidity, and calendar period. Additionally, we stratified the analysis on preexisting MI/stroke status. RESULTS AND LIMITATIONS: Of 31,571 prostate cancer patients, 9204 (29%) received medical endocrine therapy and 2060 (7%) were orchidectomized. Patients treated with medical endocrine therapy had an increased risk for MI and stroke with adjusted HRs of 1.31 (95% confidence interval [CI], 1.16-1.49) and 1.19 (95% CI, 1.06-1.35), respectively, compared with nonusers of ADT. We found no increased risk for MI (HR: 0.90; 95% CI, 0.83-1.29) or stroke (HR: 1.11; 95% CI, 0.90-1.36) after orchiectomy. One limitation of the study is that information on prognostic lifestyle factors was not included and might have further informed our estimates. CONCLUSIONS: In this nationwide cohort study of >30 000 prostate cancer patients, we found that endocrine hormonal therapy was associated with increased risk for MI and stroke. In contrast, we did not find this association after orchiectomy. PMID- 23433806 TI - Active surveillance, quality of life, and cancer-related anxiety. PMID- 23433808 TI - Renal cancer therapy: going forward by going backward? PMID- 23433809 TI - Forced withdrawal from methadone maintenance therapy in criminal justice settings: a critical treatment barrier in the United States. AB - The World Health Organization classifies methadone as an essential medicine, yet methadone maintenance therapy remains widely unavailable in criminal justice settings throughout the United States. Methadone maintenance therapy is often terminated at the time of incarceration, with inmates forced to withdraw from this evidence-based therapy. We assessed whether these forced withdrawal policies deter opioid-dependent individuals in the community from engaging methadone maintenance therapy in two states that routinely force inmates to withdraw from methadone (N = 205). Nearly half of all participants reported that concern regarding forced methadone withdrawal during incarceration deterred them engaging methadone maintenance therapy in the community. Participants in the state where more severe methadone withdrawal procedures are used during incarceration were more likely to report concern regarding forced withdrawal as a treatment deterrent. Methadone withdrawal policies in the criminal justice system may be a broader treatment deterrent for opioid-dependent individuals than previously realized. Redressing this treatment barrier is both a health and human rights imperative. PMID- 23433810 TI - Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia. AB - Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P=0.01) and GSTP1 (P=0.02). The EPHX1 haplotype was marginally associated with risk (P=0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology. PMID- 23433812 TI - Reduction of dNTP levels enhances DNA replication fidelity in vivo. AB - ATP is the most important energy source for the maintenance and growth of living cells. Here we report that the impairment of the aerobic respiratory chain by inactivation of the ndh gene, or the inhibition of glycolysis with arsenate, both of which reduce intracellular ATP, result in a significant decrease in spontaneous mutagenesis in Escherichia coli. The genetic analyses and mutation spectra in the ndh strain revealed that the decrease in spontaneous mutagenesis resulted from an enhanced accuracy of the replicative DNA polymerase. Quantification of the dNTP content in the ndh mutant cells and in the arsenate treated cells showed reduction of the dNTP pool, which could explain the observed broad antimutator effects. In conclusion, our work indicates that the cellular energy supply could affect spontaneous mutation rates and that a reduction of the dNTP levels can be antimutagenic. PMID- 23433811 TI - Checkpoint protein Rad9 plays an important role in nucleotide excision repair. AB - Rad9, an evolutionarily conserved checkpoint gene with multiple functions for preserving genomic integrity, has been shown to play important roles in homologous recombination repair, base excision repair and mismatch repair. However, whether Rad9 has an impact on nucleotide excision repair remains unknown. Here we demonstrated that Rad9 was involved in nucleotide excision repair and loss of Rad9 led to defective removal of the UV-derived photoproduct 6 4PP (6,4 pyrimidine-pyrimidone) and the BPDE (anti-benzo(a)pyrene-trans-7,8 dihydrodiol-9,10-epoxide)-DNA adducts in mammalian cells. We also demonstrated that Rad9 could co-localize with XPC in response to local UV irradiation. However, our data showed that Rad9 was not required for the photoproducts recognition step of nucleotide excision repair. Further investigation revealed that reduction of Rad9 reduced the UV-induced transcription of the genes of the nucleotide excision repair factors DDB2, XPC, DDB1 and XPB and DDB2 protein levels in human cells. Interestingly, knockdown of one subunit of DNA damage recognition complex, hHR23B impaired Rad9-loading onto UV-damaged chromatin. Based on these results, we suggest that Rad9 plays an important role in nucleotide excision repair through mechanisms including maintaining DDB2 protein level in human cells. PMID- 23433813 TI - Time-dependent changes in the risk of death in pure bronchiolitis obliterans syndrome (BOS). AB - BACKGROUND: The timing of disease onset may affect the prognosis in chronic lung allograft dysfunction (CLAD). The relationship between the timing of disease onset and the prognosis of CLAD and its sub-types, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), was examined. METHODS: Clinical records and pulmonary function data of 597 patients who underwent bilateral lung transplantation from 1996 to 2010 and survived for >3 months were examined. RESULTS: Among 155 patients with a final diagnosis of BOS, patient survival after disease onset was significantly different according to disease onset timing (BOS onset/post-BOS median survival: overall/1,438 days; <1 year/511 days; 1-2 years/1,199 days; 2-3 years/1,403 days; >3 years/did not reach median survival; p < 0.0001). The prognosis of RAS was generally poorer than that of BOS (overall post-RAS median survival, 377 days). Treating non-CLAD, CLAD, BOS, and RAS as time-dependent covariates, recipient sex-adjusted and age-adjusted Cox regression analysis demonstrated an overall mortality risk of BOS (reference: no CLAD) of 6.7 (95% confidence interval, 4.6-9.9). However, when patients survived 3 years without CLAD, the mortality risk of subsequent BOS was only 1.9 (95% confidence interval, 0.8-4.4) compared with no CLAD. The number of RAS patients was too small to obtain sufficient power to estimate time-dependent mortality risk. CONCLUSION: Late-onset BOS showed a better prognosis than early-onset BOS. Studies that do not distinguish BOS from RAS may overestimate the mortality risk of BOS. Multicenter studies will be required to further elucidate risk factors toward the development of better management strategies for CLAD. PMID- 23433814 TI - NIHSS-time score easily predicts outcomes in rt-PA patients: the SAMURAI rt-PA registry. AB - BACKGROUND: We aimed to devise a scale comprising a simple multiplication of initial National Institutes of Health Stroke Scale (NIHSS) score and onset-to treatment time (OTT) as a scale for predicting outcomes after recombinant tissue plasminogen activator (rt-PA) therapy. METHODS: Data from rt-PA patients in 10 stroke centers in Japan were investigated. NIHSS-time score was calculated as initial NIHSS score*OTT. RESULTS: Subjects comprised 526 patients. Median NIHSS score was 12 (7-18), and median OTT was 2.42 h (2.00-2.75 h). Median NIHSS-time score was 27.7 (16.9-41.7). Good (modified Rankin Scale [mRS] 0-1) and poor (mRS 4-6) outcome rates at 3months for patients with NIHSS-time scores <= 10 were 71.1% and 7.8%, compared to 54.7% and 16.5% for scores >10 and <= 20, 38.9% and 31.9% for scores >20 and <= 30, 25.0% and 44.6% for scores >30 and <= 40, and 17.4% and 61.8% for scores >40, respectively. Cut-off NIHSS-time scores to predict good and poor outcomes with 50% probability were defined as 20 and 40, respectively. Multivariate logistic regression analysis revealed NIHSS-time score as an independent predictor of good (odds ratio [OR], 0.587; 95% confidence interval [CI], 0.422-0.818, p=0.002) and poor (OR, 1.756; 95%CI, 1.227-2.514, p=0.002) outcomes after adjusting for age, sex, NIHSS score, OTT, Alberta Stroke Program Early CT Score, internal carotid artery occlusion, and glucose level. CONCLUSIONS: NIHSS-time score predicts clinical outcomes in rt-PA patients. PMID- 23433815 TI - Pediatric isolated bilateral iliac aneurysm. AB - Aneurysms are rare in children. Isolated iliac artery aneurysms are very rare, especially bilateral aneurysms. Pediatric aneurysms are usually secondary to connective tissue disorders, arteritis, or mycotic causes. We present a case of a 3-year-old child with bilateral idiopathic common iliac aneurysms that were successfully repaired with autogenous vein grafts. PMID- 23433816 TI - Best management options for chronic iliac vein stenosis and occlusion. AB - BACKGROUND: Iliac vein stenting technology is rapidly emerging as a minimally invasive alternative to traditional open venovenous bypass procedures for iliac vein stenoses and chronic total occlusions. METHODS: Peer-reviewed publications meeting eligibility criteria were retrieved and reviewed from public domain databases. RESULTS: Reviewed reports encompass ~1500 patients. Evidence quality was judged moderate, with a grade 1B recommendation (benefits outweigh risks) for patients with disabling symptoms in whom conservative therapy had failed. A grade 2B recommendation was assigned for patients with less severe symptoms. Iliac vein stenting is safe, with negligible morbidity (<1%). Patency was 90% to 100% for nonthrombotic disease and 74% to 89% for post-thrombotic disease at 3 to 5 years. Clinical relief of pain was 86% to 94%, and relief from swelling was 66% to 89%. From 58% to 89% of venous ulcers healed. Procedural success in recanalization of chronic total occlusions was 83% to 95%. Hybrid techniques for complex cases are in evolution. CONCLUSIONS: Iliac vein stenting is emerging as a safe and effective alternative to traditional open surgery to correct iliac vein obstruction. PMID- 23433817 TI - Durability of branches in branched and fenestrated endografts. AB - OBJECTIVE: Branched and fenestrated repair has been shown to be effective for treatment of complex aortic aneurysms. However, the long-term durability of branches is not well reported. METHODS: Prospective data collected for all patients enrolled in a physician-sponsored investigational device exemption trial for branched and fenestrated endografts were analyzed. Retrospective review of imaging studies and electronic records was used to supplement the dataset. Incidences of branch stent secondary intervention, stent fracture, migration, branch-related rupture, and death were calculated. A time-to-event analysis was performed for secondary intervention for any branch. Univariable and multivariable analyses were performed to identify related variables. Branch instability, a composite outcome of any branch event, was reported as a function of exponential decay to capture the loss of freedom from complications over time. RESULTS: Between the years 2001 and 2010, 650 patients underwent endovascular aortic repair with branched or fenestrated devices. Over 9 years of follow-up (mean [standard deviation], 3 [2.3] years), secondary procedures were performed for 0.6% of celiac, 4% of superior mesenteric artery (SMA), 6% of right renal artery, and 5% of left renal artery stents. Mean time to reintervention was 237 (354) days. The 30-day, 1-year, and 5-year freedom from branch intervention was 98% (95% confidence interval [CI], 96%-99%), 94% (95% CI, 92%-96%), and 84% (95% CI, 78%-90%), respectively. Death from branch stent complications occurred in three patients, two related to SMA thrombosis and one due to an unstented SMA scallop. Multivariable analysis revealed no factors as independent predictors of need for branch reintervention. CONCLUSIONS: Branches, after branched or fenestrated aortic repair, appear to be durable and are rarely the cause of patient death. The absence of long-term data on branch patency in open repair precludes comparison, yet the lower morbidity and mortality risk coupled with longer-term durability data will further alter the balance of repair options. PMID- 23433819 TI - Computational fluid dynamic evaluation of the side-to-side anastomosis for arteriovenous fistula. AB - OBJECTIVE: The goal of this research was to compare side-to-side (STS) and end-to side (ETS) anastomoses in a computer model of the arteriovenous fistula with computational fluid dynamic analysis. METHODS: A matrix of 17 computer arteriovenous fistula models (SolidWorks, Dassault Systemes, France) of artery vein pairs (3-mm-diameter artery + 3-mm-diameter vein and 4-mm-diameter artery +6 mm-diameter vein elliptical anastomoses) in STS, 45 degrees ETS, and 90 degrees ETS configurations with cross-sectional areas (CSAs) of 3.5 to 18.8 mm(2) were evaluated with computational fluid dynamic software (STAR-CCM+; CD-adapco, Melville, NY) in simulations at defined flow rates from 600 to 1200 mL/min and mean arterial pressures of 50 to 140 mm Hg. Models and configurations were evaluated for pressure drop across the anastomosis, arterial inflow, venous outflow, arterial outflow, velocity vector, and wall shear stress (WSS) profile. RESULTS: Pressure drop across the anastomosis was inversely proportional to anastomotic CSA and to venous outflow and was proportional to arterial inflow. Pressure drop was greater in 3 + 3 models than in 4 + 6 STS models; 90 degrees ETS configurations had the lowest pressure drops and were nearly identical, whereas 45 degrees ETS configurations had the highest pressure drops. Venous outflow in the 4 + 6 model in STS configurations, evaluated at 100 mm Hg arterial inflow pressure, was 390, 592, 610, and 886 mL/min in anastomotic CSAs of 3.5, 5.3, 7.1, and 18.8 mm(2), respectively, and was similar in 90 degrees ETS (609 and 908 mL/min) and lower in 45 degrees ETS (534 and 562 mL/min) configurations at CSAs of 5.3 and 18.8 mm(2). The mean increase in venous outflow was 69 mL/min (range, -59 to 134) between 3 + 3 and 4 + 6 models at 100 mm Hg arterial inflow. The most uniform WSS profile occurs in STS anastomoses followed by 45 degrees ETS and then 90 degrees ETS anastomoses. CONCLUSIONS: The STS and 90 degrees ETS anastomoses have high venous outflow and a tendency toward reversed arterial outflow. The 45 degrees ETS anastomosis has reduced venous outflow but resists reversed arterial outflow. The STS anastomosis has more uniform WSS characteristics compared with the 45 degrees and 90 degrees ETS anastomoses. PMID- 23433820 TI - Evidence of delayed nigrostriatal dysfunction in corticobasal syndrome: a SPECT follow-up study. AB - OBJECTIVE: To demonstrate that degeneration of substantia nigra neurons may occur at later stages of disease in some patients with corticobasal syndrome (CBS) who evidenced preserved nigrostriatal pathway at a baseline FP-CIT SPECT study. BACKGROUND: Current pathological criteria for the definite diagnosis of corticobasal degeneration consider substantia nigra cell loss as a mandatory finding. However, dopamine transporter SPECT imaging performed in a large cohort of CBS patients showed about 10% of normal scans. METHODS: We describe 4 patients with clinical diagnosis of CBS and normal FP-CIT SPECT at baseline whose tracer uptake resulted pathological at 1-year follow-up scan. Clinical assessment has been performed at the time of SPECT scan. A semi-quantitative approach was performed for striatal FP-CIT binding values. RESULTS: Baseline SPECT scans have been performed after 2.3 +/- 1.5 years from onset. All CBS patients presented asymmetric rigid-akinetic parkinsonism (mean Hoehn-Yahr stage 2.5; UPDRS motor score 18) with poor levodopa response and ideo-motor limb apraxia. At follow-up, neurological examination revealed some additional features, including limb dystonia, language impairment, postural instability, ocular gaze impairment, alien limb. All patients showed pathological FP-CIT uptake at the SPECT performed 10-15 months apart from the baseline scan. CONCLUSIONS: Our longitudinal FP-CIT SPECT findings support in vivo the hypothesis that substantia nigra neuronal loss may occur at later stages in some patients with CBS, despite early extrapyramidal symptoms. PMID- 23433821 TI - [Anterior chamber migration of a dexamethasone implant in a pseudophakic patient with a scleral-fixated posterior chamber intraocular lens]. AB - We report the case of anterior chamber migration of a dexamethasone implant (Ozurdex((r))) in a 54-year-old woman with macular edema due to a central retinal vein occlusion. The patient had undergone complicated cataract surgery 5 years previously with a scleral-fixated posterior chamber lens implant. An uneventful intravitreal Ozurdex((r)) implant injection was performed. One month later, the patient presented emergently with painless visual loss. Slit-lamp examination revealed the presence of discrete corneal edema associated with the implant in the anterior chamber. The implant was surgically removed from the anterior chamber 24 hours later with complete resolution of corneal edema. PMID- 23433822 TI - Criminal justice referral and incentives in outpatient substance abuse treatment. AB - A substantial number of substance abusers entering outpatient psychosocial counseling treatment are referred from the criminal justice (CJ) system. This secondary analysis of previously published findings from a large (N=415) multi site trial of a prize-based abstinence incentive intervention (Petry et al., 2005) examined the influence of CJ referral on usual care outcomes and response to the incentive procedure. CJ referrals (n=138) were more likely than those not CJ referred (n=277) to provide stimulant negative urine samples whether missing samples were counted as positive (50 versus 41%, p=.016) or as missing (96 versus 91%, p<.001). A significant interaction term was found only for percentage of treatment completers (p=.027). However, on that retention variable, and three additional drug use measures, significant incentive effects were confined to participants who entered treatment without referral from the criminal justice system. The study suggests that abstinence incentives should be offered as a first priority to stimulant users entering treatment without criminal justice referral. However, incentives can be considered for use with CJ-referred stimulant users based on the observation that best outcomes were obtained in CJ referrals who also received the abstinence incentive program. PMID- 23433823 TI - Staff and patient perspectives on the purpose of psychotropic prescribing in prisons: care or control? AB - OBJECTIVE: The objective was to explore perspectives on reasons for psychotropic medication use in prisons. METHOD: We recruited a purposive sample of healthcare staff and patients prescribed psychotropic medicines from four East of England prisons. Participants took part in qualitative, semistructured interviews, which were recorded, transcribed and analyzed thematically. RESULTS: While patients and healthcare staff viewed psychotropic medicines primarily as a treatment for reducing symptoms of mental illness, they were also used as a coping strategy and to reduce insomnia. Appropriate psychotropic prescribing was also thought to contribute towards the rehabilitation agenda and helped to maintain order in prisons. Staff voiced concerns regarding possible overreliance on psychotropic medicines. However, patients perceived insufficient access to alternative, nonpharmacological forms of treatment and support in prison. CONCLUSION: Psychotropic medicines are used for multiple purposes in prisons and are generally considered a useful resource. Nonetheless, further work may be needed to find the right balance between psychotropic medicines and alternative, nonpharmacological therapies. PMID- 23433824 TI - Optimization of the immunomagnetic selection in microcythemic donors enrolled for haploidentical transplantation. AB - BACKGROUND: Immunomagnetic cell selection (ICS) cells is increasingly used in allogeneic hematopoietic transplantation in order to reduce the T cells quantity. The aim of this study was to evaluate an protocol based on Ficoll method before ICS. STUDY DESIGN AND METHODS: The automated procedure was compared with the standard method. In the group 1 the cell processing involves the extraction of the buffy-coat by Ficoll before incubation with antibodies. This procedure was performed with the Sepax S-100 device. The efficacy of this automated procedure was compared with the group 2. In this group, the cell washing and the incubation were performed through the standard method. The CD34+ cells collected by apheresis (HPC-A) were selected with ICS. RESULTS: The results obtained after Ficoll procedure, showed a total nucleated cells (TNCs) and CD34+ cells recovery of 85.73% (75.90-90.63; SD 4.25) and 79.31% (51.77-112.31; SD 18.40), respectively. The TNC and CD34+ cells recovery after the pre-incubation washing performed through the standard method, was 75.54% (38.36-97.76; SD 22.5) and 61.51% (30.87-81.79; SD 19.3), respectively. The CD34+ cells recovery after ICS was 79% (51.77-100; SD 18.40) and 44% (15.57-88.24; SD 25.91) in the group 1 and the group 2, respectively. This difference was statistically significant (p=0.001). CONCLUSION: The efficacy of the ICS which resulted to be higher in the group 1 compared to the group 2. Overall, our data suggest that the Ficoll procedure before incubation is suitable for the clinical routine in the ICS for haploidentical transplantation in patients affected by thalassemia. PMID- 23433825 TI - Blood group genotyping in multi-transfused patients. AB - BACKGROUND: In chronically transfused patients, the classical hemagglutination assays may be inaccurate in defining the RBC phenotypes of the patients due to previous transfusions. DESIGN: DNA samples from 39 multi-transfused patients including thalassemia and sickle cell disease were used for red blood cell genotyping. The Rh-Type and KKD-Type (BAGene, BAG Healthcare) were used to determine the polymorphisms associated with antigen expression for RHD, RHCE and Kell, Kidd, Duffy blood group systems, respectively. Results were compared with previously determined phenotyping results for RhD, RhCcEe and Kell by hemagglutination method. RESULTS: Nineteen out of the 37(51%) patients had discrepancies between genotyping and phenotyping results in a total of 25 alleles. In 12 patients, the discrepancies had the potential of alloimmunization. CONCLUSION: Blood group genotyping has vital importance in transfusion management of chronically transfused patients especially if the patients were not phenotyped before starting the initial transfusions. PMID- 23433826 TI - Platelet-derived microparticles augment the adhesion and neovascularization capacities of circulating angiogenic cells obtained from atherosclerotic patients. AB - OBJECTIVE: The neovascularization-related capacities of circulating angiogenic cells (CACs) are impaired in atherosclerotic patients, which may explain the unsatisfactory effects of therapeutic angiogenesis with atherosclerotic patient derived CACs. Platelet-derived microparticles (PMPs) were reported to augment the re-endothelialization capacity of CACs. Accordingly, we investigated whether PMPs could augment the neovascularization-related capacities of atherosclerotic patient-derived CACs in vitro and in vivo and if so, the associated mechanisms. METHODS AND RESULTS: We isolated mononuclear cells and PMPs from atherosclerotic patient-derived peripheral blood and generated PMP-pretreated CACs (PMP-CACs) by co-culture of the mononuclear cells and PMPs. Although the migration capacity of PMP-CACs was similar to that of CACs, the adhesion capacity of PMP-CACs was greater. PMPs released RANTES into the culture medium, and the receptors were similarly expressed on the surfaces of CACs and PMP-CACs. Intravenous injection of PMP-CACs to rats with hindlimb ischemia augmented neovascularization of the ischemic limbs more than the injection of CACs. The number of PMP-CACs incorporated into the capillaries of the ischemic limbs was greater than that of incorporated CACs. The augmented adhesion and neovascularization capacities by PMP-CACs were canceled out by a RANTES neutralizing antibody. CONCLUSIONS: PMP secreted RANTES may play a role in the augmenting adhesion and neovascularization capacities of CACs. Injection of PMP-CACs may be a new strategy to augment the effects of therapeutic angiogenesis for limb ischemia in atherosclerotic patients. PMID- 23433827 TI - Hedgehog signalling pathway in adult liver: a major new player in hepatocyte metabolism and zonation? AB - Metabolic Zonation, i.e. the heterogeneous distribution of different metabolic pathways in different zones of the lobules, forms the basis of proper function of the liver in metabolic homeostasis and its regulation. According to recent results, Metabolic Zonation is controlled by the Wnt/beta-catenin signalling pathway. Here, we hypothesize that hedgehog signalling via Indian hedgehog ligands plays an equal share in this control although, up to now, hedgehog signalling is considered not to be active in healthy adult hepatocytes. We provide broad evidence taken mainly by analogy from other mature organs that hedgehog signalling in adult hepatocytes may particularly control liver lipid and cholesterol metabolism as well as certain aspects of hormone biosynthesis. Like Wnt/beta-catenin signalling, it seems to act on a very low level forming a porto central gradient in the lobules opposite to that of Wnt/beta-catenin signalling with which it is interacting by mutual inhibition. Consequently, modulation of hedgehog signalling by endogenous and exogenous agents may considerably impact on liver lipid metabolism and beyond. If functioning improperly, it may possibly contribute to diseases like non-alcoholic fatty liver disease (NAFLD) and other diseases such as lipodystrophy. PMID- 23433828 TI - Adenosine-induced torsade de pointes complicating a fractional flow reserve measurement in a right coronary artery intermediate stenosis. AB - We present the case of a 57 year-old patient that presented to our Institution with a positive treadmill stress test. Coronary angiography revealed an intermediate stenosis of the right coronary artery evaluated with a fractional flow reserve (FFR), complicated by torsade de pointes. Despite this being a very rare arrhythmic complication during FFR, its prompt recognition and treatment are of utmost importance. PMID- 23433829 TI - Loss and retrieval of a coronary angioplasty stent balloon. AB - A case is presented in which a breakage of the coronary stent delivery catheter occurred as retrieval of the stent balloon was attempted after stent implantation. The broken distal balloon shaft with its stuck balloon was retrieved by controlled pulling on the guiding catheter in which a new balloon was inflated, thus trapping the distal shaft. The case underscores the importance of adequate lesion assessment and preparation. PMID- 23433830 TI - Variation in antimullerian hormone concentration during the menstrual cycle may change the clinical classification of the ovarian response. AB - OBJECTIVE: To assess the variability of antimullerian hormone (AMH) concentrations in women with "adequate ovarian reserve" during unstimulated menstrual cycles and to determine the impact on clinical classifications. DESIGN: Pilot cohort study. SETTING: Private fertility clinic. PATIENT(S): Twelve consecutive women (aged 29 to 43 years) referred to a fertility service, with AMH measurements repeated throughout unstimulated cycle, and who had at least one AMH measurement indicating "adequate ovarian reserve." INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): AMH concentrations assessed in 82 serum samples from 12 women compared against the published cutoffs for reduced ovarian reserve and for risk of excessive response to ovarian stimulation. RESULT(S): Over half the women (7 of 12) were reclassified as a result of testing AMH concentrations at different phases of the menstrual cycle. Over one-third (4 or 5 of 12) crossed a cutoff for reduced ovarian reserve; 2 of 12 crossed cutoffs predicting hyperstimulation. There was a statistically significant change in AMH concentration according to the day of the cycle, with a negative trend of the median AMH concentration from the follicular to luteal phase. The maximum change in median AMH concentration over cycle was 7.9 pmol/L, and the mean difference between the maximum and minimum AMH was 6.7 pmol/L. CONCLUSION(S): In this pilot study, the AMH concentration varied during menstrual cycle, and the clinical classification of the ovarian response was altered. PMID- 23433831 TI - Optimal waiting period for subsequent fertility treatment after various hysteroscopic surgeries. AB - OBJECTIVE: To investigate the endometrial wound healing duration after a hysteroscopic surgery. DESIGN: Prospective study. SETTING: Tertiary university hospital. PATIENT(S): One hundred sixty-three women who underwent hysteroscopic surgeries for endometrial polyp (n = 37), submucous myoma (n = 65), uterine septum (n = 16), and intrauterine adhesion (IUA; n = 45). INTERVENTION(S): Postoperative office hysteroscopy was consecutively done until complete endometrial wound healing. If there was newly formed IUA occurring at the endometrial wounds, adhesiolysis was immediately done with the tip of the office hysteroscope. MAIN OUTCOME MEASURE(S): Office hysteroscopic inspection of endometrial wound healing and the presence of newly formed IUA. RESULT(S): Thirty two of 37 women (86%) achieved a fully healed endometrium 1 month after polypectomy, a higher rate than those after myomectomy (18%), septal incision (19%), and adhesiolysis (67%). Postoperative office hysteroscopy revealed that 88% and 76% of the women had new IUA formation after septal incision and adhesiolysis, respectively, more than those after myomectomy (40%) and polypectomy (0%). Women with postoperative new IUA formation were less likely to achieve endometrial wound healing within 1 month compared with those who had no new IUA formation (31% vs. 61%). CONCLUSION(S): The duration of endometrial wound healing is different after various hysteroscopic surgeries. Postoperative new IUA formation is an important factor influencing endometrial wound healing. PMID- 23433832 TI - Antibiotic therapy in acute calculous cholecystitis. AB - Acute calculous cholecystitis may progress in a variety of ways from mild cases treatable with (or even without) oral antibiotics to severe cases complicated by bile peritonitis that require emergency surgical or radiological intervention. A sample of bile should always be sent for microbial cultures to identify aerobic and anaerobic bacterial organisms. Empirically selected broad spectrum antibiotic therapy (with a defined duration, dosage and administration route) should be prescribed according to the severity of the cholecystitis, an associated history of recent antibiotic therapy, and local bacterial susceptibility patterns. As soon as causative organisms have been identified, antibiotic therapy should be adjusted to a narrower spectrum antimicrobial agent based on the specific micro organism(s) and the results of sensitivity testing. PMID- 23433833 TI - Ischemic colitis: the ABCs of diagnosis and surgical management. AB - Ischemic colitis (IC) is a rare condition. As ischemia is often transient and clinical symptoms are reversible, its exact incidence is unknown. In current clinical practice, two types of IC are described according to the severity: severe IC, with transmural colonic ischemia and/or multi-organ failure (MOF), and mild IC, without MOF and spontaneous favourable evolution in most cases. Two clinical contexts are encountered: spontaneous IC (SIC) and postoperative IC (POIC), mainly after aortic surgery. As there is no specific clinico-biologic symptom of IC, emergent CT-scan and rectosigmoidoscopy are required for diagnosis confirmation, surgical decision and prognosis analysis. IC surgical treatment is not consensual but can be standardized according to organ function and the degree of ischemia: surgical treatment in case of colonic necrosis with deep ischemia and/or MOF; observation for superficial ischemia without organ dysfunction; systematic medical care. Surgery is required in 20% of cases, and consists in extended colectomy without continuity restoration and prophylactic cholecystectomy. Continuity restoration is feasible in one third of survivors, who are exposed to a high risk of severe cardiovascular events. PMID- 23433834 TI - Side-to-end duodenojejunostomy (Gregoire's technique modified by Stoppa). PMID- 23433835 TI - Temporal and spatial variation in Hg accumulation in zebra mussels (Dreissena polymorpha): possible influences of DOC and diet. AB - Zebra mussels (Dreissena polymorpha) are filter feeders located near the base of the foodweb and these animals are able to utilize a variety of carbon sources that may also vary seasonally. We conducted both a spatial and a temporal study in order to test the hypotheses: (1) dissolved organic carbon (DOC) concentrations influence Hg accumulation in zebra mussels sampled from a series of lakes and (2) seasonal variations in diet influence Hg accumulation. In the spatial study, we found a significant negative relationship between Hg concentrations and DOC concentrations, suggesting an influence of DOC on Hg bioaccumulation. In the temporal study, we used stable isotope ratios of nitrogen (delta(15)N) and carbon (delta(13)C) as ecological tools to provide a temporally integrated description of the feeding ecology of zebra mussels. Both delta(15)N and delta(13)C varied seasonally in a similar manner: more depleted values occurred in the summer and more enriched values occurred in the fall. Mercury concentrations also varied significantly over the year, with highest concentrations occurring in the summer, followed by a progressive decrease in concentrations into the fall. The C/N ratio of zebra mussels also varied significantly over the year with the lowest values occurring mid-summer and then values increased in the fall and winter, suggesting that there was significant variation in lipid stores. These results indicate that in addition to any effect of seasonal dietary changes, seasonal variation in energy stores also appeared to be related to Hg levels in the zebra mussels. Collectively results from this study suggest that DOC concentrations, seasonal variation in diet and seasonal depletion of energy stores are all important variables to consider when understanding Hg accumulation in zebra mussels. PMID- 23433836 TI - Distribution of alpha-, beta-, gamma-, and delta-hexachlorocyclohexane in soil plant-air system in a tea garden. AB - The residue of hexachlorocyclohexane (HCH) isomers (mainly alpha-, beta-, gamma-, and delta-HCH) in the soils, plant tissues and atmosphere were measured in a typical tea garden in Fujian, a major tea-producing province in China, and this study focused on the distribution and accumulation of HCHs. HCHs could accumulate in most of the plant tissues, with the highest HCH concentration of 3.0+/-2.9ng/g dw in old leaves. Uptake of HCHs by the roots from soil was the possible pathway for HCHs accumulation in plants, and the accumulation was an isomer-selective process, with the highest concentration factor of 10.3 for alpha-HCH. The higher percentages of alpha- and gamma-HCH in roots (28.1 percent and 43.7 percent) than those in soil (14.0% and 34.1 percent) also implied the isomer-selective accumulation of HCHs. SigmaHCHs in the gaseous phase (157+/-97pg/m(3)) were significantly higher than those in particle phase (19+/-20pg/m(3)). Volatilization of HCHs from soils and uptake by the plant's aerial tissues might be the pathway for HCHs accumulation in leaves and stems, and beta-HCH showed the highest accumulation capacity in young leaves. The percentage distribution pattern of the dust on plant leaves were similar to that in soils, suggesting that the dust on the leaves were mainly from the soils. High gamma-HCH concentrations and low alpha-/gamma-HCH ratios in plant's aerial tissues suggested the input of lindane in tea garden. PMID- 23433837 TI - Antibiotic resistant Escherichia coli in hospital and municipal sewage and their emission to the environment. AB - The spreading of antibiotic resistant bacteria in the environment is a threat to human health but little is known about the transmission of extended-spectrum beta lactamases (ESBL)-producing Escherichia coli from the hospital and municipal sewage to the water basin and to the air at the WWTPs (Waste Water Treatment Plants) area and their surroundings. Accordingly, it seems particularly interesting to trace the fate of these bacteria and their genes encoding antibiotic resistance in both untreated sewage from hospitals, and in sewage after different stages of purification, and finally to examine the degree of their emissions to environment. Although wastewater treatment processes reduce number of bacteria in sewage up to 99%, in the presented study it was reported that more than 2.7*10(3) CFU/mL E. coli reached the receiving water and contributed to dissemination of resistant bacteria into the environment. We received 395 E. coli strains from sewage and environmental samples and we investigated their antibiotic susceptibility and the presence of bla gene encoding TEM, CTX, OXA and SHV. From among 167 and 147 E. coli strains isolated from hospital effluents and municipal sewage in Olsztyn, Poland, up to 37.1% and 17.7%, respectively, were ESBL-positive. From among 38 and 43 strains isolated from river water and the air up to 18.4% and 27.9%, respectively, were ESBL producers. The blaCTX-M (blaCTX-M-1, blaCTX-M-3, blaCTX-M-5, blaCTX-M-15) genes were the predominant group of the plasmid-coded ESBLs. More than 38% out of ESBL producing isolates carried several bla genes. The multiple-antibiotic-resistant (MAR) indexes for ESBL-positive were higher than for ESBL-negative isolates and ranged from 0.45 to 0.63. The MAR indexes for E. coli from hospital effluents and air samples were greater than the indexes calculated for strains isolated from other samples. Presumably, the preliminary disinfection of hospital sewage before its inflow into the sewage system might minimize the spreading of antibiotic resistant bacteria to the environment. PMID- 23433838 TI - The uptake of nickel and chromium from irrigation water by potatoes, carrots and onions. AB - Heavy metals, in general, can migrate from polluted soil and/or irrigation water to tuber plants, leading, after chronic consumption, to health problems. The scope of this study was to investigate the uptake of chromium and nickel by carrots (Daucus carrota), onions (Allium cepa) and potatoes (Solanum tuberosum) in a greenhouse experiment simulating the open-field irrigation conditions in the two biggest tuber producing regions of Greece (Asopos river in Viotia and Messapia in Evia). The study included cultivation of tubers for a period of approximately 4 months in six irrigation lines, each one provided by a water solution containing different levels of Cr(VI) and Ni(II) ranging from 0MUg/l (control) to 250MUg/l. The soil used was obtained from a certified organic greenhouse. Uptake of Cr was observed in onion leaves between 0 and 10MUg/l water concentrations (+109.2 percent, p=0.006), 0MUg/l and 20MUg/l (+47.5 percent, p=0.006), 0MUg/l and 50MUg/l (+202.8 percent, p=0.006), 0MUg/l and 100MUg/l (+89.9 percent, p=0.028), 0MUg/l and 250MUg/l (+61.3 percent, p=0.009). Uptake of Ni was observed: (a) in onion leaves between 0 and 250MUg/l water concentrations (+90.2 percent, p=0.076), (b) in onion shoots between 0 and 10MUg/l (+39.1 percent, p=0.045), 0 and 250MUg/l (+55 percent, p=0.047) and (c) in potatoes between 0 and 20MUg/l (+28.1 percent, p=0.083). Our results suggest that irrigation water containing Cr and Ni can cross-contaminate onions and potatoes cultivated in a soil never previously polluted, anthropogenically, with heavy metals. No such results were found for carrots. PMID- 23433839 TI - Physical health care for people with mental illness: training needs for nurses. AB - AIM: People diagnosed with serious mental illness have higher rates of physical morbidity and decreased longevity, yet these people are not adequately served by health care systems. Nurses may provide improved physical health support to consumers with serious mental illness but this is partly dependent on nurses having necessary skills and interest in training opportunities for this component of their work. This survey investigated Australian nurses' interest in training across areas of physical health care including lifestyle factors, cardiovascular disease, and identifying health risks. METHODS: A nation-wide online survey of nurse members of the Australian College of Mental Health Nurses. The survey included an adapted version of a sub-section of the Physical Health Attitudes Scale. Participants were asked to indicate their interest in various aspects of physical health care training. RESULTS: Most (91.6%) participants viewed educating nurses in physical health care as of moderate or significant value in improving the physical health of people with serious mental illness. Interest in training in all areas of physical health care was over 60% across the health care settings investigated (e.g. public, private, primary care). Forty-two percent sought training in all nine areas of physical health care, from supporting people with diabetes, to assisting consumers with sexually-related and lifestyle issues. CONCLUSIONS: The findings suggest that nurses in mental health services in Australia acknowledge the importance of training to improve physical health care of consumers with serious mental illness. Training programs and learning opportunities for nurses are necessary to reduce inequalities in health of people with serious mental illness. PMID- 23433840 TI - The effectiveness of an e-learning program on pediatric medication safety for undergraduate students: a pretest-post-test intervention study. AB - BACKGROUND: Safe medication management is a major competency taught in the nursing curriculum. However, administering pediatric medications is considered a common clinical stressor for Taiwanese students. A supplemental e-learning program that helps students fill the gap between basic nursing skills and pediatric knowledge on medication safety was developed. OBJECTIVE: To evaluate the effectiveness of an e-learning program to increase pediatric medication management among students who take pediatric nursing courses. DESIGN: This intervention study used a historical comparison design. SETTING: A university in Northern Taiwan. PARTICIPANTS: A total of 349 undergraduate nursing students who took pediatric nursing courses participated. Eighty students in the comparison group received regular pediatric courses, including the lectures and clinical practicum; 269 students in the intervention group received an e-learning program, in addition to the standard pediatric courses. METHODS: Between February 2011 and July 2012 pediatric medication management, including pediatric medication knowledge and calculation ability, was measured at the beginning of the first class, at the completion of the lectures, and at the completion of the clinical practicum. The program was evaluated qualitatively and quantitatively. RESULTS: The intervention group had significantly higher pediatric medication management scores at completion of the lecture course and at the completion of the clinical practicum than the comparison group based on the first day of the lecture course, after adjusting for age, nursing program, and having graduated from a junior college in nursing. Overall, the students appreciated the program that included various teaching modalities content that related to the administration of medication. CONCLUSION: Using an e-learning program on pediatric medication management is an effective learning method in addition to sitting in a regular lecture course. The different emphases in each module, provided by experienced instructors, enabled the students to be more aware of their role in pediatric medication safety. PMID- 23433841 TI - Up-regulation of components of the renin-angiotensin system in liver fibrosis in the rat induced by CCL4. AB - The purpose of this study was to investigate the components of renin-angiotensin system (RAS), liver function and histology in liver fibrogenesis in the rats induced by low-dose chronic carbon tetrachloride (CCL4) administration and evaluate the relationship between biochemical variables and components of RAS. Male Sprague-Dawley (SD) rats were randomly divided into the CCL4 group which received intraperitoneal injection of 40% CCL4 dissolved in olive oil every three days for four consecutive weeks (Initial dose was 5 mL/kg, other dose: 3 mL/kg) and the control group which received the same dose of olive oil. The micro structure of the liver was examined by H&E. Hepatic Ang II and Ang(1-7) was detected. Real-time PCR and Western-blot were performed to determine the gene and protein expression of the RAS. The components of RAS were all up-regulated in CCL4 group, and the increased extent of ACE-Ang II-AT1 axis was higher than the ACE2-Ang(1-7)-Mas axis. There was a significant correlation between ACE and ACE2 gene expression, AT1 and MAS gene expression, Ang II and Ang(1-7) in the liver of rats. ACE (or ACE2) gene expression strongly correlated with the index of liver injury significantly. These results suggest hepatic fibrogenesis induced by chronic CCL4 administration may be associated with the relationship of ACE-Ang II AT1 axis and ACE2-Ang(1-7)-MAS axis. PMID- 23433842 TI - [Steroid intake before leukemia diagnosis impairs outcome in childhood acute lymphoblastic leukemia]. AB - The aim of this study was to show that steroid therapy taken before the diagnosis of acute lymphoblastic leukemia (ALL) can alter the management of the disease. PATIENTS AND METHODS: We conducted a multicenter retrospective study on 11 children treated between 2005 and 2011, who received oral steroids ranging from 0.6 to 3.3mg/kg/day prednisolone equivalent for a duration of 2 to 15 days during the 2 months prior to diagnosis of ALL. RESULTS: Four children had febrile pancytopenia. Among them, 2 had severe infections and a noncontributive bone marrow aspiration. One of them presented a severe tumoral lysis syndrome and was hospitalized twice in the intensive care unit. Two teenagers had central nervous system involvement at diagnosis of T-ALL, 1 having associated cutaneous locations, the second one showing pulmonary and central nervous system (CNS) leukostasis with renal failure and disseminated intravascular coagulation. One child died of septic shock during the induction phase of steroid-resistant T-ALL. Four children had no complications during the induction phase. Steroid resistance occurred in 5 cases and steroid sensitivity could not be evaluated in 3 cases. Three allogeneic bone marrow transplants were performed: the first one because of early CNS relapse, the 2 others because of initial treatment resistance. CONCLUSION: Steroids can induce a delay in the management of ALL and seem to favor initial complications, and possibly increase diffuse locations as well as steroid resistance. Their prescription needs to be carefully managed, especially for uncharacteristic infectious symptoms. Then a complete blood count should be done. PMID- 23433843 TI - [Sodium dichloroisocyanurate-induced acute lung injury in a child]. AB - Intoxication, by cyanurate and its chlorated derivatives in children, is increasingly reported in the literature due to accidental ingestion compared to accidental inhalation. We report a case in a 5-year-old child who presented with acute lung injury due to accidental inhalation of gas formed after a reaction of sodium dichloroisocyanurate tablets with water. Prevention remains the best way to reduce the risk of children being intoxicated by inhalation of the gas formed after contact of tablets with water. PMID- 23433844 TI - [Primary familial erythromelalgia. A case report]. AB - Erythromelalgia is a rare disease whose etiology is poorly understood. It is characterized by paroxysmal attacks of erythema, pain, and warmth of the extremities and can be primary or secondary. We report a case of primary familial erythromelalgia and stress the difficulties in its therapeutic management. We provide a brief update on the pathophysiology and treatment of primary erythromelalgia. PMID- 23433845 TI - [Systemic adverse effects of topical ocular instillation of atropine in two children]. AB - A medication-related cause must be sought when unusual symptoms occur. Topical treatments, including eye drops, whose side effects are more common in exposed children, need to be verified. We report here the cases of two children who developed systemic symptoms after the administration of atropine-based mydriatic eye drops. A 6-month-old boy was admitted to the emergency department with acute urine retention lasting 36h. Investigations identified only eye drop treatment 3h before the onset of symptoms, with 2 drops of homatropine 1 %, as a cause. No other urinary retention was observed during the 1-year follow-up. A 2-year-old boy was admitted to the emergency department for drowsiness, thirst, and dry mouth 30min after the administration of three eye drops of atropine 1 % instead of atropine 0.3 % (error made by the pharmacy). Symptoms disappeared after 6h. Both observations highlight the possible side effects related to mydriatic eye drops. Indeed, because of small penetration of such medications in the eye, a high concentration of the active part of the medication is contained in each drop. In young children, at least 20 to 40 % of the volume of a drop drains into the nasolacrimal duct and thereby into the systemic circulation, without passage through the liver. A close national pharmacologic vigilance follow-up has been set up for atropine-based mydriatic eye drops in young children, who are the most exposed to systemic and potentially severe complications of these medications. We emphasize the appropriate procedure for the use of eye drops in young children to limit systemic passage, with only a 0.3 % maximum atropine concentration in infants, compression of the internal angle of the eye for at least 1min, and at least a 15-mins interval between two eye drop administrations. PMID- 23433846 TI - A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. AB - OBJECTIVE: This is the first clinical study of the MEK1/2 inhibitor AZD8330 (ARRY 424704). This phase I study defined the maximum tolerated dose (MTD) and assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8330 in patients with advanced malignancies. METHODS: Patients with refractory cancer or cancer with no standard therapy received either once-daily (OD) or twice-daily (BID) oral AZD8330 on day 1 followed by a 7-day washout period and continuous dosing from day 8. The starting dose was 0.5 mg with dose escalations in subsequent cohorts until a non-tolerated dose was reached. RESULTS: Eighty-two patients received AZD8330 across 11 cohorts. The most frequent AZD8330-related adverse events were acneiform dermatitis (13/82, 16%), fatigue (11/82, 13%), diarrhoea (11/82, 13%) and vomiting (9/82, 11%). Four patients experienced dose limiting toxicities: mental status changes (40 mg OD; 2/9 patients and 60 mg OD; 1/3) and rash (20 mg BID; 1/9). The MTD was defined as 20mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5-60 mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses >=3 mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration >3 months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors. CONCLUSION: AZD8330 has a manageable toxicity profile at the MTD of 20 mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response. PMID- 23433847 TI - A single-chain fragment against prostate specific membrane antigen as a tool to build theranostic reagents for prostate cancer. AB - Prostate carcinoma is the most common non-cutaneous cancer in developed countries and represents the second leading cause of death. Early stage androgen dependent prostate carcinoma responds well to conventional therapies, but relatively few treatment options exist for patients with hormone-refractory prostate cancer. One of the most suitable targets for antibody-mediated approaches is prostate specific membrane antigen (PSMA) which is a well known tumour associated antigen. PSMA is a type II integral cell-surface membrane protein that is not secreted, and its expression density and enzymatic activity are increased progressively in prostate cancer compared to normal prostate epithelium, thereby making PSMA an ideal target for monoclonal antibody imaging and therapy. To obtain a small protein that can better penetrate tissue, we have engineered a single-chain variable fragment (scFv) starting from the variable heavy and light domains of the murine anti-PSMA monoclonal antibody D2B. scFvD2B was analysed in vitro for activity, stability, internalisation ability and in vivo for targeting specificity. Maintenance of function and immunoreactivity as well as extremely high radiolabelling efficiency and radiochemical purity were demonstrated by in vitro assays and under different experimental conditions. Despite its monovalent binding, scFvD2B retained a good strength of binding and was able to internalise around 40% of bound antigen. In vivo we showed its ability to specifically target only PSMA expressing prostate cancer xenografts. Due to these advantageous properties, scFvD2B has the potential to become a good theranostic reagent for early detection and therapy of prostate cancers. PMID- 23433848 TI - Enacting global health in the nursing classroom. AB - Globalization presents nurses with the challenges and an ethical responsibility of being competent caregivers within a global society. The link between globalization and global health, and the contributions nursing can make to the global health environment are described in the delivery of a new required course for undergraduate nursing students in a four year degree program. Innovative approaches for the delivery of this course are described, which even though living locally, can encourage nursing students to think globally. The need for nursing programs to acknowledge the shared responsibilities for examining global health challenges is now part of our reality in many countries. PMID- 23433849 TI - The roles of macromolecules in imatinib resistance of chronic myeloid leukemia cells by Fourier transform infrared spectroscopy. AB - Imatinib is a first generation tyrosine kinase inhibitor, which is used for the treatment of chronic myeloid leukemia. However, resistance to imatinib is an important problem. Different mechanisms have been explained for imatinib resistance. In this study, we examined the roles of macromolecules in imatinib resistance in K562 cells at the molecular level using Fourier Transform Infrared (FT-IR) spectroscopy. An amount of 3 MUM imatinib resistant cells were generated by our group and named as K562/IMA-3 cells. Changes in macromolecules in parental and resistant cells were studied by FT-IR spectroscopy. Imatinib resistance caused changes, which indicated decreases in the level of glycogen and increases in the membrane order. The amount of unsaturated lipids increased in the imatinib resistant cells indicating lipid peroxidation. Imatinib resistance caused changes in the lipid/protein ratio. The relative protein content increased with respect to nucleic acids indicating higher transcription and protein expression and structural/organizational changes in the nucleus were evident as revealed by frequency changes in the nucleic acid bands. Changes in the amide bands revealed changes in the proteome of the resistant cells. Protein secondary structural changes indicated that the antiparallel beta sheet's structure increased, however the alpha helix structure, beta sheet structure, random coil structure and turns decreased in the resistant cells. These results indicate that the FT-IR technique provides a suitable method for analyzing drug resistance related structural changes in leukemia and other cancer types. PMID- 23433850 TI - Recombinant human interleukin-1 receptor antagonist reduces acute lethal toxicity and protects hematopoiesis from chemotoxicity in vivo. AB - Cyclophosphamide (CY), targeting to fast dividing cells, results in bone marrow (BM) suppression, which is the most common side effect of cancer chemotherapy. Interleukin-1 receptor antagonist (IL-1Ra), activated by variety of chemotherapeutic drugs, is a natural inhibitor of interleukin-1 (IL-1) and blocks the functional IL-1 receptor signaling. Our previous studies showed the protective effect of recombinant murine IL-1Ra on hematopoiesis in mice after treatment with chemotherapeutic agent 5-fluorouracil. In this report, we demonstrate that the pretreatment use of recombinant human IL-1Ra (rhIL-1Ra) significantly alleviated chemotherapy-induced peripheral blood injury in mice, and reduced the incidence and severity of neutropenia in beagle dogs. Moreover, acute lethal toxicity in single and repeated CY treatment was markedly reduced by rhIL-1Ra administration. The chemoprotective role of rhIL-1Ra is attributed to the attenuated BM damage, accelerated recovery of BM cells, and enhanced survival of hematopoietic progenitor cells which expressed high level of aldehyde dehydrogenase and IL-1 receptor type I. Thus, our data strongly suggest that the prophylactic use of exogenous rhIL-1Ra renders BM primitive hematopoietic cells resistant to chemotherapy, which provides novel strategies to prevent BM suppression in clinical settings. PMID- 23433851 TI - Arginine homozygosity in codon 72 of p53 correlates with failure to imatinib response in chronic myeloid leukemia. AB - PURPOSE: In this study, the role of the polymorphism at codon 72 of tumor protein p53 gene (TP53) was investigated regarding the response to treatment with imatinib in chronic myeloid leukemia (CML). METHODS: A total of 85 patients with CML were treated according to the Brazilian National Cancer Institute (INCA) guidelines and at the end of the 18th month a blood sample were collected for genotyping. Genomic DNA was extracted and TP53 codon 72 genotyping was performed by allele-specific polymerase chain reaction (AS-PCR), which detects argine or proline alleles. RESULT: Of the 85 CML samples, 27 samples were homozygous for arginine (Arg/Arg), 12 homozygous for proline (Pro/Pro) and 46 samples heterozygous (Arg/Pro). TP53 codon 72 polymorphism was in Hardy-Weinberg equilibrium (chi(2)=1.17, P=0.37). We did not find significant association between codon 72 polymorphism and age at diagnosis and sex (P=0.76 and P=0.33, respectively). High Sokal score are significantly associated with Arg/Arg genotype carriers (Odds ratio, OR=4.09; 95% confidence interval, CI 1.01=15.89; P=0.036). The arginine allele in homozygosis also have an increased risk of failure response to imatinib when compared with both, the heterozygous (Arg/Pro) and proline homozygous patients (P=0.021; OR=2.99, 95% CI=1.16-7.67). Additionally, interaction analysis with age at diagnosis revealed that among patients over 40-yr old, Arg/Arg genotype was significantly associated with non responder patients (P=0.007; OR=5.13, 95% CI=1.5-17.55). CONCLUSION: The findings suggest that in CML patients, TP53 codon 72 polymorphism may contribute to a high Sokal score and failure to imatinib treatment. PMID- 23433852 TI - Safety and durability in a cohort of HIV-1 positive patients treated with once and twice daily darunavir-based therapy (SCOLTA Project). AB - OBJECTIVE: To evaluate safety and durability of once-daily and twice-daily darunavir/ritonavir (DRV/r)-based treatment in HIV patients in clinical practice. METHODS: The Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) project is a prospective, observational, multicenter cohort created to assess the incidence of adverse events in patients receiving new antiretroviral drugs. Twenty-five Italian infectious diseases centers enroll patients and collect their data through this on-line system. Periodical evaluations of these patients, including physical examination and laboratory tests, were performed at baseline and every 6 months. RESULTS: Four hundred and twenty-nine patients were enrolled since May 2006. Eighty-five patients (19.8%) were prescribed once-daily DRV/r; 31 of them were treatment-naive (36.5%). Among 54 (63.5%) treatment-experienced patients, 21 (38.9%) had undetectable viral load and started once-daily DRV/r as a simplification regimen. Patients on twice-daily regimen were older, more frequently lipodystrophic, HCV-coinfected, and in CDC stage C. In the following 24 months of follow-up, the viral load steadily decreased as well as the CD4 cell count rose. The reason for discontinuation did not significantly differ between groups. Mean blood glucose (BG) change from baseline did not show significant difference between groups, as well as high density lipoprotein cholesterol (HDL C), triglycerides (TGL) and alanine transaminase (ALT). The survival curve shows that patients in the once-daily regimen withdrew treatment more frequently than those on twice-daily regimen (Log Rank Chi(2)P=0.009). CONCLUSION: Our study showed that DRV/r administrated both once daily or twice daily was safe and well tolerated with few discontinuations due to adverse events. PMID- 23433853 TI - Everolimus combined with cisplatin has a potential role in treatment of urothelial bladder cancer. AB - Cisplatin (CDDP)-based chemotherapy is a commonly treatment for advanced urothelial carcinoma. However, episodes of cisplatin resistance have been referenced. Recently it has been reported that everolimus (RAD001) could have an important role to play in bladder-cancer treatment and that mTOR inhibitors may restore chemosensitivity in resistant tumours. The aim of this study was to assess RAD001 in vitro ability to enhance CDDP cytotoxicity in three human bladder-cancer cell lines. Over the course of 72h, the cells were exposed to different concentrations of CDDP and RAD001, isolated or combined. Treatment with CDDP statistically (P<0.05) decreased cell proliferation in cell lines in a dose dependent manner. The anti-proliferative activity of CDDP used in combination with RAD001 was statistically significant (P<0.05) in the cell lines at all concentrations tested. RAD001 had a therapeutic effect when used in combination with CDDP and could therefore be a useful anti-cancer drug combination for patients with bladder cancer. PMID- 23433854 TI - Ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) and adenosine deaminase (ADA) activities in prostate cancer patients: influence of Gleason score, treatment and bone metastasis. AB - The relation between adenine nucleotides and cancer has already been described in literature. Considering that the enzymes ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) and adenosine deaminase (ADA) act together to control nucleotide levels, we aimed to investigate the role of these enzymes in prostate cancer (PCa). E-NPP and ADA activities were determined in serum and platelets of PCa patients and controls. We also verified the influence of the Gleason score, bone metastasis and treatment in the enzyme activities. Platelets and serum E-NPP activity increased, whereas ADA activity in serum decreased in PCa patients. In addition, Gleason score, metastasis and treatment influenced E-NPP and ADA activities. We may propose that E-NPP and ADA are involved in the development of PCa. Moreover, E-NPP and ADA activities are modified in PCa patients with distinct Gleason score, with bone metastasis, as well as in patients under treatment. PMID- 23433855 TI - Prognostic relationship of metabolic profile obtained of melanoma B16F10. AB - Melanoma is a type of cancer that reaches more people in the world, characterized by genetic mutations that trigger the growth of disorganized cells. The diagnosis of skin tumors by invasive techniques has become a risk to the patients, so the search for new non-invasive techniques has been the subject of research in recent years. The objective of this work is to propose a non-invasive method prognosis based on the identification of specific biomarkers of the cancer, known as metabolomics analysis. For this study, we used B16F10 melanoma tumor cells and metabolic profiles were obtained at three time-periods by (1)HNMR and comparison with the cell cycle, apoptosis pathways and proliferation index. The metabolic profiles show the relationship between the metabolites found with energy metabolism, pathways of apoptosis and proliferation, which showed increases in proportion during growth and progression. Were found 29 metabolites, of which the differentially expressed are: lactate, aspartate, glycerol, lipids, alanine, myo inositol, phosphocholine, choline, acetate, creatine and taurine. Choline and creatine are closely related with tumor progression, and are inversely expressed in later stages of tumor growth, which demonstrates the ability to be markers of tumor progression or monitoring the pharmacological efficacy when combined with other therapies. We conclude that the metabolome appeared as effective non invasive technique predicts, besides providing possible biomarkers of melanoma. PMID- 23433856 TI - Differences in functional connectivity in major depression versus bipolar II depression. AB - BACKGROUND: Objective methods of differentiating unipolar versus bipolar depression would enhance our ability to treat these disorders by providing more accurate diagnoses. One first step towards developing diagnostic methodology is determining whether brain function as assessed by functional MRI (fMRI) and functional connectivity analyses might differentiate the two disorders. METHODS: Fourteen subjects with bipolar II depression and 26 subjects with recurrent unipolar depression were studied using fMRI and functional connectivity analyses. RESULTS: The first key finding of this study was that functional connectivity of the right posterior cingulate cortex differentiates bipolar II and unipolar depression. Additionally, results suggest that functional connectivity of this region is associated with suicidal ideation and depression severity in unipolar but not bipolar II depression. LIMITATIONS: The primary limitation is the relatively small sample size, particularly for the correlational analyses. CONCLUSIONS: The functional connectivity of right posterior cingulate cortex may differential unipolar from bipolar II depression. Further, connectivity of this region may be associated with depression severity and suicide risk in unipolar but not bipolar depression. PMID- 23433857 TI - Regional gray matter reductions are associated with genetic liability for anxiety and depression: an MRI twin study. AB - BACKGROUND: The influence of genetic and/or environmental factors on the volumetric brain changes observed in subjects affected by anxiety and depression disorders remains unclear. The current study aimed to investigate whether genetic and environmental liabilities make different contributions to abnormalities in gray matter volume (GMV) in anxiety and depression using a concordant and discordant MZ twin pairs design. METHODS: Fifty-three magnetic resonance imaging (3T) brain scans were obtained from monozygotic (MZ) twins concordant (6 pairs) and discordant (10 pairs) for lifetime anxiety and depression disorders and from healthy twins (21 subjects). We applied voxel-based morphometry to analyse GMV differences. Concordant affected twins were compared to healthy twins and within pairs comparisons were performed in the discordant group. RESULTS: GMV reductions in bilateral fusiform gyrus and amygdala were observed in concordant affected twins for anxiety and depression compared to healthy twins. No intrapair differences were found in GMV between discordant affected twins and their healthy co-twins. LIMITATIONS: The sample size was modest. This might explain why no intrapair differences were found in the discordant MZ twin group. CONCLUSIONS: As concordant affected MZ twins are believed to have a particularly high genetic liability for the disorder, our findings suggest that fusiform gyrus and amygdala gray matter reductions are related to a genetic risk for anxiety and depression. Discrepancies in regard to brain abnormalities in anxiety and depression may be related to the admixture of patients with GMV abnormalities mainly accounted for by genetic factors with patients presenting GMV mainly accounted for by environmental factors. PMID- 23433858 TI - Validation of the Temps-A in university student population in Serbia. AB - BACKGROUND AND AIMS: The TEMPS-A scale is a self-evaluation measure which assesses five affective temperaments. This study is a comparative analysis of affective temperament types in different educational fields, and the first validation of the Serbian version of the TEMPS-A. METHODS: The TEMPS-A questionnaire has been adapted following the translation-back translation methodology from English to Serbian. It was then administered to 770 undergraduate students from eight different faculties. RESULTS: Five factors were extracted through Principal Component Analysis (Varimax rotation), each including ten items with loadings above 0.40. The internal consistency of this abbreviated 50-item scale was alpha=0.77 and the average test-retest coefficient (rho=0.82) indicates a stable reliability. The correlations among the temperaments ranged from weak to moderate, with the highest positive correlations obtained between the depressive and cyclothymic, and, depressive and anxious scales. The highest score was detected among the hyperthymic (0.64) and lowest among the depressive temperament (0.15). The male participants attained significantly higher scores for the hyperthymic temperament, while female scored significantly higher on the depressive and anxious temperaments. The students of physical education showed significantly lower results on the depressive and anxious subscales and higher on the hyperthymic, in comparison to other educational fields. LIMITATIONS: The student sample is not representative of the general population, therefore further investigation in older population would be necessary for the evaluation of norms in additional age categories. The external validation with other personality scales has not been the subject of this research, but will be a part of some future studies. CONCLUSIONS: The Serbian 50-item version of the TEMPS-A showed good overall internal consistency and reliability, and the results generally cohere with those from previously validated versions in other languages. PMID- 23433859 TI - Cardiomyopathy in neurological disorders. AB - According to the American Heart Association, cardiomyopathies are classified as primary (solely or predominantly confined to heart muscle), secondary (those showing pathological myocardial involvement as part of a neuromuscular disorder) and those in which cardiomyopathy is the first/predominant manifestation of a neuromuscular disorder. Cardiomyopathies may be further classified as hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or unclassified cardiomyopathy (noncompaction, Takotsubo-cardiomyopathy). This review focuses on secondary cardiomyopathies and those in which cardiomyopathy is the predominant manifestation of a myopathy. Any of them may cause neurological disease, and any of them may be a manifestation of a neurological disorder. Neurological disease most frequently caused by cardiomyopathies is ischemic stroke, followed by transitory ischemic attack, syncope, or vertigo. Neurological disease, which most frequently manifests with cardiomyopathies are the neuromuscular disorders. Most commonly associated with cardiomyopathies are muscular dystrophies, myofibrillar myopathies, congenital myopathies and metabolic myopathies. Management of neurological disease caused by cardiomyopathies is not at variance from the same neurological disorders due to other causes. Management of secondary cardiomyopathies is not different from that of cardiomyopathies due to other causes either. Patients with neuromuscular disorders require early cardiologic investigations and close follow-ups, patients with cardiomyopathies require neurological investigation and avoidance of muscle toxic medication if a neuromuscular disorder is diagnosed. Which patients with cardiomyopathy profit most from primary stroke prevention is unsolved and requires further investigations. PMID- 23433860 TI - Selection for axillary clearance in breast cancer (ultrasound negative, sentinel node positive patients have low rates of further metastases). AB - BACKGROUND: The aim of this study was to determine whether we could identify a subset of axillary clearance patients in whom the procedure yielded negative nodes and was therefore of no therapeutic benefit. METHODS: Over a three year period 138 patients underwent axillary clearance at our unit. The axillae of all patients were assessed preoperatively with clinical examination, ultrasound (USS) and FNAC if suspicious nodes identified. Patients with clinically malignant nodes or positive FNAC underwent axillary node clearance where appropriate, whilst completion axillary node clearance was performed in those who had no preoperative evidence of metastatic axillary disease but positive sentinel node biopsy (SNB)/axillary node sample (ANS). RESULTS: Of the 138 patients, the indications for axillary clearance were positive FNAC or clinically malignant nodes in 89 and positive SNB/ANS in the remaining 49. Patients with preoperative evidence of axillary metastases had significantly more positive nodes compared to those who underwent SNB and completion ANC 4.6 vs. 3.1 p = 0.037. Of the patients with ultrasonographically normal axillae but positive SNB, 8.7% had further nodal metastases at completion ANC. This was significantly less than in those with abnormal USS (negative FNAC) and positive SNB (41.7%); p = 0.033. CONCLUSIONS: Preoperative ultrasound in conjunction with FNAC and clinical judgement identifies most patients with positive axillary nodes and such patients have more widespread disease. The additional value of completion axillary ANC in patients with ultrasonographically normal axillae but positive SNB appears small as sentinel node 'biopsy' serves to clear the axilla of metastases in most of these patients. PMID- 23433862 TI - Jose Obeso: on a pilgrimage to unravel Parkinson's disease. PMID- 23433861 TI - Effect of interrupted eruption on the enamel organ of the rat incisor. AB - The aim of this study was to investigate the behavior of rat incisor tissues during the inhibition of tooth eruption. Twenty Sprague-Dawley rats were used in this study, and incisor eruption was inhibited by a screw pin. Animals were sacrificed 1, 3, 7 and 14 days after the start of the experiment. Cross-sections at the mesial point of the mandibular first molar and sagittal sections of the mandibular tooth germ area were examined using immunohistochemical and immunofluorescence methods. For morphometric analysis, numbers of TRAP-positive cells were calculated against the total number of cells. In cross-sections from the experimental group, dentin was thickened and pulp tissue was constricted day by day. On days 1, 3 and 7, nestin-positive cells were observed in all odontoblast cell bodies and processes, while on day 14 fewer nestin-positive cells were seen than in the control group. On day 14, the mesial area of the periodontal ligament was constricted and the number of TRAP-positive cells in the mesial area was significantly higher than in the control group. In sagittal sections, enamel formation was found to be increased on days 7 and 14. Furthermore, in the enamel matrix amelogenin was expressed more strongly than in the control group. PCNA-positive cells were significantly increased in cells of the tooth germ compared with the control group. These results suggest that inhibition of tooth eruption accelerates the apical elongation with resorption of the mesial area of the alveolar bone and stimulates cell proliferation with thickened enamel towards the apical end. PMID- 23433863 TI - Isidre Ferrer: a revolutionary in neuropathology. PMID- 23433864 TI - Arriving too early. PMID- 23433865 TI - Small RNA sequencing of Potato leafroll virus-infected plants reveals an additional subgenomic RNA encoding a sequence-specific RNA-binding protein. AB - Potato leafroll virus (PLRV) is a positive-strand RNA virus that generates subgenomic RNAs (sgRNA) for expression of 3' proximal genes. Small RNA (sRNA) sequencing and mapping of the PLRV-derived sRNAs revealed coverage of the entire viral genome with the exception of four distinctive gaps. Remarkably, these gaps mapped to areas of PLRV genome with extensive secondary structures, such as the internal ribosome entry site and 5' transcriptional start site of sgRNA1 and sgRNA2. The last gap mapped to ~500 nt from the 3' terminus of PLRV genome and suggested the possible presence of an additional sgRNA for PLRV. Quantitative real-time PCR and northern blot analysis confirmed the expression of sgRNA3 and subsequent analyses placed its 5' transcriptional start site at position 5347 of PLRV genome. A regulatory role is proposed for the PLRV sgRNA3 as it encodes for an RNA-binding protein with specificity to the 5' of PLRV genomic RNA. PMID- 23433866 TI - Synonymous codon changes in the oncogenes of the cottontail rabbit papillomavirus lead to increased oncogenicity and immunogenicity of the virus. AB - Papillomaviruses use rare codons with respect to the host. The reasons for this are incompletely understood but among the hypotheses is the concept that rare codons result in low protein production and this allows the virus to escape immune surveillance. We changed rare codons in the oncogenes E6 and E7 of the cottontail rabbit papillomavirus to make them more mammalian-like and tested the mutant genomes in our in vivo animal model. While the amino acid sequences of the proteins remained unchanged, the oncogenic potential of some of the altered genomes increased dramatically. In addition, increased immunogenicity, as measured by spontaneous regression, was observed as the numbers of codon changes increased. This work suggests that codon usage may modify protein production in ways that influence disease outcome and that evaluation of synonymous codons should be included in the analysis of genetic variants of infectious agents and their association with disease. PMID- 23433867 TI - Defining acute renal dysfunction as a criterion for the severity of Clostridium difficile infection in patients with community-onset vs hospital-onset infection. AB - BACKGROUND: Acute renal dysfunction can be used to define severe Clostridium difficile infection (CDI). The Society for Healthcare Epidemiology of America (SHEA) and Infectious Disease Society of America (IDSA) guidelines define acute renal dysfunction as serum creatinine (SrCr) >=1.5 times the premorbid level. AIM: To determine the ability to assess premorbid SrCr in hospitalized patients with CDI, stratified into community-onset CDI (CO-CDI) and hospital-onset CDI (HO CDI); and to evaluate differing definitions for premorbid SrCr as a criterion for acute renal dysfunction. METHODS: Hospitalized patients with CDI were stratified into CO-CDI and HO-CDI. The ability to assess premorbid SrCr was determined, and the incidence of acute renal dysfunction and the severity of CDI were compared using varying definitions of premorbid SrCr. FINDINGS: In total, 293 patients with CDI were evaluated; of these, 135 (46%) had CO-CDI and 158 (54%) had HO-CDI. Premorbid SrCr data were not available for 37 (27%) patients with CO-CDI and one (<1%) patient with HO-CDI (P < 0.0001). Depending on the definition of premorbid SrCr used, acute renal dysfunction ranged from 17% to 24% for patients with CO CDI (P = 0.26), and from 13% to 14% for HO-CDI (P = 0.81). The severity of CDI could not be determined for 43 out of 293 (15%) patients, primarily due to the lack of premorbid SrCr data (N = 38). CONCLUSION: Assessment of acute renal dysfunction and the severity of CDI was not possible for many patients with CO CDI using the current SHEA/IDSA guidelines. Given the increasing incidence of CO CDI, an alternative definition of acute renal dysfunction may be required. PMID- 23433868 TI - Measles immunity and measles vaccine acceptance among healthcare workers in Paris, France. AB - BACKGROUND: In Europe, including France, a measles outbreak has been ongoing since 2008. Unprotected healthcare workers (HCWs) may contract and spread the infection to patients. AIM: The objective of this study was to evaluate HCWs' measles immunity and vaccine acceptance in our setting. METHODS: In a survey based study conducted in three university hospitals in Paris, 351 HCWs were included between April and June 2011. The following data were collected at enrolment: age, hospital unit, occupation, history of measles infection and vaccination, previous measles serology and acceptance of a measles vaccination in case of seronegativity. Sera were tested for the presence of specific anti measles IgG antibodies using the CAPTIA((r)) measles enzyme-linked immunosorbent assay. FINDINGS: The mean age of the participating HCWs was 36 years (range: 18 67) and 278 (79.2%) were female. In all, 104 four persons (29.6%) declared a history of measles, and 90 (25.6%) declared never having received a measles vaccination. Among the 351 HCWs included in the study, 322 (91.7%) were immunized against measles (IgG >90 mIU/mL). The risk factors for not being protected were age [18-29 years, adjusted odds ratio: 2.7 (95% confidence interval: 1.1-6.9) compared with >=30 years], no history of measles infection or vaccination. The global acceptance rate for a measles vaccination, before knowing their results, was 78.6%. CONCLUSION: In this cohort of HCWs, 8.3% were susceptible to measles; the group most represented were aged <30 years. Acceptance of the measles vaccine was high. A vaccination campaign in healthcare settings should target specifically healthcare students and junior HCWs. PMID- 23433869 TI - Content validity of the Dutch version of the Neck Bournemouth Questionnaire. AB - OBJECTIVE: Mechanical neck pain is a common human phenomenon. In most cases, no patho-anatomical lesion can be identified with the limitations of current radiological imaging. Therefore it is preferable to assess patients with neck pain with a focus on functioning and health, within a biopsychosocial model. The Neck Bournemouth Questionnaire aims to assess biopsychosocial aspects of neck pain. However, the content validity of the Neck Bournemouth Questionnaire Dutch language version (NBQ-NL) in relation to the International Classification of Functioning, Disability and Health (ICF) is unknown. The purpose of the study was to examine the content validity of the NBQ-NL in relation to the health components of the ICF. METHOD: Content validity was assessed in relation to the ICF, by means of Discriminant Content Validity (DCV). RESULTS: The results indicate that the NBQ-NL measures four components of the five ICF (impairment, activity, participation and personal factors). CONCLUSION: The NBQ is a multidimensional questionnaire, representing four of the five components of the ICF. PMID- 23433870 TI - Depression and social anxiety in help-seeking patients with an ultra-high risk for developing psychosis. AB - Knowledge on associations between ultra-high risk (UHR) for developing psychosis and on non-psychotic psychopathology in help-seeking populations is limited with respect to differences between male and female patients. The present study tests the hypothesis that both social anxiety and depression are highly prevalent in an UHR population, particularly among women. From February 2008 to February 2010 baseline data were collected from help-seeking subjects (14-35 years) who were included in the Dutch Early Detection and Intervention Evaluation (EDIE-NL) trial. Two recruiting strategies were used: a two-stage screening strategy in a population of consecutive help-seeking and distressed subjects of secondary mental health services, and a referral strategy. This study included 201 patients with a mean age of 22.7 years. Of these, 102 (51%) were female, 58% of the patients met the criteria for clinical depression on the Beck Depression Inventory and 42% met the criteria for clinical social phobia on the Social Interaction Anxiety Scale. Women showed more depression and social anxiety than men. The results support the hypothesis that UHR is associated with depression and social anxiety, particularly in women. Screening a help-seeking population with depression and anxiety may be effective in detecting patients at UHR for developing psychosis. PMID- 23433871 TI - Are the rates of schizophrenia unusually high in Canada? A comparison of Canadian and international data. AB - Two major risk factors for schizophrenia are present in Canada, high latitude and a large and growing immigrant population. Consequently, one would expect unusually high rates of schizophrenia and an increase in these rates over time. This systematic review tests these two hypotheses. Searches of electronic databases were performed through 2011. Out of 45 studies 12 fulfilled all the inclusion criteria. The means of Canadian and international rates were compared by one-tailed unequal variance t-test. Trends with time in Canadian rates were tested by the Spearman rank correlation coefficient. Prevalence and incidence rates in Canada were significantly higher than those in international studies. Rates increased over time, with a significant increase for prevalence and a trend for incidence. This rise was supported by historical data, recent hospital admission data, and the only Canadian cohort study. The findings of elevated rates in Canada and their increase over time give concern due to the serious personal, social, and financial burden of schizophrenia. These results, based on a small number of studies, warrant confirmation by specially designed studies. They could explain the discrepant results of the risk associated with immigration in Canadian studies. PMID- 23433872 TI - Neuropsychological correlates of symptom dimensions in inpatients with major depressive disorder. AB - Symptoms of major depressive disorder (MDD) manifest variably across individuals. Accordingly, recent models of the disorder imply that MDD may be characterized according to independent symptom dimensions. In particular, several studies reveal that depression may be characterized along dimensions of negative affect, agitation and hostility, and lassitude and malaise. No research has examined the relationship between these dimensions and neuropsychological function. Towards this end, 133 in patients with unipolar MDD and 17 people without psychiatric illness were administered a brief battery of neuropsychological tests and the MMPI-2. Paralleling earlier research, principal component analysis of the MMPI-2 revealed symptom dimensions of negative affect, agitation, and lassitude and malaise. Multiple regression analyses showed that the negative affect and agitation dimensions accounted for significant variance on measures of executive function, speed of information processing, new learning, dexterity, and overall impairment. Lassitude and malaise failed to correspond with neuropsychological performance. Implications of these data for clinical practice and neural models of MDD are discussed. PMID- 23433873 TI - Authors' reply to "Recommendations for conducting mindfulness based cognitive therapy trials". PMID- 23433874 TI - Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. AB - BACKGROUND: Theta Burst stimulation (TBS) applied via transcranial magnetic stimulation (TMS) effectively modulates human neocortical excitability but repeated applications of the same TBS protocol at short intervals may be not simply accumulative. OBJECTIVE: Our aim was to investigate the impact of multiple blocks of either intermittent (iTBS) or continuous TBS (cTBS) on the expression of neuronal activity marker proteins in rat cortex. METHODS: Up to four iTBS- or cTBS-blocks of 600 stimuli were applied to urethane-anesthetized rats followed by immunohistochemical and Western blot analyses. RESULTS: The effects of iTBS and cTBS were similar but slightly differed with regard to the number of stimuli applied. The expression of the 65-kD isoform of glutamic acid decarboxylase (GAD65) increased with each stimulation block, while that of the 67-kD isoform (GAD67), and that of the calcium-binding proteins (CaBP) Parvalbumin (PV) and Calbindin (CB) and that of the immediate early gene c-Fos progressively decreased. Both TBS protocols increased the expression of the vesicular glutamate transporter 1 (VGLUT1) with 1200-1800 stimuli but then decreased them after the 4th block. CONCLUSION: Our findings indicate that repeated TBS elicits no simple accumulative dose-dependent effect for all activity-markers but distinct profiles with threshold characteristics and a waxing-and-waning effect especially for the markers of inhibitory activity CB and GAD67. Interestingly, somatic activity markers, such as c-Fos for mainly excitatory and GAD67, CB and PV for inhibitory neurons, decreased with repeated stimulation while synaptic activity markers mainly increased which could be a result of the artificial stimulation of axons. PMID- 23433875 TI - Monotherapy with tDCS for Schizophrenia: a case report. PMID- 23433876 TI - Performance of electroconvulsive therapy in a patient with clipping (Yasargil Titanium Clip) of an aneurysm of the internal carotid artery without vascular complications. PMID- 23433877 TI - Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution white-light endoscopy and narrow-band imaging. AB - BACKGROUND: Sessile serrated adenomas/polyps (SSAs/Ps) are premalignant lesions susceptible to being easily overlooked by endoscopists. A detailed description of the endoscopic appearance of SSAs/Ps might help endoscopists to recognize these lesions to improve the effectiveness of colonoscopy. OBJECTIVE: To identify various endoscopic features of SSAs/Ps using high-resolution white-light endoscopy (HR-WLE) and narrow-band imaging (NBI). DESIGN: Retrospective image evaluation study. SETTING: Single tertiary referral center. PATIENTS: Forty-5 patients with serrated polyposis syndrome undergoing surveillance colonoscopies. INTERVENTION: HR-WLE and NBI images of 150 polyps (50 SSAs/Ps, 50 hyperplastic polyps [HPs], and 50 adenomas) were systematically assessed by 5 experts using various endoscopic descriptors. MAIN OUTCOME MEASUREMENTS: The prevalence of specific endoscopic features observed in SSAs/Ps versus HPs. RESULTS: Multivariate analysis demonstrated that indistinct borders (OR, 3.11; 95% CI, 1.57-6.15) and a cloud-like surface (OR, 2.65; 95% CI, 1.21-5.78) were associated with SSA/P histology on HR-WLE. On NBI, a cloud-like surface (OR, 4.91; 95% CI, 2.42-9.97), indistinct borders (OR, 2.38; 95% CI, 1.14-4.96), irregular shape (OR, 3.17; 95% CI, 1.59-6.29), and dark spots inside the crypts (OR, 2.05; 95% CI, 1.02-4.11) were found to be endoscopic predictors of SSA/P histology. The sensitivity, specificity, and accuracy of NBI for differentiating serrated polyps containing either none or all 4 endoscopic SSA/P features were, respectively, 89%, 96%, and 93%. LIMITATIONS: Retrospective, image evaluation analysis. CONCLUSIONS: The current study demonstrates that SSAs/Ps possess several specific endoscopic features compared with HPs. Recognition of these characteristics might assist endoscopists in the differentiation of these lesions and could possibly facilitate endoscopic detection of these rather subtle lesions. PMID- 23433878 TI - A prospective, comparative trial to optimize sampling techniques in EUS-guided FNA of solid pancreatic masses. AB - BACKGROUND: There is no standardization of the use of suction during puncturing of a target in pancreatic EUS-guided FNA (EUS-FNA). It is also debatable whether expressing aspirates from the needle by the traditional method of reinserting the stylet is more effective than by air flushing, which is easier and safer. OBJECTIVE: To optimize sampling techniques in pancreatic EUS-FNA. DESIGN: Prospective, comparative trial. SETTING: Tertiary-care referral center. PATIENTS: Eighty-one consecutive patients with solid pancreatic masses. INTERVENTION: Four punctures were performed for each mass in random order by a 2 * 2 factorial design. Sample quality and diagnostic yield were compared between samples with suction (S+) versus no suction (S-) and expressed by reinserting the stylet (RS) versus air flushing (AF). MAIN OUTCOME MEASUREMENTS: Sample quality by the number of diagnostic samples, cellularity, bloodiness, and air-drying artifact; diagnostic yield by accuracy, sensitivity, and specificity. RESULTS: The number of diagnostic samples (72.8% vs 58.6%; P = .001), cellularity (odds ratio [OR] 2.12; 95% confidence interval [CI], 1.37-3.30; P < .001), bloodiness (OR 1.46; CI, 1.28-1.68; P < .001), accuracy (85.2% vs 75.9%; P = .004), and sensitivity (82.4% vs 72.1%; P = .005) were higher in S+ than in S-. Bloodiness was lower in AF than in RS (OR 1.16; CI, 1.03-1.30; P = .017). LIMITATIONS: Single-center trial, 2 kinds of needle gauges, and no immediate cytopathology evaluation. CONCLUSION: Puncturing with suction and expressing by air flushing may be used preferentially in pancreatic EUS-FNA because they were more effective and convenient techniques. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01354795.). PMID- 23433880 TI - Renal tumors with clear cells. A review. AB - The spectrum of primary renal tumors in which clear cells may appear is revisited in this review. The pathologist's viewpoint of this topic is pertinent because not all the tumors with clear cells are carcinomas and not all renal cell carcinomas with clear cells are clear cell renal cell carcinomas. In fact, some of them are distinct entities according to the new WHO classification. The morphological approach is combined with genetics. Renal cell carcinoma related to von Hippel-Lindau disease is reviewed first because many of the genetic disorders underlying this disease are also present in sporadic, conventional renal cell clear cell carcinomas. Subsequently, conventional renal cell clear cell carcinomas, familial, non von Hippel-Lindau-associated renal cell carcinomas, translocation carcinomas, hereditary papillary renal cell carcinomas, carcinomas associated to tuberous sclerosis and to Birt-Hogg-Dube syndrome, chromophobe renal cell carcinomas, carcinomas associated with end-stage renal disease, and clear cell tubulopapillary carcinomas are reviewed. Finally, epithelioid angiomyolipoma is also considered in this review. PMID- 23433879 TI - Education policies and health inequalities: evidence from changes in the distribution of Body Mass Index in France, 1981-2003. AB - This paper contributes to the debate over the effectiveness of education policies in reducing overall health inequalities as compared to public health actions directed at the less-educated. Recentered Influence Function (RIF) regressions are used to decompose the contribution of education to the changing distribution of Body Mass Index (BMI) in France, between 1981 and 2003, into a composition effect (the shift in population education due to a massive educational expansion), and a structure effect (a changing educational gradient in BMI). Educational expansion has reduced overall BMI inequality by 3.4% for women and 2.3% for men. However, the structure effect on its own has produced a 10.9% increase in overall inequality for women, due to a steeper education gradient starting from the second quartile of the distribution. This structure effect on overall inequality is also large (7.6%) for men, albeit insignificant as it remains concentrated in the last decile. Educational expansion policies can thus reduce overall BMI inequalities; but attention must still be paid to the BMI gradient in education even for policies addressing overall rather than socioeconomic health inequalities. PMID- 23433881 TI - [Benefit of a short atherosclerosis prevention program on post-stroke vascular risk reduction]. AB - INTRODUCTION: Atherosclerosis is a major cause of ischemic stroke. Despite important therapeutic advances, the risk of recurrence of vascular events remains very high. The partial failure of these strategies is to some extent related to the lack of patient adherence to their treatments and to the fact that therapeutic targets are not reached. The aim of the present study was to evaluate the influence of a short atherosclerosis prevention program on vascular risk reduction in stroke patients. PATIENTS AND METHODS: Ninety-five patients with a first ischemic stroke related to atherosclerosis or with a high vascular risk profile were recruited. Three months later, a global evaluation of the atherosclerotic disease and of the vascular risk factors was performed combined with several education sessions on vascular risk factors and way of life. A follow-up evaluation was performed several months later to investigate the number of vascular events and the vascular risk profile. RESULTS: Median follow-up was 684 days after stroke. At follow-up, 91.3% of patients were taking a cholesterol lowering drug, 95.6% an anti-thrombotic agent, and 78% an angiotensin converting enzyme inhibitor. A persistent decrease in tobacco use and an improvement in glycemic control were observed. During follow-up, 3.2% of patients died; none of the deaths were related to a vascular event. During the 22-month follow-up, 7.6% of patients experienced a major vascular event, acute coronary syndrome or stroke. CONCLUSION: Compared with results in the literature, this study illustrates the positive influence of a short atherosclerosis prevention program combining depiction of atherosclerotic lesions and education of vascular risk factors on the quality of long-term post-stroke prevention. PMID- 23433882 TI - Performance evaluation of thick film open tubular silica capillary by reversed phase liquid chromatography. AB - The unquestioned potential of open tubular column design for miniaturized liquid chromatography systems has been assessed recently. Instrument limitation and insufficient mass loadability of the columns, however, have prevented experimental breakthrough in this field, the latter requiring new methods for the deposition of thick films as the stationary phase. In this work, a previously proposed synthesis strategy has been applied for the preparation of a C8 modified 15MUm inner diameter variant of 3m length, providing a silica porous layer with a thickness of approximately 500nm. The capillary column has been evaluated in terms of usability, permeability and chromatographic efficiency in reversed phase mode. Data was compared to both a monolithic and a particulate, commercially available C18 capillary column. High theoretical plate numbers have been generated in a test mixture separation composed of small molecules and the applicability of this new type of column was demonstrated by two reversed phase applications. PMID- 23433883 TI - Modeling of mixed-mode chromatography of peptides. AB - Mixed-mode chromatographic materials are more and more often used for the purification of biomolecules, such as peptides and proteins. In many instances they in fact exhibit better selectivity values and therefore improve the purification efficiency compared to classical materials. In this work, a model to describe biomolecules retention in cation-exchange/reversed-phase (CIEX-RP) mixed mode columns under diluted conditions has been developed. The model accounts for the effect of the salt and organic modifier concentration on the biomolecule Henry coefficient through three parameters: alpha, beta and gamma. The alpha parameter is related to the adsorption strength and ligand density, beta represents the number of organic modifier molecules necessary to displace one adsorbed biomolecule and gamma represents the number of salt molecules necessary to desorb one biomolecule. The latter parameter is strictly related to the number of charges on the biomolecule surface interacting with the ion-exchange ligands and it is shown experimentally that its value is close to the biomolecule net charge. The model reliability has been validated by a large set of experimental data including retention times of two different peptides (goserelin and insulin) on five columns: a reversed-phase C8 column and four CIEX-RP columns with different percentages of sulfonic groups and various concentration values of the salt and organic modifier. It has been found that the percentage of sulfonic groups on the surface strongly affects the peptides adsorption strength, and in particular, in the cases investigated, a CIEX ligand density around 0.04MUmol/m(2) leads to optimal retention values. PMID- 23433884 TI - Fully-automated on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometric analysis at sub-ng/L levels of selected estrogens in surface water and wastewater. AB - A fully-automated on-line solid phase extraction liquid chromatographic/electrospray ionization tandem mass spectrometric method for the analysis of estrone (E1), 17-beta-estradiol (beta-E2), 17-alpha-ethinylestradiol (EE2), 17-alpha-estradiol (alpha-E2) and estriol (E3) in surface water and wastewater was developed. The method showed a very good linearity from 250 ng/L down to compound specific quantification limits, which were included between 0.25 and 2.00 ng/L. These limits were obtained with 2.5 mL aliquots of injected sample and the total analysis time per sample was slightly less than 10 min. Under these conditions, detection limits were 0.15 ng/L for E1, 0.31 ng/L for beta-E2, 0.52 ng/L for EE2, 0.59 ng/L for alpha-E2 and 0.95 ng/L for E3. The method reliability was tested on different kinds of real samples spiked with the estrogens, obtaining recoveries approximately included between 71 and 95%. The application to samples collected in rivers, lakes and wastewater treatment plants evidenced the presence of the investigated compounds at sub-ng/L or low ng/L concentration levels. PMID- 23433885 TI - Derivatization reactions for use with the electron-capture detector. AB - The electron-capture detector is a structure-selective detector with a wide response range for organic compounds. It is predominantly used to determine halogen-containing compounds, nitroaromatic compounds, and compounds with conjugated systems connecting at least two weak electrophore groups. High sensitivity and selectivity make it a general choice for trace analysis. For compounds with reactive functional groups and weak electron capture properties, derivatization affords a facile method to facilitate their detection. Reagents and reaction conditions for the formation of derivatives with electron-capturing properties are described in this review. The common methods for introducing an electrophore into organic compounds with polar functional groups include silylation, acylation, alkylation, esterification, Schiff base reagents, addition of halogens, and cyclic derivatives formed with bifunctional compounds. These reactions include reagents for general use as well as functional group selective reagents. In addition to the selection of reagents, the effect of the detector operating parameters on its response and details of the electron-capture mechanism for common derivatives are discussed. PMID- 23433886 TI - Chromatography modelling to describe protein adsorption at bead level. AB - Chromatographic modelling can be used to describe and further understand the behaviour of biological species during their chromatography separation on adsorption resins. Current modelling approaches assume uniform rate parameters throughout the column. Software and hardware advances now allow us to consider what can be learnt from modelling at bead level, enabling simulation of heterogeneity in bead and packed bed structure due to design or due to changes during operation. In this paper, a model has been developed to simulate at bead level protein loading in 1.5 MUl microfluidic columns. This model takes into account the heterogeneity in bead sizes and the spatial variations of the characteristics of a packed bed, such as bed void fraction and dispersion, thus offering a detailed description of the flow field and mass transfer phenomena. Simulations were shown to be in good agreement with published experimental data. PMID- 23433887 TI - Innovation in internship preparation: an operative anatomy course increases senior medical students' knowledge and confidence. AB - BACKGROUND: An operative anatomy course was developed within the construct of a surgical internship preparatory curriculum. This course provided fourth-year medical students matching into a surgical residency the opportunity to perform intern-level procedures on cadavers under the guidance of surgical faculty members. METHODS: Senior medical students performed intern-level procedures on cadavers with the assistance of faculty surgeons. Students' confidence, anxiety, and procedural knowledge were evaluated both preoperatively and postoperatively. Preoperative and postoperative data were compared both collectively and based on individual procedures. RESULTS: Student confidence and procedural knowledge significantly increased and anxiety significantly decreased when preoperative and postoperative data were compared (P < .05). Students reported moderate to significant improvement in their ability to perform a variety of surgical tasks. CONCLUSIONS: The consistent improvement in confidence, knowledge, and anxiety justifies further development of an operative anatomy course, with future assessment of the impact on performance in surgical residency. PMID- 23433888 TI - Late results after laparoscopic fundoplication denote durable symptomatic relief of gastroesophageal reflux disease. AB - BACKGROUND: Late outcomes after laparoscopic Nissen fundoplication are only now becoming available. This study was undertaken to document late outcomes after laparoscopic Nissen fundoplication. METHODS: Five hundred ten patients underwent laparoscopic Nissen fundoplication >10 years ago and were prospectively followed. Preoperatively and postoperatively, patients scored the frequency and severity of symptoms (from 0 = never/not bothersome to 10 = always/very bothersome). Symptom scores before and after fundoplication were compared. Median symptom scores are presented. RESULTS: Early after fundoplication, significant improvements were noted in the frequency and severity of symptoms (e.g., for heartburn, from 8 to 0 and from 8 to 0, respectively, P < .001 for each). Late after fundoplication, significant improvements were maintained in the palliation of symptoms (e.g., frequency and severity for heartburn, 2, 1; respectively). At latest follow-up, 89% of patients were pleased with their symptom resolution. CONCLUSIONS: With long-term follow-up, laparoscopic Nissen fundoplication durably and significantly palliates symptoms of gastroesophageal reflux disease. This trial promotes the application of laparoscopic Nissen fundoplication. PMID- 23433889 TI - Internal pancreatic duct stent does not decrease pancreatic fistula rate after pancreatic resection: a meta-analysis. AB - BACKGROUND: The use of an internal pancreatic duct stent to improve postoperative outcomes of pancreatic anastomosis remains a matter of debate. METHODS: A meta analysis including comparative studies providing data on patients with and without internal stenting during pancreaticojejunostomy anastomosis was performed. RESULTS: Seven articles including 724 patients were identified for inclusion: 1 randomized controlled trial, 1 quasi-randomized controlled trial, and 5 observational clinical studies. The meta-analysis revealed that there were no significant differences between groups regarding operative outcomes. The use of an internal pancreatic duct stent was not associated with a statistically significant reduction in pancreatic fistula (P = .31), hospital mortality (P = .64), or delayed gastric emptying (P = .17), but it was associated with a higher risk of pancreatic fistulas in soft pancreases (P = .05) and overall morbidity (P = .04). CONCLUSIONS: The current literature suggests that the use of an internal pancreatic duct stent does not help to reduce the leakage rate of pancreatic anastomosis after pancreatic resection, and it may increase the risk of pancreatic fistulas in soft pancreases. PMID- 23433890 TI - Surgical implications of a left-sided gallbladder. AB - BACKGROUND: A left-sided gallbladder in a normally positioned liver is considered to be a very uncommon anomaly. Laparoscopic cholecystectomy can be performed safely, but bile duct injury is not unusual. It is associated with anomalous intrahepatic portal and biliary systems which impacts any form of partial hepatectomy. METHODS: We performed a retrospective review of patients with left sided gallbladder who were managed by the hepatobiliary surgeons at our institution since 1996. RESULTS: Nineteen patients with left-sided gallbladder underwent a hepatobiliary procedure. Of the 13 patients with gallstones, only 1 was diagnosed before cholecystectomy. Nine operations were completed laparoscopically, whereas 4 required an open procedure. Two patients were referred with bile duct injuries. There was 1 liver resection for a colorectal metastasis. Left-sided gallbladders in 3 deceased organ donors resulted in major implications in the performance of liver transplantation. CONCLUSIONS: Left-sided gallbladders are probably more common than generally believed but are rarely diagnosed before cholecystectomy. Associated bile duct injury appears to be not infrequent. Because of the aberrant vasculobiliary anatomy, any form of liver resection requires careful planning. PMID- 23433891 TI - Squamous cell carcinogenesis and squamous cell carcinoma of the urinary bladder: a contemporary review with focus on nonbilharzial squamous cell carcinoma. AB - Bladder squamous cell carcinoma, squamous metaplasia, and transitional cell carcinoma with squamous differentiation are infrequent findings in Western countries. A common risk factor for their development consists of chronic bladder irritation and inflammation. The prognostic and clinical relevance and natural history of squamous cell lesions has been under investigation, revealing individual premalignant characteristics. Recent developments in molecular characterization of squamous alterations of the urinary tract indicate pathogenetic similarities and interrelations and might lead to more precise tumor classification and risk stratification in the future. Nevertheless, current clinical management of patients with premalignant and malignant bladder squamous cell lesions remains challenging, as high evidence level studies are not available and prognosis of invasive squamous carcinoma is poor. Our review summarizes the available data on clinical presentation, treatment, and outcome of bladder squamous cell carcinoma, metaplastic lesions, and transitional cell carcinoma with squamous differentiation and discusses implementable current advances in the understanding of bladder cancer tumorigenesis. PMID- 23433892 TI - Phase II trial of bevacizumab and satraplatin in docetaxel-pretreated metastatic castrate-resistant prostate cancer. AB - BACKGROUND: Satraplatin is an oral platinum compound that has demonstrated efficacy and tolerability in prostate cancer. Preclinical synergy between bevacizumab and platinum has been noted. METHODS: Docetaxel-pretreated metastatic castrate-resistant prostate cancer patients with disease progression were eligible. Satraplatin 80 mg/m(2) orally on days 1 to 5, prednisone 5mg twice daily, and bevacizumab 10mg/kg on day 1, and 15 mg/kg on day 15 were administered in 35-day cycles. RESULTS: Thirty one patients were enrolled. Grade 3 or 4 toxicities were pulmonary embolism in 2 patients and thrombocytopenia in 1 patient. 31% of the patients had a >= 30% decline in prostate-specific antigen. Median time to progression was 7.0 months (90% confidence interval [CI] 4.7 8.5mo) and median overall survival was 11.2 months (90% CI 9.1-16.4 mo). Polymorphism in the excision repair cross-complementation-1 (ERCC-1) gene was associated with time to progression (hazard ratio = 1.91). A circulating tumor cell count >= 5 was moderately prognostic of overall survival (hazard ratio = 1.49) as compared with CTC <5. CONCLUSIONS: The combination was tolerable, and revealed promising efficacy in metastatic castrate-resistant prostate cancer. ERCC1 genotype maybe predictive of clinical benefit with platinum-based therapy in metastatic prostate cancer. PMID- 23433893 TI - The current role and limitations of surrogate endpoints in advanced prostate cancer. AB - OBJECTIVES: The identification of appropriate surrogate endpoints for evaluating cancer therapeutics has been of ongoing interest across various tumor types. Metastatic castrate-resistant prostate cancer (mCRPC) has been a particularly challenging area. As more targeted and novel therapies are being developed in this disease space, an urgent need exists to identify surrogate endpoints in mCRPC. The ability to discern patient benefit in the absence of patient death or other complications would facilitate both drug development and more appropriate patient care. METHODS AND MATERIALS: We reviewed the available literature and guidelines used in the development and approval of recent agents for mCRPC. RESULTS: The majority of regulatory approvals of new medications have relied on overall survival (OS) or prevention of complications such as skeletal related events (SRE's). Progression-free survival measures, such as bone scans, computed tomography scans, and prostate-specific antigen related changes, have not been validated nor uniformly accepted as outcome surrogates. All of the successful recent pivotal Phase III trials designed to achieve regulatory approval in mCRPC have used either OS or SRE's as the primary endpoint. CONCLUSIONS: There are significant problematic issues that exist associated with defining and implementing surrogate markers in mCRPC beyond survival and complications. Suggestions are made as to how the current situation might be improved. PMID- 23433895 TI - Monitoring aroma changes during human milk storage at +4 degrees C by sensory and quantification experiments. AB - BACKGROUND & AIMS: The effect of human milk storage in the refrigerator has been investigated with regard to sensory changes and modifications to the molecular composition of the milk odour-active volatiles. METHODS: In the present study, characteristic odorants from fat oxidation, known from previous studies, as well as free fatty acids were quantified as representative marker substances by means of stable isotope dilution assays of fresh milk samples and milk samples stored at +4 degrees C for one and three days, respectively. RESULTS: Sensory evaluation showed that rancid and sweaty odour attributes were generated during storage, resulting in an unpleasant aroma profile for adults; however, odour changes were not as pronounced as those observed in our previous study for freeze storage. Fatty and buttery odour notes and a cooked milk-like smell were also generated. In total eight odorants from fat oxidation were determined and some potent odorants showed slight concentration increases. Moreover, five free fatty acids were determined and these all showed drastic concentration increases, even after storage for just one day. CONCLUSIONS: These investigations support our previous findings that storage recommendations for breast milk might need to be slightly reconsidered in view of potential sensory changes; on the other hand, no negative physiological effects are to be expected from these changes. PMID- 23433894 TI - Combined therapeutic effects of adenoviral vector-mediated GLIPR1 gene therapy and radiotherapy in prostate and bladder cancer models. AB - OBJECTIVES: The objectives of this study are to explore the potential benefits of combining AdGlipr1 (or AdGLIPR1) gene therapy with radiotherapy using subcutaneous prostate and bladder cancer models. MATERIALS AND METHODS: Combination adenoviral vector-mediated gene therapy and radiotherapy were applied to 178-2 BMA and TSU-Pr1 cells in vitro and colony formation and apoptosis were analyzed. In addition, combination therapies were administered to mice bearing subcutaneous 178-2 BMA and TSU-Pr1 tumors, and tumor growth suppression and survival extension were compared with the monotherapies (AdGlipr1/AdGLIPR1 and radiotherapy) or control vector Adv/CMV/betagal, as well as single-cycle treatment with 2-cycle treatment. RESULTS: Combination treatment significantly suppressed colony formation and increased apoptosis in vitro. In vivo, combination therapy produced significant 178-2 BMA and TSU-Pr1 tumor growth suppression and survival extension compared with the monotherapies or the control. Further tumor growth suppression and survival extension were observed after 2 cycles of the combination treatment. CONCLUSIONS: Combining AdGlipr1 (AdGLIPR1) with radiotherapy may achieve additive or synergistic tumor control in selected prostate and bladder tumors, and additional therapeutic effects may result with repeated treatment cycles. PMID- 23433896 TI - Hanging drop: an in vitro air toxic exposure model using human lung cells in 2D and 3D structures. AB - Using benzene as a candidate air toxicant and A549 cells as an in vitro cell model, we have developed and validated a hanging drop (HD) air exposure system that mimics an air liquid interface exposure to the lung for periods of 1h to over 20 days. Dose response curves were highly reproducible for 2D cultures but more variable for 3D cultures. By comparing the HD exposure method with other classically used air exposure systems, we found that the HD exposure method is more sensitive, more reliable and cheaper to run than medium diffusion methods and the CULTEX((r)) system. The concentration causing 50% of reduction of cell viability (EC50) for benzene, toluene, p-xylene, m-xylene and o-xylene to A549 cells for 1h exposure in the HD system were similar to previous in vitro static air exposure. Not only cell viability could be assessed but also sub lethal biological endpoints such as DNA damage and interleukin expressions. An advantage of the HD exposure system is that bioavailability and cell concentrations can be derived from published physicochemical properties using a four compartment mass balance model. The modelled cellular effect concentrations EC50cell for 1h exposure were very similar for benzene, toluene and three xylenes and ranged from 5 to 15 mmol/kgdry weight, which corresponds to the intracellular concentration of narcotic chemicals in many aquatic species, confirming the high sensitivity of this exposure method. PMID- 23433897 TI - Bisphenol A treatment by the hot persulfate process: oxidation products and acute toxicity. AB - In this study, a thermally activated persulfate oxidation process was investigated to treat aqueous Bisphenol A (BPA) solution. The effect of temperature (40-50-60-70 degrees C), initial pH (pH=3.0, 6.5, 9.0 and 11.0) and persulfate concentration (0-20mM) on bisphenol A (BPA) and TOC removals was examined. The activation energy for hot persulfate oxidation of BPA was calculated as 184 +/- 12 kJ/mol. Acidic and neutral pH values were more favorable for BPA oxidation than basic pH values. TOC removals did not exhibit a specific pattern with varying initial pHs. Gas chromatography/mass spectrometry was employed to identify oxidation products. Several aromatic and a few aliphatic compounds could be detected including benzaldehyde, p-isopropenyl phenol, 2,3 dimethyl benzoic acid, 3-hydroxy-4-methyl-benzoic acid, ethylene glycol monoformate and succinic acid. Acute toxicity tests conducted with Vibrio fischeri indicated that the inhibitory effect of 88 MUM BPA solution originally being 58%, increased to 84% after 30 min and decreased to 22% after 90 min hot persulfate treatment that could be attributed to the formation and subsequent disappearance of oxidation products. PMID- 23433898 TI - Age, period, and cohort effects in heavy episodic drinking in the US from 1985 to 2009. AB - BACKGROUND: Evaluating population-level patterns of heavy episodic drinking by age, period, and cohort is critical to understanding population-level influences on rates over time and to forecasting future trends for public health planning efforts. The present study examined trends in heavy episodic drinking in the US from 1985 through 2009 in a nationally representative sample that included adolescents and adults. METHODS: Data are drawn from repeated cross-sectional surveys of US households as part of the National Household Survey on Drug Use and Health conducted in 1985, 1988, and annually from 1990 though 2009, inclusive (N=809,281). Heavy episodic drinking was defined as any instance of consuming five or more drinks in one sitting in the past month. Age-period-cohort models were identified using the Intrinsic Estimator algorithm. RESULTS: Heavy episodic drinking is decreasing in the US among adolescents and young adults, with the most recently born cohorts (born in the 1990s) at lower odds of heavy episodic drinking compared with cohorts born in the 1960s, 1970s, and 1980s. Results were consistent across sex and race/ethnicity, with the exception that the decrease is not apparent among Hispanics. CONCLUSIONS: These data are promising in that young cohorts appear to be reducing heavy episodic drinking, however the lack of decrease among Hispanics suggests targeted intervention and prevention as well as increased surveillance are necessary. PMID- 23433899 TI - The effect of drinking goals at treatment entry on longitudinal alcohol use patterns among adults with alcohol dependence. AB - BACKGROUND: Drinking goals at treatment entry are a promising, yet under-studied mechanism of change in alcohol use following treatment. It is not known who, upon treatment entry, is likely to desire abstinence as a drinking goal and whether desiring abstinence as a drinking goal influences alcohol use following treatment. METHODS: Data from a 2.5-year longitudinal study of alcohol-dependent adults from 3 treatment sites is examined in a secondary data analysis. At treatment entry, participants reported sociodemographic and clinical characteristics, as well as whether they desired abstinence as a drinking goal or not. At each subsequent wave, participants reported their alcohol use. RESULTS: Bivariate analyses showed that individuals from a VA outpatient treatment site, men, and racial or ethnic minorities were most likely to desire abstinence as a drinking goal at treatment entry. Multi-level mixed effects regression models indicated that individuals who at baseline desired abstinence as a drinking goal sustained higher percentage of days abstinent and higher percentage of days since last drink 2.5 years following treatment entry, compared to individuals who did not desire abstinence. CONCLUSIONS: Understanding who is most likely to desire the specific drinking goal of abstinence can assist clinicians in anticipating client response to goal setting. Furthermore, by understanding the benefits and risks associated with drinking goals, clinicians can focus attention to individuals who desire a more risk-laden goal, including goals of non-abstinence, and tailor interventions, including motivational interviewing techniques, to support effective goals. PMID- 23433900 TI - A Kunitz-type FXa inhibitor affects tumor progression, hypercoagulable state and triggers apoptosis. AB - Cancer is linked to hypercoagulability, and many studies have shown that anticoagulant drugs affect tumor progression. In this study was demonstrated that the Amblyomin-X (which is a recombinant protein that exerts similarity to the Kunitz-type inhibitors and shows pro-apoptotic effects in different tumor cell lines) and heparin (a classic anticoagulant) have similar effects on cancer progression and on normalization of the hypercoagulable state. However, Amblyomin X showed a distinct mechanism in triggering its effects in vitro, because it exerted a cytotoxic effect in cancer cells by inducing apoptosis and promoting cell cycle arrest. PMID- 23433901 TI - The additional diagnostic value of contemporary evaluation of FDG PET/CT scan and contrast enhanced CT imaging both acquired by a last generation PET/CT system in oncologic patients. AB - Last generation PET tomographs are equipped with a state-of-the-art CT scanner. Normally, CT images are acquired with suboptimal parameters and without intravenous contrast media, being used for attenuation correction and localization only. For this reason, no CT report is usually provided. Most of the patients who are referred for an FDG PET/CT scan, however, present with a diagnostic CT indicating that a PET/CT is required to characterize otherwise equivocal findings and, in the end, undergo both the techniques to reach a final diagnosis. The aim of this study was to evaluate the impact of the contemporary execution of both the techniques employing a PET/CT scanner on the conclusiveness of the final report. Secondary aim was to verify the concordance of the two reports. PATIENTS AND METHODS: Thirty-eight patients affected by hypermetabolic malignant diseases (15F-23M, mean age 58+/-17 years) were enrolled. Twenty-two were in staging, 16 in restaging. They underwent a standard FDG PET/CT scan immediately followed by a diagnostic contrast enhanced (ce)CT scan acquired on the same tomograph. The PET/CT scan was reported by a nuclear medicine physician while the ceCT by a radiologist, independently. Then, they wrote a conclusive paragraph formulated by consensus. The results were compared in terms of stage (FDG PET/CT vs. ceCT and vs. final stage by consensus) and positivity of T, N and M by the inter-rater agreement K. RESULTS: In all the patients, a final, conclusive and agreed stage was reached. There was a high concordance in terms of stage between FDG PET/CT and ceCT (K=0.874), ceCT and final stage (K=0.936), FDG PET/CT and final stage (K=0.938). In two cases, ceCT contributed significantly to the final stage, while PET/CT in four patients. More in details, for the detection of T, there was a complete concordance between PET/CT and ceCT, despite PET/CT wasn't able to provide an accurate evaluation of nearby structures infiltration. K was 0.785 for the assessing of N and 0.718 for M. In general, ceCT was more sensitive for the detection of lung and brain metastasis. FDG PET/CT was more accurate for the identification of nodal metastasis and small distant lesions, especially in the abdomen. DISCUSSION: Our data show that the execution of PET/ceCT in the same session by using the same hybrid tomography increases the quality of the final report by nuclear physician and radiologist and provides clear diagnostic information to the clinician. PMID- 23433903 TI - 3-T high-b-value diffusion-weighted MR imaging in hyperacute ischemic stroke. AB - BACKGROUND AND PURPOSE: In patients with hyperacute ischemic stroke, early demonstration of infarction is essential. Diffusion weighted imaging (DWI) is the key method for detecting hyperacute infarction. The value of high b-value DWI in hyperacute ischemic stroke is controversial at 1.5 T, and is unknown at 3 T. The aim of this study is to explore the value of high b-value versus standard b-value DWI at 3T in hyperacute stroke with quantitative and qualitative analysis. MATERIAL AND METHODS: This study prospectively included 104 consecutive patients with hyperacute stroke. At 3 T, conventional MR sequences and DWI were performed. The examination included a standard DWI (b = 1000 s/mm(2)) and two high b-value DWI (b = 3000 s/mm(2) and b = 5000 s/mm(2)). Qualitative and quantitative analysis was performed. RESULTS: With increasing b value, DW images appeared noisier. The number of detected lesions was significantly higher on b = 3000 images than on the other DW images and higher on b = 5000 images than on b = 1000 images. The number of lesions greater than 1 cm was not significantly different. Lesion conspicuity was higher, boundary better seen, lesion extent bigger, and estimation of final infarct size was better on high b-value than on standard b value DWI. Contrast-to-noise-ratio (CNR) and signal-to-noise-ratio (SNR) decreased and contrast ratio (CR) increased on high b-value DWI compared to standard b-value DWI. CONCLUSION: At 3 T, high b-value DWI was superior to standard b-value DWI in detection of hyperacute infarction and prediction of final infarct size in spite of increasing imaging artifacts. PMID- 23433902 TI - Correlation between lateral geniculate nucleus atrophy and damage to the optic disc in glaucoma. AB - PURPOSE: To investigate the relationship between morphological changes in the lateral geniculate nucleus (LGN), as measured by magnetic resonance imaging (MRI), and damage to the optic disc in primary open-angle glaucoma (POAG) patients. METHODS: A total of 23 patients with POAG and 23 age- and gender matched non-glaucomatous subjects were enrolled. Every patient had structural damage to the optic disc. Cup-to-disc ratio (CDR) and retinal nerve fiber layer thickness (RNFLT) were measured, and 3.0-Tesla MRI examinations performed. Bilateral LGNs were identified and manually extracted, and their maximum heights and volumes compared with the clinical damage to the optic disc. RESULTS: In POAG patients, morphological changes in LGNs and RNFLT were consistently varied (P<0.05), while a negative correlation between LGN measurements and CDR was observed (P<0.05). LGN height was more significantly correlated with damage to the optic disc than was LGN volume. In contrast, no significant correlation was found between morphological changes in LGNs and age or optic disc parameters in the non-glaucomatous controls (P>0.05). CONCLUSION: LGN atrophy in POAG patients was altered in a manner consistent with damage to the optic disc. Morphological changes in LGNs as measured by MRI and especially LGN maximum height may be useful ways to detect optic nerve neuropathy in glaucoma. PMID- 23433904 TI - MRI patterns of global hypoxic-ischemic injury in adults. AB - BACKGROUND AND PURPOSE: To assess MRI patterns and associated clinical outcome in adults with global hypoxic-ischemic injury. MATERIALS AND METHODS: In order to identify the patients with evidence of global hypoxic-ischemic injury, we retrospectively searched our radiology information system for reports of brain MRI studies from 01/01/2004 to 12/31/2010, containing the keywords - "hypoxia", "hypoxic", "anoxia" and "anoxic". A board certified neuroradiologist visually inspected the corresponding MR images for the presence, location and extent (focal versus diffuse) of ischemic findings. Clinical data for these patients was collected from the electronic medical records, including mechanism of the hypoxic ischemic injury, and clinical outcome was measured using modified Rankin Scale (mRS). RESULTS: Review of radiology reports identified 151 cases, of which 64 patients remained after exclusion of normal studies ("no hypoxia" in the report), pediatric patients and patients with remote perinatal hypoxia. Five patients had relatively favorable clinical outcome (mRS of 1 to 3) and 59 had poor outcome (mRS of 4 to 6). Patterns associated with relatively favorable clinical outcome were: a) watershed pattern and b) basal ganglia without cortical involvement. Patterns associated with poor clinical outcome were: a) diffuse cortical and deep grey matter pattern, with and without perirolandic sparing; (b) medial occipital with perirolandic involvement; c) precentral gyrus involvement; d) diffuse white matter involvement; e) brainstem involvement; f) cerebellar involvement and g) hippocampal involvement. CONCLUSION: The vast majority of patients with MRI patterns of hypoxic-anoxic injury have a poor clinical outcome, independently of the observed pattern, with the only relative exception being the watershed pattern and the basal ganglia pattern without cortical involvement. PMID- 23433905 TI - Percutaneous removal of a soft tissue cement leakage complicating a percutaneous vertebroplasty by the mean of a supple biopsy forceps. PMID- 23433906 TI - Endovascular treatment for dural arteriovenous fistula at the foramen magnum: report of five consecutive patients and experience with balloon-augmented transarterial Onyx injection. AB - BACKGROUND: Foramen magnum dural arteriovenous fistulas (DAVF) with perimedullary venous drainage represent a small minority of intracranial DAVF, and only a number of small series with limited cases have been reported. The purpose of this retrospective study is to summarize experience of transarterial Onyx embolisation in the treatment of these lesions, with emphasis on the balloon-augmented technique. METHODS: Five consecutive patients with DAVF at the foramen magnum were treated by transarterial embolisation using the Onyx system. Their symptoms included myelopathy (n=4) and SAH (n=1). Suppliers were from the vertebral artery (VA) (n=4), occipital artery (OA) (n=4), and ascending pharyngeal artery (APA) (n=2), with drainage to the perimedullary veins. After catheterization of the dilated supplier, the fistulous connections, proximal draining veins and appropriate distal segment of the feeders of these DAVF were transarterial embolized using Onyx-18. In three patients, balloon-augmented technique was used to assist embolisation. The technical feasibility of the procedure, angiographic results, and clinical outcome were evaluated. RESULTS: In every case, complete obliteration was achieved. Neither intraprocedural vessel rupture nor other procedure-related complications occurred. The results remained stable in all patients on follow-up angiograms (mean, 7.2 months). At the last clinical follow up (mean, 17.6 months), two patients showed complete resolution of the initial symptoms, and three patients showed significant improvement. CONCLUSION: We found that Onyx embolisation is a feasible and safe alternative to open surgery in the treatment of selective DAVF at the foramen magnum. The balloon-augmented technique widens indications for transarterial Onyx packing of these lesions, and improved safety of the procedure. PMID- 23433907 TI - Brain perfusion SPECT in patients with Behcet's disease. AB - The aim of this study was to detect brain functional deficits in patients with Behcet's disease (BD) and signs or symptoms of central nervous system (CNS) involvement at different times in their clinical history. A total of 24 patients aged 20 to 53years (median age 39years; 20 women, four men) with Behcet's syndrome fulfilling the diagnosis as defined by the syndrome classification were enrolled in this study. Single-photon emission computed tomography (SPECT) with (99m)Technetium (Tc)-hexamethylpropyleneamine oxime (HMPAO) as the perfusion tracer was performed to detect brain lesions. The results of (99m)Tc-HMPAO brain SPECT scans showed impaired perfusion in all cases with neurological complaints (24 out of 24, 100%). Temporal lobes and basal ganglia were the most common areas with such lesions. In contrast, brain MRI and CT images were normal or non specific in all cases. In conclusion, (99m)Tc-HMPAO brain SPECT imaging is a powerful and sensitive tool for disclosing brain involvement in numerous clinical situations, even including patients with subtle neurological symptoms/signs such as headaches and dizziness. It is also a useful modality for evaluating the effects of treatment and disease monitoring to prevent CNS damage. PMID- 23433908 TI - MR spectroscopy in paraneoplastic cerebellar degeneration. PMID- 23433909 TI - Distant white-matter diffusion changes caused by tumor growth. AB - OBJECTIVES: Various reports have suggested that the involvement of normal-looking white matter with tumors is not limited to just signal abnormalities detectable on conventional imaging. Thus, the purpose of this study was to investigate the distant effects of glioblastomas and metastases on white matter using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Data for 21 patients harboring a glioblastoma (n=12) or a metastasis (n=9) located at a distance of smaller or equal to 10mm from a DTI-based reconstruction of the pyramidal tract were analyzed, using regions of interest (ROIs) placed along the pyramidal tracts in the cerebral peduncle distant (>15 mm) from the tumor. RESULTS: For the whole study population, fractional anisotropy (FA) was significantly lower on the side ipsilateral to the tumor (P<0.001), a difference that was also observed in the glioblastoma and metastasis subgroups. The trace value was significantly higher on the ipsilateral side in the whole population and metastasis subgroup, but not in the glioblastoma subgroup. The decrease in FA and the trace value increase were significant in a subgroup of patients with motor deficits, but not in those without such deficits. CONCLUSION: Hemispheric glioblastomas and metastases located close to the pyramidal tract induce diffusion changes in the tract that are observable at a distance of greater than 15 mm from the tumor border in the absence of T2 signal changes. These changes are different in glioblastomas and metastases, and mechanisms other than Wallerian degeneration may be contributing to the observed changes. PMID- 23433910 TI - Adenovirus mediated CTLA4Ig transgene therapy alleviates abortion by inhibiting spleen lymphocyte proliferation and regulating apoptosis in the feto-placental unit. AB - Pregnancy is thought to be a state of immunological tolerance. The mechanisms underlying this phenomenon are still poorly understood. In our previous study, adenovirus mediated CTLA4Ig transgene (Ad-CTLA4Ig) therapy was demonstrated to improve pregnancy outcome in an abortion-prone mouse model by skewing the Th2/Th1 cytokine balance, expanding peripheral CD4(+) CD25(+) regulatory T cell populations and inducing indoleamine 2,3 dioxygenase (IDO) mRNA expression at the maternal-fetal interface. However, it is still not clear whether other mechanisms are involved in the protective effect of CTLA-4 on pregnancy outcome in abortion prone matings. In this study, we focused on the effect of CTLA4Ig on spleen lymphocyte proliferation and apoptosis at the maternal-fetal interface. We demonstrated that Ad-CTLA4Ig therapy inhibited the proliferation of CBA/J splenocytes and IL-2 secretion in response to DBA/2 stimulator cells in the abortion-prone mice model. Ad-CTLA4Ig therapy also skewed cytokine production toward a Th2 bias and regulated the expression of anti-apoptosis factor Bcl-2 and pro-apoptosis factor Bax at the maternal-fetal interface. However, it did not influence the apoptosis and cell cycles of splenocytes in pregnant CBA/J mice. On the whole, these findings indicated that Ad-CTLA4Ig therapy could ameliorate the outcome of spontaneous abortion by inhibiting proliferation of maternal spleen lymphocytes and regulating apoptosis in the feto-placental unit. PMID- 23433911 TI - Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. PMID- 23433912 TI - [Treatment of major sexually transmitted infections]. PMID- 23433913 TI - [Aging and HIV infection: 4 years follow-up of 149 HIV infected patients older than 60 years in West Paris agglomeration (COREVIH Ile-de-France Ouest)]. AB - In France, patients over 50 years represent more than 23.6% of all registered cases in the French Hospital Database for HIV (FHDH), and 18% of newly HIV diagnosed patients. OBJECTIVE: To describe the long-term evolution after 4 years of a cohort of HIV infected patients older than 60 years recruited in COREVIH Ile de-France Ouest. RESULTS: One hundred and forty-nine participants, 115 men (77%) and 34 women (23%), were included in the cohort analysis in 2004, and baseline characteristics were: median age 65.4 years (60.3-86.3), CDC stage C: 36%, HBV and HCV co-infections: four (2.7%) and eight (5.4%) patients, median time from first HIV infection diagnosis: 8.5 years (0.25-19.5), ongoing HAART regimen: 88%, median duration of ARV treatment: 7.5 years (0.2-15.5), baseline CD4 cells count: 372/mm(3) (18-1860), HIV viral load less than 200 c/ml: 104 (70%). After a 4-year follow-up, 111 patients were alive, all but one treated with HAART, 17/149 (11.5%) were lost for follow-up, and 21/149 were deceased (14%). Causes of death were acute cardiovascular disease (4/21), neoplasia (11/21), neurological disease 1/21, end stage liver disease 3/21, unknown 2/21. The prevalence of co morbidities after 4 years of follow-up were: arterial hypertension 40/111 (36%), hypercholesterolemia 48/111 (43%), diabetes 23/111 (21%), kidney disease with renal insufficiency (creatinine clairance<60 ml/min): 36/111 (32%). At the end of follow-up, median CD4 cells count was 494/mm(3), and viral load was undetectable less than 200 c/ml in 107/111 patients (96%). No new opportunistic infection occurred during the 4-year follow-up, but 24 patients had a new diagnosis of neoplasia (incidence 40/1000 person-year). Cancer was the cause of death in 11/24. CONCLUSION: Clinical and immunological improvement was continuous under HAART in these aged HIV infected patients, but co-morbidities are frequently observed in this population, with high incidence of cardiovascular disease and neoplasia, and related mortality. A multidisciplinary approach, with preventive consultations, oncology and cardiovascular screening, as done in geriatrics, is warranted in the aging HIV population. PMID- 23433914 TI - [What's new in the diagnosis and treatment of Neisseria gonorrhoeae]. AB - Bacterial culture remains the gold standard for symptomatic infection. Nucleic Acid Amplification Tests (NAATs) have better sensitivity and specificity for rectal and pharyngeal specimens. A bacterial culture with antibiogram must be done for all NAAT positive specimens in order to modify antibiotics prescription if needed. We must fear a diffusion of extensively drug-resistant Neisseria gonorrhoeae in the future. Nevertheless, ceftriaxone 500 mg intramuscular with 1 g of azithromycin against Chlamydia trachomatis remains the treatment of N. gonorrhoeae infections. Screening of partners of identified cases and other STDs is the main measure to add to the treatment of gonorrhea. PMID- 23433915 TI - The concept of "silencing the self" in low-income, aging, HIV-infected African American women: a 10-year community-based participatory program of research with results. AB - Despite a resilient spirit, the challenges that face low-income, aging Black women living with HIV infection are immense. This article describes a 10-year iterative history of using the Theory of Silencing the Self (TSTS) as an explanatory model that was found to be gender sensitive, culturally relevant, and helpful in guiding a community-based participatory research group of low-income, HIV-infected Black women living in Boston, Massachusetts. The group, called Sistah Powah, used the TSTS to design and implement a structured writing intervention in a women's drop-in center targeting low-income, aging Black women living with HIV infection as a way to give them and others a voice. PMID- 23433916 TI - Health literacy and adherence to antiretroviral therapy among HIV-infected youth. AB - Health literacy has been associated with adherence to antiretroviral therapy (ART) in HIV-infected adults, but this association has not been demonstrated in HIV-infected adolescents. Using an expanded health literacy model, we examined the relationship between health literacy, functional literacy, beliefs about ART, media use, and adherence to ART. A convenience sample of HIV-infected adolescents (n = 50) was recruited for this cross-sectional study. The primary outcome of adherence was measured with 3-day self-reports. Health literacy as measured by the Test of Functional Health Literacy in Adults (TOFHLA) was not predictive of adherence (p = .15). Participants with higher positive outcome expectancy scores regarding ART were more likely to report 100% adherence, and participants with below-grade-level reading were less likely to report 100% adherence (p < .05). Our findings highlight the importance of assessing both health beliefs and reading skills as part of adherence support for HIV-infected youth. PMID- 23433917 TI - Vaccinations for international travellers travelling from Greece. AB - The aim of this prospective, questionnaire-based study is to assess pre-travel vaccinations for international travellers who receive pre-travel advice in Greece. A total of 2494 travellers were studied from January 1, 2009 through December 31, 2010. Travellers sought pre-travel advice at a median of 16 days (range: 0-349 days) before departure. Sub-Saharan Africa was the most common destination (34.7%). Most travellers (60.8%) travelled for <1 month, for recreation purposes (58.9%), stayed in hotels (65.3%), and in urban areas (53.6%). Yellow fever, tetravalent meningococcal, typhoid fever, cholera, and rabies vaccines were administered to 1629 (65.3%), 666 (26.7%), 615 (24.7%), 28 (1.1%), and/or 12 (0.5%) travellers, respectively. Of those who received Yellow fever vaccine, 737 (45.2%) travelled to sub-Saharan Africa, 332 (20.4%) travelled to South America, 949 (58.3%) stayed for short term, and 762 (46.8%) stayed in urban areas. Of the 1629 travellers vaccinated against Yellow fever, 150 (9.2%) and 226 (13.8%) travelled to areas of sub-Saharan Africa and South America respectively, where the vaccine is not or generally not recommended. Of those travellers who received meningococcal vaccine, 327 (49.1%) travelled to the Middle East for the Hajj, 251 (29%) travelled to sub-Saharan Africa, 410 (61.6%) for short term, and 540 (64.4%) stayed in urban areas. Of those travellers who received typhoid vaccine, 241 (39.2%) travelled to sub-Saharan Africa, 78 (12.7%) to the Indian subcontinent, 234 (38%) for short term, and 419 (68.1%) stayed in urban areas. Regarding routine vaccines, tetanus-diphtheria, poliomyelitis, and measles-mumps-rubella vaccines were administered to 707 (28.3%), 639 (25.6%) and/or 149 (6%) travellers, respectively. Of those to whom poliomyelitis vaccine was recommended, 295 (46.2%) and 137 (21.4%) travelled to sub-Saharan Africa and the Middle East, respectively, and 362 (56.7%) travelled for short term. In conclusion, this study revealed that there is a need for more selective vaccine recommendations for travellers to developing countries, taking under consideration travellers and travel characteristics as well. Strategies to target travel health consultants should be developed in order to increase awareness in travel health issues. PMID- 23433918 TI - Damage control: Rorgammat+ innate lymphoid cells in tissue regeneration. AB - Innate lymphoid cells (ILC) function at the crossroads of innate and adaptive immunity. ILC expressing Rorgammat are involved in lymphoid organ formation during embryonic development and mucosal homeostasis and immunity after birth in both mice and man. Mucosal ILC can express natural cytotoxicity receptors NKp44 and NKp46 and produce IL-22, a cytokine pivotal in the control of epithelial innate defenses. The requirements for mouse Rorgammat+ ILC development are well charted and in recent years factors involved in differentiation of human ILC have also been identified. In this review we will focus on recent observations that uncovered Rorgammat+ ILC as mediators of epithelial tissue regeneration after radiation-induced damage. PMID- 23433919 TI - A new option for hypopharyngeal reconstruction with transverse cervical artery perforator flap: a case report. AB - We report a case of a 61-year-old man with T2N2M0 hypopharyngeal carcinoma. In this case, the right vertical hemipharyngolaryngectomy (VHPL) and the right radical neck dissection were performed. At the same time, flap was taken from the superficial branch of transverse cervical artery for hypopharyngeal reconstruction. Postoperative wound healed smoothly. The patient resumed normal oral intake and was free of the tracheal tube at the 12th and 15th days after surgery, respectively. The superficial branch of transverse cervical artery flap is a new option to successfully reconstruct hypopharynx and has many advantages, such as no additional incision, a thin shape, local transfer, and a reliable blood supply. PMID- 23433920 TI - Results of a national study on the awareness of and attitudes toward acute otitis media (AOM) among clinicians and the estimated direct healthcare costs in Turkey (TR-AOM Study). AB - AIMS: Acute otitis media (AOM) is one of the most frequent diagnoses and reasons for prescribing antibiotics in children. The aims of this prospective study were the following: (1) to assess the continuing education of physicians and the sources of information about AOM; (2) to assess the current knowledge of and attitudes toward AOM as well as the compliance with AOM guidelines; (3) to evaluate opinions about vaccines against AOM; and (4) to estimate the potential costs of AOM on the healthcare system in Turkey. METHODS: This is a web-based cross-sectional survey of a national convenience sample of 600 physicians in Turkey (325 pediatricians (PEDs), 214 family physicians/general practitioners (FP&GPs) and 61 otolaryngologists (ENTs)). RESULTS: Approximately 38.6% of participants (39.4% of PEDs, 44.3% of GP&FPs and 14.7% of ENTs) stated that pneumatic otoscopy is essential for AOM diagnosis. Regarding the most common etiological agents of AOM in children, 54.2% of PEDs, 51.4% of FP&GPs and 57.4% of ENTs stated that the most common causative agents of AOM are Streptococcus pneumoniae and non-typeable Haemophilus influenzae. Nearly 76% of participants indicated they use direct antibiotic therapy when they diagnose AOM in certain situations. The first-line choice of antibiotic therapy is amoxicillin clavulanate, and 67% of participants prefer to use antibiotic therapy for 7-10 days. Approximately 31% of all participants stated that "viruses" are the main cause of AOM; however, 62% of these participants reported using antibiotic therapy. In comparison, 32% participants from private clinics prefer to treat AOM primarily with observation, a rate that is significantly higher than that of other clinical settings. Physicians who prefer to use observation strategy also prefer the combination of paracetamol and NSAIDs. Approximately 41% of participants have undergone postgraduate medical education on the topic of AOM. In total, 73% of all participant physicians believe that otitis media is a vaccine-preventable disease. With the information from all of the participants, the calculated mean cost per case of AOM is 28 +/- 4 USD. In Turkey, the estimated incidence of AOM is 24,000-33,000 cases per 10,000 children <5 years of age (1,820,000-2,100,000 cases per year), and the estimated total cost of AOM is 61,152,000 USD (not including acute otitis media-related complications and otitis media-related hospitalizations). CONCLUSION: The medical and economic burden of AOM to the health economics in Turkey is considerable. Specific educational programs and evidence-based national guidelines concerning AOM should be implemented. Improving diagnostic accuracy with education will lead to improved management, judicious use of antibiotics, decreased antibiotic resistance, and potential economic benefits. A more prudent use of antibiotics would also lower the economic burden of this disease. Vaccination seems to be promising for the prevention of AOM. PMID- 23433921 TI - Complementary and alternative medicine use among patients presenting to a pediatric otolaryngology clinic. AB - OBJECTIVES: This study sought to quantify and characterize complementary and alternative medicine (CAM) use among patients presenting to a pediatric otolaryngology clinic with the aim of increasing CAM use awareness for the practicing pediatric otolaryngologist. METHODS: Four hundred thirty-four caregivers of patients presenting to a pediatric otolaryngology clinic were surveyed regarding their child's use of CAMs. Demographic information, perceived benefits, and sources of information regarding CAM was collected. Spearman correlation coefficient was used to assess strength of associations. RESULTS: Three-hundred and sixty-four caregivers completed the survey (83.9% response rate). The children of 69% of respondents had utilized CAM, and 46% were using CAM at the time of the survey. Higher income and chronic illness in the child were significant predictors of CAM use. The children of older and married parents were more likely to have utilized CAM (non-significant). The most common agents were multivitamins (43%) and vitamin D (32%). Parents whose children used more CAMs were more likely to perceive a benefit. CONCLUSIONS: A significant proportion of pediatric otolaryngology patients utilized CAM in our study population. The most commonly used agents are mostly benign, but others may have more unknown consequences. It is crucial that otolaryngologists ask specifically about these agents, as they potentially interact with prescription medications and some may lead to surgical complications. PMID- 23433922 TI - Fiber-optic sleep endoscopy in children with persistent obstructive sleep apnea: inter-observer correlation and comparison with awake endoscopy. AB - OBJECTIVE: Evaluate the inter-observer correlation of sleep endoscopy findings in children with persistent obstructive sleep apnea (OSA) with awake office fiber optic endoscopy. METHOD: DESIGN: retrospective case series; blinded review. SETTING: tertiary care children's hospital. PATIENTS: Children with persistent obstructive sleep apnea. INTERVENTIONS: Both awake and drug induced sleep endoscopy were performed. Endoscopy video recordings were mixed at random on a DVD. Two pediatric otolaryngologists and two pediatric pulmonologists independently scored each recording using an upper airway endoscopy scoring survey. MAIN OUTCOME MEASURES: reviewers scored the following parameters: each structure's contribution (nose, nasopharynx, lateral pharyngeal walls, tongue base, supraglottis) to the obstruction, the main site in which the obstruction occurs, the severity of OSA (mild, moderate, severe), the level of confidence of endoscopy findings (poor, fair, good). RESULTS: When reviewing sleep endoscopy recordings for the upper airway obstruction site, the highest correlation among the four observers was found for the nasopharynx and the supraglottis (Kappa score: 0.6 and 0.5, respectively). Compared to awake endoscopy, sleep endoscopy demonstrated more cases of airway obstruction caused by collapse of lateral pharyngeal walls and base of tongue (McNemar test for symmetry, P value<0.05). Level of confidence among the four observers was higher in older children and lower in children with severe OSA. CONCLUSIONS: Sleep endoscopy is a consistently reliable tool for identifying the site of obstruction in children with persistent OSA. Though anesthetic induced sleep is not a perfect model for real sleep, the technique demonstrably guides further therapy better than awake endoscopy. PMID- 23433923 TI - Determination of pharmaceutical and illicit drugs in oral fluid by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - A simple and extremely fast procedure for the quantitative determination in oral fluid samples of 44 substances, including the most common drugs of abuse and several pharmaceutical drugs, was developed and fully validated. Preliminary sample treatment was limited to protein precipitation. The resulting acetonitrile solution was directly injected into an ultra-high performance liquid chromatograph (UHPLC) equipped with a C18 column (100mm*2.1mm, 1.7MUm). The mobile phase eluted with linear gradient (water/formic acid 5mM: acetonitrile/formic acid 5mM; v:v) from 98:2 to 0:100 in 5.0min, followed by isocratic elution at 100% B for 1.0min. The flow rate was 0.6mL/min and the total run time was 9.0min including re-equilibration at the initial conditions. The analytes were revealed by a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode. The method proved to be simple, accurate, rapid and highly sensitive, allowing the simultaneous detection of all compounds. The ease of sample treatment, together with the wide range of detectable substances, all with remarkable analytical sensitivity, make this procedure ideal for the screening of large populations in several forensic and clinical contexts, whenever oral fluid sampling has to be preferred to blood sampling, as for example in short retrospective investigations. PMID- 23433924 TI - Ultra high performance liquid chromatography-tandem mass spectrometry method for cyclosporine a quantification in biological samples and lipid nanosystems. AB - Cyclosporine A (CyA) is an immunosuppressant cyclic undecapeptide used for the prevention of organ transplant rejection and in the treatment of several autoimmune disorders. An ultra high performance liquid chromatography-tandem mass spectrometry method (UHPLC-MS/MS) to quantify CyA in lipid nanosystems and mouse biological matrices (whole blood, kidneys, lungs, spleen, liver, heart, brain, stomach and intestine) was developed and fully validated. Chromatographic separation was performed on an Acquity UPLC((r)) BEH C18 column with a gradient elution consisting of methanol and 2mM ammonium acetate aqueous solution containing 0.1% formic acid at a flow rate of 0.6mL/min. Amiodarone was used as internal standard (IS). Retention times of IS and CyA were 0.69min and 1.09min, respectively. Mass spectrometer operated in electrospray ionization positive mode (ESI+) and multiple reaction monitoring (MRM) transitions were detected, m/z 1220.69->1203.7 for CyA and m/z 646->58 for IS. The extraction method from biological samples consisted of a simple protein precipitation with 10% trichloroacetic acid aqueous solution and acetonitrile and 5MUL of supernatant were directly injected into the UHPLC-MS/MS system. Linearity was observed between 0.001MUg/mL-2.5MUg/mL (r>=0.99) in all matrices. The precision expressed in coefficient of variation (CV) was below 11.44% and accuracy in bias ranged from -12.78% to 7.99% including methanol and biological matrices. Recovery in all cases was above 70.54% and some matrix effect was observed. CyA was found to be stable in post-extraction whole blood and liver homogenate samples exposed for 6h at room temperature and 72h at 4 degrees C. The present method was successfully applied for quality control of lipid nanocarriers as well as in vivo studies in BALB/c mice. PMID- 23433925 TI - Collagen-specific peptide conjugated HDL nanoparticles as MRI contrast agent to evaluate compositional changes in atherosclerotic plaque regression. AB - OBJECTIVES: This study sought to develop magnetic resonance contrast agents based on high-density lipoprotein (HDL) nanoparticles to noninvasively visualize intraplaque macrophages and collagen content in mouse atherosclerotic plaques. BACKGROUND: Macrophages and collagen are important intraplaque components that play central roles in plaque progression and/or regression. In a Reversa mouse model, plaque regression with compositional changes (from high macrophage, low collagen to low macrophage, high collagen) can be induced. METHODS: This study labeled HDL nanoparticles with amphiphilic gadolinium chelates to enable target specific imaging of intraplaque macrophages. To render HDL nanoparticles specific for the extracellular matrix, labeled HDL nanoparticles were functionalized with collagen-specific EP3533 peptides (EP3533-HDL) via poly(ethylene glycol) spacers embedded in the HDL lipid layers. The association of nanoparticles with collagen was examined in vitro by optical methods. The in vivo magnetic resonance efficacy of these nanoparticles was evaluated in a Reversa mouse model of atherosclerosis regression. Ex vivo confocal microscopy was applied to corroborate the in vivo findings and to evaluate the fate of the different HDL nanoparticles. RESULTS: All nanoparticles had similar sizes (10 +/- 2 nm) and longitudinal relaxivity r1 (9 +/- 1 s(-1) mmol/l(-1)). EP3533-HDL showed strong association with collagen in vitro. After 28 days of plaque regression in Reversa mice, EP3533-HDL showed significantly increased (p < 0.05) in vivo magnetic resonance signal in aortic vessel walls (normalized enhancement ratio [NERw] = 85 +/- 25%; change of contrast-to-noise ratio [DeltaCNRw] = 17 +/- 5) compared with HDL (NERw = -7 +/- 23%; DeltaCNRw = -2 +/- 4) and nonspecific control EP3612-HDL (NERw = 4 +/- 24%; DeltaCNRw = 1 +/- 6) at 24 h after injection. Ex vivo confocal images revealed the colocalization of EP3533-HDL with collagen. Immunohistostaining analysis confirmed the changes of collagen and macrophage contents in the aortic vessel walls after regression. CONCLUSIONS: This study shows that the HDL nanoparticle platform can be modified to monitor in vivo plaque compositional changes in a regression environment, which will facilitate understanding plaque regression and the search for therapeutic interventions. PMID- 23433926 TI - Predicting the risk for acute type B aortic dissection in hypertensive patients using anatomic variables. AB - OBJECTIVES: This study sought to identify possible anatomic predictors of acute type B aortic dissection (AAD) in hypertensive patients using multidetector computed tomography angiography (CTA). BACKGROUND: Although hypertension remains one of the most significant risk factors for AAD development, it is unlikely to be the only risk factor for AAD. Few studies have assessed anatomical predictors of AAD development. METHODS: CTA of normotensive patients without AAD (group 1, n = 35), hypertensive patients without AAD (group 2, n = 37), and hypertensive patients with AAD (group 3, n = 37) were compared. The length, diameter, volume, and tortuosity of the aorta as well as arch vessel angulation were measured for each patient and normalized to group 1 averages. Stepwise logistic regression identified significant anatomical associations; the model was validated based on 1,000 bootstrapped samples. RESULTS: The demographics of the groups were similar. The length of the proximal and entire aorta, the diameters in the proximal ascending aorta and aortic arch, and the aortic volumes were all greater (p < 0.0001, p = 0.0064 for ascending aortic diameter) in group 3 than in groups 1 and 2, as was entire aortic tortuosity (p < 0.0001). An AAD risk model was developed based on aortic arch diameter, length from the aortic root to the iliac bifurcation, and angulation of the brachiocephalic artery origin from the aorta. The bootstrap estimate of the area under the receiver operating curve was 0.974. CONCLUSIONS: Enlargement of the ascending aorta and aortic arch and increased aortic tortuosity reflect an aortopathy which enhances the probability of AAD. A model based on 3 anatomical variables demonstrates significant associations with AAD: it may allow identification by aortic imaging of the hypertensive patient most at risk, and permit implementation of aggressive medical management and consideration of pre-emptive surgery to prevent dissection. PMID- 23433927 TI - Appropriate use criteria for stress echocardiography: impact of updated criteria on appropriateness ratings, correlation with pre-authorization guidelines, and effect of temporal trends and an educational initiative on utilization. AB - OBJECTIVES: This study evaluated utilization of stress echocardiography (SE) at our institution, the impact of the updated 2011 appropriate use criteria (AUC) on appropriateness ratings, correlation of AUC to radiology benefits managers' (RBM) pre-certification guidelines and the effect of temporal trends and an AUC-based educational project on appropriateness. BACKGROUND: The AUC for SE have been developed to improve efficiency of utilization and promote optimal patient care. METHODS: We classified the appropriateness of 209 SEs from 2008 using the original and updated AUC. We also performed pre-authorization determinations on these SEs using the guidelines of 2 RBMs. We then classified and compared the appropriateness of 209 SEs from 2011 using the updated criteria to that of the 2008 cohort. Finally, we rated and compared 111 SEs requested by cardiologists after an educational project to 111 SEs referred before the intervention. RESULTS: Overall, nearly one-third of SEs were requested for inappropriate indications. Using 2011 AUC, the original ratings of 52 (25%) studies by AUC 2008 were changed and the number of unclassified SE decreased from 20 (9.6%) to 2 (1%). Correlation between RBM pre-authorization determination and AUC ratings was substantial for the first RBM (kappa = 0.625) and fair for the second (kappa = 0.358). However, 12.9% and 41.9% of studies classified as appropriate or uncertain by the AUC would not have received pre-authorization according to the guidelines of the first and second RBMs, respectively. Referrals of inappropriate SE did not decrease over time or with an educational intervention. CONCLUSIONS: The revisions in the updated AUC improve their clinical application by encompassing nearly all indications for SE. The limited correlation between AUC ratings and RBM determinations suggests a need for greater consistency. The large number of SE requested for inappropriate indications at our institution did not decrease with time or education. PMID- 23433928 TI - Physician-preferred versus policy-based testing: where do appropriate use criteria fit in? PMID- 23433929 TI - CMR for sudden cardiac death risk stratification: are we there yet? PMID- 23433930 TI - Can we still rely on the ECG for detecting past myocardial injury? PMID- 23433931 TI - Prognostic role of CMR in patients presenting with ventricular arrhythmias. AB - OBJECTIVES: The goal of this study was to explore whether fibrosis detected by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) is an independent predictor of hard cardiovascular events in patients presenting with ventricular arrhythmia. BACKGROUND: In patients at risk of sudden cardiac death, risk stratification for device therapy remains challenging. METHODS: A total of 373 consecutive patients with sustained ventricular tachycardia (VT) (n = 204) or nonsustained ventricular tachycardia (NSVT) (n = 169) underwent LGE-CMR. The group was prospectively followed up for a median of 2.6 years (range 11 months to 11 years). The predetermined endpoint was a composite of cardiac death/arrest, new episode of sustained VT, or appropriate implantable cardioverter defibrillator discharge. RESULTS: Mean left ventricular (LV) ejection fraction (EF) was 60 +/- 13%. The presence of fibrosis was a strong and independent predictor of the primary outcome for the whole group (hazard ratio [HR]: 3.3, 95% confidence interval [CI]: 1.8 to 5.8, p < 0.001). In the sustained VT subset, both LV fibrosis and severely impaired systolic function (LVEF <35%) were significant independent predictors in the multivariate model (HR: 3.0, 95% CI: 1.4 to 6.2, p = 0.001; and HR: 2.5, 95% CI: 1.1 to 6.2, p = 0.038, respectively). In the NSVT subset, the presence of fibrosis was the only independent predictor of the endpoint (HR: 4.2, 95% CI: 1.7 to 10.1, p = 0.006). CONCLUSIONS: LGE-CMR detected fibrosis is an independent predictor of adverse outcomes in patients with ventricular arrhythmia and may have an important role in risk stratification. (The Prognostic Significance of Fibrosis Detection in Ischemic and Non-Ischemic Cardiomyopathy; NCT00930735). PMID- 23433932 TI - Pathological Q waves in myocardial infarction in patients treated by primary PCI. AB - OBJECTIVES: In the present study, we investigated the association of pathological Q waves with infarct size. Furthermore, we investigated whether Q-wave regression was associated with improvement of left ventricular ejection fraction (LVEF), infarct size, and left ventricular dimensions in ST-segment elevation myocardial infarction (STEMI) patients with early Q-wave formation compared with patients without or persistent pathological Q waves. BACKGROUND: The criteria for pathological Q waves after acute myocardial infarction (MI) have changed over the years. Also, there are limited data regarding correlation of Q-wave regression and preservation of LVEF in patients with an initial Q-wave MI. METHODS: Standard 12-lead electrocardiograms (ECGs) were recorded in 184 STEMI patients treated with primary percutaneous coronary intervention (PCI). ECGs were recorded before and following PCI, as well as at 1, 4, 12, and 24 months of follow-up. An ECG was scored as Q-wave MI when it showed Q waves in 2 or more contiguous leads according to the 4 readily available clinical definitions used over the years: "classic" criteria, Thrombolysis In Myocardial Infarction criteria, and 2000 and 2007 consensus criteria. Cardiac magnetic resonance (CMR) examination was performed at 4 +/- 2 days after reperfusion and repeated after 4 and 24 months. Contrast-enhanced CMR was performed at baseline and 4 months. RESULTS: The classic ECG criteria showed strongest correlation with infarct size as measured by CMR. The incidence of Q-wave MI according to the classic criteria was 23% 1 h after PCI. At 24 months of follow-up, 40% of patients with initial Q-wave MI displayed Q-wave regression. Patients with a Q-wave MI had larger infarct size and lower LVEF on baseline CMR (24 +/- 10% LV mass and 37 +/- 8%, respectively) compared with patients with non-Q-wave MI (17 +/- 9% LV mass, p < 0.01, and 45 +/ 8%, p < 0.001, respectively). Patients with Q-wave regression displayed significantly larger LVEF improvement in 24 months (9 +/- 11%) as compared with both persistent Q-wave MI (2 +/- 8%) as well as non-Q-wave MI (3 +/- 8%, p = 0.04 for both comparisons). CONCLUSIONS: Association of Q waves with infarct size is strongest when using the classic Q-wave criteria. Q-wave regression is associated with the largest improvement of LVEF as assessed with CMR. PMID- 23433934 TI - [Ketamine in status asthmaticus]. PMID- 23433933 TI - [Enhanced recovery following uncomplicated elective caesarean section in France: a survey of national practice]. AB - INTRODUCTION: Enhanced recovery is a concept currently recognised and adopted in a number of surgical specialties. In obstetrics however, this concept remains surprisingly underdeveloped. The purpose of this survey was to study the practice of obstetric anaesthetists in France as regards the recovery of women undergoing uncomplicated, elective caesarean section. MATERIAL AND METHOD: An online 39 point questionnaire was displayed for 2months on the Caro (Club d'anesthesie reanimation en obstetrique) website. The questionnaire related to uncomplicated, elective Caesarean sections and aimed to define the following: preoperative information given regarding the recovery period, intraoperative care - both anaesthetic and surgical, postoperative analgesia, measures taken to prevent post partum haemorrhage, reintroduction of fluids and diet, return to mobility, local practices designed to promote bonding between mother and baby. RESULTS: The overall response rate for our survey was 45%. Forty-nine percent of practitioners report that patients are provided with specific information on the recovery period preoperatively. Sixty percent of those surveyed state the absence of any specific recovery protocol for this patient population in their hospital. Eighty one percent of respondents state that, in the majority of cases, patients are admitted on the eve of surgery and remain hospitalised for more than 72hours (89%). Ninety-nine percent of practitioners employ a regional technique to deliver anaesthesia for elective section and 44% rely on intrathecal morphine for postoperative analgesia. The concept of 'Patient Controlled Oral Analgesia' (PCOA), although widely recognised, is used by only 17% of practitioners. Forty one percent of practitioners report the reintroduction of fluids as soon as patients return to the ward following surgery and at the same time as the urinary catheter is removed (51%). Diet is commenced 4 to 6hours following surgery amongst 40% of those surveyed. Fifty-one percent of practitioners report removal of the intravenous catheter 24hours postoperatively. Finally, 49% of practitioners feel patients are independently functioning and mobile within 24hours of surgery. CONCLUSION: This survey of national practice shows that the concept of 'enhanced recovery' following elective caesarean section can be again developed. Standardisation of practice with the design of local protocols relating to postoperative analgesia, timing of removal of the intravenous access and urinary catheter, time to first mobilisation and to commencement of diet would appear to be warranted. Surely this surgery, more than any other, merits an expeditious and effective return to normal and independent function, allowing mother to better look after baby. PMID- 23433935 TI - pH-Dependent reactivity of oxidants formed by iron and copper-catalyzed decomposition of hydrogen peroxide. AB - The decomposition of hydrogen peroxide catalyzed by iron and copper leads to the generation of reactive oxidants capable of oxidizing various organic compounds. However, the specific nature of the reactive oxidants is still unclear, with evidence suggesting the production of hydroxyl radical or high-valent metal species. To identify the reactive species in the Fenton system, the oxidation of a series of different compounds (phenol, benzoic acid, methanol, Reactive Black 5 and arsenite) was studied for iron- and copper-catalyzed reactions at varying pH values. At lower pH values, more reactive oxidants appear to be formed in both iron and copper-catalyzed systems. The aromatic compounds, phenol and benzoic acid, were not oxidized under neutral or alkaline pH conditions, whereas methanol, Reactive Black 5, and arsenite were oxidized to a different degree, depending on the catalytic system. The oxidants responsible for the oxidation of compounds at neutral and alkaline pH values are likely to be high-valent metal complexes of iron and copper (i.e., ferryl and cupryl ions). PMID- 23433936 TI - Origin of the anomalous decrease in the apparent density of polymer gels observed by multi-echo reflection ultrasound spectroscopy. AB - Multi-echo reflection ultrasound spectroscopy (MERUS), which enables one to simultaneously evaluate the attenuation coefficient alpha, the sound velocity v and the density rho, has been developed for measurements of elastic moduli. In the present study, the technique was further developed to analyze systems undergoing gelation where an unphysical decrease in the apparent density was previously observed after polymerization. The main reason for this problem was that the shrinkage accompanying the gelation led to a small gap between the cell wall and the sample, resulting in the superposition of the reflected signals which were not separable into individual components. By taking into account the multiply reflecting echoes at the interface of the gap, the corrected densities were systematically obtained and compared with the results for the floating test. The present technique opens a new route to simultaneously evaluate the three parameters alpha, v and rho and also the sample thickness for solid thin films. PMID- 23433937 TI - Upgrading the sleeping brain with targeted memory reactivation. AB - A fundamental feature of human memory is the propensity for beneficial changes in information storage after initial encoding. Recent research findings favor the possibility that memory consolidation during sleep is instrumental for actively maintaining the storehouse of memories that individuals carry through their lives. The information that ultimately remains available for retrieval may tend to be that which is reactivated during sleep. A novel source of support for this idea comes from demonstrations that neurocognitive processing during sleep can benefit memory storage when memories are covertly cued via auditory or olfactory stimulation. Investigations of these subtle manipulations of memory processing during sleep can help elucidate the mechanisms of memory preservation in the human brain. PMID- 23433938 TI - LOX-1 is a novel marker for peripheral artery disease in patients with type 2 diabetes. AB - OBJECTIVE: The aim of this study was to investigate whether serum soluble lectin like oxidized low-density lipoprotein receptor-1 (sLOX-1), which mediates initiation and progression of atherosclerosis in endothelial cells, could be a novel marker for peripheral artery disease (PAD) in patients with type 2 diabetes. METHODS: We evaluated relationships of serum sLOX-1 to ankle-brachial index (ABI) and examined the association of serum sLOX-1 with PAD in 410 patients with type 2 diabetes. RESULTS: Serum sLOX-1 was inversely correlated with ABI (r= 0.197, P<0.0001). Stepwise regression analysis demonstrated that serum sLOX-1 (beta=-0.168, F=5.571, P<0.05) was independently associated with ABI, and multiple logistic regression analysis demonstrated that serum sLOX-1 (16.254 (1.237-213.651), P=0.0339) was independently associated with PAD. CONCLUSIONS: Serum sLOX-1 is associated with ABI and it could be a novel marker for PAD in patients with type 2 diabetes. PMID- 23433939 TI - Postprandial metabolism of docosapentaenoic acid (DPA, 22:5n-3) and eicosapentaenoic acid (EPA, 20:5n-3) in humans. AB - The study of the metabolism of docosapentaenoic acid (DPA, 22:5n-3) in humans has been limited by the unavailability of pure DPA and the fact that DPA is found in combination with eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) in natural products. In this double blind cross over study, pure DPA and EPA were incorporated in meals served to healthy female volunteers. Mass spectrometric methods were used to study the chylomicron lipidomics. Plasma chylomicronemia was significantly reduced after the meal containing DPA compared with the meal containing EPA or olive oil only. Both EPA and DPA were incorporated into chylomicron TAGs, while there was less incorporation into chylomicron phospholipids. Lipidomic analysis of the chylomicron TAGs revealed the dynamic nature of chylomicron TAGs. The main TAG species that EPA and DPA were incorporated into were EPA/18:1/18:1, DPA/18:1/16:0 and DPA/18:1/18:1. There was very limited conversion of DPA and EPA to DHA and there were no increases in EPA levels during the 5h postprandial period after the DPA meal. In conclusion, EPA and DPA showed different metabolic fates, and DPA hindered the digestion, ingestion or incorporation into chylomicrons of the olive oil present in the meal. PMID- 23433940 TI - Effect of partial, distal epicondylectomy on reduction of ulnar nerve strain: a cadaver study. AB - PURPOSE: To compare the decrease in ulnar nerve strains using a modification of medial epicondylectomy by removing the distal half of the medial epicondyle with in situ decompression and partial medial epicondylectomy. METHODS: Using 20 elbows of 10 fresh human cadavers, we measured the strain on the ulnar nerve using a microstrain gauge before and after in situ decompression. Then, we repeated the measurements after partial medial epicondylectomy on left elbows, and after distal medial epicondylectomy on right elbows. We compared the mean strain values with 2-way analysis of variance. RESULTS: The decrease in mean ulnar nerve strain with in situ decompression from 5.4% to 5.2% on the right side and 5.4% to 5.0% on the left was not statistically significant. The decrease to 2.9% on the left elbows after partial and to 1.9% on the right elbows after distal medial epicondylectomy was statistically significant. In addition, the remaining ulnar nerve strain after distal medial epicondylectomy was significantly less compared with that after partial medial epicondylectomy. We observed nerve subluxation only with partial medial epicondylectomy. CONCLUSIONS: In situ decompression alone does not change ulnar nerve strains. The significant change in ulnar nerve strain with partial or distal medial epicondylectomy underlines the role of medial epicondyle on stretching of the ulnar nerve. Excision of the distal half of the medial epicondyle sets the contact point of the nerve with the bone proximally and decreases the strain on ulnar nerve more effectively than partial epicondylectomy. However, its efficacy and complications need to be studied clinically. CLINICAL RELEVANCE: The results of the present cadaveric study suggest that excision of the distal half of the medial epicondyle in cubital tunnel syndrome may decrease ulnar nerve strain effectively. The clinical effect of decrease in nerve strain and the indications for the procedure need to be investigated. PMID- 23433941 TI - Essential hand surgery procedures for mastery by graduating orthopedic surgery residents: a survey of program directors. AB - PURPOSE: To establish the essential hand surgery procedures that should be mastered by graduating orthopedic surgery residents. This framework can then be used as a guideline for developing an Objective Structured Assessment of Technical Skill to teach and document technical skill in hand surgery. METHODS: A select group of 10 expert hand surgeons was surveyed regarding the essential hand surgery procedures that should be mastered by graduating orthopedic surgery residents. The top 10 procedures from this survey were then used to survey all 155 American Council of Graduate Medical Education-approved orthopedic surgery program directors regarding the essential procedures that should be mastered by graduating orthopedic surgery residents. RESULTS: We had a 39% response rate to the program director survey. The top 8 hand surgery procedures as determined by the orthopedic surgery program directors included open carpal tunnel release, open A1 pulley release, open reduction internal fixation of distal radius fracture, flexor tendon sheath steroid injection, excision of dorsal or volar ganglion, closed reduction and percutaneous pinning of metacarpal fracture, open cubital tunnel release, and incision and drainage of flexor tendon sheath for flexor tenosynovitis. CONCLUSIONS: Surgical educators need to develop objective methods to teach and document technical skill. The Objective Structured Assessment of Technical Skill is a valid method to accomplish this task. However, there has been no consensus regarding which hand surgery procedures should be mastered by graduating orthopedic surgery residents. We have identified 8 procedures that were overwhelmingly supported by orthopedic surgery program directors. These 8 procedures can be used as a guideline for developing an Objective Structured Assessment of Technical Skill to teach and document technical skill in hand surgery. CLINICAL RELEVANCE: This study addresses the future of orthopedic surgery education as it pertains to hand surgery. PMID- 23433942 TI - MMP-1, MMP-9, and TIMP-1 levels in oral lichen planus patients with gingivitis or periodontitis. AB - OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory disease of unknown aetiology. The aim of this study was to investigate matrix metalloproteinase (MMP)-1, MMP-9, and MMP inhibitor-1 (TIMP-1) levels in gingival crevicular fluid (GCF) by enzyme-linked immunosorbent assay and to investigate MMP-1, MMP-9, and TIMP-1 levels in gingival tissue by immunohistochemical staining of samples from patients with and without OLP. DESIGN: Twenty-seven patients with OLP (gingivitis, OLPG; chronic periodontitis, OLPP) and thirty healthy non-OLP patients (gingivitis, HG; chronic periodontitis, HP) were included in this study. The MMP-1, MMP-9, and TIMP-1 levels in GCF were determined by enzyme-linked immunosorbent assay. The MMP-1, MMP-9, and TIMP-1 levels in gingival tissue were determined by immunohistochemical staining. RESULTS: The mean levels of MMP-1 and MMP-9 in the GCF of OLPP patients were significantly higher and TIMP-1 was significantly lower than in HP patients; similarly, the mean levels of MMP-1 and MMP-9 were higher and TIMP-1 was significantly lower in OLPG patients than in HG patients. Our findings illustrate that tissue MMP-9 levels were statistically higher and TIMP-1 level were significantly lower in the OLPP group in comparison to the HP group, and the OLPG group in comparison to the HG group. The tissue MMP 1 level in the non-OLP group was found to be lower when compared with the OLP groups. But not statistically significant. CONCLUSIONS: Increased levels of MMP-1 and MMP-9 with decreased levels of TIMP-1 in GCF and increased MMP-1, MMP-9 levels and decreased TIMP-1 levels in the gingival tissue of OLP patients in combination with poor oral hygiene may cause increased tissue breakdown. The results of our study provide information about the effects of the periodontal status on the enzyme profiles in GCF and gingival tissue of OLP and non-OLP patients. PMID- 23433944 TI - Phantom limb pain after amputation in diabetic patients does not differ from that after amputation in nondiabetic patients. AB - There is a commonly held belief that diabetic amputees experience less phantom limb pain than nondiabetic amputees because of the effects of diabetic peripheral neuropathy; however, evidence to verify this claim is scarce. In this study, a customised postal questionnaire was used to examine the effects of diabetes on the prevalence, characteristics, and intensity of phantom limb pain (PLP) and phantom sensations (PS) in a representative group of lower-limb amputees. Participants were divided into those who had self-reported diabetes (DM group) and those who did not (ND group). Participants with diabetes were further divided into those with long-duration diabetes (>10years) and those with short-duration diabetes. Two hundred questionnaires were sent, from which 102 responses were received. The overall prevalence of PLP was 85.6% and there was no significant difference between the DM group (82.0%) and the ND group (89.4%) (P=0.391). There was also no difference in the prevalence of PS: DM group (66.0%), ND group (70.2%) (P=0.665). The characteristics of the pain were very similar in both groups, with sharp/stabbing pain being most common. Using a 0-10 visual analogue scale, the average intensity of PLP was 3.89 (+/-0.40) for the DM group and 4.38 (+/-0.41) for the ND group, which was not a statistically significant difference (P=0.402). Length of time since diagnosis of diabetes showed no correlation with average PLP intensity. Our findings suggest that there is no large difference in the prevalence, characteristics, or intensity of PLP when comparing diabetic and nondiabetic amputees, though a larger adjusted comparison would be valuable. PMID- 23433943 TI - Medical use, medical misuse, and nonmedical use of prescription opioids: results from a longitudinal study. AB - The objective of this study was to examine the prevalence and patterns associated with past-year medical use, medical misuse, and nonmedical use of prescription opioids (NMUPO) among adolescents over a 2-year time period and to examine substance abuse, sleeping problems, and physical pain symptoms associated with these patterns of medical use, medical misuse, and NMUPO. A Web-based survey was self-administered by a longitudinal sample of 2050 middle and high school students in 2009-2010 (Year 1) and again in 2010-2011 (Year 2). The study was set in 2 southeastern Michigan school districts. The longitudinal sample consisted of 50% females, 67% Whites, 28% African-Americans, and 5% from other racial/ethnic categories. Main outcome measures were past-year medical use, medical misuse, and NMUPO. Of those reporting appropriate medical use of prescription opioids in Year 1, approximately 34% continued medical use in Year 2. Of those reporting past year NMUPO in Year 1, approximately 25% continued NMUPO in Year 2. Appropriate medical use and NMUPO for pain relief was more prevalent among girls than boys. Multiple logistic regression analyses indicated that the odds of a positive screen for substance abuse in Year 2 were greater for adolescents who reported medical misuse or NMUPO for non-pain-relief motives in Year 1 compared with those who did not use prescription opioids. The findings indicate an increased risk for substance abuse among adolescents who report medical misuse or NMUPO for non-pain relief motives over time. The findings have important clinical implications for interventions to reduce medical misuse and NMUPO among adolescents. PMID- 23433945 TI - Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis. AB - Opioids are a key risk factor for postoperative nausea and vomiting (PONV). As intravenous (i.v.) acetaminophen reduces postoperative pain and opioid requirements, one would expect i.v. acetaminophen to be associated with a lower incidence of opioid-induced side effects, including PONV. We conducted a systematic search using Medline and Cochrane databases supplemented with hand search of abstract proceedings to identify randomized-controlled trials of i.v. acetaminophen. Inclusion criteria were (a) randomized for i.v. acetaminophen vs a placebo control, (b) general anesthesia, and (c) reported or obtainable PONV outcomes. Primary outcome was postoperative nausea and secondary outcome was postoperative vomiting. We included 30 studies with 2364 patients (1223 in the acetaminophen group, 1141 in the placebo group). The relative risk (95% confidence interval) was 0.73 (0.60-0.88) for nausea and 0.63 (0.45-0.88) for vomiting. Data showed significant heterogeneity for both nausea (P=0.02, I(2)=38%) and vomiting (P=0.006, I(2)=47%), but were homogeneous when studies were grouped according to timing of first administration: i.v. acetaminophen reduced nausea when given prophylactically either before surgery, 0.54 (0.40 0.74), or before arrival in the postanesthesia care unit, 0.67 (0.55-0.83); but not when given after the onset of pain, 1.12 (0.85-1.48). When i.v. acetaminophen was given prophylactically, the reduction of nausea correlated with the reduction of pain (odds ratio 0.66, 0.47-0.93), but not with reduction in postoperative opioids (odds ratio 0.89, 0.64-1.22). Prophylactically administered i.v. acetaminophen reduced PONV, mainly mediated through superior pain control. PMID- 23433946 TI - The neurocognitive basis of insight into illness in anorexia nervosa: a pilot metacognitive study. AB - The primary goal of the present study was to explore the neuropsychological basis of insight into illness in anorexia nervosa by evaluating its differential and joint links with cognitive vs. metacognitive performance. Participants in the study were 25 women with anorexia nervosa (AN) and 25 healthy comparisons (HC). All participants completed a computerized version of the Wisconsin Card Sorting Task (WCST) and the Computerized Body-Size Discrimination task (CBSD). In addition to the standard administration of the tasks, subjects were also asked to rate their level of confidence in the correctness of each sort and to choose whether they wanted each sort to be "counted" toward their overall performance score on the test. Insight into illness in the AN group was assessed with the Scale of Unawareness of Mental Disorder (SUMD). Prediction of poor insight was significantly improved when adding the new, free-choice metacognitive measures to the conventional measures in both tasks, but not the other way around. These preliminary results suggest that metacognition might be an important mediator between basic cognitive deficits and poor insight and that it might be even more relevant to poor insight than cognitive deficits per se. PMID- 23433947 TI - Mock juror sensitivity to forensic evidence in drug facilitated sexual assaults. AB - Mock jurors' reactions to variations in the quality of toxicological evidence regarding the presence of drugs in a sexual assault trial were examined. In Study 1, participants received a trial summary in which a negative test result, a negative test result plus expert testimony, or no test result was presented. The time taken by the complainant to report the alleged sexual assault was manipulated. The negative test result influenced participants' judgments, but this effect was minimized by the presence of expert testimony. The complainant's delay in reporting had little impact on judgments. In Study 2, complainant time to report was again manipulated along with the outcome of the test result (negative finding and no result). Results revealed that men were less conviction prone when the negative test result was obtained early as opposed to late. In contrast, when the test result was unavailable, men were more conviction prone when the complainant reported late as oppose to early. PMID- 23433948 TI - Poor desynchronisation of resting-state eyes-open cortical alpha rhythms in obese subjects without eating disorders. AB - OBJECTIVE: Obese subjects without eating disorders were characterised by poor electroencephalographic (EEG) alpha rhythms during resting-state eye-closed condition (Babiloni et al., 2011b). Is this true also for the desynchronisation of alpha rhythms during resting-state eyes opening? METHODS: EEG data were recorded in 15 underweight, 20 normal-weight, and 18 overweight/obese subjects during resting-state eyes-closed and -open conditions. EEG sources were estimated by LORETA for alpha 1 (8-10.5 Hz) and alpha 2 (10.5-13 Hz). The alpha desynchronisation was calculated as the difference eyes-open minus -closed condition. RESULTS: The occipital alpha 1 desynchronisation was lower in overweight/obese and underweight subjects compared with normal-weight subjects (p < 0.000005). The same was true for parietal, occipital and temporal alpha 2 (10.5 13 Hz) desynchronisation (p < 0.000002). The parietal and temporal alpha 1 desynchronisation was lower in overweight/obese than in normal-weight subjects (p < 0.00001). These effects spatially matched those observed in the resting-state eyes-closed condition. CONCLUSION: Subjects with abnormal weight and normal eating behaviour are characterised by poor alpha desynchronisation during resting state eyes opening. SIGNIFICANCE: Obese subjects without eating disorders show abnormal mechanisms of cortical neural synchronisation and desynchronisation of alpha rhythms in the resting state condition. PMID- 23433949 TI - Occupational leg oedema is more reduced by antigraduated than by graduated stockings. AB - INTRODUCTION: Elastic compression stockings exerting a progressive pressure, higher at the calf than at the ankle (progressive elastic compression stockings, PECS), have already proved to be more comfortable, easier to put on and more effective in improving venous pumping function compared to graduated compression elastic stockings (GECS). Nevertheless, PECS could have a negative effect on the prevention and treatment of oedema or even favour oedema formation. The aim of the present study was to investigate if, in normal volunteers, PECS are able to prevent leg swelling during their working shift. METHODS: A total of 30 normal volunteers (14 males, 16 females aged 36.4 +/- 6.6 years) staying standing or sitting during their shift were enrolled into the study. Their leg volume was measured at the beginning and at the end of their working shift on 2 consecutive days. On one day, the volunteers did not put on any stockings; on the other day, they wore GECS on one leg and PECS on the other. The difference between the leg volume measured at the end of the shift and the basal volume in the morning was called 'occupational oedema'. Interface pressure at points B1 and C was measured immediately after stockings' application and before removal. The volunteers were asked to report about difficulty of putting on the stockings and comfort during wearing time. The results were submitted to statistical analysis. RESULTS: The GECS and PECS groups had similar baseline leg volumes (3143 vs. 3154 ml) and occupational oedema (134 vs. 137.5 ml); after putting on the stockings, occupational oedema was reduced in both legs but the reduction was significantly greater with PECS (20 vs. 40 ml with GECS) (P < 0.05). Interface pressure at ankle level is higher with GECS both in supine and in standing position while at calf level it is higher with PECS both in supine and standing position. PECS are easier to put on and slightly more comfortable. CONCLUSION: PECS are easier to put on and more comfortable and produce a significantly higher reduction of occupational oedema compared with GECS in normal volunteers. Nevertheless leg volumetry, providing a global leg-volume evaluation, is not able to localise the oedema reduction and to assess if it occurs more in the calf or the ankle area. Theoretically, despite a global volume reduction, PECS could even promote a slight oedema formation at ankle level over-compensated by a greater oedema reduction at calf level. Further studies need to concentrate on patients with venous disease and on the local distribution of this global effect. PMID- 23433950 TI - Investigation of outcomes following recombinant activated FVII use for refractory bleeding during abdominal aortic aneurysm repair. AB - OBJECTIVE: To evaluate the outcomes following recombinant activated factor VII (rFVIIa) use during abdominal aortic aneurysms (AAA) repair. DESIGN: AAA patients were selected from the Australian and New Zealand Haemostasis Registry (ANZHR) who received off-licence rFVIIa to control critical bleeding. METHODS: Patient characteristics and outcomes were compared between responders (bleeding stopped/attenuated) and non-responders (bleeding continued) to rFVIIa, stratified by aneurysm status (ruptured (r-AAA) vs. non-ruptured (nr-AAA)). Patients were also scored using POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) and Hardman Index mortality predictive models. RESULTS: In total, 77 AAA patients were included in the analysis. Approximately 73% (n = 56) of them had ruptured aneurysms and about 50% (n = 35/70 with known data) responded positively to rFVIIa. Eleven incidents of thromboembolic adverse events were reported in 9 patients (6 r-AAA and 3 nr-AAA). Responders in both ruptured and non-ruptured groups had significantly lower 28 day mortality than non-responders (r-AAA: 40% (10/25) vs. 92% (24/26); P < 0.001; nr-AAA: 30% (3/10) vs. 67% (6/9); P < 0.01). Mortality predictive models did not show any difference between overall observed and expected mortality in ANZHR patients. CONCLUSION: Patients who responded to rFVIIa had a lower mortality than those who did not respond to the treatment. PMID- 23433951 TI - Endograft repair of complicated acute type B aortic dissections. AB - OBJECTIVES: This study aims to assess patient outcomes and aortic remodelling following coverage of the proximal entry tear with an endograft in complicated acute type B aortic dissections (caTBADs). MATERIAL AND METHODS: All patients with caTBAD treated with a thoracic endograft in three high-volume vascular centres were retrospectively studied. Inclusion criteria were branch-vessel malperfusion, impending or overt aortic rupture, maximal aortic diameter >= 40 mm and persistent pain or uncontrolled hypertension despite maximum pharmacological treatment. Postoperative aortic remodelling was evaluated using computed tomography angiography (CTA) on a three-dimensional (3D) imaging workstation. RESULTS: A total of 52 patients (71% male, median age 65 years) were included in the study. Median inclusion criteria per patient were 2 (range 1-4). Branch vessel malperfusion was diagnosed in 42% and impending aortic rupture in 33% of 52 patients. Median follow-up was 25 months (range 2-109 months). The 30-day mortality rate was 9.6% (5/52); patient survival according to the Kaplan-Meier method was 90.4% at 12 months and 87.6% at 24 months. Secondary interventions were performed in seven patients a median of 3 days after the initial procedure (range 2-865). Imaging follow-up at 12 months was performed in 36 patients (69%): 75% presented stable or shrinking (> 5 mm) maximal aortic diameters and 86% had a completely thrombosed false lumen (vs. 5% before initial procedure) at thoracic level. CONCLUSION: Endograft treatment of complicated caTBAD is associated with favourable early outcomes and possibly promotes aortic remodelling in the majority of patients. PMID- 23433952 TI - Comparison of open and endovascular treatments of post-carotid endarterectomy restenosis. AB - AIM OF THE STUDY: To compare early and long term results of open and endovascular treatment of post-carotid endarterectomy (CEA) restenosis in a single centre experience. METHODS: From January 2005 to December 2011, ninety-nine consecutive interventions for primary severe post-CEA restenosis were performed: in 41 cases (41%, Group 1) open repair was carried out, whereas the remaining 58 patients (59%, group 2) underwent an endovascular treatment. Data concerning these interventions were prospectively collected in a dedicated database containing main pre, intra and postoperative variables. Early results in terms of 30-day stroke and death rates were analysed and compared with chi(2) test. Follow-up results were analysed with Kaplan Meier curves and compared with log-rank test. RESULTS: Mean time from primary CEA was 75 months in group 1 and 42 months in group 2 (p = 0.002; 95% CI 12-52). There were no differences between the two groups in terms of demographic data, comorbidities, risk factors for atherosclerosis, preoperative clinical status or degree of stenosis on the operated side. In group 1 interventions consisted of redo-CEA in 37 patients and of carotid bypass in the remaining 4; all the patients in group 2 underwent stent placement with cerebral protection device. No perioperative deaths and ipsilateral neurological events occurred in both groups. One patient in group 1 suffered from a non-fatal acute myocardial infarction. Other six patients (14.5%) experienced transient cranial nerve injuries, with complete regression at 1-month follow-up; two patients had postoperative dysphagia due to neck haematoma, which was medically managed. Neither access-related nor systemic complications were recorded in group 2. Follow-up was available in 98% of the patients with a median duration of 24 months (range 3-72). There were no differences in terms of 4-year estimated survival and stroke-free survival, whereas patients in group 1 were more likely to develop severe (>80%) secondary restenosis (28.3% and 6.5%, respectively, p = 0.01, log rank 6.3) and to undergo secondary reintervention (22% and 11%, respectively p = 0.01, log rank 6). CONCLUSIONS: despite the selection limits and bias of this study, in our experience open and endovascular surgery provided similar perioperative results in the management of post-CEA restenosis. Long term outcomes are similar, too, despite a slight increase in secondary restenosis and recurrent reinterventions among open surgery patients, warranting further studies and analysis. PMID- 23433953 TI - Computed tomography angiography in acute gastrointestinal and intra-abdominal bleeding in children: preliminary experience. PMID- 23433954 TI - "Boots on the ground" radiology: practical strategy and value innovation for local radiology practices. PMID- 23433955 TI - Scope and potential of halogenases in biosynthetic applications. AB - A large and diverse series of halogenated natural products exist. In many of these compounds the halogen is important to biological activity and bioavailability. We now recognise that nature has developed many different halogenation strategies for which well-known enzyme classes such as haem oxidases or flavin-dependent oxidases have been adapted. Enzymes capable of halogenating all kinds of different chemical groups from electron-rich to electron-poor, from aromatic to aliphatic have been characterised. Given that synthetic halogenation reactions are not trivial transformations and that halogenated molecules possess pharmaceutical usefulness, it will be worth investing into further research of halogenating enzymes. PMID- 23433956 TI - [Are advance directives useful for doctors and what for?]. AB - OBJECTIVES: In France, the law has introduced the possibility to write advance directives since 2005. In this paper, we will present the results of a study designed for checking how much people over 75 years are interested by this new tool. METHODS: The inquiry consisted in deep qualitative interviews (around 45') to further understand what people included in the study have to say about advance directives, but also about the conditions of ageing and dying. The study sample was composed of 8 over 75 years subgroups, chosen for being illustrative of different health status and/or disabling status. Finally, a last subgroup was also included, called "referent", because composed of people, all members of the "Association pour le droit a mourir dans la dignite" (ADMD), and as such supposed to be pro-advance directives. Interviews content was analysed through qualitative analysis referent methods ("Analyse qualitative en sciences humaines et sociales", Paille et Muschielli, "Grounded Theory", Glaser). POPULATION OF THE STUDY: One hundred and eighty-six patients were included (106 female, 80 male, mean age 82.7 ans), 167 in the general group and 19 in the "ADMD" group. RESULTS: Ninety percent in the general group said that they never heard about advance directives before the inquiry. After having been informed by us about what advance directives were for, 83% remained not interested they said, some because they felt they were not personally concerned, others expressed that the tool appears to them inefficient - "things never happen the way you planned it", not useful - "doctors will act as they will decide whatever will be written", or even more potentially dangerous - "writing advance directives might lead doctors not to be as much therapeutically aggressive as for other people". Only 28 persons in the general group (17%), together with the 19 of the ADMD group, said they were interested by advance directives. They all were quite similar according to their personal character: they were quite strong and voluntary people, claiming firmly about their autonomy, independently of any sociodemographic profile. Furthermore, the interest for advance directives appears to be completely independent from the health or disabling status. Another important result of the study is that patients generally express themselves as being very confident and trustful in their doctors. They do not fear to be over-treated and having to support any futile treatment. CONCLUSION: Around 20% of people are very much concerned by advance directives and do really expect that their wishes will be respected. The authors suggest that advance directives should be for them really respected, even if the French law let doctors free at this point to decide what the best interest of the patient actually is and if they should or not respect in this case what the patient wrote as advance directives. Around 30% of other people appear interested to speak with someone of the time they will still live. Their concern is more to express what is important for them in terms of still living and quality of life, than to express very clear advance directives about the way they would like to dye. The last learning of the study is that there is still a lot to do if we want more people precisely express something on the conditions of their dying. Doctors might have a fundamental pedagogic role in that respect: they should better inform patients about the limits of medicine and tell them more about the new complexity of medical decision-making at the end of life due to recent improvements in techniques. PMID- 23433957 TI - Nerve-conduits or nerve-guides? When terminology matters. PMID- 23433958 TI - Normal development and function but impaired memory phenotype of CD8+ T cells in transgenic mice expressing HIV-1 Nef in its natural target cells. AB - We studied the impact of HIV Nef on CD8(+) T cells in a mouse model of AIDS, the CD4C/HIV(Nef) transgenic (Tg) mice. We found that negative and positive thymic selections of CD8(+) T cells proceeded normally in Nef Tg mice bred respectively with HY or OT-1 TCR Tg mice. Tg peripheral CD8(+) T cells showed an activated phenotype and enhanced cell division in vivo and proliferated efficiently when stimulated in vitro with antigenic peptide. When challenged with LCMV(Armstrong), Nef Tg mice developed a strong acute CD8(+) T cell response and cleared the virus as efficiently as wild-type mice. However, maintenance of LCMV-specific CD8(+) memory T cells was impaired in Nef Tg mice, a defect partially rescued by adoptive transfer of non-Tg naive CD4(+) T cells. Thus, despite severe abnormalities of their precursors, the double-positive CD4(+)CD8(+) thymocytes, Tg CD8(+) T cells have conserved important functions. PMID- 23433959 TI - Identification of candidate transcription factor binding sites in the cattle genome. AB - A resource that provides candidate transcription factor binding sites (TFBSs) does not currently exist for cattle. Such data is necessary, as predicted sites may serve as excellent starting locations for future omics studies to develop transcriptional regulation hypotheses. In order to generate this resource, we employed a phylogenetic footprinting approach-using sequence conservation across cattle, human and dog-and position-specific scoring matrices to identify 379,333 putative TFBSs upstream of nearly 8000 Mammalian Gene Collection (MGC) annotated genes within the cattle genome. Comparisons of our predictions to known binding site loci within the PCK1, ACTA1 and G6PC promoter regions revealed 75% sensitivity for our method of discovery. Additionally, we intersected our predictions with known cattle SNP variants in dbSNP and on the Illumina BovineHD 770k and Bos 1 SNP chips, finding 7534, 444 and 346 overlaps, respectively. Due to our stringent filtering criteria, these results represent high quality predictions of putative TFBSs within the cattle genome. All binding site predictions are freely available at http://bfgl.anri.barc.usda.gov/BovineTFBS/ or http://199.133.54.77/BovineTFBS. PMID- 23433960 TI - Tocilizumab for polymyalgia rheumatica: report of two cases and review of the literature. AB - BACKGROUND: Glucocorticoids (GC) are the mainstay of treatment of polymyalgia rheumatica (PMR). However GC-related adverse events occur frequently, particularly in patients with relapsing disease. Several studies have demonstrated that IL-6 is a key player in the pathogenesis of PMR. OBJECTIVES: To report 2 patients with PMR treated with the anti-IL-6 receptor monoclonal antibody tocilizumab (TCZ) and to review the published evidence on the efficacy and safety of TCZ in patients with PMR. METHODS: We treated 2 GC-naive patients with newly diagnosed pure PMR with monthly TCZ infusions (8mg/kg body weight) for 6 months. Disease activity and drug tolerability were assessed clinically, by laboratory tests, and bilateral shoulder ultrasonography before starting the treatment and subsequently every month during TCZ therapy. We performed a systematic literature search (PubMed until July 2012) using the terms "tocilizumab," "anti-IL-6-receptor," "polymyalgia rheumatica," "giant cell arteritis", and "large-vessel vasculitis" to identify published reports of patients with PMR treated with TCZ. RESULTS: One of our patients responded well to TCZ, while the other patient required GC therapy after the 2nd TCZ infusion because of lack of appreciable clinical response. Both patients tolerated TCZ well. The review of the literature revealed 4 reports with a total of 9 patients who received TCZ for PMR. In 7 of these 9 patients, PMR was associated with giant cell arteritis. Including our patients, 5 patients received TCZ alone and 6 TCZ plus GC. A good response to TCZ treatment was observed in all patients reported in the literature without any major adverse events. CONCLUSIONS: TCZ both as monotherapy and in association with GC appears to be mostly effective and safe to treat patients with PMR. However, larger controlled studies are required to confirm these favorable data. PMID- 23433961 TI - The role of extracellular modulators of canonical Wnt signaling in bone metabolism and diseases. AB - OBJECTIVES: The Wnt signaling pathway is a key pathway in various processes, including bone metabolism. In this review, current knowledge of all extracellular modulators of the canonical Wnt signaling in bone metabolism is summarized and discussed. METHODS: The PubMed database was searched using the following keywords: canonical Wnt signaling, beta-catenin bone metabolism, BMD, osteoblast, osteoporosis, Wnt, LRPs, Frizzleds, sFRPs, sclerostin or SOST, dickkopfs, Wif1, R spondins, glypicans, SOST-dc1 and kremen, all separately as well as in different combinations. RESULTS: Canonical Wnt signaling is considered to be one of the major pathways regulating bone formation. Consequently, a large number of studies were performed to elucidate the role of numerous proteins in canonical Wnt signaling and bone metabolism. These studies led to the identification of novel modulators of the pathway like the R-spondin and glypican protein families. Furthermore novel insights are gained in the regulatory role of the different Wnt proteins. Finally, due to its function in bone formation, the pathway is an interesting target for the development of therapeutics for osteoporosis and other bone diseases. In this review, we discuss the promising results of the Wnt modulators sclerostin, Dkk1 and sFRP1 as targets for osteoporosis treatment. CONCLUSION: The increasing number of studies into the exact function of all proteins in the canonical Wnt pathway in general and in bone metabolism already led to novel insights in the regulation of the canonical Wnt pathway. In this review we covered the current knowledge of all extracellular modulators of canonical Wnt signaling. PMID- 23433962 TI - Efficacy and safety of interferon-gamma-targeted therapy in Crohn's disease: a systematic review and meta-analysis of randomized controlled trials. AB - AIMS: To evaluate the efficacy and safety of interferon-gamma-targeted therapy in Crohn's disease (CD). METHODS: Keyword and MeSH searches of MEDLINE/PubMed, EMBASE, the Cochrane Database, Science Citation Index and the Chinese Biomedical Database, from the inception of each database to March 2012, were used to identify all available randomized controlled trials. Summary estimates of treatment effects and safety were produced with Review Manager, using relative risks (RR) of clinical response, clinical remission and adverse events rates. RESULTS: Only three randomized controlled trials comparing anti-interferon-gamma therapy with placebo were qualified for the meta-analysis according to inclusion criteria. There were significant differences in clinical remission rates between groups (at week 6: RR=2.01, 95% confidence interval [CI]: 1.18-3.45; at week 8: RR=1.98, 95% CI: 1.17-3.33). There was also a significant difference in clinical response rates at week 8 (RR=1.60, 95% CI: 1.12-2.27). However, there was no statistically significant difference between anti-interferon-gamma therapy and placebo on adverse events rates (RR=0.98, 95% CI: 0.79-1.20). CONCLUSIONS: Anti interferon-gamma therapy is safe and effective for treating active CD despite slow onset of action. PMID- 23433963 TI - Reduced expression of TRIF in chronic HBV infected Iranian patients. AB - BACKGROUND AND AIMS: TRIF is one of the main intracellular adaptor proteins required for TLR3 and 4 signaling. Abnormal gene expression of TRIF may lead to abrogated immune responses against viral infections including hepatitis B infection. The aim of this study was to identify the mRNA levels of TRIF in PBMCs isolated from chronic HBV (CHB) infected patients. MATERIAL AND METHODS: mRNA was isolated from 63 CHB patients and 60 healthy controls and transcript levels of TRIF were examined in parallel with beta-actin (as housekeeping gene) using Real Time PCR techniques. RESULTS: Our results demonstrated that expression of TRIF was significantly decreased in PBMCs isolated from CHB patients when compared to healthy controls. CONCLUSIONS: Based on the results reported here, it seems that CHB patients are unable to express appropriate levels of the TRIF gene, which may attenuate TLR3 and 4 signaling subsequent to HBV infection. Our results suggest a possible mechanism, which may explain why hepatitis B infection is stable in CHB patients. PMID- 23433964 TI - Resolution of chronic hepatitis delta infection after five years of peginterferon adefovir: lessons from a case report. AB - There is still some controversy about the treatment of hepatitis delta virus (HDV) infection and the treatment endpoints. A 48-year-old patient was treated with a combination of peginterferon-alpha and adefovir, and HDV RNA clearance occurred after 3 years of treatment. However, treatment was continued until HBs antigen (Ag) seroconversion, which occurred after 5 years of therapy. One year after the end of the treatment, the patient was still HBs Ag and HDV RNA negative. This case report suggests that combined peginterferon-alpha and adefovir may be effective in treating HDV infection and, if given over a longer period, may result in hepatitis B surface antigen (HBsAg) seroconversion. It highlights the interest of using HBsAg quantification associated with a sensitive RT-PCR approach for monitoring the treatment of chronic hepatitis delta. HBsAg seroconversion, or at least significant decrease, could be a more relevant endpoint than HDV RNA undetectability for discontinuing HDV treatment and preventing the occurrence of virological relapses. PMID- 23433965 TI - Large hepatic angiomyolipoma. PMID- 23433966 TI - Self-efficacy as a predictor of weight change and behavior change in the PREMIER trial. AB - OBJECTIVES: Determine whether self-efficacy independently predicted weight loss in a behavioral intervention and explore factors that influence the path between self-efficacy and weight change. DESIGN: Secondary analysis of the PREMIER trial, a randomized controlled trial testing effects of lifestyle interventions on blood pressure. SETTING: Four academic medical centers. PARTICIPANTS: PREMIER recruited adults (n = 810) with pre-hypertension/stage 1 hypertension, not currently receiving medication. This analysis excluded participants in the control arm, resulting in n = 537. INTERVENTIONS: Participants were randomly assigned to 1 of 3 groups: advice only, established lifestyle recommendations, or established lifestyle recommendations plus Dietary Approaches to Stop Hypertension dietary pattern. MAIN OUTCOME MEASURES: Self-efficacy (dietary self-efficacy [DSE], exercise self-efficacy [ESE]), dietary intake, fitness. ANALYSIS: Pearson correlations, 1-way analysis of variance, mediation analyses. RESULTS: Despite an overall decrease in DSE/ESE, change in DSE/ESE significantly predicted weight change at 6 (beta = -.21, P < .01; beta = -.19, P < .01, respectively) and 18 months (beta = -.19, P < .01; beta = -.35, P < .01). Change in percent calories from fat partially mediated the DSE/weight change relationship at 6 months. Change in fitness partially mediated the ESE/weight change relationship at 18 months. CONCLUSIONS AND IMPLICATIONS: Changes in DSE/ESE were not associated with behavior change as hypothesized. Additional research is needed to identify mediators between self-efficacy and adoption of behaviors that influence weight loss. PMID- 23433967 TI - Systematic review of dietary interventions with college students: directions for future research and practice. AB - OBJECTIVE: To clarify directions for research and practice, research literature evaluating nutrition and dietary interventions in college and university settings was reviewed. DESIGN: Systematic search of database literature. SETTING: Postsecondary education. PARTICIPANTS: Fourteen research articles evaluating randomized controlled trials or quasi-experimental interventions targeting dietary outcomes. MAIN OUTCOME MEASURES: Diet/nutrition intake, knowledge, motivation, self-efficacy, barriers, intentions, social support, self-regulation, outcome expectations, and sales. ANALYSIS: Systematic search of 936 articles and review of 14 articles meeting search criteria. RESULTS: Some in-person interventions (n = 6) show promise in improving students' dietary behaviors, although changes were minimal. The inclusion of self-regulation components, including self-monitoring and goal setting, may maximize outcomes. Dietary outcomes from online interventions (n = 5) were less promising overall, although they may be more effective with a subset of college students early in their readiness to change their eating habits. Environmental approaches (n = 3) may increase the sale of healthy food by serving as visual cues-to-action. CONCLUSIONS AND IMPLICATIONS: A number of intervention approaches show promise for improving college students' dietary habits. However, much of this research has methodological limitations, rendering it difficult to draw conclusions across studies and hindering dissemination efforts. PMID- 23433968 TI - Orange juice, a marker of diet quality, contributes to essential micronutrient and antioxidant intakes in the United States population. AB - OBJECTIVE: To evaluate the impact of 100% orange juice (OJ) on the healthy diet and micronutrient intakes of the United States population. METHODS: Cross sectional study of 13,971 people in the United States aged >= 4 years using 2 24 hour diet recalls from the National Health and Nutrition Examination Survey, 2003 2006. RESULTS: Consumption of OJ was higher among 4- to 8-year-old children, older adults (> 50 y old), non-Hispanic blacks, those with lower body mass index, those of lower income level, nonsmokers, dietary supplement users, and those participating in regular exercise (P < .05). Consumption of OJ was positively associated with the percentage of participants meeting MyPyramid recommendations for fruit consumption. Increased OJ consumption was correlated with increased daily intakes of certain micronutrients and antioxidants (P < .05). Percentages of participants with intakes below Estimated Average Requirements for these micronutrients decreased with increased OJ consumption (P < .001). CONCLUSIONS AND IMPLICATIONS: The implicated nutritional and potential health benefits of OJ warrant further investigation in clinical research studies. PMID- 23433969 TI - 'You've got m@il: fluoxetine coming soon!': accessibility and quality of a prescription drug sold on the web. AB - BACKGROUND: The increasing phenomenon of online pharmacies has potential for serious public health problems. This study aimed to evaluate the possibility of accessing a prescription drug in the absence of a prescription for an Italian purchaser. METHODS: Fluoxetine pills were ordered from several online pharmacies. The study included website analysis, and the quality of the received product including packaging, chemical and microbiological analyses. RESULTS: Orders could be placed correctly on 61 of the 98 selected websites, and a sales transaction was concluded successfully on 17 websites. Thirteen drug samples were eventually received. In one case it was necessary to fill in a questionnaire before ordering the drugs. All websites displayed aggressive marketing strategies. There was wide variation in terms of domain registration, company base (when declared) and manufacturer's location (mostly India). All pills were delivered in sealed blister packs showing the lot number and manufacturer's details. A leaflet was enclosed in one case only. In three cases we received more pills than ordered, and in one case Viagra pills as a free gift. Pharmacopoeia microbiological requirements were satisfied. Chemical analysis revealed that the active principle was always present, although many samples did not meet the Pharmacopoeia "other impurities" or "total impurities" criteria. Heavy metals and solvents regulated by the Pharmacopoeia did not exceed the set limits; some of the non-regulated ones were also assessed, in some cases with a positive result (e.g. styrene). CONCLUSION: About 20% of purchase attempts resulted in delivery of the drugs, even in the absence of a medical prescription. Traceability was poor and drug quality was generally worse compared to conventional pharmacy-purchased products. Based on all these broad-spectrum results, user safety appears not to be globally guaranteed. PMID- 23433971 TI - Synthesis, characterization, and catalytic activity for hybrids of multi-walled carbon nanotube and amphiphilic poly(propyleneimine) dendrimer immobilized with silver and palladium nanoparticle. AB - Four types of new multi-walled carbon nanotube (MWCNT) based nanohybrid catalysts were prepared through simple methods. Initially, MWCNT was functionalized with carboxyl group and subsequently bonded with amphiphilic poly(propyleneimine) dendrimer (APPI) having generation (G2) and (G3). They are abbreviated as MWCNT APPI (G2) and MWCNT-APPI (G3). Silver nanoparticles (AgNPs) and palladium nanoparticles (PdNPs) were separately immobilized to each hybrid to obtain four types of MWCNT based nanohybrid catalysts. The pseudo-first order rate constants for reduction of 4-nitrophenol revealed that among the four types of MWCNT nanohybrid catalysts, MWCNT-APPI (G3)-PdNPs was more efficient than the other catalysts with five-fold higher efficiency than the homogeneous PPI (G3)-PdNPs. For the same reaction with MWCNTs-APPI (G3)-PdNPs catalyst, the variation of [catalyst] and [NaBH4] was directly proportional to kobs. The study of reusability of MWCNT-APPI (G3)-PdNPs proved no loss in activity even after recycling the catalyst for five times. PMID- 23433970 TI - Surgical management of patients with synchronous colorectal liver metastasis: a multicenter international analysis. AB - BACKGROUND: The goal of this study was to investigate the surgical management and outcomes of patients with primary colorectal cancer (CRC) and synchronous liver metastasis (sCRLM). STUDY DESIGN: Using a multi-institutional database, we identified 1,004 patients treated for sCRLM between 1982 and 2011. Clinicopathologic and outcomes data were evaluated with uni- and multivariable analyses. RESULTS: A simultaneous CRC and liver operation was performed in 329 (33%) patients; 675 (67%) underwent a staged approach ("classic" staged approach, n = 647; liver-first strategy, n = 28). Patients managed with the liver-first approach had more hepatic lesions and were more likely to have bilateral disease than those in the other 2 groups (p < 0.05). The use of staged operative strategies increased over the time of the study from 58% to 75% (p < 0.001). Liver-directed therapy included hepatectomy (90%) or combined resection + ablation (10%). A major resection (>3 segments) was more common with a staged approach (39% vs 24%; p < 0.001). Overall, 509 patients (50%) received chemotherapy in either the preoperative (22%) or adjuvant (28%) settings, with 11% of patients having both. There were 197 patients (20%) who had a complication in the postoperative period, with no difference in morbidity between staged and simultaneous groups or major vs minor hepatectomies (p > 0.05). Ninety-day postoperative mortality was 3.0%, with no difference between simultaneous and staged approaches (p = 0.94). The overall median and 5-year survivals were 50.9 months and 44%, respectively; long-term survival was the same regardless of the operative approach (p > 0.05). CONCLUSIONS: Simultaneous and staged resections for sCRLM can be performed with comparable morbidity, mortality, and long-term oncologic outcomes. PMID- 23433972 TI - Improved thermooxidation and sedimentation stability of covalently-coated carbonyl iron particles with cholesteryl groups and their influence on magnetorheology. AB - Sedimentation of particles in magnetorheological suspensions represents a crucial problem that concerns their efficient long-term application in practice. Prepared carbonyl iron (CI) microparticles coated with a low density substance, cholesteryl chloroformate, via a two-step reaction and immersed in silicone oil, exhibit three positive aspects: (1) the CI particle modification increased the compatibility between the particles and the silicone oil resulting in improved long-term stability (reduction in sedimentation); (2) the coating provided the particles with enhanced thermal stability in the oxygen atmosphere; and (3) rheological measurements proved a promising magnetorheological performance at different particle weight fractions. PMID- 23433973 TI - Study of the micelle-to-vesicle transition and smallest possible vesicle size by temperature-jumps. AB - We have investigated the temperature induced micelle-to-vesicle transition in a binary non-ionic surfactant/water system, for which the spontaneous curvature decreases with increasing temperature. Temperature jumps with variable rate were performed in a microwave oven, from a micellar phase at 5 degrees C to a lamellar phase region at 35 degrees C, passing a liquid-liquid two phase region where dilute and concentrated micellar solutions coexist. It is shown that the obtained vesicle size decreases with increasing heating rate through this two phase region. Moreover, we demonstrate that there exists a minimum vesicle radius, Rv(*), as is also predicted by theory. In the present system we find Rv(*)~50nm, in reasonable agreement with a theoretical estimate. PMID- 23433974 TI - A chimpanzee skull in the devil's cave. PMID- 23433975 TI - Organic acids pretreatment effect on Rosa bourbonia phyto-biomass for removal of Pb(II) and Cu(II) from aqueous media. AB - The sorption of Pb(II) and Cu(II) form aqueous media by Rosa bourbonia waste phyto-biomass (RBWPB) pretreated with organic acids was investigated as a function of biosorbent dosage, initial metal ions concentration and contact time. The equilibrium biosorption data was analyzed using two kinetic models (pseudo first order and pseudo-second order) and two isotherm models (Langmuir and Freundlich). The RBWPB was successfully applied for sequestration of both heavy metal ions; however, organic acids pretreatments decreased the metal adsorption capacity of RBWPB. The Langmuir model fitted well to the data, and the pseudo second order kinetic equation could best describe the biosorption kinetics of Pb(II) and Cu(II) metal ions. Gibbs free energy indicated the spontaneous adsorption of Pb(II) and Cu(II) onto RBWPB. PMID- 23433976 TI - Effective biochemical decomposition of chlorinated aromatic hydrocarbons with a biocatalyst immobilized on a natural enzyme support. AB - The enzymatic decomposition of 4-chlorophenol metabolites using an immobilized biocatalyst was investigated in this study. Catechol 1,2-dioxygenase for ortho ring cleavage obtained via cloning of the corresponding gene cphA-I from Arthrobacter chlorophenolicus A6 was overexpressed and purified. It was found that the cphA-I enzyme could catalyze the degradation of catechol, 4 chlorocatechol, and 3-methylcatechol. The expressed enzyme was immobilized onto a natural enzyme support, fulvic acid-activated montmorillonite. The immobilization yield was as high as 63%, and the immobilized enzyme maintained high substrate utilization activity, with only a 15-24% reduction in the specific activity. Kinetic analysis demonstrated marginal differences in numax and KM values for the free and immobilized enzymes, indicating that inactivation of the immobilized enzyme was minimal. The immobilized enzyme exhibited notably increased stability against changes in the surrounding environment (temperature, pH, and ionic strength). Our results provide useful information for the effective enzymatic biochemical treatment of hazardous organic compounds. PMID- 23433977 TI - Determination of optimum conditions for dairy wastewater treatment in UAASB reactor for removal of nutrients. AB - In this study, the granular sludge was generated for simultaneous nitrification, denitrification and phosphorus removal (SNDPR) and studied on a laboratory scale. Analyzing the nutrients removal percentages from wastewater were scrutinized by using an optimization of the variables, i.e., COD:N:P ratio, OLR, aeration time, MLSS, F:M and HRT. These 6 interrelated parameters were evaluated as the process response. Microscopic observations of the performance of the SNDPR process revealed that the granules included Bacillus sp. in the bacterial community. According to these results, the UAASB system produced an effluent that lends dairy wastewater suitable for land irrigation and that this an attractive process of using granular sludge is appropriate for achieving carbon, nitrogen and phosphorus removal from nutrient-rich wastewater by a biological method. PMID- 23433978 TI - Saline catholytes as alternatives to phosphate buffers in microbial fuel cells. AB - Highly saline solutions were examined as alternatives to chemical buffers in microbial fuel cells (MFCs). The performance of two-chamber MFCs with different concentrations of saline solutions in the cathode chamber was compared to those with a buffered catholyte (50mM PBS). The use of a NaCl catholyte improved the CE to 43-60% (28% with no membrane) due to a reduction in oxygen transfer into the anolyte. The saline catholyte also reduced the membrane and solution resistance to 23Omega (41Omega without a membrane). The maximum power density of 491mW/m(2) (240mM NaCl) was only 17% less than the MFC with 50mM PBS. The decrease in power output with highest salinity was due to reduced proton transfer due to the ion exchange membrane, and pH changes in the two solutions. These results show that MFC performance can be improved by using a saline catholyte without pH control. PMID- 23433979 TI - Metabolic engineering of Bacillus subtilis for the efficient biosynthesis of uniform hyaluronic acid with controlled molecular weights. AB - Bacillus subtilis was engineered into an efficient hyaluronic acid (HA) producer by introducing two inducible artificial operons carrying HA synthase gene from Pasteurella multocida and precursor genes encoding enzymes involved in synthesis of the sugar precursors. A two-stage induction strategy was established for metabolic engineering of recombinant B. subtilis to efficiently produce uniform HA with controlled molecular weights. Strain TPG223 produced larger HA molecules (yield=6.8 g/L; molecular weight=4.5 MDa) than strain PG6181 (yield=2.4 g/L; molecular weight=13 KDa), indicating that the enzymes involved in the synthesis of UDP-glucuronic acid are essential for HA biosynthesis. Strain TPG223 was able to synthesize HA molecules ranging in molecular weight from 8 KDa to 5.4 MDa indicating that size control is achievable in vivo through appropriate tools. The work reported here not only advanced mechanisms research of size control in vivo, but also could be an attractive alternative for commercial preparation of uniform size-defined HA. PMID- 23433980 TI - Heart failure with preserved and reduced ejection fraction: different phenotypes in old-elderly patients? AB - BACKGROUND: Patients with heart failure with preserved ejection fraction (HFPEF) represent an important group of patients presenting in clinical practice. However, whether it is an earlier stage of heart failure with reduced ejection fraction (HFREF) remains uncertain. We evaluated the potential progression of HFPEF to HFREF. METHODS AND RESULTS: We evaluated retrospectively 178 patients (mean age 80.5+/-5.8 years; 75.3% females) with heart failure with preserved ejection fraction from a specialized Internal Medicine unit, offering an integrated usual care. Diagnosis of heart failure with preserved ejection fraction was made according to European guidelines. The main objective was to evaluate the progression to systolic dysfunction, defined by left ventricular ejection fraction less than 45%. Mean baseline left ventricular ejection fraction was 64.6+/-7.2. After a mean follow-up of 24-months, mean baseline ejection fraction was 67.1+/-9.3%. Only five patients (2.8%) progressed to HFREF. Brain natriuretic peptide values were significantly higher in those patients who progressed. CONCLUSIONS: These results strongly suggest that heart failure with preserved and reduced ejection fraction could be distinct pathophysiological entities, at least in elderly patients. PMID- 23433981 TI - Physiotherapy students' experiences of bullying on clinical internships: an exploratory study. AB - OBJECTIVES: To consider the prevalence and type of bullying behaviours experienced whilst on clinical placement in a cohort of final-year BSc undergraduate students. DESIGN: Cross-sectional survey. SETTING: University in the West Midlands, UK. PARTICIPANTS: Fifty-two final-year undergraduate students. MAIN OUTCOME: Prevalence of incivility and bullying behaviours. RESULTS: Twenty five percent of students reported at least one incident of bullying behaviour. The perpetrator of the bullying behaviour was most often the clinical educator (8/13, 62%). Despite the negative effects caused, the majority of students (11/13, 84%) did not report this experience to the university. CONCLUSION: Bullying behaviour may take many forms and can have a negative effect on the well being of students. It should be addressed by all stakeholders including universities, National Health Service trusts and researchers. Possible strategies to move forwards and better protect the future of the physiotherapy profession are briefly considered. PMID- 23433982 TI - Patients' potential role in the transmission of health care-associated infections: prevalence of contamination with bacterial pathogens and patient attitudes toward hand hygiene. AB - BACKGROUND: Transmission of health care-associated infections (HAIs) has been primarily attributed to health care workers, and hand hygiene is considered the most important means to reduce transmission. Whereas hand hygiene research has focused on reducing health care worker hand contamination and improving hand hygiene compliance, contamination of patients' hands and their role in the transmission of HAIs remains unknown. METHODS: Patients' hands were sampled by a "glove juice" recovery method and enumerated for the presence of common health care-associated pathogens. Patient demographics and other covariates were collected to determine their association with patient hand contamination. Patient attitudes and practices toward hand hygiene were also surveyed and analyzed. RESULTS: Of the 100 patients in the study, 39% of hands were contaminated with at least 1 pathogenic organism, and 8% were contaminated with 2 or more pathogens 48 hours after admission. Patient admission from or discharge to an outside institution and self-reported functional limitations were the only covariates that were significantly associated with hand contamination. CONCLUSION: Pathogenic organisms can be frequently detected on hands of acute care patients. Future studies are needed to better understand the relationship between patient hand contamination and the acquisition of HAIs in addition to the role patient hand hygiene can play in reducing HAIs. PMID- 23433983 TI - Methicillin-resistant Staphylococcus aureus colonization among pediatric health care workers from different outpatient settings. AB - Staphylococcus aureus colonization rates in pediatric health care workers from different types of outpatient settings were determined from December 2008 through May 2010. Colonization rates for Staphylococcus aureus and, specifically, methicillin-resistant Staphylococcus aureus (MRSA) rates were similar to the rates that have been reported for the general population. The predominant MRSA pulsed-field gel electrophoresis type associated with colonization in these health care workers is not MRSA USA300. PMID- 23433984 TI - [Cost awareness at emergencies: multicentric survey among prescribers]. AB - AIM: Regular increasing of health-care expense brought about the development of medical implication in prescription control and the will to give more responsibility to prescribers. Emergency departments account for a large part of hospital expenses. This study was carried out to evaluate cost awareness among French emergency physicians. METHODS: A questionnaire was sent to 160 physicians (junior and senior grade) working at the emergency department of 12 hospitals in the Lyon region (France). Every participant had to estimate the true hospital costs of a selection of drugs, blood products, laboratory tests and imaging modalities. RESULTS: One hundred and seven questionnaires (68%) were returned and analysed: 48 filled in by juniors (45%), 59 by seniors (55%). Only 26 physicians accurately estimated costs within 50% of the true cost. Response errors were underestimations averaging 4695+/-226euros, i.e. -59+/-3% of the total sum (7899euros). Drug prescriptions were significantly (P<0.001) the most underestimated (-74+/-3%), when compared to both imaging modalities (-23+/-5%) or blood products prescriptions (-37+/-6%). High-cost drugs (>1000euros) were the most overestimated pharmaceuticals (-82+/-2%). Laboratory tests were rather overestimated (+12+/-8%). Junior grade physicians underestimated more costs than senior physicians (P=0.04). DISCUSSION: Physicians had a poor understanding of prescription costs at the emergencies, especially regarding high-cost drugs. Much progress is required to integrate the cost-containment problem in daily prescriptions at the emergency department. PMID- 23433985 TI - Nasal eucoleosis in a symptomatic dog from Italy. AB - A dog with chronic muco-purulent nasal discharge, sneezing, reverse sneezing and impaired scenting ability was diagnosed as being affected by nasal eucoleosis based upon rhinoscopic evidence of Eucoleus boehmi in situ, identification of the adult parasites in nasal biopsies, and eggs in the faeces by light and scanning electron microscopy. The dog was successfully treated with a single administration of moxidectin. A second course of moxidectin was required for about 10 weeks after the first treatment, because clinical signs recurred due to a likely re-infection. This second administration, along with measures undertaken to prevent geo- and coprophagic pica, resolved the parasitism, as demonstrated by negative copromicroscopic and rhinoscopic examinations, and prevented reinfestation for the next 4 months. To the best of the authors' knowledge, this represents the first report describing a clinical case of nasal eucoleosis with a demonstration of the adult parasites in situ in a dog from Italy where, until recently, infestation of E. boehmi was only detected by a coprological examination. Veterinarians and parasitologists should be aware of the occurrence of canine infection with E. boehmi. They should include this parasite in the differential diagnoses for animals suffering from upper airway distress and look systematically for it during rhinoscopic and copromicroscopic examinations. PMID- 23433986 TI - Molecular identification of nematode larvae different from those of the Trichinella genus detected by muscle digestion. AB - Although larvae of the genus Trichinella are the most common parasite species detected in vertebrate muscles using artificial digestion, nematode larvae belonging to other genera are sometimes detected and incorrectly identified as Trichinella. However, it is often very difficult to identify these larvae at the species, genus or family level using microscopy because of the absence of specific morphological characters or cuticle damage, and the only means of identification is PCR and sequencing of specific molecular markers (12S mtDNA; COI; 18S rDNA; and ITS1). From 2008 to 2011, 18 nematode isolates not belonging to the genus Trichinella were collected from different host species. Eleven of these isolates were successfully identified at the species, genus or superfamily level: larvae from two common kestrels, three hooded crows, a hen harrier and a domestic pig were identified as Toxocara cati; larvae from a badger were identified as Toxocara canis; larvae from a domestic pig were identified as a free-living nematode of the genus Panagrolaimus; larvae from a wild boar were identified as belonging to the Metastrongylus genus; and larvae from a rough legged buzzard were identified as belonging to the superfamily Filarioidea. The recovery of nematodes belonging to genera other than Trichinella during routine meat inspection suggests that the persons performing the analyses need to be informed of the possibility of false positives and that a molecular-based identification system that allows for a rapid and reliable response must be adopted (i.e., a DNA barcoding-like system). PMID- 23433987 TI - The opportunistic nature of Trichinella--exploitation of new geographies and habitats. AB - For more than 100 years, Trichinella spiralis (former Trichina spiralis) was considered a zoonotic parasite of the domestic habitat involving pigs, synanthropic rats and humans. In the last 70 years, there has been increasing evidence that the biomass of nematodes of the genus Trichinella is greater in wild animals than in domestic animals. Omnivores and carnivores (mammals, birds and some reptiles), mainly those with cannibalistic and scavenger behaviour, act primarily as reservoirs for the 12 Trichinella taxa recognized to date. The distribution areas of Trichinella spp. hosts can help to identify the environmental suitability where the different Trichinella taxa can be detected. Both the survival of larvae in decaying muscles of their hosts, which is favoured by high humidity and low temperatures, and human behaviour in the domestic and wild habitats play roles in the transmission patterns of these nematodes. Although Trichinella taxa develop in different host species circulating in different geographical regions, there is a common denominator among the hosts, namely their scavenging behaviour. PMID- 23433988 TI - Trichinella detection: identification and statistical evaluation of sources of error in the magnetic stirrer method for pooled sample digestion. AB - Proficiency testing (PT) is the use of inter-laboratory comparisons to determine the performance of individual laboratories for specific tests or measurements, and to monitor a laboratory's performance. Participation in proficiency testing provides laboratories with an objective means of assessing and demonstrating the reliability of the data they are producing. To ensure the reliability of Trichinella detection and meat hygiene within the European Union and afford optimal protection to the consumer, PT is conducted under the direction of the European National Reference Laboratories for Trichinella. Evaluation of data from the national PT showed that lab-internal shortcomings are frequent. These shortcomings are specifically related to: (1) improper sample collection and preparation; (2) incorrect transposition and application of the protocol as laid down in Annex I, Chapter I, Nr. 3 (a-g) of the Commission Regulation (EC) No. 2075/2005; (3) insufficient sedimentation times; and (4) improper equipment.(e.g. Prost and Nowakowski, 1990; Rossi and Pozio, 2008; Forbes and Gajadhar, 1999; Rossi and Pozio, 2008). To test the hypothesis that both method based errors as well as internal lab errors can influence the accuracy and precision of the magnetic stirrer method for pooled sample digestion (MSM), we initiated a study to evaluate the analytical uncertainty of the MSM. Results presented here are based on: (i) data from PT in Germany (2008, 2009, and 2010); (ii) within-lab performance conducting high volumes of MSM; (iii) larval recovery experiments; and (iv) statistical evaluation of data resulting from these procedures. Quantitative data from the PT show that on average only 60% of Trichinella larvae were detected. Even laboratories that showed relatively good performance (>80% larva recovery, no false negative or false positive results), frequently reported samples with an unexpectedly low larval count (loss of >2 larvae). In our own laboratory, high numbers of repeated analyses of standards and re-analyses of residual fluids indicated that these outliers could be described by a binomial distribution based on a laboratory-specific Trichinella-detection probability. Results of recovery experiments indicate that only a part of the total larval losses can be attributed to lab-internal shortcomings inasmuch as a significant number of L1 could be isolated from the residual and washing fluids. PMID- 23433989 TI - Identifying risk factors for symptoms of severe trichinellosis--a case study of 143 infected persons in Brasov, Romania 2001-2008. AB - The presence of the parasite Trichinella spiralis in humans does not always manifest itself with obvious clinical symptoms; the clinical manifestations of trichinellosis are polymorphic and can cause diagnostic difficulties. Our aim was to identify risk factors that can be linked to the severity of the disease. We conducted a retrospective analysis of 143 cases of trichinellosis admitted to the Infectious Disease Hospital in Brasov, Romania during 2001-2008. We found that children 10 and younger were less prone to exhibit medium or severe symptoms. Patients with leukocytosis had a 1.75 times higher risk of developing medium to severe symptoms relative to those with normal white blood cell counts. Patients with high eosinophil counts had a 2.05 times higher risk of exhibiting average or serious symptoms relative to those with low or normal eosinophil counts. Repeated consumption of contaminated meat increased the chances of developing discernible forms of the disease by 5.25 fold when compared to those who only occasionally ate meat contaminated with Trichinella. Regular consumption of raw or undercooked meat increased the chances of developing medium or severe forms of this disease by 1.67 times when compared to those who consume meat that had been thoroughly cooked. PMID- 23433990 TI - How safe is the meat inspection based on artificial digestion of pooled samples for Trichinella in pork? A scenario from wildlife to a human patient in a non endemic region of Europe. AB - The occurrence of trichinellosis in a resident of the Netherlands prompted us to examine the likelihood of this originating from infected rats in spite of prevailing biosecurity and testing procedures. In so doing, we sought to calculate the possible risks for trichinellosis in countries deemed non-endemic. The infection risk was determined by simulating a scenario from a reservoir of minimally contaminated wildlife to pigs to humans. Results indicate that humans might become infected even in the event that artificial digestion had been performed on individually tested pig carcasses. Our conclusions justify reconsidering Trichinella control strategies based on the current testing protocol, and emphasize the importance of proper cooking as further insurance against human infection. PMID- 23433991 TI - A study on the suitability of inactivated Trichinella spiralis larvae for proficiency samples. AB - The consumption of raw or undercooked Trichinella infected meat, especially pork and horse meat, can have important implications for public health. Therefore each animal carcass from a Trichinella susceptible species intended for human consumption must be examined for Trichinella. Laboratories carrying out testing of official control samples must undergo a quality assurance program and should regularly participate in proficiency testing schemes. To date, Trichinella proficiency samples are prepared with live larvae, which, as a level 2 pathogen, require specific shipping and disinfection procedures. Therefore, the suitability of using inactivated Trichinella larvae as proficiency samples was tested. We found that Trichinella larvae treated with 2% formaldehyde for 24h had lost their infectivity and showed a comparable recovery rate to naive larvae after artificial digestion, albeit with a prolonged sedimentation time. PMID- 23433992 TI - Trichinella: what is going on during nurse cell formation? AB - Recent molecular studies have revealed that many genes are mobilized during nurse cell formation, including those involved in activation and proliferation of satellite cells, dedifferentiation, cell cycle re-entry and arrest, apoptosis and transformation. This article reviews the kinetics of gene expression from a cellular biology point-of-view in an effort to dissect the complex events that lead to unusual pathological changes after a Trichinella infection. PMID- 23433993 TI - An Italian family with inherited achalasia. PMID- 23433994 TI - Otoprotective effect of recombinant erythropoietin in a model of newborn hypoxic ischemic encephalopathy. AB - OBJECTIVE: The aim of this study is to test the hypotheses that central auditory pathology as well as inner ear pathology is contributing mechanisms to observed hypoxic-ischemic encephalopathy (HIE) induced hearing loss and that recombinant erythropoietin (rhEPO) will reduce this cellular pathology and attenuate hearing loss. METHODS: Twenty-eight 7-day Wistar albino rat pups were divided into four groups: Control group (n=8) was given only intraperitoneal saline solution. Sham group (n=5) had only a midline neck incisions without carotid ligation under general anesthesia and administration of intraperitoneal saline solution. HIE group (n=8) and rhEPO treated group (n=7) were subjected to left common carotid artery ligation followed by 2.5h hypoxia exposure to a mixture of 8% oxygen and 92% pure nitrogen. HIE group was injected with intraperitoneal saline solution, while the rhEPO treated group received rhEPO 100 U/kg within the same volume as the saline-alone solution. At the end of the seventh week of age hearing (ABRs) was evaluated in response to clicks, 6 kHz and 8 kHz tone burst stimuli. Animals were sacrificed and both temporal lobes, cochleas and brainstems of the animals were collected. Tissue samples were evaluated with light microscopy, immunohistochemical studies, including TUNEL and caspase-3 stainings, and electron microscopy. RESULTS: Hearing thresholds were elevated in HIE animals. In rhEPO treated animals, ABR values were similar to controls. HIE caused apoptotic changes in brainstem structures as shown by light microscopy and immunohistochemical methods. Apoptotic changes also were found within the organ of Corti, spiral ganglion cells and neurons of temporal lobe by electron microscopic investigation. In rhEPO animals many of these apoptotic changes were observed, but reduced compared to untreated animals. CONCLUSIONS: Mechanisms underlying HIE-induced hearing loss are based on apoptosis in inner ear; however central auditory pathway pathology occurs as well, likely contributing to changes in auditory processing and perception of complex signals not reflected by the ABR threshold shifts. For both clinical and basic significance 'rhRPO' is found to reduce those effects. PMID- 23433995 TI - Discharge after tonsillectomy in pediatric sleep apnea patients. AB - OBJECTIVES: Outpatient tonsillectomy has gained favor in recent years, however patients with obstructive sleep apnea/hypopnea syndrome have been excluded from outpatient surgery criteria. It is the practice of the senior author to discharge patients after tonsillectomy with a respiratory disturbance or apnea hypopnea index of 5 or less. The purpose of this study is to examine the respiratory complication rate based on respiratory disturbance or apnea hypopnea index, and co-morbidities in order to determine which pediatric patients with obstructive sleep apnea/hypopnea syndrome can be safely discharged after tonsillectomy. METHODS: All patients undergoing tonsillectomy with the diagnosis of obstructive sleep apnea made by polysomnography by a single surgeon from 2008 to 2011 were included. Decision to admit was based on respiratory disturbance or apnea hypopnea index, body mass index, and comorbidities. All inpatient notes, phone calls, and follow up visit documentation were monitored and reviewed for post operative complications. RESULTS: 104 patients were included, 74 patients were admitted post operatively, and 30 were discharged home. There were no complications in the group that was discharged home. In the group that was admitted, there was two minor and two intermediate complications, including desaturations to 92% and 83% requiring oxygen, and wheezing requiring breathing treatment. All complications occurred in patients with respiratory disturbance or apnea hypopnea index of 11 or greater. CONCLUSION: Our data suggest there is a correlation between higher respiratory disturbance or apnea hypopnea index and post operative complications. Patients with an RDI of <5.0, and minimal co morbidities can be safely discharged home following tonsillectomy for OSAHS. Complications related to sleep apnea were not seen in patients with RDI <11.0, suggesting that patients with an RDI between 5 and 10, who are not obese and have no significant comorbidities may also be sent home after surgery. PMID- 23433996 TI - Pediatric nasal bone fractures: does delayed treatment really lead to adverse outcomes? AB - OBJECTIVES: It is recommended that pediatric nasal bone fractures be treated earlier than in adults, within 3-7 days of the injury. This study was aimed at evaluating if delayed treatment could affect surgical outcomes of pediatric nasal bone fractures. METHODS: Pediatric patients (<=17 years) with nasal bone fractures, who underwent corrective surgery between 2003 and 2011, were reviewed. Patients who underwent previous septo/rhinoplasty, or who had a previous nasal fractures and combined facial bone fracture, were excluded. A telephone survey was conducted, and clinical data and results from early (<=7 days) and delayed (>7 days) treatment groups were evaluated. RESULTS: Out of 56 eligible patients, 48 (85.7%) underwent closed reduction (CR) only, and eight (14.3%) were given combined rhinoplastic (CR+) approaches. Out of 35 patients who underwent CR alone or CR+ and responded to the telephone interview, the long-term cosmetic results were good, with a median score of 2; the long-term nasal obstruction was minimal with a median score of 1. The median follow up period was 62 months (range 6 109). The elapsed time from injury to surgery did not affect patient satisfaction in terms of cosmetic outcomes (P=0.939) and nasal obstruction (P=0.264). CONCLUSIONS: In pediatric nasal bone fractures, regardless of delayed or early treatment, the cosmetic outcome was consistently good, and nasal obstruction was nearly absent. Based on the time period from injury to surgery, the surgical outcome of delayed treatment group was also good. PMID- 23433997 TI - The results of metal-on-metal hip resurfacing in patients under 30 years of age. AB - Degenerative hip conditions most commonly affect older patients. However, many cases occur in younger patients. Total hip arthroplasty is the conventional approach; however, hip resurfacing is a viable option. Fifty-three metal-on-metal resurfacings in 46 patients under age 30 were performed. Patients had a variety of etiologies, and were followed clinically and radiographically with mean follow up of 98.2 months. Clinical scores and x-rays were compared pre-operatively and post-operatively. The last follow-up SF-12 and UCLA scores significantly improved post-operatively (P<0.0001). Range of motion scores also improved (P<0.001), and the mean Harris Hip Score was 88. There were 6 revisions. The Kaplan-Meier survivorship estimate at 8 years was 95%. Metal-on-metal hip resurfacing appears to be an effective procedure for younger patients. Longer-term data are needed for confirmation. PMID- 23433999 TI - Management of narcolepsy during pregnancy. AB - BACKGROUND: The management of pregnancy in patients with narcolepsy poses many questions regarding therapy, including the risk to the mother and fetus related to the disease, potential risks at the time of conception, the risk to both the mother and the fetus of the medications used to treat narcolepsy, and the risk to the infant from medications that might be secreted in breast milk. There are no detailed practice parameters on the treatment of narcolepsy patients during pregnancy. We surveyed narcolepsy specialists from around the world to determine their clinical approach to the management of patients with narcolepsy at the time of conception, during pregnancy and while breastfeeding. METHODS: Survey invitations were sent via e-mail to 75 clinicians worldwide between 2/2011 and 3/2011 with 34 responses (USA, n=10; Brazil, n=3; Czech Republic, n=2; France, n=2; Italy; n=2; Netherlands, n=2; Canada, n=1; Denmark, n=1; Finland, n=1; Germany, n=1; Japan, n=1; Spain, n=1; unknown n=7). Responders who completed the survey had 20 years (median range, 5-35) of experience in sleep medicine practice with a median number of five narcolepsy patients seen per week. The number of pregnant narcoleptic patients followed per physician was five (median range 1 40). RESULTS: The survey results indicated that the management of patients with narcolepsy varies greatly from clinician to clinician and from country to country. The majority of the clinicians stopped the narcolepsy medications at the time of conception, during pregnancy, and during breastfeeding some reduced the dose and others did not change the dosage, depending on the particular medication. CONCLUSIONS: The findings from our survey and literature review suggest that the perceived risks of narcolepsy medication during pregnancy to the mother and the fetus usually are overestimated, as the risk for teratogenic effects from narcolepsy medications in therapeutic doses is essentially nonexistent. However, the potential for rare complications during pregnancy and congenital abnormalities cannot be excluded. Most narcolepsy patients have vaginal delivery without complications. In rare cases patients had cataplexy that interfered with delivery, but if caesarian is required there appears to be no increased anaesthetic or surgical risks. Further prospective information for the appropriate treatment of narcolepsy patients during pregnancy is needed. PMID- 23433998 TI - Incidence of venous thromboembolism before treatment in cervical cancer and the impact of management on venous thromboembolism after commencement of treatment. AB - INTRODUCTION: Silent venous thromboembolism (VTE) often occurs before treatment in ovarian or endometrial cancer and management can decrease VTE after treatment. However, the incidence of VTE before treatment and the impact of management are still unclear in cervical cancer. MATERIALS AND METHODS: We investigated the incidence of VTE before treatment in 272 consecutive patients with cervical cancer, and the impact of management on prevention of VTE during and after treatment. D-dimer levels before treatment were examined in all patients. Venous ultrasonography of the lower extremities was performed in patients with D-dimer >=1.5MUg/ml. Deep vein thrombosis (DVT) in the pelvis or abdomen was diagnosed by enhanced computed tomography. RESULTS: Thirteen patients (4.8%; 3 preoperatively, 10 before radiotherapy or concurrent chemoradiotherapy) were diagnosed with DVT, although DVT was symptomatic in only 1 patient. None of the 13 patients showed pulmonary embolism on pulmonary scanning. Although 4 of 128 patients (3.1%) developed VTE after radical hysterectomy, none of the 124 patients who underwent radiotherapy or concurrent chemoradiotherapy developed VTE during or after treatment. CONCLUSIONS: These data suggest that VTE before treatment occurs less frequently with cervical cancer than with ovarian or endometrial cancer. However, management may decrease VTE during and after treatment, especially radiotherapy. PMID- 23434000 TI - [Pulmonary nocardiosis and sarcoidosis]. AB - Infectious complications are rarely observed in the course of sarcoidosis. Only small series or cases reports of infection are described in sarcoidosis. Corticosteroids-induced immune suppression, pulmonary fibrosis and T-CD4 lymphopenia, are often present. Pulmonary nocardiosis is an important cause of opportunistic infection in immunosuppressed patients, and the incidence of this infection is increasing. Pulmonary nocardiosis manifests as an acute, subacute or chronic infection with a marked tendency towards remissions and exacerbations. We report a case of pulmonary nocardiosis in a patient with sarcoidosis followed for pulmonary fibrosis receiving corticosteroids. During the investigation of pyrexia and dyspnea, evidence of Nocardia spp. infection was found in the bronchial secretions. Six months of trimethoprim/sulfamethoxazole therapy ensured further resolution of this pleuropulmonary infection. Pulmonary nocardiosis is exceptional in sarcoidosis and mainly occur, in patients receiving corticosteroids, and with CD4+ T-lymphocytopenia. Sarcoidosis by itself does not appear to be a risk factor of opportunistic infection. PMID- 23434001 TI - [Hemoptysis complicating bronchopulmonary mucormycosis in a diabetic patient]. AB - INTRODUCTION: Mucormycosis are the fungal infections caused by emerging ubiquitous filamentous fungi classified as zygometes and order as mucorales. They occur mainly in immunosuppressed patients and diabetics. The onset of hemoptysis, in this context, may rapidly become life-threatening. OBSERVATION: We report the case of a man of 83 years, Caribbean with a history of non-insulindependent diabetes and HTLV1 seropositive. At admission he presented with fever, cough and cachexia. Chest X-ray revealed a snapshot of excavation within alveolar consolidation. Endoscopy showed a mucopurulent plug obstructing lingula. The histological appearance of bronchial biopsies was in favor of mucormycosis. A combined treatment with liposomal amphotericin B and posaconasole was implemented, but the occurrence of abundant hemoptysis led us to make a left upper lobectomy. Finally, the outcome was favorable and the patient was discharged after hospitalization of 56 days. CONCLUSION: A medicosurgical treatment during mucormycosis complicating bronchopulmonary hemoptysis not controlled by medical treatment alone seems to offer an effective therapeutic strategy. PMID- 23434003 TI - Reflections on the state of nursing implementation science. PMID- 23434002 TI - [About new treatments in thoracic oncology]. PMID- 23434004 TI - Understanding the functions of tumor stroma in resistance to ionizing radiation: emerging targets for pharmacological modulation. AB - Maintenance of both normal epithelial tissues and their malignant counterparts is supported by the host tissue stroma. The tumor stroma mainly consists of the basement membrane, fibroblasts, extracellular matrix, immune cells, and vasculature. Although most host cells in the stroma possess certain tumor suppressing abilities, the stroma will change during malignancy and eventually promote growth, invasion, and metastasis. There is growing evidence that the stroma influences importantly the response to radiation therapy (RT). On the one hand, irradiation releases numerous inflammatory cytokines within the extracellular matrix and activates tumor specific antigens presentation, triggering an immune reaction that contributes to the antitumor effect seen after RT. On the other hand, the stroma significantly contributes to radioresistance but also increases the metastatic risk. Indeed, fibroblasts, which are major actors of the impact of stroma on tumor response, are involved in activation of autocrine and paracrine molecular signaling pathways regulating tumor cell proliferation, cell death, response to hypoxia, DNA repair systems and mesenchymal-epithelial transition. They are also actors of the peritumoral desmoplastic reaction, which decreases tumor radiosensitivity. The irradiated stroma can also contribute to tumor relapse after RT through recruitment of bone marrow-derived progenitors that contribute to local tumor relapse through neovascularization. It is therefore time to question preclinical models that would not take into account this impact of stroma. The increasing knowledge of the relationship between stroma and response to IR could help developing innovative strategies for potentially improve antitumor effect of RT. PMID- 23434005 TI - Does improved insulin sensitivity by irbesartan at the highest tolerated dose provide a benefit in non-diabetic patients with systolic heart failure already receiving standardized treatment? PMID- 23434006 TI - Magnetocardiography in patients with acute chest pain and bundle branch block. PMID- 23434007 TI - Association between length of stay, frequency of in-hospital death, and causes of death in Japanese patients with acute heart failure syndromes. PMID- 23434008 TI - Evolving pattern of on-prasugrel and on-ticagrelor platelet reactivity over time in ST elevation myocardial infarction patients. PMID- 23434009 TI - Muscle strength in heart failure male patients complicated by diabetes mellitus. PMID- 23434010 TI - Safety of using anti-TNF-alpha blockers in cardiac failure associated with systemic inflammatory disease and the risk of Kounis syndrome. PMID- 23434011 TI - Do we just assess the left ventricle in pregnant women with structural heart disease? PMID- 23434012 TI - Cattle tick-associated bacteria exert anti-biofilm and anti-Tritrichomonas foetus activities. AB - Research on microbiota in cattle tick and the evaluation of its activity against other microorganisms can contribute to identify new molecules potentially useful to control infections caused by bacteria and protozoa. Biofilms pose increasing problems worldwide, mainly due to their resistance to antimicrobial therapies and host immune response. In this study we investigate the ability Rhipicephalus (Boophilus) microplus-associated bacteria may exhibit to produce anti-biofilm and trichomonicidal compounds. Gut, ovary, salivary glands, and Gene organ were collected from engorged R. microplus female. Homogenates of each tissue were inoculated onto 15 distinct culture media. Anti-biofilm and trichomonicidal activities were analyzed by culturing each bacterium isolated in a liquid medium. Results showed that R. microplus cattle tick microflora varies for different tissues. Bacteria belonging to different genera (Aeromonas, Bacillus, Brevibacillus, Castelaniella, Comamonas, Kocuria, and Microbacterium) were identified. Interestingly, all bacterial species found displayed pronounced activity against Staphylococcus epidermidis and Pseudomonas aeruginosa biofilms, and also against the cattle pathogen Tritrichomonas foetus, confirming the hypothesis that cattle tick could be a source of bacteria active against pathogens. This is the first study showing that bacteria isolated from a tick exert anti-biofilm and trichomonicidal activities. PMID- 23434013 TI - The enterohemorrhagic Escherichia coli effector protein NleF binds mammalian Tmp21. AB - The human pathogens enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC), as well as the mouse pathogen Citrobacter rodentium encode type III secretion system (T3SS) effector proteins to promote their survival in the infected host. The mechanisms of action and the host targets of T3SS effectors are under active investigation because of their importance to bacterial virulence. The non-locus of enterocyte effacement (LEE)-encoded protein F, NleF, contributes to E. coli and C. rodentium colonization of piglets and mice, respectively. Here we sought to characterize the host binding partners of NleF. Using a yeast two-hybrid screen, we identified Tmp21, a type-I integral membrane protein and COPI-vesicle receptor involved in trans-Golgi network function, as an NleF-binding partner. We confirmed this interaction using immunoprecipitation and bimolecular fluorescence complementation (BiFC). We expressed a temperature sensitive vesicular stomatitis virus glycoprotein (tsVSVG) to monitor protein trafficking and determined that NleF slows the intracellular trafficking of tsVSVG from the endoplasmic reticulum to the Golgi. PMID- 23434014 TI - Suppression of NK cells and regulatory T lymphocytes in cats naturally infected with feline infectious peritonitis virus. AB - A strong cell-mediated immunity (CMI) is thought to be indispensable for protection against infection with feline infectious peritonitis virus (FIPV) in cats. In this study, the role of natural killer (NK) cells and regulatory T cells (Tregs), central players in the innate and adaptive CMI respectively, was examined during natural FIPV infection. When quantified, both NK cells and Tregs were drastically depleted from the peripheral blood, mesenteric lymph node (LN) and spleen in FIP cats. In contrast, mesentery and kidney from FIP cats did not show any difference when compared to healthy non-infected control animals. In addition, other regulatory lymphocytes (CD4+CD25-Foxp3+ and CD3+CD8+Foxp3+) were found to be depleted from blood and LN as well. Phenotypic analysis of blood derived NK cells in FIP cats revealed an upregulation of activation markers (CD16 and CD25) and migration markers (CD11b and CD62L) while LN-derived NK cells showed upregulation of only CD16 and CD62L. LN-derived NK cells from FIPV infected cats were also significantly less cytotoxic when compared with healthy cats. This study reveals for the first time that FIPV infection is associated with severe suppression of NK cells and Tregs, which is reflected by cell depletion and lowered cell functionality (only NK cells). This will un-doubtfully lead to a reduced capacity of the innate immune system (NK cells) to battle FIPV infection and a decreased capacity (Tregs) to suppress the immunopathology typical for FIP. However, these results will also open possibilities for new therapies targeting specifically NK cells and Tregs to enhance their numbers and/or functionality during FIPV infection. PMID- 23434015 TI - Identification of a major immunogenic region of equine herpesvirus-1 glycoprotein E and its application to enzyme-linked immunosorbent assay. AB - A major immunogenic region of equine herpesvirus (EHV)-1 glycoprotein E (gE) was identified. Firstly, the various fragments of EHV-1 gE were expressed as fusion proteins with glutathione S-transferase (GST) in Escherichia coli and their antigenicities were compared by immunoblot analysis using sera from horses experimentally infected with EHV-1. Thirty-three amino acids of gE (a.a. 169-201) specifically and sensitively reacted with the antibodies induced by EHV-1 but not EHV-4 infection. The corresponding region of EHV-4 gE (a.a. 169-199) did not react with antibodies to EHV-1, indicating that this region is specific for each virus. In addition, when the antigenicities of three 20-mer synthetic peptides of EHV-1 gE, gE1(169-188), gE1(176-195) and gE1(182-201) were compared by enzyme linked immunosorbent assay (ELISA), gE1(169-188) was found to contain a major B cell epitope. ELISA using two synthetic peptides, gE1(169-188) and gG4(319-330), previously identified as the major EHV-4-specific epitope in gG, was developed and could specifically detect antibodies to EHV-1 and EHV-4, respectively. In Japan, the EHV-1 deleted in gE gene (EHV-1 DeltagE) virus is expected to be introduced in the field as a new modified live vaccine. This ELISA did not react with antibodies induced by inoculation with EHV-1 DeltagE, indicating that it is a useful method to differentiate between EHV-1 infection and EHV-1 DeltagE inoculation. In conclusion, the ELISA described herein, using synthetic peptides, is a simple method to distinguish between EHV-1 and EHV-4 infections and will be suitable as a vaccine marker after introduction of EHV-1 DeltagE into field horses. PMID- 23434016 TI - [Recommendations for neonatal transport]. AB - During pregnancy, it is not always possible to identify maternal or foetal risk factors. Infants requiring specialised medical care are not always born in centres providing intensive care and will need to be transferred to a referral centre where intensive care can be provided. Therefore Neonatal Transport needs to be considered as part of the organisation of perinatal health care. The aim of Neonatal Transport is to transfer a newborn infant requiring intensive care to a centre where specialised resources and experience can be provided for the appropriate assessment and continuing treatment of a sick newborn infant. Intrauterine transfer is the ideal mode of transport when the birth of an infant with risk factors is diagnosed. Unfortunately, not all problems can be detected in advance with enough time to safely transfer a pregnant woman. Around 30- 50% of risk factors will be diagnosed during labour or soon after birth. Therefore, it is important to have the knowledge and resources to resuscitate and stabilise a newborn infant, as well as a specialised neonatal transport system. With this specialised transport it is possible to transfer newly born infants with the same level of care that they would receive if they had been born in a referral hospital, without increasing their risks or affecting the wellbeing of the newborn. The Standards Committee of the Spanish Society of Neonatology reviewed and updated recommendations for intrauterine transport and indications for neonatal transfer. They also reviewed organisational and logistic factors involved with performing neonatal transport. The Committee review included the type of personnel who should be involved; communication between referral and receiving hospitals; documentation; mode of transport; equipment to stabilise newly born infants; management during transfer, and admission at the referral hospital. PMID- 23434017 TI - 123I-MIBG, 18F-DOPA and 18F-FDG in a patient with MEN2 syndrome and recurrent pheochromocytoma. AB - Pheochromocytoma is a rare tumor located in the medulla of the adrenal gland that is characterized by high catecholamine synthesis. Surgery is the treatment of choice and is usually curative if appropriately diagnosed and excised. Imaging methods, both morphological and functional, are of great importance in presurgical evaluation. We report the case of a female patient with multiple endocrine neoplasia syndrome type 2, with bilateral adrenalectomy due to two pheochromocytomas and progressive elevation of urinary metanephrine. Magnetic resonance imaging showed a nodular image in the right adrenal fossa. The patient was referred to our unit in order to confirm suspicion of recurrence. Due to the absence of pathological findings in the (123)I-MIBG scintigraphy and high suspicion of recurrence, PET/CT imaging with (18)F-DOPA and (18)F-FDG were performed, and the diagnosis was confirmed. PMID- 23434018 TI - 18FDG PET/CT imaging of schwannoma mimicking colorectal cancer metastasis. PMID- 23434019 TI - Reply to 'Measurement validity of childbirth perceptions' by H. Shepherd and L.L. Glenn. PMID- 23434020 TI - Effects of perinatal loss on current pregnancy in Turkey. AB - OBJECTIVE: to evaluate how a history of pregnancy loss in the perinatal period (from 20 weeks of gestation to seven days post partum) affects women during subsequent pregnancies. DESIGN: cross-sectional, descriptive study. SETTING: Istanbul Medical School, Istanbul University between January and October 2009. PARTICIPANTS: 128 pregnant women with a history of pregnancy loss and 214 pregnant women without a history of pregnancy loss. MEASUREMENTS AND FINDINGS: in all women, antenatal attachment was measured using the Prenatal Attachment Inventory, depression was measured using the Center for Epidemiologic Studies' Depression Scale, and coping with stress was measured using the Scale of Ways of Coping with Stress. The rates of undergoing tests (other than routine tests) (p<0.001), calling medical professionals (p<0.001) and visiting an obstetrician more than once per month (p<0.001) were higher in women with a history of pregnancy loss compared with women without a history of pregnancy loss. No difference was found between the groups in terms of coping with stress (p>0.05) and antenatal attachment (p=0.384). However, depressive symptoms were higher in women with a history of pregnancy loss (p=0.008). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: levels of depression, antenatal attachment and coping with stress should be evaluated meticulously in women with a history of pregnancy loss, and appropriate interventions should be performed. PMID- 23434021 TI - Home care after early discharge: impact on healthy mothers and newborns. AB - OBJECTIVE: to compare early discharge with home care versus standard postpartum care in terms of mothers' sense of security; contact between mother, newborn and partner; emotions towards breast feeding; and breast-feeding duration at one and three months after birth. DESIGN: retrospective case-control study. SETTING: a labour ward unit in Stockholm, Sweden handling both normal and complicated births. PARTICIPANTS: 96 women with single, uncomplicated pregnancies and births, and their healthy newborns. INTERVENTION: early discharge at 12-24 hours post partum with 2-3 home visits during the first week after birth. The intervention group consisted of women who had a normal vaginal birth (n=45). This group was compared with healthy controls who received standard postnatal care at the hospital (n=51). INSTRUMENTS: mothers' sense of security was measured using the Parents' Postnatal Sense of Security Scale. Contact between mother, child and father, and emotions towards breast feeding were measured using the Alliance Scale, and breast-feeding rates at one and three months post partum were recorded. FINDINGS: women in the intervention group reported a greater sense of security in the first postnatal week but had more negative emotions towards breast feeding compared with the control group. At three months post partum, 74% of the newborns in the intervention group were fully breast fed versus 93% in the control group (p=0.021). Contact between the mother, newborn and partner did not differ between the groups. CONCLUSION: early discharge with home care is a feasible option for healthy women and newborns, but randomised controlled studies are needed to investigate the effects of home care on breast-feeding rates. PMID- 23434022 TI - A mixed-method study of factors associated with differences in caesarean section rates at community level: the case of rural China. AB - OBJECTIVE: to assess population-based caesarean section (CS) rates in rural China and explore determinants and reasons for choosing a CS. DESIGN: cross-sectional study, quantitative and qualitative methods, statistical modelling. SETTING: two rural counties in Anhui province, China. PARTICIPANTS: (a) household survey participants: 2326 women who gave birth in the two counties from January 2005 to December 2006; (b) qualitative study participants: health providers at township and village level and maternal health-care providers (N=58). MEASUREMENTS AND FINDINGS: the household survey were conducted among 2326 women, collecting data on socio-economic and health status and utilisation of maternal health services. Eleven Focus Group Discussions with health-care providers and users to explore perceptions surrounding CS. the CS rate in the two areas were 46.0% and 64.7%. There were complex and different interactions among social-economic and clinical determinants associated with differences in CS rates. The main determinants that emerged were maternal age, maternal education, yearly income, primiparity, uptake of antenatal care and recorded obstetric complications with complex and differing interactions for each county. Maternal fear of pain, worry about mothers' and infants' safety, not satisfied with doctors' competences and physicians' low confidence in vaginal delivery, and absence of a strong midwifery cadre together contributed to final determination of CS. KEY CONCLUSIONS: the CS rates were extremely high in the two counties in rural China. Maternal socio-economic, clinic characteristics and health providers' preference contributed together to the high rates of CS. IMPLICATIONS FOR PRACTICE: evidence-based knowledge and methods to reduce unnecessary CS should be communicated to medical professionals and women. Greater comprehensive attention needs to be paid to a complex pattern of medical, socio-cultural, political and economic contexts of maternity care. PMID- 23434023 TI - Returning birth: the politics of midwifery implementation on First Nations reserves in Canada. AB - OBJECTIVE: to explore the role of midwives in the implementation of an elective birthing programme in one remote First Nation community in Canada, and to identify current barriers and challenges to the practice of midwifery in these settings DESIGN: the study is a multisited ethnography based on 15 months of fieldwork in Manitoba, Canada. Thirty-nine individual qualitative, semi structured interviews were completed. The data from the interviews were coded into themes and presented in the paper. SETTING: the study focuses on one First Nation community and their process of implementation of midwifery services. This case study is used to address broader themes of midwifery and policy at a national level. PARTICIPANTS: participants included Aboriginal midwives from across Canada, policy makers from provincial and federal jurisdictions, medical professionals involved in Aboriginal health care, Aboriginal political leadership, and Aboriginal women and their families. FINDINGS: national policy and issues of jurisdiction among levels of government were shown to be a barrier to midwifery implementation. KEY CONCLUSIONS: the current policy of evacuation in most Aboriginal communities does not effectively address the Millennium Development Goal of having a skilled birth attendant at every birth. The role of midwifery is central to the process of returning birth to Aboriginal communities, and steps must be taken at both the policy and clinical level to ensure that midwifery implementation and education can become an option for all Aboriginal communities in Canada. IMPLICATIONS FOR PRACTICE: when considering midwifery implementation in communities, midwives must engage in both political and clinical negotiations to ensure their ability to practice effectively. Understanding the complexity of the policy discourse, along with the place of midwifery within the existing clinical guidelines is integral to the success of this process. PMID- 23434024 TI - Early physical contact between a mother and her NICU-infant in two university hospitals in Finland. AB - OBJECTIVE: the first aim of this two-phase study was to describe and compare, between two university hospitals, the early physical contact of mothers and their preterm or sick newborn infants in the delivery room. Secondly, the staff's perceptions of factors facilitating and promoting or impeding this contact were evaluated. Thirdly, the association between early physical contact and the initiation of breast feeding was examined. DESIGN AND SETTING: a structured survey was conducted between November 2008 and March 2009 in two university hospitals in Finland. PARTICIPANTS: in phase I, the sample consisted of all preterm or sick infants who needed NICU care and whose questionnaires were completed by labour ward staff (hospital A, n=178/185, hospital B, n=203/235). In phase II, a subsample of these infants (A, n=76, B, n=94) and their mothers who completed their questionnaires participated in the study. MEASUREMENTS: structured questionnaires developed for this study were used. FINDINGS: the implementation of early physical contact differed between the study hospitals. The infants had physical contact with their mothers more often in hospital A than in hospital B whether they were sick full-term (83% versus 58%, p<0.001) or late preterm (49% versus 34%, p=0.051). None of the very preterm infants (<32 weeks) had early physical contact in the delivery room in either hospital. An infant's unstable condition and delivery by caesarean section were the most common obstacles against early contact. There was a moderate association between early contact and the initiation of breast feeding. KEY CONCLUSION AND IMPLICATIONS FOR PRACTICE: caring practices concerning early physical contact seemed to be different in the study hospitals. The obstacles impeding early contact should be re-evaluated. Guidelines might enhance early physical contact between preterm or sick infants and their mothers. PMID- 23434025 TI - Applying organisation theory to understand barriers and facilitators to the implementation of baby-friendly: A multisite qualitative study. AB - OBJECTIVES: (a) to apply an organisation-level, pre-implementation theory to identify and describe factors that may impact hospitals' readiness to achieve the Ten Steps and (b) to explore whether/how these factors vary across hospitals. DESIGN: a multisite, descriptive, qualitative study of eight hospitals that used semi-structured interviews of health-care professionals. Template analyses identified factors that related to organisation-level theory. Cross-site comparative analyses explored how factors varied across hospitals. SETTING: thirty-four health-care professionals from eight North Carolina hospitals serving low-wealth populations. The hospitals are participating in a quality improvement project to support the implementation of the Ten Steps. This study occurred during the pre-implementation phase. FINDINGS: several factors emerged relating to collective efficacy (i.e., the shared belief that the group, as a whole, is able to implement the Steps) and collective commitment (i.e., the shared belief that the group, as a whole, is committed to implementing the Steps) to implement the Ten Steps. Factors relating to both constructs included 'staff age/experience,' 'perceptions of forcing versus supporting mothers,' 'perceptions of mothers' culture,' and 'reliance on lactation consultants.' Factors relating to commitment included 'night versus day shift,' 'management support,' 'change champions,' 'observing mothers utilize breastfeeding support.' Factors relating to efficacy included 'staffing,' 'trainings,' and 'visitors in room.' Commitment factors were more salient than efficacy-factors among the three large hospitals. Efficacy-factors were more salient than commitment-factors among the smaller hospitals. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: interventions focused on implementing the Ten Step may benefit from improving collective efficacy and collective commitment. Potential approaches could include skills-based, hands-on training highlighting benefits for mothers, staff, and the hospital, and addressing context-specific misconceptions about the Steps. PMID- 23434026 TI - Elective caesarean delivery: a mixed method qualitative investigation. AB - BACKGROUND: the rates of primary, repeat, and elective caesarean deliveries have risen dramatically over the past several decades. The reasons for the rise are complex and likely reflect a cultural shift to a greater acceptance of surgical birth as a reasonable option, which may favour infant over maternal outcomes. The purpose of this interpretive qualitative study was to explore the complexities of women's and clinicians' choices around elective caesarean delivery. METHOD: this analysis was part of an institutional ethnography to understand the complex issues of childbearing care. Two English National Health Service Maternity Service Providers in an inner city setting were chosen for their reputation for commitment to normalising birth and decreasing caesarean birth rate. A sample of 27 women and 34 clinicians (midwifery, obstetric, anaesthesia) were interviewed and/or observed in practice settings. We also conducted a documentary analysis of local policy guidelines on elective caesarean delivery. Narrative analysis was conducted on interview, field observation, and document review data. Coding was conducted by three independent analysts and checked for consistency using Atlas.ti qualitative software. RESULTS: variations on elective caesarean choice and outcomes seemed to reflect how the team worked together and their underlying philosophies and commitments about caesarean birth. Four themes reflected the issues around elective caesarean birth: (1) the culture of caesarean, (2) caesarean counseling, (3) perceptions of choice and (4) negotiating the rules. CONCLUSIONS: counselling about elective caesarean and vaginal birth after a prior caesarean is complex and reflects an intersection of culture and science. Women and clinicians enter the discussion with different backgrounds and concerns, but ultimately want the best outcome possible. Future exploration should address shared decision-making, evidence-based clinical guidelines, and the social context of care. PMID- 23434027 TI - Effects of pregnancy and breastfeeding on the multiple sclerosis disease course. AB - Multiple sclerosis (MS) commonly affects young women of childbearing age. Thus, the challenges of the disease are often faced simultaneously with the challenges of early adult life and family planning. This has led to great interest in the effects of pregnancy and breastfeeding on MS. It is now well known that the risk of MS relapse declines during pregnancy but increases in the first 3-4 months postpartum. However, important gaps in knowledge remain and are the focus of this review. What factors predict postpartum relapses? Are there modifiable factors, such as breastfeeding, particularly exclusive breastfeeding, that could reduce the risk of postpartum relapses? Does pregnancy or breastfeeding have any long term effects on MS disease course? What immunological mechanisms underlie the effects of pregnancy and breastfeeding? Answering these questions will improve our ability to care for women with MS and may provide a greater understanding of the pathophysiology of the disease. PMID- 23434028 TI - Non-coding transcription and large-scale nuclear organisation of immunoglobulin recombination. AB - The enormous antigen receptor loci in lymphocytes are a paradigm of dynamic nuclear organisation, which is integral to their need to move extensively in 3D space to achieve distal gene synapse for V(D)J recombination and allelic exclusion. The loci undergo extensive 3D looping to bring distal genes together, controlled by several tissue-specific and ubiquitous factors, but how these factors achieve looping, synapsis and V(D)J recombination has been a mystery. Now several studies provide evidence that non-coding transcription, often proposed to play a role, is indeed an important driver, and furthermore has a specific nuclear destination for recombination. Both local transcription-independent looping and longer range factor-mediated transcription-dependent looping play separate roles in altering AgR architecture to enable V(D)J recombination. PMID- 23434029 TI - Discovery of biological evaluation of pyrazole/imidazole amides as mGlu5 receptor negative allosteric modulators. AB - Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4 acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti depressant activities. PMID- 23434030 TI - Anti-hepatitis B virus lignans from the root of Streblus asper. AB - Four new lignans, strebluslignanol F (1), (7'R,8'S,7"R,8"S)-erythro strebluslignanol G (2), isomagnaldehyde (3) and isostrebluslignanaldehyde (4), along with 12 known lignans (5-16) were isolated from the ethyl acetate-soluble part of MeOH extract of the root of Streblus asper. Their structures were elucidated through various spectroscopic methods, including 1D NMR ((1)H NMR, (13)C NMR), 2D NMR (HMQC, HMBC and NOESY) and HRMS. The stereochemistry at the chiral centers was determined using CD spectra, as well as analyses of coupling constants and optical rotation data. The isolated lignans were evaluated for their anti-HBV activities in vitro using the HBV transfected HepG2.2.15 cell line. The most active lignans, (7'R,8'S,7"R,8"S)-erythro-strebluslignanol G, magnolol, isomagnolol and isolariciresinol, exhibited significant anti-HBV activities with IC50 values of 1.58, 2.03, 10.34 and 3.67 MUM, respectively, for HBsAg with no cytotoxicity, and of 3.24, 3.76, 8.83 and 14.67 MUM, respectively, for HBeAg with no cytotoxicity. (7'R,8'S,7"R,8"S)-erythro-Strebluslignanol G and magnolol showed significant anti-HBV activities to inhibit the replication of HBV DNA with the IC50 values of 9.02 and 8.67 MUM, respectively. PMID- 23434031 TI - Design, synthesis and SAR of novel glucokinase activators. AB - Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes. PMID- 23434033 TI - Weight management during pregnancy: a systematic review of qualitative evidence. AB - BACKGROUND: increasing overweight and obesity rates in pregnant women present health risks to mother and unborn infant. OBJECTIVES: to identify barriers and facilitators to implementing and carrying out maternal weight management interventions. SEARCH STRATEGY: searches were carried out in medical, midwifery and nursing databases, augmented by hand searching of midwifery journals. SELECTION CRITERIA: articles were included that were published in the UK after 1990, with a focus on women's and health professional's views about weight management during pregnancy. DATA COLLECTION AND ANALYSIS: from 6423 citations, 126 full text papers were retrieved. Of these, 18 (reporting 17 studies) fulfilled the inclusion criteria. Included papers were assessed for quality. Reported findings were analysed and synthesised using thematic analysis. MAIN RESULTS: a major theme was access to relevant and appropriate information; advice was reported as vague or inadequate. Overweight or obese women reported feelings of stigmatisation during routine examinations. Health professionals reported a reluctance to discuss weight with larger women. Perceived risk to the fetus as well as changes in women's physiological responses to pregnancy, were reported barriers to optimal physical activity and dietary intake. Perceptions of control were related to women's feelings about their body image. CONCLUSION: evidence suggests that the complexity of interactions with advice sources, bodily changes, feelings of control, as well as perceived risks may explain the relative ineffectiveness of weight management interventions during pregnancy. Focusing on healthy diet and physical activity levels may be more useful and less stigmatising than focusing on weight. PMID- 23434032 TI - FKBP10 depletion enhances glucocerebrosidase proteostasis in Gaucher disease fibroblasts. AB - Lysosomal storage diseases (LSDs) are often caused by mutations compromising lysosomal enzyme folding in the endoplasmic reticulum (ER), leading to degradation and loss of function. Mass spectrometry analysis of Gaucher fibroblasts treated with mechanistically distinct molecules that increase LSD enzyme folding, trafficking, and function resulted in the identification of nine commonly downregulated and two jointly upregulated proteins, which we hypothesized would be critical proteostasis network components for ameliorating loss-of-function diseases. LIMP-2 and FK506 binding protein 10 (FKBP10) were validated as such herein. Increased FKBP10 levels accelerated mutant glucocerebrosidase degradation over folding and trafficking, whereas decreased ER FKBP10 concentration led to more LSD enzyme partitioning into the calnexin profolding pathway, enhancing folding and activity to levels thought to ameliorate LSDs. Thus, targeting FKBP10 appears to be a heretofore unrecognized therapeutic strategy to ameliorate LSDs. PMID- 23434034 TI - Urinary incontinence and weight changes during pregnancy and post partum: a pending challenge. AB - OBJECTIVE: to analyse the association between urinary incontinence and maternal weight, and its variations in pregnancy and post partum. DESIGN: observational study of a cohort of women from the start of pregnancy until six months post partum. SETTING: Hospital San Pedro in La Rioja, Spain. PARTICIPANTS: 402 pregnant women without urinary incontinence at the start of pregnancy. MEASUREMENTS AND FINDINGS: the dependent variable was urinary incontinence, assessed using the Urogenital Distress Inventory-Short Form questionnaire. The main independent variables were body mass index (BMI) at the first antenatal visit and six months post partum, weight gain during pregnancy, postpartum weight loss, and weight retained from the start of pregnancy to six months post partum. The association between urinary incontinence and the main independent variables was measured using Student's t-test. Three simple logistic regression models were used to assess the strength of this association, one for each of the independent variables that showed a significant association with urinary incontinence (p<0.05), and three multiple regression models that included the possible variable effect modifiers were also used. At the start of pregnancy, 20.1% of the women were overweight and 8.7% were obese. Six months post partum, 30.3% of the women were overweight and 11.4% were obese. The mean (+/-standard deviation) retained weight was 2 (+/-3.1) kg. Postpartum urinary incontinence was associated with BMI at six months post partum, postpartum weight loss and retained weight at six months post partum (p<0.05). The association of urinary incontinence with these variables was significant, and remained stable in both simple and multiple regression analyses with BMI at six months post partum [odds ratio (OR) 1.09 versus 1.08], weight loss from delivery to six months post partum (OR 0.88 versus 0.88), and retained weight from the beginning of pregnancy until six months post partum (OR 1.23 versus 1.19). KEY CONCLUSIONS: high BMI and weight retention at six months post partum increase the risk of urinary incontinence, whereas postpartum weight loss decreases the risk of urinary incontinence, even if other urinary incontinence risk factors co-exist. IMPLICATIONS FOR PRACTICE: primary care midwifes can make a major contribution towards the prevention and rehabilitation of urinary incontinence in women. It is important for the midwife and the woman to keep in contact in the first six months post partum. Individualised advice about eating and exercise habits to avoid weight retention after pregnancy may have a considerable impact on decreasing the risk of urinary incontinence. PMID- 23434035 TI - [Interest for evaluation of bronchial inflammation in asthma]. AB - Asthma is a heterogeneous chronic inflammatory disease. The respiratory functional tests are sometimes insufficient to confirm the diagnosis. Other tools are developed to estimate the bronchial inflammation such as tests of bronchial provocation, measure of exhaled nitric oxide, induced sputum and exhaled breath condensate. This review presents these non-invasive methods, approaches their interests on the identification of the disease and the treatment. PMID- 23434037 TI - Incidence of myeloperoxidase anti-neutrophil cytoplasmic antibody positivity and microscopic polyangitis in the course of idiopathic pulmonary fibrosis. AB - BACKGROUND: Pulmonary fibrosis is a manifestation of microscopic polyangitis (MPA), and often precedes the detection of MPA. The prevalence and sequence of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and MPA in patients initially diagnosed with idiopathic pulmonary fibrosis (IPF) have not been precisely elucidated. METHODS: We enrolled 61 consecutive patients with IPF and measured the MPO-ANCA titers at initial presentation and during the follow-up period. Clinical, radiologic and histologic features of MPO-ANCA-positive cases were examined. RESULTS: Of 61 patients, 3 (4.9%) had positive MPO-ANCA titers at the initial presentation of IPF. During the disease course, MPO-ANCA-positive conversion occurred in 6 patients and the prevalence of ANCA increased to 14.8%. Among the nine patients positive for MPO-ANCA, two patients developed MPA during follow-up. Histologic features of MPO-ANCA-positive pulmonary fibrosis were compatible with the usual interstitial pneumonia pattern in which alveolar hemorrhage and capillaritis were not observed. The patients with MPO-ANCA positive conversion showed increased percentages of bronchoalveolar lavage eosinophils and more frequent complication of pulmonary emphysema compared to those with MPO-ANCA-negative IPF. CONCLUSIONS: The findings of the present study demonstrated that patients with an initial diagnosis of IPF occasionally acquire MPO-ANCA, which develops to MPA during the disease course of IPF. The presence of pulmonary eosinophilia and low attenuation areas on computed tomography scans might be predictive of MPO-ANCA positive conversion. PMID- 23434036 TI - [Etiologies of non tuberculous empyema in adult patients infected with HIV in a service of pneumology, Abidjan (Ivory Coast)]. AB - OBJECTIVES: To identify the main bacteria that cause thoracic empyema of HIV infected patients. METHODS: Retrospective study analyzing the etiology of thoracic empyema in patients admitted to the pneumology clinic of the university hospital center in Abidjan from January 1998 to December 2010. We included all patients with bacteriologically confirmed thoracic empyema and had serological test for HIV. We compared the different pathogens based on HIV status. RESULTS: There were 42 patients of thoracic empyema composed of 24 (63.3%) HIV-infected patients [15 (62.5%) males and nine (37.5%) women] and 18 (36.7%) HIV-negative patients [13 (72.22%) men and five (27.78%) women]. The average age of HIV infected patients was 41.2 years and 44.8 years for HIV-negative patients. HIV status was known only for 4.76% patients at admission, and most of them had a severe stage of immune suppression, (the average T CD4 cell count was 96/mm(3)). Pleurisy was monomicrobial in 83.33% HIV-infected patients and 94.4% HIV-negative patients. It was polymicrobial in 16.67% immunocompromised patients and 5.56% HIV negative patient. Gram-negative bacteria were isolated from 58.33% HIV-infected patients. Streptococcus Pneumoniae was observed in 61.11% HIV-negative patients. CONCLUSIONS: Gram-negative bacteria are the main causes of thoracic empyema in patients HIV-infected. PMID- 23434038 TI - Truck traffic related air pollution associated with asthma symptoms in young boys: a cross-sectional study. AB - OBJECTIVES: The aim of this study was to evaluate the influence of intensity of truck traffic on asthma symptomatology, and its relationship with age and gender. STUDY DESIGN: A cross-sectional study was conducted on children and adolescents from Galicia (North-West Spain). METHODS: Following the methodology of the International Study of Asthma and Allergies in Childhood (ISAAC): children from schools randomly selected, answered a self-administered questionnaire included questions on asthma symptoms and some risk factors. The association between self reported truck traffic on the street of residence and symptoms of asthma were investigated by logistic regression adjusted for body mass index, maternal education and parental smoking. RESULTS: Almost 40% of children in Galicia are exposed to the frequent and constant passing of heavy goods vehicles. The odds of 6-7 year-old boys having severe or exercise induced asthma is tripled when they live in streets with the constant passing of heavy goods vehicles, compared with those living in streets where these vehicles never pass. In adolescents and 6-7 year-old girls, no relationship was observed between truck traffic and asthma symptoms. CONCLUSIONS: The results of this study appear to support a distinct effect of truck traffic on asthma symptoms depending on the age and sex of the exposed population, being more harmful for young males. PMID- 23434039 TI - Measuring the burden of chronic diseases in Korea in 2007. AB - OBJECTIVES: This study was performed to measure the burden of disease from premature death and disability for chronic diseases in Korea in 2007. STUDY DESIGN: Chronic diseases were defined using the WHO definitions. Disability adjusted life years (DALY) were used to analyse insurance claim data. METHODS: This was a population-based study and included the total population of Korea. DALYs were used to analyse insurance claim data. Years of life lost (YLL) and years lost to disability (YLD) were measured in terms of incidence rate and number of deaths. DALYs were aggregated to YLL and YLD. To ensure code validity, only patients who had visited a tertiary hospital or a clinic three or more times for the same disease were included. RESULTS: Cerebrovascular disease was the leading contributor to the chronic disease burden, with a value of 907.4, followed by diabetes mellitus (899), ischaemic heart disease (710), cirrhosis of the liver (616.5), chronic obstructive pulmonary disease (512.9), asthma (503.1), hypertensive heart disease (407.5), stomach cancer (356) and peptic ulcer disease (292.5). As these results demonstrate, the highest ranked diseases were cardio cerebrovascular or related diseases, as well as the fact that hypertension, diabetes mellitus and related complications, which are associated diseases, have became increasingly severe problems. And the rural areas have a higher burden of disease than metropolitan cities. According to difference in social status, Medicaid 2 group has more burden of disease than other groups. CONCLUSIONS: It has been possible to present evidence regarding the burden of diseases and the relatively high risk of cardio-cerebrovascular disease. If the various types of cancer were combined and then the calculating tool applied, the burden would likely be greater than that of cardio-cerebrovascular disease. However, based on DALY, ischaemic heart disease demonstrated a remarkable increase compared to the rate in the previous study based on 2002 data. Underprivileged people in particular have been struggling - with chronic diseases. PMID- 23434041 TI - Use of naltrexone for alcohol use disorders in the Veterans' Health Administration: a national study. AB - BACKGROUND: This study aimed to determine the proportion of patients with alcohol use disorders who were prescribed naltrexone in Veterans Administration (VA) Healthcare system for fiscal year (FY) 2010 and socio-demographic and clinical factors associated with its use. METHODS: VA national administrative data were used to identify all veterans who had an alcohol use disorder diagnosis (ICD-9-CM codes 303.9x or305.0x) in fiscal year (FY 2010) and were not prescribed any opioids (n=224,319). Patients in this group who filled a naltrexone prescription during this period were identified. Bivariate analysis was used to evaluate differences between veterans who received naltrexone prescription and those who did not on baseline characteristics and diagnoses. Multivariate logistic regression analysis identified measures that were independently related to receipt of naltrexone. RESULTS: 6172 (2.75%) of the 224,319 patients with a diagnosis of alcohol use disorder who did not receive a prescription for opioid medications received naltrexone prescription. Bivariate analyses showed that patients taking naltrexone were 69 times more likely to have a co-morbid axis I diagnosis. Multivariate logistic regression analysis showed that a history of any substance abuse outpatient visit, any psychiatric outpatient visit or any mental health inpatient hospitalization, were significantly related to filling a prescription for naltrexone. CONCLUSIONS: The rate of use of naltrexone by clinicians and patients remains low and having a co-morbid axis I diagnosis and receiving specialty mental health care were strong predictors of receiving a naltrexone prescription. Understanding the reasons for these findings may further naltrexone's clinical usefulness. PMID- 23434042 TI - Synergetic stress of acids and ammonium on the shift in the methanogenic pathways during thermophilic anaerobic digestion of organics. AB - Combined effects of acids and ammonium on functional pathway and microbial structure during organics methanization were investigated by stable isotopic method and quantitative PCR. The results showed that the stress from acids and ammonium was synergetic, resulted in different inhibition for acetoclastic and hydrogenotrophic methanogenesis and syntrophic acetate oxidation, leading to pathway shift. Methane production from acetate was affected more by acetate than by ammonium until the ammonium concentration reached 6-7 g-N/L. When the ammonium concentration exceeded 6 g-N/L, ammonium inhibition was strengthened by the increased concentration of acetate. At a low acetate concentration (50 mmol/L), acetoclastic methanogenesis dominated, regardless of ammonium concentration. At higher acetate concentrations (150 and 250 mmol/L) and at low-medium ammonium levels (1-4 g-N/L), acetate was mainly degraded by acetoclastic methanogenesis, while residual acetate was degraded by a combination of acetoclastic methanogenesis and the syntrophic reaction of syntrophic acetate oxidization and hydrogenotrophic methanogenesis with the latter dominating at 250 mmol/L acetate. At high ammonium levels (6-7 g-N/L), the degradation of acetate in the 150 mmol/L treatment was firstly through a combination of acetoclastic methanogenesis and the syntrophic pathway and then gradually shifted to the syntrophic pathway, while the degradation of acetate in the 250 mmol/L treatment was completely by the syntrophic pathway. PMID- 23434043 TI - Attachment surface energy effects on nitrification and estrogen removal rates by biofilms for improved wastewater treatment. AB - Submerged biofilm systems, such as integrated fixed-film activated sludge (IFAS) and moving bed bioreactors (MBBRs), are increasingly being used for domestic wastewater treatment, often to improve nitrification. Little is known about whether and how biofilm attachment surface chemical properties affect treatment performance, although surface chemistry is known to affect attachment in other systems, and work with pure strains has suggested that attachment of nitrifying bacteria may be enhanced on high surface energy surfaces. The objective of this research was to systematically evaluate the effects of surface chemistry on biofilm quantity and rates of nitrification and estrogen removal. Biofilms were grown on four plastic attachment surfaces with a range of hydrophobicity and surface energy values (nylon, melamine, high-density-polyethylene [HDPE], and acetal polymeric plastic) by immersing them in a full scale nitrifying activated sludge wastewater treatment system, followed by batch test experiments. The attachment surface water contact angles ranged from 53 degrees to 98 degrees and surface energies ranged from 48.9 to 20.9 mJ/m(2). Attachment surface hydrophilicity and surface energy were positively correlated with total biomass attachment, with more than twice as much biomass on the highest surface energy, most hydrophilic surface (nylon) than on the lowest surface energy, least hydrophilic surface (acetal plastic). Absolute and specific nitrification rates were also correlated with hydrophilicity and surface energy (varying by factors of 5 and 2, respectively), as were absolute and specific removal first order rate constants of the hormones estrone (E1), beta-estradiol (E2) and 17alpha ethynylestradiol (EE2). These results suggested that attachment surface chemistry may be a useful design parameter for improving biofilm performance for removal of ammonia and endocrine disrupting hormones from wastewater. Further research is required to verify these results at longer time scales and with typical media geometries. PMID- 23434040 TI - A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap. AB - A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease. PMID- 23434044 TI - Concentration polarization phenomenon during the nanofiltration of multi-ionic solutions: influence of the filtrated solution and operating conditions. AB - One of the major difficulties for the prediction of separation performances in the case of multi-ionic mixtures nanofiltration lies in the description of the concentration polarization phenomenon. Usual models available in literature do not take account of the polarization phenomenon or only describe it cursorily. Very few studies dedicated to the understanding and the specific description of the concentration polarization phenomenon are available in literature and a 2-D multi-ionic model describing the layer heterogeneity along the membrane length has never been proposed yet. The model used in the present work, called Pore and Polarization Transport Model (PPTM), allows an accurate description of the concentration polarization layer occurring during the filtration of multi-ionic solutions by taking account of the radial electromigrative transport in the layer, the turbulence, as well as the axial heterogeneity. In this context, the present paper aims at proposing a numerical investigation of the influence of operating conditions on the behavior of the polarization layer occurring at the membrane vicinity. The input parameters governing the transport through the membrane have been assessed in a previous study in the same experimental conditions so that only the polarization layer is investigated here. The proposed model which was previously validated on experimental observed rejection curves is then used to understand how operating conditions, such as applied pressure, feed flow-rate, or divalent ion proportion, govern the polarization phenomenon. For this purpose, concentration and thickness axial profiles along the membrane length and radial profiles within the polarization layer are investigated for various conditions. Finally, the impact of the type of divalent ion and the number of ions is also studied on various mixtures. PMID- 23434045 TI - Letter to the editor: the RO1 grant bottleneck. PMID- 23434046 TI - Global genomic arrangement of bacterial genes is closely tied with the total transcriptional efficiency. AB - The availability of a large number of sequenced bacterial genomes allows researchers not only to derive functional and regulation information about specific organisms but also to study the fundamental properties of the organization of a genome. Here we address an important and challenging question regarding the global arrangement of operons in a bacterial genome: why operons in a bacterial genome are arranged in the way they are. We have previously studied this question and found that operons of more frequently activated pathways tend to be more clustered together in a genome. Specifically, we have developed a simple sequential distance-based pseudo energy function and found that the arrangement of operons in a bacterial genome tend to minimize the clusteredness function (C value) in comparison with artificially-generated alternatives, for a variety of bacterial genomes. Here we extend our previous work, and report a number of new observations: (a) operons of the same pathways tend to group into a few clusters rather than one; and (b) the global arrangement of these operon clusters tend to minimize a new "energy" function (C(+) value) that reflects the efficiency of the transcriptional activation of the encoded pathways. These observations provide insights into further study of the genomic organization of genes in bacteria. PMID- 23434047 TI - MeRIP-PF: an easy-to-use pipeline for high-resolution peak-finding in MeRIP-Seq data. AB - RNA modifications, especially methylation of the N(6) position of adenosine (A) m(6)A, represent an emerging research frontier in RNA biology. With the rapid development of high-throughput sequencing technology, in-depth study of m(6)A distribution and function relevance becomes feasible. However, a robust method to effectively identify m(6)A-modified regions has not been available yet. Here, we present a novel high-efficiency and user-friendly analysis pipeline called MeRIP PF for the signal identification of MeRIP-Seq data in reference to controls. MeRIP-PF provides a statistical P-value for each identified m(6)A region based on the difference of read distribution when compared to the controls and also calculates false discovery rate (FDR) as a cut off to differentiate reliable m(6)A regions from the background. Furthermore, MeRIP-PF also achieves gene annotation of m(6)A signals or peaks and produce outputs in both XLS and graphical format, which are useful for further study. MeRIP-PF is implemented in Perl and is freely available at http://software.big.ac.cn/MeRIP-PF.html. PMID- 23434048 TI - Is allometric scaling really a panacea for flow-mediated dilation? Commentary on paper by Atkinson and Batterham. PMID- 23434049 TI - Identifying risk factors of immune reconstitution inflammatory syndrome in AIDS patients receiving highly active anti-retroviral therapy. AB - Immune reconstitution inflammation syndrome typically occurs within days after patients undergo highly active anti-retroviral therapy and is a big hurdle for effective treatment of AIDS patients. In this study, we monitored immune reconstitution inflammation syndrome occurrence in 238 AIDS patients treated with highly active anti-retroviral therapy. Among them, immune reconstitution inflammation syndrome occurred in 47 cases (19.7%). Immune reconstitution inflammation syndrome patients had significantly higher rate of opportunistic infection (p<0.001) and persistently lower CD4(+) cell count (p<0.001) compared to the non-immune reconstitution inflammation syndrome patients. In contrast, no significant differences in HIV RNA loads were observed between the immune reconstitution inflammation syndrome group and non-immune reconstitution inflammation syndrome group. These data suggest that a history of opportunistic infection and CD4(+) cell counts at baseline may function as risk factors for immune reconstitution inflammation syndrome occurrence in AIDS patients as well as potential prognostic markers. These findings will improve the management of AIDS with highly active anti-retroviral therapy. PMID- 23434050 TI - Posterior arm flap in management of axillary contracture. AB - INTRODUCTION: Management of post burn contracture can be difficult, particularly for the axilla. Any handicap related to upper limb has a detrimental physical, psycohological, and economical effect. PATIENTS AND METHODS: We have released 20 axillae in 16 patients. These patients had axillary contracture for long duration and 5 had been operated previously by release and skin graft. We used posterior arm fasciocutaneous flaps for coverage of the defect after release of contracture. RESULTS AND CONCLUSION: All the patients had a good post op release. Their range of movement is excellent. No post op splintage was utilised in any of the cases with no incidence of recontracture. PMID- 23434051 TI - Why does the lifetime prevalence of major depressive disorder in the elderly appear to be lower than in younger adults? Results from a national representative sample. AB - BACKGROUND: The explanation of the lower lifetime prevalence rate of major depressive disorder (MDD) in older adults compared to younger people in community surveys is debated. This study examines the hypothesis that the decrease of the lifetime prevalence of MDD in older adults may be due to an age-related difference in the lifetime prevalence of subthreshold hypomania and, to a lesser extent, to the increased rate of medical induced-depression. METHODS: Data were derived from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a national representative sample of 43,093 adults of the United States population. We examined lifetime prevalence rates of pure MDD and MDD plus subthreshold hypomania (D(m)) by age, assuming that the lifetime prevalence of pure MDD in older adults would be similar to that in the youngest cohort, consequent to an inverse age-D(m) relationship. We further considered non hierarchical MDD (i.e., general medical condition depressive disorders were not ruled out) with the same method. RESULTS: The lifetime prevalence of D(m) among depressed adults aged 65 years and over was substantially lower compared to the youngest group. When considering non-hierarchical MDD, the odds ratio of the lifetime prevalence estimates of non-hierarchical pure MDD in older adults compared to the youngest group appeared not significantly different from 1. CONCLUSIONS: Findings indicate that the decrease of lifetime prevalence of MDD in older adults may be due to an age-related difference in the lifetime prevalence of subthreshold hypomania and, to a lesser extent, to the increased rate of medical induced-depression. PMID- 23434052 TI - Active zone protein expression changes at the key stages of cerebellar cortex neurogenesis in the rat. AB - Signal transduction and neurotransmitter release in the vertebrate central nervous system are confined to the structurally complex presynaptic electron dense projections called "active zones." Although the nature of these projections remains a mystery, genetic and biochemical work has provided evidence for the active zone (AZ) associated proteins i.e. Piccolo/Aczonin, Bassoon, RIM1/Unc10, Munc13/Unc13, Liprin-alpha/SYD2/Dliprin and ELKS/CAST/BRP and their specific molecular functions. It still remains unclear, however, what their precise contribution is to the AZ assembly. In our project, we studied in Wistar rats the temporal and spatial distribution of AZ proteins and their colocalization with Synaptophysin in the developing cerebellar cortex at key stages of cerebellum neurogenesis. Our study demonstrated that AZ proteins were already present at the very early stages of cerebellar neurogenesis and exhibited distinct spatial and temporal variations in immunoexpression throughout the course of the study. Colocalization analysis revealed that the colocalization pattern was time dependent and different for each studied protein. The highest collective mean percentage of colocalization (>85%) was observed at postnatal day (PD) 5, followed by PD10 (>83%) and PD15 (>80%). The findings of our study shed light on AZ protein immunoexpression changes during cerebellar cortex neurogenesis and help frame a hypothetical model of AZ assembly. PMID- 23434053 TI - Defibrillation success is not associated with near field electrogram complexity or shock timing. AB - BACKGROUND: It has been suggested that more-complex fibrillation requires higher energy shocks to terminate. Furthermore, animal studies have demonstrated that shock timing also plays a role. The objective of this study was to test these assertions in a clinical context. METHODS: Near- and far-field electrograms were collected during defibrillation threshold testing. Fibrillation complexity was measured by quantifying the organization in the signals with wavelet-based methods, scaling exponent, and cross-correlation analysis. Receiver operator characteristic curves were used to determine predictive value. The effect of the phase at which defibrillation shocks were applied was also determined. RESULTS: No measure was able to classify whether a particular shock would be successful. All performed very poorly. Shock timing played no role in defibrillation outcome. CONCLUSIONS: Signal organization of a local electrogram and phase of shock delivery do not relate to minimum defibrillation shock energy immediately after ventricular fibrillation onset. PMID- 23434054 TI - Frequency of fibroblast growth factor receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome. AB - OBJECTIVES: Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 (FGFR1) amplification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 amplification in OTSCC. MATERIALS AND METHODS: The frequency of FGFR1 amplification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 amplification with clinical characteristics and outcome were determined. RESULTS: FGFR1 gene amplification was present in 9.3% (10/107) of cases and was significantly associated with smoking status (P = 0.03). FGFR1 amplification was seen more commonly in males (9/10 amplified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P>0.05). Outcome was not significantly different between FGFR1 amplified and non-amplified patients. CONCLUSIONS: Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing amplification of the gene. FGFR1 amplification may represent a therapeutic target in OTSCC. PMID- 23434055 TI - Cell cycle-regulatory cyclins and their deregulation in oral cancer. AB - Oral cancer is a growth-related disorder, and cyclins are the prime regulators of cell division. Cyclins are associated with the pathogenesis of oral cancer and are considered valuable biomarkers for diagnosis and prognosis. These important molecules are regulated in many ways to achieve a gain in function and are involved in promoting neoplastic growth. While the causes of most cyclin overexpression are varied, these cyclins may be induced by buccal mucosal insult mainly with carcinogens that alter various pathways propelling oral cancer. Substantial experimental evidences support a link between oncogenic signaling pathways and the deregulation of cyclins in oral cancer. This review focuses on the mechanisms by which cyclins are regulated and promote oral oncogenesis. PMID- 23434056 TI - Breeding and rearing of the two striped cardinalfish, Apogon quadrifasciatus (Cuvier, 1828) in captive condition. AB - The present study describes captive breeding, reproductive behavior and larval/juvenile rearing of Apogon quadrifasciatus. Spawning occurred 25 days after stocking in the breeding tank. Clutch size varied from 2500 to 3100. The males incubated the eggs, the incubation period was approximately five days at a mean temperature of 29 degrees C. The average total length of the newly hatched larvae was 2.6mm with an average mouth gape of 160 MUm. Two experiments were conducted to determine the most suitable food items for the larvae. In the first (planktonic phase, day 1-13) larvae fed with copepod nauplli showed the highest survival (33%). In the second experiment (settlement phase, 14-26 days, copepod, Artemia sp. and Cyclop-Eeze), also showed that copepods were the preferred feed by the post hatching larvae. After 26 days, post hatching larvae were fed a diet that followed a protocol designed in accordance to the mouth size. Culture was maintained up to six months, and juveniles attained a maximum total length of 46.3 mm and a weight of about 3500 mg. Captive breeding and rearing of A. quadrifasciatus can help in restoring the wild populations impacted by local trawling activities as well as to supply this species to the ornamental fish trade, in a sustainable way. PMID- 23434057 TI - Effect of interval between inseminations when using frozen-thawed boar sperm on fertility and fetal paternity in mature gilts. AB - Multiple artificial inseminations (AI) are used in swine to compensate for variation in time of ovulation and following each insemination, a uterine immune response occurs to remove dead and damaged sperm. There are more dead and damaged sperm inseminated with use of frozen-thawed-semen (FTS) and closer insemination intervals are required to compensate for the reduced lifespan of the sperm. Therefore, the objectives of this experiment were to evaluate the effect of interval between inseminations and estrus to ovulation interval (EOI) on fertility and the impact of each AI using fetal paternity in mature gilts when using FTS. Semen from 11 boars was collected and frozen in 0.5mL straws at 1.4*10(9)cells/mL. Time of estrus was synchronized in gilts (n=191) using Matrix((r)) and assigned at estrus to AI treatment: (1) AI at a 4h interval (34 and 38h); (2) AI at an 8h interval (30 and 38h); or (3) AI at a 16h interval (22 and 38h). Ultrasonography was performed to determine time of ovulation. In each treatment, the first and second AI were from unique sires to allow for paternity identification using microsatellite markers. Each sire was represented across first and second inseminations. Gilts received an AI with 2*10(9) motile FTS in 80mL of extender. Pregnancy rate and litter size were assessed at slaughter on Day 33 following AI. Interval between inseminations affected pregnancy rate (P<0.01) with AI intervals of 8 (80%) and 16h (75%) greater than the 4h interval (55%). The EOI also affected pregnancy rate (P<0.001) with increased pregnancy rate for gilts having ovulations by 36h (85%) compared to those having ovulations by 24 (55%) and 60h (47%) but did not differ from those having ovulations at 48h (74%). Total fetuses (10.7), number of normal fetuses (10.2) and embryo survival (70.4%) were not affected by interval between inseminations or EOI (P>0.05). There was an interaction of treatment with EOI (P<0.05). Gilts inseminated at 8 or 16h intervals and with 36 or 48h EOI showed changes (P<0.05) in the proportion of offspring sired by the second AI while gilts inseminated at a 4h interval did not. The results of this study indicate that intervals between inseminations and time of ovulation each affects pregnancy rates but not litter size, but interacts to affect the proportion of offspring sired by the second insemination. This study suggests no detrimental effect of reduced amount of time between inseminations on the fertility of sperm used in a second insemination. For practical application, in a twice daily estrous detection and double AI, the greatest pregnancy rates occur when inseminations are spaced at 8 or 16h intervals to compensate for variation in ovulation. PMID- 23434058 TI - Methotrexate: new therapeutic approaches. AB - Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab. PMID- 23434059 TI - The role of simulation in surgical skills training in gynaecological endoscopy. AB - Minimal-access surgery has revolutionised diagnosis and management in many surgical specialties, including gynaecology. It is well known that the surgical skill set required to carry out endoscopic surgery is essentially different from open surgery, creating a longer learning curve. Fewer opportunities exist for trainees as a result of reduced working hours and also the use of less invasive procedures, such as endometrial ablation procedures, Mirena((r)) intrauterine system, and methotrexate in treating ectopic pregnancies. Significant work has been undertaken to introduce simulation to enhance laparoscopic training and to test the construct validity and face validity of different simulators. In this chapter, we summarise the evidence on simulation training in minimal-access gynaecology, and provide practical recommendations to develop an evidence-based simulation-training curriculum. PMID- 23434060 TI - Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. AB - Monocytes and macrophages are important effectors and regulators of inflammation, and both can be divided into distinct subsets based on their phenotypes. The developmental and functional relationship between individual subsets of monocytes and those of macrophages has not been fully elucidated, although Ly6C(+)CCR2(+) inflammatory and Ly6C(-)CCR2(-) resident monocytes are generally thought to differentiate into M1 (classically activated) and M2 (alternatively activated) macrophages, respectively. Here we show that inflammatory monocytes recruited to allergic skin acquired an M2-like phenotype in response to basophil-derived interleukin-4 (IL-4) and exerted an anti-inflammatory function. CCR2-deficient mice unexpectedly displayed an exacerbation rather than alleviation of allergic inflammation, in spite of impaired recruitment of inflammatory monocytes to skin lesions. Adoptive transfer of inflammatory monocytes from wild-type but not IL-4 receptor-deficient mice dampened the exacerbated inflammation in CCR2-deficient mice. Thus, inflammatory monocytes can be converted from being proinflammatory to anti-inflammatory under the influence of basophils in allergic reactions. PMID- 23434061 TI - Phosphate balance in continuous venovenous hemofiltration. PMID- 23434062 TI - Inpatient health care utilization in the United States among children, adolescents, and young adults with nephrotic syndrome. AB - BACKGROUND: Data describing inpatient health care utilization in children with nephrotic syndrome and related severe complications are limited. Our goals were to describe the charges, length of stay (LOS), and number of hospitalizations among children, adolescents, and young adults with nephrotic syndrome. STUDY DESIGN: A cross-sectional analysis of the Kids' Inpatient Database (KID) database from the Healthcare Cost and Utilization Project (HCUP). The HCUP-KID is an all payer database of hospital discharges for children, adolescents, and young adults in the United States compiled every 3 years by the Agency for Healthcare Research and Quality. SETTING & PARTICIPANTS: HCUP-KID data were obtained for the 2006 and 2009 cohort years. We identified patients by searching discharges for nephrotic syndrome International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. PREDICTOR: Patient demographics, disease complications in children, adolescents, and young adults hospitalized with nephrotic syndrome. OUTCOME: Number of hospitalizations, mean charges, and LOS for children, adolescents, and young adults hospitalized with nephrotic syndrome. RESULTS: There were 6,308 hospitalization discharges in children, adolescents, and young adults with a primary or secondary diagnosis of nephrotic syndrome reported by 38 and 44 states in 2006 and 2009, respectively, representing an estimated 9,934 discharges nationally. Nephrotic syndrome resulted in an estimated 48,700 inpatient days and charges totaling $259 million. The mean charge per hospitalization was ~$26,500 (SE, $1,100) and LOS was 5 days (SE, 0.1). 16% of discharges for nephrotic syndrome had a diagnosis code for at least one severe complication, including thromboembolism (3.6%), septicemia (3.8%), peritonitis (2.6%), pneumonia (5.4%), or diabetes (2.4%). Multivariable analysis showed age 15 years or older, race, higher socioeconomic status, acute renal failure, thromboembolic disease, hypertension, and infections predicted higher mean hospitalization charges. LIMITATIONS: The HCUP-KID database collects data on a hospitalization level. Consequently, health care utilization on an individual patient level or in the outpatient environment is not possible. CONCLUSIONS: We present a comprehensive description of inpatient health care utilization in children, adolescents, and young adults with nephrotic syndrome. The complications of nephrotic syndrome, including thromboembolism, infection, and hypertension, contribute significantly to these charges. PMID- 23434063 TI - Unbalanced neuronal circuits in addiction. AB - Through sequential waves of drug-induced neurochemical stimulation, addiction co opts the brain's neuronal circuits that mediate reward, motivation to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it. PMID- 23434064 TI - Neuroimmune signaling: a key component of alcohol abuse. AB - Molecular and behavioral studies corroborate a pivotal role for the innate immune system in mediating the acute and chronic effects of alcohol and support a neuroimmune hypothesis of alcohol addiction. Changes in expression of neuroimmune genes and microglial transcripts occur in postmortem brain from alcoholics and animals exposed to alcohol, and null mutant animals lacking certain innate immune genes show decreased alcohol-mediated responses. Many of the differentially expressed genes are part of the toll like receptor (TLR) signaling pathway and culminate in an increased expression of pro-inflammatory immune genes. Compounds known to inhibit inflammation, microglial activation, and neuroimmune gene expression have shown promising results in reducing alcohol-mediated behaviors in animal models, indicating that neuroimmune signaling pathways offer unexplored targets in the treatment of alcohol abuse. PMID- 23434065 TI - A study to compare circulating flunixin, meloxicam and gabapentin concentrations with prostaglandin E2 levels in calves undergoing dehorning. AB - The purpose of this study was to investigate the pharmacokinetics of intravenous flunixin (2.2 mg/kg b.w.), oral meloxicam (1mg/kg b.w.), oral gabapentin (15 mg/kg b.w.) alone or co-administrated with meloxicam as well as the effects of these compounds on prostaglandin E2 (PGE2) synthesis in calves subjected to surgical dehorning. Plasma samples collected up to 24h after drug administration were analyzed by liquid chromatography/mass spectrometry, whereas blood PGE2 levels were measured by immunoenzymatic assay. In plasma, the terminal half-live of flunixin, meloxicam and gabapentin were 6.0 h (range, 3.4-11.0 h), 16.7h (range, 13.7-21.3h) and 15.3h (range, 11-32.9h), respectively. The co administration of single doses of gabapentin and meloxicam did not seem to affect the pharmacokinetic profile of the two drugs except for gabapentin that reached significantly (P<0.05) higher maximum serum concentration (Cmax) when co administered with meloxicam, than when administered alone. At 5, 360 and 720 min after dehorning, a significant (P<0.01) decrease in PGE2 concentration was observed in flunixin-treated animals compared with control calves. Moreover, circulating log PGE2 concentrations were inversely proportional to log flunixin concentrations (R(2)=0.75; P<0.0001). None of the other drugs significantly affected blood PGE2 levels. Further assessment of oral meloxicam and gabapentin in established pain models is required to formulate science based analgesic recommendations to enhance animal well-being after dehorning. PMID- 23434066 TI - Pharmacokinetics of marbofloxacin in rabbit after intravenous, intramuscular, and subcutaneous administration. AB - The disposition kinetics of marbofloxacin, a fluoroquinolone antibiotic, after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration was determined in rabbits at a single dose of 2 mg/kg. Plasma concentrations of marbofloxacin were determined by high performance liquid chromatography with fluorescence detection. The concentration-time data were analysed by compartmental and non-compartmental pharmacokinetic methods. Steady-state volume of distribution (V(ss)) and clearance (Cl) of marbofloxacin after i.v. administration were 1.99+/-0.27 L/kg and 0.42+/-0.04 L/h kg, respectively. Following i.m. and s.c. administration marbofloxacin achieved maximum plasma concentrations of 2.04+/-0.32 and 1.64+/-0.15 mg/L at 0.33+/-0.16 and 0.50+/-0.18 h, respectively. The absolute bioavailabilities after i.m. and s.c. routes were 123.30+/-17.64% and 114.81+/-12.11%, respectively. From these data (kinetic parameters and absence of adverse reactions) marbofloxacin is likely to be effective in rabbits. PMID- 23434067 TI - Chromatin-tethered MAPKs. AB - Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that are essential nodes in many cellular regulatory circuits including those that take place on DNA. Most members of the four MAPK subgroups that exist in canonical three kinase cascades-extracellular signal-regulated kinases 1 and 2 (ERK1/2), ERK5, c-Jun N-terminal kinases (JNK1-3), and p38 (alpha, beta, gamma, and delta) families-have been shown to perform regulatory functions on chromatin. This review offers a brief update on the variety of processes that involve MAPKs and available mechanisms garnered in the last two years. PMID- 23434068 TI - Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. AB - Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal epithelial transition (MET), are essential during development and in the regulation of stem cell pluripotency, yet these processes are also activated in pathological contexts, such as in fibrosis and cancer progression. In EMT and MET, diverse signaling pathways cooperate in the initiation and progression of the EMT and MET programs, through regulation at transcriptional, post transcriptional, translational, and post-translational levels. MicroRNAs recently emerged as potent regulators of EMT and MET, with their abilities to target multiple components involved in epithelial integrity or mesenchymal traits. By affecting EMT and MET processes, microRNAs are involved in the regulation of stem cell pluripotency and the control of tumor progression. PMID- 23434069 TI - Control of the epithelial stem cell epigenome: the shaping of epithelial stem cell identity. AB - The squamous epithelium covering the skin and oral mucosa relies on epithelial stem cells for tissue renewal. Dynamic changes in DNA methylation, histone methylation and acetylation, and higher order chromatin structure are required to preserve their self-renewal capacity while orchestrating the timely execution of cell differentiation programs. This complex network of epigenetic modifications shapes the epithelial stem cell identity and fate. Pathological alterations can be perceived by aberrant chromatin sensors, such as the INK4/ARF locus, which initiate tumor suppressive cell senescence programs, and can often result in epithelial stem cell exhaustion. Unveiling the mechanisms controlling the epigenome in epithelial stem cells may help protect against the loss of their tissue regenerative capacity, thereby preventing premature aging without increasing cancer risk. PMID- 23434070 TI - Infantile facioscapulohumeral muscular dystrophy revisited: Expansion of clinical phenotypes in patients with a very short EcoRI fragment. AB - Contrary to the classical form, infantile facioscapulohumeral muscular dystrophy (FSHD) usually denotes a severe phenotype and is frequently associated with extramuscular involvements. To elucidate the genotype-phenotype correlation in this severe subgroup, we identified a cohort of nine patients with infantile FSHD who also carried a very short (10-13kb) EcoRI fragment. Their current age ranged from 8 to 33 years and age of onset ranged from 0.4 to 5 years. One patient even manifested his first FSHD-related symptoms at as early as 5 months of age, including inability to smile, poor response to call, and infantile spasms. To date, four patients were wheelchair-bound and six patients had asymmetric weakness. Sensorineural hearing loss and abnormal fundoscopic findings were observed in eight and all of patients respectively. Three with the smallest EcoRI fragments (10-11kb, with normal length being 50-300kb) had mental retardation. Two of these had epilepsy. Cardiac arrhythmias were found in five patients. Restrictive ventilatory defects were observed in seven patients, with one progressing to chronic respiratory failure. Two had swallowing difficulties; one of these required gastrostomy. We identified several rarely reported phenotypes in infantile FSHD, including cardiac arrhythmia, respiratory insufficiency, and swallowing difficulties. There seems to be a correlation between the severity of phenotype and the very short EcoRI fragment in the chromosome 4q35 region. We conclude that the high frequency of multi-organ involvements in this severe FSHD variant suggests the need for an early and multidisciplinary intervention. PMID- 23434072 TI - Effect of inhibition of the FGFR-MAPK signaling pathway on the development of ocular toxicities. AB - By the introduction of molecularly targeted anti-cancer drugs, that are designed to intervene with specific pathways aberrant in cancers with distinct mutations, the type of adverse events encountered has changed greatly compared to the adverse events profile of classical chemotherapeutic agents. Ocular toxicities, such as serous retinal detachment and retinal vein occlusion, are observed in the treatment with several protein kinase inhibitors, such as MEK inhibitors. This review discusses the pathophysiology, diagnosis and advice for clinical management of these toxicities, and focuses on the current understanding of the underlying molecular mechanisms. Some ocular toxicities can be considered a class effect and a direct result of intervening with the MAPK pathway. Effective recording and monitoring will contribute to increased understanding of the prevalence and of adequate management of these ocular toxicities, but further research is warranted to elucidate the exact underlying mechanisms and to optimize treatment of these undesirable toxicities. PMID- 23434071 TI - [Co-authorship and Spanish pediatric scientific collaboration networks (2006 2010)]. AB - INTRODUCTION: Scientific collaboration is very important, as it is the basis of the scientific development of every discipline. The aim of this paper is to identify the indicators of scientific collaboration and co-authorship networks of Spanish researchers and institutions publishing in national and international paediatric, multidisciplinary or other knowledge areas journals during the period 2006-2010. METHODS: The papers studied were obtained from the databases including, Science Citation Index Expanded, Scopus, Indice Medico Espanol and Indice Bibliografico Espanol en Ciencias de la Salud, by means of applying different search profiles. All the papers signed by co-authors were quantified in order to identify the authorship and institutional collaboration networks. Furthermore the degree, betweenness index, and closeness index were obtained as a measurement of the structural analysis. Co-authorships were represented graphically by the network analysis and display software Pajek. RESULTS: A total of 7971 articles were published during the period 2006-2010, with 90.55% completed in collaboration. Using a threshold of 10 or more co-authorships, 77 research groups in Pediatrics were identified. Most papers were published in collaboration between institutions of the same Autonomous Community (42.28%), and 14.84% with international collaboration. The analysis of institutional participation enabled a large nucleus or institutional collaboration network to be identified, with 52 linked institutions. International collaboration was led by the USA and European countries, such as United Kingdom, Germany and Italy. DISCUSSION: Authors, institutions and the most active working groups in Spanish pediatrics were identified, which is very interesting information to establish contacts to increase the existing networks, to prevent redundancies, and to take advantage of the new emerging groups. It is necessary to promote the collaboration of Spanish researchers, especially with their international colleagues, since a positive relationship is found between international collaboration and quality and impact of publications measured by citation analysis. PMID- 23434073 TI - Revisiting ovarian cancer preclinical models: implications for a better management of the disease. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite progress in identifying "hallmark" genetic alterations associated with the main subtypes of epithelial ovarian cancer, the survival rate of women with EOC changed little since platinum-based treatment was introduced more than 30years ago. The successful identification of new, effective anticancer drugs largely depends on appropriate preclinical experimental models that should ideally mimic the complexity of different cancer forms. This review examines the preclinical ovarian cancer models available for a better understanding of the biological mechanisms of the development, progression, invasion and metastasis of EOC. We provide evidence that the preclinical models have been instrumental for a better understanding of the pathological events at the basis of ovarian carcinoma. The genetically engineered mouse (GEM) models of ovarian cancer have overcome some of the weaknesses of the xenograft models, such as the fact that these tumors arise orthotopically in immunologically intact mice and more closely resemble the behavior of human cancers. We envisage that in the near future these GEM models will play a key role in pre-selecting drug regimens with the greatest promise of efficacy in human clinical trials, making it easier and certainly less expensive to test new, different drug combinations. PMID- 23434074 TI - HER2-targeted therapy in breast cancer: a systematic review of neoadjuvant trials. AB - Targeting human epidermal growth factor receptor 2 (HER2) during or in sequence with chemotherapy improves overall survival in metastatic and early HER2 overexpressing breast cancer. In this paper we systematically review neoadjuvant clinical trial data in HER2-positive breast cancer and discuss key unanswered clinical questions. All trials of HER2-targeted neoadjuvant therapy were identified through non-date-limited searches of PubMED(r) and Biosis(r) and congress abstract book searches from 2000-2011. Eligible trials were prospective, had at least 10 patients and a clear definition of pathological complete response (pCR) rate. A total of 50 trials fulfilled the eligibility criteria; 41 single arm phase II studies were identified, 37 with trastuzumab and 4 with lapatinib, with significant variability in baseline tumour characteristics and pCR rates (range 12-66.7%). Of 9 randomised phase II/III trials, 4 assessed the addition of trastuzumab to chemotherapy and a further 5 randomised trials assessed different HER2-targeting approaches. Four of these studies assessed dual HER2-targeting approaches, which universally increased pCR at the expense of increased non cardiac toxicity when lapatinib, but not pertuzumab, was added to trastuzumab. Significant advances have been made in HER2 targeting, resulting in a marked increase in the number of breast cancer patients experiencing tumour pCR. Mature data from randomised neoadjuvant and adjuvant studies are awaited for survival outcomes with combination targeted approaches. Unanswered questions centre on the individualisation of therapy and include; which, if any, chemotherapy backbone should be used, and which patients need dual HER2 blockade? PMID- 23434075 TI - Exercise & Sports Science Australia (ESSA) position statement on exercise and chronic kidney disease. AB - OBJECTIVES: Chronic kidney disease (CKD) is prevalent, affecting 13% of adult Australians and poses increased risk for cardiovascular morbidity and mortality. This position article provides evidence-based guidelines on the role of exercise training for CKD patients and provides recommendations for prescribing and delivering exercise training. DESIGN: Position stand. METHODS: Synthesis of published work within the field of exercise training and chronic kidney disease. RESULTS: Exercise training likely to provide benefits to CKD patients, including improvements in cardio-respiratory fitness, quality of life, sympatho-adrenal activity, muscle strength and increased energy intake and possible reduction in inflammatory biomarkers. Existing studies generally report small sample sizes, brief training periods and relatively high attrition rates. Exercise training appears to be safe for CKD patients with no deaths directly related to exercise training in over 30,000 patient-hours, although strict medical exclusion criteria in previous studies resulted in 25% of patients being excluded potentially impacting the generalisability of the findings. CONCLUSIONS: Aerobic exercise at an intensity of >60% of maximum capacity is recommended to improve cardio respiratory fitness. Few data are available on resistance training and it is unclear whether this form of training retards catabolic/inflammatory processes typical of CKD. However, it should be considered important due to its proven beneficial effects on bone density and muscle mass. Due to the high prevalence and incidence of co-morbidities in CKD patients, exercise training programs should be prescribed and delivered by individuals with appropriate qualifications and experience to recognise and accommodate co-morbidities and associated complications. PMID- 23434076 TI - Adsorption and desorption behavior of selected pesticides as influenced by decomposition of maize mulch. AB - Assessing pesticide fate in conservation agricultural systems requires a detailed understanding of their interaction with decomposing surface crop residues (mulch). Adsorption and desorption behavior of glyphosate, s-metolachlor and epoxiconazole was investigated on maize mulch residues decomposed under laboratory and field conditions. Our conceptual approach included characterization of chemical composition and hydrophobicity of mulch residues in order to generate parameters to predict sorption behavior. Adsorption of s metolachlor and epoxiconazole greatly increased with mulch decomposition, whereas glyphosate adsorption was less affected but its desorption was increased. Mulch characteristics including aromaticity, hydrophobicity and polarity indices were strongly correlated to Koc of the non-ionic pesticides. A predictive model based on compositional data (CoDa) analysis revealed that the sorption capacity of decomposing mulch can be predicted from descriptors such as aromatic and alkyl C corresponding respectively to lignin and NDF biochemical fractions. The decomposition degree of mulch residues should be taken into account while predicting the fate of pesticides. PMID- 23434077 TI - Characterizing the release of cadmium from 13 purple soils by batch leaching tests. AB - Cadmium (Cd), through human activities, has severely accumulated in purple soil. Purple soil is considered as one of the most important types of agricultural soil in Southern China. In this study, we investigated the release of Cd from 13 purple soils with a wide range of total Cd content collected from vegetable fields and forestlands in Sichuan Basin. Soil batch extraction and column leaching experiments were conducted to determine the influence of chemical speciation, soil properties, soil water contact time, and soil/water ratio on the release characteristics of Cd from soil. Results indicate that Cd release was primarily present in exchangeable, carbonate-bound, and organically bound fractions. Moreover, precipitation-induced, long-term saturated conditions enhance the release of Cd from soil to water. Multiple regression analysis also shows that the release of Cd from soil is related to pH level, organic matter amount, and total Cd content in native soil. This finding explains the Cd release variation of 86% and 95% during batch extraction and column leaching experiments, respectively. Finally, this investigation provides a more convenient way of evaluating potential ecological risks of Cd in purple soil by determining the properties of several common soil types. PMID- 23434078 TI - The role of plant metabolism in the mutagenic and cytotoxic effects of four organophosphorus insecticides in Salmonella typhimurium and in human cell lines. AB - This study used a cell/microbe co-incubation assay to evaluate the effect of four organophosphorus insecticides (parathion-methyl, azinphos-methyl, omethoate, and methamidophos) metabolized by coriander (Coriandrum sativum). The reverse mutation of Salmonella typhimurium strains TA98 and TA100 was used as an indicator of genetic damage. Treatments with these insecticides inhibited peroxidase activity in plant cells by between 17% (omethoate) and 98% (azinphos methyl) and decreased plant protein content by between 36% (omethoate) and 99.6% (azinphos-methyl). Azinphos-methyl was the most toxic when applied directly. In the Ames test, treatments applied directly to strain TA100 killed the bacteria; however, the presence of plant metabolism detoxified the system and permitted the growth of bacteria. In strain TA98, plant metabolites of insecticides were mutagenic. This result suggests that the tested pesticides produce mutations through frameshifting. The same pesticides were applied to human skin (HaCaT) and lung (NL-20) cell lines to evaluate their effects on cell viability. Pesticides applied directly were more cytotoxic than the combination of pesticide plus coriander metabolic fraction. Omethoate and methamidophos did not affect the viability of HaCaT cells, but azinphos-methyl and parathion-methyl at 100 and 1000MUgmL(-1) significantly decreased viability (p<0.05). The NL-20 cell line was remarkably sensitive to the direct application of insecticides. All of the treatment conditions caused decreases in NL-20 cell viability (e.g., viability decreased to 12.0% after parathion-methyl treatment, to 14.7% after azinphos methyl treatment, and to 6.9% after omethoate treatment). Similar to the Ames test, all of the insecticides showed decreased toxicity in human cells when they were cultured in the presence of plant metabolism. In conclusion, when the studied organophosphorus insecticides were plant-metabolized, they induced mutations in the bacterial strain TA98. In human cell lines, plant metabolism reduced the cytotoxic properties of the insecticides, and human keratinocytes were more resistant to mortality than bronchial cells. PMID- 23434079 TI - Seasonal and spatial distributions and possible sources of polychlorinated biphenyls in surface sediments of Yangtze Estuary, China. AB - The surface sediment samples taken from 30 sites of the Yangtze Estuary in both the flood and dry seasons were analyzed to reveal the spatial and seasonal distributions of polychlorinated biphenyls (PCBs). Samples collected in the flood season showed higher PCB concentrations, larger PCB fluctuations and higher portions of large grain sediments in the inner estuary area compared with those collected in the dry season, indicating significant seasonal variations of PCBs. The effects of the physicochemical characteristics (TOC and grain size) of surface sediments on the distributions of PCBs were also investigated. Masked by various other factors, the TOC contents and sediment grain sizes did not exhibit a strong influence on the distributions of PCBs. Analysis of the PCB homolog and congener distribution patterns revealed a predominant proportion of light PCBs with 2-3 chlorines. According to the PCB homolog profiles and principal component analysis (PCA) of source contributions, non-point sources including atmospheric deposition and surface runoff associated with stormwater were suggested to be the major sources of PCBs in the surface sediments of the Yangtze Estuary. PMID- 23434080 TI - [Fecal calprotectin in the diagnosis of inflammatory bowel diseases]. AB - The diagnosis of inflammatory bowel diseases has classically been based on assessment of digestive symptoms. The development of these symptoms usually results in colonoscopy, which has a low diagnostic yield. Likewise, there is an increasing tendency to base treatment of inflammatory bowel disease on objective data, since the disappearance of signs of activity on colonoscopy (called " mucosal cure ") has been associated with sustained clinical remission and reduced rates of hospitalization and surgery. Consequently, there is a need for biomarkers that would aid the selection of those patients who would derive most benefit from an endoscopic examination. One substance that has been proposed as a biomarker of bowel inflammation is fecal calprotectin. This substance allows inflammatory bowel disease to be distinguished from irritable bowel syndrome and shows a better correlation with the degree of inflammation than clinical indicators and serological markers. In addition, it could also be useful to predict mucosal cure and the risk of recurrence. PMID- 23434081 TI - The combination effects of acetaminophen and N-acetylcysteine on cytokines production and NF-kappaB activation of lipopolysaccharide-challenged piglet mononuclear phagocytes in vitro and in vivo. AB - Lipopolysaccharide (LPS) is a known activator of mononuclear phagocytes. LPS activates the pro-inflammatory gene expression and induces the release of mediators/cytokines by TLR4-NF-kappaB signaling pathway. The purpose of this study was to investigate the effects of acetaminophen (AAP) and N-acetylcysteine (NAC), individually as well as in combination on LPS-induced cytokines production and NF-kappaB activation in piglets. AAP (0.125-1.0mM) and NAC (0.0625-1.0mM) down-regulate the expression of cytokines and inhibit NF-kappaB p65 protein transfer from the cytoplasm to the nucleus in vitro. NAC enhances the inhibition action of AAP on cytokines expression in vitro. IL-6 in piglet plasma of the AAP group (mixed feed concentration of 600 mg/kg) was significantly reduced (P<0.05) at 3h after LPS-challenge as compared with the LPS control group. IL-10 also significantly reduced (P<0.05) at 24h after LPS injection. The levels of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-10) in piglet plasma of the NAC group (mixed feeding concentration of 1200 mg/kg) were significantly lower at 3h after LPS stimulation (P<0.05). IL-10 was significantly decreased in the NAC group at 24h after LPS stimulation (P<0.05). AAP or NAC treated alone could reduce the NF-kappaB p65 concentration ratio. The levels of cytokines (TNF alpha, IL-1beta, IL-6, and IL-10) in the group with piglet plasma of AAP (mixed feed concentration of 600 mg/kg) plus NAC (mixed feeding concentration of 1200 mg/kg) group were significantly lower (P<0.05) at 3h after LPS activation. The level of IL-10 in the group with AAP plus NAC was significantly lower (P<0.05) at 24h after LPS stimulation, while the rest of the inflammatory cytokines were returned to the original levels. The NF-kappaB p65 concentration ratio had significantly reduced (P<0.05) when AAP and NAC were used in combination. In summary, NAC could enhance the anti-inflammatory effects of AAP both in vitro and in vivo. PMID- 23434082 TI - Facile preparation of organic-silica hybrid monolith for capillary hydrophilic liquid chromatography based on "thiol-ene" click chemistry. AB - In this work, a one-step approach to facile preparation of organic-inorganic hybrid monoliths was successfully developed. After vinyl-end organic monomers and azobisisobutyronitrile (AIBN) were mixed with hydrolyzed tetramethoxysilane (TMOS) and 3-mercaptopropyltrimethoxysilane (MPTMS), the homogeneous mixture was introduced into a fused-silica capillary for simultaneous polycondensation and "thiol-ene" click reaction to form the organic-silica hybrid monoliths. By employing this strategy, two types of organic-silica hybrid monoliths with positively charged quaternary ammonium and amide groups were prepared, respectively. The functional groups were successfully introduced onto the monoliths during the sol-gel process with "thiol-ene" click reaction, which was demonstrated by zeta-potential assessment, energy dispersive X-ray spectroscopy (EDX), and Fourier transform infrared (FT-IR) spectroscopy. The porous structure of the prepared monolithic columns was examined by scanning electron microscopy (SEM), nitrogen adsorption-desorption measurement, and mercury intrusion porosimetry. These results indicate the prepared organic-silica hybrid monoliths possess homogeneous column bed, large specific surface area, good mechanical stability, and excellent permeability. The prepared monolithic columns were then applied for anion-exchange/hydrophilic interaction liquid chromatography. Different types of analytes, including benzoic acids, inorganic ions, nucleosides, and nucleotides, were well separated with high column efficiency around 80,000-130,000 plates/m. Taken together, we present a facile and universal strategy to prepare organic-silica hybrid monoliths with a variety of organic monomers using one-step approach. PMID- 23434083 TI - An ion-pair principle for enantioseparations of basic analytes by nonaqueous capillary electrophoresis using the di-n-butyl L-tartrate-boric acid complex as chiral selector. AB - A chiral recognition mechanism of ion-pair principle has been proposed in this study. It rationalized the enantioseparations of some basic analytes using the complex of di-n-butyl l-tartrate and boric acid as the chiral selector in methanolic background electrolytes (BGEs) by nonaqueous capillary electrophoresis (NACE). An approach of mass spectrometer (MS) directly confirmed that triethylamine promoted the formation of negatively charged di-n-butyl l-tartrate boric acid complex chiral counter ion with a complex ratio of 2:1. And the negatively charged counter ion was the real chiral selector in the ion-pair principle enantioseparations. It was assumed that triethylamine should play its role by adjusting the apparent acidity (pH*) of the running buffer to a higher value. Consequently, the effects of various basic electrolytes including inorganic and organic ones on the enantioseparations in NACE were investigated. The results showed that most of the basic electrolytes tested were favorable for the enantioseparations of basic analytes using di-n-butyl l-tartrate-boric acid complex as the chiral ion-pair selector. PMID- 23434084 TI - Quality of life and clinical symptom improvement support prostatic artery embolization for patients with acute urinary retention caused by benign prostatic hyperplasia. AB - PURPOSE: To show that prostatic artery embolization (PAE) improves quality of life (QoL) and lower urinary tract symptoms in patients with acute urinary retention caused by benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: This was a single-center prospective study of PAE in 11 patients with BPH managed with indwelling urinary catheters. International Prostate Symptom Score (IPSS), ultrasound, magnetic resonance (MR) imaging, QoL, and urodynamic tests were used to assess outcomes. Prostate size ranged from 30 to 90 g, and embolizations were performed with 300-500-MUm Embosphere microspheres. RESULTS: The rate of technical success (ie, bilateral PAE) was 75%, and the rate of clinical success (ie, catheter removal and symptom improvement) was 91% (10 of 11 patients). Postembolization syndrome manifested as mild pain in the perineum, retropubic area, and/or urethra. Ten of 11 patients urinated spontaneously after Foley catheter removal 4-25 days after PAE (mean, 12.1 d). No major complications were observed. Follow-up ranged from 19 to 48 months. In an asymptomatic patient, a discrete area of hypoperfusion suggesting small ischemia of the bladder was observed on 30-day MR imaging follow-up, but the bladder was normal on 90-day MR imaging. After 1 year, mean prostate volume reduction was greater than 30%, symptoms were mild (mean IPSS, 2.8 +/- 2.1; P = .04), no erectile dysfunction was observed, and QoL improved significantly (mean, 0.4 +/- 0.5; P = .001) using the paired t test. CONCLUSIONS: Patients with severe symptoms and acute urinary retention caused by BPH can be treated safely by PAE, which improves clinical symptoms and QoL. PMID- 23434085 TI - Balloon-assisted deep intubation of guide catheter for direct thromboaspiration in acute myocardial infarction--a technical report. PMID- 23434086 TI - Levels of vitamin D and its effects on bone metabolism and cardiovascular system should be assessed after isolation of confounding factors. PMID- 23434087 TI - Causative pathogens, antibiotic sensitivity, resistance patterns, and severity in a contemporary series of Fournier's gangrene. AB - OBJECTIVE: To identify the causative pathogens and evaluate the antibiotic sensitivity, resistance patterns, and virulence in a contemporary series of patients with Fournier's gangrene. MATERIALS AND METHODS: The medical records of 41 consecutive cases of Fournier's gangrene were evaluated. The patient demographics, causative pathogens, antibiotic sensitivity, and resistance patterns were assessed. The Fournier's gangrene severity index and length of stay were analyzed statistically to determine any differences by causative pathogen. RESULTS: A total of 122 pathogens were cultured. The wound cultures were polymicrobial for 34 patients (83%). Most common pathogens cultured were Bacteroides sp (43.9%), Escherichia coli (36.6%), and Prevotella sp (34.1%). E coli was resistant to fluoroquinolones and trimethoprim/sulfamethoxazole in 13.3%, and 40% of isolates respectively. The wound cultures were monomicrobial for 7 patients (17.0%). A monomicrobial isolate of methicillin-resistant Staphylococcus aureus was cultured that was susceptible to clindamycin and trimethoprim/sulfamethoxazole. Resistance to ampicillin-sulbactam was seen in Providencia sp, Klebsiella sp, E coli, and methicillin-resistant S aureus. Resistance to ceftriaxone and gentamicin was seen in methicillin-resistant S aureus and E coli, respectively. No resistance to clindamycin was demonstrated. No statistically significant difference was detected between the Fournier's gangrene severity index or length of stay and the causative pathogens. CONCLUSION: Fournier's gangrene remains a community-acquired polymicrobial infection, with anaerobic bacteria as the most common causative pathogens. Candida and methicillin-resistant S aureus are emerging causative pathogens, but methicillin-resistant S aureus remains sensitive to clindamycin and trimethoprim/sulfamethoxazole. Although resistance was demonstrated by some causative pathogens, together, the currently recommended broad-spectrum antibiotics adequately covered all pathogens. Coverage with agents such as fluconazole, vancomycin, or piperacillin-tazobactam is indicated in patients at risk of fungal or hospital-acquired organisms. PMID- 23434088 TI - Editorial comment. PMID- 23434090 TI - Editorial comment. PMID- 23434092 TI - Three-dimensional structure of a parameatal urethral cyst by scanning electron microscopy. AB - We report scanning electron microscopy (SEM) for a case of parameatal urethral cyst. A 6-year-old Japanese boy presented with a cyst on the right lateral side of the urethral meatus. Histological examination revealed a cyst lined with columnar epithelium. An immunohistochemical study showed positive staining for CK7, CK13, and CEA, and negative for CK20 in luminal cells. On SEM examination, the inner surface of the cyst showed ridges arranged in a gyrus-like manner at lower magnification. Higher magnification revealed luminal cells with short microvillus projections. Some cells showed apocrine, merocrine, and possibly holocrine-type secretions. PMID- 23434093 TI - Hemostatic effect of new surgical glue in animal partial nephrectomy models. AB - OBJECTIVE: To evaluate the hemostatic effect of newly developed medical adhesive in animal partial nephrectomy models. MATERIALS AND METHODS: A total of 30 experimental rabbits were used in the first study. After clamping the renal vessels, partial nephrectomy was performed up to the opening of the calices. Bioglue was applied to the resection stumps using the new glue (group 1, n = 10) or fibrin glue (group 2, n = 10) for 2 minutes, and the blood loss was measured after unclamping the vessels. Simple unclamping without glue (group 3, n = 10) was also evaluated. For the second study, we used 9 dogs with blood pressure monitoring. After preparation similar to that for the first study, the new glue was applied in 3 dogs (group 4), fibrin glue in 3 dogs (group 5) and no glue in 3 dogs (group 6). Histologic evaluation was performed at 7 days and 1 month after surgery. RESULTS: The mean blood loss was significantly less in group 1 (1.45 g) than in groups 2 (6.59 g) and 3 (19.77 g; P <.001 for both). It was also significantly less in group 4 (12.5 g) than in group 5 (182.5 g; P <.001). Group 4 maintained their initial blood pressure throughout the study, but a significant decrease was observed in group 5. No hematoma was observed at day 7. CONCLUSION: The new glue showed acceptable hemostasis when applied to the resection stumps after partial nephrectomy in both the rabbit and the dog models. These findings indicate that it could be useful for hemostasis after partial nephrectomy. PMID- 23434095 TI - Molecular mechanisms of urolithiasis. PMID- 23434096 TI - The impact of ventral oral graft bulbar urethroplasty on sexual life. AB - OBJECTIVE: To evaluate the pre- and postoperative aspects of sexual life (SL) in patients with bulbar urethral stricture who underwent ventral oral graft urethroplasty. METHODS: Between 2009 and 2010, 52 men (mean age 36 years) were enrolled in our prospective study to ascertain sexual disorders before and after surgery. The validated Male Sexual Health Questionnaire-Long Form (MSHQ-LF) was completed pre- and postoperatively; the unvalidated but adapted Post Urethroplasty Sexual Questionnaire (PUSQ) was completed postoperatively. Data were compared using the non parametric Wilcoxon test. RESULTS: Before urethroplasty, most of the patients reported sexual disorders, in particular reduced ejaculatory stream (85%); many of them (35%) feared the risk of a postoperative worsening in the quality of SL. After urethroplasty, nobody reported a worsened erection, while most of the patients noticed a significant improvement in erection, ejaculation, relationship with their partner, sexual activity, and desire. Modifications in the scrotoperineal sensitivity were reported by 42% and 15% noticed esthetic changes without impact on SL. All patients reported an improvement in quality of life (QOL) and were satisfied with the outcome of urethroplasty. CONCLUSION: Urethral stricture disease may be responsible for sexual disorders that have a significant impact upon SL. Patients confessed a marked anxiety tackling urethroplasty and declared that one of their deepest fears regarded a potential further deterioration in the quality of SL. At short-term follow-up, the minimally invasive ventral graft urethroplasty does not cause sexual complications, apart from the post-ejaculation dribbling. On the contrary, this technique showed to restore SL in all its aspects. PMID- 23434097 TI - Defining good candidates for extraperitoneal cystectomy: results from random peritoneum biopsies of 136 cases. AB - OBJECTIVE: To define who are good candidates for extraperitoneal cystectomy. METHODS: Between April 2009 and April 2012, 136 consecutive patients (median age 63.8 years, range 35-87 years) scheduled for transperitoneal radical cystectomy were included in this study. After the bladder was removed, the peritoneum covering the bladder was detached. Any suspicious macroscopic abnormalities on the peritoneum were sampled and examined. A 6-8 point random biopsy of the peritoneum was performed for patients without gross macroscopic abnormality. RESULTS: The study group consisted of 41 patients with pT1, 48 patients with pT2, 34 patients with pT3, and 13 patients with pT4. The transitional cell carcinoma (TCC) group consisted of 123 of 136 patients (90.4%) and nonurothelial histologies of 13 of 136 patients (9.6%). In general, 8 of 136 patients (5.9%) and 14 of 816 biopsies (1.7%) were confirmed positive for peritoneum biopsies. Among them, 0 of 89 patients with pT1/2, 5 of 34 patients with pT3 (14.7%), and 3 of 13 patients with pT4 (23.1%) had positive biopsies (P <.001). In addition, 5 of 123 patients (4.9%) with TCC, 1 of 7 patients (14.3%) with adenocarcinoma, 1 of 2 patients (50%) with sarcomatoid carcinoma, and 1 of 2 patients (50%) with small cell tumors had positive peritoneum biopsies (P = .006). Among patients with positive lymph nodes, 5 of 34 patients (14.7%) had positive biopsies, compared with 3 of 102 patients (2.9%) in the lymph node-negative group (P = .012). CONCLUSION: We found that tumor stage and lymph node status are independent predictors of peritoneal involvement. Extraperitoneal cystectomy should be performed with great caution, only indicated for those patients who have a high likelihood of stage pT1 and pT2. However, patients with cT2-4, positive lymph nodes, or nonurothelial histologies should not have the peritoneum covering the bladder preserved. PMID- 23434098 TI - Improvement of chronic Peyronie's disease symptoms after diabetic compensation: a retrospective study. AB - OBJECTIVE: To look for a link between compensation of diabetes in patients with uncompensated/undiagnosed diabetes with chronic Peyronie's disease (PD) and improvement of their PD symptoms. METHODS: Thirty-six nonsmoking patients with uncompensated diabetes and PD were studied. The plaque area and pain (ie, PD symptoms) were compared before and after a strict control of hemoglobin A1c and of glycemia at a timeframe of 37 +/- 13 weeks. Thirty-two nonsmoking nondiabetic patients with PD who had their PD symptoms assessed twice with a mean time lag of 39 +/- 11 weeks were used as controls. The differences in PD symptoms between the 2 assessments were evaluated using the Wilcoxon test. A Spearman rank correlation test was used to identify any correlation between glycemia before diabetic compensation and the percentage of decrease in the size of plaque of patients with diabetes. RESULTS: Plaque area and pain diminished in patients with diabetes, coincidentally with diabetes compensation and antidiabetic therapy administration. On the other hand, the controls had their plaque area significantly increased while their pain was not modified. The Spearman tests found a significant correlation between glycemia before diabetic compensation and the percentage of decrease in the size of plaque of patients with diabetes. CONCLUSION: Diabetes compensation and/or antidiabetic therapy improved PD symptoms. PMID- 23434099 TI - RENAL nephrometry score is associated with complications after renal cryoablation: a multicenter analysis. AB - OBJECTIVE: To analyze outcomes and complications of percutaneous (PRC) and laparoscopic renal cryoablation (LRC) using the radius, endophytic, nearness to collecting system, anterior/posterior, and location (RENAL) nephrometry system. METHODS: Retrospective multicenter analysis of 154 consecutive patients who underwent either ultrasound-guided LRC (n = 88) or computed tomography (CT) guided PRC (n = 66) from March 2003 to December 2011. RENAL score and demographics were compared to postoperative complications (Clavien). Multivariable analysis was carried out for factors associated with development of postprocedure complications. RESULTS: Mean age was 68 years (94 men/60 women). Median follow-up was 34 months (range 23.6-45.6 months). Mean tumor size was 2.6 +/- 1 cm. Mean RENAL score was 5.2 +/- 1.4. Differences in (A)nterior/posterior component and (H)ilar domain of the RENAL scores were noted, with PRC favoring posterior tumors and hilar lesions compared to LRC (P < .001 and P = .044, respectively). There were 14.9% complications, all of which were low-grade (Clavien 1,2). There were no differences in complications between LRC and PRC (15.9% vs 13.6%, P = .82). Most common complication type was hemorrhagic in 9 of 154 patients (5.8%); significant increase in the hemorrhagic complication rate was noted for patients with "N" ("nearness") component score of 2 or 3 (5/36, or 13.9%), compared to patients with "N" score of 1 (4/115 or 3.5%, P = .033). multivariable analysis demonstrated that increasing RENAL score was associated with postprocedure complications (odds ratio [OR] = 1.37, P = .025). When separated into individual domains, multivariable analysis revealed that "N" score 3 was significantly associated with postoperative complications (OR 16.15, P = .027). CONCLUSION: Increasing RENAL score was associated development of postprocedure complications after renal cryotherapy. Further investigation is requisite to elucidate the role of RENAL nephrometry score in risk stratification prior to renal cryotherapy. PMID- 23434100 TI - Impact of robot-assisted radical prostatectomy on lower urinary tract symptoms and predictive factors for symptom changes: a longitudinal study. AB - OBJECTIVE: To investigate the longitudinal changes in lower urinary tract symptoms (LUTS) after robot-assisted radical prostatectomy (RARP). METHODS: Data on 127 patients who underwent RARP and completed the American Urological Association Symptom Score (AUASS) preoperatively and at 3, 6, and 12 months after surgery were collected prospectively and reviewed retrospectively. Based on the preoperative AUASS, the patients were divided into 2 groups: mild vs moderate to severe. RESULTS: In patients with moderate to severe LUTS, the AUASS gradually decreased after RARP. However, in patients with mild LUTS, the AUASS increased significantly at 3 months postoperatively; although LUTS began to improve at 6 months postoperatively. In multivariate logistic regression analysis, higher body mass index (BMI) was associated with an exacerbation of LUTS at 3 months postoperatively (odds ratio [OR] = 1.148, P <.05). Within the moderate to severe LUTS group, urinary continence at 3 months after RARP was independently associated with the symptom improvement of LUTS at 1 year after surgery (OR = 4.772, P <.05). In a subgroup analysis, lower BMI and urinary continence at 3 months after RARP predicted a significant improvement in storage symptoms at 12 months postoperatively (OR = 0.856, P <.05, and OR = 3.828, P <.05, respectively). CONCLUSION: After RARP, LUTS significantly improved over a 1-year period in patients with moderate to severe LUTS. However, in the immediate postoperative setting, LUTS was exacerbated in patients with mild LUTS. Increased BMI was associated with a lack of improvement in LUTS, whereas early recovery of urinary continence after surgery predicted better symptomatic improvement in LUTS, especially storage symptoms. PMID- 23434101 TI - Topical anesthetic agents for premature ejaculation: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of topical anesthetic agents for patients with premature ejaculation (PE). METHODS: Eligible randomized controlled trials (RCTs) were identified from electronic databases (Cochrane Central Register of Controlled Trials, Medline, and EMBASE) without language restrictions. The database search, quality assessment, and data extraction were performed independently by 2 reviewers. The main outcome for the efficacy of topical anesthetic agents was intravaginal ejaculatory latency time (IELT). Efficacy and safety were explored using Review Manager, version 5.1.0 (Cochrane Collaboration, Oxford, UK). RESULTS: Eight trials met the inclusion criteria. Our pooled analysis showed that IELT in the topical anesthetic agent group was significantly improved compared to the placebo group (random-effect model; mean difference [MD] 5.82, 95% confidence interval [CI] 3.50-8.14, P <.00001). According to the subgroup analysis, a significant improvement was obtained in the domains of ejaculatory control, sexual satisfaction, and distress in the Index of Premature Ejaculation (IPE) questionnaire (random-effect model, MD 4.53, 95% CI 3.05-6.01, P <.00001). In terms of adverse events (AEs), the pooling outcome showed that the overall incidence of AEs was significantly higher in the topical anesthetic agent group than in the placebo group (random-effect model, relative risk [RR] 4.28, 95% CI 1.63-11.24, P = .003). However, nearly all of the AEs were mild and transient. CONCLUSION: Topical anesthetic agents have been shown to be effective and well tolerated for patients with primary PE, providing a significant improvement in IELT with a higher incidence of AEs that were not long lasting or severe. High-quality RCTs are necessary to confirm the efficacy and safety of topical anesthetics for PE. PMID- 23434102 TI - Does positive family history of prostate cancer increase the risk of prostate cancer on initial prostate biopsy? AB - OBJECTIVE: To assess the role of family history (FH) in the risk of a positive prostate biopsy (PBx) in a large North American biopsy population as earlier reports showed increased risk of prostate cancer (PCa) in men with a FH, but the risk has been limited to low grade prostate cancer in smaller studies, and the REDUCE trial found no such risk in North American patients. METHODS: We evaluated 4360 men undergoing initial extended biopsy (8-14 cores). Indications were elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). Variables including age, FH of PCa, race, PSA, and DRE results were included in our analysis to assess risk factors associated with PCa, high grade prostate cancer (HGPCa), and low-grade prostate cancer (LGPCa). RESULTS: Two hundred sixty-eight patients had an FH of PCa whereas 4092 had negative FH. Positive biopsy was found in 1976 patients with HGPCa in 1149 and LGPCa in 827. Among 268 patients with an FH, overall PCa was found in 144 of 268 patients (54%); HGPCa in 79 of 144 patients (55%) and LGPCa in 65 of 144 patients (45%). FH was a significant risk factor for PCa, HGPCa, and LGPCa in univariate and multivariate analysis (P = .0001, .02, and .02, respectively). Also, FH was associated with high-risk benign pathology in the form of atypical small acinar cell proliferation (ASAP) or high-grade prostatic intraepithelial neoplasm (HGPIN) (P = .04). CONCLUSION: Men in North America with an FH of PCa who undergo prostate biopsy are more likely to be diagnosed with both HGPCa and LGPCa. PMID- 23434103 TI - Editorial comment. PMID- 23434105 TI - Editorial comment. PMID- 23434106 TI - Wear performance evaluation of a contemporary dual mobility hip bearing using multiple hip simulator testing conditions. AB - The dual mobility hip bearing concept combines a small bearing with a large diameter bearing through a dual articulation system, potentially increasing the stability of the hip. Bearings with two articulations introduce concerns of whether or not wear might be increased compared to a conventional bearing. We therefore evaluated the wear performance of a dual mobility hip bearing using sequentially cross-linked and annealed polyethylene under the conditions of impingement, abrasion, and when the mobile liner becomes immobilized at either the inner or outer diameter. We found the wear performance of this dual mobility hip is dictated by the conditions experienced by the smaller inner articulation and by the polyethylene material. The highest wearing group wore 75% less than a single articulating conventional gamma/inert polyethylene bearing. PMID- 23434107 TI - Continuous femoral versus epidural block for attainment of 120 degrees knee flexion after total knee arthroplasty: a randomized controlled trial. AB - We conducted the prospective randomized controlled trial to test that continuous femoral nerve block (CFNB) improves attainment of 120 degrees knee flexion compared to continuous epidural analgesia (CEA). Sixty-six patients scheduled for unilateral total knee arthroplasty were randomized into two groups; infusion of ropivacaine 0.15% into CEA or CFNB to third postoperative days. We studied the time required to attain 120 degrees knee flexion, variations in thigh and calf circumferences around the treated knee, pain scores, rehabilitation milestones, the need for adjuvant analgesics, and side effects. CFNB patients attained earlier knee flexion to 120 degrees , lower variations in thigh and calf circumferences, less pain during rehabilitation, and less need for adjuvant analgesics. CFNB is a better pain management strategy that accelerates knee flexion rehabilitation. PMID- 23434108 TI - Patterns of changes in femoral bone mineral density up to five years after hip resurfacing. AB - This is a prospective study of 26 patients (29 hips) on the patterns of change in the Bone Mineral Density (BMD) in various zones of the femoral neck and proximal femur five years after hip resurfacing. We have found that BMD continues to positively change up to five years after hip resurfacing. This was observed primarily in the trochanteric and superior neck regions. In both these regions BMD had decreased by up to 10% at six-weeks and three-months after surgery and then had recovered to preoperative level by one year. A regression analysis to assess the influence of age, gender, BMI, preoperative BMD, component size and orientation revealed that the best predictor of change in BMD at five years in the trochanteric area was acetabular component inclination. PMID- 23434109 TI - The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals. AB - OBJECTIVE: Elevated plasma homocysteine (HCY) levels have been associated with increased risk for cardiovascular disease. Aortic distensibility and aortic pulse wave velocity (PWV) are indices of aortic elasticity. The potential effect of acute hyperhomocysteinemia (HHCY) on the elastic properties of the aorta in healthy individuals is not known. The aim of the present study was to determine the effect of acute methionine-induced HHCY on aortic distensibility and PWV in healthy individualsand the effect of acute HHCY on myocardial performance of the left ventricle (Tei index). METHODS: Thirty healthy volunteers were included in this crossover study. An oral methionine (100 mg/kg) or water load was given in random order on separate days at weekly intervals. Aortic distensibility and Tei index were determined non-invasively by ultrasonography at baseline and 3 h after methionine or water consumption, while PWV was measured by applanation tonometry at baseline and every 1 h for the same time interval. RESULTS: Oral methionine induced an increase in total plasma HCY concentrations (P < 0.001), whereas HCY concentrations did not change after water consumption. Aortic distensibility decreased 3 h after methionine load (P < 0.001) and Tei index increased (P < 0.001), suggesting worsening compared with baseline values. Water consumption had no effect on aortic distensibility or Tei index values. PWV values did not change after either methionine or water consumption. CONCLUSIONS: Acute methionine induced HHCY reduces aortic distensibility and worsens myocardial performance in healthy individuals. Further research is warranted to examine in the long term the direct effects of HHCY on cardiovascular function and the indirect effects on structural remodeling. PMID- 23434110 TI - A hospital discharge risk score for 1-year all-cause mortality or non-fatal cardiovascular events in patients with lower-extremity peripheral artery disease, with and without revascularisation. AB - OBJECTIVES: This study aims to determine a hospital discharge prognostic risk score for patients with lower-extremity peripheral artery disease (PAD) with and without revascularisation. DESIGN, MATERIALS AND METHODS: A prognostic score on mortality or non-fatal cardiovascular events was determined using the database of a multicentre prospective study enrolling consecutive patients hospitalised for PAD (COhorte de Patients ARTeriopathes, COPART). RESULTS: We analysed the data of 640 patients in the derivation cohort and 517 in the validation cohort. The risk score (and corresponding points) included the following factors: age 75-84 years (+2), >= 85 years (+3); previous myocardial infarction (+1); creatinine clearance: <= 30 ml min(-1) 1.73 m-2 (+1.5), 0.30-0.59 (+1), ankle-brachial index: <0.3 (+2), 0.3-0.49 (+1.5) and >1.3 (+2); C-reactive protein (CRP) >= 70 mg l-1 (+2); and association of statins, anti-platelet agents and renin angiotensin system inhibitors (-1.5). The frequency of the composite outcome increased significantly with the predicted risk: low risk (<= 0 point), 2%; medium (0.5-2 points), 12.8%; high (2.5-4 points), 23%; very high (>= 4.5 points): 42.2%. The model had a good performance in terms of discrimination (C statistic 0.74 and 0.76) and calibration (Hosmer-Lemeshow 0.65). CONCLUSIONS: We propose the validated COPART risk score for hospitalised severe PAD. This prognostic risk score is based on six variables easily identifiable in clinical practice. Our study highlights the favourable prognostic impact of the prescription at discharge of combined drug therapies. PMID- 23434111 TI - Functional outcome following upper limb soft tissue sarcoma resection with flap reconstruction. AB - BACKGROUND: Upper limb preservation after soft tissue sarcoma resection often requires flap reconstruction. The aim of this study was to compare pre- and post operative upper limb function following shoulder, elbow or wrist/hand sarcoma resection and soft tissue reconstruction with a pedicled or free flap. PATIENTS: Between 1989 and 2008, 113 patients underwent resection of an upper limb soft tissue sarcoma and required flap reconstruction. Perioperative morbidity, mortality and flap loss were studied. Functional outcome was assessed pre and postoperatively using the Toronto Extremity Salvage Score (TESS), a measure of disability, and the Musculoskeletal Tumour Society Rating Scale (MSTS), a measure of impairment. Statistical analyses were performed to evaluate the relationship between flap type and functional outcome scores. RESULTS: Patients underwent soft tissue sarcoma excision in the shoulder (n = 64), elbow (n = 27) or wrist/hand (n = 22) region with soft tissue reconstruction using either a pedicled (n = 76) or free flap (n = 37). Comparison of the post-operative MSTS (n = 88) and TESS (n = 84) revealed no significant differences between the free and pedicled flap groups. A significant pre- to post-operative difference was identified in MSTS 87 scores for patients in both the pedicled (p < 0.02) and free flap groups (p < 0.04). Comparison of the pre- and post-operative MSTS 93 scores also revealed a significant difference (p < 0.01) but this was limited to the free flap group. The most notable post-operative score reductions in these patients were due to major joint, nerve, tendon or muscle group resection. CONCLUSION: Reconstruction of the soft tissue defect following sarcoma resection in the upper limb maintains a similar satisfactory level of upper limb activity with either pedicled or free flap reconstructions. Based on TESS scores, patients rated themselves as having better function compared to impairment measures such as MSTS. PMID- 23434112 TI - The aberrant flexor carpi ulnaris and its clinical implications. PMID- 23434113 TI - Entering the era of bacterial epigenomics with single molecule real time DNA sequencing. AB - DNA modifications, such as methylation guide numerous critical biological processes, yet epigenetic information has not routinely been collected as part of DNA sequence analyses. Recently, the development of single molecule real time (SMRT) DNA sequencing has enabled detection of modified nucleotides (e.g. 6mA, 4mC, 5mC) in parallel with acquisition of primary sequence data, based on analysis of the kinetics of DNA synthesis reactions. In bacteria, genome-wide mapping of methylated and unmethylated loci is now feasible. This technological advance sets the stage for comprehensive, mechanistic assessment of the effects of bacterial DNA methyltransferases (MTases)-which are ubiquitous, extremely diverse, and largely uncharacterized-on gene expression, chromosome structure, chromosome replication, and other fundamental biological processes. SMRT sequencing also enables detection of damaged DNA and has the potential to uncover novel DNA modifications. PMID- 23434114 TI - Chemical attenuation of pilus function and assembly in Gram-negative bacteria. AB - Bacteria express a multitude of hair-like adhesive appendages on their cell surfaces, together referred to as pili or fimbriae. In Gram-negative bacteria, these proteinaceous structures are assembled through a number of dedicated secretion pathways including the chaperone-usher pathway, the nucleation/precipitation pathway and the type IV pilus pathway. Pili are prevalent in pathogenic strains and play important roles in the establishment and persistence of bacterial infections by mediating host cell adhesion, cell invasion or biofilm formation. Their indispensible roles in pathogenesis render them attractive targets for directed therapeutic intervention. Here, we describe the recent advances in the chemical attenuation of pilus-associated virulence in Gram-negative bacteria. PMID- 23434115 TI - ACTN1 mutations cause congenital macrothrombocytopenia. AB - Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes alpha-actinin-1, a member of the actin crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered alpha-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP. PMID- 23434116 TI - Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. AB - Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized. PMID- 23434118 TI - From bioethics to a sociology of bio-knowledge. AB - Growing recognition of bioethics' shortcomings, associated in large part with its heavy reliance on abstract principles, or so-called principlism, has led many scholars to propose that the field should be reformed or reconceptualised. Principlism is seen to de-contextualise the process of ethical decision-making, thus restricting bioethics' contributions to debate and policy on new and emergent biotechnologies. This article examines some major critiques of bioethics and argues for an alternative normative approach; namely, a sociology of bio knowledge focussing on human rights. The article discusses the need for such an approach, including the challenges posed by the recent rise of 'the bio-economy'. It explores some potential alternative bases for a normative sociology of bio knowledge, before presenting the elements of the proposed human rights-focused approach. This approach, it is argued, will benefit from the insights and concepts offered by various fields of critical scholarship, particularly the emergent sociology of human rights, science and technology studies, Foucaultian scholarship, and feminist bioethics. PMID- 23434117 TI - Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies. Mutations in approximately 45 genes have been identified as being associated with CMT. Nevertheless, the genetic etiologies of at least 30% of CMTs have yet to be elucidated. Using a genome-wide linkage study, we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29. Subsequent exome sequencing of two affected first cousins revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4 (Gbeta4), to cosegregate with the CMT phenotype in the family. Further analysis of GNB4 in an additional 88 unrelated CMT individuals uncovered another de novo mutation, c.265A>G (p.Lys89Glu), in this gene in one individual. Immunohistochemistry studies revealed that Gbeta4 was abundant in the axons and Schwann cells of peripheral nerves and that expression of Gbeta4 was significantly reduced in the sural nerve of the two individuals carrying the c.158G>A (p.Gly53Asp) mutation. In vitro studies demonstrated that both the p.Gly53Asp and p.Lys89Glu altered proteins impaired bradykinin-induced G-protein coupled-receptor (GPCR) signaling, which was facilitated by the wild-type Gbeta4. This study identifies GNB4 mutations as a cause of CMT and highlights the importance of Gbeta4-related GPCR signaling in peripheral-nerve function in humans. PMID- 23434119 TI - Exploration of health risks related to air pollution and temperature in three Latin American cities. AB - This paper explores whether the health risks related to air pollution and temperature extremes are spatially and socioeconomically differentiated within three Latin American cities: Bogota, Colombia, Mexico City, Mexico, and Santiago, Chile. Based on a theoretical review of three relevant approaches to risk analysis (risk society, environmental justice, and urban vulnerability as impact), we hypothesize that health risks from exposure to air pollution and temperature in these cities do not necessarily depend on socio-economic inequalities. To test this hypothesis, we gathered, validated, and analyzed temperature, air pollution, mortality and socioeconomic vulnerability data from the three study cities. Our results show the association between air pollution levels and socioeconomic vulnerabilities did not always correlate within the study cities. Furthermore, the spatial differences in socioeconomic vulnerabilities within cities do not necessarily correspond with the spatial distribution of health impacts. The present study improves our understanding of the multifaceted nature of health risks and vulnerabilities associated with global environmental change. The findings suggest that health risks from atmospheric conditions and pollutants exist without boundaries or social distinctions, even exhibiting characteristics of a boomerang effect (i.e., affecting rich and poor alike) on a smaller scale such as areas within urban regions. We used human mortality, a severe impact, to measure health risks from air pollution and extreme temperatures. Public health data of better quality (e.g., morbidity, hospital visits) are needed for future research to advance our understanding of the nature of health risks related to climate hazards. PMID- 23434120 TI - Reply: To PMID 22575251. PMID- 23434121 TI - The cardio-metabolic risk of moderate and severe obesity in children and adolescents. AB - OBJECTIVE: To compare the cardio-metabolic risk profile between moderately obese and severely obese children and adolescents. STUDY DESIGN: Cross-sectional study involving 463 obese 6- to 19-year-olds who were referred to an inpatient weight loss program. Anthropometric data were assessed and fasting blood samples were analyzed for lipid and glucose metabolism, adipokines, and inflammatory markers. Moderately obese individuals (percentiles corresponding to body mass index >= 30 to 35 kg/m(2) at age 18 years) and severely obese individuals (percentiles corresponding to body mass index >= 35 kg/m(2) at age 18 years) were defined by sex and age-specific cut-offs according to the International Obesity Task Force. RESULTS: The prevalence of the metabolic syndrome was three times higher in severely obese individuals compared with those who are moderately obese. Mean values for proinsulin, insulin, homeostatic model assessment-insulin resistance, triglycerides, and interleukin-6 were 30%-50% higher in severe obesity compared with moderate obesity. Concentrations of leptin and high-sensitive C-reactive protein were about 1.5-fold higher, adiponectin levels were 12% lower, and resistin levels 10% higher in severely obese individuals compared with moderately obese (all P < .001). CONCLUSION: Severely obese individuals have a markedly more unfavorable cardio-metabolic risk profile than those who are moderately obese. The results of this study underscore the substantial effect of severe obesity on health and highlights that these children need to receive particular attention regarding obesity treatment. PMID- 23434122 TI - Childhood alcohol use may predict adolescent binge drinking: a multivariate analysis among adolescents in Brazil. AB - OBJECTIVES: To test the hypothesis that first alcohol use during childhood is associated with heavy drinking patterns during adolescence and with parental drinking patterns and parental rules about alcohol consumption. STUDY DESIGN: A national cross-sectional survey of 17,371 high-school students. Students were drawn from 789 public and private schools in all the Brazilian state capitals using a multistage probabilistic sampling method and a self-report questionnaire. Weighted data were analyzed through logistic regression testing for differences on the associated factors for first use of alcohol during childhood. Survival analysis and Cox proportional hazard models were used to confirm results. RESULTS: Among the 82% alcohol lifetime users, 11% had first used alcohol before age 12 years. The lack of perception of possible punishment by parents is associated with childhood alcohol use (OR 2.22, 95% CI 1.67-2.95). Adolescents who first used alcohol during childhood compared with those who only used alcohol at later ages are more likely to engage in binge drinking behaviors (OR 1.57, 95% CI 1.17-2.10), to have a pattern of heavy alcohol use (OR 1.98, 95% CI 1.26 3.09), and to have recently used illegal drugs (OR 1.74, 95% CI 1.39-2.16). According to hazard ratios, students with an earlier age of onset were more likely to have used tobacco and any illegal drug in the past year. CONCLUSIONS: Childhood alcohol may be a risk factor for the most dangerous patterns of alcohol use in adolescence and is associated with parental alcohol use. Parental rules about child alcohol use must be clear because perception of punishment might delay the age of first alcohol use. PMID- 23434123 TI - Cerebral and peripheral regional oxygen saturation during postnatal transition in preterm neonates. AB - OBJECTIVE: To evaluate peripheral regional oxygen saturation (rpSO2) and cerebral regional oxygen saturation (rcSO2) during the immediate postnatal transition in late preterm infants with and without the need for respiratory support. STUDY DESIGN: This was a prospective observational study using near-infrared spectroscopy to evaluate changes in rpSO2 and rcSO2. These variables were measured during the first 15 minutes of life after elective cesarean delivery. Peripheral oxygen saturation (SpO2) and heart rate were measured continuously by pulse oximetry, and cerebral fractional tissue oxygen extraction (cFTOE) was calculated. Two groups were compared based on their need for respiratory support: a respiratory support group and a normal transition group. Positive-pressure ventilation was delivered with a T-piece resuscitator, and oxygen was adjusted based on SpO2 values. A Florian respiratory function monitor was used to record the ventilation variables. RESULTS: There were 21 infants in the normal transition group and 21 infants in the respiratory support group. Changes in heart rate over time were similar in the 2 groups. SpO2, rcSO2, and rpSO2 values were consistently higher in the normal transition group. In the respiratory support group, cFTOE values remained significantly elevated for a longer period. CONCLUSION: This systematic analysis of rpSO2, rcSO2, and cFTOE in late preterm infants found significantly lower oxygen saturation values in infants who received respiratory support compared with a normal transition group. We hypothesize that the elevated cFTOE values in the respiratory support group represent compensation for lower oxygen delivery. PMID- 23434124 TI - Feasibility of interactive technology for symptom monitoring in patients with fibromyalgia. AB - Use of health information technology (IT) integrated with clinical services has the potential to empower self-management and decrease health care utilization for chronic disorders such as fibromyalgia (FM). However, the appropriate methodology that systematically facilitates the integration of health IT with clinical services between patients and nurses partnering to manage FM is unclear. The purpose of this study was to determine the feasibility of technology-enhanced monitoring that engages FM patients using a mobile device. A quantitative and qualitative descriptive design was used in a convenience sample of 20 FM patients. Patients used a mobile monitoring device for one week; nurses responded to patient e-mailed symptom reports on a daily basis. Analysis was primarily descriptive-percent, frequencies, and means for individual questionnaire items and subscales were calculated. For qualitative data, a 1 hour focus group was audio-recorded, transcribed verbatim, and then analyzed using content analysis. All participants used a mobile phone in their daily lives; half used a smart phone. Participants were interested in using a smart phone to monitor their health and to communicate with health care providers. Participants used the study mobile device an average of 5.2 days out of the 7 day study period. Most participants (80%) reported that monitoring symptoms using the device was easy to do. Sixty-five percent felt that using the device helped them to promptly address their symptoms. Results from this study indicated that health IT integrated with clinical services is feasible to monitor FM symptoms and to communicate with the care team. PMID- 23434125 TI - Obstructive sleep apnoea in adults: a common chronic condition in need of a comprehensive chronic condition management approach. AB - Obstructive sleep apnoea (OSA) is a common disorder that has all the characteristics of a chronic condition. As with other chronic conditions, OSA requires ongoing management of treatments and problems, such as residual symptoms, deficits and co-morbidities. Also, many OSA patients have modifiable lifestyle factors that contribute to their disease, which could be improved with intervention. As health systems are in the process of developing more comprehensive chronic care structures and supports, tools such as chronic condition management programs are available to enable OSA patients and their health care providers to further engage and collaborate in health management. This review explains why the OSA patient group requires a more comprehensive approach to disease management, describes the chronic care model as a platform for management of chronic conditions, and assesses the suitability of particular chronic disease management programs in relation to the needs of the OSA population. Implementation of an evidence-based health-professional-led chronic condition management program into OSA patient care is likely to provide a context in which health risks are properly acknowledged and addressed. Such programs present an important opportunity to enable more optimal health outcomes than is possible by device-focused management alone. PMID- 23434126 TI - Thread emerges from three papers on pain, chronic fatigue, and sleep: avenues for deeper understanding. PMID- 23434127 TI - Emissions from U.S. waste collection vehicles. AB - This research is an in-depth environmental analysis of potential alternative fuel technologies for waste collection vehicles. Life-cycle emissions, cost, fuel and energy consumption were evaluated for a wide range of fossil and bio-fuel technologies. Emission factors were calculated for a typical waste collection driving cycle as well as constant speed. In brief, natural gas waste collection vehicles (compressed and liquid) fueled with North-American natural gas had 6-10% higher well-to-wheel (WTW) greenhouse gas (GHG) emissions relative to diesel fueled vehicles; however the pump-to-wheel (PTW) GHG emissions of natural gas waste collection vehicles averaged 6% less than diesel-fueled vehicles. Landfill gas had about 80% lower WTW GHG emissions relative to diesel. Biodiesel waste collection vehicles had between 12% and 75% lower WTW GHG emissions relative to diesel depending on the fuel source and the blend. In 2011, natural gas waste collection vehicles had the lowest fuel cost per collection vehicle kilometer travel. Finally, the actual driving cycle of waste collection vehicles consists of repetitive stops and starts during waste collection; this generates more emissions than constant speed driving. PMID- 23434128 TI - An index to quantify street cleanliness: the case of Granada (Spain). AB - Urban surfaces receive waste deposits from natural and human sources, which create a negative visual impact and are identified as potentially significant contributors to water and air pollution. Local councils are usually responsible for the sweep of roads and footpaths to keep the environment clean and free of litter. Quality controls are useful in order to check whether the services are being executed according to the quantity, quality and performance standards that are provided. In this sense, several factors might affect the efficiency of the management of cleaning and waste collection services; however, only a few contributions are available in the literature on the various aspects associated with the level of street cleanliness. In this paper, the suitability of a Cleanliness Index has been checked, for the case of Granada (South of Spain), in order to contribute to the proper management of public expenditure, improving the quality and cost of an essential service for any municipality. Results have concluded that the city exhibits a good level of cleanliness, although the standard of cleaning varied from one area of the city to another. The Cleaning Index fits well to the general situation of the different districts of Granada and thus, it could be considered a useful tool for measuring the level of cleanliness of the streets of the city and for evaluating the organization of the cleaning service, such that an outsourced company would not be responsible for controlling all the cleaning services. PMID- 23434129 TI - Genetic variability of HEV isolates: inconsistencies of current classification. AB - Many HEV and HEV-like sequences have been reported during the last years, including isolates which may represent a number of potential new genera, new genotypes or new subtypes within the family Hepeviridae. Using the most common classification system, difficulties in the establishment of subtypes have been reported. Moreover the relevance of subtype classification for epidemiology can be questioned. In this study we have performed phylogenetic analyses based on whole capsid gene and complete HEV genomic sequences in order to evaluate the current classification of HEV at genotype and subtype levels. The results of our analyses modify the current taxonomy of genotype 3 and refine the established system for typing of HEV. In addition we suggest a classification for hepeviruses recently isolated from bats, ferrets, rats and wild boar. PMID- 23434131 TI - Semisynthetic studies identify mitochondria poisons from botanical dietary supplements--geranyloxycoumarins from Aegle marmelos. AB - Bioassay-guided isolation and subsequent structure elucidation of a Bael tree Aegle marmelos lipid extract yielded two unstable acylated geranyloxycoumarin mixtures (1-2), six geranyloxycoumarins (3-8), (+)-9'-isovaleroxylariciresinol (9), and dehydromarmeline (10). In a T47D cell-based reporter assay, 1 and 2 potently inhibited hypoxia-induced HIF-1 activation (IC50 values 0.18 and 1.10 MUgmL(-1), respectively). Insufficient material and chemical instability prevented full delineation of the fatty acyl side chain olefin substitution patterns in 1 and 2. Therefore, five fatty acyl geranyloxycoumarin ester derivatives (11-15) were prepared from marmin (3) and commercial fatty acyl chlorides by semisynthesis. The unsaturated C-6' linoleic acid ester derivative 14 that was structurally most similar to 1 and 2, inhibited HIF-1 activation with comparable potency (IC50 0.92 MUM). The octanoyl (11) and undecanoyl (12) ester derivatives also suppressed HIF-1 activation (IC50 values 3.1 and 0.87 MUM, respectively). Mechanistic studies revealed that these geranyloxycoumarin derivatives disrupt mitochondrial respiration, primarily at complex I. Thus, these compounds may inhibit HIF-1 activation by suppressing mitochondria-mediated hypoxic signaling. One surprising observation was that, while less potent, the purported cancer chemopreventive agent auraptene (8) was found to act as a mitochondrial poison that disrupts HIF-1 signaling in tumors. PMID- 23434130 TI - Problem drinking is associated with increased prevalence of sexual risk behaviors among men who have sex with men (MSM) in Lima, Peru. AB - BACKGROUND: Alcohol use is an important but understudied HIV risk factor among men who have sex with men (MSM), particularly in Latin America. We studied the relationship between problem drinking and sexual risk among MSM in Lima, Peru. METHODS: We recruited 718 participants from 24 neighborhoods for a study on sexually transmitted infections and community-building among MSM. Multivariate analysis was used to identify factors independently associated with problem drinking, which was defined via the CAGE Questionnaire. RESULTS: Of 718 participants, 58% met criteria for problem drinking. In univariate analysis, problem drinkers were significantly more likely to report failing to always use condoms, use alcohol or drugs prior to their most recent sexual encounter, report a history of sexual coercion and to engage in transactional sex. Problem drinkers also reported significantly higher numbers of recent and lifetime sexual partners. In multivariate analysis, factors independently associated with problem drinking included a history of sexual coercion [OR 1.8 95%, CI 1.2-2.6], having consumed alcohol prior to the most recent sexual encounter [OR 2.1 95%, CI 1.5 2.9], receiving compensation for sex in the last six months [OR 1.6, 95% CI 1.1 2.2] or having reported a prior HIV+ test [OR 0.5, 95% CI 0.2-0.9]. DISCUSSION: We found a high prevalence of problem drinking among MSM in Lima, Peru, which was associated with increased sexual risk in our study. Of note, individuals who were already HIV-infected were less likely to be problem drinkers. Further studies and targeted interventions to reduce problem drinking among MSM are warranted. PMID- 23434132 TI - Quercetin-POC conjugates: Differential stability and bioactivity profiles between breast cancer (MCF-7) and colorectal carcinoma (HCT116) cell lines. AB - In the course of our ongoing efforts to develop novel quercetin conjugates with enhanced stability profiles, we introduced an isopropyloxycarbonylmethoxy (POC) group to 7-OH and/or 3-OH of quercetin and prepared three novel quercetin conjugates. The quercetin-POC conjugates were stable up to 96 h in PBS but slowly hydrolyzed with half-lives of 1-54 h in cell-free culture medium, which is reminiscent of the stability profiles of the previously reported quercetin-POM (pivaloxymethyl) conjugates. However, the quercetin-POC conjugates were more susceptible to passive transport, intracellular hydrolysis, and metabolism in breast cancer (MCF-7) cell line compared with their POM congeners to result in low concentration of quercetin in this cell line and thereby low antiproliferative effect. In contrast, upon incubation with colorectal carcinoma HCT116 cells, the quercetin-POC conjugates were shown to undergo slow hydrolysis and metabolism to maintain concentrations of the active quercetin species high enough to exert enhanced cytotoxicity. Taken together, the quercetin-POC conjugates synthesized in this study exhibited cell type-specific stability as well as bioactivity profiles, which warrants further investigation into the underlying mechanisms and therapeutic potential. PMID- 23434133 TI - Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization. AB - A novel dipeptidyl peptidase IV inhibitor hit (5, IC50=0.86 MUM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC50=1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T1/2: 2h vs 4.9h). PMID- 23434134 TI - (+)-Usnic acid enamines with remarkable cicatrizing properties. AB - Wound healing is a significant concern in many pathologies (post-surgeries, burns, scars) and the search for new chemical entities is advisable. The lichen compound (+)-usnic acid (1) has found application in dermatological and cosmetic preparations, due to its bacteriostatic and antioxidant activities. The compound has also been shown to stimulate the wound closure of keratinocyte monolayers at subtoxic doses. Here we describe the design and synthesis of usnic acid enamines (compounds 2-11), obtained through nucleophilic attack of amino acids or decarboxyamino acids at the acyl carbonyl of the enolized 1,3 diketone. The wound repair properties of these derivatives were evaluated using in vitro and in vivo assays. Compounds 8 and 9 combine low cytotoxicity with high wound healing performance, suggesting their possible use in wound healing-promoting or antiage skin preparations. PMID- 23434135 TI - Novel antiobesity agents: synthesis and pharmacological evaluation of analogues of Rimonabant and of LH21. AB - Searching for novel antiobesity agents, a series of cannabinoid LH21 and of Rimonabant-fatty acid amide analogues have been prepared. Synthesis of pyrazoles 2a-2c was achieved by a two steps simple methodology via alpha,beta-unsaturated ketones. Carboxamides 8a-8h were obtained in good yields from esters 7a-7c by a one-pot procedure which takes place under mild conditions. New compounds have been evaluated in vivo as anorectic agents. Some of them showed interesting properties reducing food intake in rats by a mechanism which does not involve the endocannabinoid system. PMID- 23434136 TI - Probing functional diversity in pactamycin toward antibiotic, antitumor, and antiprotozoal activity. AB - A total of eight new analogs of pactamycin were prepared and tested alongside pactamycin and three of its natural congeners for antibacterial, anticancer, and antiprotozoal activities. The present study highlights the effects of changing the urea and aniline groups especially with regard to anticancer and antiprotozoal activities. PMID- 23434137 TI - Synthesis and properties of cationic oligopeptides with different side chain lengths that bind to RNA duplexes. AB - A series of artificial peptides bearing cationic functional groups with different side chain lengths were designed, and their ability to increase the thermal stability of nucleic acid duplexes was investigated. The peptides with amino groups selectively increased the stability of RNA/RNA duplexes, and a relationship between the side chain length and the melting temperature (Tm) of the peptide-RNA complexes was observed. On the other hand, while peptides with guanidino groups exhibited a similar tendency with respect to the peptide structure and thermal stability of RNA/RNA duplexes, those with longer side chain lengths, such as L-2-amino-4-guanidinobutyric acid (Agb) or L-arginine (Arg) oligomers, stabilized both RNA/RNA and DNA/DNA duplexes, and those with shorter side chain lengths exhibited a higher ability to selectively stabilize RNA/RNA duplexes. In addition, peptides were designed with different levels of flexibility by introducing glycine (Gly) residues into the L-2-amino-3 guanidinopropionic acid (Agp) oligomers. It was found that insertion of Gly did not affect the thermal stability of the peptide-RNA complexes, but an alternate arrangement of Gly and Agp apparently decreased the thermal stability. Therefore, in the Agp oligomer, consecutive Agp sequences are essential for increasing the stability of RNA/RNA duplexes. PMID- 23434138 TI - Fungal metabolites of xanthohumol with potent antiproliferative activity on human cancer cell lines in vitro. AB - Xanthohumol (1) and xanthohumol D (2) were isolated from spent hops. Isoxanthohumol (3) was obtained from xanthohumol by isomerisation in alkaline solution. Six metabolites were obtained as a result of transformation of xanthohumol (1) by selected fungal cultures. Their structures were established on the basis of their spectral data. One of them: 2"-(2'''-hydroxyisopropyl) dihydrofurano-[4",5":3',4']-4',2-dihydroxy-6'-methoxy-alpha,beta-dihydrochalcone (6) has not been previously reported in the literature. The antioxidant properties of hops flavonoids and xanthohumol derivatives were investigated using the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. The effects of these compounds on proliferation of MCF-7, PC-3 and HT-29 human cancer cell lines were determined by the SRB assay. With the exception of one metabolite, all tested compounds showed antiproliferative activity against the tested human cancer lines. alpha,beta-Dihydroxanthohumol (4), obtained through the biotransformation of xanthohumol, showed higher antiproliferative activity against MCF-7 human breast carcinoma cell line than cisplatin, a widely used anticancer therapeutic agent, and a comparably high activity against PC-3 human prostate cancer cell line. PMID- 23434139 TI - Synthesis and biological activity of 5-chloro-N4-substituted phenyl-9H pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor 2 inhibitors and antiangiogenic agents. AB - Inhibition of receptor tyrosine kinase (RTK) signaling pathways is an important area for the development of novel anticancer agents. Numerous multikinase inhibitors (MKIs) have been recently approved for the treatment of cancer. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the principal mediator of tumor angiogenesis. In an effort to develop ATP-competitive VEGFR-2 selective inhibitors the 5-chloro-N(4)-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4 diamine scaffold was designed. The synthesis of the target compounds involved N (4,5-dichloro-9H-pyrimido[4,5-b]indol-2-yl)-2,2-dimethylpropanamide) as a common intermediate. A nucleophilic displacement of the 4-chloro group of the common intermediate by appropriately substituted anilines afforded the target compounds. Biological evaluation indicated that compound 5 is a potent and selective VEGFR-2 inhibitor comparable to sunitinib and semaxinib. PMID- 23434140 TI - Substituted indolin-2-ones as p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors: Molecular docking simulation and structure-activity relationship analysis. AB - A series of novel indolin-2-ones inhibitors against p90 ribosomal S6 protein kinase 2 (RSK2) were designed and synthesized and their structure-activity relationship (SAR) was studied. The most potent inhibitor, compound 3s, exhibited potent inhibition against RSK2 with an IC50 value of 0.5 MUM and presented a satisfactory selectivity against 23 kinases. The interactions of these inhibitors with RSK2 were investigated based on the proposed binding poses with molecular docking simulation. Four compounds and six compounds exhibited moderate anti proliferation activities against PC 3 cells and MCF-7 cells, respectively. PMID- 23434141 TI - LSN MS guidelines for the management of multiple sclerosis. AB - OBJECTIVE: The prevalence of multiple sclerosis (MS) in Lebanon is unknown, as there are no available or reliable epidemiological studies to date. The circumstances of Middle East countries are different from those of Europe and North America in terms of differential diagnoses and disease management. The aim of the conference is to establish guidelines for diagnosis, treatment, follow-up and management of patients with MS in Lebanon. Another objective is to discuss and participate in research projects based on epidemiology, clinical trials and more fundamental aspects of the disease in the future. METHODS: Under the authority of the Lebanese Society of Neurology (LSN), a group of neurologists took the initiative to participate in this LSN MS committee with the purpose of establishing a consensus for the management of patients with MS, and under the supervision of a Coordinator (A.T.) designed by the LSN board. RESULTS: Diagnostic and therapeutic, follow-up and research recommendations were proposed with special emphasis on the specific needs and circumstances of Lebanon. The experts highlighted the importance of considering particular needs, the identification of patients at high risk of developing MS in order to maximize therapeutic opportunities, and cost-effective control of treatment efficacy, as well as global assessment of disability. CONCLUSIONS: The experts established guidelines concerning diagnosis, treatment, and follow-up of patients with MS in Lebanon. Furthermore, they recommended some clinical and fundamental research projects. PMID- 23434142 TI - [Heterotopic gray matter: A rare cause of epilepsy]. AB - Various etiologic diagnoses are put forward for certain forms of infant epilepsy. We report four cases illustrating a rare cause: gray matter heterotopia. There were three girls and one boy, aged 3 months to 4 years at onset of seizures and 8 to 30 years at diagnosis of gray matter heterotopia. All patients sought healthcare because of repeated seizures. One patient also presented severe mental retardation. No consanguinity was noted. Magnetic resonance imaging showed the interposition of an ectopic ribbon of gray matter within the white matter in all cases. Ectopic gray matter formed bilateral subependymal nodules in one patient and bilateral nodules in the subcortical region suggestive of concentric laminar organization in another. The two other patients presented both of these forms. Other anomalies were associated: partial agenesis of the corpus callosum associated with colpocephaly causing cortical atrophy in one patient and hippocampal sclerosis in another. PMID- 23434143 TI - [Synaesthesia, an augmented sensory world: phenomenology and literature review]. AB - Synaesthetic people are probably more numerous than usually thought. This unique sensory phenomenon may concern up to 4% of the general population. Physicians are not very aware of synaesthesias because synaesthetes ignore themselves and most often consider this perceptive faculty as common and not pathological. We report in detail a grapheme-phoneme to colour developmental synaesthesia in a 54-year old woman. The major contribution of research over the last two decades is also summarized. PMID- 23434144 TI - The impact of age on outcome after major surgical procedures. AB - PURPOSE: The aim of this study was to investigate the effects of age on outcome in a large cohort of surgical intensive care unit (ICU) patients. METHODS: In this retrospective analysis of prospectively collected data, all 11537 adult patients admitted directly from the operating room to our 50-bed surgical ICU between January 1, 2004, and January 31, 2009, were included. Patients were classified into 5 subgroups according to age (18-50 [reference category], 51-65, 66-75, 76-85, >85 years). RESULTS: Severity scores and the incidence of comorbid conditions on ICU admission increased steadily with age. Intensive care unit and hospital mortality rates were 4.4% and 8.7%, respectively, and increased with age to reach 12.4% and 28.2%, respectively, in patients older than 85 years. In multivariate logistic regression analysis, age was an independent risk factor for in-hospital death (odds ratio, 1.04; 95% confidence interval, 1.03-1.04, per year; P < .001). Gastrointestinal surgery was independently associated with a higher risk of in-hospital mortality in patients older than 50 years, whereas neurosurgery was associated with a higher risk of in-hospital death only in patients older than 65 years. CONCLUSIONS: Mortality rates increase with age, with an exponential increase in patients older than 65 years. Age is an independent risk factor for in-hospital death, irrespective of the type of surgical intervention. PMID- 23434145 TI - Molecular markers of therapeutic resistance in breast cancer. AB - Resistance to chemotherapy and endocrine therapy is a serious obstacle in the treatment of breast cancer. Highly specific biomarkers for predicting therapeutic resistance have not yet been identified. In this study, the amounts of aldehyde dehydrogenase 1, cleaved caspase 3, cyclooxygenase 2, phosphorylated Akt, Ki-67, and H2AX proteins were measured by immunohistochemical staining in 113 breast cancer tissues, and their predictive ability for therapeutic resistance was investigated. The patients were receiving chemotherapy (n = 30), endocrine therapy (n = 22), or combined chemotherapy and endocrine therapy (n = 61). Expression of aldehyde dehydrogenase 1, cleaved caspase 3, and cyclooxygenase 2 correlated significantly with a higher relapse rate (P < .05 or P < .01) and shorter survival (P < .01 or P < .001) in triple-negative patients receiving chemotherapy. In addition, cyclooxygenase 2 expression was an independent predictor of a poor prognosis (P < .05). On the other hand, aldehyde dehydrogenase 1 expression correlated significantly with shorter survival in patients receiving combined therapy (P < .01) but showed no association with relapse. No correlation was observed between Ki-67, phosphorylated Akt, and H2AX expression and survival or relapse in any group of patients. These data suggest that aldehyde dehydrogenase 1, cleaved caspase 3, and cyclooxygenase 2 are useful markers for therapeutic resistance in breast cancer. PMID- 23434146 TI - Renal cell carcinoma with areas mimicking renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma. AB - We present a cohort of 8 renal carcinomas that displayed a variable (5%-95% extent) light microscopic appearance of renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma (RAT/CCPRCC) without fulfilling the criteria for these tumors. All but 1 case predominantly (75%-95% extent) showed histopathologic features of conventional clear cell renal cell carcinoma. In 5 of 7 cases with mostly conventional clear renal cell carcinoma (CRCC) morphology, a diagnosis of CRCC was supported by the molecular genetic findings (presence of von Hippel-Lindau tumor suppressor [VHL] mutation and/or VHL promoter methylation and/or loss of heterozygosity [LOH] for 3p). Of the other 2 cases with predominantly characteristic CRCC morphology, 1 tumor did not reveal any VHL mutation, VHL promoter methylation, or LOH for 3p, and both chromosomes 7 and 17 were disomic, whereas the other tumor displayed polysomy for chromosomes 7 and 17 and no VHL mutation, VHL promoter methylation, or LOH for 3p. One tumor was composed primarily (95%) of distinctly RAT/CCPRCC-like morphology, and this tumor harbored a VHL mutation and displayed polysomy for chromosomes 7 and 17. Of the 5 cases with both histomorphologic features and molecular genetic findings of CRCC, we detected significant immunoreactivity for alpha-methylacyl-CoA racemase in 2 cases and strong diffuse immunopositivity for cytokeratin 7 in 3 cases. Despite the combination of positivity for alpha-methylacyl-CoA racemase and cytokeratin 7 in 2 cases, there was nothing to suggest of the possibility of a conventional papillary renal cell carcinoma with a predominance of clear cells. PMID- 23434147 TI - Modulation of intracellular pathways by anandamide and its evolving role in oncology. PMID- 23434148 TI - Expression of Engrailed-2 (EN2) protein in bladder cancer and its potential utility as a urinary diagnostic biomarker. AB - Despite significant advances in our understanding of the molecular pathology of bladder cancer, it remains a significant health problem with high morbidity and mortality associated with muscle-invasive bladder cancer (stages T2+), and high costs associated with the surveillance of non-muscle-invasive bladder cancer (NMIBC, stages Ta/T1/Tis). Moreover, current diagnostic biomarkers are suboptimal and of poor utility for low grade disease and surveillance. In this study, we show that the Engrailed-2 (EN2) transcription factor is expressed in, and secreted by, bladder cancer cell lines and patient tumour specimens, justifying an evaluation of urinary EN2 as a diagnostic biomarker in bladder cancer using archived samples from an established biospecimen collection. In patients with NMIBC, urinary EN2 was detected in most cases with an overall sensitivity of 82% and specificity of 75%. The sensitivity for stage Ta and T1 tumours was 71% and 76%, respectively, and 94% for stage T2+ tumours. This compares favourably with existing markers. The sensitivity for tumour grades 1, 2 and 3 was 69%, 78% and 87%, respectively. Thus urinary EN2 has the potential to be a more sensitive and specific protein biomarker for NMIBC than currently available tests. PMID- 23434149 TI - Pretreatment body mass index as an independent prognostic factor in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy: findings from a randomised trial. AB - OBJECTIVE: To investigate the relationship between the pretreatment body mass index (BMI) and the clinical outcomes in patients with locoregionally advanced nasopharyngeal carcinoma treated with combination of chemotherapy and radiotherapy. METHODS: From August 2002 to April 2005, 400 patients with stage III or stage IVa nasopharyngeal carcinoma were recruited for a randomised clinical trial of induction chemotherapy combined with radiotherapy or concurrent chemoradiotherapy. The patients were divided into four groups of underweight (BMI<18.5kg/m(2)), normal weight (BMI 18.5-22.9kg/m(2)), overweight (BMI 23.0 27.4kg/m(2)) or obese (BMI>=27.5kg/m(2)) according to the World Health Organization classifications for Asian populations. The differences in the long term survival, of these four BMI groups were analysed. RESULTS: The 5-year failure-free survival rates for the underweight, normal weight, overweight and obese groups were 44%, 61%, 68% and 73%, respectively (p=0.014), and the 5-year overall survival rates were 51%, 68%, 80% and 72% (p=0.001), respectively. BMI was a strongly favoured prognostic factor of overall survival and failure-free survival in a Cox regression model. CONCLUSIONS: Pretreatment body mass index was a simple, reliable independent prognostic factor for patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. PMID- 23434151 TI - Anandamide inhibits the Wnt/beta-catenin signalling pathway in human breast cancer MDA MB 231 cells. PMID- 23434150 TI - Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers? AB - BACKGROUND: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. METHODS: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). RESULTS: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52). CONCLUSIONS: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome. PMID- 23434152 TI - [Impact of the use of ICT on pharmacy costs. The incorporation of the electronic prescription]. PMID- 23434153 TI - The greener synthesis of nanoparticles. AB - In this review, we examine 'greener' routes to nanoparticles of zerovalent metals, metal oxides, and salts with an emphasis on recent developments. Products from nature or those derived from natural products, such as extracts of various plants or parts of plants, tea, coffee, banana, simple amino acids, as well as wine, table sugar and glucose, have been used as reductants and as capping agents during synthesis. Polyphenols found in plant material often play a key role in these processes. The techniques involved are simple, environmentally friendly, and generally one-pot processes. Tea extracts with high polyphenol content act as both chelating/reducing and capping agents for nanoparticles. We discuss the key materials used in the field: silver, gold, iron, metal alloys, oxides, and salts. PMID- 23434154 TI - Antibacterial surfaces: the quest for a new generation of biomaterials. AB - In this review we attempt to clarify the notion of what is meant by the term antibacterial surfaces and categorise the approaches that are commonly used in the design of antibacterial surfaces. Application of surface coatings and the modification of the surface chemistry of substrata are generally considered to be a chemical approach to surface modification (as are surface polymerisation, functionalisation, and derivatisation), whereas, modification of the surface architecture of a substrate can be considered a physical approach. Here, the antifouling and bactericidal effects of antibacterial surfaces are briefly discussed. Finally, several recent efforts to design a new generation of antibacterial surfaces, which are based on mimicking the surface nanotopography of natural surfaces, are considered. PMID- 23434155 TI - Acute soft tissue injury management: past, present and future. PMID- 23434156 TI - What are the main contributions to the total enthalpy of displacement accompanying the adsorption of some multivalent metals at the silica-electrolyte interface? AB - The integral molar enthalpies of displacement, Deltadplh, accompanying adsorption of Mg(II), Ca(II), Sr(II), Ba(II), Cd(II), Co(II), Zn(II), and Eu(III) cations from aqueous solutions of metal nitrate onto Spherosil XO75LS at 298K were determined based on the combination of liquid flow calorimetry and classical adsorption for two degrees of surface coverage: 0.035MUmolm(-2) and 0.08MUmolm( 2), in the presence of 0.1molL(-1) sodium nitrate in the aqueous phase at pH 5, 6, and 7. The displacement was shown to be endothermic and quite independent of the chemical specificity of the adsorbing metal. Two enthalpy effects were postulated to contribute mostly to the positive Deltadplh values, depending on the experimental pH value: (i) cation dehydration upon adsorption and (ii) deprotonation of surface silanols to create negatively charged SiO(-) sites. Changing proportions among the various adsorbed species, including "free" Eu(3+) or Cd(2+) cations and hydrolyzed Eu(OH)(2+), Eu(OH)2(+) or Cd(OH)(+) cations, were accepted to explain the downward trends in Deltadplh with increasing extent of adsorption for Eu(III) and Cd(II). PMID- 23434157 TI - Risk factors for distant metastasis in squamous cell carcinoma of the oral cavity. AB - PURPOSE: This study aimed to identify risk factors for distant metastasis (DM) in patients with squamous cell carcinoma of the oral cavity. MATERIALS AND METHODS: A retrospective analysis of 516 patients with squamous cell carcinoma of the oral cavity from 1986 through 2009 was performed. DM was classified as 2 types based on whether patients had locoregional failure (LRF). The frequency and clinicopathologic risk factors for the 2 types of DM were evaluated separately using univariate chi(2) tests and multivariate logistic regression models. Overall survival was evaluated with the Kaplan-Meier method and compared by the log-rank test. RESULTS: Fifty-four patients (10%) developed DM, 16 with isolated DM and 38 with DM with LRF. The 5-year survival rate from a DM diagnosis in patients with isolated DM was 13%, significantly higher than the rate of those with DM with LRF (0%; log-rank test, P < .05). Multivariate analysis indicated unique risk factors and common risk factors for the 2 types of DM. The common factors were nonsurgical treatment and the presence of pathologic positive nodes. The unique factors for isolated DM were histologic grade G3 and the later treatment period (after 1998). Conversely, the unique factor for DM with LRF was extracapsular spread. CONCLUSION: The risk of isolated DM development after 1998 was 2.6 times higher than that before 1997. Histologic grade G3 and the presence of pathologic positive nodes may play a causative role in isolated DM. PMID- 23434158 TI - Floor-of-mouth dermoid cysts: report of 3 variants and a suggested change in terminology. AB - PURPOSE: Dermoid cyst is a frequently used descriptive term, but its definition changes according to the clinician (eg, dermatologists, neurologists, gynecologists, oral and maxillofacial surgeons, and plastic surgeons). It is sometimes used synonymously with teratoma. In oral and maxillofacial surgery, it is applied to describe congenital floor-of-mouth cysts of 3 histologic types: epidermoid, dermoid, and teratoid. This terminology is confusing and has led to some ambiguity in the literature. The purpose of this report is to document 3 cases illustrating the utility of a more specific term, congenital germline fusion cyst of the floor of the mouth. PATIENTS AND METHODS: Patients who presented with floor-of-mouth swelling were evaluated by history, clinical examination, and imaging studies (magnetic resonance imaging and computed tomography). RESULTS: Three cases (1 epidermoid variant, 1 dermoid variant, and 1 teratoid variant) are documented to illustrate the new terminology. CONCLUSION: Congenital germline fusion cyst is more reflective of the embryologic origins of the lesion than dermoid cyst and is inclusive of all 3 histologic variants. PMID- 23434159 TI - Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. AB - PURPOSE: The aim of this prospective hospital-based study was to refine a surgical protocol for tooth extractions in patients with a history of intravenous use of a potent bisphosphonate by modifying a previously reported protocol to produce a significantly shortened operating time. PATIENTS AND METHODS: Prospective patients with a follow-up of at least 4 months were included. Tooth extractions were performed without a vestibular split-thickness flap; healing was stimulated by filling the extraction site with autologous plasma rich in growth factors (PRGF System, BTI Biotechnology Institute, Vitoria, Spain). Local and systemic infection control was obtained with dental hygiene and antibiotic therapy. RESULTS: Sixty-three patients participated in the study. Two hundred two tooth extractions were performed. Differences between the present and previous protocols (the previous protocol used a vestibular flap) were analyzed and the surgical time proved significantly shorter for the present approach (P = .00). CONCLUSIONS: The proposed surgical protocol appears to be a better choice for patients treated with intravenous bisphosphonates who need tooth extraction, because it seems to be faster and simpler than the previously reported successful protocol. PMID- 23434160 TI - Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome. AB - We reviewed the records of 391 patients who had presented with a Clinically Isolated Syndrome and selected 205 who had performed a baseline spinal tap and MRI scan. We studied cerebrospinal fluid (CSF) and serum IgM oligoclonal bands (IgMOB) using agarose gel isoelectric focusing and analyzed the impact of baseline clinical, MRI and CSF variables on the risk of conversion to clinically definite multiple sclerosis, i.e. on the risk of a clinical relapse. At survival analysis, a lower age at onset, an onset with optic neuritis and the presence of CSF-restricted IgMOB increased the risk of a relapse. Only the presence of CSF restricted IgMOB predicted a relapse within one year. PMID- 23434161 TI - Sequence variations in the von Hippel-Lindau tumor suppressor gene in patients with intracranial aneurysms. AB - BACKGROUND: The rupture of intracranial aneurysms leads to subarachnoid hemorrhage, which is often associated with poor outcome. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the lack of candidate genes precludes identifying patients at risk by genetic analyses. We observed intracranial aneurysms in 2 patients with von Hippel-Lindau (VHL) disease and the known disease-causing mutation c.292T > C (p.Tyr98His) in the VHL tumor suppressor gene. This study investigates whether the VHL gene is a possible candidate gene for aneurysm formation. METHODS: Patients with intracranial aneurysms admitted to our department between 2006 and 2009 were enrolled. The peripheral leukocyte DNA of 200 patients was investigated for sequence variations in the VHL gene using denaturing high performance liquid chromatography. Peripheral leukocyte DNA of 100 randomly sampled probands was investigated as a control group. The allelic frequencies of sequence variations between both groups were compared using the Fisher exact test. RESULTS: Fourteen of 200 patients with intracranial aneurysms had sequence variations at 6 different loci in the VHL gene. In contrast, no sequence variations were identified in 100 probands in the control group (P = 0.0062). However, none of the single-sequence variations had a statistically significant difference in the allelic frequencies compared to the control group. CONCLUSIONS: There is accumulating evidence for a genetic basis of aneurysm development. Our investigations lead to the conclusion that the VHL gene is potentially involved in the formation of intracranial aneurysms in a subset of patients. Additional candidate genes need to be identified in order to develop sensitive genetic screening for at-risk patients. PMID- 23434162 TI - Hypertension increases the risk of cerebral microbleed in the territory of posterior cerebral artery: a study of the association of microbleeds categorized on a basis of vascular territories and cardiovascular risk factors. AB - BACKGROUND: It has been suggested that the etiology of cerebral microbleeds (CMBs) differs according to their location in the brain, with lobar microbleeds being caused by cerebral amyloid angiopathy and deep or infratentorial microbleeds resulting from hypertension and atherosclerosis. We hypothesized that there were associations between cerebral arterial branches, cardiovascular risk factors, and the occurrence of CMBs. We examined these relationships in the current study. METHODS: Three hundred ninety-three patients with CMBs were analyzed in this study. The CMBs were listed according to the various arterial territories, and these were assessed for their relationship with cardiovascular risk factors, markers of small vessel disease, and their presence and location using multiple logistic regression. RESULTS: Systolic blood pressure had a significant association with CMBs in the territory of the posterior cerebral artery and the deep and infratentorial locations. The presence of lacunar infarcts, hemorrhage, and white matter changes were associated with CMBs in nearly all arterial territories. CONCLUSIONS: Hypertension increases the risk of microbleeds in the territory of the posterior cerebral artery and the deep and infratentorial locations. Cerebral amyloid angiopathy may be responsible for the microbleeds in the lobar area of brain. PMID- 23434163 TI - Characterizing the consequences of chronic climbing-related injury in sport climbers and boulderers. AB - OBJECTIVE: To describe the association between chronic climbing-related injuries and functional and quality-of-life impairments in chronically injured sport climbers and boulderers. METHODS: A retrospective, cross-sectional, anonymous survey was developed to assess the association between chronic climbing-related injuries and severity of injury-related pain, impact on activities of daily living, and impact on continued pursuit of rock climbing and other athletic endeavors. This survey was administered to a convenience sample of chronically injured sport climbers and boulderers recruited from several highly trafficked rock climbing websites. RESULTS: Four hundred thirty-nine respondents submitted surveys adequate for analysis. These respondents reported 863 chronic injuries. A majority of these were in the upper extremity. Approximately half of respondents reported injury-related pain or functional limitation more than 10 days a month, one quarter reported that their pain caused moderate to severe interference with activities of daily living, most altered their climbing habits as a result of their injuries, and one third indicated that their pain moderately or severely affected their ability to pursue other sports. CONCLUSIONS: This study is the first to suggest that a subset of chronically injured climbers exists whose injuries may cause significant pain and activities-of-daily-living and sports related functional limitation. PMID- 23434164 TI - Personal use of performance-enhancing drugs at high altitude. PMID- 23434165 TI - Effects of food or sleep deprivation during civilian survival training on clinical chemistry variables. AB - OBJECTIVE: To describe clinical chemistry and weight changes after short-term food or sleep deprivation or multiple deprivations during civilian survival training. METHODS: Data from one baseline-controlled two-period crossover study designed to compare sleep deprivation for up to 50 hours with food deprivation for up to 66 hours (n = 12) and data from regular multiple-deprivations survival training comparing participants (n = 33) with nondeprived instructors (n = 10). RESULTS: Food deprivation was associated with decreased body weight, blood glucose, serum triglycerides, sodium, chloride, and urine pH, and there were increases in blood and urine ketones and serum free fatty acids. Sleep deprivation was associated with a minor decrease in hemoglobin and erythrocyte particle count and volume fraction and an increase in leukocytes. CONCLUSIONS: The clinical chemistry and body weight changes associated with food deprivation were qualitatively similar to those observed in fasting obese patients but developed quicker in the survival training setting. Sleep deprivation had few effects on the clinical chemistry profile except for hematological variables. Physicians evaluating clinical chemistry data from patients subjected to short term food or sleep deprivation should take the physiological state into account in their assessment. PMID- 23434166 TI - "Performance enhancing" drugs at high altitude. PMID- 23434167 TI - Ibuprofen for prevention of acute mountain sickness: is bigger really better? PMID- 23434168 TI - In response to WMS practice guidelines for eye injuries and illnesses. PMID- 23434169 TI - Measuring arterial oxygenation in a high altitude field environment: comparing portable pulse oximetry with blood gas analysis. AB - OBJECTIVE: High altitude environments present unique medical treatment challenges. Medical providers often use small portable pulse oximetry devices to help guide their clinical decision making. A significant body of high altitude research is based on the use of these devices to monitor hypoxia, yet there is a paucity of evidence that these devices are accurate in these environments. We studied whether these devices perform accurately and reliably under true mountain conditions. METHODS: Healthy unacclimatized active-duty military volunteers participating in mountain warfare training at 2100 m (6900 feet) above sea level were evaluated with several different pulse oximetry devices while in a cold weather, high altitude field environment and then had arterial blood gases (ABG) drawn using an i-STAT for comparison. The pulse oximeter readings were compared with the gold standard ABG readings. RESULTS: A total of 49 individuals completed the study. There was no statistically significant difference between any of the devices and the gold standard of ABG. The best performing device was the PalmSAT (PS) 8000SM finger probe with a mean difference of 2.17% and SD of 2.56 (95% CI, 1.42% to 2.92%). In decreasing order of performance were the PS 8000AA finger probe (mean +/- SD, 2.54% +/- 2.68%; 95% CI, 1.76% to 3.32%), the PS 8000Q ear probe (2.47% +/- 4.36%; 95% CI, 1.21% to 3.75%), the Nonin Onyx 9500 (3.29% +/- 3.12%; 95% CI, 2.39% to 4.20%), and finally the PS 8000R forehead reflectance sensor (5.15% +/- 2.97%; 95% CI, 4.28% to 6.01%). CONCLUSIONS: Based on the results of this study, results of the newer portable pulse oximeters appear to be closely correlated to that of the ABG measurements when tested in true mountain conditions. PMID- 23434170 TI - Accidental poisoning by death cap mushrooms: be careful what you eat. PMID- 23434171 TI - Sickle cell disease and perioperative considerations: review and retrospective report. AB - PURPOSE: To review the current literature on sickle cell disease (SCD) and patient management in the perioperative setting and to retrospectively evaluate the treatment and complications of oral and maxillofacial surgical patients with SCD treated in the Regional Medical Center at Memphis. MATERIALS AND METHODS: A literature review was performed, with the main search criteria of SCD, anesthesia, and oral and maxillofacial surgery. In addition, a retrospective record analysis was performed of patients with SCD seen at the Regional Medical Center over 9 years. Criteria recorded included the procedure, type of anesthesia, use of intravenous fluids, thermoregulation (use of warm fluids and blankets covering the patient), supplemental oxygen, antibiotic prophylaxis, and postoperative complications. RESULTS: In total, 33 clinic visits were reviewed, with 29 patients and 21 procedures performed. Patients were managed quite differently each time, with no consistent protocol. Intravenous fluids were used in only 9 of 21 procedures, supplemental oxygen was recorded for 11 of 21 patients, and preoperative antibiotics were given to 14 of 21 patients. A small sample and the lack of an established protocol did not provide significant statistics. CONCLUSION: Patients with SCD are at risk for various perioperative complications, and it is imperative that the surgeons be educated and prepared so they can effectively manage these patients. No significant complications were found through the outpatient treatment of patients with SCD in this analysis. It may be concluded that treating patients with SCD in the outpatient setting is not contraindicated and may be a safe alternative to inpatient treatment or no treatment at all. PMID- 23434172 TI - Effect of simvastatin injections on temporomandibular joint inflammation in growing rats. AB - PURPOSE: Juvenile idiopathic arthritis often affects the temporomandibular joint (TMJ), resulting in facial deformities, and intra-articular injections of anti inflammatory steroids used in treatment may inhibit bone growth in the developing condyle. The purpose of this pilot study was to evaluate the anti-inflammatory properties of simvastatin (SIM), a bone anabolic drug, compared with the common steroid triamcinolone hexacetonide (TH) in experimental TMJ arthritis of growing rats. METHODS: Joint inflammation was induced by injecting complete Freund's adjuvant (CFA) into the TMJs of 32 growing (4-week-old) Sprague-Dawley rats while simultaneously receiving 1) ethanol drug carrier, 2) 0.1 mg of SIM, 3) 0.5 mg of SIM, or 4) 0.15 mg of TH. Six rats had no treatment to the TMJ. Animals were euthanized 28 days later, and TMJs were decalcified and stained with hematoxylin eosin. RESULTS: Histopathologic TMJ results showed that CFA injection along with drug carrier induced increased thickness of the articular layer on the head of the condyle and inflammation of the retrodiscal area (CFA and ethanol). Although both TH and SIM reduced the articular layer thickness, 0.5 mg of SIM was more effective at reducing subsynovial inflammation. CONCLUSIONS: Intra-articular simvastatin showed anti-inflammatory properties in this TMJ model, prompting its further study in the growing TMJ, where bone anabolic properties would be important. PMID- 23434173 TI - Primary and secondary leiomyosarcoma of the oral and perioral region- clinicopathological and immunohistochemical analysis of a rare entity with a review of the literature. AB - PURPOSE: Leiomyosarcoma (LMS) rarely occurs in the head and neck region. These tumors present with a wide range of clinical features, so the diagnosis is predicated on conventional microscopic findings coupled with immunohistochemical analysis. PATIENTS AND METHODS: Clinical and histologic data of 7 patients with LMS of the head and neck were recorded retrospectively. In addition to routine immunohistochemistry, staining for cell cycle regulator proteins p16 and p21 was performed. RESULTS: Five LMSs (4 intraoral, 1 dermal cheek) occurred primarily in the oral and perioral region. Two LMSs (parietal and sinonasal) were diagnosed as metastases originating from the uterus and pelvis. Treatment of the primary LMSs consisted of radical tumor resection with clear margins. Distant metastases from LMSs were irradiated or excised as palliative treatment. Three of 5 patients (60%) with primarily excised LMS developed recurrence after an average of 7 months, with lung metastases occurring after 17 months. In 1 patient, cervical lymph node metastases were detected after 10 months. Of all patients, 5 died after an average survival period of 2.4 years. The mean survival period of the 5 patients with primary LMS of the head and neck was 3.3 years. All tumors were positive for vimentin and alpha-smooth muscle actin, with 57% of tumors showing positive nuclear expression of p16 and 71% of p21. Lack of p16 nuclear expression was associated with a shorter mean survival time (1.3 vs 4.3 yr for p16 positivity). CONCLUSION: Lung and cervical lymph node metastases often occur in LMS of the head and neck. Presurgical staging, including gynecologic examination, whole-body computed tomography, and sometimes positron-emission or computed tomography, to rule out LMS metastasis is mandatory. Surgical resection of the tumor should be given top priority. Lack of p16 reactivity may have a prognostic value for LMS because it was related to a trend toward poorer survival. PMID- 23434174 TI - Normal electrocardiographic QT interval in race-fit Standardbred horses at rest and its rate dependence during exercise. AB - OBJECTIVES: Cardiac repolarization, measured as QT and Tpeak to Tend (TpTe) intervals on the ECG, is important, as irregularities caused by diseases, ventricular hypertrophy, drugs and genetic defects can trigger arrhythmias which predispose human patients to syncope and sudden cardiac death. In horses, repolarization is not well described and therefore QT analysis cannot yet be used diagnostically. Therefore, we sought to describe reference values for the normal QT and TpTe intervals in Standardbreds and to determine the best method for heart rate (HR) correction. ANIMALS: 30 Standardbreds. METHODS: QT and TpTe intervals were measured during rest and exercise and plotted against HR converted to Rpeak to Rpeak interval (RR). Data were fitted with relevant regression models. Intra- and inter-observer agreement was assessed using Bland-Altman analyses. RESULTS: Data were best described by a piecewise linear model (r(2) > 0.97). Average prediction error of this model was smaller than for both Bazett and Fridericia corrections. Coefficient of repeatability of intra- and inter-observer variability was 8.76 ms and 5.64 ms respectively and coefficient of variation was 1.77% and 2.76% respectively. TpTe increased with RR in stallions. CONCLUSIONS: The QT interval in Standardbred horses shortens with decreasing RR interval (increasing HR) as in humans, but in a markedly different order as it clearly follows a piecewise linear model. The equine QT interval can be measured easily and there is small intra- and inter-observer variability. This model of the equine QT interval provides clinicians with a method that could support a diagnosis of repolarization disturbances in horses. PMID- 23434175 TI - Five things physicians and patients should question in hospice and palliative medicine. AB - Overuse or misuse of tests and treatments exposes patients to potential harm. The American Board of Internal Medicine Foundation's Choosing Wisely(r) campaign is a multiyear effort to encourage physician leadership in reducing harmful or inappropriate resource utilization. Via the campaign, medical societies are asked to identify five tests or procedures commonly used in their field, the routine use of which in specific clinical scenarios should be questioned by both physicians and patients based on the evidence that the test or procedure is ineffective or even harmful. The American Academy of Hospice and Palliative Medicine (AAHPM) was invited, and it agreed to participate in the campaign. The AAHPM Choosing Wisely Task Force, with input from the AAHPM membership, developed the following five recommendations: 1) Don't recommend percutaneous feeding tubes in patients with advanced dementia; instead, offer oral-assisted feeding; 2) Don't delay palliative care for a patient with serious illness who has physical, psychological, social, or spiritual distress because they are pursuing disease directed treatment; 3) Don't leave an implantable cardioverter-defibrillator activated when it is inconsistent with the patient/family goals of care; 4) Don't recommend more than a single fraction of palliative radiation for an uncomplicated painful bone metastasis; and 5) Don't use topical lorazepam (Ativan(r)), diphenhydramine (Benadryl(r)), and haloperidol (Haldol(r)) (ABH) gel for nausea. These recommendations and their supporting rationale should be considered by physicians, patients, and their caregivers as they collaborate in choosing those treatments that do the most good and avoid the most harm for those living with serious illness. PMID- 23434177 TI - Effective follow-up consultations: the importance of patient-centered communication and shared decision making. AB - Paediatricians spend a considerable proportion of their time performing follow-up visits for children with chronic conditions, but they rarely receive specific training on how best to perform such consultations. The traditional method of running a follow-up consultation is based on the doctor's agenda, and is problem oriented. Patients and parents, however, prefer a patient-centered, and solution focused approach. Although many physicians now recognize the importance of addressing the patient's perspective in a follow-up consultation, a number of barriers hamper its implementation in practice, including time constraints, lack of appropriate training, and a strong tradition of the biomedical, doctor centered approach. Addressing the patient's perspective successfully can be achieved through shared decision making, clinicians and patients making decisions together based on the best clinical evidence. Research shows that shared decision making not only increases patient, parent, and physician satisfaction with the consultation, but also may improve health outcomes. Shared decision making involves building a physician-patient-parent partnership, agreeing on the problem at hand, laying out the available options with their benefits and risks, eliciting the patient's views and preferences on these options, and agreeing on a course of action. Shared decision making requires specific communication skills, which can be learned, and should be mastered through deliberate practice. PMID- 23434176 TI - The association of cardiac vagal control and executive functioning--findings from the MIDUS study. AB - Cardiac vagal control (CVC), an index of parasympathetic contribution to cardiac regulation, has been linked to enhanced executive functioning (EF). However, findings to date have been based on small or unique samples. Additionally, previous studies assessed the CVC-EF link only during rest or recovery period from a cognitive challenge, but not during both states. In the present study, data on 817 socioeconomically diverse participants were obtained from the Midlife Development in the United States (MIDUS) study. As part of this study, participants completed cognitive tests, including EF, along with laboratory-based measures of CVC during rest and following recovery from a cognitive challenge. Regression analyses adjusting for respiratory rate revealed no effect of CVC at rest or during recovery on a global index of EF. However, exploratory post-hoc analyses of the components of the global EF index revealed a significant association between faster vagal recovery and better attention-switching and response inhibition abilities, as indexed by faster reaction time to the mixed SGST. This association remained significant after controlling for demographic, clinical (BMI, diseases and medications altering cardiac autonomic functioning, etc.), and health behavior covariates (Beta = .148, p = .010). Our findings suggest that future studies may need to investigate the links of CVC to specific EF abilities, rather than global measures of EF. Additionally, our results highlight the importance of assessing CVC during both rest and recovery from a cognitive challenge. The authors discuss the putative neurobiological underpinning of this link, as well as suggestions for future basic and clinical research. PMID- 23434178 TI - Using communication skills to improve adherence in children with chronic disease: the adherence equation. AB - Nonadherence to maintenance medication is common in paediatric chronic conditions. Despite the common belief that nonadherence is therapy-resistant, and the apparent lack of evidence for successful interventions to improve adherence, there is, in fact, a considerable body of evidence suggesting that adherence can be improved by applying specific communicative consultation skills. These can be summarized as the adherence equation: adherence=follow-up+dialogue+barriers and beliefs+empathy and education => concordance. Close follow-up of children with a chronic condition is needed to establish a therapeutic partnership with the family. Teaching self management skills is not a unidirectional process of providing information, but requires a constructive and collaborative dialogue between the medical team and the family. Identifying barriers to adherence can be achieved in a non-confrontational manner, by showing a genuine interest what the patient's views and preferences are. In particular, parental illness perceptions and medication beliefs should be identified, because they are strong drivers of nonadherence. Through empathic evidence-based education, such perceptions and beliefs can be modified. By applying these strategies, concordance between the child's family and the medical team can be achieved, resulting in optimal adherence to the jointly created treatment plan. PMID- 23434179 TI - Human milk and related oligosaccharides as prebiotics. AB - Human milk oligosaccharides (HMO) are believed to have a range of biological activities beyond providing nutrition to the infant. Principal among these is that they may act as prebiotics. Prebiotics are dietary ingredients, usually oligosaccharides that provide a health benefit to the host mediated by the modulation of the human gut microbiota. While it is clear that such oligosaccharides may have potential applications in infants and adults alike, this potential is limited by the difficulties in manufacturing HMO. Consequently functional alternatives such as galacto-oligosaccharides (GOS) are under investigation. GOS are produced enzymatically from lactose for commercial use in food applications--including addition to infant formulae--as similar to breast milk oligosaccharides, they encourage a gut bacteria population that promotes health and reduces the incidence of intestinal infections. New methods for separation and concentration of complex, breast milk-like oligosaccharides from bovine milk industrial streams that contain only low amounts of these valuable oligosaccharides are providing the opportunity to investigate other viable sources of specific oligosaccharides for use as prebiotics in supplements or food products. PMID- 23434180 TI - Plant metabolic engineering: future prospects and challenges. PMID- 23434181 TI - Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. AB - BACKGROUND: Autophagy plays distinct roles in apoptosis and the inflammatory process. Understanding the role of autophagy in sepsis-induced acute lung injury (ALI) may provide new insights into developing novel therapeutic strategies for this group of patients. The aim of this study was to investigate the regulation of autophagy in the septic lung and to use pharmacologic agents to modulate autophagy to study its functional significance. METHODS: Mice were subjected to cecal ligation and puncture (CLP) or a sham operation. At 1 hour after CLP, mice were treated with vehicle, activated protein C (APC), rapamycin, or bafilomycin A1. Mice were humanely killed at 4 or 24 hours after the operation or were observed for <= 7 days. RESULTS: CLP induced a systemic inflammatory response and significantly decreased survival. In lung tissue, increased leukocyte infiltration, inflammation, and apoptosis were observed. In contrast, autophagy was suppressed after CLP such that the expression of LC3II, Atg5, and Rab7 were downregulated. Rapamycin activated autophagy, limited the CLP-induced proinflammatory response, and downregulated apoptotic activity after CLP. The administration of APC after CLP had an effect similar to that of rapamycin. Both medications significantly improved survival 7 days after CLP. CONCLUSION: The downregulation of autophagy may lead to systemic inflammation and ALI after sepsis. The direct or indirect modification of autophagy using rapamycin or APC, respectively, resulted in improved survival. Enhancing or restoring autophagy early after sepsis seems to be a potential strategy for the treatment of sepsis induced ALI. PMID- 23434182 TI - Sperm cryopreservation of sex-reversed seven-band grouper, Epinephelus septemfasciatus. AB - Seven-band grouper Epinephelus septemfasciatus is a protogynous hermaphrodite. The male individuals' number is more less than the female one. Thus, it is necessary for artificial reproduction and crossbreeding to research the sperm cryopreservation of sex-reversed seven-band grouper. In present study, the spermatozoa of sex-reversed immature fish were frozen using the different cryopreserving solutions for cryopreservation. The several factors that may affect the freezing survival rate of seven-band grouper spermatozoa such as the spermatozoa diluent, the concentration and composition of cryoprotective agent have been studied. The results showed that ES1-3 (60g/L glucose+10g/L NaCl+0.5g/L NaHCO3) was significantly better as a diluent compared with MPRS, TS-2 and other series of diluent ES1. The further experiment revealed that the optimal cryoprotectants were 10% dimethyl sulfoxide (DMSO) or 10% 1,2-propylene glycol (PG) with the post-thaw sperm motility was 76.67+/-0.00% and 75.00+/-5.00%, respectively. In addition, salinity of seawater is an important motility stimulator because that the highest motility of 96.00+/-1.73% was obtained at salinity 300/00. In crossbreeding test with fresh unfertilized eggs of kelp grouper Epinephelus moara, the ratio of fertilization and hatchability had no significant differences between the cryopreserved sperm and fresh sperm of seven band grouper. It is suggested that the frozen sperm of seven-band grouper could be applied in artificial reproduction and crossbreeding. PMID- 23434183 TI - Unsuccessful switch from insulin to sulfonylurea therapy in permanent neonatal diabetes mellitus due to an R201H mutation in the KCNJ11 gene: a case report. AB - Mutations in KCNJ11 are a common cause of permanent neonatal diabetes mellitus. Previously, all patients carrying an R201H mutation in the KCNJ11 gene showed successful switches from insulin to sulfonylurea. Here, we report an unsuccessful switch in an 18-year-old patient carrying the common R201H mutation in the KCNJ11 gene. PMID- 23434184 TI - Polysaccharide biosynthesis protein CapD is a novel pathogenicity-associated determinant of Haemophilus parasuis involved in serum-resistance ability. AB - The capD gene, encoding a polysaccharide biosynthesis protein, was identified previously as a differential gene between Haemophilus parasuis virulent strain Nagasaki and avirulent strain SW114; however, the characteristics of this gene associating with the pathogenicity of H. parasuis remain unclear. Here, the capD deletion mutant (DeltacapD) and its complement strain (C-capD) were generated in H. parasuis virulent strain SH0165. The deletion of capD gene significantly attenuated the pathogenicity of the SH0165 strain, while the complementation of this gene largely recovered the pathogenicity to piglets. Additionally, the DeltacapD strain could not be recovered from piglets after challenge, while both SH0165 and C-capD strains were recovered from most systemic sites. Moreover, the DeltacapD strain exhibited an extreme sensitivity to the complement-mediated killing compared with SH0165 strain, while its serum-resistance ability largely restored with the capD gene complementation. These data present the evidence that the capD gene is a novel pathogenicity-associated determinant and involved in serum-resistance ability of H. parasuis. PMID- 23434185 TI - Identification of chicken intestinal microbiota correlated with the efficiency of energy extraction from feed. AB - The microbiota of the gastrointestinal tract is a complex community of many different species of microorganisms, dominated by bacteria. This diverse population provides the host with an extensive array of enzymes and substrates which, together with the host's metabolic capabilities, provides an extensive metabolome available for nutrient and energy collection. We investigated broiler chickens to determine whether the abundance of certain members of the microbiota was correlated with the relative ability to extract energy from a typical wheat soybean diet. A number of mostly uncultured phylotypes were identified that significantly differed in abundance between birds with high apparent metabolizable energy (AME), measured as the difference between energy consumed and energy excreted, and those with low AME. Among the phylotypes that were more prevalent in birds with high energy efficiency, most were closely associated with isolates of bacterial groups that are commonly recognized as producing enzymes that degrade cellulose and/or resistant starch. Phylotypes that were negatively correlated with performance were all unknown and uncultured, a significant number belonging to an unknown class of Firmicutes. The identification of bacterial phylotypes correlated with the efficiency of energy use opens up the possibility of harnessing these bacteria for the manipulation of the host's ability to utilize energy. Increasing the ability to convert food to body weight is of interest to the agricultural industries, while the opposite is applicable in weight management and obesity control in humans. PMID- 23434186 TI - MRSA carriage in the equine community: an investigation of horse-caretaker couples. AB - Equine methicillin-resistant Staphylococcus aureus (MRSA) carriage entails a risk of both equine and zoonotic transmission and infection. In Europe, CC398, the livestock-associated (LA-)MRSA is highly prevalent in horses and veterinary personnel at equine clinics. The extent of the MRSA reservoir created by healthy horses from the general population and associated health hazard for their daily caretakers is, however, unknown. This study aimed at screening healthy horse caretaker couples from a broad range of home farms. At five equine gatherings, 166 couples were selected for MRSA screening in the anterior nares and participation in an epidemiologic survey. All MRSA isolates were subjected to genotyping and antimicrobial susceptibility testing. Only 4 humans (2.4%) and 2 of their horses (1.2%) tested MRSA positive. Within the 2 couples where both partners were positive, man and horse carried isolates belonging to identical, livestock-associated spa types (t011 and t2330) and demonstrating equal antimicrobial susceptibility patterns. For all LA-MRSA positive humans (n=3) and animals (n=2) regular (in)direct contact with the veterinary sector was reported. A significant association between the horses' carriage status and transportation to an event could not be demonstrated (P=1.00). In conclusion, outside equine clinics, the extent of the MRSA reservoir in horses and their caretakers was low. Travel to an equine gathering could not be withheld as a risk factor for equine MRSA carriage, whereas indications were found that contact with veterinary care may predispose both healthy horses and their handlers to carriage. PMID- 23434187 TI - Experimental infection of Carrion crows (Corvus corone) with two European West Nile virus (WNV) strains. AB - West Nile virus (WNV) has become a wide-spread arbovirus in Europe and the Mediterranean Basin countries. This emerging zoonotic disease disseminated 13 years ago in North America where its impact on animal and public health has been considerable. Although American corvids have been the most reliable avian sentinels for WN surveillance in the United States, there is so far no data available about the susceptibility of their Western European counterparts to WNV. Clinical follow-up and serum, oral swabs and feathers viral RNA load monitoring was herein performed on wild-caught Carrion crows (Corvus corone) experimentally inoculated with two WNV strains, Is98 that was isolated from a stork in Israel where it elicited high rates of avian deaths in 1998, and Fr2000 which was only associated to sporadic equine cases in Camargue, France in 2000. Inoculated crows were sensitive to both WNV infections and, as expected from the available epidemiological data, Is98 induced a higher mortality rate (100% vs. 33%) and a quicker fatal outcome, with higher viral RNA loads detected in the serum, oral swabs and feathers than in the Fr2000 group. Therefore, Carrion crows should also be a target species for WNV surveillance in Western Europe, where reporting for abnormal mortalities could be completed by viral detection in the herein described avian matrices. These experimental findings also emphasize the peculiarity of the European situation where a large spectrum of WNV genetic and pathotypic variants have been so far isolated despite limited WN disease reports in wild birds. PMID- 23434188 TI - Detection of equid herpesviruses 2 and 5 in a herd of 266 Lipizzaners in association with ocular findings. AB - A herd of Lipizzaners (n=266) in three locations [Federal stud Piber (Styria), Heldenberg (Lower Austria) and the Spanish Riding School Vienna (Vienna)] were examined for ocular diseases and tested for herpesviruses (HVs) in PBMCs, nasal- and conjunctival swabs. In 167 (62.8%) horses equid herpesvirus-2 (EHV-2) nucleic acid was identified in at least one of the investigated samples, and 136 (51.1%) horses were positive for equid herpesvirus-5 (EHV-5) nucleic acid in at least one of the samples. One hundred and five (39.5%) of the horses mentioned above were identified with EHV-2/EHV-5 double infections. The results were correlated with potential influence factors such as age, gender, location, and housing. Statistical analysis demonstrated a significantly higher percentage of horses diagnosed with HV infections stabled in one location (Piber); also, housing in free stalls was associated with a higher rate of HV infections. Horses carrying EHV-2 or EHV-5 nucleic acid were significantly younger than the negative group. Statistical analysis of PCR results and ophthalmic findings did not prove a significant association between any disease pattern and presence of the equid gammaherpesviruses EHV-2 and EHV-5. The results of this herd survey indicate that horses younger than eight years of age, housed in free stalls with high population densities have a significantly increased risk for infection with EHV-2 and EHV-5. However no prediction can be made whether this results in ophthalmic disease. This is the first ophthalmic-virologic survey of this magnitude in a single horse breed. PMID- 23434189 TI - Avian leukosis virus subgroup A and B infection in wild birds of Northeast China. AB - To analyze the status of wild birds infected with avian leukosis virus (ALV) in China, we collected 300 wild birds from various areas. Virus isolation and PCR showed that wild birds were infected by ALV-A and ALV-B. Two ALV-A and 4 ALV-B env sequences were obtained by PCR using primers designed to detect ALV-A and -B respectively. Our results showed that the gp85 genes of the 2 ALV-A strains have the highest homology with RAV-1, 99.8%, and more than 92% homology with other American strains. However, the gp85 genes of the two ALV-A strains showed slightly lower homology with Chinese strains (87.2-92.6%). Additionally, the 4 ALV-B strains have high homology with the prototype strain (RAV-2), from 99.1 to 99.4%, but they have slightly lower identity with Schmidt-Ruppin B and Prague subgroup B, from 93.3 to 98.4%. The 4 ALV-B strains showed the lowest identity with SDAU09C2 and SDAU09E3 (90%). In total, these results suggested that avian leukosis virus has infected wild birds in China. PMID- 23434190 TI - Education programmes preparing independent prescribers in Scotland: an evaluation. AB - BACKGROUND: Nurse prescribing (NP) is part of the modernisation of the health care workforce and contributes to patient care by improving access to quality services and medication, through utilisation of advanced professional skills. Nurses and midwives need to complete additional education in order to prescribe. This paper explores pedagogical issues relevant to professional training programmes. OBJECTIVES: To assess if programmes of education for nurse prescribing in Scotland were fit for purpose, from both the student and educator perspective with recommendations for future educational delivery. DESIGN: Data were collected using several methods: a questionnaire to all course members on prescribing programmes followed by focus-groups; and interviews with programme providers. RESULTS: Nurses and midwives training as prescribers work in a wide range of healthcare settings, in different geographic environments. They tended to be experienced, educated to degree level and most are over forty years of age. Most undertook the course to develop professionally and to improve patient care. Existing provision of education for prescribing is deemed appropriate and fit for purpose. The NP programme greatly enhances pharmacological knowledge building on existing clinical experience. The nature of these programmes works well and should be retained. However, whilst the educational programmes were centrally funded, less than half of students were provided with any allocated study time from their employers preventing nurses from maximising the gain from the educational preparation for prescribing. CONCLUSIONS: Nurse and midwife generic preparation for independent nurse prescribing in Scotland greatly increases professional expertise and is appropriate and fit for purpose. As other countries beyond Scotland and the UK seek to further progress nursing roles, learning from this controlled and structured development of prescribing underpinned by evidence could be of significant benefit. PMID- 23434191 TI - Analysing the role of the PICU nurse to guide education of new graduate nurses. AB - BACKGROUND: One strategy to address the current nursing shortage in specialty areas has been to introduce graduate nurse programs. However introducing novice nurses to specialty areas raises concerns around education and competency which, in turn, highlights the need to identify and prioritise the elements of competent paediatric intensive care unit (PICU) nursing care considered essential to safe practice. OBJECTIVES: To determine the key knowledge, skills and attributes of competent level PICU nurses. METHODS: A practice analysis survey of 15 nurse educators was conducted in all eight Australian and New Zealand PICUs during 2008. Three areas of practice essential to PICU nursing competence were explored: patients most commonly cared for; frequency and criticality of activities performed; and level of independence against critical care nursing competency standards. Data were analysed using descriptive statistics. RESULTS: Cardiac and respiratory problems accounted for over 50% of patients cared for by competent level nurses. Cardiac and respiratory activities were therefore also ranked as the most important activities. Respondents identified that competency domains of teamwork and professional practice are performed with minimal supervision, whereas clinical problem solving requires supervision and assistance. CONCLUSIONS: PICU nurses are performing activities and caring for a breadth of complex patients within a year of entering the workforce. Using a practice analysis to define actual practice and expectations can assist in the identification and prioritisation of content for graduate and other educational programs. PMID- 23434192 TI - The calm before the storm? Burnout and compassion fatigue among undergraduate nursing students. AB - Studies have consistently highlighted the deleterious impact of burnout and compassion fatigue on professional nurses' well-being and willingness to remain in the profession. Yet, as to what extent these noxious conditions are suffered among nursing students is still unclear. In this study 436 undergraduate nursing students completed surveys assessing their experiences of emotional exhaustion, depersonalization, lack of personal accomplishment, burnout, secondary traumatic stress, and compassion satisfaction (factors of burnout and compassion fatigue). There were no significant differences found between 3rd and 4th year students' reports of detrimental conditions and those of the 1st or 2nd year students. Furthermore, 4th year students reported significantly higher levels of personal accomplishment compared to 1st and 2nd year students. Semi-structured in-depth interviews with 3rd and 4th year students revealed that their clinical exposure during these years (especially during the 4th year) may enhance their other orientation as well as promote role actualization, which may serve as protective features. Students did, however, express concern regarding an inevitable onset of burnout at some point during their professional careers. It is suggested that a key to understanding the onset and experience of burnout and compassion fatigue among nurses is to continue to examine the transition from student to professional nurse and the cultural atmosphere of nursing education compared to professional practice. PMID- 23434193 TI - The role of omega-3 derived resolvins in arthritis. AB - Omega-3 polyunsaturated fatty acids (PUFAs) are known to alleviate joint stiffness and pain in rheumatoid arthritis patients. However, the mechanisms by which omega-3s exert their beneficial effects has not been fully explored. Herein we discuss a novel class of bioactive lipid mediators, which are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins. These lipid mediators exert anti inflammatory and pro-resolving properties and are log-orders more potent than their precursors. We also highlight that formation of pro-resolving mediators can be enhanced by widely used anti-inflammatory and cardioprotective drugs (aspirin and statins) via the modification of cyclooxygenase-2 enzymatic activity. These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of dietary supplementation with fish oils, and offer new avenues for developing therapeutics for inflammatory conditions such as rheumatoid arthritis. PMID- 23434194 TI - The bisphosphonates: risks and benefits of long term use. AB - Bisphosphonates are widely used globally as the main treatment for osteoporosis. Both safety and efficacy have only been rigorously evaluated in studies of relatively short duration (3-5 years), with smaller extension studies. The evidence for benefit beyond five years in intervention studies is limited and does not include proven efficacy against nonvertebral fractures. Observational studies suggest a sustained benefit against hip fractures. Bisphosphonates are stored in the skeleton for months to years, depending on the degree of bone turnover and the binding properties of the bisphosphonate in question. The effects of continued treatment on bone strength is not known but there are concerns that osteonecrosis of the jaw and atypical femur fractures may stem from long term bisphosphonate use. PMID- 23434195 TI - Double combined Z-plasty for wide-scar contracture release. AB - Z-plasty is one of the most widely employed techniques in plastic surgery and mainly serves the following purposes: elongation along the axis of the scar, dispersal of the scar followed by breaking up the straight-line scar and realigning the scar within the lines of minimal tension. It is useful especially to release linear-scar contracture, yet difficult for wide scars. This report describes a novel technique to release contracture effectively for any wide scars using a new design called double combined Z-plasty. The design is simple. The main limb is set to incise the wide scar, and this main limb is shared as a peripheral limb by two other Z-plasty designs. From the main limb, each central limb is designed along the margin of the scar in the opposite direction. The main and central limbs have 90 degrees between them. Other peripheral limbs are then designed facing laterally to the intact skin to make 60 degrees for the central limb. After skin incision, two triangular intact skin flaps could be inserted into the wide scar from both sides, making it possible to release contracture. We performed this technique on eight patients. All wounds healed well and scar contracture was satisfactorily released. This procedure is very useful for wide scar contracture, compared to conventional Z-plasty. PMID- 23434196 TI - Pentraxin 3, a novel cardiovascular biomarker, is expressed in aortic specimens of patients with coronary artery disease with and without rheumatoid arthritis. AB - BACKGROUND: The aims were to evaluate the presence and extent of pentraxin 3 depositions in specimens from the outer layers of the aorta and from the internal thoracic artery of patients with coronary artery disease with and without rheumatoid arthritis and to search for relationships between pentraxin 3 and vascular inflammation. METHODS: Using histochemistry and immunohistochemistry, we examined biopsies from the aortic adventitia and from the internal thoracic artery (both with adjacent perivascular tissue), removed during coronary artery bypass grafting in 19 rheumatoid arthritis and 20 non-rheumatoid-arthritis patients, for presence/extent of pentraxin 3 depositions, inflammatory cell infiltrates, and fibrosis. RESULTS: In the aorta, pentraxin 3 deposition occurred in all specimens, mostly at sites with inflammatory cell infiltrates or fibrosis, and their extent was related to the extent of inflammatory cell infiltrates (rho=0.43, 95% confidence interval: 0.13-0.66, P=.007). The extent of pentraxin 3 and inflammatory cell infiltrates in the aorta was similar in rheumatoid arthritis and non-rheumatoid-arthritis patients, but rheumatoid arthritis patients had more fibrosis and a lower proportion of T-cells in inflammatory cell infiltrates. In the internal thoracic artery, pentraxin 3 occurred only in 36% patients, and inflammatory cell infiltrates and fibrosis occurred in none. CONCLUSIONS: Pentraxin 3 depositions in the outer aortic layers are common and are related to the local inflammation. On the other hand, they occur less frequently in the internal thoracic artery, i.e., a vessel highly resistant to atherosclerosis. Rheumatoid arthritis patients had more pronounced fibrosis in the aortic specimens and a different leukocytic response than non-rheumatoid arthritis patients. In theory, pentraxin 3 might modulate the inflammatory process involved in the pathogenesis of cardiovascular disease and represent a target for new therapies. PMID- 23434197 TI - Uninodular combined hepatocellular and cholangiocarcinoma with multiple non neoplastic hypervascular lesions appearing in the liver of a patient with HIV and HCV coinfection. AB - A 42-year-old man suffering from haemophilia A and coinfection of human immunodeficiency virus (HIV) and hepatitis C virus was referred to our institution because of multiple liver tumours. He had been receiving highly active antiretroviral therapy for HIV infection. Ultrasonography showed multiple hypoechoic space-occupying lesions in the liver. Contrast-enhanced dynamic computed tomography (CT) and magnetic resonance imaging revealed multiple ring enhanced hypervascular lesions in the liver. An ultrasonography-guided biopsy was performed and histological evaluation indicated one of the lesions to be combined hepatocellular and cholangiocarcinoma and others to be non-neoplastic. The patient underwent partial hepatic resection and is currently alive without recurrence for 15 months. Multiple ring-enhanced lesions have been undetectable in postoperative follow-up CT examinations. PMID- 23434198 TI - Sensitivity of individual items of the Positive and Negative Syndrome Scale (PANSS) and items subgroups to differentiate between placebo and drug treatment in schizophrenia. AB - Lack of hard clinical endpoints is an essential problem in schizophrenia research. Disease state and treatment outcomes are measured using rating scales, e.g. Positive and Negative Syndrome Scale (PANSS). However, the PANSS score cannot always differentiate between placebo and drug treatment, even for established antipsychotics. The goal of this study was to identify the individual items of PANSS and subscales of selected items which are most sensitive to differentiate between placebo and drug effect. We analysed data from seven clinical trials of different antipsychotics. "Mini-PANSS" scales consisting of the most sensitive items were created and analysed statistically. The power of these scales to show a significant difference between placebo and drug treatment was compared with the power of total PANSS. Furthermore, pharmacokinetic pharmacodynamic analysis was performed to determine which of these scales shows the highest drug effect on top of the placebo effect. The results reveal that all 30 items of the PANSS scale show a therapeutic drug effect. The magnitude of placebo effect was not predictive for the power to detect drug effect. Mini-PANSS scales consisting of items with the largest drug treatment response and the scale with the largest mean-to-SD ratio are somewhat better in differentiating between placebo and drug treatment than the total PANSS. However, the difference between these scales and total PANSS is small. Therefore, our analysis does not support replacement of the total PANSS by a reduced scale in the analysis of primary endpoints. PMID- 23434199 TI - GJB2 and GJB6 screening in Tunisian patients with autosomal recessive deafness. AB - Autosomal recessive nonsyndromic deafness (ARNSD or DFNB) is a very common genetically heterogenous disorder. Although DFNB1 mutations are known to be the most frequent cause of this disorder, they are largely dependent on ethnic groups. The aims of our study are to specify the prevalence and the spectrum of GJB2 mutations as well as the prevalence of GJB6 large deletion in Tunisian population. PATIENTS AND METHODS: 95 unrelated patients with moderate to severe sensorineural hearing loss have been tested. The GJB2 coding region has been studied by PCR/Sequencing and the del(GJB6-D13S1830) mutation has been screened by fluorescent PCR multiplex. RESULTS: 27.36% of patients present mutations on both alleles of GJB2 gene and no one has the del(GJB6-D13S1830) mutation. The c.35delG mutation represents 86.5% of GJB2 deafness alleles and is found in homozygous state in 22 patients and in heterozygous state in one patient. Four other mutations are detected in four probands: two are compound heterozygous for the p.V37I/p.E47X and the c.35delG/p.R184P mutations, and two are homozygous for the p.E47X and the c.333-334delAA mutations. CONCLUSION: Our results showed that c.35delG is the most common but not the only GJB2 mutation and that the del(GJB6 del D13S1830) is absent in our cohort. Consequently, we propose a systematic sequencing of GJB2 coding region for ARNSD Tunisian patients and we suggest additional studies to specify the real prevalence of del(GJB6-D13S1830) in our population. PMID- 23434200 TI - Patterns of Internet and smartphone use by parents of children attending a pediatric otolaryngology service. AB - OBJECTIVES: To assess Internet use and the influence of smartphones on health information seeking by parents and carers of children with ENT conditions. METHODS: A paper-based questionnaire was circulated to parents attending otolaryngology services in both the out-patient and day-case settings at a tertiary referral centre. RESULTS: 79.5% of questionnaires were returned. 29.9% had consulted the Internet for ENT-related information. Factors associated with increased rates of ENT-related online activity included younger age, university education, and access to a smartphone (all p <= 0.001). 65.7% and 57.7% had found the information which they had found online to be understandable and helpful, respectively; however, just 25.5% felt that it had influenced the medical decisions they had made for their child. 50.3% had previously or intended to discuss information found online with their surgeon. 9.2% had searched online for information regarding their child's surgeon; 19.6% of these said that this had been a factor in choosing that particular surgeon. On ranking 8 information sources in terms of importance (scale 0-5), the ENT Surgeon ranked as most important (mean=4.63), whilst the Internet ranked lowest (3.10). 48.6% of respondents or their partners had an Internet-enabled smartphone; 45.2% said they would definitely use an iPhone app regarding their child's condition if one was available. 36.1% reported they would definitely use the Internet in the future. CONCLUSIONS: Whilst online sources must increasingly be considered in the dialogue with parents, it is clear that parents still rate the clinical team as most important for information gathering. Clinician-provided websites and smartphone applications may be the key to ensuring the provision of quality information into the future. PMID- 23434201 TI - Serum lipids alterations in adenoid hypertrophy or adenotonsillar hypertrophy children with sleep disordered breathing. AB - OBJECTIVES: We aimed to investigate metabolic parameters in children with adenoid hypertrophy (AH) only or adenotonsillar hypertrophy (ATH) and compare them with healthy controls. METHODS: Forty-four prepubertal children aged 6-12 years who were obstructive symptoms and 16 healthy children were recruited in this study. All children underwent a complete otolaryngologic examination and sleep screening. The patients were divided into three groups according to obstruction type: normal, AH (adenoid grade III or IV, tonsil grade 1 or 2), and ATH (adenoid grade III or IV, tonsil grade 3 or 4). All participants underwent hematologic and biochemical tests including fasting blood glucose, insulin, and plasma lipids. RESULTS: (1) The children with AH and ATH had lower high-density lipoprotein cholesterol (HDL-C), when compared to normal children. (2) The level of HDL-C was negatively correlated with the sum of adenoid and tonsillar size scores and the apnea-hypopnea index (AHI) (r=-0.477, p<0.001 vs. r=-0.548, p<0.001, respectively). There was a modest association between HDL-C and minimal SpO2 (r=0.332, p=0.009). (3) Stepwise multiple regression analysis identified the AHI, triglycerides, and fasting insulin as independent predictors for HDL-C. CONCLUSIONS: Patients with adenoid and tonsil hypertrophy had low HDL-C. HDL-C levels are inversely related to the sum of adenoid and tonsillar size scores and AHI in SDB children. HDL-C may be a sensitive indicator of serum lipids changes in SDB children. PMID- 23434202 TI - Automated volumetric breast density estimation: a comparison with visual assessment. AB - AIM: To compare automated volumetric breast density (VBD) measurement with visual assessment according to Breast Imaging Reporting and Data System (BI-RADS), and to determine the factors influencing the agreement between them. MATERIALS AND METHODS: One hundred and ninety-three consecutive screening mammograms reported as negative were included in the study. Three radiologists assigned qualitative BI-RADS density categories to the mammograms. An automated volumetric breast density method was used to measure VBD (% breast density) and density grade (VDG). Each case was classified into an agreement or disagreement group according to the comparison between visual assessment and VDG. The correlation between visual assessment and VDG was obtained. Various physical factors were compared between the two groups. RESULTS: Agreement between visual assessment by the radiologists and VDG was good (ICC value = 0.757). VBD showed a highly significant positive correlation with visual assessment (Spearman's rho = 0.754, p < 0.001). VBD and the x-ray tube target was significantly different between the agreement group and the disagreement groups (p = 0.02 and 0.04, respectively). CONCLUSION: Automated VBD is a reliable objective method to measure breast density. The agreement between VDG and visual assessment by radiologist might be influenced by physical factors. PMID- 23434203 TI - Quality and strength: the GRADE system for formulating recommendations in clinical practice guidelines. PMID- 23434204 TI - Follicular-phase concentrations of progesterone, estradiol-17beta, LH, FSH, and a PGF2alpha metabolite and daily clustering of prolactin pulses, based on hourly blood sampling and hourly detection of ovulation in heifers. AB - Circulating concentrations of hormones were determined each hour in 13 heifers from the end of the luteolytic period to ovulation (follicular phase, 3.5 days). Diameter of the preovulatory follicle was determined every 8 hours, and the time of ovulation was determined hourly. The diameter of the preovulatory follicle decreased 0.8 +/- 0.1 mm/h in heifers when there was 1 to 3 hours between the last two diameter measurements before ovulation. The concentration of progesterone (P4) after the end of the luteolytic period (P4 < 1 ng/mL) changed (P < 0.0001), as shown by a continued decrease until Hour -57 (Hour 0 = ovulation), then was maintained at approximately 0.2 ng/mL until 2 hours before the peak of the LH surge at Hour -26, and then a decrease to 0.1 ng/mL along with a decrease in estradiol-17beta. Concentrations of LH gradually increased (P < 0.007) and concentrations of FSH gradually decreased (P < 0.0001) after the end of luteolysis until the beginning nadirs of the respective preovulatory surges. A cluster of prolactin (PRL) pulses occurred (P < 0.0001) each day with approximately 24 hours between the maximum value of successive clusters. Hourly concentrations of a PGF2alpha metabolite decreased (P < 0.007) until Hour -40, but did not differ among hours thereafter. Novel observations included the gradual increase in LH and decrease in FSH until the beginning of the preovulatory surges and follicle diameter decrease a few hours before ovulation. Results supported the following hypotheses: (1) change in the low circulating P4 concentrations during the follicular phase are temporally associated with change in LH concentrations; and (2) PRL pulses occur in a cluster each day during the follicular phase of the estrous cycle. PMID- 23434205 TI - In vitro culture of equine preantral follicles obtained via the Biopsy Pick-Up method. AB - The objective was to conduct a preliminary evaluation of the efficacy of two media for in vitro culture of equine preantral follicles. Ovarian cortical strips were obtained from mares (N = 10) via the Biopsy Pick-Up method during the breeding season. Ovarian tissue was immediately submitted to histological analysis (noncultured control; D0) or cultured in situ for 1 day (D1) or 7 days (D7) in either alpha-MEM or TCM-199 and submitted to histological analysis, generating five treatment groups: noncultured control, alpha-MEM:D1, TCM-199:D1, alpha-MEM:D7, and TCM-199:D7. Preantral follicles were evaluated for follicle class (primordial, transitional, primary, and secondary) and morphology (normal vs. abnormal). A total of 142 preantral follicles were analyzed in five replicates. No follicles were observed in the TCM-199:D7 treatment group. The proportion of primordial follicles was higher (P < 0.03) in the control compared to the alpha-MEM:D7 treatment group. The proportion of primary follicles was higher (P < 0.04) in the alpha-MEM:D7 treatment group compared to the control. The proportion of developing follicles (transitional, primary, and secondary) was higher (P < 0.03) in the alpha-MEM:D7 treatment group compared to the control group. There was a greater (P < 0.004) percentage of morphologically normal developing follicles in the alpha-MEM:D1 treatment group compared to the TCM 199:D1 treatment group. Overall, the percentage of morphologically normal follicles was higher in the control group (72%; P < 0.02) and alpha-MEM:D1 group (84%; P < 0.0001) compared to the alpha-MEM:D7 (27%) treatment group. Mean follicle diameter was greater (P < 0.04) in the alpha-MEM:D7 treatment group (40.6 +/- 1.1 MUm) compared to the control group (37.3 +/- 0.7 MUm). Mean oocyte diameter was greater in the alpha-MEM:D1 (31.0 +/- 0.7 MUm; P < 0.006), TCM 199:D1 (30.7 +/- 1.8 MUm; P < 0.006), and alpha-MEM:D7 (33.2 +/- 1.8 MUm; P < 0.006) treatment groups compared to the control group (27.4 +/- 0.9 MUm). In conclusion, based on these preliminary data, in vitro culture of equine ovarian fragments obtained in vivo via the Biopsy Pick-Up method promoted preantral follicle development and follicle and oocyte growth in alpha-MEM for 7 days, with some follicles remaining morphologically normal throughout the culture period. PMID- 23434206 TI - Peripapillary scleral deformation and retinal nerve fiber damage in high myopia assessed with swept-source optical coherence tomography. AB - PURPOSE: To study peripapillary morphologic changes in highly myopic eyes using swept-source optical coherence tomography at a longer wavelength. DESIGN: Prospective cross-sectional study. METHODS: Peripapillary regions of 196 eyes of 107 patients with high myopia (refractive error, <-8.0 diopters or axial length, >26.0 mm) were analyzed quantitatively and qualitatively with an swept-source optical coherence tomography prototype system that uses a tunable laser light source operated at a 100,000-Hz A-scan repetition rate in the 1-MUm wavelength region. The visual field was evaluated by standard automated perimetry. Area of peripapillary atrophy beta and presence of scleral protrusion temporal to the optic disc were assessed. RESULTS: Peripapillary atrophy beta area, but not disc area, was significantly larger in eyes with visual field defect (3.16 +/- 2.70 mm(2); range, 0.00 to 12.85 mm(2)) than those without visual field defect (2.31 +/- 2.83 mm(2); range, 0.00 to 17.70 mm(2)). Temporal scleral protrusion was detected by color stereo disc photography in 22 (19.5%) of 113 eyes with visual field defect and in 4 (4.8%) of 83 eyes without visual field defect. Scleral bending demonstrated a wide range of angles (mean, 31.0 +/- 21.1 degrees; range, 2 to 80 degrees). The angle of scleral bending, but not the distances from scleral bend to disc margin or foveal center, correlated significantly with retinal nerve fiber layer thickness above the bend (r = -0.557, P = .007) and visual field defect severity (r = -0.445, P = .038). CONCLUSIONS: Swept-source optical coherence tomography visualizes peripapillary deep structures in high myopia. Some cases of high myopia may be affected by direct scleral compression or stretching at the peripapillary region. PMID- 23434207 TI - Excimer laser phototherapeutic keratectomy in eyes with corneal stromal dystrophies with and without a corneal graft. AB - PURPOSE: To evaluate and compare the visual outcomes and recurrence patterns of corneal stromal dystrophies after excimer laser phototherapeutic keratectomy (PTK) in eyes with and without a corneal graft. DESIGN: Retrospective, comparative case series. METHODS: setting: Cornea Service, Wills Eye Institute, Philadelphia Pennsylvania. study population: The patients were divided into 2 groups. Group 1 comprised patients with no graft who underwent PTK (22 eyes of 15 patients), and group 2 comprised patients who underwent PTK over a previous full thickness graft (18 eyes of 14 patients). intervention: All patients underwent PTK for decreased vision, symptoms of recurrent erosions, or both. main outcome measures: Visual outcomes and recurrence patterns of corneal stromal dystrophies. RESULTS: Preoperative and postoperative best-corrected visual acuities were 0.46 +/- 0.25 and 0.51 +/- 0.27 (P = .56), respectively, in group 1 and 0.16 +/- 0.13 and 0.21 +/- 0.18 (P = .25), respectively, in group 2. Mean preoperative spherical equivalent was 1.54 +/- 2.59 diopters (D) and -5.10 +/- 5.81 D (P = .01) in groups 1 and 2, respectively, and mean postoperative spherical equivalent was 0.44 +/- 1.8 D and -1.8 +/- 4.25 D (P = .19) in groups 1 and 2, respectively. There was no statistically significant difference in the efficacy (P = .73) and safety (P = .62) indices between the 2 groups. In group 1, mild recurrence was seen in 7 eyes (32%) and significant recurrence was seen in 4 eyes (18%) at a mean of 32 and 47 months after PTK, respectively. In group 2, mild recurrence was seen in 5 eyes (28%) and significant recurrence was seen in 5 eyes (28%) at a mean of 36 and 50 months after PTK, respectively. CONCLUSIONS: PTK improved central corneal clarity, alleviated symptoms resulting from recurrent erosions, and improved visual acuity in both groups. PMID- 23434208 TI - Prediction of the prognosis after liver transplantation in severe hepatitis B induced liver failure and clinical decision for liver transplantation. AB - BACKGROUND: Severe hepatitis B-induced liver failure (SHBLF) patients who require liver transplantation represent a particular challenge. We sought to explore the prognostic factors and establish a new scoring model, the SHBLF prognosis model (SHBLFPM), which can aid in clinical decision making. MATERIALS AND METHODS: A total of 98 patients who underwent liver transplantation for SHBLF in our center were retrospectively recruited between January 1, 1999, and December 31, 2010. The clinical and biochemical data were analyzed using the Cox proportional hazards model and log-rank test. The receiver operating characteristic curves were obtained for the King's College Hospital (KCH) criterion, the model for end stage liver disease (MELD), and the new model; the areas under the curves were compared using a z-test. RESULTS: The independent factors predicting the prognosis were the age of the patient (AP, P = 0.017), hepatic encephalopathy (HE, P = 0.013), the serum total bilirubin concentration (TBiL, P < 0.001), and the international normalized ratio for prothrombin time (INR, P = 0.001), as identified using a multivariate Cox regression analysis. The area under the curve of the new regression model (0.881) was significantly larger than that of the MELD (0.783) and KCH scores (0.596) (P < 0.05). Patients with a preoperative SHBLFPM score <23.57 had a significantly better prognosis than those with higher scores (P < 0.001). CONCLUSIONS: Age of patient, hepatic encephalopathy, serum total bilirubin concentration, and international normalized ratio for prothrombin time are independent factors affecting the posttransplantation mortality of SHBLF patients. SHBLFPM may be a criterion for the clinical decision for liver transplantation in SHBLF patients with a greater prognostic predictive ability than the MELD and KCH models. PMID- 23434209 TI - Perioperative venous thromboembolic events (VTE): can we lower the risk ever further? PMID- 23434210 TI - Intestinal alkaline phosphatase prevents the systemic inflammatory response associated with necrotizing enterocolitis. PMID- 23434212 TI - Exploring National Surgical Quality Improvement Program respiratory comorbidities: developing a predictive understanding of postoperative respiratory occurrences, Clavien 4 complications, and death. AB - BACKGROUND: For preoperative risk stratification, little is known about the implications of respiratory comorbidities in relation to postoperative complications in the diverse population of surgical patients. We hypothesized that patients with preoperative respiratory comorbidities would be at increased risk of postoperative respiratory occurrences and death. METHODS: Under the data use agreement and with the approval of the Henry Ford Health System Institutional Review Board (IRB #6830), we reviewed 5 y (2005-2009) of National Surgical Quality Improvement Program participant use files. Respiratory comorbidities were defined as current smoker, chronic obstructive pulmonary disease, dyspnea, and current pneumonia. Respiratory outcomes tracked in the National Surgical Quality Improvement Program included reintubation, postoperative pneumonia, and prolonged ventilation. We defined Clavien 4 and 5 outcomes to include postoperative septic shock, postoperative dialysis, pulmonary embolism, myocardial infarction, cardiac arrest, prolonged ventilatory requirements, need for reintubation, and death. RESULTS: Of 971,455 patients identified, 361,412 had respiratory comorbidities. As the number of respiratory comorbidities increased, we found a statistically significant increase in the occurrence of postoperative respiratory adverse events, including Clavien 4 and 5 complications. Multivariate regression analysis showed that respiratory comorbidities and age were independent predictors of mortality. All data reported here were significant at P < 0.001. CONCLUSIONS: This study showed a significant association between respiratory comorbidities and postoperative adverse events, including Clavien 4 complications and death. Further prospective studies are required to explore this association. PMID- 23434211 TI - Effects of glycine, pyruvate, resveratrol, and nitrite on tissue injury and cytokine response in endotoxemic rats. AB - BACKGROUND: Glycine, pyruvate, resveratrol, and nitrite are well-known protective compounds among others in ischemic tissue injury. Here, we compared their effects in acute lipopolysaccharide (LPS)-induced shock in rats to assess whether inhibition of the proinflammatory cytokine response is a prerequisite for their protective actions. MATERIALS AND METHODS: Rats (six or eight per group) were anesthetized, received LPS as an intravenous bolus (2.5 mg/kg), and were observed for 5 h. Glycine, sodium pyruvate, resveratrol, and sodium nitrite were continuously infused starting 30 min before LPS administration. Parameters included histopathologic changes, organ-specific cytokine levels, plasma nitrite and nitrate concentrations, and time courses of biomonitoring parameters, marker enzyme activities, and plasma cytokine concentrations. RESULTS: Glycine, pyruvate, resveratrol, and nitrite enhanced arterial blood pressure after LPS induced shock. Also, parameters reflecting tissue ischemia were significantly improved and plasma markers of organ injury ameliorated by all substances. Of the plasma cytokine concentrations increased by LPS, some were differently decreased or even further increased by the substances. None of them reduced the elevated plasma nitrite and nitrate concentration. Glycine diminished the increases in tissue cytokine levels organ specifically, pyruvate decreased some cytokine concentrations in all organs, and nitrite significantly affected only a few cytokine concentrations in some organs, whereas the levels of many cytokines were raised by resveratrol. All substances except resveratrol decreased granulocyte infiltrates in the liver. CONCLUSIONS: The present results demonstrate that glycine, pyruvate, resveratrol, and nitrite protect against LPS-induced shock and tissue injury (cell death) in rats and suggest that inhibition of the proinflammatory cytokine response is not mandatory for their protective actions. PMID- 23434213 TI - Ventilator-associated pneumonia in severe traumatic brain injury: the clinical significance of admission chest computed tomography findings. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) in severe traumatic brain injury (STBI) is a significant morbidity. Bilateral dependent consolidation (BDC) can be seen on admission chest computed tomography (CCT) in STBI. We hypothesize that this finding may be associated with VAP. MATERIALS AND METHODS: We retrospectively studied patients who sustained STBI after blunt injury and survived >48 h, who were admitted over a 40-mo period. We defined STBI as an admission Glasgow Coma Scale Score <= 8. We identified VAP by an elevated white blood cell count, a new infiltrate on chest x-ray, and a positive respiratory culture in a ventilated patient. Variables included demographics, injury, admission CCT, and culture data. We compared BDC-positive and BDC-negative patients. RESULTS: There were 33 cases of VAP in 94 study patients (35.1%), in whom the incidence of intracranial pressure (ICP) monitoring (66.7% versus 39.3%; P = 0.011) was significantly increased. Ventilator-associated pneumonia was significantly increased in the 28 patients (29.8%) in the BDC-positive group (16 [57.1%] versus 17 (25.6%); P = 0.004). Bilateral dependent consolidation independently predicted VAP. In the 33 VAP cases, gram-negative organisms were present in 27 patients (81.8%), with a predominance of Enterobacteriaceae (16 patients [48.5%]). Culture results did not significantly differ between the early (<4 d) versus late or BDC-positive versus BDC-negative VAP groups. CONCLUSIONS: Ventilator-associated pneumonia is common after STBI, and BDC is independently associated; however, there is no predilection for specific organisms. Admission CCT findings may prove useful in identifying a group of STBI patients at higher risk for VAP. PMID- 23434214 TI - Exercise therapy and custom-made insoles are effective in patients with excessive pronation and chronic foot pain--a randomized controlled trial. AB - BACKGROUND: Excessive foot pronation is a causal mechanisms described in relation to injuries of the lower extremities. Evidence to support an effective treatment is insufficient. OBJECTIVE: To investigate the effect of exercise and custom-made insoles to patients with excessive pronation and chronic pain conditions in the foot at short and long term follow-up. METHODS: Single blinded Randomized Controlled Trial with 80 subjects randomized: (1) Standard Intervention, (2) Insole, (3) Exercise, and (4) Insole+Exercise. Exercise - 12 week supervised program. Insoles - individually molded and posted. Pain was measured during walking, resting and running. Static and dynamic foot postures were measured as calcaneal angle, navicular drift, drop and height. RESULTS: The average duration of foot pain was 7.3 years. There was a significant pain reduction during walking within all groups at 4 and 12 months follow-up. No differences were seen between groups in any of the pain parameters. Weak correlations between changes in pain and foot postures were observed at baseline and one-year follow-up. CONCLUSION: A significant pain reduction was seen in all groups, none of the treatment modalities seem to be superior with the number of patients included. Compliance in the standard intervention group was a concern at 12 months. PMID- 23434215 TI - A comparison of methods for the determination of sound velocity in biological materials: a case study. AB - Non-destructive ultrasonic methods for testing biological materials are applied in medicine as well as in food engineering to determine the physical parameters and the quality of agricultural products and raw materials such as meat. The purpose of this work was to identify the simplest and the most accurate of five methods for sound velocity determination across the fibers of the porcine longissimus dorsi muscle. The through-transmission technique (TT) was used for ultrasound signal acquisition with 2MHz transducers. The first two methods (M1, M2) are based on the acquisition of a single ultrasound signal in the analyzed material, another two methods (M3, M4) rely on the acquisition of two ultrasound signals in samples with different thicknesses (two-distance method) and the last method (M5) involves the acquisition of a single ultrasound signal in the analyzed material and the acquisition of a single ultrasound signal in distilled water at the same distance between ultrasonic transducers (relative method). The results were processed by the nonparametric Kruskal-Wallis test and compared with published data. The mean values of sound velocity obtained with the use of the above methods in pork samples at post-storage, room and vital temperatures were as follows: method M1-1549.2/1581.7/1597.4m/s, method M2-1477.7/1509.8/1597.4m/s, method M3-1552.0/1599.0/1623.3m/s, method M4-1557.4/1598.3/1623.6m/s, method M5 1554.3/1583.7/1598m/s. The experiment indicates that the choice of method for determining sound velocity significantly influences the results. Two of the five analyzed methods (namely M3 and M4), which involved measurements of the time of sound wave propagation through samples of the same material with varied thickness, produced velocity values most consistent with published data. PMID- 23434216 TI - Optical patient interface in femtosecond laser-assisted cataract surgery: contact corneal applanation versus liquid immersion. AB - PURPOSE: To compare 2 optical patient interface designs used for femtosecond laser-assisted cataract surgery. SETTING: Optimedica Corp., Santa Clara, California, USA, and Centro Laser, Santo Domingo, Dominican Republic. DESIGN: Experimental and clinical studies. METHODS: Laser capsulotomy was performed during cataract surgery with a curved contact lens interface (CCL) or a liquid optical immersion interface (LOI). The presence of corneal folds, incomplete capsulotomy, subconjunctival hemorrhage, and eye movement during laser treatment were analyzed using video and optical coherence tomography. The induced rise of intraocular pressure (IOP) was measured in porcine and cadaver eyes. RESULTS: Corneal folds were identified in 70% of the CCL cohort; 63% of these had areas of incomplete capsulotomies beneath the corneal folds. No corneal folds or incomplete capsulotomies were identified in the LOI cohort. The mean eye movement during capsulotomy creation (1.5 sec) was 50 MUm with a CCL and 20 MUm with an LOI. The LOI cohort had 36% less subconjunctival hemorrhage than the CCL cohort. During suction, the mean IOP rise was 32.4 mm Hg +/- 3.4 (SD) in the CCL group and 17.7 +/- 2.1 mm Hg in the LOI group. CONCLUSIONS: Curved contact interfaces create corneal folds that can lead to incomplete capsulotomy during laser cataract surgery. A liquid interface eliminated corneal folds, improved globe stability, reduced subconjunctival hemorrhage, and lowered IOP rise. PMID- 23434217 TI - Use of a calibrated force gauge in clear corneal cataract surgery to quantify point-pressure manipulation. AB - PURPOSE: To develop and evaluate a calibrated force gauge designed to simulate the effect of patient-induced manipulation of the eye with resultant elevation of intraocular pressure (IOP) and use the device to determine the stability of cataract incisions. SETTING: Three private practice study sites. DESIGN: Clinical trials. METHODS: A calibrated force gauge was developed to apply controlled and quantifiable amounts of force to the eye. In study 1, the calibrated force gauge was used to evaluate the change in IOP during application of 1 oz of external force in a group of healthy volunteers. In studies 2 and 3, the calibrated force gauge was used to assess wound leakage of clear corneal incisions that were subjected to stromal hydration or sutures, respectively. RESULTS: In study 1, with the application of 1.00 oz of external force, the mean IOP rose from a baseline of 17.49 mm Hg to 43.44 mm Hg. In study 2 (stromal hydration) using up to 1.00 oz of force, the leak rate was 67% for the main incision. The overall leak rate for study 3 (sutures) using up to 1.00 oz of force was 23.8%. No adverse events or serious adverse events occurred during these studies. CONCLUSIONS: Study 1 confirmed that 1.00 oz of force is a realistic approximation of the amount of force a patient's eye may experience during rubbing. After clear corneal cataract surgery, the application of 1.00 oz of force to the ocular surface for approximately 2 to 3 seconds may simulate the propensity for postoperative wound leak resulting from patient manipulation. PMID- 23434218 TI - Oral glucocorticoids diminish the efficacy of allergen-specific immunotherapy in experimental feline asthma. AB - Allergen-specific rush immunotherapy (RIT) shows promise in treating asthma; however, pet cats will likely require at least initial concurrent glucocorticoids (GCs) to control serious clinical signs. How the immunosuppressive effects of GCs would impact RIT in cats is unknown. The hypothesis of this study was that oral, but not inhaled GCs will diminish the efficacy of RIT in experimental feline asthma. Cats (n=6/group) were sensitized using Bermuda grass allergen (BGA) and randomized to receive BGA-specific RIT for 9 months with an oral GC (prednisolone 10mg daily), inhaled GC (fluticasone 220 MUg twice daily), or placebo administered for the first 6 months. Bronchoalveolar lavage fluid (BALF) percent eosinophils and other immunological assays were performed. Eosinophilic airway inflammation was suppressed in all groups at month 6 of RIT (group mean +/- SD, 5 +/- 2%, 13 +/- 4%, and 7 +/- 2% for oral GC, inhaled GC, and placebo, respectively; P=0.291). BALF percent eosinophils significantly increased over time only in oral GC/RIT cats between months 6 and 9 (P=0.031). Placebo/RIT cats had significant decreases over time in BGA-specific serum IgE (P=0.031). Concentration of interleukin (IL)-5 in BALF significantly increased over time in inhaled GC/RIT cats (P=0.031). No significant differences were found between groups at month 6 or over time in each group for BGA-specific lymphocyte blastogenesis, percent blood T regulatory cells, or number of IL-10-producing cells. Given the significant increase of airway eosinophilia over time in RIT cats initially treated with an oral GC, inhaled GCs might be better for dampening eosinophilic inflammation until RIT normalizes the dysregulated immune system. PMID- 23434219 TI - The occurrence and suspected mode of inheritance of congenital subaortic stenosis and tricuspid valve dysplasia in Dogue de Bordeaux dogs. AB - The Dogue de Bordeaux (DdB) breed has gone through several genetic 'bottle necks' and has a relatively small effective population size. Importing new stock into Israel has been limited, further narrowing the already restricted local gene-pool and increasing the chances of inherited defects. In 56 DdB dogs examined between 2003 and 2010, the authors sought to study the proportion congenital subaortic stenosis (SAS) and tricuspid valve dysplasia (TVD). The aim was also to identify a probable mode of inheritance (MOI) using segregation and pedigree analyses of genealogical data available from 13/21 DdB dogs diagnosed with these conditions between 2004 and 2007. Among all breeds in the country, TVD was highest in the DdB breed, which also displayed the second highest proportion of SAS. Echocardiographic measurements and selected physical examination findings from 26 normal DdB dogs, 18 DdB dogs with SAS, and 12 DdB dogs with TVD are reported. Based on pedigree and segregation analyses, the most probable MOI appeared to be autosomal recessive. Pedigree analyses helped to identify three ancestors that might have introduced these two congenital heart defects into the local DdB population. Excluding those three dogs and their progeny from future mating could therefore reduce the prevalence of these diseases in the DdB population in Israel. The unusual local breeding circumstances may offer a unique opportunity to identify associated SAS and TVD genes in the DdB, as well as in other dog breeds. PMID- 23434220 TI - American Brachytherapy Society (ABS) consensus statement for sarcoma brachytherapy. AB - PURPOSE: To present recommendations for the use of brachytherapy (BT) in patients with soft tissue sarcoma (STS). METHODS: A group of practitioners with expertise and experience in sarcoma BT formulated recommendations for BT in STS based on clinical experience and literature review. RESULTS: The indications for adjuvant BT are discussed. There is no consensus on the use of BT alone or in combination with external beam radiation therapy (EBRT), but factors that influence the selection of this modality include tumor grade and size, prior surgeries, and tumor recurrence. Low-dose-rate, high-dose-rate, and pulsed-dose-rate radiation are all acceptable BT modalities to use for STS. Recommendations are made for patient selection, techniques, dose rates, and dosages. Outcome data and toxicity data are reviewed. CONCLUSIONS: BT is a useful component of the treatment of STS. The advantages of BT are the targeted dose distribution, low integral dose, and short treatment times. Ultimately the clinician should select the modality or combination of modalities that are most familiar to the treatment team and suitable to the patient. PMID- 23434221 TI - Endoluminal high-dose-rate brachytherapy for early stage and recurrent esophageal cancer in medically inoperable patients. AB - PURPOSE: The management of superficial primary and recurrent esophageal cancer (EC) in medically inoperable patients is complex. Endoluminal high-dose-rate (HDR) brachytherapy has shown mixed results in terms of toxicity and local control. In this study, we examined the outcomes and toxicities in a set of patients with superficial primary and recurrent EC treated with a consistent HDR technique. METHODS AND MATERIALS: Between 8/2008 and 7/2011, 14 patients were treated with HDR intraluminal brachytherapy, 10 (71.4%) with recurrent disease, and 4 (28.6%) with previously unirradiated lesions. Patients received three weekly fractions to a median dose of 12 Gy (range, 10-15 Gy); dose was prescribed to 7-mm median depth with mucosal dose limited to 8-10 Gy using a 12-14-mm applicator. RESULTS: Median followup was 15.4 months. Overall freedom from failure (OFFF) and overall survival (OS) at 18 months were 30.8% (95% confidence interval [CI]: 5.2, 56.4) and 72.7% (95% CI: 45.3, 100), respectively. For patients with recurrent disease, OFFF and OS at 18 months were 11.1% (95% CI: 0, 32.1) and 55.6% (95% CI: 15.4, 95.8), respectively. For patients with previously unirradiated disease, OFFF and OS at 18 months were 75.0% (95% CI: 31.6, 100) and 100.0%, respectively. Eight (57.1%) patients had Grade 1 acute adverse effects; 6 (42.9%) patients had chronic Grade 1 adverse effects; 1 (7.1%) patient developed Grade 2 stricture. Grade 3 tracheoesophageal fistula occurred in 1 (7.1%) patient. One patient died before completion of treatment of unrelated causes. CONCLUSIONS: HDR endoluminal brachytherapy is a well-tolerated treatment for superficial primary and recurrent EC in medically inoperable patients. PMID- 23434222 TI - Effect of co-incubation of oocytes with a decreasing number of spermatozoa on embryo quality. AB - Shortened exposure of oocytes to spermatozoa has been reported to improve embryo quality. This technique requires extra manipulation of gametes in order to remove oocytes from the spermatozoa. This study presents a fertilization method that does not require additional manipulation and interference of oocytes during fertilization. To determine the benefits of this method, a prospective controlled study using sibling oocytes was conducted. The oocytes of patients were randomly allocated to study and control groups. Fertilization rates, embryo cleavage rates, day-3 embryo morphology and clinical pregnancy rates were compared between the two groups. The normal fertilization rates (2PN) of the two groups were comparable. The percentage of usable embryos (transferred plus cryopreserved embryos) was significantly higher in the treatment group compared with the control group (66.9+/-23.3% versus 57.6+/-26.7%; P=0.03). The mean embryo quality score of the treatment group was higher than the control group (18.3+/-4.8 versus 15.2+/-5.1; P=0.02). The results of this study demonstrated that this method can improve embryo quality, but further studies with additional IVF patients are needed to confirm the beneficial effects. A new method is presented which decreases the negative effects of an excessive number of spermatozoa on oocytes during the fertilization process without any manipulation and interference of oocytes. The method is easy to perform in a clinical IVF laboratory and led to improved embryo quality in our sibling-oocyte controlled study. PMID- 23434223 TI - A one-pot domino synthesis and discovery of highly functionalized dihydrobenzo[b]thiophenes as AChE inhibitors. AB - A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6 dicarbonitriles have been synthesized regioselectively in good yields through the one-pot domino reactions of 5-aryldihydro-3(2H)-thiophenones, malononitrile and aromatic aldehydes in the presence of morpholine. This transformation presumably involves Knoevenagel condensation-Michael addition-intramolecular Thorpe-Ziegler cyclization-Tautomerization-Elimination sequence of reactions. These compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and 5 amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile was found to be the most potent against AChE with IC50 4.16 MUmol/L. PMID- 23434224 TI - Pyridine to aniline: an exceptional biologically driven rearrangement. AB - During the course of our study on the innovative ligand for nicotinic acetylcholinergic receptors, LNAChR, and in order to assess activity and toxicity profiles of the drug's metabolites, synthesis of the main metabolites was undertaken. This synthesis work was done in parallel by organic chemistry and by biotransformation of LNAChR. Filamentous fungus Aspergillus alliaceus (NRRL 315) neatly afforded three of the main metabolites, one of which arose from a very unexpected and very uncommon rearrangement. PMID- 23434225 TI - Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 9: Synthesis, characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1), a high affinity ligand for opioid receptors. AB - Derivatives of the lead compound N-BPE-8-CAC (1) where each CH of the biphenyl group was individually replaced by N were prepared in hopes of identifying high affinity ligands with improved aqueous solubility. Compared to 1, binding affinities of the five possible pyridinyl derivatives for the MU opioid receptor were between threefold lower to fivefold higher with the Ki of the most potent compound being 0.064 nM. Docking of 8-CAC (2) into the unliganded binding site of the mouse MU opioid receptor (pdb: 4DKL) revealed that 8-CAC and beta-FNA (from 4DKL) make nearly identical interactions with the receptor. However, for 1 and the new pyridinyl derivatives 4-8, binding is not tolerated in the 8-CAC binding mode due to the steric constraints of the large N-substituents. Either an alternative binding mode or rearrangement of the protein to accommodate these modifications may account for their high binding affinity. PMID- 23434226 TI - Identification and characterization of small molecule inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening. AB - Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers that harbor aberrantly-active STAT3. In this study, a series of small molecules were identified as novel inhibitors of STAT3 signaling pathway through virtual screening. A tricyclic scaffold containing compound, 6, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 26.68 MUM. In addition, this compound inhibited Tyr705 phosphorylation of STAT3 and had no obvious effect on upstream tyrosine kinases. Thus, compound 6 is a potential lead structure and valuable for further drug development. PMID- 23434227 TI - Synthesis and cytotoxicity evaluation of oleanolic acid derivatives. AB - Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC50=0.39 MUM) and compound 28 displayed the best activity against A549 cell line (IC50=0.22 MUM). SAR analysis indicates that H-donor substitution at C 3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines. PMID- 23434228 TI - Synthesis and photochemical behavior of coumarin-caged cholesterol. AB - The syntheses of three coumarin-caged cholesterols are reported that contain the 6-diethylaminocoumarin (DEACM), 6-bromo-7-hydroxycoumarin (BHC) and 6-bromo-7 methoxycoumarin (BMCM) photocleavable groups. Upon photolysis, the best caged derivative was found to be BHC-cholesterol whose quantum yield was determined to be 0.032 at 350 nm. PMID- 23434229 TI - Synthesis, crystal structures, DNA binding and cytotoxicity of two novel platinum(II) complexes containing 2-(hydroxymethyl)pyridine and pyridine-2 carboxylate ligands. AB - Two new platinum(II) complexes, trans-[Pt(2-mpy)(2)].4H(2)O (1) and [PtCl(2 pyc)(2-hmpy)].H(2)O (2), where 2-hmpy=2-(hydroxymethyl)pyridine, 2 mpy=deprotonated 2-hmpy and 2-pyc=pyridine-2-carboxylate, have been synthesized and characterized by elemental analysis, IR, NMR, and X-ray crystallography. The DNA binding affinities of these complexes for Fish Sperm DNA (FS-DNA) were investigated using fluorescence, viscosity, thermal denaturation and gel electrophoresis measurements. Fluorescence analysis indicates that complex 1 binds to DNA by a single intercalative mechanism, while complex 2 exhibits two types of interactions such as intercalation and covalent binding. Gel electrophoresis assay demonstrates ability of the complexes to cleavage the supercoiled pBR322 plasmid DNA. The in vitro cytotoxicities of both complexes were preliminarily evaluated and the cytotoxicity of complex 1 against the human lung cancer cells (H1299) is similar to oxaliplatin, but higher than transplatin and carboplatin. PMID- 23434230 TI - Evaluation of HIV-1 inhibition by stereoisomers and analogues of the sesquiterpenoid hydroquinone peyssonol A. AB - Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized racemically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure-activity relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A are responsible for its potency, while the stereochemical configuration of the substituents on the aliphatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues tested were as potent as the parent natural product, several exhibited greater therapeutic indices due to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic. PMID- 23434231 TI - Emerging therapies for postmenopausal vaginal atrophy. AB - Symptoms related to vaginal atrophy are a significant problem for postmenopausal women and estrogen has been the gold standard for its treatment. A number of recent reviews of vaginal estrogen products are available. This review will, therefore, focus on other products and potential products for this indication, including the tissue selective estrogen complex and selective estrogen receptor modulators. Additionally, lesser-studied approaches will be discussed. PMID- 23434232 TI - Fatigue of the resin-dentin interface: a new approach for evaluating the durability of dentin bonds. AB - There are concerns regarding the longevity of resin composite restorations and the clinical relevance of in vitro bond strength testing to the durability of dentin bonds in vivo. OBJECTIVE: The objectives of this investigation were to: (1) develop a new method of experimental evaluation for quantifying the durability of dentin bonds, (2) apply this method to characterize the interfacial strength of a selected commercial system under both monotonic and cyclic loading, and (3) distinguish mechanisms contributing to the interface degradation and failure. METHODS: A new method for fatigue testing the resin-dentin interface was developed based on a four-point flexure arrangement that includes two identical bonded interfaces. Cyclic loading of specimens comprised of coronal dentin bonded to a commercial resin composite and controls of resin composite was performed to failure within a hydrated environment. Scanning electron microscopy and nanoscopic dynamic mechanical analysis were used to evaluate failure mechanisms. RESULTS: The fatigue strength of the resin-dentin interface was significantly lower (p<=0.0001) than that of the resin composite and reported for dentin over the entire finite life regime. Defined at 1*10(7) cycles, the apparent endurance limit of the resin-dentin interface was 13MPa, in comparison to 48MPa and 44MPa for the resin composite and dentin, respectively. The ratio of fully reversed endurance limit to ultimate strength of the interface (0.26) was the lowest of the three materials. SIGNIFICANCE: The proposed approach for characterizing the fatigue strength of resin-dentin bonds may offer new insights concerning durability of the bonded interface. PMID- 23434234 TI - Diagnostic value of four clinical tests for the evaluation of subscapularis integrity. AB - HYPOTHESIS: The lift-off, internal rotation lag sign, belly-press, and bear-hug tests are widely used to evaluate the integrity of the subscapularis. We hypothesized that these tests might reflect different types of subscapularis tears and sought to ascertain whether these tests accurately determine the severity of the internal rotation strength deficit and fatty degeneration. METHODS: Isokinetic testing and the 4 clinical tests were used preoperatively to evaluate 312 patients who had undergone arthroscopic rotator cuff surgery. Of these, 37 patients had a full-thickness subscapularis tear, 96 had a partial thickness tear, and 179 had no tear. RESULTS: For differentiating any tears from an intact subscapularis, the most sensitive test was the belly-press test (27.8%), and the most specific test was the lift-off test (100%). For differentiating a full-thickness tear from a partial tear, the most sensitive test was the belly-press test (56.8%), and the most specific was the lift-off test (96.9%). A positive lift-off test also most reflected loss of internal rotation strength (mean, 72.2%; 95% confidence interval, 61.9-82.5), followed by the internal rotation lag sign (55.1%; 44.2-66.1) and the belly-press test (45.9%; 36.4-54.4). CONCLUSIONS: A positive lift-off test was highly specific for the detection of a full-thickness subscapularis tear and to reflect severe fatty degeneration. The lift-off, internal rotation lag sign, belly-press, and bear-hug tests sequentially predict internal rotation strength deficit and provide discrimination of internal rotation strength impairment. PMID- 23434233 TI - Enhancement in dentin collagen's biological stability after proanthocyanidins treatment in clinically relevant time periods. AB - OBJECTIVE: To investigate whether proanthocyanidins (PA) is capable of improving dentin collagen's biological stability through cross-linking within time periods that are clinically relevant. MATERIALS AND METHODS: Demineralized dentin collagen slabs were treated with 3.75 wt% PA solution for 10s, 1 min, 30 min, 60 min, 120 min, 360 min, and 720 min, respectively. The resultant cross-linked collagen samples were subject to digestion with 0.1% collagenase at 37 degrees C for 2h, 6h, 12h, 24h, 36 h, and 48 h. The percentage of weight loss after digestion was calculated to evaluate PA-treated collagen's resistance toward enzymatic degradation. Fourier-transformed infrared (FTIR) spectroscopy was used to probe evidences of PA-collagen interactions after various periods of PA treatment. RESULTS: The collagenase digestion assay suggests that PA treatment as short as 10s can enhance collagen's resistance toward enzymatic challenge. The FTIR spectroscopy further verifies that PA is indeed incorporated into collagen regardless of treatment time, possibly via a mechanism involving the chemical interactions between PA and collagen. SIGNIFICANCE: This study confirmed that PA can effectively cross-link collagen and improve its biological stability in time periods as short as 10s. The use of PA as a priming agent is therefore clinically feasible and is a promising approach to improving the durability of current dentin bonding systems. PMID- 23434235 TI - A novel method for retinal vessel tracking using particle filters. AB - Extraction of a proper map from the vessel paths in the retinal images is a prerequisite for many applications such as identification. In this paper, we present a new approach based on particle filtering to determine and locally track the vessel paths in retina. Particle filter needs to use an acceptable probability density function (PDF) describing the blood vessels which must be provided by the retinal image. For this purpose, the product of the green and blue channels of the RGB retinal images is considered and after a median filtering stage, it is used as a PDF for tracking procedure. Then a stage of optic disc localization is performed to localize the starting points around the optic disc. With a proper set of starting points, the iterative tracking procedure initiates. First, a uniform propagation of the particles on an annular ring around each point (including starting points or ones determined as central points in the previous iteration) is performed. The particle weights are evaluated and accordingly, each particle is decided to be inside or outside the vessel. The subsequent stage is to analyze the hypothetical vectors between a central point and each of the inside vessel particles to find ones located inside vessel. Afterwards, the particles are clustered using quality threshold clustering method. Finally, each cluster introduces a central point for pursuing the tracking procedure in the next iteration. The tracking proceeds towards a bifurcation or the end of the vessels. We introduced two criteria: automatic/manually tracked ratio (AMTR) and false/manually tracked ratio (FMTR) for evaluating the tracking results. Apart from the labeling accuracy, the average values of AMTR and FMTR were 0.7746 and 0.2091, respectively. The proposed method successfully deals with the bifurcations with robustness against noise and tracks the thin vessels. PMID- 23434236 TI - Early detection of oral cancer: dentists' opinions and practices before and after educational interventions in Northern-Germany. AB - INTRODUCTION: The question whether educational programmes improve dentists' knowledge of oral cancer is still an unexplored subject. The aim of this study was to assess dentists' opinions and practices concerning oral cancer using a standardised survey after educational intervention over one year. MATERIAL AND METHODS: Following a baseline survey which was mailed to every dentist in Schleswig-Holstein, Germany (n = 2280), the results were analysed to produce a multifaceted educational programme. After educational intervention, the same survey was redistributed and the results before and after intervention were compared. RESULTS: The results are based on 394 surveys. Following intervention, 62% of responders, compared to 49% at baseline, described their overall knowledge as current. The percentage of dentists routinely investigating older patients at the recall appointment increased from 28% at baseline to 37% if the responders had attended a continuing education course during the period of intervention. Similar improvements were observed at initial appointment for older patients, with results improving from 33% to 38% for responders who attended a further educational course. CONCLUSIONS: Our results showed that a 1-year educational intervention with a multifaceted approach was successful. They underline that continuing education programmes improve the competence of dentists performing examination of the oral cavity. Therefore, regular participation in continuing educational courses is recommended. PMID- 23434237 TI - Maxillary growth in a congenital cleft palate canine model for surgical research. AB - We have recently presented the Old Spanish Pointer dog, with a 15-20% spontaneous congenital cleft palate rate, as a unique experimental model of this disease. This study aimed to describe the cleft palate of these dogs for surgical research purposes and to determine whether congenital cleft palate influences maxillofacial growth. Seven newborn Old Spanish Pointer dogs of both sexes, comprising a cleft palate group (n = 4) and a normal palate group (n = 3), were fed using the same technique. Macroscopic photographs and plaster casts from the palate, lateral radiographs and computer tomograms of the skull were taken sequentially over 41 weeks, starting at week 5. The cleft morphology, the size and the tissue characteristics in these dogs resembled the human cleft better than current available animal models. During growth, the cleft width varies. Most of the transverse and longitudinal measures of the palate were statistically lower in the cleft palate group. The cleft palate group showed hypoplasia of the naso-maxillary complex. This model of congenital cleft palate seems suitable for surgical research purposes. A reduced maxillofacial pre- and post-natal development is associated to the congenital cleft palate in the Old Spanish Pointer dog. PMID- 23434238 TI - Preformed titanium cranioplasty after resection of skull base meningiomas - a technical note. AB - INTRODUCTION: Meningiomas of the fronto-basal skull are difficult to manage as the treatment usually includes extensive resection of the lesion, consecutive reconstruction of the meninges and of the skull. Especially after removal of spheno-orbital and sphenoid-wing meningiomas, the cosmetic result is of utmost importance. In this technical note, we present our institutional approach in the treatment of skull base meningiomas, focussing on the reconstruction of the neurocranium with individually preformed titanium cranioplasty (CRANIOTOP((r)), CL Instruments, Germany). CASE REPORT: Two female patients (40 years, 64 years) are presented. Both patients presented with skull base lesions suggestive of meningiomas. The preoperative thin-sliced CT scan was processed to generate a 3D model of the skull. On it, the resection was mapped and following a simulated resection, the cranioplasty was manufactured. Intra-operatively, the titanium plate served as a template for the skull resection and was implanted after microsurgical tumour removal, consecutively. The cosmetic result was excellent. Immediate postoperative CT scan revealed accurate fitting and complete tumour removal. Control Magnetic Resonance Imaging (MRI) within 12 weeks was possible without any artifacts. DISCUSSION: The comprehensive approach described indicates only one surgical procedure for tumour removal and for reconstruction of the skull. The titanium plate served as an exact template for complete resection of the osseous parts of the tumour. Cosmetic outcome was excellent and control MRI was possible post operatively. CONCLUSION: CRANIOTOP((r)) cranioplasty is a safe and practical tool for reconstruction of the skull after meningioma surgery. PMID- 23434239 TI - Post-operative orbital haematomas over a 12-year period. A description of three cases among 280 orbital procedures. AB - PURPOSE: To evaluate the incidence of orbital haematoma requiring surgical treatment following procedures including fracture repairs and orbital osteotomies over a 12-year period and to discuss their management. METHODS: The records of all the patients who underwent a procedure involving the orbits from 1998 to 2011 were reviewed for evidence of post-operative haematomas. Medical data including clinical presentation, time between diagnosis and treatment, management and subsequent outcome were collected. RESULTS: 280 patients were included, 257 procedures for orbital or zygomato orbital fractures and 23 osteotomies for dysthyroid orbitopathy or malunited orbital fractures. Three cases (1.07%) of post-operative haematomas were observed as follows: 2/257 orbital fractures (0.77%) and 1/23 osteotomies (4.34%). All cases occurred in the early post operative period of less than 6 h. No spontaneous loss of vision or pain was described by patients. All could be operated on as soon as the diagnosis was established; no CT-scans were required. Orbital drainage was successfully performed in all cases. CONCLUSION: Post-operative orbital haematomas are uncommon complications. Diagnosis is based on a clinical examination, including pain, proptosis and alteration in visual acuity. Surgical treatment should be undertaken immediately following diagnosis. PMID- 23434240 TI - Effect of intended manual condylar positioning on skeletal and dental changes in Skeletal Class III deformities: CBCT-generated half-cephalograms. AB - INTRODUCTION: To investigate the effect of intended manual condylar positioning on skeletal changes from preoperative stage to posttreatment stage. MATERIALS AND METHODS: The sample comprised 23 patients divided into two groups according to surgery type: mandible-only setback surgery (group I) versus 2-jaw surgery (group II). CBCT-generated Half-Cephalograms were fabricated to evaluate the skeletal, dental, and condylar positioning changes for each subject at three time points (preoperatively (T0), immediate-postoperatively (T1), and posttreatment (T2)). RESULTS: The angle of the proximal segment in group II was reduced immediate postoperatively. In both groups, the result showed a negative mean value for the horizontal mandibular position (B point to N-perpendicular plane at T2-T1 stage). In group II, the vertical mandibular position (B point to FH plane at T2-T1 stage) also had a negative mean value. In group I, the change of the B point to N perpendicular plane (T2-T1) had statistically significant correlations with the change of the Cd to Po-perpendicular plane (T2-T1). In group II, the change of the B point to the N-perpendicular plane (T2-T1) had statistically significant correlations with the change of the 10-15 s) was evenly distributed among groups (8 cats in each). Summated Doppler transmitral flow and mitral annular tissue velocity waves were separated during vagal maneuvers in 71% and 72% of cats, respectively. No adverse effects were observed. CONCLUSIONS: Vagal maneuvers may be utilized as a simple non pharmacologic tool in the Doppler evaluation of LV diastolic function in healthy cats. PMID- 23434243 TI - Cardiomyocyte calcium cycling in a naturally occurring German shepherd dog model of inherited ventricular arrhythmia and sudden cardiac death. AB - OBJECTIVE: To further characterize arrhythmic mechanisms in German shepherd dogs (GSDs) affected with inherited ventricular arrhythmias by evaluating intracellular calcium cycling and expression of calcium handling genes. ANIMALS: Twenty five GSDs, 9 backcross dogs, and 6 normal mongrel dogs (controls) were studied. The GSDs and backcross dogs were from a research colony of inherited ventricular arrhythmias. The control research dogs were purchased. METHODS: Action potentials (APs) and pseudo-electrocardiograms (ECG) were recorded from left ventricular (LV) wedge preparations of GSDs and normal dogs. Midmyocardial (Mid) LV cells from GSDs and normal mongrels were isolated by enzymatic digestion. Cells were either field stimulated or voltage clamped and calcium transients were measured by confocal microscopy using the indicator Fluo-3AM. Expression of calcium handling genes was measured by quantitative RT-PCR. RESULTS: Mean calcium transient decay (tau) was not different between affected GSDs and control dogs, but striking cell-to-cell variability for tau was observed within affected GSDs and between affected GSDs and controls (P < 0.0001 each); within-dog variability accounted for 75% of total variability. Calcium sparks and afterdepolarizations occurred in GSD but not control cells. ATP2A2/SERCA2a expression was significantly reduced (P = 0.0063) in affected GSDs and inversely correlated (P = 0.0006) with severity of ventricular arrhythmias. CONCLUSIONS: German shepherd dogs with inherited ventricular arrhythmias have electrophysiologic abnormalities in calcium cycling associated with reduced ATP2A2/SERCA2a expression. These animals provide a unique opportunity to study calcium remodeling at the genetic and molecular level in familial ventricular arrhythmias. PMID- 23434244 TI - Congenital bicuspid aortic valve in an English bulldog. AB - A bicuspid aortic valve (BAV) demonstrating moderate valvular stenosis and mild insufficiency was identified in an asymptomatic 1-year-old male cryptorchid English bulldog by transthoracic and transesophageal echocardiography. The BAV was most consistent with type 3 morphology, based upon human classification. Pulmonary valve dysplasia with mild pulmonary stenosis and a suspected persistent left cranial vena cava were also identified. Although BAV is the most common congenital cardiac malformation in humans, it is rare in the dog. PMID- 23434245 TI - The electrocardiogram of anesthetized captive adult emus (Dromaius novaehollandiae). AB - OBJECTIVE: To characterize the electrocardiogram (ECG) of anesthetized adult emus (Dromaius novaehollandiae). ANIMALS: Ten clinically healthy adult emus anesthetised for routine physical examination and an electrocardiogram, for both monitoring and investigation into any evidence of cardiac disease. METHODS: The ECGs for each emu were obtained in right lateral recumbency, using a modified electrode placement that replicated the standard bipolar leads used in small mammals. Lead II was used for waveform analysis. RESULTS: Median P wave amplitude was 0.55 mV (range: 0.2-0.92 mV) and P wave duration was 0.06 s (0.04-0.09 s). S wave amplitude measured 1.42 mV (0.92-2.12 mV), T wave amplitude 0.67 mV (0.16 0.83 mV) and QRS duration was 0.07 s (0.07-0.12 s). Ninety percent of the QRS complexes were of rS type. CONCLUSION: Our study provides electrocardiographic baseline data for anesthetized adult emus. PMID- 23434246 TI - Innate immune activation after transfusion of stored red blood cells. AB - The transfusion of red blood cells (RBCs), although necessary for treatment of anemia and blood loss, has also been linked to increased morbidity and mortality. RBCs stored for longer durations and transfused in larger volumes are often cited as contributory to adverse outcomes. The potential mechanisms underlying deleterious effects of RBC transfusion are just beginning to be elucidated. In this narrative review, we explore the hypothesis that prolonged RBC storage results in elaboration of substances which may function as danger associated molecular pattern molecules that activate the innate immune system with consequences unfavorable to healthy homeostasis. The nature of these chemical mediators and the biological responses to them offers insight into the mechanisms of these pathological responses. Three major areas of activation of the innate immune apparatus by stored RBCs have been tentatively identified: RBC hemolysis, recipient neutrophil priming, and reactive oxygen species production. The possible mechanisms by which each might perturb the innate immune response are reviewed in a search for potential novel pathways through which transfusion can lead to an altered inflammatory response. PMID- 23434247 TI - D-dimer and clinicoradiologic features in cerebral venous thrombosis. AB - OBJECTIVES: Cerebral venous thrombosis (CVT) is a disease with varying clinical presentation and diagnosis presents many challenges in clinical practice. We investigated, whether D-dimer levels reflect clinical presentation, radiologic features, and outcome in CVT. METHODS: We included all consecutive patients with CVT treated in our hospital from 1987 to 2010 with D-dimer levels measured before initiation of anticoagulant treatment. D-dimer was categorized as low (<0.5mg/L), intermediate (0.6-2.0mg/L), and high (>2.0mg/L). Based on delay from symptom onset to hospital presentation mode of onset was categorized as acute (<2 days), subacute (2-14 days), or chronic (>14 days). RESULTS: In 71 patients included median level of D-dimer was 1.40 mg/L (range 0.05-13.0mg/L). In 9 (12%) patients D-dimer was low, and of these, 7 presented with subacute and 2 with chronic mode of symptom duration. Elevated D-dimer levels were associated with thrombosis in multiple sinuses (P=0.044). Longer symptom duration was correlated with low D dimer levels (P=0.010). CONCLUSIONS: In clinical practice, low levels of D-dimer cannot rule out CVT in patients with subacute or chronic disease. High D-dimer levels correlate with greater thrombus extension and acute onset of symptoms. PMID- 23434251 TI - Choosing wisely: cardiothoracic surgeons partnering with patients to make good health care decisions. PMID- 23434250 TI - Emergence of extended-spectrum beta-lactam resistance among Escherichia coli at a US academic children's hospital is clonal at the sequence type level for CTX-M 15, but not for CMY-2. AB - Resistance to extended-spectrum beta-lactams is increasing worldwide among Escherichia coli and has been linked to a small number of emergent clones (e.g. ST38, ST131 and ST405) recovered from extraintestinal infections in community and hospital settings. There are, however, limited data about the relative contributions of bacterial strains, plasmids and beta-lactamase genes to extended spectrum beta-lactam resistance in paediatric infections. We performed an extensive molecular analysis of phylogenetic, virulence and antibiotic resistance related properties of 49 previously reported serial E. coli isolates recovered during 1999-2007 at Seattle Children's Hospital (Seattle, WA). Class C enzyme CMY 2 and class A enzyme CTX-M-15 were the most prominent extended-spectrum beta lactam resistance enzymes in the collection, first appearing in this patient population in 2001 and 2003, respectively, and then steadily increasing in frequency over the remainder of the study period. Among 19 CMY-2-positive isolates, 16 distinct STs were detected (D = 98.25%, 95% CI 96-100.25%), indicating that CMY spread is non-clonal at the host strain level. In contrast, among ten CTX-M-15-positive isolates, three STs were detected (D = 37.78%, 95% CI 2.36-73.20%), of which eight represented the worldwide-disseminated ST131 lineage, consistent with clonal spread of CTX-M-15-associated resistance. fimHTR subtyping of ten ST131 isolates (including two CTX-M-negative isolates) revealed that, within ST131, carriage of allele fimHTR30 correlated with CTX-M-15 positivity, whilst carriage of non-fimHTR30 alleles correlated with carriage of non-CTX-M enzymes. Thus, spread of CMY-2 is non-clonal at the ST level, but clonal spread of CTX-M-15 may be associated with a specific fimHTR-defined sublineage of ST131. PMID- 23434252 TI - A new classification for right top pulmonary vein. AB - BACKGROUND: The right top pulmonary vein (PV) has been defined as an anomalous branch of the right superior PV draining into the left atrium (LA); however, various PV anomalies and terminologies have been reported. To clarify the concept of the right top PV, we reviewed the literature and our cases. METHODS: We reviewed the literature on the right top PV, right PV passing behind the intermediate bronchus (BIB), and related PV anomalies. We also reviewed our anomalous PV cases, which were analyzed using 3-dimensional computed tomography (3D-CT). RESULTS: Authors of the previous reports were radiologists, surgeons, and cardiologists. The terminologies used in the literature included PV branch crossing BIB, right upper lobe vein posterior to the bronchus intermedius, and right isolated superior posterior branch. The frequency of the anomaly in the literature ranged from 0.3% to 9.3%. Anomalous PVs originated from either the right upper lobe or the lower lobe. We found the following among 303 patients with chest disorders at our hospital: 10 (3.3%) of these PV anomalies were observed-4 drained directly into the LA and the other 4 drained into the right superior PV. Among 9 patients who were analyzed and had complete interlobar fissures between the upper and lower lobes, 4 patients had drainage from both the right upper and the lower lobes. Eight PVs passed BIB, 1 passed behind the main bronchus (BMB), and the other passed both BIB and BMB. CONCLUSIONS: We propose that the term right top PV should be used in a broad sense, being defined as "an anomalous branch of PV draining directly into the left atrium (LA)," and that it be classified into 6 types. PMID- 23434253 TI - Ladd's procedure in functional single ventricle and heterotaxy syndrome: does timing affect outcome? AB - BACKGROUND: Infants with univentricular hearts often require intervention, such as a systemic to pulmonary shunt, as part of a staged surgical palliation. This physiology is inherently unstable, and interim mortality ranges from 4% to 15%. Heterotaxy syndrome confers a high incidence of intestinal rotation and fixation abnormalities. Controversy persists as to the need for elective Ladd's procedure. The purpose of this study is to review our experience in children with heterotaxy syndrome and functionally univentricular hearts who underwent Ladd's procedure. METHODS: A retrospective chart review (2005 to 2010) from our institutional database identified patients with heterotaxy syndrome who underwent a Ladd's procedure. RESULTS: Nine patients (3 boys and 6 girls) underwent Ladd's procedure. Patient demographics were as follows: median gestational age, 38 weeks (range, 37 to 39); median birth weight, 2.7 kg (range, 2 to 3.4 kg); and median age at Ladd's procedure, 180 days (range, 7 to 1,080). Four patients (44%) exhibited feeding intolerance with documented intestinal rotation and fixation abnormalities. Two of these patients underwent Ladd's procedure before cardiac surgery, 1 of whom had subsequent pulmonary artery banding, had recurrent necrotizing enterocolitis, and died. Two children had Ladd's procedure after initial cardiac palliation; both had shunt thrombosis during abdominal surgery, with a mortality of 50%. Five patients who were asymptomatic underwent Ladd's procedure after second-stage palliation. Mortality in this group was 0%. CONCLUSIONS: Ladd's procedure in single ventricle heterotaxy patients who are tolerating enteral feeding should be performed after physiologic palliation to a more balanced circulation, ideally after cavopulmonary connection. Symptomatic neonates pose management challenges. Timing of abdominal surgery should be carefully considered, given the significant risk of mortality in these patients. PMID- 23434254 TI - Endoscopic one-way valve implantation in patients with prolonged air leak and the use of digital air leak monitoring. AB - BACKGROUND: Prolonged alveolar-pleural air leaks are associated with increased morbidity and mortality. Endoscopic valve therapy has been recently introduced as a potential less invasive treatment option. We aimed at quantifying the effects of valve therapy on air leak flow and clinical outcomes in patients with prolonged air leaks. METHODS: We report on a series of 16 patients with high comorbidity and evidence of continuous air leak flow in whom chest tubes remained in place for at least 7 days. After identification of the source of the air leak by use of the balloon occlusion technique, endobronchial one-way valves were implanted. Digital chest tube monitoring was used to assess air leak flow before, during, and after valve implantation until chest tube removal. RESULTS: The source of the air leak was endoscopically identified in 13 patients (81%). After valve implantation, air leak flow decreased significantly from 871+/-551 mL/min to 61+/-72 mL/min immediately after the intervention (p<0.001). The mean duration of chest tube drainage was 18+/-8 days before and 9+/-6 days after the intervention (p<0.01). Ten patients were considered responders, and 3 patients were nonresponders. Responders demonstrated consistent air leak flow levels below 100 mL/min until chest tube removal. Long-term follow-up was available for 9 patients. No adverse events related to the valve implants were reported at follow up. Seven patients underwent valve removal without any further complications. CONCLUSIONS: Endoscopic implantation of one-way valves leads to a significant reduction in air leakage flow and may thus be a valuable treatment option in patients with prolonged air leakage. PMID- 23434255 TI - "Supercharged" isoperistaltic colon interposition for long-segment esophageal reconstruction. AB - BACKGROUND: When the stomach is not available, long-segment esophageal reconstruction remains a surgical challenge. Since 2005, we have used a "supercharged" isoperistaltic colon interposition conduit for long-segment esophageal reconstruction that reestablishes a dual blood supply. METHODS: An institutional database search of 449 patients who underwent esophagectomy from 2005 to 2012 identified 11 consecutive patients who underwent long-segment esophageal reconstruction using an isoperistaltic supercharged right (n=9) or left (n=2) colon conduit. All conduits were routed through the anterior mediastinum, maintaining the middle colic (right) or ascending left colic vessels (left) in situ, with reimplantation of the ileocolic vessels (right) or middle colic vessels (left) into the left internal thoracic artery and brachiocephalic vein to improve distal conduit blood flow. RESULTS: Patients were a mean age of 64 years (range, 47 to 76 years). Seven patients had a history of malignancy and 4 had a benign process. The stomach was unavailable for reconstruction due to prior gastric operations (n=9) or neoplastic involvement (n=2). All reimplanted vessels demonstrated excellent flow by Doppler evaluation. Esophagocolonic healing was successful in all patients; however, 1 patient required a temporary stent. CONCLUSIONS: Supercharged isoperistaltic colon interposition appears to be an excellent option for the challenging situation where long-segment esophageal reconstruction is needed and the stomach is not available. The additional effort required to reestablish a dual blood supply appears justified to minimize ischemic-related morbidity. Unlike long-segment small bowel "supercharged" techniques, adequate blood supply to the distal conduit may still be present in case thrombosis of the reimplanted vessels occurs. PMID- 23434256 TI - Surgical reconstruction of pulmonary stenosis with ventricular septal defect and major aortopulmonary collaterals. AB - BACKGROUND: Pulmonary stenosis with ventricular septal defect and major aortopulmonary collaterals (PS/VSD/MAPCAs) is an extremely rare form of congenital heart defect. Although it has been assumed that PS/VSD/MAPCAs would be similar to pulmonary atresia (PA) with VSD/MAPCA, there are currently no data to support this conjecture. This study reviewed our surgical experience with reconstruction of PS/VSD/MAPCA. METHODS: This was a retrospective review of 25 patients (14 boys, 11 girls) who were born with PS/VSD/MAPCA and underwent surgical reconstruction. Preoperative pulmonary angiography was used to define the central branch pulmonary arteries and MAPCA. Patients were a median age of 4 months at the first operation. RESULTS: There was one operative death (4%) in this cohort of 25 patients, and complete repair was achieved in the 24 survivors (96%). There were two distinct subgroups of patients: 11 demonstrated cyanosis in the neonatal timeframe and underwent an initial procedure to augment pulmonary blood flow (+PBF). The remaining 14 patients formed the second group (-PBF). The median age at the first operation was 0.8 months in the +PBF group and 5.2 months in the -PBF group (p<0.005). Complete repair was achieved in 91% of patients in the +PBF group and in 100% in the -PBF group; however, the average number of procedures to achieve complete repair was 2.8 in the +PBF group vs 1.0 in the PBF group (p<0.005). CONCLUSIONS: Outcomes for PS/VSD/MAPCAs as a whole were excellent, with a low surgical mortality and high rate of complete repair. There were two identifiable subgroups with distinctive differences required in their surgical management. These results provide a prognostic outlook for patients with PS/VSD/MAPCAs that can be compared and contrasted with PA/VSD/MAPCAs. PMID- 23434257 TI - Does morbid obesity worsen outcomes after esophagectomy? AB - BACKGROUND: With worldwide increases in esophageal cancer and obesity, esophagectomies in the morbidly obese (MO) will only increase. Risk stratification and patient counseling require more information on the morbidity associated with esophagectomy in the obese. METHODS: We studied nonemergent subtotal or total esophagectomies with reconstruction in the National Surgical Quality Improvement Project (NSQIP) database from 2005 to 2010. After excluding patients with disseminated disease and body mass index (BMI) less than 18.5, we compared outcomes of patients with normal BMI (18.5-25) to those of MO patients (BMI >= 35). Outcomes were mortality and morbidity. Multivariable regression controlled for age and comorbidities differing between groups. RESULTS: Of 794 patients, 578 (73%) had a normal BMI and 216 (27%) patients were morbidly obese (MO). The population was 75% men, with a mean age of 62 years. Patients with a normal BMI were older and more likely to smoke (p < 0.001). MO patients had a higher incidence of hypertension (65% versus 41%) and diabetes (20% versus 10%), and fewer had preoperative weight loss greater than 10% (9% versus 31%) (p < 0.001). Overall, morbidity was 48.5% and mortality was 3%; there was no difference between the groups. On multivariable analysis, all outcomes were the same between groups except deep space infections and pulmonary embolism (PE), for which the obese were at 52% and 48% higher risk, respectively (p = 0.02). CONCLUSIONS: In our study, postoperative mortality and pulmonary, cardiac, and thromboembolic morbidity were similar between MO patients and patients with a normal BMI. MO increased the odds of deep wound infections. Overall, BMI greater than 35 does not confer significant morbidity after esophagectomy. Patients with esophageal pathologic conditions should not be denied resection based on MO alone. PMID- 23434258 TI - Reversible pulmonary trunk banding VIII: Intermittent overload causes harmless hypertrophy in adult goat. AB - BACKGROUND: Traditional pulmonary artery banding (PAB) is not always suitable for mature subpulmonary ventricle retraining. We sought to assess in detail the myocardial morphologic adaptations of two different protocols for inducing right ventricular (RV) hypertrophy in an adult animal model. METHODS: Eighteen adult goats were distributed into three groups: sham (no systolic overload), traditional (continuous systolic overload), and intermittent (daily 12-hour systolic overload). Systolic overload was adjusted to achieve a 0.7 RV-to-aortic pressure ratio. All animals underwent weekly echocardiographic studies, and hemodynamic evaluations were performed 3 times a week. After 4 weeks, the animals were humanely killed for morphologic assessment. RESULTS: A 37.2% increase was observed in the RV wall thickness of the intermittent group (p<0.05), but no significant echocardiographic changes were observed in the other two groups. The intermittent and traditional groups had a 55.7% and 36.7% increase in RV mass, respectively, compared with the sham group (p<0.05). No differences were observed in myocardial water content of the three groups (p=0.27). RV myocardial fiber and nuclei diameters were increased in the intermittent group compared with the sham group (p<0.05). The area of collagen deposition in the RV interstitium was increased 98% in traditional group compared with the sham group (p<0.05). No significant cellular proliferation occurred in any group. CONCLUSIONS: This study suggests that a more effective and harmless hypertrophy can be achieved in adult animals using intermittent PAB compared with the traditional approach. PMID- 23434259 TI - Esophagogastric metaplasia relates to nodal metastases in adenocarcinoma of esophagus and cardia. AB - BACKGROUND: Immunohistochemical profiles of esophageal and cardia adenocarcinoma differ according to the presence or absence of Barrett's epithelium (BIM) and gastric intestinal metaplasia (GIM) in the fundus and antrum. Different lymphatic spreading has been demonstrated in esophageal adenocarcinoma. We investigated the correlation among the presence or absence of intestinal metaplasia in the esophagus and stomach and lymphatic metastases in patients who underwent radical surgery for esophageal and cardia adenocarcinoma. METHODS: The mucosa surrounding the adenocarcinoma and the gastric mucosa were analyzed. The BIM+ patients underwent subtotal esophagectomy and gastric pull up, and the BIM- patients underwent esophagectomy at the azygos vein, total gastrectomy, and esophagojejunostomy. The radical thoracic (station numbers 2, 3, 4R, 7, 8, and 9) and abdominal (station numbers 15 through 20) lymphadenectomy was identical in both procedures except for the greater curvature. RESULTS: One hundred ninety four consecutive patients were collected in three major groups: BIM+/GIM-, 52 patients (26.8%); BIM-/GIM-, 90 patients (46.4%); BIM-/GIM+, 50 patients (25.8%). Two patients (1%) were BIM+/GIM+. A total of 6,010 lymph nodes were resected: 1,515 were recovered in BIM+, 1,587 in BIM-/GIM+, and 2,908 in BIM-/GIM- patients. The percentage of patients with pN+ stations 8 and 9 was higher in BIM+ (p=0.001), and the percentage of patients with pN+ perigastric stations was higher in BIM- (p=0.001). The BIM-/GIM- patients had a number of abdominal metastatic lymph nodes higher than did the BIM-/GIM+ patients (p=0.0001). CONCLUSIONS: According to the presence or absence of BIM and GIM in the esophagus and cardia, adenocarcinoma correspond to three different patterns of lymphatic metastasization, which may reflect different biologic and carcinogenetic pathways. PMID- 23434260 TI - Response of biofilm bacterial communities to antibiotic pollutants in a Mediterranean river. AB - Antibiotics are emerging contaminants, which wing to their bioactivity, may lead to short-term and long-term alterations of natural microbial communities in aquatic environment. We investigated the effects of antibiotics on biofilm bacterial communities in the Llobregat River (Northeast Spain). Three sampling sites were selected: two less polluted sites and one hotspot. River water was collected from each site and used both as inoculum and medium for growing biofilms in independent mesocosms. After 25d of biofilm colonization, we exposed the colonized biofilms to river waters from the downstream sites (progressively contaminated by antibiotics). A control from each site was maintained where the growing biofilm was always exposed to water from the same site. The bacterial community composition, bacterial live/dead ratio and extracellular enzyme activities of the biofilms were measured before and 9d after exposing the biofilms to increasing contaminated waters. Sixteen antibiotic compounds were detected in the water from the three sampling sites. At each site, the antibiotics present in the highest concentrations were sulfonamides, followed by quinolones and macrolides. Bacterial communities of biofilms grown with the three river waters differed markedly in their structure, but less so in terms of functional descriptors. After switching the medium water to increasing pollution, biofilms exhibited increased levels of actinobacteria (HGC), a trend that was associated to the higher antibiotic concentrations in the water. These biofilms also showed increased bacterial mortality, and decreased extracellular leucine aminopeptidase and alkaline phosphatase. There was a significant correlation between antibiotic concentrations and biofilm responses. Our results indicate that the continuous entrance of antibiotics in running waters cause significant structural and functional changes in microbial attached communities. PMID- 23434261 TI - Immunoglobulin G4-associated inflammatory pseudotumor of urinary bladder: a case report. AB - A previously healthy 72-year old woman was admitted with a chief complaint of gross hematuria and fecaluria for 4 months. On initial computed tomographic examination, a lobulated shaped intravesical protruding mass with adhesion to the sigmoid colon was identified. Under a clinical diagnosis of bladder cancer with vesicosigmoid fistula vs sigmoid colon cancer with vesicosigmoid fistula, a frozen section evaluation of the bladder mass was performed to determine the origin of the tumor. Because the frozen section diagnosis of the bladder mass was an inflammatory origin, a partial cystectomy with segmental resection of the adherent sigmoid colon was elected. The microscopic examination of the partial resection of the urinary bladder revealed suburothelial inflammatory mass lesion, involving the entire wall of bladder with extension to the sigmoid colon, which was composed of spindle cells without significant atypia admixed with many lymphocytes, plasma cells, and some scattered eosinophils. Chronic inflammation around nerve bundles, sclerotic fibrosis, and prominent lymphoid follicles with plasma cells were the main features of the mass. No urothelial dysplasia or malignancy was seen. An average of 57 plasma cells per 1 high-power field was immunoreactive for immunoglobulin (Ig) G4 with IgG4/IgG ratio of more than 40%, a diagnostic feature of IgG4-associated inflammatory pseudotumor (IPT), arising in the bladder with the secondary involvement of the sigmoid colon. Recent studies reported many IPTs associated with IgG4 in other locations; however, to the best of our knowledge, IgG4-associated IPT in the urinary bladder has not been reported. We describe herein the first case of IgG4-associated IPT, lymphoplasmacytic type in the urinary bladder. PMID- 23434262 TI - Vision and falls: a multidisciplinary review of the contributions of visual impairment to falls among older adults. AB - Falls are a leading cause of mortality among older adults worldwide. With the increasing aging population, falls are rapidly becoming a public health concern. Numerous internal and external factors have been associated with an older adult's increased risk of falling. Most notably visual impairments are gaining recognition for their critical role in fall events, particularly related to trips, slips and falls due to environmental hazards. This review presents the issue of vision and falls from a multidisciplinary health professional perspective. Discussions include the influence of visual impairment on mobility and activities of daily living, the effects of medications on vision, visual cognitive factors on falls risk and visual training interventions. Finally, implications for multidisciplinary health professional practice and suggestions for future research are offered. PMID- 23434263 TI - Comparison of the analgesic effects of robenacoxib, buprenorphine and their combination in cats after ovariohysterectomy. AB - The aim of this study was to compare the postoperative analgesic effects of robenacoxib and buprenorphine alone or in combination, in cats after ovariohysterectomy. Thirty healthy cats were randomly assigned to receive buprenorphine (0.02 mg/kg, n=10; GB), robenacoxib (2mg/kg, n=10; GR) or their combination at the same dosages (n=10; GBR) SC. After 30 min cats were sedated with an IM administration of medetomidine (0.02 mg/kg) and ketamine (5mg/kg). General anaesthesia was induced with propofol and after intubation was maintained with isoflurane. Before premedication and at 1, 2, 3, 4, 6, 8, 12 and 24h after extubation, pain and sedation were assessed using a simple descriptive pain scale, ranging from 0 (no pain/no sedation) to 4 (intense pain/ deep sedation). If the pain score was >= 3, rescue analgesia was provided using buprenorphine (0.02 mg/kg) administered IM. Pain score was higher in GB at 2, 3, 4, 6 and 8h compared to baseline and compared to GBR at the same study times. Moreover, the pain score was also higher in GB compared to GR at 2, 3, 4 and 6h. Pain score was similar at all study times between GR and GBR. Sedation at 1 and 2h was higher than baseline values in all groups. Cats in GB received rescue analgesia more often than cats assigned to GR or GBR. Robenacoxib was an effective analgesic drug in cats up to 24h after ovariohysterectomy. The addition of buprenorphine did not provide any additional analgesic effects compared to robenacoxib alone. PMID- 23434264 TI - Influence of racing on the serum concentrations of the cardiac biomarkers troponin I and creatine kinase myocardial band (CK-MB) in racing greyhounds. AB - The objective of this study was to investigate the effect of racing on the serum concentrations of cardiac troponin I (cTnI) and creatine kinase myocardial band (CK-MB) in 32 racing greyhounds. Blood samples were collected 24h prior to a 7 km race (T0), within 2h of completion of the race (T1), and 24h post-race (T2). Blood samples were also collected from 20 non-racing greyhounds. The median cTnI concentration in the racing greyhounds was not significantly different from that in the non-racing greyhounds (0.045 ng/mL). Before racing, the median cTnI concentration in the racing greyhounds was 0.050 ng/mL. Following the 7 km race, 31/32 greyhounds showed increases in cTnI concentrations which were significantly higher than the pre-race concentrations (P<0.0001). cTnI concentrations dropped back 24h post-race to values not significantly different from the pre-race concentrations. Following the race, 5/32 greyhounds showed mild increases in CK MB concentrations but these were not significantly different from the pre-race values. These findings could be of importance when evaluating greyhounds with suspected cardiac disease that have recently performed hard exercise. PMID- 23434265 TI - Resolving the challenges in the international comparison of health systems: the must do's and the trade-offs. AB - Countries are increasingly publishing health system performance statistics alongside those of their peers, to identify high performers and achieve a continuously improving health system. The aim of the paper is to identify, and discuss resolution of, some key methodological challenges, which arise when comparing health system performance. To illustrate the issues, we focus on two OECD flagship initiatives: the System of Health Accounts (SHA) and the Health Care Quality Indicators (HCQI) project and refer to two main actors: a coordinating agency, which proposes and collates performance data and second, data correspondents in constituent health systems, who submit data to the coordinating centre. Discussion is structured around two themes: a set of must do's (legitimacy of the coordinating centre, validity of proposed indicators, feasibility of data collection and technical support for data correspondents) and a set of trade-offs (depth vs. breadth in the number of system elements compared, aggregation vs. granularity of data, flexibility vs. consistency of indicator definitions and inclusion criteria). Robust fulfillment of the must-do's and transparent resolution of the trade-offs both depend upon effective collaboration between the coordinating centre and data correspondents, and a close working relationship between a technical secretariat and a body of experts. PMID- 23434266 TI - A new risk factor for type 2 diabetes may offer a teachable moment for prevention. PMID- 23434267 TI - Smarter lunchrooms can address new school lunchroom guidelines and childhood obesity. AB - New US Department of Agriculture regulations have altered what foods schools offer for lunch, but schools cannot require students to eat specific foods. An intervention using the behavioral science principle known as "libertarian paternalism" led junior-senior high school students to eat more fruits and vegetables by making these foods more convenient, attractive, and normative. PMID- 23434268 TI - Evaluation of the possible role of copper ions in drinking water in the pathogenesis of oral submucous fibrosis: a pilot study. AB - We aimed to investigate the concentration of copper ions in drinking water and to assess whether copper has a role in the pathogenesis of oral submucous fibrosis (OSMF). We studied 50 patients with clinically and histologically diagnosed OSMF from the Yadgir district of Karnataka in India. Fifty healthy people matched for age and sex were used as controls. In both groups concentrations of copper ions in serum, saliva, and home drinking water were measured using atomic absorption spectroscopy and intelligent nephelometry technology. Serum ceruloplasmin concentrations were also estimated in both groups. The mean (SD) concentration of copper in the home drinking water of patients with OSMF was significantly higher (764.3 (445.9)MUmol/L) than in the controls (305.7 (318.5)MUmol/L) (p<0.001). Patients with OSMF also had a significantly higher copper concentrations in serum and saliva, and serum ceruloplasmin than controls (p<0.001). For the first time these data have shown a positive association between copper concentrations in home drinking water and OSMF. It raises the possibility that increased copper in drinking water contributes to the development of OSMF, and adds to that ingested when areca nut is chewed. PMID- 23434269 TI - Secondary correction of posttraumatic orbital wall adhesions by membranes laminated with amniotic membrane. AB - The objective of the study was to find out if human amniotic membrane could be used for corrective surgery after trauma to the orbital wall. Because of its proposed antiadhesive qualities, it seemed to be potentially suitable. We studied 8 men (mean age 37 (range 19-74) years) who had deficient ocular movement after fractures of the orbital floor. Five of them had already been operated on. Inclusion criteria were trauma dating back more than 4 months and a soft tissue stricture in the orbital floor diagnosed by magnetic resonance imaging. Patients were treated secondarily with lysis of adhesions and insertion of allogeneic human amniotic membrane laminated on to polyglactin 910/polydioxanone foil, which functioned as the carrier material. Patients were followed up for 3 months, by which time disorders of motility of the ocular bulb had disappeared completely in 5. Two patients had improved motility and a reduction in both their subjective and objective symptoms. One patient had no improvement. The considerable reduction in adhesions and scarring after insertion of the membrane confirms previous assumptions, according to which the epithelial side of the human amniotic membrane has an antiadhesive effect because of its smooth surface. PMID- 23434271 TI - Emotional psychopathology and increased adiposity: follow-up study in adolescents. AB - Based on data from a three-year longitudinal study, we assess the effect, according to gender, of emotional psychopathology in preadolescence on anthropometric and body composition parameters in adolescence (N = 229). Psychopathology was assessed using the Screen for Childhood Anxiety and Related Emotional Disorders, the Children's Depression Inventory and the MINI International Neuropsychiatric Interview for Kids. Body fat percentage (%BF), waist circumference (WC) and body mass index (BMI) were also determined. Following analysis with adjusted multiple regression models, the results indicated that symptoms of depression and separation anxiety were significantly associated with increased WC and BMI in boys, and that somatic symptoms were associated with increased WC and %BF in girls. Diagnosis of social phobia, panic disorder or dysthymia led to significantly increased WC and/or BMI in boys and dysthymia increased WC in girls. These findings suggest that emotional psychopathology in preadolescence is associated with increased weight gain and abdominal fat in adolescence. PMID- 23434270 TI - Investigation of the effect of movement and irrigation systems on temperature in the conventional drilling of cortical bone. AB - We have compared the results of the external irrigation technique with those of a double irrigation technique with continuous intermittent movement. Maximum thermal measurements were made in the cortical part of 10 samples of bovine ribs during osteotomy to simulate the preparation of a surgical bed for the installation of dental implants at a depth of 10 mm. Twenty specimens were drilled for each group: external irrigation and continuous movement (control group 1, CG1); external irrigation and intermittent movement (control group 2, CG2); double irrigation and continuous movement (test group 1, TG1); and double irrigation and intermittent movement (test group 2, TG2). The double irrigation technique gave significantly better results regardless of the drilling movement used. Thermal increases between samples was 19.2% in group CG1, 10.4% in CG2, 5.4% in TG1, and 3.4% in TG2. The double irrigation technique produced a significantly smaller increase in temperature in the cortical bone during both types of drilling (p=0.001), which illustrated its greater efficiency compared with that of the external irrigation technique. PMID- 23434272 TI - A comparison of the effects of ankle taping styles on biomechanics during ankle inversion. AB - OBJECTIVE: This study was designed to compare the effects of different ankle taping methods on lower leg EMG and subtalar kinematics. METHODS: Twelve healthy volunteers were tested on an inversion platform in one of three taping conditions: non-elastic basketweave, elastic adhesive bandage wrap and non-taped control. Muscle activation and range of motion data were collected during an inversion of 35 degrees using a Biometrics((r)) datalogger. Testing was done before and after 30minutes of treadmill running. RESULTS: Significant differences were noted in total inversion, time to peak inversion and rate of inversion. While total inversion did not differ between tape conditions, the rate of inversion in the non-elastic condition was lower than the elastic adhesive condition, which was lower than the control. There was no effect of ankle taping style on latency of the peroneus longus. CONCLUSIONS: The choice of ankle taping style can have significant effects on ankle biomechanics and the use of non elastic tape reduces the rate of inversion. While the rate increased after 30minutes of running, it was still lower than the other conditions. PMID- 23434273 TI - Seasonal and pandemic influenza H1N1 viruses induce differential expression of SOCS-1 and RIG-I genes and cytokine/chemokine production in macrophages. AB - BACKGROUND: Infection with pandemic (pdm) A/H1N1 virus induces high levels of pro inflammatory mediators in blood and lungs of experimental animals and humans. METHODS: To compare the involvement of seasonal A/PR/8/34 and pdm A/H1N1 virus strains in the regulation of inflammatory responses, we analyzed the changes in the whole-genome expression induced by these strains in macrophages and A549 epithelial cells. We also focused on the functional implications (cytokine production) of the differential induction of suppressors of cytokine signaling (SOCS)-1, SOCS-3, retinoid-inducible gene (RIG)-I and interferon receptor 1 (IFNAR1) genes by these viral strains in early stages of the infection. RESULTS: We identified 130 genes differentially expressed by pdm A/H1N1 and A/PR/8/34 infections in macrophages. mRNA levels of SOCS-1 and RIG-I were up-regulated in macrophages infected with the A/PR/8/34 but not with pdm A/H1N1 virus. mRNA levels of SOCS-3 and IFNAR1 induced by A/PR/8/34 and pdm A/H1N1 strains in macrophages, as well as in A549 cells were similar. We found higher levels of IL 6, TNF-alpha, IL-10, CCL3, CCL5, CCL4 and CXCL8 (p < 0.05) in supernatants from cultures of macrophages infected with the pdm A/H1N1 virus compared to those infected with the A/PR/8/34 strain, coincident with the lack of SOCS-1 and RIG-I expression. In contrast, levels of INF-alpha were higher in cultures of macrophages 48h after infection with the A/PR/8/34 strain than with the pdm A/H1N1 virus. CONCLUSIONS: These findings suggest that factors inherent to the pdm A/H1N1 viral strain may increase the production of inflammatory mediators by inhibiting SOCS-1 and modifying the expression of antiviral immunity-related genes, including RIG-I, in human macrophages. PMID- 23434274 TI - Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-kappaB-mediated inflammatory genes expression. AB - Accumulating evidence suggests that inflammatory processes are involved in the development of diabetic nephropathy (DN). However, there are no effective interventions for inflammation in the diabetic kidneys. Here, we tested the hypothesis that Astragaloside IV(AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bge, ameliorates DN in streptozotocin (STZ)-induced diabetic rats through anti-inflammatory mechanisms. Diabetes was induced with STZ (65 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats were divided into three groups (n=8/each group), namely, diabetic rats, diabetic rats treated with AS-IV at 5 and 10 mgkg(-1)d(-1), p.o., for 8 weeks. The normal rats were chosen as nondiabetic control group (n=8). The rats were sacrificed 10 weeks after induction of diabetes. AS-IV ameliorated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. Renal NF kappaB activity, as wells as protein and mRNA expression were increased in diabetic kidneys, accompanied by an increase in mRNA expression and protein content of TNF-alpha, MCP-1 and ICAM-1 in kidney tissues. The alpha1-chain type IV collagen mRNA was elevated in the kidneys of diabetic rats. All of these abnormalities were partially restored by AS-IV. AS-IV also decreased the serum levels of TNF-alpha, MCP-1 and ICAM-1 in diabetic rats. These findings suggest that AS-IV, a novel anti-inflammatory agent, attenuated DN in rats through inhibiting NF-kappaB mediated inflammatory genes expression. PMID- 23434275 TI - Effect of preoperative body mass index on weight loss after obesity surgery. AB - BACKGROUND: Previous studies suggest that individuals with body mass index (BMI) above versus below 60 kg/m(2) attain lower percentage of excess weight loss (%EWL) after bariatric surgery. The objectives of this study were to (1) test whether conclusions drawn about the effect of preoperative BMI on postoperative weight loss depend on the outcome measure, (2) test for evidence of a threshold effect at BMI = 60 kg/m(2), and (3) test the effect from surgery to 12-month follow-up, relative to 12- to 36-month follow-up. METHODS: Retrospective analyses of participants grouped according to preoperative BMI: 35-39.9 (n = 232); 40-49.9 (n = 1166); 50-59.9 (n = 429);>=60 (n = 166). RESULTS: As anticipated, individuals with higher versus lower preoperative BMI had greater total weight loss but lower %EWL at all postoperative time points (all, P<.0005). However, these individuals also had lower percentage of initial weight loss (%IWL) at all time points beyond 1 month postsurgery (all, P<.0005). From 12- to 36-months, individuals with BMI 35-39.9 had 3.2+/-14.3 %IWL (P<.0001); 40-49.9 had 1.0+/-8.9 %IWL (P<.0005); 50-59.9 had-2.4+/-10.0 %IWL (P<.0005); and>=60 had-3.6+/-11.5 %IWL (P<.0005). Overall F3,1989 = 20.2, P< .0005. CONCLUSIONS: Conclusions drawn about the effect of preoperative BMI may depend on the outcome measure. A dosage effect of preoperative BMI was apparent, with heavier individuals showing lower percentages of initial and excess weight loss, regardless of BMI above or below 60 kg/m(2). Finally, this effect was particularly apparent after the initial 12 month rapid weight loss phase, when less obese (BMI<50) individuals continued losing weight, while heavier individuals (BMI>=50) regained significant weight. PMID- 23434276 TI - Is body mass index an adequate measure for individualized clinical decision making? PMID- 23434277 TI - Training non-neurologists to diagnose epilepsy. AB - PURPOSE: Narrowing the epilepsy treatment gap in the world's poorest countries is one of the greatest challenges that the epilepsy community faces. The reliable diagnosis of epilepsy is the first step in this. In well-off countries, doctors, often neurologists, carry this out but this is unrealistic in the developing world where there are often no neurologists, particularly in the rural areas where most people live. Other health professionals therefore need to acquire the skills to diagnose epilepsy. METHOD: A trainee doctor and a nurse accompanied an experienced neurologist on epilepsy camps in Nepal. Answers to a defined set of about 50 questions were obtained from each patient. The two participants made the diagnosis, of epilepsy or not epilepsy, independently of each other and of the neurologist. Their diagnoses were then compared with those of the neurologist who then explained the reasons for his diagnosis. RESULTS: Agreement between each participant and the neurologist increased from about 50% at the start to over 90% after 20 patients. In one of the participants a high level of agreement was maintained 12 months later. CONCLUSION: It is possible to train non-neurologists to diagnose epilepsy like a neurologist after exposure to only 20 patients in the company of that neurologist. This is a way in which experienced neurologists can help narrow the treatment gap in poorer parts of the world. PMID- 23434279 TI - Coldness triggers northward flight in remigrant monarch butterflies. AB - Each fall, eastern North American monarch butterflies (Danaus plexippus) migrate from their northern range to their overwintering grounds in central Mexico. Fall migrants are in reproductive diapause, and they use a time-compensated sun compass to navigate during the long journey south. Eye-sensed directional cues from the daylight sky (e.g., the horizontal or azimuthal position of the sun) are integrated in the sun compass in the midbrain central complex region. Sun compass output is time compensated by circadian clocks in the antennae so that fall migrants can maintain a fixed flight direction south. In the spring, the same migrants remigrate northward to the southern United States to initiate the northern leg of the migration cycle. Here we show that spring remigrants also use an antenna-dependent time-compensated sun compass to direct their northward flight. Remarkably, fall migrants prematurely exposed to overwintering-like coldness reverse their flight orientation to the north. The temperature microenvironment at the overwintering site is essential for successful completion of the migration cycle, because without cold exposure, aged migrants continue to orient south. Our discovery that coldness triggers the northward flight direction in spring remigrants solves one of the long-standing mysteries of the monarch migration. PMID- 23434278 TI - Circadian disruption leads to insulin resistance and obesity. AB - BACKGROUND: Disruption of circadian (daily) timekeeping enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. While clinical observations have suggested that insulin action is not constant throughout the 24 hr cycle, its magnitude and periodicity have not been assessed. Moreover, when circadian rhythmicity is absent or severely disrupted, it is not known whether insulin action will lock to the peak, nadir, or mean of the normal periodicity of insulin action. RESULTS: We used hyperinsulinemic-euglycemic clamps to show a bona fide circadian rhythm of insulin action; mice are most resistant to insulin during their daily phase of relative inactivity. Moreover, clock-disrupted Bmal1 knockout mice are locked into the trough of insulin action and lack rhythmicity in insulin action and activity patterns. When rhythmicity is rescued in the Bmal1 knockout mice by expression of the paralogous gene Bmal2, insulin action and activity patterns are restored. When challenged with a high-fat diet, arhythmic mice (either Bmal1-knockout mice or wild-type mice made arhythmic by exposure to constant light) were obese prone. Adipose tissue explants obtained from high-fat fed mice have their own periodicity that was longer than animals on a chow diet. CONCLUSIONS: This study provides rigorous documentation for a circadian rhythm of insulin action and demonstrates that disturbing the natural rhythmicity of insulin action will disrupt the rhythmic internal environment of insulin sensitive tissue, thereby predisposing the animals to insulin resistance and obesity. PMID- 23434280 TI - The PP2A inhibitor I2PP2A is essential for sister chromatid segregation in oocyte meiosis II. AB - Haploid gametes are generated through two consecutive meiotic divisions, with the segregation of chromosome pairs in meiosis I and sister chromatids in meiosis II. Separase-mediated stepwise removal of cohesion, first from chromosome arms and later from the centromere region, is a prerequisite for maintaining sister chromatids together until their separation in meiosis II [1]. In all model organisms, centromeric cohesin is protected from separase-dependent removal in meiosis I through the activity of PP2A-B56 phosphatase, which is recruited to centromeres by shugoshin/MEI-S332 (Sgo) [2-5]. How this protection of centromeric cohesin is removed in meiosis II is not entirely clear; we find that all the PP2A subunits remain colocalized with the cohesin subunit Rec8 at the centromere of metaphase II chromosomes. Here, we show that sister chromatid separation in oocytes depends on a PP2A inhibitor, namely I2PP2A. I2PP2A colocalizes with the PP2A enzyme at centromeres at metaphase II, independently of bipolar attachment. When I2PP2A is depleted, sister chromatids fail to segregate during meiosis II. Our findings demonstrate that in oocytes I2PP2A is essential for faithful sister chromatid segregation by mediating deprotection of centromeric cohesin in meiosis II. PMID- 23434281 TI - Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. AB - Mechanical tension is an ever-present physiological stimulus essential for the development and homeostasis of locomotory, cardiovascular, respiratory, and urogenital systems. Tension sensing contributes to stem cell differentiation, immune cell recruitment, and tumorigenesis. Yet, how mechanical signals are transduced inside cells remains poorly understood. Here, we identify chaperone assisted selective autophagy (CASA) as a tension-induced autophagy pathway essential for mechanotransduction in muscle and immune cells. The CASA complex, comprised of the molecular chaperones Hsc70 and HspB8 and the cochaperone BAG3, senses the mechanical unfolding of the actin-crosslinking protein filamin. Together with the chaperone-associated ubiquitin ligase CHIP, the complex initiates the ubiquitin-dependent autophagic sorting of damaged filamin to lysosomes for degradation. Autophagosome formation during CASA depends on an interaction of BAG3 with synaptopodin-2 (SYNPO2). This interaction is mediated by the BAG3 WW domain and facilitates cooperation with an autophagosome membrane fusion complex. BAG3 also utilizes its WW domain to engage in YAP/TAZ signaling. Via this pathway, BAG3 stimulates filamin transcription to maintain actin anchoring and crosslinking under mechanical tension. By integrating tension sensing, autophagosome formation, and transcription regulation during mechanotransduction, the CASA machinery ensures tissue homeostasis and regulates fundamental cellular processes such as adhesion, migration, and proliferation. PMID- 23434282 TI - Traces of experience in the lateral entorhinal cortex. AB - A growing body of evidence suggests that memories are stored in the hippocampus by integrating spatial information from specialized cell types in the medial entorhinal cortex (MEC) with nonspatial information from cells in the lateral entorhinal cortex (LEC). LEC neurons show little spatial modulation when rats run in empty open-field environments but fire in the vicinity of discrete objects, suggesting that they provide information about the specific content of the spatial environment. It is unclear, however, whether firing at objects is elicited purely by stimulus properties, in a sensory-like manner, or whether any higher-order property, such as the history of experience, is also relevant. To address this question, we recorded from LEC neurons in an open field where objects were present on a subset of the trials. Whereas some neurons fired at the objects, other cells developed specific firing at places where objects had been located on previous trials, providing a readout of past experience in the environment. The latter cells generally did not respond to the object when it was present, suggesting that object cells and object-trace cells are independent cell classes. These findings identify LEC as a component of the hippocampal-cortical circuit for object-place memory. PMID- 23434284 TI - Homing frequency of human T cells inferred from peripheral blood depletion kinetics after sphingosine-1-phosphate receptor blockade. PMID- 23434283 TI - The proteome of Toll-like receptor 3-stimulated human immortalized fibroblasts: implications for susceptibility to herpes simplex virus encephalitis. AB - BACKGROUND: Inborn errors in Toll-like receptor 3 (TLR3)-IFN type I and III pathways have been implicated in susceptibility to herpes simplex virus encephalitis (HSE) in children, but most patients studied do not carry mutations in any of the genes presently associated with HSE susceptibility. Moreover, many patients do not display any TLR3-IFN-related fibroblastic phenotype. OBJECTIVE: To study other signaling pathways downstream of TLR3 and/or other independent pathways that may contribute to HSE susceptibility. METHODS: We used the stable isotope labeling of amino acids in cell culture proteomics methodology to measure changes in the human immortalized fibroblast proteome after TLR3 activation. RESULTS: Cells from healthy controls were compared with cells from a patient with a known genetic etiology of HSE (UNC-93B-/-) and also to cells from an HSE patient with an unknown gene defect. Consistent with known variation in susceptibility of individuals to viral infections, substantial variation in the response level of different healthy controls was observed, but common functional networks could be identified, including upregulation of superoxide dismutase 2. The 2 patients with HSE studied show clear differences in functional response networks when compared with healthy controls and also when compared with each other. CONCLUSIONS: The present study delineates a number of novel proteins, TLR3 related pathways, and cellular phenotypes that may help elucidate the genetic basis of childhood HSE. Furthermore, our results reveal superoxide dismutase 2 as a potential therapeutic target for amelioration of the neurologic sequelae caused by HSE. PMID- 23434285 TI - The Pediatric Asthma Control and Communication Instrument asthma questionnaire: for use in diverse children of all ages. AB - BACKGROUND: National Institutes of Health asthma guidelines recommend questionnaires to assess asthma control, but these questionnaires are not useable across the entire pediatric age spectrum and have not been validated among significant numbers of minority or Spanish-speaking children. OBJECTIVE: We sought to evaluate a questionnaire designed to assess asthma control across a broad age range of minority and Spanish-speaking children cared for in an outpatient setting. METHODS: Between July 1, 2007, and September 30, 2010, we collected information using the Pediatric Asthma Control and Communication Instrument (PACCI), the Asthma Control Test (ACT; or the childhood ACT for children 4-11 years old), the Pediatric Asthma Caregiver Quality of Life Questionnaire, and lung function and clinicians' ratings of asthma status among a population of children presenting for routine asthma specialist care. The PACCI measure of asthma control was validated by evaluating accuracy, internal reliability, and concurrent, discriminative, and known-groups validity. RESULTS: We collected information on 265 English- and 52 Spanish-speaking children (mean age, 8.2 years; 58% male; 44% African American). Across all age groups and in both languages, PACCI control showed good internal reliability and strong concurrent, discriminative, and known-groups validity with ACT and Pediatric Asthma Caregiver Quality of Life Questionnaire scores and clinicians' ratings of asthma control. The accuracy of the PACCI in classifying children with uncontrolled asthma was good (area under the curve, 0.83; 95% CI, 0.79-0.88). CONCLUSIONS: The PACCI accurately measures asthma control in English- and Spanish speaking children. The PACCI should be useful to clinicians to assess and classify asthma according to National Institutes of Health asthma guidelines. PMID- 23434286 TI - Maternal microchimerism protects against the development of asthma. AB - BACKGROUND: Maternal asthma and child's sex are among the most significant and reproducible risk factors for the development of asthma. Although the mechanisms for these effects are unknown, they likely involve nonclassical genetic mechanisms. One such mechanism could involve the transfer and persistence of maternal cells to her offspring, a common occurrence known as maternal microchimerism (MMc). MMc has been associated with many autoimmune diseases but has not been investigated for a role in asthma or allergic disease. OBJECTIVE: We hypothesized that some of the observed risks for asthma may be due to different rates of transmission or persistence of maternal cells to children of mothers with asthma compared with children of mothers without asthma, or to sons compared with daughters. We further hypothesized that rates of MMc differ between children with and without asthma. METHODS: We tested these hypotheses in 317 subjects from 3 independent cohorts by using a real-time quantitative PCR assay to detect a noninherited HLA allele in the child. RESULTS: MMc was detected in 20.5% of the subjects (range 16.8%-27.1% in the 3 cohorts). We observed lower rates of asthma among MMc-positive subjects than among MMc-negative subjects (odds ratio, 0.38; 95% CI, 0.19-0.79; P = .029). Neither maternal asthma nor sex of the child was a significant predictor of MMc in the child (P = .81 and .15, respectively). CONCLUSIONS: Our results suggest for the first time that MMc may protect against the development of asthma. PMID- 23434288 TI - An epidemiological overview of malaria in Bangladesh. AB - Bangladesh is one of the four major malaria-endemic countries in South-East Asia having approximately 34% of its population at risk of malaria. This paper aims at providing an overview of the malaria situation in this country. Relevant information was retrieved from published articles and reports in PubMed and Google Scholar. Malaria in Bangladesh is concentrated in 13 districts with a prevalence ranging between 3.1% and 36%, and is mostly caused by Plasmodium falciparum. Geographical conditions pose a potential risk for Plasmodium knowlesi malaria. Resistance to a number of drugs previously recommended for treatment has been reported. Low socio-economic status, poor schooling and close proximity to water bodies and forest areas comprise important risk factors. Despite the significant steps in Long Lasting Insecticide Net (LLIN)/Insecticide Treated Net (ITN) coverage in Bangladesh, there are still many challenges including the extension of malaria support to the remote areas of Bangladesh, where malaria prevalence is higher, and further improvements in the field of referral system and treatment. PMID- 23434287 TI - Malaria in Greece: historical and current reflections on a re-emerging vector borne disease. AB - Between 2009 and September 2012, locally acquired cases of P. vivax infection were reported in Greece, mostly from the agricultural area of Evrotas, Lakonia (n = 48), but also sporadically from five other regions (n = 14), suggesting that conditions in these areas are favourable for local transmission of malaria. The risk of re-establishment of malaria in Greece will depend on whether the receptivity for disease transmission (presence of the mosquito vector and adequate ecological and climatic factors) and the vulnerability (importation of the parasite in human reservoirs or presence of infected mosquito vectors) continue to be present in the country. The continuous implementation of the integrated preparedness and response plan for malaria that covers all aspects from surveillance and laboratory diagnosis to vector control and the reorganization of public health infrastructures are necessary to prevent transmission and control the disease in the long term. However, the impact of the severe economic crisis on current health-care, public health infrastructures and vector control constitute a great challenge for the future. The current threat of renewed sustained local malaria transmission in Greece (and thus in continental Europe) merits an international response, including financial and technical support, from European and international stakeholders. PMID- 23434289 TI - [Infectious complications rate from hemodialysis catheters: experience from the French Polynesia]. AB - The arterio-venous fistula (AVF) is the most common vascular access to perform hemodialysis (HD). The HD venous central catheter use should only be proposed to old patients and/or patients without vascular access construction feasibility. These HD catheters are often responsible of infectious and thrombosis complications. We performed, for the first time in French Polynesia, a retrospective study based on 214 patients receiving 618 HD catheters, to evaluate the infectious complication rate due to HD catheters. We showed that 17.4% of HD catheters present with infection. The number of bacteraemia due to HD catheters is 2.57/1000 days-catheters and the number of infection due to HD catheter is 1.43/1000 days-catheters. Eighteen percent of patients requiring an emergency HD without AVF access are transferred in intensive care unit due to infectious HD catheter complications. We observed a similar bacteriological environment than in literature. However, the number of tunneled HD catheter is really lower to that of the number required in European recommendations and we observed an abnormal number of non-functional AVF 1 month after creation. These results involve our nephrology unit to increase the number of tunneled catheters to limit the infectious risk and also to fit with the best practices guidelines. PMID- 23434290 TI - Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression. AB - Multiple lines of evidence suggest that serotonin type 1A (5-HT(1A)) receptor dysfunction is involved in the pathophysiology of mood disorders, and that alterations in 5-HT(1A) receptor function play a role in the mechanisms of antidepressant and mood stabilizer treatment. The literature is in disagreement, however, as to whether 5-HT(1A) receptor binding abnormalities exist in bipolar disorder (BD). We acquired PET images of 5-HT(1A) receptor binding in 26 unmedicated BD subjects and 37 healthy controls using [18F]FCWAY, a highly selective 5-HT(1A) receptor radio-ligand. The mean 5-HT(1A) receptor binding potential (BP(P)) was significantly lower in BD subjects compared to controls in cortical regions where 5-HT(1A) receptors are expressed post-synaptically, most prominently in the mesiotemporal cortex. Post-hoc assessments involving other receptor specific binding parameters suggested that this difference particularly affected the females with BD. The mean BPP did not differ between groups in the raphe nucleus, however, where 5-HT(1A) receptors are predominantly expressed pre synaptically. Across subjects the BPP in the mesiotemporal cortex was inversely correlated with trough plasma cortisol levels, consistent with preclinical literature indicating that hippocampal 5-HT(1A) receptor expression is inhibited by glucocorticoid receptor stimulation. These findings suggest that 5-HT(1A) receptor binding is abnormally reduced in BD, and this abnormality may particularly involve the postsynaptic 5-HT(1A) receptor system of individuals with a tendency toward cortisol hypersecretion. PMID- 23434291 TI - Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: involvement of nitric oxide. AB - Activation of purinergic receptors by ATP (P2R) modulates glutamate release and the activation of post-synaptic P2R is speculated to induce nitric oxide (NO) synthesis. Increased glutamatergic and nitrergic signaling have been involved in the neurobiology of stress-related psychiatric disorders such as anxiety and depression. Therefore, the aim of this study was to test the effects of two P2R antagonists (PPADS and iso-PPADS) in animals submitted to models predictive of antidepressant-, anxiolytic- and anticompulsive-like effects. Swiss mice receiving PPADS at 12.5mg/kg showed reduced immobility time in the forced swimming test (FST) similarly to the prototype antidepressant imipramine (30mg/kg). This dose was also able to decrease the number of buried marbles in the marble-burying test (MBT), an anticompulsive-like effect. However, no effect was observed in animals submitted to the elevated plus maze (EPM) and to the open field test. The systemic administration of iso-PPADS, a preferential P2XR antagonist, also reduced the immobility time in FST, which was associated to a decrease in NOx levels in the prefrontal cortex. In addition, P2X7 receptor was found co-immunoprecipitated with neuronal nitric oxide synthase (NOS1) in the prefrontal cortex. These results suggest that P2X7, possibly coupled to NOS1, could modulate behavioral responses associated to stress-related disorders and it could be a new target for the development of more effective treatments for affective disorders. PMID- 23434292 TI - Drug reimbursement recommendations by the National Institute for Health and Clinical Excellence: have they impacted the National Health Service budget? AB - OBJECTIVE: Determine whether reimbursement restrictions recommended by the National Institute for Health and Clinical Excellence (NICE) have impacted the United Kingdom (UK) National Health Service (NHS) budget. METHODS: Data were abstracted from NICE guidance documents and costing statements through March 2011. Estimated maximum and adjusted potential budget impact (PBI) on the NHS was derived using estimates of the UK marketing-approved population and the annual cost for the new drug. Descriptive and logistic analyses were used to estimate the correlation between the degree of restrictions on reimbursement recommended by NICE for each new drug indication and the PBI controlling for clinical effectiveness and cost-effectiveness. RESULTS: PBI was significantly correlated with the degree of reimbursement restrictions. In descriptive analysis, the adjusted PBI for drugs that were recommended without restrictions was L20.3 million (SD = 22.2) compared with L49.8 million (SD = 90.8) for those recommended with restrictions and L71.1 million (SE = 99.9) for those not recommended. In logistic analysis, the odds ratio for less restrictive reimbursement was 0.848 (95% CI, 0.762-0.945) for each L20 million increase in the adjusted PBI. Results were similar using the maximum PBI. CONCLUSIONS: After controlling for clinical effectiveness and cost-effectiveness, the degree of reimbursement restriction recommended by NICE remains significantly correlated with the PBI, despite that fact that the NICE decision process does not consider budget impact. This correlation might be due to NICE consideration of effectiveness and cost effectiveness for subgroups of the approved population. PMID- 23434294 TI - Cognitive outcome after epilepsy surgery in children. AB - The ultimate goal of epilepsy surgery in young children is to stop seizures, interrupt the downhill course of the epileptic encephalopathy, and improve developmental capacities. Postoperative outcome after childhood epilepsy surgery should therefore not only be expressed in terms of seizure freedom, cognitive outcome is an equally important outcome measure. Insight in the mutually dependent variables that can determine pre and postoperative cognitive developmental abilities will improve prediction of outcome and presurgical counseling of parents. The purpose of this review is to discuss the literature regarding cognitive outcome and the predictors of postoperative cognitive functioning after epilepsy surgery in children, particularly those with "catastrophic" epilepsy. There are only few studies in which the relation between possible determinants and cognitive outcome or change was statistically tested in a multivariable manner. Duration of epilepsy, presurgical Developmental Quotient (DQ) or Intelligence Quotient (IQ), and postoperative seizure freedom were the only factors reported in different studies to be independently related to eventual cognitive outcome after epilepsy surgery. Underlying etiology, gender, age at surgery, presurgical DQ/IQ, postoperative seizure freedom, cessation of antiepileptic medication, and follow-up interval have all been described in different surgical cohorts to be independently related to a postoperative change of IQ or DQ scores. To appreciate how each of the pre-epileptic, presurgical, and postoperative variables may independently influence eventual cognitive outcome and postoperative cognitive improvement, we need multicenter studies with large homogenous surgical populations, using standardized tests and multivariable analyses. PMID- 23434293 TI - Reliable estimation of incoherent motion parametric maps from diffusion-weighted MRI using fusion bootstrap moves. AB - Diffusion-weighted MRI has the potential to provide important new insights into physiological and microstructural properties of the body. The Intra-Voxel Incoherent Motion (IVIM) model relates the observed DW-MRI signal decay to parameters that reflect blood flow in the capillaries (D*), capillaries volume fraction (f), and diffusivity (D). However, the commonly used, independent voxel wise fitting of the IVIM model leads to imprecise parameter estimates, which has hampered their practical usage. In this work, we improve the precision of estimates by introducing a spatially-constrained Incoherent Motion (IM) model of DW-MRI signal decay. We also introduce an efficient iterative "fusion bootstrap moves" (FBM) solver that enables precise parameter estimates with this new IM model. This solver updates parameter estimates by applying a binary graph-cut solver to fuse the current estimate of parameter values with a new proposal of the parameter values into a new estimate of parameter values that better fits the observed DW-MRI data. The proposals of parameter values are sampled from the independent voxel-wise distributions of the parameter values with a model-based bootstrap resampling of the residuals. We assessed both the improvement in the precision of the incoherent motion parameter estimates and the characterization of heterogeneous tumor environments by analyzing simulated and in vivo abdominal DW-MRI data of 30 patients, and in vivo DW-MRI data of three patients with musculoskeletal lesions. We found our IM-FBM reduces the relative root mean square error of the D* parameter estimates by 80%, and of the f and D parameter estimates by 50% compared to the IVIM model with the simulated data. Similarly, we observed that our IM-FBM method significantly reduces the coefficient of variation of parameter estimates of the D* parameter by 43%, the f parameter by 37%, and the D parameter by 17% compared to the IVIM model (paired Student's t test, p<0.0001). In addition, we found our IM-FBM method improved the characterization of heterogeneous musculoskeletal lesions by means of increased contrast-to-noise ratio of 19.3%. The IM model and FBM solver combined, provide more precise estimate of the physiological model parameter values that describing the DW-MRI signal decay and a better mechanism for characterizing heterogeneous lesions than does the independent voxel-wise IVIM model. PMID- 23434295 TI - Effects of pulmonary artery banding and retrograde aortic arch obstruction on the hybrid palliation of hypoplastic left heart syndrome. AB - OBJECTIVES: The hybrid approach achieves stage 1 palliation of hypoplastic left heart syndrome with flow and physiologic characteristics that are different from those of the surgical Norwood circulations. In addition to having branch pulmonary arterial banding regulating the balance between pulmonary and systemic blood flows, coronary and cerebral perfusion are dependent on retrograde flow through the native aortic arch when aortic atresia is present. Accordingly, we used computational modeling to assess the effects of pulmonary artery banding diameter and retrograde aortic arch hypoplasia or obstruction on the hybrid stage 1 circulation, including the influence on systemic and cerebral oxygen deliveries. METHODS: A computational modeling technique was used to couple a 3 dimensional geometry of the hybrid palliation with a hydraulic network of the entire circulation based on pre-stage 2 hemodynamics. This validated multiscale approach predicts clinically relevant outcomes, such as flow, pressure, ejection fraction, and oxygen delivery. Simulations with pulmonary artery banding varying between 1.5 and 3.5 mm were performed. To examine the effects of retrograde aortic arch hypoplasia and obstruction, models of differing aortic arch diameter (2-5 mm) and isthmus coarctation (2.5-5 mm) were studied. RESULTS: Banding the branch pulmonary arteries to 2 mm led to pulmonary and systemic blood flows closest to 1:1 and produced the highest mixed venous saturation and systemic oxygen delivery. Both cerebral and coronary perfusion decreased markedly when the retrograde aortic arch or the coarctation was less than 3 mm in diameter. Moreover, flow reversal in the carotid arteries was observed during diastole in all models. CONCLUSIONS: These computational simulations of the stage 1 hybrid palliation for hypoplastic left heart syndrome with aortic atresia suggest that small differences in the degree of branch pulmonary arterial banding can result in significant changes in the overall performance of the hybrid palliation. Furthermore, retrograde aortic arch hypoplasia or obstruction can lead to suboptimal cerebral and coronary perfusion. Precise pulmonary artery banding may be important to optimize interstage physiology in patients undergoing the hybrid approach, and pre-interventional imaging of the aortic arch and isthmus should be performed to rule out potential for post-procedural suboptimal cerebral and coronary perfusion. PMID- 23434296 TI - Differential responses of the right ventricle to abnormal loading conditions in vivo: possible pathophysiologic mechanisms. AB - OBJECTIVE: The right ventricle (RV) demonstrates differential adaptations in response to pressure versus volume loading, a phenomenon that may be important in the management of children and adults with congenital heart disease (CHD). The purpose of this study is to elucidate possible transcriptional mechanisms of the RV response to pressure versus volume loading in vivo. METHODS: Fetal lambs had aortopulmonary shunting or pulmonary artery (PA) banding. Four weeks after spontaneous delivery, ovine hearts were evaluated for hemodynamic changes and changes in expression of sarcomeric gene proteins and transcriptional factors. Western blot densitometry and chromatin immunoprecipitation were applied using standard techniques. Transactivation assays were performed using transient transfections in Schneider's Drosophila line 2 cells in culture. RESULTS: After PA banding, the RV pressure increased from 36 +/- 4 mm Hg (n = 4) to 96 +/- 8 mm Hg (n = 4, P < .05). The RVs of shunted and banded animals showed significant increases in the expression levels and promoter binding of activators myocyte enhancer factor 2, GATA-4, Nkx2.5, transcriptional enhancer factor 1, and specificity protein (Sp) 1. The transcriptional repressor Sp3 was downregulated in shunted animals, but its expression was increased paradoxically in the RV of the PA band group. Immunoprecipitation of Sp3 showed posttranslational modification to the acetylated isoform. In transient transfections of Schneider's Drosophila line 2 cells, acetylation of Sp3 converted it from a transcriptional repressor to an activator. CONCLUSIONS: Posttranslational modifications of the transcriptional repressor Sp3, by acetylation, may be an important mechanism in the differential response of the RV to abnormal loading conditions. Sp3 may serve as a biomarker for RV failure for various heart defects in children and adults with CHD. These findings may have therapeutic implications in the management of right heart failure. PMID- 23434297 TI - Medical errors: the performance gap in hypoplastic left heart syndrome and physiologic equivalents? AB - BACKGROUND: The frequency and impact of medical errors during staged palliation are unknown. METHODS: All patients with hypoplastic left heart syndrome and physiologic equivalents (N = 191) who underwent staged palliation (2001-2011) were studied. Stage 1, interstage, and stage 2 were reviewed to identify diagnostic, technical, judgment, and management errors. The impact of errors on transplant-free survival was examined by parametric competing risks and risk adjusted regressions using bootstrapping. RESULTS: Stage 1 (N = 191) errors (n = 111, 58%) were common and predominantly intraoperative (n = 84, 44%) or postoperative (n = 43, 23%). Postoperative errors were determinants of death/transplant (hazard ratio, 1.7; P = .01), whereas technical errors (n = 65, 34%) were not, but they delayed recovery and discharge (extra 24 days approximately, P = .0024). Postoperative stage 1 errors led to decrements in total strategy success of approximately 30% (78% vs 48%, P = .004). Stage 2 (N = 134) errors (n = 66, 49%) were common. Intraoperative errors were the most prevalent (n = 61, 46%) but did not compromise survival. Postoperative errors (n = 11, 8%) were determinants of death/transplant (hazard ratio, 2.4; P < .0001). Interstage errors (n = 21, 16%) led to twice the intensive care unit stay (16 vs 7 days, P < .0001) and hospital stay (30 vs 17 days, P < .02) after stage 2. Overall, a child presenting with ideal morphology and managed with no postoperative errors at stage 1 or 2 would have a predicted late survival in excess of 80%. CONCLUSIONS: Technical errors are common and delay recovery. Their effects on survival are mitigated. Intraoperative judgment errors are associated with strategy failure in a univariate model and lead to increased postoperative errors in a multivariate model. Postoperative errors are independently associated with a decrease in univentricular strategy survival. PMID- 23434298 TI - It is time for certification in cardiothoracic critical care. PMID- 23434300 TI - Importance of a diffusion-dominant small volume to activate cell-secreted soluble factor signaling in embryonic stem cell culture in microbioreactors: a mathematical model based study. AB - In our previous studies, we observed that cell-secreted BMP4 had a prominent influence on mouse embryonic stem cell (mESC) behaviors in a membrane-based two chambered microbioreactor (MB), but not in a macro-scale culture (6-well plate/6WP). In this study, we investigated how the physical aspects of these cultures regulated BMP4 signaling by developing mathematical models of the cultures. The models estimated signaling activity in the cultures by considering size of the undifferentiated mESC colonies and their growth, diffusion of BMP4, and BMP4 trafficking process in the colonies. The models successfully depicted measured profile of BMP4 concentration in the culture medium which was two times higher in the MB than that in the 6WP during 5-day culture. The models estimated that, owing to the small volume and the membrane, cells were exposed to a higher BMP4 concentration in the top chamber of the MB than that in the 6WP culture. The higher concentration of BMP4 induced a higher concentration of BMP4-bound receptor in the colony in the MB than in the 6WP, thereby leading to the higher activation of BMP4 signaling in the MB. The models also predicted that the size of the MB, but not that of the 6WP, was suitable for maximizing BMP4 accumulation and upregulating its signaling. This study will be helpful in analyzing culture systems, designing microfluidic devices for controlling ESC or other cell behavior. PMID- 23434301 TI - Human cytomegalovirus particles directly suppress CD4 T-lymphocyte activation and proliferation. AB - CD4 T cells are important regulators of the immune system and are vital for mounting a strong immune response against viral infections. Human cytomegalovirus (HCMV) is known to be a strong modulator of the innate as well as adaptive immune responses. In this study, we found that HCMV directly inhibited proliferation of CD4 T cells and rendered them unresponsive to immunological stimuli. This effect was not observed when CD4 T cells were treated with herpes simplex virus-1/2 or measles virus. When stimulated with phytohemagglutinin, concanavalin A, or phorbol myristate acetate, HCMV-treated T cells were unable to proliferate, revealing an ability of HCMV to inhibit CD4 T cell response. Furthermore, HCMV also prevented proliferation of leukemic T-cell lines. HCMV-treated CD4 T cells expressed the activation markers CD45RO and CD69, were not apoptotic and produced decreased levels of the cytokines IL-4, IFN-gamma and TNF-alpha, compared to untreated controls. The inhibitory effect of HCMV on CD4 T cell proliferation was not mediated by HCMV gH, gB or other immunogenic glycoproteins, since intravenous immunoglobulins or gB- or gH-specific neutralizing antibodies did not prevent the suppression of T-cell proliferation. Our observations show that HCMV inhibits CD4 T cell function with potential clinical consequences for both humoral and cell mediated immune responses. PMID- 23434302 TI - The effect of integrated health management model on the satisfaction among Chinese elderly. AB - The study objective was to investigate the effect of integrated health management model on the satisfaction among Chinese elderly. Using a randomized controlled trial, 600 people who are 60 and over have signed the informed consent in China were randomly assigned into management and control group. The management group received care integrated individual health management with community health management model in the follow-up 6 months. The individual health management included establishing health record, performing health evaluation, giving individual instruction, carrying out telephone consultation and follow-up. The community health management includes lectures on health knowledge, distribution of health education materials and physical fitness exercise kit. Factor analysis, t-test, chi(2)-test and logistic regression models were used. The average satisfaction scores of baseline and final of management or control group were calculated through factor analysis. The management group has shown a significant improvement in satisfaction score, no difference in control group. Logistic regression analysis of influencing factors of the elderly satisfaction showed that the satisfaction score of male, individuals without chronic disease and management group was higher. These results suggest that integrated health management model can improve the elderly satisfaction in China through realizing good communication between the elderly and medical staff in community. PMID- 23434303 TI - Realtime cerebellum: a large-scale spiking network model of the cerebellum that runs in realtime using a graphics processing unit. AB - The cerebellum plays an essential role in adaptive motor control. Once we are able to build a cerebellar model that runs in realtime, which means that a computer simulation of 1 s in the simulated world completes within 1 s in the real world, the cerebellar model could be used as a realtime adaptive neural controller for physical hardware such as humanoid robots. In this paper, we introduce "Realtime Cerebellum (RC)", a new implementation of our large-scale spiking network model of the cerebellum, which was originally built to study cerebellar mechanisms for simultaneous gain and timing control and acted as a general-purpose supervised learning machine of spatiotemporal information known as reservoir computing, on a graphics processing unit (GPU). Owing to the massive parallel computing capability of a GPU, RC runs in realtime, while reproducing qualitatively the same simulation results of the Pavlovian delay eyeblink conditioning with the previous version. RC is adopted as a realtime adaptive controller of a humanoid robot, which is instructed to learn a proper timing to swing a bat to hit a flying ball online. These results suggest that RC provides a means to apply the computational power of the cerebellum as a versatile supervised learning machine towards engineering applications. PMID- 23434304 TI - A novel rat model of osteonecrosis of the femoral head induced by periarticular injection of vascular endothelial growth factor receptor 2 antibody. AB - BACKGROUND: Traditional methods to establish animal model of osteonecrosis of the femoral head (ONFH) are not satisfactory because of the undefined underlying mechanism, low rate of the disease, and high incidence of mortality. The present study was to induce ONFH in a rat model through periarticular injection of vascular endothelial growth factor (VEGF) receptor 2 antibody. MATERIALS AND METHODS: Eighty Sprague-Dawley rats were divided into four groups randomly and equally. VEGF receptor 2 antibody solution with a concentration of 50 MUg/mL (group A), 25 MUg/mL (group B), and 12.5 MUg/mL (group C) was injected periarticularly to the capsular attachment to proximal femur, respectively. The injection lasted 4 continuous days, with a total volume of 2 mL. The rats in the fourth group were treated by saline for control (group D). Two weeks after the first injection, histologic and micro-computed tomographic examinations were used to investigate the presence of ONFH. RESULTS: Histologically, there were 90% of rats that developed ONFH in group A, 60% in group B, and 20% in group C, whereas no ONFH was found in group D. The density of intraosseous vessels was suppressed significantly by the antibody. Radiologically, the features of ONFH including deformation of the femoral head were revealed. There was no occurrence of lethal complications. CONCLUSIONS: VEGF receptor 2 antibody can induce ONFH in the rat with a high incidence of the disease. Local blockage of angiogenesis can be used as an effective method to establish animal model of ONFH. PMID- 23434305 TI - Endobronchial perfluorocarbon administration decreases lung injury in an experimental model of ischemia and reperfusion. AB - OBJECTIVE: To verify the effects of liquid endobronchial perfluorocarbon (PFC) administered before reperfusion in an animal model of lung ischemia-reperfusion injury. METHODS: Eighteen Wistar rats were subjected to an experimental model of selective left pulmonary artery clamping for 45 min followed by reperfusion for 2 h. The animals were divided into three groups: the ischemia-reperfusion (IR) group, the sham group, and the PFC group. We recorded the hemodynamic parameters, blood gas analysis, and histology. A Western blot assay was used to measure the inducible nitric oxide synthase, caspase 3, and nuclear factor ?B (subunit p65) activities. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances assay and the activity of the antioxidant enzyme superoxide dismutase. RESULTS: No significant differences were observed in lipid peroxidation among the groups. The superoxide dismutase activity was increased (P < 0.05) in the PFC treated group. The expressions of nuclear factor ?B, inducible nitric oxide synthase, and caspase 3 were significantly lower in the PFC group than in the IR group (P < 0.05). The histologic analysis showed a reduction in lung injuries in the PFC group compared with the sham and IR groups. CONCLUSION: The use of endobronchial PFC reduces the inflammatory response, preserves the alveolar structure, and protects the lungs against the hazardous effects of ischemia reperfusion injuries. PMID- 23434306 TI - Endoscopic vein harvest or not? PMID- 23434307 TI - Is benign paroxysmal vertigo of childhood a migraine precursor? AB - INTRODUCTION: Benign Paroxysmal Vertigo of Childhood (BPVC) is a common cause of vertigo in children and it is characterized by recurrent attacks of vertigo without warning resolving spontaneously after minutes to hours. It has been considered the equivalent of migraine in childhood. METHODS: Twenty-seven patients diagnosed with BPVC were recruited between 1991 and 1997 with a follow up of at least 15 years. The incidence of migraine, inner ear disorders and family medical history is analyzed. RESULTS: The average age for the onset of the attacks of BPVC was 3 years and 11 months, and for spontaneous resolution, it was around 5 years and 7 months. The average age for follow up was 18 years. Nine patients developed migraine during adulthood. Nineteen of them had a family history of migraine. CONCLUSION: We have observed that the prevalence of migraine in patients that had been diagnosed with BPVC is higher than in the general population, which leads us to propose BPVC as a precursor of migraine during childhood. PMID- 23434308 TI - Measurement validity of childbirth perceptions. PMID- 23434309 TI - A qualitative investigation of alcohol use advice during pregnancy: experiences of Dutch midwives, pregnant women and their partners. AB - OBJECTIVE: two studies aimed to explore the advice Dutch midwives give and the information Dutch pregnant women and partners of pregnant women receive about alcohol consumption in pregnancy. DESIGN: study 1 included individual semi structured interviews with midwives. Study 2 involved focus groups and individual semi-structured interviews with pregnant women and partners. Interview content was based on the I-Change Model. SETTING: study 1 was conducted nation-wide; Study 2 was conducted in the central and southern regions of the Netherlands. PARTICIPANTS: 10 midwives in Study 1; 25 pregnant women and nine partners in Study 2. MEASUREMENTS AND FINDINGS: study 1 showed that midwives intended to advise complete abstinence, although this advice was mostly given when women indicated to consume alcohol. Midwives reported to lack good screening skills and sufficient knowledge about the mechanisms and consequences of antenatal alcohol use and did not involve partners in their alcohol advice. In Study 2, the views of pregnant women and partners were congruent to the findings reported in Study 1. In addition, pregnant women and partners considered midwives as an important source of information on alcohol in pregnancy. Partners were interested in the subject, had a liberal view on antenatal alcohol use and felt ignored by midwives and websites. Pregnant women indicated to receive conflicting alcohol advice from their health professionals. KEY CONCLUSIONS: midwives' alcohol advice requires improvement with regard to screening, knowledge about mechanisms and consequences of antenatal alcohol use and the involvement of the partners in alcohol advice during pregnancy. IMPLICATIONS FOR PRACTICE: training should be given to Dutch midwives to increase their screening skills and their alcohol related knowledge to pregnant women. Research is needed to determine how the midwife's alcohol advice to the partner should be framed in order to optimise the partner's involvement concerning alcohol abstinence in pregnancy. More attention to the topic at a national level, for example via mass media campaigns, should also be considered to change views about alcohol use during pregnancy in all stakeholders. PMID- 23434310 TI - What really matters in cancer?: Putting people back into the heart of cancer policy. AB - Twenty-first century cancer is framed by the biomedical revolution. The cancer patient today enters a world dominated by the success and failures of biomedical science from gene to statistic. By any measure, bibliometric, financial, media profile or simply the lingua franca of everyday discourse about cancer, biomedicine occupies the majority of the cultural discourse around cancer. Yet the reality is that patients are people who are diagnosed, treated, survive and die with cancer in a world bounded by their personal and social experiences. Others they have known with the disease shape their values and concepts. The social determinants of cancer are of far greater importance in terms of prevention, treatment and care than is acknowledged in policy terms. In light of the demographic trend of a rapidly ageing population, increasing costs of healthcare and the urgent need to be able to deliver affordable cancer care set against the population's almost insatiable ability to absorb all types of healthcare, there is an urgent need to redress policy balance in terms of both understanding the social determinants of cancer and bringing new insights into evidence-based national cancer planning and delivery of services. PMID- 23434311 TI - The future of the US response to global HIV/AIDS. PMID- 23434312 TI - Aflatoxin contamination of wheat flour and the risk of esophageal cancer in a high risk area in Iran. AB - BACKGROUND: Golestan province in northeastern Iran has been known as a high-risk area for esophageal cancer (EC). This study was conducted to assess aflatoxin (AF) contamination of wheat flour (WF) samples in high and low EC-risk areas of Golestan province. METHODS: Four WF samples were collected randomly from each of 25 active silos throughout the province in 2009. The levels of AFs were measured using the High-performance liquid chromatography method. Using the data of EC rates obtained from Golestan population-based cancer registry, the province was divided into high and low risk areas for EC. Student t-test and multivariate regression analysis were used to compare the levels of aflatoxins as well as the condition of silos between the two areas. RESULTS: One hundred WF samples were collected. The mean levels of total aflatoxin and aflatoxin B1 was 1.99 and 0.53 ng g(-1), respectively. The levels of total AF (p = 0.03), AFG2 (p = 0.02) and AFB1 (p = 0.003) were significantly higher in samples obtained from high risk area. Multivariate regression analysis showed that humidity of silo was the most important source of difference between silos of the two areas (p = 0.04). CONCLUSION: We found a positive relationship between AF level of WF samples and the risk of EC. So, AF contamination may be a possible risk factor for EC in our region. We also found that humidity of silos was the most important determinant of AF contamination of WF. Intensive control of silos conditions including humidity and temperature are needed especially in high EC-risk areas. PMID- 23434313 TI - Temporal trends (1989-2011) in levels of mercury and other heavy metals in feathers of fledgling great egrets nesting in Barnegat Bay, NJ. AB - There is an abundance of data for levels of metals from a range of species, but relatively few long-term time series from the same location. In this paper I examine the levels of arsenic, cadmium, chromium, lead, manganese, mercury and selenium in feathers from fledgling great egrets (Ardea alba) collected at nesting colonies in Barnegat Bay, New Jersey from 1989 to 2011. The primary objectives were to test the null hypotheses that (1) There were no temporal differences in metal levels in feathers of fledgling great egrets, and (2) Great egrets nesting in different areas of Barnegat Bay (New Jersey) did not differ in metal levels. There were significant yearly variations in levels of all heavy metals in feathers of fledgling great egret, but levels decreased significantly from 1989 to 2011 only for lead (1,470 ppb to 54.3 ppb), cadmium (277 ppb to 30.5 ppb), and manganese (only since 1996; 2,669 ppb to 329 ppb)). Although mercury levels decreased from 2003-2008 (6,430 ppb to 1,042 ppb), there was no pattern before 2003, and levels increased after 2008 to 2,610 ppb in 2011. Lead, cadmium, chromium, manganese and mercury were higher in feathers from great egrets nesting in the northern part of the bay, and selenium was highest in feathers from mid bay. The lack of a temporal decline in mercury levels in feathers of great egrets is cause for concern, since the high levels in feathers from some years (means as high as 6,430 ppb) are in the range associated with adverse effects (5,000 ppb for feathers). PMID- 23434314 TI - A validated, rapid UPLC-MS/MS method for simultaneous ivabradine, reboxetine, and metoprolol analysis in human plasma and its application to clinical trial samples. AB - A recent clinical trial assessing human autonomic cardiovascular regulation applied pacemaker channel inhibition with ivabradine, norepinephrine transporter blockade with reboxetine, and beta-adrenoreceptor blockade with metoprolol. To verify patient adherence, we developed and validated a fast UPLC-MS/MS assay measuring all three compounds simultaneously. Deuterium-labeled drugs, d3 ivabradine, d5-reboxetine and d7-metoprolol, served as internal standards. Sample preparation of 200MUL human plasma consisted of a single liquid-liquid extraction step by means of ethyl acetate. Chromatographic separation was performed on a 50 mm long BEH C18 column with gradient elution using a mixture of water and methanol each containing 2mM ammonium acetate over 4.5min. The mass spectrometer was operated in the positive electrospray ionization (ESI+) mode. Characteristic product ions resulting from collision-induced dissociation of unlabeled and deuterium-labeled drugs with argon were used for quantification in the selected reaction monitoring mode. We validated the method according to the European Medicines Agency (EMA) guideline on bioanalytical method validation over the range from 1ng/mL to 500ng/mL for all three analytes. Linear responses with correlation coefficients>0.99 over that range were acquired. The LOQ value was 1ng/mL for each drug. Regulatory criteria for accuracy (80-120%) and precision (RSD<15%) were met for all drugs. The internal standard-normalized matrix factor was close to 1 for low and high analyte concentrations. We successfully measured ivabradine, reboxetine, and metoprolol concentrations in 107 human plasma samples from a clinical trial. Quality control samples processed in parallel confirmed the method's reliability in a clinical setting. PMID- 23434315 TI - A Bayesian approach to modeling the interaction between air pollution and temperature. AB - PURPOSE: Investigating the interaction between particulate matter air pollution (PM) and temperature is important for quantifying the effects of PM on mortality. One approach is stratification-estimating the effect of PM within different temperature strata-but this treats the cutpoints that define the strata as fixed, when in fact they are unknown. The purpose of this paper is to propose a new approach that appropriately accounts for uncertainty regarding the cutpoints, and to apply this approach to data from two Australian cities. METHODS: We propose a Bayesian model which allows the effects of PM to differ within different temperature strata. The cutpoints that define the strata are parameters that are jointly estimated along with the other model parameters. This is in contrast with the standard stratification approach, where cutpoints are specified a priori and treated as fixed constants. Also, the Bayesian model is formulated in a way that ensures continuity in the effects of PM at the stratum boundaries. Markov chain Monte Carlo methods are used to perform the inferences. RESULTS: Analysis of daily data over several years provides evidence for an interactive effect between PM and temperature in Sydney and no support for such an effect in Melbourne. CONCLUSIONS: The proposed Bayesian model provides a means for investigating interactions between PM and temperature which appropriately incorporates uncertainty. PMID- 23434316 TI - Temporary adalimumab dose escalation is effective in Crohn's disease patients with secondary non-response. PMID- 23434317 TI - Demography and the demise of Neandertals: a comment on 'Tenfold population increase in Western Europe at the Neandertal-to-modern human transition'. PMID- 23434318 TI - Reassessment of the La Ferrassie 3 Neandertal ossicular chain. AB - The ossicular chain in La Ferrassie 3 was briefly described in the monograph on the La Ferrassie Neandertal children, but to date has not been the subject of detailed study. We provide new data on these important fossils and re-examine some previous suggestions of derived Neandertal features in the middle ear ossicles based on more limited evidence. The malleus shows a curved lateral margin of the manubrium and a relatively large head. The incus shows a tall articular facet, a depressed area on the medial surface of the body, a straight anterior border of the long process and a more closed angle between the processes. The stapes shows an asymmetrical configuration of the crura, with an anteriorly skewed head, and generally small dimensions, including a smaller and relatively wider stapedial footplate. These same features can also be seen in the few other Neandertal ear ossicles known, suggesting that a consistent anatomical pattern characterizes the Neandertal ossicular chain. While the phylogenetic polarity of many of these features remains to be clarified, the asymmetrical stapes and anteriorly skewed stapedial head appear to be derived Neandertal features. In addition, while the larger malleus head and incus articular facet in La Ferrassie 3 might reflect larger body mass in Neandertals, the larger stapes footplates in Homo sapiens cannot be explained by changes in body mass. Indeed, H. sapiens seems to depart from the general mammalian pattern in combining an increase in stapes footplate size with a decrease in body mass. Although the malleus/incus lever ratio in La Ferrassie 3 is similar to that in H. sapiens, Neandertals appear to be characterized by a slightly different spatial relationship and articulation of the ossicular chain within the tympanic cavity. While only limited inferences can be drawn regarding hearing ability based on the ossicles, the few physiologically relevant dimensions in the La Ferrassie 3 ear bones are similar to H. sapiens. PMID- 23434319 TI - The effect on nursing home resident outcomes of creating a household within a traditional structure. AB - OBJECTIVES: Person-centered care (PCC) is a revolutionary approach to the culture change of elder care that is being adopted by nursing home providers across the nation. One aspect of PCC is the introduction of more self-contained units or households within long term care facilities. This study aimed to evaluate the effect of households on nursing home residents' physical and psychological outcomes using the Minimum Data Set (MDS) comprehensive assessment data. DESIGN: A retrospective, longitudinal study. SETTING: Two care units in a large urban nursing home within the Western New York long term care system. PARTICIPANTS: Residents living in two units (household unit and traditional care unit) within one nursing home during January 2005 to April 2007. MEASUREMENTS: The MDS 2.0 is a standardized and comprehensive assessment tool that measures long term care facility residents' functional, medical, cognitive, and psycho-social status. The de-identified MDS 2.0 records of residents living in these units during this time period were retrieved from the New York Association of Homes and Services for the Aging. The residents' cognitive patterns, mood and behavior pattern, physical functioning, pain, fall, nutritional status, number of ulcers, medication use, and special treatment were compared. Descriptive and correlational statistics were used for data analysis. RESULTS: MDS records of 35 household-unit residents and 33 traditional-unit residents were analyzed. After adjusting for baseline differences, household-unit residents had better self- performed eating ability, daytime sleepiness, and restraint use; however, more fall incidents were reported for the household unit. CONCLUSIONS: Our findings indicate that households generated some better outcomes for residents and provide preliminary evidence to support households in nursing homes. Further research is needed to overcome design issues; however, the MDS may be useful for PCC outcomes measurement. PMID- 23434320 TI - Future nursing home design: an important component in enhancing quality of life. PMID- 23434321 TI - CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and beta-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target. PMID- 23434322 TI - Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. AB - Tet proteins oxidize 5-methylcytosine (mC) to generate 5-hydroxymethyl (hmC), 5 formyl (fC), and 5-carboxylcytosine (caC). The exact function of these oxidative cytosine bases remains elusive. We applied quantitative mass-spectrometry-based proteomics to identify readers for mC and hmC in mouse embryonic stem cells (mESC), neuronal progenitor cells (NPC), and adult mouse brain tissue. Readers for these modifications are only partially overlapping, and some readers, such as Rfx proteins, display strong specificity. Interactions are dynamic during differentiation, as for example evidenced by the mESC-specific binding of Klf4 to mC and the NPC-specific binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation. PMID- 23434323 TI - The origin of the tetrapod limb: from expeditions to enhancers. AB - More than three centuries ago natural philosophers, and later anatomists, recognized a fundamental organization to the skeleton of tetrapod limbs. Composed of three segments, stylopod, zeugopod, and autopod, this pattern has served as the basis for a remarkably broad adaptive radiation from wings and flippers to hands and digging organs. A central area of inquiry has been tracing the origins of the elements of this Bauplan in the fins of diverse fish. Can equivalents of the three segments, and the developmental processes that pattern them, be seen in fish fins? In addition, if so, how do these data inform theories of the transformation of fins into limbs? Answers to these questions come from linking discoveries in paleontology with those of developmental biology and genetics. Burgeoning discoveries in the regulatory biology of developmental genes and in the genomics of diverse species offer novel data to investigate these classical questions. PMID- 23434324 TI - Phylogeny and systematic revision of the karyorelictid genus Remanella (Ciliophora, Karyorelictea) with descriptions of two new species. AB - We present here the systematic relationships and taxonomy of some newly collected karyorelictid ciliates from the genus Remanella isolated from the intertidal zone in China. Three species were investigated using observation in vivo and silver staining methods, of which two new species were identified: R. macrostoma sp. nov. and R. achroma sp. nov. Small subunit (SSU) rRNA genes were sequenced for six species and phylogenetic analyses indicated that the genus Remanella is paraphyletic, with three Loxodes species nesting within it. The monophyly of Remanella, however, could not be rejected through the approximately unbiased (AU) test (p=0.311>0.05) and therefore we considered Remanella to be a valid genus. Based on a critical review of the literature, the validity of all nominal species of Remanella was discussed. Remanella unirugosa and R. multicorpusculata were regarded as junior synonyms of R. rugosa and R. granulosa respectively. We also presented here an illustrated taxonomic key based on morphologic and morphometric characteristics and containing all Remanella species considered identifiable in this revision. PMID- 23434325 TI - Prolonged and post-term pregnancies: guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF). AB - The duration of pregnancy varies between 40(+0) and 41(+3) weeks. Conventionally, and essentially arbitrarily, a pregnancy is considered to be "prolonged" after 41(+0) weeks, but the infant is not considered "post-term" until 42(+0) weeks (Professional consensus). A term birth thus occurs during the period from 37(+0) to 41(+6) weeks. In France, prolonged pregnancies (>=41(+0)weeks) involve 15-20% of pregnant women, and post-term pregnancies (>=42(+0) weeks) approximately 1%. The frequency of post-term pregnancies is very heterogeneous: in Europe and the United States, it ranges from 0.5% to 10% according to country. In prolonged pregnancies, the cesarean section rate-especially the emergency cesarean rate-is multiplied by approximately 1.5 (grade B). From 37(0-6) to 43(0-6) weeks, the risk of perinatal mortality increases regularly, from 0.70/00 to 5.80/00. Meconium aspiration syndrome is responsible for substantial morbidity and mortality, and its incidence increases regularly between 38(+0) and 42(+6) weeks, from 0.240/00 to 1.420/00 (grade B). Similarly, the risks of neonatal acidosis (grade B), 5-min Apgar scores less than 7 (grade B) and admissions to neonatal intensive care (grade B) increase progressively between 38(+0) and 42(+6) weeks. These risks appear to double for post-term growth-restricted newborns (grade C). Ultrasound dating of the pregnancy makes it possible to reduce the risk that it will be incorrectly considered prolonged and that labor will therefore be induced unnecessarily. To harmonize practices, if the crown-rump length (CRL) is correctly measured (this measurement should be taken between 11(+0) and 13(+6) weeks, when CRL should measure from 45 to 84mm), ultrasound dating based on it should be used to determine the official date pregnancy began, regardless of its difference from the date assumed by the patient or estimated based on the date of the last menstrual period. This rule does not apply to pregnancies by IVF, for which the date pregnancy began is defined by the date of oocyte retrieval (Professional consensus). From 37(0-6) to 43(0-6) weeks, the risk of perinatal mortality increases regularly and there is no threshold at which a clear increase in perinatal mortality becomes visible. Fetal monitoring by cardiotocography (CTG) that begins at 41(+0) weeks would cover approximately 20% of women and reduce perinatal morbidity compared with monitoring that begins at 42(+0) weeks (grade C). The frequency recommended for this monitoring ranges between two and three times a week (Professional consensus). For ultrasonography assessment, measurement of the largest fluid pocket is recommended, because measurement of the amniotic fluid index (that is, the sum of the four quadrants) is accompanied by more diagnoses of oligohydramnios, inductions of labor, and cesareans for fetal distress without any improvement in neonatal prognosis (grade A). The practice of assessing the Manning biophysical score increases the number of diagnoses of oligohydramnios and fetal heart rage (FHR) abnormalities and generates an increase in the rates of inductions and cesareans without improving neonatal prognosis. The use of this biophysical score in monitoring prolonged pregnancies is therefore not recommended (grade B). In the absence of a specific disorder, induction of labor can be proposed in patients between 41(+0) and 42(+6) weeks (grade B). Nonetheless, the choice of prolongation beyond above 42(+0) weeks appears to involve an increase in fetal risk, which must be explained to the patient and balanced against the potential disadvantages of induction (Professional consensus). Stripping the membranes can reduce the duration of pregnancy by increasing the number of patients going into labor spontaneously during the week afterward (grade B). Compared to an expectant approach, it does not increase the cesarean section rate (grade A). It reduces recourse to induction by 41% at 41(+0) weeks and by 72% at 42(+0) weeks (grade B), without increasing the risk of either membrane rupture or maternal or neonatal infection (grade B). Used as a tampon or vaginal gel, prostaglandins E2 (PGE2) are an effective method of inducing labor (grade A). They can be used to induce labor successfully, regardless of cervical ripeness (grade A). If misoprostol is chosen, the lowest dose is to be preferred, starting with a vaginal dose of 25MUg every 3-6h (grade A). For misoprostol, more powerful studies remain necessary for better defining the doses, routes of administration, tolerance and indications. Misoprostol at any dose is contraindicated in women with uterine scars (grade B). Placement of an intracervical Foley catheter is an effective mechanical means of inducing labor, with less uterine hyperstimulation than prostaglandins and no increase in the cesarean section rate (grade A). Nonetheless, as the risk of infection might be increased, this technique requires more robust evaluation before entering general practice (grade B). In cases of meconium-stained amniotic fluid, pharyngeal aspiration before delivery of the shoulders is not recommended (grade A). The team managing a post-term newborn with meconium-stained amniotic fluid at birth must know how to perform intubation and, if the intubation is not helpful, endotracheal aspiration (grade C) and ventilation with a mask. Routine endotracheal intubation of a vigorous newborn is not recommended (grade A). PMID- 23434326 TI - Maternal arterial stiffness in normotensive pregnant women who subsequently deliver babies that are small for gestational age. AB - OBJECTIVE: To assess the association between maternal arterial stiffness and delivery of a baby that is small for gestational age (SGA) in normotensive pregnant women. STUDY DESIGN: Pulse wave analyses were performed to assess maternal arterial stiffness at 26-33 weeks of gestation in 40 normotensive women who subsequently delivered SGA babies (SGA group) and 111 normotensive women who delivered babies with normal growth (control group). RESULTS: Central systolic pressure (CSP), augmentation index (AIx) and AIx at a heart rate of 75 beats/min (AIx-75) were significantly higher in the SGA group compared with the control group, but this was not the case for brachial systolic pressure, brachial diastolic pressure or brachial pulse pressure. Birth weight was significantly correlated with CSP (r=-0.26, p<0.01), AIx (r=-0.33, p<0.01) and AIx-75 (r=-0.27, p<0.01), but not with brachial systolic pressure, brachial diastolic pressure or brachial pulse pressure. CONCLUSION: Increased arterial stiffness may be involved, in part, in the pathogenesis of SGA in normotensive women, suggesting an association between fetal growth and maternal endothelial function. Pulse wave analysis may be a clinically applicable method for assessment of maternal arterial stiffness, and may be more relevant to intrauterine fetal growth than conventional brachial blood pressure. PMID- 23434328 TI - [Atypical restoration of patency after thrombus of a superficial facial vein]. PMID- 23434327 TI - Circulating high-sensitivity C-reactive protein and soluble CD40 ligand are inter related in a cohort of women with polycystic ovary syndrome. AB - OBJECTIVE: Insulin resistance (IR), the fundamental metabolic alteration in women with polycystic ovary syndrome (PCOS), has recently been reported to represent, in part, a chronic low-grade inflammatory state. This study aimed to assess the inter-relationship between the plasma levels of high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand (sCD40L) - both inflammatory factors - and the pathogenesis of IR among women with PCOS. STUDY DESIGN: This study compared 44 women with PCOS with a group of control women without PCOS (n = 39). Participants were matched for age, blood pressure and degree of obesity. Enzyme linked immunosorbent assay was used to measure the two inflammatory factors. Fasting glucose and insulin were assayed and used to calculate the IR indices. RESULTS: Significant elevations in the plasma levels of both inflammatory factors were observed in women with PCOS compared with the control women: 3.17 (2.23 3.89) vs 2.05 (0.93-2.82) mg/l for hs-CRP and 2.46 (1.08-4.16) vs 0.82 (0.43 1.26) ng/ml for sCD40L, respectively. Interestingly, among women with PCOS, the two inflammatory factors were significantly positively correlated with each other (r = 0.465, p = 0.002), as well as with the IR indices. This association remained significant even after adjustment for body mass index as a measure of obesity. CONCLUSION: Independent of obesity, women with PCOS suffer low-grade inflammation that is correlated with IR. The observed inter-relationships suggest that CRP in collaboration with the CD40-CD40L system may have a role in the pathogenesis of PCOS. PMID- 23434329 TI - Effective writing and publishing scientific papers, part II: title and abstract. PMID- 23434330 TI - Effective writing and publishing scientific papers, part IV: methods. PMID- 23434331 TI - Safety and efficacy of unpreserved timolol 0.1% gel in patients controlled by preserved latanoprost with signs of ocular intolerance. AB - PURPOSE: To assess the safety and efficacy of unpreserved timolol 0.1% gel in ocular hypertensive (OHT) or glaucomatous patients controlled by preserved latanoprost 0.005% but with signs of ocular intolerance. METHODS: Patients initially treated with preserved latanoprost were randomized to receive once daily either one drop of unpreserved timolol gel in the morning or one drop of preserved latanoprost in the evening for 84 days. All patients attended three visits (D0, D28 and D84). A patient was considered as responder to primary criteria at Day 84 if the sum of the scores of the eight ocular symptoms and the six objective signs had decreased by at least 20% and if the effect on intra ocular pressure (IOP) was assessed as either satisfactory or acceptable. RESULTS: At D84, 91.5% of patients were responders to the primary combined efficacy/safety criteria under unpreserved timolol gel treatment versus 48.6% under preserved latanoprost treatment (P<0.001). As early as D28, 85.3% of patients were responders in the unpreserved timolol gel group compared to 40.3% of patients in the preserved latanoprost group (P<0.001). IOP change from baseline was not significant between treatments (P>0.05) at D28 or D84. Both signs and symptoms were significantly improved (P<0.001) with unpreserved timolol gel compared to preserved latanoprost. CONCLUSION: Unpreserved timolol 0.1% gel maintained the efficacy of preserved latanoprost and reduced signs and symptoms of intolerance in almost all glaucomatous/OHT patients on preserved latanoprost. PMID- 23434332 TI - [Mouse models of diabetic retinopathy: systematic review of the literature]. AB - INTRODUCTION: Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. A variety of species of animals have been used to investigate the pathogenesis of DR. However, the mouse model of diabetic retinopathy, which is an attractive model due to the genetic modifications which can be carried out, remains underutilized. In order to explain this discrepancy, we performed a review of the literature concerning various mouse models of diabetic retinopathy so as to define their advantages and disadvantages. MATERIAL AND METHODS: We carried out a literature review using PubMed. We selected articles describing models of DR with pericyte loss, retinal capillary abnormalities and hyperglycemia. Articles not meeting these three criteria were excluded. RESULTS: Out of 25 articles, we found seven models of DR. For each of these models, we report the method of induction of DR and the electrophysiological and histopathological features. CONCLUSION: Models obtained through genetic manipulation appear the most interesting, since the diabetes and its complications present early without additional physiologic modifications. However, since these models differ frequently by sex, this is an important parameter that must be taken into account. PMID- 23434334 TI - In reply: the King-Devick test and sports-related concussion: study of a rapid visual screening tool in a collegiate cohort. PMID- 23434335 TI - Cognitive impairment in Brazilian patients with Behcet's disease occurs independently of neurologic manifestation. AB - Neuro-Behcet's disease (NBD) presents cognitive and behavioral symptoms possibly explained by secondary dysfunction of frontal and temporal cortices due to subcortical damage, as NBD commonly involves the brainstem and basal ganglia. Nonetheless, there are reports of cognitive impairment in patients without neurological manifestations. OBJECTIVE: To evaluate cognitive function in Behcet's disease (BD) patients with and without neurological manifestations and to analyze clinical variables associated with cognitive deficits. METHODS: This is a cross-sectional study that compared healthy controls, BD patients without neurological manifestations and NBD patients. Each group comprised 24 participants. All participants underwent neuropsychological evaluation, Hamilton Anxiety Rating Scale (HAM-A), Beck Depression Inventory (BDI) application and brain MRI. Cumulative prednisone dose, years of education, and presence of white matter lesions in brain MRI were recorded. RESULTS: 41.6% of BD and 41.6% of NBD patients showed impaired language and executive function, whereas visual memory was impaired only in NBD patients. Multiple logistic regression revealed that anxiety (OR 1.09 95% CI 1.03-1.16, p=0.003) and lower educational level (OR 0.62 95% CI 0.48-0.80, p<0.0001) were independently associated with cognitive impairment. CONCLUSION: Cognitive impairment occurs frequently in patients with BD independently of neurological manifestation. Low educational level and anxiety are risk factors for cognitive impairment in BD. PMID- 23434336 TI - Children with cancer: driving the global agenda. PMID- 23434337 TI - New drugs for children and adolescents with cancer: the need for novel development pathways. AB - Despite major progress in the past 40 years, 20% of children with cancer die from the disease, and 40% of survivors have late adverse effects. Innovative, safe, and effective medicines are needed. Although regulatory initiatives in the past 15 years in the USA and Europe have been introduced, new drug development for children with cancer is insufficient. Children and families face major inequity between countries in terms of access to innovative drugs in development. Hurdles and bottlenecks are well known-eg, small numbers of patients, the complexity of developing targeted agents and their biomarkers for selected patients, limitations of US and EU regulations for paediatric medicines, insufficient return on investment, and the global economic crisis facing drug companies. New drug development pathways could efficiently address the challenges with innovative methods and trial designs, investment in biology and preclinical research, new models of partnership and funding including public-private partnerships and precompetitive research consortia, improved regulatory requirements, initiatives and incentives that better address these needs, and increased collaboration between paediatric oncology cooperative groups worldwide. Increased cooperation between all stakeholders-academia, parents' organisations and advocacy groups, regulatory bodies, pharmaceutical companies, philanthropic organisations, and government-will be essential. PMID- 23434338 TI - Sustaining innovation and improvement in the treatment of childhood cancer: lessons from high-income countries. AB - Cancer in children and adolescents is rare and biologically very different from cancer in adults. It accounts for 1.4% of all cancers worldwide, although this proportion ranges from 0.5% in Europe to 4.8% in Africa, largely because of differences in age composition and life expectancy. In high-income countries, survival from childhood cancer has reached 80% through a continuous focus on the integration of clinical research into front-line care for nearly all children affected by malignant disease. However, further improvement must entail new biology-driven approaches, since optimisation of conventional treatments has in many cases reached its limits. In many instances, such approaches can only be achieved through international collaborative research, since rare cancers are being subdivided into increasingly smaller subgroups on the basis of their molecular characteristics. The long-term effect of anticancer treatment on quality of life must also be taken into account because more than one in 1000 adults in high-income countries are thought to be survivors of cancer in childhood or adolescence. The introduction of drugs that are less toxic and more targeted than those currently used necessitates a partnership between clinical and translational researchers, the pharmaceutical industry, drug regulators, and patients and their families. This therapeutic alliance will ensure that efforts are focused on the unmet clinical needs of young people with cancer. Most children with cancer live in low-income and middle-income countries, and these countries account for 94% of all deaths from cancer in people aged 0-14 years. The immediate priority for these children is to improve access to an affordable, best standard of care in each country. Every country should have a national cancer plan that recognises the unique demographic characteristics and care needs of young people with cancer. Centralisation of the complex components of treatment of these rare diseases is essential to improve survival, accelerate research, and train the future specialist workforce. Referral routes and care pathways must take account of the large geographical distances between many patients' homes and treatment centres, and the economic, cultural, and linguistic diversity of the populations served. PMID- 23434339 TI - New policies to address the global burden of childhood cancers. AB - Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers. PMID- 23434340 TI - Paediatric cancer in low-income and middle-income countries. AB - Patterns of cancer incidence across the world have undergone substantial changes as a result of industrialisation and economic development. However, the economies of most countries remain at an early or intermediate stage of development-these stages are characterised by poverty, too few health-care providers, weak health systems, and poor access to education, modern technology, and health care because of scattered rural populations. Low-income and middle-income countries also have younger populations and therefore a larger proportion of children with cancer than high-income countries. Most of these children die from the disease. Chronic infections, which remain the most common causes of disease-related death in all except high-income countries, can also be major risk factors for childhood cancer in poorer regions. We discuss childhood cancer in relation to global development and propose strategies that could result in improved survival. Education of the public, more and better-trained health professionals, strengthened cancer services, locally relevant research, regional hospital networks, international collaboration, and health insurance are all essential components of an enhanced model of care. PMID- 23434341 TI - Changes in humeral torsion and shoulder rotation range of motion in high school baseball players over a 1-year period. AB - BACKGROUND: The torsional stress on a baseball player's throwing limb has been theorized to affect humeral retrotosion during skeletal maturity. This study investigated 1) changes in humeral retrotorsion and shoulder rotation range of motion over a 1-year period in high school baseball players, and 2) relationship between a 1-year change in dominant limb retrotorsion and the number of seasons participants played on organized baseball teams. METHODS: Humeral retrotorsion and shoulder range of motion were measured a year apart in a total of 138 high school baseball players. Baseball participation history over the year was captured using a questionnaire. Changes in bilateral humeral retrotorsion and range of motion over a year and effects of baseball participation on changes in humeral retrotorsion and range of motion were assessed using analysis of variance models. FINDINGS: Humeral retrotorsion did not significantly change over the year regardless of the number of seasons participants played baseball (P>0.05). The participants' dominant limb internal rotation range of motion decreased slightly over a year (2.0 degrees , P=0.015), while external rotation (7.8 degrees , P<0.01) and total rotation (11.9 degrees , P<0.01) range of motion decreased bilaterally among the participants who only played baseball in 1 season. INTERPRETATION: Adaptation in humeral retrotorsion seems to occur prior to high school age. Our observations suggest that change in shoulder range of motion in high school baseball players are attributed to soft tissue contracture. This provides a support that stretching exercises should be implemented when significant changes in range of motion are identified in high school baseball players. PMID- 23434342 TI - Effects of cervical orthoses on neck biomechanical responses during transitioning from supine to upright. AB - BACKGROUND: Our objectives were to use a hybrid cadaveric/surrogate model to evaluate the effects of the cervicothoracic orthosis and collar on head and neck biomechanical responses during transitioning from supine to upright. METHODS: The model consisted of an adult-male surrogate dummy with its artificial neck replaced by a human neck specimen (n=10). The model was transitioned from supine to upright using a rotation apparatus. A high-speed digital camera tracked motions of the head, vertebrae, cervicothoracic orthosis, pelvis, and rotation apparatus. Head load cell data were used to compute occipital condyle loads. Average peak spinal loads and motions were statistically compared (P<0.05) among experimental conditions (cervicothoracic orthosis: anterior strut locked and unlocked; collar; and unrestricted). FINDINGS: Loads at the occipital condyles consisted of anterior shear, compression, and extension moment. The most rigid device tested, cervicothoracic orthosis with anterior strut locked, significantly reduced axial compression neck force and increased anterior shear neck force and provided the greatest immobilization by significantly reducing spinal rotations as compared to other experimental conditions. Similar neck biomechanical responses were observed between the cervicothoracic orthosis, anterior strut unlocked, and collar. INTERPRETATION: The simple maneuver of supine-to-upright transitioning, commonly performed clinically, produced complex neck loads and motions including head protrusion which caused cervical spine snaking. Neck motions consisted of extension at the upper cervical spine and flexion at the subaxial cervical spinal levels. Of the devices tested, the cervicothoracic orthosis, with anterior strut locked, provided the greatest cervical spine immobilization thereby reducing the risk of potential secondary neck injuries. PMID- 23434343 TI - Classification of forefoot pain based on plantar pressure measurements. AB - BACKGROUND: Plantar pressure is widely used to evaluate foot complaints. However, most plantar pressure studies focus on the symptomatic foot with foot deformities. The purposes of this study were to investigate subjects without clear foot deformities and to identify differences in plantar pressure pattern between subjects with and without forefoot pain. The second aim was to discriminate between subjects with and without forefoot pain based on plantar pressure measurements using neural networks. METHODS: In total, 297 subjects without foot deformities of whom almost 50% had forefoot pain walked barefoot over a pressure plate. Foot complaints and subject characteristics were assessed with a questionnaire and a clinical evaluation. Plantar pressure was analyzed using a recently developed method, which produced pressure images of the time integral, peak pressure, mean pressure, time of activation and deactivation, and total contact time per pixel. After pre-processing the pressure images with principal component analysis, a forward selection procedure with neural networks was used to classify forefoot pain. FINDINGS: The pressure-time integral and mean pressure were significantly larger under the metatarsals II and III for subjects with forefoot pain. A neural network with 14 input parameters correctly classified forefoot pain in 70.4% of the test feet. INTERPRETATION: The differences in plantar pressure parameters between subjects with and without forefoot pain were small. The reasonable performance of forefoot pain classification by neural networks suggests that forefoot pain is related more to the distribution of the pressure under the foot than to the absolute values of the pressure at fixed locations. PMID- 23434344 TI - Transforming growth factor beta1-mediated atrial fibrotic activity and the recovery of atrial mechanical contraction after surgical maze procedure. AB - BACKGROUND: The maze procedure for atrial fibrillation (AF) is effective in restoring sinus rhythm; however, a significant proportion of patients failed to recover atrial mechanical contraction (AMC). We hypothesized that preoperative atrial fibrotic activity would be related to the AMC recovery. METHODS: In atrial tissues of 128 consecutive patients who underwent mitral valve and combined maze surgery using cryoablation for persistent AF, preoperative mRNA levels of various biomarkers were measured including transforming growth factor-beta1 (TGF-beta1), atrial natriuretic peptide, brain natriuretic peptide (BNP), C-reactive protein, connective tissue growth factor, matrix metalloproteinase, N-terminal prohormone BNP, and tissue inhibitor of metalloproteinase. Presence of AMC was assessed using Doppler echocardiographic measurement of the transmitral A-wave velocity. RESULTS: At 1-year follow-up, patients without AMC (n=62) showed higher preoperative TGF-beta1 mRNA expression (0.42 versus 0.28, P=0.01) than those with AMC (n=66). There was no significant difference between the two groups regarding the other biomarkers. Recovery rate of AMC and the increment of A-wave velocity were reduced with the increase of preoperative TGF-beta1 mRNA level. Multiple logistic regression analysis revealed that TGF-beta1 mRNA levels were independently associated with the absence of AMC (odds ratio 7.47, 95% CI 1.63 to 34.4, P=0.01). CONCLUSIONS: TGF-beta1-mediated atrial fibrotic activity might exert a detrimental effect on the reversibility of atrial mechanical contraction after the maze and combined mitral valve surgery for long-standing persistent AF. Earlier surgical intervention might be needed to preserve atrial mechanical function. PMID- 23434345 TI - Jamming of the 18F sheath's tip inside a severely calcified femoral artery. PMID- 23434346 TI - Monocarboxylate transporters and mitochondrial creatine kinase protein content in McArdle disease. AB - McArdle disease (MD) is a metabolic myopathy due to myophosphorylase deficiency. We examined monocarboxylate transporters (MCT) and creatine kinase (CK) protein content in skeletal muscle from MD patients and age-matched controls to evaluate potential cellular adaptations that compensate for the loss of glycogenolysis. Our findings of higher MCT1 and mitochondrial CK suggest that proteins related to extra-muscular fuel uptake and intra-muscular energy transduction are up regulated without change in mitochondrial mass in MD patients. PMID- 23434347 TI - A systematic review of pre-surgical exercise intervention studies with cancer patients. AB - BACKGROUND: Recent reviews suggest that enhancing fitness and functional capacity prior to surgery can accelerate post-surgery recovery and reduce mortality. However, the effect of pre-surgical exercise interventions in cancer patients is not fully explained. The aim of this paper is to systematically review the available literature regarding pre-surgery exercise training interventions in cancer patients and examine their effects on physiological outcomes as well as quality of life (QOL) and length of hospital stay. METHODS: Relevant studies were identified through a search on MEDLINE, PreMEDLINE, AMED, MEDLINE Daily Update, CINAHL and SPORTDiscus. All randomized controlled trials (RCTs) and non-RCTs that had some form of physical exercise undertaken prior to surgery were included. Descriptive characteristics such as participant characteristics, study design, types of cancer, length of study, and primary outcomes were extracted. Methodological rigour was assessed using a modified Delphi List. Due to the heterogeneity and the dearth of pre-surgical studies, we were limited to a systematic review rather than a meta-analysis. RESULTS: Eighteen studies were included consisting of a total of 966 participants. Lung cancer studies were the predominant group represented. Most of the studies prescribed an aerobic intervention programs done prior to surgery. Mode, frequency, duration, and intensity of exercise intervention varied across the different cancer groups. The majority of studies showed preliminary positive change in clinical outcomes with significant improvements in the rate of incontinence, functional walking capacity and cardiorespiratory fitness. CONCLUSION: Pre-surgical exercise may benefit cancer patients through positive effects on function and physical capacity. Surgical oncologists may consider pre-surgical exercise interventions as a potential adjuvant therapy to improve patients' outcomes. PMID- 23434348 TI - Monodisperse magnetite nanoparticle tracers for in vivo magnetic particle imaging. AB - Magnetic Particle Imaging (MPI) is a new biomedical imaging modality that produces real-time, high-resolution tomographic images of superparamagnetic iron oxide (SPIO) nanoparticle tracer distributions. In this study, we synthesized monodisperse tracers for enhanced MPI performance and investigated both, their blood clearance time using a 25 kHz magnetic particle spectrometer (MPS), and biodistribution using a combination of quantitative T2-weighted MRI and tissue histology. In vitro and in vivo MPI performance of our magnetic nanoparticle tracers (MNTs), subject to biological constraints, were compared to commercially available SPIOs (Resovist). Monodisperse MNTs showed a 2-fold greater signal per unit mass, and 20% better spatial resolution. In vitro evaluation of tracers showed that MPI performance of our MNTs is preserved in blood, serum-rich cell culture medium and gel; thus independent of changes in hydrodynamic volume and fluid viscosity - a critical prerequisite for in vivo MPI. In a rodent model, our MNTs circulated for 15 min - 3* longer than Resovist - and supported our in vitro evaluation that MPI signal is preserved in the physiological environment. Furthermore, MRI and histology analysis showed that MNTs distribute in the reticuloendothelial system (RES) in a manner similar to clinically approved SPIO agents. MNTs demonstrating long-circulation times and optimized MPI performance show potential as angiography tracers and blood-pool agents for the emerging MPI imaging modality. PMID- 23434349 TI - Poly(ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases. AB - Paclitaxel (PTX) and alendronate (ALN) are effective drugs used for the treatment of breast cancer bone metastases. Growing evidence suggests that low-dose taxanes and bisphosphonates possess anti-angiogenic properties. However, PTX is water insoluble and toxic, even if administered at anti-angiogenic dosing schedule. Polymer conjugation of PTX will increase water-solubility and improve its pharmacokinetic profile directing it to the tumor site. We further propose to combine it with ALN for active bone targeting. We conjugated ALN and PTX with poly(ethylene glycol) (PEG) forming self-assembled micelles where PTX molecules are located at the inner core and the water-soluble ALN molecules at the outer shell. PTX-PEG-ALN micelles exhibited similar in vitro cytotoxic and anti angiogenic activity as the free drugs. Biodistribution analysis demonstrated preferential tumor accumulation of FITC-labeled PTX-PEG-ALN micelles. Pharmacokinetic studies revealed longer t1/2 of the conjugate than free PTX. PTX PEG-ALN micelles achieved improved efficacy and safety profiles over free PTX in syngeneic and xenogeneic mouse models of mCherry-infected mammary adenocarcinoma in the tibia, as monitored intravitally non-invasively by a fluorescence imaging system. The described data warrants the potential use of PTX-PEG-ALN as bone targeted anticancer and anti-angiogenic therapy for breast cancer bone metastases. PMID- 23434350 TI - Lung cancer mortality in European men: trends and predictions. AB - Lung cancer mortality in men from the European Union (EU) peaked in the late 1980s at an age-standardised (world standard population) rate over 53/100,000 and declined subsequently to reach 44/100,000 in the early 2000s. To provide a comprehensive picture of recent trends in male lung cancer mortality in Europe, we analyzed available data from the World Health Organization up to 2009 and predicted future rates to 2015. Lung cancer mortality rates in EU men continued to fall over recent years, to reach a value of 41.1/100,000 in 2005-2009. The fall was similar at all-ages and in middle-aged men (less than 2% per year over most recent years), but was appreciably larger in young men (aged 20-44 years, over 5% per year). A favourable trend is thus likely to be maintained in the foreseeable future, although the predicted overall EU rate in 2015 is still over 35/100,000, i.e., higher than the US rate in 2007 (33.7/100,000). Over most recent calendar years, overall male lung cancer rates were around 35-40/100,000 in western Europe, as compared to over 50/100,000 in central and eastern Europe. Within western Europe, lung cancer rates were lower in northern countries such as Sweden, but also Finland and the UK (below 30/100,000), where the tobacco-related epidemic started earlier and rates have long been declining, whereas mortality was high in Belgium (51.6), France (42.3), the Netherlands and Spain (around 43.0), where the epidemic started later but is persisting. Widespread measures for smoking control and cessation in middle-aged European men, i.e., in the generations where smoking prevalence used to be high, would lead to appreciable reductions in male lung cancer mortality in the near future. This is particularly urgent in central and eastern European countries. PMID- 23434351 TI - Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): a phase II trial. AB - The synergistic activity of pemetrexed with platinum agents in non-small cell lung cancer (NSCLC) and the renal safety of carboplatin suggest a balanced benefit/risk profile for this combination in elderly patients. This multicenter, single-arm, phase II study included 62 patients (>=70 years) with chemonaive advanced NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 1, and assigned to receive 6 cycles of 3-weekly pemetrexed 500 mg/m(2) and carboplatin AUC 5. The primary endpoint was objective tumor response rate (ORR). Sixty-two patients received at least one dose of chemotherapy. Median age was 76.4 years [70.2-86] and all patients had PS 0 (16.1%) or PS 1 (83.9%). Stage IIIb disease in 21% patients and stage IV in 79% patients. Non-squamous cell carcinoma in 66.1% patients (adenocarcinoma 51.6%, large cell carcinoma 8.1%, other 6.5%) and squamous cell carcinoma in 33.9% patients. ORR was 28.6% (95% confidence interval [CI], 16.58-43.26), all were partial responses. Stable disease rate was 42.9%. Grade 3/4 toxicities related to study drugs were: asthenia 16.1%, anorexia 4.8%, diarrhea 3.2%, neutropenia 51.6%, leucopenia 30.7%, thrombocytopenia 29%, anemia 19.4%. One related fatal septic shock occurred. In advanced NSCLC, pemetrexed use is restricted to non-squamous histology. The combination pemetrexed-carboplatin could be a valuable treatment option in elderly patients. Neutropenia was the most common toxicity. The ORR is within the range of data reported for pemetrexed-carboplatin in the general NSCLC population (24-31%). PMID- 23434352 TI - Micropapillary components in a lung adenocarcinoma predict stump recurrence 8 years after resection: a case report. AB - We report a rare case of lung adenocarcinoma in which micropapillary components were considered to cause stump recurrence. A woman in her fifties was diagnosed with lung cancer in the right middle lobe with invasion to the upper lobe, which was treated by a right middle lobectomy together with upper lobe partial resection. The cancer was pathologically diagnosed as adenocarcinoma and had a free surgical margin. There was no recurrence during the following 5 years and 8 months, and thus periodical surveillance, including computed tomography, was stopped. However, 2 years and 7 months after this, she was discovered to have an abnormal shadow on chest radiography, and a thorough examination revealed a 3-cm sized tumor involving the previous surgical margin. Therefore, she underwent right upper lobectomy. We pathologically re-evaluated the first tumor and found that it was an adenocarcinoma with a micropapillary component in the periphery, 6mm away from the surgical margin. In addition, a few tiny clusters of tumor cells were found to be floating within the alveolar spaces near the margin. The first and second tumors showed almost the same histological mixture of components of adenocarcinoma and the same EGFR mutation. From these results, we concluded the second tumor was a stump recurrence originating from the first tumor resection. This case illustrates the importance of careful pathological investigation when an autosuture instrument is used for a partial resection in a case of lung adenocarcinoma with micropapillary components. In such cases, it is particularly important to clarify if micropapillary components are floating near a stump. PMID- 23434353 TI - Oral metronomic chemotherapy in recurrent, metastatic and locally advanced head and neck cancers. PMID- 23434354 TI - Tako-Tsubo syndrome after trastuzumab - an unusual complication of chemotherapy for breast cancer. PMID- 23434355 TI - [Tenofovir hypersensitivity to tenofovir (DRESS) syndrome in a female patient infected by HIV]. PMID- 23434356 TI - Determination of anti-inflammatory cytokine in periparturient cows for prediction of postpartum reproductive diseases. AB - Forty-one pregnant cows at 240 days of gestation were selected from the cattle herd at the Indian Veterinary Research Institute, Izatnagar, Bareilly, India. The cows were critically observed daily during the periparturient period until 45 days postpartum. The prepartum sampling day was fixed on the basis of AI date supported by the external signs of the animals approaching parturition. Blood sampling was done for each experimental animal on 15 days prepartum (-15 d), calving day (0 d), 15 days (15 d), and 30 days (30 d) postpartum, and thorough gynecological examinations were performed on 0 d, 15 d, 30 d, and 45 d for diagnosis of postpartum reproductive diseases like retained placenta (ROP), clinical metritis (CM), clinical endometritis, cervicitis, and delayed involution of the uterus. The blood serum was used for estimation of the anti-inflammatory cytokine interleukin 10 (IL-10). Determintaion of IL-10 concentration in serum was done by using a commercially available bovine-specific ELISA kit. The IL-10 concentration (pg/mL) was significantly (P < 0.01) higher for ROP (1956.96 +/- 325.30) and CM (2283.01 +/- 326.82) than normal cows (827.19 +/- 127.11) at 15 days before calving. The values for IL-10 was also significantly (P < 0.05) higher for cows with ROP and CM than for normal cows at 0 d and 15 d postpartum. However, the values for IL-10 were significantly (P < 0.05) higher for cows with clinical endometritis (1847.83 +/- 539.38) than for normal cows (770.75 +/- 29.22) at 30 d postpartum. The concentration of IL-10 was lower (P > 0.05) in cows with delayed involution of uterus than other groups of cows at all days of the periparturient period. The cytokine level in cows with delayed involution of the uterus was 328.906 +/- 107.19, 263.08 +/- 84.92, 415.26 +/- 102.14, and 386.28 +/- 111.11 on -15 d, 0 d, 15 d, and 30 d, respectively. According to the results of this study it can be concluded that increased serum concentration of IL-10 at 15 d prepartum was observed in cows that developed ROP and CM and remained significantly higher until 15 d postpartum. Therefore, this cytokine might be used as a prognostic marker to identify the cows that are going to develop ROP and CM. PMID- 23434357 TI - Detection and quantification of cell-free fetal DNA in ovine maternal plasma; use it to predict fetal sex. AB - Prediction of fetal sex in the ovine species could be useful in the management decisions, such as sex selection in breeding programs, culling decisions, and lowering the progeny test cost. In the present study detection of fetal SRY gene in maternal blood plasma using the polymerase chain reaction technique was used to predict fetal sex at different times of gestation in the ewe. The quantitative changes of fetal DNA during pregnancy were also investigated using quantitative real-time polymerase chain reaction. Fetal DNA was isolated from blood plasma of 46 pregnant ewes during the second to fifth month of gestation. The 286-base pair DNA fragment was detected in all samples with male pregnancies, but no female pregnancies. The sensitivity and specificity of tests were 100% with no false negative or false positive results. It was also determined that fetal DNA levels are significantly increased during pregnancy, up to approximately 1.65-fold in the last 2 months of pregnancy. This is the first report of fetal sex determination and circulating fetal DNA quantification by a molecular method in the ovine species. PMID- 23434358 TI - Sperm chromatin in beef bulls in tropical environments. AB - Sperm chromatin status was assessed in 565 Zebu and Zebu crossbred beef bulls in extensive tropical environments using the sperm chromatin structure assay (SCSA). The SCSA involved exposure of sperm to acid hydrolysis for 0.5 or 5.0 minutes, followed by flow cytometry to ascertain relative amounts of double-stranded (normal) and single-stranded (denatured) DNA, which was used to generate a DNA fragmentation index (%DFI). With conventional SCSA (0.5-minute SCSA), 513 bulls (91%) had <15 %DFI, 24 bulls (4%) had 15 to 27 %DFI, and 28 bulls (5%) had >27 %DFI. In 5.0-minute SCSA, 432 bulls (76%) had <15 %DFI, 68 bulls (12%) had 15 to 27 %DFI and 65 bulls (12%) had >27 %DFI. For most bulls, the SCSA was repeatable on two to four occasions; however, because most bulls had <15 %DFI, repeatability of the SCSA will need to be determined in a larger number of bulls in the 15 to 27 %DFI and >27 %DFI categories. The %DFI was negatively correlated with several bull semen parameters and the strongest negative correlation was with normal sperm. There was a strong positive correlation between %DFI and sperm head abnormalities. Based on these findings, most Zebu beef bulls in extensive tropical environments had relatively stable sperm chromatin. Based on the apparent negative correlations with conventional semen parameters, we inferred that the SCSA measured a unique feature of sperm quality, which has also been suggested for other species. Further studies on the relationships between sperm chromatin stability and fertility are required in beef bulls before chromatin status can be used as an additional predictor of the siring capacity of individual bulls in extensive multiple-sire herds. PMID- 23434359 TI - Androstenone and testosterone levels and testicular morphology of Duroc boars related to estimated breeding value for androstenone. AB - Androstenone and testosterone levels in Duroc boars with an estimated breeding value for androstenone (EBV(androstenone)) were followed in the period from birth to sexual maturity. The breeding value for androstenone had been estimated based on androstenone levels in 1202 Duroc boars at an age of 24 weeks. Testosterone and androstenone levels in plasma were recorded in 19 boars at 1 week of age and in their 15 respective litter-siblings at 3 weeks of age. Between 12 and 27 weeks of age, plasma levels were recorded weekly in a third set of 16 litter-siblings. In the last group, histomorphology was performed at 12, 16, 20, and 27 weeks of age to determine sexual maturity status. The EBV(androstenone) was positively related to plasma androstenone in animals 12 to 27 weeks of age and to plasma testosterone levels in 1- and 3-week-old animals. The EBV(androstenone) was not related to testis morphology. The concentration of fat androstenone was positively correlated to the percentage of immature seminiferous tubules and negatively correlated to the percentage of mature seminiferous tubules at 20 weeks. Testosterone in plasma showed no relationship with testis morphology. Most individuals reached puberty at 20 weeks of age, which indicates that Duroc mature later than crossbred boars. The results indicated that breeding value based on the single trait boar taint parameter EBV(androstenone) was not related to testicular development. PMID- 23434360 TI - Management of the perineal wound after abdominoperineal resection. AB - Although many options are available for the management of perineal wounds after abdominoperineal resection, ranging from direct closure to flap reconstruction, treatment remains challenging. A better understanding of the aims, drawbacks and progress in perineal wound management after abdominoperineal rectal resection can help the surgeon make better choices for each patient, but it is very difficult to propose a single, optimal, evidence-based procedure for the management of pelvic exenteration. Recent progress provided by the extralevator abdominoperineal resection technique and perforator flap concepts have changed our conception of reconstruction leading to the different technical options highlighted in this review. PMID- 23434361 TI - Video-assisted transanal proctectomy using the SILS(r) monotrocar. PMID- 23434362 TI - Introducing a nationally shared electronic patient record: case study comparison of Scotland, England, Wales and Northern Ireland. AB - AIM: To compare the experience of the four UK countries in introducing nationally accessible electronic summaries of patients' key medical details, intended for use in emergency and unscheduled care episodes, and generate transferable lessons for other countries. METHOD: Secondary analysis of data collected previously on all four schemes; cross-case comparison using a framework derived from diffusion of innovations theory. MAIN FINDINGS: Whilst all four programmes shared a similar vision, they differed widely in their strategy, budget, implementation plan, approach to clinical and public engagement and approach to evaluation and learning. They also differed, for various reasons, in stakeholder alignments, the nature and extent of resistance to the programme and the rate at which records were created. A nationally shared, widely accessible electronic record has powerful symbolic meaning; it may or may not be perceived as improving the quality and safety of care or (alternatively) as threatening patient confidentiality or the traditional role of the doctor or nurse. 'Hard' project management oriented to achieving specific milestones and deadlines sometimes appeared counterproductive when it cut across the 'softer' aspects of the programmes. CONCLUSION: When designing and implementing complex technologies with pervasive implications, policymakers must consider not only technical issues but also the personal, social and organisational aspects of the programme. A judicious blend of 'hard' and 'soft' management appears key to managing such programmes. PMID- 23434363 TI - Glucocorticoid insensitivity as a source of drug targets for respiratory disease. AB - Glucocorticoids (corticosteroids) are effective and clinically useful medicines for repressing inflammation in lung disease; however, the number of respiratory conditions that have been recognized to be refractory or insensitive to glucocorticoids is on the rise--either due to an inherent difference in the glucocorticoid sensitivity as part of the disease process or due to exogenous stressors such as cigarette smoke and other oxidative insults. Independent of causality, the aim of future therapeutic advances to conquer this frontier will no doubt be based on our growing knowledge of molecular mechanisms underlying glucocorticoid insensitivity in respiratory diseases. The current article aims to highlight the key molecular mechanisms responsible for glucocorticoid insensitivity in asthma and COPD. This new knowledge will ultimately allow us to enhance lung health by restoring glucocorticoid responsiveness in respiratory disease. In this way, our increased understanding of corticosteroid insensitivity can be exploited as a source of drug targets for respiratory disease in the future. PMID- 23434364 TI - Changing the outcomes of pediatric drug trials: APNs making a difference. PMID- 23434365 TI - Neurofibromatosis in a toddler with back pain. PMID- 23434366 TI - Enantiomer and conformer recognition of (+) and (-)-disparlure and their analogs by the pheromone binding proteins of the gypsy moth, Lymantria dispar. AB - Adult female gypsy moths produce a sex pheromone (+)-(7R,8S)-2-methyl-7,8 epoxyoctadecane, (+)-disparlure, to attract male gypsy moths. To better understand the recognition of (+)-disparlure by the male's olfactory system, we synthesized racemic and enantiopure oxa and thia analogs of (+)-disparlure (ee>98%). Ab initio calculations of the conformeric landscapes around the dihedral angles C5-6-7-8 and C7-8-9-10 of (+)-disparlure and corresponding dihedral angles of analogs revealed that introduction of the heteroatom changes the conformeric landscape around these important epitopes. The energy difference between HOMO and LUMO decreased after oxygen or sulfur was introduced into the backbone. Consistent with this, an enhancement of binding affinity between sulfur analogs and the pheromone-binding proteins (PBPs) was observed in vitro. Docking of the pheromone and analogs onto models of the two known PBPs of the gypsy moth revealed that the internal binding pocket of PBP1 showed higher selectivity than that of PBP2, consistent with in vitro binding assays. Further energy analysis revealed that enantiomers adopted different conformations with different energies when docked in the internal binding pocket of PBPs, resulting in enantiomer discrimination of PBPs towards disparlure and its analogs. PMID- 23434367 TI - 6-Oxo and 6-thio purine analogs as antimycobacterial agents. AB - 6-Oxo and 6-thio analogs of purine were prepared based on the initial activity screening of a small, diverse purine library against Mycobacterium tuberculosis (Mtb). Certain 6-oxo and 6-thio-substituted purine analogs described herein showed moderate to good inhibitory activity. N(9)-substitution apparently enhances the anti-mycobacterial activity in the purine series described herein. Several 2-amino and 2-chloro purine analogs were also synthesized that showed moderate inhibitory activity against Mtb. PMID- 23434368 TI - Discovery of novel tricyclic indole derived inhibitors of HCV NS5B RNA dependent RNA polymerase. AB - The characterization of HCV genome has identified various vital functional proteins involved in the life cycle of hepatitis C virus. This has resulted in many novel enzymatic targets that are potential for development of therapeutic agents. The HCV RNA dependent RNA polymerase (HCV NS5B) is one such essential enzyme for HCV replication that has been well characterized and studied by various groups to develop novel therapies for hepatitis C. In this paper, we describe our efforts towards the identification and structure-activity relationship (SAR) of novel tricyclic indole derivatives that bind close to the palm site of the NS5B polymerase. X-ray crystal structure of an inhibitor bound to the polymerase is also described. PMID- 23434369 TI - The utility and accuracy of computed tomography in the diagnosis of occipitocervical dissociation. AB - BACKGROUND CONTEXT: Atlantooccipital dislocation (AOD) results in profound patient morbidity and mortality and is difficult to accurately diagnose using current evaluation techniques. PURPOSE: To evaluate the utility of computed tomography (CT) images in the diagnosis of AOD and compare the revised occipital condyle-C1 interval (CCI) and the condylar sum to the current radiographic criteria used to detect AOD. STUDY DESIGN: Retrospective review to evaluate the sensitivity, specificity, and the interobserver reliability of eight radiographic criteria as applied to CT imaging. PATIENT SAMPLE: Ten cases of clinical AOD and 10 cases of non-AOD cervical injury. OUTCOME MEASURES: Measured values: revised CCI, Wholey basion-dens interval (BDI), and Harris basion-axis interval (BAI). Calculated values: Sun interspinous ratio, Powers ratio, and condylar sum. Assessment of Lee X-line and atlantooccipital joint asymmetry. METHODS: A board certified neuroradiologist, two orthopedic spine surgeons, and two medical students reviewed the CT images for each patient in the series and applied the aforementioned criteria. RESULTS: Average sensitivity between all reviewers for CCI, condylar sum, and atlantooccipital asymmetry was highest at 1.0, 1.0, and 0.96, respectively. Basion-dens interval, X-line, Sun ratio, BAI, and Powers ratio had sensitivities of 0.72, 0.54, 0.32, 0.26, and 0.26, respectively. Revised CCI and condylar sum had significantly better sensitivity than any other test (vs. BDI, p=.014, all others, p<.001) except atlantooccipital asymmetry (p>.99). Specificity for all measurements was 0.78 or greater, except X-line at 0.38. Interobserver reliabilities were the greatest for CCI, condylar sum, atlantooccipital asymmetry, and BDI. CONCLUSIONS: The revised CCI (>2.5 mm abnormal) and condylar sum (>=5 mm abnormal) are highly sensitive and reliable radiographic criteria for the detection of AOD when applied to CT imaging. PMID- 23434371 TI - Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. AB - Apoptosis is commonly thought to represent an immunologically silent or even anti inflammatory mode of cell death, resulting in cell clearance in the absence of explicit activation of the immune system. However, here we show that Fas/CD95 induced apoptosis is associated with the production of an array of cytokines and chemokines, including IL-6, IL-8, CXCL1, MCP-1, and GMCSF. Fas-induced production of MCP-1 and IL-8 promoted chemotaxis of phagocytes toward apoptotic cells, suggesting that these factors serve as "find-me" signals in this context. We also show that RIPK1 and IAPs are required for optimal production of cytokines and chemokines in response to Fas receptor stimulation. Consequently, a synthetic IAP antagonist potently suppressed Fas-dependent expression of multiple proinflammatory mediators and inhibited Fas-induced chemotaxis. Thus, in addition to provoking apoptosis, Fas receptor stimulation can trigger the secretion of chemotactic factors and other immunologically active proteins that can influence immune responsiveness toward dying cells. PMID- 23434370 TI - The MRN-CtIP pathway is required for metaphase chromosome alignment. AB - Faithful duplication of the genome in S phase followed by its accurate segregation in mitosis is essential to maintain genomic integrity. Recent studies have suggested that proteins involved in DNA transactions are also required for whole-chromosome stability. Here we demonstrate that the MRN (Mre11, Rad50, and Nbs1) complex and CtIP are required for accurate chromosome segregation. Depletion of Mre11 or CtIP, antibody-mediated inhibition of Mre11, or small molecule inhibition of MRN using mirin results in metaphase chromosome alignment defects in Xenopus egg extracts. Similarly, loss of MRN function adversely affects spindle assembly around DNA-coated beads in egg extracts. Inhibition of MRN function in mammalian cells triggers a metaphase delay and disrupts the RCC1 dependent RanGTP gradient. Addition of the Mre11 inhibitor mirin to egg extracts and mammalian cells reduces RCC1 association with mitotic chromosomes. Thus, the MRN-CtIP pathway contributes to Ran-dependent mitotic spindle assembly by modulating RCC1 chromosome association. PMID- 23434373 TI - Hsp90 regulates nongenetic variation in response to environmental stress. AB - Nongenetic cell-to-cell variability often plays an important role for the survival of a clonal population in the face of fluctuating environments. However, the underlying mechanisms regulating such nongenetic heterogeneity remain elusive in most organisms. We report here that a clonal yeast population exhibits morphological heterogeneity when the level of Hsp90, a molecular chaperone, is reduced. The morphological heterogeneity is driven by the dosage of Cdc28 and Cla4, a key regulator of septin formation. Low Hsp90 levels reduce Cla4 protein stability and cause a subpopulation of cells to switch to a filamentous form that has been previously suggested to be beneficial under certain hostile environments. Moreover, Hsp90-dependent morphological heterogeneity can be induced by environmental stress and is conserved across diverse yeast species. Our results suggest that Hsp90 provides an evolutionarily conserved mechanism that links environmental stress to the induction of morphological diversity. PMID- 23434372 TI - Class IA PI3K p110beta subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation. AB - Autophagy is an evolutionarily conserved membrane trafficking process. Induction of autophagy in response to nutrient limitation or cellular stress occurs by similar mechanisms in organisms from yeast to mammals. Unlike yeast, metazoan cells rely more on growth factor signaling for a wide variety of cellular activities including nutrient uptake. How growth factor availability regulates autophagy is poorly understood. Here we show that, upon growth factor limitation, the p110beta catalytic subunit of the class IA phosphoinositide 3-kinases (PI3Ks) dissociates from growth factor receptor complexes and increases its interaction with the small GTPase Rab5. This p110beta-Rab5 association maintains Rab5 in its guanosine triphosphate (GTP)-bound state and enhances the Rab5-Vps34 interaction that promotes autophagy. p110beta mutants that fail to interact with Rab5 are defective in autophagy promotion. Hence, in mammalian cells, p110beta acts as a molecular sensor for growth factor availability and induces autophagy by activating a Rab5-mediated signaling cascade. PMID- 23434375 TI - Detecting livestock production zones. AB - Communities are sets of nodes that are related in an important way, most likely sharing common properties and/or playing similar roles within a network. Unraveling a network structure, and hence the trade preferences and pathways, could be useful to a researcher or a decision maker. We implemented a community detection algorithm to find livestock communities, which is consistent with the definition of a livestock production zone, assuming that a community is a group of farm premises in which an animal is more likely to stay during its lifetime than expected by chance. We applied this algorithm to the network of animal movements within the state of Mato Grosso for 2007. This database holds information concerning 87,899 premises and 521,431 movements throughout the year, totaling 15,844,779 animals moved. The community detection algorithm achieved a network partition that shows a clear geographical and commercial pattern, two crucial features for preventive veterinary medicine applications; this algorithm provides also a meaningful interpretation to trade networks where links emerge based on trader node choices. PMID- 23434374 TI - ZKSCAN3 is a master transcriptional repressor of autophagy. AB - Autophagy constitutes a major cell-protective mechanism that eliminates damaged components and maintains energy homeostasis via recycling nutrients under normal/stressed conditions. Although the core components of autophagy have been well studied, regulation of autophagy at the transcriptional level is poorly understood. Herein, we establish ZKSCAN3, a zinc finger family DNA-binding protein, as a transcriptional repressor of autophagy. Silencing of ZKSCAN3 induced autophagy and increased lysosome biogenesis. Importantly, we show that ZKSCAN3 represses transcription of a large gene set (>60) integral to, or regulatory for, autophagy and lysosome biogenesis/function and that a subset of these genes, including Map1lC3b and Wipi2, represent direct targets. Interestingly, ZKSCAN3 and TFEB are oppositely regulated by starvation and in turn oppositely regulate lysosomal biogenesis and autophagy, suggesting that they act in conjunction. Altogether, our study uncovers an autophagy master switch regulating the expression of a transcriptional network of genes integral to autophagy and lysosome biogenesis/function. PMID- 23434376 TI - Countermeasures against chemical terrorism in Japan. AB - Japan has experienced numerous incidents of chemical disasters and terrorist attacks. Here we review the history of changes in countermeasures against such incidents. Since 2004, the Civil Protection Law, more formally known as the "Law Concerning the Measures for Protection of the People in Armed Attack Situations etc" was enacted to fully prepare the nation for chemical terrorism. According to this law, the Japanese government must carry out Civil Protection Exercises on an annual basis to gauge response. Problem areas that remain are chosen and addressed one by one until they are judged to be resolved in subsequent exercises. PMID- 23434377 TI - Robust estimation for area of origin in bloodstain pattern analysis via directional analysis. AB - Directional analysis provides quantitative data supporting the three-dimensional estimation of the area of origin for impact bloodstain pattern analysis. The final stage of directional analysis consists of calculating the point of origin via the arithmetic mean of top-view intersecting points and side-view heights of the virtual trajectories of single stains within the impact pattern. Given the sensitivity of the mean to the presence of outliers (droplets that have been influenced by gravitational force and aerodynamic drag), it is natural to ask whether directional analysis can be made more robust by modifying the averaging procedure. In this paper we focus our attention on two robust alternatives to the arithmetic mean: the trimmed mean and a deterministic version of the RANSAC algorithm. Our results suggest that the trimmed mean is a practical robust alternative to the arithmetic mean, whereas the deterministic RANSAC procedure is not. Since there can be no guarantee that stain selection can be free of outliers, the trimmed mean can be used as an aide in their detection. Moreover, our analysis reveals that the trimmed mean can also be used to detect outliers among the points of intersection of trajectories. Outliers of this type occur as the intersection points of trajectories emanating from stains with nearly vertical paths. PMID- 23434378 TI - Effect of ketamine on the development of Lucilia sericata (Meigen) (Diptera: Calliphoridae) and preliminary pathological observation of larvae. AB - The estimation of postmortem interval (PMI) based on the growth patterns of necrophagous arthropods is the main mission of forensic entomology in practice. The larval development rates can be affected by various drugs or toxins, causing deviation in PMI estimate. Ketamine is a widely used anesthetic and recreational drug in Asia, which is rarely focused on in the previous entomotoxicological studies. The present work investigated the effect of ketamine on the development of Lucilia sericata (Meigen) (Diptera: Calliphoridae) by the measurement of body length and weight and the analysis of relationship between the ketamine effect and drug dosage or time interval, meanwhile the difference between ketamine effect on larval body length and weight was also analyzed. Additionally, the preliminary pathological observation of larvae was also employed for evaluating the drug effect in morphology. Significant differences were observed between control and treatment colonies of L. sericata at each life stage, and the effect of ketamine displayed a dosage-and-time-dependent manner, but no differences were noticed between the effects of ketamine on larval body length and weight, which provided a useful indication for larvae sample collection in practice. The pathological observation revealed that ketamine could promote the growth of trophocytes in fat body of L. sericata. PMID- 23434379 TI - Serum procalcitonin levels in the postmortem diagnosis of sepsis. AB - Procalcitonin is regarded as a valuable marker for sepsis in living persons and even in post-mortem investigations. At the Institute of Legal Medicine, 25 autopsy cases with suspected bacterial infectious diseases or sepsis were examined using the semi-quantitative PCT-Q((r))-test (B.R.A.H.M.S., Germany) in 2010 and 2011. As controls, 75 cadavers were used for which there was no suspicion of a bacterial infectious disease or sepsis. Femoral blood was cultured from the cases and from controls, and samples from the brain, heart, lungs, liver, spleen and kidneys were examined histologically for findings seen in sepsis. Twelve cases in the sepsis/infectious disease group (48%) were classifiable as sepsis following synopsis of PCT levels, autopsy results, and histopathological and microbiological findings. This study shows that the semi quantitative PCT-Q((r))-test is a useful supplementary marker in routine autopsy investigations, capable of classifying death as due to sepsis. PMID- 23434380 TI - Illegal drugs and delinquency. AB - An interrelation between consumption of illegal drugs and committing an indictable offence has been repeatedly discussed in literature. In a retrospective study serum concentrations of illegal and legal drugs as well as data originating from police reports and examinations by physicians taking blood from individuals being suspected to be under the influence of drugs were evaluated. Results from 4816 cases were available. Property offences were the most frequent type (36%) as well as consumption of cannabinoids (55%). Psychophysiological conditions of consumers were compared with according serum concentrations. Close correlations between stimulating drugs and violence associated crime could not be found. Stimulated as well as sedated behaviour occurring following the consumption of various drugs might be the reason for no clear correlation between types of offence and consumed illegal or legal drugs in this study. PMID- 23434381 TI - Surgical site infection prevention following total hip arthroplasty in Australia: a cost-effectiveness analysis. AB - BACKGROUND: Surgical site infection (SSI) is associated with substantial costs for health services, reduced quality of life, and functional outcomes. The aim of this study was to evaluate the cost-effectiveness of strategies claiming to reduce the risk of SSI in hip arthroplasty in Australia. METHODS: Baseline use of antibiotic prophylaxis (AP) was compared with no antibiotic prophylaxis (no AP), antibiotic-impregnated cement (AP + ABC), and laminar air operating rooms (AP + LOR). A Markov model was used to simulate long-term health and cost outcomes of a hypothetical cohort of 30,000 total hip arthroplasty patients from a health services perspective. Model parameters were informed by the best available evidence. Uncertainty was explored in probabilistic sensitivity and scenario analyses. RESULTS: Stopping the routine use of AP resulted in over Australian dollars (AUD) $1.5 million extra costs and a loss of 163 quality-adjusted life years (QALYs). Using antibiotic cement in addition to AP (AP + ABC) generated an extra 32 QALYs while saving over AUD $123,000. The use of laminar air operating rooms combined with routine AP (AP + LOR) resulted in an AUD $4.59 million cost increase and 127 QALYs lost compared with the baseline comparator. CONCLUSION: Preventing deep SSI with antibiotic prophylaxis and antibiotic-impregnated cement has shown to improve health outcomes among hospitalized patients, save lives, and enhance resource allocation. Based on this evidence, the use of laminar air operating rooms is not recommended. PMID- 23434384 TI - Effects of ocean acidification on the embryos and larvae of red king crab, Paralithodes camtschaticus. AB - The effects of the decline in ocean pH, known as ocean acidification, on marine species are not well understood. To test the effects on embryos and larvae of red king crab, Paralithodes camtschaticus, ovigerous crab and their larvae were held in CO2-acidified (pH 7.7) and control (ambient; pH 8.0) seawater during development. Morphometrics, hatch duration, fecundity, survival, mineral content, and condition were measured. Acidified embryos had 4% larger eyes and 5% smaller yolks, while mean hatch duration was 33% longer and female fecundity was unaffected. Acidified embryos also resulted in 4% longer larvae while acidified larvae had lower survival. Calcium content of both larvae and female carapaces after molting increased by 5% and 19%, respectively. Although ocean acidification may increase larval size and calcium content, the implications of this are unclear and decreased survival is likely to harm red king crab populations. PMID- 23434382 TI - Overexpression of X-linked genes in T cells from women with lupus. AB - Women develop lupus more frequently than men and the reason remains incompletely understood. Evidence that men with Klinefelter's Syndrome (XXY) develop lupus at approximately the same rate as women suggests that a second X chromosome contributes. However, since the second X is normally inactivated, how it predisposes to lupus is unclear. DNA methylation contributes to the silencing of one X chromosome in women, and CD4+ T cell DNA demethylation contributes to the development of lupus-like autoimmunity. This suggests that demethylation of genes on the inactive X may predispose women to lupus, and this hypothesis is supported by a report that CD40LG, an immune gene encoded on the X chromosome, demethylates and is overexpressed in T cells from women but not men with lupus. Overexpression of other immune genes on the inactive X may also predispose women to this disease. We therefore compared mRNA and miRNA expression profiles in experimentally demethylated T cells from women and men as well as in T cells from women and men with lupus. T cells from healthy men and women were treated with the DNA methyltransferase inhibitor 5-azacytidine, then X-linked mRNAs were surveyed with oligonucleotide arrays, and X-linked miRNA's surveyed with PCR arrays. CD40LG, CXCR3, OGT, miR-98, let-7f-2*, miR 188-3p, miR-421 and miR-503 were among the genes overexpressed in women relative to men. MiRNA target prediction analyses identified CBL, which downregulates T cell receptor signaling and is decreased in lupus T cells, as a gene targeted by miR-188-3p and miR-98. Transfection with miR-98 and miR-188-3p suppressed CBL expression. The same mRNA and miRNA transcripts were also demethylated and overexpressed in CD4+ T cells from women relative to men with active lupus. Together these results further support a role for X chromosome demethylation in the female predisposition to lupus. PMID- 23434383 TI - Anatomy of a decision: potential regulatory outcomes from changes to chemistry protocols in the Canadian Disposal at Sea Program. AB - Environment Canada currently assesses dredged material proposed for disposal at sea using a two-tiered assessment framework. Tier 1 determines sediment geophysical properties and concentrations of four regulated chemical constituents (Cd, Hg, PAH and PCB), and "other chemicals of interest" based on lower action levels; this is followed by biological assessment. EC is pursuing a "data mining" approach to evaluate potential refinements by compiling sediment chemistry and toxicity datasets, and subjecting them to a series of decision protocols. This paper reports on database development and initial use, and recommends potential changes to Tier 1 chemical protocols and further work to address other aspects of the framework. Major findings include the poor performance of Hg and Cd as sentinels for other metals, the significance of the list of analytes (vs. the specific SQGs used) in decisions, and the potential for chemical upper action levels to save the expense of unnecessary toxicity testing. PMID- 23434385 TI - Autotrophic and heterotrophic denitrification by a newly isolated strain Pseudomonas sp. C27. AB - The denitrifying sulfide removal (DSR) process applied autotrophic and heterotrophic denitrification pathways to achieve simultaneous conversion of nitrate to N2, sulfide to elementary sulfur, and organic substances to CO2. The current bottlenecks impeding the development of DSR process include the need of balanced growth of both autotrophic denitrifiers and heterotrophic denitrifers in the same reactor and the capability of treating wastewaters at fix compositions. This work isolated a strain, identified as Pseudomonas sp. C27 (GenBank accession number GQ241351), which can grow on heterotrophic and mixotrophic media and can perform both autotrophic and heterotrophic denitrification in mixotrophic medium. The C27 strain can grow well on succinate, acetate, malate, priopionate and ethanol and has the optimal growth temperature at 25-30 degrees C and pH at 9.0. Pathways of DSR reactions by C27 were proposed. Discussion on the potential use of the isolated C27 in novel DSR process was available. PMID- 23434386 TI - Influenza A whole virion vaccine induces a rapid reduction of peripheral blood leukocytes via interferon-alpha-dependent apoptosis. AB - Infection with single strand RNA (ssRNA) viruses, such as influenza A virus, is known to induce protective acquired immune responses, including the production of neutralizing antibodies. Vaccination also causes a reduction in the number of peripheral blood leukocytes (PBL) shortly after inoculation, a result which may have undesirable adverse effects. The cellular mechanisms for this response have not been elucidated so far. Here we report that formalin-inactivated influenza A whole virus vaccine (whole virion) induces a significant decrease in PBL in mice 5-16 h after administration, whereas an ether-split vaccine (HA split) made from the same influenza virus strain does not induce a similar loss of PBL. Concordant with this reduction in the number of PBL, a rapidly induced and massive production of interferon (IFN)-alpha is observed when mice are injected with whole virion, but not with HA split vaccines. The role of Toll-like receptors (TLR), which are involved in signal transduction of influenza virus, and the subsequent induction of IFNalpha were confirmed using mice lacking TLR7, MyD-88, or IFNalpha/beta receptor. We further demonstrated that the observed PBL loss is caused by apoptosis in an IFNalpha-dependent manner, and not by leukocyte redistribution due to chemokine signaling failure. These findings indicate that RNA-encapsulated whole virion vaccines can rapidly induce a loss of leukocytes from peripheral blood by apoptosis, which may modulate the subsequent immune response. PMID- 23434387 TI - Live attenuated seasonal and pandemic influenza vaccine in school-age children: a randomized controlled trial. AB - BACKGROUND: The novel influenza A(H1N1pdm09) virus emerged in North America in early 2009 and rapidly spread worldwide. In this study we report the efficacy of the live attenuated monovalent H1N1pdm09 vaccine and 2009-10 seasonal influenza vaccine in a randomized double-blind placebo-controlled trial. METHODS: We enrolled 703 children aged 7-11. Each child was randomly allocated in the ratio 3:2 to receive one dose of live attenuated monovalent H1N1pdm09 vaccine or saline placebo between November 2009 and January 2010, followed after 3-10 weeks by independent random allocation to one dose of live attenuated trivalent 2009-10 seasonal influenza vaccine or saline placebo in the same ratio. Children were followed up through September 2010 with biweekly telephone calls and symptom diaries. Seasonal and pandemic influenza infections were confirmed by virologic testing of nose and throat swabs collected during acute respiratory illnesses. RESULTS: Overall, 30 children had confirmed influenza including 3 (0.43%) H1N1pdm09, 10 (1.4%) seasonal A(H3N2), and 17 (2.4%) influenza B. There were no significant differences in incidence rates of H1N1pdm09 or A(H3N2) between the four study arms, but receipt of the seasonal influenza vaccine was associated with a significant reduction in risk of influenza B (p<0.01). Vaccine efficacy against confirmed H1N1pdm09 infection associated with receipt of the monovalent H1N1pdm09 vaccine was 65% (95% confidence interval, CI: -281%, 97%). Vaccine efficacies against confirmed seasonal influenza A(H3N2) and B infection associated with receipt of the seasonal influenza vaccine were 31% (95% CI: 138%, 80%) and 96% (95% CI: 67%, 99%) respectively. CONCLUSIONS: Vaccine efficacy was consistent with other studies of the monovalent H1N1pdm09 vaccine and seasonal influenza vaccines. Our study was underpowered to provide precise estimates of vaccine efficacy due to low incidence of influenza A viruses during the study period. PMID- 23434388 TI - Herd immunity effect of the HPV vaccination program in Australia under different assumptions regarding natural immunity against re-infection. AB - Deterministic dynamic compartmental transmission models (DDCTMs) of human papillomavirus (HPV) transmission have been used in a number of studies to estimate the potential impact of HPV vaccination programs. In most cases, the models were built under the assumption that an individual who cleared HPV infection develops (life-long) natural immunity against re-infection with the same HPV type (this is known as SIR scenario). This assumption was also made by two Australian modelling studies evaluating the impact of the National HPV Vaccination Program to assist in the health-economic assessment of male vaccination. An alternative view denying natural immunity after clearance (SIS scenario) was only presented in one study, although neither scenario has been supported by strong evidence. Some recent findings, however, provide arguments in favour of SIS. We developed HPV transmission models implementing life-time (SIR), limited, and non-existent (SIS) natural immunity. For each model we estimated the herd immunity effect of the ongoing Australian HPV vaccination program and its extension to cover males. Given the Australian setting, we aimed to clarify the extent to which the choice of model structure would influence estimation of this effect. A statistically robust and efficient calibration methodology was applied to ensure credibility of our results. We observed that for non-SIR models the herd immunity effect measured in relative reductions in HPV prevalence in the unvaccinated population was much more pronounced than for the SIR model. For example, with vaccine efficacy of 95% for females and 90% for males, the reductions for HPV-16 were 3% in females and 28% in males for the SIR model, and at least 30% (females) and 60% (males) for non-SIR models. The magnitude of these differences implies that evaluations of the impact of vaccination programs using DDCTMs should incorporate several model structures until our understanding of natural immunity is improved. PMID- 23434389 TI - Managing invasive species amidst high uncertainty and novelty. PMID- 23434390 TI - Dietary protein restriction for renal patients: don't forget protein-free foods. AB - OBJECTIVE: The treatment of chronic kidney disease (CKD) consists of pharmacological, nutritional, and psychological-social approaches. The dietary therapy of CKD, namely a low-protein low-phosphorus diet, plays a crucial role in contributing to delay the onset of end-stage renal disease (ESRD) and to protect cardiovascular and nutritional status. The protein-free food products represent a very important tool for the implementation of a low-protein diet to ensure adequate energy supply, reducing the production of nitrogenous waste products. METHODS: This survey included 100 consecutive CKD patients who were asked their opinion about the use of protein-free foods. RESULTS: Ninety-eight patients (98%) reported a regular daily intake of protein-free pasta (as macaroni, spaghetti, etc.), which was the preferred product consumed. Actually, the taste and texture of protein-free pasta were considered as "good" or "very good" by 70% of patients. Conversely, 43% of CKD patients perceived the taste and texture of protein-free bread as "bad" or "very bad", and 30% found it "acceptable". Therefore, the main concern for the implementation of low-protein diets is the use and palatability of the protein-free products, bread in particular. CONCLUSIONS: The use of these products may help in reducing protein, phosphorus, and sodium intake while supplying an adequate energy intake, which represents the basis for a nutritionally safe and successful dietary treatment of advanced CKD patients. Manufacturers and food technology should make more efforts to finding new solutions to improve the taste and texture of protein-free products. PMID- 23434391 TI - Author's reply to letter to the editor. PMID- 23434392 TI - Increased mean lung density: another independent predictor of lung cancer? AB - OBJECTIVES: To investigate the relationship between emphysema phenotype, mean lung density (MLD), lung function and lung cancer by using an automated multiple feature analysis tool on thin-section computed tomography (CT) data. METHODS: Both emphysema phenotype and MLD evaluated by automated quantitative CT analysis were compared between outpatients and screening participants with lung cancer (n=119) and controls (n=989). Emphysema phenotype was defined by assessing features such as extent, distribution on core/peel of the lung and hole size. Adjusted multiple logistic regression models were used to evaluate independent associations of CT densitometric measurements and pulmonary function test (PFT) with lung cancer risk. RESULTS: No emphysema feature was associated with lung cancer. Lung cancer risk increased with decreasing values of forced expiratory volume in 1s (FEV1) independently of MLD (OR 5.37, 95% CI: 2.63-10.97 for FEV1<60% vs. FEV1>=90%), and with increasing MLD independently of FEV1 (OR 3.00, 95% CI: 1.60-5.63 for MLD>-823 vs. MLD<-857 Hounsfield units). CONCLUSION: Emphysema per se was not associated with lung cancer whereas decreased FEV1 was confirmed as being a strong and independent risk factor. The cross-sectional association between increased MLD and lung cancer requires future validations. PMID- 23434393 TI - Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. AB - Oligomeric forms of amyloid-beta peptide (Abeta) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Abeta oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Delta mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Abeta oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs. PMID- 23434395 TI - Preliminary evidence for high anti-PLAC1 antibody levels in infertile patients with repeated unexplained implantation failure. AB - OBJECTIVE: Placenta-specific1 (PLAC1) is a trophoblast-specific gene encoding for a protein that is highly expressed in human placenta, on the surface of the syncytiotrophoblast. PLAC1 was found to elicit spontaneous antibody responses in cancer patients. We aimed to determine the levels of anti-PLAC1 antibodies in infertile women with a history of unexplained repeated implantation failure after IVF cycles as compared to fertile women. STUDY DESIGN: An observational case control clinical study. MAIN OUTCOME MEASURE(S): Two groups of patients were analysed in two different experimental settings: 21 infertile women and 81 control patients were enrolled in the first group, 16 infertile women and 67 fertile controls in the second group. Anti-PLAC1 antibody levels and ranking were analysed by ELISA test. RESULTS: In both groups of infertile patients enrolled, optical densities (OD) from ELISA test ranked significantly higher than those of controls (0.27 +/- 0.2 vs. 0.13 +/- 0.1 respectively; p = 0.0009 in the first group), (0.62 +/- 0.38 vs. 0.39 +/- 0.35 respectively; p = 0.0044 in the second experiment). In the first group about one case in four (29%) had OD levels above the 95th percentile (0.337) for healthy controls (p = 0.005). In the second experiment 4 out of 16 cases (25%) had OD levels above the 95th percentile (0.878) for healthy controls (p = 0.023). CONCLUSIONS: Anti-PLAC1 antibodies could represent a biomarker associated with infertility and with high probability of repeated implantation failure after ovarian stimulation and IVF-ET, greatly improving the diagnostic work up of infertile couples. PMID- 23434394 TI - Factors involved in rosuvastatin induction of insulin sensitization in rats fed a high fat diet. AB - BACKGROUND AND AIM: To investigate whether rosuvastatin can improve insulin sensitivity in overweight rats having a high fat diet (HFD). The potential mechanisms involved in this action were evaluated, including SIRT-1, other factors involved in glucose metabolism and stress signaling pathways. METHODS AND RESULTS: Male Wistar rats (n = 30) were divided into three groups: (i) rats fed a standard diet (3.5% fat); (ii) rats fed a HFD (33.5% fat); and (iii) rats fed a HFD and treated with rosuvastatin (15 mg/kg/day). Evolution: 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Plasma levels of cholesterol, triglycerides, VLDL, glucose and insulin and leptin/adiponectin ratio were higher in HFD rats, and rosuvastatin treatment reduced them. SIRT-1, p53, PGC-1alpha, PPAR-gamma and GLUT-4 protein levels in white adipose tissue (WAT) were lower, and JNK was higher in HFD rats compared to controls. Rosuvastatin treatment normalized expression of these mediators. Endothelium-dependent relaxation was reduced in mesenteric rings from HFD rats compared to controls and rosuvastatin enhanced it in HFD rats. CONCLUSION: Rosuvastatin treatment reduced insulin resistance without affecting body weight or WAT loss in HFD rats. Reduction of leptin and JNK, and enhancement of SIRT-1, p53, PGC-1alpha, PPAR-gamma and GLUT-4 expression in WAT could contribute to insulin sensitization. Normalization of SIRT-1 expression in WAT could be considered a key novel mechanism that aids in explaining the beneficial effects of rosuvastatin on the amelioration of glucose metabolism and the arrangement of multiple signaling pathways participating in insulin resistance in overweight HFD rats. PMID- 23434396 TI - Varicella immunity in vaccinated healthcare workers. AB - BACKGROUND: Nosocomial spread of varicella-zoster virus (VZV) infection can cause severe disease among vulnerable patient-populations and healthcare personnel (HCP). Limited data are available on duration of varicella vaccine-induced protection among adults and to what extent cell-mediated immunity (CMI) and antibody avidity contribute to protection. OBJECTIVE: Evaluate humoral and cell mediated immune responses of HCP who received a 2-dose regimen of varicella vaccine, and observe the responses to a 3rd vaccine dose among HCP who were seronegative after vaccination. STUDY DESIGN: A convenience sample of HCP with documented 2 doses of varicella vaccine was used to assess acquired VZV immune parameters (cytokine production, IgG avidity). HCP seronegative after 2 doses of vaccine were offered a third dose and evaluated further. Vaccine recipients' immune responses were compared with responses from persons with history of wild type VZV infection. RESULTS: The convenience sample consisted of 101 HCP with documented 2 doses of varicella vaccine; 12 (11.9%) were seronegative post vaccination. 11.5% of 61 seropositive 2-dose recipients produced low avidity antibody, suggesting suboptimal response to vaccine. Seven 2-dose vaccinees who were VZV seronegative seroconverted after a third dose; however, 3/7 (42.9%) produced low avidity IgG. 142 persons with a history of varicella were all VZV IgG seropositive, and all had moderate to high avidity IgG. CONCLUSIONS: Measurements of serum IgG titers alone may not accurately reflect vaccine protection. Varicella vaccination of HCP remains important but further studies are needed to evaluate CMI and antibody avidity responses in HCP vaccinated with two doses of varicella vaccine. PMID- 23434397 TI - Vessel bifurcation localization based on intraoperative three-dimensional ultrasound and catheter path for image-guided catheter intervention of oral cancers. AB - We present a method to localize intraoperative target vessel bifurcations under bones for ultrasound (US) image-guided catheter interventions. A catheter path is recorded to acquire skeletons for the target vessel bifurcations that cannot be imaged by intraoperative US. The catheter path is combined with the centerlines of the three-dimensional (3D) US image to construct a preliminary skeleton. Based on the preliminary skeleton, the orientations of target vessels are determined by registration with the preoperative image and the bifurcations were localized by computing the vessel length. An accurate intraoperative vessel skeleton is obtained for correcting the preoperative image to compensate for vessel deformation. A reality check of the proposed method was performed in a phantom experiment. Reasonable results were obtained. The in vivo experiment verified the clinical workflow of the proposed method in an in vivo environment. The accuracy of the centerline length of the vessel for localizing the target artery bifurcation was 2.4mm. These results suggest that the proposed method can allow the catheter tip to stop at the target artery bifurcations and enter into the target arteries. This method can be applied for virtual reality-enhanced image guided catheter intervention of oral cancers. PMID- 23434398 TI - The participation of emergency nurses in the development of the Basic Knowledge Assessment Tool (BKAT) for the adult emergency department, the ED-BKAT2. AB - This article describes the participation of ED nurses in the development of the Basic Knowledge Assessment Tool (BKAT) for the adult emergency department (ED BKAT2(c)), developed by Jean Toth and Kathleen Ritchey and copyrighted in 1980. The research covered the span of 7 years, from 2005 to 2012. Findings include research support/evidence for both validity and reliability of the tool. Uses for the ED-BKAT2 are found in the Figure and discussed in the text. Acknowledgements are made by name, of the 60 emergency nurses across the United States of America who participated in this university/multi-hospital setting collaborative work. PMID- 23434399 TI - Blood-derived biomaterials and platelet growth factors in regenerative medicine. AB - Several biomaterials can be obtained from human blood. Some are used for clinical indications requiring a high content in fibrinogen, while others are used because they contain multiple platelet growth factors. Mimicking thrombin-induced physiological events of coagulation leading to fibrino-formation and platelet activation, blood biomaterials have critical advantages of being devoid of tissue necrotic effects and of being biodegradable by body enzymes. Fibrin-based biomaterials, known as fibrin glues or fibrin sealants, have been used for more than 30 years as surgical hemostatic and sealing agents, demonstrating benefits in essentially all surgical fields, including reconstructive plastic surgery and wound treatment. Clinical interest in platelet growth factor-rich biomaterials (often known as platelet gels or platelet-rich-plasma) has emerged more recently. Platelet gels are used in clinical situations to achieve wound healing and repair soft and hard tissues. Applications include the healing of recalcitrant ulcers and burns, and stimulation of osseous tissue regeneration in dentistry, implantology, and maxillofacial and plastic surgery. They were evaluated recently in knee osteoarthritis and for the repair of musculoskeletal tissue lesions in sports medicine. Platelet lysates are now used as a substitute for fetal bovine serum and for ex vivo clinical-scale expansion of stem cells, opening new perspectives in regenerative medicine. We present the scientific rationale that prevailed in the development of blood biomaterials, describe their modes of production and biochemical and functional characteristics, and present clinical applications in regenerative medicine. PMID- 23434400 TI - Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru. AB - OBJECTIVES: Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. METHODS: During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. RESULTS: Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5 kg/m(2) (p<0.05). In patients without and with previous TB treatment, the prevalence of multidrug-resistant TB was 23% and 26%, respectively, among patients without diabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. CONCLUSIONS: Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome. PMID- 23434401 TI - [Left hemiparesis as a sign of onset of vanishing white matter disease. Identification of a new mutation]. AB - Vanishing white matter disease is a genetic disorder of autosomal recessive inheritance that affects the brain white matter There are various phenotypes that differ in severity and age at onset. Usually, it is characterized by ataxia, spasticity and a progressive motor decline with exacerbations triggered by fever and mild head traumas. The patient was a 2.5 year-old girl who developed unstable gait, left hemiparesis and increased tendon reflexes following a mild head trauma. Brain MRI showed diffuse and symmetric white matter abnormalities with decreased signal on T1 and increased signal on T2 and FLAIR sequences. Vanishing White Matter disease was suspected. The diagnosis was confirmed by genetic molecular testing that showed 2 mutations in EIF2B5 gene. Both mutations were considered pathogenic, although one had not been previously described. Hemiparesis must be included among clinical features of vanishing white matter disease. Early diagnosis can help to avoid infections and traumas and allows families to be genetically counselled. Our case contributes with the identification of a new mutation in EIF2B5 gene (p.Gly132Ala in position 395), not previously described. Its characteristics suggest a high probability of being pathogenic. We believe that it should be considered among the complex EIF2B mutations responsible for the disease. PMID- 23434402 TI - Practice of endoscopic gynecologic surgery: a survey of Spanish gynecologists. AB - OBJECTIVE: To evaluate the implementation of endoscopic gynecologic surgery in Spanish hospitals. STUDY DESIGN: In January 2011, a questionnaire was sent to 198 gynecology departments to determine the diffusion and acceptance of specific endoscopic procedures (hysteroscopy and laparoscopy) in each hospital. RESULTS: The response rate was 52% (103/198). The practice of basic laparoscopy in Spain is high (90% of the hospitals surveyed reported that >50% of their specialists use this technique). Although advanced laparoscopic procedures are used in 83.4% of hospitals, 59.2% of these hospitals reported that <25% of gynecologists knew how to perform these techniques. In the case of adnexal masses, the approach used depends on the characteristics of the mass. Most hospitals (96.1%) reported routine use of a laparoscopic approach for benign adnexal masses measuring <10 cm, while 42% of hospitals reported routine use of a laparoscopic approach for masses that appear to be suspicious on ultrasound. Regarding hysterectomy, 38 hospitals (36.9%) reported that an abdominal approach was used in <25% of hysterectomies, 53 hospitals (51.5%) reported that a vaginal approach was used in 25-50% of hysterectomies, and 53 hospitals (52%) reported that a laparoscopic approach was used in <25% of hysterectomies. For the treatment of gynecological cancers, 53 hospitals (52%) reported that a laparoscopic approach was used in <25% of cases; this approach was reported more commonly by teaching hospitals (81.9% vs. 46.75; p<0.001) and hospitals with >200 beds (84.3% vs. 45.5%; p<0.001). In teaching hospitals, the concordance between what the respondents felt residents should be able to do, in terms of laparoscopic techniques, and what residents were actually able to do upon finishing their residency training was quite high, with the degree of concordance varying between 84.3% (adnexal mass approach) and 100% (diagnostic laparoscopy and tubal sterilization). CONCLUSIONS: More than 90% of the Spanish hospitals surveyed perform basic endoscopic techniques, and 83.4% are able to perform advanced endoscopic procedures. PMID- 23434403 TI - Female genital mutilation/cutting: knowledge, attitude and training of health professionals in inner city London. AB - OBJECTIVES: To assess the knowledge, attitude and training on female genital mutilation/cutting (FGM/C) amongst medical and midwifery professionals working in an area of high prevalence of the condition. STUDY DESIGN: Prospective observational study using a questionnaire designed to assess knowledge, attitude and training received by health care professionals on the practice of FGM/C. Factors which may affect knowledge, attitude and training were compared between groups. RESULTS: 92.9% (n=79) questionnaires were returned. All respondents were aware of FGM/C but only 27.8% correctly identified the grade from a simple diagram. Three quarters (72.4% and 77.2% respectively) were aware of the complications of FGM/C and of the legislation in the United Kingdom. Of the respondents, 13.9% agreed that a competent adult should be allowed to consent to FGM/C if requested but only 8.9% agreed that the procedure should be medicalised to reduce the associated morbidity. Less than 25% of respondents had received formal training in recognising or managing this condition. CONCLUSION: Although the majority of respondents were aware of FGM/C, their ability to identify the condition and its associated morbidity remain suboptimal; more training is recommended in larger cities with a higher prevalence of this condition. PMID- 23434404 TI - Anions mediate ligand binding in Adineta vaga glutamate receptor ion channels. AB - AvGluR1, a glutamate receptor ion channel from the primitive eukaryote Adineta vaga, is activated by alanine, cysteine, methionine, and phenylalanine, which produce lectin-sensitive desensitizing responses like those to glutamate, aspartate, and serine. AvGluR1 LBD crystal structures reveal an unusual scheme for binding dissimilar ligands that may be utilized by distantly related odorant/chemosensory receptors. Arginine residues in domain 2 coordinate the gamma-carboxyl group of glutamate, whereas in the alanine, methionine, and serine complexes a chloride ion acts as a surrogate ligand, replacing the gamma-carboxyl group. Removal of Cl(-) lowers affinity for these ligands but not for glutamate or aspartate nor for phenylalanine, which occludes the anion binding site and binds with low affinity. AvGluR1 LBD crystal structures and sedimentation analysis also provide insights into the evolutionary link between prokaryotic and eukaryotic iGluRs and reveal features unique to both classes, emphasizing the need for additional structure-based studies on iGluR-ligand interactions. PMID- 23434405 TI - Structural and functional analysis of the regulator of G protein signaling 2 galphaq complex. AB - The heterotrimeric G protein Galphaq is a key regulator of blood pressure, and excess Galphaq signaling leads to hypertension. A specific inhibitor of Galphaq is the GTPase activating protein (GAP) known as regulator of G protein signaling 2 (RGS2). The molecular basis for how Galphaq/11 subunits serve as substrates for RGS proteins and how RGS2 mandates its selectivity for Galphaq is poorly understood. In crystal structures of the RGS2-Galphaq complex, RGS2 docks to Galphaq in a different orientation from that observed in RGS-Galphai/o complexes. Despite its unique pose, RGS2 maintains canonical interactions with the switch regions of Galphaq in part because its alpha6 helix adopts a distinct conformation. We show that RGS2 forms extensive interactions with the alpha helical domain of Galphaq that contribute to binding affinity and GAP potency. RGS subfamilies that do not serve as GAPs for Galphaq are unlikely to form analogous stabilizing interactions. PMID- 23434406 TI - Kinetic, energetic, and mechanical differences between dark-state rhodopsin and opsin. AB - Rhodopsin, the photoreceptor pigment of the retina, initiates vision upon photon capture by its covalently linked chromophore 11-cis-retinal. In the absence of light, the chromophore serves as an inverse agonist locking the receptor in the inactive dark state. In the absence of chromophore, the apoprotein opsin shows low-level constitutive activity. Toward revealing insight into receptor properties controlled by the chromophore, we applied dynamic single-molecule force spectroscopy to quantify the kinetic, energetic, and mechanical differences between dark-state rhodopsin and opsin in native membranes from the retina of mice. Both rhodopsin and opsin are stabilized by ten structural segments. Compared to dark-state rhodopsin, the structural segments stabilizing opsin showed higher interaction strengths and mechanical rigidities and lower conformational variabilities, lifetimes, and free energies. These changes outline a common mechanism toward activating G-protein-coupled receptors. Additionally, we detected that opsin was more pliable and frequently stabilized alternate structural intermediates. PMID- 23434407 TI - Structure of the MST4 in complex with MO25 provides insights into its activation mechanism. AB - Mammalian STE20-like kinase MST4 regulates multiple cellular aspects such as cell polarity and proliferation. MST4 acts downstream of LKB1/MO25/STRAD complex to induce brush border formation. MO25 directly interacts with MST4 to promote its kinase activity. Here, we report the crystal structure of MST4 in complex with MO25. Association of MO25 rotates the alphaC helix of MST4 toward its catalytic core, stabilizing the alphaC helix in an active position. The kinase domain of MST4 forms a specific homodimer that is required for trans-autophosphorylation. MO25-stimulated activation of MST4 promotes apoptosis in HEK293T cells. Atomic resolution permitted the study of interface mutations capable of disrupting the MST4-MO25 interaction or the kinase-domain-mediated homodimerization. These mutations impaired MST4 kinase activation and function within the cell. Collectively, our study identifies the activation mechanism of MST4 and provides a structural basis for further functional study. PMID- 23434409 TI - Reply to the author: the measurement of carotid intima media thickness precisely and accurately for evaluating epileptic children treated with oxcarbazepine. PMID- 23434408 TI - Regulation of nuclear factor-kappaB in autoimmunity. AB - Nuclear factor (NF)-kappaB transcription factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF-kappaB signaling contribute to the pathogenesis of immunological disorders. NF-kappaB is a well known proinflammatory mediator, and its deregulated activation is associated with the chronic inflammation of autoimmune diseases. Paradoxically, NF-kappaB plays a crucial role in the establishment of immune tolerance, including both central tolerance and the peripheral function of regulatory T (Treg) cells. Thus, defective or deregulated activation of NF-kappaB may contribute to autoimmunity and inflammation, highlighting the importance of tightly controlled NF-kappaB signaling. This review focuses on recent progress regarding NF-kappaB regulation and its association with autoimmunity. PMID- 23434410 TI - A major epigenetic programming mechanism guided by piRNAs. AB - A central enigma in epigenetics is how epigenetic factors are guided to specific genomic sites for their function. Previously, we reported that a Piwi-piRNA complex associates with the piRNA-complementary site in the Drosophila genome and regulates its epigenetic state. Here, we report that Piwi-piRNA complexes bind to numerous piRNA-complementary sequences throughout the genome, implicating piRNAs as a major mechanism that guides Piwi and Piwi-associated epigenetic factors to program the genome. To test this hypothesis, we demonstrate that inserting piRNA complementary sequences to an ectopic site leads to Piwi, HP1a, and Su(var)3-9 recruitment to the site as well as H3K9me2/3 enrichment and reduced RNA polymerase II association, indicating that piRNA is both necessary and sufficient to recruit Piwi and epigenetic factors to specific genomic sites. Piwi deficiency drastically changed the epigenetic landscape and polymerase II profile throughout the genome, revealing the Piwi-piRNA mechanism as a major epigenetic programming mechanism in Drosophila. PMID- 23434411 TI - Removal of retained introns regulates translation in the rapidly developing gametophyte of Marsilea vestita. AB - The utilization of stored RNA is a driving force in rapid development. Here, we show that retention and subsequent removal of introns from pre-mRNAs regulate temporal patterns of translation during rapid and posttranscriptionally controlled spermatogenesis of the fern Marsilea vestita. Analysis of RNAseq derived transcriptomes revealed a large subset of intron-retaining transcripts (IRTs) that encode proteins essential for gamete development. Genomic and IRT sequence comparisons show that other introns have been previously removed from the IRT pre-mRNAs. Fully spliced isoforms appear at distinct times during development in a spliceosome-dependent and transcription-independent manner. RNA interference knockdowns of 17/17 IRTs produced anomalies after the time points when those transcripts would normally be spliced. Intron retention is a functional mechanism for forestalling precocious translation of transcripts in the male gametophyte of M. vestita. These results have broad implications for plant gene regulation, where intron retention is widespread. PMID- 23434413 TI - R/G-band boundaries: genomic instability and human disease. AB - The human genome is composed of large-scale compartmentalized structures resulting from variations in the amount of guanine and cytosine residues (GC%) and in the timing of DNA replication. These compartmentalized structures are related to the light- and dark-staining bands along chromosomes after the appropriate staining. Here we describe our current understanding of the biological importance of the boundaries between these light and dark bands (the so-called R/G boundaries). These R/G boundaries were identified following integration of information obtained from analyses of chromosome bands and genome sequences. This review also discusses the potential medical significance of these chromosomal regions for conditions related to genomic instability, such as cancer and neural disease. We propose that R/G-chromosomal boundaries, which correspond to regions showing a switch in replication timing from early to late S phase (early/late-switch regions) and of transition in GC%, have an extremely low number of replication origins and more non-B-form DNA structures than other genomic regions. Further, we suggest that genes located at R/G boundaries and which contain such DNA sequences have an increased risk of genetic instability and of being associated with human diseases. Finally, we propose strategies for genome and epigenome analyses based on R/G boundaries. PMID- 23434412 TI - Posttraumatic stress disorder and impaired autonomic modulation in male twins. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system might be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death. METHODS: We measured HRV by power spectral analysis on 24-hour ambulatory electrocardiogram in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD was assessed with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs. RESULTS: Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low-frequency and low-frequency HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower low-frequency HRV than their brothers without PTSD (p<.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD. CONCLUSION: In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and might reverse with remission of PTSD. PMID- 23434414 TI - Synthesis, structure-activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1. AB - A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication. PMID- 23434415 TI - Sphingosine kinase 2 inhibitor SG-12 induces apoptosis via phosphorylation by sphingosine kinase 2. AB - Sphingosine kinase (SPHK), which catalyzes the phosphorylation of sphingosine to generate sphingosine 1-phosphate, has two mammalian isotypes, SPHK1 and SPHK2. Both isozymes are promising anti-cancer therapeutic targets. In this report, we found that SG-12, a synthetic analogue of sphingosine that acts as a SPHK2 inhibitor, induces apoptosis via phosphorylation by SPHK2. The present results revealed the novel anti-cancer potential of a sphingosine analogue in the pathological setting where SPHK2 is upregulated. PMID- 23434416 TI - Reconstitution of the early steps of gliotoxin biosynthesis in Aspergillus nidulans reveals the role of the monooxygenase GliC. AB - The gliotoxin, a member of the epipolythiodioxopiperazine (ETP), has received considerable attention from the scientific community for its wide range of biological activity. Despite the identification of gliotoxin cluster, however, the sequence of steps in the gliotoxin biosynthesis has remained elusive. As an alternative to the gene knock-out and biochemical approaches used so far, here we report using a heterologous expression approach to determine the sequence of the early steps of gliotoxin biosynthesis in Aspergillus nidulans. We identified the GliC, a monooxygenases that involved in the second step of gliotoxin biosynthesis pathway through the catalyzing the hydroxylation at the alpha-position of L-Phe. PMID- 23434417 TI - 2-(Benzothiazol-2-yl)-phenyl-beta-d-galactopyranoside derivatives as fluorescent pigment dyeing substrates and their application for the assay of beta-d galactosidase activities. AB - 2-(Benzothiazol-2-yl)-phenyl-beta-d-galactopyranoside derivatives were synthesized as novel artificial fluorescent pigment dyeing substrates for beta-d galactosidase. The substrates, which exhibited non-fluorescence or weak fluorescence in solution phase, were smoothly hydrolyzed by beta-d-galactosidase from Aspergillus oryzae and yielded a water-insoluble strong fluorescent pigment. The difference of fluorescent intensity exhibited a linear relationship with the amount of enzyme. PMID- 23434418 TI - Microwave assisted nano (ZnO-TiO2) catalyzed synthesis of some new 4,5,6,7 tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine as antimicrobial agents. AB - Combined nano zinc oxide and titanium dioxide [nano (ZnO-TiO(2))] has been reported first time for the synthesis of novel series of 4,5,6,7-tetrahydro-6-((5 substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine. All the synthesized compounds (7a-7m) are novel and were screened for their antimicrobial activity against four different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis and antifungal activity was determined against two strains Candida albicans and Aspergillus niger. SAR for the newly synthesised derivatives has been developed by comparing their MIC values with ampicillin, ciprofloxacin and miconazole for antibacterial and antifungal activities, respectively. Among the synthesized compounds, 2,6 dichlorophenyl analogue (7f), 4 fluorophenyl analogue (7k) and 2,6 dichlorophenyl analogue (7l) shows promising antibacterial as well as antifungal activity whereas thiophene substituted compound (7j) shows promising antibacterial activity. PMID- 23434420 TI - Anti-HBV active constituents from Piper longum. AB - In the screening search for Hepatitis B virus inhibitory agents from medicinal plants, the ethanol extract of Piper longum Linn. was found to possess superior anti-HBV activity in vitro. Bioassay-guided fractionation coupled with repeated purification resulted in the isolation of four new compounds, involving two new glycosides longumosides A (1) and B (2) and two new amide alkaloids erythro-1-[1 oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (3), threo-1 [1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (4), as well as two compounds 3beta,4alpha-dihydroxy-2-piperidinone (5), 5,6-dihydro 2(1H)-pyridinone (6) from natural source for the first time. The structures of the four new compounds were determined by extensive analyses of the MS, IR, 1D and 2D NMR data. Besides, the compounds 2-6, together with the known compounds 7 11 obtained previously, were assayed for their anti-HBV activity by using Hep G 2.2.15 cell line in vitro. Results suggested the compound piperine (7) possessed remarkable inhibitory HBV activity, against the secretion of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) with the Selectivity Index (SI) values of 15.7 and 16.8, respectively. PMID- 23434419 TI - Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV-1 infection. AB - The G-protein coupled receptor CXCR4 is a co-receptor for HIV-1 infection and is involved in signaling cell migration and proliferation. In a previous study of non-peptide, guanide-based CXCR4-binding compounds, spermine and spermidine phenylguanides inhibited HIV-1 entry at low micromolar concentrations. Subsequently, crystal structures of CXCR4 were used to dock a series of naphthylguanide derivatives of the polyamines spermidine and spermine. Synthesis and evaluation of the naphthylguanide compounds identified our best compound, spermine tris-1-naphthylguanide, which bound CXCR4 with an IC(50) of 40 nM and inhibited the infection of TZM-bl cells with X4, but not R5, strains of HIV-1 with an IC(50) of 50-100 nM. PMID- 23434421 TI - Fluorogenic 'click-on' dendrimer reporter for rapid profiling of cell proliferation. AB - The application of small molecule fluorescent reporters to monitor biological systems is limited by their poor water solubility and background fluorescence of these reporters. Herein, we describe the synthesis and testing of a fluorogenic 'click' dendrimer reporter to monitor cellular processes. The reporter system consists of a polyamidoamine (PAMAM) dendrimer conjugated with 3-azido-7-hydroxy coumarin. After the copper(I)-catalyzed azide-alkyne cycloaddition reaction ('click' reaction) with alkyne-derivatized target molecules, the natively non fluorescent construct has a strong enhancement in fluorescence. This fluorogenic dendrimer reporter can be used to efficiently monitor biological processes and the specificity afforded by the 'click' reaction greatly reduces background noise and enhances assay flexibility. We used this fluorogenic dendrimer reporter to monitor incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into newly synthesized DNA, as a surrogate marker of cellular proliferation. We anticipate that this new class of fluorogenic reporter can be used to monitor a wide array of molecules and lends itself to high-throughput profiling of biological systems. PMID- 23434422 TI - Euryspongins A-C, three new unique sesquiterpenes from a marine sponge Euryspongia sp. AB - Three new unique sesquiterpenes, euryspongins A-C (1-3), were isolated from a marine sponge Euryspongia sp. collected at Iriomote Island, Okinawa, Japan. Compound 1 possessed a bicyclic furanosesquiterpene structure with six- and eight membered rings, whereas compounds 2 and 3 had an alpha,beta-unsaturated-gamma lactone ring instead of the furan ring in 1. Only five natural products in this class have been reported, and compounds 1-3 are the sixth-eighth examples of natural products. Compounds 1-3 had no inhibition effect against PTP1B, an important target enzyme for the treatment of diabetes, while the dehydro derivative of 1 [dehydroeuryspongin A (4)] exhibited inhibitory activity (IC(50)=3.6 MUM). PMID- 23434423 TI - Synthesis, enzymatic stability and in vitro cytostatic effect of Daunorubicin GnRH-III derivative dimers. AB - Bioconjugates containing chemotherapeutic agents attached to peptide hormones, such as gonadotropin-releasing hormone (GnRH), are developed as drug delivery systems for targeted cancer chemotherapy. We report here the synthesis and biochemical characterization of disulfide bond-linked dimeric bioconjugates in which daunorubicin was coupled via an oxime linkage to aminooxyacetylated GnRH III ([Glp-His-Trp-Ser-His-Asp-Trp-Lys(DauAoa-Cys)-Pro-Gly-NH2]2; where Glp is pyroglutamic acid and Aoa is aminooxyacetyl) and its derivatives modified in position four by N-Me-Ser and Lys(Ac). The in vitro stability/degradation of the bioconjugates was determined in human serum, as well as in the presence of rat liver lysosomal homogenate and digestive enzymes. All compounds were stable at least for 24h in human serum and in the presence of pepsin and trypsin, while they were degraded by lysosomal enzymes. The daunorubicin-GnRH-III derivative dimers were partly digested by alpha-chymotrypsin; however, they had increased stability compared to the corresponding monomers, making them potential candidates for oral administration. The in vitro cytostatic effect of the compounds was determined on MCF-7 human breast cancer cells by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. All daunorubicin GnRH-III derivative dimers exerted slightly increased in vitro cytostatic effect (IC50 values in low MUM range) than the corresponding monomeric bioconjugates. PMID- 23434424 TI - Roadmap for the development of the University of North Carolina at Chapel Hill Genitourinary OncoLogy Database--UNC GOLD. AB - BACKGROUND: The management of genitourinary malignancies requires a multidisciplinary care team composed of urologists, medical oncologists, and radiation oncologists. A genitourinary (GU) oncology clinical database is an invaluable resource for patient care and research. Although electronic medical records provide a single web-based record used for clinical care, billing, and scheduling, information is typically stored in a discipline-specific manner and data extraction is often not applicable to a research setting. A GU oncology database may be used for the development of multidisciplinary treatment plans, analysis of disease-specific practice patterns, and identification of patients for research studies. Despite the potential utility, there are many important considerations that must be addressed when developing and implementing a discipline-specific database. METHODS AND MATERIALS: The creation of the GU oncology database including prostate, bladder, and kidney cancers with the identification of necessary variables was facilitated by meetings of stakeholders in medical oncology, urology, and radiation oncology at the University of North Carolina (UNC) at Chapel Hill with a template data dictionary provided by the Department of Urologic Surgery at Vanderbilt University Medical Center. Utilizing Research Electronic Data Capture (REDCap, version 4.14.5), the UNC Genitourinary OncoLogy Database (UNC GOLD) was designed and implemented. RESULTS: The process of designing and implementing a discipline-specific clinical database requires many important considerations. The primary consideration is determining the relationship between the database and the Institutional Review Board (IRB) given the potential applications for both clinical and research uses. Several other necessary steps include ensuring information technology security and federal regulation compliance; determination of a core complete dataset; creation of standard operating procedures; standardizing entry of free text fields; use of data exports, queries, and de-identification strategies; inclusion of individual investigators' data; and strategies for prioritizing specific projects and data entry. CONCLUSIONS: A discipline-specific database requires a buy-in from all stakeholders, meticulous development, and data entry resources to generate a unique platform for housing information that may be used for clinical care and research with IRB approval. The steps and issues identified in the development of UNC GOLD provide a process map for others interested in developing a GU oncology database. PMID- 23434425 TI - The presence of positive surgical margins in patients with organ-confined prostate cancer results in biochemical recurrence at a similar rate to that in patients with extracapsular extension and PSA <= 10 ng/ml. AB - PURPOSES: We investigated whether patients with organ-confined prostate cancer (PCa) and positive surgical margins (SMs) had a similar biochemical recurrence (BCR) risk compared with patients with pT3a and preoperative prostate-specific antigen (PSA) levels <= 10ng/ml. Furthermore, we examined the effects of incorporating SM status, Gleason score (Gls), and preoperative PSA level into the discrimination accuracy of the current tumor node metastasis-staging system. MATERIALS AND METHODS: We analyzed 863 PCa patients treated with radical prostatectomy from 1999 to 2008. Only individuals with pT2N0 or pT3N0, without neoadjuvant or adjuvant therapy, were included. We performed chi-square automatic interaction detection analysis to generate a classification model for predicting BCR by analyzing interactions between age at surgery, SM status, Gls, PSA, and tumor stage, tumor volume and relative tumor volume. Cox regression analyses tested the relationship between SM status and BCR rate after stratification according to T-stage and the novel classification. The predictive and discrimination accuracy of the current T-stage and of the classification model was quantified with time-dependent receiver operating characteristics and integrated discrimination improvement. The topographical association between extracapsular extension of PCa and positive SM was analyzed in patients with pT3aR1 using a computational reconstruction diagram of the prostate. RESULTS: The chi-square automatic interaction detection analysis found interactions among pT Stage, SM status, PSA and Gls and generated a classification model for BCR prediction: pT2R0, pT2R1, pT3a PSA <= 10 ng/ml, pT3a PSA>10 ng/ml and pT3b. Men with pT2R1 had a shorter time to BCR compared with men with pT3a-PSA <= 10 ng/ml (P<0.0001). Gls>=7a was correlated with a poorer BCR rate than Gls<=7a in men with pT2R1 or pT3a PSA <= 10 ng/ml (P = 0.012). The rank order (highest to lowest) for the risk of developing BCR was pT3b>pT2R1/pT3a-PSA>10 ng/ml>pT2R1/pT3a PSA <= 10 ng/ml>pT2R0 (P<0.0001). Discrimination accuracy gains were observed when PCa was stratified according to the novel classification (P<0.0001). A topographical association between extracapsular extension and positive SM was found in patients with pT3aR1 (P = 0.01). CONCLUSION: Patients with pT2R1 develop a similar BCR risk to that of patients with pT3a PSA <= 10 ng/ml. Gls>=7b is associated with a high BCR risk in these patient groups. Including SM status, PSA, and Gls in pT stage appears to improve prognostic stratification in patients with PCa. PMID- 23434426 TI - Editorial comment. PMID- 23434427 TI - Editorial comment. PMID- 23434428 TI - Induction of apoptosis in multiple myeloma cells by a statin-thalidomide combination can be enhanced by p38 MAPK inhibition. AB - The mechanisms involved in anti-myeloma activity of statins combined with thalidomide were studied in multiple myeloma (MM) cells. In addition, the effect of p38 MAPK inhibition on the induction of apoptosis in MM cells by the combination of thalidomide and simvastatin was investigated. Thalidomide was observed to significantly potentiate the antiproliferative activity of statins and enhance the proapoptotic effect of simvastatin and lovastatin. What is more, the combination of thalidomide with statins inhibited cell migration and decreased the production of VEGF and MMP-9 in MM cells more effectively than each of these drugs used separately. The combination of simvastatin and thalidomide augmented caspase 8 and 3 activation, and the additional application of p38 MAPK inhibitor resulted in enhanced apoptosis of MM cells concomitant with increased caspase 9 and 3 activation, as well as JNK phosphorylation. The results suggest that p38 inhibitors together with the combination of simvastatin and thalidomide have the potential to be used in MM treatment. PMID- 23434429 TI - TCTP/HRF pathway and angiogenesis: a feasible intercourse in chronic lymphocytic leukemia. AB - This prospective study was planned to determine the intercourse between translationally controlled tumor protein (TCTP)/histamine releasing factor (HRF)/histamine pathway and angiogenesis in chronic lymphocytic leukemia (CLL). A total of 153 CLL patients were included. Serum histamine levels were higher in CLL patients. A positive correlation was found between microvessel density (MVD) mast cell (MC) count; MVD-TCTP/HRF and MC count-TCTP/HRF. Microvessel density, MC and ZAP 70 were significantly higher in TCTP/HRF-positive group. Time to first treatment was shorter in patients with increased MVD and TCTP/HRF. Further data is essential to ascertain the role of TCTP/HRF pathway in tumor angiogenesis and CLL prognosis. PMID- 23434430 TI - Response to the letter by F. Chatain, J. Bejui-Hugues, O. Guyen, T. Gaillard, S. Denjean, O. Tayot, and H. Chavane, JL. Delalande. PMID- 23434431 TI - Legitimate division of large datasets, salami slicing and dual publication. Where does a fraud begin? PMID- 23434432 TI - Interactions of terpyridines and their Pt(II) complexes with G-quadruplex DNAs and telomerase inhibition. AB - Three terpyridine derivatives L1-L3 and their Pt(II) complexes 1-3 have been prepared, the binding interactions with human telomeric (h-telo) and the promoter c-kit2 and c-myc G-quadruplex DNAs were investigated. All the ligands and the complexes are potent stabilisers of the G-quadruplex structures and exhibit the G quadruplex selectivity over duplex. The binding affinities of these compounds to G-quadruplexes are higher than to calf thymus DNA. Three Pt(II) complexes are also potent telomerase inhibitors. CD spectra show that both the ligands and the complexes can induce the formation of anti-parallel G-quadruplex structure of h telo in the absence and presence of K(+). Each h-telo G-quadruplex binds two ligand or complex molecules using Job plot analysis. PMID- 23434433 TI - Antibody-mediates inhibition of human C1s and the classical complement pathway. AB - Disregulation of complement activation plays a critical role in numerous inflammatory diseases and therefore, inhibition of the complement pathway is of great therapeutic interest. In the classical complement pathway, immune complexes formed by IgM, IgG1, IgG2 and IgG3 antibodies result in the activation of the C1s protease that in turn cleaves C4 and then C4-bound-C2 yielding the proteolytic fragments C4b and C2a which associate to form a C3 convertase enzyme. We report here the engineering of a potent human antibody inhibitor of C1s protease activity. Phage panning of a very large synthetic (F(AB)) antibody fragment library using a truncated version of C1s, comprising the second CCP domain and serine protease domain (CCP2-SP) and expressed in insect cells, resulted in the isolation of a F(AB) that inhibited the catalytic activity of C1s. An affinity matured variant of the F(AB) format antibody displaying subnanomolar K(D) for C1s was shown to exhibit >80% inhibition of C2 processing at a 5:1 antibody:C1s molar ratio. We show that this engineered antibody, D.35, displays potent inhibition of complement deposition and lysis of Ramos cells by the anti-CD20 therapeutic antibody rituximab relative to the approved, but less-specific, human plasma derived C1-inhibitor (CINRYZE). C1s inhibitory antibodies should be useful for delineating the role of the classical pathway in disease models and may hold promise as therapeutic agents. PMID- 23434434 TI - Modulation of immune functions in polymorphonuclear neutrophils induced by physostigmine, but not neostigmine, independent of cholinergic neurons. AB - BACKGROUND: Cholinesterase inhibitors (Ch-I) improve survival in experimental sepsis consistent with activation of the cholinergic-anti-inflammatory-pathway. So far, less is known about whether Ch-I have a direct immunomodulatory effect on immune cells (polymorphonuclear neutrophils, PMN) in the absence of cholinergic neurons. We investigated the concentration-response-effects of physostigmine and neostigmine on the oxidative burst activity (human and rat PMN) and the expression of adhesion molecules on the surface of human PMN under in vitro conditions. METHODS: PMN from 10 healthy humans or 10 rats were pretreated with 2, 10, 24, 97 MUM physostigmine or 3, 15, 30, 150 MUM neostigmine, primed with tumor-necrosis-factor-alpha (TNF-alpha) followed by stimulation with n-formyl methionyl-leucylphenylalanine (fMLP) or stimulated with phorbol-12-myristate-13 acetate (PMA). Human and rat samples were assessed by flow cytometry for the generation of oxidative free radicals. Stimulated human PMN were additionally incubated with antibodies against Mac-1 (CD11b) or L-selectin (CD62l). RESULTS: Physostigmine and neostigmine did not alter oxidative burst activity or the expression of adhesion molecules of PMN induced by receptor-dependent activators like fMLP or TNF-alpha/fMLP (rat and human PMN, p=n.s.). Physostigmine, but not neostigmine, inhibited the protein-kinase-C-mediated oxidative burst activity by PMA in a dose-dependent manner (rat and human PMN, p<0.05). Physostigmine, in the concentration range tested, suppressed the expression of CD11b following stimulation with PMA not significantly (human PMN: control: 63.1+/-10.7 vs. 97 MUM physostigmine: 49.9+/-12.8 MESF, p=n.s.). CONCLUSION: While neostigmine has no effect on functional and phenotypic changes of PMN, the lipid soluble Ch-I physostigmine causes a dose dependent reduction in PMA-induced oxidative burst, independent of neuronal released acetylcholine. PMID- 23434435 TI - The effect of alloferon on the enhancement of NK cell cytotoxicity against cancer via the up-regulation of perforin/granzyme B secretion. AB - Alloferon is a novel immunomodulatory peptide originally isolated from infected insects. It has anti-viral and anti-tumor effects via the activation of NK cells. However, specific mechanisms leading to NK cell activation and anti-tumor responses yet to be clarified. In this study, we demonstrate that alloferon increases killing activity of NK cells to cancer cells via the up-regulation of the expression of NK-activating receptors, 2B4. In addition, the production of IFN-gamma and TNF-alpha and granule exocytosis from NK cells against cancer cell were increased by alloferon. Lastly, the anti-tumor effect of alloferon was confirmed in vivo to demonstrate effective retardation of tumor growth in the human-to-mouse xenograft model. All taken together, these results suggest that alloferon has anti-tumor effects through up-regulation of NK-activating receptor 2B4 and the enhancement of granule exocytosis from NK cells. PMID- 23434436 TI - Texture analysis of bone marrow in knee MRI for classification of subjects with bone marrow lesion - data from the Osteoarthritis Initiative. AB - Visualization of bone marrow lesion (BML) can improve the diagnosis of many bone disorders that are associated with it. A quantitative approach in detecting BML could increase the accuracy and efficiency of diagnosing those bone disorders. In this paper, we investigated the feasibility of using magnetic resonance imaging (MRI)-based texture to (a) identify slices and (b) classify subjects with and without BML. A total of 58 subjects were studied; 29 of them were affected by BML. The ages of subjects ranged from 45 to 74years with a mean age of 59. Texture parameters were calculated for the weight-bearing region of distal femur. The parameters were then analyzed using Mann-Whitney U test and individual feature selection methods to identify potentially discriminantive parameters. Forward feature selection was applied to select features subset for classification. Classification results from eight classifiers were studied. Results show that 98 of the 147 parameters studied are statistically significantly different between the normal and affected marrows: parameters based on co-occurrence matrix are ranked highest in their separability. The classification of subjects achieved an area under the receiver operating characteristic curve (AUC) of 0.914, and the classification of slices achieved an AUC of 0.780. The results show that MRI-texture-based classification can effectively classify subjects/slices with and without BML. PMID- 23434437 TI - Synthesis of 3-O-methylgallic acid a powerful antioxidant by electrochemical conversion of syringic acid. AB - BACKGROUND: A kinetic study of the electrochemical oxidation of syringic acid (3,5-dimethoxy-4-hydroxybenzoic acid) by cyclic voltammetry at treated gold disk was combined with results of electrolyses at Ta/PbO2 anode in order to convert it into potentially high-added-value product. METHODS: The electrochemical oxidation of syringic acid was carried out in order to convert this compound to 3-O methylgallic acid. This latter was identified by mass spectrophotometry using LC MS/MS apparatus. The 3-O-methylgallic acid synthesis was controlled by cyclic volammetry, Ortho-diphenolicdeterminations and DPPH radical-scavenging activity. RESULTS: The proposed mechanism is based on the hypothesis of a bielectronic discharge of syringic acid molecule under free and adsorbed form involving two intermediate cation mesomers. Hydrolysis of the more stable of this last one leads to the formation of the 3,4-dihydroxy-5-methoxybenzoic acid (3-O methylgallic acid) as a major product. The latter aromatic compound was synthesized by anodic oxidation of syringic acid at PbO2 electrode. The cyclic voltammogram of the electrolysis bath of syringic acid shows that the anodic peak potential of 3-O-methylgallic acid was lower (Epa=128mV) than that of SA (Epa=320mV). And the strongest antiradical activity was detected when the 3-O methylgallic acid concentration was higher". CONCLUSION: The electrochemical oxidation using PbO2 anode is a rapid, simple and efficient method tool for a conversion of SA into 3-O-methylgallic acid, a potent antioxidant derivative GENERAL SIGNIFICANCE: The electrochemical process consists in a simple transformation of the syringic acid into 3-O-methylgallic acid having a better antioxidant capacity. This result has been justified by cyclic voltametry which shows that anodic peak of 3-O-methylgallic acid is reversible. Furthermore, its potential is lower than that of the irreversible anodic peak of syringic acid to 3-O-methylgallic acid. PMID- 23434438 TI - Disulfide reduction abolishes tissue factor cofactor function. AB - BACKGROUND: Tissue factor (TF), an in vivo initiator of blood coagulation, is a transmembrane protein and has two disulfides in the extracellular domain. The integrity of one cysteine pair, Cys186-Cys209, has been hypothesized to be essential for an allosteric "decryption" phenomenon, presumably regulating TF procoagulant function, which has been the subject of a lengthy debate. The conclusions of published studies on this subject are based on indirect evidences obtained by the use of reagents with potentially oxidizing/reducing properties. METHODS: The status of disulfides in recombinant TF1-263 and natural placental TF in their non-reduced native and reduced forms was determined by mass spectrometry. Functional assays were performed to assess TF cofactor function. RESULTS: In native proteins, all four cysteines of the extracellular domain of TF are oxidized. Reduced TF retains factor VIIa binding capacity but completely loses the cofactor function. CONCLUSION: The reduction of TF disulfides (with or without alkylation) eliminates TF regulation of factor VIIa catalytic function in both membrane dependent FX activation and membrane independent synthetic substrate hydrolysis. GENERAL SIGNIFICANCE: Results of this study advance our knowledge on TF structure/function relationships. PMID- 23434440 TI - Bile acids and liver carcinogenesis: TGR5 as a novel piece in the puzzle? PMID- 23434439 TI - Pulse width dependence of motor threshold and input-output curve characterized with controllable pulse parameter transcranial magnetic stimulation. AB - OBJECTIVE: To demonstrate the use of a novel controllable pulse parameter TMS (cTMS) device to characterize human corticospinal tract physiology. METHODS: Motor threshold and input-output (IO) curve of right first dorsal interosseus were determined in 26 and 12 healthy volunteers, respectively, at pulse widths of 30, 60, and 120 MUs using a custom-built cTMS device. Strength-duration curve rheobase and time constant were estimated from the motor thresholds. IO slope was estimated from sigmoid functions fitted to the IO data. RESULTS: All procedures were well tolerated with no seizures or other serious adverse events. Increasing pulse width decreased the motor threshold and increased the pulse energy and IO slope. The average strength-duration curve time constant is estimated to be 196 MUs, 95% CI [181 MUs, 210 MUs]. IO slope is inversely correlated with motor threshold both across and within pulse width. A simple quantitative model explains these dependencies. CONCLUSIONS: Our strength-duration time constant estimate compares well to published values and may be more accurate given increased sample size and enhanced methodology. Multiplying the IO slope by the motor threshold may provide a sensitive measure of individual differences in corticospinal tract physiology. SIGNIFICANCE: Pulse parameter control offered by cTMS provides enhanced flexibility that can contribute novel insights in TMS studies. PMID- 23434441 TI - Electron scattering cross section calculations for polar molecules over a broad energy range. AB - We report computational integral and differential cross sections for electron scattering by two different polar molecules, HCN and pyrimidine, over a broad energy range. We employ, for low energies, either the single-centre expansion (ePOLYSCAT) or the R-matrix method, while for the higher energies we select a corrected form of the independent-atom representation (IAM-SCAR). We provide complete sets of integral electron scattering cross sections from low energies up to 10,000 eV. Our present calculated data agree well with prior experimental results. PMID- 23434442 TI - Eight and a half syndrome with hemiparesis and hemihypesthesia: the nine syndrome? AB - "Eight-and-a-half" syndrome is "one-and-a-half" syndrome (conjugated horizontal gaze palsy and internuclear ophthalmoplegia) plus ipsilateral fascicular cranial nerve seventh palsy. This rare condition, particularly when isolated, is caused by circumscribed lesions of the pontine tegmentum involving the abducens nucleus, the ipsilateral medial longitudinal fasciculus, and the adjacent facial colliculus. Its recognition is therefore of considerable diagnostic value. We report a 71-year-old man who presented with eight and a half syndrome associated with contralateral hemiparesis and hemihypesthesia, in which brain magnetic resonance imaging scans revealed a lacunar pontine infarction also involving the corticospinal tract and medial lemniscus. These features could widen the spectrum of pontine infarctions, configuring a possible "nine" syndrome. PMID- 23434443 TI - Pineal calcification is associated with symptomatic cerebral infarction. AB - BACKGROUND: Pineal calcification and low melatonin have been shown to be risk factors for stroke in animal studies; however, there are limited clinical data on the association of pineal calcification and stroke in humans. METHODS: All computed tomographic (CT) scans of the brains of patients >15 years of age during the year 2011 at a university teaching hospital were retrospectively reviewed. Patient medical charts were used to obtain the risk factors for stroke, including diabetes, hypertension, dyslipidemia, age, and sex. Cerebral infarction was identified by having clinical syndromes of stroke and a positive CT scan. Patients with embolic or hemorrhagic stroke were excluded. Pineal calcification was evidenced by the CT scans. The association of various stroke risk factors and cerebral infarction were calculated using logistic regression analysis. RESULTS: A total of 1614 patients were included, and symptomatic cerebral infarction was identified in 620 patients (38.4%). Regarding stroke risk factors in symptomatic cerebral infarction patients, the majority of patients were male (356 [57.4%]), >50 years of age (525 [84.7%]), and had hypertension (361 [58.2%]); some had diabetes (199 [32.1%]) and dyslipidemia (174 [28.1%]). Pineal calcification was found in 1081 patients (67.0%), with a male:female ratio of 1.5:1. Significant factors related to cerebral infarction by univariate logistic regression were age >50 years, hypertension, diabetes, dyslipidemia, and pineal calcification. Pineal calcification as a risk factor for cerebral infarction had an adjusted odds ratio of 1.35 (95% confidence interval 1.05-1.72). CONCLUSIONS: Pineal calcification may be a potential new contributor to cerebral infarction. PMID- 23434444 TI - ER homeostasis and motility of NSCLC cell lines can be therapeutically targeted with combined Hsp90 and HDAC inhibitors. AB - BACKGROUND AND OBJECTIVE: Lung cancer remains the most common cause of cancer related death in the world for which novel systemic treatments are urgently needed. Protein homeostasis that regulates protein levels and their fold is critical for cancer cell proliferation and survival. A complex network of cellular organelles and signaling cascades is involved in control of protein homeostasis including endoplasmic reticulum (ER). Thus, proteins in control of ER homeostasis are increasingly recognized as potential therapeutic targets. Molecular chaperone heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) play an important role in ER homeostasis. Previous studies demonstrate that Hsp90 and HDAC inhibitors are individually functional against lung cancer. In this work we suggested that combined Hsp90 and HDAC inhibitors may elevate ER stress thereby enhancing the anti non small lung cancer (NSCLC) activity. METHODS AND RESULTS: Using an in vitro cell line model we demonstrated that 17-DMAG (HSP90 inhibitor) co-administration with PTACH (HDAC inhibitor) caused elevated ER stress (immunoblotting) (more than 110%?, p < 0.05) accompanied by apoptotic cell death (Annexin V) (7-21%?, p < 0.05). Moreover, 17-DMAG/PTACH treated cells lost the ability to migrate (scratch test) (57-85%? of scratch closure, p < 0.05). CONCLUSIONS: Our findings provide proof-of-concept that targeting ER homeostasis is therapeutically beneficial in lung cancer cell lines. Indeed, the elevated ER stress caused by 17-DMAG/PTACH combined treatment leads to increased cell death of NSCLC cell lines compared to the application of the drugs separately. PMID- 23434445 TI - Mucous hypersecretion and relationship to cough. AB - A variety of foreign "invaders" such as viruses, bacteria and other particulates e.g., cigarette smoke, are inhaled, deposit on the airway surface and invade the "host." Mucins produced by the surface airway epithelium and by the submucosal glands are secreted into the airway lumen. Deposited particulates adhere to the mucus and are cleared via mucociliary transport and via cough. Mucins are major constituents of mucus, which is important in the clearance of inhaled materials. Normally, secreted mucus is cleared without symptoms or interference with lung function. However, in obstructive airway diseases such as COPD, asthma, and cystic fibrosis, excessive mucus is produced. Because of the prominence of mucous hypersecretion as a cause of cough, this discussion focuses on mechanisms regulating normal production of mucins and the mechanisms underlying exaggerated mucin secretion in chronic obstructive airway diseases. Mucins are produced by airway epithelial cells via a cascade of signals (the Epidermal Growth Factor Cascade) and secreted on the luminal epithelial surface, often in response to the deposition of inhaled irritants. Normally, only minimal amounts of mucins are secreted, which assist in clearance of the inhaled particulates. However, in disease, additional pathways are induced via positive feedback systems, which lead to mucous hypersecretion. In the large conducting airways, where cough receptors are concentrated, mucous hypersecretion causes stimulation of neural receptors that result in cough. However, in small airways (e.g., bronchioles), because of their small diameters, mucous hypersecretion leads to plugging of the airways. Because there are so many small airways, their plugging is difficult to detect early, and this locus is known as a "silent zone." In chronic obstructive airway diseases, plugging of small airways may persist and increase over time, finally resulting in severe airway obstruction. Different obstructive airway diseases induce inflammatory signaling (including mucous hypersecretion) via different stimuli, but often via similar signaling pathways. Application of present knowledge of signaling that occurs with mucous hypersecretion can lead to novel therapies for hypersecretion and cough induced in conducting airways and could prevent plugging in small airways that can lead to clinical deterioration and death. PMID- 23434446 TI - Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity. AB - BACKGROUND: Guidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms. METHODS: A post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once daily inhaled bronchodilators indacaterol (150 and 300 MUg) and open-label tiotropium (18 MUg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = 'less dyspnoea'; scores >=2 = 'more dyspnoea'). Outcomes were assessed after 26 weeks. RESULTS: The analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose ('trough') forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV1 and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV1, TDI and SGRQ total scores at week 26; indacaterol 300 MUg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (>=1 point) vs placebo; and open-label tiotropium improved trough FEV1, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated. CONCLUSIONS: In patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 MUg may be a useful treatment option for patients with COPD who experience more severe breathlessness. PMID- 23434447 TI - High strength re-mineralizing, antibacterial dental composites with reactive calcium phosphates. AB - OBJECTIVE: Development of high strength dental composites with adhesive, antibacterial and re-mineralizing potential. MATERIALS: Urethane and triethylene glycol dimethacrylates were combined with HEMA (10 or 20wt%) and 2MP (2 or 10wt%), antibacterial chlorhexidine (2.5wt%) and chemical cure initiators. Reactive mono/tri calcium phosphate (CP) mixed with silica/silicon carbide nanoparticles (S) (CP:S weight ratio 1:2 or 2:1) was added (50wt%). RESULTS: Decreasing CP/S ratio and HEMA content reduced monomer conversion at 15min from 93 to 63%. Conversely, decreasing CP/S increased initial "dry" compressive (137 203MPa) and flexural (79-116MPa) strength. With high HEMA content, these decreased by ~15-20MPa upon 24h water storage. With low HEMA content, average decline was <8MPa due to reduced water sorption. Early water sorption induced mass increase, volume expansion, mono calcium phosphate dissolution and chlorhexidine release, were proportional to the initial calcium phosphate content. Furthermore, they increased ~1.5 fold upon raising HEMA wt%. These diffusion controlled processes and strength decline slowed after 24h as phosphates reaction bound water within the materials. Increasing 2MP concentration reduced calcium release but did not affect strength. Formulations with high CP/S indicated greater antibacterial activity in agar diffusion and in vitro biofilm tests. SIGNIFICANCE: New material use beneath a conventional composite could potentially reduce high failure rates associated with residual caries and bacterial microleakage. PMID- 23434448 TI - Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. AB - OBJECTIVE: Local recurrence limits long-term survival in patients with malignant pleural mesothelioma. We investigated whether hyperthermic intraoperative cisplatin chemotherapy lavage affects the interval to recurrence and overall survival among patients with favorable prognostic factors. METHODS: Using a preoperative risk assessment algorithm we had previously developed and validated, we retrospectively identified a cohort of patients treated with cytoreductive surgery from 2001 to 2009. The patients had epithelial histologic findings on biopsy and were characterized as having a low risk of early recurrence and death (ie, tumor volume <= 500 cm(3) and were either men with a hemoglobin level of >= 13 g/dL or were women). Those patients who had received hyperthermic intraoperative cisplatin chemotherapy were compared with a comparison group of those who had not. Fisher's exact test was used to determine the balance of prognostic factors. The Kaplan-Meier method and log-rank tests were used to estimate and compare the interval to recurrence and overall survival. Cox proportional hazards regression was used for multivariate analysis. RESULTS: The cohort criteria identified 103 patients: 72 who received hyperthermic intraoperative cisplatin chemotherapy and 31 who did not. The groups were balanced for prognostic factors, except for the use of neoadjuvant chemotherapy (more common in the comparison group). The hyperthermic intraoperative cisplatin chemotherapy group exhibited a significantly longer interval to recurrence (27.1 vs 12.8 months) and overall survival (35.3 vs 22.8 months) than the comparison group. The improved interval to recurrence and overall survival for the hyperthermic intraoperative cisplatin chemotherapy group were particularly evident among the subgroups of patients who had not received hemithoracic radiotherapy and who had pathologic stage N1 or N2 lymph node metastases. CONCLUSIONS: A favorable outcome and minimal incremental morbidity support the incorporation of hyperthermic intraoperative cisplatin chemotherapy into multimodality treatment strategies for patients with low-risk epithelial malignant pleural mesothelioma. PMID- 23434449 TI - Penehyclidine hydrochloride preserves the intestinal barrier function in patients undergoing cardiopulmonary bypass. AB - OBJECTIVE: The study objective was to investigate the protective effect of penehyclidine hydrochloride on intestinal barrier function integrity and its therapeutic potential on endotoxemia and systemic inflammatory response in patients undergoing cardiopulmonary bypass. METHODS: Forty patients undergoing cardiac valve replacement with cardiopulmonary bypass were enrolled in the study. All patients were randomly divided into the penehyclidine hydrochloride or control group (20 patients in each group). Patients in the penehyclidine hydrochloride group received an intravenous injection of 0.05 mg/kg penehyclidine hydrochloride 10 minutes before cardiopulmonary bypass, and those in the control group were given the same volume of saline. Blood samples for blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, serum endotoxin (lipopolysaccharide), interleukin-6, and interleukin-10 measurements were collected during the following time points: immediately after anesthesia induction (T0), 10 minutes after the release of aortic-clamping (T1), immediately after weaning from cardiopulmonary bypass (T2), 2 hours postoperatively (T3), 6 hours postoperatively (T4), and 18 hours postoperatively (T5). RESULTS: Blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, interleukin-6, and interleukin-10 were significantly increased at all postoperative time points. At specific postoperative time points, blood glucose, lactic acid, intestinal fatty acid binding protein, D lactate, lipopolysaccharide, and interleukin-6 were statistically lower in the penehyclidine hydrochloride group than in the control group. Postoperatively, interleukin-10 did not differ between the penehyclidine hydrochloride and control groups. CONCLUSIONS: Penehyclidine hydrochloride preserves intestinal barrier function integrity, attenuates endotoxemia, and inhibits systemic inflammatory response in patients undergoing cardiopulmonary bypass, possibly by improving intestinal microcirculation and depressing stress response. PMID- 23434450 TI - Temporary right ventricular mechanical circulatory support for the management of right ventricular failure in critically ill patients. AB - BACKGROUND: Management of right ventricular (RV) failure after left ventricular assist device (LVAD) implantation is not evidence based. Temporary circulatory assistance has recently been reported to be of value for managing postoperative RV failure after LVAD implantation, but only in small series of patients or isolated case reports. We report here our experience with the use of temporary right ventricular assist devices (RVADs) in LVAD recipients. METHODS: Forty-five of the 488 (9%) patients undergoing LVAD implantation between 2001 and 2011 at the Clinic for Thoracic and Cardiovascular Surgery in Bad Oeynhausen had RV failure requiring temporary RVAD. We analyzed preoperative data, complications, mortality at 6 months, and risk factors of death. RESULTS: The LVAD patients receiving temporary RVAD were younger than the 443 recipients of LVAD alone. They were more likely to have mechanical ventilation and haemofiltration and their Michigan right ventricular risk score was higher. The LVAD patients with temporary RVAD had a higher mortality at 6 months: 53%, versus 25% for patients receiving LVAD only (P < .001). The univariate risk factors for death were high blood urea nitrogen and C-reactive protein concentrations, preoperative mechanical ventilation, preoperative hemofiltration, destination therapy, the use of temporary RVAD, and the development of RV failure. Multivariate analyses did not identify predictors of death. CONCLUSIONS: The development of RV failure in LVAD recipients is a serious problem associated with high mortality. Temporary RV mechanical support is an acceptable way to manage postoperative RV failure in these severely ill LVAD recipients. PMID- 23434451 TI - Complications of cerebrospinal fluid drainage after thoracic aortic surgery: a review of 504 patients over 5 years. AB - BACKGROUND: Cerebrospinal fluid drainage, a well-established means of preventing paraplegia after thoracic aortic aneurysm surgery, can result in serious, sometimes lethal complications. In a large group of patients who underwent surgical thoracic aortic aneurysm repair with cerebrospinal fluid drainage, we examined the incidences of and potential risk factors for these outcomes. METHODS: The records were reviewed of 504 patients who underwent surgical thoracic aortic aneurysm repair with cerebrospinal fluid drainage at the Texas Heart Institute at St. Luke's Episcopal Hospital between February 2005 and December 2009. All historical data, inpatient records, and billing data were searched for evidence of complications. RESULTS: Of the 504 patients, 14 (2.8%) had intracranial hemorrhage, of whom 10 (72%) had subdural hematoma. Postdural puncture headache developed in 49 patients (9.7%), of whom 17 (34.6%) required epidural blood patch placement for resolution. Multivariable analysis identified having a connective tissue disorder (odds ratio, 3.08; 95% confidence interval, 1.33-7.13) as an independent predictor of postdural puncture headache, but not age less than 40 years (odds ratio, 0.97; 95% confidence interval, 0.94-0.99). CONCLUSIONS: Cerebrospinal fluid drainage, as performed by our method, seems to be associated with a modest rate of intracranial bleeding in patients who undergo surgical thoracic aortic aneurysm repair. In contrast, postdural puncture headache is not uncommon, particularly in patients with connective tissue disease. Clinicians caring for these patients should consider the likelihood of postdural puncture headache, and any such patient with postoperative headache should be assessed for epidural blood patch placement. PMID- 23434452 TI - Texture analysis of articular cartilage traumatic changes in the knee calculated from morphological 3.0T MR imaging. AB - OBJECTIVES: In the present work, we aim to identify changes in the cartilage texture of the injured knee in young, physically active, patients by computer analysis of MRI images based on 3.0T morphological sequences. METHODS: Fifty three young patients with training injury or trauma in one knee underwent MRI and arthroscopy. Textural features were computed from the MRI images of the knee cartilages and two classes were formed of 28 normal and 16 with pathology only in the medial femoral condyle (MFC) cartilage. RESULTS: Textural features with statistically significant differences between the two classes were found only at the MFC and the medial tibial condyle (MTC) areas. Three features-combinations, at the MFC or the MTC, maximized the between classes separation, thus, rendering alterations in cartilage texture due to injury more evident. The MFC cartilage in the pathology class was found more inhomogeneous in the distribution of gray levels and of lower texture anisotropy and the opposed MTC cartilage, though normal on MRI and arthroscopy, was found to have lower texture anisotropy than cartilage in the normal class. CONCLUSION: Texture analysis may be used as an adjunct to morphological MR imaging for improving the detection of subtle cartilage changes and contributes to early therapeutic approach. PMID- 23434453 TI - Value of 18F-FDG PET/CT in the diagnosis of primary gastric cancer via stomach distension. AB - OBJECTIVE: To clarify the usefulness of (18)F-FDG PET/CT for detecting primary gastric cancer via gastric distention using a mixture of milk and Diatrizoate Meglumine. MATERIALS AND METHODS: A total of 68 patients (male: 47, female: 21; age: 41-87 years) suspected of gastric carcinoma underwent (18)F-FDG PET/CT imaging. After whole-body PET/CT imaging in a fasting state, the patients drank a measured amount of milk with Diatrizoate Meglumine. Local gastric district PET/CT imaging was performed 30 min later. The imaging was analyzed by semi-quantitative analysis, standardized uptake value (SUV) of the primary tumor was measured in a region of interest. The diagnosis results were confirmed by gastroscopy, pathology, and follow-up results. RESULTS: Of the 68 patients, 56 malignant gastric neoplasm patients (male: 37, female: 19) were conformed. The sensitivity, specificity, positive predictive value and negative predictive value of fasting whole-body PET/CT imaging for a primary malignant tumor were 92.9%, 75.0%, 94.5%, and 69.0%, respectively. The values for distension with a mixture of milk and Diatrizoate Meglumine were 91.1%, 91.7%, 98.1%, and 68.8%, respectively. The area under the curve was 0.919 +/- 0.033 and 0.883 +/- 0.066 for the diagnosis of gastric cancer with SUVmax in a fasting state and after intake of mixture respectively, the differences were not statistically significant (P=0.359). Using gastric distension with a mixture of milk and Diatrizoate Meglumine, the mean ratio of the lesion's SUVmax to the adjacent gastric wall SUVmax increased significantly from 3.30 +/- 3.05 to 13.50 +/- 15.05, which was statistically significant (P<0.001). CONCLUSIONS: (18)F-FDG PET/CT imaging is highly accurate for the diagnosis of primary gastric carcinoma. Gastric distention can display the lesions more clearly, however, it cannot significantly improve diagnostic accuracy. PMID- 23434454 TI - A pilot study to evaluate the use of virtual lectures for undergraduate radiology teaching. AB - PURPOSE: To demonstrate that virtual lectures can substitute conventional lectures in radiology education for medical students. METHODS AND MATERIALS: During the course 2005-2006, 89 out from 191 (46.6%) third year students of a subject entitled "General Radiology", participated voluntarily in a pilot study including 22 virtual lectures (Flash presentations translated from the same PowerPoint presentations of conventional lectures, adding recorded narration and navigation tools). Participants (P) studied by means of virtual lectures, while non-participants (NP) assisted to conventional lectures. The results of the final oral exam classified from 0 to 3, and a 60-questions evaluation on image interpretation were used to compare both groups after training. Finally, 34 students from the group P (38.2%) fulfilled a 10-points scale quality survey about the project. RESULTS: Final exam qualifications were significantly higher for P than for NP (2.11 +/- 0.85 versus 1.73 +/- 1.04) as well as the number of correct answers of the evaluation on image interpretation (24.2 +/- 6.2 versus 21.2 +/- 5.4), but differences could obey to different attitudes between both groups. The usefulness of virtual lectures to learn General Radiology obtained the highest global scoring (8.82 +/- 1.00). Contents were generally better evaluated than the design of the presentations. CONCLUSION: Virtual lectures can substitute conventional lectures in radiology education for medical students with no detriment to students' learning. Their potential advantage is that magisterial lectures can be used to discuss contents with students in a more participative way if virtual lectures are provided before. PMID- 23434455 TI - An updated view on the role of dopamine in myopia. AB - A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers ("deprivation myopia", DM) or negative lenses ("lens induced myopia", LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2 receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose-response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies. PMID- 23434456 TI - Contribution of nitric oxide synthase isoforms to cholinergic vasodilation in murine retinal arterioles. AB - Nitric oxide synthases (NOSs) are critically involved in regulation of ocular perfusion. However, the contribution of the individual NOS isoforms to vascular responses is unknown in the retina. Because some previous findings suggested an involvement of inducible nitric oxide synthase (iNOS) in the regulation of retinal vascular tone, a major goal of the present study was to examine the hypothesis that iNOS is involved in mediating cholinergic vasodilation responses of murine retinal arterioles. Another subject of this study was to test the contribution of the other two NOS isoforms, neuronal (nNOS) and endothelial NOS (eNOS), to cholinergic retinal arteriole responses. Expression of individual NOS isoforms was determined in murine retinal arterioles using real-time PCR. All three NOS isoforms were expressed in retinal arterioles. However, eNOS mRNA was found to be most, and iNOS mRNA least abundant. To examine the functional relevance of iNOS for mediating vascular responses, retinal vascular preparations from gene-targeted iNOS-deficient mice (iNOS-/-) and wild-type mice were studied in vitro. Changes in luminal vessel diameter in response to the thromboxane mimetic 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha (U-46619), the endothelium-dependent vasodilator acetylcholine, and the nitric oxide donor nitroprusside were measured by video microscopy. To determine the contribution of individual NOS isoforms to cholinergic vasodilation responses, retinas from iNOS /- and wild-type mice were incubated with Nomega-nitro-l-arginine methyl ester (l NAME), a non-isoform-selective inhibitor of NOS, 7-nitroindazole, a selective nNOS blocker and aminoguanidine, a selective iNOS inhibitor. U-46619 evoked concentration-dependent vasoconstriction that was similar in retinal arterioles from iNOS-/- and wild-type mice. In retinal arterioles preconstricted with U 46619, acetylcholine and nitroprusside produced dose-dependent dilation that did not differ between iNOS-/- and wild-type mice. Remarkably, in both genotypes, vasodilation to acetylcholine was negligible after incubation with l-NAME. In contrast, pharmacological inhibition of nNOS and iNOS had no effect on acetylcholine-induced vasodilation. These findings suggest that dilation of murine retinal arterioles to acetylcholine is mediated predominantly by eNOS. PMID- 23434457 TI - [Initiation of breastfeeding and early weaning: a prospective study of the health perinatal network Loire-Nord Ardeche]. AB - OBJECTIVES: The World Health Organization recommends exclusive breastfeeding of infants up to 6months. The proportion of breastfeeding initiation and duration increased more slowly in France than in neighboring European countries. The perinatal network data are incomplete. The objective of this study is to evaluate within the perinatal network "Loire-Nord Ardeche" (ELENA), breastfeeding rates in hospital discharge and at 2months, and identify needs for maternal support. PATIENTS AND METHODS: Prospective and declarative study by written questionnaire, with all the women volunteers who gave birth in October 2011 in a maternity of our perinatal network. RESULTS: Population concerns 426 women volunteers of 968 new mothers. Two hundred and ninety-four questionnaires were used: 69% of women initiated breastfeeding, 63% have continued after the stay in the maternity and 50% at 2 months. Eighty percent chose to breastfeed before pregnancy, mainly for child health, 65% with the support of their spouse, 58% if their mother had breastfed. Simple pathologies of breastfeeding and childbirth were responsible for weaning. A third of women in difficulty have not consulted anyone, one third wanted more practical help and systematic support motherhood. DISCUSSION AND CONCLUSION: The rate of initiation of breastfeeding or duration and the great influence of the surroundings of the mother, similar in this study to literature data, call for enhanced prenatal information for parents and systematic "lactation" consultation in the early post-partum, by trained professionals and with the help of support associations for breastfeeding. This study showed a clear need to support breastfeeding. It has also allowed targeting actions that would be able to avoid the majority of early weaning. PMID- 23434458 TI - [Secondary psoas actinomycosis: a complication of an intra-uterine contraceptive device]. AB - Genital-pelvic actinomycosis is an uncommon disease which often arises on women with long term use of intrauterine device. Its diagnostic remains difficult. Even if different clinical locations has been reported, location to the psoas muscle is exceptional. We report such a case, diagnosed on a 53 years old woman. Both a tumoral and a severe infectious syndrome appeared three months after an intra uterine device removal. The septic syndrome led to a laparotomic approach. Unusual clinical presentation, delay between device removal and septic syndrome and lack of genital infection explain the issues to reach the final diagnosis. PMID- 23434459 TI - Intracellular localization of myeloperoxidase in murine peritoneal B-lymphocytes and macrophages. AB - Generation of hypochlorous acid (HOCl), an important microbicidal agent, is considered to be the main function of myeloperoxidase (MPO), an enzyme present in phagocytes. High amounts of MPO are present in neutrophil azurophilic granules, which are mobilized into the phagolysosome vacuole during phagocytosis. MPO is also present in monocytes and macrophages, although to a lesser degree than in neutrophils. In the present study, we investigated the distribution of MPO in murine peritoneal cells using flow cytometry, confocal microscopy (CM) and transmission electron microscopy (TEM). MPO was observed in macrophages, and surprisingly, we detected MPO in B lymphocytes, specifically in B1-a. MPO was present in cytoplasmic granules, vesicles, mitochondria and the nucleus of murine peritoneal cells. Together, these findings suggest that, in addition to its known microbicidal activity, MPO has a myriad of other unanticipated cellular functions. PMID- 23434460 TI - MGC29506 induces cell cycle arrest and is downregulated in gastric cancer. AB - The proapoptotic caspase adaptor protein (PACAP) is involved in cell-cycle regulation and promotes apoptosis. Both MGC29506 and PACAP are isoforms of the MGC29506 gene and are generated by differential splicing of the alternative splice-acceptor. In studying PACAP, we inadvertently constructed the eukaryotic expression vector MGC29506. At present, the function of the MGC29506 gene is largely unknown with the key exception of information obtained by bioinformatics. We studied the role of MGC29506 in gastric cancer cell proliferation, the cell cycle and apoptosis. In addition, we studied MGC29506 expression in gastric cancer patients and explored its significance. We found that the expression of MGC29506 in gastric cancer samples was lower than in samples from adjacent non tumor tissues. We found that the MGC29506 protein was localized in the cell nucleus of AGS cells and inhibited their proliferation. Higher percentages of G0/G1 and S phase cells were induced by transfection with the MGC29506 gene than were induced by transfection with the negative control. We showed that cells transfected with MGC29506 were arrested at the G0/G1 and S phases of the cell cycle. However, we found no significant increases in apoptosis of cells transfected with MGC29506 compared with cells transfected with the negative control. Our results suggested that MGC29506 has the potential of functioning as a novel suppressor gene in gastric cancer. Downregulation of MGC29506 may also promote the progression of gastric cancer. PMID- 23434462 TI - Gene expression profiling in live attenuated Edwardsiella tarda vaccine immunized and challenged zebrafish: insights into the basic mechanisms of protection seen in immunized fish. AB - Despite the importance and success of vaccine immunization against bacterial diseases in fish, little is known about the molecular mechanisms of vaccine induced immune protection in teleost fish. In this study, the live attenuated Edwardsiella tarda vaccine strain WED, which has been shown to evoke efficacious protection against edwardsiellosis and ascites diseases in fish, was extensively evaluated for multiple parameters in a 5-week immunization and challenge experiment in zebrafish. The parameters evaluated included the immunologic potency (relative percent survival, RPS), the specific IgM antibody titers and the expression profiles of multiple immune-related gene markers at multiple time points following immunization and challenge. During the 4-week immunization phase, the toll-like receptor (TLR) 5 signaling pathway, the MHC-I antigen processing pathway and cytotoxic T lymphocyte (CTL) responses were activated in succession. In contrast, the MHC-II antigen processing pathway and the markers of CD4(+) T lymphocyte activation were down-regulated, and IgM transcription and specific IgM antibody titers were not significantly induced following immunization. During the 1-week challenge phase, the induction of MHC-I and CTL responses and the inhibition of MHC-II and CD4(+) T cell responses were similarly observed in immunized zebrafish following challenge with wild E. tarda. With the 5-week immunization and challenge model, our data suggest the basic mechanism that underlying the long-lasting protective immunity elicited by WED in zebrafish. This mechanism involved the induction of the TLR-5 signaling pathway, the MHC-I antigen processing pathway and CTL effector function, and CTL function seems play a major role in the protection against E. tarda infection in zebrafish. PMID- 23434461 TI - Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. AB - Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia associated mutation. Sarco/endoplasmic reticulum calcium ATPase (SERCA) channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G0/G1 arrest in NOTCH1-mutated human leukemia cells. A small molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling in Drosophila. These studies "credential" SERCA as a therapeutic target in cancers associated with NOTCH1 mutations. PMID- 23434463 TI - Sockeye salmon retain immunoglobulin-secreting plasma cells throughout their spawning journey and post-spawning. AB - Antibody-producing plasma cells are a major source of protective immunity in vertebrates, including salmon. During the spawning phase, salmon undergo drastic, hormonally driven changes in their physiology, including elevated levels of cortisol, which are known to suppress the immune system. As adult fish need to survive their long journey to the spawning grounds, we hypothesized that humoral immunity, in the form of IgM-secreting plasma cells, remains functional until post-spawning. This was investigated by measuring changes in membrane and secreted immunoglobulin heavy chain mu and Pax5 transcripts in spleen and kidney from migrating sockeye salmon, using real-time qPCR. As an additional measurement, the abundance of developing B, mature B, and plasma cells was determined in spawning fish, using flow cytometry. Immune tissue samples were collected from fish from the Kenai River drainage and Main Bay, Prince William Sound. Our results reveal that spawning fish express high levels of secreted heavy chain mu transcripts in their spleen and anterior kidney throughout the spawning journey. Furthermore, we show that IgM-secreting PCs (HCmu++/Pax5-) remain abundant in anterior kidney and spleen of post-spawning sockeye salmon, with a concomitant loss in developing B cells (HCmu-/Pax5+). This suggests that successful spawners retain their PCs throughout the spawning journey and post spawning. PMID- 23434464 TI - The response of mRNA expression upon secondary challenge with Vibrio anguillarum suggests the involvement of C-lectins in the immune priming of scallop Chlamys farreri. AB - The enhanced immunity against a second encounter with the particular pathogen has suggested the presence of "immune priming" in scallop. In the present study, the survival rate and expression patterns of five C-lectin isoforms from scallop Chlamys farreri were explored after "vaccination" of heat-killed Vibrio anguillarum or successively challenge with V. anguillarum and Micrococcus luteus. When scallops were challenged with live bacteria, the survival rate increased significantly only in the group firstly "vaccinated" with inactivated V. anguillarum and then challenged with live V. anguillarum compared with naive scallops (from 41% to 63.6%, P<0.05), showing enhanced protective effects of inactivated bacteria with "specificity". When scallops received the challenge with V. anguillarum, the mRNA expression level of five C-lectins in scallops which were immuned previously with heat-killed V. anguillarum peaked significantly higher (26.7-, 121.7-, 60.1-, 27.4-, 16.3-fold to 0h, respectively, P<0.01) than that in non-immuned scallops (7.6-fold, P<0.05; 6.4-, 3.9-fold, P>0.05; 5.7-fold, P<0.05; 11.7-fold, P<0.01, to 0h, respectively). A significantly higher peak and 3-9h earlier response of all C-lectins mRNA expression were observed after challenge with live V. anguillarum (26.7-, 121.7-, 60.1-, 26.4- and 16.3-fold to 0h, respectively, P<0.01), compared with those only received first injection with heat-killed V. anguillarum (1.6-fold, P>0.05; 8.3 fold, P<0.05; 5.2-fold, P>0.05; 14.5-fold, P<0.01; 4.3-fold, P>0.05, to 0h, respectively). The response of mRNA expression to the secondary encounter with the same bacteria was stronger than that of successively encounter with the different class of bacteria. It was obvious that the mRNA expression of C-lectins in scallops was significantly enhanced by the successive challenge of same species of bacteria with a certain degree of specificity. All the results suggested that C-lectins might be involved in some form of immune priming, and it might provide new insights into mechanism of invertebrate immune priming. PMID- 23434465 TI - [Plagiarism. A challenge for editors]. PMID- 23434466 TI - [Applications of botulinum toxin in Neurology]. AB - At present, botulinum toxin (BT) is one of the most fundamental available drugs in Neurology, only comparable with levodopa. BT is currently used in those entities characterized by excessive muscle contraction, including dystonia and spasticity. In addition, BT has been used to control pain associated with increased muscle contraction in dystonia and spasticity, but also is useful to control chronic pain not associated with muscle contraction, such as chronic daily headache. Finally, BT is useful in sialorrhoea and bruxism. The mechanism of action is complex, mainly acting on terminal neuromuscular junction, but also exhibiting analgesic properties, probably through inhibition of pain neurotransmitters release. PMID- 23434467 TI - [Familial paraganglioma syndrome: phenotype and relevance of a new SDHB mutation]. AB - BACKGROUND AND OBJECTIVE: Advances in molecular biology have discovered new genes involved in the development of familial paraganglioma syndrome (PGL) including those encoding mitochondrial succinate dehydrogenase complex (SDH). We describe the diagnosis, clinical expression and genetic counselling in a family diagnosed of PGL due to a new SDHB mutation. PATIENTS AND METHOD: Genetic study by PCR direct sequencing SDHB gene and biochemical determination in blood/urine fractionated catecholamine 24h, metanephrines and conventional (computed tomography/magnetic resonance imaging) and functional imaging ((123)I-MIBG) in all members of a family diagnosed of PGL. RESULT: DNA sequencing showed a non described SDHB heterozygous mutation (c.287-3C>G intron3/exon4) in 5 of the subjects (71%). The estimated penetrance of the mutation's carriers was 40%, with a mean age of 35 years at diagnosis. All patients with active illness required surgical treatment after imaging and laboratory confirmation. CONCLUSIONS: We describe the pathogenicity, diagnostic algorithm, genetic counselling and clinical expression of a new SDHB mutation (c.287-3C>G) in a family diagnosed of PGL. PMID- 23434468 TI - [Patellar tendinopathy. Therapeutic model in the sport medicine]. PMID- 23434469 TI - [Lysosomal diseases]. PMID- 23434470 TI - [Practical issues of the new normative of research samples storage in Spain]. PMID- 23434471 TI - Diagnostic impact of baseline cerebral blood flow in patients with acute ischemic stroke prior to intravenous recombinant tissue plasminogen activator therapy. AB - OBJECTIVE: To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). METHODS: We measured baseline cerebral blood flow (CBF) using technetium-99m labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38-93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. RESULTS: Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08+/-0.08 (n=3) and 0.3+/-0.15 (n=49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5+/-9.5% (n=3) and 0.43+/-0.87% (n=49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. CONCLUSION: These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy. PMID- 23434472 TI - Cytomegalovirus infection and cognitive abilities in old age. AB - Cytomegalovirus infection has been implicated in cognitive impairment in studies using brief clinical assessments though findings are inconsistent. The association between cytomegalovirus infection, measured as serostatus or a semiquantitative assessment of antibody level, and cognitive abilities in a sample of older adults was examined. Cytomegalovirus status was assessed at a mean age of 70 years in 1061 participants of the Lothian Birth Cohort 1936. Cognitive ability scores were available for general cognitive ability, processing speed, memory, and vocabulary. Background demographic and environmental factors included father's social class, years of education, childhood cognitive ability, overcrowding in childhood, and access to indoor toilet facilities. Cytomegalovirus seropositive individuals had lower cognitive ability at age 70: mean IQ was 99.1 (SD, 15.1) versus 102.4 (SD, 13.1) in seronegative individuals (t = 3.65; p < 0.001). The likelihood of contracting cytomegalovirus infection by age 70 was predicted by a number of demographic and environmental factors and, after accounting for these, cytomegalovirus infection (considered as serostatus) was not cognitively detrimental. Within cytomegalovirus seropositive individuals, however, higher cytomegalovirus antibody levels were associated with lower general cognitive ability. PMID- 23434474 TI - Mathematical modeling of high-rate Anammox UASB reactor based on granular packing patterns. AB - A novel mathematical model was developed to estimate the volumetric nitrogen conversion rates of a high-rate Anammox UASB reactor based on the packing patterns of granular sludge. A series of relationships among granular packing density, sludge concentration, hydraulic retention time and volumetric conversion rate were constructed to correlate Anammox reactor performance with granular packing patterns. It was suggested that the Anammox granules packed as the equivalent simple cubic pattern in high-rate UASB reactor with packing density of 50-55%, which not only accommodated a high concentration of sludge inside the reactor, but also provided large pore volume, thus prolonging the actual substrate conversion time. Results also indicated that it was necessary to improve Anammox reactor performance by enhancing substrate loading when sludge concentration was higher than 37.8 gVSS/L. The established model was carefully calibrated and verified, and it well simulated the performance of granule-based high-rate Anammox UASB reactor. PMID- 23434473 TI - In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. AB - Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease. PMID- 23434475 TI - Development of a multi-residue enantiomeric analysis method for 9 pesticides in soil and water by chiral liquid chromatography/tandem mass spectrometry. AB - A novel and sensitive chiral liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous measuring individual enantiomers of 9 pesticides including herbicides, insecticides, and fungicides in soil and water. The separation and determination were performed using reversed-phase chromatography on an amylose chiral stationary phase, a Chiralpak AD-RH column, under gradient elution using a mixture of ACN-2mM ammonium acetate in water as the mobile phase at 0.45 mL/min flow rate. The effects of three cellulose-based columns and three amylose-based columns on the separation were also investigated. The QuEChERS (acronym for Quick, Easy, Cheap, Effective, Rugged and Safe) method and solid-phase extraction (SPE) were used for the extraction and clean-up of the soil and water samples, respectively. Parameters including the matrix effect, linearity, precision, accuracy and stability were undertaken. Under optimal conditions, the mean recoveries for all enantiomers from the soil and water samples were ranged from 77.8% to 106.2% with the relative standard deviations (RSD) less than 14.2%. Good linearity (at least R(2) >= 0.9986) was obtained for all studied analytes in the soil and water matrix calibration curves over the range from 2.0 to 125 MUg/L. The limits of detection (LOD) for all enantiomers in the soil and water were less than 1.8 MUg/kg or MUg/L, whereas the limit of quantification (LOQ) did not exceed 5.0 MUg/kg or MUg/L. The results of the method validation confirm that this proposed method is convenient and reliable for the enantioselective determination of the enantiomers of 9 chiral pesticides in soil and water. PMID- 23434476 TI - Preparation of graphene/TiO2 composites by nonionic surfactant strategy and their simulated sunlight and visible light photocatalytic activity towards representative aqueous POPs degradation. AB - A series of graphene/TiO2 composites were fabricated using a single-step nonionic surfactant strategy combined with the solvothermal treatment technique. Their phase structure, morphology, porosity, optical absorption property, as well as composition and structure, were characterized. The as-prepared composites were successfully applied to degrade aqueous persistent organic pollutants (POPs) such as rhodamine B, aldicarb, and norfloxacin in simulated sunlight (lambda>320 nm) and visible light (lambda>400 nm) irradiation. The degradation mechanism and kinetics of aqueous POPs were studied in detail. The mineralization of aqueous POPs and the recyclability of the composites were also tested in the same condition. PMID- 23434477 TI - Adsorptive denitrogenation of model fuels with porous metal-organic framework (MOF) MIL-101 impregnated with phosphotungstic acid: effect of acid site inclusion. AB - A metal-organic framework (MOF) MIL-101 was impregnated with phosphotungstic acid (PWA) and used as an adsorbent in liquid phase adsorption of nitrogen-containing compounds (NCCs) from a model fuel. The model fuel contained one sulfur containing compound (SCC), benzothiophene (BT); one basic NCC, quinoline (QUI); and one neutral NCC, indole (IND). In both MIL-101 and PWA-impregnated MIL-101s, NCC adsorption selectivity was very high compared to the SCC selectivity. Additionally, the adsorption capacity of basic QUI increased by 20% with only 1% PWA impregnation in MIL-101. The adsorption of a neutral compound, IND, was slightly reduced with PWA impregnation in the MOF. The adsorption capacity/selectivity can be remarkably improved by a slight modification of MOFs, for example, to impart acidity. The MOF impregnated with PWA may be very interesting in commercial denitrogenation, especially for coal-derived fuels which contain mainly basic NCCs, by adsorption since the selectivity for NCCs (compared to SCCs) over the adsorbent is very high and the adsorbent can be reused many times. PMID- 23434478 TI - Dithizone functionalized CdSe/CdS quantum dots as turn-on fluorescent probe for ultrasensitive detection of lead ion. AB - An ultrasensitive fluorescent probe is developed for the determination of lead ion by utilizing dithizone (Dz) functionalized CdSe/CdS quantum dots (QDs). Dithizone was bound to the QDs via a surface coordinating reaction to form QDs-Dz conjugates and quench fluorescence of the QDs by fluorescence resonance energy transfer (FRET) mechanism. Upon the addition of Pb(2+), a dramatic enhancement of the fluorescence intensity was observed, which resulted from the FRET pathway shutting off, and hence the fluorescence of the QDs was recovered. Two successive linear ranges of 0.01-1000 nmol L(-1) and 1-20 MUmol L(-1) allow a very wide determination of Pb(2+) concentration from 0.01 nmol L(-1) to 20 MUmol L(-1), with a detection limit of 0.006 nmol L(-1). The fluorescent probe was successfully applied to the determination of lead in environmental samples with satisfactory results. PMID- 23434479 TI - Amines immobilized double-walled silica nanotubes for CO2 capture. AB - Novel silica support has been required for high amine loading and good CO2 molecule diffusion into its pores to increase the performance of CO2 adsorbents. Herein, amine groups supported on double-walled silica nanotubes (DWSNTs) have been prepared via the immobilization of various aminosilanes (primary, secondary, tertiary, di-, and tri-aminosilanes) on DWSNT, and found to be a very effective adsorbent for CO2 capture. Amine groups immobilized DWSNTs captured CO2 reversibly in a temperature swing process at various adsorption temperatures (25 degrees C, 50 degrees C, 75 degrees C, and 100 degrees C). The amines on modified DWSNTs showed high CO2 capture capacity in the order of tri-, di-, primary, secondary, and tertiary amines. The CO2 capture capacity of all aminosilanes immobilized DWSNTs decreased linearly with the increase of the adsorption temperature. We expect that DWSNT would be able to inspire researchers to use it not only as a support for CO2 capture but also as a promising candidate for various applications. PMID- 23434480 TI - Evaluation of peracetic acid fog for the inactivation of Bacillus anthracis spore surrogates in a large decontamination chamber. AB - The purpose of this study was to evaluate the sporicidal (inactivation of bacterial spores) effectiveness and operation of a fogging device utilizing peracetic acid/hydrogen peroxide (PAA). Experiments were conducted in a pilot scale 24 m(3) stainless steel chamber using either biological indicators (BIs) or bacterial spores deposited onto surfaces via aerosolization. Wipe sampling was used to recover aerosol-deposited spores from chamber surfaces and coupon materials before and after fogging to assess decontamination efficacy. Temperature, relative humidity, and hydrogen peroxide vapor levels were measured during testing to characterize the fog environment. The fog completely inactivated all BIs in a test using a 60 mL solution of PAA (22% hydrogen peroxide/4.5% peracetic acid). In tests using aerosol-deposited bacterial spores, the majority of the post-fogging spore levels per sample were less than 1 log colony forming units, with a number of samples having no detectable spores. In terms of decontamination efficacy, a 4.78 log reduction of viable spores was achieved on wood and stainless steel. Fogging of PAA solutions shows potential as a relatively easy to use decontamination technology in the event of contamination with Bacillus anthracis or other spore-forming infectious disease agents, although additional research is needed to enhance sporicidal efficacy. PMID- 23434481 TI - Superoxide mediated production of hydroxyl radicals by magnetite nanoparticles: demonstration in the degradation of 2-chlorobiphenyl. AB - Increasing attention has been paid to magnetite nanoparticles (MNPs) due to their highly reductive reactivity toward environmental contaminants. However, there is little information related to the generation of reactive oxygen species (ROS) by MNPs, which in fact plays a vital role for the transformation of contaminants. In this paper, the degradation of 2-chlorobiphenyl (2-CB) by MNPs was investigated. The role of ROS generated by MNPs in this process was elucidated. The results demonstrated that hydroxyl radicals (OH) generated by MNPs at low pH could efficiently degrade 2-CB. The mechanism of the formation of OH by MNPs was divided into two steps: (i) the superoxide radical anion (O2(-)) mediated production of hydrogen peroxide (H2O2), and (ii) the reaction of formed H2O2 with Fe(II) dissolved from MNPs to produce OH through Fenton reaction. Comparison of the degradation products of 2-CB by MNPs with MNPs/ethanol and Fenton reagents further supported the involvement of OH in the degradation of 2-CB. The degradation efficiency of 2-CB by MNPs under acidic conditions was higher than that in alkaline solution. These findings provide a new insight into the understanding of reactivity of MNPs for the transformation of 2-CB and possibly other relevant environmental contaminants. PMID- 23434482 TI - A new insight into Fenton and Fenton-like processes for water treatment: Part II. Influence of organic compounds on Fe(III)/Fe(II) interconversion and the course of reactions. AB - The interconversion of Fe(III)/Fe(II) in Fenton (Fe(2+)/H2O2) and Fenton-like (Fe(3+)/H2O2) reactions has been studied to better understand their intrinsic mechanisms. The reactions were conducted at an initial pH of 3.0, with H2O2 in excess and iron in catalytic concentrations, and with nitrobenzene and atrazine as model organic compounds. The results of this study have shown that some intermediate species in the degradation of aromatic compounds can influence the interconversion of Fe(III)/Fe(II) in the Fenton and Fenton-like reactions, and hence influence the rate and course of the reactions. Thus, from the point of view of Fe(III)/Fe(II) interconversion, a Fenton-like reaction inevitably involves a classical Fenton reaction, and a Fenton reaction may also involve a Fenton-like reaction step. These two reactions may be somewhat interchangeable and proceed simultaneously. In the case of the degradation of aromatic compounds, the Fenton-like reactions display autocatalytic character, but no such effect is observed for non-aromatic compounds. PMID- 23434483 TI - Recurrent arrival of oil to Galician coast: the final step of the Prestige deep oil spill. AB - Yearly monitoring in one of the most affected coastal zones by the Prestige oil spill, namely Nemina and O Rostro beaches (NW Spain), has been carried out since 2004. Topographic data of beaches revealed seasonal altimetric changes up to 4m that would prevent the on shore persistence of oil. However, surficial and subsurficial oil was detected in the intertidal area of both beaches in all campaigns. The hydrocarbon analysis confirmed that this oil corresponded to the Prestige oil, even nine years after the accident. Tar balls were highly biodegraded suggesting that the oil was accumulated on the subtidal sediments for a long time and transported to the coast by the action of waves. The present work provides new evidence of the long term persistence of deep oil spills from wrecks in marine areas where the hydrodynamic conditions play a twofold key role, in determining the exposed coastal area to recurrent contamination and in burying and resurfacing the oil in the intertidal zone. PMID- 23434484 TI - Synergistic inactivation of anaerobic wastewater biofilm by free nitrous acid and hydrogen peroxide. AB - Free nitrous acid (FNA) was recently revealed to be a strong biocide for microbes in anaerobic biofilm, achieving approximately 1-log (90%) inactivation at a concentration of 0.2-0.3 mgHNO2-N/L with an exposure time longer than 6h. The combined biocidal effects of FNA and hydrogen peroxide (H2O2) on anaerobic wastewater biofilm are investigated in this study. H2O2 greatly enhances the inactivation of microorganisms by FNA. About 2-log (99%) of microbial inactivation was achieved when biofilms were exposed to FNA at 0.2 mgN/L or above and H2O2 at 30 mg/L or above for 6h or longer. It was found, through response surface methodology and ridge analysis, that FNA is the primary inactivation agent and H2O2 enhances its efficiency. The loss and the subsequent slow recovery of biological activity in biofilm reactors subjected to FNA and H2O2 dosing confirmed that the chemical combination could achieve higher microbial inactivation than with FNA alone. Reaction simulation shows that intermediates of reactions between FNA and H2O2, like peroxynitrite and nitrogen dioxide, would be produced at elevated levels and are likely responsible for the synergism between FNA and H2O2. The combination of FNA and H2O2 could potentially provide an effective solution to sewer biofilm control. PMID- 23434485 TI - Degradation of sulfamethazine by gamma irradiation in the presence of hydrogen peroxide. AB - The gamma irradiation-induced degradation of sulfamethazine (SMT) in aqueous solution in the presence of hydrogen peroxide (H2O2) was investigated. The initial SMT concentration was 20mg/L and it was irradiated in the presence of extra H2O2 with initial concentration of 0, 10 and 30 mg/L. The results showed that gamma irradiation was effective for removing SMT in aqueous solution and its degradation conformed to the pseudo first-order kinetics under the applied conditions. When initial H2O2 concentration was in the range of 0-30 mg/L, higher concentration of H2O2 was more effective for the decomposition and mineralization of SMT. However, the removal of total organic carbon (TOC) was not as effective as that of SMT. Total nitrogen (TN) was not removed even at absorbed dose of 5 kGy, which was highest dose applied in this study. Major decomposition products of SMT, including degradation intermediates, organic acids and some inorganic ions were detected by high performance liquid chromatography (HPLC) and ion chromatography (IC). Sulfate (SO4(2-)), formic acid (HCOOH), acetic acid (CH3COOH), 4-aminophenol, 4-nitrophenol were identified in the irradiated solutions. Possible pathways for SMT decomposition by gamma irradiation in aqueous solution were proposed. PMID- 23434486 TI - Microwave-assisted in situ synthesis of reduced graphene oxide-BiVO4 composite photocatalysts and their enhanced photocatalytic performance for the degradation of ciprofloxacin. AB - To improve the photodegradation efficiency for ciprofloxacin (CIP), a new-type microwave-assisted in situ growth method is developed for the preparation of reduced graphene oxide (RGO) -BiVO4 composite photocatalysts. The as-produced RGO BiVO4 composite photocatalysts show extremely high enhancement of CIP degradation ratio over the pure BiVO4 photocatalyst under visible light. Specially, the 2 wt% RGO-BiVO4 composite photocatalyst exhibits the highest CIP degradation ratio (68.2%) in 60 min, which is over 3 times than that (22.7%) of the pure BiVO4 particles. The enhancement of photocatalytic activities of RGO-BiVO4 photocatalysts can be attributed to the effective separation of electron-hole pairs rather than the improvement of light absorption. PMID- 23434487 TI - Enhanced visible-light-driven photocatalytic inactivation of Escherichia coli by Bi2O2CO3/Bi3NbO7 composites. AB - The Bi2O2CO3/Bi3NbO7 (BiCO/BiNbO) composite was successfully fabricated by a simple hydrothermal method and found to be an effective visible-light-driven photocatalyst for inactivation of Escherichia coli (E. coli). The BiCO/BiNbO composite was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), UV vis diffuse reflectance spectrum (UV-vis DRS), and Fourier transform infrared (FT IR) spectroscopy. The BiCO/BiNbO composite exhibited largely enhanced photocatalytic inactivation of E. coli as compared to the pure Bi3NbO7 under visible light irradiation. The enhanced photocatalytic performance can be attributed to the improved separation efficiency of the photogenerated holes and electrons. In addition, the possible bactericidal mechanism of the BiCO/BiNbO composite under visible light irradiation was discussed. PMID- 23434488 TI - Transformation of acetaminophen using manganese dioxide-mediated oxidative processes: reaction rates and pathways. AB - This study investigates the oxidative transformation kinetics of acetaminophen (APAP) by delta-MnO2 under different conditions. APAP was rapidly oxidized by delta-MnO2 with the generation of Mn(2+). The measured APAP reaction rate considerably increased with an increase in initial delta-MnO2 and APAP concentration, but decreased as pH increased. The APAP reaction rate also increased with an increase in temperature. The addition of inorganic ions (Mn(2+), Ca(2+), and Fe(3+)) and substituted phenols (guaiacol, caffeic acid, and p-coumaric acid) as co-solutes remarkably decreased the transformation rate of APAP. The UV-Vis absorption spectra exhibited the pi -> pi* transition, typical for aromatic rings. In addition, the intensity of the absorption peak gradually improved with increasing reaction time, suggesting that APAP can polymerize to form oligomers. Moreover, the secondary mass spectra of the dimers elucidated that the dimers were formed by the covalent bonding of phenol aromatic rings. Moreover, the higher-degree oligomers were formed by the coupling polymerization of phenolic and anilidic groups of dimers. These results are useful in understanding the fate of APAP in natural systems. PMID- 23434489 TI - Pollution profiles, health risk of VOCs and biohazards emitted from municipal solid waste transfer station and elimination by an integrated biological photocatalytic flow system: a pilot-scale investigation. AB - Volatile organic compounds (VOCs) and biohazards air pollution in municipal solid waste transfer station were investigated. As compressor working, the concentrations of almost all quantified 14 VOCs (0.32-306.03 MUg m(-3)) were much higher than those as compressor off (0-13.31 MUg m(-3)). Comparatively, only 3 VOCs with extremely low concentrations could be detected at control area. Total microorganism was 7567 CFU m(-3) as compressor working, which was 1.14 and 6.22 times higher than that of compressor off and control area, respectively. Bacteria were the most abundant microorganism at all three sampling places. At pilot scale, during whole 60-day treatment, for VOCs, the average removal efficiencies were over 92% after biotrickling filter-photocatalytic (BTF-PC) treatment. Although non-cancer and cancer risks of some VOCs were over the concern level before treatment, almost all VOCs were removed substantially and both potential risks were below the concern after BTF-PC treatment. Additionally, biohazard concentrations decreased dramatically and air quality was purified from polluted to cleanness after PC treatment. All results demonstrated that the integrated technology possessed high removal capacity and long stability for the removal of VOCs and biohazards at a pilot scale. PMID- 23434490 TI - In vivo effects of n-TiO2 on digestive gland and immune function of the marine bivalve Mytilus galloprovincialis. AB - Due to the increasing production of nanoparticles (NPs) and their potential release in the aquatic environment, evaluation of their biological impact on aquatic organisms represents a major concern. Suspension feeding invertebrates, in particular bivalve mollusks, may play a role in NP biotransformation and transfer through food webs and may represent a significant target for NP toxicity. In this work, the in vivo effects of titanium dioxide (n-TiO2), one of the most widespread NPs in use, were investigated in the bivalve Mytilus galloprovincialis, largely utilised as a sentinel for marine contamination. Mussels were exposed for 96h to different concentrations of n-TiO2 suspensions (1, 10 and 100MUgL(-1)) and multiple responses were evaluated in the digestive gland and immune cells, the haemocytes. In the digestive gland, n-TiO2 affected lysosomal and oxidative stress biomarkers and decreased transcription of antioxidant and immune-related genes. In the haemocytes, n-TiO2 decreased lysosomal membrane stability-LMS and phagocytosis, increased oxyradical production and transcription of antimicrobial peptides; moreover, pre-apoptotic processes were observed. The effects of n-TiO2 on digestive gland and haemocytes were distinct, also depending on the endpoint and on nominal NP concentrations, with many significant responses elicited by the lowest concentrations tested. The results show that n-TiO2, at concentrations close to predicted environmental levels, significantly affected different functional and molecular parameters of mussel digestive gland and immune cells. In particular, the observed changes in immune parameters that represent significant biomarkers of exposure at the organism level suggest that exposure to n-TiO2 may pose a serious risk to mussel health. PMID- 23434491 TI - Interaction of 17beta-estradiol and ketoconazole on endocrine function in goldfish (Carassius auratus). AB - An understanding of the effects of toxic mixtures of endocrine disrupting chemicals (EDCs) on aquatic organisms is challenging as these organisms are exposed to multiple classes of contaminants in their natural habitat. The aim of the present study was to evaluate the interactions of two classes of EDCs, 17beta estradiol (E2) and ketoconazole (KTC), on endocrine function in male goldfish (Carassius auratus), including vitellogenesis, metabolic capability and serum steroid synthesis. Changes in vitellogenin (VTG) concentration, liver 7 ethoxyresorufin-O-deethylase (EROD) activity and circulating serum E2 level were examined. The expression of related genes was also determined using quantitative real-time polymerase chain reaction. Exposure to E2 caused a significant increase in VTG concentrations which corresponded with the gene expression of VTG and estrogen receptor (ER) in males, which were further elevated after combined exposure to E2 and KTC, indicative of a synergetic relationship. Exposure to E2 also resulted in a distinct increase in serum steroid biosynthesis and associated cytochrome P450 (CYP) aromatase expression after 10 days. However, these changes were inhibited by the presence of KTC, which acted as a steroidogenic inhibitor in fish. Moreover, KTC significantly decreased liver EROD activity and increased the related gene expression of CYP1A. However, these KTC-mediated metabolic reactions in goldfish were up-regulated following exposure to KTC in combination with E2. These findings reveal complex interactions on endocrine functions in male goldfish when exposed to multiple contaminations and may provide a better understanding of the effects of toxic mixtures. PMID- 23434492 TI - How adenylate cyclase choreographs the pas de deux of the receptors heteromerization dance. AB - Our work suggests that heteromer formation, mainly involves linear motifs (LMs) found in disordered regions of proteins. Local disorder imparts plasticity to LMs. Most molecular recognition of proteins occurs between short linear segments, known as LMs. Interaction of short continuous epitopes is not constrained by sequence and has the advantage of resulting in interactions with micromolar affinities which suit transient, reversible complexes such as receptor heteromers. Electrostatic interactions between epitopes of the G-protein coupled receptors (GPCR) involved, are the key step in driving heteromer formation forward. The first step in heteromerization, involves phosphorylating Ser/Thr in an epitope containing a casein kinase 1/2-consensus site. Our data suggest that dopaminergic neurotransmission, through cAMP-dependent protein kinase A (PKA) slows down heteromerization. The negative charge, acquired by the phosphorylation of a Ser/Thr in a PKA consensus site in the Arg-rich epitope, affects the activity of the receptors involved in heteromerization by causing allosteric conformational changes, due to the repulsive effect generated by the negatively charged phosphate. In addition to modulating heteromerization, it affects the stability of the heteromers' interactions and their binding affinity. So here we have an instance where phosphorylation is not just an on/off switch, instead by weakening the noncovalent bond, heteromerization acts like a rheostat that controls the stability of the heteromer through activation or inhibition of adenylate cyclase by the neurotransmitter Dopamine depending on which Dopamine receptor it docks at. PMID- 23434493 TI - Neuromyelitis optica-like pathology is dependent on type I interferon response. AB - Neuromyelitis optica is an antibody-mediated autoimmune inflammatory disease of the central nervous system. Reports have suggested that interferon beta which is beneficial for multiple sclerosis, exacerbates neuromyelitis optica. Our aim was to determine whether type I interferon plays a role in the formation of neuromyelitis optica lesions. Immunoglobulin G from a neuromyelitis optica patient was injected intracerebrally with human complement to type I interferon receptor deficient and wildtype mice. Loss of aquaporin-4 and glial fibrillary acidic protein was reduced in type I interferon receptor deficient mice brain. Our findings suggest that type I interferon signaling contributes to neuromyelitis optica pathogenesis. PMID- 23434494 TI - A metabolite-profiling approach allows the identification of new compounds from Pistacia lentiscus leaves. AB - Pistacia lentiscus L., commonly known as Mastic tree or lentisk, is a Mediterranean evergreen shrub widely used in traditional medicine to treat such diseases as eczema, diarrhoea, and throat infections. Furthermore, other properties are currently attributed to P. lentiscus, such as antioxidant capacity, hepatoprotective action, and anti-inflammatory effects. High performance liquid chromatography with diode array coupled to electrospray ionization mass spectrometry (HPLC-ESI-QTOF-MS) was used for the comprehensive characterization of methanol extract from P. lentiscus leaves. After the optimisation of the HPLC-ESI-QTOF-MS method and the use of the negative ionization mode, 46 different compounds were identified, 20 of which were tentatively characterized for the first time in P. Lentiscus leaves. The majority of the compounds were quantified. Flavonoids, phenolic acids and their derivatives were the most abundant compounds, those with the highest concentrations being myricetin glycoside (6216.13 mg/kg of plant), catechin (3354.78 mg/kg of plant), beta-glucogallin (2214.461 mg/kg of plant), and quercitrin gallate (1160 mg/kg of plant). The importance of the knowledge of plants is increasing and our study may help in the future to formulate nutraceutical preparations and will provide the basis for new investigation into activities of the various compounds found in P. lentiscus. PMID- 23434495 TI - Identification of cytochrome P450 isoenzymes involved in metabolism of (+) praeruptorin A, a calcium channel blocker, by human liver microsomes using ultra high-performance liquid chromatography coupled with tandem mass spectrometry. AB - Angular-type pyranocoumarins (APs) show attractive prospects in anti hypertension, chemotherapy and anti-HIV treatment. Previous studies revealed extensive hepatic metabolisms of several APs following similar pathways. This study investigated the enzyme kinetics and the main CYP450 isozyme(s) involved in metabolism of (+)-praeruptorin A (dPA), an AP with significant cardio-protective activities, in human liver microsomes (HLMs) using ultra high-performance liquid chromatography coupled with a hybrid quadrupole-linear ion trap mass spectrometry (UHPLC-QT-MS/MS). dPA produced 6 metabolites via hydrolysis (M1-M3), oxidation (M4-M6), and hydrolysis followed by acyl migration (M2 or M3). Oxidation at the C 3' side chain instead of the coumarin ring was consolidated with the aromatic proton signal in NMR spectra. The major metabolite (-)-cis-khellactone (M1) followed biphasic kinetics in HLMs with high affinity (Km1 0.02MUM) and intrinsic clearance (CLint1, invitro1.29mL/min/mg protein), whereas other metabolites (M2 M6) fitted typical Michaelis-Menten kinetics with lower affinity (Km 3.85 39.13MUM). Recombinant human CYP3A4 showed the highest activity toward M1 and M4 formation, while it was CYP2C19 for M2/M3 and M5 and CYP2B6 for M6. Principal component analysis of the metabolite formation profile of dPA also revealed the highest similarity between CYP3A4 and HLMs. Both quercetin (CYP2C8 inhibitor) and ketoconazole (CYP3A4 inhibitor) showed 60-100% inhibition of M1-M4 and M6 formations in HLMs, while M5 formation was mainly inhibited by alpha naphthoflavone (CYP1A2 inhibitor, 70-80%) and quercetin (90%). Moreover, formations of all metabolites were predominantly inhibited by CYP3A4 antibody (37 68%). These findings shed a light on main involvement of CYP3A4 in human hepatic elimination of APs, indicating potential drug interactions. PMID- 23434496 TI - The relationship between building design and residents' quality of life in extra care housing schemes. AB - Well-designed housing is recognised as being an important factor in promoting a good quality of life. Specialised housing models incorporating care services, such as extra care housing (ECH) schemes are seen as enabling older people to maintain a good quality of life despite increasing health problems that can accompany ageing. Despite the variation in ECH building design little is known about the impact of ECH building design on the quality of life of building users. The evaluation of older people's living environments (EVOLVE) study collected cross-sectional data on building design and quality of life in 23 ECH schemes in England, UK. Residents' quality of life was assessed using the schedule for the evaluation of individual quality of life-direct weighting (SEIQoL-DW) and on the four domains of control, autonomy, self-realisation and pleasure on the CASP-19. Building design was measured on 12 user-related domains by means of a new tool; the EVOLVE tool. Using multilevel linear regression, significant associations were found between several aspects of building design and quality of life. Furthermore, there was evidence that the relationship between building design and quality of life was partly mediated by the dependency of participants and scheme size (number of living units). Our findings suggest that good quality building design in ECH can support the quality of life of residents, but that designing features that support the needs of both relatively independent and frail users is problematic, with the needs of highly dependent users not currently supported as well as could be hoped by ECH schemes. PMID- 23434497 TI - Test-retest reliability of a questionnaire measuring perceptions of neighborhood food environment. AB - There is a lack of validated and reliable instruments on perception of the food environment, in particular for rural environments. We estimated the test-retest reliability of a questionnaire assessing perceptions of the food environment. A total of 101 primary food shoppers in South Carolina were interviewed by phone to assess their perceptions of the food environment and presence of different food outlet types in their neighborhood. The survey was repeated approximately one month after the initial administration. The intra-class correlation (ICC) and Phi coefficient are reported as measures of reliability. The majority of questions on perceptions of the neighborhood food environment appear highly reliable (ICCs range from 0.55 to 0.71), including the 3-item scale on healthy food availability (ICC 0.71). Compared to participants in rural areas, those in urban areas demonstrated better reliability for questions on opportunities to purchase fast food and perceived presence of a supercenter. More research is needed to evaluate potential rural-urban differences in reliability. PMID- 23434498 TI - Comparative potencies of contemporary generic vancomycin lot: in vitro assay results from nine products and a reference reagent-grade sample. AB - Numerous studies of generic vancomycin (GV) lots have emerged since the 1980s, casting some doubt on product quality. Publications question the in vivo activity, even when concurrent in vitro and chemical assays meet regulatory guidelines. This study assessed contemporary GV lots by an in vitro assay capable of measuring small variations from target-benchmark (BM) activity. Nine GV lots (Hospira [6 lots; 0.5- or 1.0-g vials], Akorn [1 lot; 1.0-g vial], APP [2 lots; 1.0-g vials]) were obtained from local United States distributors. A reagent grade lot (Sigma lot 080M1341V) was tested as BM component due to the inability to purchase branded product vials in the USA. All lots of GV did not vary significantly from the analytical control when testing the 3 Staphylococcus aureus (wild-type 4B25, ATCC 25923, and 29213) and Enterococcus faecalis (ATCC 29212) strains. These MIC end points were read at 18 h of incubation, and Hospira lots averaged +3.5% potency (range, -3% to +8%), and Akorn and APP at 0% variance, e.g., acceptable performance. In conclusion, with a validated, precise multi-organism assay, current GV lots marketed in the USA showed minimal activity variations from a selected BM control lot. Generic antimicrobial products, in general, should be regularly monitored for potency, chemical purity, and in vivo activity before routine use in medical centers. PMID- 23434499 TI - The functional peroneus brevis as a third muscle component in the osteomyocutaneous fibula free-flap system. AB - Up to now, the peroneus brevis muscle was harvested as a non-functional pedicled muscle flap for defects around the ankle and the anterior lower leg. It has a reliable dual segmental vascularisation from the peroneal and the anterior tibial artery and a long, single motor nerve entering proximally. We report of a free microvascular transfer of the peroneus brevis as a neurotised functional muscle component in a composite osteo-musculo-cutaneous flow-through fibula flap. The flap components were used to reconstruct extensive radial and soft-tissue defects in a severely damaged forearm, whereas the peroneus brevis nerve was coapted to the proper flexor carpi radialis (FCR) motor nerve to counterbalance ulnar abduction, as all radial abductors were lost in the injury. Thirteen months later, the arm was fully reconstructed and an active radial abduction of 15 degrees by the contracting peroneus muscle was achieved. Donor-site complications were absent. The peroneus brevis can expand the versatility of the peroneal-vessel-flap system as a third muscular component in four possible ways: a) addition of plain muscle bulk in the middle- and lower third of the fibula if left attached to the bone, b) as a reinnervated functional muscle as presented here, c) as a distally based muscle component if released from its origin from the middle third of the fibula and pedicled on its distal segmental branches from the peroneal vessels or d) as a distally pedicled osteomuscular flap permitting individual placement of a middle fibula segment. PMID- 23434500 TI - Isolated cutis verticis gyrata of the glabella and nasal bridge: a case report and review of the literature. AB - Cutis verticis gyrata (CVG) is an uncommon morphological condition of the scalp characterised by ridges and furrows resembling the surface of the brain. We present a case of secondary CVG affecting both the glabella and nasal aesthetic unit. To our knowledge, isolated CVG of the glabella has never been reported nor has extension of CVG onto the nasal aesthetic unit of the face. We also describe an association between hyper-IgE syndrome and CVG, and review this rare disorder including options for its surgical management. PMID- 23434501 TI - Transcranial direct current stimulation (tDCS) for catatonic schizophrenia: a case study. PMID- 23434502 TI - The regulation of gene expression involved in TGF-beta signaling by ZNF804A, a risk gene for schizophrenia. AB - ZNF804A has been implicated in susceptibility to schizophrenia by several genome wide association studies (GWAS), follow-up association studies and meta-analyses. However, the biological functions of ZNF804A are not entirely understood. To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). Furthermore, we confirmed that the expression of ANKRD1, PIK3AP1, INHBE and DDIT3 at the protein level was significantly increased by ZNF804A-overexpression. This is the first report to identify genes whose protein expressions are regulated by ZNF804A. ANKRD1, PIK3AP1, INHBE and DDIT3 are related to transforming growth factor-beta (TGF beta) signaling, which plays a crucial role in cell growth and differentiation. On the other hand, recent studies have reported that TGF-beta signaling is associated with schizophrenia. These results provide basis for a more progressive investigation of ZNF804A contributions to the susceptibility or pathophysiology of schizophrenia. PMID- 23434503 TI - Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: results from a randomized controlled trial. AB - PURPOSE: This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of "hard" coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus. METHOD: Changes in FRS and metabolic syndrome status were compared between patients with BMI >= 27 and non-HDL-C >= 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise. RESULTS: The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p = 0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p = 0.0885). CONCLUSION: Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations. PMID- 23434504 TI - No effect of adjunctive, repeated dose intranasal insulin treatment on body metabolism in patients with schizophrenia. AB - OBJECTIVE: This study examined the effect of adjunctive intranasal insulin therapy on body metabolism in patients with schizophrenia. METHOD: Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and had been on stable dose of antipsychotic agent for at least one month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. The whole body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline, and repeated at week 8. RESULTS: A total number of 39 subjects completed the study (18 in the insulin group, 21 in the placebo group). There were no significant differences between the two groups in week 8 changes for body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's>0.100). The DXA assessment showed no significant differences between the two groups in week 8 changes for fat mass, lean mass or total mass (p's>0.100). CONCLUSION: In the present study, adjunctive therapy of intranasal insulin did not seem to improve body metabolism in patients with schizophrenia. The implications for future studies were discussed. PMID- 23434506 TI - Coenzyme Q10 protects Pc12 cells from cisplatin-induced DNA damage and neurotoxicity. AB - The purpose of this study was to investigate the neuroprotective effect of a water-soluble formulation of coenzyme Q10 (WS-CoQ10) in PC12 cells exposed to cisplatin, a chemotherapeutic agent with a dose-limiting factor due to neurotoxicity. In the cytokinesis-block micronucleus cytome assay (CBMN Cyt), WS CoQ10 (at concentrations of 0.1, 0.5 and 1.0MUgmL(-1)) protected PC12 cells from cisplatin-induced DNA damage (0.1MUgmL(-1)), reducing the frequency of micronuclei (MNi) and nuclear buds (NBUDs). WS-CoQ10 did not alter the mRNA expression levels of Tp53 (at a concentration of 1.0MUgmL(-1)) and exhibited neuroprotective activity by stimulating cisplatin-inhibited neurite outgrowth in nerve growth factor (NGF)-differentiated PC12 cells (at a concentration of 0.1MUgmL(-1)). In conclusion, WS-CoQ10 protected the PC12 cells from cisplatin induced DNA damage and neurotoxicity. Moreover, the neuroprotective effects of WS CoQ10 suggest a possible application in chemotherapeutic protocols. PMID- 23434505 TI - Change in neuropsychological functioning over one year in youth at clinical high risk for psychosis. AB - Schizophrenia and related psychotic disorders are associated with significant neuropsychological (NP) impairments. Yet the onset and developmental evolution of these impairments remains incompletely characterized. This study examined NP functioning over one year in a sample of youth at clinical high risk (CHR) for psychosis participating in a treatment study. We assessed functioning across six cognitive domains at two time points in a sample of 53 CHR and 32 healthy comparison (HC) subjects. Linear regression of HC one-year scores was used to predict one-year performance for CHR from baseline scores and relevant demographic variables. We used raw scores and MANOVAs of the standardized residuals to test for progressive impairment over time. NP functioning of CHR at one year fell significantly below predicted levels. Effects were largest and most consistent for a failure of normative improvement on tests of executive function. CHR who reached the highest positive symptom rating (6, severe and psychotic) on the Structured Interview of Prodromal Syndromes after the baseline assessment (n = 10/53) demonstrated a particularly large (d = -1.89), although non-significant, discrepancy between observed and predicted one-year verbal memory test performance. Findings suggest that, although much of the cognitive impairment associated with psychosis is present prior to the full expression of the psychotic syndrome, some progressive NP impairments may accompany risk for psychosis and be greatest for those who develop psychotic level symptoms. PMID- 23434507 TI - A positive feedback loop between ATOH7 and a Notch effector regulates cell-cycle progression and neurogenesis in the retina. AB - The HES proteins are known Notch effectors and have long been recognized as important in inhibiting neuronal differentiation. However, the roles that they play in the specification of neuronal fate remain largely unknown. Here, we show that in the differentiating retinal epithelium, the proneural protein ATOH7 (ATH5) is required for the activation of the transcription of the Hes5.3 gene before the penultimate mitosis of progenitor cells. We further show that the HES5.3 protein slows down the cell-cycle progression of Atoh7-expressing cells, thereby establishing conditions for Atoh7 to reach a high level of expression in S phase and induce neuronal differentiation prior to the ultimate mitosis. Our study uncovers how a proneural protein recruits a protein known to be a component of the Notch signaling pathway in order to regulate the transition between an initial phase of selection among uncommitted progenitors and a later phase committing the selected progenitors to neuronal differentiation. PMID- 23434508 TI - Structural model for tubulin recognition and deformation by kinesin-13 microtubule depolymerases. AB - To elucidate the structural basis of the mechanism of microtubule depolymerization by kinesin-13s, we analyzed complexes of tubulin and the Drosophila melanogaster kinesin-13 KLP10A by electron microscopy (EM) and fluorescence polarization microscopy. We report a nanometer-resolution (1.1 nm) cryo-EM three-dimensional structure of the KLP10A head domain (KLP10AHD) bound to curved tubulin. We found that binding of KLP10AHD induces a distinct tubulin configuration with displacement (shear) between tubulin subunits in addition to curvature. In this configuration, the kinesin-binding site differs from that in straight tubulin, providing an explanation for the distinct interaction modes of kinesin-13s with the microtubule lattice or its ends. The KLP10AHD-tubulin interface comprises three areas of interaction, suggesting a crossbow-type tubulin-bending mechanism. These areas include the kinesin-13 family conserved KVD residues, and as predicted from the crossbow model, mutating these residues changes the orientation and mobility of KLP10AHDs interacting with the microtubule. PMID- 23434509 TI - An ancient protein phosphatase, SHLP1, is critical to microneme development in Plasmodium ookinetes and parasite transmission. AB - Signaling pathways controlled by reversible protein phosphorylation (catalyzed by kinases and phosphatases) in the malaria parasite Plasmodium are of great interest, for both increased understanding of parasite biology and identification of novel drug targets. Here, we report a functional analysis in Plasmodium of an ancient bacterial Shewanella-like protein phosphatase (SHLP1) found only in bacteria, fungi, protists, and plants. SHLP1 is abundant in asexual blood stages and expressed at all stages of the parasite life cycle. shlp1 deletion results in a reduction in ookinete (zygote) development, microneme formation, and complete ablation of oocyst formation, thereby blocking parasite transmission. This defect is carried by the female gamete and can be rescued by direct injection of mutant ookinetes into the mosquito hemocoel, where oocysts develop. This study emphasizes the varied functions of SHLP1 in Plasmodium ookinete biology and suggests that it could be a novel drug target for blocking parasite transmission. PMID- 23434510 TI - Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism. AB - A new influenza-like virus genome (H17N10) was recently discovered in bats and offers a new perspective about the origin and evolution of influenza viruses. The viral envelope glycoprotein hemagglutinin (HA) is responsible for influenza virus receptor binding, fusion, and entry into the cell; therefore, the structure and function of HA H17 was characterized. The 2.70 A resolution crystal structure revealed that H17 has a typical influenza A virus HA fold, but with some special features, including a distorted putative sialic acid (SA) binding site and low thermostability. No binding to either the canonical human alpha2,6 SA-linkage or avian alpha2,3 SA-linkage receptor was observed. Furthermore, H17 glycan binding was not detected using a chip covering more than 600 glycans. Our results demonstrate that H17 is unique among characterized HAs and that the bat-derived influenza virus may use a different entry mechanism compared to canonical influenza viruses. PMID- 23434511 TI - Disease-association analysis of an inflammation-related feedback loop. AB - The IL-6-triggered positive feedback loop for NFkappaB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFkappaB and STAT3 and induces chemokines and inflammation via an NFkappaB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets. PMID- 23434513 TI - Identification of Malassezia species isolated from patients with extensive forms of pityriasis versicolor in Siena, Italy. AB - BACKGROUND: Pityriasis versicolor (PV) is an infection caused by various species of Malassezia yeast. There is no agreement in the literature concerning the species of Malassezia and the demographic, clinical, and mycological data. AIMS: To prospectively identify Malassezia species isolated from lesions of patients with extensive, long standing and recurrent forms of PV and to estimate the relationship between Malassezia species and the demographic and clinical data of the patients. METHODS: All patients with PV were enrolled over a four-year period. Malassezia species were isolated in cultures and identified by morphological features and physiological tests. In the last 2 years a PCR-based technique was used to confirm the species' identification. RESULTS: A total of 74 patients (43 males and 31 females, mean age 39.5 years) were enrolled. Only one species was isolated in 45 patients, and more than one species were identified in the remaining 28 patients (38%). M. globosa was the most frequently isolated (60.3%) species. There was a significant association between the isolation of 2 or more species and the presence of at least one predisposing factor. In the last 29 cases, which were subjected to PCR, there were no differences in the identification of isolated species as compared to traditional methods. CONCLUSIONS: The isolation of more than one species in a single lesion is not infrequent in PV and is related to the presence of one predisposing factor. The isolated species isolated were not influenced by demographic and clinical features. The traditional and more recent (PCR) procedures gave the same results in the isolated species. PMID- 23434514 TI - Investigating the possibility and probability of perinatal subdural hematoma progressing to chronic subdural hematoma, with and without complications, in neonates, and its potential relationship to the misdiagnosis of abusive head trauma. AB - The high incidence of subdural hematoma (SDH) from birthing was first identified with MRI by Looney in 2007 and was then more accurately determined by Rooks in 2008. Rooks screened 101 "normal" deliveries and demonstrated that 46% of the babies in her series and by inference, approximately 46% of the 4 million born normally in the US have SDH that formed in the perinatal (birthing) period during labor. Both metabolic strain and physical forces exerted on the head damage the capillaries within the dura (the intradural capillary bed), which is the source of the blood in the SDH that results from labor and delivery or at times from labor alone. While child abuse pediatricians relying on Rooks, maintain that no permanent complications result, her study was limited to 101 subjects and the sole criteria for resolution was the resolution of the SDH as seen on follow-up MRI. In fact, Rooks did have one patient (1%) who had complications that lead to symptoms and findings often associated with abuse. The purpose of this article is to explore if there is a complication rate for perinatal (PSDH) that supports that 1% of complications that are definable by different criteria. Next, if there are complications, how many of the roughly 2,000,000 cases of perinatal acute subdural hematoma every year in the United States will suffer them? Then, what are the clinical manifestations of the complications if they occur? Lastly, do the complications cause or mimic some or all of the findings that are offered by board certified child abuse pediatricians as evidence of child abuse? The article argues that a small percentage, but significant number of neonates, suffer birth related complications and findings secondary to the development of chronic subdural hematoma CSDH) that are often misdiagnosed as abusive head trauma. PMID- 23434512 TI - Protein phosphatase 2A catalytic subunit alpha plays a MyD88-dependent, central role in the gene-specific regulation of endotoxin tolerance. AB - MyD88, the intracellular adaptor of most TLRs, mediates either proinflammatory or immunosuppressive signaling that contributes to chronic inflammation-associated diseases. Although gene-specific chromatin modifications regulate inflammation, the role of MyD88 signaling in establishing such epigenetic landscapes under different inflammatory states remains elusive. Using quantitative proteomics to enumerate the inflammation-phenotypic constituents of the MyD88 interactome, we found that in endotoxin-tolerant macrophages, protein phosphatase 2A catalytic subunit alpha (PP2Ac) enhances its association with MyD88 and is constitutively activated. Knockdown of PP2Ac prevents suppression of proinflammatory genes and resistance to apoptosis. Through site-specific dephosphorylation, constitutively active PP2Ac disrupts the signal-promoting TLR4-MyD88 complex and broadly suppresses the activities of multiple proinflammatory/proapoptotic pathways as well, shifting proinflammatory MyD88 signaling to a prosurvival mode. Constitutively active PP2Ac translocated with MyD88 into the nuclei of tolerant macrophages establishes the immunosuppressive pattern of chromatin modifications and represses chromatin remodeling to selectively silence proinflammatory genes, coordinating the MyD88-dependent inflammation control at both signaling and epigenetic levels under endotoxin-tolerant conditions. PMID- 23434515 TI - Community-based intervention packages facilitated by NGOs demonstrate plausible evidence for child mortality impact. AB - INTRODUCTION: Evidence exists that community-based intervention packages can have substantial child and newborn mortality impact, and may help more countries meet Millennium Development Goal 4 (MDG 4) targets. A non-governmental organization (NGO) project using such programming in Mozambique documented an annual decline in under-five mortality rate (U5MR) of 9.3% in a province in which Demographic and Health Survey (DHS) data showed a 4.2% U5MR decline during the same period. To test the generalizability of this finding, the same analysis was applied to a group of projects funded by the US Agency for International Development. Projects supported implementation of community-based intervention packages aimed at increasing use of health services while improving preventive and home-care practices for children under five. METHODS: All projects collect baseline and endline population coverage data for key child health interventions. Twelve projects fitted the inclusion criteria. U5MR decline was estimated by modelling these coverage changes in the Lives Saved Tool (LiST) and comparing with concurrent measured DHS mortality data. RESULTS: Average coverage changes for all interventions exceeded average concurrent trends. When population coverage changes were modelled in LiST, they were estimated to give a child mortality improvement in the project area that exceeded concurrent secular trend in the subnational DHS region in 11 of 12 cases. The average improvement in modelled U5MR (5.8%) was more than twice the concurrent directly measured average decline (2.5%). CONCLUSIONS: NGO projects implementing community-based intervention packages appear to be effective in reducing child mortality in diverse settings. There is plausible evidence that they raised coverage for a variety of high impact interventions and improved U5MR by more than twice the concurrent secular trend. All projects used community-based strategies that achieved frequent interpersonal contact for health behaviour change. Further study of the effectiveness and scalability of similar packages should be part of the effort to accelerate progress towards MDG 4. PMID- 23434516 TI - Bone response to biomimetic implants delivering BMP-2 and VEGF: an immunohistochemical study. AB - This animal study evaluated bone healing around titanium implant surfaces biomimetically coated with bone morphogenic protein-2 (BMP-2) and/or vascular endothelial growth factor (VEGF) by examining bone matrix proteins and mineralisation. Five different implant surfaces were established: acid-etched surface (AE), biomimetic calcium phosphate surface (CAP), BMP-2 loaded CAP surface, VEGF loaded CAP surface and dual BMP-2 + VEGF loaded CAP surface. The implants were inserted into calvariae of adult domestic pigs. For the comparison of osteoconductive capacity of each surface, bone mineral density and expression of bone matrix proteins (collagen I, BMP-2/4, osteocalcin and osteopontin) inside defined chambers around the implant were assessed using light microscopy and microradiography and immunohistochemical analysis at 1, 2 and 4 weeks. In the both groups delivering BMP-2, the bone mineral density was significantly enhanced after 2 weeks and the highest value was measured for the group BMP + VEGF. In the group VEGF, collagen I and BMP-2/4 expressions were significantly up-regulated at the first and second weeks. The percentage of BMP-2/4 positive cells in the group BMP + VEGF was significantly enhanced compared with the groups AE and CAP at the second week. Although the highest osteocalcin and osteopontin expression values were observed for the group BMP + VEGF after 2 weeks, no statistically significant difference in osteocalcin and osteopontin expressions was found between all groups at any time. It was concluded that combined delivery of BMP-2 and VEGF favoured bone mineralisation and expression of important bone matrix proteins that might explain synergistic interaction between both growth factors. PMID- 23434517 TI - Pulmonary antrum radial-linear ablation for paroxysmal atrial fibrillation: interim analysis of a multicenter trial. AB - BACKGROUND: Substrate abnormality in pulmonary vein (PV) antrum plays a critical role in mechanism of atrial fibrillation (AF). The present study compares the strategy of PV antrum radial-linear (PAR) ablation to encircling PV isolation for paroxysmal AF. METHODS AND RESULTS: A total of 86 patients with paroxysmal AF were randomly assigned to PAR ablation group or PV isolation group. The average procedure time was 161+/-21 minutes in PAR ablation group and 199+/-39 minutes in PV isolation group (P<0.01). The average fluoroscopy time was 25+/-5 minutes in PAR ablation group and 32+/-9 minutes in PV isolation group (P<0.001). At 14 (15 12) months of follow-up after single procedure, 31 of 42 (74%) patients in PAR ablation group and 22 of 44 patients (50%) in PV isolation group had no recurrence of AF off antiarrhythmic drug (P=0.0249); and 36 of 42 patients (86%) in PAR ablation group and 26 of 44 patients (59%) in PV isolation group had no recurrence of AF with antiarrhythmic drug (P=0.006). In addition, PAR ablation resulted in greater reduction of left atrial diameter than encircling PV isolation. Multivariable Cox regression analysis showed that only ablation strategy was independently associated with AF recurrence (hazard ratio, 0.31; 95% confidence interval, 0.12-0.78; P=0.013). No major adverse event related to the procedures occurred. CONCLUSIONS: This study suggests that PAR ablation is a potentially effective strategy for treatment of paroxysmal AF warranting further investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org; Unique identifier: ChiCTR-TRC-11001191. PMID- 23434518 TI - Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8+ T cell function in vitro. AB - HIV infection is associated with elevated expression of IL-10 and PD-L1, contributing to impairment of T cell effector functions. In autoimmunity, tumor immunology, and some viral infections, Bregs modulate T cell function via IL-10 production. In this study, we tested the hypothesis that during HIV infection, Bregs attenuate CD8(+) T cell effector function, contributing to immune dysfunction. We determined that in vitro, TLR2-, TLR9-, and CD40L-costimulated Bregs from HIV(-) individuals exhibited a high frequency of cells expressing IL 10 and PD-L1. Compared with Bregs from HIV(-) individuals, a significantly higher percentage of Bregs from HIV(+) individuals spontaneously expressed IL-10 (P=0.0218). After in vitro stimulation with HIV peptides, Breg-depleted PBMCs from HIV(+) individuals exhibited a heightened frequency of cytotoxic (CD107a(+); P=0.0171) and HIV-specific CD8(+) T cells compared with total PBMCs. Furthermore, Breg depletion led to enhanced proliferation of total CD8(+) and CD107a(+)CD8(+) T cells (P=0.0280, and P=0.0102, respectively). In addition, augmented CD8(+) T cell effector function in vitro was reflected in a 67% increased clearance of infected CD4(+) T cells. The observed Breg suppression of CD8(+) T cell proliferation was IL-10-dependent. In HIV(+) individuals, Breg frequency correlated positively with viral load (r=0.4324; P=0.0095), immune activation (r=0.5978; P=0.0005), and CD8(+) T cell exhaustion (CD8(+)PD-1(+); r=0.5893; P=0.0101). Finally, the frequency of PD-L1-expressing Bregs correlated positively with CD8(+)PD-1(+) T cells (r=0.4791; P=0.0443). Our data indicate that Bregs contribute to HIV-infection associated immune dysfunction by T cell impairment, via IL-10 and possibly PD-L1 expression. PMID- 23434519 TI - Comparison of intracavitary brachytherapy and stereotactic body radiotherapy dose distribution for cervical cancer: in regard to Cengiz et al. PMID- 23434520 TI - Comparison of complete mitochondrial genomes of pine wilt nematode Bursaphelenchus xylophilus and Bursaphelenchus mucronatus (Nematoda: Aphelenchoidea) and development of a molecular tool for species identification. AB - We determined the complete mitochondrial genome sequences for Bursaphelenchus mucronatus, one species of pinewood nematode. The genome is a circular-DNA molecule of 14,583 bp (195 bp smaller than its congener Bursaphelenchus xylophilus) and contains 12 protein-coding genes (lacking atp8), 22 tRNA genes, and 2 rRNA genes encoded in the same direction, consistent with most other nematodes. Based on sequence comparison of mtDNA genomes, we developed a PCR based molecular assay to differentiate B. xylophilus (highly pathogenic) and B. mucronatus (relatively less virulent) using species-specific primers. The molecular identification system employs multiplex-PCR and is very effective and reliable for discriminating these Bursaphelenchus species, which are economically important, but difficult to distinguish based on morphology. The comparison of the mitochondrial genomes and molecular identification system of the two species of Bursaphelenchus spp. should provide a rich source of genetic information to support the effective control and management (quarantine) of the pine wilt disease caused by pinewood nematodes. PMID- 23434521 TI - Identification of somatic mutations in human prostate cancer by RNA-Seq. AB - RNA-Seq is a recently developed tool to characterize transcriptomes using a massively parallel sequencing technique. In spite of its broad usage in gene expression profiling, RNA-Seq can also be used to discover single nucleotide variants in transcribed regions. Here we report the result of an analysis of transcriptome sequencing data of 5 human prostate cancer tissues. A total of 116 disruptive mutations (frameshift indels or nonsynonymous nucleotide substitutions) in 92 genes are revealed with high confidence. Among these genes, several candidates are of particular interest. For example, a frameshift insertion/deletion (indel) is found in the coding region of TNFSF10, which disrupts the intact open reading frame and undermines the ability of TNFSF10 to induce apoptosis, in consequence promoting abnormal tumor progression. In summary, our findings demonstrate the use of RNA-Seq in somatic mutation screening, and provide a list of candidate genes which can be used in prostate cancer diagnosis and treatment. PMID- 23434522 TI - Anti-methicillin-resistant Staphylococcus aureus (MRSA) substance from the marine bacterium Pseudomonas sp. UJ-6. AB - A multivalent approach to discover a novel antibiotic substance against methicillin-resistant Staphylococcus aureus (MRSA), a marine bacterium, UJ-6, exhibiting an antibacterial activity against MRSA was isolated from seawater. The isolated strain was identified to be Pseudomonas sp. by the morphology, biochemical, and genetical analyses. The ethyl acetate extract of Pseudomonas sp. UJ-6 culture showed significant ant-MRSA activity. Bioassay-guided isolation of the extract using a growth inhibitory assay led to the isolation and identification of an active compound exhibiting anti-MRSA activity. Based on the analyses of the physicochemical and spectroscopic data including nuclear magnetic resonance and mass, the compound was identified to be 1-acetyl-beta-carboline. The minimum inhibitory concentration (MIC) of the compound was determined to be in a range of 32-128 MUg/ml against MRSA strains. The MIC values against MRSA were superior or equal to those of other natural compounds such as catechins, suggesting that 1-acetyl-beta-carboline would be a good candidate in applications of the treatment of MRSA infection. PMID- 23434524 TI - Hydrophilic interaction chromatography with aerosol-based detectors (ELSD, CAD, NQAD) for polar compounds lacking a UV chromophore in an intravenous formulation. AB - In this work, a high performance liquid chromatography (HPLC) method is reported for the separation and quantitation of a drug substance that is highly polar and lacking a chromophore in a mannitol intravenous (IV) formulation. Three polar stationary phases operated in hydrophilic interaction chromatography (HILIC) mode were evaluated in conjunction with an Alltech 800 ELSD detector. These columns were evaluated with respect to chromatographic properties such as buffer, pH and organic concentrations to identify the best stationary phase. The chromatographic method was then validated for the determination of mGlu2/3 receptor agonist (-) (1R, 4S, 5S, 6S)-4-Amino-2-sulfonylbicyclo [3.1.0] hexane-4,6-dicarboxylic acid (LY404039) content in a mannitol IV formulation with respect to linearity (R(2) of 0.9997), repeatability (%RSD of 0.36%), accuracy, solution stability (99.56% after 24h), specificity, intra-assay precision (%RSD 0.48%) and limit of detection (LOD, ~50 MUg/mL). In addition to the Alltech 800 ELSD detector, several other aerosol-based detectors were investigated for reproducibility, linearity and LOD. These additional detectors consisted of an Alltech 3300 evaporative light scattering detector (ELSD), a nano quantity analyte detector (NQAD) and a charged aerosol detector (CAD). Based on the data from this report, a feasible isocratic LC method was achieved using a TSKgel Amide-80 column with mobile phase conditions of 30% water with 0.2% trifluoroacetic acid (TFA) and 70% acetonitrile (ACN) using any of the four aerosol-based detectors for detection and quantitation. PMID- 23434523 TI - Evaluation of the cytotoxicity and genotoxicity of aristolochic acid I - a component of Aristolochiaceae plant extracts used in homeopathy. AB - The medicinal plants Aristolochia clematitis L. as well as Asarum europaeum L., representatives of the plant family Aristolochiaceae and mentioned in the German Homeopathic Pharmacopeia, contain aristolochic acid. We found that the mother tinctures of A. clematitis and A. europaeum inhibited DNA synthesis in human hepatoma HepG2 cells in a dose-dependent manner. One of the components of the plant extract, aristolochic acid I (AAI), is linked to the development of nephropathy and urothelial cancer in humans. Therefore, we also evaluated the cytotoxicity and genotoxicity of AAI in HepG2 cells. Cell proliferation was inhibited concentration-dependently by AAI using BrdU-ELISA and colony forming assay. AAI formed DNA adducts (measured by (32)P-postlabeling), induced chromosomal aberrations (micronuclei) and DNA strand breaks. DNA damage induced by AAI led to an arrest of cells in the S-phase which was associated with the increased expression of p53 and p21 proteins. The results are discussed under consideration of former studies. PMID- 23434525 TI - Simultaneous quantitation of 3-n-butylphthalide (NBP) and its four major metabolites in human plasma by LC-MS/MS using deuterated internal standards. AB - 3-n-Butylphthalide (NBP) is a cardiovascular drug widely used in China for the treatment of cerebral ischemic stroke. Our previous study showed that NBP underwent extensive metabolism in humans and that 10-keto-NBP (M2), 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2) and NBP-11-oic acid (M5-2) were the major circulating metabolites. A better understanding of the plasma exposures of NBP and its four major metabolites is crucial to supporting the safety evaluation, good clinic practice and discovery of new antistroke drugs. Herein, a liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of NBP, M2, M3-1, M3-2, and M5-2 in human plasma. To improve assay sensitivity and achieve simultaneous analysis, M3-1 and M5-2 were monitored in (-)ESI (electrospray) mode within the first 3.5 min and NBP, M2, and M3-2 thereafter in (+)ESI mode. Deuterated internal standards for all analytes were synthesized to compensate for the impact of matrix effects. Based on the vast differences in physicochemical properties among the five analytes and the necessary baseline separation of two isomers (i.e., M3-1 and M3-2), gradient elution comprising a mobile phase of methanol-acetonitrile-5 mM ammonium acetate was used after methanol-induced protein precipitation of plasma samples. The developed method was linear in the concentration range of 3.00-800 ng/ml for NBP and M2, and 3.00-2400 ng/ml for M3-1, M3-2, and M5-2. The lower limit of quantitation was 3.00 ng/ml for each analyte. The intra- and inter-day accuracy and precision were within acceptable limits (+/-15%) at all concentrations. The method was successfully applied to characterize the pharmacokinetic profiles of NBP and its major metabolites following a single oral administration of 200mg NBP to healthy volunteers. PMID- 23434526 TI - High performance liquid chromatography determination of prulifloxacin and five related impurities in pharmaceutical formulations. AB - A novel HPLC method for the simultaneous determination of Prulifloxacin, Ulifloxacin, its process impurities in a tablets formulation and Enrofloxacin, used as Internal Standard, is developed. The separation was successfully carried out with a new stationary phase, HILIC, under isocratic elution mode using ammonium acetate buffer (5 mM, pH 5.8) and acetonitrile (12:88, v/v) at a flow rate of 1.0 mL/min. Column was thermostated at 25 degrees C (+/-1 degrees C) and 20 MUL were injected for the analysis. Calibration curves were linear in the investigated range with correlation coefficient better than 0.9880, while the limit of quantifications ranged from 0.25 to 5 MUg/mL, depending from the analyte. The within and between batch precision (RSD%) values ranged from 0.11% to 13.9% while within and between batch trueness (bias%) values ranged from 14.0% to -11.3%. This method for the direct determination and quantification of process impurities in pharmaceutical formulations is suitable for routine analyses in quality control laboratories and was applied to evaluate for the first time, the presence and the quantities of cited analytes in commercially available formulation. PMID- 23434527 TI - A rapid liquid chromatography tandem mass spectrometry-based method for measuring propranolol on dried blood spots. AB - Propranolol, a non-selective beta blocker drug, is used in young infants and newborns for treating several heart diseases; its pharmacokinetics has been extensively evaluated in adult patients using extrapolation to treat pediatric population. The purpose of the present study was to develop and validate a method to measure propranolol levels in dried blood spots. The analysis was performed by using liquid chromatography/tandem mass spectrometry operating in multiple reaction monitoring mode. The calibration curve in matrix was linear in the concentration range of 2.5-200 MUg/L with correlation coefficient r=0.9996. Intra day and inter-day precisions and biases were less than 8.0% (n=10) and 11.5% (n=10) respectively. The recoveries ranged from 94 to 100% and the matrix effect did not result in a severe signal suppression. Propranolol on dried blood spot showed a good stability at three different temperatures for one month. This paper describes a micromethod for measuring propranolol levels on dried blood spot, which determines a great advantage in neonates or young infants during pharmacokinetic studies because of less invasive sampling and small blood volume required. PMID- 23434528 TI - Azide-alkyne cycloaddition en route to 1H-1,2,3-triazole-tethered 7 chloroquinoline-isatin chimeras: synthesis and antimalarial evaluation. AB - We describe the synthesis and antimalarial activities of 1H-1,2,3-triazole tethered 7-chloroquinoline-isatin hybrids. Activity against cultured parasites was dependent on the C-5 substituent of the isatin ring as well as the alkyl chain length between the isatin and 7-chloroquinoline moieties. Compound 8h, with an optimum alkyl chain length (n = 3) and a chloro substituent at the C-5 position of the isatin ring, displayed the best activity among the test compounds, with IC50 value of 1.21 MUM against cultured W2-strain Plasmodium falciparum. PMID- 23434529 TI - Synthesis of nordihydroguaiaretic acid derivatives and their bioactivities on S. pombe and K562 cell lines. AB - Nordihydroguaiaretic acid (NDGA) and its synthetic analogues are potentially useful in treating diseases related to cancers, diabetes, viral and bacterial infections, and inflammation. In this paper, we report the optimal synthetic methods and the bioactivity study of terameprocol 2, NDGA derivative 3, and its cyclized analogue 4. The IC50 of these three compounds 2, 3 and 4 on the growth metabolism of Schizosacchromyces pombe and K562 cell lines were determined by microcalorimetry. The preliminary results showed that the compounds 2, 3 and 4 possessed good inhibition activities on S. pombe and K562 cell lines, and exhibited bidirectional biological effect and Hormesis effect. In particular, terameprocol 2 was found to possess the most potent inhibitory effect on K562 cell lines. PMID- 23434530 TI - Susceptibility of clinical isolates of Leishmania aethiopica to miltefosine, paromomycin, amphotericin B and sodium stibogluconate using amastigote-macrophage in vitro model. AB - Cutaneous Leishmaniasis (CL) caused by Leishmania aethiopica is a public health and social problem with a sequel of severe and mutilating skin lesions. It is manifested in three forms: localized CL (LCL), mucosal CL (MCL) and diffuse CL (DCL). Unresponsiveness to sodium stibogluconate (Sb(V)) is common in Ethiopian CL patients. Using the amastigote-macrophage in vitro model the susceptibility of 24 clinical isolates of L. aethiopica derived from untreated patients was investigated. Eight strains of LCL, 9 of MCL, and 7 of DCL patients together with a reference strain (MHOM/ET/82/117/82) were tested against four antileishmanial drugs: amphotericin B, miltefosine, Sb(V) and paromomycin. In the same order of drugs, IC(50) (MUg/ml+/-SD) values for the 24 strains tested were 0.16+/-0.18, 5.88+/-4.79, 10.23+/-8.12, and 13.63+/-18.74. The susceptibility threshold of isolates originating from the 3 categories of patients to all 4 drugs was not different (p>0.05). Maximal efficacy was superior for miltefosine across all the strains. Further susceptibility test could validate miltefosine as a potential alternative drug in cases of sodium stibogluconate treatment failure in CL patients. PMID- 23434531 TI - Low frequency ultrasound and UV-C for elimination of pathogens in recirculating aquaculture systems. AB - Low frequency ultrasound (LFUS) was evaluated as a novel disinfection technique within recirculating aquaculture systems both individually and combined with UV C. Dose-dependent inactivation rates were determined for the total viable counts and model organisms representing different taxa of common fish parasites: the ciliate Paramecium sp., second larval stage (L2) of the nematode Anguillicola crassus and metanauplii of Artemia sp. Application of LFUS up to 19 kJ/L did not reduce the number of colony forming units (CFU), whilst UV-C irradiation was highly effective. Pre-treatment with LFUS reduced the mean size of suspended solids in aquaculture water and thus increased the germicidal effect of UV-C by up to 0.6 log units. LFUS was effective against the eukaryotic organisms, and the dose-dependent inactivation could be well described by functions of an exponential decay. However, the efficiency of LFUS differed greatly between species. A LFUS dose of 1.9 kJ/L (consumed energy) was sufficient to inactivate Artemia by 99%, but a ten times higher dose was necessary to inactivate 95% and 81% of Paramecium and Anguillicola larvae, respectively. In clear water, the energetic efficiency of UV-C (emitted by a low pressure lamp) against Paramecium and Anguillicola larvae was higher compared to LFUS, but LFUS was more efficient against Artemia. However, the efficiency of LFUS against ciliates or nematode larvae would be similar or even higher than UV-C in highly turbid water or if less efficient medium pressure lamps are used. This study shows that LFUS can be applied safely at energy densities that are effective against a wide range of parasites like ciliates, nematodes and crustaceans. The combination of LFUS and UV-C could provide an appropriate water treatment with regards to all relevant pathogens in recirculating aquaculture systems. PMID- 23434532 TI - New dental radiology procedure codes in perspective. PMID- 23434533 TI - Adiabatic and fast passage ultra-wideband inversion in pulsed EPR. AB - We demonstrate that adiabatic and fast passage ultra-wideband (UWB) pulses can achieve inversion over several hundreds of MHz and thus enhance the measurement sensitivity, as shown by two selected experiments. Technically, frequency-swept pulses are generated by a 12 GS/s arbitrary waveform generator and upconverted to X-band frequencies. This pulsed UWB source is utilized as an incoherent channel in an ordinary pulsed EPR spectrometer. We discuss experimental methodologies and modeling techniques to account for the response of the resonator, which can strongly limit the excitation bandwidth of the entire non-linear excitation chain. Aided by these procedures, pulses compensated for bandwidth or variations in group delay reveal enhanced inversion efficiency. The degree of bandwidth compensation is shown to depend critically on the time available for excitation. As a result, we demonstrate optimized inversion recovery and double electron electron resonance (DEER) experiments. First, virtually complete inversion of the nitroxide spectrum with an adiabatic pulse of 128ns length is achieved. Consequently, spectral diffusion between inverted and non-inverted spins is largely suppressed and the observation bandwidth can be increased to increase measurement sensitivity. Second, DEER is performed on a terpyridine-based copper (II) complex with a nitroxide-copper distance of 2.5nm. As previously demonstrated on this complex, when pumping copper spins and observing nitroxide spins, the modulation depth is severely limited by the excitation bandwidth of the pump pulse. By using fast passage UWB pulses with a maximum length of 64ns, we achieve up to threefold enhancement of the modulation depth. Associated artifacts in distance distributions when increasing the bandwidth of the pump pulse are shown to be small. PMID- 23434534 TI - Genetic linkage of blaNDM among nosocomial isolates of Acinetobacter baumannii from a tertiary referral hospital in northern India. AB - The aim of this study was to evaluate the emergence of blaNDM-1 among clinical isolates of Acinetobacter baumannii isolated from a north Indian tertiary care hospital and to assess the gene cassettes and resistance determinants located within them. In total, 74 A. baumannii were screened for MBL production by the imipenem-EDTA method and were characterised for antibiotic sensitivity. PCR was performed to detect the presence of blaNDM and the co-existence of ESBL and AmpC genes. NDM-producing isolates were typed by ERIC-PCR, and the association of integrons with blaNDM-1 and the presence of gene cassettes were determined using specific primers. The genetic location of blaNDM in ISAba125 was also determined. Transformation was performed using a heat-shock method. Three isolates were found to harbour blaNDM, all of which co-produced blaEBC, blaDHA and blaCIT AmpC beta lactamases. All MBL-producers showed resistance to cephalosporins, carbapenems, aminoglycosides, fluoroquinolones and tigecycline but were susceptible to polymyxin B. Presence of class 1 integrons was demonstrated in all three blaNDM harbouring isolates, whilst linkage between the integron and blaNDM could not be established. Detection of gene cassettes revealed the presence of dihydrofolate reductase (dhfr) and aminoglycoside 6'-N-acetyltransferase [aac(6')] genes. Presence of blaNDM in ISAba125 was also observed. These findings suggest that ISAba125 appears to be the main genetic component for dissemination of blaNDM in A. baumannii. The association of blaNDM-1 with ISAba125 and the mobility of other multiresistance region (gene cassette)-carrying integrons provide an easy way to cross species barriers and reach a level that places the patients at risk. PMID- 23434535 TI - Use of veterinary antimicrobial agents from 2005 to 2010 in Japan. PMID- 23434536 TI - Description of plasmid pSM52, harbouring the gene for the Smr efflux pump, and its involvement in resistance to biocides in a meticillin-resistant Staphylococcus aureus strain. PMID- 23434538 TI - A pilot trial of the iPad tablet computer as a portable device for visual acuity testing. AB - We evaluated the accuracy of an app for the iPad tablet computer (Eye Chart Pro) as a portable method of visual acuity (VA) testing. A total of 120 consecutive patients (240 eyes) underwent visual acuity test with an iPad 2 and a conventional light-box chart. The logMAR VA results from the iPad were significantly higher than those from the light-box (P < 0.001). Bland-Altman analysis revealed a mean difference (bias) of 0.02 logMAR units between the VA results from the iPad chart and the light-box chart, with 95% limits of agreement of -0.14 to 0.19. Two groups of patients were defined: in Group 1 there were 182 eyes with VA better than 0.1 according to the light-box VA test. The median logMAR VA by the iPad was 0.54 and by the light-box chart it was 0.52; there was no significant difference between them (P = 0.69). In Group 2 there were 58 eyes with VA equal to or worse than 0.1 according to the light-box VA test. The median logMAR VA by the iPad was 1.26 and was 1.10 by the light box; the result from the iPad was significantly lower (P < 0.001). The Eye Chart Pro app installed on the iPad is reliable for VA testing only when the Snellen VA is better than 0.1 (20/200). PMID- 23434539 TI - An evaluation of preventive sensor technology for dementia care. AB - We evaluated a commercially-available monitoring system for older people with dementia living at home. The system was designed to detect problems before they require crisis intervention. Fourteen clients from two healthcare organisations in the Netherlands used the system over a 9-month period. The formal and informal caregivers were interviewed, project group meetings were observed, nurse diaries were analysed and a cost analysis performed. Clients and informal caregivers reported enhanced feelings of safety and security as a result of having the system installed in the home. The system appeared to reduce the burden of care on the informal caregiver and had the potential to allow people to live at home for longer. There were financial savings for clients staying at home with the technology compared with the costs of staying in a nursing home: for 10 clients living at home for 2 months, the savings were 23,665 euro. The study showed that the monitoring system represents a potentially useful early warning system to detect a situation before it requires emergency intervention. PMID- 23434540 TI - Rapid and accurate identification of poliovirus strains used for vaccine production. AB - In the context of eradication of poliomyelitis the World Health Organization stimulates the development of inactivated polio vaccines based on attenuated virus strains. In addition to vaccine development, tests have to be designed to assess the vaccine quality. An important test is the identification test for poliovirus strains that are used for the vaccine production. A rapid and accurate PCR method with fluorescent probes has been developed to identify unequivocally the vaccine-specific poliovirus strains, such as Mahoney, MEF-1, Saukett H, Sabin type 1, Sabin type 2 and Sabin type 3. PMID- 23434537 TI - The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. AB - Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. GH/Insulin/insulin-like growth factor-1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases lifespan in nematodes, fruit flies and mice. The life-prolonging effects of caloric restriction are likely related to decreasing IGF-1 levels. Evidence has emerged that antidiabetic drugs are promising candidates for both lifespan extension and prevention of cancer. Thus, antidiabetic drugs postpone spontaneous carcinogenesis in mice and rats, as well as chemical and radiation carcinogenesis in mice, rats and hamsters. Furthermore, metformin seems to decrease the risk for cancer in diabetic patients. PMID- 23434541 TI - ATP-P2X4 signaling mediates NLRP3 inflammasome activation: a novel pathway of diabetic nephropathy. AB - Tubulointerstitial inflammation plays a key role in the development of diabetic nephropathy (DN). Cytokines in the IL-1 family are the key pro-inflammatory cytokines of tubulointerstitial inflammation. Extracellular ATP can cause P2X receptors to activate the NOD-like receptor 3 (NLRP3) inflammasome and cause IL 1beta and IL-18 maturation and release. We investigated the role of ATP-P2X4 signaling in NLRP3 inflammasome activation and renal interstitial inflammation characteristic of DN. Ex vivo studies, P2X4 showed increased expression in renal tubule epithelial cells in patients with nephropathy due to type 2 diabetes compared to those in the control group. Linear correlation analysis shows that P2X4 expression was positively related with urine IL-1beta and IL-18 levels. Moreover, P2X4 expression was co-localized with NLRP3, IL-1beta, and IL-18 expression. In vitro culture experiments showed NLRP3 protein expression, cleavage of caspase-1 and IL-1beta, and release of IL-1beta, IL-18 and ATP in HK 2 cells significantly increased after high glucose stimulation. However, apyrase, which consumes extracellular ATP, completely blocked the changes caused by high glucose. The P2 receptor antagonist suramin, P2X receptor antagonist TNP-ATP, P2X4 selective antagonist 5-BDBD, and P2X4 gene silencing attenuated NLRP3 expression, cleavage of caspase-1 and IL-1beta, and release of IL-1beta and IL-18 induced by high glucose. Taken together, these results suggest that ATP-P2X4 signaling mediates high glucose-induced activation of the NLRP3 inflammasome, regulates IL-1 family cytokine secretion, and causes the development of tubulointerstitial inflammation in DN. PMID- 23434542 TI - Rapid characterisation of the inherent dispersibility of respirable powders using dry dispersion laser diffraction. AB - Understanding and controlling powder de-agglomeration is of great importance in the development of dry powder inhaler (DPI) products. Dry dispersion laser diffraction measures particle size readily under controlled dispersing conditions, but has not been exploited fully to characterise inherent powder dispersibility. The aim of the study was to utilise particle size-dispersing pressure titration curves to characterise powder cohesivity and ease of de agglomeration. Seven inhaled drug/excipient powders (beclometasone dipropionate, budesonide, fluticasone propionate, lactohale 300, salbutamol base, salmeterol xinafoate and tofimilast) were subjected to a range of dispersing pressures (0.2 4.5 Bar) in the Sympatec HELOS/RODOS laser diffractometer and particle size measurements were recorded. Particle size-primary pressure data were used to determine the pressures required for complete de-agglomeration. The latter were employed as an index of the cohesive strength of the powder (critical primary pressure; CPP), and the curves were modelled empirically to derive the pressure required for 50% de-agglomeration (DA50). The powders presented a range of CPP (1.0-3.5 Bar) and DA50 (0.23-1.45 Bar) which appeared to be characteristic for different mechanisms of powder de-agglomeration. This approach has utility as a rapid pre-formulation tool to measure inherent powder dispersibility, in order to direct the development strategy of DPI products. PMID- 23434543 TI - Impact of physical parameters on particle size and reaction yield when using the ionic gelation method to obtain cationic polymeric chitosan-tripolyphosphate nanoparticles. AB - Ionic gelation is the most frequently used method to obtain chitosan tripolyphosphate nanoparticles due to its simplicity and because it does not generate waste solvents in the samples prepared. This paper presents a study of the physical factors involved in this method for obtaining nanoparticles in order to determine which of them significantly influences the particle size of polymeric nanoparticles made from low-molecular-weight chitosan, without any additional chemical treatment, with the aim of standardising and optimising the method conditions, in addition to establishing the reaction yield. The results indicate that stirring speed during ionic gelation reaction is decisive for the size of the nanoparticles obtained. Furthermore, it thus follows that the stirring speed during ionic gelation significantly affects reaction yield, and therefore, by manipulating this parameter a greater proportion of nanoparticles of a given size range can be obtained. PMID- 23434544 TI - A quality by design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction. AB - Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular within pharmaceutical industry. Although roll compaction has become an established technique for dry granulation, the influence of material properties is still not fully understood. In this study, a quality by design (QbD) approach was utilized, not only to understand the influence of different qualities of mannitol and dicalcium phosphate (DCP), but also to predict critical quality attributes of the drug product based solely on the material properties of that filler. By describing each filler quality in terms of several representative physical properties, orthogonal projections to latent structures (OPLS) was used to understand and predict how those properties affected drug product intermediates as well as critical quality attributes of the final drug product. These models were then validated by predicting product attributes for filler qualities not used in the model construction. The results of this study confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, is not prominent when using brittle materials. Some qualities of these fillers actually demonstrated improved compactability following roll compaction. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study revealed that granules from these qualities were more poor flowing than the corresponding powder blends, which was not seen for granules from traditional qualities. The QbD approach used in this study could be extended beyond fillers. Thus any new compound/ingredient would first be characterized and then suitable formulation characteristics could be determined in silico, without running any additional experiments. PMID- 23434546 TI - Depersonalization/derealization during acute social stress in social phobia. AB - The present study aimed at investigating how frequently and intensely depersonalization/derealization symptoms occur during a stressful performance situation in social phobia patients vs. healthy controls, as well as testing hypotheses about the psychological predictors and consequences of such symptoms. N=54 patients with social phobia and N=34 control participants without mental disorders were examined prior to, during, and after a standardized social performance situation (Trier Social Stress Test, TSST). An adapted version of the Cambridge Depersonalization Scale was applied along with measures of social anxiety, depression, personality, participants' subjective appraisal, safety behaviours, and post-event processing. Depersonalization symptoms were more frequent in social phobia patients (92%) than in controls (52%). Specifically in patients, they were highly positively correlated with safety behaviours and post event-processing, even after controlling for social anxiety. The role of depersonalization/derealization in the maintenance of social anxiety should be more thoroughly recognized and explored. PMID- 23434545 TI - Parenting practices, interpretive biases, and anxiety in Latino children. AB - A number of factors are believed to confer risk for anxiety development in children; however, cultural variation of purported risk factors remains unclear. We examined relations between controlling and rejecting parenting styles, parental modeling of anxious behaviors, child interpretive biases, and child anxiety in a mixed clinically anxious (n=27) and non-clinical (n=20) sample of Latino children and at least one of their parents. Families completed discussion based tasks and questionnaires in a lab setting. Results indicated that child anxiety was: linked with parental control and child interpretative biases, associated with parental modeling of anxious behaviors at a trend level, and not associated with low parental acceptance. Findings that controlling parenting and child interpretive biases were associated with anxiety extend current theories of anxiety development to the Latino population. We speculate that strong family ties may buffer Latino children from detrimental effects of perceived low parental acceptance. PMID- 23434547 TI - Investigation on the effect of zeolite precursor on the formation process of MCM 41 containing zeolite Y building units. AB - The formation process of MCM-41 containing zeolite Y building units has been investigated by UV Raman spectroscopy, (29)Si and (27)Al MAS NMR spectroscopy, X ray diffraction (XRD), N2 adsorption and electron microscopy (SEM and TEM). It is found that the precursor containing zeolite Y secondary building units promotes the formation of a metastable mesopore structure just after mixing the zeolite precursors with CTAB. In contrast, the low-polymerized aluminosilicates and well crystallized zeolite crystals cannot be assembled with CTAB at this stage. The result supports that the zeolite secondary building units should promote to the formation of the mesopore wall. This has been ascribed to its high anionic charge density as well as the appropriate multidentate coordination. Lowering down the pH value to 9.3 facilitates the further polymerization of the aluminosilicate species to build up a stable mesoporous phase. PMID- 23434548 TI - Interaction study of ciprofloxacin with human telomeric DNA by spectroscopy and molecular docking. AB - The interaction of ciprofloxacin (CIP) with human telomeric DNA was studied in vitro using multi-spectroscopy and molecular modeling methods. The hypochromic effect with a red shift in ultraviolet (UV) absorption indicated the occurrence of the interaction between CIP and DNA. The fluorescence quenching of CIP was observed with the addition of DNA and was proved to be the static quenching. The binding constant was found to be 9.62*10(4) L mol(-1). Electrospray ionization mass spectrometry (ESI-MS) result further confirmed the formation of 1:1 non covalent complex between DNA and CIP. Combined with the UV melting results, circular dichroism (CD) results confirmed the existence of groove binding mode, as well as conformational changes of DNA. Molecular docking studies illustrated the visual display of the CIP binding to the GC region in the minor groove of DNA. Specific hydrogen bonds and van der Waals forces were demonstrated as main acting forces between CIP and guanine bases of DNA. PMID- 23434549 TI - Molecular inhibitory mechanism of tricin on tyrosinase. AB - Tricin was evaluated as a type of tyrosinase inhibitor with good efficacy compared to arbutin. Tricin functioned as a non-competitive inhibitor of tyrosinase, with an equilibrium constant of 2.30 mmol/L. The molecular mechanisms underlying the inhibition of tyrosinase by tricin were investigated by means of circular dichroism spectra, fluorescence quenching and molecular docking. These assays demonstrated that the interactions between tricin and tyrosinase did not change the secondary structure. The interaction of tricin with residues in the hydrophobic pocket of tyrosinase was revealed by fluorescence quenching; the complex was stabilized by hydrophobic associations and hydrogen bonding (with residues Asn80 and Arg267). Docking results implied that the possible inhibitory mechanisms may be attributed to the stereospecific blockade effects of tricin on substrates or products and flexible conformation alterations in the tyrosinase active center caused by weak interactions between tyrosinase and tricin. The application of this type of flavonoid as a tyrosinase inhibitor will lead to significant advances in the field of depigmentation. PMID- 23434550 TI - Vibrational spectroscopy of the phosphate mineral lazulite--(Mg, Fe)Al2(PO4)2.(OH)2 found in the Minas Gerais, Brazil. AB - This research was done on lazulite samples from the Gentil mine, a lithium bearing pegmatite located in the municipality of Mendes Pimentel, Minas Gerais, Brazil. Chemical analysis was carried out by electron microprobe analysis and indicated a magnesium rich phase with partial substitution of iron. Traces of Ca and Mn, (which partially replaced Mg) were found. The calculated chemical formula of the studied sample is: (Mg0.88, Fe0.11)Al1.87(PO4)2.08(OH)2.02. The Raman spectrum of lazulite is dominated by an intense sharp band at 1060 cm(-1) assigned to PO stretching vibrations of of tetrahedral [PO4] clusters presents into the HPO4(2-) units. Two Raman bands at 1102 and 1137 cm(-1) are attributed to both the HOP and PO antisymmetric stretching vibrations. The two infrared bands at 997 and 1007 cm(-1) are attributed to the nu1PO4(3-) symmetric stretching modes. The intense bands at 1035, 1054, 1081, 1118 and 1154 cm(-1) are assigned to the nu3PO4(3-) antisymmetric stretching modes from both the HOP and tetrahedral [PO4] clusters. A set of Raman bands at 605, 613, 633 and 648 cm(-1) are assigned to the nu4 out of plane bending modes of the PO4, HPO4 and H2PO4 units. Raman bands observed at 414, 425, 460, and 479 cm(-1) are attributed to the nu2 tetrahedral PO4 clusters, HPO4 and H2PO4 bending modes. The intense Raman band at 3402 and the infrared band at 3403 cm(-1) are assigned to the stretching vibration of the OH units. A combination of Raman and infrared spectroscopy enabled aspects of the molecular structure of the mineral lazulite to be understood. PMID- 23434551 TI - Vibrational analysis of 4-chloro-3-nitrobenzonitrile by quantum chemical calculations. AB - In the present study, the experimental and theoretical harmonic and anharmonic vibrational frequencies of 4-chloro-3-nitrobenzonitrile were investigated. The experimental FT-IR (400-4000 cm(-1)) and MU-Raman spectra (100-4000 cm(-1)) of the molecule in the solid phase were recorded. Theoretical vibrational frequencies and geometric parameters (bond lengths and bond angles) were calculated using ab initio Hartree Fock (HF), density functional B3LYP and M06-2X methods with 6-311++G(d,p) basis set by Gaussian 09 W program, for the first time. The assignments of the vibrational frequencies were performed by potential energy distribution (PED) analysis by using VEDA 4 program. The theoretical optimized geometric parameters and vibrational frequencies were compared with the corresponding experimental data, and they were seen to be in a good agreement with each other. Also, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were found. PMID- 23434552 TI - Selective spectrofluorimetric determination of sulfide ion using manganese doped ZnS quantum dots as luminescent probe. AB - This work reports a spectrofluorimetric method for selective and sensitive determination of sulfide ion in aqueous solution. The ultra-small zinc sulfide quantum dots (QDs) doped with manganese (ZnS:Mn) were synthesized by using a simple and fast procedure based on the co-precipitation of nanoparticles in aqueous solution in the presence of 2-mercaptoethanol, as capping agent. The nanoparticles have exhibited two strong fluorescent emissions at about 424 and 594 nm. Luminescent surface-capped ZnS:Mn QDs, with particle size below 5 nm, have been applied for determination of sulfide anions in water samples. Under the optimum conditions, the fluorescence intensity of ZnS:Mn QDs is linearly proportional to the sulfide ion concentration in the range 1.2*10(-6) to 2.6*10( 5) mol L(-1) with a detection limit as 3.3*10(-7) mol L(-1). The relative standard deviation for five replicate measurements (for 8.0*10(-6) mol L(-1) of S(2-)) was obtained to be 2.6%. It was founded that the interference of the other anions was negligible on the quantitive determination of sulfide ion. PMID- 23434553 TI - Structural investigations of aroylhydrazones derived from nicotinic acid hydrazide in solid state and in solution. AB - Structural forms of aroylhydrazones derived from nicotinic acid hydrazide have been studied in the solid state by FT-IR spectroscopy and in solution by NMR, UV Vis and ATR spectroscopy. The studied compounds were N'-benzylidene-3 pyridinecarbohydrazide (1), N'-(2,4-dihydroxyphenylmethylidene)-3 pyridinecarbohydrazide (2), N'-(5-chloro-2-hydroxyphenylmethylidene)-3 pyridinecarbohydrazide (3), and N'-(3,5-dichloro-2 hydroxymethoxyphenylmethylidene)-3-pyridinecarbohydrazide (4). The compound 1 adopted the most stable ketoamine form (form I, -CO-NH-N=C-) in the solid state as well as in various organic solvents. In mixtures of organic solvents with water the UV-Vis and ATR spectra implied intermolecular hydrogen bonding of 1 with water molecules. The presence of both tautomeric forms I and II (form II, COH=N-N=C-) was proposed for the solid substance and highly concentrated solutions of 2, whereas form I was detected as the predominant one in diluted solutions. For compounds 3 and 4 a coexistence of forms I and III (form III, -CO NH-NH-C=C-CO-) was noticed in the solid state and in polar protic organic solvents. The conversion to form III was induced by increasing the water content in the solvent mixtures. This process was the most pronounced for compound 4. When exposed to daylight, an appearance of a new band was observed during time in the UV-Vis spectrum of 4 in organic solvent/water 1/1 mixtures, which implied that tautomeric interconversion was most likely followed by E/Z isomerisation. PMID- 23434554 TI - Spectral, thermal and electrochemical investigation of carbohydrazone derived ionophore as Fe(III) ion selective electrode. AB - Dibenzoylmethane bis(carbohydrazone) (BMBC) has been synthesized and structurally characterized on the basis of IR, (1)H NMR, mass, UV spectra and thermogravimetric analyses. BMBC has been analysed electrochemically and explored as new N, N Schiff base. It plays the role of an excellent ion carrier in the construction of iron(III) ion selective membrane sensor. This sensor shows very good selectivity and sensitivity towards iron ion over a wide variety of cations, including alkali, alkaline earth, transition and heavy metal ions. The response mechanism was discussed in the view of UV-spectroscopy and Electrochemical Impedance Spectroscopy (EIS). The proposed sensor was successfully used for the determination of iron in different samples. PMID- 23434555 TI - Sensitive and selective detection of trace copper in standard alloys, food and biological samples using a bulk optode based on N,N'-(4,4'-ethylene biphenyl) bis(3-methoxy salicylidine imine) as neutral carrier. AB - In this paper, an optical sensing film has been proposed for sensitive determination of copper (II) ion in aqueous solutions. The copper sensing membrane was prepared by incorporating N,N'-(4,4'-ethylene biphenyl) bis(3 methoxy salicylidine imine) as ionophore in the plasticized PVC membrane containing bis(2-ethylhexyl) sebacate (DOS) as plasticizer. This proposed membrane works on the basis of a cation-exchange mechanism and shows a significant absorbance signal change on exposure to acetate buffer solution of pH 4.0 containing copper ion. The proposed sensing film displays a linear range of 0.01-32.0 MUg mL(-1) with a limit of detection 0.008 MUg mL(-1). Moreover, upon the introduction of a negatively charged lipophilic additive (oleic acid) into the membrane, the optode displayed enhanced sensitivity. In addition, satisfactory analytical sensing characteristics for determining copper (II) ion were obtained in terms of the selectivity, stability and reproducibility. The response time of the optode was less than 3 min, depending on the concentration of Cu(II) ions. The optode membrane has been applied to determine Cu(II) in various real samples. PMID- 23434556 TI - Spectroscopic evaluation for VO(II), Ni(II), Pd(II) and Cu(II) complexes derived from thiosemicarbazide: a special emphasis on EPR study and DNA cleavage. AB - Some thiosemicarbazide complexes were prepared and deliberately investigated by all allowed tools. The ligand coordinates as a mono negative bidentate towards VO(II) and Ni(II) as well as a neutral bidentate towards Pd(II) and Cu(II) ions. Electronic spectral data beside the magnetic measurements facilitate the structural geometry proposal. EPR spectra of Cu(II) and VO(II) complexes were recorded in their solid state. Spin Hamiltonian parameters and molecular orbital coefficient for Cu(II) and VO(II) complexes were calculated and supporting the octahedral geometry of Cu(II) complex and a square pyramidal for VO(II) one. The biological activity investigation was studied by the use of all prepared compounds. The VO(II) and Cu(II) complexes display the susceptible biotoxicity against a gram-positive bacterium. Also, Cu(II) complex displays the same toxicity against gram-negative bacteria used. The effect of all compounds on DNA were photographed. A successive degradation for the DNA target was observed with Pd(II) and Ni(II) complexes beside their original ligand. PMID- 23434557 TI - Gold nanorods-enhanced rhodamine B-permanganate chemiluminescence and its analytical application. AB - A novel enhanced chemiluminescence system was developed by applying gold nanorods (Au NRs) as catalysts in rhodamine B-permanganate reaction. Au NRs with three different aspect ratios were synthesized by seed mediated growth method and characterized by UV-Vis spectra and transmission electron microscopy. It was demonstrated that Au NRs have much higher catalytic effect than spherical nanoparticles on rhodamine B-permanganate chemiluminescence reaction. Among various sizes of Au NRs, those with average aspect ratio of 3.0 were found to have the most remarkable catalytic activity. As an analytical application of the new chemiluminescence system, albumin as a model protein was quantified based on its interaction with NRs. Albumin binds to Au NRs active surfaces and inhibits their catalytic action and therefore decreases the intensity of chemiluminescence. This diminution effect is linearly related to the concentration of the human and bovine serum albumin over the ranges of 0.45-90 and 0.75-123 nmol L(-1), respectively with the corresponding limits of detection of 0.18 and 0.30 nmol L(-1). The method was successfully applied to the determination of albumin in human and bovine serum samples. PMID- 23434558 TI - Spectroscopic studies on the binding interaction of phenothiazinium dyes toluidine blue O, azure A and azure B to DNA. AB - In this study a detailed characterization of the binding aspects of three phenothiazinium dyes, toluidine blue O (TBO), azure A and azure B with herring testes DNA is presented employing spectroscopic techniques. The absorbance and fluorescence properties of these dyes have been remarkably modified upon binding with DNA and the interaction is manifested through noncooperative binding as revealed form non-linear Scatchard plots with negative slopes at all binding ratios. The binding clearly revealed the high preference of TBO to DNA followed by the other two dyes azure A and azure B. The affinity of TBO was higher by about two times than that of the azures. From the series of studies using absorption, steady-state emission, the effect of ferrocyanide ion-induced steady state fluorescence quenching, fluorescence polarization anisotropy, circular dichroism, the mode of binding of these dyes to the DNA double helix has been substantiated to be principally intercalative in nature. The stoichiometry of the association of these dyes to DNA was determined by the continuous variation analysis of Job from fluorescence data. The conformational aspects of the interaction was delineated from circular dichroism studies wherein higher perturbation was observed with TBO. Hydrodynamic study using viscosity measurements of linear rod like DNA confirmed that the binding was intercalative and strongest for TBO and weaker for azure A and azure B. The utility of the present work lies in exploring the potential binding applicability of these dyes to DNA for their development as effective therapeutic agents. PMID- 23434560 TI - Vibrational spectra, crystal structure, DFT quantum chemical calculations and conformation of the hydrazo-bond in 6-methyl-3-nitro-2-(2 phenylhydrazinyl)pyridine. AB - The crystal and molecular structures of 6-methyl-3-nitro-2-(2 phenylhydrazinyl)pyridine (6-methyl-3-nitro-2-phenylhydrazopyridine) have been determined by X-ray diffraction and quantum chemical DFT analysis. The crystal is monoclinic, space group C2/c, with Z=8 formula units in the elementary unit cell of dimensions a=16.791(4), b=6.635(2), c=21.704(7)A, beta=100.54(3) degrees . The molecule consists of two nearly planar pyridine subunits. A conformation of the linking hydrazo-bridge CNHNHC is bend and the dihedral angle between the planes of the phenyl and pyridine rings is 88.2(5) degrees . The hydrogen bonding of the type NH...N and possibly also CH...O favors a dimer formation in the crystal structure. The dimers are further linked by a NH...O hydrogen bond, so forming a layer parallel to the ab plane. The molecular structure of the studied compound has been determined using the DFT B3LYP/6-311G(2d,2p) approach and compared to that derived from X-ray studies. The IR and Raman wavenumbers have been calculated for the optimized geometry of a possible monomer structural model but the possibility of the dimer formation through the NH...N hydrogen bond has also been considered. The structural and vibrational properties of the intra-molecular NH...O interaction are described. PMID- 23434559 TI - Sensitive and selective chemiluminescence assay for hydrogen peroxide in exhaled breath condensate using nanoparticle-based catalysis. AB - The catalytic properties of cubiform Co3O4 nanoparticles, alpha-Fe2O3 nanorods, and NiO nanoparticles were studied using both microarray method and FI-CL method. These nanoarticles exhibit high specific catalytic effects on the chemiluminescence (CL) reaction of the luminol-H2O2 system in alkaline solution compared with other common catalysts. A reaction mechanism is described. It provides new insights into the application of nanoparticle materials. The CL method based on the use of the Co3O4 nanoparticles is ultrasensitive and particularly selective. Therefore, it was applied to the analysis of H2O2 which can be determined in the concentration range from 1.0 nM to 1000 nM, with a detection limit of 0.3 nM. The relative standard deviation is 2.1% at 0.1 MUM of H2O2 (for n=11). The method was successfully applied to the determination of trace quantities of H2O2 in exhaled breath condensate (EBC) where it is a mediator of oxidative stress and a promising biomarker for diagnosing. The assay requires a small sample and no incubation time, and has an analytical runtime of <1 min. It is timesaving and suitable for larger studies. The levels of H2O2 in EBC are found to be elevated in healthy subjects (average=0.54 nM), rheum subjects (average=0.24 nM), and feverish subjects (average=0.16 nM). Our data suggested that the average H2O2 concentration of EBC from feverish subjects was significantly higher than healthy subjects and rheumatic subjects. PMID- 23434561 TI - HRTEM and FTIR investigation of nanosized zinc ferrite irradiated with 100 MeV oxygen ions. AB - Present work aims to investigate effect of 100 MeV oxygen ion irradiation on the vibrational modes of zinc ferrite nanoparticles. Nanosize zinc ferrite systems of different crystallite size ranging from 12-62 nm were irradiated at the fluence of 1*10(13) and 5*10(13) ions/cm(2). High resolution transmission electron micrograph study indicates the structural disorder induced by ion irradiation. Bands corresponding to various vibrational modes in Fourier transform infrared spectra exhibit changes and are affected by the crystallite size/microstructure of pristine samples. The irradiation induced changes are dominated for sample ZF1000. PMID- 23434562 TI - Structural, vibrational, electronic, NMR, NLO and reactivity analyses of (3Z)-3 (2-oxo-2-phenylethylidene)-1,3-dihydro-2H-indol-2-one (OPEDI) by ab initio HF and DFT calculations. AB - This study represents the vibrational, electronic, NMR, NLO, reactivity and structural aspects of (3Z)-3-(2-oxo-2-phenylethylidene)-1,3-dihydro-2H-indol-2 one (OPEDI). A detailed interpretation of the FT-IR, FT-Raman, UV and NMR spectra were reported. Theoretical calculations were performed by ab initio HF and density functional theory (DFT)/B3LYP method using 6-311++G(d,p) basis sets. The most preferred Z isomer (cis-configuration) was confirmed through PES scan studies. The vibrational wavenumbers and potential energy distribution (PED) of various normal modes were calculated. The lower frontier orbital energy gap and high dipole moment of OPEDI illustrates the high reactivity. The stability and charge delocalization of the molecule was studied by natural bond orbital (NBO) analysis. OPEDI exhibited good nonlinear optical activity and was 13 times greater than that of urea. Molecular electrostatic potential (MEP) was carried out for predicting the reactive sites. The NMR results indicated that the observed chemical shifts depend not only on the structure of the molecule being studied, but also on the solvent used. PMID- 23434563 TI - Vibrational spectra, UV-vis spectral analysis and HOMO-LUMO studies of 2,4 dichloro-5-nitropyrimidine and 4-methyl-2-(methylthio)pyrimidine. AB - The FT-IR and FT-Raman vibrational spectra of 2,4-dichloro-5-nitropyrimidine (DCNP) and 4-methyl-2-(methylthio)pyrimidine (MTP) have been recorded in the range 4000-400 and 3600-50 cm(-1), respectively. A detailed vibrational spectral analysis has been carried out and assignments of the observed fundamental bands have been proposed on the basis of peak positions and relative intensities. The optimized molecular geometry and vibrational frequencies in the ground state are calculated using density functional B3LYP method with 6-31+G(d,p) and 6 311++G(d,p) basis set combinations. With the help of specific scaling procedures, the observed vibrational wavenumbers in FT-IR and FT-Raman spectra are analyzed and assigned to different normal modes of the molecules. The predicted first hyperpolarizability reveals that the molecules are an attractive object for future studies of non-linear optical properties. And also HOMO-LUMO energy gap explains the eventual charge transfer interaction taking place within the molecules. UV-vis spectral analysis of the title compounds has been researched by theoretical calculations. The frontier orbital energies, absorption wavelengths (lambda), oscillator strengths (f) and excitation energies (E) studied using TD DFT (B3LYP) with 6-311++G(d,p) basis set are calculated in this work. PMID- 23434564 TI - Complex formation, thermal behavior and stability competition between Cu(II) ion and Cu(0) nanoparticles with some new azo dyes. Antioxidant and in vitro cytotoxic activity. AB - Four triazole and thiadiazole-based azo chromophores namely [(E)-4-((1H-1,2,4 triazol-3-yl)diazenyl)benzene-1,3-diol.(HL(1)), (E)-4-((5-(methylthio)-1H-1,2,4 triazol-3-yl)diazenyl)benzene-1,3-diol.(HL(2)), (E)-4-((1,3,4-thiadiazol-2 yl)diazenyl)benzene-1,3-diol.(HL(3)) and (E)-4-((5-mercapto-1,3,4-thiadiazol-2 yl)diazenyl)benzene-1,3-diol.(HL(4))] were synthesized and characterized by elemental analyses, IR, UV-Vis as well as mass spectroscopy. Cu(II) complexes of the investigated azo dyes have been synthesized and characterized by elemental analyses, IR, electronic and ESR spectra, magnetic susceptibility and thermogravimetric analyses. The bond lengths and bond angles have been calculated to confirm the geometry of the ligands and their Cu(II) complexes. The mode of interaction of the azodyes to copper nanoparticles was described as coordination mode of charged dye molecules on the colloidal Cu(0) surface through anchoring OH(-) group. The apparent association constants of the colloidal copper nanoparticles azodye complexes in solution were evaluated using the spectral method and compared with the formation constant of the Cu(II) azo complexes. The antitumor and antioxidant activities of the synthesized azo dyes and their Cu(II) azo complexes have been evaluated. PMID- 23434565 TI - Cooling and performance recovery of trained athletes: a meta-analytical review. AB - PURPOSE: Cooling after exercise has been investigated as a method to improve recovery during intensive training or competition periods. As many studies have included untrained subjects, the transfer of those results to trained athletes is questionable. METHODS: Therefore, the authors conducted a literature search and located 21 peer-reviewed randomized controlled trials addressing the effects of cooling on performance recovery in trained athletes. RESULTS: For all studies, the effect of cooling on performance was determined and effect sizes (Hedges' g) were calculated. Regarding performance measurement, the largest average effect size was found for sprint performance (2.6%, g = 0.69), while for endurance parameters (2.6%, g = 0.19), jump (3.0%, g = 0.15), and strength (1.8%, g = 0.10), effect sizes were smaller. The effects were most pronounced when performance was evaluated 96 h after exercise (4.3%, g = 1.03). Regarding the exercise used to induce fatigue, effects after endurance training (2.4%, g = 0.35) were larger than after strength-based exercise (2.4%, g = 0.11). Cold-water immersion (2.9%, g = 0.34) and cryogenic chambers (3.8%, g = 0.25) seem to be more beneficial with respect to performance than cooling packs (-1.4%, g= -0.07). For cold-water application, whole-body immersion (5.1%, g = 0.62) was significantly more effective than immersing only the legs or arms (1.1%, g = 0.10). CONCLUSIONS: In summary, the average effects of cooling on recovery of trained athletes were rather small (2.4%, g = 0.28). However, under appropriate conditions (whole-body cooling, recovery from sprint exercise), postexercise cooling seems to have positive effects that are large enough to be relevant for competitive athletes. PMID- 23434566 TI - The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release. AB - OBJECTIVES: Macrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood. METHODS: We used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared with matched peripheral blood monocytes from patients with RA (n=8). RESULTS: Using in silico pathway mapping, we found that pathways downstream of the cholesterol activated liver X receptors (LXRs) and those associated with Toll-like receptor (TLR) signalling were upregulated in SF macrophages. Macrophage differentiation and tumour necrosis factor alpha promoted the expression of LXRalpha. Furthermore, in functional studies we demonstrated that activation of LXRs significantly augmented TLR-driven cytokine and chemokine secretion. CONCLUSIONS: The LXR pathway is the most upregulated pathway in RA synovial macrophages and activation of LXRs by ligands present within SF augments TLR-driven cytokine secretion. Since the natural agonists of LXRs arise from cholesterol metabolism, this provides a novel mechanism that can promote RA synovitis. PMID- 23434567 TI - A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-alpha monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients. AB - OBJECTIVE: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-alpha monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. METHODS: A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13 gene IFNGS was used to measure the pharmacological effect of sifalimumab. RESULTS: The IFNGS was suppressed by a median of 53-66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. CONCLUSIONS: Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy. PMID- 23434568 TI - The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? AB - BACKGROUND: Studies suggest that periodontitis may be a risk factor for rheumatoid arthritis (RA). The purpose of this study was to determine whether periodontitis is associated with autoantibodies characteristic of RA. METHODS: Serum samples were tested for anti-cyclic citrullinated peptide (CCP), anti mutated citrullinated vimentin (MCV), anti-citrullinated alpha-enolase peptide-1 (CEP-1), anti-citrullinated vimentin (cit-vim), anti-citrullinated fibrinogen (cit-fib) and their uncitrullinated forms anti-CParg (negative control for anti CCP), anti-arginine-containing alpha-enolase peptide-1 (REP-1), anti-vimentin and anti-fibrinogen antibodies in patients with and without periodontitis, none of whom had RA. RESULTS: Periodontitis, compared with non-periodontitis, was associated with a normal frequency of anti-CCP and anti-MCV (~1%) but a higher frequency of positive anti-CEP-1 (12% vs 3%; p=0.02) and its uncitrullinated form anti-REP-1 (16% vs 2%; p<0.001). Positive antibodies against uncitrullinated fibrinogen and CParg were also more common among those with periodontitis compared to non-periodontitis patients (26% vs 3%; p<0.001, and 9% vs 3%; p=0.06). After adjusting for confounders, patients with periodontitis had 43% (p=0.03), 71% (p=0.002) and 114% (p<0.001) higher anti-CEP-1, anti-REP-1 and anti fibrinogen titres, compared with non-periodontitis. Non-smokers with periodontitis, compared with non-periodontitis, had significantly higher titres of anti-CEP-1 (103%, p<0.001), anti-REP-1 (91%, p=0.001), anti-vimentin (87%, p=0.002), and anti-fibrinogen (124%, p<0.001), independent of confounders, confirming that the autoantibody response in periodontitis was not due to smoking. CONCLUSIONS: We have shown that the antibody response in periodontitis is predominantly directed to the uncitrullinated peptides of the RA autoantigens examined in this study. We propose that this loss of tolerance could then lead to epitope spreading to citrullinated epitopes as the autoimmune response in periodontitis evolves into that of presymptomatic RA. PMID- 23434569 TI - Clustering of hand osteoarthritis progression and its relationship to progression of osteoarthritis at the knee. AB - OBJECTIVE: To investigate patterns of osteoarthritis (OA) progression within hand joints and the relationship between hand OA progression and progression of OA at the knee. METHODS: Radiographic progression over 6 years, defined as change in osteophytes or joint space narrowing above the smallest detectable change, was assessed on hand and knee radiographs of 236 hand OA patients participating in the Genetics, Arthrosis and Progression (GARP) sibling pair cohort study using OARSI atlas. Clustering of radiographic progression between hand joint groups (DIP, PIP, IP-1 and CMC-1) was assessed using chi(2) test. Symmetry, clustering by row and ray and familial aggregation in sibling pairs were also evaluated. The association between hand OA progression and progression of OA at the knee was assessed using generalised estimating equation analysis. RESULTS: There was clustering of OA progression between hand joint groups, the strongest relationship among DIP, PIP and IP-1 joints. Other patterns were symmetry (OR 4.7 (95% CI 3.3 to 6.5)) and clustering by row (OR 2.9 (95% CI 1.9 to 4.6)) but not by ray (OR 1.3 (95% CI 0.7 to 2.4)). There was familial aggregation of hand OA progression. Patients with progression of hand OA had a higher risk for radiographic change at the knee than those without hand OA progression (OR 2.3 (95% CI 1.3 to 4.0)). CONCLUSIONS: Progression of hand OA clusters between hand joint groups, especially between IP joints, and within sibling pairs. It is associated with OA change at the knee. These findings contribute to defining hand OA subsets and suggest a role for systemic factors. PMID- 23434570 TI - Adalimumab added to a treat-to-target strategy with methotrexate and intra articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial. AB - OBJECTIVES: An investigator-initiated, double-blinded, placebo-controlled, treat to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months. METHODS: In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naive ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6-9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward. RESULTS: Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7-5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7-4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index<=2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008 0.93) between E and bioaccumulation into Chironomus tentans. Given the abundance of stable isotope labeled references and their relatively easy analysis, the IDM has the potential to become a readily adoptable tool for estimating organic contaminants bioaccessibility in various matrices. PMID- 23434574 TI - Greenhouse gas emissions from a wheat-maize double cropping system with different nitrogen fertilization regimes. AB - Here, we report on a two-years field experiment aimed at the quantification of the emissions of nitrous oxide (N2O) and methane (CH4) from the dominant wheat maize double cropping system in North China Plain. The experiment had 6 different fertilization strategies, including a control treatment, recommended fertilization, with and without straw and manure applications, and nitrification inhibitor and slow release urea. Application of N fertilizer slightly decreased CH4 uptake by soil. Direct N2O emissions derived from recommended urea application was 0.39% of the annual urea-N input. Both straw and manure had relatively low N2O emissions factors. Slow release urea had a relatively high emission factor. Addition of nitrification inhibitor reduced N2O emission by 55%. We conclude that use of nitrification inhibitors is a promising strategy for N2O mitigation for the intensive wheat-maize double cropping systems. PMID- 23434575 TI - Tracing the source of Beijing soil organic carbon: a carbon isotope approach. AB - Bulk soil organic carbon concentration and isotopic composition characterize its sources and fate, identify the anthropogenic input of organic carbon into the soil, and trace soil carbon turnover. Coal and/or coal combustion products represent the prime anthropogenic input of organic carbon into three soil profiles located in the vicinity of a steel company. Three profiles positioned away from any direct industrial contribution display vertical pattern in soil organic carbon concentration and isotopic composition that resemble more commonly observed downward gradients in soil carbon chemistry and indicate microbial soil carbon turnover. Two additional profiles located outside of the immediate industrial area display vertical carbon isotope profiles between typical of those from industrial and non-industrial areas. Eight soil profiles and their vertical distribution of bulk organic carbon isotopic composition and concentration collected in the Beijing area reveal and distinguish both anthropogenic and natural contributions of carbon to these soils. PMID- 23434576 TI - Mobility and phytoavailability of antimony in an area impacted by a former stibnite mine exploitation. AB - A mining area affected by the abandoned mine exploitation of a stibnite deposit was studied to establish the current and eventual environmental risks and to propose possible remediation practices. Soil and plant samples were collected at different places in this area and analyzed for their Sb content and distribution. Critical soil total concentrations of Sb were found, with values ranging from 585 to 3184 mg kg(-1) dry weight in the uppermost soil layer, and decreasing progressively with soil depth. The readily labile Sb contents represent <2% of the total concentrations, whereas the soil Sb contents more susceptible of being mobilized under changing environmental conditions attain values of about 4-9% of the total concentrations. Remediation measures should be undertaken to limit off site migration of Sb. Within the tolerant plant community growing in this area, the shrub Daphne gnidium L. stands out for its relatively high root Sb accumulation and low Sb translocation, suggesting its feasibility to be used in Sb phytostabilization strategies. PMID- 23434577 TI - Occupational exposure to woodsmoke and oxidative stress in wildland firefighters. AB - Experimental studies indicate that exposure to woodsmoke could induce oxidative stress. However studies have not been conducted among the general population and specialized occupational groups despite the existence of elevated woodsmoke exposure situations. Therefore, we investigated whether there were across workshift changes in oxidative stress biomarkers among wildland firefighters who are occupationally exposed to elevated levels of woodsmoke. We collected pre- and post-workshift urine samples from 19 wildland firefighters before and after prescribed burns. We measured malondialdehyde (MDA) and 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxo-dG) in the samples, and analyzed whether there were cross shift changes in their levels, and the relationships between the changes and the length of firefighting career, age of firefighter, and quantified workshift exposure to particulate matter. Overall no significant cross-shift change was observed for 8-oxodG or MDA in the urine samples of the firefighters. Changes in both biomarkers were also not associated with PM2.5, which was used as a marker of exposure. However, overall unadjusted geometric mean 8-oxo-dG levels in the samples (31 MUg/g creatinine) was relatively higher compared to those measured in healthy individuals in many occupational or general population studies. Additionally, cross-shift changes in 8-oxo-dG excretion were dependent on the length of firefighting career (p=0.01) or age of the subject (p=0.01). Significant increases in 8-oxo-dG level from pre-shift to post-shift were observed for those who had been firefighters for 2 years or less. The results indicate that oxidative stress response measured as cross-shift changes in 8-oxo dG may depend on age or the length of a firefighter's career. These results suggest the need to investigate the longer term health effects of cumulative exposure of woodsmoke exposure among wildland firefighters, because increased body burden of oxidative stress is a risk factor for many diseases and is theorized to be involved in aging. PMID- 23434578 TI - Acute exposure of water soluble fractions of marine diesel on Arctic Calanus glacialis and boreal Calanus finmarchicus: effects on survival and biomarker response. AB - The use of marine diesels in Arctic areas is expected to increase due to increased shipping transport, oil and gas activities, and the ban of heavy bunker oils in many areas. This project aimed at gathering information regarding the sensitivity of an Arctic copepod to marine diesel. The approach undertaken was to study the effects on survival (LC50s) and gene expression of a known detoxification gene (glutathione S-transferase [GST]) in Calanus glacialis following exposure to water soluble fractions (WSFs) of marine diesel (at 2 degrees C). We compared the observed LC-values of C. glacialis to the identical experimental data of the boreal Calanus finmarchicus (at 10 degrees C), and to the predicted LC50-values using regression models. The C. glacialis appeared more tolerant to the acute effects of marine diesel WSF compared to the "average pelagic crustacean" as predicted by regression models, and compared to C. finmarchicus. Although these results may be explained by a slower equilibration of petrogenic chemicals from the WSF at lower temperatures, C. glacialis also displayed higher GST expression following exposure than C. finmarchicus. In addition, the lipid content of the test organisms appears to be an important factor for the determination of acute toxicity, as copepods with high lipid content survived longer than copepods with low lipid content. PMID- 23434579 TI - Reactive transport simulation in a tropical horizontal subsurface flow constructed wetland treating domestic wastewater. AB - A promising approach to the simulation of flow and conversions in the complex environment of horizontal subsurface flow constructed wetlands (HSSF-CWs) is the use of reactive transport models, in which the transport equation is solved together with microbial growth and mass-balance equations for substrate transformation and degradation. In this study, a tropical pilot scale HSSF-CW is simulated in the recently developed CWM1-RETRASO mechanistic model. The model predicts organic matter, nitrogen and sulfur effluent concentrations and their reaction rates within the HSSF-CW. Simulations demonstrated that these reactions took place simultaneously in the same (fermentation, methanogenesis and sulfate reduction) or at different (aerobic, anoxic and anaerobic) locations. Anaerobic reactions occurred over large areas of the simulated HSSF-CW and contributed (on average) to the majority (68%) of the COD removal, compared to aerobic (38%) and anoxic (1%) reactions. To understand the effort and compare computing resources needed for the application of a mechanistic model, the CWM1-RETRASO simulation is compared to a process-based, semi-mechanistic model, run with the same data. CWM1 RETRASO demonstrated the interaction of components within the wetland in a better way, i.e. concentrations of microbial functional groups, their competition for substrates and the formation of intermediary products within the wetland. The CWM1-RETRASO model is thus suitable for simulations aimed at a better understanding of the CW system transformation and degradation processes. However, the model does not support biofilm-based modeling, and it is expensive in computing and time resources required to perform the simulations. PMID- 23434580 TI - Akt kinase targets the association of CBP with histone H3 to regulate the acetylation of lysine K18. AB - CREB binding protein (CBP) is an acetyltransferase that plays an important role in many biological processes. Here, we show that Akt phosphorylates CBP at threonine 1871 and suppresses its acetyltransferase activity by impeding the binding of CBP to histone H3, which results in a decrease in lysine K18 acetylation and dysregulation of target genes. Our results demonstrate that Akt regulates acetyltransferase activity through CBP phosphorylation, which may contribute to tumorigenesis. PMID- 23434581 TI - Stabilization of Cox1p intermediates by the Cox14p-Coa3p complex. AB - Cox14p and Coa3p have been shown to regulate translation of the mitochondrial COX1 mRNA and to be required for assembly of cytochrome oxidase. We present evidence that Cox14p and Coa3p stabilize previously identified Cox1p intermediates and that in the absence of either protein, Cox1p aggregates with itself and other mitochondrial gene products, including cytochrome b, Var1p and Cox2p. Our evidence suggests that Cox1p assembly intermediates are in close proximity to other mitochondrially translated proteins and that an important function of Cox14p and Coa3p is to prevent Cox1 from entering into unproductive aggregation pathways. PMID- 23434582 TI - Endothelin-1-induced down-regulation of NaV1.7 expression in adrenal chromaffin cells: attenuation of catecholamine secretion and tau dephosphorylation. AB - Endothelin-1 and voltage-dependent sodium channels are involved in control and suppression of neuropathological factors, which contribute to sculpting the neuronal network. We previously demonstrated that veratridine-induced NaV1.7 sodium channel activation caused intracellular calcium elevation, catecholamine secretion and tau dephosphorylation in adrenal chromaffin cells. The aim of this study was to examine whether endothelin-1 could modulate NaV1.7. Our results indicated that endothelin-1 decreased the protein level of NaV1.7 and the veratridine-induced increase in intracellular calcium. In addition, it also abolished the veratridine-induced dephosphorylation of tau and the phosphorylation of glycogen synthase kinase-3beta and extracellular signal regulated kinase. These findings suggest that the endothelin-1-induced down regulation of NaV1.7 diminishes NaV1.7-related catecholamine secretion and dephosphorylation of tau. PMID- 23434583 TI - Specificity out of clutter: a hypothetical role of G protein-coupled receptors in the non-genomic effect of steroids. AB - The non-genomic effect has been considered to underlie the rapid action of steroids. This signaling is initiated at the plasma membrane-level and does not directly influence gene expression. Recent studies have provided detailed information on their downstream pathways, but less is known about the nature of correlated membrane-bound receptors. Here, we propose that binding of steroids to a consensus motif, namely CRAC, of G protein-coupled receptors (GPCRs) shifts the agonist-binding state of receptors and accounts for this effect to a certain extent. The interaction between steroids and GPCRs is specific, while the identities of the GPCRs involved are not restrained, which can coordinate the high heterogeneity of this signaling and reconcile multiple discrepancies in the literature. PMID- 23434584 TI - The control of spindle length by Hsp70 and Hsp110 molecular chaperones. AB - Molecular chaperones are an essential group of proteins required to maintain proper protein homeostasis in the cell and include Hsp40, Hsp60, Hsp70, Hsp90, and Hsp100 among others. Hsp110 proteins form a subfamily of the Hsp70 family and seem to primarily function as nucleotide exchange factors for the Hsp70s. Data to date suggest that Hsp110 together with Hsp70 are required to ensure proper spindle assembly and nuclear distribution during cell division. More specifically, we propose that an Hsp110-Hsp70 complex modulates the activity and directionality of the kinesin-5 motor, Cin8, which is required for spindle elongation. The modulation of spindle length by molecular chaperones might be a mechanism by which cell division can be controlled especially under proteostatic stress. PMID- 23434585 TI - Observation of unphosphorylated STAT3 core protein binding to target dsDNA by PEMSA and X-ray crystallography. AB - The STAT3 transcription factor plays a central role in a wide range of cancer types where it is over-expressed. Previously, phosphorylation of this protein was thought to be a prerequisite for direct binding to DNA. However, we have now shown complete binding of a purified unphosphorylated STAT3 (uSTAT3) core directly to M67 DNA, the high affinity STAT3 target DNA sequence, by a protein electrophoretic mobility shift assay (PEMSA). Binding to M67 DNA was inhibited by addition of increasing concentrations of a phosphotyrosyl peptide. X-ray crystallography demonstrates one mode of binding that is similar to that known for the STAT3 core phosphorylated at Y705. PMID- 23434586 TI - ROCKing pulmonary fibrosis. AB - Clinical vignette: A 76-year-old man consults you for increasing shortness of breath over the past two years and an increasing requirement for home oxygen. A video-assisted thoracoscopic lung biopsy shows findings of usual interstitial pneumonitis, and he has no identifiable cause for pulmonary fibrosis, so he is considered to have idiopathic pulmonary fibrosis (IPF). His diffusing capacity for carbon monoxide (DLCO) is 45% of predicted, and his total lung capacity is 40% of predicted. Because of his advanced age, he is not considered a candidate for lung transplantation. What treatment should you recommend? PMID- 23434587 TI - HDAC4 controls histone methylation in response to elevated cardiac load. AB - In patients with heart failure, reactivation of a fetal gene program, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a hallmark for maladaptive remodeling of the LV. The mechanisms that regulate this reactivation are incompletely understood. Histone acetylation and methylation affect the conformation of chromatin, which in turn governs the accessibility of DNA for transcription factors. Using human LV myocardium, we found that, despite nuclear export of histone deacetylase 4 (HDAC4), upregulation of ANP and BNP in failing hearts did not require increased histone acetylation in the promoter regions of these genes. In contrast, di- and trimethylation of lysine 9 of histone 3 (H3K9) and binding of heterochromatin protein 1 (HP1) in the promoter regions of these genes were substantially reduced. In isolated working murine hearts, an acute increase of cardiac preload induced HDAC4 nuclear export, H3K9 demethylation, HP1 dissociation from the promoter region, and activation of the ANP gene. These processes were reversed in hearts with myocyte-specific deletion of Hdac4. We conclude that HDAC4 plays a central role for rapid modifications of histone methylation in response to variations in cardiac load and may represent a target for pharmacological interventions to prevent maladaptive remodeling in patients with heart failure. PMID- 23434588 TI - Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. AB - The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid beta clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain. PMID- 23434589 TI - Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming. AB - Insulin-secreting beta cells and glucagon-secreting alpha cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic alpha, beta, and exocrine cells. We found that, compared with exocrine and beta cells, differentiated alpha cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for beta cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in beta cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that alpha to beta cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type-specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes. PMID- 23434590 TI - Parthenogenetic stem cells for tissue-engineered heart repair. AB - Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair. PMID- 23434591 TI - Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. AB - Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders. PMID- 23434592 TI - Angiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motility. AB - Angiopoietin-like protein 1 (ANGPTL1) is a potent regulator of angiogenesis. Growing evidence suggests that ANGPTL family proteins not only target endothelial cells but also affect tumor cell behavior. In a screen of 102 patients with lung cancer, we found that ANGPTL1 expression was inversely correlated with invasion, lymph node metastasis, and poor clinical outcomes. ANGPTL1 suppressed the migratory, invasive, and metastatic capabilities of lung and breast cancer cell lines in vitro and reduced metastasis in mice injected with cancer cell lines overexpressing ANGPTL1. Ectopic expression of ANGPTL1 suppressed the epithelial to-mesenchymal transition (EMT) by reducing the expression of the zinc-finger protein SLUG. A microRNA screen revealed that ANGPTL1 suppressed SLUG by inducing expression of miR-630 in an integrin alpha(1)beta(1)/FAK/ERK/SP1 pathway dependent manner. These results demonstrate that ANGPTL1 represses lung cancer cell motility by abrogating the expression of the EMT mediator SLUG. PMID- 23434593 TI - Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia. AB - The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML. PMID- 23434595 TI - Bathing the brain. AB - The brain and spinal cord are surrounded by cerebrospinal fluid, which provides a mechanically stable environment for these delicate structures against the forces of gravity and sudden acceleration and deceleration. Neurons and glia comprising the parenchyma of the brain are enveloped in their microenvironment by interstitial fluid. Interstitial fluid has long been considered to be unaffected by the production and flow of cerebrospinal fluid outside the brain parenchyma. However, two recent papers by Iliff et al. demonstrate that cerebrospinal fluid enters the deep substance of the brain, mixes with the interstitial fluid surrounding neurons and glia, and plays an important role in the exchange and clearance of molecules in the interstitial space of the central nervous system. PMID- 23434594 TI - Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. AB - Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3beta and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions. PMID- 23434596 TI - Virgin birth: engineered heart muscle from parthenogenetic stem cells. AB - Cardiac muscle restitution, or true regeneration, is an unmet need in the treatment of myocardial infarction (MI), prompting a decade of study with stem cells of many kinds. Among key obstacles to effective cardiac cell grafting are the cost of autologous stem cell-derived cardiomyocytes, the ethical implications of using embryonic stem cell (ESC) products, immunological barriers to allogeneic cells, functional maturation beyond just the correct lineage decision, and the lack of durable engraftment. In this issue of the JCI, Didie and colleagues show that cardiomyocytes made from parthenogenetic stem cells (PSCs) and deployed as engineered heart muscle (EHM) may overcome all of these formidable barriers. PMID- 23434597 TI - Calcium flux and endothelial dysfunction during acute lung injury: a STIMulating target for therapy. AB - Bacterial pathogen-associated molecular pattern molecules (PAMPs) such as LPS activate the endothelium and can lead to lung injury, but the signaling pathways mediating endothelial injury remain incompletely understood. In a recent issue of the JCI, Gandhirajan et al. identify STIM1, an ER calcium sensor, as a key link between LPS-induced ROS, calcium oscillations, and endothelial cell (EC) dysfunction. In addition, they report that BTP2, an inhibitor of calcium channels, attenuates lung injury. This study identifies a novel endothelial signaling pathway that could be a future target for the treatment of lung injury. PMID- 23434598 TI - Creating new beta cells: cellular transmutation by genomic alchemy. AB - To address insulin insufficiency, diabetes research has long focused on techniques for replacing insulin-producing beta cells. Studies in mice have suggested that, under some conditions, alpha cells possess the capacity to transdifferentiate into beta cells, although the mechanisms that drive this conversion are unclear. In this issue, Bramswig et al. analyzed the methylation states of purified human alpha, beta, and acinar cells and found alpha cells exhibit intrinsic phenotypic plasticity associated with specific histone methylation profiles. In addition to expanding our understanding of this potential source of beta cells, this compendium of carefully generated human gene expression and epigenomic data in islet cell subtypes constitutes a truly valuable resource for the field. PMID- 23434599 TI - North American Indigenous adolescent substance use. AB - OBJECTIVES: To investigate growth in problem drinking and monthly marijuana use among North American Indigenous adolescents from the upper Midwest and Canada. METHODS: Panel data from a community-based participatory research project includes responses from 619 adolescents residing on or near 7 different reservations/reserves. All respondents were members of the same Indigenous cultural group. RESULTS: Rates of problem drinking and monthly marijuana use increased steadily across the adolescent years, with fastest growth occurring in early adolescence (before age 15). In general, female participants reported higher rates of substance use prior to age 15; however, male reports of use surpassed those of females in later adolescence. CONCLUSIONS: Results of this study highlight the importance of early adolescent substance use prevention efforts and the possible utility of gender responsive programming. PMID- 23434600 TI - A fast CT and CT-fluoroscopy registration algorithm with respiratory motion compensation for image-guided lung intervention. AB - CT-fluoroscopy (CTF) is an efficient imaging technique for guiding percutaneous lung intervention such as biopsy and ablation. In CTF-guided procedures, four to ten axial images are captured in a very short time period during breath holding to provide near real-time feedback of patients' anatomy so that physicians can adjust the needle as it is advanced toward a target lesion. Although popularly used in clinics, this procedure requires frequent scans to guide the needle, which may cause increased procedure time, complication rates, and radiation exposure to both clinicians and patients. In addition, CTF only generates a limited number of 2-D axial images and does not provide sufficient 3-D anatomical information. Therefore, how to provide volumetric anatomical information using CTF while reducing intraoperative scan is an important and challenging problem. In this paper, we propose a fast CT-CTF deformable registration algorithm that warps the inhale preprocedural CT onto the intraprocedural CTF for guidance in 3 D. In the algorithm, the deformation in the transverse plane is modeled using 2-D B-Spline, and the deformation along z-direction is regularized by smoothness constraint. A respiratory motion compensation framework is also incorporated for accurate registration. A parallel implementation strategy is adopted to accomplish the registration in several seconds. With electromagnetic tracking, the needle position can be superimposed onto the deformed inhale CT image, thereby providing 3-D image guidance during breath holding. Experiments were conducted using both simulated CTF images with known deformation and real CTF images captured during lung cancer biopsy studies. The experiments demonstrated satisfactory registration results of our proposed fast CT-CTF registration algorithm. PMID- 23434601 TI - Method to geometrically personalize a detailed finite-element model of the spine. AB - To date, developing geometrically personalized and detailed solid finite-element models (FEMs) of the spine remains a challenge, notably due to multiple articulations and complex geometries. To answer this problem, a methodology based on a free-form deformation technique (kriging) was developed to deform a detailed reference finite-element mesh of the spine (including discs and ligaments) to the patient-specific geometry of 10- and 82-year-old asymptomatic spines. Different kriging configurations were tested: with or without smoothing, and control points on or surrounding the entire mesh. Based on the results, it is recommended to use surrounding control points and smoothing. The mean node to surface distance between the deformed and target geometries was 0.3+/-1.1 mm. Most elements met the mesh quality criteria (95%) after deformation, without interference at the articular facets. The method's novelty lies in the deformation of the entire spine at once, as opposed to deforming each vertebra separately, with surrounding control points and smoothing. This enables the transformation of reference vertebrae and soft tissues to obtain complete and personalized FEMs of the spine with minimal postprocessing to optimize the mesh. PMID- 23434602 TI - Intensity integrated Laplacian-based thickness measurement for detecting human metaphase chromosome centromere location. AB - Accurate detection of the human metaphase chromosome centromere is an important step in many chromosome analysis and medical diagnosis algorithms. The centromere location can be utilized to derive information such as the chromosome type, polarity assignment, etc. Methods available in the literature yield unreliable results mainly due to high variability of morphology in metaphase chromosomes and boundary noise present in the image. In this paper, we have proposed a multistaged algorithm which includes the use of discrete curve evolution, gradient vector flow active contours, functional approximation of curve segments, and support vector machine classification. The standard Laplacian thickness measurement algorithm was enhanced to incorporate both contour information as well as intensity information to obtain a more accurate centromere location. In addition to segmentation and width profile measurement, the proposed algorithm can also correct for sister chromatid separation in cell images. The proposed method was observed to be more accurate and statistically significant as compared to a centerline-based method when tested with 226 human metaphase chromosomes. PMID- 23434603 TI - An IC-PLS framework for group corticomuscular coupling analysis. AB - Corticomuscular coupling analysis, i.e., examining the relations between simultaneously recorded brain (e.g., electroencephalography--EEG) and muscle (e.g., electro-myography-EMG) signals, is a useful tool for understanding aspects of human motor control. Traditionally, the most popular method to assess corticomuscular coupling has been the pairwise magnitude-squared coherence (MSC) between EEG and concomitant EMG recordings. In this paper, we propose assessing corticomuscular coupling by combining partial least squares (PLS) and independent component analysis (ICA), which addresses many of the limitations of MSC, such as difficulty in robustly assessing group inference and relying on the biologically implausible assumption of pairwise interaction between brain and muscle recordings. In the proposed framework, response relevance and statistical independence are jointly incorporated into a multiobjective optimization function to meaningfully combine the goals of PLS and ICA under the same mathematical umbrella. Simulations, performed under realistic assumptions, illustrated the utility of such an approach. The method was extended to address intersubject variability to robustly discover common corticomuscular coupling patterns across subjects. We then applied the proposed framework to concurrent EEG and EMG data collected in a Parkinson's disease (PD) study. The results from applying the proposed technique revealed temporal components in the EEG and EMG that were significantly correlated with one another. In addition to the expected motor areas, the corresponding spatial activation patterns demonstrated enhanced occipital connectivity in PD subjects, consistent with previous studies suggesting that PD subjects rely excessively on visual information to counteract the deficiency in being able to generate internal commands from their affected basal ganglia. PMID- 23434604 TI - Effect of orbitofrontal cortex lesions on temporal discounting in rats. AB - Although choices of both humans and animals are more strongly influenced by immediate than delayed rewards, methodological limitations have made it difficult to estimate the precise form of temporal discounting in animals. In the present study, we sought to characterize temporal discounting in rats and to test the role of the orbitofrontal cortex (OFC) in this process. Rats were trained in a novel intertemporal choice task in which the sequence of delay durations was randomized across trials. The animals tended to choose a small immediate reward more frequently as the delay for a large reward increased, and, consistent with previous findings in other species, their choice behavior was better accounted for by hyperbolic than exponential discount functions. In addition, model comparisons showed that the animal's choice behavior was better accounted for by more complex discount functions with an additional parameter than a hyperbolic discount function. Following bilateral OFC lesions, rats extensively trained in this task showed no significant change in their intertemporal choice behavior. Our results suggest that the rodent OFC may not always play a role in temporal discounting when delays are randomized and/or after extensive training. PMID- 23434605 TI - The differential effects of chronic imipramine or citalopram administration on physiological and behavioral outcomes in naive mice. AB - Tricyclics and selective serotonin reuptake inhibitors (SSRIs) are probably the most widely employed reference antidepressants in animal studies on depression. Using imipramine and citalopram, we sought to assess which drug would be more appropriate as pharmacological reference in paradigms of depression in C57BL6N mice by measuring their effect on liquid consumption, home cage activity, body weight and long-term memory in naive animals treated with each compound at generally used dose of 15 mg/kg/day. Continuous logging of home cage movement, weekly monitoring of vertical activity in a novel cage, and body weight was recorded during four-week treatment period and for four weeks after discontinuation of the antidepressant; sucrose preference was evaluated at weekly intervals during drug administration. A novel object recognition memory test was performed in mice treated the antidepressants for two weeks. Compared to control, imipramine-treated mice displayed increased sucrose and water intake, as well as enhanced home-cage and novelty exploration activities, and reduced body weight. Imipramine also impaired learning in the object recognition task, but citalopram diminished object exploration sufficiently to invalidate the test. Citalopram treated animals demonstrated no changes in a sucrose test and had elevated body mass. Thus basic physiological and behavioral outcomes in naive mice were significantly altered by the chronic administration of imipramine and, to a lesser extent, citalopram. As altered variables are crucial for the evaluation of antidepressant-like effects in mice, our data suggest that, at commonly used doses, both drugs must be applied in mouse models of depression with caution. PMID- 23434606 TI - Deep brain stimulation of the subthalamic nucleus increases premature responding in a rat gambling task. AB - Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option for the motor symptoms of Parkinson's disease (PD). However, several recent studies have found an association between STN-DBS and increased impulsivity. Currently, it is not clear whether the observed increase in impulsivity results from STN-DBS per se, or whether it involves an interaction with the underlying PD neuropathology and/or intake of dopaminergic drugs. We investigated the effects of STN-DBS on performance of intact rats on two tasks measuring impulsive responding: a novel rat gambling task (rGT) and a differential reinforcement of low rate responding (DRL20s) schedule. Following initial behavioural training, animals received electrode implantation into the STN (n=24) or sham surgery (n=24), and were re-tested on their assigned behavioural task, with or without STN-DBS. Bilateral STN-DBS administered for two hours immediately prior to testing, had no effects on rGT choice behaviour or on DRL response inhibition (p>0.05). However, STN-DBS significantly increased premature responding in the rGT task (p=0.0004), an effect that took several sessions to develop and persisted in subsequent trials when no stimulation was given. Consistent with the notion of distinct facets of impulsivity with unique neurochemical underpinnings, we observed differential effects of STN-DBS in the two tasks employed. These results suggest that STN-DBS in the absence of parkinsonism may not lead to a general loss of inhibitory control, but may instead affect impulsivity under specific conditions. PMID- 23434607 TI - 12-Deoxyphorbol 13-palmitate inhibit VEGF-induced angiogenesis via suppression of VEGFR-2-signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: 12-Deoxyphorbol 13-palmitate (G) is one toxic compound isolated from Euphorbia fischeriana, an Asian spice used for cancer treatment as a folk remedy. However, whether 12-deoxyphorbol 13-palmitate affects angiogenesis remains unclear. AIM OF THE STUDY: To explore the in vitro and in vivo antiangiogenic effects of 12-deoxyphorbol 13-palmitate and its underlying mechanisms. MATERIALS AND METHODS: We explored antigenic functions in human umbilical vein endothelial cells (HUVEC) by 12-deoxyphorbol 13-palmitate, including proliferation, migration and metastasis through matrigel plug assay, chorioallantoic membrane assay, in vitro migration assay, tube formation assay, motility assay. Antibody chip was applied to screen differentially expressed proteins modulated by 12-deoxyphorbol 13-palmitate, and was further confirmed by RT-PCR and western blot analysis. Tumor xenograft mice were applied to investigate whether 12-deoxyphorbol 13-palmitate could inhibit microvessel density in vivo. RESULTS: 12-Deoxyphorbol 13-palmitate inhibited vascular endothelial growth factor (VEGF)-induced angiogenic processes in vitro, such as proliferation, in vitro migration, and tube formation of HUVEC. In chorioallantoic membrane assay, 12-deoxyphorbol 13-palmitate significantly inhibited neovessel formation. Antibody chip technology demonstrated decreased expression of TIMP-1, TIMP-2, VEGF, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP)-2, VEGFR-2 and VEGFR-3 proteins in HUVEC after 24h. In addition, 12-deoyphorbol 13-palmitate inhibited the in vivo growth of MCF-7 cells in grafted mouse model. Immunohistochemistry staining showed decreased microvessel density (CD31) and attenuated VEGFR-2 signaling pathways by 12 deoxyphorbol 13-palmitate. CONCLUSION: 12-Deoxyphorbol 13-palmitate may be utilized to target active angiogenesis through VEGF/VEGFR2 signal pathway for cancer. PMID- 23434608 TI - Ethnobotanical survey of malaria prophylactic remedies in Odisha, India. AB - AIM OF THE STUDY: To investigate the plants traditionally used for prevention of malaria in Cuttack, Gajapati and Koraput districts of Odisha state, eastern India. MATERIALS AND METHODS: An ethnobotanical survey was carried out among 20 traditional healers who were sampled based on recommendations of local elders and local non-government organizations. Data were collected through semi-structured interview. RESULTS: The study revealed the use of 16 traditional plant species belonging to 12 families for prevention of malaria. Andrographis paniculata, Azadirachta indica, Nyctanthes arbor-tristis, Ocimum sanctum, Piper nigrum, Zingiber officinale were the most commonly reported plants for their malaria prophylactic use by the healers of three districts of Odisha. Most of the remedies were used in decoction form. CONCLUSIONS: Findings of this study provide a lead to explore traditional plants for malaria preventive potential through further pre-clinical and clinical studies. PMID- 23434609 TI - Superpixel classification based optic disc and optic cup segmentation for glaucoma screening. AB - Glaucoma is a chronic eye disease that leads to vision loss. As it cannot be cured, detecting the disease in time is important. Current tests using intraocular pressure (IOP) are not sensitive enough for population based glaucoma screening. Optic nerve head assessment in retinal fundus images is both more promising and superior. This paper proposes optic disc and optic cup segmentation using superpixel classification for glaucoma screening. In optic disc segmentation, histograms, and center surround statistics are used to classify each superpixel as disc or non-disc. A self-assessment reliability score is computed to evaluate the quality of the automated optic disc segmentation. For optic cup segmentation, in addition to the histograms and center surround statistics, the location information is also included into the feature space to boost the performance. The proposed segmentation methods have been evaluated in a database of 650 images with optic disc and optic cup boundaries manually marked by trained professionals. Experimental results show an average overlapping error of 9.5% and 24.1% in optic disc and optic cup segmentation, respectively. The results also show an increase in overlapping error as the reliability score is reduced, which justifies the effectiveness of the self-assessment. The segmented optic disc and optic cup are then used to compute the cup to disc ratio for glaucoma screening. Our proposed method achieves areas under curve of 0.800 and 0.822 in two data sets, which is higher than other methods. The methods can be used for segmentation and glaucoma screening. The self-assessment will be used as an indicator of cases with large errors and enhance the clinical deployment of the automatic segmentation and screening. PMID- 23434610 TI - Colestilan decreases weight gain by enhanced NEFA incorporation in biliary lipids and fecal lipid excretion. AB - Bile acid sequestrants (BASs) are cholesterol-lowering drugs that also affect hyperglycemia. The mechanism by which BASs exert these and other metabolic effects beyond cholesterol lowering remains poorly understood. The present study aimed to investigate the effects of a BAS, colestilan, on body weight, energy expenditure, and glucose and lipid metabolism and its mechanisms of action in high-fat-fed hyperlipidemic APOE*3 Leiden (E3L) transgenic mice. Mildly insulin resistant E3L mice were fed a high-fat diet with or without 1.5% colestilan for 8 weeks. Colestilan treatment decreased body weight, visceral and subcutaneous fat, and plasma cholesterol and triglyceride levels but increased food intake. Blood glucose and plasma insulin levels were decreased, and hyperinsulinemic-euglycemic clamp analysis demonstrated improved insulin sensitivity, particularly in peripheral tissues. In addition, colestilan decreased energy expenditure and physical activity, whereas it increased the respiratory exchange ratio, indicating that colestilan induced carbohydrate catabolism. Moreover, kinetic analysis revealed that colestilan increased [(3)H]NEFA incorporation in biliary cholesterol and phospholipids and increased fecal lipid excretion. Gene expression analysis in liver, fat, and muscle supported the above findings. In summary, colestilan decreases weight gain and improves peripheral insulin sensitivity in high-fat-fed E3L mice by enhanced NEFA incorporation in biliary lipids and increased fecal lipid excretion. PMID- 23434612 TI - Men cross America faster than women--the "Race Across America" from 1982 to 2012. AB - PURPOSE: The sex difference in ultraendurance performance has been investigated in swimmers, runners, and triathletes but not in cyclists. The purpose of this study was to examine the sex difference in the longest ultra-cycling race in the world, the Race Across America (RAAM). METHODS: Cycling speed of female and male finishers in the RAAM between 1982 and 2012 was compared. RESULTS: A total of 452 athletes including 404 men (89.4%) and 48 women (10.6%) finished. Mean cycling speed was 19.4 +/- 2.0 km/h for men and 17.5 +/- 2.0 km/h for women. Men were riding 1.9 +/- 2.0 km/h (10.9%) faster than women. The fastest cycling speed ever was 24.77 km/h for men and 21.27 km/h for women, with a sex difference of 14.2%. Between 1982 and 2012, cycling speed was 22.7 +/- 1.1 km/h for the annual fastest men and 18.4 +/- 1.6 km/h for the annual fastest women, with an unchanged sex difference of 19.4% +/- 7.3% (P > .05). For the annual top 3 men, cycling speed was 21.8 +/- 0.9 km/h with no change across years (P > .05). The annual top 3 women achieved a cycling speed of 16.6 +/- 1.0 km/h with no change over time (P > .05). The sex difference of 24.6% +/- 3.0% showed no change across years (P > .05). CONCLUSIONS: In the last 30 y, men crossed America faster than women, and it seems unlikely that women will overtop men in the near future in the RAAM. However, the sex difference was only 14-15% among top competitors. Future studies need to analyze anthropometric, psychological, and physiological characteristics of successful female and male ultracyclists. PMID- 23434611 TI - Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats. AB - Ginsenoside Rb1 (Rb1), a natural compound extracted from ginseng, exerts anti obesity activity and improves insulin sensitivity in high-fat diet (HFD)-induced obese rats. The objective of the current study was to evaluate the protective effect of Rb1 on fatty liver in HFD-induced obese rats and to elucidate underlying mechanisms. After chronic intraperitoneal administration, Rb1 (10 mg/kg) significantly ameliorated hepatic fat accumulation in HFD-induced obese rats, as demonstrated by reduced liver weight, hepatic triglyceride content, and histological evaluation of liver sections by hematoxylin and eosin and Oil Red O staining. Using primary cultured rat hepatic cells, we found that the rate of fatty acid oxidation and the activity of carnitine palmitoyltransferase 1 (CPT1), a key enzyme in fatty acid beta-oxidation, were significantly elevated in Rb1 treated hepatocytes compared with those of vehicle-treated cells. HPLC analysis revealed that Rb1 increased the cellular AMP/ATP ratio, which is associated with elevated activation of hepatic AMP-activated protein kinase (AMPK) and phosphorylated acetyl-CoA carboxylase. Consistent with the activation of AMPK, Rb1 stimulated the expression of genes encoding fatty acid oxidative enzymes and proteins, and suppressed the expression of genes encoding enzymes or proteins that function in lipogenesis, assessed by quantitative PCR. We conclude that Rb1 has a potent ability to reduce hepatic fat accumulation and might be useful as a therapeutic agent for fatty liver disorder. PMID- 23434613 TI - Development and feasibility of a self-management intervention for chronic obstructive pulmonary disease delivered with motivational interviewing strategies. AB - BACKGROUND: Self-management is proposed as the standard of care in chronic obstructive pulmonary disease (COPD), but details of the process and training required to deliver effective self-management are not widely available. In addition, recent data suggest that patient engagement and motivation are critical ingredients for effective self-management. This article carefully describes a self-management intervention using motivational interviewing skills, aimed to increase engagement and commitment in severe COPD patients. METHODS: The intervention was developed and pilot tested for fidelity to protocol, for patient and interventionist feedback (qualitative) and effect on quality of life. Engagement between patient and interventionists was measured by the Working Alliance Inventory. The intervention was refined on the basis of the results of the pilot study and delivered in the active arm of a prospective randomized study. RESULTS: The pilot study suggested improvements in quality of life, fidelity to theory, and patient acceptability. The refined self-management intervention was delivered 540 times in the active arm of a randomized study. We observed a retention rate of 86% (patients missing or not available for only 14% the scheduled encounters). CONCLUSIONS: A self-management intervention that includes motivational interviewing as the way if guiding patients into behavior change is feasible in severe COPD and may increase patient engagement and commitment to self-management. This provides a very detailed description of the process for the specifics of training and delivering the intervention, which facilitates replicability in other settings and could be translated to cardiac rehabilitation. PMID- 23434614 TI - Shedding light on the interactions of guanine quadruplexes with tricationic metalloporphyrins. AB - G-quadruplex DNA presents a potential target for the design and development of novel anticancer drugs. The porphyrin TMPyP4 was early reported to be a suitable motif for G-quadruplex DNA interaction. We inserted various metal ions such as Zn(II), Cu(II), Co(III) in the center of the aromatic core of tricationic TMPyP4 like porphyrin and examined their interactions with an antiparallel G-quadruplex DNA by a combination of spectroscopy and Job plot methods. Porphyrin metallation allowed the conclusion that the presence of one axial ligand perpendicular to the aromatic plane did not hamper pi-pi stacking interactions between quadruplex and the aromatic parts of porphyrin on the other face while porphyrin with two axial ligands was unable to undergo such interaction due to geometrical factors. Free base porphyrin and porphyrin without axial ligands are able to stabilize the quadruplex structure to a greater extent than the other metal complexes and thus may be potential anti-cancer drugs. PMID- 23434615 TI - Importance of material model in wall stress prediction in abdominal aortic aneurysms. AB - BACKGROUND: Results of biomechanical simulation of the abdominal aortic aneurysm (AAA) depend on the constitutive description of the wall. Based on in vitro and in vivo experimental data several constitutive models for the AAA wall have been proposed in the literature. Those models differ strongly from each other and their impact on the computed stress in biomechanical simulation is not clearly understood. METHODS: Finite element (FE) models of AAAs from 7 patients who underwent elective surgical repair were used to compute wall stresses. AAA geometry was reconstructed from CT angiography (CT-A) data and patient-specific (PS) constitutive descriptions of the wall were derived from planar biaxial testing of anterior wall tissue samples. In total 28 FE models were used, where the wall was described by either patient-specific or previously reported study average properties. This data was derived from either uniaxial or biaxial in vitro testing. Computed wall stress fields were compared on node-by-node basis. RESULTS: Different constitutive models for the AAA wall cause significantly different predictions of wall stress. While study-average data from biaxial testing gives globally the same stress field as the patient-specific wall properties, the material model based on uniaxial test data overestimates the wall stress on average by 30 kPa or about 67% of the mean stress. A quasi-linear description based on the in vivo measured distensibility of the AAA wall leads to a completely altered stress field and overestimates the wall stress by about 75 kPa or about 167% of the mean stress. CONCLUSION: The present study demonstrated that the constitutive description of the wall is crucial for AAA wall stress prediction. Consequently, results obtained using different models should not be mutually compared unless different stress gradients across the wall are not taken into account. Highly nonlinear material models should be preferred when the response of AAA to increased blood pressure is investigated, while the quasi linear model with high initial stiffness produces negligible stress gradients across the wall and thus, it is more appropriate when response to mean blood pressure is calculated. PMID- 23434616 TI - Clinical risk factors to predict deep venous thrombosis post-endovenous laser ablation of saphenous veins. AB - OBJECTIVE: Endovenous laser ablation of saphenous veins is an alternative in treating symptomatic varicose veins. Deep venous thrombosis (DVT) has been reported in up to 7.7% of patients undergoing such procedure. We sought to establish clinical risk factors that predict DVT post-endovenous laser ablation. METHOD: Patients who underwent endovenous laser ablation were prospectively followed. Clinical data and post-interventional duplex ultrasound were analysed. A P value <0.05 was accepted as representing a significant difference. RESULTS: From 2007 to 2008, 360 consecutive patients were followed. Nineteen DVTs were found on follow-up ultrasound. Eighteen cases involved either the saphenofemoral or saphenopopliteal junctions; only one case involved the deep venous system. Age >66 (P = 0.007), female gender (P = 0.048) and prior history of superficial thrombophlebitis (SVT) (P = 0.002) were associated with increased risk of DVT postprocedure. CONCLUSION: Age >66, female gender and history of SVT were significant predictors of DVT post-endovenous laser ablation of saphenous veins. PMID- 23434617 TI - Haemostatic activation and inflammatory response after three methods of treatment of great saphenous vein incompetence. AB - OBJECTIVE: The purpose of this study was to compare the activation of haemostasis and inflammatory response after three different methods of treatment of great saphenous vein (GSV) incompetence. MATERIAL AND METHODS: Forty-five patients with GSV incompetence were assigned to one of the three types of treatment: high ligation and stripping (HL&S), radiofrequency ablation with ClosureFast (RFA) and endovenous laser ablation (EVLA) with 810 nm diode laser with miniphlebectomy if required. Peripheral blood samples were obtained in the morning before the surgery and 24 hours and 10 days after the procedure. The concentrations of C reactive protein (CRP), D-dimer, prothrombin fragment 1 + 2 (F1 + 2), antigen of tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) antigen and activity of plasminogen activator inhibitor (PAI-1) were determined. The results were statistically analysed with SPSS for Windows 15.0. RESULTS: Thirty-eight patients completed the study: 13 from RFA, 14 from EVLA and 11 from HL&S group. The baseline data did not differ among groups. There was a significant increase of D-dimer in HL&S group after 24 hours (P = 0.002). The changes in RFA and EVLA groups did not show statistical significance (P = 0.092). PAI-1 decreased in RFA patients after 24 hours (P = 0.02), did not change in EVLA patients, and tended to increase after HL&S (P = 0.08). The highest CRP increase was observed in HL&S group (P = 0.003). No significant changes in F1 + 2, t-PA and vWF were observed in any group of patients at 24 hours. At 10 days, a further significant increase of D-dimer (P = 0.04) and CRP (P = 0.018) concentrations in HL&S but not RFA and EVLA patients was observed. CONCLUSIONS: Endovenous thermal ablation is associated with significantly less activation of haemostasis and inflammatory response when compared with HL&S. PMID- 23434618 TI - Gender preference and awareness regarding sex determination among antenatal mothers attending a medical college of eastern India. AB - AIM: There are many women "missing" due to an unfavourable sex ratio in India, which has strong patriarchal norms and a preference for sons. Female gender discrimination has been reported in health care, nutrition, education, and resource allocation due to man-made norms, religious beliefs, and recently by ultrasonography resulting in lowered sex ratio. METHODS: The present study attempts to find out the level of awareness regarding sex determination and to explore preference of gender and factors associated among antenatal mothers attending a medical college in eastern India. Interviews were done by predesigned pretested proforma over 6 months. The data were analysed by SPSS 16.0 software for proportions with chi-squared tests and binary logistic regression analysis. RESULTS: Most women who were multigravida did not know about contraceptives; 1.8% of mothers knew the sex of the fetus in present pregnancy while another 34.7% expressed willingness; 13.6% knew of a place which could tell sex of the fetus beforehand; 55.6% expressed their preference of sex of the baby for present pregnancy while 50.6% of their husbands had gender preference. Gender preference was significantly high in subjects with: lower socioeconomic status (p=0.011); lower level of education of mother (p=0.047) and husband (p=0.0001); multigravida (p=0.002); presence of living children (p=0.0001); and husband having preference of sex of baby (p=0.0001). CONCLUSIONS: Parental education, socioeconomic background, and number of living issues were the main predictors for gender preference. Awareness regarding gender preference and related law and parental counselling to avoid gender preference with adoption of small family norm is recommended. PMID- 23434619 TI - Tissue voltage discordance during tachycardia versus sinus rhythm: implications for catheter ablation. AB - BACKGROUND: Electroanatomic mapping systems are an important tool to identify cardiac chamber voltage and assess channels of slow conduction. OBJECTIVE: To assess the correlation between electroanatomic mapping voltage maps obtained during macroreentrant tachycardia compared to sinus rhythm (SR) with a contact mapping system. METHODS: We retrospectively evaluated patients with atrial flutter (AFL) referred for radiofrequency ablation with electroanatomic voltage maps obtained during AFL and SR. The atrium was divided into predetermined segments. Overall atrial and segmental peak-to-peak bipolar voltages in AFL and SR were assessed. To directly compare a region within the same patient, tissue voltage differences during AFL and SR were assessed on the basis of mean voltage difference. RESULTS: Sixteen patients (87% men) had available voltage maps. Eighty-one percent had typical cavotricuspid isthmus-dependent right AFL. A mean of 441.7+/-153.9 vs 398.1+/-125.4 total points (P = .22) were sampled during AFL and SR, with a mean of 99.5+/-58.9 vs 91.2+/-60.4 points (P = .45) sampled per region. Overall right atrial mean voltage was significantly higher during AFL than SR (0.554+/-0.092mV vs 0.473+/-0.079mV; P<=.001), with the lateral wall (0.707+/-0.120mV vs 0.573+/-0.097mV; P = .0004) and the cavotricuspid isthmus (0.559+/-0.100mV vs 0.356+/-0.066mV; P<.0001) also showing higher mean voltage during AFL. When compared within an individual patient, 19% (14 of 75) of the patient regions had a>0.5mV mean voltage difference and 40% (30 of 75) had a>0.25mV mean voltage difference. CONCLUSIONS: These data suggest that voltage maps performed during macroreentrant atrial arrhythmias often vary significantly from maps obtained during SR. PMID- 23434620 TI - Mechanism and diagnostic potential of reciprocal ECG changes induced by acute coronary artery occlusion in pigs. AB - BACKGROUND: Reciprocal ST-segment depression simulating additional subendocardial ischemia is commonly observed in ST-segment elevation myocardial infarction. OBJECTIVE: To study the mechanism and characterization of the whole reciprocal electrocardiogram (ECG) patterns induced by acute coronary artery occlusion at different locations in the absence of additional subendocardial ischemia in pigs. METHODS: Conventional 12-lead ECG and/or local extracellular epicardial, mid myocardial, and endocardial electrograms were recorded during the acute occlusion of right coronary (RC) and left anterior descending (LAD) coronary arteries in the in situ (n = 9) or in the isolated perfused (n = 5) pig hearts. RESULTS: Mid RC occlusion induced reciprocal ST-segment depression (-0.43 +/- 0.14 mV; P<.01) and S-wave deepening (-0.74 +/- 0.23 mV; P<.01) in anterior ECG leads. Mid-LAD occlusion induced reciprocal S-wave deepening (-0.43 +/- 0.37 mV; P = .02) but not ST-segment depression in inferior leads. Proximal LAD induced reciprocal ST segment depression (-0.21 +/- 0.20 mV; P = .03) and S-wave deepening (-0.56 +/- 0.58 mV; P = .04) in inferior leads. Reciprocal QRS widening was observed only during proximal LAD occlusion. Local extracellular recordings did not show significant reciprocal QRS and ST-segment changes. CONCLUSIONS: In the absence of additional subendocardial ischemia, acute coronary artery occlusion induces reciprocal ST-segment and S-wave changes in the 12-lead ECG that allow better differentiation between proximal and mid-LAD occlusion. Reciprocal ECG changes depend on conventional lead system design and not on the transmission of injury currents from the ischemic border zone to distant normal myocardium. PMID- 23434621 TI - Impact of the Advisa MRI pacing system on the diagnostic quality of cardiac MR images and contraction patterns of cardiac muscle during scans: Advisa MRI randomized clinical multicenter study results. AB - BACKGROUND: The Advisa MRI system is designed to safely undergo magnetic resonance imaging (MRI). Its influence on image quality is not well known. OBJECTIVE: To evaluate cardiac magnetic resonance (CMR) image quality and to characterize myocardial contraction patterns by using the Advisa MRI system. METHODS: In this international trial with 35 participating centers, an Advisa MRI system was implanted in 263 patients. Of those, 177 were randomized to the MRI group and 150 underwent MRI scans at the 9-12-week visit. Left ventricular (LV) and right ventricular (RV) cine long-axis steady-state free precession MR images were graded for quality. Signal loss along the implantable pulse generator and leads was measured. The tagging CMR data quality was assessed as the percentage of trackable tagging points on complementary spatial modulation of magnetization acquisitions (n=16) and segmental circumferential fiber shortening was quantified. RESULTS: Of all cine long-axis steady-state free precession acquisitions, 95% of LV and 98% of RV acquisitions were of diagnostic quality, with 84% and 93%, respectively, being of good or excellent quality. Tagging points were trackable from systole into early diastole (360-648 ms after the R wave) in all segments. During RV pacing, tagging demonstrated a dyssynchronous contraction pattern, which was not observed in nonpaced (n = 4) and right atrial paced (n = 8) patients. CONCLUSIONS: In the Advisa MRI study, high-quality CMR images for the assessment of cardiac anatomy and function were obtained in most patients with an implantable pacing system. In addition, this study demonstrated the feasibility of acquiring tagging data to study the LV function during pacing. PMID- 23434622 TI - Cellular mechanisms of developmental and sex differences in the rapid hormonal modulation of a social communication signal. AB - Some gymnotiform electric fish species rapidly modify their electric signal waveforms by altering the action potential (AP) waveforms of their electrocytes, the excitable cells that produce the electric organ discharge (EOD). The fish Brachyhypopomus gauderio alters EOD amplitude and pulse duration as a social signal in accordance with the prevailing social conditions, under the dual regulation of melanocortins and androgens. We show here that B. gauderio uses two distinct cellular mechanisms to change signal amplitude, and its use of these two mechanisms varies with age and sex of the signaler. EOD amplitude and waveform are regulated by the coordinated timing and shaping of two APs generated from two opposing excitable membranes in each electrocyte. The two membranes fire in sequence within 100 MUs of each other with the second AP being broader than the first. We have shown previously that mature males increase EOD amplitude and duration when melanocortin peptide hormones act directly on electrocytes to selectively broaden the second AP and increase the delay between the two APs by approximately 25 MUs. Here we show that females selectively broaden only the second AP as males do, but increase amplitude of both APs with no change in delay between them, a previously unreported second mechanism of EOD amplitude change in B. gauderio. Juvenile fish broaden both APs and increase the delay between the APs. Cellular mechanisms of EOD plasticity are therefore shaped during development, presumably by sex steroids, becoming sexually dimorphic at maturity. PMID- 23434623 TI - Neighbor-favoring weight reinforcement to improve random walk-based disease gene prioritization. AB - BACKGROUND: Finding candidate genes associated with a disease is an important issue in biomedical research. Recently, many network-based methods have been proposed that implicitly utilize the modularity principle, which states that genes causing the same or similar diseases tend to form physical or functional modules in gene/protein relationship networks. Of these methods, the random walk with restart (RWR) algorithm is considered to be a state-of-the-art approach, but the modularity principle has not been fully considered in traditional RWR approaches. Therefore, we propose a novel method called ORIENT (neighbor-favoring weight reinforcement) to improve the performance of RWR through proper intensification of the weights of interactions close to the known disease genes. RESULTS: Through extensive simulations over hundreds of diseases, we observed that our approach performs better than the traditional RWR algorithm. In particular, our method worked best when the weights of interactions involving only the nearest neighbor genes of the disease genes were intensified. Interestingly, the performance of our approach was negatively related to the probability with which the random walk will restart, whereas the performance of RWR without the weight-reinforcement was positively related in dense gene/protein relationship networks. We further found that the density of the disease gene projected sub-graph and the number of paths between the disease genes in a gene/protein relationship network may be explanatory variables for the RWR performance. Finally, a comparison with other well-known gene prioritization tools including Endeavour, ToppGene, and BioGraph, revealed that our approach shows significantly better performance. CONCLUSION: Taken together, these findings provide insight to efficiently guide RWR in disease gene prioritization. PMID- 23434624 TI - Blood pressure and diabetes: vicious twins. PMID- 23434625 TI - Coronary heart disease: what hope for the developing world? PMID- 23434626 TI - Clinical outcomes in patients with implantable cardioverter defibrillators and Sprint Fidelis leads. AB - OBJECTIVE: The performances of implantable cardioverter defibrillators and leads are important issues for healthcare providers and patients. In 2007 Sprint Fidelis leads were found to be associated with an increased failure rate and so the purpose of the study was to evaluate long-term mortality and clinical outcomes in patients implanted with Sprint Fidelis leads compared with Sprint Quattro leads. DESIGN, SETTING, PATIENTS: 508 patients with Sprint Fidelis leads and 468 with Sprint Quattro leads were prospectively followed in 12 Italian cardiology centres. MAIN OUTCOME MEASURES: Information on hospitalisations and other clinical events were collected during scheduled and unscheduled hospital visits. Deaths were identified from medical records or via phone contacts with patients' family members or through the National Office of Vital Statistics. RESULTS: Over a mean follow-up of 27+/-18 months 141 deaths occurred in the overall population. No death was observed in patients with diagnosed failing lead. Kaplan-Meier patient survival differed between the two lead groups (80+/-2% in Fidelis leads vs 70+/-4% in the Sprint Quattro leads at 4 years, p=0.002). Multivariate analyses showed that mortality was neither associated with lead type nor with diagnosed failed lead. The annual rate of lead failure was 1.8% patient year for Fidelis leads and 0.2% for the Sprint Quattro leads. CONCLUSIONS: In our multicentre research, the clinical outcomes of patients with Fidelis leads differed from those of patients with Sprint Quattro leads. Nevertheless, neither mortality nor the combined endpoint of mortality and heart failure hospitalisations was associated with the lead type. http://clinicaltrials.gov/ct2/show/NCT01007474. PMID- 23434627 TI - Identification of chromosomal copy number variations and novel candidate loci in hereditary nonpolyposis colorectal cancer with mismatch repair proficiency. AB - The pathogenesis of microsatellite stable hereditary non-polyposis colorectal cancers (MSS HNPCC) is unclear. To identify genomic regions that might be involved in MSS HNPCC pathogenesis, we selected 20 pairs of MSS HNPCC for a genome-wide study using copy number variation targeted (CNV-targeted) CytoScan HD Array. A remarkably increased frequency of 20q gain (70%) and high levels of copy neutral loss of heterozygosity (40%) were observed. The most frequent tumor specific CNVs included amplifications (7p21.3-15.1, 8q13.3-24.3, 13q14.1-33.3 and 20q12-13.33) and deletions (8p11.23-23.1, 15q11.2-26.1, 17p13.1-13.3 and 18q11.2 21.33). In addition, 10 novel CNVs were discovered and led to identification of WDR16 and RAPGEF5 as candidate genes involved in tumorigenesis, displaying a robust correlation between expression and genomic alterations. Moreover, WDR16 and RAPGEF5 exhibited altered protein expression levels as assessed by immunohistochemistry (IHC) in 41 other independent samples. Finally, high consistencies (68-84%) were observed between CNVs by Array and quantitative PCR. These findings are important for further elucidating MSS HNPCC pathogenesis. PMID- 23434628 TI - Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. AB - The recently approved ALK kinase inhibitor crizotinib has demonstrated successful treatment of metastatic and late stage ALK fusion positive non-small cell lung cancer (NSCLC). However, the median duration of clinical benefit is ~10-11months due to the emergence of multiple and simultaneous resistance mechanisms in these tumors. Mutations in the ALK kinase domain confer resistance to crizotinib in about one-third of these patients. We developed a multiplex deep sequencing method using semiconductor sequencing technology to quickly detect resistance mutations within the ALK kinase domain from tumor biopsies. By applying a base pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALK kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting. PMID- 23434629 TI - De novo transcriptome sequencing in Frankliniella occidentalis to identify genes involved in plant virus transmission and insecticide resistance. AB - The western flower thrips (WFT), Frankliniella occidentalis, a world-wide invasive insect, causes agricultural damage by directly feeding and by indirectly vectoring Tospoviruses, such as Tomato spotted wilt virus (TSWV). We characterized the transcriptome of WFT and analyzed global gene expression of WFT response to TSWV infection using Illumina sequencing platform. We compiled 59,932 unigenes, and identified 36,339 unigenes by similarity analysis against public databases, most of which were annotated using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Within these annotated transcripts, we collected 278 sequences related to insecticide resistance. GO and KEGG analysis of different expression genes between TSWV-infected and non infected WFT population revealed that TSWV can regulate cellular process and immune response, which might lead to low virus titers in thrips cells and no detrimental effects on F. occidentalis. This data-set not only enriches genomic resource for WFT, but also benefits research into its molecular genetics and functional genomics. PMID- 23434630 TI - Microarray analysis of gene expression profile in resistant and susceptible Bombyx mori strains reveals resistance-related genes to nucleopolyhedrovirus. AB - To investigate the molecular mechanism of silkworm resistance to BmNPV infection, we constructed a near-isogenic line (BC8) with BmNPV resistance using highly resistant (NB) and highly susceptible parental strains (306). We investigated variations in the gene expression in the midguts of BmNPV-infected BC8 and 306 at 12 h pi using the microarray. 92 differentially expressed genes were identified. Real-time qPCR analysis confirmed that 10 genes were significantly up-regulated or down-regulated in the midguts of BC8 and NB compared to 306. To our knowledge, we first defined the role of the amino acid transporter and 26S proteasome in insect antiviral. However, serine protease was not completely consistent with data of reported previously in insect antiviral. The role of the 5 genes (Bm123, Bm122, COP beta', aquaporin, glycoside hydrolases) was also demonstrated in insect antiviral. Our results provided new insights into the molecular mechanism of the Bombyx mori immune response against BmNPV infection. PMID- 23434631 TI - Microchimerism in the human brain: more questions than answers. AB - Recently, our group reported the presence of microchimerism (Mc) in the human brain by performing quantitative PCR on female human brain tissues to amplify male DNA. We found brain Mc to be relatively frequent in humans and widely distributed in this organ. Our data also suggested a lower prevalence of brain Mc in women without Alzheimer disease than women without neurological disease. Altogether, these findings suggest that Mc could sometimes influence health and disease of the brain. As further research will be required to clarify this issue, here we discuss some of the questions that could be addressed to improve our understanding. PMID- 23434632 TI - Biological network extraction from scientific literature: state of the art and challenges. AB - Networks of molecular interactions explain complex biological processes, and all known information on molecular events is contained in a number of public repositories including the scientific literature. Metabolic and signalling pathways are often viewed separately, even though both types are composed of interactions involving proteins and other chemical entities. It is necessary to be able to combine data from all available resources to judge the functionality, complexity and completeness of any given network overall, but especially the full integration of relevant information from the scientific literature is still an ongoing and complex task. Currently, the text-mining research community is steadily moving towards processing the full body of the scientific literature by making use of rich linguistic features such as full text parsing, to extract biological interactions. The next step will be to combine these with information from scientific databases to support hypothesis generation for the discovery of new knowledge and the extension of biological networks. The generation of comprehensive networks requires technologies such as entity grounding, coordination resolution and co-reference resolution, which are not fully solved and are required to further improve the quality of results. Here, we analyse the state of the art for the extraction of network information from the scientific literature and the evaluation of extraction methods against reference corpora, discuss challenges involved and identify directions for future research. PMID- 23434633 TI - The Rat Genome Database 2013--data, tools and users. AB - The Rat Genome Database (RGD) was started >10 years ago to provide a core genomic resource for rat researchers. Currently, RGD combines genetic, genomic, pathway, phenotype and strain information with a focus on disease. RGD users are provided with access to structured and curated data from the molecular level through the organismal level. Those users access RGD from all over the world. End users are not only rat researchers but also researchers working with mouse and human data. Translational research is supported by RGD's comparative genetics/genomics data in disease portals, in GBrowse, in VCMap and on gene report pages. The impact of RGD also goes beyond the traditional biomedical researcher, as the influence of RGD reaches bioinformaticians, tool developers and curators. Import of RGD data into other publicly available databases expands the influence of RGD to a larger set of end users than those who avail themselves of the RGD website. The value of RGD continues to grow as more types of data and more tools are added, while reaching more types of end users. PMID- 23434635 TI - Decision making and experience level influence frontal plane knee joint biomechanics during a cutting maneuver. AB - The purpose of this study was to examine the combined impact of experience and decision making on frontal plane knee joint biomechanics during a cutting maneuver. Kinematic and kinetic data were collected from 12 recreationally active and 18 NCAA Division I female athletes during execution of anticipated and unanticipated single-leg land-and-cut maneuvers. Knee joint abduction angles and external knee joint abduction torques were calculated and discrete peak stance phase variables were extracted. Angle and torque time-series data were also submitted to separate functional data analyses. Variables derived from the functional data analyses indicated that decision making influenced knee abduction angle and torque time series in the recreational group only. Specifically, these variables pointed to greater knee abduction at the end of stance as well as a greater, albeit delayed peak in knee abduction torque at the beginning of landing in the recreational athletes during the unanticipated condition. In addition, the recreational athletes displayed greater discrete peak knee abduction angles than the Division I athletes regardless of condition. Discrete peak knee abduction torque did not differ between groups or conditions. PMID- 23434636 TI - Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. AB - Cancer is considered as one of the most serious health problems. Despite the presence of many effective chemotherapeutic agents, their severe side effects together with the appearance of mutant tumors limit the use of these drugs and increase the need for new anticancer agents. Eg5 represents an attractive target for medicinal chemists since Eg5 is overexpressed in many proliferative tissues while almost no Eg5 is detected in nonproliferative tissues. Many Eg5 inhibitors displayed potent anticancer activity against some of the mutant tumors with limited side effects. The present review provides an overview about the progress in the discovery of Eg5 inhibitors especially from 2009 to 2012 as well as the clinical trials conducted on some of these inhibitors. PMID- 23434634 TI - Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. AB - Recent applications of mass spectrometry technology have dramatically increased our understanding of the proteomic diversity of high density lipoproteins (HDL). Depending on the method of HDL isolation, upwards of 85 proteins have been identified, and the list continues to grow. In addition to proteins consistent with traditionally accepted roles in lipid transport, HDL carries surprising constituents, such as members of the complement pathway, protease inhibitors involved in hemostasis, acute-phase response proteins, immune function mediators, and even metal-binding proteins. This compositional diversity fits well with hundreds of studies demonstrating a wide functional pleiotrophy, including roles in lipid transport, oxidation, inflammation, hemostasis, and immunity. This review summarizes the progression of our understanding of HDL proteomic complexity and points out key experimental observations that reinforce the functional diversity of HDL. The possibility of specific HDL subspecies with distinct functions, the evidence supporting this concept, and some of the best examples of experimentally defined HDL subspecies are also discussed. Finally, key challenges facing the field are highlighted, particularly the need to identify and define the function of HDL subspecies to better inform attempts to pharmacologically manipulate HDL for the benefit of cardiovascular disease and possibly other maladies. PMID- 23434637 TI - Synthesis and SAR study of modulators inhibiting tRXRalpha-dependent AKT activation. AB - RXRalpha represents an intriguing and unique target for pharmacologic interventions. We recently showed that Sulindac and a designed analog could bind to RXRalpha and modulate its biological activity, including inhibition of the interaction of an N-terminally truncated RXRalpha (tRXRalpha) with the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K). Here we report the synthesis, testing and SAR of a series of novel analogs of Sulindac as potential modulators for inhibiting tRXRalpha-dependent AKT activation. A new compound 30 was identified to have improved biological activity. PMID- 23434638 TI - Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2). AB - Novel 4-substituted 2-pyridin-2-ylamides were developed using in-silico ligand based drug design (LBDD) in an attempt to identify inhibitors of SH2-containing 5'-inositol phosphatase 2 (SHIP2), which is implicated in insulin-resistant type 2 diabetes. Among the compounds synthesized, N-[4-(4-chlorobenzyloxy)pyridin-2 yl]-2-(2,6-difluorophenyl)- acetamide (CPDA, 4a) was identified as a potent SHIP2 inhibitor. CPDA was found to enhance in vitro insulin signaling through the Akt pathway more efficiently than the previously reported SHIP2 inhibitor AS1949490, and ameliorated abnormal glucose metabolism in diabetic (db/db) mice. PMID- 23434639 TI - Synthesis, biological evaluation of new oxazolidino-sulfonamides as potential antimicrobial agents. AB - A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 MUg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 MUg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented. PMID- 23434640 TI - Synthesis and cytotoxicity of 3-aryl acrylic amide derivatives of the simplified saframycin-ecteinascidin skeleton prepared from L-dopa. AB - Twenty four compounds with diversified 3-aryl acrylic amide side chains of the simplified saframycin-ecteinascidin pentacyclic skeleton were synthesized via a 14-step stereospecific route starting from L-dopa. The cytotoxicities of these compounds were tested against eight human tumor cell lines including HCT-8, BEL 7402, BGC-803, A549, A2780, MCF-7, MX-1, and MDA-MB-231. Most of these compounds exhibited potent antitumor activity, and a preliminary structure-activity relationship (SAR) was discussed. Compound 28 with 3-thiophenyl acrylic amide side chain exhibited selective cytotoxicity against MDA-MB-231 cell line with the IC50 value of 50 nM. PMID- 23434641 TI - New 2-benzylsulfanyl-nicotinic acid based 1,3,4-oxadiazoles: their synthesis and biological evaluation. AB - A novel series of 5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl 1,3,4-oxadiazoles 6a-j were synthesized from key intermediate 5-(2-benzylsulfanyl pyridin-3-yl)-3H-[1,3,4]oxadiazole-2-thione 5. Nucleophilic substitution reactions with different electrophiles (E+), such as haloacetate and haloalkyl groups, were performed to get target compounds 6a-j. Compounds were characterized by NMR, mass, IR spectra and C, H, N analyses. All compounds were evaluated for their antimicrobial and antimycobacterial activities; selected analogs were screened for their anticancer activity on 60 tumor cell lines at single dose 1.00(-5) M. Unfortunately, none of the compounds showed a significant antitumor activity on 60 human tumor cell lines. However, compounds 6g and 6f with benzothiazole moiety (12.5 and 25 MUg/ml) showed promising activity against Escherichia coli compared to ampicillin; compounds 6d, 6j bearing triazole and morpholine, respectively, showed promising antitubercular activity (25 MUg/ml) compared to rifampicin. PMID- 23434642 TI - Improving patient and worker safety: exploring opportunities for synergy. PMID- 23434643 TI - Nurses in health care governance: is the picture changing? PMID- 23434644 TI - Nurses at the highest level of decision making: in the boardroom. PMID- 23434645 TI - Isolation of microarray-quality RNA from primary human cells after intracellular immunostaining and fluorescence-activated cell sorting. AB - Microarrays have made it possible to perform high-throughput, genome-wide analyses of RNA expression from an extremely wide range of sources. This technology relies on the ability to obtain RNA of sufficient quantity and quality for this type of application. While there are means to circumvent limitations in the former, recovery of RNA suitable for microarray analysis still represents a major issue when working with some biological samples, particularly those treated with and preserved in nucleic acid-modifying organic reagents. In the present report we describe a procedure for the isolation of RNA suitable for microarray analysis from cells purified by fluorescence-activated cell sorting after fixation, permeabilization and intracellular staining with fluorochrome conjugated antibodies. We show that - although the RNA isolated from these samples presented some degradation - it performed remarkably well in microarray analysis. The method we describe here makes it available to genome-wide expression profiling a variety of biological samples that so far were confined to single-gene analysis. PMID- 23434647 TI - The Interaction of Adrenomedullin and Macrophages Induces Ovarian Cancer Cell Migration via Activation of RhoA Signaling Pathway. AB - Tumor-associated macrophages (TAMs) are correlated with poor prognosis in many human cancers; however, the mechanism by which TAMs facilitate ovarian cancer cell migration and invasion remains unknown. This study was aimed to examine the function of adrenomedullin (ADM) in macrophage polarization and their further effects on the migration of ovarian cancer cells. Exogenous ADM antagonist and small interfering RNA (siRNA) specific for ADM expression were treated to macrophages and EOC cell line HO8910, respectively. Then macrophages were cocultured with HO8910 cells without direct contact. Flow cytometry, Western blot and real-time PCR were used to detect macrophage phenotype and cytokine production. The migration ability and cytoskeleton rearrangement of ovarian cancer cells were determined by Transwell migration assay and phalloidin staining. Western blot was performed to evaluate the activity status of signaling molecules in the process of ovarian cancer cell migration. The results showed that ADM induced macrophage phenotype and cytokine production similar to TAMs. Macrophages polarized by ADM promoted the migration and cytoskeleton rearrangement of HO8910 cells. The expression of RhoA and its downstream effector, cofilin, were upregulated in macrophage-induced migration of HO8910 cells. In conclusion, ADM could polarize macrophages similar to TAMs, and then polarized macrophages promote the migration of ovarian cancer cells via activation of RhoA signaling pathway in vitro. PMID- 23434646 TI - Production of pharmaceutical proteins in solanaceae food crops. AB - The benefits of increased safety and cost-effectiveness make vegetable crops appropriate systems for the production and delivery of pharmaceutical proteins. In particular, Solanaceae edible crops could be inexpensive biofactories for oral vaccines and other pharmaceutical proteins that can be ingested as minimally processed extracts or as partially purified products. The field of crop plant biotechnology is advancing rapidly due to novel developments in genetic and genomic tools being made available today for the scientific community. In this review, we briefly summarize data now available regarding genomic resources for the Solanaceae family. In addition, we describe novel strategies developed for the expression of foreign proteins in vegetable crops and the utilization of these techniques to manufacture pharmaceutical proteins. PMID- 23434648 TI - Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint. AB - G protein-coupled receptor (GPCR) structures are of interest as a means to understand biological signal transduction and as tools for therapeutic discovery. The growing number of GPCR crystal structures demonstrates that the extracellular loops (EL) connecting the membrane-spanning helices show tremendous structural variability relative to the more structurally-conserved seven transmembrane alpha helical domains. The EL of the LPA(1) receptor have not yet been conclusively resolved, and bear limited sequence identity to known structures. This study involved development of a peptide to characterize the intrinsic structure of the LPA(1) GPCR second EL. The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA(1) CC-EL2 peptide). The ensemble of structures from multi-dimensional NMR experiments demonstrated that a robust coiled-coil formed without noticeable deformation due to the EL2 sequence. In contrast, the EL2 sequence showed well defined structure only near its C-terminal residues. The NMR ensemble was combined with a computational model of the LPA(1) receptor that had previously been validated. The resulting hybrid models were evaluated using docking. Nine different hybrid models interacted with LPA 18:1 as expected, based on prior mutagenesis studies, and one was additionally consistent with antagonist affinity trends. PMID- 23434649 TI - Phospholipids in milk fat: composition, biological and technological significance, and analytical strategies. AB - Glycerophospholipids and sphingolipids are quantitatively the most important phospholipids (PLs) in milk. They are located on the milk fat globule membrane (MFGM) and in other membranous material of the skim milk phase. They include principally phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine, while sphingomyelin is the dominant species of sphingolipids There is considerable evidence that PLs have beneficial health effects, such as regulation of the inflammatory reactions, chemopreventive and chemotherapeutic activity on some types of cancer, and inhibition of the cholesterol absorption. PLs show good emulsifying properties and can be used as a delivery system for liposoluble constituents. Due to the amphiphilic characteristics of these molecules, their extraction, separation and detection are critical points in the analytical approach. The extraction by using chloroform and methanol, followed by the determination by high pressure liquid chromatography (HPLC), coupled with evaporative light scattering (ELSD) or mass detector (MS), are the most applied procedures for the PL evaluation. More recently, nuclear magnetic resonance spectrometry (NMR) was also used, but despite it demonstrating high sensitivity, it requires more studies to obtain accurate results. This review is focused on milk fat phospholipids; their composition, biological activity, technological properties, and significance in the structure of milk fat. Different analytical methodologies are also discussed. PMID- 23434650 TI - Measurement of the Interaction Between Recombinant I-domain from Integrin alpha 2 beta 1 and a Triple Helical Collagen Peptide with the GFOGER Binding Motif Using Molecular Force Spectroscopy. AB - The role of the collagen-platelet interaction is of crucial importance to the haemostatic response during both injury and pathogenesis of the blood vessel wall. Of particular interest is the high affinity interaction of the platelet transmembrane receptor, alpha 2 beta 1, responsible for firm attachment of platelets to collagen at and around injury sites. We employ single molecule force spectroscopy (SMFS) using the atomic force microscope (AFM) to study the interaction of the I-domain from integrin alpha 2 beta 1 with a synthetic collagen related triple-helical peptide containing the high-affinity integrin binding GFOGER motif, and a control peptide lacking this sequence, referred to as GPP. By utilising synthetic peptides in this manner we are able to study at the molecular level subtleties that would otherwise be lost when considering cell-to collagen matrix interactions using ensemble techniques. We demonstrate for the first time the complexity of this interaction as illustrated by the complex multi peaked force spectra and confirm specificity using control blocking experiments. In addition we observe specific interaction of the GPP peptide sequence with the I-domain. We propose a model to explain these observations. PMID- 23434651 TI - Monovalent ions and water dipoles in contact with dipolar zwitterionic lipid headgroups-theory and MD simulations. AB - The lipid bilayer is a basic building block of biological membranes and can be pictured as a barrier separating two compartments filled with electrolyte solution. Artificial planar lipid bilayers are therefore commonly used as model systems to study the physical and electrical properties of the cell membranes in contact with electrolyte solution. Among them the glycerol-based polar phospholipids which have dipolar, but electrically neutral head groups, are most frequently used in formation of artificial lipid bilayers. In this work the electrical properties of the lipid layer composed of zwitterionic lipids with non zero dipole moments are studied theoretically. In the model, the zwitterionic lipid bilayer is assumed to be in contact with aqueous solution of monovalent salt ions. The orientational ordering of water, resulting in spatial variation of permittivity, is explicitly taken into account. It is shown that due to saturation effect in orientational ordering of water dipoles the relative permittivity in the zwitterionic headgroup region is decreased, while the corresponding electric potential becomes strongly negative. Some of the predictions of the presented mean-field theoretical consideration are critically evaluated using the results of molecular dynamics (MD) simulation. PMID- 23434652 TI - In vitro and in vivo evaluation of lactoferrin-conjugated liposomes as a novel carrier to improve the brain delivery. AB - In this study, lactoferrin-conjugated PEGylated liposomes (PL), a potential drug carrier for brain delivery, was loaded with radioisotope complex, 99mTc labeled N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (99mTc-BMEDA) for in vitro and in vivo evaluations. The hydrophilicity of liposomes was enhanced by PEGylation which was not an ideal brain delivery system for crossing the blood brain barrier (BBB). With the modification of a brain-targeting ligand, lactoferrin (Lf), the PEGylated liposome (PL) might become a potential brain delivery vehicle. In order to test the hypothesis in vitro and in vivo, 99mTc BMEDA was loaded into the liposomes as a reporter with or without Lf conjugation. The mouse brain endothelia cell line, bEnd.3 cells, was cultured to investigate the potential uptake of liposomes in vitro. The in vivo uptake by the mouse brain of the liposomes was detected by tissue biodistribution study. The results indicated that Lf-conjugated PEGylated liposome showed more than three times better uptake efficiency in vitro and two-fold higher of brain uptake in vivo than PEGlyated liposome. With the success of loading the potential Single Photon Emission Tomography (SPECT) imaging probe, 99mTc-BMEDA, Lf-PL might serve as a promising brain delivery system for loading diagnostics or therapeutics of various brain disorders. PMID- 23434653 TI - Compound K, a Ginsenoside Metabolite, Inhibits Colon Cancer Growth via Multiple Pathways Including p53-p21 Interactions. AB - Compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, has been shown to inhibit cell growth in a variety of cancers. However, the mechanisms are not completely understood, especially in colorectal cancer (CRC). A xenograft tumor model was used first to examine the anti-CRC effect of CK in vivo. Then, multiple in vitro assays were applied to investigate the anticancer effects of CK including antiproliferation, apoptosis and cell cycle distribution. In addition, a qPCR array and western blot analysis were executed to screen and validate the molecules and pathways involved. We observed that CK significantly inhibited the growth of HCT-116 tumors in an athymic nude mouse xenograft model. CK significantly inhibited the proliferation of human CRC cell lines HCT-116, SW 480, and HT-29 in a dose- and time-dependent manner. We also observed that CK induced cell apoptosis and arrested the cell cycle in the G1 phase in HCT-116 cells. The processes were related to the upregulation of p53/p21, FoxO3a-p27/p15 and Smad3, and downregulation of cdc25A, CDK4/6 and cyclin D1/3. The major regulated targets of CK were cyclin dependent inhibitors, including p21, p27, and p15. These results indicate that CK inhibits transcriptional activation of multiple tumor-promoting pathways in CRC, suggesting that CK could be an active compound in the prevention or treatment of CRC. PMID- 23434654 TI - Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration. AB - Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, including DNA. Furthermore, mitochondria may be especially important in this process because the reactive oxygen species produced in their electron transport chain can damage cellular components. Therefore, the cellular response to DNA damage, expressed mainly through DNA repair, may play an important role in AMD etiology. In several studies the increase in mitochondrial DNA (mtDNA) damage and mutations, and the decrease in the efficacy of DNA repair have been correlated with the occurrence and the stage of AMD. It has also been shown that mitochondrial DNA accumulates more DNA lesions than nuclear DNA in AMD. However, the DNA damage response in mitochondria is executed by nucleus-encoded proteins, and thus mutagenesis in nuclear DNA (nDNA) may affect the ability to respond to mutagenesis in its mitochondrial counterpart. We reported that lymphocytes from AMD patients displayed a higher amount of total endogenous basal and oxidative DNA damage, exhibited a higher sensitivity to hydrogen peroxide and UV radiation, and repaired the lesions induced by these factors less effectively than did cells from control individuals. We postulate that poor efficacy of DNA repair (i.e., is impaired above average for a particular age) when combined with the enhanced sensitivity of retinal pigment epithelium cells to environmental stress factors, contributes to the pathogenesis of AMD. Collectively, these data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis. PMID- 23434655 TI - 2-(2-Hydroxy-5-nitrobenzylidene)-1,3-indanedione versus Fluorescein Isothiocyanate in Interaction with Anti-hFABP Immunoglobulin G1: Fluorescence Quenching, Secondary Structure Alteration and Binding Sites Localization. AB - The first step in determining whether a fluorescent dye can be used for antibody labeling consists in collecting data on its physical interaction with the latter. In the present study, the interaction between the 2-(2-hydroxy-5 nitrobenzylidene)-1,3-indanedione (HNBID) dye and the IgG1 monoclonal mouse antibody anti-human heart fatty acid binding protein (anti-hFABP) has been investigated by fluorescence and circular dichroism spectroscopies and complementary structural results were obtained by molecular modeling. We have determined the parameters characterizing this interaction, namely the quenching and binding constants, classes of binding sites, and excited state lifetimes, and we have predicted the localization of HNBID within the Fc region of anti-hFABP. The key glycosidic and amino acid residues in anti-hFABP interacting with HNBID have also been identified. A similar systematic study was undertaken for the well known fluorescein isothiocyanate fluorophore, for comparison purposes. Our results recommend HNBID as a valuable alternative to fluorescein isothiocyanate for use as a fluorescent probe for IgG1 antibodies. PMID- 23434656 TI - Nature's Timepiece-Molecular Coordination of Metabolism and Its Impact on Aging. AB - Circadian rhythms are found in almost all organisms from cyanobacteria to humans, where most behavioral and physiological processes occur over a period of approximately 24 h in tandem with the day/night cycles. In general, these rhythmic processes are under regulation of circadian clocks. The role of circadian clocks in regulating metabolism and consequently cellular and metabolic homeostasis is an intensively investigated area of research. However, the links between circadian clocks and aging are correlative and only recently being investigated. A physiological decline in most processes is associated with advancing age, and occurs at the onset of maturity and in some instances is the result of accumulation of cellular damage beyond a critical level. A fully functional circadian clock would be vital to timing events in general metabolism, thus contributing to metabolic health and to ensure an increased "health-span" during the process of aging. Here, we present recent evidence of links between clocks, cellular metabolism, aging and oxidative stress (one of the causative factors of aging). In the light of these data, we arrive at conceptual generalizations of this relationship across the spectrum of model organisms from fruit flies to mammals. PMID- 23434657 TI - Flavonoids as antioxidants and developmental regulators: relative significance in plants and humans. AB - Phenylpropanoids, particularly flavonoids have been recently suggested as playing primary antioxidant functions in the responses of plants to a wide range of abiotic stresses. Furthermore, flavonoids are effective endogenous regulators of auxin movement, thus behaving as developmental regulators. Flavonoids are capable of controlling the development of individual organs and the whole-plant; and, hence, to contribute to stress-induced morphogenic responses of plants. The significance of flavonoids as scavengers of reactive oxygen species (ROS) in humans has been recently questioned, based on the observation that the flavonoid concentration in plasma and most tissues is too low to effectively reduce ROS. Instead, flavonoids may play key roles as signaling molecules in mammals, through their ability to interact with a wide range of protein kinases, including mitogen activated protein kinases (MAPK), that supersede key steps of cell growth and differentiation. Here we discuss about the relative significance of flavonoids as reducing agents and signaling molecules in plants and humans. We show that structural features conferring ROS-scavenger ability to flavonoids are also required to effectively control developmental processes in eukaryotic cells. PMID- 23434658 TI - Expression of a functional recombinant human basic fibroblast growth factor from transgenic rice seeds. AB - Basic fibroblast growth factor (FGF-2) is an important member of the FGF gene family. It is widely used in clinical applications for scald and wound healing in order to stimulate cell proliferation. Further it is applied for inhibiting stem cell differentiation in cultures. Due to a shortage of plasma and low expression levels of recombinant rbFGF in conventional gene expression systems, we explored the production of recombinant rbFGF in rice grains (Oryza sativa bFGF, OsrbFGF). An expression level of up to 185.66 mg/kg in brown rice was obtained. A simple purification protocol was established with final recovery of 4.49% and resulting in a yield of OsrbFGF reaching up to 8.33 mg/kg OsrbFGF. The functional assay of OsrbFGF indicated that the stimulating cell proliferation activity on NIH/3T3 was the same as with commercialized rbFGF. Wound healing in vivo of OsrbFGF is equivalent to commercialized rbFGF. Our results indicate that rice endosperm is capable of expressing small molecular mass proteins, such as bFGF. This again demonstrates that rice endosperm is a promising system to express various biopharmaceutical proteins. PMID- 23434661 TI - Preparation of a Facilitated Transport Membrane Composed of Carboxymethyl Chitosan and Polyethylenimine for CO2/N2 Separation. AB - The miscibility of carboxymethyl chitosan/polyethylenimine (CMCS/PEI) blends was analyzed by FT-IR, TGA and SEM. Defect-free CMCS/PEI blend membranes were prepared with polysulfone (PSf) ultrafiltration membranes as support layer for the separation of CO(2)/N(2) mixtures. The results demonstrate that the CMCS/PEI blend is miscible, due to the hydrogen bonding interaction between the two targeted polymers. For the blended membrane without water, the permeability of CO(2) gas is 3.6 * 10-7 cm3 cm-2 s-1 cmHg-1 and the corresponding separation factor for CO(2) and N(2) gas is about 33 at the pressure of 15.2 cmHg. Meanwhile, the blended membrane with water has the better permselectivity. The blended membrane containing water with PEI content of 30 wt% has the permeance of 6.3 * 10-4 cm3 cm-2 s-1 cmHg-1 for CO(2) gas and a separation factor of 325 for CO(2)/N(2) mixtures at the same feed pressure. This indicates that the CO(2) separation performance of the CMCS/PEI blend membrane is higher than that of other facilitated transport membranes reported for CO(2)/N(2) mixture separation. PMID- 23434660 TI - Epidermal growth factor stimulates extracellular-signal regulated kinase phosphorylation of a novel site on cytoplasmic Dynein intermediate chain 2. AB - Extracellular-signal regulated kinase (ERK) signaling is required for a multitude of physiological and patho-physiological processes. However, the identities of the proteins that ERK phosphorylates to elicit these responses are incompletely known. Using an affinity purification methodology of general utility, here we identify cytoplasmic dynein intermediate chain 2 (DYNC1I-2, IC-2) as a novel substrate for ERK following epidermal growth factor receptor stimulation of fibroblasts. IC-2 is a subunit of cytoplasmic dynein, a minus-end directed motor protein necessary for transport of diverse cargos along microtubules. Emerging data support the hypothesis that post-translational modification regulates dynein but the signaling mechanisms used are currently unknown. We find that ERK phosphorylates IC-2 on a novel, highly conserved Serine residue proximal to the binding site for the p150Glued subunit of the cargo adapter dynactin. Surprisingly, neither constitutive phosphorylation nor a phosphomimetic substitution of this Serine influences binding of p150Glued to IC-2. These data suggest that ERK phosphorylation of IC-2 regulates dynein function through mechanisms other than its interaction with dynactin. PMID- 23434659 TI - Annexin A2: the importance of being redox sensitive. AB - Hydrogen peroxide (H(2)O(2)) is an important second messenger in cellular signal transduction. H(2)O(2)-dependent signalling regulates many cellular processes, such as proliferation, differentiation, migration and apoptosis. Nevertheless, H(2)O(2) is an oxidant and a major contributor to DNA damage, protein oxidation and lipid peroxidation, which can ultimately result in cell death and/or tumourigenesis. For this reason, cells have developed complex antioxidant systems to scavenge ROS. Recently, our laboratory identified the protein, annexin A2, as a novel cellular redox regulatory protein. Annexin A2 possesses a reactive cysteine residue (Cys-8) that is readily oxidized by H(2)O(2) and subsequently reduced by the thioredoxin system, thereby enabling annexin A2 to participate in multiple redox cycles. Thus, a single molecule of annexin A2 can inactivate several molecules of H(2)O(2). In this report, we will review the studies detailing the reactivity of annexin A2 thiols and the importance of these reactive cysteine(s) in regulating annexin A2 structure and function. We will also focus on the recent reports that establish novel functions for annexin A2, namely as a protein reductase and as a cellular redox regulatory protein. We will further discuss the importance of annexin A2 redox regulatory function in disease, with a particular focus on tumour progression. PMID- 23434662 TI - Analysis of the enhanced stability of r(+)-alpha lipoic Acid by the complex formation with cyclodextrins. AB - R(+)-alpha lipoic acid (RALA) is one of the cofactors for mitochondrial enzymes and, therefore, plays a central role in energy metabolism. RALA is unstable when exposed to low pH or heat, and therefore, it is difficult to use enantiopure RALA as a pharma- and nutra-ceutical. In this study, we have aimed to stabilize RALA through complex formation with cyclodextrins (CDs). alpha-CD, beta-CD and gamma CD were used for the formation of these RALA-CD complexes. We confirmed the complex formation using differential scanning calorimetry and showed by using HPLC analysis that complexed RALA is more stable than free RALA when subjected to humidity and high temperature or acidic pH conditions. Scanning electron microscopy studies showed that the particle size and shape differed depending on the cyclodextrin used for complexation. Further, the complexes of CD and RALA showed a different particle size distribution pattern compared with that of CD itself or that of the physical mixture of RALA and CD. PMID- 23434663 TI - Rapid and Sensitive Determination of Timosaponin AIII in Rat Plasma by LC-MS/MS and Its Pharmacokinetic Application. AB - A rapid sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for determination of timosaponin AIII (TA-III) in rat plasma, using ginsenoside Re as an internal standard (IS). TA-III and the IS were detected in MRM mode with a negative ionization electrospray mass spectrometer. The calibration curves were linear over the concentration ranges from 11.14 to 1114 ng/mL and the lower limit of quantification (LLOQ) was 11.14 ng/mL. Intra-day and inter-day precisions (RSD) were within 10%, and accuracy ranged from 6.4% to 9.1%. The extraction recovery at three concentrations ranged from 92.3% to 95.5%. The validated method was successfully applied to monitor the concentrations of TA-III in rat plasma after intragastric administration. The best fit pharmacokinetic model to estimate the pharmacokinetic parameters was a single compartment model with weight of 1/x2 for oral administration groups of rats for TA-III. PMID- 23434664 TI - Synthesis and Characterization of the Inclusion Complex of beta-cyclodextrin and Azomethine. AB - A beta-cyclodextrin (beta-Cyd) inclusion complex containing azomethine as a guest was prepared by kneading method with aliquot addition of ethanol. The product was characterized by Fourier Transform Infrared (FTIR) spectrometer, 1H Nuclear Magnetic Resonance (1H NMR) and Thermogravimetric Analyzer (TGA), which proves the formation of the inclusion complex where the benzyl part of azomethine has been encapsulated by the hydrophobic cavity of beta-Cyd. The interaction of beta Cyd and azomethine was also analyzed by means of spectrometry by UV-Vis spectrophotometer to determine the formation constant. The formation constant was calculated by using a modified Benesi-Hildebrand equation at 25 degrees C. The apparent formation constant obtained was 1.29 * 104 L/mol. Besides that, the stoichiometry ratio was also determined to be 1:1 for the inclusion complex of beta-Cyd with azomethine. PMID- 23434666 TI - Covalent Coupling of Nanoparticles with Low-Density Functional Ligands to Surfaces via Click Chemistry. AB - We demonstrate the application of the 1,3-dipolar cycloaddition ("click" reaction) to couple gold nanoparticles (Au NPs) functionalized with low densities of functional ligands. The ligand coverage on the citrate-stabilized Au NPs was adjusted by the ligand:Au surface atom ratio, while maintaining the colloidal stability of the Au NPs in aqueous solution. A procedure was developed to determine the driving forces governing the selectivity and reactivity of citrate stabilized and ligand-functionalized Au NPs on patterned self-assembled monolayers. We observed selective and remarkably stable chemical bonding of the Au NPs to the complimentarily functionalized substrate areas, even when estimating that only 1-2 chemical bonds are formed between the particles and the substrate. PMID- 23434665 TI - NADPH oxidase biology and the regulation of tyrosine kinase receptor signaling and cancer drug cytotoxicity. AB - The outdated idea that reactive oxygen species (ROS) are only dangerous products of cellular metabolism, causing toxic and mutagenic effects on cellular components, is being replaced by the view that ROS have several important functions in cell signaling. In aerobic organisms, ROS can be generated from different sources, including the mitochondrial electron transport chain, xanthine oxidase, myeloperoxidase, and lipoxygenase, but the only enzyme family that produces ROS as its main product is the NADPH oxidase family (NOX enzymes). These transfer electrons from NADPH (converting it to NADP-) to oxygen to make O(2)*-. Due to their stability, the products of NADPH oxidase, hydrogen peroxide, and superoxide are considered the most favorable ROS to act as signaling molecules. Transcription factors that regulate gene expression involved in carcinogenesis are modulated by NADPH oxidase, and it has emerged as a promising target for cancer therapies. The present review discusses the mechanisms by which NADPH oxidase regulates signal transduction pathways in view of tyrosine kinase receptors, which are pivotal to regulating the hallmarks of cancer, and how ROS mediate the cytotoxicity of several cancer drugs employed in clinical practice. PMID- 23434667 TI - Exercise Therapy Downregulates the Overexpression of TLR4, TLR2, MyD88 and NF kappaB after Cerebral Ischemia in Rats. AB - Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) are considered to mediate the inflammatory reaction of cerebral ischemia injury, and exercise can inhibit the activity of the Toll-like receptor signaling pathway in the peripheral blood of humans. Although physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings, the underlying mechanism remains unclear. To clarify this critical issue, this study investigated the effects of treadmill training on the recovery of neurological function and the expression of TLR2 and TLR4 and their main downstream targets, nuclear factor-kappaB (NF-kappaB) and myeloid differentiation factor 88 (MyD88), in the ischemic rat brain after middle cerebral artery occlusion-reperfusion (MCAo/R). Rats were divided into seven groups: sham control without MCAo/R and five, nine and 16 days post-ischemic exercise or non-exercise. The neurological function and infarct volume were measured, and reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression of TLR2, TLR4, NF-kappaB and MyD88 in ischemic brain tissue. The results indicated that treadmill training promoted functional recovery and reduced the overexpression of TLR2, TLR4, NF-kappaB and MyD88 in rat brain tissue after ischemia, a finding that may have implications for understanding the mechanism of exercise therapy after brain ischemia and indicating new therapeutic strategies for the pharmacological modulation of TLR signaling. PMID- 23434668 TI - Crosstalk between Oxidative Stress and SIRT1: Impact on the Aging Process. AB - Increased oxidative stress has been associated with the aging process. However, recent studies have revealed that a low-level oxidative stress can even extend the lifespan of organisms. Reactive oxygen species (ROS) are important signaling molecules, e.g., being required for autophagic degradation. SIRT1, a class III protein deacetylase, is a crucial cellular survival protein, which is also involved in combatting oxidative stress. For instance, SIRT1 can stimulate the expression of antioxidants via the FoxO pathways. Moreover, in contrast to ROS, SIRT1 inhibits NF-kappaB signaling which is a major inducer of inflammatory responses, e.g., with inflammasome pathway. Recent studies have demonstrated that an increased level of ROS can both directly and indirectly control the activity of SIRT1 enzyme. For instance, ROS can inhibit SIRT1 activity by evoking oxidative modifications on its cysteine residues. Decreased activity of SIRT1 enhances the NF-kappaB signaling, which supports inflammatory responses. This crosstalk between the SIRT1 and ROS signaling provokes in a context-dependent manner a decline in autophagy and a low-grade inflammatory phenotype, both being common hallmarks of ageing. We will review the major mechanisms controlling the signaling balance between the ROS production and SIRT1 activity emphasizing that this crosstalk has a crucial role in the regulation of the aging process. PMID- 23434670 TI - A Comparison of B16 Melanoma Cells and 3T3 Fibroblasts Concerning Cell Viability and ROS Production in the Presence of Melatonin, Tested Over a Wide Range of Concentrations. AB - Melatonin is a pleiotropic molecule with many cellular and systemic actions, including chronobiotic effects. Beneficial effects are widely documented concerning the treatment of neoplastic diseases in vivo as well as reductions in viability of cultured cells from melanoma, one of the most aggressive cancers in humans. However, studies of its effects on non-tumor cells in vitro have not focused on viability, except for experiments aiming to protect against oxidotoxicity or other toxicological insults. Furthermore, there is no agreement on the range of effective melatonin concentrations in vitro, and the mechanisms that reduce cell viability have remained unclear. Tumor cell-specific increases in the production of reactive oxygen and nitrogen species (ROS/RNS) may provide a possible explanation. Our aim was to analyze the potential inhibition of tumor (B16 melanoma 4A5) and non-tumor cell (3T3 Swiss albino) viability using a wide range of melatonin concentrations (10-11-10-2 M), and to determine whether intracellular ROS enhancement was involved in this process. In the absence of fetal bovine serum (FBS), low melatonin concentrations (10-9-10-5 M) reduced the proliferation of melanoma cells with no effect in fibroblasts, whereas, in the presence of FBS, they had no effect or even increased the proliferation of both fibroblast and melanoma cells. Melatonin concentrations in the upper millimolar range increased ROS levels and reduced the viability of both cell types, but more markedly so in non-tumor cells. Thus, low melatonin concentrations reduce proliferation in this specific melanoma cell line, whereas high concentrations affect the viability of both tumor (B16 4A5 melanoma) and non-tumor (3T3 fibroblasts) cells. Increased ROS levels in both lines indicate a role for ROS production in the reduction of cell viability at high-but not low-melatonin concentrations, although the mechanism of action still remains to be elucidated. PMID- 23434671 TI - Proteome Analysis of Rice (Oryza sativa L.) Mutants Reveals Differentially Induced Proteins during Brown Planthopper (Nilaparvata lugens) Infestation. AB - Although rice resistance plays an important role in controlling the brown planthopper (BPH), Nilaparvata lugens, not all varieties have the same level of protection against BPH infestation. Understanding the molecular interactions in rice defense response is an important tool to help to reveal unexplained processes that underlie rice resistance to BPH. A proteomics approach was used to explore how wild type IR64 and near-isogenic rice mutants with gain and loss of resistance to BPH respond during infestation. A total of 65 proteins were found markedly altered in wild type IR64 during BPH infestation. Fifty-two proteins associated with 11 functional categories were identified using mass spectrometry. Protein abundance was less altered at 2 and 14 days after infestation (DAI) (T1, T2, respectively), whereas higher protein levels were observed at 28 DAI (T3). This trend diminished at 34 DAI (T4). Comparative analysis of IR64 with mutants showed 22 proteins that may be potentially associated with rice resistance to the brown planthopper (BPH). Ten proteins were altered in susceptible mutant (D1131) whereas abundance of 12 proteins including S-like RNase, Glyoxalase I, EFTu1 and Salt stress root protein "RS1" was differentially changed in resistant mutant (D518). S-like RNase was found in greater quantities in D518 after BPH infestation but remained unchanged in IR64 and decreased in D1131. Taken together, this study shows a noticeable level of protein abundance in the resistant mutant D518 compared to the susceptible mutant D1131 that may be involved in rendering enhanced level of resistance against BPH. PMID- 23434672 TI - Expression and functions of fibroblast growth factor 10 in the mouse mammary gland. AB - Fibroblast growth factor 10 (FGF10) is important as a mesenchymal mediator of epithelial growth and morphogenesis. In this study, the expression and localization of the FGF10 protein were detected by laser scanning confocal microscopy during mouse postnatal mammary gland development. Mammary explants were cultured to investigate the functions of FGF10. The results revealed that FGF10 localizes mainly in the mesenchyme near the ductal epithelial cells and the alveolar epithelial cells of the mammary gland. Peak FGF10 expression levels were observed at lactation day 10. FGF10 induced FGFR2-IIIb expression in the mammary epithelium, except in virgin or pregnant mice. FGF10 promoted the proliferation of mammary gland epithelial cells and reduced apoptosis. FGF10 is important during the mouse mammary gland growth, development, and reconstruction, and its effects are mediated by FGFR2-IIIb. PMID- 23434669 TI - Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics. AB - The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics. PMID- 23434673 TI - International journal of molecular science best paper award 2013. AB - Since 2012, International Journal of Molecular Science has instituted an annual award to recognize outstanding papers in the area of chemistry, molecular physics and molecular biology that meet the aims, scope and high standards of this journal [1]. We are pleased to announce the second "International Journal of Molecular Science Best Paper Award" for 2013. Nominations were made by the Section Editor-in-Chiefs of International Journal of Molecular Science, with all papers published in 2009 eligible for consideration. The awards are issued for reviews and articles separately. PMID- 23434674 TI - Modified PAMAM dendrimer with 4-carbomethoxypyrrolidone surface groups reveals negligible toxicity against three rodent cell-lines. AB - Modification of the surface groups of dendrimers is one of the methods to improve their biocompatibility. This article presents results of experiments related to the toxicity of a modified polyamidoamine (PAMAM) dendrimer of the fourth generation with 4-carbomethoxypyrrolidone surface groups (PAMAM-pyrrolidone dendrimer). The cytotoxic activity of the dendrimer was tested on Chinese hamster fibroblasts (B14), embryonic mouse hippocampal cells (mHippoE-18) and rat liver derived cells (BRL-3A). The same cell lines were used to investigate the influence of pyrrolidone dendrimer on the mitochondrial membrane potential, intracellular ROS level and its ability to induce apoptosis or necrosis. The analyzed dendrimer showed only minor toxicity and no ability to induce apoptosis. The most important finding is the lack of influence of the PAMAM-pyrrolidone dendrimer on intracellular ROS level and mitochondrial membrane potential. FROM THE CLINICAL EDITOR: The authors demonstrate that pyrrolidone-functionalized PAMAM dendrimers have very low toxicity in the tested cell lines, as evidenced by no alteration of mitochondrial membrane potential and no increase of ROS production. PMID- 23434675 TI - Marine actinobacterial mediated gold nanoparticles synthesis and their antimalarial activity. AB - Streptomyces sp LK-3 (JF710608) mediated Gold nanoparticles (Au-N-LK3) were found within the size range of 5-50 nm. Au-N-LK3 treatment in Plasmodium berghei ANKA (PbA) infected mice delayed the parasitemia rise (~6%) compared to PbA infection on 8 days post infection. Survivability of mice increases to ~85% in Au-N-LK3 treated mice in contrast to in PbA (~50%) infected mice in 8 dpi with respect to control. During Au-N-LK3 treatment in PbA infection, histomorphological analysis revealed as such no change in spleen and liver tissue during 8 dpi. Our results confirmed up-regulation of TGF-beta and down-regulation of TNF-alpha in tissue and serum level in PbA infected Au-N-LK3 treated mice compared to PbA infection. No significant changes were found in the hatchability of Artemia embryos upto 8 mg. The results obtained suggest that the Au-N-LK3 possess anti-malarial activity and could be considered as a potential source for anti-malarial drug development. FROM THE CLINICAL EDITOR: These investigators present a method of marine actinobacteria mediated synthesis of gold nanoparticles, resulting in nanoparticles that possess anti-malarial activity and could be considered in future anti-malarial drug development. PMID- 23434676 TI - Tissue and cellular localization of nanoparticles using 35S labeling and light microscopic autoradiography. AB - Microscopical visualization of nanoparticles in tissues is essential for assessing their distribution in whole organisms and their interaction with the cellular microenvironment, including possible toxic effects. However, labeling of nanoparticles with fluorescent dyes may affect their physicochemical properties. Moreover, the detection of organic nanoparticles in their tissue context often poses a particular challenge due to their closer similarities with biomolecules. As part of a biodistribution and toxicity study on organic anti-inflammatory nanoscaled dendritic polyglycerol sulfate amine (dPGS amine) we have established light microscopic autoradiography (LMA) for the tracking of (35)S labeled dPGS in standard histopathological tissue samples following intravenous injection in mice. The dPG(35)S amine was specifically localized in hepatic Kupffer cells with no histopathologic evidence of toxic, degenerate or inflammatory side effects. The combination of radiolabeling of organic nanoparticles with LMA offers a novel approach for their localization in microscopical slides, also allowing for a simultaneous standard toxicopathology analysis. FROM THE CLINICAL EDITOR: In this study, a novel light microscopic autoradiography utilizing (35)S isotope demonstrates a combined approach to visualize nanoparticle locations in microscopic slides with no obvious toxicity to the studied cells and with minimal external hazard. PMID- 23434677 TI - Intelligent nanomaterials for medicine: carrier platforms and targeting strategies in the context of clinical application. AB - Nanomedical approaches are a major transforming factor in medical diagnosis and therapies. Based on important earlier work in the field of liposomal drug delivery and metallic nanomaterials, the last decade has brought a broad array of new and improved intelligent nanoscale platforms which are not only suited to deliver drugs and imaging agents but also to carry advanced functionality including internal and external stimuli-responsiveness in a highly targeted fashion to a diseased area. This review focuses on required properties and differences of basic delivery platforms in regard to deliver smart functionality, on building blocks suited to enhance tissue-, cell- and receptor-specific targeting and on nano-bio interaction. Further it discusses advantages and disadvantages of those platforms for future clinical application with regard to the subject of complement activation and hypersensitivity reactions in particular against polyethylene glycol (PEG) and possible functionalization with nanosize switches. FROM THE CLINICAL EDITOR: This review focuses on the properties of platforms designed to deliver smart functionality, using appropriate building blocks to enhance tissue-, cell-, and receptor-specific targeting. The authors also discuss potential complications such as complement activation and hypersensitivity reactions, and possible functionalization with nanosize switches. PMID- 23434678 TI - Complement activation by PEG-functionalized multi-walled carbon nanotubes is independent of PEG molecular mass and surface density. AB - Carboxylated (4%) multi-walled carbon nanotubes were covalently functionalized with poly(ethylene glycol)1000 (PEG1000), PEG1500 and PEG4000 with a PEG loading of approximately 11% in all cases. PEG loading generated non-uniform and heterogeneous higher surface structures and increased nanotube width considerably, but all PEGylated nanotube species activated the complement system in human serum equally. Increased PEG loading, through adsorption of methoxyPEG2000(or 5000)-phospholipid conjugates, generated fewer complement activation products; however, complement activation was never completely eliminated. Our observations address the difficulty in making carbon nanotubes more compatible with innate immunity through covalent PEG functionalization as well as double PEGylation strategies. FROM THE CLINICAL EDITOR: Complement mediated toxicity is a major limiting factor in certain nanomedicine applications. This study clarifies that PEGylation of carbon nanotubes is unlikely to address this complication. PMID- 23434679 TI - Matrigel alters the pathophysiology of orthotopic human breast adenocarcinoma xenografts with implications for nanomedicine evaluation. AB - Matrigel, a mouse sarcoma-derived basement membrane protein mixture, is frequently used to facilitate human tumor xenograft growth in rodents. Despite its known effects on tumor growth and metastasis, its impact on tumor pathophysiology and preclinical evaluation of nanomedicines in tumor xenografts has not been reported previously. Herein bilateral MDA435 tumors were established orthotopically with (Mat+) or without (Mat-) co-injection of Matrigel. Tumor perfusion, morphology and nanoparticle retention were evaluated. As compared to Mat- tumors, Mat+tumors exhibited enhanced vascular perfusion and lymphatic flow, greater blood vessel and lymphatic growth within the tumor core, and more deformation and collapse of lymphatics in tumor-associated lymph nodes. These changes were accompanied by reduced nanoparticle retention in Mat+tumors. The results suggest that Matrigel is not a passive medium for tumor growth, but rather significantly alters long-term tumor architecture. These findings have significant implications for the evaluation of therapeutic nanomedicine in xenograft mouse models. FROM THE CLINICAL EDITOR: Matrigel is utilized in facilitating human tumor xenograft growth in rodents. The authors demonstrate that Matrigel is not a passive medium for tumor growth; instead it significantly alters long-term tumor architecture, with major implications in the evaluation of therapeutic nanomedicine in xenograft mouse models. PMID- 23434680 TI - Annexin A7 trafficking to alveolar type II cell surface: possible roles for protein insertion into membranes and lamellar body secretion. AB - A role for annexin A7 (A7) is postulated in the obligatory fusion between lamellar bodies and the plasma membrane during surfactant secretion in alveolar type II cells. This study investigated if surfactant secretagogues increase cell surface A7, which could support A7 insertion into plasma membrane as annexin proteins reportedly lack membrane penetration ability. In vivo trafficking of A7 to cell surface was determined by immuno-staining after non-permeabilizing fixation of alveolar type II cells. Stimulation with various secretagogues increased protein kinase-dependent staining for A7 and ABCA3 in comparison to control cells. Biotin-labeling of surface proteins showed ~4% of total A7 in control cells, which increased ~3-4 folds in stimulated type II cells. Increased cell surface A7 was also observed by protein cross-linking studies showing ~70kDa A7-adduct in the membranes but not in the cytosol fraction of PMA- or A23187 stimulated cells. In vitro phosphorylation increased the Ca(2+)-dependent binding of recombinant A7 to lung plasma membranes; and subsequent cross-linking showed increased levels of ~70kDa A7-adduct. PMA-stimulation of type II cells increased A7 trafficking to lipid rafts suggesting that the latter are involved in A7 trafficking to the cell surface. However, in vitro membrane insertion of recombinant A7 and its tryptophan mutants as determined by fluorescence quenching with doxylPC suggested only shallow membrane insertion by A7. Together, our studies support in vivo association between surfactant secretion and cell surface A7 occurring by insertion into plasma membrane and by fusion of A7 containing lamellar bodies. PMID- 23434681 TI - New insights into the function and regulation of mitochondrial fission. AB - Mitochondrial morphology changes dynamically by coordinated fusion and fission and cytoskeleton-based transport. Cycles of outer and inner membrane fusion and fission are required for the exchange of damaged mitochondrial genome DNA, proteins, and lipids with those of healthy mitochondria to maintain robust mitochondrial structure and function. These dynamics are crucial for cellular life and death, because they are essential for cellular development and homeostasis, as well as apoptosis. Disruption of these functions leads to cellular dysfunction, resulting in neurologic disorders and metabolic diseases. The cytoplasmic dynamin-related GTPase Drp1 plays a key role in mitochondrial fission, while Mfn1, Mfn2 and Opa1 are involved in fusion reaction. Here, we review current knowledge regarding the regulation and physiologic relevance of Drp1-dependent mitochondrial fission: the initial recruitment and assembly of Drp1 on the mitochondrial fission foci, regulation of Drp1 activity by post translational modifications, and the role of mitochondrial fission in cell pathophysiology. PMID- 23434682 TI - Protein O-mannosylation: what we have learned from baker's yeast. AB - BACKGROUND: Protein O-mannosylation is a vital type of glycosylation that is conserved among fungi, animals, and humans. It is initiated in the endoplasmic reticulum (ER) where the synthesis of the mannosyl donor substrate and the mannosyltransfer to proteins take place. O-mannosylation defects interfere with cell wall integrity and ER homeostasis in yeast, and define a pathomechanism of severe neuromuscular diseases in humans. SCOPE OF REVIEW: On the molecular level, the O-mannosylation pathway and the function of O-mannosyl glycans have been characterized best in the eukaryotic model yeast Saccharomyces cerevisiae. In this review we summarize general features of protein O-mannosylation, including biosynthesis of the mannosyl donor, characteristics of acceptor substrates, and the protein O-mannosyltransferase machinery in the yeast ER. Further, we discuss the role of O-mannosyl glycans and address the question why protein O mannosylation is essential for viability of yeast cells. GENERAL SIGNIFICANCE: Understanding of the molecular mechanisms of protein O-mannosylation in yeast could lead to the development of novel antifungal drugs. In addition, transfer of the knowledge from yeast to mammals could help to develop diagnostic and therapeutic approaches in the frame of neuromuscular diseases. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. PMID- 23434683 TI - Forming disulfides in the endoplasmic reticulum. AB - Protein disulfide bonds are an important co- and post-translational modification for proteins entering the secretory pathway. They are covalent interactions between two cysteine residues which support structural stability and promote the assembly of multi-protein complexes. In the mammalian endoplasmic reticulum (ER), disulfide bond formation is achieved by the combined action of two types of enzyme: one capable of forming disulfides de novo and another able to introduce these disulfides into substrates. The initial process of introducing disulfides into substrate proteins is catalyzed by the protein disulfide isomerase (PDI) oxidoreductases which become reduced and, therefore, have to be re-oxidized to allow for further rounds of disulfide exchange. This review will discuss the various pathways operating in the ER that facilitate oxidation of the PDI oxidoreductases and ultimately catalyze disulfide bond formation in substrate proteins. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. PMID- 23434684 TI - beta-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1. AB - The steroid receptor coactivator p/CIP, also known as SRC-3, is an oncogene commonly amplified in breast and ovarian cancers. p/CIP is known to associate with coactivator arginine methyltransferase 1 (CARM1) on select estrogen responsive genes. We have shown, using a ChIP-on-chip approach, that in response to stimulation with 17beta-estradiol (E2), the p/CIP/CARM1 complex is recruited to 204 proximal promoters in MCF-7 cells. Many of the complex target genes have been previously implicated in signaling pathways related to oncogenesis. Jak2, a member of the Jak/Stat signaling cascade, is one of the direct E2-dependent targets of the p/CIP/CARM1 complex. Following E2-treatment, histone modifications at the Jak2 promoter are reflective of a transcriptionally permissive gene, and modest changes in RNA and protein expression lead us to suggest that an additional factor(s) may be required for a more notable transcriptional and functional response. Bioinformatic examination of the 204 proximal promoter sequences of p/CIP/CARM1 targets supports the idea that transcription factor crosstalk is likely the favored mechanism of E2-dependent p/CIP/CARM1 complex recruitment. This data may have implications towards understanding the oncogenic role of p/CIP in breast cancer and ultimately allow for the identification of new prognostic indicators and/or viable therapeutic targets. PMID- 23434685 TI - Experimental studies on the effect of different metallic substrates on marine biofouling. AB - In the wake of adoption of the resolution by the International Maritime Organization to control biofouling on vessels, which is recognized as a major vector for transfer of invasive species, this study attempts to create a baseline data on major hard-shelled biofouling organisms in the harbour waters. This study was primarily focused towards understanding the biofouling and corrosion pattern on various metals and their performance under immersed condition in a marine environment, at 0.3 and 3.0m depths. Furthermore, the study attempts to understand the surface dependent characteristics of barnacle base plate and its adhesion strength. Barnacle, mussels and oysters were the major fouling organisms accounting for 72.33% of the variation. Stainless steel and Titanium panels showed the highest average biofouling load of 176.36 and 168.35 g/300 cm(2), respectively. The variance in biofouling between metals and depths was highly significant at p<0.001 and p<0.01, respectively. Morphology of barnacle base plate interfacial surface varied between metals. Barnacles with 8-9 mm base diameter showed the maximum adhesion strength in shear of 6.86+/-0.95 kPa. PMID- 23434686 TI - Enhancing antibacterial activity of surface-grafted chitosan with immobilized lysozyme on bioinspired stainless steel substrates. AB - Bacterial infections have been widely recognized as a major cause of the failure of medical implants and devices. One promising strategy to reduce the incidence of infections is to impart the material surfaces with bactericidal function for inhibiting bacterial adhesion and biofilm formation. In this study, stainless steel (SS) surface was first activated by a biomimetic dopamine anchor to provide active amino groups, followed by covalently immobilizing chitosan (CS) with glutaraldehyde (GA) as a bifunctional linker. Hen egg white lysozyme, a natural defensive enzyme, was finally conjugated to the grafted chitosan to enhance biocidal functionality. The antibacterial assay results demonstrated substantial enhancement in bactericidal efficiency against Staphylococcus aureus (S. aureus) on the lysozyme-immobilized SS substrates under the neutral pH conditions as compared to the chitosan-grafted SS substrates. With the inherent advantages of robust anchoring ability of dopamine and specific functionality of lysozyme, the metallic substrates can be readily tailored with antibacterial property to combat biomaterial-centered infection for potential biomedical applications. PMID- 23434687 TI - Lateral diffusion of lipids separated from rotational and translational diffusion of a fluid large unilamellar vesicle. AB - A new method to separate lateral diffusion of lipids in spherical large unilamellar vesicles from the rotational and the translational diffusion of the vesicle as a whole is proposed. The lateral diffusion coefficient DL is obtained as a time-dependent part of the observed diffusion coefficient in vesicles of 800 nm diameters, by systematically changing the diffusion time interval of the high field-gradient NMR measurement. Although the lipid is in a confined space, the DL of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine is (1.5+/-0.6)*10(-11) m(2) s(-1) in the fluid state at 45 degrees C, more than one order of magnitude faster than the rotational and the translational diffusion coefficients of the vesicle by the hydrodynamic continuum model. The method provides a potential for quantifying the lateral diffusion of lipids and proteins in fluid bilayer vesicles as model cell membranes in a natural manner. PMID- 23434688 TI - Exploring DNA binding properties and biological activities of dihydropyrimidinones derivatives. AB - The effects of substituent modifications for three dihydropyrimidinones derivatives on DNA binding properties were investigated using viscometry in combination with spectroscopy and isothermal titration calorimetry (ITC). The results indicated that substitution in 4 rd position of benzene ring has significant effects on DNA binding mode, affinity and energetics. Electron donating substitution was favorable for intercalating into DNA bases and had higher DNA binding affinity. However, electron-withdrawing substitution was preferable to bind to DNA in partial intercalation mode with relatively weak DNA binding affinity. Simultaneously, electron-donating substitution could result in more favorable binding enthalpy relative to electron-donating substitution and the parent compound. Antitumor activities of these analogs over BEL-7402 and PC 12 cells were studied to explore the structure activity relationships (SARs), which suggested that electron-donating substitution in 4 rd position of benzene ring could greatly enhance the antitumor activities. However, electron withdrawing substitution has little effect on the antitumor activity. The present results favor the development of potential drugs related with dihydropyrimidinones derivatives in the treatment of some diseases. PMID- 23434689 TI - Enhanced osteoblastic cell response on zirconia by bio-inspired surface modification. AB - Excellent esthetic properties and limited plaque adhesion make zirconia ceramics an ideal material for implants in the fields of dentistry and orthopedics. Unfortunately, the physicochemical stability of zirconia makes it difficult to improve biocompatibility through surface modification. The dopamine-derived residue, 3,4-dihydroxy-L-phenylalanine (L-DOPA), has been identified as an important molecule secreted by marine mussels for the formation of adhesive pads. This study coated zirconia with L-DOPA to improve the biocompatibility of ZrO2. As confirmed by contact angle and X-ray photoelectron spectroscopy (XPS), the formation of L-DOPA film can be controlled by varying the process temperature. Results from scanning electron microscopy (SEM) and atomic force microscopy (AFM) show that the topography of the zirconia substrate was preserved after being coated with a film of L-DOPA. Specifically, the thickness of the coating and initial cell spreading ability were both enhanced by preparing samples at higher temperatures. L-DOPA coated zirconia demonstrated better cyto-compatibility than uncoated specimens, as indicated by cell responses such as cell spreading and proliferation. These preliminary results suggest that L-DOPA film could be used to improve the cyto-compatibility of zirconia and further has the potential to immobilize other biofunctional molecules in biomedical applications. PMID- 23434690 TI - A novel reusable PAni-PVA-Amylase film: activity and analysis. AB - Alpha-amylase was immobilized onto polyaniline-polyvinyl alcohol (PAni-PVA) film by cross linking with glutaraldehyde. The activity yield and immobilization efficiency was calculated as 13.58% and 30.60% respectively. The PAni-PVA-Amylase films were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and amylase activity assay. The immobilized alpha-amylase had its optimum activity at pH 7.0 and 25 degrees C. The immobilization of alpha-amylase onto the PAni-PVA films protected the enzyme from Fe(2+) inhibition. The PAni-PVA-Amylase films could be used effectively for 30 cycles with 60% retention of the activity. PMID- 23434691 TI - One-step in situ fabrication of a granular semi-IPN hydrogel based on chitosan and gelatin for fast and efficient adsorption of Cu2+ ion. AB - The novel granular semi-IPN hydrogels were in situ prepared in an aqueous solution by the free-radical grafting and crosslinking reactions among chitosan (CTS), acrylic acid (AA), gelatin (GE) and N,N'-methylene-bis-acrylamide. The FTIR spectra and elemental analysis confirmed that the AA monomers were grafted onto CTS backbone, and the GE macromolecular chains interpenetrated through the CTS-g-PAA network. The hydrogels are granular, which are composed of numerous micro-spheres according to the scanning electron microscope observations. The gel strength, adsorption, reuse and recovery properties of the hydrogels for Cu(2+) ion were systematically investigated. The results indicate the hydrogel with 2 wt% GE has the highest adsorption capacity of 261.08 mg/g with the recovery ratio of 95.2%. And the incorporation of 10 wt% GE enhanced the storage modulus by 103.4% (omega=100 rad/s) and 115.1% (omega=0.1 rad/s), and the adsorption rate by 5.67%. Moreover, the adsorption capacity of the hydrogel is still as high as 153.9 mg/g, after five cycles of adsorption-desorption. It was found that the ion exchange and complexation interactions between the functional groups (-COO(-) and -NH2) of the hydrogels and Cu(2+) ion are the predominant adsorption mechanisms. PMID- 23434692 TI - Fabrication and characterization of a triple functionalization of graphene oxide with Fe3O4, folic acid and doxorubicin as dual-targeted drug nanocarrier. AB - A novel triple functionalized drug delivery system was synthesized by encapsulation of superparamagnetic graphene oxide (GO) and doxorubicin (DOX) with folic acid (FA) conjugated chitosan (CHI). The carrier exhibited a high loading efficiency (0.98 mg/mg), a high saturation magnetization (10.5 emu/g) and a prolonged release rate. A real-time monitoring method on the drug release from graphene oxide (GO) was reported using DOX as the model drug. The release mechanism of DOX at different pH was investigated via monitoring the time dependency of the accumulative drug release. Results show that the drug release of DOX was pH sensitive as observed at pH 5.3 and pH 7.4 PBS solutions, the lower pH values lead to weaker hydrogen bonds and degradation of CHI, and thus result in a higher release rate of DOX. Especially, this system could be applied as a dual-targeted drug nanocarrier by combined biological (active) and magnetical (passive) targeting capabilities. Our research suggests that a novel triple functionalized, pH-responsive nanocarrier for anticancer drug has been synthesized. PMID- 23434693 TI - Improved immobilization of biomolecules to quinone-rich polydopamine for efficient surface functionalization. AB - Polydopamine (PDA), a bio-inspired polymer, has been very attractive for diverse functional applications by immobilizing biomolecules. In this work, a novel approach of using PDA for improved biomolecule immobilization was developed. A thin PDA layer was strategically coated onto 316L stainless steel and thermally treated at 150 degrees C (PDA-Th150). Subsequently, amino-terminated polyethylene glycol (mPEG-NH2) or vascular endothelial growth factor (VEGF) was immobilized onto PDA and PDA-Th150 surface. The results of attenuated total reflection Fourier transform-infrared spectroscopy (ATR-FTIR) and X-ray photoelectron spectroscopy (XPS) showed higher coverage of quinine on PDA-Th150 surface. The functionalized PDA-Th150 significantly improved its ability of immobilizing mPEG NH2 or VEGF, as shown by platelet adhesion test and endothelial cell proliferation experiments. This novel approach may also be used for efficient immobilization of biomolecules on different metal devices. PMID- 23434694 TI - Biosynthesis, characterization and cytotoxic effect of plant mediated silver nanoparticles using Morinda citrifolia root extract. AB - Silver has been used since time to control bodily infection, prevent food spoilage and heal wounds by preventing infection. The present study aims at an environmental friendly method of synthesizing silver nanoparticles, from the root of Morinda citrifolia; without involving chemical agents associated with environmental toxicity. The obtained nanoparticles were characterized by UV-vis absorption spectroscopy with an intense surface plasmon resonance band at 413 nm clearly reveals the formation of silver nanoparticles. Fourier transmission infra red spectroscopy (FTIR) showed nanopartilces were capped with plant compounds. Field emission-scanning electron microscopy (FE-SEM) and Transmission electron microscopy (TEM) showed that the spherical nature of the silver nanoparticles with a size of 30-55 nm. The X-ray diffraction spectrum XRD pattern clearly indicates that the silver nanoparticles formed in the present synthesis were crystalline in nature. In addition these biologically synthesized nanoparticles were also proved to exhibit excellent cytotoxic effect on HeLa cell. PMID- 23434695 TI - Structural attributes affecting peptide entrapment in PEO brush layers. AB - A more quantitative understanding of peptide loading and release from polyethylene oxide (PEO) brush layers will provide direction for development of new strategies for drug storage and delivery. In this work we recorded selected effects of peptide structure and amphiphilicity on adsorption into PEO brush layers based on covalently stabilized Pluronic((r))F 108. Optical waveguide lightmode spectroscopy and circular dichroism measurements were used to characterize the adsorption of poly-l-glutamic acid, poly-l-lysine, and the cationic amphiphilic peptide WLBU2, to the brush layers. The structure of WLBU2 as well as that of the similarly-sized homopolymers was controlled between disordered and more ordered (helical) forms by varying solution conditions. Adsorption kinetic patterns were interpreted with reference to a simple model for protein adsorption, in order to evaluate rate constants for peptide adsorption and desorption from loosely and tightly bound states. While more ordered peptide structure apparently promoted faster adsorption and elution rates, resistance to elution while in the PEO layer was dependent on peptide amphiphilicity. The results presented here are compelling evidence of the potential to create anti fouling surface coatings capable of storing and delivering therapeutics. PMID- 23434696 TI - Biogenic silver nanoparticles for cancer treatment: an experimental report. AB - A generation of nanoparticles research has discussed recently. It is mandatory to elaborate the applications of biogenic nanoparticles in general and anticancereous property in particular. The present study was aimed to investigate the in vitro cytotoxicity effect of biogenic silver nanoparticles (AgNPs) against human breast cancer (MCF-7) cells towards the development of anticancer agent. Biogenic AgNPs were achieved by employing Sesbania grandiflora leaf extract as a novel reducing agent. It was well characterized by FESEM, EDAX and spectral studies showed spherical shaped nanoparticles in the size of 22 nm in slightly agglomerated form. It was surprising that biogenic AgNPs showed cytotoxic effect against MCF-7 cell lines were confirmed by MTT, AO-EB, Hochest and COMET assays. There was an immediate induction of cellular damage in terms of loss of cell membrane integrity, oxidative stress and apoptosis were found in the cell which treated with AgNPs. This may be a first report on anti-MCF-7 property of biogenic AgNPs in the fourth generation of nanoparticles research. It is necessary to study the formulation and clinical trials to establish the nano drug to treat cancer cells. PMID- 23434697 TI - Camptothecine encapsulated composite drug delivery system for colorectal peritoneal carcinomatosis therapy: biodegradable microsphere in thermosensitive hydrogel. AB - In this work, we developed a biodegradable and injectable composite drug delivery system (DDS), camptothecine (CPT) loaded polymeric microsphere in thermosensitive hydrogel, for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(epsilon-caprolactone)-poly(ethylene glycol) poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administrated to form microsphere or thermosensitive hydrogel, respectively. Therefore, the composite DDS was composed of CPT loaded microsphere (CPT-MS) and thermosensitive hydrogel. CPT-MS was prepared by CPT and PCEC copolymer (Mn=31,600) using an oil-in-water emulsion solvent evaporation method. Besides, biodegradable and injectable thermosensitive PCEC hydrogel (Mn=3150) with lower sol-gel transition temperature at around body temperature was also prepared. The CPT-MS in thermosensitive hydrogel (CPT MS/hydrogel) composite is a free-flowing sol at ambient temperature and instantly converts into a non-flowing gel at body temperature. Furthermore, cytotoxicity assay indicated that both microsphere and hydrogel were biocompatible with very low cytotoxicity. In vitro release profile demonstrated a significant difference between rapid release of free CPT and much slower and sustained release of CPT MS/hydrogel. In addition, intraperitoneal administration of CPT-MS/hydrogel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, and prolonged the survival of tumor bearing mice. Compared with CPT-MS or free CPT, CPT-MS/hydrogel induced a stronger anti-tumor effect by increasing apoptosis of tumor cells and inhibiting microvessel density of tumor tissue. Besides, side effects of CPT were also alleviated in CPT-MS/hydrogel-treated mice. Thus, our results suggested that CPT-MS/hydrogel may have great potential applications in clinic. PMID- 23434698 TI - Steric and electrostatic surface forces on sulfonated PEG graft surfaces with selective albumin adsorption. AB - Addition of ionized terminal groups to PEG graft layers may cause additional interfacial forces to modulate the net interfacial interactions between PEG graft layers and proteins. In this study we investigated the effect of terminal sulfonate groups, characterizing PEG-aldehyde (PEG-CHO) and sulfonated PEG (PEG SO3) graft layers by XPS and colloid probe AFM interaction force measurements as a function of ionic strength, in order to determine surface forces relevant to protein resistance and models of bio-interfacial interaction of such graft coatings. On the PEG-CHO surface the measured interaction force does not alter with ionic strength, typical of a repulsive steric barrier coating. An analogous repulsive interaction force of steric origin was also observed on the PEG-SO3 graft coating; however, the net interaction force changed with ionic strength. Interaction forces were modelled by steric and electrical double layer interaction theories, with fitting to a scaling theory model enabling determination of the spacing and stretching of the grafted chains. Albumin, fibrinogen, and lysozyme did not adsorb on the PEG-CHO coating, whereas the PEG graft with terminal sulfonate groups showed substantial adsorption of albumin but not fibrinogen or lysozyme from 0.15 M salt solutions. Under lower ionic strength conditions albumin adsorption was again minimized as a result of the increased electrical double-layer interaction observed with the PEG-SO3 modified surface. This unique and unexpected adsorption behaviour of albumin provides an alternative explanation to the "negative cilia" model used by others to rationalize observed thromboresistance on PEG-sulfonate coatings. PMID- 23434699 TI - Drug delivery and tissue engineering applications of biocompatible pectin chitin/nano CaCO3 composite scaffolds. AB - In this work, we have developed a nanocomposite scaffold using a mixture of pectin, chitin and nano CaCO3 using the technique of lyophilization, with an intended use towards biomedical applications such as tissue engineering and drug delivery. The prepared composite scaffold was characterized using scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and X ray diffraction (XRD). In addition, swelling, degradation and biomineralization capability of the composite scaffold was evaluated. The developed composite scaffold showed controlled swelling and degradation in comparison with the control scaffold. Cytocompatibility evaluation of the scaffold was tested on NIH3T3, L929 and human dermal fibroblast (HDF) cells, showed negligible toxicity towards cells. Cell attachment and proliferation studies were also conducted using these cells, which showed that cells attached onto the scaffolds and started to proliferate after 48 h of incubation. Further, drug delivery through the scaffold was examined using a bisphosphonate called Fosamax. These results suggest that the developed composite scaffold possess the essential requisites for their application in the fields of tissue engineering and drug delivery. PMID- 23434700 TI - Tamoxifen loaded folic acid armed PEGylated magnetic nanoparticles for targeted imaging and therapy of cancer. AB - Magnetic nanoparticles (MNPs) have been widely used as drug delivery nanosystems and contrast agent for imaging and detection. To engineer multifunctional nanomedicines for simultaneous imaging and therapy of cancer cells, in the current study, we synthesized tamoxifen (TMX) loaded folic acid (FA) armed MNPs to target the folate receptor (FR) positive cancer cells. To this end, Fe3O4 nanoparticles (NPs) were synthesized through thermal decomposition of Fe(acac)3. Polyethylene glycol (PEG) was treated with excess bromoacetyl chloride (BrAc) and then with 3-aminopropyltriethoxysilane (APS) to synthesize bromoacetyl-terminal polyethylene glycol silane (APS-PEG-BrAc). The latter complex was treated with protected ethylene diamine to form a bifunctional PEG compound containing triethoxysilane at one end and amino group at the other end (APS-PEG-NH2). The Fe3O4-APS-PEG-NH2 NPs were prepared through self-assembly of APS-PEG-NH2 on MNPs, while the amino groups at the end of Fe3O4-APS-PEG-NH2 were conjugated with folic acid (FA), then loaded with TMX (Fe3O4-APS-PEG-FA-TMX). The average size of "Fe3O4-APS-PEG-FA-TMX" NPs was approximately 40 nm. The engineered MNPs were further characterized and examined in the human breast cancer MCF-7 cells that express FR. The TMX loaded MNPs (with loading efficiency of 49.1%) showed sustained liberation of TMX molecules (with 90% release in 72 h). Fluorescence microcopy and flow cytometry analyses revealed substantial interaction of Fe3O4 APS-PEG-FA-TMX NPs with the FR-positive MCF-7 cells. Cytotoxicity analysis resulted in significant growth inhibition in MCF-7 cells treated with Fe3O4-APS PEG-FA-TMX NPs. Based on these findings, the TMX-loaded FA-armed PEGylated MNPs as a novel multifunctional nanomedicine/theranostic for concurrent targeting, imaging and therapy of the FR-positive cancer cells. PMID- 23434701 TI - Dual role of outer epicuticular lipids in determining the wettability of dragonfly wings. AB - Numerous natural surfaces possess superhydrophobicity and self-cleaning properties that would be extremely beneficial when applied in industry. Dragonfly wings are one example of such surfaces, and while their general surface structure is known, their precise chemical composition is not. Here, the epicuticular lipids of dragonfly wing membranes were characterized to investigate their significance in contributing to self-cleaning and superhydrophobic properties. After just 10s of lipid extraction using chloroform, the water contact angles exhibited by the wings decreased below the accepted threshold for superhydrophobicity (150 degrees ). Infrared spectra collected at the Australian Synchrotron contained characteristic absorption bands of amide, ester and aliphatic hydrocarbons moieties on the wing surfaces, the latter of which was decreased post-extraction with chloroform. GC-MS data analysis revealed that the epicuticular wax components were dominated by n-alkanes with even-numbered carbons, especially n-hexacosane, and palmitic acid. SEM and AFM data analysis conducted on the untreated and chloroform-extracted wing surfaces demonstrated that surface topography changed after extraction; the surface nanostructure was progressively lost with extended extraction times. The data presented here indicate that epicuticular lipids contribute not only to self-cleaning and superhydrophobic properties through their inherent hydrophobic nature, but also by forming the physical structure of the wing surface. This knowledge will be extremely valuable for reconstruction of dragonfly wing structures as a biomimetic template. PMID- 23434702 TI - A comparative study on long-term MTX controlled release from intercalated nanocomposites for nanomedicine applications. AB - The feasibility of some mesoporous materials such as SBA-15 and MCM-41 silica, LDH (layered double hydroxide) (Mg3Al-NO3) and MC (mesoporous carbon) have been comparatively evaluated for oral drug delivery applications, in order to broaden the range of matrices and implicitly to develop the class of drug delivery systems based on diffusion mechanism. As well known, methotrexate (MTX) is used widely to treat various neoplastic diseases such as acute lymphoblast leukemia, lymphoma and solid cancers and autoimmune diseases such as psoriasis and rheumatoid arthritis. The commercially available formulations of this drug have disadvantages due to the traditional release process that occurs in the body. Thus, this work is focused on the long-term controlled MTX delivery because this one could eliminate over or underdosing, could maintain drug levels in desired range, could increase patient compliance and prevent the side effects. Therefore, the mesoporous materials are used and efficient MTX-delivery systems, based on above-mentioned mesoporous materials, are successfully prepared by intercalation. The obtained drug carriers were tested in the controlled MTX-drug release process and the influence of the pore morphology and geometry on MTX release profiles was extensively studied comparatively. The prepared MTX delivery systems were characterized by FTIR and UV-vis spectroscopy, N2 sorption measurements. Then, the data obtained from the in vitro release studies have been analyzed, and in order to evaluate the MTX-release mechanism and kinetics, the Korsmeyer-Peppas equation has been applied. PMID- 23434703 TI - Dyeing regions of oxidative hair dyes in human hair investigated by nanoscale secondary ion mass spectrometry. AB - To develop more effective oxidative hair coloring products, it is important to understand the localization of colored chromophores, which are formed from oxidative dyes, in the fine structure of hair. However, the dyeing regions of oxidative hair dyes in the fine structure of hair have not been extensively examined. In this study, we investigated the distribution and localization of colored chromophores formed by an oxidative hair coloring product in the fine structure of human hair by using a stable isotope-labeled oxidative dye with nanoscale secondary ion mass spectrometry (NanoSIMS). First, formation of the colored chromophore from a deuterium-labeled oxidative dye was examined by visible spectra similarly to a study of its formation using nonlabeled oxidative dye. Furthermore, the formation of binuclear indo dye containing deuterium in its chemical structure was confirmed using time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis. As a result of the NanoSIMS image on a cross sectional dyed hair, although deuterium ions were detected in whole hair cross section, quite a few of them were detected at particulate regions. These particulate regions of the dyed black hair in which deuterium ions were intensely detected were identified as melanin granules, by comparing the dyeing behaviors of black and white hair. NanoSIMS analysis revealed that melanin granules of black human hair are important dyeing regions in oxidative hair coloring. PMID- 23434704 TI - An electrochemical sensor based on poly (solochrome dark blue) film coated electrode for the determination of dopamine and simultaneous separation in the presence of uric acid and ascorbic acid: a voltammetric method. AB - In this paper, the carbon paste electrode (CPE) was modified with poly- Solochrome dark blue (poly-SDB), through polymerization process, and it was used for the sensitive and selective determination of dopamine (DA). The simultaneous determination of Dopamine (DA) Ascorbic acid (AA) and Uric acid (UA) in 0.1 M Phosphate buffer solution (PBS) of pH 6.0 was carried out by employing differential pulse voltammetric technique (DPV). The effect of pH, concentration, scan rate, accumulation time, repetability and reproducibility of DA was studied at poly-SDB film modified electrode. The poly-SDBCPE exhibited a strong electrocatalytic action toward the oxidation of DA, AA and UA. The overlapping voltammetric response of biomolecules separated in to three well defined peaks with lower oxidation potential and significant increase in the anodic peak currents in the presence of poly-SDBCPE was achieved. The results showed a good sensitivity, selectivity and high reproducibility of electro synthesized polymer electrode. The limit of detection, limit of quantification and correlation coefficient of DA at poly-SDBCPE was 0.8 MUM, 2.8 MUM and 0.99765 respectively. The effect of interference was studied by DPV technique. The developed modified electrode was used for the analysis of DA in pharmaceutical formulations with satisfactory results. The interfacial electron transfer behavior of DA was studied by electrochemical impedance spectroscopy (EIS) and results showed that the charge transfer rate was enhanced at poly- SDBCPE, when compared with bare CPE, glassy carbon electrode (GCE) and platinum electrode (Pt). PMID- 23434705 TI - Bio-silica coated with amorphous manganese oxide as an efficient catalyst for rapid degradation of organic pollutant. AB - A novel rapid green one-step method is developed for the preparation of bio silica coated with amorphous MnO2 nanoparticles by treating bio-silica with an acidic permanganate solution. The method developed has the advantage of selectively coating the surface of either one or both sides of the porous silica structure with a thin catalytic active amorphous MnO2 layer in a controlled way. The uncoated and MnO2 coated bio-silica are characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The catalytic activity of amorphous MnO2-coated bio-silica is examined by degrading organic dye at ambient condition. The as-synthesized samples show highly efficient and rapid degradation of Rhodamine B. The simplicity and cost effectiveness of the materials and method can be very useful for highly efficient degradation of organic pollutants for environmental remediation. PMID- 23434706 TI - Voltammetric oxidation and determination of atorvastatin based on the enhancement effect of cetyltrimethyl ammonium bromide at a carbon paste electrode. AB - An electrochemical method has been described for the voltammetric oxidation and determination of an antihyperlipoproteinemic drug, atorvastatin (ATOR), at a carbon paste electrode (CPE) in the presence of an enhancing agent, cetyltrimethyl ammonium bromide (CTAB) using cyclic and differential pulse voltammetry (DPV). The results indicated that the voltammetric response of ATOR was improved distinctly in the low concentration of CTAB, suggesting that CTAB exhibits noticeable enhancement effect to the determination of ATOR. The dependence of current on pH, concentration and scan rate were investigated to optimize the experimental conditions for the determination of ATOR. The anodic peak was characterized and the process was adsorption-controlled. The number of electrons transferred in the oxidation process was calculated and a plausible oxidation mechanism was proposed. In the range of 0.05-10 MUM, the current measured by DPV presents a good linear property as a function of the concentration of ATOR with a detection limit of 4.08 nM with good selectivity and sensitivity. The proposed method was successfully applied to ATOR determination in pharmaceutical samples and urine as a real sample. This method can be employed in clinical analysis, quality control and routine determination of drugs in pharmaceutical formulations. PMID- 23434707 TI - Augmentation of PCR efficiency using highly thermostable gold nanoparticles synthesized from a thermophilic bacterium, Geobacillus stearothermophilus. AB - Biogenic gold nanoparticles were synthesized from the Geobacillus stearothermophilus cell-free extract. These nanoparticles were characterized by UV-vis spectroscopy, FTIR, TEM, and XRD. The gold nanoparticles showed an absorption maximum at 522 nm. The TEM micrograph revealed the formation of monodispersed particles. The high degree of stability of the nanoparticle solution could be attributed to the secretion of certain capping proteins by the bacterium in the reaction mixture which was confirmed by the FTIR and UV-vis spectrometric analyses. The heat transfer property of the gold nanoparticles in aqueous solution has been explored in the current study for augmenting the PCR efficiency. The highly thermostable biogenic gold nanoparticles effectively increased the yield, product specificity besides reducing the reaction time of the PCR. PMID- 23434708 TI - One-step facile construction of high aspect ratio Fe3O4 decorated CNFs with distinctive porous morphology: potential multiuse expectations. AB - The objective of our study was to develop a new class of Fe3O4 nanocrystals decorated CNFs with characteristic porous morphology by straightforward approach. The utilized CNFs-Fe3O4 hybrid was prepared by sol-gel electrospinning employing polyacrylonitrile and iron (III) nitrate nonahydrate as precursors. Scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy and X-ray diffraction techniques were employed to characterize novel CNFs-Fe3O4 composite. Nanofibers are having porous morphology, diameter size in the range of ~260+/-20 nm. In order to demonstrate the broad applicability of CNFs-Fe3O4 scaffold, we performed different analysis. The antibacterial activity was tested using Escherichia coli as model organism. With NIH 3T3 mouse fibroblasts, cytotoxicity of prepared high aspect ratio CNFs-Fe3O4 composite was evaluated by thiazoyl blue tetrazolium-bromide (MTT) assay, and fibroblast cell growth behavior with electrospun porous scaffolds was also examined. Interestingly, the prepared nanofibers exhibited enhanced bactericidal performance (minimum inhibition concentrations (MIC) from 5 MUg/mL to 80 MUg/mL) and CNFs-Fe3O4 composite as scaffolds indicated favorable enhancement in cell proliferation. Results from this study suggest that CNFs-Fe3O4 scaffold with small diameters coincidence with unique porous configuration can mimic the natural extracellular matrix (ECM) well and provide potential promises for applications in the fields of tissue engineering and regenerative medicine. Our findings clearly suggest wide application potentials of this (CNFs-Fe3O4) multifunctional composite and the nanofiberous mat can be a very good candidate as a filter for water purification, antibiofouling filtration and ECM for tissue engineering. PMID- 23434709 TI - Superhydrophobic surface supported bioassay--an application in blood typing. AB - This study presents a new application of superhydrophobic surfaces in conducting biological assays for human blood typing using a liquid drop micro reactor. The superhydrophobic substrate was fabricated by a simple printing technique with Teflon powder. The non-wetting and weak hysteresis characteristics of superhydrophobic surfaces enable the blood and antibody droplets to have a near spherical shape, making it easy for the haemagglutination reaction inside the droplet to be photographed or recorded by a digital camera and then analyzed by image analysis software. This novel blood typing method requires only a small amount of blood sample. The evaluation of assay results using image analysis techniques offers potential to develop high throughput operations of rapid blood typing assays for pathological laboratories. With the capability of identifying detailed red blood cell agglutination patterns and intensities, this method is also useful for confirming blood samples that have weak red blood cell antigens. PMID- 23434710 TI - Electrochemical polymerized 5-amino-2-mercapto-1,3,4-thiadiazole modified single use sensors for detection of quercetin. AB - In this study, electrochemical polymerized 5-amino-2-mercapto-1,3,4-thiadiazole (poly-AMT)-modified single-use graphite electrodes were fabricated for electrochemical monitoring of bisflavonoid, quercetin. The surfaces of p-AMT modified pencil graphite electrodes (PGEs) were firstly characterized by scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS) analysis. The conditions for electrochemical polymerization by using cyclic voltammetry (CV), such as scan rate and different potential cycles were optimized. Electrochemical behaviors of these electrodes were also investigated using differential pulse voltammetry (DPV) and EIS. A six-fold increase at quercetin signal was obtained by using p-AMT modified PGEs compared to unmodified electrodes. PMID- 23434711 TI - Respirable liquid marble for the cultivation of microorganisms. AB - A liquid marble has a porous and superhydrophobic shell, which prevents the liquid core within the marble from making any contact with outside surfaces, but at the same time allows gases to transport freely across the shell. In this study we demonstrated the use of this unique property of liquid marbles to build respirable micro-biological reactors to cultivate microorganisms. Liquid marbles loaded with two kinds of microorganism cultures with different preference to oxygen were studied. Due to the presence of oxygen in the cultivation environment, significant differences in cell proliferation between the two microorganisms were observed within the liquid marbles. Furthermore, we found that this respirable bioreactor provides a more suitable environment for the growth of an aerobe than that in McCartney bottles with shaking incubation; cell concentration increased more rapidly in liquid marbles. PMID- 23434712 TI - Enzymatic synthesis of phosphatidylserine using bile salt mixed micelles. AB - Phosphatidylserine (PS) rich in polyunsaturated fatty acids of the n-3 series was obtained by enzymatic synthesis with phospholipase D (PLD) and a marine lipid extract as substrate. Synthesis was performed using mixed micelles composed of either sodium deoxycholate (SDC) or sodium cholate (SC). To limit the use of surfactant and to monitor the performance of PLD, the mixed micelles were characterized both in terms of bile salt/lipid molar ratio in the aggregates and of mean diameter. A fractional factorial experiment was selected to study the effect of pH, temperature, enzyme, L-serine concentrations, bile salt/lipid molar ratio and Ca(2+) content (in the case of SC only) on PS synthesis. The amount of L-serine was the main factor governing the equilibrium between transphosphatidylation and hydrolysis reaction. Increasing the bile salt/lipid molar ratio decreased PS synthesis yield. In contrast, pH (6.5-8) and temperature (35-45 degrees C) did not affect PLD activity in the tested conditions. This statistical approach allowed determining a combination of parameters (pH, temperature, bile salt/lipid molar ratio, enzyme and alcohol acceptor concentrations) for PS synthesis. After 24 h, the transphosphatidylation reaction led to 57+/-2% and 56+/-3% of PS in the phospholipid mixtures with SDC and SC, respectively. In both cases, about 10% of phosphatidic acid was present as a side product. On the whole, this work provided fundamental basis for a possible development of enzymatic PLD technology using food-grade emulsifiers to produce PS complying with industrial constraints for nutritional applications. PMID- 23434713 TI - Modulation of cell adhesion and detachment on thermo-responsive polymeric surfaces through the observation of surface dynamics. AB - Various thermo-responsive polymeric surfaces were evaluated in terms of cell adhesion/detachment and surface analysis. Three kinds of thermo-responsive poly(N isopropylacrylamide) (PIPAAm) surfaces were prepared by an electron beam irradiation (PIPAAm-EB), a reversible addition fragmentation polymerization (PIPAAm-RAFT), and a redox polymerization (PIPAAm-Redox). Although cell adhesion and detachment on surfaces of PIPAAm-EB and PIPAAm-RAFT were able to be modulated by altering their surface characters with changing the amounts of polymers, the adhesion and detachment were hardly controlled on PIPAAm-Redox surfaces, even though the amounts of polymers on the surface were able to be modulated. Atomic force microscopy (AFM) probed the interactions between AFM tip and the polymeric surface for further investigating a different conformation of polymeric surface. The modification of AFM tip surface coated with octadecyltrichlorosilane was found to change the interaction between the thermo-responsive surface and the tip. Adhesion force analysis clearly showed changes in the hydrophilic/hydrophobic characters of three kinds of thermo-responsive surfaces immediately after a change in temperature. From the kinetics study of AFM, PIPAAm EB and PIPAAm-RAFT surfaces became hydrophilic less than 30 min after temperature decrease, but PIPAAm-Redox surfaces required 120 min to become hydrophilic after temperature reduction. These results indicated that a faster conformational change triggered cell detachment and a slow conformation change hardly affected cell detachment. Therefore, polymeric conformation on solid substrate was an important factor for modulating cell adhesion and detachment. PMID- 23434714 TI - Spontaneous ultra fast synthesis of gold nanoparticles using Punica granatum for cancer targeted drug delivery. AB - Rapid synthesis of mono-dispersed gold nanoparticles through economically feasible green chemistry approach is highly desirable. In this study, we have developed a method to synthesize mono-dispersed gold nanoparticles (PAuNPs) by mixing gold solution with fruit peel extract of Punica granutum without using any surfactant or external energy. In this method, physiologically stable, biocompatible PAuNPs were formed within 60s. Casein, being a biocompatible polymer, is used to couple the prepared PAuNPs for functionalization of folic acid, which is highly expressed in cancer cells. These functionalized PAuNPs could be used for targeted drug delivery for cancer with enhanced therapeutic efficacy and minimal side effects. PAuNPs were characterized by UV, IR, TEM, Particle size analyzer and zeta potential measurement. In vitro stability of the PAuNPs was also analyzed. Hemocompatibility of PAuNPs was evaluated in human blood samples and found that the particles were hemocompatible. The toxicity of the PAuNPs, 5-Fu and 5Fu@PAuNPs was analyzed in zebrafish embryos. The in vitro cytotoxicity of free 5-Fu, 5Fu@PAuNPs-Fa was investigated against MCF-7 cells (breast cancer) and observed that the amount of 5-Fu required to achieve 50% of growth of inhibition (Ic50) was much lower when compared to free 5-Fu. PMID- 23434715 TI - The influence of cardiolipin on phosphatidylglycerol/phosphatidylethanolamine monolayers--studies on ternary films imitating bacterial membranes. AB - In this work the properties of ternary systems composed of phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs) and cardiolipin (CL) were studied with the Langmuir monolayer technique and Brewster Angle Microscopy. In all the investigated mixed films the PE:PG=3:1, which reflects the proportion of these lipids classes in various Gram Negative bacteria. The content of cardiolipin was varied from 5 to 20%, which is in the range of CL concentration in bacterial membranes. The experiments were performed for POPE/POPG/CL and POPE/DPPG/CL films spread on water subphase and on NaCl solution. It was found that the components of the studied films mix nonideally in the investigated range of the composition, however, the addition of cardiolipin weakens the interactions between the molecules. Thermodynamically unfavorable influence of CL results from the structure of this lipid, which due to sterical reasons disturbs the organization of POPE/PG film. It was also found that the presence of sodium ions in the subphase causes the increase of the area per molecule values and in general weakens the interactions between molecules in ternary films. However, the foregoing effect of NaCl both on binary PE/PG films as well as ternary PE/PG/CL monolayers was stronger on DPPG-containing films. The analysis of the collected data evidenced that the influence of cardiolipin as well as inorganic electrolyte on the properties of the studied films is directly connected with molecular structure of monolayers components. PMID- 23434716 TI - Interactions of antileishmanial drugs with monolayers of lipids used in the development of amphotericin B-miltefosine-loaded nanocochleates. AB - The emergence of strains of Leishmania resistant to existing drugs complicates the treatment of life-threatening visceral leishmaniasis. The development of new lipid formulation (nanocochleates), containing two active drugs: amphotericin B (AmB) and miltefosine (hexadecylphosphocholine, HePC), could increase effectiveness, decrease toxicity and reduce the risk of appearance of resistance. Nanocochleates are cigar-shaped structures of rolled negatively charged lipid bilayers bridged by calcium, prepared from dioleoylphosphatidylserine (DOPS) and cholesterol (Cho) and able to accommodate drugs. To determine the interaction, the orientation and the stability of the amphiphilic drugs in the lipid mixture and the optimal drugs/lipids ratio, the Langmuir film balance and BAM (Brewster angle microscopy) were used. The drugs were mixed with the lipids (DOPS or 9DOPS/1Cho) and spread at the air-water interface. A stability study showed that DOPS maintained HePC at the interface at low molar fraction of HePC; this effect became more marked in the presence of Cho. The fact that HePC can be stably associated with the monolayer at low molar fraction (below 10%) suggests that in the nanocochleates HePC is inserted between the lipid molecules rather than between the bilayers. Phase diagrams and BAM images showed that, even at low pressure, DOPS maintains AmB at low molar fraction (below 10%) in the "erect" rather than the horizontal form at the interface and that the presence of Cho reinforces this effect. These results allowed us to predict the organization and the orientation of these drugs in the nanocochleates and to determine the optimal drugs/lipids ratio. PMID- 23434718 TI - The activity of LE10 peptide on biological membranes using molecular dynamics, in vitro and in vivo studies. AB - Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) are generally defined as small cationic peptides with the ability to interact with lipidic membranes, in a process driven by electrostatic and hydrophobic processes. The interaction with CPPs is known to lead to its translocation across the membrane, while with AMPs lead to membrane damage. Here we present one synthetic anionic peptide, LE10 (LELELELELELELELELELE), which strongly interacts with model membranes, showing properties of CPPs (translocation through lipidic membranes on a mechanism usually described for cationic CPPs) and AMPs (membrane disruption) in molecular dynamic studies, experimental studies with liposomes and mammalian cells in vitro. Based on the LE10 properties here demonstrated, small modifications in its structure could make it a very promising tool for drug delivery. PMID- 23434717 TI - Controlling the adsorption and desorption of double-stranded DNA on functionalized carbon nanotube surface. AB - We demonstrated controlled adsorption and desorption of double-stranded DNA (dsDNA) on single-walled carbon nanotube (SWNT) surface functionalized with polyethyleneglycol (PEG SWNT). First, when dsDNA molecules were mixed with the PEG SWNT solution, the DNA molecules spontaneously adsorbed onto the PEG SWNT surface and formed dsDNA-PEG SWNT conjugates without sonication. Next, we succeeded in detaching the dsDNA adsorbed on PEG SWNT by annealing at 95 degrees C for 30 min. These results were confirmed using atomic force microscopy, agarose gel electrophoresis, and micro-Raman spectroscopy. In contrast, when we used the usual SWNT produced by the high-pressure carbon monoxide method (HiPco SWNT), the DNA molecules were fragmented during the adsorption process as sonication was necessary for the hybridization of DNA-SWNT conjugates. Furthermore, detachment of DNA molecules from HiPco SWNT by annealing was impossible. Our method may be useful for developing DNA devices using SWNTs as substrates when it is combined with previously established various biochemical techniques. PMID- 23434719 TI - Controlled silanization-amination reactions on the Ti6Al4V surface for biomedical applications. AB - Formation of thin films on titanium alloys incorporating bioactive small molecules or macromolecules is a route to improve their biocompatibility. Aminoalkylsilanes are commonly employed as interface reagents that combine good adhesion properties with an amino tail group susceptible of further functionalization. This article introduces a reproducible methodology to obtain a cross-linked polymer-type brush structure of covalently-bonded aminoalkylsiloxane chains on Ti6Al4V. The experimental protocol can be fine-tuned to provide a high density of surface-coated amino groups (threshold value: 2.1+/-0.1*10(-8) mol cm( 2)) as proven by chemical and spectrophotometric analyses. Using a model reaction involving the condensation of 3-aminopropyltrimethoxysilane (APTMS) on Ti6Al4V alloy, we herein show the effects of reaction temperature, reaction time and solvent humidity on the composition and structure of the film. The stability of the resulting coating under physiological-like conditions as well as the possibility of surface re-silanization has also been evaluated. To verify if detrimental effects on the biological performance of the Ti6Al4V alloy were induced by this coverage, human primary osteoblasts behavior, Staphylococci adhesion and biofilm formation have been tested and compared to the Ti6Al4V oxidized surface. Reaction with trans-cinnamaldehyde has used in order to determine useful amino groups at aminosilanized surface, XPS and UV analyses of imino derivatives generated reveal that almost a 50% of these groups are actually available at the siloxane chains. PMID- 23434720 TI - Membrane interaction between Span 80 vesicle and phospholipid vesicle (liposome): Span 80 vesicle can perturb and hemifuse with liposomal membrane. AB - We have focused on the interaction between the Span 80 vesicle and phospholipid vesicle (liposome). The Span 80 vesicle was mixed with a phospholipid vesicle (liposome), used as a simplified model of plasma membrane. From calcein leakage experiments, it was revealed that the interaction between the Span 80 vesicles and the liposomes could perturb the liposome membrane. In the experiments based on fluorescence resonance energy transfer, the lipid mixing between Span 80 vesicle and liposome was observed. The above phenomena were also supported by the fluorescence spectroscopic analysis using laurdan, resulting in the variation in the membrane properties of liposome after its mixing with Span 80 vesicle. These results suggest that the Span 80 vesicles can easily interact and hemifuse with the liposome membrane, which depend on the membrane properties of the Span 80 vesicle, "flexible" and "molecular structure" of the components. PMID- 23434721 TI - Endovascular treatment of postpartum deep venous thrombosis: report of three cases. AB - Pregnancy and the postpartum period are generally considered as contraindications for thrombolysis. We evaluate in this report the safety and effectiveness of using ultrasound-accelerated catheter-directed thrombolysis (UACDT) in treating three symptomatic postpartum deep vein thrombosis (DVT). UACDT was performed using a recombinant human tissue plasminogen activator (alteplase) which was delivered using the EKOS EkoSonic(r) system. Postprocedure venography was repeated after treatment which include stenting if stenosis was present. The treatment was successful in all three cases of iliofemoral DVT and symptom relief was achieved in all cases. Minor bleeding at the catheter insertion site in one patient was observed but none of the patients suffered from major bleeding or symptomatic pulmonary embolism. UACDT is a safe and effective treatment for restoration of the venous flow in patients with postpartum iliofemoral DVT. Residual venous obstruction should be treated by angioplasty and stent insertion to avoid early re-thrombosis. PMID- 23434722 TI - Insomnia symptoms in South Florida military veterans with epilepsy. AB - BACKGROUND: Despite the high prevalence of insomnia in veterans with epilepsy, it remains understudied. Our aim was to identify the associations of insomnia with epilepsy, comorbidities, and treatment-related variables in South Florida veterans. METHODS: We performed a cross-sectional analysis of veterans attending an epilepsy clinic over 18 months. Participants completed standardized assessments of seizure and sleep. Insomnia was defined as 1) difficulty with sleep onset, maintenance, or premature awakenings with daytime consequences or 2) sedative-hypnotic use on most nights of the previous month. RESULTS: One hundred sixty-five veterans (87% male, age 56 +/- 15 years) were included: 66 reporting insomnia (40%). In logistic regression analysis, insomnia was significantly associated with post-traumatic seizure etiology, lamotrigine prescription, and mood and psychotic disorders. Female gender and levetiracetam treatment were associated with lower odds for insomnia. CONCLUSION: Insomnia was associated with post-traumatic epilepsy, mood/psychotic comorbidities, and antiepileptic regimen. Insomnia represents an under-recognized opportunity to improve comprehensive epilepsy care. PMID- 23434723 TI - Assessment and comparison of health-related quality-of-life (HRQOL) in patients with epilepsy in India. AB - Seizure frequency, medical and psychiatric morbidities, number and nature of antiepileptic drugs, and medication side effects have been correlated with decreased HRQOL scores in patients with epilepsy. Quality of Life in Epilepsy-31 patient inventory was translated and validated in two regional languages and administered to 80 patients with epilepsy who were on first-line antiepileptic drugs and classified as responders and nonresponders. The outcomes were measured based on 7 domains, such as seizure worry, overall QOL, emotional well-being, and energy/fatigue and based on the overall score of the scale. For both translations, Cronbach's alpha (coefficient) was greater than 0.70 [except for the seizure worry scale (0.69) in the Hindi questionnaire]. There was statistical difference (p<0.0001) of HRQOL scores between responders and nonresponders of epilepsy. The HRQOL score was lower in nonresponders. The most affected domain was emotional well-being in both groups, and the least affected domains were energy/fatigue in responders and medication effect in nonresponders. PMID- 23434725 TI - Exploring the impact of a summer sport-based youth development program. AB - The purpose of this study was to examine the benefits of youth participation in a sport-based youth development summer program, the National Youth Sport Program (NYSP). This study also identified areas of programmatic strength within the program, as well as areas for improvement. 193 participants in NYSP completed a pre- and post-test that assessed belonging, social competence, athletic competence, and competence related to eight specific sports. Significant improvements in perceptions of overall athletic competence and competence related to five specific sports were found. Although perceptions of social competence and belonging increased from pre-to-post test, findings were not statistically significant. Site observations resulted in the identification of strengths and areas that also inform areas for programmatic improvement. Implications for the design, implementation, and evaluation of sport-based youth development programs are discussed. PMID- 23434724 TI - Predictors of treatment satisfaction among older adults with anxiety in a primary care psychology program. AB - Increasing numbers of patients are treated in integrated primary care mental health programs. The current study examined predictors of satisfaction with treatment in patients from a randomized clinical trial of late-life generalized anxiety disorder (GAD) in primary care. Higher treatment satisfaction was associated with receiving CBT rather than enhanced usual care. Treatment credibility, treatment expectancies, social support, and improvements in depression and anxiety symptoms predicted higher treatment satisfaction in the total sample. In the CBT group, only credibility and adherence with treatment predicted satisfaction. This suggests that older patients receiving CBT who believe more strongly in the treatment rationale and follow the therapist's recommendations more closely are likely to report satisfaction at the end of treatment. In addition, this study found that adherence mediated the relationship between treatment credibility and treatment satisfaction. In other words, patients' perceptions that the treatment made sense for them led to greater treatment adherence which then increased their satisfaction with treatment. PMID- 23434726 TI - 129I in the Baltic Proper and Bothnian Sea: application for estimation of water exchange and environmental impact. AB - We report here new data and a mass balance model for (129)I in the Baltic Proper and the Bothnian Sea covering the period from November-December 2009. The results showed that the general (129)I concentrations in the Bothnian Sea were two-four folds lower than in the Baltic Proper for both surface and deep water. Water exchange between the two basins based on the (129)I mass balance model suggests fluxes from the Baltic Proper to the Bothnian Sea and vice versa at 980 km(3)/y (600-1400 km(3)/y) and 1180 km(3)/y (780-1600 km(3)/y) respectively. Water retention time (residence time) in the Bothnian Sea was estimated at up to 4 years. Applying the (129)I exchange model, an estimate of total phosphorus and nitrogen inflow from the Baltic Proper to the Bothnian Sea indicates values of 20 +/- 7 * 10(3) tons/y and 300 +/- 50 * 10(3) tons/y respectively. The values for the outflow from the Bothnian Sea to the Baltic Proper hold 12 +/- 3 * 10(3) tons/y for total phosphorus and 283 +/- 55 * 10(3) tons/y for total nitrogen. These data and application of (129)I as a tracer of water masses provide information on small scale salinity changes which are vital for accurate understanding of the Baltic Sea ecosystems evolution through time. PMID- 23434729 TI - Comparative assessment of the timing of sexual maturation in male Wistar Han and Sprague-Dawley rats. AB - Given the increasing use of Wistar Han (WH) rats in regulatory toxicology studies, these studies were performed to characterize the onset of sexual maturation in maturing WH rats as compared to Sprague-Dawley (SD) rats. Beginning on postnatal day (PND) 38 through PND 91 groups (n=8) of untreated WH rats were evaluated for maturation of the male reproductive system. Testicular spermatid head counts increased beginning on PND 42 until PND 70. Sperm were detected in the caput, corpus, and cauda epididymis on PND 45, 49, and 49, respectively, and counts increased through PND 91. Sperm motility was at adult levels by PND 63. The morphology of the testis/epididymis of all animals at day 70 or older was consistent with qualitative sexual maturity. Based on these endpoints, WH rats were determined to be sexually mature at PND 70, and many of these endpoints evaluated in SD rats exhibited nearly identical trends. PMID- 23434727 TI - Modeling cadmium exposures in low- and high-exposure areas in Thailand. AB - BACKGROUND: Previous U.S. population modeling studies have reported that urinary cadmium (Cd) excretion patterns differ with age, sex, and dietary exposure; associations between Cd exposures and health outcomes also have differed by age and sex. Therefore, it is important to test models used to estimate Cd exposures across an expanded Cd-exposure range. OBJECTIVES: We estimated relative Cd exposures from both diet and smoking in low- and high-exposure scenarios to provide data for improving risk assessment calculations. METHODS: We used a Cd toxicokinetic-based model to estimate Cd exposures based on urinary Cd levels measured for 399 persons in a low-exposure area (Bangkok) and 6,747 persons in a high-exposure area (Mae Sot) in Thailand. RESULTS: In Bangkok, we estimated dietary Cd exposures of 50-56 ug/day for males and 21-27 ug/day for females 20-59 years of age who never smoked. In Mae Sot, we estimated dietary Cd exposures of 188-224 ug/day for males and 99-113 ug/day for females 20-59 years of age who never smoked. In Bangkok, we estimated Cd exposures from smoking to be 5.5-20.4 ug/day for male smokers 20-59 years of age. In Mae Sot, we estimated Cd exposures from smoking to be 9.8-26 ug/day for male heavy smokers and 26 ug/day for female heavy smokers. CONCLUSION: This study provides estimates of Cd exposures from diet and smoking in low- and high-exposure scenarios. Our findings suggest a relatively small safety margin between the established tolerable Cd reference exposure of 62 ug/day and exposure levels previously associated with evidence of kidney and bone effects in Mae Sot residents, where dietary Cd exposures among women were only 1.6-2.1 times the reference value. PMID- 23434730 TI - A G polymorphism in the CRBN gene acts as a biomarker of response to treatment with lenalidomide in low/int-1 risk MDS without del(5q). PMID- 23434731 TI - Cleavage of BCR-ABL transcripts at the T315I point mutation by DNAzyme promotes apoptotic cell death in imatinib-resistant BCR-ABL leukemic cells. AB - The BCR-ABL fusion transcript encodes the BCR-ABL tyrosine kinase (TK), which causes chronic myelogenous leukemia (CML). Although the TK inhibitor imatinib mesylate, which targets the BCR-ABL protein, has been proven to be effective in controlling leukemic growth, imatinib resistance has been observed with disease relapse because of point mutations in the ABL gene that inhibit imatinib efficacy. In this study, we designed oligodeoxyribozymes (DNAzymes) that specifically target and cleave both the junction sequence and the site of the point mutation (T315I), conferring imatinib resistance in BCR-ABL mRNA. DNAzymes significantly induced apoptosis and inhibited proliferation in wild-type and T315I-mutant BCR-ABL-positive cells. Selective cleavage of T315I-mutant ABL mRNA by DNAzyme (T315I Dz) led to cell cycle arrest in G0/G1 phase, with induction of caspase-3/-7 in imatinib-resistant BCR-ABL-positive cells harboring the T315I mutation. Moreover, cotreatment with the DNAzyme targeting the T315I mutation and imatinib resulted in enhanced inhibition of proliferation and induction of apoptosis in T315I leukemic cells as compared with imatinib alone, thereby antagonizing imatinib resistance in CML cells bearing T315I-mutant BCR-ABL. Therefore, cleavage of T315I-mutant ABL mRNA by DNAzyme combined with imatinib treatment may be an alternative approach to overcoming imatinib resistance in leukemic cells. PMID- 23434732 TI - Filtering ground reaction force data affects the calculation and interpretation of joint kinetics and energetics during drop landings. AB - An inverse dynamic analysis and subsequent calculation of joint kinetic and energetic measures is widely used to study the mechanics of the lower extremity. Filtering the kinematic and kinetic data input to the inverse dynamics equations affects the calculated joint moment of force (JMF). Our purpose was to compare selected integral values of sagittal plane ankle, knee, and hip joint kinetics and energetics when filtered and unfiltered GRF data are input to inverse dynamics calculations. Six healthy, active, injury-free university student (5 female, 1 male) volunteers performed 10 two-legged landings. JMFs were calculated after two methods of data filtering. Unfiltered: marker data were filtered at 10 Hz, GRF data unfiltered. Filtered: both GRF and marker data filtered at 10 Hz. The filtering of the GRF data affected the shape of the knee and hip joint moment time curves, and the ankle, knee and hip joint mechanical power-time curves. We concluded that although the contributions of individual joints to the support moment and to total energy absorption were not affected, the attenuation of high frequency oscillations in both JMF and JMP time curves will influence interpretation of CNS strategies during landing. PMID- 23434733 TI - Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer. AB - PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86 9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. RESULTS: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. CONCLUSION: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. PMID- 23434734 TI - The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. AB - PURPOSE: The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred. We explored the sorafenib treatment escape mechanisms to overcome their drawbacks. EXPERIMENTAL DESIGN: Immunoprecipitation, Western blotting, and immunohistochemistry were used to analyze the mTOR pathway [mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)]. Cell viability, colony growth, and cell migration were evaluated in different osteosarcoma cell lines (MNNG-HOS, HOS, KHOS/NP, MG63, U-2OS, SJSA-1, and SAOS-2) after scalar dose treatment with sorafenib (10-0.625 MUmol/L), rapamycin-analog everolimus (100-6.25 nmol/L), and combinations of the two. Cell cycle, reactive oxygen species (ROS) production, and apoptosis were assessed by flow cytometry. Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice injected with MNNG-HOS cells were used to determine antitumor and antimetastatic effects. Angiogenesis and vascularization were evaluated in vitro by exploiting endothelial branching morphogenesis assays and in vivo in xenografted mice and chorioallantoic membranes. RESULTS: After sorafenib treatment, mTORC1 signaling was reduced (downstream target P-S6), whereas mTORC2 was increased (phospho-mTOR Ser2481) in MNNG-HOS xenografts compared with vehicle-treated mice. Combining sorafenib with everolimus resulted in complete abrogation of both mTORC1 [through ROS-mediated AMP-activated kinase (AMPK) activation] and mTORC2 (through complex disassembly). The sorafenib/everolimus combination yielded: (i) enhanced antiproliferative and proapoptotic effects, (ii) impaired tumor growth, (iii) potentiated antiangiogenesis, and (iv) reduced migratory and metastatic potential. CONCLUSION: mTORC2 activation is an escape mechanism from sorafenib treatment. When sorafenib is combined with everolimus, its antitumor activity is increased by complete inhibition of the mTOR pathway in the preclinical setting. PMID- 23434735 TI - Chimerism and use of mesenchymal stem cells in umbilical cord blood transplantation. AB - We performed a retrospective single-center analysis of 50 umbilical cord blood transplantations (UCBTs), focusing on chimerism development. Complete donor chimerism (DC) was associated with acute graft-vs.-host disease (aGVHD) grades II IV for the CD3 (+) cell lineage (p = 0.01) and, in multivariate analysis, with total body irradiation (TBI) for all lineages (p < 0.01). Overall survival (OS) was negatively associated with patient age, (p < 0.001); aGVHD grades III-IV, (p < 0.001); and treatment with mesenchymal stem cells (MSCs) (p = 0.027). In conclusion, though multiple factors may have contributed, the association of TBI and DC might be worthy of consideration in the treatment of patients with malignant disease in the UCBT setting. The negative influence of MSCs on OS may be a reason for more careful usage of this treatment modality in combination with UCBT. PMID- 23434736 TI - ARHGDIA: a novel gene implicated in nephrotic syndrome. AB - BACKGROUND: Congenital nephrotic syndrome arises from a defect in the glomerular filtration barrier that permits the unrestricted passage of protein across the barrier, resulting in proteinuria, hypoalbuminaemia, and severe oedema. While most cases are due to mutations in one of five genes, in up to 15% of cases, a genetic cause is not identified. We investigated two sisters with a presumed recessive form of congenital nephrotic syndrome. METHODS AND RESULTS: Whole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that ARHGDIA that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor alpha (RhoGDIalpha, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies. The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIalpha, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)). Rho-GTPases are critical regulators of the actin cytoskeleton and when bound to RhoGDIalpha, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDIalpha was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDIalpha was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDIalpha was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDIalpha to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function. CONCLUSIONS: Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome. PMID- 23434738 TI - Comparative field permeability measurement of permeable pavements using ASTM C1701 and NCAT permeameter methods. AB - Fully permeable pavement is gradually gaining support as an alternative best management practice (BMP) for stormwater runoff management. As the use of these pavements increases, a definitive test method is needed to measure hydraulic performance and to evaluate clogging, both for performance studies and for assessment of permeability for construction quality assurance and maintenance needs assessment. Two of the most commonly used permeability measurement tests for porous asphalt and pervious concrete are the National Center for Asphalt Technology (NCAT) permeameter and ASTM C1701, respectively. This study was undertaken to compare measured values for both methods in the field on a variety of permeable pavements used in current practice. The field measurements were performed using six experimental section designs with different permeable pavement surface types including pervious concrete, porous asphalt and permeable interlocking concrete pavers. Multiple measurements were performed at five locations on each pavement test section. The results showed that: (i) silicone gel is a superior sealing material to prevent water leakage compared with conventional plumbing putty; (ii) both methods (NCAT and ASTM) can effectively be used to measure the permeability of all pavement types and the surface material type will not impact the measurement precision; (iii) the permeability values measured with the ASTM method were 50-90% (75% on average) lower than those measured with the NCAT method; (iv) the larger permeameter cylinder diameter used in the ASTM method improved the reliability and reduced the variability of the measured permeability. PMID- 23434737 TI - Immunogenicity and safety of different formulations of an adjuvanted glycoprotein D genital herpes vaccine in healthy adults: a double-blind randomized trial. AB - Herpes simplex virus (HSV) type 2 (HSV-2) is the main cause of genital and neonatal herpes and is highly prevalent worldwide. Previous phase I and II studies showed the immunogenicity and safety of the candidate prophylactic HSV-2 glycoprotein D-based subunit vaccine (gD2-AS04), containing aluminum hydroxide and 3-O-deacylated monophosphoryl lipid A (MPL) as adjuvant (AS04), in healthy adults. The primary objective of the study presented here was to compare the immunogenicity and safety of five different vaccine formulations: 3 different antigen doses [20, 40 or 80 MUg of truncated glycoprotein D from HSV-2 strain (gD 2t)], different aluminum salts [AlPO4 or Al(OH)3], different preservatives or different volumes of vaccine (0.5 or 1 ml). One hundred and fifty healthy men and women aged 18-45 years, with negative serological markers for HSV-1 and HSV-2 infection, were vaccinated with one of 5 formulations of the gD2-AS04 candidate vaccine according to a 0-, 1-, 6-month schedule. No statistically significant difference was observed in humoral or cellular immune responses between different antigen doses or the different aluminum salts, preservatives or volumes of vaccine. The gD2-AS04 vaccine was well tolerated by study participants for the duration of the study period. Local symptoms were more frequently reported than general symptoms, with muscle stiffness and/or injection site redness being the most frequently reported. Overall, the incidence of adverse events was comparable in all groups. Based on these results the gD2-AS04 formulation, containing 20 MUg of gD-2t, was selected for evaluation of prophylactic efficacy in further clinical trials. PMID- 23434739 TI - The biomechanical determinants of concussion: finite element simulations to investigate brain tissue deformations during sporting impacts to the unprotected head. AB - Concussion is an injury of specific interest in collision and contact sports, resulting in a need to develop effective preventive strategies. A detailed finite element model of the human head was used to approximate the regional distribution of tissue deformations in the brain by simulating reconstructions of unhelmeted concussion and no-injury head impacts. The results were evaluated using logistic regression analysis and it was found that angular kinematics, in the coronal plane, and maximum principal strains, in all regions of the brain, were significantly associated with concussion. The results suggested that impacts to the temporal region of the head cause coronal rotations, which render injurious strain levels in the brain. Tentative strain tolerance levels of 0.13, 0.15, and 0.26 in the thalamus, corpus callosum, and white matter, respectively, for a 50% likelihood of concussion were determined by logistic regression. The tentative strain tolerance levels compared well with previously reported results from reconstruction studies of American football and single axon, optic nerve, and brain slice culture model studies. The methods used in the current study provide an opportunity to collect unique kinematic data of sporting impacts to the unprotected head, which can be employed in various ways to broaden the understanding of concussion. PMID- 23434740 TI - Electrochemical oxidation of butein at glassy carbon electrodes. AB - The electrochemical oxidation of flavonoid butein is studied at glassy carbon electrodes in phosphate and citrate buffer solutions of different pH values, and 1M perchloric acid aqueous solutions by cyclic and square wave voltammetries. The oxidation peak corresponds to the 2e(-), 2H(+) oxidation of the 3,4-dihydroxy group in B ring of butein, given the corresponding quinone species. The overall electrode process shows a quasi-reversible behavior and an adsorption/diffusion mixed control at high butein bulk concentrations. At low butein concentrations, the electrode process shows mainly an adsorption control. Butein surface concentration values were obtained from the charge associated with the adsorbed butein oxidation peaks, which are in agreement with those values expected for the formation of a monolayer of adsorbate in the concentration range from 1 to 5MUM. Square wave voltammetry was used to perform a full thermodynamic and kinetics characterization of the butein surface redox couple. Therefore, from the combination of the "quasi-reversible maximum" and the "splitting of the net square wave voltammetric peak" methods, values of (0.386+/-0.003) V, (0.46+/ 0.04), and 2.7*10(2)s(-1) were calculated for the formal potential, the anodic transfer coefficient, and the formal rate constant, respectively, of the butein overall surface redox process in pH4.00 citrate buffer solutions. These results will be then used to study the interaction of butein, and other flavonoids with the deoxyribonucleic acid, in order to better understand the potential therapeutic applications of these compounds. PMID- 23434741 TI - Current world literature. PMID- 23434743 TI - Distinct expression patterns of syndecans in the embryonic zebrafish brain. AB - Axon pathfinding in the neuroepithelium of embryonic brain is dependent on a variety of short and long range guidance cues. Heparan sulfate proteoglycans such as syndecans act as modulators of these cues and their importance in neural development is highlighted by their phylogenetic conservation. In Drosophilia, a single syndecan is present on the surface of axon growth cones and is required for chemorepulsive signalling during midline crossing. Understanding the role of syndecans in the vertebrate nervous system is challenging given that there are four homologous genes, syndecans 1-4. We show here that syndecans 2-4 are expressed in the zebrafish embryonic brain during the major period of axon growth. These genes show differing expression patterns in the brain which provides putative insights into their functional specificity. PMID- 23434747 TI - Hiccups in the neuro ICU: a problem of respiratory support. PMID- 23434744 TI - Source attribution of health benefits from air pollution abatement in Canada and the United States: an adjoint sensitivity analysis. AB - BACKGROUND: Decision making regarding air pollution can be better informed if air quality impacts are traced back to individual emission sources. Adjoint or backward sensitivity analysis is a modeling tool that can achieve this goal by allowing for quantification of how emissions from sources in different locations influence human health metrics. OBJECTIVES: We attributed short-term mortality (valuated as an overall "health benefit") in Canada and the United States to anthropogenic nitrogen oxides (NO(x)) and volatile organic compound (VOC) emissions across North America. METHODS: We integrated epidemiological data derived from Canadian and U.S. time-series studies with the adjoint of an air quality model and also estimated influences of anthropogenic emissions at each location on nationwide health benefits. RESULTS: We found significant spatiotemporal variability in estimated health benefit influences of NO(x) and VOC emission reductions on Canada and U.S. mortality. The largest estimated influences on Canada (up to $250,000/day) were from emissions originating in the Quebec City-Windsor Corridor, where population centers are concentrated. Estimated influences on the United States tend to be widespread and more substantial owing to both larger emissions and larger populations. The health benefit influences calculated using 24-hr average ozone (O(3)) concentrations are lower in magnitude than estimates calculated using daily 1-hr maximum O(3) concentrations. CONCLUSIONS: Source specificity of the adjoint approach provides valuable information for guiding air quality decision making. Adjoint results suggest that the health benefits of reducing NO(x) and VOC emissions are substantial and highly variable across North America. PMID- 23434748 TI - Hypoxia and chest radiography changes after low-dose, short-duration carbamazepine therapy. PMID- 23434749 TI - Neuroanesthesiology update. AB - We provide a review of both clinical and basic science literature from 2012 relevant to care of the patient with neurological disease. Our review addresses the following major areas: general neurosurgical procedures, stroke, traumatic brain injury, spine surgery, anesthetic neurotoxicity, neuroprotective strategies, electrophysiological monitoring, history, and graduate medical education. We have focused on research describing new and innovative concepts and recurring themes. This review is intended to be of interest to those working in the clinical arena and also to neuroscientists. PMID- 23434750 TI - A transient acute neurological event in a patient undergoing GPI microelectrode mapping: diagnostic dilemma. PMID- 23434751 TI - Exacerbation of involuntary movements after propofol anesthesia in a patient with Huntington disease. PMID- 23434752 TI - Does the detailed formula of propofol matter in studies focusing on inflammatory response? PMID- 23434753 TI - In reply. PMID- 23434754 TI - CPEB1 coordinates alternative 3'-UTR formation with translational regulation. AB - More than half of mammalian genes generate multiple messenger RNA isoforms that differ in their 3' untranslated regions (3' UTRs) and therefore in regulatory sequences, often associated with cell proliferation and cancer; however, the mechanisms coordinating alternative 3'-UTR processing for specific mRNA populations remain poorly defined. Here we report that the cytoplasmic polyadenylation element binding protein 1 (CPEB1), an RNA-binding protein that regulates mRNA translation, also controls alternative 3'-UTR processing. CPEB1 shuttles to the nucleus, where it co-localizes with splicing factors and mediates shortening of hundreds of mRNA 3' UTRs, thereby modulating their translation efficiency in the cytoplasm. CPEB1-mediated 3'-UTR shortening correlates with cell proliferation and tumorigenesis. CPEB1 binding to pre-mRNAs not only directs the use of alternative polyadenylation sites, but also changes alternative splicing by preventing U2AF65 recruitment. Our results reveal a novel function of CPEB1 in mediating alternative 3'-UTR processing, which is coordinated with regulation of mRNA translation, through its dual nuclear and cytoplasmic functions. PMID- 23434755 TI - Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. AB - Although haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche, most published experimental manipulations of the HSC niche have affected the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs and restricted progenitors reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine CXCL12 for HSC and restricted progenitor maintenance. Cxcl12(DsRed) knock-in mice (DsRed-Express2 recombined into the Cxcl12 locus) showed that Cxcl12 was primarily expressed by perivascular stromal cells and, at lower levels, by endothelial cells, osteoblasts and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or nestin-cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12 from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12 from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cells into circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors but not HSCs or myeloerythroid progenitors, and did not mobilize these cells into circulation. Different stem and progenitor cells thus reside in distinct cellular niches in bone marrow: HSCs occupy a perivascular niche and early lymphoid progenitors occupy an endosteal niche. PMID- 23434756 TI - CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. AB - Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells, CXCL12-abundant reticular cells, leptin-receptor-positive stromal cells, and nestin-green fluorescent protein (GFP)-positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C-X-C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1-cre (Prx1 also known as Prrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs. PMID- 23434757 TI - Rapid, quantitative, reverse transcription PCR in a polymer microfluidic chip. AB - Quantitative PCR (qPCR) techniques have become invaluable, high-throughput tools to study gene expression. However, the need to measure gene expression patterns quickly and affordably, useful for applications such as stem cell biomanufacturing requiring real-time observation and control, has not been adequately met by rapid qPCR instrumentation to date. We report a reverse transcription, microfluidic qPCR system and its application to DNA and RNA amplification measurement. In the system, an environmental control fixture provides mechanical and thermal repeatability for an infrared laser to achieve both accurate and precise open-loop temperature control of 1 MUl reaction volumes in a low-cost polymer microfluidic chip with concurrent fluorescence imaging. We have used this system to amplify serial dilutions of lambda-phage DNA (10(5) 10(7) starting copies) and RNA transcripts from the GAPDH housekeeping gene (5.45 ng total mouse embryonic stem cell RNA) and measured associated standard curves, efficiency (57%), repeatability (~1 cycle threshold), melting curves, and specificity. This microfluidic qRT-PCR system offers a practical approach to rapid analysis (~1 h), combining the cost benefits of small reagent volumes with the simplicity of disposable polymer microchips and easy setup. PMID- 23434758 TI - Selective virus detection in complex sample matrices with photonic crystal optical cavities. AB - Rapid, sensitive, and selective detection of viruses is critical for applications in medical diagnostics, biosecurity, and environmental safety. In this article, we report the application of a point-defect-coupled W1 photonic crystal (PhC) waveguide biosensor to label-free optical detection of viruses. Fabricated on a silicon-on-insulator (SOI) substrate using electron-beam (e-beam) lithography and reactive-ion-etching, the PhC sensing platform allows optical detection based on resonant mode shifts in response to ambient refractive index changes produced by infiltration of target biomaterial within the holes of the PhC structure. Finite difference time domain (FDTD) calculations were performed to assist with design of the sensor, and to serve as a theoretical benchmark against which experimental results could be compared. Using Human Papillomavirus virus-like particles (VLPs) spiked in 10% fetal bovine serum as a model system, we observed a limit of detection of 1.5 nM in simple (buffer only) or complex (10% serum) sample matrices. The use of anti-VLP antibodies specific for intact VLPs with the PhC sensors provided highly selective VLP detection. PMID- 23434759 TI - Electrochemical immunosensor for ultrasensitive detection of microcystin-LR based on graphene-gold nanocomposite/functional conducting polymer/gold nanoparticle/ionic liquid composite film with electrodeposition. AB - The study developed an electrochemical immunosensor for ultrasensitive detection of microcystin-LR in water. Graphene oxide and chloroauric acid were alternately electrodeposited on the surface of glassy carbon electrode for 20 cycles to fabricate graphene-gold nanocomposite. The composite was characterized and its apparent heterogeneous electron transfer rate constant (37.28+/-0.16 cm s (-1)) was estimated by Laviron's model. To immobilize microcystin-LR antibody and improve the electrical conductivity, 2,5-di-(2-thienyl)-1-pyrrole-1-(p-benzoic acid) and chloroauric acid were electrodeposited on the modified electrode in sequence. The ionic liquid was then dropped on the electrode surface and finally microcystin-LR antibody was covalently connected to the conducting polymer film. Experiment showed the electrochemical technique offers control over reaction parameters and excellent repeatability. The graphene-gold nanocomposite and gold nanoparticles enhance electron transfer of Fe(CN)6(3-/4-) to the electrode. The ionic liquid, 1-isobutyl-3-methylimidazolium bis(trifluoromethane-sulfonyl)imide, improves stability of the antibody. The sensor displays good repeatability (RSD=1.2%), sensitive electrochemical response to microcystin-LR in the range of 1.0*10(-16)-8.0*10(-15)M and detection limit of 3.7*10(-17)M (S/N=3). The peak current change of the sensor after and before incubation with 2.0*10(-15)M of microcystin-LR can retain 95% over a 20-weeks storage period. Proposed method presents remarkable improvement of sensitivity, repeatability and stability when compared to present microcystin-LR sensors. It has been successfully applied to the microcystin-LR determination in water samples with a spiked recovery in the range of 96.3-105.8%. PMID- 23434760 TI - Health in all policies as a priority in Finnish health policy: a case study on national health policy development. AB - This article describes national level development towards a Health in All Policies approach in Finland over the past four decades. In the early 1970s, improving public health became a political priority, and the need to influence key determinants of health through sectors beyond the health sector became evident. The work began with policy on nutrition, smoking and accident prevention. Intersectoral health policy was developed together with the World Health Organization (WHO). When Finland joined the European Union in 1995, some competencies were delegated to the EU which complicated national intersectoral work. The priority in the EU is economy, but the Constitution's requirement to protect health in all policies gives legal backing for including health consideration in the EU-level work. To promote that, Finland adopted 'Health in All Policies' (HiAP) as the health theme for its EU Presidency in 2006. The intersectoral work on health has developed from tackling single health problems, through large-scale programmes, further to systematic work based on legislation and permanent structures. In the 2000s, work at local level was strengthened by introducing more focused and tighter legislation and by providing expert support for implementation. Recently, emphasis has been on broad objectives and Governmental intersectoral programmes, and actors outside the administrative machinery. Great improvements in the population health have been gained over the past few decades. However, health inequalities across social groups have remained unacceptably large. Major decisions on economic policy with varying impacts by the social groups have been made without health impact assessment, or ignoring assessments conducted. PMID- 23434761 TI - Seabird diets provide early warning of sardine fishery declines in the Gulf of California. AB - Small pelagic fisheries show wide fluctuations, generally attributed to oceanographic anomalies. Most data on these fisheries come from landings, often reporting sustained catches-per-unit-effort (CPUEs) until a decline occurs. Fishery-independent data are important as management tools. In this study we show that the proportions of Pacific Sardine and Northern Anchovy in the diet of three seabird species (California Brown Pelicans, Heermann's Gulls, and Elegant Terns) nesting in spring in the Gulf of California show significant relationships with CPUEs during the following season in gulls and terns, or during the same season in pelicans. As sardine availability for seabirds declines, CPUEs remain high until the fishery falls, one or two seasons later. A declining proportion of sardines in the seabirds' diet, combined with the status of the Pacific warm phase anomaly (El Nino), give a reliable forecast of diminishing CPUEs and signals the need to reduce fishing efforts in the ensuing season. PMID- 23434762 TI - Juvenile hormone titer and wing-morph differentiation in the vetch aphid Megoura crassicauda. AB - Most aphids exhibit wing polyphenism, in which winged and wingless females are produced depending on aphid densities. Although juvenile hormone (JH) has been implicated in the regulation of aphid wing polyphenism, relatively few studies examining the direct relationship between JH titer and resultant wing morphs have been undertaken. We therefore investigated the relationship between JH III titer and the development of wing morphs in the vetch aphid Megoura crassicauda during postembryonic development. JH III measurements by liquid chromatography-mass spectrometry (LC-MS) revealed that, at the third instar, presumptive wingless nymphs had significantly higher JH III titers than winged nymphs. In winged nymphs at the third instar, JH III application inhibited wing development resulting in the appearance of winged/wingless intermediates as well as juvenilized individuals with supernumerary molting. These results suggest that JH III plays an important role in wing-morph differentiation during postembryonic development. PMID- 23434763 TI - Mutations in WNT1 are a cause of osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually due to dominant mutations in COL1A1 or COL1A2. Rare recessive forms of OI, caused by mutations in genes involved in various aspects of bone formation, have been described as well. OBJECTIVE: To identify the cause of OI in eight children with severe bone fragility and a clinical diagnosis of OI type IV who had had negative results on COL1A1/COL1A2 Sanger sequencing. METHODS: Whole exome sequencing was performed in genomic DNA samples from all eight individuals. RESULTS: WNT1 mutations were found in four children from three families. WNT1 was the only gene where mutations were found in all of these four patients. Two siblings from a consanguineous family had a homozygous missense mutation affecting a highly conserved cysteine residue in WNT1 (c.428G>T (p.Cys143Phe)). One girl had a homozygous frameshift deletion (c.287_300del(p.Gln96Profs)). A girl from a third family was compound heterozygous for a frameshift insertion and a missense mutation affecting a conserved amino acid (c.946_949insAACA (p.Ser317Lysfs); c.1063G>T (p.Val355Phe)). All of these children had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life. The Wnt signalling pathway is one of the key regulators of osteoblast activity. CONCLUSIONS: Recessive inactivating mutations in WNT1 are a new cause of OI type IV. PMID- 23434764 TI - Reactive oxygen species and the free radical theory of aging. AB - The traditional view in the field of free radical biology is that free radicals and reactive oxygen species (ROS) are toxic, mostly owing to direct damage of sensitive and biologically significant targets, and are thus a major cause of oxidative stress; that complex enzymatic and nonenzymatic systems act in concert to counteract this toxicity; and that a major protective role is played by the phenomenon of adaptation. Another part of the traditional view is that the process of aging is at least partly due to accumulated damage done by these harmful species. However, recent workers in this and in related fields are exploring the view that superoxide radical and reactive oxygen species exert beneficial effects. Thus, such ROS are viewed as involved in cellular regulation by acting as (redox) signals, and their harmful effects are seen mostly as a result of compromised signaling, rather than due to direct damage to sensitive targets. According to some followers of this view, ROS such as hydrogen peroxide and superoxide are not just causative agents of aging but may also be agents that increase the life span by acting, for example, as prosurvival signals. The goal of this review is to recall that many of the effects of ROS that are interpreted as beneficial may actually represent adaptations to toxicity and that some of the most extravagant recent claims may be due to misinterpretation, oversimplification, and ignoring the wealth of knowledge supporting the traditional view. Whether it is time to abandon the free radical (oxidative stress) theory of aging is considered. PMID- 23434766 TI - Dimerumic acid attenuates receptor for advanced glycation endproducts signal to inhibit inflammation and diabetes mediated by Nrf2 activation and promotes methylglyoxal metabolism into d-lactic acid. AB - This study was designed to evaluate the effects of dimerumic acid (DMA) on receptor for advanced glycation endproducts (RAGE) signal activation and THP-1 monocyte inflammation treated with S100b, a specific ligand of RAGE. We found that DMA inhibited inflammatory cytokine production via upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and alleviated oxidative stress through attenuation of p47phox translocation to the membrane of S100b-treated THP 1 monocytes. We found that DMA activated Nrf2 mediated by the p38 kinase pathway in THP-1 monocytes. However, anti-inflammatory activity of DMA was attenuated by Nrf2 siRNA treatment. In an animal model, methylglyoxal (MG; 200mg/kg bw) was chosen to induce diabetes in Balb/C mice (6 weeks) in this work. The in vivo verification of anti-inflammation in peripheral blood mononuclear cells by DMA treatment was confirmed by tumor necrosis factor-alpha and interleukin-1beta measurements. Oral glucose tolerance test, insulin tolerance test, hyperinsulinemia, and hyperglycemia were improved in MG-treated mice by DMA treatment and these effects were greater than those of silymarin and N acetylcysteine. Furthermore, DMA increased hepatic glyoxalase mRNA and glutathione mediated by Nrf2 activation to metabolize MG into d-lactic acid, thereby reducing serum and hepatic AGE levels and suppressing inflammatory factor generation in MG-treated mice. However, DMA did not exert the antiglycation activity in MG-bovine serum albumin incubation. Taken together, the results indicate that DMA is a novel antioxidant and Nrf2 activator that lowers AGE levels and may prove to be an effective treatment for diabetes. PMID- 23434767 TI - Does MitoSOD protect against the toxicity of paraquat toward mitochondria by acting as a superoxide dismutase mimic? PMID- 23434765 TI - Regulation of Nrf2-an update. AB - Nrf2:INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear factor that controls the expression and coordinated induction of a battery of genes that encode detoxifying enzymes, drug transporters, antiapoptotic proteins, and proteasomes. In the basal state, Nrf2 is constantly degraded in the cytoplasm by its inhibitor, INrf2. INrf2 functions as an adapter for Cul3/Rbx1 E3 ubiquitin ligase-mediated degradation of Nrf2. Chemicals, including antioxidants, tocopherols including alpha-tocopherol (vitamin E), and phytochemicals, and radiation antagonize the Nrf2:INrf2 interaction and lead to the stabilization and activation of Nrf2. The signaling events involve preinduction, induction, and postinduction responses that tightly control Nrf2 activation and repression back to the basal state. Oxidative/electrophilic signals activate unknown tyrosine kinases in a preinduction response that phosphorylates specific residues on Nrf2 negative regulators, INrf2, Fyn, and Bach1, leading to their nuclear export, ubiquitination, and degradation. This prepares nuclei for unhindered import of Nrf2. Oxidative/electrophilic modification of INrf2 cysteine 151 followed by PKC phosphorylation of Nrf2 serine 40 in the induction response results in the escape or release of Nrf2 from INrf2. Nrf2 is thus stabilized and translocates to the nucleus, resulting in a coordinated activation of gene expression. This is followed by a postinduction response that controls the "switching off" of Nrf2-activated gene expression. GSK3beta, under the control of AKT and PI3K, phosphorylates Fyn, leading to Fyn nuclear localization. Fyn phosphorylates Nrf2 Y568, resulting in nuclear export and degradation of Nrf2. The activation and repression of Nrf2 provide protection against oxidative/electrophilic stress and associated diseases, including cancer. However, deregulation of INrf2 and Nrf2 due to mutations may lead to nuclear accumulation of Nrf2 that reduces apoptosis and promotes oncogenesis and drug resistance. PMID- 23434768 TI - A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial. AB - OBJECTIVE: To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). DESIGN: We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. SETTING: The CHAMPION PLATFORM trial. PATIENTS: Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). INTERVENTIONS: Cangrelor versus placebo. MAIN OUTCOME MEASURES: The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. RESULTS: Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48 h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). CONCLUSIONS: Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI. PMID- 23434770 TI - Where the rubber hits the road: the translational pulse of reproductive biology. PMID- 23434769 TI - Telephone contact to improve adherence to dual antiplatelet therapy after drug eluting stent implantation. AB - BACKGROUND: Many patients delay or interrupt dual antiplatelet therapy (DAT) after drug-eluting stent (DES) implantation, which increases the risk of stent thrombosis and death. OBJECTIVE: To test the hypothesis that simple telephone contact made by nurses would improve adherence to and persistence of DAT. DESIGN: Randomised controlled trial. PATIENTS AND INTERVENTION: A total of 300 patients (mean+/-SD 64+/-10 years, 73% male) were recruited immediately after DES implantation performed between June 2009 and June 2010. The last patient recruited reached the 1-year follow-up time point in June 2011. Patients were randomised to one of two groups: intervention, with four telephone follow-ups, versus a control group. In the intervention group, phone calls were made within 7 days of the DES implantation and at 1, 6 and 9 months to support drug adherence. Control patients were followed as per usual clinical practice. Pharmacy data were collected to assess drug prescription filling and refill. SETTING: Tertiary care university cardiovascular centre and community. MAIN OUTCOME MEASURES: The primary end point was the proportion of days covered with aspirin and clopidogrel over the year after discharge as assessed by pharmacy refill data. Secondary outcome measures included persistence of aspirin and clopidogrel treatment, defined as no gaps longer than 14 days during follow-up. RESULTS: Most patients (73%) underwent DES implantation in the context of an acute coronary syndrome. All patients had drug insurance cover, either from the public plan (59%) or through private plans (41%). Complete pharmacy follow-up data were available for 96% of the cohort. At 12 months, median scores (25th-75th centile) for adherence to aspirin and clopidogrel were 99.2% (97.5-100%) and 99.3% (97.5-100%), respectively, in the intervention group compared with 90.2% (84.2-95.4%) and 91.5% (85.1-96.0%), respectively, in the control group (p<0.0001 for aspirin and clopidogrel). Patients in the intervention group were significantly more persistent in the aspirin and clopidogrel treatment than those in the control group. For clopidogrel, 87.2% of patients in the intervention group were still persistent at 12 months compared with only 43.1% in the control group (p<0.0001). CONCLUSIONS: A simple approach of four telephone calls to patients after DES implantation significantly improved 1-year drug adherence to near-perfect scores. Persistence of DAT was also significantly improved by the intervention. PMID- 23434771 TI - Transformation of four silver/silver chloride nanoparticles during anaerobic treatment of wastewater and post-processing of sewage sludge. AB - The increasing use of silver (Ag) nanoparticles [containing either elemental Ag (Ag-NPs) or AgCl (AgCl-NPs)] in commercial products such as textiles will most likely result in these materials reaching wastewater treatment plants. Previous studies indicate that a conversion of Ag-NPs to Ag2S is to be expected during wastewater transport/treatment. However, the influence of surface functionality, the nature of the core structure and the effect of post-processing on Ag speciation in sewage sludge/biosolids has not been investigated. This study aims at closing these knowledge gaps using bench scale anaerobic digesters spiked with Ag nitrate, three different types of Ag-NPs, and AgCl-NPs at environmentally realistic concentrations. The results indicate that neither surface functionality nor the different compositions of the NP prevented the formation of Ag2S. Silver sulfides, unlike the sulfides of other metals present in sewage sludge, were stable over a six month period simulating composting/stockpiling. PMID- 23434772 TI - Particle size, chemical composition, seasons of the year and urban, rural or remote site origins as determinants of biological effects of particulate matter on pulmonary cells. AB - Particulate matter (PM), a complex mix of chemical compounds, results to be associated with various health effects. However there is still lack of information on the impact of its different components. PM2.5 and PM1 samples, collected during the different seasons at an urban, rural and remote site, were chemically characterized and the biological effects induced on A549 cells were assessed. A Partial Least Square Discriminant Analysis has been performed to relate PM chemical composition to the toxic effects observed. Results show that PM-induced biological effects changed with the seasons and sites, and such variations may be explained by chemical constituents of PM, derived both from primary and secondary sources. The first-time here reported biological responses induced by PM from a remote site at high altitude were associated with the high concentrations of metals and secondary species typical of the free tropospheric aerosol, influenced by long range transports and aging. PMID- 23434773 TI - Enhancement of water solubility and mobility of phenanthrene by natural soil nanoparticles. AB - Nanoparticles (NPs) in soils may participate in essential ecological services, since they have special characteristics arising from their nanoscale sizes and large surface areas. We did aqueous solubility enhancement experiments to derive the partition coefficients of phenanthrene between water and six natural soil NPs. The coefficients were approximately exponentially reduced with increasing concentrations of NPs, low concentrations of NPs (50 mg L(-1)) had significant high adsorption capacities for phenanthrene. Further experiments based on dynamic light scattering technique and column tests were performed to examine the aggregation and mobility of soil NPs and how they influence phenanthrene mobility in porous media. NPs have high and reversible adsorption on surfaces of porous media with aggregation taking place during their transport and they largely control the mobility of phenanthrene in sand columns. PMID- 23434774 TI - Modelling mercury concentrations in prey fish: derivation of a national-scale common indicator of dietary mercury exposure for piscivorous fish and wildlife. AB - The National Descriptive Model for Mercury in Fish (NDMMF) was applied to a Canada - wide dataset of fish mercury (Hg) concentrations to derive a common indicator of dietary methylmercury (MeHg) exposure (HgPREY) to piscivorous fish and wildlife. The NDMMF provided unbiased parameter estimates and strong spatial biases in prediction error were not apparent. Prediction error was comparatively higher when sample sizes were small and events with high Hg concentrations. Estimates of HgPREY from 1936 locations between 1990 and 2010 averaged 0.09 +/- 0.07 MUg g(-1) (wet wt) and increased from west to east in a manner consistent with independent measures of MeHg exposure in piscivorous wildlife and conceptual models of aquatic ecosystem sensitivity to Hg methylation and bioaccumulation. The HgPREY dataset offers an approach to evaluate the risk of MeHg exposure to piscivorous fish and wildlife on a continental scale. PMID- 23434775 TI - An ecotoxicological screening tool to prioritise acid mine drainage impacted streams for future restoration. AB - Streams impacted by acid mine drainage (AMD) typically present water exhibiting low pH and high metal concentrations. These factors result in the environmental degradation of watercourses. The objective of this study was to develop and evaluate an ecotoxicological screening tool (EST) to prioritise future remediation of streams impacted by AMD. The Bloubank stream drainage system in South Africa, served as study area for this purpose. In the initial EST development phase physicochemical variables were assessed while in the second phase, epilithic filamentous green algae biomass (chl-a mg m(-2)), diatoms and filamentous green algae community structures were employed as bioindicators as well as Daphnia magna toxicity assays. Using a weight of evidence approach, the first three sites receiving AMD were critically and seriously modified, followed by site 4 that was modified. Sites 1-3 with EST scores <=70% were assessed as priority candidates for future restoration. PMID- 23434776 TI - Milk composition in the Weddell seal Leptonychotes weddellii: evidence for a functional role of milk carbohydrates in pinnipeds. AB - We propose that secretion of milk sugar has important consequences for the metabolic economies of lactating phocid seals and their pups. Milk was collected from 21 Weddell seals Leptonychotes weddellii in McMurdo Sound, Antarctica, and assayed by standard methods. Milk composition changed over the course of lactation, but at mid- to late lactation (16-40 d postpartum), Weddell seal milk composition was relatively constant at 33.8% +/- 0.82% water, 54.0% +/- 0.80% fat, 10.1% +/- 0.16% crude protein, 0.84% +/- 0.03% sugar, 0.75% +/- 0.02% ash, and 23.3 +/- 0.3 kJ g-1 whole milk (WM). At this stage, milk composition varied among individual seals in all assayed constituents except ash. The concentration of sugar in the aqueous phase of Weddell seal milk ( 24.9 +/- 0.6g sugar L-1 water) was ca. 44%-77% of levels found in terrestrial carnivores, indicating that the low sugar concentration of WM is primarily due to its high fat content, not alteration of the aqueous phase. In early lactation, fasting Weddell seals were estimated to devote 39 g d(-1) glucose to milk sugar synthesis, an amount similar to the estimated demand of the maternal brain. This additional glucose demand must be covered by gluconeogenesis in fasting animals and represents a considerable additional drain on maternal resources. However, provision of sugar to offspring at rates sufficient to meet neonatal substrate requirements appears to be essential for efficient fat and protein deposition and thus may be an important component of the phocid reproductive strategy of rapid growth and early weaning. PMID- 23434777 TI - Structural and performance costs of reproduction in a pure capital breeder, the Children's python Antaresia childreni. AB - Females often manage the high energy demands associated with reproduction by accumulating and storing energy in the form of fat before initiating their reproductive effort. However, fat stores cannot satisfy all reproductive resource demands, which include considerable investment of amino acids (e.g., for the production of yolk proteins or gluconeogenesis). Because capital breeders generally do not eat during reproduction, these amino acids must come from internal resources, typically muscle proteins. Although the energetic costs of reproduction have been fairly well studied, there are limited data on structural and performance costs associated with the muscle degradation required to meet amino acid demands. Thus, we examined structural changes (epaxial muscle width) and performance costs (constriction and strength) over the course of reproduction in a pure capital breeder, the children's python (Antaresia childreni). We found that both egg production (i.e., direct resource allocation) and maternal care (egg brooding) induce muscle catabolism and affect performance of the female. Although epaxial muscle loss was minimal in nonreproductive females, it reached up to 22% (in females after oviposition) and 34% (in females after brooding) of initial muscle width. Interestingly, we found that individuals with higher initial muscular condition allocated more of their muscle into reproduction. The amount of muscle loss was significantly linked to clutch mass, underscoring the role of structural protein in egg production. Egg brooding significantly increased proteolysis and epaxial loss despite no direct allocation to the offspring. Muscle loss was linked to a significant reduction in performance in postreproductive females. Overall, these results demonstrate that capital breeding females experience dramatic costs that consume structural resources and jeopardize performance. PMID- 23434778 TI - Pheomelanin-based plumage coloration predicts survival rates in birds. AB - Higher vertebrates synthesize two forms of melanin: eumelanin and pheomelanin. While the adaptive functions of eumelanin are diverse, those of pheomelanin, which is phototoxic and whose production consumes a key intracellular antioxidant (glutathione), are not clear apart from being involved in color patterns that confer concealment. The factors that have favored the evolution of pheomelanin thus remain a mystery, causing this pigment even to have been considered an "accident of nature." A recent hypothesis posits that pheomelanin has evolved because it represents an alternative mechanism to remove excess dietary cysteine, which can be toxic because of its oxidation. We tested for links between pheomelanin-based color and survival in both an intraspecific study of barn swallows Hirundo rustica and an interspecific study of 58 species of birds from North and Central America. As predicted on the basis that birds degrade excess dietary amino acids by transferring their amino group to uric acid synthesis, we found that under equal levels of uric acid in plasma, individuals or species with a higher intensity or greater proportion of plumage colored by pheomelanin (brown and chestnut coloration) had higher relative annual survival rates while controlling for the potentially confounding effects of age, sex, body size, and phylogenetic descent. Likewise, barn swallows with more intense pheomelanin-based coloration had higher prospects to survive the winter after controlling statistically for age, sex, body size, and level of uric acid. This supports the idea that pheomelanic traits evolve because of the removal of excess cysteine in nonstressful conditions, thus avoiding its toxic effects. PMID- 23434779 TI - Linking immune patterns and life history shows two distinct defense strategies in land snails (gastropoda, pulmonata). AB - Life history integration of the defense response was investigated at intra- and interspecific levels in land snails of the family Helicidae. Two hypotheses were tested: (i) fitness consequences of defense responses are closely related to life history traits such as size at maturity and life span; (ii) different pathways of the immune response based on "nonspecific" versus "specific" responses may reflect different defense options. Relevant immune responses to a challenge with E. coli were measured using the following variables: blood cell density, cellular or plasma antibacterial activity via reactive oxygen species (ROS) level, and bacterial growth inhibition. The results revealed that the largest snails did not exhibit the strongest immune response. Instead, body mass influenced the type of response in determining the appropriate strategy. Snails with a higher body mass at maturity had more robust plasma immune responses than snails with a lower mass, which had greater cell-mediated immune responses with a higher hemocyte density. In addition, ROS appeared also to be a stress mediator as attested by differences between sites and generations for the same species. PMID- 23434780 TI - Selective mobilization of saturated fatty acids in isolated adipocytes of hibernating 13-lined ground squirrels Ictidomys tridecemlineatus. AB - Fatty acids are not mobilized from adipocyte triacylglycerols uniformly but rather some are preferentially mobilized while others are preferentially retained. In many vertebrate species, the pattern of differential mobilization is determined by the physical and chemical properties of each fatty acid. Fatty acids with shorter chains and more double bonds tend to be more readily mobilized than others, a pattern observed both in whole-animal studies and in isolated adipocytes. Several hibernating species seem to break this pattern, however, and retain 18:2omega6 (linoleic acid) while mobilizing saturated fatty acids such as 18:0. We sought to confirm this pattern in adipocytes of a hibernator, the 13 lined ground squirrel Ictidomys tridecemlineatus, and to investigate mobilization patterns for the first time at hibernation temperature. We isolated adipocytes from summer active and winter torpid squirrels and incubated them with 1 MUM norepinephrine at 4 degrees C (7 h) and 37 degrees C (90 min). We measured the proportion of each fatty acid in the adipose tissue and in the buffer at the end of incubation. Patterns of mobilization were similar in both seasons and incubation temperatures. Saturated fatty acids (18:0 and 16:0) were highly mobilized relative to the average, while some unsaturated fatty acids (notably, 18:1omega9 and 18:2omega6) were retained. We conclude that hibernators have unique mechanisms at the level of adipose tissue that preferentially mobilize saturated fatty acids. Additionally, we found that adipocytes from hibernating squirrels produced more glycerol than those from summer squirrels (regardless of temperature), indicating a higher lipolytic capacity in hibernating squirrels. PMID- 23434781 TI - Elucidating causes of Diporeia decline in the Great Lakes via metabolomics: physiological responses after exposure to different stressors. AB - The benthic macroinvertebrate Diporeia spp. have been extirpated from many areas of the Laurentian Great Lakes, but the mechanisms underlying such declines are not fully understood. Diporeia declines coinciding with the invasion of exotic dreissenid mussels (zebra and quagga) have led to the hypothesis that Diporeia declines are a result of decreased food availability from increasing competition with dreissenids for diatoms. There is additional evidence that Diporeia are negatively affected when in close proximity to dreissenids, probably because of exposure to toxins present in the mussels' pseudofeces. Diporeia are also known to be sensitive to anthropogenic contaminants (such as polychlorinated biphenyls [PCBs]) present in Great Lakes sediments. To better understand the physiological responses of Diporeia to diverse stressors, we conducted three 28-d experiments evaluating changes in the metabolomes of Diporeia (1) fed diatoms (Cyclotella meneghiniana) versus starved, (2) exposed (from Lake Michigan and Cayuga Lake) to quagga mussels (Dreissena bugensis), and (3) exposed to sediments contaminated with PCBs. The metabolomes of samples were examined using both two-dimensional gas and liquid chromatography coupled with mass spectrometry. Each stressor elicited a unique metabolome response characterized by enhanced citric acid cycle, fatty acid biosynthesis, and protein metabolism in diatom-fed Diporeia; impaired glycolysis, protein catabolism, and folate metabolism in Diporeia from Lake Michigan irrespective of quagga mussel exposure, suggesting lake-specific adaptation mechanisms; and altered cysteine and phospholipid metabolism during PCB exposure. Subsequent comparisons of these stressor-specific metabolic responses with metabolomes of a feral Diporeia population would help identify stressors affecting Diporeia populations throughout the Great Lakes. PMID- 23434782 TI - Pond acidification may explain differences in corticosterone among salamander populations. AB - Physiological tolerances play a key role in determining species distributions and abundance across a landscape, and understanding these tolerances can therefore be useful in predicting future changes in species distributions that might occur. Vertebrates possess several highly conserved physiological mechanisms for coping with environmental stressors, including the hormonal stress response that involves an endocrine cascade resulting in the increased production of glucocorticoids. We examined the function of this endocrine axis by assessing both baseline and acute stress-induced concentrations of corticosterone in larvae from eight natural breeding populations of Jefferson's salamander Ambystoma jeffersonianum. We surveyed individuals from each pond and also examined a variety of environmental pond parameters. We found that baseline and stress induced corticosterone concentrations differed significantly among ponds. Population-level baseline corticosterone concentrations were negatively related to pH and positively related to nitrate, and stress-induced concentrations were again negatively related to pH, positively related to nitrate, and positively related to temperature. We followed the field survey with an outdoor mesocosm experiment in which we manipulated pH and again examined baseline and acute stress-induced corticosterone in A. jeffersonianum larvae. As in the field survey, we observed an increase in the baseline corticosterone concentration of individuals exposed to the lowest pH treatment (pH 5-5.8). Examining physiological indices using a combined approach of field surveys and experiments can be a powerful tool for trying to unravel the complexities of environmental impacts on species distributions. PMID- 23434783 TI - Metabolic and cardiac responses of cunner Tautogolabrus adspersus to seasonal and acute changes in temperature. AB - The cunner is a marine teleost that exhibits winter dormancy (i.e., becomes inactive and stops feeding) when seawater temperatures fall below 5 degrees C. To examine whether this dormant state is also associated with active metabolic depression, the effect of season on routine metabolic rate (MR(rout)) was measured at five different times throughout the year: early spring (5 degrees C), late spring (9 degrees C), summer (14 degrees C), late fall (5 degrees C), and winter (0 degrees C). In addition, cardiac function (cardiac output, heart rate, and stroke volume) was measured at the last three measurement time points, and the ability of fall- and winter-acclimated cunner to adjust MR(rout) and cardiac function when challenged with acute temperature changes was assessed. The cunner actively depressed MR(rout) between fall and winter as temperature fell from 5 degrees to 0 degrees C ([Formula: see text]). In addition, MR(rout) showed a substantial but smaller Q(10) (4.3) when the MR(rout) at 0 degrees C (winter) was compared with the value recorded during the previous spring at ~5 degrees C. These seasonal changes were essentially mirrored by the response of MR(rout) to acute 5 degrees C increases and decreases in temperature. Similar to MR(rout), cardiac output (Q) decreased dramatically as temperature fell from 5 degrees C (fall) to 0 degrees C (winter) in the seasonal study ([Formula: see text]) and increased substantially when temperature was acutely increased from 0 degrees to 5 degrees C ([Formula: see text]). However, when subjected to an acute temperature decrease (from 5 degrees to 0 degrees C), the Q(10) for Q was only approximately 2-3. These results show that (1) cunner actively depress their metabolism in the fall and winter and that this is associated with a large decrease in cardiac function and (2) there is a decoupling between Q and MR(rout) when 5 degrees C seasonally acclimated cunner are exposed to an acute temperature decrease to 0 degrees C. PMID- 23434784 TI - Optimum temperature in juvenile salmonids: connecting subcellular indicators to tissue function and whole-organism thermal optimum. AB - Temperature affects processes at all levels of biological organization, but it is unclear whether processes at different levels have similar thermal optima (T(opt)). Here, we compare the T(opt) for aerobic scope, a whole-organism measure of performance, with both the Arrhenius breakpoint temperature for maximum heart rate (HR-ABT), a measure of tissue level performance, and the temperature at which AMP-activated protein kinase (AMPK) is phosphorylated in the heart, an indicator of an increase in dependence on anaerobic energy metabolism at the cellular level in juvenile rainbow trout Oncorhynchus mykiss. The T(opt) for aerobic scope was 19 degrees C, with aerobic scope being maintained at >=90% of maximum (termed a "T(opt) window") from 16.5 degrees to 20.5 degrees C. HR-ABT occurred at [Formula: see text], while the profile of AMPK phosphorylation started to change from baseline at 19 degrees C, suggesting that these processes have similar thermal sensitivities as a fish is warmed to T(opt). The effects of temperature on AMPK phosphorylation were also measured in coho salmon Oncorhynchus kisutch hearts and compared with previously published values for HR ABT and aerobic scope T(opt). AMPK phosphorylation in coho hearts began to change at temperatures above 17 degrees C, which again is comparable with the published T(opt) for aerobic scope (17 degrees C) and HR-ABT ([Formula: see text]) in these individuals. Thus, the thermal sensitivity of these subcellular, tissue, and whole-organism functions are highly correlated in both rainbow trout and coho salmon and may depend on each other. PMID- 23434785 TI - Upper thermal limits of insects are not the result of insufficient oxygen delivery. AB - Most natural environments experience fluctuating temperatures that acutely affect an organism's physiology and ultimately a species' biogeographic distribution. Here we examine whether oxygen delivery to tissues becomes limiting as body temperature increases and eventually causes death at upper lethal temperatures. Because of the limited direct, experimental evidence supporting this possibility in terrestrial arthropods, we explored the effect of ambient oxygen availability on the thermotolerance of insects representing six species (Acheta domesticus, Hippodamia convergens, Gromphadorhina portentosa, Pogonomyrmex occidentalis, Tenebrio molitor, and Zophobus morio), four taxonomic orders (Blattodea, Coleoptera, Hymenoptera, and Orthoptera), and multiple life stages (e.g., adults vs. larvae or nymphs). The survival curves of insects exposed to temperatures (45 degrees or 50 degrees C) under normoxic conditions (21% O(2)) were compared with those measured under altered oxygen levels (0%, 10%, 35%, and 95% O(2)). Kaplan Meier log rank analyses followed by Holm-Sidak pairwise comparisons revealed that (1) anoxia sharply diminished survival times in all groups studied, (2) thermotolerance under moderate hyperoxia (35% O(2)) or moderate hypoxia (10% O(2)) was the same as or lower than that under normoxia, (3) half of the experimental treatments involving extreme hyperoxia (95% O(2)) caused reduced thermotolerance, and (4) thermotolerance differed with developmental stage. Adult G. portentosa exhibited much higher thermotolerance than their first-instar nymphs, but responses from larval and adult Z. morio were equivocal. We conclude that some factor(s) separate from oxygen delivery is responsible for death of insects at upper lethal temperatures. PMID- 23434786 TI - Experimental evaluation of fatty acid profiles as a technique to determine dietary composition in benthic elasmobranchs. AB - Fatty acid (FA) analysis is a tool for dietary investigation that complements traditional stomach content analyses. Controlled feeding experiments were used to determine the extent to which the FA composition of diet is reflected in the liver and muscle tissue of the Port Jackson shark Heterodontus portusjacksoni. Over 10 wk, two groups of sharks were fed prawns or squid, which have distinct FA profiles. The percentage of total FA was significantly different for shark liver and muscle tissue when comparing controls with prawn- and squid-fed sharks. Compared with experimentally fed sharks, control shark muscle and liver had higher levels of 18:1n-9 and 20:2n-9. When comparing prawn- and squid-fed sharks, only liver tissue showed a significant difference in FA profiles. The livers of prawn-fed sharks were comparatively higher in 18:1n-7, 22:5n-3, 20:0, and 18:1n 9, while the squid-fed sharks had higher levels of 16:0 and 22:6n-3. These FAs in shark liver tissue were all reflective of higher amounts in their respective dietary items, demonstrating the conservative transfer of FA from diet to liver tissue. This study shows that liver and muscle FA profiles can be used as indicators of dietary change through the comparison of controls and fed sharks. The timescale of this study may not have been sufficient for capturing the integration of FA into muscle tissue because only liver FA profiles were useful to distinguish between sharks fed different diets. These findings have important implications for sampling design where FA profiles are used to infer dietary preferences. PMID- 23434787 TI - An experimental test of the capture-restraint protocol for estimating the acute stress response. AB - Stress-induced increases in glucocorticoids (GCs) modulate behavior and are key in directing energy reserves. The capture-restraint protocol was developed to experimentally stimulate and quantify the magnitude of the acute stress response by comparing baseline GC levels with those collected after restraining a subject for a period of time, typically 30 min. This protocol has been used extensively in the field and lab, yet few studies have investigated whether it parallels hypothalamic-pituitary-adrenal (HPA) activation under natural acute stressors. We examined the hypothesis that acute stress from the capture-restraint protocol accurately mimics the adrenocortical response induced by a natural acute stressor. Using wild-caught rock pigeons Columba livia in a repeated-measures design, we compared plasma corticosterone (CORT) concentrations at baseline, after exposure to acute capture-restraint (30 min in a cloth bag), after tethering in a harness (30 min), and after a real but nonlethal attack by a predatory raptor. As found in previous studies, the capture-restraint treatment significantly increased CORT levels of pigeons compared with baseline. However, we also found that when pigeons were exposed to an attack by a raptor, their CORT levels were more than twice as high compared with the capture-restraint treatment. Our results provide evidence that an authentic acute stressor can activate the HPA axis to a greater extent than the capture-restraint protocol and also suggest that real predation attempts can have a significant effect on acute stress levels of wild birds. PMID- 23434788 TI - Sexual and reproductive health in a UK cohort of young adults perinatally infected with HIV. AB - OBJECTIVES: To assess sexual health and behaviour outcomes of young adults with perinatally acquired HIV-1 (PaHIV), and audit sexual health interventions against published standards of care. METHODS: Retrospective case note audit of 16-25-year olds with PaHIV attending a dedicated transition clinic from January 2005 to 2011. RESULTS: Fifty-two young adults, 31 women, median age 20 years. 41 were sexually active; median age of coitarche 16 years. Median number of lifetime partners was 3.5, and five reported non-consensual sex. All had a sexually transmitted infection (STI) screen; 6 were diagnosed with an STI, genital warts (human papilloma virus) most frequently. The median interval from coitarche to first STI screen was 2 years. The pregnancy incidence was 103 per 1000 person years. 18/25 (72%) sexually active women had a cervical smear, four had colposcopy. All patients had hepatitis B virus (HBV) serology. 47 had not been vaccinated against HBV prior to transition. 23 completed HBV vaccination of which 11 had surface antibody >100 IU/ml at 1 year. CONCLUSIONS: The majority of our cohort was sexually active while still under the care of paediatric health services. Cervical screening and hepatitis B vaccination rates fell short of audit standards. Vaccination for hepatitis B should be considered prior to transfer of care to adult HIV services. PMID- 23434790 TI - Perception of braided river landscapes: implications for public participation and sustainable management. AB - Over the past century, the ecologically-diverse, braided Magra River in Italy has narrowed, incised, and lost many gravel bars due to the riparian vegetation encroachment following the decrease in bedload supply and channel degradation. Motivated by the European Water Framework Directive, river scientists and managers are beginning to plan projects to conserve and restore these dynamic mosaics of rare habitats and processes. To support this objective, a study was conducted to assess how braided rivers are perceived by different social groups in the area. In June, 2006, 127 people were surveyed using a photo-questionnaire consisting of ten photographs that depicted riverscapes with different proportions of water, vegetation, and bed material. Respondents were asked to score each photograph in terms of aesthetic value, beneficial uses, and river management needs. Results showed that the photographs depicting gravel bars were perceived as less aesthetically pleasing, so therefore they need an active management. However, these perceptions differed amongst groups of participants, reflecting their interests and objectives. This paper identifies a distance between scientific and popular attitudes and discusses implications for public participation, support for braided river restoration policy, and environmental education. PMID- 23434789 TI - HIV surveillance in MENA: recent developments and results. AB - OBJECTIVES: To provide an overview of the current level of development and results from the national HIV surveillance systems of the 23 countries of the Middle East and North Africa (MENA), and to assess the quality of HIV surveillance systems in the period 2007-2011. METHODS: A questionnaire was used to collect the information about the structure, activities and the results of HIV surveillance systems from the National AIDS Programmes. Assessment of the quality was based on four indicators: timeliness of data collection, appropriateness of populations under surveillance, consistency of the surveillance sites and groups measured over time, and coverage of the surveillance system. RESULTS: Only in four countries did surveillance systems enable assessment of epidemic trends in the same populations and locations over time, such as in pregnant women (Morocco, Iran), injecting drug users (Iran, Pakistan), female sex workers (Djibouti, Morocco) and male sex workers (Pakistan). There is increasing evidence of HIV infection being firmly established in at least one of the populations most at risk of HIV in nine MENA countries, while lower risk populations show elevated HIV prevalence in South Sudan, Djibouti and some parts of Somalia. CONCLUSIONS: The performance of HIV surveillance systems in several of the MENA countries has improved in recent years. The extent of HIV epidemics in the populations most at risk of HIV is still largely unknown in 10 countries. Multiple data sources that most of the countries still lack would enable indirectly estimation not only of the patterns of HIV epidemics but also the effectiveness of HIV responses. PMID- 23434791 TI - Impact of calcium carbonate and temperature on survival of Escherichia coli in soil. AB - Spreading of waste organic matter on agricultural lands is considered to enhance soil microbial activities and physical properties and improves soil nutrient status. However, organic wastes have also been shown to be a source of microbial contaminants including pathogens. Related risks are governed by pathogens' survival and transport particularities. We evaluated the significance of high levels of CaCO3, common in arid and semi-arid soils, on survival of Escherichia coli NAR at different temperatures. Amendments of 0, 5, 10, 15 or 25 g CaCO3 were mixed into variable soil amounts to obtain 100 g soil-CaCO3 mixtures. Both sterile and non-sterile soil mixtures were tested. Suspensions of a nalidixic acid-resistant E. coli strain (E. coli NAR) were added to the mixtures at a rate of 10(6) cell g(-1) soil. Mixtures were incubated at 4, 15, or 37 degrees C at the soil's field capacity for water (i.e. 0.13 g g(-1)). Each treatment was tested in triplicate. Persistence of culturable E. coli NAR was verified throughout the incubation period. The recovery rates of culturable E. coli NAR were significantly correlated to CaCO3 concentrations (P < 0.05). Incubation temperature (T) was the most significant factor (P < 0.01). In non-sterile mixtures the largest decline in survival rates of E. coli NAR was measured for treatments with larger CaCO3 content (i.e. 15 and 25%). Interaction of temperature and CaCO3 was significant for E. coli NAR die-off. Sterilization of soil caused non-uniform fluctuations in the effect of treatments. The maximum calculated decay rate for E. coli NAR was 0.83 d(-1) for the 15 g CaCO3 non sterile mixture incubated at 37 degrees C while the minimum was 0.09 d(-1) for the control unamended sterile soil incubated at 15 degrees C. A combination of high temperature, large CaCO3 concentrations and a non-sterile, biologically active soil created the least favorable conditions for E. coli survival. PMID- 23434792 TI - Novel RNA regulatory mechanisms revealed in the epitranscriptome. AB - Methyl-6-adenosine (m (6)A) has been hypothesized to exist since the 1970s, (1) but little has been known about the specific RNAs, or sites within them, that are affected by this RNA modification. Here, we report that recent work has shown RNA modifications like m (6)A, collectively called the "epitranscriptome," are a pervasive feature of mammalian cells and likely play a role in development and disease. An enrichment of m (6)A near the last CDS of thousands of genes has implicated m (6)A in transcript processing, translational regulation and potentially a mechanism for regulating miRNA maturation. Also, because the sites of m (6)A show strong evolutionary conservation and have been replicated in nearly identical sites between mouse and human, strong evolutionary pressures are likely being maintained for this mark. (2)(,) (3) Finally, we note that m (6)A is one of over 100 modifications of RNA that have been reported, (4) and with the combination of high-throughput, next-generation sequencing (NGS) techniques, immunoprecipitation with appropriate antibodies and splicing-aware peak-finding, the dynamics of the epitranscriptome can now be mapped and characterized to discern their specific cellular roles. PMID- 23434793 TI - Effect of two loading rates on the elasticity of the human anterior rectus sheath. AB - Tensile properties of connective tissues of the abdominal wall are necessary to better analyze the mechanical response of the human abdominal wall. Some tensile properties of these tissues have been reported in the past but data are still missing regarding the dependence of the elasticity on the loading rate, especially for the rectus sheath. Thus the aim of this study was to assess for the variation of human anterior rectus sheath elasticity using two loading rates. Seventeen samples of the rectus sheath were taken from three human post-mortem subjects and tested under tension at two different loading rates (0.01s(-1) and 50s(-1)). The mean value (standard deviation) of the quasi-static elasticity is 5.6 (3.2)MPa for the rectus sheath. The values at the high loading rate are 14 (8.3)MPa. The failure strength and the elasticity (at 50s(-1)) are significantly correlated (r2=0.79, p<0.01). Such a relationship opens the way to the estimation of the failure strength by a unique measurement of the elasticity. The loading rate influence was statistically significant with a linear elasticity 2.5 times greater at 50s(-1) than 0.01s(-1). Thus the loading rate influence on the mechanical properties would have to be taken into account in models considering transitory loading such as coughing and sneezing. PMID- 23434794 TI - The relationship between different body mass index categories and chair rise performance in adult women. AB - An important prerequisite to carry out daily activities is the sit-to-stand movement. However, in obese people, this movement is characterized by altered biomechanics, which might lead to daily life activity impairments. The aim of this study was to investigate whether there are differences in kinetic and kinematic variables between three different BMI categories when performing a specific sit-to-stand test. Thirty-six adult women (BMI = 17-45 kg/m2) performed the sit-to stand test five times consecutively and as quickly as possible. Analyses of variance were used to determine differences between three BMI groups (normal or overweight: BMI < 30 kg/m2; obese: 30 <= BMI < 35; severely obese: BMI >= 35). Peak and mean vertical sacrum velocity indicated a decrease in severely obese subjects. Obese and severely obese individuals did not show higher fatigue over the five consecutive movements. Peak force and rate of force development decreased in normal or overweight subjects. The ability to successfully complete the test decreased with a higher BMI, probably due to a reduced ability to rapidly generate a high force. PMID- 23434795 TI - Augmented pulmonary responses to acute ozone exposure in obese mice: roles of TNFR2 and IL-13. AB - BACKGROUND: Acute ozone (O(3)) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice. OBJECTIVES: We examined the hypothesis that these augmented responses to O(3) are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13. METHODS: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2(-/-)) mice, and obese Cpe(fat) and TNFR2-deficient Cpe(fat) mice (Cpe(fat)/TNFR2(-/-)), to O(3) (2 ppm for 3 hr) either with or without treatment with anti-IL-13 or left them unexposed. RESULTS: O(3)-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpe(fat) than in WT mice. In lean mice, TNFR2 deficiency ablated O(3)-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O(3)-induced AHR but reduced inflammatory cell recruitment. O(3) increased pulmonary expression of IL-13 in Cpe(fat) but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13-expressing CD(4+) cells in Cpe(fat) versus WT mice after O(3) exposure. In Cpe(fat) mice, anti-IL-13 treatment attenuated O(3)-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti-IL 13 treatment were not observed in Cpe(fat)/TNFR2(-/-) mice. There was no effect of anti-IL-13 treatment in WT mice. CONCLUSIONS: Pulmonary responses to O(3) are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O(3) induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O(3)-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR. PMID- 23434797 TI - Isolation and structural elucidation of chondrosterins F-H from the marine fungus Chondrostereum sp. AB - The marine fungus Chondrostereum sp. was collected from a soft coral of the species Sarcophyton tortuosum from the South China Sea. Three new compounds, chondrosterins F-H (1, 4 and 5), together with three known compounds, incarnal (2), arthrosporone (3), and (2E)-decene-4,6,8-triyn-1-ol (6), were isolated. Their structures were elucidated primarily based on NMR and MS data. Incarnal (2) exhibited potent cytotoxic activity against various cancer cell lines. PMID- 23434796 TI - Jellyfish stings and their management: a review. AB - Jellyfish (cnidarians) have a worldwide distribution. Despite most being harmless, some species may cause local and also systemic reactions. Treatment of jellyfish envenomation is directed at: alleviating the local effects of venom, preventing further nematocyst discharges and controlling systemic reactions, including shock. In severe cases, the most important step is stabilizing and maintaining vital functions. With some differences between species, there seems to be evidence and consensus on oral/topical analgesics, hot water and ice packs as effective painkillers and on 30 s application of domestic vinegar (4%-6% acetic acid) to prevent further discharge of unfired nematocysts remaining on the skin. Conversely, alcohol, methylated spirits and fresh water should be carefully avoided, since they could massively discharge nematocysts; pressure immobilization bandaging should also be avoided, as laboratory studies show that it stimulates additional venom discharge from nematocysts. Most treatment approaches are presently founded on relatively weak evidence; therefore, further research (especially randomized clinical trials) is strongly recommended. Dissemination of appropriate treatment modalities should be deployed to better inform and educate those at risk. Adequate signage should be placed at beaches to notify tourists of the jellyfish risk. Swimmers in risky areas should wear protective equipment. PMID- 23434798 TI - Probing a coral genome for components of the photoprotective scytonemin biosynthetic pathway and the 2-aminoethylphosphonate pathway. AB - Genome sequences of the reef-building coral, Acropora digitifera, have been decoded. Acropora inhabits an environment with intense ultraviolet exposure and hosts the photosynthetic endosymbiont, Symbiodinium. Acropora homologs of all four genes necessary for biosynthesis of the photoprotective cyanobacterial compound, shinorine, are present. Among metazoans, these genes are found only in anthozoans. To gain further evolutionary insights into biosynthesis of photoprotective compounds and associated coral proteins, we surveyed the Acropora genome for 18 clustered genes involved in cyanobacterial synthesis of the anti-UV compound, scytonemin, even though it had not previously been detected in corals. We identified candidates for only 6 of the 18 genes, including tyrP, scyA, and scyB. Therefore, it does not appear that Acropora digitifera can synthesize scytonemin independently. On the other hand, molecular phylogenetic analysis showed that one tyrosinase gene is an ortholog of vertebrate tyrosinase genes and that the coral homologs, scyA and scyB, are similar to bacterial metabolic genes, phosphonopyruvate (ppyr) decarboxylase and glutamate dehydrogenase (GDH), respectively. Further genomic searches for ppyr gene-related biosynthetic components indicate that the coral possesses a metabolic pathway similar to the bacterial 2-aminoethylphosphonate (AEP) biosynthetic pathway. The results suggest that de novo synthesis of carbon-phosphorus compounds is performed in corals. PMID- 23434800 TI - Current world literature. PMID- 23434799 TI - New steroids from the soft coral Nephthea chabrolii. AB - A new cytotoxic 19-oxygenated steroid, nebrosteroid Q(1) and two new cytotoxic 19 norergosterols, nebrosteroids R and S (2 and 3) were isolated from the soft coral Nephthea chabrolii collected at San-Hsian-Tai. The structures of nebrosteroids Q S (1-3) were elucidated by spectral analysis, and their cytotoxicity against selected cancer cells as well as antiviral activity against human cytomegalovirus (HCMV) were measured in vitro. PMID- 23434802 TI - Caenorhabditis elegans ATR checkpoint kinase ATL-1 influences life span through mitochondrial maintenance. AB - ATR is highly conserved in all eukaryotes and functions as a cell-cycle nuclear checkpoint kinase. In mammals, ATR is essential whose complete absence results in early embryonic lethality and its hypomorphic mutation causes a complex disease known as Seckel syndrome. However, molecular mechanisms that cause a wide variety of symptoms including accelerated aging have remained unclear. Similarly, in the nematode Caenorhabditis elegans, a deletion mutant of ATR ortholog atl-1 appears to develop into normal adults, but their eggs do not hatch and die at early embryogenesis. Here we show that the parental worms of atl-1 defective mutant achieved longevity. Transcription levels of certain superoxide dismutase genes, sod-3 and -5 and enzymatic activity of superoxide dismutases significantly increased in the mutant. Furthermore, lipid peroxidation such as a formation of malondialdehyde was attenuated. Expressions of other genes regulated by DAF 16/FOXO transcription factor were also altered. In contrast, the mutant became hypersensitive to rotenone and ethidium bromide. Compared with the wild type the mitochondrial DNA copy number in the mutant was lesser and its proliferation is more severely inhibited in the presence of rotenone. These results suggest that C. elegans ATL-1 is involved not only in the nuclear checkpoint control but also in the mitochondrial maintenance, and its dysfunction activates mild oxidative stress response, resulting in an alteration of life span. PMID- 23434803 TI - Thermal analysis on the process of microwave-assisted biodiesel production. AB - The aim of this work was firstly to do a precise thermal analysis of microwave assisted production of biodiesel. In this paper, the effective permittivity of biodiesel synthesis was updated with two methods: a traditional method and a bivariate function of temperature and concentration of one component, then the thermal analysis of the reaction process were accomplished with multi-physics calculation. The results show that there exists large distinction in temperature between these two simulation results calculated by the two methods. The two hot spots locate in the opposite side and their temperature's difference is up to 9 degrees C when the reaction is just carried out for 18s. But the temperature risings and distributions calculated by the new method are closer to the measured results. The thermal analysis based on the new method will be helpful for the industrial design of biodiesel production. PMID- 23434804 TI - Life-cycle energy efficiency and environmental impacts of bioethanol production from sweet potato. AB - Life-cycle assessment (LCA) was used to evaluate the energy efficiency and environmental impacts of sweet potato-based bioethanol production. The scope covered all stages in the life cycle of bioethanol production, including the cultivation and treatment, transport, as well as bioethanol conversion of sweet potato. Results show that the net energy ratio of sweet potato-based bioethanol is 1.48 and the net energy gain is 6.55 MJ/L. Eutrophication is identified as the most significant environmental impact category, followed by acidification, global warming, human toxicity, and photochemical oxidation. Sensitivity analysis reveals that steam consumption during bioethanol conversion exerts the most effect on the results, followed by sweet potato yields and fertilizers input. It is suggested that substituting coal with cleaner energy for steam generation in bioethanol conversion stage and promotion of better management practices in sweet potato cultivation stage could lead to a significant improvement of energy and environmental performance. PMID- 23434805 TI - Bacterial degradation of pyrene in minimal salt medium mediated by catechol dioxygenases: enzyme purification and molecular size determination. AB - In vitro degradation of pyrene was studied in MSM by three bacterial strains individually, designated as BP10, NJ2 and P2. Among these strains, NJ2 was the highest degrader (60%) of pyrene, followed by BP10 (44%) and the least was P2 (42%) in MSM with pyrene (50 MUg ml(-1)) in 8 days. During pyrene degradation, catechol 1,2 dioxygenase (C12O) activity was induced by 13 folds in BP10 and 17 folds in P2 as compared to catechol 2,3 dioxygenase (C23O). However, in NJ2, C23O activity was augmented 1.3 times more than C12O. This clearly indicated that C12O played a major role in pyrene degradation by BP10 and P2, while in NJ2, C23O contributed more to degradation process than C12O. Molecular weight of highly inducible C12O was determined as ~64 kDa by size exclusion chromatography and as ~32 kDa on denaturing SDS PAGE in BP10 which indicated dimeric nature of the enzyme. PMID- 23434806 TI - Production of protein-rich fungal biomass in an airlift bioreactor using vinasse as substrate. AB - The potential for large-scale production of an edible fungus, Rhizopus oligosporus, on a liquid residue from sugar-to-ethanol production, vinasse, was investigated. An airlift bioreactor (2.5-L working volume) was used for cultivating the fungus on 75% (v/v) vinasse with nutrient supplementation (nitrogen and phosphorus) at 37 degrees C and pH 5.0. Aeration rates were varied from 0.5, 1.0, 1.5 to 2.0 volume(air)/volume(liquid)/min (vvm). The fungal biomass yield depended on the aeration rate, and the highest fungal biomass obtained was 8.04+/-0.80 (g(biomass increase)/g(initial biomass)) at 1.5vvm. The observed reductions in organic content by 80% (as soluble chemical oxygen demand) suggest the potential of recycling treated effluent as process water for in-plant use or for land applications. The fungal biomass contained ~50% crude protein and the essential amino acids contents were comparable to commercial protein sources for aquatic feeds (fishmeal and soybean meal), with the exception of methionine and phenylalanine. PMID- 23434807 TI - Enzymatic hydrolysis of aspen biomass into fermentable sugars by using lignocellulases from Armillaria gemina. AB - A white rot fungus, identified as Armillaria gemina SKU2114 on the basis of morphological and phylogenetic analyses, was found to secrete efficient lignocellulose-degrading enzymes. The strain showed maximum endoglucanase, cellobiohydrolase, and beta-glucosidase activities of 146, 34, and 15 U/mL, respectively, and also secreted xylanase, laccase, mannanase, and lignin peroxidase with activities of 1270, 0.16, 57, and 0.31 U/mL, respectively, when grown with rice straw as a carbon source. Among various plant biomasses tested for saccharification, aspen biomass produced the maximum amount of reducing sugar. Response surface methodology was used to optimize the hydrolysis of aspen biomass to achieve the highest level of sugar production. A maximum saccharification yield of 62% (429 mg/g-substrate) was obtained using Populus tomentiglandulosa biomass after 48 h of hydrolysis. A. gemina was shown to be a good option for use in the production of reducing sugars from lignocellulosic biomass. PMID- 23434808 TI - Microbial lipid production from xylose by Mortierella isabellina. AB - Culture conditions including nitrogen source and concentration, xylose concentration, and inoculum level were evaluated for the effect on cell growth and lipid production of an oleaginous fungus, Mortierella isabellina, grown on xylose. Yeast extract and ammonium sulfate were found to be the best amongst the organic and inorganic nitrogen sources tested, respectively. Subsequent combination of these two nitrogen sources at a nitrogen ratio of 1:1 further enhanced lipid production. The highest cell biomass 28.8 g L(-1) and lipid 18.5 g L(-1) were obtained on a medium containing 100 g L(-1) xylose and 50.4 mM nitrogen with a spore concentration of 10(8) mL(-1). Specifically, nitrogen concentration and inoculum level were demonstrated to be important for obtaining a high lipid yield on xylose consumed of 0.182 g g(-1). The results suggest that M. isabellina holds great potential to be a candidate for biofuel production from xylose, the second most abundant sugar from lignocellulose. PMID- 23434809 TI - Bio-electrolytic conversion of acidogenic effluents to biohydrogen: an integration strategy for higher substrate conversion and product recovery. AB - Feasibility of integrating Microbial electrolysis cell (MEC) process with dark fermentation process for additional hydrogen recovery as well as substrate degradation was demonstrated in the present study. MEC was employed in order to utilize the residual organic fraction present in the acidogenic effluents of dark fermentation process as substrate for hydrogen production with input of small electric current. MEC was operated at volatile fatty acids (VFA) concentration of 3000 mg/l under different poised potentials (0.2, 0.5, 0.6, 0.8 and 1.0 V) using anaerobic consortia as biocatalyst. Maximum hydrogen production rate (HPR), cumulative hydrogen production (CHP) (0.53 mmol/h and 3.6 mmol), dehydrogenase activity (1.65 MUg/ml) and VFA utilization (49.8%) was recorded at 0.6 V. Bio electrochemical behavior of mixed consortia was evaluated using cyclic voltammetry and by Tafel slope analysis. Microbial diversity analysis using denaturing gradient gel electrophoresis confirmed the presence of gamma proteobacteria (50%), Bacilli (25%) and Clostridia (25%). PMID- 23434810 TI - Sugarcane bagasse ozonolysis pretreatment: effect on enzymatic digestibility and inhibitory compound formation. AB - Sugarcane bagasse was pretreated with ozone to increase lignocellulosic material digestibility. Bagasse was ozonated in a fixed bed reactor at room temperature, and the effect of the two major parameters, ozone concentration and sample moisture, was studied. Acid insoluble and total lignin decreased whereas acid soluble lignin increased in all experiments. Pretreatment barely attacked carbohydrates, with cellulose and xylan recovery rates being >92%. Ozonolysis increased fermentable carbohydrate release considerably during enzymatic hydrolysis. Glucose and xylose yields increased from 6.64% and 2.05%, for raw bagasse, to 41.79% and 52.44% under the best experimental conditions. Only xylitol, lactic, formic and acetic acid degradation compounds were found, with neither furfural nor HMF (5-hydroxymethylfurfural) being detected. Washing detoxification provided inhibitor removal percentages above 85%, increasing glucose hydrolysis, but decreasing xylose yield by xylan solubilization. SEM analysis showed structural changes after ozonization and washing. PMID- 23434811 TI - A comparison of mass transfer coefficients between trickle-bed, hollow fiber membrane and stirred tank reactors. AB - Trickle-bed reactor (TBR), hollow fiber membrane reactor (HFR) and stirred tank reactor (STR) can be used in fermentation of sparingly soluble gasses such as CO and H2 to produce biofuels and bio-based chemicals. Gas fermenting reactors must provide high mass transfer capabilities that match the kinetic requirements of the microorganisms used. The present study compared the volumetric mass transfer coefficient (K(tot)A/V(L)) of three reactor types; the TBR with 3 mm and 6 mm beads, five different modules of HFRs, and the STR. The analysis was performed using O2 as the gaseous mass transfer agent. The non-porous polydimethylsiloxane (PDMS) HFR provided the highest K(tot)A/V(L) (1062 h(-1)), followed by the TBR with 6mm beads (421 h(-1)), and then the STR (114 h(-1)). The mass transfer characteristics in each reactor were affected by agitation speed, and gas and liquid flow rates. Furthermore, issues regarding the comparison of mass transfer coefficients are discussed. PMID- 23434812 TI - The dehydration of fructose to 5-hydroxymethylfurfural efficiently catalyzed by acidic ion-exchange resin in ionic liquid. AB - The efficient dehydration of fructose to 5-hydroxymethylfurfural (HMF) was developed in ionic liquids (ILs) with acidic ion-exchange resins as catalyst. By screening different resins and ILs respectively, it was found that the structure of resins and ILs had a prominent effect on the dehydration of fructose. In 1 butyl-3-methylimidazolium chloride ([Bmim]Cl), D001-cc resin showed a high activity. And then the effects of reaction temperatures, dosages of D001-cc, and different initial fructose loadings on the dehydration of fructose were studied in detail. The system of D001-cc resin and [Bmim]Cl exhibited a constant activity at 75 degrees C for 20 min and a 86.2% yield of HMF was obtained after seven recycles. At 75 degrees C for 20 min, a 93.0% yield of HMF from the dehydration of fructose was obtained. PMID- 23434813 TI - A thermostable and organic-solvent tolerant esterase from Pseudomonas putida ECU1011: catalytic properties and performance in kinetic resolution of alpha hydroxy acids. AB - A novel esterase, rPPE01, from Pseudomonas putida ECU1011 was heterologously expressed in Escherichia coli and identified for enzymatic resolution of hydroxy acids via O-deacetylation. alpha-Acetoxy carboxylates were converted with approximately 50% yield and excellent enantioselectivity (E>200) at a substrate concentration of 100 mM. The half-lives of rPPE01 were 14 days at 50 degrees C and 30 days at 30 degrees C, indicating the enzyme has relatively high thermostability. Another remarkable advantage of rPPE01 is that both the activity and thermostability were enhanced significantly in the presence of hydrophobic alkanes and ethers. rPPE01 retained 159% of its initial activity after incubation with 50% (v/v) n-heptane at 30 degrees C for 60 days. The attractive organic solvent tolerance, good thermostability and high enantioselectivity towards alpha acetoxy carboxylates endow rPPE01 with the potential of practical application for the production of enantiopure hydroxy acids. PMID- 23434814 TI - Optimization of furfural production from D-xylose with formic acid as catalyst in a reactive extraction system. AB - Furfural is one of the most promising platform chemicals derived from biomass. In this study, response surface methodology (RSM) was utilized to determine four important parameters including reaction temperature (170-210 degrees C), formic acid concentration (5-25 g/L), o-nitrotoluene volume percentage (20-80 vt.%), and residence time (40-200 min). The maximum furfural yield of 74% and selectivity of 86% were achieved at 190 degrees C for 20 g/L formic acid concentration and 75 vt.% o-nitrotoluene by 75 min. The high boiling solvent, o-nitrotoluene, was recommended as extraction solvent in a reactive extraction system to obtain high furfural yield and reduce furfural-solvent separation costs. Although the addition of halides to the xylose solutions enhanced the furfural yield and selectivity, the concentration of halides was not an important factor on the furfural yield and selectivity. PMID- 23434815 TI - Utilization of hydrothermally pretreated wheat straw for production of bioethanol and carotene-enriched biomass. AB - In this work hydrothermally pretreated wheat straw was used for production of bioethanol by Saccharomyces cerevisiae and carotene-enriched biomass by red yeasts Rhodotorula glutinis, Cystofilobasidium capitatum and Sporobolomyces roseus. To evaluate the convertibility of pretreated wheat straw into ethanol, simultaneous saccharification and fermentation of S. cerevisiae was performed under semi-anaerobic conditions. The highest ethanol production efficiency of 65 66% was obtained following pretreatment at 200 degrees C without the catalytic action of acetic acid, and at 195 and 200 degrees C respectively in the presence of catalyst. Red yeast strain S. roseus produced 1.73-2.22 mg g(-1) of ergosterol on the filter cake, 1.15-4.17 mg g(-1) of ergosterol and 1.23-1.56 mg g(-1) of beta-carotene on pretreated wheat straw hydrolysates and also the highest amount of carotenoids and ergosterol on untreated wheat straw (1.70 and 4.17 mg g(-1), respectively). PMID- 23434816 TI - Lipid extraction methods from microalgal biomass harvested by two different paths: screening studies toward biodiesel production. AB - Microalgae can grow rapidly and capture CO2 from the atmosphere to convert it into complex organic molecules such as lipids (biodiesel feedstock). High scale economically feasible microalgae based oil depends on optimizing the entire process production. This process can be divided in three very different but directly related steps (production, concentration, lipid extraction and transesterification). The aim of this study is to identify the best method of lipid extraction to undergo the potentiality of some microalgal biomass obtained from two different harvesting paths. The first path used all physicals concentration steps, and the second path was a combination of chemical and physical concentration steps. Three microalgae species were tested: Phaeodactylum tricornutum, Nannochloropsis gaditana, and Chaetoceros calcitrans One step lipid extraction-transesterification reached the same fatty acid methyl ester yield as the Bligh and Dyer and soxhlet extraction with n-hexane methods with the corresponding time, cost and solvent saving. PMID- 23434817 TI - Systematic review of Chinese studies of short-term exposure to air pollution and daily mortality. AB - Health effects attributable to air pollution exposure in Chinese population have been least understood. The authors conducted a meta-analysis on 33 time-series and case-crossover studies conducted in China to assess mortality effects of short-term exposure to particulate matter with aerodynamic diameters less than 10 and 2.5 MUm (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) and carbon monoxide (CO). Significant associations between air pollution exposure and increased mortality risks were observed in the pooled estimates for all pollutants of interest. In specific, each 10 MUg/m(3) increase in PM2.5 was associated with a 0.38% (95% Confidence Interval, CI: 0.31, 0.45) increase in total mortality, a 0.51% (95% CI: 0.30, 0.73) in respiratory mortality, and a 0.44% (95% CI: 0.33, 0.54) in cardiovascular mortality. When current annual PM2.5 levels in mega-Chinese cities to be reduced to the WHO Air Quality Guideline (AQG) of 10 MUg/m(3), mortality attributable to short-term exposure to PM2.5 could be reduced by 2.7%, 1.7%, 2.3%, and 6.2% in Beijing, Shanghai, Guangzhou and Xi'an, respectively. The authors recommend future studies on the nature of air pollution concentration and health effect relationships in Chinese population to support setting stringent air quality standards to improve public health. PMID- 23434818 TI - Tobacco smoke increases the risk of otitis media among Greenlandic Inuit children while exposure to organochlorines remain insignificant. AB - BACKGROUND: Prenatal exposure to environmental levels of organochlorines (OCs) has been demonstrated to have immunotoxic effects in humans. We investigated the relationship between prenatal exposure to OCs and the occurrence of otitis media (OM) among Inuit children in Greenland. METHODS: We estimated the concentration of 14 PCB congeners and 11 pesticides in maternal and cord blood samples and in breast milk in a population-based cohort of 400 mother-child pairs. At follow-up, we examined the children's ears and used their medical records to assess the OM occurrence and severity. Multivariate regression analyses were used with adjustments for passive smoking, crowding, dietary habits, parent's educational level, breast feeding and the use of child-care. RESULTS: The children were 4-10 years of age at follow-up and 223 (85%) participated. We found no association between prenatal OC exposure and the development of OM. Factors associated with the child's hazard of OM during the first 4 years of life were: mother's history of OM (HR 1.70, 95% CI 1.11-2.59, p=0.01); mother's smoking habits: current (HR 2.47, 95% CI 1.45-4.21, p<0.01) and previous (HR 2.00, 95% CI 1.19-3.36, p<0.01); number of smokers in the home (HR 1.17, 95% CI 1.05-1.31, p<0.01). After adjustment mothers' smoking habits remained significant. CONCLUSION: We found no relationship between high levels of prenatal exposure of OCs and occurrence of OM. Passive smoking was found as the strongest environmental risk factor for the development of OM. Interventions to reduce passive smoke in children's environment are needed. PMID- 23434819 TI - Inverse age-dependent accumulation of decabromodiphenyl ether and other PBDEs in serum from a general adult population. AB - Polybromodiphenyl ethers (PBDEs), including the decabromodiphenyl congener (BDE 209), were determined in the serum of 731 individuals from a general adult population (18-74 years) collected in 2002 in Catalonia (north-eastern Spain). The BDE-209 was the predominant congener (median 3.7 ng/g lipid) followed by BDE 47 (2.6 ng/g lipid) and BDE-99 (1.2 ng/g lipid). PBDEs in this population (median 15.4 ng/g lipid) ranked amongst the highest of previously described concentrations in populations in Europe, Asia, New Zealand and Australia, yet it was lower than those found in North American reports. Age was clearly the socio demographic factor of highest influence on the PBDE distributions. However, unlike usual trends of higher accumulation of POPs through age, the higher concentrations were found in young individuals (<30 years) rather than in adults (>=30 years), with differences of 14%, 31% and 46% in the most abundant congeners (i.e. BDE-209, BDE-99 and BDE-47, respectively). This age-dependent distribution of PBDEs (including the case for BDE-209, which is shown for the first time in this study) is explained by the higher and widespread use of these compounds since the 1980s. In view that these compounds remain highly used, this accumulation pattern is likely to evolve, anticipating an increasing level of PBDE concentrations in future general population surveys, yet probably assuming an age-dependent increase pattern. Socio-economic level was also a determinant of BDE-47 concentrations, but only relevant for the least affluent class, suggesting that lifestyle and environmental conditions in the dwelling place may also contribute to exposure. Nonetheless, gender, body mass index, place of birth, parity and education level did not show any statistically significant influence on the observed PBDE distributions. PMID- 23434820 TI - Direct evidence for significant spin-polarization of EuS in Co/EuS multilayers at room temperature. AB - The new era of spintronics promises the development of nanodevices, where the electron spin will be used to store information and charge currents will be replaced by spin currents. For this, ferromagnetic semiconductors at room temperature are needed. We report on significant room-temperature spin polarization of EuS in Co/EuS multilayers recorded by x-ray magnetic circular dichroism (XMCD). The films were found to contain a mixture of divalent and trivalent europium, but only Eu(++) is responsible for the ferromagnetic behavior of EuS. The magnetic XMCD signal of Eu at room temperature could unambiguously be assigned to magnetic ordering of EuS and was found to be only one order of magnitude smaller than that at 2.5 K. The room temperature magnetic moment of EuS is as large as the one of bulk ferromagnetic Ni. Our findings pave the path for fabrication of room-temperature spintronic devices using spin polarized EuS layers. PMID- 23434821 TI - HCM-linked ?160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular remodeling in transgenic mice. AB - Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Delta160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Delta160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Delta160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage dependent. The latter findings were concordant with measures of calcium regulatory protein abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfunction. We conclude that the observed clinical severity of the cTnT Delta160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound dysregulation of Ca(2+) homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling. PMID- 23434822 TI - Caffeine enhances osteoclast differentiation and maturation through p38 MAP kinase/Mitf and DC-STAMP/CtsK and TRAP pathway. AB - The consumption of caffeine from some common beverages has been associated with low bone mass by inducing urinary calcium loss and deceasing bone mineral density. However, the effect of caffeine on osteoclast differentiation is still unclear. Here, we demonstrate that caffeine directly enhances osteoclast differentiation and maturation. TRAP staining showed that the number of larger (>100 MUm) osteoclastic cells as well as of TRAP-positive multinucleated cells was increased by caffeine treatment. Among the MAP kinases, caffeine specifically activated p38 MAP kinase, which in turn, controlled osteoclast differentiation and maturation. This is evidenced by the abolishment of activated p38 MAP kinase by pretreatment with SB203580, a p38-specific inhibitor, resulting in suppressed osteoclast differentiation and maturation that should be increased by caffeine. Caffeine significantly induced the expression of Mitf and pretreatment with SB203580 markedly suppressed the expression of Mitf induced by caffeine. Whereas it failed to regulate the expression of NFATc1 and Oscar, the expressions of Cathepsin K and TRAP were induced by caffeine treatment in primary preosteoclasts. Real-time PCR and luciferase assays showed that the increase of osteoclastic cell-cell fusion by caffeine was through the transcriptional up regulation of DC-STAMP expression but not of Atp6v0d2. These results strongly suggest that caffeine directly enhances osteoclast differentiation and maturation through p38 MAP kinase activation, thus inducing Mitf expression and transcriptional activation of DC-STAMP, and finally CtsK and TRAP. PMID- 23434823 TI - Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. AB - A key issue in cancer biology is whether oncogenic transformation of different cell types of origin within an adult tissue gives rise to distinct tumour subtypes that differ in their prognosis and/or treatment response. We now show that initiation of prostate tumours in basal or luminal epithelial cells in mouse models results in tumours with distinct molecular signatures that are predictive of human patient outcomes. Furthermore, our analysis of untransformed basal cells reveals an unexpected assay dependence of their stem cell properties in sphere formation and transplantation assays versus genetic lineage tracing during prostate regeneration and adult tissue homeostasis. Although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, cross-species bioinformatic analyses indicate that tumours of luminal origin are more aggressive than tumours of basal origin, and identify a molecular signature associated with patient outcome. Our results reveal the inherent plasticity of basal cells, and support a model in which different cells of origin generate distinct molecular subtypes of prostate cancer. PMID- 23434824 TI - Nrf2 regulates haematopoietic stem cell function. AB - Coordinating the balance between haematopoietic stem cell (HSC) quiescence and self-renewal is crucial for maintaining haematopoiesis lifelong. Equally important for haematopoietic function is modulating HSC localization within the bone marrow niches, as maintenance of HSC function is tightly controlled by a complex network of intrinsic molecular mechanisms and extrinsic signalling interactions with their surrounding microenvironment. In this study we demonstrate that nuclear factor erythroid 2-related factor 2 (Nfe2l2, or Nrf2), well established as a global regulator of the oxidative stress response, plays a regulatory role in several aspects of HSC homeostasis. Nrf2 deficiency results in an expansion of the haematopoietic stem and progenitor cell compartment due to cell-intrinsic hyperproliferation, which was accomplished at the expense of HSC quiescence and self-renewal. We further show that Nrf2 modulates both migration and retention of HSCs in their niche. Moreover, we identify a previously unrecognized link between Nrf2 and CXCR4, contributing, at least partially, to the maintenance of HSC function. PMID- 23434825 TI - Characterization of the adipocyte cellular lineage in vivo. AB - Mature adipocytes are generated through the proliferation and differentiation of precursor cells. Our previous studies identified adipocyte progenitors in white adipose tissue (WAT) as Lin(-):CD29(+):CD34(+):Sca-1(+):CD24(+) (CD24(+)) cells that are capable of generating functional WAT (ref. ). Here, we employ several Cre recombinase mouse models to identify the adipocyte cellular lineage in vivo. Although it has been proposed that white adipocytes are derived from endothelial and haematopoietic lineages, we find that neither of these lineages label white adipocytes. However, platelet-derived growth factor receptor alpha (PdgfRalpha) Cre trace labels all white adipocytes. Analysis of WAT from PdgfRalpha-Cre reporter mice identifies CD24(+) and Lin(-):CD29(+):CD34(+):Sca-1(+): CD24(-) (CD24(-)) cells as adipocyte precursors. We show that CD24(+) cells generate the CD24(-) population in vivo and the CD24(-) cells express late markers of adipogenesis. From these data we propose a model where the CD24(+) adipocyte progenitors become further committed to the adipocyte lineage as CD24 expression is lost, generating CD24(-) preadipocytes. This characterization of the adipocyte cellular lineage will facilitate the study of the mechanisms that regulate WAT formation in vivo and WAT mass expansion in obesity. PMID- 23434826 TI - Can antibiotic treatment in preweaning rats alter body composition in adulthood? AB - BACKGROUND: It is suggested that antibiotherapy in infancy might program adult body composition and thus could be a determinant of obesity risk. Although not convincingly substantiated by existing literature, this assumption is plausible since antibiotics affect intestinal microbiota, whose composition in adulthood is potentially programmable during infancy and which is able to interact with both fat development and central control of appetite. OBJECTIVES: In order to substantiate the link between antibiotherapy and programming of adult body composition, the present study investigated the impact of a course of amoxicillin treatment in neonatal period on subsequent growth and body composition in rats. METHODS: Suckling rat pups were treated by oral gavage with an amoxicillin solution (150 mg.kg(-1)) or vehicle from postnatal day (PND)5 to PND15. All animals were fully weaned at PND21 then fed a standard diet until PND130. Animal growth and food intake were followed up until PND130, when body composition and plasma leptin were measured. Faecal microbiota was typified at regular intervals using real-time quantitative polymerase chain reaction. RESULTS: Preweaning amoxicillin treatment affected the composition of the faecal microbiota of pups at PND21 but this impact did not sustain long beyond the antibiotic supplementation. Immediately after weaning, a transient increase in food intake (+11%) was noticed in amoxicillin-treated animals. However, no significant impact on either growth or body composition at adulthood was observed. CONCLUSIONS: In a neonatal animal model there is no evidence of a programming of adult body weight and composition by wide-spectrum antibiotic treatment in early life. PMID- 23434827 TI - Trophic level transfer of microplastic: Mytilus edulis (L.) to Carcinus maenas (L.). AB - This study investigated the trophic transfer of microplastic from mussels to crabs. Mussels (Mytilus edulis) were exposed to 0.5 MUm fluorescent polystyrene microspheres, then fed to crabs (Carcinus maenas). Tissue samples were then taken at intervals up to 21 days. The number of microspheres in the haemolymph of the crabs was highest at 24 h (15 033 ml(-1) +/- SE 3146), and was almost gone after 21 days (267 ml(-1) +/- SE 120). The maximum amount of microspheres in the haemolymph was 0.04% of the amount to which the mussels were exposed. Microspheres were also found in the stomach, hepatopancreas, ovary and gills of the crabs, in decreasing numbers over the trial period. This study is the first to show 'natural' trophic transfer of microplastic, and its translocation to haemolymph and tissues of a crab. This has implications for the health of marine organisms, the wider food web and humans. PMID- 23434828 TI - Accounting for the dissociating properties of organic chemicals in LCIA: an uncertainty analysis applied to micropollutants in the assessment of freshwater ecotoxicity. AB - In life cycle impact assessment (LCIA) models, the sorption of the ionic fraction of dissociating organic chemicals is not adequately modeled because conventional non-polar partitioning models are applied. Therefore, high uncertainties are expected when modeling the mobility, as well as the bioavailability for uptake by exposed biota and degradation, of dissociating organic chemicals. Alternative regressions that account for the ionized fraction of a molecule to estimate fate parameters were applied to the USEtox model. The most sensitive model parameters in the estimation of ecotoxicological characterization factors (CFs) of micropollutants were evaluated by Monte Carlo analysis in both the default USEtox model and the alternative approach. Negligible differences of CFs values and 95% confidence limits between the two approaches were estimated for direct emissions to the freshwater compartment; however the default USEtox model overestimates CFs and the 95% confidence limits of basic compounds up to three orders and four orders of magnitude, respectively, relatively to the alternative approach for emissions to the agricultural soil compartment. For three emission scenarios, LCIA results show that the default USEtox model overestimates freshwater ecotoxicity impacts for the emission scenarios to agricultural soil by one order of magnitude, and larger confidence limits were estimated, relatively to the alternative approach. PMID- 23434829 TI - Upregulation of drug transporter expression by osteopontin in prostate cancer cells. AB - Multidrug resistance is a major cause of chemotherapy failure. Recent studies indicate that drug resistance can be rapidly induced by some soluble factors, such as cytokines, chemokines, growth factors, and cell adhesion factors in the tumor microenvironment. Osteopontin (OPN), an extracellular matrix protein, has a functional arginine-glycine-aspartic acid (RGD) domain for binding to integrin. Here we found OPN expression to be upregulated by hypoxic condition in PC-3 prostate tumor cells. OPN increased the mRNA and protein expression of p glycoprotein (P-gp), a subfamily of ATP-binding cassette transporter in a concentration- and time-dependent manner. The increase in P-gp transporter by OPN was mediated by binding to alphavbeta3 integrin. Daunomycin (DUN), a chemotherapeutic agent with autofluorescence, was used to evaluate the pump activity, and OPN increased the drug pumping-out activity. OPN inhibited DUN induced cell death, which was antagonized by alphavbeta3 monoclonal antibody. Long-term treatment with DUN further enhanced the expression of OPN. Knockdown of endogenous OPN potentiated the DUN-induced apoptosis of PC-3 cells. Furthermore, knockdown of OPN enhanced cell death caused by other drugs, including paclitaxel, doxorubicin, actinomycin-D, and rapamycin, which are also P-gp substrates. The animal studies also showed that OPN knockdown enhanced the cytotoxic action of DUN. These results indicate that OPN is a potential therapeutic target for cancer therapy to reduce drug resistance in sensitive tumors. PMID- 23434830 TI - In vitro acylation of okadaic acid in the presence of various bivalves' extracts. AB - The dinoflagellate Dinophysis spp. is responsible for diarrhetic shellfish poisoning (DSP). In the bivalves exposed to the toxic bloom of the dinoflagellate, dinophysistoxin 3 (DTX3), the 7-OH acylated form of either okadaic acid (OA) or DTX1, is produced. We demonstrated in vitro acylation of OA with palmitoyl CoA in the presence of protein extract from the digestive gland, but not other tissues of the bivalve Mizuhopecten yessoensis. The yield of 7-O palmitoyl OA reached its maximum within 2 h, was the highest at 37 degrees C followed by 28 degrees C, 16 degrees C and 4 degrees C and was the highest at pH 8 in comparison with the yields at pH 6 and pH 4. The transformation also proceeded when the protein extract was prepared from the bivalves Corbicula japonica and Crassostrea gigas. The OA binding protein OABP2 identified in the sponge Halichondria okadai was not detected in the bivalve M. yessoensis, the bivalve Mytilus galloprovincialis and the ascidian Halocynthia roretzi, though they are known to accumulate diarrhetic shellfish poisoning toxins. Since DTX3 does not bind to protein phosphatases 1 and 2A, the physiological target for OA and DTXs in mammalian cells, the acylation of DSP toxins would be related to a detoxification mechanism for the bivalve species. PMID- 23434832 TI - Construction of monophosphoryl lipid A producing Escherichia coli mutants and comparison of immuno-stimulatory activities of their lipopolysaccharides. AB - The lipid A moiety of Escherichia coli lipopolysaccharide is a hexaacylated disaccharide of glucosamine phosphorylated at the 1- and 4'-positions. It can be recognized by the TLR4/MD-2 complex of mammalian immune cells, leading to release of proinflammatory cytokines. The toxicity of lipid A depends on its structure. In this study, two E. coli mutants, HW001 and HW002, were constructed by deleting or integrating key genes related to lipid A biosynthesis in the chromosome of E. coli W3110. HW001 was constructed by deleting lacI and replacing lacZ with the Francisella novicida lpxE gene in the chromosome and only synthesizes monophosphoryl lipid A. HW002 was constructed by deleting lpxM in HW001 and synthesizes only the pentaacylated monophosphoryl lipid A. The structures of lipid A made in HW001 and HW002 were confirmed by thin layer chromatography and electrospray ionization mass spectrometry. HW001 and HW002 grew as well as the wild-type W3110. LPS purified from HW001 or HW002 was used to stimulate murine macrophage RAW264.7 cells, and less TNF-alpha were released. This study provides a feasible way to produce interesting lipid A species in E. coli. PMID- 23434831 TI - Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway. AB - Here we first demonstrate that asperolide A, a very recently reported marine derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 MUM asperolide A (2 * IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies. PMID- 23434833 TI - Identification of three genes encoding for the late acyltransferases of lipid A in Cronobacter sakazakii. AB - Lipid A, the hydrophobic anchor of lipopolysaccharide, is an essential component in the outer membrane of most Gram-negative bacteria. Food-borne pathogen Cronobacter sakazakii synthesizes two lipid A species, differing by the length of the secondary acyl chain. In this work, we identified three genes ESA02293, ESA02951 and ESA01386 encoding for the late acyltransferases of lipid A biosynthesis pathway in C. sakazakii. Based on the sequence alignment, proteins YP_001438378.1 encoded by ESA02293, YP_001439016.1 encoded by ESA02951, and YP_001437482.1 encoded by ESA01386 are homologous to E. coli LpxL, LpxP and LpxM, respectively. Functions of the three acyltransferases were confirmed by overexpressing the genes in E. coli, isolating lipid As and analyzing their structures using an ESI/MS. C. sakazakii LpxL and LpxM transfer a C14:0 secondary acyl chain to the 2'- and 3'-position of lipid A, respectively. C. sakazakii LpxP can transfer either a C16:1 or a C14:0 secondary acyl chains to the 2'-position of lipid A. PMID- 23434834 TI - Corin, an enzyme with a putative role in spiral artery remodeling, is up regulated in late secretory endometrium and first trimester decidua. AB - STUDY QUESTION: What is the nature of cellular Corin expression in human gestational tissues? SUMMARY ANSWER: CORIN is expressed in non-pregnant late secretory phase endometrium, first trimester human implantation sites and is up regulated with decidualization ex vivo. WHAT IS KNOWN ALREADY: Adequate trophoblast invasion and spiral artery remodeling/transformation is critical for successful implantation. CORIN, best known for its role in activating atrial natruietic peptide (ANP) to regulate blood pressure, has recently been proposed to be centrally involved in trophoblast invasion and spiral artery remodeling. It is postulated that ANP, activated by CORIN, promotes trophoblast invasion and that a deficiency causes pre-eclampsia. Mice deficient in either Corin or ANP displayed poor trophoblast invasion, impaired spiral artery remodeling and phenocopied human pre-eclampsia. However, the precise cellular localization of CORIN within human gestational tissues has not been well characterized. STUDY DESIGN, SIZE, DURATION: We measured CORIN protein localization in a number of human gestational tissues relevant to early embryo/placental implantation: non pregnant (NP) endometrial biopsies (n = 5 per phase of the menstrual cycle), first trimester placental bed biopsies (n = 12) and pre-term control (n = 10) and severe early onset preeclamptic placentas (n = 15). Endometrial stromal cells were isolated from human endometrial biopsies (n = 5) and induced to decidualize ex vivo. Finally, CORIN concentrations were measured in serum obtained from pregnant women during the first trimester of whom, 56 subsequently ended up with a healthy term delivery (controls), 18 developed fetal growth restriction (FGR) and 21 had a miscarriage. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed immunohistochemistry to assess CORIN localization. Changes in Corin mRNA expression in human endometrial stromal cells decidualized ex vivo were measured by quantitative RT-PCR, and levels of CORIN within human sera were measured by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: CORIN was expressed in both NP late secretory phase endometrium and first trimester decidua within placental bed biopsies. Importantly, decidualization of primary human endometrial cells ex vivo significantly increased Corin expression (P < 0.05). CORIN was also detected within the villous cytotrophoblast, but there was no change in mRNA levels in placentas complicated by severe preterm pre-eclampsia when compared with pre-term controls. Although CORIN was detected in first trimester serum, levels did not change across gestation, nor could they predict miscarriage or FGR (other disorders of impaired placental invasion). LIMITATIONS, REASONS FOR CAUTION: Owing to the fact that we utilized early pregnancy human specimens, this is mainly a descriptive study with a limited amount of functional experiments. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to thoroughly characterize Corin mRNA and protein expression in human gestational tissue. Our findings support recent data from murine studies collectively suggesting that CORIN plays a critical role in trophoblast migration and spiral artery remodeling during early pregnancy in humans. Therefore, further studies of CORIN biology in early pregnancy may identify new therapeutic targets to improve implantation quality in early pregnancy and potentially reduce the rates of pregnancy complications caused by inadequate implantation (pre-eclampsia, FGR and miscarriage). STUDY FUNDING/COMPETING INTEREST(S): This study was supported by The National Health and Medical Research Council of Australia (Salary support #490970, #490995). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare that no competing interests exist. PMID- 23434835 TI - The relation between growth phases, cell volume changes and metabolism of adherent cells during cultivation. AB - In biotechnology, mathematical models often consider changes in cell numbers as well as in metabolite conversion to describe different cell growth phases. It has been frequently observed that the cell number is only a delayed indicator of cell growth compared to the biomass, which challenges the principle structure of corresponding models. Here, we evaluate adherent cell growth phases in terms of cell number and biomass increase on the basis of detailed experimental data of three independent cultivations for Madin Darby canine kidney cells. We develop a model linking cell numbers and mean cell diameters to estimate cell volume changes during growth without the need for diameter distribution measurements. It simultaneously describes the delay between cell number and cell volume increase, cell-specific volume changes and the transition from growth to maintenance metabolism while taking different pre-culture conditions, which affect the cell diameter, into account. In addition, inspection of metabolite uptake and release rates reveals that glucose is mainly used for generation of cellular energy and glutamine is not required for cellular maintenance. Finally, we conclude that changes in cell number, cell diameter and metabolite uptake during cultivation contribute to the understanding of the time course of intracellular metabolites during the cultivation process. PMID- 23434837 TI - An improved constraint filtering technique for inferring hidden states and parameters of a biological model. AB - MOTIVATION: In systems biology, kinetic models represent the biological system using a set of ordinary differential equations (ODEs). The correct values of the parameters within these ODEs are critical for a reliable study of the dynamic behaviour of such systems. Typically, it is only possible to experimentally measure a fraction of these parameter values. The rest must be indirectly determined from measurements of other quantities. In this article, we propose a novel statistical inference technique to computationally estimate these unknown parameter values. By characterizing the ODEs with non-linear state-space equations, this inference technique models the unknown parameters as hidden states, which can then be estimated from noisy measurement data. RESULTS: Here we extended the square-root unscented Kalman filter SR-UKF proposed by Merwe and Wan to include constraints with the state estimation process. We developed the constrained square-root unscented Kalman filter (CSUKF) to estimate parameters of non-linear state-space models. This probabilistic inference technique was successfully used to estimate parameters of a glycolysis model in yeast and a gene regulatory network. We showed that our method is numerically stable and can reliably estimate parameters within a biologically meaningful parameter space from noisy observations. When compared with the two common non-linear extensions of Kalman filter in addition to four widely used global optimization algorithms, CSUKF is shown to be both accurate and computationally efficient. With CSUKF, statistical analysis is straightforward, as it directly provides the uncertainty on the estimation result. AVAILABILITY AND IMPLEMENTATION: Matlab code available upon request from the author. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23434836 TI - Caregivers of patients with cancer fatigue: a high level of symptom burden. AB - Fatigue is the problematic symptom identified by patients with cancer. However, fatigue has not been widely examined in caregivers of patients with cancer. In this study, 131 caregivers of patients diagnosed with advanced stage cancer and actively receiving radiotherapy reported experiencing the most difficulties with fatigue (mean 46.9; on a 0-100 scale, with a 10-point difference having clinical meaning) at baseline and at a 6-month follow-up (mean 48.3). This is in sharp contrast to other domains of quality of life and functioning being rated in the 60s, 70s and 80s by the caregivers of patients with cancer. Given the level of fatigue reported by the caregivers of patients with cancer, if confirmed by other investigators in larger and more diverse samples, interventions targeting caregiver fatigue should be explored. PMID- 23434838 TI - Light and electron microscope structural study of the zona radiata in the oocyte of zebrafish (Danio rerio). AB - Teleosts account for more than half of the vertebrate species. A key feature of the evolutionary success of teleosts is their reproductive systems, which are efficient and functional under all aquatic environmental conditions. The zona radiata (ZR) is a non- cellular envelope over oolemma of teleost fish oocytes. The morphology of the ZR varies in different ovarian developmental stages and also among various fish species, which reflects adaptation to ecological conditions. In this research the structure of the ZR in the oocytes of zebrafish in different stages of ovarian development and oocyte growth were studied. The fish ovary was fixed in Bouin's solution. Histological sections were studied by light and scanning electron microscope after subjecting them to tissue preparation stages. In immature and primary growth stages (I and II), the ZR was not observed. In stage III, the ZR was observed as a thin layer around the oocyte. It increased in thickness at stage IV (vitellogenesis) but reduced in stage V (maturation). In early stage III, the ZR striations started to appear and in stage IV (vitellogenesis) fence-like striations were completely formed. SEM micrographs showed stria to be deep with crenelated margin. In late stage IV fence-like striations disappeared gradually and in matured egg (V) the stria turned into pit-like remnants. In zebrafish no adhesive filaments were observed and the ZR surface was smooth. PMID- 23434839 TI - An essential role for the ATG8 ortholog LC3C in antibacterial autophagy. AB - Autophagy defends the mammalian cytosol against bacterial invasion. Efficient bacterial engulfment by autophagy requires cargo receptors that bind (a) homolog(s) of the ubiquitin-like protein Atg8 on the phagophore membrane. The existence of multiple ATG8 orthologs in higher eukaryotes suggests that they may perform distinct functions. However, no specific role has been assigned to any mammalian ATG8 ortholog. We recently discovered that the autophagy receptor CALCOCO2/NDP52, which detects cytosol-invading Salmonella enterica serovar Typhimurium (S. Typhimurium), preferentially binds LC3C. The CALCOCO2/NDP52-LC3C interaction is essential for cell-autonomous immunity against cytosol-exposed S. Typhimurium, because cells lacking either protein fail to target bacteria into the autophagy pathway. The selectivity of CALCOCO2/NDP52 for LC3C is determined by a novel LC3C interacting region (CLIR), in which the lack of the key aromatic residue of canonical LIRs is compensated by LC3C-specific interactions. Our findings provide a new layer of regulation to selective autophagy, suggesting that specific interactions between autophagy receptors and the ATG8 orthologs are of biological importance. PMID- 23434840 TI - Comparison of knee mechanics among risky athletic motions for noncontact anterior cruciate ligament injury. AB - It has been suggested that noncontact anterior cruciate ligament injury commonly occurs during sports requiring acute deceleration or landing motion and that female athletes are more likely to sustain the injury than male athletes. The purpose of this study was to make task-to-task and male-female comparisons of knee kinematics and kinetics in several athletic activities. Three-dimensional knee kinematics and kinetics were investigated in 20 recreational athletes (10 males, 10 females) while performing hopping, cutting, turning, and sidestep and running (sharp deceleration associated with a change of direction). Knee kinematics and kinetics were compared among the four athletic tasks and between sexes. Subjects exhibited significantly lower peak flexion angle and higher peak extension moment in hopping compared with other activities (P < .05). In the frontal plane, peak abduction angle and peak adduction moment in cutting, turning, and sidestep and running were significantly greater compared with hopping (P < .05). No differences in knee kinematics and kinetics were apparent between male and female subjects. Recreational athletes exhibited different knee kinematics and kinetics in the four athletic motions, particularly in the sagittal and frontal planes. Male and female subjects demonstrated similar knee motions during the four athletic activities. PMID- 23434841 TI - Fundamental equations for species-area theory. AB - Species-area theory is an important concept in ecology. However, debates still surround the species-area relationship (SAR) or endemics-area relationship (EAR) and their relations to expected extinction rates. In this paper, I introduce the concept of overlap-area relationship (OAR) to link SAR and EAR. Two fundamental equations are derived from the relationship between the area and species number in a limited whole area A: 1) the sum of species number in area a and species number, here defined as endemics, in area A - a is the total species number in area A; 2) the number of species common to both areas a and A - a (overlapping species) equals the species number in area a minus the endemics number in area a. Thus, we should carefully consider the total area on which EAR depends, when estimating extinction rate based on SAR. PMID- 23434842 TI - Alcohol- or drug-use disorders and motor vehicle accident mortality: a retrospective cohort study. AB - A large body of research has linked alcohol consumption and motor vehicle accidents (MVAs), but far fewer studies have estimated the risk of MVA fatality among drug users. Our study addresses this gap. We identified cohorts of individuals hospitalized in California from 1990 to 2005 with ICD-9 diagnoses of methamphetamine- (n=74,170), alcohol- (n=592,406), opioids- (n=68,066), cannabis- (n=47,048), cocaine- (n=48,949), or polydrug-related disorders (n=411,175), and these groups were followed for up to 16 years. Age-, sex-, and race-adjusted standardized mortality rates (SMRs) for deaths due to MVAs were generated in relation to the California general population. Standardized MVA mortality ratios were elevated across all drug cohorts: alcohol (4.5, 95% CI, 4.1-4.9), cocaine (3.8, 95% CI, 2.3-5.3), opioids (2.8, 95% CI, 2.1-3.5), methamphetamine (2.6, 95% CI, 2-3.1), cannabis (2.3, 95% CI, 1.5-3.2) and polydrug (2.6, 95% CI, 2.4-2.9). Males and females had similar MVA SMRs. Our large, population-based study found elevated risk of MVA mortality across all cohorts of individuals with alcohol- or drug-use disorders. Given that illicit drug users are often unaware of or misperceive the impacts of drug use on safe driving, it may be important for health-service or public-health interventions to address such biases and improve road safety. PMID- 23434843 TI - Economic worry and the presence of safety hazards on farms. AB - In recent years the agricultural sector has experienced historical levels of economic challenges. Yet, the effects of these economic conditions on the physical safety of farm work environments remain poorly understood. We studied these possible etiological relationships in a cross-sectional analysis. A baseline survey of 2390 Saskatchewan farm operations was conducted in 2007. A single respondent from each farm provided information about the farm operation, its residents, perceptions of worry surrounding farm economic conditions, and the presence of six types of physical hazards. Binomial regression analyses were used to study the focal relationships between economics and safety while simultaneously adjusting for confounders at the farm level. Farms with high perceived levels of economic worry experienced elevations in risk for: the absence of well maintained buildings (RR 1.52; 95% CI: 1.27-1.87), the absence of safety shields on combines (RR 1.41; 95% CI: 1.05-1.89), and the absence of safety shields on augers (RR 1.15; 95% CI: 1.02-1.30). No apparent differences were observed by level of economic worry for the presence of ROPS on tractors, ladder safety cages on grain bins, and barriers around water hazards. We observed that financial conditions on farms appear to contribute to the decisions that farm operators make about safety. These are not innocuous choices as they in turn affect the health and safety of the entire population that works and lives in these occupational environments. Farm operators need to be supported in decisions to invest the physical safety of their farms. They also require evidence that investments in safety are indeed economically sensible and healthy management decisions. PMID- 23434844 TI - The effects of a new traffic safety law in the Republic of Serbia on driving under the influence of alcohol. AB - The aim of the study presented here has been to see what the effects of the new traffic safety law are, 2 years into its initial implementation, on driving under the influence of alcohol. Until the end of 2009, the legal limit for blood concentration for drivers in Serbia was 0.5g/l; however, the new traffic safety law stipulates the new limit to be 0.3g/l. A retrospective autopsy study was performed over a 6-year period (from 2006 to 2011) whose sample covered cases of fatally injured drivers who had died at the scene of the incident, before being admitted to hospital. A total of 161 fatally injured drivers were examined for their blood alcohol concentration. The average age for these drivers was 40.2+/ 15.4 years, with a significant male predominance of 152 men to 9 women (chi(2)=152.000, p<0.001). This study has shown no decrease in the ratio of drivers under the influence of alcohol vs. all drivers (Pearson chi(2)=4.415, df=5, p=0.491), nor in the number of drivers under the influence of alcohol (Pearson chi(2)=6.629, df=5, p=0.250), nor a decrease in the mean blood alcohol concentration in drivers (1.72+/-0.87 vs. 1.68+/-0.95g/l, t=0.177, df=80, p=0.860). The conclusion of this study is that the new law has had a limited effect on driving under the influence of alcohol, which still remains one of the major human factors, responsible for road-traffic crashes in Serbia. PMID- 23434846 TI - Deplazes, P., Eckert, J., von Samson-Himmelstjerna, G. and Zahner, H.: Lehrbuch der Parasitologie fur die Tiermedizin [Textbook of Parasitology for Veterinary Medicine]. Third Edition. PMID- 23434845 TI - The effects of age and traffic density on street-crossing behavior. AB - Past research has shown that road users accept shorter time gaps when the waiting time/number of vehicles they let pass before attempting to merge into the traffic increases. While elderly pedestrians are known to be an extremely vulnerable group of road users, very few studies dealt with the effect of environmental constraints and crossing complexity on this population's safety. The present study aimed at determining whether or not street-crossing decisions and behavior of younger and older pedestrians were differently affected by a traffic flow. In an interactive street-crossing task, we assessed whether mean time gap and crossing decisions depended on the position of the gap pedestrians selected into the traffic stream. Results revealed that irrespective of their age pedestrians accepted a smaller time gap when they chose the second interval of the traffic compared to the first one. Contrasting with previous hypotheses, this traffic related behavior was not accompanied by an increase in the decisions risk. The findings also showed that the transition threshold from rejecting to accepting time gaps was shorter when the second interval was selected compared to the first one. This increment in task constraints might help younger and older pedestrians alike to perceive action possibilities more accurately and to be better attuned to traffic conditions by comparing gaps between each other. This opens an interesting perspective in the understanding and the training of the ability of elderly road users to remain accurate in their judgements. PMID- 23434847 TI - The molecular architecture of the bacteriophage T4 neck. AB - A hexamer of the bacteriophage T4 tail terminator protein, gp15, attaches to the top of the phage tail stabilizing the contractile sheath and forming the interface for binding of the independently assembled head. Here we report the crystal structure of the gp15 hexamer, describe its interactions in T4 virions that have either an extended tail or a contracted tail, and discuss its structural relationship to other phage proteins. The neck of T4 virions is decorated by the "collar" and "whiskers", made of fibritin molecules. Fibritin acts as a chaperone helping to attach the long tail fibers to the virus during the assembly process. The collar and whiskers are environment-sensing devices, regulating the retraction of the long tail fibers under unfavorable conditions, thus preventing infection. Cryo-electron microscopy analysis suggests that twelve fibritin molecules attach to the phage neck with six molecules forming the collar and six molecules forming the whiskers. PMID- 23434848 TI - All repeats are not equal: a module-based approach to guide repeat protein design. AB - Repeat proteins composed of tandem arrays of a short structural motif often mediate protein-protein interactions. Past efforts to design repeat protein-based molecular recognition tools have focused on the creation of templates from the consensus of individual repeats, regardless of their natural context. Such an approach assumes that all repeats are essentially equivalent. In this study, we present the results of a "module-based" approach in which modules composed of tandem repeats are aligned to identify repeat-specific features. Using this approach to analyze tetratricopeptide repeat modules that contain three tandem repeats (3TPRs), we identify two classes of 3TPR modules with distinct structural signatures that are correlated with different sets of functional residues. Our analyses also reveal a high degree of correlation between positions across the entire ligand-binding surface, indicative of a coordinated, coevolving binding surface. Extension of our analyses to different repeat protein modules reveals more examples of repeat-specific features, especially in armadillo repeat modules. In summary, the module-based analyses that we present effectively capture key repeat-specific features that will be important to include in future repeat protein design templates. PMID- 23434850 TI - Animal models of cholangiocarcinoma. AB - PURPOSE OF REVIEW: Even though recent accumulated data can help to understand fundamental molecular mechanisms of progression of cholangiocarcinoma (CCA), its incidence and mortality still keep increasing worldwide with poor prognosis. As appropriate animal disease models are critical to fill the gap between the findings from in vitro and the applications to human diseases, lack of effective and patient-like CCA animal models may contribute to limits of controlling progression of CCA. This review is focusing to provide the information about recently developed CCA animal models. RECENT FINDINGS: Recent advancements in cell and molecular biology make it possible to mimic the pathogenicity of human CCA using various animal models. In this review, several up-to-date techniques and the examples to induce CCA in animal models (xenograft and orthotopic models, carcinogen-induced CCA model, genetically engineered mouse model for CCA) with resemblance of human CCA are discussed. SUMMARY: Not only establishing animal models relevant to CCA is beneficial for its early diagnosis and therapy but also well suited experimental CCA models will guide the development of applicable treatment strategy for the hard-to-cure CCA. PMID- 23434849 TI - Regulation of minD by oxyR in Neisseria gonorrhoeae. AB - In Neisseria gonorrhoeae, cytokinesis involves Escherichia coli homologues of minC, minD and minE which are encoded as part of a min operon. MinD, a 30 kD protein component of the MinC-MinD septum inhibitory complex, together with MinE, mediates cell division site selection. Gonococci mutated in minD display aberrant cytokinesis, abnormal morphology, defective microcolony formation and virulence. minD is 274 bp upstream of oxyR, another min operon gene in N. gonorrhoeae, which encodes a redox-responsive transcriptional regulator implicated in responses to oxidative stress. In this study, we aimed to examine the oxyR-mediated regulation of minD. We observed the cotranscription of oxyR with the minCDE gene cluster. The mutation of oxyR resulted in non-midline formation of the division septum, anomalous DNA segregation, and increased aggregation of bacterial cells. qRT-PCR and Western Blot analysis revealed upregulation of minD in an oxyR mutant as compared to its isogenic wild-type N. gonorrhoeae strain in stationary phase. Furthermore, the exposure to oxidative stress in the form of H2O2 increased MinD expression levels in wild-type N. gonorrhoeae. Using beta-galactosidase activity based promoter assays, we found that oxyR negatively regulates the promoter region (PminD) upstream of minD. Our results demonstrate the involvement of oxyR in cell division and minD expression in N. gonorrhoeae. PMID- 23434851 TI - Antarctic bacterial haemoglobin and its role in the protection against nitrogen reactive species. AB - In a cold and oxygen-rich environment such as Antarctica, mechanisms for the defence against reactive oxygen and nitrogen species are needed and represent important components in the evolutionary adaptations. In the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125, the presence of multiple genes encoding 2/2 haemoglobins and a flavohaemoglobin strongly suggests that these proteins fulfil important physiological roles, perhaps associated to the peculiar features of the Antarctic habitat. In this work, the putative role of Ph-2/2HbO, encoded by the PSHAa0030 gene, was investigated by in vivo and in vitro experiments in order to highlight its involvement in NO detoxification mechanisms. The PSHAa0030 gene was cloned and then over-expressed in a flavohaemoglobin-deficient mutant of Escherichia coli, unable to metabolise NO, and the resulting strain was studied analysing its growth properties and oxygen uptake in the presence of NO. We here demonstrate that Ph-2/2HbO protects growth and cellular respiration of the heterologous host from the toxic effect of NO-donors. Unlike in Mycobacterium tuberculosis 2/2 HbN, the deletion of the N-terminal extension of Ph-2/2HbO does not seem to reduce the NO scavenging activity, showing that the N-terminal extension is not a requirement for efficient NO detoxification. Moreover, the ferric form of Ph-2/2HbO was shown to catalyse peroxynitrite isomerisation in vitro, confirming its potential role in the scavenging of reactive nitrogen species. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23434852 TI - Lysine and arginine biosyntheses mediated by a common carrier protein in Sulfolobus. AB - LysW has been identified as a carrier protein in the lysine biosynthetic pathway that is active through the conversion of alpha-aminoadipate (AAA) to lysine. In this study, we found that the hyperthermophilic archaeon, Sulfolobus acidocaldarius, not only biosynthesizes lysine through LysW-mediated protection of AAA but also uses LysW to protect the amino group of glutamate in arginine biosynthesis. In this archaeon, after LysW modification, AAA and glutamate are converted to lysine and ornithine, respectively, by a single set of enzymes with dual functions. The crystal structure of ArgX, the enzyme responsible for modification and protection of the amino moiety of glutamate with LysW, was determined in complex with LysW. Structural comparison and enzymatic characterization using Sulfolobus LysX, Sulfolobus ArgX and Thermus LysX identify the amino acid motif responsible for substrate discrimination between AAA and glutamate. Phylogenetic analysis reveals that gene duplication events at different stages of evolution led to ArgX and LysX. PMID- 23434853 TI - Allosteric inhibition of hypoxia inducible factor-2 with small molecules. AB - Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of protumorigenic pathways. Though transcription factors are typically considered 'undruggable', the PAS-B domain of the HIF-2alpha subunit contains a large cavity within its hydrophobic core that offers a unique foothold for small-molecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high sequence identity between HIF-2alpha and HIF-1alpha, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas. PMID- 23434855 TI - Long term impact of sulfur mustard exposure on peripheral blood mononuclear subpopulations--Sardasht-Iran Cohort Study (SICS). AB - The most important long-term morbidity problem of sulfur mustard (SM) toxicity is pulmonary complications but the pathogenesis of these complications is not clearly understood. This study evaluates the peripheral blood mononuclear sub sets and their correlation with pulmonary function in SM exposed civilian cases 20 years post-exposure as gathered in the context of the Sardasht-Iran Cohort Study (SICS). Samples were randomly selected from two groups, SM-exposed (n=372) and control (n=128), with the same ethnicity, culture, and demography. Three color flow cytometry was applied for peripheral blood mononuclear sub-population determination. Results indicated a significant decrease in CD45+/CD3+, CD45+/CD3+/CD4+, and an increase in CD3+/CD16+56+ percentages. It was also found that absolute count of NK cells was highly increased in peripheral blood of exposed cases. There was a significant increase in NK cell count of SM exposed group with pulmonary problems as compared to the same group without pulmonary problems (p-value<0.04) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The findings showed a significant negative correlation between absolute numbers of T lymphocyte and FVC % and positive correlation with FEV1/FVC%. The results also demonstrated that absolute numbers of monocytes had a negative correlation with FVC %. We propose that NK and T cells are probably involved in the pathogenesis or immune reactions to the delayed pulmonary complications induced by SM. This hypothesis should be tested in a more severe pulmonary complicated group. PMID- 23434854 TI - Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations. AB - BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis. PMID- 23434856 TI - Ameliorative effects of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis and their mechanisms in rats. AB - The aim of the present study was to investigate the therapeutic effect and mechanism of 3,4-oxo-isopropylidene-shikimic acid (ISA) on 2,4,6 trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. (50, 100, 200 mg/kg) was administered for 14 days, 1 day after the induction of colitis by TNBS. The colonic injury and inflammation were assessed by macroscopic damage scores and myeloperoxidase (MPO) activity. Malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in plasma were measured with biochemical methods. Prostaglandin E2 (PGE2) level in colon was determined by radioimmunoassay. Expressions of inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2 (COX-2), inhibitor kappa B-alpha (IkappaBalpha) and nuclear factor kappa B (NF-kappaB) p65 proteins in the colonic tissue were detected with immunohistochemistry. Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in the animals clystered with TNBS, which was manifested as the significant increase in colon mucosal damage index, MPO activity, levels of MDA, NO and PGE2, as well as the expressions of iNOS, COX-2 and NF-kappaB p65 proteins in the colonic mucosa, and the significant decrease in expressions of IkappaBalpha proteins in the colonic mucosa. However, these parameters were found to be significantly ameliorated in rats treated with ISA at given doses, especially at 100 mg/kg and 200 mg/kg. Administration of ISA may have significant therapeutic effects on experimental colitis in rats, probably due to its mechanism of antioxidation, its inhibition of arachidonic acid metabolism and its modulation of the IkappaBalpha/NF-kappaB p65 expression. PMID- 23434858 TI - Sinapyl alcohol derivatives from the lipo-soluble part of Dichrocephala benthamii C. B. Clarke. AB - Four new sinapyl alcohol derivatives dichrocephols A-D (compounds 1-4) were isolated from the lipo-soluble part of the whole herb of Dichrocephala benthamii C. B. Clarke, together with the known compound syringenin isovalerate (5). Their structures were elucidated on the basis of spectroscopic analysis. Their absolute configurations were established by the method of alkaline hydrohysis. Compounds 1 3 showed moderate cytotoxity against HeLa cells, with IC50 values of 14.8 MUM, 51.6 MUM and 81.6 MUM, respectively. This is the first time that sinapyl alcohol derivatives were isolated from the genus Dichrocephala. PMID- 23434857 TI - CTLA4-Ig immunosuppressive activity at the level of dendritic cell/T cell crosstalk. AB - Immunosuppressive cytotoxic T lymphocyte associated antigen-4 immunoglobulin fusion proteins (CTLA4-Ig) block the CD28:CD80/86 costimulatory pathway. On a cellular level, CTLA4-Ig is understood to dampen T cell responses. As a mechanism, CTLA4-Ig has been reported to affect dendritic cell (DC) function via inducing the immunosuppressive indoleamine 2,3 dioxygenase (IDO) pathway and promoting a DC regulatory phenotype. We here probed cellular mechanisms of CTLA4 Ig immunoregulation in an allogeneic setting using C57BL/6 splenic or bone marrow derived DCs (BMDCs) as stimulators of allogeneic Balb/c derived T cells. To address whether CTLA4-Ig immunosuppression affected DCs, we pre-exposed C57BL/6 splenic or BMDCs to CTLA4-Ig and removed unbound CTLA4-Ig before co-culture with allogeneic T cells. CTLA4-Ig disappeared rapidly (within 4 h) from the cell membrane by combined internalization and dissociation. These CTLA4-Ig pre-exposed DCs were fully capable of stimulating allogeneic T cell proliferation, suggesting that CTLA4-Ig does not impair the DC stimulatory capacity. Only the presence of CTLA4-Ig during DC/T cell co-culture resulted in the expected inhibition of proliferation. C57BL/6 splenic or BMDCs exposed to CTLA4-Ig did not display IDO activity. We conclude that CTLA4-Ig immunosuppressive activity does not depend on a DC regulatory phenotype but on its presence during DC/T cell interaction. PMID- 23434859 TI - Anti-mycobacterial activity of marine fungus-derived 4-deoxybostrycin and nigrosporin. AB - 4-Deoxybostrycin is a natural anthraquinone compound isolated from the Mangrove endophytic fungus Nigrospora sp. collected from the South China Sea. Nigrosporin is the deoxy-derivative of 4-deoxybostrycin. They were tested against mycobacteria, especially Mycobacterium tuberculosis. In the Kirby-Bauer disk diffusion susceptibility test, they both had inhibition zone sizes of over 25 mm. The results of the absolute concentration susceptibility test suggested that they had inhibitory effects against mycobacteria. Moreover, 4-deoxybostrycin exhibited good inhibition which was even better than that of first line anti-tuberculosis (TB) drugs against some clinical multidrug-resistant (MDR) M. tuberculosis strains. The gene expression profile of M. tuberculosis H37Rv after treatment with 4-deoxybostrycin was compared with untreated bacteria. One hundred and nineteen out of 3,875 genes were significantly different in M. tuberculosis exposed to 4-deoxybostrycin from control. There were 46 functionally known genes which are involved in metabolism, information storage and processing and cellular processes. The differential expressions of six genes were further confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). The present study provides a useful experiment basis for exploitation of correlative new drugs against TB and for finding out new targets of anti-mycobacterial therapy. PMID- 23434860 TI - Ganoderma tsugae hepatoprotection against exhaustive exercise-induced liver injury in rats. AB - Several studies have been shown that accelerated apoptosis is involved in post exercise lymphocytopenia and tissue damage after high-intensity exercise. Ganoderma tsugae (GT) is one of the well-known medicinal mushrooms that possess various pharmacological functions. This mushroom has traditionally been used for health promotion purposes. This study investigates the hepatoprotective effects of GT on exhaustive exercise-induced liver damage. Twenty-four male Sprague Dawley rats were randomly divided into four groups and designated as exhaustive exercise only (E), exhaustive exercise with low dosage (EL), medium dosage (EM) and high dosage (EH) GT at 0, 0.1875, 0.9375 and 1.875 g/kg/day, respectively. After 30 days all rats were euthanized immediately after an exhaustive running challenge on a motorized treadmill. The rat livers were immediately harvested. Evidence of apoptotic liver cell death was revealed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspases mediated cascade events. DNA fragmentation, an apoptosis process, can be examined using TUNEL assay. A few TUNEL-positive hepatocytes, compared to the exercise only group, were observed in the livers from exhaustive animals supplemented with GT. Immunoblot analysis also showed that caspase-6-mediated specific cleavage of lamin A/C was increased significantly in the livers of group E, but was significantly decreased in the EM and EH groups. Our observations demonstrate that GT possesses anti-apoptotic and hepatoprotective potential after exhaustive exercise. PMID- 23434861 TI - Microwave-enhanced cross-coupling reactions involving alkynyltrifluoroborates with aryl bromides. AB - Palladium-catalyzed alkynylation has emerged as one of the most reliable methods for the synthesis of alkynes which are often used in natural product syntheses and material science. An efficient method for coupling alkynyltrifluoroborates with various aryl bromides in the presence of a palladium catalyst has been developed using microwave irradiation. The microwave reactions are rapid and efficient. PMID- 23434862 TI - Antioxidant capacity of two novel bioactive Fe(III)-cyclophane complexes. AB - The cyclophanes 2,9,25,32-tetraoxo-4,7,27,30-tetrakis(carboxymethyl)-1,4,7,10, 24,27,30,33-octaaza-17,40-dioxa[10.1.10.1]paracyclophane (PO) and 2,9,25,32 tetraoxo-4,7,27,30-tetrakis(carboxymethyl)-1,4,7,10,24,27,30,33 octaaza[10.1.10.1]paracyclophane (PC) were coordinated with iron to form cationic binuclear Fe(III) Fe2PO and Fe2PC complexes, respectively. Their antioxidant capacity, superoxide dismutase and peroxidase mimetic activity, as well as their toxicity toward peripheral blood mononuclear cells (PBMCs) were evaluated. Both Fe2PO and Fe2PC are interesting biomimetics with antioxidant capacity similar to that of ascorbic acid that prevent mortality in cultured PBMCs, with the potential to have bioactive and protective functions in disease animal models. PMID- 23434863 TI - Effects of adenosine extract from Pholiota adiposa (Fr.) quel on mRNA expressions of superoxide dismutase and immunomodulatory cytokines. AB - Pholiota adiposa is a kind of edible mushroom which has long been known for its health care applications. To reveal the exact mechanism of its protective functions in humans, in this study we isolated and identified the active compound PB3 of P. adiposa for the first time by a combination of chromatography techniques, including NKA macroporous resin and Sephadex G-15. PB3, with molecular mass of 267.2 Da and molecular formula of C10H13N5O4 discovered by mass spectrum (MS) was identified to be adenosine. Mice were injected intraperitoneally with purified fraction PB3. Seven days after injection, we found a 1.5-fold increase of IL10 at the mRNA level, while a down regulated expression of IL-2, IL-6 and IFN-gamma to 49.0%, 56.9% and 73.4%, respectively, was detected in spleen by real-time quantitative PCR. What's more, SOD expression level was significantly increased by 1.6-fold compared to control. Fraction PB3 displayed anti-inflammatory potency and heightened SOD activity on the transcriptional level, which could be considered of further pharmaceutical or medication value. PMID- 23434864 TI - Two new koumine-type indole alkaloids from Gelsemium elegans Benth. AB - Two new indole alkaloids, 21-oxokoumine (1) and furanokoumine (2), were isolated from the roots of Gelsemium elegans Benth together with three known compounds. The structures of the two novel compounds were elucidated by spectroscopic methods, including NMR, HR-ESI-MS, UV, IR, CD and molecular modeling. Compound 1 is the first instance of a koumine-type alkaloid with a carbonyl at the C-21 position, while compound 2 possesses a tetrahydrofuran ring located on C-20 and C 21. PMID- 23434865 TI - Pharmacological actions of multi-target-directed evodiamine. AB - Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodiae fructus. With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and thermo-regulative effects. Evodiamine has evolved a superior ability to bind various proteins, so we also argue that it is good starting point for multi-target drugs. This review is primarily addressed to the description of the recent advances in the biological activity studies of evodiamine, with a focus on pharmacological mechanism. The present review also includes the pharmacokinetics and the detailed exploration of target-binding properties of evodiamine in an attempt to provide a direction for further multi-target drug design. PMID- 23434867 TI - Anti-Helicobacter pylori and urease inhibition activities of some traditional medicinal plants. AB - Different parts of Acacia nilotica (L.) Delile, Calotropis procera (Aiton) W.T. Aiton, Adhatoda vasica Nees, Fagoniaar abica L. and Casuarina equisetifolia L. are traditionally used in folk medicine for the treatment of a variety of common ailments like nausea, cold, cough, asthma, fevers, diarrhea, sore throat, swelling, etc. The present study was aimed to evaluate the anti-Helicobacter pylori and urease inhibition activities of extracts produced from the above selected medicinal plants native to Soon Valley (home to an old civilization) in the Punjab province of Pakistan. Methanol, acetone and water extracts of the plants were evaluated for anti-bacterial activity against thirty four clinical isolates and two reference strains of H. pylori. Minimum inhibitory concentrations (MICs) of the extracts were determined using the agar dilution method and compared with some standard antibiotics like amoxicillin (AMX), clarithromycin (CLA), tetracycline (TET) and metronidazole (MNZ), used in the triple therapy for H. pylori eradication. H. pylori urease inhibition activity of the extracts was assessed by the phenol red method, wherein, Lineweaver-Burk plots were used to determine Michaelis-Menten constants for elucidating the mechanism of inhibition. Methanol and acetone extracts from Acacia nilotica and Calotropis procera exhibited stronger anti-H. pylori activity than MNZ, almost comparable activity with TET, but were found to be less potent than AMX and CLT. The rest of the extracts exhibited lower activity than the standard antibiotics used in this study. In the H. pylori urease inhibitory assay, methanol and acetone extracts of Acacia nilotica and Calotropis procera showed significant inhibition. Lineweaver-Burk plots indicated a competitive mechanism for extract of Acacia nilotica, whereas extract of Calotropis procera exhibited a mixed type of inhibition. PMID- 23434866 TI - Development and molecular characterization of 55 novel polymorphic cDNA-SSR markers in faba bean (Vicia faba L.) using 454 pyrosequencing. AB - Faba bean (Vicia faba L.) is a major food source and fodder legume, popularly known for its high content of seed-protein. Its role is critical in crop rotation, and for fixing nitrogen effectively. Polymorphic simple sequence repeat markers from transcript sequences (cDNA; simple sequence repeat [SSR]) were developed for faba bean (Vicia faba). We found that 1,729 SSR loci from 81,333 individual sequence reads and 240 primer pairs were designed and synthesized. In total, 55 primer pairs were found to be polymorphic and scorable consistently when screened in 32 accessions. The number of alleles ranged from 2 to 15, frequency of major alleles per locus varied from 0.17 to 0.91, the genotypes number ranged from 2 to 17, observed and expected heterozycosity values ranged from 0.00 to 0.44 and 0.17 to 0.89 and overall PIC values ranged from 0.16 to 0.88 respectively. These markers will be a useful tool for assessing the genetic diversity, understanding the population structure, and breeding patterns of faba bean. PMID- 23434868 TI - Volatiles and water- and fat-soluble precursors of Saanen goat and cross Suffolk lamb flavour. AB - This paper evaluates the concentrations of water- and fat-soluble precursors of meat flavour, with the aim of characterising the effect of species on the volatile profile of grilled goat and lamb meat. Compared to goat, lamb meat had higher levels of saturated fatty acids--SFA, monounsaturated fatty acids--MUFA and polyunsaturated fatty acids--PUFA and similar levels of sugars and free amino acids, except for lysine and glycine, which were higher in goat. Major differences were detected in lipid-derived volatiles; only pyrazine, thiazole, and some Strecker aldehydes were at different concentrations in these species. Volatile compounds derived from the oxidation of linoleic acid were at higher levels in meat from lamb due to the higher concentration of the latter, while compounds formed from alpha-linolenic acid were at higher levels in goat. It can be concluded that lamb meat has a stronger flavour profile compared to goat meat because it has the highest concentrations of lipid-derived volatile compounds, primarily straight saturated alkanals, pyrazines and thiazole. PMID- 23434869 TI - Antibacterial/antifungal activity and synergistic interactions between polyprenols and other lipids isolated from Ginkgo biloba L. leaves. AB - Polyprenols separated from lipids are promising new components from Ginkgo biloba L. leaves (GBL). In this paper, ginkgo lipids were isolated by extraction with petroleum ether, saponification, and molecular distillation. Eight known compounds: isophytol (1), nerolidol (2), linalool (3), beta-sitosterol acetate (4), beta-sitosterol (5), stigmasterol (6), ergosterol (7), beta-sitosterol-3-O beta-D-glucopyranoside (8) and Ginkgo biloba polyprenols (GBP) were separated from GBL by chromatography and identified mainly by NMR. The separated and identified compounds 1, 2 and 3 are reported here for the first time in GBL. The 3D-DAD-HPLC-chromatogram (190-232 nm) of GBP was recorded. This study provides new evidence as there are no previous reports on antibacterial/antifungal activities and synergistic interactions between GBP and the compounds separated from GBL lipids against Salmonella enterica, Staphylocococus aureus and Aspergillus niger. Nerolidol (2) showed the highest activity among all the tested samples and of all mixture groups tested the GBP with isophytol (1) mixture had the strongest synergistic effect against Salmonella enterica among the three tested strains. A proportion of isophytol and GBP of 38.19%:61.81% (wt/wt) was determined by mixture design as the optimal proportion for the synergistic effect of GBP with isophytol against Salmonella enterica. PMID- 23434870 TI - Gelam honey protects against gamma-irradiation damage to antioxidant enzymes in human diploid fibroblasts. AB - The present study was designed to determine the radioprotective effects of Malaysian Gelam honey on gene expression and enzyme activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) of human diploid fibroblasts (HDFs) subjected to gamma-irradiation. Six groups of HDFs were studied: untreated control, irradiated HDFs, Gelam honey-treated HDFs and HDF treated with Gelam honey pre-, during- and post-irradiation. HDFs were treated with 6 mg/mL of sterilized Gelam honey (w/v) for 24 h and exposed to 1 Gray (Gy) of gamma rays at the dose rate of 0.25 Gy/min. Gamma-irradiation was shown to down-regulate SOD1, SOD2, CAT and GPx1 gene expressions (p < 0.05). Conversely, HDFs treated with Gelam honey alone showed up-regulation of all genes studied. Similarly, SOD, CAT and GPx enzyme activities in HDFs decreased with gamma irradiation and increased when cells were treated with Gelam honey (p < 0.05). Furthermore, of the three different stages of study treatment, pre-treatment with Gelam honey caused up-regulation of SOD1, SOD2 and CAT genes expression and increased the activity of SOD and CAT. As a conclusion, Gelam honey modulates the expression of antioxidant enzymes at gene and protein levels in irradiated HDFs indicating its potential as a radioprotectant agent. PMID- 23434871 TI - An efficient chemoselective reduction of furan series unsaturated dinitriles. AB - An efficient reduction of double bonds conjugated with nitrile groups and acid or base sensitive furan rings with 2-phenylbenzimidazoline generated in situ has been successfully accomplished with high yields and excellent selectivity. The employed reducing agent was prepared in one step from ordinary chemicals. The other advantages of the presented method include mild and convenient reaction conditions, a benign and cost effective reagent, simple work-up and separation of the products. As this process does neither affect cyano and nitro groups nor furan rings, it is a valuable alternative when metal-catalyzed hydrogenations or borohydride reductions have failed. PMID- 23434872 TI - Preparation of an immunoaffinity column with amino-silica gel microparticles and its application in sample cleanup for aflatoxin detection in agri-products. AB - This study established an immunoaffinity column for selective extraction of aflatoxins in agri-products. Specifically, the immunoaffinity column was developed by covalently coupling monoclonal antibody 1C11 against aflatoxins to amino-silica gel microparticles and then packing these into a cartridge. The extraction conditions were thoroughly optimized in terms of loading, washing and eluting solutions. Under the optimal conditions, the immunoaffinity column had a capacity of 200 ng of aflatoxins. The detection limits (S/N = 3) for aflatoxin G1, B1, G2 and B2 were 0.03, 0.07, 0.05 and 0.09 MUg.kg-1, and the corresponding quantification limits (S/N = 10) were 0.10, 0.25, 0.18 and 0.30 MUg.kg-1, respectively. The recoveries of aflatoxins in samples were 90.1%-104.4% and RSDs were <4.4%. The developed method was further applied to the determination of aflatoxins in peanut, vegetable oil and tea samples, and the results indicated that peanut (26.9%), vegetable oils (28.0%) and tea (5.3%) samples were contaminated with aflatoxins, with levels ranging from 0.49 to 20.79 MUg.kg-1. PMID- 23434873 TI - New spiral gamma-lactone enantiomers from the plant endophytic fungus Pestalotiopsis foedan. AB - (-)-(4S, 8S)-Foedanolide (1a) and (+)-(4R, 8R)-foedanolide (1b), a pair of new spiro-gamma-lactone enantiomers, were isolated from the fermentation broth of the plant endophytic fungus Pestalotiopsis foedan by HPLC using a chiral column, achieving over 7% ee. Their structures and absolute configurations were determined on the basis of extensive analysis of NMR spectra combined with computational methods via calculation of the electronic circular dichroism (ECD) and optical rotation (OR). Compounds 1a and 1b showed moderate activities against HeLa, A-549, U-251, HepG2 and MCF-7 tumor cell lines. PMID- 23434874 TI - Growth of fullerene fragments using the Diels-Alder cycloaddition reaction: first step towards a C60 synthesis by dimerization. AB - Density Functional Theory has been used to model the Diels-Alder reactions of the fullerene fragments triindenetriphenilene and pentacyclopentacorannulene with ethylene and 1,3-butadiene. The purpose is to prove the feasibility of using Diels-Alder cycloaddition reactions to grow fullerene fragments step by step, and to dimerize fullerene fragments, as a way to obtain C60. The dienophile character of the fullerene fragments is dominant, and the reaction of butadiene with pentacyclopentacorannulene is favored. PMID- 23434875 TI - Pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune hepatitis. AB - OBJECTIVE: The association between celiac disease (CD) and liver disease in pediatrics is widely recognized, but its prevalence is unknown. This study aims to conduct a systematic review and meta-analysis to evaluate the prevalence of CD in children with cryptogenic persistent hypertransaminasemia (HTS) or autoimmune hepatitis (AIH), and vice versa. METHODS: We searched MEDLINE/PubMed, the Cochrane Library, Web of Science, and MD Consult from 1977 to May 2012 for studies reporting either CD and HTS or AIH. Pooled prevalences with 95% confidence intervals (CI) and relative risk (RR) were calculated. RESULTS: Nine studies (2046 patients) were identified. Pooled prevalences of CD in children with mild, nonspecific cryptogenic persistent HTS and vice versa were 12.0% (95% CI 4.17-29.96) and 36.0% (95% CI 32.15-40.11), respectively. A gluten-free diet normalized transaminase levels in 77% to 100% of patients with CD within 4 to 8 months. Pooled prevalences of CD in children with AIH and vice versa were 6.3% (95% CI 3.87-11.73) and 1.4% (95% CI 0.84-2.15), respectively. The RR of HTS in children with CD versus the general population, and of CD in children with HTS was 6.55 (95% CI 5.65-7.60) and 11.59 (95% CI 3.80-35.33), respectively. The corresponding RR of AIH in children with CD was 188.54 (95% CI 92.23-385.43). The RR of CD in children with AIH was 6.63 (95% CI 3.86-11.40). CONCLUSIONS: CD is associated with elevated transaminase levels in about one-third of newly diagnosed children. Cryptogenic persistent HTS may signal gluten-dependent nonspecific mild hepatitis (12.0% of cases) or more rarely (6.3%) severe CD related autoimmune hepatopathy. RRs confirm these trends in the considered associations. PMID- 23434876 TI - A new set of reversibly photoswitchable fluorescent proteins for use in transgenic plants. AB - Fluorescent reporter proteins that allow repeated switching between a fluorescent and a non-fluorescent state in response to specific wavelengths of light are novel tools for monitoring of protein trafficking and super-resolution fluorescence microscopy in living organisms. Here, we describe variants of the reversibly photoswitchable fluorescent proteins rsFastLime, bsDronpa, and Padron that have been codon-optimized for the use in transgenic Arabidopsis plants. The synthetic proteins, designated rsFastLIME-s, bsDRONPA-s, and PADRON C-s, showed photophysical properties and switching behavior comparable to those reported for the original proteins. By combining the 'positively switchable' PADRON C-s with the 'negatively switchable' rsFastLIME-s or bsDRONPA-s, two different fluorescent reporter proteins could be imaged at the same wavelength upon transient expression in Nicotiana benthamiana cells. Thus, co-localization analysis can be performed using only a single detection channel. Furthermore, the proteins were used to tag the RNA-binding protein AtGRP7 (Arabidopsis thaliana glycine-rich RNA binding protein 7) in transgenic Arabidopsis plants. Because the new reversibly photoswitchable fluorescent proteins show an increase in signal strength during each photoactivation cycle, we were able to generate a large number of scans of the same region and reconstruct 3-D images of AtGRP7 expression in the root tip. Upon photoactivation of the AtGRP7:rsFastLIME-s fusion protein in a defined region of a transgenic Arabidopsis root, spreading of the fluorescence signal into adjacent regions was observed, indicating that movement from cell to cell can be monitored. Our results demonstrate that rsFastLIME-s, bsDRONPA-s, and PADRON C-s are versatile fluorescent markers in plants. Furthermore, the proteins also show strong fluorescence in mammalian cells including COS-7 and HeLa cells. PMID- 23434877 TI - Simultaneous quantification of cefpodoxime proxetil and clavulanic acid in human plasma by LC-MS using solid phase extraction with application to pharmacokinetic studies. AB - A simple, rapid and selective high performance liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (HPLC-APCI-MS) method was developed and validated for the simultaneous estimation of cefpodoxime proxetil (CDPX) and clavulanic acid (CA) in human plasma. Extraction of samples was done by solid phase extraction technique (SPE) and chloramphenicol used as internal standard. Chromatographic separation was carried out on a reverse phase Princeton SPHER C18 (150mm*4mm i.d., 5MUm) column using mixture of methanol: acetonitrile: 2mM ammonium acetate (25:25:50, v/v, pH 3.5) at 0.8mL/min flow rate. Detection was performed on a single quadrupole MS by selected ion monitoring (SIM) mode via APCI source. The calibration curve was linear within the concentration range, 0.04-4.4MUg/mL and 0.1-10.0MUg/mL for CDPX and CA respectively. Pharmacokinetic parameters of tablet (CDPX 200mg, CA 125mg) were evaluated. Cmax, Tmax, T1/2, elimination rate constant (Kel), AUC0-t, and AUC0-infinity of tablet were 2.13+/ 0.06MUg/mL, 2h, 3.05+/-0.15h, 0.24+/-0.37h(-1), 6.81+/-0.14MUg h/mL and 7.72+/ 0.23MUg h/mL respectively for cefpodoxime (CP), 5.34+/-0.28MUg/mL, 2h, 2.73+/ 0.25h, 0.26+/-0.31h(-1), 15.37+/-0.16MUg h/mL and 16.59+/-0.53MUg h/mL respectively for CA. PMID- 23434878 TI - Effect of heel construction on muscular control potential of the ankle joint in running. AB - The purpose of this study was to investigate the effect of heel construction on ankle joint mechanics during the early stance phase of running. Kinematic and kinetic parameters (ankle joint angles, angular velocities and joint moments, lever arms of ground reaction force, triceps surae muscle tendon unit lengths, and rates of muscle tendon unit length change) were calculated from 19 male subjects running at 3.3 m/s in shoes with different heel constructions. Increasing heel height and posterior wedging amplified initial plantar flexion velocity and range. The potential for a muscle to control the movement of a joint depends upon its ability to produce joint moments. Runners in this study showed decreased external eversion moments and an increase in eversion range. Maximum eversion angles were not significantly affected by shoe conditions. Without considerable tendon prestretch, joint moment generation potentials of triceps surae and deep plantar flexors might be inhibited due to rapid plantar flexion based on the force-velocity relationship. It could be speculated that increasing ankle inversion at heel strike could be a strategy to keep maximum eversion angles inside an adequate range, if joint moment generation potentials of deep plantar flexors are inhibited due to rapid plantar flexion. PMID- 23434879 TI - Controlled assembly of Sb2S3 nanoparticles on silica/polymer nanotubes: insights into the nature of hybrid interfaces. AB - Silica nanotubes can serve as high aspect ratio templates for the deposition of inorganic nanoparticles to form novel hybrids. However, the nature of the interfacial binding is still an unresolved challenge when considered at the atomic level. In this work, novel nanocomposites have been successfully fabricated by the controlled nucleation and assembly of Sb2S3 nanoparticles on the surface of mercaptopropyl-functionalized silica/polymer hybrid nanotubes (HNTs). The Sb2S3 nanoparticles were strongly attached to the HNTs surface by interactions between the pendent thiol groups and inorganic sulfur atoms. Detailed analysis of the geometric and electronic structure using first-principle density functional theory demonstrates charge transfer from the nanoparticles to the underlying HNTs at the Sb2S3/HNTs interfaces. Formation of a packed array of Sb2S3 nanoparticles on the HNTs results in mixing of the electronic states of the components, and is mediated by the mercaptopropyl bridges between Sb2S3 and the outer layer of the HNTs. PMID- 23434880 TI - Proteins of duck influenza virus responsible for acquisition of pathogenicity in chickens. AB - Influenza virus rgVac1sub-P0 (H5N1) (rgVac1-P0), in which a pair of dibasic amino acid residues was introduced at the cleavage site of the HA of a reassortant of H5N2 and H7N1 viruses of duck origin, was low pathogenic in chickens. Vac1sub-P3 (H5N1) (Vac1-P3) was selected as a highly pathogenic avian influenza virus by 3 consecutive passages in chickens from low pathogenic strain rgVac1-P0. Comparison of amino acid sequences of the virus proteins and experimental infection of chickens with a series of recombinant viruses demonstrated that in addition to the HA, each of the PA, NP, M1, and M2 of Vac1-P3 are responsible for the acquisition of pathogenicity in chickens. These 4 proteins of Vac1-P3 synergistically contributed to efficient virus replication in chickens. PMID- 23434881 TI - Spelling recognition after exposure to misspellings: implications for abstractionist vs. episodic theories of orthographic representations. AB - University students made spelling accuracy judgments about correctly and incorrectly spelled words that had been seen incorrectly spelled (Experiments 1 and 2). In contrast to results for spelling production, studying a misspelling produced a small benefit in classification of the correct word at test. When the studied misspelling was re-presented at test, there was a substantial cost in accuracy. Testing spelling recognition in an old context had a biassing effect, but there was little evidence of context re-instatement effects for studied words. In Experiment 3 students decided whether a correctly spelled word was spelled the same way at study and test. Participants' poor performance with words studied misspelled supports a priming explanation of the benefit for correct words. The differential effects for correct and incorrect test words cannot be explained in terms of updating abstract lexical representations, and the limitations on participants' item and context memory challenge episodic accounts of lexical representations. PMID- 23434882 TI - [Preparing patients with chronic pulmonary disease for air travel]. AB - Flying is the most important way of travelling in the continually growing international tourism. Number of passengers and those with preexisting diseases, mainly with cardiopulmonary problems, is increasing over years. One of the main tasks of the pre-travel advice is to assess tolerance to hypoxia of the traveler, and specify the necessity, as well as the type and volume of supplementary oxygen therapy. It is indispensable to know the cabin-environment and impact of that on the travelers' health. Travel medicine specialist has to be aware of the examinations which provide information for the appropriate decision on the fit-to fly condition of the patient. The physician who prepares the patient with chronic obstructive pulmonary disease for repatriation by regular flight and the escorting doctor have to be fully aware of the possibilities, modalities, advantages and contraindications of the on-board oxygen supply and therapy. In this review, the authors give a summary of literature data, outline the tools of in-flight oxygen therapy as well as discuss possibilities for the preflight assessment of patients' condition including blood gas parameters required for safe air travel, as recommended in international medical literature. The preparation process for repatriation of patients with chronic obstructive pulmonary disease is also discussed. PMID- 23434883 TI - [Endoscopic ultrasound-guided fine needle aspiration cytology in the mediastinum]. AB - INTRODUCTION: Endoscopic ultrasound and endoscopic ultrasound-guided fine needle aspiration in the posterior mediastinum is technically a relatively simple and safe procedure, and it can provide important information for the further management of patients. AIM: To analyze and compare the results of mediastinal endoscopic ultrasound-guided fine needle aspiration with the data available in the literature. PATIENTS AND METHODS: The authors retrospectively analyzed their prospective database on mediastinal endoscopic ultrasound-guided fine needle aspiration of 49 patients referred to their endoscopy centre between 1 November 2009 and 1 November 2012. For the fine needle aspiration 22 and 25 G needles were used. Two to six needle passes were performed in each patient. All slides were prepared at the endoscopy unit and analyzed at the cytology laboratory. RESULTS: The authors performed mediastinal endoscopic ultrasound-guided fine needle aspiration for enlarged lymph nodes or suspected mediastinal malignancy in all but 4 patients (2 suspected oesophageal cancers, 1 suspected benign oesophageal stenosis with wall thickening and 1 cardia tumour, all with non-diagnostic endoscopic biopsies). Five patients were excluded from the analysis since fine needle aspiration was not performed in them. Benign lesions were suspected based on the endoscopic ultrasound morphology in 7, and malignant disease in 37 patients. In 3 cases samples obtained by biopsy were not informative for cytological analysis. Cytology confirmed all benign lesions and showed malignancy in 28 cases. Cytology failed to reveal malignancy in 6 patients, although it was suspected based upon endoscopic ultrasound finding. Furthermore, endoscopic ultrasound-guided fine needle aspiration provided the diagnosis in 15 of the 17 patients when bronchoscopy was non-diagnostic. The diagnostic accuracy of the EUS FNA was the following: sensitivity 82%, specificity 100%, positive predictive value 1.0, negative predictive value 0.54. Only one infectious complication was encountered after fine needle aspiration despite antibiotic prophylaxis. DISCUSSION: Endoscopic ultrasound-guided fine needle aspiration of mediastinal pathology is an accurate, safe and technically relatively easy procedure, however it requires practice and skills in mediastinal anatomy. It has an excellent positive predictive value, a very good sensitivity, but slightly poor negative predictive value. The results of this study are concordant with the literature data. The authors suggest that at least 4 needle passes in the absence of on-site pathologist should be performed in order to minimize the number of false-negative results. PMID- 23434884 TI - [Examination of late pulmonary toxicity in children treated for malignancies]. AB - INTRODUCTION: The present investigation was based on a survey in 2005, in which the authors found pulmonary function abnormalities in survivors of childhood cancer, who were treated with anticancer therapy. AIM: The purpose of the present study was to follow-up childhood cancer survivors and detect late pulmonary toxicity. PATIENTS AND METHODS: Lung function test was performed with spirometry in 26 survivors participated in this study (10 females and 16 males; mean age, 19.4 years at the time of the second follow-up evaluation). The average time periods from treatment until the first and second follow-up evaluation were 4.5 and 10 years, respectively. RESULTS: The authors found 14 patients with pathological pulmonary function tests results at the time of the first follow-up evaluation, from which 7 patients had obstructive, 5 patients had mixed and 2 patients had restrictive abnormalities. However, there were only 6 patients who had abnormal pulmonary function at the time of the second follow-up evaluation (2 patients with obstructive and 4 patients with restrictive pulmonary function tests (p<0.05). CONCLUSION: Restrictive pulmonary disorder was detected in only small part of the treated patients. The obstructive pulmonary abnormalities caused by the treatment showed an improving tendency over time. PMID- 23434885 TI - [In the labyrinth of calcium metabolism]. AB - The authors present the case of a 27-year-old male patient. In 2010, he suffered from a bone fracture of the pelvis. As imaging techniques showed multiple osseal lytic lesions, diagnostic investigations were performed for multiple myeloma. Later, a mass lesion measuring 37 mm in size was removed from the left side of his mandible. Histology revealed a giant-cell tumour of the bone and oncologic therapy was considered. However, before this planned treatment a PET-CT was performed, which showed numerous distinct lesions with enhanced glucose metabolism in the skeleton as well as in soft tissue behind the right lobe of the thyroid. Hence, the patient was referred to endocrinologists. On the basis of severe hypercalcemia (serum calcium 3.66 mmol/l) and high serum parathyroid hormone level (162.5 pmol/l) the diagnosis of a right sided parathyroid tumour was established. After surgical excision of the parathyroid tumour, high levels of serum calcium and parathyroid hormone returned to normal. Histology failed to show malignancy and the patient recovered soon. This case report may shed some light on the importance of serum calcium measurements and the differential diagnostic significance of primary hyperparathyroidism. PMID- 23434888 TI - Studies on the detection of concealed objects using the neutron reflection method. AB - The increment of reflected thermal and 1.45 eV resonance neutrons vs. the thickness of the reflector has been measured and described by an analytical expression. Macroscopic, Sigmabeta, and microscopic, sigmabeta, reflection cross sections averaged over the bulk reflector substances were deduced for some elements and compounds. It was found that the sigmabeta values are additive even for bulk samples and so the sigmabetamol could be given for some illicit drugs, explosives and hiding materials. PMID- 23434889 TI - A novel approach for predicting the response of the spectrometer for INTEGRAL satellite. AB - A basic phenomenological approach has been presented in three recent papers (Kshetri R., 2012. JINST 7, P04008; Kshetri R., 2012. JINST 7, P07006; Kshetri R., 2012. JINST 7, P12007) for understanding the operation of encapsulated type composite detectors including the SPI spectrometer. In the present paper, we have considered the fact that the experimental two-fold events between two detectors include the three and higher fold events between the same two detectors. The formalism has been further developed and the peak-to-total ratio of a general composite detector are predicted for energy region with no direct experimental information about them. At 8MeV, the peak-to-total ratio for the SPI spectrometer and a very large detector (comprising of infinite number of single HPGe modules) are found to be 9% and 12%, respectively. The predictions for fold distribution of the SPI spectrometer are found to be in agreement with experimental data. Our formulation does not include ad-hoc fits, but expressions that are justifiable by probability flow arguments. Instead of using an empirical method or simulation, we present a novel approach for calculating the peak-to-total ratio of the SPI spectrometer for high gamma energies. PMID- 23434890 TI - The effect of biological shielding on fast neutron and photon transport in the VVER-1000 mock-up model placed in the LR-0 reactor. AB - The paper is intended to show the effect of a biological shielding simulator on fast neutron and photon transport in its vicinity. The fast neutron and photon fluxes were measured by means of scintillation spectroscopy using a 45*45 mm(2) and a 10*10 mm(2) cylindrical stilbene detector. The neutron spectrum was measured in the range of 0.6-10 MeV and the photon spectrum in 0.2-9 MeV. The results of the experiment are compared with calculations. The calculations were performed with various nuclear data libraries. PMID- 23434891 TI - Modeling the effect of cell division on genetic oscillators. AB - Many genetic oscillators (circadian clocks, synthetic oscillators) continue to oscillate across the cell division cycle. Since cell divisions create discontinuities in the dynamics of genetic oscillators the question about the resilience of oscillations and the factors that contribute to the robustness of the oscillations may be raised. We study here, through stochastic simulations, the effect of the cell division cycle on genetic oscillations using the Repressilator-a genetic oscillator developed in the context of synthetic biology. We consider intrinsic noise (molecular noise due to the limited number of molecules) and extrinsic noise (variability in the cell division time and in the partition of the molecules into daughter cells, cell-cell variability in kinetic parameters, etc). Our numerical simulations show that, although noisy, oscillations are quite resilient to cell division and that cell-cell heterogeneity may be the main source of variability observed experimentally. Finally, similar simulations performed with another model, the Goodwin model, show that oscillations may be entrained and synchronized by cell division. This highlights the influence of the clock architecture on the robustness of genetic oscillations. Our approach provides a general framework to study the effect of cell division on dynamical systems and several possible extensions are described. PMID- 23434892 TI - Tissue mechanics and fibrosis. AB - Mechanical forces are essential to the development and progression of fibrosis, and are likely to be as important as soluble factors. These forces regulate the phenotype and proliferation of myofibroblasts and other cells in damaged tissues, the activation of growth factors, the structure and mechanics of the matrix, and, potentially, tissue patterning. Better understanding of the variety and magnitude of forces, the characteristics of those forces in biological tissues, and their impact on fibrosis in multiple tissues is needed and may lead to identification of important new therapeutic targets. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. PMID- 23434893 TI - Fat-free mass and fasting glucose values in patients with and without statin therapy assigned to age groups between <60 and >75 years. AB - OBJECTIVE: The aging-associated changes in body composition result in an increased cardiometabolic risk. A tremendous reduction of cardiovascular morbidity and mortality can be obtained by statin therapy. Statins are well tolerated, with myopathy as the most serious negative side effect. Some recently published studies indicate that the incidence of type 2 diabetes might be increased during intensified statin therapy. The aim of our study was to investigate whether statin therapy has an influence on the aging-associated changes in fat-free mass (FFM). METHODS: A total of 3,280 persons attending a medical outdoor center between January 2005 and July 2011 were assigned to 3 age groups from <60 to >75 years. Clinical data, body mass index (BMI), and body composition were evaluated in the different age groups in patients with and without statin therapy. To analyze the impact of statin use on FFM, we regressed a patient's FFM on an interaction term between statin use and age and other control variables. RESULTS: Aging was associated with a decrease in BMI and FFM, while fat mass continuously increased up to the age of >75 years. This was paralleled by a continuous increase in fasting glucose levels in patients with and without statin therapy. The loss of FFM between the age group <60 years and >75 years was more pronounced in statin-treated patients (10.88%) than in non statin users (8.47%). Creatine phosphokinase values revealed a decrease of 7.77 U/l between the age groups <60 and >75 years in non-statin users and of 14.75 U/l in statin users. Statistical analysis indicated that the effect of statin therapy on FFM is more pronounced in younger than in older patients. CONCLUSIONS: Patients under statin therapy seem to be more vulnerable to the aging-associated lowering of FFM. Diagnostic procedures and interventions to prevent a loss of muscle mass might be of particular advantage in elderly patients under statin therapy. PMID- 23434894 TI - A new metaphyseal bone defect model in osteoporotic rats to study biomaterials for the enhancement of bone healing in osteoporotic fractures. AB - The intention of this study was to establish a new critical size animal model that represents clinically relevant situations with osteoporotic bone status and internally fixated metaphyseal defect fractures in which biomaterials for the enhancement of fracture healing in osteoporotic fracture defects can be studied. Twenty-eight rats were ovariectomized (OVX) and treated with a calcium-, phosphorus-, vitamin D3-, soy- and phytoestrogen-free diet. After 3months Dual energy X-ray absorptiometry measurements showed statistically significant reductions in bone mineral density of the spine of -25.9% and of the femur of 21.3% of the OVX rats compared with controls, confirming osteoporosis in the OVX rats. The OVX rats then underwent either 3 or 5mm wedge-shaped osteotomy of the distal metaphyseal area of the femur that was internally stabilized with a T shaped mini-plate. After 42days biomechanical testing yielded completely unstable conditions in the 5mm defect femora (bending stiffness 0Nmm(-2)) and a bending stiffness of 12,500Nmm(-2) in the 3mm defects, which showed the beginning of fracture consolidation. Micro-computed tomography showed statistically significant more new bone formation in the 3mm defects (4.83+/-0.37mm(2)), with bridging of the initial fracture defect area, compared with the 5mm defects (2.68+/-0.34mm(2)), in which no bridging of the initial defect was found. These results were confirmed by histology. In conclusion, the 5mm defect can be considered as a critical size defect model in which biomaterials can be tested. PMID- 23434895 TI - Blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia. AB - PURPOSE OF REVIEW: In patients with community-acquired pneumonia (CAP), blood biomarkers can help to substantially improve individual decisions involving initiation, (de-)intensification, and cessation of antibiotics, and initial risk stratification, site-of-care assignment (outpatient versus ward versus ICU), and discharge. To illustrate these processes, this review summarizes recent findings from trials investigating the use of two hormokines, procalcitonin (PCT) or proadrenomedullin (ProADM), in personalized treatment and management decisions in CAP patients. RECENT FINDINGS: Many biomarkers from distinct pathophysiological pathways have been evaluated in observational studies. However, only few analytes have been tested for efficacy and safety in numerous, large observational studies or in prospective, randomized, interventional trials. Among the latter, PCT has been demonstrated to be well tolerated and highly effective for monitoring and de escalating antibiotic therapy. ProADM has shown higher accuracy for short-term and long-term adverse outcome prediction and improves prognostic accuracy when combined with current clinical risk scores, that is, Pneumonia Severity Index, the CURB65 (confusion, uremia, respiratory rate, blood pressure, age at least 65 years) score, and Risk of Early Admission to ICU, compared to applying the respective score alone. ProADM use has - in a pilot interventional study - improved site-of-care decisions and tended to shorten length hospitalization. SUMMARY: Inclusion of biomarker data in clinical algorithms improves individual decision-making in CAP patients. Interventional trials should be conducted to determine these markers' ultimate utility in patient management. PMID- 23434896 TI - Antimicrobial stewardship in the management of community-acquired pneumonia. AB - PURPOSE OF REVIEW: Antimicrobial stewardship can be applied to the management of community-acquired pneumonia (CAP) to optimize management while maintaining or improving the quality of patient outcomes. We discuss such applications, in general, and review the relevant recent literature. RECENT FINDINGS: Clinical pathways or care plans are a means to standardize care for a given disease state and thus improve or optimize the utilization of treatment modalities while at the same time maintaining or improving patient outcomes. Most recent publications describe the application of clinical pathways for the management of CAP in both pediatric and adult populations, reporting success in achieving compliance with national treatment guidelines. As a variation of clinical management pathways, audit tools have also been described that assist in determining the location and length of therapy and proper route of administration of antimicrobial agents with the aim of optimal resource utilization. Emerging rapid diagnostic tools allowing for early identification of pathogens and their antimicrobial susceptibility have great promise for early optimization of therapy for CAP. SUMMARY: There is a growing body of evidence that antimicrobial stewardship initiatives can be applied successfully and effectively to the management of CAP, benefiting both healthcare systems and patients. Such successful applications will likely grow as new techniques and technologies continue to evolve. PMID- 23434897 TI - How should we dose antibiotics for pneumonia in the ICU? AB - PURPOSE OF REVIEW: Pneumonia continues to be a common reason for, or complication of, ICU admission. Associated morbidity and mortality remain high, with an increasing incidence of multidrug-resistant organisms. Appropriate antibiotic therapy, both in terms of spectrum of cover and dose, remains the cornerstone of effective management. RECENT FINDINGS: Critically ill patients will frequently manifest significantly altered end-organ function, as compared with an ambulatory or ward-based setting. Such changes can have profound effects on antibiotic drug handling, promoting subtherapeutic concentrations, treatment failure or the selection of resistant organisms. Standard antibiotic regimens typically fail to consider such issues, with recent literature highlighting the need for improved dosing to achieve sufficient intrapulmonary concentrations, particularly in the setting of augmented elimination. Although recent clinical trials utilizing strategies that optimize drug exposure (either through the use of agents with improved penetration, or continuous infusions) demonstrate superior surrogate outcomes, a mortality benefit is still uncertain. SUMMARY: Antibiotic dosing strategies that are adapted to a critical care environment are urgently needed, both to improve clinical outcomes and ensure therapeutic longevity. Similarly, study protocols investigating emerging antibiotics must also be designed accordingly, to prevent potential setbacks in drug availability. PMID- 23434898 TI - Current world literature. PMID- 23434900 TI - Racial disparities in posttraumatic stress after diagnosis of localized breast cancer: the BQUAL study. AB - BACKGROUND: Little is known about the development of posttraumatic stress disorder (PTSD) over time among women diagnosed with breast cancer. This study examines changes in PTSD symptoms in the first 6 months after diagnosis and assesses racial/ethnic differences in PTSD symptomatology over time. METHODS: We recruited women with newly diagnosed breast cancer, stages I to III, from three sites in the United States. Three telephone interviews were conducted: baseline at about 2 to 3 months after diagnosis, first follow-up at 4 months after diagnosis, and second follow-up at 6 months after diagnosis. We measured traumatic stress in each interview using the Impact of Events Scale; recorded sociodemographic, tumor, and treatment factors; and used generalized estimating equations and polytomous logistic regression modeling to examine the associations between variables of interest and PTSD. RESULTS: Of 1139 participants, 23% reported symptoms consistent with a diagnosis of PTSD at baseline, 16.5% at first follow-up, and 12.6% at the second follow-up. Persistent PTSD was observed among 12.1% participants, as defined by having PTSD at two consecutive interviews. Among participants without PTSD at baseline, 6.6% developed PTSD at the first follow-up interview. Younger age at diagnosis, being black (odds ratio [OR] = 1.48 vs white, 95% confidence interval [CI] =1.04 to 2.10), and being Asian (OR = 1.69 vs white, 95% CI = 1.10 to 2.59) were associated with PTSD. CONCLUSIONS: Nearly one-quarter of women newly diagnosed with breast cancer reported symptoms consistent with PTSD shortly after diagnosis, with increased risk among black and Asian women. Early identification of PTSD may present an opportunity to provide interventions to manage symptoms. PMID- 23434901 TI - The clinical relevance of cancer cell lines. AB - Although advances in genomics during the last decade have opened new avenues for translational research and allowed the direct evaluation of clinical samples, there is still a need for reliable preclinical models to test therapeutic strategies. Human cancer-derived cell lines are the most widely used models to study the biology of cancer and to test hypotheses to improve the efficacy of cancer treatment. Since the development of the first cancer cell line, the clinical relevance of these models has been continuously questioned. Based upon recent studies that have fueled the debate, we review the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models. All cancer cell lines do not have equal value as tumor models. Some have been successful, whereas others have failed. However, the success stories should not obscure the growing body of data that motivates us to develop new in vitro preclinical models that would substantially increase the success rate of new in vitro-assessed cancer treatments. PMID- 23434902 TI - Selenistasis: epistatic effects of selenium on cardiovascular phenotype. AB - Although selenium metabolism is intricately linked to cardiovascular biology and function, and deficiency of selenium is associated with cardiac pathology, utilization of selenium in the prevention and treatment of cardiovascular disease remains an elusive goal. From a reductionist standpoint, the major function of selenium in vivo is antioxidant defense via its incorporation as selenocysteine into enzyme families such as glutathione peroxidases and thioredoxin reductases. In addition, selenium compounds are heterogeneous and have complex metabolic fates resulting in effects that are not entirely dependent on selenoprotein expression. This complex biology of selenium in vivo may underlie the fact that beneficial effects of selenium supplementation demonstrated in preclinical studies using models of oxidant stress-induced cardiovascular dysfunction, such as ischemia-reperfusion injury and myocardial infarction, have not been consistently observed in clinical trials. In fact, recent studies have yielded data that suggest that unselective supplementation of selenium may, indeed, be harmful. Interesting biologic actions of selenium are its simultaneous effects on redox balance and methylation status, a combination that may influence gene expression. These combined actions may explain some of the biphasic effects seen with low and high doses of selenium, the potentially harmful effects seen in normal individuals, and the beneficial effects noted in preclinical studies of disease. Given the complexity of selenium biology, systems biology approaches may be necessary to reach the goal of optimization of selenium status to promote health and prevent disease. PMID- 23434904 TI - Selenium content in seafood in Japan. AB - Selenium is an essential micronutrient for humans, and seafood is one of the major selenium sources, as well as red meat, grains, eggs, chicken, liver and garlic. A substantial proportion of the total amount of selenium is present as selenium containing imidazole compound, selenoneine, in the muscles of ocean fish. In order to characterize the selenium content in seafood, the total selenium levels were measured in the edible portions of commercially important fish and shellfish species. Among the tested edible portions, alfonsino muscle had the highest selenium levels (concentration of 1.27 mg/kg tissue). High levels of selenium (1.20-1.07 mg/kg) were also found in the salted ovary products of mullet and Pacific herring. In other fish muscles, the selenium levels ranged between 0.12 and 0.77 mg/kg tissue. The selenium levels were closely correlated with the mercury levels in the white and red muscles in alfonsino. The selenium content in spleen, blood, hepatopancreas, heart, red muscle, white muscle, brain, ovary and testis ranged between 1.10 and 24.8 mg/kg tissue in alfonsino. PMID- 23434905 TI - Fat depots, free fatty acids, and dyslipidemia. AB - Body fat deposition and excess free fatty acid (FFA) metabolism contribute to dyslipidemia and the adverse health consequences of obesity. Individuals with upper body obesity have impaired functioning of adipocytes, the primary fatty acid storage site. Excess visceral fat is strongly associated with impaired suppression of FFA release in response to insulin, as well as with hypertriglyceridemia and low concentrations of high density lipoprotein (HDL) cholesterol. High FFA concentrations can induce insulin resistance in muscle and liver. Furthermore, failure of hyperinsulinemia to normally suppress FFA is associated with impaired carbohydrate oxidation and muscle glucose storage, reduced hepatic insulin clearance and elevated triglycerides. Understanding the impact of body fat distribution on FFA metabolism and dyslipidemia is critical for determining the link between overweight and obesity and cardiovascular disease risk. In the current review, we will explore the relationship between adipose tissue, body fat depots, and FFA metabolism. PMID- 23434903 TI - Plant sterols as anticancer nutrients: evidence for their role in breast cancer. AB - While many factors are involved in the etiology of cancer, it has been clearly established that diet significantly impacts one's risk for this disease. More recently, specific food components have been identified which are uniquely beneficial in mitigating the risk of specific cancer subtypes. Plant sterols are well known for their effects on blood cholesterol levels, however research into their potential role in mitigating cancer risk remains in its infancy. As outlined in this review, the cholesterol modulating actions of plant sterols may overlap with their anti-cancer actions. Breast cancer is the most common malignancy affecting women and there remains a need for effective adjuvant therapies for this disease, for which plant sterols may play a distinctive role. PMID- 23434906 TI - Do fat supplements increase physical performance? AB - Fish oil and conjugated linoleic acid (CLA) belong to a popular class of food supplements known as "fat supplements", which are claimed to reduce muscle glycogen breakdown, reduce body mass, as well as reduce muscle damage and inflammatory responses. Sport athletes consume fish oil and CLA mainly to increase lean body mass and reduce body fat. Recent evidence indicates that this kind of supplementation may have other side-effects and a new role has been identified in steroidogenensis. Preliminary findings demonstrate that fish oil and CLA may induce a physiological increase in testosterone synthesis. The aim of this review is to describe the effects of fish oil and CLA on physical performance (endurance and resistance exercise), and highlight the new results on the effects on testosterone biosynthesis. In view of these new data, we can hypothesize that fat supplements may improve the anabolic effect of exercise. PMID- 23434907 TI - Reduced glutathione: a radioprotector or a modulator of DNA-repair activity? AB - The tripeptide glutathione (GSH) is the most abundant intracellular nonprotein thiol, and it is involved in many cellular functions including redox-homeostatic buffering. Cellular radiosensitivity has been shown to be inversely correlated to the endogenous level of GSH. On the other hand, controversy is raised with respect to its role in the field of radioprotection since GSH failed to provide consistent protection in several cases. Reports have been published that DNA repair in cells has a dependence on GSH. Subsequently, S-glutathionylation (forming mixed disulfides with the protein-sulfhydryl groups), a potent mechanism for posttranslational regulation of a variety of regulatory and metabolic proteins when there is a change in the celluar redox status (lower GSH/GSSG ratio), has received increased attention over the last decade. GSH, as a single agent, is found to affect DNA damage and repair, redox regulation and multiple cell signaling pathways. Thus, seemingly, GSH does not only act as a radioprotector against DNA damage induced by X-rays through glutathionylation, it may also act as a modulator of the DNA-repair activity. Judging by the number of publications within the last six years, it is obvious that the field of protein glutathionylation impinges on many aspects of biology, from regulation of protein function to roles of cell cycle and apoptosis. Aberrant protein glutathionylation and its association with cancer and other diseases is an area of increasing interest. PMID- 23434908 TI - Effects of lutein and docosahexaenoic Acid supplementation on macular pigment optical density in a randomized controlled trial. AB - We studied the macular pigment ocular density (MPOD) in patients with early age macular degeneration (AMD) before and 1 year after nutritional supplementation with lutein and docosahexaenoic acid (DHA). Forty-four patients with AMD were randomly divided into two groups that received placebo (n = 21) or a nutritional supplement (n = 23, 12 mg of lutein and 280 mg of DHA daily). Heterochromatic flicker photometry was used to determine the MPOD. At baseline, the MPOD in AMD patients with placebo was 0.286 +/- 0.017 meanwhile in AMD patients with supplementation it was 0.291 +/- 0.016. One year later, the mean MPOD had increased by 0.059 in the placebo group and by 0.162 in patients receiving lutein and DHA. This difference between groups was significant (p < 0.05). Lutein and DHA supplementation is effective in increasing the MPOD and may aid in prevention of age related macular degeneration. PMID- 23434909 TI - Effects of dietary carbohydrate replaced with wild rice (Zizania latifolia (Griseb) Turcz) on insulin resistance in rats fed with a high-fat/cholesterol diet. AB - Wild rice (WR) is a very nutritious grain that has been used to treat diabetes in Chinese medicinal practice. City diet (CD) is based on the diet consumed by Asian area residents in modern society, which is rich in saturated fats, cholesterol and carbohydrates. The present study was aimed at evaluating the effects of replacing white rice and processed wheat starch of CD with WR as the chief source of dietary carbohydrates on insulin resistance in rats fed with a high fat/cholesterol diet. Except the rats of the low-fat (LF) diet group, the rats of the other three groups, including to high-fat/cholesterol (HFC) diet, CD and WR diet, were fed with high-fat/cholesterol diets for eight weeks. The rats fed with CD exhibited higher weight gain and lower insulin sensitivity compared to the rats consuming a HFC diet. However, WR suppressed high-fat/cholesterol diet induced insulin resistance. WR decreased liver homogenate triglyceride and free fatty acids levels, raised serum adiponectin concentration and reduced serum lipocalin-2 and visfatin concentrations. In addition, the WR diet potently augmented the relative expressions of adiponectin receptor 2, peroxisome proliferator-activated receptors, alpha and gamma, and abated relative expressions of leptin and lipocalin-2 in the tissues of interest. These findings indicate that WR is effective in ameliorating abnormal glucose metabolism and insulin resistance in rats, even when the diet consumed is high in fat and cholesterol. PMID- 23434910 TI - The sleeping child outplays the adult's capacity to convert implicit into explicit knowledge. AB - When sleep followed implicit training on a motor sequence, children showed greater gains in explicit sequence knowledge after sleep than adults. This greater explicit knowledge in children was linked to their higher sleep slow-wave activity and to stronger hippocampal activation at explicit knowledge retrieval. Our data indicate the superiority of children in extracting invariant features from complex environments, possibly as a result of enhanced reprocessing of hippocampal memory representations during slow-wave sleep. PMID- 23434911 TI - Low hippocampal PI(4,5)P2 contributes to reduced cognition in old mice as a result of loss of MARCKS. AB - Cognitive and motor performances decline during aging. Although it is clear that such signs reflect synaptic compromise, the underlying mechanisms have not been defined. We found that the levels and activity of the synaptic plasticity modulators phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2) and phospholipase Cgamma (PLCgamma) were substantially reduced in hippocampal synaptic membranes from old mice. In addition, these membranes contained reduced levels of the PI(4,5)P2-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS). Consistent with a cause-effect relationship, raising MARCKS levels in the brain of old mice led to increased synaptic membrane clustering of PI(4,5)P2 and to PLCgamma activation. MARCKS overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide resulted in enhanced long-term potentiation and improved memory. These results reveal one of the mechanisms involved in brain dysfunction during aging. PMID- 23434912 TI - Neural pattern similarity predicts long-term fear memory. AB - Although certain changes in the brain may reflect fear learning, there are no known markers that indicate whether an aversive experience will develop into fear memory. We examined the moment-to-moment dynamics of human fear learning by applying multi-voxel pattern analysis to single-trial blood oxygen level dependent magnetic resonance imaging data. We found that the long-term behavioral expression of fear memory could be predicted from neural patterns at the time of learning. PMID- 23434913 TI - Scratch regulates neuronal migration onset via an epithelial-mesenchymal transition-like mechanism. AB - During neocortical development, the neuroepithelial or neural precursor cells that commit to neuronal fate need to delaminate and start migration toward the pial surface. However, the mechanism that couples neuronal fate commitment to detachment from the neuroepithelium remains largely unknown. Here we show that Scratch1 and Scratch2, members of the Snail superfamily of transcription factors, are expressed upon neuronal fate commitment under the control of proneural genes and promote apical process detachment and radial migration in the developing mouse neocortex. Scratch-induced delamination from the apical surface was mediated by transcriptional repression of the adhesion molecule E-cadherin. These findings suggest that Scratch proteins constitute a molecular link between neuronal fate commitment and the onset of neuronal migration. On the basis of their similarity to proteins involved in the epithelial-mesenchymal transition (EMT), we propose that Scratch proteins mediate the conversion of neuroepithelial cells to migrating neurons or intermediate neuronal progenitors through an EMT related mechanism. PMID- 23434914 TI - Deep brain stimulation restores frontostriatal network activity in obsessive compulsive disorder. AB - Little is known about the underlying neural mechanism of deep brain stimulation (DBS). We found that DBS targeted at the nucleus accumbens (NAc) normalized NAc activity, reduced excessive connectivity between the NAc and prefrontal cortex, and decreased frontal low-frequency oscillations during symptom provocation in patients with obsessive-compulsive disorder. Our findings suggest that DBS is able to reduce maladaptive activity and connectivity of the stimulated region. PMID- 23434915 TI - Summary statistics in auditory perception. AB - Sensory signals are transduced at high resolution, but their structure must be stored in a more compact format. Here we provide evidence that the auditory system summarizes the temporal details of sounds using time-averaged statistics. We measured discrimination of 'sound textures' that were characterized by particular statistical properties, as normally result from the superposition of many acoustic features in auditory scenes. When listeners discriminated examples of different textures, performance improved with excerpt duration. In contrast, when listeners discriminated different examples of the same texture, performance declined with duration, a paradoxical result given that the information available for discrimination grows with duration. These results indicate that once these sounds are of moderate length, the brain's representation is limited to time averaged statistics, which, for different examples of the same texture, converge to the same values with increasing duration. Such statistical representations produce good categorical discrimination, but limit the ability to discern temporal detail. PMID- 23434916 TI - To the beat of your own drum: cortical regularization of non-integer ratio rhythms toward metrical patterns. AB - Humans perceive a wide range of temporal patterns, including those rhythms that occur in music, speech, and movement; however, there are constraints on the rhythmic patterns that we can represent. Past research has shown that sequences in which sounds occur regularly at non-metrical locations in a repeating beat period (non-integer ratio subdivisions of the beat, e.g. sounds at 430ms in a 1000ms beat) are represented less accurately than sequences with metrical relationships, where events occur at even subdivisions of the beat (integer ratios, e.g. sounds at 500ms in a 1000ms beat). Why do non-integer ratio rhythms present cognitive challenges? An emerging theory is that non-integer ratio sequences are represented incorrectly, "regularized" in the direction of the nearest metrical pattern, and the present study sought evidence of such perceptual regularization toward integer ratio relationships. Participants listened to metrical and non-metrical rhythmic auditory sequences during electroencephalogram recording, and sounds were pseudorandomly omitted from the stimulus sequence. Cortical responses to these omissions (omission elicited potentials; OEPs) were used to estimate the timing of expectations for omitted sounds in integer ratio and non-integer ratio locations. OEP amplitude and onset latency measures indicated that expectations for non-integer ratio sequences are distorted toward the nearest metrical location in the rhythmic period. These top down effects demonstrate metrical regularization in a purely perceptual context, and provide support for dynamical accounts of rhythm perception. PMID- 23434918 TI - Nanoparticle- and biomaterials-mediated oral delivery for drug, gene, and immunotherapy. PMID- 23434917 TI - Pitch discrimination without awareness in congenital amusia: evidence from event related potentials. AB - Congenital amusia is a lifelong disorder characterized by a difficulty in perceiving and producing music despite normal intelligence and hearing. Behavioral data have indicated that it originates from a deficit in fine-grained pitch discrimination, and is expressed by the absence of a P3b event-related brain response for pitch differences smaller than a semitone and a bigger N2b-P3b brain response for large pitch differences as compared to controls. However, it is still unclear why the amusic brain overreacts to large pitch changes. Furthermore, another electrophysiological study indicates that the amusic brain can respond to changes in melodies as small as a quarter-tone, without awareness, by exhibiting a normal mismatch negativity (MMN) brain response. Here, we re examine the event-related N2b-P3b components with the aim to clarify the cause of the larger amplitude observed by Peretz, Brattico, and Tervaniemi (2005), by experimentally matching the number of deviants presented to the controls according to the number of deviants detected by amusics. We also re-examine the MMN component as well as the N1 in an acoustical context to investigate further the pitch discrimination deficit underlying congenital amusia. In two separate conditions, namely ignore and attend, we measured the MMN, the N1, the N2b and the P3b to tones that deviated by an eight of a tone (25 cents) or whole tone (200 cents) from a repeated standard tone. The results show a normal MMN, a seemingly normal N1, a normal P3b for the 200 cents pitch deviance, and no P3b for the small 25 cents pitch differences in amusics. These results indicate that the amusic brain responds to small pitch differences at a pre-attentive level of perception, but is unable to detect consciously those same pitch deviances at a later attentive level. The results are consistent with previous MRI and fMRI studies indicating that the auditory cortex of amusic individuals is functioning normally. PMID- 23434919 TI - Barriers to physical activity and restorative care for residents in long-term care: a review of the literature. AB - Despite the benefits of physical activity, residents living in long-term care (LTC) are relatively sedentary. Designing successful physical activity and restorative care programs requires a good understanding of implementation barriers. A database search (2002-2013) yielded seven studies (nine articles) that met our inclusion criteria. We also reviewed 31 randomized controlled trials (RCTs) to determine if the authors explicitly discussed the barriers encountered while implementing their interventions. Eleven RCTs (13 articles) included a discussion of the barriers. Hence, a total of 18 studies (22 articles) were included in this review. Barriers occurred at resident (e.g., health status), environmental (e.g., lack of space for physical activity), and organizational (e.g., staffing and funding constraints) levels. These barriers intersect to adversely affect the physical activity of older people living in LTC. Future studies targeting physical activity interventions for residents living in LTC are needed to address these multiple levels of influence. PMID- 23434920 TI - The role of water content in triboelectric charging of wind-blown sand. AB - Triboelectric charging is common in desert sandstorms and dust devils on Earth; however, it remains poorly understood. Here we show a charging mechanism of sands with the adsorbed water on micro-porous surface in wind-blown sand based on the fact that water content is universal but usually a minor component in most particle systems. The triboelectric charging could be resulted due to the different mobility of H(+)/OH(-) between the contacting sands with a temperature difference. Computational fluid dynamics (CFD) and discrete element method (DEM) were used to demonstrate the dynamics of the sand charging. The numerically simulated charge-to-mass ratios of sands and electric field strength established in wind tunnel agreed well with the experimental data. The charging mechanism could provide an explanation for the charging process of all identical granular systems with water content, including Martian dust devils, wind-blown snow, even powder electrification in industrial processes. PMID- 23434921 TI - A randomized trial of the topical effect of antifibrinolytic epsilon aminocaproic Acid on coronary artery bypass surgery without cardiopulmonary bypass. AB - We assessed the effect of the topical application of epsilon-aminocaproic antifibrinolytic acid (EACA) on the pericardium of patients submitted to coronary artery bypass graft (CABG) without the use of cardiopulmonary bypass (CPB). This is a prospective, randomized, and double-blind study. We evaluated 26 patients with chronic coronary heart disease indicated for CABG without CPB (EACA and placebo groups). The analysis of the postoperative hematological results showed no difference between groups in hemoglobin and hematocrit. There was no difference between the groups regarding the postoperative bleeding through the drains in the first 24 hours, 48 hours, and accumulated loss until removal of drains. The use of EACA in patients undergoing CABG without CPB presented no difference in the reduction of the amount of bleeding and the need for blood transfusions. PMID- 23434922 TI - SYNTAX score predicts the left ventricle thrombus development in patients undergoing primary percutaneous coronary intervention for first anterior myocardial infarction. AB - OBJECTIVES: The aim of this study is to investigate the relationship between left ventricular thrombus (LVT) developments and the SYNTAX score (SS) in patients undergoing primary percutaneous coronary intervention (PPCI) for first anterior wall ST-segment elevation myocardial infarction (STEMI). METHODS: We enrolled 160 patients. All participants were evaluated by serial transthoracic echocardiography. Baseline clinical, echocardiographic, and procedural features of PPCI were analyzed to find predictors of LVT development. RESULTS: The LVT was detected in 32 (20%) patients. Left ventricular ejection fraction (LVEF) and SS-I were found to be independent predictors of LVT development. Receiver-operating characteristic curve analysis revealed a cutoff value >19.5 for SS-I (area under the curve: 0.697, 95% confidence interval 0.620-0.767, P < .001) with a specificity of 45.3% and a sensitivity of 84.3%. CONCLUSION: High SS which was obtained through diagnostic angiogram of PPCI may be associated with LVT development in patients with first anterior wall STEMI. PMID- 23434923 TI - Dissolution media simulating the proximal canine gastrointestinal tract in the fasted state. AB - Human biorelevant media have been shown to be a useful tool in pharmaceutical development and to provide input for in silico prediction of pharmacokinetic profiles after oral dosing. Dogs, in particular Beagles, are often used as animal models for preclinical studies. Key differences in the composition of human and canine gastric and intestinal fluids are described in the literature and underscore the need to develop a discrete set of biorelevant media, adapted to the conditions of the proximal canine gastrointestinal (GI) tract, to improve forecast and interpretation of preclinical results using in vitro dissolution studies. Canine biorelevant media can also be used in the development of oral dosage forms for companion animals, which is a rapidly growing market. The compositions of Fasted State Simulated Gastric Fluid canine (FaSSGFc) and Fasted State Simulated Intestinal Fluid canine (FaSSIFc) are adapted to the physiological composition of the corresponding gastrointestinal fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid, and free fatty acid content (in terms of concentration and reported subtypes). It was demonstrated that canine Fasted State Simulated Intestinal Fluid (FaSSIFc) is superior in predicting the solubility of model compounds in Canine Intestinal Fluid (CIF) compared to the human biorelevant media (FaSSIF and FaSSIF-V2). Two different versions of FaSSGFc, composed at pH 1.5 and pH 6.5, offer the possibility to design in vitro studies which correspond to the in vivo study design, depending on whether pentagastrin is used to decrease the gastric pH in the dogs or not. Canine biorelevant media can therefore be recommended to achieve more accurate forecasting and interpretation of pharmacokinetic studies of oral drug products in dogs. PMID- 23434924 TI - Purification and partial characterization of aminopeptidase from barley (Hordeum vulgare L.) seeds. AB - Aminopeptidases (EC 3.4.11) are proteolytic enzymes, which hydrolyze one amino acid from N-terminus of peptidic substrates. Inhibitors of plant aminopeptidases can find an application in agriculture as herbicides. Isolation and partial characterization of aminopeptidase from barley (Hordeum vulgare L.) seeds has been described. The enzyme was purified to molecular homogeneity using a six-step purification procedure (precipitation with (NH4)2SO4, followed by chromatography on Sephadex G-25, DEAE-Sepharose, Sephacryl HR 300, Macro-Prep Q and Phenyl Sepharose HP columns). The enzyme was purified 365-fold with recovery above 18%. The molecular weight of the purified enzyme was determined by SDS-PAGE and gel filtration as 58 kDa, and was found to be a monomer. Its pH and temperature optima were 7.5 and 52 degrees C, respectively. The enzyme behaves as standard leucine aminopeptidase by preferring bulky amino acids at the N-terminus, with phenylalanine being of choice. PMID- 23434925 TI - Effect of vulculic acid produced by Nimbya alternantherae on the photosynthetic apparatus of Alternanthera philoxeroides. AB - The effect of the toxin vulculic acid produced by Nimbya alternantherae, on the photosynthetic apparatus of Alternanthera philoxeroides, was investigated via the photochemical activity and SDS-PAGE of protein on thylakoid membranes, fast chlorophyll a fluorescence transient measurements and the JIP-test. The electron transport rate of photosystem II (PSII), non-cyclic photophosphorylation activity, as well as the activity of chloroplast ATPase and Rubisco reduced significantly after vulculic acid treatment. Vulculic acid affected the O-J-I-P fluorescence induction kinetics, showing an increase of the parameters FV/FO, VK and VJ and a decrease of FO, FM, PIABS, phiPo, psiEo, phiEo, phiRo, deltaRo and PItotal. In addition, it significantly decreased the amounts of major photosystem I (PSI) and PSII proteins. It is concluded that vulculic acid is a photosynthetic inhibitor with multiple action sites. The main targets are the light harvesting complex (LHC) and the oxygen evolving complex (OEC) on the PSII donor side. Vulculic acid blocks electron transport beyond QA and on the PSI acceptor side by digesting major PSI and PSII proteins. PMID- 23434926 TI - Changes in potato phenylpropanoid metabolism during tuber development. AB - Phenylpropanoid metabolite and transcript expression during different developmental stages were examined in field grown potatoes. Carbohydrate and shikimic acid metabolism was assessed to determine how tuber primary metabolism influences phenylpropanoid metabolism. Phenylpropanoid concentrations were highest in immature tubers, as were some transcript levels and enzyme activities including phenylalanine ammonia lyase (PAL). Phenylpropanoid concentration differences between mature and immature tubers varied by genotype, but in some cases were approximately three-fold. The most abundant phenylpropanoid was chlorogenic acid (5CGA), which decreased during tuber maturation. Hydroxycinnamoyl-CoA:quinate hydroxycinnamoyl transferase (HQT) transcripts were highly expressed relative to other phenylpropanoid genes, but were not well correlated with 5CGA concentrations (r = -0.16), whereas HQT enzyme activity was. In contrast to 5CGA, less abundant chlorogenic isomers increased during development. Concentrations of hydroxycinnamic acid amides were higher in immature tubers, as was expression of arginine- and ornithine decarboxylases. Expression of several genes involved in carbohydrate or shikimate metabolism, including sucrose synthase and DAHP, showed similar developmental patterns to phenylpropanoid pools, as did shikimate dehydrogenase enzyme activity. Sucrose, glucose and fructose concentrations were highest in immature tubers. Exogenous treatment of potatoes with sugars stimulated phenylpropanoid biosynthesis, suggesting sugars contribute to the higher phenylpropanoid concentrations in immature tubers. These changes in phenylpropanoid expression suggest the nutritional value of potatoes varies during development. PMID- 23434927 TI - Dissecting the stress metabolic alterations in in vitro Cyrtanthus regenerants. AB - Metabolic plasticity in plants allows for continuous adjustments of defence strategies in suboptimal environments. Proline and other metabolites figure prominently in most stress-mediated responses. This study examined the expression of salinity and osmotic adjustments in the enzymatic activity and accumulation of solutes and metabolites in response to imposed water and salt stress in Cyrtanthus contractus N.E. Br. and Cyrtanthus guthrieae L. Bolus regenerants. In vitro-derived plantlets were cultured on solid Murashige and Skoog (MS) media with three different polyethylene glycol (PEG)-induced osmotic levels and four NaCl stress-induced levels at 25 degrees C. The levels of proline and phenolic compounds measured at intervals of three, four and five weeks from initial plantlet culture increased in a stress-dependent pattern. The levels of these metabolites also showed a significant increase with an increase in the duration of plantlets under stress conditions. The highest proline concentration (9.98 MUmol g(-1) FW) was recorded in C. contractus at 300 MUM NaCl after five weeks. A corresponding high level of total phenolic compounds (147 mg GAE g(-1) DW) was also recorded in the same treatment for the same species. The activity of proline dehydrogenase (PDH) (EC 1.5.99.8) was shown to decrease with an increase in proline levels from week three to week five in almost all the stress conditions. The high levels, particularly of phenolic compounds obtained under osmotic and salinity stress conditions in this study present a promising potential of manipulating culture and/or growing conditions for improved secondary compound production and hence medicinal benefits. PMID- 23434928 TI - Sense-, antisense- and RNAi-4CL1 regulate soluble phenolic acids, cell wall components and growth in transgenic Populus tomentosa Carr. AB - Regulation of lignin biosynthesis affects plant growth and wood properties. Transgenic downregulation of 4-coumarate:coenzyme A ligase (4CL, EC 6.2.1.12) may reduce lignin content in cell walls, which could improve the qualities of pulp in papermaking and increase the efficiency of bioenergy applications. To determine the effects of Ptc4CL1 on lignin biosynthesis and plant growth, Populus tomentosa Carr. was transformed using sense-, antisense-, and RNAi-4CL1 genes. The growth properties, gene expression, enzyme activity, lignin content and composition and content of soluble phenolic acids were investigated in 1-year-old field-grown transgenic poplar trees. Transgenic up- and down-regulation of 4CL1 altered lignin content and composition in transgenic poplars, but there were no negative effects on the growth of transgenic plants. In addition, the severe changes in auxin observed in transgenic lines led to significantly enhanced growth performance. Furthermore, lignin content was tightly correlated with the alteration of 4CL1 enzymatic activity, which was correlated with 4CL1 gene expression. A significant increase in S units in lignin with a slight increase in sinapic acid was observed in 4CL1 down-regulated transgenic poplars. These results suggest that 4CL1 is a traffic control gene in monolignol biosynthesis and confirm that 4CL1 activity has been implicated with sinapoyl activation. Finally, our data demonstrate that there is cross-correlation among 4CL1 gene expression, 4CL1 enzyme activity, soluble phenolic acid, lignin monomer biosynthesis, and lignin content. PMID- 23434929 TI - Amelioration of hypoglycemia via somatostatin receptor type 2 antagonism in recurrently hypoglycemic diabetic rats. AB - Selective antagonism of somatostatin receptor type 2 (SSTR2) normalizes glucagon and corticosterone responses to hypoglycemic clamp in diabetic rats. The purpose of this study was to determine whether SSTR2 antagonism (SSTR2a) ameliorates hypoglycemia in response to overinsulinization in diabetic rats previously exposed to recurrent hypoglycemia. Streptozotocin diabetic rats (n = 19), previously subjected to five hypoglycemia events over 3 days, received an insulin bolus (10 units/kg i.v.) plus insulin infusion (50 mU/kg/min i.v.) until hypoglycemia ensued (<=3.9 mmol/L) (experimental day 1 [Expt-D1]). The next day (Expt-D2), rats were allocated to receive either placebo treatment (n = 7) or SSTR2a infusion (3,000 nmol/kg/min i.v., n = 12) 60 min prior to the same insulin regimen. On Expt-D1, all rats developed hypoglycemia by ~90 min, while on Expt D2, hypoglycemia was attenuated with SSTR2a treatment (nadir = 3.7 +/- 0.3 vs. 2.7 +/- 0.3 mmol/L in SSTR2a and controls, P < 0.01). Glucagon response to hypoglycemia on Expt-D2 deteriorated by 20-fold in the placebo group (P < 0.001) but improved in the SSTR2a group (threefold increase in area under the curve [AUC], P < 0.001). Corticosterone response deteriorated in the placebo-treated rats on Expt-D2 but increased twofold in the SSTR2a group. Catecholamine responses were not affected by SSTR2a. Thus, SSTR2 antagonism after recurrent hypoglycemia improves the glucagon and corticosterone responses and largely ameliorates insulin-induced hypoglycemia in diabetic rats. PMID- 23434930 TI - Functional redundancy of CXCR3/CXCL10 signaling in the recruitment of diabetogenic cytotoxic T lymphocytes to pancreatic islets in a virally induced autoimmune diabetes model. AB - Cytotoxic T lymphocytes (CTLs) constitute a major effector population in pancreatic islets from patients suffering from type 1 diabetes (T1D) and thus represent attractive targets for intervention. Some studies have suggested that blocking the interaction between the chemokine CXCL10 and its receptor CXCR3 on activated CTLs potently inhibits their recruitment and prevents beta-cell death. Since recent studies on human pancreata from T1D patients have indicated that both ligand and receptor are abundantly present, we reevaluated whether their interaction constitutes a pivotal node within the chemokine network associated with T1D. Our present data in a viral mouse model challenge the notion that specific blockade of the CXCL10/CXCR3 chemokine axis halts T1D onset and progression. PMID- 23434931 TI - TCF7L2 variation and proliferative diabetic retinopathy. AB - Proliferative diabetic retinopathy (PDR) is the most severe vision-threatening complication of diabetes. For investigation of genetic association between TCF7L2 and PDR in Caucasian type 2 diabetes mellitus (T2DM) and its functional consequences, 383 T2DM patients with PDR (T2DM-PDR) and 756 T2DM patients without diabetic retinopathy (T2DM-no DR) were genotyped with rs7903146 in TCF7L2. We found that risk allele (T) frequency of rs7903146 was significantly higher in T2DM-PDR patients (allelic P = 2.52E-04). In lymphoblastoid cells induced to undergo endoplasmic reticulum (ER) stress by treatment of tunicamycin, higher fold change of TCF7L2 and VEGFA mRNA levels were observed in rs7903146-TT cells than in rs7903146-CC cells (P = 0.02 for TCF7L2; P = 0.004 for VEGFA), suggesting that ER stress plays a role in PDR pathogenesis. Silencing TCF7L2 resulted in decreased mRNA levels of both TCF7L2 and VEGFA (P < 0.001). Retinas of oxygen induced retinopathy mice (a model for PDR) had higher TCF7L2 and VEGFA mRNA levels than those of controls (P = 2.9E-04 for TCF7L2; P = 1.9E-07 for VEGFA). Together, data from our study show that TCF7L2-rs7903146 is associated with PDR in Caucasian T2DM and suggest that TCF7L2 promotes pathological retinal neovascularization via ER stress-dependent upregulation of VEGFA. PMID- 23434932 TI - Hyperglycemia mediates a shift from cap-dependent to cap-independent translation via a 4E-BP1-dependent mechanism. AB - Diabetes and its associated hyperglycemia induce multiple changes in liver function, yet we know little about the role played by translational control of gene expression in mediating the responses to these conditions. Here, we evaluate the hypothesis that hyperglycemia-induced O-GlcNAcylation of the translational regulatory protein 4E-BP1 alters hepatic gene expression through a process involving the selection of mRNA for translation. In both streptozotocin (STZ) treated mice and cells in culture exposed to hyperglycemic conditions, expression of 4E-BP1 and its interaction with the mRNA cap-binding protein eIF4E were enhanced in conjunction with downregulation of cap-dependent and concomitant upregulation of cap-independent mRNA translation, as assessed by a bicistronic luciferase reporter assay. Phlorizin treatment of STZ-treated mice lowered blood glucose concentrations and reduced activity of the cap-independent reporter. Notably, the glucose-induced shift from cap-dependent to cap-independent mRNA translation did not occur in cells lacking 4E-BP1. The extensive nature of this shift in translational control of gene expression was revealed using pulsed stable isotope labeling by amino acids in cell culture to identify proteins that undergo altered rates of synthesis in response to hyperglycemia. Taken together, these data provide evidence for a novel mechanism whereby O-GlcNAcylation of 4E BP1 mediates translational control of hepatic gene expression. PMID- 23434933 TI - Circadian regulation of lipid mobilization in white adipose tissues. AB - In mammals, a network of circadian clocks regulates 24-h rhythms of behavior and physiology. Circadian disruption promotes obesity and the development of obesity associated disorders, but it remains unclear to which extent peripheral tissue clocks contribute to this effect. To reveal the impact of the circadian timing system on lipid metabolism, blood and adipose tissue samples from wild-type, ClockDelta19, and Bmal1(-/-) circadian mutant mice were subjected to biochemical assays and gene expression profiling. We show diurnal variations in lipolysis rates and release of free fatty acids (FFAs) and glycerol into the blood correlating with rhythmic regulation of two genes encoding the lipolysis pacemaker enzymes, adipose triglyceride (TG) lipase and hormone-sensitive lipase, by self-sustained adipocyte clocks. Circadian clock mutant mice show low and nonrhythmic FFA and glycerol blood content together with decreased lipolysis rates and increased sensitivity to fasting. Instead circadian clock disruption promotes the accumulation of TGs in white adipose tissue (WAT), leading to increased adiposity and adipocyte hypertrophy. In summary, circadian modulation of lipolysis rates regulates the availability of lipid-derived energy during the day, suggesting a role for WAT clocks in the regulation of energy homeostasis. PMID- 23434934 TI - From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy. AB - Genome-wide association studies have proven to be highly effective at defining relationships between single nucleotide polymorphisms (SNPs) and clinical phenotypes in complex diseases. Establishing a mechanistic link between a noncoding SNP and the clinical outcome is a significant hurdle in translating associations into biological insight. We demonstrate an approach to assess the functional context of a diabetic nephropathy (DN)-associated SNP located in the promoter region of the gene FRMD3. The approach integrates pathway analyses with transcriptional regulatory pattern-based promoter modeling and allows the identification of a transcriptional framework affected by the DN-associated SNP in the FRMD3 promoter. This framework provides a testable hypothesis for mechanisms of genomic variation and transcriptional regulation in the context of DN. Our model proposes a possible transcriptional link through which the polymorphism in the FRMD3 promoter could influence transcriptional regulation within the bone morphogenetic protein (BMP)-signaling pathway. These findings provide the rationale to interrogate the biological link between FRMD3 and the BMP pathway and serve as an example of functional genomics-based hypothesis generation. PMID- 23434935 TI - Dual inhibition of classical protein kinase C-alpha and protein kinase C-beta isoforms protects against experimental murine diabetic nephropathy. AB - Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy with proteinuria and peritubular extracellular matrix production. We have previously shown that the PKC isoforms alpha and beta mediate different cellular effects. PKC-beta contributes to hyperglycemia-induced renal matrix production, whereby PKC-alpha is involved in the development of albuminuria. We further tested this hypothesis by deletion of both isoforms and used a PKC inhibitor. We analyzed the phenotype of nondiabetic and streptozotocin (STZ)-induced diabetic homozygous PKC-alpha/beta double-knockout mice (PKC alpha/beta(-/-)). After 8 weeks of diabetes mellitus, the high-glucose-induced renal and glomerular hypertrophy as well as transforming growth factor-beta1) and extracellular matrix production were diminished in the PKC-alpha/beta(-/-) mice compared with wild-type controls. Urinary albumin/creatinine ratio also was significantly reduced, however, it was not completely abolished in diabetic PKC alpha/beta(-/-) mice. Treatment with CGP41252, which inhibits PKC-alpha and PKC beta, is able to prevent the development of albuminuria and to reduce existing albuminuria in type 1 (STZ model) or type 2 (db/db model) diabetic mice. These results support our hypothesis that PKC-alpha and PKC-beta contribute to the pathogenesis of diabetic nephropathy, and that dual inhibition of the classical PKC isoforms is a suitable therapeutic strategy in the prevention and treatment of diabetic nephropathy. PMID- 23434936 TI - UCP2 regulates the glucagon response to fasting and starvation. AB - Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2(-/-)) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created alpha-cell-specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted alpha-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, alpha-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal alpha-cell glucose sensing and the maintenance of euglycemia. PMID- 23434937 TI - Systemic free fatty acid disposal into very low-density lipoprotein triglycerides. AB - We measured the incorporation of systemic free fatty acids (FFA) into circulating very low-density lipoprotein triglycerides (VLDL-TGs) under postabsorptive, postprandial, and walking conditions in humans. Fifty-five men and 85 premenopausal women with BMI 18-24 (lean) and 27-36 kg/m(2) (overweight/obese) received an intravenous bolus injection of [1,1,2,3,3-(2)H5]glycerol (to measure VLDL-TG kinetics) and either [1-(14)C]palmitate or [9,10-(3)H]palmitate to determine the proportion of systemic FFA that is converted to VLDL-TG. Experiments started at 0630 h after a 12-h overnight fast. In the postabsorptive protocol, participants rested and remained fasted until 1330 h. In the postprandial protocol, volunteers ingested frequent portions of a fat-free smoothie. In the walking protocol, participants walked on a treadmill for 5.5 h at ~3* resting energy expenditure. Approximately 7% of circulating FFA was converted into VLDL-TG. VLDL-TG secretion rates (SRs) were not statistically different among protocols. Visceral fat mass was the only independent predictor of VLDL-TG secretion, explaining 33-57% of the variance. The small proportion of systemic FFA that is converted to VLDL-TG can confound the expected relationship between plasma FFA concentration and VLDL-TG SRs. Regulation of VLDL-TG secretion is complex in that, despite a broad spectrum of physiological FFA concentrations, VLDL-TG SRs did not vary based on different acute substrate availability. PMID- 23434938 TI - Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon like Peptide 1 receptor deficiency. AB - Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery. PMID- 23434939 TI - Combined cholecystectomy in gastric cancer surgery. AB - BACKGROUND: Many studies have described the risk factors of gallstone formation in gastric cancer patients after gastrectomy, but few studies focus on the management of asymptomatic gallstones. Our goal is to examine the rationale of simultaneous cholecystectomy during gastric cancer surgery, and influence of surgical mortality, morbidity and overall survival after combined cholecystectomy and gastrectomy. METHODS: We retrospectively reviewed 445 gastric cancer patients and the gallbladders evaluated by abdominal ultrasound or computed tomography preoperatively and postoperatively. Clinicopathologic factors, including surgical morbidity, mortality and overall survival of combined surgery, were compared between patients receiving gastrectomy with simultaneous cholecystectomy and patients receiving gastrectomy only. We also evaluated the risk factors of gallstone formation after gastrectomy and the probability of subsequent cholecystectomy after gastrectomy in gastric cancer patients with or without asymptomatic gallstones. RESULTS: Of 445 gastric cancer patients, 52 (11.7%) patients had asymptomatic gallstones upon diagnosis of gastric cancer. Among patients with healthy gallbladders, 15.2% developed gallstones after gastrectomy. Men and older patients (age over 60) had significantly higher risk of gallstone formation. Rate of subsequent cholecystectomy in patients with and without preoperative asymptomatic gallstones was 30.8% and 4.5%, respectively (p = 0.005). The rates of mortality and morbidity were not significantly different between combined surgery (3.4%, 24.2%) and gastrectomy only (3.1%, 22%). There was also no significant difference in 5-year survival between combined surgery (61%) and gastrectomy only (63%) groups. CONCLUSION: Combined cholecystectomy for asymptomatic gallstone in gastric cancer surgery may be considered. It was not associated with increased surgical morbidity or mortality, and had no significant effect on overall survival. PMID- 23434940 TI - The need for additional procedures in patients undergoing proximal hypospadias repairs as reported in the pediatric health information system database. AB - PURPOSE: Using administrative data from freestanding pediatric hospitals in the United States, we characterized the frequency and type of additional procedures required in patients undergoing proximal hypospadias repair in a larger cohort than in published case series across multiple surgeons and institutions. MATERIALS AND METHODS: A search of the Pediatric Health Information System (PHIS) database by CPT code between January 1, 2005 and June 30, 2010 identified patients undergoing 1 or 2-stage repair for proximal hypospadias. Patient records with inconsistent coding or the suggestion of an alternate pathological condition were excluded from study. A forward query to June 30, 2011 identified additional hypospadias related interventions by CPT codes. RESULTS: We identified 1,679 patients from a total of 37 hospitals. Potential followup was 1 to 6.5 years. One stage repair was performed in 85.7% of patients at a median age of 10 months. In patients undergoing 2-stage repair the median age at initial repair was 10 months and the median interval between stages was 6 months. Of all patients 26.2% required 1 or more additional interventions beyond definitive repair. Of all additional interventions 84.0% were open, 7.2% were endoscopic treatment for stricture, 0.4% were combined endoscopic and open interventions, and 8.4% were endoscopic evaluation. The median interval from definitive repair to the first intervention was 9 months. CONCLUSIONS: These data indicate that more than a quarter of patients who underwent proximal hypospadias repair at pediatric hospitals required additional intervention(s) after what was thought to be definitive repair. These data help create a broader context in a contemporary cohort of patients treated with proximal hypospadias repair. PMID- 23434941 TI - Re: "trifecta" in partial nephrectomy: A. J. Hung, j. Cai, M. N. Simmons and I. S. Gill j Urol 2013; 189: 36-42. PMID- 23434942 TI - Response to Letter to the Editor. PMID- 23434943 TI - Impact of clinical and histopathological parameters on disease specific survival in patients with collecting duct renal cell carcinoma: development of a disease specific risk model. AB - PURPOSE: Collecting duct renal cell carcinoma is a rare, aggressive histological subtype of renal cell carcinoma. Since few groups have evaluated the oncological prognosis in these patients based on clinical and pathological parameters, we assessed parameters prognostic for disease specific mortality. MATERIALS AND METHODS: From a cohort of 14,047 patients with renal cell carcinoma we retrieved the records of 95 with collecting duct renal cell carcinoma at a total of 16 European and American centers of the CORONA (Collaborative Research on Renal Neoplasms Association) and SATURN (Surveillance and Treatment Update Renal Neoplasms) projects, and another 2 centers. Multivariable Cox regression analysis was applied to determine the influence of parameters on disease specific mortality. Median followup was 48.1 months (IQR 24-103). RESULTS: The disease specific survival rate at 1, 2, 5 and 10 years was 60.4%, 47.3%, 40.3% and 32.8%, respectively. American Society of Anesthesiologists (ASA) score 3-4, tumor size greater than 7 cm, stage M1, Fuhrman grade 3-4 and lymphovascular invasion independently predicted disease specific mortality. Based on these parameters, patients were divided into 26 (27%) at low, 13 (14%) at intermediate and 56 (59%) at high risk with a 5-year disease specific survival rate of 96%, 62% and 8%, respectively (bootstrap corrected c-index 0.894, 95% CI 0.820-0.967, p <0.001). CONCLUSIONS: While patients with collecting duct renal cell carcinoma are commonly diagnosed at advanced stage and have poor prognosis after surgery, a subset has excellent survival. Histopathological features can help risk stratify patients based on the described, highly accurate risk model to predict disease specific mortality, facilitating patient counseling and risk based clinical decision making for adjuvant therapy and clinical trial inclusion. PMID- 23434944 TI - Trends in percutaneous nephrolithotomy use and outcomes in the United States. AB - PURPOSE: We investigated recent trends in the use and perioperative outcomes of percutaneous nephrolithotomy in the United States in a population based cohort. MATERIALS AND METHODS: We obtained the records of patients treated with percutaneous nephrolithotomy between 1999 and 2009 from the Nationwide Inpatient Sample (NIS). A weighted sample was used to estimate national utilization rates. Trends in age, comorbidity, perioperative complications and in-hospital mortality were analyzed. Temporal trends were quantified by the estimated annual percent change. We evaluated the association between patient and hospital characteristics, including complications, prolonged length of stay and in hospital mortality, using logistic regression models adjusted for clustering. RESULTS: During 1999 to 2009, percutaneous nephrolithotomy use increased in men and women from 3.0/100,000 and 2.99/100,000 to 3.63/100,000 and 4.07/100,000, respectively. Women showed the largest increases in percutaneous nephrolithotomy use with an estimated annual percent change of 4.49% (95% CI 2.7-6.3, p <0.001) vs 2.90% (95% CI 1.5-4.3, p = 0.003) in men. Baseline comorbidity in patients undergoing percutaneous nephrolithotomy increased with time. Overall complications increased from 12.2% to 15.6% (p <0.001), while mortality remained stable at 0.0% to 0.4%. The transfusion rate was 4.0%. Sepsis increased from 1.2% to 2.4% of cases (p <0.001). Patients were at risk for complications if they were older, more ill and treated in more recent years. Age was significantly associated with increased odds of mortality. CONCLUSIONS: Percutaneous nephrolithotomy use in the United States has increased and females are now the majority gender. Although mortality remains low, rates of sepsis and overall complications have increased. Broad use of percutaneous nephrolithotomy, especially in older and more ill patients, may account for these changes. PMID- 23434945 TI - Preoperative pulmonary embolism does not predict poor postoperative outcomes in patients with renal cell carcinoma and venous thrombus. AB - PURPOSE: Patients with renal cell carcinoma who present with pulmonary embolism and venous thrombus may not be offered surgery because of presumed poor postoperative outcomes. In this multicenter study we evaluated perioperative mortality, recurrence and cancer specific survival in patients with renal cell carcinoma and venous thrombus diagnosed with preoperative pulmonary embolism. MATERIALS AND METHODS: We reviewed consecutive patient records from our 3 tertiary hospitals to identify patients with renal cell carcinoma and venous thrombus treated with surgery from 2000 to 2011. Univariate and multivariate Cox proportional hazards analysis was used to evaluate whether preoperative pulmonary embolism or other clinical variables were associated with postoperative disease recurrence or cancer specific survival. RESULTS: Pulmonary embolism was identified preoperatively in 35 of 782 patients (4.4%) with renal cell carcinoma. Those with pulmonary embolism preoperatively were more likely to have higher level thrombus and higher T stage (p <0.01). No differences were found in other clinical or pathological features between the groups. There was no difference in 90-day mortality in patients diagnosed with pulmonary embolism preoperatively. Of 395 patients without metastasis preoperatively 147 (37.2%) showed metastatic renal cell carcinoma at a median followup of 22 months. There was no difference in the recurrence rate of renal cell carcinoma in patients with pulmonary embolism (p = 0.36). Recurrence in the lung was not more common in patients with vs without pulmonary embolism preoperatively (p = 0.71). Also, preoperative pulmonary embolism was not predictive of worse cancer specific survival (p = 0.58). CONCLUSIONS: Preoperative pulmonary embolism is not associated with worse early mortality, recurrence or cancer specific survival in patients with renal cell carcinoma and tumor thrombus. PMID- 23434946 TI - Reproducibility and reliability of semen analysis in youths at risk for infertility. AB - PURPOSE: There are few normative data on semen analyses in youths at risk for but not presenting with infertility. Standard practice among infertility specialists includes evaluation of 2 separate semen samples, given the degree of within subject variability. We hypothesized that males transitioning from pediatric to adult care who are at risk for infertility would similarly have this variability. MATERIALS AND METHODS: We retrospectively reviewed patients with a history of cryptorchidism or varicocele who submitted 2 semen samples for evaluation of fertility potential. The within subject coefficient of variation and intraclass correlation coefficient were calculated for each semen parameter to evaluate reproducibility and reliability, respectively. RESULTS: A total of 79 subjects were studied. Mean +/- SD age was 18.8 +/- 1.2 years (range 17.8 to 24.7). The within subject coefficient of variation was high for each semen parameter, ranging from 36% for volume and motility to 82% for total motile count. Intraclass correlation coefficient for a single semen analysis ranged from 0.55 for motility to 0.88 for total count. Intraclass correlation coefficient for total motile count was 0.78 (95% CI 0.67-0.85), consistent with substantial reliability. CONCLUSIONS: Although we observed within patient variability of individual semen analysis parameters, overall there was substantial agreement between consecutive semen analyses in this population at risk for infertility, particularly regarding total motile count, which is the most important determinant of fertility from a semen analysis. Therefore, it is possible to appropriately classify some young men based on the result of a single measurement as they transition from pediatric to adult care. PMID- 23434947 TI - Foreword: prebiotics that modulate the endogenous microbiota are also very important. PMID- 23434948 TI - Probiotics in Clostridium difficile infection: reviewing the need for a multistrain probiotic. AB - In the past two years an enormous amount of molecular, genetic, metabolomic and mechanistic data on the host-bacterium interaction, a healthy gut microbiota and a possible role for probiotics in Clostridium difficile infection (CDI) has been accumulated. Also, new hypervirulent strains of C. difficile have emerged. Yet, clinical trials in CDI have been less promising than in antibiotic associated diarrhoea in general, with more meta-analysis than primary papers on CDI-clinical trials. The fact that C. difficile is a spore former, producing at least three different toxins has not yet been incorporated in the rational design of probiotics for (recurrent) CDI. Here we postulate that the plethora of effects of C. difficile and the vast amount of data on the role of commensal gut residents and probiotics point towards a multistrain mixture of probiotics to reduce CDI, but also to limit (nosocomial) transmission and/or endogenous reinfection. On the basis of a retrospective chart review of a series of ten CDI patients where recurrence was expected, all patients on adjunctive probiotic therapy with multistrain cocktail (Ecologic(r)AAD/OMNiBiOTiC(r) 10) showed complete clinical resolution. This result, and recent success in faecal transplants in CDI treatment, are supportive for the rational design of multistrain probiotics for CDI. PMID- 23434949 TI - Challenges in translational research on probiotic lactobacilli: from in vitro assays to clinical trials. AB - Beneficial effects of certain probiotic strains have been established in the treatment and prevention of various immune and intestinal disorders in humans, including allergic diseases, chronic inflammatory diseases and diarrhoea. The proposed mechanisms underlying the immunomodulatory effects of probiotics in humans are not understood in precise detail but include enhancement of intestinal barrier function, altered epithelial signalling, competition with pathogens and effects on immune cells and immunity depending on the probiotic strain. The publication of controversial or inconclusive probiotic studies in humans highlights the need for a better understanding of the mechanisms and improved strain selection criteria. This review focuses on the immunomodulatory properties of lactobacilli and bifidobacteria in vitro and in vivo, current knowledge concerning the mechanisms in vivo and challenges in translational research on probiotics. A better understanding of the molecular mechanisms of probiotics, the effect of probiotic mixtures versus single strains, the effect of formulation of probiotics and the fate of ingested probiotics should help to clarify the value of immune assays as selection criteria for probiotics. PMID- 23434950 TI - Consumer perception of beneficial effects of probiotics for human health. AB - The purpose of this study was to evaluate the knowledge, perception and buying behaviour of probiotics. 72 participants in Middelburg, the Netherlands, filled out a detailed questionnaire regarding probiotics and their customer and consumer behaviour. It can be concluded from this study that the concept of probiotics is generally poorly understood. Health-conscious consumers seem to be the group most aware of the correct meaning of the term probiotics. Almost 50% of the participants did not believe that probiotics had any health effect. Independent organisations and/or government agencies appeared to be the preferred source of information on the functionality of probiotics. PMID- 23434952 TI - The right to sight. PMID- 23434953 TI - Clinical profile of patients presenting with breast cancer in Nepal. AB - BACKGROUND: Breast cancer is the second most common cancer in women in Nepal. Even though the evaluation and treatment of patients is done as per western guidelines, there are considerable variations in risk factors, presenting stage and prognostic factors such as receptor status. OBJECTIVE: To evaluate the clinical profile of patients presenting with breast cancer in Nepal. METHOD: The study was conducted at Department of Radiotherapy and Oncology, Bir Hospital and Department of Radiation Oncology, BP Koirala Memorial Cancer Hospital, Bharatpur from 16th July 2007 to 15th June 2008 for a period of one year and 114 patients were enrolled. Detailed history, clinical examination and necessary investigations performed. Histological features including receptor status were recorded. Tumor Node Metastasis (TNM) staging system was as per American Joint Committee on Cancer (AJCC), fifth edition. Data was collected in preformed case report form and was managed using SPSS version 13. RESULTS: The incidence was high (34.2%) among perimenopausal women age ranging from 41 to 50. The majority of women presented with lump (98.2%) and others with pain (21.9%), nipple retraction (16.7%), ulceration (7.9%), discharge (7%), or symptoms of metastasis (6.1%). Regarding receptor status, the majority (64.0%) were Estrogen receptor (ER) and Progesterone receptor (PR) negative with 21.9 percent. ER+PR+, Younger women were more likely to be both ER and PR negative. Where available, Her- 2 immunohistochemistry showed that 45.0 % of post menopausal women were Her-2 neative, compared to 64.0 % of premenopausal women. Incidence of Triple negative disease was 41.3 %. The most common stage at presentation was stage III (26.3%). CONCLUSION: Majority of patients were perimenopausal, presenting with locally advanced disease (Stage III and Stage II) and with average tumor size two to five cm and were hormonal receptor negative. These findings are similar to other South Asian population but is inverse than profile reported in Western populations. PMID- 23434954 TI - Women having abortion in urban Nepal: 2005 and 2010 compared. AB - BACKGROUND: The use of abortion services at the Maternity Hospital clinic, the largest public sector abortion clinic in Nepal, has risen over the years. Whether the profile of the clients, reasons for abortion, and contraceptive use have changed are not known and need to be investigated. OBJECTIVES: This paper evaluates changes between 2005 and 2010 in the socio-demographic profile of abortion users, reasons for seeking abortion, and contraceptive use of two cohorts of women who had first-trimester abortion at the Maternity Hospital. METHODS: We used data from two similar surveys conducted in 2005 and 2010 among 672 and 392 women, respectively, who obtained first-trimester surgical abortion in a large public sector clinic. We analyzed trend data in service utilization and carried out a cost analysis. RESULTS: The number of women having abortions has steadily increased over the years, and cumulatively about 19,800 women have received services. The profile of the clients at this clinic remained essentially the same between 2005 and 2010. The typical users of abortion services at the clinic has were 27 years old with two living children, mostly married, with the majority not wanting to have more children. About half of them used a contraceptive method-mostly condoms, withdrawal, the pill and rhythm-in the month of unintended pregnancy, suggesting failures with these methods. Health concerns, dislike of available methods, and perceived low risk of pregnancy were common reasons for not using a contraceptive method. CONCLUSION: Despite increases in the number of clients, the socio-demographic profile of the abortion clients has remained similar over the years. The linkage between the abortion and family planning clinics needs to be strengthened. PMID- 23434955 TI - A study of prevalence of Taenia infestation and associated risk factors among the school children of Dharan. AB - BACKGROUND: Taenia prevalence has remained high among certain ethnic groups and occupational diseases in Nepal. Taenia saginata and Taenia solium species are worldwide in distribution. Infection is found most often in rural areas of developing countries with poor hygiene and living in close contact with pigs and eating undercooked pork meats. This allows the tapeworm infection to be completed and its cycle to continue. OBJECTIVES: To measure the prevalence of taenia infestation and to identify risk factors associated with taenia infestation among the school children of Dharan. METHODS: A cross sectional study was conducted among 935 Government and private school going children of Grade VI, VII, and VIII of Dharan during 2007 to 2008. Stratified random sampling method was applied to choose the schools and the study subjects. The prevalence was calculated, Chi square test was used to measure the association of risk factors and taenia infestation. RESULTS: Taenia species was found to be high (5.5%) among the school children of Dharan. Infection rate of taenia among the male children (6.0%) was slightly higher than female (4.8%). There were no cases of taenia infestation found among children washing hands with soap. Regarding meat consumption in the non-vegetarian group, taenia infestation was found higher (6.5%) among pork eating than nonpork eating (4.7%). No significant relationship was traced among the factors in the causation of taenia infestation although slight indications present. CONCLUSION: Taenia species was found very high among the school children of Dharan. No such association was found with the risk factors. PMID- 23434956 TI - Risk factors for stunting among children: a community based case control study in Nepal. AB - BACKGROUND: Stunting, a chronic condition, is an underlying cause of child morbidity and mortality in Nepal. This study intends to identify the factors causing stunting among children that will help to prioritize the strategies at the district level. OBJECTIVE: The objective of the study was to identify the risk factors for stunting among children of age between 6 to 59 months. METHODS: The study was based on community-based case control design in the mid-west, Surkhet Nepal from August to September 2010. The cases were stunted children and controls were the children without stunting. Data was collected by interviewing those children's mothers and measured length/height of 118 children as cases and 236 children as controls. Logistic regression analysis was performed to identify the best model of factors leading to stunting. Odds ratio and 95% confidence interval were used as a measure of association. RESULTS: Socio-economic risk factors for stunting comprised mothers without earning (OR=3.11, 95% CI 1.26 7.65), food deficit families (OR=4.26, 95% CI 1.73-10.45) and care taker of the children other than mother (OR=3.02, 95% CI 1.19-7.70). Environmental risk factors for stunting consisted of kitchen without ventilation and children exposed to pesticide. Inappropriate exclusive breast feeding (OR=6.90, 95% CI 2.81-16.97), complementary feeding less than four times a day (OR=3.60, 95% CI 1.32-9.95) and dietary diversity below WHO standard (OR=4.06, 95% CI 1.70-9.67) were factors of stunted children. Diarrhea was found significantly associated with stunting (OR=7.46, 95% CI 2.98-18.65). CONCLUSIONS: Stunting was found to be as a result of multiple factors such as socio-economic, environmental and inappropriate feeding practices. PMID- 23434958 TI - Relationship between arterial oxygen saturation and hematocrit, and effect of slow deep breathing on oxygen saturation in Himalayan high altitude populations. AB - BACKGROUND: The oxygen saturation of haemoglobin is reduced in high altitude living organisms. Increase in the hematocrit is responsible for rise in the hemoglobin concentration so that the oxygen carrying capacity in the hypobaric hypoxic subject is elevated. OBJECTIVES: To compare two different high altitude populations, in order to study the relationship between arterial oxygen saturation and hematocrit. METHODS: In the cross-sectional study of two populations residing at altitude of 2800 m and 3760 m are compared for the difference in hematocrit. The oxygen carrying capacity of arterial haemoglobin (SaO2) is determined by pulse oximetry. The sample is drawn from the natives of two small villages, Thini at Jomsom (2800 m) and Jharkot (3760 m) in Mustang district of Nepal. The natives at 2800 m are termed as lower high altitude population and local residents at 3760 m are said to be higher altitude population in this study. The sample blood was drawn by venipuncture and packed cell volume was determined by Wintrobe's method. RESULTS: The hematocrit obtained from 3760 m altitude population and the lower high altitude population at altitude of 2800 m differ significantly with the p value < 0.0001and the SaO2 in both the population fails to show any difference with p value > 0.05. Deep breathing exercise in these populations however increased SaO2 significantly. CONCLUSION: The higher altitude natives have greater arterial oxygen saturation than lower altitude population which is due to rise in red cell concentration. The slow deep breathing raises oxygen saturation irrespective of altitude. PMID- 23434957 TI - Comparison of ketamine, fentanyl and clonidine as an adjuvant during bupivacaine caudal anaesthesia in paediatric patients. AB - BACKGROUND: Caudal epidural analgesia with bupivacaine is very popular in paediatric anaesthesia for providing intra- and postoperative analgesia. Several adjuvants have been used to prolong the action of bupivacaine. OBJECTIVES: To compare the efficacy of ketamine, fentanyl and clonidine in terms of quality and duration of analgesia they produce when added with caudal bupivacaine by single shot technique in children. METHODS: Eighty children, age one to ten years, undergoing sub-umbilical surgery, were prospectively randomized to one of four groups: caudal analgesia with 0.75 ml/ kg of 0.25% bupivacaine in normal saline (Group B) or caudal analgesia with 0.75 ml/kg of 0.25% bupivacaine with 1 MUg/kg of clonidine in normal saline (Group BC) or caudal analgesia with 0.75 ml/kg of 0.25% bupivacaine with ketamine 0.5mg/kg (Group BK) or caudal analgesia with 0.75 ml/kg of 0.25% bupivacaine with fentanyl 1 mcg/kg (Group BF). Post-operative pain was assessed for 24 hours using the FLACC scale. RESULTS: The mean duration of analgesia was significantly longer in Group BC (629.06 +/- 286.32 min) than other three groups P < 0.05. The pain score assessed using FLACC scale was compared between the four groups, and children in Group BC had lower pain scores, which was statistically significant. The requirement of rescue medicine was lesser in Group BC. Clonidine in a dose of 1 MUg/kg added to 0.25% bupivacaine for caudal analgesia, during sub-umbilical surgeries, prolongs the duration of analgesia of bupivacaine, without any side effects in compare to fentanyl or ketamine. CONCLUSION: We conclude that clonidine in a dose of 1 MUg/kg, added to 0.25% bupivacaine for caudal analgesia and administered as a 0.75 ml/kg mixture in children, for subumbilical surgery, significantly prolongs the duration of post operative analgesia when compared to 0.75 ml/kg of 0.25% bupivacaine in normal saline than 0.75 ml/kg of 0.25% bupivacaine with ketamine 0.5 mg/kg or 0.75 ml/kg of 0.25% bupivacaine with fentanyl 1 mcg/kg or 0.75 ml/kg of 0.25% bupivacaine alone, without any side effects. PMID- 23434959 TI - Prevalence and associated risk factors of hypertension among people aged 50 years and more in Banepa Municipality, Nepal. AB - BACKGROUND: Hypertension is a cardiovascular disorder rapidly emerging as a major public health problem in developing countries and is the most widely recognized modifiable risk factor for cardiovascular diseases. OBJECTIVE: The objective of this study was to find out the prevalence and associated risk factors with hypertension among people aged 50 years and more in Banepa Municipality, Kavre, Nepal. METHODS: It is a cross- sectional, population based study which was carried out in Banepa Municipality from May 15 to June 15, 2009. Among total 11 wards of Banepa municipally, wards number 1, 3, 5, 6, 7, and 10 were selected by using Simple Random Sampling Technique and 405 subjects of people aged 50 years and more were selected for study from the selected wards by using Cluster Sampling. The structured interview method was used for collection of data. Mercury sphygmomanometers with standard cuff were used to measure the indirect auscultatory arterial blood pressure. Two consecutive blood pressure readings were taken and average of them was calculated to determine single value of blood pressure. RESULTS: The prevalence of hypertension was 44.9 percent (47.75% in male and 42.73% in females). Among them, only 32.9 percent (60/182) were previously diagnosed as hypertension. The higher proportion of hypertensive cases were in age > 65 years (55.49%) than in the age group < 65 years (36.32%). The prevalence of hypertension was seen positively associated with non vegetarian eating habits, alcohol consumption, and > 25 Body max index. Taking green leafy vegetable at least once a week was negatively associated with the prevalence of the hypertension. CONCLUSION: These findings provide important information on the prevalence, associated factors of hypertension in Banepa Municipality. Effective public health measures and strategies are needed to improve prevention, diagnosis and access to treatment of these 50 years and above population. PMID- 23434960 TI - Pattern of pediatric poisoning and accident in Patan Hospital. AB - BACKGROUND: Kerosene, drugs, pesticides are chemicals used in home and farms. But because of parents' or caretakers' negligence, accidents and poisoning in children may take life of a child. OBJECTIVE: To study the common causes and outcome of pediatric accident and poisoning cases admitted in Patan Hospital. METHOD: A prospective (2068-69) and retrospective (2066-67) studies of pediatric accident and poisoning cases admitted in Patan Hospital (2066-chaitra 2069) were done. RESULT: Out of 44 registered cases total 35 cases were collected in last 4 years. Twenty one in prospective and 14 in retrospective study. Male female ratio was 1.2:1. Most vulnerable age group was 1-5 years (21) and 11-15 yrs (8). Most common poison was pesticide (11), kerosene (9) and drugs (7). Twenty percent were suicidal, 3% were homicidal and rest was accidental. Suicidal poisoning was common in 11-14 years. Accidental poisoning was: taking kerosene from mineral water bottle for water. Small children took drugs and pesticides due its easy availability or careless storing. Five common accidents were near drowning (2), hot water scald, hanging and fall from height. Outcome was 2 expired; 1 Organo phosphorous and 1 food poisoning. Mortality was 6%. One hanging survived as vegetation. CONCLUSION: Accident and poisoning are preventable. We need to make our home and surrounding poison and accident proof. Small children should never be left unattended. Drugs, pesticides, hot things, and sharp instruments should be kept out of reach of children and in child proof container in separate places. Pesticide should not be sold to children. PMID- 23434961 TI - Comparison of lipid profile in type-2 obese diabetics and obese non-diabetic individuals. a hospital based study from Western Nepal. AB - BACKGROUND: Type-2 diabetes mellitus is an independent risk factor for coronary artery disease and risk of coronary disease is three to four fold increased in patients with diabetes compared with non-diabetic population and 60-80% 0f type-2 diabetics are obese. METHODS: This study was conducted in Nepalgunj Teaching Hospital, Kohalpur, Banke, Nepal, between 1st March, 2011 and 28th February, 2012. A total of 150 samples were taken to assess the lipid profile in type-2 diabetic patients associated with obesity and 25 obese controls for their lipid profile. Venous blood samples were taken from all the subjects in the morning after fasting overnight. Exclusion criteria included pregnancy, chronic infectious disease, heart failure; renal failure and drug allergy were confirmed from the subject's personal physician report and a detailed history. The data was analyzed using Excel 2003, R 2.8.0 Statistical Package for the Social Sciences (SPSS) for Windows Version 16.0 (SPSS Inc; Chicago, IL, USA) and the EPI Info 3.5.1 Windows Version. RESULTS: The mean +/- SD age of diabetic patients with obesity was 53.76+/- 6.23 while the mean +/- SD age of control was 49.61 +/- 4.8. Out of 150 patients 105 (70%) were males and 45 (30%) were females. Among control subjects 16 (64%) were males and 9 (36%) were females. Obese type-2 diabetic patients when compared to obese control subjects showed statistically significant increase in the levels of serum total cholesterol (p < 0.001), serum triglycerides (p < 0.001), serum LDL-cholesterol (p < 0.001) while serum HDL cholesterol levels did not show statistically significant difference in the two group (p > 0.05). CONCLUSION: This study showed obese diabetic individuals have dyslipidemia and more prone to develop cardiovascular diseases. PMID- 23434962 TI - Occupational radiation exposure in health care facilities. AB - BACKGROUND: Radiation, which is used extensively to diagnose and treat human diseases, poses an occupational health risk for the concerned health workers. Personal dosimetry is an important tool to monitor occupational radiation exposures. OBJECTIVE: This study was conducted to reveal and to describe the situation of occupational radiation exposure monitoring among staffs in different health care facilities in Nepal. METHODS: A cross-sectional study was performed among the 35 Health Care Facilities. Information about types and number of X-ray procedures performed, types and number of personnel involved, workload and the availability of personal dosimetry service were collected. RESULTS: Six Health Care Facilities had personal dosimetry service available for a total of 149 personnel. Of a total of nearly one million X-ray procedures performed in the 35 Health Care Facilities in 2007, 76 percent was performed by non-monitored personnel. The majority of the facilities performing high dose procedures, like catheterisation, angiography and intestinal barium procedures did not offer personal dosimetry for the involved personnel. CONCLUSION: There are a limited number of personnel being monitored with personal dosimetry. There are no regulatory dose limits for occupationally exposed staff. Thus, there is an urgent need to establish a national radiation protection authority to regulate the use of radiation in Nepal. PMID- 23434963 TI - Phaeochromocytoma in Nepal--a single centre experience. AB - BACKGROUND: Phaeochromocytomas are rare tumors of chromaffin cells of neural crest that classically present with symptoms of catecholamine excess such as palpitations, headache and sweating. They are diagnosed by measuring plasma or urinary levels of catecholamines or their metabolites. Anatomic localization is done by computed tomographic scan or magnetic resonance imaging, or meta iodobenzyl guanidine scan in certain cases. Adequate preoperative catecholamine blockade prevents perioperative hemodynamic instability. OBJECTIVES: To study the clinical spectrum and management of phaeochromocytomas in a tertiary care centre, Tribhuvan University Teaching Hospital, in Nepal. METHODS: Retrospective review of case records of histologically proven cases of phaeochromocytomas from 2008 2011 was done, and data collected on clinical spectrum, diagnostic modalities, perioperative management and follow-up. RESULTS: Twelve cases of phaeochromocytomas were operated. The mean age was 36.41+/-14.07 years. There were 2 bilateral phaeochromocytomas and 1 extraadrenal paraganglioma. Apart from the common symptoms of catecholamine excess, patients had atypical presentations like psychiatric manifestations and blurred vision. A combination of urinary Vanillyl Mandelic Acid and computed tomographic scan was used for diagnosis, and open surgery was done in all cases. Pre-operative blood pressure control was achieved by prazocin or calcium channel blockers. Ten patients had intraoperative surge in blood pressure. There were no major morbidity or mortality. Three patients had high blood pressure postoperatively, but were effectively managed with antihypertensives. CONCLUSION: Phaeochromocytomas can have variable presentation. Good preoperative preparation and perioperative management can result in an excellent outcome. PMID- 23434964 TI - Depression among undergraduate medical students. AB - BACKGROUND: Psychological stress is common in medical school and associated with depression. Medical education is grooming in Nepal, but only few studies are done concerning mental health of medical students. OBJECTIVE: To assess the prevalence of depression among medical students at different levels of education and find about their stressors. METHODS: A cross sectional, questionnaire-based survey was carried out among the undergraduate medical students of B.P.Koirala Institute of Health Sciences, Nepal. 50 students each from Bachelor of Medicine and Bachelor of Surgery (MBBS) first and third year were enrolled in the study conducted between November 2008 to January 2009. The depression levels were assessed using Zung depression scale. Students were asked to complete the questionnaire and then the depression levels calculated .The stress inducing factors during their course of medical education were also assessed. RESULTS: The overall prevalence of depression among the students was 29.78 percent. The prevalence of depression in first and third year was 36.74and 22.22 percent respectively. The prevalence of depression was 32.43 percent among female students versus 28.07 percent in male students. Both first and third year students gave high ratings to academic stress and hectic lifestyle as the main stress inducing factors. CONCLUSION: The prevalence of depression is seen especially in the first year medical students. So, attempts should be made to alleviate the stressors right from the time they join medical school. Since academic stress proved to be one of the major factors, measures to make the academic curriculum more student-friendly are suggested. PMID- 23434965 TI - Understanding of tobacco and lung cancer among medical students in Kathmandu University School of Medical Sciences (KUSMS). AB - BACKGROUND: Often, lung cancer is diagnosed at terminal stages. Poor awareness about the symptoms or risk factors of lung cancer among medics may be one of the factors for delayed diagnosis. OBJECTIVE: We explored the knowledge of medical students and their behavior with the patients of lung cancer. METHOD: Qualitative and quantitative approaches were used for data collection from 153 medical student of Kathmandu University School of Medical Sciences from December 2011 to May 2012. RESULTS: Among the results, eighty-nine students had over 80% knowledge of the 14 cancer warning signs, among them 83% knew the nine risk factors for lung cancer. Twenty-three students told lung cancer can be hereditary. Sixty five percent of all participants believed that lung cancer can be detected at early stage; of them 81% told that it can be treated. About 24% of the total students were current or exsmokers and about half of them believed that lung cancer does not occur in light smokers. Only 10% have heard of Framework Convention on Tobacco Control in Nepal. CONCLUSION: Study finds that all medical students who know about any cancers may not necessarily have knowledge about lung cancers. Their perception about the cause of lung cancer may be influenced by their smoking behavior and there was little knowledge of public health measures for smoking control. Awareness about national policies needs to be increased. PMID- 23434966 TI - Alveolar bone biology in extrusion splint technique. AB - The moment after the tooth avulsion, blood supply to the pulp is interrupted and the periodontal ligament cells are exposed to injury from the external environment. Complete healing is possible if the tooth can be immediately replanted and favorable environment is created .A case of report of intruded and mobile upper left central incisor due to Road Traffic Accident of a twenty-two year-old patient is presented here. In which, intentional extrusion traumatized tooth and then flexible acrylic wire splinting was done to stabilize it. Previously there was no periapical bone support but with nine months maintenance follow up bone has shown a significant improvement towards healing. PMID- 23434967 TI - Large gastric lipoma. AB - Gastric lipoma is a rare benign tumor and seen in five percent of gastro intestinal lipomas and accounts for less than one percent of all gastric tumors. Gastric lipomas are located submucosally and usually in antral region of Stomach. Computed tomography is considered as valuable tool in the diagnosis of gastrointestinal lipomas. Due to their relative rarity, gastric lipomas are often left out of the differential diagnosis for upper gastro-intestinal submucosal masses. We report a case of 70 year female that presented with upper abdominal pain since last two years. Abdominal Computed tomography revealed a large gastric lipoma in antral region. Patient refused for any surgical intervention due to old age. Patient was provided symptomatic treatment and was under regular followup. PMID- 23434968 TI - Eosinophilic fascitis: a rare fibrosing disorder. AB - Eosinophilic fasciitis is a rare systemic disease characterized by inflammatory thickening of the skin and underlying fascia, peripheral eosinophilia, elevated inflammatory markers and typical biopsy findings. Internal organ involvement is rare unlike in other fibrosing disorders. Though this is usually a benign disease, it is often difficult to diagnose and the course may also be variable. Glucocorticoids are the mainstay of therapy, but in many cases steroid sparing immunosuppressive drugs are required particularly if the diseases has protracted course. The author reports a typical case of this rare disorder which could well be a first report from Nepal. PMID- 23434969 TI - Ruptured primary ovarian pregnancy: a rare case report. AB - Ovarian pregnancy is an uncommon presentation of ectopic gestation and usually, it ends with rupture before the end of the first trimester. Its presentation often is difficult to distinguish from that of tubal ectopic pregnancy and hemorrhagic ovarian cyst. We report a rare primary ruptured ovarian pregnancy in a 26 years lady. PMID- 23434970 TI - A fatal presentation of dermatomyositis. AB - Dermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood. We present a 40-year-old male who presented with four months history of generalized skin lesion, pain and weakness. He had elevated transaminases with detectable muscle weakness. This case highlights the need to consider dermatomyositis with skin lesion and weakness; and the use of aggressive immunosuppressive therapies due to its associated vasculopathies. PMID- 23434971 TI - Oral adenoid/acantholytic squamous cell carcinoma: a report of two cases with review of literature. AB - Adenoid squamous cell carcinoma (ASCC) is an uncommon but well recognized variant of squamous cell carcinoma. It has been reported to originate in the sun exposed skin of the head and neck region. Although rare, there are cases in records which have reported within the oral cavity and nasopharynx. Histologically the lesion shows areas of conventional squamous cell carcinoma along with atypical epithelial cells forming an adenoid pattern. There are insufficient reported cases to establish likely behaviour. Here we report two additional cases of adenoid squamous cell carcinoma, one developing in the floor of mouth and another in the maxillary sinus both were reported in March 2010 in Mangalore, India. PMID- 23434972 TI - Combined orthodontic and surgical correction of an adolescent patient with thin palatal cortex and vertical maxillary excess. AB - This paper describes the treatment of a male patient aged 14 years who presented with a skeletal class I, vertical maxillary excess, marked increase in overjet, thin palatal cortex and a gummy smile. Considering the severity of his malocclusion and its impact severity on his psychosocial well being, he was managed with a combined approach of Fixed Orthodontic therapy and Orthognathic surgery, even though his growth was not complete. Records of Pre treatment, Post treatment and three years in retention were analyzed and the functional and esthetic results were found to be fairly stable. PMID- 23434973 TI - Within- and between-session variety effects in a food-seeking habituation paradigm. AB - Appetitive behavior is stronger when organisms are given a variety of foods than when they are repeatedly given the same food (the variety effect). Two experiments examined the variety effect in an operant food-seeking task. In both experiments, rats received a 45-mg food pellet for every 4th lever press over a series of daily 30-min sessions. The rats responded at a high rate early in the session, but the rate declined systematically over time within the session. In Experiment 1, alternating unpredictably between grain and sucrose pellets caused a higher level of responding, and a slower within-session decline in responding, than presenting either type of pellet consistently. In groups receiving one pellet consistently, a switch to the alternate pellet caused lawful changes in response rate that reflected both habituation and incentive contrast processes. In Experiment 2, an experimental group received grain only and sucrose only in daily alternating sessions. In sucrose sessions, they responded more than controls that always received either sucrose or grain (a type of variety effect); in grain sessions, they responded less than the controls. The results indicated a within-session variety effect that was controlled by habituation processes and a between-session variety effect that was controlled by incentive contrast. Both types of processes can come into play when organisms are exposed to food variety. PMID- 23434974 TI - A piece in the puzzle of puberty. PMID- 23434975 TI - Brain microglia: watchdogs with pedigree. PMID- 23434976 TI - Circuits supporting the grid. PMID- 23434977 TI - Multiplexed memories: a view from human cortex. PMID- 23434979 TI - Influence of launch-beam distribution on bandwidth in step-index plastic optical fibers. AB - The power-flow equation is employed to calculate bandwidth of step-index plastic optical fibers (POFs) for different launch conditions. The outcome specifies bandwidth as a function of the mean input angle and width of the launch-beam distribution. For small distribution widths, bandwidth is shown to decrease with increasing mean input angle of the launch-beam distribution. For large distribution widths, bandwidth becomes independent of the launch angle. Launch beam distribution, mode-dependent attenuation, and mode dispersion and coupling in POFs strongly influence the bandwidth of data transmission systems. PMID- 23434978 TI - Reading and writing the neural code. AB - It has been more than 20 years since Bialek and colleagues published a landmark paper asking a seemingly innocuous question: what can we extract about the outside world from the spiking activity of sensory neurons? Can we read the neural code? Although this seemingly simple question has helped us shed light on the neural code, we still do not understand the anatomical and neurophysiological constraints that enable these codes to propagate across synapses and form the basis for computations that we need to interact with our environment. The sensitivity of neuronal activity to the timing of synaptic inputs naturally suggests that synchrony determines the form of the neural code, and, in turn, regulation of synchrony is a critical element in 'writing' the neural code through the artificial control of microcircuits to activate downstream structures. In this way, reading and writing the neural code are inextricably linked. PMID- 23434980 TI - Characteristic analysis of aspheric quasi-optical lens antenna in millimeter-wave radiometer imaging system. AB - Quasi-optical imaging systems require low blurring effect and large depth of focus (DOF) to get an acceptable sharpness of the image. To reduce aberration limited blurring, the aspheric convex plano lenses with an aperture diameter of 350 mm are designed in W-band. We analyzed theoretically and experimentally the millimeter-wave band lens characteristics, such as beam spot size, spatial resolution (SR), and DOF, via f-number. It is first used to verify the DOF through f-number in the system-level test with the developed W-band radiometer imaging system. We have confirmed that the larger f-number of quasi-optical lens leads to a larger DOF but a lower SR. PMID- 23434981 TI - Optical excitation cross section of erbium in GaN. AB - Epilayers of erbium-doped GaN (GaN:Er) were synthesized by metal-organic chemical vapor deposition, and the optical excitation cross section (sigma(exc)) of Er ions in this host material were determined. Photoluminescence (PL) measurements were made using laser diodes at excitation wavelengths of 375 and 405 nm, and the integrated emission intensity at 1.54 MUm was measured as a function of excitation photon flux. Together with time-resolved PL measurements, values of sigma(exc) of Er ions in GaN:Er were obtained. For excitation at 375 nm, the observed excitation cross section was found to be 4.6*10(-17) cm(-2), which is approximately three orders of magnitude larger than that using resonant excitation. Based on the present and previous works, the optical excitation cross section sigma(exc) of Er ions in GaN:Er as a function the excitation wavelength has been obtained. The large values of sigma(exc) with near-band-edge excitation makes GaN:Er attractive for realization of chip-scale photonic devices for optical communications. PMID- 23434982 TI - Orthonormal aberration polynomials for optical systems with circular and annular sector pupils. AB - Using the Zernike circle polynomials as the basis functions, we obtain the orthonormal polynomials for optical systems with circular and annular sector pupils by the Gram-Schmidt orthogonalization process. These polynomials represent balanced aberrations yielding minimum variance of the classical aberrations of rotationally symmetric systems. Use of the polynomials obtained is illustrated with numerical examples. PMID- 23434984 TI - Ultrastable bonding of glass with femtosecond laser bursts. AB - We report on the welding of fused silica with bursts of ultrashort laser pulses. By optimizing the burst frequency and repetition rate, we were able to achieve a breaking resistance of up to 96% of the bulk material, which is significantly higher than conventional high repetition rate laser bonding. The main reason for this stability increase is the reduced stress in the surroundings of the laser induced weld seams, which is proven by measurements of the stress-induced birefringence. A detailed analysis of the shape of the molten structures shows elongated structures in the burst regime. This can be attributed to stronger heating, which is supported by our thermodynamic simulations of the laser melting and bonding process. PMID- 23434985 TI - Slow light in an alternative row of ellipse-hole photonic crystal waveguide. AB - High normalized delay-bandwidth product (NDBP) and wideband slow light are achieved in an alternative row of ellipse-hole photonic crystal waveguide. Two different criteria of flat ratio are adopted. Under a constant group index criterion, a high NDBP of 0.446 with a group index of 42 and a bandwidth of 16.4 nm are obtained by plane wave expansion calculations, while under a low dispersion criterion, the NDBP, group index, and bandwidth come to 0.352, 41, 13.1 nm, respectively. Low dispersion slow light propagation is numerically demonstrated by studying the relative temporal pulse-width spreading with the two dimensional finite-difference time-domain method. As a whole, the presented results give indications about the "ultimate" possible improvement of slow light waveguide metrics by using noncircular holes. PMID- 23434986 TI - All-fiber time-delay spectrometer for simultaneous spectral and temporal laser pulse characterization in the nanosecond range. AB - We have realized a modified time-delay spectrometer based on a step-chirped fiber Bragg grating array. This method allows simultaneous spectral and temporal characterization of pulsed light sources in the nanosecond regime, which can also be applied to the investigation of single pulses. With a spectral resolution in the 100 pm range, pulse spectrograms are measured and exemplarily used to explore the emission behavior of a wavelength-stabilized laser diode directly modulated in the nanosecond range. PMID- 23434987 TI - Low-loss high-speed speckle reduction using a colloidal dispersion. AB - We present a simple and robust approach to reduce laser speckle, which has limited the adoption of lasers in imaging and display applications. We use colloidal solutions that can quickly reduce speckle contrast due to the Brownian motion of the scattering particles. The high insertion loss associated with propagation through a colloidal solution was overcome by using white paint to cover the sides of the cuvette and an optical fiber to deliver the laser light deep into the colloidal solution, enabling transmission greater than 90%. The diffused laser output followed a Lambertian distribution and produced speckle contrast below 4% at an integration time of 129 MUs. The ability for colloidal solutions to achieve fast speckle reduction without power consumption while maintaining high transmission, low cost, a compact size, and a long lifetime makes our approach useful for a wide range of laser imaging and projection applications. PMID- 23434988 TI - Flexible near-infrared diffuse optical tomography with varied weighting functions of edge-preserving regularization. AB - In this paper, a flexible edge-preserving regularization algorithm based on the finite element method is proposed to reconstruct the optical-property images of near-infrared diffuse optical tomography. This regularization algorithm can easily incorporate with varied weighting functions, such as a generalized Lorentzian function, an exponential function, or a generalized total variation function. To evaluate the performance, results obtained from Tikhonov or edge preserving regularization are compared with each other. As found, the edge preserving regularization with the generalized Lorentzian function is more attractive than that with other functions for the estimation of absorption coefficient images concerning functional tomographic images to discover functional information of tested phantoms/tissues. PMID- 23434989 TI - Randomly displaced phase distribution design and its advantage in page-data recording of Fourier transform holograms. AB - For Fourier transform holography, an effective random phase distribution with randomly displaced phase segments is proposed for obtaining a smooth finite optical intensity distribution in the Fourier transform plane. Since unitary phase segments are randomly distributed in-plane, the blanks give various spatial frequency components to an image, and thus smooth the spectrum. Moreover, by randomly changing the phase segment size, spike generation from the unitary phase segment size in the spectrum can be reduced significantly. As a result, a smooth spectrum including sidebands can be formed at a relatively narrow extent. The proposed phase distribution sustains the primary functions of a random phase mask for holographic-data recording and reconstruction. Therefore, this distribution is expected to find applications in high-density holographic memory systems, replacing conventional random phase mask patterns. PMID- 23434990 TI - All-reflective optical bifocal zooming system without moving elements based on deformable mirror for space camera application. AB - The space camera with variable focal length is capable of capturing images with variable resolution and variable field of view. This is useful for space-borne reconnaissance because the camera can switch between coarse and fine reconnaissance flexibly. However, the traditional optical zooming relies on moving elements which might influence the momentum balance of the satellite platform. Therefore, we present a prototype design using the piezo deformable mirror (PDM) to realize an all-reflective optical bifocal zooming system. By changing the curvature radius of the PDM, the focal length can be switched between 48 and 192 mm without moving elements involved. With the focal length experiencing 4* magnification, the system performance is still approaching diffraction-limited performance, and the maximum stroke of the PDM is also within its physical limits. Experiments demonstrate that the principle is correct and the design is successful. PMID- 23434991 TI - Femtosecond laser-induced microwelding of silver and copper. AB - Femtosecond (fs) laser irradiation has been shown to be effective for welding transparent materials and for transparent materials to metals. However, to date there is little work regarding similar applications in welding/bonding of metals. In this article, we for the first time to the best of our knowledge report on fs laser-induced microwelding of Ag microwires and Cu substrates. The influence of laser pulse number and fluence on fs laser microwelding is studied to explore an optimum welding window. Morphology analysis indicates that the primary weld of the Ag microwire and the Cu substrate was located at the edge of the Ag microwire and produced via the redeposition and local melting-induced welding of the ablated materials. PMID- 23434992 TI - Ultracompact ring resonator microwave photonic filters based on photonic crystal waveguides. AB - We design two microwave photonic filters (notch filter and bandpass filter) based on silicon on insulator (SOI) photonic crystal waveguides for a 60 GHz single sideband signal radio-over-fiber (ROF) system. By perturbing the radii of the first two rows of holes adjacent to the photonic crystal waveguide, we obtained a broad negligible dispersion bandwidth and a corresponding constant low group velocity. With the slow light effect, the delay line of filters can be significantly reduced while providing the same delay time as fiber based delay lines. The simulation results show that the delay-line length of the notch filter is only about 25.9 MUm, and it has a free spectral range of 130 GHz, a baseband width (BW) of 4.12 GHz, and a notch depth of 22 dB. The length of the bandpass filter is 62.4 MUm, with a 19.6 dB extinction ratio and a 4.02 GHz BW, and the signal-to-noise ratio requirement of received data can be reduced by 9 dB for the 10(-7) bit-error ratio. Demonstrated microwave photonic crystal filters could be used in a future high-frequency millimeter ROF system. PMID- 23434993 TI - Mode-locked thulium-bismuth codoped fiber laser using graphene saturable absorber in ring cavity. AB - We demonstrate mode locking of a thulium-bismuth codoped fiber laser (TBFL) operating at 1901.6 nm, using a graphene-based saturable absorber (SA). In this work, a single layer graphene is mechanically exfoliated using the scotch tape method and directly transferred onto the surface of a fiber pigtail to fabricate the SA. The obtained Raman spectrum characteristic indicates that the graphene on the core surface has a single layer. At 1552 nm pump power of 869 mW, the mode locked TBFL self starts to generate an optical pulse train with a repetition rate of 16.7 MHz and pulse width of 0.37 ps. This is a simple, low-cost, stable, and convenient laser oscillator for applications where eye-safe and low-photon-energy light sources are required, such as sensing and biomedical diagnostics. PMID- 23434994 TI - Comprehensive analysis of escape-cone losses from luminescent waveguides. AB - Luminescent waveguides (LWs) occur in a wide range of applications, from solar concentrators to doped fiber amplifiers. Here we report a comprehensive analysis of escape-cone losses in LWs, which are losses associated with internal rays making an angle less than the critical angle with a waveguide surface. For applications such as luminescent solar concentrators, escape-cone losses often dominate all others. A statistical treatment of escape-cone losses is given accounting for photoselection, photon polarization, and the Fresnel relations, and the model is used to analyze light absorption and propagation in waveguides with isotropic and orientationally aligned luminophores. The results are then compared to experimental measurements performed on a fluorescent dye-doped poly(methyl methacrylate) waveguide. PMID- 23434995 TI - Iterative method of baffle design for modified Ritchey-Chretien telescope. AB - We developed a baffle design method based on a combination of the results of optical design software and analytical relations formulated herein. The method finds the exact solution for baffle parameters of a modified Ritchey-Chretien telescope by iteratively solving the analytical relations using the actual ray coordinates of the telescope computed with the aid of optical design software. The baffle system so designed not only blocks the direct rays of stray light reaching the image plane but also provides minimum obscuration to imaging light. Based on the iterative method, we proposed a baffle design approach for a rectangular-image-format telescope. PMID- 23434996 TI - Ultrafast Fabry-Perot fiber-optic pressure sensors for multimedia blast event measurements. AB - A shock wave (SW) is characterized as a large pressure fluctuation that typically lasts only a few milliseconds. On the battlefield, SWs pose a serious threat to soldiers who are exposed to explosions, which may lead to blast-induced traumatic brain injuries. SWs can also be used beneficially and have been applied to a variety of medical treatments due to their unique interaction with tissues and cells. Consequently, it is important to have sensors that can quantify SW dynamics in order to better understand the physical interaction between body tissue and the incident acoustic wave. In this paper, the ultrafast fiber-optic sensor based on the Fabry-Perot interferometric principle was designed and four such sensors were fabricated to quantify a blast event within different media, simultaneously. The compact design of the fiber-optic sensor allows for a high degree of spatial resolution when capturing the wavefront of the traveling SW. Several blast event experiments were conducted within different media (e.g., air, rubber membrane, and water) to evaluate the sensor's performance. This research revealed valuable knowledge for further study of SW behavior and SW-related applications. PMID- 23434997 TI - Stabilization of LCD devices via geometric alteration. AB - Glass bending in LCD displays is an inherent problem that has challenged many engineers. As a solution to this problem, we propose a methodology that can tackle the root of the phenomenon in terms of linear elastic beam theory. Using this hypothesis, we devised a background theory and a solution. In this paper, we present a glass panel to which geometrical changes, such as furrow, groove, and curb have been applied. These geometrical changes are applied to the nonactive area of the glass panel. To confirm the validity of our approach, we conducted simulation tests as well as hands-on experiments to observe the thermo-mechanical behavior of the device under various conditions. The simulation results using the Ansys simulator show that the proposed technique can reduce the deformation level of panel bending by 40%. In the experiment using a bare cell with polarizer films attached and with performing the high temperature reliability test, the deformation level of panel bending is reduced by half compared to the reference glass panel without any geometric alteration. PMID- 23434998 TI - Measurement of normalized spectral responsivity of digital imaging devices by using a LED-based tunable uniform source. AB - We present an instrumentation solution for measurement of normalized spectral responsivity of digital imaging sensors and cameras. The instrument consists of multiple light-emitting diodes (LEDs), a single-grating monochromator, and a small-size integrating sphere. Wavelength tuning is achieved by a proper selection of LED in accordance with the monochromator setting in a range from 380 to 900 nm. High spectral purity with a bandwidth of 5 nm is realized without using double gratings and order-sorting filters. Experimental characteristics and calibration of the instrument are described with the related error and uncertainty sources. The performance is demonstrated by measuring a monochrome charge-coupled device and a trichromatic complementary metal-oxide-semiconductor device. The measurement uncertainty is evaluated to be less than 1% (k=2) except several wavelengths with low LED power. PMID- 23434999 TI - Diode-pumped 2 MUm tunable single-frequency Tm:LuAG laser with intracavity etalons. AB - We report a laser-diode-pumped 2 MUm single-frequency Tm:LuAG laser at room temperature. Two fused-silica etalons were used as mode selectors for the single frequency operation. The maximum single-frequency output power was 616 mW at wavelength of 2021 nm, with a relative power stability of 0.61%. The wavelength tuning range of the single-frequency Tm:LuAG laser was 11 nm from 2018.714 to 2029.876 nm. The M(2) factors were measured to be 1.38 and 1.36 in the x and y directions, respectively. PMID- 23435000 TI - Evaluations of phase-only double random phase encoding based on key-space analysis. AB - Although initial research shows that double-random phase encoding (DRPE) is vulnerable to known-plaintext attacks that use phase retrieval algorithms, subsequent research has shown that phase-only DRPE, in which the Fourier amplitude component of an image encrypted with classical DRPE remains constant, is resistant to attacks that apply phase retrieval algorithms. Herein, we numerically analyze the key-space of DRPE and investigate the distribution property of decryption keys for classical and phase-only DRPE. We determine the difference in the distribution property of successful decryption keys for these DRPE techniques from the numerical analysis results and then discuss the security offered by them. PMID- 23435001 TI - Polarization calibration with large apertures in full field of view for a full Stokes imaging polarimeter based on liquid-crystal variable retarders. AB - Currently, polarization calibration for full Stokes imaging polarimeters is limited by the apertures of the retarders. In this paper, an improved polarization calibration with large apertures in full field of view for full Stokes imaging polarimeters based on liquid-crystal variable retarders is proposed and investigated theoretically and experimentally. The experimental precision of polarization calibration is 1.7% for linear polarization states and 8.8% for circular ones for an imaging polarimeter with a 100 mm aperture and 10 degrees field of view. The feasibility for full Stokes polarization image is also confirmed in experiment for identifying objects due to degree of polarization and degree of circular polarization images. PMID- 23435002 TI - Native fluorescence spectra of human cancerous and normal breast tissues analyzed with non-negative constraint methods. AB - The native fluorescence spectra of human cancerous and normal breast tissues were investigated using the selected excitation wavelength of 340 nm to excite key building block molecules, such as reduced nicotinamide adenine dinucleotide (NADH), collagen, and flavin. The measured emission spectra were analyzed using a non-negative constraint method, namely multivariate curve resolution with alternating least-squares (MCR-ALS). The results indicate that the biochemical changes of tissue can be exposed by native fluorescence spectra analysis. The MCR ALS-extracted components corresponding to the key fluorophores in breast tissue, such as collagen, NADH, and flavin, show differences of relative contents of fluorophores in cancerous and normal breast tissues. This research demonstrates that the native fluorescence spectroscopy measurements are effective for detecting changes of fluorophores composition in tissues due to the development of cancer. Native fluorescence spectroscopy analyzed by MCR-ALS may have the potential to be a new armamentarium. PMID- 23435003 TI - Deterministic ion beam material adding technology for high-precision optical surfaces. AB - Although ion beam figuring (IBF) provides a highly deterministic method for the precision figuring of optical components, several problems still need to be addressed, such as the limited correcting capability for mid-to-high spatial frequency surface errors and low machining efficiency for pit defects on surfaces. We propose a figuring method named deterministic ion beam material adding (IBA) technology to solve those problems in IBF. The current deterministic optical figuring mechanism, which is dedicated to removing local protuberances on optical surfaces, is enriched and developed by the IBA technology. Compared with IBF, this method can realize the uniform convergence of surface errors, where the particle transferring effect generated in the IBA process can effectively correct the mid-to-high spatial frequency errors. In addition, IBA can rapidly correct the pit defects on the surface and greatly improve the machining efficiency of the figuring process. The verification experiments are accomplished on our experimental installation to validate the feasibility of the IBA method. First, a fused silica sample with a rectangular pit defect is figured by using IBA. Through two iterations within only 47.5 min, this highly steep pit is effectively corrected, and the surface error is improved from the original 24.69 nm root mean square (RMS) to the final 3.68 nm RMS. Then another experiment is carried out to demonstrate the correcting capability of IBA for mid-to-high spatial frequency surface errors, and the final results indicate that the surface accuracy and surface quality can be simultaneously improved. PMID- 23435004 TI - Optical trapping Rayleigh dielectric spheres with focused anomalous hollow beams. AB - Focusing properties of anomalous hollow beams (AHBs) are theoretically and numerically investigated. The radiation forces acting upon a Rayleigh dielectric sphere produced by focused AHBs are also studied. Results show that focused AHBs can be used to trap and manipulate microsized dielectric spheres with high refractive index at the focal point. Finally, the stability conditions for effective trapping particles are analyzed in detail. The results presented here are of interest in some possible applications by making use of AHBs. PMID- 23435005 TI - Time-dependent theory for random lasers in the presence of an inhomogeneous broadened gain medium such as PbSe quantum dots. AB - Time-dependent model is presented to simulate random lasers in the presence of an inhomogeneous gain medium. PbSe quantum dots (QDs) with an arbitrary size distribution are treated as an inhomogeneous gain medium. By introducing inhomogeneity of the PbSe QDs in polarization, rate, and Maxwell's equations, our model is constructed for a one-dimensional disordered system. By employing the finite difference time-domain method, the governing equations are numerically solved and lasing spectra and spatial distribution of the electric field are calculated. The effect of increasing the pumping rate on the laser characteristics is investigated. The results show that the number of lasing modes and their intensities increase with pumping rate. It is also demonstrated that the emission spectra depend on the standard deviation of the Gaussian distribution function. Increasing the standard deviation leads to reduction of the laser intensity. PMID- 23435006 TI - Optical absorption analysis and optimization of gold nanoshells. AB - Gold nanoshells, consisting of a nanoscale dielectric core coated with an ultrathin gold shell, have wide biomedical applications due to their strong optical absorption properties. Gold nanoshells with high absorption efficiencies can help to improve these applications. We investigate the effects of the core material, surrounding medium, core radius, and shell thickness on the absorption spectra of gold nanoshells by using the light-scattering theory of a coated sphere. Our results show that the position and intensity of the absorption peak can be tuned over a wide range by manipulating the above-mentioned parameters. We also obtain the optimal absorption efficiencies and structures of hollow gold nanoshells and gold-coated SiO(2) nanoshells embedded in water at wavelengths of 800, 820, and 1064 nm. The results show that hollow gold nanoshells possess the maximum absorption efficiency (5.42) at a wavelength of 800 nm; the corresponding shell thickness and core radius are 4.8 and 38.9 nm, respectively. They can be used as the ideal photothermal conversation particles for biomedical applications. PMID- 23435007 TI - Separability between pedestrians in hyperspectral imagery. AB - The popularity of hyperspectral imaging (HSI) in remote sensing continues to lead to it being adapted in novel ways to overcome challenging imaging problems. This paper reports on research efforts exploring the phenomenology of using HSI as an aid in detecting and tracking human pedestrians. An assessment of the likelihood of distinguishing between pedestrians based on the measured spectral reflectance of observable materials and the presence of noise is presented. The assessments included looking at the spectral separation between pedestrian material subregions using different spectral-reflectance regions within the full range (450-2500 nm), as well as when the spectral content of the pedestrian subregions are combined. In addition to the pedestrian spectral-reflectance data analysis, the separability of pedestrian subregions in remotely sensed hyperspectral images was assessed using a unique data set garnered as part of this work. Results indicated that skin was the least distinguishable material between pedestrians using the spectral Euclidean distance metric. The clothing, especially the shirt, offered the most salient feature for distinguishing the pedestrian. Additionally, significant spectral separability performance is realized when combining the reflectance information of two or more subregions. PMID- 23435008 TI - Simultaneous retrieval of atmospheric CO2 and light path modification from space based spectroscopic observations of greenhouse gases: methodology and application to GOSAT measurements over TCCON sites. AB - This paper presents an improved photon path length probability density function method that permits simultaneous retrievals of column-average greenhouse gas mole fractions and light path modifications through the atmosphere when processing high-resolution radiance spectra acquired from space. We primarily describe the methodology and retrieval setup and then apply them to the processing of spectra measured by the Greenhouse gases Observing SATellite (GOSAT). We have demonstrated substantial improvements of the data processing with simultaneous carbon dioxide and light path retrievals and reasonable agreement of the satellite-based retrievals against ground-based Fourier transform spectrometer measurements provided by the Total Carbon Column Observing Network (TCCON). PMID- 23435009 TI - Microlens array-based high-gain screen design for direct projection head-up displays. AB - Head-up display (HUD) systems have been used in recent car models to provide essential information to the drivers while keeping their eyes on the road. Virtual image HUD systems have been the preferred method, but they have the drawback of requiring a large volume of space in order to accommodate the relay optics that creates the virtual image. This is especially significant as the desired field of view increases. Direct projection HUD systems have been developed with a separate stand-alone microlens array (MLA)-based transparent screen on the dashboard, offering a compact solution. In this paper, we propose a direct projection HUD system based on a unique, windshield-embedded see-through screen that uses minimal space under the dashboard, offering an elegant and compact solution to the HUD problem. The screen is based on MLAs with varying surface normal angles such that the light from the projector is directed to the viewer's eyes from all positions across the field of view. Varying tilts provide an efficient relay and high brightness even with a low-lumen output projector. The calculated screen gain is about 69 and the eyebox area is about 30 cm*30 cm. PMID- 23435010 TI - Hypoxia is a key regulator of limbal epithelial stem cell growth and differentiation. AB - The aim of this study was to determine whether the growth and differentiation of limbal epithelial stem cell cultures could be controlled through manipulation of the oxygen tension. Limbal epithelial cells were isolated from corneoscleral disks, and cultured using either feeder cells in a growth medium supplemented with serum (3T3 system) or without feeder cells in a dedicated serum-free medium (EpiLife). During the culture, the cells were maintained either at ambient oxygen tension (20%) or at different levels of hypoxia (15, 10, 5, and 2% oxygen). The effect of oxygen on cell growth, progression through cell cycle, colony forming efficiency (CFE), and expression of stem cell (ABCG2 and p63alpha) and differentiation (CK3) markers was determined throughout the culture period of up to 18 days. Low oxygen levels favored a stem cell phenotype with a lower proliferative rate, high CFE, and a relatively higher expression of ABCG2 and p63alpha, while higher levels of oxygen led not only to decreased CFE but also to increased proportion of differentiated cells positive for CK3. Hypoxic cultures may thus potentially improve stem cell grafts for cultured limbal epithelial transplantation (CLET). PMID- 23435011 TI - Use of screen-printed microelectrodes working as generator/collector systems for the determination of the antioxidant capacity of phenolic compounds. AB - A new method using cheap homemade dual-electrodes has been developed to measure the antioxidant capacity of phenolic compounds. These micro-sized electrodes are elaborated by successive screen-printing of conductive ink and insulator layers and are then used as generator/collector sensors. Cyclic voltammetry and chronoamperometry with a bipotentiostat have been used to test and characterize these sensors. The antioxidant capacity values found by this new method are compared with a classical method (using a macro-sized electrode) to demonstrate its reliability. PMID- 23435012 TI - Protraction of anaphase B in lymphocyte mitosis with ageing: possible contribution to age-related cancer risk. AB - Ageing is associated with a reduction in the fidelity of cell division as shown by increases in trisomic and polyploid cells; however, to date, the underlying age-specific changes in cell division have not been identified. Understanding these specific changes in cell division could give insight into the aetiology some age-related illnesses, especially cancer. Using blood collected from 72 women aged 18-53 years, this study recorded the frequencies of cells in each of the stages of mitosis in synchronised lymphocyte cultures harvested at controlled temperature without microtubule inhibitors. Factor analysis identified four components that accounted for >67.5% of the variance in the data. The component we named 'Spindle elongation efficiency', which was primarily influenced by the time taken to complete anaphase B, showed a major change with age: women aged >=36 showed a highly statistically significant protraction of anaphase B compared with those aged <=35 (t = -2.74, df = 70, P = 0.006) and linear regression showed a logarithmic change in this component with age (R = 0.297, P = 0.011). This phosphorylation-dependent phase of the cycle is responsible for increasing the distance between the two sets of daughter chromosomes and in older subjects the daughter nuclei at telophase were often poorly separated. Inefficient spindle elongation with ageing probably results from decreased cellular energy. Insufficient force at anaphase B might fail to resolve merotelic kinetochore attachments such that lagging at anaphase would be uncorrected and lead to trisomy and polyploidy in daughter cells. PMID- 23435013 TI - Association of P2X7R gene polymorphisms with systemic lupus erythematosus in a Chinese population. AB - The P2X7 receptor is a ligand-gated cationic channel receptor that is actived by ATP and normally expressed by a variety of immune system cells, including macrophages and lymphocytes. Because it leads to release of IL-1beta and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of autoimmune inflammatory diseases, such as systemic lupus erythematosus (SLE). The P2X7R gene is highly polymorphic, and many single-nucleotide polymorphisms (SNPs) have been detected. A case-control study was performed to investigate the associations of SNPs in the P2X7R gene (rs1718119, rs2230911 and rs3751143) with susceptibility to SLE in 535 Chinese SLE patients and 532 controls. Results showed that rs1718119 was associated with SLE; in particular carriers of the A allele and AA/AG/(AG+AA) genotypes were at lower risk of the disease [A versus G, P < 0.001, odds ratio (OR) = 0.543, 95% CI: 0.424-0.697; AG versus GG, P = 0.018, OR = 0.659, 95% CI: 0.466-0.931; AA versus GG, P = 0.011, OR = 0.176, 95% CI: 0.046-0.668; AG+AA versus GG, P = 0.004, OR = 0.607, 95% CI: 0.433-0.850], but no significant differences in rs2230911 and rs3751143 were observed between SLE patients and controls. Stratification of cases for the presence of nephritis showed that rs2230911 G allele and CG/(CG+GG) genotypes were at a lower risk of SLE with nephritis (LN) (G versus C, P = 0.011, OR = 0.640, 95% CI: 0.454-0.903; CG versus CC, P = 0.035, OR = 0.645, 95% CI: 0.429 0.970; GG versus CC, P = 0.101, OR = 0.349, 95% CI: 0.099-1.228; CG+GG versus CC, P = 0.015 OR = 0.612, 95% CI: 0.411-0.910), but rs1718119 and rs3751143 were not associated with LN. Analysis of the haplotypes revealed one haplotype (ACA) that appeared to be a significantly 'protective' haplotype (P = 0.009, OR = 0.708, 95% CI: 0.546-0.918) with SLE. The findings suggest that the P2X7R gene might contribute to SLE susceptibility in the Chinese population. PMID- 23435014 TI - Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma. AB - Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify susceptibility factors to asbestos. PMID- 23435017 TI - Invited reviews: a new addition to Menopause. PMID- 23435018 TI - Risk of first-time heart disease higher for hormone therapy users with metabolic syndrome. PMID- 23435016 TI - Changing glucocorticoid action: 11beta-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. AB - Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Despite the identification of 11beta-HSD in liver in 1953 (which we now know to be 11beta HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11beta-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11beta-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11beta-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11beta-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11beta-HSD1 in inflammation. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23435019 TI - You are not what you weigh but what you think of it. PMID- 23435020 TI - Benefits and recently identified limitations of bazedoxifene acetate for postmenopausal symptoms. PMID- 23435015 TI - Steroidogenesis in the skin: implications for local immune functions. AB - The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Delta-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23435021 TI - Coronary heart disease events in the Women's Health Initiative hormone trials: effect modification by metabolic syndrome: a nested case-control study within the Women's Health Initiative randomized clinical trials. AB - OBJECTIVE: Our objective was to determine whether metabolic syndrome (MetS) or its components modified the effect of hormone therapy (HT) on the risk of coronary heart disease (CHD) events in the Women's Health Initiative clinical trials. METHODS: We performed a nested case-control study of incident CHD events during the first 4 years of follow-up in the Women's Health Initiative HT trials (estrogen plus progestin therapy [EPT] and estrogen therapy [ET]). There were 359 incident cases of CHD during follow-up. After the exclusion of women with cardiovascular disease (n = 90), diabetes, or hypertension at baseline (n = 103), 166 CHD cases were matched to 524 controls on age, randomization date, and hysterectomy status. MetS classification required at least three of five Adult Treatment Panel III criteria. Analyses by chi and t tests for heterogeneity and logistic regression were performed. Postmenopausal women (n = 27,347) aged 50 to 79 years from 40 US clinical centers participated. Daily conjugated equine estrogens (0.625 mg) and medroxyprogesterone acetate (2.5 mg; EPT) or conjugated equine estrogens (0.625 mg; ET) were compared with placebo. The main outcome measure was the odds for CHD with HT use versus placebo by MetS status. RESULTS: MetS modified the risk of CHD events with HT. In the pooled analysis, risk was increased with HT versus placebo in women with MetS (odds ratio, 2.26; 95% CI, 1.26-4.07), whereas women without MetS were not found to have an increased risk for a CHD event with HT (odds ratio, 0.97; 95% CI, 0.58-1.61; P for interaction = 0.03). Results of the EPT and ET trials, when examined separately, were similar. The constellation of MetS variables was more predictive of risk from HT than MetS components assessed individually. When women with diabetes or hypertension were included in the analysis, statistically significant effect modification was not detected. CONCLUSIONS: MetS at baseline in women without prior cardiovascular disease, diabetes, or hypertension at baseline identifies women who are more likely to have had adverse coronary outcomes on HT. CHD risk stratification is recommended before initiating HT. The basis for the greater risk of CHD events with HT among women with MetS requires further study. PMID- 23435022 TI - Relapse of vasomotor symptoms after discontinuation of the selective serotonin reuptake inhibitor escitalopram: results from the menopause strategies: finding lasting answers for symptoms and health research network. AB - OBJECTIVE: Vasomotor symptoms (VMS) recur after discontinuation of hormonal therapy. Selective serotonin reuptake inhibitors (SSRIs) are used increasingly to treat VMS, but whether VMS recur after cessation of SSRI is unknown. We hypothesized that relapse of VMS to baseline levels after SSRI cessation would be common and predicted by menopausal and psychological characteristics. METHODS: Recurrence of VMS (frequency, severity, and bother) was measured with daily diaries for 3 weeks after cessation of escitalopram, which was administered to perimenopausal/postmenopausal women with hot flashes and night sweats in an 8 week randomized, placebo-controlled trial. Blinding of staff and participants was maintained throughout. Relapse was defined as mean daily VMS frequency, severity, or bother 20% or less lower than pretreatment levels. RESULTS: Of 76, 57, and 51 women included in the analysis for VMS frequency, severity, and bother, 34.2%, 38.6%, and 37.3%, respectively, had relapse of VMS frequency, severity, and bother. In adjusted models, VMS frequency relapse was predicted by higher levels of pretreatment insomnia symptoms (P = 0.02) and a weaker response to escitalopram (P = 0.03). CONCLUSIONS: Among women whose VMS improved with escitalopram, approximately one third relapsed swiftly after discontinuation of the medication. Those with pretreatment insomnia and those with a weaker response to escitalopram may be at greatest risk for VMS relapse after treatment discontinuation. Women should be educated about the likelihood of VMS symptom relapse when they discontinue SSRIs after receiving benefits from short-term treatment. PMID- 23435023 TI - Racial differences in perception of healthy body weight in midlife women: results from the Do Stage Transitions Result in Detectable Effects study. AB - OBJECTIVE: Perception of healthy body weight may influence health behaviors, including physical activity level, nutritional habits, and health outcomes, and these perceptions may vary importantly by race. Midlife is a critical period for women that typically includes weight gain. We assessed the associations between perception of healthy body weight and body mass index (BMI) and whether they vary by race. METHODS: In the Do Stage Transitions Result in Detectable Effects study, BMI and perception of body weight (healthy, underweight, or overweight) were measured at baseline examination. Multinomial logistic regression models examined the associations, with race (white vs black) as moderator variable. RESULTS: Of 729 women enrolled, 689 women (95%; black, n = 145; white, n = 544) were included in these analyses. Even though the average BMI was higher for black women than for white women (33.1 vs 29.2 kg/m, respectively; P < 0.0001), black women were less likely to report that they weighed too much (relative risk ratio, 0.4; 95% CI, 0.2-0.9; P = 0.022) and more likely to think that they did not weigh enough (relative risk ratio, 14.2; 95% CI, 1.8-110; P = 0.011). CONCLUSIONS: Although black women, in general, face a greater threat of morbidity from weight-related chronic diseases, they are more likely to be accepting of their weight at higher BMIs relative to whites. Weight loss interventions and counseling about healthy body size may influence healthy behavior and reduce the risk of chronic diseases. PMID- 23435024 TI - Effects of bazedoxifene alone and with conjugated equine estrogens on coronary and peripheral artery atherosclerosis in postmenopausal monkeys. AB - OBJECTIVE: The objectives of this study were to evaluate the effects of bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, on coronary and peripheral artery atheroscleroses and to determine if it would antagonize the atheroprotective effects of conjugated equine estrogens (CEE) on a monkey model. METHODS: Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and randomized to receive no treatment or women's equivalent doses of BZA (20 mg/d), CEE (0.45 mg/d), or BZA + CEE. The experimental period lasted for 20 months (equivalent to approximately 5 y in humans) during which interim measures of cardiovascular risk factors were made. At the end of the experimental period, the extent and severity of coronary and iliac artery atheroscleroses were quantified. RESULTS: Body weight, adiposity, fasting glucose concentrations, and plasma lipid profiles were not different among treatment conditions. BZA had no adverse effects on the extent or severity of coronary or common iliac artery atherosclerosis when compared with no treatment. CEE, administered soon after inducing menopause, had robust atheroprotective effects on both the extent and the severity of iliac and coronary artery atheroscleroses. The addition of BZA to CEE treatment antagonized the atheroprotective effects of CEE. CONCLUSIONS: In this nonhuman primate trial, treatment with BZA alone, CEE alone, and combined BZA and CEE does not have significant effects on plasma lipid profiles. CEE markedly inhibits the progression and complications of both coronary and iliac artery atheroscleroses. BZA has no adverse effects on atherosclerosis but attenuates the atheroprotective effects of CEE. PMID- 23435025 TI - Increased long-term recreational physical activity is associated with older age at natural menopause among heavy smokers: the California Teachers Study. AB - OBJECTIVE: Although physical activity modulates the hypothalamic-pituitary ovarian axis, the few studies that have investigated whether physical activity is associated with age at natural menopause have yielded mixed results. We set out to determine whether physical activity is associated with the timing of natural menopause in a large cohort of California women overall and by smoking history. METHODS: We investigated the association between long-term physical activity (h/wk/y) and age at natural menopause among 97,945 women in the California Teachers Study. Multivariable Cox proportional hazards regression methods were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The impact of cigarette smoking (never smoker, former light smoker, former heavy smoker, current light smoker, and current heavy smoker) as an effect modifier was evaluated. RESULTS: In a multivariable model adjusted for body mass index at age 18 years, age at menarche, race/ethnicity, and age at first full-term pregnancy, increased physical activity was statistically significantly associated with older age at natural menopause (P(trend) = 0.005). Higher body mass index at age 18 years (P(trend) = 0.0003) and older age at menarche (P(trend) = 0.0003) were also associated with older age at natural menopause. Hispanic ethnicity (vs non Hispanic whites; HR, 1.17; 95% CI, 1.09-1.26), current smokers (vs never smokers; HR, 1.68; 95% CI, 1.60-1.75 for current light smokers; HR, 1.38; 95% CI, 1.33 1.44 for current heavy smokers), and older age at first full-term pregnancy (HR(>=29, 2+ full-term pregnancies) vs HR(<29, 2+ full-term pregnancies), 1.10; 95% CI, 1.06-1.14) were associated with earlier age at natural menopause. Upon stratification by smoking history, increased physical activity was statistically significantly associated with older age at natural menopause among heavy smokers only (HR(highest quartile) vs HR(lowest quartile), 0.88; 95% CI, 0.81-0.97; P(trend) = 0.02 for former heavy smokers; HR(highest quartile) vs HR(lowest quartile), 0.89; 95% CI, 0.80-0.99; P(trend) = 0.04 for current heavy smokers). CONCLUSIONS: Age at natural menopause is a complex trait; the determinants of age at natural menopause, including physical activity, may differ by smoking status. PMID- 23435026 TI - Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial. AB - OBJECTIVE: The use of estrogen and progesterone to manage vasomotor symptoms (ie, hot flashes and night sweats) has declined because of concerns about their risks, and there is an increased interest in alternate, effective, and low-risk treatments. This study reports the results of a randomized controlled trial of clinical hypnosis for treating vasomotor symptoms among postmenopausal women. METHODS: This is a randomized, single-blind, controlled, clinical trial involving 187 postmenopausal women reporting a minimum of seven hot flashes per day (or at least 50 hot flashes a week) at baseline between December 2008 and April 2012. Eligible participants received five weekly sessions of either clinical hypnosis or structured-attention control. Primary outcomes were hot flash frequency (subjectively and physiologically recorded) and hot flash score assessed by daily diaries on weeks 2 to 6 and week 12. Secondary outcomes included measures of hot flash-related daily interference, sleep quality, and treatment satisfaction. RESULTS: In a modified intent-to-treat analysis that included all randomized participants who provided data, reported subjective hot flash frequency from baseline to week 12 showed a mean reduction of 55.82 (74.16%) hot flashes for the clinical hypnosis intervention versus a mean reduction of 12.89 (17.13%) hot flashes for controls (P < 0.001; 95% CI, 36.15-49.67). The mean reduction in hot flash score was 18.83 (80.32%) for the clinical hypnosis intervention as compared with 3.53 (15.38%) for controls (P < 0.001; 95% CI, 12.60-17.54). At 12-week follow-up, the mean reduction in physiologically monitored hot flashes was 5.92 (56.86%) for clinical hypnosis and 0.88 (9.94%) for controls (P < 0.001; 95% CI, 2.00-5.46). Secondary outcomes were significantly improved compared with controls at 12-week follow-up: hot flash-related interference (P < 0.001; 95% CI, 2.74 4.02), sleep quality (P < 0.001; 95% CI, 3.65-5.84), and treatment satisfaction (P < 0.001; 95% CI, 7.79-8.59). CONCLUSIONS: Compared with structured-attention control, clinical hypnosis results in significant reductions in self-reported and physiologically measured hot flashes and hot flash scores in postmenopausal women. PMID- 23435027 TI - Brain blood flow and cardiovascular responses to hot flashes in postmenopausal women. AB - OBJECTIVE: This study tested two related hypotheses: (1) brain blood flow is reduced during postmenopausal hot flashes, and (2) the magnitude of this reduction in brain blood flow is greater during hot flashes when blood pressure is reduced. METHODS: Eleven healthy, normotensive postmenopausal women rested in a temperature-controlled laboratory (~ 25 degrees C) for approximately 120 minutes while waiting for a hot flash to occur. The onset of a hot flash was objectively identified by an abrupt increase in sternal sweat rate (capacitance hygrometry). Middle cerebral artery blood velocity (MCAv; transcranial Doppler) and mean arterial pressure (Finometer) were measured continuously. Each hot flash was divided into eight equal segments, and the segment with the largest reduction in MCAv and mean arterial pressure was identified for each hot flash. RESULTS: During experimental sessions, 25 hot flashes occurred (lasting a mean [SD] of 6.2 [2.8] min, with a mean frequency of 3 [1] hot flashes per participant). Seventy six percent of hot flashes were accompanied by a clear reduction (>5%) in brain blood flow. For all hot flashes, the mean maximal decrease in MCAv was 12% (9%) (7 [6] cm s). This value did not correlate with corresponding changes in mean arterial pressure (R = 0.36). CONCLUSIONS: These findings demonstrate that hot flashes are often accompanied by clear reductions in brain blood flow that do not correspond with short-term reductions in mean arterial blood pressure. PMID- 23435029 TI - Unique symptoms at midlife of women with osteoporosis and cardiovascular disease in Taiwan. AB - OBJECTIVE: This study compared symptoms at midlife, menopause attitudes, and depression among three groups of late peri- or postmenopausal women, namely, women with cardiovascular disease (CVD group), women with osteoporosis (Os group), and women in generally good health (Co group). METHODS: We used a cross sectional method. Participants were purposively sampled from a medical center and a residential community in southern Taiwan. A total of 500 women between 45 and 60 years of age participated in the study. Four measures were used: a demographics and health habits questionnaire, the Women's Health Initiative Symptom Scale, the Attitudes Towards Menopause Scale, and the Center for Epidemiological Studies-Depression Scale. RESULTS: Significant demographic differences among the groups were found in age, number of children, educational level, family income, employment status, exercise duration per session, smoking status, daily cigarette consumption, and number of years smoking. After significant covariates had been controlled for, the CVD group reported significantly more severe symptoms at midlife than did the Co group; significantly more severe "psychosomatic symptoms" than did the Co group; and significantly more severe "gastrointestinal symptoms and swelling" and "vasomotor symptoms" than did either the Os group or the Co group. The CVD group also reported significantly greater depressive symptoms than did the Os group. CONCLUSIONS: This study identified a number of differences in symptoms at midlife and depressive symptoms among the three groups. Results support the importance of providing unique care for peri- and postmenopausal women in different health categories. Findings may help healthcare professionals better appreciate the diversity of menopausal experiences and support the development of appropriate care strategies. PMID- 23435028 TI - Phytoestrogen and fiber intakes in relation to incident vasomotor symptoms: results from the Study of Women's Health Across the Nation. AB - OBJECTIVE: Although reduction of vasomotor symptoms (VMS; hot flashes and night sweats) has been reported in postmenopausal women who used isoflavones, a clear dose response has not been shown, has largely not been reported for perimenopausal women, and has largely only been reported for reducing prevalent VMS, not preventing newly developing VMS. We analyzed longitudinal data from the Study of Women's Health Across the Nation for the relation of dietary phytoestrogen and fiber intake to incident VMS in this multiracial/ethnic cohort. METHODS: The Study of Women's Health Across the Nation included 3,302 premenopausal and early perimenopausal women, 1,651 of whom reported no VMS at baseline and were followed with annual visits for 10 years. Dietary intakes of isoflavones, coumestrol, lignans, and fiber were assessed by a food frequency questionnaire at baseline and in annual visits 5 and 9 and interpolated for intervening years. The number of days experiencing VMS in the past 2 weeks was self-reported annually. Using multinomial logistic regression with generalized estimating equations, we modeled incident VMS in relation to isoflavones, lignans, fiber, coumestrol, or total phytoestrogen intake and covariates. RESULTS: No consistent monotonic relations were observed between any dietary phytoestrogen or fiber and incident VMS, although adjusted odds ratios for some individual quartiles were statistically significant. CONCLUSIONS: For certainty of any effect of dietary phytoestrogens or fiber on the prevention of incident VMS, a randomized, placebo-controlled, double-masked trial with sufficient numbers of women in different racial/ethnic, menopausal status, and metabolic groups over years of follow-up is required, but our results suggest that a clinically significant or large effect is improbable. PMID- 23435030 TI - Modulation of higher-primate adrenal androgen secretion with estrogen-alone or estrogen-plus-progesterone intervention. AB - OBJECTIVE: Circulating adrenal steroids rise during the menopausal transition in most middle-aged women and may contribute to differences in between-women symptoms and ultimate health outcomes. However, the mechanisms for this shift in adrenal steroid production in middle-aged women are not known. This study aims to determine whether hormone therapy (HT) for 1 year can modulate adrenal androgen production. METHODS: Younger (9.8 [0.4] years, n = 20) and older (22.7 [0.4] years, n = 37) female laboratory macaques were ovariectomized, and each group was treated with different regimens of HT for up to 1 year. Changes in adrenal histology and circulating adrenal androgens were monitored after estrogen-alone (E) or estrogen plus progesterone (E + P) treatment, and these changes were compared with the same measures in similarly aged animals given vehicle. RESULTS: Zona reticularis area, serum dehydroepiandrosterone (DHEA), and serum dehydroepiandrosterone sulfate (DHEAS) were higher in younger vehicle-treated animals compared with older vehicle-treated animals (P < 0.02). Both E and E + P treatments decreased circulating DHEAS in the younger group (P < 0.05). Although E treatment also decreased DHEAS in the older group, this was not statistically significant. In contrast, E + P treatment in the older group resulted in a rise in DHEAS over vehicle, which was significantly higher than the results of E treatment (P < 0.01). Circulating concentrations of DHEA exhibited similar trends, but these changes did not reach statistical significance. CONCLUSIONS: These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determine adrenal response. PMID- 23435031 TI - Dehydroepiandrosterone sulfate levels reflect endogenous luteinizing hormone production and response to human chorionic gonadotropin challenge in older female macaque (Macaca fascicularis). AB - OBJECTIVE: We propose that the adrenal gland of an older higher primate female animal model will respond to human chorionic gonadotropin (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically castrated animals will provide proof of concept and a validated animal model for future studies to explore the rise in DHEAS during the menopausal transition of women. METHODS: Twenty-four 18- to 26-year-old female cynomolgus monkeys were screened for ovarian function and then either ovariectomized (n = 4) or treated with a gonadotropin-releasing hormone agonist (GnRHa; n = 20) to block ovarian steroid production. After a recovery period from surgical procedure or down-regulation, a single-dose challenge (1,000 IU/animal, IM) of hCG was then administered to determine if luteinizing hormone (LH)/chorionic gonadotropin could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH, and urinary metabolites of ovarian sex steroids were monitored before, during, and after these treatments. RESULTS: Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days postadministration of GnRHa. Urinary metabolites of estradiol and progesterone remained low after the surgical procedure or a flare reaction to GnRHa. Circulating DHEAS levels were increased after hCG administration, and the increase in individual animals was proportional to the pretreatment DHEAS at baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to hCG challenge and were subsequently further elevated by the hCG challenge while no concomitant change in ovarian steroid hormone excretion was observed. CONCLUSIONS: These data demonstrate a positive adrenal androgen response to LH/chorionic gonadotropin in older female higher primates and suggest a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon. PMID- 23435032 TI - Hyaluronic acid concentration in postmenopausal facial skin after topical estradiol and genistein treatment: a double-blind, randomized clinical trial of efficacy. AB - OBJECTIVE: The aim of this work was to compare the effects of estradiol and genistein treatment on hyaluronic acid (HA) concentration in postmenopausal facial skin. METHODS: In this study, 30 postmenopausal women were evaluated in a prospective, randomized, double-blind trial. The volunteers were postmenopausal women treated in the Gynecology Department of the Federal University of Sao Paulo. The participants were divided into two groups: group E, treated with 0.01% 17beta-estradiol gel (n = 15), and group G, treated with 4% genistein gel (isoflavones, n = 15). The treatment lasted for 24 consecutive weeks. Preauricular skin biopsies were performed for each participant at baseline (E1 and G1) and after treatment (E2 and G2) to evaluate HA concentration in tissue. The materials were processed using immunohistochemical and biochemical methods. RESULTS: After 24 weeks of treatment, HA concentration increased in both groups, but the effect was greater for estradiol treatment than for genistein treatment. CONCLUSIONS: Our data suggest that both treatments may enhance HA concentration in postmenopausal skin but that estrogen produces results that are greater than those produced by isoflavones. PMID- 23435033 TI - Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future. AB - OBJECTIVE: This work aims to review preclinical/clinical cardiovascular studies that led to randomized trials of the risks and benefits of postmenopausal hormone therapy (HT), the pathobiological basis for the timing hypothesis, and subset analyses of randomized trials that tend to support the timing hypothesis; to elaborate experimental data that might inform the results of recent trials; and to summarize evidence regarding how early is early enough for the initiation of HT. METHODS: This work used interpretive literature review. RESULTS: Preclinical and large observational studies provided what was considered at the time to be convincing evidence that HT provided protection against progressing coronary artery atherosclerosis. Those findings prompted three randomized, placebo controlled, prospective trials to determine the risks and benefits of HT. None provided any evidence that HT had any beneficial effects on preexisting coronary artery atherosclerosis. Monkey studies provided clear evidence that HT was effective in slowing the progression of coronary artery atherosclerosis only when administered soon after surgical menopause and that benefit was lost if estrogen therapy was delayed until the plaques had become complicated. The phenomenon was referred to as the "timing hypothesis," and evidence for its translation into postmenopausal women was sought in subset analyses of data from the Women's Health Initiative and from newly planned prospective trials. CONCLUSIONS: Current data are both supportive and not supportive of the timing hypothesis. However, evidence indicating that estrogens administered in the perimenopausal transition or early in menopause are not harmful to the cardiovascular system and, when given for a few years for the treatment of menopausal symptoms, may slow the progression of atherosclerosis and reduce the postmenopausal cardiovascular disease burden seems convincing. PMID- 23435035 TI - Letters to the editor. PMID- 23435034 TI - Breast cancer susceptibility associated with rs1219648 (fibroblast growth factor receptor 2) and postmenopausal hormone therapy use in a population-based United States study. AB - OBJECTIVE: Genomewide association studies have consistently found variants in fibroblast growth factor receptor 2 (FGFR2) to be associated with breast cancer. Recent reports suggest that postmenopausal hormone therapy (HT) use may modify the association between single nucleotide polymorphisms (SNPs) in FGFR2 and breast cancer risk. We assessed the hypothesis that the association between rs1219648 (FGFR2) SNP and breast cancer risk is modified by postmenopausal HT use in a population-based case-control study. METHODS: We evaluated rs1219648 SNP for an association with breast cancer risk using data obtained from 869 postmenopausal breast cancer cases diagnosed between 1995 and 2000 and from 808 postmenopausal community controls who participated in a study conducted in three US states. Detailed postmenopausal HT information was collected through a structured telephone interview, and DNA samples were collected by mail using an established mouthwash protocol. Odds ratios and 95% confidence intervals (CIs) were calculated using logistic regression models adjusted for age and state of residence. RESULTS: We observed a significant association between rs1219648 and breast cancer risk (per-allele odds ratio, 1.22; 95% CI, 1.06-1.41; P = 0.007), which did not vary significantly by ever use of estrogen plus progestogen therapy (interaction P = 0.48). There was stronger evidence of an interaction between ever use of estrogen-only HT and increasing number of rs1219648 risk alleles to increase breast cancer risk (interaction P = 0.08). CONCLUSIONS: Our results are consistent with a risk association with FGFR2 but provide limited support for interaction with HT use. The study raises the possibility that the FGFR2 rs1219648 variant is more strongly associated with risk in estrogen-only hormone users, although this observation needs to be examined in larger studies. PMID- 23435036 TI - Letters to the editor. PMID- 23435037 TI - Letters to the editor. PMID- 23435038 TI - Letters to the editor. PMID- 23435039 TI - What a jerk: perils in the assessment of psychogenic movement disorders. PMID- 23435040 TI - Targeted therapy in thyroid cancer. AB - PURPOSE OF REVIEW: Recent advances in the understanding of the biological basis for thyroid cancer have identified molecular changes in thyroid cancer cells. These changes form the basis for targeted therapies, which have been investigated with some success in patients with advanced, inoperable thyroid cancers and are the subject of this review. RECENT FINDINGS: For patients with advanced differentiated thyroid cancers, sorafenib, selumetinib, pazopanib and sunitinib have been investigated with promising results. In the setting of advanced medullary thyroid cancer, vandetanib now has FDA approval, whereas sorafenib, sunitinib and cabozantinib have shown activity in early studies. For patients with anaplastic thyroid cancer, no targeted therapy has been proven to be effective in vivo, although preclinical work on various kinase inhibitors has shown promise. Despite the potential for disease response, significant cardiac, gastrointestinal and skin-related side effects are reported for all therapies, limiting their application outside the setting of incurable disease. SUMMARY: Inoperable thyroid cancer still has a poor prognosis, however, the introduction of targeted therapies offers the hope of longer quality of meaningful life for this small group of patients. PMID- 23435041 TI - Iodine and thiocyanate in goiter - house of bamboo. PMID- 23435043 TI - Introduction to the recombinant human TSH (rhTSH) symposium articles. PMID- 23435042 TI - The clinical approach to the detection of lipodystrophy - an AACE consensus statement. PMID- 23435044 TI - The role of recombinant human thyrotropin for diagnostic monitoring of patients with differentiated thyroid cancer. AB - OBJECTIVE: To describe the evolving role of recombinant human thyrotropin in the diagnostic evaluation of patients treated for differentiated thyroid carcinoma. METHODS: A systematic review was performed of published English language articles appearing in PubMed using terms "recombinant thyrotropin" and "thyroid cancer". The author selected articles for inclusion based upon potential for clinical impact of the reported findings. RESULTS: The addition of recombinant human thyrotropin to diagnostic testing replaced the requirement for thyroid hormone withdrawal and symptomatic hypothyroidism that had been necessary to generate sufficient endogenous thyrotropin for radioiodine scanning and thyroglobulin testing. The high negative predictive value of stimulated thyroglobulin testing removed the need for serial radioiodine scanning for many patients, but repeated stimulated testing rarely appeared to add significantly. The development of highly sensitive second generation thyroglobulin assays may replace the need for stimulated testing in a subset of patients. CONCLUSION: Recombinant human thyrotropin-stimulated testing continues to be a valuable component of follow-up testing in the first year after initial treatment of differentiated thyroid cancer. PMID- 23435045 TI - Unusual problems in the management of hyperthyroid Graves' disease. PMID- 23435046 TI - "What if" being overweight was good for you? PMID- 23435049 TI - Frequency noise properties of lasers for interferometry in nanometrology. AB - In this contribution we focus on laser frequency noise properties and their influence on the interferometric displacement measurements. A setup for measurement of laser frequency noise is proposed and tested together with simultaneous measurement of fluctuations in displacement in the Michelson interferometer. Several laser sources, including traditional He-Ne and solid state lasers, and their noise properties are evaluated and compared. The contribution of the laser frequency noise to the displacement measurement is discussed in the context of other sources of uncertainty associated with the interferometric setup, such as, mechanics, resolution of analog-to-digital conversion, frequency bandwidth of the detection chain, and variations of the refractive index of air. PMID- 23435050 TI - Architecture for multi-technology real-time location systems. AB - The rising popularity of location-based services has prompted considerable research in the field of indoor location systems. Since there is no single technology to support these systems, it is necessary to consider the fusion of the information coming from heterogeneous sensors. This paper presents a software architecture designed for a hybrid location system where we can merge information from multiple sensor technologies. The architecture was designed to be used by different kinds of actors independently and with mutual transparency: hardware administrators, algorithm developers and user applications. The paper presents the architecture design, work-flow, case study examples and some results to show how different technologies can be exploited to obtain a good estimation of a target position. PMID- 23435051 TI - Investigations on a novel inductive concept frequency technique for the grading of oil palm fresh fruit bunches. AB - From the Malaysian harvester's perspective, the determination of the ripeness of the oil palm (FFB) is a critical factor to maximize palm oil production. A preliminary study of a novel oil palm fruit sensor to detect the maturity of oil palm fruit bunches is presented. To optimize the functionality of the sensor, the frequency characteristics of air coils of various diameters are investigated to determine their inductance and resonant characteristics. Sixteen samples from two categories, namely ripe oil palm fruitlets and unripe oil palm fruitlets, are tested from 100 Hz up to 100 MHz frequency. The results showed the inductance and resonant characteristics of the air coil sensors display significant changes among the samples of each category. The investigations on the frequency characteristics of the sensor air coils are studied to observe the effect of variations in the coil diameter. The effect of coil diameter yields a significant 0.02643 MHz difference between unripe samples to air and 0.01084 MHz for ripe samples to air. The designed sensor exhibits significant potential in determining the maturity of oil palm fruits. PMID- 23435052 TI - Label-free potentiometry for detecting DNA hybridization using peptide nucleic acid and DNA probes. AB - Peptide nucleic acid (PNA) has outstanding affinity over DNA for complementary nucleic acid sequences by forming a PNA-DNA heterodimer upon hybridization via Watson-Crick base-pairing. To verify whether PNA probes on an electrode surface enhance sensitivity for potentiometric DNA detection or not, we conducted a comparative study on the hybridization of PNA and DNA probes on the surface of a 10-channel gold electrodes microarray. Changes in the charge density as a result of hybridization at the solution/electrode interface on the self-assembled monolayer (SAM)-formed microelectrodes were directly transformed into potentiometric signals using a high input impedance electrometer. The charge readout allows label-free, reagent-less, and multi-parallel detection of target oligonucleotides without any optical assistance. The differences in the probe lengths between 15- to 22-mer dramatically influenced on the sensitivity of the PNA and DNA sensors. Molecular type of the capturing probe did not affect the degree of potential shift. Theoretical model for charged rod-like duplex using the Gouy-Chapman equation indicates the dominant effect of electrostatic attractive forces between anionic DNA and underlying electrode at the electrolyte/electrode interface in the potentiometry. PMID- 23435053 TI - Rapid characterization of vegetation structure with a Microsoft Kinect sensor. AB - The importance of vegetation structure and biomass in controlling land-atmosphere exchange is widely recognized, but measurements of canopy structure are challenging, time consuming, and often rely on destructive methods. The Microsoft Kinect is an infrared sensor designed for video gaming that outputs synchronized color and depth images and that has the potential to allow rapid characterization of vegetation structure. We compared depth images from a Kinect sensor with manual measurements of plant structure and size for two species growing in a California grassland. The depth images agreed well with the horizontal and vertical measurements of plant size made manually. Similarly, the plant volumes calculated with a three-dimensional convex hulls approach was well related to plant biomass. The Kinect showed some limitations for ecological observation associated with a short measurement range and daytime light contamination. Nonetheless, the Kinect's light weight, fast acquisition time, low power requirement, and cost make it a promising tool for rapid field surveys of canopy structure, especially in small-statured vegetation. PMID- 23435054 TI - An infrastructureless approach to estimate vehicular density in urban environments. AB - In Vehicular Networks, communication success usually depends on the density of vehicles, since a higher density allows having shorter and more reliable wireless links. Thus, knowing the density of vehicles in a vehicular communications environment is important, as better opportunities for wireless communication can show up. However, vehicle density is highly variable in time and space. This paper deals with the importance of predicting the density of vehicles in vehicular environments to take decisions for enhancing the dissemination of warning messages between vehicles. We propose a novel mechanism to estimate the vehicular density in urban environments. Our mechanism uses as input parameters the number of beacons received per vehicle, and the topological characteristics of the environment where the vehicles are located. Simulation results indicate that, unlike previous proposals solely based on the number of beacons received, our approach is able to accurately estimate the vehicular density, and therefore it could support more efficient dissemination protocols for vehicular environments, as well as improve previously proposed schemes. PMID- 23435055 TI - Fusion of building information and range imaging for autonomous location estimation in indoor environments. AB - We present a novel approach for autonomous location estimation and navigation in indoor environments using range images and prior scene knowledge from a GIS database (CityGML). What makes this task challenging is the arbitrary relative spatial relation between GIS and Time-of-Flight (ToF) range camera further complicated by a markerless configuration. We propose to estimate the camera's pose solely based on matching of GIS objects and their detected location in image sequences. We develop a coarse-to-fine matching strategy that is able to match point clouds without any initial parameters. Experiments with a state-of-the-art ToF point cloud show that our proposed method delivers an absolute camera position with decimeter accuracy, which is sufficient for many real-world applications (e.g., collision avoidance). PMID- 23435056 TI - An incremental target-adapted strategy for active geometric calibration of projector-camera systems. AB - The calibration of a projector-camera system is an essential step toward accurate 3-D measurement and environment-aware data projection applications, such as augmented reality. In this paper we present a two-stage easy-to-deploy strategy for robust calibration of both intrinsic and extrinsic parameters of a projector. Two key components of the system are the automatic generation of projected light patterns and the incremental calibration process. Based on the incremental strategy, the calibration process first establishes a set of initial parameters, and then it upgrades these parameters incrementally using the projection and captured images of dynamically-generated calibration patterns. The scene-driven light patterns allow the system to adapt itself to the pose of the calibration target, such that the difficulty in feature detection is greatly lowered. The strategy forms a closed-loop system that performs self-correction as more and more observations become available. Compared to the conventional method, which requires a time-consuming process for the acquisition of dense pixel correspondences, the proposed method deploys a homography-based coordinate computation, allowing the calibration time to be dramatically reduced. The experimental results indicate that an improvement of 70% in reprojection errors is achievable and 95% of the calibration time can be saved. PMID- 23435057 TI - A unified framework for activity recognition-based behavior analysis and action prediction in smart homes. AB - In recent years, activity recognition in smart homes is an active research area due to its applicability in many applications, such as assistive living and healthcare. Besides activity recognition, the information collected from smart homes has great potential for other application domains like lifestyle analysis, security and surveillance, and interaction monitoring. Therefore, discovery of users common behaviors and prediction of future actions from past behaviors become an important step towards allowing an environment to provide personalized service. In this paper, we develop a unified framework for activity recognition based behavior analysis and action prediction. For this purpose, first we propose kernel fusion method for accurate activity recognition and then identify the significant sequential behaviors of inhabitants from recognized activities of their daily routines. Moreover, behaviors patterns are further utilized to predict the future actions from past activities. To evaluate the proposed framework, we performed experiments on two real datasets. The results show a remarkable improvement of 13.82% in the accuracy on average of recognized activities along with the extraction of significant behavioral patterns and precise activity predictions with 6.76% increase in F-measure. All this collectively help in understanding the users" actions to gain knowledge about their habits and preferences. PMID- 23435058 TI - A proteomic portrait of atherosclerosis. AB - We have arranged in this review the main evidence about proteome alterations in different cell and body fluid compartments along the progression of atherosclerosis. With time the description of the molecular phenomena is becoming more and more detailed yet the complex interrelationships among different factors are still elusive and previously neglected aspects (such as size for lipoprotein particles) emerge as not less relevant than the absolute abundance of individual proteins. Physiological limits to the kinetics of protein distribution through the biological fluids seem to hinder the early diagnosis of acute conditions through plasma analysis but suggest urine analysis as a workable alternative for the assessment of chronic conditions. The survey of literature data is complemented with a few unpublished results from our laboratories, featuring 2DE maps of the proteins extracted from human thrombi. PMID- 23435059 TI - A proteomic investigation of apple fruit during ripening and in response to ethylene treatment. AB - A proteomic approach employing a two dimensional electrophoresis (2-DE) technique with SYPRO Ruby, a fluorescent stain with improved sensitivity and quantitative accuracy, was performed to separate the total proteins from apple fruit at different stages of ripening and senescence. After imaging and statistical analyses were performed on 2340 spots, a total of 316 spots, or approximately 13.5% of the total protein population, was found to be significantly changed in this study. Of the 316 proteins, 219 spots were only present at a specific ripening stage, while 97 spots were significantly different (p<0.05) throughout fruit ripening and in response to ethylene treatment. From 316 candidate spots, 221 proteins were further identified by liquid chromatography and mass spectrometry analysis with protein sequence and express sequence tag (EST) data searching. Analysis and identification of proteins revealed that apple fruit ripening is associated with increase of abundance of many proteins with functions such as ethylene production, antioxidation and redox, carbohydrate metabolism, oxidative stress, energy, and defense response. Ethylene treatment increased a group of unique proteins that were not present during normal fruit ripening and have not been previously reported. It also reduced some proteins involved in primary metabolism, including those of the last few steps of the glycolytic pathway. This study demonstrated the complexity and dynamic changes of protein profiles of apple fruit during ripening and in response to exogenous ethylene treatment. Identifying and tracking protein changes may allow us to better understand the mechanism of ripening in climacteric fruit. BIOLOGICAL SIGNIFICANCE: Postharvest physiology and biochemistry has been conducted on apple fruit for many years. Ethylene plays an important role in ripening and senescence in many climacteric fruit. However, little information is available at the proteome level to investigate fruit ripening and effect of ethylene treatment. The significance of this paper is that it is the first study employing 2-DE and fluorescent dye in the investigation of the apple fruit ripening and influence of ethylene treatment. It reveals some significant biological changes in association with these events and demonstrates significant changed proteins under these conditions. Therefore, our study links the biological events with proteomic information and provides detailed peptide information on all identified proteins. Through the function analysis, those significantly changed proteins are also analyzed. These findings from this paper provide not only proteome information on fruit ripening, but also pave the ground for further quantitative studies using SMR to investigate certain proteins and pathways under the hypothesis involved in fruit ripening. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23435060 TI - Spatial and temporal trends of persistent organic pollutants and mercury in beluga whales (Delphinapterus leucas) from Alaska. AB - Remote locations, such as the Arctic, are often sinks for persistent contaminants which can ultimately bioaccumulate in local wildlife. Assessing temporal contaminant trends in the Arctic is important in understanding whether restrictions on legacy persistent organic pollutants (POPs) have led to concentration declines. Beluga whale (Delphinapterus leucas) tissue samples were collected from two subpopulations (Cook Inlet, Alaska and the eastern Chukchi Sea) between 1989 and 2006. Several POPs (polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethane and related compounds (DDTs), chlordanes, hexachlorocyclohexanes (HCHs), chlorobenzenes, mirex, polybrominated diphenyl ethers (PBDEs) and semi-quantitatively hexabromocyclododecanes (HBCDs)) were measured in 70 blubber samples, and total mercury (Hg) was measured in 67 liver samples from a similar set of individuals. Legacy POPs (PCBs, chlordanes, DDTs, and HCHs) were the predominant organic compound classes in both subpopulations, with median concentrations of 2360ng/g lipid for Sigma80PCBs and 1890 ng/g lipid for Sigma6DDTs. Backward stepwise multiple regressions showed that at least one of the four independent variables (subpopulation, sampling year, sex, and animal length) influenced the POP and Hg concentrations. SigmaPCBs, SigmaDDTs, Sigmachlordanes, Sigmachlorobenzenes, mirex, and Hg were significantly higher in belugas from the eastern Chukchi Sea than from the Cook Inlet (p<=0.0001). In contrast, Sigma8PBDE and alpha-HBCD concentrations were significantly lower in belugas from the eastern Chukchi Sea than from the Cook Inlet (p<0.0001). Significant temporal increases in concentrations of Sigma8PBDE and alpha-HBCD were observed for both subpopulations (p<=0.0003), and temporal declines were seen for SigmaHCHs and Sigmachlorobenzenes in eastern Chukchi Sea belugas only (p<=0.0107). All other POP and Hg concentrations were stable, indicating either a lagging response of the Arctic to source reductions or the maintenance of concentrations by unregulated sources. Sex and length also significantly influenced some concentrations, and these findings are discussed. PMID- 23435061 TI - Effects of organic fractions on the formation and control of N-nitrosamine precursors during conventional drinking water treatment processes. AB - Knowledge of N-nitrosamine precursors from dissolved organic matter (DOM) is important for water professionals to better control N-nitrosamine formation. The characterization of DOM from the Luan River in Northern China was conducted using Amberlite XAD resins and ultra-filtration methods. N-nitrosamine formation potentials were investigated for various DOM fractions. The removal of the DOM during water treatment were evaluated using dissolved organic carbon (DOC) and ultraviolet absorbance at 254 nm (UV254) bulk parameters as well as size exclusion chromatography and fluorescence spectroscopy. The results indicated that the XAD-4 hydrophilic fraction, with normalized yields of N nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR), N-nitrosomorpholine (NMOR), and N-nitrosopiperidine (NPIP) of 27.2, 5.2, 5.9, and 6.1 ng/mg-DOC, respectively, tended to form more N-nitrosamines than the hydrophobic and the transphilic fractions. The DOM fraction with a molecular weight (MW) below 1 kDa, with normalized yields of NDMA, NPYR, NMOR, and NPIP of 39.6, 8.1, 14.7, and 3.3 ng/mg-DOC, respectively, tended to form more N-nitrosamines than those with a higher MW. The limited removal of the hydrophilic fraction and the lower MW DOM faction during conventional water treatment processes suggests that the process may not effectively remove the nitrosamine precursors. PMID- 23435062 TI - Association between PON1 genetic polymorphisms and miscarriage in Mexican women exposed to pesticides. AB - BACKGROUND: Placental oxidative stress has been involved in the pathogenesis of certain reproductive adverse effects, including miscarriage. Paraxonase 1 (PON1) is a high-density lipoprotein(HDL)-linked enzyme that prevents oxidation of low density lipoproteins (LDL) and is involved in detoxification from organophosphate pesticides. OBJECTIVE: To assess the association between maternal PON1 polymorphisms (PON1192Q/R, PON155 L/M y PON1-108C/T) and the risk of miscarriage in women chronically exposed to organophosphate pesticides in Mexico. METHODS: In a cross-sectional study, socio-demographic data, reproductive history data, environmental exposures, and other variables of concern were collected by means of a questionnaire from 264 women (floriculturists and wives of floriculturists) who had been pregnant sometime during the 10 years preceding the study. Blood samples were also collected from them. PON1192 and PON155 genotypes were determined by PCR amplification, and PON1-108 genotypes, by a TaqMan real-time polymerase chain reaction assay. Complete information regarding the results of pregnancy and maternal genotype tests was obtained for 514 pregnancies (35 miscarriages and 479 controls). The association between PON1 genotypes and miscarriage was evaluate through GEE models. RESULTS: The risk of miscarriage by mothers with PON1192RR genotype was 2.2 higher than by mothers with PON1192QR/PON1192QQ genotype (95% CI 0.93-5.17). The risk was close to 4 times higher in mothers with PON155MM/PON155LM genotype than in mothers with PON155LL genotype (OR=3.9; 95% CI 1.38-11.0). No significant differences were found in risk of miscarriage based on the maternal PON1-108C/T genotype. No evidence was found of an interaction between the various PON1 genotypes and the mothers' floricultural activity during pregnancy. CONCLUSIONS: This study suggests that there is an effect of genetic maternal PON1 polymorphisms on miscarriage and provides additional evidence that combines with the growing information about the ways in which certain PON1 genotypes can affect the development of the fetus in utero. PMID- 23435063 TI - Roads in northern hardwood forests affect adjacent plant communities and soil chemistry in proportion to the maintained roadside area. AB - The spatial extent of the transported materials from three road types was studied in forest soil and vegetative communities in Vermont. Hypotheses were two-fold: 1) soil chemical concentrations above background environment would reflect traffic volume and road type (highway>2-lane paved>gravel), and 2) plant communities close to the road and near roads with greater traffic will be disturbance-tolerant and adept at colonization. Soil samples were gathered from 12 randomly identified transects for each of three road types classified as "highway," "two-lane paved," and "gravel." Using GIS mapping, transects were constructed perpendicular to the road, and samples were gathered at the shoulder, ditch, backslope, 10 m from the edge of the forest, and 50 m from road center. Sample locations were analyzed for a suite of soil elements and parameters, as well as percent area coverage by plant species. The main effects from roads depended on the construction modifications required for a roadway (i.e., vegetation clearing and topography modification). The cleared area defined the type of plant community and the distance that road pollutants travel. Secondarily, road presence affected soil chemistry. Metal concentrations (e.g., Pb, Cd, Cu, and Zn) correlated positively with road type. Proximity to all road types made the soils more alkaline (pH 7.7) relative to the acidic soil of the adjacent native forest (pH 5.6). Roadside microtopography had marked effects on the composition of plant communities based on the direction of water flow. Ditch areas supported wetland plant species, greater soil moisture and sulfur content, while plant communities closer to the road were characteristic of drier upland zones. The area beyond the edge of the forest did not appear to be affected chemically or physically by any of the road types, possibly due to the dense vegetation that typically develops outside of the managed right-of-way. PMID- 23435064 TI - Change of PAHs with evolution of paddy soils from prehistoric to present over the last six millennia in the Yangtze River Delta region, China. AB - To evaluate the influence of hydroponics management on soil organic components with evolution of paddy soil over the last six millennia, PAHs, as a biomarker, as well as total organic carbon content were used to explore changes of paddy soil organic carbon in two entirely buried ancient paddy soil profiles. The results showed that hydroponics management can cause organic carbon deposition in rice paddy. The changing of total PAH concentrations was not always in accordance with the changing of total organic carbon contents in layers of the buried ancient paddy soils. The PAHs in 6280 BP prehistoric paddy soil layer was 3 ring>5-ring>4-ring>6-ring, while in layers of the present paddy soil and the prehistoric upland were 3-ring>4-ring>5-ring>6-ring. The contribution of phenanthrene to total PAHs in two profiles and the increasing ratio of phenanthrene to alkylated PAHs from parent material/6280 BP prehistoric upland to 6280 BP paddy suggested substantial increase of the anthropogenic influence of hydroponics management on rice paddy soil. And in view of the (14)C age and bioremains in the two profiles, it was only possible for PAHs to be derived from hydroponics management with evolution of the paddy soils form the Neolithic age. Cadalene could be used as an indicator for biological sources of PAHs released by rice plant residues, and benzo[g,h,i]fluoranthene and benzo[g,h,i]perylene for pyrogenic sources released by field vegetation fires. PMID- 23435065 TI - Individual breast milk consumption and exposure to PCBs and PCDD/Fs in Hungarian infants: a time-course analysis of the first three months of lactation. AB - Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are persistent, bioaccumulative and toxic chemicals. These compounds are transferred to breast milk, therefore breastfed infants are at risk of being exposed to considerable amounts of PCBs and PCDD/Fs during this sensitive age. In the present study individual breast milk samples were collected at three time points (days 5, 12 and 84 postpartum) from 22 mothers who delivered their infants during 2007 in Baranya County, Hungary. Breast milk samples were analyzed for 17 PCDD/Fs, 12 dioxin-like (DL) PCBs and 7 non-dioxin-like (NDL) PCBs using high-resolution gas chromatography/high resolution mass spectrometry. Each infant's daily breast milk consumptions have been measured biweekly over three months. The concentration of several PCB and PCDD congeners in breast milk decreased significantly during lactation, with a main decline between days 5 and 12. The total toxic equivalent (TEQ) concentrations, derived from PCDD/Fs and DL-PCBs, were 3.17+/-1.72, 2.70+/-1.57 and 2.41+/-1.47 pg TEQ/g fat at the three time points, respectively. The corresponding NDL-PCB concentrations were 33.5+/-29.2, 27.4+/-20.6 and 26.9+/ 24.8 ng/g fat, respectively. The results highlight the importance of timing of breast milk sampling for consistent exposure assessment estimation. Levels of pollutants in Hungarian breast milk samples were at the lower concentration range when data from Europe are considered. This is the first study in Hungary where each infant's daily intakes of PCBs and PCDD/Fs via breast milk have been measured. The daily intakes of PCDD/Fs and DL-PCBs via breastfeeding per kg body weight were 11.79+/-6.42, 16.54+/-13.02 and 11.59+/-7.70 pg TEQ/kg bw on days 5, 12 and 84, respectively. The exposure was the highest on day 12 but at all three time points each infants' daily exposure to PCDD/Fs and DL-PCBs via breastfeeding exceeded the tolerable daily intake (TDI) of 2 pg TEQ/kg bw per day. These levels are still lower than corresponding levels recently measured in many European countries. Whether the milk-derived POP exposure levels of infants reported here constitute any health risk that may manifest later in life awaits further scrutiny. PMID- 23435066 TI - An approach for quantitative analysis of vitamins D and B9 and their metabolites in human biofluids by on-line orthogonal sample preparation and sequential mass spectrometry detection. AB - An approach for quantitative analysis of two vitamins with different polarities (vitamins D and B9) and their metabolites is presented here. The approach is based on an experimental setup based on hyphenation of an automated workstation for preparation of liquid samples and an LC-MS/MS system with a triple quadrupole mass spectrometer. This configuration enabled development of an orthogonal protocol for sequential SPE retention of analytes with different polarities for subsequent elution and chromatographic separation prior to detection. The resulting method was validated by application to three human biofluids. Estimation of recovery factors in the SPE step led to values from 85.2 to 100% for vitamin D and metabolites and from 93.1 to 100% for vitamin B9 and metabolites (folic acid and folates). The influence of sample matrix variability by analysis of human serum, urine and breast milk was minimized with a complete optimization of the SPE step. The utility of the proposed configuration is shown by the sensitivity and precision of the method, expressed as limits of detection (between 0.2 and 0.30 ng mL(-1) or 4 and 60 pg on-column) and within-laboratory reproducibility (lower than 6.7%, as relative standard deviation). The present application represents an example of determination methods involving targeted analysis of compounds with different polarities using a single aliquot of the sample. PMID- 23435067 TI - Measuring guide-tree dependency of inferred gaps in progressive aligners. AB - MOTIVATION: Multiple sequence alignments are generally reconstructed using a progressive approach that follows a guide-tree. During this process, gaps are introduced at a cost to maximize residue pairing, but it is unclear whether inferred gaps reflect actual past events of sequence insertions or deletions. It has been found that patterns of inferred gaps in alignments contain information towards the true phylogeny, but it is as yet unknown whether gaps are simply reflecting information that was already present in the guide-tree. RESULTS: We here develop a framework to disentangle the phylogenetic signal carried by gaps from that which is already present in the guide-tree. Our results indicate that most gaps are incorrectly inserted in patterns that, nevertheless, follow the guide-tree. Thus, most gap patterns in current alignments are not informative per se. This affects different programs to various degrees, PRANK being the most sensitive to the guide-tree. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23435068 TI - Genetic Simulation Resources: a website for the registration and discovery of genetic data simulators. AB - SUMMARY: Many simulation methods and programs have been developed to simulate genetic data of the human genome. These data have been widely used, for example, to predict properties of populations retrospectively or prospectively according to mathematically intractable genetic models, and to assist the validation, statistical inference and power analysis of a variety of statistical models. However, owing to the differences in type of genetic data of interest, simulation methods, evolutionary features, input and output formats, terminologies and assumptions for different applications, choosing the right tool for a particular study can be a resource-intensive process that usually involves searching, downloading and testing many different simulation programs. Genetic Simulation Resources (GSR) is a website provided by the National Cancer Institute (NCI) that aims to help researchers compare and choose the appropriate simulation tools for their studies. This website allows authors of simulation software to register their applications and describe them with well-defined attributes, thus allowing site users to search and compare simulators according to specified features. AVAILABILITY: http://popmodels.cancercontrol.cancer.gov/gsr. PMID- 23435069 TI - BioJS: an open source JavaScript framework for biological data visualization. AB - SUMMARY: BioJS is an open-source project whose main objective is the visualization of biological data in JavaScript. BioJS provides an easy-to-use consistent framework for bioinformatics application programmers. It follows a community-driven standard specification that includes a collection of components purposely designed to require a very simple configuration and installation. In addition to the programming framework, BioJS provides a centralized repository of components available for reutilization by the bioinformatics community. AVAILABILITY AND IMPLEMENTATION: http://code.google.com/p/biojs/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23435070 TI - Improvements on bicriteria pairwise sequence alignment: algorithms and applications. AB - MOTIVATION: In this article, we consider the bicriteria pairwise sequence alignment problem and propose extensions of dynamic programming algorithms for several problem variants with a novel pruning technique that efficiently reduces the number of states to be processed. Moreover, we present a method for the construction of phylogenetic trees based on this bicriteria framework. Two exemplary cases are discussed. RESULTS: Numerical results on a real dataset show that this approach is very fast in practice. The pruning technique saves up to 90% in memory usage and 80% in CPU time. Based on this method, phylogenetic trees are constructed from real-life data. In addition of providing complementary information, some of these trees match those obtained by the Maximum Likelihood method. AVAILABILITY AND IMPLEMENTATION: Source code is freely available for download at URL http://eden.dei.uc.pt/paquete/MOSAL, implemented in C and supported on Linux, MAC OS and MS Windows. PMID- 23435071 TI - [Epidemiological trends 1992-2007 in a neonatal intensive care unit]. AB - INTRODUCTION: progressive advances in neonatal care are expected to change the epidemiological profile of patients and conditions seen in neonatal intensive care units (NICU). Thus, the objective of this study was to identify such changes in a NICU in Mexico City. METHODS: retrospectively, we analyzed age, gender, weight at admission, hospital stay,diagnoses at discharge and cause of death in 5,192 patients admitted from 1992-2007. RESULTS: in the study period,patients were admitted at a progressively older age (median of 3 days old in 1992 to 9 in 2007; rS = 0.87) and lower weight (2,800-2,343 g; rS = -0.56), while length of hospital stay was stable (approximately, 9 days). Over 90% patients had cardiological, digestive and/or pulmonary diseases, and most patients (71.4%) had conditions for which a surgical approach is the usual treatment. Cardiological and neurologic problems increased (rS = 0.86 and 0.85, respectively),while pulmonary diseases decreased (rS = -0.79). Mortality and autopsy rate diminished from 26 to 15% (rS = -0.80),and from 32.5 to 10.7% (rS = -0.53), respectively. Conditions more frequently associated with death were urologic/nephrologic and infectious diseases. CONCLUSION: epidemiological patterns in our NICU are clearly changing, and thus searching for similar time trends in other NICU is warranted. PMID- 23435072 TI - [Knowledge about herpes simplex virus type 2 and human papillomavirus, and risk perception to acquire infections among college students]. AB - INTRODUCTION: herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) are the most frequent sexually transmitted infections (STI) among college students 18-24 years old. Educational interventions for STI prevention can help to decrease viral STI prevalence among students. OBJECTIVE: to know the change in knowledge, perception of risk and sexual behavior among 182 students of the Autonomous University of the State of Morelos. MATERIAL AND METHOD: a community intervention trial (before-after) was carried out, using brochures for prevention of HSV-2 and HPV, including information about these STI, with emphasis on the risk factors identified in students of the same university. RESULTS: we found a change in the perception of STI risk during the intervention (56.5 before vs. 67.7% after intervention), possibly the brochures assisted students to learn more about their own risk behaviors. Likewise, there was an increase in knowledge in both HPV and HSV-2. CONCLUSIONS: it is necessary to increase the sample size in future interventions to assess further the change in knowledge, sexual behaviors and the prevalence of infections. PMID- 23435073 TI - [Dental fluorosis prevalence in eight cohorts of Mexicans born during the implementation of the Fluoridated Domestic Salt National Program]. AB - OBJECTIVE: to determine the effect of birth cohort on dental fluorosis in Mexican schoolchildren during the implementation of the national program to fluoridate domestic salt. MATERIAL AND METHODS: in a cross-sectional study we examined 1,644 schoolchildren 6-13 years old born between 1985-1992 in Campeche, Mexico; a community where there is negligible naturally available fluoride in water supplies. Dental fluorosis was assessed with the Dean's index in the permanent dentition. Questionnaires were used to identify diverse socio-demographic and socio-economic variables. In the statistical analysis logistic regression was used. RESULTS: the prevalence of fluorosis was 15.5%. In the multivariate model,we observed fluorosis was associated with larger family sizes (OR: 0.91; 95% CI: 0.84-0.99) and female sex (OR: 0.74; 95%CI: 0.57-0.98). Furthermore, using the cohort of 1985 as a comparison group, no significant dental fluorosis differences were found with those born between 1986-1987; in contrast, in the cohorts born between 1989-1992 the risk of dental fluorosis increased by almost four times (p < 0.05). CONCLUSION: the prevalence of fluorosis was low compared to other studies in Mexico. In this community with negligible fluoride in water supplies the likelihood of dental fluorosis increased as the windows of susceptibility in birth cohorts were closer to the chronologic beginning of the national domestic salt fluoridation program in 1991. This trend was more apparent after 1991. PMID- 23435074 TI - [Lifestyle and probabilty of dementia in the elderly]. AB - INTRODUCTION: there is evidence of a relationship between physical and cognitive activity and the development of dementia, although this hypothesis has not been tested in Mexican population. OBJECTIVE: analyze the association between an increased participation in physical and cognitive activities and the probability of having dementia, using a Mexican open population sample. MATERIALS AND METHODS: we made a cross sectional survey in open Mexican population of residents in urban and rural areas of 65 of age and older; we performed cognitive assessments to identify subjects with dementia, as well as questionnaires to assess the level of participation in physical and cognitive activities. We performed a binary logistic regression analysis to establish the association between participation and the probability of having dementia. RESULTS: we included 2003 subjects, 180 with diagnosis of dementia. Subjects with dementia were older, had less education and higher prevalence of some chronic diseases. The low participation in cognitive activities was associated with a higher probability of developing dementia. Patients with dementia had significantly lower scores on physical activity scales. CONCLUSIONS: this study supports the hypothesis of a relationship between low cognitive and physical activity and the presentation of dementia. PMID- 23435075 TI - [Micronutrients supplementation in women with hypertensive states in pregnancy]. AB - Pregnancy presents a large number of metabolic adaptations and requirements of micro and macronutrients could be increased, which are not always covered by the diet making necessary to supplement some of them. The micronutrients are an important part of metabolic reactions and both; their deficiency as their excess could participate in damage to organs and tissues of the mother and the fetus. Actually the hypertension pregnant states (HPS) participate in the leading causes of death during pregnancy, making necessary the search for interventions to prevent or reduce the consequences.The oxidative stress levels are linked with the risk to develop HPS, which has created assumptions about the use of micronutrients with antioxidant power and its possible role as protectors in these pathologies, however, the information is still uncertain and the metabolic action of the use of micronutrients supplementation is not precisely known because some micronutrients have shown a protective effect on the development of HPS. It is necessary to evaluate the nutritional status before and during pregnancy, as well to realize more studies about it and strengthen public policies about the use of micronutrients during the pregnancy. PMID- 23435076 TI - [A bibliometric review of infant feeding in Mexico]. AB - OBJECTIVE: a bibliometric analysis on published articles about infant feeding, in Mexican biomedical journals, during 2000-2009, is presented. METHODS: six journals, edited by public institutions or medical associations, published at least one article dealing with the selected theme. From a total of 3,077 articles published, only 2.5% were about infant feeding (78). Title, abstracts, frequency of keywords and institutional affiliation of main author of those articles were analyzed; the contents were classified in seven thematic nodes. RESULTS: the most frequent node was feeding model;breastfeeding appeared 10 times as key word; the authorial institutional affiliation followed Lotka's Law. The results indicate a predominant univocal feeding model; the assumption on universality of mother infant dyad; the focus on medical and clinical entities; and an absence about social agents involved in the feeding process. CONCLUSION: hence,if the bibliometry elucidates the explicit knowledge and illustrates the current biomedical discourses, this analysis shows that the required knowledge for design and operation of public policies related to maternal and infant welfare, in Mexico, are still insufficient for fulfilling international public health recommendations. PMID- 23435077 TI - [Damage control surgery: a review]. AB - OBJECTIVE: To present a monographic review of the damage control surgery. DATA COLLECTION: Consult and literature review (131 references). SELECTION OF STUDIES: We analyzed these relevant articles in relation to damage control surgery. DATA EXTRACTION: From each reference we obtain concepts, data and techniques derivates of damage control surgery. RESULTS: Damage control surgery is a surgical technique that attempts to avoid the triad of coagulopathy,hypothermia and acidosis through application of three phases in patients with multiple lesions. These phases are: Initial laparotomy, stabilization in ICU and definitive surgery. During initial laparotomy efforts are made to controlling the surgical and non surgical bleeding (through packing) and avoid peritoneal contamination. During the stabilization phase the hypothermia, acidosis and coagulopathy are corrected in ICU. In definitive surgery, packing is removed and makes the definitive repair of lesions. CONCLUSION: For the trauma surgeon is important the knowledge about the concepts related to damage control surgery. This is applicable to multiple trauma patients, and disaster situations like terrorism acts and natural disasters. PMID- 23435078 TI - [Transfusion safety. Introduction and identifying the problem]. AB - The problems that exist in our country in the security of the transfusion chain affect every step in the recruitment, donor selection, and aseptic collection, screening tests, production of blood components, storage, transportation and transfusion to recipient. Some of which can lead to fatal cases or moving slowly because of the fragmentation of our health system.With the principles of ethics, we must move towards a unified national blood system overcoming the conflicts of interest that affect the impact on administrative certifications; decrease the irrational use of resources, optimize costs and achieve a transfusion medicine security system and haemovigilance of the at the hospital. There has to be some regional blood banks well-coordinated in health institutions, with central management systems of quality and more specialized procedures,the latter can be achieved with more than 150 public blood banks, transforming them into positions of blood collection of voluntary donation of repetition. The resources would be released equip regional banks. Also required to provide education and legislation ad hoc for goals in voluntary blood donation and focused mainly the university population and centralize information for haemovigilance based computer systems specific hospitals, that reduce errors and restrict risk blood components involved in fatal cases, and reduce the possibility of punitive actions. It has international advice of the whole transfusion chain. PMID- 23435079 TI - [Antibodies, human leukocyte antigens, and biomodulators in transfusion-related acute adverse effects]. AB - With the onset of the AIDS epidemic, major changes occurred in blood banking and transfusion medicine. These changes occurred mainly in donor selection and screening tests for infectious diseases, blood centers modified their organizational philosophy regarding quality. Transfusion of blood products are procedures that allow us to correct the haematology deficiencies for which was indicated. But today, despite the strict controls that precede transfusion,recipients may have undesirable effects, which are known as adverse effects or adverse reactions to transfusion. Antibodies and antigens of the HLA system plays a role in a series of events related to transfusion, such as immunological platelet refractoriness, febrile non-haemolytic transfusion reactions, transfusion related acute lung injury (TRALI) and transfusion associated graft-versus-host disease. The determination of anti-HLA antibodies is evidence that in most developed countries is used on a daily basis in the regular assessment of patients multitransfused or waiting lists for organs from deceased donors. The biomodulators are able to modify biological responses which act in sequence to lead to the differentiation of T lymphocytes. These agents may subcategorizes those which facilitate a normal immune response, those stimulates the immune response, those are capable of inducing immunosuppression not cytotoxic, and those enhancing the ability of the host to tolerate damage by cytotoxic treatment (transfusion or transplant). PMID- 23435080 TI - [Transfusion risk related to female/male plasma use. Analysis and debate]. AB - Transfusion-related acute lung injury (TRALI) is a syndrome characterized by acute respiratory distress following the transfusion of blood components. The pathophysiological hallmark of TRALI is increased pulmonary microvascular permeability. Several reports demonstrate that the majority of TRALI cases are precipitated by transfusion of donor antibodies directed against HLA (human leukocyte antigens) or HNA (human neutrophil antigens) expressed on the neutrophils' surface of the recipient. This antibody-antigen interaction is thought to directly cause neutrophils activation and release of cytotoxic agents, with subsequent endothelial damage and capillary leak. Following plasma transfusion is an important and underreported adverse event. Some blood centers have limited the collection of plasma from female donors due to their propensity for developing anti HLA antibodies after pregnancy. PMID- 23435081 TI - [Acute adverse effects in transfusion. Proposals for the hemosurveillance system]. AB - The management model based on risk prevention has become a major influence in shaping policies for transfusion safety. There are approximately sixty interactions between the health worker and the patient during the transfusion process,representing the number of times where you have the opportunity to make a mistake.We present an analysis of the weaknesses of the National Blood System, with particular attention to the haemovigilance donor and patient. The proposals include the implementation of the National Blood containing the need to establish from the National Blood Safety, significant changes in the regulatory framework and the internal regulations of the Ministry of Health, the CNTS and COFEPRIS. Is required to promote and coordinate the collection of accurate information from the committees of transfusion medicine, which will be accompanied by an initial diagnosis from the National Survey of Blood. Requires notice to other forms of funding to ensure the viability of the projects operating blood bank. Finally, as a strategic resource, the blood is of public, so access should not be restricted. PMID- 23435082 TI - [Liver abscess syndrome with lung involvement secondary to hypermucoviscosity Klebsiella pneumoniae]. AB - Klebsiella pneumoniae liver abscess syndrome (KLAS) is an emerging infection characterized by primary monomicrobial liver abscess, bacteremia and metastatic complications. KLAS is endemic in Taiwan but additional cases has also been described in other world regions. It's caused by strains of K. pneumonia serotype K1, rmpA, magA positive, displaying hypermucoviscosity. We present the case of a previously healthy 69 years old patient who developed fever, liver abscess,septic shock, bacteremia, and pneumonia. In cultures grew hypermucoviscous phenotype of K. pneumonia characterized by positive "string test". The patient responded favourably to antibiotic therapy with ceftriaxone, meropenem, amykacin and percutaneous drainage of the abscess. Increased awareness about this globally emerging infection by physicians could allow earlier detection and optimal treatment. PMID- 23435083 TI - [The Hospital of the people of San Marcos. First in Aguascalientes, Mexico]. AB - For centuries, the major hospital of San Juan de Dios has been historically considered the first hospital in Aguascalientes,Mexico, founded on 1685. However, in this paper we report that the Hospital of the people of San Marcos, in operation at least since 1630, was really the first hospital in the state in functions and which services to the needy population continued until today's last notice, as of 1728. As evidence, we offer various first-hand documentary sources obtained in different archive files, which give credit to this modest charity institution. The aforementioned for the memory and pride of the history of health care in Aguascalientes and Mexico. PMID- 23435084 TI - Hyperimmune bovine colostrum for treatment of GI infections: a review and update on Clostridium difficile. AB - Hyperimmune bovine colostrum (HBC), produced by vaccination of a cow during gestation, is rich in targeted immunoglobulins, and can be used to treat a variety of diseases. The published history of HBC use for treating gastrointestinal infections in humans has developed over the past several decades and demonstrates the promise of this type of therapeutic for GI infectious disease. HBC, or purified derivative products, have been used successfully for treatment or prevention of cryptosporidiosis, shigellosis, rotavirus, enterotoxigenic E. coli, and C. difficile infection (CDI). Given the positive results of previous studies using HBC for treatment of CDI, we have produced HBC with antibodies against the two most important virulence factors of C. difficile, TcdA and TcdB, using a novel recombinant vaccine. Our preliminary results demonstrate efficacy of the HBC product for treatment of CDI in the gnotobiotic piglet model, and warrant more thorough investigation. HBC may provide an effective treatment alternative to antibiotics, which can spare the normal gut microflora, and reduce rates of recurrence and antibiotic resistance. PMID- 23435085 TI - Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution. AB - Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ~500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms. PMID- 23435086 TI - De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. AB - Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans. PMID- 23435087 TI - OsLG1 regulates a closed panicle trait in domesticated rice. AB - Reduction in seed shattering was an important phenotypic change during cereal domestication. Here we show that a simple morphological change in rice panicle shape, controlled by the SPR3 locus, has a large impact on seed-shedding and pollinating behaviors. In the wild genetic background of rice, we found that plants with a cultivated-like type of closed panicle had significantly reduced seed shedding through seed retention. In addition, the long awns in closed panicles disturbed the free exposure of anthers and stigmas on the flowering spikelets, resulting in a significant reduction of the outcrossing rate. We localized the SPR3 locus to a 9.3-kb genomic region, and our complementation tests suggest that this region regulates the liguleless gene (OsLG1). Sequencing analysis identified reduced nucleotide diversity and a selective sweep at the SPR3 locus in cultivated rice. Our results suggest that a closed panicle was a selected trait during rice domestication. PMID- 23435090 TI - The evolutionary biography of chronic lymphocytic leukemia. PMID- 23435091 TI - Prediction of acute clinical response following a first episode of non affective psychosis: results of a cohort of 375 patients from the Spanish PAFIP study. AB - OBJECTIVE: Predicting response to antipsychotic treatment might optimize treatment strategies in early phases of schizophrenia. We aimed to investigate sociodemographic, premorbid and clinical predictors of response to antipsychotic treatment after a first episode of non-affective psychosis. METHOD: 375 (216 males) patients with a diagnosis of non affective psychosis entered the study. The main outcome measure was clinical response at 6 weeks and variables at baseline were evaluated as predictors of response. ANOVA for continuous and chi square for categorical data were used to compare responders and non-responders. Multivariate logistic regression was used to establish a prediction model. RESULTS: 53.3% of study subjects responded to antipsychotic treatment. The following variables were associated with an unfavorable response: 1.--lower severity of symptoms at baseline; 2.--diagnosis of schizophrenia; 3.--longer DUI and DUP; 4.--poorer premorbid adjustment during adolescence and adulthood; 5.- family history of psychosis, and 6.--hospitalization. Patients with a family history of psychosis, longer DUP, poor premorbid functioning and lower severity of psychotic symptoms at intake have a reduced likelihood of responding to antipsychotic treatment. CONCLUSION: Helping clinicians to identify those first episode patients with a lower probability of having a favorable clinical response is meant as a first step to achieve a successful initial treatment. PMID- 23435088 TI - Using population admixture to help complete maps of the human genome. AB - Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces using the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning 4 million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified 8 new large interchromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed at the RNA level and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies. PMID- 23435089 TI - The draft genome of the fast-growing non-timber forest species moso bamboo (Phyllostachys heterocycla). AB - Bamboo represents the only major lineage of grasses that is native to forests and is one of the most important non-timber forest products in the world. However, no species in the Bambusoideae subfamily has been sequenced. Here, we report a high quality draft genome sequence of moso bamboo (P. heterocycla var. pubescens). The 2.05-Gb assembly covers 95% of the genomic region. Gene prediction modeling identified 31,987 genes, most of which are supported by cDNA and deep RNA sequencing data. Analyses of clustered gene families and gene collinearity show that bamboo underwent whole-genome duplication 7-12 million years ago. Identification of gene families that are key in cell wall biosynthesis suggests that the whole-genome duplication event generated more gene duplicates involved in bamboo shoot development. RNA sequencing analysis of bamboo flowering tissues suggests a potential connection between drought-responsive and flowering genes. PMID- 23435092 TI - Role of gap junction involved with endothelium-derived hyperpolarizing factor for the quercetin-induced vasodilatation in rat mesenteric artery. AB - AIMS: Modulation of vasodilating actions by quercetin, a kind of flavonoid, was investigated using rat mesenteric arterial ring strips. MAIN METHODS: Ring strips (1mm) of rat mesenteric artery were used. The specimens were kept at 36.5 degrees C in Krebs-Henseleit solution oxygenated with 95% O(2) and 5% CO(2). KEY FINDINGS: Quercetin (0.1 to 100 MUM) dilated the contraction induced by norepinephrine (1 MUM) in a concentration-dependent manner. The quercetin-induced vasodilatation was almost resistant to both 100 MUM L-N(G)-nitro arginine methyl ester (L-NAME) and 100 MUM indomethacin. At 1mM tetraethylammonium (a KCa channel inhibitor) decreased the quercetin-induced vasodilatation, which was resistant to L-NAME and indomethacin, but not significantly. L-NAME- and indomethacin resistant quercetin-induced vasodilatation was significantly attenuated by 100 MUM 18alpha- and 50 MUM 18beta-glycyrrhetinic acids (gap junction inhibitors). Endothelium removal as well significantly attenuated the vasodilatation to the same extent. SIGNIFICANCE: These results indicate that quercetin dilates the mesenteric artery via endothelium-dependent mechanisms, and the dilatation is mainly mediated by gap junctions closely involved with endothelium-derived hyperpolarizing factor (EDHF). PMID- 23435094 TI - Dental fear and anxiety in children and adolescents: qualitative study using YouTube. AB - BACKGROUND: Dental fear and anxiety (DFA) refers to the fear of and anxiety towards going to the dentist. It exists in a considerable proportion of children and adolescents and is a major dilemma in pediatric dental practice. As an Internet social medium with increasing popularity, the video-sharing website YouTube offers a useful data source for understanding health behaviors and perceptions of the public. OBJECTIVE: Using YouTube as a platform, this qualitative study aimed to examine the manifestations, impacts, and origins of DFA in children and adolescents from the public's perspective. METHODS: To retrieve relevant information, we searched YouTube using the keywords "dental fear", "dental anxiety", and "dental phobia". Videos in English expressing a layperson's views or experience on children's or adolescent's DFA were selected for this study. A video was excluded if it had poor audiovisual quality, was irrelevant, was pure advertisement or entertainment, or contained only the views of professionals. After the screen, we transcribed 27 videos involving 32 children and adolescents, which were reviewed by a panel of 3 investigators, including a layperson with no formal dental training. Inductive thematic analysis was applied for coding and interpreting the data. RESULTS: The videos revealed multiple manifestations and impacts of DFA, including immediate physical reactions (eg, crying, screaming, and shivering), psychological responses (eg, worry, upset, panic, helplessness, insecurity, resentment, and hatred), and uncooperativeness in dental treatment. Testimonials from children, adolescents, and their parents suggested diverse origins of DFA, namely personal experience (eg, irregular dental visits and influence of parents or peers), dentists and dental auxiliaries (eg, bad manner, lack of clinical skills, and improper work ethic), dental settings (eg, dental chair and sounds), and dental procedures (eg, injections, pain, discomfort, and aesthetic concerns). CONCLUSIONS: This qualitative study suggests that DFA in children and adolescents has multifaceted manifestations, impacts, and origins, some of which only became apparent when using Internet social media. Our findings support the value of infodemiological studies using Internet social media to gain a better understanding of health issues. PMID- 23435095 TI - Identifying causal networks of neuronal sources from EEG/MEG data with the phase slope index: a simulation study. AB - The investigation of functional neuronal synchronization has recently become a growing field of research. With high temporal resolution, electroencephalography and magnetoencephalography are well-suited measurement techniques to identify networks of interacting sources underlying the recorded data. The analysis of the data in terms of effective connectivity, nevertheless, contains intrinsic issues such as the problem of volume conduction and the non-uniqueness of the inverse solution. Here, we briefly introduce a series of existing methods assessing these problems. To determine the locations of interacting brain sources robust to volume conduction, all computations are solely based on the imaginary part of the cross-spectrum as a trustworthy source of information. Furthermore, we demonstrate the feasibility of estimating causal relationships of systems of neuronal sources with the phase slope index in realistically simulated data. Finally, advantages and drawbacks of the applied methodology are highlighted and discussed. PMID- 23435096 TI - Glucocerebrosidase, a new player changing the old rules in Lewy body diseases. AB - Mutations in the gene encoding glucocerebrosidase (GBA1) cause Gaucher disease (GD), a lysosomal storage disease with recessive inheritance. Glucocerebrosidase (GCase) is a lysosomal lipid hydrolase that digests glycolipid substrates, such as glucosylceramide and glucosylsphingosine. GBA1 mutations have been implicated in Lewy body diseases (LBDs), such as Parkinson's disease and dementia with Lewy bodies. Parkinsonism occurs more frequently in certain types of GD, and GBA1 mutation carriers are more likely to have LBDs than non-carriers. Furthermore, GCase is often found in Lewy bodies, which are composed of alpha-synuclein fibrils as well as a variety of proteins and vesicles. In this review, we discuss potential mechanisms of action of GBA1 mutations in LBDs with particular emphasis on alpha-synuclein aggregation by reviewing the current literature on the role of GCase in lysosomal functions and glycolipid metabolism. PMID- 23435097 TI - Evaluation of the metal binding sites in a recombinant coagulation factor VIII identifies two sites with unique metal binding properties. AB - Coagulation factor VIII is a glycosylated, non-covalent heterodimer consisting of a heavy chain (A1-A2-B domains) and a light chain (A3-C1-C2 domains). The association of the chains, and the stability and function of the dimer depend on the presence of metal ions. We applied X-ray fluorescence, X-ray crystallographic structure determination with anomalous signals at different wavelengths, and colorimetric measurements to evaluate the metal binding sites in a recombinant factor VIII molecule, turoctocog alfa. We identified a metal binding site in domain A3 dominated by Cu(+) binding and a site in domain A1 dominated by Zn(2+) binding. PMID- 23435093 TI - From evolution to revolution: miRNAs as pharmacological targets for modulating cholesterol efflux and reverse cholesterol transport. AB - There has been strong evolutionary pressure to ensure that an animal cell maintains levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL) cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies. PMID- 23435098 TI - Biochemical characterization of an S-adenosyl-l-methionine-dependent methyltransferase (Rv0469) of Mycobacterium tuberculosis. AB - Tuberculostearic acid (l0-methylstearic acid, TSA) is a major constituent of mycobacterial membrane phospholipids, and its biosynthesis involves the direct methylation of oleic acid esterified as a component of phospholipids. The methyltransferases of mycobacteria were long proposed to be involved in the synthesis of methyl-branched short-chain fatty acids, but direct experimental evidence is still lacking. In this study, we identified the methyltransferase encoded by umaA in Mycobacterium tuberculosis H37Rv as a novel S-adenosyl-l methionine (SAM)-dependent methyltransferase capable of catalyzing the conversion of olefinic double bond of phospholipid-linked oleic acid to biologically essential TSA. Therefore, UmaA, catalyzing such modifications, offer a viable target for chemotherapeutic intervention. PMID- 23435099 TI - Progress towards standardization: an IFCC Scientific Division Perspective. PMID- 23435100 TI - Harmonization in laboratory medicine: the complete picture. AB - Evidence of the acute lack of interchangeable laboratory results and consensus in current practice among clinical laboratories has underpinned greater attention to standardization and harmonization projects. Although the focus is mainly on the standardization of measurement procedures, the scope of harmonization goes beyond method and analytical results: it includes all other aspects of laboratory testing, including terminology and units, report formats, reference intervals and decision limits, as well as test profiles and criteria for the interpretation of results. This review provides further insight on the issue of harmonization in laboratory medicine in view of the urgent need for a complete picture now that old and new drivers are calling for more effective efforts in this field. The main drivers for standardization and harmonization projects are first and foremost patient safety, but also the increasing trends towards consolidation and networking of clinical laboratories, accreditation programs, clinical governance, and advances in Information Technology (IT), including the electronic patient record. The harmonization process, which should be considered a three-tier approach involving local, national and international fronts, must go beyond the harmonization of methods and analytical results to include all other aspects of laboratory testing. A pertinent example of the importance of a complete picture in harmonization programs is given by the National Bone Health Alliance working in the field of bone turnover markers in cooperation with scientific societies including the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). PMID- 23435101 TI - All aboard! Helping new grads navigate nursing. PMID- 23435102 TI - Innovations in social media: the MappyHealth experience. PMID- 23435103 TI - Updating telemetry practices to improve the culture of safety. PMID- 23435105 TI - Security risk! Accessing and sharing data. PMID- 23435106 TI - Evaluating nursing practices beyond our borders. PMID- 23435107 TI - Making the grade: Charge nurse education improves job performance. PMID- 23435108 TI - Healthcare reform in 2013: Enduring and universal challenges. PMID- 23435109 TI - Documenting the minutes at professional meetings. PMID- 23435110 TI - Make it a habit: 2 weeks to bedside report. PMID- 23435111 TI - How do you define competence? PMID- 23435112 TI - Silver nanoparticles decorated filter paper via self-sacrificing reduction for membrane extraction surface-enhanced Raman spectroscopy detection. AB - Silver nanoparticles (AgNPs) decorated filter papers combining solid-phase extraction (SPE) with surface enhanced Raman spectroscopy (SERS) achieved rapid collection of analytes and in situ detection. The AgNPs were fabricated by cellulose self-sacrificing reduction. Aqueous Ag(NH3)2OH was reduced by hydroxyl groups in cellulose under alkaline conditions. The AgNPs were highly uniform and firmly adhered to the microfibers. Reaction conditions were optimized by the probe molecule p-aminothiophenol (PATP) to attain the best Raman enhancement. Methylene blue trihydrate (MB) and 6-thioguanine (6-TG) were detected by flow through method. The results exhibited outstanding SERS effect and an obvious improvement in detection limit was observed compared to common immersion methods. SERS detection was quantitative as the log-log plot of Raman intensity against MB and 6-TG concentrations showed a linear relationship. The SERS-active paper is degradable because it could be burned after analyte detection. PMID- 23435113 TI - Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells. AB - The nonsense-mediated mRNA decay (NMD) pathway is well known as a translation coupled quality control system that recognizes and degrades aberrant mRNAs with truncated open reading frames (ORF) due to the presence of a premature termination codon (PTC). However, a more general role of NMD in posttranscriptional regulation of gene expression is indicated by transcriptome wide mRNA profilings that identified a plethora of physiological mRNAs as NMD targets. In this review, we focus on mechanistic aspects of target mRNA identification and degradation in mammalian cells, based on the available biochemical and genetic data, and point out knowledge gaps. Translation termination in a messenger ribonucleoprotein particle (mRNP) environment lacking necessary factors for proper translation termination emerges as a key determinant for subjecting an mRNA to NMD, and we therefore review recent structural and mechanistic insight into translation termination. In addition, the central role of UPF1, its crucial phosphorylation/dephosphorylation cycle and dynamic interactions with other NMD factors are discussed. Moreover, we address the role of exon junction complexes (EJCs) in NMD and summarize the functions of SMG5, SMG6 and SMG7 in promoting mRNA decay through different routes. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23435114 TI - Olfactory impairment in posterior cortical atrophy. PMID- 23435115 TI - Did you see that? Dissociating advanced visual information and ball flight constrains perception and action processes during one-handed catching. AB - The integration of separate, yet complimentary, cortical pathways appears to play a role in visual perception and action when intercepting objects. The ventral system is responsible for object recognition and identification, while the dorsal system facilitates continuous regulation of action. This dual-system model implies that empirically manipulating different visual information sources during performance of an interceptive action might lead to the emergence of distinct gaze and movement pattern profiles. To test this idea, we recorded hand kinematics and eye movements of participants as they attempted to catch balls projected from a novel apparatus that synchronised or de-synchronised accompanying video images of a throwing action and ball trajectory. Results revealed that ball catching performance was less successful when patterns of hand movements and gaze behaviours were constrained by the absence of advanced perceptual information from the thrower's actions. Under these task constraints, participants began tracking the ball later, followed less of its trajectory, and adapted their actions by initiating movements later and moving the hand faster. There were no performance differences when the throwing action image and ball speed were synchronised or de-synchronised since hand movements were closely linked to information from ball trajectory. Results are interpreted relative to the two-visual system hypothesis, demonstrating that accurate interception requires integration of advanced visual information from kinematics of the throwing action and from ball flight trajectory. PMID- 23435116 TI - On the effects of second language immersion on first language production. AB - The present study was aimed at investigating how the effects of a second language (L2) immersion on first language (L1) production are modulated by lexical frequency and the cognate status of words. By means of a picture naming and a semantic fluency task, we longitudinally explored the changes in L1 performance of a group of immersed learners. Our results revealed slower naming latencies at the end than at the beginning of the immersion period but only for those pictures whose corresponding names were low frequency and non-cognates. Moreover, the semantic fluency task revealed a decrease in the percentage of non-cognate words produced at the end of the immersion period. The observed decline in the accessibility to L1 words after a short L2 immersion period is explained in terms of the general bilingual lexical access disadvantage and studies of L1 attrition in speech production. Specifically, the present findings are more in line with theoretical accounts that consider lexical difficulties to be the result of changes in the frequency of use of the L1 during a short L2 immersion period. PMID- 23435117 TI - Does random tree puzzle produce Yule-Harding trees in the many-taxon limit? AB - It has been suggested that a random tree puzzle (RTP) process leads to a Yule Harding (YH) distribution, when the number of taxa becomes large. In this study, we formalize this conjecture, and we prove that the two tree distributions converge for two particular properties, which suggests that the conjecture may be true. However, we present statistical evidence that, while the two distributions are close, the RTP appears to converge on a different distribution than does the YH. By way of contrast, in the concluding section we show that the maximum parsimony method applied to random two-state data leads a very different (PDA, or uniform) distribution on trees. PMID- 23435118 TI - Modeling human postural sway using an intermittent control and hemodynamic perturbations. AB - Ground reaction force during human quiet stance is modulated synchronously with the cardiac cycle through hemodynamics [1]. This almost periodic hemodynamic force induces a small disturbance torque to the ankle joint, which is considered as a source of endogenous perturbation that induces postural sway. Here we consider postural sway dynamics of an inverted pendulum model with an intermittent control strategy, in comparison with the traditional continuous-time feedback controller. We examine whether each control model can exhibit human-like postural sway, characterized by its power law behavior at the low frequency band 0.1-0.7Hz, when it is weakly perturbed by periodic and/or random forcing mimicking the hemodynamic perturbation. We show that the continuous control model with typical feedback gain parameters hardly exhibits the human-like sway pattern, in contrast with the intermittent control model. Further analyses suggest that deterministic, including chaotic, slow oscillations that characterize the intermittent control strategy, together with the small hemodynamic perturbation, could be a possible mechanism for generating the postural sway. PMID- 23435119 TI - RNA-mediated interference and reverse transcription control the persistence of RNA viruses in the insect model Drosophila. AB - How persistent viral infections are established and maintained is widely debated and remains poorly understood. We found here that the persistence of RNA viruses in Drosophila melanogaster was achieved through the combined action of cellular reverse-transcriptase activity and the RNA-mediated interference (RNAi) pathway. Fragments of diverse RNA viruses were reverse-transcribed early during infection, which resulted in DNA forms embedded in retrotransposon sequences. Those virus retrotransposon DNA chimeras produced transcripts processed by the RNAi machinery, which in turn inhibited viral replication. Conversely, inhibition of reverse transcription hindered the appearance of chimeric DNA and prevented persistence. Our results identify a cooperative function for retrotransposons and antiviral RNAi in the control of lethal acute infection for the establishment of viral persistence. PMID- 23435121 TI - Integrating cognitive bias modification into a standard cognitive behavioural treatment package for social phobia: a randomized controlled trial. AB - OBJECTIVE: The aim of the current study was to integrate recent developments in the retraining of attentional biases towards threat into a standard cognitive behavioural treatment package for social phobia. METHOD: 134 participants (M age 32.4: 53% female) meeting DSM-IV criteria for social phobia received a 12-week cognitive behavioural treatment program. They were randomly allocated to receive on a daily basis using home practice, either an additional computerised probe procedure designed to train attentional resource allocation away from threat, or a placebo variant of this procedure. Measures included diagnostic severity, social anxiety symptoms, life interference, and depression as well as state anxiety in response to a laboratory social threat. RESULTS: At the end of treatment there were no significant differences between groups in attentional bias towards threat or in treatment response (all p's>0.05). Both groups showed similar and highly significant reductions in diagnostic severity, social anxiety symptoms, depression symptoms, and life interference at post-treatment that was maintained and in most cases increased at 6 month follow-up (uncontrolled effect sizes ranged from d=0.34 to d=1.90). CONCLUSIONS: The current results do not indicate that integration of information processing-derived attentional bias modification procedures into standard treatment packages as conducted in this study augments attentional change or enhances treatment efficacy. Further refinement of bias modification techniques, and better methods of integrating them with conventional approaches, may be needed to produce better effects. PMID- 23435120 TI - The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. AB - Dendritic cells (DCs) are critical in immune responses, linking innate and adaptive immunity. We found here that DC-specific deletion of the transcription factor STAT5 was not critical for development but was required for T helper type 2 (TH2), but not TH1, allergic responses in both the skin and lungs. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of the expression of costimulatory molecules and chemokine production. Furthermore, TH2 responses in mice with DC-specific loss of STAT5 resembled those seen in mice deficient in the receptor for TSLP. Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces. PMID- 23435122 TI - Therapeutic alliance and weight gain during cognitive behavioural therapy for anorexia nervosa. AB - This study examined the relationship between therapeutic alliance and primary symptom change (weight gain) during CBT for anorexia nervosa. The aims were threefold: (1) to establish the strength of the therapeutic alliance across the treatment, (2) to determine whether early therapeutic alliance is associated with the completion of CBT for this client group, and (3) to determine the direction of the relationship between therapeutic alliance and weight gain. Adult outpatients (N=65) with a diagnosis of anorexia nervosa (or atypical anorexia nervosa) completed a measure of alliance at session six and at the end of treatment. Weight was recorded at the start of treatment, session six and at the end of treatment. The strength of the alliance was consistently high in the sample. However, early therapeutic alliance was not associated with either the likelihood of completing treatment or subsequent weight gain. In contrast, both early and later weight gain were associated with the strength of subsequent alliance. These findings indicate that it might be advisable to focus on techniques to drive weight gain rather than rely on the therapeutic alliance to bring about therapeutic change. PMID- 23435123 TI - Marker-free dual-axis tilt series alignment. AB - Dual-axis tilt series in electron tomography are collected by successively tilting the object about two approximately orthogonal tilt axes. Here we report on the extension of marker-free image registration based on cross-correlation techniques to dual-axis tilt series. A simultaneous geometry refinement yields accurate parameters for the computation of the final reconstruction. Both, image registration and 3D-reconstruction operate on the combined data from the paired single axis series rather than computing individual single axis tomograms followed by a separate combination step. We show that with simultaneous registration and reconstruction of dual-axis tilt series, tomograms with higher resolution are obtained than by merging separately computed tomograms. PMID- 23435124 TI - A 35 kD Phyllanthus niruri protein modulates iron mediated oxidative impairment to hepatocytes via the inhibition of ERKs, p38 MAPKs and activation of PI3k/Akt pathway. AB - It has been reported that the herb, Phyllanthus niruri, possess antioxidant, anti infection, anti-asthmatic, anti-diuretic, anti-soresis and many more beneficial activities. The goal of our present study was to evaluate the protective role of a 35 kD protein (PNP) isolated from this herb against iron-induced cytotoxicity in murine hepatocytes. Exposure of hepatocytes to iron (FeSO4) caused elevation of reactive oxygen species (ROS) production, enhanced lipid peroxidation and protein carbonylation, depleted glutathione levels, decreased the antioxidant power (FRAP) of the cells and reduced cell viability. Iron mediated cytotoxicity disrupted mitochondrial membrane potential (Deltapsim) and thereby caused apoptosis mainly by the intrinsic pathway via the down-regulation of IkappaBalpha with a concomitant up-regulation of NF-kB as well as the phosphorylation of ERKs and p38 MAP kinases. In addition, iron-induced cytotoxicity disrupted the normal balance of Bcl-2 family proteins in hepatocytes. Incubation of hepatocytes with PNP, however, protected the cells from apoptosis by stabilizing the mitochondria and arresting the release of cytochrome c. It also suppressed caspase activation and cleavage of PARP. Moreover, this protein has strong free radical scavenging activity and thereby scavenged ROS extensively. Combining all, results suggest that simultaneous treatment with PNP might suppress the iron-induced cytotoxicity in hepatocytes. PMID- 23435125 TI - Single-photon emission computed tomography-computed tomography in imaging infection. AB - This review focuses on the current evidence available on the use of single-photon emission computed tomography-computed tomography (SPECT-CT) in infection imaging. The single-photon functional agents commonly used to image infection include In 111-labelled or Tc-99m-labelled leucocytes, Ga-67 citrate, Tc-99m-biphosphonates and radiolabelled antigranulocyte antibodies. Although many of these agents have been available for a long time, the development of hybrid SPECT-CT technology has led to a wider use of these agents. This review shows that the application of CT to single-photon imaging techniques for imaging infection can significantly improve the accuracy of the technique by increasing the specificity and better defining the location and extent of suspected disease. Hybrid fusion images also increase the confidence of the individual in reporting and seem to be applicable to a wide range of clinical situations. We believe that, overall, SPECT-CT, by providing a clearer assessment of whether infection is present and an accurate localization of the disease so that optimum treatment can be initiated, has a role in infection imaging. PMID- 23435127 TI - Duodenal switch operation for juxtapapillary duodenal diverticula. AB - BACKGROUND/AIMS: Since the first case of juxtapapillary diverticlum reported by Lemmel, several reports have demonstrated an association between periampullary diverticulum and gallstone disease. Thus, we compared the efficiency of the duodenal switch operation and choledchojejunostomy for patients who underwent surgery for cholangitis with juxtapapillary duodenal diverticula. METHODOLOGY: We retrospectively studied 17 patients who had cholangitis associated with juxtapapillary duodenal diverticula. These patients were divided into 2 groups on the basis of the operative procedure: the duodenal switch operation group (DS group) and the choledochojejunostomy group (CJ group). RESULTS: The mean operative time and blood loss were significantly lesser in the DS group than in the CJ group (p<0.0001 and p<0.0005, respectively); however, the duration of nasogastric suction requirement and time after which oral ingestion of solid diet could be safely resumed after surgery were significantly longer in the DS group than in the CJ group (p<0.0001 and p<0.0001, respectively). Gallstone formation after the surgery did not occur in both groups. CONCLUSIONS: Duodenal switch operation is useful and less invasive for cholangitis associated with juxtapapillary duodenal diverticula and for preventing cholangitis for a long period after the operation; however, gastric stasis still remains a problem with this procedure. PMID- 23435128 TI - Malignant biliary obstruction significantly increases serum lipid levels: a novel biochemical tumor marker? AB - BACKGROUND/AIMS: We aimed to investigate the alterations in serum lipid levels due to biliary obstruction associated with benign and malignant cases. Also, we aimed to examine the possibility of the theory that extremely high serum lipid levels can predict the malignant biliary obstruction in the differantial diagnosis. METHODOLOGY: Three hundred twenty two patients who were performed endoscopic retrograde cholangiopancreatography with the intrahepatic and extrahepatic cholestasis were reviewed in the period from September 2007 to October 2010. RESULTS: In the malignant obstruction group, meaningfully higher total cholesterol (p<0,001), low-density lipoprotein (p>0.05) and triglycerides (p<0.05) were observed but high-density lipoprotein (p<0.05) levels were lower. The receiver operating characteristic analysis showed that total cholesterol (246.74 mg/dL or less, sensitivity: 84.3%, specificity: 83.3%, area under the curve: 0.705 (0.620-0.790) (p<0.001)) and high-density lipoprotein cholesterol (area under the curve: 0.577 (0.444-0.710)) were predictors of malignant biliary obstruction. CONCLUSIONS: Serum lipid profile may be used as an applicant marker to identify malignant reasons of the obstructive jaundice. PMID- 23435129 TI - Evaluation of the clinical features of HCC following hepatectomy for different stages of HCC. AB - BACKGROUND/AIMS: This study was to evaluate and compare the clinical and pathological characteristics and patient outcomes after hepatic resection for different stages of HCC according to the Barcelona Clinic Liver Cancer (BCLC) classification system. METHODOLOGY: Three hundred and sixteen primary hepatectomies for HCC were divided into stage 0-c, according to BCLC classification. The clinicopathological variables of the patients in each group were compared statistically. RESULTS: There were significant differences in the incidence of capsular invasion, alpha-fetoprotein, blood loss, blood transfusion and tumor related number among each of the stage 0-C, respectively (p<0.05). Disease-free survival was influenced by histopathological grade (p=0.000), tumor capsule (p=0.015), tumor related number (p=0.000) and BCLC (p=0.000). Overall survival was influenced by histopathological grade (p=0.000), tumor capsule (p=0.035), tumor related number (p=0.005), cirrhosis (p=0.000) and BCLC (p=0.000). CONCLUSIONS: HCC in stage 0 and A were closely correlated with a better prognosis, which reflected the relatively benign pathobiological features of HCC at an early developmental stage. In comparison, HCC in stages B and C exhibited a tendency towards a more aggressive phenotype. Our findings suggest that stage B classification is optimal for estimating the biological behavior and clinical prognosis of patients undergoing partial hepatectomy for early stage HCC. PMID- 23435130 TI - Segmental colitis associated with diverticulosis: systematic evaluation of 486 cases with meta-analysis. AB - BACKGROUND/AIMS: Segmental colitis associated with colonic diverticulosis is a new and emerging entity. We systematically evaluated 486 cases of this entity and performed qualitative meta-analysis on this information. METHODOLOGY: This diagnosis was made on a 64-year old man by colonoscopic biopsy. His clinical symptoms included hematochezia and crampy lower abdominal pain. PubMed Search using terms such as segmental colitis, colitis associated with diverticulosis was made without language or time barrier. Additional papers were manually added from the reference lists of key articles. Qualitative meta-analysis was done using the well-established methods of qualitative research, e.g. diagramming, theme repetition without serious contradiction, theme saturation and investigator reflexivity. To facilitate qualitative meta-analysis, summary sheets of publications were created. RESULTS: This search produced 486 cases with this entity. The prevalence in patients with diverticulosis is 0.3% to 1.3%. There were 58.7% men. The mean age was 63.6 (range 26-87) years. The most common presenting symptoms were rectal bleeding, diarrhea and abdominal pain. Fever, leucocytosis and rectal involvement were characteristically absent. Endoscopic appearance and histology may resemble ulcerative colitis. Many of these patients have a benign course with spontaneous resolution or may respond to 5 aminosalucylates or steroids. CONCLUSIONS: This is a new and emerging entity. There is male predominance and it occurs in relatively elderly patients. It can be distinguished from acute diverticulitis by clinical, endoscopic and histological features. Most have a benign course. PMID- 23435131 TI - Role of the enteric nervous system in the colon of patients with idiopathic megacolon. AB - BACKGROUND/AIMS: To clarify the physiological significance of the enteric nervous system (ENS) in the colon of patients with idiopathic megacolon (IM), we investigated the enteric nerve responses on lesional and normal bowel segments derived from patients with IM and patients who underwent colon resection for colonic cancers. METHODOLOGY: Eighteen preparations were taken from the lesional colon of 5 patients with IM (4 men and 1 woman, aged 46-70 yrs, mean age 55.8 yrs); 42 were taken from the normal colon of 14 patients with colonic cancer (10 men and 4 woman, aged 48-68 yrs, mean age 54.2 yrs). A mechanographic technique was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) of the adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers. RESULTS: 1) Responses to EFS before blockade of adrenergic and cholinergic nerves. The muscle strips in both normal and IM colon demonstrated relaxation reactions rather than contraction reactions by EFS. The relaxation reaction to EFS in the IM was significantly stronger than that in the normal colon (p=0.0366). 2) Responses to EFS after blockade of the adrenergic and cholinergic nerves. The muscle strips in both normal and IM colon demonstrated relaxation reactions rather than contraction reactions by EFS. The relaxation reaction to EFS in the IM was stronger than that in the normal colon (p=0.0467). 3) Tetrodotoxin abolished the EFS responses in the muscle strips in both normal colon and abnormal colon with IM. CONCLUSIONS: An increase of NANC inhibitory nerves plays an important role in the impaired motility observed in the colon of patients with IM. PMID- 23435132 TI - Cytomegalovirus colitis in immunocompetent patients: a clinical and endoscopic study. AB - BACKGROUND/AIMS: Cytomegalovirus (CMV) colitis occurs rarely in immunocompetent patients and little detail is known about the clinical features, endoscopic findings and prognosis of CMV colitis in immunocompetent patients. The aim of this study was to investigate the clinical and endoscopic features of CMV colitis and its prognosis in immunocompetent patients. METHODOLOGY: We retrospectively reviewed the medical records and the endoscopic findings of twelve immunocompetent patients who were diagnosed with CMV colitis by immunostaining for CMV antibodies based on the histological examination of tissue biopsies obtained during colonoscopy. The patients were six men and six women and their median age was 66 years (range 44-88). RESULTS: Patients infected with CMV colitis had comorbidities including diabetes mellitus (n=4), chronic renal failure (n=3) and ischemic heart disease (n=2). The most common initial presenting symptom was gastrointestinal bleeding (n=7) and the associated symptoms were diarrhea and abdominal pain. Endoscopic examination showed three types: well-demarcated ulcerative type (n=6), ulceroinfiltrative type (n=3), and pseudomembranous colitis-associated type (n=3). All patients were treated with an antiviral agent (ganciclovir) within two weeks following onset of main presenting symptom and all showed clinical and endoscopic improvement except one died later from severe pneumonia. CONCLUSIONS: CMV colitis in immunocompetent patients presented in older patients and in those with other comorbidities. Gastrointestinal bleeding was the most common initial presentation. Despite aggressive clinical manifestations, the prognosis of CMV colitis is good if diagnosed and treated early. PMID- 23435133 TI - Reduced population of interstitial cells of Cajal in Chagasic megacolon. AB - BACKGROUND/AIMS: In Chagasic megacolon, there is a reduction in the population of interstitial cells of Cajal. It was aimed to evaluate density of Cajal cells in the resected colon of Chagasic patients compared to control patients and to verify possible association between preoperative and postoperative bowel function of megacolon patients and cell count. METHODOLOGY: Sixteen megacolon patients (12 female; mean age 54.4 (31-73)) were operated on. Pre- and postoperative evaluation using Cleveland clinic constipation score was undertaken. Resected colons were examined. Cajal cells were identified by immunohistochemistry (anti CD117). The mean cell number was compared to resected colons from 16 patients (7 female; mean age 62.8 (23-84)) with non-obstructive sigmoid cancer. Association between pre- and postoperative constipation scores and cell count for megacolon patients was evaluated using the Pearson test (r). RESULTS: A reduced number of Cajal cells (per field: 2.84 (0-6.6) vs. 9.68 (4.3-13); p<0.001) were observed in the bowel of megacolon patients compared to cancer patients. No correlation between constipation score before (r=- 0.205; p=0.45) or after surgery (r=0.291; p=0.28) and cell count in megacolon was observed. CONCLUSIONS: Patients with megacolon display marked reduction of interstitial cells of Cajal. An association of constipation severity and Cajal cells depopulation was not demonstrated. PMID- 23435134 TI - Role of vasoactive intestinal peptide on the proximal and distal parts from the dentate line in the normal human internal anal sphincter. AB - BACKGROUND/AIMS: To clarify the functional differences of vasoactive intestinal peptide (VIP) in the human internal anal sphincter (IAS) between the proximal and distal parts from the dentate line, we investigated the VIPergic nerve responses of normal proximal and distal IAS in vitro. METHODOLOGY: Normal IAS specimens derived from 20 patients with lower rectal cancer (14 men and 6 women aged from 48 to 77 years, average 66.5 years) were used. These IAS muscles were divided into 2 parts [oral site IAS from dentate line; proximal part (PIAS; n=20), anal site IAS from dentate line; distal part (DIAS; n=20)]. A mechanogram was used to evaluate in vitro muscle strip responses to VIP after treatment with various autonomic nerve blockers. RESULTS: 1) Response to VIP after blockade of the adrenergic and cholinergic nerves: VIP showed relaxation reaction in both PIAS and DIAS. The percentage of relaxation responses via VIP nerves in the PIAS was significantly greater than that in the DIAS (p=0.0350). 2) VIP responses in the PIAS and DIAS were not completely blocked by tetrodotoxin. These results indicated that VIP acts through both nerves and directly on the IAS muscle. CONCLUSIONS: There are functional differences in the regulation of VIPergic nerves between the PIAS and DIAS. Relaxation reaction via VIPergic nerves was mainly involved in the regulation of enteric nerve responses in the PIAS. PMID- 23435135 TI - Prognostic significance of CD44 and c-erb-B2 protein overexpression in patients with gastric cancer. AB - BACKGROUND/AIMS: The aim of the study is to evaluate the correlation between c erb-B2 and CD44 overexpression and survival of patients with gastric cancer. METHODOLOGY: The paraffin blocks of 48 patients with gastric carcinoma were retrospectively analyzed. The pathological specimens were stained with CD44 and c erb-B2 by immunohistochemical methods. RESULTS: The positivity of c-erb-B2 was detected in 9 patients. In six of them, predominantly strong cytoplasmic staining was observed. The remaining three tumors were predominantly membranous stained. No correlation was found between the c-erb-B2 positivity and overall survival (OS). Seventeen specimens (35.4%) were CD44 positive, all localized in cell membrane. The median OS time of CD44 positive patients was worse than that of patients with CD44 negative (11 vs. 17 months, respectively). This difference was statistically significant (p=0.03). In 5 patients both CD44 and c-erb-B2 were detected as positive. However, there were 23 patients with both CD44 negative and c-erb-B2 negative. The median OS time for patients with both CD44 and cerb- B2 negative was better than those of patients with both CD44 and c-erb-B2 positive (37 vs. 11 months, respectively, p=0.03). The relationship between CD44 and c-erb B2 positivities and clinicopathological factors (p>0.05). CONCLUSIONS: Our results showed that there was no correlation between c-erb-B2 positivity and OS, except for CD44. In addition, we found significant association of simultaneous positivities of c-erb-B2 and CD44 with OS of patients with gastric cancer. CD44 alone can be taken as a prognostic factor and also simultaneous overexpression of CD44 and c-erb-B2 may be used as a marker of poor prognosis. PMID- 23435136 TI - CT detection of dry peritoneal seeding in patients with advanced gastric cancer. AB - BACKGROUND/AIMS: To determine the significant CT findings of dry peritoneal seeding (DPS) in patients with advanced gastric cancer (AGC) and to assess whether radiologists' performance in the detection of DPS can be improved using these significant CT findings. METHODOLOGY: Two radiologists reviewed CT images of AGC patients with DPS and without seeding for the presence or absence of various CT findings suggesting peritoneal seeding, in consensus. Significant CT findings for DPS were determined using Fisher's exact test. Two other observers, blinded to the results of the consensus review during the first session but not during the second session, evaluated the presence or absence of DPS independently on a five-point scale. Each observer's performance was evaluated using a pair wise comparison of the receiver operating characteristic (ROC) curves. RESULTS: Soft tissue nodule or plaque on the peritoneal surface was the only significant CT finding of DPS (p=0.014). The areas under the ROC curves of the two observers were not significantly different between the two review sessions. CONCLUSIONS: Soft tissue nodule or plaque on the peritoneal surface was a significant CT finding for the detection of DPS. However, radiologists' performance for the detection of DPS did not improve despite knowledge of this finding. PMID- 23435137 TI - Intramucosal gastric cancer with fifteen metastatic lymph nodes: report of a case. AB - This report describes very rare intramucosal gastric cancer with metastasis to 15 lymph nodes. A 65-year-old Japanese man was admitted to our hospital with epigastralgia. Endoscopic examination revealed a 3.5 cm type IIc ulcerated lesion on the posterior wall near the lesser curvature of the angle of the stomach with mucosal tumor invasion. Neither enlarged lymph nodes nor distant metastasis was revealed by abdominal computer tomography. He was treated by pylorus-preserving gastrectomy with lymph node dissection. A histological examination of biopsy specimens revealed signet-ring cell carcinoma with ulcer scar that was limited to the mucosal layer. Although lymphatic vessel invasion was not evident, 15 of 23 retrieved nodes were actually involved. The final diagnosis was stage II gastric cancer, designated T1N2M0 according to the Japanese classification of gastric carcinoma. Twelve months after surgery, the patient remains alive without recurrence. PMID- 23435138 TI - Suppression of BCRP expression and restoration of sensitivity to chemotherapy in multidrug-resistant HCC cell line HEPG2/ADM by RNA interference. AB - BACKGROUND/AIMS: Breast cancer resistance protein (BCRP) is an ATP-binding cassette multidrug transporter that confers resistance to various anticancer drugs like Adriamycin. Overexpression of BCRP confers multidrug resistance (MDR) in hepatocellular carcinoma cells and is a frequent impediment to successful chemotherapy. METHODOLOGY: We evaluated a new approach using RNA interference for the specific knockdown of BCRP in hepatocellular carcinoma cells. To overcome the BCRP-mediated atypical multidrug drug resistance, one small interfering RNA construct (RNAi) targeting one special region of BCRP gene were designed to inhibit the atypical MDR expression by transfecting them into HepG2/ADM cell lines. RESULTS: We found that the overexpression of BCRP gene was suppressed efficiently by the introduction of small interfering RNA, which caused sequence specific gene silence. The level of BCRP mRNA reduced to 22.55% after transfected by pSUPER-BCRPs compared with those of the controls. Similarly, the level of BCRP decreased too. Furthermore, the sensitivity to Adriamycin of pSUPER-BCRPs-treated HEPG2/ADM cells is increased 3.55-fold compared to their control (p<0.05). The relative reverse rate of HepG2/ADM cell to Adriamycin is 72.2%. CONCLUSIONS: These data indicated that pSUPER-BCRPs could modulate MDR and may present a new approach to overcome BCRP-mediated drug resistance in HEPG2/ADM cells. It may reverse multidrug resistance phenotype and therefore provide promising therapeutic modalities in the treatment of hepatocellular carcinoma. PMID- 23435139 TI - Curcumin improves the survival rate after a massive hepatectomy in rats. AB - BACKGROUND/AIMS: Curcumin possesses anti-inflammatory and antioxidant effects. Curcumin pretreatment provided a hepatoprotective effect in rat models of chemically-induced hepatotoxicities and ischemia/reperfusion injuries. In this study, we examined whether curcumin could improve the survival rate of rats undergoing a 90% hepatectomy. METHODOLOGY: Rats were administered 340 mg/kg oral curcumin formulated with phosphatidylcholine (curcumin group) or vehicle (control group) for 7 consecutive days and 2 hours prior to the massive hepatectomy. RESULTS: Six of the 13 rats pretreated with curcumin survived, whereas all 13 rats pretreated with vehicle died within day 2 following a massive hepatectomy. A histological examination showed the lobular structure to be disturbed in the rats pretreated with vehicle, whereas the hepatic lobular structure remained relatively stable without necrosis in the rats pretreated with curcumin. The contents of heme oxygenase-1 (HO-1) protein in the control group were low in the preoperative phase. In contrast, the levels of HO-1 protein in the curcumin group were high at the preoperative phase, and thereafter remained at high levels until day 7 following surgery. CONCLUSIONS: Our results suggest that curcumin improves the survival rate by increasing the antioxidant activity in rats after a massive hepatectomy. PMID- 23435140 TI - Is hepatic resection for recurrent or persistent hepatocellular carcinoma justified? AB - BACKGROUND/AIMS: The safety and effectiveness of hepatic resection for recurrent or refractory hepatocellular is not established, particularly in cases treated by non-surgical treatment. METHODOLOGY: Surgical outcomes of 38 patients who underwent curative hepatic resection for recurrent or refractory disease after previous treatment were evaluated. Univariate and multivariate analyses were performed to identify prognostic predictors. RESULTS: There were no postoperative deaths, morbidity occurred in 9 patients (prolonged ascites retention, 5; biliary fistula, 3; intraabdominal abscess, 1), and all of them were treated conservatively. Recurrence-free and overall 1, 3 and 5-year-survival rate was 54, 28 and 24%, and 78, 60 and 55%, respectively. Multivariate analysis revealed hepatitis B or C virus infection (HR=12.8; 95% CI=2.3-245.1), tumor size >5 cm (HR=5.9; 95% CI=5.9-25.6), and vasculo- biliary invasion (HR=5.2; 95% CI=1.4 21.0) were independent predictors of poor overall survival. Type of previous treatment did not influence prognosis. CONCLUSIONS: Hepatic resection for recurrent or refractory hepatocellular carcinoma is safe and achieves long survival in selected patients. PMID- 23435141 TI - Surfactant protein-D is more useful than Krebs von den Lungen 6 as a marker for the early diagnosis of interstitial pneumonitis during pegylated interferon treatment for chronic hepatitis C. AB - BACKGROUND/AIMS: To examine the usefulness of serum Krebs von den Lungen 6 (KL-6) and surfactant protein-D (SP-D) as markers of interstitial pneumonitis. Many antiviral therapies have become available for chronic hepatitis C, including pegylated interferon (PEGIFN) plus ribavirin. Since interstitial pneumonitis is a serious adverse drug reaction during interferon therapy, interferon treatment requires caution in respiratory disease patients. Hence, the predictors of interstitial pneumonitis have not been elucidated. METHODOLOGY: Fifty-two chronic hepatitis C patients who received PEG-IFN plus ribavirin were studied; 14 patients received PEGIFN-alpha 2a, and 38 received PEG-IFN-alpha 2b. Serum KL-6 and SP-D levels were measured during treatment. Time changes in serum KL-6 and SP D levels, as well as the presence of interstitial pneumonitis, were investigated. RESULTS: No cases of pneumonitis in which both markers were below the standard values were seen. Interstitial pneumonitis developed in 1 of the 5 patients in whom both markers were above standard values. Patients whose KL-6 levels alone exceeded the standard value had bacterial pneumonia and emphysema, not interstitial pneumonitis. Though no correlation between SP-D and KL-6 levels was observed, KL-6 levels tended to increase after interstitial pneumonitis was detected on imaging, but SP-D levels increased before imaging detection. CONCLUSIONS: It is important to monitor changes in levels of serum markers and other factors to avoid interstitial pneumonitis during PEG-IFN therapy. SP-D in particular may be important for early detection of interstitial pneumonitis. PMID- 23435142 TI - Characteristics and surgical outcome of HCC patients with low platelet count. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) patients often have low platelet count (LPC). The aim of this study was to determine unique features of HCC patients with LPC. METHODOLOGY: HCC patients who underwent surgery were divided into two groups: LPC group (platelet count <=100,000/mm3, n=84) and control group (platelet count >100,000/mm3, n=240). Surgical outcomes, risk factors for postoperative complications and prognostic factors were retrospectively compared. RESULTS: HCC patients with LPC had poorer liver function, smaller tumors, less anatomical resection and more frequent postoperative liver failure than control group patients. Postoperative survival was not different between the two groups. Tumor invasion to the main branch or trunk of portal vein (Vp3, 4) was the only risk factor for postoperative substantial complications in the LPC group. Postoperative survival was worse in patients with tumor diameter >=4 cm or multiple tumors and in those who underwent preoperative transcatheter arterial chemoembolization (TACE) in the LPC group by multivariate analysis. Among them, preoperative TACE were not prognostic factors in the control group. CONCLUSIONS: In HCC patients with LPC, Vp3, 4 patients should be carefully monitored after surgery and preoperative TACE is not recommended for long-term postoperative survival. PMID- 23435143 TI - The beneficial effects of Kampo medicine Dai-ken-chu-to after hepatic resection: a prospective randomized control study. AB - BACKGROUND/AIMS: After hepatic resection, delayed flatus and impaired bowel movement often cause problematic postoperative ileus. Kampo medicine, Dai-kenchu to (DKT), is reported to have a various beneficial effects on bowel systems. The aim of this study was to prospectively evaluate effects of DKT after hepatic resection. METHODOLOGY: Thirty-two patients who underwent hepatic resection between July 2007 and August 2008 in Tokushima University Hospital were prospectively divided into DKT group (n=16) and control group (n=16). In DKT group, 2.5 g of DKT was administered orally three times a day from postoperative day (POD) 1. Blood was examined on POD 1, 3, 5 and 7. Postoperative first flatus, bowel movement and full recovery of oral intake, hospital stays and complications were checked. RESULTS: In DKT group, levels of c-reactive protein and beta-(1-3) D-glucan on POD 3 were significantly decreased (p<0.05). Moreover, postoperative periods for the first flatus, bowel movement and the full recovery of oral intake were significantly shortened in DKT group (p<0.05). CONCLUSIONS: DKT suppressed inflammatory reaction, stimulated bowel movement and improved oral intake after hepatic resection, which may decrease serious morbidity after hepatic resection. PMID- 23435144 TI - Preoperative transarterial chemoembolization for hepatocellular carcinoma. AB - BACKGROUND/AIMS: The effects of transarterial chemoembolization (TACE) prior to hepatectomy for patients with hepatocellular carcinoma (HCC) are controversial. METHODOLOGY: Clinicopathological profiles and prognosis were compared between patients who underwent hepatic resection following preoperative TACE (Group A, 69 patients) or only resection (Group B, 158 patients). Univariate and multivariate analyses were used to evaluate whether TACE influenced patient prognosis. RESULTS: Profiles of Group A were comparable with those of Group B except for younger age, higher frequency of major hepatectomy, higher incidence of positive surgical margin, vascular invasion and poorly differentiated HCC. Overall survival was significantly worse in Group A than in Group B (5-year survival rate; 29% vs. 69%; p<0.001). A subset of patients in Group A with complete tumor necrosis by TACE showed comparable survival with Group B. Multivariate analysis revealed that preoperative TACE (hazard ratio (HR)=4.3; 95% confidential interval (CI), 2.8-6.6), non-anatomic resection (HR=1.6; 95% CI, 1.1-2.4), blood loss >1L (HR=1.8; 95% CI=1.1-2.8) and vascular invasion (HR=2.3; 95% CI=1.4-3.6) were independent predictors of poor survival. Preoperative TACE was also an independent predictor of extrahepatic metastases (odds ratio, 2.8; 95% CI=1.1 7.1). CONCLUSIONS: Preoperative TACE should not be routinely applied for HCC. PMID- 23435145 TI - The impact of pegylated-interferon alpha-2b on partial and massive hepatectomy model in rats. AB - BACKGROUND/AIMS: The impact of pegylated-interferon (PEG-IFN) alpha-2b on liver regeneration has not yet been elucidated. METHODOLOGY: Rats were divided into the following four groups: 70% hepatectomy (Hx); 70% Hx+PEG-IFN; 90% Hx and 90% Hx+PEG-IFN group (n=6 each). Rats were pretreated with subcutaneous of PEGIFN alpha-2b (1.5 MUg/kg) administration 24 hours before Hx. Samples were taken 24, 48 and 72 hours after Hx and the following parameters were investigated: blood analysis (AST, WBC, PLT); liver weight to body weight ratio (Lw/Bw ratio); survival and PCNA labeling index (LI). RESULTS: In the 90% Hx model, there was no significant difference between the Hx+PEG-IFN group and the Hx alone group in blood analysis; AST after postoperative 24 hours (2511 vs. 2466 IU/L), WBC (1200 vs. 1290) and PLT (107 vs. 111 x 104/mm3), in Lw/Bw ratio at postoperative 0, 24, 48, 72 hours, respectively (0.38, 0.60, 1.14, 1.69 vs. 0.37, 0.64, 1.12, 1.63), in postoperative survival (40% vs. 45%), and in PCNA LI at postoperative 0, 24, 48, 72 hours, respectively (10.4%, 16.8%, 14.6%, 12.8% vs. 10.0%, 17.1%, 15.6%, 13.7%). In the 70% Hx model, there was no significant difference between the Hx+PEG-IFN group and the Hx alone group for all parameters. CONCLUSIONS: Our data demonstrated that PEG-IFN alpha-2b did not affect liver regeneration and the early use of PEG-IFN alpha-2b would cause no problems after liver transplantation using partial grafts including living donor liver transplantation. PMID- 23435146 TI - Successful treatment of severe hepatorenal syndrome with living donor liver transplantation. AB - Hepatorenal syndrome is defined as renal failure caused by acute or chronic liver failure without any laboratory or histological reasons. The exact etiology of this syndrome is unknown. However, vasodilatation in the splanchnic area as a result of cirrhosis and portal hypertension, reflex systemic and splanchnic vasoconstriction are the basic pathophysiological reasons of this syndrome. The decrease of renal perfusion, decrease in glomerular filtration rate, sodium retention and deterioration of excretion of free water are the major renal problems and these remain progressive according to the stage of liver disease. The treatment of this syndrome is correction of the underlying problem. Here, we report a patient who was having hemodialysis due to renal failure as a consequence of liver cirrhosis for three months and returned back to his normal life without a need for dialysis after liver transplantation. PMID- 23435147 TI - Pancreaticogastrostomy in patients with considerably dilated pancreatic ducts. AB - BACKGROUND/AIMS: Patency of pancreaticogastrostomy (PG) is one of the most important factors affecting the function of the remnant pancreas and quality of life. We evaluated the early postoperative changes in pancreatic duct dilation after pancreaticoduodenectomy (PD) and PG with duct-to-mucosa anastomosis in patients with remarkably dilated pancreatic ducts. METHODOLOGY: We retrospectively analyzed 26 patients who had remarkably dilated pancreatic ducts (diameter, >=7 mm) and who underwent PD followed by PG. They were divided into 2 groups on the basis of the endoscopic findings of the anastomotic orifice of PG: Group A, clear pancreatic duct orifice with pancreatic juice output; and Group B, unclear pancreatic duct orifice with pancreatic juice output. RESULTS: The mean diameter of the duct of the remnant pancreas after the surgery was smaller in Group A than in Group B. With regards to postoperative pancreatic exocrine function, there was no significant difference between the 2 groups. CONCLUSIONS: Invagination with duct-to-mucosa anastomosis is a useful technique to prevent pancreatic leakage; however, it is difficult to prevent inflammation and fibrosis around the anastomotic site of PG, and this can lead to anastomotic stricture in patients with a remarkably dilated pancreatic duct (diameter >=7 mm). PMID- 23435148 TI - Manometric study in patients with or without preserved lower esophageal sphincter 2 years or more after total gastrectomy reconstructed by Roux-en-Y for gastric cancer. AB - BACKGROUND/AIMS: Physiological assessments in patients with or without preserved lower esophageal sphincter (LES) after total gastrectomy reconstructed by Roux-en Y (TGRY) are still inconclusive. This study aims to clarify the significance of LES functions in patients, especially prevention of alkali reflux esophagitis (ARE) after TGRY for gastric cancer. METHODOLOGY: Forty-eight patients after TGRY were divided into 2 groups. Group A: 20 patients without preserved LES and group B: 28 patients with preserved LES, and compared with 20 control subjects. The mean follow-up time from operation of TGRY was 27.1 months. Postoperative interview and endoscopic findings for ARE were conducted and esophageal manometry was performed on all patients in order to assess length of LES (LLES; cm) and maximum LES pressure (MLESP; mmHg). RESULTS: Both symptoms and endoscopic findings for ARE in group A were significantly higher than those in group B. The LLES in group A was significantly shorter than that in groups B and C. The MLESP in group A was significantly lower than in groups B and C. CONCLUSION: ARE after TGRY is due to an impairment of LES functions. Preservation of the LES may be necessary to prevent ARE after TGRY. PMID- 23435149 TI - The results of the surgical treatment of alkaline reflux gastritis. AB - BACKGROUND/AIMS: Alkaline reflux gastritis (ARG) is a major complication of gastric surgery. The symptoms of ARG may be intractable and remedial surgery may be required in this patients. The goal of this study was to present our experience reviewing surgical treatment of reflux gastritis. METHODOLOGY: During a 19-year period, we surgically treated 35 patients who had refractory ARG. Previously, gastric surgery was distal gastrectomy-gastrojejunostomy in 20 patients; truncal vagotomy-gastrojejunostomy in 11 and truncal vagotomy pyloroplasty in 4 patients. Of 20 patients who underwent distal gastrectomy, 13 were treated with Roux-en-Y gastrojejunostomy, 6 with jejunal segment between the gastric pouch and duodenum (Henley technique) and one with conversion of Billroth II to Billroth I. Of 11 patients who initially underwent vagotomy gastrojejunostomy, 8 were treated with Billroth II type gastrectomy and Roux-en-Y gastrojejunostomy and 3 with dismantling of a gastrojejunostomy, conversion of pyloroplasty. Four patients who originally underwent vagotomy pyloroplasty were managed with Billroth II type gastrectomy and Roux-en-Y gastrojejunostomy. RESULTS: Mortality rate of this series was zero. Long-term follow-up was obtained in 29 (83.0%) patients. According to Visick criteria, twelve patients (41.4%) reported exellent; ten (34.5%) good; three (10.3%) fair and four (13.8%) unsatisfactory results respectively. CONCLUSIONS: Remedial gastric surgery can be indicated in patients who had persistent ARG symptoms despite conservative management. Careful patient selection is essential to achieve best results. PMID- 23435150 TI - Multiple circular-circular correlation coefficients for the quantification of phase synchronization processes in the brain. AB - Phase synchronization is discussed as a potential mechanism for large-scale integration in the brain. Therefore, the quantification of such synchrony is a crucial topic in brain science research. Furthermore, these cerebral integration processes are likely to involve entire brain areas; therefore, the analysis of multiple couplings is of particular interest. Because phase values are circular variables, it is possible to use circular statistical methods for their examination. In particular, circular-circular correlation coefficients form a suitable measurement to estimate the extent of phase synchronization between different signals. As a multiple circular-circular correlation concept is still pending, two new multiple circular-circular correlation coefficients are presented in this article that can be used to quantify phase couplings between one dependent and an arbitrary number of predictor signals. PMID- 23435151 TI - The Asian project for collaborative derivation of reference intervals: (1) strategy and major results of standardized analytes. AB - BACKGROUND: A multicenter study conducted in Southeast Asia to derive reference intervals (RIs) for 72 commonly measured analytes (general chemistry, inflammatory markers, hormones, etc.) featured centralized measurement to clearly detect regionality in test results. The results of 31 standardized analytes are reported, with the remaining analytes presented in the next report. METHOD: The study included 63 clinical laboratories from South Korea, China, Vietnam, Malaysia, Indonesia, and seven areas in Japan. A total of 3541 healthy individuals aged 20-65 years (Japan 2082, others 1459) were recruited mostly from hospital workers using a well-defined common protocol. All serum specimens were transported to Tokyo at -80 degrees C and collectively measured using reagents from four manufacturers. Three-level nested ANOVA was used to quantitate variation (SD) of test results due to region, sex, and age. A ratio of SD for a given factor over residual SD (representing net between-individual variations) (SDR) exceeding 0.3 was considered significant. Traceability of RIs was ensured by recalibration using value-assigned reference materials. RIs were derived parametrically. RESULTS: SDRs for sex and age were significant for 19 and 16 analytes, respectively. Regional difference was significant for 11 analytes, including high density lipoprotein (HDL)-cholesterol and inflammatory markers. However, when the data were limited to those from Japan, regionality was not observed in any of the analytes. Accordingly, RIs were derived with or without partition by sex and region. CONCLUSIONS: RIs applicable to a wide area in Asia were established for the majority of analytes with traceability to reference measuring systems, whereas regional partitioning was required for RIs of the other analytes. PMID- 23435152 TI - The Asian project for collaborative derivation of reference intervals: (2) results of non-standardized analytes and transference of reference intervals to the participating laboratories on the basis of cross-comparison of test results. AB - BACKGROUND: The 2009 Asian multicenter study for derivation of reference intervals (RIs) featured: 1) centralized measurements to exclude reagent dependent variations; 2) inclusion of non-standardized analytes (hormones, tumor makers, etc.) in the target; and 3) cross-check of test results between the central and local laboratories. Transferability of centrally derived RIs for non standardized analytes based on the cross-check was examined. METHODS: Forty non standardized analytes were centrally measured in sera from 3541 reference individuals recruited by 63 laboratories. Forty-four laboratories collaborated in the cross-check study by locally measuring aliquots of sera from 9 to 73 volunteers (average 22.2). Linear relationships were obtained by the major-axis regression. Error in converting RIs using the regression line was expressed by the coefficient of variation of slope b [CV(b)]. CV(b) <10% was set as the cut off value allowing the conversion. The significance of factors for partitioning RIs was determined similarly as in the first report. RESULTS: Significant sex-, age-, and region-related changes in test results were observed in 17, 15, and 11 of the 40 analytes, respectively. In the cross-comparison study, test results were not harmonized in the majority of immunologically measured analytes, but their average CV(b)s were <10% except for total protein, cystatin C, CA19-9, free thyroxine, and triiodothyronine. After conversion, 74% of centrally derived RIs were transferred to each local laboratory. CONCLUSIONS: Our results point to the feasibility of: 1) harmonizing test results across different laboratories; and 2) sharing centrally derived RIs of non-standardized analytes by means of comparative measurement of a set of commutable specimens. PMID- 23435153 TI - Partial reconstruction of the ergot alkaloid pathway by heterologous gene expression in Aspergillus nidulans. AB - Ergot alkaloids are pharmaceutically and agriculturally important secondary metabolites produced by several species of fungi. Ergot alkaloid pathways vary among different fungal lineages, but the pathway intermediate chanoclavine-I is evolutionarily conserved among ergot alkaloid producers. At least four genes, dmaW, easF, easE, and easC, are necessary for pathway steps prior to chanoclavine I; however, the sufficiency of these genes for chanoclavine-I synthesis has not been established. A fragment of genomic DNA containing dmaW, easF, easE, and easC was amplified from the human-pathogenic, ergot alkaloid-producing fungus Aspergillus fumigatus and transformed into Aspergillus nidulans, a model fungus that does not contain any of the ergot alkaloid synthesis genes. HPLC and LC-MS analyses demonstrated that transformed A. nidulans strains produced chanoclavine I and an earlier pathway intermediate. Aspergillus nidulans transformants containing dmaW, easF, and either easE or easC did not produce chanoclavine-I but did produce an early pathway intermediate and, in the case of the easC transformant, an additional ergot alkaloid-like compound. We conclude that dmaW, easF, easE, and easC are sufficient for the synthesis of chanoclavine-I in A. nidulans and expressing ergot alkaloid pathway genes in A. nidulans provides a novel approach to understanding the early steps in ergot alkaloid synthesis. PMID- 23435154 TI - Effect of gating modifier toxins on membrane thickness: implications for toxin effect on gramicidin and mechanosensitive channels. AB - Various gating modifier toxins partition into membranes and interfere with the gating mechanisms of biological ion channels. For example, GsMTx4 potentiates gramicidin and several bacterial mechanosensitive channels whose gating kinetics are sensitive to mechanical properties of the membrane, whereas binding of HpTx2 shifts the voltage-activity curve of the voltage-gated potassium channel Kv4.2 to the right. The detailed process by which the toxin partitions into membranes has been difficult to probe using molecular dynamics due to the limited time scale accessible. Here we develop a protocol that allows the spontaneous assembly of a polypeptide toxin into membranes in atomistic molecular dynamics simulations of tens of nanoseconds. The protocol is applied to GsMTx4 and HpTx2. Both toxins, released in water at the start of the simulation, spontaneously bind into the lipid bilayer within 50 ns, with their hydrophobic patch penetrated into the bilayer beyond the phosphate groups of the lipids. It is found that the bilayer is about 2 A thinner upon the binding of a GsMTx4 monomer. Such a thinning effect of GsMTx4 on membranes may explain its potentiation effect on gramicidin and mechanosensitive channels. PMID- 23435155 TI - Emergy accounting for regional studies: case study of Canada and its provinces. AB - Sustainable regional management (development) requires an understanding of interactions between the social, economic, and ecological systems within the boundaries of a region. In this paper, application of emergy (an environmental accounting method) for regional planning is discussed through a case study. Emergy (spelled with an "m") methodology is an environmental accounting technique that evaluates the energy system for the thermodynamics of an open system. Major renewable and non-renewable resource fluxes to a region, including energy, matter, human activities, and money can be converted to emergy by using corresponding transformity functions. As a case study, this paper discusses the emergy accounting of Canada and its provinces with various emergy-based indicators. Moreover, emergy maps were generated in a form of emergy geography. These maps are multi-dimensional illustrations that show resource consumption, emergy per person, and emergy density across Canada under two parameters: (1) the quantities of resources consumed and (2) the location of consumption. Emergy analysis also highlights concentrations of renewable and natural resources in Canada and distinguishes the provinces with the highest resource consumption. Analysis of emergy indicator for Canadian provinces shows that Alberta with the highest EYR (7.35) provides energy to the economy of Canada. However, ELR value of Alberta (8.5) indicates that the province's current economic approach is not sustainable as it relies mainly on non-renewable emergy inputs (mainly from fossil fuels). ELR of British Columbia and Manitoba indicates that these two provinces created a firm balance between emergy use of renewable and non renewable resources. The characterizations of regions provided in this paper can be used for future land planning and management both in federal and provincial levels. PMID- 23435156 TI - An environmental impact calculator for greenhouse production systems. AB - Multiple web-based calculators have come on the market as tools to support sustainable decision making, but few are available to agriculture. Life cycle assessment (LCA) has proved to be an objective, transparent tool for calculating environmental impacts throughout the life cycle of products and services, but can often be too complex for non-specialists. The objective of this study was therefore to develop an environmental support tool to determine the environmental impacts of protected crops. An effort was made to provide an easy-to-use tool in order to reach a wide audience and help horticulture stakeholders choose efficient options to mitigate the environmental impacts of protected crops. Users can estimate the environmental performance of their crops by entering a limited amount of data and following a few easy steps. A questionnaire must be answered with data on the crop, greenhouse dimensions, substrate, waste management, and the consumption of water, energy, fertilisers and pesticides. The calculator was designed as a simplified LCA, based on two scenarios analysed in detail in previous tasks of the EUPHOROS project and used as reference systems in this study. Two spreadsheets were provided based on these reference scenarios: one for a tomato crop in a multi-tunnel greenhouse under Southern European climate conditions and the other for a tomato crop in a Venlo glass greenhouse under Central European climate conditions. The selected functional unit was one tonne of tomatoes. Default data were given for each reference system for users who did not have complete specific data and to provide results for comparison with users' own results. The results were presented for water use as an inventory indicator and for the impact categories abiotic depletion, acidification, eutrophication, global warming, photochemical oxidation and cumulative energy demand. In the multi-tunnel greenhouse, the main contributors based on the default data were the structure, fertilisers and auxiliary equipment, whereas, for the Venlo glass greenhouse, the main contributors were energy consumption for heating and, to a lesser extent, the structure. The results were evaluated for alternative options of electricity, fertilisers, pesticides and means of transport, as these areas were found to have potential variability, depending on the characterisation model and datasets used. The resulting calculator is a useful tool to simulate the environmental performance of protected horticultural production systems and is also helpful to growers and advisers for evaluating the efficiency of input reduction options. PMID- 23435157 TI - All-cause and cardiovascular mortality in middle-aged people with type 2 diabetes compared with people without diabetes in a large U.K. primary care database. AB - OBJECTIVE: Middle-aged people with diabetes have been reported to have significantly higher risks of cardiovascular events than people without diabetes. However, recent falls in cardiovascular disease rates and more active management of risk factors may have abolished the increased risk. We aimed to provide an up to-date assessment of the relative risks associated with type 2 diabetes of all cause and cardiovascular mortality in middle-aged people in the U.K. RESEARCH DESIGN AND METHODS: Using data from the General Practice Research Database, from 2004 to 2010, we conducted a cohort study of 87,098 people, 40-65 years of age at baseline, comparing 21,798 with type 2 diabetes and 65,300 without diabetes, matched on age, sex, and general practice. We produced hazard ratios (HRs) for mortality and compared rates of blood pressure testing, cholesterol monitoring, and use of aspirin, statins, and antihypertensive drugs. RESULTS People with type 2 diabetes, compared with people without diabetes, had a twofold increased risk of all-cause mortality (HR 2.07 [95% CI 1.95-2.20], adjusted for smoking) and a threefold increased risk of cardiovascular mortality (3.25 [2.87-3.68], adjusted for smoking). Women had a higher relative risk than men, and people <55 years of age had a higher relative risk than those >55 years of age. Monitoring and medication rates were higher in those with diabetes (all P < 0.001). CONCLUSIONS: Despite efforts to manage risk factors, administer effective treatments, and develop new therapies, middle-aged people with type 2 diabetes remain at significantly increased risk of death. PMID- 23435158 TI - Reduced heart rate variability is associated with increased arterial stiffness in youth with type 1 diabetes: the SEARCH CVD study. AB - OBJECTIVE: Reduced heart rate variability (HRV) and increased arterial stiffness (AS) are both present in youth with type 1 diabetes. However, it is unclear whether they are associated and whether their association is independent of cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS: The SEARCH Cardiovascular Disease (SEARCH CVD) study explored the cross-sectional relationships between HRV and several measures of AS in youth with (n = 344) and without (n = 171) type 1 diabetes. The SphygmoCor device (AtCor Medical, Sydney, Australia) was used to measure HRV using SD of normal R-R interval (SDNN), as well as AS, using pulse wave velocity in the carotid to femoral segment (PWV trunk) and augmentation index adjusted to a heart rate of 75 bpm (AIx75). Brachial distensibility (BrachD), another index of AS, was measured with a DynaPulse instrument (Pulse Metric, San Diego, CA). Multiple linear regression analyses explored the associations between HRV and each of the three AS measures, after adjusting for demographic characteristics and traditional CVD risk factors (blood pressure, lipids, obesity, microalbuminuria, and smoking) separately, for youth with and without type 1 diabetes. RESULTS: Among youth with type 1 diabetes, lower SDNN was associated with peripheral AS (lower BrachD, P = 0.01; r(2) = 0.30) and central AS (higher PVW-trunk, P < 0.0001; r(2) = 0.37; and higher AIx75, P = 0.007; r(2) = 0.08). These associations were attenuated with adjustment for CVD risk factors, but remained statistically significant for BrachD and PWV-trunk. While a similar association between HRV and BrachD was present in control youth, lower HRV was not associated with increased central AS or with AIx75. CONCLUSIONS: Longitudinal studies are needed to understand the pathways responsible for these associations. PMID- 23435160 TI - Changes in A1C levels are significantly associated with changes in levels of the cardiovascular risk biomarker hs-CRP: results from the SteP study. AB - OBJECTIVE: The effect of therapeutic strategies on cardiovascular (CV) disease can be evaluated by monitoring changes in CV risk biomarkers. This study investigated the effect of a structured self-monitoring of blood glucose (SMBG) protocol and the resulting improvements in glycemic control on changes in high sensitivity C-reactive protein (hs-CRP) in insulin-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Structured Testing Program (STeP) study was a prospective, cluster-randomized, multicenter trial in which 483 poorly controlled, insulin-naive patients with type 2 diabetes were randomized to active control (ACG) or structured testing (STG) that included quarterly structured SMBG. Changes in A1C, hs-CRP, and glycemic variability (STG subjects only) were measured at baseline and quarterly. RESULTS: Reductions in geometric mean hs-CRP values were significantly greater in the STG group at months 3 (P = 0.005), 6 (P = 0.0003), and 12 (P = 0.04) than in the ACG group. STG patients at high CV risk (>3 mg/L) showed significantly greater reductions in hs-CRP levels than ACG patients at high CV risk: -3.64 mg/dL (95% CI -4.21 to -3.06) versus 2.18 mg/dL (-2.93 to -1.43), respectively (P = 0.002). There was a strong correlation between reductions in hs-CRP and A1C in both groups: standardized coefficient (beta) was 0.25 for the entire cohort (P < 0.0001), 0.31 for STG (P < 0.0001), and 0.16 for ACG (P = 0.02). CONCLUSIONS: Reductions in hs-CRP level are associated with reductions in A1C but not reductions in lipids or glycemic variability. Comprehensive structured SMBG-based interventions that lower A1C may translate into improvements in CV risk, as evidenced by levels of the biomarker hs-CRP. PMID- 23435159 TI - Randomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial. AB - OBJECTIVE: Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (<= 0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI). RESULTS: Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG <70 mg/dL occurred in 16% of patients in the basal bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL; P = 0.76). CONCLUSIONS: The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D. PMID- 23435161 TI - Brain metastases from esophageal cancer: clinical review of 26 cases. AB - OBJECTIVE: To assess the frequency of brain metastasis in patients with primary esophageal cancer and to describe the clinical characteristics, diagnosis, and prognosis. METHODS: Of 1612 patients with primary esophageal carcinoma treated at a single institution from 2000-2010, a retrospective analysis of the medical files of 26 consecutive patients with central nervous system involvement was carried out. The clinical history, imaging, and pathologic findings were analyzed. RESULTS: Of the 26 patients, 12 initially presented with a single cerebral metastatic lesion, and 14 had multiple brain lesions. There were 4 patients with adenocarcinoma and 22 with squamous cell carcinoma. Treatments were as follows: 5 patients underwent surgery followed by whole-brain radiation, 5 underwent stereotactic radiosurgery, 13 received whole-brain radiation, and 3 received chemotherapy. The median survival was 4.2 months; 1-year survival rate was 5.8%. CONCLUSIONS: In this retrospective study of 1612 patients with esophageal carcinoma at a single medical center, 1.61% (26 of 1612) of the patients had a diagnosis of brain metastasis. The prognosis is poor for patients with brain metastasis from esophageal carcinoma. A solitary brain lesion, surgical treatment, and a good Karnofsky Performance Status may indicate a good prognosis. PMID- 23435162 TI - Traumatic brain injury and hypopituitarism: a legal relationship? PMID- 23435163 TI - A ratiometric fluorescent probe for hydrophobic proteins in aqueous solution based on aggregation-induced emission. AB - A novel fluorescent probe 1 is reported here with ratiometric response to hydrophobic proteins (casein) or proteins with hydrophobic pockets (BSA, HSA) through hydrophobic interaction. Probe 1 underwent deprotonation in aqueous solution at pH 7.4 and emitted blue fluorescence at 436 nm. Upon the addition of BSA, HSA or casein, the aggregation-induced emission fluorescence of 1 at 518 nm was turned on. The fluorescence intensity ratio, I518/I436 was linearly related to the concentrations of these proteins. The detection limits for BSA, HSA and casein based on IUPAC (CDL = 3Sb m(-1)) were 16.2 MUg mL(-1), 10.5 MUg mL(-1) and 5.7 MUg mL(-1), respectively. PMID- 23435164 TI - Inequality in child mortality across different states of India: a comparative study. AB - The burden of social inequality falls disproportionately on child health and survival. This inequality raises the question of how wide this gap is, or what its relation is with the level of child mortality. Whether these disparities are increasing or declining with the development and how they differ from region to region or from state to state within the country needs to be looked into. As a measure of inequality and to compare the disparities between different states of India, concentration curves and indices are constructed from infant and under five mortality data classified under different quintiles of wealth index from the National Family Health Survey (NFHS-3) data of India. Inequality measures indicate that inequality in child mortality is more concentrated in the comparatively developed states than the poorer states in India. PMID- 23435165 TI - Resilience as a protective factor for the behavioral problems in school-aged children with atopic dermatitis. AB - This study investigates the relationships between resilience and behavioral problems in school-aged children with atopic dermatitis (AD) and identifies factors associated with these behavioral problems. A total of 102 school-aged children suffering from chronic AD were administered a self-report questionnaire on resilience, and the Korean version of the Child Behavior Checklist, to measure their internalizing/externalizing behavioral problems. The means of the internalizing and externalizing behavioral problems of children with AD were 6.58 and 7.26, respectively. Both resilience and economic status were negatively correlated with the internalizing, r = -0.262, p < 0.05, and externalizing, r = 0.248, p < 0.05, behaviors in children. The higher the children's school achievements, the less externalizing behavioral problems were reported, r = 0.327, p < 0.05. Resilience was identified as the single potent variable affecting children's behavioral problems. The higher the children's resilience scores, the lower was the chance of both internalizing, beta = -1.648, p = 0.034, and externalizing behavioral problems, beta = -1.382, p = 0.041. To prevent possible behavioral problems in children with chronic AD, a care plan enhancing their resilience (i.e. promoting parenting skills and social supports for children) should be developed. PMID- 23435166 TI - Health care access disparities among children entering kindergarten in Nevada. AB - The objective of this study was to advance our understanding and appreciation of the health status of young children in the state of Nevada in addition to their discrepancies in accessing health care. This study used the 2008-2009 Nevada Kindergarten Health Survey data of 11,073 children to assess both independent and combined effects of annual household income, race/ethnicity, primary language spoken in the family, rural/urban residence, and existing medical condition on access to health care. Annual household income was a significant predictor of access to health care, with middle and high income respondents having regular access to care compared to low income counterparts. Further, English proficiency was associated with access to health care, with English-speaking Hispanics over 2.5 times more likely to have regular access to care than Spanish-speaking Hispanics. Rural residents had decreased odds of access to preventive care and having a primary care provider, but unexpectedly, had increased odds of having access to dental care compared to urban residents. Finally, parents of children with no medical conditions were more likely to have access to care than those with a medical condition. The consequences for not addressing health care access issues include deteriorating health and well-being for vulnerable socio demographic groups in the state. Altogether these findings suggest that programs and policies within the state must be sensitive to the specific needs of at risk groups, including minorities, those with low income, and regionally and linguistically isolated residents. PMID- 23435167 TI - Structural characterization of novel extracellular liamocins (mannitol oils) produced by Aureobasidium pullulans strain NRRL 50380. AB - Aureobasidium pullulans is a common, ubiquitous fungus, which is used industrially to produce the polysaccharide pullulan. We have previously shown that A. pullulans produces various heavier-than-water oils, first named here as liamocins, that accumulate in fermentations. Here we report the structural characterization of four liamocins, A1, A2, B1, and B2, produced by A. pullulans strain NRRL 50380 using a combination of MALDI-TOF/MS, quadrupole-TOF/MS, isotopic labeling, NMR, GC/MS, and classical carbohydrate analysis. The data showed that the liamocins are composed of a single mannitol headgroup partially O acylated with three (for liamocin A1 and A2) or four (for liamocin B1 and B2) 3,5 dihydroxydecanoic ester groups. Liamocins A1 and B1 are non-acetylated, whereas A2 and B2 each contain a single 3'-O-acetyl group. Each of these compounds is characterized by pseudomolecular [M+Na](+) ions in the MALDI-TOF/MS spectra at m/z 763.22, 949.35, 805.22, and 991.37, respectively. The 186Da mass difference between A-type and B-type liamocins corresponds to one O-linked 3,5 dihydroxydecanoate group. HMBC NMR showed that one 3,5-dihydroxydecanoate carbonyl group is ester linked to a primary hydroxyl on the mannitol. Other long range (13)C-(1)H couplings across 1,5-ester bridges showed that the 3,5 dihydroxydecanoate groups form 1-5-linked polyester chains, similar in structure to the antibiotic substance exophilin A. Moreover, the MS analysis identified several non-conjugated poly-3,5-dihydroxydecanoate esters as minor components that are tentatively assigned as exophilins A1, A2, B1, and B2. The liamocins, and three of the exophilins, are new, previously unreported structures. PMID- 23435168 TI - Tin-catalyzed efficient conversion of carbohydrates for the production of 5 hydroxymethylfurfural in the presence of quaternary ammonium salts. AB - An efficient and tin-catalyzed production of 5-hydroxymethyl furfural (5-HMF) from carbohydrates is reported. The efficient conversion of glucose has been investigated using the combination of SnCl4 and different quaternary ammonium salts. It was found that tetrabutyl ammonium bromide (TBAB) was able to efficiently promote conversion of glucose to 5-HMF in the presence of SnCl4. For instance, a 69.1% yield of 5-HMF was obtained with SnCl4-tetrabutyl ammonium bromide (SnCl4-TBAB) system in DMSO for 2h at 100 degrees C in air. The effects of catalyst amount, reaction time, and reaction temperature were investigated in detail. Furthermore, the SnCl4-TBAB was also employed to the conversion of fructose, sucrose, inulin, starch, and cellulose. The competitive results were obtained under mild conditions. PMID- 23435169 TI - The problems facing epilepsy therapy. PMID- 23435170 TI - Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. AB - Delayed T cell recovery and restricted T cell receptor (TCR) diversity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and cancer relapse. Technical challenges have limited faithful measurement of TCR diversity after allo-HSCT. Here we combined 5' rapid amplification of complementary DNA ends PCR with deep sequencing to quantify TCR diversity in 28 recipients of allo-HSCT using a single oligonucleotide pair. Analysis of duplicate blood samples confirmed that we accurately determined the frequency of individual TCRs. After 6 months, cord blood-graft recipients approximated the TCR diversity of healthy individuals, whereas recipients of T cell-depleted peripheral-blood stem cell grafts had 28 fold and 14-fold lower CD4(+) and CD8(+) T cell diversities, respectively. After 12 months, these deficiencies had improved for the CD4(+) but not the CD8(+) T cell compartment. Overall, this method provides unprecedented views of T cell repertoire recovery after allo-HSCT and may identify patients at high risk of infection or relapse. PMID- 23435171 TI - Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. AB - Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism. PMID- 23435172 TI - Arabidopsis scaffold protein RACK1A interacts with diverse environmental stress and photosynthesis related proteins. AB - Scaffold proteins are known to regulate important cellular processes by interacting with multiple proteins to modulate molecular responses. RACK1 (Receptor for Activated C Kinase 1) is a WD-40 type scaffold protein, conserved in eukaryotes, from Chlamydymonas to plants and humans, expresses ubiquitously and plays regulatory roles in diverse signal transduction and stress response pathways. Here we present the use of Arabidopsis RACK1A, the predominant isoform of a 3-member family, as a bait to screen a split-ubiquitin based cDNA library. In total 97 proteins from dehydration, salt stress, ribosomal and photosynthesis pathways are found to potentially interact with RACK1A. False positive interactions were eliminated following extensive selection based growth potentials. Confirmation of a sub-set of selected interactions is demonstrated through the co-transformation with individual plasmid containing cDNA and the respective bait. Interaction of diverse proteins points to a regulatory role of RACK1A in the cross-talk between signaling pathways. Promoter analysis of the stress and photosynthetic pathway genes revealed conserved transcription factor binding sites. RACK1A is known to be a multifunctional protein and the current identification of potential interacting proteins and future in vivo elucidations of the physiological basis of such interactions will shed light on the possible molecular mechanisms that RACK1A uses to regulate diverse signaling pathways. PMID- 23435173 TI - Aquaporin genes GintAQPF1 and GintAQPF2 from Glomus intraradices contribute to plant drought tolerance. AB - Arbuscular mycorrhizal (AM) symbiosis, established between AM fungi (AMF) and roots of higher plants, occurs in most terrestrial ecosystems. It has been well demonstrated that AM symbiosis can improve plant performance under various environmental stresses, including drought stress. However, the molecular basis for the direct involvement of AMF in plant drought tolerance has not yet been established. Most recently, we cloned two functional aquaporin genes, GintAQPF1 and GintAQPF2, from AM fungus Glomus intraradices. By heterologous gene expression in yeast, aquaporin localization, activities and water permeability were examined. Gene expressions during symbiosis in expose to drought stress were also analyzed. Our data strongly supported potential water transport via AMF to host plants. As a complement, here we adopted the monoxenic culture system for AMF, in which carrot roots transformed by Ri-T DNA were cultured with Glomus intraradices in two-compartment Petri dishes, to verify the aquaporin gene functions in assisting AMF survival under polyethylene glycol (PEG) treatment. Our results showed that 25% PEG significantly upregulated the expression of two aquaporin genes, which was in line with the gene functions examined in yeast. We therefore concluded that the aquaporins function similarly in AMF as in yeast subjected to osmotic stress. The study provided further evidence to the direct involvement of AMF in improving plant water relations under drought stresses. PMID- 23435174 TI - The impact of low-temperature seasonal aquifer thermal energy storage (SATES) systems on chlorinated solvent contaminated groundwater: modeling of spreading and degradation. AB - Groundwater systems are increasingly used for seasonal aquifer thermal energy storage (SATES) for periodic heating and cooling of buildings. Its use is hampered in contaminated aquifers because of the potential environmental risks associated with the spreading of contaminated groundwater, but positive side effects, such as enhanced contaminant remediation, might also occur. A first reactive transport study is presented to assess the effect of SATES on the fate of chlorinated solvents by means of scenario modeling, with emphasis on the effects of transient SATES pumping and applicable kinetic degradation regime. Temperature effects on physical, chemical, and biological reactions were excluded as calculations and initial simulations showed that the small temperature range commonly involved (DeltaT<15 degrees C) only caused minor effects. The results show that a significant decrease of the contaminant mass and (eventually) plume volume occurs when degradation is described as sediment-limited with a constant rate in space and time, provided that dense non-aqueous phase liquid (DNAPL) is absent. However, in the presence of DNAPL dissolution, particularly when the dissolved contaminant reaches SATES wells, a considerably larger contaminant plume is created, depending on the balance between DNAPL dissolution and mass removal by degradation. Under conditions where degradation is contaminant-limited and degradation rates depend on contaminant concentrations in the aquifer, a SATES system does not result in enhanced remediation of a contaminant plume. Although field data are lacking and existing regulatory constraints do not yet permit the application of SATES in contaminated aquifers, reactive transport modeling provides a means of assessing the risks of SATES application in contaminated aquifers. The results from this study are considered to be a first step in identifying the subsurface conditions under which SATES can be applied in a safe or even beneficial manner. PMID- 23435176 TI - Reflections on leadership. PMID- 23435177 TI - Comparison of serum antibody responses and host protection against parasite Ichthyophthirius multifiliis between channel catfish and channel * blue hybrid catfish. AB - There is limited information available on the immune protection of channel catfish Ictalurus punctatus * blue catfish I. furcatus (CB) hybrid against the fish parasite Ichthyophthirius multifiliis (Ich). The objective of this study was to compare serum antibody response and host protection between channel catfish and CB hybrid catfish using a cohabitation model. Channel catfish and CB hybrid catfish were immunized with live theronts by immersion or by IP injection at the dose of 10,000-20,000 theronts per fish in two trials. The fish were then challenged with theronts to compare serum antibody response and protection against the parasite between channel catfish and CB hybrid catfish. The immunized channel catfish and CB hybrid catfish showed a significantly higher (p < 0.05) serum anti-Ich antibody (titer > 1120) compared to non-immunized controls (titer = 0). After being challenged with live theronts, the immunized channel catfish and CB hybrid catfish had none or a low number of the parasites (<50 trophonts per fish) and showed a significantly higher (p < 0.05) survival (90-100%) than non-immunized controls (0%). Overall results indicated that there was no statistical (p > 0.05) difference on serum anti-Ich antibody, parasite infection and fish survival between immunized channel catfish and CB hybrid catfish. PMID- 23435178 TI - Overexpression of a C-type lectin enhances bacterial resistance in red swamp crayfish Procambarus clarkii. AB - C-type lectins play important roles in the innate immune system of crustaceans. In this study, a novel C-type lectin gene, designated as PcLec4, was obtained from the red swamp crayfish (Procambarus clarkii). Quantitative real-time polymerase chain reaction revealed that PcLec4 is mainly expressed in the crayfish hepatopancreas and intestine, and the PcLec4 mRNA expression is upregulated after challenged with the bacteria Vibrio anguillarum. PcLec4 was recombinantly expressed in Escherichia coli and anti-PcLec4 polyclonal antiserum was prepared. Binding experiments revealed that the recombinant PcLec4 binds to various bacteria and polysaccharides on the bacterial surface, which suggests that PcLec4 recognizes bacterial pathogens. Overexpression of PcLec4 in crayfish using the pIeLec4 vector was performed. The results show that the crayfish overexpressing PcLec4 eliminate injected V. anguillarum more quickly than the control, which suggests that PcLec4 elicits further immune response for removing invading bacteria. The results of the survival experiment confirmed the function of PcLec4 in resisting V. anguillarum because PcLec4 overexpression in crayfish significantly increased the crayfish survival rate. These results reveal that PcLec4 has an important role in the antibacterial immunity of crayfish, and in vivo PcLec4 overexpression might be used as a disease control strategy in aquiculture. PMID- 23435179 TI - Botulinum toxins: mechanisms of action, antinociception and clinical applications. AB - Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram positive, spore-forming, anaerobic bacterium, Clostridum botulinum. There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G. Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ~100 kDa and a light chain (L) of ~50 kDa held together by a single disulfide bond. Each serotype demonstrates its own varied mechanisms of action and duration of effect. The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs. The light chain acts to cleave SNAP 25, which inhibits synaptic exocytosis, and therefore, disables neural transmission. The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxin's apparent analgesic activity. Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions. PMID- 23435181 TI - Proteome analysis for profiling infertility markers in male mouse sperm after carbon ion radiation. AB - Ion radiation or radiotherapy is used to treat male patients with oligozoospermia, azoospermia, temporarily infertility, or even permanent infertility. The present study aims to investigate the potential infertility mechanism of sperm in mice after carbon ion radiation (CIR). The caudal epididymal sperm of male mice whole-body irradiated with carbon ion beam (0.5Gy and 4Gy) were used 7 days after irradiation. A two-dimensional gel electrophoresis approach was employed to investigate the changes in protein expression in the caudal edididymal sperm. Spot detection and matching were performed using the PDQuest 8.0 software. The criteria used to select spots for the analysis were more than a threefold difference in protein quantities (normalized spot volume), which allowed the detection of six differentially expressed proteins. Protein identification was performed using MALDI-TOF-TOF. Six specific proteins were identified by searching the NCBI protein sequence database. Among these proteins, HSP 70-2, PLC, GPX4, beta-tubulin, and GAPDHS were associated with sperm motility, which can affect fertility. beta-tubulin is important in axoneme migration flagellar movement and regulation, and GAPDHS is related to sperm energy supply. We analyzed their expressions using immunoblotting and immunofluorescence. The changes in sperm protein expression after CIR are mainly associated with motility. These proteins are potential markers for the mechanisms of infertility in space or radiotherapy. PMID- 23435180 TI - Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid. AB - The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARalpha) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARalpha agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARalpha target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans. PMID- 23435182 TI - Effects of mining-associated lead and zinc soil contamination on native floristic quality. AB - We assessed the quality of plant communities across a range of lead (Pb) and zinc (Zn) soil concentrations at a variety of sites associated with Pb mining in southeast Missouri, USA. In a novel application, two standard floristic quality measures, Mean Coefficient of Conservatism (Mean C) and Floristic Quality Index (FQI), were examined in relation to concentrations of Pb and Zn, soil nutrients, and other soil characteristics. Nonmetric Multidimensional Scaling and Regression Tree Analyses identified soil Pb and Zn concentrations as primary explanatory variables for plant community composition and indicated negative relationships between soil metals concentrations and both Mean C and FQI. Univariate regression also demonstrated significant negative relationships between metals concentrations and floristic quality. The negative effects of metals in native soils with otherwise relatively undisturbed conditions indicate that elevated soil metals concentrations adversely affect native floristic quality where no other human disturbance is evident. PMID- 23435183 TI - Composting toilets a misnomer: excessive ammonia from urine inhibits microbial activity yet is insufficient in sanitizing the end-product. AB - End-product from 16 public mixed latrine style composting toilets (CTs) at 12 sites between 50 and 2100 m.a.s.l. in Western North America was tested in order to evaluate the effect of composting variables (TS%, NH3-N, temperature, and material age) on compost quality and hygiene (VS%, Escherichia coli, [Formula: see text] -N, and pH). Principal component analysis indicated that TS%, temperature, and material age equally contributed to reduction in VS%. NH3-N had the greatest effect on [Formula: see text] -N, E. coli, and pH. Nitrification was significantly inhibited above 386 mg/kg NH3-N, but no such limit was found for E. coli, despite a significant (p = 0.016) but weak (r(2) = 0.11) negative relationship. It may be possible to amplify the sanitizing effect of ammonia and overcome pathogen resistance due to low temperatures and re-contamination (caused by poor design) with generous dosing of urea and ash. However, even sanitized, the fertilization effect of discharged material on the natural environment may not be desired or permitted in parks or protected areas where many CTs were found. To this end, operators of CTs need to evaluate their primary management objectives and ensure congruency with proven system capabilities. PMID- 23435184 TI - A risk score for identifying overweight adolescents with dysglycemia in primary care settings. AB - OBJECTIVE: To develop a clinical risk scoring system for identifying adolescents with dysglycemia (prediabetes or diabetes) who need further confirmatory testing and to determine whether the addition of non-fasting tests would improve the prediction of dysglycemia. STUDY DESIGN: A sample of 176 overweight and obese adolescents (10-17 years) had a history/physical exam, a 2-h oral glucose tolerance test, and non-fasting tests [hemoglobin A1c, 1-h glucose challenge test (GCT), and random glucose test] performed. Given the low number of children with diabetes, we created several risk scoring systems combining the clinical characteristics with non-fasting tests for identifying adolescents with dysglycemia and compared the test performance. RESULTS: Sixty percent of participants were white and 32% were black; 39.2% had prediabetes and 1.1% had diabetes. A basic model including demographics, body mass index percentile, family history of diabetes, and acanthosis nigricans had reasonable test performance [area under the curve (AUC), 0.75; 95% confidence interval (95% CI), 0.68-0.82]. The addition of random glucose (AUC, 0.81; 95% CI, 0.75-0.87) or 1-h GCT (AUC, 0.82; 95% CI, 0.75-0.88) to the basic model significantly improved the predictive capacity, but the addition of hemoglobin A1c did not (AUC, 0.76; 95% CI, 0.68-0.83). The clinical score thresholds to consider for the basic plus random glucose model are total score cutoffs of 60 or 65 (sensitivity 86% and 65% and specificity 60% and 78%, respectively) and for the basic plus 1-h GCT model are total score cutoffs of 50 or 55 (sensitivity 87% and 73% and specificity 59% and 76%, respectively). CONCLUSIONS: Pending a validation in additional populations, a risk score combining the clinical characteristics with non-fasting test results may be a useful tool for identifying children with dysglycemia in the primary care setting. PMID- 23435185 TI - Mitragyna speciosa Korth leaves extracts induced the CYP450 catalyzed aminopyrine N-demethylase (APND) and UDP-glucuronosyl transferase (UGT) activities in male Sprague-Dawley rat livers. AB - BACKGROUND: Mitragyna speciosa leaves have been abused by drug addicts as some of the alkaloids (mainly mitragynine) from the plant possess opiate and cocaine-like effects. These bring to its prohibition in Malaysia in 2004 as consumption of M. speciosa leaves has been perceived to lead to the abuse of other drugs such as cannabis and heroin. METHODS: In the current study, the in vitro and in vivo effects of M. speciosa methanolic, aqueous and total alkaloid leaves extracts on drug metabolizing enzymes, namely, cytochrome P450s (CYP450s) and UDP glucuronosyl transferase (UGT) had been evaluated in rat liver cytosolic fraction and microsomes. Aminopyrine and p-nitrophenol (pNP) were employed as probe substrates in aminopyrine N-demethylase (APND) and UGT enzyme assays, respectively. Furthermore, mitragynine was also tested in vitro for its likelihood to inhibit APND and UGT activity. The assessment of the enzyme activity was conducted using spectrophotometric methods. RESULTS: In vitro, the IC50 value could only be obtained for the methanolic extract in APND study (595.30+/-30.78 ug/mL) and not in other studies due to the enzyme percentage inhibitions being <70%. In contrast to the in vitro study, the oral treatment of male Sprague-Dawley rats for 14 days with 50, 100 and 200 mg/kg of methanolic and aqueous extracts and with 5, 10 and 20 mg/kg of total alkaloid extract showed a profound increment on the APND and UGT activities. CONCLUSIONS: The current findings showed that possibilities exist for herb-drug interaction with increased clearance of drugs, which are primarily metabolized by CYP450s and UGT1A6 among M. speciosa leaves extract users. PMID- 23435186 TI - Brain and liver oxidative stress after sertraline and haloperidol treatment in mice. AB - BACKGROUND: Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal side effects. Sertraline is an antidepressant drug which has been reported to cause extrapyramidal symptoms. We aimed to see whether treatment with sertraline would worsen the effect of haloperidol on oxidative stress in the brains of mice. METHODS: Sertraline (10 or 20 mg/kg), haloperidol (2 mg/kg), haloperidol combined with sertraline or saline was administered daily via the subcutaneous route and mice were euthanized 10 days later when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (nitrite) levels, total antioxidant capacity (TAC), acetylcholinesterase (AChE), catalase and paraoxonase 1 (PON1) activities were determined in the brain and liver. RESULTS: Sertraline monotherapy did not alter GSH, MDA, TAC or nitrite in the brain. Haloperidol decreased GSH and TAC and increased MDA and nitrite. The combined treatment with sertraline and haloperidol resulted in increased MDA, but to a lesser extent than haloperidol monotherapy. A significant increase in GSH and TAC and decreased nitrite was observed after the combination treatment was compared with haloperidol monotherapy. Catalase activity decreased with sertraline or haloperidol treatment. PON1 activity decreased with sertraline and haloperidol monotherapy and showed a further decrease with the combination therapy compared with haloperidol monotherapy. AChE activity decreased after haloperidol and increased with the combination treatment compared with haloperidol monotherapy. In the liver, GSH was unaltered after sertraline, haloperidol or their combination. MDA increased with sertraline, haloperidol and their combination. TAC decreased after combination therapy. Nitric oxide increased after sertraline, haloperidol or their combination. PON1 activity decreased with sertraline, haloperidol and with sertraline-haloperidol co-treatment. CONCLUSIONS: Sertraline did not worsen brain oxidative stress induced with haloperidol, however, liver peroxidation increased. Sertraline decreased catalase and PON1 activity which might expose the brain to further oxidative insults. PMID- 23435187 TI - What is the effect of ghrelin on rat uterine contractility in vitro? AB - BACKGROUND: Ghrelin, a recently isolated gastric hormone, is an endogenous ligand for growth hormone secretagogue receptors. There is novel evidence that ghrelin might be expressed in rat ovaries, placental tissues, and the uterus. It has been reported to have modulatory effects on smooth muscle contractility. In this study, we investigated the effects of ghrelin on spontaneous and oxytocin-induced contractions in the rat uterus in vitro and tried to detect its signaling pathway. METHODS: Myometrium strips were removed from virgin female albino Wister rats and placed in a jacketed tissue bath. After initiation of spontaneous contractions, ghrelin was added to the tissue bath alone or after administration of indomethacin or NG-nitro-L-arginine methyl ester (L-NAME) or propranolol HCl. Student's t-test was used for statistical analysis. RESULTS: Our results revealed an inhibitory effect of ghrelin on both spontaneous and oxytocin-induced myometrial contractions. This effect was not affected by the application of indomethacin or L-NAME but was blocked after propranolol HCl administration. CONCLUSIONS: Ghrelin has an inhibitory effect on basal and oxytocin-induced rat myometrial contractions in vitro, and this myometrial response to ghrelin might be mediated by beta-receptor signaling pathway. PMID- 23435189 TI - Lysophosphatidic acid-induced interleukin expression by human periosteum-derived cells. PMID- 23435188 TI - Blood and breath levels of selected volatile organic compounds in healthy volunteers. AB - Gas chromatography with mass spectrometric detection (GC-MS) was used to identify and quantify volatile organic compounds in the blood and breath of healthy individuals. Blood and breath volatiles were pre-concentrated using headspace solid phase micro-extraction (HS-SPME) and needle trap devices (NTDs), respectively. The study involved a group of 28 healthy test subjects and resulted in the quantification of a total of 74 compounds in both types of samples. The concentrations of the species under study varied between 0.01 and 6700 nmol L(-1) in blood and between 0.02 and 2500 ppb in exhaled air. Limits of detection (LOD) ranged from 0.01 to 270 nmol L(-1) for blood compounds and from 0.01 to 0.7 ppb for breath species. Relative standard deviations for both measurement regimes varied from 1.5 to 14%. The predominant chemical classes among the compounds quantified were hydrocarbons (24), ketones (10), terpenes (8), heterocyclic compounds (7) and aromatic compounds (7). Twelve analytes were found to be highly present in both blood and exhaled air (with incidence rates higher than 80%) and for 32 species significant differences (Wilcoxon signed-rank test) between room air and exhaled breath were observed. By comparing blood, room air and breath levels in parallel, a tentative classification of volatiles into endogenous and exogenous compounds can be achieved. PMID- 23435190 TI - Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. AB - BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy, ocular and systemic safety, and systemic exposure of two formulations of 0.5% AR-12286 Ophthalmic Solution. METHODS: This was a double-masked, single-centre, crossover study in 18 normal adult volunteers. Volunteers were randomised to one of two dosing sequences: Formulation A once daily, both eyes (OU) for 8 days, a 7-day minimum washout, and then Formulation B, or the reverse. The main outcome measures were ocular tolerability, intraocular pressure (IOP) and blood levels of AR-12286 and its metabolites. RESULTS: Systemic absorption was low, with a majority of subjects showing no measurable drug concentration in plasma (<1 ng/ml) at any time point with either formulation. The most frequent ocular adverse events were conjunctival hyperaemia, eye irritation, instillation site reaction, increased lacrimation, and blurred vision which were relatively short-lived and judged as not clinically significant. Both formulations of AR-12286 produced substantial reductions from baseline IOP ranging from 3 to 7 mm Hg (p<0.0001). CONCLUSIONS: No differences were noted in ocular safety between formulations of AR-12286 0.5%, dosed once daily in the morning for 8 days. AR-12286 produced little systemic exposure to the parent compound or two known metabolites. Clinically and statistically significant reductions in IOP were seen in these normotensive subjects. PMID- 23435191 TI - Combined therapy of cyclosporine A and mycophenolate mofetil for the treatment of birdshot retinochoroidopathy: a 12-month follow-up. AB - PURPOSE: To retrospectively report a 12-month follow up for combined therapy with systemic cyclosporine A (CSA) and mycophenolate mofetil (MM) in treatment of patients with birdshot retinochoroidopathy (BSRC). PARTICIPANTS: Ninety-eight eyes of patients who received CSA and MM for the treatment of BSRC were included in the study. METHODS: All patients were followed for at least five visits during the study, or until treatment failure, or loss of follow-up. Clinical data were analysed using a Student paired t-test, Wilcoxon signed-rank test, McNemar's test, and Kaplan -Meier survival curve. Side effects related to therapy were also recorded. Main outcome measures included best-corrected logarithm of the minimum angle of resolution visual acuity, vitreous inflammation, fluorescein angiography pathologic features, and electroretinogram recordings. RESULTS: Vitreous inflammation scores at baseline and at 1 year were statistically significantly reduced in both eyes (p<0.001; p=0.001). The presence of angiographic leakage at the 1-year follow-up was significantly reduced (p=0.004). However, the presence of cystoid macular oedema (p=0.32) and comparison of electroretinogram 30-Hz amplitude revealed no significant reduction between baseline and 1-year values for either eye (p=0.61, p=0.87); nonetheless, 30-Hz implicit times were statistically significantly shorter at the end of follow-up for both eyes (p<0.001, p=0.035). Thirty-one patients (67.4%) achieved inflammation control at the 1-year endpoint. Side effects were transient, and resolved after lowering or withholding IMT for a few weeks in the majority of patients. CONCLUSIONS: These results suggest that combined IMT with CSA and MM for BSRC is well tolerated and associated with long-term control of inflammation. PMID- 23435192 TI - Branch retinal vein occlusion and optic nerve head topographic parameters: the Singapore Indian eye study. AB - AIM: To examine the association between branch retinal vein occlusion (BRVO) and quantitative optic disc topographic parameters. METHODS: The Singapore Indian Eye Study (SINDI) is a population-based study of 3400 Singapore Indians aged 40+ years. BRVO was defined and graded from retinal photographs. Optic disc parameters were quantified using the Heidelberg Retinal Tomograph III (HRT III). Associations were evaluated for individual eyes; the generalised estimating equation was used to account for correlation between fellow eyes. RESULTS: 6173 eyes (comprising 19 BRVO) had gradable retinal photographs and HRT images. After controlling for age, gender, and systemic (hypertension, diabetes, myocardial infarction) and ocular factors (intraocular pressure, glaucoma, central corneal thickness, axial length, previous laser photocoagulation), BRVO was associated with larger optic disc area (OR highest vs lowest tertile, 4.70; 95% CI 1.00 to 22.01; p=0.036), larger cup area (OR highest vs lowest tertile, 4.80; 95% CI 1.03 to 22.35; p=0.029) and larger cup-disc area ratio (OR highest vs lowest tertile, 4.44; 95% CI 0.95 to 20.66; p=0.037). After excluding glaucoma eyes, BRVO remained significantly associated with these parameters (p=0.027, p=0.018, p=0.024, respectively). CONCLUSIONS: Quantitative optic disc parameters (optic cup and disc area) are associated with BRVO, even in non-glaucomatous eyes. Optic nerve head morphology may play a role in BRVO pathogenesis. PMID- 23435193 TI - Development of lexical-semantic language system: N400 priming effect for spoken words in 18- and 24-month old children. AB - Our aim was to investigate whether developing language system, as measured by a priming task for spoken words, is organized by semantic categories. Event-related potentials (ERPs) were recorded during a priming task for spoken words in 18- and 24-month-old monolingual French learning children. Spoken word pairs were either semantically related (e.g., train-bike) or unrelated (e.g., chicken-bike). The results showed that the N400-like priming effect occurred in 24-month-olds over the right parietal-occipital recording sites. In 18-month-olds the effect was observed similarly to 24-month-olds only in those children with higher word production ability. The results suggest that words are categorically organized in the mental lexicon of children at the age of 2 years and even earlier in children with a high vocabulary. PMID- 23435194 TI - Zinc sensitizes prostate cancer cells to sorafenib and regulates the expression of Livin. AB - In prostate carcinogenesis, normal zinc-accumulating epithelial cells are transformed into malignant cells that do not accumulate zinc. Increased levels of zinc have been shown to induce apoptosis through a caspase-dependent mechanism with down-regulated anti-apoptotic proteins in prostate cancer cells. Our previous study showed that, as a member of the inhibitor of apoptosis proteins (IAPs) family, Livin could play an important role in the initiation of human prostate cancer and promote cell proliferation by altering the G1-S cell cycle transition. In the present study, we measured the apoptosis sensitivity of prostate cancer cells to zinc and sorafenib and found that zinc sensitized prostate cancer cells to sorafenib-induced apoptosis. Surprisingly, we also found that, unlike its counterparts Survivin and cIAP2, Livin was not decreased all the time; instead, it was compensatively increased in zinc-mediated apoptosis at 48 h in prostate cancer cells. Our results offer potential treatment combinations that may augment the effect of sorafenib, and also reveal, for the first time, that increased Livin expression may play a role in the early cell death response of prostate cancer cells to zinc. PMID- 23435195 TI - Low concentrations of the recombinant toxin protein rLj-RGD3 suppress TNF-alpha induced human renal carcinoma cell invasion. AB - A hallmark of renal cell carcinoma (RCC) invasion is the degradation of the extracellular matrix (ECM) by the local production of gelatinase enzymes. Matrix metalloproteinase-9 (MMP-9)-induced cancer cell invasion is one of the pivotal steps in cancer metastasis. It has been reported that tumor necrosis factor-alpha (TNF-alpha), a regulator of MMP-9, can induce invasion in human renal carcinoma cells. Previous work in our laboratory has shown that rLj-RGD3, a recombinant RGD (Arg-Gly-Asp)-toxin protein from the buccal gland secretion of Lampetra japonica, possesses anti-tumor activity. In this study, we demonstrated that rLj-RGD3 suppressed TNF-alpha-induced MMP-9 secretion in 786-0 cells (human renal carcinoma cells). To investigate the regulatory effect of rLj-RGD3 on TNF-alpha induced MMP-9 secretion, we pre-treated cells with rLj-RGD3. Interestingly, rLj RGD3 had no significant effect on the constitutive secretion of MMPs. However, low concentrations of rLj-RGD3 decreased TNF-alpha-induced MMP-9 secretion. Functional studies revealed that rLj-RGD3 induced apoptosis and significantly inhibited the proliferation, migration, and invasion of 786-0 cells. Furthermore, the actin architecture in cells pre-treated with rLj-RGD3 was aggregated and disorganized. Our findings suggest that rLj-RGD3 may be used as a potential drug in renal cancer therapy. PMID- 23435196 TI - Foreign body in the airway: when imaging is not enough. PMID- 23435198 TI - Facile synthesis of functionalizated carbon nanospheres for determination of Cu2+. AB - In this research, quantities of carbon nanospheres (CNSs) were prepared with a convenient and low cost method at atmospheric pressure and functionalized with the xanthate group in a simple way. The materials were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), Fourier transform infrared spectra (FT-IR), and X-ray photoelectron spectroscopy (XPS). In addition, the carbon nanospheres (CNSs) xanthate was applied to fabricate a modified carbon paste electrode (CPE) for the selective and sensitive determination of Cu(2+). Also, the xanthate with a -CS2 group was applied as a chelating agent to enrich Cu(2+) in the determination of Cu(2+) ions. In square wave stripping voltammetry (SWSV), the carbon nanospheres xanthate-modified CPE displayed linear response to Cu(2+) in the concentration range of 8.0 * 10(-8) M to 2.2 * 10(-6) M with a detection limit (S/N = 3) of 3.55 * 10(-8) M. The modified electrode exhibited excellent analytical performance in terms of high repeatability. Finally, it was applied to detect Cu(2+) in the wastewater samples with high accuracy and good recovery, indicating its promising application in the routine analysis of metal ions. PMID- 23435199 TI - Duration of fluoroscopic-guided spine interventions and radiation exposure is increased in overweight patients. AB - BACKGROUND: The impact of patient body mass index (BMI) on image-guided spine interventions remains unknown. Higher BMI is known to complicate the acquisition of radiographic images. Therefore it can be hypothesized that the patient's body habitus can influence the delivery of a spinal injection. OBJECTIVE: To quantify the impact of patient BMI on the length of fluoroscopy and procedure times during spine interventions. DESIGN: Secondary analysis of 2 prospective observational studies. SETTING: All injections were performed in an outpatient university setting. PARTICIPANTS: A total of 209 patients in whom spine injections were performed (99 women), with a mean age of 54.6 years. METHODS: The fluoroscopy times for 202 participants and total procedure times for 137 participants were recorded. Additional participant characteristics, including age, gender, BMI, and actual procedures performed, also were collected. Analysis of covariance and linear and nonlinear model analysis were performed to assess the effect of BMI on fluoroscopy and procedure times. MAIN OUTCOME MEASUREMENTS: Fluoroscopy time and procedure duration times. RESULTS: Participants had a mean age of 54.6 years, 51% were men, and 77% (n = 155) were overweight (BMI >=25). Participants received the following interventions: 40 zygapophyseal joint injections, 33 medial branch nerve blocks, 113 transforaminal epidural injections, and 16 combined zygapophyseal joint injections and epidural injections. Gender, procedure number, and procedure type did not differ between groups. The overweight group demonstrated a 30% increase in mean fluoroscopy time and a 35% increase in mean procedure time. Controlling for other variables, we found that differences in fluoroscopy time and procedure time were significant (P = .032 and P = .031, respectively) between the 2 groups. CONCLUSIONS: Significantly prolonged procedure time and fluoroscopy time in overweight patients increase the risks associated with spine interventions, not only to the patients but also to the operating room staff exposed to ionizing radiation. PMID- 23435200 TI - New propanoyloxy derivatives of 5beta-cholan-24-oic acid as drug absorption modifiers. AB - A series of final twelve propanoyloxy derivatives of 5beta-cholan-24-oic acid (O propanoyl derivatives of cholic acid) as potential drug absorption modifiers (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by 1H NMR, 13C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (log S), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukemia cell line and breast adenocarcinoma cell line. One compound showed selective cytotoxicity against human skin fibroblast cells and another compound possessed the highest cytotoxicity against all the tested cell lines. Only one compound expressed anti-proliferative effect on leukemia cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37 MUM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effect are discussed in this article. PMID- 23435201 TI - Association of exposure to phenols and idiopathic male infertility. AB - Widespread human exposure to phenols has been documented recently, and some phenols which are potential endocrine disruptors have demonstrated adverse effects on male reproduction in animal and in vitro studies. However, implications about exposure to phenols and male infertility are scarce in humans. Case-control study of 877 idiopathic infertile men and 713 fertile controls was conducted. Urinary levels of bisphenol A, benzophenone-3, pentachlorophenol, triclosan, 4-tert-octylphenol (4-t-OP), 4-n-octylphenol (4-n-OP) and 4-n nonylphenol (4-n-NP) and semen parameters were measured. After multivariate adjustment, we found 4-t-OP, 4-n-OP and 4-n-NP exposure was associated with idiopathic male infertility (p-value for trend: <0.0001, 0.014 and 0.001, respectively). Aside from these associations, 4-t-OP and 4-n-NP exposure was also associated with idiopathic male infertility with abnormal semen parameters. Moreover, we observed significant associations between sum alkylphenols (APs) exposure and idiopathic male infertility. There were no relationships between exposure to other phenols and idiopathic male infertility in the present study. Our study provides the first evidence that exposure to APs (4-t-OP, 4-n-OP and 4 n-NP) is associated with idiopathic male infertility. PMID- 23435202 TI - Modification and characterization of PET fibers for fast removal of Hg(II), Cu(II) and Co(II) metal ions from aqueous solutions. AB - A new chelating fiber (PET-TSC) was prepared with PET for fast removal of Hg(2+), Cu(2+) and Co(2+) from water. Elemental analysis, SEM, BET surface area, (13)C NMR, FTIR and X-ray diffraction spectra were used to characterize PET-TSC. The higher uptake capacity of the studied metal ions was observed at higher pH values. Kinetic study indicated that the adsorption of Hg(2+), Cu(2+) and Co(2+) followed the pseudo-second-order equation, suggesting chemical sorption as the rate-limiting step of the adsorption process. The best interpretation for the equilibrium data was given by Langmuir isotherm, and the maximum adsorption capacities were 120.02, 96.81 and 78.08 mg/g for Hg(2+), Cu(2+) and Co(2+) ions, respectively. 1M HCl or 0.1M EDTA could be used as effective eluant to desorb the Hg(2+), Cu(2+) and Co(2+) adsorbed by PET-TSC, and the adsorption capacity of PET TSC for the three heavy metal ions could still be maintained at about 90% level at the 5th cycle. Accordingly, it is expected that PET-TSC could be used as a promising adsorbent for fast removal of heavy metal ions from water, and the present work also might provide a simple and effective method to reuse the waste PET fibers. PMID- 23435203 TI - Adsorption of uranium from aqueous solution by PAMAM dendron functionalized styrene divinylbenzene. AB - A new polymeric chelating resin was prepared by growing third generation poly(amido)amine (PAMAMG3) dendron on the surface of styrene divinylbenzene (SDB) and characterized by FTIR, TGA and SEM. The ideal branching of dendron in the chelating resin was determined from potentiometric titration. Adsorption of uranium (VI) from aqueous solution using PAMAMG3-SDB chelating resin was studied in a series of batch experiments. Effect of contact time, pH, ionic strength, adsorbent dose, initial U(VI) concentration, dendron generation and temperature on adsorption of U(VI) were investigated. Kinetic experiments showed that U(VI) adsorption on PAMAMG3-SDB followed pseudo-second-order kinetics model appropriately and equilibrium data agreed well with the Langmuir isotherm model. Thermodynamic parameters (DeltaH degrees , DeltaS degrees , DeltaG degrees ) were evaluated from temperature dependent adsorption data and the uranium adsorption on PAMAMG3-SDB was found to be endothermic and spontaneous in nature. The sticking probability value (5.303 * 10(-9)), kinetic and isotherm data reveal the chemisorption of uranium on PAMAMG3-SDB and adsorption capacity of the chelating resin was estimated to be 130.25 mg g(-1) at 298 K. About 99% of adsorbed U(VI) can be desorbed from PAMAMG3-SDB by a simple acid treatment suggesting that the chelating resin is reusable. PMID- 23435204 TI - A camp-based psychosocialiIntervention to promote independence and social function in individuals with spina bifida: moderators of treatment effectiveness. AB - PURPOSE: To replicate and extend O'Mahar and colleagues' (O'Mahar, K., Holmbeck, G. N., Jandasek, B., & Zuckerman, J. [2010]. A camp-based intervention targeting independence among individuals with spina bifida. Journal of Pediatric Psychology, 35, 848-856) findings in a new and larger sample of youth and young adults with spina bifida who participated in a modified camp-based intervention targeting independence and social skills. Moderators of intervention effectiveness and clinical significance were examined. METHOD: In all, 119 campers aged 7-41 years participated in an intervention that included goal setting and interactive workshops. Campers and parents completed measures of campers' goal attainment, independence, and social functioning at preintervention and postintervention; counselors reported on campers' goal attainment daily throughout the intervention. RESULTS: Parents and campers reported improvements in campers' goal attainment, management of health-related self-care, and independence. Although benefits were found for most campers, cognitive functioning and family income moderated some outcomes. Campers who improved most on their social goals perceived the intervention to be more effective. CONCLUSIONS: Further support is provided for the effectiveness of a camp-based intervention targeting independence and social skills for individuals with spina bifida. More attention should be directed toward those with cognitive difficulties and low-income backgrounds. PMID- 23435205 TI - Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma. AB - Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking induced cancer. PMID- 23435206 TI - Separable networks for top-down attention to auditory non-spatial and visuospatial modalities. AB - A central question for cognitive neuroscience is whether there is a single neural system controlling the allocation of attention. A dorsal frontoparietal network of brain regions is often proposed as a mediator of top-down attention to all sensory inputs. We used functional magnetic resonance imaging in humans to show that the cortical networks supporting top-down attention are in fact modality specific, with distinct superior fronto-parietal and fronto-temporal networks for visuospatial and non-spatial auditory attention respectively. In contrast, parts of the right middle and inferior frontal gyri showed a common response to attentional control regardless of modality, providing evidence that the amodal component of attention is restricted to the anterior cortex. PMID- 23435207 TI - Internal ventilation system of MR scanners induces specific EEG artifact during simultaneous EEG-fMRI. AB - During simultaneous EEG-fMRI acquisition, the EEG signal suffers from tremendous artifacts caused by the scanner "environment". Particularly, gradient artifacts and the ballistocardiogram have been well characterized, along with methods to eliminate them. Here, we describe another systematic artifact in the EEG signal, which is induced by the internal ventilation system of Siemens TRIO and VERIO MR scanners. A ventilation-level dependent vibration induces specific peaks in the frequency spectrum of the EEG. These frequency peaks are in the range of physiologically relevant brain rhythms (gamma frequency range), and thus interfere with their reliable acquisition. This ventilation dependent artifact was most prominent on the electrodes placed directly on the subject's head, so it is not sufficient to simply place the EEG's amplifier outside the scanner tube. Instead, the ventilator must be switched off to fully eliminate the ventilator's artificial manipulation of EEG recordings. Without the internal ventilator system being on, the temperature within the scanner tube may rise, thus requiring shorter scanning sessions or an additional external ventilation system. PMID- 23435209 TI - The role of the thalamic nuclei in recognition memory accompanied by recall during encoding and retrieval: an fMRI study. AB - The present functional imaging study aimed at investigating the contribution of the mediodorsal nucleus and the anterior nuclei of the thalamus with their related cortical networks to recognition memory and recall. Eighteen subjects performed associative picture encoding followed by a single item recognition test during the functional magnetic resonance imaging session. After scanning, subjects performed a cued recall test using the formerly recognized pictures as cues. This post-scanning test served to classify recognition trials according to subsequent recall performance. In general, single item recognition accompanied by successful recall of the associations elicited stronger activation in the mediodorsal nucleus of the thalamus and in the prefrontal cortices both during encoding and retrieval compared to recognition without recall. In contrast, the anterior nuclei of the thalamus were selectively active during the retrieval phase of recognition followed by recall. A correlational analysis showed that activation of the anterior thalamus during retrieval as assessed by measuring the percent signal changes predicted lower rates of recognition without recall. These findings show that the thalamus is critical for recognition accompanied by recall, and provide the first evidence of a functional segregation of the thalamic nuclei with respect to the memory retrieval phase. In particular, the mediodorsal thalamic-prefrontal cortical network is activated during successful encoding and retrieval of associations, which suggests a role of this system in recall and recollection. The activity of the anterior thalamic-temporal network selectively during retrieval predicts better memory performances across subjects and this confirms the paramount role of this network in recall and recollection. PMID- 23435208 TI - Applying tensor-based morphometry to parametric surfaces can improve MRI-based disease diagnosis. AB - Many methods have been proposed for computer-assisted diagnostic classification. Full tensor information and machine learning with 3D maps derived from brain images may help detect subtle differences or classify subjects into different groups. Here we develop a new approach to apply tensor-based morphometry to parametric surface models for diagnostic classification. We use this approach to identify cortical surface features for use in diagnostic classifiers. First, with holomorphic 1-forms, we compute an efficient and accurate conformal mapping from a multiply connected mesh to the so-called slit domain. Next, the surface parameterization approach provides a natural way to register anatomical surfaces across subjects using a constrained harmonic map. To analyze anatomical differences, we then analyze the full Riemannian surface metric tensors, which retain multivariate information on local surface geometry. As the number of voxels in a 3D image is large, sparse learning is a promising method to select a subset of imaging features and to improve classification accuracy. Focusing on vertices with greatest effect sizes, we train a diagnostic classifier using the surface features selected by an L1-norm based sparse learning method. Stability selection is applied to validate the selected feature sets. We tested the algorithm on MRI-derived cortical surfaces from 42 subjects with genetically confirmed Williams syndrome and 40 age-matched controls, multivariate statistics on the local tensors gave greater effect sizes for detecting group differences relative to other TBM-based statistics including analysis of the Jacobian determinant and the largest eigenvalue of the surface metric. Our method also gave reasonable classification results relative to the Jacobian determinant, the pair of eigenvalues of the Jacobian matrix and volume features. This analysis pipeline may boost the power of morphometry studies, and may assist with image based classification. PMID- 23435210 TI - A note on the phase locking value and its properties. AB - We investigate the properties of the Phase Locking Value (PLV) and the Phase Lag Index (PLI) as metrics for quantifying interactions in bivariate local field potential (LFP), electroencephalography (EEG) and magnetoencephalography (MEG) data. In particular we describe the relationship between nonparametric estimates of PLV and PLI and the parameters of two distributions that can both be used to model phase interactions. The first of these is the von Mises distribution, for which the sample PLV is a maximum likelihood estimator. The second is the relative phase distribution associated with bivariate circularly symmetric complex Gaussian data. We derive an explicit expression for the PLV for this distribution and show that it is a function of the cross-correlation between the two signals. We compare the bias and variance of the sample PLV and the PLV computed from the cross-correlation. We also show that both the von Mises and Gaussian models are suitable for representing relative phase in application to LFP data from a visually-cued motor study in macaque. We then compare results using the two different PLV estimators and conclude that, for this data, the sample PLV provides equivalent information to the cross-correlation of the two complex time series. PMID- 23435211 TI - Processing of featural and configural aspects of faces is lateralized in dorsolateral prefrontal cortex: a TMS study. AB - Facial recognition relies on distinct and parallel types of processing: featural processing focuses on the individual components of a face (e.g., the shape or the size of the eyes), whereas configural (or "relational") processing considers the spatial interrelationships among the single facial components (e.g., distance of the mouth from the nose). Previous neuroimaging evidence has suggested that featural and configural processes may rely on different brain circuits. By using rTMS, here we show for the first time a double dissociation in dorsolateral prefrontal cortex for different aspects of face processing: in particular, TMS over the left middle frontal gyrus (BA8) selectively disrupted featural processing, whereas TMS over the right inferior frontal gyrus (BA44) selectively interfered with configural processing of faces. By establishing a causal link between activation in left and right prefrontal areas and different modes of face processing, our data extend previous neuroimaging evidence and may have important implications in the study of face-processing deficits, such as those manifested in prosopagnosia and autistic spectrum disorders. PMID- 23435212 TI - Neural evidence for a 3-state model of visual short-term memory. AB - Recent research has suggested that short-term memory (STM) can be partitioned into three distinct states. By this model, a single item is held in the focus of attention making it available for immediate processing (focus of attention), a capacity-limited set of additional items is actively maintained for future processing (direct access region), and other recently presented information is passively active, but can nevertheless influence ongoing cognition (activated portion of long-term memory). While there is both behavioral and neural support for this 3-state model in verbal STM, it is unclear whether the model generalizes to non-verbal STM. Here, we tested a 3-state model of visual STM using fMRI. We found a triple dissociation of regions involved in the access of each hypothesized state. The inferior parietal cortex mediated access to the focus of attention, the medial temporal lobe (MTL) including the hippocampus mediated access to the direct access region, and the left ventrolateral prefrontal cortex (VLPFC) mediated access to the activated portion of long-term memory. Direct comparison with previously collected verbal STM data revealed overlapping neural activations involved in the access of each state across different forms of content suggesting that mechanisms of access are domain general. These data support a 3-state model of STM. PMID- 23435214 TI - Validation of parametric methods for [11C]PE2I positron emission tomography. AB - OBJECTIVES: The radioligand [(11)C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [(11)C]PE2I. The purpose of this study was to evaluate different methods for producing [(11)C]PE2I parametric images, showing binding potential (BPND) and relative delivery (R1) at the voxel level, using clinical data as well as simulations. METHODS: Investigations were made in twelve subjects either with social anxiety disorder (n=6) or parkinsonian syndrome (n=6), each receiving an 80 min dynamic PET scan. All subjects underwent a T1-weighted MRI scan which was co-registered to the PET images and used for definition of regions of interest using a probabilistic template (PVElab). Two basis function implementations (receptor parametric mapping: RPM, RPM2) of the simplified reference tissue model (SRTM) and three multilinear reference tissue models (MRTMo, MRTM and MRTM2) were used for computation of parametric BPND and R1 images. In addition, reference Logan and standard uptake value ratio (SUVr) were investigated. Evaluations of BPND and R1 images were performed using linear regression to compare the parametric methods to region-based analyses with SRTM and cerebellar gray matter as reference region. Accuracy and precision of each method were assessed by simulations. RESULTS: Correlation and slope of linear regression between parametric and region-based BPND and R1 values in both striatum and extra-striatal regions were optimal for RPM (R(2)=0.99 for both BPND and R1; slopes 0.99 and 0.98 for BPND and R1, respectively, in striatum). In addition, accuracy and precision were best for RPM and RPM2. CONCLUSION: The basis function methods provided more robust estimations of the parameters compared to the other models and performed best in simulations. RPM, a basis function implementation of SRTM, is the preferred method for voxel level analysis of [(11)C]PE2I PET studies. PMID- 23435213 TI - Probabilistic atlases for face and biological motion perception: an analysis of their reliability and overlap. AB - Neuroimaging research has identified several category-selective regions in visual cortex that respond most strongly when viewing an exemplar image from a preferred category, such as faces. Recent studies, however, have suggested a more complex pattern of activation that has been heretofore unrecognized, e.g., the presence of additional patches of activation to faces beyond the well-studied fusiform face area, and the activation of ostensible face selective regions by animate motion of non-biological forms. Here, we characterize the spatial pattern of brain activity evoked by viewing faces or biological motion in large fMRI samples (N>120). We create probabilistic atlases for both face and biological motion activation, and directly compare their spatial patterns of activation. Our findings support the suggestion that the fusiform face area is composed of at least two separable foci of activation. The face-evoked response in the fusiform and nearby ventral temporal cortex has good reliability across runs; however, we found surprisingly high variability in lateral brain regions by faces, and for all brain regions by biological motion, which had an overall much lower effect size. We found that faces and biological motion evoke substantially overlapping activation distributions in both ventral and lateral occipitotemporal cortices. The peaks of activation for these different categories within these overlapping regions were close but distinct. PMID- 23435215 TI - Dynamic causal modeling suggests serial processing of tactile vibratory stimuli in the human somatosensory cortex--an fMRI study. AB - Sensitivity to location and frequency of tactile stimuli is a characterizing feature of human primary (S1), and secondary (S2) somatosensory cortices. Recent evidence suggests that S1 is predominantly receptive to stimulus location, while S2 is attuned to stimulus frequency. Although it is well established in humans that tactile frequency information is relayed serially from S1 to S2, a recent study, using functional magnetic resonance imaging (fMRI) in combination with dynamic causal modeling (DCM), suggested that somatosensory inputs are processed in parallel in S1 and S2. In the present fMRI/DCM study, we revisited this controversy and investigated the specialization of the human somatosensory cortical areas with regard to tactile stimulus representations, as well as their effective connectivity. During brain imaging, 14 participants performed a somatosensory discrimination task on vibrotactile stimuli. Importantly, the model space for DCM was chosen to allow for direct inference on the question of interest by systematically varying the information transmission from pure parallel to pure serial implementations. Bayesian model comparison on the level of model families strongly favors a serial, instead of a parallel processing route for tactile stimulus information along the somatosensory pathway. Our fMRI/DCM data thus support previous suggestions of a sequential information transmission from S1 to S2 in humans. PMID- 23435216 TI - Fluctuating charge-density waves in a cuprate superconductor. AB - Cuprate materials hosting high-temperature superconductivity (HTS) also exhibit various forms of charge and spin ordering whose significance is not fully understood. So far, static charge-density waves (CDWs) have been detected by diffraction probes only at particular doping levels or in an applied external field . However, dynamic CDWs may also be present more broadly and their detection, characterization and relationship with HTS remain open problems. Here we present a method based on ultrafast spectroscopy to detect the presence and measure the lifetimes of CDW fluctuations in cuprates. In an underdoped La(1.9)Sr(0.1)CuO4 film (T(c) = 26 K), we observe collective excitations of CDW that persist up to 100 K. This dynamic CDW fluctuates with a characteristic lifetime of 2 ps at T = 5 K that decreases to 0.5 ps at T = 100 K. In contrast, in an optimally doped La(1.84)Sr(0.16)CuO4 film (T(c) = 38.5 K), we detect no signatures of fluctuating CDWs at any temperature, favouring the competition scenario. This work forges a path for studying fluctuating order parameters in various superconductors and other materials. PMID- 23435217 TI - Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer. AB - BACKGROUND: Preclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models. METHODS: We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response. RESULTS: Thirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade >=2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) >=6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD>=6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD>=6 months or uPR. Correlation between grade of rash and rate of SD>=6 months/PR was observed (p less than 0.01). CONCLUSION: The combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC. PMID- 23435218 TI - Efficacy of ventilation and ventilation adjuncts during in-water-resuscitation--a randomized cross-over trial. AB - INTRODUCTION: Drowning is a common cause of death in young adults. The 2010 guidelines of the European Resuscitation Council call for in-water-resuscitation (IWR). There has been controversy about IWR amongst emergency and diving physicians for decades. The aim of the present study was assessing the efficacy of IWR. METHODS: In this randomized cross-over trial, nineteen lifeguards performed a rescue manoeuvre over a 100 m distance in open water. All subjects performed the procedure four times in random order: with no ventilation (NV) and transportation only, mouth-to-mouth ventilation (MMV), bag-mask-ventilation (BMV) and laryngeal tube ventilation (LTV). Tidal volumes, ventilation rate and minute volumes were recorded using a modified Laerdal Resusci Anne manikin. Furthermore, water aspiration and number of submersions of the test mannequin were assessed, as well as the physical effort of the lifeguard rescuers.One lifeguard subject did not complete MMV due to exhaustion and was excluded from analysis. RESULTS: NV was the fastest rescue manoeuvre (advantage ~40s). MMV and LTV were evaluated as efficient and relatively easy to perform by the lifeguards. While MMV (mean 199 ml) and BMV (mean 481 ml) were associated with a large amount of aspirated water, aspiration was significantly lower in LTV (mean 118 ml). The efficacy of ventilation was consistently good in LTV (Vt=447 ml), continuously poor in BMV (Vt=197) and declined substantially during MMV (Vt=1,019 ml initially and Vt=786 ml at the end). The physical effort of the lifeguards was remarkably higher when performing IWR: 3.7 in NV, 6.7 in MMV, 6.4 in BMV and 4.8 in LTV as measured on the 0-10 visual analogue scale. CONCLUSION: IWR in open water is time consuming and physically demanding. The IWR training of lifeguards should put more emphasis on a reduction of aspiration. The use of ventilation adjuncts like the laryngeal tube might ease IWR, reduce aspiration of water and increase the efficacy of ventilation during IWR. PMID- 23435221 TI - An efficient and heterogeneous recyclable silicotungstic acid with modified acid sites as a catalyst for conversion of fructose and sucrose into 5 hydroxymethylfurfural in superheated water. AB - Acidity modified silver exchanged silicotungstic acid (AgSTA) catalyst was prepared and characterized by X-ray diffraction, FT-IR spectroscopy, Raman spectroscopy, FT-IR pyridine adsorption, SEM imaging, EDX mapping, and antimicrobial activity was also tested. The catalytic activity was evaluated for the dehydration of fructose and sucrose in superheated water. As a result, 98% conversion of fructose with 85.7% HMF yield and 87.4% HMF selectivity in 120 min reaction time at 120 degrees C reaction temperature using 10 wt.% of AgSTA catalyst was achieved. While, 92% sucrose conversion with 62.5% of HMF yield was obtained from sucrose at uniform condition in 160 min. The effect of reaction parameters, such as reaction temperature, time, catalyst dosage, and effect acidity on HMF yield was also investigated. The AgSTA catalyst was separated from the reaction mixture by filtration process at end of the reaction and reused eight times without loss of catalytic activity. PMID- 23435222 TI - Comparison of automated and partial coherence keratometry and resulting choice of toric IOL. AB - PURPOSE: Consistent astigmatism correction with implantation of a toric intraocular lens (IOL) requires accurate preoperative keratometry. This article compares corneal astigmatism determined by an autokeratometer (Topcon KR-7100) and a partial coherence interferometry keratometer (IOLMaster 500) and considers if any discrepancy ultimately alters in final cylindrical power of the toric IOL for implantation. METHODS: Keratometry of 235 eyes was performed using both instruments. Corneal astigmatism was transformed into vector components J0 and J45 and cylindrical power at the IOL plane calculated. Comparisons were made using paired t test and correlation and Bland-Altman analyses. RESULTS: Although interinstrument differences for J0 (p = 0.013), J45 (p = 0.012), and toric IOL cylindrical power (p < 0.001) were statistically significant, a high correlation for these (R = 0.96, 0.90, and 0.90, respectively) was observed. IOLMaster tended to overestimate corneal astigmatism by 0.13 (+/-0.31) diopters and toric IOL cylinder by 0.11 (+/-0.18) diopters. Difference in calculated toric IOL cylindrical power correlated poorly with corneal curvature (R = 0.007) and astigmatism (R = -0.004). CONCLUSIONS: The two keratometers were generally concordant in measuring corneal astigmatism. However, the resultant choice of toric IOL cylinder power differed appreciably in 40% of eyes examined. Therefore, postoperative visual outcome with toric IOL implantation may be optimized by a thorough analysis of biometry data before IOL selection, paying special attention to any difference in corneal astigmatism as measured by more than one instrument. PMID- 23435223 TI - Symptomatic and morphological differences between choroidal excavations. AB - PURPOSE: The purpose of this report is to describe the morphological and clinical features of two patients with focal choroidal excavation in an attempt to understand more about this rare condition. CASE REPORT: Spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography, and indocyanine green angiography were used to assess the morphological characteristics of the patients' choroidal excavations. Both patients showed the following features on SD-OCT: (1) the retinal pigment epithelium band and inner/outer segment junction followed the contour of the choroidal excavation, which involved the outer nuclear layers up to the outer limiting membrane; (2) the sclerochoroidal junction was smooth and undisturbed, but large choroidal vessels were present beneath each excavation. The patient with metamorphopsia showed separation between the photoreceptor outer segment and the retinal pigment epithelium as well as disturbance of the inner/outer segment junction on SD-OCT volume scans and hyperfluorescence and hypofluorescence in the foveal region on indocyanine green angiography. CONCLUSIONS: Symptomatic and morphological differences between focal choroidal excavations suggested anatomical alterations between the photoreceptor tips and the retinal pigment epithelium or location of choroidal excavation as the cause of metamorphopsia. We speculate that the pathogenesis of focal choroidal excavation involves outward traction on the macula caused by choroidal vascular abnormalities because of embryonic developmental failure of the choroid. PMID- 23435224 TI - Repeatability of a new method for measuring tear evaporation rates. AB - PURPOSE: The purpose of this study was to evaluate the repeatability of tear evaporimetry based on infrared thermography in a clinical room setting and to test the effect of changing environmental humidity on ocular surface temperature (OST) and tear evaporation rates (TERs) in a controlled adverse environmental (CAE) chamber. METHODS: Twenty-six healthy participants were enrolled, of whom 16 underwent repeatability measurements in a clinical room and 10 were exposed to a constant temperature of 30 degrees C with a humidity of 45 and 65% in a CAE. Participants were acclimatized to each condition for at least 20 minutes before OSTs were taken. Tear film breakup time was assessed in the CAE only. Number of blinks and OSTs were continuously measured for 20 seconds for the cornea, conjunctiva, and overall ocular surface with an infrared camera; corresponding TERs were calculated. RESULTS: The OSTs and TERs showed acceptable strength of agreement between the first and second measurements. The coefficients of repeatability were 0.4 degrees C for OST and 6.0 W m for TER. An increase in chamber humidity (from 45 to 65%) increased OST (p < 0.05). The TER was not changed significantly (p > 0.05). The tear film breakup time and number of blinks were not significantly affected by different humidity conditions. CONCLUSIONS: This technique has acceptable repeatability and has potential to document individual tear evaporation changes with time where humidity may differ by less than 20%. PMID- 23435225 TI - Complications associated with Boston keratoprosthesis type 1 and glaucoma drainage devices. AB - BACKGROUND/AIMS: To compare the complications leading to best-corrected visual acuity (BCVA) loss in patients with Boston keratoprosthesis type 1 (KPro) and glaucoma drainage device (GDD) and those with KPro alone. METHODS: Retrospective case series of all patients who underwent KPro surgery at the Centre Hospitalier de l'Universite de Montreal between 2008 and 2011. Preoperative diagnoses, BCVA and complications were tabulated and analysed. RESULTS: KPro surgery was performed in 96 eyes: 18 eyes (19%) had KPro and GDD while 78 eyes (81%) had KPro only. Median BCVA at postoperative 6 months was 20/150 in both groups. Seven eyes (39%) with KPro and GDD experienced vision loss due to complications such as glaucoma progression (three eyes, 22%), tube occlusion (four eyes, 22%) and choroidal haemorrhage (three eyes, 17%). Vitreous incarceration was the most common cause of tube occlusion. Vitreoretinal, glaucoma and infectious complications caused BCVA loss in 16 eyes (21%) with KPro alone (p=0.13). CONCLUSIONS: Glaucoma progression is a major cause of visual decline post-KPro. However, GDD implantation should only be performed in carefully selected patients. Because of a high risk of vitreous incarceration within the tube, a complete pars plana vitrectomy should be performed prior to GDD implantation. PMID- 23435226 TI - Linker histone H1.0 interacts with an extensive network of proteins found in the nucleolus. AB - The H1 linker histones are abundant chromatin-associated DNA-binding proteins. Recent evidence suggests that linker histones also may function through protein protein interactions. To gain a better understanding of the scope of linker histone involvement in protein-protein interactions, we used a proteomics approach to identify H1-binding proteins in human nuclear extracts. Full-length H1.0 and H1.0 lacking its C-terminal domain (CTD) were used for protein pull downs. A total of 107 candidate H1.0 binding proteins were identified by LC MS/MS. About one-third of the H1.0-dependent interactions were mediated by the CTD, and two-thirds by the N-terminal domain-globular domain fragment. Many of the proteins pulled down by H1.0 were core splicing factors. Another group of H1 binding proteins functions in rRNA biogenesis. H1.0 also pulled down numerous ribosomal proteins and proteins involved in cellular transport. Strikingly, nearly all of the H1.0-binding proteins are found in the nucleolus. Quantitative biophysical studies with recombinant proteins confirmed that H1.0 directly binds to FACT and the splicing factors SF2/ASF and U2AF65. Our results demonstrate that H1.0 interacts with an extensive network of proteins that function in RNA metabolism in the nucleolus, and suggest that a new paradigm for linker histone action is in order. PMID- 23435227 TI - Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies. AB - Polymorphisms in the target mRNA sequence can greatly affect the binding affinity of microarray probe sequences, leading to false-positive and false-negative expression quantitative trait locus (QTL) signals with any other polymorphisms in linkage disequilibrium. We provide the most complete solution to this problem, by using the latest genome and exome sequence reference data to identify almost all common polymorphisms (frequency >1% in Europeans) in probe sequences for two commonly used microarray panels (the gene-based Illumina Human HT12 array, which uses 50-mer probes, and exon-based Affymetrix Human Exon 1.0 ST array, which uses 25-mer probes). We demonstrate the impact of this problem using cerebellum and frontal cortex tissues from 438 neuropathologically normal individuals. We find that although only a small proportion of the probes contain polymorphisms, they account for a large proportion of apparent expression QTL signals, and therefore result in many false signals being declared as real. We find that the polymorphism-in-probe problem is insufficiently controlled by previous protocols, and illustrate this using some notable false-positive and false-negative examples in MAPT and PRICKLE1 that can be found in many eQTL databases. We recommend that both new and existing eQTL data sets should be carefully checked in order to adequately address this issue. PMID- 23435228 TI - The RNA-binding region of human TRBP interacts with microRNA precursors through two independent domains. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through RNA interference. Human miRNAs are generated through a series of enzymatic processing steps. The precursor miRNA (pre-miRNA) is recognized and cleaved by a complex containing Dicer and several non-catalytic accessory proteins. HIV TAR element binding protein (TRBP) is a constituent of the Dicer complex, which augments complex stability and potentially functions in substrate recognition and product transfer to the RNA-induced silencing complex. Here we have analysed the interaction between the RNA-binding region of TRBP and an oncogenic human miRNA, miR-155, at different stages in the biogenesis pathway. We show that the region of TRBP that binds immature miRNAs comprises two independent double-stranded RNA-binding domains connected by a 60-residue flexible linker. No evidence of contact between the two double-stranded RNA-binding domains was observed either in the apo- or RNA-bound state. We establish that the RNA-binding region of TRBP interacts with both pre-miR-155 and the miR-155/miR-155* duplex through the same binding surfaces and with similar affinities, and that two protein molecules can simultaneously interact with each immature miRNA. These data suggest that TRBP could play a role before and after processing of pre miRNAs by Dicer. PMID- 23435229 TI - The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover. AB - The androgen receptor (AR) is a key molecule involved in prostate cancer (PC) development and progression. Post-translational modification of the AR by co regulator proteins can modulate its transcriptional activity. To identify which demethylases might be involved in AR regulation, an siRNA screen was performed to reveal that the demethylase, KDM4B, may be an important co-regulator protein. KDM4B enzymatic activity is required to enhance AR transcriptional activity; however, independently of this activity, KDM4B can enhance AR protein stability via inhibition of AR ubiquitination. Importantly, knockdown of KDM4B in multiple cell lines results in almost complete depletion of AR protein levels. For the first time, we have identified KDM4B to be an androgen-regulated demethylase enzyme, which can influence AR transcriptional activity not only via demethylation activity but also via modulation of ubiquitination. Together, these findings demonstrate the close functional relationship between AR and KDM4B, which work together to amplify the androgen response. Furthermore, KDM4B expression in clinical PC specimens positively correlates with increasing cancer grade (P < 0.001). Consequently, KDM4B is a viable therapeutic target in PC. PMID- 23435230 TI - The crystal structure of the DNA-binding domain of vIRF-1 from the oncogenic KSHV reveals a conserved fold for DNA binding and reinforces its role as a transcription factor. AB - Kaposi's sarcoma-associated herpesvirus encodes four viral homologues to cellular interferon regulatory factors (IRFs), where the most studied is vIRF-1. Even though vIRF-1 shows sequence homology to the N-terminal DNA-binding domain (DBD) of human IRFs, a specific role for this domain in vIRF-1's function has remained uncertain. To provide insights into the function of the vIRF-1 DBD, we have determined the crystal structure of it in complex with DNA and in its apo-form. Using a thermal stability shift assay (TSSA), we show that the vIRF-1 DBD binds DNA, whereas full-length vIRF-1 does not, suggesting a cis-acting regulatory mechanism in similarity to human IRFs. The complex structure of vIRF-1 DBD reveals interactions with the DNA backbone and the positioning of two arginines for specific recognition in the major grove. A superimposition with human IRF-3 reveals a similar positioning of the two specificity-determining arginines, and additional TSSAs indicate binding of vIRF-1 to an IRF-3 operator consensus sequence. The results from this study, therefore, provide support that vIRF-1 has evolved to bind DNA and plays a role in DNA binding in the context of transcriptional regulation and might act on some of the many operator sequences controlled by human IRF-3. PMID- 23435231 TI - CompaRNA: a server for continuous benchmarking of automated methods for RNA secondary structure prediction. AB - We present a continuous benchmarking approach for the assessment of RNA secondary structure prediction methods implemented in the CompaRNA web server. As of 3 October 2012, the performance of 28 single-sequence and 13 comparative methods has been evaluated on RNA sequences/structures released weekly by the Protein Data Bank. We also provide a static benchmark generated on RNA 2D structures derived from the RNAstrand database. Benchmarks on both data sets offer insight into the relative performance of RNA secondary structure prediction methods on RNAs of different size and with respect to different types of structure. According to our tests, on the average, the most accurate predictions obtained by a comparative approach are generated by CentroidAlifold, MXScarna, RNAalifold and TurboFold. On the average, the most accurate predictions obtained by single sequence analyses are generated by CentroidFold, ContextFold and IPknot. The best comparative methods typically outperform the best single-sequence methods if an alignment of homologous RNA sequences is available. This article presents the results of our benchmarks as of 3 October 2012, whereas the rankings presented online are continuously updated. We will gladly include new prediction methods and new measures of accuracy in the new editions of CompaRNA benchmarks. PMID- 23435232 TI - Characterization of an unusual bipolar helicase encoded by bacteriophage T5. AB - Bacteriophage T5 has a 120 kb double-stranded linear DNA genome encoding most of the genes required for its own replication. This lytic bacteriophage has a burst size of ~500 new phage particles per infected cell, demonstrating that it is able to turn each infected bacterium into a highly efficient DNA manufacturing machine. To begin to understand DNA replication in this prodigious bacteriophage, we have characterized a putative helicase encoded by gene D2. We show that bacteriophage T5 D2 protein is the first viral helicase to be described with bipolar DNA unwinding activities that require the same core catalytic residues for unwinding in either direction. However, unwinding of partially single- and double-stranded DNA test substrates in the 3'-5' direction is more robust and can be distinguished from the 5'-3' activity by a number of features including helicase complex stability, salt sensitivity and the length of single-stranded DNA overhang required for initiation of helicase action. The presence of D2 in an early gene cluster, the identification of a putative helix-turn-helix DNA-binding motif outside the helicase core and homology with known eukaryotic and prokaryotic replication initiators suggest an involvement for this unusual helicase in DNA replication initiation. PMID- 23435235 TI - Genetic diversity of spike, 3a, 3b and e genes of infectious bronchitis viruses and emergence of new recombinants in Korea. AB - The nucleotide sequences of a region including S1, S2, 3a, 3b and E genes of twenty-seven infectious bronchitis virus (IBV) isolates in Korea between 1990 2011 were determined and phylogenetic and computational recombination analyses were conducted. The sizes of coding regions of some genes varied among IBV isolates due to deletion or insertion of nucleotides; the nucleotide similarities of S1, S2, 3a, 3b and E genes among the 27 isolates were 75.9%-100.0%, 85% 100.0%, 64.0%-100.0%, 60.4%-100.0% and 83.1%-100.0%, respectively. According to phylogenetic analysis of S1 gene, the 27 isolates were divided into five genotypes, Mass, Korean-I (K-I), QX-like, KM91-like and New cluster 1. The phylogenetic trees based on the S2, 3a, 3b, E genes and S1-S2-3a-3b-E (S1-E) region nucleotide sequences did not closely follow the clustering based on the S1 sequence. The New cluster 1 prevalent during 2009 and 2010 was not found in 2011 but QX-like viruses became prevalent in 2011. The recombination analysis revealed two new S gene recombinants, 11036 and 11052 which might have been derived from recombinations between the New cluster 1 and QX-like viruses and between the K-I and H120 (vaccine) viruses, respectively. In conclusion, multiple IBV genotypes have co-circulated; QX-like viruses have recurred and new recombinants have emerged in Korea. This has enriched molecular epidemiology information of IBV and is useful for the control of IB in Korea. PMID- 23435234 TI - Arenavirus budding: a common pathway with mechanistic differences. AB - The Arenaviridae is a diverse and growing family of viruses that includes several agents responsible for important human diseases. Despite the importance of this family for public health, particularly in Africa and South America, much of its biology remains poorly understood. However, in recent years significant progress has been made in this regard, particularly relating to the formation and release of new enveloped virions, which is an essential step in the viral lifecycle. While this process is mediated chiefly by the viral matrix protein Z, recent evidence suggests that for some viruses the nucleoprotein (NP) is also required to enhance the budding process. Here we highlight and compare the distinct budding mechanisms of different arenaviruses, concentrating on the role of the matrix protein Z, its known late domain sequences, and the involvement of cellular endosomal sorting complex required for transport (ESCRT) pathway components. Finally we address the recently described roles for the nucleoprotein NP in budding and ribonucleoprotein complex (RNP) incorporation, as well as discussing possible mechanisms related to its involvement. PMID- 23435236 TI - Identifying the viral genes encoding envelope glycoproteins for differentiation of Cyprinid herpesvirus 3 isolates. AB - Cyprinid herpes virus 3 (CyHV-3) diseases have been reported around the world and are associated with high mortalities of koi (Cyprinus carpio). Although little work has been conducted on the molecular analysis of this virus, glycoprotein genes identified in the present study seem to be valuable targets for genetic comparison of this virus. Three envelope glycoprotein genes (ORF25, 65 and 116) of the CyHV-3 isolates from the USA, Israel, Japan and Korea were compared, and interestingly, sequence insertions or deletions were observed in these target regions. In addition, polymorphisms were presented in microsatellite zones from two glycoprotein genes (ORF65 and 116). In phylogenetic tree analysis, the Korean isolate was remarkably distinguished from USA, Israel, Japan isolates. These findings may be suitable for many applications including isolates differentiation and phylogeny studies. PMID- 23435237 TI - Low copper and high manganese levels in prion protein plaques. AB - Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system. PMID- 23435238 TI - Predicted peptides from non-structural proteins of porcine reproductive and respiratory syndrome virus are able to induce IFN-gamma and IL-10. AB - This work describes peptides from non-structural proteins (nsp) of porcine reproductive and respiratory syndrome virus (PRRSV) predicted as potential T cell epitopes by bioinfornatics and tested for their ability to induce IFN-gamma and IL-10 responses. Pigs immunized with either genotype 1 or genotype 2 PRRSV attenuated vaccines (n=5/group) and unvaccinated pigs (n = 4) were used to test the peptides. Swine leukocyte antigen haplotype of each pig was also determined. Pigs were initially screened for IFN-gamma responses (ELISPOT) and three peptides were identified; two of them in non-conserved segments of nsp2 and nsp5 and the other in a conserved region of nsp5 peptide. Then, peptides were screened for IL 10 inducing properties. Six peptides were found to induce IL-10 release in PBMC and some of them were also able to inhibit IFN-gamma responses on PHA-stimulated cells. Interestingly, the IFN-gamma low responder pigs against PRRSV were mostly homozygous for their SLA haplotypes. In conclusion, these results indicate that nsp of PRRSV contain T-cell epitopes inducing IFN-gamma responses as well as IL 10 inducing segments with inhibitory capabilities. PMID- 23435233 TI - Learning from the messengers: innate sensing of viruses and cytokine regulation of immunity - clues for treatments and vaccines. AB - Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs), recognizing distinct conserved pathogen-associated molecular patterns (PAMPs). The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs) and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus-host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs) and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response. PMID- 23435241 TI - Localization, concentration, and transmission efficiency of Banana bunchy top virus in four asexual lineages of Pentalonia aphids. AB - Banana bunchy top virus (BBTV) is the most destructive pathogenic virus of banana plants worldwide. The virus is transmitted in a circulative non-propagative manner by the banana aphid, Pentalonia nigronervosa Coquerel. In this work, we examined the localization, accumulation, and transmission efficiency of BBTV in four laboratory-established lineages of Pentalonia aphids derived from four different host plants: taro (Colocasia esculenta), heliconia (Heliconia spp.), red ginger (Alpinia purpurata), and banana (Musa sp.). Mitochondrial sequencing identified three and one lineages as Pentalonia caladii van der Goot, a recently proposed species, and P. nigronervosa, respectively. Microsatellite analysis separated the aphid lineages into four distinct genotypes. The transmission of BBTV was tested using leaf disk and whole-plant assays, both of which showed that all four lineages are competent vectors of BBTV, although the P. caladii from heliconia transmitted BBTV to the leaf disks at a significantly lower rate than did P. nigronervosa. The concentration of BBTV in dissected guts, haemolymph, and salivary glands was quantified by real-time PCR. The BBTV titer reached similar concentrations in the guts, haemolymph, and salivary glands of aphids from all four lineages tested. Furthermore, immunofluorescence assays showed that BBTV antigens localized to the anterior midguts and the principal salivary glands, demonstrating a similar pattern of translocations across the four lineages. The results reported in this study showed for the first time that P. caladii is a competent vector of BBTV. PMID- 23435242 TI - Novel switchable sensor for phosphate based on the distance-dependant fluorescence coupling of cysteine-capped cadmium sulfide quantum dots and silver nanoparticles. AB - A novel switchable sensor was developed for the determination of phosphate based on Ce(3+) induced aggregation and phosphate triggered disaggregation of cysteine (Cys)-capped CdS quantum dots (QDs) and silver nanoparticles (AgNPs). The rare earth metal Ce(3+) could aggregate a mixture of QDs and AgNPs, which induced electron or energy transfer between CdS QDs and AgNPs and serious fluorescence quenching. However, phosphate dissociated the formed aggregation of CdS QDs and AgNPs, restoring the enhanced fluorescence of Cys-capped CdS triggered by AgNPs. Although, CdS QDs alone could also be used to detect phosphate through the aggregation-disaggregation mechanism adjusted by Ce(3+) and phosphate. It was found that the distance-dependent interaction between AgNPs and CdS QDs driven by Ce(3+) and phosphate could lead to enhanced quenching or enhancement of the fluorescence of Cys-capped CdS to form a more sensitive detection system for phosphate. The developed method was applied in the detection of phosphate in real water samples with acceptable and satisfactory results. PMID- 23435239 TI - Directional spread of alphaherpesviruses in the nervous system. AB - Alphaherpesviruses are pathogens that invade the nervous systems of their mammalian hosts. Directional spread of infection in the nervous system is a key component of the viral lifecycle and is critical for the onset of alphaherpesvirus-related diseases. Many alphaherpesvirus infections originate at peripheral sites, such as epithelial tissues, and then enter neurons of the peripheral nervous system (PNS), where lifelong latency is established. Following reactivation from latency and assembly of new viral particles, the infection typically spreads back out towards the periphery. These spread events result in the characteristic lesions (cold sores) commonly associated with herpes simplex virus (HSV) and herpes zoster (shingles) associated with varicella zoster virus (VZV). Occasionally, the infection spreads transsynaptically from the PNS into higher order neurons of the central nervous system (CNS). Spread of infection into the CNS, while rarer in natural hosts, often results in severe consequences, including death. In this review, we discuss the viral and cellular mechanisms that govern directional spread of infection in the nervous system. We focus on the molecular events that mediate long distance directional transport of viral particles in neurons during entry and egress. PMID- 23435240 TI - Intrathecal humoral immunity to encephalitic RNA viruses. AB - The nervous system is the target for acute encephalitic viral infections, as well as a reservoir for persisting viruses. Intrathecal antibody (Ab) synthesis is well documented in humans afflicted by infections associated with neurological complications, as well as the demyelinating disease, multiple sclerosis. This review focuses on the origin, recruitment, maintenance, and biological relevance of Ab-secreting cells (ASC) found in the central nervous system (CNS) following experimental neurotropic RNA virus infections. We will summarize evidence for a highly dynamic, evolving humoral response characterized by temporal alterations in B cell subsets, proliferation, and differentiation. Overall local Ab plays a beneficial role via complement-independent control of virus replication, although cross or self-reactive Ab to CNS antigens may contribute to immune-mediated pathogenesis during some infections. Importantly, protective Ab exert anti-viral activity not only by direct neutralization, but also by binding to cell surface expressed viral glycoproteins. Ab engagement of viral glycoproteins blocks budding and mediates intracellular signaling leading to restored homeostatic and innate functions. The sustained Ab production by local ASC, as well as chemokines and cytokines associated with ASC recruitment and retention, are highlighted as critical components of immune control. PMID- 23435243 TI - Halarchaeum rubridurum sp. nov., a moderately acidophilic haloarchaeon isolated from commercial sea salt samples. AB - Six halo-acidophilic archaeal strains were isolated from four commercial salt samples obtained from seawater in the Philippines, Indonesia (Bali) and Japan (Okinawa) on agar plates at pH 4.5. Cells of the six strains were pleomorphic, and stained Gram-negative. Two strains were pink-red pigmented, while four other strains were orange-pink pigmented. Strain MH1-16-3(T) was able to grow at 9-30% (w/v) NaCl [with optimum at 18% (w/v) NaCl], at pH 4.5-6.8 (optimum, pH 5.5) and at 20-50 degrees C (optimum, 42 degrees C). The five other strains grew at slightly different ranges. The six strains required at least 1 mM Mg(2+) for growth. The 16S rRNA gene sequences of the six strains were almost identical, sharing 99.9 (1-2 nt differences) to 100% similarity. The closest relatives were Halarchaeum acidiphilum MH1-52-1(T) and Halarchaeum salinum MH1-34-1(T) with 97.7% similarity. The DNA G+C contents of the six strains were 63.2-63.7 mol%. Levels of DNA-DNA relatedness amongst the six strains were 79-86%, while those between MH1-16-3(T) and H. acidiphilum MH1-52-1(T) and H. salinum MH1-34-1(T) were both 43 and 45% (reciprocally), respectively. Based on the phenotypic, genotypic and phylogenetic analyses, it is proposed that the six isolates represent a novel species of the genus Halarchaeum, for which the name Halarchaeum rubridurum sp. nov. is proposed. The type strain is MH1-16-3(T) ( =JCM 16108(T) =CECT 7535(T)). PMID- 23435244 TI - Lysinibacillus contaminans sp. nov., isolated from surface water. AB - A Gram-positive-staining, aerobic, endospore-forming bacterium, isolated as a contamination from an enrichment of enteric bacteria from surface water, was studied using a polyphasic taxonomic approach. 16S rRNA gene sequence similarity comparisons revealed that strain FSt3A(T) was grouped in the genus Lysinibacillus, most closely related to Lysinibacillus xylanilyticus XDB9(T) (98.1%), Lysinibacillus parviboronicapiens BAM-582(T) and Lysinibacillus sphaericus DSM 28(T) (both 98.0%). The 16S rRNA gene sequence similarity to other species of the genus Lysinibacillus was <97.5%. The allocation to the genus Lysinibacillus was supported by a detailed chemotaxonomic characterization revealing a cell wall containing alanine, glutamic acid, aspartic acid and the diagnostic diamino acid lysine in a molar ratio of 1.6:1:0.9:0.8 (peptidoglycan type A4alpha), the major menaquinones MK-7 and MK-6, and polar lipids consisting of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, four unknown phospholipids, one unknown aminophospholipid and one unidentified aminolipid. The major fatty acids were iso- and anteiso-branched fatty acids. DNA DNA hybridizations with the type strains of the most closely related species, L. parviboronicapiens DSM 25242(T), L. xylanilyticus DSM 23493(T) and L. sphaericus DSM 28(T), in addition to the results of physiological and biochemical tests, allowed genotypic and phenotypic differentiation of strain FSt3A(T) from these related species. Thus, FSt3A(T) represents a novel species of the genus Lysinibacillus, for which the name Lysinibacillus contaminans sp. nov. is proposed, with FSt3A(T) ( =CCM 8383(T) =DSM 25560(T) =CIP 110362(T)) as the type strain. PMID- 23435245 TI - Tumebacillus flagellatus sp. nov., an alpha-amylase/pullulanase-producing bacterium isolated from cassava wastewater. AB - A novel alpha-amylase/pullulanase-producing bacterium, designated strain GST4(T), was isolated from samples collected from the wastewater of a cassava starch factory in Nanning, Guangxi Autonomous Region, southern China. Cells of strain GST4(T) were rod-shaped bacilli containing ellipsoidal terminal spores and found to be Gram-reaction-positive, aerobic, motile, oxidase-positive, catalase negative and formed light yellow colonies on agar plates. Strain GST4(T) was able to grow at pH 4.5-8.5 (optimum at pH 5.5), temperatures ranging from 20 to 42 degrees C (optimum at 37 degrees C) and salt concentrations of 0-1% (w/v) NaCl (optimum at 0.5%, w/v) on R2A medium. Strain GST4(T) grew heterotrophically on complex carbon substrates and chemolithoautotrophically on inorganic sulfur compounds, as demonstrated by growth on sodium thiosulfate and sulfite as sole electron donors. It can reduce nitrate and nitrite. Strain GST4(T) contained iso C(15:0) and anteiso-C(15:0) as the major cellular fatty acids and menaquinone 7 (MK-7) as the major respiratory quinone. The cell-wall peptidoglycan was of type A1gamma. The genomic DNA G+C content of strain GST4(T) was 53.7 mol%. Physiological and chemotaxonomic characteristics combined with phylogenetic analysis based on 16S rRNA gene sequences revealed that strain GST4(T) was a member of the genus Tumebacillus and most closely related to Tumebacillus permanentifrigoris DSM 18773(T) and Tumebacillus ginsengisoli DSM 18389(T) with 97.3 and 94.5% sequence similarity, respectively. The DNA-DNA relatedness values between strain GST4(T) and T. permanentifrigoris DSM 18773(T), and strain GST4(T) and T. ginsengisoli DSM 18389(T) were 44.0 and 60.4%, respectively. The new isolate differed from those species of the genus Tumebacillus in that it has peritrichous flagella for motility. Based on the evidence obtained from this study, strain GST4(T) represents a novel species of the genus Tumebacillus, for which the name Tumebacillus flagellatus sp. nov. is proposed. The type strain is GST4(T) ( =CGMCC 1.12170(T) =DSM 25748(T)). PMID- 23435246 TI - Dyella jiangningensis sp. nov., a gamma-proteobacterium isolated from the surface of potassium-bearing rock. AB - A Gram-stain-negative, aerobic, motile with one polar flagellum gamma proteobacterium, designated strain SBZ3-12(T), was isolated from surfaces of weathered potassic trachyte. Phylogenetic analysis of this strain based on 16S rRNA gene sequences showed that it was most closely related to Dyella japonica XD53(T) (97.9% 16S rRNA gene sequence similarity), Dyella terrae JS14-6(T) (97.7%), Dyella soli JS12-10(T) (97.5%) and Dyella koreensis BB4(T) (97.0%). The DNA G+C content of strain SBZ3-12(T) was 64.0 mol%. In addition, iso C(17:1)omega9c, iso-C(15:0) and iso-C(16:0) were the major cellular fatty acids and ubiquinone Q-8 was the predominant respiratory quinone. The low DNA-DNA relatedness values between strain SBZ3-12(T) and recognized species of the genus Dyella and the many phenotypic properties supported the classification of strain SBZ3-12(T) as a representative of a novel species of the genus Dyella, for which the name Dyella jiangningensis sp. nov. is proposed. The type strain is SBZ3 12(T) ( =CCTCC AB 2012160(T) =KACC 16539(T) =DSM 26119(T)). PMID- 23435247 TI - Cyclobacterium caenipelagi sp. nov., isolated from a tidal flat sediment, and emended description of the genus Cyclobacterium. AB - A Gram-staining-negative, aerobic, non-flagellated, non-gliding and ring-like or horseshoe-shaped bacterial strain, designated HD-17(T), was isolated from a tidal flat sediment in the Korean peninsula. Strain HD-17(T) grew optimally at pH 7.0 8.0, at 25 degrees C and in the presence of 2.0% (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain HD-17(T) fell within the clade comprising species of the genus Cyclobacterium. Strain HD-17(T) exhibited 16S rRNA gene sequence similarity values of 93.8-98.8% to the type strains of species of the genus Cyclobacterium. Strain HD-17(T) contained MK-7 as the predominant menaquinone and iso-C(15:0), summed feature 3 (C(16:1)omega6c and/or C(16:1)omega7c), anteiso-C(15:0) and iso-C(15:1) G as the major fatty acids. The major polar lipids of strain HD-17(T) were phosphatidylcholine, phosphatidylethanolamine and two unidentified lipids. The DNA G+C content of strain HD-17(T) was 43.8 mol% and its DNA-DNA relatedness values with Cyclobacterium amurskyense KCTC 12363(T), Cyclobacterium qasimii KCTC 23011(T) and Cyclobacterium marinum KCTC 2917(T) were 10.4, 7.6 and 5.3%, respectively. The phylogenetic and genetic distinctiveness and several differentiating phenotypic properties revealed that strain HD-17(T) was separate from other species of the genus Cyclobacterium. On the basis of the data presented, strain HD-17(T) represents a novel species of the genus Cyclobacterium, for which the name Cyclobacterium caenipelagi sp. nov. is proposed. The type strain is HD-17(T) ( = KCTC 32178(T) =CCUG 63247(T)). An emended description of the genus Cyclobacterium is also provided. PMID- 23435248 TI - Reyranella soli sp. nov., isolated from forest soil, and emended description of the genus Reyranella Pagnier et al. 2011. AB - A Gram-stain-negative, non-motile, rod-shaped bacterial strain, designated KIS14 15(T), was isolated from forest soil of Baengnyeong Island in the Yellow Sea in Korea and its taxonomic position was investigated by using a polyphasic study. Strain KIS14-15(T) grew optimally at 30 degrees C, at pH 6.0-7.0 and without NaCl. In the neighbour-joining phylogenetic tree based on 16S rRNA gene sequences, strain KIS14-15(T) formed a cluster with the strains of Reyranella massiliensis with a bootstrap resampling value of 100%. Strain KIS14-15(T) exhibited 16S rRNA gene sequence similarity values of 98.0% to R. massiliensis 521(T) and of less than 89% to the type strains of other taxa. The mean level of DNA-DNA relatedness between strain KIS14-15(T) and R. massiliensis KACC 16548(T) was 21% (reciprocal, 24%). The predominant ubiquinone found in strain KIS14-15(T) and R. massiliensis KACC 16548(T) was ubiquinone-10 (Q-10). The predominant fatty acids of strain KIS14-15(T) and R. massiliensis KACC 16548(T) were C(18:1)omega7c, C(18:1) 2-OH and 11-methyl C(18:1)omega7c. Total polar lipids of strain KIS14-15(T) were phosphatidylmonomethylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unknown aminolipid and one unknown lipid. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, demonstrated that strain KIS14-15(T) is distinguishable from R. massiliensis. On the basis of the data presented, strain KIS14-15(T) is considered to represent a novel species of the genus Reyranella, for which the name Reyranella soli sp. nov. is proposed. The type strain is KIS14-15(T) ( = KACC 13034(T) =NBRC 108950(T)). PMID- 23435250 TI - Aequorivita viscosa sp. nov., isolated from an intertidal zone, and emended descriptions of Aequorivita antarctica and Aequorivita capsosiphonis. AB - An aerobic, Gram-stain-negative, short rod-shaped, non-motile and non-sporulating bacterium, designed strain 8-1b(T), was isolated from seaweed collected from the intertidal zone of Zhoushan sea area, East China Sea. Strain 8-1b(T) grew at 4-39 degrees C (optimum, 28-32 degrees C) and at pH 6.0-9.5 (optimum, 7.0-8.5), and with 0.5-8% (w/v) NaCl (optimum, 1-3%) and 0.5-10% (w/v) sea salts (optimum, 2 3%). Analysis of 16S rRNA gene sequences revealed that strain 8-1b(T) was related closely to Aequorivita capsosiphonis JCM 15070(T) (96.7% similarity). The DNA G+C content of strain 8-1b(T) was 36.6 mol%. Compared with reference strains, cells of strain 8-1b(T) showed positive activities for H2S production and utilization of D-mannose, DL-lactic acid, L-asparagine and glycyl L-aspartic acid. The major fatty acids of strain 8-1b(T) were iso-C(15:0), iso-C(17:0) 3-OH, iso-C(15:1) G and iso-C(17:1)omega9c. The main respiratory quinone was menaquinone 6. The polar lipids of strain 8-1b(T) consisted of phosphatidylethanolamine (PE), three uncharacterized aminolipids (AL1-3), four uncharacterized glycolipids (GL1-4) and five uncharacterized lipids (L1-5). Based on the phenotypic and genotypic characterization, strain 8-1b(T) represents a novel species of the genus Aequorivita, for which the name Aequorivita viscosa sp. nov. is proposed. The type strain is strain 8-1b(T) ( =CGMCC 1.11023(T) = JCM 18497(T)). Emended descriptions of Aequorivita antarctica and Aequorivita capsosiphonis are also presented. PMID- 23435249 TI - Pseudomonas formosensis sp. nov., a gamma-proteobacteria isolated from food-waste compost in Taiwan. AB - A taxonomic study was carried out on a novel aerobic bacterial strain, designated CC-CY503(T), isolated from food-waste compost in Taiwan. Cells were Gram-stain negative short rods, motile by means of a monopolar flagellum. Strain CC-CY503(T) was able to grow at 20-50 degrees C and pH 6.0-10.0 and to tolerate <6% NaCl (w/v). Phylogenetic analysis of 16S rRNA gene sequences showed that this bacterium belonged to the genus Pseudomonas, with Pseudomonas pertucinogena ATCC 190(T) as the closest neighbour, sharing a sequence similarity of 97.9%. The DNA DNA relatedness value of strain CC-CY503(T) with P. pertucinogena ATCC 190(T) was 37.8 +/- 2.3%. The phylogenetic trees reconstructed based on gyrB and rpoB gene sequences supported the classification of strain CC-CY503(T) as a novel member of the genus Pseudomonas. The predominant quinone system was ubiquinone (Q-9) and the DNA G+C content was 63.1 +/- 0.4 mol%. The major fatty acids were C(12:0), C(16:0), C(17:0) cyclo, C(19:0) cyclo omega8c and summed features 3 and 8 consisting of C(16:1)omega7c/C(16:1)omega6c and C(18:1)omega7c/C(18:1)omega6c, respectively. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidylcholine. On the basis of its distinct phylogenetic, phenotypic and chemotaxonomic features, strain CC-CY503(T) ( =BCRC 80437(T) =JCM 18415(T)) is proposed to represent a novel species within the genus Pseudomonas, for which the name Pseudomonas formosensis sp. nov. is proposed. PMID- 23435251 TI - Ferrimonas pelagia sp. nov., isolated from seawater. AB - A Gram-stain-negative bacterium, designated strain CBA4601(T), was isolated from a seawater sample obtained off the coast of Jeju Island, Korea. The organism grew in the presence of 0-4% (w/v) NaCl and at 20-35 degrees C and pH 7.0-9.0, with optimal growth in 2% NaCl, and at 25 degrees C and pH 8.0. Phylogenetic trees based on 16S rRNA gene sequences showed that strain CBA4601(T) was related to the genus Ferrimonas within the class Gammaproteobacteria. 16S rRNA gene sequence similarity between strain CBA4601(T) and Ferrimonas marina A4D-4(T), the most closely related species, was 96.9%. The G+C content of the genomic DNA from strain CBA4601(T) was 54.2 mol%, and the isoprenoid quinones menaquinone 7 (MK 7), ubiquinone 7 (Q-7) and ubiquinone 8 (Q-8) were detected. The major fatty acids were C(17:1)omega8c, C(18:1)omega9c and C(16:0), and the major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and an unidentified ninhydrin positive phospholipid. On the basis of this taxonomic study using a polyphasic approach, strain CBA4601(T) represents a novel species of the genus Ferrimonas, for which the name Ferrimonas pelagia sp. nov. is proposed. The type strain is CBA4601(T) ( =KACC 16695(T) =KCTC 32029(T) =JCM 18401(T)). PMID- 23435252 TI - Asinibacterium lactis gen. nov., sp. nov., a member of the family Chitinophagaceae, isolated from donkey (Equus asinus) milk. AB - A novel bacterial strain, designated LCJ02(T), was isolated on R2A agar from donkey (Equus asinus) milk powder and subjected to a taxonomic study using a polyphasic approach. Strain LCJ02(T) showed a Gram-negative reaction, was non motile, non-spore-forming and possessed rod-shaped cells and yellow-pigmented colonies. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel isolate formed a cluster with several uncultured bacterial clones and with cultured members of the genera Hydrotalea, Sediminibacterium and Lacibacter (family Chitinophagaceae, phylum Bacteroidetes). The gene sequence similarities with respect to the type strains of recognized species from the above genera and other phylogenetic neighbours ranged from 89.3 to 92.9%. The G+C content of the genomic DNA was 49.2 mol%, the only isoprenoid quinone was MK-7 and the major fatty acids were iso-C(15:0), iso-C(17:0) 3-OH, iso-C(15:1) G and summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH). The major polar lipids of strain LCJ02(T) were phosphatidylethanolamine, two unidentified aminophospholipids, one unidentified aminolipid and five unidentified lipids. The results of physiological and biochemical tests allowed phenotypic differentiation of strain LCJ02(T) from its closest phylogenetic neighbours. On the basis of the evidence of this polyphasic study, isolate LCJ02(T) represents a novel genus and species in the family Chitinophagaceae for which the name Asinibacterium lactis gen. nov., sp. nov. is proposed. The type strain is LCJ02(T) ( =KCCM 90108(T) =JCM 18484(T)). PMID- 23435253 TI - Hwangdonia seohaensis gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from a tidal flat sediment. AB - A Gram-staining-negative, aerobic, non-flagellated, non-gliding and rod-shaped bacterial strain, HD-3(T), was isolated from a tidal flat sediment of Hwangdo in the Yellow Sea, South Korea. Strain HD-3(T) grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2-3% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain HD-3(T) joined the cluster comprising the type strains of Jejuia pallidilutea and Hyunsoonleella jejuensis. Strain HD 3(T) exhibited 16S rRNA gene sequence similarity values of 93.8% to each of the type strains of J. pallidilutea and Hyunsoonleella jejuensis. Strain HD-3(T) contained MK-6 as the only menaquinone and iso-C(15:0), iso-C(15:1) G, iso C(17:0) 3-OH and iso-C(15:0) 3-OH as the major fatty acids. The polar lipid profile of strain HD-3(T), which contained phosphatidylethanolamine and one unidentified lipid as major components and one unidentified phospholipid as a significant component, differed slightly from those of the type strains of J. pallidilutea and Hyunsoonleella jejuensis. The DNA G+C content of strain HD-3(T) was 42.3 mol%. Differential phenotypic and chemotaxonomic properties and phylogenetic data of strain HD-3(T) demonstrated that this strain is distinguishable from J. pallidilutea and Hyunsoonleella jejuensis. On the basis of the data presented, strain HD-3(T) is considered to represent a novel genus and species, for which the name Hwangdonia seohaensis gen. nov., sp. nov. is proposed. The type strain is HD-3(T) ( =KCTC 32177(T) =CCUG 63246(T)). PMID- 23435254 TI - Screening for type 2 diabetes does not reduce mortality over 10 years. PMID- 23435255 TI - Pre-interventional haemostatic assessment: Guidelines from the French Society of Anaesthesia and Intensive Care. AB - Recently the French Society of Anaesthesia and Intensive Care (Societe Francaise d'Anesthesie et de Reanimation [SFAR]) issued recommendations for the prescription of routine preoperative testing before a surgical or non-surgical procedure, requiring any type of anaesthesia. Thirty clinical specialists performed a systematic analysis of the literature, and recommendations were then developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. One part of these guidelines is dedicated to haemostatic assessment. The goal of pre-anaesthetic screening for congenital or acquired haemostatic disorders is to prevent perioperative haemorrhagic complications through appropriate medical and surgical management. Preoperative assessment of bleeding risk requires a detailed patient interview to determine any personal or family history of haemorrhagic diathesis, and a physical examination is necessary in order to detect signs of coagulopathy. Laboratory investigation of haemostasis should be prescribed, not systematically, but depending on clinical evaluation and patient history. Standard tests (prothrombin time, activated partial thromboplastin time, platelet count) have a low positive predictive value for bleeding risk in the general population. Patients with no history of haemorrhagic diathesis and no conditions liable to interfere with haemostasis should not undergo pre-interventional haemostasis testing. Conversely, the existence of a positive history or a disease that could interfere with haemostasis should be an indication for clinically appropriate testing. PMID- 23435256 TI - Molecular characterization of virulent Leptospira interrogans serogroup icterohaemorrhagiae isolated from Cavia aperea. AB - Leptospirosis is a worldwide zoonotic infection caused by pathogenic Leptospira. Synanthropic rodents are recognized carriers of leptospires; however, the role of wild rodents in the epidemiology of the disease is still incipient. In this work, we describe Leptospira strain isolated from Cavia aperea (Brazilian guinea pig). The isolated strain was characterized by partial rpoB gene sequencing, variable number tandem-repeats and histopathological analysis. The strain was identified as Leptospira interrogans, serogroup Icterohaemorrhagiae and caused clinical signs of leptospirosis in the hamster model, attesting to its virulence. In conclusion, these findings could be useful for elucidating the epidemiological role of C. aperea in leptospirosis. PMID- 23435257 TI - Associating portal congestive gastropathy and hepatic fibrosis in hepatosplenic mansoni schistosomiasis. AB - Upper digestive bleeding is one of the most serious complications of mansoni schistosomiasis, and portal congestive gastropathy (PCG) is responsible for 25 30% of the cases of bleeding instead of bleeding due to esophageal varices. This study aimed to investigate the association between PCG with parameters of portal hypertension and the intensity of periportal fibrosis assessed by ultrasonography, in patients with mansoni schistosomiasis. A prospective study was made of 71 patients whether or not they had a history of upper digestive bleeding, and who had not been previously treated for portal hypertension (splenectomy, use of beta blockers or endoscopic treatment). Patients with other liver diseases were excluded. After signing a form of consent, the patients underwent endoscopy, as well as ultrasonography of the abdomen, and hematological, biochemical and viral markers tests. Chi-square and Fischer's exact tests were used in the statistical analysis. The mean age of the 71 patients was 50 +/- 14.5 years of whom 59.2% were women. 45.1% had antecedents of upper digestive bleeding. PCG was observed in 39 patients (54.9%): severe in 8.5%, and mild in 46.5%. A positive association was observed between PCG and the grade of esophageal varices (p=0.017); and the pattern of periportal fibrosis (p=0.041). A negative association was observed between PCG and red spots on the varices (p=0.024). PCG in patients with mansoni schistosomiasis not submitted to treatment for portal hypertension is associated with the sonographic pattern of hepatic fibrosis, as well as with the grade of esophageal varices. PMID- 23435258 TI - TALEN-mediated precise genome modification by homologous recombination in zebrafish. AB - We report gene targeting via homologous recombination in zebrafish. We co injected fertilized eggs with transcription activator-like effector nuclease mRNAs and a donor vector with long homologous arms targeting the tyrosine hydroxylase (th) locus, and we observed effective gene modification that was transmitted through the germ line. We also successfully targeted two additional genes. Homologous recombination in zebrafish with a dsDNA donor expands the utility of this model organism. PMID- 23435259 TI - Predicting the molecular complexity of sequencing libraries. AB - Predicting the molecular complexity of a genomic sequencing library is a critical but difficult problem in modern sequencing applications. Methods to determine how deeply to sequence to achieve complete coverage or to predict the benefits of additional sequencing are lacking. We introduce an empirical bayesian method to accurately characterize the molecular complexity of a DNA sample for almost any sequencing application on the basis of limited preliminary sequencing. PMID- 23435260 TI - Neutron-encoded mass signatures for multiplexed proteome quantification. AB - We describe a protein quantification method called neutron encoding that exploits the subtle mass differences caused by nuclear binding energy variation in stable isotopes. These mass differences are synthetically encoded into amino acids and incorporated into yeast and mouse proteins via metabolic labeling. Mass spectrometry analysis with high mass resolution (>200,000) reveals the isotopologue-embedded peptide signals, permitting quantification. Neutron encoding will enable highly multiplexed proteome analysis with excellent dynamic range and accuracy. PMID- 23435261 TI - Immunofluorescence and fluorescent-protein tagging show high correlation for protein localization in mammalian cells. AB - Imaging techniques such as immunofluorescence (IF) and the expression of fluorescent protein (FP) fusions are widely used to investigate the subcellular distribution of proteins. Here we report a systematic analysis of >500 human proteins comparing the localizations obtained in live versus fixed cells using FPs and IF, respectively. We identify systematic discrepancies between IF and FPs as well as between FP tagging at the N and C termini. The analysis shows that for 80% of the proteins, IF and FPs yield the same subcellular distribution, and the locations of 250 previously unlocalized proteins were determined by the overlap between the two methods. Approximately 60% of proteins localize to multiple organelles for both methods, indicating a complex subcellular protein organization. These results show that both IF and FP tagging are reliable techniques and demonstrate the usefulness of an integrative approach for a complete investigation of the subcellular human proteome. PMID- 23435262 TI - Botulinum neurotoxins. PMID- 23435263 TI - Rational development of novel leads from animal secretion based on coagulation and cell targets: 1. In silico analysis to explore a peptide derivative as lipocalins' signature. AB - Animal venoms and secretions have been screened, in our research group, to discover, identify and isolate peptide molecules active in the mammalian haemostatic system. As result, this kind of research has provided a portfolio of promising drug candidates. These novel recombinant proteins have turned out to be multifunctional molecules, and are currently under different development phases. Lopap from bristles of the Lonomia obliqua moth caterpillar, for instance, is a prothrombin activator which belongs to the lipocalin family. It displays serine protease-like activity with procoagulant effect, and also induces cytokine secretion and antiapoptotic pathways in human cultured endothelial cells. Furthermore, a Lopap-derived peptide has showed to induce collagen synthesis in fibroblast culture and in animal dermis. Here, the molecular properties (steric, electronic, hydrophobic, geometric), which are strongly dependent on chemical structure, were investigated by applying chemometric and computational chemistry methods. It was considered different patterns of amino acid substitution related to the lipocalins' motif 2, which was recently shown to modulate cell survival. The calculated molecular properties were generally maintained in all investigated peptides extracted from three-dimensional structures of Protein Data Bank (1t0v, 1bbp, 1kxo, 2hzr, 1iiu, 1jyj, 1gka, 1s44, 3ebw) when compared to Lopap-derived peptide, specially the molecular shape and electronic density distribution, validating the lipocalin sequence signature previously reported. Indeed, those two properties are quite important for the molecular recognition process. PMID- 23435264 TI - Simulations and phantom evaluations of magnetic resonance electrical impedance tomography (MREIT) for breast cancer detection. AB - MREIT is a new imaging modality that can be used to reconstruct high-resolution conductivity images of the human body. Since conductivity values of cancerous tissues in the breast are significantly higher than those of surrounding normal tissues, breast imaging using MREIT may provide a new noninvasive way of detecting early stage of cancer. In this paper, we present results of experimental and numerical simulation studies of breast MREIT. We built a realistic three-dimensional model of the human breast connected to a simplified model of the chest including the heart and evaluated the ability of MREIT to detect cancerous anomalies in a background material with similar electrical properties to breast tissue. We performed numerical simulations of various scenarios in breast MREIT including assessment of the effects of fat inclusions and effects related to noise levels, such as changing the amplitude of injected currents, effect of added noise and number of averages. Phantom results showed straightforward detection of cancerous anomalies in a background was possible with low currents and few averages. The simulation results showed it should be possible to detect a cancerous anomaly in the breast, while restricting the maximal current density in the heart below published levels for nerve excitation. PMID- 23435265 TI - Kidney injury molecule-1 and osteopontin: new markers for prediction of early kidney transplant rejection. AB - BACKGROUND: Kidney injury molecule-1 (KIM-1) and osteopontin (OPN) play important roles in immune regulation. We hypothesized that serum KIM-1 and OPN might serve as biomarkers for predicting early acute rejection after kidney transplantation (KTx). METHODS: We conducted a single-center study of 155 subjects, who were classified into acute rejection group (ARG, n=32), non-rejection group (NRG, n=45) and healthy controls (HC, n=78). Serum KIM-1 and OPN levels were measured by Luminex. RESULTS: The pre-transplant levels of serum KIM-1 and OPN in all KTx recipients were higher than those of HC (P<0.01). Compared with NRG, ARG showed significantly high serum levels of KIM-1 on day 0 (pre-KTx) and on the 1st, 4th, and 7th post-KTx days, and significantly high OPN levels on day 0 and the 7th day. Kaplan-Meier survival analysis showed that the higher levels of KIM-1 on day 0, the 1st and 4th days and OPN on day 0 and the 7th day were significantly associated with the lower probabilities of rejection-free survival. ROC analyses highlight the superiority of KIM-1 on the 1st day and OPN on the 7th day over those on other post-KTx days in prediction of acute rejection episodes. Multivariate logistic analysis revealed that the serum KIM-1 levels on the 1st post-KTx day and the OPN level on the 7th day were independent and powerful predictors of acute rejection episodes. An optimal predictive model was built by combining KIM-1 on the 1st day and OPN on the 7th day, and this model had the highest AUC (0.922). CONCLUSIONS: This study was the first to demonstrate that serum KIM-1 and OPN may be the promising and elegant markers for prediction of early acute kidney allograft rejection. PMID- 23435266 TI - Bayesian inference of phylogeny, morphology and range evolution reveals a complex evolutionary history in St. John's wort (Hypericum). AB - The genus Hypericum L. ("St. John's wort", Hypericaceae) comprises nearly 500 species of shrubs, trees and herbs distributed mainly in temperate regions of the Northern Hemisphere, but also in high-altitude tropical and subtropical areas. Until now, molecular phylogenetic hypotheses on infra-generic relationships have been based solely on the nuclear marker ITS. Here, we used a full Bayesian approach to simultaneously reconstruct phylogenetic relationships, divergence times, and patterns of morphological and range evolution in Hypericum, using nuclear (ITS) and plastid DNA sequences (psbA-trnH, trnS-trnG, trnL-trnF) of 186 species representing 33 of the 36 described morphological sections. Consistent with other studies, we found that corrections of the branch length prior helped recover more realistic branch lengths in by-gene partitioned Bayesian analyses, but the effect was also seen within single genes if the overall mutation rate differed considerably among sites or regions. Our study confirms that Hypericum is not monophyletic with the genus Triadenum embedded within, and rejects the traditional infrageneric classification, with many sections being para- or polyphyletic. The small Western Palearctic sections Elodes and Adenotrias are the sister-group of a geographic dichotomy between a mainly New World clade and a large Old World clade. Bayesian reconstruction of morphological character states and range evolution show a complex pattern of morphological plasticity and inter continental movement within the genus. The ancestors of Hypericum were probably tropical shrubs that migrated from Africa to the Palearctic in the Early Tertiary, concurrent with the expansion of tropical climates in northern latitudes. Global climate cooling from the Mid Tertiary onwards might have promoted adaptation to temperate conditions in some lineages, such as the development of the herbaceous habit or unspecialized corollas. PMID- 23435268 TI - The impact of emotion on the perception of graded magnitudes of respiratory resistive loads. AB - Emotional state can modulate the perception of respiratory loads but the range of respiratory load magnitudes affected by emotional state is unknown. We hypothesized that viewing pleasant, neutral and unpleasant affective pictures would modulate the perception of respiratory loads of different load magnitudes. Twenty-four healthy adults participated in the study. Five inspiratory resistive loads of increasing magnitude (5, 10, 15, 20, 45 cm H(2)O/L/s) were repeatedly presented for one inspiration while participants viewed pleasant, neutral and unpleasant affective picture series. Participants rated how difficult it was to breathe against the load immediately after each presentation. Only at the lowest load, magnitude estimation ratings were greater when subjects viewed the unpleasant series compared to the neutral and pleasant series. These results suggest that negative emotional state increases the sense of respiratory effort for single presentations of a low magnitude resistive load but high magnitude loads are not further modulated by emotional state. PMID- 23435267 TI - Phylogenetic relationships of Trachylepis skink species from Madagascar and the Seychelles (Squamata: Scincidae). AB - Lizards of the genus Trachylepis are a species-rich group of skinks mainly inhabiting Africa, Madagascar, and several other islands in the western Indian Ocean. All except one probably introduced species of Madagascan Trachylepis are endemic. Two species groups have been distinguished on the basis of subocular scale shape but their phylogenetic relationships remained unclear. We inferred a multilocus phylogeny of the Madagascan Trachylepis species, based on a concatenated dataset of 3261 bp from 3 mitochondrial and 4 nuclear genes with a dense Madagascan taxon sampling and find high support for the monophyly of the endemic Madagascan Trachylepis. The two species groups in Madagascar are highly supported as clades. The highland species T. boettgeri is nested in the T. aureopunctata species group of mainly arid-adapted species, suggesting a colonization of highland swamps by ancestors inhabiting dry western Madagascar. The Seychellois species were sister to the T. maculilabris/T. comorensis clade, suggesting their origin directly out of Africa as with Seychellois chameleons. In Madagascar, a high intraspecific molecular variation was confirmed for T. gravenhorstii, T. elegans, and T. vato, indicating a need for taxonomic revision. PMID- 23435269 TI - Chronic family stress moderates the association between a TOMM40 variant and triglyceride levels in two independent Caucasian samples. AB - TOMM40 SNP rs157580 has been associated with triglyceride levels in genome-wide association studies (GWAS). Chronic caregiving stress moderates the association between triglyceride levels and a nearby SNP rs439401 that is associated with triglyceride levels in GWAS. Here, we report data from two independent Caucasian samples (242 U.S. women and men; 466 Danish men) testing the hypothesis that chronic family stress also moderates the association between rs157580 and triglyceride levels. The interaction of rs157580 and family stress in predicting triglyceride levels was statistically significant in the U.S. sample (p=0.004) and marginally significant (p=0.075) in the Danish sample. The G allele of rs157580 was associated with increased triglyceride levels among family stressed cases in both samples compared with A/A cases, but not among controls. Chronic family stress moderates the association of rs157580 variants with triglyceride levels and should be taken into account for disease risk assessment and potential intervention. PMID- 23435270 TI - A generalized strategy for immobilizing uniformly oriented membrane proteins at solid interfaces. AB - We have developed a method based on self-assembly of thiols on Au substrates to immobilize membrane proteins at interfaces. Using water soluble nitrilotriacetic acid (NTA)-terminated oligo(ethylene glycol) thiols, a histidine-tagged G protein coupled membrane receptor (GPCR) was captured in a defined orientation with little nonspecific binding. PMID- 23435271 TI - Longitudinal associations between attitudes towards binge drinking and alcohol free drinks, and binge drinking behavior in adolescence. AB - Alcohol attitudes are often considered an important predecessor of drinking behavior, although the literature is equivocal. Lately, attention has turned to enhancing positive cognitions on alcoholic-free drinks to discourage heavy drinking. The current study was the first to longitudinally examine associations between attitudes towards binge drinking and alcohol-free drinks and binge drinking behavior in a cross-lagged path model in Mplus. Participants were 293 adolescents (131 boys, M(age)=16.1 years) who filled in two online questionnaires with a six-month interval. Binge drinking behavior and attitudes towards binge drinking and alcohol-free drinks were all significantly correlated at both waves. The multivariate model, however, showed that only higher levels of binge drinking at T1 were prospectively related to more positive binge drinking attitudes at T2, and not vice versa. Analyses were controlled for sex, educational level, and age. Findings discard the Theory of Planned Behavior, but rather seem consistent with the Theory of Cognitive Dissonance, i.e., adolescents may adapt their cognitions to their behavior. More longitudinal research with several time points and over a longer period of time is needed to further examine the development of attitudes and drinking behavior. PMID- 23435272 TI - Risky drinking and its detection among medical students. AB - The drinking patterns of physicians may affect their own health and how they treat patients with substance use disorders. This is why we wanted to find out risky drinking among medical students. A questionnaire was delivered to all medical students at the University of Tampere and risky alcohol drinking was defined as a minimum score of five for women and six for men in the AUDIT-C alcohol screen (rating 0 to 12). The respondent rate was 94% (n=465). Of the whole sample 33% were risky drinkers, 24% of women and 49% of men. After the first study year the female risky drinkers significantly decreased and men increased their drinking. Significantly more men but not women with moderate alcohol use reduced drinking during the first year of studies compared with risky drinkers of the same gender. The AUDIT-C scored higher in the subgroups of risky drinkers willing to reduce drinking compared with those who did not want to cut down drinking (7.3. and 6.5., p<0.001). In the male sample the third AUDIT-C sub question on binge drinking (=AUDIT-3, rating 0 to 4) at a cut-off point of >=2 was nearly as effective as the whole AUDIT-C at a cut-off point of >=6. This was not the case in the female sub-sample. Risky drinking is common among medical students and continues throughout the studies especially among men. AUDIT-3 is a short and reliable screening tool for male but not for female students. PMID- 23435273 TI - Temporal patterns of adherence to medications and behavioral treatment and their relationship to patient characteristics and treatment response. AB - BACKGROUND: The primary analyses of the COMBINE Study revealed significant naltrexone and Combined Behavioral Intervention (CBI) main effects on drinking outcomes but failed to find additional benefits of the combination of treatments. Investigating differences in patterns of adherence over time may shed light on the treatment effects in COMBINE. The goals of the study were to identify trajectories of medication adherence and participation in CBI, to estimate predictive and moderating effects of adherence trajectories on drinking outcomes and to characterize subjects in adherence trajectories. The results of these analyses may suggest approaches to improving adherence in order to ultimately improve treatment outcome. METHODS: We used a trajectory-based approach to identify patterns of treatment adherence separately for naltrexone, acamprosate and CBI adherence. Logistic regression and general linear models assessed associations among adherence trajectories, drinking outcomes and patient characteristics. RESULTS: Three trajectories of adherence were identified for each treatment: "excellent adherers", "late non-adherers" and "early non adherers" and there was good agreement among adherence trajectories with different treatments. "Excellent adherers" had significantly higher percent days abstinent (PDA) and lower percent heavy drinking days (PHDD). CBI significantly decreased PHDD for subjects on acamprosate in the "early non-adherers with medication" trajectory (p=0.01). Either naltrexone or acamprosate was associated with lower PHDD than placebo for "early non-adherers with CBI" (p<0.01). Receiving active medication decreased the likelihood to be in the excellent medication adherence trajectory. Younger age, greater drinking severity, dissatisfaction with the medicine and session frequency, adverse events and lack of benefit were related to less favorable medication adherence trajectories. "Excellent adherers with CBI" were significantly more satisfied with the CBI counselor. CONCLUSIONS: Patterns of treatment adherence appear to be a participant characteristic. Individuals who fail to adhere early in treatment have worse outcomes regardless of treatment. However, treatment outcomes of participants who exhibit early problems with adherence to one treatment modality could potentially be improved by offering an alternative behavioral or pharmacologic treatment. PMID- 23435274 TI - Effects of chronic ketamine use on frontal and medial temporal cognition. AB - BACKGROUND: Recreational ketamine use has been on the rise worldwide. Previous studies have demonstrated that it disrupts various memory systems, but few studies have examined how it affects learning and frontal functioning. The present study investigates the effects of repeated ketamine self-administration on frontal fluency, attention, learning, and memory along the verbal/nonverbal axis. METHODS: Twenty-five ketamine users and 30 healthy controls took a battery of neuropsychological tests. Frontal fluency was measured by the Verbal Fluency Test for semantic organization ability and the Figural Fluency Test for nonverbal executive functioning. Learning and memory were measured with the Chinese Auditory-Verbal Learning Test for acquisition and retention abilities of verbal information, as well as with the Continuous Visual Memory Test for nonverbal information. Participants also took several tests tapping subdomains of attention. To test for the potential effects of other drug use, 10 polydrug controls were included for comparison with the ketamine users and healthy controls. RESULTS: Ketamine users had impaired verbal fluency, cognitive processing speed, and verbal learning. Verbal learning impairment was strongly correlated with estimated lifetime ketamine use. Ketamine users showed no impairments in figural fluency, sustained attention, selective attention, visual learning, or verbal/nonverbal memory. However, heavier lifetime ketamine use was significantly correlated with deficits in verbal memory (both immediate recall and delayed recall) and visual recognition memory. Deficits in cognitive processing speed and verbal learning persisted even after polydrug controls were included in the control group, but their inclusion did make the impairment in verbal fluency barely reach statistical significance. CONCLUSIONS: This study suggests that repeated ketamine use causes differential impairment to multiple domains of frontal and medial temporal functioning, possibly specific to verbal information processing. PMID- 23435275 TI - Are they all the same? An exploratory, categorical analysis of drinking game types. AB - Drinking games have become a ubiquitous part of the college student drinking culture and are associated with drinking to intoxication and increased alcohol consequences. Contemporary research commonly considers drinking games holistically, with little to no consideration to the different drinking game types. The current study describes the creation of a novel DG categorization scheme and reports differences between DG categories. Participants were 3421 college students (58% female) who completed online surveys. Based on participant responses, 100 distinct drinking games were identified and defined. Two student focus groups were conducted in which drinking game definitions and rules were verified by students. Drinking games were then categorized into five mutually exclusive categories: Targeted and Skill games, Communal games, Chance games, Extreme Consumption games, and Even Competition games. Finally, the frequency of games played in each category and typical player profiles were reported. Differences in peak drinks and frequency of specific alcohol consequences were documented according to game categories. The findings provide a novel drinking game categorization scheme and an exploratory analysis of basic differences between game categories. PMID- 23435276 TI - Improving pediatric compliance with EEG: decreasing procedural anxiety and behavioral distress. AB - Behavioral distress in EEG can be a barrier to medical care, and behavioral interventions may be a solution. This study evaluates the effectiveness of a brief intervention to decrease procedural distress during an EEG. We hypothesized that children and parents who received psychoeducation and distraction interventions would exhibit less anxiety and distress during an EEG procedure, as compared to those receiving standard care, and this would not add to EEG duration. One hundred and thirty-nine children (0-6 years) and their parents referred for routine EEGs were enrolled. Data were analyzed separately for both infants and children due to differences in the presentation of psychoeducational materials. Results demonstrated less parental anxiety and less distress vocalizations during the EEG. Interestingly, the intervention did not increase the duration of the EEG. While the data suggest positive effects, study limitations raise more questions as to the feasibility and impact of psychoeducation and distraction interventions with extended medical procedures. PMID- 23435277 TI - Prophylactic treatment with melatonin after status epilepticus: effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy. AB - Melatonin is a potent antioxidant which showed anticonvulsant activities both in experimental and clinical studies. In the present study, we examined the effect of melatonin treatment (10mg/kg/day, diluted in drinking water, 8 weeks) during epileptogenesis on the consequences of a kainate (KA)-induced status epilepticus (SE) in rats. Melatonin increased the latency in the appearance of spontaneous recurrent seizures (SRSs) and decreased their frequency only during the treatment period. The behavioral alterations associated with hyperactivity, depression-like behavior during the light phase, and deficits in hippocampus-dependent working memory were positively affected by melatonin treatment in rats with epilepsy. Melatonin reduced the neuronal damage in the CA1 area of the hippocampus and piriform cortex and recovered the decrease of hippocampal serotonin (5-HT) level in rats with epilepsy. Taken together, long-term melatonin treatment after SE was unable to suppress the development of epileptogenesis. However, it showed a potential in reducing some of the deleterious alterations that develop during the chronic epileptic state in a diurnal phase-dependent mode. PMID- 23435278 TI - Epidural analgesia and postoperative orthostatic haemodynamic changes: observational study. AB - CONTEXT: In thoracic and abdominal surgery, epidural analgesia provides excellent pain relief, but associated postural hypotension can delay mobilisation. OBJECTIVES: To assess postoperative orthostatic haemodynamic changes in patients receiving epidural analgesia after major surgery. DESIGN: Prospective observational study. Physiological intervention. SETTINGS: Montreal General Hospital tertiary teaching hospital. PATIENTS OR OTHER PARTICIPANTS: Patients scheduled for thoracic or abdominal surgery with thoracic epidural analgesia using a mixture of bupivacaine 0.1% and fentanyl 3 MUg ml(-1). INTERVENTION(S): Arterial blood pressure and heart rate were measured in supine, sitting and standing position before surgery and daily for the first 3 postoperative days. MAIN OUTCOME MEASURE: Orthostatic hypotension, defined as a drop in SBP of more than 20 mmHg during the orthostatic tests, was investigated as a predictor of inability to mobilise during the postoperative period. RESULTS: One hundred and sixty-one patients were enrolled in the study. Hypotension was detected in 59 (37%) of the patients on postoperative day 1, 20 (12%) on day 2 and four (2.5%) on day 3. On day 1, 43% of the patients walked, 39% only sat and 17% were bedridden. Supine SBP less than 90 mmHg, haemodynamic changes during the orthostatic tests, dizziness or nausea, did not predict inability to walk. Only blood loss more than 500 ml and supine mean BP less than 70 mmHg were negative predictors of mobilisation on day 1. CONCLUSION: Epidural analgesia is associated with arterial hypotension in the postoperative period. However, haemodynamic assessment does not predict inability to walk after thoracic and abdominal surgery. Early mobilisation should be tried irrespective of BP or orthostatic changes in postoperative patients with epidural analgesia. PMID- 23435279 TI - A painful forefoot mass. PMID- 23435280 TI - An autonomous photosynthetic device in which all charge carriers derive from surface plasmons. AB - Solar conversion to electricity or to fuels based on electron-hole pair production in semiconductors is a highly evolved scientific and commercial enterprise. Recently, it has been posited that charge carriers either directly transferred from the plasmonic structure to a neighbouring semiconductor (such as TiO2) or to a photocatalyst, or induced by energy transfer in a neighbouring medium, could augment photoconversion processes, potentially leading to an entire new paradigm in harvesting photons for practical use. The strong dependence of the wavelength at which the local surface plasmon can be excited on the nanostructure makes it possible, in principle, to design plasmonic devices that can harvest photons over the entire solar spectrum and beyond. So far, however, most such systems show rather small photocatalytic activity in the visible as compared with the ultraviolet. Here, we report an efficient, autonomous solar water-splitting device based on a gold nanorod array in which essentially all charge carriers involved in the oxidation and reduction steps arise from the hot electrons resulting from the excitation of surface plasmons in the nanostructured gold. Each nanorod functions without external wiring, producing 5 * 10(13) H2 molecules per cm(2) per s under 1 sun illumination (AM 1.5 and 100 mW cm(-2)), with unprecedented long-term operational stability. PMID- 23435281 TI - Delayed onset of peroneal neuropathy after minor ankle torsion in a 9-year-old boy. AB - Ankle sprain is only rarely reported as the cause of peroneal nerve palsy and occurs predominantly in adults. Peroneal nerve palsy following an ankle sprain is extremely rare in children. Furthermore, peroneal nerve palsy most commonly results from a severe ankle sprain with considerable pain and edema. Peroneal nerve palsy after minor ankle torsion without major clinical symptoms of ankle sprain is uncommon. Here, we report the case of a 9-year-old boy who developed right peroneal neuropathy, leading to foot drop, following minor ankle plantar flexion/inversion torsion. Electrophysiological findings confirmed a focal neuropathy around the fibular head. The neurologic symptoms resolved completely 4 months after the injury. This case emphasizes that peroneal neuropathy can occur after minor ankle torsion without evident ankle sprain symptoms. Moreover, electrophysiological evaluation is very helpful to confirm the diagnosis and is important for prognostic evaluation. PMID- 23435282 TI - Toward the development of the International Classification of Functioning Core Sets for children with cerebral palsy: a global expert survey. AB - The goal of the International Classification of Functioning is to standardize the classification of health and function of children around the world. To facilitate the application of this classification, International Classification of Functioning-based tools like the "Core Sets" are being developed. We conducted an international survey of professional experts to identify the most relevant areas of functioning in children with cerebral palsy. The questionnaire covered each component of the classification. In total, 193 professionals completed the survey (response rate 78%). Overall, 9706 answers were linked to the classification (pediatric version) by 2 professionals. From the experts' perspective, movement related areas and social participation are the most relevant areas of functioning. Experts suggest a more comprehensive profile of functioning in particular in areas of personal capacity and social participation. The results of this survey will inform the development of the International Classification of Functioning Core Sets for children with cerebral palsy. PMID- 23435283 TI - Thinking ethically about medical mistakes. AB - Medical mistakes, especially ones with significant adverse events, can erode the trust and bonds between and among parents, patients, and health care professionals. Prevention of medical mistakes should be the goal of every health care organization, and participation in quality improvement processes aimed at patient safety is an ethical duty for all health care professionals. But when mistakes occur, health care organizations and professionals should rapidly move toward disclosure and apology. These duties of honesty, disclosure and apology are based ethically on core health care principles and values. Health care organizations should require disclosure-and-apology training, especially for front-line personnel; provide assistance to clinicians with these difficult conversations; and invest in resources to address the moral distress experienced by professionals, who are often the "second victims" of medical mistakes. PMID- 23435284 TI - Statistical challenges in drug approval trials that use patient-reported outcomes. AB - This article describes challenging aspects of the use of patient-reported outcome instruments in clinical trials for drug approval, in our perspective as statistical reviewers at the US Food and Drug Administration. We discuss aspects of planning and interpreting results in clinical trials (1) adapting an existing patient-reported outcome instrument for use in clinical trials, (2) using multi item patient-reported outcomes and (3) missing patient-reported outcome values from many subjects over time. These challenges are illustrated with multiple examples from different clinical trials for different indications. We finally discuss important considerations in labeling. PMID- 23435285 TI - Improved homopolymer separation to enable the application of 1H NMR and HPLC for the determination of the reaction parameters of the graft copolymerization of acrylic acid onto starch. AB - Graft copolymers of starch with acrylic acid are a promising green, bio based material with many potential applications. The grafting of acrylic acid onto cassava starch in an aqueous medium initiated by Fenton's reagent has been studied. Common grafting result parameters are add-on (yield) and graft efficiency (selectivity). However, the analysis of the reaction products and an accurate determination of these parameters stand or fall with a complete separation of the entangled but ungrafted homopolymer from the grafted product. Therefore, this separation is the core of the newly developed analytical procedure. An appropriate solvent has been selected with dedicated testing from the range methanol, ethanol, acetone, dioxane, 2-propanol, and 1-propanol. Acetone showed the best performance in many respects. It has a high dissolving power for the homopolymer, as well as the highest yield of precipitation for the starch derivatives and it is the most economical in use. After the successful separation, the precipitated graft copolymers could be analyzed quantitatively by nuclear magnetic resonance. The liquid with homopolymer and unreacted monomer was analyzed by high pressure liquid chromatography. Proof of grafting has been found by FTIR and TGA analyses. The mass balance calculation shows a systematic error which appears fairly consistent: 18.0+/-2.5 wt%. This was used as a correction factor in the calculation of the grafting parameters but more importantly, it means that the method we developed has a high level of repeatability, in the order of 97%. PMID- 23435287 TI - Compared to standard physician care for diabetes, nurse specialists provide similar care in terms of quality of life. PMID- 23435286 TI - Sortal concepts and pragmatic inference in children's early quantification of objects. AB - It is typically assumed that count nouns like fork act as logical sortals, specifying whether objects are countable units of a kind (e.g., that a whole fork counts as "one fork") or not (e.g., that a piece of a fork does not count as "one fork"). In four experiments, we provide evidence from linguistic and conceptual development that nouns do not specify units of quantification, but include both whole objects and their arbitrary parts in their denotations. We argue that, to restrict quantification to whole objects, nominal concepts are enriched pragmatically, via contrast with concepts denoted by alternative descriptions: a piece of a fork is not counted as "one fork" because it is "one piece of fork." Experiment 1 replicated previous findings that children count pieces of broken objects as whole objects (e.g., two pieces of fork as "two forks"), and showed that children also accept whole object labels as descriptions of object pieces (e.g., "two forks" to describe two pieces of fork). Experiment 2 showed that although children accept such descriptions in isolation, they prefer measure phrases (e.g., "two pieces of fork") when they are explicitly presented as alternatives. Experiment 3 found that children were better at excluding pieces from their counts of whole objects when measure phrases were primed prior to counting, making them accessible as alternatives to whole object labels. Finally, Experiment 4 taught children names for novel objects, and found that they do not count parts that are given unique labels or that have non-linguistic properties that suggest they are members of distinct object kinds (e.g., unique functions or physical affordances). Together, our results suggest that for children and adults alike, nominal concepts do not provide necessary and sufficient criteria for excluding parts from object kinds. To specify units of quantification--and do the work of sortals--concepts are contrasted with one another and enriched pragmatically. PMID- 23435288 TI - Integration of plant viruses in electron beam lithography nanostructures. AB - Tobacco mosaic virus (TMV) is the textbook example of a virus, and also of a self assembling nanoscale structure. This tubular RNA/protein architecture has also found applications as biotemplate for the synthesis of nanomaterials such as wires, as tubes, or as nanoparticle assemblies. Although TMV is, being a biological structure, quite resilient to environmental conditions (temperature, chemicals), it cannot be processed in electron beam lithography (eBL) fabrication, which is the most important and most versatile method of nanoscale structuring. Here we present adjusted eBL-compatible processes that allow the incorporation of TMV in nanostructures made of positive and negative tone eBL resists. The key steps are covering TMV by polymer resists, which are only heated to 50 degrees C, and development (selective dissolution) in carefully selected organic solvents. We demonstrate the post-lithography biochemical functionality of TMV by selective immunocoating of the viral particles, and the use of immobilized TMV as direct immunosensor. Our modified eBL process should be applicable to incorporate a wide range of sensitive materials in nanofabrication schemes. PMID- 23435290 TI - Platinum-based drugs and proteins: reactivity and relevance to DNA adduct formation. AB - The mechanism of action of clinically used Pt-based drugs is through the formation of stable DNA adducts occurring at the nitrogen in position 7 of guanine (N7) and involving one or two spatially closed residues. Nevertheless, proteins can represent alternative targets since in particular sulfur groups, present in cysteine or methionine residues, can efficiently coordinate platinum. Here we have characterized the reactivity profile of cisplatin, transplatin and of two trans-platinum amine derivatives (TPAs) towards three different proteins, bovine alpha-lactalbumin (alpha-LA), hen egg lysozyme (LYS) and human serum albumin (HSA). Our results demonstrate that generally the tested metal complexes react with the selected target causing protein oligomerization, likely through a cross-linking reaction. Interestingly, the extent of such a process is largely modulated by the target protein and by the chemical features of the metal complex, TPAs being the most efficient platinating agents. From a structural point of view the resulting reaction products turned out to be depending on the nature of the metal complexes. However, in all instances, a transfer reaction of the metal complex to DNA can also occur, maintaining the relevance of nucleic acids as a biological target. These results can be used to better rationalize the different pharmacological profiles reported for cisplatin and TPAs and can help in designing more predictive SARs within the series. PMID- 23435292 TI - The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults. AB - We explored the associations of the CD4/CD8 ratio with markers of immunoactivation, immunosenescence and T-cell subsets, in 37 vertically HIV infected children and adolescents. CD4/CD8 ratio inversion was associated with higher frequencies of activated, senescent and activated/exhausted CD4+ and CD8+ T-cells, and a skewed T-cell phenotype from naive toward effector memory which persisted after the multivariate analysis. Thus, the CD4/CD8 ratio may identify patients with higher immunoactivation despite ART. PMID- 23435289 TI - Mitochondrial deficiency in Cockayne syndrome. AB - Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction. PMID- 23435293 TI - Performance of creatinine and cystatin C-based glomerular filtration rate estimating equations in a European HIV-positive cohort. AB - OBJECTIVE: To validate glomerular filtration rate (GFR) estimating equations in white HIV-infected patients based on serum creatinine and/or serum cystatin C. DESIGN: Single-center, cross-sectional evaluation of the predictive performance of GFR estimators. METHODS: GFR was measured by iohexol plasma clearance. Serum creatinine (Scr) and serum cystatin C (Scyst) were measured by traceable and standardized methods. We evaluated the performance of the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations. We also studied the performance of the cystatin C-based equation (CKD-EPI Scyst) and the combined cystatin and creatinine-based equation (CKD-EPI combined), as recently proposed by the CKD-EPI group. RESULTS: Two hundred and three participants (18% of women) were included. Mean age was 49 +/- 10 years. Mean measured GFR (mGFR) was 95 +/- 24 ml/min per 1.73 m2. CKD-EPI and CKD-EPI combined significantly outperformed the MDRD equation. The percentage of estimating results within 30% of mGFR was 75, 82 and 81% for the MDRD, CKD-EPI and CKD-EPI combined equation, respectively. Results favoring the CKD-EPI and CKD EPI combined equation were especially observed for patients with mGFR over 90 ml/min per 1.73 m2. CONCLUSION: In our European HIV cohort, we confirmed that the creatinine-based CKD-EPI equation should replace the MDRD study equation. However, global performance of this equation remains worse than the performance observed in the general population. This lesser performance is particularly relevant in patients with measured GFR under and around 60 ml/min per 1.73 m2. Moreover, the specific interest of Scyst-based equations is not confirmed in this population. PMID- 23435294 TI - GPS-measured distance to clinic, but not self-reported transportation factors, are associated with missed HIV clinic visits in rural Uganda. AB - OBJECTIVE: Studies of the association between transportation barriers and HIV related health outcomes have shown both positive and negative effects, possibly because a reliable, validated measure of transportation barriers has not been identified. DESIGN: Prospective cohort study of HIV-infected patients in rural Uganda. METHODS: Participants were enrolled from the HIV clinic at the regional referral hospital in Mbarara, Uganda as part of the Uganda AIDS Rural Treatment Outcomes (UARTO) Study. We collected the following measures of transportation barriers to HIV clinic: global positioning systems (GPS)-tracked distance measured by driving participants to their homes along their typical route; straight-line GPS distance from clinic to home, calculated with the Great Circle Formula; self-reported travel time; and self-reported travel cost. We assessed inter-measure agreement using linear regression, correlation coefficients and kappa statistics (by measure quartile) and validated measures by fitting linear regression models to estimate associations with days late for clinic visits. RESULTS: One hundred and eighty-eight participants were tracked with GPS. Seventy six percent were women, with a median age of 40 years and median CD4 cell count of 193 cells/MUl. We found a high correlation between GPS-based distance measures (beta=0.74, P<0.001, R2=0.92, kappa=0.73), but little correlation between GPS based and self-reported measures (all R2<=0.4). GPS-based measures were associated with days late to clinic (P<0.001); but neither self-reported measure was associated (P>0.85). CONCLUSION: GPS-measured distance to clinic is associated with HIV clinic absenteeism and should be prioritized over self reported measures to optimally risk-stratify patients accessing care in rural, resource-limited settings. PMID- 23435295 TI - Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV study. AB - Among 127 HIV-infected women, the magnitude of high-density lipoprotein cholesterol (HDLc) increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in low-density lipoprotein cholesterol (LDLc) and inflammation were unrelated. In the same population, predicted risk of coronary heart disease, based upon levels of standard clinical risk factors, was similar before and after HAART. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of cardiovascular disease (CVD). PMID- 23435296 TI - The contribution of HIV to pregnancy-related mortality: a systematic review and meta-analysis. AB - OBJECTIVES: Although much is known about the contribution of HIV to adult mortality, remarkably little is known about the mortality attributable to HIV during pregnancy. In this article we estimate the proportion of pregnancy-related deaths attributable to HIV based on empirical data from a systematic review of the strength of association between HIV and pregnancy-related mortality. METHODS: Studies comparing mortality during pregnancy and the postpartum in HIV-infected and HIV-uninfected women were included. Summary estimates of the relative and attributable risks for the association between HIV and pregnancy-related mortality were calculated through meta-analyses. Varying estimates of HIV prevalence were used to predict the impact of the HIV epidemic on pregnancy related mortality at the population level. RESULTS: Twenty-three studies were included (17 from sub-Saharan Africa). Meta-analysis of the risk ratios indicated that HIV-infected women had eight times the risk of a pregnancy-related death compared with HIV-uninfected women [pooled risk ratio 7.74, 95% confidence interval (95% CI) 5.37-11.16]. The excess mortality attributable to HIV among HIV infected pregnant and postpartum women was 994 per 100,000 pregnant women. We predict that 12% of all deaths during pregnancy and up to 1-year postpartum are attributable to HIV/AIDS in regions with a prevalence of HIV among pregnant women of 2%. This figure rises to 50% in regions with a prevalence of 15%. CONCLUSION: The substantial excess of pregnancy-related mortality associated with HIV highlights the importance of integrating HIV and reproductive health services in areas of high HIV prevalence and pregnancy-related mortality. PMID- 23435297 TI - Patients in transition: avoiding detours on the road to HIV treatment success. PMID- 23435298 TI - Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AB - OBJECTIVE: Here we evaluated whether neurocognitive disorders in HIV-infected individuals on effective antiretroviral therapy (ART) are associated with persistent monocyte activation as indexed by levels of soluble CD163 (sCD163), shed by monocyte/macrophages. DESIGN: Chronically, HIV-infected individuals were examined at two consecutive visits median [interquartile range (IQR)] 16 (7-32) months apart. All patients were on ART and durably virologically suppressed (plasma HIV RNA <50 copies/ml) at all visits. Thirty-four age-matched HIV seronegative patients were used as controls. METHODS: A global deficit score (GDS) was calculated based on comprehensive neuropsychological assessment according to standard methods. Neuropsychological and medical data were used to assign neurocognitive status according to published guidelines for HIV-associated neurocognitive disorders (HAND) as follows: neuropsychologically normal (NP-nml), asymptomatic neuropsychological impairment (ANI) and minor neurocognitive disorder (MND). sCD163 in plasma and cerebrospinal fluid was measured using ELISA. RESULTS: GDS-impaired patients had higher plasma sCD163 than those who were not impaired [median (IQR) 1401 ng/ml (1057-2258) versus 955 ng/ml (586 1313); Wilcoxon P=0.028]. Patients with MND (N=6) had significantly higher plasma sCD163 than ANI (P=0.04) or NP-nml (P=0.02). Whereas plasma sCD163 levels dropped in patients who were stably GDS-unimpaired after the first visit (P<0.032), levels remained elevated in those who remained GDS-impaired (P=0.50). INTERPRETATION: These findings are consistent with persistent monocyte/macrophage activation in neurophysiologically impaired HIV-infected individuals despite virally suppressive ART. Overall, these observations underscore the significance of monocyte/macrophage immune responses in HIV, persistent monocyte activation in HAND and the value of sCD163, as a plasma marker of neurocognitive impairment. PMID- 23435299 TI - Vitamin D attenuates nucleoside reverse transcriptase inhibitor induced human skeletal muscle mitochondria DNA depletion. AB - OBJECTIVE: To evaluate the impact of the active metabolite of vitamin D, 1alpha,25-dihydroxycholecalciferol (1,25D3), on nucleoside reverse transcriptase inhibitor (NRTI) induced mitochondrial DNA (mtDNA) depletion in human skeletal muscle myoblasts and myotubes. DESIGN: mtDNA was quantified in human skeletal muscle myoblasts and myotubes following 1,25D3 and NRTI treatment using real-time PCR. METHODS: Human skeletal muscle myoblasts and myotubes were treated with didanosine (ddI), stavudine (d4T), zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) alone or in combination either in the presence or absence of 1,25D3 for 5 days. Cells were harvested, DNA extracted and mtDNA quantified. RESULTS: ddI and ddI-d4T significantly decreased both myoblast and myotube mtDNA in the absence of 1,25D3 compared with untreated controls (P<=0.029). In addition, the ZDV-3TC combination resulted in a 47% decrease in myotube mtDNA (P=0.005). 1,25D3 increased myotube mtDNA levels in ddI, ZDV, 3TC, ABC, ddI-d4T, d4T-3TC, ZDV-3TC, ZDV-ABC and ZDV-3TC-ABC-containing regimens and myoblast mtDNA levels in ddI, d4T, ZDV, 3TC, ddI-d4T, ZDV-3TC and ZDV-ABC-containing regimens. Of note, 1,25D3 protected against myotube mtDNA depletion following ZDV-3TC treatment, rendering them similar to 1,25D3 untreated controls (P=0.62), and increased both myotube and myoblast mtDNA two to three-fold in ddI-containing regimens (P<0.05). CONCLUSION: 1,25D3 confers a protective effect against NRTI induced mitochondrial toxicity in skeletal muscle myoblasts and myotubes. These findings support a protective role for vitamin D in preventing mitochondrial toxicity and suggest that supplemental vitamin D may protect against NRTI associated mitochondrial toxicity. PMID- 23435300 TI - Evidence for risk stratification when monitoring for toxicities following initiation of combination antiretroviral therapy. AB - OBJECTIVE: Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000 2010 across the United States. DESIGN: Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort. METHODS: Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation. RESULTS: A total of 3470 individuals contributed 3639 person-years. Median age, pre-cART CD4, and follow-up duration were 40 years, 206 cells/MUl, and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post-cART initiation were as follows: lipid=49 [95% confidence interval (CI) 41-58]; hematologic=44 (40-49); hepatic=24 (20-27); and renal=9 (7-11), dropping substantially during weeks 17-104 of cART to lipid=23 (18-29); hematologic=5 (4 6); hepatic=6 (5-8); and renal=2 (1-3) (all P<0.05). Among patients receiving initial cART with no prior abnormality (N=1889), strongest associations for hepatic abnormalities after 16 weeks were hepatitis B and C [hazard ratio=2.3 (95% CI 1.2-4.5) and hazard ratio=3.0 (1.9-4.5), respectively]. The strongest association for renal abnormalities was hypertension [hazard ratio=2.8 (1.4 5.6)]. CONCLUSION: New abnormalities decreased after week 16 of cART. For abnormalities not present by week 16, subsequent monitoring should be guided by comorbidities. PMID- 23435301 TI - Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection. AB - OBJECTIVE: Some antiretroviral treated HIV-infected patients develop Kaposi's sarcoma despite long-term suppression of HIV replication. These Kaposi's sarcoma lesions are consistent with Kaposi's sarcoma observed in the elderly uninfected population ('classical Kaposi's sarcoma'). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence. DESIGN: We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposi's sarcoma (cases, n = 19) and from treated individuals without Kaposi's sarcoma (controls, n = 47). RESULTS: There was increased frequency of CD4+ and CD8+ T cells with an immunosenescence phenotype (CD57+ and CD28-) in cases vs. controls (CD4+ T cells: CD57+ 7.4 vs. 3.7%, P = 0.025; CD28- 9.1 vs. 4.8%, P = 0.025; CD8+ T cells: CD57+ 41.5 vs. 27.7%, P = 0.003; CD28- 60.5 vs. 51.3%, P = 0.041). Cases had lower proportions of naive T cells (CD27+ CD28+ CD45RA+) in CD4+ (23.0 vs. 32.2%, P = 0.023) and CD8+ (11.3 vs. 20.7%, P < 0.001) T-cell compartments. CCR5 was more highly expressed in CD4+ (16.3 vs. 11.0%, P = 0.025), and CD8+ (43.1 vs. 28.3%, P < 0.001) T-cell compartments in cases vs. controls. There was no difference in telomere length or telomerase activity in peripheral blood mononuclear cells, or in T-cell expression of activation markers (HLADRCD38). CONCLUSION: Among antiretroviral treated patients, increased frequencies of T cells with an immunosenescence phenotype and lower frequencies of naive T cells were associated with presence of Kaposi's sarcoma among effectively treated patients. These data suggest that certain immunologic perturbations--including those associated with aging--might be causally associated with development of Kaposi's sarcoma. PMID- 23435302 TI - Tenofovir-based combination therapy for HIV/HBV co-infection: factors associated with a partial HBV virological response in patients with undetectable HIV viraemia. AB - OBJECTIVE: The aim of this study was to identify and describe patients with detectable hepatitis B virus (HBV) DNA in the presence of undetectable HIV RNA after 48 weeks of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC) treatment. DESIGN: Case-control study. Cases or delayed responders were defined as detectable HBV DNA (>20 IU/ml) with undetectable HIV RNA (<40 c/ml) after 48 weeks TDF/3(F)TC combination therapy. Controls or virological responders were defined as both undetectable HIV and HBV after 48 weeks TDF/3(F)TC therapy. RESULTS: Twenty-three cases were identified and matched to 24 controls. 87% cases and 46% controls were eAg-positive (P=0.005). Nine of 23 (39%) cases and seven of 24 (29%) controls had 3TC monotherapy prior to TDF. Similar proportions had 3TC/FTC resistance pre-TDF (30% cases, 24% controls). The cases had significantly higher baseline HBV DNA pre-3TC (median 1.2*10(8) vs. 3.1*10(6) IU/ml; P=0.009) and pre-TDF (1.1*10(8) vs. 2.6*10(4) IU/ml; P=0.012). Sixteen of 23 cases eventually achieved undetectable HBV DNA after 42.2 (27.2, 54.9) months. Six of 23 still have detectable HBV DNA after 46.2 (28.2, 65.6) months. Only one delayed responder patient developed a new 3(F)TC mutation and they received intensification with entecavir and achieved undetectable HBV DNA. No patient developed TDF resistance. CONCLUSION: We report the largest series of HIV/HBV co-infected patients failing to achieve undetectable HBV after 48 weeks TDF/3(F)TC despite undetectable HIV viraemia. This outcome was associated with positive eAg and higher baseline HBV DNA. Our data suggest that clinicians should not intensify therapy with entecavir unless there is evidence of new 3TC/FTC mutations as the majority of patients go on to suppress HBV. TDF resistance was not seen. PMID- 23435303 TI - Outcomes of home visits for pregnant mothers and their infants: a cluster randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of home visits by community health workers (CHWs) on maternal and infant well being from pregnancy through the first 6 months of life for women living with HIV (WLH) and all neighborhood mothers. DESIGN AND METHODS: In a cluster randomized controlled trial in Cape Town townships, neighborhoods were randomized within matched pairs to either standard care, comprehensive healthcare at clinics (n=12 neighborhoods; n=169 WLH; n=594 total mothers); or Philani Intervention Program, home visits by CHWs in addition to standard care (PIP; n=12 neighborhoods; n=185 WLH; n=644 total mothers). Participants were assessed during pregnancy (2% refusal) and reassessed at 1 week (92%) and 6 months (88%) postbirth. We analyzed PIP's effect on 28 measures of maternal and infant well being among WLH and among all mothers using random effects regression models. For each group, PIP's overall effectiveness was evaluated using a binomial test for correlated outcomes. RESULTS: Significant overall benefits were found in PIP compared to standard care among WLH and among all participants. Secondarily, compared to standard care, PIP WLH were more likely to complete tasks to prevent vertical transmission, use one feeding method for 6 months, avoid birth-related medical complications, and have infants with healthy height-for-age measurements. Among all mothers, compared to standard care, PIP mothers were more likely to use condoms consistently, breastfeed exclusively for 6 months, and have infants with healthy height-for-age measurements. CONCLUSION: PIP is a model for countries facing significant reductions in HIV funding whose families face multiple health risks. PMID- 23435304 TI - HIV-1 epidemic in Warao Amerindians from Venezuela: spatial phylodynamics and epidemiological patterns. AB - OBJECTIVES: We previously reported HIV-1 infection in Warao Amerindians from Venezuela. The aim of this study was to evaluate the extent and the dynamic of HIV-1 dissemination in eight Warao communities. DESIGN AND SETTING: HIV-1 infection was evaluated in 576 Warao Amerindians from the Orinoco Delta. Partial HIV-1 pol sequences were analyzed to reconstruct the spatiotemporal and demographic dynamics of the epidemic. RESULTS: HIV-1 antibodies were present in 9.55% of Warao Amerindians, ranging from 0 to 22%. A significantly higher prevalence was found in men (15.6%) compared with women (2.6%), reaching up to 35% in men from one community. All but one isolates were classified as subtype B. Warao's HIV-1 subtype-B epidemic resulted from a single viral introduction at around the early 2000s. After an initial phase of slow growth, the subtype B started to spread at a fast rate (0.8/year) following two major routes of migration within the communities. CONCLUSION: A dramatic high prevalence was documented in almost all the communities of Warao Amerindians from the Orinoco Delta tested for HIV-1 infection. This epidemic resulted from the dissemination of a single HIV-1 subtype B founder strain introduced about 10 years ago and its size is probably doubling every year, creating a situation that can be devastating for this vulnerable Amerindian group. PMID- 23435305 TI - Endoplasmic reticulum aminopeptidase 2 haplotypes play a role in modulating susceptibility to HIV infection. AB - OBJECTIVE: Haplotype-specific alternative splicing of the endoplasmic reticulum (ER) aminopeptidase type 2 (ERAP2) gene results in either full-length (FL, haplotype A) or alternatively spliced (AS, haplotype B) mRNA. As ERAP2 trims peptides loaded on major histocompatibility complex (MHC) class I and CD8 T lymphocytes protect against viral infections, we analysed its role in resistance to HIV-1 infection. METHODS: ERAP2 polymorphisms were genotyped using a TaqMan probe, and human leukocyte antigen (HLA) typing of class-I HLAB locus was performed by single specific primers-polymerase chain reaction method. To verify whether ERAP2 genotype influences susceptibility to HIV-1 infection in vitro we performed HIV-1 infection assay. We evaluated antigen presentation pathway with PCR array and the viral antigen p24 with ELISA. RESULTS: Genotype analysis in 104 HIV-1-exposed seronegative individuals (HESNs) exposed to HIV through IDU-HESN and 130 controls from Spain indicated that hapA protects from HIV infection. Meta analysis with an Italian cohort of sexually exposed HESN yielded a P value of 7.6 * 10. HLAB typing indicated that the HLA-B*57 allele is significantly more common than expected among HESN homozygous for haplotype A (homoA). Data obtained in a cohort of 139 healthy Italian controls showed that following in-vitro HIV-1 infection the expression of ERAP2-FL and a number of genes involved in antigen presentation as well as of MHC class I on the surface of CD45 cells was significantly increased in homoA cells; notably, homoA peripheral blood mononuclear cells, but not isolated CD4 cells, were less susceptible to HIV-1 infection. CONCLUSION: ERAP2 hapA is correlated with resistance to HIV-1 infection, possibly secondarily to its effect on antigen processing and presentation. PMID- 23435306 TI - Single- versus multi-vehicle bicycle road crashes in Victoria, Australia. AB - The aim of the study is to compare trends, circumstances and outcomes of single- versus multi-vehicle bicycle on-road crashes in Victoria, Australia, through the analysis of police records and hospital admissions between January 2004 and December 2008. The results show that over 80% of on-road single-vehicle bicycle crashes occurred as a result of the cyclist losing control of the bicycle with the remainder involving collisions with objects. Compared with multi-vehicle crashes, single-vehicle crashes were more likely to occur in the dark, in wet conditions and in rural areas. Over half of the cyclists hospitalised as result of on-road crashes were injured in single-vehicle crashes and this proportion seems to be increasing over time. Single-vehicle crashes were associated with hospitalised injuries as severe as those resulting from multivehicle crashes. The findings highlight the significant burden of serious injury associated with single-vehicle bicycle road crashes. Further research is needed to investigate in greater detail the risk factors of these crashes and the effectiveness of countermeasures to reduce their burden. PMID- 23435307 TI - Can student-perpetrated college crime be predicted based on precollege misconduct? AB - OBJECTIVES: Many colleges assess criminal histories during the admissions process, in part, to address violence on campus. This study sought to examine the utility of screening as a means of reducing violence. METHODS: Using cohort and case-control analyses, we identified college misconduct through college records and self-reports on a confidential survey of graduating seniors, and examined precollege behaviour as indicated on admissions records, a survey and criminal background checks. RESULTS: One hundred and twenty students met our case definition of college misconduct, with an estimated OR of 5.28 (95% CI 1.92 to 14.48) associated with precollege misconduct revealed on the college application. However, only 3.3% (95% CI 1.0% to 8.0%) of college seniors engaging in college misconduct had reported precollege criminal behaviours on their applications and 8.5% (95% CI 2.4% to 20.4%) of applicants with a criminal history engaged in misconduct during college. DISCUSSION: Though precollege behaviour is a risk factor for college misconduct, screening questions on the application are not adequate to detect which students will engage in college misconduct. This pilot work would benefit from replication to determine the utility of criminal background investigations as part of admissions. PMID- 23435308 TI - Generation of multicellular tumor spheroids of breast cancer cells: how to go three-dimensional. AB - The multicellular tumor spheroid model is a widely used culture system to mimic the three-dimensionality of tumors. Several methods and an even larger number of protocols are available to prepare spheroids from regular monolayers. This paper describes the assessment of several techniques frequently used to culture spheroids of breast cancer cells. We found that some methods produced suboptimal results. Ultimately, an adapted liquid overlay technique generated tight, compact and robust spheroids of the breast cancer cells tested. PMID- 23435309 TI - A capillary electrophoretic assay for acetyl coenzyme A carboxylase. AB - A simple off-column capillary electrophoretic (CE) assay for measuring acetyl coenzyme A carboxylase holoenzyme (holo-ACC) activity and inhibition was developed. The two reactions catalyzed by the holo-ACC components, biotin carboxylase (BC) and carboxyltransferase (CT), were simultaneously monitored in this assay. Acetyl coenzyme A (CoA), malonyl-CoA, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) were separated by capillary electrophoresis, and the depletion of ATP and acetyl-CoA as well as the production of ADP and malonyl CoA were monitored. Inhibition of holo-ACC by the BC inhibitor, 2-amino-N,N dibenzyloxazole-5-carboxamide, and the carboxyltransferase inhibitor, andrimid, was confirmed using this assay. A previously reported off-column CE assay for only the CT component of ACC was optimized, and an off-column CE assay for the BC component of ACC also was developed. PMID- 23435310 TI - The novel antiviral pipeline to treat severe neonatal viral infections. PMID- 23435311 TI - Treating acute otitis media in young children: what constitutes success? PMID- 23435312 TI - NAMPT/PBEF1 enzymatic activity is indispensable for myeloma cell growth and osteoclast activity. AB - Multiple myeloma (MM) cells typically grow in focal lesions, stimulating osteoclasts that destroy bone and support MM. Osteoclasts and MM cells are hypermetabolic. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is not only essential for cellular metabolism; it also affects activity of NAD-dependent enzymes, such as PARP-1 and SIRT-1. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin, encoded by PBEF1) is a rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide. Coculture of primary MM cells with osteoclasts induced PBEF1 upregulation in both cell types. PBEF1 expression was higher in experimental myelomatous bones than in nonmyelomatous bone and higher in MM patients' plasma cells than in healthy donors' counterparts. APO866 is a specific PBEF1 inhibitor known to deplete cellular NAD(+). APO866 at low nanomolar concentrations inhibited growth of primary MM cells or MM cell lines cultured alone or cocultured with osteoclasts and induced apoptosis in these cells. PBEF1 activity and NAD(+) content were reduced in MM cells by APO866, resulting in lower activity of PARP-1 and SIRT-1. The inhibitory effect of APO866 on MM cell growth was abrogated by supplementation of extracellular NAD(+) or NAM. APO866 inhibited NF-kappaB activity in osteoclast precursors and suppressed osteoclast formation and activity. PBEF1 knockdown similarly inhibited MM cell growth and osteoclast formation. In the SCID-rab model, APO866 inhibited growth of primary MM and H929 cells and prevented bone disease. These findings indicate that MM cells and osteoclasts are highly sensitive to NAD(+) depletion and that PBEF1 inhibition represents a novel approach to target cellular metabolism and inhibit PARP-1 and bone disease in MM. PMID- 23435314 TI - Molecular and functional characterization of human bone marrow adipocytes. AB - Adipocytes are a cell population largely located in the human bone marrow cavity. In this specific microenvironment where adipocytes can interact with a variety of different cells, the role of fat is mainly unknown. To our knowledge, this report is the first to characterize mature adipocytes isolated from human bone marrow (BM-A) molecularly and functionally to better understand their roles into the hematopoietic microenvironment. Healthy BM-A were isolated after collagenase digestion and filtration. We studied the morphology of BM-A, their gene expression and immunophenotypic profile and their functional ability in the hematopoietic microenvironment, comparing them with adipocytes derived from adipose tissue (AT-A). BM-A showed a unilocular lipid morphology similar to AT-A and did not lose their morphology in culture; they showed a comparable pattern of stem cell-surface antigens to AT-A. In line with these observations, molecular data showed that BM-A expressed some embryonic stem cells genes, such as Oct4, KLf4, c-myc, Gata4, Tbx1, and Sox17, whereas they did not express the stem cell markers Sox2 and Nanog. Moreover, BM-A had long telomeres that were similar to bone marrow mesenchymal stem cells. Notably, BM-A supported the survival and differentiation of hematopoietic stem cells in long-term cultures. These results showed that BM-A are stromal cells with a gene expression pattern that distinguished them from AT-A. BM-A showed stem cell properties through their hematopoietic supporting function, which was certainly linked to their role in the maintenance of the bone marrow microenvironment. Depending on specific demands, BM-A may acquire different functions based on their local environment. PMID- 23435313 TI - Isolated Hoxa9 overexpression predisposes to the development of lymphoid but not myeloid leukemia. AB - Hoxa9 is expressed in hematopoietic stem and progenitor cells, although this expression is usually diminished as these cells undergo differentiation. In addition, aberrant expression of Hoxa9 is strongly associated with both T cell and myeloid leukemia in mice and humans. Despite this strong association, enforced expression of Hoxa9 in murine bone marrow or thymus has only shown a modest ability to transform cells. To investigate this question, we used Vav regulatory elements to generate a transgenic mouse that targets Hoxa9 overexpression to all hematopoietic tissues. High-level expression of the Hoxa9 transgene in the hematopoietic compartment was associated with embryonic lethality, as no pups from founders that expressed high levels of the transgene were born live. However, offspring of an additional founder line, which expressed lower levels of Hoxa9, developed a precursor T cell lymphoblastic leukemia/lymphoma, accompanied by spontaneous Notch1 mutations. In contrast to most murine models of leukemia associated with Hoxa9 overexpression, the Vav Hoxa9 mice did not overexpress other Hoxa cluster genes, mir196b (a microRNA that is embedded in the Hoxa locus), Meis1, or Pbx3. The Hoxa9 transgenic mouse reported in this study provides a suitable system for the study of Hoxa9 collaborators that drive myeloid and lymphoid malignant transformation. PMID- 23435315 TI - Mussel-inspired green synthesis of silver nanoparticles on graphene oxide nanosheets for enhanced catalytic applications. AB - We report a facile green approach to the synthesis of silver nanoparticles (Ag NPs) on the surface of graphene oxide nanosheets functionalized with mussel inspired dopamine (GO-Dopa) without additional reductants or stabilizers at room temperature. The resulting hybrid Ag/GO-Dopa exhibits good dispersity and excellent catalytic activity in the reduction of nitroarenes. PMID- 23435316 TI - Power spectral analysis of heart rate variability in cynomolgus monkeys in safety pharmacology studies: comparative study with beagle dogs. AB - INTRODUCTION: Power spectral analysis of heart rate variability is a tool known to provide information of interest on the autonomic control of heart rate in human. However, its use and its conditions of application and interpretation for safety purposes are not well defined for cardiovascular safety pharmacology studies. Likewise, data of power spectral analysis of heart rate variability in cynomolgus monkeys, a species often appropriate for use as second non rodent species in preclinical safety programmes, are not available. This study was designed to evaluate the relevance of this biomarker in this non human primate species, and to compare results with those from beagle dogs under the conditions of safety evaluation studies. METHODS: Power spectral analysis of heart rate variability was performed on data collected in both species by telemetry following a standard design for cardiovascular safety pharmacology studies. Various pharmacological agents were tested in order to compare the profile of responses in both species after modifying the autonomic nervous balance. RESULTS: Heart rate variability in cynomolgus monkeys is mainly driven by the parasympathetic nervous system as in beagle dogs although vagal tone is less than in dogs. Power spectral analysis of heart rate variability allows detection of interaction with the autonomic nervous system in both species in all investigated situations, i.e. sympatholytic/sympathomimetic and parasympatholytic/parasympathomimetic drug induced effects. However, due to species difference in the autonomic control of heart rate, cynomolgus monkeys are likely to be more sensitive than beagle dogs for assessment of sympatholytic properties. DISCUSSION: This study confirms that power spectral analysis of heart rate variability from data derived from ECG recordings in telemetry studies is applicable in cardiovascular safety pharmacology studies and may provide relevant information about possible interaction with the autonomic nervous system when new drug entities are evaluated in either species. However, interspecies differences in autonomic control must be taken into account when interpreting possible drug effects. PMID- 23435317 TI - SPA: a short peptide assembler for metagenomic data. AB - The metagenomic paradigm allows for an understanding of the metabolic and functional potential of microbes in a community via a study of their proteins. The substrate for protein identification is either the set of individual nucleotide reads generated from metagenomic samples or the set of contig sequences produced by assembling these reads. However, a read-based strategy using reads generated by next-generation sequencing (NGS) technologies, results in an overwhelming majority of partial-length protein predictions. A nucleotide assembly-based strategy does not fare much better, as metagenomic assemblies are typically fragmented and also leave a large fraction of reads unassembled. Here, we present a method for reconstructing complete protein sequences directly from NGS metagenomic data. Our framework is based on a novel short peptide assembler (SPA) that assembles protein sequences from their constituent peptide fragments identified on short reads. The SPA algorithm is based on informed traversals of a de Bruijn graph, defined on an amino acid alphabet, to identify probable paths that correspond to proteins. Using large simulated and real metagenomic data sets, we show that our method outperforms the alternate approach of identifying genes on nucleotide sequence assemblies and generates longer protein sequences that can be more effectively analysed. PMID- 23435318 TI - Two-step model of stop codon recognition by eukaryotic release factor eRF1. AB - Release factor eRF1 plays a key role in the termination of protein synthesis in eukaryotes. The eRF1 consists of three domains (N, M and C) that perform unique roles in termination. Previous studies of eRF1 point mutants and standard/variant code eRF1 chimeras unequivocally demonstrated a direct involvement of the highly conserved N-domain motifs (NIKS, YxCxxxF and GTx) in stop codon recognition. In the current study, we extend this work by investigating the role of the 41 invariant and conserved N-domain residues in stop codon decoding by human eRF1. Using a combination of the conservative and non-conservative amino acid substitutions, we measured the functional activity of >80 mutant eRF1s in an in vitro reconstituted eukaryotic translation system and selected 15 amino acid residues essential for recognition of different stop codon nucleotides. Furthermore, toe-print analyses provide evidence of a conformational rearrangement of ribosomal complexes that occurs during binding of eRF1 to messenger RNA and reflects stop codon decoding activity of eRF1. Based on our experimental data and molecular modelling of the N-domain at the ribosomal A site, we propose a two-step model of stop codon decoding in the eukaryotic ribosome. PMID- 23435320 TI - Effects of verapamil on the immediate-early gene expression of bone marrow mesenchymal stem cells stimulated by mechanical strain in vitro. AB - BACKGROUND: To study the effects of verapamil on the immediate-early genes (IEGs) expression of bone marrow mesenchymal stem cells (MSCs) stimulated by cyclic mechanical strain, in order to deduce the role of calcium ion channel in the cell signaling responses of MSCs to mechanical strain. MATERIAL AND METHODS: MSCs were isolated and cultured, and the passage of 3-6 MSCs were stimulated by mechanical strain and pretreated with or without verapamil. After that, flow cytometry was used to measure the fluorescence intensity of intracellular Ca(2+) immediately. The expression of early-response genes/proteins (c-fos, c-jun and c-myc) were examined by RT-PCR, immunohistochemistry and Western blot. RESULTS: Intracellular Ca(2+) concentration of MSCs significantly changed when stimulated by cyclic strain, and the expression of c-fos, c-jun and c-myc remarkably increased in both mRNA and protein levels, while verapamil pre-treatment partially inhibited these effects (P<0.01). CONCLUSIONS: The changes of the intracellular calcium concentration of MSCs induced by mechanical strain, dependent on the regulation of calcium channel activation, might play a role in the early response of MSCs to cyclic strain. PMID- 23435319 TI - G-quadruplexes for luminescent sensing and logic gates. AB - G-quadruplexes represent a versatile sensing platform for the construction of label-free molecular detection assays owing to their diverse structures that can be selectively recognized by G-quadruplex-specific luminescent probes. In this Survey and Summary, we highlight recent examples of the application of the label free strategy for the development of G-quadruplex-based luminescent detection platforms with a view towards the potential application of tetraplex structures in the design of DNA logic gates. PMID- 23435321 TI - T cells: Memories of the future. PMID- 23435330 TI - Tumour immunology: Give it a rest. PMID- 23435333 TI - A conjunctive diiodoheptaene for the synthesis of C2-symmetric carotenoids. AB - (2E,4E,6E,8E,10E,12E,14E)-2,15-Diiodo-6,11-dimethylhexadeca-2,4,6,8,10,12,14 heptaene, prepared by homometathesis, has been used in palladium-catalyzed Suzuki and Stille cross-coupling reactions with the appropriate partners to construct the C2-symmetric carotenoids beta,beta-carotene, lycopene, synechoxanthin and 4,4'-diapo-psi,psi-carotene-4,4'-dial. PMID- 23435334 TI - Carpe diem. PMID- 23435331 TI - Neutrophil recruitment and function in health and inflammation. AB - Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites. PMID- 23435332 TI - Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. AB - Complex barriers separate immune-privileged tissues from the circulation. Here, we propose that cell entry to immune-privileged sites through barriers composed of tight junction-interconnected endothelium is associated with destructive inflammation, whereas border structures comprised of fenestrated vasculature enveloped by tightly regulated epithelium serve as active and selective immune skewing gates in the steady state. Based on emerging knowledge of the central nervous system and information from other immune-privileged sites, we propose that these sites are endowed either with absolute endothelial-based barriers and epithelial gates that enable selective and educative transfer of trafficking leukocytes or with selective epithelial gates only. PMID- 23435335 TI - Patterns of attendance of care home residents to an Emergency Department. PMID- 23435336 TI - Orbital ultrasound in the selective screening of a dural-cavernous sinus fistula. PMID- 23435337 TI - Recreational amitriptyline toxicity mimicking basilar artery stroke. PMID- 23435338 TI - Positive computed tomography rate for lone acute severe headache: a potential quality marker for emergency care? PMID- 23435339 TI - Endotracheal intubation with the Pentax-Airwayscope and Macintosh laryngoscope during chest compression. PMID- 23435340 TI - Reply to letter: Tracheal intubation during chest compressions performed by qualified emergency physicians unfamiliar with the Pentax-Airwayscope. PMID- 23435341 TI - Critical care transport following balloon tamponade of variceal haemorrhage. PMID- 23435342 TI - A 1-h simulation-based course on basic life support durably enhances confidence among medical students. PMID- 23435343 TI - A simplified and completely automated workflow for regulated LC-MS/MS bioanalysis using cap-piercing direct sampling and evaporation-free solid phase extraction. AB - Automated sample extraction for regulated bioanalysis by liquid chromatography/tandem mass spectrometry (LC-MS/MS) still presents significant challenges. A new sample preparation methodology with a simplified and completely automated workflow was developed to overcome these challenges using cap piercing for direct biofluid transfer and evaporation-free solid phase extraction (SPE). Using pierceable cap sample tubes, a robotic liquid handler was able to sample without uncapping or recapping during sample preparation. Evaporation for SPE was eliminated by using a mobile phase-compatible elution solvent followed by sample dilution prior to LC-MS/MS analysis. Presented here are three LC-MS/MS assays validated using this methodology to support three CNS drug development programs: (1) BMS-763534 and its metabolite, BMS-790318, in dog plasma; (2) BMS-694153 in monkey plasma; and (3) Pexacerfont (BMS-562086) and two metabolites, BMS-749241 and DPH-123554, in human plasma. These assays were linear from 1.00 to 1000 or 2.00 to 2000ng/mL for each analyte with excellent assay accuracy, precision and reproducibility. These assays met acceptance criteria for regulated bioanalysis and have been successfully applied to drug development study samples. The methodology described here successfully eliminated all manual intervention steps achieving fully automated sample preparation without compromising assay performance. Importantly, this methodology eliminates the potential exposure of the bioanalyst to any infectious biofluids during sample preparation. PMID- 23435344 TI - A universal, high recovery assay for protein quantitation through temperature programmed liquid chromatography (TPLC). AB - As an alternative to direct UV absorbance measurements, estimation of total protein concentration is typically conducted through colorimetric reagent assays. However, for protein-limited applications, the proportion of the sample sacrificed to the assay becomes increasingly significant. This work demonstrates a method for quantitation of protein samples with high recovery. Temperature programmed liquid chromatography (TPLC) with absorbance detection at 214nm permits accurate estimation of total protein concentration from samples containing as little as 0.75MUg. The method incorporates a temperature gradient from 25 to 80 degrees C to facilitate elution of total protein into a single fraction. Analyte recovery, as measured from 1 and 10MUg protein extracts of Escherichia coli, is shown to exceed 93%. Extinction coefficients at 214nm were calculated across the human proteome, providing a relative standard deviation of 21% (versus 42% at 280nm), suggesting absorbance values at 214nm provide a more consistent measure of protein concentration. These results translate to a universal protein detection strategy exhibiting a coefficient of variation below 10%. Together with the sensitivity and tolerance to contaminants, TPLC with UV detection is a favorable alternative to colorimetric assay for total protein quantitation, particularly in sample-limited applications. PMID- 23435345 TI - A rugged and accurate liquid chromatography-tandem mass spectrometry method for the determination of asunaprevir, an NS3 protease inhibitor, in plasma. AB - Asunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) non-structural protein protease inhibitor currently in Phase III clinical trials for the treatment of HCV infection. A rugged and accurate LC-MS/MS method was developed and validated for the quantitation of asunaprevir in rat, dog, monkey, rabbit and mouse plasma. A systematic method screening and optimization strategy was applied to achieve optimized mass spectrometry, chromatography, and sample extraction conditions. The validated method utilized stable-isotope labeled D9-asunaprevir as the internal standard. The samples were extracted by liquid-liquid extraction using 10% ethyl acetate in hexane. Chromatographic separation was achieved with gradient elution on a Waters Atlantis dC18 analytical column. Analyte and its internal standard were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 5.00 to 2000ng/mL for asunaprevir, was fitted to a 1/x(2) weighted linear regression model. The intra assay precision was within +/-3.6% CV, inter-assay precision was within +/-4.0% CV, and the assay accuracy was within +/-8.1% of the nominal values in all the species. The method was successfully applied to support multiple pre-clinical toxicokinetic studies in different species. PMID- 23435346 TI - HPLC-UV method for measuring nicotinamide N-methyltransferase activity in biological samples: evidence for substrate inhibition kinetics. AB - Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to produce 1-methylnicotinamide. Enhanced NNMT activity is a feature of many types of cancer, and has been linked to processes such as tumour metastasis, resistance to radiotherapy and tumour drug resistance. As such, inhibition of NNMT activity is a promising therapeutic target for cancer therapy. To screen for NNMT inhibitors, there is a need for a standardised, rapid and cost-effective NNMT assay. Here, we describe a cell-free assay coupled with ion-pairing reverse phase HPLC-UV detection of 1-methylnicotinamide which requires minimal sample manipulation, is linear over 2.5 orders of magnitude with limits of detection and quantification of 0.05 and 0.15nmol 1-methylnicotinamide/100MUL injection respectively. The assay was sufficiently sensitive to measure basal hepatic 1 methylnicotinamide concentration and NNMT activity in mouse, rabbit and human liver. 1-Methylnicotinamide concentration and the NNMT kinetic parameters specific activity, Vmax and Km all demonstrated species differences. NNMT also demonstrated substrate inhibition kinetics in all three species, which again was species-specific in term of calculated Ki. This assay demonstrates improved sensitivity over other previously published methods whilst lacking many of their drawbacks such as extensive sample preparation, use of non-physiological substrates and radioisotopic labelling. PMID- 23435347 TI - Fabrication of single and coupled metallic nanocantilevers and their nanomechanical response at resonance. AB - We fabricate and explore the resonance characteristics of self-supporting thin film based metallic nanocantilever systems. Nanocantilevers of Au and Ag are fabricated from self-supporting (polycrystalline) thin films (~100 nm) grown via a surfactant mediated process. Focused ion beam assisted milling and manipulation techniques are used to fabricate the nanocantilevers. The resonance characteristics of the cantilevers are investigated by the piezoelectric base excitation method and the frequencies of their first resonance modes are determined by digitally processing and analysing scanning electron microscopy images captured during the study. The resonance characteristics of the nanocantilevers are observed to deviate from the Euler-Bernoulli description. We suggest a polynomial expression to describe the peculiar dimensional dependence of resonance frequency of a mechanically vibrating nanocantilever, where the zeroth order term in the polynomial expression represents an Euler-Bernoulli like form. We also demonstrate a fabrication and measurement technique for an elastically coupled Au nanocantilever system and analysis of its vibration characteristics by means of an analogous mass-spring system. PMID- 23435348 TI - Effect of epimedium polysaccharide-propolis flavone immunopotentiator on immunosuppression induced by cyclophosphamide in chickens. AB - Two hundred and fifty 11-day-old chickens were randomly assigned into 5 groups and except normal control group injected with cyclophosphamide once a day for 3 successive days. At day-14-old, all chickens were vaccinated with Newcastle disease vaccine. At the same time of the first vaccination, the chickens in three experimental groups were injected respectively with epimedium polysaccharide propolis flavone immunopotentiator (EPI) at three dosages, once a day for 3 successive days. On days 7, 14, 21 and 28 after the first vaccination, the serum antibody titer and IgG, IgM, IFN-gamma and IL-6 concentrations, peripheral lymphocyte proliferation, including immune organ index on day 28, were measured. The results demonstrated that EPI at high and medium doses could significantly enhance antibody titer and IgG, IgM, IFN-gamma and IL-6 concentrations, promote lymphocyte proliferation and enlarge immune organ index as compared with model control group. This indicated that EPI could effectively resist the immunosuppression. PMID- 23435349 TI - Extracellular acidosis modulates the endocytosis and maturation of macrophages. AB - Extracellular acidosis is involved in various pathological situations of central nervous system and the effects are largely mediated by acid sensing ion channels (ASICs). However, it remains unclear whether extracellular acidosis affects immune cells. Macrophages are immune cells that play important role in immune reactions. In this study we investigated the impact of extracellular acidosis on the function of bone marrow derived macrophages (BMMs). The results showed that extracellular acidosis upregulated the endocytosis, surface molecular expression and interleukin-10 secretion of BMMs, in which the expression of ASIC1 and ASIC3 was detected. Notably, extracellular acidosis stimulated endocytosis and upregulation of surface molecules expression in BMMs could be abolished by amiloride, a blocker of ASICs, and nonsteroid anti-inflammatory drugs. Our findings provide new insight into the role of extracellular acidosis in the regulation of immune function and suggest ASICs as new targets for the modulation of immune response. PMID- 23435350 TI - Recreational Music-Making alters gene expression pathways in patients with coronary heart disease. AB - BACKGROUND: Psychosocial stress profoundly impacts long-term cardiovascular health through adverse effects on sympathetic nervous system activity, endothelial dysfunction, and atherosclerotic development. Recreational Music Making (RMM) is a unique stress amelioration strategy encompassing group music based activities that has great therapeutic potential for treating patients with stress-related cardiovascular disease. MATERIAL/METHODS: Participants (n=34) with a history of ischemic heart disease were subjected to an acute time-limited stressor, then randomized to RMM or quiet reading for one hour. Peripheral blood gene expression using GeneChip(r) Human Genome U133A 2.0 arrays was assessed at baseline, following stress, and after the relaxation session. RESULTS: Full gene set enrichment analysis identified 16 molecular pathways differentially regulated (P<0.005) during stress that function in immune response, cell mobility, and transcription. During relaxation, two pathways showed a significant change in expression in the control group, while 12 pathways governing immune function and gene expression were modulated among RMM participants. Only 13% (2/16) of pathways showed differential expression during stress and relaxation. CONCLUSIONS: Human stress and relaxation responses may be controlled by different molecular pathways. Relaxation through active engagement in Recreational Music Making may be more effective than quiet reading at altering gene expression and thus more clinically useful for stress amelioration. PMID- 23435353 TI - Modulation of A-type K+ channels by the short-chain cobrotoxin through the protein kinase C-delta isoform decreases membrane excitability in dorsal root ganglion neurons. AB - A-type K(+) channels are crucial in controlling neuronal excitability, and their regulation in sensory neurons may alter pain sensation. In this study, we identified the functional role of cobrotoxin, the short-chain alpha-neurotoxin isolated from Naja atra venom, which acts in the regulation of the transient A type K(+) currents (IA) and membrane excitability in dorsal root ganglion (DRG) neurons via the activation of the muscarinic M3 receptor (M3R). Our results showed that cobrotoxin increased IA in a concentration-dependent manner, whereas the sustained delayed rectifier K(+) currents (IDR) were not affected. Cobrotoxin did not affect the activation of IA markedly, however, it shifted the inactivation curve significantly in the depolarizing direction. The cobrotoxin induced IA response was blocked by the M3R-selective antagonists DAU-5884 and 4 DAMP. An siRNA targeting the M3R in small DRG neurons abolished the cobrotoxin induced IA increase. In addition, dialysis of the cells with the novel protein kinase C-delta isoform (PKC-delta) inhibitor deltav1-1 or an siRNA targeting PKC delta abolished the cobrotoxin-induced IA response, whereas inhibition of PKA or classic PKC activity elicited no such effects. Moreover, we observed a significant decrease in the firing rate of the neuronal action potential induced by M3R activation. Pretreatment of the cells with 4-aminopyridine, a selective blocker of IA, abolished this effect. Taken together, these results suggest that the short-chain cobrotoxin selectively enhances IA via a novel PKC-delta dependent pathway. This effect occurred via the activation of M3R and might contribute to its neuronal hypoexcitability in small DRG neurons. PMID- 23435352 TI - Circadian clock-regulated physiological outputs: dynamic responses in nature. AB - The plant circadian clock is involved in the regulation of numerous processes. It serves as a timekeeper to ensure that the onset of key developmental events coincides with the appropriate conditions. Although internal oscillating clock mechanisms likely evolved in response to the earth's predictable day and night cycles, organisms must integrate a range of external and internal cues to adjust development and physiology. Here we introduce three different clock outputs to illustrate the complexity of clock control. Clock-regulated diurnal growth is altered by environmental stimuli. The complexity of the photoperiodic flowering pathway highlights numerous nodes through which plants may integrate information to modulate the timing of flowering. Comparative analyses among ecotypes that differ in flowering response reveal additional environmental cues and molecular processes that have developed to influence flowering. We also explore the process of cold acclimation, where circadian inputs, light quality, and stress responses converge to improve freezing tolerance in anticipation of colder temperatures. PMID- 23435354 TI - Pro-inflammatory and pathogenic properties of Annexin-A1: the whole is greater than the sum of its parts. AB - According to Aristotle, "The whole is greater than the sum of its parts" and yet, although a long time has passed still, we seem to struggle to accept this universal concept. Searching in the literature for the biological function of Annexin-A1, one would find a wealth of information on its homeostatic and protective anti-inflammatory effects. However, very little has been said on its emerging role in a wide variety of pathological conditions ranging from cancer to autoimmunity. In this commentary, we will focus our attention on this novel pro inflammatory and pathogenic "dark side" of Annexin-A1. We will summarize our current understanding of the signaling pathways regulated by this protein and link it to clinical and experimental evidences. Finally we will discuss assets and limitations of Annexin-A1 therapeutic strategies. Most importantly, we hope that this commentary will provide scientific support to "controversial" findings one might encounter while studying this fascinating protein. PMID- 23435351 TI - Global approaches for telling time: omics and the Arabidopsis circadian clock. AB - The circadian clock is an endogenous timer that anticipates and synchronizes biological processes to the environment. Traditional genetic approaches identified the underlying principles and genetic components, but new discoveries have been greatly impeded by the embedded redundancies that confer necessary robustness to the clock architecture. To overcome this, global (omic) techniques have provided a new depth of information about the Arabidopsis clock. Our understanding of the factors, regulation, and mechanistic connectivity between clock genes and with output processes has substantially broadened through genomic (cDNA libraries, yeast one-hybrid, protein binding microarrays, and ChIP-seq), transcriptomic (microarrays, RNA-seq), proteomic (mass spectrometry and chemical libraries), and metabolomic (mass spectrometry) approaches. This evolution in research will undoubtedly enhance our understanding of how the circadian clock optimizes growth and fitness. PMID- 23435355 TI - Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. AB - Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialized countries. The discovery of food components that can ameliorate NAFLD is therefore of interest. Betulinic acid (BA) is a triterpenoid with many pharmacological activities, but the effect of BA on fatty liver is as yet unknown. To explore the possible anti-fatty liver effects and their underlying mechanisms, we used insulin-resistant HepG2 cells, primary rat hepatocytes and liver tissue from ICR mice fed a high-fat diet (HFD). Oil Red O staining revealed that BA significantly suppressed excessive triglyceride accumulation in HepG2 cells and in the livers of mice fed a HFD. Ca(+2) calmodulin dependent protein kinase kinase (CAMKK) and AMP-activated protein kinase (AMPK) were both activated by BA treatment. In contrast, the protein levels of sterol regulatory element-binding protein 1 (SREBP1), mammalian target of rapamycin (mTOR) and S6 kinase (S6K) were all reduced when hepatocytes were treated with BA for up to 24h. We found that BA activates AMPK via phosphorylation, suppresses SREBP1 mRNA expression, nuclear translocation and repressed SREBP1 target gene expression in HepG2 cells and primary hepatocytes, leading to reduced lipogenesis and lipid accumulation. These effects were completely abolished in the presence of STO-609 (a CAMKK inhibitor) or compound C (an AMPK inhibitor), indicating that the BA-induced reduction in hepatic steatosis was mediated via the CAMKK-AMPK-SREBP1 signaling pathway. Taken together, our results suggest that BA effectively ameliorates intracellular lipid accumulation in liver cells and thus is a potential therapeutic agent for the prevention of fatty liver disease. PMID- 23435357 TI - Molecular aspects of cancer cell resistance to chemotherapy. AB - Cancer cell resistance to chemotherapy is still a heavy burden that impairs treatment of cancer patients. Both intrinsic and acquired resistance results from the numerous genetic and epigenetic changes occurring in cancer cells. Most of the hallmarks of cancer cells provide general mechanisms to sustain stresses such as the ones induced by chemotherapeutic drugs. Moreover, specific changes in the target bring resistance to specific drugs like modification in nucleotide synthesis enzymes upon anti-metabolite exposure, in microtubule composition upon spindle poison treatment, in topoisomerase activity upon topoisomerase inhibitor incubation or in intracellular signaling pathways when targeting tyrosine kinase receptors. Finally, the stemness properties of a few cancer cells as well as components of the tumor stroma, like fibroblasts and tumor-associated macrophages but also hypoxia, also help tumor to resist to anticancer agents. These processes provide an additional level of complexity to the understanding of the tumor resistance phenomenon. This review aims to describe the different general mechanisms as well as some examples of specific on target modifications inducing cancer cell resistance to chemotherapy at the molecular level. Perspectives to develop more efficient treatment, using genomic signature or more specific biomarkers to characterize putative resistance mechanisms in patients before choosing the more appropriate treatment, will also be discussed. PMID- 23435356 TI - Tryptophan hydroxylase-2: an emerging therapeutic target for stress disorders. AB - Serotonin (5-HT) has been long recognized to modulate the stress response, and dysfunction of 5-HT has been implicated in numerous stress disorders. Accordingly, the 5-HT system has been targeted for the treatment of stress disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. With a decade of extensive investigation, it is now recognized that: (1) TPH2 exhibits a highly flexible gene expression that is modulated by an increasing number of internal and external environmental factors including the biological clock, stressors, endogenous hormones, and antidepressant therapies; and (2) genetically determined TPH2 activity is linked to a growing body of stress-related neuronal correlates and behavioral traits. These findings reveal an active role of TPH2 in the stress response and provide new insights into the long recognized but not yet fully understood 5-HT-stress interaction. As a major modulator of 5-HT neurotransmission and the stress response, TPH2 is of both pathophysiological and pharmacological significance, and is emerging as a new therapeutic target for the treatment of stress disorders. Given that numerous antidepressant therapies influence TPH2 gene expression, TPH2 is already inadvertently targeted for the treatment of stress disorders. With increased understanding of the regulation of TPH2 activity we can now purposely utilize TPH2 as a target to develop new or optimize current therapies, which are expected to greatly improve the prevention and treatment of a wide variety of stress disorders. PMID- 23435358 TI - Changes in morphometry and association between whole-body fatty acids and steroid hormone profiles in relation to bioaccumulation patterns in salmon larvae exposed to perfluorooctane sulfonic or perfluorooctane carboxylic acids. AB - In the present study, we have used salmon embryos whose continuous exposure to waterborne PFOA or PFOS at 100 MUg/L started as freshly fertilized eggs, and lasted for a total of 52 days. PFOS and PFOA were dissolved in methanol (carrier vehicle) whose concentration never exceeded 0.01% of total tank volume. Samples were collected at day 21, 28, 35, 52, 49 and 56 after the start of the exposure. Note that days 49 and 56 represent end of exposure and 1 week after a recovery period, respectively. Tissue bioaccumulations were determined by HPLC/MS/MS, steroid hormones, fatty acids (FAs) and lipids were determined by GC-MS, while mRNA expression levels of genes were determined by qPCR in whole body homogenate. We observed that PFOS and PFOA showed a steady increase in whole body burden during the exposure period, with a slight decrease after the recovery period. Calculated somatic indexes showed that PFOA produced increases in heart-, thymus , liver- and kidney somatic indexes (HSI, TSI, LSI and KSI). PFOA and PFOS exposure produced significant decreases in whole body dehydroepiandrosterone (DHEA), estrone and testosterone at sampling day 21 and a strong increase of cortisol and cholesterol at the end of recovery period (day 56). PFOA and PFOS effects differed with DHEA and estrone. While PFOS decreased DHEA levels, PFOA produced an increase at day 49, and while PFOS decreased estrone, PFOA produced a slight increase at day 56. We observed changes in FA composition that predominantly involved increases in FA methyl esters (FAMEs), mono- and poly unsaturated FA (MUFA and PUFA) and a decrease in n-3/n-6 PUFA ratio by both PFOA and PFOS. Particularly, an increase in - pentadecenoic MUFA (15:1), two n-3 PUFAs alpha-linolenic acid [ALA: 18:3 n3] and eicosapentaenoic acid [EPA: 20:5 n-3] and n-6 PUFA: arachidonic acid [ARA: 20:4 n6], docosapentaenoic acid (DPA) by PFOA and PFOS were observed. These effects were associated with changes in mRNA expression of FA elongase (FAE), Delta5-desaturase (FAD5) and Delta6-desaturase (FAD6) genes. In summary, the changes in hormonal and FA profiles may represent cellular and/or physiological adaptation to continuous PFOS and PFOA exposure by increasing membrane fluidity, and/or overt developmental effects. The present findings provide some potential insights and basis for a better understanding on the possible mechanisms of PFCs toxicity in fish. PMID- 23435360 TI - Grover disease with features of epidermolytic hyperkeratosis. PMID- 23435361 TI - Follicular density and ratios in scarring and nonscarring alopecia. AB - Follicular counts from transverse sectioning of scalp biopsies have not been statistically scrutinized across disease entities in a standardized fashion. We applied uniform histological criteria and strict statistical measures to compare nonscarring and scarring alopecia. We studied 700 consecutive cases including 355 nonscarring alopecia [136 telogen effluvium, 115 alopecia areata (AA), 95 androgenetic alopecia, and 9 trichotillosis] and 345 scarring alopecia [238 central centrifugal cicatricial alopecia, 29 traction alopecia, 26 lichen planopilaris, 21 end-stage alopecia, 20 lupus erythematosus, 11 folliculitis decalvans]. We counted follicular units, anagen, catagen/telogen, and vellus-like follicles at the central follicular unit level. We calculated follicular density per square centimeter, anagen percentage, telogen percentage, anagen to telogen ratio, and terminal to vellus ratio (TVR). The following achieved statistical significance (P < 0.05): follicular density was 249.4 +/- 4.6 in nonscarring alopecia versus 120.1 +/- 3.8 in scarring alopecia, follicular density of telogen effluvium was 273.5 +/- 7.0 (36.5 +/- 12.5 above nonscarring alopecia mean), TVR of androgenetic alopecia was 1.6 +/- 0.1 (3.6 +/- 0.5 below nonscarring alopecia mean), TVR of AA was 3.2 +/- 0.4 (1.5 +/- 0.6 below nonscarring alopecia mean), anagen percentage of AA was 26.8 +/- 1.8 (26.3 +/- 3.0 below nonscarring alopecia mean), anagen to telogen ratio of AA was 1.6 +/- 0.4 (3.9 +/- 0.7 below nonscarring alopecia mean), and telogen percentage of AA was 59.0 +/- 2.3 (31.0 +/- 3.5 above nonscarring alopecia mean). There exists a great overlap of densities and ratios across the various disorders due to the limited nature of the punch biopsy sample, variations in scalp anatomy, disease biology and duration, patient gender, and age, etc. Our data provide a bell curve distribution that helps analyze hair counts in the clinicopathologic context. PMID- 23435359 TI - The gut microbiota--masters of host development and physiology. AB - Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host. PMID- 23435362 TI - Primary cutaneous spindle-cell B-cell lymphoma of follicle center cell origin. PMID- 23435363 TI - A tumoriform lesion of the vulva with features of mammary-type fibrocystic disease. AB - : Fibrocystic disease is a common benign lesion of the breast. Variably sized cysts, apocrine metaplasia, fibrosis, calcification, chronic inflammation, and epithelial hyperplasia are the basic morphological changes seen in mammary fibrocystic disease. We report a rare tumoriform lesion of the vulva with features of fibrocystic disease, which seems to be the first description of this condition in the vulva. The pertinent literature is discussed. The reported lesion further demonstrates the analogy between tumors of anogenital mammary-like glands and mammary neoplasms. PMID- 23435364 TI - BRAF inhibitor induced verrucal keratosis. PMID- 23435365 TI - Follow-up practice in endometrial cancer and the association with patient and hospital characteristics: a study from the population-based PROFILES registry. AB - OBJECTIVE: To examine to what extent endometrial cancer survivors experienced follow-up according to the Dutch national guidelines, and to identify associations between follow-up care consumption and socio-demographic and clinical characteristics, Health-Related Quality of Life (HRQL), and worry (including fear of recurrence). Patients' preferences with the received follow-up care were also evaluated. METHODS: All patients diagnosed with endometrial cancer FIGO stages I-II between 1999 and 2007, registered in the Eindhoven Cancer Registry (ECR), received a questionnaire including patients' follow-up care consumption, preferences regarding the follow-up schedule, HRQL (SF36 and EORTC QLQ-EN24), and worry (IOCv2). RESULTS: 742 (77%) endometrial cancer survivors returned a completed questionnaire. Overall, 19% reported receiving more follow up visits than recommended by the guidelines. Overconsumption of follow-up care was lowest in follow-up year 1 (13%), and highest in follow-up years 6-10 (27%). In addition, overconsumption was associated with having a comorbid condition, a higher score on the worry subscale, and hospital of treatment. Most patients (83%) felt comfortable with their follow-up schedule. Patients in follow-up years 6-10 felt least comfortable (69%). CONCLUSION: Follow-up frequency was higher than recommended in a large group of endometrial cancer survivors, mainly in follow-up years 6-10. Moreover, a substantial variation in follow-up practice was observed between the different hospitals. Despite limited evidence to support the use of intensive follow-up schedules, the current study suggests that intensive routine follow-up after endometrial cancer continues to be standard practice. Possibly, patients should be better informed in order to reduce overconsumption and worry. PMID- 23435366 TI - Expression of ghrelin and GHSR-1a in mammary glands of dairy goat during the lactation and the effects of gherlin on regulation of mammary function in vitro. AB - Recent studies have implicated the peripheral actions of ghrelin in reproductive tissues. The present study provides novel evidence for the expression of ghrelin and its functional receptor (GHSR-1a) in the mammary glands of dairy goat during lactation and the effects of ghrelin on regulation of mammary function in vitro. Ghrelin and GHSR-1a mRNA and protein were persistently detected in goat mammary glands throughout the lactation, and patterns of expression of ghrelin, GHSR-1a and beta-casein were generally similar, with highest levels during peak milk yield (day 60-120 of lactation) and lower levels during late (day 180) of lactation. The distribution of ghrelin and GHSR-1a in the mammary glands were substantiated by immunohistochemical method, alveolar and ductal epithelial cells showed distinct immunoreactivity at the different stages of lactation, strong reactivity was seen in most epithelial cells during peak stage, in some alveoli, the vast majority of the epithelial cells were immunoreactivity. Ghrelin and GHSR 1a mRNA expression were demonstrated in cultured primary mammary epithelial cells (MECs). In addition, the results showed that ghrelin could induce a dose dependent promotion on beta-casein expression in cultured mammary tissues and MECs, and the stimulative effects on beta-casein expression were blocked by D Lys3-GHRP6 (a GHSR-1a antagonist). Additionally, ghrelin induced a dose-dependent promotion on cell proliferation. Our present findings suggest that ghrelin may play an important role in regulation of mammary function in lactating dairy goats via GHSR-1a. PMID- 23435367 TI - Transcriptional regulation of human ferredoxin 1 in ovarian granulosa cells. AB - Ferredoxin 1 (FDX1; adrenodoxin) is an iron-sulfur protein that is involved in various metabolic processes, including steroid hormone synthesis in mammalian tissues. We investigated the transcriptional regulation of FDX1 in ovarian granulosa cells. Previously, we reported that the NR5A family, including steroidogenic factor-1 (SF-1) and liver receptor homolog-1 could induce differentiation of human mesenchymal stem cells (hMSCs) into steroidogenic cells. A ChIP assay showed that SF-1 could bind to the FDX1 promoter in differentiated hMSCs. Luciferase reporter assays showed that transcription of FDX1 was synergistically activated by the NR5A family and 8Br-cAMP treatment through two SF-1 binding sites and a CRE-like sequence in a human ovarian granulosa cell line, KGN. Knockdown of FDX1 attenuated progesterone production in KGN cells. These results indicate transcription of FDX1 is regulated by the NR5A family and cAMP signaling, and participates in steroid hormone production in ovarian granulosa cells. PMID- 23435368 TI - A catalytic multicomponent coupling reaction for the enantioselective synthesis of spiroacetals. AB - The first multicomponent catalytic asymmetric synthesis of spiroacetals has been described. Hybrid molecules comprising a spiroacetal scaffold (a natural-product inspired scaffold) and an alpha-amino acid motif (a privileged fragment) are easily available through a gold phosphate-catalysed one-pot three component coupling reaction of alkynols, anilines and glyoxylic acid. PMID- 23435369 TI - Highly sensitive detection of telomerase based on a DNAzyme strategy. AB - The present study demonstrated a highly sensitive strategy for measuring telomerase activity in cell extracts. Furthermore, we applied the new strategy for in situ detection of telomerase at the cellular level in cancer cells, together with a normal cell as the negative control. PMID- 23435370 TI - Ultrasound may promote fracture healing but this does not necessarily accelerate return of function. PMID- 23435371 TI - Compression improves healing of venous leg ulcers compared with no compression, with differences between different compression systems. PMID- 23435372 TI - The fabrication of long-range ordered nanocrescent structures based on colloidal lithography and parallel imprinting. AB - A method for fabricating nanocrescent structures is presented based on a combination of colloidal lithography and parallel imprinting. In this process, non-close-packed colloidal spheres were prepared by a simple lift-up soft lithography technique, and subsequently the individual particles were used as shadow masks to angle deposit a layer of silver on the silicon substrates. Then, the silver-coated samples were etched to get silicon crescent nanohole arrays, which served as templates to mold patterned photocurable resin membranes. The patterned photocurable resin membranes were used to print gold nanocrescent nanostructures onto glass substrates. The size of the opening and the width of the gold nanostructures could be freely adjusted by changing the azimuth angle and tilt angle. Very importantly, the central angle of the nanocrescents could be adjusted in the range of 0 degrees -360 degrees . This method provides a low-cost and highly reproducible way to prepare complex nanostructure arrays for applications related to near field enhancement materials, optical sensors and surface-enhanced Raman spectroscopy, etc. PMID- 23435373 TI - MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. AB - Because it is a member of the miR-106b~25 cluster, microRNA-25 (miR-25) is known to be dysregulated in human cancers. However, the expression and role of miR-25 in colon cancer remain unclear. In this study, miR-25 was found to be down regulated in human colon cancer tissues when compared to those in matched, non neoplastic mucosa tissues. Functional studies revealed that restoration of miR-25 expression inhibited cell proliferation and migration. In contrast, miR-25 inhibition could promote the proliferation and migratory ability of cells. Stable over-expression of miR-25 also suppressed the growth of colon cancer-cell xenografts in vivo. Furthermore, bioinformatic predictions and experimental validation were used to identify Smad7 as a direct target of miR-25. Functional reverse experiments indicated that the antitumor effects of miR-25 were probably mediated by its repression of Smad7. These results suggest that miR-25 may function as a tumor suppressor by targeting Smad7 in colon cancer. Thus, miR-25 may serve as a potential therapeutic agent or target for cancer therapy. PMID- 23435375 TI - (V600E)BRAF promotes invasiveness of thyroid cancer cells by decreasing E cadherin expression through a Snail-dependent mechanism. AB - BRAF is a main oncogene in human thyroid cancer. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with BRAF inhibitor PLX4720 decreases migration and invasion in thyroid cancer cells expressing oncogenic (V600E)BRAF through a MEK/ERK-dependent mechanism, since treatment with the MEK inhibitor U0126 exerts the same effect. Moreover, over-expression of (V600E)BRAF increases migration and invasion of wild-type BRAF thyroid cells. Using the same strategies, we demonstrate that these effects are mediated by upregulation of the transcriptional repressor Snail with a concomitant decrease of its target E-cadherin, both hallmarks of EMT. These results reveal a novel (V600E)BRAF-induced mechanism in thyroid tumours progression and provides a rationale for using the PLX4720 inhibitor to target (V600E)BRAF signalling to effectively control progression of thyroid cancer. PMID- 23435374 TI - Plasmid-based E6-specific siRNA and co-expression of wild-type p53 suppresses the growth of cervical cancer in vitro and in vivo. AB - The E6 protein of the oncogenic HPV-16 functions by interfering with the normal cell cycle control mechanisms, particularly those controlled by p53. In this study, we developed a dual expression plasmid that coexpressed-E6-specific siRNA and wild type p53, and to evaluate its effects on cervical cancer growth. We found that simultaneous expression of pSi-E6-P53 caused a robust suppression of tumor growth when compared to the controls either E6-specific siRNA or p53 alone. In conclusion, our findings demonstrate that a combined strategy of co-expressed E6-specific siRNA and p53 synergistically and more effectively suppressed cervical tumor growth when compared with single treatment. PMID- 23435376 TI - MicroRNA-146a acts as a metastasis suppressor in gastric cancer by targeting WASF2. AB - Previous studies have shown that miR-146a acts as either an oncogene or a tumor suppressor in various cancers. In this study, we investigated the role of miR 146a in gastric cancer cells and its potential target genes. The results showed that miR-146a expression correlated inversely with WASF2 protein expression in gastric cancer cell lines. Overexpression of miR-146a suppressed the migration and invasion of gastric cancer cells, and also the protein level of WASF2. WASF2 was shown to be a direct target gene of miR-146a by luciferase assays. Restoration of WASF2 promoted the migration and invasion of gastric cancer cells, similar to that mediated by miR-146a inhibition. This study has identified an onco-suppressive role of miR-146a in gastric cancer cells by its reduction of WASF2 expression. The newly identified miR-146a/WASF2 axis partially reveals the molecular mechanism underlying the migration and invasion of gastric cancer cells and represents a new potential therapeutic target for gastric cancer. PMID- 23435378 TI - Editorial. PMID- 23435377 TI - Bioavailability of phytochemicals and its enhancement by drug delivery systems. AB - Issues of poor oral bioavailability of cancer chemopreventives have hindered progress in cancer prevention. Novel delivery systems that modulate the pharmacokinetics of existing drugs, such as nanoparticles, cyclodextrins, niosomes, liposomes and implants, could be used to enhance the delivery of chemopreventive agents to target sites. The development of new approaches in prevention and treatment of cancer could encompass new delivery systems for approved and newly investigated compounds. In this review, we discuss some of the delivery approaches that have already made an impact by either delivering a drug to target tissue or increasing its bioavailability by many fold. PMID- 23435379 TI - Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. AB - G protein-coupled receptors (GPCRs) mediate transmembrane signaling. Before ligand binding, GPCRs exist in a basal state. Crystal structures of several GPCRs bound with antagonists or agonists have been solved. However, the crystal structure of the ligand-free basal state of a GPCR, the starting point of GPCR activation and function, had not yet been determined. Here we report the X-ray crystal structure of the ligand-free basal state of a GPCR in a lipid membrane like environment. Oligomeric turkey beta1-adrenergic receptors display two dimer interfaces. One interface involves the transmembrane domain (TM) 1, TM2, the C terminal H8 and extracellular loop 1. The other interface engages residues from TM4, TM5, intracellular loop 2 and extracellular loop 2. Structural comparisons show that this ligand-free state is in an inactive conformation. This provides the structural basis of GPCR dimerization and oligomerization. PMID- 23435380 TI - Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. AB - SIX1 interacts with EYA to form a bipartite transcription factor essential for mammalian development. Loss of function of this complex causes branchio-oto-renal (BOR) syndrome, whereas re-expression of SIX1 or EYA promotes metastasis. Here we describe the 2.0-A structure of SIX1 bound to EYA2, which suggests a new DNA binding mechanism for SIX1 and provides a rationale for the effect of BOR syndrome mutations. The structure also reveals that SIX1 uses predominantly a single helix to interact with EYA. Substitution of a single amino acid in this helix is sufficient to disrupt SIX1-EYA interaction, SIX1-mediated epithelial mesenchymal transition and metastasis in mouse models. Given that SIX1 and EYA are overexpressed in many tumor types, our data indicate that targeting the SIX1 EYA complex may be a potent approach to inhibit tumor progression in multiple cancer types. PMID- 23435381 TI - A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. AB - PTEN is a tumor-suppressor gene that has been shown to be under the regulatory control of a PTEN pseudogene expressed noncoding RNA, PTENpg1. Here, we characterize a previously unidentified PTENpg1-encoded antisense RNA (asRNA), which regulates PTEN transcription and PTEN mRNA stability. We find two PTENpg1 asRNA isoforms, alpha and beta. The alpha isoform functions in trans, localizes to the PTEN promoter and epigenetically modulates PTEN transcription by the recruitment of DNA methyltransferase 3a and Enhancer of Zeste. In contrast, the beta isoform interacts with PTENpg1 through an RNA-RNA pairing interaction, which affects PTEN protein output through changes of PTENpg1 stability and microRNA sponge activity. Disruption of this asRNA-regulated network induces cell-cycle arrest and sensitizes cells to doxorubicin, which suggests a biological function for the respective PTENpg1 expressed asRNAs. PMID- 23435382 TI - Characterization of prion-like conformational changes of the neuronal isoform of Aplysia CPEB. AB - The neuronal isoform of cytoplasmic polyadenylation element-binding protein (CPEB) is a regulator of local protein synthesis at synapses and is critical in maintaining learning-related synaptic plasticity in Aplysia. Previous studies indicate that the function of Aplysia CPEB can be modulated by conversion to a stable prion-like state, thus contributing to the stabilization of long-term memory on a molecular level. Here, we used biophysical methods to demonstrate that Aplysia CPEB, like other prions, undergoes a conformational switch from soluble alpha-helix-rich oligomer to beta-sheet-rich fiber in vitro. Solid-state NMR analyses of the fibers indicated a relatively rigid N-terminal prion domain. The fiber form of Aplysia CPEB showed enhanced binding to target mRNAs as compared to the soluble form. Consequently, we propose a model for the Aplysia CPEB fibers that may have relevance for functional prions in general. PMID- 23435384 TI - Apical bullae and spontaneous pneumothorax. PMID- 23435383 TI - Structure of the MutLalpha C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site. AB - Mismatch-repair factors have a prominent role in surveying eukaryotic DNA replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutLalpha (Mlh1-Pms1 heterodimer) C terminal domain (CTD) from Saccharomyces cerevisiae, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutLalpha as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutLalpha(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs. PMID- 23435385 TI - High-frequency percussive ventilation for severe inhalation injury. PMID- 23435386 TI - Switchable delivery of small interfering RNA using a negatively charged pH responsive polyethylenimine-based polyelectrolyte complex. AB - A small interfering RNA (siRNA)-loaded polyelectrolyte constructed with branched polyethylenimine (bPEI) and copolymers, consisting of polyethylene glycol (PEG), histidine (His), and glutamic acid (Glu), was developed in order to provide a tumor acidosis-triggered delivery system with low cytotoxicity. PMID- 23435387 TI - Phase-controlled supramolecular photochirogenesis in cyclodextrin nanosponges. AB - Pyromellitate-bridged cyclodextrin nanosponges (CDNSs) evolved from sol into gel state upon gradual increase of the concentration from 0.2 to 2000 mg mL(-1) in water. The enantiodifferentiating geometrical photoisomerizations of (Z) cyclooctene and (Z,Z)-1,3-cyclooctadiene sensitized by CDNS at various concentrations were critically affected by the phase transition of CDNS to afford the corresponding (E)- and (E,Z)-isomers in the highest enantiomeric excesses in the gel state. PMID- 23435388 TI - Vascular injuries caused by acupuncture. A systematic review. AB - AIM: The aim of the study was to systematically review the literature on vascular injuries caused by acupuncture. METHODS: This was a systematic literature search in Medline and PubMed. RESULTS: Thirty-one cases were identified and the majority developed symptoms in direct connection with the acupuncture treatment. Three patients died, two from pericardial tamponade and one from an aortoduodenal fistula. There were seven more tamponades, eight pseudoaneurysms, two with ischemia, two with venous thrombosis, one with compartment syndrome and seven with bleeding (five in the central nervous system). The two patients with ischemia had remaining sequeleae. Information on follow-up was suboptimal with no information in fourteen patients. CONCLUSION: Vascular injuries are rare, bleeding and pseudoaneurysm dominating. Follow-up is insufficient in the hitherto published papers. PMID- 23435389 TI - Consensus Document of the International Union of Angiology (IUA)-2013. Current concept on the management of arterio-venous management. AB - Arterio-venous malformations (AVMs) are congenital vascular malformations (CVMs) that result from birth defects involving the vessels of both arterial and venous origins, resulting in direct communications between the different size vessels or a meshwork of primitive reticular networks of dysplastic minute vessels which have failed to mature to become 'capillary' vessels termed "nidus". These lesions are defined by shunting of high velocity, low resistance flow from the arterial vasculature into the venous system in a variety of fistulous conditions. A systematic classification system developed by various groups of experts (Hamburg classification, ISSVA classification, Schobinger classification, angiographic classification of AVMs,) has resulted in a better understanding of the biology and natural history of these lesions and improved management of CVMs and AVMs. The Hamburg classification, based on the embryological differentiation between extratruncular and truncular type of lesions, allows the determination of the potential of progression and recurrence of these lesions. The majority of all AVMs are extra-truncular lesions with persistent proliferative potential, whereas truncular AVM lesions are exceedingly rare. Regardless of the type, AV shunting may ultimately result in significant anatomical, pathophysiological and hemodynamic consequences. Therefore, despite their relative rarity (10-20% of all CVMs), AVMs remain the most challenging and potentially limb or life-threatening form of vascular anomalies. The initial diagnosis and assessment may be facilitated by non- to minimally invasive investigations such as duplex ultrasound, magnetic resonance imaging (MRI), MR angiography (MRA), computerized tomography (CT) and CT angiography (CTA). Arteriography remains the diagnostic gold standard, and is required for planning subsequent treatment. A multidisciplinary team approach should be utilized to integrate surgical and non surgical interventions for optimum care. Currently available treatments are associated with significant risk of complications and morbidity. However, an early aggressive approach to elimiate the nidus (if present) may be undertaken if the benefits exceed the risks. Trans-arterial coil embolization or ligation of feeding arteries where the nidus is left intact, are incorrect approaches and may result in proliferation of the lesion. Furthermore, such procedures would prevent future endovascular access to the lesions via the arterial route. Surgically inaccessible, infiltrating, extra-truncular AVMs can be treated with endovascular therapy as an independent modality. Among various embolo-sclerotherapy agents, ethanol sclerotherapy produces the best long term outcomes with minimum recurrence. However, this procedure requires extensive training and sufficient experience to minimize complications and associated morbidity. For the surgically accessible lesions, surgical resection may be the treatment of choice with a chance of optimal control. Preoperative sclerotherapy or embolization may supplement the subsequent surgical excision by reducing the morbidity (e.g. operative bleeding) and defining the lesion borders. Such a combined approach may provide an excellent potential for a curative result. Conclusion. AVMs are high flow congenital vascular malformations that may occur in any part of the body. The clinical presentation depends on the extent and size of the lesion and can range from an asymptomatic birthmark to congestive heart failure. Detailed investigations including duplex ultrasound, MRI/MRA and CT/CTA are required to develop an appropriate treatment plan. Appropriate management is best achieved via a multi-disciplinary approach and interventions should be undertaken by appropriately trained physicians. PMID- 23435390 TI - Abdominal aortic aneurysm and new WHO criteria for screening. AB - Does screening of abdominal aortic aneurysm (AAA) fulfil the recently revised the World Health Organization WHO criteria for screening? Contemporary data from the literature are used to analyze whether the ten recent WHO criteria can be used to motivate AAA screening. Although the prevalence of AAA seems to decrease, at least screening of 65-year old males saves lives and is cost-effective. Ultrasonographic screening for AAA in risk populations fulfils the new WHO criteria for screening. PMID- 23435391 TI - Practical importance and modern methods of the evaluation of skin microcirculation during chronic lower limb ischemia in patients with peripheral arterial occlusive disease and/or diabetes. AB - Skin ischemia is one of the crucial phenomena during chronic lower limb ischemia in patients with peripheral arterial occlusive disease and/or diabetes. However, risk stratification for development of ischemic ulceration and/or skin necrosis in those patients is not easy, mostly due to the complex structure of the dermal vascular bed and limited possibilities for studying the skin capillaries in everyday practice. All definitions of critical limb ischemia thus far have considered mostly the clinical symptoms and the degree of macrocirculatory impairment. Despite the fact that the reduction of absolute dermal perfusion and improper distribution of perfusion in ischemic feet, primarily diminished perfusion or even a complete loss of blood flow in nutritional capillaries, rather than arterial occlusion per se, is the eventual reason for critical limb ischemia symptoms, the vessels of the microcirculation are not routinely assessed in clinical practice. Monitoring of microcirculatory parameters, as a part of integrated diagnostic approach, may have a considerable value in the evaluation of risk, progression of the disease and the effectiveness of therapeutic intervention in individual patients. Relative simplicity and availability of different non-invasive methods, including video capillaroscopy and laser Doppler fluxmetry, should constitute a premise to their wider application in clinical management of chronic limb ischemia. PMID- 23435392 TI - Mechanical thrombectomy using the Rotarex catheter in the treatment of acute and subacute occlusions of peripheral arteries: immedite results, long-term follow up. AB - AIM: The aim of this paper was to evaluate the immediate and long-term results of mechanical thrombectomy using the Rotarex catheter in the treatment of acute and subacute occlusions of peripheral arteries. METHODS: Patients with acute or subacute occlusions of peripheral arteries were selected consecutively for treatment with the Rotarex system. The average age of our patients was 44-92 years (median [m] 75 years). The duration of symptoms ranged from 1 to 90 days (m 14 days). RESULTS: Seventy-three interventions in 65 patients were performed. Occlusion length varied from 1 to 37 cm (m 10 cm). Immediate successful recanalization was achieved in 69 interventions (95%). Peripheral embolization represented the most frequent transitory complication (6%). Acute reocclusion following 69 successful interventions occurred in a total of 7 procedures (10%). Cumulative patency rates were 56% after 6 months, 47% after 12 months, 41% after 18 months, 37% after 24 months, 33% after 30 months and 29% after 36 months. The ankle/brachial pressure index prior to intervention ranged from 0 to 0.83 (m 0.53) and increased to 0.42-1.44 (m 0.9) post intervention (P<0.001). Its values after 6, 12, 18, 24, 30 and 36 months were statistically significantly higher than those before procedure. Major amputation was performed in 10% of cases. CONCLUSIONS: Rotarex thrombectomy represents an effective and safe modality for treating acute and subacute occlusions of peripheral arteries with excellent immediate and satisfactory long-term results. Compared to thrombolysis, the principal advantage of thrombectomy is the rapid recanalization of the given artery. PMID- 23435393 TI - Stent-graft repair for blunt traumatic aortic injury: functional and survival outcomes. AB - AIM: Traumatic aortic injury is usually lethal, most often because of serious associated wounds. The short- and midterm outcome of endovascular exclusion was assessed as the current treatment of choice due to a lower mortality and morbidity than open surgical treatment. METHODS: We reviewed the cases of 8 patients (5 male, mean age 33 years) undergoing endovascular repair of a traumatic thoracic aortic lesion, confirmed by computed tomographic angiography, at our centre. Most patients showed a contained lesion limited to the aortic isthmus and severe associated injuries. RESULTS: Intrahospital mortality was 37.5% (N.=3) and mostly due to posttraumatic brain injury (N.=2). Most patients were hemodynamically stable at the time of endovascular repair (N.=6). The median time to surgery was 12 hours (3-48 hours). The endografts used were TAG(r) (W.L. Gore and Associates, Flagstaff) in three patients, and Valiant(r) (Medtronic, Santa Rosa, CA) in four. The technical success rate was 100%. In one case, the left subclavian artery was occluded without signs of arm ischemia. There were no cases of paraplegia or stroke related to treatment. No revision procedures were needed during follow-up. CONCLUSION: Endovascular repair shortly after injury seems to be effective and safe with a low associated morbidity and mortality. PMID- 23435394 TI - Early and late outcomes of inflammatory abdominal aortic aneurysms: comparison with the outcomes after open surgical and endovascular aneurysm repair in literature reviews. AB - AIM: The aim of this study was to analyze the clinical characteristics, operative management and early and late outcomes of Inflammatory abdominal aortic aneurysms (IAAAs) in our vascular service, retrospectively and to compare with the outcomes of open and endovascular aneurysm repair (EVAR) in the patients with IAAAs in literature reviews. METHODS: Between January 1990 and December 2011, this series included twenty-four patients with IAAAs who underwent surgical treatment. The mean length of follow-up was 37.6 months (range 3-108). Kaplan-Meier life tables were used to calculate survival rate. RESULTS: Fifteen patients (60%) were symptomatic including 3 patients with hydronephrosis. Seven patients with severe symptoms underwent emergency operations. Twenty four patients underwent open surgical AAA repair. The 30 - day mortality rates were 0%. All patients had successful post operative courses and followed as outpatients in an elective situation. The ten year cumulative survival rate was 70%. The early and late mortality was the same for open repair compared to non-inflammatory AAA. CONCLUSIONS: IAAA compared with non-IAAA is associated with a higher incidence of preoperative morbidity, however operative mortality rates are lower. EVAR has lower early operative mortality rates, however, there are some problems such as remaining periaortic fibrosis and hydronephrosis in approximately half of IAAA patients after EVAR. PMID- 23435395 TI - Differing association of macrophage subsets with atherosclerotic plaque stability. AB - AIM: While initial research suggests that M2 macrophages are athero-protective, more recently, proatherogenic functions, such as a greater uptake of lipid than M1 macrophages, have been demonstrated, raising the question of their actual association with plaque stability. The present study, therefore, assessed the association between macrophage subset and plaque stability. Furthermore, it examined whether the fibrocyte, that we have previously identified in the plaque, represents a subset of M2 macrophages. METHODS: Twenty human carotid atherosclerotic plaque specimens were examined for the presence of macrophages using immunohistochemistry for pan macrophages (CD68), M1 (CD64, CD86) and M2 (CD163, CD206) subsets. The slides were assessed by digital whole slide scanning/image analysis to quantify the expression of these markers in the plaque. Comparisons in marker distribution and quantity relative to plaque stability were made. Adoption of a fibrocyte phenotype was assessed by double immunofluorescence staining of the markers with procollagen I. RESULTS: M1 and M2 macrophages were present throughout the plaque including the core and cap. While the levels of CD68 (pan macrophage maker) and CD86 negatively correlated with cap thickness, the levels of the M2 marker, CD163, did not and moreover, did not differ between plaques when they were separated into stable and unstable groups. Notably, collagen production was evident in most but not all M2 macrophages. CONCLUSION: Our findings demonstrate that while macrophage levels in general negatively correlate with plaque cap thickness, levels of M2 macrophages do not. This may be in part due to their ability to produce collagen (ie adopt a fibrocyte phenotype) in the plaque. PMID- 23435396 TI - Calcium channel blocker effect on insulin resistance and inflammatory markers in essential hypertension patients. AB - AIM: Insulin resistance, inflammation and oxidative stress (OS), are among the mechanisms that have been implicated in pathogenesis of essential hypertension (EH). Peripheral polymorphonuclear leukocytes (PMNLs) are primed in EH patients, releasing uncontrolled superoxide anion contributing to OS in these patients. PMNL priming correlates with insulin resistance and with PMNL intracellular calcium ([Ca2+]i). Recent studies have attributed to the anti-hypertensive drug lercanidipine, a third generation calcium-channel blocker, and additional anti ischemic and anti-oxidative characteristics. Aim of the study was to evaluate the possible non-traditional effect of two months of lercanidipine treatment on insulin resistance and on PMNL-related inflammation in EH patients. METHODS: Non smoking EH patients with untreated mild to moderate high blood pressure (BP) were included. Low-graded inflammation was reflected by WBC and PMNL counts and by PMNL apoptosis. Systemic inflammation was measured by plasma fibrinogen, CRP and albumin levels. Fasting serum insulin levels served as a marker of insulin resistance. RESULTS: Two months of lercanidipine treatment showed significant decrease in BP, in WBC and PMNL counts, in PMNL apoptosis, in CRP and serum insulin levels and significant increase in serum albumin levels. Rates of superoxide release from PMNLs, WBC and PMNL counts and insulin levels positively correlated with mean arterial blood pressure values. CONCLUSION: We imply that use of this CCB lercanidipine can be favored in EH patients due to its combined anti-PMNL priming and anti-inflammatory effects, in addition to its anti hypertensive characteristics. PMID- 23435397 TI - Double-blind, randomized, crossover, controlled clinical trial of NaCl + Chitosan 3% versus NaCl on mild or moderate high blood pressure during the diet and lifestyle improvement period before possible prescription of an antihypertensive treatment. AB - AIM: The aim of the study was to examine the effect on blood pressure of replacing NaCl sea salt by NaCl + chitosan 3% (Symbiosal) during the diet and lifestyle improvement period prescribed to patients before any antihypertensive treatment. METHODS: This was a double-blind, randomized, crossover, controlled clinical trial of Symbiosal (NaCl + chitosan 3%) versus NaCl over two eight-week periods on 40 patients with mild hypertension for which they had never previously been treated. RESULTS: The effect of Symbiosal appeared as early as the first period of the crossover trial showing a reduction in systolic blood pressure (SBP) from 149.2 +/- 4.9 mmHg to 136.1 +/- 9.5 mmHg in patients on Symbiosal (reduction of 13.1 +/- 10.8 mmHg) versus a reduction from 149.7 +/- 4.6 mmHg to 142.9 +/- 7.7 mmHg in patients on traditional NaCl (reduction of 6.8 +/- 7.5 mmHg) (P=0.0404). Similar results were observed for diastolic blood pressure (DBP) with a reduction of 11.2 +/- 7.4 mmHg versus 7 +/- 8 mmHg (P=0.0560). HBP was brought under control (SBP <= 140 and DBP <= 90) in 76.2% (16/21) versus 36.8% (7/19)% of patients, respectively (P=0.0119). The crossover analysis confirmed the results showing Symbosial effects for both SBP (P=0.0156) and DBP (P=0.0285). CONCLUSION: Replacing traditional NaCl by Symbiosal in conjunction with recommended alterations to lifestyle and diet significantly contributes to better control of hypertension and may postpone the prescription of antihypertensive drugs. PMID- 23435398 TI - The development of phlebology in Hungary. AB - Angiology as an independent discipline together with phlebology started in Hungary with the work of Karoly Bugar-Meszaros. Major chapters can be read on venous diseases in his book published in 1944. A milestone in pharmacological phlebology was the discovery of the flavonoids by Albert Szentgyorgyi. After World War II Geza de Takats played an important role in the development of modern venous surgery in the USA. On the initiative of Lajos Soltesz, the Phlebological Section of the Hungarian Society of Angiology was founded in 1979, chaired by Gyorgy Rado. Andras Hetenyi, Tamas Sandor and Viktoria Varkonyi assisted the organisation of the section. In the 1980s centers were formed throughout the country where up-to-date phlebological treatments were performed. International relationships were built mainly with Austrian and German experts such as Robert May and Oswald Petter. From 1987, under the direction of Gyorgy Acsady a large scale phlebological activity developed in the country. The section organised courses and training sessions, Hungarian phlebologists presented papers at international conferences, foreign experts visited Hungary. After Gyorgy Vas's monograph, Attila Nemes and Imre Bihari wrote books on venous diseases. The 1st European Congress of the Union Internationale de Phlebologie, with 1000 participants including the leading phlebologists of the world was held in Budapest in 1993. Erbetegsegek (Vascular Diseases) the official journal of the Hungarian Society of Angiology and Vascular Surgery was published in 1994 and The Club of Sclerotherapists was formed in 1997. At the regular meetings of the Club, which is now called Hungarian Venous Forum, the lectures cover every aspect of venous diseases and overlapping disciplines as well. Eva Mesko and Zsolt Pecsvarady have played outstanding roles in the organisation of internal medical phlebology. Emil Monos, the investigator of physiological control of haemodynamics of the venous system is a well-known scientist all over the world. Other presidents of the Phlebological Section were Andras Hetenyi who investigated the pathomechanism of chronic venous insufficiency, Tamas Sandor a specialist of the prophylaxis of venous thromboembolism and Gabor Menyhei an expert of venous operations including subfascial endoscopic perforant surgery. A leading person of the phlebology in the country is Imre Bihari who is an expert of sclerotisation, editor of the journal Vascular Diseases, founder of the 'Venous Forum' and present chair of the Phlebological Section. Nowadays Hungarian phlebologists and vascular surgeons are treating the patients all over the world. Peter Gloviczki Professor of Vascular Surgery of Mayo Clinic as well as the 15th president of the American Venous Forum, and Zoltan Varady Professor and founder of the Vein Clinic in Frankfurt support our work in every way. Internationally acknowledged Hungarian phlebologists are Peter Conrad and George Somjen in Australia, Roberto Varnagy and Peter-Pablo Komlos in South America and Attila Puskas in Transylvania. PMID- 23435399 TI - Targeted inhibition of Vav1 activity does not favour development of colitis associated colon cancer. PMID- 23435400 TI - Ulcerative colitis with rare chromosomal abnormalities: report of 2 patients. PMID- 23435401 TI - Pneumocystis jiroveci pneumonia in patients with inflammatory bowel disease: a survey of prophylaxis patterns among gastroenterology providers. AB - BACKGROUND: The use of combination immunosuppressive agents is associated with reports of pneumocystis jiroveci pneumonia (PJP). The aim of this study was to determine practice patterns among gastroenterology providers for PJP prophylaxis in patients with inflammatory bowel disease (IBD) on immunosuppressive therapy. METHODS: An internet-based survey of 14 questions was sent through e-mail to a random sampling of 4000 gastroenterologists, nurse practitioners, and physician assistants between November 2011 and February 2012. Three reminder e-mails were sent to providers who had not completed the survey. RESULTS: The invitation e mail that contained the link to the survey was clicked by 504 providers and the completed surveys were returned by 123 of them (78% physicians, 11% nurse practitioners, 11% physician assistants). The response rate was 24.4%. Seventy nine percent of the respondents had managed >25 patients with IBD in the past year, with as much as one-third of all respondents managing >100 patients. Eight percent of the respondents reported patients who had developed PJP on immunosuppressive therapy, 11% reported initiating PJP prophylaxis, mostly for patients on triple immunosuppressive therapy. Prescription of PJP prophylaxis was not significantly associated with the number of years in practice or the number of IBD patients treated. However, providers with patients that had developed PJP were 7.4 times more likely to prescribe prophylaxis (P = 0.01). In addition, providers in academic centers were 4 times more likely to initiate PJP prophylaxis than those in nonacademic centers (P = 0.03). The most common reasons for not prescribing PJP prophylaxis included the absence of guidelines on the benefits of prophylaxis, lack of personal experience with PJP, and the lack of knowledge on the need for prophylaxis in patients with IBD on combination immunosuppressive therapy. CONCLUSIONS: The lack of guidelines seems to influence the decision on not to prescribe PJP prophylaxis in patients with IBD. Additional studies are needed to determine PJP risk factors and risks and benefits of prophylaxis. PMID- 23435402 TI - Five-year mortality in colorectal cancer patients with ulcerative colitis or Crohn's disease: a nationwide population-based cohort study. AB - BACKGROUND: The impact of inflammatory bowel disease (IBD) on colorectal cancer (CRC) prognosis, taking into account other comorbidities, is not clear. We studied the overall mortality in CRC patients with a history of ulcerative colitis (UC) or Crohn's disease (CD) compared with non-IBD-CRC patients. METHODS: Data on all CRC and IBD patients diagnosed with CRC between 1977 and 2009 were retrieved from Danish medical registries. One-year and 5-year overall mortality were evaluated with the Kaplan-Meier method and with Cox regression, adjusting for year of CRC diagnosis, sex, Duke's stage, age at CRC diagnosis, and Charlson Comorbidity Index score. RESULTS: We identified 653 CRC patients diagnosed with UC, 238 patients with CD, and 107,024 CRC patients without IBD. The patients with IBD were younger at diagnosis than patients without IBD. The Duke's stage distribution was similar for UC-CRC patients and non-IBD-CRC patients. The CD-CRC patients had a lower frequency of Duke's A and B stage tumors (36% versus 42%), a higher frequency of Duke's C stage tumors (31% versus 27%) and Duke's D-stage tumors (23% versus 21%), and a similar frequency of unknown stage tumors (10%) compared with non-IBD-CRC patients. After 5-years of follow-up, 59% of the UC and the non-UC-CRC patients had died compared with 62% of the patients with CD and 56% of the non-CD-CRC patients. The 5-year adjusted mortality rate ratios for patients with UC or CD were 1.14 (95% confidence interval, 1.03-1.27) and 1.26 (95% confidence interval, 1.07-1.49), respectively, compared with patients without IBD. CONCLUSION: A history of IBD in patients with CRC may be associated with increased mortality. PMID- 23435403 TI - Infliximab-associated psoriasis in children with Crohn's disease may require withdrawal of anti-tumor necrosis factor therapy. PMID- 23435404 TI - Diabetes education kiosks in a latino community. AB - PURPOSE: The purpose of this study was to examine the implementation, use, and sustainability of a computerized touch-screen diabetes education kiosk (Diosk) designed to provide "on-demand" education in a predominantly Latino community in South Texas. METHODS: A pilot study was conducted to examine the implementation, use, and sustainability of the Diosk in 5 settings (e.g., clinics, community centers, and pharmacies) serving low-income, low-literacy populations. Both quantitative and qualitative data from embedded computerized usage tracking, user surveys, and key stakeholder interviews were collected and analyzed using descriptive statistics. RESULTS; There were more than 5300 uses of the Diosk in the different sites during the 11-month study. The majority of users were female, between the ages of 36 and 64 years, and Latino, and they identified themselves as having or being at risk for type 2 diabetes. Several challenges were faced in maintaining the Diosk during the study, such as organizational capacity to host wireless Internet and establishing "office champions" responsible for overseeing the Diosk. At the end of the study, 3 of the 5 sites committed to sustaining the Diosk on their own. CONCLUSIONS: This pilot study testing the feasibility and acceptability of the Diosk demonstrated that a Diosk can be implemented, used, and sustained in a population with high rates of diabetes and limited prior use of disease management programs. Computerized technology offers one solution to expanding the reach of diabetes education through easily accessible community and clinical settings. PMID- 23435405 TI - Synthesis and structures of tridentate ketoiminate zinc complexes bearing trifluoromethyl substituents that act as L-lactide ring opening polymerization initiators. AB - A series of NNO ketoimines bearing trifluoromethyl substituents were synthesized from the Schiff base condensation of 1,3-diketones (1,1,1-trifluoro-5,5-dimethyl 2,4-hexanedione, 4,4,4-trifluoro-1-phenyl-1,3-butanedione, and 1,1,1-trifluoro 2,4-pentanedione, 1,1,1,5,5,5-hexafluoroacetylacetone) and 8-aminoquinoline or 8 amino-2-methylquinoline and isolated in 40-70% yield. The ketoimines were combined with zinc bis-(trimethylsilyl)amide to prepare a zinc amide complex in 41% yield or were combined with zinc bis-(trimethylsilyl)amide and 2,6-di-tert butylphenol to prepare zinc phenoxide complexes in 81-94% yield. The ketoimines and zinc complexes were characterized with (1)H, (13)C, and (19)F NMR, absorbance spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. The mononuclear solid state structures of the zinc amide and phenoxide complexes showed tridentate coordination of the zinc center by the ketoiminate and monodentate coordination by the amide or phenoxide. The zinc complexes were assessed for their ability to catalyze the ring opening polymerization (ROP) of L lactide into poly-lactic acid (PLA) with some complexes reaching 100% conversion in 3 h. As the monomer to catalyst ratio increased, the molecular weight of the isolated polymeric material increased in a nearly linear fashion while retaining a narrow molecular weight distribution. Homonuclear decoupled (1)H NMR spectra of the isolated polymeric material showed the retention of stereochemistry in the isotactic poly-L-lactic acid. Kinetic studies, where the substituents on the ketoiminate and quinolyl moiety were varied, showed that lower electron density on the Zn metal center yielded lower ROP catalytic activity than their electron rich counterparts. The complexes are proposed to use the coordination-insertion mechanism for living polymerization of L-lactide. PMID- 23435406 TI - Associations between indicators of screen time and adiposity indices in Portuguese children. AB - OBJECTIVES: To examine associations between three types of screen time (TV, electronic games (EG), and personal computer (PC)) and two proxies of adiposity (body mass index (BMI) and sum of skinfolds) in children. DESIGN: The sample comprised 17,509 children aged 2-13 years who participated in the 2009/10 Portuguese Prevalence Study of Obesity in Childhood. METHODS: Complex samples generalised linear models, using school as a cluster variable were ran separately for each combination of ST predictor and adiposity-related outcome, adjusting for covariates including age, sex, physical activity, diet, and parental factors. Missing values in predictors and covariates were imputed. RESULTS: Watching TV for >2h/day compared to <1h/day was associated with higher age- and sex-specific BMI standard deviation score (coefficient: 0.06, 95% CI: 0.01 to 0.12, linear trend p=0.008) and sum of skinfolds (logged and back transformed 0.04, 0.02 to 0.07, p=<0.001). We also found weak evidence for an inverse association between PC and BMI. CONCLUSIONS: Associations between ST and adiposity differ by both type of ST and type of adiposity marker. Only TV viewing was consistently associated with adiposity. Studies using a single adiposity marker looking at total screen time or total sedentary behaviour time may miss or confound type specific associations. PMID- 23435407 TI - A new two-dimensional oligothiophene end-capped with alkyl cyanoacetate groups for highly efficient solution-processed organic solar cells. AB - A new two-dimensional small molecule (DCA3T(VT)BDT) with an acceptor-donor acceptor framework showed a high power conversion efficiency of 4% with a high fill factor of up to 0.63 in solution-processed organic solar cells. PMID- 23435408 TI - Expression of the transcription factor Sp1 and its regulatory hsa-miR-29b in peripheral blood mononuclear cells from patients with Alzheimer's disease. AB - Altered gene expression occurs in central nervous system disorders, including Alzheimer's disease (AD). Transcription factor Sp1 (specificity protein 1) can regulate the expression of several AD-related proteins, including amyloid-beta protein precursor and tau. Sp1 is regulated by oxidative stress, and Sp1 mRNA was found to be upregulated in AD cortex and hippocampus. The distribution of three single nucleotide polymorphisms (SNPs), including rs7300593, rs17695156, and rs12821290, covering 100% Sp1 genetic variability, has been determined in a population of 393 AD patients as compared with 412 controls. In addition, expression analysis of Sp1 and its regulatory microRNAs (hsa-miR-29b and hsa-miR 375) has been performed in peripheral blood mononuclear cells (PBMCs), together with Sp1 protein analysis. No differences in all three SNP distributions were observed in AD patients as compared with controls. Stratifying according to gender, a significantly decreased frequency of Sp1 rs17695156 T allele was observed in male patients versus male controls. Significantly increased Sp1 relative expression levels were observed in PBMCs from AD patients as compared with controls. Western blot analysis paralleled mRNA increase in AD patients versus controls and correlated positively with Sp1 mRNA levels. Significantly decreased relative expression levels of hsa-miR-29b, but not of hsa-miR-375, were observed in AD patients versus controls and correlated negatively with Sp1 mRNA levels. According to these results, Sp1 and its regulatory hsa-miR-29b are deregulated in AD patients, possibly leading to aberrant production of downstream target genes involved in the pathogenesis. Moreover, Sp1 rs176951056 T allele is likely a protective factor in the male population. PMID- 23435409 TI - Novel evidence of phenotypical variability in the hexanucleotide repeat expansion in chromosome 9. AB - C9ORF72 repeat expansion is currently considered as a major genetic cause of amyotrophic lateral sclerosis (ALS) and, in particular, of combined frontotemporal dementia-motor neuron disorder (FTD-MND) pedigrees. Studies of large series of patients have indicated that various phenotypic presentations may be observed even in the same family. Here, we describe four patients carrying a C9ORF72 mutation with heterogeneous clinical presentation sharing a rapid disease course. Cases #1 and #2 presented with predominant semantic deficits, accompanied in one patient by clinical signs of ALS. Case #3 showed a phenotype compatible with a diagnosis of behavioral variant of FTD. Case #4 presented with memory impairments, apathy, and social withdrawal, and had negative cerebrospinal fluid markers for Alzheimer's disease. Two patients showed a positive familiar history of MND and dementia (at least one first-degree family member affected). The two other patients were apparently sporadic cases. Our data provide further evidence for the heterogeneity of phenotypes associated with the C9ORF72 mutation and indicate its association with a fluent progressive aphasia phenotype. The present findings confirm the importance of screening for the hexanucleotide repeat expansion in chromosome 9 in the case not only of familial, but also of sporadic FTD, and in the presence of atypical cognitive disorders. PMID- 23435410 TI - Pre-progression rates in Alzheimer's disease revisited. AB - BACKGROUND: Pre-progression rates (PPR) in Alzheimer's disease (AD) have been reported to be associated with cognitive and functional decline. OBJECTIVE: The objective was to reevaluate PPRs in a prospective cohort of AD patients. METHODS: A prospective AD cohort was analyzed. Multiple regression was used to examine associations of PPRs with short term decline on different cognitive and functional scales (MMSE, instrumental and basic ADL, GDS, UPDRS III). RESULTS: PPRs were only associated with first year instrumental ADL declines. CONCLUSION: The predictive abilities of PPRs could partially be confirmed. These findings can help to adapt patient care shortly after diagnosis. PMID- 23435411 TI - Molecular mechanism of tau aggregation induced by anionic and cationic dyes. AB - Abnormal tau filaments are a hallmark of Alzheimer's disease. Anionic dyes such as Congo Red, Thiazine Red, and Thioflavin S are able to induce tau fibrillization in vitro. SH-SY5Y cells were incubated with each dye for seven days leading to intracellular aggregates of tau protein, with different morphological characteristics. Interestingly, these tau aggregates were not observed when the Methylene Blue dye was added to the cell culture. In order to investigate the molecular mechanisms underlying this phenomenon, we developed a computational model for the interaction of the tau paired helical filament (PHF) core with every dye by docking analysis. The polar/electrostatic and nonpolar contribution to the free binding energy in the tau PHF core-anionic dye interaction was determined. We found that the tau PHF core can generate a positive net charge within the binding site localized at residuesLys311 and Lys340 (numbering according to the longest isoform hTau40). These residues are important for the binding affinity of the negative charges present in the anionic dyes causing an electrostatic environment that stabilizes the complex. Tau PHF core protofibril-Congo Red interaction has a stronger binding affinity compared to Thiazine Red or Thioflavin S. By contrast, the cationic dye Methylene Blue does not bind to nor stabilize the tau PHF core protofibrils. These results characterize the driving forces responsible for the binding of tau to anionic dyes leading to their self-aggregation and suggest that Methylene Blue may act as a destabilizing agent of tau aggregates. PMID- 23435412 TI - Alzheimer's disease: the downside of a highly evolved parietal lobe? AB - Clinical grade Alzheimer's disease (AD) is only described in humans. Recent imaging studies in early AD patients showed that the parietal areas display the most prominent metabolic impairments. So far, neuroimaging studies have not been able to explain why the medial parietal regions possess this hub characteristic in AD. Paleoneurological and neuroanatomical studies suggest that our species, Homo sapiens, has a unique and derived organization of the parietal areas, which are involved in higher cognitive functions. Combining evidence from neuroimaging, paleontology, and comparative anatomy, we suggest that the vulnerability of the parietal lobe to neurodegenerative processes may be associated with the origin of our species. The species-specific parietal morphology in modern humans largely influenced the brain spatial organization, and it involved changes in vascularization and energy management, which may underlie the sensitivity of these areas to metabolic impairment. Metabolic constraints and anatomical evolutionary changes in the medial parietal regions of modern humans may be important in early AD onset. Taking into account the species-specific adaptations of the modern human parietal areas and their association with AD, we hypothesize that AD can be the evolutionary drawback of the specialized structure of our parietal lobes. The cognitive advantage is associated with increased sensitivity to neurodegenerative processes which, being limited to the post-reproductive period, have a minor effect on the overall genetic fitness. The changes of energy requirements associated with form and size variations at the parietal areas may support the hypothesis of AD as a metabolic syndrome. PMID- 23435414 TI - Dynamic analysis of modified transcutaneous lower blepharoplasty based on biochemical and biophysical principles. AB - In this study, we analyzed the key parameters of modified transcutaneous lower blepharoplasty based on multidisciplinary principles (biochemical findings and biophysical wrinkling theory). A total of 408 female patients received our subciliary lower blepharoplasty between March 2002 and January 2010. The severity of the eyebags (dynamic wrinkle numbers and prolapse) was evaluated through preoperative and postoperative photography, whereas the excised lower eyelid skin specimens from 56 patients were investigated with hematoxylin and eosin staining. The modified techniques produced significant improvements in the severity of eyebags in all age groups (P < 0.001). Poor surgical outcome was found to correlate significantly with preoperative dynamic wrinkle numbers (P < 0.001). Age, dynamic wrinkle numbers, and prolapse correlated significantly with dermal fiber density (P = 0.004, 0.000, and 0.000, respectively) but not epidermal, rete ridge, and dermal thickness or the number of rete ridges. In conclusion, modified transcutaneous lower blepharoplasty provides significant improvement to dynamic wrinkles and prolapse in the eyebags. Periorbital aging progressively disturbs the dermal compactness (fiber density) until the structure can no longer hold its integrity at the critical age (around the age of 40). PMID- 23435415 TI - Selective regulation of p38beta protein and signaling by integrin-linked kinase mediates bladder cancer cell migration. AB - Integrin-linked kinase (ILK) and p38(MAPK) are protein kinases that transduce extracellular signals regulating cell migration and actin cytoskeletal organization. ILK-dependent regulation of p38(MAPK) is critical for mammalian kidney development and in smooth muscle cell migration, however, specific p38 isoforms has not been previously examined in ILK-regulated responses. Signaling by ILK and p38(MAPK) is often dysregulated in bladder cancer, and here we report a strong positive correlation between protein levels of ILK and p38beta, which is the predominant isoform found in bladder cancer cells, as well as in patient matched normal bladder and tumor samples. Knockdown by RNA interference of either p38beta or ILK disrupts serum-induced, Rac1-dependent migration and actin cytoskeletal organization in bladder cancer cells. Surprisingly, ILK knockdown causes the selective reduction in p38beta cellular protein level, without inhibiting p38beta messenger RNA (mRNA) expression. The loss of p38beta protein in ILK-depleted cells is partially rescued by the 26S proteasomal inhibitor MG132. Using co-precipitation and bimolecular fluorescent complementation assays, we find that ILK selectively forms cytoplasmic complexes with p38beta. In situ proximity ligation assays further demonstrate that serum-stimulated assembly of endogenous ILK-p38beta complexes is sensitive to QLT-0267, a small molecule ILK kinase inhibitor. Finally, inhibition of ILK reduces the amplitude and period of serum-induced activation of heat shock protein 27 (Hsp27), a target of p38beta implicated in actin cytoskeletal reorganization. Our work identifies Hsp27 as a novel target of ILK-p38beta signaling complexes, playing a key role in bladder cancer cell migration. PMID- 23435416 TI - JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells. AB - Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and characteristically show features of developing skeletal muscle. The alveolar subtype is frequently associated with a PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated myogenic phenotype of RMS cells. Histone methylation of lysine residues controls developmental processes in both normal and malignant cell contexts. Here we show that JARID2, which encodes a protein known to recruit various complexes with histone-methylating activity to their target genes, is significantly overexpressed in RMS with PAX3-FOXO1 compared with the fusion gene-negative RMS (t-test; P < 0.0001). Multivariate analyses showed that higher JARID2 levels are also associated with metastases at diagnosis, independent of fusion gene status and RMS subtype (n = 120; P = 0.039). JARID2 levels were altered by silencing or overexpressing PAX3-FOXO1 in RMS cell lines with and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein. Silencing JARID2 resulted in reduced cell proliferation coupled with myogenic differentiation, including increased expression of Myogenin (MYOG) and Myosin Light Chain (MYL1) in RMS cell lines representative of both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a decrease in JARID2 levels and this phenotype could be rescued by overexpressing JARID2. Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent on EED, a core component of the polycomb repressive complex 2 (PRC2). Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients. PMID- 23435417 TI - CD84 is a survival receptor for CLL cells. AB - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and bone marrow. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the signaling lymphocyte activating molecule family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both downmodulation of CD84 expression and its immune-mediated blockade induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 (milatuzumab), shows a decrease in CD84 messenger RNA and protein levels in milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 expression. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway. PMID- 23435418 TI - HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade. AB - Treatment with histone deacetylase inhibitors (HDACI) results in potent cytotoxicity of a variety of cancer cell types, and these drugs are used clinically to treat hematological tumors. They are known to repress the transcription of ERBB2 and many other oncogenes, but little is known about this mechanism. Using global run-on sequencing (GRO-seq) to measure nascent transcription, we find that HDACI cause transcriptional repression by blocking RNA polymerase II elongation. Our data show that HDACI preferentially repress the transcription of highly expressed genes as well as high copy number genes in HER2+ breast cancer genomes. In contrast, genes that are activated by HDACI are moderately expressed. We analyzed gene copy number in combination with microarray and GRO-seq analysis of expression level, in normal and breast cancer cells to show that high copy number genes are more likely to be repressed by HDACI than non-amplified genes. The inhibition of transcription of amplified oncogenes, which promote survival and proliferation of cancer cells, might explain the cancer-specific lethality of HDACI, and may represent a general therapeutic strategy for cancer. PMID- 23435419 TI - CTGF is a therapeutic target for metastatic melanoma. AB - Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF 1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression. PMID- 23435420 TI - siRNA screening identifies differences in the Fanconi anemia pathway in BALB/c Trp53+/- with susceptibility versus C57BL/6-Trp53+/- mice with resistance to mammary tumors. AB - BALB/c mice heterozygous for Trp53 develop a high proportion of spontaneous mammary tumors, a phenotype distinct from other mouse strains. BALB/c-Trp53+/- female mice, thus, resemble the hereditary Li-Fraumeni syndrome (LFS) characterized by early-onset of breast cancer, even though LFS involves TP53 mutations, which may involve not only loss- but also gain-of-function. Previous analysis of tumors in BALB/c-Trp53+/- females showed frequent loss of heterozygosity involving the wild-type allele of Trp53 and displayed characteristics indicative of mitotic recombination. Critical involvement of DNA double-strand break (DSB) repair dysfunction, particularly of homologous recombination (HR), was also noticed in the etiology of human breast cancer. To better define functional alterations in BALB/c-Trp53+/- mice, we applied a fluorescence-based DSB repair assay on mouse embryonic fibroblasts (MEFs) from BALB/c-Trp53+/- versus C57BL/6J-Trp53+/- mice. This approach revealed deregulation of HR but not non-homologous end-joining (NHEJ) in BALB/c-Trp53+/-, which was further confirmed for mammary epithelial cells. Screening of a small interfering RNA-library targeting DSB repair, recombination, replication and signaling genes, identified 25 genes causing differences between homologous DSB repair in the two strains upon silencing. Interactome analysis of the hits revealed clustering of replication-related and fanconi anemia (FA)/breast cancer susceptibility (BRCA) genes. Further dissection of the functional change in BALB/c-Trp53+/- by immunofluorescence microscopy of nuclear 53BP1, Replication protein A (RPA) and Rad51 foci uncovered differences in crosslink and replication associated repair. Chromosome breakage, G2 arrest and biochemical analyses indicated a FA pathway defect downstream of FancD2 associated with reduced levels of BRCA2. Consistent with polygenic models for BRCA, mammary carcinogenesis in BALB/c-Trp53+/- mice may, therefore, be promoted by a BRCA modifier allele in the FA pathway in the context of partial p53 loss-of-function. PMID- 23435421 TI - PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling. AB - It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease. PMID- 23435422 TI - MYC activity is negatively regulated by a C-terminal lysine cluster. AB - The MYC oncogene is not only deregulated in cancer through abnormally high levels of expression, but also through oncogenic lesions in upstream signalling cascades. Modelling MYC deregulation using signalling mutants is a productive research strategy. For example, the MYC threonine-58 to alanine substitution mutant (T58A) within MYC-homology box 1 is more transforming than wild-type (WT) MYC, because of decreased apoptosis and increased protein stability. Understanding the regulatory mechanisms controlling T58 phosphorylation has led to new approaches for the development of MYC inhibitors. In this manuscript, we have extensively characterized a MYC signalling mutant in which six lysine residues near the highly conserved MYC homology box IV and basic region have been substituted to arginines (6KR). Previous literature suggests these lysines can undergo both ubiquitylation and acetylation. We show MYC 6KR is able to fully rescue the slow growth phenotype of HO15.19 MYC-null fibroblasts, and promote cell cycle entry of serum-starved MCF10A cells. Remarkably, 6KR increased anchorage-independent colony growth compared with WT MYC in both SH-EP and MCF10A cells. Moreover, it was also more potent in promoting xenograft tumour growth of Rat1A and SH-EP cells. Combined, our data identify this region and these six lysines as important residues for the negative regulation of MYC-induced transformation. Mechanistically, we demonstrate that, unlike T58A, the increased transformation is not a result of increased protein stability or a reduced capacity for 6KR to induce apoptosis. Through expression analysis and luciferase reporter assays, we show that 6KR has increased transcriptional activity compared with WT MYC. Combined, through a comprehensive evaluation across multiple cell types, we identify an important regulatory region within MYC. A better understanding of the full scope of signalling through these residues will provide further insights into the mechanisms contributing to MYC-induced tumorigenesis and may unveil novel therapeutic strategies to target Myc in cancer. PMID- 23435423 TI - The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion. AB - The epithelial-mesenchymal transition (EMT), a prerequisite for cancer progression and metastasis formation, is regulated not only at the transcriptional but also at the post-transcriptional level, including at the level of alternative pre-mRNA splicing. Several recent studies have highlighted the involvement of splicing factors, including epithelial splicing regulatory proteins (Esrps) and RNA-binding Fox protein 2 (Rbfox2), in this process. Esrps regulate epithelial-specific splicing, and their expression is downregulated during EMT. By contrast, the role of Rbfox2 is controversial because Rbfox2 regulates epithelial as well as mesenchymal splicing events. Here, we have used several established cell culture models to investigate the functions of Rbfox2 during EMT. We demonstrate that induction of an EMT upregulates the expression of Rbfox2, which correlates with an increase in Rbfox2-regulated splicing events in the cortactin (Cttn), Pard3 and dynamin 2 (Dnm2) transcripts. At the same time, however, the epithelial-specific ability to splice the Enah, Slk and Tsc2 transcripts is either reduced or lost completely by Rbfox2, which might be due, in part, to downregulation of the expression of the Esrps cooperative factors. Depletion of Rbfox2 during EMT did not prevent the activation of transforming growth factor-beta signaling, the upregulation of mesenchymal markers or changes in cell morphology toward a mesenchymal phenotype. In addition, this depletion did not influence cell migration. However, depletion of Rbfox2 in cells that have completed an EMT significantly reduced their invasive potential. Taken together, our results suggest that during an EMT, Rbfox2-regulated splicing shifts from epithelial-to mesenchymal-specific events, leading to a higher degree of tissue invasiveness. PMID- 23435424 TI - IGFBP-2 nuclear translocation is mediated by a functional NLS sequence and is essential for its pro-tumorigenic actions in cancer cells. AB - IGFBP-2 is highly expressed in both the serum and tumor tissues of most cancers, and is considered one of the most significant genes in the signature of major cancers. IGFBP-2 mainly modulates IGF actions in the pericellular space; however, there is considerable evidence to suggest that IGFBP-2 may also act independently of the IGFs. These IGF-independent actions of IGFBP-2 are exerted either via interactions at the cell surface or intracellularly, via interaction with cytoplasmic or nuclear-binding partners. The precise mechanism underlying the intracellular/intranuclear localization of IGFBP-2 remains unclear. In this study, we investigated IGFBP-2 nuclear localization in several common cancer cells with the aim of dissecting the mechanism of its nuclear trafficking. IGFBP 2 is detected in the nuclei of common cancer cells, including breast, prostate and several neuroblastoma cell lines, using cell fractionation and confocal microscopy. Via nuclear import assays, we show that nuclear entry of IGFBP-2 is mediated by the classical nuclear import mechanisms, primarily through importin alpha, as demonstrated by the use of blocking, competition and co immunoprecipitation assays. Bioinformatics analysis of the IGFBP-2 protein sequence with PSORT II identified a classical nuclear localization signal (cNLS) sequence at 179PKKLRPP185, within the IGFBP-2 linker domain, mutagenesis of which abolishes IGFBP-2 nuclear import. Accordingly, the NLSmutIGFBP-2 fails to activate the VEGF promoter, which would otherwise occur in the presence of wild type IGFBP-2. As a consequence, no activation of angiogenic processes were observed in NLSmutIGFBP-2 expressing SHEP cells when implanted onto our in vivo quail chorio-allantoic membrane model. Taken together, these data show for the first time that IGFBP-2 possesses a functional NLS sequence and that IGFBP-2 actively translocates into the nucleus by a classical nuclear import mechanism, involving formation of IGFBP-2 complexes with importin-alpha. Nuclear IGFBP-2 is required for the activation of VEGF expression and consequent angiogenesis. PMID- 23435425 TI - ELF3 is a repressor of androgen receptor action in prostate cancer cells. AB - The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and consequently deregulation of cofactor expression and/or activity impacts the expression of genes whose products can have a role in PC pathogenesis. Here we report that E74-like factor 3 (ELF3), a member of the ETS family of transcription factors, is a repressor of AR transcriptional activity. Exogenous expression of ELF3 represses AR transcriptional activity when assessed using reporter-based transfection assays or when evaluated on endogenous AR target genes. Conversely, ELF3 knock down increases the AR transcriptional activity. Biochemical dissection of this activity indicates that it results from the physical interaction between ELF3 and AR and that this interaction inhibits the recruitment of AR to specific androgen response elements within target gene promoters. Significantly, we observed that depletion of ELF3 expression in LNCaP cells promotes cell migration, whereas increased ELF3 expression severely inhibits tumor growth in vitro and in a mouse xenograft model. Taken together, these results suggest that modulation of ELF3 expression and/or AR/ELF3 interaction may have utility in the treatment of PC. PMID- 23435426 TI - PELO negatively regulates HER receptor signalling and metastasis. AB - The HER family is composed of four receptor tyrosine kinases, which are frequently deregulated in several types of cancer. Activated HER receptors initiate intracellular signalling pathways by attracting to the plasma membrane a plethora of adaptor and signalling molecules. Although there are more than a dozen HER-interacting proteins that regulate signal transduction and have been extensively studied, recent proteomic studies have shown the existence of many novel but largely uncharacterized factors that may bind HER receptors. In this report, we describe a cell-based identification of several new HER2-binding proteins, including HAX1, YWHAZ, PELO and ACP1. Analysis of these factors showed that one of them, PELO, binds to active HER2 and epidermal growth factor receptor and thereby attenuates phosphatidylinositol 3-kinase (PI3K)/AKT signalling, likely through regulation of the recruitment of p85-PI3K to activated receptor. Functional characterization of PELO showed that it negatively regulates cell migration and metastasis in vivo. These results reveal that PELO is a novel regulator of HER-signalling and therefore is likely to have a role in inhibiting tumour progression and invasion. PMID- 23435427 TI - HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome. AB - Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene previously identified in a metastasis screen by our group, contributes to melanoma progression. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveals upregulation of factors involved in diverse cytokine pathways that include the transforming growth factor beta (TGFbeta) signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion in melanoma cells. Transcriptome profiling also shows HOXA1's ability to potently downregulate expression of microphthalmia associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression de differentiates cells into a pro-invasive cell state concomitant with TGFbeta activation. Our analysis of publicly available data sets indicate that the HOXA1 induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors. Together, these validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFbeta therapy in adjuvant settings. Moreover, further analysis of HOXA1 target genes in melanoma may reveal new pathways or targets amenable to therapeutic intervention. PMID- 23435428 TI - Activation of beta-catenin/TCF targets following loss of the tumor suppressor SNF5. AB - The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies beta-catenin hyperactivation and that SNF5 is essential for regulating Wnt/beta-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control. PMID- 23435429 TI - NF-kappaB is a critical mediator of BRCA1-induced chemoresistance. AB - BRCA1 mediates resistance to apoptosis in response to DNA-damaging agents, causing BRCA1 wild-type tumours to be significantly more resistant to DNA damage than their mutant counterparts. In this study, we demonstrate that following treatment with the DNA-damaging agents, etoposide or camptothecin, BRCA1 is required for the activation of nuclear factor-kappaB (NF-kappaB), and that BRCA1 and NF-kappaB cooperate to regulate the expression of the NF-kappaB antiapoptotic targets BCL2 and XIAP. We show that BRCA1 and the NF-kappaB subunit p65/RelA associate constitutively, whereas the p50 NF-kappaB subunit associates with BRCA1 only upon DNA damage treatment. Consistent with this BRCA1 and p65 are present constitutively on the promoters of BCL2 and XIAP, whereas p50 is recruited to these promoters only in damage treated cells. Importantly, we demonstrate that the recruitment of p50 onto the promoters of BCL2 and XIAP is dependent upon BRCA1, but independent of its NF-kappaB partner subunit p65. The functional relevance of NF-kappaB activation by BRCA1 in response to etoposide and camptothecin is demonstrated by the significantly reduced survival of BRCA1 wild type cells upon NF-kappaB inhibition. This study identifies a novel BRCA1-p50 complex, and demonstrates for the first time that NF-kappaB is required for BRCA1 mediated resistance to DNA damage. It reveals a functional interdependence between BRCA1 and NF-kappaB, further elucidating the role played by NF-kappaB in mediating cellular resistance of BRCA1 wild-type tumours to DNA-damaging agents. PMID- 23435430 TI - ATM kinase activity modulates ITCH E3-ubiquitin ligase activity. AB - Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3 ubiquitin ligase that modulates the ubiquitination of several targets, therefore participating to the regulation of several cellular responses, such as the DNA damage response, tumor necrosis factoralpha (TNFalpha), Notch and Hedgehog signaling, and the differentiation of 'naive' lymphocytes into T helper type 2 cells. Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. ATM activity enhances ITCH enzymatic activity, which in turn drives the ubiquitination and degradation of c-FLIP-L and c-Jun, previously identified as ITCH substrates. Importantly, ATM-deficient mice show resistance to hepatocyte cell death, similarly to Itch-deficient animals, providing in vivo genetic evidence for this circuit. Our data identify ITCH as a novel component of the ATM dependent signaling pathway and suggest that the impairment of the correct functionality of ITCH caused by Atm deficiency may contribute to the complex clinical features linked to Ataxia Telangiectasia. PMID- 23435431 TI - Myocyte enhancer factor 2C in hematopoiesis and leukemia. AB - MEF2C is a selectively expressed transcription factor involved in different transcriptional complexes. Originally identified as an essential regulator of muscle development, ectopic expression of MEF2C as a result of chromosomal rearrangements is now linked to leukemia. Specifically, high MEF2C expression has been linked to mixed lineage leukemia-rearranged acute myeloid leukemia as well as to the immature subgroup of T-cell acute lymphoblastic leukemia. This review focuses on the role of MEF2C in the hematopoietic system and on aberrant MEF2C expression in human leukemia. PMID- 23435432 TI - Polyelectrolyte mediated intra and intermolecular crosslinking in microgel-based etalons for sensing protein concentration in solution. AB - Biotin modified polycationic polymers are capable of penetrating the Au overlayer of poly(N-isopropylacrylamide)-co-acrylic acid microgel-based etalons. Once penetrated, the polycations crosslink the polyanionic microgels, causing them to collapse, resulting in a concomitant blue shift of the spectral peaks in the reflectance spectrum. We show that the magnitude of the blue shift depends on the concentration of the biotinylated polycation solution exposed to the etalon. This behavior is subsequently used for biosensing applications. PMID- 23435433 TI - The effect of Medicaid physician fees on take-up of public health insurance among children in poverty. AB - I investigate how changes in fees paid to Medicaid physicians affect take-up among children in low-income families. The existing literature suggests that the low level of Medicaid fee payments to physicians reduces their willingness to see Medicaid patients, thus creating an access-to-care problem for these patients. For the identical service, current Medicaid reimbursement rates are only about 65 percent of those covered by Medicare. Increasing the relative payments of Medicaid would increase its perceived value, as it would provide better access to health care for Medicaid beneficiaries. Using variation in the timing of the changes in Medicaid payment across states, I find that increasing Medicaid generosity is associated with both an increase in take-up and a reduction in uninsured rate. These results provide a partial answer to the puzzling question of why many low-income children who are eligible for Medicaid remain uninsured. PMID- 23435434 TI - Effects of intracerebroventricular ghrelin on food intake and Fos expression in the arcuate nucleus of the hypothalamus in female rats vary with estrous cycle phase. AB - Intracerebroventricular (icv) injection of ghrelin increases food intake via activation of neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons, which express growth hormone secretagogue receptor type 1a (GHS-R1a), in the arcuate nucleus of the hypothalamus (Arc) in male rats. Conversely, elevation in endogenous estrogens or exogenous estrogens decreases food intake, but the precise mechanism mediating this estrogenic effect is unknown. We studied whether the effects of icv ghrelin on food intake and on the expression of Fos, a marker of neuron activation, vary with estrous cycle phase in female rats. Icv ghrelin (100pmol) significantly increased food intake after injection in diestrus, but it did not affect food intake in proestrus during light phase. Icv ghrelin increased the number of Fos-positive neurons in the Arc both in proestrus and diestrus; however, a significantly larger number of Fos-positive neurons appeared in diestrus than in proestrus. Real-time RT-PCR analysis showed no significant difference in GHS-R1a mRNA expression levels in the mediobasal hypothalamus between diestrus and proestrus. These results indicated that not only the orexigenic effect but also the Fos-inducing effect of icv ghrelin were influenced by the estrous cycle phase; and both effects were reduced in proestrus but not in diestrus. Most NPY/AgRP neurons seemed to be influenced indirectly by estrogens during proestrus because only a few of the NPY/AgRP neurons present in the Arc express ERalpha. The change in GHS-R1a expression levels in the hypothalamus during estrous cycle is not probably involved in the estrous cycle-induced changes in ghrelin action because there was no difference in GHS-R1a mRNA expression between diestrus and proestrus. PMID- 23435435 TI - A highly enantioselective four-component reaction for the efficient construction of chiral beta-hydroxy-alpha-amino acid derivatives. AB - An enantioselective four-component reaction of a diazoketone, water, an aniline and ethyl glyoxylate in the presence of catalytic Rh2(OAc)4 and a chiral Bronsted acid was developed to efficiently produce beta-hydroxy-alpha-amino acid derivatives in good yields with high diastereoselectivity and enantioselectivity. PMID- 23435436 TI - Synthesis and catalytic activity of iron complexes with bidentate NHC ligands. AB - A family of well-defined Fe(II) complexes of the type {BnN(N-CH2(CH2)n-N'-tert butyl-imidazole-2-ylidene)2}FeCl2 (Bn = benzyl; n = 1 (1) or 2 (2)), {BnN(N CH2(CH2)n-N'-methylbenzimidazole-2-ylidene)2}FeCl2 (n = 1 (3) or 2 (4)) and {BnN(N-CH2CH2CH2-N'-methylbenzimidazole-2-ylidene)2}FeBr2 (5) has been synthesized. These complexes are rare examples of Fe species supported by bidentate NHC ligands. Complexes 2, 3, 4 and 5 were characterized by X-ray crystallography and in all cases a distorted tetrahedral geometry is observed around the Fe center. The magnetic data is consistent with the complexes containing non interacting high spin Fe(II) centers (S = 2) and indicates that a large zero-field splitting (D) is present. The new complexes are highly active pre-catalysts for the homo-coupling of Grignard reagents. PMID- 23435437 TI - Weekly topotecan for recurrent ovarian, fallopian tube and primary peritoneal carcinoma: tolerability and efficacy study--the Israeli experience. AB - OBJECTIVES: The purpose of this study was to assess the clinical activity and toxicity of weekly topotecan in a large cohort of epithelial ovarian (EOC), primary peritoneal (PPC), and tubal cancer patients. METHODS: Records of patients with recurrent EOC, PPC, and tubal cancer who were treated with weekly topotecan (4.0 mg/m on days 1, 8, and 15 on a 28-day cycle) after failure of more than 1 prior regimen were retrospectively reviewed in 8 centers in Israel. RESULTS: Two hundred four patients were evaluated for efficacy and toxicity. Median age was 62 years (range, 27-89 years); 121 (59.3%) were platinum sensitive. Patients were exposed to a median of 2 previous lines (range, 1-9), and 48.5% received only 1 prior chemotherapy regimen. Median follow-up was 15.5 months (range, 2.5-112 months). Overall response rate was 26.5%, of which 11 patients (5.4%) had complete response, and 43 patients (21.1%) had partial response. Clinical benefit rate (complete response + partial response + stable disease) was 65.7%. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.5-4.5 months). There was no significant difference between platinum-sensitive and platinum-resistant patients regarding response rate or progression-free survival. Median overall survival from disease diagnosis was 45.0 months (95% CI, 40.04 49.6 months) and 16.0 months (95% CI, 12.3-19.7 months) from initiation of topotecan therapy. Overall survival was significantly different between patients with platinum-sensitive and platinum-resistant disease (19.9 vs. 10.8 months, respectively, P = 0.003; 95% CI, 8.1-16.3 months). Multivariate analysis showed that only platinum sensitivity and topotecan line were associated with overall survival. Weekly topotecan was well tolerated-with only 16.7% of patients experiencing grade 3 to 4 hematologic toxicities. There were no other grade 4 toxicities, and only 6.9% grade 3 toxicities. CONCLUSIONS: In this large cohort of recurrent EOC, PPC, and tubal cancer, weekly topotecan was well tolerated with good clinical benefit rate, comparable to previous studies. PMID- 23435438 TI - Stages I to II WHO 2003-defined low-grade endometrial stromal sarcoma: how much primary therapy is needed and how little is enough? AB - OBJECTIVE: Before 2003, invasive endometrial stromal sarcomas (ESS) were classified into 2 categories, low-grade and high-grade ESS, according to the mitotic index. In 2003, the World Health Organization changed the definition and the diagnostic criteria. Before 2003, 20% to 35% low-grade ESS recurred, but WHO 2003-defined low-grade ESS has 10 years' recurrence rates of less than 10%. With so few recurrences, the balance between treatment guaranteeing cure and overtreatment ("not too little" or "too much") becomes increasingly important. However, primary treatment practices range from limited surgery only to extensive surgery combined with adjuvant chemotherapy and radiotherapy. We focused on the primary treatment of early-stage WHO 2003-defined low-grade ESS. METHODS: We evaluated the effect of different therapeutic strategies in 57 patients with International Federation of Gynecology and Obstetrics 2009 stages I to II expert reviewed WHO 2003-defined low-grade ESS treated at a single institution between 1992 and 2007. RESULTS: The patients' median age was 43 years (range, 19-63 years). After 68 months' median follow-up (range, 17-140 months), recurrence and mortality rates were 9% and 2%, respectively. The patients with WHO 2003-defined low-grade ESS with ovary-preserving primary surgery had a much higher recurrence rate (75%) than those without (2%; P < 0.0001). Lymphadenectomy, radical abdominal hysterectomy, and omentectomy did not influence survival. Ten patients refused chemotherapy. With univariate analysis, multiple-agent chemotherapy improved the prognosis (P = 0.02) With multivariate analysis, only ovary preservation-or-not surgery had independent prognostic value. CONCLUSIONS: In International Federation of Gynecology and Obstetrics 2009 stage I to stage II WHO 2003-defined low-grade ESS, total abdominal hysterectomy with bilateral salpingo-oophorectomy is sufficient surgery, but ovary-preserving primary surgery increases the risk of recurrence. More extensive surgical procedures than total abdominal hysterectomy with bilateral salpingo-oophorectomy do not improve prognosis in early-stage WHO 2003-defined low-grade ESS. Chemotherapy may improve progression-free survival in early-stage low-grade ESS, but a large sample size is needed to confirm this. PMID- 23435439 TI - Growth hormone deficiency: an update. AB - Growth hormone (GH) deficiency (GHD) in humans manifests differently according to the individual developmental stage (early after birth, during childhood, at puberty or in adulthood), the cause or mechanism (genetic, acquired or idiopathic), deficiency intensity and whether it is the only pituitary-affected hormone or is combined with that of other pituitary hormones or forms part of a complex syndrome. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise mutation types and mechanisms for previously described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic, although less frequently when they are congenital and/or familial. The clinical and biochemical diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, probably because the diagnosis based on the so-called GH secretion stimulation tests will prove to be of limited usefulness for predicting therapy indications. PMID- 23435440 TI - Diagnosis and treatment of multiple endocrine neoplasia type 1 (MEN1). AB - Multiple endocrine neoplasia type 1 (MEN1; formerly known as Wermer syndrome) is a rare disorder characterized by the combined occurrence of two or more tumors involving parathyroid, pancreatic islets and anterior pituitary glands; some other tumors have also been described. In most cases it is inherited in an autosomic dominant manner but it may occur sporadically. The MEN1 gene (MEN1) is located on chromosome 11q13, it is composed of ten exons that encode a 610 amino acid protein called menin. Menin, with no homology to any other known protein, interacts with several different proteins and plays an important role in regulation of cell growth, cell cycle, genome stability and synapse plasticity. Familiar MEN1 has a high degree of penetrance with clinical or biochemical manifestations of the disease in 80% and 98%, respectively, by the fifth decade. Clinical manifestations are related to tumor localizations and their secretory products. Hyperparathyroidism is the most common feature of MEN1 (95% of patients), pancreatic islet tumors or pancreatic NET (neuroendocrine tumor) occur in 40-70% and pituitary tumors in 30-40% of MEN 1 patients. In addition, other tumors, such as adrenal cortical tumors, carcinoid tumors, lipomas, angiofibromas, colagenomas and meningiomas may be present. Occurrence of de novo mutations appear in 10% of all patients with MEN1. A correlation between genotype and phenotype has not been found and, even more, combinations of these tumors may be different in members of the same family. Untreated patients have a decreased life expectancy, with a 50% probability of death by the age of 50 years and the cause of death is mostly directly related to MEN1, being the most important causes malignant pancreatic neuroendocrine tumors (NET) and thymic carcinoids. Treatment for each type of endocrine tumor is generally similar as in non-MEN1 associated tumors, but results are less successful according to multiplicity of tumors, higher metastatic disease, larger and more aggressive tumors and more resistant to treatment. The prognosis might improve by preclinical tumor diagnosis and appropriated treatment. PMID- 23435441 TI - Glycemic management of diabetes by insulin therapy. AB - Recent technological innovations as insulin analogue formulation, devices for insulin delivery and glucose monitoring have allowed diabetic patients to improve their glycemic control and decrease their level of burden due to diabetes. Intensive insulin therapy via insulin pens, subcutaneous or intraperitoneal insulin infusions using pumps instead of vials and syringes, are associated with improved absorption reproducibility, HbA1c levels, reduced risk of hypo- or hyperglycemia, and increased quality of patient's life. These currently used systems are discussed in this review as well as the future of exogenous insulin therapy: closed loop system, the artificial pancreas, and oral insulin delivery. Glucose homeostasis is directly linked to glycemic regulated by portal insulin administration, thus endogenous insulin therapy might be the most promising treatment to "cure" diabetes. Consequently, pancreas and islet transplantation, and the bioartificial pancreas are described. PMID- 23435442 TI - Bariatric surgery for type 2 diabetes: to whom and when? AB - Achieving clinical and biochemical targets in type 2 diabetes mellitus (diabetes) is fundamental to preventing diabetic microvascular and macrovascular complications. These clinical imperatives are made more challenging in the setting of obesity. This review examines the evidence for bariatric surgery as a means of optimizing diabetes care, addressing diabetes resolution, glucose and lipid metabolism and cardiac effects. Mechanistic evidence of diabetes amelioration is summarized. The question of when bariatric surgery should be offered in the course of obesity-associated diabetes is discussed. Current guidelines and specialist society recommendations for bariatric surgery in diabetes are summarized. PMID- 23435443 TI - Overweight in polycystic ovary syndrome. An update on evidence based advice on diet, exercise and metformin use for weight loss. AB - AIM: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women affecting 5-10%. Nearly 50% are overweight or obese, which result in a more severe phenotype of PCOS. Weight loss is therefore considered the first line treatment in overweight women with PCOS. The aim of this study was to appoint evidence based and clinically applicable advises on weight loss in overweight women with PCOS. METHODS: A review of the existing literature on weight loss through lifestyle modification and/or metformin treatment in overweight women with PCOS. The primary outcome was weight loss. The clinical manifestations of hyperandrogenism and menstrual cyclicity were secondary outcomes. Metabolic parameters were not included in the present review. RESULTS: Weight loss is most effectively achieved through a 12-1500 kcal/day diet, which results in a clinically relevant weight loss. The type of diet has no implications for degree of weight loss. Physical activity has no significant additive effect on weight loss. Metformin combined with a low calorie diet has subtle additive effect on weight loss and level of androgens when compared to diet alone. CONCLUSION: Weight loss through life style changes, preferably a low calorie diet, should be the first line treatment in overweight/obese women with PCOS. Metformin can be considered as an additional treatment but has subtle additive effect. PMID- 23435444 TI - Perioperative management of pheochromocytoma: the heart of the issue. AB - Pheochromocytoma is an endocrine tumor derived from the adrenal medulla and paraganglia. Pheochromocytoma presents with a wide spectrum of symptoms, from a silent adrenal mass to cardiac arrest. Perioperative management of pheochromocytoma is critical for preventing perioperative cardiovascular complications. Traditionally, perioperative management focuses on blood pressure control, which has generated considerable controversy. In this review, we suggest that perioperative management should focus more on treating subclinical and clinical pheochromocytoma-induced cardiomyopathy. We first describe the natural history of pheochromocytoma and illustrate that cardiomyopathy is present to various degrees in patients with pheochromocytoma. We then classify pheochromocytomas into 3 groups according to the risks of developing clinical cardiomyopathy. After going over perioperative physiological changes, we propose that the need for preoperative preparation depends on the risk level of the pheochromocytoma. We present the regimens for perioperative management, emphasizing that the goals of perioperative management should extend beyond blood pressure control and include improvement of cardiac function. Perioperative management in unique clinical situations is also discussed. PMID- 23435445 TI - Insulin therapy: unmet needs and new perspectives. AB - Insulin therapy is the most physiological and effective glucose-lowering treatment for diabetic patients, in which the risk of complications increases proportionally to HbA1c levels. Intensive glucose therapy has been demonstrated to be capable of reducing microvascular risk, a benefit maintained in the long period and also accompanied by a reduction in risk of cardiovascular (CV) disease, but increasing hypoglycaemic episodes. The aim of this review is to provide an overview starting from the burden of disease and critical aspects of acceptance and self-management of insulin therapy, and a comparison of the clinical pharmacology of human and insulin analogues available at present. Insulin is an important component of intensive type 2 diabetes management but some patient/physician barriers - hypoglycemia, fear of reduced quality of life (QoL), absence of insulin preparations that allow one to fully tailor treatment to individual needs, etc. - don't make it possible to obtain an optimal insulin therapy and often also produce a low compliance with the insulin regimen (missing injections have to be considered when analyzing the reasons for suboptimal glycaemic control). Current rapid and long-acting analogues only partially solve problems linked to insulin therapy like flexibility and QoL, but hypoglycaemia still represents an important cause of hospitalization, increased health expenditure and CV mortality. New insulin preparations, like degludec, should be helpful in the future for getting over barriers linked to insulin therapy. PMID- 23435446 TI - Long-term effectiveness and safety of liraglutide in clinical practice. AB - AIM: The rising adoption of liraglutide in clinical practice calls for an update on its long-term effectiveness and safety. The aims of this paper were to review characteristics of patients treated with liraglutide under routine clinical practice conditions, to describe therapeutic schemes, to assess the durability of liraglutide after two years of therapy, to evaluate changes in clinical parameters obtained after 20-24 months and to identify elective phenotype of patients that are able to respond better to this treatment. METHODS: One diabetes outpatient clinic in Italy systematically collected data of patients receiving liraglutide every four months during a two-year follow-up. Mean levels and changes vs. baseline of HbA1c, fasting blood glucose (FBG), body weight, body mass index, waist circumference, blood pressure and lipid profile were evaluated. Rate of treatment discontinuation and side effects were also investigated. RESULTS: Overall, 205 patients were analyzed. Liraglutide was prescribed as an add-on drug in 39% of patients and as a replacement in 61%. It was used both in patients with short (21% <=5 years) and long (32% >15 years) diabetes duration and both in obese and non-obese individuals (38% BMI<=30 Kg/m2). Liraglutide was used within many different therapeutic schemes, also including insulin (20%). On average, HbA1c levels were reduced of 1% vs. baseline at each visit, but magnitude of reduction was inversely related to diabetes duration, i.e., to the preservation of beta-cell function. However, clinically relevant improvements of glycaemic control were obtained and sustained during two years in all subgroups of patients, despite of classes of diabetes duration, BMI and antidiabetic therapeutic regimen. Durability of effectiveness on body weight and waist circumference was also documented. Liraglutide treatment was also associated with a reduction of systolic blood pressure and improvement of lipid profile. Side effects, that occurred in 20% of patients during the first four months of treatment, decreased at 2% at 20 months. The rate of drop-out was 16.1% of the patients treated. CONCLUSION: The analysis of our clinical practice shows that treatment with liraglutide was safe, well tolerated and effective in reducing HbA1c, fasting blood glucose and body weight significantly, with positive effects on systolic blood pressure and lipid profile. Therefore, results of LEAD studies are substantially reproduced in the context of routine clinical practice. Even if the maximum effectiveness of liraglutide occurs in patients with short disease duration, preferably treated with metformin, also in patients with long duration of disease, treated with several drugs or in insulin therapy, the use of this GLP 1 analogue allows to obtain more than satisfactory results. Improvements in metabolic control and body weight are maintained after two years, suggesting durability and safety of liraglutide in the long run. PMID- 23435447 TI - The 17beta-hydroxysteroid dehydrogenase type 3 deficiency: a case report of an 18 year patient and review of the literature. AB - Deficiency of 17beta-hydroxysteroid dehydrogenase type 3 (17betaHSD3), an enzyme converting androstenedione (A) to testosterone (T), is a rare cause of autosomal recessive 46,XY disorder of sexual development (DSD). A 18-years phenotypically female patient from southern Italy presented with primary amenorrhea. She had deep voice, macrocephaly, enlarged and bulbous nasal tip, macrostomia, facial acne, breast asymmetry, hypoplasia of the first finger of right hand, proximal implant of the fifth metatarsus bilaterally as well as an increased muscle mass and hirsutism, with hair distribution on face, neck, chest, abdomen, pubic region and on upper and lower limbs. Genital exam showed thickened labra majora with absence of labra minora and a blind-ending pseudo-vagina with clitoris enlargement. Karyotype analysis showed a male genotype (46,XY). Hormonal evaluation showed decreased T (188 ng/dL-6.5 nmol/L) and increased A (10 ng/mL 34,96 nmol/L), considering male reference ranges, resulting in a decreased T/A ratio (0,186). MRI identified testicles in inguinal regions. Human Chorionic Gonadotropin test showed T/A ratio permanently under 0,8. These evidences were suggestive of a 46,XY DSD due to 17betaHSD3 deficiency. An homozygous mutation (IVS3 -1 G>C or c.326-1G>C) of the 17betaHSD3 gene was discovered. Psychologist identified a well determined female gender identity. It was decided to proceed with gonadectomy and vaginal enlargement by use of dilatators. CONCLUSION: The case described represents a new case of DSD due to 17betaHSD3 deficiency. This patient, raised as a girl, is diagnosed in a very late stage. The identified mutation, previously reported only in Dutch and Brazilian population, is one of 27 presently known mutations of 17betaHSD3 gene and is never reported in Italian population. PMID- 23435448 TI - Sensitisation to cereal flour allergens is a major determinant of elevated exhaled nitric oxide in bakers. AB - OBJECTIVE: Various studies of the usefulness of fractional exhaled nitric oxide (FeNO) in occupational settings remain inconclusive. The objective was to investigate the determinants of increased FeNO in bakery workers. METHODS: A cross-sectional study of 424 supermarket bakery workers used a questionnaire and serum specific IgE to wheat, rye and alpha-amylase. FeNO during the work shift were assessed using a hand-held portable sampling device (NIOX MINO). RESULTS: The median FeNO was 15 ppb, in atopics 21 ppb and current smokers 12 ppb. Increased FeNO was strongly associated with IgE to wheat independent of smoking and atopy status. In the multivariate model, IgE to wheat, current smoking, atopy and age were significantly associated with FeNO. Stratified analysis in a subgroup of atopic non-smokers demonstrated the strongest relationship between FeNO and various clinical endpoint such as wheat (OR=9.43) or rye (OR=11.76) sensitisation, work-related allergic rhinitis (OR=8.13) or asthma (OR=5.44), and probable baker's asthma (OR=6.72). CONCLUSIONS: Sensitisation to cereal flour allergens rather than asthma symptoms is a major determinant of elevated FeNO among bakers. This relationship is modified by atopy and current smoking status. PMID- 23435449 TI - Conformationally restricted short peptides inhibit human islet amyloid polypeptide (hIAPP) fibrillization. AB - hIAPP fibrillization implicated in Type 2 diabetes pathology involves formation of oligomers toxic to insulin producing pancreatic beta-cells. We report design, synthesis, 3D structure and functional characterization of dehydrophenylalanine (DeltaF) containing peptides which inhibit hIAPP fibrillization. The inhibitor protects beta-cells from hIAPP induced toxicity. PMID- 23435450 TI - Online rapid sampling microdialysis (rsMD) using enzyme-based electroanalysis for dynamic detection of ischaemia during free flap reconstructive surgery. AB - We describe an enzyme-based electroanalysis system for real-time analysis of a clinical microdialysis sampling stream during surgery. Free flap tissue transfer is used widely in reconstructive surgery after resection of tumours or in other situations such as following major trauma. However, there is a risk of flap failure, due to thrombosis in the flap pedicle, leading to tissue ischaemia. Conventional clinical assessment is particularly difficult in such 'buried' flaps where access to the tissue is limited. Rapid sampling microdialysis (rsMD) is an enzyme-based electrochemical detection method, which is particularly suited to monitoring metabolism. This online flow injection system analyses a dialysate flow stream from an implanted microdialysis probe every 30 s for levels of glucose and lactate. Here, we report its first use in the monitoring of free flap reconstructive surgery, from flap detachment to re-vascularisation and overnight in the intensive care unit. The on-set of ischaemia by both arterial clamping and failure of venous drainage was seen as an increase in lactate and decrease in glucose levels. Glucose levels returned to normal within 10 min of successful arterial anastomosis, whilst lactate took longer to clear. The use of the lactate/glucose ratio provides a clear predictor of ischaemia on-set and subsequent recovery, as it is insensitive to changes in blood flow such as those caused by topical vasodilators, like papaverine. The use of storage tubing to preserve the time course of dialysate, when technical difficulties arise, until offline analysis can occur, is also shown. The potential use of rsMD in free flap surgery and tissue monitoring is highly promising. PMID- 23435451 TI - Quantum dots on electrodes--new tools for bioelectroanalysis. AB - The review covers recent developments in which quantum dots (QDs) are combined with electrodes for detection of analytes. Special focus will be on the generation of photocurrents and the possibility of spatially resolved, light directed analysis. Different modes for combining biochemical reactions with QDs will be discussed. Other applications involve the use of QDs as labels in binding analysis. Different methods have been developed for read-out. In addition to photocurrent analysis, voltammetric detection of metals and electrochemiluminescence (ECL) can be used. In the latter, light is the sensor signal. ECL-based systems combine the advantage of very sensitive analytical detection with rather simple instrumentation. PMID- 23435452 TI - Probing site-specific 13C/15N-isotope enrichment of spider silk with liquid-state NMR spectroscopy. AB - Solid-state nuclear magnetic resonance (NMR) has been extensively used to elucidate spider silk protein structure and dynamics. In many of these studies, site-specific isotope enrichment is critical for designing particular NMR methods for silk structure determination. The commonly used isotope analysis techniques, isotope-ratio mass spectroscopy and liquid/gas chromatography-mass spectroscopy, are typically not capable of providing the site-specific isotope information for many systems because an appropriate sample derivatization method is not available. In contrast, NMR does not require any sample derivatization or separation prior to analysis. In this article, conventional liquid-state (1)H NMR was implemented to evaluate incorporation of (13)C/(15)N-labeled amino acids in hydrolyzed spider dragline silk. To determine site-specific (13)C and (15)N isotope enrichments, an analysis method was developed to fit the (1)H-(13)C and (1)H-(15)N J-splitting (J CH and J NH) (1)H NMR peak patterns of hydrolyzed silk fiber. This is demonstrated for Nephila clavipes spiders, where [U-(13)C3,(15)N] Ala and [1-(13)C,(15)N]-Gly were dissolved in their water supplies. Overall, contents for Ala and Gly isotopomers are extracted for these silk samples. The current methodology can be applied to many fields where site-specific tracking of isotopes is of interest. PMID- 23435453 TI - Homeostatic mechanisms and treatment of tinnitus. AB - Tinnitus, the phantom percept of sound, is a potentially debilitating disorder affecting up to ten percent of the general population. After decades of effort, we still lack an effective treatment for tinnitus, partly because of its diverse underlying etiology. Recent studies have yielded hypotheses for central mechanisms underlying hearing loss-induced tinnitus, the most common form of tinnitus. Here we review recent evidence that homeostatic down-regulation of phasic and tonic inhibition is a mechanism underlying hearing loss-induced tinnitus. We propose to treat tinnitus through novel strategies of sensory training and targeted pharmacological intervention to reverse the homeostatic changes induced by hearing loss. PMID- 23435454 TI - Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid organ transplant recipients. AB - BACKGROUND: Incidence, characteristics, and risk factors for tuberculosis (TB) associated immune reconstitution inflammatory syndrome (IRS) in solid-organ transplant (SOT) recipients are not known. METHODS: Patients are composed of 64 consecutive SOT recipients with TB followed for 12 months. IRS was defined based on previously proposed criteria. RESULTS: IRS developed in 14% (9/64) of the patients, a median of 47 days after the use of anti-TB therapy. Liver versus other types of organ transplant recipients (adjusted odds ratio [OR], 6.11; 95% confidence interval [CI], 1.08-34.86), prior cytomegalovirus infection (adjusted OR, 5.65; 95% CI, 0.93-34.47), and rifampin use (adjusted OR, 4.56; 95% CI, 0.74 27) were associated with a higher risk of IRS. The presence of more than one factor (liver transplantation, cytomegalovirus infection, and rifampin use) when compared with none of these factors conferred a 19-fold increase in the risk of IRS (P=0.01). Mortality at 1 year after diagnosis was 33.3% in patients with IRS and 17.2% in those without IRS (P=0.31). CONCLUSIONS: IRS was documented in 14% of the SOT recipients with TB. We determined clinically identifiable factors that may be useful in assessing the risk of tuberculosis-associated posttransplantation IRS. PMID- 23435455 TI - Why offered pancreases are refused in the allocation process-a descriptive study using routine data from eurotransplant. AB - BACKGROUND: The majority of pancreases, offered in allocation, are discarded. This pancreas underutilization is not well understood yet. METHODS: We analyzed the detailed allocation protocols of all Eurotransplant-registered German whole pancreas donors (2005-2009; n=1758). Outcome measures included donor characteristics, number of refusals per organ, and proportion of different refusal reasons in the whole sample and subgroups. RESULTS: Thirty-seven percent of offered pancreases were transplanted; among these, 62% of pancreases were of potentially high quality (favorable donor age and pre-procurement pancreas allocation suitability score, no malignancy, n=290). A pancreas was placed after four offers (median) or withdrawn after eight offers (median). Seventy-five percent of refusal reasons were donor related (e.g., "lab results", "age", "macroscopy", and "long intensive care unit [ICU] stay"). Among pancreases refused for "diabetes" or "malignancy" at least once, the proportion of transplanted organs was less than 10%; pancreases refused due to "trauma", "age", or "resuscitation" were later transplanted in 48%, 32%, and 28%, respectively. The impact of donor age and ICU stay on organ refusal varied substantially: organs were refused due to length of ICU stay even if donors stayed 7 days or less; some organs were transplanted without ever being refused due to ICU stay in donors who stayed 8 days or more in ICU. There were no clinically significant disparities between donors of used and unused pancreases, except age (median, 31 vs. 42 years). DISCUSSION: The loss of several pancreases seems avoidable. Many refusal reasons are not plausible, because there is no evidence supporting the refusal and because many of these organs were transplanted by other centers. This increases inefficiency in the allocation system. PMID- 23435456 TI - Impact of positive flow cytometry crossmatch on outcomes of intestinal/multivisceral transplantation: role anti-IL-2 receptor antibody. AB - BACKGROUND: Positive crossmatch may be associated with an increased risk of acute rejection (AR) and worse overall outcomes after intestinal/multivisceral (MV) transplantation. However, the evidence from published studies in this setting is sparse and contradictory. This study reports the impact of positive flow cytometry crossmatch on clinical outcomes after intestinal/MV transplantation and the use of anti-interleukin (IL)-2 receptor antibody as a maintenance immunosuppressant. METHODS: Records of all intestinal/MV transplants from 2003 to 2010 were reviewed. Flow cytometry was used to evaluate T- and B-cell crossmatch status. Standard immunosuppression included rabbit anti-thymocyte globulin rituximab induction with tacrolimus and steroid maintenance. From 2008 onwards (second era), monthly anti-IL-2 receptor antibody was added to the maintenance immunosuppression in patients receiving liver-excluding transplants. RESULTS: Of 131 intestinal/MV transplants, 27 (21%) had a positive crossmatch. Positive crossmatch was not associated with an increased incidence of AR and graft loss (30% and 37% vs. 29% and 47%; P=0.94 and 0.35, respectively). This effect was maintained in liver-excluding transplants. Overall rate of AR decreased from 39% to 22% in the second era. In liver-excluding transplants, there was a significant decrease in AR from 75% to 44% with the use of anti-IL-2 receptor antibody therapy. CONCLUSIONS: With rabbit anti-thymocyte globulin-rituximab induction, positive crossmatch status is not associated with worse outcomes after intestinal/MV transplantation. Use of anti-IL-2 receptor antibody as a part of maintenance immunosuppression may be beneficial in liver-excluding transplants. PMID- 23435457 TI - Low-grade proteinuria and microalbuminuria in renal transplantation. AB - Nephrotic-range proteinuria has been known for years to be associated with poor renal outcome. Newer evidence indicates that early (1-3 months after transplantation) low-grade proteinuria and microalbuminuria (1) provide information on the graft in terms of donor characteristics and ischemia/reperfusion injury, (2) may occur before the development of donor specific antibodies, (3) predict the development of diabetes and cardiovascular events, and (4) are associated with reduced long-term graft and patient survivals. Low-grade proteinuria and microalbuminuria are also predictive of diabetes, cardiovascular morbidity, and death in nontransplanted populations, which may help us to understand the pathophysiology of low-grade proteinuria or microalbuminuria in renal transplantation. The impact of immunosuppressive medications, including mammalian target of rapamycin inhibitors, on graft survival is still discussed, and the effect on proteinuria is crucial to the debate. The fact that chronic allograft rejection may exist as early as 3 months after renal transplantation indicates that optimal management of low-grade proteinuria or microalbuminuria should occur very early after transplantation to improve long-term renal function and the overall outcome of renal transplant recipients. The presence of low-grade proteinuria or microalbuminuria early after transplantation must be taken into account to choose adequate immunosuppressive and antihypertensive medications. Limited information exists regarding the benefit of therapeutic interventions to reduce low-grade proteinuria or microalbuminuria. Whether renin angiotensin blockade results in optimal nephroprotection in patients with low-grade proteinuria or microalbuminuria is not proven, especially in the absence of chronic allograft nephropathy. Observational studies and randomized clinical trials yield conflicting results. Finally, randomized clinical trials are urgently needed. PMID- 23435459 TI - Congenital axis dysmorphism in a medieval skeleton : ...secunda a vertendo epistropheus.... AB - PURPOSE: We describe here the axis dysmorphism that we observed in the skeletal remains of a human child dug up from a fifteenth century cemetery located in north-eastern Italy. This bone defect is discussed in the light of pertinent literature. METHODS: We performed macroscopical examination and CT scan analysis of the axis. RESULTS: Axis structure was remarkably asymmetric. Whilst the left half exhibited normal morphology, the right one was smaller than normal, and its lateral articular surface showed horizontal orientation. In addition, the odontoid process appeared leftward deviated and displayed a supplementary articular-like facet situated on the right side of its surface. CONCLUSIONS: These findings suggest a diagnosis of unilateral irregular segmentation of atlas and axis, a rare dysmorphism dependent upon disturbances of notochordal development in early embryonic life. Likewise other malformations of the craniovertebral junction, this axis defect may alter the delicate mechanisms of upper neck movements and cause a complex series of clinical symptoms. This is an emblematic case whereby human skeletal remains may provide valuable information on the anatomical defects of craniovertebral junction. PMID- 23435460 TI - Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. AB - Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought. PMID- 23435461 TI - TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. AB - The purpose of this analysis was to provide 6-year follow-up of the CLL3X trial, which studied reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) in patients with poor-risk chronic lymphocytic leukemia (CLL), and to investigate the effect of TP53, SF3B1, and NOTCH1 mutations on HSCT outcome. For 90 allografted patients, 6-year overall survival (OS) was 58% and 6 year event-free survival (EFS) was 38%. TP53, SF3B1, and NOTCH1 mutations were found in 30%, 26%, and 14% of the trial population, respectively. By univariate and multivariate analyses, the mutational status of the TP53, SF3B1, and NOTCH1 genes had no significant effect on OS and EFS. Studies of minimal residual disease confirmed durability of CLL eradication in mutated patients. We conclude that HSCT can provide long-term disease control in patients with poor-risk CLL independent of the presence of TP53, SF3B1, and NOTCH1 mutations. The trial has been registered at the US National Cancer Institute as #EU-20554, NCT00281983. PMID- 23435462 TI - Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation. AB - We investigated the use of adoptively transferred donor-derived cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) as immune reconstitution postallogeneic transplant in a phase 2 study. Fifty patients were infused with a single dose of 2 * 10(7)cells/m(2) after day 28 post-transplant. Twenty-six patients reactivated CMV posttransplant (only 5 post-CTL infusion) and 9 required therapy with ganciclovir or foscarnet (only 1 post-CTL infusion). There was 1 case of fatal CMV disease, attributable to high levels of antithymocyte globulin at the time of T cell infusion. We compared the patients in the phase 2 study with a group of contemporaneous controls also treated at the trial centers. There was no increase in acute or chronic graft-versus-host disease attributable to CTL infusion; overall and progression-free survival were similar in both groups. There was a reduction in the percentage of patients who required CMV directed antiviral therapy (17% vs 36%, P = .01) and in the total number of treatment days in the cohort receiving CTL (3.4 days vs 8.9 days, P = .03) without a reduction in CMV reactivation rates. We postulate that adoptively transferred cells are able to expand in response to viral antigen, limit viral replication, and prevent progression to tissue infection. This study was registered on the Australian Clinical Trial Registry as #ACTRN12605000213640 and #ACTRN12607000224426. PMID- 23435463 TI - The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. AB - The NPM1 mutation is the most frequent genetic alteration thus far identified in acute myeloid leukemia (AML). Despite progress in the clinical and biological characterization of NPM1-mutated AML, the role of NPM1 mutation in leukemogenesis in vivo has not been fully elucidated. We report a novel mouse model that conditionally expresses the most common human NPM1 mutation (type A) in the hematopoietic compartment. In Npm1-TCTG/WT;Cre(+) mice, the NPM1 mutant localized in the cytoplasm (NPMc(+)) of bone marrow (BM) cells. The mutant mice developed no AML after 1.5-year follow-up. However, NPMc(+) expression determined a significant platelet count reduction and an expansion of the megakaryocytic compartment in the BM and spleen. Serum thrombopoietin levels overlapped in mutant vs control mice, and BM cells from Npm1-TCTG/WT;Cre(+) mice formed more megakaryocytic colonies in vitro. Moreover, we demonstrated the up-regulation of microRNAs (miRNAs; miR-10a, miR-10b, and miR-20a) inhibiting megakaryocytic differentiation along with increased expression of HOXB genes. Notably, these findings mimic those of human NPM1-mutated AML, which also exhibits a similar miRNA profile and expansion of the megakaryocytic compartment. Our mouse model provides evidence that the NPM1 mutant affects megakaryocytic development, further expanding our knowledge of the role of NPM1 mutant in leukemogenesis. PMID- 23435465 TI - Morphology and phase controlled cobalt nanostructures in magnetic polypropylene nanocomposites: the role of alkyl chain-length in maleic anhydride grafted polypropylene. AB - A novel function of maleic anhydride grafted polypropylene (PP) with different backbone chain-lengths was demonstrated, i.e., in controlling the cobalt morphologies (dispersed polyhedral vs. assembled chain nanostructure), crystalline structures (epsilon- vs. beta-phase), and magnetic property (242 vs. 808 Oe) in the synthesized magnetic PP nanocomposites. PMID- 23435466 TI - Impacts of land cover changes on climate trends in Jiangxi province China. AB - Land-use/land-cover (LULC) change is an important climatic force, and is also affected by climate change. In the present study, we aimed to assess the regional scale impact of LULC on climate change using Jiangxi Province, China, as a case study. To obtain reliable climate trends, we applied the standard normal homogeneity test (SNHT) to surface air temperature and precipitation data for the period 1951-1999. We also compared the temperature trends computed from Global Historical Climatology Network (GHCN) datasets and from our analysis. To examine the regional impacts of land surface types on surface air temperature and precipitation change integrating regional topography, we used the observation minus reanalysis (OMR) method. Precipitation series were found to be homogeneous. Comparison of GHCN and our analysis on adjusted temperatures indicated that the resulting climate trends varied slightly from dataset to dataset. OMR trends associated with surface vegetation types revealed a strong surface warming response to land barrenness and weak warming response to land greenness. A total of 81.1% of the surface warming over vegetation index areas (0-0.2) was attributed to surface vegetation type change and regional topography. The contribution of surface vegetation type change decreases as land cover greenness increases. The OMR precipitation trend has a weak dependence on surface vegetation type change. We suggest that LULC integrating regional topography should be considered as a force in regional climate modeling. PMID- 23435464 TI - Characterizing virulence-specific perturbations in the mitochondrial function of macrophages infected with Mycobacterium tuberculosis. AB - To probe how the pathogen Mycobacterium tuberculosis controls host cellular death pathways, we compared mitochondrial responses in human macrophages infected either with the avirulent mycobacterial strain H37Ra, or its virulent counterpart H37Rv. Following H37Ra infection, induction of the apoptotic response was foreshadowed by the early suppression of stress-induced mitochondrial activity. In contrast, mitochondria in H37Rv-infected cells displayed robust activity with increased membrane potential and ATP synthesis. An examination of the mitochondrial proteome revealed that attenuation of mitochondrial function was also coupled with the vigorous activation of bactericidal mechanisms in H37Ra infected cells. In contrast, augmentation of mitochondrial activity by H37Rv enabled manipulation of host cellular mechanisms to inhibit apoptosis on the one hand, while ensuring fortification against anti-microbial pathways on the other. These results thus provide novel insights into the molecular interplay that facilitates adaptation of virulent mycobacteria within the hostile intracellular milieu of the host macrophage. PMID- 23435467 TI - Work-life balance among shift workers: results from an intervention study about self-rostering. AB - PURPOSE: The aims of the study were to explore the effects of the implementation of IT-based tools for planning of rosters among shift workers on work-family related outcomes and to interpret the results in light of the different implementation processes. METHODS: A quasi-experimental intervention study was conducted with 12-month follow-up at 14 intervention and 14 reference worksites in Denmark. Workplaces planning to introduce IT-supported self-rostering were recruited, and three different kinds of interventions were implemented. Intervention A and B aimed at increasing workers satisfaction and well-being, while intervention C was designed to optimize the personnel resources. Questionnaire data were collected from 840 employees at baseline and 784 at follow-up. Process evaluation encompassed interviews with about 25 employees and 15 managers at baseline and follow-up. Work-family-related outcomes were work life conflicts, work-life facilitation, marital conflicts and time with children. RESULTS: An overall decline in work-family conflicts and increase in work-family facilitation were found in the total intervention group. More specifically, in group B, work-family conflicts and marital conflicts decreased while work-family facilitation increased. In group C, work-family conflicts increased while work family facilitation and time spend with children decreased, and no significant changes were observed in the reference group and in group A. CONCLUSION: An overall positive effect of the implementation of self-rostering was found on the balance between work and private life. However, results from the process evaluation suggested that the organizational aim with the intervention was crucial for the effect. PMID- 23435468 TI - No difference in high-magnification morphology and hyaluronic acid binding in the selection of euploid spermatozoa with intact DNA. AB - In this study, we compared conventional sperm selection with high-magnification morphology based on the motile sperm organellar morphology examination (MSOME) criteria, and hyaluronic acid (HA) binding for sperm chromosome aneuploidy and DNA fragmentation rates. Semen from 50 severe male factor cases was processed through density gradient centrifugation, and subjected to sperm selection by using the conventional method (control), high magnification at *6650 or HA binding. Aneuploidy was detected by fluorescence in situ hybridization with probes for chromosomes 13, 18, 21, X and Y, and DNA fragmentation by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method. Spermatozoa selected under high-magnification had a lower DNA fragmentation rate (2.6% vs. 1.7%; P=0.032), with no significant difference in aneuploidy rate (0.8% vs 0.7%; P=0.583), than those selected by the HA binding method. Spermatozoa selected by both methods had much lower aneuploidy and DNA fragmentation rate than the controls (7% aneuploidy and 26.8% DNA fragmentation rates, respectively). In the high-magnification group, the aneuploidy rate was lower when the best spermatozoa were selected than when only the second-best spermatozoa were available for selection, but the DNA fragmentation rate was not different. In conclusion, sperm selection under high magnification was more effective than under HA binding in selecting spermatozoa with low DNA fragmentation rate, but the small difference (0.9%) might not be clinically meaningful. Both methods were better than the conventional method of sperm selection. PMID- 23435469 TI - Long-term effect of vasectomy on spermatogenesis in men: a morphometric study. AB - Spermatogenic damage may occur after vasectomy, and the damage is pressure mediated, occurring when the occluded reproductive tract is unable to accommodate additional sperm produced by the testis. This study aimed to determine the long term effect of vasectomy on spermatogenesis in humans and clarify how the balance between sperm production in the testis and sperm storage in or removal from the tract might be maintained. During inguinal hernia repair, an open biopsy was performed to obtain testicular tissue blocks from 51 Chinese men (aged >=50 years), of whom 25 (control group) had not undergone vasectomy and 26 (vasectomized group) had undergone bilateral vasectomy 22-42 years before. Methacrylate resin-embedded testicular sections were made, and morphometric studies were performed using light microscopy. In addition, sizes of the testis and epididymis were estimated with ultrasonography. The testicular tissue blocks obtained from one control and seven vasectomized men consisted almost completely of connective tissue. In the other 43 men, significant differences were not found between the two groups in the testicular or epididymal size, qualitative histology or quantitative parameters including the mean diameter or volume fraction of the seminiferous tubules. In conclusion, sperm production and sperm storage/removal reached a static equilibrium after vasectomy, likely due to spermatogenic degeneration or less sperm production as a result of aging or due to vasectomy-induced testicular (interstitial) fibrosis. Thus, complications that might occur in association with overproduction of sperm and distension of the tract would disappear or be relieved with time. PMID- 23435470 TI - COUP-TFII, a prognostic marker and therapeutic target for prostate cancer. PMID- 23435471 TI - Quantitative proteomic determination of diethylstilbestrol action on prostate cancer. AB - Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P<0.01) were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins (>1.3 fold; P<0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P=0.006) and HSPB1 (P=0.046). PMID- 23435472 TI - Prostate cancer biomarker: a key field to explore. PMID- 23435473 TI - Penile prosthesis implantation and tunica albuginea incision without grafting in the treatment of Peyronie's disease with erectile dysfunction. AB - We evaluated penile prosthesis implantation with tunica albuginea-relaxing incisions without grafting in the treatment of Peyronie's disease associated with erectile dysfunction. Between April 2005 and June 2011, 62 patients underwent surgery due to severe Peyronie's disease associated with erectile dysfunction. Malleable and inflatable penile prostheses were inserted in 49 and 13 cases, respectively. Penile prostheses were inserted into the corpora cavernosa using the standard ventral approach. After lifting the neurovascular bundle, the tunica albuginea was incised and opened at the plaque region to correct the deformities and to lengthen the penis. Subsequently, the wide neurovascular bundle was replaced, and all incisions of the tunica albuginea were covered to prevent corporal grafting. In the median follow-up of 35 months (range 14-82 months), the penis was completely straightened in 59 (95%) patients. Numbness of the glans, which the patients found initially upsetting, decreased or disappeared spontaneously 3-6 months later. Penile prosthesis implantation with tunica albuginea incisions is a viable alternative in the treatment of Peyronie's disease because the extensive dissection of the neurovascular bundle allows a good approach to the plaque and provides excellent covering of the incised tunica albuginea without additional grafting. PMID- 23435474 TI - The opportunity cost of androgen suppression in locally advanced prostate cancer. PMID- 23435475 TI - Highly efficient and selective photocatalytic hydroamination of alkynes by supported gold nanoparticles using visible light at ambient temperature. AB - The direct hydroamination of alkynes driven by visible light can be achieved in high yield and selectivity at ambient temperature using supported gold nanoparticles (AuNPs) as photocatalysts. Aniline molecules interact with visible light activated AuNPs meanwhile alkynes could be activated at active sites on the support. The findings reveal a new green approach for synthesis of fine organic compounds and provide insight into catalyst design for the activation of C=C triple bonds and amines. PMID- 23435476 TI - Boron complexes of redox-active diimine ligand. AB - Boron complexes (dpp-bian)BCl2 (1) and (dpp-bian)BX (X = Cl, 2; Br, 3) (dpp-bian = 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) have been prepared by reacting mixtures dpp-bian-BX3 (1 : 1) with one (1) and two (2 and 3) equivalents of sodium correspondingly in toluene. Complexes 2 and 3 reveal a moderate stability against ambient oxygen and moisture. The reaction of complex 2 with PhC=CLi gave compound (dpp-bian)B-C=CPh (4). Treatment of 2 with potassium hydroxide afforded complexes (dpp-bian)B-OH (5) and (dpp-bian)B-OK (6). Boron amide (dpp-bian)B-NH2 (7) has been isolated from the reaction of compound 1 with sodium in liquid ammonia. Borane (dpp-bian)B-H (8) can be prepared by the reactions of complexes 2 and 3 with LiAlH4. Diamagnetic compounds 2-8 have been characterized by IR, (1)H and (11)B NMR spectroscopy; paramagnetic complex 1 has been studied by the ESR method. Molecular structures of 2, 5, 7 and 8 have been determined by X-ray crystallography. PMID- 23435477 TI - Switchable viscosity triggered by CO2 using smart worm-like micelles. AB - We report two CO2-responsive aqueous solutions having switchable viscosity. The solution of sodium octadecyl sulfate and 2-(dimethylamino)ethanol forms viscoelastic worm-like micelles in the presence of CO2 but not in its absence at 60 degrees C. Another solution of sodium stearate and sodium nitrate has high viscosity only if CO2 is absent. PMID- 23435478 TI - Theoretical study on the structures and properties of mixtures of urea and choline chloride. AB - In this work, we investigated in detail the structural characteristics of mixtures of choline chloride and urea with different urea contents by performing molecular dynamic (MD) simulations, and offer possible explanations for the low melting point of the eutectic mixture of choline chloride and urea with a ratio of 1:2. The insertion of urea molecules was found to change the density distribution of cations and anions around the given cations significantly, disrupting the long-range ordered structure of choline chloride. Moreover, with increasing urea concentration, the hydrogen bond interactions between choline cations and Cl(-) anions decreased, while those among urea molecules obviously increased. From the hydrogen bond lifetimes, it was found that a ratio of 1:2 between choline chloride and urea is necessary for a reasonable strength of hydrogen bond interaction to maintain the low melting point of the mixture of choline chloride with urea. In addition, it was also deduced from the interaction energies that a urea content of 67.7 % may make the interactions of cation-anion, cation-urea and anion-urea modest, and thus results in the lower melting point of the eutectic mixture of choline chloride and urea. The present results may offer assistance to some extent for understanding the physicochemical properties of the eutectic mixture of choline chloride and urea, and give valuable information for the further development and application of deep eutectic solvents. PMID- 23435479 TI - Studies on structures and electron affinities of the simplest alkyl dithio radicals and their anions with gaussian-3 theory and density functional theory. AB - The equilibrium geometries and electron affinities of the R-SS/R-SS(-)(R=CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, t-C4H9, n-C5H11) species have been studied using the higher level of the Gaussian-3(G3) theory and 21 carefully calibrated pure and hybrid density functionals (five generalized gradient approximation (GGA) methods, seven hybrid GGAs, three meta GGA methods, and six hybrid meta GGAs) in conjunction with diffuse function augmented double-zeta plus polarization (DZP++) basis sets. The geometries are fully optimized with each method and discussed. The reliable adiabatic electron affinity has been presented by means of the high level of G3 technique. With the DZP++ DFT method, three measures of neutral/anion energy differences reported in this work are the adiabatic electron affinity, the vertical electron affinity, and the vertical detachment energy. The adiabatic electron affinities, obtained at the BP86, M05-2X, B3LYP, M06, B98, M06-2X, mPW1PW91, HCTH, B97-1, M05, PBE1PBE, and VSXC methods, are in agreement with the G3 results. These methods perform better for EA prediction and are considered to be reliable. PMID- 23435480 TI - Adolescent bariatric surgery: "you may ask yourself: how did I get here?". PMID- 23435481 TI - A twin study of the relationships among inattention, hyperactivity/impulsivity and sluggish cognitive tempo problems. AB - We investigated the etiological relationships between the three ADHD dimensions of Inattentive Problems (INP), Hyperactivity-Impulsivity Problems (HIP) and Sluggish Cognitive Tempo (SCT) as measured by the CBCL 6-18 questionnaire. Multivariate models were applied to 398 twin pairs (374 boys and 422 girls) aged 8 to 17 years (M = 13.06, SD = 2.59) belonging to the population-based Italian Twin Registry. The INP, HIP and SCT problem scores were moderately-to substantially (range 0.29-0.47) intercorrelated. The best fitting model showed that these 3 dimensions are correlated both at the genetic (correlations' range: 0.65-0.83) and the environmental (correlations: 0.29 and 0.44) levels, but they are also distinct. While SCT showed moderate heritability and large non-shared environmental influences, variance for both INP and HIP was substantially explained by genetic influences. We also found evidence of negative sibling interaction for INP, implying that a given behavior in one twin leads to an opposite behavior in the co-twin. Our results support at the etiological level the findings of previous psychometric and longitudinal studies of ADHD, which yielded evidence of the 3 distinct-albeit correlated-problem dimensions of inattentiveness, hyperactivity-impulsivity, and sluggish cognitive tempo. PMID- 23435482 TI - The interim service preferences of parents waiting for children's mental health treatment: a discrete choice conjoint experiment. AB - Parents seeking help for children with mental health problems are often assigned to a waiting list. We used a discrete choice conjoint experiment to model preferences for interim services that might be used while waiting for the formal assessment and treatment process to begin. A sample of 1,059 parents (92 % mothers) seeking mental health services for 4 to 16 year olds chose between hypothetical interim services composed by experimentally varying combinations of the levels of 13 interim service attributes. Latent Class analysis yielded a four segment solution. All segments preferred interim options helping them understand how agencies work, enhancing their parenting knowledge and skill, and providing an opportunity to understand or begin dealing with their own difficulties. The Group Contact segment (35.1 %) preferred interim services in meetings with other parents, supported by phone contacts, frequent checkup calls, and wait-time updates. Virtual Contact parents (29.2 %) preferred to meet other parents in small internet chat groups supported by e-mail contact. Membership in this segment was linked to higher education and computer skills. Frequent Contact parents (24.4 %) preferred face-to-face interim services supported by weekly progress checks and wait time updates. Limited Contact parents (11.3 %) were less intent on using interim services. They preferred to pursue interim services alone, with contacts by phone, supported by fewer check-up calls and less frequent wait time updates. All segments were more likely to enroll in interim services involving their child. PMID- 23435483 TI - [Acute cholecystitis: a civilization disease at the intersection of internal medicine and surgery]. PMID- 23435484 TI - [Minimally invasive surgical therapy of acute cholecystitis]. AB - Acute cholecystitis is the most common complication of cholecystolithiasis. It develops in about 10 % of symptomatic patients and gangrenous cholecystitis, gallbladder perforation, gallbladder empyema, or abscesses are typical complications. Cholecystectomy is the most relevant therapy to achieve pain reduction, to prevent the progression of inflammation or local complications and to minimize the risk of recurrence. Surgical therapy can be supported by medical and interventional treatment modalities depending on the severity of the disease. The present review summarizes the surgical aspects in acute cholecystitis with a focus on laparoscopic cholecystectomy which is the gold standard of therapy. PMID- 23435486 TI - The pathogenesis of ulnar polydactyly in humans. AB - The pathogenesis of ulnar polydactyly in humans is not known. There are numerous syndromes that are associated with ulnar polydactyly. We have noted that the genetic defects in these syndromes lead to a disturbance of the normal balance between the two forms of the Gli3 protein (the active and repressor forms of Gli3, which are known as Gli3-A and Gli3-R, respectively), leading to a relative increase in the Gli3-R protein. We offer the hypothesis of a unified pathogenesis of ulnar polydactyly through the relative predominance of Gli3-R. PMID- 23435485 TI - [The intensive care gallbladder as shock organ: symptoms and therapy]. AB - Acute acalculous cholecystitis (AAC) represents a severe disease in critically ill patients. The pathogenesis of acute necroinflammatory gallbladder disease is multifactorial and intensive care unit (ICU) patients show multiple risk factors. In addition AAC is difficult to diagnose because of the vague physical and non specific technical findings. Only the combination of clinical and technical findings including the challenging physical examination of critically ill patients, laboratory results and ultrasound or computed tomography (CT) scan, will lead to the diagnosis. The condition of AAC has a rapid progress to gallbladder necrosis, gangrene and perforation and these complications are reflected in the high morbidity and mortality rates, therefore, therapy should be promptly initiated. If there are no clinical contraindications for an operative approach cholecystectomy is the definitive treatment and both open and laparoscopic procedures have been used. In unstable, critically ill patients percutaneous cholecystostomy should be immediately performed. In addition, transpapillary endoscopic drainage is also possible if there are contraindications for percutaneous cholecystostomy. Patients who fail to improve or deteriorate following interventional drainage should be reconsidered for cholecystectomy. Due to the fact that more than 90 % of patients treated with percutaneous cholecystostomy showed no recurrence of symptoms during a period of more than 1 year, it is still unclear if percutaneous cholecystostomy is the definitive treatment of AAC for unstable patients or if delayed cholecystectomy is still necessary. PMID- 23435487 TI - Patient-reported outcomes following carpal tunnel decompression in patients over 80 years old. PMID- 23435488 TI - Painful, palpable and pathological: anomalous flexor digitorum superficialis brevis in the palm, comparative anatomical context, and an updated classification of anomalies of the flexor digitorum superficialis. AB - Anomalies of the flexor digitorum superficialis are rare and can present a diagnostic dilemma. Patients present with a painful or palpable mass, or symptoms of carpal tunnel syndrome. This review article summarizes previously reported anomalies of the flexor digitorum superficialis, reports a further case, and proposes a new classification. PMID- 23435489 TI - A new technique for closed management of displaced intra-articular fractures of metacarpal and phalangeal head delayed on presentation: report of eight cases. AB - We present the outcomes of the delayed management of eight displaced intra articular fractures of the metacarpal and phalangeal heads treated with capsuloligamentotaxis using the Penning mini-external fixator. Closed anatomical reduction with a 2 mm over-distraction was achieved at the time of operation at an average of 20 days after the initial injury. Excellent outcomes in terms of function and pain were obtained at 6 month's follow-up in all cases. This technique is simple, minimally invasive, and effective, with minimal complications. PMID- 23435490 TI - Prevalence of carpal tunnel syndrome and wrist osteoarthritis in long-term paraplegic patients compared with controls. AB - We compared functional and structural changes in the hands, in particular the prevalence of carpal tunnel syndrome, in 56 paraplegic patients who had been wheelchair dependent for over 25 years with a group of able-bodied volunteers (with matching criteria for gender and age). The hands were assessed by clinical examination, electrophysiology, disabilities of the arm shoulder and hand score and magnetic resonance imaging. Hand function was worse and wrist pain was experienced more often in the paraplegic patients, and they also had a significantly higher prevalence of carpal tunnel syndrome both clinically and electrophysiologically. The prevalence of wrist and trapeziometacarpal osteoarthritis was significantly higher in the right hand. PMID- 23435491 TI - Performance of a knotless four-strand flexor tendon repair with a unidirectional barbed suture device: a dynamic ex vivo comparison. AB - With increased numbers of reports using barbed sutures for tendon repairs we felt the need to design a specific tendon repair method to draw the best utility from these materials. We split 30 sheep deep flexor tendons in two groups of 15 tendons. One group was repaired with a new four-strand barbed suture repair method without knot. The other group was repaired with a conventional four-strand cross-locked cruciate repair method (Adelaide repair) with knot. Dynamic testing (3-30 N for 250 cycles) and additional static pull to failure was performed to investigate gap formation and final failure forces. The barbed suture repair group showed higher resistance to gap formation throughout the test. Additionally final failure force was higher for the barbed suture group compared with the conventional repair group. When used appropriately, barbed suture materials could be beneficial to use in tendon surgery, especially with regard to early loading of the repair site and gap formation. PMID- 23435493 TI - The role of ultrasound. PMID- 23435492 TI - Aneurysmal bone cyst within fibrous dysplasia of the anterior skull base: continued intracranial extension after endoscopic resections requiring craniofacial approach with free tissue transfer reconstruction. PMID- 23435494 TI - Endometrial receptivity: evaluation with ultrasound. AB - An adequate endometrial receptivity is a crucial factor for embryo implantation. We describe endometrial morphology (endometrial appearance or pattern, endometrial thickness, volume, and delimitation), based on the concepts and possibilities of the new ultrasound modalities (3-dimensional/4-dimensional ultrasound, automatic volume calculation, virtual organ computer-aided analysis, tomographic ultrasound image, inverse mode, and 3-dimensional Doppler angiography) as markers of endometrial receptivity. PMID- 23435495 TI - Clinically suspected adnexal mass. PMID- 23435496 TI - Gender-selective neural populations: evidence from event-related fMRI repetition suppression. AB - Accurate recognition of gender in another individual is integral to successful human social interaction and to mate selection. When we encounter another person, we are effortlessly able to identify their gender, most often through the information conveyed by their facial features. Faces comprise the most abundantly encountered cue used to classify human gender. Considering the importance of facial information in gender perception, relatively little is known about the mechanisms involved in perceiving gender through human facial cues. We used an event-related fMRI repetition suppression paradigm to explore the neural circuitry underlying gender perception from facial information. Participants viewed brief consecutive images consisting of either gender-same face pairings (two male faces or two female faces) or images of gender-different face pairings (a male face preceded or followed by a female face), while attending to facial attractiveness in both conditions. Using a region-of-interest approach, we found repetition suppression on gender-same trials within the left ventral temporal fusiform gyrus and in the right collateral sulcus. Whole-brain voxel-wise analyses revealed selectivity for face gender again in the right collateral sulcus, in addition to the left cuneus and the right lateral occipital gyrus. Our results indicate that in addition to the face-selective FFA, cortical areas that are not traditionally considered to be "face-selective" are involved in the perception of gender-based facial cues. PMID- 23435497 TI - Post-disaster depression and vigilance: a functional near-infrared spectroscopy study. AB - The present study was designed to explore the relationships between post-disaster self-reports of depression, vigilance task performance, and frontal cerebral oxygenation. Forty participants (20 women) performed vigilance tasks following a magnitude 7.1 earthquake in Christchurch, New Zealand. In addition to performance, we measured self-reports of depression, anxiety, and stress anchored to the initial earthquake event, and frontal cerebral activity with functional near-infrared spectroscopy. Among the participants, one case may have been an outlier with extremely elevated levels of self-reported depressivity. Excluding the extreme case, there was a correlation between change in response time (response slowing) and depressivity. Including the case there was a correlation between depressivity and right hemisphere oxygenation. These results provide some support for a relationship between moderate depressivity and sustained attention difficulties. PMID- 23435499 TI - Remote detection NMR imaging of gas phase hydrogenation in microfluidic chips. AB - The heterogeneous hydrogenation reaction of propene into propane in microreactors is studied by remote detection (RD) nuclear magnetic resonance (NMR). The reactors consist of 36 parallel microchannels (50 * 50 MUm(2) cross sections) coated with a platinum catalyst. We show that RD NMR is capable of monitoring reactions with sub-millimeter spatial resolution over a field-of-view of 30 * 8 mm(2) with a steady-state time-of-flight time resolution in the tens of milliseconds range. The method enables the visualization of active zones in the reactors, and time-of-flight is used to image the flow velocity variations inside the reactor. The overall reaction yields determined by NMR varied from 10% to 50%, depending on the flow rate, temperature and length of the reaction channels. The reaction yield was highest for the channels with the lowest flow velocity. Propane T1 relaxation time in the channels, estimated by means of RD NMR images, was 270 +/- 18 ms. No parahydrogen-induced polarization (PHIP) was observed in experiments carried out using parahydrogen-enriched H2, indicating fast spreading of the hydrogen atoms on the sputtered Pt surface. In spite of the low concentration of gases, RD NMR made imaging of gas phase hydrogenation of propene in microreactors feasible, and it is a highly versatile method for characterizing on-chip chemical reactions. PMID- 23435498 TI - An analysis and prediction of nucleosome positioning based on information content. AB - Nucleosome positioning plays a key role in the regulation of many biological processes. In this study, the statistical difference of information content was investigated in nucleosome and linker DNA regions across eukaryotic organisms. By analyzing the information redundancy, D k , in Saccharomyces cerevisiae, Drosophila melanogaster, and Caenorhabditis elegans genomes, the short-range dominance of nucleotide correlation in nucleosome and linker DNA regions was confirmed. Significant difference of the D k value between the nucleosome and linker DNA regions was also found. The underlying reason for many successful oligonucleotide-based predictions of nucleosome positioning in eukaryotic model organisms may be attributed to the short-range dominance of nucleotide correlation in the nucleosome and linker DNA regions. When applying power spectrum analysis to the nucleosome and linker DNA regions, some obvious differences in sequence periodic signals were observed. The parameter F k was introduced to describe particular base correlation. Furthermore, the support vector machine combining F k was used to classify nucleosome and linker DNA regions in Homo sapiens, Oryzias latipes, C. elegans, Candida albicans, and S. cerevisiae. Independent test demonstrated that a good performance can be achieved by using this algorithm. This result further revealed that base correlation information has an important role in nucleosome positioning. PMID- 23435500 TI - The influence of exercise training status on antigen-stimulated IL-10 production in whole blood culture and numbers of circulating regulatory T cells. AB - Highly trained athletes are associated with high resting antigen-stimulated whole blood culture interleukin (IL)-10 production. The purpose of the present study was to examine the effects of training status on resting circulating T regulatory (Treg) cell counts and antigen-stimulated IL-10 production and the effect of acute bout of exercise on the Treg response. Forty participants volunteered to participate and were assigned to one of the four groups: sedentary (SED), recreationally active (REC), sprint-trained athletes and endurance-trained athletes (END). From the resting blood sample, CD4(+)CD25(+)CD127(low/-) Treg cells and in vitro antigen-stimulated IL-10 production were assessed. Ten REC subjects performed 60 min cycling at 70 % of maximal oxygen uptake and blood samples for Treg analysis were collected post- and 1 h post-exercise. IL-10 production was greater in END compared with the other groups (P < 0.05). END had a higher Treg percentage of total lymphocyte count compared with SED (P < 0.05). A smaller proportion of Treg CD4(+) cells were observed in SED compared with all other groups (P < 0.05). IL-10 production significantly correlated with the proportion of Tregs within the total lymphocyte population (r s = 0.51, P = 0.001). No effect of acute exercise was evident for Treg cell counts in the REC subjects (P > 0.05). Our results demonstrate that high training loads in END are associated with greater resting IL-10 production and Treg cell count and suggest a possible mechanism for depression of immunity commonly reported in athletes engaged in high training loads. PMID- 23435501 TI - Effect of ester on rhodium-catalyzed intermolecular [5+2] cycloaddition of 3 acyloxy-1,4-enynes and alkynes. AB - We systematically examined the effect of different esters on the rhodium catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes with a concomitant 1,2-acyloxy migration. Significant rate acceleration was observed for benzoate substrates bearing an electron-donating substituent. The cycloaddition can now be conducted under much more practical conditions for most terminal alkynes. PMID- 23435503 TI - Madelung's disease: comorbidities, fatty mass distribution, and response to treatment of 22 patients. AB - BACKGROUND: Madelung's disease (MD) is an uncommon pathology characterized by the presence of multiple masses of unencapsulated adipose tissue that is symmetrically distributed. The aim of this study was to investigate clinical and epidemiological features of patients diagnosed with MD in our department. Associated diseases and evolution after treatment were also investigated. METHODS: We reviewed the clinical histories of 22 patients diagnosed with MD from 1990 to 2010 and obtained their epidemiological and clinical characteristics. RESULTS: We found 21 patients with MD type 1 and one patient with MD type 2 according to Enzi's classification. All patients were male, 95.5% with high alcohol intake, and 59.1% with some hepatic disease. No family antecedents were significant; 40.9% had dyslipidemia, 22.7% arterial hypertension, 22.7% chronic obstructive pulmonary disease (COPD), 13.6% hyperuricemia, 9.1% hypothyroidism, 4.5% diabetes mellitus type 2, and 4.5% carbohydrate intolerance; 40.9% had a body mass index>30, and 27.3% presented gynecomastia/lipomastia. The region most frequently affected by fatty deposits was the neck. CONCLUSIONS: Madelung's disease affects mainly alcoholic males in their fourth decade of life. Hepatic diseases appear in most patients. Also associated with MD are high lipid blood levels, arterial hypertension, COPD, hyperuricemia, and obesity. MD type 1 is the most frequent phenotype and the neck the most common location for fatty masses. Recurrence after surgery, in the same location or different locations, is a frequent event, even in patients who later abstain from alcohol intake. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266 . PMID- 23435502 TI - MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis. AB - MicroRNAs have important functions in the nervous system through post transcriptional regulation of neurogenesis genes. Here we show that microRNA let 7d, which has been implicated in cocaine addiction and other neurological disorders, targets the neural stem cell regulator TLX. Overexpression of let-7d in vivo reduced neural stem cell proliferation and promoted premature neuronal differentiation and migration, a phenotype similar to those induced by TLX knockdown or overexpression of its negatively-regulated target, microRNA-9. We found a let-7d binding sequence in the tlx 3' UTR and demonstrated that let-7d reduced TLX expression levels in neural stem cells, which in turn, up-regulated miR-9 expression. Moreover, co-expression of let-7d and TLX lacking its 3' UTR in vivo restored neural stem cell proliferation and reversed the premature neuronal differentiation and migration. Therefore, manipulating let-7d and its downstream targets could be a novel strategy to unravel neurogenic signaling pathways and identify potential interventions for relevant neurological disorders. PMID- 23435504 TI - The impact of surgical breast reduction on the postural control of women with breast hypertrophy. AB - BACKGROUND: Previous studies have demonstrated the impact of breast reduction surgery on the daily lives of women, including impacts directly related to changes in postural control such as a reduced center-of-pressure displacement. However, postural control is a dynamic process that depends on the integration of sensory information to organize a proper motor strategy to overcome the balance demands of the task. This study evaluated sensory integration in the postural control of women with breast hypertrophy after breast reduction surgery. METHODS: In this study, 14 women with breast hypertrophy were evaluated before surgery and 6 months afterward. A force platform was used to assess how the somatosensory, visual, and vestibular systems contributed to postural control. Four conditions were used: eyes open/fixed platform (normal condition), eyes closed/fixed platform, eyes open/mobile platform, and eyes closed/mobile platform. For each condition, a nonparametric Friedman test was applied to compare the area and velocity of the center-of-pressure displacement between pre- and post-surgery tests. RESULTS: After surgery, the women demonstrated a smaller displacement area under normal conditions and in the eyes closed/fixed platform condition. The mean velocity in the forward-backward direction was significantly reduced after surgery when the women's eyes were closed on a mobile platform. CONCLUSIONS: After breast reduction surgery, women were found to control their posture with a smaller center-of-pressure displacement area when all sensory information was available and when their vision was suppressed with a fixed platform. Furthermore, the velocities were smaller when vision was suppressed with inaccurate somatosensory information. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23435505 TI - Perioperative nausea and vomiting: much ado about nothing? PMID- 23435506 TI - Submental area rejuvenation by digastric corset: anatomical study and clinical application in 20 cases. AB - Knowing the difficulties and limitations of surgery for rejuvenating the submental area during a cervicofacial rhytidectomy, we came up with the concept of the digastric corset, which is described in this article along with the surgical importance of the platysma, digastric and mylohyoid muscles based on anatomical dissections. A study of ten cadavers was conducted to describe precisely the limits of the submental area, the mandibular edge between the two Furnas ligaments, and the hyoid bone. Each anatomical item was dissected plane by plane: the skin, platysma, digastrics muscles, and mylohyoid muscle. The sliding of each muscle relative to the others was studied, photographed, and recorded. Feldman's corset technique was tested on two cadavers and a digastric corset was performed on eight cadavers. After suprahyoid fat lipectomy, we suture the digastric retaining ligaments to the mylohyoid muscles using a running suture, like a corset, then the platysma muscles are put aside on the median line followed by lateral platysma suspension. The different steps are presented and the results of 20 patients who underwent this procedure are presented after 1 year of follow-up. This study showed that the technique of a digastric corset anchored on the mylohyoid allows for one-step reconstruction of the floor of the mouth and a well-defined anterior cervical angle, a sign of a youthful-looking neck. This technique is indicated for difficult necks, when lateral repositioning of the platysma alone gives insufficient results. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23435507 TI - Synthetic hair implantation and squamous cell carcinoma of the scalp. PMID- 23435508 TI - Melanoma of the umbilicus: an incidental diagnosis during fat-harvesting donor site selection. PMID- 23435509 TI - Capsular flap: new applications. AB - Breast augmentation with silicone implants is one of the most commonly performed procedures for women seeking improvement in their body image. Because the number of breast augmentation operations is growing, the number of subsequent reoperations is increasing. Causes for repeated operative procedures include infection, capsular contracture, silicone implant replacement, and breast reaugmentation. As the average volume of silicone implants used is steadily growing according to patients' wishes and fashion requirements, the plastic surgeon often is asked to replace the silicone implants with larger implants. Replacing breast implants with a similar sized implant is a relatively simple operation, but insertion of larger implants may present a challenge due to insufficient soft tissue coverage of the lower pole of the larger breast implant, especially in thin subjects. Total coverage of the breast implant can be achieved by use of tissue substitutes (TS), such as acellular dermal matrices. Usage of TS, however, is prone to complications and very costly, and these factors influence the implementation of TS in a private practice setup. This report describes a capsular flap used to cover the lower pole of breast implants. The flap guarantees multilayered stable wound closure and prevents displacement of the inframammary fold. The capsular flap also was used to correct an inferiorly displaced inframammary fold as a consequence of the breast augmentation. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23435511 TI - Rapid and sensitive LC-MS approach to quantify non-radioactive transition metal impurities in metal radionuclides. AB - A rapid and sensitive LC-MS approach for the quantification of non-radioactive metal contaminants present in metal radionuclide formulations was developed. Traditional (12)C/(1)H and heavy stable isotope (13)C/(2)H-labeled chelator-amino acid conjugates are used as chelating agents to quantify contaminating transition metals, allowing for determination of effective specific activity of radio metals. PMID- 23435510 TI - Temperature shift effect on the Chlorobaculum tepidum chlorosomes. AB - Chlorobaculum [Cba.] tepidum is known to grow optimally at 48-52 degrees C and can also be cultured at ambient temperatures. In this paper, we prepared constant temperature, temperature shift, and temperature shift followed by backshift cultures and investigated the intrinsic properties and spectral features of chlorosomes from those cultures using various approaches, including temperature dependent measurements on circular dichroism (CD), UV-visible, and dynamic light scattering. Our studies indicate that (1) chlorosomes from constant temperature cultures at 50 and 30 degrees C exhibited more resistance to heat relative to temperature shift cultures; (2) as temperature increases bacteriochlorophyll c (BChl c) in chlorosomes is prone to demetalation, which forms bacteriopheophytin c, and degradation under aerobic conditions. Some BChl c aggregates inside reduced chlorosomes prepared in low-oxygen environments can reform after heat treatments; (3) temperature shift cultures synthesize and incorporate more BChl c homologs with a smaller substituent at C-8 on the chlorin ring and less BChl c homologs with a larger long-chain alcohol at C-17(3) versus constant-temperature cultures. We hypothesize that the long-chain alcohol at C-17(3) (and perhaps together with the substituent at C-8) may account for thermal stability of chlorosomes and the substituent at C-8 may assist self-assembling BChls; and (4) while almost identical absorption spectra are detected, chlorosomes from different growth conditions exhibited differences in the rotational length of the CD signal, and aerobic and reduced chlorosomes also display different Qy CD intensities. Further, chlorosomes exhibited changes of CD features in response to temperature increases. Additionally, we compare temperature-dependent studies for the Cba. tepidum chlorosomes and previous studies for the Chloroflexus aurantiacus chlorosomes. Together, our work provides useful and novel insights on the properties and organization of chlorosomes. PMID- 23435512 TI - Effects of different cold-air exposure intensities on the risk of cardiovascular disease in healthy and hypertensive rats. AB - Ten-week-old male Wistar rats (systolic blood pressure, 106-116 mmHg; body weight, 300-320 g) and spontaneously hypertensive rats (systolic blood pressure, 160-176 mmHg; body weight, 210.9-244.9 g) were used as healthy and hypertensive subjects to determine the effects of varying degrees of cold-air exposure in a climate chamber box. The three cold-air ranks were cold air I [minimum temperature (TMIN) 6.4 degrees C, ??T48 8.6 degrees C], cold air II (TMIN 3.8 degrees C, ??T48 11.2 degrees C), and cold air III (TMIN -0.3 degrees C, ??T48 15.3 degrees C), as established from the cold-air data of Zhangye City, China. Each cold-air rank consisted of a temperature drop and a temperature increase with the same initial and terminal temperatures (15 degrees C). After cold-air exposure, the risk factors for cardiovascular disease (CVD) such as systolic blood pressure, whole blood viscosity (10/s and 150/s), plasma fibrinogen, and blood lipids of the rats were determined. The results indicated that the CVD risk factors of the healthy and hypertensive rats increased significantly with cold air exposure intensities. The increase in systolic blood pressure was greater during temperature drops, whereas the increases in whole blood viscosity and plasma fibrinogen were greater after cold-air exposure. The effects of cold-air exposure on the CVD risk factors of healthy rats, particularly the systolic blood pressure, whole blood viscosity (150/s), and LDL/HDL, were greater than those in hypertensive rats. In conclusion, CVD risk may increase with cold-air ranks. Blood pressure-induced CVD risk may be greater during cold-air temperature drop, whereas atherosclerosis-induced CVD risk may be greater after cold-air exposure. The effect of cold air on the CVD risk factors in healthy subjects may be more significant than those in hypertensive subjects. PMID- 23435513 TI - Fifteen-year phenological plant species and meteorological trends in central Italy. AB - The present study was carried out in a phenological garden in central Italy that contains vegetative clones of shrubs and trees common to several international phenological gardens, such as Cornus sanguinea L.; Corylus avellana L.; Ligustrum vulgare L.; Robinia pseudoacacia L.; Salix acutifolia Willd. and Sambucus nigra L. Vegetative plant growth monitoring was carried out weekly using common international keys: BBCH07, bud break and leaf unfolding; BBCH19, young unfolded leaf; BBCH91, adult leaves; BBCH93, beginning of leaf colouring. The phenological dates thus obtained provide a model of the development for these different species in relation to the 15-year period of observation (1997-2011). From a meteorological point of view, temperature and precipitation trends were studied, with the highest anomalies during the study period recorded during the first 2 months of the year (January, February). There was relative invariance in the manifestation of the open bud phase and the contemporary advance of the young open leaves phase, particularly from 2006. This was accompanied by shortening of the leaf opening period, which appeared due to more rapid spring temperature increases over the last few years. The advance tendency of the BBCH91 phase showed adult leaves from the first summer weeks with fully green foliage monitored for a long time. Generally, the autumn leaf colouring phase tended to remain constant, with the exception of Salix acutifolia and Sambucus nigra, for which, on the other hand, the first leaf development phases appeared to be most likely influenced by the photoperiod. PMID- 23435514 TI - Potassium, zinc, and magnesium complexes of a bulky OOO-tridentate bis(phenolate) ligand: synthesis, structures, and studies of cyclic ester polymerisation. AB - Reaction of the OOO-coordinating tridentate bis(phenolate) protio-ligand 2,2' {oxybis(methylene)}bis{4,6-di(1-methyl-1-phenylethyl)phenol} (L(O3)-H2), with 1 equiv. of KN(SiMe3)2 in toluene or THF yielded [K(L(O3)-H)] (1) or [K(L(O3) H)(THF)] (2), respectively. Single-crystal X-ray diffraction studies of 1 and 2 revealed mononuclear structures with the phenyl rings of the bulky ligand displaying stabilising pi-interactions to the potassium centre. L(O3)-H2 also reacts with 1 equiv. of ZnEt2 or Mg(n)Bu2 to give [M2(L(O3))2] (M = Zn (3) or Mg (4)) in good yield. The molecular structures of complex 3 and 4 reveal dinuclear species in which the metal centres are tetra-coordinated to the three oxygen atoms of one L(O3) ligand, and to the bridging oxygen atom of one phenolate group of another. Complexes 1-4 are catalysts for ring-opening polymerisation of epsilon-caprolactone and L- and rac-lactide in the presence of benzyl alcohol (BnOH) and also other initiators to give the corresponding polyesters. Kinetic studies for the ROP of epsilon-caprolactone using 3 and BnOH gives an unusual rate expression R(p) = -d[CL]/dt = k(p)[BnOH]0[3]0(0.5) for which a tentative kinetic model is proposed. PMID- 23435515 TI - Bronchiolitis obliterans after allogeneic hematopoietic SCT: further insight--new perspectives? AB - Bronchiolitis obliterans (BO) is a late non-infectious pulmonary complication after allogeneic hematopoietic SCT. Among 982 patients after myeloablative hematopoietic SCT between January 2000 and October 2010, 68 were diagnosed with BO according to NIH criteria. The median onset of BO was 18 months post transplant, 5-year cumulative incidence was 5.8% and 5-year mortality 41%. BO prevalence rate was 10% among all long-term surviving hematopoietic SCT recipients and 12% among chronic GVHD-patients. Chronic GVHD, peripheral SCT and ABO blood group incompatibility were identified as risk factors associated with BO. IgG levels were significantly decreased at the onset of BO (6.7 g/L+/-0.7, P=0.001), the mean exhaled NO concentrations were lower in BO-patients than in stem cell recipients without BO (14 p.p.b.+/-0.9 vs 20 p.p.b.+/-2.1) or healthy controls (25 p.p.b.+/-2.4, P<0.001). Hypoxia-inducible factor 1 alpha (HIF 1alpha) was significantly elevated in BO as compared with healthy controls or GVHD-patients without lung involvement (340+/-61 vs 127+/-22 vs 140+/-32, P=0.02). Calculated 5-year survival was superior in female than in male BO patients (86 vs 45%, P=0.04). These results emphasize the relevance of BO as serious late complication with substantial mortality and point to essential pathophysiological changes due to regulatory responses to hypoxia. PMID- 23435516 TI - Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma. AB - Allogeneic hematopoietic SCT (HSCT) has been shown to be an effective treatment option for advanced renal cell cancer (RCC). However, tumor resistance/relapse remains as the main post transplant issue. Therefore, enhancing graft-versus tumor (GVT) activity without increasing GVHD is critical for improving the outcome of HSCT. We explored the GVT effect of haploidentical-SCT (haplo-SCT) against RCC in murine models. Lethally irradiated CB6F1 (H2K(b/d)) recipients were transplanted with T-cell-depleted BM cells from B6CBAF1 (H2K(b/k)) mice. Haplo-SCT combined with a low-dose haploidentical (HI) T-cell infusion (1 * 10(5)) successfully provided GVT activity without incurring GVHD. This effect elicited murine RCC growth control and consequently displayed a comparative survival advantage of haplo-SCT recipients when compared with MHC-matched (B6D2F1?CB6F1) and parent-F1 (B6?CB6F1) transplant recipients. Recipients of haplo-SCT had an increase in donor-derived splenic T-cell numbers, T-cell proliferation and IFN-gamma-secreting donor-derived T-cells, a critical aspect for anti-tumor activity. The splenocytes from B6CBAF1 mice had a higher cytotoxicity against RENCA cells than the splenocytes from B6 and B6D2F1 donors after tumor challenge. These findings suggest that haplo-SCT might be an innovative immunotherapeutic platform for solid tumors, particularly for renal cell carcinoma. PMID- 23435517 TI - A temperature-concentration (T-X) phase diagram calculated using the mean field theory for liquid crystals. AB - Phase-line equations for smectic-hexatic phase transitions in liquid crystals were derived using the Landau phenomenological theory. In particular, second order transitions for the smectic-A-smectic-C (SmA-SmC) and hexatic-B-hexatic-F (or HexI) transitions were studied and the tricritical points for these transitions were located. The calculated phase-line equations were fitted (using experimental data for various liquid crystals) to construct a generalized T-X phase diagram. It was shown that the T-X phase diagram calculated from the free energy adequately describes the observed behavior of liquid crystals during smectic-hexatic transitions. PMID- 23435518 TI - Energetics of liposomes encapsulating silica nanoparticles. AB - Nanoparticles may be taken up into cells via endocytotic processes whereby the foreign particles are encapsulated in vesicles formed by lipid bilayers. After uptake into these endocytic vesicles, intracellular targeting processes and vesicle fusion might cause transfer of the vesicle cargo into other vesicle types, e.g., early or late endosomes, lysosomes, or others. In addition, nanoparticles might be taken up as single particles or larger agglomerates and the agglomeration state of the particles might change during vesicle processing. In this study, liposomes are regarded as simple models for intracellular vesicles. We compared the energetic balance between two liposomes encapsulating each a single silica nanoparticle and a large liposome containing two silica nanoparticles. Analytical expressions were derived that show how the energy of the system depends on the particle size and the distance between the particles. We found that the electrostatic contributions to the total energy of the system are negligibly small. In contrast, the van der Waals term strongly favors arrangements where the liposome snugly fits around the nanoparticle(s). Thus the two separated small liposomes have a more favorable energy than a larger liposome encapsulating two nanoparticles. PMID- 23435519 TI - Adsorption and decomposition mechanism of hexogen (RDX) on Al(111) surface by periodic DFT calculations. AB - The adsorption of hexogen (RDX) molecule on the Al(111) surface was investigated by the generalized gradient approximation (GGA) of density functional theory (DFT). The calculations employ a supercell (4*4*3) slab model and three dimensional periodic boundary conditions. The strong attractive forces between RDX molecule and aluminum atoms induce the N-O and N-N bond breaking of the RDX. Subsequently, the dissociated oxygen atoms, NO2 group and radical fragment of RDX oxidize the Al surface. The largest adsorption energy is -835.7 kJ mol(-1). We also investigated the adsorption and decomposition mechanism of RDX molecule on the Al(111) surface. The activation energy for the dissociation steps of V4 configuration is as large as 353.1 kJ mol(-1), while activation energies of other configurations are much smaller, in the range of 70.5-202.9 kJ mol(-1). The N-O is even easier than the N-NO2 bond to decompose on the Al(111) surface. PMID- 23435520 TI - Preoperative serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen level predicts postoperative distant metastasis in patients with non small-cell lung cancer. AB - OBJECTIVES: To examine the relationship between preoperative serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (I-CTP) levels and postoperative distant metastasis in patients with non-small-cell lung cancer (NSCLC). METHODS: We retrospectively reviewed 143 patients in whom preoperative serum I-CTP level was measured from January 2006 to March 2011, including 91 males and 52 females with an average age of 70.1 +/- 8.2 years. Histological subtypes included adenocarcinoma (n = 95), squamous cell carcinoma (n = 34) and other (n = 14). Preoperative serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) levels were also measured. Patients with abnormal renal function or preoperative bone fractures were excluded. RESULTS: The mean preoperative serum I-CTP level was 4.1 +/- 1.6 ng/ml, and the preoperative serum I-CTP level was elevated (>4.5 ng/ml) in 29 patients. Distant metastasis was detected in 21 patients during the 39 +/- 18 (range 1-79) months of follow-up. The rate of distant metastasis was significantly higher in patients with elevated preoperative serum I-CTP levels than those with normal preoperative I-CTP levels (<=4.5 ng/ml) (P < 0.0001). The 5-year recurrence-free survival rate was lower in patients with elevated preoperative serum I-CTP levels than those with normal preoperative I-CTP levels (41.8 vs 92.9%; P < 0.0001). CONCLUSIONS: An elevated preoperative serum I-CTP level predicts postoperative distant metastasis in patients with NSCLC. PMID- 23435521 TI - Distal anastomotic patency of the Cardica C-PORT(R) xA system versus the hand sewn technique: a prospective randomized controlled study in patients undergoing coronary artery bypass grafting. AB - OBJECTIVES: The C-Port(r) Distal Anastomosis Systems (Cardica, Inc., Redwood City, CA, USA) demonstrated favourable results in feasibility trials. However, distal vein anastomoses created with the C-Port(r) or C-Port xA(r) system have never been compared with hand-sewn distal vein anastomoses. The objective of this study was to compare distal end-to-side anastomoses facilitated with the C-Port xA(r) System with the traditional hand-sewn method. METHODS: This single-centre prospective randomized controlled study comprised 71 patients (device group n = 35, control group n = 36) who underwent primary elective coronary artery bypass grafting between June 2008 and April 2011. The primary study end-point was 12 month distal anastomotic patency, which was assessed with prospective ECG-gated 256-multislice computed tomographic coronary angiography using a step-and-shoot scanning protocol. For the primary end-point, a per-protocol analysis was used. RESULTS: In the device group, four (11%) anastomoses were converted to hand-sewn anastomoses, and additional stitches to achieve haemostasis were necessary in 22 (76%) patients. There was no hospital mortality in either group. During the 12 month follow-up, a single death occurred in the Device group and was unrelated to the device. Twenty-nine patients in the device group and 32 in the control group completed 12-month CT coronary angiography. The overall patency of 160 studied distal vein graft anastomoses was 93%. Comparison of the end-to-side target anastomosis showed 12-month patencies of 86 and 88% in the device group and the control group, respectively. CONCLUSIONS: According to these preliminary results and despite the limited number of patients, the use of the C-Port xA(r) System is safe enough to perform distal end-to-side vein graft anastomosis, with respect to 12-month end-to-side distal venous anastomotic patency. Although there are some technical challenges with this device, the incidence of complications is comparable to the traditional hand-sewn technique. PMID- 23435522 TI - The use of internal thoracic artery grafts in patients with aortic coarctation. AB - The choice of conduits for surgical revascularization in patients with aortic coarctation can be puzzling, as the internal thoracic arteries can be dilated, atherosclerotic and unsuitable for grafting. Reports in the literature are controversial: in some cases, the internal thoracic artery was not suitable for revascularization, while in others, it could be used with discordant outcomes. Here, we review the literature on the subject. PMID- 23435523 TI - Remote access perfusion for minimally invasive cardiac surgery: to clamp or to inflate? AB - OBJECTIVES: Endoaortic balloon occlusion (EBO) and aortic transthoracic clamping (TTC) are the dominant methods of remote access perfusion (RAP) in minimally invasive cardiac surgery. The aim of the study was to compare the two methods in terms of feasibility, success and complications. METHODS: From June 2001 to November 2011, 307 (median age; range) (57; 16-77 years) and 460 (62; 11-88 years) patients underwent minimally invasive CABG, ASD and mitral valve surgery using EBO and TTC, respectively. Perioperative procedure feasibility, success and postoperative complications were recorded. RESULTS: Overall 30-day mortality was 0 and 2 (0.43%) for the EBO and TTC groups, respectively (P = 0.52). Overall and RAP-associated conversions were noted in 21 (6.8%) and 4 (1.3%) patients in the EBO and in 9 (2%) and 6 (1.3%) patients in the TTC groups (P < 0.001, P = 1.00, respectively). Incidence of major complications, including aortic dissection, major vessel perforation, injury of intrapericardial structures, limb ischaemia, myocardial infarction and neurologic events, was similar [EBO: 12 (4%); TTC: 11 (2.4%); P = 0.23]. Minor complications such as minor vessel injury, groin bleeding or lymphatic fistula were noted in 31 (10.1%) and 35 (7.6%), respectively (P = 0.23). Successful RAP procedures defined as absence of RAP associated conversions and major complications were equal [EBO: 295 (96%); TTC: 449 (97.6%); P = 0.23]. Complications detected during follow-up included pain: 30 of 249 (12%) and 13 of 279 (4.7%) (P = 0.002); sensational disturbances: 60 of 249 (24.1%) and 40 of 278 (14.4%) (P = 0.005) and wound-healing complications: 49 of 249 (19.7%) and 42 of 277 (15.2%) (P = 0.172) for EBO and TTC, respectively. CONCLUSIONS: RAP can be successfully and safely implemented in minimally invasive cardiac surgery. EBO and transthoracic clamping of the ascending aorta are performing equally in terms of feasibility and procedural success. PMID- 23435524 TI - Off-pump surgery in preventing perioperative stroke after coronary artery bypass grafting: a retrospective multicentre study. AB - OBJECTIVES: To determine the effect of the off-pump technique in preventing stroke development during the early perioperative period after coronary artery bypass graft surgery (CABG). METHODS: Patients undergoing isolated CABG surgery were enrolled from 21 Spanish cardiac-surgery centres. Baseline variables related to perioperative stroke risk were recorded in the preoperative (age, gender, diabetes mellitus, arterial hypertension, prior stroke, cardiac failure: preoperative New York Heart Association class III-IV and/or left ventricular ejection fraction <40%, non-elective priority of surgery, peripheral arteriopathy, chronic renal failure) and intraoperative periods (on/off-pump performance). The Northern New England Cardiovascular Disease Study Group (NNECDSG) stroke risk schema was used to stratify stroke risk and compare observed neurological outcomes in this study. RESULTS: A total of 26 347 patients were included in the study. Global perioperative stroke incidence was 1.38%. Non elective priority of surgery (OR = 2.37), peripheral arteriopathy (OR = 1.62), cardiac failure (OR = 2.98), prior stroke (OR = 1.57) and chronic renal failure (OR = 6.16) were found to be independent risk factors for perioperative stroke in uni- and multivariate models; Hosmer-Lemeshow test: chi(2) = 4.62, P = 0.59. Perioperative stroke incidence increased whenever NNECDSG score or the number of preoperative risk factors increased. However, on- vs off-pump surgery did not show statistical differences in NNECDSG strata. For patients with two or more preoperative independent risk factors, off-pump surgery showed a significant reduction in perioperative stroke incidence (4.29 vs 6.76%, P < 0.05), particularly when one of these factors was chronic renal failure or preoperative cardiac failure. However, when both factors were present concomitantly there was no difference between on and off-pump techniques, P < 0.0001. CONCLUSIONS: Off pump surgery has a lower perioperative stroke incidence than on-pump only in cases associated with cardiovascular stroke-risk factors, in particular, with chronic renal failure and preoperative cardiac failure, but also with peripheral arteriopathy, prior stroke and non-elective surgery. The perioperative stroke rate remains high in cases with two or more preoperative stroke risk factors, even when using the off-pump technique, particularly when chronic renal failure is present. PMID- 23435525 TI - Marfan syndrome with antineutrophil cytoplasmic antibody-associated systemic vasculitis presenting as severe anaemia and haematuria after the Bentall procedure. AB - One month previously, a 28-year old male underwent an emergency modified Bentall procedure because of Marfan syndrome with acute aortic dissection Stanford Class A. Computed tomography of the chest did not reveal severe graft stenosis of the anastomosis. To explore the cause of anaemia, renal dysfunction and macroscopic haematuria, the patient was tested for antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV). Antimyeloperoxidase antibodies (MPO)-ANCA and antiproteinase 3 antibodies (PR3)-ANCA were strongly positive. Corticosteroid therapy was applied, followed by cyclophosphamide and azathioprine. In response to treatment, the MPO-ANCA and PR3-ANCA levels gradually decreased, proteinuria was alleviated and haemoglobin levels returned to normal after 6 months. This is the first report to highlight haemolytic anaemia and AASV with Marfan syndrome after surgery for aortic dissection. PMID- 23435527 TI - Foldamer-based chiral supramolecular alternate block copolymers tuned by ion-pair binding. AB - A chiral supramolecular alternate block copolymer has been self-assembled from a ureidopyrimidinone (UPy)-terminated arylamide-based hydrogen bonded foldamer and a structurally flexible pentamer, which is driven by the ion-pair binding of the two arylamide segments toward chiral ammonium and carboxylate guests. PMID- 23435526 TI - Triclosan-coated sutures reduce surgical site infection after open vein harvesting in coronary artery bypass grafting patients: a randomized controlled trial. AB - OBJECTIVES: The incidence of surgical site infection (SSI) after open vein harvesting in coronary artery bypass grafting (CABG) patients ranges in different studies between 2 and 20%. Triclosan is an antibacterial substance that reduces the growth of bacteria by inhibiting fatty acid synthesis. We hypothesized that wound closure with triclosan-coated sutures would reduce SSI after open vein harvesting. METHODS: An investigator-initiated prospective randomized double blind single-centre study was performed with 374 patients, randomized to subcutaneous and intracutaneous leg-wound closure with either triclosan-coated sutures (Vicryl Plus and Monocryl Plus, Ethicon, Somerville, NJ, USA) (n = 184) or identical sutures without triclosan (n = 190) from the same manufacturer. All patients were followed up after 30 days (clinical visit) and 60 days (telephone interview). Primary endpoint was SSI within 60 days after surgery according to the definition of Center for Disease Control. Predefined secondary endpoints included culture-proven and antibiotic-treated SSI. RESULTS: The primary endpoint occurred in 23 patients (12.5%) with triclosan-coated sutures and in 38 patients (20.0%) in the group without triclosan (P = 0.0497, risk ratio 0.63, (95% confidence interval 0.39-1.00). Corresponding figures for culture-proven infections were 7.6 vs 12.1%, (P = 0.15), and for antibiotic-treated infections, 10.9 vs 18.4%, (P = 0.039). Staphylococcus aureus and coagulase-negative staphylococci were the most common pathogens in both groups. Insulin-treated diabetes and vein-harvesting time were associated with SSI after vein harvesting. CONCLUSIONS: Leg-wound closure with triclosan-coated sutures in CABG patients reduces SSIs after open vein harvesting. (ClinicalTrials.gov number NCT01212315). PMID- 23435528 TI - Amphibian chytrid prevalence in an amphibian community in arid Australia. PMID- 23435529 TI - Lower sperm DNA fragmentation after r-FSH administration in functional hypogonadotropic hypogonadism. AB - PURPOSE: An observational clinical and molecular study was designed to evaluate the effects of the administration of recombinant human FSH on sperm DNA fragmentation in men with a non-classical form of hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia. METHODS: In the study were included 53 men with a non-classical form of hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia. In all patients, sperm DNA fragmentation index (DFI), assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) in situ DNA nick end-labelling (TUNEL) assay, was evaluated before starting the treatment with 150 IU of recombinant human FSH, given three times a week for at least 3 months. Patients' semen analysis and DNA fragmentation index were re-evaluated after the 3-month treatment period. RESULTS: After recombinant human FSH therapy, we did not find any differences in terms of sperm count, motility and morphology. The average DNA fragmentation index was significantly reduced (21.15 vs 15.2, p<0.05), but we found a significant reduction in patients with high basal DFI values (>15 %), while no significant variation occurred in the patients with DFI values <= 15 %. CONCLUSIONS: Recombinant human FSH administration improves sperm DNA integrity in hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia men with DNA fragmentation index value >15 % . PMID- 23435530 TI - Effects of supplement therapy on sperm parameters, protamine content and acrosomal integrity of varicocelectomized subjects. AB - PURPOSE: Surgical repair of varicocele has long been a procedure to correct spermatogenesis. However, the outcome has been reported to be inadequate. We combined varicocelectomy with supplement therapy to evaluate the concurrent effect of these procedures. METHODS: A prospective randomized controlled study was undertaken to investigate the effects of zinc sulfate, folic acid and zinc sulfate/folic acid on sperm quality, protamine content and acrosomal integrity following surgical repair of varicocele. Male subjects with palpable varicocele were included in the study and randomized into four groups. Subjects received Zinc sulfate, Folic acid, Zinc sulfate/Folic acid or placebo for 6 months. A semen sample was obtained before surgery and 3 and 6 months after surgical repair. Semen samples were evaluated for sperm parameters as well as chromatin content and acrosomal integrity. RESULTS: Most of the evaluated parameters showed a mild improvement after varicocelectomy in the placebo group. Interestingly, co administration of Zinc sulfate and folic acid improved most factors significantly. Folic acid administration but not zinc sulfate could increase sperm number. Hence, Zinc sulfate was better than folic acid when change in morphology was assessed, and none of them was significantly effective in sperm motility. In Zinc sulfate and Folic acid groups, protamine content and halo formation rate significantly improved. CONCLUSIONS: We may conclude that co administration of zinc and folic acid significantly improved sperm parameters and increased varicocelectomy outcomes. So, medical treatment with compatible drugs after surgery might be advantageous for obtaining acceptable results. PMID- 23435531 TI - In vitro and in vivo responses to high and low doses of nitrogen-containing bisphosphonates suggest engagement of different mechanisms for inhibition of osteoclastic bone resorption. AB - The effects of nitrogen-containing bisphosphonates (N-BPs) on osteoclasts (Ocs) may differ with dose and regimen. N-BPs reduce Oc bone resorption by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), an effect counteracted by geranylgeraniol (GGOH), which restores geranylgeranylation downstream of FPPS. We assessed GGOH effects on inhibition of bone resorption by the N-BPs alendronate (ALN), ibandronate (IBN), and zoledronate (ZOL) in an assay of rabbit Oc resorption of bovine cortical bone. GGOH blocked inhibition of resorption at low, but not high, N-BP concentrations, with a 14- to 20-fold increase in IC50 values for each N-BP. In vivo, growing male rats were administered doses calculated to mimic bioavailable exposures in daily (ALN, IBN), weekly (ALN), monthly (IBN), and yearly (ZOL) clinical regimens. Tibiae were harvested at 48 h, and metaphyses were analyzed. With lower ALN and IBN doses, Oc numbers rose by 26-48 %, morphology was normal, and there was no increase in apoptotic Ocs. In contrast, with higher IBN and ZOL doses, bone-associated Ocs were generally rounded in appearance and numbers of nuclei/Oc versus vehicle increased 42 and 31 %, respectively (P < 0.05). With ZOL, there was no rise in Oc number, but there was a 6.5-fold increase in apoptotic Ocs versus vehicle and a >=13.5-fold increase versus lower-dose ALN or IBN (P < 0.05). With higher-dose IBN there was no rise in Oc number but 7- and 14-fold increases in Oc apoptosis versus low-dose ALN and IBN (P < 0.02). These results suggest that different mechanisms may come into play across the dosing spectrum of N-BPs. PMID- 23435532 TI - Can the Liverpool Care Pathway make a recovery? PMID- 23435533 TI - Narrative medicine as a means of indirectly seeking parental opinion in children's palliative care. PMID- 23435534 TI - Grading clinical guidelines for the use of transmucosal immediate-release fentanyl products in breakthrough pain. AB - Pain is a complex symptom that is commonly feared in palliative care owing to its significant effects on patients' quality of life (QoL), and is directly associated with morbidity. More specifically, the management of breakthrough pain (BTP) is particularly important. Opioids play a major part in the management of BTP, and the various transmucosal immediate-release fentanyl (TIRF) products are a common treatment choice. This paper considers the strength of the evidence underlying recommendations regarding the use of TIRF. Failure to consider the quality of evidence in practice can lead to misguided recommendations. Guidelines should therefore be used to inform clinicians of the quality of the underlying evidence and whether recommendations are strong or weak. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach is increasingly being adopted worldwide as it provides a system for rating quality of evidence and strength of recommendations that is clear, comprehensive, transparent, and practical. This paper adopts the GRADE approach to assess the strength of recommendations made in a 2011 review by Zeppetella in order to develop guidelines for the use of TIRF. The recommendations include that TIRF products can be considered for first-line treatment and that they should be individualised to patients who are on a background opioid. PMID- 23435535 TI - Educating families about end-of-life care in advanced dementia: acceptability of a Canadian family booklet to nurses from Canada, France, and Japan. AB - BACKGROUND: The families of people with late-stage dementia need to be informed about the course of the dementia and the comfort/palliative care option. A booklet was written for that purpose and can be provided to family members by physicians and nurses. METHODS: The acceptability of the booklet for nurses was tested in Canada (French and English version), France (French Canadian version) and Japan (translated and adapted version). RESULTS: Overall, 188 nurses completed a survey questionnaire. The booklet was accepted best in Canada and less so in France and Japan. Despite regional variation, the majority of the nurses perceived the booklet as useful for families. The French and Japanese nurses also reported a greater need for palliative care education in advanced dementia. CONCLUSION: The booklet may help nurses educate families about end-of life issues in dementia palliative care, but local adaptation of the booklet content and physician engagement are necessary. PMID- 23435536 TI - Attitudes regarding life-sustaining measures in people born in Japan, China, and Vietnam and living in Texas. AB - Cultural beliefs about and preferences for care at the end of life are diverse and unique in many respects. This descriptive qualitative study presents findings about the attitudes and preferences of people born in Japan, China, and Vietnam and living in the southern part of the USA regarding life-sustaining measures. In depth personal and focus group interviews were conducted with 46 participants and thematic analysis completed. The findings reflected some similarities and differences among the three groups concerning initiation and discontinuance of artificial nutrition and mechanical ventilation. They also demonstrated the requirement for sensitivity to individual needs when honouring the wishes of patients and surrogate decision makers. Interventional studies should follow that test educational strategies to improve practice outcomes for health-care providers who care for these populations at this vulnerable time of life. PMID- 23435537 TI - Working in a medicalised world: the experiences of palliative care nurse specialists and midwives. AB - AIM: This paper reports a study that explored birth and death care experiences from the perspectives of midwives and palliative care clinical nurse specialists (CNSs). METHODS: A grounded theory approach illuminated the social processes associated with caring during birth and death. Data was collected during 2011 through in-depth semi-structured interviews with eight participants: four midwives and four CNSs from UK NHS Trusts. FINDINGS: Four categories were identified through thematic analysis: memories, one act, advocate, and medical event. These integrated to create a core category: working to counter the pathologisation of birth and death. CONCLUSION: The participants illustrate the impact of medicalisation on the experience of birth and death and struggle with the negative effects of this. Health professionals should work toward practice that emphasises the importance of holistic care. PMID- 23435538 TI - The role of a community palliative care specialist nurse team in caring for people with metastatic breast cancer. AB - An audit was undertaken of people with a diagnosis of breast cancer who were referred to a community palliative care specialist nursing team over a 12-month period, to explore the reasons for referral to the service and the duration of involvement with the service. Breast cancer patients accounted for 10% of the total referrals to the specialist service, with symptom management (including pain control) and emotional support being the main reasons for referral. The majority of people referred with breast cancer had metastatic breast cancer (87%); interestingly, 13% had primary breast cancer. The mean duration of intervention was 3 months and 1 week. Referrals seemed to occur late in patients' disease trajectories, and total numbers were lower than might be expected. It may be concluded that there is scope for the specialist palliative care team to be a more integral part of care for patients with metastatic breast cancer. PMID- 23435541 TI - Attenuation by statins of membrane raft-redox signaling in coronary arterial endothelium. AB - Membrane raft (MR)-redox signaling platforms associated with NADPH oxidase are involved in coronary endothelial dysfunction. Here, we studied whether statins interfere with the formation of MR-redox signaling platforms to protect the coronary arterial endothelium from oxidized low-density lipoprotein (OxLDL) induced injury and from acute hypercholesterolemia. In cultured human coronary arterial endothelial cells, confocal microscopy detected the formation of an MRs clustering when they were exposed to OxLDL, and such MR platform formation was inhibited markedly by statins, including pravastatin and simvastatin. In these MR clusters, NADPH oxidase subunits gp91(phox) and p47(phox) were aggregated and were markedly blocked by both statins. In addition, colocalization of acid sphingomyelinase (ASM) and ceramide was induced by OxLDL, which was blocked by statins. Electron spin resonance spectrometry showed that OxLDL-induced superoxide (O2(.-)) production in the MR fractions was substantially reduced by statins. In coronary artery intima of mice with acute hypercholesterolemia, confocal microscopy revealed a colocalization of gp91(phox), p47(phox), ASM, or ceramide in MR clusters. Such colocalization was rarely observed in the arteries of normal mice or significantly reduced by pretreatment of hypercholesterolemic mice with statins. Furthermore, O2(.-) production in situ was 3-fold higher in the coronary arteries from hypercholesterolemic mice than in those from normal mice, and such increase was inhibited by statins. Our results indicate that blockade of MR-redox signaling platform formation in endothelial cell membrane may be another important therapeutic mechanism of statins in preventing endothelial injury and atherosclerosis and may be associated with their direct action on membrane cholesterol structure and function. PMID- 23435542 TI - Pharmacological characterization of GSK573719 (umeclidinium): a novel, long acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. AB - Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4 [hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1 azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 MUg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 MUg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases. PMID- 23435543 TI - Climate change and levels of violence in socially disadvantaged neighborhood groups. AB - The current study examines the link between climate change and neighborhood levels of violence using 20 years of monthly climatic and crime data from St. Louis, MO, USA. St. Louis census tracts are aggregated in neighborhood groups of similar levels of social disadvantage, after which each group is subjected to time series analysis. Findings suggest that neighborhoods with higher levels of social disadvantage are very likely to experience higher levels of violence as a result of anomalously warm temperatures. The 20 % of most disadvantaged neighborhoods in St. Louis, MO, USA are predicted to experience over half of the climate change-related increase in cases of violence. These results provide further evidence that the health impacts of climate change are proportionally higher among populations that are already at high risk and underscore the need to comprehensively address climate change. PMID- 23435544 TI - Chloride transport and novel insights into salt-sensitive hypertension. PMID- 23435550 TI - First structurally characterized self-assembly of bipodal N-thiophosphorylated bis-thiourea with Co(II): magnetic properties and thermal decomposition. AB - Reaction of piperazine with isothiocyanate (iPrO)2P(S)NCS leads to N thiophosphorylated bis-thiourea (iPrO)2P(S)NHC(S)NC4H8NC(S)NHP(S)(OiPr)2 (H2L). Recrystallization of H2L from DMSO leads to the formation of the new ligand (iPrO)2P(S)NC4H8NP(S)(OiPr)2 (1). Reaction of doubly deprotonated L with Co(II) leads to the [Co2L2] complex. The thermal properties of [Co2L2] in an air atmosphere were studied by means of TGA with the observed final residue corresponding to [CoPS3]2. The crystal structure of [Co2L2] was elucidated by single crystal X-ray diffraction. Two metal cations are in a tetrahedral 1,5 S2S'2 environment formed by the C=S and P=S sulfur atoms. Investigation of the temperature dependence of the magnetic susceptibility is consistent with two effectively non-interacting Co(II) S = 3/2 ions. PMID- 23435549 TI - Parenting stress and externalizing behavior symptoms in children: the impact of emotional reactivity. AB - This study investigated whether the parenting stress-child externalizing behavior link is moderated by children's emotional reactivity, as indexed by skin conductance responses (SCRs). Participants were 61 children aged 9-12 years and their mothers. Mothers completed measures of parenting stress and their children's externalizing symptoms; children also reported on their externalizing behavior. Children's SCRs were assessed during the viewing of standardized pleasant, unpleasant, and neutral pictures. Cluster analysis on SCRs identified two groups, labeled Lower SCRs and Higher SCRs. Regression analyses indicated that among children with lower SCRs, those exposed to increased parenting stress reported more externalizing symptoms, whereas those who experienced low parenting stress reported similar rates of externalizing problems as children with higher SCRs. No effect of parenting stress emerged for children with higher SCRs. Findings suggest that higher parenting stress renders children with lower, as opposed to higher, SCRs to emotional stimuli more vulnerable to externalizing problems. PMID- 23435551 TI - Radioactive Cs capture in the early solar system. AB - Barium isotopic compositions of primitive materials in the solar system are generally affected by s- and r-process nucleosynthetic components that hide the contribution of the isotopic excess of (135)Ba formed by decay of radioactive (135)Cs. However, the Ba isotopic composition of the chemical separates from chondrules in the Sayama CM2 chondrite shows an excess of (135)Ba isotopic abundance up to (0.33 +/- 0.06)%, which is independent of the isotopic components from s- and r-process nucleosyntheses. The isotopic excesses of (135)Ba correlate with the elemental abundance of Ba relative to Cs, providing chemical and isotopic evidence for the existence of the presently extinct radionuclide (135)Cs (t(1/2) = 2.3 million years) in the early solar system. The estimated abundance of (135)Cs/(133)Cs = (6.8 +/- 1.9) * 10(-4) is more than double that expected from the uniform production model of the short-lived radioisotopes, suggesting remobilization of Cs including (135)Cs in the chondrules of the meteorite parent body. PMID- 23435552 TI - The impact of handgrip exercise duty cycle on brachial artery flow-mediated dilation. AB - Endothelial function is essential for vasoprotection and regulation of vascular tone. Using handgrip exercise (HGEX) to increase blood flow-associated shear stress is an increasingly popular method for assessing brachial artery endothelial function via flow-mediated dilation (FMD). However, different exercise duty cycles [ratio of handgrip relaxation: contraction (seconds)] produce different patterns of brachial artery shear stress with distinct antegrade/retrograde magnitudes. To determine the impact of HGEX duty cycle on brachial artery %FMD, three distinct duty cycles were employed while maintaining a uniform mean shear stress. Brachial artery diameter and mean blood velocity were assessed via echo and Doppler ultrasound in 16 healthy male subjects. Shear stress was estimated as shear rate (SR = blood velocity/brachial artery diameter) and the target mean SR during HGEX was 75 s(-1). Subjects performed three 6-min HGEX trials on each of 2 days (like trials averaged). In each trial, subjects performed one of the three randomly ordered HGEX duty cycles (1:1, 3:1, 5:1). %FMD was calculated from baseline to the end of HGEX and (subset N = 10) during each minute of HGEX. Data are mean +/- SD. As intended, mean SR was uniform across duty cycles (6 min HGEX average: 72.9 +/- 4.9s(-1), 72.6 +/- 3.6s(-1), 72.8 +/- 3.5 s(-1), p = 0.835), despite differences in antegrade/retrograde SR (p < 0.001). End-exercise %FMD (4.0 +/- 1.3 %, 4.1 +/- 2.2 %, 4.2 +/- 1.4 %, p = 0.860) and %FMD during exercise (p = 0.939) were not different between duty cycles. These data indicate that the endothelium responds to the mean shear stress and is not specifically sensitive to the contraction/relaxation or retrograde shear stress created by a range of HGEX protocols. PMID- 23435553 TI - Exploring the multifunctionality of thioflavin- and deferiprone-based molecules as acetylcholinesterase inhibitors for potential application in Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of people worldwide. With no prevention or cure available, this progressive disease has a significant impact on society - dementia patients and their caretakers, healthcare systems, and the economy. Previously, we have reported initial developments of multifunctional drug candidates for AD based on two scaffolds - thioflavin-T and deferiprone. Individually, these molecules have shown several favorable functionalities, including dissociation of toxic amyloid beta aggregates, antioxidant and/or metal chelating ability that can pacify reactive oxygen species, plaque targeting, and blood-brain barrier penetration. In this work, the two scaffolds are augmented with a new functionality - acetylcholinesterase inhibition. This functionality is incorporated by derivatization with a carbamate group, which is the active group in some AD drugs currently in the market. We present the rationale for designing three novel compounds, their synthesis and characterization, including X-ray crystallographic data, and encouraging results from in vitro and computational acetylcholinesterase inhibition studies. Also, we evaluate the compounds as potential drug candidates by Lipinski's rules and cytotoxicity studies in a neuronal cell line. Overall, we demonstrate the feasibility of improving on two well established scaffolds, as well as show in vitro efficacy plus initial mode of action and biological compatibility data. PMID- 23435554 TI - Fluorescent probe for biological gas SO2 derivatives bisulfite and sulfite. AB - A coumarin-hemicyanine dye was reported for ratiometric fluorescent detection of SO2 derivatives HSO3(-) and SO3(2-) based on a novel addition-rearrangement cascade reaction. PMID- 23435555 TI - Evidence that self-incentives increase fruit consumption: a randomized exploratory trial among high-risk romanian adolescents. AB - High mortality rates associated with cancer and cardiovascular disease in Romania have been partly attributed to low fruit consumption. The aim of the present research was to test whether self-incentives delivered via implementation intentions could increase fruit consumption among 238 high-risk Romanian adolescents. Participants were randomly allocated to either: (1) a control condition (asked to plan to increase their fruit intake but given no further instruction), (2) a standard implementation intention condition (asked to form an implementation intention using standard open-ended instructions), or (3) a self incentivizing implementation intention condition (asked to reward themselves at the end of the week if they had successfully consumed an extra portion of fruit each day). There were significant increases in fruit consumption in the self incentivizing implementation intention condition, but not in the control condition or-contrary to predictions-in the standard implementation intention condition. The findings support the use of implementation intentions to deliver self-incentives and increase fruit consumption, and suggest that providing children with a structured prompt might enhance the effectiveness of implementation intention-based interventions compared with standard implementation intention instructions. PMID- 23435556 TI - Understanding and controlling hot spots of crime: the importance of formal and informal social controls. AB - Primary, secondary, and tertiary prevention programs that address opportunity or structural factors related to crime are usually delivered to entire cities, sections of cities or to specific neighborhoods, but our results indicate geographically targeting these programs to specific street segments may increase their efficacy. We link crime incidents to over 24,000 street segments (the two block faces on a street between two intersections) over a 16-year period, and identify distinct developmental patterns of crime at street segments using group based trajectory analysis. One of these patterns, which we term chronic crime hot spots, includes just 1 % of street segments but is associated with 23 % of crime in the city during the study period. We then employ multinomial regression to identify the specific risk and protective factors that are associated with these crime hot spots. We find that both situational opportunities and social characteristics of places strongly distinguish chronic crime hot spots from areas with little crime. Our findings support recent efforts to decrease crime opportunities at crime hot spots through programs like hot spots policing, but they also suggest that social interventions directed at crime hot spots will be important if we are to do something about crime problems in the long run. We argue in concluding that micro level programs which focus crime prevention efforts on specific street segments have the potential to be less costly and more effective than those targeted at larger areas such as communities or neighborhoods. PMID- 23435557 TI - The cubic [Ti8F36]4- anion found in the crystal structures of K4Ti8F36.8HF and Rb4Ti8F36.6HF. AB - X-ray diffraction study of K4Ti8F36.8HF and Rb4Ti8F36.6HF reveals a novel type of octameric cubic [M8F36](4-) anion built from eight M(IV)F6 octahedra. PMID- 23435558 TI - A case of streptomycin-induced pneumonitis. PMID- 23435559 TI - Severity assessment of Japanese cedar pollinosis using the practical guideline for the management of allergic rhinitis in Japan and the allergic rhinitis and its impact on asthma guideline. AB - BACKGROUND: This study intended to assess the severity of Japanese cedar pollinosis using the Practical Guideline for the Management of Allergic Rhinitis in Japan (PG-MARJ) and the Allergic Rhinitis and its Impact on Asthma (ARIA) Guideline. METHODS: An Internet questionnaire survey of patients with pollinosis was conducted in mid-May 2011 and responses were obtained from 3382 individuals who had potential symptoms of Japanese cedar pollinosis from February to early May 2011 and who had experienced such symptoms for at least two pollen seasons. RESULTS: According to PG-MARJ, 23.5% of the respondents had severest rhinitis, 29.4% severe rhinitis, 31.3% moderate rhinitis, 13.8% mild rhinitis and 2.0% asymptomatic rhinitis. According to ARIA, 67.2% of them had moderate/severe persistent rhinitis, 23.8% moderate/severe intermittent rhinitis, 4.4% mild persistent rhinitis and 4.6% mild intermittent rhinitis. CONCLUSIONS: Moderate to severe rhinitis was diagnosed in more than 80% of the respondents according to PG MARJ, while moderate/severe rhinitis was diagnosed in more than 90% of the respondents according to ARIA. Most of the respondents suffered relatively severe pollinosis. More than 80% of the respondents had all the three major symptoms (i.e., sneezing, rhinorrhea and nasal blockage). Disagreement in the severity assessment between the two guidelines was noted in approximately 20% of the respondents. PMID- 23435560 TI - Different fish-eating habits and cytokine production in chronic urticaria with and without sensitization against the fish-parasite Anisakis simplex. AB - BACKGROUND: Anisakis simplex sensitization has been associated with acute, but also with chronic urticaria. The objective of this study is to characterize chronic urticaria with (CU+) and without sensitization (CU-) against the ubiquitous fish parasite A. simplex in a transversal and longitudinal evaluation. METHODS: 16 CU+ and 22 CU- patients were included and assessed for Urticaria activity score (UAS), fish-eating habits by standardized questionnaire and cytokine production (assessed by flow cytometric bead-based array) of peripheral blood mononuclear cells after stimulation with A. simplex extract or Concanavalin A (Con A). Patients were randomly put on a fish-free diet for three months and UAS, as well as cytokine production were again assessed. A difference of >=1 in UAS was defined as improvement. RESULTS: There was no difference in UAS in both groups. Anisakis induced IL-2, IL-4 and IFN-gamma production was higher in CU+. Con A induced IL-6 and IL-10 production was higher in CU+. CU+ was associated with higher total fish intake, whereas CU- was associated with oily fish intake. The correlation of UAS was positive with oily fish, but negative with total fish intake. There was a better UAS-based prognosis in CU+ without diet. Improvement was associated with higher Con A induced IL-10/IFN-gamma as well as IL-10/IL-6 ratios. Further, previous higher oily fish intake was associated with improvement. CONCLUSIONS: Our data confirm the different clinical and immunological phenotype of CU+. Our results show a complex relationship between fish-eating habits, cytokine production and prognosis, which could have important consequences in dietary advice in patients with CU. When encountering A. simplex sensitization, patients should not be automatically put on a diet without fish in order to reduce contact with A. simplex products. PMID- 23435561 TI - Application of SPR imaging sensor for detection of individual living cell reactions and clinical diagnosis of type I allergy. AB - A technique to visualize living cell activation in a real time manner without any labeling is required in the fields of life sciences and medicine. We have reported that surface plasmon resonance (SPR) sensors detect large changes of refractive index (RI) with living cells, such as mast cells, human basophils and lymphocytes. However conventional SPR sensors detect only an average change of RI with thousands of cells at detectable area on a sensor chip. Therefore, we developed an SPR imaging (SPRI) sensor with a CMOS camera and an objective lens in order to visualize RI of individual living cells and their changes upon stimuli. The SPRI sensor we developed could detect reactions of individual rat basophilic leukemia (RBL-2H3) cells and mouse keratinocyte cells in response to specific or nonspecific stimuli. Moreover, the sensor could detect the reactions of individual human basophils isolated from patients in response to antigens (allergens). Thus the technique can visualize the effect of various stimuli, inhibitors and/or conditions on cell reactions as change of intracellular RI distribution at single cell levels. Establishment of the technique to rapidly isolate cells from patient blood should enable us to utilize SPRI system as a high throughput screening system in clinical diagnosis, such as type I hypersensitivity and drug hypersensitivity, and as a tool to reveal novel phenomena in evanescent fields around plasma membranes. PMID- 23435563 TI - A STUbL wards off telomere fusions. PMID- 23435562 TI - Structural basis for the nuclear export activity of Importin13. AB - Importin13 (Imp13) is a bidirectional karyopherin that can mediate both import and export of cargoes. Imp13 recognizes several import cargoes, which include the exon junction complex components Mago-Y14 and the E2 SUMO-conjugating enzyme Ubc9, and one known export cargo, the translation initiation factor 1A (eIF1A). To understand how Imp13 can perform double duty, we determined the 3.6-A crystal structure of Imp13 in complex with RanGTP and with eIF1A. eIF1A binds at the inner surface of the Imp13 C-terminal arch adjacent and concomitantly to RanGTP illustrating how eIF1A can be exported by Imp13. Moreover, the 3.0-A structure of Imp13 in its unbound state reveals the existence of an open conformation in the cytoplasm that explains export cargo release and completes the export branch of the Imp13 pathway. Finally, we demonstrate that Imp13 is able to bind and export eIF1A in vivo and that its function is essential. PMID- 23435564 TI - A direct proofreader-clamp interaction stabilizes the Pol III replicase in the polymerization mode. AB - Processive DNA synthesis by the alphaepsilontheta core of the Escherichia coli Pol III replicase requires it to be bound to the beta2 clamp via a site in the alpha polymerase subunit. How the epsilon proofreading exonuclease subunit influences DNA synthesis by alpha was not previously understood. In this work, bulk assays of DNA replication were used to uncover a non-proofreading activity of epsilon. Combination of mutagenesis with biophysical studies and single molecule leading-strand replication assays traced this activity to a novel beta binding site in epsilon that, in conjunction with the site in alpha, maintains a closed state of the alphaepsilontheta-beta2 replicase in the polymerization mode of DNA synthesis. The epsilon-beta interaction, selected during evolution to be weak and thus suited for transient disruption to enable access of alternate polymerases and other clamp binding proteins, therefore makes an important contribution to the network of protein-protein interactions that finely tune stability of the replicase on the DNA template in its various conformational states. PMID- 23435565 TI - Struggling to let go: a non-coding RNA directs its own extension and destruction. PMID- 23435566 TI - NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15. AB - Primary cilia are antenna-like sensory organelles protruding from the plasma membrane. Defects in ciliogenesis cause diverse genetic disorders. NDR2 was identified as the causal gene for a canine ciliopathy, early retinal degeneration, but its role in ciliogenesis remains unknown. Ciliary membranes are generated by transport and fusion of Golgi-derived vesicles to the pericentrosome, a process requiring Rab11-mediated recruitment of Rabin8, a GDP GTP exchange factor (GEF) for Rab8, and subsequent Rab8 activation and Rabin8 binding to Sec15, a component of the exocyst that mediates vesicle tethering. This study shows that NDR2 phosphorylates Rabin8 at Ser-272 and defects in this phosphorylation impair preciliary membrane assembly and ciliogenesis, resulting in accumulation of Rabin8-/Rab11-containing vesicles at the pericentrosome. Rabin8 binds to and colocalizes with GTP-bound Rab11 and phosphatidylserine (PS) on pericentrosomal vesicles. The phospho-mimetic S272E mutation of Rabin8 decreases affinity for PS but increases affinity for Sec15. These results suggest that NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by triggering the switch in binding specificity of Rabin8 from PS to Sec15, thereby promoting local activation of Rab8 and ciliary membrane formation. PMID- 23435567 TI - Pharmacological and non-hormonal treatment of hot flashes in breast cancer survivors: CEPO review and recommendations. AB - PURPOSE: Breast cancer patients frequently report hot flashes. Given that conventional hormone replacement therapy is generally contraindicated for them, other therapeutic modalities must be considered. The purpose of this review was to develop evidence-based recommendations on non-hormonal pharmacological interventions, including natural health products, for managing hot flashes in women undergoing treatment for breast cancer or with a history of breast cancer. METHODS: A review of the scientific literature published between January 2000 and December 2011 was performed. A total of 26 randomized trials were identified. RESULTS: Studies showed that serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, antihypertensives and anticonvulsants significantly reduced the frequency and severity of hot flashes in breast cancer patients. CONCLUSIONS: Considering the evidence available to date, the CEPO recommends the following: (1) for breast cancer patients being treated with tamoxifen: (a) the use of venlafaxine, citalopram, clonidine, gabapentin and pregabalin be considered effective in treating hot flashes and (b) the use of paroxetine and fluoxetine be avoided, given that they may reduce the efficacy of tamoxifen; (2) for breast cancer patients not being treated with tamoxifen: (a) the use of venlafaxine, paroxetine, citalopram, clonidine, gabapentin and pregabalin be considered effective in treating hot flashes and (b) fluoxetine not be used to treat hot flashes, given that there is insufficient evidence for its therapeutic efficacy and (3) for breast cancer survivors, sertraline, phytoestrogens, black cohosh and St. John's wort not be used to treat hot flashes. PMID- 23435568 TI - Cost-effectiveness of radioguided occult lesion localization (ROLL) versus wire guided localization (WGL) in breast conserving surgery for nonpalpable breast cancer: results from a randomized controlled multicenter trial. AB - BACKGROUND: Accurate preoperative localization of nonpalpable breast cancer is essential to achieve complete resection. Radioguided occult lesion localization (ROLL) has been introduced as an alternative for wire-guided localization (WGL). Although efficacy of ROLL has been established in a randomized controlled trial, cost-effectiveness of ROLL compared with WGL is not yet known. The objective of this study was to determine whether ROLL has acceptable cost-effectiveness compared with WGL. METHODS: An economic evaluation was performed along with a randomized controlled trial (ClinicalTrials.gov, No. NCT00539474). Women (>18 years) with histologically proven nonpalpable breast cancer and eligible for breast conserving treatment with sentinel node procedure were randomized to ROLL (n = 162) or WGL (n = 152). Empirical data on direct medical costs were collected, and changes in quality of life were measured over a 6-month period. Bootstrapping was used to assess uncertainty in cost-effectiveness estimates, and sensitivity of the results to the missing data approach was investigated. RESULTS: In total, 314 patients with 316 invasive breast cancers were enrolled. On average ROLL required the same time as WGL for the surgical procedure (119 vs 118 min), resulted in a 7 % higher reinterventions risk, and 13 % more complications. Quality of life effects were similar (difference 0.00 QALYs 95 % CI (-0.04-0.05). Total costs were also similar for ROLL and WGL (+26 per patient 95 % CI -250-311). CONCLUSION: ROLL is comparable to WGL with respect to both costs and quality of life effects as measured with the EQ5D and will therefore not lead to more cost-effective medical care. PMID- 23435569 TI - POSSUM and P-POSSUM as predictors of postoperative morbidity and mortality in patients undergoing hepato-biliary-pancreatic surgery: a meta-analysis. AB - BACKGROUND: Physiologic and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) models are used extensively to predict postoperative morbidity and mortality in general surgery. The aim was to undertake the first meta-analysis of the predictive value of these models in patients undergoing hepato-biliary-pancreatic surgery. METHODS: Eligible articles were identified by searches of electronic databases from 1991 to 2012. All data were specific to hepato-biliary-pancreatic surgery. Predictive value of morbidity and mortality were assessed by calculating weighted observed to expected (O/E) ratios. Subanalysis was also performed. RESULTS: Sixteen studies were included in final review. The morbidity analysis included nine studies on POSSUM with a weighted O/E ratio of 0.78 [95 % confidence interval (CI) 0.68-0.88]. The mortality analysis included seven studies on POSSUM and nine studies on P-POSSUM (Portsmouth predictor equation for mortality). Weighted O/E ratios for mortality were 0.35 (95 % CI 0.17-0.54) for POSSUM and 0.95 (95 % CI 0.65-1.25) for P POSSUM. POSSUM had more accuracy to predict morbidity after pancreatic surgery (O/E ratio 0.82; 95 % CI 0.72-0.92) than after hepatobiliary surgery (O/E ratio 0.66; 95 % CI 0.57-0.74), in large sample size studies (O/E ratio 0.90; 95 % CI 0.85-0.96) than in small sample size studies (O/E ratio 0.69; 95 % CI 0.59-0.79). CONCLUSIONS: POSSUM overpredicted postoperative morbidity after hepato-biliary pancreatic surgery. Predictive value of POSSUM to morbidity was affected by the type of surgery and the sample size of studies. Compared with POSSUM, P-POSSUM was more accurate for predicting postoperative mortality. Modifications to POSSUM and P-POSSUM are needed for audit in hepato-biliary-pancreatic surgery. PMID- 23435570 TI - Minimizing surgical skin incision scars with a latex surgical glove. PMID- 23435571 TI - Immunohistochemical evaluation of the effects of paraffin section storage on biomarker stability. AB - Environmental stresses can alter immunoreactivity of biomarkers in stored tissue sections. The effect of temperature and lighting on 49 cellular or microbial antigens was evaluated in 4 serial paraffin sections, cut 12 months, 10 months, 8 months, 5 months, 3 months, 1 month, 3 days, and 1 day before immunohistochemistry. Slides were stored at room temperature (RT) in the dark, at 4 degrees C in the dark, at RT under fluorescent light, or at RT with windowpane exposure to sunlight. Immunohistochemistry was performed simultaneously in an automated immunostainer. Immunoreactivity was compared with that in the corresponding 1-day-old section and scored as 4 (<10% reduction), 3 (10%-25% reduction), 2 (26%-60% reduction), 1(>60% reduction), or 0 (no reactivity). Any loss of immunoreactivity was proportional to the tissue section age and was least in sections stored in the dark. Immunoreactivity was only completely lost in light-exposed sections and as early as 1 month for CD45. Other markers with complete loss of immunoreactivity were bovine viral diarrhea virus, CD18 (only with fluorescent light), CD31, CD68, canine parvovirus, chromogranins, and thyroid transcription factor-1. Markers with complete loss after light exposure also had reduced immunoreactivity when stored in the dark, as early as day 3. Eight markers (Bartonella spp, CD11d, high molecular weight cytokeratins, feline coronavirus, GATA-4, insulin, p63, progesterone receptor) had minimal decrease in immunoreactivity, regardless of treatment. In conclusion, light-induced antigen decay (tissue section aging) is antigen dependent and could explain unexpectedly weak or negative immunohistochemical reactions in stored paraffin sections. PMID- 23435572 TI - Diagnostic exercise: Multiple skin nodules in a cat. AB - A 10-year-old, neutered, male, domestic short-haired cat had numerous, small, firm, round, red, nonpruritic, nonpainful, dermal nodules 5-16 mm in diameter that ruptured within 48 hours of their appearance and subsequently crusted over. The masses were located in all regions of the body. One mass was excised from the dorsal right carpus and examined histologically, and 2 masses from the interscapular region were cultured for bacteria. The excised dermal mass from the carpus effaced normal dermal architecture, pressed tightly against the epidermis, and was composed of tightly packed round to polyhedral cells that extended to the deep margins of the sections. The overlying epidermis was extensively ulcerated and vesiculated with intraepidermal nests of cells identical to those in the dermis. There was marked anisokaryosis in the deeper regions of the mass with numerous multinucleated cells and cells with giant bizarre nuclei. The histological appearance and CD18 immunocytochemical staining of this mass are consistent with a diagnosis of feline progressive epitheliotropic dendritic cell histiocytosis. PMID- 23435573 TI - Intermittent high doses of vitamin D: a need for further studies? PMID- 23435574 TI - Independent and joint associations between multiple measures of the built and social environment and physical activity in a multi-ethnic urban community. AB - Physical activity is associated with reduced risk of a number of health outcomes, yet fewer than half of adults in the United States report recommended levels of physical activity. Analyses of structural characteristics of the built environment as correlates of physical activity have yielded mixed results. We examine associations between multiple aspects of urban neighborhood environments and physical activity in order to understand their independent and joint effects, with a focus on the extent to which the condition of the built environment and indicators of the social environment modify associations between structural characteristics and physical activity. We use data from a stratified, multi-stage proportional probability sample of 919 non-Hispanic Black, non-Hispanic White, and Hispanic adults in an urban community, observational data from their residential neighborhoods, and census data to examine independent and joint associations of structural characteristics (e.g., street network connectivity), their condition (e.g., sidewalk condition), and social environments (e.g., territoriality) with physical activity. Our findings suggest that sidewalk condition is associated with physical activity, above and beyond structural characteristics of the built environment. Associations between some structural characteristics of the built environment and physical activity were conditional upon street condition, physical deterioration, and the proportion of parks and playgrounds in good condition. We found modest support for the hypothesis that associations between structural characteristics and physical activity are modified by aspects of the social environment. Results presented here point to the value of and need for understanding and addressing the complexity of factors that contribute to the relationships between the built and social environments and physical activity, and in turn, obesity and co-morbidities. Bringing together urban planners, public health practitioners and policy makers to understand and address aspects of urban environment associated with health outcomes is critical to promoting health and health equity. PMID- 23435575 TI - Suppression of gamma-aminobutyric acid (GABA) transaminases induces prominent GABA accumulation, dwarfism and infertility in the tomato (Solanum lycopersicum L.). AB - Tomatoes accumulate gamma-aminobutyric acid (GABA) at high levels in the immature fruits. GABA is rapidly converted to succinate during fruit ripening through the activities of GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH). Although three genes encoding GABA-T and both pyruvate- and alpha ketoglutarate-dependent GABA-T activities have been detected in tomato fruits, the mechanism underlying the GABA-T-mediated conversion of GABA has not been fully understood. In this work, we conducted loss-of-function analyses utilizing RNA interference (RNAi) transgenic plants with suppressed pyruvate- and glyoxylate-dependent GABA-T gene expression to clarify which GABA-T isoforms are essential for its function. The RNAi plants with suppressed SlGABA-T gene expression, particularly SlGABA-T1, showed severe dwarfism and infertility. SlGABA-T1 expression was inversely associated with GABA levels in the fruit at the red ripe stage. The GABA contents in 35S::SlGABA-T1(RNAi) lines were 1.3-2.0 times and 6.8-9.2 times higher in mature green and red ripe fruits, respectively, than the contents in wild-type fruits. In addition, SlGABA-T1 expression was strongly suppressed in the GABA-accumulating lines. These results indicate that pyruvate- and glyoxylate-dependent GABA-T is the essential isoform for GABA metabolism in tomato plants and that GABA-T1 primarily contributes to GABA reduction in the ripening fruits. PMID- 23435576 TI - BEST-TROSY experiments for time-efficient sequential resonance assignment of large disordered proteins. AB - The characterization of the conformational properties of intrinsically disordered proteins (IDPs), and their interaction modes with physiological partners has recently become a major research topic for understanding biological function on the molecular level. Although multidimensional NMR spectroscopy is the technique of choice for the study of IDPs at atomic resolution, the intrinsically low resolution, and the large peak intensity variations often observed in NMR spectra of IDPs call for resolution- and sensitivity-optimized pulse schemes. We present here a set of amide proton-detected 3D BEST-TROSY correlation experiments that yield the required sensitivity and spectral resolution for time-efficient sequential resonance assignment of large IDPs. In addition, we introduce two proline-edited 2D experiments that allow unambiguous identification of residues adjacent to proline that is one of the most abundant amino acids in IDPs. The performance of these experiments, and the advantages of BEST-TROSY pulse schemes are discussed and illustrated for two IDPs of similar length (~270 residues) but with different conformational sampling properties. PMID- 23435577 TI - Establish a flow cytometric method for quantitative detection of Beclin-1 expression. AB - Flow cytometry is an advanced technology for efficient, rapid, specific and multi parameter analysis of single cells in various basic research fields including cytobiology, immunology, genetic, hematology and other basic research. Beclin-1 protein is an important indicator in monitoring autophagic activity. However, quantitative flow cytometry had been rarely reported till now to be applied in the detection of Beclin-1 expression. The present study was aimed to establish a flow cytometric method for quantitative detection of Beclin-1 expression by employing the autophagy inhibitor 3-methyladenine as the control. A multi parameter optimal method for Beclin-1 protein staining is as follows. 2 % bovine serum albumin in phosphate buffered saline was used for sample block. Concentration of primary antibody was 0.004 MUg/MUL. Samples were incubated at room temperature (25 degrees C) for 30 min. The prepared samples had better to be detected immediately or to be stored at 4 degrees C and detected within 6 h, otherwise the samples should be fixed in 1 % paraformaldehyde storing at 4 degrees C and detected within 3 d. Furthermore, we employed the immunohistochemistry to validate the method in vivo, the results confirmed flow cytometric method. The established flow cytometric analysis for Beclin-1 protein has the advantage of simpleness, speediness, sensitivity and reproducibility. PMID- 23435580 TI - Use of fluorescent gold nanoclusters for the construction of a NAND logic gate for nitrite. AB - We have developed a Boolean NAND logic gate for the fluorescent detection of nitrite ions by using bovine serum albumin (BSA) functionalized gold nanoclusters. PMID- 23435579 TI - Psammomatoid juvenile ossifying fibroma: case study and a review. AB - BACKGROUND: The group of fibro-osseous lesions from the maxillofacial region is very heterogeneous, but what they all have in common is the substitution of normal bone by fibroblasts with the consequent formation of collagen fibers, as well as substitution by different types of mineralized tissues which may be similar to bone or cement. Within this group of lesions, the juvenile ossifying fibroma is found, considered a rare and recurrent benign fibro-osseous neoplasia. The term juvenile ossifying fibroma has been used in the literature to describe two histopathological variations of conventional ossifying fibroma. These variations are trabecular juvenile ossifying fibroma and psammomatoid juvenile ossifying fibroma. Psammomatoid juvenile ossifying fibroma is an uncommon bone forming neoplasm with aggressive local growth. Diagnostic of this lesion occurs after the correlation of clinical, imaging, and histopathological findings. Proposed treatments range from enucleation and curettage to resection of the tumor. OBJECTIVES: The present article has as its objectives to report an uncommon case of a 4-year-old male patient treated by conservative approach and revise the literature on juvenile ossifying fibroma. CONCLUSIONS: Psammomatoid juvenile ossifying fibroma, for its being very uncommon, warrants further investigation in order to establish the best treatment, principally in children, with a view to minimizing mutilating treatments. In the case examined, a conservative treatment was chosen, where the surgeon established curette and cryotherapy, and the reintegration of the child in his social environment, without relapse during the first year of therapy. PMID- 23435581 TI - [Juvenile idiopathic arthritis. Thoughts on the current classification]. PMID- 23435578 TI - Implants in bone: part I. A current overview about tissue response, surface modifications and future perspectives. AB - PURPOSE: The aim of study paper is to present an overview of osseointegration of dental implants, focusing on tissue response, surface modifications and future perspective. DISCUSSION: Great progress has been made over the decades in the understanding of osseous peri-implant healing of dental implants, leading to the development of new implant materials and surfaces. However, failures and losses of implants are an indicator that there is room for improvement. Of particular importance is the understanding of the biological interaction between the implant and its surrounding bone. CONCLUSION: The survival rates of dental implants in bone of over 90 % after 10 years show that they are an effective and well established therapy option. However, new implant materials and surface modifications may be able to improve osseointegration of medical implants especially when the wound healing is compromised. Advanced techniques of evaluation are necessary to understand and validate osseointegration in these cases. An overview regarding the current state of the art in experimental evaluation of osseointegration of implants and implant material modifications will be given in Part II. PMID- 23435582 TI - Arginine supplementation for improving maternal and neonatal outcomes in hypertensive disorder of pregnancy: a systematic review. AB - OBJECTIVE: This meta-analysis was performed to assess whether arginine supplementation could reduce preeclampsia or eclampsia incidence and improve the outcomes of hypertensive disorders in pregnancy, and to evaluate the safety of L arginine supplementation. METHODS: The Cochrane Central Register of Controlled Trials (2011), MEDLINE (1980-2011) and Embase (1980-2011) were searched through July 2012, and randomized controlled trials (RCTs) comparing intravenous and/or oral L-arginine supplementation with placebo, or RCTs comparing any treatment with arginine were included. Qualities of RCTs were assessed with the Jadad method. Meta-analyses were performed with fixed- or random-effects models according to heterogeneity of studies. RESULTS: Data from seven RCTs involving 916 patients were enrolled. The meta-analysis showed L-arginine was more effective in reducing preeclampsia or eclampsia incidence (odds ratio 0.384; 95% confidence limits 0.25, 0.58) than the placebo; meanwhile, L-arginine could prolong pregnancy weeks (MD 11.54; 95% CL 5.23, 17.85) than placebo; and its effect on blood pressure was unbalanced (diastolic pressure (MD 4.86; 95% CL 4.19, 5.52) and systolic pressure (MD 3.20; 95% CL -1.54, 7.94)) while the difference in increased neonatal weight (MD 256.24; 95% CL -28.66, 541.13) was not clear. Three of these studies reported some adverse effects, and no teratogenic or lethal effects were noted. CONCLUSION: This study demonstrates L arginine supplementation is superior to placebo in lowering diastolic pressure and prolonging pregnancy in patients with gestational hypertension with or without proteinuria, but the effect on lowering systolic pressure and increasing neonatal weight was not statistically significant. PMID- 23435583 TI - A novel method for the identification of synchronization effects in multichannel ECoG with an application to epilepsy. AB - In this paper, we present a novel method for the identification of synchronization effects in multichannel electrocorticograms (ECoG). Based on autoregressive modeling, we define a dependency measure termed extrinsic-to intrinsic power ratio (EIPR) which quantifies directed coupling effects in the time domain. Hereby, a dynamic input channel selection algorithm assures the estimation of the model parameters despite the strong spatial correlation among the high number of involved ECoG channels. We compare EIPR to the partial directed coherence, show its ability to indicate Granger causality and successfully validate a signal model. Applying EIPR to ictal ECoG data of patients suffering from temporal lobe epilepsy allows us to identify the electrodes of the seizure onset zone. The results obtained by the proposed method are in good accordance with the clinical findings. PMID- 23435584 TI - Shape assisted fabrication of fluorescent cages of squarate based metal-organic coordination frameworks. AB - Micronic cage structures of squarate based metal-organic coordination frameworks (MOCFs) have been fabricated for the first time by specific anion selective etching of metal squarate cubes. Time and stoichiometry dependent synthesis and the corresponding microscopic studies have provided mechanistic insight into the cage formation. Furthermore, a non-covalent post-synthetic strategy has been adopted to functionalize the micronic cubes or cages with chromophores rendering the resulting hybrids green fluorescent. PMID- 23435585 TI - Compressed carbon nanotubes: a family of new multifunctional carbon allotropes. AB - The exploration of novel functional carbon polymorphs is an enduring topic of scientific investigations. In this paper, we present simulations demonstrating metastable carbon phases as the result of pressure induced carbon nanotube polymerization. The configuration, bonding, electronic, and mechanical characteristics of carbon polymers strongly depend on the imposed hydrostatic/non hydrostatic pressure, as well as on the geometry of the raw carbon nanotubes including diameter, chirality, stacking manner, and wall number. Especially, transition processes under hydrostatic/non-hydrostatic pressure are investigated, revealing unexpectedly low transition barriers and demonstrating sp(2)->sp(3) bonding changes as well as peculiar oscillations of electronic property (e.g., semiconducting->metallic->semiconducting transitions). These polymerized nanotubes show versatile and superior physical properties, such as superhardness, high tensile strength and ductility, and tunable electronic properties (semiconducting or metallic). PMID- 23435586 TI - Assessment of the levels of airborne bacteria, Gram-negative bacteria, and fungi in hospital lobbies. AB - AIMS: We assessed the levels of airborne bacteria, Gram-negative bacteria (GNB), and fungi in six hospital lobbies, and investigated the environmental and hospital characteristics that affected the airborne microorganism levels. METHODS: An Andersen single-stage sampler equipped with appropriate nutrition plate agar was used to collect the samples. The three types of microorganisms were repeatedly collected at a fixed location in each hospital (assumed to be representative of the entire hospital lobby) from 08:00 through 24:00, with a sampling time of less than 5 min. Temperature and relative humidity were simultaneously monitored. RESULTS: Multiple regression analysis was used to identify the major factors affecting microorganism levels. The average levels of bacteria (7.2 * 10(2) CFU/m(3)), GNB (1.7 * 10 CFU/m(3)), and fungi (7.7 * 10 CFU/m(3)) indicated that all hospital lobbies were generally contaminated. Season was the only factor that significantly affected the levels of all microorganisms (p < 0.0001), where contamination was the highest during the summer, significantly higher than during the winter. Other significant factors varied by microorganism, as follows: airborne bacteria (number of people in the lobby, sampling time), GNB (scale of hospital), and fungi (humidity and air temperature). CONCLUSIONS: Hospital lobby air was generally contaminated with microorganisms, including bacteria, GNB, and fungi. Environmental factors that may significantly influence the airborne concentrations of these agents should be managed to minimize airborne levels. PMID- 23435587 TI - Infectious risk assessment of unsafe handling practices and management of clinical solid waste. AB - The present study was undertaken to determine the bacterial agents present in various clinical solid wastes, general waste and clinical sharp waste. The waste was collected from different wards/units in a healthcare facility in Penang Island, Malaysia. The presence of bacterial agents in clinical and general waste was determined using the conventional bacteria identification methods. Several pathogenic bacteria including opportunistic bacterial agent such as Pseudomonas aeruginosa, Salmonella spp., Klebsiella pneumoniae, Serratia marcescens, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes were detected in clinical solid wastes. The presence of specific pathogenic bacterial strains in clinical sharp waste was determined using 16s rDNA analysis. In this study, several nosocomial pathogenic bacteria strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Lysinibacillus sphaericus, Serratia marcescens, and Staphylococcus aureus were detected in clinical sharp waste. The present study suggests that waste generated from healthcare facilities should be sterilized at the point of generation in order to eliminate nosocomial infections from the general waste or either of the clinical wastes. PMID- 23435588 TI - Comparison of health status and health care services utilization between migrants and natives of the same ethnic origin--the case of Hong Kong. AB - Based on the 2009 Thematic Household Survey in Hong Kong, this study compared health status and utilization of health care services in Hong Kong between migrants from Mainland China and natives. Overall, Mainland migrants reported lower socioeconomic conditions, worse health status, and less health care services utilization than the natives. After controlling for socio-demographic factors, we found that the migrants were 1.2 times more likely to report fair or poor health and 0.78 times less likely to report having a usual source of care, compared with the natives. Mainland migrants also had fewer physician visits and relied more on the public sector. Within the migrant group, those who had language advantage had more visits, and the recent arrivals who stayed in Hong Kong for three years or less had fewer visits and were far less likely to have a usual source of care. The findings underscore migration as an important social determinant of health in Hong Kong. A combination of targeted social and health policies is needed to help Mainland migrants better integrate into society and to improve their access to care. Programs should be tailored to address varying needs from different subgroups among migrants. PMID- 23435589 TI - The long-term relationship between population growth and vegetation cover: an empirical analysis based on the panel data of 21 cities in Guangdong Province, China. AB - It is generally believed that there is an inverse relationship between population growth and vegetation cover. However, reports about vegetation protection and reforestation around the World have been continuously increasing in recent decades, which seems to indicate that this relationship may not be true. In this paper, we have taken 21 cities in Guangdong Province, China as the study area to test the long-term relationship between population growth and vegetation cover, using an AVHRR NDVI data set and the panel cointegrated regression method. The results show that there is a long-term inverted N-shaped curve relationship between population growth and vegetation cover in the region where there are frequent human activities and the influence of climate change on vegetation cover changes is relatively small. The two turning points of the inverted N-shaped curve for the case of Guangdong Province correspond to 2,200 persons . km(-2) and 3,820 persons . km(-2), and they can provide a reference range for similar regions of the World. It also states that the population urbanization may have a negative impact on the vegetation cover at the early stage, but have a positive impact at the later stage. In addition, the Panel Error Correction Model (PECM) is used to investigate the causality direction between population growth and vegetation cover. The results show that not only will the consuming destruction effect and planting construction effect induced by the population growth have a great impact on vegetation cover changes, but vegetation cover changes in turn will also affect the population growth in the long term. PMID- 23435590 TI - Developing an exploratory framework linking Australian Aboriginal peoples' connection to country and concepts of wellbeing. AB - Aboriginal people across Australia suffer significant health inequalities compared with the non-Indigenous population. Evidence indicates that inroads can be made to reduce these inequalities by better understanding social and cultural determinants of health, applying holistic notions of health and developing less rigid definitions of wellbeing. The following article draws on qualitative research on Victorian Aboriginal peoples' relationship to their traditional land (known as Country) and its link to wellbeing, in an attempt to tackle this. Concepts of wellbeing, Country and nature have also been reviewed to gain an understanding of this relationship. An exploratory framework has been developed to understand this phenomenon focusing on positive (e.g., ancestry and partnerships) and negative (e.g., destruction of Country and racism) factors contributing to Aboriginal peoples' health. The outcome is an explanation of how Country is a fundamental component of Aboriginal Victorian peoples' wellbeing and the framework articulates the forces that impact positively and negatively on this duality. This review is critical to improving not only Aboriginal peoples' health but also the capacity of all humanity to deal with environmental issues like disconnection from nature and urbanisation. PMID- 23435591 TI - Placental transfer of persistent organic pollutants: a preliminary study on mother-newborn pairs. AB - The aim of this study was to characterize the placental transfer of some environmental pollutants, and to explore the possibility of quantitatively predicting in utero exposure to these contaminants from concentrations assessed in maternal blood. Levels of toxic substances such as pesticides (p,p'-DDE, beta HCH, and HCB), polychlorinated biphenyls (PCBs), perfluorooctane sulfonate (PFOS), and perfluorooctanoic acid (PFOA) were determined in serum samples of 38 pregnant women living in Rome and in samples of cord blood from their respective newborns. The study was carried out in the years 2008-2009. PCB mean concentrations in maternal serum and cord serum ranged from 0.058 to 0.30, and from 0.018 to 0.064 ng/g . fw respectively. Arithmetic means of PFOS and PFOA concentrations in mothers and newborns were 3.2 and 1.4 ng/g . fw, and 2.9 and 1.6 ng/g . fw. A strong correlation was observed between concentrations in the maternal and the foetal compartment for PFOS (Spearman r = 0.74, p < 0.001), PFOA (Spearman r = 0.70, p < 0.001), PCB 153 (Spearman r = 0.60, p < 0.001), HCB (Spearman r = 0.68, p < 0.001), PCB 180 (Spearman r = 0.55, p = 0.0012), and p,p' DDE (Spearman r = 0.53, p = 0.0099). A weak correlation (p < 0.1) was observed for PCBs 118 and 138. PMID- 23435592 TI - Ontogenetic variation in cold tolerance plasticity in Drosophila: is the Bogert effect bogus? AB - Ontogenetic variation in plasticity is important to understanding mechanisms and patterns of thermal tolerance variation. The Bogert effect postulates that, to compensate for their inability to behaviourally thermoregulate, less-mobile life stages of ectotherms are expected to show greater plasticity of thermal tolerance than more-mobile life stages. We test this general prediction by comparing plasticity of thermal tolerance (rapid cold-hardening, RCH) between mobile adults and less-mobile larvae of 16 Drosophila species. We find an RCH response in adults of 13 species but only in larvae of four species. Thus, the Bogert effect is not as widespread as expected. PMID- 23435593 TI - Left atrial volumetry from routine diagnostic work up prior to pulmonary vein ablation is a good predictor of freedom from atrial fibrillation. AB - AIMS: This study aimed to identify whether left atrial (LA) volume assessed by multidetector computed tomography (MDCT) is related to the long-term success of pulmonary vein ablation (PVA). MDCT is used to guide PVA for the treatment of atrial fibrillation (AF). MDCT permits accurate sizing of LA dimensions. METHODS AND RESULTS: We analysed data from 368 ablation procedures of 279 consecutive patients referred for PVA due to drug-refractory symptomatic AF (age 62 +/- 10; 58% men; 71% paroxysmal AF). Prior to the procedure, all patients underwent ECG gated 64-MDCT scan for assessment of LA and PV anatomy, LA thrombus evaluation, LA volume estimation, and electroanatomical mapping integration. Within a mean follow-up of 356 +/- 128 days, 64% of the patients maintained sinus rhythm after the initial ablation, and 84% when including repeat PVA. LA diameter (P = 0.004), LA volume (P = 0.002), and type of AF (P = 0.001) were independent predictors of AF recurrence in univariate analysis. There was a relatively low correlation between the echocardiographic LA diameter and LA volume from MDCT (P = 0.01, r = 0.5). In multivariate analysis, paroxysmal AF (P < 0.006) and LA volume below the median value of 106 mL (P = 0.042) were significantly associated with the success of PVA, whereas LA diameter was not (P = 0.245). Analysing receiver-operator characteristics, the area under the curve for LA volume was 0.73 (P = 0.001) compared with 0.60 (P = 0.09) for LA diameter from echocardiography. CONCLUSION: LA volume assessed by MDCT is a better predictor of AF recurrence after PVA than echocardiograpic LA diameter and can be derived from the pre-procedural imaging data set. PMID- 23435594 TI - Water and ammonia on Cu{110}: comparative structure and bonding. AB - Water and ammonia are arguably the two most important inorganic molecular species in the modern world, and their interaction with metal surfaces is key to unlocking their further potential in a number of spheres. In this comparative study, conducted on the Cu{110} substrate, we present results from first principles density functional theory that highlight the similarities and differences between these chemical cousins. We find that ammonia is less likely than water to undergo thermally induced partial dissociation, although we nevertheless identify the most likely product of electron-stimulated or defect induced dissociation to be a surface amino species. We predict that ammonia, like water, will adopt a bilayer structure at high coverage, but that unlike water the net intermolecular interaction will be repulsive, despite the formation of a weak hydrogen-bonded network. Furthermore, we suggest that coadsorption of water and ammonia can give rise to an intimately mixed overlayer in which ammonia molecules are bound directly to the surface whilst water molecules are attached only via hydrogen bonds from below. PMID- 23435595 TI - Associations between voice quality and swallowing function in patients treated for oral or oropharyngeal cancer. AB - PURPOSE: The purpose of this study was to investigate associations between voice quality and swallowing function in patients treated for oral or oropharyngeal cancer. METHODS: Recordings of speech and videofluoroscopy of 51 patients after treatment for oral or oropharyngeal cancer were analysed. Acoustic voice parameters (fundamental frequency (F0), perturbation (jitter %, shimmer %), harmonics-to-noise ratio (HNR), and intensity (extracted from the vowels /a/, /i/, and /u/)) were compared to swallowing function parameters as assessed via videofluoroscopy (oral, oropharyngeal, and total transit time; estimated percent of oral, oropharyngeal, and total residue; oropharyngeal swallowing efficiency (OPSE), and the penetration/aspiration (PA-) scale). RESULTS: Stepwise multivariate regression analyses revealed that jitter, shimmer, and HNR were not associated with swallowing function. Higher voice intensity in all three vowels /a/, /i/, and /u/ was significantly associated with a higher score on the PA scale (more penetration and aspiration). Higher voice intensity and F0 were significantly associated with lower OPSE. CONCLUSION: Higher voice intensity was significantly associated with higher amount of penetration/aspiration, and higher voice intensity and fundamental frequency were significantly associated with swallowing inefficiency. Possible explanations may be found in overcompensation by increased laryngeal muscular strength resulting in increased intensity and pitch during phonation. However, the physiology of associated voice and swallowing function is yet unclear, and more research is recommended. PMID- 23435596 TI - Lymphedema: experience of a cohort of women with breast cancer followed for 4 years after diagnosis in Victoria, Australia. AB - PURPOSE: The aim of this work was to study the incidence and prevalence of self reported lymphedema in breast cancer survivors between 2 and 4 years following diagnosis, the factors associated with the development of lymphedema and the impact of lymphedema on psychological well-being. METHODS: We assessed self reported lymphedema in the BUPA Health Foundation Health and Wellbeing After Breast Cancer Study, a questionnaire-based study of 1,683 women newly diagnosed with their first episode of invasive breast cancer in Victoria, Australia. Psychological well-being was assessed using the Psychological General Well-being Index. RESULTS: Two years after diagnosis, nearly 20 % of women reported lymphedema and this proportion remained above 18 % 2 years later. However, self reported lymphedema was a dynamic phenomenon, with the condition resolving in some women and others reporting onset for the first time up to 4 years from diagnosis. Lymphedema 2 years from diagnosis was positively associated with the number of nodes removed at initial surgery, although this variable only explained a small proportion of the likelihood of reporting lymphedema. The presence of lymphedema was associated with lower psychological general well-being. CONCLUSIONS: Lymphedema after breast cancer treatment frequently has a dynamic pattern and may emerge as an issue for women several years after their initial treatment. It is associated with a lower level of general well-being. PMID- 23435597 TI - Acupuncture for cancer-related fatigue: a systematic review of randomized clinical trials. AB - PURPOSE: Managing cancer-related fatigue (CRF) is an important element of the palliative care of cancer patients. The aim of this systematic review was to critically evaluate the effectiveness of acupuncture (AT) or electroacupuncture (EA) for CRF. METHODS: Fourteen databases were searched from their respective inception to November 2012. Randomized clinical trials (RCTs) of AT or EA for the treatment of CRF were considered for inclusion. The risk of bias/methodological quality was assessed using the method suggested by the Cochrane Collaboration. RESULTS: Seven RCTs met the eligibility criteria. Most were small pilot studies with serious methodological flaws. Four of the RCTs showed effectiveness of AT or AT in addition to usual care (UC) over sham AT, UC, enhanced UC, or no intervention for alleviating CRF. Three RCTs showed no effect of AT/EA over sham treatment. CONCLUSION: Overall, the quantity and quality of RCTs included in the analysis were too low to draw meaningful conclusions. Even in the positive trials, it remained unclear whether the observed outcome was due to specific effects of AT/EA or nonspecific effects of care. Further research is required to investigate whether AT/EA demonstrates specific effects on CRF. PMID- 23435599 TI - Racial differences in allergic sensitization: recent findings and future directions. AB - Racial disparities are present in many facets of health and disease. Allergy and asthma are no exceptions. Secondary results from cross-sectional and cohort studies have provided information on the scope of racial disparities in allergic sensitization in the United States. African American/Black individuals tend to be sensitized more frequently than White individuals. Little is known about rates in other race groups. Genetics are unlikely to be the sole or major cause of the observed differences. Home dust allergen and endotoxin levels cannot explain the differences. Studies that have been designed to specifically address the sources of these racial disparities are needed. A "Multilevel Framework" that considers the roles of the individual, family and community presents an excellent approach to guide design of future studies of the causes of these disparities. Understanding the causes of the disparities could lead to interventions that would improve the health of all individuals. PMID- 23435600 TI - Using surveillance data to inform community action: the effect of alcohol sale restrictions on intentional injury-related ambulance pickups. AB - Youth violence disproportionately affects inner city, urban minority communities in the USA. This article illustrates the use of surveillance data to inform and evaluate community action directed at this serious problem. Community efforts in response to surveillance data indicating high rates of violence surrounding convenience stores with unrestricted alcohol beverage licenses provided a natural experiment to examine the impact of imposing licensing restrictions on intentional injury rates. Rates of ambulance pickups for intentional injuries in the 15- to 24-year-old population in five census tracts where alcoholic beverage sales were restricted were compared to five census tracts with similar demographic characteristics near stores where restrictions were not instituted. Time periods included an 18-month baseline period, a 6-month period during which restrictions were in effect in the intervention communities, and an 18-month period following lifting of this restriction resulting from legal action by store owners. The monthly average rate of ambulance pickups for violent injuries showed a significantly greater baseline-to-intervention phase decrease in the intervention communities (i.e., from 19.6 to 0 per 1,000) than in the control communities (i.e., 7.4 to 3.3 per 1,000). This rate subsequently increased to 11.4 in the intervention communities after the restriction was removed. This study illustrates the potential value of surveillance data for guiding community mobilization efforts and for evaluating the impact of such efforts. It also demonstrates the potential impact of restricting inexpensive, single-serve alcoholic beverages on rates of violence. PMID- 23435602 TI - Chemopreventive effect of cactus (Opuntia humifusa) extracts: radical scavenging activity, pro-apoptosis, and anti-inflammatory effect in human colon (SW480) and breast cancer (MCF7) cells. AB - Cactus (Opuntia spp) is widely cultivated as a vegetable, fruit, and forage crop and has been used in traditional medicine in American Indian, Mexican, and Korean cultures. Accumulative evidence from both in vitro and in vivo studies using cacti suggests their biological and pharmacological activities, such as their anti-cancer and anti-inflammatory roles in different cancer cells. In this study, the Opuntia humifusa stem (OHS) was extracted with different solvents and screened for radical scavenging activity using 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) (ABTS(+)) and 1,1-diphenyl-2-picryl hydrazyl (DPPH). In addition, the total phenolic and flavonoid contents of each extract were analyzed using the Folin-Ciocalteu method and high performance liquid chromatography, respectively. Further, the cacti's bioactive fractions were evaluated for cell cytotoxicity and to understand their mechanism of action on human colon cancer (SW480) and breast cancer (MCF7) cells. An ethyl acetate (EtOAc) extract exhibited the highest cytotoxicity and resulted in an up regulated expression of the pro-apoptotic protein Bax (bcl-2 associated X protein) and a down-regulated expression of the anti-apoptotic protein Bcl2 in both SW480 and MCF7 cells. The apoptosis was mediated through activation of caspase 8, 9, and 3/7 activities as well as PARP cleavage in SW480 cells, while the same extract activated only a caspase 9 activity in MCF7 cells. Furthermore, incubation of cells with the EtOAc extract down-regulated the expression of inflammatory molecules such as cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) in SW480 cells but not in MCF7 cells. Taken together, these results suggest that SW480 colon cancer cells are more susceptible to bioactive compounds present in OHS and may have potential in the prevention of cancer through modulation of apoptosis markers and inhibition of inflammatory pathways. PMID- 23435603 TI - Case-control studies: measures of risk. PMID- 23435604 TI - Dark satanic mills. PMID- 23435605 TI - Poor coding by health boards has masked true length of Scotland's waiting lists. PMID- 23435606 TI - Pressure grows on government to act on obesity as figures show effect on health and the NHS. PMID- 23435609 TI - Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. AB - BACKGROUND: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. METHODS: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. RESULTS: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed. CONCLUSIONS: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations. PMID- 23435610 TI - Th22, but not Th17 might be a good index to predict the tissue involvement of systemic lupus erythematosus. AB - PURPOSE: T-helper (Th) cells abnormalities are considered to be associated with the pathogenesis of Systemic lupus erythematosus (SLE). Recently, The Th22 cells have been identified and implicated in the pathogenesis of autoimmune diseases such as Rheumatoid arthritis (RA), although therir role in Systemic lupus erythematosus (SLE) remains unclear. The present study intends to investigate their roles in SLE. METHODS: Clinical data were collected in 65 SLE patients and 30 healthy controls. The patients were divided into active and inactive groups. CD4(+)IFN-gamma(-)IL-17(-)IL-22(+)Tcells (Th22 cells),CD4(+) IFN-gamma(-)IL-22( )IL-17(+)T cells (Th17 cells),and CD4(+) IFN-gamma(+) (Th1 cells) were assayed by flow cytometry. Serum interleukin-22 (IL-22) and IL-17 levels were measured by enzyme-linked immunosorbent assay. RESULTS: The main observation focused on increased Th22 cells in patients with sole lupus skin disease and decreased Th22 cells in patients with sole lupus nephritis. Likewise, concentrations of serum IL 22 were increased in patients with sole lupus skin disease, and decreased in patients with sole lupus nephritis. Additionally, there was a positive correlation between the percentage of Th22 cells and IL-22 production. The percentage of Th17 cells or concentration of serum IL-17 correlated positively with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). CONCLUSION: Th22 seems to be a more significant index to predict the tissue involvement of SLE than Th17, although Th17 may play a role in the activity of SLE. PMID- 23435611 TI - Land use change on coffee farms in southern Guatemala and its environmental consequences. AB - Changes in commodity prices, such as the fall in coffee prices from 2000 to 2004, affect land use decisions on farms, and the environmental services they provide. A survey of 50 farms showed a 35% loss in the area under coffee between 2000 and 2004 below 700 m with the majority of this area (64 %) being coffee agroforest systems that included native forest species. Loss of coffee only occurred on large and medium-scale farms; there was no change in area on cooperatives. Coffee productivity declined below 1,100 m altitude for sun and Inga shade coffee, but only below 700 m altitude for agroforest coffee. Coffee productivity was 37-53% lower under agroforests than other systems. Increases in rubber and pasture were related to low altitude large-scale farms, and bananas and timber plantations to mid-altitude farms. Average aboveground carbon stocks for coffee agroforests of 39 t C ha(-1) was similar to rubber plantations, but one-third to one half that of natural forest and timber plantations, respectively. Coffee agroforests had the highest native tree diversity of the productive systems (7-12 species ha(-1)) but lower than natural forest (31 species ha(-1)). Conversion of coffee agroforest to other land uses always led to a reduction in the quality of habitat for native biodiversity, especially avian, but was concentrated among certain farm types. Sustaining coffee agroforests for biodiversity conservation would require targeted interventions such as direct payments or market incentives specifically for biodiversity. PMID- 23435612 TI - Type 2 diabetes and fractures: more information is needed. PMID- 23435613 TI - Allelic imbalance in sporadic parathyroid carcinoma and evidence for its de novo origins. AB - Parathyroid cancer is a rare, clinically aggressive cause of primary hyperparathyroidism, and whether these malignancies generally evolve from pre existing benign adenomas or arise de novo is unclear. Furthermore, while inactivation of the CDC73 (HRPT2) tumor suppressor gene, encoding parafibromin, is a major contributor, other genes essential to parathyroid carcinogenesis remain unknown. We sought to identify genomic regions potentially harboring such oncogenes or tumor suppressor genes, and to gain insight into the origins and molecular relationship of malignant versus benign parathyroid tumors. We performed genome-wide copy-number and loss of heterozygosity analysis using Affymetrix 50K SNP mapping arrays and/or comparative genomic hybridization on 16 primary parathyroid carcinomas, local recurrences or distant metastases, and matched normal controls, from 10 individuals. Recurrent regions of allelic loss were observed on chromosomes 1p, 3, and 13q suggesting that key parathyroid tumor suppressor genes are located in these chromosomal locations. Recurrent allelic gains were seen on chromosomes 1q and 16, suggesting the presence of parathyroid oncogenes on these chromosomes. Importantly, the most common alteration in benign parathyroid adenomas, loss of 11q, was not found as a recurrent change in the malignant parathyroid tissues. Molecular allelotyping using highly polymorphic microsatellite markers provided further confirmation that the prevalence of 11q loss is markedly and significantly lower in carcinomas as compared with adenomas. Our observations provide molecular support for the concept that sporadic parathyroid cancer usually arises de novo, rather than evolving from a pre existing typical benign adenoma. Furthermore, these results help direct future investigation to ultimately determine which of the candidate genes in these chromosomal locations make significant contributions to the molecular pathogenesis of parathyroid cancer. PMID- 23435614 TI - Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications. AB - PURPOSE: Pharmacogenomics investigates interindividual genetic variability in the DNA sequence of drug targets, drug-metabolizing enzymes or disease genes, RNA expression, or protein translation of genes affecting drug response and drug safety. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications with well-documented variation in patient response in terms of efficacy and safety. This variation may in part be explained by pharmacogenomics. METHODS: In this paper I review data on the pharmacogenomics of aspirin and other NSAIDs focusing on clinical implications. RESULTS: Existing scientific evidence supports the pharmacogenomic basis of interindividual variation in treatment response to aspirin and NSAIDs, with clinical implications for antiplatelet action, cancer chemoprevention, and drug safety. However, further research efforts are needed before knowledge on the pharmacogenomics of aspirin and NSAIDs can be implemented in clinical practice. CONCLUSION: The outcome of these research efforts would be anticipated to have added value for both science and society, contributing to the enhanced efficacy and safety of these agents through patient selection. PMID- 23435616 TI - Recycling behaviour of householders living in multicultural urban area: a case study of Jarva, Stockholm, Sweden. AB - The recycling behaviour of multicultural householders was investigated in the urban area of Jarva, northwest Stockholm, Sweden, which is home to a significant proportion of immigrants from different parts of the world. Different ethnic minorities currently make up an important proportion of the urban population in Sweden, but little is known about their recycling behaviour and attitudes. Using quantitative (questionnaire) and qualitative (interviews) methodology, possible determinants of recycling behaviour were investigated among Jarva householders. It was found that attitude toward the importance of recycling had a positive correlation and was the main determinant of recycling behaviour among these householders. In contrast, environmental concern, satisfaction with the facilities provided, recycling confidence, community identity and socio demographical factors showed no correlation with their recycling behaviour. Other results of the study indicated a need to investigate the specific behaviour of multicultural householders regarding source-separated collection and the recycling of hazardous, electronic and bulky wastes. PMID- 23435615 TI - The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers. AB - PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment. PMID- 23435617 TI - Resection rectopexy--laparoscopic neuromapping reveals neurogenic pathways to the lower segment of the rectum: preliminary results. AB - PURPOSE: Nerve sparing in functional pelvic floor surgery is strongly recommended as intraoperative damage to the autonomic nerves may predispose to persistent or worsened anorectal and urogenital function. The aim of this study was to investigate the intraoperative neural topography above the pelvic floor in patients undergoing laparoscopic resection rectopexy in combination with electrophysiologic neuromapping. METHODS: Ten consecutive female patients underwent laparoscopic resection rectopexy for rectal prolapse. Intraoperative identification of pelvic autonomic nerves was carried out with a novel intraoperative neuromonitoring system based on electric stimulation under simultaneous electromyography of the internal anal sphincter and manometry of the bladder. Neuromonitoring results were compared to patients' preoperative anorectal and urogenital function and their functional results at the 3-month follow-up. RESULTS: Laparoscopy in combination with electrophysiologic neuromapping revealed neurogenic pathways to the lower segment of the rectum during surgical mobilization. In all procedures, intraoperative neuromonitoring finally confirmed functional nerve integrity to the internal anal sphincter and the bladder. Patients with preoperatively diagnosed fecal incontinence were continent at the 3-month follow-up. The Wexner score improved in median from preoperative 4 (range 1-18) to 1 (range 0-3) at follow-up (p = 0.012). Cleveland Clinical Constipation Score improved in median from 10 (range 5-17) to 3 (range 1 7; p = 0.005). In none of the investigated patients a new onset of urinary dysfunction did occur. No change in sexual function was observed. CONCLUSIONS: Laparoscopy in combination with electrophysiologic neuromapping during nerve sparing resection rectopexy identified and preserved neurogenic pathways heading to the lower segment of the rectum above the level of the pelvic floor. PMID- 23435618 TI - Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. AB - Ganglioglioma is a rare CNS tumor with a benign biological behavior. Recently, the BRAF V600E mutation was identified in approximately 20 % of gangliogliomas. Here, we analyzed a total of 71 gangliogliomas for BRAF V600E mutational status by VE1 immunohistochemistry and direct DNA sequencing. The BRAF V600E mutation was detected in 41/71 (58 %) gangliogliomas by immunohistochemistry. DNA sequencing was concordant in 60 of 62 analyzed cases. BRAF status was compared with clinical, histological and immunohistochemical data. Presence of the BRAF V600E mutation was associated with expression of synaptophysin in the tumor (p = 0.0008), presence of dysplastic neurons (p = 0.011) and lymphocytic cuffs (p = 0.018), and with younger age (p = 0.0054). Extensive hemosiderin deposition within the tumor was significantly associated with BRAF wild-type status (p = 0.042). No significant association was found with proliferation (p = 0.053), presence of phospho ERK (p = 0.1) or senescence marker p16(INK4a) (p = 0.22). Using VE1, we localized the BRAF V600E-mutated protein predominantly to the neuronal compartment, indicating that BRAF mutations occur in cells that have the capacity to differentiate into ganglionic cells. In many cases mutant BRAF is additionally expressed by the glial compartment, indicating that in these cases the cell targeted by BRAF mutation was likely capable of differentiating along both the ganglionic and glial lineages. No cases with an exclusive expression of BRAF V600E in the glial compartment were observed. Thus, using VE1 we identified the neuronal compartment as an essential part of this mixed glioneuronal tumor. PMID- 23435619 TI - Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: pooled analysis of the literature reviews and report of six new cases. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disorder which is increasingly recognized to occur in systemic lupus erythematosus (SLE). OBJECTIVE: The purpose of this study was to identify the characteristics of SLE patients with PRES and the associated factors of the poor outcome among them. METHODS: We investigated SLE patients who developed PRES between 2005-2011 at the Universiti Kebangsaan Malaysia Medical Centre. A comprehensive literature search was done to find all published cases of PRES in SLE. Pooled analysis was conducted to identify the factors associated with poor outcome. RESULTS: There were 103 cases of PRES in SLE published in the literature but only 87 cases were included in the analysis in view of incomplete individual data in the remaining cases. The majority of the cases were Asians (74.2%), female (95.4%) with mean age of 26.3 +/- 8.8 years. PRES was highly associated with active disease (97.5%), hypertension (91.7%) and renal involvement (85.1%). We found that 79 patients had a full recovery (90.8%) with a mean onset of full clinical recovery in 5.6 +/- 4.1 days. On univariate analysis and logistic regression analysis the predictors of poor outcome, defined as incomplete clinical recovery or death, were intracranial hemorrhage, odds ratio (OR) 14 (1.1 187.2), p=0.04 and brainstem involvement in PRES, OR 10.9 (1.3-90.6), p=0.003. CONCLUSION: Intracranial hemorrhage and brainstem involvement were the two important predictors of poor outcome of PRES. Larger prospective studies are needed to further delineate the risk of poor outcome among them. PMID- 23435620 TI - A new platform for a convenient genotyping system. AB - The high SNP discrimination ratio of 360 : 1, 100% target-specific hybridization at 25 degrees C, detection limit of 10(1) copies, and differentiation of 10(1) to 10(7) copies of the PCR product of high-risk HPV genotypes in clinical samples ensure the application of the 9G membrane in a convenient platform for DNA genotyping. PMID- 23435621 TI - One-pot synthesis of benzamide over a robust tandem catalyst based on center radially fibrous silica encapsulated TS-1. AB - A center radially fibrous silica encapsulated TS-1 zeolite (TS-1@KCC-1) has been synthesized in a microemulsion system for the first time. Supporting the Rh(OH)3 species, this novel core-shell structured material serves as a robust bifunctional catalyst for one-pot synthesis of benzamide from benzaldehyde, ammonia and hydrogen peroxide, in which the aldehyde ammoximation and oxime rearrangement occur in a tandem way. PMID- 23435622 TI - A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer. AB - PURPOSE: Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer. METHODS: A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m(2)) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin. RESULTS: There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm (P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone. CONCLUSIONS: The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer. PMID- 23435623 TI - [Carotid artery stenting--an update]. AB - CLINICAL/METHODICAL ISSUE: Therapy of carotid stenosis should be based on an accurate assessment of the stenosis and a differentiation between symptomatic and asymptomatic patients. STANDARD RADIOLOGICAL METHODS: According to current guidelines carotid artery stenting (CAS) can be considered as an established therapeutic alternative to carotid endarterectomy (CEA). METHODICAL INNOVATIONS: For the therapy of carotid stenosis CAS has become established as a minimally invasive alternative to CEA because the complication rate has been reduced due to growing experience, technical innovations and external quality assessment. PERFORMANCE: The CAS procedure should be performed in centers with documented complication rates of < 3 % for asymptomatic and < 6 % for symptomatic stenoses. ACHIEVEMENTS: Overall there are no significant differences between CAS and CEA in the treatment of carotid stenosis concerning the secondary prophylactic effect. PRACTICAL RECOMMENDATIONS: Ideally an interdisciplinary approach should be chosen for the therapy regime. Revascularization of asymptomatic stenoses should be considered critically as these patients might profit from optimized conservative medicinal therapy. PMID- 23435624 TI - [Liquid embolic agents--Onyx as problem solver]. AB - CLINICAL/METHODICAL ISSUE: Liquid embolic agents are used for permanent occlusion of capillaries but optimal administration properties are lacking. STANDARD RADIOLOGICAL METHODS: The lack of visualization by fluoroscopy and the risk of serious complications are disadvantages of conventional embolic agents, such as ethanol and Histoacryl. METHODICAL INNOVATIONS: Onyx is a liquid embolic agent consisting of ethylene vinyl alcohol copolymer dissolved in various concentrations of dimethyl sulfoxide (DMSO) and suspended micronized tantalum powder to provide contrast for fluoroscopy. PERFORMANCE: The physicochemical characteristics of Onyx allow controlled application, forming a defined cast and permanent occlusion. Disadvantages are the high costs. Furthermore, the solvent DMSO requires special catheter material and causes pain during Onyx application. ACHIEVEMENTS: Onyx has been primarily used for interventional neuroradiological treatment but peripheral applications are becoming increasingly more common. PRACTICAL RECOMMENDATIONS: Currently, Onyx is mainly used for embolotherapy of endoleaks after endovascular aortic aneurysm repair, for treatment of acute arterial bleeding and for treatment of arteriovenous malformations. PMID- 23435625 TI - [Mechanical recanalization in acute stroke. Torture or choice]. AB - CLINICAL/METHODICAL ISSUE: Stroke is the third most common cause of death in the developed world and the leading cause of disability worldwide. The present demographic development will lead to increased numbers of stroke patients in the future. STANDARD RADIOLOGICAL METHODS: Patient selection takes place by using various computer tomographic (CT) or magnetic resonance (MR) imaging modalities. For endovascular stroke treatment a modern biplane angiography suite is recommended. METHODICAL INNOVATIONS: Intra-arterial chemical thrombolysis was shown to be effective in achieving recanalization and improving clinical outcome. Mechanical devices were introduced in the late 1990s and the highly effective stent retriever was recently included. PERFORMANCE: Mechanical devices allows a recanalization rate of up to 90 % of affected brain vessels. ACHIEVEMENTS: The advantage of a stent retriever compared to other mechanical devices seems to be an improvement in good clinical outcome. PRACTICAL RECOMMENDATIONS: Currently, the stent retriever seems to be the definitive first choice in the use of mechanical devices for intra-arterial recanalization treatment in acute ischemic stroke. PMID- 23435626 TI - A cross-sectional survey of pain in palliative care in Portugal. AB - OBJECTIVE: The purpose of this work is to study the prevalence, intensity, and treatment of pain in Portuguese palliative care teams. METHODS: Twenty-one palliative care teams were invited to participate in a cross-sectional survey. Ten of these accepted and were included in the study. Data of all patients observed on the 18th week of 2011 were collected. The data collected concerning pain were: demographic data, pain intensity, drugs prescribed, and invasive techniques. The intensity of pain was rated using a five-point verbal rating scale from none to maximum. The Pain Management Index (PMI) was used to calculate the adequacy of the analgesia. RESULTS: A total of 164 patients were included in this study. One hundred fifty-one (92 %) had cancer. The median age was 71 years (16 to 95). Eighty-four (51 %) were females. Pain was directly assessed in 136 (83 %) of the patients, whereas 27 patients could not report pain because of cognitive failure. Of those directly assessed, 77 (57 %) had pain when they were assessed: 42 (55 %) mild, 25 (32 %) moderate, 9 (12 %) severe, and 1 (1 %) maximum. Non-opioid analgesics were used: paracetamol in 61 (37 %) and NSAID in 20 (12 %). Tramadol was the only opioid for mild to moderate pain used in 25 (15 %) patients. The opioids most used for moderate to intense pain were: morphine 74 (45 %), transdermal (TD) fentanyl 32 (20 %), and buprenorphine TD 28 (17 %). The adjuvants most used were: corticosteroids 38 (23 %), gabapentin 37 (23 %), and amitriptyline 15 (9 %). Only five (4 %) patients had a negative PMI, meaning an inadequate analgesia. CONCLUSION: The general prevalence of pain is similar to that reported by other. The prevalence of moderate to severe pain is also similar to that reported in other studies, although severe pain is somewhat lower than indicated in most reports. According to the PMI, pain control was acceptable to good. PMID- 23435627 TI - Milk protein hydrolysates activate 5-HT(2C) serotonin receptors: influence of the starting substrate and isolation of bioactive fractions. AB - Milk protein hydrolysates generated with different starting substrates, including sodium caseinate (NaCN), acid casein (Acid CN), skim milk powder (SMP) and glycomacropeptide (GMP) were demonstrated to behave as serotonin 2C (5-HT(2C)) receptor agonists. The 5-HT(2C) receptor activating potential of NaCN hydrolysates correlated with an increased protein hydrolysis, most likely due to enhanced release of bioactive peptides over the time course of hydrolysis. In its unhydrolysed form, GMP was the only starting substrate showing 5-HT(2C) serotonin receptor agonist activity. The 5-HT(2C) serotonin receptor agonist activity of its corresponding hydrolysate (GMPH-240 min) was significantly higher (P < 0.05). Fractionation of the 240 min NaCNH using ultrafiltration (UF), solid-phase extraction (SPE), semi-preparative reverse-phase high performance liquid chromatography (RP-HPLC) and isoelectric focusing (IEF) was carried out. Characterisation of the fractions obtained shows that the bioactive peptides had a relatively low molecular mass (<1 kDa), were hydrophobic in nature and had a pI between 8.6 and 13.2. These different physicochemical characteristics together with the stability of NaCNH-240 min to simulated intestinal digestion, allow prediction of a favourable outcome regarding the bioavailability of the bioactive peptides therein. These results reinforce the potential of milk-derived bioactive peptides to be developed into functional foods targeted at 5-HT(2C) receptor modulation. PMID- 23435628 TI - We infer light in space. AB - In studies of lightness and color constancy, the terms lightness and brightness refer to the qualia corresponding to perceived surface reflectance and perceived luminance, respectively. However, what has rarely been considered is the fact that the volume of space containing surfaces appears neither empty, void, nor black, but filled with light. Helmholtz (1866/1962) came closest to describing this phenomenon when discussing inferred illumination, but previous theoretical treatments have fallen short by restricting their considerations to the surfaces of objects. The present work is among the first to explore how we infer the light present in empty space. It concludes with several research examples supporting the theory that humans can infer the differential levels and chromaticities of illumination in three-dimensional space. PMID- 23435629 TI - Color preferences in infants and adults are different. AB - Adults commonly prefer blues most and greenish yellows least, but these hue preferences interact with lightness and saturation (e.g., dark yellow is particularly disliked: Palmer & Schloss (Proceedings of the National Academy of Sciences 107:8877-8882, 2010)). Here, we tested for a similar hue-by-lightness interaction in infant looking preferences, to determine whether adult preferences are evident early in life. We measured looking times for both infants and adults in the same paired-comparison task using all possible pairs of eight colors: four hues (red/yellow/green/blue) at two lightness levels (dark/light). The adult looking data were strikingly similar to other adults' explicit preference responses, indicating for the first time that adults look longer at colors that they like. Infants showed a significant hue-by-lightness interaction, but it was quite different from the adult pattern. In particular, infants had a stronger looking preference for dark yellow and a weaker preference for light blue than did adults. The findings are discussed in relation to theories on the origins of color preference. PMID- 23435630 TI - Trametes versicolor extract modifies human fecal microbiota composition in vitro. AB - Trametes versicolor is a mushroom used as a traditional Chinese medicine (Yun zhi) for a wide array of seemingly disparate conditions. We hypothesized that many of its multiple purported activities could be mediated through stimulation of beneficial mutualist components of the microbiota. Human fecal microbiota was cultured anaerobically to determine its ability to ferment a common extract of T. versicolor, designated polysaccharide peptide (PSP), and the ability of PSP to alter the composition of the microbial community. The presence of PSP and fructooligosaccharides (FOS, a common prebiotic) in the medium, but not cellulose, significantly increased levels of Bifidobacterium spp. PSP also elevated Lactobacillus spp., while reducing Clostridium spp., Staphylococcus spp. and Enterococcus spp. Levels of Streptococcus spp., Bacteroides spp. and Escherichia did not significantly change. Fermentation of PSP increased the concentration of organic acids (lactate and short-chain fatty acids), decreased the pH, and induced beta-galactosidase and beta-glucosidase activities. The genera of the human microbiota that are promoted by FOS and other prebiotics are also stimulated by the Trametes versicolor extract, PSP. Thus, Trametes versicolor, a common East Asian botanical, contains putative prebiotic agents that alter human gut microbiota and pH. This prebiotic-like activity may help explain some of the plethora of the health benefits attributed to this traditional Chinese medicine. PMID- 23435631 TI - Micropropagation effect on the anti-carcinogenic activitiy of polyphenolics from Mexican oregano (Poliomintha glabrescens Gray) in human colon cancer cells HT-29. AB - Phenolic extracts obtained from spices are known to have anti-carcinogenic activities but little is known about the effect of micropropagation on these beneficial effects. The main objective of this study was to evaluate the cytotoxic activity of flavonoid-enriched extracts (FEE) from the leaves of wild (WT), in vitro (IN), and ex vitro (EX) grown oregano plants in colon cancer cells HT-29 and the non-cancer cells CCD-18Co. Cell proliferation of HT-29 cells was reduced to 50 % by WT, IN, and EX at concentrations of 4.01, 1.32, and 4.84 mg of gallic acid equivalents (GAE)/L, respectively. In contrast, in CCD-18Co cells, higher concentrations were required for the same cytotoxic effect. At 6 mg GAE/L, WT and IN reduced the production of reactive oxygen species (ROS) of lipopolysaccharides (LPS)-stimulated control cells to 59.89 and 59.43 %, respectively, and EX to 73.89 %. The mRNA of Caspase-3 was increased 1.53-fold when cells were treated with 4 mg GAE/L of IN extract, and tumor necrosis factor receptor superfamily, member 6 (FAS), and BCL2-associated X protein (BAX) mRNA increased 2.55 and 1.53 fold, respectively. Results on protein expression corroborated the apoptotic effects with a significant decrease of B-cell lymphoma 2 (BCL2) expression for all treatments but more remarkable for EX that also showed the most intense signal of BAX. Overall, FEE extracts derived from micropropagation had increased pro-apoptotic effects, however extracts from the in vitro plants produced more efficacy at the transcriptional level while extracts from the ex vitro plant were superior at the traductional level. PMID- 23435632 TI - C4.4A expression is associated with a poor prognosis of esophageal squamous cell carcinoma. AB - BACKGROUND: C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. We examined clinical relevance of C4.4A expression in 111 esophageal squamous cell carcinoma (ESCC) tissue samples. METHODS: Anti-human C4.4A antibody that recognizes the glycosylphosphatidyl inositol (GPI) anchor signaling sequence (C4.4A-GPI Ab) and anti-human C4.4A-119 polyclonal antibody (C4.4A-119 Ab) were used for immunohistochemistry and Western blot testing. RESULTS: Both antibodies detected the C4.4A protein expression at the parabasal layer of normal epithelium of the esophagus. In tumor tissues, the C4.4A protein was detected in 66 (59.5 %) and 95 (85.6 %) of 111 ESCCs by the C4.4A-GPI Ab and the C4.4A-119 Ab, respectively. The C4.4A-GPI Ab mainly detected membranous C4.4A expression (83.3 %, 55 of 66 positive cases), while the C4.4A-119 Ab exclusively detected cytoplasmic C4.4A expression (100 %, 73 cytoplasm alone and 22 cytoplasm plus membrane in 95 positive cases). Western blot analysis indicated that normal epithelium expressed the band of C4.4A at 70 kDa, whereas the tumor tissues displayed the band at the lower molecular weight. Survival analysis indicated that the C4.4A-positive ESCCs had significantly worse 5-year overall survival than the C4.4A-negative ESCC samples (P = 0.021) when using the C4.4A-GPI Ab, but not when using the C4.4A-119 Ab. This difference was most evident with membranous expression of C4.4A (P = 0.005). CONCLUSIONS: C4.4A expression was associated with a poor prognosis of ESCC when the GPI-related antibody was used. On the other hand, the C4.4A-119 Ab may be a useful diagnostic tool for ESCC because of its high detection rate. PMID- 23435633 TI - The effect of age on race-related breast cancer survival disparities. AB - BACKGROUND: Breast cancer survival disparities by race are likely multifactorial. In a small pilot cohort, we demonstrated a statistical interaction between age and race. The purpose of this study was to validate earlier findings in a larger, more diverse cohort and to test the hypothesis that breast cancer survival is influenced by the dependent relationship of age and race. METHODS: We conducted a retrospective analysis of a multi-institutional breast cancer database for patients treated between 1999 and 2009. Study variables included age and disease stage at diagnosis, race, treatment (surgery, chemotherapy, radiotherapy, hormone therapy) and overall survival. Statistical analysis and regression models were performed by Stata software. RESULTS: A total of 9,249 patients were included in this study. African American, Hispanic, and Asian patients were more likely to present at a younger age with metastases. African American and Hispanic race were associated with increased mortality after adjusting for stage, age, and treatment. A 2-way interaction between age and race was identified in the Cox regression model (p < 0.001). To further define this interaction, a postestimation analysis was performed to determine the predicted relative hazard for each race with age fixed at 40, 50, 60, 70, and 80 years. At younger ages, the predicted relative hazard was significantly higher for both African American and Hispanic race. CONCLUSIONS: Despite adjusting for stage and treatment differences, African American and Hispanic race predicted poor survival. The effect of age and treatment on breast cancer survival differs across races. Additional research is needed to accurately determine the reasons for worsened survival. PMID- 23435635 TI - Advantages of electrodes with dendrimer-protected platinum nanoparticles and carbon nanotubes for electrochemical methanol oxidation. AB - Electrochemical sensors consisting of electrodes loaded with carbon nanotubes and Pt nanoparticles (PtNPs) protected by dendrimers have been developed using a facile method to fabricate them on two types of disposable electrochemical printed chips with a screen-printed circular gold or a screen-printed circular glassy carbon working electrode. The electrochemical performance of these sensors in the oxidation of methanol was investigated by cyclic voltammetry. It was revealed that such sensors possess stable durability and high electrocatalytic activity: the potential and the current density of an anodic peak in the oxidation of methanol increased with increasing content of PtNPs on the electrodes, indicating the promotion of electrocatalytic activity in relation to the amount of catalyst. The low anodic potential suggests the easy electrochemical reaction, and the high catalyst tolerance supports the almost complete oxidation of methanol to carbon dioxide. The significant performance of these sensors in the detection of methanol oxidation comes from the high electrocatalytic ability of PtNPs, excellent energy transfer of carbon nanotubes and the remarkable ability of dendrimers to act as binders. Thus these systems are effective for a wide range of applications as chemical, biomedical, energy and environmental sensors and as units of direct methanol fuel cells. PMID- 23435636 TI - Postpancreatectomy hemorrhage (PPH): predictors and management from a prospective database. AB - BACKGROUND: Postpancreatectomy hemorrhage (PPH) is a dreaded complication in pancreatic surgery. Today, there is a definition and grading of PPH without therapeutic consensus. We reviewed our prospective database to identify predictors and assess therapeutic strategy. METHOD: We included all patients who underwent pancreatectomy between 2005 and 2010. Data were collected prospectively. We used the International Study Group Of Pancreatic Surgery (ISGPS) definition for PPH to include patients in the PPH group. RESULTS: Forty six of 285 patients showed a PPH (16.1 %). The ISGPS classification was graded A = 3, B = 26, and C = 17. The average time to the onset of PPH was 7 days. CT-scan identified the origin of PPH in 43.5 % of the cases. PPH was responsible for a longer duration of hospital stay (p = 0.004), a higher hospital mortality (21.7 vs 2.5 %, p < 0.0001) and a lower survival (40 vs 70 % (p = 0.05) at 36 months). The first-intention treatment of PPH was conservative in 32 % and interventional in 68 %: endoscopy (6.4 %), transcatheter arterial embolization (TAE, 30.4 %), and surgical (30.4 %). In multivariate analysis, predictors of PPH were: pancreatic fistula (24 vs 8 % p = 0.028), pancreatoduodenectomy (70 vs 43 % p = 0.029), age (61.6 vs 58.8 %, p = 0.03), and nutritional risk index (NRI) (p = 0.048). CONCLUSION: In our series, risk factors for PPH were age, pancreatic fistula, pancreatoduodenectomy, and NRI. Its occurrence is associated with significantly higher hospital mortality and a lower survival rate. Our first-line treatment was radiological TAE. Surgical treatment is offered in case of failure of interventional radiology or in case of uncontrolled hemodynamic. PMID- 23435638 TI - Two cases of bacterial suppurative thyroiditis caused by Streptococcus anginosus. AB - Acute suppurative thyroiditis (AST) is a rare clinical condition. Streptococcus anginosus has a propensity of producing empyema in the head and neck. Here, we reported two cases of AST caused by S. anginosus. A 44-year-old man presented with anterior neck tender swelling and odynophagia for 12 days. He had thyrotoxicosis. He was initially diagnosed as thyroid cancer due to the misleading computed tomography report. Fine needle aspiration (FNA) yielded pus and neutrophils. S. anginosus was isolated from pus. After aspiration of abscess and treatment with sensitive antibiotics, he recovered uneventfully with 3 weeks treatment. He was euthyroid 3 months later. The other case is a 40-year-old women complained of fever and left neck swelling for 20 days. Magnetic resonance imaging showed left neck inflammatory changes. FNA revealed pus and inflammatory cells infiltration. She had moderately decreased level of thyroid-stimulating hormone (TSH). Blood cultures were positive for S. anginosus. After penicillin treatment, TSH level returned to normal range, and the nodule gradually resolved. She recovered uneventfully after 5 weeks treatment. S. anginosus has a previously unappreciated clinical niche in AST. Once AST is clinically concerned, FNA procedure should be performed as early as possible. PMID- 23435637 TI - Stem cells and cancer stem-like cells in endocrine tissues. AB - Cancer stem-like cells are a subpopulation of self-renewing cells that are more resistant to chemotherapy and radiation therapy than the other surrounding cancer cells. The cancer stem cell model predicts that only a subset of cancer cells possess the ability to self-renew and produce progenitor cells that can reconstitute and sustain tumor growth. Evidence supporting the existence of cancer stem-like cells in the thyroid, pituitary, and in other endocrine tissues is rapidly accumulating. These cells have been studied using specific biomarkers including: CD133, CD44, Nestin, Nanog, and aldehyde dehydrogenase enzyme. Putative cancer stem-like cells can be studied in vitro using serum-free media supplemented with basic fibroblast growth factor and epidermal growth factor grown in low attachment plates or in extracellular matrix leading to sphere formation in vitro. Cancer stem-like cells can also be separated by fluorescent cell sorting and used for in vitro or in vivo studies. Injection of enriched populations of cancer stem-like cells (also referred to as tumor initiating cells) into immunodeficient mice results in growth of xenografts which express cancer stem-like biomarkers. Human cancer stem-like cells have been identified in thyroid cancer cell lines, in primary thyroid cancers, in normal pituitary, and in pituitary tumors. Other recent studies suggest the existence of stem cells and cancer stem-like cells in endocrine tumors of the gastrointestinal tract, pancreas, lungs, adrenal, parathyroid, and skin. New discoveries in this field may lead to more effective therapies for highly aggressive and lethal endocrine cancers. PMID- 23435641 TI - Towards directional assembly of hierarchical structures: aniline oligomers as the model precursors. AB - Hierarchical architectures attract a large number of scientists and engineers because of their unique physicochemical properties compared with bulk materials and their precursors. It is believed that intermolecular interactions play a key role in the formation of these hierarchical architectures. However, the principle of coordination of various intermolecular interactions in the self-assembly process is not clear. Here, an aniline oligomer is used as a model brick to study the formation process of well-defined hierarchical architectures, and the directional growth mechanism is proposed. It is assumed that aniline oligomer molecules are asymmetric, and driven by intermolecular attractive forces to aggregate in various manners. Combined with the interactions between the aniline oligomer and molecules from the medium, three-dimensional assemblies, flower-like and urchin-like microspheres, can be formed. The variability and complexity of morphologies produced in the process was analyzed according to the intermolecular interactions, which includes hydrogen bonding, pi-pi stacking, hydrophobic interaction, etc. The applicability of these special hierarchical architectures, such as in the preparation of superhydrophobic surfaces, is also discussed. PMID- 23435639 TI - The ONSTEP inguinal hernia repair technique: initial clinical experience of 693 patients, in two institutions. AB - PURPOSE: Experience with a novel hernioplasty procedure--the ONSTEP approach--for inguinal hernia repair in a large series of patients performed by two surgeons at two institutions is described, focusing in particular on the duration of surgery, the time taken to return to normal activities, chronic pain, complication and recurrence rates. METHODS: Adult patients underwent inguinal hernia repair using the ONSTEP approach. The hernia defect was repaired using a PolySoftTM hernia patch. Patients were followed up for 1 year for pain, complications and recurrences. RESULTS: A total of 693 patients underwent ONSTEP inguinal hernia repair. The mean duration of surgery (+/- SD) was 17 +/- 6 min; the time to discharge from hospital was less than 24 h in all patients; and the mean time to return to normal daily activities was 6.1 +/- 3.0 days. The overall complication rate was 1.0 % and the overall recurrence rate was 0.6 %. Residual pain was present in 4 patients at 6 months and was cured by removal of the memory ring in 3 patients and disappeared spontaneously in one case, so that there was no case of chronic pain at 1 year. CONCLUSIONS: The ONSTEP inguinal hernia repair technique described is simple, quick to perform, produces consistent results and is associated with very low overall complication, chronic pain and recurrence rates. It may offer an alternative to both Lichtenstein and laparoscopic inguinal hernia repair. PMID- 23435643 TI - Newer developments in the immunotherapy of malignant melanoma. AB - Individuals with malignant melanoma present a variety of immune abnormalities including but not limited to cellular immune dysfunction, antigen presentation deficits, and cytokine production defects. Therefore, enhancing the immune system potential represents an appealing avenue for melanoma therapy. The authors review the immune therapies currently in clinical use as well as the most promising immunotherapy candidates. Ipilimumab, a monoclonal antibody against the CTLA-4, was approved for the therapy of advanced melanoma in 2011. In addition, sizeable anti-melanoma activity has recently been shown with the use of other agents including anti-PD-1/anti-PD-1 ligand antibodies. Consequently, these experimental immunotherapy agents may soon become important items in the anti-melanoma armamentarium. PMID- 23435642 TI - Pyrrolizidine alkaloid composition influences cinnabar moth oviposition preferences in Jacobaea hybrids. AB - Plants produce a variety of secondary metabolites (PSMs) that may be selective against herbivores. Yet, specialist herbivores may use PSMs as cues for host recognition, oviposition, and feeding stimulation, or for their own defense against parasites and predators. This summarizes a dual role of PSMs: deter generalists but attract specialists. It is not clear yet whether specialist herbivores are a selective force in the evolution of PSM diversity. A prerequisite for such a selective force would be that the preference and/or performance of specialists is influenced by PSMs. To investigate these questions, we conducted an oviposition experiment with cinnabar moths (Tyria jacobaeae) and plants from an artificial hybrid family of Jacobaea vulgaris and Jacobaea aquatica. The cinnabar moth is a specialist herbivore of J. vulgaris and is adapted to pyrrolizidine alkaloids (PAs), defensive PSMs of these plants. The number of eggs and egg batches oviposited by the moths were dependent on plant genotype and positively correlated to concentrations of tertiary amines of jacobine-like PAs and some otosenine-like PAs. The other PAs did not correlate with oviposition preference. Results suggest that host plant PAs influence cinnabar moth oviposition preference, and that this insect is a potential selective factor against a high concentration of some individual PAs, especially those that are also involved in resistance against generalist herbivores. PMID- 23435644 TI - Accuracy of urine pH testing in a regional metabolic renal clinic: is the dipstick accurate enough? AB - Urine pH is a useful marker for assessing treatment need and efficacy in patients with nephrolithiasis. Though the gold standard of measurement is with a pH electrode, dipsticks offer the convenience of cost, ease of use, and the possibility of patients measuring their own values outside the clinic. The aim of this study was to determine whether dipsticks offer the same accuracy as the electrode. Paired measurements of freshly voided urine pH with both electrode and dipstick were analysed in a multidisciplinary renal clinic. We found that although there was a high Pearson correlation between the samples (0.89, p = 0.001), urine dipstick measurements carried an approximately 1 in 4 risk of producing clinically significant differences (pH differences > 0.5 pH unit) from meter values. We also found that at high and low urine pH, the dipstick tended to over- and underestimate true pH readings, respectively. Examining the values in the 98 patients where a need for pharmacological urinary pH manipulation was indicated by the true pH, we found 14 who would not have been appropriately treated, and 5 who would have been unnecessarily medicated, if the stick pH value had been used. We conclude that dipstick pH measurement is insufficiently reliable for guiding clinical decision-making. PMID- 23435645 TI - Synchronization of an excitatory integrate-and-fire neural network. AB - In this paper, we study the influence of the coupling strength on the synchronization behavior of a population of leaky integrate-and-fire neurons that is self-excitatory with a population density approach. Each neuron of the population is assumed to be stochastically driven by an independent Poisson spike train and the synaptic interaction between neurons is modeled by a potential jump at the reception of an action potential. Neglecting the synaptic delay, we will establish that for a strong enough connectivity between neurons, the solution of the partial differential equation which describes the population density function must blow up in finite time. Furthermore, we will give a mathematical estimate on the average connection per neuron to ensure the occurrence of a burst. Interpreting the blow up of the solution as the presence of a Dirac mass in the firing rate of the population, we will relate the blow up of the solution to the occurrence of the synchronization of neurons. Fully stochastic simulations of a finite size network of leaky integrate-and-fire neurons are performed to illustrate our theoretical results. PMID- 23435646 TI - [Intraprostatic injection therapy in patients with benign prostatic syndrome]. AB - Intraprostatic injection therapy is a minimally invasive treatment of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and could be a therapeutic alternative in increasingly older and co-morbid patients. Nowadays only botulinum neurotoxin A (BoNT/A), absolute ethanol, NX-1207 and PRX302 are of relevance but none of these substances has yet been authorized for treatment use (off-label use). There have been only three randomized, placebo controlled trials (RCTs) for BoNT/A, whereas none exist for ethanol and the results of existing studies are inconsistent and without convincing proof of efficacy. NX-1207 is a protein with selective pro-apoptotic properties and non inferiority compared to finasteride has been demonstrated. PRX302 is a modified proaerolysin that can be activated by prostate-specific antigen and is therefore (prostate) cell-specific. Safety and efficacy are well documented; however, intraprostatic injection therapy should presently only be performed in clinical trials, irrespective of the substance used. PMID- 23435647 TI - pH-sensitive DNA cleaving agents: in situ activation by ring contraction of benzo fused cyclobutanols. AB - Benzo-fused cyclobutanols were developed as novel DNA cleaving molecules. The molecules nick a strand of supercoiled DNA under acidic conditions. By contrast, almost no activity was observed under neutral or basic conditions. PMID- 23435648 TI - The efficacy of patellar decompression for improving anterior knee pain following total knee arthroplasty without patellar resurfacing. AB - BACKGROUND: Anterior knee pain remains common following total knee arthroplasty (TKA). In this study, we evaluated the efficacy of patellar decompression via drilling for the treatment of anterior knee pain following TKA without patellar resurfacing. METHODS: A prospective cohort study was performed in 271 consecutive patients who underwent primary total knee replacement with patellar decompression (study group, n = 131) or without decompression (control group, n = 140). The patients were assessed according to the Knee Society rating, clinical anterior knee pain score, and British Orthopaedic Association patient-satisfaction score in each group. Each assessment was performed without the examiner knowing whether the patella had been decompressed. Radiographic evaluations were also performed according to the Knee Society scoring system for functional activity and our own severity grade system for patellofemoral articular change. RESULTS: There were no adverse events following patellar decompression. The overall prevalence of anterior knee pain was not significantly different between groups (p = 0.71). However, patients presenting pain over grade II after the operation in the study group were statistically low (p = 0.01). The overall postoperative knee scores were higher in the study group, but there were no significant differences between groups (p = 0.0731). Analyses of the radiographs revealed similar postoperative outcomes in both groups of knees. CONCLUSIONS: As we observed significantly lower rates of anterior knee pain and no patellar complications following patellar decompression via drilling in TKA without patellar resurfacing, we recommend performing patellar decompression in cases of total knee replacement without patellar resurfacing. PMID- 23435649 TI - Marine ecosystem health status assessment through integrative biomarker indices: a comparative study after the Prestige oil spill "Mussel Watch". AB - Five integrative biomarker indices are compared: Bioeffects Assessment Index (BAI), Health Status Index (HSI), integrated biological response (IBR), ecosystem health condition chart (EHCC) and Integrative Biomarker Index (IBI). They were calculated on the basis of selected biomarker data collected in the framework of the Prestige oil spill (POS) Mussel Watch monitoring (2003-2006) carried out in Galicia and the Bay of Biscay. According to the BAI, the health status of mussels was severely affected by POS and signals of recovery were evidenced in Galicia after April-04 and in Biscay Bay after April-05. The HSI (computed by an expert system) revealed high levels of environmental stress in 2003 and a recovery trend from April-04 to April-05. In July-05, the health status of mussels worsened but in October-05 and April-06 healthy condition was again recorded in almost all localities. IBR/n and IBI indicated that mussel health was severely affected in 2003 and improved from 2004 onwards. EHCC reflected a deleterious environmental condition in 2003 and a recovery trend after April-04, although a healthy ecosystem condition was not achieved in April-06 yet. Whereas BAI and HSI provide a basic indication of the ecosystem health status, star plots accompanying IBR/n and IBI provide complementary information concerning the mechanisms of biological response to environmental insult. Overall, although the integrative indices based on biomarkers show different sensitivity, resolution and informative output, all of them provide coherent information, useful to simplify the interpretation of biological effects of pollution in marine pollution monitoring. Each others' advantages, disadvantages and applicability for ecosystem health assessment are discussed. PMID- 23435650 TI - Effects of historical lead-zinc mining on riffle-dwelling benthic fish and crayfish in the Big River of southeastern Missouri, USA. AB - The Big River (BGR) drains much of the Old Lead Belt mining district (OLB) in southeastern Missouri, USA, which was historically among the largest producers of lead-zinc (Pb-Zn) ore in the world. We sampled benthic fish and crayfish in riffle habitats at eight sites in the BGR and conducted 56-day in situ exposures to the woodland crayfish (Orconectes hylas) and golden crayfish (Orconectes luteus) in cages at four sites affected to differing degrees by mining. Densities of fish and crayfish, physical habitat and water quality, and the survival and growth of caged crayfish were examined at sites with no known upstream mining activities (i.e., reference sites) and at sites downstream of mining areas (i.e., mining and downstream sites). Lead, zinc, and cadmium were analyzed in surface and pore water, sediment, detritus, fish, crayfish, and other benthic macro invertebrates. Metals concentrations in all materials analyzed were greater at mining and downstream sites than at reference sites. Ten species of fish and four species of crayfish were collected. Fish and crayfish densities were significantly greater at reference than mining or downstream sites, and densities were greater at downstream than mining sites. Survival of caged crayfish was significantly lower at mining sites than reference sites; downstream sites were not tested. Chronic toxic-unit scores and sediment probable effects quotients indicated significant risk of toxicity to fish and crayfish, and metals concentrations in crayfish were sufficiently high to represent a risk to wildlife at mining and downstream sites. Collectively, the results provided direct evidence that metals associated with historical mining activities in the OLB continue to affect aquatic life in the BGR. PMID- 23435651 TI - Diagnosis and evaluation of intestinal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation following reduced-intensity and myeloablative conditioning regimens. AB - Colonoscopic evaluation of mucosal tissues after allogeneic hematopoietic stem cell transplantation (HSCT) is very useful in evaluating pathogenesis and diagnosis of intestinal graft-versus-host disease (GVHD). However, information on the timing and sites of biopsies and the immunohistological evaluation of mucosal tissues for diagnosing intestinal GVHD, especially following reduced-intensity (RIC) regimens, remains very limited. A total of 33 patients with histologically proven GVHD after allogeneic HSCT with RIC (n = 23) and myeloablative conditioning (MAC, n = 10) regimens were enrolled in the present study. Colonoscopy was performed due to gastrointestinal symptoms, especially diarrhea and anorexia. Sites of biopsies with the worst histopathological grading were the terminal ileum in 67 % of patients. In the RIC group, the onset of diarrhea prior to colonoscopy examination was later (median: RIC, 57 vs. MAC, 27 days) and the number of patients who developed abdominal pain tended to be higher (RIC, 70 % vs. MAC, 30 %). A lower number of CD4+ cells and a higher ratio of Foxp3+ cells to CD4+ cells were detected in the involved lesions of intestinal GVHD following RIC. These differences in the RIC and MAC groups suggest that regimen-specific therapeutic strategies are required for diagnosing intestinal GVHD. PMID- 23435652 TI - The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. AB - Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not 'routine'. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s). PMID- 23435653 TI - Midazolam for urethral catheterisation in female infants with suspected urinary tract infection: a case-control study. AB - OBJECTIVES: Based on the 2010 Israeli Medical Association recommendations, young children with suspected urinary tract infection (UTI) are mildly sedated with oral or intranasal midazolam to reduce the distress associated with urethral catheterisation (UC). The primary objective of this study was to examine the rate of urine culture contamination (UCC) in infants who underwent UC with and without sedation. Other objectives were to evaluate serious adverse events and emergency department (ED) length of stay. METHODS: A retrospective case-control study was conducted in a paediatric ED. RESULTS: Two cohorts of patients who underwent UC were compared, 164 female infants who were sedated with midazolam (case subjects) and 173 who were not (controls). Cases and controls had a mean temperature of 38.3 degrees C and 38.2 degrees C, respectively. One hundred and forty-one patients were treated with oral midazolam and 23 received the drug intranasally. Cases and controls had a UCC rate of 20/164 (12%) and 45/173 (26%), respectively. Compared with controls, cases had lower odds of UCC (OR=0.39, 95% CI 0.21 to 0.73).Serious adverse events related to midazolam were not recorded. Case subjects and controls had a mean ED length of stay of 2.96 h and 2.50 h, respectively. The difference between the groups was statistically significant (p<0.014, 95% CI 0.10 to 0.90 for difference between means). CONCLUSIONS: In this cohort of febrile infants, sedation with oral or intranasal midazolam reduced the risk of culture contamination during UC without causing serious adverse events. However, patients who were treated with sedation had longer length of stay in the ED. PMID- 23435654 TI - Proceedings of the XXXIth Seminar of the French-Speaking Society for Theoretical Biology. PMID- 23435656 TI - A measure of within-participant response consistency. AB - In this article, we introduce a measure of within-participant response consistency for use in the analysis of performance in decision-making tasks. The measure is an estimate of the correlation between the responses associated with two identical blocks of trials, the second of which has yet to be conducted. We derive a formula for the measure that can be applied to data from any two-choice decision task, including yes/no detection and two-alternative forced choice (2AFC). The estimate is easily calculated from the observed frequencies of hits, misses, false alarms, and correct rejections. We utilized data from an actual 2AFC experiment to compare estimated and observed consistency values; the estimates accounted for more than 90 % of the variability in observed consistency scores. We also discuss potential applications of the measure. PMID- 23435657 TI - Objective age of acquisition norms for a set of 286 words in Russian: relationships with other psycholinguistic variables. AB - Normative data on the objective age of acquisition (AoA) for 286 Russian words are presented in this article. In addition, correlations between the objective AoA and subjective ratings, name agreement, picture name agreement, imageability, familiarity, word frequency, and word length are provided, as are correlations between the objective AoA and two measures of exemplar dominance (exemplar generation frequency and the number of times an exemplar was named first). The correlations between the aforementioned variables are generally consistent with the correlations reported in other normative studies. The objective AoA data are highly correlated with the subjective AoA ratings, whereas the correlations between the objective AoA and other psycholinguistic variables are moderate. The correlations between the objective AoA of Russian words and similar data for other languages are moderately high. The complete word norms may be downloaded from supplementary material. PMID- 23435658 TI - BLIND: a set of semantic feature norms from the congenitally blind. AB - Feature-based descriptions of concepts produced by subjects in a property generation task are widely used in cognitive science to develop empirically grounded concept representations and to study systematic trends in such representations. This article introduces BLIND, a collection of parallel semantic norms collected from a group of congenitally blind Italian subjects and comparable sighted subjects. The BLIND norms comprise descriptions of 50 nouns and 20 verbs. All the materials have been semantically annotated and translated into English, to make them easily accessible to the scientific community. The article also presents a preliminary analysis of the BLIND data that highlights both the large degree of overlap between the groups and interesting differences. The complete BLIND norms are freely available and can be downloaded from http://sesia.humnet.unipi.it/blind_data . PMID- 23435659 TI - Divergent properties of prolamins in wheat and maize. AB - Cereal grains are an important nutritional source of amino acids for humans and livestock worldwide. Wheat, barley, and oats belong to a different subfamily of the grasses than rice and in addition to maize, millets, sugarcane, and sorghum. All their seeds, however, are largely devoid of free amino acids because they are stored during dormancy in specialized storage proteins. Prolamins, the major class of storage proteins in cereals with preponderance of proline and glutamine, are synthesized at the endoplasmic reticulum during seed development and deposited into subcellular structures of the immature endosperm, the protein bodies. Prolamins have diverged during the evolution of the grass family in their structure and their properties. Here, we used the expression of wheat glutenin Dx5 in maize to examine its interaction with maize prolamins during endosperm development. Ectopic expression of Dx5 alters protein body morphology in a way that resembles non-vitreous kernel phenotypes, although Dx5 alone does not cause an opaque phenotype. However, if we lower the amount of gamma-zeins in Dx5 maize through RNAi, a non-vitreous phenotype emerges and the deformation on the surface of protein bodies is enhanced, indicating that Dx5 requires gamma-zeins for its proper subcellular organization in maize. PMID- 23435660 TI - The Arabidopsis elongator complex subunit2 epigenetically regulates plant immune responses. AB - The Arabidopsis thaliana Elongator complex subunit2 (ELP2) genetically interacts with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1), a key transcription coactivator of plant immunity, and regulates the induction kinetics of defense genes. However, the mechanistic relationship between ELP2 and NPR1 and how ELP2 regulates the kinetics of defense gene induction are unclear. Here, we demonstrate that ELP2 is an epigenetic regulator required for pathogen-induced rapid transcriptome reprogramming. We show that ELP2 functions in a transcriptional feed-forward loop regulating both NPR1 and its target genes. An elp2 mutation increases the total methylcytosine number, reduces the average methylation levels of methylcytosines, and alters (increases or decreases) methylation levels of specific methylcytosines. Interestingly, infection of plants with the avirulent bacterial pathogen Pseudomonas syringae pv tomato DC3000/avrRpt2 induces biphasic changes in DNA methylation levels of NPR1 and PHYTOALEXIN DEFICIENT4 (PAD4), which encodes another key regulator of plant immunity. These dynamic changes are blocked by the elp2 mutation, which is correlated with delayed induction of NPR1 and PAD4. The elp2 mutation also reduces basal histone acetylation levels in the coding regions of several defense genes. Together, our data demonstrate a new role for Elongator in somatic DNA demethylation/methylation and suggest a function for Elongator-mediated chromatin regulation in pathogen-induced transcriptome reprogramming. PMID- 23435662 TI - India draws up emergency plan to tackle H1N1 outbreak. PMID- 23435663 TI - Life should end as well as it starts, conference hears. PMID- 23435661 TI - Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59. AB - Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCF(COI1), which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA responsive genes that are suppressed by SA are significantly enriched in the JA responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC box fused to the beta-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCF(COI1)-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID- 23435664 TI - Postoperative seizure in a neurosurgical patient: Should tranexamic acid be on the differential? PMID- 23435665 TI - A new indicator for the measurement of change with ordinal scores. AB - BACKGROUND: Studies on how to better measure change have been published at least since the third decade of the last century, but no general indicator or strategy of measurement is currently agreed upon. The aim of this study is to propose a new indicator, the indicator of positive change, as an option for the assessment of change when ordinal scores are used in pretest and posttest designs. METHODS: The basic idea is to measure the proportion of possible (positive) change inside a group that can be attributed to an intervention. The approach is based on the joint distribution of the before and after scores (differences), represented by the cells (i, j) of a contingency table m * m (m is the number of classes of the ordinal measurement scale; i and j are the lines and columns of the table, respectively). By convention, higher classes are the most unfavorable on the scale such that subjects that improve "migrate" from the higher to the lower classes as a result of an intervention and vice versa. RESULTS: The introduced indicator offers a new strategy for the analysis of change when dealing with repeated measurements of the same subject, assuming that the measured variable is ordinal (e.g., clinician-rating scales). CONCLUSION: The presented approach is easily interpretable and avoids the problems that arise, for instance, in those cases where a large concentration of high/low scores is present at the baseline. PMID- 23435666 TI - Commentary on "A new indicator for the measurement of change with ordinal scores". PMID- 23435668 TI - The making of iLiquids--the chemist's equivalent of the iPhone. AB - In this viewpoint we discuss the contributions from John S. Wilkes and Michael J. Zaworotko concerning the discovery of stable ionic liquids (ILs) and their accompanying structural studies (J. Chem. Soc., Chem. Commun., 1992, 965) and Robin D. Rogers and James H. Davis et al. who described the rational modification of ILs for specific applications - so-called task-specific ionic liquids (TSILs) (Chem. Commun., 2001, 135). These were quite simply groundbreaking discoveries that inspired the scientific community, leading to enormous growth in the field and the wide and diverse range of ILs and their applications. The multitude of 'apps' of ILs warrants an analogy with the iPhone and our use of the term iLiquids. PMID- 23435667 TI - Satisfaction with oncology care among patients with advanced cancer and their caregivers. AB - PURPOSE: Satisfaction with care is important for quality assurance in oncology, but may differ between patients and caregivers. We aimed to assess satisfaction with cancer care in paired analyses of these groups, examine differences between them, and identify areas for potential intervention. METHODS: Patients with advanced cancer and their caregivers were recruited from 24 medical oncology outpatient clinics. Satisfaction with care was measured using the FAMCARE (caregivers) and FAMCARE-Patient (patients) scales. Quality of life (QOL) was measured with the Caregiver QOL Index-Cancer (caregivers) and FACIT-Sp (patients). The paired t test assessed differences in overall satisfaction and individual scores. In addition, scores were dichotomized into satisfied versus not satisfied, and McNemar's test was used to assess differences. Multivariable linear regression analyses assessed predictors of patient and caregiver satisfaction, respectively. RESULTS: Satisfaction ratings in the 191 patient caregiver pairs were high, but patients were more satisfied (p = 0.02). Both groups were least satisfied with information regarding prognosis and pain management. Caregivers were significantly less satisfied than patients regarding coordination of care (p = 0.001) and family inclusion in treatment/care decisions (p < 0.0001). In both groups, higher education was associated with lower satisfaction (p <= 0.01), while better QOL predicted greater satisfaction (p < 0.0001). CONCLUSIONS: Communication regarding pain control and prognosis were identified as key areas for improvement. Caregivers seem to desire greater involvement in treatment decisions, though this must be balanced with patient autonomy. PMID- 23435669 TI - Numerical analysis of blood flow distribution in 4- and 3-branch vascular grafts. AB - Trifurcated arch grafts (3-branch grafts) are now being used to repair the thoracic aorta in addition to conventional arch grafts (4-branch grafts). The anatomical shape of the 3-branch graft is different from the original vessel, so it is necessary for clinical application to evaluate blood flow distribution in the graft to assess whether there is adequate blood flow to the target organs. To achieve this, we developed a computational fluid dynamics (CFD) method to evaluate blood flow distribution in the grafts. Aortic blood flow was measured by phase-contrast magnetic resonance imaging (PC-MRI), and flow distribution into the branched vessels was obtained. The MRI image was used to create a patient specific image model that represents the geometry of the aortic arch. The CFD analysis method was employed to determine a boundary condition of the blood flow analysis in the aorta using a patient-specific image model. We also created simplified models of 4-branch and 3-branch grafts and used our CFD analysis method to compare blood flow distribution among simplified models. It was found that blood flow distribution in the descending aorta was 71.3 % for the 4-branch graft and 67.7 % for the 3-branch graft, indicating that a sum of branching flow in the 3-branch graft was almost the same as the one in the 4-branch graft. Therefore, there is no major concern about implanting a new 3-branch graft. Our CFD analysis method may be applied to estimate blood flow distribution of a newly developed vascular graft prior to its clinical use and provide useful information for safe use of the graft. PMID- 23435670 TI - Which patients respond best to hepatitis B vaccination after a hepatitis B virus related liver transplantation? AB - BACKGROUND: A combination of hepatitis B immunoglobulin and nucleos(t)ide analogues is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, frequent immunoglobulin treatment is expensive and inconvenient. This study investigated the efficacy of hepatitis B virus (HBV) vaccination in preventing the recurrence of hepatitis B after living donor OLT. METHODS: Twenty-seven patients who had undergone living donor OLT participated in the study; five had acute HBV infected liver failure (ALF-OLT) and 22 had HBV related liver cirrhosis (LC-OLT). Hepatitis B surface antigen (HBsAg)-containing vaccine was administered to them for at least 1 year after transplantation and continued once monthly for up to 36 months post-OLT. Patients who had anti-HBs antibody titers above 100 mIU/mL for a minimum of 6 months without immunoglobulin administration were defined as good responders; the others were defined as poor responders. Interferon-gamma enzyme-linked immunospot assays against HBs and HBc antigens were used to assay cellular immune responses. RESULTS: All five of the ALF-OLT patients had good responses after a median of four (range 2.5-5) vaccinations. Nine of the 22 LC-OLT patients had good responses after a median of 19 (range 11.5-30) vaccinations. Among the LC-OLT group, those with livers donated by relatively higher-aged, marital and high titer anti-HBs antibody donors were good responders. LC-OLT patients classed as good responders showed interferon-gamma responses comparable to those of the ALF OLT patients. CONCLUSIONS: The ALF-OLT and LC-OLT patients who received livers from relatively higher-aged, marital, high-titer anti-HBs antibody donors were the best candidates for HBV vaccine administration. Boosting donors before transplantation may facilitate later vaccine response of the recipients. PMID- 23435671 TI - KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. AB - BACKGROUND: It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC). METHODS: AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). RESULTS: KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc. CONCLUSION: This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC. PMID- 23435672 TI - The law and the laboratory. PMID- 23435673 TI - Aggressive statin therapy and the risk of malignancy. AB - The advent of pharmacologic agents which partially inhibit the rate limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl Co-A reductase) provided a major advance in preventive medicine. Clinical trials in both primary and secondary prevention have demonstrated reduction in cardiovascular events by statin therapy. However, early epidemiologic studies proposed an inverse relationship between cholesterol levels and mortality. While the epidemiologic studies were controversial and did not establish a cause and effect relationship, concern was raised that aggressive lipid lowering by pharmacological means may be associated with increased risk for noncardiac mortality, including malignancy. The theoretical concern was intensified by meta-analysis of statin trials, which confirmed the reduction in cardiovascular mortality but also demonstrated a potential increase in cancer risk. This review evaluates the epidemiologic and prospective trial data which address the potential relationship between aggressive statin therapy and the risk of malignancy. PMID- 23435674 TI - Fluorescence spectroscopy of PTCDA molecules on the KCl(100) surface in the limit of low coverages: site selection and diffusion. AB - We performed fluorescence (FL) and fluorescence excitation (FLE) spectroscopy on the model molecule perylene-3,4,9,10-tetracarboxyl acid dianhydride (PTCDA) for very low coverages (below 1% of a monolayer) on thin (100) oriented KCl films. Two different states of PTCDA molecules can be distinguished in the spectra: an initial state, which is observed directly after deposition of the molecules onto the cold sample at 20 K, and a final state, which is found after intensive optical excitation or thermal annealing of the sample. The spectrum of the final state is blue-shifted with respect to that of the initial state by 130 +/- 15 cm( 1) and exhibits lines with significantly reduced widths. This can be explained by diffusion of molecules from initially populated terrace sites to energetically favoured step edge sites. Polarization dependent spectroscopy reveals the same azimuthal orientation of the molecules on both adsorption sites and leads to a model of the adsorption geometry of PTCDA at the KCl step sites. Our experiment demonstrates how optical spectroscopy can be used to investigate kinetic processes of fluorescent molecules on surfaces. PMID- 23435675 TI - Metabolic transit of N(epsilon)-carboxymethyl-lysine after consumption of AGEs from bread crust. AB - Our aim was to investigate carboxymethyl-lysine (CML) intake and excretion after feeding rats with diets containing advanced glycation end-products (AGEs) from bread crust (BC) or its soluble or insoluble fractions, and to identify the factors responsible for the effects observed. CML in serum and different tissues was measured to detect possible accumulations. For 88 days, weanling rats were fed with either a control diet or one containing BC, or its soluble low molecular weight (LMW), soluble high molecular weight (HMW) or insoluble fractions. In the last week of the assay, faeces and urine were collected daily and stored as a 1 week pool. After sacrifice, blood was drawn to obtain serum and some organs were removed. CML analysis was performed by HPLC/MS/MS in diets, faeces, urines, serum and tissues. Faecal excretion of CML was strongly influenced by dietary CML levels and represents the major route of excretion (i.e. 33.2%). However, the urinary elimination of CML was probably limited or saturated, especially when more complex compounds were present in the diet. BC consumption increased CML in the cardiac tissue (170 +/- 18 vs. 97 +/- 3 MUmol per mol lysine for BC and control groups), which correlated with the CML intake. The levels of this AGE in bone were unaffected by the dietary treatment, but in tail tendons CML was greatly increased in the animals that consumed the BC diet (102 +/- 13 vs. 51 +/- 8 MUmol per mol lysine for BC and control groups, P = 0.006), which was associated with the intake of soluble LMW compounds present in BC. Despite the CML accumulation detected in different tissues, serum levels of protein-bound CML were unchanged, indicating the importance of measuring the free CML in this fluid as a real index of dietary CML. PMID- 23435676 TI - Karydakis flap for recurrent pilonidal disease. AB - BACKGROUND: Patients undergoing surgery for recurrent pilonidal disease are at high risk of developing re-recurrence. The present retrospective analysis was performed to compare long-term results in patients with recurrent disease undergoing midline excision surgery compared to patients undergoing the Karydakis flap procedure. METHODS: Only patients with previous excision surgery apart from simple abscess incision were included. Disease recurrence was defined as the need for repeat surgery. RESULTS: A total of 124 patients underwent surgery for recurrent pilonidal disease. Group 1 consisted of 37 patients (25 excision + midline closure, 12 excision + lay-open). Group 2 consisted of 87 patients (Karydakis flap). There were no statistically significant differences between the groups with regard to patient's age, duration of disease, body mass index, or sex. The average number of previous surgeries was significantly higher in group 1 patients (2.1 vs. 1.8, p = 0.019). The overall 1-year recurrence rate was 43 % in group 1 and 3 % in group 2 (p < 0.0001). The wound dehiscence rate after the Karydakis flap procedure was as high as 43 % between years 2005 and 2009, but it fell to 10 % thereafter (p = 0.02). CONCLUSIONS: Karydakis flap procedure is superior to midline excision surgery in patients presenting with recurrent pilonidal disease. PMID- 23435677 TI - Evaluation of gastrectomy in patients with delayed gastric emptying after antireflux surgery or large hiatal hernia repair. AB - BACKGROUND: Revision antireflux surgery and large hiatal hernia repair require extensive dissection at the gastroesophageal junction. This may lead to troublesome symptoms due to delayed gastric emptying, eventually requiring gastrectomy. The aim of this study was to evaluate the outcome of gastrectomy for severely delayed gastric emptying after large hiatal hernia repair or redo antireflux surgery. METHODS: Eleven patients were treated between 1995 and 2010 and entered in the study. Preoperative and operative data were retrospectively collected. Standardized questionnaires were sent to all of the patients to evaluate symptomatic outcome. RESULTS: The primary intervention was Nissen fundoplication in nine patients, Toupet fundoplication in one, and cruroplasty in another. The repairs were for refractory gastroesophageal reflux disease in five patients and a symptomatic large hiatal hernia in six. Subsequent gastrectomy was partial in four patients, subtotal in six, and total in one. There was one minor postoperative complication. After a mean (+/-SD) duration of 102 +/- 59 months, nine patients were available for symptomatic follow-up. Eight patients experienced daily symptoms related to dumping. Daily symptoms indicative of delayed gastric emptying were present in seven patients at follow-up. Mean general quality of life was increased from 3.8 +/- 2.2 before gastrectomy to 5.4 +/- 1.8 at follow-up. Eight patients reported gastrectomy as worthwhile. CONCLUSION: Gastrectomy after previous antireflux surgery or large hiatal hernia repair is safe with the potential to improve quality of life. Although upper gastrointestinal symptoms tend to persist, gastrectomy can be considered a reasonable, last-resort surgical option for alleviating upper gastrointestinal symptoms after this kind of surgery. PMID- 23435678 TI - Adjuvant hepatic arterial infusion chemotherapy after hepatic resection of hepatocellular carcinoma with macroscopic vascular invasion. AB - BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) with macroscopic vascular invasion is extremely poor even after hepatic resection. We aimed to clarify the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) for HCC with vascular invasion. METHODS: A total of 73 HCC patients with macroscopic vascular invasion were divided into two groups: 38 with hepatectomy with HAI (HAI group) and 35 with hepatectomy alone (non-HAI group). From 1997 to 2007, HAI was performed via an implanted injection port. The treatment comprised three courses of weekly infusion of HAI, which comprised cisplatin (10 mg daily on days 1-5) followed by 5-fluorouracil (5-FU; 250 mg daily on days 1-5) infusion. From 2007, cisplatin (60 mg/m(2)), 5-FU (600 mg/m(2)), and a mixture of mitomycin C (3 mg/m(2)) and degradable starch microspheres were administered for two courses. RESULTS: Overall, 92 % of patients completed adjuvant HAI. In the HAI and non-HAI groups, the 5-year disease-free survival (DFS) rates were 33.1 % and 11.8 %, respectively (p = 0.029), and the 5-year overall survival (OS) rates were 46.7 % and 32.7 %, respectively (p = 0.318). Among the patients with Vp3/4 or Vv3 (n = 32) in the HAI group, the 3-year DFS and OS rates were 33.7 % and 56.8 %, respectively (p = 0.049). Those in the non-HAI group were 8.3 % and 12.0 %, respectively (p = 0.023). Cox proportional multivariate analysis for DFS revealed that HAI was an independent favorable prognostic factor in all 73 patients (hazard ratio 0.536; p = 0.029). CONCLUSIONS: Adjuvant HAI for HCC patients with vascular invasion might reduce the risk of recurrence. PMID- 23435679 TI - Bilateral anterior thoracotomy (clamshell incision) is the ideal emergency thoracotomy incision: an anatomic study. AB - BACKGROUND: Emergency thoracotomy (ET) is a procedure that provides rapid access to intrathoracic structures for thoracic trauma patients arriving at the hospital in extremis. This study assesses the accessibility of intrathoracic structures provided by six different ET incisions. We hypothesize that the bilateral anterior thoracotomy ("clamshell" incision) provides the most rapid and definitive accessibility to intrathoracic structures. METHODS: Six ET incision types (left anterolateral thoracotomy, right anterolateral thoracotomy, left 2nd intercostal space incision, left 3rd intercostal space incision, median sternotomy, and bilateral anterior thoracotomy) were performed multiple times on eight cadavers. The critical intrathoracic structures were assessed for rapid accessibility and control, and they were characterized as "readily accessible," "accessible," and "inaccessible" on anatomic accessibility maps. RESULTS: Median sternotomy provided better access to intrathoracic structures than left and right anterior thoracotomies. Definitive control of the origin of the left subclavian artery was difficult with left 2nd or 3rd intercostal space incisions. Bilateral anterior thoracotomy, the clamshell incision, was easy to perform and gave superior access to all intrathoracic structures. CONCLUSIONS: In severe thoracic trauma, specific injuries are unknown, even if they can be anticipated. The best incision is therefore one that provides the most rapid and definitive access to all thoracic structures for assessment and control. While the right and left anterolateral incisions may be successfully employed by surgeons with extensive experience in ET, the clamshell incision remains the superior incision choice. PMID- 23435681 TI - Utilizing Tb3+ as an energy transfer bridge to connect Eu(2+)-Sm3+ luminescent centers: realization of efficient Sm3+ red emission under near-UV excitation. AB - The Eu(2+) -> Tb(3+) -> Sm(3+) energy transfer scheme has been proposed to realize the sensitization of Sm(3+) ion emission by Eu(2+) ions. Following this energy transfer model, near-UV convertible Sm(3+)-activated orange phosphors have been obtained in Sr3Y(PO4)3:Eu(2+), Tb(3+), Sm(3+) powders. PMID- 23435680 TI - Mathematical insights in evaluating state dependent effectiveness of HIV prevention interventions. AB - Mathematical models have been used to simulate HIV transmission and to study the use of preexposure prophylaxis (PrEP) for HIV prevention. Often a single intervention outcome over 10 years has been used to evaluate the effectiveness of PrEP interventions. However, different metrics express a wide variation over time and often disagree in their forecast on the success of the intervention. We develop a deterministic mathematical model of HIV transmission and use it to evaluate the public-health impact of oral PrEP interventions. We study PrEP effectiveness with respect to different evaluation methods and analyze its dynamics over time. We compare four traditional indicators, based on cumulative number or fractions of infections prevented, on reduction in HIV prevalence or incidence and propose two additional methods, which estimate the burden of the epidemic to the public-health system. We investigate the short and long term behavior of these indicators and the effects of key parameters on the expected benefits from PrEP use. Our findings suggest that public-health officials considering adopting PrEP in HIV prevention programs can make better informed decisions by employing a set of complementing quantitative metrics. PMID- 23435682 TI - Synthesis and properties of meso-unsubstituted 3-pyrrolyl boron dipyrromethene. AB - We report the synthesis of meso-free 3-pyrrolyl boron dipyrrin (3-pyrrolyl BODIPY) and fully unsubstituted meso-free boron dipyrrin (parent BODIPY) in one pot under simple reaction conditions by treating meso-free dipyrromethane with pyrrole in CHCl3 followed by oxidation with DDQ, neutralization with triethylamine and complexation with BF3.OEt2. The compounds were separated by column chromatography on silica and isolated in 6-10 % yields. The compounds are characterized by HR-MS mass, NMR, absorption, electrochemical and fluorescence techniques. The meso-free 3-pyrrolyl BODIPY exhibit red shifted absorption and emission bands compared to meso-free BODIPY. The meso-free BODIPY exhibit green fluorescence and meso-free 3-pyrrolyl BODIPY exhibit orange fluorescence in solution. Furthermore, compared to meso-phenyl 3-pyrrolyl BODIPY, the meso-free 3 pyrrolyl BODIPY is more strongly fluorescent with nearly 41 % increase in quantum yield. Electrochemical studies showed that meso-free 3-pyrrolyl BODIPY exhibit one irreversible reduction and one ill-defined oxidation indicating that the compound is not stable under redox conditions. Computational studies revealed that meso-free pyrrolyl BODIPY has reduced HOMO-LUMO gap compared to parent meso free BODIPY. Furthermore, the meso-free 3-pyrrolyl BODIPY exhibit much higher quantum yield compared to meso-aryl analogue of 3-pyrrolyl BODIPY. PMID- 23435683 TI - Re-examination of the genotoxic activity of water taken from the Songhua River in P. R. China. AB - The Songhua River, in northeast China, has heavy organic contamination due to domestic sewage and industrial wastewater. Thus, it is important to further determine its genotoxic activity, which is a potential hazard for human health. Short-term genotoxic bioassays using Salmonella, the cytokinesis-block micronucleus cytome assay, and mouse liver cell comet assay were employed to further examine the genotoxic activity of diethyl ether extracts of water samples taken from the Songhua River. Ames test results showed that there were still frame-shift mutagens, both direct and indirect, in water samples at doses of 5.0 or 7.0 L water equivalent/plate. The mutagenicity seems to be less when compared with the results from 2002 to 2003. A dose-response relationship was also obtained between DNA damage in mouse liver cells by comet assay and micronuclei formation by CBMN assay. These results indicate that the water samples showed genotoxic activity with a mutagenic potency. 88 and 104 compounds, respectively, were identified in summer and winter water sample extracts by gas chromatography mass spectrometry analysis. Four priority pollutants listed by the United States Environmental Protection Agency and six priority pollutants listed by the Chinese Environment Protection Agency were found in summer or winter water samples, respectively. The results indicate that the diethyl ether extracts of surface water samples taken from the Songhua River still show genotoxic activity (>=3.0 L water). The risks of potential carcinogenicity for human health in the Songhua River should be studied further. PMID- 23435684 TI - Spatial trends and factors affecting mercury bioaccumulation in freshwater fishes of Washington State, USA. AB - Twenty-four lakes in Washington State, United States, were sampled for largemouth and smallmouth bass as well as water chemistry parameters during 2005 to 2009 to evaluate trends in mercury (Hg) concentrations. We analyzed spatial patterns in bass Hg levels across a gradient of land and climate types, lake chemistry parameters, and physical watershed characteristics to identify factors influencing Hg bioaccumulation. Across the state, bass Hg levels followed rainfall patterns and were statistically greater on the coastal west side of the state and lowest in the drier eastern region. Lake and watershed variables with the strongest correlations to Hg bioaccumulation in bass were annual watershed precipitation (+) and lake alkalinity (-). Principal component analysis (PCA) explaining 50.3 % of the variance in the dataset indicated that wet, forested landscapes were more likely to contain lakes with greater fish Hg levels than alkaline lakes in drier agriculture-dominated or open space areas. The PCA did not show wetland abundance and lake DOC levels as variables influencing bass Hg levels, but these were generally associated with small, shallow lakes containing greater chlorophyll levels. The effect of in-lake productivity may have counteracted the role of wetlands in Hg bioaccumulation among this study's lakes. PMID- 23435685 TI - Interleukin-1 family members are enhanced in psoriasis and suppressed by vitamin D and retinoic acid. AB - Interleukin (IL)-1 family comprise 11 members that play an important role in immune regulation and inflammatory process. Retinoids exert complex effects on the immune system, having anti-inflammatory effects in chronic dermatological diseases. Vitamin D (vitD) and analogs have been shown to suppress TNF-alpha induced IL-1alpha in human keratinocytes (KCs). In the present study, we investigated IL-1 family members in psoriasis and the effects of vitD and retinoic acid (RA) on these members. We analyzed IL-1 family members gene expression in psoriatic skin and in ex vivo skin organ culture exposed to TNF alpha, IL-17 or broadband UVB; afterwards, treatment with vitD or RA was performed and IL-1 family members mRNA was evaluated. Similarly, KCs were stimulated with IL-17 and subsequently treated with vitD. IL-1 family members were enhanced in psoriatic skin and in ex vivo skin organ cultures after pro inflammatory stimuli (TNF-alpha, IL-17 and UVB). RA and vitD were able to suppress this enhancement. PMID- 23435687 TI - Avoidance behaviour response and esterase inhibition in the earthworm, Lumbricus terrestris, after exposure to chlorpyrifos. AB - The avoidance response of earthworms to polluted soils has been standardised using a simple and low-cost test, which facilitates soil toxicity screening. In this study, the avoidance response of Lumbricus terrestris was quantified in chlorpyrifos-spiked soils, depending on the pesticide concentration and exposure duration. The inhibition of acetylcholinesterase (AChE) and carboxylesterase (CbE) activities was also determined as indirect measures of pesticide bioavailability. The effects of different chlorpyrifos concentrations were examined in a standardised test (two-chamber system) with 0.6, 3 and 15 mg/kg chlorpyrifos. A modification of the test involved a pre-exposure step (24, 48 or 72 h) in soils spiked with 15 mg/kg. In both protocols, earthworms were unable to avoid the contaminated soils. However, the esterase activities showed that all earthworms were exposed to chlorpyrifos. Acetylcholinesterase activity did not change in earthworms in the standardised behavioural test (0.58 +/- 0.20 U/mg protein, mean +/- SD; n = 72), whereas the CbE activity was significantly inhibited (62-87 % inhibition) in earthworms exposed to 3 and 15 mg/kg. In the modified test, earthworms had greatly inhibited AChE activity (0.088 +/- 0.034 U/mg protein, n = 72), which was supported by reactivation of the inhibited enzyme activity in the presence of pralidoxime (2-PAM). Similarly, the CbE activity was significantly inhibited in earthworms with all treatments. This study suggests that the avoidance behaviour test for organophosphorus contaminated soils could be supported by specific biomarkers to facilitate a better understanding of pesticide exposure and toxicity during this test. PMID- 23435688 TI - Long-term sustainability of hand hygiene improvements in the hemodialysis setting. AB - PURPOSE: In a previous observational intervention study, we achieved a more than 100 % increase in overall hand hygiene (HH) compliance in the hemodialysis setting by increasing the number of hand rubs (HR) performed and concomitantly optimizing HH standard operating procedures (SOPs). SOPs were mainly aimed at reducing the number of avoidable opportunities due to a less than perfect workflow. However, the long-term sustainability of this successful intervention was not evaluated. The present study was carried out to evaluate the long-term effects of our previous successful intervention. METHODS: We conducted a follow up observational study 1 year after the first intervention study in the same hemodialysis unit to assess the sustainability. No HH-related interventions were performed in the 1 year between studies. The main outcome was HH compliance, and the secondary outcome was opportunities per hemodialysis procedure. RESULTS: A total of 1,574 opportunities for HH and 871 hand rubs (HR) were observed during the follow-up observational study. Overall, compliance was 55 %, which was significantly than that at the end of the first study (62 %; p < 0.0001), but significantly higher than that at the start and mid-term phases of the first study (37 and 49 %, p < 0.0001). Both the decrease in HH opportunities and the increase in HR were sustained over the course of this observational study. The number of avoidable opportunities in the present study was similar to that at the end of the previous study. Thus, in 320 opportunities (20 %), gloves were worn instead of HR performed, representing 46 % of all missed HR. CONCLUSIONS: Despite a decrease in HH compliance compared to the last postintervention period, a multifaceted intervention focusing on standardization and workflow optimization resulted in a sustained improvement in HH. We therefore propose that standardization of the hemodialysis workflow aimed at improving HH is a promising avenue for improving the quality of patient care and outcome. PMID- 23435689 TI - Surface-enhanced Raman scattering spectra of adsorbates on Cu2O nanospheres: charge-transfer and electromagnetic enhancement. AB - Surface-enhanced Raman scattering (SERS) spectra of 4-mercaptobenzoic acid (4 MBA) have been investigated on the surface of Cu2O nanospheres. The SERS signals were believed to originate from the static chemical enhancement, resonant chemical enhancement and electromagnetic enhancement. The coupling between the adsorbates and the semiconductor, evidenced by the shift in absorption spectrum of modified Cu2O and the enhancement of non-totally symmetric modes of the 4-MBA and 4-mercaptopyridine (4-MPY) molecules, were invoked to explain the experimental results. Furthermore, simulations were employed to investigate the nature of the enhancement mechanisms operative between the molecules and the semiconductor. Density functional theory (DFT) calculations suggested a charge transfer (CT) transition process between the molecules and the Cu2O nanospheres. Three-dimensional finite-difference time domain (3D-FDTD) simulations were conducted to map out the electromagnetic field around the Cu2O nanospheres. The experimental and simulation results have revealed the promise of the Cu2O nanospheres as a good SERS substrate and the prospect of using the SERS substrate as a valuable tool for in situ investigation and assay of the adsorption behavior on semiconductor surfaces. PMID- 23435691 TI - Influence of multiple courses of therapy on aminoglycoside clearance in adult patients with cystic fibrosis. AB - OBJECTIVES: To investigate factors affecting aminoglycoside clearance in adult patients with cystic fibrosis who received multiple courses of antibiotic therapy over a period of up to 15 years. METHODS: Aminoglycoside concentration-time data and relevant clinical characteristics were collated from clinical pharmacokinetic databases established in Glasgow, Scotland and The Hague, The Netherlands. Data from Glasgow (1993-2009) were used for population model development; data from The Hague (2002-11) were used for model validation. NONMEM was used to determine structural and covariate models, with a particular focus on between-occasion variability and changes in aminoglycoside handling over multiple courses of therapy. RESULTS: The Glasgow dataset comprised 1075 courses of aminoglycoside therapy (96% tobramycin and 4% gentamicin) in 166 patients and included 2238 concentration measurements. The data were best described by a two-compartment model with creatinine clearance and height influencing aminoglycoside clearance, and height influencing volume of distribution. Between-subject and between occasion variabilities in clearance were low, at 18% and 11%, respectively; between-subject variability was 12% for volume of distribution. Internal and external model validations were satisfactory. Multiple courses of therapy (ranging from 2 to 28 courses per patient) were not associated with any systematic changes in aminoglycoside clearance. CONCLUSIONS: Height was a better descriptor of aminoglycoside pharmacokinetics than weight in adult patients with cystic fibrosis. No changes in clearance were observed over time, even in patients who had received multiple courses of therapy over several years. PMID- 23435690 TI - Effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine therapeutic drug monitoring. AB - OBJECTIVES: The pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM). METHODS: Data from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification. RESULTS: Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification. CONCLUSIONS: With increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation. PMID- 23435692 TI - Rapid detection of antibiotic resistance in Acinetobacter baumannii using quantitative real-time PCR. AB - OBJECTIVES: The rapid detection of antibiotic resistance in clinical isolates of Acinetobacter baumannii would shorten the period during which patients receive empirical therapy and facilitate the early initiation of directed antibiotic therapy. The objective of this study was to evaluate the ability of a real-time PCR assay to detect antibiotic resistance to four clinically relevant antibiotics from different antibiotic classes in clinical isolates of A. baumannii. METHODS: The growth of 48 clinical isolates of A. baumannii with a broad range of MICs of imipenem, ciprofloxacin, colistin and amikacin was evaluated using a real-time PCR assay targeting a highly conserved region of the ompA gene. Fold changes in the number of copies of genomic DNA after 6 h of growth were used to determine resistance and the results were compared with those obtained using broth microdilution. RESULTS: The results obtained using the real-time PCR assay were concordant with broth microdilution for 184 of 192 determinations (95.8%). The global values for specificity (97.5%), sensitivity (92.9%), positive predictive value (95.6%) and negative predictive value (96.0%) indicated that the real-time PCR assay was able to reliably differentiate between resistant and non-resistant strains. CONCLUSIONS: The use of real-time PCR to monitor bacterial growth in the presence of antibiotics is effective for rapidly identifying antibiotic resistance in A. baumannii. PMID- 23435693 TI - Comparison of the Truview PCDTM and the GlideScope((r)) video laryngoscopes with direct laryngoscopy in pediatric patients: a randomized trial. AB - INTRODUCTION: The GlideScope((r)) video laryngoscope has a 60 degrees angled blade and the blade of the Truview PCDTM video laryngoscope has an optical lens that provides a 46 degrees refraction of the viewing angle. Despite successful results using the GlideScope in adults, few studies have been published regarding its use in pediatric patients. We therefore tested our joint primary hypothesis that the GlideScope and the Truview PCD video laryngoscopes provide superior visualization to direct laryngoscopy and are non-inferior regarding time to intubation. METHODS: One hundred thirty-four patients (neonate to ten years of age, American Society of Anesthesiologists physical status I-III) scheduled for general surgical procedures were randomized to tracheal intubation using the Truview PCD or GlideScope video laryngoscope or direct laryngoscopy (Macintosh blade). The laryngoscopic view was scored using the Cormack-Lehane scale. Time to intubation (defined as the time from the moment the device entered the patient's mouth until end-tidal CO2 was detected) and the number of attempts were recorded. RESULTS: The Cormack-Lehane views attained using the GlideScope (P > 0.99) and Truview PCD (P = 0.18) were not superior to the views attained with direct laryngoscopy. Furthermore, the view attained using the GlideScope was significantly worse than that attained using direct laryngoscopy (P < 0.001). Fewer patients showed Cormack-Lehane grade I views with the GlideScope than with the Truview PCD (14% vs 82%, respectively; 95% confidence interval [CI] -91% to 46%). The observed median [Q1, Q3] times to intubation were: 39 [31, 59] sec, 44 [28, 62] sec, and 23 [21, 28] sec with the GlideScope, Truview PCD, and direct laryngoscopy, respectively, with median differences of 14 sec (95% CI 7 to 26, GlideScope - direct laryngoscopy) and 17 sec (95% CI 6 to 28, Truview PCD - direct laryngoscopy). CONCLUSION: The Cormack-Lehane views attained using the GlideScope and the Truview PCD video laryngoscopes were not superior to views attained using direct laryngoscopy. Visualization with the GlideScope was significantly worse than with direct laryngoscopy. Use of the GlideScope and Truview PCD systems should be restricted to patients with specific indications. PMID- 23435695 TI - Stepwise ligand transformations through [2+2] photodimerization and hydrothermal in situ oxidation reactions. AB - The SCSC transformation of a 1D polymer [Cd(1,3-bdc)(4-spy)2]n produced a 2D polymer [Cd(1,3-bdc)(4-spy)(HT-ppcb)0.5]n through the [2+2] photodimerization reaction. Hydrothermal reactions of HT-ppcb with CdCl2, 1,3-H2bdc and H2O2 afforded another 2D polymer {[Cd(H2O)(1,3-bdc)(bpbpf)].H2O}n in which HT-ppcb underwent in situ oxidation to form a unique furan-based ligand bpbpf. PMID- 23435694 TI - Potential functional replacement of the plastidic acetyl-CoA carboxylase subunit (accD) gene by recent transfers to the nucleus in some angiosperm lineages. AB - Eukaryotic cells originated when an ancestor of the nucleated cell engulfed bacterial endosymbionts that gradually evolved into the mitochondrion and the chloroplast. Soon after these endosymbiotic events, thousands of ancestral prokaryotic genes were functionally transferred from the endosymbionts to the nucleus. This process of functional gene relocation, now rare in eukaryotes, continues in angiosperms. In this article, we show that the chloroplastic acetyl CoA carboxylase subunit (accD) gene that is present in the plastome of most angiosperms has been functionally relocated to the nucleus in the Campanulaceae. Surprisingly, the nucleus-encoded accD transcript is considerably smaller than the plastidic version, consisting of little more than the carboxylase domain of the plastidic accD gene fused to a coding region encoding a plastid targeting peptide. We verified experimentally the presence of a chloroplastic transit peptide by showing that the product of the nuclear accD fused to green fluorescent protein was imported in the chloroplasts. The nuclear gene regulatory elements that enabled the erstwhile plastidic gene to become functional in the nuclear genome were identified, and the evolution of the intronic and exonic sequences in the nucleus is described. Relocation and truncation of the accD gene is a remarkable example of the processes underpinning endosymbiotic evolution. PMID- 23435697 TI - Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AB - Adherence is a critical component of the success of antiretroviral-based pre exposure prophylaxis (PrEP) in averting new HIV-infections. Ensuring drug availability at the time of potential HIV exposure relies on self-directed product use. A deeper understanding of how to best support sustained PrEP adherence remains critical to current and future PrEP efforts. This paper provides a succinct synthesis of the adherence support experiences from four pivotal PrEP trials--Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, FEM-PrEP, Iniciativa Prophylaxis (iPrEx), and Vaginal and Oral Interventions to Control the Epidemic (VOICE). Notwithstanding variability in the design, population/cohort, formulation, drug, dosing strategy, and operationalization of adherence approaches utilized in each trial, the theoretical basis and experiences in implementation and monitoring of the approaches used by these trials provide key lessons for optimizing adherence in future research and programmatic scale-up of PrEP. Recommendations from across these trials include participant-centered approaches, separating measurement of adherence from adherence counseling, incorporating tailored strategies that go beyond education, fostering motivation, and addressing the specific context in which an individual incorporates and negotiates PrEP use. PMID- 23435698 TI - Acceptability and feasibility of cash transfers for HIV prevention among adolescent South African women. AB - Women are at increased risk of HIV infection in much of sub-Saharan Africa. Longitudinal and cross-sectional studies have found an association between school attendance and reduced HIV risk. We report feasibility and acceptability results from a pilot of a cash transfer intervention conditional on school attendance paid to young women and their families in rural Mpumalanga, South Africa for the prevention of HIV infection. Twenty-nine young women were randomised to intervention or control and a cash payment based on school attendance made over a 2-month period. Quantitative (survey) and qualitative (focus group and interview) data collection was undertaken with young women, parents, teachers and young men in the same school. Qualitative analysis was conducted in Atlas.ti using a framework approach and basic descriptive analysis in Excel was conducted on the quantitative data. Results indicate it was both feasible and acceptable to introduce such an intervention among this population in rural South Africa. There was good understanding of the process of randomisation and the aims of the study, although some rumours developed in the study community. We address some of the changes necessary to ensure acceptability and feasibility of the main trial. PMID- 23435696 TI - Multicenter study of short- and long-term outcomes of laparoscopic palliative resection for incurable, symptomatic stage IV colorectal cancer in Japan. AB - BACKGROUND: This Japanese multicenter retrospective study evaluated short- and long-term outcomes of palliative laparoscopic procedures for symptomatic stage IV colorectal cancer compared with conventional open procedures. METHODS: Of 968 eligible patients with stage IV colorectal cancer enrolled during January 2006 December 2007 from 41 participating surgical units (Japan Society of Laparoscopic Colorectal Surgery Group), we studied 409 patients who underwent palliative resection of symptomatic primary colorectal tumor. RESULTS: Data from patients with laparoscopic resection (n = 98) and open colorectal resection (n = 311) were analyzed. Eleven (11.2 %) laparoscopic operations were converted to an open procedure. Fewer complications were reported for laparoscopic resections than for open procedures (13.3 vs. 26.7 %; p = 0.0042). Postoperative hospital stay was significantly shorter in the laparoscopic vs. open resection group (median, 14 vs. 17 days; p = 0.0242). Postoperative chemotherapy treatment was administered to 245 (78.9 %) patients in the open and 78 (79.6 %) patients in the laparoscopic resection group. Time from surgery to start of postoperative chemotherapy was significantly shorter in the laparoscopic vs. open resection group (median, 32 vs. 27 days; p = 0.0487). Median survival time between the two groups was not significantly different (22.0 vs. 22.2 months; p = 0.948). CONCLUSIONS: Laparoscopic palliative resection results in reduced postoperative complications and earlier recovery with acceptable long-term outcomes comparable with open surgery. When performed by experienced surgeons in selected patients, it may be a safe and feasible option. Because of the potential of significant bias arising from the included studies, further randomized controlled trials should be undertaken to confirm this bias. PMID- 23435699 TI - Pancreatic surgery in the very old: face to face with a challenge of the near future. AB - BACKGROUND: The proportion of octogenarians requiring surgery for pancreatic disease is rapidly growing. This trend will be continued during the next decades, posing a challenge to surgeons and the health care system worldwide. This study aimed to analyze the results of pancreatic surgery in octogenarians in terms of safety and survival based on a cohort of patients at a European high-volume center. METHODS: During a 7-year period, 1,705 operations were performed, 76 in patients >= 80 years of age. Data on the octogenarians were retrospectively reviewed and compared to those of the whole collective and to contemporary data from the literature. Primary endpoints were mortality, morbidity, and survival. RESULTS: Overall, 80 % had a malignant disease, and resections were performed in 50 % of all cases. Mortality was 11.8 % and morbidity 72.4 %. There were significantly more medical than surgical complications: 56.6 versus 34.2 %. Pancreatic fistula occurred in 5.3 %, postoperative bleeding in 3.9 %, and delayed gastric emptying in 19.7 %. The median hospital stay was 15 days and the intensive care unit stay 2 days. Mean survival was 28.2 months and in patients with cancer 22.6 months. The 1-, 3-, and 5-year survival rates were 61.4, 31.3, and 18.8 %, respectively. CONCLUSIONS: Despite high mortality and morbidity rates, surgery remains the only chance for cure in most octogenarians with pancreatic disease. Careful patient selection is the key to success and improved long-term survival in this group, which will represent a substantial fraction of the population in the near future. PMID- 23435700 TI - Single-port cholecystectomy versus multi-port cholecystectomy: a prospective cohort study with 222 patients. AB - BACKGROUND: The aim of this study was to compare single-port access cholecystectomy (SPA) with the standard laparoscopic technique (LC) regarding the duration of the operation, complications, learning curve, late postoperative quality of life (QoL) and the incidence of incisional hernias. METHODS: Between June 2009 and December 2011, a total of 122 SPA cholecystectomies were performed in our hospital. Simultaneously, 310 patients were operated on with the LC technique. In the LC group, 100 patients met the same criteria defined for SPA surgery. The two groups (SPA and LC) were compared by multivariable regression analysis. Endpoints of this study were quality of life (QoL) after 6 months by the EQ-5D questionnaire 5L and the incidence of incisional hernia 1 year after surgery. Operating time, hospital stay, and perioperative complications were also measured and compared. The median follow-up was 9.2 months (3-25 months). RESULTS: The patients in the SPA group were younger and more often female. The mean operating time for group SPA was 73 min (35-136 min)-significantly longer than that for group LC with 60 min (33-190 min) (p < 0.001). Additional trocars were used in 8 of 122 (6.5 %) SPA patients. A conversion to open cholecystectomy was not necessary in SPA patients. The conversion rate in the LC group to open cholecystectomy was 2 % (2/100). The perioperative and postoperative complications and incisional hernia (5.5 %) were the same in both groups. QoL was significantly better in the SPA group in terms of mobility (p = 0,002), usual activity (p = 0.036), and overall anxiety (p = 0.026). CONCLUSIONS: SPA cholecystectomy is safe, although the operation is significantly longer. No differences in terms of major complications or the incidence of incisional hernia were seen after 1 year. QoL was significantly better in patients operated on with the SPA technique. PMID- 23435701 TI - Outcomes after hepatic and pulmonary metastasectomies compared with pulmonary metastasectomy alone in patients with colorectal cancer metastasis to liver and lungs. AB - BACKGROUND: Surgical resection is the most effective treatment for colorectal cancer that has metastasized to the liver. Similarly, surgical resection improves survival for selected patients with pulmonary colorectal metastases. However, the indication for pulmonary metastasectomy is not clear in patients with both hepatic and pulmonary colorectal metastases. Therefore, we evaluated outcomes after pulmonary resection of colorectal metastases in patients with or without a history of curative hepatic metastasectomy. METHODS: We retrospectively analyzed 96 patients who underwent pulmonary metastasectomy from March 1999 to November 2009. Patients were grouped according to treatment: resection of pulmonary metastases alone (lung metastasectomy group) or resection of both hepatic and pulmonary metastases (liver and lung metastasectomy group). Overall survival (OS) and disease-free survival (DFS) were evaluated by Kaplan-Meier analysis. Survival curves were compared using the log-rank test. RESULTS: The 5-year OS for all patients was 61.3 %, and the 5-year DFS was 26.7 %. Group comparisons showed that the 5-year OS of the lung metastasectomy group was significantly better than that of the liver and lung metastasectomy group (69 vs. 43 %; p = 0.030). However, the 5-year DFS rates of the lung metastasectomy group (25.8 %) and liver and lung metastasectomy group (28.0 %) did not differ significantly. Recurrence was higher after resection of both hepatic and pulmonary metastases than after pulmonary metastases alone (79 vs. 45 %; p = 0.025). CONCLUSIONS: Resection of pulmonary colorectal metastases may increase survival. However, the combination of liver and lung metastasectomies had a worse prognosis than pulmonary metastasectomy alone. In selected patients, combined liver and lung metastasectomy can be beneficial and result in acceptable DFS. PMID- 23435702 TI - Application of long-range polymerase chain reaction in the diagnosis of X-linked dystonia-parkinsonism. PMID- 23435704 TI - Cryopreservation of Galanthus elwesii Hook. apical meristems by droplet vitrification. AB - The aim of this study was to develop an efficient cryopreservation protocol for the geophyte giant snowdrop (Galanthus elwesii Hook.) that guarantees a high rate of survival and plant regeneration after cryopreservation. The excised apical meristems were obtained from cultures of in vitro grown bulb scales. Using a vitrification procedure and optimizing the duration of the exposure to the loading solution (LS), meristem post-rewarm survival rates higher than 90 percent were achieved. Also regrowth percentages were very high, ranging from 87 to 91 percent. After optimizing the time of exposure to the plant vitrification solution (PVS2), the survival rate was between 83 and 97 percent. During post rewarm regeneration, good growth recovery was as high as 76 percent; however, hyperhydration and callusing were also observed. The results demonstrate that cryopreservation of Galanthus elwesii germplasm seems to be feasible. PMID- 23435703 TI - Sickle cell disease and venous thromboembolism: what the anticoagulation expert needs to know. AB - Venous thromboembolism (VTE) is common in patients with sickle cell disease (SCD). The etiology of increased risk of VTE in SCD patients is multifactorial and is related to both traditional factors and SCD-specific factors. Traditional risk factors such as central venous catheters, frequent hospitalization, orthopedic surgeries for avascular necrosis, and pregnancy may lead to increased incidence of VTE in the SCD population. In addition, SCD itself appears to be a hypercoagulable state, and many SCD-specific factors such as thrombophilic defects, genotype and splenectomy may modify the risk of VTE. SCD complications such as acute chest syndrome and pulmonary hypertension may also be related to VTE. Anticoagulation experts should be aware of these factors to help inform prophylaxis and treatment decisions. PMID- 23435705 TI - Cryopreservation of osteoblasts by use of a programmed freezer with a magnetic field. AB - In order to determine a suitable condition for osteoblasts cryopreservation, murine osteoblasts were freezed by programmed freezer with a magnetic field (CAS freezer). After 7 days cryopreservation at -150 degrees , the number of survival cells immediately after thawing and the growth rate of cultured cells for 48 hours were examined. Gene and protein expression of alkaline phosphatase (ALP), osteopontin (OPN) and bone sialoprotein (BSP) were compared between cryopreserved and non-cryopreserved groups. As a result, a plunging temperature of -30 degrees , a hold-time at -5 degrees for 15 minutes and a 0.1 mT of magnetic field led to the largest survival and growth rate. Moreover, there was no significant difference in ALP, OPN and BSP mRNA and protein expression between cryopreserved and control groups. From these results, it was suggested that the CAS freezer is available for osteoblast cryopreservation and bone tissue banking can be established in the future. PMID- 23435706 TI - Evaluation of adipocytic changes after a simil-lipocryolysis stimulus. AB - Lipocryolysis is considered as an effective, well-tolerated non-invasive procedure to reduce local adiposities. However there is little information about its mechanism of action by the procedure. It is proposed that lipid phase transition or crystallization may be an unleashed apoptotic stimulus. Yet, the post-lipocryolysis apoptosis is not easily confirmed, least of all is its correlation with crystallization. In this study adipocytes from rat fat tissue were exposed to a lipocryolysis-session-like stimulus. Lipid changes were observed in all test sample. PMID- 23435707 TI - Fertilizing ability of cryopreserved pollinia of Luisia macrantha, an endemic orchid of Western Ghats. AB - A successful protocol for long-term preservation of pollinia of Luisia macrantha Blatter and McCann., an endemic and endangered orchid of Western Ghats has been devised through different pollen cryopreservation methods and by confirming fertilizing ability. Pollinia subjected to 0-30 min dehydration at 27 +/- 67 percent in desiccated controls and 54 percent in LN treated samples. The treated pollinia retained fertilizing ability, giving 100 percent fruit set upon sib mating. Pollinia dried under charged silica gel for 120 min gave 51 - 52 percent pollen germination, in LN treated and desiccated control samples. Exposure to vitrification solution (PVS2) was optimized at 10 min to achieve 57 percent and 56 percent germination in control and LN treated samples, respectively. These pollinia exhibited 51 percent pollen germination after 668 days storage in LN. Cryopreserved pollinia (10 min PVS2) used for hybridization with Vanda tessellata gave 87 percent fruit set and 21 percent viable seeds. The viable seeds germinated and developed into healthy seedlings. Thus cryopreservation has been proved useful for the successful storage of L. macrantha germplasm and their utilization in breeding. PMID- 23435708 TI - A life cycle model to enable research of cryostorage recalcitrance in temperate woody species: the case of sitka spruce (Picea sitchensis). AB - Empirical testing of protocols and fundamental investigations are the approaches usually applied to study germplasm storage recalcitrance in temperate plants. However, they can fall short of practicable solutions, even after exhaustive experimentation, and the generation of negative survival data makes it difficult to plan further investigations. Picea sitchensis somatic embryos are amenable to cryopreservation whereas in vitro shoot meristems, although able to survive, are incapable of sustained recovery. Differential Scanning Calorimetry (DSC) revealed that these disparate responses could not be attributed to biophysical factors. A model is presented hypothesising that in some cases life cycle adaptations (cold hardening, dormancy) may have opposing influences on survival causing delayed onset, cryogenically-induced loss of viability in temperate tree species. PMID- 23435709 TI - Numerical simulation of water transport and intracellular ice formation for freezing of endothelial cells. AB - Endothelial cell detachment may cause failure of blood vessel and corneal cryopreservation, and thus successful cryopreservation of endothelial cells is regarded to be the first step to optimize cryopreservation of endothelial cells containing tissues. In this study, the pre-determined biophysical parameters were incorporated into the model for intracellular ice formation (IIF) and the growth of intracellular ice crystals (ICG) to calculate cell water loss, supercooling of intracellular solution, intracellular ice formation and the growth of intracellular ice crystals. The optimal protocols were determined according to the combination effect of both solution injury and IIF injury. PMID- 23435710 TI - Development of soya milk extender for semen cryopreservation of Karan Fries (crossbreed cattle). AB - Egg yolk based semen extenders are used widely, with the potential risk of xenobiotic contamination. This study was designed to develop a soya milk based extender to substitute egg yolk based extender for bovine semen cryopreservation. In the first experiment soya milk was prepared from fresh soya bean (Glycine max). Concentration of soya milk in tris based extender was standardized based on quality parameters of spermatozoa during liquid preservation at 5 degrees C up to 72 h and compared with egg yolk tris (EYT) extender. Sperm in soya milk tris (SMT) extender with 25 percent soya milk showed no significant (P > 0.05) differences in all the quality parameters like motility, viability, membrane integrity and acrosome integrity, as compared to sperm in EYT extender up to 72h in liquid dilution. In the second experiment the Karan Fries semen was cryopreserved in SMT extender with 25 percent soya milk (selected from the first experiment) using different concentration of glycerol, as cryoprotectant, ranging from 6-7 percent with a difference of 0.2 percent to standardize optimum concentration based on post thaw motility of spermatozoa. Glycerol at a final concentration of 6.4 percent was found to be the best among all. Further, semen samples were split and cryopreserved in newly developed SMT extender containing 6.4 percent glycerol and compared with conventional EYT extender for post thaw sperm quality parameters and degree of cryocapacitation. There were no significant (P > 0.05) differences between sperm in EYT extender and SMT extender for post thaw motility, viability, membrane integrity, acrosome integrity and cryocapacitation. In conclusion, the newly developed SMT extender maintained comparable semen quality as compared to EYT extender hence it can. PMID- 23435711 TI - Molecular and genetic aspects of protein cold denaturation. AB - The phenomenon of cold-induced denaturation of proteins is reviewed. Examples of low temperature-induced changes in quaternary, tertiary and secondary structure of protein molecules are cited. Genetic aspects of cold-stability and functioning of structural proteins and enzymes from cold-tolerant organisms under low temperature conditions are discussed. Disorganisation of supramolecular assemblies under low-temperature influence is considered as one of the key factors contributing to cell cold-induced injuries. PMID- 23435712 TI - Identification of differentially regulated micrornas in cold-hardy insects. AB - Freeze tolerance in insects is associated with cryoprotectant synthesis and strong metabolic suppression. Freeze avoidance, an alternative strategy in cold hardy insects, is also characterized by hypometabolism, but possesses significant cellular and physiological differences when compared with freeze tolerance. We hypothesized that microRNAs, non-coding transcripts that bind to mRNA, could play a role in the regulation of energy-expensive mRNA translation in insects exposed to low temperatures. Expression levels of microRNA species were evaluated during cold acclimation of freeze tolerant Eurosta solidaginis and freeze-avoiding Epiblema scudderiana, comparing control (5 degree C) conditions with larvae given sequential exposures to -5 degree C and -15 degree C. MiR-1 levels were significantly elevated in frozen E. solidaginis larvae at -15 degree C, whereas miR-34 levels were unchanged. MiR-1 and miR-34 levels remained stable in E. scudderiana. These data demonstrate differential microRNA expression in frozen versus control insect larvae and highlight contrasting microRNA signatures between freeze tolerant and freeze avoiding species. PMID- 23435713 TI - Silkworm (Bombyx mori) cryopreservation: embryonic development as revealed by microscopic studies. AB - Embryo cryopreservation offers a way to safeguard against unwelcome mutations and inadvertent selection that can change its unique genetic makeup. Having a genetic repository of the silkworm genetic resources would ensure preservation of original genetic makeup and will permit to study what genes may have been lost in the selection process. For cryopreservation of eggs and embryos of silkworm, the determination of embryonic stages is a prerequisite. This study reports microscopic observations on embryonic development. The embryonic stages in the dechorionated eggs were determined in parallel comparison with the embryos isolated from intact eggs of different developmental ages. PMID- 23435714 TI - The architecture of Norway spruce ectomycorrhizae: three-dimensional models of cortical cells, fungal biomass, and interface for potential nutrient exchange. AB - Gathering realistic data on actual fungal biomass in ectomycorrhized fine root systems is still a matter of concern. Thus far, observations on architecture of ectomycorrhizae (ECMs) have been limited to analyses of two-dimensional (2-D) images of tissue sections. This unavoidably causes stereometrical problems that lead to inadequate assumptions about actual size of cells and their arrangement within ECM's functional compartments. Based on extensive morphological investigations of field samples, we modeled the architectural components of an average-sized Norway spruce ECM. In addition to our comprehensive and detailed quantitative data on cell sizes, we studied actual shape and size, in vivo arrangement, and potential nutrient exchange area of plant cortical cells (CCs) using computer-aided three-dimensional (3-D) reconstructions based on semithin serial sections. We extrapolated a factual fungal biomass in ECMs (Hartig net (HN) included) of 1.71 t ha(-1) FW (0.36 t ha(-1) DW) for the top 5 cm of soil for an autochthonous, montane, optimum Norway spruce stand in the Tyrolean Alps. The corresponding potential nutrient exchange area in ECMs including main axes of ECM systems, which is defined as the sum of interfaces between plant CCs and the HN, amounts to at least 3.2 * 10(5) m(2) ha(-1). This is the first study that determines the contribution of the HN to the total fungal biomass in ECMs as well as the quantification of its contact area. Our results may stimulate future research on fungal below-ground processes and their impact on the global carbon cycle. PMID- 23435715 TI - Promoting public awareness and engagement in genome sciences. AB - Public understanding of genetic concepts and associated ethical and policy issues can enable informed deliberation and decision-making. Effective strategies for increasing public understanding involve providing forums incorporating the unique perspectives and attitudes of the public, while allowing opportunities to learn first-hand from scientists about genome research and related applications. Through a partnership between the Duke Institute for Genome Sciences & Policy (IGSP) and the Museum of Life and Science in Durham, NC, we developed and piloted a program aimed to bridge the concepts of formal (public school) and informal (community-based science museum) science learning with the experiential context of family and participatory learning. Called Genome Diner, we piloted the program with 40 genetic/genomic researchers, 76 middle school students and their parents (n = 83) from Durham, NC. Program impact was assessed via pre/post surveys for each participant group. Following participation, parents were significantly more likely to correctly interpret the implications of a genome research finding, and both students and parents indicated higher interest in research as well as higher confidence in accessing and understanding genome research. Genetic literacy of parents and students was not affected by participation in the program, likely due to the relatively high knowledge scores pre-Diner: 88.3 % and 78.5 %, respectively. The interactive format of Genome Diner provided an opportunity for students and parents to explore and discuss interests and issues about genomic research alongside genome scientists, positively influencing attitudes toward genetic research and researchers themselves. These interactions are critical for maintaining public interest and knowledge about genomic research and applications. PMID- 23435716 TI - Physical activity recommendations for patients with electrophysiologic and structural congenital heart disease: a survey of Canadian health care providers. AB - Determining safe levels of physical activity for children and adolescents with electrophysiologic and structural congenital heart disease is a challenging clinical problem. The body of evidence for making these recommendations is limited and likely based on expert opinion, medicolegal concerns, and perceived risks of sudden cardiac death (SCD) with activity. The Bethesda Conference has established consensus guidelines for determining the eligibility of athletes with cardiovascular abnormalities for competitive sports and their disqualification from them. However, literature on guidelines for noncompetitive physical activity is not available. A survey was designed to determine practice patterns for patients with electrophysiologic and structural congenital heart disease. Between July 2011 and December 2011, approximately 350 health care providers working with this group of patients were recruited by email or while attending professional meetings. The survey received 81 responses, primarily from pediatric cardiologists (70 %). The findings indicate that the majority of Canadian cardiac care providers surveyed are only partially implementing current recommendations. Areas of variance included physical activity recommendations for hypertrophic cardiomyopathy, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and heart transplantation, among others. The development of comprehensive consensus guidelines for activity recommendations was supported by 96 % of the respondents. The heterogeneity of responses may be attributable to conflicting and poorly evidenced information in the literature, a lack of emphasis on recreational activity, an entrenched tendency toward bed rest in the cardiology community, and a lack of awareness by cardiac care providers regarding the actual risk associated with physical activity in electrophysiologic and structural congenital heart disease. A balanced discussion is required in considering both the significant benefit of physical activity in reducing cardiovascular risk factors and the small possibility of SCD in children and young adults with electrophysiologic and structural congenital heart disease. PMID- 23435717 TI - Clinical implications of a new model of Kawasaki disease arteriopathy. PMID- 23435718 TI - Presence of Epstein-Barr virus in cerebrospinal fluid from patients with aseptic meningitis appears to be common. PMID- 23435719 TI - A rare case of Lemierre's syndrome caused by Porphyromonas asaccharolytica. AB - Lemierre's syndrome is only very rarely caused by Porphyromonas asaccharolytica. Here, we report the case of a 35-year-old man who developed a left peritonsillar abscess, thrombophlebitis of the left internal jugular vein, and septic embolization of both lungs. Anaerobic P. asaccharolytica was isolated in the blood cultures, and we subsequently confirmed the diagnosis as Lemierre's syndrome. Our case indicates that although P. asaccharolytica is not commonly found in oral cavities, this organism may still cause Lemierre's syndrome. Consequently, when it is detected in blood cultures, the treating physician should perform the medical examination while keeping in mind the possibility that the patient could have Lemierre's syndrome. PMID- 23435720 TI - The potential impact of biomarker-guided triage decisions for patients with urinary tract infections. AB - OBJECTIVES: Current guidelines provide limited evidence as to which patients with urinary tract infection (UTI) require hospitalisation. We evaluated the currently used triage routine and tested whether a set of criteria including biomarkers like proadrenomedullin (proADM) and urea have the potential to improve triage decisions. METHODS: Consecutive adults with UTI presenting to our emergency department (ED) were recruited and followed for 30 days. We defined three virtual triage algorithms, which included either guideline-based clinical criteria, optimised admission proADM or urea levels in addition to a set of clinical criteria. We compared actual treatment sites and observed adverse events based on the physician judgment with the proportion of patients assigned to treatment sites according to the three virtual algorithms. Adverse outcome was defined as transfer to the intensive care unit (ICU), death, recurrence of UTI or rehospitalisation for any reason. RESULTS: We recruited 127 patients (age 61.8 +/ 20.8 years; 73.2 % females) and analysed the data of 123 patients with a final diagnosis of UTI. Of these 123 patients, 27 (22.0 %) were treated as outpatients. Virtual triage based only on clinical signs would have treated only 22 (17.9 %) patients as outpatients, with higher proportions of outpatients equally in both biomarker groups (29.3 %; p = 0.02). There were no significant differences in adverse events between outpatients according to the clinical (4.5 %), proADM (2.8 %) or urea groups (2.8 %). The mean length of stay was 6.6 days, including 2.2 days after reaching medical stability. CONCLUSIONS: Adding biomarkers to clinical criteria has the potential to improve risk-based triage without impairing safety. Current rates of admission and length of stay could be shortened in patients with UTI. PMID- 23435721 TI - Is the HDV seroprevalence in patients admitted to a university hospital representative for all HBV carriers in Germany? PMID- 23435722 TI - Prospective study of transobturator mesh kit (ProliftTM) in pelvic reconstructive surgery with vaginal hysterectomy after 3 years' follow-up. AB - INTRODUCTION AND HYPOTHESIS: This study is to analyze prospectively the anatomical and functional outcomes of transvaginal pelvic reconstructive surgery using the ProliftTM system for pelvic organ prolapse (POP) with hysterectomy. METHODS: A prospective, observational, noncomparative study was conducted in 80 patients with prolapse >= 2. Postoperative pelvic organ prolapse quantification stage was the main outcome measure. Anatomical cure was defined as vaginal vault stage 0 and improvement as stage 1. Secondary outcomes include pelvic floor distress inventory-20, incontinence impact questionnaire short form-7, and pelvic floor impact questionnaire short form-7. RESULTS: A total of 80 patients were recruited. The cure and improvement rates were 96.3 % (77/80) and 3.7 % (3/80) respectively at 1 year. At the follow-up of 3-years, the cure rates were 93.3 % (70/75). Among the five patients, three had stage 2 anterior wall prolapse, two had stage 2 posterior wall prolapse. Only one patient with intraoperative adverse event (rectal perforation) was encountered. Postoperative complications included prolonged catheterization in three patients (3.7 %), postoperative stress urinary incontinence in five patients (6.25 %) and asymptomatic mesh extrusions in five patients (6.25 %). All of them occurred within 1 year follow-up. Significant improvements in quality of life were detected at 1 and 3 years compared with baseline. CONCLUSION: The total ProliftTM system surgery represents a safe, simple and useful treatment for severe POP with satisfactory objective clinical outcomes. PMID- 23435723 TI - Abdominal electromyography in laboring and non-laboring pregnant women at term and its clinical implications. AB - OBJECTIVE: To determine the patterns of uterine action potentials in laboring and non-laboring women at term using the non-invasive abdominal electromyography technique. METHODS: One hundred pregnant women at term who fulfilled the inclusion criteria were enrolled in the study and equally divided into two groups. Group I consisted of 50 women in active labor, while group II included 50 women not in labor. After enrollment, the cardiotocograph was applied to all women. Abdominal electromyographic recording was started and for every burst of action potential, we measured the amplitude, frequency and duration of action potential. The results were tabulated and statistically analyzed. RESULTS: Both groups were comparable in demographic characteristics. Four patterns of EMG were detected. The amplitude of action potentials was significantly higher in laboring compared to non-laboring women (77.44 +/- 11.25 vs 13.71 +/- 8.57, P < 0.001). Similar significantly longer durations of electrical bursts were also noted in laboring women (45.94 +/- 8.77 vs 7.11 +/- 4.68 s, P < 0.001). Specific electromyographic changes were noted in women passing from the non-laboring to laboring state and in women who required oxytocin augmentation during labor. CONCLUSION: Abdominal electromyography may help to distinguish between women in true active labor from those who are not. It also may help to identify women who will enter into labor within 24-72 h and those who require augmentation of labor. PMID- 23435724 TI - Valproic acid suppresses cervical cancer tumor progression possibly via activating Notch1 signaling and enhances receptor-targeted cancer chemotherapeutic via activating somatostatin receptor type II. AB - PURPOSE: We investigated the effects of the anti-epilepsy drug valproic acid (VPA) alone and in combination in treating cervical cancer. METHODS: VPA was investigated for its effects on cervical cancer Hela cell proliferation and tumor growth via in vitro and in vivo assays. RESULTS: VPA induce cell growth suppression and cell cycle arrest, with an increase of Notch1 that acts as a tumor suppressor and the change of other tumor-associated genes such as p21, p63 and PCNA. VPA was also found to induce cell morphological change, with an increase of certain cell transformation markers such as snail1, snail2 and N cadherin. Moreover, VPA could significantly up-regulate somatostatin receptor type II (SSTR2). Our in vivo study further demonstrated that VPA via inducing SSTR2 up-regulation extremely enhanced the anti-tumor ability of the SSTR2 preferential cytotoxic COL-SST conjugate in xenografts. CONCLUSIONS: VPA could not only suppress tumor progression but also provide a novel promising therapeutic choice in combination with a receptor-targeted cytotoxic conjugate via activating the specific receptor. PMID- 23435725 TI - Endometrial stromal sarcoma: clinicopathological and immunophenotypic study of 16 cases. AB - PURPOSE: Endometrial stromal sarcomas (ESSs) are rare tumors and are divided into two groups: low-grade endometrial stromal sarcoma (ESS-LG) and undifferentiated endometrial sarcoma (UES). The purpose of this study was to compare the clinicopathological features and immunophenotypes of ESS-LG and UES. METHODS: The authors evaluated 16 patients diagnosed with ESS at the Hyogo Cancer Center, reviewed their files and data, and performed an immunohistochemical study for oncogenic proteins (EGFR, PDGFR-alpha, and PDGFR-beta) and cell cycle regulators (cyclin D1, cyclin E, p16(INK4a), p21(cip1), p27(kip1), and p53) to compare ESS LG and UES using the World Health Organization (WHO) classification. RESULTS: Four cases (25 %) were classified as ESS-LGs and 12 (75 %) as UES. Patients with UES had a significantly worse overall survival than did those with ESS-LG (p = 0.0445). Although no ESS-LGs showed expression of p16(INK4a), 10 of 12 (83 %) UESs showed expression of p16(INK4a). UESs showed a trend toward higher expression of cyclin D1, p21(cip1), and p53 compared with ESS-LGs. CONCLUSIONS: Our data emphasize the clinical importance of the WHO classification of ESS. It is of utmost importance to establish a proper classification to increase the consistency of data that may be useful for improving clinical and therapeutic management of patients with ESS. PMID- 23435726 TI - Virtual autopsy: time for a clinical trial. PMID- 23435727 TI - Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis trans isomerase from the human malarial parasite Plasmodium vivax. AB - The immunosuppressive drug FK506 binding proteins (FKBPs), an immunophilin family with the immunosuppressive drug FK506 binding property, exhibit peptidylprolyl cis-trans isomerase (PPIase) activity. While the cyclophilin-catalyzed peptidylprolyl isomerization of X-Pro peptide bonds has been extensively studied, the mechanism of the FKBP-mediated peptidylprolyl isomerization remains uncharacterized. Thus, to investigate the binding of FKBP with its substrate and the underlying catalytic mechanism of the FKBP-mediated proline isomerization, here we employed the FK506 binding domain (FKBD) of the human malarial parasite Plasmodium vivax FK506 binding protein 35 (PvFKBP35) and examined the details of the molecular interaction between the isomerase and a peptide substrate. The crystallographic structures of apo PvFKBD35 and its complex with the tetrapeptide substrate succinyl-Ala-Leu-Pro-Phe-p-nitroanilide (sALPFp) determined at 1.4 A and 1.65 A resolutions, respectively, showed that the substrate binds to PvFKBD35 in a cis conformation. Nuclear magnetic resonance (NMR) studies demonstrated the chemical shift perturbations of D55, H67, V73, and I74 residues upon the substrate binding. In addition, the X-ray crystal structure, along with the mutational studies, shows that Y100 is a key residue for the catalytic activity. Taken together, our results provide insights into the catalytic mechanism of PvFKBP35-mediated cis-trans isomerization of substrate and ultimately might aid designing substrate mimetic inhibitors targeting the malarial parasite FKBPs. PMID- 23435728 TI - Activator and repressor functions of the Mot3 transcription factor in the osmostress response of Saccharomyces cerevisiae. AB - Mot3 and Rox1 are transcriptional repressors of hypoxic genes. Both factors recently have been found to be involved in the adaptive response to hyperosmotic stress, with an important function in the adjustment of ergosterol biosynthesis. Here, we determine the gene expression profile of a mot3 rox1 double mutant under acute osmostress at the genomic scale in order to identify the target genes affected by both transcription factors upon stress. Unexpectedly, we find a specific subgroup of osmostress-inducible genes to be under positive control of Mot3. These Mot3-activated stress genes also depend on the general stress activators Msn2 and Msn4. We confirm that both Mot3 and Msn4 bind directly to some promoter regions of this gene group. Furthermore, osmostress-induced binding of the Msn2 and Msn4 factors to these target promoters is severely affected by the loss of Mot3 function. The genes repressed by Mot3 and Rox1 preferentially encode proteins of the cell wall and plasma membrane. Cell conjugation was the most significantly enriched biological process which was negatively regulated by both factors and by osmotic stress. The mating response was repressed by salt stress dependent on Mot3 and Rox1 function. Taking our findings together, the Mot3 transcriptional regulator has unanticipated diverse functions in the cellular adjustment to osmotic stress, including transcriptional activation and modulation of mating efficiency. PMID- 23435729 TI - Molecular rearrangement reactions in the gas phase triggered by electron attachment. AB - Bond formation and rearrangement reactions in gas phase electron attachment were studied through dissociative electron attachment (DEA) to pentafluorotoluene (PFT), pentafluoroaniline (PFA) and pentafluorophenol (PFP) in the energy range 0 14 eV. In the case of PFA and PFP, the dominant processes involve formation of [M - HF](-) through the loss of neutral HF. This fragmentation channel is most efficient at low incident electron energy and for PFP it is accompanied by a substantial conformational change of the anionic fragment. At higher energy, HF loss is also observed as well as a number of other fragmentation processes. Thermochemical threshold energies have been computed for all the observed fragments and classical trajectories of the electron attachment process were calculated to elucidate the fragmentation mechanisms. For the dominant reaction channel leading to the loss of HF from PFP, the minimum energy path was calculated using the nudged elastic band method. PMID- 23435731 TI - Fusion of nacre, mussel, and lotus leaf: bio-inspired graphene composite paper with multifunctional integration. AB - Multifunctional integration is an inherent characteristic for biological materials with multiscale structures. Learning from nature is an effective approach for scientists and engineers to construct multifunctional materials. In nature, mollusks (abalone), mussels, and the lotus have evolved different and optimized solutions to survive. Here, bio-inspired multifunctional graphene composite paper was fabricated in situ through the fusion of the different biological solutions from nacre (brick-and-mortar structure), mussel adhesive protein (adhesive property and reducing character), and the lotus leaf (self cleaning effect). Owing to the special properties (self-polymerization, reduction, and adhesion), dopamine could be simultaneously used as a reducing agent for graphene oxide and as an adhesive, similar to the mortar in nacre, to crosslink the adjacent graphene. The resultant nacre-like graphene paper exhibited stable superhydrophobicity, self-cleaning, anti-corrosion, and remarkable mechanical properties underwater. PMID- 23435730 TI - Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. AB - Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic differences involving HSP47 between AE-IPF and stable (S) IPF. Subjects comprised 20 AE-IPF and 33 S-IPF patients. Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, SP-D, and lactate dehydrogenase (LDH) were measured. Immunohistochemical analysis of lung HSP47 expression was determined in biopsy and autopsy tissues diagnosed as diffuse alveolar damage (DAD) and usual interstitial pneumonia (UIP). Serum levels of HSP47 were significantly higher in AE-IPF than in S-IPF patients, whereas serum levels of KL-6, SP-A, and SP-D did not differ significantly. Receiver operating characteristic curves revealed that HSP47 was superior for discriminating AE-IPF and S-IPF. The cutoff for HSP47 resulting in the highest diagnostic accuracy was 559.4 pg/mL; sensitivity, specificity, and diagnostic accuracy were 100.0%, 93.9%, and 96.2%, respectively. Immunohistochemical analysis revealed that pulmonary HSP47 expression was greater in DAD than UIP tissues. Serum HSP47 was significantly higher in AE-IPF than in S-IPF patients, suggesting that underlying fibrogenic mechanisms involving HSP47 differ in the two conditions. PMID- 23435732 TI - GATA3 mutations found in breast cancers may be associated with aberrant nuclear localization, reduced transactivation and cell invasiveness. AB - Somatic and germline mutations in the dual zinc-finger transcription factor GATA3 are associated with breast cancers expressing the estrogen receptor (ER) and the autosomal dominant hypoparathyroidism-deafness-renal dysplasia syndrome, respectively. To elucidate the role of GATA3 in breast tumorigenesis, we investigated 40 breast cancers that expressed ER, for GATA3 mutations. Six different heterozygous GATA3 somatic mutations were identified in eight tumors, and these consisted of: a frameshifting deletion/insertion (944_945delGGinsAGC), an in-frame deletion of a key arginine residue (991_993delAGG), a seven nucleotide frameshifting insertion (991_992insTGGAGGA), a frameshifting deletion (1196_1197delGA), and two frameshifting single nucleotide insertions (1224_1225insG found in three tumors and 1224_1225insA). Five of the eight mutations occurred in tumors that retained GATA3 immunostaining, indicating that absence of GATA3 immunostaining is an unreliable predictor of the presence of GATA3 mutations. Luciferase reporter assays, electrophoretic mobility shift assays, immunofluorescence, invasion and proliferation assays demonstrated that the GATA3 mutations resulted in loss (or reduction) of DNA binding, decrease in transactivational activity, and alterations in invasiveness but not proliferation. The 991_992insTGGAGGA (Arg330 frameshift) mutation led to a loss of nuclear localization, yet the 991_993delAGG (Arg330deletion) retained nuclear localization. Investigation of the putative nuclear localization signal (NLS) sites showed that the NLS of GATA3 does not conform to either a classical mono- or bi-partite signal, but contains multiple cooperative NLS elements residing around the N-terminal zinc-finger which comprises residues 264-288. Thus, approximately 20 % ER-positive breast cancers have somatic GATA3 mutations that lead to a loss of GATA3 transactivation activity and altered cell invasiveness. PMID- 23435733 TI - Combined linkage and association mapping of flowering time in Sunflower (Helianthus annuus L.). AB - Association mapping and linkage mapping were used to identify quantitative trait loci (QTL) and/or causative mutations involved in the control of flowering time in cultivated sunflower Helianthus annuus. A panel of 384 inbred lines was phenotyped through testcrosses with two tester inbred lines across 15 location * year combinations. A recombinant inbred line (RIL) population comprising 273 lines was phenotyped both per se and through testcrosses with one or two testers in 16 location * year combinations. In the association mapping approach, kinship estimation using 5,923 single nucleotide polymorphisms was found to be the best covariate to correct for effects of panel structure. Linkage disequilibrium decay ranged from 0.08 to 0.26 cM for a threshold of 0.20, after correcting for structure effects, depending on the linkage group (LG) and the ancestry of inbred lines. A possible hitchhiking effect is hypothesized for LG10 and LG08. A total of 11 regions across 10 LGs were found to be associated with flowering time, and QTLs were mapped on 11 LGs in the RIL population. Whereas eight regions were demonstrated to be common between the two approaches, the linkage disequilibrium approach did not detect a documented QTL that was confirmed using the linkage mapping approach. PMID- 23435734 TI - Identification of mitochondrial DNA sequence variation and development of single nucleotide polymorphic markers for CMS-D8 in cotton. AB - Cytoplasmic male sterility (CMS), which is a maternally inherited trait and controlled by novel chimeric genes in the mitochondrial genome, plays a pivotal role in the production of hybrid seed. In cotton, no PCR-based marker has been developed to discriminate CMS-D8 (from Gossypium trilobum) from its normal Upland cotton (AD1, Gossypium hirsutum) cytoplasm. The objective of the current study was to develop PCR-based single nucleotide polymorphic (SNP) markers from mitochondrial genes for the CMS-D8 cytoplasm. DNA sequence variation in mitochondrial genes involved in the oxidative phosphorylation chain including ATP synthase subunit 1, 4, 6, 8 and 9, and cytochrome c oxidase 1, 2 and 3 subunits were identified by comparing CMS-D8, its isogenic maintainer and restorer lines on the same nuclear genetic background. An allelic specific PCR (AS-PCR) was utilized for SNP typing by incorporating artificial mismatched nucleotides into the third or fourth base from the 3' terminus in both the specific and nonspecific primers. The result indicated that the method modifying allele specific primers was successful in obtaining eight SNP markers out of eight SNPs using eight primer pairs to discriminate two alleles between AD1 and CMS-D8 cytoplasms. Two of the SNPs for atp1 and cox1 could also be used in combination to discriminate between CMS-D8 and CMS-D2 cytoplasms. Additionally, a PCR-based marker from a nine nucleotide insertion-deletion (InDel) sequence (AATTGTTTT) at the 59-67 bp positions from the start codon of atp6, which is present in the CMS and restorer lines with the D8 cytoplasm but absent in the maintainer line with the AD1 cytoplasm, was also developed. A SNP marker for two nucleotide substitutions (AA in AD1 cytoplasm to CT in CMS-D8 cytoplasm) in the intron (1,506 bp) of cox2 gene was also developed. These PCR-based SNP markers should be useful in discriminating CMS-D8 and AD1 cytoplasms, or those with CMS-D2 cytoplasm as a rapid, simple, inexpensive, and reliable genotyping tool to assist hybrid cotton breeding. PMID- 23435735 TI - Auditory cortex is implicated in tinnitus distress: a voxel-based morphometry study. AB - Neuroimaging studies of tinnitus suggest the involvement of wide-spread neural networks for perceptual, attentional, memory, and emotional processes encompassing auditory, frontal, parietal, and limbic areas. Despite sparse findings for tinnitus duration and laterality, tinnitus distress has been shown to be related to changes in non-auditory cortical areas. The aim of this study was to correlate tinnitus characteristics with grey matter volume in two large samples of tinnitus patients. High-resolution brain images were obtained using a 1.5 T magnetic resonance imaging scanner and analysed by means of voxel-based morphometry. In sample one (n = 257), tinnitus distress correlated negatively with grey matter volume in bilateral auditory areas including the Heschl's gyrus and insula, that is, the higher the tinnitus distress the lower the grey matter volume. The effects of this correlation were small, but stable after correction for potential confounders such as age, gender, and audiometric parameters. This negative correlation was replicated in a second independent sample (n = 78). Our results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects. The distress observed was dependent on grey matter alterations in the auditory cortex, which could reflect reverberations between perceptual and distress networks. PMID- 23435736 TI - Socio-economic position over the life course and all-cause, and circulatory diseases mortality at age 50-87 years: results from a Swedish birth cohort. AB - Both child and adult socio-economic position (SEP) predict adult mortality, but little is known about the variation in the impact of SEP across the life course. The Uppsala Birth Cohort Study is a representative birth cohort born 1915-1929 in Uppsala, Sweden. For the 5,138 males and 5,069 females alive in 1980, SEP was available at birth; in adulthood (age 31-45); and in later life (age 51-65). Follow-up for mortality (all-cause, and circulatory disease) was from 1980 to 2002. To test which life course model best described the association between SEP and mortality, we compared the fit of a series of nested Cox proportional hazards regression models (representing either the critical, accumulation or sensitive period models) with a fully saturated model. For all-cause mortality in both genders, the sensitive period model best described the influence of SEP across the life course with a heightened effect in later adult life (males: Hazard Ratio (95 % CI) for advantaged SEP: 0.89 (0.81-0.97) at birth, 0.90 (0.81-0.98) in adulthood, 0.74 (0.67-0.82) in later life; females: 0.87 (0.78-0.98), 0.95 (0.86 1.06), 0.73 (0.64-0.83)). The effect of SEP on circulatory diseases mortality in males was cumulative (HR: 0.84 (0.80-0.87) per unit time in advantaged SEP). For circulatory disease mortality among females, a sensitive period model was selected due to SEP in later adult life (HR: 0.64 (0.52-0.80)). These findings suggest that reducing inequality throughout the life course might reduce all cause and circulatory disease mortality. PMID- 23435737 TI - Total synthesis of cyclic heptapeptide Rolloamide B. AB - The first total synthesis of Rolloamide B, a cyclic proline-enriched heptapeptide, is reported. This work features solution phase benzotriazole mediated peptide synthesis ligating native amino acids. PMID- 23435738 TI - Hereditary pancreatitis: endoscopic and surgical management. AB - INTRODUCTION: Hereditary pancreatitis is a rare cause of chronic pancreatitis. In recent years, genetic mutations have been characterized. The rarity of this disorder has resulted in a gap in clinical knowledge. The aims were to characterize patients with hereditary pancreatitis and establish clinical guidelines. METHODS: Pediatric and adult endoscopic, surgical, radiologic, and genetic databases from 1998 to 2012 were searched. Patients with recurrent acute or chronic pancreatitis and genetic mutation for either PRSS-1, SPINK-1, or CFTR or those who met the family history criteria were included. Patients with pancreatitis due to other causes, without a positive family history, familial pancreatic cancer, or cystic fibrosis, were excluded. RESULTS: Eighty-seven patients were identified. Genetic testing confirmed the diagnosis in 54 patients (62 %). Eighty-five patients (98 %) underwent 263 endoscopic procedures including sphincterotomy (72 %), stone removal (49 %), and pancreatic duct stenting (82 %). Twenty-eight patients (32 %) have undergone 37 operations which included 19 resections and 18 drainage procedures. The interval between procedures for recurrent pain was longer for surgery than for endoscopic therapy (9.1 vs. 3.4 years, p < 0.05). CONCLUSIONS: Most children and young adults with hereditary pancreatitis can be managed initially with endoscopic therapy. When surgery is undertaken, the procedure should be tailored to the pancreatic anatomy and cancer risk. PMID- 23435740 TI - Does preinterventional flat-panel computer tomography pooled blood volume mapping predict final infarct volume after mechanical thrombectomy in acute cerebral artery occlusion? AB - PURPOSE: Decreased cerebral blood volume is known to be a predictor for final infarct volume in acute cerebral artery occlusion. To evaluate the predictability of final infarct volume in patients with acute occlusion of the middle cerebral artery (MCA) or the distal internal carotid artery (ICA) and successful endovascular recanalization, pooled blood volume (PBV) was measured using flat panel detector computed tomography (FPD CT). MATERIALS AND METHODS: Twenty patients with acute unilateral occlusion of the MCA or distal ACI without demarcated infarction, as proven by CT at admission, and successful Thrombolysis in cerebral infarction score (TICI 2b or 3) endovascular thrombectomy were included. Cerebral PBV maps were acquired from each patient immediately before endovascular thrombectomy. Twenty-four hours after recanalization, each patient underwent multislice CT to visualize final infarct volume. Extent of the areas of decreased PBV was compared with the final infarct volume proven by follow-up CT the next day. RESULTS: In 15 of 20 patients, areas of distinct PBV decrease corresponded to final infarct volume. In 5 patients, areas of decreased PBV overestimated final extension of ischemia probably due to inappropriate timing of data acquisition and misery perfusion. CONCLUSION: PBV mapping using FPD CT is a promising tool to predict areas of irrecoverable brain parenchyma in acute thromboembolic stroke. Further validation is necessary before routine use for decision making for interventional thrombectomy. PMID- 23435739 TI - Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. AB - BACKGROUND AND OBJECTIVE: Chronic localized pancreatic inflammation in the form of chronic pancreatitis is an established risk factor for human pancreatic ductal adenocarcinoma (PDAC) development. Constitutive activation of inflammation related signal transducer and activator of transcription (Stat)3 signaling has been implicated in the development and progression a number of malignancies, including PDAC. Although, the Janus Kinase (Jak)/Stat pathway is a potential drug target, clinicopathological, molecular, and prognostic features of Stat3 activated PDAC remain uncertain. Our aim was to determine the clinicopathological impact of this inflammatory pathway in resectable PDAC. METHODS: Using a tissue microarray-based cohort of PDAC from 86 patients undergoing pancreaticoduodenectomy with curative intent and complete clinicopathological data available, we evaluated expression of the interleukin-6 receptor (IL 6R)/Jak/Stat pathway by immunohistochemistry. IL-6R, Jak, phospho (p)-Jak, Stat3, pStat3(Tyr705), and pStat3(Ser727) were assessed in PDAC and pancreatic intraepithelial neoplasia. A Cox regression multivariate analysis model was used to determine factors influencing survival. Activation of the IL-6R/Jak/Stat3 pathway was compared with the systemic inflammatory response as measured by serum C-reactive protein levels. RESULTS: High pJak was associated with reduced overall survival in multivariate analysis when compared with those with moderate or low expression (p = 0.036; hazard ratio (HR) = 1.68) as was pStat3(Tyr705) (p < 0.001; HR = 2.66) independent of lymph node status and tumor grade. Patients with a combination of pJakhigh/pStat3(Tyr705) high expression had an especially poor prognosis (median survival of 8.8 months; 95 % CI, 4.4-13.2). While the IL 6R/Jak/Stat pathway did not correlate with serum C-reactive protein levels, high pStat3 expression was associated with a reduction in the density of the local tumoral immune response. CONCLUSION: Activation of the Jak/Stat3 pathway via phosphorylation was associated with adverse outcome following resection of PDAC with curative intent supporting potential roles for pJak and pStat3 as prognostic biomarkers markers and therapeutic targets. PMID- 23435741 TI - Systematic review of infrapopliteal drug-eluting stents: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Drug-eluting stents (DES) have been proposed for the treatment of infrapopliteal arterial disease. We performed a systematic review to provide a qualitative analysis and quantitative data synthesis of randomized controlled trials (RCTs) assessing infrapopliteal DES. MATERIALS AND METHODS: PubMed (Medline), EMBASE (Excerpta Medical Database), AMED (Allied and Complementary medicine Database), Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), online content, and abstract meetings were searched in September 2012 for eligible RCTs according to the preferred reporting items for systematic reviews and meta-analyses selection process. Risk of bias was assessed using the Cochrane Collaboration's tool. Primary endpoint was primary patency defined as absence of >=50 % vessel restenosis at 1 year. Secondary outcome measures included patient survival, limb amputations, change of Rutherford-Becker class, target lesion revascularization (TLR) events, complete wound healing, and event free survival at 1 year. Risk ratio (RRs) were calculated using the Mantel Haenszel fixed effects model, and number-needed-to-treat values are reported. RESULTS: Three RCTs involving 501 patients with focal infrapopliteal lesions were analyzed (YUKON-BTX, DESTINY, and ACHILLES trials). All three RCTs included relatively short and focal infrapopliteal lesions. At 1 year, there was clear superiority of infrapopliteal DES compared with control treatments in terms of significantly higher primary patency (80.0 vs. 58.5 %; pooled RR = 1.37, 95 % confidence interval [CI] = 1.18-1.58, p < 0.0001; number-needed-to-treat (NNT) value = 4.8), improvement of Rutherford-Becker class (79.0 vs. 69.6 %; pooled RR = 1.13, 95 % CI = 1.002-1.275, p = 0.045; NNT = 11.1), decreased TLR events (9.9 vs. 22.0 %; pooled RR = 0.45, 95 % CI = 0.28-0.73, p = 0.001; NNT = 8.3), improved wound healing (76.8 vs. 59.7 %; pooled RR = 1.29, 95 % CI = 1.02-1.62, p = 0.04; NNT = 5.9), and better overall event-free survival (72.2 vs. 57.3 %; pooled RR = 1.26, 95 % CI = 1.10-1.44, p = 0.0006; NNT = 6.7). CONCLUSION: DES for focal infrapopliteal lesions significantly inhibit vascular restenosis and thereby improve primary patency, decrease repeat procedures, improve wound healing, and prolong overall event-free survival. PMID- 23435742 TI - Root cause analysis of gastroduodenal ulceration after yttrium-90 radioembolization. AB - INTRODUCTION: A root cause analysis was performed on the occurrence of gastroduodenal ulceration after hepatic radioembolization (RE). We aimed to identify the risk factors in the treated population and to determine the specific mechanism of nontarget RE in individual cases. METHODS: The records of 247 consecutive patients treated with yttrium-90 RE for primary (n = 90) or metastatic (n = 157) liver cancer using either resin (n = 181) or glass (n = 66) microspheres were reviewed. All patients who developed a biopsy-proven microsphere-induced gastroduodenal ulcer were identified. Univariate and multivariate analyses were performed on baseline parameters and procedural data to determine possible risk factors in the total population. Individual cases were analyzed to ascertain the specific cause, including identification of the culprit vessel(s) leading to extrahepatic deposition of the microspheres. RESULTS: Eight patients (3.2 %) developed a gastroduodenal ulcer. Stasis during injection was the strongest independent risk factor (p = 0.004), followed by distal origin of the gastroduodenal artery (p = 0.004), young age (p = 0.040), and proximal injection of the microspheres (p = 0.043). Prolonged administrations, pain during administration, whole liver treatment, and use of resin microspheres also showed interrelated trends in multivariate analysis. Retrospective review of intraprocedural and postprocedural imaging showed a probable or possible culprit vessel, each a tiny complex collateral vessel, in seven patients. CONCLUSION: Proximal administrations and those resulting in stasis of flow presented increased risk for gastroduodenal ulceration. Patients who had undergone bevacizumab therapy were at high risk for developing stasis. PMID- 23435743 TI - Reducing blood-borne exposure in interventional radiology: what the IR should know. AB - Interventional radiologists are at risk of exposure to blood-borne pathogens in their day-to-day practice. Percutaneous exposure from unsafe sharps handling, mucocutaneous exposure from body fluid splashes, and glove perforation from excessive wear can expose the radiologist to potentially infectious material. The increasing prevalence of blood-borne pathogens, including hepatitis B and C, and human immunodeficiency virus, puts nurses, residents, fellows, and interventional radiologists at risk for occupational exposure. This review outlines suggestions to establish a culture of safety in the interventional suite. PMID- 23435744 TI - Staged transcatheter treatment of portal hypoplasia and congenital portosystemic shunts in children. AB - PURPOSE: Congenital portosystemic shunts (CPSS) with portal venous hypoplasia cause hyperammonemia. Acute shunt closure results in portal hypertension. A transcatheter method of staged shunt reduction to afford growth of portal vessels followed by shunt closure is reported. METHODS: Pressure measurements and angiography in the CPSS or superior mesenteric artery (SMA) during temporary occlusion of the shunt were performed. If vessels were diminutive and the pressure was above 18 mmHg, a staged approach was performed, which included implantation of a tailored reducing stent to reduce shunt diameter by ~50 %. Recatheterization was performed approximately 3 months later. If the portal pressure was below 18 mmHg and vessels had developed, the shunt was closed with a device. RESULTS: Six patients (5 boys, 1 girl) with a median age of 3.3 (range 0.5-13) years had CPSS portal venous hypoplasia and hyperammonemia. Five patients underwent staged closure. One patient tolerated acute closure. One patient required surgical shunt banding because a reducing stent could not be positioned. At median follow-up of 3.8 (range 2.2-8.4) years, a total of 21 procedures (20 transcatheter, 1 surgical) were performed. In all patients, the shunt was closed with a significant reduction in portal pressure (27.7 +/- 11.3 to 10.8 +/- 1.8 mmHg; p = 0.016), significant growth of the portal vessels (0.8 +/- 0.5 to 4.0 +/ 2.4 mm; p = 0.037), and normalization of ammonia levels (202.1 +/- 53.6 to 65.7 +/- 9.6 MUmol/L; p = 0.002) with no complications. CONCLUSION: Staged CPSS closure is effective in causing portal vessel growth and treating hyperammonemia. PMID- 23435745 TI - Balloon coating with rapamycin using an on-site coating device. AB - PURPOSE: The efficacy of drug-eluting balloons has been demonstrated in clinical trials. The drug predominantly used is paclitaxel because of its lipophilic properties and the rapid onset of action. The aim of the investigation was to evaluate the feasibility and efficacy of an alternative balloon coating with rapamycin that can be applied on site. METHODS: The balloon coating (3.0/18 and 3.0/12 mm, Cathy No. 4, Translumina GmbH) with rapamycin was conducted with a coating machine (Translumina GmbH). Concentrations were 2, 2 * 2, 3, and 4 %. Measurements regarding the amount of substance released to the vessel wall were carried out on explanted porcine coronaries by means of ultraviolet and visible light spectroscopy. Inflation time varied between 30 and 120 s. The biological effect of the coating was evaluated in a porcine peripheral overstretch and stent implantation model. RESULTS: The amount of rapamycin on the balloon surface ranged from 558 +/- 108 MUg for the 2 % solution to 1,441 +/- 228 MUg in the 4 % solution. An amount of 95 +/- 63-193 +/- 113 MUg was released into the vessel wall. The quantitative measurements of the angiographic examinations 4 weeks after treatment revealed a reduction of diameter stenosis from 20.6 +/- 17.4 % in the control group to 11.6 +/- 5.5 % in the drug-eluting balloon group. CONCLUSION: A balloon coating with rapamycin omitting an excipient is possible with a dose-adjustable coating machine. However, the biological effects are moderate, which make further optimization of the coating process and evaluation of appropriate excipients necessary. PMID- 23435746 TI - Coupling the valley degree of freedom to antiferromagnetic order. AB - Conventional electronics are based invariably on the intrinsic degrees of freedom of an electron, namely its charge and spin. The exploration of novel electronic degrees of freedom has important implications in both basic quantum physics and advanced information technology. Valley, as a new electronic degree of freedom, has received considerable attention in recent years. In this paper, we develop the theory of spin and valley physics of an antiferromagnetic honeycomb lattice. We show that by coupling the valley degree of freedom to antiferromagnetic order, there is an emergent electronic degree of freedom characterized by the product of spin and valley indices, which leads to spin-valley-dependent optical selection rule and Berry curvature-induced topological quantum transport. These properties will enable optical polarization in the spin-valley space, and electrical detection/manipulation through the induced spin, valley, and charge fluxes. The domain walls of an antiferromagnetic honeycomb lattice harbors valley-protected edge states that support spin-dependent transport. Finally, we use first principles calculations to show that the proposed optoelectronic properties may be realized in antiferromagnetic manganese chalcogenophosphates (MnPX3, X = S, Se) in monolayer form. PMID- 23435748 TI - Secondary prophylaxis in an adult patient with severe haemophilia A. Factor VIII consumption and effectiveness. AB - Primary prophylaxis has been proven as the gold standard for preserving joint function in severe haemophilia. Secondary prophylaxis in children has also been shown to have a more beneficial effect on joint protection as on-demand treatment. The outcome of delayed secondary prophylaxis started in adulthood is rarely studied. The case of a man (age: 47 years) with severe haemophilia A demonstrates the successful switch from on-demand therapy to prophylaxis with subsequent reduction of annual bleeding rate and number of days of work lost. The small increase of factor VIII consumption (16%) and the decrease of bleeding rate are compared with data from two recently published prospective studies. CONCLUSION: An optimal dosing schedule needs to be discussed and larger and longer prospective studies targeting the benefits of secondary prophylaxis with factor VIII started in adulthood are necessary. PMID- 23435747 TI - Extra-esophageal manifestations of GERD: who responds to GERD therapy? AB - Gastroesophageal reflux disease (GERD) is a common disease that is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms. In addition to the esophageal manifestations of heartburn and regurgitation, the role of GERD in causing extra-esophageal symptoms, such as laryngitis, asthma, cough, chest pain, and dental erosions, is increasingly recognized with renewed interest. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPI) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. In those who are unresponsive to such therapy, other diagnostic testing such as impedance/pH monitoring may be reasonable in order to exclude continued acid or weakly acid reflux. Recent data suggest that patients with extra-esophageal symptoms who have concomitant typical symptoms, moderate-sized hiatal hernia and moderate reflux on pH testing may respond better to acid suppressive therapy. This group only accounts for 20-30 % of patients commonly referred for suspected GERD. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal signs and symptoms and continued PPI therapy in this group is not recommended. PMID- 23435749 TI - Pseudomyogenic hemangioendothelioma (epithelioid sarcoma-like hemangioendothelioma, fibroma-like variant of epithelioid sarcoma) of the thoracic spine. AB - PURPOSE: Pseudomyogenic hemangioendothelioma is a soft tissue tumor found in young adults, predominantly males. The tumor has been reported in various locations in the body, including the head, neck, chest wall, abdominal wall, genital region, and extremities. Until now, there has been no indication of occurrence in the spine. METHODS: A 25-year-old male presented with spinal cord compression, due to an extradural tumor involving the third and fourth thoracic vertebrae with extension into the right pleural cavity. RESULTS: Histopathologic examination revealed a pseudomyogenic hemangioendothelioma, also described as epithelioid sarcoma-like hemangioendothelioma, or fibroma-like variant of epithelioid sarcoma. CONCLUSION: We describe the first occurrence of pseudomyogenic hemangioendothelioma in the thoracic spine. According to previous reports based on other locations, the tumor has an indolent clinical course with a small risk of metastasis, therefore complete macroscopic excision is the treatment of choice. Local recurrence may occur even with complete surgical resection, requiring close follow-up; adjuvant therapy is warranted. PMID- 23435750 TI - Pharmacy and self-report adherence measures to predict virological outcomes for patients on free antiretroviral therapy in Tamil Nadu, India. AB - Over 480,000 individuals receive free antiretroviral therapy (ART) in India yet data associating ART adherence with HIV viral load for populations exclusively receiving free ART are not available. Additionally estimates of adherence using pharmacy data on ART pick-up are not available for any population in India. After 12-months ART we found self-reported estimates of adherence were not associated with HIV viral load. Individuals with <100% adherence using pharmacy data predicted HIV viral load, and estimates combining pharmacy data and self-report were also predictive. Pharmacy adherence measures proved a feasible method to estimate adherence in India and appear more predictive of virological outcomes than self-report. Predictive adherence measures identified in this study warrant further investigation in populations receiving free ART in India to allow for identification of individuals at risk of virological failure and in need of adherence support. PMID- 23435751 TI - An optimized sericin-1 expression system for mass-producing recombinant proteins in the middle silk glands of transgenic silkworms. AB - The middle silk gland (MSG) of silkworm is thought to be a potential host for mass-producing valuable recombinant proteins. Transgenic MSG expression systems based on the usage of promoter of sericin1 gene (sericin-1 expression system) have been established to produce various recombinant proteins in MSG. However, further modifying the activity of the sericin-1 expression system to yield higher amounts of recombinant proteins is still necessary. In this study, we provide an alternative modification strategy to construct an efficient sericin-1 expression system by using the hr3 enhancer (hr3 CQ) from a Chongqing strain of the Bombyx mori nuclear polyhedrosis virus (BmNPV) and the 3'UTRs of the fibroin heavy chain (Fib-HPA), the fibroin light chain (Fib-LPA), and Sericin1 (Ser1PA) genes. We first analyzed the effects of these DNA elements on expression of luciferase, and found that the combination of hr3 CQ and Ser1PA was most effective to increase the activity of luciferase. Then, hr3 CQ and Ser1PA were used to modify the sericin1 expression system. Transgenic silkworms bearing these modified sericin1 expression vectors were generated by a piggyBac transposon mediated genetic transformation method. Our results showed that mRNA level of DsRed reporter gene in transgenic silkworms containing hr3 CQ and Ser1PA significantly increased by 9 fold to approximately 83 % of that of endogenous sericin1. As the results of that, the production of recombinant RFP increased by 16 fold to 9.5 % (w/w) of cocoon shell weight. We conclude that this modified sericin-1 expression system is efficient and will contribute to the MSG as host to mass produce valuable recombinant proteins. PMID- 23435752 TI - Expression of the human granulocyte-macrophage colony stimulating factor (hGM CSF) gene under control of the 5'-regulatory sequence of the goat alpha-S1-casein gene with and without a MAR element in transgenic mice. AB - Expression of the human granulocyte-macrophage colony-stimulating factor (hGM CSF) gene under the control of the 5'-regulatory sequence of the goat alpha-S1 casein gene with and without a matrix attachment region (MAR) element from the Drosophila histone 1 gene was studied in four and eight transgenic mouse lines, respectively. Of the four transgenic lines carrying the transgene without MAR, three had correct tissues-specific expression of the hGM-CSF gene in the mammary gland only and no signs of cell mosaicism. The concentration of hGM-CSF in the milk of transgenic females varied from 1.9 to 14 MUg/ml. One line presented hGM CSF in the blood serum, indicating ectopic expression. The values of secretion of hGM-CSF in milk of 6 transgenic lines carrying the transgene with MAR varied from 0.05 to 0.7 MUg/ml, and two of these did not express hGM-CSF. Three of the four examined animals from lines of this group showed ectopic expression of the hGM CSF gene, as determined by RT-PCR and immunofluorescence analyses, as well as the presence of hGM-CSF in the blood serum. Mosaic expression of the hGM-CSF gene in mammary epithelial cells was specific to all examined transgenic mice carrying the transgene with MAR but was never observed in the transgenic mice without MAR. The mosaic expression was not dependent on transgene copy number. Thus, the expected "protective or enhancer effect" from the MAR element on the hGM-CSF gene expression was not observed. PMID- 23435754 TI - Progress in metagenomics requires a balanced appraisal of the available technologies. PMID- 23435753 TI - Rhinovirus infections in western Sweden: a four-year molecular epidemiology study comparing local and globally appearing types. AB - Human rhinovirus (HRV) is a highly prevalent pathogen and a major cause of acute respiratory tract infection (ARTI). HRV express less seasonality than other viral ARTIs, which typically appear as seasonal epidemics lasting for 1-2 months. The aim of this study was to investigate the seasonal patterns of HRV types over four consecutive years in one geographic region. HRV identified in respiratory samples from 114 patients over a four-year period were analysed by VP4/VP2 sequencing. HRV-A was found in 64, HRV-B in 11 and HRV-C in 37 cases. Overall, 33 different HRV-A types, nine B types and 21 C types were found. As many as 21 of the HRV types appeared during several seasons, with a maximum time-span of four years. Some types appeared during successive seasons and, in some cases, phylogenetic analysis indicated extended periods of circulation locally. Most of the strains were closely related to HRV identified in other parts of the world during the same time period. HRV strains that circulate locally represent many types and seem to reflect that HRV infections are highly globalised. The existence of simultaneous or successive epidemics with different HRV types in combination with the ability of each type to remain in the local population over extended periods of time may contribute to explaining the high rate of HRV infections. PMID- 23435755 TI - Genetic counseling services and training of genetic counselors in Israel: an overview. AB - Genetic counseling services have existed in Israel since 1964 and are available in almost all the major hospitals. Given the socialized healthcare system and small country size, genetic services are generally accessible and often free. The existence of founder mutations in various communities in Israel makes genetic testing easier to perform. Yet, the ethnic, cultural and religious diversity of the population has major implications on the design of the screening programs and the use of genetic services. The Israeli Association of Genetic Counselors (IAGC) was established in 2008 and had existed informally since 1989. There are two Master level genetic counseling training programs (6 students/class, 2 year program): Hebrew University-Hadassah Medical School (established in 1997) and the Technion (established in 2009). Genetic counselors' clinical training is largely observational and 2 years of supervised counseling sessions post degree are required for board exam eligibility. Genetic counselors are licensed and lead counseling sessions individually, but currently must work under medical geneticist supervision. This is the first article to summarize the history and training of Master level genetic counselors in Israel. Genetic services, coverage and regulations are also described. PMID- 23435760 TI - Equilibrium between Fe(IV) porphyrin and Fe(III) porphyrin radical cation: new insight into the electronic structure of high-valent iron porphyrin complexes. AB - UV-Vis, NMR, and Mossbauer studies have revealed that [Fe(TMP)(N3)2], showing the Mossbauer parameters quite similar to those of the ferryl species of MauG, CytP450BM3, Cyt P450CAM, and CPO, exists as equilibrium mixtures of Fe(IV) porphyrin and Fe(III) porphyrin radical cation. PMID- 23435761 TI - Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study. AB - AIMS: Reduced physical activity is associated with increased risk of heart failure (HF) in middle-aged individuals. We hypothesized that physical inactivity is also associated with greater HF risk in older individuals, and examined if the association was consistent for HF with preserved ejection fraction (HFPEF) vs. HF with a reduced ejection fraction (HFREF). METHODS AND RESULTS: We evaluated 1142 elderly participants (mean age 76 years) from the Framingham Study without prior myocardial infarction and who attended a routine examination when daily physical activity was assessed systematically with a questionnaire. A composite score, the physical activity index (PAI), was calculated and modelled as tertiles, and related to incidence of HF, HFPEF, and HFREF on follow-up using proportional hazards regression models adjusting for age and sex, and then additionally for standard HF risk factors. Participants with HF and EF <45% vs. >=45% were categorized as HFREF and HFPEF, respectively. On follow-up (mean 10 years), 250 participants developed HF (108 with HFPEF, 106 with HFREF, 36 with unavailable EF). In age- and sex-adjusted models, the middle and highest PAI tertiles were associated with a 15-56% lower risk of any HF, of HFREF, and of HFPEF, with a graded response across tertiles. In multivariable models, the association of higher PAI with lower risk of any HF and with HFPEF was maintained, whereas the association with HFREF was attenuated. CONCLUSIONS: Our study of an older community-based sample extends to the elderly and to HFPEF previous findings of a protective effect of physical activity on HF risk. PMID- 23435762 TI - Update on foreign bodies in the esophagus: diagnosis and management. AB - Foreign body impaction in the esophagus is an important emergency that carries significant morbidity and potential mortality. The most common cause of esophageal foreign body obstruction in adults is meat bolus impaction above a pre existing distal esophageal (mucosal) ring, peptic or malignant esophageal stricture, or eosinophilic esophagitis. Immediate evaluation of the airway, assessment of the urgency of removal, radiological evaluation to localize the object, endoscopic or surgical retrieval, and subsequent monitoring for complications are essential steps in the management. PMID- 23435763 TI - Determining phenomenological rate coefficients from a time-dependent, multiple well master equation: "species reduction" at high temperatures. AB - In this article we discuss at length the determination of phenomenological rate coefficients from the solution to a time-dependent, multiple-well master equation. Both conservative and non-conservative formulations are considered. The emphasis is placed on how to handle the situation when a CSE (chemically significant eigenvalue of the transition matrix) merges with the quasi-continuum of IEREs (internal energy relaxation eigenvalues), indicating that one or more chemical reactions begin to take place on vibrational-rotational relaxation time scales. The methodology is illustrated with four examples. PMID- 23435764 TI - The inhibitory function of Fc-ST2 depends on cell type; IL-1RAcP and ST2 are necessary but insufficient for IL-33 activity. AB - IL-33 (IL-1F11) is a member of IL-1 family ligand, which stimulates the production of inflammatory cytokines. IL-33 receptor complex is comprised of IL-1 receptor accessory protein (IL-1RAcP) and ST2 that are activated by IL-33 ligand binding. ST2 is a ligand-binding chain of the IL-33 receptor component, and the soluble ST2 form possesses antagonistic activity. Here, we expressed the extracellular domain of ST2-fused to the immunoglobulin of IgG1 constant region in order to generate a soluble recombinant Fc-ST2. Human and mouse recombinant Fc ST2 protein were expressed in Chinese hamster ovary cells and purified using a mini-protein A affinity chromatography. The recombinant Fc-ST2 protein was used to examine inhibitory function in IL-33-induced cytokine production in different cell types. The human Fc-ST2 abolished IL-33-induced IL-8 production in human mast cells, but mouse Fc-ST2 failed to inhibit IL-33-induced TNFalpha production in mouse Raw 264.7 macrophage cells. We further investigated the expression of IL 33 receptor component with various cell lines. IL-33 receptors expression pattern and Fc-ST2 inhibitory activity in different cell types suggest that IL-1RAcP and ST2 are necessary but insufficient for IL-33 activity. Our results suggest that an additional receptor component may participate in the biological activity of IL 33. PMID- 23435765 TI - PTSD risk and mental health care engagement in a multi-war era community sample of women veterans. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is common in women veterans (WVs), and associated with significant co-morbidity. Effective treatment is available; however, PTSD is often unrecognized. OBJECTIVES: Identify PTSD prevalence and mental healthcare (MHC) use in a representative national WV sample. DESIGN AND PARTICIPANTS: Cross-sectional, population-based 2008-2009 national survey of 3,611 WVs, weighted to the population. MAIN MEASURES: We screened for PTSD using a validated instrument, and also assessed demographic characteristics, health characteristics, and MHC use in the prior 12 months. Among those screening positive, we conducted multivariate logistic regression to identify independent predictors of MHC use. KEY RESULTS: Overall, 13.0 % (95 % confidence interval [CI] 9.8-16.2) of WVs screened PTSD-positive. Veterans Health Administration (VA) healthcare was used by 31.1 % of PTSD-positives and 11.4 % of PTSD-negatives (p<0.001). Among those screening positive, 48.7 % (95 % CI 35.9 61.6) used MHC services (66.3 % of VA-users, 40.8 % of VA-nonusers; p<0.001). Having a diagnosis of depression (OR=8.6; 95 % CI 1.5-48.9) and VA healthcare use (OR=2.7; 95 % CI 1.1-7.0) predicted MHC use, whereas lacking a regular provider for health care (OR=0.2; 95 % CI 0.1-0.4) and household income below the federal poverty level (OR=0.2; 95 % CI 0.1-0.5) predicted nonuse. CONCLUSIONS: More than one in eight WVs screened positive for PTSD. Though a majority of VA-users received MHC, low income predicted nonuse. Only a minority of VA-nonusers received MHC. The majority of WVs use non-VA healthcare providers, who may be unaware of their veteran status and PTSD risk. VA outreach to educate VA-nonusers and their healthcare providers about WVs' PTSD risk and available evidence-based VA treatment options is one approach to extend the reach of VA MHC. Research to characterize barriers to VA MHC use for VA-nonusers and low income VA-users is warranted to better understand low service utilization, and to inform program development to engage more WVs in needed MHC. PMID- 23435766 TI - Evaluation of VA Women's Health Fellowships: developing leaders in academic women's health. AB - BACKGROUND: The Department of Veterans Affairs (VA) instituted the VA Women's Health Fellowship (VAWHF) Program in 1994, to accommodate the health needs of increasing numbers of female veterans and to develop academic leaders in women's health. Despite the longevity of the program, it has never been formally evaluated. OBJECTIVE: To describe the training environments of VAWHFs and career outcomes of female graduates. DESIGN AND PARTICIPANTS: Cross-sectional web-based surveys of current program directors (2010-2011) and VAWHF graduates (1995-2011). RESULTS: Responses were received from six of seven program directors (86 %) and 42 of 74 graduates (57 %). The mean age of graduates was 41.2 years, and mean time since graduation was 8.5 years. Of the graduates, 97 % were female, 74 % trained in internal medicine, and 64 % obtained an advanced degree. Those with an advanced degree were more likely than those without an advanced degree to pursue an academic career (82 % vs. 60 %; P<0.01). Of the female graduates, 76 % practice clinical women's health and spend up to 66 % of their time devoted to women's health issues. Thirty percent have held a VA faculty position. Seventy nine percent remain in academics, with 39 % in the tenure stream. Overall, 94 % had given national presentations, 88 % had received grant funding, 79 % had published in peer-reviewed journals, 64 % had developed or evaluated curricula, 51 % had received awards for teaching or research, and 49 % had held major leadership positions. At 11 or more years after graduation, 33 % of the female graduates in academics had been promoted to the rank of associate professor and 33 % to the rank of full professor. CONCLUSIONS: The VAWHF Program has been successful in training academic leaders in women's health. Finding ways to retain graduates in the VA system would ensure continued clinical, educational, and research success for the VA women veteran's healthcare program. PMID- 23435767 TI - Coming home from war. AB - Many American military personnel who served in the Iraq and Afghanistan wars will need long-term management of war-related conditions. There is pressing need for expertise in veterans' care outside of the Military Health System (MHS) and Department of Veterans Affairs (VA), as many will seek care elsewhere: Veterans receive free MHS care only while on active duty; enhanced eligibility for VA healthcare ends 5 years after military discharge; many veterans eligible for VA healthcare use non-VA services instead; and the Affordable Care Act will expand Medicaid coverage for uninsured veterans. Families of veterans also may need care for conditions related to war service. Most medical schools lack veteran-focused curricula beyond VA clerkships, which often do not provide specific training on service-related conditions. The VA, Department of Defense (DoD), veterans groups, and medical professional organizations should partner to develop technical competencies in veteran and family health care for clinicians at all career stages, and cultural competencies to ensure contextually appropriate care. National and state licensing boards should assess these competencies formally. Partnerships between VA, DoD, and the community for care delivery can improve transitions and the quality of veterans' post-deployment care. PMID- 23435768 TI - Nonmalignant superior vena cava syndrome. PMID- 23435769 TI - Five visits. PMID- 23435770 TI - Under the sheets. PMID- 23435772 TI - The clinical breast exam: a skill that should not be abandoned. AB - The clinical breast exam (CBE) is an important tool in the care of women. However, the utility of the screening CBE has been called into question. This article discusses the importance of the CBE as a physical diagnosis tool. Recommendations regarding screening with CBE are reviewed, and evidence surrounding breast cancer screening using CBE is briefly summarized. Clinicians should strive to provide high quality CBEs as part of the general clinical exam for women, particularly those who present with breast complaints, and for patients who choose to have CBE screening. In conclusion, there is a role for the CBE in the care of women, and clinicians should be proficient at performing these exams. Simulation teaching technologies are now available at Department of Veteran Affairs (VA) facilities to enable clinicians to improve their CBE skills. PMID- 23435773 TI - Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis. AB - Thrombotic microangiopathies (TMAs) can be due to inherited or acquired ADAMTS13 deficiency. Acquired deficiency is mainly associated with autoantibodies directed to ADAMTS13, including drug-induced forms. A few cases of TMA have been reported in association with interferon-alpha treatment and more rarely with interferon beta. We report the case of a 52-year-old male with TMA-associated severe renal failure secondary to severe ADAMTS13 deficiency due to an anti-ADAMTS13 IgG antibody which developed after interferon-beta treatment for multiple sclerosis. Treatment included interferon-beta discontinuation, immediate plasma exchange therapy, corticosteroids, and hemodialysis. After an initial hematologic improvement, early hemolysis relapse led us to introduce rituximab allowing durable hematologic recovery. This is the first reported case of interferon-beta induced TMA due to acquired ADAMTS13 deficiency that was treated by rituximab. PMID- 23435774 TI - Isolated primary renal echinococcosis: a rare entity. AB - Primary renal echinococcosis, a rare entity in diseases involving the kidney, accounts for 2-3 % of all cases. We present a case of 37-year-old female presenting with pain in the right iliac fossa. Radiologically, both ultrasound abdomen and CECT diagnosed as hydatid cyst, mild to moderate hydronephrosis, proximal hydroureterosis, and a possibility of rupturing into the pelvicalyceal system. Renal sparing surgery is the treatment of choice in most cases (75 %) with nephrectomy being reserved for non-functioning kidney as in our case. Histopathological examination of the nephrectomy specimen confirmed the diagnosis. PMID- 23435775 TI - Alcohol is not a risk factor for oral cancer in nonsmoking, betel quid non chewing individuals. A meta-analysis update. AB - BACKGROUND: Alcohol drinking is associated with high oral cancer (OC) risk. This association is particularly evident in tobacco smoking/betel quid (BQ) chewing subjects. In a previous stratified meta-analysis (Petti S et al., Cancer Epidemiol 2012) we reported that drinking was inversely associated with OC in non smoking BQ non-chewing individuals, while this association was reversed in smoking individuals. However, the previous study could be excessively influenced by a large primary study, which yielded more than 50% of the weight of all the primary studies. Therefore, we updated this analysis using only recent studies. METHODS: Case-control studies published between 2010 and 2012 were searched. In each study, non-smoking/ BQ non-chewing exposed (ever routine drinkers) and unexposed (never drinkers) subjects with (cases)/without (controls) OC were extracted and odds ratio (OR) calculated. Between-study heterogeneity was assessed with Cochran's Q. Publication bias was formally assessed with trim and fill method. Sensitivity analysis to inclusion criteria was made. The pooled OR was assessed with the fixed- and random-effect methods and corrected for publication bias. RESULTS: Seven of these studies met the inclusion criteria: they were not heterogeneous enough. Correction for publication bias was not necessary and provided only one missing study. The OR estimates were 0.70 (95% confidence interval -95CI, 0.51-0.98), 0.70 (95CI, 0.51-0.96), 0.75 (95CI, 0.54 1.03) with the three methods. Sensitivity analysis did not change the OR estimates considerably. CONCLUSIONS: This analysis corroborated the results of the previous analysis, confirming that drinking was inversely associated with OC in non-smoking, BQ non-chewing subjects. PMID- 23435776 TI - Proactive evaluation of clinical risk: a FMECA analysis in pediatric chemotherapy. AB - In 2010-2011, we used FMECA to prospectively assess risk-management in chemotherapy of children with cancer, in a third level Italian children's Hospital (Ospedale Pediatrico Bambino Gesu; OPBG). We designed a flow chart representing the entire process; we described potential failure points for each step of the process, as well as their potential underlying causes. We calculated the risk priority number (RPN) of each failure point based on the severity of the failure, the frequency of occurrence, and the likelihood of detecting the failure prior to completion of the process. All FMECA activities were supported by a web based tool. The highest RPN values were observed for failure points of the paper based chemotherapy medication orders sent from clinicians to Pharmacy, the transcription of the orders into the Pharmacy paper-based work-sheet for medication preparation, and the selection of medications to be used for chemotherapy preparation. Causes of these failures were mostly related to illegible or incomplete handwriting. As a consequence of these results, the implementation of an electronic ordering process for children's chemotherapy medications was proposed as risk-reducing action. PMID- 23435777 TI - Evaluation of some cardiovascular risk parameters in health professionals exposed to night work. AB - BACKGROUND: Shift work and night work in particular represent a risk factor for the health of exposed workers; aim of our study is to evaluate whether night work may cause alteration of some cardiovascular risk parameters in health workers. MATERIALS AND METHODS: The research was carried out on 415 health workers, 163 exposed to night work and 252 not exposed. A blood sample was taken from each worker, between 8.00 a.m. and 10.00 a.m. before lunch time, to test total cholesterol, HDL cholesterol, and triglycerides. Blood pressure and heart rate were also measured. Workers with cardiovascular diseases, thyroid diseases, diabetes mellitus, dyslipidemia, those who made use of antihypertensive drugs, hypoglycemic and/or lipid-lowering drugs, subjects with body mass index (BMI) (kg/m2) higher than 30 were excluded. RESULTS: In the group of exposed compared to controls, increasing values of arterial pressure and heart rate, were not significant. The mean values of total cholesterol and triglycerides were significantly higher in exposed compared to controls while values of HDL cholesterol were significantly lower. CONCLUSIONS: Night workers have clinically significant changes in blood levels of total cholesterol, HDL cholesterol and triglycerides, such alterations are presumably related to poor food hygiene and to psychosocial stressors. PMID- 23435778 TI - Analytical techniques to study microbial biofilm on abiotic surfaces: pros and cons of the main techniques currently in use. AB - Biofilm is a bacterial lifestyle widespread in microbial world and represents a concern in health care. Despite the great life expectancy related to advanced health care, the increasing numbers of biofilm-mediated infections remain a significant public health challenge. Moreover, the problem of biofilm-mediated infections becomes much more severe when biofilm colonizes medical devices and biomaterials. The public health risk due to microbial biofilm-related infections is a concern that requires full attention. However, the complexity of biofilm makes difficult its exhaustive analysis. Although biofilm represents a major challenge in both microbiological and hygiene areas, at now methods aimed to analyse biofilm formation and development are not standardized yet. Different methods have been employed to qualitatively and quantitatively evaluate biofilm each of which is useful to estimate a peculiar aspect of biofilm lifestyle. In the present review, fifteen assays for the qualitative and quantitative evaluation of bacterial biofilm colonizing abiotic substrates, such as medical devices, prosthesis or surfaces for food production together with advantages and limitations of each method were described and compared. Some methods are suited to quantify biofilm matrix while others are capable to evaluate both living and dead cells or quantify exclusively viable cells in biofilm. In particular, colorimetric methods to evaluate biofilm matrix (crystal violet; 1,9-dimethyl methylen blue and fluorescein-di-acetate methods) or viable cells (LIVE/DEAD BacLight, BioTimer Assay, resazurin, tetrazolium hydroxide salt methods) and genetic methods to estimate the bacterial population (PCR and FISH) are reported. Moreover, a section is dedicated to examine the performances of advanced microscopic techniques employed to study microbial biofilms (mass spectrometry; confocal laser scanning microscopy; Raman spectroscopy and electron microscopy). Because of its complexity, an exhaustive study of biofilm requires a combination of different experimental approaches as biochemical, genetic or physical ones. PMID- 23435779 TI - [A full economic evaluation of extensive vaccination against rotavirus with RIX4414 vaccine at National and Regional level in Italy]. AB - Vaccination of all healthy children against rotavirus (RV) has been recommended, since the availability of vaccines, both in Europe (PIDJ) and Italy (pediatricians). The aims of universal vaccination against RV include the protection of children against moderate/severe gastroenteritis forms by RV (GARV), prevent hospitalizations, reduce the severity and duration of the disease, and reduce morbidity and socioeconomic costs. Payers need to informed regarding the efficacy and the healthcare utilization related to RV vaccination in order to decide in favour of its extensive implementation. The aim of this paper is to assess the clinical and financial impact of the extensive vaccination aganist RV both at National and Regional level. Particular attention, compared to the previous analysis (Standaert et al, 2008) has been given to the influence of herd immunity (HI) on cost-utility results of vaccination against-RV. Methods. The analysis was conducted with the Markovian model previously used by Standaert B et al and updated for comparing costs and benefits associated with a situation of vaccination anti-RV that includes efficacy data due to HI, with a situation without vaccination. For the base case is assumed an annual coverage of 90%, where the effect of HI is present in the population at risk (0-5 years) and extended to children who have not been vaccinated, adding as conservative assumption, a further 10% to the efficacy of the vaccine, compared to 15% determined by several published studies. Two analysis have been made based on this model: a cost-utility analysis that compared vaccination with two doses of RIX441410 administered at 2 and 3 months after birth compared with no vaccination from National Health Service and Society perspective; a budget impact analysis at National and Regional level. The evaluation has as its main element the reduction of cases of infection through universal vaccination and consequent reduction of Garv events and nosocomial infections. Results. From the NHS perspective, in a cohort of 555,791 born in Italy in 2011, the annual number of hospitalizations due to RV infections in the absence of vaccination is estimated to be 14,550 units. Assuming that 90% of newborns receive two doses of the vaccine, and including an additional effect of HI to the efficacy of the vaccine, vaccination would lead to a reduction of 71% of cases of Garv (176,804 cases in less) and a 86% of hospitalizations due to Garv (12,913 fewer cases), with an impact on quality of life and mortality as a consequence of vaccination. The introduction of the vaccine would lead to a gain of 0.0014 QALYs and 0.0022 life-years gained per child compared to a situation without vaccination (assuming a discount rate of 3% on future benefits). The reduction of GARV also would lead to a strong economic impact. The introduction of the vaccine would lead to a saving of ? 25.41 per child or a saving of more than ? 14 million for the whole population included in the analysis. Cost reduction increase significantly from the perspective of society and introducing the indirect costs due to lost productivity. In this case, the savings due to the introduction of vaccination would increase to ? 67,747,654 in the total cohort, or ? 121.89 per child. In an alternative scenario, where HI is excluded, RIX4414 remains dominant (0.0013 QALYs gained and ? 22.14 per child saved). The budget impact analysis shows that, as early as the second year, the additional cost of the vaccine is more than offset by a reduction in costs of the disease, which leads to savings for the NHS, which increases from year 3. In a time horizon of 5 years (without the discount rate), the savings for the NHS amount to ? 34,440,314. These savings would amount to a cost reduction of ? 4.64 per child over 5 years (? 0.93 per year). The savings due to the introduction of the vaccine were mainly due to a reduction in costs associated with hospitalizations. The budget impact analysis at regional level, has taken a vaccine cost of ? 30.00 per dose. Cases of diarrhoea before after vaccination are reduced in each region, based on the number of births, ranging from a minimum of 399 cases avoided for Valle d'Aosta to a maximum of 31,116 cases avoided in Lombardy. In a similar way, the number of hospitalizations due to GARV are reduced considerably, from a minimum of 36 cases in Valle d'Aosta to a maximum of 3,096 in Lombardy. Obviously, these reductions are greater in regions with 30,000 or more births per year. Conclusions. This study suggests that a universal vaccination anti-RV with 2 doses of RIX4414 brings significant clinical and economic benefits both at National and Regional level. The indirect effects of the vaccine (HI) could generate protection even in unvaccinated children with health gain and a number of cases by GARV much less than those that would vaccinating small groups of children and with a cost of illness, for NHS, which would be reduced significantly, despite the additional costs of the vaccine as early as the second year of vaccination. Productivity losses due to absence from work of a parent, as well as all other costs included in the model, show that is precisely the society to pay the consequences, from economic and social point of view. Considering the citizen in the role of private payer, we must stress as for him, the savings generated by vaccination, whether universal or with demand for cost-sharing by the health service, prove significant with a major health gain for the population under study. PMID- 23435780 TI - Candidemia in Neurosurgical Intensive Care Unit: preliminary analysis of the effect of topical Nystatin prophylaxis and adequate source control on patients with early tracheostomy intubation. AB - INTRODUCTION: The present study represents a preliminary evaluation of the impact of topical nystatin prophylaxis administration and adequate CVC management on reducing the chance of developing candidemia in neurosurgical intensive care unit (NICU) patients. MATERIALS AND METHODS: We conducted a case-control study at the nine bed NICU of the Policlinico "Umberto I" teaching hospital in Rome, Italy, during the period from January 2011 to July 2012. We compared eight patients with culture proven Candida bloodstream infection (CBSI) with a control group of 19 patients who did not have evidence of CBSI. RESULTS: When the CBSI group was compared with the control group, the former were more likely than controls to not have received nystatin prophylaxis and adequate catheter care (p= 0,008). When CBSI group was matched with patients with no adequate source control and nystatin prophylaxis, average NICU stay (71.13 days vs 19.0 days) was significant (mean difference = -52.12 days, 95% CI -97.11 to -7.14, p= 0.028). The same was true for mean time of glucocorticoid exposure (mean difference = -10.5 days, 95% CI 17.35 to -3.65, p<0.01). Binary logistic regression analysis demonstrated no significant association between topical nystatin prophylaxis (p= 0.99), length of NICU stay (p= 0.99), time of glucocorticoid exposure (p= 0.99) and candidemia. CONCLUSION: Topical prophylaxis with nystatin and adequate source control proved to be effective in preventing invasive candidiasis in patients admitted to the NICU. PMID- 23435781 TI - [The surveillance of Candida spp. infections related to health care in the Neonatal Intensive Care of University Hospital Federico II of Naples, Italy]. AB - BACKGROUND: In neonatal intensive care unit (NICU) invasive fungal infections are predominantly supported by Candida species, with an increasing frequency of C. non-albicans. This work aims to demonstrate the need for monitoring of these infections for the purposes of a more effective prevention strategy. METHODS: This study, conducted for 15 months on 365 patients admitted to the NICU of the University Hospital "Federico II" of Naples, examines the colonization and nosocomial infections by Candida species in relation to the most significant risk factors such as prematurity, low birth weight and the application of relief devices. RESULTS: It was detected a statistically significant association between infections and pharyngeal colonization (p = 0.002), gestational age <28 weeks (p = 0.001) and central venous catheterization (p = 0.01). 12% of the 336 patients cared for more than 48 hours had pharyngeal colonization by Candida spp, especially C. albicans, while 2% develops sepsis due to C. parapsilosis. CONCLUSIONS: The results demonstrate the importance and validity of the procedures used for the surveillance of infections in NICU. PMID- 23435782 TI - Prevalence survey of healthcare-associated infections in the University Hospital Federico II of Naples, Italy. AB - BACKGROUND: Healthcare Associated Infections (HAI) are the most serious complication associated with health care. They cause diseases for patients and economic damage for Public Health. A prevalence survey at the University Hospital "Federico II" of Naples was conducted according to ECDC criteria in order to analyze the infectious phenomenon of healthcare assistance and assess possible correlations with risk factors as healthcare procedure and clinical condition of patients. METHODS: Were enrolled 450 patients. The collected data were then analyzed using univariate and multivariable logistic regression. RESULTS: It was found a prevalence rate of infections of 9.3%, with a prevalence rate of HAI of 4.4%. Statistical analysis showed correlation between HAI and ultimately-fatal disease (P <0.04) and between HAI and the use of invasive devices as CVC (P<0.005), PVC (P<0.004) and intubation (P<0.01). CONCLUSIONS: The epidemiological surveillance strategies are part of preventive measures and monitoring of the HAI, implemented to ensure safety and quality of care. PMID- 23435783 TI - Emergence and re-emergence of zoonoses. Context and consequences. AB - Zoonoses have been and are still considered merely a "veterinary problem". Instead, the understanding of their emergence, re-emergence and persistence is more effectively addressed in the context of a "struggle" between pathogens, animals and man. The expression properties of pathogens are related with three interfaces: human-environment, environment-animal and human-animal. Animals and man can be either reservoirs or vectors of pathogens, while interfaces can amplify the clinical impact in all the species involved. The disease course is similar in animals and humans in terms of infection, clinical approach and control. Thus, this "epidemiological model" may be the key to an "updated" interpretation of infectious diseases involving humans and animals. Control and prevention should be carried out in an interdisciplinary context, without separating the medical and veterinary domains, in light of the fact that the activity of pathogenic microorganisms is not species-dependent. Finally, if human public health and veterinary public health are closely linked, knowledge and information can be pooled and used for mutual benefit. PMID- 23435784 TI - Role of endogenous IL-6 in the neonatal expansion and functionality of Wistar rat pancreatic alpha cells. AB - AIMS/HYPOTHESIS: Plasma glucagon concentrations rise sharply during the early postnatal period. This condition is associated with increased alpha cell mass. However, the trophic factors that regulate alpha cell turnover during the perinatal period have not been studied. Macrophage infiltrations are present in the neonatal pancreas, and this cell type releases cytokines such as IL-6. Alpha cells have been identified as a primary target of IL-6 actions. We therefore investigated the physiological relevance of IL-6 to neonatal pancreatic alpha cell maturation. METHODS: Histochemical analyses were performed to quantify alpha cell mass, replication and apoptosis. Pancreatic Il6 expression was determined by quantitative RT-PCR. The biological effect of IL-6 was tested in two in vivo rat models of IL-6 blockade and chronic undernutrition. RESULTS: Alpha cell mass increased sharply shortly after birth but decreased significantly after weaning. Pancreatic alpha cell proliferation was as high as 2.5% at the beginning of suckling but diminished with time to 1.2% in adulthood. Similarly, alpha cell neoformation was remarkably high on postnatal day (PN) 4, whereas alpha cell apoptosis was low throughout the neonatal period. Moreover, Il6 mRNA exhibited developmental upregulation in the pancreas of suckling rats, with the highest expression on PN2. Neutralisation of IL-6 reduced alpha cell mass expansion and glucagon production. IL-6 staining was detected within the islets, mainly in the alpha cells. Finally, undernourished neonates showed altered alpha cell number and function and delayed appearance of IL-6 in the pancreas. CONCLUSIONS/INTERPRETATION: These data point to a potential role for local IL-6 in the regulation of alpha cell growth and function during suckling. PMID- 23435785 TI - Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro. AB - AIMS/HYPOTHESIS: In steroid diabetes insulin secretion does not adequately compensate for enhanced hepatic gluconeogenesis and peripheral insulin resistance. Previous studies suggest that activation of the transcription factor forkhead box O1 (FOXO1) contributes to glucocorticoid-induced beta cell death. This study examines the role and regulation of FOXO1 in insulin-secreting cells. METHODS: INS-1E cells and mouse islet cells were cultured in the presence of dexamethasone. Signalling pathways were modified pharmacologically or by small interfering (si)RNA-mediated inhibition of protein synthesis. Changes in protein abundance and phosphorylation were analysed by western blotting, and subcellular localisation was assessed using confocal microscopy. Transcript levels were examined by RT-PCR. RESULTS: Surprisingly, downregulation of FOXO1 by siRNA did not affect dexamethasone-induced apoptosis or Bim expression, but it prevented the effects of the pan protein kinase B (AKT) inhibitor (Akti-1/2). Indeed, dexamethasone and Akti-1/2 synergistically increased beta cell death and Bim expression. Akti-1/2 triggered dephosphorylation and nuclear translocation of FOXO1. Glucocorticoid-receptor activation stimulated Foxo1 transcription, but FOXO1 phosphorylation was unchanged and the cytosolic concentration of FOXO1 remained high in relation to its nuclear concentration. However, subcellular fractionation revealed a significant increase in both cytosolic and nuclear FOXO1 compared with untreated cells. Dexamethasone diminished Pdx1 mRNA level, an effect which was not reversed by siRNA against Foxo1. Downregulation of AKT isoforms and serum/glucocorticoid-regulated kinase 1 (SGK1) suggests that only sustained suppression of all three AKT isoforms caused dephosphorylation and nuclear accumulation of FOXO1. CONCLUSIONS/INTERPRETATION: This study reveals that FOXO1 is not the main mediator of glucocorticoid-receptor-induced beta cell apoptosis, but rather that it escalates beta cell death when AKT activity is inhibited by distinct pathways. PMID- 23435786 TI - Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AB - In the kidney, human organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are the major transporters for the secretion of cationic drugs into the urine. In the human kidney, OCT2 mediates the uptake of drugs from the blood at the basolateral membrane of tubular epithelial cells, and MATE1 and MATE2-K secrete drugs from cells into the lumen of proximal tubules. However, the expression of these transporters depends on the species of the animal. In the rodent kidney, OCT1 and OCT2 are expressed at the basolateral membrane, and MATE1 localizes at the brush-border membrane. Together, these transporters recognize various compounds and have overlapping, but somewhat different, substrate specificities. OCTs and MATEs can transport important drugs, such as metformin and cisplatin. Therefore, functional variation in OCTs and MATEs, including genetic polymorphisms or inter-individual variation, may seriously affect the pharmacokinetics and/or pharmacodynamics of cationic drugs. In this review, we summarize the recent findings and clinical importance of these transporters. PMID- 23435787 TI - The pronator quadratus muscle after plating of distal radius fractures: is the muscle still working? AB - The purpose of this study is to define the function of the pronator quadratus muscle after plating of a distal radius fracture using anterior (volar) approach. Fourteen cases with volar plating after for a distal radius fracture were included in the study. Sixteen healthy volunteers were selected to determine the effect of dominant arm on pronation torque of the forearm for the control group. Biodex System 4 PRO (Biodex Medical Systems Inc., New York) torque meter was used for pronation torque measurement. In healthy volunteer group, there was no statistically significant difference in mean pronation torque values between the dominant arm and nondominant arms. The mean loss of pronator strength was 18.5 % and the mean loss of pronator durability was 12.9 % indicating a pronator insufficiency in the cases operated by a volar approach compared to uninjured forearm. Two patients among the operated group, who had further strengthening exercises beyond their own rehabilitation regimes, had improved pronator torque compared to uninjured forearm. In conclusion, the results of this study indicate that following volar plating of distal radius fractures, there is a significant loss in pronator strength of the forearm. As the two of the patients had improved pronator strength of their operated forearm, further rehabilitation regimes should be considered to prevent pronator weakness following volar plating for distal radius fractures. PMID- 23435788 TI - Porcine bioprosthetic valve in the pulmonary position: mid-term results in the right ventricular outflow tract reconstruction. AB - Pulmonary valve replacement (PVR) for pulmonary valve insufficiency (PVI) currently represents the most frequent reoperation performed for adults with congenital heart disease. A variety of pulmonary valve substitutes have been used, but none has proved to be ideal. This report reviews the authors' experience using a porcine prosthetic valve in the pulmonary position. Between January 2001 and December 2011, 76 patients (mean age, 36 years; range, 18-64 years) underwent PVR for chronic PVI using a porcine bioprosthesis. All the patients had previously undergone surgery: 65 for repair of tetralogy of Fallot and 11 for pulmonary surgical valvotomy. Magnetic resonance imaging (MRI) evaluations before surgery and at the 1-year postoperative follow-up evaluation were compared. Aside from the PVR, 59 patients (59/65, 78 %) received 94 associated cardiac surgical procedures. Two hospital deaths occurred. The mean hospital stay was 13 days (range, 7-48 days). At the 1-year control MRI, pulmonary regurgitation fraction, right ventricular end diastolic volume (RVEDV), and RV/LV EDV had improved significantly. During a mean follow-up period of 52 months (range, 6-132 months), one patient died. All the patients were categorized as New York heart association (NYHA) functional class 1. No episodes of structural valve deterioration, endocarditis, or thromboembolic event were noted. Echocardiography showed trivial or no PVI in all the patients. The porcine bioprosthetic valves demonstrated excellent midterm results in the RV outflow tract reconstruction. The hemodynamic characteristics of this valve are comparable with those of homografts or valved conduits. It is easy to implant and allows for avoiding extensive dissection, especially of the pulmonary arteries. PMID- 23435789 TI - Dexmedetomidine: antiarrhythmic effects in the pediatric cardiac patient. AB - This report aims to provide a general description of the cardiovascular effects of dexmedetomidine, emphasizing its effects on conduction, and to give an evidence-based review of the literature regarding the use of dexmedetomidine to treat and prevent tachyarrhythmias in infants and children. A computerized bibliographic search of the literature on the use of dexmedetomidine to treat and prevent arrhythmias in infants and children was conducted. The cardiovascular effects of dexmedetomidine have been well studied in animal and adult human models. Growing experience, mostly in the pediatric population, has demonstrated the potential therapeutic applications of dexmedetomidine in the acute treatment of arrhythmias. Additionally, its use during cardiac surgery has been associated with a decreased incidence of postoperative ventricular and supraventricular tachyarrhythmias. Although dexmedetomidine is not currently approved by the Food and Drug Administration for the pediatric population, findings have shown it to be effective in various clinical scenarios for sedation. In addition, recent studies show that dexmedetomidine may have promising properties for the acute treatment and prevention of tachyarrhythmias. PMID- 23435791 TI - A vinylcyclobutane substrate designed as a cyclopropylcarbinyl radical probe. AB - Appending a spirocyclopropane linkage to bicyclo[3.2.0]hept-2-ene is achieved by selective kinetic cyclopropanation of 6-methylenebicyclo[3.2.0]hept-2-ene. The resultant vinylcyclobutane undergoes [1,3] migration as the dominant thermal process. A minor cyclopropylcarbinyl (CPC) rearrangement product clearly implicates a diradical transition structure. The presence and absence of other potential thermal products have enabled us to construct a detailed mechanistic proposal to account for all viable dynamic processes. PMID- 23435790 TI - EpiHealth: a large population-based cohort study for investigation of gene lifestyle interactions in the pathogenesis of common diseases. AB - The most common diseases affecting middle-aged and elderly subjects in industrialized countries are multigenetic and lifestyle related. Several attempts have been made to study interactions between genes and lifestyle factors, but most such studies lack the power to examine interactions between several genes and several lifestyle components. The primary objective of the EpiHealth cohort study is to provide a resource to study interactions between several genotypes and lifestyle factors in a large cohort (the aim is 300,000 individuals) derived from the Swedish population in the age range of 45-75 years regarding development of common degenerative disorders, such as cardiovascular diseases, cancer, dementia, joint pain, obstructive lung disease, depression, and osteoporotic fractures. The study consists of three parts. First, a collection of data on lifestyle factors by self-assessment using an internet-based questionnaire. Second, a visit to a test center where blood samples are collected and physiological parameters recorded. Third, the sample is followed for occurrence of outcomes using nationwide medical registers. This overview presents the study design and some baseline characteristics from the first year of data collection in the EpiHealth study. PMID- 23435792 TI - Daytime pulse oximetry measurements may not predict nocturnal desaturations in adult sickle cell patients. PMID- 23435793 TI - What intervention is best practice for vestibular schwannomas? A systematic review of controlled studies. AB - OBJECTIVE: Largely, watchful waiting is the initial policy for patients with small-sized or medium-sized vestibular schwannoma, because of slow growth and relatively minor complaints, that do not improve by an intervention. If intervention (microsurgery, radiosurgery or fractionated radiotherapy) becomes necessary, the choice of intervention appears to be driven by the patient's or clinician's preference rather than by evidence based. This study addresses the existing evidence based on controlled studies of these interventions. DESIGN: A systematic Boolean search was performed focused on controlled intervention studies. The quality of the retrieved studies was assessed based on the Sign-50 criteria on cohort studies. DATA SOURCES: Pubmed/Medline, Embase, Cochrane Central Register of Controlled Trials and reference lists. STUDY SELECTION: Six eligibility criteria included a controlled intervention study on a newly diagnosed solitary, vestibular schwannoma reporting on clinical outcomes. Two prospective and four retrospective observational, controlled studies published before November 2011 were selected. DATA ANALYSIS: Two reviewers independently assessed the methodological quality of the studies and extracted the outcome data using predefined formats. RESULTS: Neither randomised studies, nor controlled studies on fractionated radiotherapy were retrieved. Six studies compared radiosurgery and microsurgery in a controlled way. All but one were confined to solitary tumours less than 30 mm in diameter and had no earlier interventions. Four studies qualified for trustworthy conclusions. Among all four, radiosurgery showed the best outcomes: there were no direct mortality, no surgical or anaesthesiological complications, but better facial nerve outcome, better preservation of useful hearing and better quality of life. CONCLUSIONS: The available evidence indicates radiosurgery to be the best practice for solitary vestibular schwannomas up to 30 mm in cisternal diameter. PMID- 23435794 TI - Estimating the relative contribution of parasitic infections and nutrition for anaemia among school-aged children in Kenya: a subnational geostatistical analysis. AB - OBJECTIVES: To quantify geographical variation in the relative contribution of parasitic infections, socioeconomic factors and malnutrition in the aetiology of anaemia among schoolchildren across Kenya, thereby providing a rational basis for the targeting of an integrated school health package. DESIGN: Nationally representative cross-sectional survey data were collected using standard protocols. For all included children, data were recorded on haemoglobin (Hb) concentration and common parasitic infections (Plasmodium falciparum, hookworm and schistosomes) and socioeconomic indicators. Ecological proxies of malnutrition and food security were generated using Demographic and Health Survey and UN Food and Agriculture Organization food security data, respectively. Spatially explicit, multilevel models were used to quantify impact upon child Hb concentration. SETTING: Randomly selected schools in ecologically diverse settings across Kenya. MAIN OUTCOME MEASURES: Mean Hb concentration adjusted for infection, nutritional and socioeconomic risk factors; associated risk ratios and adjusted Population Attributable Fractions (PAFs) for anaemia, by region. RESULTS: Data were available for 16 941 children in 167 schools; mean Hb was 122.1 g/l and 35.3% of children were anaemic. In multivariate analysis, mean Hb was significantly lower in boys and younger children. Severe malnutrition and interactions between P falciparum and hookworm infections were significantly associated with lower Hb, with greater impacts seen for coinfected children. The contribution of risk factors to anaemia risk varied by province: in 14-year-old girls, PAFs ranged between 0% and 27.6% for P falciparum, 0% and 29% for hookworm and 0% and 18.4% for severe malnutrition. CONCLUSIONS: The observed geographical heterogeneity in the burden of anaemia attributable to different aetiological factors has important implications for the rational targeting of antianaemia interventions that can be included in an integrated school health programme. PMID- 23435795 TI - Design and baseline characteristics of the PODOSA (Prevention of Diabetes & Obesity in South Asians) trial: a cluster, randomised lifestyle intervention in Indian and Pakistani adults with impaired glycaemia at high risk of developing type 2 diabetes. AB - OBJECTIVES: To describe the design and baseline population characteristics of an adapted lifestyle intervention trial aimed at reducing weight and increasing physical activity in people of Indian and Pakistani origin at high risk of developing type 2 diabetes. DESIGN: Cluster, randomised controlled trial. SETTING: Community-based in Edinburgh and Glasgow, Scotland, UK. PARTICIPANTS: 156 families, comprising 171 people with impaired glycaemia, and waist sizes >=90 cm (men) and >=80 cm (women), plus 124 family volunteers. INTERVENTIONS: Families were randomised into either an intensive intervention of 15 dietitian visits providing lifestyle advice, or a light (control) intervention of four visits, over a period of 3 years. OUTCOME MEASURES: The primary outcome is a change in mean weight between baseline and 3 years. Secondary outcomes are changes in waist, hip, body mass index, plasma blood glucose and physical activity. The cost of the intervention will be measured. Qualitative work will seek to understand factors that motivated participation and retention in the trial and families' experience of adhering to the interventions. RESULTS: Between July 2007 and October 2009, 171 people with impaired glycaemia, along with 124 family volunteers, were randomised. In total, 95% (171/196) of eligible participants agreed to proceed to the 3-year trial. Only 13 of the 156 families contained more than one recruit with impaired glycaemia. We have recruited sufficient participants to undertake an adequately powered trial to detect a mean difference in weight of 2.5 kg between the intensive and light intervention groups at the 5% significance level. Over half the families include family volunteers. The main participants have a mean age of 52 years and 64% are women. CONCLUSIONS: Prevention of Diabetes & Obesity in South Asians (PODOSA) is one of the first community-based, randomised lifestyle intervention trials in a UK South Asian population. The main trial results will be submitted for publication during 2013. TRIAL REGISTRATION: Current controlled trials ISRCTN25729565 (http://www.controlled-trials.com/isrctn/). PMID- 23435796 TI - The Needs and Provision Complexity Scale: a multicentre prospective cohort analysis of met and unmet needs and their cost implications for patients with complex neurological disability. AB - OBJECTIVE: To provide a brief overview of the Needs and Provision Complexity Scale (NPCS) and report its first application to describe the level of 'met' and 'unmet' health/social care needs, and to estimate their costs in community-based patients with complex neurological disability. DESIGN: A multicentre prospective cohort analysis. SETTING: Consecutive discharges to the community from the nine tertiary specialist inpatient neurorehabilitation units in London over 12 months (2010/2011). PARTICIPANTS: Patients responding at follow-up (n=211). Mean age 50.2(SD14) years, males:females 127/84. Diagnosis 157(74%) brain injury, 27(13%) spinal cord injury/peripheral neuropathy; 27(13%) other. PRIMARY OUTCOME MEASURE: The NPCS is a brief, pragmatic, directly costable instrument for measuring both an individual's needs for rehabilitation and support (NPCS-Needs) and the levels of service provided (NPCS-Gets) within a given period. METHODS: The 'NPCS-Needs' was completed by the treating clinical team at discharge. Patients and/or their carers self-reported 'NPCS-Gets' after 6 months by a postal/online questionnaire supported by a follow-up telephone interview. RESULTS: Needs for medical/nursing care and accommodation were generally well met. Significant shortfalls in provision were identified in the subscales of Rehabilitation (paired t test: t 9.7, p<0.001, effect size (ES)=-0.85), Social support (t -5.8, p<0.001, ES=-0.48) and Equipment (t -5.6, p<0.001, ES=-0.44). Item-level analysis demonstrated that the frequency of Personal care received exceeded predicted needs (Wilcoxon z= 3.3, p<0.001). In 80% of cases, this care was provided/paid for by families. Translated into mean costs/patient/year, the estimated underspends on Rehabilitation (-L2320) and Social support (-L1790) were exceeded >3.5-fold by excess costs of Personal care (L10 313) and Accommodation (L4296). CONCLUSIONS: The results identify underprovision of community-based rehabilitation and support services compared with needs, which may contribute directly to excess care burden and costs to family carers. The NPCS requires further evaluation but has potential use as a simple, directly costable tool to inform both clinical decision-making and population-based service planning and delivery. PMID- 23435797 TI - Neurological assessment of preterm infants for predicting neuromotor status at 2 years: results from the LIFT cohort. AB - OBJECTIVE: To develop a predictive risk stratification model for the identification of preterm infants at risk of 2-year suboptimal neuromotor status. DESIGN: Population-based observational study. SETTING: Regional preterm infant follow-up programme (Loire Infant Follow-up Team (LIFT) cohort) implemented in 2003. PARTICIPANTS: 4030 preterm infants were enrolled in the LIFT cohort, and examined by neonatologists using a modified version of the Amiel-Tison neurological assessment tool. MAIN OUTCOME CRITERIA: 2 year neuromotor status based on clinical examinations was conducted by trained paediatricians and parents' responses to the Ages and Stages Questionnaire were reported. RESULTS: At 2 years of corrected age, 3321 preterm infants were examined, and suboptimal neuromotor status was found in 355 (10.7%). The study population was divided into training and validation sets. In the training set, 13 neonatal neurological items were associated with a 2-year suboptimal neuromotor status. Having at least one abnormal item was defined as an abnormal neurological status at term. In the validation set, these data predicted a 2-year suboptimal neuromotor status with a sensitivity of 0.55 (95% CI 0.47 to 0.62) and a specificity of 0.65 (95% CI 0.62 to 0.67). Two predictive risk stratification trees were built using the training set, which were based on the neurological assessment at term along with either gestational age or severe cranial lesions or birth weight. Using the validation set, the first tree identified a subgroup with a relatively low risk of suboptimal neuromotor status (3%), representing 32% of infants, and the second tree identified a subgroup with a risk of 5%, representing 42% of infants. CONCLUSION: A normal neurological assessment at term allows the identification of a subgroup of preterm infants with a lower risk of non-optimal neuromotor development at 2 years. PMID- 23435798 TI - Diastasis of rectus abdominis in the immediate puerperium: correlation between imaging diagnosis and clinical examination. AB - AIM: Diastasis of rectus abdominis is a condition defined as a separation between this muscle and the linea alba, which leads to weakness in the abdominal muscles. Later, such weakness will influence the biomechanical posture causing back pain in women. In the present study, our aim was to assess the accuracy of clinical examination in measuring diastasis of rectus abdominis in the postpartum period. METHOD: Puerperal women (n=106) were selected for this study, including caesarean delivery (62 %) and vaginal delivery (38 %). Diastasis of rectus abdominis was measured in the postpartum period using clinical examination and ultrasonography, at four levels of the anterior sheath of the rectus abdominis, in the region above the umbilical scar. RESULTS: At each level of measurement, the results were statistically analyzed using the Student's t and Pearson tests (confidence interval 95 %), Bland-Altman plot, and Kappa test. The Student t test showed no significant difference between clinical examination and ultrasonography. The Pearson test showed correlation with positive coefficients; moderate correlation (r > 0.5) in the first levels (3, 6, and 9 cm) and a strong correlation (r > 0.75) in the last level (12 cm). In the Kappa test, 65 % of diagnoses given in the clinical examination were confirmed by ultrasonography. CONCLUSIONS: These results show a good agreement between both forms of examination, allowing clinical examination to be used in the diagnosis of rectus muscle diastasis, when ultrasonography is not available. PMID- 23435799 TI - Visual outcomes of topography-guided excimer laser surgery for treatment of patients with irregular astigmatism. AB - The aim of this study was to evaluate the efficacy, safety, and predictability of topography-guided treatments to enhance refractive status following other corneal surgical procedures. In a prospective case series study, 28 consecutive eyes of 26 patients with irregular astigmatism after radial keratotomy, corneal transplant, small hyperopic and myopic excimer laser optical zones, and corneal scars were operated. Laser-assisted in situ keratomileusis (LASIK) (n = 8) and photorefractive keratectomy (PRK) (n = 20) were performed using the ALLEGRETTO WAVE excimer laser and topography-guided customized ablation treatment software. Preoperative and postoperative uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), manifest and cycloplegic refraction, and corneal topography with asphericity were analyzed in 12 months follow-up. Uncorrected visual acuity (UCVA) changed from 0.2 +/- 0.2 or (20/100 +/- 20/100) to 0.51 +/- 0.31 or (20/40 +/- 20/60) in the LASIK group (P = 0.01) and from 0.34 +/- 0.16 or (20/60 +/- 20/120) to 0.5 +/- 0.23 or (20/40 +/- 20/80) in the PRK group (P = 0.01). Refractive cylinder decreased from -3.2 +/- 0.84 diopters (D) to -2.06 +/- 0.42 D in the LASIK group (P = 0.07) and from -2.25 +/- 0.39 D to -1.5 +/- 0.23 D in the PRK group (P = 0.008). Best corrected visual acuity did not change significantly in either group. Topography-guided treatment is effective in correcting the irregular astigmatism after refractive surgery. Topography-guided PRK can significantly reduce irregular astigmatism and increase the UCVA and BCVA. PMID- 23435800 TI - Facial biometrics of peri-oral changes in Crohn's disease. AB - Crohn's disease is a chronic relapsing and remitting inflammatory condition which affects any part of the gastrointestinal tract. In the oro-facial region, patients can present peri-oral swellings which results in severe facial disfigurement. To date, assessing the degree of facial changes and evaluation of treatment outcomes relies on clinical observation and semi-quantitative methods. In this paper, we describe the development of a robust and reproducible measurement strategy using 3-D facial biometrics to objectively quantify the extent and progression of oro-facial Crohn's disease. Using facial laser scanning, 32 serial images from 13 Crohn's patients attending the Oral Medicine clinic were acquired during relapse, remission, and post-treatment phases. Utilising theories of coordinate metrology, the facial images were subjected to registration, regions of interest identification, and reproducible repositioning prior to obtaining volume measurements. To quantify the changes in tissue volume, scan images from consecutive appointments were compared to the baseline (first scan image). Reproducibility test was performed to ascertain the degree of uncertainty in volume measurements. 3-D facial biometric imaging is a reliable method to identify and quantify peri-oral swelling in Crohn's patients. Comparison of facial scan images at different phases of the disease revealed precisely profile and volume changes. The volume measurements were highly reproducible as adjudged from the 1% standard deviation. 3-D facial biometrics measurements in Crohn's patients with oro-facial involvement offers a quick, robust, economical and objective approach for guided therapeutic intervention and routine assessment of treatment efficacy on the clinic. PMID- 23435801 TI - The effect of a single session of short duration biofeedback-induced deep breathing on measures of heart rate variability during laboratory-induced cognitive stress: a pilot study. AB - This study examines the acute effect of heart rate variability (HRV) biofeedback on HRV measures during and immediately after biofeedback and during the following laboratory-induced stress. Eighteen healthy males exposed to work-related stress were randomised into an HRV biofeedback group (BIO) or a comparative group (COM). Subjects completed a modified Stroop task before (Stroop 1) and after (Stroop 2) the intervention. Both groups had similar physiological responses to stress in Stroop 1. In Stroop 2, the COM group responded similarly to the way they did to Stroop 1: respiratory frequency (RF) and heart rate (HR) increased, RMSSD and high frequency (HF) power decreased or had a tendency to decrease, while low frequency (LF) power showed no change. The BIO group responded differently in Stroop 2: while RF increased and LF power decreased, HR, RMSSD and HF power showed no change. In the BIO group, RMSSD was higher in Stroop 2 compared to Stroop 1. In conclusion, HRV biofeedback induced a short term carry-over effect during both the following rest period and laboratory-induced stress suggesting maintained HF vagal modulation in the BIO group after the intervention, and maintained LF vagal modulation in the COM group. PMID- 23435804 TI - Ultrafast dynamics of the ns (n = 3,4) and 3d Rydberg states of O2. AB - The ultrafast dynamics of the lowest optically accessible Rydberg states of molecular oxygen (O2) has been studied by time resolved transient ionization. The process was triggered by the absorption of two pump photons in the 304 nm-220 nm range which corresponds to an energy range of 8.2 eV-11.3 eV, and probed by ionization with photons at 800 nm. From the analysis of the experimental data different time constants ranging from a few femtoseconds to hundreds of picoseconds were found. The identification of the states responsible for the measured lifetimes revealed important facts about the dynamics of the Rydberg states in this energy range, underlying the importance of the coupling between Rydberg and valence states in the relaxation mechanisms of the molecule. PMID- 23435803 TI - IgM monoclonal gammopathy in gastric MALToma. PMID- 23435805 TI - Hydrogen-bond-driven 'homogeneous intercalation' for rapid, reversible, and ultra precise actuation of layered clay nanosheets. AB - The use of hydrogen bonds permits a fluidic motion of differently sized alcohol molecules across the interlayer gap in LDH, which enables rapid and reversible tuning of interlayer spacing of the LDH at sub-Angstrom precision by changing the mole ratio of the different alcohols. PMID- 23435806 TI - Genetic susceptibility testing for chronic disease and intention for behavior change in healthy young adults. AB - Genetic testing for chronic disease susceptibility may motivate young adults for preventive behavior change. This nationally representative survey gave 521 young adults hypothetical scenarios of receiving genetic susceptibility results for heart disease, type 2 diabetes, and stroke and asked their (1) interest in such testing, (2) anticipated likelihood of improving diet and physical activity with high- and low-risk test results, and (3) readiness to make behavior change. Responses were analyzed by presence of established disease-risk factors. Respondents with high phenotypic diabetes risk reported increased likelihood of improving their diet and physical activity in response to high-risk results compared with those with low diabetes risk (odds ratio (OR), 1.82 (1.03, 3.21) for diet and OR, 2.64 (1.24, 5.64) for physical activity). In contrast, poor baseline diet (OR, 0.51 (0.27, 0.99)) and poor physical activity (OR, 0.53 (0.29, 0.99)) were associated with decreased likelihood of improving diet. Knowledge of genetic susceptibility may motivate young adults with higher personal diabetes risk for improvement in diet and exercise, but poor baseline behaviors are associated with decreased intention to make these changes. To be effective, genetic risk testing in young adults may need to be coupled with other strategies to enable behavior change. PMID- 23435807 TI - Real-time particle size analysis using focused beam reflectance measurement as a process analytical technology tool for a continuous granulation-drying-milling process. AB - Focused beam reflectance measurement (FBRM) was used as a process analytical technology tool to perform inline real-time particle size analysis of a proprietary granulation manufactured using a continuous twin-screw granulation drying-milling process. A significant relationship between D20, D50, and D80 length-weighted chord length and sieve particle size was observed with a p value of <0.0001 and R(2) of 0.886. A central composite response surface statistical design was used to evaluate the effect of granulator screw speed and Comil(r) impeller speed on the length-weighted chord length distribution (CLD) and particle size distribution (PSD) determined by FBRM and nested sieve analysis, respectively. The effect of granulator speed and mill speed on bulk density, tapped density, Compressibility Index, and Flowability Index were also investigated. An inline FBRM probe placed below the Comil-generated chord lengths and CLD data at designated times. The collection of the milled samples for sieve analysis and PSD evaluation were coordinated with the timing of the FBRM determinations. Both FBRM and sieve analysis resulted in similar bimodal distributions for all ten manufactured batches studied. Within the experimental space studied, the granulator screw speed (650-850 rpm) and Comil(r) impeller speed (1,000-2,000 rpm) did not have a significant effect on CLD, PSD, bulk density, tapped density, Compressibility Index, and Flowability Index (p value > 0.05). PMID- 23435808 TI - Mixed corticomedullary adrenal carcinoma. AB - Truly mixed corticomedullary tumors (MCMTs) are extremely rare and present as a single tumor mass composed of an intimately admixed population of both adrenal cortical cells and pheochromocytes. The current study describes the first case of a mixed corticomedullary adrenal carcinoma. In addition, we also review the published data on MCMTs to determine their clinical features, biochemical characteristics, pathological findings, and management. In order to compose this review, a search of the international literature for MCMTs was conducted. Fifteen related articles were found. The clinical and pathological information was obtained for all reported cases. MCMTs were found almost exclusively in females. In the vast majority of patients, the symptoms were related to the tumor's hormone hypersecretion. Hypertension and diabetes were present in 80 and 40 % of cases, respectively. Cushing's syndrome was reported in eight cases (53.33 %). A final diagnosis was made in all cases after surgery based on the pathological results. As of the writing of this article, all published cases of MCMTs had benign clinical behavior, with no instances of metastasis or death due to the tumor. MCMTs are currently considered to be benign tumors. Ours is the first case of malignant MCMT reported in the literature. The potential for malignancy should therefore be considered for these tumors. PMID- 23435809 TI - Photodynamic detection and management of intraperitoneal spreading of primary peritoneal papillary serous carcinoma in a man: report of a case. AB - As a peritoneal surface malignancy, primary peritoneal papillary serous carcinoma (PPPSC) almost always occurs in women. Our search of the literature found only two previous case reports of men with PPPSC, both with very short survival. We report the case of a 63-year-old man with PPPSC, treated effectively with cytoreductive surgery and docetaxel-based hyperthermic intraperitoneal chemotherapy following six cycles of docetaxel-based laparoscopic neoadjuvant intraperitoneal and cisplatin-based systemic chemotherapy. Furthermore, we detected intraoperative intraperitoneal spreading of the tumor after the oral administration of 5-amino levulinic acid (5-ALA). The patient remains in good health without ascites 18 months after his diagnosis. Thus, primary peritoneal papillary serous carcinoma should be managed by intraperitoneal chemotherapy combined with peritonectomy procedures. Moreover, the intraoperative detection of the intraperitoneal spreading of the tumor after administering oral 5-ALA shows that this is an exciting and promising diagnostic technique, which needs to be confirmed by further studies. PMID- 23435810 TI - Characterization of neuron-like cells derived from canine bone marrow stromal cells. AB - Regenerative therapy using bone marrow stromal cells (BMSCs) has begun to be clinically applied in humans and dogs for neurological disorders such as spinal cord injury. Under appropriate conditions in vitro, BMSCs differentiate into neuronal cells, which may improve the effects of regenerative therapy. In this study, we evaluated canine neuron-like cells (NLCs) derived from BMSCs. We speculated on their suitability for neuro-transplantation from the point of view of their morphological features, long-term viability, abundant availability, and ability to be subcultured. Canine NLCs were differentiated as follows: third passage BMSCs were maintained in pre-induction medium containing 2 mercaptoethanol and dimethylsulfoxide for 5 h, and then cells were transferred to neuronal induction medium containing fetal bovine serum, basic fibroblast growth factor, epidermal growth factor, dibutyryl cyclic AMP, and isobutylmethylxanthine for 7 or 14 days. Canine NLCs fulfilled the transplantation criteria and expressed markers of both immature neurons (nestin, 84.7 %) and mature neuronal cells (microtubule-associated protein-2, 95.7 %; betaIII-tubulin protein, 12.9 %; glial fibrillary acidic protein, 9.2 %). These results suggest that canine BMSCs can be induced to differentiate into neuronal cells and may be suitable for neuro transplantation. This study may provide information for improving cellular therapy for neurological diseases. PMID- 23435811 TI - Spatial and temporal occurrence of N-nitrosamines in seven drinking water supply systems. AB - The spatiotemporal presence of eight N-nitrosamines in the water of seven supply systems in Quebec considered to be susceptible to these emerging disinfection by products was evaluated. This is the first study on the presence of N-nitrosamines in drinking water utilities in Quebec. Seven sampling campaigns were carried out at several sampling points in each of the systems over a period of 1 year. The results show that N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), were not commonly detected in the water of the facilities under study (10 % of samples). The concentrations measured were lower than those reported in recent North American studies. None of the 195 samples taken exceeded the Ontario standard of 9 ng/L for NDMA (maximum value observed of 3.3 ng/L). N nitrosomethylethylamine and N-nitrosopiperidine were detected once, with concentrations of 3.7 and 6.0 ng/L, respectively. Chloramination was identified as being the main risk factor regarding the presence of N-nitrosamines, but water quality and some operating parameters, in particular disinfectant residual, also seem to be related to their presence. NDMA concentrations at the end of the distribution systems were generally higher than water leaving the plant. No seasonal trends were observed for the formation of N-nitrosamines in the investigated supply systems. Finally, an association between the presence of N nitrosamines and the levels of trihalomethanes and haloacetic acids was observed in some facilities. PMID- 23435812 TI - Viral vectors: a look back and ahead on gene transfer technology. AB - No matter what their origin, strain and family, viruses have evolved exquisite strategies to reach and penetrate specific target cells where they hijack the cellular machinery to express viral genes and produce progeny particles. The ability to deliver and express genetic information to cells is the basis for exploiting viruses as "Trojan horses" to genetically modify the natural cell target or, upon manipulation of the viral receptor to retarget the virus, to genetically engineer different cell types. This process, known as transduction, is accomplished using viral vectors derived from parental wild type viruses whose viral genes, essential for replication and virulence, have been replaced with the heterologous gene(s) required for cell manipulation. Rearrangement of the viral genome to impede replication or generation of infectious virions but maintaining the ability to deliver nucleic acids has been the object of intense research since the early 1980s. Technological advances and the ever-growing knowledge of molecular virology and virus-host cell relationships have constantly improved the safety profile of viral vectors that are now used in vitro and in vivo to study cellular gene function, correct genetic defects (gene therapy), express therapeutic proteins, vaccinate against infectious agents and tumors, produce experimental animal models, and for other purposes. This review illustrates the strategies used to generate some of the most used viral vectors, and their advantages, limitations and principal applications. PMID- 23435813 TI - Management of HIV infection after triple class failure. AB - Resistance of Human Immunodeficiency Virus (HIV) to antiretrovirals is a clinically important issue despite the availability of five antiretroviral drug classes. Although the incidence of HIV resistance might have stabilized or even decreased in patients starting their first Highly Active Antiretroviral Therapy (HAART) regimen in recent years, the prevalence of failure to the three original antiretroviral classes is estimated to range from 2.1% to 16% after HAART initiation. International guidelines recommend the use of at least two active drugs in constructing a new antiretroviral regimen to obtain virologic success, and adding a compound with a different mechanism of action often increases the chances of virologic response. With the introduction of new drug classes and new generation compounds of older classes in the antiretroviral armamentarium, the chances of achieving virologic success in patients with resistance to all three original antiretroviral classes are certainly higher than in the past. Patients who experience virologic failure and show resistance to new antiretrovirals are, however, described both in randomized trials and clinical settings. Although HAART regimens using various associations of the newest antiretrovirals led to very high rates of virologic success in patients with previous failure to all three original drug classes, there are circumstances in which patients cannot benefit from two fully active drugs, especially after prior exposure to several suboptimal therapies or functional monotherapies. These patients often need a holding regimen while awaiting new and effective antiretrovirals. This article reviews strategies that might be effective options to obtain virologic success in patients with triple class failure, and treatment strategies for patients who do not have two active drugs to construct a new effective antiretroviral regimen after virologic failure. PMID- 23435814 TI - Detection of serum IgA to HSV1 and its diagnostic role in sudden hearing loss. AB - A viral etiology of sudden hearing loss has been hypothesized by many authors. HSV1 neurotropism and its involvement in sudden hearing loss has implicated HSV1 as one of the most accredited etiological agents. A non-invasive method such as the titration of HSV1-specific IgA was evaluated to determine the role of HSV1 as a possible cause sudden hearing loss. A prospective study was carried out by titration of serum IgA to HSV1 in 93 patients and in a control group of 50 healthy subjects and 35 subjects suffering from recent herpes labialis reactivation. Statistical analysis of the results disclosed that IgA titers to HSV1 higher than 1:80 are suggestive for the association of HSV1 infection and sudden hearing loss. Moreover, acyclovir therapy was effective in 81% of patients who showed high specific IgA titers. Overall, the titration of specific serum IgA to HSV1 can be a useful tool to determine the viral etiology of certain cases of sudden hearing loss. This method is simple to perform and minimally invasive. It can lead to a rapid presumptive diagnosis and to prompt specific therapy, reducing the need for corticosteroids. PMID- 23435815 TI - Panton-Valentine leukocidin positive sequence type 80 methicillin-resistant Staphylococcus aureus carrying a staphylococcal cassette chromosome mec type IVc is dominant in neonates and children in an Algiers hospital. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major antimicrobial drug resistant pathogen causing serious infections. It was first detected in healthcare settings, but in recent years it has also become disseminated in the community. Children and young adults are most susceptible to infection by community-acquired (CA) MRSA strains. In this study 25 MRSA isolates implicated in infections of neonates and children admitted to an Algiers hospital during an 18 month period were characterized by molecular methods including staphylococcal cassette chromosome (SCC) mec typing, PCR amplification of pvl genes, pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Fifteen out of 25 isolates were from hospital-acquired infections. Twenty-four isolates carried SCCmec type IVc and belonged to the sequence type (ST) 80, one isolate carried SCCmec type II and was ST 39. Twenty-two out of 24 ST80-MRSA-IVc isolates carried pvl genes. Our results suggest that the Panton-Valentine leukocidin positive ST80- MRSA-IVc is the dominant MRSA clone causing disease in neonates and children in Algiers. PMID- 23435816 TI - Comparative analysis of different methods to detect Clostridium difficile infection. AB - The increased incidence and severity of Clostridium difficile infection, particularly in North America and Europe, have brought renewed focus on the most appropriate method to detect C. difficile and/or its toxins in stools. This prospective study evaluated the usefulness of the Illumigene TM C. difficile assay in diagnostic practice for the detection of toxigenic C. difficile DNA in clinical samples. A total of 88 out of 306 stool samples analysed were positive both by Illumigene and the combination of toxigenic C. difficile culture (TC) and immunochromatographic assay (IC) with a concordance of 100%. Of the 218 samples negative by the combination of TC and IC, 204 were negative also by Illumigene with a concordance of 93.57%. In our experience, compared to conventional assays Illumigene assay proved to be easy to perform, accurate and prompt giving results within 1 hour at a cost of 28 euro per sample. PMID- 23435817 TI - Real-time polymerase chain reaction with melting analysis of positive blood culture specimens in bloodstream infections: diagnostic value and turnaround time. AB - A Real-time polymerase chain reaction (PCR) with melting analysis was devised to target bacterial and fungal genes together with the most prevalent antimicrobial resistance genes in 250 positive blood culture broths. This method allowed the blood culture cultivated pathogens to be classified into clinically relevant groups such as Enterobacteriaceae, oxidase-positive bacilli, oxidase-positive coccobacilli, S. aureus and yeast. Enterococci and streptococci could be distinguished from CoNS only by the Gram stain. Gram-positive bacilli were discriminated from Gram-positive cocci by Gram stain. Furthermore, the most important antimicrobial resistant genes such as mecA, vanA, bla TEM , bla SHV and bla CTX-M could be identified. All results were obtained with a turnaround time of three hours from the moment of blood culture positivity compared to 24-72 hours for phenotypic methods. In conclusion, the proposed approach can allow the clinician to implement proper early management of sepsis patients. PMID- 23435818 TI - Migration patterns of HIV-1 subtype B virus in Northern Italy. AB - Gene flow analysis is used to identify the migration patterns of viruses within a geographical area and /or in different populations. 883 HIV-1 B subtype pol gene sequences were analyzed. The gene analysis among different geographical areas of the Bergamo district and from different transmission risk groups showed 25% of the observed gene flow was from people living in the north valleys to lowland and 40.5% from a heterosexual risk group to injecting drug users. Injecting drug users seem to be the central link, mercenary sex being the common route of transmission (and gene flow) between this group and both heterosexual and homosexual individuals. PMID- 23435819 TI - Seroprevalence of West Nile virus antibodies in blood donors living in the metropolitan area of Milan, Italy, 2009-2011. AB - A seroprevalence study for anti-West Nile virus-specific antibodies was carried out in healthy blood donors resident in the metropolitan area of Milan in two different years, 2009 and 2011. In 2009 no positive sera were found, whereas 5 positive sera were found in 2011, revealing viral circulation in this naive area. The seroprevalence rate identified in 2011 was 0.57%, suggesting that the area of WNV circulation in Italy is larger than that previously identified. PMID- 23435820 TI - Detection of Simkania negevensis in cell culture by using a monoclonal antibody. AB - In the present study, a monoclonal antibody (mAb), D5-14, raised in our laboratory against Chlamydia trachomatis LGV2 serotype, stained Simkania negevensis inclusions in S. negevensis-infected cells by using the immunofluorescence test. D5-14 mAb, reacting in immunoblot with an approximately 64-66-kDa protein of C. trachomatis LGV2 serotype, recognized a protein with the same molecular mass when tested with S. negevensis elementary bodies. PMID- 23435821 TI - Immune reconstitution inflammatory syndrome involving the central nervous system in a patient with HIV infection: a case report and review of literature. AB - IRIS is described as a paradoxical deterioration of clinical status upon initiation of combined anti-retroviral therapy (cART) in patients with HIV infection. Immune reconstitution inflammatory syndrome (CNS-IRIS) involving the central nervous system is rarely reported. We describe the case of 57-year-old man who developed a fatal case of CNS- IRIS. A rapid deterioration of neurological status was associated with progression of patchy T2-weighted hyperintensities involving different vascular territories on brain MRI. Diagnosis of CNS-IRIS is based of laboratory and radiologic findings, however brain biopsy is supportive. Despite immune restoration being involved in clinical deterioration, discontinuation of cART is not recommended. The use of corticosteroids is highly controversial. Prompt recognition of CNS-IRIS is crucial for preventing neurological complications and ensuing sequelae. PMID- 23435822 TI - When phylogenetic analysis complements the epidemiological investigation: a case of HIV-2 infection, Italy. AB - Human immunodeficiency virus type 2 (HIV-2) infection is geographically restricted, affecting West African countries such as Guinea- Bissau and Cape Verde. We describe a recent case of HIV-2 infection in an Italian patient. Phylogenetic analysis of the V3 region of HIV-2 indicated that the Italian patient was infected by HIV-2 subtype A2. The sequence obtained from the Italian patient clustered significantly with a sequence isolated from Senegal. A phylogenetic doubt may arise from a Guinea Bissau sequence because it was in a major clade with the Italian and Senegal sequences, but was not statistically significant. The discovery of another Italian case over a short time frame stresses the importance of strengthening the surveillance system for HIV-2 because of the increase in migration from endemic areas to Italy. PMID- 23435823 TI - Acute pancreatitis in children and rotavirus infection. Description of a case and minireview. AB - This report describes a case of acute pancreatitis in a 2-year-old boy following rotavirus gastroenteritis. Its characteristics are analyzed and discussed in the light of another 4 cases of pancreatitis associated with rotavirus infection found through a systematic review of the international literature. None of the five children underwent surgery or was referred to an intensive care unit and all 5 children recovered with normalization of pancreatic enzymes within 5-10 days. The pathogenesis of this rare complication remains unsettled, and its actual incidence may be higher than reported. Although acute pancreatitis associated with rotavirus gastroenteritis seems to be a mild disease, attention must be paid by the pediatrician fearing possible complications. Rotavirus infection should be amended to the differential diagnosis panel of pancreatitis in toddlers. PMID- 23435824 TI - Imported hantavirus cardiopulmonary syndrome in an Italian traveller returning from Cuba. AB - Hantavirus hemorrhagic fever with renal syndrome is endemic in Europe and Asia, while hantavirus cardiopulmonary syndrome (HCPS) is endemic in Northern, Central and Southern America. The first case of imported HCPS involving an Italian traveller returning from Cuba is reported. PMID- 23435825 TI - Multifocal diffusion of a KPC-3 producing ST512 K. pneumoniae clone in Northern Italy. AB - Sequence Type 258 (ST258) together with its allelic single- and double-locus variants have mostly been associated with the dissemination of KPC-producing Klebsiella pneumoniae in Europe. A total of 56 nonreplicate K. pneumoniae isolates with decreased carbapenem-susceptibility, collected at 7 different hospitals located in Northern Italy were investigated for the occurrence of blaKPC-type genes. PCR and sequencing results highlighted the presence of blaKPC2 or blaKPC-3 determinants in 10/56 and 5/56 cases respectively. Here we describe the intra- and inter-hospital spread in Northern Italy of a K. pneumoniae ST512 clone harboring the blaKPC-3 gene. PMID- 23435826 TI - A perspective on the history and evolution of an Oceans and Human Health "metadiscipline" in the USA. AB - We review recent history and evolution of Oceans and Human Health programs and related activities in the USA from a perspective within the Federal government. As a result of about a decade of support by the US Congress and through a few Federal agencies, notably the National Science Foundation, National Institute of Environmental Health Sciences, and National Ocean and Atmospheric Administration, robust Oceans and Human Health (OHH) research and application activities are now relatively widespread, although still small, in a number of agencies and academic institutions. OHH themes and issues have been incorporated into comprehensive federal ocean research plans and are reflected in the new National Ocean Policy enunciated by Executive Order 13547. In just a decade, OHH has matured into a recognized "metadiscipline," with development of a small, but robust and diverse community of science and practice, incorporation into academic educational programs, regular participation in ocean and coastal science and public health societies, and active engagement with public health decision makers. In addition to substantial increases in scientific information, the OHH community has demonstrated ability to respond rapidly and effectively to emergency situations such as those associated with extreme weather events (e.g., hurricanes, floods) and human-caused disasters (e.g., the Deep Water Horizon oil spill). Among many other things, next steps include development and implementation of agency health strategies and provision of specific services, such as ecological forecasts to provide routine early warnings for ocean health threats and opportunities for prevention and mitigation of these risks. PMID- 23435827 TI - The ammonia oxidizing and denitrifying prokaryotes associated with sponges from different sea areas. AB - Marine sponges have been suggested to play an important role in the marine nitrogen cycling. However, the role of sponge microbes in the nitrogen transformation remains limited, especially on the bacterial ammonia oxidization and denitrification. Hence, in the present study, using functional genes (amoA, nirS, nirK, and nxrA) involved in ammonia oxidization and denitrification and 16S rRNA genes for specific bacterial groups as markers, phylogenetically diverse prokaryotes including bacteria and archaea, which may be involved in the ammonia oxidization and denitrification processes in sponges, were revealed in seven sponge species. Ammonia oxidizers were found in all species, whereas three sponges (Placospongia sp., Acanthella sp., and Pericharax heteroraphis) harbor only ammonia-oxidizing bacteria (AOB), two sponges (Spirastrellidae diplastrella and Mycale fibrexilis) host only ammonia-oxidizing archaea (AOA), while the remaining two sponges (Haliclona sp. and Lamellomorpha sp.) harbor both AOB and AOA. S. diplastrella and Lamellomorpha sp. also harbor denitrifying bacteria. Nitrite reductase gene nirK was detected only in Lamellomorpha sp. with higher phylogenetic diversity than nirS gene observed only in S. diplastrella. The detected functional genes related to the ammonia oxidization and nitrite reduction in deep-sea and shallow-water sponges highlighted the potential ecological roles of prokaryotes in sponge-related nitrogen transformation. PMID- 23435828 TI - Perfectionism and life aspirations in intrinsically and extrinsically religious individuals. AB - Religiosity is related to positive health and life satisfaction but the pathways through which this occurs have not been clearly delineated. The purpose of this study was to examine potential mediators of the relationships between intrinsic and extrinsic religiosity and negative affect and life satisfaction. Perfectionism and life aspirations are two possible pathways through which religious orientation is related to outcome. It was hypothesized that adaptive perfectionism and intrinsic life aspirations would act as mediators between intrinsic religiosity and negative affect and life satisfaction, and that maladaptive perfectionism and extrinsic life aspirations would act as mediators between the extrinsic religiosity and negative affect and life satisfaction. Two consecutive samples of religious college students (N = 540 and N = 485) completed measures of the Age Universal Religious Orientation Index, the Frost Multi Dimensional Perfectionism Scale, the Aspiration Index, the Beck Depression Inventory-II, the Spielberger State-Trait Anxiety Inventory, and the Satisfaction with Life Scale. Intrinsic religiosity had a direct negative relationship with negative affect and positive relationship with life satisfaction. Contrary to the hypotheses, intrinsic religiosity had its strongest indirect effect via maladaptive perfectionism such that increased intrinsic religiosity was related to decreased maladaptive perfectionism which in turn lead to better negative affect and life satisfaction. Extrinsic religiosity was related to increased maladaptive perfectionism and thereby indirectly contributed to worse negative affect and life satisfaction. Interestingly, when the effects of maladaptive perfectionism were controlled, the direct effects of extrinsic religiosity were related to reduced negative affect and increased life satisfaction. Overall, the strongest mediator in this study of both intrinsic and extrinsic religiosity was maladaptive perfectionism, with intrinsic religiosity related to decreased maladaptive perfectionism and extrinsic religiosity related to increased maladaptive perfectionism. PMID- 23435829 TI - Absorption patterns of meals containing complex carbohydrates in type 1 diabetes. AB - AIMS/HYPOTHESIS: Successful postprandial glycaemia management requires understanding of absorption patterns after meals containing variable complex carbohydrates. We studied eight young participants with type 1 diabetes to investigate a large low-glycaemic-load (LG) meal and another eight participants to investigate a high-glycaemic-load (HG) meal matched for carbohydrates (121 g). METHODS: On Visit 1, participants consumed an evening meal. On follow-up Visit 2, a variable-target glucose clamp was performed to reproduce glucose and insulin levels from Visit 1. Adopting stable-label tracer dilution methodology, we measured endogenous glucose production on Visit 2 and subtracted it from total glucose appearance measured on Visit 1 to obtain meal-attributable glucose appearance. RESULTS: After the LG meal, 25%, 50% and 75% of cumulative glucose appearance was at 88 +/- 21, 175 +/- 39 and 270 +/- 54 min (mean +/- SD), whereas glucose from the HG meal appeared significantly faster at 56 +/- 12, 100 +/- 25 and 153 +/- 39 min (p < 0.001 to 0.003), and resulted in a 50% higher peak appearance (p < 0.001). Higher apparent bioavailability by 15% (p = 0.037) was observed after the LG meal. We documented a 20 min deceleration of dietary mixed carbohydrates compared with dietary glucose for the HG meal and a twofold deceleration for the LG meal. CONCLUSIONS/INTERPRETATION: Absorption patterns may be influenced by glycaemic load and/or meal composition, affecting optimum prandial insulin dosing in type 1 diabetes. PMID- 23435831 TI - Recovery, dependence or death after discharge. PMID- 23435830 TI - PIK3CA mutation is associated with poor survival among patients with metastatic colorectal cancer following anti-EGFR monoclonal antibody therapy: a meta analysis. AB - PURPOSE: PIK3CA mutation appears to predict a lack of response to anti-EGFR monoclonal antibody (mAb) treatment in patients with metastatic colorectal cancer (mCRC). However, the predictive value of PIK3CA mutations for survival remains inconclusive. Here, we pooled the data from published studies to estimate the association between PIK3CA mutation and survival outcomes in mCRC patients treated with anti-EGFR mAbs. METHODS: Studies investigating the association of PIK3CA mutations with clinical survival outcomes of mCRC patients treated with anti-EGFR mAbs were systematically identified. The overall hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between trails. RESULTS: Eight studies that reported survival outcome in 839 mCRC patients were included. In unselected patients, we found that PIK3CA mutations were significantly associated with poorer PFS [8 studies, 839 patients; HR = 1.53; 95 % confidence interval (CI) 1.28-1.84; P < 0.001] and OS (5 studies; 587 patients; HR = 1.28; 95 % CI 1.05-1.56; P = 0.015). With increased predictive power in KRAS wild-type patients (3 studies; 275 patients), the overall HR for PFS was 2.44 (95 % CI 1.33-4.48; P = 0.004) and was statistically significant. We also observed a worse OS in KRAS wild-type patients with PIK3CA mutations (2 studies; 163 patients; HR = 1.37; 95 % CI 0.80-2.35; P = 0.258), although the result was not statistically significant due to small sample size. CONCLUSIONS: PIK3CA mutation is a promising predictive biomarker for poor survival in mCRC patients treated with anti-EGFR mAbs, particularly in KRAS wild type patients. PMID- 23435832 TI - Therapists perspectives on the effective elements of consultation following training. AB - Consultation is an effective implementation strategy to improve uptake of evidence-based practices for youth. However, little is known about what makes consultation effective. The present study used qualitative methods to explore therapists perspectives about consultation. We interviewed 50 therapists who had been trained 2 years prior in cognitive-behavioral therapy for child anxiety. Three themes emerged regarding effective elements of consultation: (1) connectedness with other therapists and the consultant, (2) authentic interactions around actual cases, and (3) the responsiveness of the consultant to the needs of individual therapists. Recommendations for the design of future consultation endeavors are offered. PMID- 23435833 TI - Risk factors for rising incidence of esophageal and gastric cardia adenocarcinoma. AB - INTRODUCTION: In the last 30 years, the incidence of esophageal and gastric cardia adenocarcinoma has steadily increased. The increase in incidence is approximately seven-fold, which is a more substantial increase than that of several malignancies, including melanoma, breast cancer, and prostate cancer. DISCUSSION: The rising incidence has led to a steady increase in mortality from 2 to 15 deaths per 100,000 in the last three decades. The etiologic factors involved in the development of these malignancies include gastroesophageal reflux disease, Barrett's esophagus, acid-suppressive medication use, obesity, and tobacco use. This article discusses the contribution of these etiologic risk factors to this increase in incidence. PMID- 23435834 TI - Intraperitoneal hyperthermic chemotherapy: which drugs? PMID- 23435836 TI - Transjugular approach for successful recanalization and stenting for inferior vena cava stenosis. AB - Budd-Chiari syndrome is a rare disease characterized by obstruction of outflow in the hepatic vein and/or the inferior vena cava (IVC). Percutaneous transluminal angioplasty and stent placement is nowadays considered to be the first-line treatment for central venous disease because of its minimal-invasive approach. IVC reconstruction by surgical approach is not preferred due to increased morbidity and disappointing patency rates. We describe a case of a long-segment, thrombotic, chronic total occlusion of the IVC that was dilated and stented using a recanalization technique involving the use of Brokenborough septal puncture needle, Mullin dilator and Accura balloon from the jugular approach. PMID- 23435835 TI - Prospects of nano-material in breast cancer management. AB - Breast cancer evaluation and early diagnosis are core complexity worldwide and an ambiguity for scientists till date. Nano-materials are innovative tools for rapid diagnosis and therapy, which may induce an immense result in the field of oncology. Their exceptional size-dependent properties make them special and superior materials and quite indispensable in several fields of the human activities. The major obstacle in finding cure for malignant breast cancer is to increase in development of resistances for tumors to the therapeutic treatments. The widespread mammo-graph particle is being developed by nations to diagnosis disease in primitive stage to decline the mortality rates caused by breast carcinoma. The advancement of nano-particle based diagnostic tools facilitates in evaluation and provides encouraging development in breast cancer therapeutics. In this compact review, efforts have been made to compose the current advancements in the area of functional nano-particles. Furthermore, in vivo and in vitro applications of nano-materials in breast cancer management are also discussed. PMID- 23435838 TI - New insights into two-photon absorption properties of functionalized aza-BODIPY dyes at telecommunication wavelengths: a theoretical study. AB - Special attention has been paid to understanding the structural effect on electronic structure and absorption spectra for an extensive series of functionalized aza-BODIPY molecules. We have employed the quadratic response theory as well as a sum-over-states approach involving few intermediate states to calculate the two-photon cross section (deltamax). The results suggest that chemical modifications on the aza-BODIPY core and peripheral moieties using various substituents can finely tune their linear and nonlinear optical properties. Therefore, some new fluorophores absorbing in the near infrared region and featuring considerably high deltamax at telecommunication wavelengths are proposed, which are excellent candidates for nonlinear transmission and fluorescent labeling materials. The investigation contributes a useful starting point for further design of more effective aza-BODIPY dyes and can be valuable as a foundation for future experimental research and development. PMID- 23435837 TI - A high MELD score, combined with the presence of hepatitis C, is associated with a poor prognosis in living donor liver transplantation. AB - PURPOSE: The feasibility of performing living donor liver transplantation (LDLT) for patients with high end-stage liver disease (MELD) scores needs to be assessed. METHODS: A total of 357 patients who underwent LDLT were included in this analysis. RESULTS: Overall, 46 patients had high MELD scores (>= 25) and their graft survival was similar to that in patients with low MELD scores (<25; n = 311; p = 0.395). However, among patients with high MELD scores, a multivariate analysis showed that the presence of hepatitis C (p = 0.013) and LDLT in Era-I (p = 0.036) was significantly associated with a poorer prognosis. Among patients with hepatitis C (n = 155), the 5-year graft survival rate was significantly lower in patients with high MELD scores (33.7 %, p < 0.001) than in patients with low MELD scores. The 5-year graft survival rate was significantly lower in patients in Era-I (n = 119) compared with those in Era-II/III when stratified by low (73.0 vs. 82.5 %, p = 0.040) and high (55.0 vs. 86.1 %, p = 0.023) MELD scores. Among the patients with high MELD scores, those with hepatitis C and LDLT in Era-I had the worst 5-year graft survival rate (14.3, p < 0.001). CONCLUSION: The graft outcomes in patients with high MELD scores and the presence of hepatitis C were found to be particularly poor. PMID- 23435839 TI - Expression of inflammation-mediated cluster of genes as a new marker of canine mammary malignancy. AB - Because canine mammary tumours constitute a serious clinical problem and there are no good prognostic markers (only histopathological variables are used), the aim of the presented study was to find new malignancy markers as well as to identify intracellular pathways and biological processes characteristic for canine mammary malignancy. We compared gene expression of the most malignant mammary tumours (poorly differentiated cancers of the 3rd grade of malignancy) with less malignant tumours (well differentiated cancers of the 1st grade of malignancy). The results of our study indicated that in dogs the number of tumour infiltrating myeloid cells or expression of myeloid-specific antigens by cancer cells is related to the cancer progression and may constitute a new marker of malignancy, however further studies in this field are required. PMID- 23435840 TI - Effect of racing on the serum concentrations of cardiac troponin I and creatine kinase myocardial band in racing camels (Camelus dromedarius). AB - This study was designed to investigate the effect of racing on the serum concentrations of cardiac troponin I (cTnI) and creatine kinase myocardial (CK MB) in healthy racing camels (Camelus dromedarius). Twenty-three racing camels scheduled for a 5 km race were investigated in this study. From each camel, 3 blood samples were collected: 24 h before racing (T0), within 2 h after the race (T1) and 24 h post-race (T2). Following the 5 km race, 91.3 % of the racing camels had increases in serum cTnI concentrations, while concentrations remained unchanged in 8.7 %. The cTnI concentration (median 0.06 ng/mL; range, 0.03-0.15 ng/mL) was significantly higher (P < 0.001) than the pre-race values (median 0.04 ng/mL; range, 0.01-0.07 ng/mL). Twenty-four hours post-race, the cTnI concentrations had returned very nearly to their pre-race values (median 0.04 ng/mL; range, 0.00-0.09 ng/mL) and were not significantly different (P = 0.35) from the pre-race values. Following the 5 km race, increases in CK-MB mass were seen in 17.4 % of the camels, with no changes in 4.3 % and decreases in 78.3 %. The CK-MB mass (median 0.41 ng/mL; range, 0.19-0.60 ng/mL) did not differ significantly (P = 0.84) when compared to the pre-race values (median 0.42 ng/mL; range, 0.32-0.55 ng/mL). Twenty-four hours post-race, the CK-MB mass concentrations (median 0.41 ng/mL; range, 0.15-0.55 ng/mL) did not differ significantly (P > 0.05) compared to pre-race or immediate post-race values. Resting cTnI concentrations in the racing camels were initially low, but increased above the baseline level in most of the camels immediately after racing, and returned to pre-race values within the 24-h post-race period. CK-MB is a less sensitive biomarker for myocardial activity as compared with cTnI. These findings could be of importance when evaluating racing camels with suspected cardiac disease after recent hard exercise. PMID- 23435841 TI - Pathogenesis of type 1 (European genotype) porcine reproductive and respiratory syndrome virus in male gonads of infected boar. AB - The objective of this study was to determine the pathogenesis of experimental infection with a type 1 porcine reproductive and respiratory syndrome virus (PRRSV) by defining the sites of viral replication and apoptosis in male gonads from infected boars for a period of 21 days after intranasal inoculation. Microscopically, hypospermatogenesis and abundant germ cell depletion and death were observed in the testes. Such germ cell death occurs by apoptosis, as determined by a characteristic histological patterns and evidence of massive DNA fragment detected in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) reaction. PRRSV was detected in the testicular tissue of infected boars only. Viral nucleic acid was localized in spermatogonia, spermatocytes and spermatids but not in the vesicular and bulbourethral gland. In serial sections, PRRSV-positive cells did not co-localized with apoptotic cells. TUNEL-positive apoptotic cells were more numerous than PRRSV-positive cells in testicular sections. The present study demonstrated that type 1 PRRSV infects the spermatogonia and their progeny, and induces apoptosis in these germ cells. PMID- 23435843 TI - Retroperitoneal follicular lymphoma presenting with gastric varices and splenic artery pseudoaneurysm. PMID- 23435842 TI - Comparison of advanced adenocarcinomas of esophagogastric junction and distal stomach in Japanese patients. AB - BACKGROUND: There have been no reports on the incidence, characteristics, treatment outcomes, and prognosis of inoperably advanced or recurrent adenocarcinoma of the esophagogastric junction (AEGJ) in Japan. METHODS: We investigated the clinicopathological characteristics, treatment outcomes, and prognosis for 816 patients with esophagogastric junctional and gastric adenocarcinoma who received first-line chemotherapy between 2004 and 2009. RESULTS: Of 816 patients, 82 (10 %) had AEGJ. The patients with AEGJ had significantly more lung and lymph node metastasis, but less peritoneal metastasis, than those with gastric adenocarcinoma (GAC). The objective response rate to first-line chemotherapy was 23.3 % for patients with AEGJ and 22.6 % in patients with GAC (p = 0.90). The median survival was 13.0 months in AEGJ and 11.8 months in GAC (p = 0.445). In no patient was tumor site a significant prognostic factor (p = 0.472). In patients with AEGJ, ECOG PS >= 2, presence of liver metastasis, and absence of lung metastasis were significantly associated with poor prognosis. CONCLUSIONS: No significant differences were observed in treatment outcomes between advanced AEGJ and GAC. Therefore, the same chemotherapy regimen can be given as a treatment arm in future Japanese clinical trials to both patients with inoperably advanced or recurrent AEGJ and those with GAC. PMID- 23435844 TI - Low expression of glucocorticoid receptor alpha isoform in adult immune thrombocytopenia correlates with glucocorticoid resistance. AB - The expression of glucocorticoid receptor (GR) isoforms has been linked to glucocorticoid (GC) resistance in various diseases treated with GC. However, existing data are conflicting in these diseases, and little information is available regarding immune thrombocytopenia (ITP). To further investigate the role of GR isoforms in GC resistance in adult ITP patients, we measured the mRNA expression of GR isoforms (GRalpha, GRbeta, GRgamma, GRp) in peripheral blood mononuclear cells (PBMC) from 54 newly diagnosed ITP patients, including GC sensitive (GCS) and GC-resistant (GCR) patients and 35 healthy volunteers. The GRalpha and GRbeta proteins in PBMC, nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) in the nucleus were detected by Western blotting. Compared to normal subjects, both GRalpha and GRbeta mRNAs were significantly increased in ITP patients (p < 0.05), while there was no significant difference in the mRNA expression of GRgamma and GRp. Compared to GCR patients, the expressions of GRalpha mRNA and GRalpha protein were significantly higher in GCS patients (p < 0.05). Moreover, no significant difference in the mRNA expression of the GRbeta, GRgamma, and GRp isoforms was observed between GCS and GCR patients and the GRbeta protein could not be detected. Compared to GCS group, the expression of p65/NF-kappaB was significantly higher in the GCR group (p < 0.05). Overall, we did not find differences in c-Jun/AP-1 protein expression between GCS and GCR patients. In summary, GC resistance in adult ITP patients is associated with a reduced expression of GRalpha, which may be related with increased NF kappaB. GRbeta was very low and may not be involved in GC resistance in adult ITP, warranting further exploration. PMID- 23435845 TI - Sustained complete remission in an elderly patient with a blastic plasmacytoid dendritic cell neoplasm following autologous peripheral blood stem cell transplantation. PMID- 23435846 TI - Characterization of vulvar skin of healthy Thai women: influence of sites, age and menopause. AB - Although the physiological characteristics of vulvar skin have been characterized in Caucasians, little is known about the vulvar skin of Asian women. This study assessed the moisture content, transepidermal water loss (TEWL) and pH of vulvar skin of 99 healthy Asian women residing in Bangkok, aged 20-69 years, during their non-menstrual period, including 39 post-menopausal women. Skin pH was acidic at all sites, and the pH of the vulvar areas was significantly higher than the control sites (inner thigh, inner forearm). Skin moisture was slightly, but significantly, lower around the vulvar area and the thigh than around the forearm. TEWL was significantly higher in vulvar areas than control sites. Ageing and menopause did not cause notable alterations in most properties of vulvar skin. In conclusion, the vulvar skin of Asian women has similar properties to that of Caucasians. PMID- 23435847 TI - Impact of childhood-onset type 1 diabetes on schooling: a population-based register study. AB - AIMS/HYPOTHESIS: We investigated the impact of type 1 diabetes on educational achievements in compulsory and upper secondary school, as well as potential long lasting effects. METHODS: Altogether 2,485 individuals with type 1 diabetes, diagnosed at the age of <15 years and born in 1972-1978, were selected from the Swedish Childhood Diabetes Register, which was linked to national population registers including the Swedish Education Register. For each individual, four controls from the general population, matched for year of birth and residence at the time of diagnosis, were selected by Statistics Sweden (n = 9,940). We analysed the impact of diabetes on final school grades at 16 years (compulsory school) and 19 years (upper secondary school) and on participation in the labour market at 29 years using linear, logistic, ordered logistic and quantile regression analyses, controlling for demographics and socioeconomic background. RESULTS: Diabetes had a negative effect on mean final grades (scale of 1-5) in compulsory school (-0.07, p < 0.001) and theoretical programmes in upper secondary school (-0.07, p = 0.001). Children with early-onset diabetes (0-4 years) suffered a greater disadvantage as a result of the disease (-0.15, p = 0.001 in compulsory school). The strongest effect was seen in the lowest deciles of the conditional distribution on mean final grades. At age 29, individuals with diabetes were less likely to be gainfully employed (OR 0.82, 95% CI 0.73, 0.91). CONCLUSIONS/INTERPRETATION: The small but significant negative effect of type 1 diabetes on schooling could affect opportunities for further education and career development. Attention must be paid in school to the special needs of children with diabetes. PMID- 23435848 TI - Assessment of heavy metals (Cd and Pb) and micronutrients (Cu, Mn, and Zn) of paddy (Oryza sativa L.) field surface soil and water in a predominantly paddy cultivated area at Puducherry (Pondicherry, India), and effects of the agricultural runoff on the elemental concentrations of a receiving rivulet. AB - The concentrations of toxic heavy metals-Cd and Pb and micronutrients-Cu, Mn, and Zn were assessed in the surface soil and water of three different stages of paddy (Oryza sativa L.) fields, the stage I-the first stage in the field soon after transplantation of the paddy seedlings, holding adequate amount of water on soil surface, stage II-the middle stage with paddy plants of stem of about 40 cm length, with sufficient amount of water on the soil surface, and stage III-the final stage with fully grown rice plants and very little amount of water in the field at Bahour, a predominantly paddy cultivating area in Puducherry located on the southeast Coast of India. Comparison of the heavy metal and micronutrient concentrations of the soil and water across the three stages of paddy field showed their concentrations were significantly higher in soil compared with that of water (p < 0.05) of the fields probably because of accumulation and adsorption in soil. The elemental concentrations in paddy soil as well as water was in the ranking order of Cd > Mn > Zn > Cu > Pb indicating concentration of Cd was maximum and Pb was minimum. The elemental concentrations in both soil and water across the three stages showed a ranking order of stage II > stage III > stage I. The runoff from the paddy fields has affected the elemental concentrations of the water and sediment of an adjacent receiving rivulet. PMID- 23435849 TI - Automated riverine landscape characterization: GIS-based tools for watershed scale research, assessment, and management. AB - River systems consist of hydrogeomorphic patches (HPs) that emerge at multiple spatiotemporal scales. Functional process zones (FPZs) are HPs that exist at the river valley scale and are important strata for framing whole-watershed research questions and management plans. Hierarchical classification procedures aid in HP identification by grouping sections of river based on their hydrogeomorphic character; however, collecting data required for such procedures with field-based methods is often impractical. We developed a set of GIS-based tools that facilitate rapid, low cost riverine landscape characterization and FPZ classification. Our tools, termed RESonate, consist of a custom toolbox designed for ESRI ArcGIS(r). RESonate automatically extracts 13 hydrogeomorphic variables from readily available geospatial datasets and datasets derived from modeling procedures. An advanced 2D flood model, FLDPLN, designed for MATLAB(r) is used to determine valley morphology by systematically flooding river networks. When used in conjunction with other modeling procedures, RESonate and FLDPLN can assess the character of large river networks quickly and at very low costs. Here we describe tool and model functions in addition to their benefits, limitations, and applications. PMID- 23435850 TI - Effects of bridge construction on songbirds and small mammals at Blennerhassett Island, Ohio River, USA. AB - Construction of man-made objects such as roads and bridges may have impacts on wildlife depending on species or location. We investigated songbirds and small mammals along the Ohio River, WV, USA at a new bridge both before and after construction and at a bridge crossing that was present throughout the study. Comparisons were made at each site over three time periods (1985-1987 [Phase I] and 1998-2000 [Phase II] [pre-construction], 2007-2009 [Phase III] [post construction]) and at three distances (0, 100, 300 m) from the bridge or proposed bridge location. Overall, 70 songbirds and 10 small mammals were detected during the study. Cliff swallows (Petrochelidon pyrrhonota) and rock pigeons (Columba livia) showed high affinity for bridges (P < 0.05). Combined small mammal abundances increased between Phases I and II (P < 0.05), but did not differ between Phases II and III (P > 0.05). Species richness and diversity for songbirds and small mammals did not differ before and after bridge construction (P > 0.05). We found that most species sampled did not respond to the bridge crossing, and believe that the bridge is not causing any measurable negative density impacts to the species we investigated. The new bridge does provide habitat for exotic rock pigeons that are adjusted to man-made structures for nesting. PMID- 23435851 TI - Assessment of animal impacts on bacterial water quality in a South Carolina, USA tidal creek system. AB - Fecal pollution may adversely impact water quality in coastal ecosystems. The goal of this study was to determine whether cattle were a source of fecal pollution in a South Carolina watershed. Surface water samples were collected in June 2002 and February through March 2003 in closed shellfish harvesting waters of Toogoodoo Creek in Charleston County, SC. Fecal coliform concentrations in 70 % of the water samples taken for this study exceeded shellfish harvesting water standards. Ribotyping was performed in order to identify animal sources contributing to elevated fecal coliform levels. Escherichia coli isolates (n = 253) from surface water samples were ribotyped and compared to a ribotype library developed from known sources of fecal material. Ribotypes from water samples that matched library ribotypes with 90 % maximum similarity or better were assigned to that source. Less than half of the unknown isolates (38 %) matched with library isolates. About half (53 %) of the matched ribotypes were assigned to cattle isolates and 43 % to raccoon. Ribotyping almost exclusively identified animal sources. While these results indicate that runoff from cattle farms was a likely source of fecal pollution in the watershed, wildlife also contributed. Given the small size of the library, ribotyping was moderately useful for determining the impact of adjacent cattle farms on Toogoodoo Creek. Increasing the number and diversity of the wildlife sources from the area would likely increase the usefulness of the method. PMID- 23435852 TI - Stream sediment and nutrient loads in the Tahoe Basin--estimated vs monitored loads for TMDL "crediting". AB - Total maximum daily load (TMDL) programs utilize pollutant load reductions as the primary strategy to restore adversely affected waters of the USA. Accurate and defensible "crediting" for TMDL reductions of sediment and nutrients requires stream monitoring programs capable of quantitative assessment of soil erosivity and the "connectivity" between erosive areas and stream channels across the watershed. Using continuous (15-min) stream monitoring information from typical alpine, snowmelt-driven watersheds [Ward (2,521 ha), Blackwood (2,886 ha), and Homewood (260 ha, Homewood Mountain Resort--HMR) Creeks] on the west shore of the Lake Tahoe Basin, daily sediment (and nutrient for HMR) loads are determined and compared with those developed from estimated load-flow relationships developed from grab sampling data. Compared to the previously estimated sediment load discharge relationships, measured curves were slightly below those estimated, though not significantly so at Blackwood and Ward Creeks in the period 1997-2002. Based on average daily flowrates determined from calibrated hydrologic modeling during the period 1994-2004, average daily flowrate frequency distributions per year are determined from which load reduction "crediting" towards TMDL targets can be evaluated. Despite seemingly similar estimated and measured sediment load flow relationships, annual "estimated" loads exceeded those "measured" by about 40 % for Ward and Blackwood Creeks and over 300 times for HMR Creek. Similarly, though less dramatic, estimated annual nutrient loads at HMR Creek exceeded those measured by 1.7 and 6 times for total nitrogen and total phosphorus, respectively. Such results indicate that actual measured load-flow relationships are likely necessary for realistic quantitative and defensible TMDL crediting. PMID- 23435853 TI - Stable aqueous colloidal solutions of intact surfactant-free graphene nanoribbons and related graphitic nanostructures. AB - Here we demonstrate a simple, nondestructive method for the preparation of stable aqueous colloidal solutions of graphene nanoribbons and carbon nanotubes. The method includes sonication of carbon nanomaterials in hypophosphorous acid, filtration accompanied by washing the solids with water and dispersion of the solids in a fresh portion of water to form colloidal solutions. PMID- 23435854 TI - Benefit and harms of new anti-cancer drugs. AB - Phase III randomized controlled trials (RCTs) assess clinically important differences in endpoints that reflect benefit to and harm of patients. Defining benefit of cancer drugs can be difficult. Overall survival and quality of life are the most relevant primary endpoints, but difficulty in measuring these mean that other endpoints are often used, although their surrogacy or clinical relevance has not always been established. In general, advances in drug development have led to numerous new drugs to enter the market. Pivotal RCT of several new drugs have shown that benefit appeared greater for targeted anticancer agents than for chemotherapeutic agents. This effect seems particularly evident with targeted agents evaluated in biomarker-driven studies. Unfortunately, new therapies have also shown an increase in toxicity. Such toxicity is not always evident in the initial reports of RCTs. This may be a result of a statistical inability to detect differences between arms of RCTs, or occasionally due to biased reporting. There are several examples where reports of new toxicities could only be found in drug labels. In some cases, the small improvement in survival has come at a cost of substantial excess toxicity, leading some to consider such therapy as having equipoise. PMID- 23435855 TI - Establishment of rat brain endothelial cells susceptible to rat cytomegalovirus ALL-03 infection. AB - Endothelial cells have been implicated as key cells in promoting the pathogenesis and spread of cytomegalovirus (CMV) infection. This study describes the isolation and culture of rat brain endothelial cells (RBEC) and further evaluates the infectious potential of a Malaysian rat CMV (RCMV ALL-03) in these cultured cells. Brain tissues were mechanically fragmented, exposed to enzymatic digestion, purified by gradient density centrifugation, and cultured in vitro. Morphological characteristics and expression of von Willebrand factor (factor VIII-related antigen) verified the cells were of endothelial origin. RBEC were found to be permissive to the virus by cytopathic effects with detectable plaques formed within 7 d of infection. This was confirmed by electron microscopy examination which proved the existence of the viral particles in the infected cells. The susceptibility of the virus to these target cells under the experimental conditions described in this report provides a platform for developing a cell-culture-based experimental model for studies of RCMV pathogenesis and allows stimulation of further studies on host cell responses imposed by congenital viral infections. PMID- 23435856 TI - Isolation and characterization of vascular endothelial cells derived from fetal tooth buds of miniature swine. AB - The aim of the present study was to isolate endothelial cells from tooth buds (unerupted deciduous teeth) of miniature swine. Mandibular molar tooth buds harvested from swine fetuses at fetal days 90-110 were cultured in growth medium supplemented with 15% fetal bovine serum in 100-mm culture dishes until the primary cells outgrown from the tooth buds reached confluence. A morphologically defined set of pavement-shaped primary cells were picked up manually with filter paper containing trypsin/ethylenediamine tetraacetic acid solution and transferred to a separate dish. A characterization of the cellular characteristics and a functional analysis of the cultured cells at passages 3 to 5 were performed using immunofluorescence, a reverse transcriptase polymerase chain reaction assay, a tube formation assay, and transmission electron microscopy. The isolated cells grew in a pavement arrangement and showed the characteristics of contact inhibition upon reaching confluence. The population doubling time was ~48 h at passage 3. As shown by immunocytostaining and western blotting with specific antibodies, the cells produced the endothelial marker proteins such as vascular endothelial cadherin, von Willebrand factor, and vascular endothelial growth factor receptor-2. Observation with time-lapse images showed that small groups of cells aggregated and adhered to each other to form tube-like structures. Moreover, as revealed through transmission electron microscopy, these adherent cells had formed junctional complexes. These endothelial cells from the tooth buds of miniature swine are available as cell lines for studies on tube formation and use in regenerative medical science. PMID- 23435857 TI - The cell sorting process of Xenopus gastrula cells involves the acto-myosin system and TGF-beta signaling. AB - We have previously shown that the cell sorting process of animal pole cells (AC) and vegetal pole cells (VC) from Xenopus gastrulae is considered to involve two steps: concentrification and polarization. In this study, we addressed the question of what specified the spatial relationship of the AC and VC clusters during the process. First, we examined the inhibitory or facilitatory treatment for myosin 2 activity during each of the two steps. The aggregates treated with Y27632 or blebbistatin during the concentrification step showed a cluster random arrangement, suggesting the prevention of the cell sorting by inhibition of myosin 2. Meanwhile, the treatment with a Rac1 inhibitor, NSC23766, during the same step resulted in promotion of the fusion of the AC clusters and the progression of the cell sorting, presumably by an indirect activation of myosin 2. On the other hand, the treatments with any of the three drugs during the polarization step showed that the two clusters did not appose, and their array remained concentric. Thus, the modulation of cell contraction might be indispensable to each of the two steps. Next, the activin/nodal TGF-beta signaling was perturbed by using a specific activin receptor-like kinase inhibitor, SB431542. The results revealed a bimodal participation of the activin/nodal TGF-beta signaling, i.e., suppressive and promotive effects on the concentrification and the polarization, respectively. Thus, the present in vitro system, which permits not only the cell contraction-mediated cell sorting but also the TGF-beta-directed mesodermal induction such as cartilage formation, may fairly reflect the embryogenesis in vivo. PMID- 23435858 TI - The protective effect of silymarin on the carbon tetrachloride (CCl4)-induced liver injury in common carp (Cyprinus carpio). AB - Silymarin, a mixture of bioactive flavonolignans from the milk thistle (Silybum marianum), is traditionally used in herbal medicine to defend against various hepatotoxic agents. The aim of the present study was to evaluate the protective effect of silymarin against carbon tetrachloride (CCl4)-induced liver injury in fish. Common carp, with an average initial weight of 17.0 +/- 1.1 g, were fed diet containing four doses of silymarin (0, 0.1, 0.5, and 1 g/kg diet) for 60 d. Fish were then given an intraperitoneal injection of CCl4 (30% in arachis oil) at a dose of 0.5 ml/kg body weight. At 72 h after CCl4 injection, blood and liver samples were collected for the analyses of serum biochemical parameters, liver index, peroxidation product, glutathione, and antioxidant enzyme activities. The results showed that administration of silymarin at 0.5 and 1 g/kg diet for 60 d prior to CCl4 intoxication significantly reduced the elevated activities of glutamate pyruvate transaminase, glutamate oxalate transaminase, lactate dehydrogenase (LDH), and increased the reduced levels of total protein and albumin in the serum. The reduced levels of liver index, superoxide dismutase, glutathione peroxidase, catalase, glutathione, and total antioxidant capacity were markedly increased, and malondialdehyde formation was significantly restrained in the liver. However, these parameters, except LDH, were not significantly changed in fish fed with silymarin at 0.1 g/kg diet. Based on the results, it can be concluded that silymarin has protective effect against CCl4 induced hepatotoxicity in fish. It is suggested that silymarin may be used as a hepatoprotective agent to prevent liver diseases in fish. PMID- 23435859 TI - Peer acceptance protects global self-esteem from negative effects of low closeness to parents during adolescence and early adulthood. AB - Having a distant relationship with parents seems to increase the risk of developing a more negative global self-esteem. This article describes a longitudinal study of 1,090 Norwegian adolescents from the age of 13-23 (54 % males) that explored whether peer acceptance can act as a moderator and protect global self-esteem against the negative effects of experiencing low closeness in relationships with parents. A quadratic latent growth curve for global self esteem with closeness to parents and peer acceptance as time-varying covariates was modeled, taking partial measurement invariance in global self-esteem into account. Peer acceptance was found to have a general protective effect on global self-esteem for all adolescents. In addition, at most ages, peer acceptance was found to have a protective-stabilizing effect on the relationship between closeness to parents and global self-esteem. This indicates that peer acceptance can be an especially valuable source of global self-esteem when closeness to parents is low. PMID- 23435860 TI - The role of exposure to self-injury among peers in predicting later self-injury. AB - While researchers are beginning to reach consensus around key psychological correlates of non-suicidal self-injury (NSSI), comparatively less work has been done investigating the role and influence of peers. Given evidence that engagement in this behavior may be susceptible to peer influence, especially during the early stages of its course, the current study prospectively explored whether knowing a friend who self-injures is associated with the onset, severity, and subsequent engagement in NSSI. The moderating roles of adverse life events, substance use and previous suicidal behavior in this relationship also were explored. Self-report data were collected from 1,973 school-based adolescents (aged 12-18 years; 72 % female) at two time points, 1 year apart. Knowing a friend who self-injured, negative life events, psychological distress and thoughts of NSSI differentiated those who self-injured from those who did not, and also predicted the onset of NSSI within the study period. Further, adverse life events and previous thoughts of NSSI moderated the relationship between exposure to NSSI in peers and engaging in NSSI at Time 2. However, the effect of having a friend who self-injures was not related to the severity of NSSI. Having a friend who self-injures appears to be a risk factor for self-injury among youth who are experiencing high levels of distress. Implications of these findings are discussed. PMID- 23435861 TI - Cost effectiveness of pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous stem cell transplantation in patients with lymphoma and myeloma: an economic evaluation of the PALM Trial. AB - BACKGROUND: Use of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) filgrastim accelerates neutrophil recovery following myelosuppressive chemotherapy. Since filgrastim requires multiple daily administrations, forms of rhG-CSF with a longer half life, including pegfilgrastim, have been developed. Pegfilgrastim is safe and effective in supporting neutrophil recovery and reducing febrile neutropenia after conventional chemotherapy. Pegfilgrastim has also been successfully used to support patients undergoing peripheral blood stem cell (PBSC) transplantation for haematological malignancies. To our knowledge, no cost-effectiveness analysis (CEA) of pegfilgrastim in this setting has been published yet. OBJECTIVE: We undertook a CEA to compare a single injection of pegfilgrastim versus repeated administrations of filgrastim in patients who had undergone PBSC transplantation for lymphoma or myeloma. The CEA was set in France and covered a period of 100 +/- 10 days from transplant. METHODS: The CEA was designed as part of an open-label, multicentre, randomized phase II trial. Costs were assessed from the hospital's point of view and are expressed in 2009 euros. Costs computation focused on inpatient, outpatient, and home care. Costs in the two arms of the study were compared using the Mann-Whitney test. When differences were statistically significant, multiple regression analyses were performed in order to identify cost drivers. Incremental cost-effectiveness ratios (ICER) were calculated for the major endpoints of the trial; i.e., duration of febrile neutropenia (absolute neutrophil count [ANC] <0.5 * 10(9)/L and temperature >=38 degrees C), duration of neutropenia (ANC <1.0 * 10(9)/L and ANC <0.5 * 10(9)/L), duration of thrombopenia (platelets <50 * 10(9)/L and <20 * 10(9)/L), and days with a temperature >=38 degrees C). Uncertainty around the ICER was captured by a probabilistic analysis using a non-parametric bootstrap method. RESULTS: 151 patients were enrolled at ten French centres from October 2008 to September 2009. The mean total cost in the pegfilgrastim arm of the study (n = 74) was 25,024 (SD 9,945). That in the filgrastim arm (n = 76) was 28,700 (SD 20,597). Pegfilgrastim strictly dominated filgrastim for days of febrile neutropenia avoided, days of neutropenia (ANC <1.0 * 10(9)/L) avoided, days of thrombopenia (platelets <20 * 10(9)/L) avoided, and days with temperature >=38 degrees C) avoided. Pegfilgrastim was less costly and less effective than filgrastim for the number of days with ANC <0.5 * 10(9)/L avoided and the number of days with platelets <50.0 * 10(9)/L avoided. Taking uncertainty into account, the probabilities that pegfilgrastim strictly dominated filgrastim were 67 % for febrile neutropenia, 86 % for neutropenia (ANC <1.0 * 10(9)/L), 59 % for thrombopenia (platelets <20 * 10(9)/L), 86 % for temperature >=38 degrees C, 32 % for neutropenia (ANC <0.5 * 10(9)/L), and 43 % for thrombopenia (platelets <50 * 10(9)/L). Conversely, the probability that filgrastim strictly dominated pegfilgrastim for neutropenia (ANC <0.5 * 10(9)/L) is 5 %. CONCLUSION: This study found no evidence that the use of pegfilgrastim is associated with greater cost in lymphoma and myeloma patients after high-dose chemotherapy and PBSC transplantation. PMID- 23435863 TI - Novel anti-platelet agents: focus on thrombin receptor antagonists. AB - Platelets are the key in the pathogenesis of atherothrombotic disease such as acute coronary syndromes, stroke, and peripheral arterial disease. Current anti platelet treatments are mainly based on inhibition of two important pathways of platelet activation: thromboxane A2 (TXA2) mediated (aspirin) and adenosine diphosphate (ADP)-P2Y12 receptor mediated (clopidogrel, prasugrel, and ticagrelor). Despite the dual anti-platelet therapy with aspirin and P2Y12 inhibitors have reduced ischemic events in patients with acute coronary syndromes (ACS), the rate of recurrent ischemic complication after ACS remains high. Combination of multiple anti-platelet agents is also associated with increased risk of bleeding. Thrombin is a potent platelet agonist and the increase of its activity has been reported in patients with ACS. Platelet effects of thrombin are mediated by protease-activated receptors (PAR), and PAR-1 is the most important receptor in human platelets. Two PAR-1 antagonists, vorapaxar and atopaxar, have undergone clinical investigation. In this review, we will describe the pharmacology of PAR-1 antagonists and will review and discuss results of randomized clinical trials with PAR-1 antagonists. PMID- 23435864 TI - Occurrence and seasonal prevalence of the coconut mite, Aceria guerreronis (Eriophyidae), and associated arthropods in Oman. AB - The coconut palm is an important crop in the sub arid coastal plain of Dhofar, Oman, for the high demand for its nut water and its use as ornamental plant. Damage of coconut fruits by the eriophyid mite Aceria guerreronis Keifer was first reported in that region in the late 1980s, but background information about the ecology of the pest in Oman was missing. Four surveys were conducted in different seasons from 2008 to 2009, to assess the distribution and prevalence of the coconut mite and its damage as well as the presence of natural enemies. Infestation by the coconut mite was conspicuous on most (99.7 %) palm trees, with 82.5 % damaged fruits. The average (+/- SE) density of coconut mites per fruit was 750 +/- 56; this level of infestation led to the incidence of over 25 % of surface damage on more than half of the fruits. The mite appeared more abundant at the end of the cold season through the summer. No significant differences were observed between infestation levels on local varieties, hybrids and on dwarf varieties. Neoseiulus paspalivorus (De Leon), Cydnoseius negevi (Swirski & Amitai) and Amblyseius largoensis (Muma) were the predatory mites found under the bracts of over 30 % of the coconut fruits and on 68 % of the coconut trees. Considering all sampling dates and all varieties together, average (+/- SE) phytoseiid density was 1.4 +/- 1.19 per fruit. Other mites found in the same habitat as A. guerreronis included the tarsonemids Steneotarsonemus furcatus De Leon and Nasutitarsonemus omani Lofego & Moraes. The pathogenic fungus Hirsutella thompsonii Fisher was rarely found infecting the coconut mite in Dhofar. Other fungal pathogens, namely Cordyceps sp. and Simplicillium sp., were more prevalent. PMID- 23435865 TI - Intraoperative low-field MR-guided frameless stereotactic biopsy for intracerebral lesions. AB - BACKGROUND: To present our intraoperative low-field magnetic resonance imaging (ioMRI) technique for stereotactic brain biopsy in various intracerebral lesions. METHOD: Seventy-eight consecutive patients underwent stereotactic biopsies with the PoleStar N-20/N-30 ioMRI system and data were evaluated retrospectively. Biopsy technique included ioMRI before surgery, followed by insertion of the biopsy cannula in the lesion, and ioMRI before and after biopsy. Statistical analysis was performed to compare subgroups using Excel and SPSS statistic software. RESULTS: In all patients, stereotactic biopsy was possible, with a mean intraoperative surgery time of 86.2 +/- 28.6 min and a mean hospital stay of 11.6 +/- 4.6 days. In 97.4 % (n = 76), histology was conclusive, representing 58 brain tumors and 18 other pathologies. Five patients were biopsied previously without conclusive diagnosis, and all biopsies were conclusive this time. Mean cross sectional lesion size in MRI T1 with contrast (n = 64) was 6.9 +/- 5.7 cm(2), and in lesions without T1 contrast enhancement (n = 14), T2 mean cross-sectional lesion size was 5.5 +/- 3.9 cm(2). Mean distance from the cortex surface to the lesion was 3.4 +/- 1.2 cm. One patient suffered from a postoperative wound dehiscence; neither clinically or radiologically significant hemorrhage after surgery, nor intraoperative complications occurred. CONCLUSIONS: Low-field ioMR guided frameless stereotactic biopsy accurately diagnosed different intracerebral lesions without major complications for the patients, and within an acceptable surgery time and hospital stay. In repeated non-conclusive biopsies in particular, low-field ioMRI offers a technique for arriving at a diagnosis. PMID- 23435866 TI - The combined use of mechanical thrombectomy devices is feasible for treating acute carotid terminus occlusion. AB - BACKGROUND: Mechanical thrombectomy devices have recently been developed and approved for recanalization of intracranial arterial occlusion. Here, we investigated the feasibility of combined stent-assisted and clot aspiration mechanical thrombectomy for effective recanalization of acute carotid terminus occlusion (CTO). METHODS: Ten consecutive patients with acute ischemic stroke secondary to CTO who underwent intra-arterial (IA) treatment with both stent retrieval and negative-pressured clot aspiration systems were enrolled. Periprocedural and radiologic findings and clinical outcomes were evaluated. RESULTS: The median age was 69 years (range, 47-86 years), and the median initial NIHSS score was 17.5 (range, 12-33). Mechanical thrombectomy was performed using a combination of the Solitaire stents and Penumbra system. Thrombolysis in cerebral ischemia [TICI] grade II-III was achieved in eight patients (80.0 %); complete recanalization of the CTO (TICI III) was achieved in three of those patients. Any type of intracranial hemorrhages occurred in four patients (40.0 %), but parenchymal hematoma type 2 was not observed. Four patients died within 3 months (40.0 %). CONCLUSIONS: Combined mechanical thrombectomy treatment was effective for recanalization of acute CTO. The combination of Solitaire and Penumbra devices can be considered as a treatment option for CTO. PMID- 23435867 TI - Visualization of angiographical arteriovenous shunting in perisylvian glioblastomas. AB - BACKGROUND: Arteriovenous shunting visualized by angiography is one of the major features of glioblastomas, and the visualization is dependent on the presence of extensive shunting. Extensive arteriovenous shunting is associated with the risk of poorly controlled intraoperative bleeding. When a tumor with extensive arteriovenous shunting is located in close proximity to the eloquent regions of the brain, a meticulous surgical procedure is necessary. In the present study, the site-oriented visualization of angiographical arteriovenous shunting was evaluated from the perspective of surgical treatment, with a particular focus on the perisylvian region that is in close proximity to motor and language regions (dominant hemisphere), as well as large arteries and veins. METHODS: Twenty-six consecutive patients underwent a resection of glioblastoma between February 2007 and September 2012. All patients were presurgically examined using digital subtraction angiography. The patients were subdivided into the following two groups based on the location of the tumor: 1) perisylvian glioblastoma (18 patients) and 2) non-perisylvian glioblastoma (eight patients). Angiography to detect the arteriovenous shunting was performed. In addition, the number of intratumoral vessels, tumor proliferative activity (MIB-1 labeling index), and volume of intraoperative bleeding were evaluated and compared between the two groups. RESULTS: Angiographical arteriovenous shunting was definitively visualized in 13 of 18 (72 %) perisylvian glioblastomas, in contrast to only one of eight (13 %) non-perisylvian glioblastomas (p = 0.007). There were no significant differences between the two groups with respect to the number of intratumoral vessels, MIB-1 labeling index, and volume of intraoperative bleeding. However, massive intraoperative bleeding of > 2,000 mL occurred in one perisylvian glioblastoma patient. CONCLUSIONS: Glioblastomas in the perisylvian region tend to be associated with extensive arteriovenous shunting that can be definitively visualized by performing an angiography. Because arteriovenous shunting carries the risk of intraoperative bleeding, perisylvian glioblastomas particularly in the dominant hemisphere-should be resected with a meticulous surgical procedure and strategy. PMID- 23435868 TI - Dermoid cyst of the lateral wall of the cavernous sinus presenting with isolated abducens nerve palsy. PMID- 23435869 TI - Neuroprotective effect of resveratrol on ischemia/reperfusion injury in rats through TRPC6/CREB pathways. AB - Previous studies have provided evidences that resveratrol can protect the brain from ischemia/reperfusion injury; the mechanisms of its neuroprotective effects remain unknown. To investigate whether resveratrol has neuroprotective effects on ischemia and reperfusion injury and whether resveratrol exerts its neuroprotective effects through inhibition of calpain proteolysis of TRPC6, a transient middle cerebral artery occlusion (MCAO) model was employed in rats. Western blot analysis was performed to detect the protein levels of aII-spectrin, transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylated cAMP/Ca(2+) response element-binding protein (p-CREB). The immunoreactivity of p CREB and TRPC6 were measured by quantum dot-based immunofluorescence analysis. Our results showed that MCAO rats showed large cortical infarct volumes and neurological scores. By contrast, resveratrol, when applied for 7 days before MCAO onset, significantly reduced infarct volumes and enhanced neurological scores at 24 h after reperfusion, and these results were accompanied by elevated TRPC6 and p-CREB activity and decreased calpain activity. When MEK or CaMKIV activity was inhibited by the addition of PD98059 or KN62, the neuroprotective effects of resveratrol were attenuated, and we observed a correlated decrease in CREB activity. Our results demonstrated that resveratrol prevented the brain from ischemia/reperfusion injury through the TRPC6-MEK-CREB and TRPC6-CaMKIV-CREB pathways. PMID- 23435870 TI - Carotenoids as electron or excited-state energy donors in artificial photosynthesis: an ultrafast investigation of a carotenoporphyrin and a carotenofullerene dyad. AB - Photophysical investigations of molecular donor-acceptor systems have helped elucidate many details of natural photosynthesis and revealed design principles for artificial photosynthetic systems. To obtain insights into the factors that govern the partition between excited-state energy transfer (EET) and electron transfer (ET) processes among carotenoids and tetrapyrroles and fullerenes, we have designed artificial photosynthetic dyads that are thermodynamically poised to favor ET over EET processes. The dyads were studied using transient absorption spectroscopy with ~100 femtosecond time resolution. For dyad , a carotenoporphyrin, excitation to the carotenoid S2 state induces ultrafast ET, competing with internal conversion (IC) to the carotenoid S1 state. In addition, the carotenoid S1 state gives rise to ET. In contrast with biological photosynthesis and many artificial photosynthetic systems, no EET at all was detected for this dyad upon carotenoid S2 excitation. Recombination of the charge separated state takes place in hundreds of picoseconds and yields a triplet state, which is interpreted as a triplet delocalized between the porphyrin and carotenoid moieties. In dyad , a carotenofullerene, excitation of the carotenoid in the S2 band results in internal conversion to the S1 state, ET and probably EET to fullerene on ultrafast timescales. From the carotenoid S1 state EET to fullerene occurs. Subsequently, the excited-state fullerene gives rise to ET from the carotenoid to the fullerene. Again, the charge separated state recombines in hundreds of picoseconds. The results illustrate that for a given rate of EET, the ratio of ET to EET can be controlled by adjusting the driving force for electron transfer. PMID- 23435871 TI - [The hospital-borne tetanus in the reference service of the Donka National Hospital in Conakry (2001-2011)]. AB - Become almost non-existent in the developed countries, the hospital-borne tetanus always stays of current events in our country in spite of the forensic problem which it puts. The objectives of this study were to determine prevalence of this affection, to describe its clinical picture and to determine its lethality. It is about a retrospective study of a duration of 11 years realized in the service of the infectious diseases of Conakry. Among 8649 hospitalizations from 2001 till 2012 we brought together 239 cases of tetanus (2.7%) among which 60 hospital borne tetanus (0.7%). Men represented 73% of these cases, with a sex-ratio M/F of 2.7. The age bracket of 20-40 years was the most affected with 32 cases (53.3%). A single patient had begun his vaccinal calendar which had remained incomplete. Both national hospitals of the CHU of Conakry and private hospitals were the biggest suppliers of this hospital-borne tetanus with respectively 22 and 27 cases (36.6 and 45%). Tetanus related to IM of quinine represented 26 cases (43.3%) whereas the hernial cure was found in 16 cases (26.6%). The average duration of invasion and incubation was respectively 1.5 days and 6 days for the dead (n = 45.7%) and 2 days and 10.5 days for the survivors. Three-quarters of 60 patients died. The fight against this type of tetanus passes inevitably by an improvement of the working conditions, a strict application of the rules of asepsis and the in-service training of the medical and paramedical staff. PMID- 23435872 TI - Regorafenib for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi-target inhibitor. AB - Intracellular signals for cancer cell growth, proliferation, migration, and survival are frequently triggered by protein tyrosine kinases (TKs). The possibility of disrupting core disease pathways has led to development and widespread clinical use of specific TK inhibitors that in the past decade have markedly changed treatment strategies and impacted on overall outcomes. However, intrinsic resistance may limit the benefit of these drugs, and multiple escape routes compensate for the inhibited signaling. The disruption of several points of the same pathway and the simultaneous interference with different intracellular oncogenic processes have both been recognized as valuable strategies to maximize the therapeutic potential of this class of agents. In this scenario, regorafenib has emerged as a novel, orally active, multitarget compound with potent activity against a number of angiogenic and stromal TKs, including vascular endothelial growth factor receptor 2 (VEGFR-2), tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE-2), fibroblast growth factor receptor 1 (FGFR-1), and platelet-derived growth factor receptor (PDGFR). Moreover, the drug has the capability of blocking KIT, RET and V600 mutant BRAF. Starting from interesting preclinical results, this review describes the clinical development of regorafenib in gastrointestinal malignancies, focusing on data derived from cutting edge clinical trials that have provided evidence of efficacy in pretreated patients with advanced colorectal cancer or gastrointestinal stromal tumors. PMID- 23435874 TI - Toll-like receptors in human papillomavirus infection. AB - Infection with human papillomaviruses (HPVs) often causes cutaneous benign lesions, cervical cancer, and a number of other tumors. The mechanisms of host immune system to prevent and control HPV infection still remain poorly understood. Toll-like receptors (TLRs) are specific pattern recognition molecules that bind to microbial components to trigger innate immunity and direct adaptive immunity in the face of immunological danger. TLRs have been established to play an essential role in sensing and initiating antiviral immune responses. Recent accumulating evidence demonstrated that HPVs modulate TLR expression and interfere with TLR signaling pathways, leading to persistent viral infection and carcinogenesis. This review summarizes current knowledge on the roles of TLR during HPV infection, focusing on TLR recognition, modulation of TLR expression and signaling, regulatory receptors involved in TLR signaling, and cross-talk of TLRs with antimicrobial peptides. Immunotherapeutic strategies based on TLR agonists have emerged to be one of the novel promising avenues in treatment of HPV-associated diseases in the future. PMID- 23435873 TI - Lung surfactant protein D (SP-D) response and regulation during acute and chronic lung injury. AB - BACKGROUND: Surfactant protein D (SP-D) is a collection that plays important roles in modulating host defense functions and maintaining phospholipid homeostasis in the lung. The aim of current study was to characterize comparatively the SP-D response in bronchoalveolar lavage (BAL) and serum in three murine models of lung injury, using a validated ELISA technology for estimation of SP-D levels. METHODS: Mice were exposed to lipopolysaccharide, bleomycin, or Pneumocystis carinii (Pc) and sacrificed at different time points. RESULTS: In lipopolysaccharide-challenged mice, the level of SP-D in BAL increased within 6 h, peaked at 51 h (4,518 ng/ml), and returned to base level at 99 h (612 ng/ml). Serum levels of SP-D increased immediately (8.6 ng/ml), peaked at 51 h (16 ng/ml), and returned to base levels at 99 h (3.8 ng/ml). In a subacute bleomycin inflammation model, SP-D levels were 4,625 and 367 ng/ml in BAL and serum, respectively, 8 days after exposure. In a chronic Pc inflammation model, the highest level of SP-D was observed 6 weeks after inoculation, with BAL and serum levels of 1,868 and 335 ng/ml, respectively. CONCLUSIONS: We conclude that serum levels of SP-D increase during lung injury, with a sustained increment during chronic inflammation compared with acute inflammation. A quick upregulation of SP-D in serum in response to acute airway inflammation supports the notion that SP-D translocates from the airways into the vascular system, in favor of being synthesized systemically. The study also confirms the concept of using increased SP-D serum levels as a biomarker of especially chronic airway inflammation. PMID- 23435875 TI - Increasing reducing power output (NADH) of glucose catabolism for reduction of xylose to xylitol by genetically engineered Escherichia coli AI05. AB - Anaerobic homofermentative production of reduced products requires additional reducing power (NADH and/or NADPH) output from glucose catabolism. Previously, with an anaerobically expressed pyruvate dehydrogenase operon (aceEF-lpd), we doubled the reducing power output to four NADH per glucose (or 1.2 xylose) catabolized anaerobically, which satisfied the NADH requirement to establish a non-transgenic homoethanol pathway (1 glucose or 1.2 xylose --> 2 acetyl-CoA + 4 NADH --> 2 ethanol) in the engineered strain, Escherichia coli SZ420 (?frdBC ?ldhA ?ackA ?focA-pflB ?pdhR::pflBp6-pflBrbs-aceEF-lpd). In this study, E. coli SZ420 was further engineered for reduction of xylose to xylitol by (1) deleting the alcohol dehydrogenase gene (adhE) to divert NADH from the ethanol pathway; (2) deleting the glucose-specific PTS permease gene (ptsG) to eliminate catabolite repression and allow simultaneous uptake of glucose and xylose; (3) cloning the aldose reductase gene (xylI) of Candida boidinii to reduce xylose to xylitol. The resulting strain, E. coli AI05 (pAGI02), could in theory simultaneously uptake glucose and xylose, and utilize glucose as a source of reducing power for the reduction of xylose to xylitol, with an expected yield of four xylitol for each glucose consumed (YRPG = 4) under anaerobic conditions. In resting cell fermentation tests using glucose and xylose mixtures, E. coli AI05 (pAGI02) achieved an actual YRPG value of ~3.6, with xylitol as the major fermentation product and acetate as the by-product. PMID- 23435876 TI - A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer. AB - BACKGROUND: Preclinical studies demonstrated antiproliferative synergy of 1,25-D3 (calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose (RP2D) of 1,25-D3 with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer. METHODS: Patients were >=18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D3 intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D3 were 30, 45, 60, and 80 mcg/m(2). A two-stage design was employed for phase II portion. We correlated CYP24A1 tagSNPs with clinical outcome and 1,25-D3 pharmacokinetics (PK). RESULTS: 34 patients were enrolled. At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D3 was 60 mcg/m(2). Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI 3.4, 6.5), and median overall survival 8.7 months (95 % CI 7.6, 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (P = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (P = 0.08). There was no association between 1,25-D3 PK and CYP24A1 SNPs. CONCLUSIONS: The RP2D of 1,25-D3 with docetaxel and cisplatin was 60 mcg/m(2) every 21 days. Pre-specified endpoint of 50 % confirmed RR was not met in the phase II study. Functional SNPs in CYP24A1 may inform future studies individualizing 1,25-D3. PMID- 23435877 TI - Sorafenib enhances the chemotherapeutic efficacy of S-1 against hepatocellular carcinoma through downregulation of transcription factor E2F-1. AB - PURPOSE: Sorafenib and S-1 (one mixed formulation containing 5-FU prodrug and dihydropyrimidine dehydrogenase inhibitor) were two effective agents against hepatocellular carcinoma (HCC), but whether they had synergistic effects remained unclear. The present study aimed at evaluating their synergistic effects against HCC and its mechanisms. METHODS: Inhibitory effects of sorafenib, 5-FU and their combination on HCC cells PLC/PRF/5 and SK-HEP-1 were evaluated. Expressions of transcription factor E2F-1 and its downstream thymidylate synthetase (TS) in the treated cells were determined using real-time PCR and Western blot. In vivo anti tumoral efficacy of S-1 plus sorafenib on HCC was evaluated in NOD/SCID mice. E2F 1 and TS expressions in tumors were determined by immunohistochemical staining. RESULTS: Sorafenib inhibited growth of HCC cells in dose-dependent manner, with IC50 of 5.4 +/- 0.3 MUmol/L for PLC/PRF/5 and 5.3 +/- 0.5 MUmol/L for SK-HEP-1. Sorafenib (1 MUmol/L) enhanced inhibitory efficacy of 5-FU on HCC cells in vitro, dropping IC50 of 5-FU from 167.7 +/- 12.1 to 105.4 +/- 8.4 MUmol/L for PLC/PRF/5 and 115 +/- 10.2 to 82 +/- 7.4 MUmol/L for SK-HEP-1 (both p < 0.01). Sorafenib downregulated E2F-1 and TS expressions on HCC cells, and its combination with 5 FU yielded a synergistic downregulation of TS expression on HCC cells. In NOD/SCID mice with subcutaneously inoculated HCC, sorafenib combined with S-1 yielded greater inhibition on tumor growth and remarkable TS suppression when compared with sorafenib or S-1 alone (all p < 0.05). CONCLUSIONS: Sorafenib enhanced therapeutic efficacy of 5-FU/S-1 against HCC through downregulation of E2F-1 and TS expressions. Sorafenib combined with S-1 might represent as valuable therapeutic regimen against HCC. PMID- 23435878 TI - Establishment of cellobiose utilization for lipid production in Rhodococcus opacus PD630. AB - Rhodococcus opacus PD630, which is known for its ability to accumulate large amounts of triacylglycerols (TAG), was metabolically engineered, and a cellobiose utilization pathway was introduced. Activities of beta-glucosidases were determined, and recombinant strains accumulated fatty acids up to 39.5 +/- 5.7% (wt/wt) of cell dry mass from cellobiose. PMID- 23435879 TI - The Burkholderia contaminans MS14 ocfC gene encodes a xylosyltransferase for production of the antifungal occidiofungin. AB - Burkholderia contaminans strain MS14 produces the antifungal compound occidiofungin, which is responsible for significant antifungal activities against a broad range of plant and animal fungal pathogens. Occidiofungin is a cyclic glycolipopeptide made up of eight amino acids and one xylose. A 56-kb ocf gene cluster was determined to be essential for occidiofungin production. In this study, the ocfC gene, which is located downstream of ocfD and upstream of the ocfB gene in the ocf gene cluster, was examined. Antifungal activity of the ocfC gene mutant MS14KC1 was reduced against the indicator fungus Geotrichum candidum compared with that of the wild-type strain. Furthermore, the analysis of the protein sequence suggests that the ocfC gene encodes a glycosyltransferase. Biochemical analyses using nuclear magnetic resonance (NMR) and mass spectroscopy revealed that the ocfC mutant produced the occidiofungin without the xylose. The purified ocfC mutant MS14KC1 product had a level of bioactivity similar to that of the wild-type product. The revertant MS14KC1-R of the ocfC mutant produced the same antifungal activity level on plate assays and the same antifungal compound based on high-performance liquid chromatography (HPLC) and mass spectroscopy analysis as wild-type strain MS14. Collectively, the study demonstrates that the ocfC gene encodes a glycosyltransferase responsible to add a xylose to the occidiofungin molecule and that the presence of the xylose is not important for antifungal activity against Candida species. The finding provides a novel variant for future studies aimed at evaluating its use for inhibiting clinical and agricultural fungi, and the finding could also simplify the chemical synthesis of occidiofungin variants. PMID- 23435880 TI - Biochemical and genetic characterization of the Enterococcus faecalis oxaloacetate decarboxylase complex. AB - Enterococcus faecalis encodes a biotin-dependent oxaloacetate decarboxylase (OAD), which is constituted by four subunits: E. faecalis carboxyltransferase subunit OadA (termed Ef-A), membrane pump Ef-B, biotin acceptor protein Ef-D, and the novel subunit Ef-H. Our results show that in E. faecalis, subunits Ef-A, Ef D, and Ef-H form a cytoplasmic soluble complex (termed Ef-AHD) which is also associated with the membrane. In order to characterize the role of the novel Ef-H subunit, coexpression of oad genes was performed in Escherichia coli, showing that this subunit is vital for Ef-A and Ef-D interaction. Diminished growth of the oadA and oadD single deletion mutants in citrate-supplemented medium indicated that the activity of the complex is essential for citrate utilization. Remarkably, the oadB-deficient strain was still capable of growing to wild-type levels but with a delay during the citrate-consuming phase, suggesting that the soluble Ef-AHD complex is functional in E. faecalis. These results suggest that the Ef-AHD complex is active in its soluble form, and that it is capable of interacting in a dynamic way with the membrane-bound Ef-B subunit to achieve its maximal alkalinization capacity during citrate fermentation. PMID- 23435881 TI - No protective effects of high-dosage dietary zinc oxide on weaned pigs infected with Salmonella enterica serovar typhimurium DT104. AB - Twenty-eight-day-old weaned pigs were fed diets with a low (LZn), medium (MZn), or high (MZn) Zn concentration (50 to 80, 150, or 2,500 mg Zn/kg of diet, respectively) provided as zinc oxide (ZnO)(24 pigs per group). They were infected orally with Salmonella enterica serovar Typhimurium DT104 on day 32. Salmonellae were cultivated from feces (up to 42 days postinfection [dpi]) and organs (2 and 42 dpi). Activation of the adaptive systemic and mucosal immune systems was investigated by recording anti-Salmonella IgG levels and levels of B and T lymphocyte subpopulations in blood and gut-associated lymphatic tissue. Growth performance was recorded as well. Salmonellae were shed at higher levels and for longer periods in the HZn group (P < 0.05), with no differences in the tissues. At 2 dpi, the relative percentages of CD4(+) T helper cells (P < 0.01) and of CD2(+) T and NK cells (P < 0.01) in blood were reduced from the relative cell counts obtained at 0 dpi, irrespective of the Zn group. The lowest percentage of cytotoxic T cells was found 14 dpi in the HZn group relative to the MZn (P < 0.05) and LZn (P < 0.01) groups. Supplementation of the feed with 2,500 mg Zn/kg of diet immediately after weaning could positively affect the immune responses of piglets infected with Salmonella Typhimurium, but for a short period only. After 2 weeks, all positive effects disappeared, and rather negative effects, such as higher shedding of salmonellae, lower T cell frequencies, and worse performance, occurred. Thus, supplementation with ZnO at high levels in the pig industry should be limited to 2 to 3 weeks. PMID- 23435882 TI - Characterization of the achromobactin iron acquisition operon in Sodalis glossinidius. AB - Sodalis glossinidius is a facultative, extra- and intracellular symbiont found in most tissues of the tsetse fly (Glossinia sp.). Sodalis has a putative achromobactin siderophore iron acquisition system on the pSG1 plasmid. Reverse transcription (RT)-PCR analysis revealed that the achromobactin operon is transcribed as a single polycistronic molecule and is expressed when Sodalis is within the tsetse fly. Expression of the achromobactin operon was repressed under iron-replete conditions; in a mutant that lacks the iron-responsive transcriptional repressor protein Fur, expression was aberrantly derepressed under these iron-replete conditions, indicating that the Fur protein repressed achromobactin gene expression when iron was plentiful. A putative Fur binding site within the Sodalis achromobactin promoter bound Fur in Escherichia coli Fur titration assays. Wild-type Sodalis produced detectable siderophore in vitro, but a mutation in the putative achromobactin biosynthesis gene acsD eliminated detectable siderophore production in Sodalis. Reduced growth of the siderophore synthesis mutant was reconstituted by addition of exogenous achromobactin, suggesting the strain retains a functional siderophore transport system; however, reduced growth of a Sodalis ferric-siderophore outer membrane receptor mutant with a mutation in acr was not reconstituted by exogenous siderophore due to its defective transporter. The Sodalis siderophore synthesis mutant showed reduced growth in tsetse that lacked endogenous symbionts (aposymbiotic) when the flies were inoculated with Sodalis intrathoracically, but not when inoculated per os. Our findings suggest that Sodalis siderophores play a role in iron acquisition in certain tsetse fly tissues and provide evidence for the regulation of iron acquisition mechanisms in insect symbionts. PMID- 23435883 TI - Predation in homogeneous and heterogeneous phage environments affects virulence determinants of Pseudomonas aeruginosa. AB - The rise of bacterial variants in the presence of lytic phages has been one of the basic grounds for evolution studies. However, there are incongruent results among different studies investigating the effect of phage resistance acquisition on bacterial fitness and virulence. We used experimental evolution to generate three classes of Pseudomonas aeruginosa variants under selective pressure from two different homogeneous phage environments and one heterogeneous phage environment. The fitness and virulence determinants of the variants, such as growth, motility, biofilm formation, resistance to oxidative stress, and the production of siderophores and chromophores, changed significantly compared to the control. Variants with similar colony morphology that were developed through different phage treatments have different phenotypic traits. Also, mRNA transcription for genes associated with certain phenotypic traits changed significantly; however, sequencing did not reveal any point mutations in selected gene loci. Furthermore, the appearance of small colony variants and melanogenic variants and the increase in pyocyanin and pyoverdin production for some variants are believed to affect the virulence of the population. The knowledge gained from this study will fundamentally contribute to our understanding of the evolutionary dynamics of bacteria under phage selective pressure which is crucial to the efficient utilization of bacteriophages in medical contexts. PMID- 23435884 TI - Simultaneous quantification of multiple food- and waterborne pathogens by use of microfluidic quantitative PCR. AB - The direct quantification of multiple pathogens has been desired for diagnostic and public health purposes for a long time. In this study, we applied microfluidic quantitative PCR (qPCR) technology to the simultaneous detection and quantification of multiple food- and waterborne pathogens. In this system, multiple singleplex qPCR assays were run under identical detection conditions in nanoliter-volume chambers that are present in high densities on a chip. First, we developed 18 TaqMan qPCR assays that could be run in the same PCR conditions by using prevalidated TaqMan probes. Specific and sensitive quantification was achieved by using these qPCR assays. With the addition of two previously validated TaqMan qPCR assays, we used 20 qPCR assays targeting 10 enteric pathogens, a fecal indicator bacterium (general Escherichia coli), and a process control strain in the microfluidic qPCR system. We preamplified the template DNA to increase the sensitivity of the qPCR assays. Our results suggested that preamplification was effective for quantifying small amounts of the template DNA without any major impact on the sensitivity, efficiency, and quantitative performance of qPCR. This microfluidic qPCR system allowed us to detect and quantify multiple pathogens from fecal samples and environmental water samples spiked with pathogens at levels as low as 100 cells/liter. These results suggest that the routine monitoring of multiple pathogens in food and water samples is now technically feasible. This method may provide more reliable information for risk assessment than the current fecal contamination indicator approach. PMID- 23435885 TI - Comparison of the microbial community structures of untreated wastewaters from different geographic locales. AB - Microbial sewage communities consist of a combination of human fecal microorganisms and nonfecal microorganisms, which may be residents of urban sewer infrastructure or flowthrough originating from gray water or rainwater inputs. Together, these different microorganism sources form an identifiable community structure that may serve as a signature for sewage discharges and as candidates for alternative indicators specific for human fecal pollution. However, the structure and variability of this community across geographic space remains uncharacterized. We used massively parallel 454 pyrosequencing of the V6 region in 16S rRNA genes to profile microbial communities from 13 untreated sewage influent samples collected from a wide range of geographic locations in the United States. We obtained a total of 380,175 high-quality sequences for sequence based clustering, taxonomic analyses, and profile comparisons. The sewage profile included a discernible core human fecal signature made up of several abundant taxonomic groups within Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. DNA sequences were also classified into fecal, sewage infrastructure (i.e., nonfecal), and transient groups based on data comparisons with fecal samples. Across all sewage samples, an estimated 12.1% of sequences were fecal in origin, while 81.4% were consistently associated with the sewage infrastructure. The composition of feces-derived operational taxonomic units remained congruent across all sewage samples regardless of geographic locale; however, the sewage infrastructure community composition varied among cities, with city latitude best explaining this variation. Together, these results suggest that untreated sewage microbial communities harbor a core group of fecal bacteria across geographically dispersed wastewater sewage lines and that ambient water quality indicators targeting these select core microorganisms may perform well across the United States. PMID- 23435886 TI - Multiple propionyl coenzyme A-supplying pathways for production of the bioplastic poly(3-hydroxybutyrate-co-3-hydroxyvalerate) in Haloferax mediterranei. AB - Haloferax mediterranei is able to accumulate the bioplastic poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) with more than 10 mol% 3 hydroxyvalerate (3HV) from unrelated carbon sources. However, the pathways that produce propionyl coenzyme A (propionyl-CoA), an important precursor of 3HV monomer, have not yet been determined. Bioinformatic analysis of H. mediterranei genome indicated that this strain uses multiple pathways for propionyl-CoA biosynthesis, including the citramalate/2-oxobutyrate pathway, the aspartate/2 oxobutyrate pathway, the methylmalonyl-CoA pathway, and a novel 3 hydroxypropionate pathway. Cofeeding of pathway intermediates and inactivating pathway-specific genes supported that these four pathways were indeed involved in the biosynthesis of 3HV monomer. The novel 3-hydroxypropionate pathway that couples CO2 assimilation with PHBV biosynthesis was further confirmed by analysis of (13)C positional enrichment in 3HV. Notably, (13)C metabolic flux analysis showed that the citramalate/2-oxobutyrate pathway (53.0% flux) and the 3 hydroxypropionate pathway (30.6% flux) were the two main generators of propionyl CoA from glucose. In addition, genetic perturbation on the transcriptome of the DeltaphaEC mutant (deficient in PHBV accumulation) revealed that a considerable number of genes in the four propionyl-CoA synthetic pathways were significantly downregulated. We determined for the first time four propionyl-CoA-supplying pathways for PHBV production in haloarchaea, particularly including a new 3 hydroxypropionate pathway. These results would provide novel strategies for the production of PHBV with controllable 3HV molar fraction. PMID- 23435887 TI - Genome sequencing identifies two nearly unchanged strains of persistent Listeria monocytogenes isolated at two different fish processing plants sampled 6 years apart. AB - Listeria monocytogenes is a food-borne human-pathogenic bacterium that can cause infections with a high mortality rate. It has a remarkable ability to persist in food processing facilities. Here we report the genome sequences for two L. monocytogenes strains (N53-1 and La111) that were isolated 6 years apart from two different Danish fish processers. Both strains are of serotype 1/2a and belong to a highly persistent DNA subtype (random amplified polymorphic DNA [RAPD] type 9). We demonstrate using in silico analyses that both strains belong to the multilocus sequence typing (MLST) type ST121 that has been isolated as a persistent subtype in several European countries. The purpose of this study was to use genome analyses to identify genes or proteins that could contribute to persistence. In a genome comparison, the two persistent strains were extremely similar and collectively differed from the reference lineage II strain, EGD-e. Also, they differed markedly from a lineage I strain (F2365). On the proteome level, the two strains were almost identical, with a predicted protein homology of 99.94%, differing at only 2 proteins. No single-nucleotide polymorphism (SNP) differences were seen between the two strains; in contrast, N53-1 and La111 differed from the EGD-e reference strain by 3,942 and 3,471 SNPs, respectively. We included a persistent L. monocytogenes strain from the United States (F6854) in our comparisons. Compared to nonpersistent strains, all three persistent strains were distinguished by two genome deletions: one, of 2,472 bp, typically contains the gene for inlF, and the other, of 3,017 bp, includes three genes potentially related to bacteriocin production and transport (lmo2774, lmo2775, and the 3'-terminal part of lmo2776). Further studies of highly persistent strains are required to determine if the absence of these genes promotes persistence. While the genome comparison did not point to a clear physiological explanation of the persistent phenotype, the remarkable similarity between the two strains indicates that subtypes with specific traits are selected for in the food processing environment and that particular genetic and physiological factors are responsible for the persistent phenotype. PMID- 23435888 TI - Behavior of Escherichia coli in a heterogeneous gelatin-dextran mixture. AB - In a gelatin-dextran mixture, changing the (relative and/or absolute) concentration of the components leads to the formation of different microstructures. Confocal laser scanning microscopy illustrated that the nature of the microstructure determines the location and morphology of Escherichia coli colonies. Observations indicate that bacterial growth preferentially occurs in the dextran phase, regardless of the microstructure. PMID- 23435889 TI - Evolution, multiple acquisition, and localization of endosymbionts in bat flies (Diptera: Hippoboscoidea: Streblidae and Nycteribiidae). AB - Bat flies are a diverse clade of obligate ectoparasites on bats. Like most blood feeding insects, they harbor endosymbiotic prokaryotes, but the origins and nature of these symbioses are still poorly understood. To expand the knowledge of bacterial associates in bat flies, the diversity and evolution of the dominant endosymbionts in six of eight nominal subfamilies of bat flies (Streblidae and Nycteribiidae) were studied. Furthermore, the localization of endosymbionts and their transmission across developmental stages within the family Streblidae were explored. The results show diverse microbial associates in bat flies, with at least four ancestral invasions of distantly related microbial lineages throughout bat fly evolution. Phylogenetic relationships support the presence of at least two novel symbiont lineages (here clades B and D), and extend the geographic and taxonomic range of a previously documented lineage ("Candidatus Aschnera chinzeii"; here clade A). Although these lineages show reciprocally monophyletic clusters with several bat fly host clades, their phylogenetic relationships generally do not reflect current bat fly taxonomy or phylogeny. However, within some endosymbiont clades, congruent patterns of symbiont-host divergence are apparent. Other sequences identified in this study fall into the widely distributed, highly invasive, insect-associated Arsenophonus lineage and may be the result of symbiont replacements and/or transient infections (here clade C). Vertical transmission of endosymbionts of clades B and D is supported by fluorescent signal (fluorescent in situ hybridization [FISH]) and microbial DNA detection across developmental stages. The fluorescent bacterial signal is consistently localized within structures resembling bacteriomes, although their anatomical position differs by host fly clade. In summary, the results suggest an obligate host-endosymbiont relationship for three of the four known symbiont clades associated with bat flies (clades A, B, and D). PMID- 23435890 TI - Effect of tannic acid on the transcriptome of the soil bacterium Pseudomonas protegens Pf-5. AB - Tannins are a diverse group of plant-produced, polyphenolic compounds with metal chelating and antimicrobial properties that are prevalent in many soils. Using transcriptomics, we determined that tannic acid, a form of hydrolysable tannin, broadly affects the expression of genes involved in iron and zinc homeostases, sulfur metabolism, biofilm formation, motility, and secondary metabolite biosynthesis in the soil- and rhizosphere-inhabiting bacterium Pseudomonas protegens Pf-5. PMID- 23435891 TI - Comparative genomic analysis of phylogenetically closely related Hydrogenobaculum sp. isolates from Yellowstone National Park. AB - We describe the complete genome sequences of four closely related Hydrogenobaculum sp. isolates (>= 99.7% 16S rRNA gene identity) that were isolated from the outflow channel of Dragon Spring (DS), Norris Geyser Basin, in Yellowstone National Park (YNP), WY. The genomes range in size from 1,552,607 to 1,552,931 bp, contain 1,667 to 1,676 predicted genes, and are highly syntenic. There are subtle differences among the DS isolates, which as a group are different from Hydrogenobaculum sp. strain Y04AAS1 that was previously isolated from a geographically distinct YNP geothermal feature. Genes unique to the DS genomes encode arsenite [As(III)] oxidation, NADH-ubiquinone-plastoquinone (complex I), NADH-ubiquinone oxidoreductase chain, a DNA photolyase, and elements of a type II secretion system. Functions unique to strain Y04AAS1 include thiosulfate metabolism, nitrate respiration, and mercury resistance determinants. DS genomes contain seven CRISPR loci that are almost identical but are different from the single CRISPR locus in strain Y04AAS1. Other differences between the DS and Y04AAS1 genomes include average nucleotide identity (94.764%) and percentage conserved DNA (80.552%). Approximately half of the genes unique to Y04AAS1 are predicted to have been acquired via horizontal gene transfer. Fragment recruitment analysis and marker gene searches demonstrated that the DS metagenome was more similar to the DS genomes than to the Y04AAS1 genome, but that the DS community is likely comprised of a continuum of Hydrogenobaculum genotypes that span from the DS genomes described here to an Y04AAS1-like organism, which appears to represent a distinct ecotype relative to the DS genomes characterized. PMID- 23435892 TI - Development of a transferable bimolecular fluorescence complementation system for the investigation of interactions between poly(3-hydroxybutyrate) granule associated proteins in Gram-negative bacteria. AB - Poly(3-hydroxybutyrate) (PHB) granules are organelle-like multienzyme-polymer complexes (carbonosomes) and are widespread storage compounds in prokaryotes. The interaction of three PHB granule-bound proteins (PHB synthase PhaC1, phasin PhaP5, and PHB/DNA binding protein PhaM) was studied in vivo by bimolecular fluorescence complementation (BiFC) microscopy in Ralstonia eutropha. To this end, a mobilizable 2-plasmid system for arabinose-controlled expression of protein fusions with the N-terminal (YN) and C-terminal (YC) parts of the enhanced yellow fluorescent protein (eYfp) in Gram-negative bacteria was developed. Both plasmids were stably expressed in Escherichia coli and in transconjugants of R. eutropha. Homo-oligomerization of PhaC1, PhaP5, and PhaM and interactions between PhaC1 and PhaM and between PhaM and PhaP5 were detected in R. eutropha and colocalized with PHB granules under PHB-permissive conditions. PhaM-PhaC1 complexes were detected near the midcell/nucleoid region in the absence of PHB. Expression of BiFC complexes in R. eutropha with PhaM (PhaM homo oligomers or PhaM-PhaC1 or PhaM-PhaP5 complexes) resulted in substantial cell elongation compared to wild-type cells and in BiFC signals that were generally located near the midcell/nucleoid region. Western blot analysis of wild-type cell extracts and proteome analysis of PHB granule-bound proteins revealed that PhaM and PhaP5 are expressed in R. eutropha and that PhaM is constitutively expressed independently of the presence or absence of PHB. Size exclusion chromatography analysis in combination with cross-linking experiments of purified PhaP5-His6 and PhaM-His6 showed that PhaP5 forms dimers and that PhaM is present in oligomeric (dodecamer) form. Implications of this finding for subcellular PHB localization and initiation of PHB granule formation in R. eutropha will be discussed. PMID- 23435893 TI - Role of PelF in pel polysaccharide biosynthesis in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa produces three exopolysaccharides, Psl, Pel, and alginate, that play vital roles in biofilm formation. Pel is a glucose-rich, cellulose-like exopolysaccharide. The essential Pel biosynthesis proteins are encoded by seven genes, pelA to pelG. Bioinformatics analysis suggests that PelF is a cytosolic glycosyltransferase. Here, experimental evidence was provided to support this PelF function. A UDP-glucose dehydrogenase-based assay was developed to quantify UDP-glucose. UDP-glucose was proposed as the substrate for PelF. The isogenic pelF deletion mutant accumulated 1.8 times more UDP-glucose in its cytosol than the wild type. This suggested that PelF, which was found localized in the cystosol, uses UDP-glucose as substrate. Additionally, in vitro experiments confirmed that PelF uses UDP-glucose as substrate. To analyze the functional roles of conserved residues in PelF, site-directed mutagenesis was performed. The presence of the EX7E motif is characteristic for various glycosyltransferase families, and in PelF, E405/E413 are the conserved residues in this motif. Replacement of E405 with A resulted in a reduction of PelF activity to 30.35% +/- 3.15% (mean +/- standard deviation) of the wild-type level, whereas replacement of the second E, E413, with A did not produce a significant change in the activity of PelF. Moreover, replacement of both E residues did not result in a loss of PelF function, but replacement of the conserved R325 or K330 with A resulted in a complete loss of PelF activity. Overall, our data show that PelF is a soluble glycosyltransferase that uses UDP-glucose as the substrate for Pel synthesis and that conserved residues R325 and K330 are important for the activity of PelF. PMID- 23435894 TI - Comparative transcriptomic analysis of the Burkholderia cepacia tyrosine kinase bceF mutant reveals a role in tolerance to stress, biofilm formation, and virulence. AB - The bacterial tyrosine-kinase (BY-kinase) family comprises the major group of bacterial enzymes endowed with tyrosine kinase activity. We previously showed that the BceF protein from Burkholderia cepacia IST408 belongs to this BY-kinase family and is involved in the biosynthesis of the exopolysaccharide cepacian. However, little is known about the extent of regulation of this protein kinase activity. In order to examine this regulation, we performed a comparative transcriptome profile between the bceF mutant and wild-type B. cepacia IST408. The analyses led to identification of 630 genes whose expression was significantly changed. Genes with decreased expression in the bceF mutant were related to stress response, motility, cell adhesion, and carbon and energy metabolism. Genes with increased expression were related to intracellular signaling and lipid metabolism. Mutation of bceF led to reduced survival under heat shock and UV light exposure, reduced swimming motility, and alteration in biofilm architecture when grown in vitro. Consistent with some of these phenotypes, the bceF mutant demonstrated elevated levels of cyclic-di-GMP. Furthermore, BceF contributed to the virulence of B. cepacia for larvae of the Greater wax moth, Galleria mellonella. Taken together, BceF appears to play a considerable role in many cellular processes, including biofilm formation and virulence. As homologues of BceF occur in a number of pathogenic and plant associated Burkholderia strains, the modulation of bacterial behavior through tyrosine kinase activity is most likely a widely occurring phenomenon. PMID- 23435896 TI - Atypical glycolysis in Clostridium thermocellum. AB - Cofactor specificities of glycolytic enzymes in Clostridium thermocellum were studied with cellobiose-grown cells from batch cultures. Intracellular glucose was phosphorylated by glucokinase using GTP rather than ATP. Although phosphofructokinase typically uses ATP as a phosphoryl donor, we found only pyrophosphate (PPi)-linked activity. Phosphoglycerate kinase used both GDP and ADP as phosphoryl acceptors. In agreement with the absence of a pyruvate kinase sequence in the C. thermocellum genome, no activity of this enzyme could be detected. Also, the annotated pyruvate phosphate dikinase (ppdk) is not crucial for the generation of pyruvate from phosphoenolpyruvate (PEP), as deletion of the ppdk gene did not substantially change cellobiose fermentation. Instead pyruvate formation is likely to proceed via a malate shunt with GDP-linked PEP carboxykinase, NADH-linked malate dehydrogenase, and NADP-linked malic enzyme. High activities of these enzymes were detected in extracts of cellobiose-grown cells. Our results thus show that GTP is consumed while both GTP and ATP are produced in glycolysis of C. thermocellum. The requirement for PPi in this pathway can be satisfied only to a small extent by biosynthetic reactions, in contrast to what is generally assumed for a PPi-dependent glycolysis in anaerobic heterotrophs. Metabolic network analysis showed that most of the required PPi must be generated via ATP or GTP hydrolysis exclusive of that which happens during biosynthesis. Experimental proof for the necessity of an alternative mechanism of PPi generation was obtained by studying the glycolysis in washed cell suspensions in which biosynthesis was absent. Under these conditions, cells still fermented cellobiose to ethanol. PMID- 23435895 TI - Susceptibility of intact germinating Arabidopsis thaliana to human fungal pathogens Cryptococcus neoformans and C. gattii. AB - The fungus Cryptococcus contributes a large global burden of infectious death in both HIV-infected and healthy individuals. As Cryptococcus is an opportunistic pathogen, much of the evolutionary pressure shaping virulence occurs in environments in contact with plants and soil. The present studies investigated inoculation of intact seeds of the common weed Arabidopsis thaliana with fungal cells over a 21-day period. C. gattii was the more virulent plant pathogen, resulting in disrupted germination as well as increased stem lodging, fungal burden, and plant tissue colocalization. C. neoformans was a less virulent plant pathogen but exhibited prolonged tissue residence within the cuticle and vascular spaces. Arabidopsis mutants of the PRN1 gene, which is involved in abiotic and biotic signaling affecting phenylalanine-derived flavonoids, showed altered susceptibility to cryptoccocal infections, suggesting roles for this pathway in cryptococcal defense. The fungal virulence factor laccase was also implicated in plant pathogenesis, as a cryptococcal lac1Delta strain was less virulent than wild-type fungi and was unable to colonize seedlings. In conclusion, these studies expand knowledge concerning the ecological niche of Cryptococcus by demonstrating the pathogenic capacity of the anamorphic form of cryptococcal cells against healthy seedlings under physiologically relevant conditions. In addition, an important role of laccase in plant as well as human virulence may suggest mechanisms for laccase retention and optimization during evolution of this fungal pathogen. PMID- 23435897 TI - Anaerobic alpha-amylase production and secretion with fumarate as the final electron acceptor in Saccharomyces cerevisiae. AB - In this study, we focus on production of heterologous alpha-amylase in the yeast Saccharomyces cerevisiae under anaerobic conditions. We compare the metabolic fluxes and transcriptional regulation under aerobic and anaerobic conditions, with the objective of identifying the final electron acceptor for protein folding under anaerobic conditions. We find that yeast produces more amylase under anaerobic conditions than under aerobic conditions, and we propose a model for electron transfer under anaerobic conditions. According to our model, during protein folding the electrons from the endoplasmic reticulum are transferred to fumarate as the final electron acceptor. This model is supported by findings that the addition of fumarate under anaerobic (but not aerobic) conditions improves cell growth, specifically in the alpha-amylase-producing strain, in which it is not used as a carbon source. Our results provide a model for the molecular mechanism of anaerobic protein secretion using fumarate as the final electron acceptor, which may allow for further engineering of yeast for improved protein secretion under anaerobic growth conditions. PMID- 23435898 TI - Activated zeolite--suitable carriers for microorganisms in anaerobic digestion processes? AB - Plant cell wall structures represent a barrier in the biodegradation process to produce biogas for combustion and energy production. Consequently, approaches concerning a more efficient de-polymerisation of cellulose and hemicellulose to monomeric sugars are required. Here, we show that natural activated zeolites (i.e. trace metal activated zeolites) represent eminently suitable mineral microhabitats and potential carriers for immobilisation of microorganisms responsible for anaerobic hydrolysis of biopolymers stabilising related bacterial and methanogenic communities. A strategy for comprehensive analysis of immobilised anaerobic populations was developed that includes the visualisation of biofilm formation via scanning electron microscopy and confocal laser scanning microscopy, community and fingerprint analysis as well as enzyme activity and identification analyses. Using SDS polyacrylamide gel electrophoresis, hydrolytical active protein bands were traced by congo red staining. Liquid chromatography/mass spectroscopy revealed cellulolytical endo- and exoglucanase (exocellobiohydrolase) as well as hemicellulolytical xylanase/mannase after proteolytic digestion. Relations to hydrolytic/fermentative zeolite colonisers were obtained by using single-strand conformation polymorphism analysis (SSCP) based on amplification of bacterial and archaeal 16S rRNA fragments. Thereby, dominant colonisers were affiliated to the genera Clostridium, Pseudomonas and Methanoculleus. The specific immobilisation on natural zeolites with functional microbes already colonising naturally during the fermentation offers a strategy to systematically supply the biogas formation process responsive to population dynamics and process requirements. PMID- 23435899 TI - Growth of the yeast Kluyveromyces marxianus CBS 6556 on different sugar combinations as sole carbon and energy source. AB - The yeast Kluyveromyces marxianus has been pointed out as a promising microorganism for a variety of industrial bioprocesses. Although genetic tools have been developed for this yeast and different potential applications have been investigated, quantitative physiological studies have rarely been reported. Here, we report and discuss the growth, substrate consumption, metabolite formation, and respiratory parameters of K. marxianus CBS 6556 during aerobic batch bioreactor cultivations, using a defined medium with different sugars as sole carbon and energy source, at 30 and 37 degrees C. Cultivations were carried out both on single sugars and on binary sugar mixtures. Carbon balances closed within 95 to 101 % in all experiments. Biomass and CO2 were the main products of cell metabolism, whereas by-products were always present in very low proportion (<3 % of the carbon consumed), as long as full aerobiosis was guaranteed. On all sugars tested as sole carbon and energy source (glucose, fructose, sucrose, lactose, and galactose), the maximum specific growth rate remained between 0.39 and 0.49 h( 1), except for galactose at 37 degrees C, which only supported growth at 0.31 h( 1). Different growth behaviors were observed on the binary sugar mixtures investigated (glucose and lactose, glucose and galactose, lactose and galactose, glucose and fructose, galactose and fructose, fructose and lactose), and the observations were in agreement with previously published data on the sugar transport systems in K. marxianus. We conclude that K. marxianus CBS 6556 does not present any special nutritional requirements; grows well in the range of 30 to 37 degrees C on different sugars; is capable of growing on sugar mixtures in a shorter period of time than Saccharomyces cerevisiae, which is interesting from an industrial point of view; and deviates tiny amounts of carbon towards metabolite formation, as long as full aerobiosis is maintained. PMID- 23435900 TI - Enhanced heme protein expression by ammonia-oxidizing communities acclimated to low dissolved oxygen conditions. AB - This study has investigated the acclimation of ammonia-oxidizing communities (AOC) to low dissolved oxygen (DO) concentrations. Under controlled laboratory conditions, two sequencing batch reactors seeded with activated sludge from the same source were operated at high DO (near saturation) and low DO (0.1 mg O2/L) concentrations for a period of 220 days. The results demonstrated stable and complete nitrification at low DO conditions after an acclimation period of approximately 140 days. Acclimation brought about increased specific oxygen uptake rates and enhanced expression of a particular heme protein in the soluble fraction of the cells in the low DO reactor as compared to the high DO reactor. The induced protein was determined not to be any of the enzymes or electron carriers present in the conventional account of ammonia oxidation in ammonia oxidizing bacteria (AOB). Further research is required to determine the specific nature of the heme protein detected; a preliminary assessment suggests either a type of hemoglobin protein or a lesser-known component of the energy-transducing pathways of AOB. The effect of DO on AOC dynamics was evaluated using the 16S rRNA gene as the basis for phylogenetic comparisons and organism quantification. Ammonium consumption by ammonia-oxidizing archaea and anaerobic ammonia-oxidizing bacteria was ruled out by fluorescent in situ hybridization in both reactors. Even though Nitrosomonas europaea was the dominant AOB lineage in both high and low DO sequencing batch reactors at the end of operation, this enrichment could not be linked in the low DO reactor to acclimation to oxygen-limited conditions. PMID- 23435901 TI - Total synthesis of antibiotics: recent achievements, limitations, and perspectives. AB - Several recently accomplished total syntheses of antibiotic natural products were summarized in this review in order to present current trends in this area of research. Compounds from different substance classes, including polyketide, depsipeptide, polyketide-polypeptide hybrid, and saccharide, were chosen to demonstrate the advancement in both chemical methodology and corresponding synthetic strategy. PMID- 23435902 TI - Genetics of Cordyceps and related fungi. AB - Ascomycete Cordyceps sensu lato consists of hundreds of species of fungi capable of infecting different insects. Species of these fungi are either valued traditional Chinese medicines or used for biocontrol of insect pests. Phylogenomic analysis indicated that fungal entomopathogenicity has evolved for multiple times, and the species of Cordyceps were diverged from the mycoparasite or plant endophyte. Relative to plant pathogens and saprophytes, Cordyceps species demonstrate characteristic genome expansions of proteases and chitinases that are used by the fungi to target insect cuticles. Only a single mating-type gene identified in the sequenced species of Cordyceps sensu lato indicates that these fungi are sexually heterothallic, but the gene structure of the mating-type loci and frequency in performing sexual cycle are considerably different between different species. Similar to the model fungus Neurospora crassa, Cordyceps and related fungi contain the full components for RNA interference pathways. However, the mechanism of repeat-induced point mutation varies between different fungi. Epigenetic rather than genetic alterations are majorly responsible for the frequent occurrence of culture degeneration in Cordyceps-related species. Future genetic and epigenetic studies of fungal sexuality controls and culture degeneration mechanisms will benefit the cost-effective applications of Cordyceps and related fungi in pharmaceuticals and agriculture. PMID- 23435903 TI - Validation of admittance computed left ventricular volumes against real-time three-dimensional echocardiography in the porcine heart. AB - The admittance and Wei's equation is a new technique for ventricular volumetry to determine pressure-volume relations that addresses traditional conductance related issues of parallel conductance and field correction factor. These issues with conductance have prevented researchers from obtaining real-time absolute ventricular volumes. Moreover, the time-consuming steps involved in processing conductance catheter data warrant the need for a better catheter-based technique for ventricular volumetry. We aimed to compare the accuracy of left ventricular (LV) volumetry between the new admittance catheterization technique and transoesophageal real-time three-dimensional echocardiography (RT3DE) in a large animal model. Eight anaesthetized pigs were used. A 7 French admittance catheter was positioned in the LV via the right carotid artery. The catheter was connected to an admittance control unit (ADVantage; Transonic Scisense Inc.), and data were recorded on a four-channel acquisition system (FA404; iWorx Systems). Admittance catheterization data and transoesophageal RT3DE (X7-2; Philips) data were simultaneously obtained with the animal ventilated, under neuromuscular blockade and monitored in baseline conditions and during dobutamine infusion. Left ventricular volumes measured from admittance catheterization (Labscribe; iWorx Systems) and RT3DE (Qlab; Philips) were compared. In a subset of four animals, admittance volumes were compared with those obtained from traditional conductance catheterization (MPVS Ultra; Millar Instruments). Of 37 sets of measurements compared, admittance- and RT3DE-derived LV volumes and ejection fractions at baseline and in the presence of dobutamine exhibited general agreement, with mean percentage intermethod differences of 10% for end-diastolic volumes, 14% for end systolic volumes and 9% for ejection fraction; the respective intermethod differences between admittance and conductance in eight data sets compared were 11, 11 and 12%. Admittance volumes were generally higher than those obtained by RT3DE, especially among the larger ventricles. It is concluded that it is feasible to derive pressure-volume relations using admittance catheterization in large animals. This study demonstrated agreements between admittance and RT3DE to within 10-14% mean intermethod difference in the estimation of LV volumes. Further investigation will be required to examine the accuracy of volumes in largest ventricles, where intermethod divergence is greatest. PMID- 23435904 TI - Coverage methods for early groundwater contamination detection. AB - A method based on space-filling coverage designs to optimize groundwater monitoring networks for plume detection and quantification is proposed. Space filling objective functions are then compared with more classical functions. The method was applied to a hypothetical case-study with 160 candidate locations, resulting in final optimal design monitoring networks with 40 locations. Results show that the method is superior to those based strictly on the probability of contamination detection for quantifying maximum and mean values. In the light of these results fractal properties of space-filling coverage methods and of simulated annealing are also discussed. PMID- 23435905 TI - A chemodosimeter for ratiometric detection of cyanide in aqueous media and human blood serum. AB - A highly selective and sensitive chemodosimeter for detection of cyanide ions in HEPES buffer and in the presence of blood serum using a ratiometric approach through dual UV-Vis and fluorescence channels with the lowest detection limit of 0.08 ppb has been synthesized. PMID- 23435906 TI - Multistep divergent synthesis of benzimidazole linked benzoxazole/benzothiazole via copper catalyzed domino annulation. AB - An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothiazoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was converted into benzimidazole bis heterocycles, via the intermediacy of benzimidazole linked ortho-chloro amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annulation reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed intramolecular C-O and C-S cross coupling reactions furnished the angularly oriented bis-heterocycles which bear a close resemblance to the streptomyces antibiotic UK-1. PMID- 23435908 TI - Experimental analysis on the main contents of Rhizoma gastrodiae extract and inter-transformation throughout the fermentation process of Grifola frondosa. AB - Gastrodin (GA), p-hydroxylbenzaldehyde (HBA), p-hydroxybenzyl alcohol (gastrodigenin, HA) and parishin not only are the major active ingredients of Rhizoma gastrodiae, but exist transformed relations from each other throughout the fermentation process of Grifola frondosa in this work. We had found that parishin (non-free gastrodin) almost could completely transformed into gastrodin (GA, free gastrodin) after R. gastrodiae alcohol extract was sterilized by moist heat (121 degrees C, 30 min), but before was added into submerged cultivation of G. frondosa. However, interestingly and importantly, gastrodin re-synthesized of parishin after R. gastrodiae alcohol extract's addition into submerged cultivation of G. frondosa. In addition, the reduction of p-hydroxylbenzaldehyde and p-hydroxybenzyl alcohol in G. frondosa fermentation process reconfirmed that the G. frondosa strain 51616 really could synthesize gastrodin into parishin by submerged fermentation. This paper firstly also reported G. frondosa's effects on R. gastrodiae. PMID- 23435907 TI - Mutation screen and RNA analysis disclose the changed splicing of the E-cadherin transcription in gastric cancer. AB - Gastric cancer (GC) is considered to be one of the leading cancers in East Asians, and mutations in the CDH1 gene and the reduced expression of E-cadherin are the most frequent genetic alterations in gastric cancer. In this paper, we reported two novel germline CDH1 nonsynonymous mutations, c.1296 C>G (N432 K) and c.1297 G>A (D433 N) detected in sporadic Chinese GC patients. RNA splicing analysis was used to evaluate mutations' effects on E-cadherin transcription and exon definition. We revealed that the c.1296 C>G (N432 K) variant can generate the E-cadherin exon9-skipping and may be a disease-causing mutation, while the c.1297 G>A (D433 N) mutation not. Moreover, we demonstrated the E-cadherin 1054del83 transcript is a frequent event in Chinese GC patients. PMID- 23435909 TI - Three new nor-dammarane triterpenoids from Dysoxylum hainanense with particular cytotoxicity against glioma cell line. AB - Three new nor-dammarane triterpenoids, 12beta-O-acetyl-15alpha-hydoxy-3-oxo-17-en 20,21,22-23,24,25,26,27-octanordammanran (1), 12beta,28-O-diacetyl-15alpha-hydoxy 3-oxo-17-en-20,21,22-23,24,25,26,27-octanordammanran (2), 12beta-hydoxy-3,15 dioxo-20,21,22-23,24,25,26,27-octanordammanran (3), together with one known compound, 12beta-O-acetyl-15alpha,28-dihydoxy-3-oxo-17-en-20,21,22-23,24,25,26,27 octanordammanran (4), were isolated from the 95 % EtOH extract of Dysoxylum hainanense. The structures of the new compounds were elucidated by spectral methods. All the triterpenoids were in vitro evaluated for their cytotoxic activities against four tumor cell lines (BGC-823, U251, HepG2 and SGC-7901). All the three nor-dammarane triterpenoids exhibited particular significant cytotoxic activities against glioma cell line. PMID- 23435910 TI - Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats. AB - Sinapic acid is a member of the phenylpropanoid family and is abundant in cereals, nuts, oil seeds, and berries. It exhibits a wide range of pharmacological properties. In this study, we investigated the hepatoprotective and antifibrotic effects of sinapic acid on dimethylnitrosamine (DMN)-induced chronic liver injury in rats. Sinapic acid remarkably prevented DMN-induced loss of body weight. This was accompanied by a significant increase in levels of serum alanine transaminase, aspartate transaminase, and liver malondialdehyde content. Furthermore, sinapic acid reduced hepatic hydroxyproline content, which correlated with a reduction in the expression of type I collagen mRNA and histological analysis of collagen in liver tissue. Additionally, the expression of hepatic fibrosis-related factors such as alpha-smooth muscle actin and transforming growth factor-beta1 (TGF-beta1), were reduced in rats treated with sinapic acid. Sinapic acid exhibited strong scavenging activity. In conclusion, we find that sinapic acid exhibits hepatoprotective and antifibrotic effects against DMN-induced liver injury, most likely due to its antioxidant activities of scavenging radicals, its capacity to suppress TGF-beta1 and its ability to attenuate activation of hepatic stellate cells. This suggests that sinapic acid is a potentially useful agent for the protection against liver fibrosis and cirrhosis. PMID- 23435911 TI - Application of Carbopol/PVP interpolymer complex to prepare mucoadhesive floating granule. AB - Novel mucoadhesive floating granule was prepared using Carbopol/PVP interpolymer complex to deliver hydrophilic drugs in a controlled manner. Acetaminophen was used as a model drug. Maximum floatability of the granules was obtained at the ratio of 1/1, where 95 % of the granules floated for 12 h. As the concentration of sodium bicarbonate increased, both the floating duration and the release rate of the drug increased. The granules without sodium bicarbonate floated only for 2 h and floating onset time was 15 min. The release rate of drug gradually increased as the drug content in the granule increased. As the drug content in the granules increased, duration of adhesion decreased. However, the decrease in adhesion duration was minimal up to 40 % of drug content. The release rate from the granules prepared by dry granulation method was faster than that by wet granulation. The granules prepared by dry granulation method led to formation of highly porous structure; whereas, that by wet granulation method showed non porous structure. The optimum size of the granules to retard the release of the model drug was within the range of 3-4 mm. Based on both mucoadhesive and buoyant properties, the floating granules are expected to reside in the upper part of the stomach for sufficient period of time and release the drug in a sustained manner. PMID- 23435912 TI - Anti-metastatic effect of cantharidin in A549 human lung cancer cells. AB - Cancer metastasis is represented by migration and invasion of cancer cells. Cancer cells invade into the blood or lymphatic vessels and this leads to the spread of cancer into the organs in distant sites. For cancer cells to migrate, extracellular matrix (ECM) must be degraded. Cantharidin, a compound derived from blister beetles, is known for its anti-cancer effect in several cancer cells. Here we report that cantharidin inhibits migration and invasion of A549 human lung cancer cell. We found that cantharidin inhibits activation of phosphatidylinositol 3-kinase/Akt signaling pathway. This leads to the selective attenuation of one of the gelatinases, matrix metalloproteinase 2, which can degrade components of ECM, and inhibits migration and invasion of A549 human lung cancer cell. PMID- 23435913 TI - Simple and sensitive liquid chromatography-tandem mass spectrometry methods for quantification of tadalafil in rat plasma: application to pharmacokinetic study in rats. AB - A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated in rat plasma for quantification of tadalafil, a novel therapeutic agent for erectile dysfunction. Tadalafil and acebutolol (internal standard) were extracted by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was performed on a reverse phase C18 column with a mobile phase consisting of 0.1 % formic acid and acetonitrile (45:55, v/v) at a flow rate of 0.3 mL/min. The protonated analyte was quantitated by multiple reaction monitoring with a Waters Quattro microTM API mass spectrometer. The calibration curve was linear over a concentration range of 2-2000 ng/mL, and the lower limit of quantification was 2 ng/mL with a precision (CV %) of 10.9 %. Acceptable intra-day and inter-day precision and accuracy were obtained at 3 concentration levels (3, 200, and 1500 ng/mL). Tadalafil was found to be stable in a battery of studies, including bench top, freeze-thaw, and autosampler conditions. The validated method was successfully used to determine tadalafil concentration in rat plasma samples after oral administration at a dose of 1 mg/kg. PMID- 23435914 TI - Menadione serves as a substrate for P-glycoprotein: implication in chemosensitizing activity. AB - Based on its chemosensitizing effect, we questioned whether menadione is an inhibitor or a substrate of P-glycoprotein (P-gp). To test this hypothesis, we assessed the effect of menadione on P-gp activity and examined the P-gp dependency of cellular accumulation and cytotoxicity of menadione as well. Treatment with menadione resulted in the concentration-dependent increase of rhodamine 123 (Rh123) accumulation in P-gp-overexpressing MDCKII/MDR1 and NCI/ADR RES cells, suggesting that menadione inhibits Rh123 extrusion by P-gp. Compared with MDCKII or MCF-7, intracellular distribution of [(3)H]-menadione was significantly lower in MDCKII/MDR1 or NCI/ADR-RES cells, which could be restored by the P-gp inhibitors, verapamil and quinidine. Consistent with these results, MDCKII/MDR1 or NCI/ADR-RES cells were more resistant to the cytotoxicity of menadione than MDCKII or MCF-7 cells, respectively. Such resistance was abolished by the combined treatment of verapamil and quinidine in NCI/ADR-RES cells. Our study identified menadione as a substrate of P-gp, which presumably, acts as the mechanism for the chemosensitizing effect. Menadione may be a promising chemotherapeutic enhancer by its ability of circumventing drug resistance, in addition to its own anti-cancer activity. PMID- 23435915 TI - The characteristics of genistin-induced inhibitory effects on intestinal motility. AB - Genistin belongs to isoflavones. Based on the facts that genistin exerts inhibitory effects on the contractility of vascular smooth muscle,the present study was designed to characterize the effects of genistin on intestinal contractility and evaluate its potential clinical implication. Ex vivo [isolated jejunal segment (IJS) of rat], in vitro, and in vivo assays were used in the study. The results indicated that genistin (5-80 MUmol/L) inhibited the contraction of IJS in a dose-dependent manner and inhibited the increased contractility of IJS induced by acetylcholine (ACh), histamine, high Ca(2+), and erythromycin, respectively. The inhibitory effects of genistin were correlated with the stimulation of alpha adrenergic and beta adrenergic receptors since these inhibitory effects were significantly blocked in the presence of phentolamine and propranolol respectively. No further inhibitory effects of genistin were observed in the presence of verapamil or in Ca(2+)-free condition, indicating genistin-induced inhibitory effects are Ca(2+)-dependent. Genistin decreased myosin light chain kinase (MLCK) protein contents and MLCK mRNA expression in IJS, and inhibited both phosphorylation and Mg(2+)-ATPase activity of purified myosin, implicating that the decrease of MLCK contents and inhibition of MLCK activity are involved in the genistin-induced inhibitory effects. The study suggests the potential clinical implications of genistin in relieving intestinal hypercontractility. PMID- 23435916 TI - Anti-inflammatory effect of pristimerin on lipopolysaccharide-induced inflammatory responses in murine macrophages. AB - Pristimerin, a quinonemethide triterpenoid derived from Celastraceae and Hippocrateaceae, has recently been found to suppress tumor promotion, metastasis and angiogenesis. In the present study, we evaluated the anti-inflammatory potentials of pristimerin in a cell culture system. Pristimerin suppressed not only the generation of nitric oxide (NO) and prostaglandin E2, but also the expression of inducible NO synthase and cyclooxygenase-2 induced by lipopolysacharide (LPS) in murine macrophage RAW264.7 cells. Similarly, pristimerin inhibited the release of pro-inflammatory cytokines, namely, tumor necrosis factor-alpha and interleukin-6, induced by LPS. The underlying mechanism of the anti-inflammatory action of pristimerin was correlated with down regulation of nuclear factor-kappaB and the mitogen-activated protein kinase signal pathway. PMID- 23435917 TI - Purification and characterization of a novel antinociceptive peptide from venom of Agkistrodon halys Pallas. AB - Venom of Agkistrodon halys Pallas can control severe pain such as cancer pain and neuropathic pain, but it is made up of complicated components. Aim of this study is to separate major analgesic fraction from venom of A. halys Pallas, and to reveal its biochemical and pharmacological properties. Three steps with ion exchange column first and molecular sieve columns next were used to separate and purify the fractions of venom. Analgesic effects were evaluated by hot plate tests and writhing tests in mice. The molecular weight (MW), isoelectric point, amino acid sequence, purity were respectively determined by SDS-PAGE electrophoresis, isoelectric focusing, Edman degradation and HPLC. The dependence and tolerance were observed by withdrawal test in rats, and analgesic effects were observed in mice during 7 days administration. Fourteen fractions were obtained by separation; the best analgesic fraction named Pallanalgesin was selected by ED50 and LD50. It had single band in electrophoresis, relative purity 92.16 %, MW 16.6 kDa, isoelectric point 8.8, and former sequence of ten amino acids H-L-L-Q-F-R-K-M-I-K. It showed significant analgesic effect without tolerance and dependence. As a novel analgesic, Pallanalgesin has been found to explain the function of venom of A. halys Pallas on severe pain control in traditional uses. PMID- 23435918 TI - Racial/Ethnic and nativity differences in birth outcomes among mothers in New York City: the role of social ties and social support. AB - Immigrants have lower rates of low birth weight (LBW) and to some extent preterm birth (PTB), than their US-born counterparts. This pattern has been termed the 'immigrant health paradox'. Social ties and support are one proposed explanation for this phenomenon. We examined the contribution of social ties and social support to LBW and PTB by race/ethnicity and nativity among women in New York City (NYC). The NYC Pregnancy Risk Assessment Monitoring System survey (2004 2007) data, linked with the selected items from birth certificates, were used to examine LBW and PTB by race/ethnicity and nativity status and the role of social ties and social support to adverse birth outcomes using bivariate and multivariable analyses. SUDAAN software was used to adjust for complex survey design and sampling weights. US- and foreign-born Blacks had significantly increased odds of PTB [adjusted odds ratio (AOR) = 2.43, 95 % CI 1.56, 3.77 and AOR = 2.6, 95 % CI 1.66, 4.24, respectively] compared to US-born Whites. Odds of PTB among foreign-born Other Latinas, Island-born Puerto Ricans' and foreign-born Asians' were not significantly different from US-born Whites, while odds of PTB for foreign-born Whites were significantly lower (AOR = 0.47, 95 % CI 0.26, 0.84). US and foreign-born Blacks' odds of LBW were 2.5 fold that of US-born Whites. Fewer social ties were associated with 32-39 % lower odds of PTB. Lower social support was associated with decreased odds of LBW (AOR 0.69, 95 % CI 0.50, 0.96). We found stronger evidence of the immigrant health paradox across racial/ethnic groups for PTB than for LBW. Results also point to the importance of accurately assessing social ties and social support during pregnancy and to considering the potential downside of social ties. PMID- 23435919 TI - Adolescence as a critical stage in the MCH Life Course Model: commentary for the Leadership Education in Adolescent Health (LEAH) interdisciplinary training program projects. AB - The Life Course Perspective (LCP), or Model, is now a guiding framework in Maternal and Child Health (MCH) activities, including training, supported by the Health Resources and Services Administration's Maternal and Child Health Bureau. As generally applied, the LCP tends to focus on pre- through post-natal stages, infancy and early childhood, with less attention paid to adolescents as either the "maternal" or "child" elements of MCH discourse. Adolescence is a distinct developmental period with unique opportunities for the development of health, competence and capacity and not merely a transitional phase between childhood and adulthood. Adequately addressing adolescents' emergent and ongoing health needs requires well-trained and specialized professionals who recognize the unique role of this developmental period in the LCP. PMID- 23435920 TI - Neospora caninum surface antigen (p40) is a potential diagnostic marker for cattle neosporosis. AB - Neospora caninum is an intracellular protozoan that infects domestic and wild canids as well as many warm-blooded animals as shown by the isolation of viable parasites. The effectiveness of diagnostic tests for detecting specific antibodies against N. caninum is hampered by potential cross-reaction with other Coccidia. So, there is currently an urgent need for a sensitive and specific diagnostic assay for detecting N. caninum in animals. The N. caninum 40-kD surface antigen (p40), similar to NcSAG1 and NcSRS2, was shown to belong to surface antigen super family and thus represents an excellent marker for the diagnosis of neosporosis. In order to test the hypothesis, recombinant Ncp40 (rNcp40) was expressed in Escherichia coli, and an indirect ELISA test was developed using recombinant NCp40 antigen for N. caninum serodiagnosis. The antigen used in this study did not have cross-reactivity with anti-Toxoplasma gondii serum. Anti-p40 antibodies were detected by ELISA in the sera of Yellow cattle and were compared with (IFAT). Optimal sensitivity and specificity (98.2 and 98.6 %) were identified by IFAT. Additionally, 37 positive sera of T. gondii were detected and there was no significant difference with the negative serum of N. caninum. The rNcp40 ELISA developed here provides a specific and sensitive assay for detecting neosporosis in cattle. PMID- 23435921 TI - Gastrointestinal helminths of Gentoo penguins (Pygoscelis papua) from Stranger Point, 25 de Mayo/King George Island, Antarctica. AB - The aim of this work is to contribute to the knowledge of gastrointestinal parasites of the Gentoo penguin (Pygoscelis papua) from 25 de Mayo/King George Island (South Shetlands, Antarctica). Gastrointestinal tracts of 37 fresh dead individuals (21 chicks, 10 juveniles, and 6 adults) were collected from December 2006 to February 2012 and examined for macroparasites. Four adult parasite species were found: one Cestoda species (Parorchites zederi), two Nematoda species (Stegophorus macronectes and Tetrameres wetzeli), and one Acanthocephalan (Corynosoma shackletoni). Two species of immature acanthocephalans, Corynosoma hamanni and Corynosoma bullosum, were found in a single host. This is the first record of Tetrameres wetzeli in Gentoo penguins. The low parasite richness observed could be related to the stenophagic and pelagic diet of this host species which feeds almost exclusively on krill. PMID- 23435922 TI - Effect of Allium sativum and Allium cepa oils on different stages of Boophilus annulatus. AB - The study is aimed to investigate the acaricidal effect of Allium sativum (garlic) and Allium cepa (onion) oils on different stages of Boophilus annulatus hard tick. Engorged B. annulatus females were collected from naturally infected cattle. A number of engorged ticks were incubated at 28 degrees C and 85 % relative humidity to lay eggs, which were incubated to obtain larvae that were used in the study. The used garlic and onion oils were prepared by steam distillation and were analyzed by gas chromatography. These oils were dissolved in ethanol, methanol alcohols, and, partially, in water. The oils were tested in different concentrations; 1, 2, 5, 10, and 20 %. These concentrations were applied on adult ticks by adult immersion test; on larvae by larval immersion technique and on eggs. The 20, 10, and 5 % of garlic oil dilutions in ethanol and methanol killed all adult ticks and larvae within 24 h. Similar results were obtained for 10 and 20 % garlic oil dissolved in water. The effect of 10 % aqueous solution of garlic oil on embryonated eggs was clear as its addition to these eggs led to their in ability to hatch, deformity in shape, and change in color. The 10 and 20 % onion oil in ethanol and methanol alcohols killed 76-86 % of the adult ticks within 72 h post-application. While, all larvae died within 24 h postsubjected to these two concentrations. These concentrations (10 and 20 %) of onion oil in water killed 56-80 % of the treated ticks. Moreover, 10 % aqueous solution of onion oil prevented hatching of embyonated eggs. We concluded that garlic and onion oils have acaricidal effect on all stages of B. annulatus at concentrations higher than 5 %. Only garlic oil could kill 100 % of adult ticks at concentrations from 5 % in alcohols. PMID- 23435923 TI - Macrophage migration inhibitory factor (MIF) of the protozoan parasite Eimeria influences the components of the immune system of its host, the chicken. AB - Macrophage migration inhibitory factor (MIF) is a soluble factor produced by sensitized T lymphocytes that inhibits the random migration of macrophages. Homologues of MIF from invertebrates have been identified, making it an interesting molecule from a functional perspective. In the present study, the localization of a parasite MIF protein as well as its effect on the host was characterized. Western blot analysis shows that Eimeria MIF (EMIF) is found during all parasite developmental stages tested. Transmission electron microscopy shows that MIF is distributed throughout cytosol and nucleus of Eimeria acervulina merozoites. Immunohistochemical analysis suggests that EMIF may be released into the surrounding tissues as early as 24 h after infection, while later during oocyst formation, MIF expression is localized to areas immediately surrounding the oocysts, as well as in wall-forming bodies. The chemotaxis assay revealed an inhibitory function of EMIF on chicken monocyte migration. Quantitative real-time PCR was performed to examine the effect of EMIF on host immune system by measuring the transcripts of inflammatory mediators. An ex vivo stimulation study showed that E. acervulina MIF (EaMIF) enhanced expression of pro-inflammatory cytokines and chemokines in the presence of lipopolysaccharide (LPS). Furthermore, sequential treatment of adherent peripheral blood mononuclear cells with EaMIF, chicken MIF, and LPS in 2-h intervals led to the highest levels of interleukin (IL)-1B, chemokine CCLi3, IL-18, and interferon-gamma mRNA expression. This study shows that parasite MIF is widely expressed and may have potential effects on the immune system of the host. PMID- 23435924 TI - Characteristics and incidence of large eggs in Trichuris muris. AB - The production of small numbers of large eggs among the standard-sized eggs of Trichuris trichiura is well known. Large eggs have also been observed in Trichuris muris, but they have not been studied previously. This paper compares the characteristics of the large eggs (LEs, >=74.5 MUm long) and standard-sized eggs (SEs, <74.5 MUm long) in cultures of T. muris. Among 112,554 cultured eggs, LEs occurred at very low frequency (0.03 %, i.e., about three large eggs per 10(4) cultured eggs). Embryonated eggs represented 93.72 % of SEs, but only 25.00 % of LEs were embryonated. Embryonated LEs and SEs contained fully matured larvae. An atypical category of unembryonated egg, which contained an incompletely developed larva, an abnormal larva, or granular components, was common among the LEs. However, similar atypical unembryonated SEs were rarely observed. These observations suggest that the LEs that occur very infrequently in T. muris result from an abnormality of embryonation (larval development). PMID- 23435925 TI - Further insecticidal activities of essential oils from Lippia sidoides and Croton species against Aedes aegypti L. AB - This study assessed new insecticidal activities of essential oils from Lippia sidoides and Croton species (Croton zehntneri, Croton nepetaefolius, Croton argyrophylloides, and Croton sonderianus) against Aedes aegypti mosquito. In addition, the acute toxicity upon mice was determined. All essential oils showed inhibition of egg hatching, with IC50 values ranging from 66.4 to 143.2 MUg mL( 1), larvicidal activity with LC50 ranging from 25.5 to 94.6 MUg mL(-1), and pupicidal action with PC50 ranging from 276.8 to over 500 MUg mL(-1). Only L. sidoides, C. zehntneri, and C. argyrophylloides essential oils were able to inhibit the oviposition of female gravid mosquitoes with OD50 values of 35.3, 45.3, and 45.8 MUg mL(-1), respectively. Oral acute toxicity in mice showed that C. sonderianus and C. argyrophylloides oils are nontoxic (LD50 > 6,000 mg.kg(-1)) while C. nepetaefolius, C. zehntneri, and L. sidoides oils are moderately toxic (LD50 3,840; 3,464, and 2,624 mg.kg(-1), respectively). The results indicate that these oils are promising sources of bioactive compounds, showing low or no toxicity to mammals. PMID- 23435926 TI - A rat model of intragastric infection with Anisakis spp. live larvae: histopathological study. AB - Anisakiasis is a fish-borne parasitic disease caused by consumption of raw or undercooked fish or cephalopods parasited by Anisakis spp. third stage larvae. The pathological effects of the infection are the combined result of the mechanical action of the larva during tissue invasion, the direct tissue effects of the excretory/secretory products released by the parasite, and the complex interaction between the host immune system and the Anisakis antigens. The aim of this study was to develop an experimental model of infection with Anisakis spp. live larvae in rats, useful to study the acute and chronic histopathological effects of the Anisakis infection. Sprague-Dawley rats were subjected to esophageal catheterization to place larvae directly into the stomach. Reinfections at different intervals after the first infection were preformed. Live larvae were found anchored to the mucosa and passing through the wall of the stomach and showed a strong resistance being able to stay alive at different sites and at the different pH. Migration of larvae from the stomach to other organs out of the gastrointestinal tract was also observed. The histopathological study showed the acute inflammatory reaction, with predominance of polymorphonuclear eosinophils and a mild fibrotic reaction. The model of infection described is valid to study the behavior of the larvae inside the host body, the histopathological changes at the invasion site, and the effects of the repeated infections by ingestion of live larvae. PMID- 23435928 TI - Optical studies of single metal nanoparticles. PMID- 23435927 TI - Sustained efficacy and safety of repeated incobotulinumtoxinA (Xeomin((r))) injections in blepharospasm. AB - IncobotulinumtoxinA (Xeomin((r)), NT 201) is a purified botulinum toxin type A free from accessory (complexing) proteins. Previous studies evaluated single sets of incobotulinumtoxinA injections for the treatment of blepharospasm. Individualized injection intervals and other potential determinants of efficacy and safety need to be evaluated in a prospective, longitudinal study. Subjects with blepharospasm who completed a <= 20 weeks double-blind, placebo-controlled main period entered a <= 69 weeks open-label extension period (OLEX) and received <= 5 additional incobotulinumtoxinA treatments at flexible doses (<= 50 U per eye) and flexible injection intervals (minimum of 6 weeks). Outcome measures included Jankovic Rating Scale (JRS) (sumscore, severity subscore and frequency subscore), Blepharospasm Disability Index, and adverse events. All 102 subjects who completed the main period entered the OLEX; 82 subjects completed the study, 56 received the maximum five injections. From each injection visit to a control visit 6 weeks later, investigator-rated JRS sumscores and subscores, and patient rated Blepharospasm Disability Index were significantly improved (p <= 0.001 for all). All scores were still significantly improved at trial termination compared with the first injection visit (p < 0.05 for all). The most frequently reported adverse events were eyelid ptosis (31.4 %) and dry eye symptoms (17.6 %). The injection interval had no impact on the incidence of adverse events (post hoc analysis). No subject developed neutralizing antibodies during the study. Repeated incobotulinumtoxinA injections, administered at flexible doses and injection intervals from 6 to 20 weeks according to subjects' needs, provide sustained efficacy in the treatment of blepharospasm with no new or unexpected safety risks. PMID- 23435930 TI - Gadobutrol: a review of its use for contrast-enhanced magnetic resonance imaging in adults and children. AB - Since the introduction of the first gadolinium-based contrast agent (GBCA) approximately 25 years ago, magnetic resonance imaging (MRI) using GBCAs has revolutionized diagnostic and follow-up imaging of pathological lesions, with clinical applications expanded to encompass almost all fields of medicine. Intravenous gadobutrol (GadovistTM [EU]; Gadavist((r)) [USA]) is a second generation extracellular non-ionic macrocyclic GBCA that is used in patients undergoing diagnostic contrast-enhanced MRI for visualization of pathological lesions in the CNS and all other body regions or for contrast-enhanced magnetic resonance angiography (MRA) to evaluate perfusion and flow-related abnormalities. Its unique physicochemical profile, along with the high thermostability of macrocyclic GBCAs, means gadobutrol is formulated at twice the gadolinium ion concentration of other currently licensed GBCAs. This reduces the injection volume and provides a narrower bolus, thereby improving image enhancement. Based on extensive clinical experience in a broad range of patients, including paediatric and adult patients (younger and elderly adults), and those with moderate to severe hepatic or renal impairment or cardiovascular disorders, gadobutrol is an effective and generally well tolerated extracellular GBCA for patients undergoing diagnostic contrast-enhanced MRI and contrast-enhanced MRA. As with all macrocyclic GBCAs, the potential for gadobutrol to cause nephrogenic systemic fibrosis appears to be lower than with linear GBCAs. PMID- 23435931 TI - Fitness costs associated with low-level dimethoate resistance in Phytoseiulus macropilis. AB - Phytoseiulus macropilis Banks (Acari: Phytoseiidae) is an effective predator of tetranychid mites, but there are no data on its response to pesticides. We investigated the resistance of the predatory mite P. macropilis to the acaricides abamectin and dimethoate, and we examined the fitness costs associated with resistance. Two populations were tested: one from conventional cultivation and another from an area not commercially exploited. After the application of acaricides to the predator, we determined the lethal effects of the acaricides, the instantaneous rate of population increase (r(i)), the predation on Tetranychus urticae Koch (Acari: Tetranychidae) and its ability to locate prey in an olfactometer. P. macropilis exhibited resistance to dimethoate only. The low level of resistance (9.4x) of the predator did not affect their ability to locate prey. However, the dimethoate resistant population was not as effective in contatining prey population when in lower density and exhibited a more pronounced decrease of r(i) in the presence of this acaricide, due to the reduced oviposition of the predator, a likely consequence of the different genetic background of this population. PMID- 23435932 TI - Protective effect of gossypol on lipopolysaccharide-induced acute lung injury in mice. AB - OBJECTIVE: Gossypol has been reported to have anti-inflammatory properties. The purpose of this study was to evaluate the effect of gossypol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. METHODS: Male BALB/c mice were pretreated with gossypol 1 h before intranasal instillation of LPS. Then, 7 h after LPS administration, the myeloperoxidase in histology of lungs, lung wet/dry ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in the BALF were measured by ELISA. The extent of phosphorylation of IkappaB-alpha, p65 NF-kappaB, p46-p54 JNK, p42-p44 ERK, and p38 were detected by western blot. RESULTS: Gossypol markedly attenuated the LPS-induced histological alterations in the lung and inhibited the production of TNF-alpha, IL-1beta and IL-6. Additionally, gossypol reduced the inflammatory cells in BALF, decreased the wet/dry ratio of lungs and inhibited the phosphorylation of IkappaB-alpha, p65 NF-kappaB, p46-p54 JNK, p42-p44 ERK, and p38 caused by LPS. CONCLUSION: The data suggest that anti-inflammatory effects of gossypol against the LPS-induced ALI may be due to its ability of inhibition of the NF-kappaB and MAPKs signaling pathways. Gossypol may be a promising potential therapeutic reagent for ALI treatment. PMID- 23435933 TI - Association of interleukin-1 receptor-associated kinase (IRAK1) gene polymorphisms (rs3027898, rs1059702) with systemic lupus erythematosus in a Chinese Han population. AB - OBJECTIVE: The purpose of this study was to examine the association of interleukin-1 receptor-associated kinase (IRAK1) polymorphisms (rs3027898, rs1059702) with systemic lupus erythematosus (SLE) in a Chinese Han population. METHODS: A total of 667 SLE patients and 667 healthy controls were collected in this study. The genotyping of polymorphisms (rs3027898, rs1059702) was determined by TaqMan allele discrimination assay on the 7300 real-time polymerase chain reaction system. The statistical analysis was conducted by chi square test or Fisher's exact test. RESULTS: The frequency of C allele for rs3027898 in patients was significantly higher than in controls (C versus A: OR = 1.438, 95 % CI = 1.180-1.753, p < 0.001), and a similar association was shown in rs1059702 (A versus G: OR = 1.383, 95 % CI = 1.143-1.674, p = 0.001). Interestingly, the C allele of rs3027898 was associated with a decreased risk for patients with oral ulcers. However, no significant difference was detected in IRAK1 rs1059702 polymorphism and the clinical manifestations. CONCLUSIONS: Our data demonstrate that the polymorphisms rs3027898 and rs1059702 of IRAK1 gene are associated with SLE in the Chinese Han population. PMID- 23435934 TI - Oxymorphone insufflation associated with acute sensorineural hearing loss: case files of the University of Massachusetts medical toxicology fellowship. PMID- 23435935 TI - Microbial community biogeographic patterns in the rhizosphere of two Brazilian semi-arid leguminous trees. AB - Arid environments are regular and well distributed over all continents and display drought characteristics whether full-time or seasonal. This study aims to characterize how the microbial communities of the rhizosphere of two leguminous trees from the Brazilian semi-arid biome the Caatinga are geographically and seasonally shaped, as well as the factors driving this variation. With that purpose, the soil rhizosphere from two leguminous trees (Mimosa tenuiflora and Piptadenia stipulacea (Benth.) Ducke) were sampled in two different seasons: rainy and drought at five different sites. Assessment of bacterial and archaeal communities occurred by T-RFLP analysis of 16S rRNA and archaeal amoA genes. By these means, it was observed that the seasons (wet and dry periods) are the factors that most influence the composition of the microbial community from both analyzed plants, except for the results obtained from the CCA applied to Archaeas. Furthermore, soil physical-chemical factors also had a significant influence on the community and indicated a geographical pattern of the bacterial community. It was not possible to observe significant modifications in the composition in relation to the plant species. We have seen that soil characteristics and rainfall were the factors that most influenced the microbial composition. Also, the bacterial community had a significant correlation with soil characteristics that indicates that these rhizosphere communities might be selected by environmental characteristics. Furthermore, the data suggest that climate plays a key role in structuring the microbial community of this biome. PMID- 23435936 TI - Lynch syndrome-associated neoplasms: a discussion on histopathology and immunohistochemistry. AB - It was a century ago that Warthin, a pathologist, first described the clinical condition now known as Lynch syndrome. One hundred years later, our understanding of this syndrome has advanced significantly. Much of the progress took place over the last 25 years and was marked by a series of interacting developments from the disciplines of clinical oncology, pathology, and molecular genetics, with each development serving to guide or enhance the next. The advancement of our understanding about the pathology of Lynch syndrome associated tumors exemplifies such intimate interplay among disciplines. Today, accumulative knowledge has enabled surgical pathologists to detect tumors that are likely to be associated with Lynch syndrome, and the pathologist is playing an increasingly more important role in the care of these patients. The pathologist's ability is afforded primarily by information gained from tumor histopathology and by DNA mismatch repair protein immunohistochemistry. It is therefore pertinent both for the pathologists to accurately ascertain this morphologic information, and for all that are involved in the care of these patients to thoroughly understand the implications of such information. This article provides an overview of the development of histopathology and immunohistochemistry in Lynch syndrome associated tumors, particularly in colorectal and endometrial cancers, and outlines the issues and current status of these specific pathologic aspects in not only the major tumors but also those less commonly seen or only newly reported in Lynch syndrome patients. PMID- 23435937 TI - Nitrate signals determine the sensing of nitrogen through differential expression of genes involved in nitrogen uptake and assimilation in finger millet. AB - In order to understand the molecular basis of high nitrogen use efficiency of finger millet, five genes (EcHNRT2, EcLNRT1, EcNADH-NR, EcGS, and EcFd-GOGAT) involved in nitrate uptake and assimilation were isolated using conserved primer approaches. Expression profiles of these five genes along with the previously isolated EcDof1 was studied under increased KNO3 concentrations (0.15 to 1,500 MUM) for 2 h as well as at 1.5 MUM for 24 h in the roots and shoots of 25 days old nitrogen deprived two contrasting finger millet genotypes (GE-3885 and GE 1437) differing in grain protein content (13.76 and 6.15 %, respectively). Time kinetics experiment revealed that, all the five genes except EcHNRT2 in the leaves of GE-3885 were induced within 30 min of nitrate exposure indicating that there might be a greater nitrogen deficit in leaves and therefore quick transportation of nitrate signals to the leaves. Exposing the plants to increasing nitrate concentrations for 2 h showed that in roots of GE-3885, NR was strongly induced while GS was repressed; however, the pattern was found to be reversed in leaves of GE-1437 indicating that in GE-3885, most of the nitrate might be reduced in the roots but assimilated in leaves and vice-versa. Furthermore, compared with the low-protein genotype, expression of HNRT2 was strongly induced in both roots and shoots of high-protein genotype at the least nitrate concentration supplied. This further indicates that GE-3885 is a quick sensor of nitrogen compared with the low-protein genotype. Furthermore, expression of EcDof1 was also found to overlap the expression of NR, GS, and GOGAT indicating that Dof1 probably regulates the expression of these genes under different conditions by sensing the nitrogen fluctuations around the root zone. PMID- 23435938 TI - FTY720 (fingolimod) attenuates beta-amyloid peptide (Abeta42)-induced impairment of spatial learning and memory in rats. AB - Imbalanced lipid metabolism and increase in the ceramide-to-S1P ratio in the brain have been postulated to play a role in amyloidogenesis, neuroinflammatory reactions, and neuronal apoptosis in Alzheimer's disease (AD) pathology. FTY720, the immunomodulatory sphingosine 1-phosphate (S1P) analog, has recently gained interest because of its CNS-directed effects. In addition to its immunomodulatory functions in multiple sclerosis, FTY720 possesses anti-inflammatory and neuroprotective roles in different cerebral ischemia models. In the present study, we examined the effects of FTY720 in a rat model of AD. Memory deficit was induced by bilateral intrahippocampus injection of beta-amyloid peptide (Abeta(42)) and examined through the Morris water maze test. The extent of histological injury in the hippocampus and the activation of caspase-3 were determined respectively by Nissl staining and Western blotting. Chronic daily administration of FTY720 (1 mg/kg, i.p., 14 days) significantly attenuated the Abeta(42)-induced learning and memory impairment and prevented the hippocampus neuronal damage as well as caspase-3 activation. These data show for the first time that FTY720 has a beneficial effect in restoring memory loss in Abeta(42) induced neurotoxicity and also suggest that S1P receptors and signaling pathways may provide a potential target for the treatment of AD. PMID- 23435939 TI - Degradation of quinolizidine alkaloids of lupin by Rhizopus oligosporus. AB - Rhizopus oligosporus has proven beneficial in the detoxification of lupin seeds. The fermentation process is mainly affected by the initial pH in the medium. In the range of growth of mold, there are maximum enzymatic activities in pH of 3.5 and 5.5. Metabolism change occurs at these pH levels; therefore, we studied the growth, pH changes, dry matter intake, and alkaloid degradation within 48 h of fermentation. Cultures of lupin agar (LA) with pH of 3.5 and 5.5 were made in Petri dishes with lupin flour. Results showed pH directly affects the degradation of alkaloids and fungal growth. Detoxification levels achieved were 16.58 and 63.23 % in treatments LA 3.5 and LA 5.5, respectively. Fungal growth was 0.919 mg/cm(2) in LA 3.5 and 1.081 mg/cm(2) in LA 5.5. Maximum degradation rate in LA 5.5 was given between 16 and 20 h, which coincided with maximum fungal growth. Despite having similar dry matter intake in both treatments, a pH of 3.5 did not show the same degree of detoxification. The analysis with exponential, yield of growth, yield of dry matter intake and luedeking and piret equations, confirm the relation between intake and growth with detoxification. Dry matter intake equation predicts with R (2) of 0.94 the detoxification in LA 5.5. A pH of 5.5 is directly related with detoxification and fungal development. PMID- 23435940 TI - Extrachromosomal, extraordinary and essential--the plasmids of the Roseobacter clade. AB - The alphaproteobacterial Roseobacter clade (Rhodobacterales) is one of the most important global players in carbon and sulfur cycles of marine ecosystems. The remarkable metabolic versatility of this bacterial lineage provides access to diverse habitats and correlates with a multitude of extrachromosomal elements. Four non-homologous replication systems and additional subsets of individual compatibility groups ensure the stable maintenance of up to a dozen replicons representing up to one third of the bacterial genome. This complexity presents the challenge of successful partitioning of all low copy number replicons. Based on the phenomenon of plasmid incompatibility, we developed molecular tools for target-oriented plasmid curing and could generate customized mutants lacking hundreds of genes. This approach allows one to analyze the relevance of specific replicons including so-called chromids that are known as lifestyle determinants of bacteria. Chromids are extrachromosomal elements with a chromosome-like genetic imprint (codon usage, GC content) that are essential for competitive survival in the natural habitat, whereas classical dispensable plasmids exhibit a deviating codon usage and typically contain type IV secretion systems for conjugation. The impact of horizontal plasmid transfer is exemplified by the scattered occurrence of the characteristic aerobic anoxygenic photosynthesis among the Roseobacter clade and the recently reported transfer of the 45-kb photosynthesis gene cluster to extrachromosomal elements. Conjugative transmission may be the crucial driving force for rapid adaptations and hence the ecological prosperousness of this lineage of pink bacteria. PMID- 23435941 TI - Nitrogen cycling and relationships between ammonia oxidizers and denitrifiers in a clay-loam soil. AB - This study investigated the effect of municipal solid waste (MSW) compost (0, 50, and 100 t/ha) on N cycling and the microorganisms involved in it, in a clay-loam soil. After a release of nitrates (NO3(-)-N) in the first 6 days after compost incorporation, soil NO3(-)-N content remained constant in all the treatments until day 62, suggesting N immobilization induced by the soil used in this study. Then, soil NO3(-)-N content increased in all treatments and especially in the highest compost dose, providing evidence that immobilization effect has been at least partially relieved. amoA gene copies of ammonia-oxidizing archaea (AOA) and bacteria (AOB) followed the overall pattern of soil NO3(-)-N content; however, no differences were found in amoA gene copies among treatments, except in the last sampling, an effect attributed to the slight differences in the potential nitrification rate among them. Ammonia oxidizer pattern provided evidence that both groups were involved in ammonia oxidation and changes in their abundance can be used as 'indicator' to predict changes in soil nitrification status. Moreover, the strong correlation between AOA and AOB amoA copies (R(2) = 0.94) and the high slope (13) of the curve suggest that AOA had probably an important role on ammonia oxidation. Denitrifying genes (nirS, nirK, nosZ) also followed the general pattern of soil NO3(-)-N, and they were strongly correlated with both groups of ammonia oxidizers, and particularly AOA, suggesting strong interrelationships among them. Losses of N through denitrification, as they were estimated by total nitrogen, were inversely related to soil NO3(-)-N content. Similar to ammonia oxidizers, denitrifying gene copies did not differ among compost treatments an effect that could be probably explained by the low availability of organic-C in the MSW compost and hence the competition with aerobic heterotrophs. PMID- 23435942 TI - A review on cholinesterase inhibitors for Alzheimer's disease. AB - Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Abeta) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Abeta-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Abeta deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD. PMID- 23435943 TI - Hepatoprotective effects of reynosin against thioacetamide-induced apoptosis in primary hepatocytes and mouse liver. AB - The aim of this study was to identify the hepatoprotective effects of reynosin, sesquiterpenes from the leaves of Laurus nobilis, against thioacetamide (TAA) induced apoptosis in primary hepatocyte cultures and an in vivo mouse model. Rat hepatocytes were isolated and pretreated with 0.13, 0.64, or 3.22 MUM reynosin and then exposed to 100 mM TAA. Reynosin treatment significantly inhibited TAA induced apoptosis and hepatocellular DNA damage in primary rat hepatocytes. We observed an increase in levels of antiapoptotic Bcl-2, Bcl-XL mRNA and a decrease in levels of proapoptotic Bax mRNA following reynosin treatment of hepatocytes. Apoptosis in BALB/c mice was induced with intra-peritoneal injection of 200 mg/kg TAA for 2 weeks every other day. Then reynosin (5 mg/kg) and TAA were intragastrically given for 3 weeks every other day. Aspartate aminotransferase and alanine aminotransferase levels in the blood of mice were decreased in the reynosin administration group. Bcl-2 and Bcl-XL mRNA levels were increased, and the Bax mRNA level was decreased in reynosin-treated mice. Thus, reynosin inhibited TAA-induced apoptosis in primary hepatocytes and an in vivo mouse model. PMID- 23435944 TI - Multiple biological properties of macelignan and its pharmacological implications. AB - Macelignan found in the nutmeg mace of Myristica fragrans obtains increasing attention as a new avenue in treating various diseases. Macelignan has been shown to possess a spectrum of pharmacological activities, including anti-bacterial, anti-inflammatory, anti-cancer, anti-diabetes, and hepatoprotective activities; recently, it has also been shown to have neuroprotective activities. This review summarizes the current research on the biological effects of macelignan derived from M. fragrans, with emphasis on the importance in understanding and treating complex diseases such as cancer and Alzheimer's disease. PMID- 23435945 TI - Implications and mechanism of action of gabapentin in neuropathic pain. AB - Gabapentin is an anti-epileptic agent but now it is also recommended as first line agent in neuropathic pain, particularly in diabetic neuropathy and post herpetic neuralgia. alpha2delta-1, an auxillary subunit of voltage gated calcium channels, has been documented as its main target and its specific binding to this subunit is described to produce different actions responsible for pain attenuation. The binding to alpha2delta-1 subunits inhibits nerve injury-induced trafficking of alpha1 pore forming units of calcium channels (particularly N type) from cytoplasm to plasma membrane (membrane trafficking) of pre-synaptic terminals of dorsal root ganglion (DRG) neurons and dorsal horn neurons. Furthermore, the axoplasmic transport of alpha2delta-1 subunits from DRG to dorsal horns neurons in the form of anterograde trafficking is also inhibited in response to gabapentin administration. Gabapentin has also been shown to induce modulate other targets including transient receptor potential channels, NMDA receptors, protein kinase C and inflammatory cytokines. It may also act on supra spinal region to stimulate noradrenaline mediated descending inhibition, which contributes to its anti-hypersensitivity action in neuropathic pain. PMID- 23435946 TI - Cytotoxic and anti-inflammatory constituents from the seeds of Descurainia sophia. AB - A new sinapoyl glycoside, 1,3-di-O-sinapoyl-beta-D-glucopyranose (1) along with 13 known compounds, including, sinapoyl glycosides (2 and 3), cardenolide glycoside (4), flavonoids (5-10), lignan (11), phenolic acids (12 and 13), and phytosterol (14), were isolated from the seeds of Descurainia sophia by chromatographic separation methods. The structures of 1-14 were determined by the interpretation of spectroscopic data as well as by comparison of that data with previously reported values. Compounds 2, 3, 5, 6, and 11 were identified in and isolated from this plant for the first time in this study. All isolates were evaluated for in vitro cytotoxic activities against seven human cancer cell lines and for in vitro anti-inflammatory potential using LPS-stimulated RAW264.7 murine macrophages. Compound 4 showed potent cytotoxicity (IC50 values ranging from 0.034 to 0.596 MUM) against all human cancer cell lines tested and was identified as the main active cytotoxic constituent of this plant. Compound 8 (ED50 = 5.45 MUM) and 11 (ED50 = 10.02 MUM) exerted dose-dependent inhibitory effects on NO production in LPS-stimulated RAW264.7 cells. PMID- 23435929 TI - A multinational, observational study to investigate the efficacy, safety and tolerability of acarbose as add-on or monotherapy in a range of patients: the Gluco VIP study. AB - BACKGROUND AND OBJECTIVES: The burden of type 2 diabetes mellitus is growing rapidly, particularly in the Asia-Pacific region. The aim of this international, large-scale, observational study was to investigate the efficacy and tolerability of the antidiabetic agent acarbose as add-on or monotherapy in a range of patients with type 2 diabetes, including those with cardiovascular morbidities. The majority of practices were included from high-burden regions (predominantly those in the Asia-Pacific region). METHODS: This was an observational study conducted in 15 countries/regions. Adults with pre-treated or untreated type 2 diabetes prescribed acarbose as add-on or monotherapy were eligible. Two-hour postprandial blood glucose (2-h PPG), glycosylated haemoglobin (HbA1c) and fasting blood glucose (FBG) were measured over a 3-month observation period. RESULTS: A total of 15,034 patients were valid for the efficacy analysis and 15,661 for the safety analysis (mean age was 57.6 years and 92.6 % of patients were Asian). Mean (SD) 2-h PPG decreased by -71.9 (62.3) mg/dL, to 170.2 (46.5) mg/dL at final visit (after 12.8 [4.1] weeks). Mean HbA1c decreased by -1.1 % (1.3) to 7.2 % (1.1) and mean FBG decreased by -33.0 (43.3) mg/dL to 124.8 (30.5) mg/dL. Acarbose was effective regardless of the presence of cardiovascular co morbidities or diabetic complications. The efficacy of acarbose was rated 'very good' or 'good' in 85.5 % of patients, and tolerability as 'very good' or 'good' in 84.9 % of patients. Drug-related adverse events, mainly gastrointestinal, were reported in 490/15,661 patients (3.13 %). CONCLUSION: The results of this observational study support the notion that acarbose is effective, safe and well tolerated in a large cohort of Asian patients with type 2 diabetes. PMID- 23435947 TI - A new phenanthrene derivative and two diarylheptanoids from the roots of Brassica rapa ssp. campestris inhibit the growth of cancer cell lines and LDL-oxidation. AB - Brassica rapa ssp. campestris (Brassicaceae) is a conical, deep purple, edible root vegetable commonly known as a turnip. We initiated phytochemical and pharmacological studies to search for biological active compounds from the roots of B. rapa ssp. campestris. We isolated a novel phenanthrene derivative, 6 methoxy-1-[10-methoxy-7-(3-methylbut-2-enyl)phenanthren-3-yl]undecane-2,4-dione, named brassicaphenanthrene A (3) along with two known diarylheptanoid compounds, 6-paradol (1) and trans-6-shogaol (2), through the repeated silica gel (SiO2), octadecyl silica gel, and Sephadex LH-20 column chromatography. The chemical structures of the compounds were determined by spectroscopic data analyses including nuclear magnetic resonance, mass spectrometry, ultraviolet spectroscopy, and infra-red spectroscopy. All compounds exhibited high inhibitory activity against the growth of human cancer lines, HCT-116, MCF-7, and HeLa, with IC50 values ranging from 15.0 to 35.0 MUM and against LDL-oxidation with IC50 values ranging from 2.9 to 7.1 MUM. PMID- 23435948 TI - Potent alpha-glucosidase and protein tyrosine phosphatase 1B inhibitors from Artemisia capillaris. AB - As a part of our ongoing effort to identify anti-diabetic constituents from natural sources, we examined the inhibitory activity of the methanol extracts of 12 species of the genus Artemisia, against alpha-glucosidase and protein tyrosine phosphatase 1B (PTP1B). The methanol extracts of different species exhibited promising alpha-glucosidase and PTP1B inhibitory activities. Since the methanol extract of Artemisia capillaris exhibited the highest alpha-glucosidase inhibitory activity together with significant PTP1B inhibitory activity, it was selected for further investigation. Repeated column chromatography based on bioactivity guided fractionation yielded 10 coumarins (esculetin, esculin, scopolin, isoscopolin, daphnetin, umbelliferone, 7-methoxy coumarin, scoparone, scopoletin, 6-methoxy artemicapin C), 8 flavonoids (hyperoside, quercetin, isorhamnetin, cirsilineol, arcapillin, isorhamnetin 3-robinobioside, linarin, isorhamnetin 3-glucoiside), 6 phenolic compounds (1,5-dicaffeoylquinic acid, 3,4 dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid methyl ester, 4,5-dicaffeoylquinic acid, 3-caffeoylquinic acid), and one chromone (capillarisin). Among these compounds, esculetin, scopoletin, quercetin, hyperoside, isorhamnetin, 3,5-dicaffeoylquinic acid methyl ester, 3,4 dicaffeoylquinic acid, and 1,5-dicaffeoylquinic acid exhibited potent alpha glucosidase inhibitory activity when compared to the positive control acarbose. In addition, esculetin and 6-methoxy artemicapin C displayed PTP1B inhibitory activity. Interestingly, all isolated dicaffeoylquinic acids showed significant PTP1B inhibitory activity. Therefore, the results of the present study clearly demonstrate the potential of the A. capillaris extract to inhibit alpha glucosidase and PTP1B. These inhibitory properties can be largely attributed to a combination of different chemical structures, including coumarins, flavonoids, and dicaffeoylquinic acids, which could be further explored to develop therapeutic or preventive agents for the treatment of diabetes. PMID- 23435949 TI - Everything started on a rainy day in Santiago. PMID- 23435950 TI - Incidence of milrinone blood levels outside the therapeutic range and their relevance in children after cardiac surgery for congenital heart disease. AB - PURPOSE: To evaluate whether variability in milrinone blood levels (MBL) occurs during administration to critically ill children after surgical repair of congenital heart disease, and the clinical relevance of this variability. METHODS: Prospective cohort study conducted in the pediatric intensive care unit of a tertiary care teaching and referral hospital. MBL were measured at three time periods after starting milrinone infusion (9-12, 18-24, 40-48 h) and at the end of the infusion. MBL were categorized as within (100-300 ng/ml) or outside the therapeutic range. Low cardiac output syndrome was defined by elevation of either lactate (>2 mmol/l) or arteriovenous oxygen difference (>30%). Five other clinical outcomes were evaluated. Regression analyses evaluated the relationships between MBL and outcomes. RESULTS: Sixty-three patients were included with a total of 220 MBL. Quantification of MBL was by high-performance liquid chromatography. Overall, 114 (52%) MBL were outside the therapeutic range: 78 (36%) subtherapeutic, and 36 (16%) supratherapeutic. Repeated-measures analysis found a significant association between supratherapeutic MBL and low cardiac output syndrome (p = 0.02), and supratherapeutic MBL were associated with arterial-central venous oxygen saturation difference >30% at time 3 (p = 0.007). CONCLUSIONS: In this cohort, nontherapeutic MBL were common. Further investigation of milrinone dosing recommendations may improve the postoperative outcomes of children. PMID- 23435951 TI - The luck of the draw: physician-related variability in end-of-life decision making in intensive care. AB - PURPOSE: To critically analyze physician-related variability in end-of-life decision-making in intensive care. METHODS: An ethical analysis of factors contributing to physician-related variability in end-of-life decision-making. RESULTS: There is variability in decision-making about life support, both within and between intensive care units. Physician age, race, religion, attitude to risk, and personality factors have been associated with decisions to provide or limit life-sustaining treatment, though it is unclear how much these factors affect patient outcome. Inconsistency in decision-making appears worryingly arbitrary, and may mean that patients' values are sometimes being ignored or overridden. However, physician influence on decisions may also sometimes be appropriate and unavoidable, particularly where patient values are unclear. CONCLUSIONS: We argue that, although physician-related variability in end-of-life care can never be eliminated entirely, it is potentially ethically problematic. We outline four potential strategies for reducing the "roster lottery." PMID- 23435952 TI - Antigenic variation of H1N1, H1N2 and H3N2 swine influenza viruses in Japan and Vietnam. AB - The antigenicity of the influenza A virus hemagglutinin is responsible for vaccine efficacy in protecting pigs against swine influenza virus (SIV) infection. However, the antigenicity of SIV strains currently circulating in Japan and Vietnam has not been well characterized. We examined the antigenicity of classical H1 SIVs, pandemic A(H1N1)2009 (A(H1N1)pdm09) viruses, and seasonal human-lineage SIVs isolated in Japan and Vietnam. A hemagglutination inhibition (HI) assay was used to determine antigenic differences that differentiate the recent Japanese H1N2 and H3N2 SIVs from the H1N1 and H3N2 domestic vaccine strains. Minor antigenic variation between pig A(H1N1)pdm09 viruses was evident by HI assay using 13 mAbs raised against homologous virus. A Vietnamese H1N2 SIV, whose H1 gene originated from a human strain in the mid-2000s, reacted poorly with post-infection ferret serum against human vaccine strains from 2000-2010. These results provide useful information for selection of optimal strains for SIV vaccine production. PMID- 23435953 TI - High prevalence of torque teno sus virus in China and genetic diversity of the 5' non-coding region. AB - Members of the family Anelloviridae are emerging circular DNA viruses infecting many species of vertebrates including pigs. To date, members of two distinct genera, Iotatorquevirus, including torque teno sus virus 1a and torque teno sus virus 1b (TTSuV1a and TTSuV1b), and Kappatorquevirus, including torque teno sus virus k2a and torque teno sus virus k2b (TTSuVk2a and TTSuVk2b), have been identified in domestic pigs and wild boars. The goal of this study was to evaluate the prevalence and genetic diversity of these viruses based on 5' non coding genes in Chinese swine herds experiencing clinical symptoms. One hundred eighty-five clinical samples from 11 different regions, collected during 2008 2009, were analyzed using a PCR method, and the results revealed a high TTSuV positive rate of 78.9 % (146/185) in pigs. Moreover, we detected co-infection with multiple TTSuV strains in the same pig. Nucleotide sequencing results revealed greater genetic diversity within the genus Kappatorquevirus than within the genus Iotatorquevirus. In addition, TTSuVk2b, a novel virus discovered in New Zealand in 2012, was also identified in this study. In summary, the present work helps us obtain more knowledge about the epidemiology and genetic diversity of TTSuVs. PMID- 23435954 TI - Resveratrol mitigates genotoxicity induced by iodine-131 in primary human lymphocytes. AB - The purpose of this study was to investigate the radioprotective effects of resveratrol as a natural product that protects against genotoxic actions of (131)I in cultured human lymphocytes. Whole-blood samples from human volunteers were treated with resveratrol at doses of 0.5, 1, 5, and 50 MUg/mL for 1 h, after which the lymphocytes were incubated with (131)I (100 MUCi/1.5 mL) for 2 h. The lymphocyte cultures were then mitogenically stimulated to enable evaluation of the number of micronuclei in cytokinesis-blocked binucleated cells. Incubation of lymphocytes with (131)I induced genotoxicity, which was reflected by an increase in micronuclei frequency. At the doses tested, resveratrol significantly reduced micronuclei frequency. Maximal protective effects occurred at a dose of 1 MUg/mL, with total micronuclei values being reduced by 65 % compared to controls. In conclusion, our results indicate protective effects of resveratrol at low doses against genetic damage and adverse effects induced by (131)I administration. PMID- 23435955 TI - Intergenerational programming of metabolic disease: evidence from human populations and experimental animal models. AB - We are in the midst of unparalleled epidemics of obesity and type 2 diabetes complex phenotypes originating at the intersection of genetic and environmental risk. As detailed in other chapters, evidence indicates that non-genetic, or environmental, risk may initiate during prenatal and early postnatal life [1]. Striking examples in humans include the association of low birth weight (LBW) and/or accelerated early growth with increased risk of insulin resistance, obesity, type 2 diabetes (T2DM), and cardiovascular disease (CVD), and the close relationship between maternal obesity or diabetes with childhood obesity. In this chapter, we will focus on the intriguing emerging data from both human and animal models that indicate that intrauterine and childhood exposures can also influence risk for diabetes and cardiovascular disease in subsequent generations. Understanding the mechanisms responsible for these effects is critical in order to develop effective metabolic and nutritional interventions to interrupt such vicious intergenerational cycles potentiating risk for metabolic disorders. PMID- 23435956 TI - Decreased expression of DNA repair genes (XRCC1, ERCC1, ERCC2, and ERCC4) in squamous intraepithelial lesion and invasive squamous cell carcinoma of the cervix. AB - Reduced DNA repair might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer (CC), to persistent HPV infection, and hence to cervical pre-cancer and cancer. We assessed the variation in baseline expression of base excision repair gene XRCC1 and three nucleotide excision repair genes ERCC1, ERCC2, and ERCC4 and the risk of developing cervical cancer. A hospital-based case-control study was designed with 50 invasive cervical cancer patients, 40 squamous intraepithelial lesions (SIL) patients and 85 controls subjects. RT-qPCR and Western blotting was used to quantitate in vitro the mRNA and protein levels in fresh CC, SIL and normal cervix tissue. The levels of XRCC1, ERCC2, ERCC4, and ERCC1 transcripts and their respective proteins were lower in cervical cancer and SILs as compared to controls (p <= 0.001, 0.001, 0.001, and 0.025, respectively). In multivariate logistic regression analysis (adjusting for parity, age at first child birth, use of oral contraceptives, smoking status), low expression of XRCC1, ERCC2, ERCC4, and ERCC1 was associated with a significant increased risk for CC and SIL. Our results suggest that individuals whose expression of XRCC1, ERCC4, ERCC2, and ERCC1 are reduced may be at a higher risk of developing SIL which eventually leads to invasive cervical carcinoma. Moreover, independently also the reduced expression of these genes can directly lead to cervical cancer progression. PMID- 23435957 TI - Silence of ezrin modifies migration and actin cytoskeleton rearrangements and enhances chemosensitivity of lung cancer cells in vitro. AB - Ezrin, primarily acts as a linker between the plasma membrane and the cytoskeleton, is involved in many cellular functions, including regulation of actin cytoskeleton, control of cell shape, adhesion, motility, and modulation of signaling pathways. Although ezrin is now recognized as a key component in tumor metastasis, its roles and the underlying mechanisms remain unclear. In the present study, we chose highly metastatic human lung carcinoma 95D cells, which highly express the ezrin proteins, as a model to examine the functional roles of ezrin in tumor suppression. An ezrin-silenced 95D cell line was established using lentivirus-mediated short hairpin RNA method. CCK-8 assay and soft agar assay analysis showed that downregulation of ezrin significantly suppressed the tumorigenicity and proliferation of 95D cells in vitro. cell migration and invasion studies showed that ezrin-specific deficiency in the cells caused the substantial reduction of the cell migration and invasion. In parallel, it also induced rearrangements of the actin cytoskeleton. Flow cytometry assay showed that changes in the ezrin protein level significantly affected the cell cycle distribution and eventual apoptosis. Furthermore, further studies showed that ezrin regulated the expression level of E-cadherin and CD44, which are key molecules involved in cell growth, migration, and invasion. Meanwhile, the suppression of ezrin expression also sensitized cells to antitumor drugs. Altogether, our results demonstrated that ezrin played an important role in the tumorigenicity and metastasis of lung cancer cells, which will benefit the development of therapeutic strategy for lung cancer. PMID- 23435958 TI - p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain. AB - Mechanical stimuli play a significant role in the regulation of bone remodeling during orthodontic tooth movement. However, the correlation between mechanical strain and bone remodeling is still poorly understood. In this study, we used a model of continuous mechanical strain (CMS) on bone mesenchymal stem cells (BMSCs) to investigate the proliferation and osteogenic differentiation of BMSCs and the mechanism of mechano-transduction. A CMS of 10 % at 1 Hz suppressed the proliferation of BMSCs and induced early osteogenic differentiation within 48 h by activating Runx2 and increasing alkaline phosphatase (ALP) activity and mRNA expression of osteogenesis-related genes (ALP, collagen type I, and osteopontin). Regarding mitogen-activated protein kinase (MAPK) activation, CMS induced phased phosphorylation of p38 consisting of a rapid induction of p38 MAPK at 10 min and a rapid decay after 1 h. Furthermore, the potent p38 inhibitor SB203580 blocked the induction of p38 MAPK signaling, but had little effect on subsequent osteogenic events. These results demonstrate that mechanical strain may act as a stimulator to induce the differentiation of BMSCs into osteoblasts, which is a vital function for bone formation in orthodontic tooth movement. However, activation of the p38 signaling pathway may not be involved in this process. PMID- 23435959 TI - Apolipoprotein A-I mimetic peptide reverse D-4F improves the biological functions of mouse bone marrow-derived late EPCs via PI3K/AKT/eNOS pathway. AB - Apolipoprotein A-I (ApoA-I) mimetic peptide inhibits the development of atherosclerosis (AS) in apolipoprotein E-deficient mice; however, the underlying mechanism remains unclear. Endothelial progenitor cells (EPCs) can prevent AS progression through repairing proatherogenic factors impaired endothelium. In the present study, we examined the effect of reverse D-4F, one of apoA-I mimetic peptide on the proliferation, migration, and tube formation of mouse bone marrow derived late EPCs. The present study showed that reverse D-4F (10-100 MUg/ml) significantly improved the proliferation, migration, and tube formation of EPCs in a dose-dependent manner, and activated phospho-AKT at serine residue 473 and phospho-eNOS at serine residue 1177. LY294002 (PI3-kinase inhibitor) and L-NAME (NOS inhibitor) significantly inhibited reverse D-4F mediated improvement of EPCs biological functions, and LY294002 significantly decreased reverse D-4F stimulated activation of phospho-AKT (473) and phospho-eNOS (1177). The results indicate that reverse D-4F mediated improvement of EPCs functions is dependent on the PI3K/AKT/eNOS pathway. PMID- 23435961 TI - Kudoa azevedoi n. sp. (Myxozoa, Multivalvulida) from the oocytes of the Atlantic horse mackerel Trachurus trachurus (Perciformes, Carangidae) in Tunisian coasts. AB - A new species Kudoa azevedoi sp. n. (Myxozoa, Multivalvulida) is described in Trachurus trachurus Linnaeus, 1758 (Carangidae) from fishing harbors in Tunisian coasts using spore morphology and SSU rDNA sequence data. The parasite occurs only in ovaries within oocytes of mature and immature specimens. Spores are quadrate in shape in apical view with rounded edges, having four shell valves and four symmetrical polar capsules. They are of small sizes and measure 3.5+/-0.41 (3-4.2)*4.5+/-0.44 (4-5.2) length by width. The polar capsules are pyriform in shape measuring 1.5+/-0.22 (1.5-2)*0.75+/-0.14 (0.5-1) MUm. Infected oocytes are hypertrophied, whitish colored, and filled with mature spores. Plasmodia are tubular and ramified from the inner membrane toward the center of the oocyte. Phylogenetic analysis based on small subunit ribosomal DNA sequences shows the highest similarity (96%) with the ovary parasite Kudoa ovivora. Some morphological details and spore dimensions support the creation of a new species in the genus Kudoa. Mean prevalence among examined females is of about 55.5%. It varies between localities and length of fish. The present myxosporea is the second Kudoa species reported in fish ovaries. PMID- 23435962 TI - Paraquat poisonings in France during the European ban: experience of the Poison Control Center in Marseille. AB - Paraquat, a widely used herbicide in the world, has caused severe and fatal poisonings. Because of its high toxicity, the European Union withdrew paraquat from its market in July 2007. The purpose of this report is to describe cases of paraquat poisoning recorded at the Poison Control Center in Marseille over the 9 year period starting and ending 4.5 years before and after the paraquat ban. Data analysis showed that the most severe exposures were linked to ingestion. The fatality rate of deliberate consumption was near 50 % (34 suicide attempts and 15 deaths). Our data showed a marginal decline in total number of poisonings observed after the paraquat ban (38 vs 33 after the ban) mostly due to a decrease in the number of unintentional exposure (21 vs 16 after the ban). However, there was no apparent change in the number suicidal attempts using paraquat. Regarding geographical distribution, data showed that most poisonings in mainland France were unintentional, while poisonings in overseas French territories were mostly voluntary. Despite the European ban and the preventive measures, paraquat continues to contribute to severe and life-threatening poisonings in Southeastern and overseas France. PMID- 23435960 TI - NSAIDs may regulate EGR-1-mediated induction of reactive oxygen species and non steroidal anti-inflammatory drug-induced gene (NAG)-1 to initiate intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer. AB - This study aims to investigate the unclear molecular relationship involved in the activation of intrinsic pathway of apoptosis and NSAID-activated gene-1 (NAG-1) induction as a putative target in NSAIDs-mediated chemoprevention of colorectal cancer. Male Sprague-Dawley rats were administered with a colon-specific pro carcinogen, 1,2-dimethylhydrazine dihydrochloride to achieve the early stages of colorectal cancer. Histopathological examination was performed for the analysis of neoplastic lesions while flow cytometry was performed for the relative quantification of intracellular reactive oxygen species (ROS), differential mitochondrial membrane potential (MMP or DeltaPsi(M)), and apoptotic events. Various target biomolecules were analyzed either for their mRNA or protein expression profiles via RT-PCR and quantitative Real-Time PCR, or Western blotting and immunofluorescence, respectively. Enhanced gene as well as protein expression of pro-apoptotic agents was observed with the daily oral administration of two NSAIDs viz. Sulindac (cyclooxygenase (COX)-non-specific) and Celecoxib (a selective COX-2 inhibitor). A significant increase in early growth response-1 (EGR-1) protein expression and nuclear localization in NSAIDs co-administered animals may have positively regulated the expression of NAG-1 with a significant enhancement of intracellular ROS in turn decreasing the DeltaPsi(M) to initiate apoptosis. In silico molecular docking analysis also showed that Sulindac and Celecoxib can block the active site pocket of B-cell lymphoma-extra large (Bcl-xL, anti-apoptotic transmembrane mitochondrial protein) which could be a putative mechanism followed by these NSAIDs to overcome anti apoptotic properties of the molecule. NSAIDs-mediated up-regulation of EGR-1 and thereby NAG-1 along with implication of higher ROS load may positively regulate the intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer. PMID- 23435963 TI - Validation study of the UICC TNM classification of malignant tumors, seventh edition, in breast cancer. AB - BACKGROUND: The TNM classification of the Unio Internationalis Contra Cancrum was revised for the seventh edition. The major change concerning breast cancer is a change in the stages for patients with T0 or T1N1miM0. In the present study, the seventh edition of the TNM classification was validated in breast cancer. METHODS: The stages of 416 breast cancer patients, treated at our hospital in 1996, were classified according to the TNM classification, sixth and seventh editions, and their prognoses were compared. RESULTS: Case distribution using the sixth edition was stage 0, 56 cases (13.5 %); stage I, 158 cases (38.0 %); stage II, 130 [A, 102; B, 28] cases (31.2 [A, 24.5; B, 6.7] %); and stage III, 72 [A, 31; B, 8; C, 33] cases (17.3 [A, 7.5; B, 1.9; C, 7.9] %). According to the seventh edition, the stages for 20 patients, accounting for 19.6 % of IIA cases according to the sixth edition, decreased from IIA to IB. The 10-year overall survivals were stage 0, 91.1 %; stage I, 88.6 %; stage II, 80.8 %; and stage III, 63.9 % according to the sixth edition; and stage 0, 91.1 %; stage I, 88.8 %; stage II, 79.1 %; and stage III, 63.9 % according to the seventh edition. Although no significant differences were seen among the survival rates for stages 0 to II according to the sixth edition, there was a significant difference between stage I and II according to the seventh edition (p = 0.026). CONCLUSION: The latest revision of the TNM classification is appropriate for breast cancer from the perspective of prognosis. PMID- 23435964 TI - Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury. AB - Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)-dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-kappaB's regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IkappaBa (the inhibitory protein of NF-kappaB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation. PMID- 23435965 TI - Cyclooxygenase-2 positively regulates Akt signalling and enhances survival of erythroleukemia cells exposed to anticancer agents. AB - Cyclooxygenase-2 (COX-2) has been found to be highly expressed in many types of cancers and to contribute to tumorigenesis via the inhibition of apoptosis, increased angiogenesis and invasiveness. In hematological malignancies, COX-2 expression was found to correlate with poor patient prognosis. However, the exact role of COX-2 expression in these malignancies, and particularly in erythroleukemias, remains unclear. The aim of this work was to describe and understand the relationships between COX-2 expression and apoptosis rate in erythroleukemia cells after apoptosis induction by several anticancer agents. We used three different erythroleukemia cell lines in which COX-2 expression was modulated by transfection with either COX-2 siRNA or COX-2 cDNA. These cellular models were then treated with apoptosis inducers and apoptosis onset and intensity was followed. Cell signalling was evaluated in unstimulated transfected cells or after apoptosis induction. We found that COX-2 inhibition rendered erythroleukemia cells more sensitive to apoptosis induction and that in cells overexpressing COX-2 apoptosis induction was reduced. We demonstrated that COX-2 inhibition decreased the pro-survival Akt signalling and activated the negative regulator of Akt signalling, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Conversely, in COX-2 overexpressing cells, Akt signalling was activated and PTEN was inhibited. In these last cells, inhibition of casein kinase 2 or Akt signalling restored sensitivity to apoptotic agents. Our findings highlighted that COX-2 can positively regulate Akt signalling mostly through PTEN inhibition, partly via casein kinase 2 activation, and enhances survival of erythroleukemia cells exposed to anticancer agents. PMID- 23435966 TI - Live cell imaging in a micro-array of acoustic traps facilitates quantification of natural killer cell heterogeneity. AB - Natural killer (NK) cells kill virus-infected or cancer cells through the release of cytotoxic granules into a tight intercellular contact. NK cell populations comprise individual cells with varying sensitivity to distinct input signals, leading to disparate responses. To resolve this NK cell heterogeneity, we have designed a novel assay based on ultrasound-assisted cell-cell aggregation in a multiwell chip allowing high-resolution time-lapse imaging of one hundred NK target cell interactions in parallel. Studying human NK cells' ability to kill MHC class I deficient tumor cells, we show that approximately two thirds of the NK cells display cytotoxicity, with some NK cells being particularly active, killing up to six target cells during the assay. We also report that simultaneous interaction with several susceptible target cells increases the cytotoxic responsiveness of NK cells, which could be coupled to a previously unknown regulatory mechanism with implications for NK-mediated tumor elimination. PMID- 23435967 TI - Peptide directed transmembrane transport and nuclear localization of Ru(II) polypyridyl complexes in mammalian cells. AB - The targeted delivery of luminescent Ru(II) polypyridyl complexes to the nucleus of live mammalian cells by a Nuclear Localisation Signal (NLS) peptide; NF-kappaB is demonstrated. PMID- 23435968 TI - Research ethics committee auditing: the experience of a university hospital. AB - The authors report the first Italian experience of a research ethics committee (REC) audit focused on the evaluation of the REC's compliance with standard operating procedures, requirements in insurance coverage, informed consent, protection of privacy and confidentiality, predictable risks/harms, selection of subjects, withdrawal criteria and other issues, such as advertisement details and justification of placebo. The internal audit was conducted over a two-year period (March 2009-February 2011) divided into quarters to better value the influence of the new insurance coverage regulation that came into effect in March 2010 (Ministerial Decree of 14 July, 2009) and expand the requirements to safeguard participants in clinical drug trials including other critical items as information and consent and the risks to benefits ratio. Out of a total of 639 REC's opinions and research studies, 316 were reviewed. Regarding the insurance policy requirements, Auditor/REC non-compliance occurred only in one case. The highest number of Auditor/REC non-compliance was in regard to information and consent, which should have incurred a suspended decision rather than a favorable opinion. This internal audit shows the importance and the difficulty of the review process. For this reason, specific courses for members of the research ethics committee and for those who aspire to become auditors will be provided. There may also be efforts to improve the standard operating procedures already in place. PMID- 23435969 TI - Evaluating rare variants in complex disorders using next-generation sequencing. AB - Determining the genetic architecture of liability for complex neuropsychiatric disorders like autism spectrum disorders and schizophrenia poses a tremendous challenge for contemporary biomedical research. Here we discuss how genetic studies first tested, and rejected, the hypothesis that common variants with large effects account for the prevalence of these disorders. We then explore how the discovery of structural variation has contributed to our understanding of the etiology of these disorders. The rise of fast and inexpensive oligonucleotide sequencing and methods of targeted enrichment and their influence on the search for rare genetic variation contributing to complex neuropsychiatric disorders is the next focus of our article. Finally, we consider the technical challenges and future prospects for the use of next-generation sequencing to reveal the complex genetic architecture of complex neuropsychiatric disorders in both research and the clinical settings. PMID- 23435970 TI - Neuroimaging in pedophilia. AB - Paraphilia is a set of disorders characterized by abnormal sexual desires. Perhaps most discussed amongst them, pedophilia is a complex interaction of disturbances of the emotional, cognitive and sexual experience. Using new imaging techniques such as functional magnetic resonance imaging, neural correlates of emotional, sexual and cognitive abnormalities and interactions have been investigated. As described on the basis of current research, altered patterns of brain activity, especially in the frontal areas of the brain, are seen in pedophilia. Building on these results, the analysis of neural correlates of impaired psychological functions opens the opportunity to further explore sexual deviances, which may contribute ultimately to the development of tools for risk assessment, classification methods and new therapeutic approaches. PMID- 23435971 TI - The effect of topical anal captopril on resting anal pressure in healthy volunteers: the first human pilot study. AB - BACKGROUND: Previous laboratory studies have shown that angiotensin II is produced locally in the rat internal anal sphincter causing potent contraction. The aim of this first human study was to evaluate the safety and manometric effects of topical application of captopril (an ACE inhibitor) on the resting anal pressure in healthy adult volunteers. METHODS: Ten volunteers, mean age 32.5 years (range, 19-48 years), underwent anorectal manometric evaluation of the mean anal resting pressure (MRAP) and the length of the high-pressure zone (HPZ) before 20 and 60 min after topical application of captopril (0.28 %) cream. Cardiovascular variables (systolic blood pressure, diastolic blood pressure and pulse) were measured before and for up to 1 h after cream application. Side effects were recorded. Adverse events and patient comfort after the cream application were evaluated within a 24-h period by completing a questionnaire. RESULTS: There was no significant change overall in MRAP following captopril administration, although in half the patients, there were reductions in MRAP after treatment. Half the patients had a reduction in the mean resting HPZ length; however, there was no overall difference between pre- and post-treatment values. There was no effect on basic cardiovascular parameters and no correlation between manometric and cardiovascular variables. CONCLUSIONS: Topical application of captopril cream may result in a reduction in MRAP in volunteers without anorectal disease. Its use is associated with minimal side effects. It may be a new potential therapeutic option in the treatment of anal fissure. Further studies are required to determine the optimal concentration, dose and frequency of application. PMID- 23435972 TI - Disulfide bond oxidoreductase DsbA2 of Legionella pneumophila exhibits protein disulfide isomerase activity. AB - The extracytoplasmic assembly of the Dot/Icm type IVb secretion system (T4SS) of Legionella pneumophila is dependent on correct disulfide bond (DSB) formation catalyzed by a novel and essential disulfide bond oxidoreductase DsbA2 and not by DsbA1, a second nonessential DSB oxidoreductase. DsbA2, which is widely distributed in the microbial world, is phylogenetically distinct from the canonical DsbA oxidase and the DsbC protein disulfide isomerase (PDI)/reductase of Escherichia coli. Here we show that the extended N-terminal amino acid sequence of DsbA2 (relative to DsbA proteins) contains a highly conserved 27 amino-acid dimerization domain enabling the protein to form a homodimer. Complementation tests with E. coli mutants established that L. pneumophila dsbA1, but not the dsbA2 strain, restored motility to a dsbA mutant. In a protein folding PDI detector assay, the dsbA2 strain, but not the dsbA1 strain, complemented a dsbC mutant of E. coli. Deletion of the dimerization domain sequences from DsbA2 produced the monomer (DsbA2N), which no longer exhibited PDI activity but complemented the E. coli dsbA mutant. PDI activity was demonstrated in vitro for DsbA2 but not DsbA1 in a nitrocefin-based mutant TEM beta-lactamase folding assay. In an insulin reduction assay, DsbA2N activity was intermediate between those of DsbA2 and DsbA1. In L. pneumophila, DsbA2 was maintained as a mixture of thiol and disulfide forms, while in E. coli, DsbA2 was present as the reduced thiol. Our studies suggest that DsbA2 is a naturally occurring bifunctional disulfide bond oxidoreductase that may be uniquely suited to the majority of intracellular bacterial pathogens expressing T4SSs as well as in many slow-growing soil and aquatic bacteria. PMID- 23435974 TI - Clarifying the role of two-component regulation in antibiotic killing. PMID- 23435973 TI - Induction of the Yersinia pestis PhoP-PhoQ regulatory system in the flea and its role in producing a transmissible infection. AB - Transmission of Yersinia pestis is greatly enhanced after it forms a bacterial biofilm in the foregut of the flea vector that interferes with normal blood feeding. Here we report that the ability to produce a normal foregut-blocking infection depends on induction of the Y. pestis PhoP-PhoQ two-component regulatory system in the flea. Y. pestis phoP-negative mutants achieved normal infection rates and bacterial loads in the flea midgut but produced a less cohesive biofilm both in vitro and in the flea and had a greatly reduced ability to localize to and block the flea foregut. Thus, not only is the PhoP-PhoQ system induced in the flea gut environment, but also this induction is required to produce a normal transmissible infection. The altered biofilm phenotype in the flea was not due to lack of PhoPQ-dependent or PmrAB-dependent addition of aminoarabinose to the Y. pestis lipid A, because an aminoarabinose-deficient mutant that is highly sensitive to cationic antimicrobial peptides had a normal phenotype in the flea digestive tract. In addition to enhancing transmissibility, induction of the PhoP-PhoQ system in the arthropod vector prior to transmission may preadapt Y. pestis to resist the initial encounter with the mammalian innate immune response. PMID- 23435975 TI - FK506 maturation involves a cytochrome p450 protein-catalyzed four-electron C-9 oxidation in parallel with a C-31 O-methylation. AB - FK506, structurally similar to FK520 and rapamycin, is an alpha-keto amide bonding-containing, macrolide natural product that exhibits potent immunosuppressive activity and moderate antifungal activity. FK506 biosynthesis requires a hybrid polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) system to construct the skeleton of the macrolide. The mechanism for tailoring this macrolide to furnish FK506 remains poorly understood. In this study, we report a maturation paradigm common for FK506, FK520, and rapamycin, by characterizing two conserved regiospecific, post-PKS-NRPS modifications in an FK506-producing Streptomyces tsukubaensis strain. A cytochrome P450 protein, FkbD, catalyzes a less common, four-electron oxidation at C-9 to give a rarely found alpha-keto amide group, whereas a methyltransferase, FkbM, is responsible for O-methylation at C-31 to afford a methoxy group. Both FkbD and FkbM are highly tolerant in their substrate choice; therefore, the order of FkbD- and FkbM catalyzed reactions is interchangeable in the FK506 biosynthetic pathway. Inactivation of fkbD produced a new intermediate, 9-deoxo-FK506, which displayed antifungal activity lower than that of FK506. Taking previously reported bioassay results regarding the intermediates 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl FK506 into account, it is clear that the modifications catalyzed by FkbD and FkbM are of importance to reach the full biological activity of FK506 by forming a key structure motif that is necessary for interaction of the molecule with the receptor and, subsequently, the downstream intracellular responses. PMID- 23435976 TI - Genetic examination of initial amino acid oxidation and glutamate catabolism in the hyperthermophilic archaeon Thermococcus kodakarensis. AB - Amino acid catabolism in Thermococcales is presumed to proceed via three steps: oxidative deamination of amino acids by glutamate dehydrogenase (GDH) or aminotransferases, oxidative decarboxylation by 2-oxoacid:ferredoxin oxidoreductases (KOR), and hydrolysis of acyl-coenzyme A (CoA) by ADP-forming acyl-CoA synthetases (ACS). Here, we performed a genetic examination of enzymes involved in Glu catabolism in Thermococcus kodakarensis. Examination of amino acid dehydrogenase activities in cell extracts of T. kodakarensis KUW1 (DeltapyrF DeltatrpE) revealed high NADP-dependent GDH activity, along with lower levels of NAD-dependent activity. NADP-dependent activities toward Gln/Ala/Val/Cys and an NAD-dependent threonine dehydrogenase activity were also detected. In KGDH1, a gene disruption strain of T. kodakarensis GDH (Tk-GDH), only threonine dehydrogenase activity was detected, indicating that all other activities were dependent on Tk-GDH. KGDH1 could not grow in a medium in which growth was dependent on amino acid catabolism, implying that Tk-GDH is the only enzyme that can discharge the electrons (to NADP(+)/NAD(+)) released from amino acids in their oxidation to 2-oxoacids. In a medium containing excess pyruvate, KGDH1 displayed normal growth, but higher degrees of amino acid catabolism were observed compared to those for KUW1, suggesting that Tk-GDH functions to suppress amino acid oxidation and plays an anabolic role under this condition. We further constructed disruption strains of 2-oxoglutarate:ferredoxin oxidoreductase and succinyl-CoA synthetase. The two strains displayed growth defects in both media compared to KUW1. Succinate generation was not observed in these strains, indicating that the two enzymes are solely responsible for Glu catabolism among the multiple KOR and ACS enzymes in T. kodakarensis. PMID- 23435977 TI - Campylobacter jejuni Dps protein binds DNA in the presence of iron or hydrogen peroxide. AB - Iron is an essential cofactor for many enzymes; however, this metal can lead to the formation of reactive oxygen species. Ferritin proteins bind and oxidize Fe(2+) to Fe(3+), storing this metal in a nonreactive form. In some organisms, a particular subfamily of ferritins, namely, Dps proteins, have the ability to bind DNA. Here we show that the Campylobacter jejuni Dps has DNA binding activity that is uniquely activated by Fe(2+) or H2O2 at below neutral pH. The Dps-DNA binding activity correlated with the ability of Dps to self-aggregate. The Dps-DNA interaction was inhibited by NaCl and Mg(2+), suggesting the formation of ionic interactions between Dps and DNA. Alkylation of cysteines affected DNA binding in the presence of H2O2 but not in the presence of Fe(2+). Replacement of all cysteines in C. jejuni Dps with serines did not affect DNA binding, excluding the participation of cysteine in H2O2 sensing. Dps was able to protect DNA in vitro from enzymatic cleavage and damage by hydroxyl radicals. A C. jejuni dps mutant was less resistant to H2O2 in vivo. The concerted activation of Dps-DNA binding in response to low pH, H2O2, and Fe(2+) may protect C. jejuni DNA during host colonization. PMID- 23435978 TI - Modular evolution of TnGBSs, a new family of integrative and conjugative elements associating insertion sequence transposition, plasmid replication, and conjugation for their spreading. AB - Integrative and conjugative elements (ICEs) have a major impact on gene flow and genome dynamics in bacteria. The ICEs TnGBS1 and TnGBS2, first identified in Streptococcus agalactiae, use a DDE transposase, unlike most characterized ICEs, which depend on a phage-like integrase for their mobility. Here we identified 56 additional TnGBS-related ICEs by systematic genome analysis. Interestingly, all except one are inserted in streptococcal genomes. Sequence comparison of the proteins conserved among these ICEs defined two subtypes related to TnGBS1 or TnGBS2. We showed that both types encode different conjugation modules: a type IV secretion system, a VirD4 coupling protein, and a relaxase and its cognate oriT site, shared with distinct lineages of conjugative elements of Firmicutes. Phylogenetic analysis suggested that TnGBSs evolved from two conjugative elements of different origins by the successive recruitment of a transposition module derived from insertion sequences (ISs). Furthermore, TnGBSs share replication modules with different plasmids. Mutational analyses and conjugation experiments showed that TnGBS1 and TnGBS2 combine replication and transposition upstream promoters for their transfer and stabilization. Despite an evolutionarily successful horizontal dissemination within the genus Streptococcus, these ICEs have a restricted host range. However, we reveal that for TnGBS1 and TnGBS2, this host restriction is not due to a transfer incompatibility linked to the conjugation machineries but most likely to their ability for transient maintenance through replication after their transfer. PMID- 23435979 TI - Requirement of the lipopolysaccharide O-chain biosynthesis gene wxocB for type III secretion and virulence of Xanthomonas oryzae pv. Oryzicola. AB - Xanthomonas oryzae pv. oryzicola causes bacterial leaf streak of rice. A mutant disrupted in wxocB, predicted to encode an enzyme for lipopolysaccharide (LPS) synthesis, was previously shown to suffer reduced virulence. Here, we confirm a role for wxocB in virulence and demonstrate its requirement for LPS O-chain assembly. Structure analysis indicated that wild-type LPS contains a polyrhamnose O chain with irregular, variant residues and a core oligosaccharide identical to that of other Xanthomonas spp. and that the wxocB mutant lacks the O chain. The mutant also showed moderate impairment in exopolysaccharide (EPS) production, but comparison with an EPS-deficient mutant demonstrated that this impairment could not account entirely for the reduced virulence. The wxocB mutant was not detectably different from the wild type in its induction of pathogenesis-related rice genes, type II secretion competence, flagellar motility, or resistance to two phytoalexins or resveratrol, and it was more, not less, resistant to oxidative stress and a third phytoalexin, indicating that none of these properties is involved. The mutant was more sensitive to SDS and to novobiocin, so increased sensitivity to some host-derived antimicrobials cannot be ruled out. However, the mutant showed a marked decrease in type III secretion into plant cells. This was not associated with any change in expression of genes for type III secretion or the ability to attach to plant cells in suspension. Thus, virulence of the wxocB mutant is likely reduced due primarily to a direct, possibly structural, effect of the loss of the O chain on type III delivery of effector proteins. PMID- 23435980 TI - DNA-damaging agents induce the RecA-independent homologous recombination functions of integrating conjugative elements of the SXT/R391 family. AB - Integrating conjugative elements (ICEs) of the SXT/R391 family are major contributors to the spread of antibiotic resistance genes. These elements also catalyze their own diversity by promoting inter-ICE recombination through the action of the RecA-independent homologous recombination system that they encode. Here, we report that expression of this recombination system, which consists of the single-stranded DNA annealing protein Bet and the exonuclease Exo, is induced by DNA-damaging agents via ICE-encoded transcriptional regulators. We show that the bet and exo genes are part of a large polycistronic transcript that contains many conserved ICE genes that are not involved in the main integration/excision and conjugative transfer processes. We show that although the recombination genes are highly transcribed, their translation is subject to additional strong regulatory mechanisms. We also show that an ICE-encoded putative single-stranded DNA binding protein (Ssb) limits hybrid ICE formation. Finally, a thorough in silico analysis reveals that orthologues of Bet and Exo are widely distributed in bacterial strains belonging to very distantly related bacterial species and are carried by various mobile genetic elements. Phylogenetic analyses suggest that the annealing proteins and exonucleases that compose these systems sometimes have different evolutionary origins, underscoring the strong selective pressure to maintain the functionality of these unrelated cooperating proteins. PMID- 23435981 TI - Roles of predicted glycosyltransferases in the biosynthesis of the Rhizobium etli CE3 O antigen. AB - The Rhizobium etli CE3 O antigen is a fixed-length heteropolymer. The genetic regions required for its synthesis have been identified, and the nucleotide sequences are known. The structure of the O antigen has been determined, but the roles of specific genes in synthesizing this structure are relatively unclear. Within the known O-antigen genetic clusters of this strain, nine open reading frames (ORFs) were found to contain a conserved glycosyltransferase domain. Each ORF was mutated, and the resulting mutant lipopolysaccharide (LPS) was analyzed. Tricine SDS-PAGE revealed stepwise truncations of the O antigen that were consistent with differences in mutant LPS sugar compositions and reactivity with O-antigen-specific monoclonal antibodies. Based on these results and current theories of O-antigen synthesis, specific roles were deduced for each of the nine glycosyltransferases, and a model for biosynthesis of the R. etli CE3 O antigen was proposed. In this model, O-antigen biosynthesis is initiated with the addition of N-acetyl-quinovosamine-phosphate (QuiNAc-P) to bactoprenol-phosphate by glycosyltransferase WreU. Glycosyltransferases WreG, WreE, WreS, and WreT would each act once to attach mannose, fucose, a second fucose, and 3-O-methyl-6 deoxytalose (3OMe6dTal), respectively. WreH would then catalyze the addition of methyl glucuronate (MeGlcA) to complete the first instance of the O-antigen repeat unit. Four subsequent repeats of this unit composed of fucose, 3OMe6dTal, and MeGlcA would be assembled by a cycle of reactions catalyzed by two additional glycosyltransferases, WreM and WreL, along with WreH. Finally, the O antigen would be capped by attachment of di- or tri-O-methylated fucose as catalyzed by glycosyltransferase WreB. PMID- 23435982 TI - Host cell contact induces expression of virulence factors and VieA, a cyclic di GMP phosphodiesterase, in Vibrio cholerae. AB - Vibrio cholerae, a noninvasive bacterium, colonizes the intestinal epithelium and secretes cholera toxin (CT), a potent enterotoxin that causes the severe fluid loss characteristic of the disease cholera. In this study, we demonstrate that adherence of V. cholerae to the intestinal epithelial cell line INT 407 strongly induces the expression of the major virulence genes ctxAB and tcpA and the virulence regulatory gene toxT. No induction of toxR and tcpP, which encode transcriptional activators of toxT, was observed in adhered bacteria, and the adherence-dependent upregulation of toxT expression was independent of ToxR and TcpP. A sharp increase in the expression of the vieA gene, which encodes a cyclic di-GMP (c-di-GMP) phosphodiesterase, was observed in INT 407-adhered V. cholerae immediately after infection. Induction of toxT, ctxAB, and tcpA in INT 407 adhered vieA mutant strain O395 DeltavieA was consistently lower than in the parent strain, although no effect was observed in unadhered bacteria, suggesting that VieA has a role in the upregulation of toxT expression specifically in host cell-adhered V. cholerae. Furthermore, though VieA has both a DNA binding helix turn-helix domain and an EAL domain conferring c-di-GMP phosphodiesterase activity, the c-di-GMP phosphodiesterase activity of VieA is necessary and sufficient for the upregulation of toxT expression. PMID- 23435983 TI - Utilization of Saccharomyces cerevisiae recombinant strain incapable of both ethanol and glycerol biosynthesis for anaerobic bioproduction. AB - The yeast Saccharomyces cerevisiae produces ethanol and glycerol as major unwanted byproducts, unless ethanol and glycerol are the target compounds. Minimizing the levels of these byproducts is important for bioproduction processes using yeast cells. In this study, we constructed a yeast strain in which both ethanol and glycerol production pathways were disrupted and examined its culture characteristics. In wild-type yeast strain, metabolic pathways that produce ethanol and glycerol play an important role in reoxidizing nicotinamide adenine dinucleotide (NADH) generated during glycolysis, particularly under anaerobic conditions. Strains in which both pathways were disrupted therefore failed to grow and consume glucose under anaerobic conditions. Introduction of desired metabolic reaction(s) coupled with NADH oxidation enabled the engineered strain to consume substrate and produce target compound(s). Here we introduced NADH-oxidization-coupled L-lactate production mechanisms into a yeast strain incapable of ethanol and glycerol biosynthesis, based on in silico simulation using a genome-scale metabolic model of S. cerevisiae. From the results of in silico simulation based on flux balance analysis, a feasible anaerobic non growing metabolic state, in which L-lactate yield approached the theoretical maximum, was identified and this phenomenon was verified experimentally. The yeast strain incapable of both ethanol and glycerol biosynthesis is a potentially valuable host for bioproduction coupled with NADH oxidation under anaerobic conditions. PMID- 23435984 TI - SEC2-induced superantigen and antitumor activity is regulated through calcineurin. AB - Once the TCR-SAg-MHC II ternary complex is established, it triggers a variety of intracellular signal transduction pathways, which provoke extreme responses in the immune system. However, the signaling events that involved in SAg-induced immune activation are not well understood. In this study, we demonstrated that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signaling pathway was involved in SEC2-induced immune activation, and selective blockade of CaN by its inhibitor cyclosporine A (CsA) can completely inhibited the SEC2 induced T-cell stimulating potency. In addition, we selected an engineered SEC2 mutant named SAM-1 based on a series of biological activity tests, and our further studies on it not only confirmed that the CaN activity and gene transcription of its key substrates were proportional to the SEC2/SAM-1-induced T cell stimulating potency, but also suggested that intensified Ca(2+)/CaN/NFAT signaling transduction induced by SAM-1 resulted in enhanced T-cell stimulating potency, production of cytokines and cytotoxicity, which finally elicit the improved antitumor activity of SAM-1 in vivo. PMID- 23435985 TI - alpha-Ketoglutaric acid production from rapeseed oil by Yarrowia lipolytica yeast. AB - The possibility of using rapeseed oil as a carbon source for microbiological production of alpha-ketoglutaric acid (KGA) has been studied. Acid formation on the selective media has been tested in 26 strains of Yarrowia lipolytica yeast, and the strain Y. lipolytica VKM Y-2412 was selected as a prospective producer of KGA from rapeseed oil. KGA production by the selected strain was studied in dependence on thiamine concentration, medium pH, temperature, aeration, and concentration of oil. Under optimal conditions (thiamine concentration of 0.063 MUg g cells(-1), pH 3.5, 30 degrees C, high dissolved oxygen concentration (pO2) of 50 % (of air saturation), and oil concentration in a range from 20 to 60 g l( 1)), Y. lipolytica VKM Y-2412 produced up to 102.5 g l(-1) of KGA with the mass yield coefficient of 0.95 g g(-1) and the volumetric KGA productivity (QKGA) of 0.8 g l(-1) h(-1). PMID- 23435986 TI - Membrane stress caused by octanoic acid in Saccharomyces cerevisiae. AB - In order to compete with petroleum-based fuel and chemicals, engineering a robust biocatalyst that can convert renewable feedstocks into biorenewable chemicals, such as carboxylic acids, is increasingly important. However, product toxicity is often problematic. In this study, the toxicity of the carboxylic acids hexanoic, octanoic, and decanoic acid on Saccharomyces cerevisiae was investigated, with a focus on octanoic acid. These compounds are completely inhibitory at concentrations of magnitude 1 mM, and the toxicity increases as chain length increases and as media pH decreases. Transciptome analysis, reconstruction of gene regulatory network, and network component analysis suggested decreased membrane integrity during challenge with octanoic acid. This was confirmed by quantification of dose-dependent and chain length-dependent induction of membrane leakage, though membrane fluidity was not affected. This induction of membrane leakage could be significantly decreased by a period of pre-adaptation, and this pre-adaptation was accompanied by increased oleic acid content in the membrane, significantly increased production of saturated lipids relative to unsaturated lipids, and a significant increase in the average lipid chain length in the membrane. However, during adaptation cell surface hydrophobicity was not altered. The supplementation of oleic acid to the medium not only elevated the tolerance of yeast cells to octanoic acid but also attenuated the membrane leakiness. However, while attempts to mimic the oleic acid supplementation effects through expression of the Trichoplusia ni acyl-CoA Delta9 desaturase OLE1(TniNPVE desaturase) were able to increase the oleic acid content, the magnitude of the increase was not sufficient to reproduce the supplementation effect and increase octanoic acid tolerance. Similarly, introduction of cyclopropanated fatty acids through expression of the Escherichia coli cfa gene was not helpful for tolerance. Thus, we have provided quantitative evidence that carboxylic acids damage the yeast membrane and that manipulation of the lipid content of the membrane can increase tolerance, and possibly production, of these valuable products. PMID- 23435987 TI - Elbow arthroscopy in stiff elbow. AB - PURPOSE: The purpose of this study was to evaluate and review the functional outcomes after arthroscopic surgery in post-traumatic and degenerative elbow contractures. METHODS: Between 2004 and 2008, 243 patients with post-traumatic or degenerative elbow stiffness were treated with arthroscopic surgery. A total of 212 patients were reviewed at an average of 58 months follow-up (SD +/- 17.3). The patients were divided into two groups: group A with post-traumatic stiffness, and group B with degenerative stiffness. Arthroscopic procedures performed included: synovectomy, debridement of osteophytes, removal of loose bodies, anterior and posterior capsulectomy, radial head excision. Ulnar nerve neurolysis was usually performed. The following data were recorded and analysed: sex, age, paraesthesia, previous surgical treatment and complications. Patient outcome was assessed pre- and post-operatively by a visual analogue scale and by the Mayo Elbow Performance Index (MEPI), which assesses pain, ROM, stability and function. RESULTS: The total average ROM improved by 33 degrees in group A and 20 degrees in Group B. The MEPI improved from 60 to 81 in group A, and from 65 to 91 in group B. CONCLUSIONS: Arthroscopic surgery in post-traumatic and degenerative elbow contractures can be considered a safe, useful, with a long learning curve procedure that offers important improvement of the ROM decreasing surgical morbidity. PMID- 23435988 TI - Thyroid hormone and cardiovascular system: from basic concepts to clinical application. AB - Experimental and clinical findings strongly support the concept that thyroid hormone (TH) plays a fundamental role in the cardiovascular (CV) homeostasis. CV diseases represent a major public health care and economic problem being one of the principal causes of morbidity, mortality and hospitalization. In particular, chronic heart failure (HF) is one of the most common reasons for general practitioners consultations in people >65-70 years old. TH derangement may have a key role in the evolution process of HF. In HF, the main and earlier alteration of the thyroid function is referred to as "low-T3" syndrome characterized by the reduction in serum total T3 and free T3 with normal levels of thyroxine (T4) and thyrotropin (TSH). This syndrome may affect till one-third of advanced HF patients. The main goal of this mini-review is to examine the main pathophysiological and clinical links between an altered thyroid metabolism and CV diseases, namely HF during progression of disease from organ specific to systemic disorder. PMID- 23435989 TI - Integrating complementary medicine in supportive cancer care models across four continents. AB - The need to integrate complementary medicine (CM) consultation in supportive care of patients with cancer is acknowledged by oncologists owing to the ongoing research on CM efficacy and awareness of its potential risks. In this article, we aim to provide oncologists with models for CM integration within supportive care. Descriptive analysis of key elements which facilitate CM integration is presented by physicians leading six integrative cancer care programs across four continents. Perspectives of integration are supplemented by a literature review, quantitative data on the clinical activity in each center, and qualitative narrative-based citations of seven oncology patients and healthcare providers. It is recommended that CM consultation be provided by physicians with extensive CM training. The following key elements were identified as essential for integrative program design within oncological supportive care: (1) Location of the integrative physician (IP) room within the oncology department area, (2) Required oncologist referral to CM consultation, (3) Allocated time to IP-oncologist communication, (4) Research-based integrative practice, (5) Inclusion of paid professional CM practitioners, (6) Institutional cost covered service. Integration of CM consultation within oncological supportive care needs to take in account six key elements that ensure high-quality evidence-based concomitant integrative practice. PMID- 23435991 TI - Cytoneme-mediated cell-to-cell signaling during development. AB - Cell-to-cell communication is vital for animal tissues and organs to develop and function as organized units. Throughout development, intercellular communication is crucial for the generation of structural diversity, mainly by the regulation of differentiation and growth. During these processes, several signaling molecules function as messengers between cells and are transported from producing to receptor cells. Thus, a tight spatial and temporal regulation of signaling transport is likely to be critical during morphogenesis. Despite much experimental and theoretical work, the question as to how these signals move between cells remains. Cell-to-cell contact is probably the most precise spatial and temporal mechanism for the transference of signaling molecules from the producing to the receiving cells. However, most of these molecules can also function at a distance between cells that are not juxtaposed. Recent research has shown the way in which cells may achieve direct physical contact and communication through actin-based filopodia. In addition, increasing evidence is revealing the role of such filopodia in regulating spatial patterning during development; in this context, the filopodia are referred to as cytonemes. In this review, we highlight recent work concerning the roles of these filopodia in cell signaling during development. The processes that initiate and regulate the formation, orientation and dynamics of cytonemes are poorly understood but are potentially extremely important areas for our knowledge of intercellular communication. PMID- 23435990 TI - Association between single nucleotide polymorphisms of the transforming growth factor-beta1 gene and overall survival in unresectable locally advanced non-small cell lung cancer patients treated with radio(chemo)therapy in a Chinese population. AB - The outcome is variable for unresectable locally advanced non-small-cell lung cancer (ULANSCLC) patients treated with radio(chemo)therapy. The aim of this study is to investigate whether single-nucleotide polymorphisms (SNPs) in the transforming growth factor-beta1 (TGF-beta1) gene are associated with overall survival (OS) in ULANSCLC patients treated with definitive radio(chemo)therapy. A total of 109 patients who had available blood samples and complete clinical and follow-up information were enrolled. DNA from blood was genotyped for two SNPs: TGF-beta1 C-509T and T+869C. Kaplan-Meier survival analysis, log-rank test, and Cox's proportional hazard model were used to evaluate associations between genotypes and OS. Log-rank test showed that TGF-beta1 C-509T significantly correlated with OS (pooled P = 0.017). Both univariate and multivariate analyses showed that TGF-beta1 C-509T CC genotype was significantly associated with better OS than CT or TT genotypes. These results indicate that TGF-beta1 C-509T CC genotype is significantly associated with better OS in ULANSCLC patients treated with radio(chemo)therapy as a potential independent survival predictor. PMID- 23435992 TI - Naturally occurring neuronal plasticity in visual wulst of the Baya weaver, Ploceus philippinus (Linnaeus, 1766). AB - The visual wulst (VW), the rostro-dorsal surface of the avian telencephalon extending from the midline to the lateral region of the brain, is a laminated "bulge" consisting in four histologically distinct rostro-caudally arranged laminae with a specific sequence: hyperpallium apicale, interstitial nucleus of hyperpallium apicale, hyperpallium intercalatum and hyperpallium densocellulare. The VW has been proposed to be the avian equivalent of the mammalian striate cortex. Various behavioral studies including lesion experiments have indicated the importance of the VW, which receives visual and/or auditory cues. We have investigated qualitatively and quantitatively the fascinating structural changes occurring in VW neurons of the seasonally breeding bird, Ploceus philippinus (Linnaeus, 1766). The Golgi method was used to study the seasonal fluctuations in the neuronal classes of the VW with regard to dendritic thickness, spine morphology and spine density during both the non-breeding and breeding periods of male Baya weaver birds. Significant variations in parameters studied among the various neuronal types located in the different well-demarcated regions of the VW are believed to contribute to the functional differences reported among the wulst regions. Thus, this study extends our view demonstrating naturally occurring neuronal plasticity in a seasonally dynamic avian brain of a bird that hones not only its learning and memorizing system but also its social and sexual system in preparation for the breeding season. PMID- 23435993 TI - Insights into cell-to-cell and cell-to-blood-vessel communications in the brain: in vivo multiphoton microscopy. AB - A complex and reciprocal communication of cells with each other and with relevant parts of the tissue stroma governs many biological processes in both health and disease. However, in the past, the study of these anatomical and molecular interactions has suffered from a lack of appropriate experimental models. An imaging methodology aimed at changing this should allow intravital display and quantification in an intact non-traumatized organ, imaging over a wide range of time spans including extended periods (i.e., months), many repetitive measurements of the same cell or area to permit the study of the cause and consequence of biological processes, the display of various cell types and their reciprocal interaction with each other in three dimensions, the co-registration of relevant physiological parameters and reporters for selected molecular pathways and as high as possible resolution to visualize sub-cellular structures such as organelles. Remarkably, intravital multiphoton microscopy (in vivo MPLSM) through a chronic cranial window allows us to do all these things, making the brain the inner organ of choice for this technology. Here, we give an overview of the application of in vivo MPLSM to study the choreography of cellular, vascular and molecular interactions in the healthy brain and in neurological diseases. We focus on brain tumor formation, progression and response to therapies. This review further aims at demonstrating that we stand at the beginning of full exploitation of the opportunities provided by this technology and gives clues to future directions that appear most promising. PMID- 23435994 TI - Cell-to-cell communication: current views and future perspectives. PMID- 23435995 TI - Knowledge on osteoporosis in guardians of hip fracture patients. AB - Treatment gap between the treatment guideline and real clinical practice of osteoporosis has been found to be worldwide. Although insufficient knowledge of guardians on osteoporosis might be one important obstacle to diagnose and treatment of osteoporotic patients, there was not a study on the knowledge of guardians. We evaluated the guardians' knowledge on osteoporosis compared with the knowledge of orthopedic doctors, using a self-administered questionnaire, a modified Facts on Osteoporosis Quiz (FOOQ). In March and April 2012, the knowledge of osteoporosis was measured in 40 guardians of hip fracture patients and 40 orthopedic surgeons using, a modified FOOQ. In terms of treatment and prevention of osteoporosis, the modified FOOQ score of the guardians have inadequate knowledge and understanding about the osteoporosis, compared with orthopedic doctors (p < 0.001). The level of guardians' knowledge on osteoporosis should be considered and improved to achieve satisfactory osteoporosis treatment in hip fracture patients. PMID- 23435996 TI - Growth and sex effects on the expression of syndecan-4 and glypican-1 in turkey myogenic satellite cell populations. AB - The adult skeletal muscle stem cells, satellite cells, are responsible for skeletal muscle growth and regeneration. Satellite cells represent a heterogeneous cell population that differentially express cell surface markers. The membrane-associated heparan sulfate proteoglycans, syndecan-4, and glypican 1, are differentially expressed by satellite cells during the proliferation and differentiation stages of satellite cells. However, how the population of syndecan-4- or glypican-1-positive satellite cells changes during proliferation and differentiation, and how sex and muscle growth potential affect the expression of these genes is unknown. Differences in the amount of satellite cells positive for syndecan-4 or glypican-1 would affect the process of proliferation and differentiation which would impact both muscle mass accretion and the regeneration of muscle. In the current study, the percentage of satellite cells positive for syndecan-4 or glypican-1 from male and female turkeys from a Randombred Control Line 2 and a line (F) selected for increased 16-week body weight were measured during proliferation and differentiation. Growth selection altered the population of syndecan-4- and glypican-1-positive satellite cells and there were sex differences in the percentage of syndecan-4- and glypican-1 positive satellite cells. This study provides new information on dynamic changes in syndecan-4- and glypican-1-positive satellite cells showing that they are differentially expressed during myogenesis and growth selection and sex affects their expression. PMID- 23435997 TI - Trypomastigotes and amastigotes of Trypanosoma cruzi induce apoptosis and STAT3 activation in cardiomyocytes in vitro. AB - The haemoflagellate Trypanosoma cruzi is the causative agent of Chagas' disease that occurs in approximately 8 million people in Latin America. Patients infected with T. cruzi frequently suffer of cardiomegaly and may die of myocardial failure. Here we show that T. cruzi trypomastigotes (extracellular form) increased in vitro apoptosis of rat cardiomyocytes. Additionally, we demonstrated that amastigotes (intracellular form), for which a method for purification was established, were also able to induce cardiomyocyte apoptosis. Increase of apoptosis was associated with up-regulation of the apoptotic gene bax by trypomastigotes, while expression of the anti-apoptotic gene bcl-2 was down regulated by amastigotes. The transcription factor STAT3 but not STAT1 was activated in cardiomyocytes by trypomastigotes. In addition, tlr7 gene expression was up-regulated in cardiomyocytes incubated with trypomastigotes, suggesting that this Toll-like receptor is involved in the intracellular recognition after host cell invasion by T. cruzi. Glycosylphosphatidylinositols purified from trypomastigotes did not induce cardiomyocyte apoptosis and STAT activation but down-regulated tlr7 gene expression. In conclusion, cardiomyopathy observed in Chagas' disease might be in part due to apoptosis of cardiomyocytes induced directly by the parasite. PMID- 23435998 TI - Upregulation of DR5 receptor by the diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4 methoxy phenyl amino) thiazole] triggers an independent extrinsic pathway of apoptosis in colon cancer cells with compromised pro and antiapoptotic proteins. AB - Mitochondria mediated signalling is the more common way of apoptosis induction exhibited by many chemotherapeutic agents in cancer cells. Death receptor mediated signalling for apoptosis in many cells also requires further amplification from the mitochondrial pathway activation through tBid. Thus the potential of most chemotherapeutic agents in tumours with intrinsic apoptosis resistance due to changes in molecules involved in the mitochondrial pathway is limited. Diaminothiazoles were shown earlier to bind to tubulin thereby exhibiting cytotoxicity towards different cancer cells. We observed that the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] could induce apoptosis in the colon cancer cell line HCT116 by both pathways. However, in contrast to many other chemotherapeutic agents, DAT1 triggered apoptosis where the intrinsic pathway was blocked by changing the pro and antiapoptotic proteins. An independent extrinsic pathway activation triggered by the upregulation of DR5 receptor accounted for that. The induction of DR5 occurred in the transcriptional level and the essential role of DR5 was confirmed by the fact that siRNA downregulation of DR5 significantly reduced DAT1 induced apoptosis. HCT116 cells were earlier shown to have a type II response for apoptosis induction where extrinsic pathway was connected to the intrinsic pathway via the mediator protein tBid. Our finding thus indicates that the signalling events in the manifestation of apoptosis depend not only on the cancer cell type, but also on the inducer. Our results also place diaminothiazoles in a promising position in the treatment of tumours with compromised apoptotic factors. PMID- 23436001 TI - The impact of undergraduate education in radiation oncology. AB - Many medical practitioners provide care to patients for whom radiotherapy [radiation oncology (RO)] is a recommended treatment or who have received radiotherapy treatment for cancer. A basic level of understanding about this modality is important to ensure a continuum of good patient care. This study aimed to explore the current teaching practices in RO across medical schools in Canada and understand the perception of RO as a career choice among final-year medical students. Ethics approval and/or consent was obtained from each medical school prior to sending an electronic survey to the Undergraduate Medical Education office and to the final-year medical school class. Only six of the 14 Canadian medical schools participated in the surveys. Four of the 14 refused external surveys. The response rate was 8 % (155/1,917) for all final-year medical students and 17 % (155/897) for students from participating medical schools. Didactic lectures are the primary means of delivering RO knowledge. One in five students reports that they did not receive any RO teaching, and 65 % received <2 h. The level of interest in RO as a career choice (scale of 1-5) was greater in students who received >2 h of RO teaching (2.85 vs. 3.18, p = 0.012) and those that took part in a RO elective (2.86 vs. 3.53, p < 0.001). This study confirms the underrepresentation of RO teaching within the Canadian undergraduate medical curriculum. Interest in this specialty is minimal but does appear to be influenced by exposure to RO teaching. It is important to highlight the limitations of conducting a survey study within the Canadian medical undergraduate system. Steps to conduct such studies in a more seamless fashion are required, in order to assist curriculum development in RO and enhance the understanding of the specialty as a career choice. PMID- 23436000 TI - Increased PELP1 expression in rat periodontal ligament tissue in response to estrogens treatment. AB - Estrogens and their receptors are important factors involved in periodontal ligament (PDL) tissue health. As a regulator of estrogen receptors (ER), the proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) may play a role in alveolar bone formation and PDL homeostasis. The aim of the present study was to observe PELP1 expression in rat PDL tissue during estrogen levels manipulations. Twenty-one 8-week old normal female Sprague-Dawley rats were randomly divided into three equal groups: sham-operated controls, ovariectomized (OVX) group, and OVX given 17beta-estradiol intraperitoneally (OVX + E2) for 16 weeks. PELP1 expression was down-regulated in the OVX group and was up-regulated in the OVX + E2 group. Periodontal ligament fibroblast cells (PDLFCs) were isolated from PDL tissue, and characterized by immunohistochemical staining. Estradiol treatment of PDLFCs induced PELP1 protein level compared to untreated cells. PELP1 mRNA expression in estradiol-treated cells was relatively low at the beginning of treatment and then steadily increased from hour 4. In conclusion, results indicate that PELP1 is expressed in rat PDL tissue and PDLFCs, and that its expression is up-regulated during estrogen treatment. PMID- 23436002 TI - Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder. AB - Ataxia-telangiectasia-like disorder (ATLD) due to mutations in the MRE11 gene is a very rare autosomal recessive disease, described so far in only 20 patients. Little is known about the onset of the first symptoms or the clinical course of the disease. The present report contributes to the diagnosis of ATLD and its prognosis at onset. We report 30 years of clinical and ophthalmic observations and the results of quantitative magnetic resonance (MR), MR spectroscopy (proton magnetic resonance spectroscopic imaging) and neuropsychological assessment in the first Italian siblings identified with ATLD. Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age. The patients developed eye and head motor strategies to compensate ocular motor apraxia. MR measurements and MR spectroscopy disclosed widespread neuronal and axonal involvement. ATLD should be considered in patients with ocular apraxia and ataxia in infancy. The long follow-up provided insights into clinical outcome, with functional neuroimaging studies shedding light on the pathogenetic mechanisms of this rare disease. PMID- 23436004 TI - Blue fluorescent emitters: design tactics and applications in organic light emitting diodes. AB - Organic light-emitting diodes (OLEDs) are competitive candidates for the next generation flat-panel displays and solid state lighting sources. Efficient blue emitting materials have been one of the most important prerequisites to kick off the commercialization of OLEDs. This tutorial review focuses on the design of blue fluorescent emitters and their applications in OLEDs. At first, some typical blue fluorescent materials as dopants are briefly introduced. Then nondoped blue emitters of hydrocarbon compounds are presented. Finally, the nondoped blue emitters endowed with hole-, electron- and bipolar-transporting abilities are comprehensively reviewed. The key issues on suppressing close-packing, achieving pure blue chromaticity, improving thermal and morphological stabilities, manipulating charge transporting abilities, simplifying device structures and the applications in panchromatic OLEDs are discussed. PMID- 23436003 TI - Cognitive and emotional deficits in chronic alcoholics: a role for the cerebellum? AB - It is now widely accepted that in addition to motor coordination, the cerebellum is also involved in the modulation of cognitive and affective processes. Despite alcoholic cerebellar degeneration (ACD) being the most common form of cerebellar disorder, little systematic investigation of cerebellar-mediated cognitive and affective deficits has occurred in chronic alcoholics. Forty-nine chronic alcoholics and 29 healthy control participants underwent testing of cognitive and affective function, along with measurement of cerebellar ataxia using the International Cooperative Ataxia Rating Scale (Trouillas et al., Journal of the Neurological Sciences 145:205-11, 1997). The alcoholic group demonstrated significantly poorer performance as compared to the control group in a number of domains, including visuospatial and language skills, psychomotor speed, new learning and memory, executive functioning, and emotional regulation and affect processing. There were no differences between the alcoholic and control groups in immediate attention and working memory abilities. Years of heavy drinking and total period of abstinence were found to be the best predictors of cognitive and emotional function in the alcoholic group. After accounting for alcohol chronicity, there was still a relationship between the degree of clinical signs of ACD and some areas of cognitive and emotional functioning, including language, executive functioning, processing speed and affect processing. The results suggest that some of the cognitive and affective deficits observed in chronic alcoholics may be mediated, at least in part, by cerebellar dysfunction. These findings add support to the theory of disruption to bidirectional cerebro cerebellar circuitry underlying cognitive and affective deficits in chronic alcoholics. PMID- 23436005 TI - Why does a protein's evolutionary rate vary over time? AB - The sequences of different proteins evolve at different rates. The relative evolutionary rate (ER) of a single protein also changes over evolutionary time. The cause of this ER fluctuation remains uncertain, and study of this phenomenon may shed light on protein evolution more broadly. We have characterized ER fluctuation in mammals and Drosophila. We found little correlation between the amount of rate variation observed for a protein and such factors as its expression level or phylogenetic distribution. Perhaps more surprisingly, we found little correlation between our measure of rate variation and ER itself. We also investigated the extent to which the ERs of different domains of a protein vary independently. We found that rates of different domains do tend to vary together. In fact, rates at positions in different domains are coupled just as strongly as rates at equally distant positions in the same domain. These findings provide clues to the protein evolutionary process. PMID- 23436006 TI - Classification criteria: peripheral spondyloarthropathy and psoriatic arthritis. AB - Recent proposals for re-classification of spondyloarthropathies according to the predominance of peripheral and axial manifestations and for non-radiographic ankylosing spondylitis to be re-named axial spondyloarthritis are reviewed. It is argued that such proposals are less likely to advance knowledge in the study of spondyloarthopathies and that accurate classification criteria for defined diseases, for example psoriatic arthritis, remain as necessary now as they ever did. The CASPAR criteria remain the best performing classification criteria for psoriatic arthritis. PMID- 23436007 TI - An efficient route for the synthesis of phosphorus-selenium macro-heterocycles. AB - Four-membered ring [PhP(Se)(MU-Se)]2 (Woollins' reagent, WR) reacts with disodium alkenyl-diols followed by in situ ring-closure reaction with appropriate dibromoalkanes affording a series of unusual nine- to fifteen-membered organoselenophosphorus macrocycles bearing the O-P-Se-Cn-Se-P-O or O-P-Se-Cn-O-P Se linkage. PMID- 23436008 TI - Clinical heterogeneity of patients with complex sleep apnea syndrome. AB - BACKGROUND: The definition of complex sleep apnea (CompSAS) encompasses patients with obstructive sleep apnea (OSA) who develop central apnea activity upon restitution of airway patency. Presence of arterial hypertension (HTN), coronary artery disease (CAD) and heart failure (HF) have been proposed as risk factors for CompSAS among OSA patients. Using our database of patients with CompSAS, we examined the prevalence of these risk factors and defined other clinical characteristics of patients with CompSAS. METHODS: Through retrospective search of the database, we examined the medical and clinical characteristics of consecutive patients diagnosed with CompSAS between 11/1/2006 and 6/30/2011 at NorthShore University HealthSystem. RESULTS: One hundred and fifty patients with CompSAS were identified. Among patients included in the study, 97 (64.7 %) had at least one risk factor for CompSAS, while 53 (35.3 %) did not have any of them. Prevalence of low left ventricular ejection fraction and hypocapnia were low. Therapeutic interventions consisted of several positive airway pressure therapies, mainly adaptive servo ventilation. A hundred and ten patients (73.3 %) complied with recommended therapy and improved clinically. CONCLUSIONS: Although most patients with CompSAS have cardiac comorbidities, about one third of patients do not have any risk factors of CompSAS prior to sleep testing. Further research on factors involved in development of CompSAS will allow for better tailoring of therapy to pathophysiology involved in an individual case. PMID- 23436009 TI - Adhesive capsulitis of the knee. AB - The authors describe the case of a 42-year-old woman presenting with significant knee pain and disability. Her imaging findings using contrast MR imaging and FDG PET/CT suggested adhesive capsulitis, which was confirmed by arthroscopy, histology, and the clinical outcome. PMID- 23436012 TI - Measuring the prevalence of chronic diseases using population surveys by pooling self-reported symptoms, diagnosis and treatments: results from the World Health Survey of 2003 for South Asia. AB - OBJECTIVES: Measuring disease prevalence poses challenges in countries where information systems are poorly developed. Population surveys soliciting information on self-reported diagnosis also have limited capacity since they are influenced by informational and recall biases. Our aim is to propose a method to assess the prevalence of chronic disease by combining information on self reported diagnosis, self-reported treatment and highly suggestive symptoms. METHODS: An expanded measure of prevalence was developed using data from the World Health Survey for Bangladesh, India and Sri Lanka. Algorithms were constructed for six chronic diseases. RESULTS: The expanded measures of chronic disease increase the prevalence estimates. Prevalence varies across socio demographic characteristics, such as age, education, socioeconomic status (SES), and country. Finally, the association, as also risk factor, between chronic disease status and poor self-rated health descriptions increases significantly when one takes into account highly suggestive symptoms of diseases. CONCLUSIONS: Our expanded measure of chronic disease could form a basis for surveillance of chronic diseases in countries where health information systems have been poorly developed. It represents an interesting trade-off between the bias associated with usual surveillance data and costs. PMID- 23436013 TI - Primary CNS germ cell tumors: current epidemiology and update on treatment. AB - Primary central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of lesions that account for 0.5 % of all primary brain and CNS tumors, occurring at an incidence rate of 0.10 per 100,000 person-years in the United States with approximately 90 % of the cases before the age of 20 years. Primary CNS GCTs demonstrate a remarkable difference in incidence based on gender and location within the brain with males having a 15:1 incidence in the pineal region while the gender incidence is nearly 1:1 in the rest of the brain. Also, historically the incidence was noted to be significantly higher in Japan and East Asia, but recent studies in Japan demonstrate similar incidence as in the United States. They are broadly classified as germinomas and non-germinomatous germ cell tumors (NGGCTs) based on clinicopathologic features. Germinomas are sensitive to treatment with radiotherapy and chemotherapy with high cure rates and carry an excellent prognosis, while NGGCTs display various forms of differentiation, have a poorer prognosis and are refractory to therapy. Standard management of CNS GTCs remains unsettled and ongoing research aims to achieve best possible survival rates and post-treatment quality of life by reduction in treatment intensity. PMID- 23436014 TI - Time-varying pattern of recurrence risk for gastric cancer patients. AB - This study analyzed the time-varying pattern of the recurrence risk for gastric cancer after surgery. A total of 1,222 gastric patients undergoing D2 resection surgery were studied retrospectively. The annual recurrence hazard curve for all of the populations showed one early peak and a late rise within 10 years after the surgery. The first major recurrence peak covers the first 3 years after the surgery, rising to a maximum at 1.5 years after surgery, followed by a decline until 7.5 years after the surgery, at which point the curve began to rise again. A subgroup analysis of this pattern also revealed that the curves of the patients with bigger tumors, poorly differentiated/undifferentiated adenocarcinomas, lymphatic/venous invasion, T3 and T4, node positive or with fewer lymph nodes retrieved were steeper. Chemotherapy can reduce the hazard rate for recurrence of gastric cancer. Our study confirms the time-varying pattern of the recurrence risk for gastric cancer, and it further supports the hypothesis of tumor dormancy after surgery. To effectively reduce the recurrence risk, new adjuvant therapies beyond chemotherapy may be needed. PMID- 23436015 TI - Comment on P.-T. Wu et al.: Acromio-clavicular dislocation with coraco-clavicular ligament clavicular avulsion fracture. PMID- 23436016 TI - Reply to letter to the editor by S. Ozyurek et. al. PMID- 23436018 TI - An exceptional case of MSA-P. PMID- 23436019 TI - ITIH4 and Gpx3 are potential biomarkers for amyotrophic lateral sclerosis. AB - The diagnosis of amyotrophic lateral sclerosis (ALS) is difficult due to lack of definitive biomarkers. Our aim was to identify characteristic serum protein patterns that could provide candidate biomarkers for ALS. We divided mutant superoxide dismutase-1 (SOD1)(H46R) rats into three groups based on disease progression: pre-symptom (90 days), onset, and end-stage. After separation of serum proteins using two-dimensional electrophoresis, we selected clear protein spots and identified two candidate proteins-inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and glutathione peroxidase 3 (Gpx3). The 120 kDa ITIH4 increased at the onset of the disease and the 85 kDa ITIH4, a cleaved form, at the end stage in the sera of the SOD1(H46R) rats. Expression of the 85 kDa ITIH4 was substantial in ALS compared with controls or patients with muscular dystrophy, Alzheimer diseases, or Parkinson diseases. The Gpx3 protein levels in the sera of SOD1(H46R) rats were upregulated pre-symptom and gradually decreased as the disease progressed. The Gpx3 protein levels were lower in the sera of the patients with ALS than in other diseases. These results indicate that ITIH4 and Gpx3 are potential biomarkers for ALS. PMID- 23436020 TI - Supply determines demand: influence of partner quality and quantity on the interactions between bats and pitcher plants. AB - Interspecific relationships such as mutualism and parasitism are major drivers of biodiversity. Because such interactions often comprise more than two species, ecological studies increasingly focus on complex multispecies systems. However, the spatial heterogeneity of multi-species interactions is often poorly understood. Here, we investigate the unusual interaction of a bat (Kerivoula hardwickii hardwickii) and two pitcher plant species (Nepenthes hemsleyana and N. bicalcarata) whose pitchers serve as roost for bats. Nepenthes hemsleyana offers roosts of higher quality, indicated by a more stable microclimate compared to N. bicalcarata but occurs at lower abundance and is less common than the latter. Whereas N. hemsleyana benefits from the roosting bats by gaining nitrogen from their feces, the bats' interaction with N. bicalcarata seems to be commensal or even parasitic. Bats stayed longer in roosts of higher quality provided by N. hemsleyana and preferred them to pitchers of N. bicalcarata in a disturbance experiment. Moreover, bats roosting only in pitchers of N. hemsleyana had a higher body condition and were less infested with parasites compared to bats roosting in pitchers of N. bicalcarata. Our study shows how the local supply of roosts with different qualities affects the behavior and status of their inhabitants and-as a consequence-how the demand of the inhabitants can influence evolutionary adaptations of the roost providing species. PMID- 23436021 TI - Production, purification and partial characterization of four lipases from a thermophile isolated from Deception Island. AB - Four lipases were purified from ID17, a thermophilic bacterium belonging to Geobacillus genus isolated from Deception Island, Antarctica. Lipase activity was detected by opacity test and p-nitrophenyl laurate methods. Lipase production was better in a medium containing tryptone as the carbon and nitrogen source, without non-ionic detergents and pH 7.5. Proteins were ultrafiltered from supernatant and separated using anion exchange and size exclusion chromatography resulting in four distinct fractions with lipase activity (called Lip1-4). Purified lipases showed an optimal pH at 9.0, 9.5, 10.0 and 8.0 and temperature at 65, 70, 75 and 80 degrees C for Lip1-4, respectively. Lip1 and Lip2 showed higher activity using p-nitrophenol decanoate as substrate, whereas Lip3 and Lip4 prefer p nitrophenol laurate. Based on their molecular weight Lip1 and Lip2 are trimeric and pentameric proteins, respectively, whereas Lip3 and Lip4 are monomeric proteins. Lip1 was exceptionally thermostable maintaining 70 % of its activity after incubating it at 70 degrees C for 8 h. Based on their characteristics, the four lipases obtained from ID17 are good candidates to understand the mechanisms of lipase stability and to be used in different types of industrial applications. PMID- 23436022 TI - Disparities in health care utilization by smoking status in Canada. AB - OBJECTIVES: To examine the association between smoking status and the utilization of health care services in Canada. METHODS: The study uses data from the 2007 Canadian Community Health Survey, which contains information on the number of visits to general practitioner (GP), specialists (SP) and the number of nights spent in a hospital. The finite mixture estimation method is used in order to account for heterogeneity among smokers. RESULTS: Multivariate regression results indicate differential effects of smoking on health care utilization for at least two different groups of health care users: low and high users. In particular, we find that among the low-use group, smokers use less GP and SP services than never smokers. However, for the low-use and high-use groups, smokers have more hospitalizations than never smokers. The incidence of hospitalization is higher for the low-use group after controlling for need, socio-demographic characteristics and province fixed effects. Former smokers who recently quit use more health care services. CONCLUSIONS: Tobacco consumption elevates the use of health care services, especially among the high-use group. PMID- 23436023 TI - Industrial use of immobilized enzymes. AB - Although many methods for enzyme immobilization have been described in patents and publications, relatively few processes employing immobilized enzymes have been successfully commercialized. The cost of most industrial enzymes is often only a minor component in overall process economics, and in these instances, the additional costs associated with enzyme immobilization are often not justified. More commonly the benefit realized from enzyme immobilization relates to the process advantages that an immobilized catalyst offers, for example, enabling continuous production, improved stability and the absence of the biocatalyst in the product stream. The development and attributes of several established and emerging industrial applications for immobilized enzymes, including high-fructose corn syrup production, pectin hydrolysis, debittering of fruit juices, interesterification of food fats and oils, biodiesel production, and carbon dioxide capture are reviewed herein, highlighting factors that define the advantages of enzyme immobilization. PMID- 23436025 TI - Solid-vapour reactions as a post-synthetic modification tool for molecular crystals: the enclathration of benzene and toluene by Werner complexes. AB - The enclathration of benzene and toluene by Werner complexes has been described. In the case of toluene, time-lapse PXRD analysis reveals that solid-liquid and solid-vapour reactions proceed according to different pathways. These preliminary results suggest that solid-liquid reactions destroy the host structure, whereas the solid-vapour reactions allow post-synthetic modification. PMID- 23436024 TI - Viral hepatitis: review of arthritic complications and therapy for arthritis in the presence of active HBV/HCV. AB - Chronic infection with hepatitis B (HBV) or C (HCV) virus, which currently affect approximately 7 % of the world population, is encountered with the same frequency among patients with arthritis starting biological or non-biological disease modifying anti-rheumatic drugs (DMARDs). Treatment with biological agents, including anti-tumor necrosis factor agents, rituximab, and abatacept, without appropriate antiviral therapy has been associated with reactivation of HBV infection which in some cases can lead to life-threatening complications, indicating the need for appropriate screening and treatment of these patients. In this review, the latest data regarding HBV or HCV-related arthritic complications and treatment of rheumatic diseases in the presence of chronic HBV or HCV infection will be critically presented. PMID- 23436026 TI - The expression of HDAC1 and HDAC2 during cerebellar cortical development. AB - Histone deacetylases (HDACs) are epigenetic regulatory proteins that repress gene transcription by changing DNA conformation. The regulation of gene expression through histone deacetylation is an important mechanism for the development of the central nervous system. Although the disruption of the balance in epigenetic gene regulation has been implicated in many CNS developmental abnormalities and diseases, the expression pattern of HDACs in various cell types in the brain during its maturation process has had limited exploration. Therefore, in this study, we investigate the cell type-specific and developmental stage-specific expression pattern of HDAC1 and HDAC2 in the mouse cerebellum. Our experimental results show that the cerebellar progenitors and glial cells express high levels of HDAC1 and low levels of HDAC2. On the other hand, the post-mitotic migrating neuronal cells of the cerebellar cortex show strong HDAC2 and weak HDAC1 expressions. In more differentiated neuronal cells, including Purkinje cells, granule cells, unipolar brush cells, and GABAergic interneurons, we found a consistent expression pattern, high levels of HDAC2 and low levels of HDAC1. Therefore, our data provide support for the potential important roles of HDAC1 in cell proliferation and HDAC2 in migration and differentiation. PMID- 23436028 TI - MEFV gene variations in patients with systemic lupus erythematosus. AB - OBJECTIVE: The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE). METHODS: The study group comprised 190 SLE patients and 101 healthy controls of Turkish origin with no clinical features of FMF. All individuals were genotyped for the four most common MEFV gene variations (M694V, M680I, V726A and E148Q) by PCR-restriction fragment length polymorphism analysis. RESULTS: The frequency of carrying any of the four MEFV gene variations under study was 15 % in patients with SLE and 10 % in the healthy controls (p = 0.23). After the exclusion of the less penetrant E148Q variation, re-analysis for the three penetrant mutations revealed a significant association between exon 10 variations and pericarditis [p = 0.038, odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.0-12.1], and pleural effusion (p = 0.043, OR 5.2, 95 % CI 0.8 30.9). No significant association was detected between the MEFV gene variations and a higher acute phase response. CONCLUSIONS: The MEFV gene variations analyzed in our study do not seem to increase the overall susceptibility to SLE and do not have any strong association with its clinical manifestations. The possibility of a modest effect of penetrant exon 10 MEFV variants on the development of serosal effusions needs to be explored in a larger series of patients. PMID- 23436027 TI - Development and padronization of three multiplex PCRs for the diagnosis of Chlamydia trachomatis, Toxoplasma gondii, herpes simplex viruses 1 and 2, and Cytomegalovirus. AB - To develop multiplex PCRs (mPCRs) that allows simultaneous diagnosis of the infectious agents Chlamydia trachomatis, Toxoplasma gondii, HSV 1/2, and Cytomegalovirus (CMV). The study included patients with clinical suspicion of these agents, and clinical samples were blood, cerebrospinal fluid, urine, vaginal swabs, and amniotic fluid. After the extraction of DNA, this was used as a template in amplification by PCR of selected genes. The following conditions were tested: primer concentration, MgCl2 concentration, and annealing temperature. Three mPCRs were developed: multiplex I (CMV, HSV 1/2), multiplex II (CMV, HSV 1/2, T. gondii), and multiplex III (C. trachomatis, T. gondii, HSV 1/2, and CMV). The primer pairs used were shown to be specific for each infectious agent, and the specificity of mPCR assays was 100 %. Both the reactions of the monoplex PCR and mPCR produced a detection limit of 2 * 10(-5) to 6 * 10(-7) ng/MUl of different DNAs. Upon conclusion, amplified products of expected size were obtained in 3 different reactions, and all the infectious agents were detected simultaneously in each mPCR. The concordant results of the study suggest that mPCR can be a powerful tool to improve the diagnostics of infectious diseases. PMID- 23436029 TI - Suicide plasmid-dependent IS1-element untargeted integration into Aeromonas veronii bv. sobria generates brown pigment-producing and spontaneous pelleting mutant. AB - Foodborne Gram-negative pathogens belonging to the genus Aeromonas are variable in harboring insertion sequence (IS) elements that play an important role in the generation of dysfunctional relatives of known genes. Using suicide plasmids carrying an IS1-element, untargeted integration is a common problem during experimental trials to generate specific mutations by homologous recombination. In this work, different strains of Aeromonas veronii bv. sobria (AeG1 and ATCC 9071T), A. hydrophila ATCC 19570, and A. sobria ATCC 43979T are examined for acquisition of IS1-element from pYAK1 suicide plasmid. It was found that untargeted integration of IS1-element is encountered only in ATCC 9071T strain. Such untargeted integration generates a novel brown pigment-producing and spontaneous pelleting (BP(+)SP(+)) mutant. Furthermore, BP(+)SP(+) mutant strain secretes significantly higher quantity of PilF homologous protein than the wild type strain and displays an enhanced protein tyrosine phosphorylation activity. Thus, current work shows that Aeromonas spp. strains are variable in their susceptibility for suicide plasmid-dependent IS1-element untargeted integration as well as the susceptible strain is changed to mimic pigment-producing and spontaneous pelleting strains that are naturally occurring among heterogeneous group of foodborne aeromonads. PMID- 23436031 TI - Metastatic liposarcoma of the heart. Case series and brief literature review. AB - Secondary cardiac tumors are 20-40 times more frequent than primary lesions. Primary cardiac lesions are represented by myxomas when related to benign tumors, and by sarcomas in terms of malignant disease. Metastases to the heart from liposarcomas are very rare. We present three cases of secondary liposarcomas involving the left atrium, the right atrium, and the pericardium. PMID- 23436033 TI - Intraosseous venous drainage of pretibial varices. AB - In this study, we present the case of a 74-year-old male patient who presented with a painful pretibial swelling. The patient had a history of varices of the ipsilateral leg for which he had undergone stripping and ligation. At physical examination, pretibial varices and an associated soft tissue swelling were found. Ultrasound revealed pretibial varices, one of which caused a defect on the anterior tibial cortex. Plain radiography showed a small subcortical lucency of the tibial shaft. MRI confirmed the presence of pretibial varices, one of which perforated through the anterior tibial cortex and then coursed intramedullary as an enlarged intraosseous vein. Based on these findings, the diagnosis of varices with an intraosseous venous drainage anomaly was made. The patient was subsequently successfully treated by ambulatory minisurgical phlebectomy. Knowledge and recognition of this intraosseous venous drainage anomaly, which is a rare condition, is pivotal for correct patient management. We review clinical and imaging findings, and discuss previously reported cases. PMID- 23436032 TI - Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants. AB - Oxidative stress is considered to play an important role in the pathogenesis of diabetes-induced cardiovascular disease (CVD), which is invariably associated with abnormal blood lipid profile, insulin resistance and metabolic syndrome. Stress, smoking, high saturated fat intake as well as low fruit and vegetable intakes have been shown to increase oxidative stress and hyperlipidemia, which increase the predisposition of diabetic subjects to atherosclerosis, stroke and coronary heart disease. The oxidation of low-density lipoprotein by oxidative stress is essential for the development of atherosclerosis, and the reduction in oxidative stress as well as blood glucose and cholesterol is considered critical for the prevention of diabetes-induced CVD. Although epidemiological studies have demonstrated that vitamin C and vitamin E decrease the incidence of coronary heart disease, different clinical trials have failed to support the beneficial effect of these antioxidants. Nonetheless, it has been suggested that natural forms of these vitamins may be more efficacious than synthetic vitamins, and this may explain the inconsistencies in results. Antioxidants, N-acetyl-L-cysteine and resveratrol, have also been shown to attenuate the diabetes-induced cardiovascular complications. It has been indicated that the antioxidant therapy may be effective in a prevention strategy rather than as a treatment for CVD. The evidence presented here supports the view that cardiovascular complications in diabetes may be induced by oxidative stress and appropriate antioxidant therapy may be promising for attenuating the progression of diabetes-induced CVD. PMID- 23436034 TI - Preventing urinary incontinence during pregnancy and postpartum: a review. AB - Urinary incontinence (UI) is a common condition in association with pregnancy. Incident UI in pregnancy or postpartum are significant risk factors for UI later in life. Epidemiological studies on UI during pregnancy and postpartum list numerous variables associated with UI. For women, the main focus is on pelvic floor muscle training to prevent UI. However, several other modifiable risk factors are likely to contribute to prevention of UI during pregnancy and postpartum. This review investigated modifiable risk factors for UI during pregnancy and postpartum and also reviewed randomized controlled trials on prevention of UI in association with pregnancy. Systematic searches for publications until September 2012 on prevention of UI during pregnancy and postpartum were performed. Based on available evidence, the following recommendations to prevent UI during pregnancy and postpartum were made: women should be advised not to smoke before or during pregnancy (grade B), aim at normal weight before pregnancy (grade B), and aim at regaining prepregnancy weight postpartum (grade B). Occasional low-intensity training should be advocated (grade B), and constipation should be avoided during pregnancy (grade B) and postpartum (grade C). Women should be advised to perform pelvic floor muscle training during pregnancy and postpartum (grade A) and to use perineal warm packs during delivery (grade B). Cesarean section to prevent UI cannot be recommended (grade D). If lifestyle recommendations are addressed in association with pregnancy, incidence of UI during pregnancy and postpartum is likely to decrease. PMID- 23436036 TI - Lower urinary tract symptoms in women with benign joint hypermobility syndrome: a case-control study. AB - INTRODUCTION AND HYPOTHESIS: Benign joint hypermobility syndrome (BJHS) is a connective tissue disorder associated with joint hypermobility. BJHS is under recognised by medical professionals and is poorly managed. The aim of our study was to determine whether lower urinary tract symptoms (LUTS), including urinary incontinence (UI) and anterior compartment prolapse, are more common in women with BJHS than in the normal population. METHODS: This was a prospective case control study. Women diagnosed with BJHS according to the Brighton criteria were recruited from a tertiary referral clinic. Controls were recruited from hospital personnel. Both groups completed the King's Health Questionnaire (KHQ) and the Prolapse Quality of Life Questionnaire (P-QoL). Objective assessment of pelvic organ prolapse (POP) was undertaken using the Pelvic Organ Prolapse Quantification (POP-Q) system. Analyses were performed using SPSS version 17.0. The statistical difference was analysed using McNemar's test. Comparison of QoL scores was performed with the Wilcoxon signed-rank test. RESULTS: Sixty individuals were recruited and matched with 60 healthy women. The prevalence of UI in those with BJHS was significantly higher than in controls(73.3 % vs. 48.3 %). The impact of UI on QoL was statistically significant in all domains of the KHQ. There was a significant difference between groups in most urinary-specific symptoms of the KHQ. A significant number of women with BJHS suffer from voiding difficulties. Prolapse of the anterior vaginal wall was objectively more severe in those with BJHS. CONCLUSIONS: Women with BJHS have LUTS and anterior compartment prolapse, which significantly impair their QoL. It is important to identify women who are symptomatic. The addition of a systematic active case finding approach may be more effective in identifying these cases. PMID- 23436035 TI - Stress urinary incontinence in pregnant women: a review of prevalence, pathophysiology, and treatment. AB - INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) is the most common type of urinary incontinence (UI) in pregnant women and is known to have detrimental effects on the quality of life in approximately 54.3 %. Pregnancy is the main risk factor for the development of SUI. This review provides details of the pathophysiology leading to SUI in pregnant women and SUI prevalence and treatment during pregnancy. METHODS: We conducted a PubMed search for English language and human-study articles registered from January 1990 to September 2012. This search was performed for articles dealing with prevalence and treatment of SUI during pregnancy. In the intervention studies, we included studies that used a randomized controlled trial (RCT) design or studies comparing a treatment intervention to no treatment. RESULTS: A total of 534 articles were identified; 174 full-text articles were reviewed, and 28 of them met eligibility criteria and are reported on here. The mean prevalence of SUI during pregnancy was 41 % (18.6 60 %) and increased with gestational age. The increasing pressure of the growing uterus and fetal weight on pelvic-floor muscles (PFM) throughout pregnancy, together with pregnancy-related hormonal changes, may lead to reduced PFM strength as well as their supportive and sphincteric function. These cause mobility of the bladder neck and urethra, leading to urethral sphincter incompetence. Pelvic floor muscle exercise (PFME) is a safe and effective treatment for SUI during pregnancy, without significant adverse effects. CONCLUSIONS: Understanding these issues can be useful for health-care professionals when informing and counseling pregnant women to help prevent SUI during pregnancy and the postpartum period. PMID- 23436037 TI - Assessment of trabecular meshwork width using swept source optical coherence tomography. AB - PURPOSE: Measurements of the angle width by ultrasound biomicroscopy or anterior segment optical coherence tomography are usually performed 500 MUm from the scleral spur, as the anterior part of trabecular meshwork (TM) is assumed to lie within this distance. The aim of this study was to measure TM width using swept source optical coherence tomography (SS-OCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan), and to investigate factors influencing this measurement. METHODS: Participants underwent gonioscopy and SS-OCT imaging in the dark. High-definition SS-OCT images were corrected for refractive distortion; and customized software (ImageJ; National Institutes of Health, Bethesda, MD, USA) was utilized to measure TM width (distance between the scleral spur and Schwalbe's line). Linear regression analysis was performed to assess the relationship between TM width with demographic and angle parameters. RESULTS: One hundred and forty eight Chinese subjects were analyzed. The majority was female (62.4 %); the mean age was 59.2 +/- 8.68 years. Identification of the scleral spur and Schwalbe's line with SS-OCT was possible in 590 (99.7 %) and 585 angle quadrants (98.8 %) respectively. TM width was wider in the inferior and superior quadrants (mean 889 [SD 138] and 793 [136] MUm), compared to the nasal and temporal quadrants (712 [137] and 724 [115] MUm, P<0.001). There was a difference in average TM width between open (789 [100]) and closed angle eyes (753 [86]) (P=0.048). There was no significant association between TM width and angle parameters, laterality, or demographic factors. CONCLUSIONS: In SS-OCT HD images, the mean TM width varied from 710 to 890 MUm in the different quadrants of the eye, and the inferior quadrant TM was the widest compared to other quadrants. PMID- 23436038 TI - HIV sexual risk behavior and family dynamics in a Dominican tourism town. AB - Expansion of the tourism industry in the Dominican Republic has had far-reaching health consequences for the local population. Research suggests families with one or more members living in tourism areas experience heightened vulnerability to HIV/STIs due to exposure to tourism environments, which can promote behaviors such as commercial and transactional sex and elevated alcohol use. Nevertheless, little is known about how tourism contexts influence family dynamics, which, in turn, shape HIV risk. This qualitative study examined family relationships through in-depth interviews with 32 adults residing in Sosua, an internationally known destination for sex tourism. Interviewees situated HIV risk within a context of limited employment opportunities, high rates of migration, heavy alcohol use, and separation from family. This study has implications for effective design of health interventions that make use of the role of the family to prevent HIV transmission in tourism environments. PMID- 23436039 TI - Venovenous extracorporeal membrane oxygenation is effective against post cardiotomy acute respiratory failure in adults. AB - BACKGROUND: Acute respiratory failure is a serious issue that occasionally occurs after weaning from cardiopulmonary bypass (CPB) after heart surgery. This condition can be refractory to mechanical ventilation and the mortality rate is high. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is applied to treat acute lung failure after CPB at our institution. This report describes the use of VV-ECMO after cardiac surgery at a single institution. METHODS: We analyzed the outcomes of 11 patients who developed severe acute respiratory failure requiring VV-ECMO after undergoing heart surgery with a cardiopulmonary bypass. RESULTS: Four (36.4%) patients died in hospital. One patient required conversion from VV- to venoarterial (VA-) ECMO because of circulatory instability. One patient each died of respiratory failure and heart failure and two died of ischemic colitis. Lung damage secondarily developed in these four patients to other disabled organs. Seven (63.6%) patients whose lungs were primarily disabled were weaned from VV-ECMO upon recovery from respiratory failure and were ambulatory at the time of discharge from hospital. The ratio of PaO2/FIO2 (P/F) at 24 h after starting VV-ECMO did not significantly differ between survivors and non-survivors (187.9 +/- 57.7 vs. 135.5 +/- 20.5, p = 0.10), but tended to be higher in survivors. Non-survivors were significantly older than survivors. CONCLUSION: Patients who develop severe acute respiratory failure after undergoing heart surgery using cardiopulmonary bypass derive a survival benefit from VV-ECMO. PMID- 23436040 TI - Repair of mitral paravalvular leak with double left atrial wall folding. AB - Mitral paravalvular leaks can be repaired by alternative repair techniques instead of direct suture repair of the leak site. We report our technique of double left atrial wall folding for repair of posterior mitral paravalvular leaks. PMID- 23436041 TI - Exercise therapy for claudication: latest advances. AB - OPINION STATEMENT: Peripheral artery disease (PAD) creates a significant national and international healthcare burden. A first line treatment for PAD is supervised walking exercise in hospitals and clinics. Specifically, supervised walking exercise seeks to improve the classic symptom associated with PAD, intermittent claudication (IC), which is characterized by cramping, aching, and pain of the muscles in the lower extremities during walking. While effective, supervised walking exercise is often not prescribed or utilized due to a number of treatment barriers such as lack of transportation to clinical centers and lack of insurance reimbursement. Walking exercise in community settings is an option that has gained attention due to the limitations of supervised walking exercise, as community walking is generally more convenient in terms of a patient's schedule and may circumvent potential barriers such as treatment cost and transportation difficulties. However, more research is needed to improve the effectiveness of community-based walking programs since far less is known about the optimal structure of such programs. Other exercise therapy options are becoming available for PAD patients in addition to walking exercise. These modalities include but are not limited to leg and arm ergometry, polestriding and resistance training. These exercise therapy options have not to date been as well validated as supervised walking exercise. However, they may potentially be used in the event supervised walking exercise is not feasible or patient preference warrants an alternative exercise strategy. PMID- 23436042 TI - Stress response of Caenorhabditis elegans induced by space crowding in a micro column array chip. AB - Crowding stress has been reported to play an important role in affecting physiological behaviour. To study this process, a reliable analytical method under confined space is essential. In this work, we demonstrated a microfluidic approach for investigating physiological responses of C. elegans to confined spaces. The PDMS microfluidic chip consisting of arrays of micro-columns enabled us to mimic different crowding conditions by changing the intervals among micro columns. C. elegans were transferred into this micro-column array and the subcellular distribution of DAF-16, which is a well-known transcription factor regulating different stress responses, was monitored for analysing the physiological responses to the confined spaces. We found that the worms exhibited a gradual increase in DAF-16 nuclear localization in the micro-column array with intervals from 200 MUm to 40 MUm. Moreover, the results showed that the absence of food and crowding stress could cooperate to promote increased DAF-16 nuclear localization. Finally, loss-of-function mutations in mec-4 and mec-10, which are amiloride-sensitive Na(+) channel genes expressed in all six gentle touch neurons, accelerated the velocity of DAF-16 nuclear localization, induced by confined space, revealing that mec-4/mec-10 were not required for this stress response. Thus, this device will provide a versatile, reliable and controllable platform for crowding stress studies. PMID- 23436044 TI - Cycloaddition reactions between dicyclohexylboron azide and alkynes. AB - The room temperature 1,3-dipolar cycloaddition reactions of the boron azide, Cy2BN3 with the electron-poor acetylenes RCO2C=CCO2R, EtC=CCOMe and HC=CP(=O)Ph2 afforded new 1,2,3-triazoles. In the case of RCO2C=CCO2R, a new macrocyclic product was isolated with loss of the R group. PMID- 23436045 TI - Obesity and susceptibility to severe outcomes following respiratory viral infection. AB - During the 2009 H1N1 influenza pandemic, obesity was convincingly identified as a novel, independent risk factor for multiple markers of disease severity. Associations between numerous nosocomial and community-acquired clinical infections have previously been established; yet, little is known about the mechanisms underpinning the increased susceptibility to severe outcomes following pandemic H1N1/09 infection in obesity. Here, we present a brief synthesis of the recent advances in our understanding of the immunomodulatory effects of obesity on outcomes following respiratory viral infection, with a particular focus on pandemic influenza. PMID- 23436046 TI - Hepatitis B virus infection status is an independent risk factor for multiple myeloma patients after autologous hematopoietic stem cell transplantation. AB - The purposes of this study were to evaluate the infection by hepatitis B virus (HBV) and its impact on survival and to provide a clinical reference for monitoring and treating HBV during and after autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A retrospective analysis of HBV infections was performed in 70 MM patients who received a sequential bortezomib-containing induction therapy and ASCT in our department from June 2006 to February 2012. Among the 70 patients in our study, 11 cases (15.7 %) were hepatitis B surface antigen positive (HBsAg+), and 23 cases (33.3 %) were hepatitis B core antibody positive (HBcAb+). Eight cases were HBsAg, hepatitis B e antibody (HBeAb), and HBcAb positive, while one case was HBsAg, hepatitis B e antigen (HBeAg), and HBcAb positive. The median follow-up times for the HBsAg+ group and the HBsAg-negative (HBsAg-) group were 27.0 (7.6-85.2) months and 28.7 (7.1-111.0) months, respectively. The 1-year, 2-year, and 3-year overall survival rates of the HBsAg+ group were 90.9, 80.8, and 34.6 %, respectively, and the median survival time was 31.2 months (95 % CI, 24.8-37.6). The 1-year, 2-year, and 3-year overall survival rates of the HBsAg- group were 98.2, 94, and 84.6 %, respectively, while the median survival time was not yet available. There was a statistically significant difference (p=0.008) in the overall survival rate between the two groups. By Cox regression analysis, we found that the HBsAg+ status was a prognostic factor, which could independently influence the overall survival rate for ASCT. In conclusion, the HBsAg+ status is an independent risk factor for patients with MM receiving ASCT. The application of standard antiviral treatment might help to overcome this risk factor. PMID- 23436047 TI - Concurrent chemoradiotherapy with or without adjuvant chemotherapy in intermediate and locoregionally advanced nasopharyngeal carcinoma. AB - Concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control and clinical outcome in patients with intermediate and locoregionally advanced nasopharyngeal carcinoma (NPC) (stage II, III and IVA+B). However, there has been debate about the contribution and application of additional adjuvant chemotherapy (AC) to a CCRT regime. This study aims to evaluate the additional value of AC in the treatment of intermediate and locally advanced NPC with regard to toxicity and clinical outcomes. A total of 189 patients with American Joint Committee on Cancer (AJCC) stage II to stage IVB NPC were retrospectively identified. Patient characteristics, toxicity, compliance with treatment and clinical outcomes, including response to treatment, overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), freedom from local recurrence (FLR) and freedom from distant metastasis (FDM), were analyzed. The overall response rate of CCRT and CCRT/AC groups was 97.92 % and 97.83 %, respectively (P=0.643). The 5-year OS rate was 68.2 % in the CCRT group and 75.9 % in the CCRT/AC group (P=0.53). The 5-year PFS rate was 66.7 % and 71.4 % in CCRT and CCRT/AC groups, respectively (P=0.96). This study showed no evidence of an additional value of AC in CCRT treatment in disease control and clinical outcomes in patients with locally advanced NPC in endemic regions. Moreover, three additional cycles of AC after CCRT appeared to be poorly tolerated in patients. Therefore, AC should not be routinely used for treatment, although clinical trials may be justified. PMID- 23436048 TI - Aquaporin 5 promotes the proliferation and migration of human gastric carcinoma cells. AB - Aquaporin 5 (AQP5) promotes the progression and invasion of several cancers, but its role in the tumorigenesis of human gastric carcinoma (GC) has not been clearly defined. Here, we investigated the potential functions of AQP5 in the proliferation and migration of human GC. RT-PCR and western blotting were used to detect the expression of AQP5 in human GC cell lines. Immunohistochemistry was applied to evaluate the expression of AQP5 in human GC tissues and corresponding normal tissues. Following ectopic overexpression of AQP5 or inhibition of AQP5 by its inhibitor, acetazolamide (AZA), cell proliferation and migration of AGS cells were analyzed by MTT assay, colony formation assay, and wound healing assay. Heterogeneous expression of AQP5 mRNA and protein was observed in human GC cell lines MKN45, MKN28, AGS, and SGC7901. AQP5 was up-regulated in GC tissues in comparison to corresponding normal tissues. AQP5 protein was mainly localized in the cell membrane. Overexpression of AQP5 was correlated with enhanced lymph node metastasis. In vitro, overexpression of AQP5 notably enhanced, while inhibition of AQP5 by AZA significantly attenuated the proliferation and migration of AGS cells. Our data indicate that AQP5 may play an important role in the tumorigenesis and progression of human GC and suggest that AQP5 is a potential therapeutic target against GC. PMID- 23436050 TI - Visualization and measurements of flows in micro silicon Y-channels. AB - Velocities and accelerations are measured and visualized in silicon microchannels using particle tracking velocimetry (PTV). Both pulsatile and stationary flows are generated in channels with different geometry. Distinct differences between flow regimes and geometries are shown. Flow separation occurred at Re = 84 for the channel with an expanded bifurcation shown by streamlines from long exposed images. Moving least squares are used to find the ensemble-averaged positions of the measured velocities from tracking. This is needed to find the local and convective accelerations. PMID- 23436049 TI - Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder. AB - Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways. PMID- 23436051 TI - Neuroimaging of rapidly progressive dementias, part 1: neurodegenerative etiologies. AB - Most dementias begin insidiously, developing slowly and generally occurring in the elderly age group. The so-called rapidly progressive dementias constitute a different, diverse collection of conditions, many of which are reversible or treatable. For this reason, prompt identification and assessment of acute and subacute forms of dementia are critical to effective treatment. Numerous other entities within this category of presenile rapid-onset dementias are untreatable such as the prion-related diseases. Neuroimaging aids in the diagnosis and evaluation of many of these rapidly progressive dementias, which include myriad conditions ranging from variations of more common neurodegenerative dementias, such as Alzheimer disease, dementia with Lewy bodies, and frontotemporal dementia; infectious-related dementias such as acquired immune deficiency syndrome dementia; autoimmune and malignancy-related conditions; to toxic and metabolic forms of encephalopathy. This first of a 2-part review will specifically address the ability of MR imaging and ancillary neuroimaging strategies to support the diagnostic evaluation of rapidly progressive dementias due to neurodegenerative causes. PMID- 23436052 TI - MR imaging assessment of tumor perfusion and 3D segmented volume at baseline, during treatment, and at tumor progression in children with newly diagnosed diffuse intrinsic pontine glioma. AB - BACKGROUND AND PURPOSE: DIPG is among the most devastating brain tumors in children, necessitating the development of novel treatment strategies and advanced imaging markers such as perfusion to adequately monitor clinical trials. This study investigated tumor perfusion and 3D segmented tumor volume as predictive markers for outcome in children with newly diagnosed DIPG. METHODS: Imaging data were assessed at baseline, during, and after RT, and every other month thereafter until tumor progression for 35 patients (ages 2-16 years) with newly diagnosed DIPG enrolled in the phase I clinical study, NCT00472017. Patients were treated with conformal RT and vandetanib, a vascular endothelial growth factor receptor 2 inhibitor. RESULTS: Tumor perfusion increased and tumor volume decreased during combined RT and vandetanib therapy. These changes slowly diminished in follow-up scans until tumor progression. However, increased tumor perfusion and decreased tumor volume during combined therapy were associated with longer PFS. Apart from a longer OS for patients who showed elevated tumor perfusion after RT, there was no association for tumor volume and other perfusion variables with OS. CONCLUSIONS: Our results suggest that tumor perfusion may be a useful predictive marker for the assessment of treatment response and tumor progression in children with DIPG treated with both RT and vandetanib. The assessment of tumor perfusion yields valuable information about tumor microvascular status and its response to therapy, which may help better understand the biology of DIPGs and monitor novel treatment strategies in future clinical trials. PMID- 23436053 TI - Metabolic changes in patients with aneurysmal subarachnoid hemorrhage apart from perfusion deficits: neuronal mitochondrial injury? AB - BACKGROUND AND PURPOSE: Neuronal damage in aSAH apart from perfusion deficits has been widely discussed. We aimed to test if cerebral injury occurs in aSAH independently from visible perfusion deficit by measuring cerebral metabolites in patients with aSAH without infarction or impaired perfusion. MATERIALS AND METHODS: We performed 3T MR imaging including (1)H-MR spectroscopy, DWI, and MR perfusion in 58 patients with aSAH and 11 age-matched and sex-matched control patients with incidental aneurysm. We compared changes of NAA, Cho, Glx, Lac, and Cr between all patients with aSAH and controls, between patients with and without visible perfusion deficit or infarction and controls, and between patients with and without visible perfusion deficit or infarction by using the Wilcoxon signed rank test. RESULTS: We found that NAA significantly (P < .005) decreased in all patients with aSAH. Cho was significantly increased in all patients compared with controls (P < .05). In patients without impaired perfusion or infarction, Glx was significantly decreased compared with both controls (P = .005) and patients with impaired perfusion or infarction (P = .006). CONCLUSIONS: The significant decrease of NAA and Glx in patients with aSAH but without impaired perfusion or infarction strongly suggests global metabolic changes independent from visible perfusion deficits that might reflect neuronal mitochondrial injury. Further, impaired perfusion in aSAH seems to induce additional metabolic changes from increasing neuronal stress that might, to some extent, mask the global metabolic changes. PMID- 23436054 TI - Brain injury patterns in hypoglycemia in neonatal encephalopathy. AB - BACKGROUND AND PURPOSE: Low glucose values are often seen in term infants with NE, including HIE, yet the contribution of hypoglycemia to the pattern of neurologic injury remains unclear. We hypothesized that MR features of neonatal hypoglycemia could be detected, superimposed on the predominant HIE injury pattern. MATERIALS AND METHODS: Term neonates (n = 179) with NE were prospectively imaged with day-3 MR studies and had glucose data available for review. The predominant imaging pattern of HIE was recorded as watershed, basal ganglia, total, focal-multifocal, or no injury. Radiologic hypoglycemia was diagnosed on the basis of selective edema in the posterior white matter, pulvinar, and anterior medial thalamic nuclei. Clinical charts were reviewed for evidence of NE, HIE, and hypoglycemia (<46 mg/dL). RESULTS: The predominant pattern of HIE injury imaged included 17 watershed, 25 basal ganglia, 10 total, 42 focal-multifocal, and 85 cases of no injury. A radiologic diagnosis of hypoglycemia was made in 34 cases. Compared with laboratory-confirmed hypoglycemia, MR findings had a positive predictive value of 82% and negative predictive value of 78%. Sixty (34%) neonates had clinical hypoglycemia before MR imaging. Adjusting for 5-minute Apgar scores and umbilical artery pH with logistic regression, clinical hypoglycemia was associated with a 17.6-fold higher odds of MR imaging identification (P < .001). Selective posterior white matter and pulvinar edema were most predictive of clinical hypoglycemia, and no injury (36%) or a watershed (32%) pattern of injury was seen more often in severe hypoglycemia. CONCLUSIONS: In term infants with NE and hypoglycemia, specific imaging features for both hypoglycemia and hypoxia-ischemia can be identified. PMID- 23436055 TI - On the role of screening for intracranial aneurysms in autosomal dominant polycystic kidney disease. PMID- 23436056 TI - An MRI rating scale for amyloid-related imaging abnormalities with edema or effusion. AB - BACKGROUND AND PURPOSE: Immune therapy against amyloid-beta appears to be a promising target in Alzheimer disease. However, a dose-related risk for ARIA on FLAIR images thought to represent parenchymal vasogenic edema or sulcal effusion (termed "ARIA-E"), has been observed in clinical trials. To assess the intensity of ARIA-E presentation, an MR imaging scale that is both reproducible and easily implemented would assist in monitoring and evaluating this adverse event. MATERIALS AND METHODS: On the basis of a review of existing cases from a phase II bapineuzumab study, a scale was constructed with a 6-point score for the 6 regions on each side of the brain (range, 0-60). Scores would be obtained for both parenchymal and sulcal hyperintensities and frequently co-occurring gyral swelling. Inter-rater reliability between 2 neuroradiologists was evaluated in 20 patients, 10 with known ARIA-E and 10 without, by using the intraclass correlation coefficient. RESULTS: The 2 raters had excellent agreement in the identification of ARIA-E cases. A high inter-rater agreement was observed for scores of parenchymal hyperintensity (ICC = 0.83; 95% CI, 48-96) and sulcal hyperintensity (ICC = 0.89; 95% CI, 63-97) and for the combined scores of the 2 ARIA-E findings (ICC = 0.89; 95% CI, 62-97). Gyral swelling scores were observed to have lower inter-rater agreement (ICC = 0.54; 95% CI, -0.06-0.86). CONCLUSIONS: The proposed rating scale provides a reliable and easily implemented instrument to grade ARIA-E imaging findings. We currently do not recommend including swelling. PMID- 23436057 TI - Pattern formation in auxin flux. AB - The plant hormone auxin is fundamental for plant growth, and its spatial distribution in plant tissues is critical for plant morphogenesis. We consider a leading model of the polar auxin flux, and study in full detail the stability of the possible equilibrium configurations. We show that the critical states of the auxin transport process are composed of basic building blocks, which are isolated in a background of auxin depleted cells, and are not geometrically regular in general. The same model was considered recently through a continuous limit and a coupling to the von Karman equations, to model the interplay of biochemistry and mechanics during plant growth. Our conclusions might be of interest in this setting, since, for example, we establish the existence of Lyapunov functions for the auxin flux, proving in this way the convergence of pure transport processes toward the set of equilibrium points. PMID- 23436058 TI - Circadian rhythms and period expression in the Hawaiian cricket genus Laupala. AB - Daily activity times and circadian rhythms of crickets have been a subject of behavioral and physiological study for decades. However, recent studies suggest that the underlying molecular mechanism of cricket endogenous clocks differ from the model of circadian rhythm generation in Drosophila. Here we examine the circadian free-running periods of walking and singing in two Hawaiian swordtail cricket species, Laupala cerasina and Laupala paranigra, that differ in the daily timing of mating related activities. Additionally, we examine variation in sequence and daily cycling of the period (per) gene transcript between these species. The species differed significantly in free-running period of singing, but did not differ significantly in the free-running period of locomotion. Like in Drosophila, per transcript abundance showed cycling consistent with a role in circadian rhythm generation. The amino acid differences identified between these species suggest a potential of the per gene in interspecific behavioral variation in Laupala. PMID- 23436059 TI - Changes of metal-induced toxicity by H2O 2/NO modulators in Scenedesmus quadricauda (Chlorophyceae). AB - Effect of nitric oxide donor (sodium nitroprusside, SNP, 500 MUM) or hydrogen peroxide scavenger (dithiothreitol, DTT, 500 MUM) on cadmium (Cd) or copper (Cu) uptake (150 MUM solutions) and toxicity using Scenedesmus quadricauda was studied. Combined treatments (Cd or Cu + DTT or SNP) usually ameliorated metal induced toxicity at the level of pigments, proteins, and mineral nutrients in comparison with respective metal alone. Viability tests (MTT and TTC) showed the lowest values preferentially in Cu treatments, indicating higher toxicity in comparison with Cd. Cd showed low impact on amino acids while strong Cu-induced depletion was mitigated by DTT and SNP. Amount of ROS and NO showed the most pronounced responses in SNP variants being rather reciprocal than parallel and regulated ascorbate peroxidase activity. Blot gel analyses of hsp70 protein did not reveal extensive changes after given exposure period. Phenols were elevated by DTT alone while all Cu treatments revealed depletion. Total Cu content decreased while total Cd content increased in metal + SNP or metal + DTT. Subsequent experiment using lower Cd, SNP or DTT doses (10 and 100 MUM) revealed concentration-dependent impact on Cd uptake. Overall, DTT was found to be more suitable for the amelioration of metal-induced toxicity. PMID- 23436061 TI - Spontaneous vegetation succession at different central European mining sites: a comparison across seres. AB - We performed detrended correspondence analysis (DCA) ordination to compare seven successional seres running in stone quarries, coal mining spoil heaps, sand and gravel pits, and extracted peatlands in the Czech Republic in central Europe. In total, we obtained 1,187 vegetation samples containing 705 species. These represent various successional stages aged from 1 to 100 years. The successional seres studied were more similar in their species composition in the initial stages, in which synathropic species prevailed, than in later successional stages. This vegetation differentiation was determined especially by local moisture conditions. In most cases, succession led to a woodland, which usually established after approximately 20 years. In very dry or wet places, by contrast, where woody species were limited, often highly valuable, open vegetation developed. Except in the peatlands, the total number of species and the number of target species increased during succession. Participation of invasive aliens was mostly unimportant. Spontaneous vegetation succession generally appears to be an ecologically suitable and cheap way of ecosystem restoration of heavily disturbed sites. It should, therefore, be preferred over technical reclamation. PMID- 23436060 TI - Microbial and physicochemical parameters associated with Legionella contamination in hot water recirculation systems. AB - Hot water recirculation systems (HWRS) in hotels and nursing homes, which are common in countries such as Spain, have been related to outbreaks of legionellosis. To establish the relationships of microbial and physicochemical parameters, especially protozoa, with the occurrence of Legionella in HWRS, 231 samples from hotels and nursing homes were analysed for Legionella, protozoa, heterotrophic plate counts (HPC) at 22 and 37 degrees C, Pseudomonas, metals, temperature and others. Legionella pneumophila was the dominant species isolated, and 22 % were sg. 1. The sampling method became particularly important in order to define which factors were involved on the occurrence of Legionella. Results showed that the bacteria and the accompanying microbiota were more abundant in the first flush water whose temperature was lower. The bacteria occurred in those samples with high HPC and were inversely correlated with high temperatures. Multivariate regression showed that a concentration above 1 * 10(5) CFU/100 mL of HPC at 37 degrees C, Fe above 0.095 ppm and the presence of protozoa increased significantly the risk of Legionella colonization, while univariant regression showed that the presence of Cu above 0.76 ppm and temperature above 55 degrees C diminished it. Therefore, to reduce the risk associated with Legionella occurrence in HWRS these parameters should be taken into consideration. PMID- 23436062 TI - Removal of carbamazepine and clofibric acid from water using double templates molecularly imprinted polymers. AB - A novel double templates-molecularly imprinted polymer (MIP) was prepared by precipitation polymerization using carbamazepine (CBZ) and clofibric acid (CA) as the double templates molecular and 2-vinylpyridine as functional monomer. The equilibrium data of MIP was well described by the Freundlich isotherm model. Two kinetic models were adopted to describe the experimental data, and the pseudo second-order model well-described adsorption of CBZ and CA on the MIP. Adsorption experimental results showed that the MIP had good selectivity and adsorption capacity for CBZ and CA in the presence of competitive compounds compared with non-imprinted polymer, commercial powdered activated carbon, and C18 adsorbents. The feasibility of removing CBZ and CA from water by the MIP was demonstrated using tap water, lake water, and river water. PMID- 23436063 TI - Life cycle and economic assessment of source-separated MSW collection with regard to greenhouse gas emissions: a case study in China. AB - In China, the continuously increasing amount of municipal solid waste (MSW) has resulted in an urgent need for changing the current municipal solid waste management (MSWM) system based on mixed collection. A pilot program focusing on source-separated MSW collection was thus launched (2010) in Hangzhou, China, to lessen the related environmental loads. And greenhouse gas (GHG) emissions (Kyoto Protocol) are singled out in particular. This paper uses life cycle assessment modeling to evaluate the potential environmental improvement with regard to GHG emissions. The pre-existing MSWM system is assessed as baseline, while the source separation scenario is compared internally. Results show that 23 % GHG emissions can be decreased by source-separated collection compared with the base scenario. In addition, the use of composting and anaerobic digestion (AD) is suggested for further optimizing the management of food waste. 260.79, 82.21, and -86.21 thousand tonnes of GHG emissions are emitted from food waste landfill, composting, and AD, respectively, proving the emission reduction potential brought by advanced food waste treatment technologies. Realizing the fact, a modified MSWM system is proposed by taking AD as food waste substitution option, with additional 44 % GHG emissions saved than current source separation scenario. Moreover, a preliminary economic assessment is implemented. It is demonstrated that both source separation scenarios have a good cost reduction potential than mixed collection, with the proposed new system the most cost-effective one. PMID- 23436064 TI - Implications for long-range atmospheric transport of polycyclic aromatic hydrocarbons in Lhasa, China. AB - The Tibetan Plateau is suggested to be an important indicator region to study the global long-range atmospheric transport of persistent organic pollutants. In this study, atmospheric polycyclic aromatic hydrocarbons (PAHs) were studied in Lhasa City in the Tibetan Plateau, China. Air samples in gas and particle phases were concurrently collected by a modified high-volume air sampler from 5 August 2008 to 13 July 2009. The concentration of Sigma16PAHs ranged from 18 to 160 ng m(-3) (with a geometric mean of 68 ng m(-3)). The most abundant PAHs were phenanthrene and benzo(b)fluoranthene in gas and particle phases, respectively. Compared with other two similar studies in Beijing and Harbin, different temporal trends were found between gas and particle phases PAHs in Lhasa. The influences of meteorological parameters (ambient temperature and relative humidity) and air masses from China, India, Southeast Asia, and West Asia were the two important reasons for explaining the difference, which was confirmed by the 5-day backward trajectories. This is the first comprehensive study to provide the evidence for the different influences of long-range atmospheric transport on gas and particle phases PAHs pollution in the Tibetan Plateau. PMID- 23436065 TI - Synergistic effect and mechanism of vitamin A and vitamin D on inducing apoptosis of prostate cancer cells. AB - To explore the mechanism and synergistic effect of vitamin A and vitamin D in inducing apoptosis of prostate cancer cells. The cell proliferation activity was determined by MTT assay. The proportion of apoptotic cells was analyzed by FACS and fluorescence intensity. TUNEL was used to evaluate vitamin A and vitamin D's induction of apoptosis in prostate cancer cells. The protein and mRNA expression level of Cyclin D1 and Bax were determined by real time-PCR and western blot. The results of MTT showed vitamin A and vitamin D's inhibition on proliferation ratio in prostate cancer cells is time and concentration dependent. FACS and fluorescence intensity analysis proved that the proportion of apoptotic cells increased after vitamin A and vitamin D treatment. TUNEL showed vitamin A and vitamin D induced prostate cancer cells apoptosis. The combination of vitamin A and vitamin D markedly enhanced the expression of Bax and reduced the expression of Cyclin D1 by real time-PCR and western blot assay. In conclusion, vitamin A and vitamin D could synergistically induce apoptosis in prostate cancer cells. PMID- 23436067 TI - 18F-FDG PET/CT-based treatment response evaluation in locally advanced rectal cancer: a prospective validation of long-term outcomes. AB - PURPOSE: To prospectively evaluate the usefulness of (18)F-FDG PET/CT) imaging for predicting histopathological response and long-term clinical outcomes in locally advanced rectal cancer (LARC). METHODS: This prospective study included 38 patients with a confirmed diagnosis of LARC (cT3-4 or cN+) who underwent (18)F FDG PET/CT before and after neoadjuvant therapy (NAT). Total mesorectal excision was scheduled 6 weeks after NAT and was followed by an expert histopathological analysis of the surgical specimen. Baseline variables and previously identified maximum FDG standardized uptake value (SUVmax) cut-off values before NAT (SUVmaxPRE >=6) and after NAT (SUVmaxPOST >=2), and the absolute and percentage reductions from baseline SUVmax (?SUVmax <4 and ?SUVmax% <65 %, respectively) were applied to differentiate patients showing a metabolic tumour response from nonresponders. These features were correlated with tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS). RESULTS: Significantly higher 5-year DFS and OS were seen in 19 responders (TRG 3 or 4) than in 19 nonresponders (TRG 0-2; 94.4 vs. 48.8 %, p = 0.001; 94.7 vs. 63.2 %, p = 0.02, respectively). In multivariate analysis the only PET/CT SUVmax-based parameter significantly correlated with the likelihood of recurrence and survival was ?SUV% <65 % (HR = 5.95, p = 0.02, for DFS; HR = 5.26, p = 0.04, for OS) CONCLUSION: This prospective study proved that (18)F-FDG PET/CT is a valuable imaging tool for assessing rectal cancer TRG and long-term prognosis, and could potentially serve as an intermediate endpoint in treatment optimization research and rectal cancer patient care. PMID- 23436069 TI - Nuclear medicine training and practice in France. PMID- 23436068 TI - Functional imaging of head and neck squamous cell carcinoma with diffusion weighted MRI and FDG PET/CT: quantitative analysis of ADC and SUV. AB - PURPOSE: Head and neck squamous cell carcinoma (HNSCC) may cause a decreased apparent diffusion coefficient (ADC) on diffusion-weighted magnetic resonance imaging (DW MRI) and an increased standardized uptake value (SUV) on fluorodeoxyglucose (FDG) positron emission tomography (PET/CT). We analysed the reproducibility of ADC and SUV measurements in HNSCC and evaluated whether these biomarkers are correlated or independent. METHODS: This retrospective analysis of DW MRI and FDG PET/CT data series included 34 HNSCC in 33 consecutive patients. Two experienced readers measured tumour ADC and SUV values independently. Statistical comparison and correlation with histopathology was done. Intra- and inter-observer agreement for ADC and SUV measurements was assessed. RESULTS: Intraclass correlation coefficient (ICC) analysis showed almost perfect reproducibility (>0.90) for ADCmean, ADCmin, SUVmax and SUVmean values for intra observer and inter-observer agreement. Mean ADCmean and ADCmin in HNSCC were 1.05 +/- 0.34 * 10(-3) mm(2)/s and 0.65 +/- 0.29 * 10(-3) mm(2)/s, respectively. Mean SUVmean and mean SUVmax were 7.61 +/- 3.87 and 12.8 +/- 5.0, respectively. Although statistically not significant, a trend towards higher SUV and lower ADC was observed with increasing tumour dedifferentiation. Pearson's correlation analysis showed no significant correlation between ADC and SUV measurements (r 0.103, -0.051; p 0.552, 0.777). CONCLUSION: Our data suggest that ADC and SUV values are reproducible and independent biomarkers in HNSCC. PMID- 23436071 TI - Comment on Mertens et al.: Standardized added metabolic activity (SAM): a partial volume independent marker of total lesion glycolysis in liver metastases. PMID- 23436070 TI - In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer's disease patients. AB - PURPOSE: Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer's disease (AD). ((R)-1-(2-chlorophenyl)-N-[(11)C] methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([(11)C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2 [(18)F]fluoroethyl-5-methoxybenzyl)acetamide ([(18)F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [(18)F]FEDAA1106 to TSPO in control subjects and AD patients. METHODS: Seven controls (five men, two women, age 68+/-3 years, MMSE score 29+/-1) and nine AD patients (six men, three women, age 69+/-4 years, MMSE score 25+/-3) were studied with [(18)F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V T) and binding potential (BP(ND)=k3/k4). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V(ND 1-15 min)). Binding potential (BP(ND)) was also calculated as: V(T)/V(ND 1 15 min) - 1. RESULTS: No statistically significant differences in V(T), k3/k4 or BP(ND) were observed between controls and AD patients. CONCLUSION: This study suggests that TSPO imaging with [(18)F]FEDAA1106 does not enable the detection of microglial activation in AD. PMID- 23436072 TI - Comment on Grippaudo et al.: Radiolabelled white blood cell scintigraphy in the work-up of dermal filler complications. PMID- 23436074 TI - The emerging role of FDG PET/CT in rectal cancer management: is it time to use the technique for early prognostication? PMID- 23436073 TI - 18F-fluorodeoxyglucose PET/CT predicts tumour progression after transarterial chemoembolization in hepatocellular carcinoma. AB - PURPOSE: (18)F-FDG PET monitoring of FDG uptake may be a useful tool for assessment of the biological behaviour of hepatocellular carcinoma (HCC). We evaluated the correlation between FDG uptake on (18)F-FDG PET and clinical characteristics and prognosis. METHODS: In total, 58 HCC patients undergoing (18)F-FDG PET before transarterial chemoembolization (TACE) between May 2007 and May 2010 at Seoul St. Mary's Hospital were evaluated retrospectively. The predictive value of the ratio of maximal tumour standardized uptake value (SUV) to mean liver SUV (T(SUVmax)/L(SUVmean)) was tested. Primary endpoints were the clinical characteristics and treatment response according to T(SUVmax)/L(SUVmean). The secondary endpoint was time to progression (TTP). RESULTS: A high SUV ratio (cutoff value 1.70) correlated significantly with tumour size (>=5 cm) and serum AFP level (>=400 ng/mL). Objective response rates were significantly different between those with a ratio above (15.7 %) and those with a ratio below (66.6 %) the cutoff value (P = 0.023). Patients in the low SUV ratio group had a median TTP of 16.8 months compared with 8.1 months in the high SUV ratio group (P = 0.011). Overall survival in the high SUV ratio group was worse than in the low SUV ratio group (median 56.5 vs. 23.3 months), although the difference was not statistically significant in a multivariate analysis. CONCLUSION: Tumour metabolic activity (T(SUVmax)/L(SUVmean)), assessed by PET/CT, is an independent predictor of response to TACE in patients with intermediate stage HCC. T(SUVmax)/L(SUVmean) can be used to predict tumour progression. Thus, (18)F-FDG PET can provide valuable information for prediction of prognosis and aid in decisions regarding treatment strategy. PMID- 23436075 TI - Trajectories of femoral neck strength in relation to the final menstrual period in a multi-ethnic cohort. AB - The purpose of this study was to describe the evolution of femoral neck strength relative to load across the menopause transition. It declined significantly over the 10 years bracketing the final menstrual period, and the rate of decline was modified by body mass index, race/ethnicity, and smoking status. INTRODUCTION: Composite indices of femoral neck strength, which integrate dual energy X-ray absorptiometry (DXA)-derived bone mineral density and bone size with body size, are inversely associated with hip fracture risk. Our objective was to describe longitudinal trajectories of the strength indices across the menopausal transition. METHODS: Data came from the Study of Women's Health Across the Nation; participants were pre- or early peri-menopausal, ages 42-53 at baseline, and were followed up for 9.1 +/- 1.8 years. Composite indices of femoral neck strength in different failure modes (compression, bending, and impact) were created in 921 women who had three or more hip DXA scans and had definable final menstrual period (FMP) dates. We used mixed effects models to fit piecewise linear growth curves to the baseline-normalized strength indices as a function of time to/after the FMP. RESULTS: Compression and impact strength indices did not decline until 1 year prior to the FMP, and declined rapidly thereafter, with some slowing of decline 1 year after the FMP. Bending strength index increased slightly until 2 years prior to the FMP, then plateaued, and began to decline at the FMP. Mean decline in strength indices over 10 years was 6.9 % (compression), 2.5 % (bending), and 6.8 % (impact). Women with higher body mass index had larger declines in two of the three indices. Other major modifiers of rates of decline were race/ethnicity and smoking status. CONCLUSIONS: Femoral neck strength relative to load declines significantly during the menopausal transition, with declines commencing 1 to 2 years prior to the FMP. PMID- 23436076 TI - Long-term treatment of osteoporotic women with bisphosphonates does not impair the response to subsequently administered intravenous pamidronate. AB - We addressed the question whether the response of osteoporotic patients to bisphosphonate treatment is reduced with time. Bisphosphonate-treated women with postmenopausal or glucocorticoid-induced osteoporosis showed adequate and consistent changes of bone markers to subsequently administered intravenous pamidronate. Response of osteoporotic patients to bisphosphonates is not impaired during their long-term administration. INTRODUCTION: Inadequate response to bisphosphonate treatment has been described in patients with Paget's disease of bone but has not been addressed in osteoporosis although treatment failure is a clinically relevant problem. METHODS: Twenty one women with postmenopausal osteoporosis (PMO) aged 68 +/- 8.2 years and 14 women with glucocorticoid-induced osteoporosis (GIOP) aged 65 +/- 10 years were treated with tri-monthly intravenous infusions of 45 mg of pamidronate for 1 year. All patients had been previously treated with bisphosphonates (alendronate, risedronate, pamidronate) for a mean period of 6.2 years (range, 1.3-14 years). Blood samples were taken for measurement of the bone resorption marker C-terminal crosslinking telopeptide of type I collagen (CTX-I) on days 1 and 4 and of the bone formation marker procollagen type I N propeptide, (P1NP) on day 1 of every tri-monthly treatment course. RESULTS: With each treatment course there was a significant decrease in serum CTX-I on day 4 and an increase to baseline values 3 months after each infusion in both PMO (mean values, day 1: 291.33 +/- 160.78 pg/ml vs. day 4: 131 +/- 91.7 pg/ml, p < 0.001) and GIOP (day 1: 219.3 +/- 114.8 pg/ml vs. day 4: 98.8 +/- 51.6 pg/ml, p < 0.001). Serum P1NP remained stable during the whole year of treatment. CONCLUSIONS: Long-term bisphosphonate treatment of women with either PMO or GIOP does not impair the response to subsequently administered intravenous pamidronate suggesting that inadequate response to long-term bisphosphonate treatment is not responsible for treatment failure. PMID- 23436078 TI - A water soluble Mn(II) polymer with aqua metal bridges. AB - The first water soluble and crystallographically determined polynuclear Mn(II) complex, with water molecules bridging every two Mn centers, is reported. This is an unusual feature in 1D oligomer Mn(II) compounds with a nuclearity higher than 2. The polymer structure is largely preserved in water. PMID- 23436077 TI - Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis. AB - Indolent systemic mastocytosis (ISM) can trigger bone loss. However, the clinical relevance of different mast cell infiltration patterns for bone remains to be clarified. Here, we report increased bone turnover in individuals with ISM, and its extent is rather related to the type of mast cell distribution within the bone marrow than to the presence or absence of cutaneous manifestations. INTRODUCTION: It is well established that ISM can trigger osteopenia or osteoporosis. However, neither the clinical relevance of the infiltration pattern of mast cells within the bone marrow nor the impact of the presence or absence of cutaneous mast cell infiltration has been elucidated. METHODS: We retrospectively analysed 300 cases with histologically proven ISM of the bone marrow and performed quantitative histomorphometry for a subgroup of 159 patients that did not receive any treatment before the biopsies were taken. Most importantly, since 66 % of the patients displayed ISM without the characteristic skin lesions, we were able to compare ISM with or without cutaneous manifestation. RESULTS: We found that both forms of ISM were not only characterized by a decreased trabecular bone mass but also by an increased number of osteoclasts and osteoblasts. Interestingly, when we analysed these data in relation to mast cell distribution, we found that the bone cell numbers in cases with mast cell granulomas were significantly increased compared to cases with diffuse mast cell distribution. Moreover, evidence of increased bone turnover was also found in 16 patients displaying osteosclerosis. CONCLUSION: Based on the largest cohort of bone biopsies from patients with ISM analysed so far, we could demonstrate high bone turnover, more specifically increased osteoblast and osteoclast numbers and surface indices, as a cause of the skeletal changes. Moreover, the severity of the bone disease is presumably rather dependent on the amount of mast cells and their distribution within the bone marrow irrespective of the presence or absence of cutaneous involvement. PMID- 23436079 TI - Sensitivity of fluorescein angiography alone or with SD-OCT for the diagnosis of myopic choroidal neovascularization. AB - BACKGROUND: Myopic choroidal neovascularization (mCNV) has certain characteristics and features that distinguish it from choroidal neovascularization secondary to age-related macular degeneration. There may be angiographic diagnostic difficulties even when using the scanning laser ophthalmoscope, which gives more contrast and better definition than traditional angiography. The aim of the study is to compare the sensitivity of fluorescein angiography (FA) alone or combined with Spectral Domain Optical Coherence Tomography (SD-OCT) for assessing the incidence of mCNV. METHODS: In this retrospective study, two authors reviewed the charts and images of patients with recent (<30 days) vision deterioration, pathologic myopia, axial length >26 mm, documentation or suspicion of mCNV or macular exudative pathologies at FA and OCT. They only examined the images at first presentation obtained by the multi modal imaging system that combines Infrared reflectance, FA, and SD-OCT, (Spectralis, Heidelberg Engineering, Germany). The images selected were then evaluated by three other investigators in blinded, independent conditions, in order to make their diagnosis, which was noted or rated as doubtful if it could not be decided on the basis of FA alone. SD-OCT images were then shown and compared to IR and FA by each of the three investigators individually to formulate a conclusive diagnosis. RESULTS: A total of 71 eyes of 69 patients were suitable for the study, mean age 65.97+/-14.57 years, spherical equivalent refraction -8.82 +/- 2.51 diopters. Concordance between the three examiners' interpretations of FA features and FA-guided SD-OCT was 50/71 (70.4 %) and 67/71 (94 %) respectively. Total agreement on diagnosis between the three examiners was achieved in 55 % of cases for FA (kappa = 0.53, p < 0.001), and 94 % for FA guided SD-OCT (k = -0.01, p = 0.5). The final diagnosis with FA and FA-guided SD OCT differed in 29 cases (40 %; 95 % C.I. 29-42 %), whereas 12 (17 %) mCNV were overlooked at FA, and in 11 (15 %) cases none of the examiners reached a diagnosis based on FA alone. CONCLUSIONS: On the basis of FA alone, active mCNV can be misdiagnosed. The use of SD-OCT combined with FA should therefore be strongly considered. PMID- 23436080 TI - Laparoscopic sigmoidectomy in moderate and severe diverticulitis: analysis of short-term outcomes in a continuous series of 121 patients. AB - BACKGROUND: The role of laparoscopic surgery has been shown to be safe, feasible, and equivalent to open surgery for moderate diverticulitis, but its role in severe disease is still being elucidated. The aim of this study was to compare short-term outcomes in patients who underwent laparoscopic sigmoidectomy for moderate and severe diverticulitis. METHODS: All patients who had elective laparoscopic sigmoidectomy for diverticulitis between April 2003 and September 2011 at the University Hospital of Luxembourg were selected from a retrospective database. The patients were divided in two groups: moderate acute diverticulitis (MAD) included patients with an episode of left-lower-quadrant pain, elevated inflammatory markers, and radiologic evidence of diverticulitis, and severe acute diverticulitis (SAD) included patients with diverticula associated with abscess, phlegmon, perforation, fistula, obstruction, bleeding, or stricture. RESULTS: A total of 121 patients (81 MAD and 40 SAD) underwent elective laparoscopic sigmoidectomy with primary anastomosis. There were no significant differences between the two groups with respect to demographic characteristics, except for sex ratio. In this series the overall morbidity rate at 30 postoperative days (POD) was 12.4 %, with no significant differences between MAD and SAD (16.0 vs. 5 %, respectively; P = 0.083). No significant differences were found with respect to mean length of hospital stay (6.7 vs. 7.7 days; P = 0.399) as well. The overall conversion rate to open surgery was 2.5 % (3 patients), with no difference between the two groups. Conversion to laparotomy was associated with an increased morbidity rate (11.0 % for full laparoscopy vs. 66.6 % for conversion; P = 0.040) and a longer length of stay (6.8 vs. 16.7 days; P = 0.008). There were no deaths within 30 POD. CONCLUSIONS: Elective laparoscopic sigmoidectomy is safe and feasible for patients with moderate and severe acute diverticulitis and the outcomes are equivalent. PMID- 23436081 TI - Laparoscopic esophagogastroplasty: a minimally invasive alternative to esophagectomy in the surgical management of megaesophagus with axis deviation. AB - INTRODUCTION: The results of cardiomyotomy in patients of achalasic megaesophagus with axis deviation are not satisfactory, and several authors have advocated an esophagectomy in these patients. We describe the technical details and outcomes of a novel technique of laparoscopic esophagogastroplasty for end-stage achalasia. METHODS: Patients with end-stage achalasia, characterized by tortuous megaesophagus were selected. The surgery was performed in supine position using five abdominal ports. The steps included mobilization of the gastroesophageal junction and lower intrathoracic esophagus, straightening and anchoring the pulled intrathoracic esophagus into the abdomen, and a side-side esophagogastroplasty. RESULTS: Four patients with megaesophagus due to end-stage achalasia underwent this procedure. The average duration of surgery was 177.5 (range, 120-240) min. All patients could be ambulated on the first postoperative day. Oral feeding was initiated by the third postoperative day, and all patients had significant improvements in their dysphagia scores. All patients had excellent cosmetic results and were discharged by the fifth postoperative day. An upper gastrointestinal contrast study done at 6 weeks after surgery did not show any hold up of contrast, and there was decrease in the convolutions and diameter of the esophagus. At a mean follow-up of 10.5 (range, 3-15) months, all patients are euphagic without significant symptoms of gastroesophageal reflux. CONCLUSIONS: Laparoscopic esophagogastroplasty is an effective option for relieving dysphagia in megaesophagus due to achalasia with axis deviation and is a reasonable alternative before subjecting to a major and potentially morbid esophagectomy. PMID- 23436082 TI - Removable and repositionable covered metal self-expandable stents for leaks after upper gastrointestinal surgery: experiences in a tertiary referral hospital. AB - BACKGROUND: Anastomotic leakages are severe complications of upper gastrointestinal surgery with serious morbidity and mortality. Until recently, only abscess drainage was possible. Since 2007, removable and repositionable covered metal self-expandable stents (RReCoMSeS) have been used in our hospital to cover leaks. METHODS: Patients with postsurgical gastrointestinal leaks treated with RReCoMSeS between January 2007 and March 2010 were retrospectively evaluated and described. RESULTS: Twenty-six patients were treated with RReCoMSeS (totally covered Choo/Hanaro and partially covered Endoflex stents). Included patients had anastomotic leaks after esophagectomy (15) and bariatric surgery (11). Overall successful sealing of the leak occurred in 81 % (including multiple procedures). In total 33 RReCoMSeS were used (mean 1.3 stents and 1.7 procedures per patient). Twenty-one of 33 RReCoMSeS succeeded in sealing the leak (64 %). Migration occurred in 24 % RReCoMSeS, and 9 % disintegrated. One stent (3 %) caused a perforation. CONCLUSIONS: RReCoMSeS are a safe alternative for treating postsurgical leaks in the upper gastrointestinal tract. In 81 % of patients and with 64 % of the inserted stents, leaks were sealed successfully, with few complications. Fewer stents per patient were needed thanks to their repositionability. Stent migration is a major problem. PMID- 23436083 TI - The ANUBISCOPE(r) flexible platform ready for prime time: description of the first clinical case. PMID- 23436084 TI - Automatic smoke evacuation in laparoscopic surgery: a simplified method for objective evaluation. AB - BACKGROUND: Although its theoretical usefulness has been reported, the true value of automatic smoke evacuation system in laparoscopic surgery remains unknown. This is mainly due to the lack of objective evaluation. The purpose of this study was to determine the efficacy of the automatic smoke evacuator in laparoscopic surgery, by real-time objective evaluation system using an industrial smoke detection device. METHODS: Six pigs were used in this study. Three surgical ports were placed and electrosurgical smoke was generated in a standard fashion, using either a high-frequency electrosurgical unit (HF-ESU) or laparosonic coagulating shears (LCS). The smoke was evacuated immediately in the evacuation group but not in the control nonevacuation group. The laparoscopic field-of-view was subjectively evaluated by ten independent surgeons. The composition of the surgical smoke was analyzed by mass spectrometry. The residual smoke in the abdominal cavity was aspirated manually into a smoke tester, and stains on a filter paper were image captured, digitized, and semiquantified. RESULTS: Subjective evaluation indicated superior field-of-view in the evacuation group, compared with the control, at 15 s after activation of the HF-ESU (P < 0.05). The smoke comprised various chemical compounds, including known carcinogens. The estimated volume of intra-abdominal residual smoke after activation of HF-ESU was significantly lower in the evacuation group (47.4 +/- 16.6) than the control (76.7 +/- 2.4, P = 0.0018). Only marginal amount of surgical smoke was detected in both groups after LCS when the tissue pad was free from burnt tissue deposits. However, the amount was significantly lower in the evacuation group (21.3 +/- 10.7) than the control (75 +/- 39.9, P = 0.044) when the tissue pad contained tissue sludge. CONCLUSIONS: Automatic smoke evacuation provides better field-of view and reduces the risk of exposure to harmful compounds. PMID- 23436085 TI - Aortic injury during laparoscopic esophageal hiatoplasty. AB - A 75-year-old female patient with a type III hiatal hernia was submitted to laparoscopic mesh hiatoplasty. Soon after the last suture fixed the mesh to the left crura, a hemorrhage was observed. Conversion to open surgery was not performed. The most common sources of bleeding (liver, phrenic arteries, crura, spleen, and short gastric vessels) were discarded as the cause of the hemorrhage. The mesh was set free in order to explore the lower mediastinum. The source of the hemorrhage was identified: it was the last suture fixing the mesh to the left crura, which was found passing through the aortic wall. The hemorrhage stopped as soon as the suture was removed. When facing a hemorrhage during this kind of surgery, it is essential to be methodical to discover the source of the bleeding. First of all, the most common sources of bleeding must be checked out. Injury of the inferior vena cava must also be ruled out, because it is an uncommon but potentially lethal complication. Afterwards, the lower mediastinum must be explored. Conversion to an open approach is needed if the patient becomes unstable or the surgeon does not have enough laparoscopic skills to find and solve the bleeding. Most of the reported cases of aortic injury during laparoscopic hiatoplasty are secondary to vascular injuries during port insertion. When a suture is the cause of bleeding, the removal of the stitch should be enough to stop the bleeding. If there is a tear of the aortic wall, a patch should be employed for the repair. In conclusion, left crura and thoracic aorta are very close to one another. The surgeon must be very careful when working near the left crura, mostly in old patients with a dilated and aneurysmatic aorta. PMID- 23436086 TI - Defining technical errors in laparoscopic surgery: a systematic review. AB - BACKGROUND: Technical errors, a distinct subcomponent of surgical proficiency, have a significant impact on patient safety and clinical outcomes. To date, only a few studies have been designed to describe and evaluate these errors. This review was performed to assess technical errors described in laparoscopic surgery. METHODS: A literature search of Medline, Cochrane, EMBASE, and OVID databases (1946-2012, week 14) using the terms "technical/medical error," "technical skill," and "adverse event" in combination with the terms "laparoscopy/laparoscopic surgery" was conducted. English language peer review articles with a description of technical errors were included. Opinion papers, reviews, and articles not addressing laparoscopic surgery were excluded. RESULTS: The search returned 2,282 articles. Application of the inclusion criteria reduced the number of articles to 21. Of these 21 articles, 14 (67 %) were observational studies, 3 (14 %) were randomized trials, 2 (10 %) were prospective interventional studies, and 2 (10 %) were retrospective analyses. Eight articles (38 %) applied error analysis as an approach to determine error rates within routine procedures. The remaining 13 articles (62 %) used the assessment of errors to describe and quantify surgical skill in an educational setting. CONCLUSIONS: A number of approaches for the assessment of surgical technical errors exist. The error definitions vary greatly, making a comparison of error rates between groups impossible. Complexity of scale design and subjectivity in ratings have resulted in limited use of these scores outside the experimental setting. To facilitate error analysis as a self-assessment method of continuous learning and quality control, further research and better tools are required. PMID- 23436087 TI - Does Roux-en-Y gastrectomy for gastric cancer influence glucose homeostasis in lean patients? AB - BACKGROUND: Cancer gastrectomy seems to benefit type 2 diabetes; however, results are conflicting. In a prospective protocol, including retrospective information, the aim was assessment of changes in glucose profile in patients with both normal and deranged preoperative glucose homeostasis. METHODS: Patients (N = 164) with curative subtotal or total Roux-en-Y gastrectomy for gastric cancer (n = 92), or Roux-en-Y gastric bypass for morbid obesity (RYGB, n = 72) were preoperatively classified into diabetes (including prediabetes) and control group. Postoperative diabetes outcome was stratified as responsive or refractory, and results in controls were correspondingly defined as stable or new-onset diabetes (NOD), according to fasting blood glucose and HbA1c. Dietary intake and biochemical profile was documented. Statistical methods included analysis of variance, multivariate logistic regression, and propensity score matching according to postoperative weight loss. RESULTS: Age of cancer cases was 67.9 +/- 11.5 years, 56.5 % males, initial body mass index (BMI) 24.7 +/- 3.7, current BMI 22.6 +/- 3.8 kg/m(2), and follow-up 102.1 +/- 51.0 months, whereas in bariatric individuals age was 51.4 +/- 10.1 years, 15.3 % males, initial BMI 56.7 +/- 12.2, current BMI 34.8 +/- 8.1 kg/m(2), and follow-up 104.1 +/- 29.7 months. Refractory disease corresponded to 62.5 % (cancer) versus 23.5 % (bariatric) (P = 0.019), whereas NOD represented 69.2 versus 23.8 % respectively (P = 0.016). Weight loss (DeltaBMI) was associated with diabetes response in cancer patients but not with NOD. No difference between subtotal and total gastrectomy was detected. Divergent outcomes (refractory vs. responsive) were confirmed in BMI-similar, propensity matched cancer gastrectomy patients with preoperative diabetes, consistent with weight-dependent and -independent benefits. CONCLUSIONS: Diabetes response was confirmed, however with more refractory cases than in bariatric controls, whereas high proportions of NOD occurred. Such dichotomous pattern seems unusual albeit consistent with previous studies. PMID- 23436088 TI - Laparoendoscopic single-site common bile duct exploration using the manual manipulator. AB - BACKGROUND: Laparoendoscopic single-site (LESS) surgery has developed as a new surgical modality that has increased cosmetic benefits over conventional endoscopic surgery. However, there are no reports about LESS surgery in common bile duct exploration. This report presents a LESS surgery to manage CBD stones by laparoscopic choledochotomy and C-tube placement with favorable outcomes. METHODS: This retrospective review analyzes 13 patients who underwent LESS CBD exploration with C-tube drainage for choledocholithiasis. The technique is herein described and the outcomes measured. The Radius Surgical System (Tubingen Scientific Medical, Tubingen, Germany) is a flexible manual manipulator that was applied for suturing and ligation to overcome the difficulties associated with LESS surgery. RESULTS: The diameters of the CBDs ranged from 12 to 20 mm, the median number of stones was 5.8, and the median diameter of stones was 9 mm. All of the routine procedures including choledochotomy, intraoperative ultrasound, choledochoscopy, and intraoperative cholangiography guidance were performed. Stone clearance from the CBD was achieved for all but one of the patients. It was possible to close the common bile duct opening with regular forceps, but this required extra effort compared to conventional laparoscopic surgery. On the other hand, the manual manipulator enabled the optimal penetration angle and was useful for both intracorporeal suturing and ligation for the closure of the common bile duct opening. The manual manipulator also helped to overcome in-line viewing and hand/instruments collisions, which are common problems in LESS surgery. No mortality was associated with this procedure, and two wound infections were drained without anesthesia. No recurrent stones were observed during the follow up period. CONCLUSIONS: LESS surgery was successfully applied to CBD exploration as an available alternative to conventional laparoscopic surgery. This method is technically feasible and produces superior cosmetic results. The manual manipulator may therefore have several advantages for performing LESS surgery. PMID- 23436089 TI - Combined endoscopic techniques for closure of a chronic post-surgical gastrocutaneous fistula: case report and review of the literature (with video). AB - Several techniques have been proposed to seal post-operative leaks endoscopicaly, however, chronic fibrosed fistulas remain a tenacious problem. We describe the success of a combination of minimally invasive peroral endoscopic techniques to seal and permanently close a chronic gastrocutaneous fistula complicating a laparoscopic gastric bypass, these techniques included: fistuloscopy, argon plasma coagulation, mucosal stripping and the novel over-the-scope clips. PMID- 23436090 TI - Laparoscopic left hemihepatectomy a consideration for acceptance as standard of care. AB - INTRODUCTION: Since the inception of laparoscopic liver surgery, the left-lateral sectionectomy has become the standard of care for resection of lesions located in segments II and III. However, few centers employee laparoscopic left hemihepatectomy on a routine basis. This study evaluated the safety and efficacy of the laparoscopic left hemihepatectomy as a standard of care. METHODS: An international database of 1,620 laparoscopic liver resections was established and outcomes analyzed comparing the laparoscopic left lateral sectionectomy (L lat) to laparoscopic left hemihepatectomy (LH). All data are presented as mean +/- standard deviation. RESULTS: A total of 222 laparoscopic L lat and 82 LH were identified. The L lat group compared with LH group had a higher incidence of cirrhosis (27 vs. 21 %; p = 0.003) and cancer (48 vs. 35 %; p = 0.043). Tumors were larger in the LH group (7.09 +/- 4.2 vs. 4.89 +/- 3.1 cm; p = 0.001). Operating time for LH was longer than L lat (3.9 +/- 2.3 vs. 2.9 +/- 1.4 h; p < 0.001). Operative blood loss was higher in LH (306 vs. 198 cc; p = 0.003). Patient morbidity (20 vs. 18 %; p = 0.765) was equivalent with a longer length of stay (7.1 +/- 5.1 vs. 2.5 +/- 2.3 days; p < 0.001) for LH. Patient mortality and tumor recurrence were equivalent. CONCLUSIONS: Laparoscopic left hemihepatectomy is a more technically challenging and often time-consuming procedure than a left lateral sectionectomy. This international multi-institutional confirmed that intraoperative blood loss, complications, and conversions are more than acceptable for laparoscopic left hemihepatectomy in expert hands. Postoperative morbidity and mortality rates together with adequate surgical margins and long term recurrence are not compromised by the laparoscopic approach. PMID- 23436091 TI - Pure transvaginal umbilical hernia repair. AB - BACKGROUND: Transvaginal natural orifice transluminal endoscopic surgery (NOTES) procedures are at the forefront of minimally invasive innovation, remarkable for shorter recovery times and decreased postoperative pain [1, 2]. Most transvaginal procedures are performed as hybrid procedures [3]. To our knowledge, this is the first video depiction of a pure transvaginal umbilical hernia repair in a human. METHODS: This is a 38-year-old woman, body mass index 36.4 kg/m(2), with a symptomatic port site hernia in the umbilical region after a previous laparoscopic cholecystectomy. The patient was positioned in stirrups in a steep Trendelenburg position. Sterilization of vaginal cavity was performed with 10 % povidone-iodine solution. A 2 cm transverse incision at the posterior fornix was made, and a SILS port (Covidien, North Haven, CT) was introduced. One 12 mm trocar and two 5 mm trocars were placed through SILS port. Standard straight laparoscopic instruments were used. A 12 cm round Parietex mesh (Covidien) was placed in a specimen retrieval bag and deployed into the peritoneal cavity. The mesh was extracted, unfolded in the abdominal cavity, and circumferentially fixated to the abdominal wall with an AbsorbaTack device (Covidien). The colpotomy incision was closed with a running absorbable suture. RESULTS: The procedure lasted 103 min and was performed on an outpatient basis. No intraoperative complications occurred. The patient was doing well and had no pain or recurrence at 2, 6, and 9 months' follow-up. CONCLUSIONS: Our initial experience with transvaginal ventral hernia repair in humans suggests that this procedure is feasible and safe. This approach may improve cosmesis and decrease the risk of future ventral hernias. Potential cons may include a longer operative time, mesh infection, and risk of visceral injury with a pure transvaginal approach. As transvaginal surgery evolves, techniques and devices will become increasingly refined to tackle these challenges. PMID- 23436092 TI - Teaching and training in laparoscopic inguinal hernia repair (TAPP): impact of the learning curve on patient outcome. AB - BACKGROUND: On the basis of lower incidence of postoperative pain and faster recovery compared with open techniques, the laparoscopic transabdominal preperitoneal patch plastic (TAPP) technique was established as a leading mode of inguinal hernia repair. In contrast to open hernia repairs, which are well integrated in the training of young surgeons, TAPP is still considered a more difficult surgical procedure, raising the questions of how to include this technique in trainee programs and how to provide appropriate training. METHODS: Out of 15,101 TAPP procedures performed in our department between 1993 and 2007, we analyzed 254 operations that occurred from April 2004 to February 2007 by young trainees (between the second and fourth years of surgical training). The analysis compared the trainees' TAPP operations with 3,200 TAPP procedures performed by experienced surgeons in the same time period, and with the first 254 TAPP operations in our department performed by pioneers who introduced this technique in 1993. RESULTS: In the 254 operations performed by young trainees, the mean operation time was 59 min, the morbidity rate was 3.2 %, and the recurrence rate was 0.4 %. Compared to experienced surgeons, we found no significant difference in recurrence rate and morbidity. For operation time, however, the young trainees demonstrated a learning curve with continuous improvement until the end of the study period approaching expert level. Pioneers also demonstrated a clear learning curve in operation time and additionally also regarding morbidity and recurrence rate. CONCLUSIONS: Our study demonstrates that the TAPP learning curve of young trainees is only related to operation time. Therefore, TAPP is a safe and reproducible technique when performed by young trainees under the supervision of experienced laparoscopic surgeons. With an adequate program, the technique can be learned quickly, skillfully, and safely when a standardized technique is used. It should be included as a fundamental part of state-of-the-art trainee programs. PMID- 23436093 TI - Initial experience of a surgical fellow in laparoscopic colorectal cancer surgery under training protocol and supervision: comparison of short-term results for 70 early cases (under supervision) and 73 late cases (without supervision). AB - PURPOSE: Laparoscopic colorectal surgery is a technically challenging procedure for beginners, such as surgical fellows. The purpose of this study was to assess the safety, feasibility, and short-term surgical outcomes of laparoscopic colorectal cancer surgery by a single surgical fellow. METHODS: The study analyzed the data from 143 consecutive patients who underwent laparoscopic colorectal resection by a single surgical fellow between August 2009 and October 2010. The patients were divided into two groups: the early group-the first 70 patients (under supervision of experienced surgeon), and the late group-the last 73 patients (without supervision). The short-term surgical results were compared between two groups. RESULTS: The operations were 24 right colon resections, two transverse colectomies, six left colectomies, 36 anterior resections, 57 low anterior resections, 12 intersphincteric resections, two abdominoperineal resections, three Hartmann's operations, and 1 total colectomy. The mean operating time, mean amounts of blood loss, and conversion rate were similar between the two groups. The morbidity rate, anastomosis leak rate, and mortality rate within 30 days of surgery did not differ significantly. The mean number of lymph nodes was larger in the late group (23.8 vs. 31.7, P = 0.017). In terms of low anterior resection, the mean number of endo-linear staplers used was smaller in the late group (2.46 +/- 0.81 vs. 1.97 +/- 0.83, P = 0.028). The anastomosis leakage rate in rectal cancer surgery was not significantly different between the two groups. CONCLUSIONS: This study demonstrates that laparoscopic colorectal resections can be independently performed safely after a period of supervision and training by an experienced surgeon. PMID- 23436094 TI - Laparoscopic colectomy reduces morbidity and mortality in obese patients. AB - BACKGROUND: Obesity is a growing epidemic in the US and increases the difficulty of laparoscopic surgery. Randomized, controlled trials of laparoscopic vs. open colectomy have shown equivalence but often exclude obese patients thus not answering whether obese patients may specifically benefit from laparoscopy. We hypothesized that obese patients would benefit from use of laparoscopy for colectomy. METHODS: We used the National Surgical Quality Improvement Program database from 2005 to 2009 and chose elective laparoscopic and open segmental colectomy and ileocecal resections. We compared patients' demographics, comorbidities, and outcomes. We used multivariate models to assess for predictors of complications in obese patients. These models included demographics, comorbidities, and outcomes. RESULTS: 35,998 patients were identified who underwent elective colectomy with primary anastomosis. Forty-four percent of the included cases were laparoscopic and 31 % of patients had a BMI greater than 30 (obese). Obese patients were more likely to have diabetes, hypertension, prior percutaneous coronary intervention, and dyspnea on exertion. We constructed a new variable called any complication that included all complications except 30-day mortality. In our multivariate analysis, laparoscopic approach in obese patients independently decreased the relative risk of superficial (odds ratio (OR) 0.72, 95 % confidence interval (CI) 0.63-0.82) and deep (OR 0.44, CI 0.31-0.61) surgical site infections, intra-abdominal infection (OR 0.61, CI 0.49-0.78), dehiscence (OR 0.50, CI 0.35-0.69), pneumonia (OR 0.60, CI 0.44-0.81), failure to wean from the ventilator (OR 0.64, CI 0.47-0.87), renal failure (OR 0.58, CI 0.35 0.96), urinary tract infection (OR 0.62, CI 0.49-0.79), sepsis (OR 0.53, CI 0.43 0.66), septic shock (OR 0.65, CI 0.47-0.90), any complication (OR 0.61, CI 0.55 0.67) and 30-day mortality (OR 0.56, CI 0.31-0.98). CONCLUSIONS: Due to the significant decrease in the risk of morbidity and mortality, laparoscopic colectomy should be offered to obese patients whenever feasible. PMID- 23436095 TI - Surgery! Only when it causes troubles? PMID- 23436096 TI - Learning curve on the TrEndo laparoscopic simulator compared to an expert level. AB - BACKGROUND: The aim of this study was to determine growth in trainee laparoscopic skill as recorded by the TrEndo laparoscopic simulator during a laparoscopic training course, compared to an expert level. METHODS: A prospective observational cohort study was conducted between February 1 and November 31, 2010. Trainees in laparoscopic surgery completed a basic laparoscopic suturing task on a laparoscopic box trainer at three successive assessment points during a laparoscopic training course. Experts were assessed only once to define an expert level. The TrEndo recorded four motion analysis parameters (MAPs) individually for each hand and the amount of time taken to complete the suturing task. RESULTS: Seventy-two residents and 56 experts were included in this study. Overall, the amount of time taken on the suturing task and seven out of eight MAPs significantly increased toward an expert level during the course, representing an improvement in task efficiency. During the first training day, the amount of time spent on the suturing task and five out of eight MAPs improved significantly. After the retention period, five out of eight MAPS demonstrated a significant improvement compared to the end of the first training day. CONCLUSIONS: Laparoscopic skill of trainees as recorded by the TrEndo laparoscopic simulator grows toward an expert level during a laparoscopic training course in a large and heterogeneous study group. Construct validity of the TrEndo is established. PMID- 23436097 TI - Refractory gastroesophageal reflux disease as diagnosed by impedance-pH monitoring can be cured by laparoscopic fundoplication. AB - BACKGROUND: Some patients with typical (heartburn/regurgitation) symptoms of gastroesophageal reflux disease (GERD) are refractory to proton pump inhibitor (PPI) therapy. Impedance-pH monitoring can identify PPI-refractory patients who could benefit from laparoscopic fundoplication, but outcome data are scarce. We aimed to assess whether PPI-refractory GERD as diagnosed by impedance-pH monitoring can be cured by laparoscopic fundoplication. METHODS: Forty-four consecutive GERD patients with heartburn/regurgitation refractory to high-dose PPI therapy entered a 3-year outcome assessment following robot-assisted laparoscopic fundoplication. Preoperative on-PPI impedance-pH diagnostic criteria consisted of positive symptom association probability (SAP)/symptom index (SI), and/or abnormal percentage esophageal acid exposure time (%EAET), and/or abnormal number of total refluxes. GERD cure was defined by 3-year postoperative off-PPI normal impedance-pH findings with persistent symptom remission. RESULTS: Preoperatively, 24 of 38 (63 %) patients who completed the outcome assessment had a positive SAP/SI, 20 of 38 (53 %) for weakly acidic refluxes; 3 of 38 (8 %) patients had an abnormal %EAET, 11 of 38 (29 %) an abnormal number of total refluxes only. Postoperatively, heartburn/regurgitation recurred in 3 patients; abnormal impedance-pH findings were found in two of them, and they responded to PPI therapy. GERD cure was achieved in 34 of 38 (89 %) patients, 11 of 11 with an abnormal number of total refluxes as the only preoperative abnormal impedance-pH finding. Postoperatively, there was a significant decrease of the %EAET (1 vs. 0.1 %, P = 0.002) and of the number of total refluxes (68 vs. 8, P = 0.001), with the latter finding mainly due to a decrease in the number of weakly acidic refluxes. CONCLUSIONS: Normal reflux parameters and persistent symptom remission at 3-year follow-up can be achieved with laparoscopic fundoplication in the majority of patients with PPI-refractory GERD as diagnosed by impedance-pH monitoring. On-PPI impedance-pH diagnostic criteria should include SAP/SI positivity, an abnormal %EAET, and an abnormal number of total refluxes. Weakly acidic refluxes have a major role in the pathogenesis of PPI-refractory GERD. PMID- 23436098 TI - Effective and efficient learning in the operating theater with intraoperative video-enhanced surgical procedure training. AB - BACKGROUND: INtraoperative Video Enhanced Surgical procedure Training (INVEST) is a new training method designed to improve the transition from basic skills training in a skills lab to procedural training in the operating theater. Traditionally, the master-apprentice model (MAM) is used for procedural training in the operating theater, but this model lacks uniformity and efficiency at the beginning of the learning curve. This study was designed to investigate the effectiveness and efficiency of INVEST compared to MAM. METHODS: Ten surgical residents with no laparoscopic experience were recruited for a laparoscopic cholecystectomy training curriculum either by the MAM or with INVEST. After a uniform course in basic laparoscopic skills, each trainee performed six cholecystectomies that were digitally recorded. For 14 steps of the procedure, an observer who was blinded for the type of training determined whether the step was performed entirely by the trainee (2 points), partially by the trainee (1 point), or by the supervisor (0 points). Time measurements revealed the total procedure time and the amount of effective procedure time during which the trainee acted as the operating surgeon. Results were compared between both groups. RESULTS: Trainees in the INVEST group were awarded statistically significant more points (115.8 vs. 70.2; p < 0.001) and performed more steps without the interference of the supervisor (46.6 vs. 18.8; p < 0.001). Total procedure time was not lengthened by INVEST, and the part performed by trainees was significantly larger (69.9 vs. 54.1 %; p = 0.004). CONCLUSIONS: INVEST enhances effectiveness and training efficiency for procedural training inside the operating theater without compromising operating theater time efficiency. PMID- 23436099 TI - Robotic thyroidectomy by bilateral axillo-breast approach: review of 1,026 cases and surgical completeness. AB - BACKGROUND: Good postoperative and excellent cosmetic results have been achieved with bilateral axillo-breast approach (BABA) robotic thyroidectomy (RoT). This study was performed to analyze the surgical outcomes and evaluate the surgical completeness and safety of BABA RoT. METHODS: Between February 2008 and February 2012, a total of 1026 cases of BABA RoT were performed. The clinicopathologic characteristics, operation types, and postoperative outcomes of patients were analyzed. RESULTS: Of the 1026 cases analyzed, 968 cases were a malignant tumor and 58 cases were benign thyroid disease. Mean operating times for BABA total RoT with central lymph node dissection included 38 +/- 13 min (range 20-90 min) of working space creation and 75 +/- 26 min (range 25-175) of console time. Among the 872 patients who underwent total thyroidectomy with central lymph node dissection, transient hypoparathyroidism occurred in 39.1 %, transient vocal cord palsy occurred in 14.2 %, and permanent hypoparathyroidism and permanent vocal cord palsy occurred in 1.5 % and 0.2 % of patients, respectively. The median stimulated thyroglobulin (Tg) level of patients after their first radioactive iodine therapy was 0.4 ng/mL, with 65.1 % of patients having a stimulated Tg level of <1.0 ng/mL. The median suppressed Tg level at 3 postoperative months of patients without radioactive iodine therapy was <0.1 ng/mL, with 99.4 % of patients showing a suppressed Tg level of< 1.0 ng/mL. There was no recurrence or mortality after a median follow-up of 23 months. CONCLUSIONS: BABA RoT is a safe and effective method that provides good surgical completeness and has low rates of postoperative complications and recurrence. PMID- 23436100 TI - Oncologic safety of stent as bridge to surgery compared to emergency radical surgery for left-sided colorectal cancer obstruction. AB - BACKGROUND: There are still concerns about the oncologic safety of stent insertion for colorectal cancer obstruction. This study investigated whether the use of stents as a bridge to surgery negatively affect the long-term outcome compared to curative surgery for left-sided colorectal cancer obstruction. METHODS: Between January 2004 and December 2009, patients with left-sided colorectal cancer obstruction without distant metastasis were retrospectively reviewed. Forty-three patients underwent radical resection after preoperative stent insertion (stent group), whereas 48 underwent emergency surgery with curative intent (surgery group). The short- and long-term outcomes between the two groups were compared. RESULTS: The stent and surgery groups had similar demographics. There were no significant differences in primary anastomosis, laparoscopic-assisted surgery, operation time, time until first defecation and oral intake after surgery, postoperative hospital stay, and reoperation. The stent group had an average hospital stay 7 days longer than the surgery group. During the median follow-up period of 48.1 months, the 5-year disease-free survival rates were not significantly different between the stent and surgery groups (47.2 vs. 48.9%, respectively; p = 0.499). Overall, the 5-year survival rate was also similar in the two groups (70.4 vs. 76.4%, respectively; p = 0.941). CONCLUSIONS: For left-sided colorectal cancer obstruction, stent insertion followed by surgery showed short-term advantages and similar oncologic outcomes compared to surgery without preoperative intervention. Stent insertion as a bridge to surgery is a safe and feasible treatment option for patients with colorectal cancer obstruction. PMID- 23436101 TI - Over-the-scope clip (OTSC) represents an effective endoscopic treatment for acute GI bleeding after failure of conventional techniques. AB - BACKGROUND: Through-the-scope clips are commonly used for endoscopic hemostasis of gastrointestinal (GI) bleeding, but their efficacy can be suboptimal in patients with complex bleeding lesions. The over-the-scope clip (OTSC) could overcome the limitations of through-the-scope clips by allowing compression of larger amounts of tissue, allowing a more efficient hemostasis. We analyzed the use of OTSC in a consecutive case series of patients with acute GI bleeding unresponsive to conventional endoscopic treatment modalities. METHODS: In a retrospective analysis of prospectively collected data in tertiary referral centers, patients undergoing emergency endoscopy for severe acute nonvariceal GI bleeding were treated with the OTSC after failure of conventional techniques. All patients underwent repeat endoscopy 2-4 days after the procedure. Data analysis included primary hemostasis, complications, and 1-month follow-up clinical outcome. RESULTS: During a 10-month period, 30 patients entered the study consecutively. Bleeding lesions unresponsive to conventional endoscopic treatment (saline/adrenaline injection and through-the-scope clipping) were located in the upper and lower GI tract in 23 and 7 cases, respectively. Primary hemostasis was achieved in 29 of 30 cases (97 %). One patient with bleeding from duodenal bulb ulcer required emergent selective radiological embolization. Rebleeding occurred in two patients 12 and 24 h after the procedure; they were successfully treated with conventional saline/adrenaline endoscopic injection. CONCLUSIONS: OTSC is an effective and safe therapeutic option for severe acute GI bleeding when conventional endoscopic treatment modalities fail. PMID- 23436102 TI - Predictors for underestimated pathology in forceps biopsy compared with resection specimen of colorectal neoplasia; focus on surface appearance. AB - BACKGROUND: There have been substantial differences in pathologic results between forceps biopsies (FB) and resection specimen (RS) of the colorectal neoplasm. The aim of this study was to investigate predictive factors of the underestimated pathology in FB compared with RS. METHODS: Data from 248 consecutive patients with colorectal intraepithelial neoplasm >=10 mm, which was removed by endoscopic mucosal resection or endoscopic submucosal dissection, were reviewed retrospectively. We excluded patients with no FB on the neoplasm before the resection. Demographic data and tumor characteristics including size, locations, surface appearances, and the number of FB fragments were evaluated as potential factors associated with the discrepancies by logistic regression analysis. RESULTS: Overall, 179 lesions from 171 patients were included in the study (size, 28.37 +/- 12.00 mm; range 10-80 mm). The overall number of discrepancy cases was 103 (57.5%), where 90 (50.3%) were underestimated in FB and 13 (7.2%) downgraded in their RS. In the multivariate analysis, round [odds ratio (OR) 4.46, 95% confidence interval (CI) 1.76-11.30, p = 0.002], depressed (OR 3.23, 95% CI 1.11 9.39, p = 0.031), and mixed type of surface appearance (OR 5.47, 95% CI 2.38 12.60, p < 0.001), and tumor size >=30 mm (OR 2.14, 95% CI 1.12-4.10, p = 0.021) were significant predictive factors for underestimated pathology in FB. CONCLUSIONS: Underestimation in FB is remarkable in colorectal tumors >=10 mm in size. This discrepancy is associated with the tumor characteristics, such as surface appearance and size. Endoscopic characteristics of tumor should be carefully examined for an adequate management strategy of colorectal epithelial neoplasm. PMID- 23436109 TI - Testing for tetrahydrobiopterin responsiveness in patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. AB - INTRODUCTION: Pharmacological levels of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin (BH4), reduce plasma phenylalanine levels in some patients with phenylketonuria (PKU), providing the first pharmacological therapy for PKU. Responsiveness to this therapy must be determined empirically through a BH4 loading test or trial. The authors have analyzed the loading tests currently in use in light of the numerous factors that can influence their results. Sapropterin dihydrochloride is a stable, synthetic form of BH4 approved for treatment of PKU in responsive patients. METHODS: An expert panel identified evidence from published reports of clinical experience. Reports of research involving at least 25 patients and published in English were considered. RESULTS: In all, 14 studies met both criteria; eight employing the sapropterin dihydrochloride preparation from Schircks Laboratories and six the sapropterin dihydrochloride preparation from Biomarin/Merck Serono. CONCLUSION: The arbitrary responsiveness definition of a >30% reduction in blood phenylalanine appears to be a good compromise between sensitivity and specificity for the initial screening test. However, individual patient characteristics should be considered when interpreting results, especially in patients with low baseline phenylalanine levels. PMID- 23436107 TI - Calcium handling proteins: structure, function, and modulation by exercise. AB - Heart failure is a serious public health issue with a growing prevalence, and it is related with the aging of the population. Hypertension is identified as the main precursor of left ventricular hypertrophy and therefore can lead to diastolic dysfunction and heart failure. Scientific studies have confirmed the beneficial effects of the physical exercise by reducing the blood pressure and improving the functional status of the heart in hypertension. Several proteins are involved in the mobilization of calcium during the coupling excitation contraction process in the heart among those are sarcoplasmic reticulum Ca(2+) ATPase, phospholamban, calsequestrin, sodium-calcium exchanger, L-type calcium's channel, and ryanodine receptors. Our goal is to address the beneficial effects of exercise on the calcium handling proteins in a heart with hypertension. PMID- 23436111 TI - Highlight: mitochondrial first steps found in jakobid protists. PMID- 23436110 TI - Linaclotide, novel therapy for the treatment of chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. AB - Chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C) are common gastrointestinal (GI) disorders. Current treatment options, either prescription or nonprescription medications, have limited efficacy in a subset of patients. There is significant demand for more efficacious medications for the treatment of CC and IBS-C. Linaclotide, a secretagogue, has a novel mechanism of action designed to treat patients with CC and IBS-C. It has a low oral bioavailability with negligible systemic side effects, and it acts locally in the intestinal lumen. In several clinical trials, in health and disease, linaclotide has demonstrated durable efficacy and safety in CC and IBS-C. Linaclotide received approval by the Federal Drug Administration in August 2012 to treat chronic idiopathic constipation and IBS-C. PMID- 23436108 TI - Mechanisms of subcellular remodeling in heart failure due to diabetes. AB - Diabetic cardiomyopathy is not only associated with heart failure but there also occurs a loss of the positive inotropic effect of different agents. It is now becoming clear that cardiac dysfunction in chronic diabetes is intimately involved with Ca(2+)-handling abnormalities, metabolic defects and impaired sensitivity of myofibrils to Ca(2+) in cardiomyocytes. On the other hand, loss of the inotropic effect in diabetic myocardium is elicited by changes in signal transduction mechanisms involving hormone receptors and depressions in phosphorylation of various membrane proteins. Ca(2+)-handling abnormalities in the diabetic heart occur mainly due to defects in sarcolemmal Na(+)-K(+) ATPase, Na(+)-Ca(2+) exchange, Na(+)-H(+) exchange, Ca(2+)-channels and Ca(2+)-pump activities as well as changes in sarcoplasmic reticular Ca(2+)-uptake and Ca(2+) release processes; these alterations may lead to the occurrence of intracellular Ca(2+) overload. Metabolic defects due to insulin deficiency or ineffectiveness as well as hormone imbalance in diabetes are primarily associated with a shift in substrate utilization and changes in the oxidation of fatty acids in cardiomyocytes. Mitochondria initially seem to play an adaptive role in serving as a Ca(2+) sink, but the excessive utilization of long-chain fatty acids for a prolonged period results in the generation of oxidative stress and impairment of their function in the diabetic heart. In view of the activation of sympathetic nervous system and renin-angiotensin system as well as platelet aggregation, endothelial dysfunction and generation of oxidative stress in diabetes and blockade of their effects have been shown to attenuate subcellular remodeling, metabolic derangements and signal transduction abnormalities in the diabetic heart. On the basis of these observations, it is suggested that oxidative stress and subcellular remodeling due to hormonal imbalance and metabolic defects play a critical role in the genesis of heart failure during the development of diabetic cardiomyopathy. PMID- 23436112 TI - Trace metals in upland headwater lakes in Ireland. AB - Trace elements (n = 23) in Irish headwater lakes (n = 126) were investigated to determine their ambient concentrations, fractionation (total, dissolved, and non labile), and geochemical controls. Lakes were generally located in remote upland, acid-sensitive regions along the coastal margins of the country. Total trace metal concentrations were low, within the range of natural pristine surface waters; however, some lakes (~20 %) had inorganic labile aluminum and manganese at levels potentially harmful to aquatic organisms. Redundancy analysis indicated that geochemical weathering was the dominant controlling factor for total metals, compared with acidity for dissolved metals. In addition, many metals were positively correlated with dissolved organic carbon indicating their affinity (or complexation) with humic substances (e.g., aluminum, iron, mercury, lead). However, a number of trace metals (e.g., aluminum, mercury, zinc) were correlated with anthropogenic acidic deposition (i.e., non-marine sulfate), suggesting atmospheric sources or elevated leaching owing to acidic deposition. As transboundary air pollution continues to decline, significant changes in the cycling of trace metals is anticipated. PMID- 23436113 TI - Paraneoplastic neurological syndromes: general treatment overview. AB - OPINION STATEMENT: Major recent discoveries have bringing out a revised definition of paraneoplastic neurological syndromes (PNS), bringing out the concept of antibody-mediated neurological disorders, triggered or not by cancer. Classification of these diseases is not based anymore on the clinical pattern or an underlying tumor, but on the location of the targeted antigens. Indeed, evolution, response to treatment, and pathophysiology are radically different according to the associated antibodies. In some patients with newly described antibodies targeting cell-surface antigens, humoral immunity seems to play a direct role and a dramatic improvement is observed with immunomodulator treatments. In these patients, an associated tumor is less frequent. Conversely, patients with antibodies directed against intracellular targets are, in most cases, characterized by a high degree of irreversible neuronal death mediated by cytotoxic T-cells and do not improve after immunomodulator treatments. In these patients, an associated tumor is highly frequent and must be cured as soon as possible. A third group of patients can be identified with anti-GAD65 and anti Amphiphysin antibodies. In patients with these antibodies, the efficiency of immunomodulator treatments is less clear as well as the type of immune response that could be a mix between humoral and cellular. In this last group, the antigen is intracellular, but patients may improve with immunomodulator treatments and associated tumors are rare. Thus, identification of associated antibodies should be prompt and the treatment guided according the identified antibody. Mainstream of treatment include the quest of a tumor and its cure. Immunotherapy must be promptly initiated, targeting humoral, or cellular immune response, or both, according to the associated antibodies. Furthermore, in some situations such as Lambert-Eaton Myasthenic Syndromes and Stiff-Person Syndromes, symptomatic drugs can be useful to control the symptoms. PMID- 23436114 TI - Erythropoietin in the neurology ICU. AB - OPINION STATEMENT: Erythropoietin (EPO) is an approved drug that is used in the treatment of chronic anemia associated with chronic renal failure. In the Neuro ICU, there are 2 potential uses for treatment with EPO. Anemia is common in patients with acute neurological disorders and may be a cause of secondary insults. Studies of EPO to treat anemia associated with critical illness have not conclusively shown a beneficial risk/benefit ratio. The relatively small reduction in transfusion requirement with EPO in critically ill patients is likely due to the 7-10 days required to see an effect of EPO on hematocrit. For these reasons, EPO is not recommended to treat anemia of critical illness. Neuroprotection is the other potential use for EPO in the Neuro ICU. Many experimental studies demonstrate neuroprotective effects with EPO in a variety of acute neurological disorders. To date, no clinical studies have confirmed beneficial effects of EPO on neurological outcome although some studies have suggested a reduction in mortality rate in trauma patients treated with EPO. Additional clinical studies are needed before EPO administration can be recommended for cytoprotection in neurological disorders. PMID- 23436115 TI - Dissecting the inter-substrate navigation of migrating glioblastoma cells with the stripe assay reveals a causative role of ROCK. AB - A hallmark of gliomas is the growth and migration of cells over long distances within the brain and proliferation within selected niches, indicating that the migrating cells navigate between complex substrates. We demonstrate in the present study a differential preference for migration that depends on Rho associated coil kinase (ROCK) signaling, using the alternating Bonhoeffer stripe assay. Membrane fractions from nonmyelinated and myelinated brain areas from female rats, purified myelin also from female rats, and commercial extracellular matrix were used as substrates, with each substrate being tested against the others. The human tumor cell lines exhibited a clear preference for extracellular matrix over all other substrates and for myelinated over nonmyelinated tissue. ROCK signaling was different when cells were cultured on either substrate. The ROCK inhibitor Y27632 significantly attenuated and neutralized the preference for extracellular matrix and myelin, indicating that ROCK controls the substrate selectivity. The findings of this study pave the way for navigation-targeted therapeutics. PMID- 23436117 TI - Registry of the Japanese society of lung and heart-lung transplantation: the official Japanese lung transplantation report 2012. AB - The Japanese Organ Transplant Law was amended, and the revised law took effect in July 2010 to overcome extreme donor shortage and to increase the availability of donor organs from brain-dead donors. It is now possible to procure organs from children. The year 2011 was the first year that it was possible to examine the results of this first extensive revision of the Japanese Organ Transplant Law, which took effect in 1997. Currently, seven transplant centers, including Tohoku, Dokkyo, Kyoto, Osaka, Okayama, Fukuoka and Nagasaki Universities, are authorized to perform lung transplantation in Japan, and by the end of 2011, a total of 239 lung transplants had been performed. The number of transplants per year and the ratio of brain-dead donor transplants increased dramatically after the revision of the Japanese Organ Transplant Law. The survival rates for lung transplant recipients registered with the Japanese Society for Lung and Heart-lung Transplantation were 93.3 % at 1 month, 91.5 % at 3 months, 86.3 % at 1 year, 79.0 % at 3 years, and 73.1 % at 5 years. The survival curves for brain-dead donor and living-donor lung transplantation were similar. The survival outcomes for both brain-dead and living-donor lung transplants were better than those reported by the International Society for Heart and Lung Transplantation. However, donor shortage remains a limitation of lung transplantation in Japan. The lung transplant centers in Japan should continue to make a special effort to save critically ill patients waiting for lung transplantation. PMID- 23436118 TI - Current status and perspective of EBUS-TBNA. AB - In 2002, a new bronchoscope equipped with a convex type ultrasound probe on the tip was introduced into clinical practice. This convex probe endobronchial ultrasound (CP-EBUS) provides a long axis image of surrounding structures of the major airway. The CP-EBUS combined with a dedicated biopsy needle allows real time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal and hilar lymph nodes. Samples obtained from EBUS-TBNA can be used for pathological diagnosis including immunohistochemistry. EBUS-TBNA is now being performed worldwide for several indications including mediastinal staging, mediastinal pathology and for benign diseases. For mediastinal staging in lung cancer, the diagnostic yield of EBUS-TBNA is comparable to surgical staging in patients with enlarged lymph nodes. In addition, EBUS-TBNA can be used for molecular analysis of tumor cells obtained during the procedure. DNA mutation testing using EBUS-TBNA samples was first reported in 2007 for a chondrosarcoma case. Also, isolated DNA from EBUS-TBNA samples was applied for epidermal growth factor receptor mutation testing and aberrant methylation analysis in patients with lung cancer. RNA was also isolated from properly stored EBUS-TBNA samples and used for gene expression research and aberrant fusion gene detection in lung cancer patients. Optimization of tissue banking methods of EBUS-TBNA specimens was also investigated. Currently, EBUS-TBNA samples can be used for comprehensive mRNA and miRNA expression analysis. EBUS-TBNA will become an important modality for bronchoscopists in the era of personalized medicine in lung cancer. PMID- 23436119 TI - A flood tide of systematic reviews on endodontic posts: methodological assessment using of R-AMSTAR. AB - OBJECTIVES: To help the dental practitioner solve a specific clinical problem, systematic reviews (SRs) are seen as the best guide. In addition to the unmanageable quantity of SRs, however, one should be aware of their variable quality. The present review describes the methodological quality of SRs on postendodontic restorations to work out the value of these reviews for the dental practitioner. METHODOLOGY: SRs were searched in April 2012, independently and in triplicate. Post survival was used as measure of outcome. The methodological quality of included SRs was assessed with the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) checklist. Kappa statistics were used to assess reviewer agreement. RESULTS: Three hundred sixty-three papers were retrieved from the initial search. Ten SRs were included. One SR achieved a high R-AMSTAR score, whereas the other nine SRs achieved scores that indicate a substantial lack of methodological quality. Especially the items "grey literature," "combination of findings," "likelihood of publication bias," and conflict of interest" showed low R-AMSTAR scores. The three reviews with the highest R-AMSTAR scores tended to conclude that fewer failures occurred when using nonmetal posts. The reviewer agreement was excellent (kappa ranged from 0.79 to 0.85) in the R-AMSTAR classification. CONCLUSION: The approach presented revealed a lack of SRs with high methodological quality. Thus, no decisive conclusion can be drawn with respect to this topic. It appears that there is a trend for the superiority of fiber-reinforced posts. CLINICAL RELEVANCE: SRs must be of high methodological quality. This can be achieved by taking into consideration the results of this review. Improved methodological quality would make SRs more supportive for the general practitioner. PMID- 23436120 TI - [Maxillary ameloblastoma extending into the sinonasal tract]. AB - Maxillary ameloblastomas can extensively expand into the paranasal sinuses or even the nasal cavity due to a slow growth pattern. Sinusitis is rarely the first tumor-related complaint. Due to the various growth forms of ameloblastomas the challenging histological differential diagnosis includes several other odontogenic as well as benign and malignant non-odontogenic tumors, e.g. tumors from the mucosa of the paranasal sinuses, salivary glands and Rathke's pouch. Despite the radical surgical approach a complete resection with wide margins cannot always be achieved. Maxillary ameloblastomas show the highest recurrence rates. PMID- 23436121 TI - The use of low-cost adsorbents for wastewater purification in mining industries. AB - Recently, great attention has been paid to the environmental problems in mining industry. At present there are different ways of mineral processing, as well as various methods of wastewater treatment, most of them are expensive. Work is ongoing to find low-cost treatments. In this article, low-cost adsorbents, potentially useful for wastewater treatment on mining and metallurgical plants, are reviewed; their characteristics, advantages, and disadvantages of their application are compared. Also adsorption of different metals and radioactive compounds from acidic environment similar to composition of mining and metallurgical wastewaters is considered. PMID- 23436122 TI - Photocatalytic degradation of contaminants of concern with composite NF-TiO2 films under visible and solar light. AB - This study reports the synthesis and characterization of composite nitrogen and fluorine co-doped titanium dioxide (NF-TiO(2)) for the removal of contaminants of concern in wastewater under visible and solar light. Monodisperse anatase TiO(2) nanoparticles of different sizes and Evonik P25 were assembled to immobilized NF TiO(2) by direct incorporation into the sol-gel or by the layer-by-layer technique. The composite films were characterized with X-ray diffraction, high resolution transmission electron microscopy, environmental scanning electron microscopy, and porosimetry analysis. The photocatalytic degradation of atrazine, carbamazepine, and caffeine was evaluated in a synthetic water solution and in an effluent from a hybrid biological concentrator reactor (BCR). Minor aggregation and improved distribution of monodisperse titania particles was obtained with NF TiO(2)-monodisperse (10 and 50 nm) from the layer-by-layer technique than with NF TiO(2) +monodisperse TiO(2) (300 nm) directly incorporated into the sol. The photocatalysts synthesized with the layer-by-layer method achieved significantly higher degradation rates in contrast with NF-TiO(2)-monodisperse titania (300 nm) and slightly faster values when compared with NF-TiO(2)-P25. Using NF-TiO(2) layer-by-layer with monodisperse TiO(2) (50 nm) under solar light irradiation, the respective degradation rates in synthetic water and BCR effluent were 14.6 and 9.5 * 10(-3) min(-1) for caffeine, 12.5 and 9.0 * 10(-3) min(-1) for carbamazepine, and 10.9 and 5.8 * 10(-3) min(-1) for atrazine. These results suggest that the layer-by-layer technique is a promising method for the synthesis of composite TiO(2)-based films compared to the direct addition of nanoparticles into the sol. PMID- 23436123 TI - Determinants of maternal and fetal exposure and temporal trends of perfluorinated compounds. AB - In recent years, some perfluorinated compounds (PFCs) have been identified as potentially hazardous substances which are harmful to the environment and human health. According to limited data, PFC levels in humans could be influenced by several determinants. However, the findings are inconsistent. In the present study, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were measured in paired maternal and cord serum samples (N=237) collected between 1978 and 2001 in Southern Sweden to study the relationship between these and to investigate several potential determinants of maternal and fetal exposure to PFCs. Time trends of PFCs in Swedish women were also evaluated. The study is a part of the Fetal Environment and Neurodevelopment Disorders in Epidemiological Research project. PFOS, PFOA, and PFNA levels (median) were higher in maternal serum (15, 2.1, and 0.24 ng/ml, respectively) than in cord serum (6.5, 1.7, and 0.20 ng/ml, respectively). PFC levels were among the highest in women originating from the Nordic countries and the lowest in women from the Middle East, North Africa, and sub-Saharan Africa. Multiparous women had lower serum PFOA levels (1.7 ng/ml) than primiparous women (2.4 ng/ml). Maternal age, body mass index, cotinine levels, and whether women carried male or female fetuses did not affect serum PFC concentrations. Umbilical cord serum PFC concentrations showed roughly similar patterns as the maternal except for the gestational age where PFC levels increased with advancing gestational age. PFOS levels increased during the study period in native Swedish women. In summary, PFOS levels tend to increase while PFOA and PFNA levels were unchanged between 1978 and 2001 in our study population. Our results demonstrate that maternal country of origin, parity, and gestational age might be associated with PFC exposure. PMID- 23436124 TI - Geochemical and mineralogical characterization of a neutral, low-sulfide/high carbonate tailings impoundment, Markusovce, eastern Slovakia. AB - Tailings deposits generated from mining activities represent a potential risk for the aquatic environment through the release of potentially toxic metals and metalloids occurring in a variety of minerals present in the tailings. Physicochemical and mineralogical characteristics of tailings such as total concentrations of chemical elements, pH, ratio of acid-producing to acid neutralizing minerals, and primary and secondary mineral phases are very important factors that control the actual release of potentially toxic metals and metalloids from the tailings to the environment. The aims of this study are the determination of geochemical and mineralogical characteristics of tailings deposited in voluminous impoundment situated near the village of Markusovce (eastern Slovakia) and identification of the processes controlling the mobility of selected toxic metals (Cu, Hg) and metalloids (As, Sb). The studied tailings have unique features in comparison with the other tailings investigated previously because of the specific mineral assemblage primarily consisting of barite, siderite, quartz, and minor sulfides. To meet the aims, samples of the tailings were collected from 3 boreholes and 15 excavated pits and subjected to bulk geochemical analyses (i.e., determination of chemical composition, pH, Eh, acid generation, and neutralization potentials) combined with detailed mineralogical characterization using optical microscopy, X-ray diffraction (XRD), electron microprobe analysis (EMPA), and micro-X-ray diffraction (MU-XRD). Additionally, the geochemical and mineralogical factors controlling the transfer of potentially toxic elements from tailings to waters were also determined using short-term batch test (European norm EN 12457), sampling of drainage waters and speciation-equilibrium calculations performed with PHREEQC. The tailings mineral assemblage consists of siderite, barite, quartz, and dolomite. Sulfide minerals constitute only a minor proportion of the tailings mineral assemblage and their occurrence follows the order: chalcopyrite > pyrite > tetrahedrite>arsenopyrite. The mineralogical composition of the tailings corresponds well to the primary mineralization mined. The neutralization capacity of the tailings is high, as confirmed by the values of neutralization potential to acid generation potential ratio, ranging from 6.7 to 63.9, and neutral to slightly alkaline pH of the tailings (paste pH 7.16-8.12) and the waters (pH 7.00-8.52). This is explained by abundant occurrence of carbonate minerals in the tailings, which readily neutralize the acidity generated by sulfide oxidation. The total solid-phase concentrations of metal(loid)s decrease as Cu>Sb>Hg>As and reflect the proportions of sulfides present in the tailings. Sulfide oxidation generally extends to a depth of 2 m. MU-XRD and EMPA were used to study secondary products developed on the surface of sulfide minerals and within the tailings. The main secondary minerals identified are goethite and X-ray amorphous Fe oxyhydroxides and their occurrence decreases with increasing tailings depth. Secondary Fe phases are found as mineral coatings or individual grains and retain relatively high amounts of metal(loid)s (up to 57.6 wt% Cu, 1.60 wt% Hg, 23.8 wt% As, and 2.37 wt% Sb). Based on batch leaching tests and lysimeter results, the mobility of potentially toxic elements in the tailings is low. The limited mobility of metals and metalloids is due to their retention by Fe oxyhydroxides and low solubilities of metal(loid)-bearing sulfides. The observations are consistent with PHREEQC calculations, which predict the precipitation of Fe oxyhydroxides as the main solubility-controlling mineral phases for As, Cu, Hg, and Sb. Waters discharging from tailings impoundment are characterized by a neutral to slightly alkaline pH (7.52-7.96) and low concentrations of dissolved metal(loid)s (<5-7.0 MUg/L Cu, <0.1-0.3 MUg/L Hg, 5.0-16 MUg/L As, and 5.0-43 MUg/L Sb). Primary factors influencing aqueous chemistry at the site are mutual processes of sulfide oxidation and carbonate dissolution as well as precipitation reactions and sorption onto hydrous ferric oxides abundantly present at the discharge of the impoundment waters. The results of the study show that, presently, there are no threats of acid mine drainage formation at the site and significant contamination of natural aquatic ecosystem in the close vicinity of the tailings impoundment. PMID- 23436125 TI - NAD+-dependent xylitol dehydrogenase (xdhA) and L-arabitol-4-dehydrogenase (ladA) deletion mutants of Aspergillus oryzae for improved xylitol production. AB - Xylitol dehydrogenase (XDHA) and L-arabitol dehydrogenase (LADA) are two key enzymes in xylan metabolism catalyzing the oxidation of xylitol to D-xylulose and arabitol to L-xylulose, respectively. In Aspergillus oryzae, XDHA and LADA are encoded by xdhA and ladA. We deleted xdhA and ladA and xdhA-ladA to generate mutants with decreased dehydrogenase activities and increased xylitol production. The mutants were constructed by homologous transformation into A. oryzae P4 (?pyrG) using pyrG as a selectable marker. The xylitol productivity of the mutants was measured using D-xylose as the sole carbohydrate source. xdhA, ladA, and the double-deletion mutant produced, respectively, 12.4 g xylitol/l with a yield of 0.24 g/g D-xylose, 12.4 g/l with a yield of 0.33 g/g D-xylose, and 8.6 g/l at a yield of 0.26 g/g D-xylose. PMID- 23436126 TI - Adhesion of osteoblast-like cell on silicon-doped TiO2 film prepared by cathodic arc deposition. AB - Silicon-doped TiO2 (Si-TiO2) and pure TiO2 films were deposited on titanium substrates by cathodic arc deposition technique. The surface characteristics of the films, such as surface topography, elemental composition and wettability, were studied. About 4.6 % Si was incorporated into the Si-TiO2 films with a water contact angle of about 83 degrees . The adhesive behaviors of osteoblast-like MG63 cells on both films were investigated through cell counting assay, immunocytochemistry, real-time PCR and western blotting analysis. Cells cultured on the Si-TiO2 films had a greater cellular viability, stronger cytoskeleton and focal adhesion, and more cellular spreading than those on the pure TiO2 films. Moreover, the expression levels of integrin beta1 and focal adhesion kinase (FAK) genes, FAK and the phosphorylation of FAK proteins were up-regulated in cells cultured on the Si-TiO2 films. These results indicated that the Si-TiO2 films possess significantly enhanced cytocompatibility and provide potential solutions for the surface modification of implants in the future. PMID- 23436127 TI - Calcium accumulation characterization in the aerobic granules cultivated in a continuous-flow airlift bioreactor. AB - Limited work has been done on the accumulation characterization of Ca(2+) in aerobic granules that are cultivated in a continuous-flow bioreactor. In this work, the contribution of Ca(2+) to the biogranulation in a continuous flow airlift fluidized bed (CAFB) reactor has been studied. The spatial distribution and form of calcium in the granules were investigated by scanning electron microscopy-mapping, energy dispersive X-ray and X-ray diffraction (XRD). Calcium was located throughout the Ca-rich granules, rather than accumulating in the center of the granules of the sequencing batch reactor. Furthermore, CaCO3 was detected as the main crystalline mineral form of the calcium. Calcium augmentation of the inflow promoted the accumulation of magnesium in the granules in the CAFB. The magnesium was presented as Ca7Mg2P6O24 according to XRD analyses. PMID- 23436128 TI - Enzymatic synthesis of oleic acid-based epoxy monomer for the production of value added polymers. AB - An oleic acid-based epoxy monomer was synthesized by reacting 2-hydroxyethyl acrylate with epoxy stearic acid and an immobilized lipase. NMR, electrospray ionization mass spectrometry and gel permeation chromatography were used to characterize the intermediates and products. 2-(Acryloyloxy) ethyl epoxy stearate was synthesized with a yield of 87 % w/w. After free radical polymerization, epoxy stearic acid-grafted epoxy polymer with molecular weight of 15,150 g/mol was obtained; the final yield was 81 % w/w. PMID- 23436129 TI - Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open label study in youth with fragile X syndrome. AB - RATIONALE: Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission. METHODS: We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6-17 years (mean age: 11.9 years) with FXS. RESULTS: Acamprosate use (mean dose: 1,054 +/- 422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of "very much improved" or "much improved") in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment. CONCLUSIONS: Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted. PMID- 23436130 TI - Prenatal exposure to escitalopram and/or stress in rats: a prenatal stress model of maternal depression and its treatment. AB - RATIONALE: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother. OBJECTIVE: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior. RESULTS: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle. CONCLUSIONS: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition. PMID- 23436131 TI - Screening for major depressive disorder in adults with glioma using the PHQ-9: a comparison of patient versus proxy reports. AB - When screening for depression in glioma patients, the utility of proxy carer report is unknown. We studied how patients and proxies differed in the frequency, severity and agreement of reported depressive symptoms, the external validity of these reports, and whether patient-proxy agreement was associated with cognitive function. This was a cross-sectional study within a prospective cohort study of depression in glioma. Eligible patients were adults with a new diagnosis of cerebral glioma whose cohabiting partners chose to attend study interviews. Patients completed the Patient Health Questionnaire-9 (PHQ-9, maximum score 27) to screen for major depressive disorder. Proxies independently completed the PHQ 9 'for the patient'. A structured clinical interview for MDD was then given. From 55 couples attending, 41 participated (74 %). Patient-proxy total PHQ-9 score differed by 3 or more points in 26/41 cases (63.4 %). Disagreement within dyads ranged from -7 to +10 points. Proxies observed more individual depressive symptoms than patients reported (mean 2.7 vs 1.8 symptoms respectively, p = 0.013, Wilcoxon Rank Sum Test), and a greater severity of symptom burden (mean PHQ-9 score 8.4 vs 6.8 respectively, p = 0.016, Wilcoxon Rank Sum Test). Proxies were more reliable than patients on objective behavioural symptoms of depression. Dyadic agreement was not associated with severity of patient cognitive impairment. There was frequent disagreement between glioma patients and proxies reports of depressive symptoms. Proxies reported more depressive symptoms than patients, and were more reliable when reporting observable behavioural symptoms. When diagnosing depression in glioma, collateral history should be obtained. PMID- 23436132 TI - Outcome prediction in intracranial tumor surgery: the National Surgical Quality Improvement Program 2005-2010. AB - Accurate knowledge of individualized risks is crucial for decision-making in the surgical management of patients with brain tumors. Precise delineation of those risks remains a topic of debate. We attempted to create a predictive model of outcomes in patients undergoing craniotomies for tumor resection (CTR). We performed a retrospective cohort study involving patients who underwent CTR from 2005 to 2010 and were registered in the American College of Surgeons National Quality Improvement Project database. A model for outcome prediction based on individual patient characteristics was developed. Of the 1,834 patients, 457 had meningiomas (24.9 %) and 1377 had non-meningioma tumors (75.1 %). The respective 30-day postoperative risks were 2.1 % for stroke, 1.3 % for MI, 2.7 % for death, 2.4 % for deep surgical site infection, and 6.6 % for return to the OR. Multivariate analysis demonstrated that pre-operative tumor-related neurologic deficit, stroke, altered mental status, and weight loss, were independently associated with most outcomes, including post-operative MI, death, and deep surgical site infection. An additive effect of the variables on the risk of all outcomes was observed. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated by the area under the receiver operating characteristic curve, which was 0.687, 0.929, 0.749, 0.746, and 0.679 for postoperative risk of stroke, MI, death, infection, and return to the OR, respectively. Our model can provide individualized estimates of the risks of post-operative complications based on pre-operative conditions, and can potentially be utilized as an adjunct in the decision-making for surgical intervention in brain tumor patients. PMID- 23436133 TI - Musculoskeletal tumors and tumor-like conditions: common and avoidable pitfalls at imaging in patients with known or suspected cancer: Part A: benign conditions that may mimic malignancy. AB - A wide range of musculoskeletal tumors and tumor-like conditions may be encountered when patients undergo radiological examinations. The imaging features of certain normal, reactive, benign neoplastic, inflammatory, traumatic, and degenerative processes in the musculoskeletal system may mimic malignant tumor; misinterpretation of the imaging findings can lead to inappropriate clinical management of the patient. This review describes and illustrates a number of such mimics that we have commonly encountered in our oncological imaging practice, and provides suggestions for avoiding each of these pitfalls. Because many orthopaedic surgeons interpret radiological images themselves, they need to be as aware as radiologists about these issues. PMID- 23436134 TI - Effects of Al-based additives on the hydrogen storage performance of the Mg(NH2)2 2LiH system. AB - The Mg(NH2)2-2LiH composite is a promising hydrogen storage material due to its relatively high reversible hydrogen capacity (~5.6 wt%) and suitable thermodynamic properties that allow hydrogen sorption conducting at temperatures below 90 degrees C. However, the presence of a severe kinetic barrier inhibits its low-temperature operation. In the present work, Li3AlH6 was introduced to the Mg(NH2)2-2LiH system. Experimental results show that a 3.2% mol Li3AlH6-modified Mg(NH2)2-2LiH sample released hydrogen at a rate ca. 4.5 times as fast as that of the Li3AlH6-free sample at 140 degrees C. The enhancement of desorption kinetics was simultaneously demonstrated by activation energy (Ea) of ca. 96.3 +/- 9 kJ mol(-1) which was significantly decreased by 31 kJ mol(-1) from that of the Li3AlH6-free sample. The interaction of Li3AlH6 and Mg(NH2)2 during ball milling results in the formation of LiAl(NH)2, LiNH2 and Mg3N2. LiAl(NH)2 was actually the active species for the enhancement of dehydrogenation/re-hydrogenation kinetics of the system. PMID- 23436136 TI - Planar radionuclide angiography with a dedicated cardiac SPECT camera. AB - BACKGROUND: We compared a dedicated cardiac camera with a traditional system for left ventricular (LV) functional measurements using gated blood-pool imaging. METHODS: 24-frame gated planar images were obtained from 48 patients in an LAO orientation for 6M counts/view on a standard gamma camera. Immediately thereafter, 24-frame ECG-gated data were obtained for 8 minutes on a dedicated cardiac SPECT camera. The gated SPECT image volumes were iteratively reconstructed and then transferred offline. In-house software was used to reproject the images into a 24-frame gated planar format. Both the original and the reprojected gated planar datasets were analyzed using semiautomated software to determine ejection fraction (EF), ventricular volume (end diastolic volume, EDV), peak ejection rate (PER), and peak filling rate (PFR). RESULTS: The difference in EF values averaged 0.4% +/- 4.4%. The correlation in EF was r >= 0.94 (P < .01) with a linear regression slope of 0.98. Correlation of the EDV was r >= 0.86 (P < .01), but the volumes from the dedicated cardiac camera were smaller (linear regression slope was 0.6). Correlation of PFR and PER were r = 0.91 and r >= 0.83, respectively (P < .01 for both). CONCLUSIONS: Reprojection of 24-frame gated blood-pool SPECT images is an effective means of obtaining LV functional measurements with a dedicated cardiac SPECT camera using standard 2D planar analysis tools. PMID- 23436135 TI - Assessment of oxidative, inflammatory, and fibrinolytic biomarkers and DNA strand breakage in hypercholesterolemia. AB - The aim of this study was to assess the levels of oxidative, inflammatory, and fibrinolytic biomarkers as well as DNA strand breakage in hypercholesterolemic subjects. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, total protein, albumin, apolipoprotein (Apo) A, Apo B, advanced oxidation protein products (AOPP), increased ischemia-modified albumin (IMA), -SH, NOx, IL-6, and D dimer levels were assessed, and DNA strand breakage was evaluated using comet assay in 38 patients with hypercholesterolemia and 20 healthy controls. Total cholesterol, triglycerides, LDL cholesterol, Apo A, Apo B, AOPP, IMA, IL-6, and D dimer concentrations were significantly higher in subjects with hypercholesterolemia. However, NOx and plasma -SH group concentrations were lower in hypercholesterolemic subjects, while no significant differences were observed with respect to DNA strand breakage between the two groups. Hypercholesterolemia is related to oxidative stress and inflammation. Accordingly, AOPP concentration was higher in subjects with hypercholesterolemia, and we speculate that AOPP can reflect the enhancement of protein oxidation and inflammation. PMID- 23436137 TI - The United States has lower life expectancy than other developed nations, despite having highest health care costs. PMID- 23436138 TI - Proximity to a tobacco store and smoking cessation: a cohort study. AB - BACKGROUND: It is not clear whether the availability of tobacco affects the likelihood of smoking cessation. We examined whether the proximity to a tobacco store and the number of stores were associated with smoking cessation, and compared results for proximity variables based on walking and straight-line (as the crow flies) distance. METHODS: The study population consisted of 8751 baseline smokers from the Finnish Public Sector study in 1997-2005. Smoking intensity (cigarettes/day) was determined at baseline and smoking cessation was determined from a follow-up survey in 2008-2009. Proximity was measured using straight-line and walking distance from home to the nearest tobacco store, and another exposure variable was the number of stores within 0.50 km from home. We calculated associations with log-binomial regression models, adjusting for individual-level and area-level confounders. RESULTS: Of the participants, 3482 (39.8%) quit smoking during the follow-up (mean follow-up 5.5 years, SD 2.3 years). Among men who were moderate/heavy smokers at baseline and lived <0.50 km walking distance from the nearest tobacco store, the likelihood of smoking cessation was 27% (95% CI 12% to 40%) lower compared with those living >=0.50 km from a store. Having even one store within 0.50 km walking distance from home decreased cessation in men who were moderate/heavy smokers by 37% (95% CI 19% to 51%). No decrease was found for men who were light smokers at baseline or for women. CONCLUSIONS: Living within walking distance of a tobacco store reduced the likelihood of smoking cessation among men who were moderate/heavy smokers. PMID- 23436139 TI - The effects of variant descriptors on the potential effectiveness of plain packaging. AB - OBJECTIVES: To examine the effects that variant descriptor labels on cigarette packs have on smokers' perceptions of those packs and the cigarettes contained within. METHOD: As part of two larger web-based studies (each involved 160 young adult ever-smokers 18-29 years old), respondents were shown a computer image of a plain cigarette pack and sets of related variant descriptors. The sets included terms that varied in terms of descriptors of colours as names, flavour strength, degrees of filter venting, filter types, quality, type of cigarette and numbers. For each set, respondents rated the highest and lowest of two or three of the following four characteristics: quality, strongest or weakest in taste, delivers most or least tar/nicotine, and most or least level of harm. RESULTS: There were significant differences on all four ratings. Quality ratings were the least differentiated. Except for colour descriptors, where 'Gold' rated high in quality but medium in other ratings, ratings of quality, harm, strength and delivery were all positively associated when rated on the same descriptors. CONCLUSIONS: Descriptor labels on cigarette packs, can affect smokers' perceptions of the characteristics of the cigarettes contained within. Therefore, they are a potential means by which product differentiation can occur. In particular, having variants differing in perceived strength while not differing in deliveries of harmful ingredients is particularly problematic. Any packaging policy should take into account the possibility that variant descriptors can mislead smokers into making inappropriate product attributions. PMID- 23436140 TI - Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors. AB - A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC50 1.1 MUM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-alpha and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents. PMID- 23436142 TI - Economic evaluations of trastuzumab in HER2-positive metastatic breast cancer: a systematic review and critique. AB - BACKGROUND: Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs). OBJECTIVES: This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions. METHODS: A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator. RESULTS: Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective. CONCLUSION: There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting. PMID- 23436143 TI - A prospective randomized study of conservative versus surgical treatment of unstable palmar plate disruption in the proximal interphalangeal finger joint. AB - The aim of this study was to assess the effect of conservative versus operative treatment for unstable palmar plate disruption in the proximal interphalangeal (PIP) joint of the fingers with respect to preservation of joint stability, mobility, and pain. The study was conducted as a prospective study in which 83 patients were randomly assigned into 2 groups: (1) conservative treatment with a rigid splint for 2 weeks, (2) surgical reattachment of the palmar plate in local anesthesia followed by 2 weeks of immobilization in a plaster cast. Both groups were thereafter treated by taping to the neighboring finger for 3 weeks. With regard to hyperextension instability, stiffness, and pain, there is no significant difference in outcome between patients with traumatic palmar plate lesions and hyperextension instability treated with surgical repair and patients treated conservatively with a splint. We do not recommend primary surgical repair of unstable isolated palmar plate lesions in the proximal interphalangeal joints of the 4 ulnar fingers. Type of study/level of evidence Therapeutic, Level II. PMID- 23436141 TI - Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. AB - Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation. TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria. Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene. Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases. This implies that drugs or substances that modify these pathways may prevent or improve the abovementioned diseases. Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6 shogaol, cinnamon extract, N-acetylcysteine, melatonin, and molecular hydrogen. The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many "civilization" disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders. PMID- 23436144 TI - Medical ethics, bioethics and research ethics education perspectives in South East Europe in graduate medical education. AB - Ethics has an established place within the medical curriculum. However notable differences exist in the programme characteristics of different schools of medicine. This paper addresses the main differences in the curricula of medical schools in South East Europe regarding education in medical ethics and bioethics, with a special emphasis on research ethics, and proposes a model curriculum which incorporates significant topics in all three fields. Teaching curricula of Medical Schools in Bulgaria, Bosnia and Herzegovina, Croatia, Serbia, Macedonia and Montenegro were acquired and a total of 14 were analyzed. Teaching hours for medical ethics and/or bioethics and year of study in which the course is taught were also analyzed. The average number of teaching hours in medical ethics and bioethics is 27.1 h per year. The highest national average number of teaching hours was in Croatia (47.5 h per year), and the lowest was in Serbia (14.8). In the countries of the European Union the mean number of hours given to ethics teaching throughout the complete curriculum was 44. In South East Europe, the maximum number of teaching hours is 60, while the minimum number is 10 teaching hours. Research ethics topics also show a considerable variance within the regional medical schools. Approaches to teaching research ethics vary, even within the same country. The proposed model for education in this area is based on the United Nations Educational, Scientific and Cultural Organization Bioethics Core Curriculum. The model curriculum consists of topics in medical ethics, bioethics and research ethics, as a single course, over 30 teaching hours. PMID- 23436145 TI - The challenges of incorporating cultural ecosystem services into environmental assessment. AB - The ecosystem services concept is used to make explicit the diverse benefits ecosystems provide to people, with the goal of improving assessment and, ultimately, decision-making. Alongside material benefits such as natural resources (e.g., clean water, timber), this concept includes-through the 'cultural' category of ecosystem services-diverse non-material benefits that people obtain through interactions with ecosystems (e.g., spiritual inspiration, cultural identity, recreation). Despite the longstanding focus of ecosystem services research on measurement, most cultural ecosystem services have defined measurement and inclusion alongside other more 'material' services. This gap in measurement of cultural ecosystem services is a product of several perceived problems, some of which are not real problems and some of which can be mitigated or even solved without undue difficulty. Because of the fractured nature of the literature, these problems continue to plague the discussion of cultural services. In this paper we discuss several such problems, which although they have been addressed singly, have not been brought together in a single discussion. There is a need for a single, accessible treatment of the importance and feasibility of integrating cultural ecosystem services alongside others. PMID- 23436146 TI - Parents served by assertive community treatment: prevalence, treatment services, and provider attitudes. AB - Assertive Community Treatment (ACT) is an evidence-based practice for individuals with severe mental illness. Although studies estimate at least half of all people with severe mental illness are parents, little is known about ACT policies and services for consumers who are parents. ACT providers from 67 teams completed a survey assessing policies for identifying parent consumers of ACT, estimated prevalence of parent consumers, available treatment services, and attitudes about parent consumers. Participants estimated that 18% of ACT consumers are parents. However, less than half of participants (47.8%) reported formally asking about parental status during intake and only 22.4% reported providing programs or services designed for parent consumers. Most participants (about 80%) reported negative or mixed attitudes about parenting with severe mental illness. Findings suggest the need for more attention and focus on parent consumers, including the formal identification of consumers' parental status and availability of parent related treatment services. PMID- 23436147 TI - The "central vein sign": is there a place for susceptibility weighted imaging in possible multiple sclerosis? AB - OBJECTIVES: Susceptibility weighted imaging (SWI) may have the potential to depict the perivenous extent of white matter lesions (WMLs) in multiple sclerosis (MS). We aimed to assess the discriminatory value of the "central vein sign" (CVS). METHODS: In a 3-T magnetic resonance imaging (MRI) study, 28 WMLs in 14 patients with at least one circumscribed lesion >5 mm and not more than eight non confluent lesions >3 mm were prospectively included. Only WMLs in FLAIR images with a maximum diameter of >5 mm were correlated to their SWI equivalent for CVS evaluation. RESULTS: Five patients fulfilled the revised McDonald criteria for MS and nine patients were given alternative diagnoses. Nineteen MS-WMLs and nine non MS-WMLs >5 mm were detected. Consensus reading found a central vein in 16 out of 19 MS-WMLs (84 %) and in one out of nine non-MS-WMLs (11 %), respectively. The CVS proved to be a highly significant discriminator (P < 0.001) between MS-WMLs and non-MS-WMLs with a sensitivity, specificity, positive and negative predictive value and accuracy of 84 %, 89 %, 94 %, 73 % and 86 %, respectively. Inter-rater agreement was good (kappa = 0.77). CONCLUSIONS: Even though the CVS is not exclusively found in MS-WMLs, SWI may be a useful adjunct in patients with possible MS. KEY POINTS: * MRI continues to yield further information concerning MS lesions. * SWI adds diagnostic information in patients with possible MS. * The "central vein sign" was predominantly seen in MS lesions. * The "central vein sign" helps discriminate between MS and non-MS lesions. PMID- 23436151 TI - Potential of kenaf (Hibiscus cannabinus L.) and corn (Zea mays L.) for phytoremediation of dredging sludge contaminated by trace metals. AB - The potential of kenaf (Hibiscus cannabinus L.) and corn (Zea mays L.) for accumulation of cadmium and zinc was investigated. Plants have been grown in lysimetres containing dredging sludge, a substratum naturally rich in trace metals. Biomass production was determined. Sludge and water percolating from lysimeters were analyzed by atomic absorption spectrometry. No visible symptoms of toxicity were observed during the three- month culture. Kenaf and corn tolerate trace metals content in sludge. Results showed that Zn and Cd were found in corn and kenaf shoots at different levels, 2.49 mg/kg of Cd and 82.5 mg/kg of Zn in kenaf shoots and 2.1 mg/kg of Cd and 10.19 mg/kg in corn shoots. Quantities of extracted trace metals showed that decontamination of Zn and Cd polluted substrates is possible by corn and kenaf crops. Tolerance and bioaccumulation factors indicated that both species could be used in phytoremediation. PMID- 23436150 TI - Cell signaling abnormalities may drive neurodegeneration in familial Alzheimer disease. AB - Presenilins (PSs) are catalytic components of the gamma-secretase complex that produces Abeta peptides. Substrates of gamma-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived gamma-secretase substrates are cleaved at gamma (gamma) sites to produce Abeta while cleavage at the epsilon (epsilon) site produces AICD proposed to function in transcription. In addition to APP, gamma-secretase promotes the epsilon-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling. A common hypothesis suggests that Alzheimer's disease (AD) is caused by Abeta peptides or their products. Treatment of patients with inhibitors of Abeta production however, showed no therapeutic benefits while inducing cytotoxicity. Similarly, treatments with anti-Abeta antibodies yielded disappointing results. Importantly, recent evidence shows that PS familial AD (FAD) mutations cause a loss of gamma secretase cleavage activity at epsilon site of substrates thus inhibiting production of biologically important cell signaling peptides while promoting accumulation of membrane-bound cytotoxic substrates. These data support a hypothesis that FAD mutations may increase neurotoxicity by inhibiting the gamma secretase-catalyzed epsilon cleavage of substrates thus interfering with cell signaling while also promoting accumulation of cytotoxic peptides. Similar mechanisms may explain gamma-secretase inhibitor-associated toxicities observed in clinical trials. Here we discuss evidence that FAD neurodegeneration may be caused by loss of gamma-secretase cleavage function at epsilon sites of substrates. PMID- 23436152 TI - Bilateral scapular fractures in adults. AB - PURPOSE: Bilateral scapular fracture is a very rare injury. Most of these fractures result from electrical shock or epileptic seizure. We treated six patients with such injuries, all of them caused by direct violence. The aim of this study was to report on the patients and to present an overview of the cases published so far. METHODS: Between January 2011 and August 2012, we treated six patients with bilateral scapular fractures (four men and two women, age range 20 78 years). Another 11 cases were found in the literature. All cases were analysed in terms of injury mechanism, fracture pattern and the manner of diagnosis. RESULTS: Our six patients increased the total number of recorded cases to 17 and the number of patients with traumatic bilateral scapular fractures from four to ten. In five of our cases, the injuries were classified as being the result of high-energy trauma. Computed tomography (CT) examination of the affected scapulae was performed in all six cases, in five in combination with 3D CT reconstruction; in one polytraumatised female patient, only axial CT scans were obtained. In all five high-energy trauma cases, bilateral fracture of the scapular body was recorded, of which one was classified as open. Four of the 11 cases found in the literature were caused by direct violence: in six patients, the fractures resulted from muscle spasms associated with epileptiform seizure or electrical shock, and one patient suffered a pathological fracture associated with amyloidosis. The most frequently recorded fracture in all 17 patients (34 fractures) was of the scapular body, i.e. 24 fractures, followed by 12 fractures of the glenoid fossa. CONCLUSION: According to data in the literature, bilateral scapular fracture is a rare injury. One reason may be that the potential incidence is often neglected. With the increasing number of patients with polytrauma, the potential for scapular fracture should always be taken into account, together with the fact that this injury may be bilateral. Of vital importance in diagnosing these injuries is CT scanning, including 3D CT reconstructions. PMID- 23436158 TI - Magnolol pretreatment prevents sepsis-induced intestinal dysmotility by maintaining functional interstitial cells of Cajal. AB - The purpose of this study was to investigate the mechanism by which magnolol treatment prevents lipopolysaccharide (LPS)-induced septic dysmotility in mice. Sepsis was induced by intravenous tail vein injection of LPS (4 mg/kg body weight). Animals were divided into three groups: the magnolol-treated septic group, the placebo-treated septic group, and the control group. Intestinal transit and circular smooth muscle contraction were measured 12 h after LPS injection, and immunocytochemisty was performed to study the morphology of interstitial cells of Cajal (ICCs). Stem cell factor (SCF) expression and c-kit phosphorylation were determined by Western blot analysis, and the mRNA levels of inducible NO synthase (iNOS) were determined by RT-PCR. Nitric oxide (NO) content, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) concentration were detected using commercial kits. Intestinal transit and muscular contractility were significantly lower in the LPS-treated group than in the control group. Immunocytochemical experiments showed that the total number of ICCs, and the total and average lengths of the ICC processes were significantly decreased in the LPS-treated group compared with those in the control group. In LPS-treated animals, magnolol pretreatment significantly accelerated intestinal transit, increased circular muscle contraction, and prevented ICC morphology changes. Phosphorylation of c-kit and expression of SCF were significantly downregulated in LPS-treated animals compared with control animals. Magnolol pretreatment prevented sepsis-induced decreases in c-kit phosphorylation and SCF expression in LPS-treated animals. Magnolol pretreatment prevented the sepsis induced increase in NO concentration, iNOS expression, and MDA concentration, and decrease in SOD activity in LPS-treated animals. Our results suggest that magnolol treatment prevents sepsis-induced intestinal dysmotility by regulating SCF/c-kit and NO signaling to maintain functional ICCs. PMID- 23436159 TI - Gustatory sensory cells express a receptor responsive to protein breakdown products (GPR92). AB - The ingestion of dietary protein is of vital importance for the maintenance of fundamental physiological processes. The taste modality umami, with its prototype stimulus, glutamate, is considered to signal the protein content of food. Umami was thought to be mediated by the heterodimeric amino acid receptor, T1R1 + T1R3. Based on knockout studies, additional umami receptors are likely to exist. In addition to amino acids, certain peptides can also elicit and enhance umami taste suggesting that protein breakdown products may contribute to umami taste. The recently deorphanized peptone receptor, GPR92 (also named GPR93; LPAR5), is expressed in gastric enteroendocrine cells where it responds to protein hydrolysates. Therefore, it was of immediate interest to investigate if the receptor GPR92 is expressed in gustatory sensory cells. Using immunohistochemical approaches we found that a large population of cells in murine taste buds was labeled with an GPR92 antibody. A molecular phenotyping of GPR92 cells revealed that the vast majority of GPR92-immunoreactive cells express PLCbeta2 and can therefore be classified as type II cells. More detailed analyses have shown that GPR92 is expressed in the majority of T1R1-positive taste cells. These results indicate that umami cells may respond not only to amino acids but also to peptides in protein hydrolysates. PMID- 23436160 TI - Aligning physician and hospital incentives: editorial comment. PMID- 23436162 TI - Implant material and design alter construct stiffness in distal femur locking plate fixation: a pilot study. AB - BACKGROUND: Construct stiffness affects healing of bones fixed with locking plates. However, variable construct stiffness reported in the literature may be attributable to differing test configurations and direct comparisons may clarify these differences. QUESTIONS/PURPOSES: We therefore asked whether different distal femur locking plate systems and constructs will lead to different (1) axial and rotational stiffness and (2) fatigue under cyclic loading. METHODS: We investigated four plate systems for distal femur fixation (AxSOS, LCP, PERI-LOC, POLYAX) of differing designs and materials using bone substitutes in a distal femur fracture model (OTA/AO 33-A3). We created six constructs of each of the four plating systems. Stiffness under static and cyclic loading and fatigue under cyclic loading were measured. RESULTS: Mean construct stiffness under axial loading was highest for AxSOS (100.8 N/mm) followed by PERI-LOC (80.8 N/mm) and LCP (62.6 N/mm). POLYAX construct stiffness testing showed the lowest stiffness (51.7 N/mm) with 50% stiffness of AxSOS construct testing. Mean construct stiffness under torsional loading was similar in the group of AxSOS and PERI-LOC (3.40 Nm/degree versus 3.15 Nm/degree) and in the group of LCP and POLYAX (2.63 Nm/degree versus 2.56 Nm/degree). The fourth load level of > 75,000 cycles was reached by three of six AxSOS, three of six POLYAX, and two of six PERI-LOC constructs. All others including all LCP constructs failed earlier. CONCLUSIONS: Implant design and material of new-generation distal femur locking plate systems leads to a wide range of differences in construct stiffness. CLINICAL RELEVANCE: Assuming construct stiffness affects fracture healing, these data may influence surgical decision-making in choosing an implant system. PMID- 23436161 TI - Nano-ceramic composite scaffolds for bioreactor-based bone engineering. AB - BACKGROUND: Composites of biodegradable polymers and bioactive ceramics are candidates for tissue-engineered scaffolds that closely match the properties of bone. We previously developed a porous, three-dimensional poly (D,L-lactide-co glycolide) (PLAGA)/nanohydroxyapatite (n-HA) scaffold as a potential bone tissue engineering matrix suitable for high-aspect ratio vessel (HARV) bioreactor applications. However, the physical and cellular properties of this scaffold are unknown. The present study aims to evaluate the effect of n-HA in modulating PLAGA scaffold properties and human mesenchymal stem cell (HMSC) responses in a HARV bioreactor. QUESTIONS/PURPOSES: By comparing PLAGA/n-HA and PLAGA scaffolds, we asked whether incorporation of n-HA (1) accelerates scaffold degradation and compromises mechanical integrity; (2) promotes HMSC proliferation and differentiation; and (3) enhances HMSC mineralization when cultured in HARV bioreactors. METHODS: PLAGA/n-HA scaffolds (total number = 48) were loaded into HARV bioreactors for 6 weeks and monitored for mass, molecular weight, mechanical, and morphological changes. HMSCs were seeded on PLAGA/n-HA scaffolds (total number = 38) and cultured in HARV bioreactors for 28 days. Cell migration, proliferation, osteogenic differentiation, and mineralization were characterized at four selected time points. The same amount of PLAGA scaffolds were used as controls. RESULTS: The incorporation of n-HA did not alter the scaffold degradation pattern. PLAGA/n-HA scaffolds maintained their mechanical integrity throughout the 6 weeks in the dynamic culture environment. HMSCs seeded on PLAGA/n-HA scaffolds showed elevated proliferation, expression of osteogenic phenotypic markers, and mineral deposition as compared with cells seeded on PLAGA scaffolds. HMSCs migrated into the scaffold center with nearly uniform cell and extracellular matrix distribution in the scaffold interior. CONCLUSIONS: The combination of PLAGA/n-HA scaffolds with HMSCs in HARV bioreactors may allow for the generation of engineered bone tissue. CLINICAL RELEVANCE: In cases of large bone voids (such as bone cancer), tissue-engineered constructs may provide alternatives to traditional bone grafts by culturing patients' own MSCs with PLAGA/n-HA scaffolds in a HARV culture system. PMID- 23436163 TI - Double acetabular wall--a misleading point for hip arthroplasty: an anatomical, radiological, clinical study. AB - PURPOSE: Despite the great attention focused on cup positioning in primary total hip arthroplasty (PTHA), it is surprising to find so few studies that have dealt with cup placement. A common thwarting problem for correct cup placement during PTHA is the existence of osteophytes, which obscure the anatomical landmarks. In this study we aimed to evaluate the morphology of acetabular osteophyte formation in patients with osteoarthritis. METHOD: We evaluated 276 patients with hip complaints, using plain X-rays and CT scans. RESULTS: Of these patients, 57 underwent surgery. We developed a staging system for central osteophytes in hip osteoarthritis based on the radiographic and anatomical findings of our patients. CONCLUSION: We recommend routine use of CT scans for patients scheduled for PTHA in order to assess the stage of osteophyte before surgery and, thus, reduce the risk of failure resulting from the interrupted acetabular landmarks. PMID- 23436165 TI - The ineligible patient: how to treat patients not included in clinical studies. AB - PURPOSE: Targeted therapies are currently the standard of care for metastatic renal cell carcinoma (mRCC). Five VEGF pathway inhibitors (sorafenib, sunitinib, bevacizumab in combination with interferon-alpha, pazopanib, and axitinib) and two mTOR inhibitors (everolimus and temsirolimus) are now FDA approved for mRCC based on results from phase III randomized clinical trials (RCTs). However, several subgroups of patients are excluded from enrollment due to strict eligibility criteria. The toxicity and efficacy of targeted therapies in these populations are unknown. METHODS: PubMed was searched for citations of the pivotal phase III RCTs leading to FDA approval. These publications were cross referenced with their associated entries on www.ClinicalTrials.gov, and both were abstracted for eligibility criteria for patient enrollment. Based on this data, PubMed was searched for both prospective and retrospective studies evaluating toxicity and efficacy of targeted therapies for mRCC in these ineligible patient subgroups. RESULTS: We reviewed published toxicity and efficacy data in several ineligible patient subgroups, including patients with non-clear cell renal cell carcinoma, poor performance status, poor renal function, CNS metastases, significant cardiac comorbidities, and prior systemic therapy. CONCLUSIONS: Targeted therapies appear to be safe in most ineligible patient populations, including patients with poor renal function. However, patients with preexisting cardiac comorbidities are at greater risk of developing cardiac toxicity on sunitinib. Targeted therapies appear to have some efficacy in maintaining stable disease in these subgroups, but are limited to rare partial responses. Prospective cohort studies are needed to accurately assess the safety and efficacy of targeted therapies in ineligible patient subgroups. PMID- 23436167 TI - Detection and occurrence of microconstituents in reclaimed water used for irrigation--a potentially overlooked source. AB - An online SPE-HPLC-HESI-MS/MS method and an online SPE-HPLC-APPI-MS/MS method were developed to analyze 72 microconstituents in reclaimed water. In this study, 55 reclaimed water samples were collected from the sprinkler system for a year long period at Florida International University Biscayne Bay Campus, where reclaimed water was reused for daily irrigation. Analysis results showed that several analytes were continuously detected in all reclaimed water samples and others will show rather transient signal increases. Coprostanol, bisphenol A, and DEET's maximum concentration exceeded 10,000 ng/L. The four most frequently detected compounds were diphenhydramine (100%), DEET (98%), atenolol (98%) and carbamazepine (96%). PMID- 23436166 TI - Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with a disease-specific mortality of approximately 40 %. The association of MCC with a recently discovered polyomavirus, combined with the increased incidence and mortality of MCC among immunocompromised patients, highlight the importance of the immune system in controlling this cancer. Initial management of MCC is summarized within the NCCN guidelines and in recently published reviews. The high rate of recurrent and metastatic disease progression in MCC, however, presents a major challenge in a cancer that lacks mechanism-based, disease-specific therapies. Traditional treatment approaches have focused on cytotoxic chemotherapy that, despite frequent initial efficacy, rarely provides durable responses and has high morbidity among the elderly. In addition, the immunosuppressive nature of chemotherapy is of concern when treating a virus associated cancer for which survival is unusually tightly linked to immune function. With a median survival of 9.6 months after development of an initial metastasis (n = 179, described herein), and no FDA-approved agents for this cancer, there is an urgent need for more effective treatments. We review diverse management options for patients with advanced MCC, with a focus on emerging and mechanism-based therapies, some of which specifically target persistently expressed viral antigens. These treatments include single-dose radiation and novel immunotherapies, some of which are in clinical trials. Due to their encouraging efficacy, low toxicity, and lack of immune suppression, these therapies may offer viable alternatives to traditional cytotoxic chemotherapy. PMID- 23436168 TI - Assessment of silicone as support to investigate the transformation routes of organic chemicals under environmental conditions and UV exposure. Application to selected fungicides. AB - The suitability of bulk silicone as support to follow the degradation of chemical compounds under environmental conditions and UV radiation is illustrated selecting three fungicides (fenhexamid, FEN; triadimenol, TRI and difenoconazole, DIF) as model compounds. These precursor species were first absorbed in silicone supports (10 mm length * 2 mm i.d. and 0.5 mm thickness) and then kept outdoors for several days (up to 2 months) or exposed to UV radiation (254 nm), from a low pressure mercury lamp, in the laboratory. Degradation of precursor fungicides and by-products formation was followed by liquid chromatography (LC) quadrupole time of-flight (QTOF) mass spectrometry (MS), after desorption of silicone supports using 0.5 mL of acetonitrile. Half-lives (t(1/2)) measured under UV exposure varied from 5 to 100 min. As regards environmental conditions, the most stable fungicide was DIF, degraded by just 15 % after 2 months; whereas, t(1/2) values of 30 and 83 h were calculated for FEN during summer and autumn, respectively. Supports contained by-products arising from precursor species through de chlorination, cleavage, hydroxylation, intra-molecular cyclation and oligomerization reactions. Most of them have been previously identified in soil surface, vegetable leaves and water after application of fungicides in agriculture fields. The low cost of silicone tubes (ca. 0.4 Euros), added to their excellent chemical stability and capability to retain precursor species and their by-products, make them ideal supports to follow the transformation routes of organic compounds under environmental and simulated conditions, even for relatively stable species with t(1/2) in the range of weeks or months. PMID- 23436169 TI - Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS. AB - The antihelminthic drug Levamisole can enhance cocaine effects by conversion into the amphetamine-like drug aminorex. We describe an LC-MS method for the determination of levamisole and its metabolite aminorex in human urine. Selectivity is given, calibration curves were linear within the calibration range 2.5-250 ng/mL; limits of the method were LoD 0.51 ng/mL, LoQ 1.02 ng/mL for levamisole and LoD 0.65 ng/mL, LoQ 0.76 ng/mL for aminorex. Precision data was in accordance with the guidelines (intraday precision for aminorex ranged between 5.75 and 11.0 % for levamisole between 8.36 and 10.9 %; interday precision for levamisole 10.9-16.9 % and for aminorex 7.64-12.7 %; accuracy data for levamisole -1.96 to -14.3 % and for aminorex-11.9 to-18.5 %). The validated method was successfully applied to study the urinary excretion of levamisole after the administration of 100 mg of levamisole orally. Levamisole and aminorex could be detected in post-administration urine samples. Levamisole could be detected up to 39 h after ingestion, while aminorex was detectable up to 54 h. Maximum aminorex concentrations were 45 ng/mL urine. Further metabolites of levamisole after oral ingestion by means of liquid chromatography hybrid quadrupole time-of-flight high resolution mass spectrometry (LC-QTOF-HRMS) were identified. Only 0.5 % of the ingested drug was quantified as unchanged levamisole in urine. Besides aminorex, five isomers of aminorex and 4 hydroxy-metabolites of aminorex or its isomers were found. Furthermore, levamisole is also hydroxylated and eliminated free or conjugated with sulfate or glucuronide into urine. PMID- 23436170 TI - Recent advances in microchip electrophoresis for amino acid analysis. AB - With the maturation of microfluidic technologies, microchip electrophoresis has been widely employed for amino acid analysis owing to its advantages of low sample consumption, reduced analysis time, high throughput, and potential for integration and automation. In this article, we review the recent progress in amino acid analysis using microchip electrophoresis during the period from 2007 to 2012. Innovations in microchip materials, surface modification, sample introduction, microchip electrophoresis, and detection methods are documented, as well as nascent applications of amino acid analysis in single-cell analysis, microdialysis sampling, food analysis, and extraterrestrial exploration. Without doubt, more applications of microchip electrophoresis in amino acid analysis may be expected soon. PMID- 23436171 TI - Total and inorganic arsenic in dietary supplements based on herbs, other botanicals and algae--a possible contributor to inorganic arsenic exposure. AB - The content of total and inorganic arsenic was determined in 16 dietary supplements based on herbs, other botanicals and algae purchased on the Danish market. The dietary supplements originated from various regions, including Asia, Europe and USA. The contents of total and inorganic arsenic was determined by inductively coupled plasma mass spectrometry (ICP-MS) and anion exchange HPLC-ICP MS, respectively, were in the range of 0.58 to 5.0 mgkg(-1) and 0.03 to 3.2 mg kg(-1), respectively, with a ratio between inorganic arsenic and total arsenic ranging between 5 and 100%. Consumption of the recommended dose of the individual dietary supplement would lead to an exposure to inorganic arsenic within the range of 0.07 to 13 MUg day(-1). Such exposure from dietary supplements would in worst case constitute 62.4% of the range of benchmark dose lower confidence limit values (BMDL01 at 0.3 to 8 MUg kg bw(-1) kg(-1) day(-1)) put down by European Food Safety Authority (EFSA) in 2009, for cancers of the lung, skin and bladder, as well as skin lesions. Hence, the results demonstrate that consumption of certain dietary supplements could contribute significantly to the dietary exposure to inorganic arsenic at levels close to the toxicological limits established by EFSA. PMID- 23436172 TI - 3rd International Cancer Research Symposium 2012: defining & translating science for disease prevention and therapy, Kolkata, West Bengal, India, December 18-21, 2012. PMID- 23436173 TI - Induction of endodormancy in crown buds of leafy spurge (Euphorbia esula L.) implicates a role for ethylene and cross-talk between photoperiod and temperature. AB - Leafy spurge is a model for studying well-defined phases of dormancy in underground adventitious buds (UABs) of herbaceous perennial weeds, which is a primary factor facilitating their escape from conventional control measures. A 12 week ramp down in both temperature (27 -> 10 degrees C) and photoperiod (16 -> 8 h light) is required to induce a transition from para- to endo-dormancy in UABs of leafy spurge. To evaluate the effects of photoperiod and temperature on molecular networks of UABs during this transition, we compared global transcriptome data-sets obtained from leafy spurge exposed to a ramp down in both temperature and photoperiod (RDtp) versus a ramp down in temperature (RDt) alone. Analysis of data-sets indicated that transcript abundance for genes associated with circadian clock, photoperiodism, flowering, and hormone responses (CCA1, COP1, HY5, MAF3, MAX2) preferentially increased in endodormant UABs. Gene-set enrichment analyses also highlighted metabolic pathways involved in endodormancy induction that were associated with ethylene, auxin, flavonoids, and carbohydrate metabolism; whereas, sub-network enrichment analyses identified hubs (CCA1, CO, FRI, miR172A, EINs, DREBs) of molecular networks associated with carbohydrate metabolism, circadian clock, flowering, and stress and hormone responses. These results helped refine existing models for the transition to endodormancy in UABs of leafy spurge, which strengthened the roles of circadian clock associated genes, DREBs, COP1-HY5, carbohydrate metabolism, and involvement of hormones (ABA, ethylene, and strigolactones). We further examined the effects of ethylene by application of 1-aminocyclopropane-1-carboxylate (ACC) to paradormant plants without a ramp down treatment. New vegetative growth from UABs of ACC-treated plants resulted in a dwarfed phenotype that mimicked the growth response in RDtp induced endodormant UABs. The results of this study provide new insights into dormancy regulation suggesting a short-photoperiod treatment provides an additive cross-talk effect with temperature signals that may impact ethylene's effect on AP2/ERF family members. PMID- 23436174 TI - Mental health problems and recidivism among detained male adolescents from various ethnic origins. AB - This study examines differences in self-reported mental health problems between detained youths from Dutch, Moroccan, and Surinamese origin and the usefulness of mental health problems to predict violent and property recidivism in these juveniles. A sample of 296 detained boys aged between 12 and 18 years were assessed by means of the Strengths and Difficulties Questionnaire (SDQ). Official information regarding criminal history and recidivism was collected 3-6 years later. In general, Dutch youths and Surinamese youths reported more conduct problems than Moroccan youths, while Dutch youths also reported more hyperactivity than Surinamese youths. Mental health problems were not predictive of violent recidivism in any of the ethnic groups, while being related with property recidivism in Dutch and Surinamese youths. The current study showed that Moroccan youths present themselves on the SDQ as a less seriously disturbed group of youths than their Dutch and Surinamese counterparts. Our results also clearly showed that SDQ self-report scores are not predictive of future violent crimes in any of the three ethnic groups. Implications of the findings and limitations of the current study are discussed. PMID- 23436175 TI - In memoriam: Professor Cornelis Schroder--8 April 1951-19 September 2012. PMID- 23436176 TI - Cystatin C adaptation in the first month of life. AB - Je-Hyan Lee et al. have published a study on cystatin C concentrations in the first 30 days of life in 127 pre-term and 119 term neonates in this edition of Pediatric Nephrology, thereby closing a knowledge gap of detailed cystatin C concentrations beyond 72 h of life by day of life and by post-conceptional age. While the study objective has merit and a large number of measurements were included, there are some methodological limitations that bring the validity of the data into question as pure reference intervals for children up to 1 month of age, mostly because of the inclusion of patients that potentially could have an impaired glomerular filtration rate (GFR), for instance due to exposure to nephrotoxic drugs. We discuss the strengths and weaknesses of the study and outline an approach to definitely close this knowledge gap. We call for a worldwide collaboration to use Box-Cox transformations similar to the methodology used with growth charts to calculate age-independent z-scores and percentiles of neonatal and infant markers of GFR. This could also lead to better definitions of acute kidney injury in infants if GFR markers cross the percentiles based on post conceptional or chronological age. PMID- 23436177 TI - Cure of relapsing nephrosis by an allogeneic marrow graft for chronic myelogenous leukemia. AB - BACKGROUND: Minimal-change nephrotic syndrome has recently been attributed to an immature, dysfunctional T-cell population. CASE-DIAGNOSIS/TREATMENT: A woman, now 23 years old, developed nephrotic syndrome when she was 6 years old. Despite treatment with steroids and immunosuppressants such as cyclosporine, mizoribine, mycophenolate mofetil, and tacrolimus, the patient relapsed 14 times. At the age of 19 years, she developed chronic myelogenous leukemia, against which imatinib achieved cytogenetic remission. The patient received an allogeneic bone marrow graft transplantation from an unrelated marrow bank donor, with an uncomplicated recovery and molecular genetic remission. Immunosuppressants were withdrawn within 6 months. The patient is now without drug treatment. Complete remission of nephrotic syndrome has also been maintained for over 4 years without any drug administration. CONCLUSIONS: The patient's course supports suggestions that immunological dysfunction in nephrosis is associated with abnormality of immature, relatively unclassified T cells (CD34(+)) representing hematopoietic stem cells, as opposed to mature T cells (CD34(-)). PMID- 23436178 TI - Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs. AB - The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5-99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination. PMID- 23436179 TI - Neurobehavioral and genotoxic evaluation of (-)-linalool in mice. AB - (-)-Linalool is a monoterpene compound commonly found as a major component of the essential oil of several aromatic species. It has been shown to exert several actions in the central nervous system (CNS) and is able to inhibit glutamate receptors. This study investigated the effect of (-)-linalool in depression and genotoxicity models. Mice were given (-)-linalool (10, 50, 100 or 200 mg/kg i.p.) and were evaluated using the tail suspension test (TST). Genotoxic and antigenotoxic effects in blood and brain were investigated using the alkaline comet assay. In the TST, the animals that received doses of 100 and 200 mg/kg presented a decrease in immobility times. No increase in DNA damage was observed in either tissue, and resistance to DNA oxidative damage induced by hydrogen peroxide did not increase. (-)-Linalool showed an antidepressant-like activity in the TST and was unable to cause damage/protection to DNA in brain tissue and peripheral blood. This investigation provides evidence of an important effect of (-)-linalool on the CNS; however, more studies are necessary to support its possible clinical uses. PMID- 23436181 TI - Increased density of dystrophin protein in the lateral versus the vermal mouse cerebellum. AB - Dystrophin, present in muscle, also resides in the brain, including cerebellar Purkinje neurons. The cerebellum, although historically associated with motor abilities, is also implicated in cognition. An absence of brain dystrophin in Duchenne muscular dystrophy (DMD) and in the mdx mouse model results in cognitive impairments. Localization studies of cerebellar dystrophin, however, have focused on the vermal cerebellum, associated with motor function, and have not investigated dystrophin distribution in the lateral cerebellum, considered to mediate cognitive function. The present study examined dystrophin localization in vermal and lateral cerebellar regions and across subcellular areas of Purkinje neurons in the mouse using immunohistochemistry. In both vermal and lateral cerebellum, dystrophin was restricted to puncta on somatic and dendritic membranes of Purkinje neurons. The density of dystrophin puncta was greater in the lateral than the vermal region. Neither the size of puncta nor the area of Purkinje neuron somata differed between regions. Results support the view that cognitive deficits in the DMD and the mdx model may be mediated by the loss of dystrophin, particularly in the lateral cerebellum. Findings have important implications for future studies examining the neurophysiological sequelae of neuronal dystrophin deficiency and the role of the lateral cerebellum in cognition. PMID- 23436180 TI - Regulation of ribosome biogenesis by nucleostemin 3 promotes local and systemic growth in Drosophila. AB - Nucleostemin 3 (NS3) is an evolutionarily conserved protein with profound roles in cell growth and viability. Here we analyze cell-autonomous and non-cell autonomous growth control roles of NS3 in Drosophila and demonstrate its GTPase activity using genetic and biochemical assays. Two null alleles of ns3, and RNAi, demonstrate the necessity of NS3 for cell autonomous growth. A hypomorphic allele highlights the hypersensitivity of neurons to lowered NS3 function. We propose that NS3 is the functional ortholog of yeast and human Lsg1, which promotes release of the nuclear export adapter from the large ribosomal subunit. Release of the adapter and its recycling to the nucleus are essential for sustained production of ribosomes. The ribosome biogenesis role of NS3 is essential for proper rates of translation in all tissues and is necessary for functions of growth-promoting neurons. PMID- 23436182 TI - Removal of nutrient limitations in forest gaps enhances growth rate and resistance to cavitation in subtropical canopy tree species differing in shade tolerance. AB - A 4-year fertilization experiment with nitrogen (N) and phosphorus (P) was carried out in natural gaps of a subtropical forest in northeastern Argentina. Saplings of six dominant canopy species differing in shade tolerance were grown in five control and five N + P fertilized gaps. Hydraulic architectural traits such as wood density, the leaf area to sapwood area ratio (LA : SA), vulnerability to cavitation (P50) and specific and leaf-specific hydraulic conductivity were measured, as well as the relative growth rate, specific leaf area (SLA) and percentage of leaf damage by insect herbivores. Plant growth rates and resistance to drought-induced embolisms increased when nutrient limitations were removed. On average, the P50 of control plants was -1.1 MPa, while the P50 of fertilized plants was -1.6 MPa. Wood density and LA : SA decreased with N + P additions. A trade-off between vulnerability to cavitation and efficiency of water transport was not observed. The relative growth rate was positively related to the total leaf surface area per plant and negatively related to LA : SA, while P50 was positively related to SLA across species and treatments. Plants with higher growth rates and higher total leaf area in fertilized plots were able to avoid hydraulic dysfunction by becoming less vulnerable to cavitation (more negative P50). Two high-light-requiring species exhibited relatively low growth rates due to heavy herbivore damage. Contrary to expectations, shade-tolerant plants with relatively high resistance to hydraulic dysfunction and reduced herbivory damage were able to grow faster. These results suggest that during the initial phase of sapling establishment in gaps, species that were less vulnerable to cavitation and exhibited reduced herbivory damage had faster realized growth rates than less shade-tolerant species with higher potential growth rates. Finally, functional relationships between hydraulic traits and growth rate across species and treatments were maintained regardless of soil nutrient status. PMID- 23436183 TI - Signal inhibitory receptor on leukocytes-1 (SIRL-1) negatively regulates the oxidative burst in human phagocytes. AB - ROS production is an important effector mechanism mediating intracellular killing of microbes by phagocytes. Inappropriate or untimely ROS production can lead to tissue damage, thus tight regulation is essential. We recently characterized signal inhibitory receptor on leukocytes-1 (SIRL-1) as an inhibitory receptor expressed by human phagocytes. Here, we demonstrate that ligation of SIRL-1 dampens Fc receptor-induced ROS production in primary human phagocytes. In accordance, SIRL-1 engagement on these cells impairs the microbicidal activity of neutrophils, without affecting phagocytosis. The inhibition of ROS production may result from reduced ERK activation, since co-ligation of Fc receptors and SIRL-1 on phagocytes inhibited phosphorylation of ERK. Importantly, we demonstrate that microbial and inflammatory stimuli cause rapid downregulation of SIRL-1 expression on the surface of primary neutrophils and monocytes. In accordance, SIRL-1 expression levels on neutrophils in bronchoalveolar lavage fluid from patients with neutrophilic airway inflammation are greatly reduced. We propose that SIRL-1 on phagocytes sets an activation threshold to prevent inappropriate production of oxygen radicals. Upon infection, SIRL-1 expression is downregulated, allowing microbial killing and clearance of the pathogen. PMID- 23436184 TI - The association of type 2 diabetes patient and spouse illness representations with their well-being: a dyadic approach. AB - BACKGROUND: The aim of this study was to examine the relation between certain illness representations and the physical and psychological well-being of persons with type 2 diabetes mellitus and their spouses. PURPOSE: In this study, we examined the relation of type 2 diabetes patients and their spouses' representations of illness consequences and timeline (chronicity and cyclicality/predictability) to the physical and psychological well-being of both. The interaction between patient and spouse illness representations was also studied. METHODS: A dyadic analysis approach was employed, while the Actor Partner Interdependence Model was used to examine dyadic effects. One hundred and sixty-eight individuals nested in 84 couples participated. RESULTS: Regarding illness representations, both actor (i.e., the effects of a person's own characteristics on own outcomes) and partner (i.e., the effects of the partner's characteristics on a person's outcomes) effects were identified but only for patients' well-being. Certain significant interactions were also found: patients' timeline-cyclical representations were weakly associated with their anxiety and depression symptoms when spouses perceived diabetes as less unpredictable. Also, spouses' perceptions of consequences were more strongly related to their anxiety when patients perceived diabetes as less burdensome. CONCLUSIONS: Overall, the findings indicate a type of synergy between patient and spouse illness representations. They also emphasize the interdependence between diabetes patients and their partners, and the need to examine adaptation to illness within a dyadic-regulation framework as well. PMID- 23436185 TI - Health anxiety, cognitive coping, and emotion regulation: a latent variable approach. AB - BACKGROUND: Health anxiety, the fear or conviction of suffering from a severe disorder, represents a dimensional and multifactorial construct consisting of cognitive, behavioral, affective, and perceptual components. It has recently been proposed that dysfunctional emotion regulation strategies contribute to health anxiety, but the empirical evidence for this claim is sparse. PURPOSE: The current research was aimed at broadly exploring and clarifying possible relationships between dimensions of health anxiety and cognitive coping and emotion regulation strategies. METHOD: In two studies with non-clinical samples (n study 1 = 172; n study 2 = 242), health anxiety, cognitive coping, and emotion regulation strategies were assessed using multidimensional self-report measures. Functional (e.g., reappraisal) and dysfunctional (e.g., rumination) cognitive coping and emotion regulation strategies were differentiated. RESULTS: Using structural equation modeling, the results of Study 1 revealed significant and consistent associations between the dimensions of health anxiety and dysfunctional coping and emotion regulation strategies. Study 2 replicated and extended the main findings of Study 1 by demonstrating that the associations between health anxiety and strategies of coping and emotion regulation were independent of the current level of depressive symptoms. CONCLUSION: Health anxiety was found to be associated with dysfunctional coping and emotion regulation strategies (e.g., suppression). The positive associations between behavioral dimensions of health anxiety (e.g., seeking reassurance) and dysfunctional coping strategies may suggest that behavioral dimensions of health anxiety serve as a compensatory strategy to overcome difficulties in cognitive coping. PMID- 23436186 TI - Refining estimates of catastrophic healthcare expenditure: an application in the Indian context. AB - Empirics of catastrophic healthcare expenditure, especially in the Indian context, are often based on consumption expenditure data that inadequately informs about the ability to pay. Use of such data can generate a pro-rich bias in the estimation of catastrophic expenditure thereby suggesting greater concentration of such expenditures among richer households. To improve upon the existing approach, this paper suggests a multidimensional approach to comprehend the incidence of catastrophic expenditure. Here, we integrate the information on health expenditure with other social and economic parameters of deprivation. An empirical illustration is provided by using nationally representative survey on morbidity and healthcare in India. The results of the multidimensional approach are consistent with the theoretical underpinnings of the ability-to-pay approach and emphasizes on the severity of the problem in rural areas. The suggested methodology is flexible and allows for context-specific prioritization in selection of parameters of vulnerability while estimating the incidence of catastrophic expenditures. PMID- 23436188 TI - Voriconazole is cytotoxic at locally delivered concentrations: a pilot study. AB - BACKGROUND: Fungal infections are rare but major problems when they involve orthopaedic implants. Preferred treatment in North America is two-staged: resection and then delayed reconstruction, with local delivery of an antifungal between stages. The effect of voriconazole, a hydrophobic antifungal, on local tissues and wound healing is unclear. QUESTIONS/PURPOSES: We asked: (1) Is voriconazole cytotoxic to fibroblasts or osteoblasts at target concentrations for local delivery? And (2) if cytotoxic, can fibroblasts or osteoblasts resume proliferation after voriconazole is removed? METHODS: We exposed 5000 fibroblasts or osteoblasts/well to voriconazole concentrations of 0, 1, 5, 10, 25, 100, 500, 1000, 5000, 10,000, and 20,000 MUg/mL (n=4 wells/concentration) in 24-well plates. At 3 and 7 days, cell growth was assessed with alamarBlue(r) and light microscopy. After Day 7, exposure to voriconazole was stopped and incubation continued for 4 days in medium with no voriconazole. On Day 11, cell growth (recovery) was assessed with alamarBlue(r) and light microscopy. RESULTS: Increasing voriconazole concentration to more than 100 MUg/mL decreased osteoblast and fibroblast growth. Cell growth recovered after 7 days' exposure to 1000 MUg/mL or less. CONCLUSIONS: Voriconazole is cytotoxic to osteoblasts and fibroblasts, but cell growth recovers over 4 days after exposure to 1000 MUg/mL or less. CLINICAL RELEVANCE: Cytotoxicity seen from voriconazole to mouse osteoblasts and fibroblasts occurs at concentrations achievable clinically from local delivery. It may be prudent to limit the dose of voriconazole in antibiotic loaded bone cement. PMID- 23436189 TI - Surgical publishing. PMID- 23436187 TI - Analysis of genetic variability and phylogenetic analysis of selected Czech and French strains of rabbit haemorrhagic disease virus (RHDV). AB - The objective of this study was to analyse the genetic variability and phylogenetic analysis of six strains of rabbit haemorrhagic disease virus (RHDV), including four Czech strains (CAMPV-351, CAMPV-561, CAMPV-562, CAMPV-558) and two French strains (Fr-1, Fr-2), on the basis of a fragment of the VP60 capsid structural protein-coding gene N-terminal region. The results of our own studies were compared to 26 RHDV strains obtained from GenBank. The analysis of the genetic variability of six RHDV strains indicated that the CAMPV-561 strain is the most genetically variable. Less variable were the Fr-1 and Fr-2 strains, while the least variable was CAMPV-351. In turn, the genetic distance among the six analysed strains and 26 strains obtained from GenBank was the greatest for CAMPV-351 and Whn/China [11.3 % according to the observed divergence (OD) method and 12.2 % according to the maximum likelihood (ML) method], while it was the lowest for CAMPV-351 and FRG (0.8 % in both the OD and ML methods). In turn, the scale of the genetic distances among the six analysed strains and five RHDVa strains (99-05, NY-01, Whn/China, Triptis, Iowa2000) ranged from 9.3-10.3 % in the OD method to 10.3-13.7 % in the ML method. The image of phylogenetic dependencies generated for the strains analysed and those obtained from GenBank revealed their distribution to be in five genetic groups (G1-G5), whereas the analysed strains were included in genetic groups 2 and 3. PMID- 23436190 TI - Immunization in practice - clearing the cobwebs. AB - Vaccination is one of the most cost effective methods of prevention of diseases without even raising the socioeconomic status of the community. Small pox eradication from the world is the perfect example of the role of mass vaccination of the entire community of the universe. India is feeling proud to be polio free for the last 1 y and it is expected that the world would be polio free very soon. The most important purpose of National immunization program of any country is to prevent deaths due to vaccine preventable diseases followed by severe disability and morbidity in that order. Therefore keeping in view the above principle, Govt of India has included Baciilus Calmette Guerrin (BCG), Oral polio vaccine (OPV), Diphtheria, Pertussis & Tetanus (DPT), Measles, Hepatitis-B and now Hemophilus influenza type b (Hib) vaccines in the armamentarium of the National schedule. Every child in the country should receive basic vaccines as per Govt. of India schedule and is available free of cost at all health centers in India. PMID- 23436191 TI - Molecular genetic studies in isolated growth hormone deficiency (IGHD). AB - OBJECTIVE: To screen Isolated Growth Hormone Deficiency (IGHD) patients with congenital Familial Isolated (FIGHD) and Nonfamilial Isolated Growth Hormone Deficiency (NFIGHD) for GH1gene deletions (6.7 kb,7.6 kb,7 kb) and Growth hormone releasing hormone receptor GHRHR(E72X) gene mutation and study genotype/phenotype correlation in this multicentre study. METHODS: Clinical, auxologic (Ht.SDS <= 2.5), hormonal and MRI evaluation of hypothalamic/pituitary (HP) axis, IGF1, IGFBP3 estimation and GH stimulation test confirmed IGHD in 107 patients. Of these 107 patients, 97 consented for molecular genetic studies. Height, weight and Bone Age (BA) were obtained. PCR based restriction digestion method was used for molecular genetic analysis of patients and families. Ethics committee approval was obtained. RESULTS: Based on the genotype, these 97 patients (M60,F37;1.62:1) age 3 mo to 17 y belonging to 80 families (consanguinity, 15/80), were categorized into Group I with GH1 gene deletion, n = 17 (17.5 %) from 14 families, Group II with GHRHR (E72X) mutation n = 34 (35 %) from 24 families, Group III, n = 46 (47 %) from 42 families having neither of these deletions/mutations (but with sibling involvement). In Group I, homozygous 6.7 kb and 7.6 kb deletions involved 76 % and 18 %. 6.7 kb deletion with characteristic IGHD phenotype predominated in nonconsanguineous community from Rajasthan having lowest mean FBS (55.6 mg/dl, p < 0.001) and peak GH (0.03 ng/dl, p < 0.01). In Group II phenotype was IB. Twenty one of the 23 FIGHD had homozygous GHRHR(E72X) mutation and four with IGHD had heterozygous GHRHR(E72X) mutation. IGF1 and IGFBP3 were low. MRI showed hypoplastic anterior pituitary (APH) in all. Group III is not discussed in detail. CONCLUSIONS: Genetic background is more likely in congenital Growth Hormone Deficiency (GHD). GH1gene deletions and GHRHR(E72X) mutation with characteristic phenotypes are encountered in North Western region of India. Regional studies are essential. PMID- 23436192 TI - Role of hematological parameters in predicting retinopathy of prematurity (ROP) in preterm neonates. AB - OBJECTIVES: To study the role of hematological parameters in predicting retinopathy of prematurity (ROP) in preterm neonates. METHOD: Two hundred forty eight babies less than 34 wk and/or with a birth weight of less than 2,000 g were evaluated. Peripheral blood smear and complete blood count were done on day one of life. Ophthalmological examination was done as per guidelines and grades of ROP classified and followed up till 40 wk of gestation for complete vascularisation. Cases were matched with similar number of controls (n = 67) and the sensitivity, specificity and positive predictive value of different parameters were assessed. RESULTS: The incidence of ROP on screening was found to be 27%. Sixty seven cases were matched with 67 controls as per birth weight and gestational age. Significant risk factors for ROP included longer duration of ventilation, higher FiO2, culture proven sepsis and apnea requiring pharmacotherapy. The incidence of Stage I was 10.5% (n = 7), Stage II 58.2% (n = 39) and Stage III was 31.3% (n = 21). The absolute nucleated RBC (ANRBC) count was found to be the only parameter which was significantly higher in babies with ROP (p < 0.001). The ANRBC was higher with increasing severity of ROP (p = 0.003). The sensitivity, specificity and positive predictive value of ANRBC with ROP was higher than other parameters. CONCLUSIONS: Increase in ANRBC count correlated with intrauterine hypoxia. Hence, an increase in ANRBC count could be used as a screening tool for the early prediction of ROP in babies. PMID- 23436193 TI - Intricacies of body temperature measurement. PMID- 23436194 TI - A case of rabies after squirrel bite. PMID- 23436195 TI - Protein kinase Ceta is targeted to lipid droplets. AB - Protein kinase C (PKC) is a family of kinases that regulate numerous cellular functions. They are classified into three subfamilies, i.e., conventional PKCs, novel PKCs, and atypical PKCs, that have different domain structures. Generally, PKCs exist as a soluble protein in the cytosol in resting cells and they are recruited to target membranes upon stimulation. In the present study, we found that PKCeta tagged with EGFP distributed in lipid droplets (LD) and induced a significant reduction in LD size. Two other novel PKCs, PKCdelta and PKCepsilon, also showed some concentration around LDs, but it was less distinct and less frequent than that of PKCeta. Conventional and atypical PKCs (alpha, betaII, gamma, and zeta) did not show any preferential distribution around LDs. 1,2 Diacylglycerol, which can activate novel PKCs without an increase of Ca(2+) concentration, is the immediate precursor of triacylglycerol and exists in LDs. The present results suggest that PKCeta modifies lipid metabolism by phosphorylating unidentified targets in LDs. PMID- 23436196 TI - [Ranibizumab in diabetic macular edema. Evaluation of functional and morphological aspects]. AB - BACKGROUND: Intravitreal anti-VEGF (vascular endothelial growth factor) therapy with ranibizumab has been shown to be an effective therapeutic option for foveal diabetic macular edema (DME). This prospective study evaluated the functional and morphological retinal changes after intravitreal ranibizumab treatment. MATERIAL AND METHODS: A consecutive prospective series of DME patients treated with intravitreal ranibizumab were examined before and after 3 and 6 months of intravitreal ranibizumab therapy. Best-corrected visual acuity (BCVA) according to the ETDRS protocol, retinal thickness in the macular area and central retinal thickness (CRT) measured with spectral-domain optical coherence tomography (SD OCT) was determined. In addition, microperimetric functional macular mapping was determined before therapy and 4 weeks after the third injection. RESULTS: A total of 41 eyes from 33 patients were evaluated. During the 6-month observational period patients received a mean number of 5.2 injections. The mean BCVA increased significantly from 26 +/- 14 to 33 +/- 13 letters 4 weeks after the third injection and to 34 +/- 14 letters 6 months after starting the treatment. The mean CRT decreased significantly from 509 +/- 147 um to 385 +/- 121 um after the third injection and to 383 +/- 110 um after 6 months. After 3 injections, the thickness of the most prominent central retinal area was less than 445 um in 68.3% of patients and after a further 3 months of treatment in 78.0%. CONCLUSION: The presented data demonstrate that intravitreal ranibizumab is effective for DME in everyday clinical practice and results are comparable to those of registration trials. After three initial injections significant structural and functional improvements were observed in a considerable number of patients. PMID- 23436198 TI - An ultra scale-down characterization of low shear stress primary recovery stages to enhance selectivity of fusion protein recovery from its molecular variants. AB - Fusion proteins offer the prospect of new therapeutic products with multiple functions. The primary recovery is investigated of a fusion protein consisting of modified E2 protein from hepatitis C virus fused to human IgG1 Fc and expressed in a Chinese hamster ovary (CHO) cell line. Fusion protein products inevitably pose increased challenge in preparation and purification. Of particular concerns are: (i) the impact of shear stress on product integrity and (ii) the presence of product-related contaminants which could prove challenging to remove during the high resolution purification steps. This paper addresses the use of microwell based ultra scale-down (USD) methods to develop a bioprocess strategy focused on the integration of cell culture and cell removal operations and where the focus is on the use of operations which impart low shear stress levels even when applied at eventual manufacturing scale. An USD shear device was used to demonstrate that cells exposed to high process stresses such as those that occur in the feed zone of a continuous non-hermetic centrifuge resulted in the reduction of the fusion protein and also the release of glycosylated intracellular variants. In addition, extended cell culture resulted in release of such variants. USD mimics of low shear stress, hydrohermetic feed zone centrifugation and of depth filtration were used to demonstrate little to no release during recovery of these variants with both results verified at pilot scale. Furthermore, the USD studies were used to predict removal of contaminants such as lipids, nucleic acids, and cell debris with, for example, depth filtration delivering greater removal than for centrifugation but a small (~10%) decrease in yield of the fusion protein. These USD observations of product recovery and carryover of contaminants were also confirmed at pilot scale as was also the capacity or throughput achievable for continuous centrifugation or for depth filtration. The advantages are discussed of operating a lower yield cell culture and a low shear stress recovery process in return for a considerably less challenging purification demand. PMID- 23436197 TI - Myelodysplasia: new approaches. AB - The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myelogenous leukemia (AML). A precise diagnosis is critical, because there is overlap between the clinical and laboratory findings of MDS and other malignant and nonmalignant hematologic disorders. Several prognostic scoring systems (IPSS, WPSS, LR-PSS, and IPSS-R) assess a patient's risk of progression to AML and overall survival. Many patients are elderly, so age and comorbidities are an important consideration. Patients with lower-risk disease are treated with growth factors (erythropoietin stimulating agents and/or G-CSF) and immunomodulatory agents (antithymocyte globulin and/or lenalidomide). Patients with higher-risk disease have a higher risk of progression to AML and are treated with hypomethylating agents (azacitidine or decitabine) and allogeneic stem cell transplantation if appropriate. Recent laboratory studies have increased our understanding of the pathophysiology of this disease. Mutations in genes effecting ribosomes, splicing of RNA and epigenetics have been discovered. It is likely that these breakthroughs will lead to newer classes of targeted therapies against this disease. PMID- 23436199 TI - New year, new approaches. PMID- 23436200 TI - Social inequality in health, responsibility and egalitarian justice. AB - Are social inequalities in health unjust when brought about by differences in lifestyle? A widespread idea, luck egalitarianism, is that inequality stemming from individuals' free choices is not to be considered unjust, since individuals, presumably, are themselves responsible for such choices. Thus, to the extent that lifestyles are in fact results of free choices, social inequality in health brought about by these choices is not in tension with egalitarian justice. If this is so, then it may put in question the justification of free and equal access to health care and existing medical research priorities. However, personal responsibility is a highly contested issue and in this article we first consider the case for, and second the case against, personal responsibility for health in light of recent developments in philosophical accounts of responsibility and equality. We suggest-but do not fully establish-that at the most fundamental level people are never responsible in such a way that appeals to individuals' own responsibility can justify inequalities in health. PMID- 23436201 TI - Comment on Marchman Andersen et al.: social inequality in health, responsibility and egalitarian justice. PMID- 23436202 TI - Comment on Marchman Andersen et al.: social inequality in health, responsibility and egalitarian justice. PMID- 23436203 TI - Slum upgrading review: methodological challenges that arise in systematic reviews of complex interventions. PMID- 23436204 TI - NICE public health update. PMID- 23436205 TI - Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction. AB - OBJECTIVE: To identify changes in gene expression in mice with osteoarthritis (OA) in order to explore the mechanisms of the disease. METHODS: Gene expression profiling was performed in cartilage from mice with surgically induced OA. We used wild-type (WT) mice and Adamts5Deltacat mice, in which ADAMTS-5 activity is lacking and aggrecan loss and cartilage erosion are inhibited, to distinguish gene expression changes that are independent of ADAMTS-5 activity and cartilage breakdown. Mechanical instability was introduced into the knee joints of 10-week old male mice via surgical destabilization of the medial meniscus (DMM). Cartilage from the developing lesion in the destabilized medial meniscus and corresponding regions in sham-operated joints was harvested by microdissection at 1, 2, and 6 weeks postsurgery, and RNA was extracted, amplified, and hybridized to whole-genome microarrays. RESULTS: Several previously identified OA-related genes, including Ptgs2, Crlf1, and Inhba, and novel genes, such as Phdla2 and Il11, were up-regulated in both WT mice and Adamts5Deltacat mice, indicating that they are independent of ADAMTS-5 activity. The altered expression of other genes, including Col10a1, the sentinel marker of cartilage hypertrophy, and Wnt/beta catenin pathway genes, required ADAMTS-5 activity. Cell death pathway genes were dysregulated, and Tp53, Foxo4, and Xbp1 endoplasmic reticulum-stress transcriptional networks were activated. Analysis of degradome genes identified up-regulation of many proteases, including Mmp3, Capn2, and the novel cartilage proteases Prss46 and Klk8. Comparison with other studies identified 16 genes also dysregulated in rat and human OA as priorities for study. CONCLUSION: We have identified, for the first time, several genes that have an ADAMTS-5-independent role in OA, identifying them as possible OA initiation candidates. This work provides new insights into the sequence of gene dysregulation and the molecular basis of cartilage destruction in OA. PMID- 23436207 TI - The microstructural and functional changes in the macula of heavy habitual smokers. AB - To investigate whether heavy habitual smoking affects microstructures and functions of the macula, 45 age- (20-39 years old) and sex-matched adult smokers (>=1 box/day for >=5 years) and 45 nonsmokers (controls) were enrolled in this case-control study. Central macular thickness (CMT), macular autofluorescent pigment density (MAPD), macular electroretinogram (ERG), and photostress recovery time (PRT) measurements were performed. The mean age of smokers and nonsmokers was 32.9 +/- 3.9 and 33.1 +/- 4.1 years, respectively (p = 0.43), and smoking duration was 11 +/- 5.6 years. CMT in smokers (220 +/- 28 MUm) and nonsmokers (217.2 +/- 31 MUm; p = 0.57) was similar. Smokers had lower MAPD values (124.6) than nonsmokers (138.2) (p = 0.010). Multifocal ERG parameters in the central (6 degrees ) hexagon were similar in both groups (p > 0.05 for latency and amplitudes of P1 and N1). PRT in smokers and nonsmokers was similar (7.2 +/- 1.2 and 7.4 +/- 1.9 min, respectively; p = 0.33); however, foveal threshold value (FTV) at the first minute after photostress was statistically higher in smokers (36.1 +/- 1.04 dB) than nonsmokers (34.8 +/- 1.05 dB) (p = 0.011). We conclude that decreased MAPD and altered response to photostress may be indicative of early nicotine toxicity in microstructurally sound macula of adult chronic smokers. PMID- 23436208 TI - Share and enjoy: anatomical models database--generating and sharing cardiovascular model data using web services. AB - Sharing data between scientists and with clinicians in cardiac research has been facilitated significantly by the use of web technologies. The potential of this technology has meant that information sharing has been routinely promoted through databases that have encouraged stakeholder participation in communities around these services. In this paper we discuss the Anatomical Model Database (AMDB) (Gianni et al. Functional imaging and modeling of the heart. Springer, Heidelberg, 2009; Gianni et al. Phil Trans Ser A Math Phys Eng Sci 368:3039-3056, 2010) which both facilitate a database-centric approach to collaboration, and also extends this framework with new capabilities for creating new mesh data. AMDB currently stores cardiac geometric models described in Gianni et al. (Functional imaging and modelling of the heart. Springer, Heidelberg, 2009), a number of additional cardiac models describing geometry and functional properties, and most recently models generated using a web service. The functional models represent data from simulations in geometric form, such as electrophysiology or mechanics, many of which are present in AMDB as part of a benchmark study. Finally, the heartgen service has been added for producing left or bi-ventricle models derived from binary image data using the methods described in Lamata et al. (Med Image Anal 15:801-813, 2011). The results can optionally be hosted on AMDB alongside other community-provided anatomical models. AMDB is, therefore, a unique database storing geometric data (rather than abstract models or image data) combined with a powerful web service for generating new geometric models. PMID- 23436209 TI - Paeoniflorin, a natural neuroprotective agent, modulates multiple anti-apoptotic and pro-apoptotic pathways in differentiated PC12 cells. AB - Numerous studies have shown robust neuroprotective effects of paeoniflorin (PF), a natural compound derived from the herbal medicine Paeony radix. In the present study, we determined associations of PF neuroprotection with its modulation of various apoptotic and anti-apoptotic pathways. PF (50-400 MUM) pretreatment significantly improved viability of differentiated PC12 cells exposed to methyl-4 phenylpyridine ion (MPP(+)), a neurotoxin, and inhibited over-release of lactate dehydrogenase, a biomarker of neuronal cell death. PF also ameliorated MPP(+) induced nuclear and mitochondrial apoptotic alteration and intracellular calcium overload. PF treatment reversed MPP(+) suppression of activity of B cell lymphoma extra large, which is a mitochondrial membrane molecule that protects cells from DNA damage-induced apoptosis, and strikingly inhibited the enhanced level of cleaved poly(ADP-ribose)polymerase, which is involved in the process of apoptosis. PF alone and coadministration with MPP(+) enhanced phospho activation of extracellular signal-regulated kinases, Akt, and its downstream element glycogen synthase kinase-3, but the effects were completely abolished in the presence of their blockers PD98059 and LY294002. The presence of the blockers also diminished the potency of PF in improving viability of MPP(+)-exposed cells. These results indicate that neuroprotective effects of PF are related to its modulation of multiple anti-apoptotic and pro-apoptotic pathways, including blockade of intracellular calcium overload, prevention of mitochondrial membrane integrity, inhibition of pro-apoptotic molecules, and up-regulation of anti apoptotic proteins associated with cell survival and proliferation. The study provides evidence supporting PF as a potential therapeutic agent used for the treatment of neurodegenerative diseases and neural injury. PMID- 23436210 TI - Finding faults: analogical comparison supports spatial concept learning in geoscience. AB - A central issue in education is how to support the spatial thinking involved in learning science, technology, engineering, and mathematics (STEM). We investigated whether and how the cognitive process of analogical comparison supports learning of a basic spatial concept in geoscience, fault. Because of the high variability in the appearance of faults, it may be difficult for students to learn the category-relevant spatial structure. There is abundant evidence that comparing analogous examples can help students gain insight into important category-defining features (Gentner in Cogn Sci 34(5):752-775, 2010). Further, comparing high-similarity pairs can be especially effective at revealing key differences (Sagi et al. 2012). Across three experiments, we tested whether comparison of visually similar contrasting examples would help students learn the fault concept. Our main findings were that participants performed better at identifying faults when they (1) compared contrasting (fault/no fault) cases versus viewing each case separately (Experiment 1), (2) compared similar as opposed to dissimilar contrasting cases early in learning (Experiment 2), and (3) viewed a contrasting pair of schematic block diagrams as opposed to a single block diagram of a fault as part of an instructional text (Experiment 3). These results suggest that comparison of visually similar contrasting cases helped distinguish category-relevant from category-irrelevant features for participants. When such comparisons occurred early in learning, participants were more likely to form an accurate conceptual representation. Thus, analogical comparison of images may provide one powerful way to enhance spatial learning in geoscience and other STEM disciplines. PMID- 23436211 TI - The role of inhibition in young children's altruistic behaviour. AB - By behaving altruistically, individuals voluntarily reduce their benefits in order to increase their partners'. This deviation from a self-interest-maximizing function may be cognitively demanding, though. This study investigates whether altruistic sharing in 4- to 6-year-old children, assessed by a dictator game (DG), is related to three measures of executive functioning, that is, inhibitory control, working memory, and cognitive flexibility. We found that children who turned out to be altruistic in the DG performed better on an inhibition task than non-altruists did. This finding lends support to the hypothesis that altruistic sharing might be somewhat constrained by the child's ability to inhibit a natural tendency to preserve his or her own resources. Much research is needed to understand the role of inhibitory control in the development of costly sharing and the consolidation of inequity aversion. PMID- 23436212 TI - Dual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2. AB - Palomid 529, a novel dual mTORC1/2 inhibitor has displayed interesting activities in experimental models and is a candidate for clinical evaluation. We have assessed the interaction of Palomid 529 with ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-gp/P-glycoprotein) and ABCG2 (BCRP/Breast Cancer Resistant Protein) by in vitro transwell assays, and their effects on the brain penetration using drug disposition analysis of i.v. and oral Palomid 529 in wild type (WT) and Abcb1 and/or Abcg2 knockout (KO) mice. Palomid 529 lacked affinity for these transporters in vitro, in contrast to GDC-0941, a small molecule PI3K inhibitor, which we used as control substance for in vitro transport. The plasma AUCi.v. of micronized and DMSO formulated Palomid 529 was similar in WT and KO mice. Importantly, the brain and brain tumor concentration of Palomid 529 at a high dose (54 mg/kg) was also similar in both strains, whereas a less than 1.4 fold difference (p < 0.05) was found at the low (5.4 mg/kg) dose. Because of poor solubility, the oral bioavailability of micronized Palomid 529 was only 5%. Olive oil or spray-dried formulation greatly improved the bioavailability up to 50%. Finally, Palomid 529 effectively inhibits the orthotopic U87 glioblastoma growth. In summary, Palomid 529 is the first mTOR targeting drug lacking affinity for ABCB1/ABCG2 and having good brain penetration. This warrants further evaluation of Palomid 529 for treatment of high-grade gliomas and other intracranial malignancies. PMID- 23436213 TI - Progressive aortic dilation and aortic stiffness in children with repaired tetralogy of Fallot. AB - Progressive aortic dilation occurs in patients with tetralogy of Fallot (TOF), possibly due to abnormal histopathology of the aortic media that weakens the aortic wall. This medial histopathology may be reflected as aortic stiffness, which in turn may predict progressive aortic dilation. To test this theory, we studied the relationship between aortic wall stiffness, measured by pulse wave velocity (PWV), and subsequent aortic dilation in 32 consecutive patients with repaired TOF. The ascending aortic diameter (AOD) was obtained by two-dimensional transthoracic echocardiography performed at baseline and at the follow-up examination, 7.6 +/- 2.0 years after baseline. TOF patients exhibited significantly greater AODs than normal reference values, at baseline (19.8 +/- 5.0 vs 14.3 +/- 3.1 mm; P = 0.0001) and at the follow-up examination (25.9 +/- 3.8 vs 18.1 +/- 2.4 mm; P = 0.0001). The observed change in AOD during the follow up period (0.83 +/- 0.43 mm/year) was significantly larger than the change that would be expected by the patient's growth (0.50 +/- 0.25 mm/year; P = 0.0001). The PWV at baseline correlated positively with both AOD at follow-up (P = 0.0018) and the annual rate of aortic dilation (P = 0.0007). On multivariate regression analysis, PWV remained a significant and independent predictor of subsequent aortic dilation. These results suggest a causative role for aortic stiffening in the progressive aortic dilation noted in TOF, indicating that incorporating aortic stiffness as well as aortic diameter in the assessment of TOF aortopathy may help better define the need for, and the timing of, medical intervention. PMID- 23436214 TI - Zotarolimus-eluting stent utilization in small-vessel coronary artery disease (ZEUS). AB - The role of the second-generation zotarolimus-eluting stent RESOLUTE in small vessel coronary artery disease is unclear. The aim of this study was examine the angiographic results of RESOLUTE in de novo coronary lesions of >=50 % diameter stenosis in target vessels <=2.5 mm. From August 2008 to April 2010, 142 symptomatic patients with 159 lesions who fitted the inclusion criteria were treated with RESOLUTE. The mean age of patients was 66 +/- 10 years, with male predominance (66 %). Diabetes mellitus was found in 62 (43.7 %) patients, whereas multivessel disease was observed in 105 (73.9 %). The mean stent size and length used were 2.33 +/- 0.13 and 22 +/- 8 mm, respectively. Follow-up angiography was performed on 143 (89.9 %) lesions in 127 (89.4 %) patients at a mean of 10.3 +/- 3.6 months. Angiographic restenosis was found in 9 (6.3 %) lesions; the late loss was 0.26 +/- 0.34 mm. At 1-year follow-up there were four cardiovascular deaths, two nonfatal myocardial infarctions, and six repeated revascularizations. The resultant major adverse cardiac event rate was 8.5 %. The use of RESOLUTE to treat small-vessel disease is associated with good clinical and angiographic outcomes at 1 year. PMID- 23436215 TI - Phase analysis in patients with reversible perfusion defects and normal coronary arteries at angiography. AB - OBJECTIVE: A count-based new technique from gated myocardial perfusion single photon emission tomography (gMPS) was developed to allow the phase analysis providing information about the left ventricular (LV) regional discordance in contractility which is a measure of LV dyssynchrony. Since the phase analysis provides data for evaluating the dyssynchronous LV contraction, it has an important role in diagnosis and management of patients with left ventricular dysfunction. The aim of the study was to assess the presence of left ventricular dyssynchrony in patients with reversible perfusion defects on gMPS scans and normal or near normal coronary arteries at angiography. METHODS: 32 patients (19 men, 59 %) with reversible mild perfusion defects on gMPS and normal coronary angiogram were retrospectively enrolled in the study. The peak of the phase histogram, the standard deviation of the phase distribution (PSD), the width of the band (PHB), and the symmetry and peakedness of the phase histogram, which are the assessment parameters for the LV dyssynchrony, were calculated from gMPS scans of patients by means of the phase analysis. RESULTS: Although, five quantitative variables are derived from the phase analysis of gMPS, PSD and PHB are two quantitative indices to assess LV global mechanical dyssynchrony and measurements of PSD (men 24.96 +/- 7.31, women 24.26 +/- 10.07) and PHB (men 70.1 +/- 13.99, women 71.0 +/- 30.4) were significantly higher than the those reported in the literature (p < 0.001). No significant differences in gMPS phase analysis indices were found between both sexes except kurtosis. CONCLUSION: As a conclusion, this study provides the phase analysis to detect LV mechanical dyssynchrony as new evidence supporting the concept that an abnormal scintigraphy finding, rather than being false-positive, may be an early marker of vasomotion changes associated with occult atherosclerosis in patients with normal coronary angiography findings. PMID- 23436216 TI - Molecular characterisation of resistance against potato wart races 1, 2, 6 and 18 in a tetraploid population of potato (Solanum tuberosum subsp. tuberosum). AB - Potato wart is caused by the obligate biotrophic fungus Synchytrium endobioticum, which is subject to quarantine regulations due to the production of long persisting spores in the soil and the lack of effective fungicides. The objective of this study was to identify quantitative trait loci (QTL) for resistance against potato wart races (R) 1, 2, 6 and 18 in a tetraploid potato population developed by crossing cv. Saturna (resistant to R1) with cv. Panda (resistant to R1, R2, R6, R18). A total of 92 progenies were used for phenotyping and genotyping. Resistance tests were performed for races 1 and 18 in 2 years and for races 2 and 6 in 1 year on 10 to 20 eyepieces per genotype. Based on amplified fragment length polymorphism (AFLP) and simple sequence repeat (SSR) markers, linkage maps were established for the female and male parent, respectively. Single marker analysis followed by a multiple regression analysis revealed initial marker-trait associations. The interval mapping routine of TetraploidMap was applied for QTL analysis. A major QTL for resistance against race 1 explaining between 46 % and 56 % of the phenotypic variation was identified near Sen1, a known resistance locus for potato wart race 1 on chromosome XI. Other resistance QTL were detected on chromosomes I (to R2), II (to R6, 18), VI (to R1, 2, 6, 18), VII (to R2, 6, 18), VIII (to R1, 2, 6, 18), X (to R2, 6, 18), XI (to R2, 6, 18) and on an unknown linkage group (to R18) explaining minor to moderate effects of the phenotypic variation. Resistance QTL against different potato wart races often overlapped, particularly concerning races 2, 6 and 18. Overall, this study gives a valuable insight into the complex inheritance of resistance against potato wart. PMID- 23436217 TI - Leisure-time physical activity does not fully explain the higher body mass index in irregular-shift workers. AB - PURPOSE: To elucidate the influence of leisure-time physical activity on body mass index (BMI), appetite-related hormones, and sleep when working irregular shifts. METHODS: A cross-sectional study was undertaken of 57 male truck drivers, 31 irregular-shift workers and 26 day-shift workers. Participants completed the International Physical Activity Questionnaire and were assessed for BMI. Subjects also provided a fasting blood sample for analysis of appetite-related hormones and wore an actigraphy device for seven consecutive days. RESULTS: Although leisure-time physical activity (LTPA) was generally low (<150 min/week) in both groups, the irregular-shift workers were more physically active than day-shift workers (99 +/- 166 vs. 23 +/- 76 min/week, p < 0.01). In spite of this, mean BMI of irregular-shift workers was 2 kg/m2 greater than day-shift workers (28.4 +/- 3.8 vs. 26.4 +/- 3.6 kg/m2, p = 0.04). Mean leptin concentration was 61 % higher in irregular-shift workers (5,205 +/- 4,181 vs. 3,179 +/- 2,413 pg/ml, p = 0.04). Among obese individuals, irregular-shift workers had higher leptin concentration (p < 0.01) and shorter sleep duration (p = 0.01) than obese day-shift workers. CONCLUSION: Elevated BMI was associated with high leptin and low ghrelin levels in this population of irregular-shift workers. No influence of LTPA on appetite related hormones or sleep duration was found. We conclude that moderate LTPA is insufficient to attenuate the higher BMI associated with this type of irregular shift work in truck drivers. PMID- 23436218 TI - More 'crop per drop': constraints and opportunities for precision irrigation in European agriculture. AB - Dwindling water supplies, increasing drought frequency and uncertainties associated with a changing climate mean Europe's irrigated agriculture sector needs to improve water efficiency and produce more 'crop per drop'. This paper summarizes the drivers for change, and the constraints and opportunities for improving agricultural water management through uptake of precision irrigation technologies. A multi-disciplinary and integrated approach involving irrigation engineers, soil scientists, agronomists and plant physiologists will be needed if the potential for precision irrigation within the field crop sector is to be realized. PMID- 23436219 TI - RET/PTC and PAX8/PPARgamma chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics. AB - BACKGROUND: Childhood exposure to iodine-131 from the 1986 nuclear accident in Chernobyl, Ukraine, led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited. METHODS: Mutational analysis was performed on 62 PTCs diagnosed in a Ukrainian cohort of patients who were < 18 years old in 1986 and received 0.008 to 8.6 Gy of (131) I to the thyroid. Associations between mutation types and (131) I dose and other characteristics were explored. RESULTS: RET/PTC (ret proto oncogene/papillary thyroid carcinoma) rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPARgamma (paired box 8/peroxisome proliferator-activated receptor gamma) rearrangement were identified. A significant negative association with (131) I dose for BRAF and RAS point mutations and a significant concave association with (131) I dose, with an inflection point at 1.6 Gy and odds ratio of 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPARgamma rearrangements were found. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared with point mutations, rearrangements were associated with residence in the relatively iodine-deficient Zhytomyr region, younger age at exposure or surgery, and male sex. CONCLUSIONS: These results provide the first demonstration of PAX8/PPARgamma rearrangements in post Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with (131) I dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and (131) I exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients. PMID- 23436220 TI - Effects of oral deoxynivalenol exposure on immune-related parameters in lymphoid organs and serum of mice vaccinated with porcine parvovirus vaccine. AB - Mice were exposed to deoxynivalenol (DON) via drinking water at a concentration of 2 mg/L for 36 days. On day 8 of treatment, inactivated porcine parvovirus vaccine (PPV) was injected intraperitoneally. The relative and absolute weight of the spleen was significantly decreased in the DON-treated group (DON). Antibody titers to parvovirus in serum were 47.9 +/- 2.4 in the vaccination group (Vac), but 15.2 +/- 6.5 in the group treated with DON and vaccine (DON + Vac). The IgA and IgG was not different in the DON, Vac an,d DON + Vac groups. IgM was significantly lower only in the DON + Vac group. However IgE was significantly increased in the Vac and DON + Vac group, but no change was observed between the Vac and DON + Vac groups. The concentrations of IL-2, IL-4, GM-CSF, MCP-1 and Rantes in serum, and IL-1alpha in mesenteric lymph node and MIP-1beta in spleen were significantly increased by DON treatment compared to control. The concentrations of IL-2, IL-5, IL-6, IL-9, IL-12, IL-13 and Rantes in thymus, of IL-2 in spleen, and of IL-1alpha, IL-1beta, IL-3, IL-5, IL-10, IL-17, G-CSF, GM CSF and MCP-1 in mesenteric lymph nodes were significantly decreased in mice compared to those in the Vac group, while concentrations of IL-1alpha, IL-2, IL 9, IL-13,G-CSF, GM-CSF, IFN-gamma, MCP-1, MIP-1alpha and TNF-alpha were significantly increased in serum compared to the Vac group. In conclusion, the results presented here indicate that exposure to DON at 2.0 mg/L via drinking water can disrupt the immune response in vaccinated mice by modulating cytokines and chemokines involved in their immune response to infectious disease. PMID- 23436221 TI - Extracting fumonisins from maize: efficiency of different extraction solvents in multi-mycotoxin analytics. AB - The complete extraction of analytes is of utmost importance when analyzing matrix samples for mycotoxins. Mycotoxins consist of substances with widely different physicochemical properties; therefore, the loss of toxins that occurs in multi mycotoxin methods due to compromises in the extraction solvent is currently a topic under discussion. With regard to fumonisins, several extractants from recently published multi-mycotoxin methods were investigated when analyzing unprocessed and processed maize matrices. All extractants were tested in a validated on-site method and the extraction yields were compared to those of an HPLC-FLD reference method (EN 14352). Most of the compared multi-mycotoxin methods that have been published were only for analyzing fumonisins in maize or maize-meal; we have applied the extractants of these methods to processed, complex maize matrices for the first time. Our results show that, for extractions with aqueous acetonitrile mixtures with the addition of acid, e.g. MeCN/H2O/acetic acid (79/20/1, v/v/v), higher extraction yields are obtained than with MeCN/H2O (80/20, v/v), in both spiked and naturally contaminated maize matrices. But compared to the results of the reference method EN 14352, the two extractants did not show a similar extraction efficiency. Overall, the extractant MeCN/MeOH/H2O (1/1/2, v/v/v) turned out to be the most appropriate extractant applied in all experiments, obtaining the best and most comparable extraction yields and recoveries. Furthermore, our investigations showed that, with some of the tested extraction solvents, e.g. MeCN/H2O (75/25) containing 50 mmol/l formic acid, stark differences occur when analyzing spiked and naturally contaminated matrices. With spiked matrices, recoveries of approximately 80-110% were obtained, but with naturally contaminated matrices no results comparable to the EN method have been achieved. In contrast, a double extraction with MeCN/H2O/formic acid (80/19,9/0,1, v/v/v), followed by a second polar extraction step with MeCN/H2O/formic acid (20/79,9/0,1, v/v/v), led, for most naturally contaminated samples, to comparable results with the EN method. However, for spiked samples, the same extractant led to raised recoveries of between 120 and 140 %. For some processed matrices, like taco-chips, all tested extractants showed a poor extraction efficiency for fumonisins. By extending the extraction time from 1 to 15 min, a result comparable to that of the reference method could also be obtained for the extractant using MeCN/MeOH/H2O (1/1/2, v/v/v). As this extractant has been used in our recently published method (Trebstein et al. Mycotoxin Res 25:201, 2009), this work also presents an update on this method with respect to the extended extraction time. PMID- 23436222 TI - A novel nonwoven hybrid bioreactor (NWHBR) for enhancing simultaneous nitrification and denitrification. AB - This study proposed a nonwoven hybrid bioreactor (NWHBR) in which the nonwoven fabric played dual roles as a biofilm carrier and membrane-like separation of the flocculent sludge in the reactor. The results of long-term monitoring demonstrated that the NWHBR could achieve simultaneous nitrification and denitrification (SND), with nearly complete ammonium removal and 80% removal of total nitrogen. The biofilm attached to the nonwoven fabric removed 27% of the chemical oxygen demand (COD) and 36% of the nitrate in the reactor, an enhanced elimination of nutrients that was attributed to the increased mass transfer within the biofilm due to permeate drag. The results of batch experiments showed that the flocculent sludge played a more dominant role in nitrification and denitrification (79% and 61%, respectively) than the biofilm (21% and 36%, respectively). The batch experiments also revealed that the enforced mass transfer, with an effluent recirculation rate of 4.3 L/m(2)h (which was the same as the flux during the reactor's long-term operation), improved the denitrification rate by 58% (i.e., from 9.0 to 14.2 mg-NO(3)(-)-N/h). Pyrosequencing of the 16S rRNA gene amplification revealed a high microbial diversity in both the flocculent sludge and biofilm, with Proteobacteria, Bacteroidetes and Chloroflexi as the dominant groups. A phylogenetic (P) test indicated that the NWHBR contained phylogenetically distinct microbial communities: those in the biofilm differed from those in the flocculent sludge. However, the communities on the exterior and interior of the biofilm were more similar to each other. Due to its good SND performance, low physical back-washing frequency and low air-to-water ratio, the NWHBR represents an attractive alternative for the wider application of either low-cost membrane bioreactors or biofilm reactors. PMID- 23436223 TI - Inhibition of connective tissue growth factor ameliorates disease in a murine model of rheumatoid arthritis. AB - OBJECTIVE: We have shown that connective tissue growth factor (CTGF) plays an important role in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to evaluate the effects of blockade of the CTGF pathway on the development of collagen-induced arthritis (CIA) in mice. METHODS: Arthritis was induced in DBA/1J mice by immunization with a combination of type II collagen (CII) and Freund's complete adjuvant. We evaluated the development of arthritis in mice with CIA left untreated versus treated with neutralizing anti-CTGF monoclonal antibody (mAb). RESULTS: Inhibition of CTGF in mice treated with neutralizing anti-CTGF mAb significantly ameliorated arthritis compared to the untreated mice with CIA. Serum levels of matrix metalloproteinase 3 were reduced by anti-CTGF mAb treatment. Moreover, blockade of CTGF decreased interleukin-17 expression on purified CD4+ T lymphocytes. Although the expression of the retinoic acid receptor-related orphan receptor gammat gene was not suppressed by anti-CTGF mAb treatment, that of interferon regulatory factor 4 (IRF-4) and IkappaBzeta (Nfkbiz), which are other important molecules for the differentiation of Th17 cells, was suppressed. In addition, blockade of CTGF inhibited pathologic proliferation of T lymphocytes in response to CII restimulation in vitro. Moreover, aberrant osteoclastogenesis in mice with CIA was restored by anti-CTGF mAb treatment. CONCLUSION: Our findings indicate that blockade of CTGF prevents the progression of arthritis in mice with CIA. Anti-CTGF mAb treatment suppresses pathologic T cell function and restores aberrant osteoclastogenesis in mice with CIA. CTGF may become a new target for the treatment of RA. PMID- 23436225 TI - Enzymatic hydrolysis of spent coffee ground. AB - Spent coffee ground (SCG) is the main residue generated during the production of instant coffee by thermal water extraction from roasted coffee beans. This waste is composed mainly of polysaccharides such as cellulose and galactomannans that are not solubilised during the extraction process, thus remaining as unextractable, insoluble solids. In this context, the application of an enzyme cocktail (mannanase, endoglucanase, exoglucanase, xylanase and pectinase) with more than one component that acts synergistically with each other is regarded as a promising strategy to solubilise/hydrolyse remaining solids, either to increase the soluble solids yield of instant coffee or for use as raw material in the production of bioethanol and food additives (mannitol). Wild fungi were isolated from both SCG and coffee beans and screened for enzyme production. The enzymes produced from the selected wild fungi and recombinant fungi were then evaluated for enzymatic hydrolysis of SCG, in comparison to commercial enzyme preparations. Out of the enzymes evaluated on SCG, the application of mannanase enzymes gave better yields than when only cellulase or xylanase was utilised for hydrolysis. The recombinant mannanase (Man1) provided the highest increments in soluble solids yield (17 %), even when compared with commercial preparations at the same protein concentration (0.5 mg/g SCG). The combination of Man1 with other enzyme activities revealed an additive effect on the hydrolysis yield, but not synergistic interaction, suggesting that the highest soluble solid yields was mainly due to the hydrolysis action of mannanase. PMID- 23436224 TI - Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis. AB - The fate of Foxp3(+) regulatory T (Treg) cells responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1(+) (where KLRG1 stands for killer cell lectin-like receptor G1) CNS-infiltrating Treg cells in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1(+) Treg cells showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1(-) cells. KLRG1(-) Treg cells converted into KLRG1(+) cells and this was increased in autoimmune inflammation. Conversion was unidirectional; KLRG1(+) Treg cells did not revert to a KLRG1(-) state. KLRG1(+) but notKLRG1(-) Treg cells survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was also upregulated on iTreg cells after transfer and EAE induction or on iTreg cells developing spontaneously during EAE. KLRG1(+) Treg cells produced more IL-10 and had altered effector cytokine production compared with their KLRG1(-) counterparts. Despite their differences, KLRG1(+) and KLRG1(-) Treg cells proved similarly potent in suppressing EAE. KLRG1(+) and KLRG1(-) populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg cells during EAE, and associate KLRG1 with altered Treg-cell function and senescence. PMID- 23436226 TI - Construction of the ie1-Bacmid expression system and its use to express EGFP and BmAGO2 in BmN cells. AB - The presently available expression tools and vectors (e.g., eukaryotic expression vectors and the adenovirus expression system) for studying the functional genes in Bombyx mori are insufficient. The baculovirus expression system is only used as a protein production tool; therefore, recombinant proteins expressed by B. mori using the baculovirus expression system equipped with a polyhedrin promoter cannot be used for in vivo research applications. In this work, we constructed and screened a eukaryotic expression vector for silkworm cells The EGFP and B. mori Argonaute2 proteins were found to be efficiently expressed using the screened pIEx-1 vector with the FuGENE 6 transfection reagent. Additionally, we constructed a novel nucleopolyhedrovirus ie1-Bacmid expression system for the production of recombinant protein; we then used the system to highly express the EGFP and B. mori Argonaute2 proteins. In this system, the protein of interest can be efficiently expressed 13 h after infection by controlling the B. mori nucleopolyhedrovirus immediate early ie1 promoter. The ie1-Bacmid system provides a powerful "adenovirus-like" expression tool; not only can the tool be used to study baculovirus molecular biology for the silkworm but it is also useful in other research applications as well, such as the study of gene functions involved in cellular physiological processes. PMID- 23436227 TI - Does the magnetic field of a magnetic stirrer in an optical aggregometer affect concurrent platelet aggregation? AB - Platelets are subjected to extremely low frequency electromagnetic fields during standard aggregometry measurements owing to the use of a magnetic stir bar in the instrument. This study evaluates the effects of this magnetic field exposure on platelet aggregation by comparing the results obtained in a modified aggregometer. Blood samples from healthy volunteers were anticoagulated using citrate or heparin. Platelet-rich plasma (PRP) samples were prepared. A mechanical stirring device was attached to the aggregometer instead of the magnetic stir bar system. The PRP samples were stirred using a stirring rod tip that did not produce any magnetic fields in one channel of the aggregometer; in the other channel, a stirring rod carrying a small magnet at its tip was used. As a result, a magnetic field in the extremely low frequency range and in the amplitude range of 1.9-65 mT was applied to the platelets assigned to the channel where the magnetic stirring rod tip was used. Aggregation was induced using adenosine diphosphate (ADP), collagen, or epinephrine. The slopes, maximum aggregation values, and areas under the aggregation curves were compared between the magnetic and neutral stirring rod tip groups. For samples stirred with the magnetic stirring rod tip, a significant decrease was observed in 12 of the 14 parameters evaluated for aggregations induced with ADP or collagen compared to the neutral stirring rod tip, regardless of the method used for anticoagulation. This observation indicates that the magnetic stir bars used in standard aggregometry may significantly alter aggregation parameters and platelets may be possible targets of electromagnetic fields. PMID- 23436228 TI - Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia. AB - Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p < 0.05). In severely cachectic mice, perindopril reduced tumor growth, improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ (p < 0.05), which was associated with increased oxidative enzyme capacity (succinate deyhydrogenase, p < 0.05). Perindopril attenuated the increase in MuRF 1 and IL-6 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased. These findings support the therapeutic potential of ACE inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia. PMID- 23436230 TI - Timing of antibiotic administration and outcomes in patients with chemotherapy induced febrile neutropenia. PMID- 23436229 TI - Esophageal gel-shifting technique facilitating eradicative boost or reirradiation to upper mediastinal targets of recurrent nerve lymph node without damaging esophagus. AB - We developed a new technique using hyaluronic gel injection as a spacer to safely move the esophagus away from the high-dose area during interstitial brachytherapy of a mediastinal target close to the esophagus. We percutaneously injected a high molecular-weight hyaluronic gel mixed with contrast medium to create a space between the esophagus and the target during interstitial brachytherapy. We applied this technique to two cases of relapsed recurrent nerve lymph node metastasis from esophageal cancer: one refractory tumor after 50 Gy of radiotherapy, and one recurrence after mediastinal radiotherapy of total 64 Gy. We prescribed 20 Gy and 18 Gy in one fraction to each target, with calculated esophageal D2cc (the minimum dose to the most irradiated volume of 2 cc) of 4.0 Gy and 6.8 Gy, respectively. Calculated enhancement factor by gel shifting in equivalent dose was 2.69 and 2.34, respectively. In each patient, accumulated esophageal D1cc (minimum dose to the most irradiated volume of p cc. minimum dose to the most irradiated volume of 1 cc) was 74.4 Gy and 85.6 Gy without shifting, and 59.1 Gy and 37.6 Gy with shifting, respectively. There were no procedure related complications. Four months after the brachytherapy, each tumor was remarkably diminished. No evidence of recurrences or late complications were observed 8 months and 9 months after the procedure, respectively. The esophageal gel-shifting technique may facilitate eradicative brachytherapy to upper mediastinal targets without damaging the esophagus, and can be used in conjunction with boost irradiation or reirradiation to overcome the problem of salvage failure. PMID- 23436231 TI - Does addition of NO2 to carbon-centered radicals yield RONO or RNO2? An investigation using distonic radical ions. AB - Nitrogen dioxide is used as a "radical scavenger" to probe the position of carbon centered radicals within complex radical ions in the gas phase. As with analogous neutral radical reactions, this addition results in formation of an [M + NO2](+) adduct, but the structural identity of this species remains ambiguous. Specifically, the question remains: do such adducts have a nitro- (RNO2) or nitrosoxy- (RONO) moiety, or are both isomers present in the adduct population? In order to elucidate the products of such reactions, we have prepared and isolated three distonic phenyl radical cations and observed their reactions with nitrogen dioxide in the gas phase by ion-trap mass spectrometry. In each case, stabilized [M + NO2](+) adduct ions are observed and isolated. The structure of these adducts is probed by collision-induced dissociation and ultraviolet photodissociation action spectroscopy and a comparison made to the analogous spectra of authentic nitro- and nitrosoxy-benzenes. We demonstrate unequivocally that for the phenyl radical cations studied here, all stabilized [M + NO2](+) adducts are exclusively nitrobenzenes. Electronic structure calculations support these mass spectrometric observations and suggest that, under low-pressure conditions, the nitrosoxy-isomer is unlikely to be isolated from the reaction of an alkyl or aryl radical with NO2. The combined experimental and theoretical results lead to the prediction that stabilization of the nitrosoxy-isomer will only be possible for systems wherein the energy required for dissociation of the RO-NO bond (or other low energy fragmentation channels) rises close to, or above, the energy of the separated reactants. PMID- 23436232 TI - An interplay between infrared multiphoton dissociation Fourier-transform ion cyclotron resonance mass spectrometry and density functional theory computations in the characterization of a tripodal quinolin-8-olate Gd(III) complex. AB - A new hexadentate, tripodal 8-hydroxyquinoline based ligand (QH3) and its gadolinium(III) tris-chelated (GdQ) complex with hemicage structure was investigated by using high resolution Fourier-transform ion cyclotron resonance mass spectrometry (FTICRMS). The protonated adduct of the free ligand and its hemicage tripodal Gd(III) complex, [GdQ + H](+), were first observed in experiments of electrospray ionization (ESI) with a linear ion trap (LTQ) mass spectrometer and further investigated by using high resolution FTICRMS. Gas-phase dissociation of the protonated Gd(III) complex, by infrared multiphoton dissociation (IRMPD) FTICR MS, demonstrated a fragmentation pattern with six main product cluster ions labeled as [Fn](+) (n = 1 up to 6). These product ions suggest the elimination of 7-amino-alkyl or 7-alkyl chains of the hemicage moiety. High resolution MS conditions allowed the elucidation of the fragmentation pattern and product ion structures along with the determination, among the isotopic pattern of Gd, of the chemical compositions of closely related species, which differ in terms of hydrogen content. Among the Gd six naturally stable isotopes, (158)Gd is the most abundant, and its peak within each cluster was used as a reference for distinguishing each product ions. Computational DFT investigations were applied to give support to some hypothesis of fragmentation pathways, which could not have been easily justified on the basis of the experimental work. Furthermore, computational studies suggested the coordination geometry of the protonated parent complex and the five- and four-coordinated complexes, which derive from its fragmentation. Furthermore, experimental and computational evidences were collected about the octet spin state of the parent compound. PMID- 23436233 TI - Attitudes and practices of auxiliary nurse midwives and accredited social health activists in Uttar Pradesh and Bihar regarding polio immunization in India. AB - Although India was removed from the list of polio endemic countries in January 2012, maintaining the focus on polio vaccination is critically important to prevent reintroduction of the virus. In 2009-2010, we conducted a study to assess the attitudes and practices of frontline health workers in India regarding polio immunization in Uttar Pradesh and Bihar. More than 95% of auxiliary nurse midwives (ANMs) and accredited social health activists (ASHAs) agreed that polio supplementary immunization campaigns helped in increasing acceptance of all vaccines. The majority of ANMs (60-70%) and ASHAs (56-71%) believed that polio immunization activities benefitted or greatly benefitted other activities they were carrying out. Less than 5% of ANMs and ASHAs felt they were very likely to face resistance when promoting or administering polio vaccine. This study provides information that may be useful for programs in other countries for polio eradication and in India for measles elimination. PMID- 23436234 TI - Oxidative stress in children with bacterial meningitis. AB - Bacterial meningitis is a common cause of morbidity and mortality in children. The oxidative stress in bacterial meningitis is barely determined. Forty children with bacterial meningitis were studied for their oxidants and antioxidants status in serum and cerebrospinal fluid. Fever (95%) was commonest presentation followed by seizure and vomiting. Neck rigidity and Kernig's sign were present in 37.5% and 27.5% cases, respectively. Plasma and cerebrospinal fluid malondialdehyde, protein carbonyl and nitrite levels were significantly raised in cases (p < 0.001). Plasma and cerebrospinal fluid ascorbic acid, glutathione and superoxide dismutase levels were significantly decreased in children with septic meningitis (p < 0.001). Significantly elevated malondialdehyde, nitrite and protein carbonyl levels reflect increased oxidative stress, whereas decreased concentrations of glutathione, ascorbic acid and superoxide dismutase indicates utilization of the antioxidants in septic meningitis. Thus, changes in oxidants and antioxidants observed suggest production of reactive oxygen species and their possible role in pathogenesis of septic meningitis. PMID- 23436235 TI - Comparison between transperineal ultrasound and digital detection of levator ani trauma. Can we improve the odds? AB - AIMS: To investigate the predictive ability of four digital assessment parameters to detect levator ani (LA) muscle defects (avulsion injury) and compare these to transperineal tomographic ultrasound images. METHODS: This was an observational study imbedded in a larger quasi-experimental cohort study for women with urinary incontinence. Seventy-two women, >= 60 years who had attended or were going to attend physiotherapy for treatment of urinary incontinence, were included in the study. Inclusion criteria from the parent study were symptoms of stress, urge or both types of urinary incontinence. The predictive ability of the following digital parameters: direct palpation of a discontinuity of the LA muscle from insertion on the pubic ramus; palpation of the distance between the muscle insertion sites; palpation of LA strength; palpation of LA tone, were analyzed against findings from tomographic transperineal ultrasound images. Correlation between methods was measured using Cohen's kappa for each of the individual parameters. RESULTS: Seventeen women (24%) presented with a complete or partial avulsion of the puborectalis muscle as diagnosed with tomographic ultrasound imaging. Nine women (13%) had complete avulsions, one of which was bilateral. The predictive ability of the digital assessment parameters varied from poor (k = 0.187, 95% CI [0.02-0.36]) to moderate (k = 0.569, 95% CI [0.31-0.83]). The new parameter of 'width between insertion sites' performed best. CONCLUSIONS: Adding the parameter of "width between insertion sites" appears to enhance our ability to detect avulsion of the levator ani (LA) muscle by digital examination however it does not distinguish between unilateral or bilateral avulsion. PMID- 23436236 TI - Early neuropsychiatry features in neuroferritinopathy. PMID- 23436237 TI - Gross anatomical study of bilateral megaureters associated with renal pelvis dilatation and a giant urinary bladder: an adult cadaver with a brief review of the literature. AB - Although bilateral megaureters are not an infrequent occurrence in the urinary tract, bilateral megaureters associated with bilateral renal pelvis dilatation and a giant urinary bladder appear to be rare. In this paper, a cadaver case of an adult Japanese male with bilateral megaureters is described. In addition to describing and illustrating this case, the anatomy and etiology of these anomalous structures is discussed with a brief review of the literature. PMID- 23436238 TI - Effect of porphobilinogen on the formation of garlic green pigments. AB - BACKGROUND: Garlic (Allium sativum L.) bulb is processed into various forms such as crushed garlic, garlic juice, granules, dehydrated garlic pieces and garlic powder. However, greening is often a major problem when garlic is crushed, since it affects the appearance and quality of the resulting product. Therefore study of the formation mechanism of garlic green pigments is very important for garlic processing. RESULTS: The effect of porphobilinogen (PBG) on the formation of garlic green pigments was investigated in this study. As the storage time increased, there was a significant positive correlation between garlic greening and PBG content at low temperature (4 degrees C). PBG content decreased significantly during the garlic greening process. When treated with respiration inhibitor, both garlic greening strength and PBG content decreased as the concentration of respiration inhibitor increased. The green colour was generated when extracted PBG and allicin mixed thoroughly. CONCLUSION: There was a clear relationship between PBG content and garlic greening. As a provider of pyrrolyl compounds, PBG plays an important role in the formation of garlic green pigments. PMID- 23436239 TI - Self-assembled plasmonic nanoring cavity arrays for SERS and LSPR biosensing. AB - Self-assembled plasmonic nanoring cavity arrays are formed alongside the curvature of highly packed metallic nanosphere gratings. The sub-10-nm gap size is precisely tuned via atomic layer deposition and highly ordered arrays are produced over a cm-sized area. The resulting hybrid nanostructure boosts coupling efficiency of light into plasmons, and shows an improved SERS detection limit. These substrates are used for SERS detection of the biological analyte, adenine, followed by concurrent localized surface plasmon resonance sensing. PMID- 23436240 TI - Simultaneous determination of eleven major components in Fugan Fang using high performance liquid chromatography coupled with mass spectrometry. AB - Fugan fang (FGF) is a traditional Chinese medicine (TCM) prescription that has been used in treating hepatic illnesses for many years. In this study, an analytical method is developed for the quantitative analysis of the major components of FGF. This method is based on high-performance liquid chromatography tandem mass spectrometry (HPLC-MS) on a reverse-phase C18 column. Results show that 0.01% acetic acid and acetonitrile is the optimum mobile phase in gradient elution. All compounds showed good linearity (r(2) >= 0.9948). Recoveries measured at three concentration levels varied from 83.5 to 104.8%. The method was validated with respect to precision, repeatability and accuracy and was successfully applied in the quantification of the 11 components of FGF products. The validated HPLC-MS method provides a basis for assessing the quality of TCM prescriptions containing many bioactive components. PMID- 23436242 TI - Reducing infectivity of HIV upon exposure to surfaces coated with N,N-dodecyl, methyl-polyethylenimine. AB - The infectivity of high-titer, cell-free HIV in culture media and human milk is rapidly reduced upon exposure to polyethylene slides painted with the linear hydrophobic polycation N,N-dodecyl,methyl-polyethylenimine (DMPEI). Accompanying viral p24 protein and free viral RNA analysis of solutions exposed to DMPEI coated surfaces suggests that virion attachment to the polycationic surface and its subsequent inactivation are the likely mechanism of this phenomenon. PMID- 23436243 TI - Clinical significance of 18F-alpha-methyl tyrosine PET/CT for the detection of bone marrow invasion in patients with oral squamous cell carcinoma: comparison with 18F-FDG PET/CT and MRI. AB - OBJECTIVE: L-3-[(18)F]-fluoro-alpha-methyl tyrosine ((18)F-FAMT) is an amino acid tracer for positron emission tomography/computed tomography (PET/CT) which specifically transported into cancer cells by L-type amino acid transporter 1 (LAT1). LAT1 overexpression in tumors is significantly correlated with cell proliferation and angiogenesis. (18)F-FAMT PET/CT, fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and magnetic resonance imaging (MRI) were compared for their diagnostic performance in the detection of bone marrow invasion in patients with oral squamous cell carcinoma (OSCC). METHODS: Twenty-seven patients with OSCC on the upper or lower alveolar ridge underwent staging by MRI, (18)F-FDG PET/CT and (18)F-FAMT PET/CT studies before surgery. Post-surgical pathologic examination was used as the standard to determine the final diagnoses. The possibility of bone marrow invasion on MRI, (18)F-FDG PET/CT and (18)F-FAMT PET/CT were usually graded retrospectively into five-point score. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated according to the obtained scores. RESULTS: As the sensitivity of (18)F FDG PET/CT was highest (100 %) among that of MRI (95 %) and (18)F-FAMT PET/CT (90 %), the specificity of (18)F-FAMT PET/CT was highest (85.7 %) among that of MRI (57 %) and (18)F-FDG PET/CT (14.3 %). The size of pathological tumor was accorded with that detected by (18)F-FAMT PET/CT and was smaller than that detected by (18)F-FDG PET/CT (P < 0.01). Significant difference was not found between (18)F FAMT PET tumor volume and pathological tumor volume. CONCLUSIONS: (18)F-FAMT PET/CT was useful and more specific than MRI or (18)F-FDG PET/CT in the detection of bone marrow invasion of OSCC and may contribute to minimize the extent of resection in oral surgery patient. PMID- 23436245 TI - Myeloperoxidase activity and its corresponding mRNA expression as well as gene polymorphism in the population living in the coal-burning endemic fluorosis area in Guizhou of China. AB - The myeloperoxidase (MPO) activity and its corresponding mRNA expression as well as gene polymorphism were investigated in the population who live in the endemic fluorosis area. In the study, 150 people were selected from the coal-burning endemic fluorosis area and 150 normal persons from the non-fluorosis area in Guizhou province of China. The blood samples were collected from these people. The activity of MPO in the plasma was determined by spectrophotometer; the expression of MPO mRNA was measured by employing real-time polymerase chain reaction; DNAs were extracted from the leucocytes in blood and five SNP genotypes of MPO promoter gene detected by a multiplex genotyping method, adapter-ligation mediated allele-specific amplification. The results showed that the MPO activity and its corresponding mRNA in blood were significantly increased in the population living in the area of fluorosis. The different genotype frequencies of MPO, including -1228G/A, -585T/C, -463G/A, and -163C/T, and the three haplotypes with higher frequencies, including -163C-463G-585T-1228G-1276T, -163C-463G-585T 1228G-1276C, and -163C-463G-585T-1228A-1276T, were significantly associated with fluorosis. The results indicated that the elevated activity of MPO induced by endemic fluorosis may be connected in mechanism to the stimulated expression of MPO mRNA and the changed gene polymorphism. PMID- 23436244 TI - Polarity gene discs large homolog 1 regulates the generation of memory T cells. AB - Mammalian ortholog of Drosophila cell polarity protein, Dlg1, plays a critical role in neural synapse formation, epithelial cell homeostasis, and urogenital development. More recently, it has been proposed that Dlg1 may also be involved in the regulation of T-cell proliferation, migration, and Ag-receptor signaling. However, a requirement for Dlg1 in development and function of T lineage cells remains to be established. In this study, we investigated a role for Dlg1 during T-cell development and function using a combination of conditional Dlg1 KO and two different Cre expression systems where Dlg1 deficiency is restricted to the T cell lineage only, or all hematopoietic cells. Here, using three different TCR models, we show that Dlg1 is not required during development and selection of thymocytes bearing functionally rearranged TCR transgenes. Moreover, Dlg1 is dispensable in the activation and proliferative expansion of Ag-specific TCR transgenic CD4(+) and CD8(+) T cells in vitro and in vivo. Surprisingly, however, we show that Dlg1 is required for normal generation of memory T cells during endogenous response to cognate Ag. Thus, Dlg1 is not required for the thymocyte selection or the activation of primary T cells, however it is involved in the generation of memory T cells. PMID- 23436247 TI - A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer. AB - E3 ubiquitin ligases and deubiquitylating enzymes (DUBs) are the key components of ubiquitin proteasome system which plays a critical role in cellular protein homeostasis. Any shortcoming in their biological roles can lead to various diseases including cancer. The dynamic interplay between ubiquitylation and deubiquitylation determines the level and activity of several proteins including p53, which is crucial for cellular stress response and tumor suppression pathways. In this review, we describe the different types of E3 ubiquitin ligases including those targeting tumor suppressor p53, SCF ligases and RING type ligases and accentuate on biological functions of few important E3 ligases in the cellular regulatory networks. Tumor suppressor p53 level is tightly regulated by multiple E3 ligases including Mdm2, COP1, Pirh2, etc. SCF ubiquitin ligase complexes are key regulators of cell cycle and signal transduction. BRCA1 and VHL RING type ligases function as tumor suppressors and play an important role in DNA repair and hypoxia response respectively. Further, we discuss the biological consequences of deregulation of the E3 ligases and the implications for cancer development. We also describe deubiquitylases which reverse the process of ubiquitylation and regulate diverse cellular pathways including metabolism, cell cycle control and chromatin remodelling. As the E3 ubiquitin ligases and DUBs work in a substrate specific manner, an improved understanding of them can lead to better therapeutics for cancer. PMID- 23436248 TI - Reply: To PMID 22183986. PMID- 23436249 TI - Development of a new UPLC-MSMS method for the determination of temozolomide in mice: application to plasma pharmacokinetics and brain distribution study. AB - A sensitive and accurate liquid chromatography method with mass spectrometry detection was developed and validated for the quantification of temozolomide in mouse plasma and brain. Theophyllin was used as the internal standard. A single step protein precipitation was used for plasma and brain sample preparation. The method was validated with respect to selectivity, extraction recovery, linearity, intra- and inter-day precision and accuracy, limit of quantification and stability. The method has a limit of quantification of 50 ng/mL for temozolomide in plasma and 125 ng/g in brain. This method was used successfully to perform brain and plasma pharmacokinetic studies of temozolomide in mice after intraperitoneal administration. PMID- 23436250 TI - Expert anticipation from deceptive action. AB - Expertise in sports enhances the ability to anticipate forthcoming events from the observation of a player's actions. In the present study, we investigated whether this ability is applicable to deceptive action. In three experiments, performance at anticipating the direction change of a running opponent was examined with experienced rugby players and novice counterparts. These experiments were conducted with reaction-time and temporal-occlusion tasks, in combination with eye movement recordings and the presentation of filmed actions and their point-light representations. The main finding was that the experienced players were superior to the novices in their anticipation of deceptive actions, although their performance was still impaired by the deception, in comparison with their anticipation of nondeceptive actions. We also found that the experienced players anticipated nondeceptive actions less accurately than the novices, suggesting that the players' expectations of deceptive actions worked negatively on their judgments of nondeceptive actions. The results obtained with the point-light representations closely resembled those obtained with the filmed sequences, indicating that anticipation was based on the kinematics of the running action. These results are discussed in the context of recent developments in research on expertise and deception in sports. PMID- 23436251 TI - Birth rates among female cancer survivors: a population-based cohort study in Sweden. AB - BACKGROUND: More women of fertile age are long-term survivors of cancer. However, population-based data on birth rates of female cancer survivors are rare. METHODS: A total of 42,691 women <= 45 years with a history of cancer were identified from the Swedish Multi-Generation Register and the Swedish Cancer Register, for whom relative birth rates were calculated as compared to the background population, ie, standardized birth ratios (SBRs). Independent factors associated with reduced birth rates among cancer survivors were estimated using Poisson modeling. RESULTS: Compared to the background population, cancer survivors were 27% less likely to give birth (SBR = 0.73, 95% confidence interval [CI] = 0.72-0.75). Large difference in SBRs existed by cancer site, with high SBRs for survivors of melanoma skin, thoracic, head and neck, and thyroid cancers, and low SBRs for reproductive, breast, brain and eye, and hematopoietic cancer survivors. Parity status at diagnosis affected fertility: women who already had a child at the time of diagnosis were less likely to give birth (SBR = 0.50, 95% CI = 0.48-0.53) than were nulliparous women (SBR = 0.87, 95% CI = 0.85-0.90). Multivariate analysis showed that cancer site (reproductive organs), age at onset of cancer (< 12 years), and parity status were all significant and independent predictors of a reduced probability of giving birth after diagnosis. CONCLUSIONS: Cancer survivors are less likely to give birth compared with the background population. Large variations in the likelihood to give birth after diagnosis were seen according to age at onset, cancer site, and parity status at diagnosis. PMID- 23436252 TI - The entrapment of chiral guests with gated baskets: can a kinetic discrimination of enantiomers be governed through gating? AB - The capacity of gated hosts for controlling a kinetic discrimination between stereoisomers is yet to be understood. To conduct corresponding studies, however, one needs to develop chiral, but modular and gated hosts. Accordingly, we used computational (RI-BP86/TZVP//RI-BP86/SV(P)) and experimental (NMR/CD/UV/Vis spectroscopy) methods to examine the transfer of chirality in gated baskets. We found that placing stereocenters of the same kind at the rim (R(1) =CH3, so called bottom) and/or top amide positions (R(2) =sec-butyl) would direct the helical arrangement of the gates into a P or M propeller-like orientation. With the assistance of (1)H NMR spectroscopy, we quantified the intrinsic (thermodynamic) and constrictive (kinetic) binding affinities of (R)- and (S)-1,2 dibromopropane 5 toward baskets (S3b/P)-2, (S3t/M)-3, and (S3bt/P)-4. Interestingly, each basket has a low ( <=1.3 kcal mol(-1)), but comparable (de<10%) affinity for entrapping enantiomeric (R/S)-5. In terms of the kinetics, basket (S3b/P)-2, with a set of S stereocenters at the bottom and P arrangement of the gates, would capture (R)-5 at a faster rate (kin(R)/kin(S) =2.0+/-0.2). Basket (S3t/M)-3, with a set of S centers at the top and M arrangement of the gates, however, trapped (S)-5 at a faster rate (kin(R)/kin(S) =0.30+/-0.05). In light of these findings, basket (S3bt/P)-4, with a set of S stereocenters installed at both top and bottom sites along with a P disposition of the gates, was found to have a lower ability to differentiate between enantiomeric (R/S)-5 (kin(R)/kin(S) =0.8). Evidently, the two sets of stereocenters in this "hybrid" host acted concurrently, each with the opposite effect on the entrapment kinetics. Gated baskets are hereby established to be a prototype for quantifying the kinetic discrimination of enantiomers through gating and elucidating the electronic/steric effects on the process. PMID- 23436253 TI - Reassessing an old claim: natural selection of hemizygotes and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. PMID- 23436254 TI - Microporous carbon nanoplates from regenerated silk proteins for supercapacitors. AB - Novel carbon-based microporous nanoplates containing numerous heteroatoms (H CMNs) are fabricated from regenerated silk fibroin by the carbonization and activation of KOH. The H-CMNs exhibit superior electrochemical performance, displaying a specific capacitance of 264 F/g in aqueous electrolytes, a specific energy of 133 Wh/kg, a specific power of 217 kW/kg, and a stable cycle life over 10000 cycles. PMID- 23436255 TI - Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies. AB - Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity. PMID- 23436256 TI - Antipsychotic interventions in prodromal psychosis: safety issues. AB - In recent years, psychopharmacological intervention in prodromal psychosis, also known as the ultra-high risk (UHR) mental state for psychosis, has attracted much attention. Whilst it has been shown that antipsychotic use in UHR individuals may be effective in potentially delaying or even averting progression to frank psychosis, their use in subjects that do not necessarily convert to psychosis has raised considerable ethical concerns because of their adverse effects. Recent treatment guidelines for patients at UHR for psychosis recommend the use of antipsychotics only in exceptional conditions and with great precautions. To date only a few studies have investigated the use of antipsychotic medications in UHR patients and the potential benefits and risks related to their use in prodromal psychosis remain unclear. We review here all published studies that included UHR patients treated with antipsychotics, regardless of study design. These studies were all of second-generation antipsychotics, given that first-generation antipsychotics cannot be recommended because of their adverse drug reactions. We specifically examine the available descriptions of adverse reactions of the individual antipsychotic medication in each study and discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in UHR patients. Clinical trials to date investigating potential benefits of antipsychotic treatments in preventing transition to psychosis were of relatively short duration and have involved a small number of patients. Whilst it appears that pharmacological intervention at this stage may be effective in both reducing the psychopathology and decreasing transition rates, and is potentially safe, in the absence of sufficient evidence based knowledge to guide treatment, definitive clinical recommendations and guidelines cannot be derived. Certain adverse events take time to develop, such as metabolic syndrome and endocrine-related effects, thus longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events. This can inform the development of timely strategies to prevent serious negative impacts and thus maximize the benefits of antipsychotic intervention in UHR patients that outweigh the risks associated with their use. PMID- 23436257 TI - Rationalization of interpretation of uroflowmetry for a non-caucasian (Indian) population: conceptual development and validation of volume-normalized flow rate index. AB - AIMS: We intended to define volume-normalized flow rates (cQ; VQI) and to construct and validate uroflow (Q)-volume (V) nomograms in our Indian (non Caucasian) population. METHODS: Prospective observational study. PARTICIPANTS: Group A, male healthy volunteers 18-45 years without LUTS. Group B, men >18 years with LUTS (IPSS > 7; global QOL > 2). The participants voided in standing on normal-to-strong desire into digital gravimetric uroflowmeter. Data of <50 ml void and intermittent flow was discarded. Reference cQ calculated using (i) Von Garrelts equations (=Q/VV(2)), (ii) cubic equations (=Q/VV(3)). Bladder volume (BV) rather than voided volume (VV) was considered for Q-V relation (BV = VV + PVR). VQI derived from present data were compared with the reference-VQI in terms of differences in area-under-curve of receiver operating characteristics. For comparing sensitivity, specificity and predictive values of study nomograms with Caucasian nomograms (Liverpool and Siroky), data of group-A and -B were plotted on each nomogram and no. of observations above and below the cutoffs (defined as equivalent to -1 SD) manually counted. RESULTS: Total 542 voids of group-A and 465 of group-B included for final analysis. Q-V relation was best described as [Q ? BV(2.4) ? BV(2)]. The derived VQI (=Q/BV(2.4) ? Q/BV(2)) fared significantly superior to reference VQI with VV as denominator. Nomograms, constructed on Q ? BV(2) , were less sensitive but had higher specificity and positive predictive values compared to Caucasian nomograms. CONCLUSIONS: Volume-normalized flow-rate index with BV as denominator (Q/BV(2)) is has highly discriminative value in screening for voiding dysfunction. Population-specific Q-BV nomograms are more specific and predictive than Caucasian Q-VV nomograms. PMID- 23436258 TI - Pharmacokinetic properties of anti-influenza neuraminidase inhibitors. AB - Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t(1/2) beta) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t(1/2) beta of approximately 3.0 hours). Peramivir is slowly eliminated (t(1/2) beta of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation. PMID- 23436259 TI - The pharmacokinetics and pharmacodynamics of zaleplon delivered as a thermally generated aerosol in a single breath to volunteers. AB - Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double blind, parallel-group, dose escalation study. Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours. Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1.89 (1.45, 3.08) minutes and the mean (SD) elimination half-life was 1.24 (0.24) hours. The equilibration half-life for sedation (t(1/2) k(e0) ) was 1.16 (0.62, 2.17) minutes. The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0.92 (0.82, 1.02). No clinically significant changes were noted in laboratory values, vital signs, or spirometry. The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance. Zaleplon inhalation represents a safe, well tolerated means of rapidly achieving effective plasma concentrations. PMID- 23436260 TI - Exposure-response relationship of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in a large population of patients with rheumatoid arthritis. AB - Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid E(max) (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC(50) (concentration at which 50% of E(max) on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity. PMID- 23436261 TI - The combination of exposure-response and case-control analyses in regulatory decision making. AB - To reduce the bias introduced by confounding risk factors, a case-control comparison was incorporated in the exposure-response (ER) analysis to evaluate the recommended dosing regimen for trastuzumab in a pivotal trial. Results of Kaplan-Meier survival analysis suggest that patients with metastatic gastric cancer (mGC) in the lowest quartile trough concentrations of trastuzumab in cycle 1 (C(min 1) ) had shorter overall survival (OS) than did those in other quartiles. The result of the case-matched control comparison suggests that adjusting for these risk factors, patients with the lowest quartile of trastuzumab exposure did not benefit from addition of trastuzumab treatment to chemotherapy. The identified subgroup without survival benefit and the ER relationship support the recommendation on conducting clinical trials to identify a treatment regimen with greater exposure and acceptable safety profiles and to prospectively evaluate whether this treatment regimen will result in survival benefit for the identified subgroup. PMID- 23436262 TI - Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 1: volume of distribution at steady state. AB - The authors present a comprehensive analysis on the estimation of volume of distribution at steady state (VD(ss) ) in human based on rat, dog, and monkey data on nearly 400 compounds for which there are also associated human data. This data set, to the authors- knowledge, is the largest publicly available, has been carefully compiled from literature reports, and was expanded with some in-house determinations such as plasma protein binding data. This work offers a good statistical basis for the evaluation of applicable prediction methods, their accuracy, and some methods-dependent diagnostic tools. The authors also grouped the compounds according to their charge classes and show the applicability of each method considered to each class, offering further insight into the probability of a successful prediction. Furthermore, they found that the use of fraction unbound in plasma, to obtain unbound volume of distribution, is generally detrimental to accuracy of several methods, and they discuss possible reasons. Overall, the approach using dog and monkey data in the iie-Tozer equation offers the highest probability of success, with an intrinsic diagnostic tool based on aberrant values (<0 or >1) for the calculated fraction unbound in tissue. Alternatively, methods based on dog data (single-species scaling) and rat and dog data (iie-Tozer equation with 2 species or multiple regression methods) may be considered reasonable approaches while not requiring data in nonhuman primates. PMID- 23436263 TI - Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 2: clearance. AB - A comprehensive analysis on the prediction of human clearance based on intravenous pharmacokinetic data from rat, dog, and monkey for approximately 400 compounds was undertaken. This data set has been carefully compiled from literature reports and expanded with some in-house determinations for plasma protein binding and rat clearance. To the authors- knowledge, this is the largest publicly available data set. The present examination offers a comparison of 37 different methods for prediction of human clearance across compounds of diverse physicochemical properties. Furthermore, this work demonstrates the application of each prediction method to each charge class of the compounds, thus presenting an additional dimension to prediction of human pharmacokinetics. In general, the observations suggest that methods employing monkey clearance values and a method incorporating differences in plasma protein binding between rat and human yield the best overall predictions as suggested by approximately 60% compounds within 2 fold geometric mean-fold error. Other single-species scaling or proportionality methods incorporating the fraction unbound in the corresponding preclinical species for prediction of free clearance in human were generally unsuccessful. PMID- 23436264 TI - Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. AB - Trastuzumab is a key component of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in both the early and metastatic settings. It is administered intravenously, with between 17 and 52 infusions in standard regimens over 1 year. Intravenous administration of trastuzumab requires substantial time commitments for patients and health care professionals and can result in patient discomfort. A subcutaneous formulation of trastuzumab, containing recombinant human hyaluronidase to overcome subcutaneous absorption barriers, would reduce the administration duration and remove the need to establish intravenous access, thus improving the overall convenience of trastuzumab administration. This open-label, 2-part, phase I/Ib study (NCT00800436) was undertaken in healthy male volunteers and female patients with HER2-positive early breast cancer to identify the dose of subcutaneous trastuzumab that resulted in exposure comparable with the approved intravenous trastuzumab dose. A subcutaneous trastuzumab dose of 8 mg/kg was found to result in exposure comparable with the intravenous trastuzumab dose of 6 mg/kg. The subcutaneous formulation was well tolerated, with a trend toward fewer adverse events versus intravenous administration; most adverse events were mild in intensity. These results support an ongoing phase III efficacy and safety study comparing a fixed subcutaneous trastuzumab dose with intravenous trastuzumab administration. PMID- 23436265 TI - Steady-state pharmacokinetics of etravirine and lopinavir/ritonavir melt extrusion formulation, alone and in combination, in healthy HIV-negative volunteers. AB - BACKGROUND: A previous study investigating coadministration of etravirine, a nonnucleoside reverse transcriptase inhibitor, and lopinavir/ritonavir soft-gel formulation resulted in nonclinically relevant changes in etravirine and lopinavir exposure. The current study evaluated the pharmacokinetic interaction between etravirine and the lopinavir/ritonavir melt extrusion formulation. METHOD: Sixteen human immunodeficiency virus (HIV)-negative volunteers were randomized to either treatment sequence A/B or B/A, with 14 days- washout between treatments (treatment A: etravirine 200 mg bid for 8 days; treatment B: lopinavir/ritonavir 400/100 mg bid for 16 days with etravirine 200 mg bid on days 9-16). Steady-state pharmacokinetics were assessed for all antiretrovirals alone and coadministered; pharmacokinetic parameters were obtained by noncompartmental analysis. Safety and tolerability were assessed. RESULTS: Coadministration of etravirine and lopinavir/ritonavir resulted in a 35% decrease in etravirine exposure. Smaller decreases (<13%) were observed in lopinavir and ritonavir exposure. Six volunteers reported headache; 1 grade 3 triglyceride increase was reported. CONCLUSION: Lopinavir/ritonavir induced etravirine metabolism to a similar extent as most other boosted HIV protease inhibitors. The short-term coadministration of etravirine and lopinavir/ritonavir was well tolerated and did not lead to increased incidences of adverse events. PMID- 23436266 TI - Clinical risk factors for adverse events in allopurinol users. AB - Allopurinol, one of the most commonly used uric acid-lowering agents, can cause serious adverse events. To investigate the risk factors for allopurinol-induced adverse events, the authors enrolled 94 patients who developed allopurinol induced adverse events and 378 controls who were randomly chosen from 1934 patients who used allopurinol but did not develop any adverse events in this retrospective case control study. Univariate analysis showed that patients who developed allopurinol-induced adverse events had more chronic kidney disease (46% vs 30%, P = .005), more hypertension (42% vs 30%, P = .036), less tumor lysis syndrome (P = .030), higher cholesterol (P = .013), and lower aspartate aminotransferase (P = .002) and alanine aminotransferase levels (P = .033) and more commonly used angiotensin receptor blockers (27% vs 15%, P = .007), colchicines (16% vs 5%, P = .010), or statins (19% vs 8%, P = .002) than those who did not. In multiple logistic regression analysis, the use of colchicines (odds ratio, 3.11; 95% confidence interval, 1.28-7.58; P = .012) and statins (2.10; 1.03-4.25; P = .041) was an independent risk factor predicting adverse events in allopurinol users. In conclusion, patients who use colchicine or statins are at significant risk for developing allopurinol-induced adverse events. PMID- 23436267 TI - Inhibitory effect of ketoconazole on the pharmacokinetics of a multireceptor tyrosine kinase inhibitor BMS-690514 in healthy participants: assessing the mechanism of the interaction with physiologically-based pharmacokinetic simulations. AB - BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC(infinity) of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized C(max) and AUC(infinity) of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate. PMID- 23436268 TI - Review of P-gp inhibition data in recently approved new drug applications: utility of the proposed [I(1) ]/IC(50) and [I(2) ]/IC(50) criteria in the P-gp decision tree. PMID- 23436270 TI - Validation of a screening battery to predict driving fitness in people with Parkinson's disease. AB - BACKGROUND: We previously developed a short clinical battery, consisting of contrast sensitivity, Clinical Dementia Rating, the Unified Parkinson's Disease Rating Scale-motor section (UPDRS III), and disease duration, which correctly classified 90% of drivers with Parkinson's Disease (PD). The aim of this study was to validate that screening battery in a different sample of PD drivers. METHODS: Sixty drivers with PD were enrolled to validate our original screening battery to predict driving fitness decisions (pass-fail) by a state agency where drivers underwent detailed visual, cognitive, and on-road testing. RESULTS: Twenty-four participants (40%) failed the driving evaluation. The screening battery correctly classified 46 (77%) participants (sensitivity and negative predictive value = 96%; specificity and positive predictive value = 64%). Adding other clinical predictors (e.g., age of onset, Hoehn-Yahr stage instead of UPDRS III) failed to improve the specificity of the model when the sensitivity was kept constant at 96%. However, a driving simulator evaluation improved the specificity of the model to 94%. CONCLUSIONS: The original clinical battery proved to be a valid screening tool that accurately identifies fit drivers with PD and select those who need more detailed testing at specialized centers. PMID- 23436271 TI - Process development for cell aggregate arrays encapsulated in a synthetic hydrogel using negative dielectrophoresis. AB - Spatial patterning of cells is of great importance in tissue engineering and biotechnology, enabling, for example the creation of bottom-up histoarchitectures of heterogeneous cells, or cell aggregates for in vitro high-throughput toxicological and therapeutic studies within 3D microenvironments. In this paper, a single-step process for creating peelable and resilient hydrogels, encapsulating arrays of biological cell aggregates formed by negative DEP has been devised. The dielectrophoretic trapping within low-energy regions of the DEP dot array reduces cell exposure to high field stresses while creating distinguishable, evenly spaced arrays of aggregates. In addition to using an optimal combination of PEG diacrylate pre-polymer solution concentration and a novel UV exposure mechanism, total processing time was reduced. With a continuous phase medium of PEG diacrylate at 15% v/v concentration, effective dielectrophoretic cell patterned arrays and photo-polymerisation of the mixture was achieved within a 4 min period. This unique single-step process was achieved using a 30 s UV exposure time frame within a dedicated, wide exposure area DEP light box system. To demonstrate the developed process, aggregates of yeast, human leukemic (K562) and HeLa cells were immobilised in an array format within the hydrogel. Relative cell viability for both cells within the hydrogels, after maintaining them in appropriate iso-osmotic media, over a week period was greater than 90%. PMID- 23436269 TI - Population pharmacokinetic modeling of sertraline treatment in patients with Alzheimer disease: the DIADS-2 study. PMID- 23436272 TI - Interactive influences of ethnicity, endothelin-1 gene, and everyday discrimination upon nocturnal ambulatory blood pressure. AB - BACKGROUND: Everyday discrimination scale scores are associated with increased ambulatory blood pressure (BP) and reduced nocturnal dipping, and the endothelin 1 (ET-1)/Lys198Asn polymorphism is associated with increased resting BP and exaggerated BP reactivity among African Americans compared to European Americans. Combined influences of these factors on BP control are unknown. PURPOSE: This study tested the hypothesis of a three-way interaction between ethnicity, ET-1 carrier status, and everyday discrimination upon ambulatory BP and nocturnal dipping. METHODS: Baseline laboratory anthropometrics and the everyday discrimination scale were completed by 352 (175 African American) young adult normotensives, followed by 24-h ambulatory BP monitoring. RESULTS: For nocturnal dipping, multiple regression models controlling for age, sex, ethnicity, and body mass index revealed significant three-way ET-1 * everyday discrimination * ethnicity interactions. Specifically, among African American ET-1 T-allele carriers, increases in everyday discrimination led to reduced nocturnal dipping. CONCLUSIONS: African Americans that carry the ET-1/Lys198Asn T-allele and report higher everyday discrimination scores may be at particular risk for reduced nocturnal dipping. PMID- 23436273 TI - Association between smoking and heart rate variability among individuals with depression. AB - BACKGROUND: Both depression and smoking have been independently associated with lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. However, no studies have systematically explored the effects of smoking on HRV among depressed patients. PURPOSE: This study examined differences in HRV based on smoking status among depressed individuals. METHODS: Electrophysiological data were examined among 77 adult outpatients without a history of myocardial infarction, who met criteria for major depressive disorder or dysthymia. Frequency domain [low frequency (LF), high frequency (HF), LF/HF ratio, respiratory sinus arrhythmia (RSA)] parameters of HRV, and heart rate and inter-beat interval (IBI) data were compared between depressed smokers (n = 34) and depressed nonsmokers (n = 44). RESULTS: After controlling for covariates, depressed smokers, compared to depressed nonsmokers, displayed significantly lower LF, HF, and RSA. CONCLUSIONS: Among depressed patients, smoking is associated with significantly lower HRV, indicating dysregulated autonomic modulation of the heart. PMID- 23436274 TI - The influence of perceived stress on the onset of arthritis in women: findings from the Australian Longitudinal Study on women's health. AB - BACKGROUND: Psychosocial factors are considered as risk factors for some chronic diseases. A paucity of research exists surrounding the role of perceived stress in arthritis onset. PURPOSE: Perceived stress as a risk factor for arthritis development was explored in an ageing cohort of Australian women. METHODS: This study focused on 12,202 women from the 1946-1951 cohort who completed the Australian Longitudinal Study on Women's Health surveys in 2001, 2004 and 2007. Longitudinal associations were modelled, with and without a time lag. RESULTS: Findings from the multivariate time lag modelling, excluding women with persistent joint pain, revealed that perceived stress predicted the onset of arthritis, with women experiencing minimal and moderate/high stress levels having a 1.7 and 2.4 times greater odds of developing arthritis 3 years later, respectively (p's < 0.001). CONCLUSION: Chronically perceiving life as stressful is detrimental to future health. The findings provide support for perceived stress to be considered alongside other modifiable risk factors. PMID- 23436276 TI - Moderating effect of socioeconomic status on the relationship between health cognitions and behaviors. AB - BACKGROUND: There is an established link between socioeconomic status (SES) and performance of health behaviors with more health protective and fewer health risking behaviors in higher SES groups. PURPOSE: This research is novel in testing the moderating effect of SES on the relationship among intention, self efficacy, and subsequent behavior. METHODS: Effects were tested on data from three prospective correlational studies examining smoking initiation in adolescents (N = 826), breastfeeding in primiparous women (N = 202), and physical activity in working adults (N = 509). RESULTS: Despite examining different behaviors, samples, time intervals, and measures of SES, each study showed significant interactions between intention and SES in predicting behavior. In all three tests, the intention-behavior relationship was attenuated among individuals from lower SES groups. No moderation effects of SES were found for self-efficacy. CONCLUSIONS: The intention-health behavior relationship can be attenuated in lower SES samples. This finding may contribute to our understanding of SES differences in health behaviors. PMID- 23436275 TI - Leptin and its association with somatic depressive symptoms in patients with the metabolic syndrome. AB - BACKGROUND: This study aimed to determine the association between circulating leptin levels and total depressive symptoms as well as depressive symptom dimensions (cognitive and somatic) after controlling for important confounding factors. METHODS: The study sample was comprised of 135 participants with the metabolic syndrome. Depressive symptoms were measured using the Beck Depression Inventory-II. Leptin was measured using a leptin-specific enzyme immunoassay. Inflammation was assessed using C-reactive protein and interleukin-6 levels. RESULTS: Leptin was significantly associated with somatic depressive symptoms (beta = 0.33, P = 0.018), but not total depressive symptoms (beta = 0.27, P = 0.067) or cognitive depressive symptoms (beta = 0.21, P = 0.182), after controlling for age, gender, body mass index, and insulin resistance. Further adjustment for C-reactive protein and interleukin-6 levels did not alter the relationship (beta = 0.32, P = 0.023) between circulating leptin levels and somatic depressive symptoms. CONCLUSIONS: Leptin is independently associated with somatic depressive symptoms in patients with the metabolic syndrome. PMID- 23436277 TI - Metabolic engineering of Escherichia coli for the production of fumaric acid. AB - Fumaric acid is a naturally occurring organic acid that is an intermediate of the tricarboxylic acid cycle. Fungal species belonging to Rhizopus have traditionally been employed for the production of fumaric acid. In this study, Escherichia coli was metabolically engineered for the production of fumaric acid under aerobic condition. For the aerobic production of fumaric acid, the iclR gene was deleted to redirect the carbon flux through the glyoxylate shunt. In addition, the fumA, fumB, and fumC genes were also deleted to enhance fumaric acid formation. The resulting strain was able to produce 1.45 g/L of fumaric acid from 15 g/L of glucose in flask culture. Based on in silico flux response analysis, this base strain was further engineered by plasmid-based overexpression of the native ppc gene, encoding phosphoenolpyruvate carboxylase (PPC), from the strong tac promoter, which resulted in the production of 4.09 g/L of fumaric acid. Additionally, the arcA and ptsG genes were deleted to reinforce the oxidative TCA cycle flux, and the aspA gene was deleted to block the conversion of fumaric acid into L-aspartic acid. Since it is desirable to avoid the use of inducer, the lacI gene was also deleted. To increase glucose uptake rate and fumaric acid productivity, the native promoter of the galP gene was replaced with the strong trc promoter. Fed-batch culture of the final strain CWF812 allowed production of 28.2 g/L fumaric acid in 63 h with the overall yield and productivity of 0.389 g fumaric acid/g glucose and 0.448 g/L/h, respectively. This study demonstrates the possibility for the efficient production of fumaric acid by metabolically engineered E. coli. PMID- 23436278 TI - Intergenerational effects of in utero exposure to Ramadan in Tunisia. AB - We have reported that changes in the lifestyle of pregnant women during Ramadan affect more than one generation. In a series of newborn babies in Saudi Arabia, those whose mothers had been in utero during Ramadan differed from those whose mothers had not been in utero during Ramadan. These were unexpected findings and require replication. METHODS: We examined body size at birth in 1,321 babies (682 boys and 639 girls) born in Gafsa, a small city in Tunisia. RESULTS: Babies whose mothers had been in utero during Ramadan were smaller and thinner, and had smaller placentas, than those whose mothers had not been in utero during Ramadan. After adjustment for sex, the babies were 93 g lighter (95% confidence interval, 32-153, P=0.003) than those whose mother had not been in utero during Ramadan, their mean ponderal index was 0.52 kg/m(3) lower (0.24-0.79, P<0.001) and their placental weight was 21 g lower (5-37, P=0.01). The findings did not differ by trimester of maternal exposure to Ramadan. They were similar in boys and girls and in primiparous and multiparous mothers CONCLUSION: This study provides further evidence that changes in lifestyle during Ramadan have intergenerational effects. PMID- 23436279 TI - Gambogic acid sensitizes ovarian cancer cells to doxorubicin through ROS-mediated apoptosis. AB - Ovarian cancer is one human malignancy which has response portly to doxorubicin. The anti-cancer activity of gambogic acid has been tested in in vitro and in vivo studies. In this study, we showed that gambogic acid, a natural compound, could potentiate the anticancer activity of doxorubicin in ovarian cancer through ROS mediated apoptosis. Platinum-resistant human ovarian cancer cell line (SKOV-3) was treated with gambogic acid, doxorubicin, or the combination of both to investigate cell proliferation and apoptosis. We found that the combination of gambogic acid and doxorubicin causes synergistic loss of cell viability in SKOV-3 cells and this synergistic effect correlated with increased cellular ROS accumulation. Moreover, in vivo results showed that gambogic acid and doxorubicin combination resulted in a synergistic suppressing effect on tumor growth in ovarian cancer mice model. Taken together, the results suggested that doxorubicin in combination with gambogic acid might provide a promising therapeutic strategy to enhance chemosensitivity of ovarian cancer to doxorubicin. PMID- 23436280 TI - Coupling photocatalysis and redox biocatalysis toward biocatalyzed artificial photosynthesis. AB - In green plants, solar-energy utilization is accomplished through a cascade of photoinduced electron transfer, which remains a target model for realizing artificial photosynthesis. We introduce the concept of biocatalyzed artificial photosynthesis through coupling redox biocatalysis with photocatalysis to mimic natural photosynthesis based on visible-light-driven regeneration of enzyme cofactors. Key design principles for reaction components, such as electron donors, photosensitizers, and electron mediators, are described for artificial photosynthesis involving biocatalytic assemblies. Recent research outcomes that serve as a proof of the concept are summarized and current issues are discussed to provide a future perspective. PMID- 23436281 TI - Alternative metals for homogeneous catalyzed hydroformylation reactions. AB - Transition-metal-catalyzed hydroformylation reactions constitute one of the most powerful tools for C-C bond formation in organic synthesis and represent an outstanding example of the application of homogeneous catalysis on an industrial scale. This process allows for the straightforward conversion of inexpensive chemical feedstock into broadly applicable aldehydes, which serve as major building blocks for numerous chemical products. These products are highly valuable for the chemical industry and used as plasticizers, detergents, and surfactants on a million ton scale. Moreover, aldehydes serve as versatile chemical intermediates for the production of fine chemicals and pharmaceuticals. Currently, most of the bulk hydroformylation processes rely on rhodium-based catalysts. The increasing demand and resulting high cost of this precious metal has resulted in alternative transition-metal catalysts becoming highly desirable. The following Review summarizes the progress achieved utilizing Ru, Ir, Pd, Pt, and Fe catalysts in hydroformylation reactions. PMID- 23436284 TI - Wandering spleen: a mobile target for radiotherapy. PMID- 23436283 TI - Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. AB - BACKGROUND: Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam therapy (PBT). METHODS: The authors reviewed patient-reported outcomes data collected prospectively using validated instruments that assessed bowel and urinary quality of life (QOL) for patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153) or PBT (n = 95). Clinically meaningful differences in mean QOL scores were defined as those exceeding half the standard deviation of the baseline mean value. Changes from baseline were compared within groups at the first post-treatment follow-up (2-3 months from the start of treatment) and at 12 months and 24 months. RESULTS: At the first post-treatment follow-up, patients who received 3DCRT and IMRT, but not those who received PBT, reported a clinically meaningful decrement in bowel QOL. At 12 months and 24 months, all 3 cohorts reported clinically meaningful decrements in bowel QOL. Patients who received IMRT reported clinically meaningful decrements in the domains of urinary irritation/obstruction and incontinence at the first post treatment follow-up. At 12 months, patients who received PBT, but not those who received IMRT or 3DCRT, reported a clinically meaningful decrement in the urinary irritation/obstruction domain. At 24 months, none of the 3 cohorts reported clinically meaningful changes in urinary QOL. CONCLUSIONS: Patients who received 3DCRT, IMRT, or PBT reported distinct patterns of treatment-related QOL. Although the timing of toxicity varied between the cohorts, patients reported similar modest QOL decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months. Prospective randomized trials are needed to further examine these differences. PMID- 23436285 TI - Frequency of antibodies to mutated citrullinated vimentin in chronic obstructive pulmonary disease: comment on the article by Demoruelle et al. PMID- 23436287 TI - Identification and characterization of endo-beta-N-acetylglucosaminidase from methylotrophic yeast Ogataea minuta. AB - In four yeast strains, Ogataea minuta, Candida parapolymorpha, Pichia anomala and Zygosaccharomyces rouxii, we identified endo-beta-N-acetylglucosaminidase (ENGase) homologous sequences by database searches; in each of the four species, a corresponding enzyme activity was also confirmed in crude cell extract obtained from each strain. The O. minuta ENGase (Endo-Om)-encoding gene was directly amplified from O. minuta genomic DNA and sequenced. The Endo-Om-encoding gene contained a 2319-bp open-reading frame; the deduced amino acid sequence indicated that the putative protein belonged to glycoside hydrolase family 85. The gene was introduced into O. minuta, and the recombinant Endo-Om was overexpressed and purified. When the enzyme assay was performed using an agalacto-biantennary oligosaccharide as a substrate, Endo-Om exhibited both hydrolysis and transglycosylation activities. Endo-Om exhibited hydrolytic activity for high mannose, hybrid, biantennary and (2,6)-branched triantennary N-linked oligosaccharides, but not for tetraantennary, (2,4)-branched triantennary, bisecting N-acetylglucosamine structure and core-fucosylated biantennary N-linked oligosaccharides. Endo-Om also was able to hydrolyze N-glycans attached to RNase B and human transferrin under both denaturing and nondenaturing conditions. Thus, the present study reports the detection and characterization of a novel yeast ENGase. PMID- 23436286 TI - DNA-guided metal-nanoparticle formation on graphene oxide surface. PMID- 23436292 TI - RE: Harding C, Horsburgh B, Dorkin TJ, Thorpe AC. Quantifying the effect of urodynamic catheters on urine flow rate measurement. Neurourol urodyn 2012; 31:139-42, and Dr. Agarwal's response. Neurourol urodyn 2012; 31: 1307. PMID- 23436288 TI - Annotation and structural elucidation of bovine milk oligosaccharides and determination of novel fucosylated structures. AB - Bovine milk oligosaccharides (BMOs) are recognized by the dairy and food industries, as well as by infant formula manufacturers, as novel, high-potential bioactive food ingredients. Recent studies revealed that bovine milk contains complex oligosaccharides structurally related to those previously thought to be present in only human milk. These BMOs are microbiotic modulators involved in important biological activities, including preventing pathogen binding to the intestinal epithelium and serving as nutrients for a selected class of beneficial bacteria. Only a small number of BMO structures are fully elucidated. To better understand the potential of BMOs as a class of biotherapeutics, their detailed structure analysis is needed. This study initiated the development of a structure library of BMOs and a comprehensive evaluation of structure-related specificity. The bovine milk glycome was profiled by high-performance mass spectrometry and advanced separation techniques to obtain a comprehensive catalog of BMOs, including several novel, lower abundant neutral and fucosylated oligosaccharides that are often overlooked during analysis. Structures were identified using isomer-specific tandem mass spectroscopy and targeted exoglycosidase digestions to produce a BMO library detailing retention time, accurate mass and structure to allow their rapid identification in future studies. PMID- 23436289 TI - Selective executive dysfunction but intact risky decision-making in early Huntington's disease. AB - Executive dysfunction, including problems with decision-making, inhibition of prepotent responses, and verbal fluency, are main features of Huntington's disease (HD). The decline of executive function in HD is related to the anatomical progression of HD pathology in the basal ganglia, where the earliest changes of neuronal cell death are seen in the dorsolateral caudate. To examine the specific pattern of executive dysfunction in early HD, 18 patients with early HD were assessed on: (1) the Iowa Gambling Task to measure risky decision making, (2) the Stroop test to measure inhibition of prepotent responses, and (3) the verbal fluency test to measure internally guided word search and production, necessitating suppression of retrieval/production of inappropriate words and monitoring of the output. Patients with early HD were significantly impaired on the Stroop and verbal fluency tests relative to controls. However, Iowa Gambling Task performance was comparable across the 2 groups. This pattern of selective executive dysfunction in early HD probably reflects the fact that inhibitory processing involved in both the Stroop and verbal fluency tests recruits the dorsolateral caudate and its cortical connections, which are dysfunctional in early HD, whereas risky decision-making during the Iowa Gambling Task recruits the ventromedial caudate and its connections, which remain spared early on in the disease. The current results demonstrate that the deterioration of executive functioning in HD is variable and that some types of executive processing might already be impaired in early HD, whereas others remain intact. PMID- 23436294 TI - Systemic mastocytosis in the elderly. AB - "Later onset" of systemic mastocytosis (SM) has been associated with a poorer prognosis. We examined clinical and laboratory findings, associated disorders, and survival in an older mastocytosis population. After receiving Mayo Clinic Institutional Review Board approval, we identified 42 patients aged 70 years and older at the time of diagnosis of SM. Associated disorders, cytogenetic abnormalities, laboratory findings, and survival were recorded. Only 10 patients had no associated hematologic disorder. Single or multiple chromosomal abnormalities, exclusive of the KIT Asp816Val mutation, were detected in eight patients (19%). KIT Asp816Val mutation was present in 14 patients, negative in three, and not tested in 25. Slight to marked bone marrow hypercellularity was observed in 33 patients (79%). Concurrent hematologic abnormalities included chronic myelomonocytic leukemia (n = 7), acute myelocytic leukemia (n = 1), myelodysplastic syndrome (MDS; n = 7), eosinophilia (n = 7), myelofibrosis (n = 1), myeloproliferative disorder (n = 1), multiple myeloma (n = 1), B-cell lymphoma (n = 1), and thrombocytopenia (n = 4). Eight patients had a hematologic disorder that preceded the diagnosis of SM. Tryptase levels were elevated in 38 of 39 patients tested. Survival from the diagnosis of SM was poor for patients with associated thrombocytopenia, leukemias, and MDS. In conclusion, patients with SM diagnosed at age 70 or older have an increased risk of secondary hematologic disorders and abnormal laboratory findings. Cytogenetic abnormalities are common, and survival is short in many SM patients with associated leukemias, MDS, or eosinophilia. PMID- 23436293 TI - Drug-induced liver injury: the role of drug metabolism and transport. AB - Many studies have pinpointed the significant contribution of liver-mediated drug metabolism and transport to the complexity of drug-induced liver injury (DILI). Phase I cytochrome P450 (CYP450) enzymes can lead to altered drug metabolism and formation of toxic metabolites, whilst Phase II enzymes are also associated with DILI. The emerging role of hepatic transporters in regulating the movement of endogenous and exogenous chemicals (e.g., bile acids and drugs) across cellular and tissue membranes is critical in determining the pathophysiology of liver disease as well as drug toxicity and efficacy. Genetic and environmental factors can have a significant impact on drug metabolism and transporter proteins, consequently increasing the risk of DILI in susceptible individuals. The assessment of these factors therefore represents an important approach for predicting and preventing DILI, by better understanding the pharmacological profile of a specific drug. This review focuses on the mechanisms of DILI associated with drug metabolism and hepatic transport, and how they can be influenced by underlying factors. PMID- 23436295 TI - Microfluidic devices for the isolation of circulating rare cells: a focus on affinity-based, dielectrophoresis, and hydrophoresis. AB - Circulating rare cells have attracted interest because they can be good indicators of various types of diseases. For example, enumeration of circulating tumor cells is used for cancer diagnosis and prognosis, while DNA analysis or enumeration of nucleated red blood cells is useful for prenatal diagnosis or hypoxic anemia, and that of circulating stem cells to diagnose cancer metastasis. Isolation of these cells and their downstream analyses can provide significant information such as the origin and characteristics of a disease. Novel approaches based on microfluidics have many advantages, including the continuous process and integration with other components for analysis. For these reasons, a variety of microfluidic devices have been developed to isolate and characterize rare cells. In this article, we review several microfluidic devices, with a focus on affinity based isolation (e.g. antigen-antibody reaction) and label-free separation (DEP and hydrophoresis). PMID- 23436296 TI - Using high throughput screening to define virus clearance by chromatography resins. AB - High throughput screening (HTS) of chromatography resins can accelerate downstream process development by rapidly providing information on product and impurity partitioning over a wide range of experimental conditions. In addition to the removal of typical product and process-related impurities, chromatography steps are also used to remove potential adventitious viral contaminants and non infectious retrovirus-like particles expressed by rodent cell lines used for production. This article evaluates the feasibility of using HTS in a 96-well batch-binding format to study removal of the model retrovirus xenotropic murine leukemia virus (xMuLV) from product streams. Two resins were examined: the anion exchange resin Q Sepharose Fast FlowTM (QSFF) and Capto adhereTM, a mixed mode resin. QSFF batch-binding HTS data was generated using two mAbs at various pHs, NaCl concentrations, and levels of impurities. Comparison of HTS data to that generated using the column format showed good agreement with respect to virus retentation at different pHs, NaCl concentrations and impurity levels. Results indicate that NaCl concentration and impurity level, but not pH, are key parameters that can impact xMuLV binding to both resins. Binding of xMuLV to Capto adhere appeared to tolerate higher levels of NaCl and impurity than QSFF, and showed some product-specific impact on binding that was not observed with QSFF. Overall, the results demonstrate that the 96-well batch-binding HTS technique can be an effective tool for rapidly defining conditions for robust virus clearance on chromatographic resins. PMID- 23436297 TI - The Mancozeb-containing carbamate fungicide tattoo induces mild oxidative stress in goldfish brain, liver, and kidney. AB - Tattoo belongs to the group of carbamate fungicides and contains Mancozeb (ethylene(bis)dithiocarbamate) as its main constituent. The toxicity of Mancozeb to living organisms, particularly fish, is not resolved. This work investigated the effects of 96 h of exposure to 3, 5, or 10 mg L(-1) of Tattoo (corresponding to 0.9, 1.5, or 3 mg L(-1) of Mancozeb) on the levels of oxidative stress markers and the antioxidant enzyme system of brain, liver, and kidney of goldfish, Carassius auratus). In liver, Tattoo exposure resulted in increased activities of superoxide dismutase (SOD) by 70%-79%, catalase by 23%-52% and glutathione peroxidase (GPx) by 49%. The content of protein carbonyls (CP) in liver was also enhanced by 92%-125% indicating extensive damage to proteins. Similar increases in CP levels (by 98%-111%) accompanied by reduced glucose-6-phosphate dehydrogenase activity (by 13%-15%) was observed in kidney of fish exposed to Tattoo; however, SOD activity increased by 37% in this tissue after treatment with 10 mg L(-1) Tattoo. In brain, a rise in lipid peroxide level (by 29%) took place after exposure to 10 mg L(-1) Tattoo and was accompanied by elevation of high-molecular mass thiols (by 14%). Tattoo exposure also resulted in a concentration-dependent decrease in glutathione reductase activity (by 26%-37%) in brain. The data collectively show that exposure of goldfish to 3-10 mg L(-1) of the carbamate fungicide Tattoo resulted in the development of mild oxidative stress and activation of antioxidant defense systems in goldfish tissues. PMID- 23436298 TI - Transcatheter closure of a giant communication between the right pulmonary artery and left atrium in a neonate. AB - Direct communication between the right pulmonary artery and the left atrium is an extremely rare congenital pathologic entity characterized by right to left shunt and a rare cause of cyanosis in newborn. The value of echocardiography is emphasized in making the diagnosis as well as never before reported successful treatment with the Amplatzer vascular plug in a neonate. PMID- 23436300 TI - The combined role of catalysis and solvent effects on the Biginelli reaction: improving efficiency and sustainability. AB - The traditional Biginelli reaction is a three-component condensation between urea, benzaldehyde and an acetoacetate ester to give a dihydropyrimidinone. An investigation into catalytic and solvent effects has returned the conclusion that the diketo-enol tautomerisation equilibrium of the dicarbonyl reactant dictates the yield of the reaction. Whereas the solvent is responsible for the tautomerisation equilibrium position, the catalyst only serves to eliminate kinetic control from the reaction. Generally, to preserve reaction efficiency and improve sustainability, bio-derivable p-cymene was found to be a useful solvent. The metal-enolate intermediate that results from the application of a Lewis acidic catalyst often cited as promoting the reaction appears to hinder the reaction. In this instance, a Bronsted acidic solvent can be used to return greater reactivity to the dicarbonyl reagent. PMID- 23436301 TI - Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States. AB - BACKGROUND: Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients. METHODS: The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression, and Poisson regression, respectively. RESULTS: A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 (P = .0023). The case fatality rate was 9.0% in the intensively timed DCTER (dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin [daunomycin]/idarubicin) induction and 3.8% for ADE (cytarabine, daunomycin, and etoposide) induction (adjusted odds ratio = 2.2, 95% confidence interval = 1.1 4.5). Patients treated with intensively timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials. CONCLUSIONS: Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens. PMID- 23436302 TI - Polymer nanofiber-embedded microchips for detection, isolation, and molecular analysis of single circulating melanoma cells. PMID- 23436303 TI - In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae. AB - OBJECTIVE: Alterations in the mechanical loading environment in joints may have both beneficial and detrimental effects on articular cartilage and subchondral bone, and may subsequently influence the development of osteoarthritis (OA). Using an in vivo tibial loading model, the aim of this study was to investigate the adaptive responses of cartilage and bone to mechanical loading and to assess the influence of load level and duration. METHODS: Cyclic compression at peak loads of 4.5N and 9.0N was applied to the left tibial knee joint of adult (26 week-old) C57BL/6 male mice for 1, 2, and 6 weeks. Only 9.0N loading was utilized in young (10-week-old) mice. Changes in articular cartilage and subchondral bone were analyzed by histology and micro-computed tomography. RESULTS: Mechanical loading promoted cartilage damage in both age groups of mice, and the severity of joint damage increased with longer duration of loading. Metaphyseal bone mass increased with loading in young mice, but not in adult mice, whereas epiphyseal cancellous bone mass decreased with loading in both young and adult mice. In both age groups, articular cartilage thickness decreased, and subchondral cortical bone thickness increased in the posterior tibial plateau. Mice in both age groups developed periarticular osteophytes at the tibial plateau in response to the 9.0N load, but no osteophyte formation occurred in adult mice subjected to 4.5N peak loading. CONCLUSION: This noninvasive loading model permits dissection of temporal and topographic changes in cartilage and bone and will enable investigation of the efficacy of treatment interventions targeting joint biomechanics or biologic events that promote OA onset and progression. PMID- 23436304 TI - Influence of heavy snow on the feeding behavior of Japanese macaques (macaca fuscata) in northern Japan. AB - Natural disasters can degrade primate habitat and alter feeding behavior. Here, we examined the influence of unusually heavy snow on diet and feeding-site use by Japanese macaques (Macaca fuscata) in northern Japan. To compare the winter feeding behavior under different snow conditions, we recorded the plant species foraged on by macaques in multiple transects of the Shirakami Mountains from 2008 to 2012 (excluding 2011). We used cluster analysis to describe foraged plant assemblages, and applied multiple dimensional scaling and decision tree modeling to evaluate annual variation in feeding-site use by macaques. Our cluster analysis revealed five types of foraged plant assemblages. The proportion of each type present in transects varied considerably across the years, indicating that the diet of macaques in heavy snow conditions was influenced more by resource accessibility than by preference. Multiple dimensional scaling and decision tree modeling demonstrated that heavy snow conditions restricted feeding-site use. Moreover, the distribution of refuges relative to severe external ambient environments was a stronger limiting factor for feeding-site use than was the availability of food resources. While most primate species facing unexpected starvation employ risk-prone foraging tactics (i.e., choosing the option with higher pay-off by accepting risk), Japanese macaques have a tendency to adopt risk-averse foraging behavior (i.e., minimizing energy loss when searching for preferred diet items under long-lasting heavy snow conditions), because winters with temperatures below freezing have higher thermoregulatory costs. PMID- 23436305 TI - Construction of robust enzyme nanocapsules for effective organophosphate decontamination, detoxification, and protection. AB - Nanocapsules of organophosphorous hydrolase with enhanced enzyme activity and stability are prepared via in situ polymerization, providing a novel class of nanoparticles for the decontamination and detoxification of organophosphates such as chemical warfare agents and pesticides. Using the nanocapsules as building blocks, bioactive nanocomposites are also fabricated, enabling their use for organophosphate protection. PMID- 23436306 TI - Otto Friedrich Karl Deiters (1834-1863). AB - Otto Deiters, for whom the lateral vestibular nucleus and the supporting cells of the outer auditory hair cells were named, died in 1863 aged 29. He taught in the Bonn Anatomy Department, had an appointment in the University Clinic, and ran a small private practice. He published articles on the cell theory, the structure and development of muscle fibers, the inner ear, leukaemia, and scarlet fever. He was the second of five surviving children in an academic family whose private correspondence revealed him to be a young man with limited social skills and high ambitions to complete a deeply original study of the brainstem and spinal cord. However, first his father and then his younger brother died, leaving him and his older brother responsible for a suddenly impecunious family as he failed to gain academic promotion. Otto died of typhus two years after his younger brother's death, leaving his greatest scientific achievement to be published posthumously. He showed that most nerve cells have a single axon and several dendrites; he recognized the possibility that nerve cells might be functionally polarized and produced the first illustrations of synaptic inputs to dendrites from what he termed a second system of nerve fibers. PMID- 23436308 TI - Mutations of proline-rich transmembrane protein-2 and paroxysmal kinesigenic dyskinesia in Taiwan. PMID- 23436309 TI - Software sensor design considering oscillating conditions as present in industrial scale fed-batch cultivations. AB - Investigations of inhomogeneous dynamics in industrial-scale bioreactors can be realized in laboratory simulators. Such studies will be improved by on line observation of the growth of microorganisms and their product synthesis at oscillating substrate availability which represents the conditions in industrial scale fed-batch cultivations. A method for the kinetic monitoring of such processes, supported by on line measurements accessible in industrial practice, is proposed. It consists of a software sensor (SS) system composed of a cascade structure. Process kinetics are simulated in models with a structure including time-varying yield coefficients. SSs for measured variable kinetics have classical structures. The SS design of unmeasured variables is realized after a linear transformation using a logarithmic function. For these software sensors, a tuning procedure is proposed, at which an arbitrary choice of one tuning parameter value that guarantees stability of the monitoring system allows the calculation of the optimal values of six parameters. The effectiveness of the proposed monitoring approach is demonstrated with experimental data from a glucose-limited fed-batch process of Bacillus subtilis in a laboratory two compartment scale down reactor which tries to mimic the conditions present in industrial scale nutrient-limited fed-batch cultivations. PMID- 23436310 TI - The treatment of composite defect of bone and soft tissues with a combined latissimus dorsi and serratus anterior and rib free flap. AB - BACKGROUND: Composite defects of bone and soft tissues represent a reconstructive challenge. Several techniques have been described in the medical literature; however, extensive composite defects should be reconstructed with microvascular free tissue transfer. The purpose of this report is to present the use of a composite latissimus dorsi and serratus anterior and rib free flap (LD-SA/rib) as an alternative procedure in patients who cannot undergo more commonly used vascularized bone-containing free flap reconstruction. METHODS: Since January 2009, 12 patients have undergone bone and soft tissues reconstruction with a composite LD-SA/rib flap. In this case series, indications for LD-SA/rib reconstruction were large mandibular defects after oral cancer ablation, scalp defects, and lower extremity defects. RESULTS: All flaps survived entirely. With reference to postoperative complications, haematoma occurred in four patients, scar contractures in three cases, lower lip incontinence in one patient, and local infection in one patient. Skin graft revision was performed in two cases and secondary debulking procedure in three patients. Flap viability was consistent during the 2-year follow-up. CONCLUSIONS: LD-SA/rib free flap should be regarded as an effective procedure for reconstruction of composite tissue defects in patients who are not candidates for more commonly used vascularized bone-containing free flaps. PMID- 23436311 TI - The use of wild animal models to detect evidence of environmental contamination by asbestos-like substance. PMID- 23436313 TI - Complications after Transfemoral Transcatheter Aortic Valve Replacement with a Balloon-Expandable Prosthesis: The Importance of Preventative Measures and Contingency Planning. AB - Transcatheter aortic valve replacement (TAVR) with balloon-expandable Edwards SAPIEN valve was superior to standard therapy in inoperable patients and noninferior to surgical aortic valve replacement in high surgical-risk, but operable patients, with severe symptomatic aortic stenosis in the randomized controlled PARTNER trial. Since the first case of TAVR with a balloon-expandable valve in 2002, several groups have reported their experience with balloon expandable valves with high-procedural success. In the United States, the balloon expandable Edwards-SAPIEN valve is the only transcatheter heart valve approved by the FDA for commercial use. Moreover, this is only in high-risk inoperable patients. Despite increasing experience with the TAVR procedure, it can be associated with complications, which can be technically challenging, even for an experienced operator. Complications associated with TAVR include vascular complications, valve malpositioning, regurgitation, embolization, coronary compromise, conduction abnormalities, stroke/transient ischemic attack, acute kidney injury, cardiac tamponade, and hemodynamic collapse. A thorough understanding of the procedure is essential for pre-emptive planning for procedural complications and early identification and management of complications are necessary for procedural success. We hereby review our experience of transfemoral TAVR with balloon-expandable valves, offer practical tips to maximize the likelihood of procedural success, describe pre-emptive strategies to prevent peri-procedural complications and bailout measures to manage them, should they occur. (c) 2018 Wiley Periodicals, Inc. PMID- 23436312 TI - Recent trends in cost-related medication nonadherence among stroke survivors in the United States. AB - OBJECTIVE: Recent economic and health policy changes may have affected the ability of chronically ill patients to afford their medications. We assessed changes in cost-related nonadherence to medication (CRN) before and after the implementation of Medicare Part D in 2006. METHODS: We used data from the National Health Interview Survey, an annual, population-based survey of community dwelling, noninstitutionalized US adults, to estimate CRN in 8,673 stroke survivors aged 45 years or older, representing 4.8 million survivors, for the years 1999 to 2010. The main outcome measure was CRN, defined as self-reported inability to afford prescribed medication within the past 12 months. RESULTS: During the period 1999 to 2010, 11.4% of stroke survivors, approximately 543,000 individuals, reported CRN. From 1999 to 2010, CRN more than doubled among stroke survivors aged 45 to 64 years (from 12.7 to 26.5%; ptrend = 0.01). CRN remained stable among those aged 65 years or older (from 3.8 to 7.0%; ptrend = 0.21). From 1999-2005 to 2006-2010, CRN among uninsured stroke survivors aged 45 to 64 years increased from 43.1 to 57.1% (p = 0.03). Among stroke survivors aged 65 years or older with Medicare coverage, CRN was higher among Medicare Part D participants than those without the drug benefit (7.9 vs 4.8%; p = 0.02). After adjustment for sociodemographic and clinical factors, CRN was similar among Medicare Part D enrollees and nonenrollees. INTERPRETATION: From 1999 to 2010, CRN increased significantly among stroke survivors younger than 65 years, particularly among those without health insurance. There was no evidence that Medicare Part D decreased CRN among stroke survivors with Medicare. PMID- 23436315 TI - Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury. AB - Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor. PMID- 23436316 TI - Streamlined catalytic asymmetric synthesis of atorvastatin. AB - An efficient enantioselective synthetic route to atorvastatin was developed based on a direct catalytic asymmetric aldol reaction. The expensive chiral ligand used in the initial aldol reaction was readily recovered (91 %) and reused. Implementation of an oxy-Michael reaction for the construction of the syn-1,3 diol unit eliminated several redundant steps, allowing for rapid access to the common intermediate in six steps. PMID- 23436317 TI - CD109 overexpression ameliorates skin fibrosis in a mouse model of bleomycin induced scleroderma. AB - OBJECTIVE: Transforming growth factor beta (TGFbeta) is a profibrotic cytokine, and its aberrant function is implicated in several types of fibrotic pathologies including scleroderma (systemic sclerosis [SSc]). Multiple lines of evidence show that increased TGFbeta signaling contributes to progressive fibrosis in SSc by promoting fibroblast activation, excessive extracellular matrix (ECM) deposition, and dermal thickening. We have previously identified CD109 as a TGFbeta coreceptor and have shown that it antagonizes TGFbeta signaling and TGFbeta induced ECM expression in vitro in human keratinocytes and fibroblasts. The aim of the present study was to examine the ability of CD109 to prevent skin fibrosis in a mouse model of bleomycin-induced SSc. METHODS: Transgenic mice overexpressing CD109 in the epidermis and their wild-type (WT) littermates were injected with bleomycin in phosphate buffered saline (PBS) or with PBS alone every other day for 21 days or 28 days. Dermal thickness and collagen deposition were determined histologically using Masson's trichrome and picrosirius red staining. In addition, collagen and fibronectin content was analyzed using Western blotting, and activation of TGFbeta signaling was examined by determining phospho-Smad2 and phospho-Smad3 levels using Western blotting and immunohistochemistry. RESULTS: Transgenic mice overexpressing CD109 in the epidermis showed resistance to bleomycin-induced skin fibrosis, as evidenced by a significant decrease in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels, as compared to their WT littermates. CONCLUSION: Our findings suggest that CD109 inhibits TGFbeta signaling and fibrotic responses in experimental murine scleroderma. They also suggest that CD109 regulates dermal-epidermal interactions to decrease extracellular matrix synthesis in the dermis. Thus, CD109 is a potential molecular target for therapeutic intervention in scleroderma. PMID- 23436319 TI - Transgenerational effects of variable foraging demand stress in female bonnet macaques. AB - Stress coping is an important part of mammalian life, influencing somatic and mental health, social integration, and reproductive success. The experience of early psychological stress helps shape lifelong stress coping strategies. Recent studies have shown that the effects of early stress may not be restricted to the affected generation, but may also be transmitted to offspring. Understanding whether early stress influences development in subsequent generations may help us understand somewhat why many stress-related traits and diseases, for which little genetic basis has been discovered, run in families. Experimental early life "variable foraging demand" (VFD) stress has been associated with behavioral hypo responsiveness to stress in infant and adolescent bonnet macaques. The present study examined the behavioral effects of experimental early VFD stress in adult bonnet macaques, and further investigated whether non-exposed adolescent offspring of VFD macaques were also affected. Thirty female bonnet macaques from four rearing histories were observed for behavioral response during stress: adults which had been VFD reared as infants (n = 11), adults which had been Control reared as infants (n = 9), and foraging demand naive adolescents whose mothers were VFD (n = 4) or Control reared (n = 6). Subjects were observed for behavioral response during two experimental stressor conditions, including: (1) relocation to a novel environment; and (2) relocation with exposure to a "human intruder" making eye contact. Factor analysis yielded five factors that described categories of behavior across stress conditions. While adult VFD and Control reared females unexpectedly did not differ significantly, non-exposed adolescent offspring of VFD reared mothers displayed significant hypo-responsiveness in all behavioral categories compared with non-exposed adolescent offspring of Control females. We suggest that stress hypo-responsiveness previously observed in adolescent VFD reared animals may abate with age, but is nonetheless observed in the next generation. We conclude that VFD stress affects behavioral development of subsequent generations in non-human primates. PMID- 23436320 TI - Microcystin-LR induces protein phosphatase 2A alteration in a human liver cell line. AB - Microcystin-LR (MC-LR) is a potent inhibitor of protein phosphatases 1 and 2A, and has potent hepatotoxicity and tumor promotion activity. Numerous studies on MC-LR toxicity have been conducted in rat hepatocytes, but few studies of the effects of microcystins on human hepatocytes have been done. In this study, HL7702 cells (a human normal liver cell line) were incubated in MC-LR for 24 h. The existence of MC-LR in HL7702 cells was confirmed. Furthermore, PP2A activity and the alteration of PP2A subunits were assessed. The results show that PP2A activity decreased from the concentration of 1 MUM MC-LR, showing a concentration dependent decline, to about 34% at 10 MUM MC-LR. This activity undergone opposite change with alternations of phosphorylated Y307-PP2A/C and PP2A/C subunit but showed same change with the alteration of the ratio of methylated L309-PP2A/C to PP2A/C. B55alpha, a regulatory subunit of PP2A, was slightly increases in cells treated with the highest concentration of MC-LR (10 MUM), and colocalized increasedly with rearranged-microtubules after 1 MUM MC-LR exposure. However, the proportion of early apoptotic cells did not show any change at various concentration of MC-LR for 24 h. To our knowledge, this is the first report showing MC-LR-induced alteration of PP2A phosphatase in human cultured hepatocytes, and the mechanism of action seems to be similar as described before in vitro. The alteration of PP2A and microtubule seems to be the early event induced by MC-LR exposure. PMID- 23436321 TI - Use of colonoscopy for polyp surveillance in Medicare beneficiaries. AB - BACKGROUND: Professional society guidelines recommend follow-up colonoscopy for patients with resected colonic adenomas. However, adherence to guideline recommendations in routine clinical practice has not been well characterized. METHODS: The authors used a population-based sample of Medicare beneficiaries to identify all patients aged >=70 years who had a claim for colonoscopy with polypectomy or hot biopsy during the period from 2001 to 2004. Medicare claims through 2009 identified colonoscopy within the following 5 years as well as fecal occult blood testing, sigmoidoscopy, and barium enema. RESULTS: In total, 12,771 patients were included. At 5 years, 45.7% of patients underwent another colonoscopy, and 32.3% of procedures included a polypectomy. The rates of fecal occult blood testing, flexible sigmoidoscopy, and barium enema at 5 years were 54%, 3.8%, and 2.9%, respectively. There was a marked decrease in repeat colonoscopy at 1 year, 3 years, and 5 years with more recent years of index procedures. Other predictors of undergoing repeat colonoscopy were younger age, African American race, and a colonoscopy before the index examination. There was no association with physician specialty. The decreasing use of colonoscopy with time was maintained in a multivariable analysis. CONCLUSIONS: In a sample of elderly Medicare beneficiaries, there was under use of follow-up colonoscopy at 5 years after polypectomy, and <50% of patients received a repeat examination. In particular, the use of this procedure decreased over the 4-year study period. Coupled with other data indicating the overuse of follow-up colonoscopy in patients without polyps, there appeared to be significant discordance between guidelines and actual practice. PMID- 23436322 TI - Epoxide-opening cascades triggered by a Nicholas reaction: total synthesis of teurilene. PMID- 23436323 TI - Dielectrophoretic manipulation and solubility of protein nanofibrils formed from crude crystallins. AB - Protein nanofibrils and nanotubes are now widely accepted as having potential for use in the field of bionanotechnology. For this to be a feasible alternative to existing technologies, there is a need for a commercially viable source. Previous work has identified amyloid fibrils formed from crude crystallin proteins as such a source, since these fibrils can be produced in large quantities at a low cost. Applications include use of fibrils as templates for the formation of nanowires or as biosensing scaffolds. There remains a number of practical considerations, such as stability and the ability to control their arrangement. In this study, crude crystallin amyloid fibrils are shown to be stable in a range of biological and clean room solvents, with the fibril presence confirmed by transmission electron microscopy and the thioflavin T fluorescent assay. The fibrils were also immobilised between microelectrodes using dielectrophoresis, which enabled the recording of I-V curves for small numbers of fibrils. This investigation showed the fibrils to have low conductivity, with current values in the range of 10(-10) A recorded. This low conductivity could be increased through modification, or alternately, the fibrils could be used unmodified for applications where they can act as templates or high surface area nanoscaffolds. PMID- 23436324 TI - The medial and lateral entorhinal cortex both contribute to contextual and item recognition memory: a test of the binding of items and context model. AB - It has been suggested that the role of the hippocampus for episodic memory is to selectively bind together item and contextual information. One such model, the Binding of Items and Context (BIC) model, proposed that the perirhinal cortex provides item and the postrhinal/parahippocampal cortex provides context to the hippocampus via the medial (MEC) and lateral entorhinal cortices (LEC) to be bound into an episodic representation. This model proposes that item and context information are stored and processed independently and in parallel before hippocampal processing. To evaluate this model, the present experiment evaluated the role of the MEC and LEC for item and contextual novelty detection. The present results suggest that excitotoxic lesions to the LEC primarily disrupt item novelty detection, whereas lesions to the MEC primarily disrupt contextual novelty detection. These data provide a functional double dissociation between the MEC and LEC across item and contextual processing. Despite this dissociation, the present results suggest that item and contextual information are not represented independently before hippocampal processing. These data support the basic assumptions of the BIC model, but suggest that item and context information may interact in the entorhinal cortex. PMID- 23436326 TI - Transdermal silicone patch for improving comfort in loupe-aided surgery. PMID- 23436325 TI - Intrinsic horizontal connections process global tactile features in the primary somatosensory cortex: neuroanatomical evidence. AB - To understand manual tactile functions in primates, it is essential to explore the interactions between the finger pad representations in somatosensory cortex. To this end, we used optical imaging and electrophysiological mapping to guide neuroanatomical tracer injections into distal digit tip representations of Brodmann area 3b in the squirrel monkey. Retrogradely labeled cell densities and anterogradely labeled fibers and terminal patches in somatosensory areas were plotted and quantified with respect to tangential distribution. Within area 3b, reciprocal patchy distribution of anterograde and retrograde labeling spanned the representation of the distal pad of multiple digits, indicating strong cross digit connectivity. Inter-areal connections revealed bundles of long-range fibers projecting anteroposteriorly, connecting area 3b with clusters of labeled neurons and terminal axon arborizations in area 1. Inter-areal linkage appeared to be largely confined to the representation of the injected finger. These findings provide the neuroanatomical basis for the interaction between distal finger pad representations observed by recent electrophysiological studies. We propose that intra-areal connectivity may be heavily involved in interdigit integration such as shape discrimination, whereas long-range inter-areal connections may subserve active touch in a digit-specific manner. PMID- 23436327 TI - Knockout of the Na,K-ATPase alpha2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction. AB - The alpha2-isoform of the Na,K-ATPase (alpha2) is the minor isoform of the Na,K ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing alpha2 that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of alpha2 to further define the tissue-specific role of alpha2 in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of alpha2 in the heart using beta-myosin heavy chain Cre. We have achieved a 90% knockout of alpha2 expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post transverse aortic constriction. These results suggest that heart expression of alpha2 does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of alpha2 plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of alpha2 determines its unique roles in the regulation of cardiovascular function. PMID- 23436328 TI - The functional role of electrophysiological heterogeneity in the rabbit ventricle during rapid pacing and arrhythmias. AB - Electrophysiological heterogeneity in action potential recordings from healthy intact hearts remains highly variable and, where present, is almost entirely abolished at fast pacing rates. Consequently, the functional importance of intrinsic action potential duration (APD) heterogeneity in healthy ventricles, and particularly its role during rapidly activating reentrant arrhythmias, remain poorly understood. By incorporating both transmural and apicobasal APD heterogeneity within a biventricular rabbit computational model and comparing with an equivalent homogeneous model, we directly investigated the functional importance of intrinsic APD heterogeneity under fast pacing and arrhythmogenic protocols. Although differences in APD were significantly modulated at the tissue level during pacing and further reduced as pacing frequency increased, small differences were still noticeable. Such differences were further marginally accentuated/attenuated via electrotonic effects relative to wavefront propagation directions. The remaining small levels of APD heterogeneity under the fastest pacing frequencies resulted in arrhythmia initiation via heterogeneous conduction block, in contrast to complete block in the homogeneous model. Such induction mechanisms were more evident during premature stimuli at slower paced rhythms where intrinsic heterogeneity remained to a greater degree. During sustained arrhythmias, however, intrinsic heterogeneity made little difference to overall reentrant behavior, either visually, or in terms of duration, metrics quantifying filament/phase singularity dynamics, and global electrocardiogram characteristics. These findings suggest that, despite being important during arrhythmia initiation, intrinsic electrophysiological heterogeneity plays little functional role during rapid pacing and sustained arrhythmia dynamics in the healthy ventricle and thus questions the need to incorporate such detail in computational models when simulating rapid arrhythmias. PMID- 23436329 TI - Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts. AB - Cardiac metabolism remains altered for an extended period of time after myocardial infarction. Studies have shown fibroblasts from normal hearts express KATP channels in culture. It is unknown whether fibroblasts from infarcted hearts express KATP channels and whether these channels contribute to scar and border zone electrophysiology. KATP channel subunit expression levels were determined in fibroblasts isolated from normal hearts (Fb), and scar (sMI-Fb) and remote (rMI Fb) regions of left anterior descending coronary artery (LAD) ligated rat hearts. Whole cell KATP current density was determined with patch clamp. Action potential duration (APD) was measured with optical mapping in myocyte-only cultures and heterocellular cultures with fibroblasts with and without 100 MUmol/l pinacidil. Whole heart optical mapping was used to assess KATP channel activity following LAD ligation. Pinacidil activated a potassium current (35.4 +/- 7.5 pA/pF at 50 mV) in sMI-Fb that was inhibited with 10 MUmol/l glibenclamide. Kir6.2 and SUR2 transcript levels were elevated in sMI-Fb. Treatment with Kir6.2 short interfering RNA decreased KATP currents (87%) in sMI-Fb. Treatment with pinacidil decreased APD (26%) in co-cultures with sMI-Fb. APD values were prolonged in LAD ligated hearts after perfusion with glibenclamide. KATP channels are present in fibroblasts from the scar and border zones of infarcted hearts. Activation of fibroblast KATP channels could modulate the electrophysiological substrate beyond the acute ischemic event. Targeting fibroblast KATP channels could represent a novel therapeutic approach to modify border zone electrophysiology after cardiac injury. PMID- 23436332 TI - Investigation of biomass concentration, lipid production, and cellulose content in Chlorella vulgaris cultures using response surface methodology. AB - The microalgae Chlorella vulgaris produce lipids that after extraction from cells can be converted into biodiesel. However, these lipids cannot be efficiently extracted from cells due to the presence of the microalgae cell wall, which acts as a barrier for lipid removal when traditional extraction methods are employed. Therefore, a microalgae system with high lipid productivity and thinner cell walls could be more suitable for lipid production from microalgae. This study addresses the effect of culture conditions, specifically carbon dioxide and sodium nitrate concentrations, on biomass concentration and the ratio of lipid productivity/cellulose content. Optimization of culture conditions was done by response surface methodology. The empirical model for biomass concentration (R(2) = 96.0%) led to a predicted maximum of 1123.2 mg dw L(-1) when carbon dioxide and sodium nitrate concentrations were 2.33% (v/v) and 5.77 mM, respectively. For lipid productivity/cellulose content ratio (R(2) = 95.2%) the maximum predicted value was 0.46 (mg lipid L(-1) day(-1) )(mg cellulose mg biomass(-1) )(-1) when carbon dioxide concentration was 4.02% (v/v) and sodium nitrate concentration was 3.21 mM. A common optimum point for both variables (biomass concentration and lipid productivity/cellulose content ratio) was also found, predicting a biomass concentration of 1119.7 mg dw L(-1) and lipid productivity/cellulose content ratio of 0.44 (mg lipid L(-1) day(-1) )(mg cellulose mg biomass(-1) )(-1) for culture conditions of 3.77% (v/v) carbon dioxide and 4.01 mM sodium nitrate. The models were experimentally validated and results supported their accuracy. This study shows that it is possible to improve lipid productivity/cellulose content by manipulation of culture conditions, which may be applicable to any scale of bioreactors. PMID- 23436331 TI - Sympathetic activation increases NO release from eNOS but neither eNOS nor nNOS play an essential role in exercise hyperemia in the human forearm. AB - Nitric oxide (NO) release from endothelial NO synthase (eNOS) and/or neuronal NO synthase (nNOS) could be modulated by sympathetic nerve activity and contribute to increased blood flow after exercise. We examined the effects of brachial arterial infusion of the nNOS selective inhibitor S-methyl-l-thiocitrulline (SMTC) and the nonselective NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA) on forearm arm blood flow at rest, during sympathetic activation by lower body negative pressure, and during lower body negative pressure immediately after handgrip exercise. Reduction in forearm blood flow by lower body negative pressure during infusion of SMTC was not significantly different from that during vehicle (-28.5 +/- 4.02 vs. -34.1 +/- 2.96%, respectively; P = 0.32; n = 8). However, l-NMMA augmented the reduction in forearm blood flow by lower body negative pressure (-44.2 +/- 3.53 vs. -23.4 +/- 5.71%; n = 8; P < 0.01). When lower body negative pressure was continued after handgrip exercise, there was no significant effect of either l-NMMA or SMTC on forearm blood flow immediately after low-intensity exercise (P = 0.91 and P = 0.44 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10) or high-intensity exercise (P = 0.46 and P = 0.68 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10). These results suggest that sympathetic activation increases NO release from eNOS, attenuating vasoconstriction. Dysfunction of eNOS could augment vasoconstrictor and blood pressure responses to sympathetic activation. However, neither eNOS nor nNOS plays an essential role in postexercise hyperaemia, even in the presence of increased sympathetic activation. PMID- 23436333 TI - Combined transcatheter device closure of ruptured sinus of valsalva and a post surgical residual ventricular septal defect. AB - Sinus of Valsalva aneurysms are commonly associated with ventricular septal defects (VSDs). We describe a 14-year-old boy who presented with rupture of right sinus of Valsalva (RSOV) into the right ventricular outflow tract (through two openings) along with a residual VSD, four years after surgical closure of the VSD. Both antegrade and retrograde approaches were used to close the RSOV defects. The larger defect was closed from the venous side using an Amplatzer Duct Occluder (ADO-I) device while the smaller defect was closed from the arterial end using and ADO-II device. The residual VSD was also closed percutaneously using a ADO-I device. Successful transcatheter closure of all defects was possible thereby preventing the morbidity and mortality associated with a repeat surgery. PMID- 23436334 TI - Introduction to special section on primate neuroethology. PMID- 23436335 TI - Solid-state luminescence of Au-Cu-alkynyl complexes induced by metallophilicity driven aggregation. AB - A new series of homoleptic alkynyl complexes, [{Au2Cu2(C2R)4}n] (R=C3H7O (1), C6H11O (2), C9H19O (3), C13H11O (4)), were obtained from Au(SC4H8)Cl, Cu(NCMe)4PF6, and the corresponding alkyne in the presence of a base (NEt3). Complexes 1-4 aggregate upon crystallization into polymeric chains through extensive metallophilic interactions. The cluster that contains fluorenolyl functionalities, C13H9O (5), crystallizes in its molecular form as a disolvate, [Au2Cu2(C2C13H9O)4].2THF. The substitution of weakly bound THF molecules with pyridine molecules leads to the complex [Au2Cu2(C2C13H9O)4].2py (6), thus giving two polymorphs in the solid state. Such structural diversity is established through metal-chain and hydrogen-bond formation, which depends on the stereochemical characteristics of the organic ligands. More interestingly, this solid-state structural arrangement affords good emission properties, such as intensity and spectroscopic profile, which are otherwise very weakly emissive in solution. Metallophilic aggregation of the {Au2Cu2} cluster units, as observed in the crystals, results in dramatic enhancement of the room-temperature phosphorescence, thereby reaching a maximum quantum efficiency of 95% (4). A theoretical approach further indicates a synergistic effect of the array of the metal chain upon aggregation, which greatly enhances the spin-orbit coupling and, hence, the phosphorescence, thereby opening up a new direction in the field of aggregate-enhanced emission. PMID- 23436330 TI - Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis. AB - Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction. PMID- 23436337 TI - Immunomodulation with regulatory T cells and Fas-ligand ameliorate established inflammatory colitis. PMID- 23436336 TI - Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. AB - OBJECTIVE: Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). DESIGN: Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score <=1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a >=1 point reduction in endoscopic index score from baseline. RESULTS: 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. CONCLUSION: Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild to-moderate UC. PMID- 23436338 TI - Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. AB - Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent. PMID- 23436339 TI - Solid-phase synthesis of fusaricidin/LI-F class of cyclic lipopeptides: Guanidinylation of resin-bound peptidyl amines. AB - Fusaricidins/LI-Fs and related cyclic lipopeptides represent an interesting new class of antibacterial peptides with the potential to meet the challenge of antibiotic resistance in bacteria. Our previous study (Bionda et al. ChemMedChem 2012, 7, 871-882) revealed the significance of the guanidinium group located at the termini of the lipidic tails of these cyclic lipopeptides for their antibacterial activities. Therefore, devising a synthetic strategy that will allow incorporation of guanidinium functionality into their structure is of particular practical importance. Since appropriately protected guanidino fatty acid building blocks are not commercially available, our strategy toward guanidinylated fusaricidin/LI-F analogs include solid-phase synthesis of a cyclic lipopeptide precursor possessing a lipidic tail with a terminal amino group followed by its conversion into corresponding guanidine. To find the optimal method for this conversion, we have examined commonly used guanidinylation reagents under the conditions compatible with standard solid-phase peptide synthesis. Described experimental results demonstrated superiority of N,N'-di-Boc N"-triflylguanidine in solid-phase preparation of fusaricidin/LI-F class of cyclic lipopeptides. The triflylguanidine reagent gave a single monoguanidinylated product in excellent yield independently of the type of solid support. PMID- 23436340 TI - The important role of physical activity in the prevention and management of gestational diabetes mellitus. AB - The actual pathophysiology behind gestational diabetes mellitus (GDM) is still unclear, but a deterioration in insulin resistance beyond that induced by pregnancy, combined with beta cell dysfunction, plays a key role. Interventions that help improve glucose tolerance by attenuating pregnancy-induced insulin resistance or achieve glycaemic control may therefore help in preventing and managing GDM. In non-pregnant populations, physical activity has been associated with an improvement in glucose homeostasis and insulin sensitivity and a risk reduction for type 2 diabetes mellitus (T2DM) and is a cornerstone for T2DM treatment. However, there is still controversy regarding the benefits of physical activity in preventing and managing GDM. The objective of this review is therefore to provide a comprehensive overview of the effect of prenatal physical activity-based interventions on (1) glucose tolerance, insulin sensitivity and GDM prevention and (2) glycaemic control and insulin use in GDM women. On the basis of the available literature, there is a lack of consistent evidence regarding the benefits of physical activity on improving glucose tolerance and insulin sensitivity and preventing GDM. However, it appears that physical activity may help to achieve good glycaemic control and limit insulin use in GDM women. Compliance appears to be a major problem in physical activity-based intervention studies aimed at GDM prevention. Rigorous scientific research is still required to make an informed decision about the role of physical activity in the prevention and management of GDM and to develop evidence-based physical activity guidelines for GDM prevention and management. PMID- 23436341 TI - A role for anterior thalamic nuclei in affective cognition: interaction with environmental conditions. AB - Damage to anterior thalamic nuclei (ATN) is a well-known cause of diencephalic pathology that produces a range of cognitive deficits reminiscent of a hippocampal syndrome. Anatomical connections of the ATN also extend to cerebral areas that support affective cognition. Enriched environments promote recovery of declarative/relational memory after ATN lesions and are known to downregulate emotional behaviors. Hence, the performance of standard-housed and enriched ATN rats in a range of behavioral tasks engaging affective cognition was compared. ATN rats exhibited reduced anxiety responses in the elevated plus maze, increased activity and reduced corticosterone responses when exploring an open field, and delayed acquisition of a conditioned contextual fear response. ATN rats also exhibited reduced c-Fos and phosphorylated cAMP response element-binding protein (pCREB) immunoreactivity in the hippocampal formation and the amygdala after completion of the contextual fear test. Marked c-Fos hypoactivity and reduced pCREB levels were also evident in the granular retrosplenial cortex and, to a lesser extent, in the anterior cingulate cortex. Unlike standard-housed ATN rats, enriched ATN rats expressed virtually no fear of the conditioned context. These results show that the ATN regulate affective cognition and that damage to this region may produce markedly different behavioral effects as a function of environmental housing conditions. PMID- 23436343 TI - Mechanistic studies on the SCS-pincer palladium(II)-catalyzed tandem stannylation/electrophilic allylic substitution of allyl chlorides with hexamethylditin and benzaldehydes. AB - This paper describes a mechanistic study of the SCS-pincer Pd(II)-catalyzed auto tandem reaction consisting of the stannylation of cinnamyl chloride with hexamethylditin, followed by an electrophilic allylic substitution of the primary tandem-reaction product with 4-nitrobenzaldehyde to yield homoallylic alcohols as the secondary tandem products. As it turned out, the anticipated stannylation product, cinnamyl trimethylstannane, is not a substrate for the second part of the tandem reaction. These studies have provided insight in the catalytic behavior of SCS-pincer Pd(II) complexes in the auto-tandem reaction and on the formation and possible involvement of Pd(0) species during prolonged reaction times. This has led to optimized reaction conditions in which the overall tandem reaction proceeds through SCS-pincer Pd(II) -mediated catalysis, that is, true auto-tandem catalysis. Accordingly, this study has provided the appropriate reaction conditions that allow the pincer catalysts to be recycled and reused. PMID- 23436342 TI - Magnetic resonance imaging as a predictor of pathologic response in patients treated with neoadjuvant systemic treatment for operable breast cancer. Translational Breast Cancer Research Consortium trial 017. AB - BACKGROUND: Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast. METHODS: MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR) positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 327), HR positive/HER2-positive, (n = 148), HR-negative/HER2-positive, (n = 101), and triple-negative (HR-negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2-positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed. RESULT: For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple-negative subtype (57 of 155 patients; 37%) and the HER2-positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple negative (60%) and HER2-positive (62%) subtypes. CONCLUSIONS: The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response. PMID- 23436345 TI - Continuous manipulation and separation of particles using combined obstacle- and curvature-induced direct current dielectrophoresis. AB - This paper presents a novel dielectrophoresis-based microfluidic device incorporating round hurdles within an S-shaped microchannel for continuous manipulation and separation of microparticles. Local nonuniform electric fields are generated due to the combined effects of obstacle and curvature, which in turn induce negative dielectrophoresis forces exerting on the particle that transport throughout the microchannel electrokinetically. Experiments were conducted to demonstrate the controlled trajectories of fix-sized (i.e. 10 or 15 MUm) polystyrene particles, and size-dependent separation of 10 and 15 MUm particles by adjusting the applied voltages at the inlet and outlets. Numerical simulations were also performed to predict the particle trajectories, which showed reasonable agreement with experimentally observed results. Compared to other microchannel designs that make use of either obstacle or curvature individually for inhomogeneous electric fields, the developed microchannel offers advantages such as improved controllability of particle motion, lower requirement of applied voltage, reduced fouling, and particle adhesion, etc. PMID- 23436348 TI - Molecular dynamics and ligand exchange in magnesium complexes: evidence for both dissociative and associative ligand exchange. PMID- 23436344 TI - Chronic neurotrophin delivery promotes ectopic neurite growth from the spiral ganglion of deafened cochleae without compromising the spatial selectivity of cochlear implants. AB - Cochlear implants restore hearing cues in the severe-profoundly deaf by electrically stimulating spiral ganglion neurons (SGNs). However, SGNs degenerate following loss of cochlear hair cells, due at least in part to a reduction in the endogenous neurotrophin (NT) supply, normally provided by hair cells and supporting cells of the organ of Corti. Delivering exogenous NTs to the cochlea can rescue SGNs from degeneration and can also promote the ectopic growth of SGN neurites. This resprouting may disrupt the cochleotopic organization upon which cochlear implants rely to impart pitch cues. Using retrograde labeling and confocal imaging of SGNs, we determined the extent of neurite growth following 28 days of exogenous NT treatment in deafened guinea pigs with and without chronic electrical stimulation (ES). On completion of this treatment, we measured the spread of neural activation to intracochlear ES by recording neural responses across the cochleotopically organized inferior colliculus using multichannel recording techniques. Although NT treatment significantly increased both the length and the lateral extent of growth of neurites along the cochlea compared with deafened controls, these anatomical changes did not affect the spread of neural activation when examined immediately after 28 days of NT treatment. NT treatment did, however, result in lower excitation thresholds compared with deafened controls. These data support the application of NTs for improved clinical outcomes for cochlear implant patients. PMID- 23436349 TI - Gene regulation. AB - This review concisely highlights the complexity of regulatory events. It provides examples of how interconnectivity of regulatory hubs could maintain transcriptional synergy and orchestrate the proper spatial and temporal patterns of gene expression. PMID- 23436350 TI - Isolation of nuclei for use in genome-wide DNase hypersensitivity assays to probe chromatin structure. AB - DNase hypersensitivity (DHS) analysis coupled with high-throughput DNA sequencing (DNase-seq) has emerged as a powerful tool to analyze chromatin accessibility and identify regulatory sequences in genomic DNA on a global scale. In this method, intact nuclei are isolated from fresh tissue or cultured cells and then subjected to limited digestion using DNase I. The resulting short DNA fragments released by DNase digestion, which correspond to regions of open chromatin structure, are subsequently purified and identified by high throughput next generation DNA sequencing. This chapter describes methods used to isolate intact nuclei from mouse liver suitable for DNase-seq studies. The following chapter presents a detailed protocol for DNase I digestion of liver nuclei followed by the isolation of DNase-released fragments for sequencing and genome-wide mapping of DHS sites. PMID- 23436352 TI - Isolation and analysis of DNA derived from nucleosome-free regions. AB - Precise regulation of the levels and timing of gene expression is fundamental to all biological processes and is largely determined by the activity of cis regulatory modules, containing the binding sites for transcription factors, within promoters and enhancers. The global identification of these transcriptional regulatory elements within mammalian genomes, and understanding when and where they are active, is an important effort that will require the development and implementation of several different technologies. Here we detail a means for the identification of transcriptional regulatory elements using functional assays. The success of this approach relies on focusing the functional assay on DNA derived from nucleosome-free regions (NFRs), i.e., the 2% of the genome within a given cell in which regulatory elements reside. Accordingly, we present a simple method for isolating NFR DNA, and a functional assay that can be used for the identification of promoter and enhancers components within this population. PMID- 23436351 TI - DNase I digestion of isolated nulcei for genome-wide mapping of DNase hypersensitivity sites in chromatin. AB - DNase I hypersensitivity (DHS) analysis is a powerful method to analyze chromatin structure and identify genomic regulatory elements. Integration of a high throughput detection method into DHS analysis makes genome-wide mapping of DHS sites possible at a reasonable cost. Here we describe methods for DHS analysis carried out with mouse liver nuclei, involving DNase I digestion followed by isolation of DNase I-released DNA fragments suitable for high-throughput, next generation DNA sequencing (DNase-seq). A real-time PCR-based assay used to optimize DNase I digestion conditions is also described. PMID- 23436353 TI - Acquisition of high quality DNA for massive parallel sequencing by in vivo chromatin immunoprecipitation. AB - ChIP-seq is rapidly becoming a routine technique for the determination of the genome wide association of DNA binding proteins and histone modifications. Here we provide a protocol for the isolation, purification, and immunoprecipitation of DNA fragments associated with a target transcription factor of interest. Although the method makes use of adult mouse hearts, it can, with relative ease, be adapted for the in vivo ChIP isolation of DNA from other cell and tissue sources with the intention of massive parallel sequencing. PMID- 23436354 TI - Luciferase assay to study the activity of a cloned promoter DNA fragment. AB - Luciferase based assays have become an invaluable tool for the analysis of cloned promoter DNA fragments, both for verifying the ability of a potential promoter fragment to drive the expression of a luciferase reporter gene in various cellular contexts, and for dissecting binding elements in the promoter. Here, we describe the use of the Dual-Luciferase((r)) Reporter Assay System created by Promega (Promega Corporation, Wisconsin, USA) to study the cloned 6.7 kilobases (kb) mouse (m) Tcf3 promoter DNA fragment in mouse embryonic derived neural stem cells (NSC). In this system, the expression of the firefly luciferase driven by the cloned mTcf3 promoter DNA fragment (including transcription initiation sites) is correlated with a co-transfected control reporter expressing Renilla luciferase from the herpes simplex virus (HSV) thymidine kinase promoter. Using an internal control reporter allows to normalize the activity of the experimental reporter to the internal control, which minimizes experimental variability. PMID- 23436355 TI - Promoter deletion analysis using a dual-luciferase reporter system. AB - Promoter deletion analysis is a useful tool for identifying important regulatory regions involved in transcriptional control of gene expression. In this approach, a series of promoter deletion fragments are fused to a reporter gene, such as chloramphenicol acetyltransferase or luciferase gene in a vector, and then transfected into cells for induction. Screening the expression level of the reporter gene using either a qualitative or a quantitative assay, allows to identify the regulatory regions of interest (e.g., cis-acting elements or enhancer) in the promoter.Luciferase genes have been widely used as reporter genes for their sensitivity and efficiency. Firefly and Renilla luciferases are two commonly used reporters, which oxidize different substrates to generate quantifiable luminescence. Therefore, the enzymatic activities of firefly and Renilla luciferases can be sequentially measured in a single sample by controlling reaction conditions. Here, we describe a dual-luciferase reporter assay, where the promoter of interest is fused to a firefly luciferase reporter and is co-transfected into cells with an internal control vector (pRL-CMV) to express Renilla luciferase. Both the Firefly and Renilla luciferases are measured using a dual-luciferase reporter assay system which improves experimental accuracy. PMID- 23436356 TI - Application of mRNA display for in vitro selection of DNA-binding transcription factor complexes. AB - Comprehensive analysis of DNA-protein interactions is important for mapping transcriptional regulatory networks at the genome-wide level. Here, we present a new application of mRNA display, using the in vitro virus (IVV) technology, for in vitro selection of DNA-binding protein complexes. Under optimal selection conditions using bait DNAs, many kinds of DNA-binding protein complexes can be successfully selected from an mRNA display library constructed from poly A(+) RNA after several rounds of selection. This mRNA display selection system can identify a variety of DNA-binding protein complexes in a single experiment. Remarkably, this system can also select DNA-binding protein heterooligomeric complexes. Since almost all transcription factors form heterooligomeric complexes to bind with their target DNA, this method should be broadly useful to identify DNA-binding transcription factor complexes. PMID- 23436357 TI - Isolation of intracellular protein--DNA complexes using HaloCHIP, an antibody free alternative to chromatin immunoprecipitation. AB - Mapping of protein binding sites within the genome has been significantly advanced by microarray and sequencing technologies, yet the method traditionally used to isolate protein-DNA complexes, chromatin immunoprecipitation, has remained dependent of the use of antibodies. Furthermore, cross-linking is commonly used to trap protein-DNA complexes and the challenge of using antibodies has come in recognition of the cross-linked epitopes, sometimes limiting the success of the approach. Here we present a method, HaloCHIP, which utilizes a HaloTag protein fusion and corresponding interaction resin, HaloLink, for capture of cross-linked protein-DNA complexes directly from a cellular lysate. This process alleviates the need for using an antibody, yields the DNA fragments bound to a particular protein of interest, and allows for a variety of downstream analyses such as PCR, qPCR, microarrays, and sequencing. PMID- 23436358 TI - A modified yeast one-hybrid system for genome-wide identification of transcription factor binding sites. AB - The yeast one-hybrid system is a powerful genetic method to identify DNA-protein interactions, but there is a major limitation inherent to the system. Namely, frequency of false positives generated by yeast endogenous transcription factors has been thought to be higher than that of true positives by orders of magnitude. However, our modification efficiently can eliminate the false positives. When compared to the other methods for the analysis of DNA-protein interactions on a genome-wide scale, a modified yeast one-hybrid system offers several advantages including low initial and running cost, large-scale output, and easy handling. PMID- 23436359 TI - Identifying specific protein-DNA interactions using SILAC-based quantitative proteomics. AB - A comprehensive identification of protein-DNA interactions that drive processes such as transcription and replication, both in prokaryotic and eukaryotic organisms, remains a major technical challenge. In this chapter, we present a SILAC-based DNA affinity purification method that can be used to identify specific interactions between proteins and functional DNA elements in an unbiased manner. PMID- 23436360 TI - Electrophoretic mobility-shift and super-shift assays for studies and characterization of protein-DNA complexes. AB - Gene expression is in part regulated by transcription factors that bind specific sequence motifs in genomic DNA. Transcription factors cooperate with the basal machinery to upregulate or downregulate transcription. Experimental data have revealed the importance of interactions among members of distinct families of transcription factors to form complexes that regulate gene expression. Thus, a full characterization of protein-DNA complexes is essential to understanding of gene regulation in a more complex cellular environment. Electrophoretic mobility shift assay (EMSA) is a powerful technique to resolve nucleic acid-protein complexes formed with transcription factors in nuclear extracts. Herein is described how EMSA and super-shift assays were used to characterize several complexes produced from binding of transcription factors to a regulatory DNA sequence upstream from the promoter region of the human NF-IL6 gene. PMID- 23436361 TI - Combination of native and denaturing PAGE for the detection of protein binding regions in long fragments of genomic DNA. AB - In traditional electrophoresis mobility shift assay (EMSA) a single (32)P-labeled double-stranded DNA oligonucleotide or a restriction fragment bound to a protein is separated from the unbound DNA by polyacrylamide gel electrophoresis (PAGE) under nondenaturing conditions. An extension of this method uses a population of DNA restriction fragments derived from long genomic regions for the identification of fragments containing protein binding regions. Although the method allows simultaneous analysis of large fragments, it is relatively laborious and can be used to detect only fragments containing high affinity protein binding sites. Here we describe an alternative and straightforward strategy which is based on a combination of native and denaturing PAGE. With this strategy restriction fragments, derived from genomic DNA (<10 kb), containing high as well as low affinity protein binding regions may be easily identified. PMID- 23436362 TI - Quantitative NanoProteomics approach for protein complex (QNanoPX) using gold nanoparticle-based DNA probe. AB - Affinity purification by pulldown methods using target-bound gel beads provides a powerful approach for purifying endogenous protein complexes. Such methods can be improved by using nanoparticle-based probe, coupled with immunoblot analysis or quantitative proteomics method using stable isotope labeling via liquid chromatography-mass spectrometry (LC-MS). Here, we describe sample preparation and a pulldown method using gold nanoparticle-based DNA probe for characterizing the transcriptional complex of estrogen response element (ERE). The described protocol includes the fabrication of gold nanoparticle-based probe, nuclear extract preparation, and affinity purification for the analysis by immunoblotting, as well as the subsequent trypsin digestion and stable isotope dimethyl labeling for the analysis by LC-MS. PMID- 23436363 TI - Chromatin assembly and in vitro transcription analyses for evaluation of individual protein activities in multicomponent transcriptional complexes. AB - Eukaryotic DNA and core histones form the fundamental repeating units of chromatin. Condensed c-hromatin, which has higher-order structures, prevents transcriptional complexes from accessing their target genes. Epigenetic regulation, including structural changes of chromatin, histone modification, and DNA methylation, strictly controls the pattern of gene expression and silencing. Recent studies have revealed that histone acetylation plays a crucial role in relaxing chromatin structure for initiation of transcription. Crosstalk between DNA-binding transcription factors and histone acetyltransferases (HATs) serves as a key mechanism for regulating gene expression and developmental processes. However, the precise roles of multicomponent transcriptional complexes have not been fully elucidated because of technical difficulties in using in vitro experimental systems. Previously we demonstrated that the DNA-binding transcription factor Sox9, HAT coactivator p300, and other regulatory factors (Smad3/4) cooperatively activate Sox9-dependent transcription on chromatin. Here, we describe an experimental approach to investigate the function of each component on reconstructed chromatin in vitro. Our methods offer a useful system for analyzing the additional effect of a third component in a transcriptional complex on chromatin structure. PMID- 23436364 TI - Using FRET to monitor protein-induced DNA bending: the TBP-TATA complex as a model system. AB - Proteins that bind to DNA can elicit changes in DNA conformation, such as bending and looping, which are important signals for later events such as transcription. TATA-binding protein (TBP) is one example of a protein that elicits a conformational change in DNA; TBP binds and sharply bends its recognition sequence, which is thought to facilitate the recruitment of other protein factors. Here we describe the use of fluorescence resonance energy transfer (FRET) to evaluate DNA bending using TBP as a model system. FRET is a useful technique to measure changes in DNA conformation due to protein binding because small changes in the distance between two fluorophores (2-10 nm) translate into large changes in energy transfer. PMID- 23436365 TI - Promoter independent abortive transcription assays unravel functional interactions between TFIIB and RNA polymerase. AB - TFIIB-like general transcription factors are required for transcription initiation by all eukaryotic and archaeal RNA polymerases (RNAPs). TFIIB facilitates both recruitment and post-recruitment steps of initiation; in particular, TFIIB stimulates abortive initiation. X-ray crystallography of TFIIB RNAP II complexes shows that the TFIIB linker region penetrates the RNAP active center, yet the impact of this arrangement on RNAP activity and underlying mechanisms remains elusive. Promoter-independent abortive initiation assays exploit the intrinsic ability of RNAP enzymes to initiate transcription from nicked DNA templates and record the formation of the first phosphodiester bonds. These assays can be used to measure the effect of transcription factors such as TFIIB and RNAP mutations on abortive transcription. PMID- 23436366 TI - Fluorescence Cross-correlation Spectroscopy (FCCS) to Observe Dimerization of Transcription Factors in Living Cells. AB - Fluorescence cross-correlation spectroscopy (FCCS) is an established spectroscopic method to observe the interaction between the different fluorescent molecules. Using FCCS, researchers can assess the interaction of target molecules in the aqueous condition, and can apply the technique in cultured cells. Here, we describe the method of FCCS to demonstrate direct observation of dimerization between transcription factors in a living cell. PMID- 23436367 TI - Nuclear recruitment assay as a tool to validate transcription factor interactions in Mammalian cells. AB - Identification and verification of novel transcription factor interactions is an inherent step in the discovery of molecular mechanisms driving gene transcription and regulation. Co-immunoprecipitation and GST-pull down are often key techniques in the verification process. Despite wide applicability, their use may sometimes be restricted. We provide a detailed protocol for an intracellular immunofluorescence technique that may be used as an alternative or complimentary study for transcription factor interaction verification. PMID- 23436368 TI - Preparation of cell lines for single-cell analysis of transcriptional activation dynamics. AB - Imaging molecularly defined regions of chromatin in single living cells during transcriptional activation has the potential to provide new insight into gene regulatory mechanisms. Here, we describe a method for isolating cell lines with multi-copy arrays of reporter transgenes, which can be used for real-time high resolution imaging of transcriptional activation dynamics in single cells. PMID- 23436369 TI - Peptide microarrays for profiling of serine/threonine kinase activity of recombinant kinases and lysates of cells and tissue samples. AB - Peptide microarray technology can be used to identify substrates for recombinant kinases, to measure kinase activity and changes thereof in cell lysates and lysates from fresh frozen (tumor) tissue. The effect of kinase inhibitors on the kinase activities in relevant tissues can be investigated as well. The method for performing experiments on dynamic peptide microarrays with real-time readout is described, as well as the influence of assay parameters and suggestions for optimization of experiments. PMID- 23436370 TI - Immunoaffinity purification of protein complexes from Mammalian cells. AB - In this chapter, we describe a purification scheme designed to isolate multisubunit protein complexes gently and quickly from crude extracts of mammalian cells using immunoaffinity purification of epitope tagged proteins and the multisubunit complexes with which they associate. As an example we describe isolation of the mammalian Mediator complex from HeLa S3 cells. PMID- 23436371 TI - Simple and efficient identification of chromatin modifying complexes and characterization of complex composition. AB - Affinity purification and mass spectrometry analysis have been used to identify and characterize protein complexes. Wdr82-associated chromatin modifying complexes were purified by single-step FLAG affinity purification from human cells induced to express FLAG-tagged Wdr82. Purified proteins were analyzed by SDS-PAGE and specific protein bands were identified by mass spectrometry. Subsequently, purified proteins were fractionated on sucrose gradient equilibrium centrifugation to determine overall composition of each identified complex. We describe here simple and efficient approaches for the identification of chromatin modifying complexes and subsequent characterization of complex composition. PMID- 23436372 TI - Heavy methyl-SILAC labeling coupled with liquid chromatography and high resolution mass spectrometry to study the dynamics of site-specific histone methylation. AB - Histone lysine and arginine methylation involved in gene activation and silencing is dynamically regulated. However, partly limited to the research technologies previously available, the dynamics of global histone methylation on a site specific basis have not been fully pursued. Heavy methyl-SILAC (Stable Isotope Labeling of Amino Acids in Cell Culture) labeling provides a remarkable signpost to distinguish the preexisting and newly generated methyl marks on histones. Using this technology coupled with quantitative LC-MS analysis make it possible to monitor changes in the dynamics of histone site-specific methylation. In this chapter, we comprehensively describe the experimental strategy to determine the dynamics of multiple histone methylated residues including SILAC labeling, histone extraction/purification and mass spectrometry analysis. PMID- 23436373 TI - Analysis of p300 occupancy at the early stage of stem cell differentiation by chromatin immunoprecipitation. AB - Chromatin immunoprecipitation (ChIP) is an invaluable method to study the specific interaction of regulatory proteins with genomic DNA. Since its first development, it has been modified extensively to make it applicable to many different cell types and experimental systems. The cross-linking of regulatory proteins to genomic DNA requires monolayer cells or single cell suspensions. Here, we describe a ChIP protocol using embryoid bodies formed at the early stage differentiation of pluripotent stem cells, which we have used to determine long range p300-dependent regulatory elements of myogenic-specific genes. PMID- 23436374 TI - Mammalian two-hybrid assays for studies of interaction of p300 with transcription factors. AB - The two-hybrid system is a powerful genetic assay that allows the interaction between two proteins to be detected in vivo. It was originally described in 1989 and since then it has been one of the main techniques used to identify interactions between proteins from different cellular organisms. Here we describe the methods to study the interaction of p300 with other transcription factors, specifically between p300 and two transcription factors related to hypoxia and inflammation, HIF-1alpha and NF-kappaB-p65, respectively. PMID- 23436375 TI - Fluorescence anisotropy microplate assay to investigate the interaction of full length steroid receptor coactivator-1a with steroid receptors. AB - Estrogens, acting via estrogen receptor (ER) play key roles in growth, differentiation, and gene regulation in the reproductive, central nervous, and skeletal systems. ER-mediated gene transcription contributes to the development and spread of breast, uterine, and liver cancer. Steroid receptor coactivator-1a (SRC1a) belongs to the P160 family of coactivators, which is the best known of the many coactivators implicated in ER-mediated transactivation. Binding of full length P160 coactivators to steroid receptors has been difficult to investigate in vitro. This chapter details how to investigate the interaction of SRC1a with ER using the fluorescence anisotropy/polarization microplate assay (FAMA). PMID- 23436376 TI - Use of histone deacetylase inhibitors to examine the roles of bromodomain and histone acetylation in p300-dependent gene expression. AB - The bromodomain is an evolutionarily conserved motif harbored by many transcription regulators and nearly all nuclear histone acetyltransferases including the transcriptional coactivator p300. The function of p300 is required for the expression of an array of genes, in part through histone acetylation. Here, we describe an experimental approach to examine the role of either the wild type or a bromo-deficient p300 in the expression of p300-dependant genes. The role of histone acetylation in the expression of p300-dependent genes can also be assessed by targeting histone deacetylase activities using an inhibitor approach. PMID- 23436377 TI - Histone deacetylase inhibitor valproic acid as a small molecule inducer to direct the differentiation of pluripotent stem cells. AB - Pluripotent stem cells can be directed into myogenic differentiation by small molecular inducers, which preferentially activate muscle-specific transcription networks. Here we describe how to efficiently direct the differentiation of pluripotent P19 cells into skeletal muscle lineage by using histone deacetylase inhibitor, valproic acid and the ligand of retinoic acid receptor, all-trans retinoic acid. PMID- 23436378 TI - Sedimentation and immunoprecipitation assays for analyzing complexes that repress transcription. AB - Co-repressor proteins function as platforms for the assembly of multi-subunit complexes that mediate transcriptional repression. Common components of such complexes are histone deacetylases, which catalyze the removal of acetyl groups from the tails of histones within nucleosomes, resulting in chromatin compaction and gene repression. In addition, co-repressor complexes generally interact with sequence-specific DNA-binding proteins that direct association with regulatory elements in the genome. Thus, identifying proteins that stably associate with co repressors can provide insights regarding the biochemical function and target gene specificity of these molecules. Here, we describe a density gradient fractionation method for determining whether a co-repressor is incorporated into high-molecular complexes within cells and for identifying potential constituents of these complexes. We also describe a co-immunoprecipitation assay for confirming and further studying interactions between co-repressors and other proteins that may represent functional partners. PMID- 23436379 TI - Methods for studies of protein interactions with different DNA methyltransferases. AB - There are now many methods available for studying protein interactions between DNA methltransferases (DNMTs) and their binding partners. Here we describe a step by-step procedure to identify whether proteins of interest interact with DNMTs by co-immunoprecipitation (co-IP) assay in transiently transfected cells. Though one mammalian cell is described, investigators can use the same method with other cell lines or primary cells for in vivo protein interaction studies. PMID- 23436380 TI - Femoral vessels as recipient for free tissue transfer coverage of around-the-knee defects. PMID- 23436381 TI - Late MitraClip procedure after left atrial appendage occlusion: indication and procedure description. AB - We report the first human case of percutaneous edge-to-edge mitral valve repair using MitraClip System (Abbott Vascular, Abbott Park, IL) in a patient, who previously underwent left atrial appendage closure with PLAATOTM System (ev3. Inc., Plymouth, MN). The procedure was successfully performed using the standard MitraClip technique, in the catheterization laboratory, with transesophageal echocardiographic and fluoroscopic guidance. We showed that a double percutaneous procedure for stroke prevention and mitral regurgitation treatment might be a valid approach in selected patients ineligible for chronic anticoagulation therapy and at high risk for conventional cardiac surgery. PMID- 23436382 TI - Dual factor delivery of CXCL12 and Exendin-4 for improved survival and function of encapsulated beta cells under hypoxic conditions. AB - A bioartifical pancreas (BAP) remains a promising approach for treating insulin dependent diabetes. Several obstacles to the clinical implementation of a BAP remain, including hypoxia following implantation. Within native pancreatic islets, CXCL12 and glucagon-like peptide-1 (GLP-1) act in a paracrine fashion to promote the survival, function, and proliferation of beta-cells. This work sought to investigate if the presentation of CXCL12 and delivery of a GLP-1 receptor analog, Exendin-4 (Ex-4), alone and in combination, conferred pro-survival and insulinotropic effects on an encapsulated beta-cell line, betaTC-tet, cultured under hypoxic conditions of 7.6 mmHg O2 . Our findings indicate that presentation of CXCL12 in the encapsulation matrix completely abrogated apoptosis under hypoxic conditions. Delivery of Ex-4 increased insulin secretion rate under both normoxic and hypoxic conditions, and additionally reduced apoptosis under hypoxic conditions. Furthermore, presentation of CXCL12 combined with Ex-4 delivery significantly increased insulin secretion rate under hypoxic conditions compared to delivery of Ex-4 alone. These findings demonstrate that the presentation of CXCL12 combined with the delivery of Ex-4 may constitute a promising strategy for supporting beta-cell function and survival following transplantation. PMID- 23436383 TI - Gesture use by chimpanzees (Pan troglodytes): differences between sexes in inter- and intra-sexual interactions. AB - Communication and social relationships are two of the most important aspects of primate life, but few studies have focused on linking these aspects in apes. There are some shared social pressures between the two sexes (e.g., kin selection, alliance formation, and protection against attack), but there are also differences (e.g., mate selection, dispersal, and social ranking systems). The aim of this study was to identify the communication strategies of the sexes with respect to their particular communication partner. I hypothesized the sexes use different strategies in their gestural communication based on their different social pressures. Specifically, males should have more positive intra-sexual relationships than females because of high focus on male-male alliance formation and maintaining high social rank, both of which directly affect their mating opportunities and relationships with all other members of the group. On the other hand, females should have more positive inter-sexual relationships due to the abuse they could receive from insubordination to males and because there is less focus on maintaining multiple, positive relationships with other females. Furthermore, because of differences in social pressures, males should have higher incidence of reassurance in same-sex interactions than females because it should be more important for males to mitigate negative interactions. I analyzed the characteristics of the gesture repertoire and frequency of gesture use for each sex in each of four contexts: (1) aggression, (2) submission, (3) greeting, and (4) reassurance. I looked at intra-sexual and inter-sexual interactions, separately. I found that, indeed, males and females utilize different strategies of gestural communication. I also found that females, but not males, have a distinct gesture strategy for communicating with the opposite sex than for the same sex. This study shows there are distinct strategies utilized by the two sexes and these differences may be explained by their differing social pressures. PMID- 23436384 TI - A new access to 4 H-quinolizines from 2-vinylpyridine and alkynes promoted by rhodium-N-heterocyclic-carbene catalysts. AB - Forging the lock that autolocks! Rh-NHC catalysts promote a new access to 4 H quinolizine species from 2-vinylpyridine and terminal and internal alkynes through C-H activation and C-C coupling reactions (see figure). N-Bridgehead heterocycle formation is favored for internal- over terminal-substituted butadienylpyridine derivatives in a thermal 6pi-electrocyclization process. PMID- 23436385 TI - Precision, bias, and clinical utility of the Sheiner-Tozer equation to guide phenytoin dosing in critically ill adults. PMID- 23436386 TI - Synthesis of biopterin and related pterin glycosides. AB - Certain pterins having a hydroxyalkyl side chain at C-6 have been found as glycosidic forms in certain prokaryotes, such as 2'-O-(alpha-D glucopyranosyl)biopterin from various kinds of cyanobacteria, and limipterin from a green sulfur photosynthetic bacterium. Synthetic studies on glycosides of biopterin and related pterins have been made in view of the structural proof as well as for closer examination of their biological activities and functions. The syntheses of these natural pterin glycosides have effectively been achieved, mostly through appropriately protected N(2) -(N,N-dimethylaminomethylene)-3-[2-(4 nitrophenyl)ethyl]pterin derivatives as glycosyl acceptors, and are reviewed here. PMID- 23436387 TI - Medial temporal lobe amnesia impairs performance on a free association task. AB - A growing body of evidence suggests that the hippocampus contributes to performance (or is implicated) in non-memory domains from perception to problem solving. In a previous study we found that hippocampal contribution to exemplar generation in a fluency task was determined jointly by the open-endedness of the task and its ability to elicit episodic memories (Sheldon and Moscovitch (2012) Hippocampus 22:1451-1466). In the current study, we extend these observations by exploring the role of the hippocampus in generative, goal-directed open-ended thought in patients with medial temporal lobe (MTL) amnesia on a free association task (think of words as they come to mind). Patients and control participants were asked to associate freely for one minute to cue words that varied in the open-endedness of the responses they elicited (greater for low- than high frequency words), and in the ease with which episodic memories were evoked (greater for high imageable than low imageable words). As predicted, MTL amnesia patients generated fewer words than control participants when cues were highly imageable and low in frequency, but performed equivalently to them in the other conditions. These results support our prediction that the hippocampus contributes to free association, and possibly more generally to other generative tasks that are open-ended, creative, or that elicit the use of contextual and likely episodic memories in order to derive relevant information. PMID- 23436390 TI - Prenatal peptide treatment appears promising in Down syndrome mouse model. PMID- 23436391 TI - ACOG approves new trisomy screen for high-risk pregnancies: can clinical use of the screening for the genetic disorder in low-risk pregnancies be far behind? PMID- 23436393 TI - Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia. Over the last decade, plasma Epstein-Barr virus (EBV) DNA has been developed as a tumor marker for NPC. In this study, the authors investigated whether plasma EBV DNA analysis is useful for NPC surveillance. METHODS: In total, 1318 volunteers ages 40 to 60 years were prospectively recruited. Plasma EBV DNA and serology for viral capsid antigen immunoglobulin A (IgA) were measured. Participants who had detectable plasma EBV DNA or positive IgA serology underwent nasal endoscopic examination and a follow-up plasma EBV DNA analysis in approximately 2 weeks. All participants were followed for 2 years to record the development of NPC. RESULTS: Three individuals with NPC were identified at enrolment. All of them were positive for EBV DNA and remained positive in follow-up analysis. Only 1 of those patients was positive for EBV serology. In 1 patient who had NPC with a small tumor confined to the mucosa, the tumor was not detectable on endoscopic examination. Because of a 2-fold increase in plasma EBV DNA on the follow-up analysis, that patient underwent magnetic resonance imaging, which revealed the tumor. Among the participants who did not have NPC but had initially positive plasma EBV DNA results, approximately 66% had negative EBV DNA results after a median of 2 weeks. CONCLUSIONS: Plasma EBV DNA analysis proved useful for detecting early NPC in individuals without a clinical suspicion of NPC. Repeating the test in those who had initially positive results differentiated those with NPC from those who had false-positive results. Cancer 2013. (c) 2013 American Cancer Society. PMID- 23436394 TI - Exploring the structural requirements of collagen-binding peptides. AB - Collagen synthesis and tissue remodeling are involved in many diseases; therefore, collagen-specific binding agents have been developed to study collagen changes in various tissues. Based on a recently reported collagen binding peptide, which contains unnatural biphenylalanine (Bip) amino acid residue, constructs with various structure variations were synthesized to explore the contributions of unnatural Bip residue, conformational restrain, and amino acid sequence in collagen recognition. Their binding efficiency to collagens was evaluated in vitro using pure collagens. The results indicate that the C-terminal unnatural Bip residue, rather than the peptide sequence or conformational restrain, dominated the collagen I binding. Subsequent tissue binding study showed that the selected peptide did not offer preferential selectivity over collagen I in tissue, suggesting that a simple in vitro binding assay cannot adequately model the complex biological environment. PMID- 23436395 TI - Maturation of peptide-positive synaptic arbors in the medicinal leech requires rhythmic target activity. AB - The formation and refinement of synaptic connections are dependent on the activity that emerges from nascent synaptic connections. Such activity has the effect of regulating the production and release of specific neurotransmitters. To determine the role of activity in regulating the production of peptide-positive synapses, we used antibodies against Phe-Met-Arg-Phe-NH2 and acetylated alpha tubulin as well as intracellular injections of Neurobiotin to examine varicosities belonging to heart excitor (HE) neurons on the heart tubes of medicinal leeches, Hirudo spp. We found that the production of peptide-positive varicosities increased considerably during the last week of embryogenesis, which coincided with the emergence of rhythmic activity of the heart tube. When we compromised central input to HE neurons with bicuculline or by surgical ablation of the central pattern generator during early embryogenesis, we found that activity in the heart tubes and its rhythmicity were greatly diminished. Furthermore, the activity of HE neurons had also lost its rhythmicity and appeared tonic, and production of peptide-positive varicosities was substantially reduced as well. Partial surgical ablations that preserved rhythmic activity in the heart tube while disrupting heart tube innervation by some HE neurons still resulted in peptide-positive varicosity production. Taken together, our results suggest that postsynaptic rhythmic activity of the heart tube is necessary and sufficient for the development and maturation of peptide-positive synapses. PMID- 23436397 TI - Do intrinsically disordered proteins possess high specificity in protein-protein interactions? AB - Specific protein-protein interactions are critical to cellular function. Structural flexibility and disorder-to-order transitions upon binding enable intrinsically disordered proteins (IDPs) to overcome steric restrictions and form complementary binding interfaces, and thus, IDPs are widely considered to have high specificity and low affinity for molecular recognition. However, flexibility may also enable IDPs to form complementary binding interfaces with misbinding partners, resulting in a great number of nonspecific interactions. Consequently, it is questionable whether IDPs really possess high specificity. In this work, we investigated this question from a thermodynamic viewpoint. We collected mutant thermodynamic data for 35 ordered protein complexes and 43 disordered protein complexes. We found that the enthalpy-entropy compensation for disordered protein complexes was more complete than that for ordered protein complexes. We further simulated the binding processes of ordered and disordered protein complexes under mutations. Simulation data confirmed the observation of experimental data analyses and further revealed that disordered protein complexes possessed smaller changes in binding free energy than ordered protein complexes under the same mutation perturbations. Therefore, interactions of IDPs are more malleable than those of ordered proteins due to their structural flexibility in the complex. Our results provide new clues for exploring the relationship between protein flexibility, adaptability, and specificity. PMID- 23436398 TI - Theoretical tools for predicting optimal cross-sectional shapes in micro-gas chromatography. AB - It is meaningful to explore the possibility of improving the micro-GC column performance by adjusting the column cross-sectional shape. The objective of this study was to seek the column cross-sectional shape that results in larger plate number per meter than other shapes with the same cross-sectional area and the same flow resistance coefficient. We applied a model based on the volume averaging method to derive the expression of plate height for columns with arbitrary cross-sectional shapes, and conducted the shape optimization by combining the model and an optimization tool. By varying flow resistance coefficient, we obtained a series of optimal shapes. It is found that, the optimal shape with larger flow resistance coefficient is shallower and the related plate number per meter is larger. We predicted and optimized the performance of a micro-GC column reported in literature. The prediction agrees reasonably with experimental data. More than twice the plate number per meter of the original column was predicted by using a hypothetical column with one optimal cross-sectional shape. PMID- 23436399 TI - Objective qualitative and quantitative assessment of blood flow with near infrared angiography in microvascular anastomoses in the rat model. AB - Intraoperative near-infrared indocyanine-green (ICG) angiography enables the visualization of microvascular perfusion and may help in the early detection of complications. The purpose of the present study was to examine whether the effect of microvascular stenoses can be quantitatively assessed by analysis of ICG angiography in a microvascular model. Graded stenoses and total vessel occlusion of the carotid, aorta, and femoral arteries were created in 25 Wistar rats. Stenoses were graded to reduce arterial flow by 25%, 50%, 75%, and 100% of baseline flow as measured by transit-time flowmeter analyzing the emission signal of the ICG detected and investigated by the mathematical software tool (FLOW 800). ICG angiography was performed to assess vessel perfusion and flow curves were analyzed and correlated with the stenosis rate. A total of 576 investigations were performed. The area under the curve (P < 0.001), first and second maximum (P < 0.001), and the maximum slope to the first maximum (P < 0.001) were found to be of high prognostic value in evaluating the different flow patterns. Differences were displayed in comparisons by the maximum intensity of the ICG-concentrations. The maximum slope to the second maximum was found to be predictive in selected vessel types, and specific changes of the flow curve were found to indicate compromised vascular flow. The FLOW 800 tool applied for ICG angiography has shown to be a quick and reliable method for assessing blood flow in vessels in this study. The dynamic assessment of the ICG signal allows reliable identification of microanastomotic complications with the described parameters. PMID- 23436400 TI - A squaraine-linked mesoporous covalent organic framework. PMID- 23436401 TI - Scaling down constriction-based (electrodeless) dielectrophoresis devices for trapping nanoscale bioparticles in physiological media of high-conductivity. AB - Selective trapping of nanoscale bioparticles (size <100 nm) is significant for the separation and high-sensitivity detection of biomarkers. Dielectrophoresis is capable of highly selective trapping of bioparticles based on their characteristic frequency response. However, the trapping forces fall steeply with particle size, especially within physiological media of high-conductivity where the trapping can be dissipated by electrothermal (ET) flow due to localized Joule heating. Herein, we investigate the influence of device scaling within the electrodeless insulator dielectrophoresis geometry through the application of highly constricted channels of successively smaller channel depth, on the net balance of dielectrophoretic trapping force versus ET drag force on bioparticles. While higher degrees of constriction enable dielectrophoretic trapping of successively smaller bioparticles within a short time, the ETflow due to enhanced Joule heating within media of high conductivity can cause a significant dissipation of bioparticle trapping. This dissipative drag force can be reduced through lowering the depth of the highly constricted channels to submicron sizes, which substantially reduces the degree of Joule heating, thereby enhancing the range of voltages and media conductivities that can be applied toward rapid dielectrophoretic concentration enrichment of silica nanoparticles (~50 nm) and streptavidin protein biomolecules (~5 nm). We envision the application of these methodologies toward nanofabrication, optofluidics, biomarker discovery, and early disease diagnostics. PMID- 23436402 TI - The path to oncology drug target validation: an industry perspective. AB - The advent of a variety of genomic, proteomic and other system-based scientific approaches has raised the expectations of identifying novel targets for oncology drug discovery. However, the complexity of human genome cancer alterations requires a careful analysis of the function of candidate targets identified by these efforts. The postulation and testing of a hypothesis that modulation of a protein or pathway will result in a therapeutic effect in a preclinical setting is crucial for target validation activities. In this chapter, we provide an overview on target identification and validation approaches to interrogate the functional and therapeutic relevance of a candidate cancer drug target as an essential step towards justifying the subsequent investment in drug discovery efforts. PMID- 23436403 TI - Identification of aptamers as specific binders and modulators of cell-surface receptor activity. AB - In recent years, the SELEX (Systematic Evolution of Ligands by EXponential enrichment) technology has established itself as a powerful tool in basic research with promising applications in diagnostics and therapeutics. Oligonucleotides with high-affinities to their targets, denominated as aptamers, are obtained from partially random oligonucleotide pools by reiterative in vitro selection cycles and screening for binding activity. The original technique allowing the identification of aptamers binding to soluble targets, has recently been extended in order to produce aptamers binding to complex targets including receptors and ion channels embedded in the plasma membrane as well as whole cell surfaces or parasite organisms. In addition to discussing the most recent developments with focus on possible diagnostic and therapeutic application, we provide a simple protocol which has been successfully used to select for RNA aptamers as allosteric modulators of nicotinic receptor activity. PMID- 23436404 TI - The design and structure-functional properties of DNA-based immunomodulatory sequences. AB - DNA-based immunomodulatory sequences (DIMS) are promising compounds for the treatment of different diseases, including inflammation and cancer. They act through the interaction with TLR9, a member of the Toll-like receptor family whose essential role in innate immunity was recently recognised by being awarded the Nobel Prize 2011. Combining the data obtained from in vitro and in vivo models with circular dichroism spectroscopy approach, we could show that formation of certain tertiary structures by DIMS can be connected to their specific physiologic effects such as activation of immune cells, induction of interferons and delay of the disease progression. Moreover the ability of selected DIMS compounds to form certain tertiary structures must be regarded as important for biological activities as is the presence of functional primary structure motifs such as unmethylated deoxyribodinucleotide CpG. These findings are useful when considering the design of DNA-based immunomodulators. PMID- 23436405 TI - siRNA design principles and off-target effects. AB - Short interfering RNAs (siRNAs) are a major research tool that allows for knock down of target genes via selective mRNA destruction in almost all eukaryotic organisms. siRNAs typically consist of a synthetic ~21 nucleotide (nt) RNA-duplex where one strand is designed with perfect complementarity to the target mRNA. Although siRNAs were initially thought to be very target-specific because of their design, it turned out during the last years that all siRNAs have a more or less pronounced intrinsic off-target activity which can make the interpretation of data from siRNA experiments difficult. Here we describe essential rules for siRNA design that should be taken into account in order to obtain potent siRNAs with minimal off-target activity. In addition, we describe how to control for off target activity in siRNA experiments. PMID- 23436406 TI - Western blot evaluation of siRNA delivery by pH-responsive peptides. AB - Gene silencing, via RNA interference (RNAi) technologies using small interfering RNA (siRNA), has been developed as an important tool for target identification and validation in drug discovery and has huge therapeutic potential. However, effective delivery into cells presents a major challenge to the use of siRNA. pH responsive cell-penetrating peptides have attracted considerable attention in recent years as delivery vectors due to their ability to transport their cargos across the biological membrane and/or to promote endosomal escape and prevent lysosomal degradation. To evaluate the in vitro transfection efficiency of the pH responsive peptide-based siRNA delivery system, the western blotting technique is commonly employed. This method offers a simple, efficient and economical way to study the gene silencing effect of the siRNA by analysing the protein of interest in a sample with minimum equipment requirement. This chapter provides a description of siRNA delivery and analysis by western blotting protocols for qualitatively and quantitatively assessing gene silencing efficiency and selectivity. PMID- 23436407 TI - High-throughput RNAi screening for the identification of novel targets. AB - Gene silencing through RNA interference has provided researchers with an effective way to study gene function. High-throughput RNA interference (HT-RNAi) screening has further permitted researchers to identify functionally relevant mediators of cellular response on a large scale. These screens have greatly expedited the discovery of novel targets and pathway mediators. Here, we describe the methodology for performing HT-RNAi screening of HeLa cells transfected with short interfering RNA (siRNA) libraries in 384-well microplate format. Using this plate format, the HT-RNAi assay can be easily adapted to semi-automated or fully automated platforms. The library siRNA are introduced into the cells through reverse transfection using cationic lipids. HT-RNAi screening for modulators of cell proliferation can be accomplished using a single read out reagent. This type of RNAi screening can be used with most plate-based cellular assays and can be optimized for most cultured cells lines, thus becoming a powerful tool to identify specific gene modulators and targets for drug discovery. PMID- 23436408 TI - Integration of RNAi and small molecule screens to identify targets for drug development. AB - Cellular models for siRNA and small molecule high throughput screening have been widely used in the last decade to identify targets for drug discovery. As an example, we present a two-fold readout approach based on cell viability and multipolar phenotype. To maximize the discovery of potential targets and at the same time reduce the number of false positives in our dataset, we have combined focused and rationally designed custom siRNA libraries with small molecule inhibitor libraries. Here we describe a cellular model for centrosome amplification as an example of how to design and perform a multiple readout/multiple screening strategy. PMID- 23436409 TI - CellProfiler and KNIME: open source tools for high content screening. AB - High content screening (HCS) has established itself in the world of the pharmaceutical industry as an essential tool for drug discovery and drug development. HCS is currently starting to enter the academic world and might become a widely used technology. Given the diversity of problems tackled in academic research, HCS could experience some profound changes in the future, mainly with more imaging modalities and smart microscopes being developed. One of the limitations in the establishment of HCS in academia is flexibility and cost. Flexibility is important to be able to adapt the HCS setup to accommodate the multiple different assays typical of academia. Many cost factors cannot be avoided, but the costs of the software packages necessary to analyze large datasets can be reduced by using Open Source software. We present and discuss the Open Source software CellProfiler for image analysis and KNIME for data analysis and data mining that provide software solutions which increase flexibility and keep costs low. PMID- 23436410 TI - PARP inhibition as a prototype for synthetic lethal screens. AB - Although DNA damaging chemotherapy and radiation therapy remain the main stay of current treatments for cancer patient, these therapies usually have toxic side effect and narrow therapeutic window. One of the challenges in cancer drug discovery is how to identify drugs that selectively kill cancer cells while leaving the normal cell intact. Recently, synthetic lethality has been applied to cancer drug discovery in various settings, and has become a promising approach for identifying novel agents for the treatment of cancer. A prototypical example is the synthetic lethal interaction between PARP inhibition and BRCA deficiency. PARP inhibitors represent the most advanced clinical agents targeting specifically DNA repair mechanisms in cancer therapy. In this chapter, I will review the molecular mechanism for this synthetic lethality and the clinical applications for PARP inhibitors. I will also discuss the formats of synthetic lethal screens, current progress on the utilization of these screens, and some of the advantages and challenges of synthetic lethal screens in cancer drug discovery. PMID- 23436411 TI - Structure-based target druggability assessment. AB - The focus of this chapter is on the important concepts behind the in silico techniques that are used today to assess target druggability. The first step of the assessment consists of finding cavity space in the protein using 2D and/or 3D topological concepts. These concepts underlie the geometry and energy-based pocketfinder algorithms. Analysis pursues on the physico-chemical complementarity between the binding site and the drug like molecule. Geometrical and molecular flexibility aspect are also included in this assessment. The presence of hot interaction spots are shown to be particularly important for targeting protein protein interactions. Finally, binding site promiscuity can be assessed by large scale structural comparison with other targets. Common chemical features amongst protein cavities can predict potential cross-reactivity with unwanted targets. PMID- 23436412 TI - Validating pharmacological disruption of protein-protein interactions by acceptor photobleaching FRET imaging. AB - Proteins are the major targets of drug discovery and many of the new drugs are designed to exert their effect by disrupting protein-protein interactions. Validation of the inhibition of molecular interactions is generally done by biochemical methods, however, these are often not feasible when the interaction is not stable enough. Fluorescence resonance energy transfer (FRET) is an excellent tool for determining direct molecular interactions between two molecules in the cell membrane or inside cells in their natural state. Although originally established as a flow cytometric approach, FRET has been adapted for microscopy, allowing for analysis of sub-cellular co-localization at the single cell level. In this chapter, we provide theoretical introduction to the phenomenon of FRET, and a protocol - including labeling techniques, measurement, and evaluation of microscopy images - of the simplest microscopic FRET approach, acceptor photobleaching FRET. This technique is generally usable for studying protein interactions and requires only a standard confocal laser scanning microscope. To demonstrate the value of image based FRET for testing pharmacological disruption of protein-protein interactions, we show how inhibition of the hetero-dimerization of ErbB2 and ErbB1 by the humanized monoclonal antibody pertuzumab can be validated using this technique. PMID- 23436413 TI - Systematic analysis of complex signal transduction pathways using protein fragment complementation assays. AB - The state of a signal transduction pathway can be assessed by monitoring a given point, or a signaling node, of interest within that pathway by high content analysis. The activity at these nodes may be correlated with the general effect on cell number and morphology at the same time. Here we describe a method to analyze protein-protein interactions by protein fragment complementation assays. Complex signal transduction pathways become accessible by looking at them in their native cellular context, with all competitive and feedback mechanisms in place. Analyzing protein-protein interactions directly makes this method widely usable for many protein families and is independent of an intrinsic enzymatic activity. PMID- 23436414 TI - Reverse phase protein microarrays and their utility in drug development. AB - The majority of human diseases, including cancer, are characterized by abnormal protein function. Proteins regulate virtually every cellular process and exhibit multiple kinds of post-translational modification that modulate expression levels and activation states, such as phosphorylation by protein kinases. Additionally proteins interact with each other in complex regulatory networks and signal transduction pathways modulated by feedback mechanisms. These pathways are disrupted in disease and altered by therapeutic drugs. Reverse phase protein microarray (RPMA) technology allows simultaneous measurement of numerous phosphorylated, glycosylated, cleaved, or total cellular proteins from complex mixtures in many samples at once. Therefore, RPMAs can provide a portrait of a cell's signaling pathways in diseased states, before and after treatment with drugs, and allows comparison of changes in drug-resistant and sensitive cells. Furthermore, the technology offers a means of connecting genomic abnormalities in cancer to targetable alterations in protein signaling pathways, even for genetic events that seem otherwise undruggable. Consequently, the RPMA platform has great utility in many steps of drug development including target identification, validation of a pharmaceutical agent's efficacy, understanding mechanisms of action, and discovery of biomarkers that predict or guide therapeutic response. RPMAs have become a powerful tool for drug development and are now being integrated into human clinical cancer trials, where they are being used to personalize therapy. PMID- 23436415 TI - A cell culture system that mimics chronic lymphocytic leukemia cells microenvironment for drug screening and characterization. AB - Chronic Lymphocytic Leukaemia (CLL) is an incurable disease that warrants new therapeutic treatments. CLL cells accumulate in the peripheral blood, in the bone marrow and in secondary lymphoid organs. Unlike circulating CLL cells, CLL cells resident in these last two compartments display high chemoresistance and proliferative capacity. Given the importance of the microenvironment in this disease, strategies that aim to develop new therapeutic agents need to consider this critical factor. Various cell culture conditions have been described that attempt to emulate either the different types of microenvironments in which CLL cells are found or an individual component of a particular microenvironment. Here, a methodology that partially mimics the interaction between CLL cells and the CD3+ CD4+ CD154+ T cells is described. Moreover, within this method, two protocols are presented and compared that may partially recapitulate different physiological states. The methodology can be exploited for target validation and drug development in CLL. PMID- 23436416 TI - Two-dimensional vs. three-dimensional in vitro tumor migration and invasion assays. AB - Motility and invasion are key hallmarks that distinguish benign from malignant tumors, enabling cells to cross tissue boundaries, disseminate in blood and lymph and establish metastases at distant sites. Similar properties are also utilized by activated endothelial cells during tumor-induced angiogenesis. It is now appreciated that these processes might provide a rich source of novel molecular targets with the potential for inhibitors to restrain both metastasis and neoangiogenesis. Such therapeutic strategies require assays that can rapidly and quantitatively measure cell movement and the ability to traverse physiological barriers. The need for high-throughput, however, must be balanced by assay designs that accommodate, as far as possible, the complexity of the in vivo tumor microenvironment. This chapter aims to give an overview of some commonly used migration and invasion assays to aid in the selection of a balanced portfolio of techniques for the rapid and accurate evaluation of novel therapeutic agents. PMID- 23436418 TI - The neurosphere assay applied to neural stem cells and cancer stem cells. AB - The discovery of neural stem cells (NSCs) in the mammalian brain has raised many expectations as these unique cells might recapitulate different neurological diseases, including brain tumors, both from a functional and molecular perspective. Proper in vitro culturing of NSCs has emerged as a critical methodological issue, given that it should preserve the in vivo features of NSCs, with particular emphasis on cell heterogeneity. At the same time, the methodology for NSC culturing should allow the production of large amounts of cells to be exploited not only for prospective clinical applications, but also for drug screening. Direct in vitro selection of NSCs and, very recently, cancer stem cells (CSCs) by means of defined serum-free conditions represents the most reliable methodology to obtain long-term expanding SC lines. Here we describe the methods currently employed to enrich for NSCs/CSCs based on the NeuroSphere Assay (NSA) and their adaptation to specific assays for testing the efficacy of neuroactive compounds. PMID- 23436417 TI - Tumor spheroid-based migration assays for evaluation of therapeutic agents. AB - Cell migration is a key hallmark of malignant cells that contributes to the progression of cancers from a primary, localized mass to an invasive and/or metastatic phenotype. Traditional methods for the evaluation of tumor cell migration in vitro generally employ two-dimensional (2D), homogeneous cultures that do not take into account tumor heterogeneity, three-dimensional (3D) cell cell contacts between tumor and/or host cells or interactions with extracellular matrix proteins. Here we describe a 3D tumor spheroid-based migration assay which more accurately reflects the solid tumor microenvironment and can accommodate both extracellular matrix and host cell interactions. It is a rapid and highly reproducible 96-well plate-based technique and we demonstrate its utility for the evaluation of therapeutic agents/drugs with anti-migratory properties. PMID- 23436419 TI - Genetically engineered animal models for in vivo target identification and validation in oncology. AB - In vitro approaches using human cancer cell lines aimed to identify and validate oncology targets, have pinpointed a number of key targets and signalling pathways which control cell growth and cell death. However, tumors are more than insular masses of proliferating cancer cells. Instead they are complex tissues composed of multiple distinct cell types that participate in homotypic and heterotypic interactions and depend upon each other for their growth. Therefore, many targets in oncology need to be validated in the context of the whole animal. This review provides an overview on how animal models can be generated and used for target identification and validation in vivo. PMID- 23436420 TI - Target validation in mice by constitutive and conditional RNAi. AB - Gene silencing by RNA interference (RNAi) has become a standard method for the characterization of gene function in mammalian cells. Short hairpin (sh) RNAs expressed from stably integrated vectors mediate gene knockdown both in cultured cells and in mice, presenting a fast alternative to gene knockout approaches. We describe three strategies to control gene silencing in mice that can be applied to any transcript of interest. This shRNA based approach enables either i) constitutive body-wide knockdown, ii) cell type-specific knockdown controlled by Cre recombinase, or iii) inducible body-wide knockdown controlled by doxycycline. For reliable expression the shRNA vector of interest is inserted into a Rosa26 docking site of ES cells by a site-specific recombinase. These ES cells can then be used to generate shRNA transgenic mice. This technology enables the production of adult knockdown mice within 11 months for an expedite in vivo validation of drug targets. PMID- 23436421 TI - In vivo target validation by inducible RNAi in human xenograft mouse models. AB - Proper target selection and validation are crucial to the discovery of new anti cancer agents. Since tumors depend on a suitable microenvironment for their growth, once a putative target has been identified, its validation should be performed whenever possible in vivo. This chapter deals with the generation of human xenograft mouse models genetically modified to induce the modulation of cancer-related genes as an approach to validate oncology targets. PMID- 23436422 TI - Bright-field in situ hybridization methods to discover gene amplifications and rearrangements in clinical samples. AB - Brightfield in situ hybridization (BISH) applications have significant advantages over traditional fluorescence in situ hybridization (FISH). BISH slides can be analyzed using a regular microscope while FISH slides require the use of a specialized fluorescence microscope. BISH slides allow observers for correlating the gene status (gene amplifications, gene rearrangements, and gene deletions) and tissue morphology better than FISH slides. Also, BISH slides are ideal for the permanent preservation of gene signals. Furthermore, BISH applications can be optimized using an automated tissue slide processing system. BISH applications are becoming a popular method for clinical examination of gene status for selecting cancer treatments. PMID- 23436423 TI - Combined microRNA in situ hybridization and immunohistochemical detection of protein markers. AB - MicroRNAs are short (18-23 nucleotides) non-coding RNAs involved in posttranscriptional regulation of gene expression through their specific binding to the 3'UTR of mRNAs. MicroRNAs can be detected in tissues using specific locked nucleic acid (LNA)-enhanced probes. The characterization of microRNA expression in tissues by in situ detection is often crucial following a microRNA biomarker discovery phase in order to validate the candidate microRNA biomarker and allow better interpretation of its molecular functions and derived cellular interactions. The in situ hybridization data provides information about contextual distribution and cellular origin of the microRNA. By combining microRNA in situ hybridization with immunohistochemical staining of protein markers, it is possible to precisely characterize the microRNA expressing cells and to identify the potential microRNA targets. This combined technology can also help to monitor changes in the level of potential microRNA targets in a therapeutic setting. In this chapter we present a fluorescence-based technology that allows the combination of microRNA in situ hybridization with immunohistochemistry exemplified by the in situ detection of miR-21 and miR-205 in combination with PDCD4 and smooth muscle a-actin. PMID- 23436424 TI - Iatrogenic communications between aortic root and right ventricle/left atrium after transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) has emerged as an alternative, less invasive treatment option for patients with severe symptomatic aortic stenosis, who are high-risk for conventional surgical aortic valve replacement, due to co morbidities. In addition to a 30-day 10% mortality risk there is a recognized range of complications, which commonly relate to vascular access trauma, paravalvular aortic regurgitation, and cerebrovascular events. In the following case reports, we discuss two previously unreported complications of TAVR: (i) an iatrogenic communication between the aortic root and the right ventricle and (ii) an iatrogenic communication between the aortic root and the left atrium. Informed written consent was obtained from both patients. PMID- 23436426 TI - Feeding Ecology of northern bearded sakis (Chiropotes sagulatus) in Guyana. AB - Bearded sakis (genus Chiropotes) are among the most highly specialized primate seed predators. However, long-term studies of the genus in continuous forests, with a full community of sympatric primates, are rare. Here I present data on monthly variation in the diet of Chiropotes sagulatus from a long-term study in a continuous forest in Guyana. Bearded sakis had an extremely diverse diet, exploiting more than 175 species of plants. Consistent with their highly specialized dental morphology for seed eating, seeds made up 75% of the annual diet. Sakis exploited a wide variety of mechanically protected fruits and often exploited the same plant species for more than 3 months. They consumed a high percentage of seeds in all months and seed consumption was significantly correlated with fruit abundance. When fruit became scarcer, sakis consumed a higher percentage of non-seed food items, including insects, mature fruit, and flowers. Insects were especially important during the leanest months, making up almost 40% of feeding time. Bearded saki dietary diversity (in terms of plant species) showed little variability across months. These results confirm sakis to be highly specialized seed predators. Sakis preferentially consume seeds when they are available. However, when seeds become scarce, sakis become generalists, supplementing their diet with mature fruit, insects, and flowers. The ability of bearded sakis to consume a diversity of highly abundant plant species, fruit in several stages of maturity, and a variety of different types of resources buffers them from the detrimental effects of resource scarcity. PMID- 23436425 TI - Quantitating intraparticle O2 gradients in solid supported enzyme immobilizates: experimental determination of their role in limiting the catalytic effectiveness of immobilized glucose oxidase. AB - Enzymatic O2 -dependent oxidations are receiving increased attention for use in fine chemicals synthesis. Solid supported oxidation catalysts often show poor efficiency due to pronounced O2 diffusion restriction. Internal O2 supply therefore constitutes a key parameter for optimizing the enzyme immobilization. We herein describe an optical sensing method for quantitation of space-averaged intraparticle O2 concentrations in porous Sepabeads carriers. The method applies phosphorescence lifetime measurements on Sepabeads labeled with an O2 sensitive indicator dye. Using glucose oxidase immobilized at different loadings (0.005-12 mg/g) on labeled Sepabeads, we analyzed in real time during the enzymatic reaction the formation of O2 concentration differences between bulk liquid and the intraparticle environment. We show that the O2 gradient at apparent steady state increased with increasing enzyme loading, so that O2 eventually became totally depleted from inside the highly loaded carriers. We also show that the residual intraparticle O2 concentration was correlated with the catalytic effectiveness factor (eta) of the enzyme immobilizate used, thus providing a direct measure of the magnitude of O2 diffusion limitation. Once corrected for diffusional effect, eta was no longer dependent on enzyme loading and its constant value now described the intrinsic activity of immobilized glucose oxidase. Three common procedures of enzyme immobilization, involving adsorption, cross-linking, and covalent attachment, are shown to differ widely concerning the obtained intrinsic activity. Therefore, intraparticle O2 concentration data enable distinction between diffusional restriction and activity loss as the two principal factors limiting the effectiveness of immobilized O2 dependent enzymes, and thus they inform rational design of an optimally active oxidation biocatalyst on solid support. PMID- 23436427 TI - Extracts from Epilobium sp. herbs, their components and gut microbiota metabolites of Epilobium ellagitannins, urolithins, inhibit hormone-dependent prostate cancer cells-(LNCaP) proliferation and PSA secretion. AB - Extracts from Epilobium sp. herbs have been traditionally used in the treatment of prostate-associated ailments. Our studies demonstrated that the extracts from Epilobium angustifolium, Epilobium parviflorum and Epilobium hirsutum herbs are potent prostate cancer cells (LNCaP) proliferation inhibitors with IC50 values around 35 ug/ml. The tested extracts reduced prostate specific antigen (PSA) secretion (from 325.6 +/- 25.3 ng/ml to ~90 ng/ml) and inhibited arginase activity (from 65.2 +/- 1.1 mUnits of urea/mg of protein to ~40 mUnits of urea/mg protein). Selected constituents of extracts (oenothein B, quercetin-3-O glucuronide, myricetin-3-O-rhamnoside) were proven to be active in relation to LNCaP cells. However, oenothein B was the strongest inhibitor of cells proliferation (IC50 = 7.8 +/- 0.8 MUM), PSA secretion (IC50 = 21.9 +/- 3.2 MUM) and arginase activity (IC50 = 19.2 +/- 2.0 MUM). Additionally, ellagitannins from E. hirustum extract were proven to be transformed by human gut microbiota into urolithins. Urolithin C showed the strongest activity in the inhibition of cell proliferation (IC50 = 35.2 +/- 3.7 MUM), PSA secretion (reduced PSA secretion to the level of 100.7 +/- 31.0 ng/ml) and arginase activity (reduced to the level of 27.9 +/- 3.3 mUnits of urea/mg of protein). Results of the work offer an explanation of the activity of Epilobium extracts and support the use of Epilobium preparations in the treatment of prostate diseases. PMID- 23436428 TI - Addition of cilostazol to conventional dual antiplatelet therapy reduces the risk of cardiac events and restenosis after drug-eluting stent implantation: a meta analysis. AB - This meta-analysis was performed to compare the risk of cardiac events and restenosis between triple antiplatelet therapy (TAT, addition of cilostazol to aspirin and clopidogrel) and conventional dual antiplatelet therapy (DAT, aspirin and clopidogrel) in drug-eluting stents (DES) implantation patients. We performed PUBMED, MEDLINE, EMBASE, and Cochrane CENTRAL searches for randomized clinical trials of TAT versus DAT in patients after DES implantation. Five clinical trials were involved in the study. TAT was associated with a 36% reduction in major adverse cardiac events (MACE; odds ratio (OR) = 0.64; 95% confidence interval (CI) = 0.51-0.81, P < .01), a 40% reduction (OR = 0.60, 95% CI = 0.44-0.80; P < .01) in target vessel revascularization (TVR), a 44% reduction (OR = 0.56, 95% CI = 0.34-0.91; P = .02) in target lesion revascularization (TLR) and a 47%/44% reduction in in-segment/in-stent restenosis (P < .01) and lower in-segment/in stent late loss (P < .01). As regards to the safety assessment, there was no significant difference about the risk of stent thrombosis and bleeding between TAT and DAT group, while the risk of gastrointestinal trouble was significantly higher in TAT group (OR = 2.46, 95% CI = 1.25-4.86; P < .01). Addition of cilostazol to DAT reduced the incidence of MACE, TVR, and TLR after DES implantation. TAT also reduced the risk of restenosis and late loss in patients after DES implantation. PMID- 23436429 TI - Modulation of calcineurin activity in mouse brain by chronic oral administration of cyclosporine A. AB - Calcineurin (CN) is an important phosphatase that mediates many physiological and pathological processes. The regulators of calcineurin (RCAN1) and Cu, Zn superoxide dismutase (SOD1) are two endogenous modulators of CN activity. Cyclosporine A (CsA) is a well-known exogenous inhibitor of CN and used as an immunosuppressive drug after transplantation and for the treatment of immune diseases. The degree of CN inhibition by CsA varies among each tissue. The brain accumulates low levels of CsA due to the blood-brain barrier after oral administration. In our study, we investigated RCAN1 and SOD1 expression in long term CsA-treated mouse brain. Using Western blot, we found that chronic CsA treatment had caused significant up-regulation of RCAN1-1L and RCAN1-4 protein isoforms after 25 days in mouse brain. At the same time, chronic CsA treatment also resulted in decreased expression of SOD1. We simultaneously found more dramatic CN inhibition in mouse brain. It was suspected that the significant reduction of CN activity in vivo resulted partially from up-regulated RCAN1 and down-regulated SOD1 expression. In contrast, CsA treatment in SY5Y cells affected SOD1 expression and CN activity significantly, but had no obvious effects on RCAN1-1 mRNA expression. The changes of RCAN1, SOD1, and CN activity may be part of maladaptive responses, resulting in neuropathological conditions. These data might partially explain CsA neurotoxicity despite the low concentration of CsA in brain. PMID- 23436431 TI - Isostructural unbranched alkyl-chains as tools for stabilizing beta-turn structure. AB - To investigate the structural role played by isostructural unbranched alkyl chains on the conformational ensemble and stability of beta-turn structures, the conformational properties of a designed model peptide: Plm-Pro-Gly-Pda (1, Plm: H3 C-(CH2)14-CONH-; Pda: -CONH- (CH2 )14 -CH3) have been examined and compared with the parent peptide: Boc-Pro-Gly-NHMe (2, Boc: tert-butoxycarbonyl; NHMe: N methylamide). The characteristic (13)C NMR chemical-shifts of the Pro C(beta) and C(gamma) resonances ascertained the incidence of an all-trans peptide-bond in low polarity deuterochloroform solution. Using FTIR and (1) H NMR spectroscopy, we establish that apolar alkyl-chains flanking a beta-turn promoting Pro-Gly sequence impart definite incremental stability to the well-defined hydrogen bonded structure. The assessment of (1)H NMR derived thermodynamic parameters of the hydrogen-bonded amide-NHs via variable temperature indicate that much weaker hydrophobic interactions do contribute to the stability of folded reverse turn structures. The far-UV CD spectral patterns of 1 and 2 in 2,2,2-trifluoroethanol are consistent with Pro-Gly specific type II beta-turn structure, concomitantly substantiate that the flanking alkyl-chains induce substantial bias in enhanced beta-turn populations. In view of structural as well as functional importance of the Pro-Gly mediated secondary structures, besides biochemical and biological significance of proteins lipidation via myristoylation or palmytoilation, we highlight potential convenience of the unbranched Plm and Pda moieities not only as main-chain N- and C-terminal protecting groups but also to mimic and stabilize specific isolated secondary and supersecondary structural components frequently observed in proteins and polypeptides. PMID- 23436430 TI - Changes in mortality and causes of death in the Swedish Down syndrome population. AB - During the past few decades age at death for individuals with Down syndrome (DS) has increased dramatically. The birth frequency of infants with DS has long been constant in Sweden. Thus, the prevalence of DS in the population is increasing. The aim of the present study was to analyze mortality and causes of death in individuals with DS during the period 1969-2003. All individuals with DS that died between 1969 and 2003 in Sweden, and all individuals born with DS in Sweden between 1974 and 2003 were included. Data were obtained from the Swedish Medical Birth Register, the Swedish Birth Defects Register, and the National Cause of Death Register. Median age at death has increased by 1.8 years per year. The main cause of death was pneumonia. Death from congenital heart defects decreased. Death from atherosclerosis was rare but more frequent than reported previously. Dementia was not reported in any subjects with DS before 40 years of age, but was a main or contributing cause of death in 30% of the older subjects. Except for childhood leukemia, cancer as a cause of death was rare in all age groups. Mortality in DS, particularly infant mortality, has decreased markedly during the past decades. Median age at death is increasing and is now almost 60 years. Death from cancer is rare in DS, but death from dementia is common. PMID- 23436432 TI - Chemical properties investigation of commercial cigarettes by a "pseudo" targeted method using GC-MS-selected ions monitoring. AB - A "pseudo" targeted method using GC-MS-selected ions monitoring was applied to investigate the chemical characteristics of commercial cigarettes made in China and foreign countries. To identify the components and define the quantative ions for SIM acquisition, a quality control sample was analyzed using GC-MS full scan. Acquired data were treated with a homemade software. A peak table with 312 components and their related quantitation ions was achieved for SIM acquisition. Structure elucidation was performed using library searching, retention index, standard compounds, and fitted retention time. The fitted retention time was calculated by a linear correction curve obtained using measured and library retention time to verify compounds. A total of 90 compounds were elucidated. Chemical characteristics of different cigarette brands were investigated. The data acquisition was carried out in SIM mode. The principal component and the hierarchical clustering analyses showed that the Chinese domestic flue-cured cigarettes were significantly different from the domestic blended, the foreign flue-cured, and blended cigarettes. Sixty-seven differential compounds were defined using the nonparametric Mann-Whitney test and the group blending samples comparison. Chinese domestic flue-cured cigarettes have higher concentration of saccharides and lower concentration of organic acids and amino acids. PMID- 23436433 TI - Aripiprazole-montmorillonite: a new organic-inorganic nanohybrid material for biomedical applications. AB - Poor aqueous solubility and the unpleasant taste of aripiprazole (APZ) have been recurring problems, owing to its low bioavailability and low patient tolerance, respectively. Herein, we prepared a nanohybrid system that was based on a bentonite clay material, montmorillonite (MMT), which could both mask the taste and enhance the solubility of APZ (i.e., APZ-MMT). To further improve the efficacy of this taste masking and drug solubility, APZ-MMT was also coated with a cationic polymer, polyvinylacetal diethylamino acetate (AEA). In vitro dissolution tests at neutral pH showed that the amount of drug that was released from the AEA-coated APZ-MMT was greatly suppressed (<1%) for the first 3 min, thus suggesting that AEA-coated APZ-MMT has strong potential for the taste masking of APZ. Notably, in simulated gastric juice at pH 1.2, the total percentage of APZ that was released within the first 2 h increased up to 95% for AEA-coated APZ-MMT. Furthermore, this in vitro release profile was also similar to that of Abilify(r), a commercially available medication. In vivo experiments by using Sprague-Dawley rats were also performed to compare the pharmacokinetics of AEA-coated APZ-MMT and Abilify(r). AEA-coated APZ-MMT exhibited about 20% higher systemic exposure of APZ and its metabolite, dehydro-APZ, compared with Abilify(r). Therefore, a new MMT-based nanovehicle, which is coated with a cationic polymer, can act as a promising delivery system for both taste masking and for enhancing the bioavailability of APZ. PMID- 23436435 TI - Regulation of the spatial code for BDNF mRNA isoforms in the rat hippocampus following pilocarpine-treatment: a systematic analysis using laser microdissection and quantitative real-time PCR. AB - Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity and is one of those genes that generate multiple mRNAs with different alternatively spliced 5'UTRs. The functional significance of many BDNF transcripts, each producing the same protein, is emerging. On the basis of the analysis of the four most abundant brain BDNF transcripts, we recently proposed the "spatial code hypothesis of BDNF splice variants" according to which the BDNF transcripts, through their differential subcellular localization in soma or dendrites, represent a mechanism to synthesize the protein at distinct locations and produce local effects. In this study, using laser microdissection of hippocampal laminae and reverse transcription-quantitative real-time PCR (RT qPCR), we analyzed all known BDNF mRNA variants at resting conditions or following 3 h pilocarpine-induced status epilepticus. In untreated rats, we found dendritic enrichment of BDNF transcripts encoding exons 6 and 7 in CA1; exons 1, 6, and 9a in CA3; and exons 5, 6, 7, and 8 in DG. Considering the low abundance of the other transcripts, exon 6 was the main transcript in dendrites under resting conditions. Pilocarpine treatment induced an increase of BDNF transcripts encoding exons 4 and 6 in all dendritic laminae and, additionally, of exon 2 in CA1 stratum radiatum and exons 2, 3, 9a in DG molecular layer while the other transcripts were decreased in dendrites, suggesting restriction to the soma. These results support the hypothesis of a spatial code to differentially regulate BDNF in the somatic or dendritic compartment under conditions of pilocarpine induced status epilepticus and, furthermore, highlight the existence of subfield specific differences. PMID- 23436434 TI - The use of vascular closure devices and impact on major bleeding and net adverse clinical events (NACEs) in balloon aortic valvuloplasty: a sub-analysis of the BRAVO study. AB - OBJECTIVE: To determine the impact of suture-mediated vascular closure devices (VCDs) on net adverse clinical events (NACEs) after balloon aortic valvuloplasty (BAV). BACKGROUND: Ischemic and bleeding complications are common following transfemoral BAV; however, previous studies have been single center and limited by varying definitions of major bleeding. METHODS: The Effect of Bivalirudin on Aortic Valve Intervention Outcomes (BRAVOs) study was a retrospective observational study conducted at two high-volume academic centers over a 6-year period designed to compare the effect of bivalirudin versus unfractionated heparin. This is a subanalysis of 428 consecutive patients who underwent BAV (with 10-13 French sheaths) to compare the effect of hemostasis with VCDs versus manual compression utilizing standardized definitions. NACE was defined as the composite of major bleeding and major adverse clinical events (MACEs). All events were adjudicated by an independent clinical events committee who were blinded to antithrombin use. RESULTS: Preclosure was performed in 269 (62.8%) of patients. While bivalirudin was used more frequently in those with pre-closure (60.6% vs. 37.7%, P < 0.001), a history of prior BAV (11.1% vs. 3.6%, P = 0.04) and peripheral vascular disease (30.7% vs. 19.7%, P = 0.01) was more common in those not undergoing preclosure (n = 159, 37%). Other clinical and demographic features were well balanced between groups. Vascular closure was associated with a significant reduction in NACE (24.5% vs. 10.0% P < 0.001). Results remained significant after adjusting for baseline differences and bivalirudin use (OR 0.38, 95% CI: 0.21-0.68; P = 0.001). CONCLUSIONS: Our study suggests that suture mediated vascular closure is associated with a substantial reduction in NACE after transfemoral BAV. Large randomized clinical trials should be conducted to confirm our results. PMID- 23436436 TI - Identification of multisegmental nociceptive afferents that modulate locomotor circuits in the neonatal mouse spinal cord. AB - Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. (c) 2013 Wiley Periodicals, Inc. PMID- 23436437 TI - Blood pressure lowering effect of Nigella sativa L. seed oil in healthy volunteers: a randomized, double-blind, placebo-controlled clinical trial. AB - Nigella sativa L. seeds (N. sativa) have been used as a traditional remedy for a wide range of diseases including hypertension. The present study was performed to explore the effects of N. sativa oil on blood pressure (BP) in healthy volunteers. In a double-blind, randomized study, 70 healthy volunteers aged 34 to 63 years with systolic BP from 110 to 140 mmHg and diastolic BP from 60 to 90 mmHg were randomly allocated to receive 2.5 mL N. sativa oil or placebo two times a day for 8 weeks. The systolic and diastolic BPs, body mass index and blood levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, creatinine and blood urea nitrogen were determined at baseline and endpoint. Results showed that in N. sativa oil treated group the systolic and diastolic BPs decreased significantly compared with baseline and placebo group at the endpoint. Other parameters did not significantly change in both groups at the endpoint. No adverse effects were reported. In conclusion, oral daily administration of 5 mL N. sativa oil to healthy volunteers for 8 weeks lowers systolic and diastolic BPs without any adverse effects. PMID- 23436438 TI - Death of the alpha: within-community lethal violence among chimpanzees of the Mahale Mountains National Park. AB - Chimpanzees (Pan troglodytes) are capable of extreme violence. They engage in inter-group, sometimes lethal, aggression that provides the winners with an opportunity to enlarge their territory, increase their food supply and, potentially, attract more mates. Lethal violence between adult males also occurs within groups but this is rare; to date, only four cases (three observed and one inferred) have been recorded despite decades of observation. In consequence, the reasons for within-group lethal violence in chimpanzees remain unclear. Such aggression may be rare due to the importance of coalitions between males during inter-group encounters; cooperation between males is also thought to be key in the defense or advancement of social rank within the group. Previous accounts of within-group lethal violence concern victims who were low-ranking males; here we provide the first account of the killing of an incumbent alpha male by a coalition of adult males from the same community. We found no clear evidence that the alpha male's position was under threat during the months before the lethal attack: the male dominance hierarchy was highly stable, with low rates of male male aggression, and there were no significant changes in social interactions (i.e. grooming and aggression) between the alpha male and the other adult males. Two of the four attackers were former alpha males and were the individuals with whom the victim appeared, in the period preceding his death, to be most strongly affiliated: his most frequent grooming partners and those with whom he spent most time in proximity. The lethal attack triggered a period of instability in the male hierarchy and was likely an opportunistic attempt to seize alpha status by the third-ranking male. PMID- 23436439 TI - Continuous separation of colloidal particles using dielectrophoresis. AB - Dielectrophoresis is the movement of particles in nonuniform electric fields and has been of interest for application to manipulation and separation at and below the microscale. This technique has the advantages of being noninvasive, nondestructive, and noncontact, with the movement of particle achieved by means of electric fields generated by miniaturized electrodes and microfluidic systems. Although the majority of applications have been above the microscale, there is increasing interest in application to colloidal particles around a micron and smaller. This paper begins with a review of colloidal and nanoscale dielectrophoresis with specific attention paid to separation applications. An innovative design of integrated microelectrode array and its application to flow through, continuous separation of colloidal particles is then presented. The details of the angled chevron microelectrode array and the test microfluidic system are then discussed. The variation in device operation with applied signal voltage is presented and discussed in terms of separation efficiency, demonstrating 99.9% separation of a mixture of colloidal latex spheres. PMID- 23436440 TI - Increased curvature of hollow fiber membranes could up-regulate differential functions of renal tubular cell layers. AB - Tissue engineering devices as in vitro cell culture systems in scaffolds has encountered the bottleneck due to their much lower cell functions than real tissues/organs in vivo. Such situation has been improved in some extent by mimicking the cell microenvironments in vivo from either chemical or physical ways. However, microenvironmental curvature, commonly seen in real tissues/organs, has never been manipulated to regulate the cell performance in vitro. In this regard, this paper fabricated polysulfone membranes with or without polyethylene glycol modification to investigate the impact of curvature on two renal tubular cells. Regardless the varying membrane curvatures among hollow fiber membranes of different diameters and flat membrane of zero curvature, both renal cells could well attach at 4 h of seeding and form similar confluent layers at 6 days on each membrane. Nevertheless, the renal cells on hollow fibers, though showing confluent morphology as those on flat membranes, expressed higher renal functions and, moreover, the renal functions significantly increased with the membrane curvature among hollow fibers. Such upregulation on functions was unassociated with mass transport barrier of hollow fibers, because the cultures on lengthwise cut hollow fibers without mass transfer barrier showed same curvature effect on renal functions as whole hollow fibers. It could be proposed that the curvature of hollow fiber membrane approaching to the large curvature in kidney tubules increased the mechanical stress in the renal cells and thus might up-regulate the renal cell functions. In conclusion, the increase of substrate curvature could up-regulate the cell functions without altering the confluent cell morphology and this finding will facilitate the design of functional tissue engineering devices. PMID- 23436441 TI - Biosynthesis of drosopterins, the red eye pigments of Drosophila melanogaster. AB - Drosophila melanogaster has red eyes. Scientists have been curious about the biosynthesis of the red eye pigments and have completed a number of investigations on these compounds. Scientific contributions made over the past 50 years have improved our understanding of the red eye pigments. Researchers have elucidated the chemical structures of some pigments and have successfully purified and identified the enzymes that participate in the biosynthesis of the red eye pigments. In this article, we will review the characteristics of the Drosophila red eye pigments and of the enzymes and genes involved in its biosynthetic pathway. PMID- 23436442 TI - Readily accessible fluorescent probes for sensitive biological imaging of hydrogen peroxide. AB - Hydrogen peroxide is a major component of oxygen metabolism in biological systems that, when present in high concentrations, can lead to oxidative stress in cells. Noninvasive molecular imaging of H(2)O(2) using fluorogenic systems represents an effective way to detect and measure the accumulation of this metabolite. Herein, we detail the development of robust H(2)O(2)-sensitive fluorescent probes using a boronic ester trigger appended to the fluorophore through a benzyl ether linkage. A major advantage of the probes presented here is their synthetic accessibility, with only one step needed to generate the probes on the gram scale. The sensitivity of the probes was evaluated in simulated physiological conditions, showing micromolar sensitivity to H(2)O(2). The probes were tested in biological model systems, demonstrating effective imaging of unstimulated, endogenous H(2)O(2) levels in RAW 264.7 cells and murine brain tissue. PMID- 23436443 TI - Evaluation of a non-invasive monitoring method for free flap breast reconstruction using laser doppler flowmetrie and tissue spectrophotometry. AB - BACKGROUND: Despite advances in the monitoring of free flaps, there is still a demand for new technology to detect ischemic complications at an early stage. The aim of the present study was to evaluate the reliability of the O2C-device in terms of detecting flap failure in commonly used perforator flaps for breast reconstruction. METHODS: A total of 34 patients undergoing breast reconstruction were involved in this study. The perfusion dynamics of 23 deep inferior epigastric perforator flaps and 11 superior gluteal arterial perforator flaps were assessed using the O2C-device, which combines a laser light, to determine blood flow (flow), velocity, and white light to determine hemoglobin oxygenation (SO(2)) and relative amount of hemoglobin (rHB). Measurements were carried out intra-operatively after clamping and declamping the perforator vessels. In the post-operative period measurements were carried out every hour for the first 48 hours and from 3rd to 7th for every 2 hours. These dates were compared to findings of clinical assessment. RESULTS: Several intra-operative measurements, during the clamping and declamping the different perforator vessels, revealed a high correlation for all parameters: Flow (r = 0.89, P < 0. 05), Velo (r = 0.92, P < 0. 05), SO2 (r =0.84, P <0. 05), and rHB (r =0.83 P < 0.05). Vessel occlusion was detected in five cases, of which three were due to arterial thrombosis and two further cases were due to venous occlusion. Of the five cases, one flap loss caused by venous occlusion was noted. CONCLUSION: The O2C-device seems to be a reliable, objective, and non-invasive device for the monitoring of free flaps. Thus, it may improve flap survival rates by detecting vascular compromise at an early stage. PMID- 23436444 TI - Reagent control of [1,2]-Wagner-Meerwein shift chemoselectivity following the Nazarov cyclization: application to the total synthesis of enokipodin B. AB - An approach toward the carbon framework of various sesquiterpenes from the herbertane and cuparane families is described, including the concise total synthesis of enokipodin B. The key step is the construction of the vicinal quarternary centers of the skeleton through a tandem Nazarov cyclization/Wagner Meerwein rearrangement mediated by a copper(II) complex. During this study, it was also found that changing the ligand architecture on the copper(II) promoter improved the chemoselectivity of the cationic rearrangement. PMID- 23436450 TI - Optimization of ultrasonic-assisted extraction of phenolic antioxidants from Malus baccata (Linn.) Borkh. using response surface methodology. AB - In this study, the optimum extraction conditions for maximum recovery of the content of total phenolics (TPC) and total antioxidant abilities were analyzed for Malus baccata (Linn.) Borkh. using response surface methodology. The effects of ethanol percentage (X1 ,%), ultrasonic power (X2 , W) and extraction temperature (X3 , degrees C) on the total phenolic content (Y1 ) and antioxidant ability (Y2 ) were evaluated. A second-order polynomial model produced a satisfactory fitting of the experimental data with regard to total phenolic content (R(2) = 0.9942, P < 0.0001) and antioxidant ability (R(2) = 0.9966, P < 0.0001). The optimized conditions were ethanol concentration of 61.0%, ultrasonic power of 308.6 W, extraction temperature of 51.1 degrees C for TPC and 60.5%, 311.4 W, 51.6 degrees C for antioxidant ability, the predicted values agreed well with the experimental values. Results implied that the major phenolic compounds in obtained extracts as chlorogenic acid, quercetin-3-gal/glu, quercetin-3 xyl/ara, phloretin-2-xyloside, quercetin-3- rhamnoside, and phloridzin. PMID- 23436451 TI - Cocultures of GFP(+) -granule cells with GFP(-) -pyramidal cells and interneurons for the study of mossy fiber neurotransmission with paired recordings. AB - Synaptic transmission of the granule cells (GCs) via their axons, the mossy fibers (MFs), is traditionally studied on acutely prepared or cultured slices. Usually, extracellular, bulk or minimal stimulation is used to evoke transmitter release from MF terminals, while recording from their postsynaptic target cells, the pyramidal cells and interneurons of CA3. However, the ideal method to assess MF neurotransmission, the simultaneous recording of a presynaptic GC and one of its target cells, is extremely difficult to achieve using slices. Alternatively, cultures of GCs establishing autapses have been developed, but in these, GCs do not contact their natural targets. We developed cocultures of GCs, dissociated from transgenic GFP(+) rats, with pyramidal cells and interneurons of CA3, dissociated from wild-type rats, and confirmed the expression of cell-specific markers by immunofluorescence. We conducted recordings of GFP(+) -GCs synaptically connected with their GFP(-) -target cells, and demonstrate that synaptic transmission and its plasticity have the signature of transmission of MF. Besides being strongly depressed by activation of mGluRs, high frequency activation of GC-to-pyramidal cells synapses undergo LTP, while GC-to-interneuron synapses undergo LTD. This coculture method allows a high reproducibility of recording connected pairs of identified cells, constituting a valuable tool to study MF transmission, as well as different combinations of identifiable pre- and postsynaptic cells. PMID- 23436452 TI - High-level somatic mosaicism of AKT1 c.49G>A mutation in skin scrapings from epidermal nevi enables non-invasive molecular diagnosis in patients with Proteus syndrome. PMID- 23436454 TI - Development and validation of a spectrofluorimetric method for the quantification of ceftriaxone in pharmaceutical formulations and plasma. AB - We describe the development and validation of a new, simple, sensitive and cost effective method for the determination of ceftriaxone in commercial formulations and spiked human plasma. The method proposes the conversion of ceftriaxone into a fluorescent product by reacting with ortho-phthalaldehyde (OPA) in the presence of sulfite at room temperature. The reaction medium is buffered to pH 10 using borate buffer. The derivatized reaction product is highly fluorescent and exhibits maximum fluorescence intensity at lambda(em) = 386 nm after excitation at lambda(ex) = 324 nm. The experimental parameters affecting progress of the derivatization reaction were carefully studied and optimized. Under optimum experimental conditions, the method has an excellent correlation coefficient of 0.9984 with a broad linear range of 0.4-20 ug/mL. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 1.30 * 10(-3) and 3.90 * 10( 3) ug/mL, respectively. The interference effects of common excipients on the quantification of drug were investigated and no interference effect was observed. The proposed method has been successfully applied to the determination of ceftriaxone in pharmaceutical formulations and spiked human plasma samples. The method has been validated statistically through percent recovery studies using standard addition and by comparison with a reference HPLC method. The developed method exhibits excellent inter- and intraday precision. PMID- 23436455 TI - Effect of a cognitive challenge device containing food and non-food rewards on chimpanzee well-being. AB - Exploration and problem-solving are highly motivated behaviors in non-human primates, but little research has focused on whether cognitively challenging tasks can enhance primates' psychological well-being, particularly in the absence of food rewards. We evaluated whether a novel cognitive challenge device (CCD) consisting of a maze of opaque tubes enhanced the well-being of a group of six adult chimpanzees housed at ZSL Whipsnade Zoo, UK, over a two-month period. Chimpanzees had the opportunity to interact with two versions of the CCD: the first contained tokens which fell into a transparent chamber when extracted from the CCD and could not be eaten. The second contained unshelled Brazil nuts, which could be extracted and eaten. CCD-use was low over the study, occupying on average 2.5% of observation time. However, compared to baseline levels, chimpanzees exhibited more problem-solving behaviors (directed toward the CCD) and spent significantly more time engaged in social play when the CCD was present. Cage exploration was rare whether the CCD was present or not. Chimpanzees used the CCD (including tool-use) significantly more when it contained tokens. The relationship between the presence of the CCD and self directed behavior (rough-scratching) was difficult to interpret. Although rough scratching was significantly higher in the cage when the CCD was present and 18% of these scratching events occurred within one arm's length from the CCD, rough scratching decreased when device use increased. This study provides a preliminary investigation of the CCD and two reward types, and suggests how the design could be modified to enhance its effects. PMID- 23436456 TI - Oppositional defiant disorder symptoms in relation to psychopathic traits and aggression among psychiatrically hospitalized children: ADHD symptoms as a potential moderator. AB - Oppositional defiant disorder (ODD) is associated with elevated rates of psychopathic traits and aggression. However, it remains unclear if attention deficit/hyperactivity disorder (ADHD) symptoms exacerbate these relations, particularly in samples of children who are severely clinically distressed. The purpose of the present study was to test ADHD symptoms as a potential moderator of the relations of ODD symptoms to psychopathic traits (i.e., callous unemotional [CU] traits, narcissism) and to aggressive subtypes (i.e., proactive, reactive aggression) in a large sample of children in an acute psychiatric inpatient facility (n = 699; ages 6-12). Multiple regression analyses indicated that, after controlling for child demographic variables, ADHD symptoms marginally exacerbated the relation between ODD symptoms and CU traits. Both ODD and ADHD symptoms had an additive, but not a multiplicative effect, in predicting narcissism. In addition, for a subset of the full sample for whom data were available (n =351), ADHD symptoms exacerbated the relation between ODD symptoms and both reactive and proactive aggression. These results suggest that ADHD symptoms tend to have a negative effect on the relation between ODD symptoms and markers of antisociality among children receiving acute psychiatric care. PMID- 23436457 TI - Evaluation of the antihypertensive properties of yellow passion fruit pulp (Passiflora edulis Sims f. flavicarpa Deg.) in spontaneously hypertensive rats. AB - Various species of the genus Passiflora have been extensively used in traditional medicine as sedatives, anxiolytics, diuretics and analgesics. In the present study, after the identification and quantification of phytochemical compounds from yellow passion fruit pulp by liquid chromatography-photodiode array-mass spectrometry (HPLC-PDA-MS/MS), its antihypertensive effect was investigated on spontaneously hypertensive rats. Additionally, the renal function, evaluated by kidney/body weight, serum creatinine, proteinuria, urinary flow, reduced glutathione (GSH) levels and thiobarbituric acid-reactive substances (TBARS) and mutagenicity in bone marrow cells were assessed to evaluate the safety of passion fruit consumption. Yellow passion fruit pulp (5, 6 or 8 g/kg b.w.) was administered by gavage once a day for 5 consecutive days. HLPC-PDA-MS/MS analysis revealed that yellow passion fruit pulp contains phenolic compounds, ascorbic acid, carotenoids and flavonoids. The highest dose of passion fruit pulp significantly reduced the systolic blood pressure, increased the GSH levels and decreased TBARS. There were no changes in renal function parameters or the frequency of micronuclei in bone marrow cells. In conclusion, the antihypertensive effect of yellow passion fruit pulp, at least in part, might be due to the enhancement of the antioxidant status. The exact mechanisms responsible by this effect need further investigation. PMID- 23436458 TI - Stoichiometric modeling of oxidation of reduced inorganic sulfur compounds (Riscs) in Acidithiobacillus thiooxidans. AB - The prokaryotic oxidation of reduced inorganic sulfur compounds (RISCs) is a topic of utmost importance from a biogeochemical and industrial perspective. Despite sulfur oxidizing bacterial activity is largely known, no quantitative approaches to biological RISCs oxidation have been made, gathering all the complex abiotic and enzymatic stoichiometry involved. Even though in the case of neutrophilic bacteria such as Paracoccus and Beggiatoa species the RISCs oxidation systems are well described, there is a lack of knowledge for acidophilic microorganisms. Here, we present the first experimentally validated stoichiometric model able to assess RISCs oxidation quantitatively in Acidithiobacillus thiooxidans (strain DSM 17318), the archetype of the sulfur oxidizing acidophilic chemolithoautotrophs. This model was built based on literature and genomic analysis, considering a widespread mix of formerly proposed RISCs oxidation models combined and evaluated experimentally. Thiosulfate partial oxidation by the Sox system (SoxABXYZ) was placed as central step of sulfur oxidation model, along with abiotic reactions. This model was coupled with a detailed stoichiometry of biomass production, providing accurate bacterial growth predictions. In silico deletion/inactivation highlights the role of sulfur dioxygenase as the main catalyzer and a moderate function of tetrathionate hydrolase in elemental sulfur catabolism, demonstrating that this model constitutes an advanced instrument for the optimization of At. thiooxidans biomass production with potential use in biohydrometallurgical and environmental applications. PMID- 23436459 TI - Active proteases in nephrotic plasma lead to a podocin-dependent phosphorylation of VASP in podocytes via protease activated receptor-1. AB - Focal segmental glomerulosclerosis (FSGS) is associated with glomerular podocyte injury. Podocytes undergo dramatic changes in their actin structure, with little mechanistic insight to date into the human disease. Post-transplantation recurrence of FSGS is the archetypal form of the disease caused by unknown circulating plasma 'factors'. There is increasing indication that plasma protease activity could be central to this disease. Using clinical plasma exchange material, collected from patients in relapse and remission stages of disease, the effects of FSGS plasma on human conditionally immortalized podocytes (ciPods) were studied. We show that vasodilator stimulated phosphoprotein (VASP) is phosphorylated in response to relapse plasma from ten consecutively tested patients, and not in response to paired remission plasma or non-FSGS controls. The phosphorylation signal is absent in human podocytes carrying a pathological podocin mutation. To test for a plasma ligand, inhibition of proteases in relapse plasma leads to the loss of VASP phosphorylation. By the use of siRNA technology, we show that proteases in the plasma signal predominantly via protease activated receptor-1 (PAR1) to VASP. Mechanistically, FSGS plasma increases podocyte motility, which is dependent on VASP phosphorylation. These data suggest a specific biomarker for disease activity, as well as revealing a novel and highly specific receptor-mediated signalling pathway to the actin cytoskeleton. PMID- 23436460 TI - Factors affecting drug adsorption on beta zeolites. AB - The adsorption behaviour of three commonly used drugs, namely ketoprofen, hydrochlorothiazide and atenolol, from diluted aqueous solutions on beta zeolites with different SiO2/Al2O3 ratio (i.e. 25, 38 and 360) was investigated by changing the ionic strength and the pH, before and after thermal treatment of the adsorbents. The selective adsorption of drugs was confirmed by thermogravimetry and X-ray diffraction. The adsorption capacity of beta zeolites was strongly dependent on both the solution pH and the alumina content of the adsorbent. Such a remarkable difference was interpreted as a function of the interactions between drug molecules and zeolite surface functional groups. Atenolol was readily adsorbed on the less hydrophobic zeolite, under pH conditions in which electrostatic interactions were predominant. On the other hand, ketoprofen adsorption was mainly driven by hydrophobic interactions. For undissociated molecules the adsorption capability increased with the increase of hydrophobicity. PMID- 23436461 TI - [Poor little rich country]. PMID- 23436464 TI - Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK-cell repertoire in the French population. AB - NK-cell functions are regulated by many activating and inhibitory receptors including KIR3DL1. Extensive allelic polymorphism and variability in expression can directly alter NK-cell phenotype and functions. Here we investigated the KIR3DL1(+) NK-cell repertoire, taking into account the allelic KIR3DL1/S1 polymorphism, KIR3DL1 phenotype, and function. All 109 studied individuals possessed at least one KIR3DL1 allele, with weak KIR3DL1*054, or null alleles being frequently present. In KIR3DL1(high/null) individuals, we observed a bimodal distribution of KIR3DL1(+) NK cells identified by a different KIR3DL1 expression level and cell frequency regardless of a similar amount of both KIR3DL1 transcripts, HLA background, or KIR2D expression. However, this bimodal distribution can be explained by a functional selection following a hierarchy of KIR3DL1 receptors. The higher expression of KIR3DL1 observed on cord blood NK cells suggests the expression of the functional KIR3DL1*004 receptors. Thus, the low amplification of KIR3DL1(high) , KIR3DL1*004 NK-cell subsets during development may be due to extensive signaling via these two receptors. Albeit in a nonexclusive manner, individual immunological experience may contribute to shaping the KIR3DL1 NK-cell repertoire. Together, this study provides new insight into the mechanisms regulating the KIR3DL1 NK-cell repertoire. PMID- 23436465 TI - Scanning probe microscopy beyond imaging: a general tool for quantitative analysis. AB - A simple, fast and general approach for quantitative analysis of scanning probe microscopy (SPM) images is reported. As a proof of concept it is used to determine with a high degree of precision the value of observables such as 1) the height, 2) the flowing current and 3) the corresponding surface potential (SP) of flat nanostructures such as gold electrodes, organic semiconductor architectures and graphenic sheets. Despite histogram analysis, or frequency count (Fc), being the most common mathematical tool used to analyse SPM images, the analytical approach is still lacking. By using the mathematical relationship between Fc and the collected data, the proposed method allows quantitative information on observable values close to the noise level to be gained. For instance, the thickness of nanostructures deposited on very rough substrates can be quantified, and this makes it possible to distinguish the contribution of an adsorbed nanostructure from that of the underlying substrate. Being non-numerical, this versatile analytical approach is a useful and general tool for quantitative analysis of the Fc that enables all signals acquired and recorded by an SPM data array to be studied with high precision. PMID- 23436466 TI - Cysteine-capped gold nanoparticles suppress aggregation of proteins exposed to heat stress. AB - Gold nanoparticles show a lot of promise as potential agents for drug delivery and disease diagnosis. Because of this, it is important that the interaction between gold nanoparticles and biomolecules be well characterized to avoid undesirable consequences. In this study, gold nanoparticles were synthesized by the reduction of gold salt by sodium borohydride in the presence of cysteine as the capping agent. The physical features of the nanoparticles were analyzed using Ultraviolet-Visible spectrophotometry and transmission electron microscopy. The interaction between gold nanoparticles and the following proteins: bovine serum albumin, citrate synthase, malate dehydrogenase, and human heat shock protein 70 was investigated by UV-Vis spectrophotometry. The stability of the proteins against heat stress was assessed by monitoring their aggregation at 48 degrees C, either in the presence or absence of gold nanoparticles. The gold nanoparticles were capable of suppressing the heat-induced aggregation of the proteins. Furthermore, apart from possessing independent protein-aggregation suppression function, the AuNPs also augmented the chaperone function of human heat shock protein 70. Findings from this study demonstrate that cyteine-coated gold nanoparticles exhibit chaperone-like activity and have the capability to stabilize proteins to which they may be conjugated. PMID- 23436467 TI - Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency. AB - Ganglioside GM3 synthase deficiency is a rare autosomal recessive metabolic disorder characterized by infantile onset of severe irritability and epilepsy, failure to thrive, developmental stagnation, and cortical blindness. Because of the lack of easily recognizable dysmorphism and specific neurologic manifestations, identification of patients with this condition is extremely challenging. Here we report on previously undescribed pigmentary abnormalities in 20 of 38 patients with GM3 synthase deficiency. All 20 of the patients showed freckle-like hyperpigmented macules, ranging in size from 2 to 5 mm in diameter and usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Seven of these patients also had depigmented macules and patches, especially on the face and extremities. These cutaneous changes were asymptomatic, and were not associated with the severity or particular phenotype of the neurologic disease. They became visible only after the first years of life with an increased incidence with advancing age. These distinct pigmentary features are not identified in 54 normal siblings, and may provide a useful clue in identifying patients with ganglioside metabolic disorders. PMID- 23436468 TI - Determination of ferulic acid by flow injection chemiluminescence analysis based on enhancement of the N-bromobutanimide-eosin-CrCl3 system in alkaline solution. AB - A simple and sensitive flow injection chemiluminescence method has been developed for the determination of ferulic acid (FA) based on the significant enhancement effect of FA on the CL signal of the N-bromobutanimide (NBS)-eosin-CrCl3 system in alkaline solution. Under optimum conditions, the enhanced CL intensity is linearly related to the concentration of FA in its pharmaceutical preparations and human plasma samples. The corresponding linear regression equations were established over the 4.0 * 10(-10)-1.0 * 10(-7) g/mL for FA tablets and 2.0 * 10( 10)-1.0 * 10(-7) g/mL for plasma samples. The limit of detection for FA tablets and limit of quantification for plasma samples were 2.8 * 10(-10) g/mL (3 sigma) and 3.04 * 10(-10) g/mL (10 sigma), respectively. A complete analysis could be performed within 40 s, including washing and sampling, giving a throughput of ~90/h. The proposed method was successfully applied to the determination of FA in pharmaceutical preparations and human plasma samples with satisfactory results. The recoveries of pharmaceutical preparations and human plasma samples at three different concentrations were 97.8-102.6% and 96.7-104.0%, respectively. Furthermore, the possible mechanism of CL reactions was also discussed briefly. PMID- 23436469 TI - Region- and age-specific patterns of histone acetylation related to spatial and cued learning in the water maze. AB - Epigenetic processes, such as histone acetylation, are critical regulators of learning and memory processes. In the present study, we investigated whether training in either a spatial or a cued water maze task undergoes selective changes of histone H3 and H4 acetylation within the hippocampus and the dorsal striatum of C57BL/6 mice. We also attempted to provide new insights into the relationships between deregulation in histone acetylation and age-associated memory deficits. In young mice, spatial training increased acetylation of histones H3 and H4 selectively in the dorsal hippocampal CA1 region and the dentate gyrus (DG) whereas cued training significantly enhanced acetylation of both histones selectively in the dorsal striatum. Our data also revealed age related differences in histone acetylation within the hippocampus and striatum according to task demands. Specifically, age-related spatial memory deficits were associated with opposite changes of H3 (increase) and H4 (decrease) acetylation in CA1 and DG. After cued learning, both histone acetylation levels were reduced in the striatum of aged mice compared with corresponding young-adults but remained well above those of cage-controls. Collectively, our findings suggest an important role for histone acetylation in regulating the relative contributions of the hippocampus and striatum to learning spatial and cued memory tasks. PMID- 23436470 TI - Efficient Nazarov cyclization/Wagner-Meerwein rearrangement terminated by a Cu(II)-promoted oxidation: synthesis of 4-alkylidene cyclopentenones. AB - The discovery and elucidation of a new Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways. PMID- 23436471 TI - Dielectrophoretic isolation and detection of cfc-DNA nanoparticulate biomarkers and virus from blood. AB - Dielectrophoretic (DEP) microarray devices allow important cellular nanoparticulate biomarkers and virus to be rapidly isolated, concentrated, and detected directly from clinical and biological samples. A variety of submicron nanoparticulate entities including cell free circulating (cfc) DNA, mitochondria, and virus can be isolated into DEP high-field areas on microelectrodes, while blood cells and other micron-size entities become isolated into DEP low-field areas between the microelectrodes. The nanoparticulate entities are held in the DEP high-field areas while cells are washed away along with proteins and other small molecules that are not affected by the DEP electric fields. DEP carried out on 20 MUL of whole blood obtained from chronic lymphocytic leukemia patients showed a considerable amount of SYBR Green stained DNA fluorescent material concentrated in the DEP high-field regions. Whole blood obtained from healthy individuals showed little or no fluorescent DNA materials in the DEP high-field regions. Fluorescent T7 bacteriophage virus could be isolated directly from blood samples, and fluorescently stained mitochondria could be isolated from biological buffer samples. Using newer DEP microarray devices, high-molecular-weight DNA could be isolated from serum and detected at levels as low as 8-16 ng/mL. PMID- 23436472 TI - The influence of individual differences in sensitivity to provocations on provoked aggression. AB - Using an adapted form of the Taylor Competitive reaction Time (TCRT) task [Taylor (1967). Journal of Personality, 35, 297-310], this study is the first to examine the influence of individual differences in sensitivity to provocations (SP) [Lawrence (2006). Aggressive Behavior, 32, 3, 241-252] as opposed to sensitivity to frustrations (SF) on provoked aggression (noise blasts delivered to a bogus partner). Participants (N = 144) played a competitive reaction time task against a bogus partner, who delivered increasingly loud noise blasts to participants on trials when the participant lost. The study also manipulated the partner's behavior such that, in initial trials, the partner either delivered moderate blasts to the participant or no blasts at all. While accounting for broad trait aggression, those high in SP delivered louder noise blasts to a bogus partner when provoked but not when unprovoked. These individuals also delivered more maximum blasts to the partner and delivered maximum blasts earlier in the TCRT. The effects of SP became non-significant when the partner was initially non aggressive. Similarly, an initially non-aggressive partner reduced participant aggression under later conditions of moderate provocation from the partner, but this effect became non-significant under subsequent high provocation from the partner. While being related to SP, SF did not influence provoked aggression. PMID- 23436473 TI - What evidence is there for the reimbursement of personalised medicine? PMID- 23436475 TI - Production of polymalic acid and malic acid by Aureobasidium pullulans fermentation and acid hydrolysis. AB - Malic acid is a dicarboxylic acid widely used in the food industry and also a potential C4 platform chemical that can be produced from biomass. However, microbial fermentation for direct malic acid production is limited by low product yield, titer, and productivity due to end-product inhibition. In this work, a novel process for malic acid production from polymalic acid (PMA) fermentation followed by acid hydrolysis was developed. First, a PMA-producing Aureobasidium pullulans strain ZX-10 was screened and isolated. This microbe produced PMA as the major fermentation product at a high-titer equivalent to 87.6 g/L of malic acid and high-productivity of 0.61 g/L h in free-cell fermentation in a stirred tank bioreactor. Fed-batch fermentations with cells immobilized in a fibrous-bed bioreactor (FBB) achieved the highest product titer of 144.2 g/L and productivity of 0.74 g/L h. The fermentation produced PMA was purified by adsorption with IRA 900 anion-exchange resins, achieving a ~100% purity and a high recovery rate of 84%. Pure malic acid was then produced from PMA by hydrolysis with 2 M sulfuric acid at 85 degrees C, which followed the first-order reaction kinetics. This process provides an efficient and economical way for PMA and malic acid production, and is promising for industrial application. PMID- 23436474 TI - Three-dimensional mapping of the creatine kinase enzyme reaction rate in muscles of the lower leg. AB - Phosphorus ((31) P) magnetization transfer (MT) techniques enable the non invasive measurement of metabolic turnover rates of important enzyme-catalyzed reactions, such as the creatine kinase reaction (CK), a major transducing reaction involving adenosine triphosphate and phosphocreatine. Alteration in the kinetics of the CK reaction rate appears to play a central role in many disease states. In this study, we developed and implemented at ultra-high field (7T) a novel three-dimensional (31) P-MT imaging sequence that maps the kinetics of CK in the entire volume of the lower leg at relatively high resolution (0.52 mL voxel size), and within acquisition times that can be tolerated by patients (below 60 min). We tested the sequence on five healthy and two clinically diagnosed type 2 diabetic subjects. Overall, we obtained measurements that are in close agreement with measurements reported previously using spectroscopic methods. Importantly, our spatially resolved method allowed us to measure local CK reaction rate constants and metabolic fluxes in individual muscles in a non invasive manner. Furthermore, it allowed us to detect variations of the CK rates of different muscles, which would not have been possible using unlocalized MRS methods. The results of this work suggest that 3D mapping of the CK reaction rates and metabolic fluxes can be achieved in the skeletal muscle in vivo at relatively high spatial resolution and with acquisition times well tolerated by patients. The ability to measure bioenergetics simultaneously in large areas of muscles will bring new insights into possible heterogeneous patterns of muscle metabolism associated with several diseases and serve as a valuable tool for monitoring the efficacy of interventions. PMID- 23436476 TI - Treatment engagement in eating disorders: who exits before treatment? AB - OBJECTIVE: Traditionally, drop-out has been investigated subsequent to treatment entry; yet some individuals "exit early," attending assessment but failing to commence the treatment offered. Early exit burdens administrative and clinical resources and means that individuals may not receive the care needed for recovery. This study aimed to describe the prevalence and characteristics associated with early exit at a statewide, outpatient eating disorder service. METHOD: From a pool of 972 consecutive referrals of adults and youth (16+ years), two groups were formed; an "early exit" group of individuals who attended assessment but chose to exit the service prior to treatment entry and a "non early exit" group that attended assessment and entered treatment. The groups were compared on sociodemographic, clinical, and administrative features. RESULTS: The prevalence of early exit was 18.7%. The early exit group exhibited less pathology compared with the non-early exit group; specifically, a lower presence of Axis I comorbidity (p = .04) and self-induced vomiting (p = .04). DISCUSSION: The findings, considered in the context of previous research, suggest that there are no measured features to date that are robustly associated with early exit from outpatient eating disorder services. Future research should investigate decision making processes at assessment, to inform patient-centered approaches that optimize transition to treatment. PMID- 23436478 TI - Chronic hypoxia reprograms human immature dendritic cells by inducing a proinflammatory phenotype and TREM-1 expression. AB - DCs are powerful antigen-presenting cells central in the orchestration of innate and acquired immunity. DC development, migration, and activities are intrinsically linked to the microenvironment. DCs migrate through pathologic tissues before reaching their final destination in the lymph nodes. Hypoxia, a condition of low partial oxygen pressure, is a common feature of many pathologic situations, capable of modifying DC phenotype and functional behavior. We studied human monocyte-derived immature DCs generated under chronic hypoxic conditions (H iDCs). We demonstrate by gene expression profiling the upregulation of a cluster of genes coding for antigen-presentation, immunoregulatory, and pattern recognition receptors, suggesting a stimulatory role for hypoxia on iDC immunoregulatory functions. In particular, we show that H-iDCs express triggering receptor expressed on myeloid cells(TREM-1), a member of the Ig superfamily of immunoreceptors and an amplifier of inflammation. This effect is reversible because H-iDC reoxygenation results in TREM-1 down-modulation. TREM-1 engagement promotes upregulation of T-cell costimulatory molecules and homing chemokine receptors, typical of mature DCs, and increases the production of proinflammatory, Th1/Th17-priming cytokines/chemokines, resulting in increased T cell responses. These results suggest that TREM-1 induction by the hypoxic microenvironment represents a mechanism of regulation of Th1-cell trafficking and activation by iDCs differentiated at pathologic sites. PMID- 23436479 TI - Utilizing NMR and EPR spectroscopy to probe the role of copper in prion diseases. AB - Copper is an essential nutrient for the normal development of the brain and nervous system, although the hallmark of several neurological diseases is a change in copper concentrations in the brain and central nervous system. Prion protein (PrP) is a copper-binding, cell-surface glycoprotein that exists in two alternatively folded conformations: a normal isoform (PrP(C)) and a disease associated isoform (PrP(Sc)). Prion diseases are a group of lethal neurodegenerative disorders that develop as a result of conformational conversion of PrP(C) into PrP(Sc). The pathogenic mechanism that triggers this conformational transformation with the subsequent development of prion diseases remains unclear. It has, however, been shown repeatedly that copper plays a significant functional role in the conformational conversion of prion proteins. In this review, we focus on current research that seeks to clarify the conformational changes associated with prion diseases and the role of copper in this mechanism, with emphasis on the latest applications of NMR and EPR spectroscopy to probe the interactions of copper with prion proteins. PMID- 23436480 TI - Vascular complications during transcatheter aortic valve replacement. PMID- 23436481 TI - Preclosing large venous sheaths with perclose can facilitate advanced structural heart interventions. PMID- 23436482 TI - Spreading concern of infection. PMID- 23436483 TI - Initial use of the new GORE((r)) septal occluder in patent foramen ovale closure: implantation and preliminary results. AB - BACKGROUND: A number of devices are available for percutaneous closure of a clinically significant patent foramen ovale (PFO). The new GORE((r)) septal occluder (GSO) is a nonself-centering device consisting of an expanded polytetrafluoroethylene tube supported by a frame of nitinol wire conforming into a double disk. This study reports the first clinical GSO implantation experience. METHODS: GSO implantation in 20 consecutive patients is reported. Inclusion criteria were all patients referred with a significant PFO implicated in paradoxical embolism or transient right to left shunting causing desaturation. Procedures were performed under local anaesthesia and intracardiac echocardiography (ICE) in addition to fluoroscopy. Procedural data, acute and early closure rates were examined. RESULTS: All patients underwent successful day case device implantation. Eleven patients had previous stroke, five had transient ischemic attacks, two had a history suspicious of PFO-related desaturation, and two had a history suspicious of PFO-related peripheral thromboembolism. Acute closure rates on IVC injection bubble testing were 100% at implant and 100% (14/14) at 1 month. Average PFO balloon size was 8.0 +/- 3.6(range 2.0-16.7) mm, mean fluoroscopic implantation time 3.0 +/- 1.7(range 0.7-6.3) min, radiation dose 283 +/- 340 (range 6-1,431) MUGym(2), and total procedural time 34.8 +/- 8.0 (range 22-53) min. 5 * 20 mm(2), 7 * 25 m(2), 8 * 30 mm(2) GSO devices were implanted, aiming for device size at least twice balloon PFO size. Cases included aneurysmal septums with up to 30 mm deviation and tunnels up to 12 mm long. Removal and repositioning of two devices was performed on two occasions after uncertainty about device locking. At 1 month follow-up, two patients had brief self-terminating episodes of suspected atrial fibrillation, all had normal resting ECGs. No thromboembolic/neurological events were reported. CONCLUSIONS: The GSO can be implanted under local anaesthesia and ICE with low procedural and fluoroscopy times with high procedural success as a day case. No residual shunts were seen. This initial experience suggests that it is a safe and effective device for PFO closure. PMID- 23436484 TI - Pitfalls everywhere: 60 years and still poking blindly. PMID- 23436485 TI - Interpreting drug effects on coronary flow reserve after PTCA: clarity or confusion? PMID- 23436486 TI - Coronary stent graft: "a device in need is a device indeed". PMID- 23436487 TI - Taking the high road to a coronary artery fistula. PMID- 23436488 TI - Comparative effectiveness research using electronic health records: impacts of oral antidiabetic drugs on the development of chronic kidney disease. AB - PURPOSE: Little is known about the comparative effects of common oral antidiabetic drugs ([OADs] metformin, sulfonylureas, or thiazolidinediones [THZs]) on chronic kidney disease (CKD) outcomes in patients newly diagnosed with type 2 diabetes (T2DM) and followed in community primary care practices. Electronic health records (EHRs) were used to evaluate the relationships between OAD class use and incident proteinuria and prevention of glomerular filtration rate decline. METHODS: A retrospective cohort study on newly diagnosed T2D cases requiring OADs documented in the EHRs of two primary care networks between 1998 and 2009 was conducted. CKD outcomes were new-onset proteinuria and estimated GFR (eGFR) falling below 60 ml/min/1.73 m(2). OAD exposures defined cohorts. Hazard ratios represent differential CKD outcome risk per year of OAD class use. RESULTS: A total of 798 and 977 patients qualified for proteinuria and eGFR outcome analyses, respectively. With metformin as the reference group, sulfonylurea exposure trended toward association with an increased risk of developing proteinuria ([adjusted hazard ratio; 95% CI] 1.27; 0.93, 1.74); proteinuria risk associated with THZ exposure (1.00; 0.70, 1.42) was similar to metformin. Compared with metformin, sulfonylurea exposure was associated with an increased risk of eGFR reduction to <60 ml/min/1.73 m(2) (1.41; 1.05, 1.91). THZ exposure (1.04; 0.71, 1.50) was not associated with change in the risk of eGFR decline. CONCLUSIONS: In a primary care population, metformin appeared to decrease the risk of CKD development compared with sulfonlyureas; risks of CKD development between metformin and THZs were similar. EHR use in pharmacotherapy comparative effectiveness research creates specific challenges and study limitations. PMID- 23436489 TI - Catalysis with N-heterocyclic carbenes under oxidative conditions. AB - This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed. PMID- 23436490 TI - Competitive binding of fluoroquinolone antibiotics and some other drugs to human serum albumin: a luminescence spectroscopic study. AB - Co-administration of several drugs in multidrug therapy may alter the binding of each to human serum albumin (HSA) and hence their pharmacological activity. Thirty-two frequently prescribed drug combinations, consisting of four fluoroquinolone antibiotics and eight competing drugs, have been studied using fluorescence and circular dichroism spectroscopic techniques. Competitive binding studies on the drug combinations are not available in the literature. In most cases, the presence of competing drug decreased the binding affinity of fluoroquinolone, resulting in an increase in the concentration of free pharmacologically active drug. The competitive binding mechanism involved could be interpreted in terms of the site specificity of the binding and competing drugs. For levofloxacin, the change in the binding affinity was small because in the presence of site II-specific competing drugs, levofloxacin mainly occupied site I. A competitive interference mechanism was operative for sparfloxacin, whereas competitive interference as well as site-to-site displacement of competing drugs was observed in the case of ciprofloxacin hydrochloride. For enrofloxacin, a different behavior was observed for different combinations; site to-site displacement and conformational changes as well as independent binding has been observed for various drug combinations. Circular dichroism spectral studies showed that competitive binding did not cause any major structural changes in the HSA molecule. PMID- 23436491 TI - De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome. AB - The Say-Barber/Biesecker/Young-Simpson (SBBYS) type of the blepharophimosis mental retardation syndrome group (Ohdo-like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. Mutations of the gene encoding the histone acetyltransferase KAT6B have been recently identified in individuals affected by SBBYS syndrome. SBBYS syndrome-causing KAT6B mutations cluster in a ~1,700 basepair region in the 3' part of the large exon 18, while mutations located in the 5' region of the same exon have recently been identified to cause the genitopatellar syndrome (GPS), a clinically distinct although partially overlapping malformation-intellectual disability syndrome. Here, we present two children with clinical features of SBBYS syndrome and de novo truncating KAT6B mutations, including a boy who was diagnosed at the age of 4 months. Our results confirm the implication of KAT6B mutations in typical SBBYS syndrome and emphasize the importance of genotype-phenotype correlations at the KAT6B locus where mutations truncating the KAT6B protein at the amino-acid positions ~1,350 1,920 cause SBBYS syndrome. PMID- 23436492 TI - Bioactive formulations with sugar-derived surfactants: a new approach for photoprotection and controlled release of promethazine. AB - Skin deep: A bioactive formulation for dermal delivery of antihistamines is obtained by using the original properties of catanionic associations towards self assembly in water. The drug, which participates in its own transport, is preserved from photodegradation when solubilised in the bioactive formulation. The drug release through the skin is also delayed. PMID- 23436493 TI - Mammalian cell metabolomics: experimental design and sample preparation. AB - Metabolomics represents the global assessment of metabolites in a biological sample and reports the closest information to the phenotype of the biological system under study. Mammalian cell metabolomics has emerged as a promising tool with potential applications in many biotechnology and research areas. Metabolomics workflow includes experimental design, sampling, sample processing, metabolite analysis, and data processing. Given their influence on metabolite content and biological interpretation of data, a good experimental design and the appropriate choice of a sample processing method are prerequisites for success in any metabolomic study. The use of mammalian cells in the metabolomics field involves harder sample processing methods, including metabolism quenching and metabolite extraction, as compared to the use of body fluids, although such critical issues are frequently overlooked. This review aims to overview the common experimental procedures used in mammalian cell metabolomics based on mass spectrometry, by placing special emphasis on discussing sample preparation approaches, although other aspects, such as cell metabolomics applications, culture systems, cellular models, analytical platforms, and data analysis, are also briefly covered. This review intends to be a helpful tool to assist researchers in addressing decisions when planning a metabolomics study involving the use of mammalian cells. PMID- 23436494 TI - Mifepristone for management of Cushing's syndrome. AB - Cushing's syndrome is a debilitating endocrine disorder caused by elevated circulating glucocorticoid levels. Although uncommon, Cushing's syndrome is associated with significant morbidity necessitating rapid reversal of hypercortisolemia. Primary therapy for most patients with Cushing's syndrome is surgical, but many patients will require additional treatments with radiation or drugs. Although several options for drug therapy exist, few are readily available and all have dose-limiting adverse effects. Mifepristone (RU 486), a first-in class glucocorticoid receptor antagonist, was approved by the United States Food and Drug Administration in 2012 for use in Cushing's syndrome to control hyperglycemia in patients who are not surgical candidates or have not achieved remission from surgery. The drug is approved for oral once-daily administration. In its pivotal trial, 60% of patients responded to mifepristone with significant improvements in glycemic control and 38% had a reduction in diastolic blood pressure. The most common adverse events were nausea, fatigue, headache, endometrial hyperplasia, and hypokalemia. Adrenal insufficiency occurred in fewer than 5% of patients. The recommended starting dosage of mifepristone is 300 mg/day. The dosage may be increased every 2-4 weeks up to a maximum of 1200 mg/day, although it should not exceed 20 mg/kg/day. Significant drug-drug interactions exist due to mifepristone's effects on a number of cytochrome P450 enzymes. Despite its limitations, mifepristone is a welcome addition and an appropriate alternative to the available drug therapy for Cushing's syndrome. PMID- 23436495 TI - Microduplication of 3p26.3 in nonsyndromic intellectual disability indicates an important role of CHL1 for normal cognitive function. AB - Terminal deletions of chromosome 3p26.3 confined to the CHL1 gene have previously been described in children with intellectual disability and epilepsy. Here, we report for the first time, a 3p26.3 duplication including only the CHL1 gene in an intellectually disabled girl with epilepsy. The penetrance of both deletions and duplications in 3p26.3 is reduced because all chromosomal imbalances were inherited from healthy parents. Further studies are needed to specify the pathogenic mechanism of 3p26.3 imbalances and to estimate recurrence risks in genetic counseling. However, the description of both deletions and duplications of chromosome 3p26.3 in nonsyndromic intellectual disability suggests that CHL1 is a dosage-sensitive gene with an important role for normal cognitive development. PMID- 23436496 TI - Nonlinear alignment of chromatograms by means of moving window fast Fourier transfrom cross-correlation. AB - The preprocessing of chromatograms is essential to modern chromatography for further qualitative and quantitative analysis, especially when chromatographic instruments are used for herb products analysis involving large number of samples. To accurately compare and analyze the obtained chromatograms, it is necessary to preprocess, especially align retention time shifts. Here moving window fast Fourier transform (FFT) cross-correlation is introduced to perform nonlinear alignment of high-throughput chromatograms. Since elution characteristics of chromatograms will produce local similarity in retention time shifts, moving window procedure seems to be a better substitute of segmentation steps. The retention time shifts can be calculated and accelerated by FFT cross correlation. The artifacts can be detected and eliminated from the retention time shifts profile since the continuity of moving window procedure. The proposed method is demonstrated in comparison with recursive alignment by FFT on chromatographic datasets from herb products analysis. It is shown that the proposed method can address nonlinear retention time shift problem in chromatograms with the simple moving window procedure, which will not introduce segments size optimization problem. In additional, the parameters are intuitive and easy to adjust, which makes it off-the-shelf toolbox for alignment of chromatograms. PMID- 23436497 TI - Distinguishing among weapons offenders, drug offenders, and weapons and drug offenders based on childhood predictors and adolescent correlates. AB - BACKGROUND: Weapons and drug offences incur a large cost to society and tend to be strongly associated. Improved understanding of their antecedents could inform targeted early intervention and prevention programmes. AIM: This study aimed to examine differences in criminal careers, childhood predictors and adolescent correlates among weapons-only offenders, drugs-only offenders and a versatile group of weapons + drugs offenders. METHOD: We conducted a longitudinal records study of 455 young Canadians charged with drug and/or weapons offences who started their offending in late childhood/early adolescence. RESULTS: Consistent with expectation, differences emerged in their criminal careers as the versatile group had a longer criminal career and desisted from offending at a later age than weapons-only offenders. Against prediction, weapons-only offenders experienced the greatest number of childhood predictors and adolescent correlates. CONCLUSION AND IMPLICATIONS FOR PRACTICE: The three offending groups could be differentiated on offending trajectories and developmental factors.In making links between past events and later behaviour, life-course criminology may inform development of effective early intervention and prevention strategies.As weapons-only offenders experience the greatest level of adversity in childhood and adolescence, they may benefit most (of these three groups) from early intervention and prevention programmes.A reduction in weapon carrying and use might be achieved by early identification of children risk factors (e.g. family adversity) and appropriate intervention. PMID- 23436499 TI - Editorial. PMID- 23436500 TI - Defective N-linked protein glycosylation pathway in congenital myasthenic syndromes. PMID- 23436501 TI - Dystonia: hopes for a better diagnosis and a treatment with long-lasting effect. PMID- 23436502 TI - Visual exploration in Parkinson's disease and Parkinson's disease dementia. AB - Parkinson's disease, typically thought of as a movement disorder, is increasingly recognized as causing cognitive impairment and dementia. Eye movement abnormalities are also described, including impairment of rapid eye movements (saccades) and the fixations interspersed between them. Such movements are under the influence of cortical and subcortical networks commonly targeted by the neurodegeneration seen in Parkinson's disease and, as such, may provide a marker for cognitive decline. This study examined the error rates and visual exploration strategies of subjects with Parkinson's disease, with and without cognitive impairment, whilst performing a battery of visuo-cognitive tasks. Error rates were significantly higher in those Parkinson's disease groups with either mild cognitive impairment (P = 0.001) or dementia (P < 0.001), than in cognitively normal subjects with Parkinson's disease. When compared with cognitively normal subjects with Parkinson's disease, exploration strategy, as measured by a number of eye tracking variables, was least efficient in the dementia group but was also affected in those subjects with Parkinson's disease with mild cognitive impairment. When compared with control subjects and cognitively normal subjects with Parkinson's disease, saccade amplitudes were significantly reduced in the groups with mild cognitive impairment or dementia. Fixation duration was longer in all Parkinson's disease groups compared with healthy control subjects but was longest for cognitively impaired Parkinson's disease groups. The strongest predictor of average fixation duration was disease severity. Analysing only data from the most complex task, with the highest error rates, both cognitive impairment and disease severity contributed to a predictive model for fixation duration [F(2,76) = 12.52, P <= 0.001], but medication dose did not (r = 0.18, n = 78, P = 0.098, not significant). This study highlights the potential use of exploration strategy measures as a marker of cognitive decline in Parkinson's disease and reveals the efficiency by which fixations and saccades are deployed in the build-up to a cognitive response, rather than merely focusing on the outcome itself. The prolongation of fixation duration, present to a small but significant degree even in cognitively normal subjects with Parkinson's disease, suggests a disease-specific impact on the networks directing visual exploration, although the study also highlights the multi-factorial nature of changes in exploration and the significant impact of cognitive decline on efficiency of visual search. PMID- 23436503 TI - The functional neuroimaging correlates of psychogenic versus organic dystonia. AB - The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group * task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family wise small-volume correction). These data show a cortical-subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions. PMID- 23436504 TI - The stress model of chronic pain: evidence from basal cortisol and hippocampal structure and function in humans. AB - Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations administered in 16 patients with chronic back pain and 18 healthy control subjects. Results showed that patients with chronic back pain have higher levels of cortisol than control subjects. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus, a region involved in anticipatory anxiety and associative learning. Importantly, path modelling-a statistical approach used to examine the empirical validity of propositions grounded on previous literature-revealed that the cortisol levels and phasic pain responses in the parahippocampal gyrus mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the sustained endocrine stress response observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states. PMID- 23436505 TI - Motor cortex and gait in mild cognitive impairment: a magnetic resonance spectroscopy and volumetric imaging study. AB - Gait disorders are common in the course of dementia, even at the stage of mild cognitive impairment, owing to probable changes in higher levels of motor control. Since motor control message is ultimately supported in the brain by the primary motor cortex and since cortical lesions are frequent in the dementia process, we hypothesized that impairments of the primary motor cortex may explain the early gait disorders observed in mild cognitive impairment. Our purpose was to determine whether the neurochemistry of the primary motor cortex measured with proton magnetic resonance spectroscopy, and its volume, were associated with gait performance while single and dual-tasking in mild cognitive impairment. Twenty community dwellers with mild cognitive impairment, aged 76 years (11) [median (interquartile range)] (30% female) from the 'Gait and Brain Study' were included in this analysis. Gait velocity and stride time variability were measured while single (i.e. walking alone) and dual tasking (i.e. walking while counting backwards by seven) using an electronic walkway (GAITRite System). Ratios of N acetyl aspartate to creatine and choline to creatine and cortical volume were calculated in the primary motor cortex. Participants were categorized according to median N-acetyl aspartate to creatine and choline to creatine ratios. Age, gender, body mass index, cognition, education level and subcortical vascular burden were used as potential confounders. Participants with low N-acetyl aspartate to creatine (n = 10) had higher (worse) stride time variability while dual tasking than those with high N-acetyl aspartate to creatine (P = 0.007). Those with high choline to creatine had slower (worse) gait velocity while single (P = 0.015) and dual tasking (P = 0.002). Low N-acetyl aspartate to creatine was associated with increased stride time variability while dual tasking (adjusted beta = 5.51, P = 0.031). High choline to creatine was associated with slower gait velocity while single (adjusted beta = -26.56, P = 0.009) and dual tasking (adjusted beta = -41.92, P = 0.022). Cortical volume correlated with faster gait velocity while single (P = 0.029) and dual tasking (P = 0.037), and with decreased stride time variability while single tasking (P = 0.034). Finally, the probability of exhibiting abnormal metabolite ratios in the primary motor cortex was 63% higher among participants with major gait disturbances in dual task. Those with compromised gait velocity in dual task had a 2.05-fold greater risk of having a smaller cortical volume. In conclusion, the neurochemistry and volume of the primary motor cortex were associated with gait performance while single and dual tasking. Stride time variability was mainly sensitive to neuronal function (N-acetyl aspartate to creatine), whereas gait velocity was more affected by inflammatory damage (choline to creatine) and volumetric changes. These findings may contribute to a better understanding of the higher risks of mobility decline and falls in subjects with mild cognitive impairment. PMID- 23436506 TI - Oxidative stress regulates the ubiquitin-proteasome system and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy. AB - Oxidative damage is a pivotal aetiopathogenic factor in X-linked adrenoleukodystrophy. This is a neurometabolic disease characterized by the accumulation of very-long-chain fatty acids owing to the loss of function of the peroxisomal transporter Abcd1. Here, we used the X-linked adrenoleukodystrophy mouse model and patient's fibroblasts to detect malfunctioning of the ubiquitin proteasome system resulting from the accumulation of oxidatively modified proteins, some involved in bioenergetic metabolism. Furthermore, the immunoproteasome machinery appears upregulated in response to oxidative stress, in the absence of overt inflammation. i-Proteasomes are recruited to mitochondria when fibroblasts are exposed to an excess of very-long-chain fatty acids in response to oxidative stress. Antioxidant treatment regulates proteasome expression, prevents i-proteasome induction and translocation of i-proteasomes to mitochondria. Our findings support a key role of i-proteasomes in quality control in mitochondria during oxidative damage in X-linked adrenoleukodystrophy, and perhaps in other neurodegenerative conditions with similar pathogeneses. PMID- 23436508 TI - Influence of raised plastic floors compared with pine shaving litter on environment and Pekin duck condition. AB - Commercial poultry production management practices have been under increased public scrutiny driven by concerns for food safety and animal welfare. Within the United States, wood shavings and raised plastic floors are common flooring systems used in duck production. It is intuitive that each flooring type would present different management challenges influencing physical characteristics of growing ducks. This study evaluated the relationship between flooring type and duck condition during the winter. Random samples of 20 ducks from 5 predetermined areas (n = 100) were examined in commercial duck houses (n = 9, litter; n = 11, raised plastic slats). Ducks were assessed at 7, 21, and 32 d of age for eye, nostril, and feather cleanliness, feather and foot pad quality, and gait. The data were analyzed to determine the proportion of ducks with a given score. In both housing types, the proportion of 0 scores for foot pad quality improved during the production cycle (P < 0.0001). Feather hygiene declined with age in ducks reared on litter flooring, whereas ducks reared on slatted flooring had cleaner feathers at d 32 (P < 0.011). With the exception of foot pad scores, the majority of ducks had no detectable problems for any single trait. The only main effect due to flooring pertained to feather quality with the proportion of ducks having a 0 or 1 score greater in litter flooring systems than slats (P < 0.05). Overall, the condition of ducks reared, regardless of flooring system, was considered to be good. PMID- 23436509 TI - Effects of dietary dilution source and dilution level on feather damage, performance, behavior, and litter condition in pullets. AB - An experiment was conducted to investigate the effects of dietary dilution sources and levels on feather damage, performance, feeding behavior, and litter condition in rearing pullets. It was hypothesized that dietary dilution increases feeding-related behavior and improves feather condition, particularly if insoluble nonstarch polysaccharides are used as the dilution source. In total, 864 Lohmann Brown 1-d-old non-beak-trimmed pullets were used until 18 wk of age. Four dietary treatments, a control diet without any dilution (R_0%), 7.5% diluted diet with sunflower seed extract/oat hulls (R_7.5%), 15% diluted diet with sunflower seed extract (R_15%_S), and 15% diluted diet with oat hulls (R_15%_O), with 6 replicates (1 replicate is a pen with 36 pullets) per treatment were used. On 4-wk intervals, behavioral parameters, including eating time, feather pecking, feather condition, and general behavior were evaluated. Pullets fed the control diet showed increased feather, comb, and wire pecking compared with pullets fed diluted diets. The level of feather damage decreased with increasing dietary dilution level. Pullets receiving R_15%_S and R_15%_O showed more feeding-related behavior than the pullets on R_7.5% and R_0%. Oat hulls were more effective in preventing feather damage than sunflower seed extract. Pullets did not fully compensate their feed intake if fed a dietary dilution, resulting in a proportionally reduced available ME intake. The R_15%_O pullets had 2.9% lower average BW gain compared with those fed R_0%. Average eating duration increased by 12.8, 33.2, and 42.1% in R_7.5%, R_15%_S, and R_15%_O fed pullets, respectively, compared with R_0%, whereas eating rate [feed intake (g)/pullet per eating min] was decreased in R_15%_S and R_15%_O pullets. Relative weights of empty gizzards were 3.95, 10.30, and 62.72% greater in R_7.5%, R_15%_S, and R_15%_O pullets compared with pullets fed R_0%. It was concluded that dietary dilution affected time budgets of the pullets, as shown by more feeding-related behavior, resulting in less feather pecking behavior. Based on our results, application of this feeding strategy could improve production and welfare in pullets. PMID- 23436510 TI - Response of restraint stress-selected lines of Japanese quail to heat stress and Escherichia coli challenge. AB - Japanese quail selected for divergent corticosterone response to restraint stress were evaluated for their susceptibility to heat stress and challenge with Escherichia coli. These quail lines are designated as high stress (HS), low stress (LS), and the random-bred control (CS) lines. Heat stress (35 degrees C, 8 h/d) began at 24 d until the end of the study at 39 d. Birds were challenged with an aerosol spray containing 2 * 10(9) cfu of E. coli at 25 and 32 d. At 38 d, the surviving birds were necropsied and the intestinal tract was screened for both Salmonella and Campylobacter. Body weights of the CS birds were higher than both HS and LS at 17, 25, and 32 d. At 32 d, there was no difference in mortality between males and females and the CS line had higher mortality compared with the LS line with the HS line being intermediate. At 38 d, females of the CS line that were both heat stressed and challenged had a mortality incidence of 25%, which was significantly higher than male birds of the same line and treatment (5.3%). There was an increased incidence in Salmonella enterica serotype Agona isolation after heat stress, with the LS birds having less isolation than the HS birds. Mean corticosterone levels of male birds were not significantly affected by line, heat stress, or E. coli challenge; however, the LS line subjected to heat stress had one-third the level of the HS line, a difference identical to that seen in the original selection for response to restraint stress. PMID- 23436511 TI - Dehydration indicators for broiler chickens at slaughter. AB - Freedom of (prolonged) thirst is considered to be of paramount importance for animal welfare. This emotion normally results from dehydration, which can be measured using physiological indicators. Because no reliable physiological indicator for thirst was available for broilers, we aimed to identify such a measure in this study. This indicator would ideally be integrated into quality control systems in commercial slaughter plants. In the first experiment, water deprivation was manipulated systematically by withdrawing water for different durations (total water withdrawal for 0 (control), 24, 36, or 48 h, or a 10-d period with restricted access to water for 2 times 10 min per day). A significant decrease in drained blood content and BW occurred from 36 h of total water deprivation onward (both P = 0.03), whereas long-term restricted access tended to decrease drained blood content (P = 0.05). No effect of water deprivation or restriction on skin turgor was found. In the second experiment, water was withdrawn for 0 (control), 6, 12, 24, or 48 h. Plasma chloride concentration was increased after 6 h of water withdrawal, but did not rise further with longer withdrawal. If assessed at slaughter, chloride will thus mainly reflect the catching-to-slaughter interval. In contrast, plasma creatinine and hematocrit levels showed a numerical decrease after 6 h of water withdrawal, but rose again after prolonged withdrawal. Plasma creatinine values were significantly higher in 24-h-deprived birds than in 6-h-deprived birds (P < 0.01), allowing for discernment between water withdrawal during catching and transport from dehydration that had occurred on the farm. Blood sodium concentrations and plasma osmolality showed a steady increment between 0 and 24 h of water deprivation (P < 0.001 and P < 0.001 for both), and may thus be used to assess the combined effects of water deprivation on farm and during the catching-to-slaughter interval. These findings may form the basis of an on-farm or at-slaughter test that could be included in integrated animal welfare assessment schemes. PMID- 23436512 TI - Embryonic development and the physiological factors that coordinate hatching in domestic chickens. AB - Embryonic growth and development is influenced by both endogenous and exogenous factors. The purpose of this review is to discuss the critical stages of chick embryonic development in relation to functional maturation of numerous organ systems, the acquisition of thermoregulation, and the hatching process. In addition, the mechanism of hatching, including sound synchronization and hormonal and environmental stimulation, will be discussed. Finally, the importance of effective hatching synchronization mechanisms will also be highlighted. PMID- 23436513 TI - Outcome of an artificial coccidial infection in poults under the influence of floor heating. AB - Coccidiosis is one of the most prevalent diseases in poultry. The objective of the current study was to determine the effects of floor heating when poults were artificially infected with Eimeria regarding the outcome of the infection and secondary effects on litter quality and health of the foot pad. Two trials were performed. In each trial, 4 groups of 2-wk-old turkeys were reared for a 4-wk period. All birds were fed ad libitum identical pelleted diets without any anticoccidial additive. The first 2 groups were housed on dry wood shavings, with and without floor heating; the other 2 groups were housed on wet wood shavings (35% moisture, achieved by adding water as required), with and without floor heating. Two birds only (primary seeder birds; the other 18 birds were nominated as secondary infected birds) in each of the 4 groups were experimentally infected orally with Eimeria adenoeides (~50,000 oocysts/bird). The number of oocysts eliminated via excreta was determined repeatedly. On d 42, each bird not only was scored macroscopically for coccidial lesions in the cecum but also oocyst counts were determined in the cecal contents. Finally, the foot pads were assessed weekly for external scoring and on d 42 of life for histopathological scoring. Although the counts of oocysts in seeder birds were almost identical (d 6 postinoculation), oocyst counts in excreta of secondary birds were markedly reduced in both trials when the poults were not exposed to wet litter. Moreover, in both trials using floor heating with exposure to wet litter resulted in a higher oocyst count in the excreta of secondary infected birds (3.72/3.92 in trials 1 and 2) on d 24 postinoculation compared with the other groups. Using floor heating resulted in significantly decreased foot pad dermatitis scores compared with groups housed without floor heating. In conclusion, the differences in oocyst counts indicate that the process of sporulation is affected by both the moisture and the temperature of the litter. PMID- 23436514 TI - Quicklime treatment and stirring of different poultry litter substrates for reducing pathogenic bacteria counts. AB - Testing different management practices can help to identify conditions that decrease or even eliminate pathogenic bacteria in poultry litter. A trial was conducted to evaluate the effects of daily manual stirring (rotation of the litter with a pitchfork) for the first 14 d of a bird's life (WDR), in 3 types of poultry litter substrates and quicklime treatment (CaO) during layout time between flocks on pathogenic bacteria occurrence (cfu). A total of 216 male Cobb broilers were randomly allotted to 18 pens with new litter (experimental unit). A split-plot design, with 6 treatments allotted to the main plots, was used: 1) wood shavings (WS) + WDR, 2) WS without stirring up to 14 d (WODR), 3) rice hulls (RIH) + WDR, 4) RIH + WODR, 5) mixture of 50% RIH and WS + WDR, and 6) mixture of 50% RIH and WS + WODR. Two treatments were allotted to the subplots: 0 and 300 g of CaO*m(-2) litter. After depopulation, litter samples were collected, and CaO was incorporated into the litter in the designated half of each pen. The cfu from litter samples after 7 d of the quicklime treatment were counted on Chapman agar, brain heart infusion media, and MacConkey agar. The data were analyzed using ANOVA, and the means were compared by least squares means (P < 0.05). Neither the type of substrate nor the act of stirring affected the cfu. The incorporation of 300 g of CaO*m(-2) litter efficiently reduced the cfu observed on brain heart infusion, Chapman agar, and MacConkey agar media by 57.2, 66.9, and 92.1%, respectively, compared with control (6.4, 17.9, and 46.1%; P < 0.001). In conclusion, the incorporation of 300 g/m(-2) of quicklime in poultry litter reduces the cfu, regardless of the substrate and stirring performed. PMID- 23436516 TI - The effects of yeast feed supplementation on turkey performance and pathogen colonization in a transport stress/Escherichia coli challenge. AB - A commercial yeast culture feed supplement (YC; Celmanax SCP, Vi-COR, Mason City, IA) was provided to turkeys throughout a 16-wk grow-out to determine if it would prevent the effects of stress on production and pathogen colonization. The YC was provided either continuously at 100 g/t (YC-CS) or intermittently during times of stress at 200 g/t (YC-IS). Birds were stressed with an environmental challenge of Escherichia coli and by transporting them in a vehicle for 3 h after which they were penned in new social groups, without feed or water, for an additional 9 h. Turkeys were transported and challenged at 6, 12, and 16 wk of age to model the movement of birds within a 3-stage housing system. The YC-IS was provided only for the first week after hatch and for a 1-wk period encompassing each challenge. At wk 7 and 9, a decrease in BW of challenged birds was prevented by YC-IS but not YC-CS. There were no significant differences in BW due to either challenge or YC during wk 11 and 13. At wk 16, the challenge decreased BW, but there was no improvement in either of the YC treatments. Overall feed conversion ratio (FCR) was increased by transport/E. coli (P < 0.0001). The YC-CS improved FCR of challenged birds by 21 points, whereas YC-IS improved FCR by 36 points and this effect was significant (P = 0.013). The YC-CS tended to decrease both Salmonella and Campylobacter isolation from the ceca of stressed birds (P > 0.05). The YC-IS also tended to decrease Salmonella isolation (P > 0.05) with no effect on Campylobacter isolation. These data suggest that the practice of transporting turkeys decreases performance and that YC-IS may be more effective than YC-CS for alleviating the effects of this stressor on feed efficiency. PMID- 23436515 TI - Differential expression of Toll-like receptor genes in lymphoid tissues between Marek's disease virus-infected and noninfected chickens. AB - Toll-like receptors (TLR) are trans-membrane sensors recognizing invading microbes. Toll-like receptors play a central role in initiating immune responses against several pathogens. In this study, we investigated the response of TLR and downstream genes to Marek's disease virus (MDV) infection. Forty 1-d-old chicks were randomly divided into 2 groups, with 20 chicks infected with MDV and 20 chicks mock-infected. Four chickens were euthanized respectively from infected and age-matched noninfected groups at 4, 7, 14, 21, and 28 d postinfection (dpi). Bursas, spleens, and thymuses were removed. The differential expression of TLR genes, including TLR3, TLR5, TLR7, TLR15, and TLR21, and downstream genes of TLR7, including MyD88, TRAF3, TRAF6, IFNA, IFNB, and IL6, in lymphoid tissues of MDV-infected and noninfected chickens was determined by real-time PCR. The results showed that the change of TLR genes was different in 3 lymphoid tissues. Expression of TLR7 and MyD88 was upregulated at 14 dpi and downregulated at 28 dpi in MDV-infected compared with noninfected spleens. The TRAF6 and IFNB were upregulated, and TRAF3, IFNA, and IL6 genes showed increasing trends in MDV infected compared with noninfected spleens at 14 dpi. The expression of TLR3 and TLR15 genes was downregulated in MDV-infected compared with noninfected spleens at 28 dpi. The results indicated that TLR7 and its downstream genes were a response to MDV infection at 14 dpi. However, the function of TLR was impaired when the infection entered the tumor transformation phase. In bursas, TLR3 and TLR15 genes were upregulated at 7 and 4 dpi, respectively. It indicated that TLR3 and TLR15 might be involved in response to MDV infection in bursa at early phases. However, no differential expression of TLR genes was observed between MDV infected and noninfected thymuses, which indicated that the thymus had little response to MDV infection mediated by TLR. PMID- 23436517 TI - Effects of probiotic-supplemented diets on growth performance and intestinal immune characteristics of broiler chickens. AB - This study was conducted to investigate the effects of a probiotic product incorporating Lactobacillus fermentum and Saccharomyces cerevisiae on the growth performance and intestinal immune status in broiler chickens. A total of six hundred ninety-six 1-d-old male Cobb broilers were randomly allotted by BW in 1 of 4 treatments for 6-wk trial. The dietary treatments included the basal diet (NC), and the basal diets supplemented with an antibiotic (100 mg of chlortetracycline/kg of diet; PC), 0.1%, or 0.2% probiotic product (containing 1 * 10(7) cfu/g of Lactobacillus fermentum JS and 2 * 10(6) cfu/g of Saccharomyces cerevisiae). Each treatment had 6 replicates with 29 broilers each. The ADG and feed efficiency were improved (P < 0.05) in broilers fed the probiotic diet compared with NC, and were similar to the PC group during 1 to 21 d. However, there were no significant differences in growth performance of broilers during 22 to 42 d among different dietary treatments. Chicks fed probiotics had higher proportions of CD3+, CD4+, and CD8+ T-lymphocytes, whereas the antibiotic diet decreased the proportion of CD8+ T-lymphocytes in the foregut of broilers at 21 and 42 d compared with the NC group. No significant difference was observed in the mRNA expression level of chicken B-cell marker chB6 (Bu-1) in the foregut of chickens among different treatments. Probiotic-supplemented diets increased (P < 0.05) the mRNA expression levels of Toll-like receptor (TLR) 2 and TLR 4 at 21 d, and only the TLR2 mRNA level at 42 d in the foregut of chickens, but did not change (P > 0.05) TLR7 mRNA expression compared with NC or PC. There was no significant difference in the above TLR mRNA levels in the intestine of broilers between PC and NC. These results indicated that the probiotic product incorporating Lactobacillus fermentum and Saccharomyces cerevisiae could stimulate intestinal T-cell immune system without decreasing growth performance in broilers during 1 to 21 d. PMID- 23436518 TI - Bacterial census of poultry intestinal microbiome. AB - The objective of this study was to generate a phylogenetic diversity census of bacteria identified in the intestinal tract of chickens and turkeys using a naive analysis of all the curated 16S rRNA gene sequences archived in public databases. High-quality sequences of chicken and turkey gastrointestinal origin (3,184 and 1,345, respectively) were collected from the GenBank, Ribosomal Database Project, and Silva comprehensive ribosomal RNA database. Through phylogenetic and statistical analysis, 915 and 464 species-equivalent operational taxonomic units (defined at 0.03 phylogenetic distance) were found in the chicken and the turkey sequence collections, respectively. Of the 13 bacterial phyla identified in both bird species, Firmicutes, Bacteroidetes, and Proteobacteria were the largest phyla, accounting for >90% of all the sequences. The chicken sequences represent 117 established bacterial genera, and the turkey sequences represent 69 genera. The most predominant genera found in both the chicken and the turkey sequence data sets were Clostridium, Ruminococcus, Lactobacillus, and Bacteroides, but with different distribution between the 2 bird species. The estimated coverage of bacterial diversity of chicken and turkey reached 89 and 68% at species equivalent and 93 and 73% at genus-equivalent levels, respectively. Less than 7,000 bacterial sequences from each bird species from various locations would be needed to reach 99% coverage for either bird species. Based on annotation of the sequence records, cecum was the most sampled gut segment. Chickens and turkeys were shown to have distinct intestinal microbiomes, sharing only 16% similarity at the species-equivalent level. Besides identifying gaps in knowledge on bacterial diversity in poultry gastrointestinal tract, the bacterial census generated in this study may serve as a framework for future studies and development of analytic tools. PMID- 23436519 TI - Effects of clinoptilolite and modified clinoptilolite on the growth performance, intestinal microflora, and gut parameters of broilers. AB - The purpose of this study was to evaluate the effect of natural clinoptilolite (NCLI) and modified clinoptilolite (MCLI) on broiler performance, gut morphology, and its relation to gut circumstances. A total of two hundred forty 1-d-old male chicks were randomly assigned to 3 treatments, each of which comprised 8 pens of 10 chicks per pen. Birds in the control group were fed the basal diet, whereas those in the experimental groups were fed diets supplemented with NCLI at 2% (NCLI group) or MCLI at 2% (MCLI group) for 42 d. The results showed that compared with the control, supplementation with NCLI or MCLI had no significant (P > 0.05) effects on productive parameters from d 1 to 42. Supplementation with MCLI and NCLI was associated with greater (P < 0.05) villus height in the jejunal and ileal mucosa compared with those areas in the controls from d 1 to 42. However, supplementation with NCLI and MCLI had no significant (P > 0.05) influence on the crypt depth in the jejunal and ileal mucosa compared with those in the controls. Total viable counts of Escherichia coli were significantly (P < 0.05) decreased by MCLI and NCLI from d 1 to 21. The NCLI and MCLI significantly increased the total viable counts of Lactobacillus acidophilus from d 22 to 42. Small intestine and cecal pH values in the MCLI group were found to be lower (P < 0.05) than those in other groups. Total volatile fatty acid concentrations were significantly (P < 0.05) decreased in both experimental groups from d 22 to 42. This study showed that NCLI or MCLI, as feed additives for broilers, had a positive effect on gut parameters by acting on microbial populations of the digestive tract. PMID- 23436520 TI - Influence of feed form and source of soybean meal on growth performance, nutrient retention, and digestive organ size of broilers. 2. Battery study. AB - Two experiments were conducted to determine the apparent ileal digestibility (AID) of the amino acids (AA) of 4 commercial soybean meals (SBM) from the United States (USA-1, 48.1% CP and USA-2, 46.2% CP), Brazil (BRA, 47.6% CP), and Argentina (ARG, 46.3% CP) and the effects of the inclusion of these SBM in diets in mash, crumble, or pellet form on growth performance, total tract apparent retention of nutrients, and digestive organ size in broilers reared in cages from 1 to 25 d of age. In experiment 1, the AID of Lys was higher (P < 0.05) for the USA-2 than for the BRA SBM, with the SBM from USA-1 and ARG being intermediate. In experiment 2, 12 diets were arranged as a 3 * 4 factorial with 3 feed forms (mash, crumbles, and pellets) and the 4 sources of SBM used in experiment 1. The feeds were isonutritive and the AID of the AA of the SBM obtained in experiment 1 was used for diet formulation. Broilers fed mash had lower (P < 0.001) ADFI and ADG and poorer (P < 0.001) feed-to-gain ratio than broilers fed crumbles or pellets but source of SBM did not affect growth performance. Nitrogen retention was higher (P < 0.01) in birds fed mash than in birds fed crumbles or pellets at all ages. The total tract apparent retention of nutrients was lower (P < 0.05) for the BRA and ARG SBM diets than for the USA-1 and USA-2 SBM diets. Gizzard empty relative weight (% BW) was higher and gizzard pH lower for broilers fed mash than for broilers fed crumbles or pellets (P < 0.001). The results indicate that crumbling or pelleting of the diets improved growth performance of broilers from 1 to 25 d of age. Diets formulated with analyzed rather than calculated AID of AA of the SBM sources resulted in similar broiler performance. PMID- 23436521 TI - Evaluation of carryover effects of dietary lysine intake by Cobb 500 broiler breeder hens. AB - Two experiments were conducted to examine the progeny performance of broiler breeder (BB) hens fed diets differing in digestible lysine (dLys). A total of 240 Cobb 500 BB pullets and 40 cockerels, 20 wk of age, were used for each of 2 experiments. In experiment 1, treatment diets were fed from 35 to 45 wk of age. Treatment 1 and 2 diets were formulated with common feed ingredients and BB had dLys daily intakes of 1,200 (IDL-1,200) and 1,010 mg/hen per d (ID-1,010), respectively. Treatments 3 and 4 were composed of semipurified diets formulated to dLys intakes of 1,010 (SPL-1,010) and 600 mg/hen per d (SP-600), respectively. In experiment 1, chick weight at hatch was lower (P < 0.05) for those that came from the SP-600 and SPL-1,010-fed hens, but 42 and 56 d BW was similar for all treatments. Improvements (P < 0.10) in feed conversion ratio were seen at 42 and 56 d for chicks from ID-1,010-fed hens compared with IDL-1,200 hens. For experiment 2, diets were fed to BB hens from 24 to 42 wk of age. Treatment 1 was composed of corn-soybean meal and formulated to a dLys intake of 1,000 mg/hen per d (CS-1,000). Treatments 2, 3, and 4 had inclusion of 25% distillers dried grains with solubles (DDGS) with dLys intake levels of 1,000 (DDGS-1,000), 800 (DDGS 800), and 600 (DDGS-600) mg/hen per d, respectively. Progeny performance was evaluated from eggs collected at wk 26, 31, and 36. Chick hatch weight was similar for all 3 hatches. Chicks from 26-wk-old BB hens and fed DDGS-600 diets resulted in lower (P < 0.05) BW, carcass weight, and breast weight, and higher (P < 0.05) back half (drumsticks and thighs) yield, at 42 d of age. Growout studies performed on eggs laid during wk 31 and 36 revealed no effect on growth or carcass parameters. In conclusion, the results from experiments 1 and 2 may not be comparable, and therefore, the impact on progeny performance needs to be further evaluated. PMID- 23436522 TI - Extra-phosphoric effects of superdoses of a novel microbial phytase. AB - An experiment was conducted to evaluate the influence of a novel microbial phytase on broiler performance from d 0 to 42 and tibia ash at d 21. Male Cobb 500 broilers (n = 2,016) were fed 1 of 7 experimental diets: positive control (PC) formulated to meet or exceed nutrient recommendations; PC plus dicalcium phosphate (PC+DCP) formulated to provide Ca and P at 0.10% above the PC; PC plus 500 U/kg of microbial phytase (PC+500); negative control (NC) with Ca and P reduced from the PC by 0.16 and 0.15%, respectively; and NC plus 500 (NC+500), 1,000 (NC+1,000), or 1,500 (NC+1,500) U/kg of microbial phytase. Diets were fed in 3 phases from d 0 to 21, d 22 to 42, and d 43 to 49 to 32 birds/pen and 9 replicate pens/diet. From d 0 to 21, broilers fed the NC diet had decreased (P <= 0.05) BW gain and tibia ash compared with broilers fed all other diets, except tibia ash in birds fed PC+500. Phytase supplementation at 500, 1,000, or 1,500 U/kg to the NC improved (P <= 0.05) BW gain and tibia ash comparable with the PC. Feed conversion ratio (FCR) was improved (P <= 0.05) in broilers fed NC+1,500 compared with broilers fed all other diets. From d 0 to 49, growth performance was not influenced (P > 0.05) by diet. However, FCR was improved (P <= 0.05) in broilers fed 1,500 U/kg of microbial phytase compared with broilers fed the PC, PC+DCP, and NC. There were no differences in performance or tibia ash between broilers fed the PC or PC+DCP, which would indicate the PC diet was sufficient in Ca and P. Therefore, the improvements in FCR in the NC+1500 may be associated with mitigation of the antinutrient effects of phytate rather than improved P utilization. PMID- 23436523 TI - Combined dietary effects of supplemental threonine and purified fiber on growth performance and intestinal health of young chicks. AB - Characterization of intestinal health in poultry has become imperative as specialized ingredients become more common in poultry diets. We tested whether purified fiber affects dietary Thr requirements and intestinal morphology of young chicks. In experiment 1, three diets containing 7% added silica sand (control), cellulose, or high-methoxy pectin were used. Six replicate pens of 6 chicks received dietary treatments through d 14 posthatch, at which time growth performance and nutrient digestibility were determined. In experiment 2, the effect of purified fiber on dietary Thr requirements was determined using a Thr deficient basal diet (3.2 g of Thr/kg of diet) and 7 graded levels of supplemental Thr (0 to 9.6 g/kg of diet). Six replicate pens of 5 chicks were tested from d 8 to 21 posthatch, and ileal tissue was collected at the conclusion of the study for histological evaluation. In experiment 1, pectin reduced (P < 0.05) weight gain, feed efficiency, DM digestibility, and AME(n) compared with the control diet. In experiment 2, supplemental Thr requirements were estimated by fitting growth performance data to a 1-slope, broken-line (i.e., piece-wise) regression model. For the control and cellulose- and pectin-containing diets, supplemental Thr requirements were estimated at 3.64, 2.60, and 2.38 g of Thr/kg of diet, and at 778, 737, and 576 mg of supplemental Thr intake over the 21-d study, respectively, based on BW gain. For histological measures, crypts were deepest (P < 0.03) in the cellulose treatment; total goblet cell count and density were highest (P < 0.03) in the pectin-fed birds, and mixed goblet cell counts were highest (P < 0.03) in the control treatment. The serosa was thickest in the cellulose treatment with adequate supplemental Thr, and acidic and neutral goblet cell counts were highest in the control treatment with adequate Thr supplementation (fiber * Thr, P < 0.05). These findings suggest both dietary Thr concentration and fiber source affect growth performance, intestinal morphology, and mucin secretion in young chicks, which may directly affect poultry feeding strategies. PMID- 23436524 TI - Modulation of the intestinal environment, innate immune response, and barrier function by dietary threonine and purified fiber during a coccidiosis challenge in broiler chicks. AB - Coccidiosis is a major contributor to economic losses in the poultry industry due to its detrimental effects on growth performance and nutrient utilization. We hypothesized that the combined effects of supplemental dietary Thr and purified fiber may modulate the intestinal environment and positively affect intestinal immune responses and barrier function in broiler chicks infected with Eimeria maxima. A Thr-deficient basal diet (3.1 g of Thr/kg of diet) was supplemented with 70 g/kg of silica sand (control) or high-methoxy pectin and 1 of 2 concentrations of Thr (1.8 or 5.3 g/kg of diet; 4 diets total), and fed to chicks from hatch to d 16 posthatch. On d 10 posthatch, chicks received 0.5 mL of distilled water or an acute dose of Eimeria maxima (1.5 * 10(3) sporulated oocytes) with 6 replicate pens of 6 chicks per each of 8 treatment combinations (4 diets and 2 inoculation states). Body weight gain, feed intake, and G:F increased (P < 0.01) with addition of 5.3 g of Thr/kg of diet. Eimeria maxima schizonts were present only in intestinal tissue sampled from infected birds (P < 0.01). Weights of cecal digesta were highest (P < 0.01) in pectin-fed birds, and ceca with the heaviest weights also had the highest concentrations of total short chain fatty acids. Expression of interleukin-12 in ileal mucosa was highest (P < 0.01) in infected birds receiving the control diet with 5.3 g of supplemental Thr/kg. In cecal tonsils, interferon-gamma expression was highest in infected birds receiving the control diet (fiber * infection, P < 0.05); interferon-gamma expression was lowest in infected birds fed the high Thr diet (Thr * infection, P < 0.05). There were no differences due to infection or Thr supplementation for cytokine expression in birds fed pectin-containing treatments. Overall, we conclude that although pectin has some protective function against coccidiosis, Thr supplementation had the greatest effect on intestinal immune response and maintenance of near normal growth in young broiler chicks infected with E. maxima. PMID- 23436525 TI - Trimethylamine deposition in the egg yolk from laying hens with different FMO3 genotypes. AB - The A/T polymorphism at position nt 1,034 of the chicken FMO3 cDNA sequence is associated with elevated levels of trimethylamine (TMA) in the egg yolk, which is responsible for the fishy egg flavor. This study was aimed to investigate yolk TMA deposition in eggs from different FMO3 genotype (AA, AT, TT) laying hens fed a high level of choline, and the relationship between egg yolk TMA contents and yolk acceptability. A total of 132 genotyped laying hens, 38 wk of age, were assigned to 1 of the 4 dietary treatments: 1) a control group of AA hens fed 370 mg of choline/kg of diet (practical choline level, provided by 500 mg of choline chloride/kg of diet); 2) AA hens were fed 2,960 mg of choline/kg of diet (higher dietary choline level, provided by 4,000 mg of choline chloride/kg of diet); 3) AT hens were fed 2,960 mg of choline/kg of diet; and 4) TT hens were fed 2,960 mg of choline/kg of diet. All layers were fed a 370 mg of choline/kg added diet for a period of 1-wk adaptation followed by a 6-wk trial period. A remarkable increase in yolk TMA concentration of TT hens (P < 0.001) caused by dietary choline addition at 2,960 mg/kg was observed. The relationship between TMA concentration in the egg yolk (MUg/g, y) and deposition time (1~42 d, x) for TT hens is y = 0.0005x(3) - 0.0419x(2) + 1.0924x + 0.4323 (R(2) = 0.9259). The fish flavor scores of egg yolks rose steadily (R(2) = 0.9324) as the TMA concentration increased, and there was also a corresponding decrease in the acceptance score (R(2) = 0.8276). The eggs were acceptable when the yolk TMA concentrations were less than 4.516 MUg/g of yolk. PMID- 23436526 TI - Effect of beta-hydroxy-beta-methylbutyrate calcium on growth, blood parameters, and carcass qualities of broiler chickens. AB - Beta-hydroxy-beta-methylbutyrate (HMB), the metabolite of leucine, plays an important role in muscle protein metabolism. To investigate the effect of dietary HMB calcium (HMB-Ca) on growth performance, breast muscle development, and serum parameters in broiler chickens, a total of two hundred seventy 1-d-old Arbor Acres male broiler chicks were randomly allotted into 3 dietary treatments supplemented with 0, 0.05%, or 0.1% HMB-Ca during the starter (1 to 21 d) and grower (22 to 42 d) period. The results showed that broilers fed 0.1% HMB-Ca diet had higher ADG during the starter or the whole period, and gain 148 g more BW than the chicks fed the control diet at 42 d of age (P < 0.05). At 21 d of age, birds receiving 0.1% HMB-Ca had more breast muscle yield, less abdominal fat than the control, and more dressing percentage than birds fed the control or 0.05% HMB Ca diet (P < 0.05). At 42 d of age, 0.1% HMB-Ca increased breast muscle yield than the control and decreased abdominal fat compared with the control or 0.05% HMB-Ca group (P < 0.05). In comparison with the control, feeding 0.1% HMB-Ca increased the triiodothyronine, thyroxine, triiodothyronine/thyroxine ratio and decreased the serum uric acid level at d 21 (P < 0.05). At 42 d of age, serum thyroxine level was elevated in the 0.05% HMB-Ca treatment, and the uric acid concentration was significantly decreased by the 0.1% HMB-Ca-supplemented diet (P < 0.05). Dietary HMB-Ca did not affect the growth hormone or insulin content. This study suggested that dietary supplementation of HMB-Ca improved growth performance, stimulated the breast muscle development, and decreased the abdominal fat deposition in broiler chickens, and the favorable effects were more pronounced in the starter phase. The growth promotion effect of HMB-Ca may be partly related to the increased serum thyroid hormones in broiler chickens. PMID- 23436527 TI - Biallelic expression of the L-arginine:glycine amidinotransferase gene with different methylation status between male and female primordial germ cells in chickens. AB - The basic functions of DNA methylation include in gene silencing by methylation of specific gene promoters, defense of the host genome from retrovirus, and transcriptional suppression of transgenes. In addition, genomic imprinting, by which certain genes are expressed in a parent-of-origin-specific manner, has been observed in a wide range of plants and animals and has been associated with differential methylation. However, imprinting phenomena of DNA methylation effects have not been revealed in chickens. To analyze whether genomic imprinting occurs in chickens, methyl-DNA immunoprecipitation array analysis was applied across the entire genome of germ cells in early chick embryos. A differentially methylated region (DMR) was detected in the eighth intron of the l arginine:glycine amidinotransferase (GATM) gene. When the DMR in GATM was analyzed by bisulfite sequencing, the methylation in male primordial germ cells (PGC) of 6-d-old embryos was higher than that in female PGC (57.5 vs. 35.0%). At 8 d, the DMR methylation of GATM in male PGC was 3.7-fold higher than that in female PGC (65.0 vs. 17.5%). Subsequently, to investigate mono- or biallelic expression of the GATM gene during embryo development, we found 2 indel sequences (GTTTAATGC and CAAAAA) within the GATM 3'-untranslated region in Korean Oge (KO) and White Leghorn (WL) chickens. When individual WL and KO chickens were genotyped for indel sequences, 3 allele combinations (homozygous insertion, homozygous deletion, and heterozygotes) were detected in both breeds using a gel shift assay and high-resolution melt assay. The deletion allele was predominant in KO, whereas the insertion allele was predominant in WL. Heterozygous animals were evenly distributed in both breeds (P < 0.01). Despite the different methylation status between male and female PGC, the GATM gene conclusively displayed biallelic expression in PGC as well as somatic embryonic, extraembryonic, and adult chicken tissues. PMID- 23436528 TI - Microarray analysis of early and late passage chicken embryo fibroblast cells. AB - Primary cultured cells derived from normal tissue have a limited lifespan due to replicative senescence and show distinct phenotypes such as irreversible cell cycle arrest and enlarged morphology. Studying senescence-associated genetic alterations in chicken cells will provide valuable knowledge of cellular growth characteristics, when compared with normal and rapidly growing cell lines. Microarray analysis of early- and late-passage (passage 4 and 18, respectively) primary chicken embryo fibroblast (CEF) cells was performed with a 4X44K chicken oligo microarray. A total of 1,888 differentially expressed genes were identified with a 2-fold level cutoff that included 272 upregulated and 1,616 downregulated genes in late-passage senescent CEF cells. Bioinformatic analyses were performed using Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com). Of the 1,888 differentially expressed genes in senescent CEF cells, 458 were identified as functionally known genes and only 61 genes showed upregulation. Because senescent cells generally showed the deactivated states of most cellular mechanisms for proliferation and energy metabolism, intensified analysis on upregulated genes revealed that the molecular mechanisms in senescent CEF cells are characterized by the suppression of cell cycle and proliferation, progression of cell death including apoptosis, and increased expression of various secreting factors. These regulatory pathways may be opposite to those found in the immortal CEF cell line, such as the DF-1 immortal line. Further comparison of differentially expressed genes between senescent and immortal DF-1 CEF cells showed that 35 genes overlapped and were oppositely regulated. The global gene expression profiles may provide insight into the cellular mechanisms that regulate cellular senescence and immortalization of CEF cells. PMID- 23436529 TI - Differences between fertilized and unfertilized chicken egg white proteins revealed by 2-dimensional gel electrophoresis-based proteomic analysis. AB - The egg white protein alterations during the early phase of chicken embryonic development were recently reported by our laboratory. Nevertheless, the original albumen differences between fresh unfertilized and fertilized chicken eggs have not been investigated. By using 2-dimensional gel electrophoresis (2-DE), coupled with matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF MS/MS) method, 1 ovalbumin protein spot as well as 6 ovalbumin-related protein Y spots were identified showing more than 10-fold differences (P < 0.01) in abundance between fresh unfertilized and fertilized chicken egg whites. Six of these protein spots represented higher intensity in fertilized eggs through 2-DE analysis. It was thus concluded that ovalbumin protein family, especially ovalbumin-related protein Y, may play an important role in embryonic development, which still needs to be validated. This finding will provide insight into embryogenesis to improve our understanding of the functions of ovalbumin family proteins in regulating or supporting embryonic development. PMID- 23436530 TI - Expression of microRNA and microRNA processing machinery genes during early quail (Coturnix japonica) embryo development. AB - MicroRNA (miRNA) are small regulatory RNA molecules that are implicated in regulating and controlling a wide range of physiological processes including cell division, differentiation, migration, apoptosis, morphogenesis, and organogenesis. The aim of this study was to determine the expression pattern of 32 miRNA and 18 miRNA processing machinery genes during somite formation in quail embryos. The embryos were collected at stages HH (Hamburger and Hamilton) 4, 6, and 9 of embryo development (19, 24, and 30 h of incubation, respectively). Total RNA including miRNA was isolated from 4 groups of embryos (each group consisting of 6 to 8 embryos) were collected at each of the 3 stages (19, 24, and 30 h). The expression pattern of candidate miRNA and miRNA processing machinery genes was performed using quantitative real-time PCR. The results demonstrated that 7 miRNA (let-7a, mir-122, mir-125b, mir-10b, P < 0.01; let-7b, mir-26a, and mir-126, P < 0.05) were differentially expressed during early quail embryo development. In addition, the expression profile of 18 miRNA processing machinery genes was not significantly increased at 30 h of incubation compared with both 19 and 24 h. Our results suggest that machinery genes for miRNA biogenetic pathways are functional, and hence, miRNA may be involved in the regulation of early quail development. These 7 differentially expressed miRNA are suggested to play critical roles in quail embryo somite formation. PMID- 23436531 TI - Acrosome reaction of fowl sperm: evidence for shedding of the acrosomal cap in intact form to release acrosomal enzyme. AB - The aim of this study was to determine the site of enzyme release from the acrosome and the fate of the acrosomal cap during the process of acrosome reaction (AR) in fowl sperm. Gelatin substrate coverslips with halos were subjected to scanning electron microscopy to determine the site from which acrosomal proteolytic enzyme was released to form a halo around the acrosome of individual sperm. Aliquots of sperm treated with solubilized inner perivitelline layer (IPL) containing 5 mmol CaCl(2) were simultaneously subjected to fluorescent staining with fluorescein isothiocyanate-labeled peanut agglutinin and scanning electron microscopy to evaluate AR of sperm and to examine the status of the acrosomal region, respectively. Inside the halos, a gelatin-free (proteolyzed gelatin) layer was found extending some distance around the acrosome of sperm. All of the sperm showing the formation of halos on gelatin had a single circular opening around their subacrosomal rod at the base of the acrosomal cap. Interaction of sperm with solubilized IPL in the presence of 5 mmol CaCl(2) resulted in 41.4 +/- 1.8% of the sperm to undergo AR, as evaluated by fluorescein isothiocyanate-labeled peanut agglutinin. Similarly, as observed using scanning electron microscopy, 38.2 +/- 2.3% of the sperm treated with solubilized IPL plus 5 mmol CaCl(2) had exposed subacrosomal rod. In all sperm examined, no sign of disruption of the acrosomal membrane was found in the apical region of the acrosome. Rather, the acrosomal caps were found intact detached from the acrosomal region of the sperm, indicating that AR of fowl sperm resulted in the intact removal of the acrosomal cap. Based on these experimental observations, we suggest that the process of AR in fowl sperm is unique; the release of the acrosomal proteolytic enzyme may occur through a single circular opening formed at the base of the acrosomal cap and the acrosomal cap is detached in intact form from the posterior acrosomal region of the sperm. PMID- 23436532 TI - Effect of hot water spray on broiler carcasses for reduction of loosely attached, intermediately attached, and tightly attached pathogenic (Salmonella and Campylobacter) and mesophilic aerobic bacteria. AB - Chickens are known to harbor many bacteria, including pathogenic microorganisms such as Salmonella and Campylobacter. The objective of this study was to evaluate the efficacy of hot water spray (HWS, 71 degrees C for 1 min) in reducing bacterial contamination of prechilled broiler carcasses. For each of 4 replications, skin samples from 5 broilers were collected at 3 processing stages: after bleeding (feathers removed manually), after evisceration (with/without HWS), and after water chilling. Broiler skin was quantitatively assessed for loosely attached (by rinsing the skin), intermediately attached (by stomaching the rinsed skin), and tightly attached (by grinding the rinsed/stomached skin) mesophilic aerobic bacteria (MAB) and Campylobacter as well as for the prevalence of Salmonella and Campylobacter. Broiler skins possessed 6.4 to 6.6 log cfu/g, 3.8 to 4.1 log cfu/g, and 2.8 to 3.5 log cfu/g of MAB populations after bleeding, evisceration, and chilling, respectively. The HWS resulted in more than 1 log unit of reduction in MAB immediately after evisceration and immediately after chilling regardless of microbial sampling method. Compared with MAB, the contamination of Campylobacter was low (1.7 to 2.6 log cfu/g) after bleeding, but the level was not reduced throughout the processing steps regardless of HWS. The application of HWS reduced the prevalence of Salmonella after chilling, but not for Campylobacter except for loosely attached cells. After hot water exposure, a partially cooked appearance was seen on both broiler skin and skinless breast surface. More research is required to effectively eliminate pathogenic organisms during processing and suppress any recovery of bacteria regardless of attachment type after chilling. PMID- 23436533 TI - Estimation of factors associated with the occurrence of white striping in broiler breast fillets. AB - Broiler breast fillets are sometimes characterized grossly by white parallel striations in the direction of the muscle fibers, and the condition is referred to as white striping. Depending on the severity of white striping, fillets can be classified as normal (NORM), moderate (MOD), or severe (SEV). The present study was intended to determine the factors associated with the occurrence of white striping in broiler breast fillets. Broiler birds (59 to 63 d) of 4 different commercial high-yielding strains (both males and females) fed with industrial type or phase-feeding regimens, were processed and ready-to-cook carcass weight was recorded. The carcasses were deboned at either 4 or 6 h postmortem. Fillets were scored for the degree of white striping at 24 h postmortem, and dimensions of fillets (length, width, cranial thickness, and caudal thickness), pH, color (L*, a* and b* values), cook loss, and Meullenet-Owens razor shear energy (MORSE) values were determined. About 55.8% of the birds used in the study showed some degree of white striping with MOD and SEV categories as 47.5 and 8.3%, respectively. Higher degrees of white striping were significantly (P < 0.05) related to higher cranial fillet thickness and ready-to-cook weights. The occurrence of SEV degrees of white striping was accompanied with increased b* values or yellowness of the meat. The growth differences in strains could influence the incidence of this condition, but feeding regimens and chill hour during processing did not. In addition, the degree of white striping did not show any significant (P > 0.05) relationship between various meat quality parameters such as pH, L*, a*, cook loss, and MORSE. In conclusion, the results of this study suggest that there is a greater chance of higher degrees of white striping associated with heavier birds, but the condition is not related to any major changes in cooked meat quality. PMID- 23436534 TI - Consumer preference for chicken breast may be more affected by information on organic production than by product sensory properties. AB - Conventional chicken from a fast-growing strain (CC), organic chicken from a slow growing strain (OSG), and organic chicken from a fast-growing strain (OFG) were used to assess descriptive sensory differences between organic and conventional breasts, to verify whether differences were perceived by consumers and to evaluate the effect of information about organic production on liking. A conventional quantitative-descriptive analysis was performed by a trained panel of 10 members on breast slices (1 cm thick) grilled at 300 degrees C. A 150 member consumer panel (from southern, central, and northern Italy) rated CC, OSG, and OFG breasts according to 3 types of evaluation: tasting without information (perceived liking), information without tasting (expected liking), and tasting with information (actual liking). Breasts from different sources were clearly discriminated by the trained panel as meat from CC was perceived more tender than OFG (P < 0.05) and OSG (P < 0.001), more fibrous than OFG (P < 0.05) and OSG (P < 0.001), and leaving more residue than OFG (P < 0.05) and OSG (P < 0.001), whereas OSG was assessed as less juicy before swallowing than OFG and CC (P < 0.05) and less fibrous than OFG (P < 0.05). No significant differences were observed by consumers for perceived liking. However, consumer expected liking scores were higher for organic than for conventional products (P < 0.001) and actual liking of organic breasts moved toward the expectancy. In particular, actual liking scores were higher than perceived liking in blind conditions (P < 0.001 and P < 0.01 for OFG and OSG, respectively). We conclude that trained panelists were able to discriminate chicken breasts from different sources, whereas untrained consumers were not. However, consumer liking was markedly affected by the information given on the organic production system, thus providing a tool to differentiate the product in an increasingly competitive market. PMID- 23436535 TI - Prediction of Listeria innocua survival in fully cooked chicken breast products during postpackage thermal treatment. AB - The effectiveness of postpackage hot water thermal treatment on survival of Listeria innocua in fully cooked chicken breast products was investigated at 60, 70, 80, and 90 degrees C. Primary models based on log-linear and Weibull models were used to fit bacterial survival curves at different temperatures. The prediction plot and fit statistics indicated that the Weibull model provided a better fit than the log-linear model and was selected as the primary model. A secondary model based on linear regression was developed to describe the effect of temperature on the kinetic parameters of Listeria innocua survival derived from the Weibull model. The root mean square error and coefficients of determination indicated a good fit of the secondary model. The models were validated by independent data from pilot plant tests, and the values of bias factor and accuracy factor fell into the acceptable range. The models developed in this study can assist poultry producers and risk managers in designing appropriate thermal treatment regimens to minimize the risk associated with Listeria in ready-to-eat poultry products. PMID- 23436536 TI - Effect of essential oil compound on shedding and colonization of Salmonella enterica serovar Heidelberg in broilers. AB - The objectives of this study were to determine the effect of an essential oil blend (EO; carvacrol, thymol, eucalyptol, lemon) administered in drinking water on the performance, mortality, water consumption, pH of crop and ceca, and Salmonella enterica serovar Heidelberg fecal shedding and colonization in broiler birds following Salmonella Heidelberg challenge and feed withdrawal. Chicks were randomly assigned to water treatments containing 0.05, 0.025, or 0.0125% EO or untreated controls. Treatments were administered in drinking water on 0 to 7 and 35 to 42 d. One-half of the chicks were challenged with Salmonella Heidelberg and placed in pens with unchallenged chicks on d 1. Performance, mortality, water consumption, and pH were determined during the 42-d study. Prevalence of Salmonella Heidelberg was determined on drag swabs (0, 14, and 42 d) and in the ceca and crops (42 d). The 0.05% EO administered in drinking water significantly (P < 0.05) reduced Salmonella Heidelberg colonization in crops of challenged birds, significantly lowered the feed conversion ratio, and increased weight gain compared with controls. The 0.025% and 0.015% EO in drinking water significantly lowered the feed conversion ratio and increased weight gain compared with controls, but did not significantly reduce Salmonella Heidelberg colonization in the crops. The EO in drinking water did not significantly reduce Salmonella Heidelberg colonization in ceca or fecal shedding in broilers. The EO used in the study may control Salmonella Heidelberg contamination in crops of broilers when administered in drinking water and therefore may reduce the potential for cross contamination of the carcass when the birds are processed. PMID- 23436537 TI - Salmonella Enteritidis is superior in egg white survival compared with other Salmonella serotypes. AB - Salmonella enterica subspecies enterica serotype Enteritidis is a major cause of egg-borne human salmonellosis. The ability to survive in egg albumen at chicken body temperature was hypothesized to be an important factor involved in the predominant contamination of eggs by this specific serotype. Eighty-nine Salmonella strains from different serotypes, belonging to 5 serogroups, were incubated for 24 h in egg white at 42 degrees C. The number of Salmonella Enteritidis strains that were able to survive in egg white was significantly higher compared with strains belonging to other serotypes and serogroups that were tested in this study. These data add evidence to the hypothesis that egg white survival is one of the reasons why Salmonella Enteritidis is more predominantly isolated from contaminated eggs, and helps explaining why most reported egg-borne Salmonella outbreaks in humans are caused by Salmonella Enteritidis. PMID- 23436538 TI - Transcatheter aortic valve implantation in a patient with circulatory collapse, using the LUCAS(r) chest compression system. AB - We describe a case of transcatheter aortic valve implantation (TAVI) using the LUCAS(r) Chest Compression System in an elderly high risk patient with severe aortic stenosis and heart failure. In this case, the patient developed severe aortic regurgitation following predilatation of the native aortic valve and automated cardiopulmonary resuscitation (A-CPR) was initiated. The procedure was performed under ongoing A-CPR for a total of 28 min. The patient was transferred to the intensive care unit and to a step down unit the following day. At follow up 30 days later, she showed no signs of neurologic or cardiac damage. This case report shows, that it is possible to perform the TAVI procedure under ongoing A CPR and that A-CPR, judged by invasive blood pressures, was capable of maintaining a satisfactory perfusion pressure even with a damaged aortic valve. PMID- 23436539 TI - Unmet needs of Australian and Canadian haematological cancer survivors: a cross sectional international comparative study. AB - OBJECTIVE: Few population-based studies have assessed the needs of haematological cancer survivors or conducted international comparisons. We aimed to assess and compare the unmet needs of Australian and Canadian haematological cancer survivors. METHODS: Two cross-sectional datasets were analysed. Survivors were recruited from population-based cancer registries and sent a self-report survey containing the Survivors Unmet Needs Survey. Australians were aged 18-80 years at the time of study and diagnosed in the last 3 years. Canadians were diagnosed 1-5 years prior and aged 19 years and over at diagnosis. RESULTS: A total of 268 Australian and 169 Canadian survivors returned a completed survey. 'Dealing with feeling tired' was identified as the highest concern by survivors. Country (LRchi(2)=4.0(1), p=0.045) was associated with survivors reporting a 'high/very high' unmet need with 'worry about earning money,' with Australians reporting marginally nonsignificantly higher odds than Canadians (OR 2.1; 95% CI; 0.99, 4.3). Country was not significantly associated with any other outcome. Having a personal expense in the last month as a result of having cancer, younger age at diagnosis, female sex, vocational or other level education, and consulting a health care professional for cancer treatment or concerns about cancer in the last month were associated with multiple areas of need. CONCLUSIONS: Australian and Canadian haematological cancer survivors were found to experience similar levels of unmet needs. Overall, haematological cancer survivors may require additional assistance in dealing with feeling tired. PMID- 23436540 TI - NK cells exacerbate the pathology of influenza virus infection in mice. AB - NK cells offer a first line of defense against viruses and are considered beneficial to the host during infection. Nevertheless, little is understood regarding the phenotype and function of NK cells in the lung during influenza virus infection. We found that the frequency of NK cells in mouse lung increased during influenza infection, with the majority of a mature phenotype. Cell surface CD107a and intracellular IFN-gamma were detected in cells expressing multiple NK cell receptors in infected lung, suggesting that NK cells were activated during infection. The activating receptor NKp46 was predominantly negative on such cells, possibly as a result of encountering influenza HA. Depletion of NK cells in vivo with anti-asialo GM1 or anti-NK1.1 reduced mortality from influenza infection and surviving mice recovered their body weight. Pathology induced by NK cells was only observed with high, not medium or low-dose influenza infection, indicating that the severity of infection influences NK-cell-mediated pathology. Furthermore, adoptive transfer of NK cells from influenza-infected lung, but not uninfected lung, resulted in more rapid weight loss and increased mortality of influenza-infected mice. Our results indicate that during severe influenza infection of the lung, NK cells have a deleterious impact on the host, promoting mortality. PMID- 23436541 TI - Non-invasive UPR monitoring system and its applications in CHO production cultures. AB - Unfolded protein response (UPR) is the primary signaling network activated in response to the accumulation of unfolded and/or misfolded protein in the endoplasmic reticulum (ER). The expression of high levels of recombinant proteins in mammalian cell cultures has been linked to the increased UPR. However, the dynamics of different UPR-mediated events and their impact on cell performance and recombinant protein secretion during production remain poorly defined. Here, we have created a non-invasive UPR-responsive, fluorescence-based reporter system to detect and quantify specific UPR-mediated transcriptional activation of different intracellular signaling pathways. We have generated stable antibody expressing CHO clones containing this UPR responsive system and established FACS based methods for real-time, continuous monitoring of the endogenous UPR activation in live cultures. The results showed that the UPR activation is dynamically regulated during production culture. The clones differed in their UPR patterns; both the timing and the degree of UPR-induced transcriptional activation were linked to cell performance, such as growth, and viability. In addition, the cell culture environment, such as media composition and osmolarity, significantly impacted endogenous UPR activation. Taken together, these data demonstrate a utility of this UPR monitoring system in recombinant protein production processes and the observations increase our understanding of the critical role of UPR in regulating diverse phenotypes of the cells including growth, survival and recombinant protein secretion under different culture environments and processing conditions. PMID- 23436542 TI - Experimental and theoretical evidence of the existence of gold(I)...mercury(II) interactions in solution through fluorescence-quenching measurements. AB - Heteronuclear complexes {[Hg(R)2][Au(R')(PMe3)]2}n (R=R'=C6Cl2F3 (3); R=R'=C6F5 (4); R=C6Cl2F3, R'=C6F5 (5); R=C6F5, R'=C6Cl2F3 (6)) were prepared by the treatment of the corresponding organomercury compounds, [Hg(C6X5)2], with two equivalents of [Au(C6X5)(PMe3)]. Their crystal structures, as determined by using X-ray diffraction methods, display Au...Hg interactions. Although only compound 4 and 5 show luminescence in the solid state, all of these compounds quench the fluorescence of naphthalene in solution. Solution studies of these derivatives suggest a cooperative effect of the gold(I) center in switching on the quenching capabilities of the [Hg(C6X5)2] synthon with naphthalene. Theoretical studies confirmed the quenching ability of the organomercury species in the presence of gold. PMID- 23436543 TI - NMR-based conformational analysis of perezone and analogues. AB - Complete assignment of the (1)H NMR chemical shift and coupling constant values of perezone (1), O-methylperezone (2) and 6-hydroxyperezone (3) was carried out by total-line-shape-fitting calculations using the PERCH iterative spectra analysis software (PERCH Solutions Ltd., Kuopio, Finland). The resulting simulated spectra for the three compounds showed strong similarity to their corresponding experimental spectra. Particularly, all vicinal, allylic and homoallylic coupling constant values for the side chain of the three compounds were very similar, thus revealing that the conformation of these three molecules in solution is indeed almost identical. This fact is in agreement with extended side chain conformations over folded chain conformations because 1, 2 and 3 undergo completely different intramolecular cycloaddition reactions. In addition, results of double pulsed field gradient spin echo NOESY 1D experiments performed on perezone (1) were unable to provide evidence for folded conformers. PMID- 23436544 TI - Vemurafenib-associated pancreatitis: case report. AB - Vemurafenib is a novel BRAF kinase inhibitor indicated in metastatic melanoma patients with V600E mutation. We report the first case of vemurafenib-associated pancreatitis. Two weeks after initiation of vemurafenib, a patient presented to the emergency department with severe epigastric pain and a serum lipase of 1544 units/L. Drug-induced pancreatitis was diagnosed on exclusion of all other potential causes. Vemurafenib was rechallenged at half the daily dose and the patient subsequently developed exacerbated symptoms of pancreatitis after two doses. The strong temporal relationship between drug exposure and toxicity, along with the positive results from a rechallenge study, strongly support a conclusion of causality. To our knowledge, this is the first report of vemurafenib-induced pancreatitis. PMID- 23436547 TI - Medicare reductions: what can you do legally? PMID- 23436551 TI - Implications of European corn borer, Ostrinia nubilalis, infestation in an Aspergillus flavus-biocontrolled corn agroecosystem. AB - BACKGROUND: A novel biocontrol strategy consisting of field application of bioplastic-based granules inoculated with a non-toxigenic Aspergillus flavus L. strain has recently been shown to be effective for reducing aflatoxin contamination in corn. This study focused on other factors that may affect the feasibility of this biocontrol technique, and more specifically the role of the European corn borer (ECB), Ostrinia nubilalis H., in the dispersal and infestation of A. flavus in corn and its impact on crop yield. RESULTS: In spite of the high percentage of corn ears showing larval feeding damage, ECB-bored kernels accounted for only 3 and 4% in 2009 and 2010 respectively. Most of the damaged kernels were localised in the ear tip or immediately below. More precisely, the average incidence of ECB-bored kernels in the upper end of the ear was 32%. However, less than 5% of kernels from the central body of the ear, which includes the majority of kernels, were injured by ECB. CONCLUSIONS: Although ECB larvae showed a high tolerance to aflatoxin B1 and thus had the potential to serve as vectors of the mould, fungal infection of kernels was poorly associated with insect damage. ECB infestation resulted in grain yield losses not exceeding 2.5%. PMID- 23436552 TI - A meta-analysis of the relationship of the Parkin p.Val380Leu polymorphism to Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common movement disorders. Parkin p.Val380Leu polymorphism (c.1239G > C) has been investigated as a potential genetic hallmark of PD, but studies examining the association between the polymorphism and PD have reported conflicting results. Therefore, we conducted a meta-analysis to assess the influence of Parkin p.Val380Leu polymorphism on the susceptibility of PD. Computer and hand searches of the literature were conducted using the MEDLINE, EMBASE, Cochrane Library, and China Academic Journals databases to identify studies addressing the association between the Parkin p.Val380Leu polymorphism and PD risk. We performed analyses of study characteristics, heterogeneity, and funnel plot asymmetry in analyses analogous to additive, dominant, recessive, homozygous, and heterozygous genetic models with the odds ratio (OR) as the measure of association. A total of 11 case control studies involving 2,073 PD cases and 2,131 controls were included. When all 11 studies were pooled into the analysis, the presence of the Leu allele at the Parkin p.Val389Leu polymorphism was associated with decreased risk for PD in three genetic comparison models: OR in additive model: 0.79, 95% confidence interval (CI) = 0.64-0.98, P = 0.029; OR in recessive model: 0.55, 95% CI = 0.35 0.89, P = 0.014; OR in homozygous model: 0.51, 95% CI = 0.32-0.82, P = 0.005. Begg's funnel plot and Egger's test provided visual and statistical evidences for funnel plot symmetry, without evidence presence of publication bias. We conclude that the presence of the Leu allele at the Parkin p.Val380Leu polymorphism is associated decreased risk for PD. PMID- 23436555 TI - Weak-field, multiple-cycle carrier envelope phase effects in laser excitation. AB - Although the absolute or carrier envelope phase (CEP) of a laser pulse is usually assumed to be effective for ultrashort and/or ultrastrong pulses only, it is demonstrated that these limitations can eventually be removed. Therefore, the excitation of a model positively charged homonuclear diatomic molecule, in which four electronic states are coupled by the laser field, is studied. In an initial step, nuclear wave packets in two dissociative states are prepared. Upon reaching the fragment channel, a weak pulse interacts with the system and prepares CEP dependent asymmetries associated with electron density localized on one or the other fragmentation product. PMID- 23436553 TI - Determination of endogenous brassinosteroids in plant tissues using solid-phase extraction with double layered cartridge followed by high-performance liquid chromatography-tandem mass spectrometry. AB - INTRODUCTION: Brassinosteroids (BRs) are a group of important phytohormones that play vital roles in plant growth, development and a series of physiological phenomena. In order to understand biosynthesis, degradation and metabolic pathways of BRs, a reliable analytical method of BRs with effective sample pre treatment process is favourable. OBJECTIVE: The development of a quick and effective method for the quantification of endogenous BRs in plant tissue with the aid of double layered solid-phase extraction (SPE) cartridges (graphite carbon black and primary secondary amine silica sorbent: GCB/PSA). METHOD: The method involved an initial extraction of BRs with acetonitrile, a dehydration process with anhydrous MgSO4 and NaCl, a SPE purification process with a double layered cartridge, and a further clean-up step utilising liquid-liquid extraction (LLE). The purification process was mainly realised on the GCB/PSA cartridge. GCB could eliminate hydrophobic compounds, especially those containing a pi system, and PSA was introduced to remove the polar interferences. Endogenous BRs were quantified by HPLC-ESI-MS/MS. RESULTS: Good linearities were obtained in the range of 0.4-500 ng/mL (0.0124-15 ng), with the correlation coefficients above 0.9957. The relative recoveries of BRs of this method were in the range of 71.1 113.1%, with intra- and interday relative standard deviations (RSDs) less than 16.3%. With the proposed method, the requirement of plant tissue amount was minimised to 1 g fresh weight, which is the smallest amount reported so far, to our knowledge. PMID- 23436556 TI - A theory-driven, longitudinal evaluation of the impact of team training on safety culture in 24 hospitals. AB - BACKGROUND: Effective teamwork facilitates collective learning, which is integral to safety culture. There are no rigorous evaluations of the impact of team training on the four components of safety culture-reporting, just, flexible and learning cultures. We evaluated the impact of a year-long team training programme on safety culture in 24 hospitals using two theoretical frameworks. METHODS: We used two quasi-experimental designs: a cross-sectional comparison of hospital survey on patient safety culture (HSOPS) results from an intervention group of 24 hospitals to a static group of 13 hospitals and a pre-post comparison of HSOPS results within intervention hospitals. Dependent variables were HSOPS items representing the four components of safety culture; independent variables were derived from items added to the HSOPS that measured the extent of team training, learning and transfer. We used a generalised linear mixed model approach to account for the correlated nature of the data. RESULTS: 59% of 2137 respondents from the intervention group reported receiving team training. Intervention group HSOPS scores were significantly higher than static group scores in three dimensions assessing the flexible and learning components of safety culture. The distribution of the adoption of team behaviours (transfer) varied in the intervention group from 2.8% to 31.0%. Adoption of team behaviours was significantly associated with odds of an individual reacting more positively at reassessment than baseline to nine items reflecting all four components of safety culture. CONCLUSIONS: Team training can result in transformational change in safety culture when the work environment supports the transfer of learning to new behaviour. PMID- 23436557 TI - The coating of smart pH-responsive polyelectrolyte brushes in capillary and its application in CE. AB - A novel pH-responsive coating technique was developed and applied to CE successfully in this paper. The coating was formed by bonding mixed opposite charge poly(acrylic acid) and poly(2-vinylpyridine) randomly onto the inner wall of a silica capillary. The coating processes were first characterized by ellipsometry and atomic force microscopy at macroscale and microscale, respectively. Measurements of EOF were implemented to confirm the coating. Direction and velocity of EOF became controllable from negative to positive, showing a perfect sigmoidal curve as the coating net charges alternated by the pH of BGE. The control of the EOF makes it possible to analyze different kinds of small molecules, peptides, and proteins successfully in the same capillary. Results showed that the stability and reproducibility for separations of fluoroquinolone standards were satisfactory for more than a hundred separations. A series of basic and acidic protein standards were separated with admirable efficiency and minimal adsorption using both polarities. The separation of tryptic BSA digest showed that the prepared capillary has immense potential in analyzing a single sample with both acidic and basic separations, which achieved the expectation in proteomics study by CE-MS. PMID- 23436558 TI - The cancer psychosocial care matrix: a community-derived evaluative tool for designing quality psychosocial cancer care delivery. AB - OBJECTIVE: Although the Institute of Medicine provided a vision for effective psychosocial care for cancer survivors, limited guidance exists regarding the essential components of comprehensive care or progressive steps for implementing each component. This paper describes the development of a unique tool for assessing capacity to provide quality psychosocial care to cancer survivors and the results of the first implementation of this tool in community settings. METHODS: The psychosocial working group of the National Cancer Institute Community Cancer Centers Program (NCCCP) developed the Cancer Psychosocial Care Matrix assessment tool. All NCCCP sites (n=30, enrolled in 2007 nd 2010) completed the matrix indicating their capacity for providing psychosocial care at entry into NCCCP ('baseline') after 2 years of NCCCP participation (2007 sites only) and within the coming year ('future aspirations'). RESULTS: At baseline, matrix responses reflected few or no systematic processes in place for most components of comprehensive psychosocial care. However, reported capacity to deliver specific components improved at 2 years post-NCCCP entry for the 2007 sites and in all NCCCP sites' future aspirations. CONCLUSIONS: With growing demand on cancer centers to meet new metrics of quality care, the psychosocial matrix can help centers systematically identify and develop steps to address gap areas in their capacity to meet these new standards. The Cancer Psychosocial Care Matrix appears to enable evaluation of psychosocial programs, may promote intentions to improve psychosocial services, and can facilitate communication of 'best practices' among cancer centers. PMID- 23436559 TI - Prolonged high-pressure is required for optimal stent deployment as assessed by optical coherence tomography. AB - AIMS: Optimizing stent deployment is important for both acute- and long-term outcomes. High-pressure balloon inflation is the standard for coronary stent implantation. However, there is no standardized inflation protocol. We hypothesized that prolonged high-pressure balloon inflation until stabilization of inflation pressure is superior to a rapid inflation/deflation sequence for both stent expansion and strut apposition. METHODS AND RESULTS: A high-pressure rapid inflation/deflation sequence was deployed followed by angiography to assure no residual stenosis. Optical coherence tomography (OCT) was then performed followed by prolonged inflation until balloon pressure was stabilized for 30 sec using the same balloon at the same pressure as the rapid sequence. A second OCT run was then done. Thirteen thousand nine hundred thirteen stent struts were evaluated by OCT in 12 patients undergoing successful stenting. Stent expansion improved with prolonged (206 +/- 115 sec) vs. rapid (28 +/- 17 sec) inflation for both minimal stent diameter (3.0 +/- 0.5 vs. 2.75 +/- 0.44 mm, P < 0.0001) and area (7.83 +/- 2.45 vs. 6.63 +/- 1.85 mm(2) , P = 0.0003). The number of malapposed struts decreased (45 +/- 41 vs. 88 +/- 75, P = 0.005) as did the maximal malapposed strut distance (0.31 +/- 0.2 vs. 0.43 +/- 0.2 mm, P = 0.0001). Factors related to strut malapposition after rapid inflation included localized asymmetry in 67%, stent underexpansion in 75%, and stent undersizing in 67%. CONCLUSIONS: These data demonstrate that prolonged inflation is superior to a rapid inflation/deflation technique for both stent expansion and strut apposition. We recommend for routine stent deployment a prolonged inflation protocol as described above to optimize stent deployment. PMID- 23436560 TI - The importance of study design when comparing baseline characteristics between study groups. PMID- 23436561 TI - Anti-cell death engineering of CHO cells: co-overexpression of Bcl-2 for apoptosis inhibition, Beclin-1 for autophagy induction. AB - Genetic engineering approaches to inhibit cell death in Chinese hamster ovary (CHO) cell cultures have been limited primarily to anti-apoptosis engineering. Recently, autophagy has received attention as a new anti-cell death engineering target in addition to apoptosis. In order to achieve a more efficient protection of cells from the stressful culture conditions, the simultaneous targeting of anti-apoptosis and pro-autophagy in CHO cells (DG44) was attempted by co overexpressing an anti-apoptotic protein, Bcl-2, and a key regulator of autophagy pathway, Beclin-1, respectively. Co-overexpression of Bcl-2 and Beclin-1 exhibited a longer culture period as well as higher viability during serum-free suspension culture, compared with the control (without co-overexpression of Bcl-2 and Beclin-1) and Bcl-2 overexpression only. In addition to the efficient inhibition of apoptosis by Bcl-2 overexpression, Beclin-1 overexpression successfully induced the increase in the autophagic marker protein, LC3-II, and autophagosome formation with the decrease in mTOR activity. Co immunoprecipitation and qRT-PCR experiments revealed that the enforced expression of Beclin-1 increased Ulk1 expression and level of free-Beclin-1 that did not bind to the Bcl-2 despite the Bcl-2 overexpression. Under other stressful culture conditions such as treatment with sodium butyrate and hyperosmolality, co overexpression of Bcl-2 and Beclin-1 also protected the cells from cell death more efficiently than Bcl-2 overexpression only, implying the potential of autophagy induction. Taken together, the data obtained here provide the evidence that pro-autophagy engineering together with anti-apoptosis engineering yields a synergistic effect and successfully enhances the anti-cell death engineering of CHO cells. PMID- 23436562 TI - Lack of Mycobacterium tuberculosis-specific interleukin-17A-producing CD4+ T cells in active disease. AB - Protective immunity to Mycobacterium tuberculosis (Mtb) is commonly ascribed to a Th1 profile; however, the involvement of Th17 cells remains to be clarified. Here, we characterized Mtb-specific CD4(+) T cells in blood and bronchoalveolar lavages (BALs) from untreated subjects with either active tuberculosis disease (TB) or latent Mtb infection (LTBI), considered as prototypic models of uncontrolled or controlled infection, respectively. The production of IL-17A, IFN gamma, TNF-alpha, and IL-2 by Mtb-specific CD4(+) T cells was assessed both directly ex vivo and following in vitro antigen-specific T-cell expansion. Unlike for extracellular bacteria, Mtb-specific CD4(+) T-cell responses lacked immediate ex vivo IL-17A effector function in both LTBI and TB individuals. Furthermore, Mtb-specific Th17 cells were absent in BALs, while extracellular bacteria specific Th17 cells were identified in gut biopsies of healthy individuals. Interestingly, only Mtb-specific CD4(+) T cells from 50% of LTBI but not from TB subjects acquired the ability to produce IL-17A following Mtb-specific T-cell expansion. Finally, IL-17A acquisition by Mtb-specific CD4(+) T cells correlated with the coexpression of CXCR3 and CCR6, currently associated to Th1 or Th17 profiles, respectively. Our data demonstrate that Mtb-specific Th17 cells are selectively undetectable in peripheral blood and BALs from TB patients. PMID- 23436564 TI - We should not use a modifier to describe the severity of carpal tunnel syndrome. PMID- 23436563 TI - Cervical cytokines and clearance of incident human papillomavirus infection: Hawaii HPV cohort study. AB - Mechanisms for the control and resolution of human papillomavirus (HPV) infection of the cervix include the local production of cytokines, which control recruitment and function of cells integral to pathogen control. We established a cohort of women for long-term follow-up to examine the mucosal expression of antiviral (IFN-alpha2), Type-1 (IFN-gamma, IL-12), regulatory (IL-10), and proinflammatory (IL-1alpha, IL-1beta, IL-6, IL-8, MIP-1alpha, and TNF) cytokines in association with the clearance of incident cervical HPV infection. Interviews and specimens for HPV DNA analysis and cytokine protein measurement were obtained at baseline and at 4-month intervals. A Cox proportional hazards model was used to study the relationship between clearance of 107 high-risk and 111 low-risk incident HPV infections and cytokine levels among 154 women. Positive changes from baseline levels of IL-10, IL-12, MIP-1alpha, and TNF were associated with significantly longer times to type-specific HPV clearance. Inverse trends in the hazard ratios associated with clearance of high-risk HPV infections were monotonic and significant for IL-12 (ptrend = 0.02) and TNF (ptrend = 0.02); the likelihood of high-risk HPV clearance was reduced by 65% and 67%, respectively, among women in the highest as compared with the lowest quartile of change from baseline. Our results suggest that in women with a nontransient cervical HPV infection, proinflammatory, Type-1, and regulatory cytokines are elevated, underscoring the long-term commitment of local immune mediators to viral eradication. PMID- 23436565 TI - External quality assessment of factor VIII inhibitor assays. AB - Inhibitors to coagulation factors cause prolongation of routine hemostasis laboratory test results and have clinical relevance in the management of congenital and acquired hemophilia patients. Factor VIII (FVIII) inhibitors can be either allo-antibodies (in hemophilia A) or auto-antibodies (in acquired hemophilia) directed against FVIII. The most commonly used assays for detecting these inhibitors are the classical Bethesda assay or a modified (Nijmegen) method. Previous laboratory assessments from the Royal College of Pathologists of Australia Quality Assurance Program (RCPAQAP) Haematology and other external quality assessment programs have shown wide variability in FVIII inhibitor results and method performance, as well as a significant degree of false-positive and false-negative interpretations. Despite its limitations, the Bethesda assay is still the primary assay used in laboratories for detecting the presence and strength of a FVIII inhibitor. Therefore, it is of utmost importance that this assay is performed well. The current report reviews the most recent findings from the RCPAQAP Haematology, which show there is still a need for better standardization and improvement in the detection of low-level FVIII inhibitors to ultimately provide better clinical management of affected patients. PMID- 23436567 TI - Clinical trade-offs in cross-linked ultrahigh-molecular-weight polyethylene used in total joint arthroplasty. AB - Highly cross-linked formulations of ultrahigh-molecular-weight polyethylene (XLPE) offer exceptional wear resistance for total joint arthroplasty but are offset with a reduction in postyield and fatigue fracture properties in comparison to conventional ultrahigh-molecular-weight polyethylene (UHMWPE). Oxidation resistance is also an important property for the longevity of total joint replacements (TJRs) as formulations of UHMWPE or XLPE utilizing radiation methods are susceptible to free radical generation and subsequent embrittlement. The balance of oxidation, wear, and fracture properties is an enduring concern for orthopedic polymers used as the bearing surface in total joint arthroplasty. Optimization of material properties is further challenged in designs that make use of locking mechanisms, notches, or other stress concentrations that can render the polymer susceptible to fracture due to elevated local stresses. Clinical complications involving impingements, dislocations, or other biomechanical overloads can exacerbate stresses and negate benefits of improved wear resistance provided by XLPE. This work examines trade-offs that factor into the use of XLPE in TJR implants. PMID- 23436570 TI - Design of in vitro bioactive hybrid materials from the first generation of amine dendrimers as nanobuilding blocks. AB - In this work, the first generation of poly(propyleneimine) dendrimers were functionalized with alkoxysilane terminal groups and subjected to one of two different sol-gel process that followed two different catalytic pathways, that is base- or acid-catalyzed pathways. Thus, two series of new organic-inorganic hybrid materials were obtained in the form of monolithic pieces with differences in terms of both morphology and silanol content, which originated from the different sol-gel pathway that was followed. Moreover, calcium ions were added into the hybrid composition to promote in vitro bioactivity and phosphorous sources were used during the sol-gel step to obtain an earlier bioactive response. Characterization of these organic-inorganic hybrid materials was performed by means of thermogravimetric and elemental analyses, Fourier transform infrared spectroscopy (FTIR), solid state (13)C, (29)Si and (31)P magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, N2-adsorption isotherms, mercury-intrusion porosimetry, and zeta-potential measurements. The in vitro bioactivity of the dendritic hybrid networks was evaluated by soaking the materials in simulated body fluid and the results were explained in terms of the composition of the hybrids and the sol-gel route that was followed to prepare them. PMID- 23436568 TI - The James Supportive Care Screening: integrating science and practice to meet the NCCN guidelines for distress management at a Comprehensive Cancer Center. AB - BACKGROUND: Selecting a measure for oncology distress screening can be challenging. The measure must be brief, but comprehensive, capturing patients' most distressing concerns. The measure must provide meaningful coverage of multiple domains, assess symptom and problem-related distress, and ideally be suited for both clinical and research purposes. METHODS: From March 2006 to August 2012, the James Supportive Care Screening (SCS) was developed and validated in three phases including content validation, factor analysis, and measure validation. Exploratory factor analyses were completed with 596 oncology patients followed by a confirmatory factor analysis with 477 patients. RESULTS: Six factors were identified and confirmed including (i) emotional concerns; (ii) physical symptoms; (iii) social/practical problems; (iv) spiritual problems; (v) cognitive concerns; and (vi) healthcare decision making/communication issues. Subscale evaluation reveals good to excellent internal consistency, test-retest reliability, and convergent, divergent, and predictive validity. Specificity of individual items was 0.90 and 0.87, respectively, for identifying patients with DSM-IV-TR diagnoses of major depression and generalized anxiety disorder. CONCLUSIONS: Results support use of the James SCS to quickly detect the most frequent and distressing symptoms and concerns of cancer patients. The James SCS is an efficient, reliable, and valid clinical and research outcomes measure. PMID- 23436571 TI - A simple method for fabricating patterned curvilinear microstructures in poly(dimethylsiloxane) by selective wetting. AB - The fabrication of patterned microstructures in poly(dimethylsiloxane) (PDMS) is a prerequisite for soft lithography. Herein, curvilinear surface relief microstructures in PDMS are fabricated through a simple three-stage approach combining microcontact printing (MUCP), selective surface wetting/dewetting and replica molding (REM). First, using an original PDMS stamp (first-generation stamp) with linear relief features, a chemical pattern on gold substrate is generated by MUCP using hexadecanethiol (HDT) as an ink. Then, by a dip-coating process, an ordered polyethylene glycol (PEG) polymer-dot array forms on the HDT patterned gold substrate. Finally, based on a REM process, the PEG-dot array on gold substrate is used to fabricate a second-generation PDMS stamp with microcavity array, and the second-generation PDMS stamp is used to generate third generation PDMS stamp with microbump array. These fabricated new-generation stamps are utilized in MUCP and in micromolding in capillaries (MIMIC), allowing the generation of surface micropatterns which cannot be obtained using the original PDMS stamp. The method will be useful in producing new-generation PDMS stamps, especially for those who want to use soft lithography in their studies but have no access to the microfabrication facilities. PMID- 23436572 TI - Metabolism-based synthesis, biological evaluation and structure-activity relationship analysis of spirotetramat analogues as potential lipid biosynthesis inhibitors. AB - BACKGROUND: In previous studies, scientists found that, when spirotetramat was introduced into plants or animals, it was mainly metabolised at positions C-4 and C-8. That is to say, these two functional positions potentially played an important role in spirotetramat's bioactivities. In order to develop novel insecticides or miticides, the present authors designed and synthesised 35 spirotetramat analogues based on metabolite structures. RESULTS: All of the analogues have been identified on the basis of (1)H NMR, ESI-MS and elemental analysis data. The activities of these analogues were evaluated against three organisms, and biological assays indicated that compounds 5f, 5h and 5u possessed better insecticidal activities against bean aphids (Aphis fabae) than the lead compound spirotetramat. The LC50 of 5f, 5h and 5u against bean aphids reached 0.42, 0.28 and 2.53 mg L(-1) respectively. Moreover, some compounds possessed comparable activities against carmine spider mite (Tetranychus cinnabarinus) and oriental armyworm (Mythimna sepatara) with spirotetramat. The structure-activity relationships (SARs) indicated that the flexible bridge at position C-4 of spirotetramat was important for its bioactivities, and the size of the group at position C-8 would have great influence on the activities. Furthermore, the log P values lower than 6.0 may be favourable for insecticidal activities. CONCLUSION: The present work demonstrates that some spirotetramat analogues can be used as potential lead compounds for developing novel insecticides, and preliminary SAR analysis would provide information for the utilisation of spirotetramat analogues as potential lipid biosynthesis inhibitors. PMID- 23436573 TI - On-line preconcentration and determination of six sulfonylurea herbicides in cereals by MEKC with large-volume sample stacking and polarity switching. AB - A new MEKC method with large-volume sample stacking and polarity switching was developed for on-line preconcentration and detection of sulfonylurea herbicide (SUH) residues in cereals, including nicosulfuron (NS), thifensulfuon (methyl) (TFM), tribenuron-methly (TBM), sulfometuron-methyl (SMM), pyrazosulfuron-ethyl (PSE), and chlorimuron-ethyl (CME). In order to achieve a high resolution and enrichment factor, several parameters were optimized, such as the pH of the running buffer, the concentration of the BGE and the SDS, the separate voltage, the sample size, the pH, and the electrolyte concentration of the sample. The optimal running buffer was composed of 30 mM borate and 80 mM SDS at pH 7.0. The borate concentration in the sample was 30 mM and the pH value of the sample was the same as that of the running buffer. The concentrating voltage and the separating voltage were -15 kV and 15 kV, respectively. The sample size was 1.455 kPa * 780 s (33.11 cm). Under the optimum conditions, for NS, TFM, TBM, SMM, PSE, and CME, the enrichment factors were 613, 642, 835, 570, 709, and 599; the LODs were 0.29-0.50 ng/g, 0.22-0.36 ng/g, 0.60-0.89 ng/g, 0.39-0.72 ng/g, 0.28-0.56 ng/g, and 0.31-0.57 ng/g; the LOQs of six SUHs were all 5 ng/g; the average recoveries of the spiked sample were 86.68-92.99%, 80.73-93.65%, 81.49-94.40%, 82.97-95.1%, 82.96-98.84%, and 80.41-92.94%, respectively. PMID- 23436574 TI - Cancer of mice and men: old twists and new tails. AB - In this review we set out to celebrate the contribution that mouse models of human cancer have made to our understanding of the fundamental mechanisms driving tumourigenesis. We take the opportunity to look forward to how the mouse will be used to model cancer and the tools and technologies that will be applied, and indulge in looking back at the key advances the mouse has made possible. PMID- 23436575 TI - Miscarriage in contemporary maternal-fetal medicine: targeting clinical dilemmas. PMID- 23436576 TI - Comparison between three-dimensional angiographic reconstruction and intravascular ultrasound: imaging of the left main coronary artery. AB - OBJECTIVES: The purpose of this study was to evaluate the left main (LM) coronary artery anatomy using three-dimensional (3D) quantitative coronary angiography (QCA) software as compared to intravascular ultrasound (IVUS). BACKGROUND: Percutaneous intervention of the LM coronary artery is becoming more common in selected patients with LM coronary artery disease (CAD). Quantification of LM CAD by conventional angiography can be difficult. IVUS is considered the gold standard to evaluate LM anatomy and severity of CAD but entails additional steps, catheters, and expertise. Our objective was to compare a novel quantitative angiographic analysis system with IVUS for LM anatomy. METHODS: Fifty five patients underwent both coronary angiography and IVUS of the LM. LM measurements were analyzed with 3D QCA (IC-PRO, Paieon, Israel) software using IVUS as the reference standard. The measurements included proximal, middle, distal minimal luminal diameter (MLD) and area. Additionally, lesion MLD, minimal luminal area were recorded by both systems. Bland-Altman plots were used to investigate agreement between the two imaging systems. RESULTS: Of the 55 patients in our cohort, average age was 66 +/- 11 years (25% female). By Bland-Altman analysis there was very good agreement between 3D QCA and IVUS for measures of MLD and minimal lumen area (MLA). However, there was poor concordance in the estimation of plaque burden between the two methods. CONCLUSIONS: Our data demonstrate that 3D QCA software has fair agreement when compared with IVUS for imaging of LM MLD and MLA. These results suggest that 3D QCA could potentially be helpful to guide intervention of the LM. PMID- 23436577 TI - Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner. AB - Beta2-adrenergic receptor (B2AR) signaling is known to impair Th1-cell differentiation and function in a cAMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-gamma. CD4(+) Foxp3(+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3(+) Treg cells express functional B2AR. B2AR activation in Treg cells leads to increased intracellular cAMP levels and to protein kinase A (PKA)-dependent CREB phosphorylation. We also found that signaling via B2AR enhances the in vitro suppressive activity of Treg cells. B2AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 mRNA levels in responder CD4(+) T cells and improved Treg cell-induced conversion of CD4(+) Foxp3(-) cells into Foxp3(+) induced Treg cells. Moreover, B2AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2AR signaling. PMID- 23436578 TI - Nanomechanics controls neuronal precursors adhesion and differentiation. AB - The ability to control the differentiation of stem cells into specific neuronal types has a tremendous potential for the treatment of neurodegenerative diseases. In vitro neuronal differentiation can be guided by the interplay of biochemical and biophysical cues. Different strategies to increase the differentiation yield have been proposed, focusing everything on substrate topography, or, alternatively on substrate stiffness. Both strategies demonstrated an improvement of the cellular response. However it was often impossible to separate the topographical and the mechanical contributions. Here we investigate the role of the mechanical properties of nanostructured substrates, aiming at understanding the ultimate parameters which govern the stem cell differentiation. To this purpose a set of different substrates with controlled stiffness and with or without nanopatterning are used for stem cell differentiation. Our results show that the neuronal differentiation yield depends mainly on the substrate mechanical properties while the geometry plays a minor role. In particular nanostructured and flat polydimethylsiloxane (PDMS) substrates with comparable stiffness show the same neuronal yield. The improvement in the differentiation yield obtained through surface nanopatterning in the submicrometer scale could be explained as a consequence of a substrate softening effect. Finally we investigate by single cell force spectroscopy the neuronal precursor adhesion on the substrate immediately after seeding, as a possible critical step governing the neuronal differentiation efficiency. We observed that neuronal precursor adhesion depends on substrate stiffness but not on surface structure, and in particular it is higher on softer substrates. Our results suggest that cell substrate adhesion forces and mechanical response are the key parameters to be considered for substrate design in neuronal regenerative medicine. PMID- 23436580 TI - Toll-like receptor 9 activation induces expression of membrane-bound B-cell activating factor (BAFF) on human B cells and leads to increased proliferation in response to both soluble and membrane-bound BAFF. AB - OBJECTIVES: Activation of TLR7 and TLR9 and high serum levels of BAFF have been implicated in the pathogenesis of SLE. However, little is known about the effects of TLR9 activation on BAFF expression by human B cells. We investigated the effect of the TLR9 agonist, CpG-ODN 2006, on the expression of BAFF and its receptors BAFF-R, TACI and BCMA, in isolated B cells from healthy donors. METHODS: We used RT-PCR, flow cytometry and ELISA to investigate the expression of BAFF, and flow cytometry for BAFF-R, TACI and BCMA. Functional assays assessed the responses of resting and CpG-ODN-activated B cells to exogenous soluble and membrane-bound BAFF. RESULTS: CpG-ODN did not induce BAFF secretion, but increased expression of membrane-bound BAFF on B cells. CpG-ODN also induced the expression of TACI and BCMA, but did not up-regulate BAFF-R expression. In functional studies, CpG-ODN sensitized human B cells to proliferate in response to exogenous BAFF. This effect was inhibited by a blocking antibody against BAFF R, but was not inhibited by anti-TACI or anti-BCMA antibodies. Membrane-bound BAFF, induced by CpG-ODN, co-stimulated the proliferation of B cells stimulated with anti-IgM in a manner that was dependent on the expression of surface BAFF on the CpG-ODN-treated B cells. CONCLUSION: TLR9 activation induces expression of membrane-bound BAFF on human B cells and leads to increased proliferation in response to both soluble and membrane-bound BAFF. These data extend our understanding of the role of TLR9 activation on human B cells and provide insights into the mechanisms by which TLR9 may participate in the pathogenesis of SLE. PMID- 23436581 TI - Autoimmune sensorineural hearing loss: the otology-rheumatology interface. AB - Autoimmune sensorineural hearing loss (SNHL) is a rare clinical entity characterized by a progressive fluctuating bilateral asymmetric SNHL that develops over several weeks to months. Vestibular symptoms, tinnitus and aural fullness are present in up to 50% of patients. Due to the lack of specific diagnostic tests, both clinical suspicion and responsiveness to corticosteroids are the pillars for the diagnosis of autoimmune SNHL. The evaluation of patients in whom this condition is suspected should include a detailed history and physical examination, an audiogram, an MRI and a limited laboratory workup to exclude secondary causes of hearing loss. The low frequency of this condition, the heterogeneity in the designs of the available studies and the absence of randomized trials comparing treatment responses and assessing long-term outcomes are some of the factors accounting for the limited evidence to guide the clinician in the approach to the diagnosis and treatment of autoimmune SNHL. PMID- 23436582 TI - Robot-assisted thoracoscopic surgery with simple laparoscopy for diaphragm eventration. AB - Robot-assisted thoracoscopic surgery has been applied for general thoracic operations. Its advantages include not only those of minimally invasive surgery but also those of magnified three-dimensional vision and angulation of the robotic arm. However, there are no direct tactile sensation and force feedback, which can cause unwanted organ damage. We therefore used laparoscopy simultaneously to avoid a blind intraperitoneal area during robotic surgery for diaphragmatic eventration via transthoracic approach and describe the technique herein. PMID- 23436579 TI - Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts. AB - Osteoclasts are multinucleated myeloid lineage cells formed in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL) by fusion of bone marrow-derived precursors that circulate in the blood and are attracted to sites of bone resorption in response to factors, such as sphingosine-1 phosphate signaling. Major advances in understanding of the molecular mechanisms regulating osteoclast functions have been made in the past 20 years, mainly from mouse and human genetic studies. These have revealed that osteoclasts express and respond to proinflammatory and anti-inflammatory cytokines. Some of these cytokines activate NF-kappaB and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) signaling to induce osteoclast formation and activity and also regulate communication with neighboring cells through signaling proteins, including ephrins and semaphorins. Osteoclasts also positively and negatively regulate immune responses and osteoblastic bone formation. These advances have led to development of new inhibitors of bone resorption that are in clinical use or in clinical trials; and more should follow, based on these advances. This article reviews current understanding of how bone resorption is regulated both positively and negatively in normal and pathologic states. PMID- 23436583 TI - Alternative surgical approach to treat aortic arch aneurysm after ascending aortic replacement with hybrid prosthesis. AB - We present a surgical technique to treat the distal aortic arch in patients who previously underwent ascending aortic replacement using the frozen elephant trunk. After debranching of the epiaortic vessels using a custom-made four-branch graft and systemic cooling, the extracorporeal circulation is interrupted, maintaining antegrade cerebral perfusion through the four-branch prosthesis. Then the "old" Dacron prosthesis, previously implanted for the ascending aortic replacement, is partially incised at its distal end, leaving a margin of prosthesis anastomosed to the native distal aorta, and the E-vita stent-graft is deployed under direct vision. Then the two margins of the "old" Dacron and the new Dacron E-vita prosthesis (Jotec Inc., Hechingen, Germany) are sutured together with one suture line to guarantee sealing and reconstruction of the aorta. This technique presents several advantages: the discrepancy between the graft size and the native aortic diameter is avoided, performing the anastomosis between two prosthetic materials with similar diameters is easier; there is no risk of tears in the diseased native aortic wall and related bleeding; and finally, it is easier to perform the anastomosis at the level of the ascending aorta rather than at the distal arch, especially when the disease of the aorta is extended to the descending segment. PMID- 23436585 TI - Bioluminescent microcapsules: applications in activating a photosensitizer. AB - Bioluminescent microcapsules uploading D-luciferin have been fabricated by using the covalent assembly of firefly luciferase and alginate dialdehyde through a layer-by-layer technique. Such assembled microcapsules can produce visible light in the region of 520-680 nm, which can activate the photosensitizers rose bengal (RB) and hypocrellin B (HB) after adding ATP. The microcapsules uploading photosensitizers (RB or HB) have an obvious property to prevent the proliferation of tumor cells in the dark. The assembled bioluminescent microcapsules can be potentially used as photon donors for bioimaging, ATP detection, and photodynamic therapy. PMID- 23436584 TI - Long-term regional control in the observed neck following definitive chemoradiation for node-positive oropharyngeal squamous cell cancer. AB - Traditionally, patients treated with chemoradiotherapy for node-positive oropharyngeal squamous cell carcinoma (N+ OPSCC) have undergone a planned neck dissection (ND) after treatment. Recently, negative post-treatment positron emission tomography (PET)/computed tomography (CT) imaging has been found to have a high negative predictive value for the presence of residual disease in the neck. Here, we present the first comprehensive analysis of a large, uniform cohort of N+ OPSCC patients achieving a PET/CT-based complete response (CR) after chemoradiotherapy, and undergoing observation, rather than ND. From 2002 to 2009, 302 patients with N+ OPSCC treated with 70 Gy intensity-modulated radiation therapy and concurrent chemotherapy underwent post-treatment clinical assessment including PET/CT. CR was defined as no evidence of disease on clinical examination and post-treatment PET/CT. ND was reserved for patients with =1 of the following: exam consistent with occlusive arterial injury, use of an anticoagulant within 48 hr of catheterization to restore or maintain patency of the artery, or documented occlusive arterial injury by radiologic study. RESULTS: 3,254 patients had 5,715 catheterization procedures, which included 3,859 arterial access events. 167 cases of AOAI were identified for an overall prevalence of 4.3% among arterial access events. Multiple logistic regression identified independent risk factors: weight category [<4 kg: odds ratio (OR) 4.5 (95% CI: 2.6-7.7), P < 0.001; 4-6 kg: OR 2.1 (1.3-3.5), P = 0.002, compared to 6-8 kg referent group]; largest catheter outer diameter French size [OR 1.6 (1.3-1.9), P < 0.001]; final activated clotting time (ACT) <250 sec [OR 1.9 (1.4-2.7), P < 0.001]; and need for arterial catheter exchange [OR 1.8 (1.02-3.2), P = 0.04]. CONCLUSIONS: AOAI occurred in 4.3% of pediatric cardiac catheterizations, and was most likely in smaller children and those with larger arterial catheters. Risk was also independently increased by arterial catheter exchange and having a final ACT <250 sec. These data act as an important benchmark and identify areas for intervention for future studies. PMID- 23436594 TI - Horse passports: FVE calls for a European register. PMID- 23436597 TI - Tackling TB and other challenges in Wales. AB - Christianne Glossop, the Chief Veterinary Officer for Wales, discusses the TB eradication programme in Wales, some of the other disease challenges being faced, and how thoughts are turning to how to replace the Animal Health and Welfare Strategy for Great Britain, which is due to come to an end in 2014. PMID- 23436599 TI - Canine atopic dermatitis - what have we learned? AB - Canine atopic dermatitis is a complex multifactorial disease. Here, Tim Nuttall, Maarja Uri and Richard Halliwell, representing three generations of veterinary dermatologists, describe the research underpinning our understanding of the condition and highlight its relevance to clinical practice. PMID- 23436600 TI - Progressive control of equine infectious anaemia through more accurate diagnosis. PMID- 23436601 TI - A review of RSPCA research into wildlife rehabilitation. AB - Wildlife rehabilitation is defined as 'the treatment and temporary care of injured, diseased, and displaced indigenous animals, and the subsequent release of healthy animals to appropriate habitats in the wild' (Miller 2012). Vets are frequently presented with wildlife casualties and although there are a number of texts available to help vets with the treatment of wild animals, such as the BSAVA Manual of Wildlife Casualties (Mullineaux and others 2003) and papers produced by experienced wildlife vets (eg, Bexton and Couper 2010, Couper and Bexton 2012), there still remains questions regarding which individual animals can, or should, be treated, which animals will survive treatment and which animals will survive after they have been released back to the wild. The RSPCA believes that the welfare of wildlife casualties can be improved by investigating which injuries or illnesses are most likely to result in a successful release for each species, and by collecting data on postrelease survivorship. As a result, there have been a number of papers published based on the work of the RSPCA's four wildlife centres: East Winch in Norfolk, Mallydams Wood in East Sussex, Stapeley Grange in Cheshire and West Hatch in Somerset. This paper summarises this research, to guide those in the profession with an interest in this subject to papers that may prove useful to them. PMID- 23436602 TI - Prescription of anthelmintics. PMID- 23436603 TI - Bovine TB: test sensitivity at all cost? PMID- 23436604 TI - Expanding poultry knowledge. PMID- 23436605 TI - Identifying ticks. PMID- 23436606 TI - Investigating causes of death in flatcoated retrievers. PMID- 23436607 TI - Evaluation of antenatal umbilical coiling index at 16-21 weeks of gestation as a predictor of trisomy 21 and other chromosomal defects. AB - OBJECTIVES: To determine whether there is an association between sonographically assessed hyper- or hypocoiling of the umbilical cord and the presence of trisomy 21, to provide reference values for the antenatal umbilical coiling index (aUCI) at a gestational age of 16-21 weeks and to determine whether these measurements are reliable and reproducible. METHODS: This was a prospective study of 737 pregnancies in which the aUCI was measured between 16 and 21 weeks of gestation by ultrasound at the time of amniocentesis. The aUCI was calculated as the reciprocal value of the mean length of one complete coil in centimeters. We created reference curves and studied the relationship with trisomy 21 and other chromosomal defects. In 30 pregnancies we studied the intra- and interobserver variation in measurements using Bland-Altman plots with associated 95% limits of agreement and intraclass correlation coefficients. RESULTS: aUCI was found to be non-linearly related to gestational age at 16-21 weeks and reference curves were created for the mean aUCI and the 2.3(rd) , 10(th) , 90(th) and 97.7(th) percentiles. There was no significant difference in aUCI values between the reference group (n = 714) and cases with trisomy 21 (n = 16) or other aneuploidies (n = 7) (one-way ANOVA, P = 0.716). There was good intra- and interobserver agreement in aUCI measurements. CONCLUSIONS: The aUCI can be measured reliably and varies according to gestational age at 16-21 weeks. The aUCI was not significantly associated with trisomy 21 or other chromosomal defects. PMID- 23436608 TI - Native biomolecules in the gas phase? The case of green fluorescent protein. AB - Green fluorescent protein (GFP) was ionized by native electrospray ionization and trapped for many seconds in high vacuum, allowing fluorescence emission to be measured as a probe of its biological function, to answer the question whether GFP exists in the native form in the gas phase or not. Although a narrow charge state distribution, a collision cross-section very close to that expected for correctly folded GFP, and a large stability against dissociation all support a near-native gas-phase structure, no fluorescence emission was observed. The loss of the native form is attributed to the absence of residual water in the gas phase, which normally stabilizes the para-hydroxybenzylidene imidazolone chromophore of GFP. PMID- 23436609 TI - Sampling stored-product insect pests: a comparison of four statistical sampling models for probability of pest detection. AB - BACKGROUND: Developing sampling strategies to target biological pests such as insects in stored grain is inherently difficult owing to species biology and behavioural characteristics. The design of robust sampling programmes should be based on an underlying statistical distribution that is sufficiently flexible to capture variations in the spatial distribution of the target species. RESULTS: Comparisons are made of the accuracy of four probability-of-detection sampling models - the negative binomial model,(1) the Poisson model,(1) the double logarithmic model(2) and the compound model(3) - for detection of insects over a broad range of insect densities. Although the double log and negative binomial models performed well under specific conditions, it is shown that, of the four models examined, the compound model performed the best over a broad range of insect spatial distributions and densities. In particular, this model predicted well the number of samples required when insect density was high and clumped within experimental storages. CONCLUSIONS: This paper reinforces the need for effective sampling programs designed to detect insects over a broad range of spatial distributions. The compound model is robust over a broad range of insect densities and leads to substantial improvement in detection probabilities within highly variable systems such as grain storage. PMID- 23436610 TI - Cooverexpression of alanine aminotransferase 1 in Chinese hamster ovary cells overexpressing taurine transporter further stimulates metabolism and enhances product yield. AB - Innovation in monoclonal antibody (mAb) production continues to be driven by cell engineering strategies to increase yield and improve product quality. In a previous study, to investigate the effectiveness of transporter overexpression strategies, we prepared a taurine transporter-overexpressing host cell line (DXB11/TAUT) that produced a higher proportion of high-mAb-titer strains than did the parent host cell line. In the current study, we selected a single DXB11/TAUT/mAb1 strain that remained viable for longer (up to 1 month) under common fed-batch culture conditions, and the improvement in viability could be attributed to its improved metabolic properties. It was also more productive (up to >100 pg/cell/day) and yielded more mAb1 (up to 8.1 g/L/31 days) than the parent cell line, and the mAb1 it produced was of comparable quality. These results suggested that this host cell engineering strategy has unique potential for the improvement of mAb-producing Chinese hamster ovary (CHO) cells; for example, it may be appropriate for high cell density perfusion culture. TAUT overexpressing cell lines rapidly accumulated the byproduct alanine, and our challenge in the present study was to apply a strategy for modulating cell metabolism to utilize this byproduct to achieve a high mAb yield in a shorter culture period. To accomplish this, we genetically modified the DXB11/TAUT/mAb1 strain to cooverexpress alanine aminotransferase 1 (ALT1). The resulting DXB11/TAUT/mAb1/ALT1 cooverexpressing strain gave a higher mAb yield in a shorter culture period (5.9 g/L/14 days). It is usually difficult to drive the overexpression of two functional genes while balancing competing goals. However, forced cooverexpression of TAUT and ALT1 in our DXB11/TAUT/mAb1/ALT1 strain resulted in a higher proliferation than the DXB11/TAUT/mAb1 strain, with an ideal balance between cell viability and productivity. Therefore, we have demonstrated a strategy capable of achieving an optimum balance among the goals of cell viability, productivity, and proliferative capacity. PMID- 23436611 TI - A semimechanistic model of the time-course of release of PTH into plasma following administration of the calcilytic JTT-305/MK-5442 in humans. AB - JTT-305/MK-5442 is a calcium-sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT-305/MK-5442 binds to CaSRs, thus preventing receptor activation by Ca(2+) . In the parathyroid gland, this results in the release of parathyroid hormone (PTH). Sharp spikes in PTH secretion followed by rapid returns to baseline are associated with bone formation, whereas sustained elevation in PTH is associated with bone resorption. We have developed a semimechanistic, nonpopulation model of the time-course relationship between JTT-305/MK-5442 and whole plasma PTH concentrations to describe both the secretion of PTH and the kinetics of its return to baseline levels. We obtained mean concentration data for JTT-305/MK-5442 and whole PTH from a multiple dose study in U.S. postmenopausal women at doses of 5, 10, 15, and 20 mg. We hypothesized that PTH is released from two separate sources: a reservoir that is released rapidly (within minutes) in response to reduction in Ca(2+) binding, and a second source released more slowly following hours of reduced Ca(2+) binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (Emax ) functions of JTT-305/MK-5442 concentration. Our model describes both the dose-dependence of PTH time of occurrence for maximum drug concentration (Tmax ) and maximum concentration of drug (Cmax ), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT-305/MK-5442 administration. PMID- 23436613 TI - The assessment of impurities for genotoxic potential and subsequent control in drug substance and drug product. AB - The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data. PMID- 23436614 TI - HOXA9, ISL1 and ALDH1A3 methylation patterns as prognostic markers for nonmuscle invasive bladder cancer: array-based DNA methylation and expression profiling. AB - DNA methylation patterns are associated with the development and prognosis of cancer. The aim of this study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation and RNA expression patterns in samples from long-term follow-up patients with nonmuscle invasive bladder cancer (NMIBC). A total of 187 human bladder specimens were used for microarray array or pyrosequencing (PSQ) analyses: 6 normal controls (NC) and 181 NMIBC. Tumor-specific hypermethylated genes were selected from a data set comprising 24 matched microarray-based DNA methylation and gene expression profiles (6 controls and 18 NMIBC), and their clinical relevance was verified by quantitative PSQ analysis. The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1) and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels and aggressive clinicopathological characteristics. Multivariate regression analyses showed that hypermethylation of these genes was an independent predictor of disease recurrence (HOXA9, ISL1 and ALDH1A3, either alone or in combination) and progression (ISL1 and ALDH1A3, either alone or in combination) (each p < 0.05). The results of this study suggest that these novel methylation markers are independent prognostic indicators in NMIBC patients, which may facilitate the assessment of disease recurrence and progression in NMIBC patients and inform clinical decision making regarding treatment. PMID- 23436617 TI - Overcoming regulatory T-cell suppression by a lyophilized preparation of Streptococcus pyogenes. AB - Cancer vaccines have yet to yield clinical benefit, despite the measurable induction of humoral and cellular immune responses. As immunosuppression by CD4(+) CD25(+) regulatory T (Treg) cells has been linked to the failure of cancer immunotherapy, blocking suppression is therefore critical for successful clinical strategies. Here, we addressed whether a lyophilized preparation of Streptococcus pyogenes (OK-432), which stimulates Toll-like receptors, could overcome Treg-cell suppression of CD4(+) T-cell responses in vitro and in vivo. OK-432 significantly enhanced in vitro proliferation of CD4(+) effector T cells by blocking Treg-cell suppression and this blocking effect depended on IL-12 derived from antigen presenting cells. Direct administration of OK-432 into tumor-associated exudate fluids resulted in a reduction of the frequency and suppressive function of CD4(+) CD25(+) Foxp3(+) Treg cells. Furthermore, when OK-432 was used as an adjuvant of vaccination with HER2 and NY-ESO-1 for esophageal cancer patients, NY ESO-1-specific CD4(+) T-cell precursors were activated, and NY-ESO-1-specific CD4(+) T cells were detected within the effector/memory T-cell population. CD4(+) T-cell clones from these patients had high-affinity TCRs and recognized naturally processed NY-ESO-1 protein presented by dendritic cells. OK-432 therefore inhibits Treg-cell function and contributes to the activation of high-avidity tumor antigen-specific naive T-cell precursors. PMID- 23436618 TI - Textiloma mimicking superior sulcus tumor: positron emission tomography/computed tomography findings of a pseudotumor. AB - We present an interesting case report of a 52-year-old man with a superior sulcus tumor. To evaluate the suspicious left lung tumor, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used. Increased FDG level was indicative of a malignant tumor. Left thoracotomy revealed a textiloma retained during cardiac surgery. PMID- 23436619 TI - Design of libraries targeting protein-protein interfaces. AB - TARGETING PPIS: A novel strategy for designing libraries targeting protein protein interfaces enabled us to identify diverse chemical entry points to interact with therapeutic targets for which conventional screening libraries delivered no or only few hit structures. The concept was experimentally validated by early hit evaluation in biochemical screens and early ADMET profiling. PMID- 23436620 TI - Reply: To PMID 22334169. PMID- 23436621 TI - Assessing internal contamination after the detonation of a radiological dispersion device using a 2x2-inch sodium iodide detector. AB - The detonation of a radiological dispersion device may result in a situation where individuals inhale radioactive materials and require rapid assessment of internal contamination. The feasibility of using a 2*2-inch sodium-iodide detector to determine the committed effective dose to an individual following acute inhalation of gamma-emitting radionuclides was investigated. Experimental configurations of point sources with a polymethyl methacrylate slab phantom were used to validate Monte Carlo simulations. The validated detector model was used to simulate the responses for four detector positions on six different anthropomorphic phantoms. The nuclides examined included (241)Am, (60)Co, (137)Cs, (131)I and (192)Ir. Biokinetic modelling was employed to determine the distributed activity in the body as a function of post-inhalation time. The simulation and biokinetic data were used to determine time-dependent count-rate values at optimal detector locations on the body for each radionuclide corresponding to a target committed effective dose (E50) value of 250 mSv. PMID- 23436622 TI - Analysis of wear, wear particles, and reduced inflammatory potential of vitamin E ultrahigh-molecular-weight polyethylene for use in total joint replacement. AB - Vitamin E (VE) has been added to ultrahigh-molecular-weight polyethylene (UHMWPE) acetabular cups and tibial trays primarily to reduce oxidative damage to the polymer. The aim of this study was to investigate the relative wear rates of UHMWPE-containing VE compared with virgin UHMWPE. The ability of VE to reduce the amount of inflammatory cytokines produced from stimulated peripheral blood mononuclear cells (PBMNCs) was also investigated. Stimulation was achieved by exposure of PBMNCs to either lipoplysaccharide (LPS) or VE-containing UHMWPE (VE UHMWPE). In the present study, results showed that the wear rates of UHMWPE with or without VE were not significantly different. Particles generated by UHMWPE with and without VE were not significantly different in size distribution. The production of osteolytic mediators, tumor necrosis factor-alpha, interleukin 1beta (IL-beta), IL-6, and IL-8 were significantly reduced in (PBMNCs) stimulated with either LPS + VE compared with LPS or VE-UHMWPE particles compared to virgin UHMWPE particles. This trend was also observed when VE was added as a liquid to UHMWPE wear particle-stimulated PBMNCs. The exact mechanism of how VE affects the release of inflammatory mediators from particle-stimulated macrophages is not yet understood. It is likely to involve the anti-inflammatory and/or antioxidant effects of VE. PMID- 23436623 TI - The impact of making weight on physiological and cognitive processes in elite jockeys. AB - PURPOSE: To examine the impact of making weight on aerobic work capacity and cognitive processes in a group of professional jockeys. METHODS: Nine male jockeys and 9 age-, gender-, and BMI-matched controls were recruited to take part in two experimental trials, conducted 48 hr apart. The jockeys were asked to reduce their body mass by 4% in the 48 hr between trials, and controls maintained usual dietary and physical activity habits between trials. Aerobic work capacity was assessed by performance during an incremental cycle ergometer test. Motor response, decision making, executive function, and working memory were assessed using a computerized cognitive test battery. RESULTS: The jockey group significantly reduced their body mass by 3.6 +/- 0.9% (p < .01). Mean urine specific gravity (Usg) readings increased from 1.019 +/- 0.004-1.028 +/- 0.005 (p < .01) following this reduction in body mass. Peak work capacity was significantly reduced between trials in the jockey group (213 +/- 27 vs. 186 +/- 23 W, p < .01), although VO2peak (46.4 +/- 3.7 vs. 47.2 +/- 6.3 ml.kg.min-1) remained unchanged. No changes were identified for any cognitive variable in the jockey group between trials. CONCLUSION: Simulation of race day preparation, by allocating a weight that is 4% below baseline body mass caused all jockeys to report for repeat testing in a dehydrated state, and a reduction in aerobic work capacity, both of which may impact on racing performance. PMID- 23436624 TI - Endovascular revascularization of bald aortic arch for severe cerebral ischemia. AB - Takayasu arteritis is a rare form of chronic, inflammatory arteriopathy affecting the aorta and its major branches. Obstructive lesions of all arch vessels lead to ischemic brain symptoms. There is very limited experience of endovascular revascularization in this situation. We report case of a female patient with potentially life threatening cerebral ischemic symptoms due to extra-cranial occlusion of all arch arteries. Stent supported angioplasty of brachiocephalic, right common carotid and right subclavian artery was successfully performed. This improved her cerebral blood flow and relieved her severe, disabling neurologic symptoms. PMID- 23436625 TI - Mast cell chymase: an indispensable instrument in the pathological symphony of idiopathic pulmonary fibrosis? AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease with no known etiology and treatment options. The hallmarks of the histopathology, which is characteristic of usual interstitial pneumonia (UIP) pattern, include interstitial fibrosis, honeycomb changes and fibroblast foci that develop owing to fibroblast proliferation and excessive matrix deposition. Although the complete pathomechanism is not yet understood, several molecular culprits, including transforming growth factor (TGF)-beta, Angiotensin (Ang) II, endothelin (ET)-1, matrix metalloproteinases (MMPs) and cytokines have been identified. IPF is increasingly believed to be an epithelial-driven disease; however, the literature does support an implication of altered immune response and inflammatory processes in the onset or progression of the disease. Mast cells (MCs) are multifunctional tissue resident cells involved in the inflammatory and immune response. An increasing body of evidence suggests a role of MCs and their mediator chymase in the pathology of IPF. With regard to the underlying mechanisms, it is conceivable that MC chymase may function via activation or processing of factors such as proteases, cytokines and growth factors. In this review, we will discuss how MC chymase is linked to and can potentially contribute to the development of IPF. Moreover, the findings from animal model studies will be discussed to highlight the chymase inhibitors as a promising strategy for the treatment of pulmonary fibrosis. PMID- 23436626 TI - Practical enantioselective arylation and heteroarylation of aldehydes with in situ prepared organotitanium reagents catalyzed by 3-aryl-H8-BINOL-derived titanium complexes. AB - A highly efficient and practical method for the catalytic enantioselective arylation and heteroarylation of aldehydes with organotitanium reagents, prepared in situ by the reaction of aryl- and heteroaryllithium reagents with ClTi(OiPr)3, is described. Titanium complexes derived from DPP-H8 -BINOL (3d; DPP=3,5 diphenylphenyl) and DTBP-H8 -BINOL (3e; DTBP=3,5-di-tert-butylphenyl) exhibit excellent catalytic activity in terms of enantioselectivity and turnover efficiency for the transformation, providing diaryl-, aryl heteroaryl-, and diheteroarylmethanol derivatives in high enantioselectivity at low catalyst loading (0.2-2 mol%). The reaction begins with a variety of aryl and heteroaryl bromides through their conversion into organolithium intermediates by Br/Li exchange with nBuLi, thus providing straightforward access to a range of enantioenriched alcohols from commercially available starting materials. Various 2-thienylmethanols can be synthesized enantioselectively by using commercially available 2-thienyllithium in THF. The reaction can be carried out on a 10 mmol scale at 0.5 mol% catalyst loading, demonstrating its preparative utility. PMID- 23436627 TI - Encoding anatomy: developmental gene regulatory networks and morphogenesis. AB - A central challenge of developmental and evolutionary biology is to explain how anatomy is encoded in the genome. Anatomy emerges progressively during embryonic development, as a consequence of morphogenetic processes. The specialized properties of embryonic cells and tissues that drive morphogenesis, like other specialized properties of cells, arise as a consequence of differential gene expression. Recently, gene regulatory networks (GRNs) have proven to be powerful conceptual and experimental tools for analyzing the genetic control and evolution of developmental processes. A major current goal is to link these transcriptional networks directly to morphogenetic processes. This review highlights three experimental models (sea urchin skeletogenesis, ascidian notochord morphogenesis, and the formation of somatic muscles in Drosophila) that are currently being used to analyze the genetic control of anatomy by integrating information of several important kinds: (1) morphogenetic mechanisms at the molecular, cellular and tissue levels that are responsible for shaping a specific anatomical feature, (2) the underlying GRN circuitry deployed in the relevant cells, and (3) modifications to gene regulatory circuitry that have accompanied evolutionary changes in the anatomical feature. PMID- 23436629 TI - New inputs to midbrain dopaminergic neurons: a new corticobasal ganglia model? PMID- 23436630 TI - Alpha-synuclein inoculation initiates a neurodegenerative cascade in nontransgenic mice. PMID- 23436631 TI - Chediak-Higashi syndrome presenting as young-onset levodopa-responsive parkinsonism. PMID- 23436632 TI - Commentary for "Chediak-Higashi syndrome presenting as young-onset levodopa responsive parkinsonism". PMID- 23436633 TI - The spectrum of cognitive disorders in Parkinson's disease: a data-driven approach. AB - The objective of this study was to identify different cognitive phenotypes in Parkinson's disease (PD) using a data-driven approach. A model-based cluster analysis was conducted on the neuropsychological test results of 558 PD patients from 2 European movement disorder centers (Lille, n = 403; Maastricht, n = 155). The number of clusters was determined according to their clinical relevance as well as on the basis of 3 statistical criteria: the cubic cluster criterion, the pseudo F statistic, and the total squared correlation ratio (R(2)). A factorial discriminant analysis was performed to assess the quality of the cluster's separation. Descriptive variables were used to further characterize the clusters. A 5-cluster model was considered the clinically most relevant. The 5 clusters comprised: (1) cognitively intact patients (19.39%); (2) patients without cognitive deficits but with slight mental slowing (41.29%); (3) patients with slightly impaired overall cognitive efficiency and deficits in all cognitive domains except recognition memory (12.93%); (4) patients with severe mental slowing, impaired overall cognitive efficiency, and severe cognitive impairment in all domains, including memory (23.88%); and (5) patients with very severe impairment in all cognitive domains (2.51%). Cognitively intact patients were significantly younger and had received more years of formal education. Patients in the last 3 clusters had more severe motor symptoms, longer disease duration, and more axial signs. In the last cluster, most patients were demented. Our results confirm the heterogeneity of cognitive presentations in PD, ranging from cognitively intact patients with rather high levels of performance in each cognitive domain to very severely impaired patients. PMID- 23436634 TI - Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation. AB - BACKGROUND: Recently, mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as a novel genetic factor in neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein associated neurodegeneration with brain iron accumulation (MPAN). METHODS/RESULTS: We describe the clinical phenotype and MRI of 3 newly identified individuals with MPAN due to either previously reported or novel homozygous or compound heterozygous genetic alterations in C19orf12. CONCLUSIONS: MPAN is characterized by a juvenile-onset, slowly progressive phenotype with predominant lower limb spasticity, generalized dystonia, and cognitive impairment. Typical additional features include axonal motor neuropathy and atrophy of the optic nerve. MRI showed iron deposition in the globus pallidus and substantia nigra without the eye-of-the-tiger sign, which is typical for PKAN, the most frequent form of NBIA. PMID- 23436635 TI - Atypical parkinsonism due to a D202N Gerstmann-Straussler-Scheinker prion protein mutation: first in vivo diagnosed case. AB - BACKGROUND: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with the Gerstmann Straussler-Scheinker (GSS) disease. METHODS/RESULTS: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome. Dopaminergic medication reduced her symptoms. In addition, punding-like behavior, deficits in organizing daily life and abnormal sleep behavior were reported. Neuropsychological testing, EEG, polysomnography as well as PET imaging with fluorodexyglucose (FDG), [F-18] desmethoxyfallypride (DMFP), and [C-11]-6-OH-BTA-1 (PIB) were not diagnostic. Cerebral spinal fluid analysis revealed no 14-3-3 protein, but elevated neuron specific enolase (NSE) and S100-beta and a very low phospho-tau/total-tau ratio. Analysis of the prion gene disclosed the rare D202N mutation. CONCLUSIONS: The D202N prion mutation has been associated with GSS pathology and up to now was only reported post mortem. Our patient is the very first case diagnosed in vivo. PMID- 23436636 TI - Reply to: Diabetes and risk of Parkinson's disease. PMID- 23436637 TI - Incidence and mortality of obstructive lung disease in rheumatoid arthritis: a population-based study. AB - OBJECTIVE: Pulmonary disease represents an important extraarticular manifestation of rheumatoid arthritis (RA). While the association of RA and interstitial lung disease is widely acknowledged, obstructive lung disease (OLD) in RA is less well understood. We therefore aimed to assess the incidence, risk factors, and mortality of OLD in patients with RA. METHODS: We examined a population-based incident cohort of patients with RA and a comparison cohort of individuals without RA. OLD was defined using a strict composite criterion. Cox proportional hazards models were used to compare OLD incidence between the RA and comparator cohorts to investigate risk factors and to explore the impact of OLD on patient survival. RESULTS: A total of 594 patients with RA and 596 subjects without RA were followed for a mean of 16.3 and 19.4 years, respectively. The lifetime risk of developing OLD was 9.6% for RA patients and 6.2% for subjects without RA (hazard ratio [HR] 1.54, 95% confidence interval [95% CI] 1.01-2.34). The risk of developing OLD was higher among male patients, among current or former smokers, and for individuals with more severe RA. Survival of RA patients diagnosed with OLD was worse compared to those without OLD (HR 2.09, 95% CI 1.47-2.97). CONCLUSION: Patients with RA are at higher risk of developing OLD, which is significantly associated with premature mortality. Effective diagnostic and therapeutic strategies to detect and manage OLD in patients with RA may help to improve survival in these patients. PMID- 23436638 TI - Indications for and efficacy of splenectomy for haematological disorders. AB - BACKGROUND: Splenectomy is performed for a variety of indications in haematological disorders. This study was undertaken to analyse outcomes, and morbidity and mortality rates associated with this procedure. METHODS: Patients undergoing splenectomy for the treatment or diagnosis of haematological disease were included. Indications for operation, preoperative risk, intraoperative variables and short-term outcomes were evaluated. RESULTS: From January 1997 to December 2010, 381 patients underwent splenectomy for diagnosis or treatment of haematological disease. Some 288 operations were performed by an open approach, 83 laparoscopically, and there were ten conversions. Overall 136 patients (35.7 per cent) experienced complications. Postoperative morbidity was predicted by age more than 65 years (odds ratio (OR) 1.63, 95 per cent confidence interval 1.05 to 2.55), a Karnofsky performance status (KPS) score lower than 60 (OR 2.74, 1.35 to 5.57) and a haemoglobin level of 9 g/dl or less (OR 1.74, 1.09 to 2.77). Twenty four patients (6.3 per cent) died within 30 days of surgery. Postoperative mortality was predicted by a KPS score lower than 60 (OR 16.20, 6.10 to 42.92) and a platelet count of 50,000/ul or less (OR 3.34, 1.25 to 8.86). The objective of the operation was achieved in 309 patients (81.1 per cent). The success rate varied for each indication: diagnosis (106 of 110 patients, 96.4 per cent), thrombocytopenia (76 of 115, 66.1 per cent), anaemia (10 of 16, 63 per cent), to allow further treatment (46 of 59, 78 per cent) and primary treatment (16 of 18, 89 per cent). CONCLUSION: Splenectomy is an effective procedure in the diagnosis and treatment of haematological disease in selected patients. PMID- 23436639 TI - Ranking solvent interactions and dielectric constants with [Pt(mesBIAN)(tda)]: A cautionary tale for polarity determinations in ionic liquids. AB - The solvatochromic properties of [Pt(mesBIAN)(tda)] are studied in traditional molecular solvents and ionic liquids and duly compared along established empirical solvent parameter scales. The charge-transfer absorption band of [Pt(mesBIAN)(tda)] is determined to be primarily dependent upon solvent acidity and dipolarity. Notably, ionic liquids do not obey the same well-behaved trend as molecular solvents, highlighting the complexity and domain (nano)segregation inherent to ionic liquids. PMID- 23436640 TI - Performance comparison of two novel combinative particle-size-reduction technologies. AB - The nanosizing of poorly soluble drugs as a formulation strategy can eventually enhance their dissolution rate and bioavailability. Standard comminution techniques such as high-pressure homogenization (HPH) or wet bead milling have limitations in reaching the desired mean particle size. Combinative methods have been developed to overcome these limitations. Combinations of a bottom-up step (freeze-drying or spray drying) with HPH (the so-called H 96 and H 42 technologies, respectively) are examples of combinative particle-size-reduction technologies. The precipitation step modifies the drug structure to obtain a brittle starting material for the following homogenization process. Previous experiments using the H 96 technology have shown a relation between the bottom-up conditions and the final particle size after the top-down step. Employing the H 42 process, the poorly soluble drug glibenclamide was dissolved in ethanol, containing different amounts of surfactant. The drug solution was then spray dried. Subsequently, the drug powders were homogenized using the HPH technique. The nanosuspensions produced with the spray-dried powders (high drug concentrations, standard surfactant concentration) had a smaller particle size and a narrower size distribution compared with the unmodified drug. The best sample had a 236 nm mean particle size (observed using photon correlation spectroscopy) and laser diffractometry values of 0.131 um (D50) and 0.285 um (D90) after 20 cycles of homogenization. The results were compared with the reduction effectiveness of a previous study employing the H 96 combinative process. Both combinative technologies can be successfully applied for the production of very small drug nanocrystals. PMID- 23436641 TI - Sensitive capillary electrophoretic profiling of nicotine and nornicotine in mushrooms with amperometric detection. AB - A highly sensitive capillary electrophoretic profiling of nicotine (NIC) and nornicotine (NNIC) was developed and applied to mushrooms with amperometric detection (AD). Effects of the experimental factors including detection potential, separation parameters, and sample pretreatment conditions were investigated. Under the optimal conditions, the electrophoretic analysis of NIC and NNIC was achieved within 8 min on a pencil carbon disc working electrode at 0.95 V, which was lower than those reported previously. Good calibration curves were obtained in 0.01-2.0 MUg/mL and 0.02-3.0 MUg/mL with the LOD of 2 ng/mL and 5 ng/mL for NIC and NNIC, respectively. The feasibility of the resultant method was verified. Average recoveries of different fortified levels ranged in 80.7 86.0% and 94.0-98.6% for NNIC and NIC were gained, respectively. Applied to a range of mushrooms (Boletus edulis and Lentinus edodes), the NIC contained naturally was successfully found in the level of 19.71-79.20 MUg/kg. The results obtained with CE-AD method were acceptable and close to that of HPLC-MS. PMID- 23436642 TI - Epithelial control of the human pDC response to extracellular bacteria. AB - Plasmacytoid pre-dendritic cells (pDCs) are specialized in responding to nucleic acids, and link innate with adaptive immunity. Although the response of pDCs to viruses is well established, whether pDCs can respond to extracellular bacteria remains controversial. Here, we demonstrate that extracellular bacteria such as Neisseria meningitidis, Haemophilus influenzae, and Staphylococcus aureus activate pDCs to produce IFN-alpha, TNF-alpha, IL-6, and to upregulate CD86 expression. We observed that pDCs were present within tonsillar crypts and oro nasopharyngeal epithelium, where they may contact extracellular bacteria, in situ. Tonsil epithelium-conditioned supernatants inhibited IFN-alpha, TNF-alpha, and IL-6 triggered by the direct contact of N. meningitidis or S. aureus with pDCs. However, pDC priming of naive T cells was not affected, suggesting that tonsil epithelium micro-environment limits local inflammation while preserving adaptive immunity in response to extracellular bacteria. Our results reveal an important and novel function of pDCs in the initiation of the mucosal innate and adaptive immunity to extracellular bacteria. PMID- 23436643 TI - Model selection in competing risks regression. AB - In the analysis of time-to-event data, the problem of competing risks occurs when an individual may experience one, and only one, of m different types of events. The presence of competing risks complicates the analysis of time-to-event data, and standard survival analysis techniques such as Kaplan-Meier estimation, log rank test and Cox modeling are not always appropriate and should be applied with caution. Fine and Gray developed a method for regression analysis that models the hazard that corresponds to the cumulative incidence function. This model is becoming widely used by clinical researchers and is now available in all the major software environments. Although model selection methods for Cox proportional hazards models have been developed, few methods exist for competing risks data. We have developed stepwise regression procedures, both forward and backward, based on AIC, BIC, and BICcr (a newly proposed criteria that is a modified BIC for competing risks data subject to right censoring) as selection criteria for the Fine and Gray model. We evaluated the performance of these model selection procedures in a large simulation study and found them to perform well. We also applied our procedures to assess the importance of bone mineral density in predicting the absolute risk of hip fracture in the Women's Health Initiative Observational Study, where mortality was the competing risk. We have implemented our method as a freely available R package called crrstep. PMID- 23436644 TI - Little orphan's nanny: where do genes come from and who takes care of them? PMID- 23436645 TI - Seasonal mortality patterns in primates: implications for the interpretation of dental microwear. AB - The microscopic traces of use wear on teeth have been extensively studied to provide information that will assist in elucidating the dietary habits of extinct hominin species. It has been amply documented that dental microwear provides information pertaining to diet for living animals, where there is a strong and consistent association between dental microwear patterns and different types of foods that are chewed. The details of occlusal surface wear patterns are capable of distinguishing among diets when the constituent food items differ in their fracture properties. For example, the microwear traces left on the teeth of mammals that crush hard, brittle foods such as nuts are generally dominated by pits, whereas traces left on the teeth of mammals that shear tough items such as leaves tend to be characterized by scratches. These microwear features result from and thus record actual chewing events. As such, microwear patterns are expected to be variably ephemeral, as individual features are worn away and replaced or overprinted by others as the tooth wears down in subsequent bouts of mastication. Indeed, it has been demonstrated, both in the laboratory and the wild, that short-term dietary variation can result in the turnover of microwear. Because occlusal microwear potentially reflects an individual's diet for a short time (days, weeks, or months, depending on the nature of the foods being masticated), tooth surfaces sampled at different times will display differences that relate to temporal (for example, seasonal) differences in diet. PMID- 23436646 TI - Pandora's growing box: Inferring the evolution and development of hominin brains from endocasts. AB - The brain of modern humans is an evolutionary and developmental outlier: At birth, it has the size of an adult chimpanzee brain and expands by a factor of 2 during the first postnatal year. Large neonatal brain size and rapid initial growth contrast with slow maturation, which extends well into adolescence. When, how, and why this peculiar pattern of brain ontogeny evolved and how it is correlated with structural changes in the brain are key questions of paleoanthropology. Because brains and their ontogenies do not fossilize, indirect evidence from fossil hominin endocasts needs to be combined with evidence from modern humans and our closest living relatives, the great apes. New fossil finds permit a denser sampling of hominin endocranial morphologies along ontogenetic and evolutionary time lines. New brain imaging methods provide the basis for quantifying endocast-brain relationships and tracking endocranial and brain growth and development noninvasively. Combining this evidence with ever-more detailed knowledge about actual and fossil "brain genes," we are now beginning to understand how brain ontogeny and structure were modified during human evolution and what the adaptive significance of these modifications may have been. PMID- 23436647 TI - Low weight as an independent risk factor for adverse events during cardiac catheterization of infants. AB - BACKGROUND: Studies have documented the importance of procedure type and hemodynamic variables on the incidence of procedure related adverse events (AE) after cardiac catheterization. However, little is known about the impact of low weight on the incidence and severity of AE. METHODS: Data were prospectively collected using a multicenter registry (C3PO). Infants <1 year were divided into four weight categories: <2 kg, 2-3 kg, 3-5 kg, >=5 kg. AE severity was classified as level 1-5 (none, minor, moderate, major, death). RESULTS: Eight centers submitted details on 3,679 cases (34% diagnostic) performed in infants <1 year from 2/07 to 6/10: <2 kg: 57 (1.5%), 2-3 kg: 403 (11%), 3-5 kg: 1,527 (41.5%), >=5 kg: 1,692 (46%). AE occurred in 20% of cases (<2 kg: 28%, 2-3 kg: 25%, 3-5 kg: 23%, >=5 kg: 16%) with 41% of all AE being level 3-5 AE. Death occurred more frequently in the <2 kg group (12%), 71% of which were interventional cases. The case-related mortality in all other weight groups was <1%. By multivariable analysis, weight <2 kg, 2-3 kg, and 3-5 kg were independent risk factors for high severity (level 3-5) AE (<2 kg: OR 2, 95%CI 1.1-3.6; 2-3 kg: OR 1.4, 95%CI 1-1.8; 3-5 kg: OR 1.3, 95%CI 1.1-1.5), with similar findings for all AE. Blood transfusions were more common in lower weight categories (<2 kg: 42%, 2-3 kg: 29%, 3-5 kg: 25%, >=5 kg: 15%, p<0.001). CONCLUSIONS: The risk of AE during cardiac catheterization of infants increases with lower weight. Infants who weigh less than 2 kg have a significantly higher risk of adverse events (most notably death) even after correcting for hemodynamic vulnerability and procedure type risk group. PMID- 23436648 TI - Exertional hyperckemia might be the first manifestation of a genetic disorder. PMID- 23436649 TI - Effect of dietary antioxidants, training, and performance correlates on antioxidant status in competitive rowers. AB - The beneficial effects of exercise and a healthy diet are well documented in the general population but poorly understood in elite athletes. Previous research in subelite athletes suggests that regular training and an antioxidant-rich diet enhance antioxidant defenses but not performance. PURPOSE: To investigate whether habitual diet and/or exercise (training status or performance) affect antioxidant status in elite athletes. METHODS: Antioxidant blood biomarkers were assessed before and after a 30-min ergometer time trial in 28 male and 34 female rowers. The antioxidant blood biomarkers included ascorbic acid, uric acid, total antioxidant capacity (TAC), erythrocyte- superoxide dismutase, glutathione peroxidase (GPx), and catalase. Rowers completed a 7-d food diary and an antioxidant-intake questionnaire. Effects of diet, training, and performance on resting biomarkers were assessed with Pearson correlations, and their effect on exercise-induced changes in blood biomarkers was assessed by a method of standardization. RESULTS: With the exception of GPx, there were small to moderate increases with exercise for all markers. Blood resting TAC had a small correlation with total antioxidant intake (correlation .29; 90% confidence limits, +/-.27), and the exercise-induced change in TAC had a trivial to small association with dietary antioxidant intake from vitamin C (standardized effect .19; +/-.22), vegetables (.20; +/-.23), and vitamin A (.25; +/-.27). Most other dietary intakes had trivial associations with antioxidant biomarkers. Years of training had a small inverse correlation with TAC (-.32; +/-.19) and a small association with the exercise-induced change in TAC (.27; +/-.24). CONCLUSION: Training status correlates more strongly with antioxidant status than diet does. PMID- 23436650 TI - The discovery of novel human androgen receptor antagonist chemotypes using a combined pharmacophore screening procedure. AB - Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a distinct mechanism of action or binding mode from those of bicalutamide and hydroxyflutamide, which are currently in clinical use. For that reason, the second-generation anti-androgen MDV3100 was developed. MDV3100, however, shares its 4-cyano-3-(trifluoromethyl)phenyl group with bicalutamide and hydroxyflutamide required for binding to the AR. In this work, we used a combined strategy to find new antagonist structures distinct from the 4-cyano-3 (trifluoromethyl)phenyl group to avoid cross-resistance for these compounds and to find structures without agonist activity on mutant ARs (AR W741C and AR T877A). We found two novel chemotypes with AR-antagonistic activity (IC(50): 3-6 MUM) by virtual screening and confirmed their biological activity in an androgen responsive reporter assay. The design of our computational approach was validated by the observation of strongly decreased or absence of agonistic activity on the two mutant ARs. Further structural derivatization to optimize the potency of these compounds can render these chemotypes into very promising, alternative AR antagonists for prostate cancer therapy. PMID- 23436651 TI - Insights into the field carcinogenesis of ovarian cancer based on the nanocytology of endocervical and endometrial epithelial cells. AB - Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late-stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at-risk women as they preferentially target low-grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (Ld ). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in Ld (% fold-increase > 50%, p value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with micro-RNA expression data. PMID- 23436652 TI - Structural and functional characterization of K339T substitution identified in the PB2 subunit cap-binding pocket of influenza A virus. AB - Influenza virus RNA-dependent RNA polymerase is a heterotrimer composed of PA, PB1, and PB2 subunits. RNA-dependent RNA polymerase is required for both transcription and replication of influenza viral RNA taking place in the nucleus of infected cells. A "cap-snatching" mechanism is used to generate a 5'-capped primer for transcription in which the cap-binding domain of PB2 (PB2cap) captures the 5' cap of the host pre-mRNA. Our statistical analysis of PB2 sequences showed that residue Lys(339) located in the cap-binding pocket of H5N1 PB2cap was gradually replaced by Thr(339) over the past decade. To understand the role of this amino acid polymorphism, we solved the crystal structures of PB2cap with or without a pre-mRNA cap analog, m(7)GTP, in the presence of Lys(339) or Thr(339). The structures showed that Lys(339) contributes to binding the gamma-phosphate group of m(7)GTP, and the replacement of Lys(339) by Thr eliminates this interaction. Isothermal titration calorimetry analysis showed that Thr(339) attenuated the PB2cap cap binding activity in vitro compared with Lys(339). Further functional studies confirmed that Thr(339)-PB2-containing ribonucleoprotein complex has a reduced influenza polymerase activity and RNA synthesis activity, and a reconstituted H5N1 virus containing the Thr(339) substitution exhibited a lower virulence to mice but more active replication in Madin-Darby canine kidney cells. The K339T substitution in the cap-binding pocket of PB2 modulates the polymerase activity and virulence by regulating the cap binding activity. It is informative to track variations in the cap-binding pocket of PB2 in surveillance of the evolution and spread of influenza virus. PMID- 23436653 TI - New insights into DNA recognition by zinc fingers revealed by structural analysis of the oncoprotein ZNF217. AB - Classical zinc fingers (ZFs) are one of the most abundant and best characterized DNA-binding domains. Typically, tandem arrays of three or more ZFs bind DNA target sequences with high affinity and specificity, and the mode of DNA recognition is sufficiently well understood that tailor-made ZF-based DNA-binding proteins can be engineered. We have shown previously that a two-zinc finger unit found in the transcriptional coregulator ZNF217 recognizes DNA but with an affinity and specificity that is lower than other ZF arrays. To investigate the basis for these differences, we determined the structure of a ZNF217-DNA complex. We show that although the overall position of the ZFs on the DNA closely resembles that observed for other ZFs, the side-chain interaction pattern differs substantially from the canonical model. The structure also reveals the presence of two methyl-pi interactions, each featuring a tyrosine contacting a thymine methyl group. To our knowledge, interactions of this type have not previously been described in classical ZF-DNA complexes. Finally, we investigated the sequence specificity of this two-ZF unit and discuss how ZNF217 might discriminate its target DNA sites in the cell. PMID- 23436654 TI - Specific interaction of the transcription elongation regulator TCERG1 with RNA polymerase II requires simultaneous phosphorylation at Ser2, Ser5, and Ser7 within the carboxyl-terminal domain repeat. AB - The human transcription elongation regulator TCERG1 physically couples transcription elongation and splicing events by interacting with splicing factors through its N-terminal WW domains and the hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II through its C-terminal FF domains. Here, we report biochemical and structural characterization of the C-terminal three FF domains (FF4-6) of TCERG1, revealing a rigid integral domain structure of the tandem FF repeat that interacts with the hyperphosphorylated CTD (PCTD). Although FF4 and FF5 adopt a classical FF domain fold containing three orthogonally packed alpha helices and a 310 helix, FF6 contains an additional insertion helix between alpha1 and alpha2. The formation of the integral tandem FF4-6 repeat is achieved by merging the last helix of the preceding FF domain and the first helix of the following FF domain and by direct interactions between neighboring FF domains. Using peptide column binding assays and NMR titrations, we show that binding of the FF4-6 tandem repeat to the PCTD requires simultaneous phosphorylation at Ser(2), Ser(5), and Ser(7) positions within two consecutive Y(1)S(2)P(3)T(4)S(5)P(6)S(7) heptad repeats. Such a sequence-specific PCTD recognition is achieved through CTD-docking sites on FF4 and FF5 of TCERG1 but not FF6. Our study presents the first example of a nuclear factor requiring all three phospho-Ser marks within the heptad repeat of the CTD for high affinity binding and provides a molecular interpretation for the biochemical connection between the Ser(7) phosphorylation enrichment in the CTD of the transcribing RNA polymerase II over introns and co-transcriptional splicing events. PMID- 23436655 TI - Structure of a complex phosphoglycan epitope from gp72 of Trypanosoma cruzi. AB - The parasitic protozoan organism Trypanosoma cruzi is the causative agent of Chagas disease. The insect vector-dwelling epimastigote form of the organism expresses a low abundance glycoprotein associated with the flagellum adhesion zone, called gp72. The gp72 glycoprotein was first identified with an anti carbohydrate IgG3 monoclonal antibody called WIC29.26 and has been shown to have an unusual sugar composition. Here, we describe a new way to isolate the WIC29.26 carbohydrate epitope of gp72. Using (1)H NMR and mass spectrometry before and after derivatization, we provide an almost complete primary chemical structure for the epitope, which is that of a complex phosphosaccharide: Galfbeta1 4Rhapalpha1-2Fucpalpha1-4(Galpbeta1-3)(Galpalpha1-2)Xylpbeta1-4Xylpbeta1 3(Xylpbeta1-2Galpalpha1-4(Galpbeta1-3)(Rhapalpha1-2)Fucpalpha1-4)GlcNAcp, with phosphate attached to one or other of the two Galp terminal residues and in which all residues are of the d-absolute configuration, except for fucose and rhamnose which are l. Combined with previous data (Haynes, P. A., Ferguson, M. A., and Cross, G. A. (1996) Glycobiology 6, 869-878), we postulate that this complex structure and its variants lacking one or more residues are linked to Thr and Ser residues in gp72 via a phosphodiester linkage (GlcNAcpalpha1-P-Thr/Ser) and that these units may form phosphosaccharide repeats through GlcNAcpalpha1-P-Galp linkages. The gp72 glycoprotein is associated with the flagellum adhesion zone on the parasite surface, and its ligation has been implicated in inhibiting parasite differentiation from the epimastigote to the metacyclic trypomastigote stage. The detailed structure of the unique phosphosaccharide component of gp72 reported here provides a template for future biosynthetic and functional studies. PMID- 23436657 TI - Ocular-side lateralization of adult-type chromatophore precursors: development of pigment asymmetry in metamorphosing flounder larvae. AB - The adult-type chromatophores of flounder differentiate at metamorphosis in the skin of ocular side to establish asymmetric pigmentation. In young larva and before metamorphosis, adult-type melanophores that migrate to the ocular side during metamorphosis reside at the base of the dorsal fin as latent precursors. However, the migration route taken by these precursor cells and the mechanisms by which lateralization and asymmetric pigmentation develop on the ocular side are unknown. To further investigate this migration and lateralization, we used in situ hybridization with gch2 probe, a marker for melanoblasts and xanthoblasts (precursors of adult type chromatophores), to examine the distribution of chromatophore precursors in metamorphosing larvae. The gch2-positive precursors were present in the myoseptum as well as in the skin. This finding indicated that these precursors migrated from the dorsal part of the fin to the skin via the myoseptum. Additionally, there were much fewer gch2-positive cells in the myoseptum of the blind side than in the skin and myoseptum of the ocular side, and this finding indicated either that migration of the precursor cells into the myoseptum of blind side was inhibited or that the precursors were eliminated from the myoseptum of the blind side. Therefore, we propose that the signals responsible for development of asymmetric pigmentation in flounder reside not only in the skin but on a larger scale and in multiple tissues throughout the lateral half of the trunk. PMID- 23436658 TI - Focus on emergency 2013. PMID- 23436656 TI - The overexpression of hypomethylated miR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2). AB - MicroRNAs are involved in regulating the biology of cancer cells, but their involvement in chemoresistance is not fully understood. We found that miR-663 was up-regulated in our induced multidrug-resistant MDA-MB-231/ADM cell line and that this up-regulation was closely related to chemosensitivity. In the present study, we aimed to clarify the role of miR-663 in regulating the chemoresistance of breast cancer. MicroRNA microarray and quantitative RT-PCR assays were used to identify differentially expressed microRNAs. Cell apoptosis was evaluated by annexin V/propidium iodide staining, TUNEL, and reactive oxygen species generation analysis. The expression of miR-663 and HSPG2 in breast cancer tissues was detected by in situ hybridization and immunohistochemistry. The potential targets of miR-663 were defined by a luciferase reporter assay. Bisulfite sequencing PCR was used to analyze the methylation status. We found that miR-663 was significantly elevated in MDA-MB-231/ADM cells, and the down-regulation of miR-663 sensitized MDA-MB-231/ADM cells to both cyclophosphamide and docetaxel. The overexpression of miR-663 in breast tumor tissues was associated with chemoresistance; in MDA-MB-231 cells, this chemoresistance was accompanied by the down-regulation of HSPG2, which was identified as a target of miR-663. MDA-MB 231/ADM contained fewer methylated CpG sites than its parental cell line, and miR 663 expression in MDA-MB-231 cells was reactivated by 5-aza-29-deoxycytidine treatment, indicating that DNA methylation may play a functional role in the expression of miR-663. Our findings suggest that the overexpression of hypomethylated miR-663 induced chemoresistance in breast cancer cells by down regulating HSPG2, thus providing a potential target for the development of an microRNA-based approach for breast cancer therapy. PMID- 23436659 TI - Effects of isolation rooms on the prevalence of hospital acquired pneumonia in a respiratory ICU. AB - BACKGROUND: The incidence of hospital acquired pneumonia (HAP) varies according to the type of intensive care units (ICUs). AIM: The aims of this study were to determine the frequency of hospital acquired pneumonia (HAP) and the effect of isolation rooms on the frequency of pneumonia in the ICU. MATERIALS AND METHODS: The present investigation was carried out between January 2004 and July 2008. The ICU, which was 4-bed ward-type between January 2004 and February 2006 (1st period), was reconfigured as isolated rooms with only 2 beds each after March 2006 (2nd period). 153 and 379 patients were followed up in the ICU in the 1st and 2nd periods, respectively. Blood, sputum, and deep tracheal aspiration cultures were used for the isolation of the causative agents. RESULTS: No significant difference was detected between the general characteristics of patients. HAP developed in 101 patients (19%). The prevalence of HAP was 22.9% in the 1st period and 17.4% in the 2nd period. During the 1st and 2nd periods, the HAP infection densities were 22.2 and 16.1/1000 patient-days and the ventilator associated pneumonia densities were 48.1 and 37.6/1000 ventilator-days, respectively. Eighty-six percent of HAP was ventilator-associated pneumonia (VAP). CONCLUSIONS: Isolation rooms in the ICU may be an effective strategy to control and decrease the rate of pneumonia in the ICU in addition to other preventive strategies. PMID- 23436660 TI - An evaluation of cases of pneumonia that occurred secondary to hydrocarbon exposure in children. AB - OBJECTIVE: Hydrocarbon pneumonia is distinct among the types of childhood pneumonia in that it has a different pathogenesis and treatment and is preventable. In this study, the cases of 54 children with hydrocarbon pneumonia admitted to the Dicle University Medical Faculty Pediatric Chest Diseases Unit between the years 2006 and 2010 were analyzed retrospectively. PATIENTS AND METHODS: The medical records of 54 patients diagnosed with pneumonia after ingesting/inhaling hydrocarbons were analyzed retrospectively. Age, sex, presenting symptoms, clinical status, radiological and laboratory findings and response to treatment and prognosis were noted. RESULTS: 35 (64.8%) of the patients were male, 19 (35.2%) were female and the ages of the patients ranged from 1 to 5 with an average of 2.49 +/- 0.80. The etiologies of the pneumonia were thinner (33%), naphta (3.7%) and kerosene. In 49 of the patients (90.7%), the symptoms started to occur the day the patient was exposed to hydrocarbons. The average length of hospital stay was 4.0 +/- 2.3 days. Six patients were treated in the intensive care unit (ICU), and one patient with hydrocarbon pneumonia due to kerosene ingestion died. Inhaled corticosteroids were administered to 18 patients who were progressively deteriorating and inhaled salbutamol was given to 16 patients with bronchospasm. Patients with radiological findings on their chest X-rays and auscultatory findings were found to have longer hospital stays (p < 0.05). CONCLUSIONS: To prevent chemical pneumonia, precautions must be taken to stop children under 5 years of age from using/abusing chemical substances. Although some cases of chemical pneumonia lead to death, with diligent care and treatment, the outcomes are promising. The patients in this study group responded well to treatment with inhaled corticosteroids and salbutamol. PMID- 23436661 TI - Prevention of acute renal failure post-contrast imaging in cardiology: a randomized study. AB - BACKGROUND: The contrast-induced nephropathy (CIN) is the third most common cause of acute renal failure (ARF) and the worsening in a pre-existing chronic renal failure (CRF), with a foreseeable increase of morbidity, mortality, length of the stay in hospital and, as a consequence, of the health costs. We studied the effectiveness of N-acetylcysteine (NAC) associated with sodium bicarbonate (Na2HCO3) infusion in order to prevent CIN in patients undergoing coronary angiography with administration of contrast medium. MATERIALS AND METHODS: 296 patients with indication to perform coronary angiography were included in a randomized, observational study. All patients were randomly assigned to receive pre- and post-contrast hydration with 1500 ml of 0.9% saline solution infusion (Group A) or NAC (1200 mg * 2 days) + Na2HCO3 (Group B). The primary end-point was to examine CIN appearance, defined as a raise in serum values of Cr (Creatinine) >= 0.5 mg/dl or >= 25% within 24-72 hours after the exposure to the contrast medium. RESULTS: It has been observed a frequency of CIN of 9.4% in Gr. A compared to 7.2% in Gr. B. Nevertheless, when we put these results through a more accurate screening according to gender, degree of raise in creatinine levels and the extent of change in GFR (glomerular filtration rate), we observed a very different behaviour. In patients with normal Cr and CrCl (Clearance of Creatinine) the frequency of CIN was similar in both group A and B (approximately 5%). In patients with normal Cr but reduced ClCr the use of NAC was more effective than hydration in preventing CIN (0% vs 18% in prevalence respectively in B and A group). In patients with moderately reduced Cr and CrCl, hydration with saline solution was more effective than NAC + Na2HCO3 (8.6% vs 17.6%) while in patients with severe CRF the combined use of NAC + Na2HCO3 showed off to be very successful in preventing CIN compared to the merely hydration (0% vs 50%). CONCLUSIONS: In patients affected by severe CRF who are undergoing investigations with contrast medium administration, such as coronary angiography, the combined use of NAC + Na2HCO3 infusion significantly reduces the risk of developing CIN. In other circumstances the final result is related to the degree of previous GFR or creatinine values alteration or to gender. In such situations the combined use of both substances is more questionable and sometimes ineffective. PMID- 23436662 TI - Assessment of baseline characteristics and risk factors among Emergency Department patients presenting with recent onset atrial fibrillation: a retrospective cohort study. AB - BACKGROUND: The Cardioversion of Atrial Fibrillation in Emergency (CAFE) study was an observational, retrospective, multicenter study focusing on patients with recent onset atrial fibrillation (AF) seen in six different Emergency Departments (ED) of Rome, Italy. AIM: The aim of this study was to present the baseline characteristics and risk factors of the patients enrolled to the CAFE study. MATERIALS AND METHODS: We retrospectively reviewed 3085 eligible patients diagnosed with recent onset AF in any of the EDs between January 2008 and December 2009. Inclusion criteria required documented ICD-9 primary discharge/admission diagnosis of AF in the ED and stable hemodynamic conditions at presentation (systolic blood pressure > 90 mmHg). Exclusion criteria were permanent AF or an ongoing acute coronary syndrome. RESULTS: Median age was 71 years (interquartile ranges, 62-78 years) and 50.8% were men. Palpitations was the most common symptom at ED presentation and was present in 73.5% of the study subjects. Hypertension was the most prevalent comorbidity, affecting 59.3% of the patients evaluated, and the presence of previous episode(s) of AF was also common (52.3%). Regarding home treatment, the drugs most prescribed were antiplatelets (31.2%) and diuretics (25.2%). A CHADS2 score of 0 was found in 814 patients (26.4%), while a CHADS2 score of 1 was reported in 1114 patients (36.1%). Finally, a CHADS2 score >= 2 was reported in 1157 patients (37.5%). CONCLUSIONS: The present study represents an important snapshot of demographics, comorbidities, risk factors and anticoagulation management about patients with recent onset AF. Disparities were noted in anticoagulation management, suggesting that this is still a main problem among patients with AF. PMID- 23436663 TI - Therapeutic effect of magnesium sulphate on carbon monoxide toxicity-mediated brain lipid peroxidation. AB - BACKGROUND: Carbon monoxide (CO) toxicity primarily results from cellular hypoxia caused by impedance of oxygen delivery. Studies show that CO may cause brain lipid peroxidation and leukocyte-mediated inflammatory changes in the brain. AIM: The aim of this study was to investigate whether magnesium sulphate could prevent or diminish brain lipid peroxidation caused by carbon monoxide toxicity in rats. MATERIALS AND METHODS: Fourty rats were divided into five groups of 8 rats each. Group l was not received any agent during the experiment. Group 2 was inhaled CO gas followed by intraperitoneally normal saline 30 minutes (min) later. Group 3 was inhaled CO gas followed by 100 mg/kg magnesium sulphate intraperitoneally 30 min later. Group 2 and Group 3 rats was undergone laparotomy and craniotomy while still under anesthesia at 6 hour, and tissue sample was obtained from the cerebrum. Group 4 was inhaled CO gas followed by intraperitoneally normal saline 30 min later. Group 5 was inhaled CO gas followed by 100 mg/kg magnesium sulphate intraperitoneally 30 min later. Group 4 and Group 5 rats was undergone laparotomy and craniotomy while still under anesthesia at 24 hour, and tissue sample was obtained from the cerebrum. RESULTS: Nitric oxide levels were no significantly different between all groups. Malonyldialdehyde levels increased in intoxication group (group 2) and decreased in treatment group (group 3). Activities of superoxide dismutase decreased in intoxication group (group 2) and increased in treatment group (group 3). Activities of catalase increased in intoxication group (group 2) and decreased in treatment group (group 3). Activities of glutathione peroxidase (GSH-Px) decreased in intoxication group (group 4) and increased in treatment group (group 5). CONCLUSIONS: CO poisoning caused significant damage, detected within the first 6 hours. Due to antioxidant enzymes, especially GSH-Px activity reaching the top level within 24th hours, significant oxidative damage was not observed. The protective effect against oxidative damage of magnesium sulfate has been identified within the first 6 hours. PMID- 23436664 TI - Myocardial toxicity of acute promyelocytic leukaemia drug-arsenic trioxide. AB - BACKGROUND: Arsenic trioxide (As2O3) is an environmental toxicant as well as an effective anti cancer agent against many types of cancers. It is a promising drug for patients with relapsed acute promyelocytic leukaemia (APL), but its clinical efficacy is burdened by the serious cardiac toxicities. AIM: The present study was designed to investigate the toxic mechanism of arsenic in cardiac tissue at its clinically relevant concentrations. MATERIALS AND METHODS: Experimental rats were administered with As2O3 2, 4 and 8 mg/kg body weight, orally for a period of 45 days. Cardiac toxicities were recorded by lipid peroxidation, activities of glutathione dependent antioxidant and antiperoxidative enzymes, cardiac arsenic accumulation and histopathological changes. RESULTS: In vivo studies revealed a significant rise in lipid peroxidation, decline in reduced glutathione, glutathione dependent antioxidant enzymes and antiperoxidative enzymes in the cardiac tissue of arsenic treated rats. The extent of free radical production was found increased with periodic rise in the arsenic concentration. The experimental group which received 8 mg/kg body weight of arsenic exhibited the highest deposition of arsenic in cardiac tissue. Light microscopic examination of cardiac tissues in arsenic treated rats has showed increased structural abnormalities like myocardial fibre swelling, capillary congestion and micro-haemorrhages. CONCLUSIONS: The study concludes that the mechanism of arsenic induced cardiac toxicity is associated with the accumulation of arsenic in tissue and the extent of free radical production. PMID- 23436665 TI - Incidence, clinical features and management of acute allergic reactions: the experience of a single, Italian Emergency Department. AB - OBJECTIVES: Few data on the incidence, aetiology, clinical features and management of patients with acute allergic reactions presenting to the Emergency Department are currently available. The aim of the study was to report the annual experience of a single Italian adult Emergency Department about anaphylaxis. PATIENTS AND METHODS: This is a retrospective, case-based study of adult patients attending the Emergency Department in Alessandria, Italy, during the years 2009 2010. We evaluated the medical records of patients satisfying diagnostic codes involving acute allergic reactions. Incidence, demographic data, causative agents, clinical features, management and outcome were reported. RESULTS: 390 patients with acute allergic reactions were evaluated during the year, corresponding to 0.7% of all Emergency Department visits. Causative agents were recognized in 55.1% of patients and more commonly included drugs (26.9%), insects (14.8%) and foods (8.9%). Cutaneous features were the single most common clinical presentation although two or more clinical features were frequently reported (17.7%). Anaphylaxis was diagnosed in 4.6% of patients. After therapy and a period of monitoring, 92.8% of patients were discharged directly from the Emergency Department, 7.0% were admitted and one patient died, corresponding to a fatality rate of 0.2%. CONCLUSIONS: Acute allergic reactions are common diseases referring to our Emergency Department. In the half of cases a precipitant agent was identified and cutaneous and/or mucosal changes were often the first feature. Most patients were definitely treated and discharged but about 7.0% of patients required hospitalisation. Observation Unit and Intermediate Care Unit were essential for clinical management of these patients. PMID- 23436666 TI - Metformin-associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review. AB - BACKGROUND: Metformin is known to be rarely associated with lactic acidosis, a serious condition with a poor prognosis. AIM: To review the National Pharmacovigilance Network of the Italian Medicines Agency reporting cases of metformin-associated lactic acidosis. MATERIALS AND METHODS: The National Pharmacovigilance Network of the Italian Medicines Agency, was searched for cases of lactic acidosis that occurred in a 10 years period (from November 2001 to October 2011). Data were analyzed, to identify associated clinical features. A systematic literature research was performed to identify other large case series on metformin associated lactic acidosis. RESULTS: Metformin was the antidiabetic drug most frequently associated with lactic acidosis in the assessed period. Metformin-associated lactic acidosis was the most frequent serious adverse reaction related to metformin reported to the national authority (18.2% of all 650 adverse drug reactions reported). There were 59 cases of metformin-associated lactic acidosis (mortality rate of 25.4%). In most patients (89.8%) there was at least one risk factor for the occurrence of lactic acidosis. The predictors of death were low arterial blood pH and absence of acute renal failure. The systematic research of the literature identified only six case-series with more than 30 patients. CONCLUSIONS: This is the second largest case series ever reported on metformin-associated lactic acidosis. We confirmed that this rare complication of metformin is frequently fatal. Death can be predicted when the patient arrive in the hospital with low pH and, not intuitively, if the patient has no acute kidney injury. Risk minimisation measures taken at national level to prevent this serious complication are described. PMID- 23436667 TI - Some psychological characteristics of adolescents hospitalized following a suicide attempt. AB - BACKGROUND: In most countries, suicide is second or third leading cause of death in youth. Suicidal tendencies among youth have been the subject of extensive research. Reports of increased rate of suicide attempts in the past few decades indicate that this phenomenon has not been fully understood. AIM: The aim of this study was to better understand the phenomenon of adolescent suicide behavior by defining some specific psychological characteristics of adolescents who were hospitalized at the psychiatric ward because of the suicide attempt. METHODS: 62 participants were assigned to two groups: clinical (adolescents who were hospitalized after a suicide attempt) and non-clinical (adolescents without psychiatric symptoms). They filled in a series of instruments: a questionnaire examining adolescents' demographic characteristics, Rosenberg's Self-Esteem Scale, Youth Self Report. RESULTS: Compared to the non-clinical populaton adolescents attempting suicide had significantly more frequent suicidal thoughts (chi2 = 18.627, df = 1, p < .01), higher incidence of earlier attempts (chi2 = 10.008, df = 1, p < .01), they abused substances more often (chi2 = 7.398, df=1, p < .01), had higher incidence of fathers' psychopathology (chi2 = 11.77, df = 1, p < .01), lower level of self-esteem (t = 4.23, p < .01), and more significant expression of internalized (F/1.60/ = 19.02; p < .01) as well as externalized problems (F/1.60/ = 4.41; p < .05). CONCLUSIONS: This study point to some of the characteristics of adolescents who were hospitalized after a suicide attempt. PMID- 23436668 TI - Psychiatric emergencies (part I): psychiatric disorders causing organic symptoms. AB - Psychiatric emergencies are conditions that mostly destabilize the already frenetic activity of the Emergency Department. Sometimes the emergency is clearly referable to primitive psychiatric illness. Other times, psychiatric and organic symptoms can independently coexist (comorbidity), or develop together in different conditions of substance abuse, including alcohol and prescription drugs. Differentiating between substance induced and pre-existing psychiatric disorder (dual diagnosis) may be difficult, other than controversial issue. Finally, an organic disease can hide behind a psychiatric disorder (pseudopsychiatric emergency). In this review (part I), psychiatric disorders that occur with organic symptoms are discussed. They include: (1) anxiety, conversion and psychosomatic disorders, and (2) simulated diseases. The physiologic mechanisms of the stress reaction, divided into a dual neuro-hormonal response, are reviewed in this section: (1) activation of the sympathetic nervous system and adrenal medulla with catecholamine production (rapid response), and (2) activation of the hypothalamic-pituitary-adrenal axis with cortisol production (slow response). The concept of the fight-or-flight response, its adaptive significance and the potential evolution in paralyzing response, well showing by Yerkes-Dodson curve, is explained. Abnormal short- and long-term reactions to stress evolving toward well codified cluster of trauma and stressor related disorders, including acute stress disorder, adjustment disorder and post traumatic stress disorder, are examined. A brief review of major psychiatric disorder and related behaviour abnormalities, vegetative symptoms and cognitive impairment, according to DMS IV-TR classification, are described. Finally, the reactive psychic symptoms and behavioral responses to acute or chronic organic disease, so called "somatopsychic disorders", commonly occurring in elderly and pediatric patients, are presented. The specific conditions of post-operative and intensive care unit patients, and cancer and HIV positive population are emphasized. PMID- 23436669 TI - Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases. AB - BACKGROUND: In this Part II psychiatric disorders coexisting with organic diseases are discussed. "Comorbidity phenomenon" defines the not univocal interrelation between medical illnesses and psychiatric disorders, each other negatively influencing morbidity and mortality. Most severe psychiatric disorders, such as schizophrenia, bipolar disorder and depression, show increased prevalence of cardiovascular disease, related to poverty, use of psychotropic medication, and higher rate of preventable risk factors such as smoking, addiction, poor diet and lack of exercise. Moreover, psychiatric and organic disorders can develop together in different conditions of toxic substance and prescription drug use or abuse, especially in the emergency setting population. Different combinations with mutual interaction of psychiatric disorders and substance use disorders are defined by the so called "dual diagnosis". The hypotheses that attempt to explain the psychiatric disorders and substance abuse relationship are examined: (1) common risk factors; (2) psychiatric disorders precipitated by substance use; (3) psychiatric disorders precipitating substance use (self-medication hypothesis); and (4) synergistic interaction. Diagnostic and therapeutic difficulty concerning the problem of dual diagnosis, and legal implications, are also discussed. Substance induced psychiatric and organic symptoms can occur both in the intoxication and withdrawal state. Since ancient history, humans selected indigene psychotropic plants for recreational, medicinal, doping or spiritual purpose. After the isolation of active principles or their chemical synthesis, higher blood concentrations reached predispose to substance use, abuse and dependence. Abuse substances have specific molecular targets and very different acute mechanisms of action, mainly involving dopaminergic and serotoninergic systems, but finally converging on the brain's reward pathways, increasing dopamine in nucleus accumbens. The most common substances producing an addiction status may be assembled in depressants (alcohol, benzodiazepines, opiates), stimulants (cocaine, amphetamines, nicotine, caffeine, modafinil), hallucinogens (mescaline, LSD, ecstasy) and other substances (cannabis, dissociatives, inhalants). Anxiety disorders can occur in intoxication by stimulants, as well as in withdrawal syndrome, both by stimulants and sedatives. Substance induced mood disorders and psychotic symptoms are as much frequent conditions in ED, and the recognition of associated organic symptoms may allow to achieve diagnosis. Finally, psychiatric and organic symptoms may be caused by prescription and doping medications, either as a direct effect or after withdrawal. Adverse drug reactions can be divided in type A, dose dependent and predictable, including psychotropic drugs and hormones; and type B, dose independent and unpredictable, usually including non psychotropic drugs, more commonly included being cardiovascular, antibiotics, anti-inflammatory and antineoplastic medications. PMID- 23436670 TI - Psychiatric emergencies (part III): psychiatric symptoms resulting from organic diseases. AB - An exhaustive review on the organic illnesses presenting with psychiatric manifestations, properly defined pseudopsychiatric emergencies, is presented. A systematic classification of the numerous organic causes of psychiatric disorders, based on authors' experience and literature revision, is carefully analysed, and their suitable diagnostic management in emergency setting is proposed. Moreover, the role of bedside ultrasonography in Emergency Department is emphasized. The underlying pathogenetic mechanisms are separately discussed. A particular significance is given to "neuropsychological studies", displaying the complex connection between the central nervous system and the endocrine system. The role of immune system in influencing the central nervous system, explaining the model of "sickness behaviour" in inflammatory disease, is also described, according to recent reports of "psychoneuroimmunology". Moreover, the immune-mediated mechanism explaining how neoplasm can influence brain function in the "paraneoplastic syndromes" is shown. In order to facilitate the teaching method, organic illnesses presenting with acute psychic manifestations or mimicking specific psychiatric disorders are subdivided into three groups: (1) Endocrine and metabolic disorders and deficiency states; (2) Internal diseases; (3) Neurologic disorders. PMID- 23436671 TI - Recurrent use of the Emergency Department in patients with anxiety disorder. AB - OBJECTIVE: Panic disorder is characterized by the spontaneous and unexpected occurrence of panic attacks. During panic attacks, patients (pts) refer to the Emergency Department (ED). The diagnostic work-up for any panic attack is expensive since symptoms at presentation mimic other diseases such acute coronary syndrome or neurological emergencies. The aim of the present study was to describe a 10 years cohort of pts diagnosed with panic disorder in the ED in terms of ED visit recurrence. METHODS: Case-control study, in a tertiary care, involving pts presenting to the ED and diagnosed with panic attack according to the International Classification of Diseases 9nt Revision (ICD-9). From January 2001 to Dec 2009 were extracted from the electronic clinical database 469 pts and were divided into "recurrent ED visit" (multiple ED access for panic attack) (N=361) and "no recurrent ED visit" (only one ED access for panic attack in 9 years) (N=108). RESULTS: At univariate analysis cases and controls differed for male prevalence (p < 0.01), neurological symptoms at presentation (p = 0.02) and history of other psychiatry disorder (p < 0.01). In multivariate analysis independent predictors were male gender, age under 40 year old, palpitations at presentations, 1 or more cardiovascular risk factors and previous other psychiatry conditions. CONCLUSIONS: Male under 40 years old with palpitations or cardiovascular risk and other psychiatric diseases, have a higher recurrence of panic attacks. General psychiatric evaluation and treatment with benzodiazepine in ED is not useful to prevent recurrences. Identifying those patients at high risk of panic attack and ED visit recurrence might be useful to establish ad-hoc interventions, improve patients' morbidity and save precious resources. PMID- 23436672 TI - Peripheral neuropathy after burn injury. AB - OBJECTIVES: Peripheral neuropathy is a well-documented disabling sequela of major burn injury. These lesions are associated with both thermal and electrical injuries that may be frequently undiagnosed or overlooked in clinical settings. The purpose of this study was to evaluate the prevalence of burn-related neuropathy in our database and to investigate the clinical correlates for both mononeuropathy and generalized peripheral polyneuropathy. PATIENTS AND METHODS: Out of 648 burn patients, admitted to our clinic forty-seven burn patients with the diagnosis of peripheral neuropathy were evaluated retrospectively. The demographic and clinical data collected were gender, age, degree, site and percent surface area of burn, type of burn, and the results of electrodiagnostic examination, including electromyography and nerve conduction assessments and associated pathology if existed. RESULTS: Peripheral neuropathy is the most frequent disabling neuromuscular complication of burn, that may be undiagnosed or overlooked. In current study, peripheral neuropathy associated with burn all of our patients were identified by electrodiagnostic study. After treatment in Burn Unit, clinical and electrodiagnostic studies were applied. Motor and sensory distal latencies were prolonged and sensory nerve action potentials reduced in amplitude. CONCLUSIONS: The findings of our study have shown that polyneuropathies and axonal neuropathy were more frequent than mononeuropathy and demyelination. PMID- 23436673 TI - Current practice and recent advances in pediatric pain management. AB - BACKGROUND: Differently from the adult patients, in pediatric age it is more difficult to assess and treat efficaciously the pain and often this symptom is undertreated or not treated. In children, selection of appropriate pain assessment tools should consider age, cognitive level and the presence of eventual disability, type of pain and the situation in which it is occurring. Improved understanding of developmental neurobiology and paediatric analgesic drugs pharmacokinetics should facilitate a better management of childhood pain. AIM: The objective of this review is to discuss current practice and recent advances in pediatric pain management. METHODS: Using PubMed we conducted an extensive literature review on pediatric pain assessment and commonly used analgesic agents from January 2000 to January 2012. CONCLUSIONS: A multimodal analgesic regimen provides better pain control and functional outcome in children. Cooperation and communication between the anaesthesiologist, surgeon, and paediatrician are essential for successful anaesthesia and pain management. PMID- 23436674 TI - Sigmoid colon torsion: mortality and relevant risk factors. AB - INTRODUCTION: Sigmoid volvulus is an important acute intestinal obstruction, leading to high mortality and requiring urgent operation. The purpose of this study is to analyze risk factors for mortality in patients that were operated on due to sigmoid volvulus at our Department. MATERIALS AND METHODS: The retrospective study included 158 patients, who were operated on due to sigmoid volvulus between January 1994-December 2010, in terms of age, gender, complaints at admission, physical signs, period of symptoms before admission, associated diseases, laboratory and radiological parameters, hospital stay, morbidity, and mortality. RESULTS: The study consisted of 135 men (85.4%) and 23 women (14.6%), with a mean age of 62.54 years. Cardiovascular disease and respiratory disease were present in 34 (21.5%) and 42 (26.6%) patients, respectively. Urgent operation was undertaken in 125, while 33 received elective surgery. Abdominal distension and pain was evident in all the patients. Generalized tenderness was detected in 58.2%, while 70.9% had hyperactive bowel sound with tympanism. Plain radiograph revealed an impression of "omega ans" in all patients, while free air was detected in 11.4% of them. Risk factors for mortality included age (p = 0.008), delayed admission (p = 0.001), cardiovascular and respiratory diseases (p = 0.001), fluid-electrolyte imbalance (p =0.001), presence of necrosis (p = 0.001), and major contamination (p = 0.001). Wound infection and intraabdominal abscess were more common in patients that developed mortality (p = 0.001 and p = 0.002). CONCLUSIONS: Complications like wound infection and intraabdominal abscess are more frequent in the patients with the risk of mortality. Delayed admission results in higher risk of mortality. Mortality rates can be reduced by early admission, preoperative intensive resuscitation, suitable antibiotics, and emergent and viable surgery. PMID- 23436675 TI - Procalcitonin variations after Emergency Department admission are highly predictive of hospital mortality in patients with acute infectious diseases. AB - BACKGROUND AND AIM: To evaluate the diagnostic and prognostic usefulness of procalcitonin (PCT) in patients admitted to the Emergency Department (ED) with signs of infections and to assess the prognostic value of repeated measurements in predicting hospital mortality. MATERIALS AND METHODS: A prospective, observational study was conducted in our 400-bed General Teaching Hospital. 261 patients arriving in ED with signs/symptoms of infection were enrolled. PCT was performed upon arrival in the ED (T0), and 5 days after antibiotic therapy (T5). Blood cultures were performed in all patients upon arrival in the ED. RESULTS: Mean T0 PCT value was 7.1+/-17.9 ng/ml, and at T5 3+/-9.1 ng/ml (p < 0.0001). Mean PCT in septic non-survivors was increased at T5 compared to T0 but not significantly. The PCT increase at T5 was an independent factor of mortality (OR = 1.29, p < 0.02) in septic patients. Compared to baseline mean delta % PCT decrease at T5 was 28%. Patients with a decrease delta % PCT > 28% showed a lower number of deaths, with a statistical significant difference if compared to those patients with a < 28% decrease (p < 0.004). ROC curve of delta % PCT for prediction of death has an AUC = 0.82 (p < 0.03). CONCLUSIONS: PCT is a useful marker for diagnosis of systemic and local infections, and for prognostic stratification in patients with acute infectious diseases at their arrival in ED. PCT variations after antibiotic therapy are highly predictive for in-hospital mortality. PCT normalization during antibiotic therapy suggests a good response to infection possibly leading to less infection-related deaths. PMID- 23436676 TI - From cyclopropenes to tetrasubstituted furans: tandem isomerization/alkenylation sequence with Cu/Pd relay catalysis. PMID- 23436678 TI - PKC-theta exists in an oxidized inactive form in naive human T cells. AB - PKC-theta plays a central role in TCR-induced IL-2 production and T-cell proliferation. The aim of the present study was to analyse how PKC-theta is regulated in human T cells during T-cell activation and differentiation. We show that PKC-theta is found in a high-molecular disulfide-linked complex in naive T cells, and that PKC-theta most likely is inactive in this form. In parallel with the accumulation of the major redox regulators, glutathione and thioredoxin, PKC theta is gradually reduced to the 82 kDa active form during T-cell activation. We demonstrate that PKC-theta is recruited to the plasma membrane in the disulfide linked form in naive T cells, and that activation of PKC-theta is redox dependent and requires de novo synthesis of glutathione. This is the first study that shows that the activity of PKC-theta is regulated by the intracellular redox state, and that PKC-theta is recruited to the plasma membrane in an inactive form in naive T cells. Our observations underscore the existence of major differences in TCR signaling in naive versus primed T cells. PMID- 23436677 TI - Insight into the sporulation phosphorelay: crystal structure of the sensor domain of Bacillus subtilis histidine kinase, KinD. AB - The Bacillus subtilis KinD signal-transducing histidine kinase is a part of the sporulation phosphorelay known to regulate important developmental decisions such as sporulation and biofilm formation. We have determined crystal structures of the extracytoplasmic sensing domain of KinD, which was copurified and crystallized with a pyruvate ligand. The structure of a ligand-binding site mutant was also determined; it was copurified and crystallized with an acetate ligand. The structure of the KinD extracytoplasmic segment is similar to that of several other sensing domains of signal transduction proteins and is composed of tandem Per-Arnt-Sim (PAS)-like domains. The KinD ligand-binding site is located on the membrane distal PAS-like domain and appears to be highly selective; a single mutation, R131A, abolishes pyruvate binding and the mutant binds acetate instead. Differential scanning fluorimetry, using a variety of monocarboxylic and dicarboxylic acids, identified pyruvate, propionate, and butyrate but not lactate, acetate, or malate as KinD ligands. A recent report found that malate induces biofilm formation in a KinD-dependent manner. It was suggested that malate might induce a metabolic shift and increased secretion of the KinD ligand of unknown identity. The structure and binding assays now suggests that this ligand is pyruvate and/or other small monocarboxylic acids. In summary, this study gives a first insight into the identity of a molecular ligand for one of the five phosphorelay kinases of B. subtilis. PMID- 23436679 TI - Xeroderma pigmentosum genes and melanoma risk. AB - Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility. PMID- 23436680 TI - Protein transduction domain-containing microemulsions as cutaneous delivery systems for an anticancer agent. AB - In this study, we developed cationic microemulsions containing a protein transduction domain (penetratin) for optimizing paclitaxel localization within the skin. Microemulsions were prepared by mixing a surfactant blend (BRIJ:ethanol:propylene glycol 2:1:1, w/w/w) with monocaprylin (oil phase) at 1.3:1 ratio, and adding water at 30% (ME-30), 43% (ME-43), and 50% (ME-50). Electrical conductivity and viscosity measurements indicated that ME-30 is most likely a bicontinuous system, whereas ME-43 and ME-50 are water continuous. Their irritation potential, studied in bioengineered skin equivalents, decreased as aqueous content increased. Because ME-50 was not stable in the presence of paclitaxel (0.5%), ME-43 was selected for penetratin incorporation (0.4%). The microemulsion containing penetratin (ME-P) displayed zeta potential of +5.2 mV, and promoted a 1.8-fold increase in paclitaxel cutaneous (but not transdermal) delivery compared with the plain ME-43, whereas the enhancement promoted by another cationic microemulsion containing phytosphingosine was 1.3-fold. Compared with myvacet oil, ME-P promoted a larger increase on transepidermal water loss (twofold) than the plain or the phytosphingosine-containing microemulsions (1.5 fold), suggesting that penetratin addition increases the barrier-disrupting and penetration-enhancing effects of microemulsions. The ratio Deltacutaneous/Deltatransdermal delivery promoted by ME-P was the highest among the formulations, suggesting its potential for drug localization within cutaneous tumor lesions. PMID- 23436681 TI - Comparison of Cu-ZSM-5 zeolites and Cu-MOF-505 metal-organic frameworks as heterogeneous catalysts for the Mukaiyama aldol reaction: a DFT mechanistic study. AB - The density functional theory (DFT) model ONIOM(M06L/6-311++G(2df,2p):UFF was employed to reveal the catalytic activity of Cu(II) in the paddle-wheel unit of the metal-organic framework (MOF)-505 material in the Mukaiyama aldol reaction compared with the activity of Cu-ZSM-5 zeolites. The aldol reaction between a silyl enol ether and formaldehyde catalyzed by the Lewis acidic site of both materials takes place through a concerted pathway, in which the formation of the C?C bond and the transfer of the silyl group occurs in a single step. MOF-505 and Cu-ZSM-5 are predicted to be efficient catalysts for this reaction as they strongly activate the formaldehyde carbonyl carbon electrophile, which leads to a considerably lower reaction barrier compared with the gas-phase system. Both MOF 505 and Cu-ZSM-5 catalysts stabilize the reacting species along the reaction coordinate, thereby lowering the activation energy, compared to the gas-phase system. The activation barriers for the MOF-505, Cu-ZSM-5, and gas-phase system are 48, 21, and 61 kJ mol(-1) , respectively. Our results show the importance of the enveloping framework by stabilizing the reacting species and promoting the reaction. PMID- 23436682 TI - Antedependence models for nonstationary categorical longitudinal data with ignorable missingness: likelihood-based inference. AB - Time index-ordered random variables are said to be antedependent (AD) of order (p1 ,p2 , ... ,pn ) if the kth variable, conditioned on the pk immediately preceding variables, is independent of all further preceding variables. Inferential methods associated with AD models are well developed for continuous (primarily normal) longitudinal data, but not for categorical longitudinal data. In this article, we develop likelihood-based inferential procedures for unstructured AD models for categorical longitudinal data. Specifically, we derive maximum likelihood estimators (MLEs) of model parameters; penalized likelihood criteria and likelihood ratio tests for determining the order of antedependence; and likelihood ratio tests for homogeneity across groups, time invariance of transition probabilities, and strict stationarity. We give closed-form expressions for MLEs and test statistics, which allow for the possibility of empty cells and monotone missing data, for all cases save strict stationarity. For data with an arbitrary missingness pattern, we derive an efficient restricted expectation-maximization algorithm for obtaining MLEs. We evaluate the performance of the tests by simulation. We apply the methods to longitudinal studies of toenail infection severity (measured on a binary scale) and Alzheimer's disease severity (measured on an ordinal scale). The analysis of the toenail infection severity data reveals interesting nonstationary behavior of the transition probabilities and indicates that an unstructured first-order AD model is superior to stationary and other structured first-order AD models that have previously been fit to these data. The analysis of the Alzheimer's severity data indicates that the antedependence is second order with time-invariant transition probabilities, suggesting the use of a second-order autoregressive cumulative logit model. PMID- 23436683 TI - Meta-analysis of glue versus sutured mesh fixation for Lichtenstein inguinal hernia repair. AB - BACKGROUND: Chronic pain remains a frequent complication after Lichtenstein inguinal hernia repair. As a consequence, mesh fixation using glue instead of sutures has become popular. This meta-analysis aimed to clarify which fixation technique is to be preferred for elective Lichtenstein inguinal hernia repair. METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Articles published between January 1990 and April 2012 were searched for in MEDLINE, Embase and the Cochrane Library. Randomized controlled trials (RCTs) comparing glue and sutured mesh fixation in elective Lichtenstein repair for unilateral inguinal hernia were included. The quality of the RCTs and the potential risk of bias were assessed using the Cochrane risk of bias tool. RESULTS: Of 254 papers found in the initial search, a meta-analysis was conducted of seven RCTs comprising 1185 patients. With the use of glue mesh fixation, the duration of operation was shorter (mean difference -2.57 (95 per cent confidence interval (c.i.) -4.88 to -0.26) min; P = 0.03), patients had lower visual analogue scores for postoperative pain (mean difference -0.75 (-1.18 to -0.33); P = 0.001), early chronic pain occurred less often (risk ratio 0.52, 95 per cent c.i. 0.31 to 0.87; P = 0.01), and time to return to daily activities was shorter (mean difference -1.17 (-2.30 to -0.03) days; P = 0.04). The hernia recurrence rate did not differ significantly. CONCLUSION: Elective Lichtenstein repair for inguinal hernia using glue mesh fixation compared with sutures is faster and less painful, with comparable hernia recurrence rates. PMID- 23436684 TI - A case study of an iron-deficient female Olympic 1500-m runner. AB - This case study examines the impact of low serum ferritin (sFe) on physiological assessment measures and performance in a young female 1500-m runner undertaking approximately 95-130 km/wk training. The study spans 4 race seasons and an Olympic Games. During this period, 25 venous blood samples were analyzed for sFe and hemoglobin (Hb); running economy, VO(2max), and lactate threshold were measured on 6 occasions separated by 8-10 mo. Training was carefully monitored including 65 monitored treadmill training runs (targeting an intensity associated with the onset of blood lactate accumulation) using blood lactate and heart rate. Performances at competitive track events were recorded. All data were compared longitudinally. Mean sFe was 24.5 +/- 7.6 MUg/L (range 10-47), appearing to be in gradual decline with the exception of 2 data points (37 and 47 MUg/L) after parenteral iron injections before championships, when the lowest values tended to occur, coinciding with peak training volumes. Each season, 1500-m performance improved, from 4:12.8 in year 1 to 4:03.5 in year 4. VO(2max) (69.8 +/- 2.0 mL . kg(-1) . min(-1)) and running economy (%VO(2max) at a fixed speed of 16 km/h; max 87.8%, min 80.3%) were stable across time and lactate threshold improved (from 14 to 15.5 km/h). Evidence of anemia (Hb <12 g/dL) was absent. These unique data demonstrate that in 1 endurance athlete, performance can continue to improve despite an apparent iron deficiency. Raising training volume may have caused increased iron utilization; however, the effect of this on performance is unknown. Iron injections were effective in raising sFe in the short term but did not appear to affect the long-term pattern. PMID- 23436685 TI - Reply to Drs. Kurlan, Fasano, and Evans: A clinically useful definition of stereotypies. PMID- 23436686 TI - A comprehensive characterization of membrane vesicles released by autophagic human endothelial cells. AB - The stress status of the apoptotic cell can promote phenotypic changes that have important consequences on the immunogenicity of the dying cell. Autophagy is one of the biological processes activated in response to a stressful condition. It is an important mediator of intercellular communications, both by regulating the unconventional secretion of molecules, including interleukin 1beta, and by regulating the extracellular release of ATP from early stage apoptotic cells. Additionally, autophagic components can be released in a caspase-dependent manner by serum-starved human endothelial cells that have engaged apoptotic and autophagic processes. The nature and the components of the extracellular vesicles released by dying autophagic cells are not known. In this study, we have identified extracellular membrane vesicles that are released by human endothelial cells undergoing apoptosis and autophagy, and characterized their biochemical, ultrastructural, morphological properties as well as their proteome. These extracellular vesicles differ from classical apoptotic bodies because they do not contain nucleus components and are released independently of Rho-associated, coiled-coil containing protein kinase 1 activation. Instead, they are enriched with autophagosomes and mitochondria and convey various danger signals, including ATP, suggesting that they could be involved in the modulation of innate immunity. PMID- 23436687 TI - Risk factors for falls in adults with rheumatoid arthritis: a prospective study. AB - OBJECTIVE: To investigate the association between potential risk factors and falls in community-dwelling adults with rheumatoid arthritis (RA). METHODS: We followed patients for 1 year of followup in a prospective cohort study with monthly falls calendars and telephone calls. Lower extremity muscle strength, postural stability, number of swollen and tender joints, functional status, history of falling, fear of falling, pain, fatigue, medication, and use of steroids were assessed as risk factors for falls. RESULTS: A total of 386 women and 173 men with RA (n = 559) ages 18-88 years completed baseline assessments and 535 participants (96%) completed 1-year followup. Bivariate logistic regression showed that falls risk was not associated with age or sex. Multivariate logistic regression revealed that a history of multiple falls in the previous 12 months was the most significant predictive risk factor (odds ratio [OR] 5.3, 95% confidence interval [95% CI] 2.3-12.3). The most significant modifiable risk factors were swollen and tender lower extremity joints (OR 1.7, 95% CI 1.1-2.7), psychotropic medication (OR 1.8, 95% CI 1.1-3.1), and fatigue (OR 1.13, 95% CI 1.02-1.2). CONCLUSION: Adults with RA are at high risk of falls. In clinical practice, high-risk fall patients with RA can be identified by asking whether patients have fallen in the past year. Important risk factors highlighted in this study include swollen and tender lower extremity joints, fatigue, and use of psychotropic medications. PMID- 23436688 TI - 3-Aryl-4-methyl-2-quinolones targeting multiresistant Staphylococcus aureus bacteria. AB - The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S. aureus strains, and acting as efflux pump inhibitors (EPI). In particular, 5-hydroxy-7 methoxy-4-methyl-3-phenylquinolin-2-one (6 c) presents both an EPI and an antimicrobial effect. Its efficacy and safety make it a potential candidate for further investigations. PMID- 23436689 TI - Bioluminescence determination of active caspase-3 in single apoptotic cells. AB - Caspase-3 is an executive caspase, in the central position within apoptotic machinery. Apoptosis as a way of programmed cell death is a physiological process that plays an essential role in the development and homeostasis maintenance; moreover, its deregulations are linked to tumor progression or various autoimmune disorders. Therefore, an investigation of apoptosis pathways on the level of individual cells is not only of biological but also medical importance. In this work we report on the development of a high-sensitivity instrumentation and protocol for detection of active caspase-3 in individual mammalian apoptotic cells. The technology is based on the specific cleavage of modified luciferin by caspase-3, an immediate bioluminescence reaction of free luciferin with luciferase followed by emissions of photons and their detection by photomultiplier tube working in the photon counting regime. Three different instrumental arrangements are compared for the determination of caspase-3 in free cells or tissue samples. Thus, in our best miniaturized system the mean amount as low as about 6.5 fg corresponding to 122 000 molecules of caspase-3 can be detected in individual apoptotic mouse leg cells. PMID- 23436690 TI - Long-term clinical outcomes after percutaneous coronary intervention for chronic total occlusions in elderly patients (>=75 years): five-year outcomes from a 1,791 patient multi-national registry. AB - OBJECTIVE: To investigate procedural success rates and long-term clinical outcome of percutaneous coronary intervention (PCI) for chronic total occlusions (CTO) in elderly patients. BACKGROUND: Little is known about procedural success and long term clinical outcome of PCI for CTO in the elderly. METHODS: A total of 1,791 consecutive patients with 1,852 CTO underwent PCI at three large centers in USA, Italy, and South Korea. Outcomes included procedural success and major adverse cardiac events (MACE, composite of mortality, myocardial infarction, or coronary artery bypass graft surgery [CABG]).Time-to-event analyses were performed using Kaplan-Meier statistics, and the log-rank statistic was used to test for differences between patients aged >=75 and patients aged <75 years. RESULTS: Two hundred and thirteen patients (12%) were aged >=75 years. Procedural success rates were similar in elderly patients compared with patients <75 years (63.8% vs. 69.1%, P = 0.12). Median follow-up was 890 days (IQR: 380-1,480 days). MACE rates after successful versus failed PCI were 25.8% versus 42.3% in the elderly (P = 0.02) and 11.2 versus 20.8% in younger patients (P < 0.01). In elderly patients, this reduction in MACE after successful PCI was mainly driven by a reduction in CABG (0.0% vs. 20.4%, P < 0.01), there were no significant differences in terms of mortality (19.6% vs. 24.6%, P = 0.13) or MI (11.5% vs. 8.0%, P = 0.87). CONCLUSION: CTO PCI in patients >=75 years has similar success as in patients <75 years. In elderly patients undergoing CTO PCI, MACE rates were relatively high but successful revascularization is associated with a reduction in MACE at 5-year follow-up in both elderly and younger patients. PMID- 23436691 TI - Production of high-purity single-chirality carbon nanotube hybrids by selective polymer exchange. AB - A scalable method to coat monochiral (7,5) semiconducting single-walled carbon nanotubes with a monolayer coating of a range of technologically useful polymers such as poly(3-hexylthiophene) (P3HT) and poly(9,9'-dioctylfluorene-co benzothiadiazole) (F8BT) is presented. Optical spectroscopy and atomic force microscopy measurements show that the semiconducting tube purity (>99%) obtained from the selective wrapping of nanotubes by polymers such as poly(9,9 dioctylfluorenyl-2,7-diyl) (PFO) can be transferred to these other nanotube polymer combinations by polymer exchange. PMID- 23436692 TI - Sports participation of Dutch lower limb amputees. AB - OBJECTIVE: To analyze sports participation of Dutch lower limb amputees and factors influencing sports participation. STUDY DESIGN: A cross-sectional survey was performed. Dutch lower limb amputees (N = 2039) were invited to participate in a postal survey addressing personal and amputation characteristics, physical limitations, sports participation, skin problems, and prosthesis use. Only data concerning personal and amputation characteristics together with the data concerning sports participation were used for this study. RESULTS: Of the 816 questionnaires received, 780 were suitable for statistical analysis. The mean age of the participants was 59.6 years (SD 14.8), 62% were men and 27% of the amputations was due to vascular diseases or diabetes. Only 15% of all respondents participate in sports at least 5 hours a month. Smoking (odds ratio: 0.55), an age older than 60 (odds ratio: 0.97 per year), and a vascular cause of amputation (odds ratio: 0.42) were negatively associated with sports participation. CONCLUSION: Less than 15% of the Dutch lower limb amputees participate in sports at least 5 hours per month. Older age, smoking and a vascular cause of amputation have a negative influence on the sports participation of these individuals. PMID- 23436693 TI - Treadmill training with partial body weight support compared with conventional gait training for low-functioning children and adolescents with nonspastic cerebral palsy: a two-period crossover study. AB - BACKGROUND: Partial body weight-supported treadmill training has been shown to be effective in gait training for patients with neurological disorders such as spinal cord injuries and stroke. Recent applications on children with cerebral palsy were reported, mostly on spastic cerebral palsy with single subject design. There is lack of evidence on the effectiveness of such training for nonspastic cerebral palsy, particularly those who are low functioning with limited intellectual capacity. OBJECTIVES: This study evaluated the effectiveness of partial body weight-supported treadmill training for improving gross motor skills among these clients. STUDY DESIGN: A two-period randomized crossover design with repeated measures. METHODS: A crossover design following an A-B versus a B-A pattern was adopted. The two training periods consisted of 12-week partial body weight-supported treadmill training (Training A) and 12-week conventional gait training (Training B) with a 10-week washout in between. Ten school-age participants with nonspastic cerebral palsy and severe mental retardation were recruited. The Gross Motor Function Measure-66 was administered immediately before and after each training period. RESULTS: Significant improvements in dimensions D and E of the Gross Motor Function Measure-66 and the Gross Motor Ability Estimator were obtained. CONCLUSIONS: Our findings revealed that the partial body weight-supported treadmill training was effective in improving gross motor skills for low-functioning children and adolescents with nonspastic cerebral palsy. . PMID- 23436694 TI - Influence of distance between the rotation axis of back support and the hip joint on shear force applied to buttocks in a reclining wheelchair's back support. AB - PURPOSE: The purpose of this study was to investigate the influence of the distance between the position of the rotation axis of the back support and hip joint on the changes in the shear force applied to the buttocks. STUDY DESIGN: Repeated-measures design. METHODS: The subjects were 11 healthy adult men without leg and/or trunk diseases. The shear force applied to the buttocks was measured using a force plate. This study had three experimental conditions: the position of hip joint was taken as the 3 cm, 6 cm, and 9 cm forward from the standard sitting position. RESULTS: In returning to an upright position of back support, the shear force was 15.0 +/- 2.9 %BW in the 3 cm forward condition, 16.7 +/- 3.6 %BW in the 6 cm forward condition, and 19.5 +/- 5.3 %BW in the 9 cm forward condition. Significant differences appeared between the 9 cm and the other conditions (p < 0.05). CONCLUSIONS: The results of this study suggested that the shear force applied to the buttocks changed in reclining back support and an increase in the distance between the axis of rotation of the back support and hip joint led to an increase in the remaining shear force after reclining the back support. PMID- 23436695 TI - The effect of patellofemoral bracing on walking in individuals with patellofemoral pain syndrome. AB - BACKGROUND: Although knee braces are used by individuals with patellofemoral pain syndrome, the effect of patellofemoral bracing on knee flexion during walking has not been elucidated. AIM: The purpose of this study was to evaluate the effect of patellofemoral bracing on sagittal plane knee joint kinematics and temporal spatial parameters during walking in individuals with patellofemoral pain syndrome. STUDY DESIGN: Quasi-experimental. METHODS: Ten subjects with a diagnosis of patellofemoral pain syndrome were fitted with a knee brace incorporating an infrapatellar strap. Testing was performed at baseline and after 6 weeks of use. Gait analysis and a visual analog scale were used to assess outcomes in this study. RESULTS: A 59.6% decrease in pain was reported by using bracing. Bracing significantly improved speed of walking (p <= 0.001) and step length (p <= 0.001). The mean cadence was also increased following 6 weeks of patellofemoral brace use, but this was not significant (p = 0.077). Knee flexion angles improved during initial contact, loading response, and mid-swing (p <= 0.001) after 6 weeks of patellofemoral brace use. CONCLUSION: Knee orthoses resulted in decreased pain, improved temporal spatial parameters (speed of walking and step length), and increased knee flexion angles during ambulation in patients with patellofemoral pain syndrome. PMID- 23436696 TI - A comparison between the suction suspension system and the hypobaric Iceross Seal In(r) X5 in transtibial amputees. AB - BACKGROUND: The two passive vacuum suspension systems currently available in total surface-bearing sockets are the hypobaric Iceross Seal-In((r)) and the suction suspension system. OBJECTIVES: The purpose of this study was to compare the effect of the hypobaric Iceross Seal-In((r)) liner with that of the suction suspension system for quality of life, pistoning, and prosthesis efficiency in unilateral transtibial amputees. STUDY DESIGN: Single-group repeated measures. METHODS: Ten amputees were enrolled. The pistoning test, used to compare vertical movement of the stump within the socket, and the energy cost of walking test were carried out when the amputees were wearing the suction suspension system and after 2, 5, and 7 weeks of Seal-In(r) X5 use. The Prosthesis Evaluation Questionnaire and the Houghton Scale Questionnaire of perceived mobility and quality of life with the prosthesis, and the Timed Up&Go Test and the Locomotor Capability Index for functional mobility were also administered at the beginning and end of the study. RESULTS: The hypobaric Iceross Seal-In(r) X5 led to significant pistoning reduction and improvement on the Houghton Scale Questionnaire and 3 of 9 domains of the Prosthesis Evaluation Questionnaire. No statistical changes were observed in functional mobility or the energy cost of walking tests. CONCLUSION: Replacing the suction suspension system with the hypobaric Iceross Seal-In(r) X5 improves quality of life in transtibial amputees. PMID- 23436697 TI - Genome-wide analyses on high-grade osteosarcoma: making sense of a genomically most unstable tumor. AB - High-grade osteosarcoma is an extremely genomically unstable tumor. This, together with other challenges, such as the heterogeneity within and between tumor samples, and the rarity of the disease, renders it difficult to study this tumor on a genome-wide level. Now that most laboratories change from genome-wide microarray experiments to Next-Generation Sequencing it is important to discuss the lessons we have learned from microarray studies. In this review, we discuss the challenges of high-grade osteosarcoma data analysis. We give an overview of microarray studies that have been conducted so far on both osteosarcoma tissue samples and cell lines. We discuss recent findings from integration of different data types, which is particularly relevant in a tumor with such a complex genomic profile. Finally, we elaborate on the translation of results obtained with bioinformatics into functional studies, which has lead to valuable findings, especially when keeping in mind that no new therapies with a significant impact on survival have been developed in the past decades. PMID- 23436698 TI - Attenuated TGF-beta1 responsiveness of dendritic cells and their precursors in atopic dermatitis. AB - The responsiveness of DCs and their precursors to transforming growth factor beta1 (TGF-beta1) affects the nature of differentiating DC subsets, which are essential for the severity of atopic dermatitis (AD). To evaluate TGF-beta signaling in monocytes and monocyte-derived DCs of AD patients compared with that of controls, in vitro generated Langerhans cell (LC) like DCs, expression of TGF beta receptors, phospho-Smad2/3 and Smad7 were evaluated. Furthermore, TNF-alpha expression and synergistic effects of TNF-alpha upon TGF-beta signaling and DC generation were evaluated. We found LC-like DC differentiation of monocytes from AD patients in response to TGF-beta1 was remarkably reduced and TGF-beta1 receptor expression was significantly lower compared with that of healthy controls. Attenuated TGF-beta1 responsiveness mirrored by lower phospho-Smad2/3 expression after TGF-beta1 stimulation and higher expression of inhibitory Smad7 was observed in monocytes from AD patients. During DC generation, mRNA expression of Smad7 was relatively higher in LC-like DCs of AD patients. Lower TNF-alpha expression of monocytes from AD patients might further contribute to attenuated TGF-beta signaling in the disease since TNF-alpha had synergistic effects on TGF beta1 signaling and LC generation through mediating the degradation of Smad7. Our results demonstrate alleviated TGF-beta1 signaling together with the amount of soluble co-factors might direct the nature of differentiating DCs. PMID- 23436699 TI - Causes of false-negative sentinel node biopsy in patients with breast cancer. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy has replaced axillary lymph node dissection as the routine staging procedure in clinically node-negative breast cancer. False-negative SLN biopsy results in misclassification and may cause undertreatment of the disease. The aim of this study was to investigate whether serial sectioning of SLNs reveals metastases more frequently in patients with false-negative SLNs than in patients with true-negative SLNs. METHODS: This was a case-control study. Tissue blocks from patients with false-negative SLNs, defined as tumour-positive lymph nodes excised at completion axillary dissection or a subsequent axillary tumour recurrence, were reassessed by serial sectioning and immunohistochemical staining. For each false-negative node, two true-negative SLN biopsies were analysed. Tumour and node characteristics in patients with false negative SLNs were compared with those in patients with a positive SLN by univariable and multivariable regression analysis. RESULTS: Undiagnosed SLN metastases were discovered in nine (18 per cent) of 50 patients in the false negative group and in 12 (11.2 per cent) of 107 patients in the true-negative group (P = 0.245). The metastases were represented by isolated tumour cells in 14 of these 21 patients. The risk of a false-negative SLN was higher in patients with hormone receptor-negative (odds ratio (OR) 2.50, 95 per cent confidence interval 1.17 to 5.33) or multifocal tumours (OR 3.39, 1.71 to 6.71), or if only one SLN was identified (OR 3.57, 1.98 to 6.45). CONCLUSION: SLN serial sectioning contributes to a higher rate of detection of SLN metastasis. The rate of upstaging of the tumour is similar in false- and true-negative groups of patients. PMID- 23436700 TI - Perceived social support in Spanish cancer outpatients with psychiatric disorder. AB - This study examines differences in perceived social support during oncology treatment of cancer patients, whilst taking into account the presence of psychiatric disorder. Of particular interest were cancer patients who received psychopharmacology treatment compared with those who did not. A total of 760 cancer outpatients were recruited from one hospital in Spain. Multivariate analysis of variance with the general linear model procedure was used. The Medical Outcomes Study Social Support Survey was used to assess social support perceived. The Diagnostic Interview Schedule using DSM-III-R criteria was utilized for the diagnosis of psychiatric disorders. There were significant differences between the patients diagnosed with a psychiatric disorder and those not diagnosed with psychiatric disorders in terms of perceived Emotional/Informational Support (F = 19.11, p < 0.01), Affectionate Support (F = 12.30, p < 0.01) and the Overall Support Index (F = 16.73, p < 0.01). In patients requiring psychopharmacology treatment, significant differences were presented with Structural Support (F = 4.32, p < 0.05), Emotional/Informational Support perceived (F = 7.87, p < 0.01), Instrumental Support (F = 4.17, p < 0.05) and Overall Support Index (F = 7.84, p < 0.01). Psychopharmacology treatment helped to increase the perception of social support received by the patient. Healthcare professionals could provide support that would normalize cancer patients' distress, taking into account the importance of perceived social support for the psychological well-being of patients. PMID- 23436702 TI - Molybdenum cofactor deficiency presenting with a parkinsonism-dystonia syndrome. PMID- 23436701 TI - Mass spectrometry-based methods to study protein architecture and dynamics. AB - Mass spectrometry is now an indispensable tool in the armamentarium of molecular biophysics, where it is used for tasks ranging from protein sequencing and mapping of post-translational modifications to studies of higher order structure, conformational dynamics, and interactions of proteins with small molecule ligands and other biopolymers. This mini-review highlights several popular mass spectrometry-based tools that are now commonly used for structural studies of proteins beyond their covalent structure with a particular emphasis on hydrogen exchange and direct electrospray ionization mass spectrometry. PMID- 23436703 TI - Gene-gene-environment interactions between drugs, transporters, receptors, and metabolizing enzymes: Statins, SLCO1B1, and CYP3A4 as an example. AB - Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations. PMID- 23436704 TI - Air-stable bifunctional allylation reagents for the asymmetric synthesis of differentiated syn- and anti-1,3-diols. AB - Turning the diols: Enantiomerically pure bifunctional reagents I and ent-I undergo asymmetric aldehyde allylation followed by Ir(I)-catalyzed enantioselective decarboxylative allylic etherification to give differentiated syn- and anti-1,3-diols with complete control of the absolute and relative stereochemistry (see scheme; PMP = para-methoxyphenyl, dbcot = dibenzo[a,e]cyclooctatetraene, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene). PMID- 23436705 TI - Two systemic lupus erythematosus patients with severe pleurisy: similar presentations, different causes. PMID- 23436706 TI - A concise synthesis of pyrazole analogues of combretastatin A1 as potent anti tubulin agents. AB - Combretastatin A1 (CA1) binds to the beta-subunit at the colchicine binding site of tubulin and inhibits polymerization. As such, it is both an antitumor agent and a vascular disrupting agent. It has been shown to be at least tenfold more potent than combretastatin A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive ortho-quinone species that are assumed to be directly cytotoxic in tumor cells. A series of 3,4-diarylpyrazoles were concisely synthesized, one of which, 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H pyrazol-3-yl]benzene-1,2-diol (27), proved to be a cytotoxic anti-tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and 27, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that 27 retains the ability to form ortho-quinone species, while the pyrazole ring shows high metabolic stability, suggesting that this compound might result in better pharmacokinetic profiles than CA1, with similar pharmacodynamic properties and clinical potential. PMID- 23436707 TI - Optimization of the design and preparation of nanoscale phospholipid bilayers for its application to solution NMR. AB - Despite arduous efforts and recent technological developments structural investigation of integral membrane proteins remains a challenge. The primary deterrents include difficulties with their expression, low inherent solubility, and problems associated with existing membrane mimicking systems. A relatively new class of membrane mimetics, nanodiscs, is emerging as a promising alternative. Although nanodiscs have been proven successful for several biophysical applications, they yet remain to become the system of preferred choice for structure determination. We have hereby made nanodiscs more suitable for solution NMR applications by reducing the diameter of the self-assembly complex to its potential limit. We achieved a noticeable improvement in the quality of NMR spectra obtained for the transmembrane and cytoplasmic domains of integrin alphaIIb incorporated into these smaller discs rendering them susceptible for a thorough structural investigation. In addition, we also present an on-column method for a rapid, efficient, single-step preparation of protein incorporated nanodiscs at high concentrations. These discs have been fully characterized by transmission electron microscopy, dynamic light scattering, and differential scanning calorimetry. PMID- 23436708 TI - Scanning of novel cancer/testis proteins by human testis proteomic analysis. AB - The testes are where spermatogenesis, the sperm-generating process that is unique to men, occurs. Importantly, human spermatogenesis and tumorigenesis share key similarities. Until now, only a few proteins in the human testis have been identified due to limitations of available technology. In this paper, using an advanced proteomics platform, we have identified 7346 unique proteins within the human testis with a high degree of confidence. Immunohistochemistry data from the Human Protein Atlas database show over 90% (1833/2020) of identified proteins can be detected in the human testis using specific antibodies. To make the data widely available to the scientific community, an online Human Testis Proteome Database (HTPD, http://reprod.njmu.edu.cn/htpd/) was built. Many of the identified human testicular proteins are associated with human infertility, especially human testicular predominantly expressed proteins. We characterized six novel cancer/testis genes (TMPRSS12, TPPP2, PRSS55, DMRT1, PIWIL1, HEMGN), which map to cancer-associated genetic variants positions, in both the cancer and testis tissues using genome-wide analyses. Our results provide a molecular connection between spermatogenesis and tumorigenesis and broaden the range of cancer antigen choice available for immunotherapy. PMID- 23436709 TI - UV/Vis spectra of subporphyrazines and subphthalocyanines with aluminum and gallium: a time-dependent DFT study. AB - The UV/Vis spectra of selected substituted subporphyrazines (SubPz) and subphthalocyanines (SubPc) with aluminum and gallium as central atoms are analyzed through time-dependent DFT calculations in chloroform. The results are compared with previous results with boron as the central atom to analyze the photochemical properties of these two families of compounds on varying the metal along the same group. The absorptions of SubPz (Al, Ga) are redshifted or blueshifted with respect to SubPz (B) depending on the nature of the R substituents of the molecule, whereas the absorptions of SubPc (Al, Ga) structures are redshifted and with smaller energy gaps with respect to SubPc (B) for all kinds of R substituents. Looking at their absorption spectra, these systems with aluminum and gallium may also have, as in the case of boron, promising photochemical properties. PMID- 23436710 TI - Giant coronary artery aneurysms and eosinophilic granulomatosis with polyangiitis. PMID- 23436711 TI - Relentless pulmonary vein stenosis: a contemporary approach to a recurring problem. AB - Pulmonary vein (PV) stenosis is a known complication of PV isolation procedures for atrial fibrillation. Treatment can be percutaneous or surgical. We describe in this report a case of recurring PV stenosis after both surgical and percutaneous procedures, highlighting a number of novel interventional techniques. We also provide a review of literature regarding intervening in pulmonary vein occlusion. PMID- 23436712 TI - Kaposi sarcoma trends in Uganda and Zimbabwe: a sustained decline in incidence? AB - Trends in Kaposi sarcoma (KS) incidence over four decades were described for Zimbabwe and Uganda. KS data were retrieved from the population-based cancer registries of Bulawayo (1963-1971) and Harare (1990-2005), Zimbabwe and Kyadondo, Uganda (1960-1971 and 1991-2007). Joinpoint regression models were used to analyze time trends of KS incidence. Trends were compared to HIV/AIDS trends and were also described as rates versus birth cohort by age. In both countries, an increased incidence of KS accompanied the emergence of the HIV/AIDS epidemic (p value < 0.0001). In Zimbabwe, KS incidence (both sexes, all ages) changed in parallel to that of HIV/AIDS prevalence, whereas in Uganda, despite an observed decrease in HIV/AIDS prevalence since 1992, we observed a decrease in KS incidence in men younger than 50 years (Annual Percent Change, APC after 1991 = 4.5 [-5.6; -3.4], p-value < 0.05) but not in men aged >50 years (APC after 1991 = 1.0 [-2.8; 5.0]) nor in women (APC = 1.0 [-0.6; 2.6]). In both populations, a period effect at older ages was observed, with initial increases in incidence in men followed subsequently by a downturn in rates of the same magnitude. The uniformly declining rates in younger men (aged less than 30 years) suggested that a recent cohort effect was also in operation with a reduced risk in generations born after the mid-1950s in Uganda and in the mid-1960s in Zimbabwe. The combined introduction of antiretroviral therapy and effective prevention programmes against HIV/AIDS appeared to be the key contributors to the KS decline observed in both Uganda and Zimbabwe. PMID- 23436714 TI - Nanoparticles exposing neurotensin tumor-specific drivers. AB - Nanoparticles have attracted much attention for their potential application as in vivo carriers of drugs. Labeling of nanoparticles with bioactive markers that are able to direct them toward specific biological target receptors has led to a new generation of drug delivery systems. In particular, low molecular weight peptides that remain stable in vivo could be promising tools to selectively drive nanoparticles loaded with active components to tumor cells. We reported, recently, that tetrabranched neurotensin peptides (NT4) may be used to selectively target tumor cells with liposomes. Liposomes functionalized with tetrabranched neurotensin peptide, NT4, and loaded with doxorubicin showed clear advantages in cell binding, anthracyclin internalization, and cytotoxicity in respect of not functionalized liposomes. In this study, we compare branched (NT4) versus linear (NT) peptides in the ability to drive liposomes to target cells and deliver their toxic cargo. We showed here that the more densely decorated liposomes had a better activity profile in terms of drug delivery. Presentation of peptides to the cell membranes in the grouped shape provided by branched structure facilitates liposome cell binding and fusion. PMID- 23436713 TI - Grid-based molecular footprint comparison method for docking and de novo design: application to HIVgp41. AB - Scoring functions are a critically important component of computer-aided screening methods for the identification of lead compounds during early stages of drug discovery. Here, we present a new multigrid implementation of the footprint similarity (FPS) scoring function that was recently developed in our laboratory which has proven useful for identification of compounds which bind to a protein on a per-residue basis in a way that resembles a known reference. The grid-based FPS method is much faster than its Cartesian-space counterpart, which makes it computationally tractable for on-the-fly docking, virtual screening, or de novo design. In this work, we establish that: (i) relatively few grids can be used to accurately approximate Cartesian space footprint similarity, (ii) the method yields improved success over the standard DOCK energy function for pose identification across a large test set of experimental co-crystal structures, for crossdocking, and for database enrichment, and (iii) grid-based FPS scoring can be used to tailor construction of new molecules to have specific properties, as demonstrated in a series of test cases targeting the viral protein HIVgp41. The method is available in the program DOCK6. PMID- 23436715 TI - Isothermal hybridization kinetics of DNA assembly of two-dimensional DNA origami. AB - The Watson-Crick base-pairing with specificity and predictability makes DNA molecules suitable for building versatile nanoscale structures and devices, and the DNA origami method enables researchers to incorporate more complexities into DNA-based devices. Thermally controlled atomic force microscopy in combination with nanomechanical spectroscopy with forces controlled in the pico Newton (pN) range as a novel technique is introduced to directly investigate the kinetics of multistrand DNA hybridization events on DNA origami nanopores under defined isothermal conditions. For the synthesis of DNA nanostructures under isothermal conditions at 60 degrees C, a higher hybridization rate, fewer defects, and a higher stability are achieved compared to room-temperature studies. By quantifying the assembly times for filling pores in origami structures at several constant temperatures, the fill factors show a consistent exponential increase over time. Furthermore, the local hybridization rate can be accelerated by adding a higher concentration of the staples. The new insight gained on the kinetics of staple-scaffold hybridization on the synthesis of two dimensional DNA origami structures may open up new routes and ideas for designing DNA assembly systems with increased potential for their application. PMID- 23436716 TI - Surgical innovation. PMID- 23436717 TI - Crystal structures of a bioactive 6'-hydroxy variant of sisomicin bound to the bacterial and protozoal ribosomal decoding sites. AB - Parasitic infections recognized as neglected tropical diseases are a source of concern for several regions of the world. Aminoglycosides are potent antimicrobial agents that have been extensively studied by biochemical and structural studies in prokaryotes. However, the molecular mechanism of their potential antiprotozoal activity is less well understood. In the present study, we have examined the in vitro inhibitory activities of some aminoglycosides with a 6'-hydroxy group on ring I and highlight that one of them, 6'-hydroxysisomicin, exhibits promising activity against a broad range of protozoan parasites. Furthermore, we have conducted X-ray analyses of 6'-hydroxysisomicin bound to the target ribosomal RNA A-sites in order to understand the mechanisms of both its antibacterial and antiprotozoal activities at the molecular level. The unsaturated ring I of 6'-hydroxysisomicin can directly stack on G1491, which is highly conserved in bacterial and protozoal species, through pi-pi interaction and fits closer to the guanidine base than the typically saturated and hydroxylated ring I of other structurally related aminoglycosides. Consequently, the compound adopts a lower energy conformation within the bacterial and protozoal A-sites and makes pseudo pairs to either A or G at position 1408. The A site-selective binding mode strongly suggests that 6'-hydroxysisomicin is a potential lead for the design of next-generation aminoglycosides targeting a wide variety of infectious diseases. PMID- 23436718 TI - On the design of zinc-finger models with cyclic peptides bearing a linear tail. AB - Cyclic peptides with a linear tail (CPLT) have been successfully used to model two zinc fingers (ZFs) adopting the treble-clef- and loosened zinc-ribbon folds. In this article, we examine the factors that may influence the design of such ZF models: mutations in the sequence, size of the cycle, and size of the tail. For this purpose, several peptides derived from the CPLT-based models of the treble clef- and loosened zinc-ribbon ZF were synthesized and studied. CPLT-based models appear to be robust toward mutations, accommodate various cycle sizes, and are sensible to the size of the linking region of the tail located between the cycle and the coordinating amino acids. Based on these criteria, we describe the design of a new CPLT-based model for the zinc-ribbon ZFs, LZR , and compare it to a linear analogue, LZR(lin) . The model complex Zn?LZR is able to fold correctly around the metal ion contrary to Zn?LZR(lin) , suggesting that CPLT-based models are more likely to yield structurally meaningful models of ZF sites than linear peptide models. Finally, we draw some rules that could allow the design of new CPLT-based metallopeptides with a controlled fold. PMID- 23436719 TI - Analysis of birth defects among children 3 years after conception through assisted reproductive technology in China. AB - BACKGROUND: Previous studies inconsistently suggest that assisted reproduction technology (ART) may increase the risk of birth defects in children. METHOD(S): Live birth infants, conceived by in vitro fertilization fresh embryo transfer (IVF), intracytoplasmic sperm injection fresh embryo transfer (ICSI), or frozen thawed embryo transfer (FET) in Reproductive Center of Tongji Hospital (Wuhan, China) between 1997 and 2008, were followed up at birth and after 3 years. Preterm pregnancy, multiple pregnancy, sex ratio (male/female), congenital malformation were compared. RESULT(S): A total of 4,236 children were born after ART (IVF 2,543, ICSI 908, FET 785). Compared with IVF, the rate of preterm pregnancy and sex ratio in ICSI were lower (p < 0.05); the rate of multiple pregnancy in ICSI and FET were all lower than IVF (p < 0.05). Congenital defects were comparable in all groups at birth. In total, 2,908 children participated in the second follow-up from 34 months to 60 months with an average of 40 months, and the cases of birth defects had doubled (3 years: 5.16%, birth: 2.22%). The birth defect rate in boys conceived through ICSI was significantly higher than the IVF group after 3-year follow-up (ICSI boys: 8.62%, IVF boys: 5.21% [p < 0.05]), even though there was no significant difference at birth. CONCLUSION(S): Compared with IVF, FET may not increase risk of birth defects. Children conceived through ICSI, especially males, had higher rates of congenital malformations that were inapparent at birth. So longitudinal monitoring may provide insights into the risks of ART. PMID- 23436720 TI - The current and projected economic burden of Parkinson's disease in the United States. AB - Parkinson's disease (PD), following Alzheimer's disease, is the second-most common neurodegenerative disorder in the United States. A lack of treatment options for changing the trajectory of disease progression, in combination with an increasing elderly population, portends a rising economic burden on patients and payers. This study combined information from nationally representative surveys to create a burden of PD model. The model estimates disease prevalence, excess healthcare use and medical costs, and nonmedical costs for each demographic group defined by age and sex. Estimated prevalence rates and costs were applied to the U.S. Census Bureau's 2010 to 2050 population data to estimate current and projected burden based on changing demographics. We estimate that approximately 630,000 people in the United States had diagnosed PD in 2010, with diagnosed prevalence likely to double by 2040. The national economic burden of PD exceeds $14.4 billion in 2010 (approximately $22,800 per patient). The population with PD incurred medical expenses of approximately $14 billion in 2010, $8.1 billion higher ($12,800 per capita) than expected for a similar population without PD. Indirect costs (e.g., reduced employment) are conservatively estimated at $6.3 billion (or close to $10,000 per person with PD). The burden of chronic conditions such as PD is projected to grow substantially over the next few decades as the size of the elderly population grows. Such projections give impetus to the need for innovative new treatments to prevent, delay onset, or alleviate symptoms of PD and other similar diseases. PMID- 23436722 TI - Blood conservation strategies reduce the need for transfusions in ascending and aortic arch surgery. AB - INTRODUCTION: Ascending and aortic arch surgery is associated with higher levels of blood loss and subsequent need for allogeneic blood transfusions. We hypothesized that aggressive, comprehensive blood conservation strategies may limit the need for transfusions and, subsequently, improve postoperative outcomes. METHODS: Over a five-year period, 189 patients underwent proximal aortic surgery at our institution. Fifty-one patients underwent surgery using a comprehensive blood conservation strategy (BCS), including preoperative hemoglobin optimization, antifibrinolytic therapy, intraoperative acute normovolemic hemodilution, cell salvage and meticulous surgical technique. The remaining 138 patients underwent surgery using conventional techniques (CONV). RESULTS: Patients in the BCS group required fewer transfusions during their hospital stay compared to the conventional group (56.9% vs. 72.5%, p=0.041). When examining elective cases, this trend widens, with 40.0% of BCS patients requiring any transfusions compared to 72.9% patients in the conventional group (p=0.001). Red cell (47.1% vs. 62.3%, p=0.06), plasma (43.1% vs. 61.6%, p=0.02) and platelets (27.5% vs. 47.8%, p=0.01) were also less frequently required in the BCS group than the conventional group, respectively. When a transfusion was required, patients in the BCS group received significantly fewer units of red blood cells (2.8 +/- 7.0 units) than the conventional group (5.81 +/- 9.5 units; p=0.039). Mortality was similar in both groups (BCS 7.8%, conventional 10.9%, p=0.54); however, there was significantly less morbidity in the BCS group, using a composite of any of 10 major postoperative complications (23.5% vs. 39.1%; p=0.046). Median intensive care unit (ICU) and hospital lengths of stay were 2 and 7 days in the BCS group and 2 and 8 days in the CONV group (p=0.15), respectively. CONCLUSIONS: The aggressive use of a comprehensive blood conservation strategy in ascending and aortic arch surgery can significantly reduce the need for blood transfusions and is associated with less postoperative morbidity. Further evaluation with a randomized, controlled trial is warranted. PMID- 23436721 TI - Pramipexole-induced disruption of behavioral processes fundamental to intertemporal choice. AB - Evaluating the effects of presession drug administration on intertemporal choice in nonhumans is a useful approach for identifying compounds that promote impulsive behavior in clinical populations, such as those prescribed the dopamine agonist pramipexole (PPX). Based on the results of previous studies, it is unclear whether PPX increases rats' impulsive choice or attenuates aspects of stimulus control. The present study was designed to experimentally isolate behavioral processes fundamental to intertemporal choice and challenge them pharmacologically with PPX administration. In Experiment 1, the hypothesis that PPX increases impulsive choice as a result of enhanced sensitivity to reinforcer delays was tested and disconfirmed. That is, acute PPX diminished delay sensitivity in a manner consistent with disruption of stimulus control whereas repeated PPX had no effect on delay sensitivity. Experiments 2 and 3 elaborated upon this finding by examining the effects of repeated PPX on rats' discrimination of response-reinforcer contingencies and reinforcer amounts, respectively. Accuracy of both discriminations was reduced by PPX. Collectively these results provide no support for past studies that have suggested PPX increases impulsive choice. Instead, PPX impairs stimulus control over choice behavior. The behavioral approach adopted herein could be profitably integrated with genetic and other biobehavioral models to advance our understanding of impulsive behavior associated with drug administration. PMID- 23436723 TI - Is it possible to further improve the function of pulmonary grafts by extending the duration of lung reconditioning using ex vivo lung perfusion? AB - BACKGROUND: The method of ex vivo lung perfusion (EVLP) has been suggested as a reliable means of differentiating between "good" and "poor" pulmonary grafts in marginal donors as, when grafts identified as good by this method are transplanted, the results do not differ from those using lungs fulfilling standard criteria. The EVLP method is also thought to improve pulmonary grafts by reducing lung edema and eliminating lung atelectasis. In the present study, we investigated whether the pulmonary graft could be further improved by extending the duration of EVLP. METHODS AND MATERIALS: Six Landrace pigs were used. The lungs were reconditioned and evaluated, using the EVLP method, as double lungs. After the initial evaluation, EVLP was continued for a further 90 minutes. RESULTS: The arterial oxygen level (pO2) was 60.8 +/- 4.8 kPa after the standard 60 minutes of EVLP and 67.1 +/- 2.2 kPa after 150 minutes (p = 0.48). The pulmonary vascular resistance was 453 +/- 78 dyne*s/cm(5) after 60, 90, 120 and 150 minutes of EVLP (p = 1.0). The pulmonary artery pressure was 17.8 +/- 1.0 mmHg after 60, 90, 120, and 150 minutes of EVLP (p = 1.0) and the pulmonary artery flow was 3.5 +/- 0.4 l/min after 60, 90, 120, and 150 minutes of EVLP (p = 1.0). The mean weight of the pulmonary grafts after harvesting was 574 +/- 20 g at the beginning of EVLP 541 +/- 24 g and, after 150 min of EVLP, 668 +/- 33 (p = 0.011). CONCLUSIONS: The blood gases and hemodynamic parameters in the pulmonary grafts did not improve as a result of the extra 90 minutes of EVLP. However, the weight of the pulmonary graft increased significantly with increasing duration of EVLP, indicating lung perfusion injury. PMID- 23436724 TI - Protein interacting with C kinase and neurological disorders. AB - Best known for its interaction with the alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor subunit GluA2 and for its influence on excitatory synapse activity, the protein interacting with C kinase, PICK1, is the focus of considerable attention from neurobiologists. Indeed, this PSD-95/DlgA/ZO 1 (PDZ) domain-containing protein has been shown to interact with a wide variety of neurotransmitter receptors, transporters, and enzymes, including glutamate and nicotinic acetylcholine receptors, dopamine and glutamate transporters, and the enzyme serine racemase. Through its lipid binding domain, PICK1 is targeted to the inner surface of the cell membrane where it contributes to anchoring these partners and thereby influences their synaptic localization and function. Under pathological conditions, the regulation of some PICK1-interacting partners is altered, pointing to an involvement of PICK1 in neurological disorders. Also, genetic or pharmacological manipulations of PICK1 expression, localization, or function have been shown to influence several physiological or pathological processes in which putative PICK1 partners are involved. This review will summarize recent experimental observations that highlight the involvement of PICK1 in neurological disorders, including schizophrenia, Parkinson's disease, epilepsy, chronic pain, drug abuse, and amyotrophic lateral sclerosis. PMID- 23436725 TI - Simulation of mesogenic diruthenium tetracarboxylates: Development of a force field for coordination polymers of the MMX type. AB - A classical molecular mechanics force field, able to simulate coordination polymers (CP) based on ruthenium carboxylates (Ru2 (O2CReq )4 Lax) (eq = equatorial group containing aliphatic chains, Lax = axial ligand), has been developed. New parameters extracted from experimental data and quantum calculations on short aliphatic chains model systems were included in the generalized AMBER force field. The proposed parametrization was evaluated using model systems with known structure, containing either short or long aliphatic chains; experimental results were reproduced satisfactorily. This modified force field, although in a preliminary stage, could then be applied to long chain liquid crystalline compounds. The resulting atomistic simulations allowed assessing the relative influence of the factors determining the CP conformation, determinant for the physical properties of these materials. PMID- 23436726 TI - Human enteropeptidase light chain: bioengineering of recombinants and kinetic investigations of structure and function. AB - The serine protease enteropeptidase exhibits a high level of substrate specificity for the cleavage sequence DDDDK~ X, making this enzyme a useful tool for the separation of recombinant protein fusion domains. In an effort to improve the utility of enteropeptidase for processing fusion proteins and to better understand its structure and function, two substitution variants of human enteropeptidase, designated R96Q and Y174R, were created and produced as active (>92%) enzymes secreted by Pichia pastoris with yields in excess of 1.7 mg/Liter. The Y174R variant showed improved specificities for substrates containing the sequences DDDDK (kcat /KM = 6.83 * 106 M-1 sec-1) and DDDDR (kcat /KM = 1.89 * 107 M-1 sec-1) relative to all other enteropeptidase variants reported to date. BPTI inhibition of Y174R was significantly decreased. Kinetic data demonstrate the important contribution of the positively charged residue 96 to extended substrate specificity in human enteropeptidase. Modeling shows the importance of the charge-charge interactions in the extended substrate binding pocket. PMID- 23436727 TI - C-terminus of ETA/ETB receptors regulate endothelin-1 signal transmission. AB - The dimerization of the G protein-coupled receptors for endothelin-1 (ET-1), endothelin A receptor (ETA) and endolethin B receptor (ETB), is well established. However, the signaling consequences of the homodimerization and heterodimerization of ETA and ETB is not well understood. Here, we demonstrate that peptides derived from the C-termini of these receptors regulate the signaling capacity of ET-1. The C-termini of the ETA and ETB receptors are believed to consist of three alpha-helices, which may serve as points of interaction between the receptors. The third alpha-helix in the C-terminus is of particular interest because of its amphipathic nature. In a cell line expressing only the ETA receptor, expression of residues Y430-S442, representing the third helix of the ETB C-terminus, leads to a dramatic increase in the signaling induced by ET-1. In contrast, in a cell line containing only ETB , Y430-S442 has an antagonistic effect, slightly reducing the ET-1 induced signal. Computational docking results suggest that the alpha-helical ETB -derived peptide binds to the second and third intracellular loops of the ETA receptor consistent with the alteration of its signaling capacity. Our results described here provide important insight into ETA /ETB receptor interactions and possibly a new approach to regulate specific G protein-coupled receptor signal transmission. PMID- 23436728 TI - Proteomics reveals new insights into the role of light in cadmium response in Arabidopsis cell suspension cultures. AB - Light plays an important role in plant growth, development, and response to environmental stresses. To investigate the effects of light on the plant responses to cadmium (Cd) stress, we performed a comparative physiological and proteomic analysis of light- and dark-grown Arabidopsis cells after exposure to Cd. Treatment with different concentrations of Cd resulted in stress-related phenotypes such as cell growth inhibition and decline of cell viability. Notably, light-grown cells were more sensitive to heavy metal toxicity than dark-grown cells, and the basis for this appears to be the elevated Cd accumulation, which is twice as much under light than dark growth conditions. Protein profiles analyzed by 2D DIGE revealed a total of 162 protein spots significantly changing in abundance in response to Cd under at least one of these two growing conditions. One hundred and ten of these differentially expressed protein spots were positively identified by MS/MS and they are involved in multiple cellular responses and metabolic pathways. Sulfur metabolism-related proteins increased in relative abundance both in light- and dark-grown cells after exposure to Cd. Proteins involved in carbohydrate metabolism, redox homeostasis, and anti oxidative processes were decreased both in light- and dark-grown cells, with the decrease being lower in the latter case. Remarkably, proteins associated with cell wall biosynthesis, protein folding, and degradation showed a light-dependent response to Cd stress, with the expression level increased in darkness but suppressed in light. The possible biological importance of these changes is discussed. PMID- 23436729 TI - Transcatheter treatment of SVC syndrome from histoplasmosis-related mediastinal fibrosis in a 9-year old male. AB - We report a case of mediastinal fibrosis secondary to histoplasmosis in a 9-year old male, who presented with superior vena cava syndrome. He was successfully treated by percutaneous superior vena cava stent placement in the outpatient cardiac catheterization laboratory. PMID- 23436730 TI - Kinetic profiles and management of hepatitis B virus reactivation in patients with immune-mediated inflammatory diseases. AB - OBJECTIVE: Immunosuppressive therapy may trigger hepatitis B virus (HBV) reactivation for increased morbidity and mortality. We aimed to describe HBV reactivation in patients receiving treatment for immune-mediated inflammatory diseases (IMIDs) and to evaluate a predefined algorithm for its prevention. METHODS: Physicians submitted data for patients receiving treatment for IMIDs and exhibiting HBV reactivation, defined as an increase of >1 log10 IU/ml of HBV DNA levels or DNA reappearance. We systematically reviewed cases in the literature. RESULTS: The 35 physician-collected patients had rheumatoid arthritis (n = 14), connective tissue disease (n = 7), vasculitis (n = 5), and other diseases (n = 9). At baseline, 65.7% of patients were positive for hepatitis B surface antigen (HBsAg), 31.4% had a history of HBV infection, and 2.9% had occult HBV infection. Reactivation occurred a median of 35 weeks (range 2-397 weeks) after the start of corticosteroid and/or immunosuppressive therapy. In all, 88.6% of patients were clinically asymptomatic, but 25.7% had severe hepatitis; none had fulminant hepatitis. Management was antiviral therapy for 91.4%, with discontinuation or decrease of immunosuppressive therapy for 45.7%. In pooling these 35 cases and 103 patients from the literature, 73.9% of patients were clinically asymptomatic, 33.3% had severe hepatitis, and 12.3% died and/or had fulminant hepatitis. Reactivation occurred early with rituximab or cyclophosphamide therapy and in HBsAg-positive/HBV DNA-positive patients. Using the predefined algorithm, 78% of patients with reactivation would have received preemptive antiviral therapy. CONCLUSION: We provide new insights into HBV reactivation in patients receiving treatment for IMIDs. A predefined algorithm may be effective in reducing the risk of HBV reactivation in this population. PMID- 23436731 TI - Electron transfer between hydrogen-bonded pyridylphenols and a photoexcited rhenium(I) complex. AB - Two pyridylphenols with intramolecular hydrogen bonds between the phenol and pyridine units have been synthesized, characterized crystallographically, and investigated by cyclic voltammetry and UV/Vis spectroscopy. Reductive quenching of the triplet metal-to-ligand charge-transfer excited state of the [Re(CO)3(phen)(py)](+) complex (phen = 1,10-phenanthroline, py = pyridine) by the two pyridylphenols and two reference phenol molecules is investigated by steady state and time-resolved luminescence spectroscopy, as well as by transient absorption spectroscopy. Stern-Volmer analysis of the luminescence quenching data provides rate constants for the bimolecular excited-state quenching reactions. H/D kinetic isotope effects for the pyridylphenols are on the order of 2.0, and the bimolecular quenching reactions are up to 100 times faster with the pyridylphenols than with the reference phenols. This observation is attributed to the markedly less positive oxidation potentials of the pyridylphenols with respect to the reference phenols (~0.5 V), which in turn is caused by proton coupling of the phenol oxidation process. Transient absorption spectroscopy provides unambiguous evidence for the photogeneration of phenoxyl radicals, that is, the overall photoreaction is clearly a proton-coupled electron-transfer process. PMID- 23436732 TI - Synthesis and structure of carbene-stabilized N-centered cations [L2N]+, [L2NR]2+, [LNR3]2+ , and [L3N]3+. PMID- 23436733 TI - Application of chromosomal DNA and protein targeting for the identification of Yersinia pestis. AB - PURPOSE: A comprehensive strategy was developed and validated for the identification of pathogens from closely related near neighbors using both chromosomal and protein biomarkers, with emphasis on distinguishing Yersinia pestis from the ancestral bacterium Yersinia pseudotuberculosis. EXPERIMENTAL DESIGN: Computational analysis was used to discover chromosomal targets unique to Y. pestis. Locus identifier YPO1670 was selected for further validation and PCR was used to confirm that this biomarker was exclusively present in Y. pestis strains, while absent in other Yersinia species. RT-PCR and Western blot analyses were utilized to evaluate YPO1670 expression and MRM MS was performed to identify the YPO1670 protein within cell lysates. RESULTS: The described study validated that YPO1670 was exclusive to Y. pestis. PCR confirmed the locus to be unique to Y. pestis. The associated transcript and protein were produced throughout growth with the highest abundance occurring in stationary phase and MRM MS conclusively identified the YPO1670 protein in cell extracts. CONCLUSIONS AND CLINICAL RELEVANCE: These findings validated YPO1670 as a reliable candidate biomarker for Y. pestis and that a dual DNA and protein targeting approach is feasible for the development of next-generation assays to accurately differentiate pathogens from near neighbors. PMID- 23436735 TI - Effect of thermal processing of cow and buffalo milk on the allergenic response to caseins and whey proteins in mice. AB - BACKGROUND: Heat treatment is the most common method for reducing pathogen load, but it remains controversial in reducing the incidence of hyperimmune reactions. The aim of this study was to compare the allergenicity of caseins (CSN) and whey proteins (WP) of thermally processed cow and buffalo milk in a mouse model. Swiss albino mice were sensitised by intraperitoneal injections (administered in three doses at weekly intervals) of CSN or WP from cow or buffalo milk for the evaluation of humoral response and splenocyte stimulation index. RESULTS: After 3 weeks of intraperitoneal stimulation of mice with milk proteins, the sterilised milk protein group displayed significantly lowered (P <= 0.05) serum IgG and IgE levels, while considerably increased cow milk protein-specific responses (IgE) were shown by proteins of pasteurised milk compared with those of raw milk. The stimulation index of splenocytes induced by CSN or WP of boiled and sterilised milk was also lower (P <= 0.05) than that of raw milk of both cow and buffalo. CONCLUSION: The experiment showed that boiling and sterilisation of cow and buffalo milk clearly affect the allergenicity by decreasing the humoral and cell mediated responses in mice. All results indicated that CSN and WP of sterilised milk are less allergenic than those of raw milk in mice. PMID- 23436734 TI - Nucleophosmin mutations in acute myeloid leukemia: a tale of protein unfolding and mislocalization. AB - Nucleophosmin (NPM1) is an abundant, ubiquitously expressed protein mainly localized at nucleoli but continuously shuttling between nucleus and cytoplasm. NPM1 plays a role in several cellular functions, including ribosome biogenesis and export, centrosome duplication, chromatin remodeling, DNA repair, and response to stress stimuli. Much of the interest in this protein arises from its relevance in human malignancies. NPM1 is frequently overexpressed in solid tumors and is the target of several chromosomal translocations in hematologic neoplasms. Notably, NPM1 has been characterized as the most frequently mutated gene in acute myeloid leukemia (AML). Mutations alter the C-terminal DNA-binding domain of the protein and result in its aberrant nuclear export and stable cytosolic localization. In this review, we focus on the leukemia-associated NPM1 C-terminal domain and describe its structure, function, and the effect exerted by leukemic mutations. Finally, we discuss the possibility to target NPM1 for the treatment of cancer and, in particular, of AML patients with mutated NPM1 gene. PMID- 23436736 TI - Glial-cell-mediated re-induction of the blood-brain barrier phenotype in brain capillary endothelial cells: a differential gel electrophoresis study. AB - In the neurovascular unit, brain microvascular endothelial cells develop characteristic barrier features that control the molecular exchanges between the blood and the brain. These characteristics are partially or totally lost when the cells are isolated for use in in vitro blood-brain barrier (BBB) models. Hence, the re-induction of barrier properties is crucial for the relevance of BBB models. Although the role of astrocyte promiscuity is well established, the molecular mechanisms of re-induction remain largely unknown. Here, we used a DIGE based proteomics approach to study endothelial cellular proteins showing significant quantitative variations after BBB re-induction. We confirm that quantitative changes mainly concern proteins involved in cell structure and motility. Furthermore, we describe the possible involvement of the asymmetric dimethylarginine pathway in the BBB phenotype re-induction process and we discuss asymmetric dimethylarginine's potential role in regulating endothelial function (in addition to its role as a by-product of protein modification). Our results also suggest that the intracellular redox potential is lower in the in vitro brain capillary endothelial cells displaying re-induced BBB functions than in cells with limited BBB functions. PMID- 23436737 TI - European League Against Rheumatism Sjogren's Syndrome Disease Activity Index and European League Against Rheumatism Sjogren's Syndrome Patient-Reported Index: a complete picture of primary Sjogren's syndrome patients. AB - OBJECTIVE: The European League Against Rheumatism (EULAR) Sjogren's Syndrome (SS) Disease Activity Index (ESSDAI) and the EULAR SS Patient-Reported Index (ESSPRI) were recently developed. We aimed to determine whether patients' symptoms differed between patients with and without systemic involvement and if the disease-specific indices correlated with each other in primary SS. METHODS: Fifteen French centers included 395 primary SS patients in the Assessment of Systemic Signs and Evolution in Sjogren's Syndrome Cohort. At enrollment, physicians completed the ESSDAI, the SS Disease Activity Index (SSDAI), and the Sjogren's Systemic Clinical Activity Index (SCAI), and patients completed the ESSPRI, the Sicca Symptoms Inventory, and the Profile of Fatigue and Discomfort. All scores were compared between patients with and without systemic involvement. Correlations between scores of systemic activity and patients' symptoms were obtained. RESULTS: At enrollment, 120 (30.4%) patients had never experienced systemic complication and 155 (39.2%) patients and 120 (30.4%) patients had, respectively, only past or current systemic manifestations. Past or current systemic patients had higher levels of symptoms, except dryness. The ESSDAI did not correlate with the patient-scored ESSPRI (rho = 0.06, P = 0.30), whereas the SSDAI and the SCAI, which include subjective items, did correlate (rho = 0.28 and 0.25, respectively; P < 0.0001 for both). CONCLUSION: Alterations of common patient-reported outcomes are present in all patients with primary SS, including those with systemic complications. However, patient symptoms and systemic complications are 2 different facets of primary SS. Therefore, the use of both systemic and patients' indices, such as the ESSDAI and ESSPRI, are useful. Since these 2 facets weakly overlap, one should identify which of both components is the main target of the treatment to test, when designing clinical trials in primary SS. PMID- 23436738 TI - Spin-cast bulk heterojunction solar cells: a dynamical investigation. AB - Spin-coating is extensively used in the lab-based manufacture of organic solar cells, including most of the record-setting solution-processed cells. We report the first direct observation of photoactive layer formation as it occurs during spin-coating. The study provides new insight into mechanisms and kinetics of bulk heterojunction formation, which may be crucial for its successful transfer to scalable printing processes. PMID- 23436739 TI - Progressive ataxia and palatal tremor associated with dense pontine calcification: A unique case. PMID- 23436741 TI - Accurate pKa calculation of the conjugate acids of alkanolamines, alkaloids and nucleotide bases by quantum chemical methods. AB - The pKa of the conjugate acids of alkanolamines, neurotransmitters, alkaloid drugs and nucleotide bases are calculated with density functional methods (B3LYP, M08-HX and M11-L) and ab initio methods (SCS-MP2, G3). Implicit solvent effects are included with a conductor-like polarizable continuum model (CPCM) and universal solvation models (SMD, SM8). G3, SCS-MP2 and M11-L methods coupled with SMD and SM8 solvation models perform well for alkanolamines with mean unsigned errors below 0.20 pKa units, in all cases. Extending this method to the pKa calculation of 35 nitrogen-containing compounds spanning 12 pKa units showed an excellent correlation between experimental and computational pKa values of these 35 amines with the computationally low-cost SM8/M11-L density functional approach. PMID- 23436740 TI - The induction of phagocytic activation by mixtures of the water chlorination by products, dichloroacetate- and trichloroacetate, in mice after subchronic exposure. AB - In this study, groups of B6C3F1 male mice were treated with dichloroacetate (DCA), trichloroacetate (TCA), and mixtures of the compounds (Mix I, II, and III) daily by gavage, for 13 weeks. The tested doses were 7.5, 15, and 30 mg DCA/kg/day and 12.5, 25, and 50 mg TCA/kg/day. The DCA: TCA ratios in Mix I, II, and III were 7.5:12.5, 15:25, and 30:50 mg/kg/day, respectively. Peritoneal lavage cells were collected at the end of the treatment period and assayed for the biomarkers of phagocytic activation, including superoxide anion and tumor necrosis factor-alpha production, and myeloperoxidase activity. The mixtures produced nonlinear effects on the biomarkers of phagocytic activation, with Mix I and II effects were found to be additive, but Mix III effects were found to be less than additive. PMID- 23436742 TI - Thermal and electrical conduction in ultrathin metallic films: 7 nm down to sub nanometer thickness. AB - For ultrathin metallic films (e.g., less than 5 nm), no knowledge is yet available on how electron scattering at surface and grain boundaries reduces the electrical and thermal transport. The thermal and electrical conduction of metallic films is characterized down to 0.6 nm average thickness. The electrical and thermal conductivities of 0.6 nm Ir film are reduced by 82% and 50% from the respective bulk values. The Lorenz number is measured as 7.08 * 10-8 W Omega K-2, almost a twofold increase of the bulk value. The Mayadas-Shatzkes model is used to interpret the experimental results and reveals very strong electron reflection (>90%) at grain boundaries. PMID- 23436743 TI - Pseudosymmetry analysis of molecular orbitals. AB - We introduce a pseudosymmetry analysis of molecular orbitals by means of the newly proposed irreducible representation measures. To do that we define first what we consider as molecular pseudosymmetry and the relationships of this concept with those of approximate symmetry and quasisymmetry. We develop a general algorithm to quantify the pseudosymmetry content of a given object within the framework of the finite group algebra. The obtained mathematical expressions are able to decompose molecular orbitals by means of the irreducible representations of any reference symmetry point group. The implementation and usefulness of the pseudosymmetry analysis of molecular orbitals is demonstrated in the study of sigma and pi orbitals in planar and nonplanar polycyclic aromatic hydrocarbons and the t2 g and eg character of the d-orbitals in the [FeH6](3-) anion in its high spin state along the Bailar twist pathway. PMID- 23436744 TI - Transcatheter occlusion of a persistent left superior vena cava to the left atrium using the transseptal approach. AB - A persistent left superior vena cava (LSVC) is a common venous anomaly, occurring in up to 10% of patients with congenital heart defects. Usually, a LSVC drains into the coronary sinus, then to the right atrium. The LSVC can drain directly to the left atrium, resulting in a right-to-left shunt and systemic desaturation. Historically, surgery has been used to address this lesion. Transcatheter occlusion of the LSVC is an alternative to surgery. We report the novel use of the transseptal approach to access the LSVC, and device occlusion using the Amplatzer Vascular Plug-II. PMID- 23436745 TI - Transradial coronary angiography with virtual 1 French, sheathless 3 French catheter. AB - Minimizing catheter size can reduce bleeding complications in coronary angiography. We herein report extreme slender "needle size" (19-G) coronary diagnostic catheterization using a new 3-Fr diagnostic catheter by sheathless method. A 58-year-old man having effort angina underwent coronary angiography. The 3-Fr Ikari Left diagnostic catheter, which is equal to 19-G, was inserted smoothly both for left and right coronary arteries by sheathless method. We only needed 4 min to achieve hemostasis with manual compression after catheter withdrawal in this case. PMID- 23436746 TI - Exfoliation of hexagonal boron nitride by molten hydroxides. AB - Hexagonal boron nitride (h-BN) nanosheets are prepared by a novel and effective method, in which sodium hydroxide and potassium hydroxide molten salts are used to exfoliate h-BN to obtain nanosheets. BN nanoscrolls are also obtained. The as prepared products can be readily dispersed in a wide range of solvents, including water and ethanol, and form stable dispersions. PMID- 23436747 TI - A novel graphene oxide-based surface plasmon resonance biosensor for immunoassay. PMID- 23436748 TI - Precise tuning of surface composition and electron-transfer properties of graphene oxide films through electroreduction. AB - Graphene materials are generally prepared from the exfoliation of graphite oxide (GO) to graphene oxide, followed by subsequent chemical or thermal reduction. These methods, although efficient in removing most of the oxygen functionalities from the GO material, lack control over the extent of the reduction process. We demonstrate here an electrochemical reduction procedure that not only allows for precise control of the reduction process to obtain a graphene material with a well-defined C/O ratio in the range of 3 to 10, but also one that is able to tune the electrocatalytic properties of the reduced material. A method that is able to precisely control the amount and density of the oxygen functionalities on the graphene material as well as its electrochemical behaviour is very important for several applications such as electronics, bio-composites and electrochemical devices. PMID- 23436749 TI - Understanding quantitative structure-property relationships uncertainty in environmental fate modeling. AB - In cases in which experimental data on chemical-specific input parameters are lacking, chemical regulations allow the use of alternatives to testing, such as in silico predictions based on quantitative structure-property relationships (QSPRs). Such predictions are often given as point estimates; however, little is known about the extent to which uncertainties associated with QSPR predictions contribute to uncertainty in fate assessments. In the present study, QSPR-induced uncertainty in overall persistence (POV ) and long-range transport potential (LRTP) was studied by integrating QSPRs into probabilistic assessments of five polybrominated diphenyl ethers (PBDEs), using the multimedia fate model Simplebox. The uncertainty analysis considered QSPR predictions of the fate input parameters' melting point, water solubility, vapor pressure, organic carbon-water partition coefficient, hydroxyl radical degradation, biodegradation, and photolytic degradation. Uncertainty in POV and LRTP was dominated by the uncertainty in direct photolysis and the biodegradation half-life in water. However, the QSPRs developed specifically for PBDEs had a relatively low contribution to uncertainty. These findings suggest that the reliability of the ranking of PBDEs on the basis of POV and LRTP can be substantially improved by developing better QSPRs to estimate degradation properties. The present study demonstrates the use of uncertainty and sensitivity analyses in nontesting strategies and highlights the need for guidance when compounds fall outside the applicability domain of a QSPR. PMID- 23436750 TI - Comparative proteomic analysis in children with idiopathic short stature (ISS) before and after short-term recombinant human growth hormone (rhGH) therapy. AB - This study was undertaken to identify growth hormone (GH) responsive proteins and protein expression patterns by short-term recombinant human growth hormone (rhGH) therapy in patients with idiopathic short stature (ISS) using proteomic analysis. Seventeen children (14 males and three females) with ISS were included. They were treated with rhGH at a dose of 0.31 +/- 0.078 mg/kg/week for 3 months. Immunodepletion of six highly-abundant serum proteins followed by 2D DIGE analysis, and subsequent MALDI TOF MS, were employed to generate a panel of proteins differentially expressed after short-term rhGH therapy and verify the differences in serum levels of specific proteins by rhGH therapy. Fourteen spots were differentially expressed after rhGH treatment. Among them, apo E and apo L-1 expression were consistently enhanced, whereas serum amyloid A was reduced after rhGH therapy. The differential expressions of these proteins were subsequently verified by Western blot analysis using sera of the before and after rhGH treatment. This study suggests that rhGH therapy influences lipoprotein metabolism and enhances apo L-1 protein expression in ISS patients. PMID- 23436751 TI - Accuracy of the National Institute for Neurological Disorders and Stroke/Society for Progressive Supranuclear Palsy and neuroprotection and natural history in Parkinson plus syndromes criteria for the diagnosis of progressive supranuclear palsy. AB - Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) criteria for the clinical diagnosis of "probable" PSP are thought to possess high specificity and low sensitivity. The NINDS-SPSP criteria for "possible" PSP are considered to increase sensitivity at the expense of specificity. The Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) criteria are intended to improve sensitivity while maintaining high specificity. The aim of this study was to conduct a clinicopathological evaluation of the NINDS-SPSP and NNIPPS criteria in tertiary neurological centers. Defined clinical features and their year of onset were recorded by chart review in neuropathologically diagnosed patients with PSP, Parkinsons's disease (PD), MSA parkinsonism and corticobasal degeneration from four European brain banks. Fulfillment of the clinical diagnostic criteria was verified for each year after disease onset and for the final antemortem record. We analyzed 98 PSP patients and 46 disease controls. The NINDS-SPSP "probable" criteria yielded shorter time to diagnosis, slightly higher specificity and positive predictive value (PPV), and similar sensitivity, compared with the NNIPPS criteria. Unexpectedly, the NINDS-SPSP "possible" criteria yielded the lowest sensitivity, specificity, and PPV. A combination of NINDS-SPSP possible and probable criteria yielded the highest sensitivity. We suggest that the NINDS SPSP probable criteria might be preferred for recruitment of patients for clinical trials, where an early and specific diagnosis is important. For routine clinical care, where high sensitivity is crucial, a combination of NINDS possible and probable criteria might be preferred. PMID- 23436752 TI - Innovation in global collaborations: from student placement to mutually beneficial exchanges. AB - Five years ago, an academic department in the United States and the Ann Sullivan Center of Peru (CASP) initiated an international partnership to foster research collaborations and reciprocal consultation, and to create an advanced clinical placement for occupational therapy doctoral students. CASP is a globally recognized hub for community-based research, demonstration and training for people with disabilities (most of whom are from low-income families). CASP has provided occupational therapy students and faculty with a rich cultural environment in which to learn and collaborate as well as opportunities for developing research collaborations. The purpose of this manuscript is to discuss an innovative model of international collaboration highlighting specific areas of exchange and reciprocal learning. First, we will describe the collaboration and CASP's rich learning opportunities. Second, we will discuss a model of collaboration that includes three main phases: planning and preparation, developing and sustaining the partnership, and evaluating and celebrating outcomes and benefits. We illustrate the partnership with a case example and describe exchanges between CASP and a local community agency with whom faculty have collaborated for 20 years. Finally, we discuss implications of our innovative model towards developing and sustaining global partnerships. . PMID- 23436753 TI - Shotgun proteomics of archival triple-negative breast cancer samples. AB - PURPOSE: Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers, and has a worse prognosis compared with hormone receptor-positive disease. Its unfavorable outcome and the lack of hormonal receptors determine the use of adjuvant chemotherapy as part of the standard treatment for these tumors, although several studies have documented that the current standard combination chemotherapy is suboptimal. Therefore, a new functional taxonomy of breast cancer and new targets for therapeutic development are urgently needed. EXPERIMENTAL DESIGN: In this study, we have analyzed the proteome of TNBC applying a high throughput proteomics approach to routinely archived formalin-fixed, paraffin embedded tumor tissues. RESULTS: We have been able to identify and quantify more than 1000 protein groups. Some of these proteins are of outstanding interest in the biology and clinical management of this disease, such as CD44 and PARP1. Moreover, we have characterized some signaling pathways that could be related to TNBC genesis and development. CONCLUSION AND CLINICAL RELEVANCE: Our results open up new avenues for the use of proteomics technologies in clinically relevant studies using archival samples. Shotgun LC-MS/MS studies could serve to discover new biomarkers and may provide clues to the genesis of TNBC and underlying molecular alterations. PMID- 23436754 TI - Fabrication and characterization of regenerated silk scaffolds reinforced with natural silk fibers for bone tissue engineering. AB - We introduce a novel Bombyx mori silk-based composite material developed for bone tissue engineering. Three-dimensional scaffolds were fabricated by embedding of natural degummed silk fibers in a matrix of regenerated fibroin, followed by freeze-drying. Different ratios of fibers to fibroin were investigated with respect to their influence on mechanical and biological properties. For all scaffold types, an interconnected porous structure suitable for cell penetration was proven by scanning electron microscopy. Compressive tests, carried out in static and cyclic mode under dry as well as wet conditions, revealed a strong impact of fiber reinforcement on compressive modulus and compressive stress. Cell culture experiments with human mesenchymal stem cells demonstrated that the fiber/fibroin composite scaffolds support cell attachment, proliferation, as well as differentiation along the osteoblastic lineage. Considering the excellent mechanical and biological properties, novel fiber/fibroin scaffolds appear to be an interesting structure for prospect studies in bone tissue engineering. PMID- 23436755 TI - Spiroconjugated intramolecular charge-transfer emission in non-typical spiroconjugated molecules: the effect of molecular structure upon the excited state configuration. AB - A set of terfluorenes and terfluorene-like molecules with different pendant substitutions or side groups were designed and synthesized, their photophysical properties and the excited-state geometries were studied. Dual fluorescence emissions were observed in compounds with rigid pendant groups bearing electron donating N atoms. According to our earlier studies, in this set of terfluorenes, the blue emission is from the local pi-pi* transition, while the long-wavelength emission is attributed to a spiroconjugation-like through-space charge-transfer process. Herein, we probe further into how the molecular structures (referring to the side groups, the type of linkage between central fluorene and the 2,2' azanediyldiethanol units, and-most importantly-the amount of pendant groups), as well as the excited-state geometries, affect the charge-transfer process of these terfluorenes or terfluorene-like compounds. 9-(9,9,9'',9''-tetrahexyl-9H,9'H,9''H [2,2':7',2''-terfluoren]-9'-yl)-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolone (TFPJH), with only one julolidine pendant group, was particularly synthesized, which exhibits complete "perpendicular" conformation between julolidine and the central fluorene unit in the excited state, thus typical spiroconjugation could be achieved. Notably, its photophysical behaviors resemble those of TFPJ with two pendant julolidines. This study proves that spiroconjugation does happen in these terfluorene derivatives, although their structures are not in line with the typical orthogonal pi fragments. The spiroconjugation charge-transfer emission closely relates to the electron-donating N atoms on the pendant groups, and to the rigid connection between the central fluorene and the N atoms, whereas the amount of pendant groups and the nature of the side chromophores have little effect. These findings may shed light on the understanding of the through-space charge-transfer properties and the emission color tuning of fluorene derivatives. PMID- 23436756 TI - Percutaneous recanalization of totally occluded pulmonary veins after pulmonary vein isolation-intermediate-term follow-up. AB - OBJECTIVES: Review mid-term follow-up of percutaneous intervention for post ablation total pulmonary vein occlusion (PVO). BACKGROUND: Feasibility of percutaneous intervention for PVO has been described, but information remains limited. METHODS: Patients with total PVO were retrospectively identified from our catheterization database. Medical records, catheterization reports, and outpatient follow-up were reviewed. RESULTS: Between April 2005 and February 2012, 16 patients were identified with a total of 18 PVOs. Symptoms included hemoptysis in 6/16 (46%), cough in 8/16 (50%), chest pain in 8/16 (50%), dyspnea in 13/16 (81%) with mean NYHA Class of 2.6 +/- 0.6. Recanalization was accomplished in 14/18 (78%) veins: 11 treated with balloon dilation and 3 with stents. Median follow-up for 13/14 veins was 13 (0-39) months (one patient with one PVO is awaiting follow-up). Reocclusion occurred in 7/13 (54%) at mean follow up of 3.6 +/- 1.6 months (6/10 post-balloon dilation and 1/3 post-stenting). Despite reocclusion, the reference vessel diameter increased from 4.8 +/- 2.4 to 8.5 +/- 4.2 mm (P < 0.001) between the first and second catheterization. Re recanalization and stent placement was accomplished in 5/6 (83%), with one reocclusion not attempted. At latest follow-up 9/13 (69%) recanalized vessels remained patent and percent flow to affected lung quadrant increased from 7.4 +/- 3.4% pre-intervention to 14.3 +/- 4.2% (P = 0.004). Mean NYHA Class improved to 1.4 +/- 0.4 (P < 0.001). CONCLUSIONS: Recanalization of total PVO can be accomplished with reasonable mid-term patency, improved symptoms, and lung perfusion. Reocclusion is common, but vessel growth is often observed allowing placement of a reasonably sized stent at a second intervention. Staged intervention is often necessary to maintain patency. PMID- 23436758 TI - Single and polycrystalline graphene on Rh(111) following different growth mechanisms. AB - Graphene grown on the same substrate but under different growth conditions may evolve diverse characteristics and disparate growth mechanisms. To explore this issue, graphene is prepared on Rh(111) by both ultrahigh vacuum and ambient pressure chemical vapor deposition methods and the different growth behaviors, the atomic-scale structures, and the stacking geometry are analysed, mainly by virtue of scanning tunneling microscope. Interestingly, with ultrahigh vacuum chemical vapor deposition growth at 600 degrees C, a template growth of graphene by the Rh(111) lattice is obtained, reflected with the formation of a uniform graphene moire. In comparison, with the ambient-pressure chemical vapor deposition at 1000 degrees C by different quenching processes, monolayer and randomly stacked few-layer polycrystalline graphene is achieved, probably directed by combined surface catalysis and segregation mechanisms. In this case, strong and weak interactions between graphene and Rh substrates are suggested, with the samples prepared under vacuum and ambient-pressure conditions, respectively. This work is expected to contribute greatly to the exploration of interactions between graphene and a substrate, as well as the segregation mechanism of graphene growth on polycrystalline transitional metal substrates. PMID- 23436757 TI - Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum. AB - OBJECTIVE: Autoantibodies against melanoma differentiation-associated protein 5 (MDA-5) have been described in several Asian dermatomyositis (DM) cohorts, often associated with amyopathic DM and rapidly progressive interstitial lung disease (ILD). A recent study of a DM cohort seen at a US dermatology clinic reports that MDA-5 autoantibodies are associated with a unique cutaneous phenotype. Given the widening spectrum of clinical findings, we evaluated the clinical features of anti-MDA-5-positive patients seen at a US myositis referral center. METHODS: One hundred sixty DM patients were screened for MDA-5 autoantibodies by immunoprecipitation and antibody titers were analyzed in longitudinal serum samples. Anti-MDA-5-positive patients were evaluated for the presence of additional myositis autoantibodies. Patient clinical characteristics were compared by retrospective chart review. RESULTS: MDA-5 was targeted in 11 (6.9%) of 160 patients with DM. Of these, 9 presented with a symmetric polyarthropathy, 6 demonstrated overt clinical myopathy, and 8 had ILD. Eight anti-MDA-5-positive patients exhibited the clinical attributes of the antisynthetase syndrome in the absence of Jo-1 or other antisynthetase autoantibodies. MDA-5 autoantibody titers did not correlate with clinical course. CONCLUSION: MDA-5 autoantibodies are found in DM patients presenting with a symmetric polyarthritis, clinically similar to rheumatoid arthritis. These patients often have features of the antisynthetase syndrome, but in the absence of antisynthetase autoantibodies. Most anti-MDA-5-positive patients had overt clinical myopathy and ILD. The latter, while occasionally severe, typically resolved with immunosuppressive therapy. In this cohort, the MDA-5 phenotype is frequently a clinical mimic of the antisynthetase syndrome and is not associated with rapidly progressive ILD. PMID- 23436759 TI - Human endothelial colony-forming cells expanded with an improved protocol are a useful endothelial cell source for scaffold-based tissue engineering. AB - One of the major challenges in tissue engineering is to supply larger three dimensional (3D) bioengineered tissue transplants with sufficient amounts of nutrients and oxygen and to allow metabolite removal. Consequently, artificial vascularization strategies of such transplants are desired. One strategy focuses on endothelial cells capable of initiating new vessel formation, which are settled on scaffolds commonly used in tissue engineering. A bottleneck in this strategy is to obtain sufficient amounts of endothelial cells, as they can be harvested only in small quantities directly from human tissues. Thus, protocols are required to expand appropriate cells in sufficient amounts without interfering with their capability to settle on scaffold materials and to initiate vessel formation. Here, we analysed whether umbilical cord blood (CB)-derived endothelial colony-forming cells (ECFCs) fulfil these requirements. In a first set of experiments, we showed that marginally expanded ECFCs settle and survive on different scaffold biomaterials. Next, we improved ECFC culture conditions and developed a protocol for ECFC expansion compatible with 'Good Manufacturing Practice' (GMP) standards. We replaced animal sera with human platelet lysates and used a novel type of tissue-culture ware. ECFCs cultured under the new conditions revealed significantly lower apoptosis and increased proliferation rates. Simultaneously, their viability was increased. Since extensively expanded ECFCs could still settle on scaffold biomaterials and were able to form tubular structures in Matrigel assays, we conclude that these ex vivo-expanded ECFCs are a novel, very potent cell source for scaffold-based tissue engineering. PMID- 23436760 TI - Selective isolation and analysis of glycoprotein fractions and their glycomes from hepatocellular carcinoma sera. AB - As one of the most important post-translational modifications, the discovery, isolation, and identification of glycoproteins are becoming increasingly important. In this study, a Con A-magnetic particle conjugate-based method was utilized to selectively isolate the glycoproteins and their glycomes from the healthy donor and hepatocellular carcinoma (HCC) case sera. The isolated glycoproteins and their N-linked glycans were identified by LC-ESI-MS/MS and MALDI-TOF/TOF-MS, respectively. A total of 93 glycoproteins from the healthy donors and 85 glycoproteins from the HCC cases were identified. There were 34 different glycoproteins shown between the healthy donors (21/34) and the HCC cases (13/34). Twenty-eight glycans from the healthy donors and 30 glycans from the HCC cases were detected and there were 22 different glycans shown between the healthy donors (10/22) and HCC cases (12/22). Among these glycoproteins, 50 were known to be N-linked glycoproteins and three novel glycopeptides from two predicted potential glycoproteins were discovered. Moreover, lectin blotting, Western blotting and lectin/glyco-antibody microarrays were applied to definitely elucidate the change of selective protein expressions and their glycosylation levels, the results indicated that the differences of the identified glycoproteins between the healthy donors and HCC cases were caused by the change of both protein expression and their glycosylation levels. PMID- 23436761 TI - A comparative study of the remodeling and integration of a novel AuNP-tissue scaffold and commercial tissue scaffolds in a porcine model. AB - The extracellular matrices of a variety of human and animal tissues have been utilized as scaffold materials for soft tissue applications including hernia repair, dermal grafts, and tendon, ligament, and cartilage reconstruction. While these biological scaffolds are expected to demonstrate superior tissue integration, there is very little evidence documenting the properties and behavior of these materials in vivo. This in vivo study investigated four biological scaffolds: two commercially available (a moderately crosslinked scaffold and a noncrosslinked scaffold) and two novel porcine diaphragm biological scaffolds (one with and one without the incorporation of gold nanoparticles). The scaffolds were implanted in a porcine model and evaluated over 1, 3, and 6 months. The moderately crosslinked scaffolds demonstrated the least cellular infiltration and evidence of fibrosis. The noncrosslinked scaffolds demonstrated the greatest cellular infiltration, but these scaffolds were delaminated and exhibited a rapid loss of integrity. The porcine diaphragm scaffolds with and without nanoparticles showed evidence of tissue remodeling and cellular infiltration, with no evidence of encapsulation. While there were no significant differences in the performance of the two novel scaffolds, the gold nanoparticle scaffold typically exhibited higher cellular infiltration. This study demonstrated the potential biocompatibility of a gold nanoparticle-tissue scaffold. PMID- 23436762 TI - Changes in the electrical properties at an early stage of mouse liver carcinogenesis. AB - The present investigation reports the changes in the electrical properties of hepatic tissue in the frequency range of 100 Hz to 5 MHz at an early stage of liver carcinogenesis using the four-pin electrode method. The hepatocarcinogenesis model was developed by intraperitoneal injection of N nitrosodiethylamine (NDEA) to male Balb/c mice. Histopathological assessment revealed high-grade dysplasia in the liver of NDEA-treated animals. The ultrastructural investigations indicated the presence of large and clumped cells with inconspicuous cell boundaries. The treatment resulted in significant changes in the dielectric properties of the tissues. A decrease in tissue conductivity along with an increase in relative permittivity was observed. The biophysical changes correlated well with histoarchitectural and morphological changes. The alterations in architectural arrangement and membrane structure of cells may be responsible for the observed changes in the dielectric properties. PMID- 23436763 TI - Application of ionic liquid-based microwave-assisted extraction of malachite green and crystal violet from water samples. AB - A simple, environment friendly and efficient technique, ionic liquid-based microwave-assisted extraction was first used to determine malachite green and crystal violet (CV) from water samples coupled to HPLC. The key parameters influencing extraction efficiency were investigated, such as the type of ionic liquids, the volume of ionic liquid, extraction time, and so on. Under the optimum conditions, good reproducibility of the extraction performance was obtained (RSD, 1.0% for malachite green (MG) and 5.9% for CV, n = 5). Good linearity (0.10-25 MUg L(-1)) was observed with correlation coefficients between 0.9991 and 0.9964. The detection limits of MG and CV were 0.080 and 0.030 MUg L( 1), respectively. The proposed method had been successfully applied to determine MG and CV in real water samples with recoveries ranging from 95.4 to 102.8%. Compared with the previous technologies, the proposed method required less extraction time (2 min), and provided lower detection limits and higher enrichment factors. Moreover, there were no volatile and hazardous organic solvents released. Based on these simple, environment friendly, rapid, and highly efficient results, the proposed approach provides a new and promising alternative for simultaneously extracting trace amounts of MG and CV from water. PMID- 23436764 TI - Safety and efficacy evaluation of a human acellular nerve graft as a digital nerve scaffold: a prospective, multicentre controlled clinical trial. AB - This study developed a human acellular nerve graft (hANG) as an alternative to autogenous nerve and reports on its safety and efficacy. There were two groups comprised of 72 patients that received digital nerve repair with hANG (test) and 81 that received conventional direct tension-free suture repair of the nerve defect (control). The efficacy of the treatment was evaluated by static 2-point discrimination (s2PD) and Semmes-Weinstein monofilament testing. Safety was evaluated by local wound response and laboratory testing. Mean age of patients in the test group was 33.0 +/- 11.1 years (range 18-61 years) and in the control group 36.9 +/- 13.4 years (range 15-77 years) (p = 0.0470). Mean time from injury to repair in the test group was 23.7 +/- 52 days (range 0-200 days) and in the control group 1.5 +/- 10.4 days (range 0-91 days) (p = 0.0005). Mean length of nerve graft was 1.80 +/- 0.82 cm (range 1-5 cm). All surgeries were performed successfully and without complications. The excellent and good rate of s2PD in the test group was 65.28% and 95% CI was 51.98-78.93%. s2PD in the test group improved over time and average distance was 12.81 +/- 5.99 mm at 6 months postoperatively. No serious adverse or product-related events were reported. These results indicate that hANG is a safe and effective for the repair of nerve defects of 1-5 cm in size. PMID- 23436765 TI - Systematic review and critical appraisal of validation studies to identify rheumatic diseases in health administrative databases. AB - OBJECTIVE: To evaluate the quality of the methods and reporting of published studies that validate administrative database algorithms for rheumatic disease case ascertainment. METHODS: We systematically searched MEDLINE, Embase, and the reference lists of articles published from 1980 to 2011. We included studies that validated administrative data algorithms for rheumatic disease case ascertainment using medical record or patient-reported diagnoses as the reference standard. Each study was evaluated using published standards for the reporting and quality assessment of diagnostic accuracy, which informed the development of a methodologic framework to help critically appraise and guide research in this area. RESULTS: Twenty-three studies met the inclusion criteria. Administrative database algorithms to identify cases were most frequently validated against diagnoses in medical records (83%). Almost two-thirds of the studies (61%) used diagnosis codes in administrative data to identify potential cases and then reviewed medical records to confirm the diagnoses. The remaining studies did the reverse, identifying patients using a reference standard and then testing algorithms to identify cases in administrative data. Many authors (61%) described the patient population, but few (26%) reported key measures of diagnostic accuracy (sensitivity, specificity, and positive and negative predictive values). Only one-third of studies reported disease prevalence in the validation study sample. CONCLUSION: The methods used in administrative data validation studies of rheumatic diseases are highly variable. Few studies reported key measures of diagnostic accuracy despite their importance for drawing conclusions about the validity of administrative database algorithms. We developed a methodologic framework and recommendations for validation study conduct and reporting. PMID- 23436766 TI - Cell response of anodized nanotubes on titanium and titanium alloys. AB - Titanium and titanium alloy implants that have been demonstrated to be more biocompatible than other metallic implant materials, such as Co-Cr alloys and stainless steels, must also be accepted by bone cells, bonding with and growing on them to prevent loosening. Highly ordered nanoporous arrays of titanium dioxide that form on titanium surface by anodic oxidation are receiving increasing research interest due to their effectiveness in promoting osseointegration. The response of bone cells to implant materials depends on the topography, physicochemistry, mechanics, and electronics of the implant surface and this influences cell behavior, such as adhesion, proliferation, shape, migration, survival, and differentiation; for example the existing anions on the surface of a titanium implant make it negative and this affects the interaction with negative fibronectin (FN). Although optimal nanosize of reproducible titania nanotubes has not been reported due to different protocols used in studies, cell response was more sensitive to titania nanotubes with nanometer diameter and interspace. By annealing, amorphous TiO2 nanotubes change to a crystalline form and become more hydrophilic, resulting in an encouraging effect on cell behavior. The crystalline size and thickness of the bone-like apatite that forms on the titania nanotubes after implantation are also affected by the diameter and shape. This review describes how changes in nanotube morphologies, such as the tube diameter, the thickness of the nanotube layer, and the crystalline structure, influence the response of cells. PMID- 23436767 TI - ESPRESSO: a system for estimating protein expression and solubility in protein expression systems. AB - Recombinant protein technology is essential for conducting protein science and using proteins as materials in pharmaceutical or industrial applications. Although obtaining soluble proteins is still a major experimental obstacle, knowledge about protein expression/solubility under standard conditions may increase the efficiency and reduce the cost of proteomics studies. In this study, we present a computational approach to estimate the probability of protein expression and solubility for two different protein expression systems: in vivo Escherichia coli and wheat germ cell-free, from only the sequence information. It implements two kinds of methods: a sequence/predicted structural property-based method that uses both the sequence and predicted structural features, and a sequence pattern-based method that utilizes the occurrence frequencies of sequence patterns. In the benchmark test, the proposed methods obtained F-scores of around 70%, and outperformed publicly available servers. Applying the proposed methods to genomic data revealed that proteins associated with translation or transcription have a strong tendency to be expressed as soluble proteins by the in vivo E. coli expression system. The sequence pattern-based method also has the potential to indicate a candidate region for modification, to increase protein solubility. All methods are available for free at the ESPRESSO server (http://mbs.cbrc.jp/ESPRESSO). PMID- 23436768 TI - The relationship between right-wing ideological attitudes and psychological well being. AB - The relationship between right-wing ideological attitudes and psychological well being has been intensively studied. Although some studies supported the hypothesis that right-wing attitudes are negatively related with well-being, other research yielded positive or nonsignificant relationships. We conducted a meta-analysis (total samples = 97, total N = 69,221) of measures of well-being, including positive and negative affect, life satisfaction, self-esteem, and intrinsic goal pursuit. The obtained effect sizes were generally weak and nonsignificant, except for a moderate relationship between intrinsic goal pursuit and social dominance orientation. Our results thus do not support previous theories that claim that right-wing attitudes yield substantial relationships with psychological well-being. PMID- 23436770 TI - Mood and processing of proattitudinal and counterattitudinal messages. AB - Existing research has established the effects of mood on processing of clearly mood-elevating proattitudinal messages and clearly mood-threatening counterattitudinal messages (i.e., mood-relevant messages). Little is known, however, about mood effects on processing of less mood-elevating proattitudinal messages and less mood-threatening counterattitudinal messages (i.e., mood irrelevant messages). The present research tested hypotheses regarding processing of mood-irrelevant messages based on a mood-congruent expectancies approach. Specifically, two studies were conducted in which prior attitudes were measured (Study 1) or manipulated (Study 2). As predicted, results showed higher scrutiny in negative mood given a proattitudinal message and in positive mood given a counterattitudinal message than in negative mood given a counterattitudinal message and in positive mood given a proattitudinal message. Discussion focuses on implications regarding the accumulated literature, different accounts proposed to understand mood effects on processing effort, and further research. PMID- 23436769 TI - Effects of implementation intentions on anxiety, perceived proximity, and motor performance. AB - Anxiety leads to exaggerated perceptions of distance, which may impair performance on a physical task. In two studies, we tested one strategy to reduce anxiety and induce perceived proximity to increase performance. We predicted implementation intentions that reduce anxiety would increase perceived visual proximity to goal-relevant targets, which would indirectly improve performance. In two studies, we induced performance anxiety on a physical task. Participants who formed implementation intentions to reduce anxiety perceived goal-relevant targets (e.g., golf hole, dartboard) as physically closer and performed better than both participants without a strategy (Study 1) and participants with only a goal to regulate anxiety (Study 2). Furthermore, perceived proximity improved performance indirectly by increasing subjective task ease (Study 2). Results suggest that implementation intentions can reduce anxiety and lead to perceived proximity of goal-relevant targets, which helps perceivers make progress on goals. PMID- 23436771 TI - Nonaqueous CE ESI-IT-MS analysis of Amaryllidaceae alkaloids. AB - The Amaryllidaceae are widely distributed medical plants. Lycorine, lycoramine, lycoremine, and lycobetaine are the major active alkaloids in Amaryllidaceae plants. A nonaqueous CE ESI-IT-MS method for separation, identification, and quantification of the Amaryllidaceae alkaloids has been developed. The MS(1-3) behavior has been studied and the fragmentation pathways of main fragment ions have been proposed. The effects of several factors such as composition and concentration of buffer, applied voltage, composition, and flow rate of the sheath liquid, nebulizing gas pressure, flow rate, and temperature of drying gas were investigated. Under the optimal conditions, the linear concentration range of these compounds was wide with the correlation coefficient (R(2) ) >0.99. RSDs of migration time and peak areas were <10%. The LODs were <240 ng/mL. The proposed method can be successfully applied to the determination of the related alkaloids in the Lycoris radiata roots. PMID- 23436772 TI - Assessing multiple endpoints of atrazine ingestion on gravid Northern Watersnakes (Nerodia sipedon) and their offspring. AB - Ecotoxicological studies that focus on a single endpoint might not accurately and completely represent the true ecological effects of a contaminant. Exposure to atrazine, a widely used herbicide, disrupts endocrine function and sexual development in amphibians, but studies involving live-bearing reptiles are lacking. This study tracks several effects of atrazine ingestion from female Northern Watersnakes (Nerodia sipedon) to their offspring exposed in utero. Twenty-five gravid N. sipedon were fed fish dosed with one of the four levels of atrazine (0, 2, 20, or 200 ppb) twice weekly for the entirety of their gestation period. Endpoints for the mothers included blood estradiol levels measured weekly and survival more than 3 months. Endpoints for the offspring included morphometrics, clutch sex ratio, stillbirth, and asymmetry of dorsal scales and jaw length. Through these multiple endpoints, we show that atrazine ingestion can disrupt estradiol production in mothers, increase the likelihood of mortality from infection, alter clutch sex ratio, cause a higher proportion of stillborn offspring, and affect scale symmetry. We emphasize the need for additional research involving other reptile species using multiple endpoints to determine the full range of impacts of contaminant exposure. PMID- 23436773 TI - Longitudinal Heschl's gyrus growth during childhood and adolescence in typical development and autism. AB - Heightened auditory sensitivity and atypical auditory processing are common in autism. Functional studies suggest abnormal neural response and hemispheric activation to auditory stimuli, yet the neurodevelopment underlying atypical auditory function in autism is unknown. In this study, we model longitudinal volumetric growth of Heschl's gyrus gray matter and white matter during childhood and adolescence in 40 individuals with autism and 17 typically developing participants. Up to three time points of magnetic resonance imaging data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at the time of their first scan. Consistent with previous cross-sectional studies, no group differences were found in Heschl's gyrus gray matter volume or asymmetry. However, reduced longitudinal gray matter volumetric growth was found in the right Heschl's gyrus in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical Heschl's gyrus white matter volumetric growth was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened auditory sensitivity, obtained from the Sensory Profile, was associated with reduced volumetric gray matter growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl's gyrus throughout childhood and adolescence in both typical development and autism. PMID- 23436774 TI - Prevalence of axial spondyloarthritis in United States rheumatology practices: Assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. AB - OBJECTIVE: New classification criteria for axial spondyloarthritis (SpA) have been validated by the Assessment of SpondyloArthritis international Society (ASAS) working group. We applied these criteria to estimate prevalence of SpA in randomly selected, retrospectively reviewed medical records from representative US rheumatology practices. METHODS: Rheumatologists from 101 US practices identified at-risk patients, ages 18-44 years, with chronic back pain. Medical records were reviewed against ASAS criteria. The proportion of patients meeting ASAS criteria was compared to an estimate of the total number of at-risk patients treated at participating sites and, following weighting, was extrapolated to 5,520 US rheumatology practices. US Census data were used to estimate national prevalence. RESULTS: In a sample of 816 randomly selected records, 514 (63%) at risk patients (95% confidence interval [95% CI] 59.6-66.3%) met ASAS criteria. By applying this proportion to 1,217,097 Americans estimated at risk, 766,652 were projected to meet ASAS criteria. This projection corresponds to a national prevalence of 0.70% (95% CI 0.38-1.1%) or 701 per 100,000 individuals. The prevalence estimates of ankylosing spondylitis and nonradiographic axial SpA are 0.35% (95% CI 0.18-0.554%) and 0.35% (95% CI 0.18-0.554%), respectively. Rheumatologists diagnosed axial SpA in 491 (60%) of those at risk, corresponding to 0.67% (95% CI 0.36-1.01%) prevalence overall. However, of 514 patients meeting ASAS criteria, 124 (24%) were undiagnosed by rheumatologists. CONCLUSION: This is the first systematic epidemiology study of axial SpA using ASAS criteria. Better recognition of axial symptoms is needed, as rheumatologists' expert clinical diagnoses are not always in agreement with ASAS criteria. PMID- 23436776 TI - Estimation of the breakthrough volume of selected steroids for C-18 solid-phase extraction sorbent using retention data from micro-thin layer chromatography. AB - SPE method is a very popular technique, and is commonly used for the prepurification, concentration, and isolation of different organic compounds from variable matrices. In this work, the optimization of SPE process was carried out. The breakthrough volume of solid sorbents based on octadecylsilane was determined and three methods were compared: (1) calculation one - the breakthrough volume was calculated using retention factor k determined with micro-TLC method, frontal analysis - (2) breakthrough volume was determined as volume of whole elution peak, and (3) breakthrough volume was determined as the center of peak gravity. For calculation method, the k values of key estrogens and progestogens were derived from the micro-TLC experiment reported previously. By combining these three methods, we can point the start of elution, the maximum concentration of analyte in eluate, and the whole eluent volume, which is necessary to achieve an appropriate selectivity and high extraction recovery. Proposed calculation method allows to estimate the beginning of the steroid peak, when the analyte appears in the eluate flowing from the sorbent. Such observation advances the SPE optimization protocol that was described before and was based on the correlation between raw k(SPE) and k(micro-TLC) data. PMID- 23436777 TI - Effect of nonpersistent pesticides on estrogen receptor, androgen receptor, and aryl hydrocarbon receptor. AB - Nonpersistent pesticides are considered less harmful for the environment, but their impact as endocrine disruptors has not been fully explored. The pesticide Switch was applied to grape vines, and the maximum residue concentration of its active ingredients was quantified. The transactivation potential of the pesticides Acorit, Frupica, Steward, Reldan, Switch, Cantus, Teldor, and Scala and their active compounds (hexythiazox, mepanipyrim, indoxacarb, chlorpyrifos methyl, cyprodinil, fludioxonil, boscalid, fenhexamid, and pyrimethanil) were tested on human estrogen receptor alpha (ERalpha), androgen receptor (AR) and arylhydrocarbon receptor (AhR) in vitro. Relative binding affinities of the pure pesticide constituents for AR and their effect on human breast cancer and prostate cancer cell lines were evaluated. Residue concentrations of Switch's ingredients were below maximum residue limits. Fludioxonil and fenhexamid were ERalpha agonists (EC50 -values of 3.7 and 9.0 MUM, respectively) and had time dependent effects on endogenous ERalpha-target gene expression (cyclin D1, progesterone receptor, and nuclear respiratory factor 1) in MCF-7 human breast cancer cells. Fludioxonil, mepanipyrim, cyprodinil, pyrimethanil, and chlorpyrifos-methyl were AhR-agonists (EC50 s of 0.42, 0.77, 1.4, 4.6, and 5.1 MUM, respectively). Weak AR binding was shown for chlorpyrifos-methyl, cyprodinil, fenhexamid, and fludioxonil. Assuming a total uptake which does not take metabolism and clearance rates into account, our in vitro evidence suggests that pesticides could activate pathways affecting hormonal balance, even within permitted limits, thus potentially acting as endocrine disruptors. PMID- 23436775 TI - GLI1 regulates a novel neuropilin-2/alpha6beta1 integrin based autocrine pathway that contributes to breast cancer initiation. AB - The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expressed on TNBC cells mediate autocrine signalling that contributes to tumour initiation. We discovered the VEGF receptor neuropilin-2 (NRP2) is expressed preferentially on TICs, involved in the genesis of TNBCs and necessary for tumour initiation. The mechanism by which NRP2 signalling promotes tumour initiation involves stimulation of the alpha6beta1 integrin, focal adhesion kinase-mediated activation of Ras/MEK signalling and consequent expression of the Hedgehog effector GLI1. GLI1 also induces BMI-1, a key stem cell factor, and it enhances NRP2 expression and the function of alpha6beta1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, alpha6beta1 and GLI1 that contributes to the initiation of TNBC. They also support the feasibility of NRP2 based therapy for the treatment of TNBC that targets and impedes the function of TICs. PMID- 23436778 TI - Stability and validity of an automated measure of vocal development from day-long samples in children with and without autism spectrum disorder. AB - Individual difference measures of vocal development may eventually aid our understanding of the variability in spoken language acquisition in children with autism spectrum disorder (ASD). Large samples of child vocalizations may be needed to maximize the stability of vocal development estimates. Day-long vocal samples can now be automatically analyzed based on acoustic characteristics of speech likeness identified in theoretically driven and empirically cross validated quantitative models of typical vocal development. This report indicates that a single day-long recording can produce a stable estimate for a measure of vocal development that is highly related to expressive spoken language in a group of young children with ASD and in a group that is typically developing. Autism Res 2013, 6: 103-107. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 23436780 TI - Host cell protein analysis in therapeutic protein bioprocessing - methods and applications. AB - The analysis of host cell proteins (HCPs) is one of the most important analytical requirements during bioprocess development of therapeutic moieties. In this review, we focus on the comparison of different methods for the analysis of HCPs and how cell lines, fermentation conditions, and unit operations influence HCP distribution during the process chain. Current guidelines typically require reduction of HCPs to the ppm level, depending on the intended use, the route of administration of the product, and the production system. A range of immunospecific and non-specific methods are available that have been globally accepted by regulatory bodies. Immunospecific methods, such as ELISA, are simple to use in routine analysis and can quantify low levels of HCPs when specific antibodies are available. Non-specific methods are more complex; however, they provide a holistic view of the HCP profile and qualitative information of the composition of HCP in the sample. Different methods for the comparison of bioprocessing strategies during scale-up and purification development are compared herein. The methods include immunospecific methods, such as ELISA, western blot, and threshold, and non-specific methods, such as 2D-DIGE and 2D HPLC combined with MS. PMID- 23436779 TI - A self-adjuvanting supramolecular vaccine carrying a folded protein antigen. AB - This work illustrates a strategy for the design of molecularly defined immunotherapies, using a blend of supramolecular peptide self-assembly and active site-directed protein capture. PMID- 23436781 TI - Numerical investigation into the effects of ordered particle packing and slip flow on the performance of chromatography. AB - The pressure drop and the plate height of chromatography columns packed with particles in the face-centered cubic, the body-centered cubic and the simple cubic configurations are calculated by a volume averaging method model. It is found that the Kozeny-Carman equation provides a reasonable prediction of the pressure drop when particles are in the face-centered cubic configuration, but overestimates the pressure drop when particles are in the body-centered cubic and the simple cubic configurations. The face-centered cubic configuration has the advantage to provide a smaller longitudinal dispersion coefficient than the body centered cubic, the simple cubic, and the random configurations. The pressure drop and the plate height for slip flow through particles in the face-centered cubic configuration are lower than that for no-slip flow. The values of the smallest reduced plate height of columns packed with particles in the face centered cubic configuration for no-slip flow and slip flow are about 0.084 and 0.059, respectively. The plate height of the ordered particle packing structures is smaller and the effect of slip flow on the plate height is less remarkable than results reported in literature. PMID- 23436782 TI - Proton magnetic resonance spectroscopy as a probe into the pathophysiology of autism spectrum disorders (ASD): a review. AB - Proton magnetic resonance spectroscopy ((1) H-MRS) is a safe, noninvasive way of quantifying in vivo biochemical and metabolite concentration levels in individuals with Autism Spectrum Disorders (ASD). Findings to date suggest ASD is associated with widespread reduction in N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol (mI), and glutamate plus glutamine plus gamma-Aminobutyric Acid (Glx); however, variable findings, and even substantial increases, are not uncommon depending on the study and/or region-of-interest. Widespread reduction of NAA, Cr, Cho, mI, and Glx in ASD likely reflects impaired neuronal function and/or metabolism related to abnormal neurodevelopmental processes. Future studies should attempt to relate (1) H-MRS findings to histological findings and control for variability in subject age and functioning level; this would assist in evaluating the relationship between (1) H-MRS metabolic levels and neuronal and glial cell densities, as well as neurodevelopmental process associated with ASD. Furthermore, more longitudinal (1) H-MRS studies are needed in both control and ASD subjects to attempt to standardize metabolite levels across different developmental periods in well-defined endophenotypes. This will provide for a standard rubric for which metabolic aberrations (as well as treatment responses) can be measured. With higher magnetic field strengths and spectral-editing techniques capable of quantifying less-concentrated metabolites, (1) H-MRS will continue to be an important tool in ASD research. PMID- 23436783 TI - Very high density of Chinese hamster ovary cells in perfusion by alternating tangential flow or tangential flow filtration in WAVE BioreactorTM-part II: Applications for antibody production and cryopreservation. AB - A high cell density perfusion process of monoclonal antibody (MAb) producing Chinese hamster ovary (CHO) cells was developed in disposable WAVE BioreactorTM using external hollow fiber (HF) filter as cell separation device. Tangential flow filtration (TFF) and alternating tangential flow (ATF) systems were compared and process applications of high cell density perfusion were studied here: MAb production and cryopreservation. Operations by perfusion using microfiltration (MF) or ultrafiltration (UF) with ATF or TFF and by fed-batch were compared. Cell densities higher than 10(8) cells/mL were obtained using UF TFF or UF ATF. The cells produced comparable amounts of MAb in perfusion by ATF or TFF, MF or UF. MAbs were partially retained by the MF using ATF or TFF but more severely using TFF. Consequently, MAbs were lost when cell broth was discarded from the bioreactor in the daily bleeds. The MAb cell-specific productivity was comparable at cell densities up to 1.3 * 10(8) cells/mL in perfusion and was comparable or lower in fed-batch. After 12 days, six times more MAbs were harvested using perfusion by ATF or TFF with MF or UF, compared to fed-batch and 28* more in a 1 month perfusion at 10(8) cells/mL density. Pumping at a recirculation rate up to 2.75 L/min did not damage the cells with the present TFF settings with HF short circuited. Cell cryopreservation at 0.5 * 10(8) and 10(8) cells/mL was performed using cells from a perfusion run at 10(8) cells/mL density. Cell resuscitation was very successful, showing that this system was a reliable process for cell bank manufacturing. PMID- 23436784 TI - Visual long-term memory stores high-fidelity representations of observed actions. AB - The ability to remember others' actions is fundamental to social cognition, but the precision of action memories remains unknown. To probe the fidelity of the action representations stored in visual long-term memory, we asked observers to view a large number of computer-animated actions. Afterward, observers were shown pairs of actions and indicated which of the two actions they had seen for each pair. On some trials, the previously viewed action was paired with an action from a different action category, and on other trials, it was paired with an action from the same category. Accuracy on both types of trials was remarkably high (81% and 82%, respectively). Further, results from a second experiment showed that the action representations maintained in visual long-term memory can be nearly as precise as the action representations maintained in visual working memory. Together, these findings provide evidence for a mechanism in visual long-term memory that maintains high-fidelity representations of observed actions. PMID- 23436785 TI - Sleep consolidation of interfering auditory memories in starlings. AB - Memory consolidation has been described as a process to strengthen newly formed memories and to stabilize them against interference from similar learning experiences. Sleep facilitates memory consolidation in humans, improving memory performance and protecting against interference encountered after sleep. The European starling, a songbird, has also manifested sleep-dependent memory consolidation when trained on an auditory-classification task. Here, we examined how memory for two similar classification tasks is consolidated across waking and sleep in starlings. We demonstrated for the first time that the learning of each classification reliably interferes with the retention of the other classification across waking retention but that sleep enhances and stabilizes the memory of both classifications even after performance is impaired by interference. These observations demonstrate that sleep consolidation enhances retention of interfering experiences, facilitating opportunistic daytime learning and the subsequent formation of stable long-term memories. PMID- 23436786 TI - Attention restores discrete items to visual short-term memory. AB - When a memory is forgotten, is it lost forever? Our study shows that selective attention can restore forgotten items to visual short-term memory (VSTM). In our two experiments, all stimuli presented in a memory array were designed to be equally task relevant during encoding. During the retention interval, however, participants were sometimes given a cue predicting which of the memory items would be probed at the end of the delay. This shift in task relevance improved recall for that item. We found that this type of cuing improved recall for items that otherwise would have been irretrievable, providing critical evidence that attention can restore forgotten information to VSTM. Psychophysical modeling of memory performance has confirmed that restoration of information in VSTM increases the probability that the cued item is available for recall but does not improve the representational quality of the memory. We further suggest that attention can restore discrete items to VSTM. PMID- 23436787 TI - Recombineering to homogeneity: extension of multiplex recombineering to large scale genome editing. AB - Recombineering has been an essential tool for genetic engineering in microbes for many years and has enabled faster, more efficient engineering than previous techniques. There have been numerous studies that focus on improving recombineering efficiency, which can be divided into three main areas: (i) optimizing the oligo used for recombineering to enhance replication fork annealing and limit proofreading; (ii) mechanisms to modify the replisome itself, enabling an increased rate of annealing; and (iii) multiplexing recombineering targets and automation. These efforts have increased the efficiency of recombineering several hundred-fold. One area that has received far less attention is the problem of multiple chromosomes, which effectively decrease efficiency on a chromosomal basis, resulting in more sectored colonies, which require longer outgrowth to obtain clonal populations. Herein, we describe the problem of multiple chromosomes, discuss calculations predicting how many generations are needed to obtain a pure colony, and how changes in experimental procedure or genetic background can minimize the effect of multiple chromosomes. PMID- 23436788 TI - Eye movement difficulties in autism spectrum disorder: implications for implicit contextual learning. AB - It is widely accepted that we use contextual information to guide our gaze when searching for an object. People with autism spectrum disorder (ASD) also utilise contextual information in this way; yet, their visual search in tasks of this kind is much slower compared with people without ASD. The aim of the current study was to explore the reason for this by measuring eye movements. Eye movement analyses revealed that the slowing of visual search was not caused by making a greater number of fixations. Instead, participants in the ASD group were slower to launch their first saccade, and the duration of their fixations was longer. These results indicate that slowed search in ASD in contextual learning tasks is not due to differences in the spatial allocation of attention but due to temporal delays in the initial-reflexive orienting of attention and subsequent-focused attention. These results have broader implications for understanding the unusual attention profile of individuals with ASD and how their attention may be shaped by learning. PMID- 23436789 TI - Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactorTM. Part I. Effect of the cell density on the process. AB - High cell density perfusion process of antibody producing CHO cells was developed in disposable WAVE BioreactorTM using external hollow fiber filter as cell separation device. Both "classical" tangential flow filtration (TFF) and alternating tangential flow system (ATF) equipment were used and compared. Consistency of both TFF- and ATF-based cultures was shown at 20-35 * 10(6) cells/mL density stabilized by cell bleeds. To minimize the nutrients deprivation and by-product accumulation, a perfusion rate correlated to the cell density was applied. The cells were maintained by cell bleeds at density 0.9-1.3 * 10(8) cells/mL in growing state and at high viability for more than 2 weeks. Finally, with the present settings, maximal cell densities of 2.14 * 10(8) cells/mL, achieved for the first time in a wave-induced bioreactor, and 1.32 * 10(8) cells/mL were reached using TFF and ATF systems, respectively. Using TFF, the cell density was limited by the membrane capacity for the encountered high viscosity and by the pCO2 level. Using ATF, the cell density was limited by the vacuum capacity failing to pull the highly viscous fluid. Thus, the TFF system allowed reaching higher cell densities. The TFF inlet pressure was highly correlated to the viscosity leading to the development of a model of this pressure, which is a useful tool for hollow fiber design of TFF and ATF. At very high cell density, the viscosity introduced physical limitations. This led us to recommend cell densities under 1.46 * 10(8) cell/mL based on the analysis of the theoretical distance between the cells for the present cell line. PMID- 23436792 TI - Intermolecular interactions during ultrafiltration of pegylated proteins. AB - Recent studies have demonstrated the feasibility of using membrane ultrafiltration for the purification of pegylated proteins; however, the separations have all been performed at relatively low protein concentrations where intermolecular interactions are unimportant. The objective of this study was to examine the behavior at higher PEG concentrations and to develop an appropriate theoretical framework to describe the effects of intermolecular interactions. Ultrafiltration experiments were performed using pegylated alpha lactalbumin as a model protein with both neutral and charged composite regenerated cellulose membranes. The transmission of the pegylated alpha lactalbumin, PEG, and alpha-lactalbumin all increase with increasing PEG concentration due to the increase in the solute partition coefficient arising from unfavorable intermolecular interactions in the bulk solution. The experimental results were in good agreement with a simple model that accounts for the change in Gibbs free energy associated with these intermolecular interactions, including the effects of concentration polarization on the local solute concentrations upstream of the membrane. These intermolecular interactions are shown to cause a greater than expected loss of pegylated product in a batch ultrafiltration system, and they alter the yield and purification factor that can be achieved during a diafiltration process to remove unreacted PEG. PMID- 23436791 TI - A combination strategy to inhibit Pim-1: synergism between noncompetitive and ATP competitive inhibitors. AB - Pim-1 is a serine/threonine kinase critically involved in the initiation and progression of various types of cancer, especially leukemia, lymphomas and solid tumors such as prostate, pancreas and colon, and is considered a potential drug target against these malignancies. In an effort to discover new potent Pim-1 inhibitors, a previously identified ATP-competitive indolyl-pyrrolone scaffold was expanded to derive structure-activity relationship data. A virtual screening campaign was also performed, which led to the discovery of additional ATP competitive inhibitors as well as a series of 2-aminothiazole derivatives, which are noncompetitive with respect to both ATP and peptide substrate. This mechanism of action, which resembles allosteric inhibition, has not previously been characterized for Pim-1. Notably, further evaluation of the 2-aminothiazoles indicated a synergistic inhibitory effect in enzymatic assays when tested in combination with ATP-competitive inhibitors. A synergistic effect in the inhibition of cell proliferation by ATP-competitive and ATP-noncompetitive compounds was also observed in prostate cancer cell lines (PC3), where all Pim-1 inhibitors tested in showed synergism with the known anticancer agent, paclitaxel. These results further establish Pim-1 as a target in cancer therapy, and highlight the potential of these agents for use as adjuvant agents in the treatment of cancer diseases in which Pim-1 is associated with chemotherapeutic resistance. PMID- 23436793 TI - Behavior and sleep problems in children with a family history of autism. AB - The present study explores behavioral and sleep outcomes in preschool-age siblings of children with autism spectrum disorders (ASD). This study focuses on behavior problems that are common in children with ASD, such as emotional reactivity, anxiety, inattention, aggression, and sleep problems. Infant siblings were recruited from families with at least one older child with ASD (high-risk group, n = 104) or families with no history of ASD (low-risk group, n = 76). As part of a longitudinal prospective study, children completed the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, and parents completed the Child Behavior Checklist (CBCL) and the Social Communication Questionnaire at 36 months of age. This study focuses on developmental concerns outside of ASD; therefore, only siblings who did not develop an ASD were included in analyses. Negative binomial regression analyses revealed that children in the high-risk group were more likely to have elevated behavior problems on the CBCL Anxious/Depressed and Aggression subscales. To explore sleep problems as a correlate of these behavior problems, a second series of models was specified. For both groups of children, sleep problems were associated with elevated behavior problems in each of the areas assessed (reactivity, anxiety, somatic complaints, withdrawal, attention, and aggression). These findings support close monitoring of children with a family history of ASD for both behavioral and sleep issues. PMID- 23436795 TI - Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. AB - The incidence of neuroendocrine tumors (NET) has increased dramatically in the past 30 years. This information has revitalized basic and clinical research into the molecular biology of NET and has resulted in the recent approval of new therapies for pancreatic NET (pNET), including the oral inhibitor of the mTOR everolimus. Everolimus significantly improved progression-free survival among patients with pNET in the phase III RADIANT-3 study. Here, we review the clinical studies showing the efficacy of everolimus in pNET and summarize the translational science from these studies. To understand the mechanisms of resistance and cause of treatment failure, we compared the type of progression events observed in the everolimus and placebo arms of the RADIANT-3 study. Comparison of the everolimus arm to the placebo arm indicated the fractions of progression events due to new metastasis only (21% vs. 22%), growth of preexisting lesions only (54% vs. 49%), and new metastasis along with growth of preexisting lesions (24% vs. 27%) were similar. These results suggest that although everolimus delays disease progression in patients with pNET, patients who experience disease progression while on everolimus do not appear to have a more aggressive metastatic phenotype than those whose disease progresses while on placebo. PMID- 23436794 TI - Localized immunotherapy via liposome-anchored Anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity. AB - Immunostimulatory agonists such as anti-CD137 and interleukin (IL)-2 have elicited potent antitumor immune responses in preclinical studies, but their clinical use is limited by inflammatory toxicities that result upon systemic administration. We hypothesized that by rigorously restricting the biodistribution of immunotherapeutic agents to a locally accessible lesion and draining lymph node(s), effective local and systemic antitumor immunity could be achieved in the absence of systemic toxicity. We anchored anti-CD137 and an engineered IL-2Fc fusion protein to the surfaces of PEGylated liposomes, whose physical size permitted dissemination in the tumor parenchyma and tumor-draining lymph nodes but blocked entry into the systemic circulation following intratumoral injection. In the B16F10 melanoma model, intratumoral liposome coupled anti-CD137 + IL-2Fc therapy cured a majority of established primary tumors while avoiding the lethal inflammatory toxicities caused by equivalent intratumoral doses of soluble immunotherapy. Immunoliposome therapy induced protective antitumor memory and elicited systemic antitumor immunity that significantly inhibited the growth of simultaneously established distal tumors. Tumor inhibition was CD8(+) T-cell-dependent and was associated with increased CD8(+) T-cell infiltration in both treated and distal tumors, enhanced activation of tumor antigen-specific T cells in draining lymph nodes, and a reduction in regulatory T cells in treated tumors. These data suggest that local nanoparticle anchored delivery of immuno-agonists represents a promising strategy to improve the therapeutic window and clinical applicability of highly potent but otherwise intolerable regimens of cancer immunotherapy. Cancer Res; 73(5); 1547-58. (c)2012 AACR. PMID- 23436796 TI - Chemotherapy alters monocyte differentiation to favor generation of cancer supporting M2 macrophages in the tumor microenvironment. AB - Current therapy of gynecologic malignancies consists of platinum-containing chemotherapy. Resistance to therapy is associated with increased levels of interleukin (IL)-6 and prostaglandin E2 (PGE(2)), 2 inflammatory mediators known to skew differentiation of monocytes to tumor-promoting M2 macrophages. We investigated the impact of cisplatin and carboplatin on 10 different cervical and ovarian cancer cell lines as well as on the ability of the tumor cells to affect the differentiation and function of cocultured monocytes in vitro. Treatment with cisplatin or carboplatin increased the potency of tumor cell lines to induce IL 10-producing M2 macrophages, which displayed increased levels of activated STAT3 due to tumor-produced IL-6 as well as decreased levels of activated STAT1 and STAT6 related to the PGE(2) production of tumor cells. Blockade of canonical NF kappaB signaling showed that the effect of the chemotherapy was abrogated, preventing the subsequent increased production of PGE(2) and/or IL-6 by the tumor cell lines. Treatment with the COX-inhibitor indomethacin and/or the clinical monoclonal antibody against interleukin-6 receptor (IL-6R), tocilizumab, prevented M2-differentiation. Importantly, no correlation existed between the production of PGE(2) or IL-6 by cancer cells and their resistance to chemotherapy induced cell death, indicating that other mechanisms underlie the reported chemoresistance of tumors producing these factors. Our data suggest that a chemotherapy-mediated increase in tumor-promoting M2 macrophages may form an indirect mechanism for chemoresistance. Hence, concomitant therapy with COX inhibitors and/or IL-6R antibodies might increase the clinical effect of platinum based chemotherapy in otherwise resistant tumors. PMID- 23436797 TI - Drug-gene modeling in pediatric T-cell acute lymphoblastic leukemia highlights importance of 6-mercaptopurine for outcome. AB - Patients relapsing with T-cell acute lymphoblastic leukemia (T-ALL) face a dismal outcome. The aim of this study was to identify new markers of drug resistance and clinical response in T-ALL. We measured gene expression and drug sensitivity in 15 pediatric T-ALL cell lines to find signatures predictive of resistance to 10 agents used in therapy. These were used to generate a model for outcome prediction in patient cohorts using microarray data from diagnosis specimens. In three independent T-ALL cohorts, the 10-drug model was able to accurately identify patient outcome, indicating that the in vitro-derived drug-gene profiles were clinically relevant. Importantly, predictions of outcome within each cohort were linked to distinct drugs, suggesting that different mechanisms contribute to relapse. Sulfite oxidase (SUOX) expression and the drug-transporter ABCC1 (MRP1) were linked to thiopurine sensitivity, suggesting novel pathways for targeting resistance. This study advances our understanding of drug resistance in T-ALL and provides new markers for patient stratification. The results suggest potential benefit from the earlier use of 6-mercaptopurine in T-ALL therapy or the development of adjuvants that may sensitize blasts to this drug. The methodology developed in this study could be applied to other cancers to achieve patient stratification at the time of diagnosis. PMID- 23436798 TI - Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. AB - Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis, and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT phenotype in various derivatives of MCF 7 human breast cancer cells was associated with dramatic morphologic changes and actin cytoskeleton remodeling, with CD24(-)/CD44(+)/ALDH(+) stem cell populations present exhibiting a higher degree of EMT relative to parental cells. Strikingly, acquisition of this phenotype also associated with an inhibition of CTL-mediated tumor cell lysis. Resistant cells exhibited attenuation in the formation of an immunologic synapse with CTLs along with the induction of autophagy in the target cells. This response was critical for susceptibility to CTL-mediated lysis because siRNA-mediated silencing of beclin1 to inhibit autophagy in target cells restored their susceptibility to CTL-induced lysis. Our results argue that in addition to promoting invasion and metastasis EMT also profoundly alters the susceptibility of cancer cells to T-cell-mediated immune surveillance. Furthermore, they reveal EMT and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape. PMID- 23436799 TI - PARI overexpression promotes genomic instability and pancreatic tumorigenesis. AB - Treatment options for patients with pancreatic ductal adenocarcinoma (PDAC) remain limited. Therapeutic targets of interest include mutated molecules that predispose to pancreatic cancer such as KRAS and TP53. Here, we show that an element of the homologous recombination pathway of DNA repair, the PARP-binding protein C12orf48/PARI (PARPBP), is overexpressed specifically in pancreatic cancer cells where it is an appealing candidate for targeted therapy. PARI upregulation in pancreatic cancer cells or avian DT40 cells conferred DNA repair deficiency and genomic instability. Significantly, PARI silencing compromised cancer cell proliferation in vitro, leading to cell-cycle alterations associated with S-phase delay, perturbed DNA replication, and activation of the DNA damage response pathway in the absence of DNA damage stimuli. Conversely, PARI overexpression produced tolerance to DNA damage by promoting replication of damaged DNA. In a mouse xenograft model of pancreatic cancer, PARI silencing was sufficient to reduce pancreatic tumor growth in vivo. Taken together, our findings offered a preclinical proof-of-concept for PARI as candidate therapeutic target to treat PDAC. PMID- 23436800 TI - Downregulation of the novel tumor suppressor DIRAS1 predicts poor prognosis in esophageal squamous cell carcinoma. AB - Loss of chromosome 19p is one of the most frequent allelic imbalances in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes within this region. In this study, we investigated a role in ESCCs for a candidate tumor suppressor gene located at 19p13.3, the Ras like small GTPase DIRAS1. Downregulation of DIRAS1 occurred in approximately 50% of primary ESCCs where it was associated significantly with advanced clinical stage, lymph node metastasis, and poor overall survival. LOH and promoter methylation analyses suggested that loss of DIRAS1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of DIRAS1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation. Mechanistic investigations suggested that DIRAS1 acted through extracellular signal-regulated kinase (ERK1/2; MAPK3/1) and p38 mitogen-activated protein kinase (MAPK; MAPK14) signaling to trigger BAD Ser112 dephosphorylation and matrix metalloproteinase (MMP)2/9 transcriptional inactivation to promote apoptosis and inhibit metastasis, respectively. Taken together, our results revealed that DIRAS1 has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies. PMID- 23436801 TI - Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. AB - mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC(50) of 250 pmol/L with approximately 800-fold selectivity for cellular mTOR versus phosphoinositide 3 kinase (PI3K). Torin2 also exhibited potent biochemical and cellular activity against phosphatidylinositol-3 kinase-like kinase (PIKK) family kinases including ATM (EC(50), 28 nmol/L), ATR (EC(50), 35 nmol/L), and DNA-PK (EC(50), 118 nmol/L; PRKDC), the inhibition of which sensitized cells to Irradiation. Similar to the earlier generation compound Torin1 and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORC1 signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 hours resulted in a prolonged block in negative feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single-agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clinical evaluation in a broad number of oncologic settings where mTOR signaling has a pathogenic role. PMID- 23436802 TI - Rapid removal of glycerol from frozen-thawed red blood cells. AB - The storage of red blood cells (RBCs) in a refrigerated state allows a shelf life of a few weeks, whereas RBCs frozen in 40% glycerol have a shelf life of 10 years. Despite the clear logistical advantages of frozen blood, it is not widely used in transfusion medicine. One of the main reasons is that existing post-thaw washing methods to remove glycerol are prohibitively time consuming, requiring about an hour to remove glycerol from a single unit of blood. In this study, we have investigated the potential for more rapid removal of glycerol. Using published biophysical data for human RBCs, we mathematically optimized a three step deglycerolization process, yielding a procedure that was less than 32 s long. This procedure was found to yield 70% hemolysis, a value that was much higher than expected. Consequently, we systematically evaluated three-step deglycerolization procedures, varying the solution composition and equilibration time in each step. Our best results consisted of less than 20% hemolysis for a deglycerolization time of 3 min, and it is expected that even further improvements could be made with a more thorough optimization and more reliable biophysical data. Our results demonstrate the potential for significantly reducing the deglycerolization time compared with existing methods. (c) 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:609-620, 2013. PMID- 23436803 TI - Is there a bidirectional relationship between maternal well-being and child behavior problems in autism spectrum disorders? Longitudinal analysis of a population-defined sample of young children. AB - The aim of this study was to examine whether the relationship between maternal psychological well-being and behavior problems in children with an autism spectrum disorder (ASD) is bidirectional. Data were available at 9 months, 3 years, and 5 years old for 132 children with ASD, identified from a population representative sample of UK children. Three-wave cross-lagged models examined reciprocal effects between child behavior and maternal well-being (psychological distress, physical health functioning, and life satisfaction). Results indicated that the relationships between maternal well-being and child problem behaviors were not bidirectional. Specifically, findings suggested that while early behavior problems are not a risk factor for later maternal well-being, maternal psychological distress, physical health limitations, and lower life satisfaction are risk factors for later child behavior problems. PMID- 23436804 TI - Estrogen receptor beta expression induces changes in the microRNA pool in human colon cancer cells. AB - There is epidemiological, animal and in vitro evidence that estrogen receptor beta (ERbeta) can mediate protective effects against colon cancer, but the mechanism is not completely understood. Previous research has indicated critical pathways whereby ERbeta acts in an antitumorigenic fashion. In this study, we investigate ERbeta's impact on the microRNA (miRNA) pool in colon cancer cells using large-scale genomic approaches, bioinformatics and focused functional studies. We detect and confirm 27 miRNAs to be significantly changed following ERbeta expression in SW480 colon cancer cells. Among these, the oncogenic miR-17 92 cluster and miR-200a/b are strongly downregulated. Using target prediction and anticorrelation to gene expression data followed by focused mechanistic studies, we demonstrate that repression of miR-17 is a secondary event following ERbeta's downregulatory effect on MYC. We show that re-introduction of miR-17 can reverse the antiproliferative effects of ERbeta. The repression of miR-17 also influences cell death upon DNA damage and mediates regulation of NCOA3 (SRC-3) and CLU in colon cancer cells. We further determine that the downregulation of miR-200a/b mediates increased ZEB1 while decreasing E-cadherin levels in ERbeta-expressing colon cancer cells. Changes in these genes correspond to significant alterations in morphology and migration. Our work contributes novel data of ERbeta and miRNA in the colon. Elucidating the mechanism of ERbeta and biomarkers of its activity has significant potential to impact colon cancer prevention and treatment. PMID- 23436805 TI - Glassy state and cryopreservation of mint shoot tips. AB - Vitrification refers to the physical process by which a liquid supercools to very low temperatures and finally solidifies into a metastable glass, without undergoing crystallization at a practical cooling rate. Thus, vitrification is an effective freeze-avoidance mechanism and living tissue cryopreservation is, in most cases, relying on it. As a glass is exceedingly viscous and stops all chemical reactions that require molecular diffusion, its formation leads to metabolic inactivity and stability over time. To investigate glassy state in cryopreserved plant material, mint shoot tips were submitted to the different stages of a frequently used cryopreservation protocol (droplet-vitrification) and evaluated for water content reduction and sucrose content, as determined by ion chromatography, frozen water fraction and glass transitions occurrence by differential scanning calorimetry, and investigated by low-temperature scanning electron microscopy, as a way to ascertain if their cellular content was vitrified. Results show how tissues at intermediate treatment steps develop ice crystals during liquid nitrogen cooling, while specimens whose treatment was completed become vitrified, with no evidence of ice formation. The agreement between calorimetric and microscopic observations was perfect. Besides finding a higher sucrose concentration in tissues at the more advanced protocol steps, this level was also higher in plants precultured at 25/-1 degrees C than in plants cultivated at 25 degrees C. PMID- 23436806 TI - Letting a typical mouse judge whether mouse social interactions are atypical. AB - Diagnosis of an autism spectrum disorder (ASD) requires a qualitative assessment of social aptitude: one person judging whether another person interacts in a "typical" way. We hypothesized that mice could be used to make a similar judgment if they prefer "typical" over "atypical" social interactions with mouse models relevant to ASD. We used wild-type C57BL/6 (B6) mice as "judges" and evaluated their preference for a chamber containing a "typical" (B6 or 129S6) or an "atypical" mouse. For our atypical mouse stimuli, we chose two inbred strains with well-documented social phenotypes (BTBR and BALB/c), as well a mutant line with abnormal social behavior and seizures (Gabrb3 +/-). Overall, we observed a stimulus by time interaction (P < 0.0001), with B6 mice preferring the typical mouse chamber during the last 10 min of the 30-min test. For two of the individual stimulus pairings, we observed a similar chamber by time interaction (BALB/c vs. 129S6, P = 0.0007; Gabrb3 +/- vs. 129S6, P = 0.033). For the third stimulus pairing, we found a trend for preference of the typical mouse across time (BTBR vs. B6, P = 0.051). We repeated the experiments using 129S6 mice as judges and found a significant overall interaction (P = 0.034), but only one stimulus pairing reached significance on its own (BALB/c vs. 129S6, P = 0.0021). These data suggest that a characteristic pattern of exploration in B6 mice can distinguish some socially atypical animals from controls. PMID- 23436807 TI - Study of the effect of antimicrobial peptide mimic, CSA-13, on an established biofilm formed by Pseudomonas aeruginosa. AB - The formation of a Pseudomonas aeruginosa biofilm, a complex structure enclosing bacterial cells in an extracellular polymeric matrix, is responsible for persistent infections in cystic fibrosis patients leading to a high rate of morbidity and mortality. The protective environment created by the tridimensional structure reduces the susceptibility of the bacteria to conventional antibiotherapy. Cationic steroid antibiotics (CSA)-13, a nonpeptide mimic of antimicrobial peptides with antibacterial activity on planktonic cultures, was evaluated for its ability to interact with sessile cells. Using confocal laser scanning microscopy, we demonstrated that the drug damaged bacteria within an established biofilm showing that penetration did not limit the activity of this antimicrobial agent against a biofilm. When biofilms were grown during exposure to shear forces and to a continuous medium flow allowing the development of robust structures with a complex architecture, CSA-13 reached the bacteria entrapped in the biofilm within 30 min. The permeabilizing effect of CSA-13 could be associated with the death of the bacteria. In static conditions, the compound did not perturb the architecture of the biofilm. This study confirms the potential of CSA-13 as a new strategy to combat persistent infections involving biofilms formed by P. aeruginosa. PMID- 23436808 TI - Keeping track of worm trackers. AB - C. elegans is used extensively as a model system in the neurosciences due to its well defined nervous system. However, the seeming simplicity of this nervous system in anatomical structure and neuronal connectivity, at least compared to higher animals, underlies a rich diversity of behaviors. The usefulness of the worm in genome-wide mutagenesis or RNAi screens, where thousands of strains are assessed for phenotype, emphasizes the need for computational methods for automated parameterization of generated behaviors. In addition, behaviors can be modulated upon external cues like temperature, O(subscript)2(/subscript) and CO(subscript)2(/subscript) concentrations, mechanosensory and chemosensory inputs. Different machine vision tools have been developed to aid researchers in their efforts to inventory and characterize defined behavioral "outputs". Here we aim at providing an overview of different worm-tracking packages or video analysis tools designed to quantify different aspects of locomotion such as the occurrence of directional changes (turns, omega bends), curvature of the sinusoidal shape (amplitude, body bend angles) and velocity (speed, backward or forward movement). PMID- 23436819 TI - An SRF/miR-1 axis regulates NCX1 and annexin A5 protein levels in the normal and failing heart. AB - AIMS: The expression of the sodium/calcium exchanger NCX1 increases during cardiac hypertrophy and heart failure, playing an important role in Ca(2+) extrusion. This increase is presumed to result from stress signalling induced changes in the interplay between transcriptional and post-transcriptional regulations. We aimed to determine the impact of the SRF transcription factor known to regulate the NCX1 promoter and microRNA genes, on the expression of NCX1 mRNA and protein and annexin A5 (AnxA5), a Ca(2+)-binding protein interacting with NCX1 and increased during HF. METHODS AND RESULTS: NCX1 mRNA was decreased while the protein was increased in the failing heart of the cardiomyocyte restricted SRF knock-out mice (SRF(HKO)). The induction of NCX1 mRNA by the pro hypertrophic drug phenylephrine observed in control mice was abolished in the SRF(HKO) though the protein was strongly increased. AnxA5 protein expression profile paralleled the expression of NCX1 protein in the SRF(HKO). MiR-1, a microRNA regulated by SRF, was decreased in the SRF(HKO) and repressed by phenylephrine. In vitro and in vivo manipulation of miR-1 levels and site directed mutagenesis showed that NCX1 and AnxA5 mRNAs are targets of miR-1. AnxA5 overexpression slowed down Ca(2+) extrusion during caffeine application in adult rat cardiomyocytes. CONCLUSION: Our study reveals the existence of a complex regulatory loop where SRF regulates the transcription of NCX1 and miR-1, which in turn functions as a rheostat limiting the translation of NCX1 and AnxA5 proteins. The decrease of miR-1 and increase of AnxA5 appear as important modulators of NCX1 expression and activity during heart failure. PMID- 23436820 TI - Chronic deficit in nitric oxide elicits oxidative stress and augments T-type calcium-channel contribution to vascular tone of rodent arteries and arterioles. AB - AIMS: As cardiovascular disease is characterized by reduced nitric oxide bioavailability, our aim was to determine the impact of this change on the mechanism underlying vascular tone of pressurized arteries in vitro and in vivo. METHODS AND RESULTS: We used pressurized cerebral and mesenteric arteries in vitro and skeletal muscle arterioles in vivo to study the contribution of L-type (1 umol/L nifedipine) and T-type (1 umol/L mibefradil, 3 umol/L NNC 55-0396) calcium channels to vascular tone, following acute or chronic inhibition of nitric oxide. Acute inhibition with l-NAME (10 umol/L) significantly increased the T-type, but not the L-type, channel contribution to vascular tone in vitro and in vivo, and altered the smooth muscle expression of the Cav3.1 and Cav3.2 T type channels. In pressurized mesenteric arteries of Cav3.1ko and Cav3.2ko mice, acutely treated with l-NAME, the contribution of T-type channels relative to L type channels was significantly reduced, compared with arteries from wild-type mice.Chronic l-NAME treatment (40 mg/kg/day; 14-18 days) increased blood pressure, vascular superoxide, and the contribution of T-type channels to vascular tone in vivo. The latter was reversed by acute scavenging of superoxide with tempol (1 mmol/L), or inhibition of NADPH oxidase with apocynin (500 umol/L) or DPI (5 umol/L). CONCLUSION: We conclude that nitric oxide deficit produces a significant increase in the contribution of Cav3.1 and Cav3.2 T-type calcium channels to vascular tone, by regulating the bioavailability of reactive oxygen species produced by NADPH oxidase. Our data provide evidence for a novel causal link between nitric oxide deficit, oxidative stress, and T-type calcium channel function. PMID- 23436821 TI - Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort. AB - OBJECTIVE: Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. METHODS: In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor alpha agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (>=6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. RESULTS: After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. CONCLUSION: In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice. PMID- 23436818 TI - Choosing wisely: the American College of Rheumatology's Top 5 list of things physicians and patients should question. AB - OBJECTIVE: We sought to develop a list of 5 tests, treatments, or services commonly used in rheumatology practice whose necessity or value should be questioned and discussed by physicians and patients. METHODS: We used a multistage process combining consensus methodology and literature reviews to arrive at the American College of Rheumatology's (ACR) Top 5 list. Rheumatologists from diverse practice settings generated items using the Delphi method. Items with high content agreement and perceived high prevalence advanced to a survey of ACR members, who comprise >90% of the US rheumatology workforce. To increase the response rate, a nested random sample of 390 rheumatologists received more intensive survey followup. The samples were combined and weighting procedures were applied to ensure generalizability. Items with high ratings underwent literature review. Final items were then selected and formulated by the task force. RESULTS: One hundred five unique items were proposed and narrowed down to 22 items during the Delphi rounds. A total of 1,052 rheumatologists (17% of those contacted) participated in the member-wide survey, whereas 33% of those in the nested random sample participated; respondent characteristics were similar in both samples. Based on survey results and available scientific evidence, 5 items (relating to antinuclear antibodies, Lyme disease, magnetic resonance imaging, bone absorptiometry, and biologic therapy for rheumatoid arthritis) were selected for inclusion. CONCLUSION: The ACR Top 5 list is intended to promote discussions between physicians and patients about health care practices in rheumatology whose use should be questioned and to assist rheumatologists in providing high-value care. PMID- 23436822 TI - Pediatric computed tomography imaging guideline. AB - The use of computed tomography (CT) in pediatric diagnostic imaging is demanding generally, but when coupled with an awareness to limit the radiation dose associated with this imaging modality, the procedure becomes challenging. Although new techniques have been developed in line with the introduction of faster multidetector computed tomography (MDCT) scanners to aid radiation reduction, it still remains the responsibility of the clinical practitioner to ensure each examination request is justified and the scanning protocol and parameters selected are optimized to the individual patient's requirement. It is the purpose of this article to outline the basic principle of CT radiation dose optimization based on modification of scanning parameters and application of different imaging techniques. PMID- 23436823 TI - Application value of 3T 1H-magnetic resonance spectroscopy in diagnosing breast tumors. AB - BACKGROUND: Assessment of breast lesions with magnetic resonance imaging (MRI) provides a means for lesion detection and diagnosis. Proton (hydrogen-1) magnetic resonance spectroscopy ((1)H-MRS) has been proposed as a useful diagnostic technique in providing metabolic information of suspicious breast lesions. PURPOSE: To determine the clinical significance of in-vivo single voxel (1)H-MRS at 3T in the assessment of benign and malignant breast lesions in combination with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIAL AND METHODS: Twenty-four women with known breast abnormalities from conventional imaging (mammography, ultrasonography) underwent DCE-MRI at a 3T MR scanner and 26 breast lesions were detected. Breast lesions were assessed according BI-RADS classification. Single voxel (1)H-MRS was performed after gadolinium administration and choline peak was qualitatively evaluated. All lesions were confirmed histologically from the surgically excised specimens. Sensitivity, specificity, and accuracy of the (1)H-MRS, of the BI-RADS classification and of their combination (DCE-MRI + (1)H-MRS) were calculated. RESULTS: Fifteen out of 26 lesions proved to be malignant and 11 proved to be benign. In our study (1)H MRS showed sensitivity 80%, specificity 81.8%, and accuracy 80.7%. DCE-MRI showed sensitivity 100%, specificity 63.6%, and accuracy 84.6%. The combination of DCE MRI and (1)H-MRS provided higher accuracy (96.4%), as well as higher specificity 81.8% compared to BI-RADS classification. CONCLUSION: The combined use of (1)H MRS and DCE-MRI found to have improved diagnostic performance in the assessment of equivocal breast lesions. (1)H-MRS can be used as a useful adjunct during lesion characterization in clinical routine in cases classified as BI-RADS 3 and 4. PMID- 23436824 TI - Congenital lung malformations: radiological findings and clues for differential diagnosis. AB - Congenital lung malformations encompass a wide spectrum of conditions with a broadly varying clinical presentation. They are often a source of morbidity in infants and children. Their management depends on the type of malformation and its clinical presentation. Usually, the diagnosis requires an imaging evaluation. Classifications of bronchopulmonary malformations have undergone significant revision in recent years and several theories have attempted to explain their confusing pathogenesis. There are considerable degrees of overlapping and hybrid conditions are common, with interrelated malformations showing various radiologic and pathologic features. Attending to the pathophysiological mechanisms and structures involved, lung malformations can be divided into three categories: bronchopulmonary anomalies, combined lung and vascular abnormalities, and vascular anomalies. The purpose of this article is to review the current imaging techniques for evaluating lung malformations in pediatric patients and their characteristic imaging findings. Moreover, this review discusses a useful classification and offers some clues to facilitate the differential diagnosis. PMID- 23436825 TI - Conventional MRI findings for predicting submandibular pleomorphic adenoma. AB - BACKGROUND: Although pleomorphic adenomas account for over 90% of all benign submandibular gland tumors, the imaging features of submandibular pleomorphic adenomas have not been reported in a large number of cases. PURPOSE: To assess the conventional magnetic resonance imaging (MRI) findings for predicting the submandibular pleomorphic adenoma. MATERIAL AND METHODS: MR studies of 42 pleomorphic adenomas and 28 other types of tumor were reviewed. MR images were assessed for the presence of hyperintense areas on T2-weighted images (first sign), a well-defined margin (second sign), and presence of crescent-shaped compression of the ipsilateral normal submandibular gland (third sign). RESULTS: For identifying submandibular pleomorphic adenoma, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 97.6%, 50.0%, 74.5%, 93.3%, and 78.6% for the first sign, 95.2%, 46.4% 72.7%, 86.7%, and 75.7% for the second sign, and 23.8%, 100%, 86.7%, 46.7%, and 54.3% for the third sign, respectively. Combining the first and second findings achieved to 85.7% specificity and 90.9% accuracy. CONCLUSION: Although non-specific, submandibular pleomorphic adenomas usually have hyperintense areas on T2-weighted images and well-defined margins. In addition, crescent-shaped compression of the ipsilateral normal gland seems to represent a highly specific sign. PMID- 23436826 TI - Evaluation of the growth pattern of carcinoma of colon and rectum by MDCT. AB - BACKGROUND: Colorectal cancer is a leading cause of cancer morbidity and mortality worldwide. Knowledge of colorectal cancer tumor growth is of importance for basic understanding of tumor biology and for the clinical handling of the disease. PURPOSE: To conduct a retrospective evaluation of the growth pattern of colorectal cancer by multidetector computed tomography (MDCT). MATERIAL AND METHODS: Pathologically proven adenocarcinomas of the colon and rectum in 44 patients were examined by MDCT on at least two separate occasions with an interval of >1 month in patients not receiving therapy. Maximal longitudinal diameters, wall thicknesses, and volume changes, as determined by serial CT scans, were used in calculation of growth rates. RESULTS: Mean longitudinal diameters of tumors at initial and follow-up investigations were 3.8 cm (1.0-9.1 cm) and 5.4 cm (2.5-12.2 cm), respectively. The mean growth rate of longitudinal tumor diameter was 3.4 cm/year (0-13.8 cm/year). Mean axial wall thicknesses at initial and follow-up investigations were 1.4 cm (0.6-6.6 cm) and 1.9 cm (0.8-6.8 cm), respectively. Mean growth rate of tumor axial wall thickness was 1.0 cm/year (0-3.1 cm/year). Mean tumor volumes at initial and follow-up investigations were 1975 cm(3) (172-9756 cm(3); median, 1490) and 3545 cm(3) (442-15211 cm(3); median, 2846), respectively. Mean growth rate of tumor volume was 2912 cm(3)/year (216-12548 cm(3)/year; median, 1698), and volume doubling times varied from 0.05 to 7.1 years (mean, 1.2; median, 0.7). Significant correlations were observed between initial wall thickness and volume growth rate (p = 0.004). No significant difference was observed between other initial tumor size and growth rate. CONCLUSION: The tumor growth doubling time of colorectal cancer has a very broad aspect. The initial wall thickness of the tumor on MDCT appears to be the most powerful parameter showing correlation with the volume growth rate. PMID- 23436827 TI - Evaluation of contrast-enhanced MR angiography in the follow-up of visceral arterial aneurysms after coil embolization. AB - BACKGROUND: The placement of detachable coil has become the alternative method of treating visceral arterial aneurysms (VAAs). Imaging follow-up is necessary after coil embolization because of frequent incomplete occlusion. PURPOSE: To compare contrast-enhanced magnetic resonance angiography (CE-MRA) at 3T with a reference standard of digital subtraction angiography (DSA) for the evaluation of VAAs after coil embolization. MATERIAL AND METHODS: We treated 15 patients with VAA with coil embolization; eight had splenic artery aneurysms and seven had renal artery aneurysms. We packed the aneurysmal sac preserving native arterial circulation. For follow-up, all patients underwent CE-MRA at 3T and DSA. The results were classified according to coil occlusion: Class 1, complete occlusion; Class 2, residual neck; Class 3, aneurysmal filling. RESULTS: CE-MRA revealed 11 complete occlusions and four residual necks. DSA follow-up showed 12 complete occlusions and three residual necks. No aneurysmal filling occurred after treatment. Comparison of CE-MRA and DSA findings showed 93% agreement (14/15). CE MRA allowed the detection of a residual neck in one misclassified case in which DSA showed occlusion. Coil-related artifacts were minimal and did not interfere with evaluation of the occlusion status of the VAAs. CONCLUSION: CE-MRA at 3T provides high-quality images equivalent to DSA for the evaluation of VAAs after coil embolization. We suggest that CE-MRA at 3T might be used as the primary method for follow-up of VAAs after coil embolization. PMID- 23436828 TI - X-ray dose delivered during a longitudinal micro-CT study has no adverse effect on cardiac and pulmonary tissue in C57BL/6 mice. AB - BACKGROUND: Micro-computed tomography (micro-CT) offers numerous advantages for small animal imaging, including the ability to monitor the same animals throughout a longitudinal study. However, concerns are often raised regarding the effects of X-ray dose accumulated over the course of the experiment. PURPOSE: To scan C57BL/6 mice multiple times per week for 6 weeks, in order to determine the effect of the cumulative dose on pulmonary and cardiac tissue at the end of the study. MATERIAL AND METHODS: C57BL/6 male mice were split into two groups (irradiated group = 10, control group = 10). The irradiated group was scanned (80 kVp/50 mA) three times weekly for 6 weeks, resulting in a weekly dose of 0.84 Gy, and a total study dose of 5.04 Gy. The control group was scanned on the final week. Scans from week 6 were reconstructed and the lungs and heart were analyzed. RESULTS: Overall, there was no significant difference in lung volume or lung density or in left ventricular volume or ejection fraction between the control group and the irradiated group. Histological samples taken from excised lung and myocardial tissue also showed no evidence of inflammation or fibrosis in the irradiated group. CONCLUSION: This study demonstrated that a 5 Gy X-ray dose accumulated over 6 weeks during a longitudinal micro-CT study had no significant effects on the pulmonary and myocardial tissue of C57BL/6 mice. As a result, the many advantages of micro-CT imaging, including rapid acquisition of high resolution, isotropic images in free-breathing mice, can be taken advantage of in longitudinal studies without concern for negative dose-related effects. PMID- 23436829 TI - Lumbar pain with intracranial origin. AB - A 48-year-old woman presented low-back pain radiating to the lower right leg. Magnetic resonance imaging (MRI) of the lumbar spine revealed a L4-L5 subacute subdural hematoma (SDH). The patient had no general or local cause for this lumbar SDH, such as coagulation disorder, trauma, surgery, or lumbar puncture. She had a history of post-traumatic bilateral hemorrhagic contusions of the brain and intracranial SDH because of a fall occurring several months before the current problems. A downward migration of the cerebral SDH was found as only potential explanation of the lumbar SDH. The association between the intracranial and spinal hematomas is discussed. PMID- 23436830 TI - Intra- and inter-observer repeatability of radiographic measurements for previously slipped capital femoral epiphysis at skeletal maturity. AB - BACKGROUND: Recent studies suggest that even a mild slip of the femoral capital epiphysis may lead to later degenerative changes when undiagnosed. However, little is written on the accuracy of radiographic measurements used to diagnose a slip at skeletal maturity. PURPOSE: To assess the accuracy of radiographic measurements commonly used for assessment of previously slipped capital femoral epiphysis (SCFE) at skeletal maturity. MATERIAL AND METHODS: All children born at our hospital during 1989 (n = 4006) were invited to participate in a follow-up hip trial at age 18-19 years. Erect pelvic anteroposterior and supine frog leg radiographs were obtained in a standardized fashion. For the purpose of this study, we selected a subset of 100 radiographs. To balance the data-set, we added another 28 radiographs from skeletal mature patients diagnosed and operated for a SCFE. Two observers independently measured Southwick's head-shaft angle, Murray's tilt-index, and the femoral head-neck angle. Intra- and inter-observer variation was assessed using the mean difference, with its 95% limits of agreement. RESULTS: A high percentage of the images (40%), particularly for the measurement of the Southwick's head-shaft angle, were judged immeasurable by at least one observer. Mean head-shaft angle was 11.0 degrees (SD = 17.0), head-neck angle was 8.0 degrees (SD = 12.0), and Murray's tilt-index was 1.18 (SD = 0.4). For head-shaft angle, the mean difference between measurements (Observer 2) was 0.8 degrees (SD = 2.7 degrees , 95% limits of agreement -4.5 degrees to 6.1 degrees ), while the corresponding figure for the Murray's tilt-index was 0.02 (SD = 0.08, 95% limits of agreement -0.18 to 0.14), and for the head-neck angle 0.9 degrees (SD = 4.0, 95% limits of agreement of -6.9 degrees to 8.7 degrees ). Slightly higher variance was seen for Observer 1 and between the two observers. CONCLUSION: Common radiographic measurements for the assessment of a previously slipped capital femoral epiphysis are relatively inaccurate in skeletal mature adolescents, in particular between observers (inter-observer), but also for the same observer (intra-observer). Our results underscore the importance of thorough standardization for both image and measurement technique when used in a clinical setting. PMID- 23436831 TI - MRI for occult physeal fracture detection in children and adolescents. AB - BACKGROUND: Conventional radiography has limitations in the detection of physeal fractures before the closure of the physis occurs. Fracture detection may be improved by using magnetic resonance imaging (MRI). PURPOSE: To evaluate the usefulness of MRI for the detection of occult fractures involving the physis when radiography results are negative. MATERIAL AND METHODS: In this prospective study, 24 children (age range, 3-15 years; mean age, 10.7 years) received MRI if they met the following criteria: acute joint trauma, swelling and tenderness around the joint, limitations in bearing weight, an open physis, and negative radiography results for fractures. Fractures revealed by the MRI were classified according to the Salter-Harris classification system. Joint effusion, bone marrow edema, and periosteal alterations were graded on a three-point scale. The non parametric Wilcoxon test and Fisher's exact test were used for the statistical evaluation. RESULTS: From a total of 24 MR data-sets, 23 were evaluated (one patient was excluded due to poor MR image quality). Elbow injuries were present in 10 patients (43.5%), distal tibia injuries in 10 patients (43.5%), and distal femur injuries in three patients (13%). MRI results excluded physeal fractures in 15 (65.2%) of the 23 children. An occult physeal fracture was detected with MRI in eight (34.8%) patients; of these, five (21.7%) had fractures of the elbow, two (8.7%) had fractures of the distal tibia, and one (4.3%) had a fracture of the distal femur. All of the patients with fractures and 11 of the 15 patients without fractures demonstrated bone marrow edema. CONCLUSION: The frequency of occult fracture, as detected by MRI, was 34.8%. Thus, MRI is a useful additional imaging method for the detection of occult fractures when radiography is negative. PMID- 23436832 TI - Pertinent reportable incidental cardiac findings on chest CT without electrocardiography gating: review of 268 consecutive cases. AB - BACKGROUND: Pertinent reportable cardiac findings on non-electrocardiography (ECG)-gated chest CT examinations have become easier to detect given recent advancements in multidetector CT technology. However, those findings are easily overlooked on routine chest CT without ECG gating given residual inherent cardiac motion artifact and non-cardiac indications. PURPOSE: To describe and quantify the types of pertinent reportable cardiac findings that can be detected on chest CT examinations without ECG gating and evaluate how often they were reported. MATERIAL AND METHODS: Two radiologists retrospectively reviewed (blinded to the original interpretation) 268 consecutive routine adult chest CT examinations without ECG gating for the presence of pertinent reportable cardiac findings. Retrospective interpretations were then compared with the original radiological reports. RESULTS: One hundred and sixty-three patients (61%) had pertinent reportable cardiac findings. The findings encountered included: coronary artery disease (n = 131; 80.0%), coronary artery bypass grafts (n = 10; 6.1%), left ventricular aneurysm (n = 1; 0.6%), valve calcification (n = 131; 80.0%), valve repair/replacement (n = 5; 3.1%), pericardial effusion (n = 33; 20.2%), left atrial appendage thrombus (n = 1; 0.6%), cardiac mass (n = 1; 0.6%), and cardiac chamber enlargement (n = 29; 17.8%). On the original radiological reports 22.3% of the pertinent reportable cardiac findings, detected by the two radiologists retrospectively, were not reported. CONCLUSION: Detection of pertinent reportable cardiac findings on routine chest CT examinations without ECG gating is possible. The high volume of chest CT examinations without ECG gating represents an opportunity for radiologists to comment on the presence or absence of cardiac disease which may influence future clinical decisions. PMID- 23436833 TI - AJR responsibility and accountability: the buck stops here! PMID- 23436834 TI - Complications of targeted drug therapies for solid malignancies: manifestations and mechanisms. AB - OBJECTIVE: This article reviews important complications of targeted drug therapies for solid malignancies that can be identified on diagnostic imaging. Wherever possible, known or proposed mechanistic explanations for drug complications are emphasized. CONCLUSION: Familiarity with the toxicity profiles of different targeted cancer therapies is important for identifying drug-related complications and for differentiating drug effects from disease progression. A mechanistic understanding may be useful for associating individual drugs with their complications and for predicting the complications of emerging agents. PMID- 23436835 TI - Cancer of unknown primary sites: what radiologists need to know and what oncologists want to know. AB - OBJECTIVE: In this article, we review the role of imaging in cancer of unknown primary site (CUP) diagnosis and management and the utility of immunohistochemistry, serum tumor markers, and molecular profiling in the optimized care of CUP patients. CONCLUSION: With advances in imaging, pathology, and molecular medicine, the diagnosis and management of CUP have evolved into more personalized and site-specific therapies. A multidisciplinary integrated approach among oncologists, pathologists, and radiologists is extremely important. PMID- 23436836 TI - Comparison of four prediction models to discriminate benign from malignant vertebral compression fractures according to MRI feature analysis. AB - OBJECTIVE: The purpose of this study was to identify a set of significant predictors, predominantly based on MRI features and limited demographic data, for differentiating benign from malignant vertebral compression fractures (VCFs) and to compare the diagnostic value of four different types of prediction models. MATERIALS AND METHODS: The cohort included 101 subjects (mean age, 64 years; range, 22-89 years; 39.6% were men) with 128 VCFs, 84 (65.6%) of which were proven to be malignant by biopsy or follow-up imaging. A set of 36 predictors (34 MRI features, age, and sex) was acquired for each VCF retrospectively. RESULTS: Univariate analysis and initial variable screening selected 14 moderately significant predictors. All four model types performed similarly in overall discrimination power. The median area under the curve for each model type was 0.872 for logistic regression, 0.781 for classification tree, 0.760 for support vector machine, and 0.730 for neural network, but no significant difference was found between any two model types by Student t test. Five predictors for the logistic regression model were statistically significant (p < 0.01). Focal paraspinal mass and depositlike appearance of pedicle involvement were positively correlated with VCF malignancy. Age, other compression deformities without bone marrow edema, and intravertebral fluid collection or fluid signal were negatively correlated with VCF malignancy. CONCLUSION: It is possible to estimate the malignancy risk of VCF by using a small number of MRI features and patient age. The diagnostic performance of models selected by logistic regression, support vector machine, neural network, and classification tree was similar. PMID- 23436837 TI - To shield or not to shield: application of bismuth breast shields. AB - OBJECTIVE: The purposes of this essay are to describe the effects of bismuth breast shielding on radiation exposure of the breast and posterior chest wall and to present arguments for and against the use of breast shields. CONCLUSION: Breast tissue may receive substantial radiation doses during CT examinations. Bismuth shields effectively reduce breast exposure at the expense of increased noise and artifacts. Because bismuth shields reduce radiation transmission in all directions, posterior-to-anterior irradiation results in wasted exposure of posterior tissues. Similar breast radiation reductions can be achieved without shielding by globally reducing tube current. In general, more advanced methods of reducing exposure, including dose modulation and iterative reconstruction techniques, are superior if available. PMID- 23436838 TI - Radiation dose in cardiac imaging: how should it affect clinical decisions? AB - OBJECTIVE: The purpose of this article is to discuss whether and how the risks of exposure to ionizing radiation should affect clinical decision making in patients with known or suspected cardiovascular disease. CONCLUSION: Although the prevalence of cardiovascular disease and frequency of diagnostic testing has risen dramatically, cardiovascular mortality has declined. Earlier and more accurate detection of cardiovascular disease may play an important role. Concerns regarding excessive radiation exposure from cardiovascular imaging have been raised. Efforts to reduce exposure have included selection of appropriate patients for cardiovascular testing, technologic advances, educational resources, and a directed patient-centered approach to testing. PMID- 23436839 TI - Cardiovascular imaging of the pregnant patient. AB - OBJECTIVE: The purpose of this review is to describe the selection and methods of imaging of pregnant women with cardiovascular conditions. CONCLUSION: Common cardiovascular conditions may occur in 1% of all pregnant women. The selection and methods of imaging studies require thoughtful planning. Use of radiation, radiopharmaceuticals, and contrast agents should be minimized. Pulmonary and cardiac CT angiography deliver minimal fetal radiation, and ventilation-perfusion scintigraphy presents relatively low fetal irradiation. Cardiac catheterization, coronary angiography, and electrophysiologic procedures, including complex interventions, also cause relatively low fetal exposure. Even nuclear cardiology procedures are unlikely to exceed negligible-risk (50 mGy cutoff) fetal radiation doses. PMID- 23436840 TI - Pulmonary CT angiography as first-line imaging for PE: image quality and radiation dose considerations. AB - OBJECTIVE: This article reviews dose reduction techniques in pulmonary CT angiography (CTA) for imaging pulmonary embolism (PE). Dose reduction technologies covered include tube current modulation, kilovoltage modulation, scanning length modification, dynamic z-axis collimation, iterative reconstruction, and dual-energy CT. Age- and weight-specific imaging techniques are suggested. CONCLUSION: Pulmonary CTA plays a vital role in imaging PE. Using dose reduction technologies can provide high-quality diagnostic imaging with a significant reduction in patient dose. PMID- 23436841 TI - Comparison of coronary CT angiography image quality with and without breast shields. AB - OBJECTIVE: The purpose of this study is to compare the image quality of coronary CT angiography performed with and without breast shields. MATERIALS AND METHODS: This study involved a retrospective cohort of 72 women with possible angina who underwent 64-MDCT retrospective ECG-gated coronary CT angiography at a single academic tertiary medical center. Images of 36 women scanned while wearing bismuth-coated latex breast shields and 36 control subjects scanned without shields, matched by heart rate and body mass index, were graded on a standardized Likert scale for image quality, stenosis, and plaque by two independent board certified readers blinded to breast shields. RESULTS: Seventy-two patients (mean [+/- SD] age, 53 +/- 9 years) were included. The pre scan heart rate, body mass index, and Agatston score did not differ between groups. The median estimated radiation dose was 13.4 versus 16.1 mSv for those with and without breast shields (p = 0.003). For shielded versus unshielded scans, 86% versus 83% of coronary segments were rated excellent or above average (p = 0.4), median image quality was 2.0 for both groups, mean signal was 474 +/- 75 and 452 +/- 91 HU (p = 0.27), mean noise was 33.9 +/- 8.5 and 29.8 +/- 8.3 HU (p = 0.04), and median signal-to noise ratio was 14.4 and 14.7 (p = 0.56), respectively. CONCLUSION: Breast shields for women undergoing coronary CT angiography slightly increased noise but did not negatively affect signal, signal-to-noise ratio, quality, or interpretability. Breast shield use warrants further study. PMID- 23436842 TI - Reduced radiation exposure of the female breast during low-dose chest CT using organ-based tube current modulation and a bismuth shield: comparison of image quality and radiation dose. AB - OBJECTIVE: The objective of our study was to evaluate the effect of organ-based tube current modulation and bismuth shielding on image quality and breast radiation dose in women undergoing low-dose chest CT. SUBJECTS AND METHODS: From March 2011 through July 2011, 80 women prospectively underwent low-dose chest CT to screen for lung cancer. The patients were randomly assigned to a control group (n = 20), organ-based tube current modulation group (n = 20), breast shield group (n = 20), or breast shield plus organ-based tube current modulation group (n = 20). Axial slice images of the aortic arch, carina, and inferior pulmonary vein were used to analyze image quality. Three radiologists scored the image quality in terms of artifact and noise and then characterized the overall image quality as optimal (does not affect the diagnostic accuracy) or suboptimal (affects the diagnostic accuracy). Noise levels were measured in the anterior and posterior lung in each image. A phantom dose study was conducted to measure radiation dose. RESULTS: Images with artifacts or noise were more frequently obtained in the breast shield groups; however, the overall image quality was not significantly different among the four groups. Measured noise levels in the anterior lung were significantly higher in the breast shield groups than the control group; however, no statistical significance was found among the four groups with regard to noise level in the posterior lung. In the phantom dose study, a 16-37.5% dose reduction in the breast was achieved using the breast shield, organ-based tube current modulation protocol, or both. CONCLUSION: The radiation dose in the female breast may be reduced using a breast shield or organ-based tube current modulation during low-dose chest CT with acceptable image quality. The use of organ-based tube current modulation reduced the radiation dose in the breast without inducing image quality deterioration. PMID- 23436843 TI - Image quality assessment of standard- and low-dose chest CT using filtered back projection, adaptive statistical iterative reconstruction, and novel model-based iterative reconstruction algorithms. AB - OBJECTIVE: The purpose of this article is to compare image quality between filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR) at standard dose and two preselected low-dose scans. SUBJECTS AND METHODS: Thirty patients (16 men and 14 women; mean age, 67 years) were prospectively recruited. Patients underwent three scans (one standard-dose scan and two low-dose scans at noise indexes [NIs] of 33, 60, and 70, respectively). All three scans were reconstructed with FBP, ASIR, and MBIR. Objective and subjective image qualities were compared. Dose-length products and effective doses for each scans were recorded. Mean image noise and attenuation values were compared between different reconstruction algorithms using repeated-measures analysis of variance and paired Student t tests. The interobserver variation between the two radiologists for subjective image quality and lesion assessment was estimated by using weighted kappa statistics. RESULTS: Objective image analysis supports significant noise reduction with low-dose scans using the MBIR technique (p < 0.05). There was no significant change in mean CT numbers between different reconstructions (p > 0.05). Subjective analysis reveals no significant difference between image quality and diagnostic confidence between low-dose MBIR scans compared with standard-dose scans reconstructed using ASIR (p > 0.05). Average effective doses were 3.7, 1.2, and 0.9 mSv for standard scans at NIs of 33, 60, and 70, respectively. CONCLUSION: MBIR shows superior noise reduction and improved image quality. Substantial dose reduction can be achieved by increasing the NI parameters as tested in this study without affecting image quality and diagnostic confidence. PMID- 23436844 TI - Predictors of dysplastic nodule diagnosis in patients with liver cirrhosis on unenhanced and gadobenate dimeglumine-enhanced MRI with dynamic and hepatobiliary phase. AB - OBJECTIVE: The purpose of this article is to assess whether unenhanced and gadobenate dimeglumine-enhanced MRI with dynamic and hepatobiliary phase may predict the diagnosis of dysplastic nodules in patients with liver cirrhosis. MATERIALS AND METHODS: We retrospectively analyzed 75 cirrhotic patients (47 men and 28 women; mean [+/- SD] age, 55 +/- 12 years) with 82 hepatocellular nodules, including histology-proven dysplastic nodules (n = 25; diameter, 1-3 cm) and hepatocellular carcinomas (n = 57; diameter, 2-3 cm) scanned by MRI before and after gadobenate dimeglumine injection during hepatic arterial phase (HAP), portal venous phase (PVP), equilibrium phase, and hepatobiliary phase. Nodule T1 and T2 intensities before contrast agent injection and nodule HAP, PVP, equilibrium phase, and hepatobiliary phase intensities were compared with the adjacent liver. Univariate and multivariate logistic regression analysis was conducted to assess how the nodule could predict dysplastic nodule diagnosis. RESULTS: Some imaging findings were independent predictors of dysplastic nodule diagnosis-namely, nodule T2 isohypointensity (odds ratio [OR], 12.28; 95% CI, 3.88-38.82), T1 isohyperintensity (OR, 26.74; 95% CI, 7.53-94.90), HAP isohypointensity (OR, 97.16; 95% CI, 20.06-470.49), PVP-equilibrium phase isohyperintensity (OR, 20.53; 95% CI, 5.36-78.62), and hepatobiliary phase isohyperintensity (OR, 119.6; 95% CI, 21.59-662.40). Nodule T2 and HAP isohypointensity (OR 31.47; 95% CI, 7.88-125.58), nodule T2 isohypointensity and hepatobiliary phase isohyperintensity (OR, 28.77; 95% CI, 7.79-106.19), nodule T1 isohyperintensity and HAP isohypointensity (OR, 17.22; 95% CI, 4.85-61.14), and nodule T1 and hepatobiliary phase isohyperintensity (OR, 19.39; 95% CI, 5.38 69.90) were also predictors of dysplastic nodule diagnosis. CONCLUSION: The combination of nodule appearance on T2-weighted MRI and nodule enhancement after gadobenate dimeglumine injection may predict dysplastic nodule diagnosis in patients with liver cirrhosis. PMID- 23436845 TI - Histopathologic findings of multifocal pancreatic intraductal papillary mucinous neoplasms on CT. AB - OBJECTIVE: The criteria for resection of solitary pancreatic side-branch intraductal papillary mucinous neoplasm (IPMN) have been well described by the Sendai consensus statement. However, the management of multiple pancreatic cystic lesions is less certain, with no clear guidelines in the literature to date. The purpose of this study was to evaluate the histopathologic findings in pancreatic IPMNs in patients with multiple (>= 4) pancreatic cysts. MATERIALS AND METHODS: The CT scans of all patients with a pathologically proven IPMN at our institution were reviewed, and a total of 52 patients with four or more pancreatic cysts were found. Each case was reviewed for the number of cysts and the presence of signs of invasive malignancy including a coexistent solid pancreatic mass, pancreatic ductal dilatation, and mural nodularity. RESULTS: A total of 52 patients (19 men, 33 women; mean age, 71.8 years) were found to have multifocal IPMNs, defined as four or more cysts, on CT. Of these 52 patients, nine also had evidence of a solid pancreatic mass on CT. Retrospective review of the pathologic results for the remaining 43 patients (17 men, 26 women; mean age, 71.76 years) showed 18 cases of an IPMN with either high-grade dysplasia or a coexistent invasive carcinoma. Most important, 37% (7/19 patients) had no CT findings of an invasive malignancy according to the Sendai criteria (i.e., cysts >= 3 cm in the axial plane, main pancreatic ductal dilatation >= 6 mm, or mural nodularity within a cyst) but were found to have an IPMN with either high-grade dysplasia or invasive carcinoma. When the pancreas contained 10 or more cysts, high-grade dysplasia or invasive carcinoma tended to be more likely than low- or intermediate-grade dysplasia (odds ratio, 3.83; 95% CI, 0.87-16.8; p = 0.075). CONCLUSION: The presence of multiple pancreatic cysts should be looked on with suspicion, particularly when there are a large number of cysts, even when none of the cysts individually meet the imaging criteria for resection according to the Sendai consensus recommendations. At the very least, these patients need to be followed very closely. PMID- 23436846 TI - Pretreatment microbubble-induced enhancement in hepatocellular carcinoma predicts intrahepatic distant recurrence after radiofrequency ablation. AB - OBJECTIVE: The purpose of this study is to examine whether pretreatment findings in hepatocellular carcinoma (HCC) using contrast-enhanced ultrasound can predict local or distant recurrence after radiofrequency ablation (RFA). SUBJECTS AND METHODS: Subjects of the prospective study were 54 patients with HCC lesions treated by RFA. Intensity differences between lesion and liver parenchyma at early arterial (4 seconds) and peak enhancement times and washout at late phase were provided on contrast-enhanced sonograms with perflubutane microbubble agent. The pretreatment findings were examined with respect to intrahepatic local and distant recurrence. RESULTS: Univariate analysis showed that intensity differences at the early arterial time (hazard ratio [HR], 2.2; 95% CI, 1.0-4.6; p = 0.042) and lesion frequency (HR, 2.3; 95% CI, 1.0-5.0; p = 0.044) were risk factors for distant recurrence. Multivariate analysis showed that intensity differences at the early arterial time (HR, 2.7; 95% CI, 1.2-5.8; p = 0.014) and lesion frequency (HR, 2.9; 95% CI, 1.3-6.5; p = 0.015) were risk factors for distant recurrence. The cumulative distant recurrence rate for patients with intensity differences at the early arterial time was greater at less than 10 dB than at 10 dB or higher (33.3% and 91.3% vs 23.9% and 65.1% at 1 and 2 years, respectively; p = 0.035). The cumulative distant recurrence rate was 16.5% and 61.1% at 1 and 2 years, respectively, in patients with solitary lesions and 54.7% and 77.4% at 1 and 2 years, respectively, in patients with multiple lesions (p = 0.0296). No pretreatment findings were predictive for local recurrence. CONCLUSION: HCC lesions with gradual enhancement in the early arterial time displayed potential distant recurrence risk after RFA, requiring careful posttreatment surveillance. PMID- 23436847 TI - Dynamic contrast-enhanced subtraction MRI for characterizing intratesticular mass lesions. AB - OBJECTIVE: The objective of our study was to analyze the enhancement patterns of various intratesticular mass lesions at dynamic contrast-enhanced subtraction MRI and assess the value of the technique in distinguishing between benign and malignant lesions. MATERIALS AND METHODS: We retrospectively evaluated the records and images of 44 consecutive men (11 benign and 16 malignant intratesticular lesions) who presented to the department of urology with a variety of clinical symptoms and were referred for imaging. Dynamic contrast enhanced subtraction MRI was performed using a 3D fast-field echo sequence after the administration of paramagnetic contrast medium. Patients were divided into three groups according to the final diagnosis: benign intratesticular lesions, malignant intratesticular lesions, and normal testes. The patterns of contrast enhancement of both the normal testes and the intratesticular lesions were evaluated. Time-signal intensity plots were created and classified according to shape: Type I presented a linear increase of contrast enhancement throughout the examination, type II showed an initial upstroke followed by either a plateau or a gradual increase in the late contrast-enhanced phase, and type III presented an initial upstroke followed by gradual washout of the contrast medium. The relative percentages of peak height, maximum time, and mean slope were also calculated. RESULTS: Normal testes enhanced homogeneously with a type I curve. Most benign intratesticular lesions showed inhomogeneous or homogeneous contrast enhancement and a type II curve. Testicular carcinomas showed heterogeneous contrast enhancement with a type III curve. The relative percentages of maximum time to peak proved the most important discriminating factor in differentiating malignant from benign intratesticular masses (p < 0.001). CONCLUSION: Dynamic contrast enhanced MRI may be used to distinguish between benign and malignant intratesticular mass lesions. PMID- 23436848 TI - Communicating findings: a justification and framework for direct radiologic disclosure to patients. AB - OBJECTIVE: Radiologists' delivery of imaging results to patients remains controversial. One model of communication suggests limiting disclosure to normal results. We argue that disclosing radiologic findings to patients is justified in all categories of results. CONCLUSION: Once a doctor-patient relationship has been established, we claim that it is morally justifiable for radiologists to communicate findings directly to their patients. The practice guidelines that we advocate employ a sliding scale based on the diagnostic confidence of imaging results. PMID- 23436849 TI - Relating noise to image quality indicators in CT examinations with tube current modulation. AB - OBJECTIVE: Modern CT systems use surrogates of noise-noise index (NI) and quality reference effective tube current-time product (Q)-to infer the quality of images acquired using tube current modulation. This study aimed to determine the relationship between actual noise and these surrogates for two CT scanners from two different manufacturers. MATERIALS AND METHODS: Two phantoms (adult and 1 year-old child) were imaged on two CT scanners (64 and 128 MDCT) using a clinical range of NI (6-22) and Q (30-300 mA). Each scan was performed twice, and noise was measured in the mediastinum, lung, and abdomen using an image subtraction technique. The effect on noise from changing other imaging parameters, such as beam collimation, pitch, peak kilovoltage, slice thickness, FOV, reconstruction kernel or algorithm, and patient age category (adult or pediatric), was investigated. RESULTS: On the 64-MDCT scanner, noise increased linearly along with NI, with the slope affected by changing the anatomy of interest, peak kilovoltage, reconstruction algorithm, and convolution kernel. The noise-NI relationship was independent of phantom size, slice thickness, pitch, FOV, and beam width. On the 128-MDCT scanner, noise decreased nonlinearly along with increasing Q, slice thickness, and peak tube voltage. The noise-Q relationship also depended on anatomy of interest, phantom size, age selection, and reconstruction algorithm but was independent of pitch, FOV, and detector configuration. CONCLUSION: We established how noise changes with changing image quality indicators across a clinically relevant range of imaging parameters. This work can aid in optimizing protocols by targeting specific noise levels for different types of CT examinations. PMID- 23436850 TI - Partial arc beam filtration: a novel approach to reducing CT breast radiation dose. AB - OBJECTIVE: We sought to assess the effectiveness of a novel CT radiation dose reduction strategy in which filtration was added at the x-ray tube output port between the x-ray beam and the breast area of three sizes of anthropomorphic phantoms. MATERIALS AND METHODS: To evaluate the dose-reduction potential of partial arc x-ray beam filtration, copper foil filtration or lead foil filtration was placed over CT scanners' covers when scanning anthropomorphic phantoms representative of a 5-year-old child, a 10-year-old child, and an adult female. Dose reduction was calculated as the percentage difference between the mean entrance radiation dose (on the phantoms' surfaces at locations representing the sternum and left breast) in unshielded scans compared with the mean dose in scans shielded by copper or lead foil. We also compared the CT numbers and noise sampled in regions representing the lung and the soft tissues near the sternum, left breast, and spine in CT images of the phantoms during unshielded scans relative to acquisitions shielded by copper or lead foil. RESULTS: Entrance dose at the sternum and left breast in the three anthropomorphic phantoms was reduced by 28-66% and 54-79% when using copper or lead foil filtration, respectively. However, copper foil filtration affected the CT numbers and noise in the CT images less than the lead foil filtration did (8.2% vs 32% mean increase in noise). CONCLUSION: By incorporating partial arc beam filtration into CT scanners, substantial dose reductions may be achieved with a minimal increase in image noise. PMID- 23436851 TI - Dorsal fractures of the triquetrum: MRI findings with an emphasis on dorsal carpal ligament injuries. AB - OBJECTIVE: The objective of our study was to report the MRI findings in dorsal fractures of the triquetrum, with an emphasis on dorsal carpal ligament injuries. MATERIALS AND METHODS: A total of 21 patients (16 men, five women; mean age, 41.9 years) with acute or subacute (<= 6 weeks) dorsal triquetral fractures on radiography and MRI were included in this two-center retrospective study. MRI of the wrist was performed on 3-T units with transverse T1-weighted, coronal or transverse (or both) fat-suppressed T2weighted, transverse gadolinium-enhanced fat-suppressed T1-weighted turbo spin-echo, and 3D gadolinium-enhanced fat suppressed T1-weighted gradient-recalled echo sequences. Three musculoskeletal radiologists evaluated the ulnar styloid process index (USPI) on radiographs and the following MRI features: fracture pattern (types 1-6), bone fragment size and displacement, bone marrow edema distribution, and dorsal carpal ligament tears. RESULTS: Eight type 1, one type 2, six type 3, five type 4, and one type 5 fractures were identified. These fractures were associated with 14 (66.7%), 17 (81.0%), and 16 (76.2%) tears of the dorsal radiocarpal, ulnotriquetral, and intercarpal ligaments, respectively. There was no correlation between bone marrow edema distribution and dorsal carpal ligament injuries (all p > 0.05). The mean (+/- SD) bone fragment volume and displacement were 205 +/- 157 mm(3) and 1.0 +/- 1.1 mm, respectively. The mean USPI was 0.21 +/- 0.10. CONCLUSION: Dorsal fractures of the triquetrum are frequently associated with dorsal carpal ligament injuries. Bone marrow edema distribution is not correlated with these ligament tears. PMID- 23436852 TI - A clinically useful classification of traumatic intervertebral disk lesions. AB - OBJECTIVE: Lesions of the intervertebral disk accompanying vertebral fractures are the subject of controversy regarding the extent of surgical intervention, in part due to the lack of a comprehensive classification. The purpose of this study is to present a novel and clinically useful classification system for traumatic disk lesions after vertebral fractures. MATERIALS AND METHODS: MRI of 204 disks in 102 patients with trauma-induced single-level thoracolumbar fractures referred to our trauma center between 2007 and 2011 were analyzed retrospectively. Exclusion criteria were malignant vertebral collapse, spondylodiskitis, osteoporotic fractures, and degenerative disk disease in the uninjured disks. Morphologic changes and signal alterations of the adjacent disks were determined using routine MRI of these patients and a grading system was developed. Disks were divided according to their signals into four categories from grade 0 to grade 3. Intra- and interobserver reliabilities were measured by calculating the Cohen kappa coefficient. RESULTS: Of the 204 disks studied, 28.9% (59/204) were determined to be grade 0 (uninjured), 4.9% (10/204) grade 1 (disk edema), 25.5% (52/204) grade 2 (bleeding/rupture), and 40.7% (83/204) grade 3 (displacement). The kappa value for the intra- and interobserver agreement was 0.96. CONCLUSION: This novel classification may improve communication between spine surgeons and radiologists as well as facilitate clinical decision making in spine surgery. Further studies need to be conducted to verify clinical relevance. PMID- 23436853 TI - ADC values and prognosis of malignant astrocytomas: does lower ADC predict a worse prognosis independent of grade of tumor?--a meta-analysis. AB - OBJECTIVE: The purpose of this article is to determine via meta-analysis whether apparent diffusion coefficient (ADC) predicts astrocytoma prognosis independent of grade. MATERIALS AND METHODS: Survival data were subjected to Mantel Haenszel analysis in four qualifying studies. Stratification by tumor grade was also performed. RESULTS: The survival rates of malignant astrocytomas, grade 3 and 4 (p, 0.004 and < 0.0001, respectively) were worse below a specific ADC value, independent of grade. CONCLUSION: Low ADC values correlate with poor survival in malignant astrocytomas independent of tumor grade. PMID- 23436854 TI - Reducing clinical MRI motion degradation using a prescan patient information pamphlet. AB - OBJECTIVE: Voluntary patient motion is a common cause of image degradation during MRI and leads to repeated scanning, decreasing efficiency, and increasing costs. We hypothesized that providing an educational pamphlet to patients before their MRI examination could improve image quality and decrease the number of repeated sequences needed because of motion artifacts. SUBJECTS AND METHODS: Over 12 months, we recruited patients undergoing MRI for any neurologic condition. The control group received a routine safety questionnaire concerning MRI scanning. The intervention group was given an additional pamphlet describing the examination and graphically emphasizing the value of remaining still during scanning; comprehension was confirmed by questionnaire. The radiology technologists performing the examinations were blinded to group assignments; they recorded the number of repeated sequences needed because of motion artifacts and assessed image quality on a scale of 0 to 4 (0 = unusable, 4 = perfect). RESULTS: The number of patients requiring repeated MRI sequences (control group vs intervention group: 40 vs 20, respectively; p = 0.009) and the total number of repeated MRI sequences (52 vs 27, p = 0.004) decreased in the group who read the pamphlet compared with the control group. CONCLUSION: Providing a simple educational pamphlet to patients before their MRI examinations that illustrated motion degradation and emphasized the need to remain still significantly reduced the number of repeated sequences deemed necessary by the MRI technologist. PMID- 23436855 TI - PET-based primary tumor volumetric parameters and survival of patients with non small cell lung carcinoma. AB - OBJECTIVE: The purpose of the study was to assess metabolic tumor volume and total glycolytic activity of the primary tumor as prognostic parameters for outcome in patients with non-small cell lung carcinoma (NSCLC). MATERIALS AND METHODS: Thirty-nine patients who had undergone a baseline staging PET/CT examination at our institution for the diagnosis of NSCLC were retrospectively identified. The maximum standardized uptake value (SUV(max)), metabolic tumor volume, and total glycolytic activity were segmented from PET using the gradient method; 12-month survival and overall survival at the end of follow-up were used as outcome measures. Multivariate logistic regression, receiver operating characteristic curve analysis, and Kaplan-Meier curves for survival analysis were generated and compared using the Mantel-Cox log-rank test. RESULTS: The mean gradient-based metabolic tumor volume and gradient-based total glycolytic activity were significantly greater in the patients who died (93.3 mL and 597.5 g) than in those who survived (19.3 mL and 193.9 g, respectively) (p < 0.003 and p < 0.031). There was no statistically significant difference in the mean SUV(max) between the patients who survived (12.7) at 12 months and those who had died (13.1) (p = 0.85). On multivariate analysis, gradient-based metabolic tumor volume was the only variable associated with 12-month mortality when adjusted for all other factors.(.) The area under the curve (AUC) for gradient-based metabolic tumor volume was 0.77 (p < 0.006). A significant difference in the time to survival was observed between high and low gradient-based metabolic tumor volume (log-rank p < 0.05) cohorts using the median gradient-based metabolic tumor volume (9.7 mL) as the cut point. CONCLUSION: PET-based volumetric imaging parameters are potential prognostic markers of outcome in patients with NSCLC. PMID- 23436856 TI - Yield of radiographic skeletal surveys for detection of hand, foot, and spine fractures in suspected child abuse. AB - OBJECTIVE: Previous studies have found that fractures involving the spine, hands, and feet are rare on skeletal surveys in cases of suspected child abuse, leading some authors to suggest eliminating these regions from the initial skeletal survey protocol. We assessed this recommendation by performing a historical review of these injuries in a pediatric population undergoing film screen-based radiographic skeletal surveys for suspected child abuse. MATERIALS AND METHODS: This cross-sectional retrospective study reviewed reports of initial skeletal surveys of all children younger than 2 years with suspected abuse imaged between April 1988 and December 2001. Radiographic skeletal survey imaging was performed according to American College of Radiology standards. Sixty-two percent (225/365) of all skeletal surveys had positive findings, and 44% (98/225) showed more than one fracture. Surveys with fractures involving the spine, hands, or feet were identified, and the data were tabulated and analyzed. RESULTS: Twenty of 365 studies (5.5%) yielded fractures involving the spine, hands, or feet. Of all positive skeletal surveys, 8.9% (20/225) had fractures involving the spine, hands, or feet. Of all patients with more than one fracture on skeletal survey, 20.4% (20/98) had fractures involving these regions. CONCLUSION: These data, acquired during the film-screen era, suggest that fractures of the spine, hands, and feet may not be rare in infants and toddlers in cases of suspected child abuse. The benefits of eliminating views of these regions from the initial skeletal survey should be carefully weighed against the cost of missing these potentially important injuries in at-risk pediatric populations. PMID- 23436857 TI - Relationship between radiologist training level and fluoroscopy time for voiding cystourethrography. AB - OBJECTIVE: The objective of our study was to determine whether voiding cystourethrography (VCUG) fluoroscopy time is related to the training level of the performing radiologist. MATERIALS AND METHODS: VCUG reports with normal findings from 2008 to 2011 at one institution were retrospectively reviewed. The average fluoroscopy time was calculated for first-year radiology residents, senior radiology residents, pediatric radiology fellows, and attending pediatric radiologists. The average fluoroscopy time was also calculated for radiologist sex, patient sex, and patient age group. The analysis of variance was used to evaluate differences in average fluoroscopy times between training levels of radiologists, patient age groups, and patient sexes. RESULTS: We reviewed 784 VCUG reports with normal findings: 340 (43.4%) were performed by first-year residents; 181 (23%), by senior residents; 161 (20.5%), by fellows; and 102 (13%), by attending pediatric radiologists. The overall average fluoroscopy time was 1.86 minutes (SD +/- 0.98). The attending pediatric radiologists had the shortest average fluoroscopy time (1.63 +/- 0.92 minutes), significantly shorter than senior residents (1.96 +/- 1.09 minutes; p = 0.0070) and fellows (1.91 +/- 0.85 minutes; p = 0.0255). There was no significant difference between attending radiologists and first-year residents (1.85 +/- 1.00 minutes; p = 0.0550). The male-to-female ratio of radiologists was 54% versus 46%, with identical average fluoroscopy times: male radiologists, 1.86 +/- 1.05 minutes; female radiologists, 1.86 +/- 0.90 minutes. There was no significant difference in average fluoroscopy times among patient age groups: 1.93, 1.76, and 1.78 minutes, respectively, for groups A (0-1 years), B (> 1 to <= 5 years), and C (> 5 years) (p = 0.1750, 0.4605, 0.6303). The average fluoroscopy time for male patients (2.02 +/- 1.00 minutes) was significantly longer than that for female patients (1.71 +/- 0.95 minutes; p < 0.0001). CONCLUSION: Attending pediatric radiologists have the shortest fluoroscopy time; the differences between their average time compared with the average times of pediatric radiology fellows and of senior radiology residents were statistically significant. The average fluoroscopy time is longer for male patients than for female patients. PMID- 23436858 TI - Vascular diameter measurement in CT angiography: comparison of model-based iterative reconstruction and standard filtered back projection algorithms in vitro. AB - OBJECTIVE: The purpose of this study was to evaluate the performance of model based iterative reconstruction (MBIR) in measurement of the inner diameter of models of blood vessels and compare performance between MBIR and a standard filtered back projection (FBP) algorithm. MATERIALS AND METHODS: Vascular models with wall thicknesses of 0.5, 1.0, and 1.5 mm were scanned with a 64-MDCT unit and densities of contrast material yielding 275, 396, and 542 HU. Images were reconstructed images by MBIR and FBP, and the mean diameter of each model vessel was measured by software automation. Twenty separate measurements were repeated for each vessel, and variance among the repeated measures was analyzed for determination of measurement error. For all nine model vessels, CT attenuation profiles were compared along a line passing through the luminal center on axial images reconstructed with FBP and MBIR, and the 10-90% edge rise distances at the boundary between the vascular wall and the lumen were evaluated. RESULTS: For images reconstructed with FBP, measurement errors were smallest for models with 1.5-mm wall thickness, except those filled with 275-HU contrast material, and errors grew as the density of the contrast material decreased. Measurement errors with MBIR were comparable to or less than those with FBP. In CT attenuation profiles of images reconstructed with MBIR, the 10-90% edge rise distances at the boundary between the lumen and vascular wall were relatively short for each vascular model compared with those of the profile curves of FBP images. CONCLUSION: MBIR is better than standard FBP for reducing reconstruction blur and improving the accuracy of diameter measurement at CT angiography. PMID- 23436859 TI - Frequency of and risk factors for complications after liver radiofrequency ablation under CT fluoroscopic guidance in 1500 sessions: single-center experience. AB - OBJECTIVE: The purpose of this article is to retrospectively evaluate the frequency of and risk factors for complications after liver radiofrequency ablation (RFA). MATERIALS AND METHODS: This was a retrospective study of 656 patients (with 1755 liver tumors) who underwent 1500 CT fluoroscopy-guided liver RFA sessions. Of those patients, 501 had primary liver tumor and 155 had liver metastases. Mortality and treatment-related complications were documented. Complications were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0). Major complications were defined as grade 3 or higher adverse events. Factors affecting frequent complications with a frequency of 1% or more were detected using multivariate analysis. RESULTS: Two deaths (0.1% [2/1500]) occurred. One patient died of liver failure subsequent to hemorrhage, and the other died of liver failure. The major complication rate was 2.8% (42/1500). The most frequent major complication was hemorrhage (1.1% [16/1500]). The absence of arterial embolization before RFA (p < 0.01), low hemoglobin level (p < 0.04), and elevated serum creatinine level (p < 0.04) were identified as significant risk factors for major hemorrhage. The minor complication rate was 17.1% (257/1500). Pneumothorax (7.7% [116/1500]) was the most frequent minor complication, followed by hemorrhage (7.0% [105/1500]). A transthoracic approach (p < 0.01) and subphrenic tumor location (p < 0.01) were significant risk factors for pneumothorax, and the use of a cluster needle (p < 0.02) and multiple tumors (p < 0.01) were significant risk factors for minor hemorrhage. CONCLUSION: CT fluoroscopy-guided RFA is a safe procedure with an acceptably low rate of major complications for liver tumor treatment. Factors identified in this study will help to stratify high-risk patients. PMID- 23436860 TI - Factors influencing local tumor control in patients with neoplastic pulmonary nodules treated with microwave ablation: a risk-factor analysis. AB - OBJECTIVE: This study was performed to evaluate risk factors predictive of local tumor control after microwave ablation of primary and secondary lung malignancies up to 3 cm in maximal diameter. MATERIALS AND METHODS: The single-antenna microwave ablation treatment of 91 index tumors in 57 patients was studied retrospectively. Time to local tumor progression was monitored on CT scans over the follow-up period. Estimation of overall time to local tumor progression was performed with the Cox regression model. Factors hypothesized to correlate with ablation response included tumor diameter, tumor shape (round or oval versus irregular), clear versus ill-defined tumor margin, adjacency to the pleura, adjacency to bronchi, presence of vessels at least 3 mm in diameter a maximum of 5 mm from the index tumor, energy applied to the index tumor, and the occurrence of cavernous formations after ablation. A logistic regression model was used to correlate the data. RESULTS: Thirty of 91 (33.0%) index tumors, found in 21 of 57 (36.8%) patients, underwent local progression. The mean time to local tumor progression was 8.3 +/- 5.5 months (range 2.1-25.2 months), and the estimated median time to local tumor progression was 22.6 +/- 12.4 months. The risk factors that correlated significantly with local tumor progression were a maximal diameter greater than 15.5 mm (p < 0.01), irregular shape of the index tumor (p < 0.01), pleural contact (p = 0.02), and less than 26.7 J/mm(3) applied to the index tumor (p < 0.001). After regression analysis, shape of the index tumor (p = 0.03) and energy deployed per unit volume of the index tumor (p = 0.001) were found to be independent risk factors. Conversely, tumor margin definition (p = 0.06) and proximity of cavernous formations (p = 0.19), juxtatumoral vessels (p = 0.08), and bronchi (p = 0.89) did not affect tumor progression after ablation. CONCLUSION: The independent predictive factors for local tumor progression in primary and secondary lung neoplasms up to 3 cm in diameter observed in this study were irregular shape of the index tumor and energy application of less than 26.7 J/mm(3) to the index tumor. PMID- 23436861 TI - Accuracy of CT guidance of lumbar facet joint block. AB - OBJECTIVE: Lumbar facet joint block is generally performed under fluoroscopic guidance. The purpose of this study was to assess the technical success rate of facet joint block under CT guidance. The CT scanner was operated tableside with a step-and-shoot mode for intermittent needle visualization, and the amount of radiation used to perform the procedures was estimated. CONCLUSION: CT-guided facet joint block is safe and rapid. Use of CT ensures reliable needle guidance with extremely high procedural accuracy at an effective radiation dose comparable to that of a procedure performed with 1 minute of fluoroscopic guidance. PMID- 23436862 TI - Gelfoam-assisted amplatzer vascular plug technique for rapid occlusion in proximal splenic artery embolization. AB - OBJECTIVE: The objective of this study was to prospectively investigate the role of rapid Gelfoam-assisted occlusion of the splenic artery with an Amplatzer Vascular Plug (AVP). Ten consecutive proximal splenic artery embolizations were performed with AVP as the primary embolic agent and Gelfoam slurry as an adjunct. These cases were then compared with 10 retrospective cases of splenic artery embolization performed with AVP and augmented with coils or additional AVPs, or both, in patients with similar indications. CONCLUSION: Successful proximal splenic artery embolization using a single Amplatzer Vascular Plug and Gelfoam slurry occurred in all cases. No recanalization was identified on imaging follow up at an average interval of 5.1 months. Gelfoam can be used as an adjunct to AVP in proximal splenic artery embolization. Using adjunctive Gelfoam is a simple, safe, and cost-saving method of improving the occlusion efficiency of the Amplatzer Vascular Plug. PMID- 23436863 TI - Flat ductal intraepithelial neoplasia 1A diagnosed at stereotactic core needle biopsy: is excisional biopsy indicated? AB - OBJECTIVE: This study correlates ductal intraepithelial neoplasia (DIN) 1A diagnosed at stereotactic spring core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) with the subsequent surgical histologic results or long-term follow up imaging findings to predict the likelihood of upgrade to ductal carcinoma in situ (DCIS) or invasive carcinoma. MATERIALS AND METHODS: Stereotactic imaging guided CNBs and VABs were performed principally for assessment of microcalcifications seen on mammography. DIN 1A diagnoses made at CNB or VAB were correlated with subsequent excisional biopsy results or imaging follow-up. Patients were included only if there was no concomitant CNB or VAB diagnosis of DIN 1B, atypical lobular hyperplasia, lobular carcinoma in situ or DCIS, papillary lesion, or invasive carcinoma. Surgical biopsy results were obtained for 239 patients. Upgrade was defined as a diagnosis of DCIS or invasive carcinoma at surgery. Patients who did not undergo surgical excision were followed with imaging. RESULTS: An upgrade rate of 4.2% (10 lesions in 239 patients) is reported. The remaining samples (229/239) had a surgical diagnosis of DIN 1A or DIN 1B, lobular carcinoma in situ, or a benign finding with no atypia. CONCLUSION: The upgrade rate of DIN 1A diagnosed at CNB or VAB was 4.2%. These results indicate it may be reasonable to avert immediate surgery in favor of short-term imaging follow-up. PMID- 23436864 TI - Invasive micropapillary carcinoma of the breast: imaging features with clinical and pathologic correlation. AB - OBJECTIVE: The purpose of this article is to present imaging findings of invasive ductal carcinoma with micropapillary features with clinical and pathologic correlation. MATERIALS AND METHODS: We retrospectively searched our institution's surgical pathology database for patients with pathologically proven invasive ductal carcinoma with micropapillary features. Forty-one patients with images available for review were included in the study. Mammographic, sonographic, and MRI findings were assessed using the American College of Radiology's BI-RADS lexicon. Molecular breast imaging findings were reviewed using a molecular breast imaging lexicon. Imaging findings were correlated with clinical presentation and pathologic findings. RESULTS: Mammographically, the most common finding was an irregular spiculated mass. Sonographically, the most common finding was an irregular hypoechoic mass with spiculated margins and posterior acoustic shadowing. With MRI, the most common finding was an irregular mass with washout kinetics, but we also observed diffuse heterogeneous nonmasslike enhancement throughout the breast. Molecular breast imaging was available for one patient and showed multicentric radiotracer uptake. Analysis of 39 pathologic specimens showed 27 (69%) with angiolymphatic invasion. Axillary nodal metastases were present in 23 patients (59%), nine (23%) with extranodal extension. CONCLUSION: The imaging features of invasive ductal carcinoma of the breast with micropapillary features typically were highly suggestive of malignancy. The malignancies were strongly associated with lymphovascular invasion and lymph node metastases. Radiologists should be aware of the imaging features of this unusual variant and should consider axillary sonography if this entity is found in a core needle biopsy specimen. PMID- 23436865 TI - Utility of preoperative ultrasound for predicting pN2 or higher stage axillary lymph node involvement in patients with newly diagnosed breast cancer. AB - OBJECTIVE: The objective of our study was to report the positive predictive value (PPV) of ultrasound of the axilla to predict pN2 or higher disease in breast cancer patients. MATERIALS AND METHODS: A retrospective study of 559 patients with newly diagnosed invasive breast cancer from 2005 through 2009 was performed. All patients underwent ipsilateral axillary ultrasound for staging purposes. Ultrasound findings were considered suspicious for metastasis if cortical thickening or nonhilar blood flow to the cortex was present. Suspicious lymph nodes were classified on the basis of their features as high, intermediate, or low suspicion. The standard of truth was confirmed pathologically. RESULTS: Either pN2 or pN3 disease was found in 50 of 181 (28%) patients with positive findings on an ultrasound study and 10 of 378 (3%) patients with a negative ultrasound study (p < 0.01). When two or more lymph nodes of high suspicion or a total of three or more lymph nodes of any combination of high suspicion and intermediate suspicion were detected, patients were likely to have pN2 or pN3 disease (PPV, 82%). Either pN2 or pN3 disease was found in two of 122 (2%) patients whose primary cancers were up to 10 mm and 58 of 437 (13%) patients whose primary cancers were larger than 10 mm (p < 0.001). Ultrasound of the patient with tumors larger than 10 mm showing at least two highly suspicious nodes had a PPV of 87% for predicting pN2 or higher disease. CONCLUSION: Ultrasound was useful for predicting pN2 or higher axillary disease in breast cancer patients. Preoperative ultrasound assessment for staging of axillary lymph nodes might help avoid underestimation at sentinel lymph node biopsy. PMID- 23436867 TI - Upper lobe-predominant diseases of the lung. PMID- 23436868 TI - Solitary fibrous tumors of the thorax: nomenclature, epidemiology, radiologic and pathologic findings, differential diagnoses, and management. PMID- 23436869 TI - Real-time image fusion involving diagnostic ultrasound. AB - OBJECTIVE: The aim of our article is to give an overview of the current and future possibilities of real-time image fusion involving ultrasound. We present a review of the existing English-language peer-reviewed literature assessing this technique, which covers technical solutions (for ultrasound and endoscopic ultrasound), image fusion in several anatomic regions, and electromagnetic needle tracking. CONCLUSION: The recent progress of real-time ultrasound in image fusion may provide several new possibilities, including diagnosis, treatment, and follow up of oncologic patients. PMID- 23436870 TI - Comparison between (99m)Tc-diphosphonate imaging and MRI with late gadolinium enhancement in evaluating cardiac involvement in patients with transthyretin familial amyloid polyneuropathy. AB - OBJECTIVE: Cardiac involvement is not rare in systemic amyloidosis and is associated with poor prognosis. Both (99m)Tc-diphosphonate imaging and cardiac MRI with late gadolinium enhancement are considered valuable tools in revealing amyloid deposition in the myocardium; however, to our knowledge, no comparative study between the two techniques exists. We compared findings of these two techniques in patients with transthyretin-familial amyloid polyneuropathy (FAP). SUBJECTS AND METHODS: Eighteen patients with transthyretin-FAP underwent (99m)Tc diphosphonate imaging and MRI with late gadolinium enhancement. Images were visually evaluated by independent readers to determine the presence of radiotracer accumulation or late gadolinium enhancement-positive areas at the level of cardiac chambers. RESULTS: Interobserver agreement ranged from moderate to very good for (99m)Tc-diphosphonate imaging findings and was very good for findings of MRI with late gadolinium enhancement. Left ventricle (LV) radiotracer uptake was found in 10 of 18 patients, whereas LV late gadolinium enhancement positive areas were found in eight of 18 patients (chi(2) = 0.9; p = 0.343). One hundred fifty-nine LV segments showed (99m)Tc-diphosphonate accumulation, and 57 LV segments were late gadolinium enhancement positive (p < 0.0001). Radiotracer uptake was found in the right ventricle (RV) in eight patients and in both atria in five patients, whereas MRI showed that RV was involved in three patients and both atria in six patients; the differences were not statistically significant (RV, p = 0.07; atria, p = 1). Intermodality agreement between (99m)Tc diphosphonate imaging and MRI ranged from fair to good. CONCLUSION: Our study shows that, although (99m)Tc-diphosphonate imaging and MRI with late gadolinium enhancement have similar capabilities to identify patients with myocardial amyloid deposition, cardiac amyloid infiltration burden can be significantly underestimated by visual analysis of MRI with late gadolinium enhancement compared with (99m)Tc-diphosphonate imaging. PMID- 23436871 TI - Diffuse diseases of the myocardium: MRI-pathologic review of nondilated cardiomyopathies. AB - OBJECTIVE: This article will present correlation of the key radiologic findings with gross and microscopic pathology for the characterization of diffuse myocardial diseases using advanced imaging techniques. Our goal is to provide a focused and in-depth review of the pathophysiology underlying each entity and to emphasize the structural basis for the corresponding imaging characteristics. This article is limited to those disorders characterized by ventricular wall thickening without chamber dilatation, including hypertrophic cardiomyopathy, hypertensive cardiomyopathy, and cardiac amyloidosis. CONCLUSION: For the characterization of diffuse myocardial diseases using advanced imaging techniques, it is essential to understand the underlying pathologic changes in the heart. With these techniques, such as cardiac MRI, the various cardiomyopathies can be differentiated accurately, which may potentially obviate invasive testing and endomyocardial biopsy. PMID- 23436872 TI - Diffuse diseases of the myocardium: MRI-pathologic review of cardiomyopathies with dilatation. AB - OBJECTIVE: In this radiologic-pathologic review of the cardiomyopathies, we present the pertinent imaging findings of diffuse myocardial diseases that are associated with ventricular dilatation, including ischemic cardiomyopathy, nonischemic dilated cardiomyopathy, cardiac sarcoidosis, and iron overload cardiomyopathy. CONCLUSION: Correlation of the key radiologic findings with gross and microscopic pathologic features is presented, to provide the reader with a focused and in-depth review of the pathophysiology underlying each entity and the basis for the corresponding imaging characteristics. PMID- 23436873 TI - Pancreatic neuroendocrine tumor with cystlike changes: evaluation with MDCT. AB - OBJECTIVE: The objective of our study was to determine the prevalence and CT appearance of cystlike changes of pancreatic neuroendocrine tumor (NET), particularly of small (<= 3 cm) tumors. MATERIALS AND METHODS: The clinical records, images, and pathologic reports of 74 consecutive patients (average age, 55.5 years) with surgically resected pancreatic NETs who underwent preoperative CT were retrospectively reviewed. The size and location of the pancreatic NETs were recorded. The tumors were classified on the basis of CT appearance as small (<= 3 cm) or large (> 3 cm) and as solid, partially (<= 50% or > 50%) cystic, or purely (~ 100%) cystic. Peripheral contrast enhancement on CT was characterized, and lymph node and liver metastases found by pathologic examination were recorded. RESULTS: A total of 78 pancreatic NETs were reviewed. Five were not visualized on CT, leaving 73 pancreatic NETs in 69 patients (multiple tumors were visualized on CT of three patients) for analysis. The mean size of the 73 tumors was 3.0 +/- 2.6 (SD) cm (range, 0.7-13.1 cm); 52 tumors were 3 cm or smaller and 21 tumors were larger than 3 cm. Gross pathologic results confirmed that 13 of the 73 (17.8%) tumors were predominantly (> 50% or ~ 100%) cystic: 10 of the 52 (19.2%) tumors 3 cm or smaller and three of the 21 (14.3%) tumors larger than 3 cm. Peripheral contrast enhancement was seen in 11 of the 13 (85%) predominantly cystic pancreatic NETs. Compared with solid pancreatic NETs, predominantly cystic pancreatic NETs were less commonly associated with lymph node and liver metastases. CONCLUSION: Cystic pancreatic NETs are not rare and should be included in the differential diagnosis of a cystic pancreatic mass, particularly if the cystic mass is associated with peripheral contrast enhancement. A minority of cystic pancreatic NETs can present with no peripheral enhancement. PMID- 23436874 TI - Suprapatellar fat-pad mass effect: MRI findings and correlation with anterior knee pain. AB - OBJECTIVE: The purpose of this study was to evaluate the MRI characteristics of the suprapatellar fat-pad, determine the prevalence and pattern of suprapatellar fat-pad edema, and correlate the findings with the presence of anterior knee pain, patellofemoral malalignment, and patellofemoral joint osteoarthritis. MATERIALS AND METHODS: We retrospectively reviewed 879 consecutive knee MRI examinations of 843 patients for the presence of a suprapatellar fat-pad mass effect on the suprapatellar joint recess. The relative signal intensity and the maximum anteroposterior, craniocaudal, and oblique diameters of the suprapatellar fat-pad on sagittal fat-suppressed intermediate-weighted turbo spin-echo images were measured. Findings of anterior knee pain, patellofemoral malalignment, and patellofemoral joint osteoarthritis were also recorded. The Fisher exact, Mann Whitney, and independent samples Student t tests and Spearman rank correlation coefficient were used for statistical analysis. RESULTS: The prevalence of suprapatellar fat-pad mass effect on the suprapatellar joint recess in our study population was 13.8%. The relative signal intensity (p < 0.0001) and maximum anteroposterior (p < 0.0001), craniocaudal (p = 0.0017), and oblique (p < 0.0001) diameters of the pad were significantly greater in patients with a mass effect. Significant correlation was found between the relative signal intensity and the maximum anteroposterior (rho = 0.0986, p = 0.0053), craniocaudal (rho = 0.0968, p = 0.0062), and oblique (rho = 0.123, p = 0.0005) diameters. Mass effect was not significantly associated with anterior knee pain, patellofemoral malalignment, or patellofemoral joint osteoarthritis. Six patients with suprapatellar fat-pad edema had anterior knee pain. CONCLUSION: Suprapatellar fat-pad edema with a mass effect on the suprapatellar joint recess is a common finding at MRI examinations of the knee that is rarely associated with anterior knee pain. PMID- 23436875 TI - Quantitative dynamic contrast-enhanced MRI of pelvic and lumbar bone marrow: effect of age and marrow fat content on pharmacokinetic parameter values. AB - OBJECTIVE: The purpose of this study was to determine the effects of age and fat content on quantitative dynamic contrast-enhanced MRI (DCE-MRI) parameters in the bone marrow of the lumbar spine and pelvis. The interreader reproducibility of this technique will also be assessed. MATERIALS AND METHODS: Forty-three DCE-MRI studies of the female pelvis defined the study group. Quantitative pharmacokinetic perfusion parameters of lumbar and pelvic marrow were analyzed by three readers on a DCE-MRI postprocessing platform. Linear regression analysis was performed to determine the effect of age and marrow fat fraction on the parameters of transfer constant (K(trans)), efflux rate constant (K(ep)), extravascular extracellular space (V(e)), and initial area under the gadolinium curve at 60 seconds (iAUGC(60)). Interreader agreement was assessed by means of intraclass correlation coefficient calculation. RESULTS: A weak but statistically significant correlation was established between both age and fat fraction and the parameters K(trans) (R(2) = 0.14) and K(ep) (R(2) = 0.09). There was also a weak but statistically significant correlation between fat fraction and V(e) (R(2) = 0.116) and iAUGC(60) (R(2) = 0.108), but no correlation between age and these parameters. Intraclass correlation coefficients of parameter measurements by different readers were all greater than 0.7 at the p < 0.05 level. CONCLUSION: Age and fat fraction have small measurable effects on quantitative DCE-MRI parameters in bone marrow. However, given the wide interindividual variation of these parameters, these effects are unlikely to confound changes related to malignancy or treatment. Also of note, there was strong interreader reproducibility of parameter measurements among a range of experience levels, suggesting that the reader-reader experience level may not represent a significant source of variability in bone marrow DCE-MRI. PMID- 23436877 TI - The efficacy of axillary ultrasound in the detection of nodal metastasis in breast cancer. AB - OBJECTIVE: Recent reports indicate a lack of survival benefit for axillary lymph node dissection (ALND) versus sentinel lymph node biopsy in early breast cancer. To study this issue further, we assessed the accuracy and effectiveness of ultrasound examination in detecting axillary nodal involvement in breast cancer patients with the aim of refining our current clinical pathways. MATERIALS AND METHODS: Ultrasound data were collected from breast cancer cases over 3 years. Images were reviewed by experienced radiologists and the following characteristics were assessed: size, morphology, hyperechoic hilum, and cortical thickness of the ipsilateral axillary nodes. The findings were correlated with histologic outcomes after ALND. RESULTS: Two hundred twenty-four cases were included in the analysis, 113 (50.4%) of which had evidence of metastatic nodal involvement at final histology. Of these 113 cases, ultrasound findings for 59 (52.2%) were positive. The overall positive predictive value of ultrasound for detecting metastatic nodal involvement measured 0.81. The negative predictive value was 0.60. The sensitivity was 53.7%; specificity, 85.1%; and accuracy, 67.9%. The ultrasound morphologic lymph node features with the greatest correlation with malignancy were the absence of a hyperechoic hilum (p = 0.003) and increased cortical thickness (p = 0.03). Patients with a metastatic nodal burden density of at least 20% were more likely to have abnormal findings on axillary ultrasound examination (p = 0.009). CONCLUSION: Axillary ultrasound has a low negative predictive value and negative ultrasound results do not exclude axillary node metastases with sufficient sensitivity to justify its routine clinical use. Clinical pathways need to consider an evidence-based approach, focusing on the criteria by which we select breast cancer patients for ALND. PMID- 23436878 TI - MEDICOLEGAL * Malpractice and ethical issues in radiology: ACR practice guidelines and standard of care. PMID- 23436876 TI - MRI of carotid atherosclerosis. AB - OBJECTIVE: Although MRI is widely used to observe atherosclerosis impacts on the vessel lumen, MRI also depicts the size of the plaque itself, its composition, and plaque inflammation, providing information beyond simple stenosis. This article summarizes the state of evidence for a clinical role for MRI of carotid atherosclerosis. CONCLUSION: MRI of carotid atherosclerosis has a proven role in pharmaceutical trials and may improve patient management once large-scale clinical trials have been completed. PMID- 23436879 TI - MEDICOLEGAL: Malpractice and ethical issues in radiology: reinterpreting outside mammograms prior to breast biopsy. PMID- 23436880 TI - Limitations, disabilities, and pitfalls of dynamic contrast-enhanced MRI as a diagnostic modality in prostate cancer. PMID- 23436881 TI - Relationship between polymorphisms in the sulfotransferase SULT2A1 gene and dehydroepiandrosterone sulfate concentration in children. AB - Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant circulating steroid hormone in humans, and has important physiological effects. A relationship has been suggested between variations of DHEA-S concentration and polymorphisms in the gene encoding sulfotransferase (SULT2A1), an enzyme that catalyzes the formation of DHEA-S from DHEA. We have investigated the relationship between the single nucleotide polymorphisms (SNPs) rs2637125 and rs182420 in the SULT2A1 gene and plasma DHEA-S concentration in children at two different ages. The sample population comprised 981 healthy 6-8-year-olds and 792 12-16-year-old children. In total, 12-16-year-old boys homozygous for the rare allele of rs182420 (CC) showed significantly lower DHEA-S concentration than TC boys, and both (TC and CC) had lower levels than TT boys. In all, 12-16 -year-old boy carriers of the rare allele for the rs2637125 polymorphism also showed lower levels of DHEA-S than GG carriers. No differences were observed in DHEA-S concentrations across genotypes in 6-8-year-old children. Our data show an age-related association of polymorphisms in the SULT2A1 gene with lower DHEA-S, suggesting that these polymorphisms may affect DHEA-S concentration in adults. PMID- 23436882 TI - [D-Ala2,D-Leu5]-enkephalin (DADLE) and morphine-induced postconditioning by inhibition of mitochondrial permeability transition pore, in human myocardium. AB - The aim of the study was to examine the cardioprotective effect of morphine and Delta 2 opioid D-Ala2-Leu5 enkephalin(DADLE) administered, at early reoxygenation, in isolated human myocardium exposed to hypoxia-reoxygenation. Then,we tested the involvement of mitochondrial permeability transition pore in morphine and DADLE-induced postconditioning.Human right atrial trabeculae were obtained during cardiac surgery (coronary artery bypass and aortic valve replacement).Isometrically contracting isolated human right atrial trabeculae were exposed to 30-min hypoxia and 60-min reoxygenation(control group). In treatment groups, morphine 0.5 mmol, DADLE 10 nmol, DADLE 50 nmol and DADLE 100 nmol were administered during the first 15 min of reoxygenation. In two additional groups, morphine and DADLE 100 nmol were administered in the presence of atractyloside 50 mmol, the mitochondrial permeability transition pore opener. The force of contraction at the end of 60-min reoxygenation period (FoC60 expressed as % of baseline) was compared (mean+standard deviation) between the groups by an analysis of variance. Morphine (FoC60: 81+9% of baseline), DADLE50 nmol (FoC60: 76+11% of baseline) and DADLE 100 nmol (FoC60: 81+4% of baseline) increased significantly (P,0.001) the FoC60 as compared with the control group (FoC60: 53+3% of baseline). DADLE 10 nmol did not modify the FoC60 (50+9% of baseline; P 1/4 0.60 versus control group). The enhanced recovery of FoC60 induced by morphine and DADLE 100 nmol were abolished in the presence of atractyloside (FoC60: respectively 57+6% and 44+7% of baseline;P, 0.001). In conclusion, the administration of morphine and DADLE, in early reoxygenation period, protected human myocardium, in vitro, against hypoxia-reoxygenation injury, at least in part, by the inhibition of mitochondrial permeability transition pore opening. PMID- 23436884 TI - An infected urachal cyst. AB - Urachal cysts present very uncommonly in adults. We describe a 25-year-old man who attended with a discharging umbilical swelling and pain. Ultrasonography and CT scan demonstrated an infected urachal cyst which, following cystoscopy, was excised without complication. PMID- 23436885 TI - Colitis: an unusual presentation of Wegener's granulomatosis. AB - Wegener's granulomatosis (WG) also known as granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody-positive (ANCA) vasculitis which most commonly affects the upper respiratory tract, lungs and kidneys. It is uncommon for colitis to be the primary reason for the first hospital admission related to WG. This case represents one of the few in the literature where colitis is associated with WG and in particular, where colonic involvement was the presenting symptom. The patient presented to hospital with a 3-day history of bloody diarrhoea and was treated for colitis. The disease progressed and during the second admission renal and pulmonary involvement was found. A renal biopsy showed a crescentic change and a CT-confirmed inflammatory changes in the caecum and ascending colon. A diagnosis of WG was made and appropriate treatment initiated. The patient is now in remission. PMID- 23436886 TI - Management of maxillectomy defect with a hybrid hollow bulb obturator. AB - A woman having already undergone maxillectomy came to the department complaining of difficulty in eating and speech. During the construction of an obturator, the bulb area should be hollowed to reduce weight so that the teeth and supporting tissues are not stressed unnecessarily. The conventional open design drains fluid from the adjacent mucosa, possibly increasing the weight of the prosthesis, and is difficult to clean. The closed bulb design does not drain secretions and may cause obstruction and susceptibility to infection in the paranasal and pharyngeal regions, though it is easier to maintain. An alternative to the two designs, combining their advantages, is presented in this report. As the open hollow part of the obturator was shallow, it was easy to clean. Making the inferior part of the bulb hollow and closed led to a reduction in the overall weight of the prosthesis while increasing its resonance. PMID- 23436887 TI - Caruncular neurofibroma not associated with neurofibromatosis. AB - A rare case of caruncular neurofibroma in a patient who did not have neurofibromatosis. To remember peripheral nerve sheath tumours in the differential diagnosis of caruncular lesions. Excisional biopsy proved to be adequate treatment in our case. PMID- 23436883 TI - Diabetic complications in pregnancy: is resveratrol a solution? AB - Diabetes is a metabolic disorder that, during pregnancy, may affect fetal development. Fetal outcome depends on the type of diabetes present, the concentration of blood glucose and the extent of fetal exposure to elevated or frequently fluctuating glucose concentrations. The result of some diabetic pregnancies will be embryonic developmental abnormalities, a condition referred to as diabetic embryopathy. Tight glycemic control in type 1 diabetes during pregnancy using insulin therapy together with folic acid supplementation are partially able to prevent diabetic embryopathy; however, the protection is not complete and additional interventions are needed. Resveratrol, a polyphenol found largely in the skins of red grapes, is known to have antidiabetic action and is in clinical trials for the treatment of diabetes, insulin resistance, obesity and metabolic syndrome. Studies of resveratrol in a rodent model of diabetic embryopathy reveal that it significantly improves the embryonic outcome in terms of diminishing developmental abnormalities. Improvements in maternal and embryonic outcomes observed in rodent models may arise from resveratrol's antioxidative potential, antidiabetic action and antidyslipidemic nature. Whether resveratrol will have similar actions in human diabetic pregnancy is unknown. Here, we review the potential therapeutic use of resveratrol in diabetes and diabetic pregnancy. PMID- 23436888 TI - Iatrogenic calcinosis cutis in a neonate. AB - Calcification of soft tissues occur, secondary to trauma sustained in the course of neonatal intensive care. They can present with swelling and inflammatory signs, which mimic serious infections of bone, joints and soft tissues. The etiology of the presenting inflammatory response is often unknown and the clinical picture is variable. Hence babies get subjected to more invasive procedures and medications. Recognition is by awareness and radiography the key to diagnosis. Masterly inactivity and vigilance during followup is suggested. PMID- 23436889 TI - Posterior reversible encephalopathy syndrome after bevacizumab therapy in a normotensive patient. AB - Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterised by distinct radiological features. Common precipitants of this disorder include acute medical illness, hypertensive crisis, eclampsia, immunosuppressive therapy and chemotherapy. We present the case of a patient with advanced ovarian carcinoma who developed PRES shortly after receiving bevacizumab (Avastin), an inhibitor of vascular endothelial growth factor. The patient's medical history and clinical presentation both suggest bevacizumab as the precipitator for PRES. This agent has been often overlooked as a possible cause of this rare neurological syndrome. PMID- 23436890 TI - Sleep-related eating disorder secondary to zolpidem. AB - Sleep-related eating disorder (SRED) is characterised by eating episodes during the first period of the night sleep with partial loss consciousness, and amnesia. It can rarely be induced by some drugs, including zolpidem. We present a video report of a patient with a 1-year history of SRED caused by zolpidem causing important repercussions in the sleep structure and life quality. The night eating episodes ceased promptly with discontinuation of zolpidem. Upon the follow-up, the sleep structure improved and the daily consequences disappeared. As in few reported cases of zolpidem-induced SRED, our patient was suffering from the parasomnia for a long time before the diagnosis. Active exclusion of symptoms suggestive of SRED in patients under zolpidem treatment can avoid the deleterious effect of the sleep disorder. PMID- 23436891 TI - Racing car brings tear drops in the moose. PMID- 23436892 TI - Delayed diagnosis and treatment for around 20 years of an eminently treatable cause. PMID- 23436893 TI - Recurrent primary paediatric herpetic whitlow of the big toe. AB - A 9-month-old baby girl presented multiple times with an erythematous, papular and pustular big toe in an otherwise healthy infant. A diagnosis of cellulitis was made and she was started on oral antibiotics, and bacterial swabs were taken. After 2 weeks of worsening appearance she was admitted for intravenous antibiotics. Inflammatory markers remained normal and viral swabs were taken. No improvement was seen after 2 days and she was referred for orthopaedic and dermatological opinions. The orthopaedic team recommended debridement whereas the dermatologist suspected a primary herpetic whitlow and recommended intravenous acyclovir in addition to intravenous antibiotics. A viral swab for Herpes simplex virus type 1 (HSV1) was positive by PCR on day 3. The toe continued to improve clinically and the patient received 21 days of acyclovir in total. 27 days after discharge the infection relapsed. She was treated with a further 14 days of oral acyclovir and recovered completely. PMID- 23436894 TI - The interplay of Graves' disease and twin molar pregnancy. AB - Twin molar pregnancy with coexistent viable fetus in a patient with Graves' disease is a rare entity. The patient is a 37-year-old woman who was hospitalised owing to persistent vomiting and vaginal bleeding. The pregnancy test was positive and the pelvic ultrasound disclosed twin gestation of complete mole and a coexistent viable 12-week fetus. beta-Human chorionic gonadotropin (beta-HCG) and free thyroid hormones were both elevated. The patient was also a diagnosed case of Graves' disease prior to this pregnancy. Given the risks for perinatal complications, the patient was offered early termination of pregnancy. She, however, decided to continue her pregnancy and control the hyperthyroidism with an antithyroid drug (ATD). A week after her discharge from the hospital, she had spontaneous abortion and the histopathology of the abortus revealed complete hydatidiform mole and a 13-week fetus. PMID- 23436895 TI - Urinary retention secondary to mephedrone. AB - We discuss a case of a 25-year-old man who presented to the acute medical take with a mixed overdose of mephedrone and paracetamol. Sixteen hours after ingestion, he reported that he was unable to micturate. A bladder scan confirmed that he was in urinary retention and he was catheterised. We discuss the increasingly popular recreational drug mephedrone including its more common side effects. PMID- 23436896 TI - Physical activity assessment: biomarkers and self-report of activity-related energy expenditure in the WHI. AB - We used a biomarker of activity-related energy expenditure (AREE) to assess measurement properties of self-reported physical activity and to determine the usefulness of AREE regression calibration equations in the Women's Health Initiative. Biomarker AREE, calculated as the total energy expenditure from doubly labeled water minus the resting energy expenditure from indirect calorimetry, was assessed in 450 Women's Health Initiative participants (2007 2009). Self-reported AREE was obtained from the Arizona Activity Frequency Questionnaire (AAFQ), the 7-Day Physical Activity Recall (PAR), and the Women's Health Initiative Personal Habits Questionnaire (PHQ). Eighty-eight participants repeated the protocol 6 months later. Reporting error, measured as log(self report AREE) minus log(biomarker AREE), was regressed on participant characteristics for each instrument. Body mass index was associated with underreporting on the AAFQ and PHQ but overreporting on PAR. Blacks and Hispanics underreported physical activity levels on the AAFQ and PAR, respectively. Underreporting decreased with age for the PAR and PHQ. Regressing logbiomarker AREE on logself-reported AREE revealed that self-report alone explained minimal biomarker variance (R(2) = 7.6, 4.8, and 3.4 for AAFQ, PAR, and PHQ, respectively). R(2) increased to 25.2, 21.5, and 21.8, respectively, when participant characteristics were included. Six-month repeatability data adjusted for temporal biomarker variation, improving R(2) to 79.4, 67.8, and 68.7 for AAFQ, PAR, and PHQ, respectively. Calibration equations "recover" substantial variation in average AREE and valuably enhance AREE self-assessment. PMID- 23436897 TI - Parental psychological distress during pregnancy and early growth in preschool children: the generation R study. AB - This study separately assessed the associations of maternal and paternal psychological distress during pregnancy with early growth in preschool children. The study was based on data from a population-based cohort study involving 5,283 children and their parents (with data collected beginning in early pregnancy) in Rotterdam, the Netherlands, from 2002 to 2006. Information on parental psychological distress (symptoms of depression, anxiety, hostility, and family stress) was obtained by questionnaire in the second trimester of gestation by using the Brief Symptom Inventory and the "general functioning" subscale of the McMaster Family Assessment Device. Child height, weight, and body mass index (weight (kg)/height (m)(2)) were measured repeatedly from age 3 months to age 4 years. We observed no consistent associations between overall maternal psychological symptoms, depression, anxiety, or hostility and child height, weight, or body mass index after adjustment for confounders. All maternal psychological distress scores were positively associated with the risk of overweight in childhood; however, these associations attenuated toward the null and became nonsignificant after adjusting for potential confounders. We did not observe consistent associations between paternal psychological distress and growth in childhood. These results indicate that social, behavioral, or environmental factors that cluster with parental psychological distress may explain the previously suggested associations between maternal psychological distress and early childhood growth and risk of overweight. PMID- 23436898 TI - Re: "effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy". PMID- 23436899 TI - Disparities between black and white children in hospitalizations associated with acute respiratory illness and laboratory-confirmed influenza and respiratory syncytial virus in 3 US counties--2002-2009. AB - Few US studies have assessed racial disparities in viral respiratory hospitalizations among children. This study enrolled black and white children under 5 years of age who were hospitalized for acute respiratory illness (ARI) in 3 US counties during October-May 2002-2009. Population-based rates of hospitalization were calculated by race for ARI and laboratory-confirmed influenza and respiratory syncytial virus (RSV), using US Census denominators. Relative rates of hospitalization between racial groups were estimated. Of 1,415 hospitalized black children and 1,824 hospitalized white children with ARI enrolled in the study, 108 (8%) black children and 111 (6%) white children had influenza and 230 (19%) black children and 441 (29%) white children had RSV. Hospitalization rates were higher among black children than among white children for ARI (relative rate (RR) = 1.7, 95% confidence interval (CI): 1.6, 1.8) and influenza (RR = 2.1, 95% CI: 1.6, 2.9). For RSV, rates were similar among black and white children under age 12 months but higher for black children aged 12 months or more (for ages 12-23 months, RR = 1.7, 95% CI: 1.1, 2.5; for ages 24-59 months, RR = 2.2, 95% CI: 1.3, 3.6). Black children versus white children were significantly more likely to have public insurance or no insurance (85% vs. 43%) and a history of asthma/wheezing (28% vs. 18%) but not more severe illness. The observed racial disparities require further study. PMID- 23436900 TI - A common case of gastroenteritis in a child followed by an axial torsion of Meckel diverticulum: a rare and unusual complication. AB - A 1-year-old boy presented at our hospital with common gastroenteritis symptoms such as fever, vomiting and diarrhoea. Clinical and laboratory findings were normal. An emergency ultrasound examination was performed and excluded abdominal complications. After 2 days of complete regression of symptoms, the patient began to vomit again, diarrhoea stopped with a sudden worsening of clinical conditions. Laboratory and radiological findings showed signs of an acute abdomen with differential diagnosis between an infectious and an obstructive cause. Owing to the rapid and progressive toxic condition, an emergency laparoscopy was performed. An axial torsion of a swollen and gangrenous Meckel's diverticulum was detected. PMID- 23436901 TI - Testing for herpesvirus infection is essential in children with chromosomal instability syndromes. PMID- 23436902 TI - Reply to "testing for herpesvirus infection is essential in children with chromosomal-instability syndromes". PMID- 23436904 TI - Initial quantitative proteomic map of 28 mouse tissues using the SILAC mouse. AB - Identifying the building blocks of mammalian tissues is a precondition for understanding their function. In particular, global and quantitative analysis of the proteome of mammalian tissues would point to tissue-specific mechanisms and place the function of each protein in a whole-organism perspective. We performed proteomic analyses of 28 mouse tissues using high-resolution mass spectrometry and used a mix of mouse tissues labeled via stable isotope labeling with amino acids in cell culture as a "spike-in" internal standard for accurate protein quantification across these tissues. We identified a total of 7,349 proteins and quantified 6,974 of them. Bioinformatic data analysis showed that physiologically related tissues clustered together and that highly expressed proteins represented the characteristic tissue functions. Tissue specialization was reflected prominently in the proteomic profiles and is apparent already in their hundred most abundant proteins. The proportion of strictly tissue-specific proteins appeared to be small. However, even proteins with household functions, such as those in ribosomes and spliceosomes, can have dramatic expression differences among tissues. We describe a computational framework with which to correlate proteome profiles with physiological functions of the tissue. Our data will be useful to the broad scientific community as an initial atlas of protein expression of a mammalian species. PMID- 23436905 TI - Chronic nicotine treatment impacts the regulation of opioid and non-opioid peptides in the rat dorsal striatum. AB - The chronic use of nicotine, the main psychoactive ingredient of tobacco smoking, alters diverse physiological processes and consequently generates physical dependence. To understand the impact of chronic nicotine on neuropeptides, which are potential molecules associated with dependence, we conducted qualitative and quantitative neuropeptidomics on the rat dorsal striatum, an important brain region implicated in the preoccupation/craving phase of drug dependence. We used extensive LC-FT-MS/MS analyses for neuropeptide identification and LC-FT-MS in conjunction with stable isotope addition for relative quantification. The treatment with chronic nicotine for 3 months led to moderate changes in the levels of endogenous dorsal striatum peptides. Five enkephalin opioid peptides were up-regulated, although no change was observed for dynorphin peptides. Specially, nicotine altered levels of nine non-opioid peptides derived from precursors, including somatostatin and cerebellin, which potentially modulate neurotransmitter release and energy metabolism. This broad but selective impact on the multiple peptidergic systems suggests that apart from the opioid peptides, several other peptidergic systems are involved in the preoccupation/craving phase of drug dependence. Our finding permits future evaluation of the neurochemical circuits modulated by chronic nicotine exposure and provides a number of novel molecules that could serve as potential therapeutic targets for treating drug dependence. PMID- 23436906 TI - Parallel visualization of multiple protein complexes in individual cells in tumor tissue. AB - Cellular functions are regulated and executed by complex protein interaction networks. Accordingly, it is essential to understand the interplay between proteins in determining the activity status of signaling cascades. New methods are therefore required to provide information on different protein interaction events at the single cell level in heterogeneous cell populations such as in tissue sections. Here, we describe a multiplex proximity ligation assay for simultaneous visualization of multiple protein complexes in situ. The assay is an enhancement of the original proximity ligation assay, and it is based on using proximity probes labeled with unique tag sequences that can be used to read out which probes, from a pool of probes, have bound a certain protein complex. Using this approach, it is possible to gain information on the constituents of different protein complexes, the subcellular location of the complexes, and how the balance between different complex constituents can change between normal and malignant cells, for example. As a proof of concept, we used the assay to simultaneously visualize multiple protein complexes involving EGFR, HER2, and HER3 homo- and heterodimers on a single-cell level in breast cancer tissue sections. The ability to study several protein complex formations concurrently at single cell resolution could be of great potential for a systems understanding, paving the way for improved disease diagnostics and possibilities for drug development. PMID- 23436908 TI - We must not create beings with moral standing superior to our own. PMID- 23436907 TI - An extended proteome map of the lysosomal membrane reveals novel potential transporters. AB - Lysosomes are membrane-bound endocytic organelles that play a major role in degrading cell macromolecules and recycling their building blocks. A comprehensive knowledge of the lysosome function requires an extensive description of its content, an issue partially addressed by previous proteomic analyses. However, the proteins underlying many lysosomal membrane functions, including numerous membrane transporters, remain unidentified. We performed a comparative, semi-quantitative proteomic analysis of rat liver lysosome-enriched and lysosome-nonenriched membranes and used spectral counts to evaluate the relative abundance of proteins. Among a total of 2,385 identified proteins, 734 proteins were significantly enriched in the lysosomal fraction, including 207 proteins already known or predicted as endo-lysosomal and 94 proteins without any known or predicted subcellular localization. The remaining 433 proteins had been previously assigned to other subcellular compartments but may in fact reside on lysosomes either predominantly or as a secondary location. Many membrane associated complexes implicated in diverse processes such as degradation, membrane trafficking, lysosome biogenesis, lysosome acidification, signaling, and nutrient sensing were enriched in the lysosomal fraction. They were identified to an unprecedented extent as most, if not all, of their subunits were found and retained by our screen. Numerous transporters were also identified, including 46 novel potentially lysosomal proteins. We expressed 12 candidates in HeLa cells and observed that most of them colocalized with the lysosomal marker LAMP1, thus confirming their lysosomal residency. This list of candidate lysosomal proteins substantially increases our knowledge of the lysosomal membrane and provides a basis for further characterization of lysosomal functions. PMID- 23436909 TI - Human enhancement and perfection. AB - Both, bioconservatives and bioliberals, should seek a discussion about ideas of human perfection, making explicit their underlying assumptions about what makes for a good human life. This is relevant, because these basic, and often implicit ideas, inform and influence judgements and choices about human enhancement interventions. Both neglect, and polemical but inconsistent use of the complex ideas of perfection are leading to confusion within the ethical debate about human enhancement interventions, that can be avoided by tackling the notion of perfection directly. In the recent debates, bioconservatives have prominently argued against the 'pursuit of perfection' by biotechnological means. In the first part of this paper, we show that--paradoxically--bioconservatives themselves explicitly embrace specific conceptions of human perfection and perfectionist assumptions about the good human life in order to argue against the use of enhancement technologies. Yet, we argue that the bioconservative position contains an untenable ambiguity between criticising and endorsing ideas of human perfection. Hence, they stand in need of clarifying their stance on human perfection. In the second part of the paper, we ask whether bioliberals in fact (implicitly) advocate a particular conception of perfection, or whether they are right in holding that they do not, and that discussing perfection is obsolete anyway. We show that bioliberals also rely on a specific idea of human perfection, based on the idea of autonomy. Hence, their denial of the relevance of perfection in the debate is unconvincing and has to be revised. PMID- 23436910 TI - A randomized, controlled trial of acupuncture self-needling as maintenance therapy for cancer-related fatigue after therapist-delivered acupuncture. AB - BACKGROUND: Maintenance acupuncture is advocated by clinicians after successful clinic-based acupuncture. We aimed to assess the effectiveness of maintenance acupuncture in the management of cancer-related fatigue (CRF); treatment delivered by therapists or self-acupuncture/self-needling was compared with no maintenance treatment. METHODS: Breast cancer patients who participated in a randomized trial of acupuncture for CRF management (reported elsewhere) were re randomized to receive an additional four acupuncturist-delivered weekly sessions; four self-administered weekly acupuncture sessions (self-needling); or no acupuncture. Primary outcome was general fatigue (Multidimensional Fatigue Inventory). Mood, quality of life and safety were also assessed. RESULTS: In total, 197 patients were re-randomized, with 65 to therapist-delivered sessions, 67 to self-acupuncture/self-needling and 65 to no further acupuncture. Primary outcome scores were equivalent between the therapist-delivered acupuncture and self-acupuncture (P > 0.05). A non-significant trend in improving fatigue was observed at the end of 4 weeks in the combined acupuncture arms (P = 0.07). There was no impact on mood or quality of life of the further acupuncture sessions at 18 weeks beyond the improvement observed in initial trial. CONCLUSION: Self acupuncture is an acceptable, feasible and safe maintenance treatment for patients with CRF. However, overall, maintenance acupuncture did not yield important improvements beyond those observed after an initial clinic-based course of acupuncture. TRIAL REGISTRATION NUMBER: NCT00957112. PMID- 23436911 TI - Regarding the letter to the editor 'AIB1 and its significant role in tumor pathogenesis in systemic malignancies: beyond breast carcinomas' by Kapoor and Shailendra in Annals of Oncology. PMID- 23436912 TI - CodonPhyML: fast maximum likelihood phylogeny estimation under codon substitution models. AB - Markov models of codon substitution naturally incorporate the structure of the genetic code and the selection intensity at the protein level, providing a more realistic representation of protein-coding sequences compared with nucleotide or amino acid models. Thus, for protein-coding genes, phylogenetic inference is expected to be more accurate under codon models. So far, phylogeny reconstruction under codon models has been elusive due to computational difficulties of dealing with high dimension matrices. Here, we present a fast maximum likelihood (ML) package for phylogenetic inference, CodonPhyML offering hundreds of different codon models, the largest variety to date, for phylogeny inference by ML. CodonPhyML is tested on simulated and real data and is shown to offer excellent speed and convergence properties. In addition, CodonPhyML includes most recent fast methods for estimating phylogenetic branch supports and provides an integral framework for models selection, including amino acid and DNA models. PMID- 23436913 TI - Progressive recombination suppression and differentiation in recently evolved neo sex chromosomes. AB - Recombination suppression leads to the structural and functional differentiation of sex chromosomes and is thus a crucial step in the process of sex chromosome evolution. Despite extensive theoretical work, the exact processes and mechanisms of recombination suppression and differentiation are not well understood. In threespine sticklebacks (Gasterosteus aculeatus), a different sex chromosome system has recently evolved by a fusion between the Y chromosome and an autosome in the Japan Sea lineage, which diverged from the ancestor of other lineages approximately 2 Ma. We investigated the evolutionary dynamics and differentiation processes of sex chromosomes based on comparative analyses of these divergent lineages using 63 microsatellite loci. Both chromosome-wide differentiation patterns and phylogenetic inferences with X and Y alleles indicated that the ancestral sex chromosomes were extensively differentiated before the divergence of these lineages. In contrast, genetic differentiation appeared to have proceeded only in a small region of the neo-sex chromosomes. The recombination maps constructed for the Japan Sea lineage indicated that recombination has been suppressed or reduced over a large region spanning the ancestral and neo-sex chromosomes. Chromosomal regions exhibiting genetic differentiation and suppressed or reduced recombination were detected continuously and sequentially in the neo-sex chromosomes, suggesting that differentiation has gradually spread from the fusion point following the extension of recombination suppression. Our study illustrates an ongoing process of sex chromosome differentiation, providing empirical support for the theoretical model postulating that recombination suppression and differentiation proceed in a gradual manner in the very early stage of sex chromosome evolution. PMID- 23436915 TI - Two years of growth hormone treatment in adults with Prader-Willi syndrome do not improve the low BMD. AB - BACKGROUND: Bone mineral density (BMD) in adult patients with Prader-Willi syndrome (PWS) might be low due to high bone turnover. OBJECTIVES: The objective of the study was to investigate bone mass in a group of adult PWS subjects and study the effects of GH treatment on BMD and markers of bone turnover. DESIGN: Forty-six adults with genetically verified PWS were randomized to GH or placebo for 12 months, followed by open prospective GH for 24 additional months. BMD at the lumbar spine (LS) L1-4, the total hip, and the total body was assessed by dual-energy x-ray absorptiometry at baseline and every 12th month thereafter. Markers of bone turnover were measured at baseline and at the end of the controlled study. RESULTS: In this cohort of adult subjects with PWS, baseline BMD was reduced in all compartments compared with the reference (Z-scores). Men had lower Z-scores BMD than women in LS and total body (P < .05). With 12 months of GH, LS-BMD was significantly reduced compared with placebo. No changes in BMD were observed with continuous GH treatment for 24 months. The bone formation markers increased with GH therapy compared with placebo, whereas the resorption marker did not change. CONCLUSIONS: Adult PWS subjects, especially the men, have low bone mass that was not improved with GH treatment for 2 years. Because PWS subjects are short, BMD might be underestimated and should be adjusted for. Further studies, with adequate GH and sex hormone replacement throughout puberty and early adult life, are needed to better characterize PWS. PMID- 23436914 TI - Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein. AB - OBJECTIVE: Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy. METHODS: Subgroups were prespecified and defined by age (> or <=15.5 years), systemic lupus erythematosus (SLE) duration (> or <=24 months), pubertal status (Tanner score>=4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (>= or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (>= or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP>=1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. RESULTS: Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures. CONCLUSIONS: Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00065806. PMID- 23436916 TI - A tertiary center's experience with second review of 3885 thyroid cytopathology specimens. AB - BACKGROUND: Although the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) has standardized the diagnostic terminology for thyroid fine-needle aspiration (FNA), morphological interpretation remains subjective, and interobserver discrepancies are expected. This study quantifies the frequency and magnitude of these discrepancies in a single tertiary center's experience and elucidates key factors that are associated with changes in diagnosis. METHODS: Institutional consultation for 3885 thyroid cytological samples over 45 months were reviewed. BSRTC classification made by the sending institution was compared with that of our institution. An ANOVA was performed to determine factors that may be associated with interinstitutional diagnostic differences. Histopathology diagnoses were available for 1049 (27%) nodules; the malignancy rates for inside and outside BSRTC classifications were calculated. RESULTS: There were 937 1-step changes and 301 >=2-step diagnostic discrepancies comprising 24% and 8% of all cases, respectively. Second review decreased the indeterminate rate 38% to 28% (P < .000001). Indeterminate diagnostic category before second review, low specimen cellularity, Hashimoto's thyroiditis, and low volume of consults from the sending institution were associated with discordance. Of the 1049 thyroid nodules operated for which unequivocal histopathology was available, the malignancy rates for the BSRTC categories before and after second review were compared. Categorical upgrades were associated with a malignancy rate of 84%, whereas downgrades were associated with a malignancy rate of 38% (P < .000001). CONCLUSION: This is the largest series to date of thyroid cytology second review. The BSRTC classification changed 32% of the time, potentially resulting in significant changes in clinical and surgical management. Because certain specimen characteristics (indeterminate diagnostic category before second review, low specimen cellularity, Hashimoto's thyroiditis, and low volume of consults from the sending institution) were particularly associated with a diagnosis change, morphological second review may be of potential benefit in these settings. PMID- 23436917 TI - Childhood weight gain and thyroid autoimmunity at age 60-64 years: the 1946 British birth cohort study. AB - BACKGROUND: Complex bidirectional relationships have been described between body weight, thyroid function, and risk of thyroid disorders, including thyroid autoimmunity. We used a life-course approach to examine the potential association of childhood or adult body weight with the risk of thyroid autoimmunity and other thyroid disorders at age 60-64 years in a large population-based birth cohort study. METHODS: In the UK Medical Research Council 1946 British Birth Cohort study, at age 60-64 years, 1277 women and 1185 men (78% of the target sample) responded to a postal questionnaire, which included questions on thyroid disease and thyroid medication. Circulating antithyroid peroxidase antibodies, free T4, and TSH concentrations were measured in 1057 women and 997 men at a subsequent clinic visit. Birth weight was recorded, and height and weight were measured at ages 2, 4, 6, 7, 11, 15 years and also repeatedly in adulthood. RESULTS: At age 60-64 years, 10.9% of women (139 of 1277) and 2.3% of men (27 of 1185) reported they were taking T4, and 11.5% of women (122 of 1057) and 3.3% of men (33 of 997) had positive anti-TPO antibodies (>100 IU/mL), consistent with thyroid autoimmunity. Among women, both T4 use and positive anti-TPO antibodies at age 60 64 years were positively associated with childhood body weight, childhood overweight, and adult body mass index. Childhood weight gain between 0 and 14 years of age was positively associated with later T4 use (odds ratio 1.21, 95% confidence interval 1.03-1.42) and positive anti-TPO antibodies (1.21, 1.00 1.47). Women who were overweight or obese at age 14 years (127 of 972) had a higher risk of later positive anti-TPO antibodies (2.05, 1.12-3.76). In men and women without any thyroid disorders, serum free T4 concentrations were inversely associated with concurrent body mass index (P = .002). CONCLUSIONS: Childhood weight gain and childhood overweight conferred an increased susceptibility to later hypothyroidism and thyroid autoimmunity, particularly in women. PMID- 23436918 TI - Bone metastases and skeletal-related events in patients with malignant pheochromocytoma and sympathetic paraganglioma. AB - CONTEXT: Bone metastases (BM) can cause severe pain, spinal cord compression, pathological fractures, and/or hypercalcemia. These skeletal-related events (SREs) may cause immobilization, loss of independence, poor quality of life, and reduced survival. There is limited information on the clinical effects of BM and SREs in patients with malignant pheochromocytoma or sympathetic paraganglioma (PHEO/sPGL). OBJECTIVES: We studied the prevalence and clinical characteristics of BM and SREs in patients with PHEO/sPGL and investigated the risk factors for SRE development. DESIGN: Using a large institutional database, we conducted a retrospective study of 128 patients with malignant PHEO/sPGL at The University of Texas MD Anderson Cancer Center from 1967 through 2011. RESULTS: Of the patients, 91 (71%) had BM, and 57 of these (63%) developed metachronous BM at a median time of 3.4 years (range, 5 months to 23 years) after the primary tumor diagnosis. Metastatic disease was confined exclusively to the skeleton in 26 of 128 (20%) patients. Sufficient information to assess SRE occurrence was available for 67 patients, and 48 of 67 (72%) patients had at least 1 SRE. The median overall survival for the 128 patients was 12 years for patients with only BM, 7.5 years for patients with nonosseous metastases, and 5 years for patients with both BM and nonosseous metastases (log rank test P value = .005). We were unable to identify factors predictive of SRE development, but the occurrence of a first SRE was associated with the development of subsequent SREs in 48% of subjects. In responsive patients, the use of systemic therapy was associated with fewer SREs (P < .0001). CONCLUSIONS: BM and SREs are frequent in patients with malignant PHEO/sPGL. SREs often develop shortly after the diagnosis of BM; severe pain is the most frequent SRE. These patients should be followed long-term by a multidisciplinary team to promptly identify the need for medical or surgical intervention. PMID- 23436919 TI - Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. AB - CONTEXT: Recently irisin (encoded by Fndc5 gene) has been reported to stimulate browning and uncoupling protein 1 expression in sc adipose tissue of mice. OBJECTIVE: The objective of the study was to investigate FNDC5 gene expression in human muscle and adipose tissue and circulating irisin according to obesity, insulin sensitivity, and type 2 diabetes. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURE: Adipose tissue FNDC5 gene expression and circulating irisin (ELISA) were analyzed in 2 different cohorts (n = 125 and n = 76); muscle FNDC5 expression was also evaluated in a subcohort of 34 subjects. In vitro studies in human preadipocytes and adipocytes and in induced browning of 3T3-L1 cells (by means of retinoblastoma 1 silencing) were also performed. RESULTS: In both sc and visceral adipose tissue, FNDC5 gene expression decreased significantly in association with obesity and was positively associated with brown adipose tissue markers, lipogenic, insulin pathway-related, mitochondrial, and alternative macrophage gene markers and negatively associated with LEP, TNFalpha, and FSP27 (a known repressor of brown genes). Circulating irisin and irisin levels in adipose tissue were significantly associated with FNDC5 gene expression in adipose tissue. In muscle, the FNDC5 gene was 200-fold more expressed than in adipose tissue, and its expression was associated with body mass index, PGC1alpha, and other mitochondrial genes. In obese participants, FNDC5 gene expression in muscle was significantly decreased in association with type 2 diabetes. Interestingly, muscle FNDC5 gene expression was significantly associated with FNDC5 and UCP1 gene expression in visceral adipose tissue. In men, circulating irisin levels were negatively associated with obesity and insulin resistance. Irisin was secreted from human adipocytes into the media, and the induction of browning in 3T3-L1 cells led to increased secreted irisin levels. CONCLUSIONS: Decreased circulating irisin concentration and FNDC5 gene expression in adipose tissue and muscle from obese and type 2 diabetic subjects suggests a loss of brown-like characteristics and a potential target for therapy. PMID- 23436920 TI - Low- or high-dose radioiodine remnant ablation for differentiated thyroid carcinoma: a meta-analysis. AB - CONTEXT: There is uncertainty over the dose of (131)I required for thyroid remnant ablation. Most previous studies have been inadequately powered to establish the best fixed dose of (131)I for effective ablation. OBJECTIVE: The aim of the study was to assess the effects of low- vs high-dose regimens of radioiodine in thyroid remnant ablation for patients with differentiated thyroid carcinoma. DATA SOURCES: Sources included the Cochrane Library, MEDLINE, EMBASE, and SCOPUS (all until September 2012). STUDY SELECTION: Randomized controlled trials that assess the efficacy of low- or high-dose of radioiodine ablation of thyroid remnants were collected. DATA EXTRACTION: Two authors performed the data extraction independently. DATA SYNTHESIS: Nine randomized controlled trials involving 2569 patients were included. The 1100-MBq vs the 3700-MBq radioiodine showed no statistically significant difference in successful thyroid remnant ablation (risk ratio [RR], 0.91 [0.79 to 1.04]; P = .15), both the 1100 vs the 1850 MBq (RR, 0.95 [0.83 to 1.10]; P = .52) and the 1850 vs the 3700 MBq (RR, 1.00 [0.85 to 1.17]; P = .98) also showed no significant differences (95% confidence intervals were calculated for each estimate). Also, no significant differences existed in quality-of-life scores on the SF-36 between different (131)I-dose groups both on the day of ablation (RR, 0.15 [-0.65 to 0.96], P = .71; I(2) = 29%, P = .24) and 3 months after ablation (RR, -1.1 [-2.37 to 0.17], P = .09; I(2) = 22%, P = .26). A low dose of 1100 MBq radioiodine showed significant benefits in reducing adverse effects (total RR, 0.65 [0.55 to 0.77], P < .1; I(2) = 31%, P =.14) and shorter hospital isolation (RR, 0.4 [0.32 to 0.50]; P < .05). CONCLUSIONS: The low dose of 1100 MBq radioiodine activity is sufficient for thyroid remnant ablation as compared to 3700 MBq radioiodine activity with similar quality of life, less common adverse effects, and a shorter hospital stay. PMID- 23436921 TI - The effect of voluntary iodine prophylaxis in a small rural community: the Pescopagano survey 15 years later. AB - CONTEXT: Iodine deficiency disorders are a major public health problem, and programs have been implemented to improve iodine nutrition. OBJECTIVE: The objective of the study was to verify the effects of voluntary iodine prophylaxis in a small rural community (Pescopagano, Italy). DESIGN: The design of the study was the evaluation of the prevalence of thyroid disorders 15 years after a previous survey conducted before iodine prophylaxis. SETTING: The setting for this study was a general community survey. PARTICIPANTS: One thousand one hundred forty-eight residents were examined in 2010 and 1411 in 1995. RESULTS: In 2010, 757 of 1148 subjects (65.9%) routinely used iodized salt, urinary iodine excretion being significantly higher than in 1955 (median 98.0 MUg/L, vs 55.0 MUg/L, P < .0001). The prevalence of goiter was lower in 2010 than in 1995 (25.8% vs 46.1%, P < .0001), mainly due to the reduction of diffuse goiter (10.3% vs 34.0%, P < .0001). In 2010 vs 1995, thyroid autonomy in subjects younger than 45 years old (3 of 579, 0.5% vs 25 of 1010, 2.5% P = .004) and nonautoimmune hyperthyroidism in subjects older than 45 years old (8 of 569, 1.4% vs 18 of 401, 4.5%, P = .03) were less frequent. The prevalence of hypothyroidism was higher in 2010 vs 1995 (5.0% vs 2.8%, P = .005), mainly because of an increased frequency of subclinical hypothyroidism in subjects younger than 15 years old (7 of 83, 8.4% vs 0 of 419, 0.0%, P < .0001). Accordingly, serum thyroid autoantibodies (19.5% vs 12.6%; P < .0001) and Hashimoto's thyroiditis (14.5% vs 3.5%; P < .0001) were more frequent in 2010 than in 1995. CONCLUSIONS: In the present work, the role of voluntary iodine prophylaxis was assessed in a small rural community relatively segregated, in which genetic and other environmental factors have not substantially changed between the 2 surveys. Iodine intake strongly affected the pattern of thyroid diseases, but the benefits of correcting iodine deficiency (decreased prevalence of goiter and thyroid autonomy in younger subjects and reduced frequency of nonautoimmune hyperthyroidism in older subjects) far outweighs the risk of development of thyroid autoimmunity and mild hypothyroidism in youngsters. PMID- 23436922 TI - Impact of switching from zidovudine to tenofovir disoproxil fumarate on bone mineral density and markers of bone metabolism in virologically suppressed HIV-1 infected patients; a substudy of the PREPARE study. AB - CONTEXT: In virologically suppressed, antiretroviral-treated patients, the effect of switching to tenofovir (TDF) on bone biomarkers compared to patients remaining on stable antiretroviral therapy is unknown. METHODS: We examined bone biomarkers (osteocalcin [OC], procollagen type 1 amino-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen) and bone mineral density (BMD) over 48 weeks in virologically suppressed patients (HIV RNA < 50 copies/ml) randomized to switch to TDF/emtricitabine (FTC) or remain on first-line zidovudine (AZT)/lamivudine (3TC). PTH was also measured. Between-group differences in bone biomarkers and associations between change in bone biomarkers and BMD measures were assessed by Student's t tests, Pearson correlation, and multivariable linear regression, respectively. All data are expressed as mean (SD), unless otherwise specified. RESULTS: Of 53 subjects (aged 46.0 y; 84.9% male; 75.5% Caucasian), 29 switched to TDF/FTC. There were reductions in total hip and lumbar spine BMD in those switching to TDF/FTC (total hip, TDF/FTC, -1.73 (2.76)% vs AZT/3TC, -0.39 (2.41)%; between-group P = .07; lumbar spine, TDF/FTC, -1.50 (3.49)% vs AZT/3TC, +0.25 (2.82)%; between-group P = .06), but they did not reach statistical significance. Greater declines in lumbar spine BMD correlated with greater increases in OC (r = -0.28; P = .05). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender, and ethnicity. There was no difference in change in PTH levels over 48 weeks between treatment groups (between-group P = .23). All biomarkers increased significantly from weeks 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (between-group, all biomarkers, P < .0001). CONCLUSION: A switch to TDF/FTC compared to remaining on a stable regimen is associated with increases in bone turnover that correlate with reductions in BMD, suggesting that TDF exposure directly affects bone metabolism in vivo. PMID- 23436923 TI - Changes in energy metabolism in pheochromocytoma. AB - CONTEXT: Catecholamine overproduction in pheochromocytoma affects basal metabolism, resulting in weight loss despite normal food intake. OBJECTIVE: The objective of the study was to evaluate changes in energy metabolism expressed as resting energy expenditure (REE) in patients with pheochromocytoma before and after adrenalectomy and the possible relationship with circulating inflammatory markers. DESIGN: We measured REE in 17 patients (8 women) with pheochromocytoma by indirect calorimetry (Vmax-Encore 29N system) before and 1 year after adrenalectomy. Body fat percentage was measured with a Bodystat device. Inflammatory markers (leukocytes count and C-reactive protein) and cytokines (TNF alpha, IL-6, and IL-8) were analyzed with a Luminex 200. RESULTS: REE measured in the pheochromocytoma group was 10.4% higher than the predicted value (1731 +/- 314 vs 1581 +/- 271 kcal/d; P = .004). Adrenalectomy significantly increased body mass index (P =0.004) and the percentage of body fat (P = .01), with a proportional increase in fat distribution (waist circumference, P = .045; hip circumference, P = .001). REE significantly decreased after adrenalectomy (1731 +/- 314 vs 1539 +/- 215 kcal/d; P = .002), even after adjustments in body surface and body weight (P < .001). After adrenalectomy, we found a significant decrease in leukocyte counts (P = .014) and in the levels of TNF-alpha (P < .001), IL-6 (P = .048), and IL-8 (P = .007) but not C-reactive protein (P = .09). No significant correlations among calorimetry parameters, hormones, and proinflammatory markers were detected. CONCLUSIONS: Chronic catecholamine overproduction in pheochromocytoma may lead to a proinflammatory and hypermetabolic state characterized by increased REE. Adrenalectomy leads to the normalization of energy metabolism followed by an increase in body mass index and body fat content and decreases in inflammatory markers and cytokines. PMID- 23436925 TI - Prevalence of hyperandrogenic states in late adolescent and young women: epidemiological survey on italian high-school students. AB - CONTEXT: Most of the estimates of the prevalence of hyperandrogenic states refer to the general adult population. OBJECTIVE: The objective of the study was to estimate the prevalence of hyperandrogenic states in late adolescence and youth and to evaluate potential independent predictors. DESIGN: This was a cross sectional study. SETTING: The study was conducted in high schools. PATIENTS: Patients included female students, aged 16-19 years. MAIN OUTCOME MEASURES: The study protocol was designed with 3 possible levels of participation: the first level consisted of a self-compiled questionnaire; the second level added a medical examination; and the third level added a blood sample for laboratory testing. Liquid chromatography-tandem mass spectrometry was used to measure total testosterone, and a reference interval was established in-house. RESULTS: We offered participation to 2052 students, and 1469 of those compiled the questionnaire. Of these, 1038 were examined, and 519 also provided blood samples. Two hundred three of the 1038 examined students and 125 of the 519 students who provided blood samples were subsequently excluded because of treatment with oral contraceptives or because of endocrine disorders. In the sample of women with a questionnaire + a medical examination, 13% were affected by isolated menstrual irregularity, 16.1% by isolated clinical hyperandrogenism, and 3.8% by both states. A similar prevalence of isolated menstrual irregularity (10.2%) and isolated clinical hyperandrogenism (16.7%) was found in the subsample of women with laboratory tests; in addition, 6.6% showed isolated hyperandrogenemia, and 4.3% proved to be affected by polycystic ovary syndrome. CONCLUSIONS: This study provides for the first time a reliable assessment of the prevalence of hyperandrogenic states in late adolescent and young females and confirms that hyperandrogenic disorders originate at a young age. PMID- 23436924 TI - Association of DXA-derived bone mineral density and fat mass with African ancestry. AB - CONTEXT: Both genes and environment have been implicated in determining the complex body composition phenotypes in individuals of European ancestry; however, few studies have been conducted in other race/ethnic groups. OBJECTIVE: We conducted a genome-wide admixture mapping study in an attempt to localize novel genomic regions associated with genetic ancestry. SETTING/PARTICIPANTS: We selected a sample of 842 African-American women from the Women's Health Initiative single nucleotide polymorphism (SNP) Health Association Resource for whom several dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) and fat mass phenotypes were available. METHODS: We derived both global and local ancestry estimates for each individual from Affymetrix 6.0 data and analyzed the correlation of DXA phenotypes with global African ancestry. For each phenotype, we examined the association of local genetic ancestry (number of African ancestral alleles at each marker) and each DXA phenotype at 570 282 markers across the genome in additive models with adjustment for important covariates. RESULTS: We identified statistically significant correlations of whole-body fat mass, trunk fat mass, and all 6 measures of BMD with a proportion of African ancestry. Genome-wide (admixture) significance for femoral neck BMD was achieved across 2 regions ~3.7 MB and 0.3 MB on chromosome 19q13; similarly, total hip and intertrochanter BMD were associated with local ancestry in these regions. Trunk fat was the most significant fat mass phenotype showing strong, but not genomewide significant associations on chromosome Xp22. CONCLUSIONS: Our results suggest that genomic regions in postmenopausal African-American women contribute to variance in BMD and fat mass existence and warrant further study. PMID- 23436926 TI - HER2-positive breast cancer metastatic to intracranial meningioma: a case report. PMID- 23436927 TI - Ki67 and proliferation in breast cancer. AB - New approaches to the prognostic assessment of breast cancer have come from molecular profiling studies. A major feature of this work has been to emphasise the importance of cancer cell proliferation as a key discriminative indicator of recurrence risk for oestrogen receptor positive breast cancer in particular. Mitotic count scoring, as a component of histopathological grade, has long formed part of a routine evaluation of breast cancer biology. However, there is an increasingly compelling case to include a specific proliferation score in breast cancer pathology reports based on expression of the cell cycle regulated protein Ki67. Immunohistochemical staining for Ki67 is a widely available and economical test with good tolerance of pre-analytical variations and staining conditions. However, there is currently no evidence based protocol established to derive a reliable and informative Ki67 score for routine clinical use. In this circumstance, pathologists must establish a standardised framework for scoring Ki67 and communicating results to a multidisciplinary team. PMID- 23436928 TI - A low-grade follicular lymphoma with strong expression of cyclin D1, but without evidence of CCND1 translocation or amplification. PMID- 23436929 TI - Therapeutic targets in triple negative breast cancer. AB - Outcomes have improved significantly for many women diagnosed with breast cancer. For the heterogeneous group of tumours lacking expression of the oestrogen, progesterone and HER2 receptors, 'triple negative' breast cancers (TNBC), the prognosis overall has remained quite poor. When TNBC recurs, there is often little response to chemotherapy, and there are a few treatment options in this setting. Thus, there is an urgent clinical need to identify new therapeutic targets in order to improve the outlook for these patients. This review highlights the most promising therapeutic targets identified through new sequencing technologies, as well as through studies of apoptosis. We also present mounting evidence that the developmental signalling pathways Wnt/beta-catenin, NOTCH and Hedgehog play an important role in the pathogenesis and progression of TNBC with new therapeutic approaches inhibiting these pathways in advanced preclinical studies or early clinical trials. PMID- 23436930 TI - Immunohistochemistry improves histopathologic diagnosis in primary aldosteronism. AB - BACKGROUND: In primary aldosteronism (PA) the main source of aldosterone hypersecretion is an aldosterone-producing adenoma (APA) or a bilateral hyperplasia. Histopathology of the adrenal gland from patients with PA has been difficult, as there are no morphological criteria to ascertain which are the cells that produce aldosterone. We therefore applied new specific antibodies to explore which cells in the adrenal contain the enzymes for aldosterone and cortisol production, respectively. METHODS: Adrenals from 24 patients with PA were studied. After routine preparation, consecutive sections were stained with antibodies for CYP11B1 (cortisol) and CYP11B2 (aldosterone) enzymes. RESULTS: APA had a strong immunoreactivity for CYB11B2. In adrenals from seven patients, we found no APA, but several nodules with strong CYB11B2 immunoreactivity, indicating aldosterone-producing nodular hyperplasia. CONCLUSIONS: Immunohistochemistry of adrenal steroidogenic enzymes provides novel diagnostic information. This may become an important part of routine histopathology, and contribute to improved clinical management in PA. PMID- 23436931 TI - The stem cell marker CD133 is highly expressed in sessile serrated adenoma and its borderline variant compared with hyperplastic polyp. AB - Non-dysplastic serrated polyps (ND-SP) represent a heterogeneous group of colorectal lesions that comprise hyperplastic polyp (HP) and the non-dysplastic subset of sessile serrated adenoma/polyp/lesion (SSA/P/L) and its borderline variant (BSSA/P/L). Given the observer variation in their histological typing, the identification of reliable markers that assist in the characterisation is warranted. Most important is the identification of polyp qualities that may reflect the patients' risk of developing colorectal cancer. To address these issues, CD133 may represent a potential adjunct. Here we studied the discriminatory value of CD133 expression in the classification of ND-SPs and its distribution pattern in relation to synchronous colorectal carcinoma (SCRC). 39 SSA/P/Ls, 27 BSSA/P/Ls and 21 matched HPs were immunostained for CD133. The data were further correlated to the presence of SCRC and to polyp site and size. Ignoring SCRC status, CD133 was expressed more prominently in SSA/P/Ls than in HPs. The values for BSSA/P/Ls fell in between, yet closer to the SSA/P/L scorings. This observation was retained in the context of SCRC and for SSA/P/Ls not associated with SCRC. Right-sidedness and large size of the polyps more commonly associated with increased CD133 expression. CD133 expression was not a significant discriminator as to the SCRC status. BSSA/P/Ls are more closely aligned to SSA/P/L and further that SSA/P/L and BSSA/P/Ls fundamentally differ from HP by their CD133 immunoprofile, a notion that can be exploited in the diagnostic routine practice. Recorded data further indirectly support the idea that SSA/P/Ls are more prone to neoplastic progression than are HPs. PMID- 23436932 TI - Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3. AB - Sphingosine-1-phosphate (S1P) receptors are critical for lymphocyte egress from secondary lymphoid organs, and S1P receptor modulators suppress lymphocyte circulation. However, the role of S1P receptors on monocytes is less clear. To elucidate this, we systematically evaluated monocytes in rats and mice, both in naive and inflammatory conditions, with S1P receptor modulators FTY720 and BAF312. We demonstrate that S1P receptor modulators reduce circulating monocytes in a similar time course as lymphocytes. Furthermore, total monocyte numbers were increased in the spleen and bone marrow, suggesting that S1P receptor modulation restricts egress from hematopoietic organs. Monocytes treated ex vivo with FTY720 had reduced CD40 expression and TNF-alpha production, suggesting a direct effect on monocyte activation. Similar reductions in protein expression and cytokine production were also found in vivo. Suppression of experimental autoimmune encephalomyelitis in mice and rats by FTY720 correlated with reduced numbers of lymphocytes and monocytes. These effects on monocytes were independent of S1P3, as treatment with BAF312, a S1P1,4,5 modulator, led to similar results. These data reveal a novel role for S1P receptors on monocytes and offer additional insights on the mechanism of action of S1P receptor modulators in disease. PMID- 23436933 TI - Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury. AB - Mechanical ventilation of lungs is capable of activating the innate immune system and inducing sterile inflammatory response. The proinflammatory cytokine IL-1beta is among the definitive markers for accurately identifying ventilator-induced lung inflammation. However, mechanisms of IL-1beta release during mechanical ventilation are unknown. In this study, we show that cyclic stretch activates the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasomes and induces the release of IL-1beta in mouse alveolar macrophages via caspase-1- and TLR4-dependent mechanisms. We also observed that NADPH oxidase subunit gp91(phox) was dispensable for stretch-induced cytokine production, whereas mitochondrial generation of reactive oxygen species was required for stretch-induced NLRP3 inflammasome activation and IL-1beta release. Further, mechanical ventilation activated the NLRP3 inflammasomes in mouse alveolar macrophages and increased the production of IL-1beta in vivo. IL-1beta neutralization significantly reduced mechanical ventilation-induced inflammatory lung injury. These findings suggest that the alveolar macrophage NLRP3 inflammasome may sense lung alveolar stretch to induce the release of IL-1beta and hence may contribute to the mechanism of lung inflammatory injury during mechanical ventilation. PMID- 23436935 TI - Regulation of cystic fibrosis transmembrane conductance regulator by microRNA 145, -223, and -494 is altered in DeltaF508 cystic fibrosis airway epithelium. AB - Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is altered in individuals with the DeltaF508 CFTR mutation. We previously reported differential expression of microRNA (miRNA) in CF airway epithelium; however, the role of miRNA in regulation of CFTR expression here remains unexplored. In this study, we investigated the role of upregulated miRNAs in CFTR regulation in vivo in bronchial brushings from individuals homozygous or heterozygous for DeltaF508 CFTR, validated our observations in vitro, and assessed the impact of defective chloride ion conductance, genotype, and colonization status on miRNA expression. miRNA target prediction was performed in silico, and expression of miRNA and target genes were measured by quantitative real-time PCR and/or Western blotting. Overexpression and inhibition studies were performed with pre-miRs or antimiRs, respectively, and a luciferase reporter gene was used to elucidate direct miRNA target interactions. miR-145, miR-223, and miR-494 were upregulated in CF versus non-CF bronchial brushings and cell lines; in DeltaF508 CFTR homozygotes versus heterozygotes; in subjects positive for P. aeruginosa; and in cells treated with a CFTR inhibitor or IL-1beta. Reciprocal downregulation or upregulation of CFTR gene and/or protein expression was observed after miRNA manipulation and direct miRNA-target relationships demonstrated via a reporter system containing a wild type or mutated full-length CFTR 3' untranslated region. Increased expression of miR-145, miR-223, and miR-494 in vivo in bronchial epithelium of individuals carrying the DeltaF508 CFTR mutation correlates with decreased CFTR expression. Defective CFTR function, Pseudomonas colonization, and inflammation may affect miRNA expression and contribute to the regulation of DeltaF508 CFTR. PMID- 23436934 TI - Essential role of surface-bound complement factor H in controlling immune complex induced arthritis. AB - Factor H (fH) is an endogenous negative regulator of the alternative pathway (AP) that binds polyanions as well as complement activation fragments C3b and C3d. The AP is both necessary and sufficient to develop collagen Ab-induced arthritis (CAIA) in mice; the mechanisms whereby normal control of the AP is overcome and injury develops are unknown. Although primarily a soluble circulating protein, fH can also bind to tissues in a manner dependent on the carboxyl-terminal domain containing short consensus repeats 19 and 20. We examined the role of fH in CAIA by blocking its binding to tissues through administration of a recombinant negative inhibitor containing short consensus repeats 19 and 20 (rfH19-20), which impairs fH function and amplifies surface AP activation in vitro. Administration of rfH19-20, but not control rfH3-5, significantly worsened clinical disease activity, histopathologic injury, and C3 deposition in the synovium and cartilage in wild-type and fH(+/-) mice. In vitro studies demonstrated that rfH19-20 increased complement activation on cartilage extracts and injured fibroblast-like synoviocytes, two major targets of complement deposition in the joint. We conclude that endogenous fH makes a significant contribution to inhibition of the AP in CAIA through binding to sites of immune complex formation and complement activation. PMID- 23436937 TI - Stereotactic body radiation therapy for stage I non-small-cell lung cancer: a historical overview of clinical studies. AB - Because of difficulties with stabilization, breathing motion and dosimetry, stereotactic body radiotherapy for lung cancer has only been practiced for the past 15 years. However, a large amount of case data has rapidly been accumulated in recent years. Stereotactic body radiotherapy for Stage I non-small-cell lung cancer has been actively investigated in inoperable patients since around 1995, and a number of clinical trials have been undertaken. Early studies from 2001 presented a 3-year local control rate of 94% and a 3-year overall survival rate of 66% for patients receiving 50-60 Gy in 10 fractions. Another study in 2005, using 48 Gy in four fractions, presented a 3-year local control rate of 98% and 3 year overall survival rates of 83% for Stage IA patients and 72% for Stage IB patients. A multi-institutional study showed favorable local control and survival rates in a group receiving a biologically effective dose of 100 Gy. A dose escalation study in the USA suggested a maximum tolerated dose of 60 Gy in three fractions. A Phase II clinical trial (RTOG0236) followed, with a reported 3-year local control rate of 98% and a 3-year overall survival rate of 56% for patients who received 60 Gy in three fractions. A Japanese Phase II clinical trial (JCOG0403) investigated a dose of 48 Gy in four fractions among 165 Stage IA patients, showing a 3-year survival rate of 76% and a 3-year locally progression free survival rate of 69% for the operable group. An overview of past clinical trials in stereotactic body radiotherapy for Stage I non-small-cell lung cancer and current issues is presented and discussed. PMID- 23436938 TI - Policy Transparency and College Enrollment: Did the Texas Top 10% Law Broaden Access to the Public Flagships? AB - By guaranteeing college admission to all students who graduate in the top 10% of their high school class, H.B. 588 replaced an opaque de facto practice of admitting nearly all top 10% graduates with a transparent de jure policy that required public institutions to admit all applicants eligible for the guarantee. The transparency of the new admission regime sent a clear message to students attending high schools that previously sent few students to the University of Texas at Austin and Texas A&M University. Using 18 years of administrative data to examine sending patterns, we find a sizeable decrease in the concentration of flagship enrollees originating from select feeder schools and growing shares of enrollees originating from high schools located in rural areas, small towns, and midsize cities, as well as schools with concentrations of poor and minority students. We also find substantial year-to-year persistence in sending behavior once a campus becomes a sending school, and this persistence increased after the top-10% policy was implemented. PMID- 23436936 TI - 1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting microRNA-155-SOCS1 in macrophages. AB - The negative feedback mechanism is essential to maintain effective immunity and tissue homeostasis. 1,25-dihydroxyvitamin D (1,25[OH]2D3) modulates innate immune response, but the mechanism remains poorly understood. In this article, we report that vitamin D receptor signaling attenuates TLR-mediated inflammation by enhancing the negative feedback inhibition. Vitamin D receptor inactivation leads to hyperinflammatory response in mice and macrophage cultures when challenged with LPS, because of microRNA-155 (miR-155) overproduction that excessively suppresses suppressor of cytokine signaling 1, a key regulator that enhances the negative feedback loop. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation, confirming that 1,25(OH)2D3 stimulates suppressor of cytokine signaling 1 by downregulating miR-155. 1,25(OH)2D3 downregulates bic transcription by inhibiting NF-kappaB activation, which is mediated by a kappaB cis-DNA element located within the first intron of the bic gene. Together, these data identify a novel regulatory mechanism for vitamin D to control innate immunity. PMID- 23436939 TI - Fabrication and Characterization of Three-Dimensional Macroscopic All-Carbon Scaffolds. AB - We report a simple method to fabricate macroscopic, 3-D, free standing, all carbon scaffolds (porous structures) using multiwalled carbon nanotubes (MWCNTs) as the starting materials. The scaffolds prepared by radical initiated thermal crosslinking, and annealing of MWCNTs possess macroscale interconnected pores, robust structural integrity, stability, and conductivity. The porosity of the three-dimensional structure can be controlled by varying the amount of radical initiator, thereby allowing the design of porous scaffolds tailored towards specific potential applications. This method also allows the fabrication of 3-D scaffolds using other carbon nanomaterials such as single-walled carbon nanotubes, fullerenes, and graphene indicating that it could be used as a versatile method for 3-D assembly of carbon nanostructures with pi bond networks. PMID- 23436940 TI - Ethical issues in psychiatry research: Special concerns for India. PMID- 23436941 TI - Retaliatory aggression on psychiatric patients. PMID- 23436942 TI - Retaliatory aggression on psychiatric patients and the issue of closed wards. PMID- 23436943 TI - Political abuse of psychiatry. PMID- 23436944 TI - Ejaculatory dysfunction associated with low dose amisulpride. PMID- 23436945 TI - Airway management training for electroconvulsive therapy psychiatrists. PMID- 23436946 TI - Anesthesiological training and certification for psychiatrists practising unmodified ECT. PMID- 23436947 TI - How to read a research paper: Ecological validity, apples, and oranges. PMID- 23436948 TI - Education Differences in Intended and Unintended Fertility. AB - Using a hazards framework and panel data from the National Longitudinal Survey of Youth (1979-2004), we analyze the fertility patterns of a recent cohort of white and black women in the United States. We examine how completed fertility varies by women's education, differentiating between intended and unintended births. We find that the education gradient on fertility comes largely from unintended childbearing, and it is not explained by child-bearing desires or opportunity costs, the two most common explanations in previous research. Less-educated women want no more children than the more educated, so this factor explains none of their higher completed fertility. Less-educated women have lower wages, but wages have little of the negative effect on fertility predicted by economic theories of opportunity cost. We propose three other potential mechanisms linking low education and unintended childbearing, focusing on access to contraception and abortion, relational and economic uncertainty, and consistency in the behaviors necessary to avoid unintended pregnancies. Our work highlights the need to incorporate these mechanisms into future research. PMID- 23436949 TI - Schooling Location and Economic, Occupational and Cognitive Success among Immigrants and Their Children: The Case of Los Angeles. AB - Large numbers of foreign-born residents in the United States mean that many people receive at least part of their education abroad. Despite this fact, our understanding of nativity differences in the success of adults and their children is based on research that does not empirically consider variation in the benefits to schooling depending on where it is received. We use data from the Los Angeles Family and Neighborhood Survey (L.A. FANS) to examine: a) whether the socioeconomic and cognitive returns to education depend on whether it is received in the U.S. or abroad; and b) whether schooling location partially accounts for nativity differences in these returns. We find that the returns to schooling are generally largest for adults who receive at least some of their highest level of education in the U.S. The beneficial effects of U.S. schooling are more pronounced at higher levels of educational attainment. Schooling location accounts for a sizeable fraction of the lower socioeconomic and cognitive returns of the foreign-born, relative to natives; some meaningful differences remain, however. In addition, the higher cognitive skills of the children of foreign-born adults remain unexplained. Although we cannot distinguish among the possible pathways underlying these associations (e.g., school quality, transferability of credentials, the timing of immigration) our findings suggest the importance of considering factors related to schooling location as predictors of socioeconomic and cognitive success in the United States. PMID- 23436951 TI - Mercury Contamination: Review of a Residential Response. AB - A residential elemental mercury contamination incident in Rhode Island resulted in the evacuation of an entire apartment complex.To develop recommendations for improved response, all response-related documents were examined; personnel involved in the response were interviewed; policies and procedures were reviewed; and environmental monitoring data were compiled from specific phases of the response for analysis of effect.A significant challenge of responding to residential elemental mercury contamination lies in communicating risk to residents affected py a HazMat spill. An ongoing, open and honest dialogue is emphasized where concerns of the public are heard and addressed, particularly when establishing and/or modifying policies and procedures for responding to residential elemental mercury contamination. PMID- 23436950 TI - Concepts and folk theories. AB - Human cognition is characterized by enormous variability and structured by universal psychological constraints. The focus of this chapter is on the development of knowledge acquisition because it provides important insight into how the mind interprets new information and constructs new ways of understanding. We propose that mental content can be productively approached by examining the intuitive causal explanatory "theories" that people construct to explain, interpret, and intervene on the world around them, including theories of mind, of biology, or of physics. A substantial amount of research in cognitive developmental psychology supports the integral role of intuitive theories in human learning and provides evidence that they structure, constrain, and guide the development of human cognition. PMID- 23436952 TI - Exploring Race Based Differences in Patterns of Life-Course Criminality. AB - A persistent issue facing criminologists is the challenge of developing theoretical models that provide comprehensive explanations of the onset and persistence of criminality. One promising theory to develop over the last 30 years has been life-course theory. Using multivariate analysis of variance the main question posed in this research, do elements of social development shape the trajectory of persistent offending in a race-neutral fashion, or are the dynamics shaping life-course criminality unique for people of color, was examined. The results provide a number of useful insights into the relationship between race, life-course transition factors, and longitudinal patterns of criminality. PMID- 23436953 TI - A Tale of Two Counties: Natives' Opinions Toward Immigration in North Carolina. AB - This paper compares native residents' opinions and perceptions regarding immigration using a representative survey from a pair of matched North Carolina counties-one that experienced recent growth of its foreign-born population and one that did not. Drawing from several theoretical perspectives, including group threat, contact theory, and symbolic politics, we formulate and empirically evaluate several hypotheses. Results provide limited evidence that competition and threat influence formation of opinions about immigration, with modest support for claims that parents with school-aged children harbor more negative views of immigration than their childless counterparts. Except for residents in precarious economic situations, these negative opinions appear unrelated to the immigrant composition of the community. Claims that the media promotes negative views of immigration receive limited support, but this relationship is unrelated to the volume of local immigration. Finally, sustained contacts with foreign-born residents outside work environments are associated with positive views of immigration, but superficial contacts appear to be conducive to anti-immigration sentiments. Political orientation, educational attainment and indicators of respondents' tolerance for diversity explain most of the difference between the two counties in overall support for immigration. PMID- 23436954 TI - Depression - the global crisis. PMID- 23436955 TI - Treatment of delusional infestation with olanzapine. PMID- 23436956 TI - Obsessive Compulsive Disorder due to B12 Deficiency: Justification Required. PMID- 23436957 TI - Should we not Deliberate more on Impulsivity? PMID- 23436958 TI - Fluvoxamine Plays an Integral Role in the Alteration of Sexual Behavioral Pattern more in Females than Males. PMID- 23436959 TI - MOTHER, CHILD, AND FAMILY FACTORS RELATED TO EMPLOYMENT OF SINGLE MOTHERS WITH LBW PRESCHOOLERS. AB - The purpose of this study was to identify maternal, child, and family factors related to the employment status and employment history of single mothers of low birth-weight (LBW) and full-term preschoolers. A sample of 121 female-headed, single-parent families with 3-, 4-, and 5- year-old LBW and full-term children was recruited through admission records to three Level III neonatal intensive care units (NICUs) and birth records of two normal newborn nurseries. Results show that the birth of an LBW infant was not related to employment status, number of hours employed per week, or employment history for single mothers. Employed mothers had significantly more education and more positive attitudes toward employment. Controlling for other factors, never being married, and having more children, more federal income, and less positive employment attitudes were predictive of nonemployment. Both employed and nonemployed women expressed preference for employment. PMID- 23436960 TI - The Integration of Emotions in Memories: Cognitive-Emotional Distinctiveness and Posttraumatic Stress Disorder. AB - The current study examined cognitive-emotional distinctiveness (CED), the extent to which emotions are linked with event information, in memories associated with PTSD. Participants either with PTSD (n=68) or without PTSD (n=40) completed a modified multidimensional scaling technique to measure CED for their most negative and most positive events. The results revealed that participants in the PTSD group evidenced significantly lower levels of CED. This group difference remained significant when we limited the analysis to traumatic events that led to a PTSD diagnosis (n=33) in comparison to control participants who nominated a traumatic event that did not result in PTSD (n=32). Replicating previous findings, CED levels were higher in memories of negative events, in comparison to positive events. These results provide empirical evidence that memories associated with PTSD do contain special organizational features with respect to the links between emotions and memory. Implications for understanding and treating PTSD are discussed. PMID- 23436961 TI - Story behind the wrinkle. PMID- 23436962 TI - Prevalence of diabetic nephropathy in an underserved rural community. PMID- 23436963 TI - Plasma exchange for steroid unresponsive Devic's disease. PMID- 23436964 TI - Cortical blindness in a child with acute glomerulonephritis. PMID- 23436965 TI - Everolimus for the treatment of CD20+ diffuse large B-cell lymphoma in a renal allograft recipient. PMID- 23436966 TI - Need of evidence-based practice in chronic pain. PMID- 23436967 TI - From meditation to dhyana. PMID- 23436968 TI - Mindfulness, an integrated approach for cessation of smoking in workplace. PMID- 23436969 TI - Intellectual disabilities and yoga. PMID- 23436970 TI - An Improved NAT Assay with Enhanced Sensitivity for HBV for Donor Blood Screening. PMID- 23436971 TI - Unusual Immunophenotypic Heterogeneity in B-Lineage ALL. PMID- 23436972 TI - Griscelli syndrome: hemophagocytic lymphohistiocytosis with silvery hair. PMID- 23436973 TI - Ischemic optic neuropathy and cataract extraction: What do I need to know? PMID- 23436974 TI - Management of an intrastromal corneal epithelial cyst, from simple drainage to keratoplasty. PMID- 23436975 TI - Retinal astrocytic hamartoma and Bourneville's disease. PMID- 23436976 TI - Subretinal hemorrhages associated with angioid streaks following a mild ocular trauma. PMID- 23436977 TI - Two cases with one diagnosis. PMID- 23436978 TI - Review of retinal morphology around optic disc in Peripapillary atrophy by using Spectralis Optical Coherent Tomography. PMID- 23436979 TI - Stem cells-The future. PMID- 23436980 TI - Calcification of hydrophilic acrylic intraocular lens. PMID- 23436981 TI - Theory of the Protein Equilibrium Population Snapshot by H/D Exchange Electrospray Ionization Mass Spectrometry (PEPS-HDX-ESI-MS) Method used to obtain Protein Folding Energies/Rates and Selected Supporting Experimental Evidence. AB - Protein equilibrium snapshot by hydrogen/deuterium exchange electrospray ionization mass spectrometry (PEPS-HDX-ESI-MS or PEPS) is a method recently introduced for estimating protein folding energies and rates. Herein we describe the basis for this method using both theory and new experiments. Benchmark experiments were conducted using ubiquitin because of the availability of reference data for folding and unfolding rates from NMR studies. A second set of experiments was also conducted to illustrate the surprising resilience of the PEPS to changes in HDX time, using staphylococcal nuclease and time frames ranging from a few seconds to several minutes. Theory suggests that PEPS experiments should be conducted at relatively high denaturant concentrations, where the protein folding/unfolding rates are slow with respect to HDX and the life times of both the closed and open states are long enough to be sampled experimentally. Upon deliberate denaturation, changes in folding/unfolding are correlated with associated changes in the ESI-MS signal upon fast HDX. When experiments are done quickly, typically within a few seconds, ESI-MS signals, corresponding to the equilibrium population of the native (closed) and denatured (open) states can both be detected. The interior of folded proteins remains largely un-exchanged. Amongst MS methods, the simultaneous detection of both states in the spectrum is unique to PEPS and provides a "snapshot" of these populations. The associated ion intensities are used to estimate the protein folding equilibrium constant (or the free energy change, DeltaG). Linear extrapolation method (LEM) plots of derived DeltaG values for each denaturant concentration can then be used to calculate DeltaG in the absence of denaturant, DeltaG(H(2)O). In accordance with the requirement for detection of signals for both the folded and unfolded states, this theoretical framework predicts that PEPS experiments work best at the middle of the denaturation curve where natured and denatured protein molecules are equilibrated at easily detectable ratios, namely 1:1. It also requires that closed and open states have lifetimes measurable in the time frame of the HDX experiment. Because both conditions are met by PEPS, these measurements can provide an accurate assessment of closed/open state populations and thus protein folding energies/rates. PMID- 23436982 TI - Taking Stock and Taking Steps: The Case for an Adolescent Version of the Short Assessment of Risk and Treatability. AB - The field of violence risk assessment has matured considerably, possibly advancing beyond its own adolescence. At this point in the field's evolution, it is more important than ever for the development of any new device to be accompanied by a strong rationale and the capacity to provide a unique contribution. With this issue in mind, we first take stock of the field of adolescent risk assessment in order to describe the rapid progress that this field has made, as well as the gaps that led us to adapt the Short-Term Assessment of Risk and Treatability (START; Webster, Martin, Brink, Nicholls, & Desmarais, 2009) for use with adolescents. We view the Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV; Nicholls, Viljoen, Cruise, Desmarais, & Webster, 2010; Viljoen, Cruise, Nicholls, Desmarais, & Webster, in progress) as complementing other risk measures in four primary ways: 1) rather than focusing solely on violence risk, it examines broader adverse outcomes to which some adolescents are vulnerable (including self-harm, suicide, victimization, substance abuse, unauthorized leave, self-neglect, general offending); 2) it places a balanced emphasis on adolescents' strengths; 3) it focuses on dynamic factors that are relevant to short-term assessment, risk management, and treatment planning; and 4) it is designed for both mental health and justice populations. We describe the developmentally-informed approach we took in the adaptation of the START for adolescents, and outline future steps for the continuing validation and refinement of the START:AV. PMID- 23436983 TI - Assessment of Multiple Risk Outcomes, Strengths, and Change with the START:AV: A Short-Term Prospective Study with Adolescent Offenders. AB - The Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV; Nicholls, Viljoen, Cruise, Desmarais, & Webster, 2010; Viljoen, Cruise, Nicholls, Desmarais, & Webster, in preparation) is a clinical guide designed to assist in the assessment and management of adolescents' risk for adverse events (e.g., violence, general offending, suicide, victimization). In this initial validation study, START:AV assessments were conducted on 90 adolescent offenders (62 male, 28 female), who were prospectively followed for a 3-month period. START:AV assessments had good to excellent inter-rater reliability and strong concurrent validity with Structured Assessment of Violence Risk in Youth assessments (SAVRY; Borum, Bartel, & Forth, 2006). START:AV risk estimates and Vulnerability total scores predicted multiple adverse outcomes, including violence towards others, offending, victimization, suicidal ideation, and substance abuse. In addition, Strength total scores inversely predicted violence, offending, and street drug use. During the 3-month follow-up, risk estimates changed in at least one domain for 92% of youth, and 27% of youth showed reliable changes in Strength and/or Vulnerability total scores (reliable change index, 90% confidence interval; Jacobsen & Truax, 1991). While these findings are promising, a strong need exists for further research on the START:AV, the measurement of change, and on the role of strengths in risk assessment and treatment-planning. PMID- 23436984 TI - Cost and effects of different admission screening strategies to control the spread of methicillin-resistant Staphylococcus aureus. AB - Nosocomial infection rates due to antibiotic-resistant bacteriae, e.g., methicillin-resistant Staphylococcus aureus (MRSA) remain high in most countries. Screening for MRSA carriage followed by barrier precautions for documented carriers (so-called screen and isolate (S&I)) has been successful in some, but not all settings. Moreover, different strategies have been proposed, but comparative studies determining their relative effects and costs are not available. We, therefore, used a mathematical model to evaluate the effect and costs of different S&I strategies and to identify the critical parameters for this outcome. The dynamic stochastic simulation model consists of 3 hospitals with general wards and intensive care units (ICUs) and incorporates readmission of carriers of MRSA. Patient flow between ICUs and wards was based on real observations. Baseline prevalence of MRSA was set at 20% in ICUs and hospital wide at 5%; ranges of costs and infection rates were based on published data. Four S&I strategies were compared to a do-nothing scenario: S&I of previously documented carriers ("flagged" patients); S&I of flagged patients and ICU admissions; S&I of flagged and group of "frequent" patients; S&I of all hospital admissions (universal screening). Evaluated levels of efficacy of S&I were 10%, 25%, 50% and 100%. Our model predicts that S&I of flagged and S&I of flagged and ICU patients are the most cost-saving strategies with fastest return of investment. For low isolation efficacy universal screening and S&I of flagged and "frequent" patients may never become cost-saving. Universal screening is predicted to prevent hardly more infections than S&I of flagged and "frequent" patients, albeit at higher costs. Whether an intervention becomes cost-saving within 10 years critically depends on costs per infection in ICU, costs of screening and isolation efficacy. PMID- 23436985 TI - Significantly improved HIV inhibitor efficacy prediction employing proteochemometric models generated from antivirogram data. AB - Infection with HIV cannot currently be cured; however it can be controlled by combination treatment with multiple anti-retroviral drugs. Given different viral genotypes for virtually each individual patient, the question now arises which drug combination to use to achieve effective treatment. With the availability of viral genotypic data and clinical phenotypic data, it has become possible to create computational models able to predict an optimal treatment regimen for an individual patient. Current models are based only on sequence data derived from viral genotyping; chemical similarity of drugs is not considered. To explore the added value of chemical similarity inclusion we applied proteochemometric models, combining chemical and protein target properties in a single bioactivity model. Our dataset was a large scale clinical database of genotypic and phenotypic information (in total ca. 300,000 drug-mutant bioactivity data points, 4 (NNRTI), 8 (NRTI) or 9 (PI) drugs, and 10,700 (NNRTI) 10,500 (NRTI) or 27,000 (PI) mutants). Our models achieved a prediction error below 0.5 Log Fold Change. Moreover, when directly compared with previously published sequence data, derived models PCM performed better in resistance classification and prediction of Log Fold Change (0.76 log units versus 0.91). Furthermore, we were able to successfully confirm both known and identify previously unpublished, resistance conferring mutations of HIV Reverse Transcriptase (e.g. K102Y, T216M) and HIV Protease (e.g. Q18N, N88G) from our dataset. Finally, we applied our models prospectively to the public HIV resistance database from Stanford University obtaining a correct resistance prediction rate of 84% on the full set (compared to 80% in previous work on a high quality subset). We conclude that proteochemometric models are able to accurately predict the phenotypic resistance based on genotypic data even for novel mutants and mixtures. Furthermore, we add an applicability domain to the prediction, informing the user about the reliability of predictions. PMID- 23436986 TI - Pairwise analysis can account for network structures arising from spike-timing dependent plasticity. AB - Spike timing-dependent plasticity (STDP) modifies synaptic strengths based on timing information available locally at each synapse. Despite this, it induces global structures within a recurrently connected network. We study such structures both through simulations and by analyzing the effects of STDP on pair wise interactions of neurons. We show how conventional STDP acts as a loop eliminating mechanism and organizes neurons into in- and out-hubs. Loop elimination increases when depression dominates and turns into loop-generation when potentiation dominates. STDP with a shifted temporal window such that coincident spikes cause depression enhances recurrent connections and functions as a strict buffering mechanism that maintains a roughly constant average firing rate. STDP with the opposite temporal shift functions as a loop eliminator at low rates and as a potent loop generator at higher rates. In general, studying pairwise interactions of neurons provides important insights about the structures that STDP can produce in large networks. PMID- 23436987 TI - Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model. AB - The high-resolution crystal structure of the leucine transporter (LeuT) is frequently used as a template for homology models of the dopamine transporter (DAT). Although similar in structure, DAT differs considerably from LeuT in a number of ways: (i) when compared to LeuT, DAT has very long intracellular amino and carboxyl termini; (ii) LeuT and DAT share a rather low overall sequence identity (22%) and (iii) the extracellular loop 2 (EL2) of DAT is substantially longer than that of LeuT. Extracellular zinc binds to DAT and restricts the transporter's movement through the conformational cycle, thereby resulting in a decrease in substrate uptake. Residue H293 in EL2 praticipates in zinc binding and must be modelled correctly to allow for a full understanding of its effects. We exploited the high-affinity zinc binding site endogenously present in DAT to create a model of the complete transmemberane domain of DAT. The zinc binding site provided a DAT-specific molecular ruler for calibration of the model. Our DAT model places EL2 at the transporter lipid interface in the vicinity of the zinc binding site. Based on the model, D206 was predicted to represent a fourth co-ordinating residue, in addition to the three previously described zinc binding residues H193, H375 and E396. This prediction was confirmed by mutagenesis: substitution of D206 by lysine and cysteine affected the inhibitory potency of zinc and the maximum inhibition exerted by zinc, respectively. Conversely, the structural changes observed in the model allowed for rationalizing the zinc dependent regulation of DAT: upon binding, zinc stabilizes the outward-facing state, because its first coordination shell can only be completed in this conformation. Thus, the model provides a validated solution to the long extracellular loop and may be useful to address other aspects of the transport cycle. PMID- 23436988 TI - From hub proteins to hub modules: the relationship between essentiality and centrality in the yeast interactome at different scales of organization. AB - Numerous studies have suggested that hub proteins in the S. cerevisiae physical interaction network are more likely to be essential than other proteins. The proposed reasons underlying this observed relationship between topology and functioning have been subject to some controversy, with recent work suggesting that it arises due to the participation of hub proteins in essential complexes and processes. However, do these essential modules themselves have distinct network characteristics, and how do their essential proteins differ in their topological properties from their non-essential proteins? We aimed to advance our understanding of protein essentiality by analyzing proteins, complexes and processes within their broader functional context and by considering physical interactions both within and across complexes and biological processes. In agreement with the view that essentiality is a modular property, we found that the number of intracomplex or intraprocess interactions that a protein has is a better indicator of its essentiality than its overall number of interactions. Moreover, we found that within an essential complex, its essential proteins have on average more interactions, especially intracomplex interactions, than its non essential proteins. Finally, we built a module-level interaction network and found that essential complexes and processes tend to have higher interaction degrees in this network than non-essential complexes and processes; that is, they exhibit a larger amount of functional cross-talk than their non-essential counterparts. PMID- 23436989 TI - Modelling trial-by-trial changes in the mismatch negativity. AB - The mismatch negativity (MMN) is a differential brain response to violations of learned regularities. It has been used to demonstrate that the brain learns the statistical structure of its environment and predicts future sensory inputs. However, the algorithmic nature of these computations and the underlying neurobiological implementation remain controversial. This article introduces a mathematical framework with which competing ideas about the computational quantities indexed by MMN responses can be formalized and tested against single trial EEG data. This framework was applied to five major theories of the MMN, comparing their ability to explain trial-by-trial changes in MMN amplitude. Three of these theories (predictive coding, model adjustment, and novelty detection) were formalized by linking the MMN to different manifestations of the same computational mechanism: approximate Bayesian inference according to the free energy principle. We thereby propose a unifying view on three distinct theories of the MMN. The relative plausibility of each theory was assessed against empirical single-trial MMN amplitudes acquired from eight healthy volunteers in a roving oddball experiment. Models based on the free-energy principle provided more plausible explanations of trial-by-trial changes in MMN amplitude than models representing the two more traditional theories (change detection and adaptation). Our results suggest that the MMN reflects approximate Bayesian learning of sensory regularities, and that the MMN-generating process adjusts a probabilistic model of the environment according to prediction errors. PMID- 23436990 TI - Evidence for model-based computations in the human amygdala during Pavlovian conditioning. AB - Contemporary computational accounts of instrumental conditioning have emphasized a role for a model-based system in which values are computed with reference to a rich model of the structure of the world, and a model-free system in which values are updated without encoding such structure. Much less studied is the possibility of a similar distinction operating at the level of Pavlovian conditioning. In the present study, we scanned human participants while they participated in a Pavlovian conditioning task with a simple structure while measuring activity in the human amygdala using a high-resolution fMRI protocol. After fitting a model based algorithm and a variety of model-free algorithms to the fMRI data, we found evidence for the superiority of a model-based algorithm in accounting for activity in the amygdala compared to the model-free counterparts. These findings support an important role for model-based algorithms in describing the processes underpinning Pavlovian conditioning, as well as providing evidence of a role for the human amygdala in model-based inference. PMID- 23436991 TI - Optimal properties of analog perceptrons with excitatory weights. AB - The cerebellum is a brain structure which has been traditionally devoted to supervised learning. According to this theory, plasticity at the Parallel Fiber (PF) to Purkinje Cell (PC) synapses is guided by the Climbing fibers (CF), which encode an 'error signal'. Purkinje cells have thus been modeled as perceptrons, learning input/output binary associations. At maximal capacity, a perceptron with excitatory weights expresses a large fraction of zero-weight synapses, in agreement with experimental findings. However, numerous experiments indicate that the firing rate of Purkinje cells varies in an analog, not binary, manner. In this paper, we study the perceptron with analog inputs and outputs. We show that the optimal input has a sparse binary distribution, in good agreement with the burst firing of the Granule cells. In addition, we show that the weight distribution consists of a large fraction of silent synapses, as in previously studied binary perceptron models, and as seen experimentally. PMID- 23436993 TI - Proteins secreted via the type II secretion system: smart strategies of Vibrio cholerae to maintain fitness in different ecological niches. PMID- 23436994 TI - Bacterial survival amidst an immune onslaught: the contribution of the Staphylococcus aureus leukotoxins. PMID- 23436995 TI - Random codon re-encoding induces stable reduction of replicative fitness of Chikungunya virus in primate and mosquito cells. AB - Large-scale codon re-encoding represents a powerful method of attenuating viruses to generate safe and cost-effective vaccines. In contrast to specific approaches of codon re-encoding which modify genome-scale properties, we evaluated the effects of random codon re-encoding on the re-emerging human pathogen Chikungunya virus (CHIKV), and assessed the stability of the resultant viruses during serial in cellulo passage. Using different combinations of three 1.4 kb randomly re encoded regions located throughout the CHIKV genome six codon re-encoded viruses were obtained. Introducing a large number of slightly deleterious synonymous mutations reduced the replicative fitness of CHIKV in both primate and arthropod cells, demonstrating the impact of synonymous mutations on fitness. Decrease of replicative fitness correlated with the extent of re-encoding, an observation that may assist in the modulation of viral attenuation. The wild-type and two re encoded viruses were passaged 50 times either in primate or insect cells, or in each cell line alternately. These viruses were analyzed using detailed fitness assays, complete genome sequences and the analysis of intra-population genetic diversity. The response to codon re-encoding and adaptation to culture conditions occurred simultaneously, resulting in significant replicative fitness increases for both re-encoded and wild type viruses. Importantly, however, the most re encoded virus failed to recover its replicative fitness. Evolution of these viruses in response to codon re-encoding was largely characterized by the emergence of both synonymous and non-synonymous mutations, sometimes located in genomic regions other than those involving re-encoding, and multiple convergent and compensatory mutations. However, there was a striking absence of codon reversion (<0.4%). Finally, multiple mutations were rapidly fixed in primate cells, whereas mosquito cells acted as a brake on evolution. In conclusion, random codon re-encoding provides important information on the evolution and genetic stability of CHIKV viruses and could be exploited to develop a safe, live attenuated CHIKV vaccine. PMID- 23436996 TI - The Abi-domain protein Abx1 interacts with the CovS histidine kinase to control virulence gene expression in group B Streptococcus. AB - Group B Streptococcus (GBS), a common commensal of the female genital tract, is the leading cause of invasive infections in neonates. Expression of major GBS virulence factors, such as the hemolysin operon cyl, is regulated directly at the transcriptional level by the CovSR two-component system. Using a random genetic approach, we identified a multi-spanning transmembrane protein, Abx1, essential for the production of the GBS hemolysin. Despite its similarity to eukaryotic CaaX proteases, the Abx1 function is not involved in a post-translational modification of the GBS hemolysin. Instead, we demonstrate that Abx1 regulates transcription of several virulence genes, including those comprising the hemolysin operon, by a CovSR-dependent mechanism. By combining genetic analyses, transcriptome profiling, and site-directed mutagenesis, we showed that Abx1 is a regulator of the histidine kinase CovS. Overexpression of Abx1 is sufficient to activate virulence gene expression through CovS, overcoming the need for an additional signal. Conversely, the absence of Abx1 has the opposite effect on virulence gene expression consistent with CovS locked in a kinase-competent state. Using a bacterial two-hybrid system, direct interaction between Abx1 and CovS was mapped specifically to CovS domains involved in signal processing. We demonstrate that the CovSR two-component system is the core of a signaling pathway integrating the regulation of CovS by Abx1 in addition to the regulation of CovR by the serine/threonine kinase Stk1. In conclusion, our study reports a regulatory function for Abx1, a member of a large protein family with a characteristic Abi-domain, which forms a signaling complex with the histidine kinase CovS in GBS. PMID- 23436997 TI - Induction of p16(INK4a) is the major barrier to proliferation when Epstein-Barr virus (EBV) transforms primary B cells into lymphoblastoid cell lines. AB - To explore the role of p16(INK4a) as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the CDKN2A locus encoding p16(INK4a) and p14(ARF). Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT), we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs) lacking active p16(INK4a) protein but expressing a functional 14(ARF)-fusion protein (p14/p16). The INK4a locus is epigenetically repressed by EBNA3C--in cooperation with EBNA3A--despite the absence of functional p16(INK4a). Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16(INK4a) and growth arrest, EBNA3C inactivation in the p16(INK4a)-null LCLs has no impact on the rate of proliferation, establishing that the repression of INK4a is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16(INK4a)-Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16(INK4a) expression and concomitant block to proliferation 2-4 weeks post-infection. If cells are p16(INK4a)-null, functional EBNA3C is dispensable for the outgrowth of LCLs. PMID- 23436998 TI - Intracellular bacillary burden reflects a burst size for Mycobacterium tuberculosis in vivo. AB - We previously reported that Mycobacterium tuberculosis triggers macrophage necrosis in vitro at a threshold intracellular load of ~25 bacilli. This suggests a model for tuberculosis where bacilli invading lung macrophages at low multiplicity of infection proliferate to burst size and spread to naive phagocytes for repeated cycles of replication and cytolysis. The current study evaluated that model in vivo, an environment significantly more complex than in vitro culture. In the lungs of mice infected with M. tuberculosis by aerosol we observed three distinct mononuclear leukocyte populations (CD11b(-) CD11c(+/hi), CD11b(+/lo) CD11c(lo/-), CD11b(+/hi) CD11c(+/hi)) and neutrophils hosting bacilli. Four weeks after aerosol challenge, CD11b(+/hi) CD11c(+/hi) mononuclear cells and neutrophils were the predominant hosts for M. tuberculosis while CD11b(+/lo) CD11c(lo/-) cells assumed that role by ten weeks. Alveolar macrophages (CD11b(-) CD11c(+/hi)) were a minority infected cell type at both time points. The burst size model predicts that individual lung phagocytes would harbor a range of bacillary loads with most containing few bacilli, a smaller proportion containing many bacilli, and few or none exceeding a burst size load. Bacterial load per cell was enumerated in lung monocytic cells and neutrophils at time points after aerosol challenge of wild type and interferon-gamma null mice. The resulting data fulfilled those predictions, suggesting a median in vivo burst size in the range of 20 to 40 bacilli for monocytic cells. Most heavily burdened monocytic cells were nonviable, with morphological features similar to those observed after high multiplicity challenge in vitro: nuclear condensation without fragmentation and disintegration of cell membranes without apoptotic vesicle formation. Neutrophils had a narrow range and lower peak bacillary burden than monocytic cells and some exhibited cell death with release of extracellular neutrophil traps. Our studies suggest that burst size cytolysis is a major cause of infection-induced mononuclear cell death in tuberculosis. PMID- 23436999 TI - Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforth's short tail mice. AB - Danforth's short tail (Sd) is a semidominant mutation on mouse chromosome 2, characterized by spinal defects, urogenital defects, and anorectal malformations. However, the gene responsible for the Sd phenotype was unknown. In this study, we identified the molecular basis of the Sd mutation. By positional cloning, we identified the insertion of an early transposon in the Sd candidate locus approximately 12-kb upstream of Ptf1a. We found that insertion of the transposon caused overexpression of three neighboring genes, Gm13344, Gm13336, and Ptf1a, in Sd mutant embryos and that the Sd phenotype was not caused by disruption of an as yet-unknown gene in the candidate locus. Using multiple knockout and knock-in mouse models, we demonstrated that misexpression of Ptf1a, but not of Gm13344 or Gm13336, in the notochord, hindgut, cloaca, and mesonephros was sufficient to replicate the Sd phenotype. The ectopic expression of Ptf1a in the caudal embryo resulted in attenuated expression of Cdx2 and its downstream target genes T, Wnt3a, and Cyp26a1; we conclude that this is the molecular basis of the Sd phenotype. Analysis of Sd mutant mice will provide insight into the development of the spinal column, anus, and kidney. PMID- 23437000 TI - Next-generation sequencing identifies the Danforth's short tail mouse mutation as a retrotransposon insertion affecting Ptf1a expression. AB - The semidominant Danforth's short tail (Sd) mutation arose spontaneously in the 1920s. The homozygous Sd phenotype includes severe malformations of the axial skeleton with an absent tail, kidney agenesis, anal atresia, and persistent cloaca. The Sd mutant phenotype mirrors features seen in human caudal malformation syndromes including urorectal septum malformation, caudal regression, VACTERL association, and persistent cloaca. The Sd mutation was previously mapped to a 0.9 cM region on mouse chromosome 2qA3. We performed Sanger sequencing of exons and intron/exon boundaries mapping to the Sd critical region and did not identify any mutations. We then performed DNA enrichment/capture followed by next-generation sequencing (NGS) of the critical genomic region. Standard bioinformatic analysis of paired-end sequence data did not reveal any causative mutations. Interrogation of reads that had been discarded because only a single end mapped correctly to the Sd locus identified an early transposon (ETn) retroviral insertion at the Sd locus, located 12.5 kb upstream of the Ptf1a gene. We show that Ptf1a expression is significantly upregulated in Sd mutant embryos at E9.5. The identification of the Sd mutation will lead to improved understanding of the developmental pathways that are misregulated in human caudal malformation syndromes. PMID- 23437001 TI - A retrotransposon insertion in the 5' regulatory domain of Ptf1a results in ectopic gene expression and multiple congenital defects in Danforth's short tail mouse. AB - Danforth's short tail mutant (Sd) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn) insertion within the highly conserved regulatory sequences upstream of Pancreas Specific Transcription Factor, 1a (Ptf1a). This mutation resulted in up to tenfold increased expression of Ptf1a as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5, Sd mutants exhibit ectopic Ptf1a expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5, Sd mutant mice exhibit ectopic Ptf1a expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The Sd heterozygote phenotype was not ameliorated by Ptf1a haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of Ptf1a. These data identify disruption of the spatio-temporal pattern of Ptf1a expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes. PMID- 23437002 TI - Lessons from Dwarf8 on the strengths and weaknesses of structured association mapping. AB - The strengths of association mapping lie in its resolution and allelic richness, but spurious associations arising from historical relationships and selection patterns need to be accounted for in statistical analyses. Here we reanalyze one of the first generation structured association mapping studies of the Dwarf8 (d8) locus with flowering time in maize using the full range of new mapping populations, statistical approaches, and haplotype maps. Because this trait was highly correlated with population structure, we found that basic structured association methods overestimate phenotypic effects in the region, while mixed model approaches perform substantially better. Combined with analysis of the maize nested association mapping population (a multi-family crossing design), it is concluded that most, if not all, of the QTL effects at the general location of the d8 locus are from rare extended haplotypes that include other linked QTLs and that d8 is unlikely to be involved in controlling flowering time in maize. Previous independent studies have shown evidence for selection at the d8 locus. Based on the evidence of population bottleneck, selection patterns, and haplotype structure observed in the region, we suggest that multiple traits may be strongly correlated with population structure and that selection on these traits has influenced segregation patterns in the region. Overall, this study provides insight into how modern association and linkage mapping, combined with haplotype analysis, can produce results that are more robust. PMID- 23437003 TI - Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure. AB - Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6*10-14; LOC285735, rs271170, p = 2.7*10-12; OPG, rs7839059, p = 1.2*10-10; and ESR1/C6orf97, rs6909279, p = 1.1*10-9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9*10-9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk. PMID- 23437004 TI - Properties and modeling of GWAS when complex disease risk is due to non complementing, deleterious mutations in genes of large effect. AB - Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders), and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated. PMID- 23437005 TI - Ehd4 encodes a novel and Oryza-genus-specific regulator of photoperiodic flowering in rice. AB - Land plants have evolved increasingly complex regulatory modes of their flowering time (or heading date in crops). Rice (Oryza sativa L.) is a short-day plant that flowers more rapidly in short-day but delays under long-day conditions. Previous studies have shown that the CO-FT module initially identified in long-day plants (Arabidopsis) is evolutionary conserved in short-day plants (Hd1-Hd3a in rice). However, in rice, there is a unique Ehd1-dependent flowering pathway that is Hd1 independent. Here, we report isolation and characterization of a positive regulator of Ehd1, Early heading date 4 (Ehd4). ehd4 mutants showed a never flowering phenotype under natural long-day conditions. Map-based cloning revealed that Ehd4 encodes a novel CCCH-type zinc finger protein, which is localized to the nucleus and is able to bind to nucleic acids in vitro and transactivate transcription in yeast, suggesting that it likely functions as a transcriptional regulator. Ehd4 expression is most active in young leaves with a diurnal expression pattern similar to that of Ehd1 under both short-day and long-day conditions. We show that Ehd4 up-regulates the expression of the "florigen" genes Hd3a and RFT1 through Ehd1, but it acts independently of other known Ehd1 regulators. Strikingly, Ehd4 is highly conserved in the Oryza genus including wild and cultivated rice, but has no homologs in other species, suggesting that Ehd4 is originated along with the diversification of the Oryza genus from the grass family during evolution. We conclude that Ehd4 is a novel Oryza-genus specific regulator of Ehd1, and it plays an essential role in photoperiodic control of flowering time in rice. PMID- 23437006 TI - PcG-mediated higher-order chromatin structures modulate replication programs at the Drosophila BX-C. AB - Polycomb group proteins (PcG) exert conserved epigenetic functions that convey maintenance of repressed transcriptional states, via post-translational histone modifications and high order structure formation. During S-phase, in order to preserve cell identity, in addition to DNA information, PcG-chromatin-mediated epigenetic signatures need to be duplicated requiring a tight coordination between PcG proteins and replication programs. However, the interconnection between replication timing control and PcG functions remains unknown. Using Drosophila embryonic cell lines, we find that, while presence of specific PcG complexes and underlying transcription state are not the sole determinants of cellular replication timing, PcG-mediated higher-order structures appear to dictate the timing of replication and maintenance of the silenced state. Using published datasets we show that PRC1, PRC2, and PhoRC complexes differently correlate with replication timing of their targets. In the fully repressed BX-C, loss of function experiments revealed a synergistic role for PcG proteins in the maintenance of replication programs through the mediation of higher-order structures. Accordingly, replication timing analysis performed on two Drosophila cell lines differing for BX-C gene expression states, PcG distribution, and chromatin domain conformation revealed a cell-type-specific replication program that mirrors lineage-specific BX-C higher-order structures. Our work suggests that PcG complexes, by regulating higher-order chromatin structure at their target sites, contribute to the definition and the maintenance of genomic structural domains where genes showing the same epigenetic state replicate at the same time. PMID- 23437008 TI - Patterning of leaf vein networks by convergent auxin transport pathways. AB - The formation of leaf vein patterns has fascinated biologists for centuries. Transport of the plant signal auxin has long been implicated in vein patterning, but molecular details have remained unclear. Varied evidence suggests a central role for the plasma-membrane (PM)-localized PIN-FORMED1 (PIN1) intercellular auxin transporter of Arabidopsis thaliana in auxin-transport-dependent vein patterning. However, in contrast to the severe vein-pattern defects induced by auxin transport inhibitors, pin1 mutant leaves have only mild vein-pattern defects. These defects have been interpreted as evidence of redundancy between PIN1 and the other four PM-localized PIN proteins in vein patterning, redundancy that underlies many developmental processes. By contrast, we show here that vein patterning in the Arabidopsis leaf is controlled by two distinct and convergent auxin-transport pathways: intercellular auxin transport mediated by PM-localized PIN1 and intracellular auxin transport mediated by the evolutionarily older, endoplasmic-reticulum-localized PIN6, PIN8, and PIN5. PIN6 and PIN8 are expressed, as PIN1 and PIN5, at sites of vein formation. pin6 synthetically enhances pin1 vein-pattern defects, and pin8 quantitatively enhances pin1pin6 vein-pattern defects. Function of PIN6 is necessary, redundantly with that of PIN8, and sufficient to control auxin response levels, PIN1 expression, and vein network formation; and the vein pattern defects induced by ectopic PIN6 expression are mimicked by ectopic PIN8 expression. Finally, vein patterning functions of PIN6 and PIN8 are antagonized by PIN5 function. Our data define a new level of control of vein patterning, one with repercussions on other patterning processes in the plant, and suggest a mechanism to select cell files specialized for vascular function that predates evolution of PM-localized PIN proteins. PMID- 23437007 TI - SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state. AB - SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors. PMID- 23437009 TI - Discovery of a splicing regulator required for cell cycle progression. AB - In the G1 phase of the cell division cycle, eukaryotic cells prepare many of the resources necessary for a new round of growth including renewal of the transcriptional and protein synthetic capacities and building the machinery for chromosome replication. The function of G1 has an early evolutionary origin and is preserved in single and multicellular organisms, although the regulatory mechanisms conducting G1 specific functions are only understood in a few model eukaryotes. Here we describe a new G1 mutant from an ancient family of apicomplexan protozoans. Toxoplasma gondii temperature-sensitive mutant 12-109C6 conditionally arrests in the G1 phase due to a single point mutation in a novel protein containing a single RNA-recognition-motif (TgRRM1). The resulting tyrosine to asparagine amino acid change in TgRRM1 causes severe temperature instability that generates an effective null phenotype for this protein when the mutant is shifted to the restrictive temperature. Orthologs of TgRRM1 are widely conserved in diverse eukaryote lineages, and the human counterpart (RBM42) can functionally replace the missing Toxoplasma factor. Transcriptome studies demonstrate that gene expression is downregulated in the mutant at the restrictive temperature due to a severe defect in splicing that affects both cell cycle and constitutively expressed mRNAs. The interaction of TgRRM1 with factors of the tri-SNP complex (U4/U6 & U5 snRNPs) indicate this factor may be required to assemble an active spliceosome. Thus, the TgRRM1 family of proteins is an unrecognized and evolutionarily conserved class of splicing regulators. This study demonstrates investigations into diverse unicellular eukaryotes, like the Apicomplexa, have the potential to yield new insights into important mechanisms conserved across modern eukaryotic kingdoms. PMID- 23437010 TI - Mechanisms involved in the functional divergence of duplicated GroEL chaperonins in Myxococcus xanthus DK1622. AB - The gene encoding the GroEL chaperonin is duplicated in nearly 30% of bacterial genomes; and although duplicated groEL genes have been comprehensively determined to have distinct physiological functions in different species, the mechanisms involved have not been characterized to date. Myxococcus xanthus DK1622 has two copies of the groEL gene, each of which can be deleted without affecting cell viability; however, the deletion of either gene does result in distinct defects in the cellular heat-shock response, predation, and development. In this study, we show that, from the expression levels of different groELs, the distinct functions of groEL1 and groEL2 in predation and development are probably the result of the substrate selectivity of the paralogous GroEL chaperonins, whereas the lethal effect of heat shock due to the deletion of groEL1 is caused by a decrease in the total groEL expression level. Following a bioinformatics analysis of the composition characteristics of GroELs from different bacteria, we performed region-swapping assays in M. xanthus, demonstrating that the differences in the apical and the C-terminal equatorial regions determine the substrate specificity of the two GroELs. Site-directed mutagenesis experiments indicated that the GGM repeat sequence at the C-terminus of GroEL1 plays an important role in functional divergence. Divergent functions of duplicated GroELs, which have similar patterns of variation in different bacterial species, have thus evolved mainly via alteration of the apical and the C-terminal equatorial regions. We identified the specific substrates of strain DK1622's GroEL1 and GroEL2 using immunoprecipitation and mass spectrometry techniques. Although 68 proteins bound to both GroEL1 and GroEL2, 83 and 46 proteins bound exclusively to GroEL1 or GroEL2, respectively. The GroEL-specific substrates exhibited distinct molecular sizes and secondary structures, providing an encouraging indication for GroEL evolution for functional divergence. PMID- 23437012 TI - How repeated and unpredictable experiences turn into fear-memories. PMID- 23437011 TI - The Caenorhabditis elegans JNK signaling pathway activates expression of stress response genes by derepressing the Fos/HDAC repressor complex. AB - MAP kinases are integral to the mechanisms by which cells respond to a wide variety of environmental stresses. In Caenorhabditis elegans, the KGB-1 JNK signaling pathway regulates the response to heavy metal stress. In this study, we identified FOS-1, a bZIP transcription factor, as a target of KGB-1-mediated phosphorylation. We further identified two transcriptional targets of the KGB-1 pathway, kreg-1 and kreg-2/lys-3, which are required for the defense against heavy metal stress. FOS-1 plays a critical role in the transcriptional repression of the kreg-1 gene by recruiting histone deacetylase (HDAC) to its promoter. KGB 1 phosphorylation prevents FOS-1 dimerization and promoter binding, resulting in promoter derepression. Thus, HDAC behaves as a co-repressor modulating FOS-1 mediated transcriptional regulation. This study describes the direct link from JNK signaling, Fos phosphorylation, and regulation of kreg gene transcription, which modulates the stress response in C. elegans. PMID- 23437013 TI - Moving the field: the sensorimotor perspective on autism (Commentary on "Rethinking autism: implications of sensory and motor differences," an article by Anne Donnellan, David Hill, and Martha Leary). PMID- 23437014 TI - A note on Striemer and Danckert's theory of prism adaptation in unilateral neglect. PMID- 23437015 TI - Training-induced cognitive and neural plasticity. PMID- 23437016 TI - Gasotransmitters: novel regulators of ion channels and transporters. PMID- 23437017 TI - Using fundamental knowledge of induced resistance to develop control strategies for bacterial canker of kiwifruit caused by Pseudomonas syringae pv. actinidiae. PMID- 23437018 TI - Accreditation of sleep medicine in the Kingdom of Saudi Arabia: A critical step toward quality outcomes. PMID- 23437019 TI - Diagnostic performance of interferon-Gamma assay for tuberculosis in immunocompromised patients. PMID- 23437020 TI - Authors' reply. PMID- 23437021 TI - Therapeutic thoracentesis in tuberculous pleural effusion: Needs more ammunition to prove. PMID- 23437022 TI - Authors' reply. PMID- 23437023 TI - Failure of non-invasive mechanical ventilation in acute hypercapnic respiratory failure: Still, there are more things to learn. PMID- 23437024 TI - The management of needlestick injuries. AB - BACKGROUND: An estimated 1 million needlestick injuries (NSIs) occur in Europe each year. The Council Directive 2010/32/EU on the prevention of NSIs describes minimum requirements for prevention and calls for the implementation of local, national and Europe-wide reporting systems. The Directive is to be implemented by all EU member states by 11 May 2013. The purpose of this study was to assess (and improve) the procedures for the reporting and treatment of needlestick injuries in a German tertiary-care hospital. METHODS: We carried out a prospective observational study of the NSI reporting system in the hospital over a period of 18 months and determined the incidence of NSIs, the prevalence of blood-borne pathogens among index patients, the rate of initiation of post-exposure prophylaxis, and the rate of serological testing of the affected health care personnel. RESULTS: 519 instances of NSI were reported to the accident insurance doctor over the period of the study, which consisted of 547 working days. 86.5% of the index patients underwent serological study for hepatitis B and C (HBV and HCV) and for the human immune deficiency virus (HIV); this resulted in two initial diagnoses (one each of active hepatitis B and hepatitis C) in the index patient. 92 of 449 index patients, or one in five, was infected with at least one blood-borne pathogen. HIV post-exposure prophylaxis was initiated in 41 health care workers. One case of hepatitis C virus transmission arose and was successfully treated. Other than that, no infection was transmitted. CONCLUSION: Complete reporting of NSIs is a prerequisite for the identification of risky procedures and to ensure optimal treatment of the affected health care personnel. The accident insurance doctor must possess a high degree of interdisciplinary competence in order to treat NSI effectively. PMID- 23437025 TI - Correspondence (letter to the editor): A big challenge. PMID- 23437026 TI - Correspondence (letter to the editor): Extremely low numbers of cases. PMID- 23437027 TI - Correspondence (letter to the editor): Poor sensitivity and specificity. PMID- 23437028 TI - Correspondence (letter to the editor): Relevance of prevalence values. PMID- 23437029 TI - Correspondence (letter to the editor): Questions remain unanswered. PMID- 23437030 TI - Correspondence (letter to the editor): Ultrasound-guided percutaneous ethanol injection was not mentioned. PMID- 23437031 TI - Correspondence (reply): In Reply. PMID- 23437032 TI - Postoperative care and follow-up after coronary stenting. AB - BACKGROUND: The diagnosis and treatment of coronary heart disease have improved in recent years. Most patients can return to their everyday routine a few days after a successful percutaneous coronary intervention (PCI). How should patients be followed up after the successful implantation of a coronary stent? METHOD: Selective review of the pertinent literature, including current practice guidelines and recommendations. RESULTS: After a PCI, the patient should be followed up both by the primary care physician and by the cardiologist one week after the procedure, and then every three to six months for the first year. Clinical history taking and physical examination, including an assessment of cardiovascular risk factors and of potential evidence of myocardial ischemia, constitute the best way to detect possible progression of coronary heart disease. Diagnostic coronary angiography is not routinely indicated after coronary stent implantation. If progression of heart disease is suspected, a stress test should be performed; patients who develop symptoms or show evidence of ischemia in a stress test should undergo diagnostic cardiac catheterization. CONCLUSION: Repeated history taking and physical examination play an important role after PCI. For patients at high risk of restenosis and those with complex coronary morphology, coronary angiography may be indicated regardless of the findings of non-invasive stress tests. PMID- 23437033 TI - Quantitative description of glycan-receptor binding of influenza A virus H7 hemagglutinin. AB - In the context of recently emerged novel influenza strains through reassortment, avian influenza subtypes such as H5N1, H7N7, H7N2, H7N3 and H9N2 pose a constant threat in terms of their adaptation to the human host. Among these subtypes, it was recently demonstrated that mutations in H5 and H9 hemagglutinin (HA) in the context of lab-generated reassorted viruses conferred aerosol transmissibility in ferrets (a property shared by human adapted viruses). We previously demonstrated that the quantitative binding affinity of HA to alpha2->6 sialylated glycans (human receptors) is one of the important factors governing human adaptation of HA. Although the H7 subtype has infected humans causing varied clinical outcomes from mild conjunctivitis to severe respiratory illnesses, it is not clear where the HA of these subtypes stand in regard to human adaptation since its binding affinity to glycan receptors has not yet been quantified. In this study, we have quantitatively characterized the glycan receptor-binding specificity of HAs from representative strains of Eurasian (H7N7) and North American (H7N2) lineages that have caused human infection. Furthermore, we have demonstrated for the first time that two specific mutations; Gln226->Leu and Gly228->Ser in glycan receptor binding site of H7 HA substantially increase its binding affinity to human receptor. Our findings contribute to a framework for monitoring the evolution of H7 HA to be able to adapt to human host. PMID- 23437034 TI - The interplay of intrinsic and extrinsic bounded noises in biomolecular networks. AB - After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a biomolecular network. The influence of intrinsic and extrinsic noises on biomolecular networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: (i) the Michaelis Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, (ii) a model of enzymatic futile cycle and (iii) a genetic toggle switch. In (ii) and (iii) we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possible functional role of bounded noises. PMID- 23437035 TI - Detection of genetic diversity in Campylobacter jejuni isolated from a commercial turkey flock using flaA typing, MLST analysis and microarray assay. AB - Campylobacter is genetically highly diverse and undergoes frequent intraspecific recombination. Turkeys have been identified as an important reservoir for Campylobacter jejuni which is of public health significance. The assessment of the genetic diversity among Campylobacter population is critical for our understanding of the epidemiology of this bacterium. The genetic profiles were different according to the molecular typing methods used. The performance of established flaA genotyping, multilocus sequencing typing (MLST) and DNA microarray assay based on the ArrayTubeTM technology was evaluated using 14 Campylobacter jejuni isolated from a commercial turkey flock. The flaA typing was performed using PCR-RFLP with restriction enzymes Sau3AI, AluI, a 'composite' flaA analysis of AluI and Sau3AI and DdeI. The 14 isolates were differentiated into 3, 5, 7 and 9 genotypes, respectively. Entire flaA gene and short variable region (SVR) sequences were analysed. Sequencing of the entire flaA provided 11 different genotypes. flaA-SVR sequence analysis detected 8 flaA alleles and 4 flaA peptides. One new flaA allele type (528) was identified. MLST analysis represented 10 different sequence types (STs) and 5 clonal complexes (CCs). The microarray assay recognised 14 different genotypes. The discriminatory indices were 0.560, 0.802, 0.857, and 0.912 for flaA-RFLP depending on the used enzymes, 0.890 for flaA-SVR, 0.967 for entire flaA sequencing, 0.945 for MLST and 1.00 for the DNA microarray assay. The flaA gene was genetically stable over 20 passages on blood agar. In conclusion, the different typing tools demonstrated a high level of genetic heterogeneity of Campylobacter jejuni in a turkey flock, indicating that a single flock can be infected by multiple genotypes within one rearing cycle. DNA microarray-based assays had the highest discriminatory power when compared with other genotyping tools. PMID- 23437036 TI - Learning phonemic vowel length from naturalistic recordings of Japanese infant directed speech. AB - In Japanese, vowel duration can distinguish the meaning of words. In order for infants to learn this phonemic contrast using simple distributional analyses, there should be reliable differences in the duration of short and long vowels, and the frequency distribution of vowels must make these differences salient enough in the input. In this study, we evaluate these requirements of phonemic learning by analyzing the duration of vowels from over 11 hours of Japanese infant-directed speech. We found that long vowels are substantially longer than short vowels in the input directed to infants, for each of the five oral vowels. However, we also found that learning phonemic length from the overall distribution of vowel duration is not going to be easy for a simple distributional learner, because of the large base-rate effect (i.e., 94% of vowels are short), and because of the many factors that influence vowel duration (e.g., intonational phrase boundaries, word boundaries, and vowel height). Therefore, a successful learner would need to take into account additional factors such as prosodic and lexical cues in order to discover that duration can contrast the meaning of words in Japanese. These findings highlight the importance of taking into account the naturalistic distributions of lexicons and acoustic cues when modeling early phonemic learning. PMID- 23437037 TI - The dynamics of stress p53-Mdm2 network regulated by p300 and HDAC1. AB - We construct a stress p53-Mdm2-p300-HDAC1 regulatory network that is activated and stabilised by two regulatory proteins, p300 and HDAC1. Different activation levels of [Formula: see text] observed due to these regulators during stress condition have been investigated using a deterministic as well as a stochastic approach to understand how the cell responds during stress conditions. We found that these regulators help in adjusting p53 to different conditions as identified by various oscillatory states, namely fixed point oscillations, damped oscillations and sustain oscillations. On assessing the impact of p300 on p53 Mdm2 network we identified three states: first stabilised or normal condition where the impact of p300 is negligible, second an interim region where p53 is activated due to interaction between p53 and p300, and finally the third regime where excess of p300 leads to cell stress condition. Similarly evaluation of HDAC1 on our model led to identification of the above three distinct states. Also we observe that noise in stochastic cellular system helps to reach each oscillatory state quicker than those in deterministic case. The constructed model validated different experimental findings qualitatively. PMID- 23437038 TI - Disentangling biodiversity and climatic determinants of wood production. AB - BACKGROUND: Despite empirical support for an increase in ecosystem productivity with species diversity in synthetic systems, there is ample evidence that this relationship is dependent on environmental characteristics, especially in structurally more complex natural systems. Empirical support for this relationship in forests is urgently needed, as these ecosystems play an important role in carbon sequestration. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether tree wood production is positively related to tree species richness while controlling for climatic factors, by analyzing 55265 forest inventory plots in 11 forest types across five European countries. On average, wood production was 24% higher in mixed than in monospecific forests. Taken alone, wood production was enhanced with increasing tree species richness in almost all forest types. In some forests, wood production was also greater with increasing numbers of tree types. Structural Equation Modeling indicated that the increase in wood production with tree species richness was largely mediated by a positive association between stand basal area and tree species richness. Mean annual temperature and mean annual precipitation affected wood production and species richness directly. However, the direction and magnitude of the influence of climatic variables on wood production and species richness was not consistent, and vary dependent on forest type. CONCLUSIONS: Our analysis is the first to find a local scale positive relationship between tree species richness and tree wood production occurring across a continent. Our results strongly support incorporating the role of biodiversity in management and policy plans for forest carbon sequestration. PMID- 23437040 TI - Prevention of mother-to-child transmission of HIV: cost-effectiveness of antiretroviral regimens and feeding options in Rwanda. AB - BACKGROUND: Rwanda's National PMTCT program aims to achieve elimination of new HIV infections in children by 2015. In November 2010, Rwanda adopted the WHO 2010 ARV guidelines for PMTCT recommending Option B (HAART) for all HIV-positive pregnant women extended throughout breastfeeding and discontinued (short course HAART) only for those not eligible for life treatment. The current study aims to assess the cost-effectiveness of this policy choice. METHODS: Based on a cohort of HIV-infected pregnant women in Rwanda, we modelled the cost-effectiveness of six regimens: dual ARV prophylaxis with either 12 months breastfeeding or replacement feeding; short course HAART (Sc-HAART) prophylaxis with either 6 months breastfeeding, 12 months breastfeeding, or 18 months breastfeeding; and Sc HAART prophylaxis with replacement feeding. Direct costs were modelled based on all inputs in each scenario and related unit costs. Effectiveness was evaluated by measuring HIV-free survival at 18 months. Savings correspond to the lifetime costs of HIV treatment and care avoided as a result of all vertical HIV infections averted. RESULTS: All PMTCT scenarios considered are cost saving compared to "no intervention." Sc-HAART with 12 months breastfeeding or 6 months breastfeeding dominate all other scenarios. Sc-HAART with 12 months breastfeeding allows for more children to be alive and HIV-uninfected by 18 months than Sc HAART with 6 months breastfeeding for an incremental cost per child alive and uninfected of 11,882 USD. This conclusion is sensitive to changes in the relative risk of mortality by 18 months for exposed HIV-uninfected children on replacement feeding from birth and those who were breastfed for only 6 months compared to those breastfeeding for 12 months or more. CONCLUSION: Our findings support the earlier decision by Rwanda to adopt WHO Option B and could inform alternatives for breastfeeding duration. Local contexts and existing care delivery models should be part of national policy decisions. PMID- 23437039 TI - Feedback-based, system-level properties of vertebrate-microbial interactions. AB - BACKGROUND: Improved characterization of infectious disease dynamics is required. To that end, three-dimensional (3D) data analysis of feedback-like processes may be considered. METHODS: To detect infectious disease data patterns, a systems biology (SB) and evolutionary biology (EB) approach was evaluated, which utilizes leukocyte data structures designed to diminish data variability and enhance discrimination. Using data collected from one avian and two mammalian (human and bovine) species infected with viral, parasite, or bacterial agents (both sensitive and resistant to antimicrobials), four data structures were explored: (i) counts or percentages of a single leukocyte type, such as lymphocytes, neutrophils, or macrophages (the classic approach), and three levels of the SB/EB approach, which assessed (ii) 2D, (iii) 3D, and (iv) multi-dimensional (rotating 3D) host-microbial interactions. RESULTS: In all studies, no classic data structure discriminated disease-positive (D+, or observations in which a microbe was isolated) from disease-negative (D-, or microbial-negative) groups: D+ and D- data distributions overlapped. In contrast, multi-dimensional analysis of indicators designed to possess desirable features, such as a single line of observations, displayed a continuous, circular data structure, whose abrupt inflections facilitated partitioning into subsets statistically significantly different from one another. In all studies, the 3D, SB/EB approach distinguished three (steady, positive, and negative) feedback phases, in which D- data characterized the steady state phase, and D+ data were found in the positive and negative phases. In humans, spatial patterns revealed false-negative observations and three malaria-positive data classes. In both humans and bovines, methicillin resistant Staphylococcus aureus (MRSA) infections were discriminated from non MRSA infections. CONCLUSIONS: More information can be extracted, from the same data, provided that data are structured, their 3D relationships are considered, and well-conserved (feedback-like) functions are estimated. Patterns emerging from such structures may distinguish well-conserved from recently developed host microbial interactions. Applications include diagnosis, error detection, and modeling. PMID- 23437042 TI - Toxoplasma gondii migration within and infection of human retina. AB - Toxoplasmic retinochoroiditis is a common blinding retinal infection caused by the parasite, Toxoplasma gondii. Basic processes relating to establishment of infection in the human eye by T. gondii tachyzoites have not been investigated. To evaluate the ability of tachyzoites to navigate the human retina, we developed an ex vivo assay, in which a suspension containing 1.5 * 10(7) parasites replaced vitreous in a posterior eyecup. After 8 hours, the retina was formalin-fixed and paraffin-embedded, and sections were immunostained to identify tachyzoites. To determine the preference of tachyzoites for human retinal neuronal versus glial populations, we infected dissociated retinal cultures, subsequently characterized by neuron-specific enolase or glial fibrillary acidic protein expression, and retinal cell lines, with YFP-expressing tachyzoites. In migration assays, retinas contained 110-250 live tachyzoites; 64.5-95.2% (mean =79.6%) were localized to the nerve fiber layer, but some were detected in the outer retina. Epifluorescence imaging of dissociated retinal cultures 24 hours after infection indicated preferential infection of glia. This observation was confirmed in growth assays, with significantly higher (p <= 0.005) numbers of tachyzoites measured in glial verus neuronal cell lines. Our translational studies indicate that, after entering retina, tachyzoites may navigate multiple tissue layers. Tachyzoites preferentially infect glial cells, which exist throughout the retina. These properties may contribute to the success of T. gondii as a human pathogen. PMID- 23437041 TI - Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells. AB - The purpose of this study was to investigate the effects of 17-beta-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes - nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor - NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen induced malignant breast lesions. PMID- 23437043 TI - Aedes aegypti mosquitoes exhibit decreased repellency by DEET following previous exposure. AB - DEET (N,N-Diethyl-m-toluamide) is one of the most widely used mosquito repellents. Although DEET has been shown to be extremely effective, recent studies have revealed that certain individual insects are unaffected by its presence. A genetic basis for this has been shown in Aedes aegypti mosquitoes and the fruit fly Drosophila melanogaster, but, for the triatomine bug, Rhodnius prolixus, a decrease in response to DEET occurred shortly after previous exposure, indicating that non-genetic factors may also be involved in DEET "insensitivity". In this study, we examined host-seeking behaviour and electrophysiological responses of A. aegypti after pre-exposure to DEET. We found that three hours after pre-exposure the mosquitoes showed behavioural insensitivity, and electroantennography revealed this correlated with the olfactory receptor neurons responding less to DEET. The change in behaviour as a result of pre-exposure to DEET has implications for the use of repellents and the ability of mosquitoes to overcome them. PMID- 23437044 TI - Identifying the computational requirements of an integrated top-down-bottom-up model for overt visual attention within an active vision system. AB - Computational visual attention systems have been constructed in order for robots and other devices to detect and locate regions of interest in their visual world. Such systems often attempt to take account of what is known of the human visual system and employ concepts, such as 'active vision', to gain various perceived advantages. However, despite the potential for gaining insights from such experiments, the computational requirements for visual attention processing are often not clearly presented from a biological perspective. This was the primary objective of this study, attained through two specific phases of investigation: 1) conceptual modeling of a top-down-bottom-up framework through critical analysis of the psychophysical and neurophysiological literature, 2) implementation and validation of the model into robotic hardware (as a representative of an active vision system). Seven computational requirements were identified: 1) transformation of retinotopic to egocentric mappings, 2) spatial memory for the purposes of medium-term inhibition of return, 3) synchronization of 'where' and 'what' information from the two visual streams, 4) convergence of top-down and bottom-up information to a centralized point of information processing, 5) a threshold function to elicit saccade action, 6) a function to represent task relevance as a ratio of excitation and inhibition, and 7) derivation of excitation and inhibition values from object-associated feature classes. The model provides further insight into the nature of data representation and transfer between brain regions associated with the vertebrate 'active' visual attention system. In particular, the model lends strong support to the functional role of the lateral intraparietal region of the brain as a primary area of information consolidation that directs putative action through the use of a 'priority map'. PMID- 23437045 TI - A composite method based on formal grammar and DNA structural features in detecting human polymerase II promoter region. AB - An important step in understanding gene regulation is to identify the promoter regions where the transcription factor binding takes place. Predicting a promoter region de novo has been a theoretical goal for many researchers for a long time. There exists a number of in silico methods to predict the promoter region de novo but most of these methods are still suffering from various shortcomings, a major one being the selection of appropriate features of promoter region distinguishing them from non-promoters. In this communication, we have proposed a new composite method that predicts promoter sequences based on the interrelationship between structural profiles of DNA and primary sequence elements of the promoter regions. We have shown that a Context Free Grammar (CFG) can formalize the relationships between different primary sequence features and by utilizing the CFG, we demonstrate that an efficient parser can be constructed for extracting these relationships from DNA sequences to distinguish the true promoter sequences from non-promoter sequences. Along with CFG, we have extracted the structural features of the promoter region to improve upon the efficiency of our prediction system. Extensive experiments performed on different datasets reveals that our method is effective in predicting promoter sequences on a genome-wide scale and performs satisfactorily as compared to other promoter prediction techniques. PMID- 23437046 TI - Quantitating the specificity and selectivity of Gcn5-mediated acetylation of histone H3. AB - Lysine acetyltransferases (KATs) play a unique role in regulating gene transcription as well as maintaining the epigenetic state of the cell. KATs such as Gcn5 and p300/CBP can modify multiple residues on a single histone; however, order and specificity of acetylation can be altered by factors such as histone chaperones, subunit proteins or external stimulus. While the importance of acetylation is well documented, it has been difficult to quantitatively measure the specificity and selectivity of acetylation at different residues within a histone. In this paper, we demonstrate a label-free quantitative high throughput mass spectrometry-based assay capable of quantitatively monitoring all known acetylation sites of H3 simultaneously. Using this assay, we are able to analyze the steady-state enzyme kinetics of Gcn5, an evolutionarily conserved KAT. In doing so, we measured Gcn5-mediated acetylation at six residues (K14>K9 ~ K23> K18> K27 ~ K36) and the catalytic efficiency (k(cat)/K(m)) for K9, K14, K18, and K23 as well as the nonenzymatic acetylation rate. We observed selectivity differences of up to -4 kcal/mol between K14 and K18, the highest and lowest measurable k(cat)/K(m). These data provide a first look at quantitating the specificity and selectivity of multiple lysines on a single substrate (H3) by Gcn5. PMID- 23437047 TI - Automated authorship attribution using advanced signal classification techniques. AB - In this paper, we develop two automated authorship attribution schemes, one based on Multiple Discriminant Analysis (MDA) and the other based on a Support Vector Machine (SVM). The classification features we exploit are based on word frequencies in the text. We adopt an approach of preprocessing each text by stripping it of all characters except a-z and space. This is in order to increase the portability of the software to different types of texts. We test the methodology on a corpus of undisputed English texts, and use leave-one-out cross validation to demonstrate classification accuracies in excess of 90%. We further test our methods on the Federalist Papers, which have a partly disputed authorship and a fair degree of scholarly consensus. And finally, we apply our methodology to the question of the authorship of the Letter to the Hebrews by comparing it against a number of original Greek texts of known authorship. These tests identify where some of the limitations lie, motivating a number of open questions for future work. An open source implementation of our methodology is freely available for use at https://github.com/matthewberryman/author-detection. PMID- 23437048 TI - The improved biological performance of a novel low elastic modulus implant. AB - BACKGROUND: The mismatch of the elastic modulus between implants and bone tissue can lead to stress shielding, bone resorption and poor osseointegration. Compared with normal bone tissue, this problem is much more serious in osteoporosis. The purpose of this study was designed to find out whether the novel Ti-24Nb-4Zr 7.9Sn (TNZS) implant with low elastic modulus and high strength was suitable for biomedical material, especially in osteoporosis. METHODOLOGY: In vitro study, the viability and Alkaline phosphatase (ALP) activity of osteoblasts on the TNZS and Ti-6V-4V (TAV) were observed. In vivo study, 30 adult female New Zealand rabbits were selected and divided randomly into two groups: sham-operation (SHAM, n=6) and ovariectomised in combination with methylprednisolone treatment (OVX+MP, n=24). Two implants were then placed in the tibia of each OVX + MP group rabbit, one in each side (left: TAV; right: TNZS). The OVX + MP group rabbits were sacrificed at 4 and 12 weeks after the implantation. The osteoporotic bone responses to the TNZS and TAV implants were evaluated by pull-out test, Micro-CT analyses and histological observation. PRINCIPAL FINDINGS: Compared with the TAV group, the TNZS group showed a significant increase (P<0.05) in cell viability and ALP activity, new bone formation and pull-out force. CONCLUSIONS: The novel TNZS implants show good biological performance both in vitro and in vivo, which suggests that the alloys are suitable for biomedical applications, especially in osteoporosis. PMID- 23437049 TI - Morphology-based prediction of osteogenic differentiation potential of human mesenchymal stem cells. AB - Human bone marrow mesenchymal stem cells (hBMSCs) are widely used cell source for clinical bone regeneration. Achieving the greatest therapeutic effect is dependent on the osteogenic differentiation potential of the stem cells to be implanted. However, there are still no practical methods to characterize such potential non-invasively or previously. Monitoring cellular morphology is a practical and non-invasive approach for evaluating osteogenic potential. Unfortunately, such image-based approaches had been historically qualitative and requiring experienced interpretation. By combining the non-invasive attributes of microscopy with the latest technology allowing higher throughput and quantitative imaging metrics, we studied the applicability of morphometric features to quantitatively predict cellular osteogenic potential. We applied computational machine learning, combining cell morphology features with their corresponding biochemical osteogenic assay results, to develop prediction model of osteogenic differentiation. Using a dataset of 9,990 images automatically acquired by BioStation CT during osteogenic differentiation culture of hBMSCs, 666 morphometric features were extracted as parameters. Two commonly used osteogenic markers, alkaline phosphatase (ALP) activity and calcium deposition were measured experimentally, and used as the true biological differentiation status to validate the prediction accuracy. Using time-course morphological features throughout differentiation culture, the prediction results highly correlated with the experimentally defined differentiation marker values (R>0.89 for both marker predictions). The clinical applicability of our morphology-based prediction was further examined with two scenarios: one using only historical cell images and the other using both historical images together with the patient's own cell images to predict a new patient's cellular potential. The prediction accuracy was found to be greatly enhanced by incorporation of patients' own cell features in the modeling, indicating the practical strategy for clinical usage. Consequently, our results provide strong evidence for the feasibility of using a quantitative time series of phase-contrast cellular morphology for non-invasive cell quality prediction in regenerative medicine. PMID- 23437050 TI - Role of an iron-dependent transcriptional regulator in the pathogenesis and host response to infection with Streptococcus pneumoniae. AB - Iron is a critical cofactor for many enzymes and is known to regulate gene expression in many bacterial pathogens. Streptococcus pneumoniae normally inhabits the upper respiratory mucosa but can also invade and replicate in lungs and blood. These anatomic sites vary considerably in both the quantity and form of available iron. The genome of serotype 4 pneumococcal strain TIGR4 encodes a putative iron-dependent transcriptional regulator (IDTR). A mutant deleted at idtr (Deltaidtr) exhibited growth kinetics similar to parent strain TIGR4 in vitro and in mouse blood for up to 48 hours following infection. However, Deltaidtr was significantly attenuated in a murine model of sepsis. IDTR down regulates the expression of ten characterized and putative virulence genes in nasopharyngeal colonization and pneumonia. The host cytokine response was significantly suppressed in sepsis with Deltaidtr. Since an exaggerated inflammatory response is associated with a poor prognosis in sepsis, the decreased inflammatory response could explain the increased survival with Deltaidtr. Our results suggest that IDTR, which is dispensable for pneumococcal growth in vitro, is associated with regulation of pneumococcal virulence in specific host environments. Additionally, IDTR ultimately modulates the host cytokine response and systemic inflammation that contributes to morbidity and mortality of invasive pneumococcal disease. PMID- 23437051 TI - The contribution of SAA1 polymorphisms to Familial Mediterranean fever susceptibility in the Japanese population. AB - BACKGROUND/AIMS: Familial Mediterranean Fever (FMF) has traditionally been considered to be an autosomal-recessive disease, however, it has been observed that substantial numbers of patients with FMF possess only 1 demonstrable MEFV mutation. The clinical profile of familial Mediterranean fever (FMF) may be influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. METHODOLOGY/PRINCIPAL FINDINGS: In view of the inflammatory nature of FMF, we investigated whether serum amyloid A (SAA) and interleukin-1 beta (IL 1beta) gene polymorphisms may affect the susceptibility of Japanese patients with FMF. The genotypes of the -13C/T SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 83 Japanese patients with FMF and 200 healthy controls. The same samples were genotyped for IL-1beta-511 (C/T) and IL-1 receptor antagonist (IL 1Ra) variable number of tandem repeat (VNTR) polymorphisms. There were no significant differences between FMF patients and healthy subjects in the genotypic distribution of IL-1beta -511 (C/T), IL-1Ra VNTR and SAA2 polymorphisms. The frequencies of SAA1.1 allele were significantly lower (21.7% versus 34.0%), and inversely the frequencies of SAA1.3 allele were higher (48.8% versus 37.5%) in FMF patients compared with healthy subjects. The frequency of 13T alleles, associated with the SAA1.3 allele in the Japanese population, was significantly higher (56.0% versus 41.0%, p=0.001) in FMF patients compared with healthy subjects. CONCLUSIONS/SIGNIFICANCE: Our data indicate that SAA1 gene polymorphisms, consisting of -13T/C SNP in the 5'-flanking region and SNPs within exon 3 (2995C/T and 3010C/T polymorphisms) of SAA1 gene, are associated with susceptibility to FMF in the Japanese population. PMID- 23437052 TI - A novel staining protocol for multiparameter assessment of cell heterogeneity in Phormidium populations (cyanobacteria) employing fluorescent dyes. AB - Bacterial populations display high heterogeneity in viability and physiological activity at the single-cell level, especially under stressful conditions. We demonstrate a novel staining protocol for multiparameter assessment of individual cells in physiologically heterogeneous populations of cyanobacteria. The protocol employs fluorescent probes, i.e., redox dye 5-cyano-2,3-ditolyl tetrazolium chloride, 'dead cell' nucleic acid stain SYTOX Green, and DNA-specific fluorochrome 4',6-diamidino-2-phenylindole, combined with microscopy image analysis. Our method allows simultaneous estimates of cellular respiration activity, membrane and nucleoid integrity, and allows the detection of photosynthetic pigments fluorescence along with morphological observations. The staining protocol has been adjusted for, both, laboratory and natural populations of the genus Phormidium (Oscillatoriales), and tested on 4 field-collected samples and 12 laboratory strains of cyanobacteria. Based on the mentioned cellular functions we suggest classification of cells in cyanobacterial populations into four categories: (i) active and intact; (ii) injured but active; (iii) metabolically inactive but intact; (iv) inactive and injured, or dead. PMID- 23437053 TI - The 677C>T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies. AB - BACKGROUND: The 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene is considered to have a significant effect on colorectal cancer susceptibility, but the results are inconsistent. In order to investigate the association between the MTHFR 677C>T polymorphism and the risk of colorectal cancer, a meta-analysis was held based on 71 published studies. METHODS: Eligible studies were identified through searching the MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM) and CNKI database. Odds ratios (OR) and 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with x(2) based Q-test. Begg's and Egger's test were also carried out to evaluate publication bias. Sensitive and subgroup analysis were also held in this meta analysis. RESULTS: Overall, 71 publications including 31,572 cases and 44,066 controls were identified. The MTHFR 677 C>T variant genotypes are significantly associated with increased risk of colorectal cancer. In the stratified analysis by ethnicity, significantly increased risks were also found among Caucasians for CC vs TT (OR=1.076; 95%CI= 1.008-1.150; I(2) =52.3%), CT vs TT (OR=1.102; 95%CI=1.032-1.177; I(2) =51.4%) and dominant model (OR=1.086; 95%CI=1.021-1.156; I(2) =53.6%). Asians for CC vs TT (OR =1.226; 95%CI =1.116-1.346; I(2) =55.3%), CT vs TT (OR =1.180; 95%CI =1.079-1.291; I(2) =36.2%), recessive (OR =1.069; 95%CI =1.003-1.140; I(2) =30.9%) and dominant model (OR =1.198; 95%CI =1.101-1.303; I(2) =52.4%), and Mixed populations for CT vs TT (OR =1.142; 95%CI =1.005-1.296; I(2) =0.0%). However, no associations were found in Africans for all genetic models. CONCLUSION: This meta-analysis suggests that the MTHFR 677C>T polymorphism increases the risk for developing colorectal cancer, while there is no association among Africans found in subgroup analysis by ethnicity. PMID- 23437054 TI - Critical song features for auditory pattern recognition in crickets. AB - Many different invertebrate and vertebrate species use acoustic communication for pair formation. In the cricket Gryllus bimaculatus, females recognize their species-specific calling song and localize singing males by positive phonotaxis. The song pattern of males has a clear structure consisting of brief and regular pulses that are grouped into repetitive chirps. Information is thus present on a short and a long time scale. Here, we ask which structural features of the song critically determine the phonotactic performance. To this end we employed artificial neural networks to analyze a large body of behavioral data that measured females' phonotactic behavior under systematic variation of artificially generated song patterns. In a first step we used four non-redundant descriptive temporal features to predict the female response. The model prediction showed a high correlation with the experimental results. We used this behavioral model to explore the integration of the two different time scales. Our result suggested that only an attractive pulse structure in combination with an attractive chirp structure reliably induced phonotactic behavior to signals. In a further step we investigated all feature sets, each one consisting of a different combination of eight proposed temporal features. We identified feature sets of size two, three, and four that achieve highest prediction power by using the pulse period from the short time scale plus additional information from the long time scale. PMID- 23437056 TI - Nanostructured 3D constructs based on chitosan and chondroitin sulphate multilayers for cartilage tissue engineering. AB - Nanostructured three-dimensional constructs combining layer-by-layer technology (LbL) and template leaching were processed and evaluated as possible support structures for cartilage tissue engineering. Multilayered constructs were formed by depositing the polyelectrolytes chitosan (CHT) and chondroitin sulphate (CS) on either bidimensional glass surfaces or 3D packet of paraffin spheres. 2D CHT/CS multi-layered constructs proved to support the attachment and proliferation of bovine chondrocytes (BCH). The technology was transposed to 3D level and CHT/CS multi-layered hierarchical scaffolds were retrieved after paraffin leaching. The obtained nanostructured 3D constructs had a high porosity and water uptake capacity of about 300%. Dynamical mechanical analysis (DMA) showed the viscoelastic nature of the scaffolds. Cellular tests were performed with the culture of BCH and multipotent bone marrow derived stromal cells (hMSCs) up to 21 days in chondrogenic differentiation media. Together with scanning electronic microscopy analysis, viability tests and DNA quantification, our results clearly showed that cells attached, proliferated and were metabolically active over the entire scaffold. Cartilaginous extracellular matrix (ECM) formation was further assessed and results showed that GAG secretion occurred indicating the maintenance of the chondrogenic phenotype and the chondrogenic differentiation of hMSCs. PMID- 23437055 TI - Randomized Phase I: Safety, Immunogenicity and Mucosal Antiviral Activity in Young Healthy Women Vaccinated with HIV-1 Gp41 P1 Peptide on Virosomes. AB - Mucosal antibodies harboring various antiviral activities may best protect mucosal surfaces against early HIV-1 entry at mucosal sites and they should be ideally induced by prophylactic HIV-1 vaccines for optimal prevention of sexually transmitted HIV-1. A phase I, double-blind, randomized, placebo-controlled trial was conducted in twenty-four healthy HIV-uninfected young women. The study objectives were to assess the safety, tolerability and immunogenicity of virosomes harboring surface HIV-1 gp41-derived P1 lipidated peptides (MYM-V101). Participants received placebo or MYM-V101 vaccine at 10 MUg/dose or 50 MUg/dose intramuscularly at week 0 and 8, and intranasally at week 16 and 24. MYM-V101 was safe and well-tolerated at both doses administered by the intramuscular and intranasal routes, with the majority of subjects remaining free of local and general symptoms. P1-specific serum IgGs and IgAs were induced in all high dose recipients after the first injection. After the last vaccination, vaginal and rectal P1-specific IgGs could be detected in all high dose recipients. Approximately 63% and 43% of the low and high dose recipients were respectively tested positive for vaginal P1-IgAs, while 29% of the subjects from the high dose group tested positive for rectal IgAs. Serum samples had total specific IgG and IgA antibody concentrations >= 0.4 MUg/mL, while mucosal samples were usually below 0.01 MUg/mL. Vaginal secretions from MYM-V101 vaccinated subjects were inhibiting HIV-1 transcytosis but had no detectable neutralizing activity. P1 specific Th1 responses could not be detected on PBMC. This study demonstrates the excellent safety and tolerability of MYM-V101, eliciting systemic and mucosal antibodies in the majority of subjects. Vaccine-induced mucosal anti-gp41 antibodies toward conserved gp41 motifs were harboring HIV-1 transcytosis inhibition activity and may contribute to reduce sexually-transmitted HIV-1. TRIAL REGISTRATION: ClinicalTrials.gov NCT01084343. PMID- 23437057 TI - Low SP1 expression differentially affects intestinal-type compared with diffuse type gastric adenocarcinoma. AB - Specificity protein 1 (SP1) is an essential transcription factor that regulates multiple cancer-related genes. Because aberrant expression of SP1 is related to cancer development and progression, we focused on SP1 expression in gastric carcinoma and its correlation with disease outcomes. Although patient survival decreased as SP1 expression increased (P<0.05) in diffuse-type gastric cancer, the lack of SP1 expression in intestinal-type gastric cancer was significantly correlated with poor survival (P<0.05). The knockdown of SP1 in a high SP1 expressing intestinal-type gastric cell line, MKN28, increased migration and invasion but decreased proliferation. Microarray data in SP1 siRNA-transfected MKN28 revealed that the genes inhibiting migration were downregulated, whereas the genes negatively facilitating proliferation were increased. However, both migration and invasion were decreased by forced SP1 expression in a low SP1 expressing intestinal-type gastric cell line, AGS. Unlike the intestinal-type, in a high SP1-expressing diffuse-type gastric cell line, SNU484, migration and invasion were decreased by SP1 siRNA. In contrast to previous studies that did not identify differences between the 2 histological types, our results reveal that low expression of SP1 is involved in cancer progression and metastasis and differentially affects intestinal-type compared with diffuse-type gastric adenocarcinoma. PMID- 23437058 TI - Effect of natural and ARV-induced viral suppression and viral breakthrough on anti-HIV antibody proportion and avidity in patients with HIV-1 subtype B infection. AB - BACKGROUND: Viral suppression and viral breakthrough impact the humoral immune response to HIV infection. We evaluated the impact of viral suppression and viral breakthrough on results obtained with two cross-sectional HIV incidence assays. METHODS: All samples were collected from adults in the US who were HIV infected for >2 years. Samples were tested with the BED capture enzyme immunoassay (BED CEIA) which measures the proportion of IgG that is HIV-specific, and with an antibody avidity assay based on the Genetic Systems 1/2+ O ELISA. We tested 281 samples: (1) 30 samples from 18 patients with natural control of HIV-1 infection known as elite controllers or suppressors (2) 72 samples from 18 adults on antiretroviral therapy (ART), with 1 sample before and 2-6 samples after ART initiation, and (3) 179 samples from 20 virally-suppressed adults who had evidence of viral breakthrough receiving ART (>400 copies/ml HIV RNA) and with subsequent viral suppression. RESULTS: For elite suppressors, 10/18 had BED-CEIA values <0.8 normalized optical density units (OD-n) and these values did not change significantly over time. For patients receiving ART, 14/18 had BED-CEIA values that decreased over time, with a median decrease of 0.42 OD-n (range 0.10 to 0.63)/time point receiving ART. Three patterns of BED-CEIA values were observed during viral breakthrough: (1) values that increased then returned to pre-breakthrough values when viral suppression was re-established, (2) values that increased after viral breakthrough, and (3) values that did not change with viral breakthrough. CONCLUSIONS: Viral suppression and viral breakthrough were associated with changes in BED-CEIA values, reflecting changes in the proportion of HIV-specific IgG. These changes can result in misclassification of patients with long-term HIV infection as recently infected using the BED-CEIA, thereby influencing a falsely high value for cross-sectional incidence estimates. PMID- 23437059 TI - Measles outbreak in South Africa: epidemiology of laboratory-confirmed measles cases and assessment of intervention, 2009-2011. AB - BACKGROUND: Since 1995, measles vaccination at nine and 18 months has been routine in South Africa; however, coverage seldom reached >95%. We describe the epidemiology of laboratory-confirmed measles case-patients and assess the impact of the nationwide mass vaccination campaign during the 2009 to 2011 measles outbreak in South Africa. METHODS: Serum specimens collected from patients with suspected-measles were tested for measles-specific IgM antibodies using an enzyme linked immunosorbent assay and genotypes of a subset were determined. To estimate the impact of the nationwide mass vaccination campaign, we compared incidence in the seven months pre- (1 September 2009-11 April 2010) and seven months post vaccination campaign (24 May 2010-31 December 2010) periods in seven provinces of South Africa. RESULTS: A total of 18,431 laboratory-confirmed measles case patients were reported from all nine provinces of South Africa (cumulative incidence 37 per 100,000 population). The highest cumulative incidence per 100,000 population was in children aged <1 year (603), distributed as follows: <6 months (302/100,000), 6 to 8 months (1083/100,000) and 9 to 11 months (724/100,000). Forty eight percent of case-patients were >= 5 years (cumulative incidence 54/100,000). Cumulative incidence decreased with increasing age to 2/100,000 in persons >= 40 years. A single strain of measles virus (genotype B3) circulated throughout the outbreak. Prior to the vaccination campaign, cumulative incidence in the targeted vs. non-targeted age group was 5.9-fold higher, decreasing to 1.7 fold following the campaign (P<0.001) and an estimated 1,380 laboratory-confirmed measles case-patients were prevented. CONCLUSION: We observed a reduction in measles incidence following the nationwide mass vaccination campaign even though it was conducted approximately one year after the outbreak started. A booster dose at school entry may be of value given the high incidence in persons >5 years. PMID- 23437060 TI - Intravenous glial growth factor 2 (GGF2) isoform of neuregulin-1beta improves left ventricular function, gene and protein expression in rats after myocardial infarction. AB - AIMS: Recombinant Neuregulin (NRG)-1beta has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1beta on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1beta isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. METHODS AND RESULTS: Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. CONCLUSIONS: This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans. PMID- 23437061 TI - Cytokine and antibody responses to Plasmodium falciparum in naive individuals during a first malaria episode: effect of age and malaria exposure. AB - Age- and exposure-dependent immune responses during a malaria episode may be key to understanding the role of these factors in the acquisition of immunity to malaria. Plasma/serum samples collected from naive Mozambican children (n=48), European adults (naive travelers, n=22; expatriates with few prior malaria exposures, n=15) and Mozambican adults with long-life malaria exposure (n=99) during and after a malaria episode were analyzed for IgG against merozoite proteins by Luminex and against infected erythrocytes by flow cytometry. Cytokines and chemokines were analyzed in plasmas/sera by suspension array technology. No differences were detected between children and adults with a primary infection, with the exception of higher IgG levels against 3D7 MSP-1(42) (P=0.030) and a P. falciparum isolate (P=0.002), as well as higher IL-12 (P=0.020) in children compared to other groups. Compared to malaria-exposed adults, children, travelers and expatriates had higher concentrations of IFN gamma (P <= 0.0090), IL-2 (P <= 0.0379) and IL-8 (P <= 0.0233). Children also had higher IL-12 (P=0.0001), IL-4 (P=0.003), IL-1beta (P=0.024) and TNF (P=0.006) levels compared to malaria-exposed adults. Although IL-12 was elevated in children, overall the data do not support a role of age in immune responses to a first malaria episode. A T(H)1/pro-inflammatory response was the hallmark of non immune subjects. PMID- 23437062 TI - Elucidating the landscape of aberrant DNA methylation in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC. METHODS AND FINDINGS: We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p=1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list. CONCLUSION: Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis. PMID- 23437063 TI - Monocyte activation in HIV/HCV coinfection correlates with cognitive impairment. AB - Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects' GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates. PMID- 23437064 TI - Computational analysis of KRAS mutations: implications for different effects on the KRAS p.G12D and p.G13D mutations. AB - BACKGROUND: The issue of whether patients diagnosed with metastatic colorectal cancer who harbor KRAS codon 13 mutations could benefit from the addition of anti epidermal growth factor receptor therapy remains under debate. The aim of the current study was to perform computational analysis to investigate the structural implications of the underlying mutations caused by c.38G>A (p.G13D) on protein conformation. METHODS: Molecular dynamics (MD) simulations were performed to understand the plausible structural and dynamical implications caused by c.35G>A (p.G12D) and c.38G>A (p.G13D). The potential of mean force (PMF) simulations were carried out to determine the free energy profiles of the binding processes of GTP interacting with wild-type (WT) KRAS and its mutants (MT). RESULTS: Using MD simulations, we observed that the root mean square deviation (RMSD) increased as a function of time for the MT c.35G>A (p.G12D) and MT c.38G>A (p.G13D) when compared with the WT. We also observed that the GTP-binding pocket in the c.35G>A (p.G12D) mutant is more open than that of the WT and the c.38G>A (p.G13D) proteins. Intriguingly, the analysis of atomic fluctuations and free energy profiles revealed that the mutation of c.35G>A (p.G12D) may induce additional fluctuations in the sensitive sites (P-loop, switch I and II regions). Such fluctuations may promote instability in these protein regions and hamper GTP binding. CONCLUSIONS: Taken together with the results obtained from MD and PMF simulations, the present findings implicate fluctuations at the sensitive sites (P-loop, switch I and II regions). Our findings revealed that KRAS mutations in codon 13 have similar behavior as KRAS WT. To gain a better insight into why patients with metastatic colorectal cancer (mCRC) and the KRAS c.38G>A (p.G13D) mutation appear to benefit from anti-EGFR therapy, the role of the KRAS c.38G>A (p.G13D) mutation in mCRC needs to be further investigated. PMID- 23437065 TI - Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. AB - BACKGROUND: Bmi1 is an integral component of the Polycomb Repressive Complex 1 (PRC1) and is involved in the pathogenesis of multiple cancers. It also plays a key role in the functioning of endogenous stem cells and cancer stem cells. Previous work implicated a role for cancer stem cells in the pathogenesis of pancreatic cancer. We hypothesized that Bmi1 plays an integral role in enhancing pancreatic tumorigenicity and the function of cancer stem cells in pancreatic ductal adenocarcinoma. METHODS: We measured endogenous Bmi1 levels in primary human pancreatic ductal adenocarcinomas, pancreatic intraepithelial neoplasias (PanINs) and normal pancreas by immunohistochemistry and Western blotting. The function of Bmi1 in pancreatic cancer was assessed by alteration of Bmi1 expression in several cell model systems by measuring cell proliferation, cell apoptosis, in vitro invasion, chemotherapy resistance, and in vivo growth and metastasis in an orthotopic model of pancreatic cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human pancreatic cancer xenografts after Bmi1 silencing. RESULTS: Bmi1 was overexpressed in human PanINs, pancreatic cancers, and in several pancreatic cancer cell lines. Overexpression of Bmi1 in MiaPaCa2 cells resulted in increased proliferation, in vitro invasion, larger in vivo tumors, more metastases, and gemcitabine resistance while opposite results were seen when Bmi1 was silenced in Panc-1 cells. Bmi1 was overexpressed in the cancer stem cell compartment of primary human pancreatic cancer xenografts. Pancreatic tumorspheres also demonstrated high levels of Bmi1. Silencing of Bmi1 inhibited secondary and tertiary tumorsphere formation, decreased primary pancreatic xenograft growth, and lowered the proportion of cancer stem cells in the xenograft tissue. CONCLUSIONS: Our results implicate Bmi1 in the invasiveness and growth of pancreatic cancer and demonstrate its key role in the regulation of pancreatic cancer stem cells. PMID- 23437066 TI - Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kappaB and STAT3 in transient focal stroke. AB - BACKGROUND: Ischemic brain injury is associated with neuroinflammatory response, which essentially involves glial activation and neutrophil infiltration. Transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) contribute to ischemic neuroinflammatory processes and secondary brain injury by releasing proinflammatory mediators. Kaempferol-3-O-rutinoside (KRS) and kaempferol-3-O- glucoside (KGS) are primary flavonoids found in Carthamus tinctorius L. Recent studies demonstrated that KRS protected against ischemic brain injury. However, little is known about the underlying mechanisms. Flavonoids have been reported to have antiinflammatory properties. Herein, we explored the effects of KRS and KGS in a transient focal stroke model. METHODOLOGY/PRINCIPAL FINDINGS: Rats were subjected to middle cerebral artery occlusion for 2 hours followed by 22 h reperfusion. An equimolar dose of KRS or KGS was administered i.v. at the beginning of reperfusion. The results showed that KRS or KGS significantly attenuated the neurological deficits, brain infarct volume, and neuron and axon injury, reflected by the upregulation of neuronal nuclear antigen-positive neurons and downregulation of amyloid precursor protein immunoreactivity in the ipsilateral ischemic hemisphere. Moreover, KRS and KGS inhibited the expression of OX-42, glial fibrillary acidic protein, phosphorylated STAT3 and NF-kappaB p65, and the nuclear content of NF-kappaB p65. Subsequently, these flavonoids inhibited the expression of tumor necrosis factor alpha, interleukin 1beta, intercellular adhesion molecule 1, matrix metallopeptidase 9, inducible nitric oxide synthase, and myeloperoxidase. CONCLUSION/SIGNIFICANCE: Our findings suggest that postischemic treatment with KRS or KGS prevents ischemic brain injury and neuroinflammation by inhibition of STAT3 and NF-kappaB activation and has the therapeutic potential for the neuroinflammation-related diseases, such as ischemic stroke. PMID- 23437067 TI - Physical skill training increases the number of surviving new cells in the adult hippocampus. AB - The dentate gyrus is a major site of plasticity in the adult brain, giving rise to thousands of new neurons every day, through the process of adult neurogenesis. Although the majority of these cells die within two weeks of their birth, they can be rescued from death by various forms of learning. Successful acquisition of select types of associative and spatial memories increases the number of these cells that survive. Here, we investigated the possibility that an entirely different form of learning, physical skill learning, could rescue new hippocampal cells from death. To test this possibility, rats were trained with a physically demanding and technically-difficult version of a rotarod procedure. Acquisition of the physical skill greatly increased the number of new hippocampal cells that survived. The number of surviving cells positively correlated with performance on the task. Only animals that successfully mastered the task retained the cells that would have otherwise died. Animals that failed to learn, and those that did not learn well did not retain any more cells than those that were untrained. Importantly, acute voluntary exercise in activity wheels did not increase the number of surviving cells. These data suggest that acquisition of a physical skill can increase the number of surviving hippocampal cells. Moreover, learning an easier version of the task did not increase cell survival. These results are consistent with previous reports revealing that learning only rescues new neurons from death when acquisition is sufficiently difficult to achieve. Finally, complete hippocampal lesions did not disrupt acquisition of this physical skill. Therefore, physical skill training that does not depend on the hippocampus can effectively increase the number of surviving cells in the adult hippocampus, the vast majority of which become mature neurons. PMID- 23437068 TI - Fast skeletal muscle troponin activation increases force of mouse fast skeletal muscle and ameliorates weakness due to nebulin-deficiency. AB - The effect of the fast skeletal muscle troponin activator, CK-2066260, on calcium induced force development was studied in skinned fast skeletal muscle fibers from wildtype (WT) and nebulin deficient (NEB KO) mice. Nebulin is a sarcomeric protein that when absent (NEB KO mouse) or present at low levels (nemaline myopathy (NM) patients with NEB mutations) causes muscle weakness. We studied the effect of fast skeletal troponin activation on WT muscle and tested whether it might be a therapeutic mechanism to increase muscle strength in nebulin deficient muscle. We measured tension-pCa relations with and without added CK-2066260. Maximal active tension in NEB KO tibialis cranialis fibers in the absence of CK 2066260 was ~60% less than in WT fibers, consistent with earlier work. CK-2066260 shifted the tension-calcium relationship leftwards, with the largest relative increase (up to 8-fold) at low to intermediate calcium levels. This was a general effect that was present in both WT and NEB KO fiber bundles. At pCa levels above ~6.0 (i.e., calcium concentrations <1 uM), CK-2066260 increased tension of NEB KO fibers to beyond that of WT fibers. Crossbridge cycling kinetics were studied by measuring k(tr) (rate constant of force redevelopment following a rapid shortening/restretch). CK-2066260 greatly increased k(tr) at submaximal activation levels in both WT and NEB KO fiber bundles. We also studied the sarcomere length (SL) dependence of the CK-2066260 effect (SL 2.1 um and 2.6 um) and found that in the NEB KO fibers, CK-2066260 had a larger effect on calcium sensitivity at the long SL. We conclude that fast skeletal muscle troponin activation increases force at submaximal activation in both wildtype and NEB KO fiber bundles and, importantly, that this troponin activation is a potential therapeutic mechanism for increasing force in NM and other skeletal muscle diseases with loss of muscle strength. PMID- 23437069 TI - Learning by heart: cultural patterns in the faunal processing sequence during the middle pleistocene. AB - Social learning, as an information acquisition process, enables intergenerational transmission and the stabilisation of cultural forms, generating and sustaining behavioural traditions within human groups. Archaeologically, such social processes might become observable by identifying repetitions in the record that result from the execution of standardised actions. From a zooarchaeological perspective, the processing and consumption of carcasses may be used to identify these types of phenomena at the sites. To investigate this idea, several faunal assemblages from Bolomor Cave (Valencia, Spain, MIS 9-5e) and Gran Dolina TD10-1 (Burgos, Spain, MIS 9) were analysed. The data show that some butchery activities exhibit variability as a result of multiple conditioning factors and, therefore, the identification of cultural patterns through the resulting cut-marks presents additional difficulties. However, other activities, such as marrow removal by means of intentional breakage, seem to reflect standardised actions unrelated to the physical characteristics of the bones. The statistical tests we applied show no correlation between the less dense areas of the bones and the location of impacts. Comparison of our experimental series with the archaeological samples indicates a counter-intuitive selection of the preferred locus of impact, especially marked in the case of Bolomor IV. This fact supports the view that bone breakage was executed counter-intuitively and repetitively on specific sections because it may have been part of an acquired behavioural repertoire. These reiterations differ between levels and sites, suggesting the possible existence of cultural identities or behavioural predispositions dependant on groups. On this basis, the study of patterns could significantly contribute to the identification of occupational strategies and organisation of the hominids in a territory. In this study, we use faunal data in identifying the mechanics of intergenerational information transmission within Middle Pleistocene human communities and provide new ideas for the investigation of occupational dynamics from a zooarchaeological approach. PMID- 23437070 TI - Kinetics of IL-7 and IL-15 levels after allogeneic peripheral blood stem cell transplantation following nonmyeloablative conditioning. AB - BACKGROUND: We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning. METHODS: EDTA anticoagulated plasma and serum samples were obtained before conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at -80 degrees C within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs. RESULTS: Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P=0.002), 14 (5.2 pg/mL, P<0.001), and 28 (5.1 pg/mL, P=0.03) (but not thereafter) than before transplantation (median value of 3.8 pg/mL). Median IL-15 serum levels were significantly higher on days 7 (12.5 pg/mL, P<0.001), 14 (10.5 pg/mL, P<0.001), and 28 (6.2 pg/mL, P<0.001) than before transplantation (median value of 2.4 pg/mL). Importantly, IL-7 and IL-15 levels on days 7 or 14 after transplantation did not predict grade II-IV acute GVHD. CONCLUSIONS: These data suggest that IL-7 and IL-15 levels remain relatively low after nonmyeloablative transplantation, and that IL-7 and IL-15 levels early after nonmyeloablative transplantation do not predict for acute GVHD. PMID- 23437071 TI - Human alpha4beta2 nicotinic acetylcholine receptor as a novel target of oligomeric alpha-synuclein. AB - Cigarette smoking is associated with a decreased incidence of Parkinson disease (PD) through unknown mechanisms. Interestingly, a decrease in the numbers of alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) in PD patients suggests an alpha4beta2-nAChR-mediated cholinergic deficit in PD. Although oligomeric forms of alpha-synuclein have been recognized to be toxic and involved in the pathogenesis of PD, their direct effects on nAChR-mediated cholinergic signaling remains undefined. Here, we report for the first time that oligomeric alpha-synuclein selectively inhibits human alpha4beta2-nAChR-mediated currents in a dose-dependent, non-competitive and use-independent manner. We show that pre loading cells with guanyl-5'-yl thiophosphate fails to prevent this inhibition, suggesting that the alpha-synuclein-induced inhibition of alpha4beta2-nAChR function is not mediated by nAChR internalization. By using a pharmacological approach and cultures expressing transfected human nAChRs, we have shown a clear effect of oligomeric alpha-synuclein on alpha4beta2-nAChRs, but not on alpha4beta4- or alpha7-nAChRs, suggesting nAChR subunit selectivity of oligomeric alpha-synuclein-induced inhibition. In addition, by combining the size exclusion chromatography and atomic force microscopy (AFM) analyses, we find that only large (>4 nm) oligomeric alpha-synuclein aggregates (but not monomeric, small oligomeric or fibrillar alpha-synuclein aggregates) exhibit the inhibitory effect on human alpha4beta2-nAChRs. Collectively, we have provided direct evidence that alpha4beta2-nAChR is a sensitive target to mediate oligomeric alpha-synuclein induced modulation of cholinergic signaling, and our data imply that therapeutic strategies targeted toward alpha4beta2-nAChRs may have potential for developing new treatments for PD. PMID- 23437072 TI - Longitudinal change of HBsAg in HBeAg-negative patients with genotype B or C infection. AB - BACKGROUND & AIMS: Quantitative HBsAg has been recognized to assist in the management of chronic hepatitis B virus (HBV) infection. However, its role in disease monitoring of HBeAg-negative patients remains unclear. We aimed to investigate the longitudinal HBsAg change in HBeAg-negative carriers with HBV genotype B or C infection. METHODS: This is a retrospective cohort study conducted in a university hospital. Treatment-naive HBeAg-negative carriers followed for more than 3 years were recruited. Their hepatitis activities were categorized by longitudinal HBV-DNA levels into high viral-load (HVL: HBV-DNA >/ =2000 IU/mL persistently), low viral-load (LVL: HBV-DNA <2000 IU/mL persistently) and fluctuated viral-load (FVL: HBV-DNA between HVL and LVL). The baseline and end-of-follow-up (EOF) HBsAg levels were quantified for analyses. RESULTS: We recruited 187 patients with a median follow-up of 8 years. LVL patients had a significantly lower HBsAg at baseline and EOF and a significantly greater annualized HBsAg decline compared with the FVL and HVL. The longitudinal HBsAg change was independent of genotype B or C. The lower baseline HBsAg level predicted the HBsAg decline and HBsAg loss, whereas the higher baseline HBV-DNA predicted the hepatitis flare. A baseline HBsAg <50 IU/mL predicted subsequent HBsAg loss with a sensitivity of 82% and specificity of 67%. The annualized HBsAg decline appeared non-linear, and accelerated as the HBsAg level lowered (0.054, 0.091, 0.126 log(10) IU/mL in patients with baseline HBsAg >1000, 100-999, <100 IU/mL, respectively, P for trend= .014). CONCLUSIONS: In genotype B or C HBeAg negative carriers, baseline HBsAg levels correlate with future disease activities and help to predict HBsAg decline or loss. Inactive carriers with lower baseline HBsAg levels have a greater and accelerating HBsAg decline over time, regardless of HBV genotypes. PMID- 23437073 TI - Controlled synthesis and microwave absorption property of chain-like co flower. AB - Chain-like Co flower is synthesized by simply modulating the reaction conditions via a facile liquid-phase reduction method. The morphology evolution process and transformation mechanism from particle to flower and finally to chain-like flower have been systematically investigated. [001] is the preferred growth orientation due to the existence of easy magnetic axis. The microwave loss mechanism can be attributed to the synergistic effect of magnetic loss and dielectric loss, while magnetic loss is the main loss mechanism. In addition, the special microstructure of chain-like Co flower may further enhance microwave attenuation. The architectural design of functional material morphology is critical for improving its property toward future application. PMID- 23437075 TI - Single residue mutation in active site of serine acetyltransferase isoform 3 from Entamoeba histolytica assists in partial regaining of feedback inhibition by cysteine. AB - The cysteine biosynthetic pathway is essential for survival of the protist pathogen Entamoeba histolytica, and functions by producing cysteine for countering oxidative attack during infection in human hosts. Serine acetyltransferase (SAT) and O-acetylserine sulfhydrylase (OASS) are involved in cysteine biosynthesis and are present in three isoforms each. While EhSAT1 and EhSAT2 are feedback inhibited by end product cysteine, EhSAT3 is nearly insensitive to such inhibition. The active site residues of EhSAT1 and of EhSAT3 are identical except for position 208, which is a histidine residue in EhSAT1 and a serine residue in EhSAT3. A combination of comparative modeling, multiple molecular dynamics simulations and free energy calculation studies showed a difference in binding energies of native EhSAT3 and of a S208H-EhSAT3 mutant for cysteine. Mutants have also been generated in vitro, replacing serine with histidine at position 208 in EhSAT3 and replacing histidine 208 with serine in EhSAT1. These mutants showed decreased affinity for substrate serine, as indicated by K(m), compared to the native enzymes. Inhibition kinetics in the presence of physiological concentrations of serine show that IC50 of EhSAT1 increases by about 18 folds from 9.59 uM for native to 169.88 uM for H208S-EhSAT1 mutant. Similar measurements with EhSAT3 confirm it to be insensitive to cysteine inhibition while its mutant (S208H-EhSAT3) shows a gain of cysteine inhibition by 36% and the IC50 of 3.5 mM. Histidine 208 appears to be one of the important residues that distinguish the serine substrate from the cysteine inhibitor. PMID- 23437074 TI - Transportation of nanoscale cargoes by myosin propelled actin filaments. AB - Myosin II propelled actin filaments move ten times faster than kinesin driven microtubules and are thus attractive candidates as cargo-transporting shuttles in motor driven lab-on-a-chip devices. In addition, actomyosin-based transportation of nanoparticles is useful in various fundamental studies. However, it is poorly understood how actomyosin function is affected by different number of nanoscale cargoes, by cargo size, and by the mode of cargo-attachment to the actin filament. This is studied here using biotin/fluorophores, streptavidin, streptavidin-coated quantum dots, and liposomes as model cargoes attached to monomers along the actin filaments ("side-attached") or to the trailing filament end via the plus end capping protein CapZ. Long-distance transportation (>100 um) could be seen for all cargoes independently of attachment mode but the fraction of motile filaments decreased with increasing number of side-attached cargoes, a reduction that occurred within a range of 10-50 streptavidin molecules, 1-10 quantum dots or with just 1 liposome. However, as observed by monitoring these motile filaments with the attached cargo, the velocity was little affected. This also applied for end-attached cargoes where the attachment was mediated by CapZ. The results with side-attached cargoes argue against certain models for chemomechanical energy transduction in actomyosin and give important insights of relevance for effective exploitation of actomyosin-based cargo-transportation in molecular diagnostics and other nanotechnological applications. The attachment of quantum dots via CapZ, without appreciable modulation of actomyosin function, is useful in fundamental studies as exemplified here by tracking with nanometer accuracy. PMID- 23437076 TI - The social and ecological integration of captive-raised adolescent male African elephants (Loxodonta africana) into a wild population. AB - BACKGROUND: A rapid rise in the number of captive African elephants (Loxodonta africana) used in the tourism industry in southern Africa and orphaned elephants in human care has led to concerns about their long-term management, particularly males. One solution is to release them into the wild at adolescence, when young males naturally leave their herd. However, this raises significant welfare concerns: little is known about how well released elephants integrate into wild populations and whether they pose a greater threat to humans than wild elephants. We document the release of three captive-raised adolescent male African elephants in the Okavango Delta, Botswana. METHODOLOGY/PRINCIPAL FINDINGS: Despite having been part of a herd of working elephants for at least eight years, the three males progressively integrated into the complex fission-fusion society of wild bull elephants. In the three years following release, they showed no tendency to be closer to human habitation, and there were no significant differences between wild and captive-raised adolescent males in the total number of social interactions, size of ranges and habitat use. However, the captive-raised elephants sparred less and vocalised more, and spent more time alone and in smaller social groups. Thereafter the released elephants continued to expand their ranges and interact with both mixed-sex herds and males. One male was shot by farmers 94 months after release, along with ten wild elephants, on a ranch outside the protected area. CONCLUSIONS/SIGNIFICANCE: We show that captive-raised adolescent male elephants can integrate into a wild population. Long-term studies are required to determine the longevity, breeding success, and eventual fate of released male elephants, but we identified no significant short-term welfare problems for the released elephants or recipient population. Release of captive raised mammals with complex social systems is a husbandry option that should be explored further. PMID- 23437077 TI - Handmade cloned transgenic sheep rich in omega-3 Fatty acids. AB - Technology of somatic cell nuclear transfer (SCNT) has been adapted worldwide to generate transgenic animals, although the traditional procedure relies largely on instrumental micromanipulation. In this study, we used the modified handmade cloning (HMC) established in cattle and pig to produce transgenic sheep with elevated levels of omega-3 (n-3) fatty acids. Codon-optimized nematode mfat-1 was inserted into a eukaryotic expression vector and was transferred into the genome of primary ovine fibroblast cells from a male Chinese merino sheep. Reverse transcriptase PCR, gas chromatography, and chromosome analyses were performed to select nuclear donor cells capable of converting omega-6 (n-6) into n-3 fatty acids. Blastocysts developed after 7 days of in vitro culture were surgically transplanted into the uterus of female ovine recipients of a local sheep breed in Xinjiang. For the HMC, approximately 8.9% (n =925) of reconstructed embryos developed to the blastocyst stage. Four recipients became pregnant after 53 blastocysts were transplanted into 29 naturally cycling females, and a total of 3 live transgenic lambs were produced. Detailed analyses on one of the transgenic lambs revealed a single integration of the modified nematode mfat-1 gene at sheep chromosome 5. The transgenic sheep expressed functional n-3 fatty acid desaturase, accompanied by more than 2-folds reduction of n-6/n-3 ratio in the muscle (p<0.01) and other major organs/tissues (p<0.05). To our knowledge, this is the first report of transgenic sheep produced by the HMC. Compared to the traditional SCNT method, HMC showed an equivalent efficiency but proved cheaper and easier in operation. PMID- 23437078 TI - Mitochondrial phylogenomics of modern and ancient equids. AB - The genus Equus is richly represented in the fossil record, yet our understanding of taxonomic relationships within this genus remains limited. To estimate the phylogenetic relationships among modern horses, zebras, asses and donkeys, we generated the first data set including complete mitochondrial sequences from all seven extant lineages within the genus Equus. Bayesian and Maximum Likelihood phylogenetic inference confirms that zebras are monophyletic within the genus, and the Plains and Grevy's zebras form a well-supported monophyletic group. Using ancient DNA techniques, we further characterize the complete mitochondrial genomes of three extinct equid lineages (the New World stilt-legged horses, NWSLH; the subgenus Sussemionus; and the Quagga, Equus quagga quagga). Comparisons with extant taxa confirm the NWSLH as being part of the caballines, and the Quagga and Plains zebras as being conspecific. However, the evolutionary relationships among the non-caballine lineages, including the now-extinct subgenus Sussemionus, remain unresolved, most likely due to extremely rapid radiation within this group. The closest living outgroups (rhinos and tapirs) were found to be too phylogenetically distant to calibrate reliable molecular clocks. Additional mitochondrial genome sequence data, including radiocarbon dated ancient equids, will be required before revisiting the exact timing of the lineage radiation leading up to modern equids, which for now were found to have possibly shared a common ancestor as far as up to 4 Million years ago (Mya). PMID- 23437079 TI - Violence against people with disability in England and Wales: findings from a national cross-sectional survey. AB - BACKGROUND: The recent World Report on Disability highlighted violence as a leading cause of morbidity among disabled people. However, we know little about the extent to which people with disability experience different violence types, and associated health/economic costs. The recent introduction of disability measures into the England&Wales victimization survey provided an opportunity to address this gap. METHODS AND FINDINGS: Analysis of the 2009/10 British Crime Survey (BCS), a nationally representative cross-sectional survey of 44,398 adults living in residential households in England&Wales. Using multivariate logistic regression, we estimated the relative odds of being a victim of past-year violence (physical/sexual domestic or non-domestic violence) in people with disability compared to those without, after adjusting for socio-demographics, behavioural and area confounders. 1256/44398(2.4%) participants had one or more disabilities including mental illness ('mental illness') and 7781(13.9%) had one or more disabilities excluding mental illness ('non-mental disability'). Compared with the non-disabled, those with mental illness had adjusted relative odds (aOR) of 3.0(95% confidence interval (CI) 2.3-3.8) and those with non-mental disability had aOR of 1.8(95% CI: 1.5-2.2) of being a victim of past-year violence (with similar relative odds for domestic and non-domestic violence). Disabled victims were more likely to suffer mental ill health as a result of violence than non disabled victims. The proportion of violence that could be attributed to the independent effect of disability in the general population was 7.5%(CI 5.7-9.3%), at an estimated cost of L1.51 billion. The main study limitation is the exclusion of institutionalised people with disability. CONCLUSIONS: People with disability are at increased risk of being victims of domestic and non-domestic violence, and of suffering mental ill health when victimized. The related public health and economic burden calls for an urgent assessment of the causes of this violence, and national policies on violence prevention in this vulnerable group. PMID- 23437080 TI - Interfamily transfer of dual NB-LRR genes confers resistance to multiple pathogens. AB - A major class of disease resistance (R) genes which encode nucleotide binding and leucine rich repeat (NB-LRR) proteins have been used in traditional breeding programs for crop protection. However, it has been difficult to functionally transfer NB-LRR-type R genes in taxonomically distinct families. Here we demonstrate that a pair of Arabidopsis (Brassicaceae) NB-LRR-type R genes, RPS4 and RRS1, properly function in two other Brassicaceae, Brassica rapa and Brassica napus, but also in two Solanaceae, Nicotiana benthamiana and tomato (Solanum lycopersicum). The solanaceous plants transformed with RPS4/RRS1 confer bacterial effector-specific immunity responses. Furthermore, RPS4 and RRS1, which confer resistance to a fungal pathogen Colletotrichum higginsianum in Brassicaceae, also protect against Colletotrichum orbiculare in cucumber (Cucurbitaceae). Importantly, RPS4/RRS1 transgenic plants show no autoimmune phenotypes, indicating that the NB-LRR proteins are tightly regulated. The successful transfer of two R genes at the family level implies that the downstream components of R genes are highly conserved. The functional interfamily transfer of R genes can be a powerful strategy for providing resistance to a broad range of pathogens. PMID- 23437081 TI - Negatively-marked MCQ assessments that reward partial knowledge do not introduce gender bias yet increase student performance and satisfaction and reduce anxiety. AB - Multiple-choice question (MCQ) examinations are increasingly used as the assessment method of theoretical knowledge in large class-size modules in many life science degrees. MCQ-tests can be used to objectively measure factual knowledge, ability and high-level learning outcomes, but may also introduce gender bias in performance dependent on topic, instruction, scoring and difficulty. The 'Single Answer' (SA) test is often used in which students choose one correct answer, in which they are unable to demonstrate partial knowledge. Negatively marking eliminates the chance element of guessing but may be considered unfair. Elimination testing (ET) is an alternative form of MCQ, which discriminates between all levels of knowledge, while rewarding demonstration of partial knowledge. Comparisons of performance and gender bias in negatively marked SA and ET tests have not yet been performed in the life sciences. Our results show that life science students were significantly advantaged by answering the MCQ test in elimination format compared to single answer format under negative marking conditions by rewarding partial knowledge of topics. Importantly, we found no significant difference in performance between genders in either cohort for either MCQ test under negative marking conditions. Surveys showed that students generally preferred ET-style MCQ testing over SA-style testing. Students reported feeling more relaxed taking ET MCQ and more stressed when sitting SA tests, while disagreeing with being distracted by thinking about best tactics for scoring high. Students agreed ET testing improved their critical thinking skills. We conclude that appropriately-designed MCQ tests do not systematically discriminate between genders. We recommend careful consideration in choosing the type of MCQ test, and propose to apply negative scoring conditions to each test type to avoid the introduction of gender bias. The student experience could be improved through the incorporation of the elimination answering methods in MCQ tests via rewarding partial and full knowledge. PMID- 23437082 TI - Identification and characterization of integron-mediated antibiotic resistance in the phytopathogen Xanthomonas oryzae pv. oryzae. AB - Four streptomycin-resistant isolates of Xanthomonas oryzae pv. oryzae (YNA7-1, YNA10-2, YNA11-2, and YNA12-2) were examined via PCR amplification for the presence of class 1, class 2, and class 3 integrons and aadA1 and aadA2 genes, which confer resistance to streptomycin and spectinomycin. The class 1 integrase gene intI1 and the aminoglycoside adenylyltransferase gene aadA1 were identified in all four resistant isolates but not in 25 sensitive isolates. PCR amplifications showed that 7790-bp, 7162-bp, 7790-bp, and 7240-bp resistance integrons with transposition gene modules (tni module) in 3' conserved segments existed in YNA7-1, YNA10-2, YNA11-2, and YNA12-2, respectively. Subsequent analysis of sequences indicated that the integrons of YNA7-1 and YNA11-2 carried three gene cassettes in the order |aacA3|arr3|aadA1|. The integron of YNA10-2 carried only |arr3|aadA1| gene cassettes. The integron of YNA12-2 lacked a 550-bp sequence including part of intI1 but it still carried |aacA3|arr3|aadA1| gene cassettes. The analysis of inactive mutants and complementation tests confirmed that the aacA3 gene conferred resistance to tobramycin, kanamycin, gentamicin and netilmicin; the arr3 gene conferred resistance to rifampicin; and the aadA1 gene conferred resistance to streptomycin and spectinomycin. The resistance phenotypes of the four isolates corresponded with their resistance gene cassettes, except that YNA7-1 and YNA12-2 did not show rifampicin resistance. Sequence comparison revealed that no gene cassette array in GenBank was in the same order as in the integrons of the four resistant isolates in this study and the aadA1, which was identical in the four resistant isolates, showed 99% identity with aadA1 sequences in GenBank. The result of a stability test showed that the resistance phenotype, the aadA1 gene, and the intI1 gene were completely stable in YNA7-1 and YNA12-2 but unstable in YNA10-2 and YNA11-2. To our knowledge, this is the first report of resistance integron in a phytopathogenic bacteria. PMID- 23437083 TI - Bayesian approach to model CD137 signaling in human M. tuberculosis in vitro responses. AB - Immune responses are qualitatively and quantitatively influenced by a complex network of receptor-ligand interactions. Among them, the CD137:CD137L pathway is known to modulate innate and adaptive human responses against Mycobacterium tuberculosis. However, the underlying mechanisms of this regulation remain unclear. In this work, we developed a Bayesian Computational Model (BCM) of in vitro CD137 signaling, devised to fit previously gathered experimental data. The BCM is fed with the data and the prior distribution of the model parameters and it returns their posterior distribution and the model evidence, which allows comparing alternative signaling mechanisms. The BCM uses a coupled system of non linear differential equations to describe the dynamics of Antigen Presenting Cells, Natural Killer and T Cells together with the interpheron (IFN)-gamma and tumor necrosis factor (TNF)-alpha levels in the media culture. Fast and complete mixing of the media is assumed. The prior distribution of the parameters that describe the dynamics of the immunological response was obtained from the literature and theoretical considerations Our BCM applies successively the Levenberg-Marquardt algorithm to find the maximum a posteriori likelihood (MAP); the Metropolis Markov Chain Monte Carlo method to approximate the posterior distribution of the parameters and Thermodynamic Integration to calculate the evidence of alternative hypothesis. Bayes factors provided decisive evidence favoring direct CD137 signaling on T cells. Moreover, the posterior distribution of the parameters that describe the CD137 signaling showed that the regulation of IFN-gamma levels is based more on T cells survival than on direct induction. Furthermore, the mechanisms that account for the effect of CD137 signaling on TNF alpha production were based on a decrease of TNF-alpha production by APC and, perhaps, on the increase in APC apoptosis. BCM proved to be a useful tool to gain insight on the mechanisms of CD137 signaling during human response against Mycobacterium tuberculosis. PMID- 23437084 TI - Development of a neutralization assay for influenza virus using an endpoint assessment based on quantitative reverse-transcription PCR. AB - A microneutralization assay using an ELISA-based endpoint assessment (ELISA-MN) is widely used to measure the serological response to influenza virus infection and vaccination. We have developed an alternative microneutralization assay for influenza virus using a quantitative reverse transcription PCR-based endpoint assessment (qPCR-MN) in order to improve upon technical limitations associated with ELISA-MN. For qPCR-MN, infected MDCK-London cells in 96-well cell-culture plates are processed with minimal steps such that resulting samples are amenable to high-throughput analysis by downstream one-step quantitative reverse transcription PCR (qRT-PCR; SYBR Green chemistry with primers targeting a conserved region of the M1 gene of influenza A viruses). The growth curves of three recent vaccine strains demonstrated that the qRT-PCR signal detected at 6 hours post-infection reflected an amplification of at least 100-fold over input. Using ferret antisera, we have established the feasibility of measuring virus neutralization at 6 hours post-infection, a duration likely confined to a single virus-replication cycle. The neutralization titer for qPCR-MN was defined as the highest reciprocal serum dilution necessary to achieve a 90% inhibition of the qRT-PCR signal; this endpoint was found to be in agreement with ELISA-MN using the same critical reagents in each assay. qPCR-MN was robust with respect to assay duration (6 hours vs. 12 hours). In addition, qPCR-MN appeared to be compliant with the Percentage Law (i.e., virus neutralization results appear to be consistent over an input virus dose ranging from 500 to 12,000 TCID(50)). Compared with ELISA-MN, qPCR-MN might have inherent properties conducive to reducing intra- and inter-laboratory variability while affording suitability for automation and high-throughput uses. Finally, our qRT-PCR-based approach may be broadly applicable to the development of neutralization assays for a wide variety of viruses. PMID- 23437085 TI - Leishmania major methionine sulfoxide reductase A is required for resistance to oxidative stress and efficient replication in macrophages. AB - Leishmania are protozoan parasites that proliferate within the phagolysome of mammalian macrophages. While a number of anti-oxidant systems in these parasites have been shown to protect against endogenous as well as host-generated reactive oxygen species, the potential role of enzymes involved in the repair of oxidatively damaged proteins remains uncharacterized. The Leishmania spp genomes encode a single putative methionine sulfoxide reductase (MsrA) that could have a role in reducing oxidized free and proteinogenic methionine residues. A GFP fusion of L. major MsrA was shown to have a cytoplasmic localization by immunofluorescence microscopy and subcellular fractionation. An L. major msrA null mutant, generated by targeted replacement of both chromosomal allelles, was viable in rich medium but was unable to reduce exogenous methionine sulfoxide when cultivated in the presence of this amino acid, indicating that msrA encodes a functional MsrA. The DeltamsrA mutant exhibited increased sensitivity to H(2)O(2) compared to wild type parasites and was unable to proliferate normally in macrophages. Wild type sensitivity to H(2)O(2) and infectivity in macrophages was restored by complementation of the mutant with a plasmid encoding MsrA. Unexpectedly, the DeltamsrA mutant was able to induce normal lesions in susceptible BALB/c indicating that this protein is not essential for pathogenesis in vivo. Our results suggest that Leishmania MsrA contributes to the anti oxidative defences of these parasites, but that complementary oxidative defence mechansims are up-regulated in lesion amastigotes. PMID- 23437086 TI - Effects of polymorphisms -1112C/T and +2044A/G in interleukin-13 gene on asthma risk: a meta-analysis. AB - BACKGROUND: Associations between interleukin-13 (IL-13) polymorphisms and asthma risk remained controversial and ambiguous. Therefore, we performed a meta analysis to assess the associations between IL-13 polymorphisms and asthma susceptibility. METHODS: Pubmed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wangfang databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the random-effects model. RESULTS: Thirty-four studies were included in this meta-analysis. The results indicated that IL13 -1112C/T polymorphism was significantly associated with asthma risk (OR=1.20, 95% CI 1.08 1.34, P=0.0009) in a dominant genetic model. When stratifying for race, IL13 1112C/T polymorphism exhibited increased asthma risk in Caucasians (OR=1.30, 95% CI 1.09-1.55, P=0.003), while no significant association was found in Asians and African Americans. In the subgroup analysis based on atopic status, significant association was observed in atopic patients (OR=1.25, 95% CI 1.07-1.45, P=0.004) but not in the non-atopic patients. In addition, a significant association between IL13+2044A/G polymorphism and asthma risk was observed (OR=1.18, 95% CI 1.08-1.28, P=0.0002). In the subgroup analysis by ethnicity, there were significant associations between IL13+2044A/G polymorphism and asthma risk in Asians (OR=1.19, 95% CI 1.04-1.36, P=0.01) and Caucasians (OR=1.22, 95% CI 1.06 1.40, P=0.005) but not in African Americans. In the subgroup analysis stratified by atopic status, a marginal significant association was found in atopic patients (OR=1.12, 95% CI 1.00-1.26, P=0.05). CONCLUSIONS: This meta-analysis suggested that the IL13 -1112C/T and +2044A/G polymorphisms were risk factors for asthma. PMID- 23437087 TI - Overexpression of endoglin modulates TGF-beta1-signalling pathways in a novel immortalized mouse hepatic stellate cell line. AB - Hepatic stellate cells (HSCs) play a major role in the pathogenesis of liver fibrosis. Working on primary HSCs requires difficult isolation procedures; therefore we have generated and here characterize a mouse hepatic stellate cell line expressing GFP under control of the collagen 1(I) promoter/enhancer. These cells are responsive to pro-fibrogenic stimuIi, such as PDGF or TGF-beta1, and are able to activate intracellular signalling pathways including Smads and MAP kinases. Nevertheless, due to the basal level of activation, TGF-beta1 did not significantly induce GFP expression contrasting the TGF-beta1 regulated endogenous collagen I expression. We could demonstrate that the accessory TGF beta-receptor endoglin, which is endogenously expressed at very low levels, has a differential effect on signalling of these cells when transiently overexpressed. In the presence of endoglin activation of Smad1/5/8 was drastically enhanced. Moreover, the phosphorylation of ERK1/2 was increased, and the expression of vimentin, alpha-smooth muscle actin and connective tissue growth factor was upregulated. Endoglin induced a slight increase in expression of the inhibitor of differentiation-2 while the amount of endogenous collagen type I was reduced. Therefore, this profibrogenic cell line with hepatic stellate cell origin is not only a promising novel experimental tool, which can be used in vivo for cell tracing experiments. Furthermore it allows investigating the impact of various regulatory proteins (e.g. endoglin) on profibrogenic signal transduction, differentiation and hepatic stellate cell biology. PMID- 23437088 TI - Comparative microbial analysis of paired amniotic fluid and cord blood from pregnancies complicated by preterm birth and early-onset neonatal sepsis. AB - BACKGROUND: 16S rRNA-based genomic analyses have revolutionized our understanding of infectious diseases. Many cases which were recognized as "idiopathic" are now known to have an infectious etiology. Here, we present a proof-of-concept study to examine the microbial link between intra-amniotic infection (IAI) and early onset neonatal sepsis (EONS). RESULTS: Using culture independent methods, we analyzed paired amniotic fluid (AF) and cord blood (CB) samples from 36 singleton pregnancies complicated by preterm birth (PTB), IAI, and/or EONS. PTB cases were grouped as 1) Group 1- neonatal blood culture-positive EONS (n=6). 2) Group 2- neonatal blood culture-negative presumed EONS with positive IAI (n=16). 3) Group 3- neonatal blood culture-negative presumed EONS with no IAI (n=7); 4) Group 4- no EONS or IAI (n=7). In addition, samples from term healthy deliveries (n=8) served as technical controls. A total of 31 species (15 non-redundant) were identified in AF, of which only 1/3 were cultivated. Significantly fewer microorganisms were detected in CB, with a total of 18 species (7 non-redundant) identified, of which only 2 (Escherichia coli, Streptococcus agalactiae) were cultivated. Of those, Bergeyella, Fusobacterium nucleatum, and Sneathia sanguinegens had not been detected in EONS before. The novel species identified in AF by PCR include Peptoniphilus harei and Lachnospiraceae sp. The majority (72%) of CB species were also detected in the matching AF, with E. coli and F. nucleatum as the most prevalent. The 16S rRNA sequences of paired AF and CB were 99.9-100% identical, while no identical sequences were found between different pregnancies. CONCLUSIONS: Previously unrecognized, uncultivated or difficult-to cultivate species are implicated in EONS. Microbial species in paired AF and CB likely share the same infectious origin. Given its prevalence in EONS, F. nucleatum should be placed on the same importance scale as E. coli. PMID- 23437089 TI - Lapatinib-binding protein kinases in the African trypanosome: identification of cellular targets for kinase-directed chemical scaffolds. AB - Human African trypanosomiasis is caused by the eukaryotic microbe Trypanosoma brucei. To discover new drugs against the disease, one may use drugs in the clinic for other indications whose chemical scaffolds can be optimized via a medicinal chemistry campaign to achieve greater potency against the trypanosome. Towards this goal, we tested inhibitors of human EGFR and/or VEGFR as possible anti-trypanosome compounds. The 4-anilinoquinazolines canertinib and lapatinib, and the pyrrolopyrimidine AEE788 killed bloodstream T. brucei in vitro with GI(50) in the low micromolar range. Curiously, the genome of T. brucei does not encode EGFR or VEGFR, indicating that the drugs recognize alternate proteins. To discover these novel targets, a trypanosome lysate was adsorbed to an ATP sepharose matrix and washed with a high salt solution followed by nicotinamide adenine dinucleotide (NAD(+)). Proteins that remained bound to the column were eluted with drugs, and identified by mass spectrometry/bioinformatics. Lapatinib bound to Tb927.4.5180 (termed T. brucei lapatinib-binding protein kinase-1 (TbLBPK1)) while AEE788 bound Tb927.5.800 (TbLBPK2). When the NAD(+) wash was omitted from the protocol, AEE788, canertinib and lapatinib eluted TbLBPK1, TbLBPK2, and Tb927.3.1570 (TbLBPK3). In addition, both canertinib and lapatinib eluted Tb10.60.3140 (TbLBPK4), whereas only canertinib desorbed Tb10.61.1880 (TbCBPK1). Lapatinib binds to a unique conformation of protein kinases. To gain insight into the structural basis for lapatinib interaction with TbLBPKs, we constructed three-dimensional models of lapatinib*TbLBPK complexes, which confirmed that TbLBPKs can adopt lapatinib-compatible conformations. Further, lapatinib, AEE788, and canertinib were docked to TbLBPKs with favorable scores. Our studies (a) present novel targets of kinase-directed drugs in the trypanosome, and (b) offer the 4-anilinoquinazoline and pyrrolopyrimidines as scaffolds worthy of medicinal chemistry and structural biology campaigns to develop them into anti-trypanosome drugs. PMID- 23437090 TI - Sclerotial formation of Polyporus umbellatus by low temperature treatment under artificial conditions. AB - BACKGROUND: Polyporus umbellatus sclerotia have been used as a diuretic agent in China for over two thousand years. A shortage of the natural P. umbellatus has prompted researchers to induce sclerotial formation in the laboratory. METHODOLOGY/PRINCIPAL FINDING: P. umbellatus cultivation in a sawdust-based substrate was investigated to evaluate the effect of low temperature conditions on sclerotial formation. A phenol-sulfuric acid method was employed to determine the polysaccharide content of wild P. umbellatus sclerotia and mycelia and sclerotia grown in low-temperature treatments. In addition, reactive oxygen species (ROS) content, expressed as the fluorescence intensity of mycelia during sclerotial differentiation was determined. Analysis of ROS generation and sclerotial formation in mycelia after treatment with the antioxidants such as diphenyleneiodonium chloride (DPI), apocynin (Apo), or vitamin C were studied. Furthermore, macroscopic and microscopic characteristics of sclerotial differentiation were observed. Sclerotia were not induced by continuous cultivation at 25 degrees C. The polysaccharide content of the artificial sclerotia is 78% of that of wild sclerotia. In the low-temperature treatment group, the fluorescent intensity of ROS was higher than that of the room temperature (25 degrees C) group which did not induce sclerotial formation all through the cultivation. The antioxidants DPI and Apo reduced ROS levels and did not induce sclerotial formation. Although the concentration-dependent effects of vitamin C (5-15 mg mL(-1)) also reduced ROS generation and inhibited sclerotial formation, using a low concentration of vitamin C (1 mg mL(-1)) successfully induced sclerotial differentiation and increased ROS production. CONCLUSIONS/SIGNIFICANCE: Exposure to low temperatures induced P. umbellatus sclerotial morphogenesis during cultivation. Low temperature treatment enhanced ROS in mycelia, which may be important in triggering sclerotial differentiation in P. umbellatus. Moreover, the application of antioxidants impaired ROS generation and inhibited sclerotial formation. Our findings may help to provide new insights into the biological mechanisms underlying sclerotial morphogenesis in P. umbellatus. PMID- 23437091 TI - Adolescent changes in dopamine D1 receptor expression in orbitofrontal cortex and piriform cortex accompany an associative learning deficit. AB - The orbitofrontal cortex (OFC) and piriform cortex are involved in encoding the predictive value of olfactory stimuli in rats, and neural responses to olfactory stimuli in these areas change as associations are learned. This experience dependent plasticity mirrors task-related changes previously observed in mesocortical dopamine neurons, which have been implicated in learning the predictive value of cues. Although forms of associative learning can be found at all ages, cortical dopamine projections do not mature until after postnatal day 35 in the rat. We hypothesized that these changes in dopamine circuitry during the juvenile and adolescent periods would result in age-dependent differences in learning the predictive value of environmental cues. Using an odor-guided associative learning task, we found that adolescent rats learn the association between an odor and a palatable reward significantly more slowly than either juvenile or adult rats. Further, adolescent rats displayed greater distractibility during the task than either juvenile or adult rats. Using real time quantitative PCR and immunohistochemical methods, we observed that the behavioral deficit in adolescence coincides with a significant increase in D1 dopamine receptor expression compared to juvenile rats in both the OFC and piriform cortex. Further, we found that both the slower learning and increased distractibility exhibited in adolescence could be alleviated by experience with the association task as a juvenile, or by an acute administration of a low dose of either the dopamine D1 receptor agonist SKF-38393 or the D2 receptor antagonist eticlopride. These results suggest that dopaminergic modulation of cortical function may be important for learning the predictive value of environmental stimuli, and that developmental changes in cortical dopaminergic circuitry may underlie age-related differences in associative learning. PMID- 23437092 TI - Similar trends in serum VEGF-D levels and kidney angiomyolipoma responses with longer duration sirolimus treatment in adults with tuberous sclerosis. AB - CONTEXT: We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up. OBJECTIVE: To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus. SETTING: Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1). PATIENTS: There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients. MAIN OUTCOME MEASURE(S): We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups. RESULTS: At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787 +/- 426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971 +/- 4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p=0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed. TRIAL REGISTRATION: Clinical trials.gov NCT00126672. PMID- 23437093 TI - Stair descending exercise using a novel automatic escalator: effects on muscle performance and health-related parameters. AB - A novel automatic escalator was designed, constructed and used in the present investigation. The aim of the present investigation was to compare the effect of two repeated sessions of stair descending versus stair ascending exercise on muscle performance and health-related parameters in young healthy men. Twenty males participated and were randomly divided into two equal-sized groups: a stair descending group (muscle-damaging group) and a stair ascending group (non-muscle damaging group). Each group performed two sessions of stair descending or stair ascending exercise on the automatic escalator while a three week period was elapsed between the two exercise sessions. Indices of muscle function, insulin sensitivity, blood lipid profile and redox status were assessed before and immediately after, as well as at day 2 and day 4 after both exercise sessions. It was found that the first bout of stair descending exercise caused muscle damage, induced insulin resistance and oxidative stress as well as affected positively blood lipid profile. However, after the second bout of stair descending exercise the alterations in all parameters were diminished or abolished. On the other hand, the stair ascending exercise induced only minor effects on muscle function and health-related parameters after both exercise bouts. The results of the present investigation indicate that stair descending exercise seems to be a promising way of exercise that can provoke positive effects on blood lipid profile and antioxidant status. PMID- 23437094 TI - Genetic susceptibility to non-necrotizing erysipelas/cellulitis. AB - BACKGROUND: Bacterial non-necrotizing erysipelas and cellulitis are often recurring, diffusely spreading infections of the skin and subcutaneous tissues caused most commonly by streptococci. Host genetic factors influence infection susceptibility but no extensive studies on the genetic determinants of human erysipelas exist. METHODS: We performed genome-wide linkage with the 10,000 variant Human Mapping Array (HMA10K) array on 52 Finnish families with multiple erysipelas cases followed by microsatellite fine mapping of suggestive linkage peaks. A scan with the HMA250K array was subsequently performed with a subset of cases and controls. RESULTS: Significant linkage was found at 9q34 (nonparametric multipoint linkage score (NPL(all)) 3.84, p=0.026), which is syntenic to a quantitative trait locus for susceptibility to group A streptococci infections on chromosome 2 in mouse. Sequencing of candidate genes in the 9q34 region did not conclusively associate any to erysipelas/cellulitis susceptibility. Suggestive linkage (NPL(all)>3.0) was found at three loci: 3q22-24, 21q22, and 22q13. A subsequent denser genome scan with the HMA250K array supported the 3q22 locus, in which several SNPs in the promoter of AGTR1 (Angiotensin II receptor type I) suggestively associated with erysipelas/cellulitis susceptibility. CONCLUSIONS: Specific host genetic factors may cause erysipelas/cellulitis susceptibility in humans. PMID- 23437095 TI - The thermostable direct hemolysin from Grimontia hollisae causes acute hepatotoxicity in vitro and in vivo. AB - BACKGROUND: G. hollisae thermostable direct hemolysin (Gh-TDH) is produced by most strains of G. hollisae. This toxin has been reported to be absorbed in the intestines in humans. Secondary liver injury might be caused by venous return of the toxin through the portal system. We aimed to firstly analyze the in vitro and in vivo hepatotoxicity of Gh-TDH. METHODS: Liver cells (primary human non-cancer cell and FL83B mouse cells) were treated and mice (BALB/c) were fed with this toxin to investigate its hepatotoxicity. Morphological examination and cytotoxicity assays using liver cells were also performed. Fluorescein isothiocyanate-conjugated toxin was used to analyze the localization of this protein in liver cells. Mice were subjected to liver function measurements and liver biopsies following toxin treatment and wild-type bacterial infection. PET (positron emission tomography)/CT (computed tomography) images were taken to assess liver metabolism during acute injury and recovery. RESULTS: The effect of hepatotoxicity was dose and time dependent. Cellular localization showed that the toxin was initially located around the cellular margins and subsequently entered the nucleus. Liver function measurements and liver biopsies of the mice following treatment with toxin or infection with wild-type Grimontia hollisae showed elevated levels of transaminases and damage to the periportal area, respectively. The PET/CT images revealed that the reconstruction of the liver continued for at least one week after exposure to a single dose of the toxin or bacterial infection. CONCLUSIONS: The hepatotoxicity of Gh-TDH was firstly demonstrated. The damage was located in the periportal area of the liver, and the liver became functionally insufficient. PMID- 23437096 TI - Thyroid hormones correlate with basal metabolic rate but not field metabolic rate in a wild bird species. AB - Thyroid hormones (TH) are known to stimulate in vitro oxygen consumption of tissues in mammals and birds. Hence, in many laboratory studies a positive relationship between TH concentrations and basal metabolic rate (BMR) has been demonstrated whereas evidence from species in the wild is scarce. Even though basal and field metabolic rates (FMR) are often thought to be intrinsically linked it is still unknown whether a relationship between TH and FMR exists. Here we determine the relationship between the primary thyroid hormone triiodothyronine (T3) with both BMR and FMR in a wild bird species, the black legged kittiwake (Rissa tridactyla). As predicted we found a strong and positive relationship between plasma concentrations of T3 and both BMR and mass independent BMR with coefficients of determination ranging from 0.36 to 0.60. In contrast there was no association of T3 levels with either whole-body or mass independent FMR (R(2) =0.06 and 0.02, respectively). In accordance with in vitro studies our data suggests that TH play an important role in modulating BMR and may serve as a proxy for basal metabolism in wild birds. However, the lack of a relationship between TH and FMR indicates that levels of physical activity in kittiwakes are largely independent of TH concentrations and support recent studies that cast doubt on a direct linkage between BMR and FMR. PMID- 23437097 TI - Syntactic computation in the human brain: the degree of merger as a key factor. AB - Our goal of this study is to characterize the functions of language areas in most precise terms. Previous neuroimaging studies have reported that more complex sentences elicit larger activations in the left inferior frontal gyrus (L. F3op/F3t), although the most critical factor still remains to be identified. We hypothesize that pseudowords with grammatical particles and morphosyntactic information alone impose a construction of syntactic structures, just like normal sentences, and that "the Degree of Merger" (DoM) in recursively merged sentences parametrically modulates neural activations. Using jabberwocky sentences with distinct constructions, we fitted various parametric models of syntactic, other linguistic, and nonlinguistic factors to activations measured with functional magnetic resonance imaging. We demonstrated that the models of DoM and "DoM+number of Search (searching syntactic features)" were the best to explain activations in the L. F3op/F3t and supramarginal gyrus (L. SMG), respectively. We further introduced letter strings, which had neither lexical associations nor grammatical particles, but retained both matching orders and symbol orders of sentences. By directly contrasting jabberwocky sentences with letter strings, localized activations in L. F3op/F3t and L. SMG were indeed independent of matching orders and symbol orders. Moreover, by using dynamic causal modeling, we found that the model with a inhibitory modulatory effect for the bottom-up connectivity from L. SMG to L. F3op/F3t was the best one. For this best model, the top-down connection from L. F3op/F3t to L. SMG was significantly positive. By using diffusion-tensor imaging, we confirmed that the left dorsal pathway of the superior longitudinal and arcuate fasciculi consistently connected these regions. Lastly, we established that nonlinguistic order-related and error-related factors significantly activated the right (R.) lateral premotor cortex and R. F3op/F3t, respectively. These results indicate that the identified network of L. F3op/F3t and L. SMG subserves the calculation of DoM in recursively merged sentences. PMID- 23437098 TI - Characterization of Amoeboaphelidium protococcarum, an algal parasite new to the cryptomycota isolated from an outdoor algal pond used for the production of biofuel. AB - Mass culture of algae for the production of biofuels is a developing technology designed to offset the depletion of fossil fuel reserves. However, large scale culture of algae in open ponds can be challenging because of incidences of infestation with algal parasites. Without knowledge of the identity of the specific parasite and how to control these pests, algal-based biofuel production will be limited. We have characterized a eukaryotic parasite of Scenedesmus dimorphus growing in outdoor ponds used for biofuel production. We demonstrated that as the genomic DNA of parasite FD01 increases, the concentration of S. dimorphus cells decreases; consequently, this is a highly destructive pathogen. Techniques for culture of the parasite and host were developed, and the endoparasite was identified as the Aphelidea, Amoeboaphelidium protococcarum. Phylogenetic analysis of ribosomal sequences revealed that parasite FD01 placed within the recently described Cryptomycota, a poorly known phylum based on two species of Rozella and environmental samples. Transmission electron microscopy demonstrated that aplanospores of the parasite produced filose pseudopodia, which contained fine fibers the diameter of actin microfilaments. Multiple lipid globules clustered and were associated with microbodies, mitochondria and a membrane cisternae, an arrangement characteristic of the microbody-lipid globule complex of chytrid zoospores. After encystment and attachment to the host cells, the parasite injected its protoplast into the host between the host cell wall and plasma membrane. At maturity the unwalled parasite occupied the entire host cell. After cleavage of the protoplast into aplanospores, a vacuole and lipids remained in the host cell. Amoeboaphelidium protococcarum isolate FD01 is characteristic of the original description of this species and is different from strain X-5 recently characterized. Our results help put a face on the Cryptomycota, revealing that the phylum is more diverse than previously understood and include some of the Aphelidea as well as Rozella species and potentially Microsporidia. PMID- 23437099 TI - N-3 fatty acid rich triglyceride emulsions are neuroprotective after cerebral hypoxic-ischemic injury in neonatal mice. AB - We questioned if acute administration of n-3 fatty acids (FA) carried in n-3 rich triglyceride (TG) emulsions provides neuroprotection in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury. We examined specificity of FA, optimal doses, and therapeutic windows for neuroprotection after H/I. H/I insult was induced in C57BL/6J 10-day-old mice by right carotid artery ligation followed by exposure to 8% O(2) for 15 minutes at 37 degrees C. Intraperitoneal injection with n-3-rich TG emulsions, n-6 rich TG emulsions or saline for control was administered at different time points before and/or after H/I. In separate experiments, dose responses were determined with TG containing only docosahexaenoic acid (Tri-DHA) or eicosapentaenoic acid (Tri-EPA) with a range of 0.1-0.375 g n-3 TG/kg, administered immediately after H/I insult. Infarct volume and cerebral blood flow (CBF) were measured. Treatment with n-3 TG emulsions both before- and after- H/I significantly reduced total infarct volume by a mean of 43% when administered 90 min prior to H/I and by 47% when administered immediately after H/I. In post-H/I experiments Tri-DHA, but not Tri-EPA exhibited neuroprotective effects with both low and high doses (p<0.05). Moreover, delayed post-H/I treatment with Tri-DHA significantly decreased total infarct volume by a mean of 51% when administered at 0 hr, by 46% at 1 hr, and by 51% at 2 hr after H/I insult. No protective effect occurred with Tri-DHA injection at 4 hr after H/I. There were no n-3 TG related differences in CBF. A significant reduction in brain tissue death was maintained after Tri-DHA injection at 8 wk after the initial brain injury. Thus, n-3 TG, specifically containing DHA, is protective against H/I induced brain infarction when administered up to 2 hr after H/I injury. Acute administration of TG-rich DHA may prove effective for treatment of stroke in humans. PMID- 23437100 TI - Pan-African genetic structure in the African buffalo (Syncerus caffer): investigating intraspecific divergence. AB - The African buffalo (Syncerus caffer) exhibits extreme morphological variability, which has led to controversies about the validity and taxonomic status of the various recognized subspecies. The present study aims to clarify these by inferring the pan-African spatial distribution of genetic diversity, using a comprehensive set of mitochondrial D-loop sequences from across the entire range of the species. All analyses converged on the existence of two distinct lineages, corresponding to a group encompassing West and Central African populations and a group encompassing East and Southern African populations. The former is currently assigned to two to three subspecies (S. c. nanus, S. c. brachyceros, S. c. aequinoctialis) and the latter to a separate subspecies (S. c. caffer). Forty-two per cent of the total amount of genetic diversity is explained by the between lineage component, with one to seventeen female migrants per generation inferred as consistent with the isolation-with-migration model. The two lineages diverged between 145 000 to 449 000 years ago, with strong indications for a population expansion in both lineages, as revealed by coalescent-based analyses, summary statistics and a star-like topology of the haplotype network for the S. c. caffer lineage. A Bayesian analysis identified the most probable historical migration routes, with the Cape buffalo undertaking successive colonization events from Eastern toward Southern Africa. Furthermore, our analyses indicate that, in the West-Central African lineage, the forest ecophenotype may be a derived form of the savanna ecophenotype and not vice versa, as has previously been proposed. The African buffalo most likely expanded and diverged in the late to middle Pleistocene from an ancestral population located around the current-day Central African Republic, adapting morphologically to colonize new habitats, hence developing the variety of ecophenotypes observed today. PMID- 23437101 TI - Trends in the distribution of gestational age and contribution of planned births in New South Wales, Australia. AB - BACKGROUND: There is concern that the rate of planned births (by pre-labour caesarean section or induction of labour) is increasing and that the gestation at which they are being conducted is decreasing. The aim of this study was to describe trends in the distribution of gestational age, and assess the contribution of planned birth to any such changes. METHODS: We utilised the New South Wales (NSW) Perinatal Data Collection to undertake a population-based study of all births in NSW, Australia 1994-2009. Trends in gestational age were determined by year, labour onset and plurality of birth. RESULTS: From 1994-2009, there was a gradual and steady left-shift in overall distribution of gestational age at birth, with a decline in the modal gestational age from 40 to 39 weeks. For singletons, there was a steady but significant reduction in the proportion of spontaneous births. Labour inductions increased in the proportion performed, with a gradual and changing shift in the distribution from a majority at 40 weeks to an increase at both 37-39 weeks and 41 weeks gestation. The proportion of pre labour caesareans also increased steadily at each gestational age and doubled since 1994, with most performed at 39 weeks in 2009 compared with 38 weeks up to 2001. CONCLUSIONS: Findings suggest a changing pattern towards births at earlier gestations, fewer births commencing spontaneously and increasing planned births. Factors associated with changing clinical practice and long-term implications on the health and well-being of mothers and babies should be assessed. PMID- 23437102 TI - Comparison of age-stratified seroprevalence of antibodies against norovirus GII in India and the United Kingdom. AB - Noroviruses are a common cause of gastroenteritis worldwide, but outbreaks appear to be more common in industrialized countries than in developing countries, possibly reflecting differences in exposure and immunity. In this study, age stratified sera from India and UK populations were analysed for the presence of norovirus-genogroup II specific IgG by a time resolved immunofluorescence assay and relative levels of antibodies in the two populations were compared. Antibody levels were higher among all age groups in India than in UK and increased with age in India, whereas in the UK, levels of antibody decreased in adulthood. These results indicate different patterns of exposure to noroviruses in the two countries. PMID- 23437103 TI - ABCD2 is a direct target of beta-catenin and TCF-4: implications for X-linked adrenoleukodystrophy therapy. AB - X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene that encodes the peroxisomal ATP-binding cassette (ABC) transporter subfamily D member 1 protein (ABCD1), which is referred to as the adrenoleukodystrophy protein (ALDP). Induction of the ABCD2 gene, the closest homolog of ABCD1, has been mentioned as a possible therapeutic option for the defective ABCD1 protein in X-ALD. However, little is known about the transcriptional regulation of ABCD2 gene expression. Here, through in silico analysis, we found two putative TCF-4 binding elements between nucleotide positions -360 and -260 of the promoter region of the ABCD2 gene. The transcriptional activity of the ABCD2 promoter was strongly increased by ectopic expression of beta-catenin and TCF-4. In addition, mutation of either or both TCF 4 binding elements by site-directed mutagenesis decreased promoter activity. This was further validated by the finding that beta-catenin and the promoter of the ABCD2 gene were pulled down with a beta-catenin antibody in a chromatin immunoprecipitation assay. Moreover, real-time PCR analysis revealed that beta catenin and TCF-4 increased mRNA levels of ABCD2 in both a hepatocellular carcinoma cell line and primary fibroblasts from an X-ALD patient. Interestingly, we found that the levels of very long chain fatty acids were decreased by ectopic expression of ABCD2-GFP as well as beta-catenin and TCF-4. Taken together, our results demonstrate for the first time the direct regulation of ABCD2 by beta catenin and TCF-4. PMID- 23437104 TI - Comparison between two generic questionnaires to assess satisfaction with medication in chronic diseases. AB - OBJECTIVE: The objective of this work was to compare two generic questionnaires assessing patients' satisfaction with medication. In addition we tested whether satisfaction can predict adherence to medication regimens in patients with chronic diseases, and which dimensions of satisfaction are most involved. METHODS: This prospective, observational study was conducted over one year in a heterogeneous population of patients with various chronic diseases. Satisfaction with medication was assessed by using the TSQM(r) vII and the SatMed-Q(r) questionnaires, and adherence to treatment was assessed with the Morisky-Green questionnaire. Clinical pharmacists interviewed patients to collect clinical, demographic and therapeutic data. RESULTS: 190 patients were enrolled. Both questionnaires showed excellent reliability and correlation was high (R=0.70; p<0.001). Adherence was correlated with satisfaction with medication whether assessed with the SatMed-Q(r) (R=0.23; p=0.002) or the TSQM(r) (R=0.17; p=0.02). Among different dimensions of satisfaction, convenience of use and side effects are prominent predictors of adherence. CONCLUSION: Adherence is related to the patient's satisfaction with medication whether assessed with the TSQM(r) vII or the SatMed-Q(r). Therefore, these simple questionnaires could be used as predictive tools to identify patients whos' adherence needs to be improved. PMID- 23437105 TI - Maternal diet supplemented with methyl-donors protects against atherosclerosis in F1 ApoE(-/-) mice. AB - Atherosclerosis is an inflammatory condition of the arterial wall mediated by cells of both innate and adaptive immunity. T lymphocytes play an important role in orchestrating the pathogenic immune response involved in the acceleration of atherosclerosis. Previously, we have shown that a prenatal methyl-donor supplementation diet (MS), when fed to dams during pregnancy and lactation, decreased the T cell-mediated pro-inflammatory cytokine and chemokine response in F1 mice. In the current study, we report feeding Apolipoprotein E (ApoE(-/-)) deficient dams with the MS diet during pregnancy reduces atherosclerotic plaques in F1 mice that were fed high fat diet (HFD) after weaning. F1 mice from dams on the MS diet exhibited increased global T cell DNA methylation. T-cell chemokines and their receptors (in particular CCR2, CCR5, and CXCR3) play important roles in the inflammatory cell recruitment to vascular lesions. MS diet significantly reduced Ccr2 mRNA and protein expression in CD3+ T cells but not in CD11b+ monocytes in MS F1 mice relative to controls. F1 litter size, HFD consumption, body weight, and body fat were similar between control and MS diet groups. Moreover, serum thiol metabolite levels were similar between the two groups. However, MS diet is associated with significantly higher serum HDL and lower LDL+VLDL levels in comparison to F1 mice from dams on the control diet. Inflammatory cytokines (IL-17, TNF-alpha, IL-6) were also lower in MS F1 mice serum and conditioned media from T-cell culture. Altogether, these data suggest that the MS diet ameliorates development of atherosclerosis by inhibiting the T cell Ccr2 expression, reducing inflammatory cytokines production and increasing serum HDL:LDL ratio. PMID- 23437106 TI - Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance. AB - BACKGROUND: Two recent studies demonstrated that bariatric surgery induced remission of type 2 diabetes very soon after surgery and far too early to be attributed to weight loss. In this study, we sought to explore the mechanism/s of this phenomenon by testing the effects of proteins from the duodenum-jejunum conditioned-medium (CM) of db/db or Swiss mice on glucose uptake in vivo in Swiss mice and in vitro in both Swiss mice soleus and L6 cells. We studied the effect of sera and CM proteins from insulin resistant (IR) and insulin-sensitive subjects on insulin signaling in human myoblasts. METHODOLOGY/PRINCIPAL FINDINGS: db/db proteins induced massive IR either in vivo or in vitro, while Swiss proteins did not. In L6 cells, only db/db proteins produced a noticeable increase in basal (473)Ser-Akt phosphorylation, lack of GSK3beta inhibition and a reduced basal (389)Thr-p70-S6K1 phosphorylation. Human IR serum markedly increased basal (473)Ser-Akt phosphorylation in a dose-dependent manner. Human CM IR proteins increased by about twofold both basal and insulin-stimulated (473)Ser-Akt. Basal (9)Ser-GSK3beta phosphorylation was increased by IR subjects serum with a smaller potentiating effect of insulin. CONCLUSIONS: These findings show that jejunal proteins either from db/db mice or from insulin resistant subjects impair muscle insulin signaling, thus inducing insulin resistance. PMID- 23437107 TI - Crystal structure of silkworm Bombyx mori JHBP in complex with 2-methyl-2,4 pentanediol: plasticity of JH-binding pocket and ligand-induced conformational change of the second cavity in JHBP. AB - Juvenile hormones (JHs) control a diversity of crucial life events in insects. In Lepidoptera which major agricultural pests belong to, JH signaling is critically controlled by a species-specific high-affinity, low molecular weight JH-binding protein (JHBP) in hemolymph, which transports JH from the site of its synthesis to target tissues. Hence, JHBP is expected to be an excellent target for the development of novel specific insect growth regulators (IGRs) and insecticides. A better understanding of the structural biology of JHBP should pave the way for the structure-based drug design of such compounds. Here, we report the crystal structure of the silkworm Bombyx mori JHBP in complex with two molecules of 2 methyl-2,4-pentanediol (MPD), one molecule (MPD1) bound in the JH-binding pocket while the other (MPD2) in a second cavity. Detailed comparison with the apo-JHBP and JHBP-JH II complex structures previously reported by us led to a number of intriguing findings. First, the JH-binding pocket changes its size in a ligand dependent manner due to flexibility of the gate alpha1 helix. Second, MPD1 mimics interactions of the epoxide moiety of JH previously observed in the JHBP-JH complex, and MPD can compete with JH in binding to the JH-binding pocket. We also confirmed that methoprene, which has an MPD-like structure, inhibits the complex formation between JHBP and JH while the unepoxydated JH III (methyl farnesoate) does not. These findings may open the door to the development of novel IGRs targeted against JHBP. Third, binding of MPD to the second cavity of JHBP induces significant conformational changes accompanied with a cavity expansion. This finding, together with MPD2-JHBP interaction mechanism identified in the JHBP-MPD complex, should provide important guidance in the search for the natural ligand of the second cavity. PMID- 23437108 TI - ErbB2 receptor over-expression improves post-traumatic peripheral nerve regeneration in adult mice. AB - In a transgenic mice (BALB-neuT) over-expressing ErbB2 receptor, we investigated the adult mouse median nerve in physiological and pathological conditions. Results showed that, in physiological conditions, the grip function controlled by the median nerve in BALB-neuT mice was similar to wild-type (BALB/c). Stereological assessment of ErbB2-overexpressing intact nerves revealed no difference in number and size of myelinated fibers compared to wild-type mice. By contrast, after a nerve crush injury, the motor recovery was significantly faster in BALB-neuT compared to BALB/c mice. Moreover, stereological assessment revealed a significant higher number of regenerated myelinated fibers with a thinner axon and fiber diameter and myelin thickness in BALB-neuT mice. At day-2 post-injury, the level of the mRNAs coding for all the ErbB receptors and for the transmembrane (type III) Neuregulin 1 (NRG1) isoforms significantly decreased in both BALB/c and BALB-neuT mice, as shown by quantitative real time PCR. On the other hand, the level of the mRNAs coding for soluble NRG1 isoforms (type I/II, alpha and beta) increased at the same post-traumatic time point though, intriguingly, this response was significantly higher in BALB-neuT mice with respect to BALB/c mice. Altogether, these results suggest that constitutive ErbB2 receptor over-expression does not influence the physiological development of peripheral nerves, while it improves nerve regeneration following traumatic injury, possibly through the up-regulation of soluble NRG1 isoforms. PMID- 23437109 TI - Sustained levels of FGF2 maintain undifferentiated stem cell cultures with biweekly feeding. AB - An essential aspect of stem cell culture is the successful maintenance of the undifferentiated state. Many types of stem cells are FGF2 dependent, and pluripotent stem cells are maintained by replacing FGF2-containing media daily, while tissue-specific stem cells are typically fed every 3rd day. Frequent feeding, however, results in significant variation in growth factor levels due to FGF2 instability, which limits effective maintenance due to spontaneous differentiation. We report that stabilization of FGF2 levels using controlled release PLGA microspheres improves expression of stem cell markers, increases stem cell numbers and decreases spontaneous differentiation. The controlled release FGF2 additive reduces the frequency of media changes needed to maintain stem cell cultures, so that human embryonic stem cells and induced pluripotent stem cells can be maintained successfully with biweekly feedings. PMID- 23437110 TI - Optimizing radiation dose levels in prospectively electrocardiogram-triggered coronary computed tomography angiography using iterative reconstruction techniques: a phantom and patient study. AB - AIM: To investigate the potential of reducing the radiation dose in prospectively electrocardiogram-triggered coronary computed tomography angiography (CCTA) while maintaining diagnostic image quality using an iterative reconstruction technique (IRT). METHODS AND MATERIALS: Prospectively-gated CCTA were first performed on a phantom using 256-slice multi-detector CT scanner at 120 kVp, with the tube output gradually reduced from 210 mAs (Group A) to 125, 105, 84, and 63 mAs (Group B-E). All scans were reconstructed using filtered back projection (FBP) algorithm and five IRT levels (L2-6), image quality (IQ) assessment was performed. Based on the IQ assessment, Group D(120 kVp, 84 mAs) reconstructed with L5 was found to provide IQ comparable to that of Group A with FBP. In the patient study, 21 patients underwent CCTA using 120 kV, 210 mAs with FBP reconstruction (Group 1) followed by 36 patients scanned with 120 kV, 84 mAs with IRT L5 (Group 2). Subjective and objective IQ and effective radiation dose were compared between two groups. RESULTS: In the phantom scans, there were no significant differences in image noise, contrast-to-noise ratio (CNR) and modulation transfer function (MTF) curves between Group A and the 84 mAs, 63 mAs groups (Groups D and E). Group D (120 kV, 84 mAs and L5) provided an optimum balance, producing equivalent image quality to Group A, at the lowest possible radiation dose. In the patient study, there were no significant difference in image noise, signal-to-noise ratio (SNR) and CNR between Group 1 and Group 2 (p=0.71, 0.31, 0.5, respectively). The effective radiation dose in Group 2 was 1.21 +/- 0.14 mSv compared to 3.20 +/- 0.58 mSv (Group 1), reflecting dose savings of 62.5% (p<0.05). CONCLUSION: iterative reconstruction technique used in prospectively ECG-triggered 256-slice coronary CTA can provide radiation dose reductions of up to 62.5% with acceptable image quality. PMID- 23437111 TI - The de novo assembly of mitochondrial genomes of the extinct passenger pigeon (Ectopistes migratorius) with next generation sequencing. AB - The information from ancient DNA (aDNA) provides an unparalleled opportunity to infer phylogenetic relationships and population history of extinct species and to investigate genetic evolution directly. However, the degraded and fragmented nature of aDNA has posed technical challenges for studies based on conventional PCR amplification. In this study, we present an approach based on next generation sequencing to efficiently sequence the complete mitochondrial genome (mitogenome) of two extinct passenger pigeons (Ectopistes migratorius) using de novo assembly of massive short (90 bp), paired-end or single-end reads. Although varying levels of human contamination and low levels of postmortem nucleotide lesion were observed, they did not impact sequencing accuracy. Our results demonstrated that the de novo assembly of shotgun sequence reads could be a potent approach to sequence mitogenomes, and offered an efficient way to infer evolutionary history of extinct species. PMID- 23437112 TI - Probing the effector and suppressive functions of human T cell subsets using antigen-specific engineered T cell receptors. AB - Activation of T cells through the engagement of the T cell receptors (TCRs) with specific peptide-MHC complexes on antigen presenting cells (APCs) is the major determinant for their proliferation, differentiation and display of effector functions. To assess the role of quantity and quality of peptide-MHC presentation in eliciting T cell activation and suppression functions, we genetically engineered human T cells with two TCRs that recognize HLA-A*0201-restricted peptides derived from either HIV or melanoma antigens. The engineered-TCRs are highly functional in both CD8(+) and CD4(+) T cells as assessed by the upregulation of activation markers, induction of cytokine secretion and cytotoxicity. We further demonstrated that engineered-TCRs can also be expressed on naive human T cells, which are stimulated through APCs presenting specific peptides to induce T cell proliferation and acquire effector functions. Furthermore, regulatory T cells (Tregs) ectopically expressing the engineered TCRs are activated in an antigen-specific fashion and suppress T cell proliferation. In this system, the inhibitory activity of peptide-stimulated Tregs require the presence of dendritic cells (DCs) in the culture, either as presenters or as bystander cells, pointing to a critical role for DCs in suppression by Tregs. In conclusion, the engineered-TCR system reported here advances our ability to understand the differentiation pathways of naive T cells into antigen-specific effector cells and the role of antigen-specific signaling in Treg-mediated immune suppression. PMID- 23437113 TI - Genome-wide sequence characterization and expression analysis of major intrinsic proteins in soybean (Glycine max L.). AB - Water is essential for all living organisms. Aquaporin proteins are the major facilitator of water transport activity through cell membranes of plants including soybean. These proteins are diverse in plants and belong to a large major intrinsic (MIP) protein family. In higher plants, MIPs are classified into five subfamilies including plasma membrane intrinsic proteins (PIP), tonoplast intrinsic proteins (TIP), NOD26-like intrinsic proteins (NIP), small basic intrinsic proteins (SIP), and the recently discovered X intrinsic proteins (XIP). This paper reports genome wide assembly of soybean MIPs, their functional prediction and expression analysis. Using a bioinformatic homology search, 66 GmMIPs were identified in the soybean genome. Phylogenetic analysis of amino acid sequences of GmMIPs divided the large and highly similar multi-gene family into 5 subfamilies: GmPIPs, GmTIPs, GmNIPs, GmSIPs and GmXIPs. GmPIPs consisted of 22 genes and GmTIPs 23, which showed high sequence similarity within subfamilies. GmNIPs contained 13 and GmSIPs 6 members which were diverse. In addition, we also identified a two member GmXIP, a distinct 5(th) subfamily. GmMIPs were further classified into twelve subgroups based on substrate selectivity filter analysis. Expression analyses were performed for a selected set of GmMIPs using semi quantitative reverse transcription (semi-RT-qPCR) and qPCR. Our results suggested that many GmMIPs have high sequence similarity but diverse roles as evidenced by analysis of sequences and their expression. It can be speculated that GmMIPs contains true aquaporins, glyceroporins, aquaglyceroporins and mixed transport facilitators. PMID- 23437114 TI - Exploring the dynamic core microbiome of plaque microbiota during head-and-neck radiotherapy using pyrosequencing. AB - Radiotherapy is the primary treatment modality used for patients with head-and neck cancers, but inevitably causes microorganism-related oral complications. This study aims to explore the dynamic core microbiome of oral microbiota in supragingival plaque during the course of head-and-neck radiotherapy. Eight subjects aged 26 to 70 were recruited. Dental plaque samples were collected (over seven sampling time points for each patient) before and during radiotherapy. The V1-V3 hypervariable regions of bacterial 16S rRNA genes were amplified, and the high-throughput pyrosequencing was performed. A total of 140 genera belonging to 13 phyla were found. Four phyla (Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria) and 11 genera (Streptococcus, Actinomyces, Veillonella, Capnocytophaga, Derxia, Neisseria, Rothia, Prevotella, Granulicatella, Luteococcus, and Gemella) were found in all subjects, supporting the concept of a core microbiome. Temporal variation of these major cores in relative abundance were observed, as well as a negative correlation between the number of OTUs and radiation dose. Moreover, an optimized conceptual framework was proposed for defining a dynamic core microbiome in extreme conditions such as radiotherapy. This study presents a theoretical foundation for exploring a core microbiome of communities from time series data, and may help predict community responses to perturbation as caused by exposure to ionizing radiation. PMID- 23437115 TI - The impact of organic farming on quality of tomatoes is associated to increased oxidative stress during fruit development. AB - This study was conducted with the objective of testing the hypothesis that tomato fruits from organic farming accumulate more nutritional compounds, such as phenolics and vitamin C as a consequence of the stressing conditions associated with farming system. Growth was reduced in fruits from organic farming while titratable acidity, the soluble solids content and the concentrations in vitamin C were respectively +29%, +57% and +55% higher at the stage of commercial maturity. At that time, the total phenolic content was +139% higher than in the fruits from conventional farming which seems consistent with the more than two times higher activity of phenylalanine ammonia lyase (PAL) we observed throughout fruit development in fruits from organic farming. Cell membrane lipid peroxidation (LPO) degree was 60% higher in organic tomatoes. SOD activity was also dramatically higher in the fruits from organic farming. Taken together, our observations suggest that tomato fruits from organic farming experienced stressing conditions that resulted in oxidative stress and the accumulation of higher concentrations of soluble solids as sugars and other compounds contributing to fruit nutritional quality such as vitamin C and phenolic compounds. PMID- 23437116 TI - Being an only or last-born child increases later risk of obesity. AB - BACKGROUND: Studies have suggested that number of siblings and birth order is associated with obesity. However, studies combining these exposures are needed. This study aimed at investigating obesity in children and young adults in regard to different combinations of family size and birth order. METHODS: Two cohorts selected from the general population were investigated: The Copenhagen School Health Records Register (CSHRR) and a Draft Board (DB) sample with measured heights and weights in childhood (age 13 years) and young adulthood (age 19 years), respectively. Information on birth order, number of siblings, and relevant covariates were available on 29 327 children, as well as on 323 obese young men and 575 randomly selected controls of young men representing approximately 58 000. The relation between number of siblings and birth order, respectively, and having a Body Mass Index (BMI) z-score above or equal to the 95(th) percentile in childhood or having a BMI of at least 31.00 kg/m(2) in young adulthood was analysed using logistic regression analyses adjusted for relevant confounders. RESULTS: Only children had significantly higher odds of obesity both in childhood and in young adulthood compared with children with siblings, odds ratio (OR) =1.44 (95% Confidence Interval (CI): 1.26-1.66) and OR=1.76 (95% CI: 1.18-2.61), respectively. No association between first-born status and obesity was found. The OR of last-born children being obese was also significantly increased in childhood, e.g. OR=1.93 (95% CI: 1.09-3.43) of obesity if last-born in a family of four children. This was not found in young adulthood. Additionally, higher spacing to previous sibling (average 1872 vs. 1303 days; p=0.026 in four children families) was observed in obese last-born compared to non-obese last-born children. CONCLUSION: Being an only or last-born child is associated with obesity. These associations may provide leads to targeted prevention of obesity in children. PMID- 23437117 TI - mRNA expression levels in failing human hearts predict cellular electrophysiological remodeling: a population-based simulation study. AB - Differences in mRNA expression levels have been observed in failing versus non failing human hearts for several membrane channel proteins and accessory subunits. These differences may play a causal role in electrophysiological changes observed in human heart failure and atrial fibrillation, such as action potential (AP) prolongation, increased AP triangulation, decreased intracellular calcium transient (CaT) magnitude and decreased CaT triangulation. Our goal is to investigate whether the information contained in mRNA measurements can be used to predict cardiac electrophysiological remodeling in heart failure using computational modeling. Using mRNA data recently obtained from failing and non failing human hearts, we construct failing and non-failing cell populations incorporating natural variability and up/down regulation of channel conductivities. Six biomarkers are calculated for each cell in each population, at cycle lengths between 1500 ms and 300 ms. Regression analysis is performed to determine which ion channels drive biomarker variability in failing versus non failing cardiomyocytes. Our models suggest that reported mRNA expression changes are consistent with AP prolongation, increased AP triangulation, increased CaT duration, decreased CaT triangulation and amplitude, and increased delay between AP and CaT upstrokes in the failing population. Regression analysis reveals that changes in AP biomarkers are driven primarily by reduction in I[Formula: see text], and changes in CaT biomarkers are driven predominantly by reduction in I(Kr) and SERCA. In particular, the role of I(CaL) is pacing rate dependent. Additionally, alternans developed at fast pacing rates for both failing and non failing cardiomyocytes, but the underlying mechanisms are different in control and heart failure. PMID- 23437118 TI - Activation of TGF-beta1 promoter by hepatitis C virus-induced AP-1 and Sp1: role of TGF-beta1 in hepatic stellate cell activation and invasion. AB - Our previous studies have shown the induction and maturation of transforming growth factor-beta 1 (TGF-beta1) in HCV-infected human hepatoma cells. In this study, we have investigated the molecular mechanism of TGF-beta1 gene expression in response to HCV infection. We demonstrate that HCV-induced transcription factors AP-1, Sp1, NF-kappaB and STAT-3 are involved in TGF-beta1 gene expression. Using chromatin immunoprecipitation (ChIP) assay, we further show that AP-1 and Sp1 interact with TGF-b1 promoter in vivo in HCV-infected cells. In addition, we demonstrate that HCV-induced TGF-beta1 gene expression is mediated by the activation of cellular kinases such as p38 MAPK, Src, JNK, and MEK1/2. Next, we determined the role of secreted bioactive TGF-beta1 in human hepatic stellate cells (HSCs) activation and invasion. Using siRNA approach, we show that HCV-induced bioactive TGF-beta1 is critical for the induction of alpha smooth muscle actin (alpha-SMA) and type 1 collagen, the markers of HSCs activation and proliferation. We further demonstrate the potential role of HCV-induced bioactive TGF-beta1 in HSCs invasion/cell migration using a transwell Boyden chamber. Our results also suggest the role of HCV-induced TGF-beta1 in HCV replication and release. Collectively, these observations provide insight into the mechanism of TGF-beta1 promoter activation, as well as HSCs activation and invasion, which likely manifests in liver fibrosis associated with HCV infection. PMID- 23437119 TI - Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse. AB - Mice deficient for the fibulin-5 gene (Fbln5(-/-)) develop pelvic organ prolapse (POP) due to compromised elastic fibers and upregulation of matrix metalloprotease (MMP)-9. Here, we used casein zymography, inhibitor profiling, affinity pull-down, and mass spectrometry to discover additional protease upregulated in the vaginal wall of Fbln5(-/-) mice, herein named V1 (25 kDa). V1 was a serine protease with trypsin-like activity similar to protease, serine (PRSS) 3, a major extrapancreatic trypsinogen, was optimum at pH 8.0, and predominantly detected in estrogenized vaginal epithelium of Fbln5(-/-) mice. PRSS3 was (a) localized in epithelial secretions, (b) detected in media of vaginal organ culture from both Fbln5(-/-) and wild type mice, and (c) cleaved fibulin-5 in vitro. Expression of two serine protease inhibitors [Serpina1a (alpha1-antitrypsin) and Elafin] was dysregulated in Fbln5(-/-) epithelium. Finally, we confirmed that PRSS3 was expressed in human vaginal epithelium and that SERPINA1 and Elafin were downregulated in vaginal tissues from women with POP. These data collectively suggest that the balance between proteases and their inhibitors contributes to support of the pelvic organs in humans and mice. PMID- 23437120 TI - Calreticulin induces dilated cardiomyopathy. AB - BACKGROUND: Calreticulin, a Ca(2+)-buffering chaperone of the endoplasmic reticulum, is highly expressed in the embryonic heart and is essential for cardiac development. After birth, the calreticulin gene is sharply down regulated in the heart, and thus, adult hearts have negligible levels of calreticulin. In this study we tested the role of calreticulin in the adult heart. METHODOLOGY/PRINCIPAL FINDINGS: We generated an inducible transgenic mouse in which calreticulin is targeted to the cardiac tissue using a Cre/loxP system and can be up-regulated in adult hearts. Echocardiography analysis of hearts from transgenic mice expressing calreticulin revealed impaired left ventricular systolic and diastolic function and impaired mitral valve function. There was altered expression of Ca(2+) signaling molecules and the gap junction proteins, Connexin 43 and 45. Sarcoplasmic reticulum associated Ca(2+)-handling proteins (including the cardiac ryanodine receptor, sarco/endoplasmic reticulum Ca(2+) ATPase, and cardiac calsequestrin) were down-regulated in the transgenic hearts with increased expression of calreticulin. CONCLUSIONS/SIGNIFICANCE: We show that in adult heart, up-regulated expression of calreticulin induces cardiomyopathy in vivo leading to heart failure. This is due to an alternation in changes in a subset of Ca(2+) handling genes, gap junction components and left ventricle remodeling. PMID- 23437122 TI - Propulsion in cubomedusae: mechanisms and utility. AB - Evolutionary constraints which limit the forces produced during bell contractions of medusae affect the overall medusan morphospace such that jet propulsion is limited to only small medusae. Cubomedusae, which often possess large prolate bells and are thought to swim via jet propulsion, appear to violate the theoretical constraints which determine the medusan morphospace. To examine propulsion by cubomedusae, we quantified size related changes in wake dynamics, bell shape, swimming and turning kinematics of two species of cubomedusae, Chironex fleckeri and Chiropsella bronzie. During growth, these cubomedusae transitioned from using jet propulsion at smaller sizes to a rowing-jetting hybrid mode of propulsion at larger sizes. Simple modifications in the flexibility and kinematics of their velarium appeared to be sufficient to alter their propulsive mode. Turning occurs during both bell contraction and expansion and is achieved by generating asymmetric vortex structures during both stages of the swimming cycle. Swimming characteristics were considered in conjunction with the unique foraging strategy used by cubomedusae. PMID- 23437121 TI - Ethical attitudes of German specialists in reproductive medicine and legal regulation of preimplantation sex selection in Germany. AB - BACKGROUND: Because of its ethical and social implications, preimplantation sex selection is frequently the subject of debates. METHODS: In 2006, we surveyed specialists in reproductive medicine in Germany using an anonymous questionnaire, including sociodemographic data and questions regarding ethical problems occurring in the practice of reproductive medicine. Most questions focused on preimplantation sex selection, including 10 case vignettes, since these enabled us to describe the most difficult and ethically controversial situations. This is the first survey among specialists in reproductive medicine regarding this topic in Germany. RESULTS: 114 specialists in reproductive medicine participated, 72 males (63%) and 42 females (37%), average age was 48 years (age range 29-67 years). The majority of respondents (79%) favoured a regulation that limits the use of preimplantation sex selection only for medical reasons, such as X-linked diseases (including 18%: summoning an ethics commission for every case). A minority of 18% approved of the use of sex selection for non-medical reasons (4% generally and further 14% for family balancing). 90% had received obvious requests from patients. The highest approval (46%) got the counselling guideline against a preimplantation sex selection and advising a normal pregnancy, if preimplantation sex selection would be allowed in Germany. The majority (67%) was opposed the personal use of preimplantation sex selection for non-medical reasons, but would think about it in medical cases. In opposite to woman, 14% of the men were in favour of personal use for non-medical reasons (p=0,043). 25% of specialists in reproductive medicine feared that an allowance of preimplantation sex selection would cause a shift in the sex ratio. CONCLUSIONS: The majority of German specialists in reproductive medicine opposes preimplantation sex selection for non-medical reasons while recommending preimplantation sex selection for medical reasons, e.g. X-linked diseases like haemophilia. PMID- 23437123 TI - Overexpression of miR -155 promotes proliferation and invasion of human laryngeal squamous cell carcinoma via targeting SOCS1 and STAT3. AB - MicroRNA155 plays an important role in many solid malignancies. Expression and function of miR-155 in laryngeal carcinoma have not been fully understood. This study aims to investigate the expression and function of miR-155 in laryngeal squamous cell carcinoma (LSCC), the relationship between miR-155 and its downstream target suppressor of cytokine signaling 1 (SOCS1)-STAT3 pathway, and the related clinicopathological factors. Sixty-three samples of laryngeal squamous cell carcinoma and twenty-one samples of control mucosa obtained from total laryngectomy cases were analyzed using Western blot analysis and real-time PCR. Hep-2 cells were cultured and transfected with miR-155 mimic and ASO. Cell proliferation, migration and invasion assays were used to determine the role of miR-155 in regulation of LSCC growth, migration, and invasion, respectively. The expression levels of miR-155 in LSCC were significantly higher than those in the control mucosa tissues. Downregulation of SOCS1 expression and elevated expression of STAT3 were also observed in LSCC. The relevance of the three factors were statistically significant. Moreover, knockdown of miR-155 elevated SOCS1expression level, suppressed STAT3 expression, and inhibited hep-2 cells growth, migration and invasion. Whereas overexpression of miR-155 inhibited SOCS1expression, elevated STAT3 expression, and promoted hep-2 cells growth, migration and invasion. Furthermore, the miR-155 levels in T(3) T(4) stages, and poor/moderate cell differentiation were significantly higher than those in T(2) stage and higher degree of cell differentiation. The STAT3 protein in poor/moderate cell differentiation was significantly higher than those in higher degree of cell differentiation. We firstly demonstrated the aberrant expression and function of miR-155 and itsdownstream targets in LSCC. The current findings suggest that miR-155 play promotingrole during the development of LSCC, and miR 155 may be a useful marker for the prognosis and assessment of therapeutic effects. PMID- 23437124 TI - The role of NF-kappaB signaling in the maintenance of pluripotency of human induced pluripotent stem cells. AB - NF-kappaB signaling plays an essential role in maintaining the undifferentiated state of embryonic stem (ES) cells. However, opposing roles of NF-kappaB have been reported in mouse and human ES cells, and the role of NF-kappaB in human induced pluripotent stem (iPS) cells has not yet been clarified. Here, we report the role of NF-kappaB signaling in maintaining the undifferentiated state of human iPS cells. Compared with differentiated cells, undifferentiated human iPS cells showed an augmentation of NF-kappaB activity. During differentiation induced by the removal of feeder cells and FGF2, we observed a reduction in NF kappaB activity, the expression of the undifferentiation markers Oct3/4 and Nanog, and the up-regulation of the differentiated markers WT-1 and Pax-2. The specific knockdown of NF-kappaB signaling using p65 siRNA also reduced the expression of Oct3/4 and Nanog and up-regulated WT-1 and Pax-2 but did not change the ES-like colony formation. Our results show that the augmentation of NF-kappaB signaling maintains the undifferentiated state of human iPS and suggest the importance of this signaling pathway in maintenance of human iPS cells. PMID- 23437125 TI - The Drosophila splicing factor PSI is phosphorylated by casein kinase II and tousled-like kinase. AB - Alternative splicing of pre-mRNA is a highly regulated process that allows cells to change their genetic informational output. These changes are mediated by protein factors that directly bind specific pre-mRNA sequences. Although much is known about how these splicing factors regulate pre-mRNA splicing events, comparatively little is known about the regulation of the splicing factors themselves. Here, we show that the Drosophila splicing factor P element Somatic Inhibitor (PSI) is phosphorylated at at least two different sites by at minimum two different kinases, casein kinase II (CK II) and tousled-like kinase (tlk). These phosphorylation events may be important for regulating protein-protein interactions involving PSI. Additionally, we show that PSI interacts with several proteins in Drosophila S2 tissue culture cells, the majority of which are splicing factors. PMID- 23437126 TI - Physical and emotional health problems experienced by youth engaged in physical fighting and weapon carrying. AB - Then aims of the current study were 1) to provide cross-national estimates of the prevalence of physical fighting and weapon carrying among adolescents aged 11-15 years; (2) To examine the possible effects of physical fighting and weapon carrying on the occurrence of physical (medically treated injuries) and emotional health outcomes (multiple health complaints) among adolescents within the theoretical framework of Problem Behaviour Theory. 20,125 adolescents aged 11-15 in five countries (Belgium, Israel, USA, Canada, FYR Macedonia) were surveyed via the 2006 Health Behaviour in School Aged Children survey. Prevalence was calculated for physical fighting and weapon carrying along with physical and emotional measures that potentially result from violence. Regression analyses were used to quantify associations between violence/weapon carrying and the potential health consequences within each country. Large variations in fighting and weapon carrying were observed across countries. Boys reported more frequent episodes of fighting/weapon carrying and medically attended injuries in every country, while girls reported more emotional symptoms. Although there were some notable variations in findings between different participating countries, increased weapon carrying and physical fighting were both independently and consistently associated with more frequent reports of the potential health outcomes. Adolescents engaging in fighting and weapon carrying are also at risk for physical and emotional health outcomes. Involvement in fighting and weapon carrying can be seen as part of a constellation of risk behaviours with obvious health implications. Our findings also highlight the importance of the cultural context when examining the nature of violent behaviour for adolescents. PMID- 23437127 TI - Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-kappaB. AB - BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is a central transcriptional factor and a pleiotropic regulator of many genes involved in acute lung injury. Andrographolide is found in the plant of Andrographis paniculata and widely used in Traditional Chinese Medicine, exhibiting potently anti-inflammatory property by inhibiting NF-kappaB activity. The purpose of our investigation was designed to reveal the effect of andrographolide on various aspects of LPS induced inflammation in vivo and in vitro. METHODS AND RESULTS: In vivo, BALB/C mice were subjected to LPS injection with or without andrographolide treatments to induce ALI model. In vitro, MLE-12 cells were stimulated with LPS in the presence and absence of andrographolide. In vivo, pulmonary inflammation, pulmonary edema, ultrastructure changes of type II alveolar epithelial cells, MPO activity, total cells, neutrophils, macrophages, TNF-alpha, IL-6 and IL-1beta in BALF, along with the expression of VCAM-1 and VEGF were dose-dependently attenuated by andrographolide. Meanwhile, in vitro, the expression of VCAM-1 and VEGF was also reduced by andrographolide. Moreover, our data showed that andrographolide significantly inhibited the ratios of phospho-IKKbeta/total IKKbeta, phospho IkappaBalpha/total IkappaBalpha and phospho-NF-kappaB p65/total NF-kappaB p65, and NF-kappaB p65 DNA binding activities, both in vivo and in vitro. CONCLUSIONS: These results indicate that andrographolide dose-dependently suppressed the severity of LPS-induced ALI, more likely by virtue of andrographolide-mediated NF kappaB inhibition at the level of IKKbeta activation. These results suggest andrographolide may be considered as an effective and safe drug for the potential treatment of ALI. PMID- 23437128 TI - A novel role for Arabidopsis CBL1 in affecting plant responses to glucose and gibberellin during germination and seedling development. AB - Glucose and phytohormones such as abscisic acid (ABA), ethylene, and gibberellin (GA) coordinately regulate germination and seedling development. However, there is still inadequate evidence to link their molecular roles in affecting plant responses. Calcium acts as a second messenger in a diverse range of signal transduction pathways. As calcium sensors unique to plants, calcineurin B-like (CBL) proteins are well known to modulate abiotic stress responses. In this study, it was found that CBL1 was induced by glucose in Arabidopsis. Loss-of function mutant cbl1 exhibited hypersensitivity to glucose and paclobutrazol, a GA biosynthetic inhibitor. Several sugar-responsive and GA biosynthetic gene expressions were altered in the cbl1 mutant. CBL1 protein physically interacted with AKINbeta1, the regulatory beta subunit of the SnRK1 complex which has a central role in sugar signaling. Our results indicate a novel role for CBL1 in modulating responses to glucose and GA signals. PMID- 23437129 TI - Chromosome copy number variation and control in the ciliate Chilodonella uncinata. AB - Copy number variations are widespread in eukaryotes. The unusual genome architecture of ciliates, in particular, with its process of amitosis in macronuclear division, provides a valuable model in which to study copy number variation. The current model of amitosis envisions stochastic distribution of macronuclear chromosomes during asexual reproduction. This suggests that amitosis is likely to result in high levels of copy number variation in ciliates, as dividing daughter cells can have variable copy numbers of chromosomes if chromosomal distribution during amitosis is a stochastic process. We examined chromosomal distribution during amitosis in Chilodonella uncinata, a ciliate with gene-size macronuclear chromosomes. We quantified 4 chromosomes in evolving populations of C. uncinata and modeled the amitotic distribution process. We found that macronuclear chromosomes differ in copy number from one another but that copy number does not change as expected under a stochastic process. The chromosome carrying SSU increased in copy number, which is consistent with selection to increase abundance; however, two other studied chromosomes displayed much lower than expected among-line variance. Our models suggest that balancing selection is sufficient to explain the observed maintenance of chromosome copy during asexual reproduction. PMID- 23437130 TI - Molecular mapping to species level of the tonsillar crypt microbiota associated with health and recurrent tonsillitis. AB - The human palatine tonsils, which belong to the central antigen handling sites of the mucosal immune system, are frequently affected by acute and recurrent infections. This study compared the microbiota of the tonsillar crypts in children and adults affected by recurrent tonsillitis with that of healthy adults and children with tonsillar hyperplasia. An in-depth 16S rRNA gene based pyrosequencing approach combined with a novel strategy that included phylogenetic analysis and detection of species-specific sequence signatures enabled identification of the major part of the microbiota to species level. A complex microbiota consisting of between 42 and 110 taxa was demonstrated in both children and adults. This included a core microbiome of 12 abundant genera found in all samples regardless of age and health status. Yet, Haemophilus influenzae, Neisseria species, and Streptococcus pneumoniae were almost exclusively detected in children. In contrast, Streptococcus pseudopneumoniae was present in all samples. Obligate anaerobes like Porphyromonas, Prevotella, and Fusobacterium were abundantly present in children, but the species diversity of Porphyromonas and Prevotella was larger in adults and included species that are considered putative pathogens in periodontal diseases, i.e. Porphyromonas gingivalis, Porphyromonas endodontalis, and Tannerella forsythia. Unifrac analysis showed that recurrent tonsillitis is associated with a shift in the microbiota of the tonsillar crypts. Fusobacterium necrophorum, Streptococcus intermedius and Prevotella melaninogenica/histicola were associated with recurrent tonsillitis in adults, whereas species traditionally associated with acute tonsillitis like pyogenic streptococci and Staphylococcus aureus were scarce. The findings suggest that recurrent tonsillitis is a polymicrobial infection in which interactions within consortia of taxa play an etiologic role. The study contributes to the human microbiome data, to the understanding of the etiology of infections affecting the tonsils, and forms a basis for further insight into the consequences of the intense microbe-host interactions that take place in the tonsils. PMID- 23437131 TI - Towards integrated physical activity profiling. AB - Recently, there has been some discussion of whether it is possible to score highly in one dimension of physical activity behaviour (e.g., moderate intensity exercise) whilst also scoring poorly in another (e.g., sedentary time). Interestingly, direct empirical observations to support these proposals are lacking. New technologies now enable the capture of physical activity thermogenesis on a minute-by-minute basis and over a sustained period. We used one of the best available technologies to explore whether individuals can score differently in various physiologically-important physical activity dimensions. We determined minute-by-minute physical activity energy expenditure over 7 days in 100 men aged 28 +/- 9 years. We used combined accelerometry and heart rate with branched equation modelling to estimate energy expenditure and extracted data for key physical activity outcomes and descriptors. Although some physical activity outcomes were tightly correlated, the attainment of one threshold for a given physical activity dimension did not automatically predict how well an individual scored in another dimension (with bivariate correlations ranging from 0.05 to 0.96). In one illustrative example of this heterogeneity, although 41 men showed a relatively low Physical Activity Level (total energy expenditure/resting energy expenditure <= 1.75), only 17% (n=7) of these men showed consistently low physical activity across other dimensions (moderate intensity activity, vigorous intensity activity, and sedentary time). Thus, physical activity is highly heterogeneous and there is no single outcome measure that captures all the relevant information about a given individual. We propose that future studies need to capture (rather than ignore) the different physiologically-important dimensions of physical activity via generation of integrated, multidimensional physical activity 'profiles'. PMID- 23437132 TI - TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease. AB - Thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation by promoting Th2-type responses and has become a potential therapeutic target. Using in vitro T cell differentiation cultures we were able to validate that TSLP played a more critical role in the early development of Th2 immune responses with less significant enhancement of already developed Th2 responses. Adoptive transfer of naive DO11.10 ovalbumin-specific T cells followed by airway exposure to ovalbumin showed an early impairment of Th2 immune response in TSLP-/- mice compared to wild type mice during the development of a Th2 response. In contrast, transfer of already differentiated Th2 cells into TSLP-/- mice did not change lung pathology or Th2 cytokine production upon ovalbumin challenge compared to transfer into wild type mice. An allergen-induced Th2 airway model demonstrated that there was only a difference in gob5 expression (a mucus-associated gene) between wild type and TSLP-/- mice. Furthermore, when allergic animals with established disease were treated with a neutralizing anti TSLP antibody there was no change in airway hyperreponsiveness (AHR) or Th2 cytokine production compared to the control antibody treated animals, whereas a change in gob5 gene expression was also observed similar to the TSLP-/- mouse studies. In contrast, when animals were treated with anti-TSLP during the initial stages of allergen sensitization there was a significant change in Th2 cytokines during the final allergen challenge. Collectively, these studies suggest that in mice TSLP has an important role during the early development of Th2 immune responses, whereas its role at later stages of allergic disease may not be as critical for maintaining the Th2-driven allergic disease. PMID- 23437133 TI - The association between heme oxygenase-1 gene promoter polymorphism and the outcomes of catheter ablation of atrial fibrillation. AB - A length polymorphism of GT repeats in the promoter region of the human heme oxygenase-1 (HO-1) gene modulates its gene transcription to protect against myocardial injury. The present study investigated the association between HO-1 promoter polymorphisms and the outcomes of catheter ablation of atrial fibrillation (AF). The allelic frequencies of GT repeats in the HO-1 gene promoter were screened in 205 random individuals who underwent catheter ablation for drug refractory AF.In the patients who received catheter ablation, those with AF recurrence had fewer GT repeats (53.4+/-7.1 vs. 56.1+/-6.5, p = 0.004), a lower incidence of hyperlipidemia, more non-paroxysmal AF, and a larger left atrial diameter. After conducting a multivariate logistic analysis, the number of GT repeats (Odds ratio: 0.94, 95% CI 0.90-0.99, p = 0.01) and the diameter of the left atrium (Odds ratio: 1.08, 95% CI 1.02-1.15, p = 0.01) remained independent predictors. The carriers of GT repeats, which were <29 in both alleles, were associated with a lower sinus maintenance rate after catheter ablation (38.5% vs. 60.1%, p = 0.003). The patients were divided into paroxysmal and non-paroxysmal AF groups; the number of GT repeats was associated with AF recurrence only in the patients with paroxysmal AF. The number of GT repeats, combined with LAD, was significant for predicting AF recurrence after catheter ablation (p = 0.01). The number of GT repeats was not found to be associated with differences in the left atrial diameter, the biatrial voltage, or the levels of bilirubin, ferritin, iron, C-reactive protein, or von-Willibrand factor. In conclusions, HO-1 gene promoter polymorphisms were associated with AF recurrence after catheter ablation. PMID- 23437134 TI - Prevalence of hepatitis B in insular regions of southeast China: a community based study. AB - OBJECTIVE: Hepatitis B virus (HBV) infection remains a significant public health problem. The purpose of this study was to investigate the seroepidemiology of HBV in people living in the insular regions, and to provide the most recent baseline data for planning and monitoring of health. METHODS: A cross-sectional, community based survey was conducted without age restriction, on two isolated islands, Zhoushan and Yuhuan, China. The study sample was selected by random multistage cluster sampling. Serological samples and demographic information were collected from 15878 participants. RESULTS: The prevalences of anti-HBV core antibody (anti HBc), hepatitis B virus surface antigen (HBsAg), and anti-HBV surface antibody (anti-HBs) were 33.1, 10.4, and 56.1%, respectively. We found statistically significant differences of HBV markers in men versus women (P<0.01). The prevalence of HBV infection increased with age. There were significant differences in the rates of HBsAg and anti-HBc positivity between the two islands (P<0.01). Alanine aminotransferase (ALT) levels were elevated (>38 IU/L) in 15.6% and 7.2% of the HBsAg-positive and negative groups, respectively. Elevated ALT levels were significantly higher in males (12.0%) compared with females (5.8%) (P<0.01). The alpha-fetoprotein (AFP) positivity rate was 0.6% in HBsAg-positive participants over the age of 30. CONCLUSION: Due to the geographic location, we found that the HBV prevalence and potential for the development of hepatocellular carcinoma remained high in insular regions of southeast China, and are far above the national figures. Although a vaccination program has been in effect over the last 20 years, several additional measures should be adopted by the government to limit the spread of hepatitis B. These include the management of high risk persons and the floating population living on the islands, expansion of the immune population, and increased health education for fisherman. PMID- 23437135 TI - Retention in care of HIV-infected children from HIV test to start of antiretroviral therapy: systematic review. AB - BACKGROUND: In adults it is well documented that there are substantial losses to the programme between HIV testing and start of antiretroviral therapy (ART). The magnitude and reasons for loss to follow-up and death between HIV diagnosis and start of ART in children are not well defined. METHODS: We searched the PubMed and EMBASE databases for studies on children followed between HIV diagnosis and start of ART in low-income settings. We examined the proportion of children with a CD4 cell count/percentage after after being diagnosed with HIV infection, the number of treatment-eligible children starting ART and predictors of loss to programme. Data were extracted in duplicate. RESULTS: Eight studies from sub Saharan Africa and two studies from Asia with a total of 10,741 children were included. Median age ranged from 2.2 to 6.5 years. Between 78.0 and 97.0% of HIV infected children subsequently had a CD4 cell count/percentage measured, 63.2 to 90.7% of children with an eligibility assessment met the eligibility criteria for the particular setting and time and 39.5 to 99.4% of the eligible children started ART. Three studies reported an association between low CD4 count/percentage and ART initiation while no association was reported for gender. Only two studies reported on pre-ART mortality and found rates of 13 and 6 per 100 person-years. CONCLUSION: Most children who presented for HIV care met eligibility criteria for ART. There is an urgent need for strategies to improve the access to and retention to care of HIV-infected children in resource-limited settings. PMID- 23437136 TI - Improved detection of remote homologues using cascade PSI-BLAST: influence of neighbouring protein families on sequence coverage. AB - BACKGROUND: Development of sensitive sequence search procedures for the detection of distant relationships between proteins at superfamily/fold level is still a big challenge. The intermediate sequence search approach is the most frequently employed manner of identifying remote homologues effectively. In this study, examination of serine proteases of prolyl oligopeptidase, rhomboid and subtilisin protein families were carried out using plant serine proteases as queries from two genomes including A. thaliana and O. sativa and 13 other families of unrelated folds to identify the distant homologues which could not be obtained using PSI-BLAST. METHODOLOGY/PRINCIPAL FINDINGS: We have proposed to start with multiple queries of classical serine protease members to identify remote homologues in families, using a rigorous approach like Cascade PSI-BLAST. We found that classical sequence based approaches, like PSI-BLAST, showed very low sequence coverage in identifying plant serine proteases. The algorithm was applied on enriched sequence database of homologous domains and we obtained overall average coverage of 88% at family, 77% at superfamily or fold level along with specificity of ~100% and Mathew's correlation coefficient of 0.91. Similar approach was also implemented on 13 other protein families representing every structural class in SCOP database. Further investigation with statistical tests, like jackknifing, helped us to better understand the influence of neighbouring protein families. CONCLUSIONS/SIGNIFICANCE: Our study suggests that employment of multiple queries of a family for the Cascade PSI-BLAST searches is useful for predicting distant relationships effectively even at superfamily level. We have proposed a generalized strategy to cover all the distant members of a particular family using multiple query sequences. Our findings reveal that prior selection of sequences as query and the presence of neighbouring families can be important for covering the search space effectively in minimal computational time. This study also provides an understanding of the 'bridging' role of related families. PMID- 23437137 TI - Local and regional determinants of colonisation-extinction dynamics of a riparian mainland-island root vole metapopulation. AB - The role of local habitat geometry (habitat area and isolation) in predicting species distribution has become an increasingly more important issue, because habitat loss and fragmentation cause species range contraction and extinction. However, it has also become clear that other factors, in particular regional factors (environmental stochasticity and regional population dynamics), should be taken into account when predicting colonisation and extinction. In a live trapping study of a mainland-island metapopulation of the root vole (Microtus oeconomus) we found extensive occupancy dynamics across 15 riparian islands, but yet an overall balance between colonisation and extinction over 4 years. The 54 live trapping surveys conducted over 13 seasons revealed imperfect detection and proxies of population density had to be included in robust design, multi-season occupancy models to achieve unbiased rate estimates. Island colonisation probability was parsimoniously predicted by the multi-annual density fluctuations of the regional mainland population and local island habitat quality, while extinction probability was predicted by island population density and the level of the recent flooding events (the latter being the main regionalized disturbance regime in the study system). Island size and isolation had no additional predictive power and thus such local geometric habitat characteristics may be overrated as predictors of vole habitat occupancy relative to measures of local habitat quality. Our results suggest also that dynamic features of the larger region and/or the metapopulation as a whole, owing to spatially correlated environmental stochasticity and/or biotic interactions, may rule the colonisation extinction dynamics of boreal vole metapopulations. Due to high capacities for dispersal and habitat tracking voles originating from large source populations can rapidly colonise remote and small high quality habitat patches and re establish populations that have gone extinct due to demographic (small population size) and environmental stochasticity (e.g. extreme climate events). PMID- 23437138 TI - Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. AB - OBJECTIVE: To estimate the risk of serious adverse reactions to benzathine penicillin in pregnant women for preventing congenital syphilis. METHODS: We searched for clinical trials or cohorts that assessed the incidence of serious adverse reactions to benzathine penicillin in pregnant women and the general population (indirect evidence). MEDLINE, EMBASE, Scopus and other databases were searched up to December 2012. The GRADE approach was used to assess quality of evidence. Absolute risks of each study were calculated along with their 95% confidence intervals (95% CI). We employed the DerSimonian and Laird random effects model in the meta-analyses. RESULTS: From 2,765 retrieved studies we included 13, representing 3,466,780 patients. The studies that included pregnant women were conducted to demonstrate the effectiveness of benzathine penicillin: no serious adverse reactions were reported among the 1,244 pregnant women included. In the general population, among 2,028,982 patients treated, 4 died from an adverse reaction. The pooled risk of death was virtually zero. Fifty-four cases of anaphylaxis were reported (pooled absolute risk = 0.002%; 95% CI: 0% 0.003% I(2) = 12%). From that estimate, penicillin treatment would be expected to result in an incidence of 0 to 3 cases of anaphylaxis per 100,000 treated. Any adverse reactions were reported in 6,377 patients among 3,465,322 treated with penicillin (pooled absolute risk = 0.169%; 95% CI: 0.073%-0.265% I(2) = 97%). The quality of evidence was very low. CONCLUSION: Studies that assessed the risk of serious adverse events due to benzathine penicillin treatment in pregnant women were scarce, but no reports of adverse reactions were found. The incidence of severe adverse outcomes was very low in the general population. The risk of treating pregnant women with benzathine penicillin to prevent congenital syphilis appears very low and does not outweigh its benefits. Further research is needed to improve the quality of evidence. PMID- 23437139 TI - Diversity of Termitomyces associated with fungus-farming termites assessed by cultural and culture-independent methods. AB - BACKGROUND: Fungus-cultivating termites make use of an obligate mutualism with fungi from the genus Termitomyces, which are acquired through either vertical transmission via reproductive alates or horizontally transmitted during the formation of new mounds. Termitomyces taxonomy, and thus estimating diversity and host specificity of these fungi, is challenging because fruiting bodies are rarely found. Molecular techniques can be applied but need not necessarily yield the same outcome than morphological identification. METHODOLOGY: Culture dependent and culture-independent methods were used to comprehensively assess host specificity and gut fungal diversity. Termites were identified using mitochondrial cytochrome oxidase II (COII) genes. Twenty-three Termitomyces cultures were isolated from fungal combs. Internal transcribed spacer (ITS) clone libraries were constructed from termite guts. Presence of Termitomyces was confirmed using specific and universal primers. Termitomyces species boundaries were estimated by cross-comparison of macromorphological and sequence features, and ITS clustering parameters accordingly optimized. The overall trends in coverage of Termitomyces diversity and host associations were estimated using Genbank data. RESULTS AND CONCLUSION: Results indicate a monoculture of Termitomyces in the guts as well as the isolation sources (fungal combs). However, cases of more than one Termitomyces strains per mound were observed since mounds can contain different termite colonies. The newly found cultures, as well as the clustering analysis of GenBank data indicate that there are on average between one and two host genera per Termitomyces species. Saturation does not appear to have been reached, neither for the total number of known Termitomyces species nor for the number of Termitomyces species per host taxon, nor for the number of known hosts per Termitomyces species. Considering the rarity of Termitomyces fruiting bodies, it is suggested to base the future taxonomy of the group mainly on well-characterized and publicly accessible cultures. PMID- 23437140 TI - Biological characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl) propylidene]-thiazolidine-2,4-dione (K145) as a selective sphingosine kinase-2 inhibitor and anticancer agent. AB - In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3 (4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors. PMID- 23437141 TI - Selective Akt inhibitors synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant FLT3-positive AML cells. AB - OBJECTIVES: Tyrosine kinase inhibitor (TKI)-treated acute myeloid leukemia (AML) patients commonly show rapid and significant peripheral blood blast cell reduction, however a marginal decrease in bone marrow blasts. This suggests a protective environment and highlights the demand for a better understanding of stromal:leukemia cell communication. As a strategy to improve clinical efficacy, we searched for novel agents capable of potentiating the stroma-diminished effects of TKI treatment of mutant FLT3-expressing cells. METHODS: We designed a combinatorial high throughput drug screen using well-characterized kinase inhibitor-focused libraries to identify novel kinase inhibitors capable of overriding stromal-mediated resistance to TKIs, such as PKC412 and AC220. Standard liquid culture proliferation assays, cell cycle and apoptosis analysis, and immunoblotting were carried out with cell lines or primary AML to validate putative candidates from the screen and characterize the mechanism(s) underlying observed synergy. RESULTS AND CONCLUSIONS: Our study led to the observation of synergy between selective Akt inhibitors and FLT3 inhibitors against mutant FLT3 positive AML in either the absence or presence of stroma. Our findings are consistent with evidence that Akt activation is characteristic of mutant FLT3 transformed cells, as well as observed residual Akt activity following FLT3 inhibitor treatment. In conclusion, our study highlights the potential importance of Akt as a signaling factor in leukemia survival, and supports the use of the co culture chemical screen to identify agents able to potentiate TKI anti-leukemia activity in a cytoprotective microenvironment. PMID- 23437142 TI - Body mass index, muscle strength and physical performance in older adults from eight cohort studies: the HALCyon programme. AB - OBJECTIVE: To investigate the associations of body mass index (BMI) and grip strength with objective measures of physical performance (chair rise time, walking speed and balance) including an assessment of sex differences and non linearity. METHODS: Cross-sectional data from eight UK cohort studies (total N = 16,444) participating in the Healthy Ageing across the Life Course (HALCyon) research programme, ranging in age from 50 to 90+ years at the time of physical capability assessment, were used. Regression models were fitted within each study and meta-analysis methods used to pool regression coefficients across studies and to assess the extent of heterogeneity between studies. RESULTS: Higher BMI was associated with poorer performance on chair rise (N = 10,773), walking speed (N = 9,761) and standing balance (N = 13,921) tests. Higher BMI was associated with stronger grip strength in men only. Stronger grip strength was associated with better performance on all tests with a tendency for the associations to be stronger in women than men; for example, walking speed was higher by 0.43 cm/s (0.14, 0.71) more per kg in women than men. Both BMI and grip strength remained independently related with performance after mutual adjustment, but there was no evidence of effect modification. Both BMI and grip strength exhibited non-linear relations with performance; those in the lowest fifth of grip strength and highest fifth of BMI having particularly poor performance. Findings were similar when waist circumference was examined in place of BMI. CONCLUSION: Older men and women with weak muscle strength and high BMI have considerably poorer performance than others and associations were observed even in the youngest cohort (age 53). Although causality cannot be inferred from observational cross-sectional studies, our findings suggest the likely benefit of early assessment and interventions to reduce fat mass and improve muscle strength in the prevention of future functional limitations. PMID- 23437143 TI - Estimating air temperature and its influence on malaria transmission across Africa. AB - Malaria transmission is strongly influenced by climatic conditions which determine the abundance and seasonal dynamics of the Anopheles vector. In particular, water temperature influences larval development rates whereas air temperature determines adult longevity as well as the rate of parasite development within the adult mosquito. Although data on land surface temperature exist at a spatial resolution of approximately 1 km globally with four time steps per day, comparable data are not currently available for air temperature. In order to address this gap and demonstrate the importance of using the right type of temperature data, we fitted simple models of the relationship between land surface and air temperature at lower resolution to obtain a high resolution estimate of air temperature across Africa. We then used these estimates to calculate some crucial malaria transmission parameters that strongly depend on air temperatures. Our results demonstrate substantial differences between air and surface temperatures that impact temperature-based maps of areas suitable for transmission. We present high resolution maps of the malaria transmission parameters driven by air temperature and their seasonal variation. The fitted air temperature datasets are made publicly available alongside this publication. PMID- 23437145 TI - Nucleotide polymorphisms and haplotype diversity of RTCS gene in China elite maize inbred lines. AB - The maize RTCS gene, encoding a LOB domain transcription factor, plays important roles in the initiation of embryonic seminal and postembryonic shoot-borne root. In this study, the genomic sequences of this gene in 73 China elite inbred lines, including 63 lines from 5 temperate heteroric groups and 10 tropic germplasms, were obtained, and the nucleotide polymorphisms and haplotype diversity were detected. A total of 63 sequence variants, including 44 SNPs and 19 indels, were identified at this locus, and most of them were found to be located in the regions of UTR and intron. The coding region of this gene in all tested inbred lines carried 14 haplotypes, which encoding 7 deferring RTCS proteins. Analysis of the polymorphism sites revealed that at least 6 recombination events have occurred. Among all 6 groups tested, only the P heterotic group had a much lower nucleotide diversity than the whole set, and selection analysis also revealed that only this group was under strong negative selection. However, the set of Huangzaosi and its derived lines possessed a higher nucleotide diversity than the whole set, and no selection signal were identified. PMID- 23437144 TI - Effect of calcitriol on bone turnover and osteocalcin in recent-onset type 1 diabetes. AB - BACKGROUND: Vitamin D supplementation in childhood improves the achievement of peak bone mass. We investigated the effect of supplementation with calcitriol on bone turnover in recent-onset type 1 diabetes (T1D). Moreover, the association between osteocalcin and parameters of beta-cell function and metabolic control was examined. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a post-hoc analysis of a double-blind, placebo-controlled study of calcitriol supplementation to preserve beta-cell function. 27 recent-onset T1D subjects, mean age 22 years, were randomized to 0.25 ug calcitriol per day or placebo (1:1) and followed up for one year. Changes in bone formation (osteoclacin) and resorption (beta CrossLaps) markers, and differences between placebo and calcitriol-treated group were evaluated. At baseline, osteocalcin levels were significantly lower in female than in male patients (P<0.01) while no other metabolic parameters as HbA1c and C-peptide differed between gender. No significant correlations were found in relation to HbA1c, insulin requirement and C-peptide. At 1 year follow up, no significant differences were observed between calcitriol and placebo groups for osteocalcin and beta-CrossLaps. In the placebo group osteocalcin levels were unrelated with parameters of metabolic control, such as C-peptide, insulin requirement or HbA1c. Changes of C-peptide, insulin requirement and HbA1c were not related to osteocalcin levels. CONCLUSIONS: Supplementation with 0.25 ug calcitriol per day to patients with new-onset T1D does not affect circulating markers of bone turnover. OC levels were unrelated to beta-cell function and other metabolic parameters suggesting that OC is ineffective to control pancreatic function in presence of aggressive autoimmune destruction. PMID- 23437146 TI - Hierarchical classification of protein folds using a novel ensemble classifier. AB - The analysis of biological information from protein sequences is important for the study of cellular functions and interactions, and protein fold recognition plays a key role in the prediction of protein structures. Unfortunately, the prediction of protein fold patterns is challenging due to the existence of compound protein structures. Here, we processed the latest release of the Structural Classification of Proteins (SCOP, version 1.75) database and exploited novel techniques to impressively increase the accuracy of protein fold classification. The techniques proposed in this paper include ensemble classifying and a hierarchical framework, in the first layer of which similar or redundant sequences were deleted in two manners; a set of base classifiers, fused by various selection strategies, divides the input into seven classes; in the second layer of which, an analogous ensemble method is adopted to predict all protein folds. To our knowledge, it is the first time all protein folds can be intelligently detected hierarchically. Compared with prior studies, our experimental results demonstrated the efficiency and effectiveness of our proposed method, which achieved a success rate of 74.21%, which is much higher than results obtained with previous methods (ranging from 45.6% to 70.5%). When applied to the second layer of classification, the prediction accuracy was in the range between 23.13% and 46.05%. This value, which may not be remarkably high, is scientifically admirable and encouraging as compared to the relatively low counts of proteins from most fold recognition programs. The web server Hierarchical Protein Fold Prediction (HPFP) is available at http://datamining.xmu.edu.cn/software/hpfp. PMID- 23437147 TI - Expression and purification of functional human mu opioid receptor from E.coli. AB - N-terminally his-tagged human mu opioid receptor, a G protein-coupled receptor was produced in E.coli employing synthetic codon-usage optimized constructs. The receptor was expressed in inclusion bodies and membrane-inserted in different E.coli strains. By optimizing the expression conditions the expression level for the membrane-integrated receptor was raised to 0.3-0.5 mg per liter of culture. Milligram quantities of receptor could be enriched by affinity chromatography from IPTG induced cultures grown at 18 degrees C. By size exclusion chromatography the protein fraction with the fraction of alpha-helical secondary structure expected for a 7-TM receptor was isolated, by CD-spectroscopy an alpha helical content of ca. 45% was found for protein solubilised in the detergent Fos 12. Receptor in Fos-12 micelles was shown to bind endomorphin-1 with a K(D) of 61 nM. A final yield of 0.17 mg functional protein per liter of culture was obtained. PMID- 23437148 TI - High-fidelity tissue engineering of patient-specific auricles for reconstruction of pediatric microtia and other auricular deformities. AB - INTRODUCTION: Autologous techniques for the reconstruction of pediatric microtia often result in suboptimal aesthetic outcomes and morbidity at the costal cartilage donor site. We therefore sought to combine digital photogrammetry with CAD/CAM techniques to develop collagen type I hydrogel scaffolds and their respective molds that would precisely mimic the normal anatomy of the patient specific external ear as well as recapitulate the complex biomechanical properties of native auricular elastic cartilage while avoiding the morbidity of traditional autologous reconstructions. METHODS: Three-dimensional structures of normal pediatric ears were digitized and converted to virtual solids for mold design. Image-based synthetic reconstructions of these ears were fabricated from collagen type I hydrogels. Half were seeded with bovine auricular chondrocytes. Cellular and acellular constructs were implanted subcutaneously in the dorsa of nude rats and harvested after 1 and 3 months. RESULTS: Gross inspection revealed that acellular implants had significantly decreased in size by 1 month. Cellular constructs retained their contour/projection from the animals' dorsa, even after 3 months. Post-harvest weight of cellular constructs was significantly greater than that of acellular constructs after 1 and 3 months. Safranin O-staining revealed that cellular constructs demonstrated evidence of a self-assembled perichondrial layer and copious neocartilage deposition. Verhoeff staining of 1 month cellular constructs revealed de novo elastic cartilage deposition, which was even more extensive and robust after 3 months. The equilibrium modulus and hydraulic permeability of cellular constructs were not significantly different from native bovine auricular cartilage after 3 months. CONCLUSIONS: We have developed high-fidelity, biocompatible, patient-specific tissue-engineered constructs for auricular reconstruction which largely mimic the native auricle both biomechanically and histologically, even after an extended period of implantation. This strategy holds immense potential for durable patient-specific tissue-engineered anatomically proper auricular reconstructions in the future. PMID- 23437149 TI - Profiling of RNA degradation for estimation of post mortem [corrected] interval. AB - An estimation of the post mortem interval (PMI) is frequently touted as the Holy Grail of forensic pathology. During the first hours after death, PMI estimation is dependent on the rate of physical observable modifications including algor, rigor and livor mortis. However, these assessment methods are still largely unreliable and inaccurate. Alternatively, RNA has been put forward as a valuable tool in forensic pathology, namely to identify body fluids, estimate the age of biological stains and to study the mechanism of death. Nevertheless, the attempts to find correlation between RNA degradation and PMI have been unsuccessful. The aim of this study was to characterize the RNA degradation in different post mortem tissues in order to develop a mathematical model that can be used as coadjuvant method for a more accurate PMI determination. For this purpose, we performed an eleven-hour kinetic analysis of total extracted RNA from murine's visceral and muscle tissues. The degradation profile of total RNA and the expression levels of several reference genes were analyzed by quantitative real time PCR. A quantitative analysis of normalized transcript levels on the former tissues allowed the identification of four quadriceps muscle genes (Actb, Gapdh, Ppia and Srp72) that were found to significantly correlate with PMI. These results allowed us to develop a mathematical model with predictive value for estimation of the PMI (confidence interval of +/-51 minutes at 95%) that can become an important complementary tool for traditional methods. PMID- 23437150 TI - Primary analysis of the expressed sequence tags in a pentastomid nymph cDNA library. AB - BACKGROUND: Pentastomiasis is a rare zoonotic disease caused by pentastomids. Despite their worm-like appearance, they are commonly placed into a separate sub class of the subphylum Crustacea, phylum Arthropoda. However, until now, the systematic classification of the pentastomids and the diagnosis of pentastomiasis are immature, and genetic information about pentastomid nylum is almost nonexistent. The objective of this study was to obtain information on pentastomid nymph genes and identify the gene homologues related to host-parasite interactions or stage-specific antigens. METHODOLOGY/PRINCIPAL FINDINGS: Total pentastomid nymph RNA was used to construct a cDNA library and 500 colonies were sequenced. Analysis shows one hundred and ninety-seven unigenes were identified. In which, 147 genes were annotated, and 75 unigenes (53.19%) were mapped to 82 KEGG pathways, including 29 metabolism pathways, 29 genetic information processing pathways, 4 environmental information processing pathways, 7 cell motility pathways and 5 organismal systems pathways. Additionally, two host parasite interaction-related gene homologues, a putative Kunitz inhibitor and a putative cysteine protease. CONCLUSION/SIGNIFICANCE: We first successfully constructed a cDNA library and gained a number of expressed sequence tags (EST) from pentastomid nymphs, which will lay the foundation for the further study on pentastomids and pentastomiasis. PMID- 23437151 TI - FCHSD1 and FCHSD2 are expressed in hair cell stereocilia and cuticular plate and regulate actin polymerization in vitro. AB - Mammalian FCHSD1 and FCHSD2 are homologous proteins containing an amino-terminal F-BAR domain and two SH3 domains near their carboxyl-termini. We report here that FCHSD1 and FCHSD2 are expressed in mouse cochlear sensory hair cells. FCHSD1 mainly localizes to the cuticular plate, whereas FCHSD2 mainly localizes along the stereocilia in a punctuate pattern. Nervous Wreck (Nwk), the Drosophila ortholog of FCHSD1 and FCHSD2, has been shown to bind Wsp and play an important role in F-actin assembly. We show that, like its Drosophila counterpart, FCHSD2 interacts with WASP and N-WASP, the mammalian orthologs of Drosophila Wsp, and stimulates F-actin assembly in vitro. In contrast, FCHSD1 doesn't bind WASP or N WASP, and can't stimulate F-actin assembly when tested in vitro. We found, however, that FCHSD1 binds via its F-BAR domain to the SH3 domain of Sorting Nexin 9 (SNX9), a well characterized BAR protein that has been shown to promote WASP-Arp2/3-dependent F-actin polymerization. FCHSD1 greatly enhances SNX9's WASP Arp2/3-dependent F-actin polymerization activity. In hair cells, SNX9 was detected in the cuticular plate, where it colocalizes with FCHSD1. Our results suggest that FCHSD1 and FCHSD2 could modulate F-actin assembly or maintenance in hair cell stereocilia and cuticular plate. PMID- 23437152 TI - Derivation of a germline competent transgenic Fischer 344 embryonic stem cell line. AB - Embryonic stem (ES) cell-based gene manipulation is an effective method for the generation of mutant animal models in mice and rats. Availability of germline competent ES cell lines from inbred rat strains would allow for creation of new genetically modified models in the desired genetic background. Fischer344 (F344) males carrying an enhanced green fluorescence protein (EGFP) transgene were used as the founder animals for the derivation of ES cell lines. After establishment of ES cell lines, rigorous quality control testing that included assessment of pluripotency factor expression, karyotype analysis, and pathogen/sterility testing was conducted in selected ES cell lines. One male ES cell line, F344 Tg.EC4011, was further evaluated for germline competence by injection into Dark Agouti (DA) X Sprague Dawley (SD) blastocysts. Resulting chimeric animals were bred with wild-type SD mates and germline transmissibility of the ES cell line was confirmed by identification of pups carrying the ES cell line-derived EGFP transgene. This is the first report of a germline competent F344 ES cell line. The availability of a new germline competent ES cell line with a stable fluorescence reporter from an inbred transgenic rat strain provides an important new resource for genetic manipulations to create new rat models. PMID- 23437153 TI - Multiple consequences of a single amino acid pathogenic RTK mutation: the A391E mutation in FGFR3. AB - The A391E mutation in fibroblast growth factor receptor 3 (FGFR3) is the genetic cause for Crouzon syndrome with Acanthosis Nigricans. Here we investigate the effect of this mutation on FGFR3 activation in HEK 293 T cells over a wide range of fibroblast growth factor 1 concentrations using a physical-chemical approach that deconvolutes the effects of the mutation on dimerization, ligand binding, and efficiency of phosphorylation. It is believed that the mutation increases FGFR3 dimerization, and our results verify this. However, our results also demonstrate that the increase in dimerization is not the sole effect of the mutation, as the mutation also facilitates the phosphorylation of critical tyrosines in the activation loop of FGFR3. The activation of mutant FGFR3 is substantially increased due to a combination of these two effects. The low expression of the mutant, however, attenuates its signaling and may explain the mild phenotype in Crouzon syndrome with Acanthosis Nigricans. The results presented here provide new knowledge about the physical basis behind growth disorders and highlight the fact that a single RTK mutation may affect multiple steps in RTK activation. PMID- 23437154 TI - Significant molecular and systemic adaptations after repeated sprint training in hypoxia. AB - While intermittent hypoxic training (IHT) has been reported to evoke cellular responses via hypoxia inducible factors (HIFs) but without substantial performance benefits in endurance athletes, we hypothesized that repeated sprint training in hypoxia could enhance repeated sprint ability (RSA) performed in normoxia via improved glycolysis and O(2) utilization. 40 trained subjects completed 8 cycling repeated sprint sessions in hypoxia (RSH, 3000 m) or normoxia (RSN, 485 m). Before (Pre-) and after (Post-) training, muscular levels of selected mRNAs were analyzed from resting muscle biopsies and RSA tested until exhaustion (10-s sprint, work-to-rest ratio 1:2) with muscle perfusion assessed by near-infrared spectroscopy. From Pre- to Post-, the average power output of all sprints in RSA was increased (p<0.01) to the same extent (6% vs 7%, NS) in RSH and in RSN but the number of sprints to exhaustion was increased in RSH (9.4+/-4.8 vs. 13.0+/-6.2 sprints, p<0.01) but not in RSN (9.3+/-4.2 vs. 8.9+/ 3.5). mRNA concentrations of HIF-1alpha (+55%), carbonic anhydrase III (+35%) and monocarboxylate transporter-4 (+20%) were augmented (p<0.05) whereas mitochondrial transcription factor A (-40%), peroxisome proliferator-activated receptor gamma coactivator 1alpha (-23%) and monocarboxylate transporter-1 (-36%) were decreased (p<0.01) in RSH only. Besides, the changes in total hemoglobin variations (Delta[tHb]) during sprints throughout RSA test increased to a greater extent (p<0.01) in RSH. Our findings show larger improvement in repeated sprint performance in RSH than in RSN with significant molecular adaptations and larger blood perfusion variations in active muscles. PMID- 23437155 TI - Interferon-alpha is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers. AB - Type-I interferon (IFN-I) has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFNalpha in HCV-infected subjects to model the effect of IFNalpha on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012), and IFNalpha was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001). IFNalpha was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFNalpha mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFNalpha in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003) and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009). In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003). These studies identify IFNalpha derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection. PMID- 23437156 TI - Performance of the 2010 classification criteria for rheumatoid arthritis: a systematic literature review and a meta-analysis. AB - OBJECTIVES: To evaluate the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria for rheumatoid arthritis (RA) with a systematic literature review and a meta analysis. METHODS: PubMed, Embase, Cochrane Library and the abstracts of the ACR and EULAR meetings (2010-2012) were searched for original articles or abstracts with the following inclusion criteria: 1) recent onset arthritis, with at least one swollen joint and no alternative diagnosis; 2) the ACR/EULAR 2010 criteria as index test; 3) the prescription of methotrexate (MTX) or disease modifying antirheumatic drugs (DMARDs) at any time during follow-up as reference standard. Data were pooled using the bivariate model. Three meta-analyses were performed with MTX (primary analysis), DMARDs or their combination (secondary analyses) as reference standard. Heterogeneity was formally tested and explored performing an influence analysis. RESULTS: The search identified 1,277 references. Six full papers and 4 abstracts met the inclusion criteria. With MTX as reference standard, sensitivity (95% confidence interval, CI) was 0.80 (0.74,0.85), specificity 0.61 (0.56,0.67), positive likelihood ratio (LR) 2.11 (1.92,2.32), negative LR 0.31 (0.25,0.38) and the diagnostic odds ratio (DOR) was 6.74 (5.49,8.28). Using DMARDs as reference standard, sensitivity was 0.73 (0.64,0.80), specificity was 0.74 (0.68,0.79), LR+2.85 (2.53,3.22), LR- 0.35 (0.27,0.45) and DOR 8.03 (6.4,10.09). Using the combination of MTX and DMARDs as reference standard, intermediate results were obtained. The influence analysis detected one potentially influential study. However, its exclusion from the meta analysis did not have a clinically relevant impact on the results. CONCLUSIONS: The new classification criteria have good sensitivity, lower specificity and an overall moderate diagnostic accuracy. These results confirm that the criteria have classificative and not diagnostic function. PMID- 23437157 TI - Staphylococcus aureus FepA and FepB proteins drive heme iron utilization in Escherichia coli. AB - EfeUOB-like tripartite systems are widespread in bacteria and in many cases they are encoded by genes organized into iron-regulated operons. They consist of: EfeU, a protein similar to the yeast iron permease Ftrp1; EfeO, an extracytoplasmic protein of unknown function and EfeB, also an extracytoplasmic protein with heme peroxidase activity, belonging to the DyP family. Many bacterial EfeUOB systems have been implicated in iron uptake, but a prefential iron source remains undetermined. Nevertheless, in the case of Escherichia coli, the EfeUOB system has been shown to recognize heme and to allow extracytoplasmic heme iron extraction via a deferrochelation reaction. Given the high level of sequence conservations between EfeUOB orthologs, we hypothesized that heme might be the physiological iron substrate for the other orthologous systems. To test this hypothesis, we undertook characterization of the Staphylococcus aureus FepABC system. Results presented here indicate: i) that the S. aureus FepB protein binds both heme and PPIX with high affinity, like EfeB, the E. coli ortholog; ii) that it has low peroxidase activity, comparable to that of EfeB; iii) that both FepA and FepB drive heme iron utilization, and both are required for this activity and iv) that the E. coli FepA ortholog (EfeO) cannot replace FepA in FepB-driven iron release from heme indicating protein specificity in these activities. Our results show that the function in heme iron extraction is conserved in the two orthologous systems. PMID- 23437158 TI - Polycomb domain formation depends on short and long distance regulatory cues. AB - BACKGROUND: Polycomb group (PcG) proteins dynamically define cellular identities through the epigenetic repression of key developmental genes. In Drosophila, cis regulatory regions termed PcG response elements (PREs) act as nucleation sites for PcG proteins to create large repressive PcG domains that are marked by trimethylation of lysine 27 on histone H3 (H3K27me3). In addition to an action in cis, PREs can interact over long distances, thereby enhancing PcG dependent silencing. How PcG domains are established, which factors limit their propagation in cis, and how long range interactions of PREs in trans affect the chromatin structure is largely unknown. PRINCIPAL FINDINGS: We demonstrate that the insertion of a PRE-containing transgene in the Drosophila genome generates an artificial PcG domain and we analyze its organization by quantitative ChIP and ChIP-on-chip experiments. Intriguingly, a boundary element and known insulator proteins do not necessarily interfere with spreading of H3K27me3. Instead, domain borders correlate with the presence of promoter regions bound by RNA Polymerase II and active chromatin marks. In contrast, genes that are silent during early fly development get included within the PcG domain and this incorporation interferes with gene activation at later developmental stages. Moreover, trans interaction of the transgenic PRE with its homologous endogenous PRE results in increased PcG binding, correlating with reinforced silencing of genes within the domain borders. CONCLUSIONS: Our results suggest that higher-order organization of PcG-bound chromatin can stabilize gene silencing within PcG domains. Further we propose that multi-protein complexes associated with active promoters are able to define the limits of PcG domains. Future work aimed to pinpoint the factors providing this barrier function will be required to understand the precise molecular mechanism by which active promoter regions can act as boundaries to stop spreading of H3K27me3. PMID- 23437159 TI - Fungi benefit from two decades of increased nutrient availability in tundra heath soil. AB - If microbial degradation of carbon substrates in arctic soil is stimulated by climatic warming, this would be a significant positive feedback on global change. With data from a climate change experiment in Northern Sweden we show that warming and enhanced soil nutrient availability, which is a predicted long-term consequence of climatic warming and mimicked by fertilization, both increase soil microbial biomass. However, while fertilization increased the relative abundance of fungi, warming caused only a minimal shift in the microbial community composition based on the phospholipid fatty acid (PLFA) and neutral lipid fatty acid (NLFA) profiles. The function of the microbial community was also differently affected, as indicated by stable isotope probing of PLFA and NLFA. We demonstrate that two decades of fertilization have favored fungi relative to bacteria, and increased the turnover of complex organic compounds such as vanillin, while warming has had no such effects. Furthermore, the NLFA-to-PLFA ratio for (13)C-incorporation from acetate increased in warmed plots but not in fertilized ones. Thus, fertilization cannot be used as a proxy for effects on warming in arctic tundra soils. Furthermore, the different functional responses suggest that the biomass increase found in both fertilized and warmed plots was mediated via different mechanisms. PMID- 23437160 TI - Expression of osteopontin in patients with thyroid dysfunction. AB - Thyroid dysfunctions are common endocrine problems. They are often misdiagnosed, misunderstood, and frequently overlooked. These disorders affect almost every aspect of health. Most of them remain undetected because the clinical assessment alone lacks both sensitivity and specificity. As it is not sufficient enough we require the biochemical tests to confirm the diagnosis. As a consequence there is still great interest in new biomarkers that complement existing diagnostic tools. Osteopontin, a glycoprotein that can be detected in plasma, was found to be upregulated in several patients with hyperthyroidism and downregulated in hypothyroid patients so it may represent a new biomarker. 100 patients with thyroid dysfunctions (50 hyperthyroid, 50 hypothyroid) and 100 normal subjects were included in the study. Osteopontin and other clinical parameters for diagnosis of thyroid disorders were measured. Osteopontin is positively correlated with T3 and T4 (r = 0.62 and r = 0.75 respectively) while it is negatively correlated with thyroid stimulating hormone (r = -0.52) showing a significant correlation (p-value <0.001). Our findings suggest that osteopontin might be useful as a novel prognostic biomarker in patients with impaired thyroid function. PMID- 23437161 TI - Long-term effect of manure and fertilizer on soil organic carbon pools in dryland farming in northwest China. AB - An understanding of the dynamics of soil organic carbon (SOC) as affected by farming practices is imperative for maintaining soil productivity and mitigating global warming. The objectives of this study were to investigate the effects of long-term fertilization on SOC and SOC fractions for the whole soil profile (0 100 cm) in northwest China. The study was initiated in 1979 in Gansu, China and included six treatments: unfertilized control (CK), nitrogen fertilizer (N), nitrogen and phosphorus (P) fertilizers (NP), straw plus N and P fertilizers (NP+S), farmyard manure (FYM), and farmyard manure plus N and P fertilizers (NP+FYM). Results showed that SOC concentration in the 0-20 cm soil layer increased with time except in the CK and N treatments. Long-term fertilization significantly influenced SOC concentrations and storage to 60 cm depth. Below 60 cm, SOC concentrations and storages were statistically not significant between all treatments. The concentration of SOC at different depths in 0-60 cm soil profile was higher under NP+FYM follow by under NP+S, compared to under CK. The SOC storage in 0-60 cm in NP+FYM, NP+S, FYM and NP treatments were increased by 41.3%, 32.9%, 28.1% and 17.9%, respectively, as compared to the CK treatment. Organic manure plus inorganic fertilizer application also increased labile soil organic carbon pools in 0-60 cm depth. The average concentration of particulate organic carbon (POC), dissolved organic carbon (DOC) and microbial biomass carbon (MBC) in organic manure plus inorganic fertilizer treatments (NP+S and NP+FYM) in 0-60 cm depth were increased by 64.9-91.9%, 42.5-56.9%, and 74.7-99.4%, respectively, over the CK treatment. The POC, MBC and DOC concentrations increased linearly with increasing SOC content. These results indicate that long term additions of organic manure have the most beneficial effects in building carbon pools among the investigated types of fertilization. PMID- 23437162 TI - The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. AB - Animal models have shown that regional anesthesia (combined with or without general anesthesia) would attenuate the surgical stress response by preserving immune function and result in better long-term outcome. In order to test the hypothesis that cancer patients who had surgery with epidural anesthesia (EA) would have better outcome (either overall survival [OS] or recurrence-free survival [RFS]) than those who were general anesthesia (GA), we performed this meta-analysis. By searching relevant literature, a total of 14 studies containing 18 sub-studies (seven in OS analysis and eleven in RFS analysis) were identified and meta-analyzed. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the strength of association. For OS, the random-effects model was used to analyze the data and demonstrated an OS benefit in favor of EA compared with GA alone (HR = 0.84, 95% CI 0.74-0.96, P = 0.013). The influence analysis showed the robustness of the results. Specifically, a significantly positive association between EA and improved OS was observed in colorectal cancer (HR = 0.65, 95% CI 0.43-0.99, P = 0.045). For RFS, the random-effects model was used to analyze the data and no significant relationship between RFS benefit and EA (HR = 0.88, 95% CI 0.64-1.22, P = 0.457) was detected. In conclusion, our meta analysis suggests that epidural anesthesia and/or analgesia might be associated with improved overall survival in patients with operable cancer undergoing surgery (especially in colorectal cancer), but it does not support an association between epidural anesthesia and cancer control. Prospective studies are needed to determine whether the association between epidural use and survival is causative. PMID- 23437163 TI - Negative correlation of LIV-1 and E-cadherin expression in hepatocellular carcinoma cells. AB - LIV-1, a zinc transporter, is a mediator downstream of STAT3 both in zebrafish and mammalian cells, and is involved in epithelial-mesenchymal transition (EMT). Despite LIV-1 participates in cancer growth and metastasis, little is known about the association of LIV-1 with human liver cancer development. Therefore, the expression of LIV-1 mRNA was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) in 4 cultured cell lines (3 carcinoma and 1 normal liver cell lines), and the localization of LIV-1 protein was investigated by immunohistochemistry. Expression of LIV-1 protein was analyzed by Western blot both in 4 cultured cell lines and 120 liver tissues (100 carcinoma and 20 histologically normal tissues), and the relationship between its expression and clinicopathological finding was investigated in 100 hepatocellular carcinoma(HCC) tissues. Then stable siRNA expressing Hep-G2 cells were generated to assess the function of LIV-1 in liver cancer cells. We found that LIV-1 mRNA was more highly expressed in liver cancer cell lines compared to normal liver cell line. Western blot showed the expression of LIV-1 was higher in 61% liver carcinoma tissues than that in normal liver tissues. Down-regulated LIV-1 cells showed significant inhibition of proliferation in vitro and reduction of tumor growth in vivo. Furthermore, E-cadherin expression increased in LIV-1 siRNA expressing Hep-G2. These findings indicated that LIV-1 may induce the EMT in HCC cells. PMID- 23437164 TI - Using phenotype microarrays to determine culture conditions that induce or repress toxin production by Clostridium difficile and other microorganisms. AB - Toxin production is a central issue in the pathogenesis of Clostridium difficile and many other pathogenic microorganisms. Toxin synthesis is influenced by a variety of known and unknown factors of genetics, physiology, and environment. To facilitate the study of toxin production by C. difficile, we have developed a new, reliable, quantitative, and robust cell-based cytotoxicity assay. Then we combined this new assay with Phenotype MicroArrays (PM) technology which provides high throughput testing of culture conditions. This allowed us to quantitatively measure toxin production by C. difficile type strain ATCC 9689 under 768 culture conditions. The culture conditions include different carbon, nitrogen, phosphorus, and sulfur sources. Among these, 89 conditions produced strong toxin induction and 31 produced strong toxin repression. Strong toxin inducers included adenine, guanosine, arginine dipeptides, gamma-D-Glu-Gly, methylamine, and others. Some leucine dipeptides and the triple-leucine tripeptide were among the strongest toxin repressors. While some results are consistent with previous observations, others are new observations that provide insights into toxin regulation and pathogenesis of C. difficile. Additionally, we have demonstrated that this combined assay technology can be applied broadly to a wide range of toxin producing microorganisms. This study is the first demonstration of simultaneous assessment of a large number of culture conditions influencing bacterial toxin production. The new functional cytotoxin quantitation method developed provides a valuable tool for studying toxigenic microorganisms and may also find applications in clinical and epidemiological research. PMID- 23437165 TI - Lactobacillus reuteri DSM 17938 changes the frequency of Foxp3+ regulatory T cells in the intestine and mesenteric lymph node in experimental necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine in premature infants. Lactobacillus reuteri DSM 17938 improves survival and reduces the incidence and severity of NEC in a rodent model. Foxp3(+) regulatory T cells (Tregs) maintain intestinal homeostasis by controlling inflammation and inducing tolerance. To determine whether there are insufficient numbers of Tregs to control inflammation in NEC and to determine if LR17938 increases the frequency of Tregs, we studied selected groups of newborn Sprague-Dawley rats according to feeding plan: dam+/-LR17938, formula+/-LR17938, and NEC+/-LR17938. NEC was induced by gavage feeding with special formula and exposure to hypoxic conditions. Lymphocytes isolated from ileum, mesenteric lymph nodes (MLN), spleen and thymus were labeled for T cell surface markers (CD3, CD4, CD8) and intracellular Foxp3; and labeled cells were analyzed by flow cytometry. The percentage of CD3(+) T cells and Foxp3(+) Tregs in the ileum significantly decreased in pups with NEC, compared to normal controls. Feeding LR17938 to neonatal rats with NEC increased the % of Foxp3(+) T cells in the ileum while decreasing the percentage of cells in the MLN. Administration of LR17938 to dam fed rats significantly increased Foxp3(+)Tregs in the ileum as early as day of life (DOL)1 but did not produce an increase in Tregs in formula-fed rats on DOL1. These results suggest that factors in breast milk may enhance the early immunomodulatory effects of LR17938. An anti-inflammatory effect of LR17938 in NEC was associated with the modulation of immune responses and induction and what appears to be migration of Foxp3(+) Tregs to the diseased gut. Probiotic facilitated development of Tregs might play an important role in the prevention of NEC. PMID- 23437166 TI - DNA extraction and amplification from contemporary Polynesian bark-cloth. AB - BACKGROUND: Paper mulberry has been used for thousands of years in Asia and Oceania for making paper and bark-cloth, respectively. Museums around the world hold valuable collections of Polynesian bark-cloth. Genetic analysis of the plant fibers from which the textiles were made may answer a number of questions of interest related to provenance, authenticity or species used in the manufacture of these textiles. Recovery of nucleic acids from paper mulberry bark-cloth has not been reported before. METHODOLOGY: We describe a simple method for the extraction of PCR-amplifiable DNA from small samples of contemporary Polynesian bark-cloth (tapa) using two types of nuclear markers. We report the amplification of about 300 bp sequences of the ITS1 region and of a microsatellite marker. CONCLUSIONS: Sufficient DNA was retrieved from all bark-cloth samples to permit successful PCR amplification. This method shows a means of obtaining useful genetic information from modern bark-cloth samples and opens perspectives for the analyses of small fragments derived from ethnographic materials. PMID- 23437167 TI - Phylogeography and domestication of Chinese swamp buffalo. AB - To further probe into whether swamp buffaloes were domesticated once or multiple times in China, this survey examined the mitochondrial DNA (mtDNA) Control Region (D-loop) diversity of 471 individuals representing 22 populations of 455 Chinese swamp buffaloes and 16 river buffaloes. Phylogenetic analysis revealed that Chinese swamp buffaloes could be divided into two distinct lineages, A and B, which were defined previously. Of the two lineages, lineage A was predominant across all populations. For predominant lineage A, Southwestern buffalo populations possess the highest genetic diversity among the three hypothesized domestication centers (Southeastern, Central, and Southwestern China), suggesting Southwestern China as the most likely location for the domestication of lineage A. However, a complex pattern of diversity is detected for the lineage B, preventing the unambiguous pinpointing of the exact place of domestication center and suggesting the presence of a long-term, strong gene flow among swamp buffalo populations caused by extensive migrations of buffaloes and frequent human movements along the Yangtze River throughout history. Our current study suggests that Southwestern China is the most likely domestication center for lineage A, and may have been a primary center of swamp buffalo domestication. More archaeological and genetic evidence is needed to show the process of domestication. PMID- 23437168 TI - Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-kappaB/tissue factor/Factor Xa pathway in melanoma B16F10 cells. AB - Holothurian glycosaminoglycan (hGAG) is a high-molecular-weight form of fucosylated chondroitin sulfate and has an antithrombotic effect. Our previous studies demonstrated that hGAG efficiently inhibited tumor cell metastasis. The interplays between thrombosis and tumor progression may have a major impact on hematogenous metastasis. In this study, we demonstrated that the mouse melanoma B16F10 cells treated with hGAG displayed a significant reduction of metastasis and coagulation capacity in vitro and in vivo. Mechanistic studies revealed that hGAG treatment in B16F10 cells remarkably inhibited the formation of fibrin through attenuating the generation of activated Factor Xa (FXa), without affecting the expression of urokinase (uPA) and plasminogen activator inhibitor 1 (PAI-1) that involved in fibrinolysis. Moreover, hGAG treatment downregulated the transcription and protein expression of tissue factor (TF). Promoter deletions, site mutations and functional studies identified that the nuclear transcription factor NF-kappaB binding region is responsible for hGAG-induced inhibition of TF expression. While the hGAG treatment of B16F10 cells was unable to inhibit NF kappaB expression and phosphorylation, hGAG significantly prevented nuclear translocation of NF-kappaB from the cytosol, a potential mechanism underlying the transcriptional suppression of TF. Moreover, hGAG markedly suppressed the activation of p38MAPK and ERK1/2 signaling pathways, the central regulators for the expression of metastasis-related matrix metalloproteinases (MMPs). Consequently, hGAG exerts a dual function in the inhibition of metastasis and coagulation activity in mouse melanoma B16F10 cells. Our studies suggest hGAG to be a promising therapeutic agent for metastatic cancer treatment. PMID- 23437170 TI - Carbon dioxide flux from rice paddy soils in central China: effects of intermittent flooding and draining cycles. AB - A field experiment was conducted to (i) examine the diurnal and seasonal soil carbon dioxide (CO(2)) fluxes pattern in rice paddy fields in central China and (ii) assess the role of floodwater in controlling the emissions of CO(2) from soil and floodwater in intermittently draining rice paddy soil. The soil CO(2) flux rates ranged from -0.45 to 8.62 umol.m(-2).s(-1) during the rice-growing season. The net effluxes of CO(2) from the paddy soil were lower when the paddy was flooded than when it was drained. The CO(2) emissions for the drained conditions showed distinct diurnal variation with a maximum efflux observed in the afternoon. When the paddy was flooded, daytime soil CO(2) fluxes reversed with a peak negative efflux just after midday. In draining/flooding alternating periods, a sudden pulse-like event of rapidly increasing CO(2) efflux occured in response to re-flooding after draining. Correlation analysis showed a negative relation between soil CO(2) flux and temperature under flooded conditions, but a positive relation was found under drained conditions. The results showed that draining and flooding cycles play a vital role in controlling CO(2) emissions from paddy soils. PMID- 23437169 TI - Dishevelled proteins are associated with olfactory sensory neuron presynaptic terminals. AB - Olfactory sensory neurons (OSNs) project their axons from the olfactory epithelium toward the olfactory bulb (OB) in a heterogeneous and unsorted arrangement. However, as the axons approach the glomerular layer of the OB, axons from OSNs expressing the same odorant receptor (OR) sort and converge to form molecularly homogeneous glomeruli. Axon guidance cues, cell adhesion molecules, and OR induced activity have been implicated in the final targeting of OSN axons to specific glomeruli. Less understood, and often controversial, are the mechanisms used by OSN axons to initially navigate from the OE toward the OB. We previously demonstrated a role for Wnt and Frizzled (Fz) molecules in OSN axon extension and organization within the olfactory nerve. Building on that we now turned our attention to the downstream signaling cascades from Wnt-Fz interactions. Dishevelled (Dvl) is a key molecule downstream of Fz receptors. Three isoforms of Dvl with specific as well as overlapping functions are found in mammals. Here, we show that Dvl-1 expression is restricted to OSNs in the dorsal recess of the nasal cavity, and labels a unique subpopulation of glomeruli. Dvl-2 and Dvl-3 have a widespread distribution in both the OE and OB. Both Dvl-1 and Dvl-2 are associated with intra-glomerular pre-synaptic OSN terminals, suggesting a role in synapse formation/stabilization. Moreover, because Dvl proteins were observed in all OSN axons, we hypothesize that they are important determinants of OSN cell differentiation and axon extension. PMID- 23437171 TI - Evaluating spatial overlap and relatedness of white-tailed deer in a chronic wasting disease management zone. AB - Wildlife disease transmission, at a local scale, can occur from interactions between infected and susceptible conspecifics or from a contaminated environment. Thus, the degree of spatial overlap and rate of contact among deer is likely to impact both direct and indirect transmission of infectious diseases such chronic wasting disease (CWD) or bovine tuberculosis. We identified a strong relationship between degree of spatial overlap (volume of intersection) and genetic relatedness for female white-tailed deer in Wisconsin's area of highest CWD prevalence. We used volume of intersection as a surrogate for contact rates between deer and concluded that related deer are more likely to have contact, which may drive disease transmission dynamics. In addition, we found that age of deer influences overlap, with fawns exhibiting the highest degree of overlap with other deer. Our results further support the finding that female social groups have higher contact among related deer which can result in transmission of infectious diseases. We suggest that control of large social groups comprised of closely related deer may be an effective strategy in slowing the transmission of infectious pathogens, and CWD in particular. PMID- 23437173 TI - Strongly magnetic iron nanoparticles improve the diagnosis of small tumours in the reticuloendothelial system by magnetic resonance imaging. AB - Despite advances in non-invasive medical imaging, accurate nodal staging of malignancy continues to rely on surgery. Superparamagnetic iron oxide nanoparticles (IONP) with lymphotropic qualities have shown some promise as contrast agents for MRI of the lymph nodes, but recent large-scale studies failed to show consistent detection of tumours below 5 mm. Herein we compare imaging of splenic and lymph node tissue using iron/iron oxide core/shell nanoparticles (Fe NP) that have superior magnetic qualities to IONP, to determine whether improved negative contrast in T(2)-weighted MRI can enhance the diagnosis of small tumours in the reticuloendothelial system. To provide an in vivo pre-clinical model of human lymph node micrometastases, breast cancer cells were injected into the spleens of mice, providing localised areas of tumour growth. MR images of groups of tumour-bearing and sham-treated animals were generated using a 1.5 T imaging system and analysed by two independent, blinded radiologists. Fe NP improved the sensitivity and specificity of MRI when compared to IONP, enabling accurate detection of tumours as small as 1-3 mm. The use of Fe NP as contrast agents have the potential to improve the diagnostic accuracy of MRI in cancer patients, leading to more rapid and effective treatment. PMID- 23437172 TI - Regulation of wheat seed dormancy by after-ripening is mediated by specific transcriptional switches that induce changes in seed hormone metabolism and signaling. AB - Treatments that promote dormancy release are often correlated with changes in seed hormone content and/or sensitivity. To understand the molecular mechanisms underlying the role of after-ripening (seed dry storage) in triggering hormone related changes and dormancy decay in wheat (Triticum aestivum), temporal expression patterns of genes related to abscisic acid (ABA), gibberellin (GA), jasmonate and indole acetic acid (IAA) metabolism and signaling, and levels of the respective hormones were examined in dormant and after-ripened seeds in both dry and imbibed states. After-ripening mediated developmental switch from dormancy to germination appears to be associated with declines in seed sensitivity to ABA and IAA, which are mediated by transcriptional repressions of PROTEIN PHOSPHATASE 2C, SNF1-RELATED PROTEIN KINASE2, ABA INSENSITIVE5 and LIPID PHOSPHATE PHOSPHTASE2, and AUXIN RESPONSE FACTOR and RELATED TO UBIQUITIN1 genes. Transcriptomic analysis of wheat seed responsiveness to ABA suggests that ABA inhibits the germination of wheat seeds partly by repressing the transcription of genes related to chromatin assembly and cell wall modification, and activating that of GA catabolic genes. After-ripening induced seed dormancy decay in wheat is also associated with the modulation of seed IAA and jasmonate contents. Transcriptional control of members of the ALLENE OXIDE SYNTHASE, 3-KETOACYL COENZYME A THIOLASE, LIPOXYGENASE and 12-OXOPHYTODIENOATE REDUCTASE gene families appears to regulate seed jasmonate levels. Changes in the expression of GA biosynthesis genes, GA 20-OXIDASE and GA 3-OXIDASE, in response to after-ripening implicate this hormone in enhancing dormancy release and germination. These findings have important implications in the dissection of molecular mechanisms underlying regulation of seed dormancy in cereals. PMID- 23437174 TI - Selection of reference genes for quantitative real-time PCR in bamboo (Phyllostachys edulis). AB - BACKGROUND: The Moso bamboo (Phyllostachys edulis) is one of the most important forestry resources and plays essential ecological roles in southern China. A draft nuclear genome sequence is expected to be publicly available in the near future; an explosion of gene expression data related to the unique traits of Moso bamboo will undoubtedly follow. Reverse transcription quantitative real-time PCR ((RT-)qPCR) is a widely used method for gene expression analysis. A necessary prerequisite of exact and reliable data is the accurate choice of reference genes. RESULT: In this study, 14 candidate reference genes were chosen, and their expression levels were assessed by (RT-)qPCR in a set of six tissue samples (root, stem, mature stem, leaf, flower, and leaf sheath) and at two developmental stages (before and after flowering) in bamboo specimens obtained in three locations. The stability and suitability of the candidate reference genes were validated using the geNorm, NormFinder and BestKeeper programs. The results showed that TIP41 and NTB were suitable reference genes across all the tissues and at the different developmental stages examined in this study. While the expression of the NTB, TIP41 and UBQ were the mostly stable in different plant tissues samples, the expression of the TIP41, NTB and CAC were ranked the most stable in bamboo plants at various developmental stages. AP2-like gene was further assessed by using the reference genes TIP41 and NTB in comparison to ACT. Significant difference of the expression profile of AP2-like demonstrated the importance of choosing adequate reference genes in bamboo. CONCLUSION: TIP41 and NTB were found to be homogeneously expressed and were adequate for normalization purposes, showing equivalent transcript levels in different samples. They are therefore the recommended reference genes for measuring gene expression in P. edulis. PMID- 23437176 TI - Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort. AB - BACKGROUND: Recent decades have witnessed an increase in mean maternal age at childbirth in most high-resourced countries. Advanced maternal age has been associated with several adverse maternal and perinatal outcomes. Although there are many studies on this topic, data from large contemporary population-based cohorts that controls for demographic variables known to influence perinatal outcomes is limited. METHODS: We performed a population-based cohort study using data on all singleton births in 2004-2008 from the North Western Perinatal Survey based at The University of Manchester, UK. We compared pregnancy outcomes in women aged 30-34, 35-39 and >=40 years with women aged 20-29 years using log linear binomial regression. Models were adjusted for parity, ethnicity, social deprivation score and body mass index. RESULTS: The final study cohort consisted of 215,344 births; 122,307 mothers (54.19%) were aged 20-29 years, 62,371(27.63%) were aged 30-34 years, 33,966(15.05%) were aged 35-39 years and 7,066(3.13%) were aged >=40 years. Women aged 40+ at delivery were at increased risk of stillbirth (RR = 1.83, [95% CI 1.37-2.43]), pre-term (RR = 1.25, [95% CI: 1.14-1.36]) and very pre-term birth (RR = 1.29, [95% CI:1.08-1.55]), Macrosomia (RR = 1.31, [95% CI: 1.12-1.54]), extremely large for gestational age (RR = 1.40, [95% CI: 1.25 1.58]) and Caesarean delivery (RR = 1.83, [95% CI: 1.77-1.90]). CONCLUSIONS: Advanced maternal age is associated with a range of adverse pregnancy outcomes. These risks are independent of parity and remain after adjusting for the ameliorating effects of higher socioeconomic status. The data from this large contemporary cohort will be of interest to healthcare providers and women and will facilitate evidence based counselling of older expectant mothers. PMID- 23437177 TI - Using environmental DNA to estimate the distribution of an invasive fish species in ponds. AB - Knowledge of the presence of an invasive species is critical to monitoring the sustainability of communities and ecosystems. Environmental DNA (eDNA), DNA fragments that are likely to be bound to organic matters in the water or in shed cells, has been used to monitor the presence of aquatic animals. Using an eDNA based method, we estimated the presence of the invasive bluegill sunfish, Lepomis macrochirus, in 70 ponds located in seven locales on the Japanese mainland and on surrounding islands. We quantified the concentration of DNA copies in a 1 L water sample using quantitative real-time polymerase chain reaction (qPCR) with a primer/probe set. In addition, we visually observed the bluegill presence in the ponds from the shoreline. We detected bluegill eDNA in all the ponds where bluegills were observed visually and some where bluegills were not observed. Bluegills were also less prevalent on the islands than the mainland, likely owing to limited dispersal and introduction by humans. Our eDNA method simply and rapidly detects the presence of this invasive fish species with less disturbance to the environment during field surveys than traditional methods. PMID- 23437175 TI - Comparative genomic analysis of Mycobacterium tuberculosis drug resistant strains from Russia. AB - Tuberculosis caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains is a growing problem in many countries. The availability of the complete nucleotide sequences of several MTB genomes allows to use the comparative genomics as a tool to study the relationships of strains and differences in their evolutionary history including acquisition of drug-resistance. In our work, we sequenced three genomes of Russian MTB strains of different phenotypes--drug susceptible, MDR and XDR. Of them, MDR and XDR strains were collected in Tomsk (Siberia, Russia) during the local TB outbreak in 1998-1999 and belonged to rare KQ and KY families in accordance with IS6110 typing, which are considered endemic for Russia. Based on phylogenetic analysis, our isolates belonged to different genetic families, Beijing, Ural and LAM, which made the direct comparison of their genomes impossible. For this reason we performed their comparison in the broader context of all M. tuberculosis genomes available in GenBank. The list of unique individual non-synonymous SNPs for each sequenced isolate was formed by comparison with all SNPs detected within the same phylogenetic group. For further functional analysis, all proteins with unique SNPs were ascribed to 20 different functional classes based on Clusters of Orthologous Groups (COG). We have confirmed drug resistant status of our isolates that harbored almost all known drug-resistance associated mutations. Unique SNPs of an XDR isolate CTRI-4(XDR), belonging to a Beijing family were compared in more detail with SNPs of additional 14 Russian XDR strains of the same family. Only type specific mutations in genes of repair, replication and recombination system (COG category L) were found common within this group. Probably the other unique SNPs discovered in CTRI-4(XDR) may have an important role in adaptation of this microorganism to its surrounding and in escape from antituberculosis drugs treatment. PMID- 23437178 TI - Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response. AB - Central nervous system (CNS) disorders such as ischemic stroke, multiple sclerosis (MS) or Alzheimers disease are characterized by the loss of blood-brain barrier (BBB) integrity. Here we demonstrate that the small tyrosine kinase inhibitor imatinib enhances BBB integrity in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). Treatment was accompanied by decreased CNS inflammation and demyelination and especially reduced T-cell recruitment. This was supported by downregulation of the chemokine receptor (CCR) 2 in CNS and lymph nodes, and by modulation of the peripheral immune response towards an anti-inflammatory phenotype. Interestingly, imatinib ameliorated neuroinflammation, even when the treatment was initiated after the clinical manifestation of the disease. We have previously shown that imatinib reduces BBB disruption and stroke volume after experimentally induced ischemic stroke by targeting platelet-derived growth factor receptor -alpha (PDGFR-alpha) signaling. Here we demonstrate that PDGFR-alpha signaling is a central regulator of BBB integrity during neuroinflammation and therefore imatinib should be considered as a potentially effective treatment for MS. PMID- 23437179 TI - An integrated expression profiling reveals target genes of TGF-beta and TNF-alpha possibly mediated by microRNAs in lung cancer cells. AB - EMT (epithelial-mesenchymal transition) is crucial for cancer cells to acquire invasive phenotypes. In A549 lung adenocarcinoma cells, TGF-beta elicited EMT in Smad-dependent manner and TNF-alpha accelerated this process, as confirmed by cell morphology, expression of EMT markers, capacity of gelatin lysis and cell invasion. TNF-alpha stimulated the phosphorylation of Smad2 linker region, and this effect was attenuated by inhibiting MEK or JNK pathway. Comprehensive expression analysis unraveled genes differentially regulated by TGF-beta and TNF alpha, such as cytokines, chemokines, growth factors and ECM (extracellular matrices), suggesting the drastic change in autocrine/paracrine signals as well as cell-to-ECM interactions. Integrated analysis of microRNA signature enabled us to identify a subset of genes, potentially regulated by microRNAs. Among them, we confirmed TGF-beta-mediated induction of miR-23a in lung epithelial cell lines, target genes of which were further identified by gene expression profiling. Combined with in silico approaches, we determined HMGN2 as a downstream target of miR-23a. These findings provide a line of evidence that the effects of TGF-beta and TNF-alpha were partially mediated by microRNAs, and shed light on the complexity of molecular events elicited by TGF-beta and TNF-alpha. PMID- 23437180 TI - Complex movements, philopatry and expanded depth range of a severely threatened pelagic shark, the oceanic whitetip (Carcharhinus longimanus) in the western North Atlantic. AB - Oceanic whitetip sharks (Carcharhinus longimanus) have recently been targeted for conservation in the western North Atlantic following severe declines in abundance. Pop-up satellite archival tags were applied to 11 mature oceanic whitetips (10 females, 1 male) near Cat Island in the central Bahamas 1-8 May 2011 to provide information about the horizontal and vertical movements of this species. Another large female was opportunistically tagged in the U.S. Exclusive Economic Zone (EEZ). Data from 1,563 total tracking days and 1,142,598 combined depth and temperature readings were obtained. Sharks tagged at Cat Island stayed within 500 km of the tagging site for ~30 days before dispersing across 16,422 km(2) of the western North Atlantic. Maximum individual displacement from the tagging site ranged from 290-1940 km after times at liberty from 30-245 days, with individuals moving to several different destinations (the northern Lesser Antilles, the northern Bahamas, and north of the Windward Passage). Many sharks returned to The Bahamas after ~150 days. Estimated residency times within The Bahamas EEZ, where longlining and commercial trade of sharks is illegal, were generally high (mean = 68.2% of time). Sharks spent 99.7% of their time shallower than 200 m and did not exhibit differences in day and night mean depths. There was a positive correlation between daily sea surface temperature and mean depth occupied, suggesting possible behavioral thermoregulation. All individuals made short duration (mean = 13.06 minutes) dives into the mesopelagic zone (down to 1082 m and 7.75 degrees C), which occurred significantly more often at night. Ascent rates during these dives were significantly slower than descent rates, suggesting that these dives are for foraging. The sharks tracked appear to be most vulnerable to pelagic fishing gear deployed from 0-125 m depths, which they may encounter from June to October after leaving the protected waters of The Bahamas EEZ. PMID- 23437181 TI - Gene expression analyses implicate an alternative splicing program in regulating contractile gene expression and serum response factor activity in mice. AB - Members of the CUG-BP, Elav-like family (CELF) regulate alternative splicing in the heart. In MHC-CELFDelta transgenic mice, CELF splicing activity is inhibited postnatally in heart muscle via expression of a nuclear dominant negative CELF protein under an alpha-myosin heavy chain promoter. MHC-CELFDelta mice develop dilated cardiomyopathy characterized by alternative splicing defects, enlarged hearts, and severe contractile dysfunction. In this study, gene expression profiles in the hearts of wild type, high- and low-expressing lines of MHC CELFDelta mice were compared using microarrays. Gene ontology and pathway analyses identified contraction and calcium signaling as the most affected processes. Network analysis revealed that the serum response factor (SRF) network is highly affected. Downstream targets of SRF were up-regulated in MHC-CELFDelta mice compared to the wild type, suggesting an increase in SRF activity. Although SRF levels remained unchanged, known inhibitors of SRF activity were down regulated. Conversely, we found that these inhibitors are up-regulated and downstream SRF targets are down-regulated in the hearts of MCKCUG-BP1 mice, which mildly over-express CELF1 in heart and skeletal muscle. This suggests that changes in SRF activity are a consequence of changes in CELF-mediated regulation rather than a secondary result of compensatory pathways in heart failure. In MHC CELFDelta males, where the phenotype is only partially penetrant, both alternative splicing changes and down-regulation of inhibitors of SRF correlate with the development of cardiomyopathy. Together, these results strongly support a role for CELF-mediated alternative splicing in the regulation of contractile gene expression, achieved in part through modulating the activity of SRF, a key cardiac transcription factor. PMID- 23437182 TI - Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. AB - IL-17-producing CD4(+) T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a critical involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORgammat, they expressed reduced levels of IL-23R and were unable to produce IL 17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addition, the lack of disease was associated with a reduction in autocrine IL-21 production and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clinical disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease. PMID- 23437183 TI - Implicitly priming the social brain: failure to find neural effects. AB - Humans have a fundamental need for social relationships. Rejection from social groups is especially detrimental, rendering the ability to detect threats to social relationships and respond in adaptive ways critical. Indeed, previous research has shown that experiencing social rejection alters the processing of subsequent social cues in a variety of socially affiliative and avoidant ways. Because social perception and cognition occurs spontaneously and automatically, detecting threats to social relationships may occur without conscious awareness or control. Here, we investigated the automaticity of social threat detection by examining how implicit primes affect neural responses to social stimuli. However, despite using a well-established implicit priming paradigm and large sample size, we failed to find any evidence that implicit primes induced changes at the neural level. That implicit primes influence behavior has been demonstrated repeatedly and across a variety of domains, and our goal is not to question these effects. Rather, we offer the present study as cautionary evidence that such a paradigm may not be amenable to scanning in an fMRI environment. PMID- 23437184 TI - Skeletal muscle insulin resistance associated with cholesterol-induced activation of macrophages is prevented by high density lipoprotein. AB - BACKGROUND: Emerging evidence suggests that high density lipoprotein (HDL) may modulate glucose metabolism through multiple mechanisms including pancreatic insulin secretion as well as insulin-independent glucose uptake into muscle. We hypothesized that HDL may also increase skeletal muscle insulin sensitivity via cholesterol removal and anti-inflammatory actions in macrophages associated with excess adiposity and ectopic lipid deposition. METHODS: Human primary and THP-1 macrophages were treated with vehicle (PBS) or acetylated low density lipoprotein (acLDL) with or without HDL for 18 hours. Treatments were then removed, and macrophages were incubated with fresh media for 4 hours. This conditioned media was then applied to primary human skeletal myotubes derived from vastus lateralis biopsies taken from patients with type 2 diabetes to examine insulin-stimulated glucose uptake. RESULTS: Conditioned media from acLDL-treated primary and THP-1 macrophages reduced insulin-stimulated glucose uptake in primary human skeletal myotubes compared with vehicle (primary macrophages, 168+/-21% of basal uptake to 104+/-19%; THP-1 macrophages, 142+/-8% of basal uptake to 108+/-6%; P<0.05). This was restored by co-treatment of macrophages with HDL. While acLDL increased total intracellular cholesterol content, phosphorylation of c-jun N-terminal kinase and secretion of pro- and anti-inflammatory cytokines from macrophages, none were altered by co-incubation with HDL. Insulin-stimulated Akt phosphorylation in human skeletal myotubes exposed to conditioned media was unaltered by either treatment condition. CONCLUSION: Inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre incubated with acLDL was restored by co-treatment with HDL. However, these actions were not linked to modulation of common pro- or anti-inflammatory mediators or insulin signaling via Akt. PMID- 23437185 TI - Elevated expression of H19 and Igf2 in the female mouse eye. AB - The catalogue of genes expressed at different levels in the two sexes is growing, and the mechanisms underlying sex differences in regulation of the mammalian transcriptomes are being explored. Here we report that the expression of the imprinted non-protein-coding maternally expressed gene H19 was female-biased specifically in the female mouse eye (1.9-fold, p = 3.0E-6) while not being sex biased in other somatic tissues. The female-to-male expression fold-change of H19 fell in the range expected from an effect of biallelic versus monoallelic expression. Recently, the possibility of sex-specific parent-of-origin allelic expression has been debated. This led us to hypothesize that H19 might express biallelically in the female mouse eye, thus escape its silencing imprint on the paternal allele specifically in this tissue. We therefore performed a sex specific imprinting assay of H19 in female and male eye derived from a cross between Mus musculus and Mus spretus. However, this analysis demonstrated that H19 was exclusively expressed from the maternal gene copy, disproving the escape hypothesis. Instead, this supports that the female-biased expression of H19 is the result of upregulation of the single maternal. Furthermore, if H19 would have been expressed from both gene copies in the female eye, an associated downregulation of Insulin-like growth factor 2 (Igf2) was expected, since H19 and Igf2 compete for a common enhancer element located in the H19/Igf2 imprinted domain. On the contrary we found that also Igf2 was significantly upregulated in its expression in the female eye (1.2-fold, p = 6.1E-3), in further agreement with the conclusion that H19 is monoallelically elevated in females. The female biased expression of H19 and Igf2 specifically in the eye may contribute to our understanding of sex differences in normal as well as abnormal eye physiology and processes. PMID- 23437186 TI - Characterisation of gut microbiota in Ossabaw and Gottingen minipigs as models of obesity and metabolic syndrome. AB - BACKGROUND: Recent evidence suggests that the gut microbiota is an important contributing factor to obesity and obesity related metabolic disorders, known as the metabolic syndrome. The aim of this study was to characterise the intestinal microbiota in two pig models of obesity namely Gottingen minipigs and the Ossabaw minipigs. METHODS AND FINDINGS: The cecal, ileal and colonic microbiota from lean and obese Osabaw and Gottingen minipigs were investigated by Illumina-based sequencing and by high throughput qPCR, targeting the 16S rRNA gene in different phylogenetic groups of bacteria. The weight gain through the study was significant in obese Gottingen and Ossabaw minipigs. The lean Gottingen minipigs' cecal microbiota contained significantly higher abundance of Firmicutes (P<0.006), Akkermensia (P<0.01) and Methanovibribacter (P<0.01) than obese Gottingen minipigs. The obese Gottingen cecum had higher abundances of the phyla Spirochaetes (P<0.03), Tenericutes (P<0.004), Verrucomicrobia (P<0.005) and the genus Bacteroides (P<0.001) compared to lean minipigs. The relative proportion of Clostridium cluster XIV was 7.6-fold higher in cecal microbiota of obese Gottingen minipigs as compared to lean. Obese Ossabaw minipigs had a higher abundance of Firmicutes in terminal ileum and lower abundance of Bacteroidetes in colon than lean Ossabaw minipigs (P<0.01). Obese Ossabaws had significantly lower abundances of the genera Prevotella and Lactobacillus and higher abundance of Clostridium in their colon than the lean Ossabaws. Overall, the Gottingen and Ossabaw minipigs displayed different microbial communities in response to diet induced obesity in the different sections of their intestine. CONCLUSION: Obesity related changes in the composition of the gut microbiota were found in lean versus obese Gottingen and Ossabaw minipigs. In both pig models diet seems to be the defining factor that shapes the gut microbiota as observed by changes in different bacteria divisions between lean and obese minipigs. PMID- 23437187 TI - 45-Year trends in women's use of time and household management energy expenditure. AB - CONTEXT: Relationships between socio-environmental factors and obesity are poorly understood due to a dearth of longitudinal population-level research. The objective of this analysis was to examine 45-year trends in time-use, household management (HM) and energy expenditure in women. DESIGN AND PARTICIPANTS: Using national time-use data from women 19-64 years of age, we quantified time allocation and household management energy expenditure (HMEE) from 1965 to 2010. HM was defined as the sum of time spent in food preparation, post-meal cleaning activities (e.g., dish-washing), clothing maintenance (e.g., laundry), and general housework. HMEE was calculated using body weights from national surveys and metabolic equivalents. RESULTS: The time allocated to HM by women (19-64 yrs) decreased from 25.7 hr/week in 1965 to 13.3 hr/week in 2010 (P<0.001), with non employed women decreasing by 16.6 hr/week and employed women by 6.7 hr/week (P<0.001). HMEE for non-employed women decreased 42% from 25.1 Mj/week (6004 kilocalories per week) in 1965 to 14.6 Mj/week (3486 kcal/week) in 2010, a decrement of 10.5 Mj/week or 1.5 Mj/day (2518 kcal/week; 360 kcal/day) (P<0.001), whereas employed women demonstrated a 30% decrement of 3.9 Mj/week, 0.55 Mj/day (923 kcal/week, 132 kcal/day) (P<0.001). The time women spent in screen-based media use increased from 8.3 hr/week in 1965 to 16.5 hr/week in 2010 (P<0.001), with non-employed women increasing 9.6 hr/week and employed women 7.5 hr/week (P<0.001). CONCLUSIONS: From 1965 to 2010, there was a large and significant decrease in the time allocated to HM. By 2010, women allocated 25% more time to screen-based media use than HM (i.e., cooking, cleaning, and laundry combined). The reallocation of time from active pursuits (i.e., housework) to sedentary pastimes (e.g., watching TV) has important health consequences. These results suggest that the decrement in HMEE may have contributed to the increasing prevalence of obesity in women during the last five decades. PMID- 23437188 TI - Collaborative filtering for brain-computer interaction using transfer learning and active class selection. AB - Brain-computer interaction (BCI) and physiological computing are terms that refer to using processed neural or physiological signals to influence human interaction with computers, environment, and each other. A major challenge in developing these systems arises from the large individual differences typically seen in the neural/physiological responses. As a result, many researchers use individually trained recognition algorithms to process this data. In order to minimize time, cost, and barriers to use, there is a need to minimize the amount of individual training data required, or equivalently, to increase the recognition accuracy without increasing the number of user-specific training samples. One promising method for achieving this is collaborative filtering, which combines training data from the individual subject with additional training data from other, similar subjects. This paper describes a successful application of a collaborative filtering approach intended for a BCI system. This approach is based on transfer learning (TL), active class selection (ACS), and a mean squared difference user-similarity heuristic. The resulting BCI system uses neural and physiological signals for automatic task difficulty recognition. TL improves the learning performance by combining a small number of user-specific training samples with a large number of auxiliary training samples from other similar subjects. ACS optimally selects the classes to generate user-specific training samples. Experimental results on 18 subjects, using both k nearest neighbors and support vector machine classifiers, demonstrate that the proposed approach can significantly reduce the number of user-specific training data samples. This collaborative filtering approach will also be generalizable to handling individual differences in many other applications that involve human neural or physiological data, such as affective computing. PMID- 23437189 TI - A multiple reaction monitoring (MRM) method to detect Bcr-Abl kinase activity in CML using a peptide biosensor. AB - The protein kinase Bcr-Abl plays a major role in the pathogenesis of chronic myelogenous leukemia (CML), and is the target of the breakthrough drug imatinib (GleevecTM). While most patients respond well to imatinib, approximately 30% never achieve remission or develop resistance within 1-5 years of starting imatinib treatment. Evidence from clinical studies suggests that achieving at least 50% inhibition of a patient's Bcr-Abl kinase activity (relative to their level at diagnosis) is associated with improved patient outcomes, including reduced occurrence of resistance and longer maintenance of remission. Accordingly, sensitive assays for detecting Bcr-Abl kinase activity compatible with small amounts of patient material are desirable as potential companion diagnostics for imatinib. Here we report the detection of Bcr-Abl activity and inhibition by imatinib in the human CML cell line K562 using a cell-penetrating peptide biosensor and multiple reaction monitoring (MRM) on a triple quadrupole mass spectrometer. MRM enabled reproducible, selective detection of the peptide biosensor at fmol levels from aliquots of cell lysate equivalent to ~15,000 cells. This degree of sensitivity will facilitate the miniaturization of the entire assay procedure down to cell numbers approaching 15,000, making it practical for translational applications in patient cells in which the limited amount of available patient material often presents a major challenge. PMID- 23437190 TI - Selective sweep in the Flotillin-2 region of European Drosophila melanogaster. AB - Localizing genes that are subject to recent positive selection is a major goal of evolutionary biology. In the model organism Drosophila melanogaster many attempts have been made in recent years to identify such genes by conducting so-called genome scans of selection. These analyses consisted in typing a large number of genetic markers along the genomes of a sample of individuals and then identifying those loci that harbor patterns of genetic variation, which are compatible with the ones generated by a selective sweep. In this study we conduct an in-depth analysis of a genomic region located on the X chromosome of D. melanogaster that was identified as a potential target of recent positive selection by a previous genome scan of selection. To this end we re-sequenced 20 kilobases around the Flotillin-2 gene (Flo-2) and conducted a detailed analysis of the allele frequencies and linkage disequilibria observed in this new dataset. The results of this analysis reveal eight genetic novelties that are specific to temperate populations of D. melanogaster and that may have arisen during the expansion of the species outside its ancestral sub-Saharan habitat since about 16,000 years ago. PMID- 23437191 TI - Using weakly conserved motifs hidden in secretion signals to identify type-III effectors from bacterial pathogen genomes. AB - BACKGROUND: As one of the most important virulence factor types in gram-negative pathogenic bacteria, type-III effectors (TTEs) play a crucial role in pathogen host interactions by directly influencing immune signaling pathways within host cells. Based on the hypothesis that type-III secretion signals may be comprised of some weakly conserved sequence motifs, here we used profile-based amino acid pair information to develop an accurate TTE predictor. RESULTS: For a TTE or non TTE, we first used a hidden Markov model-based sequence searching method (i.e., HHblits) to detect its weakly homologous sequences and extracted the profile based k-spaced amino acid pair composition (HH-CKSAAP) from the N-terminal sequences. In the next step, the feature vector HH-CKSAAP was used to train a linear support vector machine model, which we designate as BEAN (Bacterial Effector ANalyzer). We compared our method with four existing TTE predictors through an independent test set, and our method revealed improved performance. Furthermore, we listed the most predictive amino acid pairs according to their weights in the established classification model. Evolutionary analysis shows that predictive amino acid pairs tend to be more conserved. Some predictive amino acid pairs also show significantly different position distributions between TTEs and non-TTEs. These analyses confirmed that some weakly conserved sequence motifs may play important roles in type-III secretion signals. Finally, we also used BEAN to scan one plant pathogen genome and showed that BEAN can be used for genome-wide TTE identification. The webserver and stand-alone version of BEAN are available at http://protein.cau.edu.cn:8080/bean/. PMID- 23437192 TI - Gene- and protein-delivered zinc finger-staphylococcal nuclease hybrid for inhibition of DNA replication of human papillomavirus. AB - Previously, we reported that artificial zinc-finger proteins (AZPs) inhibited virus DNA replication in planta and in mammalian cells by blocking binding of a viral replication protein to its replication origin. However, the replication mechanisms of viruses of interest need to be disentangled for the application. To develop more widely applicable methods for antiviral therapy, we explored the feasibility of inhibition of HPV-18 replication as a model system by cleaving its viral genome. To this end, we fused the staphylococcal nuclease cleaving DNA as a monomer to an AZP that binds to the viral genome. The resulting hybrid nuclease (designated AZP-SNase) cleaved its target DNA plasmid efficiently and sequence specifically in vitro. Then, we confirmed that transfection with a plasmid expressing AZP-SNase inhibited HPV-18 DNA replication in transient replication assays using mammalian cells. Linker-mediated PCR analysis revealed that the AZP SNase cleaved an HPV-18 ori plasmid around its binding site. Finally, we demonstrated that the protein-delivered AZP-SNase inhibited HPV-18 DNA replication as well and did not show any significant cytotoxicity. Thus, both gene- and protein-delivered hybrid nucleases efficiently inhibited HPV-18 DNA replication, leading to development of a more universal antiviral therapy for human DNA viruses. PMID- 23437193 TI - Induction of apoptosis in human breast cancer cells via caspase pathway by vernodalin isolated from Centratherum anthelminticum (L.) seeds. AB - BACKGROUND: Centratherum anthelminticum (L.) seeds (CA) is a well known medicinal herb in Indian sub-continent. We recently reported anti-oxidant property of chloroform fraction of Centratherum anthelminticum (L.) seeds (CACF) by inhibiting tumor necrosis factor-alpha (TNF-alpha)-induced growth of human breast cancer cells. However, the active compounds in CACF have not been investigated previously. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we showed that CACF inhibited growth of MCF-7 human breast cancer cells. CACF induced apoptosis in MCF-7 cells as marked by cell size shrinkage, deformed cytoskeletal structure and DNA fragmentation. To identify the cytotoxic compound, CACF was subjected to bioassay-guided fractionation which yielded 6 fractions. CACF fraction A and B (CACF-A, -B) demonstrated highest activity among all the fractions. Further HPLC isolation, NMR and LC-MS analysis of CACF-A led to identification of vernodalin as the cytotoxic agent in CACF-A, and -B. 12,13-dihydroxyoleic acid, another major compound in CACF-C fraction was isolated for the first time from Centratherum anthelminticum (L.) seeds but showed no cytotoxic effect against MCF 7 cells. Vernodalin inhibited cell growth of human breast cancer cells MCF-7 and MDA-MB-231 by induction of cell cycle arrest and apoptosis. Increased of reactive oxygen species (ROS) production, coupled with downregulation of anti-apoptotic molecules (Bcl-2, Bcl-xL) led to reduction of mitochondrial membrane potential (MMP) and release of cytochrome c in both human breast cancer cells treated with vernodalin. Release of cytochrome c from mitochondria to cytosol triggered activation of caspase cascade, PARP cleavage, DNA damage and eventually cell death. CONCLUSIONS/SIGNIFICANCE: To the best of our knowledge, this is the first comprehensive study on cytotoxic and apoptotic mechanism of vernodalin isolated from the Centratherum anthelminticum (L.) seeds in human breast cancer cells. Overall, our data suggest a potential therapeutic value of vernodalin to be further developed as new anti-cancer drug. PMID- 23437194 TI - Exploring angular distance in protein-protein docking algorithms. AB - We present a two-stage hybrid-resolution approach for rigid-body protein-protein docking. The first stage is carried out at low-resolution (15 degrees ) angular sampling. In the second stage, we sample promising regions from the first stage at a higher resolution of 6 degrees . The hybrid-resolution approach produces the same results as a 6 degrees uniform sampling docking run, but uses only 17% of the computational time. We also show that the angular distance can be used successfully in clustering and pruning algorithms, as well as the characterization of energy funnels. Traditionally the root-mean-square-distance is used in these algorithms, but the evaluation is computationally expensive as it depends on both the rotational and translational parameters of the docking solutions. In contrast, the angular distances only depend on the rotational parameters, which are generally fixed for all docking runs. Hence the angular distances can be pre-computed, and do not add computational time to the post processing of rigid-body docking results. PMID- 23437195 TI - The role of stream water carbon dynamics and export in the carbon balance of a tropical seasonal rainforest, southwest China. AB - A two-year study (2009 ~ 2010) was carried out to investigate the dynamics of different carbon (C) forms, and the role of stream export in the C balance of a 23.4-ha headwater catchment in a tropical seasonal rainforest at Xishuangbanna (XSBN), southwest China. The seasonal volumetric weighted mean (VWM) concentrations of total inorganic C (TIC) and dissolved inorganic C (DIC) were higher, and particulate inorganic C (PIC) and organic C (POC) were lower, in the dry season than the rainy season, while the VWM concentrations of total organic C (TOC) and dissolved organic C (DOC) were similar between seasons. With increased monthly stream discharge and stream water temperature (SWT), only TIC and DIC concentrations decreased significantly. The most important C form in stream export was DIC, accounting for 51.8% of the total C (TC) export; DOC, POC, and PIC accounted for 21.8%, 14.9%, and 11.5% of the TC export, respectively. Dynamics of C flux were closely related to stream discharge, with the greatest export during the rainy season. C export in the headwater stream was 47.1 kg C ha(-1) yr(-1), about 2.85% of the annual net ecosystem exchange. This finding indicates that stream export represented a minor contribution to the C balance in this tropical seasonal rainforest. PMID- 23437196 TI - Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis. AB - MicroRNAs (miRNAs) have been shown to be involved in different aspects of cancer biology including tumor angiogenesis. In this study, we identified that two miRNAs, miR-199a and miR-125b were downregulated in ovarian cancer tissues and cell lines. Overexpression of miR-199a and miR-125b inhibited tumor-induced angiogenesis associated with the decrease of HIF-1alpha and VEGF expression in ovarian cancer cells. Moreover, the levels of miR-199a and miR-125b were negatively correlated with VEGF mRNA levels in ovarian tissues. We further showed that direct targets of miR-199a and miR-125b HER2 and HER3 were functionally relevant. Forced expression of HER2 and HER3 rescued miR-199a- and miR-125b inhibiting angiogenesis responses and Akt/p70S6K1/HIF-1alpha pathway. This study provides a rationale for new therapeutic approach to suppress tumor angiogenesis using miR-199a, miR-125b, or their mimics for ovarian cancer treatment in the future. PMID- 23437197 TI - Adhesion of annexin 7 deficient erythrocytes to endothelial cells. AB - Annexin 7 deficiency has previously been shown to foster suicidal death of erythrocytes or eryptosis, which is triggered by increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) and characterized by cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine exposure at the cell surface. Eryptosis following increase of [Ca(2+)](i) by Ca(2+) ionophore ionomycin, osmotic shock or energy depletion was more pronounced in erythrocytes from annexinA7-deficient mice (anxA7(-/-)) than in erythrocytes from wild type mice (anxA7(+/+)). As phosphatidylserine exposure is considered to mediate adhesion of erythrocytes to the vascular wall, the present study explored adhesion of erythrocytes from anx7(-/-) and anx7(+/+)-mice following increase of [Ca(2+)](i) by Ca(2+) ionophore ionomycin (1 uM for 30 min), hyperosmotic shock (addition of 550 mM sucrose for 2 hours) or energy depletion (removal of glucose for 12 hours). Phosphatidylserine exposing erythrocytes were identified by annexin V binding, cell volume estimated from forward scatter in FACS analysis and adhesion to human umbilical vein endothelial cells (HUVEC) utilizing a flow chamber. As a result, ionomycin, sucrose addition and glucose removal all triggered phosphatidylserine-exposure, decreased forward scatter and enhanced adhesion of erythrocytes to human umbilical vein endothelial cells (HUVEC), effects significantly more pronounced in anx7(-/-) than in anx7(+/+)-erythrocytes. Following ischemia, morphological renal injury was significantly higher in anx7( /-) than in anx7(+/+)-mice. The present observations demonstrate that enhanced eryptosis of annexin7 deficient cells is paralleled by increased adhesion of erythrocytes to the vascular wall, an effect, which may impact on microcirculation during ischemia. PMID- 23437198 TI - Global analysis of the human pathophenotypic similarity gene network merges disease module components. AB - The molecular complexity of genetic diseases requires novel approaches to break it down into coherent biological modules. For this purpose, many disease network models have been created and analyzed. We highlight two of them, "the human diseases networks" (HDN) and "the orphan disease networks" (ODN). However, in these models, each single node represents one disease or an ambiguous group of diseases. In these cases, the notion of diseases as unique entities reduces the usefulness of network-based methods. We hypothesize that using the clinical features (pathophenotypes) to define pathophenotypic connections between disease causing genes improve our understanding of the molecular events originated by genetic disturbances. For this, we have built a pathophenotypic similarity gene network (PSGN) and compared it with the unipartite projections (based on gene-to gene edges) similar to those used in previous network models (HDN and ODN). Unlike these disease network models, the PSGN uses semantic similarities. This pathophenotypic similarity has been calculated by comparing pathophenotypic annotations of genes (human abnormalities of HPO terms) in the "Human Phenotype Ontology". The resulting network contains 1075 genes (nodes) and 26197 significant pathophenotypic similarities (edges). A global analysis of this network reveals: unnoticed pairs of genes showing significant pathophenotypic similarity, a biological meaningful re-arrangement of the pathological relationships between genes, correlations of biochemical interactions with higher similarity scores and functional biases in metabolic and essential genes toward the pathophenotypic specificity and the pleiotropy, respectively. Additionally, pathophenotypic similarities and metabolic interactions of genes associated with maple syrup urine disease (MSUD) have been used to merge into a coherent pathological module.Our results indicate that pathophenotypes contribute to identify underlying co-dependencies among disease-causing genes that are useful to describe disease modularity. PMID- 23437199 TI - Granulocyte colony stimulating factor induces lipopolysaccharide (LPS) sensitization via upregulation of LPS binding protein in rat. AB - Liver is the main organ for lipopolysaccharide (LPS) clearance. Sensitization to LPS is associated with the upregulation of LPS-binding protein (LBP) in animal models. Therefore, we hypothesized that LBP could induce LPS sensitization through enhancing hepatic uptake of LPS. In this study, we examined the role of LBP in pathogenesis of LPS induced systemic inflammatory response syndrome (SIRS). LBP expression was upregulated after granulocyte colony stimulating (G CSF) pretreatment. The effect of LBP was further confirmed by blockade of LBP using LBP blocking peptide--LBPK95A. After G-CSF pretreatment, upregulation of LBP was observed in bone marrow cells and liver. The G-CSF induced LBP upregulation caused LPS hypersensitization in rats as indicated by higher mortality and severer liver damage. Of note, LBP blockade increased the survival rate and attenuated the liver injury. The LBP induced LPS hypersensitization was associated with increased hepatic uptake of LPS and augmented hepatic expression of LPS receptors, such as toll-like receptor (TLR)-4. Furthermore, LBP mediated early neutrophil infiltration, which led to increased monocyte recruitment in liver after LPS administration. In conclusion, G-CSF induced LBP expression could serve as a new model for investigation of LPS sensitization. We demonstrated the crucial role of LBP upregulation in pathogenesis of LPS induced SIRS. PMID- 23437200 TI - Identification of cellular calcium binding protein calmodulin as a regulator of rotavirus A infection during comparative proteomic study. AB - Rotavirus (RV) being the major diarrhoegenic virus causes around 527000 children death (<5 years age) worldwide. In cellular environment, viruses constantly adapt and modulate to survive and replicate while the host cell also responds to combat the situation and this results in the differential regulation of cellular proteins. To identify the virus induced differential expression of proteins, 2D DIGE (Two-dimensional Difference Gel Electrophoresis) based proteomics was used. For this, HT-29 cells were infected with RV strain SA11 for 0 hours, 3 hours and 9 hours post infection (hpi), differentially expressed spots were excised from the gel and identified using MALDI-TOF/TOF mass spectrometry. 2D-DIGE based proteomics study identified 32 differentially modulated proteins, of which 22 were unique. Some of these were validated in HT-29 cell line and in BALB/c mice model. One of the modulated cellular proteins, calmodulin (CaM) was found to directly interact with RV protein VP6 in the presence of Ca(2+). Ca(2+)-CaM/VP6 interaction positively regulates RV propagation since both CaM inhibitor (W-7) and Ca(2+) chelator (BAPTA-AM) resulted in decreased viral titers. This study not only identifies differentially modulated cellular proteins upon infection with rotavirus in 2D-DIGE but also confirmed positive engagement of cellular Ca(2+)/CaM during viral pathogenesis. PMID- 23437201 TI - Significance and suppression of redundant IL17 responses in acute allograft rejection by bioinformatics based drug repositioning of fenofibrate. AB - Despite advanced immunosuppression, redundancy in the molecular diversity of acute rejection (AR) often results in incomplete resolution of the injury response. We present a bioinformatics based approach for identification of these redundant molecular pathways in AR and a drug repositioning approach to suppress these using FDA approved drugs currently available for non-transplant indications. Two independent microarray data-sets from human renal allograft biopsies (n = 101) from patients on majorly Th1/IFN-y immune response targeted immunosuppression, with and without AR, were profiled. Using gene-set analysis across 3305 biological pathways, significant enrichment was found for the IL17 pathway in AR in both data-sets. Recent evidence suggests IL17 pathway as an important escape mechanism when Th1/IFN-y mediated responses are suppressed. As current immunosuppressions do not specifically target the IL17 axis, 7200 molecular compounds were interrogated for FDA approved drugs with specific inhibition of this axis. A combined IL17/IFN-y suppressive role was predicted for the antilipidemic drug Fenofibrate. To assess the immunregulatory action of Fenofibrate, we conducted in-vitro treatment of anti-CD3/CD28 stimulated human peripheral blood cells (PBMC), and, as predicted, Fenofibrate reduced IL17 and IFN-gamma gene expression in stimulated PMBC. In-vivo Fenofibrate treatment of an experimental rodent model of cardiac AR reduced infiltration of total leukocytes, reduced expression of IL17/IFN-y and their pathway related genes in allografts and recipients' spleens, and extended graft survival by 21 days (p<0.007). In conclusion, this study provides important proof of concept that meta-analyses of genomic data and drug databases can provide new insights into the redundancy of the rejection response and presents an economic methodology to reposition FDA approved drugs in organ transplantation. PMID- 23437202 TI - Ameliorative effects of a combination of baicalin, jasminoidin and cholic acid on ibotenic acid-induced dementia model in rats. AB - AIMS: To investigate the therapeutic effects and acting mechanism of a combination of Chinese herb active components, i.e., a combination of baicalin, jasminoidin and cholic acid (CBJC) on Alzheimer's disease (AD). METHODS: Male rats were intracerebroventricularly injected with ibotenic acid (IBO), and CBJC was orally administered. Therapeutic effect was evaluated with the Morris water maze test, FDG-PET examination, and histological examination, and the acting mechanism was studied with DNA microarrays and western blotting. RESULTS: CBJC treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Additionally, the expression levels of 19 genes in the forebrain were significantly influenced by CBJC; approximately 60% of these genes were related to neuroprotection and neurogenesis, whereas others were related to anti-oxidation, protein degradation, cholesterol metabolism, stress response, angiogenesis, and apoptosis. Expression of these genes was increased, except for the gene related to apoptosis. Changes in expression for 5 of these genes were confirmed by western blotting. CONCLUSION: CBJC can ameliorate the IBO-induced dementia in rats and may be significant in the treatment of AD. The therapeutic mechanism may be related to CBJC's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc. PMID- 23437203 TI - The antimetastatic effects of resveratrol on hepatocellular carcinoma through the downregulation of a metastasis-associated protease by SP-1 modulation. AB - BACKGROUND: The mortality and morbidity rates from cancer metastasis have not declined in Taiwan, especially because of hepatocellular carcinoma (HCC). Resveratrol has been shown to have benefits such as cardioprotection, providing antioxidative, anti-inflammatory, anti-cancer properties in previous studies. Therefore, HCC cells were subjected to treatment with resveratrol and then analyzed to determine the effects of resveratrol on the migration and invasion. METHODOLOGY AND PRINCIPAL FINDINGS: Modified Boyden chamber assays revealed that resveratrol treatment significantly inhibited cell migration and invasion capacities of Huh7 cell lines that have low cytotoxicity in vitro, even at a high concentration of 100 uM. The results of casein zymography and western blotting revealed that the activities and protein levels of the urokinase-type plasminogen activator (u-PA) were inhibited by resveratrol. Western blot analysis also showed that resveratrol inhibits phosphorylation of JNK1/2. Tests of the mRNA level, real-time PCR, and promoter assays evaluated the inhibitory effects of resveratrol on u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay showed that reactive in transcription protein of nuclear factor SP-1 was inhibited by resveratrol. CONCLUSIONS: Resveratrol inhibits u-PA expression and the metastasis of HCC cells and is a powerful chemopreventive agent. The inhibitory effects were associated with the downregulation of the transcription factors of SP-1 signaling pathways. PMID- 23437204 TI - Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies. AB - BACKGROUND: Increasing evidence suggests that diabetes mellitus (DM) may be associated with an increased risk of bladder cancer. To provide a quantitative assessment of this association, we evaluated the relation between DM and incidence and mortality of bladder cancer in an updated meta-analysis of cohort studies. Methods We identified cohort studies by searching the EMBASE and MEDLINE databases, through 31 March 2012. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with random-effects models. RESULTS: A total of 29 cohort studies (27 articles) were included in this meta-analysis. DM was associated with an increased incidence of bladder cancer (RR 1.29, 95% CI: 1.08-1.54), with significant evidence of heterogeneity among these studies (p<0.001, I(2) = 94.9%). In stratified analysis, the RRs of bladder cancer were 1.36 (1.05-1.77) for diabetic men and 1.28 (0.75-2.19) for diabetic women, respectively. DM was also positively associated with bladder cancer mortality (RR 1.33, 95% CI: 1.14-1.55), with evident heterogeneity between studies (p = 0.002, I(2) = 63.3%). The positive association was observed for both men (RR 1.54, 95% CI: 1.30-1.82) and women (RR 1.50, 95% CI: 1.05-2.14). CONCLUSION: These findings suggest that compared to non-diabetic individuals, diabetic individuals have an increased incidence and mortality of bladder cancer. PMID- 23437205 TI - Effect of Bcl-2 rs956572 polymorphism on age-related gray matter volume changes. AB - The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM) volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female) with a mean age of 56.2+/ 22.0 years (range: 21-92). Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P<.001). Moreover, the downward slope was steeper among the Bcl-2 rs956572 A allele carriers than in the G-homozygous participants. Our data provide convergent evidence for the genetic effect of the Bcl-2 functional allelic variant in brain aging. The rs956572 G-allele, which is associated with significantly higher Bcl-2 protein expression and diminished cellular sensitivity to stress-induced apoptosis, conferred a protective effect against age-related changes in brain GM volume, particularly in the cerebellum. PMID- 23437206 TI - Polarization of diploid daughter cells directed by spatial cues and GTP hydrolysis of Cdc42 budding yeast. AB - Cell polarization occurs along a single axis that is generally determined by a spatial cue. Cells of the budding yeast exhibit a characteristic pattern of budding, which depends on cell-type-specific cortical markers, reflecting a genetic programming for the site of cell polarization. The Cdc42 GTPase plays a key role in cell polarization in various cell types. Although previous studies in budding yeast suggested positive feedback loops whereby Cdc42 becomes polarized, these mechanisms do not include spatial cues, neglecting the normal patterns of budding. Here we combine live-cell imaging and mathematical modeling to understand how diploid daughter cells establish polarity preferentially at the pole distal to the previous division site. Live-cell imaging shows that daughter cells of diploids exhibit dynamic polarization of Cdc42-GTP, which localizes to the bud tip until the M phase, to the division site at cytokinesis, and then to the distal pole in the next G1 phase. The strong bias toward distal budding of daughter cells requires the distal-pole tag Bud8 and Rga1, a GTPase activating protein for Cdc42, which inhibits budding at the cytokinesis site. Unexpectedly, we also find that over 50% of daughter cells lacking Rga1 exhibit persistent Cdc42-GTP polarization at the bud tip and the distal pole, revealing an additional role of Rga1 in spatiotemporal regulation of Cdc42 and thus in the pattern of polarized growth. Mathematical modeling indeed reveals robust Cdc42 GTP clustering at the distal pole in diploid daughter cells despite random perturbation of the landmark cues. Moreover, modeling predicts different dynamics of Cdc42-GTP polarization when the landmark level and the initial level of Cdc42 GTP at the division site are perturbed by noise added in the model. PMID- 23437207 TI - Brood reduction via intra-clutch variation in testosterone--an experimental test in the great tit. AB - In birds, yolk androgen concentrations in eggs can increase or decrease over the laying sequence and common hypotheses hold that this serves to favour the competitive ability of either first- or last-hatched chicks depending on the prevailing conditions, and thus promote brood reduction or maintenance of original brood size respectively. Intra-clutch variation of testosterone can shift relative competitive ability of siblings and hence competitive dynamics. In a natural population of great tits, we experimentally investigated the effects and function of maternal testosterone on offspring phenotype in relation to the laying position of the egg in a context of hatching asynchrony. To this end, we created three types of clutches where either the first three or the last three eggs of a clutch were injected with testosterone (T) dissolved in sesame oil, and the remaining eggs with sesame oil only, or where all eggs of a clutch were injected with sesame oil. Increased levels of yolk T in the last-laid eggs resulted in the last-hatched chicks being significantly lighter and smaller than their siblings, while increased levels of T in the first-laid eggs had no direct effect on the first-hatched chicks, but an indirect negative effect on their siblings. Our results suggest that females can potentially adjust offspring phenotype by modulating, over the laying sequence, the amounts of T deposited in the eggs. These results are in contradiction, however, with current hypotheses and previous findings, which suggest that under good conditions higher levels of maternally derived T in the last-laid eggs should mitigate the negative effects of hatching asynchrony. PMID- 23437208 TI - Health and the 2008 economic recession: evidence from the United Kingdom. AB - INTRODUCTION: The economic recession which began in 2008 has resulted in a substantial increase in unemployment across many countries, including the United Kingdom. Strong association between unemployment and poor health status among individuals is widely recognised. We investigated whether the prevalence of poor health at a population level increased concurrent to the rise in unemployment during the economic recession, and whether the impact on health varied by geographical and socioeconomic circumstances. METHOD: Health, demographic and socioeconomic measures on 1.36 million survey responses aged 16-64 were extracted from the Quarterly Labour Force Survey of the United Kingdom, collected every three months, from January 2006 to December 2010. The likelihood of self reporting poor health status and specific types of health problems (depression, mental illness, cardiovascular and respiratory) across time were estimated separately using logistic regression. Explanatory variables included economic status (International Labour Organization definition), occupational class, age, gender, country of birth, ethnicity, educational qualifications, couple status, household tenure, number of dependents, and geographical region. RESULTS: Unemployment (age-gender adjusted) rose from 4.5% in January 2008 to 7.1% by September 2009. The reporting of poor health status increased from 25.7% in July 2009 to 29.5% by December 2010. Similar increases were found for cardiovascular and respiratory health problems; not depression or mental illness. The prevalence of poor health status among the unemployed decreased from 28.8% in July 2008, to 24.9% by March 2009; but this was followed by an increase in poor health experienced across all regions and by all socioeconomic groups, including those who remained employed, regardless of their occupational class. INTERPRETATION: Although our study found no exacerbation of pre-recession health inequalities, the rise in poor health status not only for the unemployed, but also among people who remained employed, regardless of their occupational class, justifies concern voiced among many public health commentators. PMID- 23437209 TI - Molecular diagnosis of malaria by photo-induced electron transfer fluorogenic primers: PET-PCR. AB - There is a critical need for developing new malaria diagnostic tools that are sensitive, cost effective and capable of performing large scale diagnosis. The real-time PCR methods are particularly robust for large scale screening and they can be used in malaria control and elimination programs. We have designed novel self-quenching photo-induced electron transfer (PET) fluorogenic primers for the detection of P. falciparum and the Plasmodium genus by real-time PCR. A total of 119 samples consisting of different malaria species and mixed infections were used to test the utility of the novel PET-PCR primers in the diagnosis of clinical samples. The sensitivity and specificity were calculated using a nested PCR as the gold standard and the novel primer sets demonstrated 100% sensitivity and specificity. The limits of detection for P. falciparum was shown to be 3.2 parasites/ul using both Plasmodium genus and P. falciparum-specific primers and 5.8 parasites/ul for P. ovale, 3.5 parasites/ul for P. malariae and 5 parasites/ul for P. vivax using the genus specific primer set. Moreover, the reaction can be duplexed to detect both Plasmodium spp. and P. falciparum in a single reaction. The PET-PCR assay does not require internal probes or intercalating dyes which makes it convenient to use and less expensive than other real-time PCR diagnostic formats. Further validation of this technique in the field will help to assess its utility for large scale screening in malaria control and elimination programs. PMID- 23437210 TI - Coordination of division and development influences complex multicellular behavior in Agrobacterium tumefaciens. AB - The alpha-Proteobacterium Agrobacterium tumefaciens has proteins homologous to known regulators that govern cell division and development in Caulobacter crescentus, many of which are also conserved among diverse alpha-Proteobacteria. In light of recent work demonstrating similarity between the division cycle of C. crescentus and that of A. tumefaciens, the functional conservation for this presumptive control pathway was examined. In C. crescentus the CtrA response regulator serves as the master regulator of cell cycle progression and cell division. CtrA activity is controlled by an integrated pair of multi-component phosphorelays: PleC/DivJ-DivK and CckA-ChpT-CtrA. Although several of the conserved orthologues appear to be essential in A. tumefaciens, deletions in pleC or divK were isolated and resulted in cell division defects, diminished swimming motility, and a decrease in biofilm formation. A. tumefaciens also has two additional pleC/divJhomologue sensor kinases called pdhS1 and pdhS2, absent in C. crescentus. Deletion of pdhS1 phenocopied the DeltapleC and DeltadivK mutants. Cells lacking pdhS2 morphologically resembled wild-type bacteria, but were decreased in swimming motility and elevated for biofilm formation, suggesting that pdhS2 may serve to regulate the motile to non-motile switch in A. tumefaciens. Genetic analysis suggests that the PleC/DivJ-DivK and CckA-ChpT-CtrA phosphorelays in A. tumefaciens are vertically-integrated, as in C. crescentus. A gain-of-function mutation in CckA (Y674D) was identified as a spontaneous suppressor of the DeltapleC motility phenotype. Thus, although the core architecture of the A. tumefaciens pathway resembles that of C. crescentus there are specific differences including additional regulators, divergent pathway architecture, and distinct target functions. PMID- 23437211 TI - Cellulose supplementation early in life ameliorates colitis in adult mice. AB - Decreased consumption of dietary fibers, such as cellulose, has been proposed to promote the emergence of inflammatory bowel diseases (IBD: Crohn disease [CD] and ulcerative colitis [UC]) where intestinal microbes are recognized to play an etiologic role. However, it is not known if transient fiber consumption during critical developmental periods may prevent consecutive intestinal inflammation. The incidence of IBD peaks in young adulthood indicating that pediatric environmental exposures may be important in the etiology of this disease group. We studied the effects of transient dietary cellulose supplementation on dextran sulfate sodium (DSS) colitis susceptibility during the pediatric period in mice. Cellulose supplementation stimulated substantial shifts in the colonic mucosal microbiome. Several bacterial taxa decreased in relative abundance (e.g., Coriobacteriaceae [p = 0.001]), and other taxa increased in abundance (e.g., Peptostreptococcaceae [p = 0.008] and Clostridiaceae [p = 0.048]). Some of these shifts persisted for 10 days following the cessation of cellulose supplementation. The changes in the gut microbiome were associated with transient trophic and anticolitic effects 10 days following the cessation of a cellulose enriched diet, but these changes diminished by 40 days following reversal to a low cellulose diet. These findings emphasize the transient protective effect of dietary cellulose in the mammalian large bowel and highlight the potential role of dietary fibers in amelioration of intestinal inflammation. PMID- 23437212 TI - Transcriptional profiles of the response of methicillin-resistant Staphylococcus aureus to pentacyclic triterpenoids. AB - Staphylococcus aureus is an important human pathogen in both hospital and the community that has demonstrated resistance to all currently available antibiotics over the last two decades. Multidrug-resistant isolates of methicillin-resistant S. aureus (MRSA) exhibiting decreased susceptibilities to glycopeptides has also emerged, representing a crucial challenge for antimicrobial therapy and infection control. The availability of complete whole-genome nucleotide sequence data of various strains of S. aureus presents an opportunity to explore novel compounds and their targets to address the challenges presented by antimicrobial drug resistance in this organism. Study compounds alpha-amyrin [3beta-hydroxy-urs-12 en-3-ol (AM)], betulinic acid [3beta-hydroxy-20(29)-lupaene-28-oic acid (BA)] and betulinaldehyde [3beta-hydroxy-20(29)-lupen-28-al (BE)] belong to pentacyclic triterpenoids and were reported to exhibit antimicrobial activities against bacteria and fungi, including S. aureus. The MIC values of these compounds against a reference strain of methicillin-resistant S. aureus (MRSA) (ATCC 43300) ranged from 64 ug/ml to 512 ug/ml. However, the response mechanisms of S. aureus to these compounds are still poorly understood. The transcription profile of reference strain of MRSA treated with sub-inhibitory concentrations of the three compounds was determined using Affymetrix GeneChips. The findings showed that these compounds regulate multiple desirable targets in cell division, two component system, ABC transporters, fatty acid biosynthesis, peptidoglycan biosynthesis, aminoacyl-tRNA synthetase, ribosome and beta-lactam resistance pathways which could be further explored in the development of therapeutic agents for the treatment of S. aureus infections. PMID- 23437213 TI - Role of androgen receptor in progression of LNCaP prostate cancer cells from G1 to S phase. AB - BACKGROUND: The androgen receptor (AR) plays a critical role in the proliferation of prostate cancer cells. However, its mechanism of action in proliferation remains unknown. An understanding of the mechanism of AR action in proliferation may lead to the development of effective strategies for the treatment of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study we report that pulse treatment of synchronized LNCaP cells with Casodex, an AR-antagonist, for 4 hours in mid-G(1) phase was sufficient to prevent cells from entering S phase. Since the assembly of pre-replication complex (pre-RC) in G(1) is required for the progression of cells from G(1) to S phase, the effect of Casodex during mid-G(1) suggested that the role of AR in proliferation might be to regulate the assembly of pre-RC. To test this possibility, we investigated the interaction between AR and Cdc6, an essential component of pre-RC in LNCaP cells. AR co-localized and co immunoprecipitated with Cdc6, and Casodex treatment disrupted this interaction. AR-immunoprecipitate (AR-IP) also contained cyclin E and cyclin A, which play a critical role in pre-RC assembly and cell cycle entry into S phase, and DNA polymerase-alpha, PCNA, and ribonucleotide reductase, which are essential for the initiation of DNA synthesis. In addition, in cells in S phase, AR co-sedimented with components of the DNA replication machinery of cells that entered S phase. CONCLUSIONS/SIGNIFICANCE: Together, these observations suggest a novel role of AR as a component of the pre-RC to exert control over progression of LNCaP cells from G(1) to S phase through a mechanism that is independent of its role as a transcription factor. PMID- 23437214 TI - Inference of cross-level interaction between genes and contextual factors in a matched case-control metabolic syndrome study: a Bayesian approach. AB - Genes, environment, and the interaction between them are each known to play an important role in the risk for developing complex diseases such as metabolic syndrome. For environmental factors, most studies focused on the measurements observed at the individual level, and therefore can only consider the gene environment interaction at the same individual scale. Indeed the group-level (called contextual) environmental variables, such as community factors and the degree of local area development, may modify the genetic effect as well. To examine such cross-level interaction between genes and contextual factors, a flexible statistical model quantifying the variability of the genetic effects across different categories of the contextual variable is in need. With a Bayesian generalized linear mixed-effects model with an unconditional likelihood, we investigate whether the individual genetic effect is modified by the group level residential environment factor in a matched case-control metabolic syndrome study. Such cross-level interaction is evaluated by examining the heterogeneity in allelic effects under various contextual categories, based on posterior samples from Markov chain Monte Carlo methods. The Bayesian analysis indicates that the effect of rs1801282 on metabolic syndrome development is modified by the contextual environmental factor. That is, even among individuals with the same genetic component of PPARG_Pro12Ala, living in a residential area with low availability of exercise facilities may result in higher risk. The modification of the group-level environment factors on the individual genetic attributes can be essential, and this Bayesian model is able to provide a quantitative assessment for such cross-level interaction. The Bayesian inference based on the full likelihood is flexible with any phenotype, and easy to implement computationally. This model has a wide applicability and may help unravel the complexity in development of complex diseases. PMID- 23437215 TI - Combined strategy of endothelial cells coating, Sertoli cells coculture and infusion improves vascularization and rejection protection of islet graft. AB - Improving islet graft revascularization and inhibiting rejection become crucial tasks for prolonging islet graft survival. Endothelial cells (ECs) are the basis of islet vascularization and Sertoli cells (SCs) have the talent to provide nutritional support and exert immunosuppressive effects. We construct a combined strategy of ECs coating in the presence of nutritious and immune factors supplied by SCs in a co-culture system to investigate the effect of vascularization and rejection inhibition for islet graft. In vivo, the combined strategy improved the survival and vascularization as well as inhibited lymphocytes and inflammatory cytokines. In vitro, we found the combinatorial strategy improved the function of islets and the effect of ECs-coating on islets. Combined strategy treated islets revealed higher levels of anti-apoptotic signal molecules (Bcl-2 and HSP-32), survival and function related molecules (PDX-1, Ki-67, ERK1/2 and Akt) and demonstrated increased vascular endothelial growth factor receptor 2 (KDR) and angiogenesis signal molecules (FAk and PLC-gamma). SCs effectively inhibited the activation of lymphocyte stimulated by islets and ECs. Predominantly immunosuppressive cytokines could be detected in culture supernatants of the SCs coculture group. These results suggest that ECs-coating and Sertoli cells co culture or infusion synergistically enhance islet survival and function after transplantation. PMID- 23437216 TI - Overexpression of the Artemisia orthologue of ABA receptor, AaPYL9, enhances ABA sensitivity and improves artemisinin content in Artemisia annua L. AB - The phytohormone abscisic acid (ABA) plays an important role in plant development and environmental stress response. In this study, we cloned an ABA receptor orthologue, AaPYL9, from Artemisia annua L. AaPYL9 is expressed highly in leaf and flower. AaPYL9 protein can be localized in both nucleus and cytoplasm. Yeast two-hybrid assay shows AaPYL9 can specifically interact with AtABI1 but not with AtABI2, AtHAB1 or AtHAB2. ABA can enhance the interaction between AaPYL9 and AtABI1 while AaPYL9-89 Pro->Ser and AaPYL9-116 His->Ala point mutations abolishes the interaction. BiFC assay shows that AaPYL9 interacts with AtABI1 in nucleus in planta. Transgenic Arabidopsis plants over-expressing AaPYL9 are more sensitive to ABA in the seed germination and primary root growth than wild type. Consistent with this, ABA report genes have higher expression in AaPYL9 overexpressing plants compared to wild type after ABA treatment. Moreover, overexpression of AaPYL9 in A. annua increases not only drought tolerance, but also artemisinin content after ABA treatment, with significant enhancement of the expression of key genes in artemisinin biosynthesis. This study provides a way to develop A. annua with high-yielding artemisinin and high drought resistance. PMID- 23437217 TI - Parallel screening of wild-type and drug-resistant targets for anti-resistance neuraminidase inhibitors. AB - Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA) drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR) influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT) and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye), which inhibited WT NA and MDR NA with IC(50) values of 3.4 and 4.5 uM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high mutation rates, such as cancer and human immunodeficiency virus type 1. PMID- 23437218 TI - Let-7b is involved in the inflammation and immune responses associated with Helicobacter pylori infection by targeting Toll-like receptor 4. AB - OBJECTIVES: Toll-like receptors (TLRs) are important initiators in native immune responses to microbial infections. TLR4 is up-regulated in response to H.pylori infection in gastric epithelial cells. However, the regulatory mechanisms for the expression of TLR4 in H.pylori infection have not been clearly defined. The aims of this study are to present the evidence that microRNA let-7b directly regulates TLR4 expression in human gastric epithelial cells, and subsequently influences the activation of NF-kappaB and the expression of the downstream genes in H.pylori infection. METHODS: The expression of let-7b was determined in gastric mucosa specimens and in two gastric epithelial cell lines using quantitative RT PCR. The expression of TLR4 was determined by immunohistochemistry staining and RT-PCR. The potential target of let-7b was identified by luciferase reporter assay and Western blot. Let-7b mimics and inhibitors were used to examine the effects of let-7b on NF-kappaB activity. The expression of the downstream genes of NF-kappaB was also determined in cells infected with H.pylori 26695. RESULTS: Let-7b was significantly decreased in gastric mucosa specimens and in gastric epithelial cell lines (AGS, GES-1) infected with H.pylori 26695 (cagA+). Let-7b was complementary to the 3'-UTR of TLR4 mRNA and regulated TLR4 expression via post-transcriptional suppression in gastric epithelium. Infection of H.pylori induced the expression of TLR4 and activated NF-kappaB in AGS and GES-1 cells. Overexpression of let-7b by mimics downregulated TLR4, and subsequently attenuated NF-kappaB, MyD88, NF-kappaB1/p50, RelA/p65. The expression of IL-8, COX-2 and CyclinD1 was inhibited in H.pylori infected cells with let-7b overexpression. Both TAK-242 (TLR4 inhibitor) and SN50 (NF-kappaB inhibitor) significantly inhibited the H.pylori induced downregulation of let-7b. CONCLUSIONS: Let-7b targets at TLR4 mRNA, and regulates the activation of NF kappaB and the expression of the downstream genes related to the inflammation and immune responses in H.pylori infection. PMID- 23437219 TI - Hereditary angioedema nationwide study in Slovenia reveals four novel mutations in SERPING1 gene. AB - Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE) or normal levels of ineffective C1 inhibitor (Type II HAE). A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function), followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T) and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T), and Glu429Lys (c.1351G>A), together with two frameshift mutations, indel (c.49delGinsTT) and deletion (c.593_594delCT). Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T) and Arg444His (c.1397G>A), respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C) was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C) might be responsible for the disease. PMID- 23437221 TI - Male songbird indicates body size with low-pitched advertising songs. AB - Body size is a key sexually selected trait in many animal species. If size imposes a physical limit on the production of loud low-frequency sounds, then low pitched vocalisations could act as reliable signals of body size. However, the central prediction of this hypothesis--that the pitch of vocalisations decreases with size among competing individuals--has limited support in songbirds. One reason could be that only the lowest-frequency components of vocalisations are constrained, and this may go unnoticed when vocal ranges are large. Additionally, the constraint may only be apparent in contexts when individuals are indeed advertising their size. Here we explicitly consider signal diversity and performance limits to demonstrate that body size limits song frequency in an advertising context in a songbird. We show that in purple-crowned fairy-wrens, Malurus coronatus coronatus, larger males sing lower-pitched low-frequency advertising songs. The lower frequency bound of all advertising song types also has a significant negative relationship with body size. However, the average frequency of all their advertising songs is unrelated to body size. This comparison of different approaches to the analysis demonstrates how a negative relationship between body size and song frequency can be obscured by failing to consider signal design and the concept of performance limits. Since these considerations will be important in any complex communication system, our results imply that body size constraints on low-frequency vocalisations could be more widespread than is currently recognised. PMID- 23437220 TI - Changes in muscle cell metabolism and mechanotransduction are associated with myopathic phenotype in a mouse model of collagen VI deficiency. AB - This study identifies metabolic and protein phenotypic alterations in gastrocnemius, tibialis anterior and diaphragm muscles of Col6a1(-/-) mice, a model of human collagen VI myopathies. All three muscles of Col6a1(-/-) mice show some common changes in proteins involved in metabolism, resulting in decreased glycolysis and in changes of the TCA cycle fluxes. These changes lead to a different fate of alpha-ketoglutarate, with production of anabolic substrates in gastrocnemius and tibialis anterior, and with lipotoxicity in diaphragm. The metabolic changes are associated with changes of proteins involved in mechanotransduction at the myotendineous junction/costameric/sarcomeric level (TN C, FAK, ROCK1, troponin I fast) and in energy metabolism (aldolase, enolase 3, triose phosphate isomerase, creatine kinase, adenylate kinase 1, parvalbumin, IDH1 and FASN). Together, these change may explain Ca(2+) deregulation, impaired force development, increased muscle-relaxation-time and fiber damage found in the mouse model as well as in patients. The severity of these changes differs in the three muscles (gastrocnemiusT polymorphism and cancer risk: a meta analysis of 28 case-control studies. AB - BACKGROUND: GSTP1, which is one major group of the glutathione S-transferase family, plays an important role in the metabolism of carcinogens and toxins, reducing damage of DNA as a suppressor of carcinogenesis. The 341C>T polymorphism of the GSTP1 has been implicated in cancer risk through cutting down its metabolic detoxification activities. However, results from previous studies remain conflicting rather than conclusive. To clarify the correlation and provide more statistical evidence for detecting the significance of 341C>T, a meta analysis was conducted. METHODOLOGY/PRINCIPAL FINDINGS: The relevant studies were identified through searching of PubMed, Embase, ISI Web of Knowledge and China National Knowledge Infrastructure in August 2012, and selected based on the established inclusion criteria for publications, then a meta-analysis was performed to quantitatively summarize the association of GSTP1 341C>T polymorphism with cancer susceptibility. Stratified analyses were employed to identify the source of heterogeneity. Publication bias was evaluated as well as sensitivity analysis. Based on 28 case-control studies with 13249 cases and 16798 controls, the pooled results indicated that the variant genotypes significantly increased the risk of cancer in homozygote comparison (TT versus CC: P = 0.012, OR = 1.40, 95% CI: 1.08-1.81, P(het.) = 0.575), and recessive model (TT versus CT/CC: P = 0.012, OR = 1.40, 95% CI: 1.08-1.81, P(het.) = 0.562). This was confirmed when stratified analyses were conducted according to ethnicity, source of control, matched control, quality score and cancer types. Moreover, significantly increased risk of cancer was also found in lung cancer (heterozygote comparison and dominant model). The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that the GSTP1 341C>T polymorphism may contribute to genetic susceptibility to cancer, especially to lung cancer, and in Asian population. Nevertheless, additional well-designed studies focusing on different ethnicity and cancer types are needed to provide a more exact and comprehensive conclusion. PMID- 23437224 TI - Citation patterns of a controversial and high-impact paper: Worm et al. (2006) "Impacts of biodiversity loss on ocean ecosystem services". AB - Citation patterns were examined for Worm et al. 2006 (Science 314:787-790), a high-impact paper that focused on relationships between marine biodiversity and ecosystem services. This paper sparked much controversy through its projection, highlighted in the press release, that all marine fisheries would be collapsed by 2048. Analysis of 664 citing papers revealed that only a small percentage (11%) referred to the 2048 projection, while 39% referred to fisheries collapse in general, and 40% to biodiversity and ecosystem services. The 2048 projection was mentioned more often in papers published soon after the original paper, in low impact journals, and in journals outside of fields that would be expected to focus on biodiversity. Citing papers also mentioned the 2048 projection more often if they had few authors (28% of single-author papers vs. 2% of papers with 10 or more authors). These factors suggest that the more knowledgeable the authors of citing papers were about the controversy over the 2048 projection, the less likely they were to refer to it. A noteworthy finding was that if the original authors were also involved in the citing papers, they rarely (1 of 55 papers, 2%) mentioned the 2048 projection. Thus the original authors have emphasized the broader concerns about biodiversity loss, rather than the 2048 projection, as the key result of their study. PMID- 23437225 TI - At the heart of the industrial boom: Australian snubfin dolphins in the Capricorn Coast, Queensland, need urgent conservation action. AB - The recent industrial boom along the Australian coastline has increased concerns about the long term conservation of snubfin dolphins along the Queensland coast. National assessment of the conservation status and management of the Australian snubfin dolphin is currently hindered by the lack of adequate biological and ecological information throughout most of its range. In response to the issue of determining the conservation status of species with broad ranges, the IUCN has provided a framework for assessing the threatened status of regional populations. In this study we assessed the conservation status of a small geographically isolated population of snubfin dolphins living in the Fitzroy River region, Queensland, Australia, against the IUCN criteria for regional populations. A review of all available sightings data and stranding information indicates that this is the southernmost resident population of snubfin dolphins in Australian waters. The Fitzroy River snubfin dolphin population is composed of less than 100 individuals, with a representative range and core area of less than 400 and 300 km(2) respectively. The area most often used by snubfin dolphins within the representative range and core area was estimated to be about 292 and 191 km(2), respectively. A decrease in representative range, core area and preferred habitat between 14 and 25% is projected to occur if a planned industrial port development were to occur. These results are robust to uncertainty and considering the low level of formal protection and future threats, a classification of this subpopulation under the IUCN Red List as "Endangered" is appropriate. PMID- 23437226 TI - Identification of special AT-rich sequence binding protein 1 as a novel tumor antigen recognized by CD8+ T cells: implication for cancer immunotherapy. AB - BACKGROUND: A large number of human tumor-associated antigens that are recognized by CD8(+) T cells in a human leukocyte antigen class I (HLA-I)-restricted fashion have been identified. Special AT-rich sequence binding protein 1 (SATB1) is highly expressed in many types of human cancers as part of their neoplastic phenotype, and up-regulation of SATB1 expression is essential for tumor survival and metastasis, thus this protein may serve as a rational target for cancer vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Twelve SATB1-derived peptides were predicted by an immuno-informatics approach based on the HLA-A*02 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from HLA-A*02(+) healthy donors and/or HLA-A*02(+) cancer patients. The recognition of HLA-A*02(+) SATB1-expressing cancer cells was also tested. Among the twelve SATB1-derived peptides, SATB1(565-574) frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and cancer patients. Importantly, SATB1(565-574) specific T cells recognized and killed HLA-A*02(+) SATB1(+) cancer cells in an HLA-I-restricted manner. CONCLUSIONS/SIGNIFICANCE: We have identified a novel HLA A*02-restricted SATB1-derived peptide epitope recognized by CD8(+) T cells, which, in turn, recognizes and kills HLA-A*02(+) SATB1(+) tumor cells. The SATB1 derived epitope identified may be used as a diagnostic marker as well as an immune target for development of cancer vaccines. PMID- 23437227 TI - Replication of association between schizophrenia and chromosome 6p21-6p22.1 polymorphisms in Chinese Han population. AB - Chromosome 6p21-p22.1, spanning the extended major histocompatibility complex (MHC) region, is a highly polymorphic, gene-dense region. It has been identified as a susceptibility locus of schizophrenia in Europeans, Japanese, and Chinese. In our previous two-stage genome-wide association study (GWAS), polymorphisms of zinc finger with KRAB and SCAN domains 4 (ZKSCAN4), nuclear factor-kappaB activating protein-like (NKAPL), and piggyBac transposable element derived 1 (PGBD1), localized to chromosome 6p21-p22.1, were strongly associated with schizophrenia. To further investigate the association between polymorphisms at this locus and schizophrenia in the Chinese Han population, we selected eight other single-nucleotide polymorphisms (SNPs) distributed in or near these genes for a case-control association study in an independent sample of 902 cases and 1,091 healthy controls in an attempt to replicate the GWAS results. Four of these eight SNPs (rs12214383, rs1150724, rs3800324, and rs1997660) displayed a nominal difference in allele frequencies between the case and control groups. The association between two of these SNPs and schizophrenia were significant even after Bonferroni correction (rs12000: allele A>G, P = 2.50E-04, odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.12-1.45; rs1150722: allele C>T, P = 4.28E 05, OR = 0.55, 95% CI = 0.41-0.73). Haplotype ATTGACGC, comprising these eight SNPs (rs2235359, rs2185955, rs12214383, rs12000, rs1150724, rs1150722, rs3800324, and rs1997660), was significantly associated with schizophrenia (P = 6.60E-05). We also performed a combined study of this replication sample and the first-stage GWAS sample. The combined study revealed that rs12000 and rs1150722 were still strongly associated with schizophrenia (rs12000: allele G>A, P(combined) = 0.0019, OR = 0.81; rs1150722: allele G>A, P(combined) = 3.00E-04, OR = 0.61). These results support our findings that locus 6p21-p22.1 is significantly associated with schizophrenia in the Chinese Han population and encourage further studies of the functions of these genetic factors. PMID- 23437229 TI - The impact of artemisinin combination therapy and long-lasting insecticidal nets on forest malaria incidence in tribal villages of India, 2006-2011. AB - INTRODUCTION: New tools for malaria control, artemisinin combination therapy (ACT) and long-lasting insecticidal nets (LLINs) were recently introduced across India. We estimated the impact of universal coverage of ACT and ACT plus LLINs in a setting of hyperendemic, forest malaria transmission. METHODS: We reviewed data collected through active and passive case detection in a vaccine trial cohort of 2,204 tribal people residing in Sundargarh district, Odisha between 2006 and 2011. We compared measures of transmission at the village and individual level in 2006-2009 versus 2010-2011 after ACT (in all villages) and LLINs (in three villages) were implemented. RESULTS: During 2006-2009 malaria incidence per village ranged from 156-512 per 1000 persons per year and slide prevalence ranged from 28-53%. Routine indoor residual spray did not prevent seasonal peaks of malaria. Post-intervention impact in 2010-2011 was dramatic with ranges of 14-71 per 1000 persons per year and 6-16% respectively. When adjusted for village, ACT alone decreased the incidence of malaria by 83% (IRR 0.17, 95%CI: 0.10, 0.27) and areas using ACT and LLINs decreased the incidence of malaria by 86% (IRR 0.14, 95%CI: 0.05, 0.38). After intervention, the age of malaria cases, their parasite density, and proportion with fever at the time of screening increased. CONCLUSIONS: ACT, and LLINs along with ACT, effectively reduced malaria incidence in a closely monitored population living in a forest ecotype. It is unclear whether LLINs were impactful when prompt and quality antimalarial treatment was available. In spite of universal coverage, substantial malaria burden remained. PMID- 23437228 TI - The relationship between cortical blood flow and sub-cortical white-matter health across the adult age span. AB - Degeneration of cerebral white matter is commonly observed in aging, and the associated degradation in neural connectivity contributes to cognitive decline in older adults. Vascular dysfunction has been implicated as a potential mechanism for general age-related neural tissue deterioration; however, no prior study has examined the direct relationship between cortical vascular health and subcortical white-matter integrity. In this work, we aimed to determine whether blood supply to the brain is associated with microstructural integrity of connective tissue, and whether such associations are regionally specific and mainly accounted for by aging. We examined the association between cerebral blood flow (CBF) in the cortical mantle, measured using arterial spin labeling (ASL), and subcortical white-matter integrity, measured using diffusion tensor imaging (DTI), in a group of healthy adults spanning early to late adulthood. We found cortical CBF to be significantly associated with white-matter integrity throughout the brain. In addition, these associations were only partially tied to aging, as they remained even when statistically controlling for age, and when restricting the analyses to a young subset of the sample. Furthermore, vascular risk was not a prominent determinant of these effects. These findings suggest that the overall blood supply to the brain is an important indicator of white-matter health in the normal range of variations amongst adults, and that the decline in CBF with advancing age may potentially exacerbate deterioration of the connective anatomy of the brain. PMID- 23437230 TI - Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre eclampsia: expression of Flt-1 and endoglin. AB - BACKGROUND: The placental syncytiotrophoblast releases micro and nanovesicles (STBM), into the maternal circulation in normal pregnancy and in increased amounts in pre-eclampsia (PE), which have proinflammatory and antiangiogenic activity and are implicated in PE pathophysiology. Better characterisation of STBM is essential to understand their role in PE. METHODS AND RESULTS: STBM prepared by placental lobe dual perfusion (pSTBM) and mechanical disruption (mSTBM) were analysed by four colour flow cytometry (4CFC), nanoparticle tracking analysis (NTA) and Western blotting to determine vesicle size, purity and Flt-1 and endoglin (Eng) expression. Biological activity of STBM associated Flt-1 and endoglin was assessed by the ability of VEGF, PlGF and TGFbeta to bind to mSTBM and inhibit mSTBM induced endothelial monolayer disruption. STBM content was consistently high (~87-95%) across the different preparations. However, surface antigen intensities differed, with significantly lower placental alkaline phosphatase (P<0.05) and Eng (P<0.05) expression on mSTBM, and Flt-1 (P<0.05) expression on pSTBM. For PE placenta derived preparations, pSTBM contained lower Eng positive STBM (P<0.05) and mSTBM Eng expression was increased (P<0.05). Western blotting revealed increased Flt-1/sFlt-1 (P<0.02) and decreased placental alkaline phosphatase (P = 0.0002) content of PE placenta pSTBM. Using NTA, perfused PE placentas released significantly larger MV (P<0.001). Finally, VEGF, PlGF and TGFbeta bound to mSTBM at physiologically relevant concentrations and inhibited mSTBM induced endothelial disruption (P<0.05-P<0.001). CONCLUSIONS: This study has found differences in physical and antigenic characteristics of normal and PE placenta STBM preparations produced by placental perfusion or mechanical disruption. We have also demonstrated that large quantities of biologically active STBM associated endoglin and Flt-1/sFlt-1 could contribute to the increased circulating levels measured in PE patients and add to the perturbation of the maternal vascular endothelium, normally attributed to non membrane bound sFlt-1 and sEndoglin. PMID- 23437231 TI - Deletion of 12/15-lipoxygenase alters macrophage and islet function in NOD Alox15(null) mice, leading to protection against type 1 diabetes development. AB - AIMS: Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin producing pancreatic beta cells. We showed previously that deletion of the 12/15 lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D. METHODS: 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD Alox15(null) macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass. RESULTS: 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null) mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass. CONCLUSIONS: These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass. PMID- 23437232 TI - In vitro characterization of echinomycin biosynthesis: formation and hydroxylation of L-tryptophanyl-S-enzyme and oxidation of (2S,3S) beta hydroxytryptophan. AB - Quinoxaline-2-carboxylic acid (QXC) and 3-hydroxyquinaldic acid (HQA) feature in quinomycin family and confer anticancer activity. In light of the significant potency against cancer, the biosynthetic gene clusters have been reported from many different Streptomyces strains, and the biosynthetic pathway were proposed mainly based on the in vivo feeding experiment with isotope labeled putative intermediates. Herein we report another gene cluster from Streptomyces griseovariabilis subsp. bandungensis subsp. nov responsible for the biosynthesis of echinomycin (a member of quinomycin family, also named quinomycin A) and presented in vitro evidence to corroborate the previous hypothesis on QXC biosynthesis, showing that only with the assistance of a MbtH-like protein Qui5, did the didomain NRPS protein (Qui18) perform the loading of a L-tryptophan onto its own PCP domain. Particularly, it was found that Qui5 and Qui18 subunits form a functional tetramer through size exclusion chromatography. The subsequent hydroxylation on beta-carbon of the loaded L-tryptophan proved in vitro to be completed by cytochrome P450-dependent hydroxylase Qui15. Importantly, only the Qui18 loaded L-tryptophan can be hydroxylated by Qui15 and the enzyme was inactive on free L-tryptophan. Additionally, the chemically synthesized (2S,3S) beta-hydroxytryptophan was detected to be converted by the tryptophan 2,3 dioxygenase Qui17 through LC-MS, which enriched our previous knowledge that tryptophan 2,3-dioxygenase nearly exclusively acted on L-tryptophan and 6-fluoro tryptophan. PMID- 23437233 TI - Tanshinone IIA inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-associated pathway. AB - We previously showed that tanshinone IIA ameliorated the hypoxia-induced pulmonary hypertension (HPH) partially by attenuating pulmonary artery remodeling. The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the major causes for pulmonary arterial remodeling, therefore the present study was performed to explore the effects and underlying mechanism of tanshinone IIA on the hypoxia-induced PASMCs proliferation. PASMCs were isolated from male Sprague-Dawley rats and cultured in normoxic (21%) or hypoxic (3%) condition. Cell proliferation was measured with 3 - (4, 5 - dimethylthiazal - 2 - yl) - 2, 5 - diphenyltetrazoliumbromide assay and cell counting. Cell cycle was measured with flow cytometry. The expression of of p27, Skp-2 and the phosphorylation of Akt were measured using western blot and/or RT PCR respectively. The results showed that tanshinone IIA significantly inhibited the hypoxia-induced PASMCs proliferation in a concentration-dependent manner and arrested the cells in G1/G0-phase. Tanshinone IIA reversed the hypoxia-induced reduction of p27 protein, a cyclin-dependent kinase inhibitor, in PASMCs by slowing down its degradation. Knockdown of p27 with specific siRNA abolished the anti-proliferation of tanshinone IIA. Moreover, tanshinone IIA inhibited the hypoxia-induced increase of S-phase kinase-associated protein 2 (Skp2) and the phosphorylation of Akt, both of which are involved in the degradation of p27 protein. In vivo tanshinone IIA significantly upregulated the hypoxia-induced p27 protein reduction and downregulated the hypoxia-induced Skp2 increase in pulmonary arteries in HPH rats. Therefore, we propose that the inhibition of tanshinone IIA on hypoxia-induce PASMCs proliferation may be due to arresting the cells in G1/G0-phase by slowing down the hypoxia-induced degradation of p27 via Akt/Skp2-associated pathway. The novel information partially explained the anti remodeling property of tanshinone IIA on pulmonary artery in HPH. PMID- 23437234 TI - A widespread and unusual RNA trans-splicing type in dinoflagellate mitochondria. AB - Cytochrome oxidase subunit 3 (Cox3) is a mitochondrion-encoded core membrane protein of complex IV of the mitochondrial respiratory chain, and consists of seven trans-membrane helices. Here we show that in diverse later-branching dinoflagellates, cox3 is consistently split into two exons in the mitochondrial genome between helices six and seven. Gene exons are transcribed as two discrete oligoadenylated precursor RNAs, and these are subsequently trans-spliced to form a complete coding mRNA. This trans-splicing is highly unusual in that some of the oligoadenylated tail is incorporated at the splice site, such that a short string of adenosines links the two coding exons. This feature is consistently represented in diverse dinoflagellates, however the number of adenosines added varies according to the size of the coding gap between the two exons. Thus we observed between zero (Amphidinium carterae) and 10 (Symbiodinium sp.) adenosines added in different taxa, but the final coding sequence length is identical with the reading frame maintained. Northern analyses show that precursor cox3 transcripts are approximately equally abundant as mature cox3 mRNAs, suggesting a slow or regulated maturation process. These data indicate that the splicing mechanism in dinoflagellate mitochondria is tolerant of variations in the length of the precursor coding sequence, and implicates the use of a splicing template, or guide molecule, during splicing that controls mature mRNA length. PMID- 23437235 TI - Rapid extraction of lexical tone phonology in Chinese characters: a visual mismatch negativity study. AB - BACKGROUND: In alphabetic languages, emerging evidence from behavioral and neuroimaging studies shows the rapid and automatic activation of phonological information in visual word recognition. In the mapping from orthography to phonology, unlike most alphabetic languages in which there is a natural correspondence between the visual and phonological forms, in logographic Chinese, the mapping between visual and phonological forms is rather arbitrary and depends on learning and experience. The issue of whether the phonological information is rapidly and automatically extracted in Chinese characters by the brain has not yet been thoroughly addressed. METHODOLOGY/PRINCIPAL FINDINGS: We continuously presented Chinese characters differing in orthography and meaning to adult native Mandarin Chinese speakers to construct a constant varying visual stream. In the stream, most stimuli were homophones of Chinese characters: The phonological features embedded in these visual characters were the same, including consonants, vowels and the lexical tone. Occasionally, the rule of phonology was randomly violated by characters whose phonological features differed in the lexical tone. CONCLUSIONS/SIGNIFICANCE: We showed that the violation of the lexical tone phonology evoked an early, robust visual response, as revealed by whole-head electrical recordings of the visual mismatch negativity (vMMN), indicating the rapid extraction of phonological information embedded in Chinese characters. Source analysis revealed that the vMMN was involved in neural activations of the visual cortex, suggesting that the visual sensory memory is sensitive to phonological information embedded in visual words at an early processing stage. PMID- 23437236 TI - Parental smoking in the vicinity of children and tobacco control policies in the European region. AB - OBJECTIVE: To ascertain patterns of parental smoking in the vicinity of children in Eastern and Western Europe and their relation to Tobacco Control Scale (TCS) scores. METHODS: Data on parental smoking patterns were obtained from the School Child Mental Health Europe (SCMHE), a 2010 cross-sectional survey of 5141 school children aged 6 to 11 years and their parents in six countries: Germany, Netherlands, Lithuania, Romania, Bulgaria and Turkey ranked by TCS into three level categories toward tobacco control policies. RESULTS: A slightly higher proportion of Eastern compared to Western European mothers (42.4 vs. 35.1%) were currently smoking in but the difference was not statistically significant after adjusting for maternal age and maternal educational attainment. About a fifth (19.3%) and a tenth (10.0%) of Eastern and Western European mothers, respectively, smoked in the vicinity of their children, and the difference was significant even after adjustment for potential confounders (p<0.001). Parents with the highest educational attainment were significantly less likely to smoke in the vicinity of their children than those with the lowest attainment. After control of these covariates lax tobacco control policies, compared to intermediate policies, were associated with a 50% increase in the likelihood of maternal smoking in the vicinity of children adjusted odds ratio (AOR) = 1.52 and 1.64. Among fathers, however, the relationship with paternal smoking and TCS seems more complex since strict policy increases the risk as well AOR = 1,40. Only one country, however belongs to the strict group. SIGNIFICANCE: Tobacco control policies seem to have influenced maternal smoking behaviors overall to a limited degree and smoking in the vicinity of children to a much greater degree. Children living in European countries with lax tobacco control policies are more likely to be exposed to second hand smoking from maternal and paternal smoking. PMID- 23437237 TI - Can mixed-species groups reduce individual parasite load? A field test with two closely related poeciliid fishes (Poecilia reticulata and Poecilia picta). AB - Predation and parasitism are two of the most important sources of mortality in nature. By forming groups, individuals can gain protection against predators but may increase their risk of being infected with contagious parasites. Animals might resolve this conflict by forming mixed-species groups thereby reducing the costs associated with parasites through a relative decrease in available hosts. We tested this hypothesis in a system with two closely related poeciliid fishes (Poecilia reticulata and Poecilia picta) and their host-specific monogenean ectoparasites (Gyrodactylus spp.) in Trinidad. Fish from three different rivers were sampled from single and mixed-species groups, measured and scanned for Gyrodactylus. The presence and abundance of Gyrodactylus were lower when fish of both species were part of mixed-species groups relative to single-species groups. This is consistent with the hypothesis that mixed-species groups provide a level of protection against contagious parasites. We discuss the importance of potentially confounding factors such as salinity and individual fish size. PMID- 23437239 TI - Contrasting diversity values: statistical inferences based on overlapping confidence intervals. AB - Ecologists often contrast diversity (species richness and abundances) using tests for comparing means or indices. However, many popular software applications do not support performing standard inferential statistics for estimates of species richness and/or density. In this study we simulated the behavior of asymmetric log-normal confidence intervals and determined an interval level that mimics statistical tests with P(alpha) = 0.05 when confidence intervals from two distributions do not overlap. Our results show that 84% confidence intervals robustly mimic 0.05 statistical tests for asymmetric confidence intervals, as has been demonstrated for symmetric ones in the past. Finally, we provide detailed user-guides for calculating 84% confidence intervals in two of the most robust and highly-used freeware related to diversity measurements for wildlife (i.e., EstimateS, Distance). PMID- 23437238 TI - The SWI/SNF chromatin remodeling complex influences transcription by RNA polymerase I in Saccharomyces cerevisiae. AB - SWI/SNF is a chromatin remodeling complex that affects transcription initiation and elongation by RNA polymerase II. Here we report that SWI/SNF also plays a role in transcription by RNA polymerase I (Pol I) in Saccharomyces cerevisiae. Deletion of the genes encoding the Snf6p or Snf5p subunits of SWI/SNF was lethal in combination with mutations that impair Pol I transcription initiation and elongation. SWI/SNF physically associated with ribosomal DNA (rDNA) within the coding region, with an apparent peak near the 5' end of the gene. In snf6Delta cells there was a ~2.5-fold reduction in rRNA synthesis rate compared to WT, but there was no change in average polymerase occupancy per gene, the number of rDNA gene repeats, or the percentage of transcriptionally active rDNA genes. However, both ChIP and EM analyses showed a small but reproducible increase in Pol I density in a region near the 5' end of the gene. Based on these data, we conclude that SWI/SNF plays a positive role in Pol I transcription, potentially by modifying chromatin structure in the rDNA repeats. Our findings demonstrate that SWI/SNF influences the most robust transcription machinery in proliferating cells. PMID- 23437240 TI - PAI-1 4G/5G polymorphism contributes to cancer susceptibility: evidence from meta analysis. AB - BACKGROUND: The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and allows the modulation of cancer growth, invasion and angiogenesis. To date, studies investigated the association between a functional polymorphism in PAI-1 (4G/5G) and risk of cancer have shown inclusive results. METHODS: A meta-analysis based on 25 case-control studies was performed to address this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with I(2) test. RESULTS: Overall, a significant increased risk of cancer was associated with the PAI-1 4G/4G polymorphism for the allele contrast (4G vs. 5G: OR = 1.10, CI = 1.03-1.18, I(2) = 49.5%), the additive genetic model (4G/4G vs. 5G/5G: OR = 1.21, CI = 1.06-1.39, I(2) = 51.9%), the recessive genetic model (4G/4G vs. 4G/5G+5G/5G: OR = 1.11, CI = 1.04-1.18, I(2) = 20.8%). In the subgroup analysis by ethnicity, the results indicated that individuals with 4G/4G genotype had a significantly higher cancer risk among Caucasians (4G/4G vs. 5G/5G: OR = 1.31, 95%CI = 1.09-1.59, I(2) = 59.6%; 4G/4G vs. 4G/5G: OR = 1.12, 95%CI = 1.04-1.21, I(2) = 3.6%; recessive model: OR = 1.12, 95%CI = 1.05-1.21, I(2) = 25.3%). CONCLUSIONS: The results of the present meta analysis support an association between the PAI-1 4G/5G polymorphism and increasing cancer risk, especially among Caucasians, and those with 4G allele have a high risk to develop colorectal cancer and endometrial cancer. PMID- 23437241 TI - LegC3, an effector protein from Legionella pneumophila, inhibits homotypic yeast vacuole fusion in vivo and in vitro. AB - During infection, the intracellular pathogenic bacterium Legionella pneumophila causes an extensive remodeling of host membrane trafficking pathways, both in the construction of a replication-competent vacuole comprised of ER-derived vesicles and plasma membrane components, and in the inhibition of normal phagosome:endosome/lysosome fusion pathways. Here, we identify the LegC3 secreted effector protein from L. pneumophila as able to inhibit a SNARE- and Rab GTPase dependent membrane fusion pathway in vitro, the homotypic fusion of yeast vacuoles (lysosomes). This vacuole fusion inhibition appeared to be specific, as similar secreted coiled-coiled domain containing proteins from L. pneumophila, LegC7/YlfA and LegC2/YlfB, did not inhibit vacuole fusion. The LegC3-mediated fusion inhibition was reversible by a yeast cytosolic extract, as well as by a purified soluble SNARE, Vam7p. LegC3 blocked the formation of trans-SNARE complexes during vacuole fusion, although we did not detect a direct interaction of LegC3 with the vacuolar SNARE protein complexes required for fusion. Additionally, LegC3 was incapable of inhibiting a defined synthetic model of vacuolar SNARE-driven membrane fusion, further suggesting that LegC3 does not directly inhibit the activity of vacuolar SNAREs, HOPS complex, or Sec17p/18p during membrane fusion. LegC3 is likely utilized by Legionella to modulate eukaryotic membrane fusion events during pathogenesis. PMID- 23437242 TI - Urinary phthalate metabolites are associated with body mass index and waist circumference in Chinese school children. AB - BACKGROUND: Lab studies have suggested that ubiquitous phthalate exposures are related to obesity, but relevant epidemiological studies are scarce, especially for children. OBJECTIVE: To investigate the association of phthalate exposures with body mass index (BMI) and waist circumference (WC) in Chinese school children. METHODS: A cross-sectional study was conducted in three primary and three middle schools randomly selected from Changning District of Shanghai City of China in 2011-2012. According to the physical examination data in October, 2011, 124 normal weight, 53 overweight, and 82 obese students 8-15 years of age were randomly chosen from these schools on the basis of BMI-based age- and sex specific criterion. First morning urine was collected in January, 2012, and fourteen urine phthalate metabolites (free plus conjugated) were determined by ultra-performance liquid chromatography coupled to tandem mass spectrometry. Multiple linear regression was used to explore the associations between naturally log-transformed urine phthalate metabolites and BMI or WC. RESULTS: The urine specific gravity-corrected concentrations of nine urine phthalate metabolites and five molar sums were positively associated with BMI or WC in Chinese school children after adjustment for age and sex. However, when other urine phthalate metabolites were included in the models together with age and sex as covariables, most of these significant associations disappeared except for mono (2-ethylhexyl) phthalate (MEHP) and monoethyl phthalate (MEP). Additionally, some associations showed sex- or age-specific differences. CONCLUSIONS: Some phthalate exposures were associated with BMI or WC in Chinese school children. Given the cross sectional nature of this study and lack of some important obesity-related covariables, further studies are needed to confirm the associations. PMID- 23437243 TI - Recombinant M2e protein-based ELISA: a novel and inexpensive approach for differentiating avian influenza infected chickens from vaccinated ones. AB - Available avian influenza (AIV) serological diagnostic tests cannot distinguish vaccinated from naturally infected birds. Differentiation of vaccinated from infected animals (DIVA) is currently advocated as a means of achieving the full control of H5N1. In this study, for the first time, recombinant ectodomain of M2 protein (M2e) of avian influenza virus (H5N1 strain) was used for the DIVA serology test. M2e was cloned into pMAL-P4X vector and expressed in E. coli cells. We used Western blot to recognize the expressed M2e-MBP protein by chicken antisera produced against live H5N1 virus. Also, the specificity of M2e-MBP protein was compared to the M2e synthetic peptide via ELISA. In M2e-MBP ELISA, all sera raised against the live avian influenza viruses were positive for M2e antibodies, whereas sera from killed virus vaccination were negative. Furthermore, M2e-MBP ELISA of the field sera obtained from vaccinated and non vaccinated chickens showed negative results, while challenged vaccinated chickens demonstrated strong positive reactions. H5N1-originated recombinant M2e protein induced broad-spectrum response and successfully reacted with antibodies against other AIV strains such as H5N2, H9N2, H7N7, and H11N6. The application of the recombinant protein instead of synthetic peptide has the advantages of continues access to an inexpensive reagent for performing a large scale screening. Moreover, recombinant proteins provide the possibility of testing the DIVA results with an additional technique such a Western blotting which is not possible in the case of synthetic proteins. All together, the results of the present investigation show that recombinant M2e-MBP can be used as a robust and inexpensive solution for DIVA test. PMID- 23437244 TI - Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta analysis of randomized controlled trials. AB - BACKGROUND: Antioxidant vitamin (vitamin E, beta-carotene, and vitamin C) are widely used for preventing major cardiovascular outcomes. However, the effect of antioxidant vitamin on cardiovascular events remains unclear. METHODOLOGY AND PRINCIPAL FINDINGS: We searched PubMed, EmBase, the Cochrane Central Register of Controlled Trials, and the proceedings of major conferences for relevant literature. Eligible studies were randomized controlled trials that reported on the effects of antioxidant vitamin on cardiovascular outcomes as compared to placebo. Outcomes analyzed were major cardiovascular events, myocardial infarction, stroke, cardiac death, total death, and any possible adverse events. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for cardiovascular outcomes with random-effect meta-analysis. Independent extraction was performed by two reviewers and consensus was reached. Of 293 identified studies, we included 15 trials reporting data on 188209 participants. These studies reported 12749 major cardiovascular events, 6699 myocardial infarction, 3749 strokes, 14122 total death, and 5980 cardiac deaths. Overall, antioxidant vitamin supplementation as compared to placebo had no effect on major cardiovascular events (RR, 1.00; 95%CI, 0.96-1.03), myocardial infarction (RR, 0.98; 95%CI, 0.92-1.04), stroke (RR, 0.99; 95%CI, 0.93-1.05), total death (RR, 1.03; 95%CI, 0.98-1.07), cardiac death (RR, 1.02; 95%CI, 0.97 1.07), revascularization (RR, 1.00; 95%CI, 0.95-1.05), total CHD (RR, 0.96; 95%CI, 0.87-1.05), angina (RR, 0.98; 95%CI, 0.90-1.07), and congestive heart failure (RR, 1.07; 95%CI, 0.96 to 1.19). CONCLUSION/SIGNIFICANCE: Antioxidant vitamin supplementation has no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, total death, and cardiac death. PMID- 23437245 TI - Early neurodevelopment and self-reported adolescent symptoms of depression and anxiety in a National Canadian Cohort Study. AB - OBJECTIVE: Little is known about the mental health outcomes of young children who experience developmental delay. The objective of this study was to assess whether delay in attaining developmental milestones was related to depressive and anxious symptoms in adolescence. METHOD: The sample included 3508 Canadian children who participated in a nationally representative prospective cohort study. The person most knowledgeable about the child reported on attainment of developmental milestones spanning several developmental domains at ages 2-3. The children were followed into adolescence and self-reported depressive and anxious symptoms were used from adolescents ages 12-13. An overall assessment of developmental milestones as well as a supplementary analysis of specific categories of developmental milestones was conducted. RESULTS: Cohort members who displayed delayed developmental milestones in early childhood were more likely to experience higher levels of depressive and anxious symptoms as adolescents. However, there was no interaction between delayed developmental milestones and stressful life events. In the supplementary analysis, two developmental domains (self-care and speech/communication) were associated with higher levels of depressive and anxious symptoms in adolescence. CONCLUSION: Delay in attainment of early developmental milestones is significantly associated with adolescent depressive and anxious symptoms. PMID- 23437246 TI - The acceptability of acupuncture for low back pain: a qualitative study of patient's experiences nested within a randomised controlled trial. AB - INTRODUCTION: The National Institute for Health and Clinical Excellence guidelines recommend acupuncture as a clinically effective treatment for chronic back pain. However, there is insufficient knowledge of what factors contribute to patients' positive and negative experiences of acupuncture, and how those factors interact in terms of the acceptability of treatment. This study used patient interviews following acupuncture treatment for back pain to identify, understand and describe the elements that contribute or detract from acceptability of treatment. METHODS: The study used semi-structured interviews. Twelve patients were interviewed using an interview schedule as a sub-study nested within a randomised controlled trial of acupuncture for chronic back pain. The interviews were analysed using thematic analysis. RESULTS AND DISCUSSION: Three over-arching themes emerged from the analysis. The first entitled facilitators of acceptability contained five subthemes; experience of pain relief, improvements in physical activity, relaxation, psychological benefit, reduced reliance on medication. The second over-arching theme identified barriers to acceptability, which included needle-related discomfort and temporary worsening of symptoms, pressure to continue treatment and financial cost. The third over-arching theme comprised mediators of acceptability, which included pre-treatment mediators such as expectation and previous experience, and treatment-related mediators of time, therapeutic alliance, lifestyle advice and the patient's active involvement in recovery. These themes inform our understanding of the acceptability of acupuncture to patients with low back pain. CONCLUSION: The acceptability of acupuncture treatment for low back pain is complex and multifaceted. The therapeutic relationship between the practitioner and patient emerged as a strong driver for acceptability, and as a useful vehicle to develop the patients' self efficacy in pain management in the longer term. Unpleasant treatment related effects do not necessarily detract from patients' overall perception of acceptability. PMID- 23437247 TI - MAP65 coordinate microtubule growth during bundle formation. AB - Microtubules (MTs) are highly dynamical structures that play a crucial role in cell physiology. In cooperation with microtubule-associated proteins (MAPs), MTs form bundles endowing cells with specific mechanisms to control their shape or generate forces. Whether the dynamics of MTs is affected by the lateral connections that MAPs make between MTs during bundle formation is still under debate. Using in vitro reconstitution of MT bundling, we analyzed the dynamics of MT bundles generated by two plant MAP65 (MAP65-1/4), MAP65-1 being the plant ortholog of vertebrate PRC1 and yeast Ase1. MAP65-1/4 limit the amplitude of MT bundle depolymerization and increase the elongation phases. The subsequent sustained elongation of bundles is governed by the coordination of MT growth, so that MT ends come in close vicinity. We develop a model based on the assumption that both MAP65-1/4 block MT depolymerization. Model simulations reveal that rescue frequencies are higher between parallel than between anti-parallel MTs. In consequence the polarity of bundled MTs by MAP65 controls the amplitude of bundle's growth. Our results illustrate how MAP-induced MT-bundling, which is finely tuned by MT polarity, robustly coordinates MT elongation within bundles. PMID- 23437248 TI - Predictable or not? Individuals' risk decisions do not necessarily predict their next ones. AB - This research examines the extent to which people may be free to make choices by testing their consistency in choosing risk options. In two experiments, participants were instructed to make the "same" type of risk decisions repeatedly. Experiment 1 showed that when the information for decision is positively framed in terms of gain, the participant's choice in a particular decision could not be predicted by his or her choice in another decision (R(2)s<.02). Experiment 2 showed a statistically significant predictability when the information is negatively framed in terms of loss, although the predictability was still very low (R(2)s<.07). These findings indicate the existence of a large room of variations in which a person may freely choose. PMID- 23437249 TI - Patient adherence and persistence with Imatinib, Nilotinib, Dasatinib in clinical practice. AB - INTRODUCTION: The aim of this study is to evaluate adherence and persistence of patients treated with Imatinib, Nilotinib or Dasatinib, also giving economic evaluations on therapy costs for Received Daily Dose (RDD). MATERIALS AND METHODS: In this retrospective study, we took into account 3 years from 1st Jan. 2009 to 31st March.2012. Treatment adherence was quantified utilizing ratio between RDD and PDD (Prescribed Daily Dose). Persistence is reckoned taking into account the actual therapy days, comparing posology with supplied dose, drawing the graph using Kaplan-Meir method. RESULTS: Adherence results in values between 0.8 and 1.0 for Nilotinib (Adh = 0.93), Imatinib (Adh = 0.83) and Dasatinib (0.85). Imatinib has better persistence, 90% of patients in treatment exceed one year of treatment versus 83.3% for Nilotinib and 80% for Dasatinib. The cost per single day of treatment (cost per RDD) was ? 39.41 for Imatinib, ? 113.60 for Nilotinib and ? 94.84 for Dasatinib. CONCLUSION: Patients with CML have a loose of adherence both in first line with Imatinib and in second line of therapy with Dasatinib and Nilotinib. Loss of adherence remains a big problem and could be minimized by a patient-oriented project invlolving physicians, nurses, pharmacists and caregiver. PMID- 23437250 TI - miR-126&126* restored expressions play a tumor suppressor role by directly regulating ADAM9 and MMP7 in melanoma. AB - The abnormal expression of several microRNAs has a causal role in tumorigenesis with either antineoplastic or oncogenic functions. Here we demonstrated that miR 126 and miR-126* play a tumor suppressor role in human melanoma through the direct or indirect repression of several key oncogenic molecules. The expression levels of miR-126&126* were elevated in normal melanocytes and primary melanoma cell lines, whereas they markedly declined in metastatic cells. Indeed, the restored expression of miR-126&126* in two advanced melanoma cell lines was accompanied by a significant reduction of proliferation, invasion and chemotaxis in vitro as well as of growth and dissemination in vivo. In accordance, the reverse functional effects were obtained by knocking down miR-126&126* by transfecting antisense LNA oligonucleotides in melanoma cells. Looking for the effectors of these antineoplastic functions, we identified ADAM9 and MMP7, two metalloproteases playing a pivotal role in melanoma progression, as direct targets of miR-126&126*. In addition, as ADAM9 and MMP7 share a role in the proteolytic cleavage of the HB-EGF precursor, we looked for the effectiveness of this regulatory pathway in melanoma, confirming the decrease of HB-EGF activation as a consequence of miR-126&126*-dependent downmodulation of ADAM9 and MMP7. Finally, gene profile analyses showed that miR-126&126* reexpression was sufficient to inactivate other key signaling pathways involved in the oncogenic transformation, as PI3K/AKT and MAPK, and to restore melanogenesis, as indicated by KIT/MITF/TYR induction. In view of this miR-126&126* wide-ranging action, we believe that the replacement of these microRNAs might be considered a promising therapeutic approach. PMID- 23437251 TI - Differentiation of human embryonic stem cells into cells with corneal keratocyte phenotype. AB - Corneal transparency depends on a unique extracellular matrix secreted by stromal keratocytes, mesenchymal cells of neural crest lineage. Derivation of keratocytes from human embryonic stem (hES) cells could elucidate the keratocyte developmental pathway and open a potential for cell-based therapy for corneal blindness. This study seeks to identify conditions inducing differentiation of pluripotent hES cells to the keratocyte lineage. Neural differentiation of hES cell line WA01(H1) was induced by co-culture with mouse PA6 fibroblasts. After 6 days of co-culture, hES cells expressing cell-surface NGFR protein (CD271, p75NTR) were isolated by immunoaffinity adsorption, and cultured as a monolayer for one week. Keratocyte phenotype was induced by substratum-independent pellet culture in serum-free medium containing ascorbate. Gene expression, examined by quantitative RT-PCR, found hES cells co-cultured with PA6 cells for 6 days to upregulate expression of neural crest genes including NGFR, SNAI1, NTRK3, SOX9, and MSX1. Isolated NGFR-expressing cells were free of PA6 feeder cells. After expansion as a monolayer, mRNAs typifying adult stromal stem cells were detected, including BMI1, KIT, NES, NOTCH1, and SIX2. When these cells were cultured as substratum-free pellets keratocyte markers AQP1, B3GNT7, PTDGS, and ALDH3A1 were upregulated. mRNA for keratocan (KERA), a cornea-specific proteoglycan, was upregulated more than 10,000 fold. Culture medium from pellets contained high molecular weight keratocan modified with keratan sulfate, a unique molecular component of corneal stroma. These results show hES cells can be induced to differentiate into keratocytes in vitro. Pluripotent stem cells, therefore, may provide a renewable source of material for development of treatment of corneal stromal opacities. PMID- 23437252 TI - Inhibition of pirfenidone on TGF-beta2 induced proliferation, migration and epithlial-mesenchymal transition of human lens epithelial cells line SRA01/04. AB - BACKGROUND: Posterior capsular opacification (PCO) is a common complication of cataract surgery. Transforming growth factor-beta2 (TGF-beta2) plays important roles in the development of PCO. The existing pharmacological treatments are not satisfactory and can have toxic side effects. METHODOLOGIES/PRINCIPAL FINDINGS: We evaluated the effect of pirfenidone on proliferation, migration and epithlial mesenchymal transition of human lens epithelial cell line SRA01/04 (HLECs) in vitro. After treatment with 0, 0.25, and 0.5 mg/ml pirfenidone, cell proliferation was measured by MTT assay. Cell viability was determined by trypan blue exclusion assay and measurement of lactate dehydrogenase (LDH) activity released from the damaged cells. And cell migration was measured by scratch assay in the absence or presence of transforming growth factor-beta2 (TGF-beta2). The expressions of TGF-beta2 and SMADs were evaluated with real-time RT-PCR, western blot, and immunofluorescence analyses. The mesenchymal phenotypic marker fibronectin (FN) was demonstrated by Immunocytofluorescence analyses. The cells had high viability, which did not vary across different concentrations of pirfenidone (0 [control] 0.3, 0.5 or 1.0 mg/ml) after 24 hours. Pirfenidone (0~0.5 mg/ml) had no significant cytotoxicity effect on SRA01/04 by LDH assay. Pirfenidone significantly inhibited the proliferation and TGF-beta2-induced cell migration and the effects were dose-dependent, and inhibited TGF-beta2-induced fibroblastic phenotypes and TGF-beta2-induced expression of FN in SRA01/04 cells. The cells showed dose-dependent decreases in mRNA and protein levels of TGF-beta2 and SMADs. Pirfenidone also depressed the TGF-beta2-induced expression of SMADs and blocked the nuclear translocation of SMADs in cells. CONCLUSION: Pirfenidone inhibits TGF-beta2-induced proliferation, migration and epithlial-mesenchymal transition of human lens epithelial cells line SRA01/04 at nontoxic concentrations. This effect may be achieved by down regulation of TGF-beta/SAMD signaling in SRA01/04 cells. PMID- 23437253 TI - The heparin-binding activity of secreted modular calcium-binding protein 1 (SMOC 1) modulates its cell adhesion properties. AB - Secreted modular calcium-binding proteins 1 and 2 (SMOC-1 and SMOC-1) are extracellular calcium- binding proteins belonging to the BM-40 family of proteins. In this work we have identified a highly basic region in the extracellular calcium-binding (EC) domain of the SMOC-1 similar to other known glycosaminoglycan-binding motifs. Size-exclusion chromatography shows that full length SMOC-1 as well as its C-terminal EC domain alone bind heparin and heparan sulfate, but not the related chondroitin sulfate or dermatan sulfate glycosaminoglycans. Intrinsic tryptophan fluorescence measurements were used to quantify the binding of heparin to full length SMOC-1 and the EC domain alone. The calculated equilibrium dissociation constants were in the lower micromolar range. The binding site consists of two antiparallel alpha helices and mutagenesis experiments have shown that heparin-binding residues in both helices must be replaced in order to abolish heparin binding. Furthermore, we show that the SMOC-1 EC domain, like the SMOC-2 EC domain, supports the adhesion of epithelial HaCaT cells. Heparin-binding impaired mutants failed to support S1EC mediated cell adhesion and together with the observation that S1EC in complex with soluble heparin attenuated cell adhesion we conclude that a functional and accessible S1EC heparin-binding site mediates adhesion of epithelial cells to SMOC-1. PMID- 23437254 TI - Ultrasound-mediated stimulation of microbubbles after acute myocardial infarction and reperfusion ameliorates left-ventricular remodelling in mice via improvement of borderzone vascularization. AB - AIMS: Post-infarction remodelling (PIR) determines left-ventricular (LV) function and prognosis after myocardial infarction. The aim of this study was to evaluate transthoracic ultrasound-mediated microbubble stimulation (UMS) as a novel gene- and cell-free therapeutic option after acute myocardial infarction and reperfusion (AMI/R) in mice. METHODS AND RESULTS: For myocardial delivery of UMS, a novel therapeutic ultrasound-system (TIPS, Philips Medical) and commercially available microbubbles (BR1, Bracco Suisse SA) were utilized in a closed-chest mouse model. UMS was performed as myocardial post-conditioning (PC) on day four after 30 minutes of coronary occlusion and reperfusion. LV-morphology, as well as global and regional function were measured repeatedly with reconstructive 3 dimensional echocardiography applying an additional low-dose dobutamine protocol after two weeks. Scar size was quantified by means of histomorphometry. A total of 41 mice were investigated; 17 received PC with UMS. Mean ejection fraction (EF) prior UMS was similar in both groups 53%+/-10 (w/o UMS) and 53%+/-14 (UMS, p = 0.5), reflecting comparable myocardial mass at risk 17%+/-8 (w/o UMS), 16%+/-13 (UMS, p = 0.5). Two weeks after AMI/R, mice undergoing UMS demonstrated significantly better global LV-function (EF = 53%+/-7) as compared to the group without PC (EF = 39%+/-11, p<0.01). The fraction of akinetic myocardial mass was significantly lower among mice undergoing UMS after AMI/R [27%+/-10 (w/o UMS), 13%+/-8 (UMS), p<0.001)]. Our experiments showed a fast onset of transient, UMS induced upregulation of vascular-endothelial and insulin-like growth factor (VEGF a, IGF-1), as well as caveolin-3 (Cav-3). The mice undergoing PC with UMS after AMI/R showed a significantly lower scar size. In addition, the microvascular density was significantly higher in the borderzone of UMS-treated animals. CONCLUSION: UMS following AMI/R ameliorates PIR in mice via up-regulation of VEGF a, IGF-1 and Cav-3, and consecutive improvement of myocardial borderzone vascularization. PMID- 23437255 TI - Progress realized: trends in HIV-1 viral load and CD4 cell count in a tertiary care center from 1999 through 2011. AB - BACKGROUND: HIV-1 RNA and CD4 cell counts are important parameters for HIV care. The objective of this study was to assess the overall trends in HIV-1 viral load and CD4 cell counts within our clinic. METHODS: Patients with at least one of each test performed by the Infectious Diseases Laboratory from 1999 through 2011 were included in this analysis. By adapting a novel statistical model, log(10) HIV-1 RNA means were estimated by month, and log(10)-transformed HIV-1 RNA means were estimated by calendar year. Geometric means were calculated for CD4 cell counts by month and calendar year. Log(10) HIV-1 RNA and CD4 cell count monthly means were also examined with polynomial regression. RESULTS: There were 1,814 individuals with approximately 25,000 paired tests over the 13-year observation period. Based on each patient's final value of the year, the percentage of patients with viral loads below the lower limit of quantitation rose from 29% in 1999 to 72% in 2011, while the percentage with CD4 counts <200 cells/uL fell from 31% to 11%. On average annually, the mean HIV-1 RNA decreased by 86 copies/mL and the mean CD4 counts increased by 16 cells/uL. For the monthly means, the correlations (R(2)) from second-order polynomial regressions were 0.944 for log(10) HIV-1 RNA and 0.840 for CD4 cell counts. CONCLUSIONS: Marked improvements in HIV-1 RNA suppression and CD4 cell counts were achieved in a large inner-city population from 1999 through 2011. This success demonstrates that sustained viral control with improved immunologic status can be a realistic goal for most individuals in clinical care. PMID- 23437256 TI - Higher fish intake is associated with a lower risk of hip fractures in Chinese men and women: a matched case-control study. AB - OBJECTIVES: Fish is rich in nutrients that are favorable to bone health, but limited data are available regarding the relationship between fish intake and hip fractures. Our study examined the association between habitual fish intake and risk of hip fractures. METHODS: A case-control study was performed between June 2009 and June 2012 in Guangdong Province, China. Five hundred and eighty-one hip fracture incident cases, aged 55 to 80 years (mean: 71 years), were enrolled from four hospitals. 1?1 matched controls by gender and age (+/-3 years) were also recruited from communities and hospitals. Face-to-face interviews were used to obtain habitual dietary intake and information on various covariates. RESULTS: Univariate conditional logistic regression analyses showed significantly dose dependent inverse correlations between the risk of hip fractures and the intake of fresh-water fish, sea fish, mollusca, shellfish, and total fish in all of the subjects (p-trend: <0.001-0.016). After adjusting for covariates, the associations were slightly attenuated but remained significant for all (p-trend: <0.001-0.017) except for fresh-water fish (p = 0.553). The ORs (95%CI) of hip fractures for the highest (vs. lowest) quartile were 0.80 (0.48-1.31) for fresh water fish, 0.31 (0.18-0.52) for sea fish, 0.55 (0.34-0.88) for mollusca and shellfish, and 0.47 (0.28-0.79) for total fish, respectively. Stratified and interaction analyses showed that the association was more significant in males than in females (p-interaction = 0.052). CONCLUSION: Higher intake of seafood is independently associated with lower risk of hip fractures in elderly Chinese. Increasing consumption of sea fish may benefit the prevention of hip fractures in this population. PMID- 23437257 TI - Avian influenza seroprevalence and biosecurity risk factors in Maryland backyard poultry: a cross-sectional study. AB - Major implications on a country's economy, food source, and public health. With recent concern over the highly pathogenic avian influenza outbreaks around the world, government agencies are carefully monitoring and inspecting live bird markets, commercial flocks, and migratory bird populations. However, there remains limited surveillance of non-commercial poultry. Therefore, a cross sectional study was conducted in backyard poultry flocks using a convenience sampling method across three regions of Maryland from July 2011 to August 2011. The objective of this study was to develop a better understanding of the ecology and epidemiology of avian influenza by investigating the prevalence and seroprevalence in this potentially vulnerable population and by evaluating biosecurity risk factors associated with positive findings. Serum, tracheal, and cloacal swabs were randomly collected from 262 birds among 39 registered premises. Analysis indicated bird and flock seroprevalence as 4.2% (11/262) and 23.1% (9/39), respectively. Based on RT-qPCR analysis, none of the samples were found to be positive for AI RNA and evidence of AI hemagglutinin subtypes H5, H7, or H9 were not detected. Although no statistically significant biosecurity associations were identified (p<=0.05), AI seroprevalence was positively associated with exposure to waterfowl, pest control, and location. AI seropositive flocks exposed to waterfowl were 3.14 times as likely to be AI seropositive than those not exposed (p = 0.15). AI seropositive flocks that did not use pest control were 2.5 times as likely to be AI seropositive compared to those that did and AI seropositive flocks located in the Northern region of Maryland were 2.8 times as likely to be AI seropositive than those that were located elsewhere. PMID- 23437258 TI - High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. AB - OBJECTIVE: Current evidence suggests high serum uric acid may increase the risk of type 2 diabetes, but the association is still uncertain. The aim of the study was to evaluate the association between serum uric acid and future risk of type 2 diabetes by conducting a meta-analysis of prospective cohort studies. DESIGN AND METHODS: We conducted a systematic literature search of the PubMed database through April 2012. Prospective cohort studies were included in meta-analysis that reported the multivariate adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs) for the association between serum uric acid and risk of type 2 diabetes. We used both fix-effects and random effects models to calculate the overall effect estimate. The heterogeneity across studies was tested by both Q statistic and I(2) statistic. Begg's funnel plot and Egger's regression test were used to assess the potential publication bias. RESULTS: We retrieved 7 eligible articles derived from 8 prospective cohort studies, involving a total of 32016 participants and 2930 incident type 2 diabetes. The combined RR of developing type 2 diabetes for the highest category of serum uric acid level compared with the lowest was 1.56(95% CI, 1.39-1.76). Dose-response analysis showed the risk of type 2 diabetes was increased by 6% per 1 mg/dl increment in serum uric acid level (RR 1.06, 95% CI: 1.04-1.07). The result from each subgroup showed a significant association between serum uric acid and risk of type 2 diabetes. In sensitive analysis, the combined RR was consistent every time omitting any one study. Little evidence of heterogeneity and publication bias was observed. CONCLUSIONS: Our meta-analysis of prospective cohort studies provided strong evidence that high level of serum uric acid is independent of other established risk factors, especially metabolic syndrome components, for developing type 2 diabetes in middle-aged and older people. PMID- 23437260 TI - Inside the "African cattle complex": animal burials in the holocene central Sahara. AB - Cattle pastoralism is an important trait of African cultures. Ethnographic studies describe the central role played by domestic cattle within many societies, highlighting its social and ideological value well beyond its mere function as 'walking larder'. Historical depth of this African legacy has been repeatedly assessed in an archaeological perspective, mostly emphasizing a continental vision. Nevertheless, in-depth site-specific studies, with a few exceptions, are lacking. Despite the long tradition of a multi-disciplinary approach to the analysis of pastoral systems in Africa, rarely do early and middle Holocene archaeological contexts feature in the same area the combination of settlement, ceremonial and rock art features so as to be multi-dimensionally explored: the Messak plateau in the Libyan central Sahara represents an outstanding exception. Known for its rich Pleistocene occupation and abundant Holocene rock art, the region, through our research, has also shown to preserve the material evidence of a complex ritual dated to the Middle Pastoral (6080-5120 BP or 5200-3800 BC). This was centred on the frequent deposition in stone monuments of disarticulated animal remains, mostly cattle. Animal burials are known also from other African contexts, but regional extent of the phenomenon, state of preservation of monuments, and associated rock art make the Messak case unique. GIS analysis, excavation data, radiocarbon dating, zooarchaeological and isotopic (Sr, C, O) analyses of animal remains, and botanical information are used to explore this highly formalized ritual and the lifeways of a pastoral community in the Holocene Sahara. PMID- 23437259 TI - CD133/prominin-1-mediated autophagy and glucose uptake beneficial for hepatoma cell survival. AB - CD133/Prominin-1 is a pentaspan transmembrane protein that has been frequently used as a biomarker for cancer stem cells, although its biological function is unclear. The aim of our study was to explore the intrinsic functions of CD133 membrane protein in hepatoma cells during autophagy, apoptosis, tumorigenesis and cell survival through expression or downregulation of CD133. In this study, CD133 was found to be dynamically released from plasma membrane into cytoplasm in both of complete medium(CM) and low glucose medium (LGM), and LGM promoted this translocation. Expression of CD133 enhanced autophagic activity in LGM, while silencing CD133 attenuated this activity in HCC LM3 and Huh-7 cells, suggesting that CD133 is associated with autophagy. Immunofluorescence and time-lapsed confocal techniques confirmed that CD133 was associated with autophagy marker, microtubule-associated protein light chain3 (LC3) and lysosome marker during the glucose starvation. We further found that Huh-7 cells with stable expression of shCD133 (Huh-7sh133) impaired the ability of cell proliferation and formation of xenograft tumors in the NOD/SCID mice. Although loss of CD133 did not affect the rates of glucose uptake in Huh-7con and Huh-7sh133 cells under the CM, Huh-7sh133 cells obviously died fast than Huh-7con cells in the LGM and decreased the rate of glucose uptake and ATP production. Furthermore, targeting CD133 by CD133mAb resulted in cell death in HepG2 cells, especially in the LGM, via inhibition of autophagic activity and increase of apoptosis. The results demonstrated that CD133 is involved in cell survival through regulation of autophagy and glucose uptake, which may be necessary for cancer stem cells to survive in tumor microenvironment. PMID- 23437261 TI - BH3-mimetics- and cisplatin-induced cell death proceeds through different pathways depending on the availability of death-related cellular components. AB - BACKGROUND: Owing to their important function in regulating cell death, pharmacological inhibition of Bcl-2 proteins by dubbed BH3-mimetics is a promising strategy for apoptosis induction or sensitization to chemotherapy. However, the role of Apaf-1, the main protein constituent of the apoptosome, in the process has yet not been analyzed. Furthermore as new chemotherapeutics develop, the possible chemotherapy-induced toxicity to rapidly dividing normal cells, especially sensitive differentiated cells, has to be considered. Such undesirable effects would probably be ameliorated by selectively and locally inhibiting apoptosis in defined sensitive cells. METHODOLOGY AND PRINCIPAL FINDINGS: Mouse embryonic fibroblasts (MEFS) from Apaf-1 knock out mouse (MEFS KO Apaf-1) and Bax/Bak double KO (MEFS KO Bax/Bak), MEFS from wild-type mouse (MEFS wt) and human cervix adenocarcinoma (HeLa) cells were used to comparatively investigate the signaling cell death-induced pathways of BH3-mimetics, like ABT737 and GX15-070, with DNA damage-inducing agent cisplatin (cis diammineplatinum(II) dichloride, CDDP). The study was performed in the absence or presence of apoptosis inhibitors namely, caspase inhibitors or apoptosome inhibitors. BH3-mimetic ABT737 required of Apaf-1 to exert its apoptosis-inducing effect. In contrast, BH3-mimetic GX15-070 and DNA damage-inducing CDDP induced cell death in the absence of both Bax/Bak and Apaf-1. GX15-070 induced autophagy based cell death in all the cell lines analyzed. MEFS wt cells were protected from the cytotoxic effects of ABT737 and CDDP by chemical inhibition of the apoptosome through QM31, but not by using general caspase inhibitors. CONCLUSIONS: BH3-mimetic ABT737 not only requires Bax/Bak to exert its apoptosis inducing effect, but also Apaf-1, while GX15-070 and CDDP induce different modalities of cell death in the absence of Bax/Bak or Apaf-1. Inclusion of specific Apaf-1 inhibitors in topical and well-localized administrations, but not in systemic ones, to avoid interferences with chemotherapeutics would be of interest to prevent chemotherapeutic-induced unwanted cell death which could improve cancer patient care. PMID- 23437262 TI - Behavioral responses to inequity in reward distribution and working effort in crows and ravens. AB - Sensitivity to inequity is considered to be a crucial cognitive tool in the evolution of human cooperation. The ability has recently been shown also in primates and dogs, raising the question of an evolutionary basis of inequity aversion. We present first evidence that two bird species are sensitive to other individuals' efforts and payoffs. In a token exchange task we tested both behavioral responses to inequity in the quality of reward (preferred versus non preferred food) and to the absence of reward in the presence of a rewarded partner, in 5 pairs of corvids (6 crows, 4 ravens). Birds decreased their exchange performance when the experimental partner received the reward as a gift, which indicates that they are sensitive to other individuals' working effort. They also decreased their exchange performance in the inequity compared with the equity condition. Notably, corvids refused to take the reward after a successful exchange more often in the inequity compared with the other conditions. Our findings indicate that awareness to other individuals' efforts and payoffs may evolve independently of phylogeny in systems with a given degree of social complexity. PMID- 23437263 TI - The effects of oral and enteric Campylobacter concisus strains on expression of TLR4, MD-2, TLR2, TLR5 and COX-2 in HT-29 cells. AB - Campylobacter concisus, a Gram-negative bacterium that colonizes the human oral cavity, has been shown to be associated with inflammatory bowel diseases (IBD). The effects of different C. concisus strains on intestinal epithelial expression of Toll like receptors (TLR) have not been investigated. This study examined the effects of C. concisus strains isolated from patients with IBD and controls on expression of TLR4, its co-receptor myeloid differentiation factor (MD)-2; TLR2, TLR5, cyclooxygenase-2 (COX-2) and interleukin (IL)-8 in HT-29 cells.Fourteen oral and enteric C. concisus strains isolated from patients with IBD and healthy controls were co-incubated with HT-29 cells. Expression of TLR4, MD-2, TLR2, TLR5 and COX-2 in HT-29 cells in response to C. concisus infection was examined by Western blot, flow cytometry analysis and immunofluorescent staining visualized by confocal microscope. Production of IL-8 was evaluated by enzyme-linked immunosorbent assay.Both oral and enteric C. concisus strains upregulated expression of TLR4 in HT-29 cells. The levels of glycosylated TLR4 (Gly-TLR4) and surface TLR4 induced by C. concisus strains isolated from patients with IBD were significantly higher than those induced by C. concisus strains isolated from the healthy controls. Four C. concisus strains isolated from patients with IBD induced more than two-fold increase of surface expression of MD-2. C. concisus did not affect expression of TLR2 and TLR5. All C. concisus strains induced production of IL-8 and COX-2 in HT-29 cells.This study shows that some C. concisus strains, most from patients with IBD, upregulate surface expression of TLR4 and MD-2 in HT-29 cells. These data suggest that a potential role of specific C. concisus strains in modulating the intestinal epithelial responses to bacterial LPS needs to be investigated. PMID- 23437264 TI - C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients. AB - A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion' patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5-17% of patients (21-41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine 'expansion-positive' patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an 'intermediate' allele with a mean size of only ~65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of 'non-expansion' FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ~65 repeats may be sufficient to cause disease. PMID- 23437265 TI - Effects of lipooligosaccharide inner core truncation on bile resistance and chick colonization by Campylobacter jejuni. AB - Campylobacter jejuni is the most common bacterium that causes diarrhea worldwide, and chickens are considered the main reservoir of this pathogen. This study investigated the effects of serial truncation of lipooligosaccharide (LOS), a major component of the outer membrane of C. jejuni, on its bile resistance and intestinal colonization ability in chickens. Genes encoding manno-heptose synthetases or glycosyltransferases were inactivated to generate isogenic mutants. Serial truncation of the LOS core oligosaccharide caused a stepwise increase in susceptibilities of two C. jejuni strains, NCTC 11168 and 81-176, to bile acids. Inactivation of hldE, hldD, or waaC caused severe truncation of the core oligosaccharide, which greatly increased the susceptibility to bile acids. Both wild-type strains grew normally in chicken intestinal extracts, whereas the mutants with severe oligosaccharide truncation were not detected 12 h after inoculation. These mutants attained viable bacterial counts in the bile acid-free extracts 24 h after inoculation. The wild-type strain 11-164 was present in the cecal contents at >10(7) CFU/g on 5 days after challenge infection and after this time period, whereas its hldD mutant was present at <10(3) CFU/g throughout the experimental period. Trans-complementation of the hldD mutant with the wild-type hldD allele completely restored the in vivo colonization level to that of the wild-type strain. Mutants with a shorter LOS had higher hydrophobicities. Thus, the length of the LOS core oligosaccharide affected the surface hydrophobicity and bile resistance of C. jejuni as well as its ability to colonize chicken intestines. PMID- 23437266 TI - Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the meninges and the choroid plexus: implications for non-neuronal sources for GABA in the developing mouse brain. AB - Neural progenitors in the developing neocortex, neuroepithelial cells and radial glial cells, have a bipolar shape with a basal process contacting the basal membrane of the meninge and an apical plasma membrane facing the lateral ventricle, which the cerebrospinal fluid is filled with. Recent studies revealed that the meninges and the cerebrospinal fluid have certain roles to regulate brain development. gamma-aminobutyric acid (GABA) is a neurotransmitter which appears first during development and works as a diffusible factor to regulate the properties of neural progenitors. In this study, we examined whether GABA can be released from the meninges and the choroid plexus in the developing mouse brain. Immunohistochemical analyses showed that glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67), both of which are GABA-synthesizing enzymes, are expressed in the meninges. The epithelial cells in the choroid plexus express GAD65. GABA immunoreactivity could be observed beneath the basal membrane of the meninge and in the epithelial cells of the choroid plexus. Expression analyses on Bestrophin 1, which is known as a GABA-permeable channel in differentiated glial cells, suggested that the cells in the meninges and the epithelial cells in the choroid plexus have the channels able to permeate non-synaptic GABA into the extracellular space. Further studies showed that GAD65/67-expressing meningeal cells appear in a manner with rostral to caudal and lateral to dorsal gradient to cover the entire neocortex by E14.5 during development, while the cells in the choroid plexus in the lateral ventricle start to express GAD65 on E11-E12, the time when the choroid plexus starts to develop in the developing brain. These results totally suggest that the meninges and the choroid plexus can work as non neuronal sources for ambient GABA which can modulate the properties of neural progenitors during neocortical development. PMID- 23437267 TI - Novel insights into E. coli's hexuronate metabolism: KduI facilitates the conversion of galacturonate and glucuronate under osmotic stress conditions. AB - Using a gnotobiotic mouse model, we previously observed the upregulation of 2 deoxy-D-gluconate 3-dehydrogenase (KduD) in intestinal E. coli of mice fed a lactose-rich diet and the downregulation of this enzyme and of 5-keto 4 deoxyuronate isomerase (KduI) on a casein-rich diet. The present study aimed to define the role of the so far poorly characterized E. coli proteins KduD and KduI in vitro. Galacturonate and glucuronate induced kduD and kduI gene expression 3 fold and 7 to 11-fold, respectively, under aerobic conditions as well as 9 to 20 fold and 19 to 54-fold, respectively, under anaerobic conditions. KduI facilitated the breakdown of these hexuronates. In E. coli, galacturonate and glucuronate are normally degraded by UxaABC and UxuAB. However, osmotic stress represses the expression of the corresponding genes in an OxyR-dependent manner. When grown in the presence of galacturonate or glucuronate, kduID-deficient E. coli had a 30% to 80% lower maximal cell density and 1.5 to 2-fold longer doubling times under osmotic stress conditions than wild type E. coli. Growth on lactose promoted the intracellular formation of hexuronates, which possibly explain the induction of KduD on a lactose-rich diet. These results indicate a novel function of KduI and KduD in E. coli and demonstrate the crucial influence of osmotic stress on the gene expression of hexuronate degrading enzymes. PMID- 23437268 TI - In vitro model of tumor cell extravasation. AB - Tumor cells that disseminate from the primary tumor and survive the vascular system can eventually extravasate across the endothelium to metastasize at a secondary site. In this study, we developed a microfluidic system to mimic tumor cell extravasation where cancer cells can transmigrate across an endothelial monolayer into a hydrogel that models the extracellular space. The experimental protocol is optimized to ensure the formation of an intact endothelium prior to the introduction of tumor cells and also to observe tumor cell extravasation by having a suitable tumor seeding density. Extravasation is observed for 38.8% of the tumor cells in contact with the endothelium within 1 day after their introduction. Permeability of the EC monolayer as measured by the diffusion of fluorescently-labeled dextran across the monolayer increased 3.8 fold 24 hours after introducing tumor cells, suggesting that the presence of tumor cells increases endothelial permeability. The percent of tumor cells extravasated remained nearly constant from1 to 3 days after tumor seeding, indicating extravasation in our system generally occurs within the first 24 hours of tumor cell contact with the endothelium. PMID- 23437269 TI - A role of kindlin-3 in integrin alphaMbeta2 outside-in signaling and the Syk-Vav1 Rac1/Cdc42 signaling axis. AB - Integrins mediate cell-cell and cell-extracellular matrix attachments. Integrins are signaling receptors because their cytoplasmic tails are docking sites for cytoskeletal and signaling proteins. Kindlins are a family of band 4.1-ezrin radixin-moesin-containing intracellular proteins. Apart from regulating integrin ligand-binding affinity, recent evidence suggests that kindlins are involved in integrin outside-in signaling. Kindlin-3 is expressed in platelets, hematopoietic cells and endothelial cells. In humans, loss of kindlin-3 expression accounts for the rare autosomal disease leukocyte adhesion deficiency (LAD) type III that is characterized by bleeding disorders and defective recruitment of leukocytes into sites of infection. Studies have shown that the loss of kindlin-3 expression leads to poor ligand-binding properties of beta1, beta2 and beta3 integrin subfamilies. The leukocyte-restricted beta2 integrin subfamily comprises four members, namely alphaLbeta2, alphaMbeta2, alphaXbeta2 and alphaDbeta2. Integrin alphaMbeta2 mediates leukocyte adhesion, phagocytosis, degranulation and it is involved in the maintenance of immune tolerance. Here we provide further evidence that kindlin-3 is required for integrin alphaMbeta2-mediated cell adhesion and spreading using transfected K562 cells that expressed endogenous kindlin-3 but not beta2 integrins. K562 stable cell line expressing si-RNA targeting kindlin-3, but not control-si-RNA, and transfected with constitutively activated integrin alphaMbeta2N329S adhered and spread poorly on iC3b. We also show that kindlin-3 is required for the integrin alphaMbeta2-Syk-Vav1 signaling axis that regulates Rac1 and Cdc42 activities. These findings reinforce a role for kindlin-3 in integrin outside-in signaling. PMID- 23437270 TI - Antioxidant effect of melatonin on the functional activity of colostral phagocytes in diabetic women. AB - Melatonin is involved in a number of physiological and oxidative processes, including functional regulation in human milk. The present study investigated the mechanisms of action of melatonin and its effects on the functional activity of colostral phagocytes in diabetic women. Colostrum samples were collected from normoglycemic (N = 38) and diabetic (N = 38) women. We determined melatonin concentration, superoxide release, bactericidal activity and intracellular Ca(2+) release by colostral phagocytes treated or not with 8-(Diethylamino) octyl-3,4,5 trimethoxybenzoate hydrochloride (TMB-8) and incubated with melatonin and its precursor (N-acetyl-serotonin-NAS), antagonist (luzindole) and agonist (chloromelatonin-CMLT). Melatonin concentration was higher in colostrum samples from hyperglycemic than normoglycemic mothers. Melatonin stimulated superoxide release by colostral phagocytes from normoglycemic but not hyperglycemic women. NAS increased superoxide, irrespective of glycemic status, whereas CMTL increased superoxide only in cells from the normoglycemic group. Phagocytic activity in colostrum increased significantly in the presence of melatonin, NAS and CMLT, irrespective of glycemic status. The bactericidal activity of colostral phagocytes against enterophatogenic Escherichia coli (EPEC) increased in the presence of melatonin or NAS in the normoglycemic group, but not in the hyperglycemic group. Luzindole blocked melatonin action on colostrum phagocytes. Phagocytes from the normoglycemic group treated with melatonin exhibited an increase in intracellular Ca(2+) release. Phagocytes treated with TMB-8 (intracellular Ca(2+) inhibitor) decreased superoxide, bactericidal activity and intracellular Ca(2+) release in both groups. The results obtained suggest an interactive effect of glucose metabolism and melatonin on colostral phagocytes. In colostral phagocytes from normoglycemic mothers, melatonin likely increases the ability of colostrum to protect against EPEC and other infections. In diabetic mothers, because maternal hyperglycemia modifies the functional activity of colostrum phagocytes, melatonin effects are likely limited to anti inflammatory processes, with low superoxide release and bactericidal activity. PMID- 23437271 TI - Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A) expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025), the proliferation marker Ki-67 (P = 0.001), and the recurrence rate of TNBC patients (P<0.001). In TNBC patients with Aur-A high expression, the risk of distant recurrence peaked at the first 3 years and declined rapidly thereafter, whereas patients with Aur-A low expression showed a relatively constant risk of recurrence during the entire follow-up period. Univariate and multivariate analysis showed that overexpression of Aur-A predicted poor overall survival (P = 0.002) and progression-free survival (P = 0.012) in TNBC. Furthermore, overexpression of Aur-A, associated with high Ki-67, predicted an inferior prognosis compared with low expression of both Aur-A and Ki 67. Importantly, we further found that Aur-A was overexpressed in TNBC cells, and inhibition of this kinase inhibited cell proliferation and prevented cell migration in TNBC. Our findings demonstrated that Aur-A was a potential therapeutic target for TNBC and inhibition of Aur-A kinase was a promising regimen for TNBC cancer therapy. PMID- 23437272 TI - Inhibition of nuclear factor-kappaB activation in pancreatic beta-cells has a protective effect on allogeneic pancreatic islet graft survival. AB - Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-kappaB activation is involved in cytokine-mediated beta-cell apoptosis and regulates the expression of pro inflammatory and chemokine genes. We therefore sought to explore the effects of beta-cell-specific inhibition of NF-kappaB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-beta transgenic mouse, where NF-kappaB signalling can specifically and conditionally be inhibited in beta-cells by expressing an inducible and non-degradable form of IkappaBalpha regulated by the tet-on system. Our results show that beta-cell-specific blockade of NF-kappaB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF kappaB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process. PMID- 23437273 TI - Biochemical characterization of CTX-M-15 from Enterobacter cloacae and designing a novel non-beta-lactam-beta-lactamase inhibitor. AB - The worldwide dissemination of CTX-M type beta-lactamases is a threat to human health. Previously, we have reported the spread of bla(CTX-M-15) gene in different clinical strains of Enterobacteriaceae from the hospital settings of Aligarh in north India. In view of the varying resistance pattern against cephalosporins and other beta-lactam antibiotics, we intended to understand the correlation between MICs and catalytic activity of CTX-M-15. In this study, steady-state kinetic parameters and MICs were determined on E. coli DH5alpha transformed with bla(CTX-M-15) gene that was cloned from Enterobacter cloacae (EC 15) strain of clinical background. The effect of conventional beta-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) on CTX-M-15 was also studied. We have found that tazobactam is the best among these inhibitors against CTX-M-15. The inhibition characteristic of tazobactam is defined by its very low IC(50) value (6 nM), high affinity (K(i) = 0.017 uM) and better acylation efficiency (k(+2)/K' = 0.44 uM(-1)s(-1)). It forms an acyl-enzyme covalent complex, which is quite stable (k(+3) = 0.0057 s(-1)). Since increasing resistance has been reported against conventional beta-lactam antibiotic inhibitor combinations, we aspire to design a non-beta-lactam core containing beta-lactamase inhibitor. For this, we screened ZINC database and performed molecular docking to identify a potential non-beta-lactam based inhibitor (ZINC03787097). The MICs of cephalosporin antibiotics in combination with this inhibitor gave promising results. Steady-state kinetics and molecular docking studies showed that ZINC03787097 is a reversible inhibitor which binds non covalently to the active site of the enzyme through hydrogen bonds and hydrophobic interactions. Though, it's IC(50) (180 nM) is much higher than tazobactam, it has good affinity for CTX-M-15 (K(i) = 0.388 uM). This study concludes that ZINC03787097 compound can be used as seed molecule to design more efficient non-beta-lactam containing beta-lactamase inhibitor that could evade pre-existing bacterial resistance mechanisms. PMID- 23437275 TI - Sex specific differences in fetal middle cerebral artery and umbilical venous Doppler. AB - BACKGROUND: The incidence of several adverse pregnancy outcomes including fetal growth restriction are higher in pregnancies where the fetus is male, leading to suggestions that placental insufficiency is more common in these fetuses. Placental insufficiency associated with fetal growth restriction may be identified by multi-vessel Doppler assessment, but little evidence exists regarding sex specific differences in these Doppler indices or placental function. This study aims to investigate sex specific differences in fetal and placental perfusion and to correlate these changes with intra-partum outcome. METHODS AND FINDINGS: This is a prospective cohort study. We measured Doppler indices of 388 term pregnancies immediately prior to the onset of active labour (<=3 cm dilatation). Fetal sex was unknown at the time of the ultrasound assessment. Information from the ultrasound scan was not made available to clinical staff. Case notes and electronic records were reviewed following delivery. We report significantly lower Middle Cerebral artery pulsatility index (1.34 vs. 1.43, p = 0.004), Middle Cerebral artery peak velocity (53.47 cm/s vs. 58.10 cm/s, p = <0.001), and Umbilical venous flow/kg (56 ml/min/kg vs. 61 ml/min/kg, p = 0.02) in male fetuses. These differences however, were not associated with significant differences in intra-partum outcome. CONCLUSION: Sex specific differences in feto-placental perfusion indices exist. Whilst the physiological relevance of these is currently unknown, the identification of these differences adds to our knowledge of the physiology of male and female fetuses in utero. A number of disease processes have now been shown to have an association with changes in fetal haemodynamics in-utero, as well as having a sex bias, making further investigation of the sex specific differences present during fetal life important. Whilst the clinical application of these findings is currently limited, the results from this study do provide further insight into the gender specific circulatory differences present in the fetal period. PMID- 23437274 TI - Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. AB - The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity. MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed. Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels. MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF alpha, whose CSF levels are elevated in autism. These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression. PMID- 23437276 TI - Cognitive performance and heart rate variability: the influence of fitness level. AB - In the present study, we investigated the relation between cognitive performance and heart rate variability as a function of fitness level. We measured the effect of three cognitive tasks (the psychomotor vigilance task, a temporal orienting task, and a duration discrimination task) on the heart rate variability of two groups of participants: a high-fit group and a low-fit group. Two major novel findings emerged from this study. First, the lowest values of heart rate variability were found during performance of the duration discrimination task, compared to the other two tasks. Second, the results showed a decrement in heart rate variability as a function of the time on task, although only in the low-fit group. Moreover, the high-fit group showed overall faster reaction times than the low-fit group in the psychomotor vigilance task, while there were not significant differences in performance between the two groups of participants in the other two cognitive tasks. In sum, our results highlighted the influence of cognitive processing on heart rate variability. Importantly, both behavioral and physiological results suggested that the main benefit obtained as a result of fitness level appeared to be associated with processes involving sustained attention. PMID- 23437277 TI - Evaluating the Strange Situation Procedure (SSP) to assess the bond between dogs and humans. AB - The Strange Situation Procedure (SSP) is increasingly being used to study attachment between dogs and humans. It has been developed from the Ainsworth Strange Situation Procedure, which is used extensively to investigate attachment between children and their parents. In this experiment, 12 female beagle dogs were tested in two treatments to identify possible order effects in the test, a potential weakness in the SSP. In one treatment (FS), dogs participated together with a 'familiar person' and a 'stranger'. In a control treatment (SS), the same dogs participated together with two unfamiliar people, 'stranger A' and 'stranger B'. Comparisons were made between episodes within as well as between treatments. As predicted in FS, dogs explored more in the presence of the familiar person than the stranger. Importantly, they also explored more in the presence of stranger A (who appeared in the same order as the familiar person and followed the same procedure) than stranger B in SS. Furthermore, comparisons between treatments, where a familiar person was present in FS and stranger A was present in SS, showed no differences in exploration. In combination, these results indicate that the effect of a familiar person on dogs' exploratory behaviour, a key feature when assessing secure attachment styles, could not be tested reliably due to the order in which the familiar person and the stranger appear. It is proposed that in the future only counterbalanced versions of the SSP are used. Alternatively, since dogs reliably initiated more contact with the familiar person compared to the strangers, it is suggested that future studies on attachment in dogs towards humans should focus either on the behaviour of the dog in those episodes of the SSP when the person returns, or on reunion behaviour in other studies, specially designed to address dog-human interactions at this time. PMID- 23437278 TI - Spatial-temporal clusters and risk factors of hand, foot, and mouth disease at the district level in Guangdong Province, China. AB - OBJECTIVE: Hand, foot, and mouth disease (HFMD) has posed a great threat to the health of children and become a public health priority in China. This study aims to investigate the epidemiological characteristics, spatial-temporal patterns, and risk factors of HFMD in Guangdong Province, China, and to provide scientific information for public health responses and interventions. METHODS: HFMD surveillance data from May 2008 to December 2011were provided by the Chinese Center for Disease Control and Prevention. We firstly conducted a descriptive analysis to evaluate the epidemic characteristics of HFMD. Then, Kulldorff scan statistic based on a discrete Poisson model was used to detect spatial-temporal clusters. Finally, a spatial paneled model was applied to identify the risk factors. RESULTS: A total of 641,318 HFMD cases were reported in Guangdong Province during the study period (total population incidence: 17.51 per 10,000). Male incidence was higher than female incidence for all age groups, and approximately 90% of the cases were children [Formula: see text] years old. Spatial-temporal cluster analysis detected four most likely clusters and several secondary clusters (P<0.001) with the maximum cluster size 50% and 20% respectively during 2008-2011. Monthly average temperature, relative humidity, the proportion of population [Formula: see text] years, male-to-female ratio, and total sunshine were demonstrated to be the risk factors for HFMD. CONCLUSION: Children [Formula: see text] years old, especially boys, were more susceptible to HFMD and we should take care of their vulnerability. Provincial capital city Guangzhou and the Pearl River Delta regions had always been the spatial-temporal clusters and future public health planning and resource allocation should be focused on these areas. Furthermore, our findings showed a strong association between HFMD and meteorological factors, which may assist in predicting HFMD incidence. PMID- 23437279 TI - ECM-dependent HIF induction directs trophoblast stem cell fate via LIMK1-mediated cytoskeletal rearrangement. AB - The Hypoxia-inducible Factor (HIF) family of transcriptional regulators coordinates the expression of dozens of genes in response to oxygen deprivation. Mammalian development occurs in a hypoxic environment and HIF-null mice therefore die in utero due to multiple embryonic and placental defects. Mouse embryonic stem cells do not differentiate into placental cells; therefore, trophoblast stem cells (TSCs) are used to study mouse placental development. Consistent with a requirement for HIF activity during placental development in utero, TSCs derived from HIF-null mice exhibit severe differentiation defects and fail to form trophoblast giant cells (TGCs) in vitro. Interestingly, differentiating TSCs induce HIF activity independent of oxygen tension via unclear mechanisms. Here, we show that altering the extracellular matrix (ECM) composition upon which TSCs are cultured changes their differentiation potential from TGCs to multinucleated syncytiotropholasts (SynTs) and blocks oxygen-independent HIF induction. We further find that modulation of Mitogen Activated Protein Kinase Kinase-1/2 (MAP2K1/2, MEK-1/2) signaling by ECM composition is responsible for this effect. In the absence of ECM-dependent cues, hypoxia-signaling pathways activate this MAPK cascade to drive HIF induction and redirect TSC fate along the TGC lineage. In addition, we show that integrity of the microtubule and actin cytoskeleton is critical for TGC fate determination. HIF-2alpha ensures TSC cytoskeletal integrity and promotes invasive TGC formation by interacting with c-MYC to induce non-canonical expression of Lim domain kinase 1-an enzyme that regulates microtubule and actin stability, as well as cell invasion. Thus, we find that HIF can integrate positional and metabolic cues from within the TSC niche to regulate placental development by modulating the cellular cytoskeleton via non-canonical gene expression. PMID- 23437280 TI - Comprehensive SNP scan of DNA repair and DNA damage response genes reveal multiple susceptibility loci conferring risk to tobacco associated leukoplakia and oral cancer. AB - Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the "maximally informative" method of SNP selection from HapMap data to non-HapMap populations was applied. Three hundred twenty-five SNPs from 11 key genes involved in double strand break repair, mismatch repair and DNA damage response pathways were genotyped on a total of 373 OSCC, 253 leukoplakia and 535 unrelated control individuals. The significantly associated SNPs were validated in an additional cohort of 144 OSCC patients and 160 controls. The rs12515548 of MSH3 showed significant association with OSCC both in the discovery and validation phases (discovery P-value: 1.43E 05, replication P-value: 4.84E-03). Two SNPs (rs12360870 of MRE11A, P-value: 2.37E-07 and rs7003908 of PRKDC, P-value: 7.99E-05) were found to be significantly associated only with leukoplakia. Stratification of subjects based on amount of tobacco consumption identified SNPs that were associated with either high or low tobacco exposed group. The study reveals a synergism between associated SNPs and lifestyle factors in predisposition to OSCC and leukoplakia. PMID- 23437281 TI - Differential microRNA regulation correlates with alternative polyadenylation pattern between breast cancer and normal cells. AB - Alternative polyadenylation (APA) could result in mRNA isoforms with variable lengths of 3' UTRs. Gain of microRNA target sites in the 3' UTR of a long mRNA isoform may cause different regulation from the corresponding short isoform. It has been known that cancer cells globally exhibit a lower ratio of long and short isoforms (LSR); that is, they tend to express larger amounts of short isoforms. The objective of this study is to illustrate the relationship between microRNA differential regulation and LSR. We retrieved public APA annotations and isoform expression profiles of breast cancer and normal cells from a high-throughput sequencing method study specific for the mRNA 3' end. Combining microRNA expression profiles, we performed statistical analysis to reveal and estimate microRNA regulation on APA patterns in a global scale. First, we found that the amount of microRNA target sites in the alternative UTR (aUTR), the region only present in long isoforms, could affect the LSR of the target genes. Second, we observed that the genes whose aUTRs were targeted by up-regulated microRNAs in cancer cells had an overall lower LSR. Furthermore, the target sites of up regulated microRNAs tended to appear in aUTRs. Finally, we demonstrated that the amount of target sites for up-regulated microRNAs in aUTRs correlated with the LSR change between cancer and normal cells. The results indicate that up regulation of microRNAs might cause lower LSRs of target genes in cancer cells through degradation of their long isoforms. Our findings provide evidence of how microRNAs might play a crucial role in APA pattern shifts from normal to cancerous or proliferative states. PMID- 23437282 TI - The interplays between autophagy and apoptosis induced by enterovirus 71. AB - BACKGROUND: Enterovirus 71 (EV71) is the causative agent of human diseases with distinct severity, from mild hand, foot and mouth disease to severe neurological syndromes, such as encephalitis and meningitis. The lack of understanding of viral pathogenesis as well as lack of efficient vaccine and drugs against this virus impedes the control of EV71 infection. EV71 virus induces autophagy and apoptosis; however, the relationship between EV71-induced autophagy and apoptosis as well as the influence of autophagy and apoptosis on virus virulence remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, it was observed that the Anhui strain of EV71 induced autophagy and apoptosis in human rhabdomyosarcoma (RD-A) cells. Additionally, by either applying chemical inhibitors or knocking down single essential autophagic or apoptotic genes, inhibition of EV71 induced autophagy inhibited the apoptosis both at the autophagosome formation stage and autophagy execution stage. However, inhibition of autophagy at the stage of autophagosome and lysosome fusion promoted apoptosis. In reverse, the inhibition of EV71-induced apoptosis contributed to the conversion of microtubule-associated protein 1 light chain 3-I (LC3-I) to LC3-II and degradation of sequestosome 1 (SQSTM1/P62). Furthermore, the inhibition of autophagy in the autophagsome formation stage or apoptosis decreased the release of EV71 viral particles. CONCLUSIONS/SIGNIFICANCE: In conclusion, the results of this study not only revealed novel aspect of the interplay between autophagy and apoptosis in EV71 infection, but also provided a new insight to control EV71 infection. PMID- 23437284 TI - CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls. AB - OBJECTIVES: Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups. METHODS: Rs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group. RESULTS: In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups. CONCLUSIONS: These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ. PMID- 23437283 TI - Pentylenetetrazol-induced epileptiform activity affects basal synaptic transmission and short-term plasticity in monosynaptic connections. AB - Epileptic activity is generally induced in experimental models by local application of epileptogenic drugs, including pentylenetetrazol (PTZ), widely used on both vertebrate and invertebrate neurons. Despite the high prevalence of this neurological disorder and the extensive research on it, the cellular and molecular mechanisms underlying epileptogenesis still remain unclear. In this work, we examined PTZ-induced neuronal changes in Helix monosynaptic circuits formed in vitro, as a simpler experimental model to investigate the effects of epileptiform activity on both basal release and post-tetanic potentiation (PTP), a form of short-term plasticity. We observed a significant enhancement of basal synaptic strength, with kinetics resembling those of previously described use dependent forms of plasticity, determined by changes in estimated quantal parameters, such as the readily releasable pool and the release probability. Moreover, these neurons exhibited a strong reduction in PTP expression and in its decay time constant, suggesting an impairment in the dynamic reorganization of synaptic vesicle pools following prolonged stimulation of synaptic transmission. In order to explain this imbalance, we determined whether epileptic activity is related to the phosphorylation level of synapsin, which is known to modulate synaptic plasticity. Using western blot and immunocytochemical staining we found a PTZ-dependent increase in synapsin phosphorylation at both PKA/CaMKI/IV and MAPK/Erk sites, both of which are important for modulating synaptic plasticity. Taken together, our findings suggest that prolonged epileptiform activity leads to an increase in the synapsin phosphorylation status, thereby contributing to an alteration of synaptic strength in both basal condition and tetanus-induced potentiation. PMID- 23437285 TI - Functional dissection of the dictyostelium discoideum dynamin B mitochondrial targeting sequence. AB - Most mitochondrial proteins are nuclear encoded and synthesized in the cytosol with an N-terminal mitochondrial targeting sequence or presequence for subsequent import into mitochondria. Here, we describe the proteolytic processing and inner membrane potential-dependent translocation of a dynamin family member by the Dictyostelium discoideum mitochondrial import system. Our results show that the unusual D. discoideum dynamin B presequence is removed through a processing mechanism that is common for mitochondrial matrix proteins. We identified a minimal segment of the dynamin B presequence containing seven lysine residues. This 47-residue region is, in combination with consensus matrix protease cleavage sites, necessary and sufficient for mitochondrial targeting. The correct positioning of these lysine residues plays a critical role for the proper processing and mitochondrial import of dynamin B in D. discoideum. Fluorescent proteins tagged with the dynamin B presequence or presequence regions supporting mitochondrial import in D. discoideum are imported with similar efficiency into the mitochondrial matrix of mammalian cells, indicating that the basic mechanisms underlying mitochondrial protein import are highly conserved from amoebozoa to mammalia. PMID- 23437286 TI - Linear regression in genetic association studies. AB - In genomic research phenotype transformations are commonly used as a straightforward way to reach normality of the model outcome. Many researchers still believe it to be necessary for proper inference. Using regression simulations, we show that phenotype transformations are typically not needed and, when used in phenotype with heteroscedasticity, result in inflated Type I error rates. We further explain that important is to address a combination of rare variant genotypes and heteroscedasticity. Incorrectly estimated parameter variability or incorrect choice of the distribution of the underlying test statistic provide spurious detection of associations. We conclude that it is a combination of heteroscedasticity, minor allele frequency, sample size, and to a much lesser extent the error distribution, that matter for proper statistical inference. PMID- 23437287 TI - Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. AB - 1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED(99) of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery. PMID- 23437288 TI - Enhancing post-expansion chondrogenic potential of costochondral cells in self assembled neocartilage. AB - The insufficient healing capacity of articular cartilage necessitates mechanically functional biologic tissue replacements. Using cells to form biomimetic cartilage implants is met with the challenges of cell scarcity and donor site morbidity, requiring expanded cells that possess the ability to generate robust neocartilage. To address this, this study assesses the effects of expansion medium supplementation (bFGF, TFP, FBS) and self-assembled construct seeding density (2, 3, 4 million cells/5 mm dia. construct) on the ability of costochondral cells to generate biochemically and biomechanically robust neocartilage. Results show TFP (1 ng/mL TGF-beta1, 5 ng/mL bFGF, 10 ng/mL PDGF) supplementation of serum-free chondrogenic expansion medium enhances the post expansion chondrogenic potential of costochondral cells, evidenced by increased glycosaminoglycan content, decreased type I/II collagen ratio, and enhanced compressive properties. Low density (2 million cells/construct) enhances matrix synthesis and tensile and compressive mechanical properties. Combined, TFP and Low density interact to further enhance construct properties. That is, with TFP, Low density increases type II collagen content by over 100%, tensile stiffness by over 300%, and compressive moduli by over 140%, compared with High density. In conclusion, the interaction of TFP and Low density seeding enhances construct material properties, allowing for a mechanically functional, biomimetic cartilage to be formed using clinically relevant costochondral cells. PMID- 23437289 TI - Gene expression and thiopurine metabolite profiling in inflammatory bowel disease - novel clues to drug targets and disease mechanisms? AB - BACKGROUND AND AIMS: Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity. METHODS: Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0 14.0 and <=4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately. RESULTS: Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn's disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes. CONCLUSIONS: Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD. PMID- 23437290 TI - Impact of soluble CD26 on treatment outcome and hepatitis C virus-specific T cells in chronic hepatitis C virus genotype 1 infection. AB - BACKGROUND: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50-80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV specific T cells. METHODS: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8(+) T cells. RESULTS: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8(+) T cells (P = 0.02). CONCLUSIONS: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8(+) T cells. PMID- 23437291 TI - Fragmentation of the habitat of wild ungulates by anthropogenic barriers in Mongolia. AB - Habitat loss and habitat fragmentation caused by anthropogenic activities are the main factors that constrain long-distance movement of ungulates. Mongolian gazelles (Procapra gutturosa) and Asiatic wild asses (Equus hemionus) in Mongolia are facing habitat fragmentation and loss. To better understand how their movements respond to potential anthropogenic and natural barriers, we tracked 24 Mongolian gazelles and 12 wild asses near the Ulaanbaatar-Beijing Railroad and the fenced international border between Mongolia and China between 2002 and 2012. None of the tracked gazelles crossed the railroad, even though gazelles were captured on both sides of the tracks at the start of the study. Similarly, we did not observe cross-border movements between Mongolia and China for either species, even though some animals used areas adjacent to the border. The both species used close areas to the anthropogenic barriers more frequently during winter than summer. These results suggest strong impacts by the artificial barriers. The construction of new railroads and roads to permit mining and other resource development therefore creates the threat of further habitat fragmentation, because the planned routes will divide the remaining non-fragmented habitats of the ungulates into smaller pieces. To conserve long-distance movement of the ungulates in this area, it will be necessary to remove or mitigate the barrier effects of the existing and planned roads and railroads and to adopt a landscape level approach to allow access by ungulates to wide ranges throughout their distribution. PMID- 23437292 TI - Adenovirus-based vaccine with epitopes incorporated in novel fiber sites to induce protective immunity against Pseudomonas aeruginosa. AB - Adenovirus (Ad) vector-based vaccines displaying pathogen-derived epitopes on Ad capsid proteins can elicit anti-pathogen immunity. This approach seems to be particularly efficient with epitopes incorporated into the Ad fiber protein. Here, we explore epitope insertion into various sites of the Ad fiber to elicit epitope-specific immunity. Ad vectors expressing the 14-mer Pseudomonas aeruginosa immune-dominant outer membrane protein F (OprF) epitope 8 (Epi8) in five distinct sites of the Ad5 fiber, loops CD (AdZ.F(CD)Epi8), DE (AdZ.F(DE)Epi8), FG (AdZ.F(FG)Epi8), HI (AdZ.F(HI)Epi8) and C terminus (AdZ.F(CT)Epi8), or the hexon HVR5 loop (AdZ.HxEpi8) were compared in their capacity to elicit anti-P. aeruginosa immunity to AdOprF, an Ad expressing the entire OprF protein. Intramuscular immunization of BALB/c mice with AdZ.F(FG)Epi8 or AdZ.F(HI)Epi8 elicited higher anti-OprF humoral and cellular CD4 and CD8 responses as well as enhanced protection against respiratory infection with P. aeruginosa compared to immunization with AdZ.F(CD)Epi8, AdZ.F(DE)Epi8, AdZ.F(CT)Epi8 or AdZ.HxEpi8. Importantly, repeat administration of the fiber- and hexon-modified Ad vectors boosted the OprF-specific humoral immune response in contrast to immunization with AdOprF. Strikingly, following three doses of AdZ.F(FG)Epi8 or AdZ.F(HI)Epi8 anti-OprF immunity surpassed that induced by AdOprF. Furthermore, in the presence of anti-Ad5 immunity, immunization with AdZ.F(FG)Epi8 or AdZ.F(HI)Epi8, but not with AdOprF, induced protective immunity against P. aeruginosa. This suggests that incorporation of epitopes into distinct sites of the Ad fiber is a promising vaccine strategy. PMID- 23437293 TI - De novo assembly of mud loach (Misgurnus anguillicaudatus) skin transcriptome to identify putative genes involved in immunity and epidermal mucus secretion. AB - Fish skin serves as the first line of defense against a wide variety of chemical, physical and biological stressors. Secretion of mucus is among the most prominent characteristics of fish skin and numerous innate immune factors have been identified in the epidermal mucus. However, molecular mechanisms underlying the mucus secretion and immune activities of fish skin remain largely unclear due to the lack of genomic and transcriptomic data for most economically important fish species. In this study, we characterized the skin transcriptome of mud loach using Illumia paired-end sequencing. A total of 40364 unigenes were assembled from 86.6 million (3.07 gigabases) filtered reads. The mean length, N50 size and maximum length of assembled transcripts were 387, 611 and 8670 bp, respectively. A total of 17336 (43.76%) unigenes were annotated by blast searches against the NCBI non-redundant protein database. Gene ontology mapping assigned a total of 108513 GO terms to 15369 (38.08%) unigenes. KEGG orthology mapping annotated 9337 (23.23%) unigenes. Among the identified KO categories, immune system is the largest category that contains various components of multiple immune pathways such as chemokine signaling, leukocyte transendothelial migration and T cell receptor signaling, suggesting the complexity of immune mechanisms in fish skin. As for mucin biosynthesis, 37 unigenes were mapped to 7 enzymes of the mucin type O-glycan biosynthesis pathway and 8 members of the polypeptide N acetylgalactosaminyltransferase family were identified. Additionally, 38 unigenes were mapped to 23 factors of the SNARE interactions in vesicular transport pathway, indicating that the activity of this pathway is required for the processes of epidermal mucus storage and release. Moreover, 1754 simple sequence repeats (SSRs) were detected in 1564 unigenes and dinucleotide repeats represented the most abundant type. These findings have laid the foundation for further understanding the secretary processes and immune functions of loach skin mucus. PMID- 23437294 TI - Differential gene expression profiling and biological process analysis in proximal nerve segments after sciatic nerve transection. AB - After traumatic injury, peripheral nerves can spontaneously regenerate through highly sophisticated and dynamic processes that are regulated by multiple cellular elements and molecular factors. Despite evidence of morphological changes and of expression changes of a few regulatory genes, global knowledge of gene expression changes and related biological processes during peripheral nerve injury and regeneration is still lacking. Here we aimed to profile global mRNA expression changes in proximal nerve segments of adult rats after sciatic nerve transection. According to DNA microarray analysis, the huge number of genes was differentially expressed at different time points (0.5 h-14 d) post nerve transection, exhibiting multiple distinct temporal expression patterns. The expression changes of several genes were further validated by quantitative real time RT-PCR analysis. The gene ontology enrichment analysis was performed to decipher the biological processes involving the differentially expressed genes. Collectively, our results highlighted the dynamic change of the important biological processes and the time-dependent expression of key regulatory genes after peripheral nerve injury. Interestingly, we, for the first time, reported the presence of olfactory receptors in sciatic nerves. Hopefully, this study may provide a useful platform for deeply studying peripheral nerve injury and regeneration from a molecular-level perspective. PMID- 23437295 TI - Convenient detection of the citrus greening (huanglongbing) bacterium 'Candidatus Liberibacter asiaticus' by direct PCR from the midrib extract. AB - A phloem-limited bacterium, 'Candidatus Liberibacter asiaticus' (Las) is a major pathogen of citrus greening (huanglongbing), one of the most destructive citrus diseases worldwide. The rapid identification and culling of infected trees and budwoods in quarantine are the most important control measures. DNA amplification including conventional polymerase chain reaction (PCR) has commonly been used for rapid detection and identification. However, long and laborious procedures for DNA extraction have greatly reduced the applicability of this method. In this study, we found that the Las bacterial cells in the midribs of infected leaves were extracted rapidly and easily by pulverization and centrifugation with mini homogenization tubes. We also found that the Las bacterial cells in the midrib extract were suitable for highly sensitive direct PCR. The performance of direct PCR using this extraction method was not inferior to that of conventional PCR. Thus, the direct PCR method described herein is characterized by its simplicity, sensitivity, and robustness, and is applicable to quarantine testing. PMID- 23437296 TI - The association between two common polymorphisms in MicroRNAs and hepatocellular carcinoma risk in Asian population. AB - BACKGROUND: Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) located in the miRNAs may influence the function of mature miRNAs and then affect the processing of carcinogenesis. It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To acquire a more precise effect of the association between these polymorphisms and HCC risk, we performed this meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: We have conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs3746444 with susceptibility to HCC in PubMed, ScienceDirect, Cochrane Central Register of Controlled Trials, and Chinese National Knowledge Infrastructure databases for the period up to Sep 10th, 2012. A total of 6 studies were identified with 2071 cases and 2350 controls for miR-146a rs2910164 polymorphism, 667 cases and 1006 controls for miR-499 rs3746444 polymorphism. It was found that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk of HCC in all genetic models. Similarly, subgroup analysis in Asian population showed no associations between the two SNPs and the susceptibility to HCC. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions. PMID- 23437297 TI - CCAAT/enhancer-binding protein-alpha suppresses lung tumor development in mice through the p38alpha MAP kinase pathway. AB - The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) is a basic leucine zipper transcription factor and is expressed in alveolar type II cells, alveolar macrophages and Clara cells in the lung. Although decrease or absence of C/EBPalpha expression in human non-small cell lung cancer suggests a possible role of C/EBPalpha as a lung tumor suppressor, there is no direct proof for this hypothesis. In this study, we investigated, for the first time, the role of C/EBPalpha in lung tumors in vivo using transgenic mice with lung epithelial specific conditional deletion of Cebpa (Cebpalpha(Delta/Delta) mice) and a urethane-induced lung tumor model. C/EBPalpha expression in the lung was dispensable, and its deletion was not oncogenic under unstressed conditions. However, at 28 wk after urethane injection, the number and size of tumors and the tumor burden were significantly higher in Cebpalpha(Delta/Delta) mice than in littermate control mice. Urethane-injected Cebpalpha(Delta/Delta) mice showed highly proliferative adenomas and adenocarcinomas in the lung, and survival time after urethane-injection was significantly shorter than that in control mice. In control mice, C/EBPalpha was strongly induced in the tumor tissues at 28 weeks after urethane-injection, but became weakened or absent as tumors progressed after long-term observation for over 1 year. Using intraperitoneal injection of p38 inhibitor (SB203580), we demonstrated that the induction of C/EBPalpha is strongly regulated by the p38 MAP kinase in murine alveolar epithelial cells. A high correlation was demonstrated between the expression of C/EBPalpha and p38alpha MAP kinase in tumor cells, suggesting that C/EBPalpha silencing in tumor cells is caused by down-regulation of p38alpha MAP kinase. In conclusion, the role of C/EBPalpha as a lung tumor suppressor was demonstrated for the first time in the present study, and the extinguished C/EBPalpha expression through p38alpha inactivation leads tumor promotion and progression. PMID- 23437298 TI - Temporal and spatial patterns of habitat use by juveniles of a small coastal shark (Mustelus lenticulatus) in an estuarine nursery. AB - Juvenile rig (Mustelus lenticulatus) were internally tagged with acoustic transmitters and tracked with acoustic receivers deployed throughout two arms of Porirua Harbour, a small (7 km(2)) estuary in New Zealand. Ten rig were tracked for up to four months during summer-autumn to determine their spatial and temporal use of the habitat. The overall goal was to estimate the size of Marine Protected Areas required to protect rig nursery areas from direct human impacts. Rig showed clear site preferences, but those preferences varied among rig and over time. They spent most of their time in large basins and on shallow sand and mud flats around the margins, and avoided deep channels. Habitat range increased during autumn for many of the rig. Only one shark spent time in both harbour arms, indicating that there was little movement between the two. Rig home ranges were 2-7 km(2), suggesting that an effective MPA would need to cover the entire Porirua Harbour. They moved to outer harbour sites following some high river flow rates, and most left the harbour permanently during or soon after a river spike, suggesting that they were avoiding low salinity water. Rig showed strong diel movements during summer, although the diel pattern weakened in autumn. Persistent use of the same day and night sites indicates that diel movements are directed rather than random. Further research is required to determine the sizes of rig home ranges in larger harbours where nursery habitat is more extensive. Marine Protected Areas do not control land-based impacts such as accelerated sedimentation and heavy metal pollution, so integration of marine and terrestrial management tools across a range of government agencies is essential to fully protect nursery areas. PMID- 23437299 TI - Altered expression pattern of molecular factors involved in colonic smooth muscle functions: an immunohistochemical study in patients with diverticular disease. AB - BACKGROUND: The pathogenesis of diverticular disease (DD) is thought to result from complex interactions among dietary habits, genetic factors and coexistence of other bowel abnormalities. These conditions lead to alterations in colonic pressure and motility, facilitating the formation of diverticula. Although electrophysiological studies on smooth muscle cells (SMCs) have investigated colonic motor dysfunctions, scarce attention has been paid to their molecular abnormalities, and data on SMCs in DD are lacking. Accordingly, the main purpose of this study was to evaluate the expression patterns of molecular factors involved in the contractile functions of SMCs in the tunica muscularis of colonic specimens from patients with DD. METHODS AND FINDINGS: By means of immunohistochemistry and image analysis, we examined the expression of Cx26 and Cx43, which are prominent components of gap junctions in human colonic SMCs, as well as pS368-Cx43, PKCps, RhoA and alphaSMA, all known to regulate the functions of gap junctions and the contractile activity of SMCs. The immunohistochemical analysis revealed significant abnormalities in DD samples, concerning both the expression and distribution patterns of most of the investigated molecular factors. CONCLUSION: This study demonstrates, for the first time, that an altered pattern of factors involved in SMC contractility is present at level of the tunica muscularis of DD patients. Moreover, considering that our analysis was conducted on colonic tissues not directly affected by diverticular lesions or inflammatory reactions, it is conceivable that these molecular alterations may precede and predispose to the formation of diverticula, rather than being mere consequences of the disease. PMID- 23437300 TI - Plant functional group composition modifies the effects of precipitation change on grassland ecosystem function. AB - Temperate grassland ecosystems face a future of precipitation change, which can alter community composition and ecosystem functions through reduced soil moisture and waterlogging. There is evidence that functionally diverse plant communities contain a wider range of water use and resource capture strategies, resulting in greater resistance of ecosystem function to precipitation change. To investigate this interaction between composition and precipitation change we performed a field experiment for three years in successional grassland in southern England. This consisted of two treatments. The first, precipitation change, simulated end of century predictions, and consisted of a summer drought phase alongside winter rainfall addition. The second, functional group identity, divided the plant community into three groups based on their functional traits- broadly described as perennials, caespitose grasses and annuals- and removed these groups in a factorial design. Ecosystem functions related to C, N and water cycling were measured regularly. Effects of functional groupidentity were apparent, with the dominant trend being that process rates were higher under control conditions where a range of perennial species were present. E.g. litter decomposition rates were significantly higher in plots containing several perennial species, the group with the highest average leaf N content. Process rates were also very strongly affected by the precipitation change treatmentwhen perennial plant species were dominant, but not where the community contained a high abundance of annual species and caespitose grasses. This contrasting response could be attributable to differing rooting patterns (shallower structures under annual plants, and deeper roots under perennials) and faster nutrient uptake in annuals compared to perennials. Our results indicate that precipitation change will have a smaller effect on key process rates in grasslandscontaining a range of perennial and annual species, and that maintaining the presence of key functional groups should be a crucial consideration in future grassland management. PMID- 23437301 TI - The role of propagule pressure, genetic diversity and microsite availability for Senecio vernalis invasion. AB - Genetic diversity is supposed to support the colonization success of expanding species, in particular in situations where microsite availability is constrained. Addressing the role of genetic diversity in plant invasion experimentally requires its manipulation independent of propagule pressure. To assess the relative importance of these components for the invasion of Senecio vernalis, we created propagule mixtures of four levels of genotype diversity by combining seeds across remote populations, across proximate populations, within single populations and within seed families. In a first container experiment with constant Festuca rupicola density as matrix, genotype diversity was crossed with three levels of seed density. In a second experiment, we tested for effects of establishment limitation and genotype diversity by manipulating Festuca densities. Increasing genetic diversity had no effects on abundance and biomass of S. vernalis but positively affected the proportion of large individuals to small individuals. Mixtures composed from proximate populations had a significantly higher proportion of large individuals than mixtures composed from within seed families only. High propagule pressure increased emergence and establishment of S. vernalis but had no effect on individual growth performance. Establishment was favoured in containers with Festuca, but performance of surviving seedlings was higher in open soil treatments. For S. vernalis invasion, we found a shift in driving factors from density dependence to effects of genetic diversity across life stages. While initial abundance was mostly linked to the amount of seed input, genetic diversity, in contrast, affected later stages of colonization probably via sampling effects and seemed to contribute to filtering the genotypes that finally grew up. In consequence, when disentangling the mechanistic relationships of genetic diversity, seed density and microsite limitation in colonization of invasive plants, a clear differentiation between initial emergence and subsequent survival to juvenile and adult stages is required. PMID- 23437302 TI - Jun is required in Isl1-expressing progenitor cells for cardiovascular development. AB - Jun is a highly conserved member of the multimeric activator protein 1 transcription factor complex and plays an important role in human cancer where it is known to be critical for proliferation, cell cycle regulation, differentiation, and cell death. All of these biological functions are also crucial for embryonic development. Although all Jun null mouse embryos die at mid gestation with persistent truncus arteriosus, a severe cardiac outflow tract defect also seen in human congenital heart disease, the developmental mechanisms are poorly understood. Here we show that murine Jun is expressed in a restricted pattern in several cell populations important for cardiovascular development, including the second heart field, pharyngeal endoderm, outflow tract and atrioventricular endocardial cushions and post-migratory neural crest derivatives. Several genes, including Isl1, molecularly mark the second heart field. Isl1 lineages include myocardium, smooth muscle, neural crest, endocardium, and endothelium. We demonstrate that conditional knockout mouse embryos lacking Jun in Isl1-expressing progenitors display ventricular septal defects, double outlet right ventricle, semilunar valve hyperplasia and aortic arch artery patterning defects. In contrast, we show that conditional deletion of Jun in Tie2-expressing endothelial and endocardial precursors does not result in aortic arch artery patterning defects or embryonic death, but does result in ventricular septal defects and a low incidence of semilunar valve defects, atrioventricular valve defects and double outlet right ventricle. Our results demonstrate that Jun is required in Isl1-expressing progenitors and, to a lesser extent, in endothelial cells and endothelial-derived endocardium for cardiovascular development but is dispensable in both cell types for embryonic survival. These data provide a cellular framework for understanding the role of Jun in the pathogenesis of congenital heart disease. PMID- 23437303 TI - Rab6a/a' are important Golgi regulators of pro-inflammatory TNF secretion in macrophages. AB - Lipopolysaccharide (LPS)-activated macrophages secrete pro-inflammatory cytokines, including tumor necrosis factor (TNF) to elicit innate immune responses. Secretion of these cytokines is also a major contributing factor in chronic inflammatory disease. In previous studies we have begun to elucidate the pathways and molecules that mediate the intracellular trafficking and secretion of TNF. Rab6a and Rab6a' (collectively Rab6) are trans-Golgi-localized GTPases known for roles in maintaining Golgi structure and Golgi-associated trafficking. We found that induction of TNF secretion by LPS promoted the selective increase of Rab6 expression. Depletion of Rab6 (via siRNA and shRNA) resulted in reorganization of the Golgi ribbon into more compact structures that at the resolution of electron microcopy consisted of elongated Golgi stacks that likely arose from fusion of smaller Golgi elements. Concomitantly, the delivery of TNF to the cell surface and subsequent release into the media was reduced. Dominant negative mutants of Rab6 had similar effects in disrupting TNF secretion. In live cells, Rab6-GFP were localized on trans-Golgi network (TGN)-derived tubular carriers demarked by the golgin p230. Rab6 depletion and inactive mutants altered carrier egress and partially reduced p230 membrane association. Our results show that Rab6 acts on TNF trafficking at the level of TGN exit in tubular carriers and our findings suggest Rab6 may stabilize p230 on the tubules to facilitate TNF transport. Both Rab6 isoforms are needed in macrophages for Golgi stack organization and for the efficient post-Golgi transport of TNF. This work provides new insights into Rab6 function and into the role of the Golgi complex in cytokine secretion in inflammatory macrophages. PMID- 23437304 TI - MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer. AB - BACKGROUND: miR-18a is one of the most up-regulated miRNAs in colorectal cancers (CRC) based on miRNA profiling. In this study, we examined the functional significance of miR-18a in CRC. METHODS: Expression of miR-18a was investigated in 45 CRC patients. Potential target genes of miR-18a were predicted by in silico search and confirmed by luciferase activity assay and Western blot. DNA damage was measured by comet assay. Gene function was measured by cell viability, colony formation and apoptosis assays. RESULTS: The up-regulation of miR-18a was validated and confirmed in 45 primary CRC tumors compared with adjacent normal tissues (p<0.0001). Through in silico search, the 3'UTR of Ataxia telangiectasia mutated (ATM) contains a conserved miR-18a binding site. Expression of ATM was down-regulated in CRC tumors (p<0.0001) and inversely correlated with miR-18a expression (r = -0.4562, p<0.01). Over-expression of miR-18a in colon cancer cells significantly reduced the luciferase activity of the construct with wild type ATM 3'UTR but not that with mutant ATM 3'UTR, inferring a direct interaction of miR-18a with ATM 3'UTR. This was further confirmed by the down-regulation of ATM protein by miR-18a. As ATM is a key enzyme in DNA damage repair, we evaluated the effect of miR-18a on DNA double-strand breaks. Ectopic expression of miR-18a significantly inhibited the repair of DNA damage induced by etoposide (p<0.001), leading to accumulation of DNA damage, increase in cell apoptosis and poor clonogenic survival. CONCLUSION: miR-18a attenuates cellular repair of DNA double strand breaks by directly suppressing ATM, a key enzyme in DNA damage repair. PMID- 23437305 TI - Association of GST genetic polymorphisms with the susceptibility to hepatocellular carcinoma (HCC) in Chinese population evaluated by an updated systematic meta-analysis. AB - BACKGROUND: Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1) and Glutathione S-transferase theta-1 (GSTT1) in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive. METHODS: A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc.) for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis. RESULTS: Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR = 1.47, 95% CI: 1.21 to 1.79, P<0.001) and GSTT1 null genotype (OR = 1.38, 95% CI: 1.14 to 1.65, P<0.001). Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR = 1.79, 95% CI: 1.26 to 2.53, P<0.001). In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1) with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR = 0.78, 95% CI: 0.60 to 1.01, P = 0.06; for GSTT1: OR = 0.94, 95% CI: 0.78 to 1.14, P = 0.546; for GSTM1-GSTT1: OR = 1.04, 95% CI: 0.81 to 1.32, P = 0.77). Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. CONCLUSIONS: Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1 are more susceptible to developing HCC. In conclusion, GST genetic polymorphisms play vital roles in the development of HCC in the Chinese population. PMID- 23437306 TI - Disease isolates of Streptococcus pseudopneumoniae and non-typeable S. pneumoniae presumptively identified as atypical S. pneumoniae in Spain. AB - We aimed to obtain insights on the nature of a collection of isolates presumptively identified as atypical Streptococcus pneumoniae recovered from invasive and non-invasive infections in Spain. One-hundred and thirty-two isolates were characterized by: optochin susceptibility in ambient and CO(2) enriched atmosphere; bile solubility; PCR-based assays targeting pneumococcal genes lytA, ply, pspA, cpsA, Spn9802, aliB-like ORF2, and a specific 16S rRNA region; multilocus sequence analysis; and antimicrobial susceptibility. By multilocus sequence analysis, 61 isolates were S. pseudopneumoniae, 34 were pneumococci, 13 were S. mitis, and 24 remained unclassified as non-pneumococci. Among S. pseudopneumoniae isolates, 51 (83.6%) were collected from respiratory tract samples; eight isolates were obtained from sterile sources. High frequency of non-susceptibility to penicillin (60.7%) and erythromycin (42.6%) was found. Only 50.8% of the S. pseudopneumoniae isolates displayed the typical optochin phenotype originally described for this species. None harbored the cpsA gene or the pneumococcal typical lytA restriction fragment length polymorphism. The Spn9802 and the specific 16S rRNA regions were detected among the majority of the S. pseudopneumoniae isolates (n = 59 and n = 49, respectively). The ply and pspA genes were rarely found. A high genetic diversity was found and 59 profiles were identified. Among the S. pneumoniae, 23 were capsulated and 11 were non-typeable. Three non-typeable isolates, associated to international non-capsulated lineages, were recovered from invasive disease sources. In conclusion, half of the atypical pneumococcal clinical isolates were, in fact, S. pseudopneumoniae and one-fourth were other streptococci. We identified S. pseudopneumoniae and non-typeable pneumococci as cause of disease in Spain including invasive disease. PMID- 23437307 TI - Periarticular osteophytes as an appendicular joint stress marker (JSM): analysis in a contemporary Japanese skeletal collection. AB - OBJECTIVE: The aim of this study was to investigate the possibility that periarticular osteophytes plays a role as a appendicular joint stress marker (JSM) which reflects the biomechanical stresses on individuals and populations. METHODS: A total of 366 contemporary Japanese skeletons (231 males, 135 females) were examined closely to evaluate the periarticular osteophytes of six major joints, the shoulder, elbow, wrist, hip, knee, and ankle and osteophyte scores (OS) were determined using an original grading system. These scores were aggregated and analyzed statistically from some viewpoints. RESULTS: All of the OS for the respective joints were correlated logarithmically with the age-at death of the individuals. For 70 individuals, in whom both sides of all six joints were evaluated without missing values, the age-standardized OS were calculated. A right side dominancy was recognized in the joints of the upper extremities, shoulder and wrist joints, and the bilateral correlations were large in the three joints on the lower extremity. For the shoulder joint and the hip joint, it was inferred by some distinctions that systemic factors were relatively large. All of these six joints could be assorted by the extent of systemic and local factors on osteophytes formation. Moreover, when the age-standardized OS of all the joints was summed up, some individuals had significantly high total scores, and others had significantly low total scores; namely, all of the individuals varied greatly in their systemic predisposition for osteophytes formation. CONCLUSIONS: This study demonstrated the significance of periarticular osteophytes; the evaluating system for OS could be used to detect differences among joints and individuals. Periarticular osteophytes could be applied as an appendicular joint stress marker (JSM); by applying OS evaluating system for skeletal populations, intra-skeletal and inter-skeletal variations in biomechanical stresses throughout the lives could be clarified. PMID- 23437308 TI - Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification. AB - Familial idiopathic basal ganglia calcification (FIBGC) is a rare, autosomal dominant disorder involving bilateral calcification of the basal ganglia. To identify gene mutations related to a Chinese FIBGC lineage, we evaluated available individuals in the family using CT scans. DNA was extracted from the peripheral blood of available family members, and both exonic and flanking intronic sequences of the SLC20A2 gene were amplified by PCR and then sequenced. Non-denaturing polyacrylamide gel electrophoresis (PAGE) was used to confirm the presence of mutations. Allele imbalances of the SLC20A2 gene or relative quantity of SLC20A2 transcripts were evaluated using qRT-PCR. A novel heterozygous single base-pair deletion (c.510delA) within the SLC20A2 gene was identified. This deletion mutation was found to co-segregate with basal ganglia calcification in all of the affected family members but was not detected in unaffected individuals or in 167 unrelated Han Chinese controls. The mutation will cause a frameshift, producing a truncated SLC20A2 protein with a premature termination codon, most likely leading to the complete loss of function of the SLC20A2 protein. This mutation may also lead to a reduction in SLC20A2 mRNA expression by approximately 30% in cells from affected individuals. In conclusion, we identified a novel mutation in SLC20A2 that is linked to FIBGC. In addition to the loss of function at the protein level, decreasing the expression of SLC20A2 mRNA may be another mechanism that can regulate SLC20A2 function in IBGC individuals. We propose that the regional expression pattern of SLC20A1 and SLC20A2 might explain the unique calcification pattern observed in FIBGC patients. PMID- 23437309 TI - Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia. AB - Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs) is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC) or 6 days (E6d HPC). Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO) was induced. The effects of these HPC protocols on hypoxia inducible factor (HIF) regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC). Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1). An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection. PMID- 23437310 TI - Social presence and use of internet-delivered interventions: a multi-method approach. AB - OBJECTIVE: Internet-delivered interventions can effectively change health risk behaviors and their determinants, but adherence to intervention websites once they are accessed is very low. This study tests whether and how social presence elements can increase website use. METHODS: A website about Hepatitis A, B, and C virus infections was used in a preparatory lab-based eye-tracking study assessing whether social presence elements attract participants' attention, because this is a prerequisite for affecting website use. In the following field study, 482 participants representative of the Dutch population were randomized to either a website with or a website without social presence elements. Participants completed a questionnaire of validated measures regarding user perceptions immediately after exposure to the website. Server registrations were used to assess website use. RESULTS: Participants in the experimental condition focused on the social presence elements, both in terms of frequency (F(1, 98) = 40.34, p<.001) and duration (F(1, 88) = 39.99, p<.001), but did not differ in website use in comparison with the control condition; neither in terms of the number of pages visited (t(456) = 1.44, p = .15), nor in terms of time on the website (t(456) = 0.01, p = .99). CONCLUSIONS: Adding social presence elements did not affect actual use of an intervention website within a public health context. Possible reasons are limited attention for these elements in comparison with the main text and the utilitarian value of intervention websites. PMID- 23437311 TI - NADPH-cytochrome P450 reductase: molecular cloning and functional characterization of two paralogs from Withania somnifera (L.) dunal. AB - Withania somnifera (L.) Dunal, a highly reputed medicinal plant, synthesizes a large array of steroidal lactone triterpenoids called withanolides. Although its chemical profile and pharmacological activities have been studied extensively during the last two decades, limited attempts have been made to decipher the biosynthetic route and identification of key regulatory genes involved in withanolide biosynthesis. Cytochrome P450 reductase is the most imperative redox partner of multiple P450s involved in primary and secondary metabolite biosynthesis. We describe here the cloning and characterization of two paralogs of cytochrome P450 reductase from W. somnifera. The full length paralogs of WsCPR1 and WsCPR2 have open reading frames of 2058 and 2142 bp encoding 685 and 713 amino acid residues, respectively. Phylogenetic analysis demonstrated that grouping of dual CPRs was in accordance with class I and class II of eudicotyledon CPRs. The corresponding coding sequences were expressed in Escherichia coli as glutathione-S-transferase fusion proteins, purified and characterized. Recombinant proteins of both the paralogs were purified with their intact membrane anchor regions and it is hitherto unreported for other CPRs which have been purified from microsomal fraction. Southern blot analysis suggested that two divergent isoforms of CPR exist independently in Withania genome. Quantitative real-time PCR analysis indicated that both genes were widely expressed in leaves, stalks, roots, flowers and berries with higher expression level of WsCPR2 in comparison to WsCPR1. Similar to CPRs of other plant species, WsCPR1 was un-inducible while WsCPR2 transcript level increased in a time dependent manner after elicitor treatments. High performance liquid chromatography of withanolides extracted from elicitor-treated samples showed a significant increase in two of the key withanolides, withanolide A and withaferin A, possibly indicating the role of WsCPR2 in withanolide biosynthesis. Present investigation so far is the only report of characterization of CPR paralogs from W. somnifera. PMID- 23437312 TI - Does antenatal maternal psychological distress affect placental circulation in the third trimester? AB - INTRODUCTION: Some types of antenatal maternal psychological distress may be associated with reduced fetal growth and birthweight. A stress-mediated reduction in placental blood flow has been suggested as a mechanism. Previous studies have examined this using ultrasound-derived arterial resistance measures in the uterine (UtA) and umbilical (UA) arteries, with mixed conclusions. However, a reduction in placental volume blood flow may occur before changes in arterial resistance measures are seen. Fetoplacental volume blood flow can be quantified non-invasively in the umbilical vein (UV). Our objective was to study whether specific types of maternal psychological distress affect the placental circulation, using volume blood flow quantification in addition to arterial resistance measures. METHODS: This was a prospective observational study of 104 non-smoking pregnant women (gestational age 30 weeks) with uncomplicated obstetric histories. Psychological distress was measured by General Health Questionnaire-28 (subscales anxiety and depression) and Impact of Event Scale-22 (subscales intrusion, avoidance and arousal). UtA and UA resistance measures and UV volume blood flow normalized for fetal abdominal circumference, were obtained by Doppler ultrasound. RESULTS: IES intrusion scores above the mean were associated with a reduction in normalized UV volume blood flow (corresponding to 0.61 SD; P = 0.003). Adjusting for UA resistance increased the strength of this association (difference -0.66 SD; P<0.001). Other distress types were not associated with UV volume blood flow. Maternal distress was not associated with arterial resistance measures, despite adjustment for confounders. CONCLUSIONS: Intrusive thoughts and emotional distress regarding the fetus were associated with reduced fetoplacental volume blood flow in third trimester. Uterine and umbilical artery resistance measures were not associated with maternal distress. Our findings support a decrease in fetoplacental blood flow as a possible pathway between maternal distress and reduced fetal growth. PMID- 23437313 TI - Local competition and metapopulation processes drive long-term seagrass-epiphyte population dynamics. AB - It is well known that ecological processes such as population regulation and natural enemy interactions potentially occur over a range of spatial scales, and there is a substantial body of literature developing theoretical understanding of the interplay between these processes. However, there are comparatively few studies quantifying the long-term effects of spatial scaling in natural ecosystems. A key challenge is that trophic complexity in real-world biological communities quickly obscures the signal from a focal process. Seagrass meadows provide an excellent opportunity in this respect: in many instances, seagrasses effectively form extensive natural monocultures, in which hypotheses about endogenous dynamics can be formulated and tested. We present amongst the longest unbroken, spatially explict time series of seagrass abundance published to date. Data include annual measures of shoot density, total above-ground abundance, and associated epiphyte cover from five Zostera marina meadows distributed around the Isles of Scilly, UK, from 1996 to 2011. We explore empirical patterns at the local and metapopulation scale using standard time series analysis and develop a simple population dynamic model, testing the hypothesis that both local and metapopulation scale feedback processes are important. We find little evidence of an interaction between scales in seagrass dynamics but that both scales contribute approximately equally to observed local epiphyte abundance. By quantifying the long-term dynamics of seagrass-epiphyte interactions we show how measures of density and extent are both important in establishing baseline information relevant to predicting responses to environmental change and developing management plans. We hope that this study complements existing mechanistic studies of physiology, genetics and productivity in seagrass, whilst highlighting the potential of seagrass as a model ecosystem. More generally, this study provides a rare opportunity to test some of the predictions of ecological theory in a natural ecosystem of global conservation and economic value. PMID- 23437314 TI - A novel selection marker for efficient DNA cloning and recombineering in E. coli. AB - Production of recombinant DNA in bacterial cells is an essential technique in molecular biology. Plasmids are usually maintained in an E. coli host by antibiotic selection. However, there are only a few antibiotic-resistance markers available in common use. Here we report the adoption of a novel selection marker, mfabI (mutant fabI) for plasmid propagation in E. coli. mfabI expands the limited repertoire of selection markers and allows for more efficient molecular manipulation and plasmid propagation in E. coli. We show that mfabI is not only an efficient plasmid selection marker, but it also possesses unique activity that may facilitate molecular manipulation of unstable sequences. Furthermore, we have incorporated mfabI in the recombineering tool kit for generating mouse gene targeting vectors and demonstrate the advantage of using mfabI-containing recombineering vectors. PMID- 23437315 TI - Prognostic value of contrast-enhanced cardiac magnetic resonance imaging in patients with newly diagnosed non-ischemic cardiomyopathy: cohort study. AB - BACKGROUND: Owing to its variable course from asymptomatic cases to sudden death risk stratification is of paramount importance in newly diagnosed non-ischemic cardiomyopathy. We tested whether late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance (CMR) imaging is a prognostic marker in consecutive patients with newly diagnosed non-ischemic cardiomyopathy. METHODS: We enrolled 185 patients who presented for evaluation of newly diagnosed non-ischemic cardiomyopathy. Coronary artery disease was excluded by coronary angiography. Following risk markers were additionally assessed: NYHA functional class (>=II), brain natriuretic peptide (>100 ng/l), troponin I (TnI, >=0.03 ug/l), left ventricular ejection fraction (LVEF, <=40%), left ventricular enddiastolic diameter (>55 mm) and QRS duration (>98 ms). Endpoint of the study was the composite of all-cause mortality, heart transplantation, aborted sudden death, sustained ventricular tachycardia or hospitalization due to decompensated heart failure within three years of follow-up. RESULTS: During median follow-up of 21 months, 54 patients (29.2%) reached the composite endpoint. Ninety-four of the 185 patients (50.8%) were judged LGE-positive. Prognosis of LGE-positive patients was significantly worse than that of LGE-negative patients (cumulative 3-year event rates of 67.4% in LGE-positive and 27.2% in LGE-negative patients, respectively; p = 0.021). However, in multivariable analysis, presence of LGE was not an independent predictor of outcome. Only LVEF <=40% and TnI >=0.03 ug/l were independent risk predictors of the composite endpoint yielding relative risks of 3.9 (95% CI 1.9-8.1; p<0.0001) and 2.2 (95% CI 1.2-4.0; p = 0.014), respectively. CONCLUSIONS: In consecutive patients presenting with newly diagnosed non-ischemic cardiomyopathy, LGE-positive patients had worse prognosis. However, only traditional risk parameters like left ventricular performance and cardiac biomarkers but not presence of LGE were independent risk predictors. PMID- 23437316 TI - A novel domain regulating degradation of the glomerular slit diaphragm protein podocin in cell culture systems. AB - Mutations in the gene NPHS2 are the most common cause of hereditary steroid resistant nephrotic syndrome. Its gene product, the stomatin family member protein podocin represents a core component of the slit diaphragm, a unique structure that bridges the space between adjacent podocyte foot processes in the kidney glomerulus. Dislocation and misexpression of slit diaphragm components have been described in the pathogenesis of acquired and hereditary nephrotic syndrome. However, little is known about mechanisms regulating cellular trafficking and turnover of podocin. Here, we discover a three amino acids comprising motif regulating intracellular localization of podocin in cell culture systems. Mutations of this motif led to markedly reduced degradation of podocin. These findings give novel insight into the molecular biology of the slit diaphragm protein podocin, enabling future research to establish the biological relevance of podocin turnover and localization. PMID- 23437317 TI - Role of IRAK-M in alcohol induced liver injury. AB - Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR) signaling pathways and interleukin receptor-associated kinase-M (IRAK-M) in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT), more immune cell infiltration and increased numbers of IFNgamma producing cells. We also found enhanced phagocytic activity in CD68(+) cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota. PMID- 23437319 TI - Cfr-mediated linezolid-resistance among methicillin-resistant coagulase-negative staphylococci from infections of humans. AB - Four methicillin-resistant coagulase-negative staphylococci (MRCoNS), one Staphylococcus haemolyticus and three Staphylococcus cohnii, from infections of humans collected via the Ministry of Health National Antimicrobial Resistance Surveillance Net (Mohnarin) program in China were identified as linezolid resistant. These four isolates were negative for the 23S rRNA mutations, but positive for the gene cfr. Mutations in the gene for the ribosomal protein L3, which resulted in the amino acid exchanges Gly152Asp and Tyr158Phe, were identified in S. haemolyticus 09D279 and S. cohnii NDM113, respectively. In each isolate, the cfr gene was located on a plasmid of ca. 35.4 kb, as shown by S1 nuclease pulsed-field gel electrophoresis and Southern blotting experiments. This plasmid was indistinguishable from the previously described plasmid pSS-02 by its size, restriction pattern, and a sequenced 14-kb cfr-carrying segment. Plasmid pSS-02 was originally identified in staphylococci isolated from pigs. This is the first time that a cfr-carrying plasmid has been detected in MRCoNS obtained from intensive care patients in China. Based on the similarities to the cfr-carrying plasmid pSS-02 from porcine coagulase-negative staphylococci, a transmission of this cfr-carrying plasmid between staphylococci from pigs and humans appears to be likely. PMID- 23437318 TI - Genotypic analysis of Klebsiella pneumoniae isolates in a Beijing Hospital reveals high genetic diversity and clonal population structure of drug-resistant isolates. AB - BACKGROUND: The genetic diversity and the clinical relevance of the drug resistant Klebsiella pneumoniae isolates from hospital settings are largely unknown. We thus conducted this prospective study to analyze the molecular epidemiology of K. pneumoniae isolates from patients being treated in the 306 Hospital in Beijing, China for the period of November 1, 2010-October 31, 2011. METHODOLOGY/PRINCIPAL FINDINGS: Antibiotic susceptibility testing, PCR amplification and sequencing of the drug resistance-associated genes, and multilocus sequence typing (MLST) were conducted. A total of 163 isolates were analyzed. The percentage of MDR, XDR and PDR isolates were 63.8% (104), 20.9 (34), and 1.8% (3), respectively. MLST results showed that 60 sequence types (STs) were identified, which were further separated by eBURST into 13 clonal complexes and 18 singletons. The most dominant ST was ST15 (10.4%). Seven new alleles and 24 new STs were first identified in this study. Multiple logistic regression analysis revealed that certain clinical characteristics were associated with those prevalent STs such as: from ICU, from medical ward, from community acquired infection, from patients without heart disease, from patients with treatment success, susceptible to extended spectrum cephalosporin, susceptible to cephamycins, susceptible to fluoroquinolones, and with MDR. CONCLUSIONS/SIGNIFICANCE: Our data indicate that certain drug-resistant K. pneumoniae clones are highly prevalent and are associated with certain clinical characteristics in hospital settings. Our study provides evidence demonstrating that intensive nosocomial infection control measures are urgently needed. PMID- 23437320 TI - A small molecule (pluripotin) as a tool for studying cancer stem cell biology: proof of concept. AB - BACKGROUND: Cancer stem cells (CSC) are thought to be responsible for tumor maintenance and heterogeneity. Bona fide CSC purified from tumor biopsies are limited in supply and this hampers study of CSC biology. Furthermore, purified stem-like CSC subpopulations from existing tumor lines are unstable in culture. Finding a means to overcome these technical challenges would be a useful goal. In a first effort towards this, we examined whether a chemical probe that promotes survival of murine embryonic stem cells without added exogenous factors can alter functional characteristics in extant tumor lines in a fashion consistent with a CSC phenotype. METHODOLOGY/PRINCIPAL FINDINGS: The seven tumor lines of the NCI60 colon subpanel were exposed to SC-1 (pluripotin), a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. A statistically significant increase in tumor formation following SC-1 treatment was observed (p<0.04). Cloning efficiencies and expression of putative CSC surface antigens (CD133 and CD44) were also increased. SC-1 treatment led to sphere formation in some colon tumor lines. Finally, SC-1 inhibited in vitro kinase activity of RSK2, and another RSK2 inhibitor increased colony formation implicating a role for this kinase in eliciting a CSC phenotype. CONCLUSIONS/SIGNIFICANCE: These findings validate a proof of concept study exposure of extant tumor lines to a small molecule may provide a tractable in vitro model for understanding CSC biology. PMID- 23437321 TI - The role of community mixing styles in shaping epidemic behaviors in weighted networks. AB - The dynamics of infectious diseases that are spread through direct contact have been proven to depend on the strength of community structure or modularity within the underlying network. It has been recently shown that weighted networks with similar modularity values may exhibit different mixing styles regarding the number of connections among communities and their respective weights. However, the effect of mixing style on epidemic behavior was still unclear. In this paper, we simulate the spread of disease within networks with different mixing styles: a dense-weak style (i.e., many edges among the communities with small weights) and a sparse-strong style (i.e., a few edges among the communities with large weights). Simulation results show that, with the same modularity: 1) the mixing style significantly influences the epidemic size, speed, pattern and immunization strategy; 2) the increase of the number of communities amplifies the effect of the mixing style; 3) when the mixing style changes from sparse-strong to dense weak, there is a 'saturation point', after which the epidemic size and pattern become stable. We also provide a mean-field solution of the epidemic threshold and size on weighted community networks with arbitrary external and internal degree distribution. The solution explains the effect of the second moment of the degree distribution, and a symmetric effect of internal and external connections (incl. degree distribution and weight). Our study has both potential significance for designing more accurate metrics for the community structure and exploring diffusion dynamics on metapopulation networks. PMID- 23437322 TI - Climate-induced elevational range shifts and increase in plant species richness in a Himalayan biodiversity epicentre. AB - Global average temperature increase during the last century has induced species geographic range shifts and extinctions. Montane floras, in particular, are highly sensitive to climate change and mountains serve as suitable observation sites for tracing climate-induced biological response. The Himalaya constitute an important global biodiversity hotspot, yet studies on species' response to climate change from this region are lacking. Here we use historical (1849-50) and the recent (2007-2010) data on temperature and endemic species' elevational ranges to perform a correlative study in the two alpine valleys of Sikkim. We show that the ongoing warming in the alpine Sikkim Himalaya has transformed the plant assemblages. This study lends support to the hypothesis that changing climate is causing species distribution changes. We provide first evidence of warmer winters in the region compared to the last two centuries, with mean temperatures of the warmest and the coldest months may have increased by 0.76+/ 0.25 degrees C and 3.65+/-2 degrees C, respectively. Warming-driven geographical range shifts were recorded in 87% of 124 endemic plant species studied in the region; upper range extensions of species have resulted in increased species richness in the upper alpine zone, compared to the 19(th) century. We recorded a shift of 23-998 m in species' upper elevation limit and a mean upward displacement rate of 27.53+/-22.04 m/decade in the present study. We infer that the present-day plant assemblages and community structure in the Himalaya is substantially different from the last century and is, therefore, in a state of flux under the impact of warming. The continued trend of warming is likely to result in ongoing elevational range contractions and eventually, species extinctions, particularly at mountaintops. PMID- 23437323 TI - The relationship between national-level carbon dioxide emissions and population size: an assessment of regional and temporal variation, 1960-2005. AB - This study examines the regional and temporal differences in the statistical relationship between national-level carbon dioxide emissions and national-level population size. The authors analyze panel data from 1960 to 2005 for a diverse sample of nations, and employ descriptive statistics and rigorous panel regression modeling techniques. Initial descriptive analyses indicate that all regions experienced overall increases in carbon emissions and population size during the 45-year period of investigation, but with notable differences. For carbon emissions, the sample of countries in Asia experienced the largest percent increase, followed by countries in Latin America, Africa, and lastly the sample of relatively affluent countries in Europe, North America, and Oceania combined. For population size, the sample of countries in Africa experienced the largest percent increase, followed countries in Latin America, Asia, and the combined sample of countries in Europe, North America, and Oceania. Findings for two-way fixed effects panel regression elasticity models of national-level carbon emissions indicate that the estimated elasticity coefficient for population size is much smaller for nations in Africa than for nations in other regions of the world. Regarding potential temporal changes, from 1960 to 2005 the estimated elasticity coefficient for population size decreased by 25% for the sample of Africa countries, 14% for the sample of Asia countries, 6.5% for the sample of Latin America countries, but remained the same in size for the sample of countries in Europe, North America, and Oceania. Overall, while population size continues to be the primary driver of total national-level anthropogenic carbon dioxide emissions, the findings for this study highlight the need for future research and policies to recognize that the actual impacts of population size on national-level carbon emissions differ across both time and region. PMID- 23437324 TI - The effects of employment conditions on smoking status and smoking intensity: the analysis of Korean labor & income panel 8(th)-10(th) wave. AB - BACKGROUND: The neoliberal policies and its socioeconomic consequences in Korea have made employment conditions insecure and affected employees' health as well. METHODS AND FINDINGS: To examine the association between employment condition and smoking status, we selected male respondents aged 20-59 that participated in all of the 8(th)-10(th) wave of Korean Labor and Income Panel Study(KLIPS) which is a nationally representative data. Precarious working was significantly associated with smoking compared to standard working even after adjusting for socioeconomic indicators and self rated health status. After controlling for overall life satisfaction, the odds ratio of smoking among precarious workers decreased, but it was still marginally significant (OR = 1.43, 95% CI = 0.99 to 2.07). A relation between precarious working and heavy smoking was also significant. Precarious working was associated with a decreased likelihood of quitting smoking, while it was not significant any more after adjusting for overall satisfaction on life. Precarious work was also related to a higher likelihood of relapse among former smokers, but was not significant after adjusting for other confounders. CONCLUSIONS: Precarious workers were more likely to be smokers and heavy smokers than standard workers. Unemployment is also a significant risk factor for decreased quitting and smoking relapse. However, insecure employment was an even more consistent determinant of current smoking behavior than unemployment. PMID- 23437325 TI - An extract of Artemisia dracunculus L. inhibits ubiquitin-proteasome activity and preserves skeletal muscle mass in a murine model of diabetes. AB - Impaired insulin signaling is a key feature of type 2 diabetes and is associated with increased ubiquitin-proteasome-dependent protein degradation in skeletal muscle. An extract of Artemisia dracunculus L. (termed PMI5011) improves insulin action by increasing insulin signaling in skeletal muscle. We sought to determine if the effect of PMI5011 on insulin signaling extends to regulation of the ubiquitin-proteasome system. C2C12 myotubes and the KK-A(y) murine model of type 2 diabetes were used to evaluate the effect of PMI5011 on steady-state levels of ubiquitylation, proteasome activity and expression of Atrogin-1 and MuRF-1, muscle-specific ubiquitin ligases that are upregulated with impaired insulin signaling. Our results show that PMI5011 inhibits proteasome activity and steady state ubiquitylation levels in vitro and in vivo. The effect of PMI5011 is mediated by PI3K/Akt signaling and correlates with decreased expression of Atrogin-1 and MuRF-1. Under in vitro conditions of hormonal or fatty acid-induced insulin resistance, PMI5011 improves insulin signaling and reduces Atrogin-1 and MuRF-1 protein levels. In the KK-A(y) murine model of type 2 diabetes, skeletal muscle ubiquitylation and proteasome activity is inhibited and Atrogin-1 and MuRF 1 expression is decreased by PMI5011. PMI5011-mediated changes in the ubiquitin proteasome system in vivo correlate with increased phosphorylation of Akt and FoxO3a and increased myofiber size. The changes in Atrogin-1 and MuRF-1 expression, ubiquitin-proteasome activity and myofiber size modulated by PMI5011 in the presence of insulin resistance indicate the botanical extract PMI5011 may have therapeutic potential in the preservation of muscle mass in type 2 diabetes. PMID- 23437326 TI - Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. In patients with colon cancer, MDSCs have recently been described as Lin(-/low)HLA-DR( )CD11b(+)CD33(+) cells correlating with cancer stage, metastasis and chemotherapy response. To learn in more detail the dynamic change and clinical relevance of circulating and tumor-infiltrating Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSC in colorectal cancer, we harvested the blood from 64 patients with varying stage of colorectal cancer and tumor and matched paraneoplastic tissues from 5 patients with advanced colorectal cancer, subjected them to multicolor flow cytometric analysis of percentage, absolute number and phenotype of MDSC and finally characterized their immunosuppressive functions. Our results demonstrate that peripheral blood from colorectal cancer patients contains markedly increased percentage and absolute number of Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSCs compared with healthy individuals, and this increase is closely correlated with clinical cancer stage and tumor metastasis but not primary tumor size and serum concentrations of cancer biomarker. A similar increase of MDSCs was also observed in the tumor tissues. Phenotyping MDSCs shows that they express high CD13 and CD39, low CD115, CD117, CD124 and PD-L1, and devoid of CD14, CD15 and CD66b, reminiscent of precursor myeloid cells. MDSCs from cancer patients but not healthy donors have the immunosuppressive activity and were able to inhibit in vitro autologous T-cell proliferation. Collectively, this study substantiates the presence of increased immunosuppressive circulating and tumor-resident Lin( /low)HLA-DR(-)CD11b(+)CD33(+) MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis, and suggests that pharmacologic blockade of MDSCs should be considered in future clinical trials. PMID- 23437327 TI - Depression-like responses induced by daytime light deficiency in the diurnal grass rat (Arvicanthis niloticus). AB - Seasonal Affective Disorder (SAD) is one of the most common mood disorders with depressive symptoms recurring in winter when there is less sunlight. The fact that light is the most salient factor entraining circadian rhythms leads to the phase-shifting hypothesis, which suggests that the depressive episodes of SAD are caused by misalignments between the circadian rhythms and the habitual sleep times. However, how changes in environmental lighting conditions lead to the fluctuations in mood is largely unknown. The objective of this study is to develop an animal model for some of the features/symptoms of SAD using the diurnal grass rats Arvichantis niloticus and to explore the neural mechanisms underlying the light associated mood changes. Animals were housed in either a 12?12 hr bright light?dark (1000lux, BLD) or dim light?dark (50lux, DLD) condition. The depression-like behaviors were assessed by sweet-taste Saccharin solution preference (SSP) and forced swimming test (FST). Animals in the DLD group showed higher levels of depression-like behaviors compared to those in BLD. The anxiety-like behaviors were assessed in open field and light/dark box test, however no significant differences were observed between the two groups. The involvement of the circadian system on depression-like behaviors was investigated as well. Analysis of locomotor activity revealed no major differences in daily rhythms that could possibly contribute to the depression-like behaviors. To explore the neural substrates associated with the depression-like behaviors, the brain tissues from these animals were analyzed using immunocytochemistry. Attenuated indices of 5-HT signaling were observed in DLD compared to the BLD group. The results lay the groundwork for establishing a novel animal model and a novel experimental paradigm for SAD. The results also provide insights into the neural mechanisms underlying light-dependent mood changes. PMID- 23437328 TI - Daily evolution of insulin sensitivity variability with respect to diagnosis in the critically ill. AB - INTRODUCTION: This study examines the likelihood and evolution of overall and hypoglycemia-inducing variability of insulin sensitivity in ICU patients based on diagnosis and day of stay. MATERIALS AND METHODS: An analysis of model-based insulin sensitivity for n=390 patients in a medical ICU (Christchurch, New Zealand). Two metrics are defined to measure the variability of a patient's insulin sensitivity relative to predictions of a stochastic model created from the same data for all patients over all days of stay. The first selectively captures large increases related to the risk of hypoglycemia. The second captures overall variability. Distributions of per-patient variability scores were evaluated over different ICU days of stay and for different diagnosis groups based on APACHE III: operative and non-operative cardiac, gastric, all other. Linear and generalized linear mixed effects models assess the statistical significance of differences between groups and over days. RESULTS: Variability defined by the two metrics was not substantially different. Variability was highest on day 1, and decreased over time (p<0.0001) in every diagnosis group. There were significant differences between some diagnosis groups: non-operative gastric patients were the least variable, while cardiac (operative and non operative) patients exhibited the highest variability. CONCLUSIONS: This study characterizes the variability and evolution of insulin sensitivity in critically ill patients, and may help inform the clinical management of metabolic dysfunction in critical care. PMID- 23437329 TI - Idiopathic orbital inflammation syndrome with retro-orbital involvement: a retrospective study of eight patients. AB - BACKGROUND: The aim of this retrospective study was to document the clinical findings and radiological features of idiopathic orbital inflammation syndrome with retro-orbital involvement. METHODS: We searched for ophthalmological patients who received orbital imaging at Zhejiang Provincial People's Hospital between October 2003 and April 2010. Seventy-three patients were diagnosed with idiopathic orbital inflammation syndrome based on clinicoradiological features, with pathological confirmation of nonspecific inflammatory conditions in 47 patients. Eight patients (11%) had MRI or CT evidence of retro-orbital involvement. All 8 patients were diagnosed with idiopathic orbital inflammation syndrome after biopsy of the orbital lesion. MR images were obtained for all 8 patients; 3 patients also had a contrast-enhanced CT scan. RESULTS: Seven out of 8 patients with retro-orbital involvement also had orbital apex lesions. Of the 65 patients without retro-orbital involvement, 19 had orbital apex lesions. The difference in the number of patients with orbital apex lesions between the two populations was significant (Fisher exact test P = .002). In all 8 patients with retro-orbital involvement, the inflammation spread through the superior orbital fissure. The retro-orbital lesions were isointense to grey matter on T1-weighted images, hypointense on T2-weighted images, and displayed uniform contrast enhancement; on contrast-enhanced CT scans, they were hyperdense relative to the contralateral mirror area and had radiological contours that were similar to those seen on MR images. The diffuse inflammation with marked sclerosis and hyalinization that we observed in the patients with retro-orbital involvement is consistent with the diagnosis of the sclerosing subtype of idiopathic orbital inflammation syndrome. All 8 patients also complained of mild to moderate periorbital pain (headache). CONCLUSIONS: In patients with idiopathic orbital inflammation syndrome, it is important to perform MRI and CT scans to identify possible retro-orbital involvement. Retro-orbital involvement is more frequent when the lesion is present in the orbital apex. PMID- 23437330 TI - Ten-a affects the fusion of central complex primordia in Drosophila. AB - The central complex of Drosophila melanogaster plays important functions in various behaviors, such as visual and olfactory memory, visual orientation, sleep, and movement control. However little is known about the genes regulating the development of the central complex. Here we report that a mutant gene affecting central complex morphology, cbd (central brain defect), was mapped to ten-a, a type II trans-membrane protein coding gene. Down-regulation of ten-a in pan-neural cells contributed to abnormal morphology of central complex. Over expression of ten-a by C767-Gal4 was able to partially restore the abnormal central complex morphology in the cbd mutant. Tracking the development of FB primordia revealed that C767-Gal4 labeled interhemispheric junction that separated fan-shaped body precursors at larval stage withdrew to allow the fusion of the precursors. While the C767-Gal4 labeled structure did not withdraw properly and detached from FB primordia, the two fan-shaped body precursors failed to fuse in the cbd mutant. We propose that the withdrawal of C767-Gal4 labeled structure is related to the formation of the fan-shaped body. Our result revealed the function of ten-a in central brain development, and possible cellular mechanism underlying Drosophila fan-shaped body formation. PMID- 23437331 TI - p62/SQSTM1 enhances NOD2-mediated signaling and cytokine production through stabilizing NOD2 oligomerization. AB - NOD2 is a cytosolic pattern-recognition receptor that senses muramyl dipeptide of peptidoglycan that constitutes the bacterial cell wall, and plays an important role in maintaining immunological homeostasis in the intestine. To date, multiple molecules have shown to be involved in regulating NOD2 signaling cascades. p62 (sequestosome-1; SQSTM1) is a multifaceted scaffolding protein involved in trafficking molecules to autophagy, and regulating signal cascades activated by Toll-like receptors, inflammasomes and several cytokine receptors. Here, we show that p62 positively regulates NOD2-induced NF-kappaB activation and p38 MAPK, and subsequent production of cytokines IL-1beta and TNF-alpha. p62 associated with the nucleotide binding domain of NOD2 through a bi-directional interaction mediated by either TRAF6-binding or ubiquitin-associated domains. NOD2 formed a large complex with p62 in an electron-dense area of the cytoplasm, which increased its signaling cascade likely through preventing its degradation. This study for the first time demonstrates a novel role of p62 in enhancing NOD2 signaling effects. PMID- 23437332 TI - Dendritic polyglycerolsulfate near infrared fluorescent (NIRF) dye conjugate for non-invasively monitoring of inflammation in an allergic asthma mouse model. AB - BACKGROUND: Non-invasive in vivo imaging strategies are of high demand for longitudinal monitoring of inflammation during disease progression. In this study we present an imaging approach using near infrared fluorescence (NIRF) imaging in combination with a polyanionic macromolecular conjugate as a dedicated probe, known to target L- and P-selectin and C3/C5 complement factors. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the suitability of dendritic polyglycerol sulfates (dPGS), conjugated with a hydrophilic version of the indocyanine green label with 6 sulfonate groups (6S-ICG) to monitor sites of inflammation using an experimental mouse model of allergic asthma. Accumulation of the NIRF-conjugated dPGS (dPGS-NIRF) in the inflamed lungs was analyzed in and ex vivo in comparison with the free NIRF dye using optical imaging. Commercially available smart probes activated by matrix metalloproteinase's (MMP) and cathepsins were used as a comparative control. The fluorescence intensity ratio between lung areas of asthmatic and healthy mice was four times higher for the dPGS in comparison to the free dye in vivo at four hrs post intravenous administration. No significant difference in fluorescence intensity between healthy and asthmatic mice was observed 24 hrs post injection for dPGS-NIRF. At this time point ex-vivo scans of asthmatic mice confirmed that the fluorescence within the lungs was reduced to approximately 30% of the intensity observed at 4 hrs post injection. CONCLUSIONS/SIGNIFICANCE: Compared with smart-probes resulting in a high fluorescence level at 24 hrs post injection optical imaging with dPGS-NIRF conjugates is characterized by fast uptake of the probe at inflammatory sites and represents a novel approach to monitor lung inflammation as demonstrated in mice with allergic asthma. PMID- 23437335 TI - Disturbance driven colony fragmentation as a driver of a coral disease outbreak. AB - In September of 2010, Brewer's Bay reef, located in St. Thomas (U.S. Virgin Islands), was simultaneously affected by abnormally high temperatures and the passage of a hurricane that resulted in the mass bleaching and fragmentation of its coral community. An outbreak of a rapid tissue loss disease among coral colonies was associated with these two disturbances. Gross lesion signs and lesion progression rates indicated that the disease was most similar to the Caribbean coral disease white plague type 1. Experiments indicated that the disease was transmissible through direct contact between colonies, and five-meter radial transects showed a clustered spatial distribution of disease, with diseased colonies being concentrated within the first meter of other diseased colonies. Disease prevalence and the extent to which colonies were bleached were both significantly higher on unattached colony fragments than on attached colonies, and disease occurred primarily on fragments found in direct contact with sediment. In contrast to other recent studies, disease presence was not related to the extent of bleaching on colonies. The results of this study suggest that colony fragmentation and contact with sediment played primary roles in the initial appearance of disease, but that the disease was capable of spreading among colonies, which suggests secondary transmission is possible through some other, unidentified mechanism. PMID- 23437334 TI - Is drug treatment for dementia followed up in primary care? A Swedish study of dementia clinics and referring primary care centres. AB - PURPOSE: It is largely unknown how the medical treatment of patients diagnosed with dementia is followed up in primary care. Therefore, we studied patient medical records from two dementia clinics and from the referring primary care centres. METHODS: A retrospective study of 241 patients was conducted from April to October 2011 in north west Stockholm, Sweden. Over half (51.5%) of the patients had Alzheimer's disease (AD), the remainder had mixed AD/vascular dementia (VaD). Eighty-four medical reports from primary care (35% of the study group) were analysed at follow-up 18 months after diagnosis. RESULTS: All four dementia drugs available on the Swedish market (three cholinesterase inhibitors [donepezil, rivastigmine and galantamine] and memantine) were prescribed at the two dementia clinics. The most commonly used dementia drug was galantamine. There were differences between the two dementia clinics in preference and combination of drugs and of treatment given to male and female patients. At follow-up, 84% were still on dementia medication. Drug use was followed up by the general practitioners (GPs) in two-thirds of the cases. Eighteen per cent of the GPs' medical records made no reference to the patient's dementia or treatment even though dementia drugs were included in the list of medications prescribed. CONCLUSIONS: The results indicate that the Swedish guidelines for treatment of cognitive symptoms in AD are being followed in primary care. However, documentation of follow-up of drug treatment was sometimes insufficient, which calls for development of guidelines for complete medical records and medication lists. PMID- 23437333 TI - Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS. AB - Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1 GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS. PMID- 23437336 TI - The impact of environmental heterogeneity and life stage on the hindgut microbiota of Holotrichia parallela larvae (Coleoptera: Scarabaeidae). AB - Gut microbiota has diverse ecological and evolutionary effects on its hosts. However, the ways in which it responds to environmental heterogeneity and host physiology remain poorly understood. To this end, we surveyed intestinal microbiota of Holotrichia parallela larvae at different instars and from different geographic regions. Bacterial 16S rRNA gene clone libraries were constructed and clones were subsequently screened by DGGE and sequenced. Firmicutes and Proteobacteria were the major phyla, and bacteria belonging to Ruminococcaceae, Lachnospiraceae, Enterobacteriaceae, Desulfovibrionaceae and Rhodocyclaceae families were commonly found in all natural populations. However, bacterial diversity (Chao1 and Shannon indices) and community structure varied across host populations, and the observed variation can be explained by soil pH, organic carbon and total nitrogen, and the climate factors (e.g., mean annual temperature) of the locations where the populations were sampled. Furthermore, increases in the species richness and diversity of gut microbiota were observed during larval growth. Bacteroidetes comprised the dominant group in the first instar; however, Firmicutes composed the majority of the hindgut microbiota during the second and third instars. Our results suggest that the gut's bacterial community changes in response to environmental heterogeneity and host's physiology, possibly to meet the host's ecological needs or physiological demands. PMID- 23437337 TI - General patterns of diversity in major marine microeukaryote lineages. AB - Microeukaryotes have vital roles for the functioning of marine ecosystems, but still some general characteristics of their current diversity and phylogeny remain unclear. Here we investigated both aspects in major oceanic microeukaryote lineages using 18S rDNA (V4-V5 hypervariable regions) sequences from public databases that derive from various marine environmental surveys. A very carefully and manually curated dataset of 8291 Sanger sequences was generated and subsequently split into 65 taxonomic groups (roughly to Class level based on KeyDNATools) prior to downstream analyses. First, we calculated genetic distances and clustered sequences into Operational Taxonomic Units (OTUs) using different distance cut-off levels. We found that most taxonomic groups had a maximum pairwise genetic distance of 0.25. Second, we used phylogenetic trees to study general evolutionary patterns. These trees confirmed our taxonomic classification and served to run Lineage Through Time (LTT) plots. LTT results indicated different cladogenesis dynamics across groups, with some displaying an early diversification and others a more recent one. Overall, our study provides an improved description of the microeukaryote diversity in the oceans in terms of genetic differentiation within groups as well as in the general phylogenetic structure. These results will be important to interpret the large amount of sequence data that is currently generated by High Throughput Sequencing technologies. PMID- 23437338 TI - Estimating the intended sound direction of the user: toward an auditory brain computer interface using out-of-head sound localization. AB - The auditory Brain-Computer Interface (BCI) using electroencephalograms (EEG) is a subject of intensive study. As a cue, auditory BCIs can deal with many of the characteristics of stimuli such as tone, pitch, and voices. Spatial information on auditory stimuli also provides useful information for a BCI. However, in a portable system, virtual auditory stimuli have to be presented spatially through earphones or headphones, instead of loudspeakers. We investigated the possibility of an auditory BCI using the out-of-head sound localization technique, which enables us to present virtual auditory stimuli to users from any direction, through earphones. The feasibility of a BCI using this technique was evaluated in an EEG oddball experiment and offline analysis. A virtual auditory stimulus was presented to the subject from one of six directions. Using a support vector machine, we were able to classify whether the subject attended the direction of a presented stimulus from EEG signals. The mean accuracy across subjects was 70.0% in the single-trial classification. When we used trial-averaged EEG signals as inputs to the classifier, the mean accuracy across seven subjects reached 89.5% (for 10-trial averaging). Further analysis showed that the P300 event-related potential responses from 200 to 500 ms in central and posterior regions of the brain contributed to the classification. In comparison with the results obtained from a loudspeaker experiment, we confirmed that stimulus presentation by out-of head sound localization achieved similar event-related potential responses and classification performances. These results suggest that out-of-head sound localization enables us to provide a high-performance and loudspeaker-less portable BCI system. PMID- 23437339 TI - Preliminary study on the effectiveness of short group cognitive behavioral therapy (GCBT) on Indonesian older adults. AB - This research aims to develop evidence based affordable psychological therapy for Indonesian older adults. An affordable psychological therapy is important as there is virtually no managed care or health insurance that covers psychological therapy in Indonesia. Multicomponent group cognitive behavior therapy (GCBGT) was chosen as a starting point due to its extensive evidence, short sessions, and success for a wide range of psychological problems. The group format was chosen to address both the economic and the cultural context of Indonesia. Then, the developed treatment is tested to common psychological problems in older adults' population (anxiety, chronic pain, depression, and insomnia). The treatment consists of 8 sessions with twice a week meetings for 2.5 hours. There are similarities and differences among the techniques used in the treatment for the different psychological problems. The final participants are 38 older adults that are divided into the treatment groups; 8 participants joined the anxiety treatment, 10 participants for the chronic pain treatment, 10 participants for depression treatment, and lastly, 10 participants joined the insomnia treatment. The research design is pre-test post-test with within group analysis. We used principal outcome measure that is specific for each treatment group, as well as additional outcome measures. Overall, the result shows statistical significance change with large effect size for the principal outcome measure. In addition, the result for the additional measures varies from slight improvement with small effect size to statistically significant improvement with large effect size. The result indicates that short multicomponent GCBT is effective in alleviating various common psychological problems in Indonesian older adults. Therefore, multicomponent GCBT may be a good starting point to develop an effective and affordable psychological therapy for Indonesian older adults. Lastly, this result adds to the accumulating body of evidence on the effectiveness of multicomponent GCBT outside western context. PMID- 23437340 TI - Possible association between suicide committed under influence of ethanol and a variant in the AUTS2 gene. AB - BACKGROUND: rs6943555 in AUTS2 has been shown to modulate ethanol consumption. We hypothesized that rs6943555 might be associated with completed suicide. METHODS: We genotyped rs6943555 in 625 completed suicides and 3861 controls using real time TaqMan Allelic Discrimination Assay. All individuals were Polish Caucasians. RESULTS: We detected an association between suicide and rs6943555 A allele (OR = 1.17, P = 0.018 for allelic comparison, OR = 1.24, P = 0.013 for dominant, and OR = 1.18, P = 0.020 for co-dominant model of inheritance). The association remained significant after adjusting for age and gender (co-dominant: P = 0.002 and dominant model: P = 0.001). After stratifying suicides according to blood ethanol concentration (BAC<= 20 mg/dl and BAC > 20 mg/dl) the association remained significant only for cases who committed suicide under influence of alcohol (co dominant: OR = 1.37, P = 0.004 and dominant model: OR = 1.45, P = 0.006). To validate this finding we genotyped another cohort of 132 cases. We reproduced the association between rs6943555 A allele and suicide under influence of ethanol (allelic comparison: OR = 1.55, P = 0.023; co-dominant : OR = 1.54, P = 0.031; dominant model: OR = 1.84, P = 0.015). Analyzing pooled suicides with BAC >20 mg/dl (N = 300) we found the association of rs6943555 A allele not only vs. controls (allelic OR = 1.41, P = 0.00029) but also vs. cases with BAC <= 20 mg/dl (N = 449, allelic OR = 1.33, P = 0.019). CONCLUSIONS: In our study rs6943555 A allele is associated with suicide committed after drinking ethanol shortly before death. The rs6943555 A allele may be linked to adverse emotional reaction to ethanol, which could explain the association with lower consumption in general population as well as the predisposition to suicide under influence of ethanol. PMID- 23437341 TI - Metropolitan social environments and pre-HAART/HAART era changes in mortality rates (per 10,000 adult residents) among injection drug users living with AIDS. AB - BACKGROUND: Among the largest US metropolitan areas, trends in mortality rates for injection drug users (IDUs) with AIDS vary substantially. Ecosocial, risk environment and dialectical theories suggest many metropolitan areas characteristics that might drive this variation. We assess metropolitan area characteristics associated with decline in mortality rates among IDUs living with AIDS (per 10,000 adult MSA residents) after highly active antiretroviral therapy (HAART) was developed. METHODS: This is an ecological cohort study of 86 large US metropolitan areas from 1993-2006. The proportional rate of decline in mortality among IDUs diagnosed with AIDS (as a proportion of adult residents) from 1993 1995 to 2004-2006 was the outcome of interest. This rate of decline was modeled as a function of MSA-level variables suggested by ecosocial, risk environment and dialectical theories. In multiple regression analyses, we used 1993-1995 mortality rates to (partially) control for pre-HAART epidemic history and study how other independent variables affected the outcomes. RESULTS: In multivariable models, pre-HAART to HAART era increases in 'hard drug' arrest rates and higher pre-HAART income inequality were associated with lower relative declines in mortality rates. Pre-HAART per capita health expenditure and drug abuse treatment rates, and pre- to HAART-era increases in HIV counseling and testing rates, were weakly associated with greater decline in AIDS mortality. CONCLUSIONS: Mortality among IDUs living with AIDS might be decreased by reducing metropolitan income inequality, increasing public health expenditures, and perhaps increasing drug abuse treatment and HIV testing services. Given prior evidence that drug-related arrest rates are associated with higher HIV prevalence rates among IDUs and do not seem to decrease IDU population prevalence, changes in laws and policing practices to reduce such arrests while still protecting public order should be considered. PMID- 23437343 TI - Audience design through social interaction during group discussion. AB - This paper contrasts two accounts of audience design during multiparty communication: audience design as a strategic individual-level message adjustment or as a non-strategic interaction-level message adjustment. Using a non interactive communication task, Experiment 1 showed that people distinguish between messages designed for oneself and messages designed for another person; consistent with strategic message design, messages designed for another person/s were longer (number of words) than those designed for oneself. However, audience size did not affect message length (messages designed for different sized audiences were similar in length). Using an interactive communication task Experiment 2 showed that as group size increased so too did communicative effort (number of words exchanged between interlocutors). Consistent with a non strategic account, as group members were added more social interaction was necessary to coordinate the group's collective situation model. Experiment 3 validates and extends the production measures used in Experiment 1 and 2 using a comprehension task. Taken together, our results indicate that audience design arises as a non-strategic outcome of social interaction during group discussion. PMID- 23437342 TI - Integration of HPV6 and downregulation of AKR1C3 expression mark malignant transformation in a patient with juvenile-onset laryngeal papillomatosis. AB - Juvenile-onset recurrent respiratory papillomatosis (RRP) is associated with low risk human papillomavirus (HPV) types 6 and 11. Malignant transformation has been reported solely for HPV11-associated RRP in 2-4% of all RRP-cases, but not for HPV6. The molecular mechanisms in the carcinogenesis of low risk HPV-associated cancers are to date unknown. We report of a female patient, who presented with a laryngeal carcinoma at the age of 24 years. She had a history of juvenile-onset RRP with an onset at the age of three and subsequently several hundred surgical interventions due to multiple recurrences of RRP. Polymerase chain reaction (PCR) or bead-based hybridization followed by direct sequencing identified HPV6 in tissue sections of previous papilloma and the carcinoma. P16(INK4A), p53 and pRb immunostainings were negative in all lesions. HPV6 specific fluorescence in situ hybridization (FISH) revealed nuclear staining suggesting episomal virus in the papilloma and a single integration site in the carcinoma. Integration-specific amplification of papillomavirus oncogene transcripts PCR (APOT-PCR) showed integration in the aldo-keto reductase 1C3 gene (AKR1C3) on chromosome 10p15.1. ArrayCGH detected loss of the other gene copy as part of a deletion at 10p14 p15.2. Western blot analysis and immunohistochemistry of the protein AKR1C3 showed a marked reduction of its expression in the carcinoma. In conclusion, we identified a novel molecular mechanism underlying a first case of HPV6-associated laryngeal carcinoma in juvenile-onset RRP, i.e. that HPV6 integration in the AKR1C3 gene resulted in loss of its expression. Alterations of AKR1C gene expression have previously been implicated in the tumorigenesis of other (HPV related) malignancies. PMID- 23437344 TI - SNPs identified as modulators of ECG traits in the general population do not markedly affect ECG traits during acute myocardial infarction nor ventricular fibrillation risk in this condition. AB - BACKGROUND: Ventricular fibrillation (VF) in the setting of acute ST elevation myocardial infarction (STEMI) is a leading cause of mortality. Although the risk of VF has a genetic component, the underlying genetic factors are largely unknown. Since heart rate and ECG intervals of conduction and repolarization during acute STEMI differ between patients who do and patients who do not develop VF, we investigated whether SNPs known to modulate these ECG indices in the general population also impact on the respective ECG indices during STEMI and on the risk of VF. METHODS AND RESULTS: The study population consisted of participants of the Arrhythmia Genetics in the NEtherlandS (AGNES) study, which enrols patients with a first STEMI that develop VF (cases) and patients that do not develop VF (controls). SNPs known to impact on RR interval, PR interval, QRS duration or QTc interval in the general population were tested for effects on the respective STEMI ECG indices (stage 1). Only those showing a (suggestive) significant association were tested for association with VF (stage 2). On average, VF cases had a shorter RR and a longer QTc interval compared to non-VF controls. Eight SNPs showed a trend for association with the respective STEMI ECG indices. Of these, three were also suggestively associated with VF. CONCLUSIONS: RR interval and ECG indices of conduction and repolarization during acute STEMI differ between patients who develop VF and patients who do not. Although the effects of the SNPs on ECG indices during an acute STEMI seem to be similar in magnitude and direction as those found in the general population, the effects, at least in isolation, are too small to explain the differences in ECGs between cases and controls and to determine risk of VF. PMID- 23437345 TI - 6-Gingerol inhibits hair shaft growth in cultured human hair follicles and modulates hair growth in mice. AB - Ginger (Zingiber officinale) has been traditionally used to check hair loss and stimulate hair growth in East Asia. Several companies produce shampoo containing an extract of ginger claimed to have anti-hair loss and hair growth promotion properties. However, there is no scientific evidence to back up these claims. This study was undertaken to measure 6-gingerol, the main active component of ginger, on hair shaft elongation in vitro and hair growth in vivo, and to investigate its effect on human dermal papilla cells (DPCs) in vivo and in vitro. 6-Gingerol suppressed hair growth in hair follicles in culture and the proliferation of cultured DPCs. The growth inhibition of DPCs by 6-gingerol in vitro may reflect a decrease in the Bcl-2/Bax ratio. Similar results were obtained in vivo. The results of this study showed that 6-gingerol does not have the ability to promote hair growth, on the contrary, can suppress human hair growth via its inhibitory and pro-apoptotic effects on DPCs in vitro, and can cause prolongation of telogen phase in vivo. Thus, 6-gingerol rather than being a hair growth stimulating drug, it is a potential hair growth suppressive drug; i.e. for hair removal. PMID- 23437346 TI - Role of CX3CR1 receptor in monocyte/macrophage driven neovascularization. AB - Monocyte/macrophages are implicated in initiation of angiogenesis, tissue/organ perfusion and atherosclerosis biology. We recently showed that chemokine receptor CX(3)CR1 is an essential regulator of monocyte/macrophage derived smooth muscle cell differentiation in the vessel wall after injury. Here we hypothesised the contribution of CX(3)CR1- CX(3)CL1 interaction to in vivo neovascularization and studied the functional consequences of genetic and pharmacologic targeting of CX(3)CR1 in formation, maturation and maintenance of microvascular integrity. Cells functionally deficient in CX(3)CR1 lacked matrix tunnelling and tubulation capacity in a 3D Matrigel assay. These morphogenic and cytokinetic responses were driven by CX(3)CL1-CX(3)CR1 interaction and totally abrogated by a Rho antagonist. To evaluate the role of CX(3)CR1 system in vivo, Matrigel plugs were implanted in competent CX(3)CR1(+/gfp) and functionally deficient CX(3)CR1(gfp/gfp) mice. Leaky microvessels (MV) were formed in the Matrigel implanted in CX(3)CR1(gfp/gfp) but not in CX(3)CR1(+/gfp) mice. In experimental plaque neovascularization immature MV phenotype was observed in CX(3)CR1(gfp/gfp) mice, lacking CX(3)CR1 positive smooth muscle-like cells, extracellular collagen and basement membrane (BM) laminin compared to competent CX(3)CR1(+/gfp) mice. This was associated with increased extravasation of platelets into the intima of CX(3)CR1(gfp/gfp) but not functionally competent CX(3)CR1 mice. Pharmacologic targeting using CX(3)CR1 receptor antagonist in wild type mice resulted in formation of plaque MV with poor BM coverage and a leaky phenotype. Our data indicate a hitherto unrecognised role for functional CX(3)CR1 in Matrigel and experimental plaque neovascularization in vivo, which may buttress MV collectively in favour of a more stable non-leaky phenotype. PMID- 23437347 TI - Apelin ameliorates TNF-alpha-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ. AB - Apelin, a novel adipokine, is the specific endogenous ligand of G protein-coupled receptor APJ. Consistent with its putative role as an adipokine, apelin has been linked to states of insulin resistance. However, the function of apelin in hepatic insulin resistance, a vital part of insulin resistance, and its underlying mechanisms still remains unclear. Here we define the impacts of apelin on TNF-alpha-induced reduction of glycogen synthesis in the hepatocytes. Our studies indicate that apelin reversed TNF-alpha-induced reduction of glycogen synthesis in HepG2 cells, mouse primary hepatocytes and liver tissues of C57BL/6J mice by improving JNK-IRS1-AKT-GSK pathway. Moreover, Western blot revealed that APJ, but not apelin, expressed in the hepatocytes and liver tissues of mice. We found that F13A, a competitive antagonist for G protein-coupled receptor APJ, suppressed the effects of apelin on TNF-alpha-induced reduction of glycogen synthesis in the hepatocytes, suggesting APJ is involved in the function of apelin. In conclusion, we show novel evidence suggesting that apelin ameliorates TNF-alpha-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ. Apelin appears as a beneficial adipokine with anti insulin resistance properties, and thus as a promising therapeutic target in metabolic disorders. PMID- 23437348 TI - Identification and characterization of miRNA transcriptome in potato by high throughput sequencing. AB - Micro RNAs (miRNAs) represent a class of short, non-coding, endogenous RNAs which play important roles in post-transcriptional regulation of gene expression. While the diverse functions of miRNAs in model plants have been well studied, the impact of miRNAs in crop plant biology is poorly understood. Here we used high throughput sequencing and bioinformatics analysis to analyze miRNAs in the tuber bearing crop potato (Solanum tuberosum). Small RNAs were analysed from leaf and stolon tissues. 28 conserved miRNA families were found and potato-specific miRNAs were identified and validated by RNA gel blot hybridization. The size, origin and predicted targets of conserved and potato specific miRNAs are described. The large number of miRNAs and complex population of small RNAs in potato suggest important roles for these non-coding RNAs in diverse physiological and metabolic pathways. PMID- 23437349 TI - Cisplatin-induced apoptosis inhibits autophagy, which acts as a pro-survival mechanism in human melanoma cells. AB - The interplay between a non-lethal autophagic response and apoptotic cell death is still a matter of debate in cancer cell biology. In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatin-induced cytotoxicity, as well as the contribution of cisplatin-induced activation of caspases 3/7 and conventional calpains. The results show that, while down-regulating Beclin-1, Atg14 and LC3-II, cisplatin treatment inhibits the basal autophagic response, impairing a physiological pro survival response. Consistently, exogenously stimulated autophagy, obtained with trehalose or calpains inhibitors (MDL-28170 and calpeptin), protects from cisplatin-induced apoptosis, and such a protection is reverted by inhibiting autophagy with 3-methyladenine or ATG5 silencing. In addition, during trehalose stimulated autophagy, the cisplatin-induced activation of calpains is abrogated, suggesting the existence of a feedback loop between the autophagic process and calpains. On the whole, our results demonstrate that in human melanoma cells autophagy may function as a beneficial stress response, hindered by cisplatin induced death mechanisms. In a therapeutic perspective, these findings suggest that the efficacy of cisplatin-based polychemotherapies for melanoma could be potentiated by inhibitors of autophagy. PMID- 23437350 TI - Chiari malformation type I: a case-control association study of 58 developmental genes. AB - Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI. PMID- 23437351 TI - Laparoscopic ablation of hepatocellular carcinoma in cirrhotic patients unsuitable for liver resection or percutaneous treatment: a cohort study. AB - The aim of this study was to demonstrate the safety and efficacy of laparoscopic ablation for cirrhotic HCC patients. Between January 2004 and December 2009, laparoscopic ablation was applied prospectively in 169 consecutive HCC patients (median age 62 years, 43% hepatitis C positive) considered ineligible for liver resection and/or percutaneous ablation. There was clinically relevant portal hypertension in 72% of cases. A significant proportion of subjects (50%) had multinodular tumors or nodules larger than 25 mm. The main ablation techniques used were radiofrequency in 103 patients (61%), microwave ablation in 8 (5%), and ethanol injection in 58 (34%). The primary endpoint was 3-year survival. There was no perioperative mortality. The overall morbidity rate was 25%. The median postoperative hospital stay was 3 days (range 1-19 days). Patients survived a median 33 months with a 3-year survival rate of 47%. Cox's multivariate analysis identified patient age, presence of diabetes, albumin <=37 g/l, and alpha fetoprotein >400 ug/l as significant preoperative predictors of survival, while the chance to undergo liver transplantation and postoperative ascites were the only independent postoperative predictor of survival. Laparoscopic ablation is a safe and effective therapeutic option for selected HCC patients ineligible for liver resection and/or percutaneous ablation. PMID- 23437352 TI - Protection by salidroside against bone loss via inhibition of oxidative stress and bone-resorbing mediators. AB - Oxidative stress is a pivotal pathogenic factor for bone loss in mouse model. Salidroside, a phenylpropanoid glycoside extracted from Rhodiola rosea L, exhibits potent antioxidative effects. In the present study, we used an in vitro oxidative stress model induced by hydrogen peroxide (H(2)O(2)) in MC3T3-E1 cells and a murine ovariectomized (OVX) osteoporosis model to investigate the protective effects of salidroside on bone loss and the related mechanisms. We demonstrated that salidroside caused a significant (P<0.05) elevation of cell survival, alkaline phosphatase (ALP) staining and activity, calcium deposition, and the transcriptional expression of Alp, Col1a1 and Osteocalcin (Ocn) in the presence of H(2)O(2). Moreover, salidroside decreased the production of intracellular reactive oxygen species (ROS), and osteoclast differentiation inducing factors such as receptor activator of nuclear factor-kB ligand (RANKL) and IL-6 induced by H(2)O(2). In vivo studies further demonstrated that salidroside supplementation for 3 months caused a decrease in malondialdehyde (MDA) and an increase in reduced glutathione (GSH) concentration in blood of ovariectomized mouse (P<0.05), it also improved trabecular bone microarchitecture and bone mineral density in the fourth lumbar vertebra and distal femur. Our study indicated that the protection provided by salidroside in alleviating bone loss was mediated, at least in part, via inhibition of the release of bone resorbing mediators and oxidative damage to bone-forming cells, suggesting that salidroside can be used as an effective remedy in the treatment or prevention of osteoporosis. PMID- 23437354 TI - Leukoaraiosis, a common brain magnetic resonance imaging finding, as a predictor of traffic crashes. AB - BACKGROUND: There are no reported studies on the relationship between traffic crashes and brain tissue changes in healthy drivers. The relationship between traffic crashes and leukoaraiosis, a common magnetic resonance imaging finding, was investigated in this study. METHODS: A total of 3,930 automobile drivers (2,037 men and 1,893 women; age, 21-87 years) who underwent brain magnetic resonance imaging as part of total health check-ups and answered a road traffic questionnaire were examined to determine whether asymptomatic leukoaraiosis was associated with various types of traffic crashes. Multiple logistic regression analysis was performed to elucidate the relationship between leukoaraiosis and various types of traffic crashes. RESULTS: Subcortical leukoaraiosis was diagnosed in 28.52% of all subjects, whereas periventricular leukoaraiosis was diagnosed in 9.57% of all subjects. Adjusted odds ratios for involvement in all types of traffic crashes were not significant for subjects with periventricular leukoaraiosis; however, they were significant for subjects with multiple and large multiple subcortical leukoaraiosis. Adjusted odds ratios for involvement in crashes at crossroads were 1.09 (95% confidence interval [CI], 0.60-2.00) for subjects with single subcortical leukoaraiosis, 3.35 (95% CI, 2.36-4.77) for subjects with multiple subcortical leukoaraiosis, and 2.45 (95% CI, 2.36-4.98) for subjects with large multiple subcortical leukoaraiosis. Periventricular leukoaraiosis was not significantly associated with crossroad crashes. Involvement in crashes of any type, parking lot crashes, and rear-end collisions showed no significant association with either subcortical or periventricular leukoaraiosis. CONCLUSIONS: Multiple subcortical leukoaraiosis, but not periventricular leukoaraiosis, is significantly associated with traffic crashes, in particular, crossroad crashes. This association is independent of sex, age, and driving exposure. To our knowledge, this is the first evidence describing the relationship between brain tissue changes and traffic crashes. PMID- 23437353 TI - 12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. AB - The purpose of the current study was to evaluate the effect of 12/15-lipoxygenase (12/15-LOX) metabolites on retinal endothelial cell (REC) barrier function. FITC dextran flux across the REC monolayers and electrical cell-substrate impedance sensing (ECIS) were used to evaluate the effect of 12- and 15 hydroxyeicosatetreanoic acids (HETE) on REC permeability and transcellular electrical resistance (TER). Effect of 12- or 15-HETE on the levels of zonula occludens protein 1 (ZO-1), reactive oxygen species (ROS), NOX2, pVEGF-R2 and pSHP1 was examined in the presence or absence of inhibitors of NADPH oxidase. In vivo studies were performed using Ins2(Akita) mice treated with or without the 12/15-LOX inhibitor baicalein. Levels of HETE and inflammatory mediators were examined by LC/MS and Multiplex Immunoassay respectively. ROS generation and NOX2 expression were also measured in mice retinas. 12- and 15- HETE significantly increased permeability and reduced TER and ZO-1 expression in REC. VEGF-R2 inhibitor reduced the permeability effect of 12-HETE. Treatment of REC with HETE also increased ROS generation and expression of NOX2 and pVEGF-R2 and decreased pSHP1 expression. Treatment of diabetic mice with baicalein significantly decreased retinal HETE, ICAM-1, VCAM-1, IL-6, ROS generation, and NOX2 expression. Baicalein also reduced pVEGF-R2 while restored pSHP1 levels in diabetic retina. Our findings suggest that 12/15-LOX contributes to vascular hyperpermeability during DR via NADPH oxidase dependent mechanism which involves suppression of protein tyrosine phosphatase and activation of VEGF-R2 signal pathway. PMID- 23437355 TI - Beta-blockers, left and right ventricular function, and in-vivo calcium influx in muscular dystrophy cardiomyopathy. AB - Beta-blockers are used to treat acquired heart failure in adults, though their role in early muscular dystrophy cardiomyopathy is unclear. We treated 2 different dystrophic mouse models which have an associated cardiomyopathy (mdx: model for Duchenne Muscular Dystrophy, and Sgcd-/-: model for limb girdle muscular dystrophy type 2F) and wild type controls (C57 Bl10) with the beta blocker metoprolol or placebo for 8 weeks at an early stage in the development of the cardiomyopathy. Left and right ventricular function was assessed with cardiac magnetic resonance imaging (MRI) and in-vivo myocardial calcium influx with manganese enhanced MRI. In the mdx mice at baseline there was reduced stroke volume, cardiac index, and end-diastolic volume with preserved left ventricular ejection fraction. These abnormalities were no longer evident after treatment with beta-blockers. Right ventricular ejection fraction was reduced and right ventricular end-systolic volume increased in the mdx mice. With metoprolol there was an increase in right ventricular end-diastolic and end-systolic volumes. Left and right ventricular function was normal in the Sgcd-/- mice. Metroprolol had no significant effects on left and right ventricular function in these mice, though heart/body weight ratios increased after treatment. In-vivo myocardial calcium influx with MEMRI was significantly elevated in both models, though metoprolol had no significant effects on either. In conclusion, metoprolol treatment at an early stage in the development of cardiomyopathy has deleterious effects on right ventricular function in mdx mice and in both models no effect on increased in vivo calcium influx. This suggests that clinical trials need to carefully monitor not just left ventricular function but also right ventricular function and other aspects of myocardial metabolism. PMID- 23437356 TI - Hand-held tidal breathing nasal nitric oxide measurement--a promising targeted case-finding tool for the diagnosis of primary ciliary dyskinesia. AB - BACKGROUND: Nasal nitric oxide (nNO) measurement is an established first line test in the work-up for primary ciliary dyskinesia (PCD). Tidal breathing nNO (TB nNO) measurements require minimal cooperation and are potentially useful even in young children. Hand-held NO devices are becoming increasingly widespread for asthma management. Therefore, we chose to assess whether hand-held TB-nNO measurements reliably discriminate between PCD, and Healthy Subjects (HS) and included Cystic Fibrosis (CF) patients as a disease control group known to have intermediate nNO levels. METHODS: In this cross sectional, single centre, single occasion, proof-of-concept study in children and adults with PCD and CF, and in HS we compared feasibility, success rates, discriminatory capacity, repeatability and agreement between a hand-held electrochemical device equipped with a nNO software application sampling at flow rates 2 ml/s or 5 ml/s, and two stationary chemiluminescence devices, applying both tidal breathing and velum closure techniques. RESULTS: Measurements were done in 16 PCD patients, 21 patients with CF and 20 HS aged between 3.8 and 60.9 years. Hand-held TB-nNO showed high success rate (96.5-100%) vs. velum closure nNO techniques (70.2-89.5%). Hand-held TB-nNO sampling at flow rate 5 ml/s showed equally high discriminative power (PCD vs. HS [p<0.0001] and PCD vs. CF [p<0.0001]) and reaching close to 100% sensitivity and specificity, superior repeatability (CV% = 10%) and equal limits of agreement compared to TB-nNO by stationary devices and even compared to velum closure sampling. CONCLUSION: Hand-held TB-nNO discriminates significantly between PCD, CF and HS and shows promising potential as a widespread targeted case-finding tool for PCD, although further studies are warranted before implementation. PMID- 23437357 TI - N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion. AB - Iron is critical for cellular proliferation and its depletion leads to a suppression of both DNA synthesis and global translation. These observations suggest that iron depletion may trigger a cellular "stress response". A canonical response of cells to stress is the formation of stress granules, which are dynamic cytoplasmic aggregates containing stalled pre-initiation complexes that function as mRNA triage centers. By differentially prioritizing mRNA translation, stress granules allow for the continued and selective translation of stress response proteins. Although the multi-subunit eukaryotic initiation factor 3 (eIF3) is required for translation initiation, its largest subunit, eIF3a, may not be essential for this activity. Instead, eIF3a is a vital constituent of stress granules and appears to act, in part, by differentially regulating specific mRNAs during iron depletion. Considering this, we investigated eIF3a's role in modulating iron-regulated genes/proteins that are critically involved in proliferation and metastasis. In this study, eIF3a was down-regulated and recruited into stress granules by iron depletion as well as by the classical stress-inducers, hypoxia and tunicamycin. Iron depletion also increased expression of the metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), and a known downstream repressed target of eIF3a, namely the cyclin dependent kinase inhibitor, p27(kip1). To determine if eIF3a regulates NDRG1 expression, eIF3a was inducibly over-expressed or ablated. Importantly, eIF3a positively regulated NDRG1 expression and negatively regulated p27(kip1) expression during iron depletion. This activity of eIF3a could be due to its recruitment to stress granules and/or its ability to differentially regulate mRNA translation during cellular stress. Additionally, eIF3a positively regulated proliferation, but negatively regulated cell motility and invasion, which may be due to the eIF3a-dependent changes in expression of NDRG1 and p27(kip1) observed under these conditions. PMID- 23437358 TI - Demarcation of stable subpopulations within the pluripotent hESC compartment. AB - Heterogeneity is a feature of stem cell populations, resulting from innate cellular hierarchies that govern differentiation capability. How heterogeneity impacts human pluripotent stem cell populations is directly relevant to their efficacious use in regenerative medicine applications. The control of pluripotency is asserted by a core transcription factor network, of which Oct4 is a necessary member. In mouse embryonic stem cells (ESCs), the zinc finger transcription factor Rex1 (Zfp42) closely tracks the undifferentiated state and is capable of segregating Oct4 positive mESCs into metastable populations expressing or lacking Rex1 that are inter-convertible. However, little is currently understood about the extent or function of heterogeneous populations in the human pluripotent compartment. Human ESCs express REX1 transcripts but the distribution and properties of REX1 expressing cells have yet to be described. To address these questions, we used gene targeting in human ESCs to insert the fluorescent protein Venus and an antibiotic selection marker under the control of the endogenous REX1 transcription regulatory elements, generating a sensitive, selectable reporter of pluripotency. REX1 is co-expressed in OCT4 and TRA-1-60 positive hESCs and rapidly lost upon differentiation. Importantly, REX1 expression reveals significant heterogeneity within seemingly homogenous populations of OCT4 and TRA-1-60 hESCs. REX1 expression is extinguished before OCT4 during differentiation, but, in contrast to the mouse, loss of REX1 expression demarcates a stable, OCT4 positive lineage-primed state in pluripotent hESCs that does not revert back to REX1 positivity under normal conditions. We show that loss of REX1 expression correlates with altered patterns of DNA methylation at the REX1 locus, implying that epigenetic mechanisms may interfere with the metastable phenotype commonly found in murine pluripotency. PMID- 23437359 TI - Neurogenesis of retinal ganglion cells is not essential to visual functional recovery after optic nerve injury in adult zebrafish. AB - Zebrafish central nervous system (CNS) possesses a strong neural regeneration ability to restore visual function completely after optic nerve injury (ONI). However, whether neurogenesis of retinal ganglion cell (RGC) contributes to functional recovery remains controversial. Our quantitative analysis of RGCs in different ONI models showed that almost all RGCs survived in optic nerve crush (ONC) model; while over 90% of RGCs survived in the first 2 weeks with 75% remaining after 7 weeks in optic nerve transection (ONT) model. Retrograde labeling from tectum revealed a surprising regeneration rate, with over 90% and over 50% of RGCs regrowing axons to tectum at the first week in ONC and ONT model respectively. In the latter one, the number of regenerative RGCs after 4 weeks had no significant difference from the control group. As for neurogenesis, newborn RGCs were rarely detected either by double retrograde labeling or BrdU marker. Since few RGCs died, microglia number showed a temporary increase at 3 days post injury (dpi) and a decrease at 14 dpi. Finally, myelin structure within retina kept integrity and optomotor response (OMR) test demonstrated visual functional restoration at 5 weeks post injury (wpi). In conclusion, our results have directly shown that RGC survival and axon regrowth are responsible for functional recovery after ONI in adult zebrafish. PMID- 23437360 TI - Quantitative genetic analysis of retinal degeneration in the blind cavefish Astyanax mexicanus. AB - The retina is the light-sensitive tissue of the eye that facilitates vision. Mutations within genes affecting eye development and retinal function cause a host of degenerative visual diseases, including retinitis pigmentosa and anophthalmia/microphthalmia. The characin fish Astyanax mexicanus includes both eyed (surface fish) and eyeless (cavefish) morphs that initially develop eyes with normal retina; however, early in development, the eyes of cavefish degenerate. Since both surface and cave morphs are members of the same species, they serve as excellent evolutionary mutant models with which to identify genes causing retinal degeneration. In this study, we crossed the eyed and eyeless forms of A. mexicanus and quantified the thickness of individual retinal layers among 115 F(2) hybrid progeny. We used next generation sequencing (RAD-seq) and microsatellite mapping to construct a dense genetic map of the Astyanax genome, scan for quantitative trait loci (QTL) affecting retinal thickness, and identify candidate genes within these QTL regions. The map we constructed for Astyanax includes nearly 700 markers assembled into 25 linkage groups. Based on our scans with this map, we identified four QTL, one each associated with the thickness of the ganglion, inner nuclear, outer plexiform, and outer nuclear layers of the retina. For all but one QTL, cavefish alleles resulted in a clear reduction in the thickness of the affected layer. Comparative mapping of genetic markers within each QTL revealed that each QTL corresponds to an approximately 35 Mb region of the zebrafish genome. Within each region, we identified several candidate genes associated with the function of each affected retinal layer. Our study is the first to examine Astyanax retinal degeneration in the context of QTL mapping. The regions we identify serve as a starting point for future studies on the genetics of retinal degeneration and eye disease using the evolutionary mutant model Astyanax. PMID- 23437361 TI - Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. AB - Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 10(7)pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNgamma, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFkappaB p65. While the expression of TGFbeta1 was not modulated by curcumin, TGFbeta Receptor II, which is required for TGFbeta signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of alpha-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation. PMID- 23437363 TI - Anopheles moucheti and Anopheles vinckei are candidate vectors of ape Plasmodium parasites, including Plasmodium praefalciparum in Gabon. AB - During the last four years, knowledge about the diversity of Plasmodium species in African great apes has considerably increased. Several new species were described in chimpanzees and gorillas, and some species that were previously considered as strictly of human interest were found to be infecting African apes. The description in gorillas of P. praefalciparum, the closest relative of P. falciparum which is the main malignant agent of human malaria, definitively changed the way we understand the evolution and origin of P. falciparum. This parasite is now considered to have appeared recently, following a cross-species transfer from gorillas to humans. However, the Plasmodium vector mosquito species that have served as bridge between these two host species remain unknown. In order to identify the vectors that ensure ape Plasmodium transmission and evaluate the risk of transfer of these parasites to humans, we carried out a field study in Gabon to capture Anopheles in areas where wild and semi-wild ape populations live. We collected 1070 Anopheles females belonging to 15 species, among which An. carnevalei, An. moucheti and An. marshallii were the most common species. Using mtDNA-based PCR tools, we discovered that An. moucheti, a major human malaria vector in Central Africa, could also ensure the natural transmission of P. praefalciparum among great apes. We also showed that, together with An. vinckei, An. moucheti was infected with P. vivax-like parasites. An. moucheti constitutes, therefore, a major candidate for the transfer of Plasmodium parasites from apes to humans. PMID- 23437362 TI - Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. AB - The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser(473) while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser(473) and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis. PMID- 23437364 TI - Monitoring of Pb exposure in waterfowl ten years after a mine spill through the use of noninvasive sampling. AB - Lead exposure in waterfowl was studied using noninvasive fecal sampling in the Guadalquivir Marshes in Spain, an area affected by the 1998 Aznalcollar mine disaster. Feces of greylag geese (Anser anser, n = 191) and purple gallinule (Porphyrio porphyrio, n = 91) were collected from three different impacted sites (Entremuros, Caracoles and Cerro de los Ansares) during the winters of 2004 to 2008. Lead and aluminium (an indicator of sediment ingestion) and Pb isotope signatures (to discriminate between sources of Pb exposure) were analyzed in freeze-dried, acid digested samples. The concentrations of fecal porphyrins and biliverdin were determined as noninvasive biomarkers to study Pb exposure effects. Results showed a decrease in Pb exposure over time in wintering greylag geese. In contrast, for purple gallinule resident in the Entremuros a clear trend was not evident. For both species, sediment ingestion appeared to be the main source of exposure to Pb. In the Entremuros, some samples from purple gallinule were detected with higher Pb levels than expected for simple soil ingestion, and these had Pb isotopic profiles compatible with mining sludge or Pb shot. Whilst fecal Pb isotopic profiles were effective in differentiating between samples from sites with different levels and sources of pollution, the combined use of element ratios (such as Pb/Al) and other non-traditional stable isotope signatures may also prove worthwhile. Overall, the fecal Pb levels detected were below those described in feces for waterfowl from other uncontaminated areas(<10 ug/g d.w.). Despite this, for both species fecal Pb levels were positively correlated with porphyrin excretion, and for purple gallinule, with the coproporphyrin III/I ratio, suggesting some subtle effects on heme synthesis in birds. Ten years after the mine spill, Pb contamination in birds by this pollution source was still detectable and subtlethal effects may persist. PMID- 23437366 TI - CD44 staining of cancer stem-like cells is influenced by down-regulation of CD44 variant isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition. AB - CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumours, and we have previously demonstrated the existence of two different CD44(high) cancer stem-like cell populations in squamous cell carcinoma, one having undergone epithelial-to-mesenchymal transition and the other maintaining an epithelial phenotype. Alternative splicing of CD44 variant exons generates a great many isoforms, and it is not known which isoforms are expressed on the surface of the two different cancer stem-like cell phenotypes. Here, we demonstrate that cancer stem-like cells with an epithelial phenotype predominantly express isoforms containing the variant exons, whereas the cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition down regulate these variant isoforms and up-regulate expression of the standard CD44 isoform that contains no variant exons. In addition, we find that enzymatic treatments used to dissociate cells from tissue culture or fresh tumour specimens cause destruction of variant CD44 isoforms at the cell surface whereas expression of the standard CD44 isoform is preserved. This results in enrichment within the CD44(high) population of cancer stem-like cells that have undergone an epithelial to-mesenchymal transition and depletion from the CD44(high) population of cancer stem-like cells that maintain an epithelial phenotype, and therefore greatly effects the characteristics of any cancer stem-like cell population isolated based on expression of CD44. As well as effecting the CD44(high) population, enzymatic treatment also reduces the percentage of the total epithelial cancer cell population staining CD44-positive, with potential implications for studies that aim to use CD44-positive staining as a prognostic indicator. Analyses of the properties of cancer stem-like cells are largely dependent on the ability to accurately identify and assay these populations. It is therefore critical that consideration be given to use of multiple cancer stem-like cell markers and suitable procedures for cell isolation in order that the correct populations are assayed. PMID- 23437365 TI - Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function. AB - Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28-49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABA(A) receptors with open Cl(-) channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral and neurobiological responses to other therapeutic- or illicit psychotropic drugs. PMID- 23437367 TI - The right planum temporale is involved in stimulus-driven, auditory attention- evidence from transcranial magnetic stimulation. AB - It is well known that the planum temporale (PT) area in the posterior temporal lobe carries out spectro-temporal analysis of auditory stimuli, which is crucial for speech, for example. There are suggestions that the PT is also involved in auditory attention, specifically in the discrimination and selection of stimuli from the left and right ear. However, direct evidence is missing so far. To examine the role of the PT in auditory attention we asked fourteen participants to complete the Bergen Dichotic Listening Test. In this test two different consonant-vowel syllables (e.g., "ba" and "da") are presented simultaneously, one to each ear, and participants are asked to verbally report the syllable they heard best or most clearly. Thus attentional selection of a syllable is stimulus driven. Each participant completed the test three times: after their left and right PT (located with anatomical brain scans) had been stimulated with repetitive transcranial magnetic stimulation (rTMS), which transiently interferes with normal brain functioning in the stimulated sites, and after sham stimulation, where participants were led to believe they had been stimulated but no rTMS was applied (control). After sham stimulation the typical right ear advantage emerged, that is, participants reported relatively more right than left ear syllables, reflecting a left-hemispheric dominance for language. rTMS over the right but not left PT significantly reduced the right ear advantage. This was the result of participants reporting more left and fewer right ear syllables after right PT stimulation, suggesting there was a leftward shift in stimulus selection. Taken together, our findings point to a new function of the PT in addition to auditory perception: particularly the right PT is involved in stimulus selection and (stimulus-driven), auditory attention. PMID- 23437368 TI - The ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in Kenyan children. AB - BACKGROUND: Plasmodium falciparum malaria remains a major cause of illness and death in sub-Saharan Africa. Young children bear the brunt of the disease and though older children and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P. falciparum infection. A better understanding of the host factors associated with immunity to clinical malaria and the ability to sustain asymptomatic P. falciparum infection will aid the development of improved strategies for disease prevention. METHODS AND FINDINGS: Here we investigate whether full differential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled at five annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured in peripheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up. This association is evident among children with asymptomatic P. falciparum infection at the time the cell counts are measured (Hazard ratio (HR) = 2.7 (95% CI 1.42, 5.01, P = 0.002) but not in those without detectable parasitaemia (HR = 1.0 (95% CI 0.74, 1.42, P = 0.9). CONCLUSIONS: We propose that the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts, reflects an individual's capacity to mount an effective immune response to P. falciparum infection. PMID- 23437369 TI - Cooperative RNA polymerase molecules behavior on a stochastic sequence-dependent model for transcription elongation. AB - The transcription process is crucial to life and the enzyme RNA polymerase (RNAP) is the major component of the transcription machinery. The development of single molecule techniques, such as magnetic and optical tweezers, atomic-force microscopy and single-molecule fluorescence, increased our understanding of the transcription process and complements traditional biochemical studies. Based on these studies, theoretical models have been proposed to explain and predict the kinetics of the RNAP during the polymerization, highlighting the results achieved by models based on the thermodynamic stability of the transcription elongation complex. However, experiments showed that if more than one RNAP initiates from the same promoter, the transcription behavior slightly changes and new phenomenona are observed. We proposed and implemented a theoretical model that considers collisions between RNAPs and predicts their cooperative behavior during multi-round transcription generalizing the Bai et al. stochastic sequence dependent model. In our approach, collisions between elongating enzymes modify their transcription rate values. We performed the simulations in Mathematica(r) and compared the results of the single and the multiple-molecule transcription with experimental results and other theoretical models. Our multi-round approach can recover several expected behaviors, showing that the transcription process for the studied sequences can be accelerated up to 48% when collisions are allowed: the dwell times on pause sites are reduced as well as the distance that the RNAPs backtracked from backtracking sites. PMID- 23437370 TI - The Shape Trail Test: application of a new variant of the Trail making test. AB - OBJECTIVE: The Trail making test (TMT) is culture-loaded because of reliance on the Latin alphabet, limiting its application in Eastern populations. The Shape Trail Test (STT) has been developed as a new variant. This study is to examine the applicability of the STT in a senile Chinese population and to evaluate its potential advantages and disadvantages. METHOD: A total of 2470 participants were recruited, including 1151 cognitively normal control (NC), 898 amnestic mild cognitive impairment (aMCI), and 421 mild Alzheimer disease (AD) patients. Besides the STT, the Mini mental state examination and a comprehensive neuropsychological battery involving memory, language, attention, executive function and visuospatial ability were administered to all the participants. In a subgroup of 100 NC and 50 AD patients, both the STT and the Color Trail Test (CTT) were performed. RESULTS: In NC, the time consumed for Part A and B (STT-A and STT-B) significantly correlated with age and negatively correlated with education (p<0.01). STT-A and B significantly differed among the AD, aMCI and NC. The number that successfully connected within one minute in Part B (STT-B-1 min) correlated well with STT-B (r = 0.71, p<0.01) and distinguished well among NC, aMCI and AD. In the receiver operating characteristic curve analysis, the AUCs (area under the curve) for STT-A, STT-B, and STT-B-1min in identifying AD were 0.698, 0.694 and 0.709, respectively. The STT correlated with the CTT, but the time for completion was longer. CONCLUSION: The TMT is a sensitive test of visual search and sequencing. The STT is a meaningful attempt to develop a "culture fair" variant of the TMT in addition to the CTT. PMID- 23437371 TI - Iron oxide nanoparticle-micelles (ION-micelles) for sensitive (molecular) magnetic particle imaging and magnetic resonance imaging. AB - BACKGROUND: Iron oxide nanoparticles (IONs) are a promising nanoplatform for contrast-enhanced MRI. Recently, magnetic particle imaging (MPI) was introduced as a new imaging modality, which is able to directly visualize magnetic particles and could serve as a more sensitive and quantitative alternative to MRI. However, MPI requires magnetic particles with specific magnetic properties for optimal use. Current commercially available iron oxide formulations perform suboptimal in MPI, which is triggering research into optimized synthesis strategies. Most synthesis procedures aim at size control of iron oxide nanoparticles rather than control over the magnetic properties. In this study, we report on the synthesis, characterization and application of a novel ION platform for sensitive MPI and MRI. METHODS AND RESULTS: IONs were synthesized using a thermal-decomposition method and subsequently phase-transferred by encapsulation into lipidic micelles (ION-Micelles). Next, the material and magnetic properties of the ION-Micelles were analyzed. Most notably, vibrating sample magnetometry measurements showed that the effective magnetic core size of the IONs is 16 nm. In addition, magnetic particle spectrometry (MPS) measurements were performed. MPS is essentially zero dimensional MPI and therefore allows to probe the potential of iron oxide formulations for MPI. ION-Micelles induced up to 200 times higher signal in MPS measurements than commercially available iron oxide formulations (Endorem, Resovist and Sinerem) and thus likely allow for significantly more sensitive MPI. In addition, the potential of the ION-Micelle platform for molecular MPI and MRI was showcased by MPS and MRI measurements of fibrin-binding peptide functionalized ION-Micelles (FibPep-ION-Micelles) bound to blood clots. CONCLUSIONS: The presented data underlines the potential of the ION-Micelle nanoplatform for sensitive (molecular) MPI and warrants further investigation of the FibPep-ION-Micelle platform for in vivo, non-invasive imaging of fibrin in preclinical disease models of thrombus-related pathologies and atherosclerosis. PMID- 23437372 TI - Poor immune reconstitution in HIV-infected patients associates with high percentage of regulatory CD4+ T cells. AB - CD4(+) regulatory T cells (Tregs) are essential for the maintenance of the immune system's equilibrium, by dampening the activation of potential auto-reactive T cells and avoiding excessive immune activation. To correctly perform their function, Tregs must be maintained at the right proportion with respect to effector T cells. Since this equilibrium is frequently disrupted in individuals infected with the human immunodeficiency virus (HIV), we hypothesize that its deregulation could hamper immune reconstitution in patients with poor CD4(+) T cell recovery under highly active antiretroviral therapy (HAART). We analysed Tregs percentages amongst CD4(+) T cells in 53 HIV-infected patients under HAART, with suppression of viral replication and distinct levels of immune reconstitution. As controls, 51 healthy individuals were also analysed. We observed that amongst the patients with Nadir values (the lowest CD4(+) T cell counts achieved) <200 cells/uL, the individuals with high Tregs percentages (>=10% of total CD4(+) T cells) had the worse CD4(+) T cell reconstitution. In accordance, the well-described direct correlation between the Nadir value and CD4(+) T cell reconstitution is clearly more evident in individuals with high Tregs proportions. Furthermore, we observed a strong negative correlation between Tregs percentages and CD4(+) T cell recovery among immunological non-responder HIV(+) individuals. All together, this work shows that high Tregs frequency is an important factor associated with sub-optimal CD4(+) T cell recovery. This is particularly relevant for immunological non-responders with low Nadir values. Our results suggest that the Tregs proportion might be of clinical relevance to define cut-offs for HAART initiation. PMID- 23437373 TI - Comparative transcriptional profiling provides insights into the evolution and development of the zygomorphic flower of Vicia sativa (Papilionoideae). AB - BACKGROUND: Vicia sativa (the common vetch) possesses a predominant zygomorphic flower and belongs to the subfamily Papilionoideae, which is related to Arabidopsis thaliana in the eurosid II clade of the core eudicots. Each vetch flower consists of 21 concentrically arranged organs: the outermost five sepals, then five petals and ten stamens, and a single carpel in the center. METHODOLOGY/PRINCIPAL FINDINGS: We explored the floral transcriptome to examine a genome-scale genetic model of the zygomorphic flower of vetch. mRNA was obtained from an equal mixture of six floral organs, leaves and roots. De novo assembly of the vetch transcriptome using Illumina paired-end technology produced 71,553 unigenes with an average length of 511 bp. We then compared the expression changes in the 71,553 unigenes in the eight independent organs through RNA-Seq Quantification analysis. We predominantly analyzed gene expression patterns specific to each floral organ and combinations of floral organs that corresponded to the traditional ABC model domains. Comparative analyses were performed in the floral transcriptomes of vetch and Arabidopsis, and genomes of vetch and Medicago truncatula. CONCLUSIONS/SIGNIFICANCE: Our comparative analysis of vetch and Arabidopsis showed that the vetch flowers conform to a strict ABC model. We analyzed the evolution and expression of the TCP gene family in vetch at a whole genome level, and several unigenes specific to three different vetch petals, which might offer some clues toward elucidating the molecular mechanisms underlying floral zygomorphy. Our results provide the first insights into the genome-scale molecular regulatory network that controls the evolution and development of the zygomorphic flower in Papilionoideae. PMID- 23437374 TI - MS-H: a novel proteomic approach to isolate and type the E. coli H antigen using membrane filtration and liquid chromatography-tandem mass spectrometry (LC MS/MS). AB - Serotyping is the long-standing gold standard method to determine E. coli H antigens; however, this method requires a panel of H-antigen specific antibodies and often culture-based induction of the H-antigen flagellar motility. In this study, a rapid and accurate method to isolate and identify the Escherichia coli (E. coli) H flagellar antigen was developed using membrane filtration and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Flagella were isolated from pure culture, digested with trypsin, and then subjected to LC-MS/MS using one of two systems (Agilent-nano-LC-QSTAR XL or Proxeon-nano-LC-LTQ-Orbitrap XL). The resulting peptide sequence data were searched against a custom E. coli flagella/H antigen database. This approach was evaluated using flagella isolated from reference E. coli strains representing all 53 known H antigen types and 41 clinical E. coli strains. The resulting LC-MS/MS classifications of H antigen types (MS-H) were concordant with the known H serogroup for all 53 reference types, and of 41 clinical isolates tested, 38 (92.7%) were concordant with the known H serogroup. MS-H clearly also identified two clinical isolates (4.9%) that were untypeable by serotyping. Notably, successful detection and classification of flagellar antigens with MS-H did not generally require induction of motility, establishing this proteomic approach as more rapid and cost-effective than traditional methods, while providing equitable specificity for typing E. coli H antigens. PMID- 23437376 TI - Cognitive abilities in Malawi cichlids (Pseudotropheus sp.): matching-to-sample and image/mirror-image discriminations. AB - The ability to recognize and distinguish between visual stimuli is fundamental for everyday survival of many species. While diverse aspects of cognition, including complex visual discrimination tasks were previously successfully assessed in fish, it remains unknown if fish can learn a matching-to-sample concept using geometrical shapes and discriminate between images and their mirror image counterparts. For this purpose a total of nine Malawi cichlids (Pseudotropheus sp.) were trained in two matching-to-sample (MTS) and three two choice discrimination tasks using geometrical, two-dimensional visual stimuli. Two out of the three discrimination experiments focused on the ability to discriminate between images and their mirror-images, the last was a general discrimination test. All fish showed quick associative learning but were unable to perform successfully in a simultaneous MTS procedure within a period of 40 sessions. Three out of eight fish learned to distinguish between an image and its mirror-image when reflected vertically; however none of the fish mastered the task when the stimulus was reflected horizontally. These results suggest a better discrimination ability of vertical compared to horizontal mirror-images, an observation that is widespread in literature on mirror-image discrimination in animals. All fish performed well in the general visual discrimination task, thereby supporting previous results obtained for this species. PMID- 23437377 TI - Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. AB - The uncarboxylated form (ucOC), but not the gamma-carboxylated form (GlaOC), of the bone-derived protein osteocalcin stimulates insulin secretion and regulates energy metabolism in insulin target tissues. Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that is released from the gut in response to food intake. We have now found that Gprc6a, a putative ucOC receptor, is expressed in epithelial cells of the mouse small intestine as well as in STC-1 enteroendocrine cells. Secretion of GLP-1 by STC-1 cells was stimulated by ucOC but not by GlaOC. The serum GLP-1 concentration in mice was increased by intraperitoneal or oral administration of ucOC, whereas GlaOC was effective in this regard only after oral application. Serum insulin levels were also increased by ucOC, and this effect was potentiated by an inhibitor of dipeptidyl peptidase IV and blocked by a GLP-1 receptor antagonist. Intravenous injection of ucOC in mice increased the serum GLP-1 concentration, and also increased the serum level of insulin. Our results suggest that ucOC acts via Gprc6a to induce GLP-1 release from the gut, and that the stimulatory effect of ucOC on insulin secretion is largely mediated by GLP-1. PMID- 23437378 TI - Is accessing dental care becoming more difficult? Evidence from Canada's middle income population. AB - OBJECTIVE: To explore trends in access to dental care among middle-income Canadians. METHODS: A secondary data analysis of six Canadian surveys that collected information on dental insurance coverage, cost-barriers to dental care, and out-of-pocket expenditures for dental care was conducted for select years from 1978 to 2009. Descriptive analyses were used to outline and compare trends among middle-income Canadians with other levels of income as well as national averages. RESULTS: By 2009, middle-income Canadians had the lowest levels of dental insurance coverage (48.7%) compared to all other income groups. They reported the greatest increase in cost-barriers to dental care, from 12.6% in 1996 to 34.1% by 2009. Middle-income Canadians had the largest rise in out-of pocket expenditures for dental care since 1978. CONCLUSIONS: This study suggests that affordability issues in accessing dental care are no longer just a problem for the lowest income groups in Canada, but are now impacting middle-income earners as a consequence of their lack of, or decreased access to, comprehensive dental insurance. PMID- 23437375 TI - Molecular basis for viral selective replication in cancer cells: activation of CDK2 by adenovirus-induced cyclin E. AB - Adenoviruses (Ads) with deletion of E1b55K preferentially replicate in cancer cells and have been used in cancer therapies. We have previously shown that Ad E1B55K protein is involved in induction of cyclin E for Ad replication, but this E1B55K function is not required in cancer cells in which deregulation of cyclin E is frequently observed. In this study, we investigated the interaction of cyclin E and CDK2 in Ad-infected cells. Ad infection significantly increased the large form of cyclin E (cyclin EL), promoted cyclin E/CDK2 complex formation and increased CDK2 phosphorylation at the T160 site. Activated CDK2 caused pRb phosphorylation at the S612 site. Repression of CDK2 activity with the chemical inhibitor roscovitine or with specific small interfering RNAs significantly decreased pRb phosphorylation, with concomitant repression of viral replication. Our results suggest that Ad-induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication. This study reveals a new molecular basis for oncolytic replication of E1b-deleted Ads and will aid in the development of new strategies for Ad oncolytic virotherapies. PMID- 23437379 TI - Transient shifts in bacterial communities associated with the temperate gorgonian Paramuricea clavata in the Northwestern Mediterranean Sea. AB - BACKGROUND: Bacterial communities that are associated with tropical reef-forming corals are being increasingly recognized for their role in host physiology and health. However, little is known about the microbial diversity of the communities associated with temperate gorgonian corals, even though these communities are key structural components of the ecosystem. In the Northwestern Mediterranean Sea, gorgonians undergo recurrent mass mortalities, but the potential relationship between these events and the structure of the associated bacterial communities remains unexplored. Because microbial assemblages may contribute to the overall health and disease resistance of their host, a detailed baseline of the associated bacterial diversity is required to better understand the functioning of the gorgonian holobiont. METHODOLOGY/PRINCIPAL FINDINGS: The bacterial diversity associated with the gorgonian Paramuricea clavata was determined using denaturing gradient gel electrophoresis, terminal-restriction fragment length polymorphism and the construction of clone libraries of the bacterial 16S ribosomal DNA. Three study sites were monitored for 4 years to assess the variability of communities associated with healthy colonies. Bacterial assemblages were highly dominated by one Hahellaceae-related ribotype and exhibited low diversity. While this pattern was mostly conserved through space and time, in summer 2007, a deep shift in microbiota structure toward increased bacterial diversity and the transient disappearance of Hahellaceae was observed. CONCLUSION/SIGNIFICANCE: This is the first spatiotemporal study to investigate the bacterial diversity associated with a temperate shallow gorgonian. Our data revealed an established relationship between P. clavata and a specific bacterial group within the Oceanospirillales. These results suggest a potential symbiotic role of Hahellaceae in the host-microbe association, as recently suggested for tropical corals. However, a transient imbalance in bacterial associations can be tolerated by the holobiont without apparent symptoms of disease. The subsequent restoration of the Hahellaceae-dominated community is indicative of the specificity and resilience of the bacteria associated with the gorgonian host. PMID- 23437380 TI - Digital reef rugosity estimates coral reef habitat complexity. AB - Ecological habitats with greater structural complexity contain more species due to increased niche diversity. This is especially apparent on coral reefs where individual coral colonies aggregate to give a reef its morphology, species zonation, and three dimensionality. Structural complexity is classically measured with a reef rugosity index, which is the ratio of a straight line transect to the distance a flexible chain of equal length travels when draped over the reef substrate; yet, other techniques from visual categories to remote sensing have been used to characterize structural complexity at scales from microhabitats to reefscapes. Reef-scale methods either lack quantitative precision or are too time consuming to be routinely practical, while remotely sensed indices are mismatched to the finer scale morphology of coral colonies and reef habitats. In this communication a new digital technique, Digital Reef Rugosity (DRR) is described which utilizes a self-contained water level gauge enabling a diver to quickly and accurately characterize rugosity with non-invasive millimeter scale measurements of coral reef surface height at decimeter intervals along meter scale transects. The precise measurements require very little post-processing and are easily imported into a spreadsheet for statistical analyses and modeling. To assess its applicability we investigated the relationship between DRR and fish community structure at four coral reef sites on Menjangan Island off the northwest corner of Bali, Indonesia and one on mainland Bali to the west of Menjangan Island; our findings show a positive relationship between DRR and fish diversity. Since structural complexity drives key ecological processes on coral reefs, we consider that DRR may become a useful quantitative community-level descriptor to characterize reef complexity. PMID- 23437381 TI - Mental rotational ability is correlated with spatial but not verbal working memory performance and P300 amplitude in males. AB - This study investigated how both sex and individual differences in a mental rotation test (MRT) influence performance on working memory (WM). To identify the neural substrate supporting these differences, brain electrical activity was measured using the event-related potential technique. No significant sex differences were observed in a test of verbal WM, however males were significantly faster than females to respond to probe stimuli in a test of spatial WM. This difference was no longer significant after controlling for differences in MRT score, suggesting that rotational ability mediates performance in the spatial memory task for both sexes. A posterior P300 was observed in both tasks as participants encoded information into memory, however the amplitude of the P300 correlated with RT in the spatial task but not in the verbal task. Individual differences in the MRT also correlated with RT and with the amplitude of the P300, but again only in the spatial task. After splitting the analysis by sex, partial correlations controlling for MRT revealed that for males, individual differences in rotational ability completely mediated the correlation between the P300 and RT in the spatial task. This mediating effect was not observed for the female participants. The results therefore suggest a relatively stronger association in males between innate mental rotational ability, spatial memory performance, and brain electrophysiological processes supporting spatial memory. PMID- 23437382 TI - Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. AB - Klotho was first identified in 1997 and has been considered as an anti-aging gene. Emerging evidence demonstrates that klotho has a close relationship with cancers, including lung cancer, breast cancer, etc, by inhibiting the proliferation and promoting apoptosis of cancer cells. Cisplatin has been the most widely used drug in the first-line chemotherapy. However, the increase in cisplatin-resistant cancer cells has become a major obstacle in clinical management of cancers. In our study, we for the first time demonstrated that klotho could attenuate the resistance of lung cancer to cisplatin based chemotherapy and the apoptosis of the resistant cells with klotho overexpression was markedly increased. However, klotho knockdown cells showed enhanced resistance to chemotherapy. Further analysis showed that inhibition of PI3K/Akt pathway with specific inhibitor (LY294002) attenuated the promotive effects on cancer growth following interfering with klotho shRNA. Moreover, we demonstrated that klotho modulated the resistance to cisplatin in a xenograft nude mice model. These observations suggested that klotho could improve the resistance of lung cancer cells to chemotherapy and may serve as a potential target for the gene therapy of lung cancers resistant to cisplatin based chemotherapy. PMID- 23437383 TI - Stimulus-response-outcome coding in the pigeon nidopallium caudolaterale. AB - A prerequisite for adaptive goal-directed behavior is that animals constantly evaluate action outcomes and relate them to both their antecedent behavior and to stimuli predictive of reward or non-reward. Here, we investigate whether single neurons in the avian nidopallium caudolaterale (NCL), a multimodal associative forebrain structure and a presumed analogue of mammalian prefrontal cortex, represent information useful for goal-directed behavior. We subjected pigeons to a go-nogo task, in which responding to one visual stimulus (S+) was partially reinforced, responding to another stimulus (S-) was punished, and responding to test stimuli from the same physical dimension (spatial frequency) was inconsequential. The birds responded most intensely to S+, and their response rates decreased monotonically as stimuli became progressively dissimilar to S+; thereby, response rates provided a behavioral index of reward expectancy. We found that many NCL neurons' responses were modulated in the stimulus discrimination phase, the outcome phase, or both. A substantial fraction of neurons increased firing for cues predicting non-reward or decreased firing for cues predicting reward. Interestingly, the same neurons also responded when reward was expected but not delivered, and could thus provide a negative reward prediction error or, alternatively, signal negative value. In addition, many cells showed motor-related response modulation. In summary, NCL neurons represent information about the reward value of specific stimuli, instrumental actions as well as action outcomes, and therefore provide signals useful for adaptive behavior in dynamically changing environments. PMID- 23437384 TI - Serum metalloproteinases 2 and 9 as predictors of gait status, pressure ulcer and mortality after hip fracture. AB - INTRODUCTION: The aim of this study is to evaluate the serum activity of metalloproteinases (MMPs) -2 and -9 as predictors of pressure ulcer (PU), gait status and mortality 6 months after hip fracture. METHODS: Eighty-seven patients over the age of 65 admitted to the orthopedic unit from January to December 2010 with hip fracture were prospectively evaluated. Upon admission, patient demographic information, including age, gender and concomitant diseases, was recorded. Blood samples were taken for analysis of MMP -2 and -9 activity by gel zymography and for biochemical examination within the first 72 hours of the patient's admission, after clinical stabilization. The fracture pattern (neck, trochanteric or subtrochanteric), time from admission to surgery, surgery duration and length of hospital stay were also recorded. RESULTS: Two patients were excluded due to the presence of pathological fractures (related to cancer), and three patients were excluded due to the presence of PU before admission. Eighty-two patients, with a mean age of 80.4 +/- 7.3 years, were included in the analysis. Among these patients, 75.6% were female, 59.8% had PU, and 13.4% died 6 months after hip fracture. All patients underwent hip fracture repair. In a univariate analysis, there were no differences in serum MMP activity between hip fracture patients with or without PU. In addition, the multiple logistic regression analysis models, which were adjusted by age, gender, length of hospital stay and C-reactive protein, showed that the pro-MMP-9 complexed with neutrophil gelatinase-associated lipocalin form (130 kDa) was associated with gait status recovery 6 months after hip fracture. CONCLUSIONS: In conclusion, serum pro-MMP-9 is a predictor of gait status recovery 6 months after hip fracture. PMID- 23437385 TI - Evolution of premotor cortical excitability after cathodal inhibition of the primary motor cortex: a sham-controlled serial navigated TMS study. AB - BACKGROUND: Premotor cortical regions (PMC) play an important role in the orchestration of motor function, yet their role in compensatory mechanisms in a disturbed motor system is largely unclear. Previous studies are consistent in describing pronounced anatomical and functional connectivity between the PMC and the primary motor cortex (M1). Lesion studies consistently show compensatory adaptive changes in PMC neural activity following an M1 lesion. Non-invasive brain modification of PMC neural activity has shown compensatory neurophysiological aftereffects in M1. These studies have contributed to our understanding of how M1 responds to changes in PMC neural activity. Yet, the way in which the PMC responds to artificial inhibition of M1 neural activity is unclear. Here we investigate the neurophysiological consequences in the PMC and the behavioral consequences for motor performance of stimulation mediated M1 inhibition by cathodal transcranial direct current stimulation (tDCS). PURPOSE: The primary goal was to determine how electrophysiological measures of PMC excitability change in order to compensate for inhibited M1 neural excitability and attenuated motor performance. HYPOTHESIS: Cathodal inhibition of M1 excitability leads to a compensatory increase of ipsilateral PMC excitability. METHODS: We enrolled 16 healthy participants in this randomized, double-blind, sham-controlled, crossover design study. All participants underwent navigated transcranial magnetic stimulation (nTMS) to identify PMC and M1 corticospinal projections as well as to evaluate electrophysiological measures of cortical, intracortical and interhemispheric excitability. Cortical M1 excitability was inhibited using cathodal tDCS. Finger-tapping speeds were used to examine motor function. RESULTS: Cathodal tDCS successfully reduced M1 excitability and motor performance speed. PMC excitability was increased for longer and was the only significant predictor of motor performance. CONCLUSION: The PMC compensates for attenuated M1 excitability and contributes to motor performance maintenance. PMID- 23437386 TI - NF-kappaB-dependent role for cold-inducible RNA binding protein in regulating interleukin 1beta. AB - The cold inducible RNA binding protein (CIRBP) responds to a wide array of cellular stresses, including short wavelength ultraviolet light (UVC), at the transcriptional and post-translational level. CIRBP can bind the 3'untranslated region of specific transcripts to stabilize them and facilitate their transport to ribosomes for translation. Here we used RNA interference and oligonucleotide microarrays to identify potential downstream targets of CIRBP induced in response to UVC. Twenty eight transcripts were statistically increased in response to UVC and these exhibited a typical UVC response. Only 5 of the 28 UVC-induced transcripts exhibited a CIRBP-dependent pattern of expression. Surprisingly, 3 of the 5 transcripts (IL1B, IL8 and TNFAIP6) encoded proteins important in inflammation with IL-1beta apparently contributing to IL8 and TNFAIP6 expression in an autocrine fashion. UVC-induced IL1B expression could be inhibited by pharmacological inhibition of NFkappaB suggesting that CIRBP was affecting NF kappaB signaling as opposed to IL1B mRNA stability directly. Bacterial lipopolysaccharide (LPS) was used as an activator of NF-kappaB to further study the potential link between CIRBP and NFkappaB. Transfection of siRNAs against CIRBP reduced the extent of the LPS-induced phosphorylation of IkappaBalpha, NF kappaB DNA binding activity and IL-1beta expression. The present work firmly establishes a novel link between CIRBP and NF-kappaB signaling in response to agents with diverse modes of action. These results have potential implications for disease states associated with inflammation. PMID- 23437387 TI - "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? AB - Cyclic peptides are increasingly being shown as powerful inhibitors of fibril formation, and have the potential to be therapeutic agents for combating many debilitating amyloid-related diseases. One such example is a cyclic peptide derivative from the human apolipoprotein C-II, which has the ability to inhibit fibril formation by the fibrillogenic peptide apoC-II(60-70). Using classical molecular dynamics and electronic structure calculations, we were able to provide insight into the interaction between the amyloidogenic peptide apoC-II(60-70) and its cyclic derivative, cyc(60-70). Our results showed that cyc(60-70) induced increased flexibility in apoC-II(60-70), suggesting that one mechanism by which cyc(60-70) inhibits fibrillisation is by destabilising apoC-II(60-70) structure, rendering it incapable of adopting fibril favouring conformations. In contrast, cyc(60-70) shows less flexibility upon binding to apoC-II(60-70), which is predominantly mediated by hydrophobic interactions between the aromatic rings of the peptides. This effectively creates a cap around the fibril-forming region of apoC-II(60-70) and generates an outer hydrophilic shell that discourages further apoC-II(60-70) peptide self-association. We showed that apoC-II(60-70) exhibited stronger binding affinity for the hydrophobic face of cyc(60-70) and weakest binding affinity for the hydrophilic side. This suggests that cyc(60-70) can be an effective fibril inhibitor due to its amphipathic character, like that of the "Janus"-type particles. This property can be exploited in the design of specific inhibitors of amyloid fibril formation. PMID- 23437388 TI - Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. AB - Epilepsy is a common neurological disorder and cause of significant morbidity and mortality. Although antiseizure medication is the first-line treatment for epilepsy, currently available medications are ineffective in a significant percentage of patients and have not clearly been demonstrated to have disease specific effects for epilepsy. While seizures are usually intractable to medication in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, vigabatrin appears to have unique efficacy for epilepsy in TSC. While vigabatrin increases gamma-aminobutyric acid (GABA) levels, the precise mechanism of action of vigabatrin in TSC is not known. In this study, we investigated the effects of vigabatrin on epilepsy in a knock-out mouse model of TSC and tested the novel hypothesis that vigabatrin inhibits the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in TSC. We found that vigabatrin caused a modest increase in brain GABA levels and inhibited seizures in the mouse model of TSC. Furthermore, vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the knock-out mice in vivo, as well as reduced mTOR pathway activation in cultured astrocytes from both knock out and control mice. This study identifies a potential novel mechanism of action of an antiseizure medication involving the mTOR pathway, which may account for the unique efficacy of this drug for a genetic epilepsy. PMID- 23437389 TI - Revisiting a sample of U.S. billionaires: how sample selection and timing of maternal condition influence findings on the Trivers-Willard effect. AB - Based on evolutionary theory, Trivers & Willard (TW) predicted the existence of mechanisms that lead parents with high levels of resources to bias offspring sex composition to favor sons and parents with low levels of resources to favor daughters. This hypothesis has been tested in samples of wealthy individuals but with mixed results. Here, I argue that both sample selection due to a high number of missing cases and a lacking specification of the timing of wealth accumulation contribute to this equivocal pattern. This study improves on both issues: First, analyses are based on a data set of U.S. billionaires with near-complete information on the sex of offspring. Second, subgroups of billionaires are distinguished according to the timing when they acquired their wealth. Informed by recent insights on the timing of a potential TW effect in animal studies, I state two hypotheses. First, billionaires have a higher share of male offspring than the general population. Second, this effect is larger for heirs and heiresses who are wealthy at the time of conception of all of their children than for self-made billionaires who acquired their wealth during their adult lives, that is, after some or all of their children have already been conceived. Results do not support the first hypothesis for all subgroups of billionaires. But for males, results are weakly consistent with the second hypothesis: Heirs but not self-made billionaires have a higher share of male offspring than the U.S. population. Heiresses, on the other hand, have a much lower share of male offspring than the U.S. average. This hints to a possible interplay of at least two mechanisms affecting sex composition. Implications for future research that would allow disentangling the distinct mechanisms are discussed. PMID- 23437390 TI - Trypanosoma cruzi coaxes cardiac fibroblasts into preventing cardiomyocyte death by activating nerve growth factor receptor TrkA. AB - RATIONALE: Cardiomyocytes express neurotrophin receptor TrkA that promotes survival following nerve growth factor (NGF) ligation. Whether TrkA also resides in cardiac fibroblasts (CFs) and underlies cardioprotection is unknown. OBJECTIVE: To test whether CFs express TrkA that conveys paracrine signals to neighbor cardiomyocytes using, as probe, the Chagas disease parasite Trypanosoma cruzi, which expresses a TrkA-binding neurotrophin mimetic, named PDNF. T. cruzi targets the heart, causing chronic debilitating cardiomyopathy in ~30% patients. METHODS AND RESULTS: Basal levels of TrkA and TrkC in primary CFs are comparable to those in cardiomyocytes. However, in the myocardium, TrkA expression is significantly lower in fibroblasts than myocytes, and vice versa for TrkC. Yet T. cruzi recognition of TrkA on fibroblasts, preferentially over cardiomyocytes, triggers a sharp and sustained increase in NGF, including in the heart of infected mice or of mice administered PDNF intravenously, as early as 3-h post administration. Further, NGF-containing T. cruzi- or PDNF-induced fibroblast conditioned medium averts cardiomyocyte damage by H(2)O(2), in agreement with the previously recognized cardioprotective role of NGF. CONCLUSIONS: TrkA residing in CFs induces an exuberant NGF production in response to T. cruzi infection, enabling, in a paracrine fashion, myocytes to resist oxidative stress, a leading Chagas cardiomyopathy trigger. Thus, PDNF-TrkA interaction on CFs may be a mechanism orchestrated by T. cruzi to protect its heart habitat, in concert with the long-term (decades) asymptomatic heart parasitism that characterizes Chagas disease. Moreover, as a potent booster of cardioprotective NGF in vivo, PDNF may offer a novel therapeutic opportunity against cardiomyopathies. PMID- 23437392 TI - Pesticide acute toxicity is a better correlate of U.S. grassland bird declines than agricultural intensification. AB - Common agricultural birds are in decline, both in Europe and in North America. Evidence from Europe suggests that agricultural intensification and, for some species, the indirect effects of pesticides mediated through a loss of insect food resource is in part responsible. On a state-by-state basis for the conterminous Unites States (U.S.), we looked at several agronomic variables to predict the number of grassland species increasing or declining according to breeding bird surveys conducted between 1980 and 2003. Best predictors of species declines were the lethal risk from insecticide use modeled from pesticide impact studies, followed by the loss of cropped pasture. Loss of permanent pasture or simple measures of agricultural intensification such as the proportion of land under crop or the proportion of farmland treated with herbicides did not explain bird declines as well. Because the proportion of farmland treated with insecticides, and more particularly the lethal risk to birds from the use of current insecticides feature so prominently in the best models, this suggests that, in the U.S. at least, pesticide toxicity to birds should be considered as an important factor in grassland bird declines. PMID- 23437391 TI - Characterisation of K+ channels in human fetoplacental vascular smooth muscle cells. AB - Adequate blood flow through placental chorionic plate resistance arteries (CPAs) is necessary for oxygen and nutrient transfer to the fetus and a successful pregnancy. In non-placental vascular smooth muscle cells (SMCs), K(+) channels regulate contraction, vascular tone and blood flow. Previous studies showed that K(+) channel modulators alter CPA tone, but did not distinguish between effects on K(+) channels in endothelial cells and SMCs. In this study, we developed a preparation of freshly isolated CPASMCs of normal pregnancy and investigated K(+) channel expression and function. CPASMCs were isolated from normal human term placentas using enzymatic digestion. Purity and phenotype was confirmed with immunocytochemistry. Whole-cell patch clamp was used to assess K(+) channel currents, and mRNA and protein expression was determined in intact CPAs and isolated SMCs with RT-PCR and immunostaining. Isolated SMCs expressed alpha-actin but not CD31, a marker of endothelial cells. CPASMCs and intact CPAs expressed h caldesmon and non-muscle myosin heavy chain-2; phenotypic markers of contractile and synthetic SMCs respectively. Whole-cell currents were inhibited by 4-AP, TEA, charybdotoxin and iberiotoxin implicating functional K(v) and BK(Ca) channels. 1 EBIO enhanced whole cell currents which were abolished by TRAM-34 and reduced by apamin indicating activation of IK(Ca) and SK(Ca) respectively. BK(Ca), IK(Ca) and SK(Ca)3 mRNA and/or protein were expressed in CPASMCs and intact CPAs. This study provides the first direct evidence for functional K(v), BK(Ca,) IK(Ca) and SK(Ca) channels in CPASMCs. These cells display a mixed phenotype implicating a dual role for CPASMCs in controlling both fetoplacental vascular resistance and vasculogenesis. PMID- 23437393 TI - Internet-based screening for dementia risk. AB - The Dementia Risk Assessment (DRA) is an online tool consisting of questions about known risk factors for dementia, a novel verbal memory test, and an informant report of cognitive decline. Its primary goal is to educate the public about dementia risk factors and encourage clinical evaluation where appropriate. In Study 1, more than 3,000 anonymous persons over age 50 completed the DRA about themselves; 1,000 people also completed proxy reports about another person. Advanced age, lower education, male sex, complaints of severe memory impairment, and histories of cerebrovascular disease, Parkinson's disease, and brain tumor all contributed significantly to poor memory performance. A high correlation was obtained between proxy-reported decline and actual memory test performance. In Study 2, 52 persons seeking first-time evaluation at dementia clinics completed the DRA prior to their visits. Their responses (and those of their proxy informants) were compared to the results of independent evaluation by geriatric neuropsychiatrists. The 30 patients found to meet criteria for probable Alzheimer's disease, vascular dementia, or frontotemporal dementia differed on the DRA from the 22 patients without dementia (most other neuropsychiatric conditions). Scoring below criterion on the DRA's memory test had moderately high predictive validity for clinically diagnosed dementia. Although additional studies of larger clinical samples are needed, the DRA holds promise for wide scale screening for dementia risk. PMID- 23437394 TI - 3-D worm tracker for freely moving C. elegans. AB - The manner in which the nervous system regulates animal behaviors in natural environments is a fundamental issue in biology. To address this question, C. elegans has been widely used as a model animal for the analysis of various animal behaviors. Previous behavioral assays have been limited to two-dimensional (2-D) environments, confining the worm motion to a planar substrate that does not reflect three-dimensional (3-D) natural environments such as rotting fruits or soil. Here, we develop a 3-D worm tracker (3DWT) for freely moving C. elegans in 3-D environments, based on a stereoscopic configuration. The 3DWT provides us with a quantitative trajectory, including the position and movement direction of the worm in 3-D. The 3DWT is also capable of recording and visualizing postures of the moving worm in 3-D, which are more complex than those in 2-D. Our 3DWT affords new opportunities for understanding the nervous system function that regulates animal behaviors in natural 3-D environments. PMID- 23437395 TI - Characterization of P2X7R and its function in the macrophages of ayu, Plecoglossus altivelis. AB - P2X purinoceptor 7 (P2X7R), an ATP-gated ion channel, plays an important role during the innate immune response in mammals. However, relatively little is known about the role of P2X7R in the fish immune system. Here, we cloned a cDNA sequence encoding ayu (Plecoglossus altivelis) P2X7R (aP2X7R). The predicted protein was composed of 574 amino acid residues with a P2X family signature, two transmembrane domains, and a long C-terminal. aP2X7R transcripts were mainly distributed in ayu immune tissues and significantly increased in all tested tissues and in macrophages after Listonella anguillarum infection. The aP2X7R protein was upregulated significantly in macrophages upon bacterial challenge. An antibody against the ectodomain of aP2X7R (aEPAb) and an antagonist (oATP) were used to block aP2X7R. aP2X7R siRNA was also used to knockdown the receptor expression in ayu macrophages. Cell death induced by ATP was significantly inhibited in ayu macrophages after aEPAb, oATP, or siRNA treatment. Moreover, aP2X7R ablation also resulted in suppression of phagocytic activity and ATP induced bacterial killing in ayu macrophages. Our results indicated that aP2X7R was upregulated after infection and mediated cell death, phagocytosis, and bacterial killing of ayu macrophages. PMID- 23437396 TI - Tight interconnection and multi-level control of Arabidopsis MYB44 in MAPK cascade signalling. AB - Abiotic stress poses a huge, ever-increasing problem to plants and agriculture. The dissection of signalling pathways mediating stress tolerance is a prerequisite to develop more resistant plant species. Mitogen-activated protein kinase (MAPK) cascades are universal signalling modules. In Arabidopsis, the MAPK MPK3 and its upstream regulator MAPK kinase MKK4 initiate the adaptation response to numerous abiotic and biotic stresses. Yet, molecular steps directly linked with MKK4-MPK3 activation are largely unknown. Starting with a yeast-two-hybrid screen for interacting partners of MKK4, we identified a transcription factor, MYB44. MYB44 is controlled at multiple levels by and strongly inter-connected with MAPK signalling. As we had shown earlier, stress-induced expression of the MYB44 gene is regulated by a MPK3-targeted bZIP transcription factor VIP1. At the protein level, MYB44 interacts with MPK3 in vivo. MYB44 is phosphorylated by MPK3 in vitro at a single residue, Ser145. Although replacement of Ser145 by a non phosphorylatable (S145A) or phosphomimetic (S145D) residue did not alter MYB44 subcellular localisation, dimerization behaviour nor DNA-binding characteristics, abiotic stress tolerance tests in stable transgenic Arabidopsis plants clearly related S145 phosphorylation to MYB44 function: Compared to Arabidopsis wild type plants, MYB44 overexpressing lines exhibit an enhanced tolerance to osmotic stress and are slightly more sensitive to abscisic acid. Interestingly, overexpression of the S145A variant revealed that impaired phosphorylation does not render the MYB44 protein non-functional. Instead, S145A lines are highly sensitive to abiotic stress, and thereby remarkably similar to mpk3-deficient plants. Its in vivo interaction with the nuclear sub-pools of both MPK3 and MKK4 renders MYB44 the first plant transcription factor to have a second function as putative MAPK cascade scaffolding protein. PMID- 23437397 TI - Dissemination and transmission of the E1-226V variant of chikungunya virus in Aedes albopictus are controlled at the midgut barrier level. AB - Emergence of arboviruses could result from their ability to exploit new environments, for example a new host. This ability is facilitated by the high mutation rate occurring during viral genome replication. The last emergence of chikungunya in the Indian Ocean region corroborates this statement since a single viral mutation at the position 226 on the E1 glycoprotein (E1-A226V) was associated with enhanced transmission by the mosquito Aedes albopictus in regions where the major mosquito vector, Aedes aegypti, is absent.We used direct competition assays in vivo to dissect out the mechanisms underlying the selection of E1-226V by Ae. albopictus. When the original variant E1-226A and the newly emerged E1-226V were provided in the same blood-meal at equal titers to both species of mosquitoes, we found that the proportion of both variants was drastically different in the two mosquito species. Following ingestion of the infectious blood-meal, the E1-226V variant was preferentially selected in Ae. albopictus, whereas the E1-226A variant was sometimes favored in Ae. aegypti. Interestingly, when the two variants were introduced into the mosquitoes by intrathoracic inoculations, E1-226V was no longer favored for dissemination and transmission in Ae. albopictus, showing that the midgut barrier plays a key role in E1-226V selection.This study sheds light on the role of the midgut barrier in the selection of novel arbovirus emerging variants. We also bring new insight into how the pre-existing variant E1-226V was selected among other viral variants including E1-226A. Indeed the E1-226V variant present at low levels in natural viral populations could rapidly emerge after being selected in Ae. albopictus at the midgut barrier level. PMID- 23437398 TI - Weekly doxorubicin increases coronary arteriolar wall and adventitial thickness. AB - BACKGROUND: Doxorubicin (DOX) is associated with premature cardiovascular events including myocardial infarction. This study was performed to determine if the weekly administration of DOX influenced coronary arteriolar medial and/or adventitial wall thickening. METHODS: Thirty-two male Sprague-Dawley rats aged 25.1+/- 2.4 weeks were randomly divided into three groups and received weekly intraperitoneal injections of normal saline (saline, n = 7), or low (1.5 mg/kg to 1.75 mg/kg, n = 14) or high (2.5 mg/kg, n = 11) doses of DOX. The animals were treated for 2-12 weeks, and euthanized at pre-specified intervals (2, 4, 7, or 10+ weeks) to obtain histopathologic assessments of coronary arteriolar lumen diameter, medial wall thickness, adventitial wall thickness, and total wall thickness (medial thickness + adventitial thickness). RESULTS: Lumen diameter was similar across all groups (saline: 315+/-34 um, low DOX: 286+/-24 um, high DOX: 242+/-27 um; p = 0.22). In comparison to animals receiving weekly saline, animals receiving weekly injections of 2.5 mg/kg of DOX experienced an increase in medial (23+/-2 um vs. 13+/-3 um; p = 0.005), and total wall thickness (51+/-4 um vs. 36+/-5 um; p = 0.022), respectively. These increases, as well as adventitial thickening became more prominent after normalizing for lumen diameter (p<0.05 to p<0.001) and after adjusting for age, weight, and total cumulative DOX dose (p = 0.02 to p = 0.01). Animals receiving low dose DOX trended toward increases in adventitial and total wall thickness after normalization to lumen diameter and accounting for age, weight, and total cumulative DOX dose (p = 0.06 and 0.09, respectively). CONCLUSION: In conclusion, these data demonstrate that weekly treatment of rats with higher doses of DOX increases coronary arteriolar medial, adventitial, and total wall thickness. Future studies are warranted to determine if DOX related coronary arteriolar effects are reversible or preventable, exacerbate the known cardiomyopathic effects of DOX, influence altered resting or stress-induced myocardial perfusion, or contribute to the occurrence of myocardial infarction. PMID- 23437400 TI - Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Sprague-Dawley rat offspring. AB - Early life events can significantly alter the development of the nociceptive circuit. In fact, clinical work has shown that maternal adversity, in the form of depression, and concomitant selective serotonin reuptake inhibitor (SSRI) treatment influence nociception in infants. The combined effects of maternal adversity and SSRI exposure on offspring nociception may be due to their effects on the developing hypothalamic-pituitary-adrenal (HPA) system. Therefore, the present study investigated long-term effects of maternal adversity and/or SSRI medication use on nociception of adult Sprague-Dawley rat offspring, taking into account involvement of the HPA system. Dams were subject to stress during gestation and were treated with fluoxetine (2*/5 mg/kg/day) prior to parturition and throughout lactation. Four groups of adult male offspring were used: 1. Control+Vehicle, 2. Control+Fluoxetine, 3. Prenatal Stress+Vehicle, 4. Prenatal Stress+Fluoxetine. Results show that post-operative pain, measured as hypersensitivity to mechanical stimuli after hind paw incision, was decreased in adult offspring subject to prenatal stress alone and increased in offspring developmentally exposed to fluoxetine alone. Moreover, post-operative pain was normalized in prenatally stressed offspring exposed to fluoxetine. This was paralleled by a decrease in corticosteroid binding globulin (CBG) levels in prenatally stressed offspring and a normalization of serum CBG levels in prenatally stressed offspring developmentally exposed to fluoxetine. Thus, developmental fluoxetine exposure normalizes the long-term effects of maternal adversity on post-operative pain in offspring and these effects may be due, in part, to the involvement of the HPA system. PMID- 23437401 TI - Characterization of a novel mouse model of multiple myeloma and its use in preclinical therapeutic assessment. AB - To aid preclinical development of novel therapeutics for myeloma, an in vivo model which recapitulates the human condition is required. An important feature of such a model is the interaction of myeloma cells with the bone marrow microenvironment, as this interaction modulates tumour activity and protects against drug-induced apoptosis. Therefore NOD/SCIDgammac(null) mice were injected intra-tibially with luciferase-tagged myeloma cells. Disease progression was monitored by weekly bioluminescent imaging (BLI) and measurement of paraprotein levels. Results were compared with magnetic resonance imaging (MRI) and histology. Assessment of model suitability for preclinical drug testing was investigated using bortezomib, melphalan and two novel agents. Cells engrafted at week 3, with a significant increase in BLI radiance occurring between weeks 5 and 7. This was accompanied by an increase in paraprotein secretion, MRI-derived tumour volume and CD138 positive cells within the bone marrow. Treatment with known anti-myeloma agents or novel agents significantly attenuated the increase in all disease markers. In addition, intra-tibial implantation of primary patient plasma cells resulted in development of myeloma within bone marrow. In conclusion, using both myeloma cell lines and primary patient cells, we have developed a model which recapitulates human myeloma by ensuring the key interaction of tumour cells with the microenvironment. PMID- 23437402 TI - Of mice, men and elephants: the relation between articular cartilage thickness and body mass. AB - Mammalian articular cartilage serves diverse functions, including shock absorption, force transmission and enabling low-friction joint motion. These challenging requirements are met by the tissue's thickness combined with its highly specific extracellular matrix, consisting of a glycosaminoglycan interspersed collagen fiber network that provides a unique combination of resilience and high compressive and shear resistance. It is unknown how this critical tissue deals with the challenges posed by increases in body mass. For this study, osteochondral cores were harvested post-mortem from the central sites of both medial and lateral femoral condyles of 58 different mammalian species ranging from 25 g (mouse) to 4000 kg (African elephant). Joint size and cartilage thickness were measured and biochemical composition (glycosaminoclycan, collagen and DNA content) and collagen cross-links densities were analyzed. Here, we show that cartilage thickness at the femoral condyle in the mammalian species investigated varies between 90 um and 3000 um and bears a negative allometric relationship to body mass, unlike the isometric scaling of the skeleton. Cellular density (as determined by DNA content) decreases with increasing body mass, but gross biochemical composition is remarkably constant. This however need not affect life-long performance of the tissue in heavier mammals, due to relatively constant static compressive stresses, the zonal organization of the tissue and additional compensation by joint congruence, posture and activity pattern of larger mammals. These findings provide insight in the scaling of articular cartilage thickness with body weight, as well as in cartilage biochemical composition and cellularity across mammalian species. They underscore the need for the use of appropriate in vivo models in translational research aiming at human applications. PMID- 23437403 TI - Lactate dehydrogenase-B is silenced by promoter methylation in a high frequency of human breast cancers. AB - OBJECTIVE: Under normoxia, non-malignant cells rely on oxidative phosphorylation for their ATP production, whereas cancer cells rely on Glycolysis; a phenomenon known as the Warburg effect. We aimed to elucidate the mechanisms contributing to the Warburg effect in human breast cancer. EXPERIMENTAL DESIGN: Lactate Dehydrogenase (LDH) isoenzymes were profiled using zymography. LDH-B subunit expression was assessed by reverse transcription PCR in cells, and by Immunohistochemistry in breast tissues. LDH-B promoter methylation was assessed by sequencing bisulfite modified DNA. RESULTS: Absent or decreased expression of LDH isoenzymes 1-4, were seen in T-47D and MCF7 cells. Absence of LDH-B mRNA was seen in T-47D cells, and its expression was restored following treatment with the demethylating agent 5'Azacytadine. LDH-B promoter methylation was identified in T 47D and MCF7 cells, and in 25/25 cases of breast cancer tissues, but not in 5/5 cases of normal breast tissues. Absent immuno-expression of LDH-B protein (<10% cells stained), was seen in 23/26 (88%) breast cancer cases, and in 4/8 cases of adjacent ductal carcinoma in situ lesions. Exposure of breast cancer cells to hypoxia (1% O(2)), for 48 hours resulted in significant increases in lactate levels in both MCF7 (14.0 fold, p = 0.002), and T-47D cells (2.9 fold, p = 0.009), but not in MDA-MB-436 (-0.9 fold, p = 0.229), or MCF10AT (1.2 fold, p = 0.09) cells. CONCLUSIONS: Loss of LDH-B expression is an early and frequent event in human breast cancer occurring due to promoter methylation, and is likely to contribute to an enhanced glycolysis of cancer cells under hypoxia. PMID- 23437404 TI - Alpha-tomatine attenuation of in vivo growth of subcutaneous and orthotopic xenograft tumors of human prostate carcinoma PC-3 cells is accompanied by inactivation of nuclear factor-kappa B signaling. AB - BACKGROUND: Nuclear factor-kappa B (NF-kappaB) plays a role in prostate cancer and agents that suppress its activation may inhibit development or progression of this malignancy. Alpha (alpha)-tomatine is the major saponin present in tomato (Lycopersicon esculentum) and we have previously reported that it suppresses tumor necrosis factor-alpha (TNF-alpha)-induced nuclear translocation of nuclear factor-kappa B (NF-kappaB) in androgen-independent prostate cancer PC-3 cells and also potently induces apoptosis of these cells. However, the precise mechanism by which alpha-tomatine suppresses NF-kappaB nuclear translocation is yet to be elucidated and the anti-tumor activity of this agent in vivo has not been examined. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we show that suppression of NF-kappaB activation by alpha-tomatine occurs through inhibition of I kappa B alpha (IkappaBalpha) kinase activity, leading to sequential suppression of IkappaBalpha phosphorylation, IkappaBalpha degradation, NF kappaB/p65 phosphorylation, and NF-kappaB p50/p65 nuclear translocation. Consistent with its ability to induce apoptosis, alpha-tomatine reduced TNF-alpha induced activation of the pro-survival mediator Akt and its inhibition of NF kappaB activation was accompanied by significant reduction in the expression of NF-kappaB-dependent anti-apoptotic (c-IAP1, c-IAP2, Bcl-2, Bcl-xL, XIAP and survivin) proteins. We also evaluated the antitumor activity of alpha-tomatine against PC-3 cell tumors grown subcutaneously and orthotopically in mice. Our data indicate that intraperitoneal administration of alpha-tomatine significantly attenuates the growth of PC-3 cell tumors grown at both sites. Analysis of tumor material indicates that the tumor suppressing effects of alpha-tomatine were accompanied by increased apoptosis and lower proliferation of tumor cells as well as reduced nuclear translocation of the p50 and p65 components of NF-kappaB. CONCLUSION/SIGNIFICANCE: Our study provides first evidence for in vivo antitumor efficacy of alpha-tomatine against the human androgen-independent prostate cancer. The potential usefulness of alpha-tomatine in prostate cancer prevention and therapy requires further investigation. PMID- 23437399 TI - A single CD4 test with 250 cells/mm3 threshold predicts viral suppression in HIV infected adults failing first-line therapy by clinical criteria. AB - BACKGROUND: In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically determined ART failure when VL is unavailable. METHODS: 3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4<100 cells/mm(3)) were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55%) participants. RESULTS: Overall, 265/361 (73%) LCM participants failed with CD4<100 cells/mm(3); only 7 (2%) switched with CD4>=250 cells/mm(3), four switches triggered by WHO events. Without CD4 monitoring, 207/314 (66%) CDM participants failed with WHO 4 events, and 77(25%)/30(10%) with single/multiple WHO 3 events. Failure/switching with single WHO 3 events was more likely with CD4>=250 cells/mm(3) (28/77; 36%) (p = 0.0002). CD4 monitoring reduced switching with viral suppression: 23/187 (12%) LCM versus 49/181 (27%) CDM had VL<400 copies/ml at failure/switch (p<0.0001). Amongst CDM participants with CD4<250 cells/mm(3) only 11/133 (8%) had VL<400 copies/ml, compared with 38/48 (79%) with CD4>=250 cells/mm(3) (p<0.0001). CONCLUSION: Multiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold 'tiebreaker' of >=250 cells/mm(3) for clinically-monitored patients failing first-line could identify ~80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 'clinical failures' would particularly avoid premature, costly switch to second-line ART. PMID- 23437405 TI - Molecular epidemiology of human oral Chagas disease outbreaks in Colombia. AB - BACKGROUND: Trypanosoma cruzi, the causative agent of Chagas disease, displays significant genetic variability revealed by six Discrete Typing Units (TcI-TcVI). In this pathology, oral transmission represents an emerging epidemiological scenario where different outbreaks associated to food/beverages consumption have been reported in Argentina, Bolivia, Brazil, Ecuador and Venezuela. In Colombia, six human oral outbreaks have been reported corroborating the importance of this transmission route. Molecular epidemiology of oral outbreaks is barely known observing the incrimination of TcI, TcII, TcIV and TcV genotypes. METHODOLOGY AND PRINCIPAL FINDINGS: High-throughput molecular characterization was conducted performing MLMT (Multilocus Microsatellite Typing) and mtMLST (mitochondrial Multilocus Sequence Typing) strategies on 50 clones from ten isolates. Results allowed observing the occurrence of TcI, TcIV and mixed infection of distinct TcI genotypes. Thus, a majority of specific mitochondrial haplotypes and allelic multilocus genotypes associated to the sylvatic cycle of transmission were detected in the dataset with the foreseen presence of mitochondrial haplotypes and allelic multilocus genotypes associated to the domestic cycle of transmission. CONCLUSIONS: These findings suggest the incrimination of sylvatic genotypes in the oral outbreaks occurred in Colombia. We observed patterns of super-infection and/or co-infection with a tailored association with the severe forms of myocarditis in the acute phase of the disease. The transmission dynamics of this infection route based on molecular epidemiology evidence was unraveled and the clinical and biological implications are discussed. PMID- 23437406 TI - Economic and disease burden of dengue in Southeast Asia. AB - BACKGROUND: Dengue poses a substantial economic and disease burden in Southeast Asia (SEA). Quantifying this burden is critical to set policy priorities and disease-control strategies. METHODS AND FINDINGS: We estimated the economic and disease burden of dengue in 12 countries in SEA: Bhutan, Brunei, Cambodia, East Timor, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Viet Nam. We obtained reported cases from multiple sources--surveillance data, World Health Organization (WHO), and published studies--and adjusted for underreporting using expansion factors from previous literature. We obtained unit costs per episode through a systematic literature review, and completed missing data using linear regressions. We excluded costs such as prevention and vector control, and long-term sequelae of dengue. Over the decade of 2001-2010, we obtained an annual average of 2.9 million (m) dengue episodes and 5,906 deaths. The annual economic burden (with 95% certainty levels) was US$950m (US$610m US$1,384m) or about US$1.65 (US$1.06-US$2.41) per capita. The annual number of disability-adjusted life years (DALYs), based on the original 1994 definition, was 214,000 (120,000-299,000), which is equivalent to 372 (210-520) DALYs per million inhabitants. CONCLUSION: Dengue poses a substantial economic and disease burden in SEA with a DALY burden per million inhabitants in the region. This burden is higher than that of 17 other conditions, including Japanese encephalitis, upper respiratory infections, and hepatitis B. PMID- 23437407 TI - Use of expansion factors to estimate the burden of dengue in Southeast Asia: a systematic analysis. AB - BACKGROUND: Dengue virus infection is the most common arthropod-borne disease of humans and its geographical range and infection rates are increasing. Health policy decisions require information about the disease burden, but surveillance systems usually underreport the total number of cases. These may be estimated by multiplying reported cases by an expansion factor (EF). METHODS AND FINDINGS: As a key step to estimate the economic and disease burden of dengue in Southeast Asia (SEA), we projected dengue cases from 2001 through 2010 using EFs. We conducted a systematic literature review (1995-2011) and identified 11 published articles reporting original, empirically derived EFs or the necessary data, and 11 additional relevant studies. To estimate EFs for total cases in countries where no empirical studies were available, we extrapolated data based on the statistically significant inverse relationship between an index of a country's health system quality and its observed reporting rate. We compiled an average 386,000 dengue episodes reported annually to surveillance systems in the region, and projected about 2.92 million dengue episodes. We conducted a probabilistic sensitivity analysis, simultaneously varying the most important parameters in 20,000 Monte Carlo simulations, and derived 95% certainty level of 2.73-3.38 million dengue episodes. We estimated an overall EF in SEA of 7.6 (95% certainty level: 7.0-8.8) dengue cases for every case reported, with an EF range of 3.8 for Malaysia to 19.0 in East Timor. CONCLUSION: Studies that make no adjustment for underreporting would seriously understate the burden and cost of dengue in SEA and elsewhere. As the sites of the empirical studies we identified were not randomly chosen, the exact extent of underreporting remains uncertain. Nevertheless, the results reported here, based on a systematic analysis of the available literature, show general consistency and provide a reasonable empirical basis to adjust for underreporting. PMID- 23437408 TI - A newly emerged cutaneous leishmaniasis focus in northern Israel and two new reservoir hosts of Leishmania major. AB - In 2006/7, 18 cases of cutaneous leishmaniasis (CL) were reported for the first time from Sde Eliyahu (pop. 650), a village in the Beit She'an valley of Israel. Between 2007-2011, a further 88 CL cases were diagnosed bringing the total to 106 (16.3% of the population of Sde Eliyahu). The majority of cases resided in the south-western part of the village along the perimeter fence. The causative parasite was identified as Leishmania major Yakimoff & Schokhor, 1914 (Kinetoplastida: Trypanosomatidae). Phlebotomus papatasi (Scopoli), 1786 (Diptera: Psychodidae) was found to be the most abundant phlebotomine species comprising 97% of the sand flies trapped inside the village, and an average of 7.9% of the females were positive for Leishmania ITS1 DNA. Parasite isolates from CL cases and a sand fly were characterized using several methods and shown to be L. major. During a comprehensive survey of rodents 164 Levant voles Microtus guentheri Danford & Alston, 1880 (Rodentia: Cricetidae) were captured in alfalfa fields bordering the village. Of these 27 (16.5%) tested positive for Leishmania ITS1 DNA and shown to be L. major by reverse line blotting. A very high percentage (58.3%-21/36) of Tristram's jirds Meriones tristrami Thomas, 1892 (Rodentia: Muridae), found further away from the village also tested positive for ITS1 by PCR. Isolates of L. major were successfully cultured from the ear of a wild jird found positive by ITS1 PCR. Although none of the wild PCR-positive voles exhibited external pathology, laboratory-reared voles that were infected by intradermal L. major inoculation, developed patent lesions and sand flies became infected by feeding on the ears of these laboratory-infected voles. This is the first report implicating M. guentheri and M. tristrami as reservoirs of Leishmania. The widespread co-distribution of M. guentheri and P. papatasi, suggests a significant threat from the spread of CL caused by L. major in the Middle East, central Asia and southern Europe. PMID- 23437409 TI - T cell hypo-responsiveness against Leishmania major in MAP kinase phosphatase (MKP) 2 deficient C57BL/6 mice does not alter the healer disease phenotype. AB - We have recently demonstrated that MAP kinase phosphatase 2 (MKP-2) deficient C57BL/6 mice, unlike their wild-type counterparts, are unable to control infection with the protozoan parasite Leishmania mexicana. Increased susceptibility was associated with elevated Arginase-1 levels and reduced iNOS activity in macrophages as well as a diminished T(H)1 response. By contrast, in the present study footpad infection of MKP-2(-/-) mice with L. major resulted in a healing response as measured by lesion size and parasite numbers similar to infected MKP-2(+/+) mice. Analysis of immune responses following infection demonstrated a reduced T(H)1 response in MKP-2(-/-) mice with lower parasite specific serum IgG2b levels, a lower frequency of IFN-gamma and TNF-alpha producing CD4(+) and CD8(+) T cells and lower antigen stimulated spleen cell IFN gamma production than their wild-type counterparts. However, infected MKP-2(-/-) mice also had similarly reduced levels of antigen induced spleen and lymph node cell IL-4 production compared with MKP-2(+/+) mice as well as reduced levels of parasite-specific IgG1 in the serum, indicating a general T cell hypo responsiveness. Consequently the overall T(H)1/T(H)2 balance was unaltered in MKP 2(-/-) compared with wild-type mice. Although non-stimulated MKP-2(-/-) macrophages were more permissive to L. major growth than macrophages from MKP 2(+/+) mice, reflecting their reduced iNOS and increased Arginase-1 expression, LPS/IFN-gamma activation was equally effective at controlling parasite growth in MKP-2(-/-) and MKP-2(+/+) macrophages. Consequently, in the absence of any switch in the T(H)1/T(H)2 balance in MKP-2(-/-) mice, no significant change in disease phenotype was observed. PMID- 23437411 TI - Regional, household and individual factors that influence soil transmitted helminth reinfection dynamics in preschool children from rural indigenous Panama. AB - BACKGROUND: Few studies have investigated the relative influence of individual susceptibility versus household exposure factors versus regional clustering of infection on soil transmitted helminth (STH) transmission. The present study examined reinfection dynamics and spatial clustering of Ascaris lumbricoides, Trichuris trichiura and hookworm in an extremely impoverished indigenous setting in rural Panama over a 16 month period that included two treatment and reinfection cycles in preschool children. METHODOLOGY/PRINCIPLE FINDINGS: Spatial cluster analyses were used to identify high prevalence clusters for each nematode. Multivariate models were then used (1) to identify factors that differentiated households within and outside the cluster, and (2) to examine the relative contribution of regional (presence in a high prevalence cluster), household (household density, asset-based household wealth, household crowding, maternal education) and individual (age, sex, pre-treatment eggs per gram (epg) feces, height-for-age, latrine use) factors on preschool child reinfection epgs for each STH. High prevalence spatial clusters were detected for Trichuris and hookworm but not for Ascaris. These clusters were characterized by low household density and low household wealth indices (HWI). Reinfection epg of both hookworm and Ascaris was positively associated with pre-treatment epg and was higher in stunted children. Additional individual (latrine use) as well as household variables (HWI, maternal education) entered the reinfection models for Ascaris but not for hookworm. CONCLUSIONS/SIGNIFICANCE: Even within the context of extreme poverty in this remote rural setting, the distinct transmission patterns for hookworm, Trichuris and Ascaris highlight the need for multi-pronged intervention strategies. In addition to poverty reduction, improved sanitation and attention to chronic malnutrition will be key to reducing Ascaris and hookworm transmission. PMID- 23437412 TI - Activities of daily living associated with acquisition of melioidosis in northeast Thailand: a matched case-control study. AB - BACKGROUND: Melioidosis is a serious infectious disease caused by the Category B select agent and environmental saprophyte, Burkholderia pseudomallei. Most cases of naturally acquired infection are assumed to result from skin inoculation after exposure to soil or water. The aim of this study was to provide evidence for inoculation, inhalation and ingestion as routes of infection, and develop preventive guidelines based on this evidence. METHODS/PRINCIPAL FINDINGS: A prospective hospital-based 1?2 matched case-control study was conducted in Northeast Thailand. Cases were patients with culture-confirmed melioidosis, and controls were patients admitted with non-infectious conditions during the same period, matched for gender, age, and diabetes mellitus. Activities of daily living were recorded for the 30-day period before onset of symptoms, and home visits were performed to obtain drinking water and culture this for B. pseudomallei. Multivariable conditional logistic regression analysis based on 286 cases and 512 controls showed that activities associated with a risk of melioidosis included working in a rice field (conditional odds ratio [cOR] = 2.1; 95% confidence interval [CI] 1.4-3.3), other activities associated with exposure to soil or water (cOR = 1.4; 95%CI 0.8-2.6), an open wound (cOR = 2.0; 95%CI 1.2 3.3), eating food contaminated with soil or dust (cOR = 1.5; 95%CI 1.0-2.2), drinking untreated water (cOR = 1.7; 95%CI 1.1-2.6), outdoor exposure to rain (cOR = 2.1; 95%CI 1.4-3.2), water inhalation (cOR = 2.4; 95%CI 1.5-3.9), current smoking (cOR = 1.5; 95%CI 1.0-2.3) and steroid intake (cOR = 3.1; 95%CI 1.4-6.9). B. pseudomallei was detected in water source(s) consumed by 7% of cases and 3% of controls (cOR = 2.2; 95%CI 0.8-5.8). CONCLUSIONS/SIGNIFICANCE: We used these findings to develop the first evidence-based guidelines for the prevention of melioidosis. These are suitable for people in melioidosis-endemic areas, travelers and military personnel. Public health campaigns based on our recommendations are under development in Thailand. PMID- 23437410 TI - Trypanosoma cruzi I and IV stocks from Brazilian Amazon are divergent in terms of biological and medical properties in mice. AB - BACKGROUND: In the Brazilian Amazon, clinical and epidemiological frameworks of Chagas disease are very dissimilar in relation to the endemic classical areas of transmission, possibly due to genetic and biological characteristics of the circulating Trypanosoma cruzi stocks. Twenty six T. cruzi stocks from Western Amazon Region attributed to the TcI and TcIV DTUs were comparatively studied in Swiss mice to test the hypothesis that T. cruzi clonal structure has a major impact on its biological and medical properties. METHODOLOGY/PRINCIPAL FINDINGS: Seventeen parameters were assayed in mice infected with 14 T. cruzi strains belonging to DTU TcI and 11 strains typed as TcIV. In comparison with TcI, TcIV stocks promoted a significantly shorter pre-patent period (p<0.001), a longer patent period (p<0.001), higher values of mean daily parasitemia (p = 0.009) and maximum of parasitemia (p = 0.015), earlier days of maximum parasitemia (p<0.001) and mortality (p = 0.018), higher mortality rates in the acute phase (p = 0.047), higher infectivity rates (p = 0.002), higher positivity in the fresh blood examination (p<0.001), higher positivity in the ELISA at the early chronic phase (p = 0.022), and a higher positivity in the ELISA at the late chronic phase (p = 0.003). On the other hand TcI showed higher values of mortality rates in the early chronic phase (p = 0.014), higher frequency of mice with inflammatory process in any organ (p = 0.005), higher frequency of mice with tissue parasitism in any organ (p = 0.027) and a higher susceptibility to benznidazole (p = 0.002) than TcIV. Survival analysis showing the time elapsed from the day of inoculation to the beginning of the patent period was significantly shorter for TcIV strains and the death episodes triggered following the infection with TcI occurred significantly later in relation to TcIV. The notable exceptions come from positivity in the hemocultures and PCR, for which the results were similar. CONCLUSION/SIGNIFICANCE: T. cruzi stocks belonging to TcI and TcIV DTUs from Brazilian Amazon are divergent in terms of biological and medical properties in mice. PMID- 23437413 TI - High content screening of a kinase-focused library reveals compounds broadly active against dengue viruses. AB - Dengue virus is a mosquito-borne flavivirus that has a large impact in global health. It is considered as one of the medically important arboviruses, and developing a preventive or therapeutic solution remains a top priority in the medical and scientific community. Drug discovery programs for potential dengue antivirals have increased dramatically over the last decade, largely in part to the introduction of high-throughput assays. In this study, we have developed an image-based dengue high-throughput/high-content assay (HT/HCA) using an innovative computer vision approach to screen a kinase-focused library for anti dengue compounds. Using this dengue HT/HCA, we identified a group of compounds with a 4-(1-aminoethyl)-N-methylthiazol-2-amine as a common core structure that inhibits dengue viral infection in a human liver-derived cell line (Huh-7.5 cells). Compounds CND1201, CND1203 and CND1243 exhibited strong antiviral activities against all four dengue serotypes. Plaque reduction and time-of addition assays suggests that these compounds interfere with the late stage of viral infection cycle. These findings demonstrate that our image-based dengue HT/HCA is a reliable tool that can be used to screen various chemical libraries for potential dengue antiviral candidates. PMID- 23437415 TI - Adaptation to Room Acoustics Using the Modified Rhyme Test. AB - The negative effect of reverberant sound energy on speech intelligibility is well documented. Recently, however, prior exposure to room acoustics has been shown to increase intelligibility for a number of listeners in simulated room environments. This room adaptation effect, a possible extension of dynamic echo suppression, has been shown to be specific to reverberant rooms and requires binaural input. Because this effect has been demonstrated only using the Coordinated Response Measure (CRM) corpus it is important to determine whether the increase in intelligibility scores reported previously was due to the specific nature of the CRM task. Here we demonstrate a comparable room-acoustic effect using the Modified Rhyme Test (MRT) corpus in multiple room environments. The results are consistent with the idea that the room adaptation effect may be a natural phenomenon of listening in reverberant environments. PMID- 23437414 TI - UCP2 deficiency helps to restrict the pathogenesis of experimental cutaneous and visceral leishmaniosis in mice. AB - BACKGROUND: Uncoupling protein 2 (UCP2) is a mitochondrial transporter that has been shown to lower the production of reactive oxygen species (ROS). Intracellular pathogens such as Leishmania upregulate UCP2 and thereby suppress ROS production in infected host tissues, allowing the multiplication of parasites within murine phagocytes. This makes host UCP2 and ROS production potential targets in the development of antileishmanial therapies. Here we explore how UCP2 affects the outcome of cutaneous leishmaniosis (CL) and visceral leishmaniosis (VL) in wild-type (WT) C57BL/6 mice and in C57BL/6 mice lacking the UCP2 gene (UCP2KO). METHODOLOGY AND FINDINGS: To investigate the effects of host UCP2 deficiency on Leishmania infection, we evaluated parasite loads and cytokine production in target organs. Parasite loads were significantly lower in infected UCP2KO mice than in infected WT mice. We also found that UCP2KO mice produced significantly more interferon-gamma (IFN-gamma), IL-17 and IL-13 than WT mice (P<0.05), suggesting that UCP2KO mice are resistant to Leishmania infection. CONCLUSIONS: In this way, UCP2KO mice were better able than their WT counterparts to overcome L. major and L. infantum infections. These findings suggest that upregulating host ROS levels, perhaps by inhibiting UPC2, may be an effective approach to preventing leishmaniosis. PMID- 23437416 TI - Amplitude modulation detection by human listeners in reverberant sound fields: Carrier bandwidth effects and binaural versus monaural comparison. AB - Previous work [Zahorik et al., POMA, 12, 050005 (2011)] has reported that for a broadband noise carrier signal in a simulated reverberant sound field, human sensitivity to amplitude modulation (AM) is higher than would be predicted based on the broadband acoustical modulation transfer function (MTF) of the listening environment. Interpretation of this result was complicated by the fact that acoustical MTFs of rooms are often quite different for different carrier frequency regions, and listeners may have selectively responded to advantageous carrier frequency regions where the effective acoustic modulation loss due to the room was less than indicated by a broadband acoustic MTF analysis. Here, AM sensitivity testing and acoustic MTF analyses were expanded to include narrowband noise carriers (1-octave and 1/3-octave bands centered at 4 kHz), as well as monaural and binaural listening conditions. Narrowband results were found to be consistent with broadband results: In a reverberant sound field, human AM sensitivity is higher than indicated by the acoustical MTFs. The effect was greatest for modulation frequencies above 32 Hz and was present whether the stimulation was monaural or binaural. These results are suggestive of mechanisms that functionally enhance modulation in reverberant listening. PMID- 23437417 TI - A coin in the heart. PMID- 23437418 TI - A heart at el kurru royal necropolis of napata (kush). PMID- 23437419 TI - The Air of History (Part II) Medicine in the Middle Ages. PMID- 23437420 TI - Conventional microscopy versus molecular and immunological methods in the diagnosis of amoebiasis. PMID- 23437421 TI - Use of the afirma(r) gene expression classifier for preoperative identification of benign thyroid nodules with indeterminate fine needle aspiration cytopathology. AB - Ruling out malignancy in thyroid nodules historically depended on thyroid resection and histopathological evaluation until fine needle aspiration (FNA) biopsy was introduced into the United States in the 1970's. Thyroid FNA biopsy identified a majority of thyroid nodules as benign, obviating the need for surgery in over half of the patients. However, 15%-30% of thyroid FNAs have indeterminate cytology that still requires operation, even though most of these operated nodules prove to be benign post-operatively. In order to predict which cytologically indeterminate thyroid nodules are benign and to potentially avoid surgery on these nodules, a recently described commercially available Gene Expression Classifier (GEC) test (Afirma(r), Veracyte, Inc., South San Francisco, CA) has been developed that can be run on the FNA sample. This paper reviews the published literature and technology assessments/guidelines by independent parties and professional groups regarding the clinical utility as well as the analytic and clinical validity of the Afirma GEC. PMID- 23437422 TI - Effects of the Pimelic Diphenylamide Histone Deacetylase Inhibitor HDACi 4b on the R6/2 and N171-82Q Mouse Models of Huntington's Disease. AB - This report represents a detailed description of experiments designed to replicate and extend the findings of a published study on the effects of treating the R6/2 Huntington's disease (HD) mouse model with ~300 CAG repeats using the pimelic diphenylamide histone deacetylase (HDAC) inhibitor, HDACi 4b (Thomas et al., 2008). In addition to testing the R6/2 mice, similar experiments examined the effects of the drug on a second transgenic HD mouse model, the N171-82Q mice. As in the original study, the drug was delivered in the drinking water. In the present study we tested larger groups of mice than in the original study. The results indicated that we were unable to replicate the significant behavioral effects of oral HDACi 4b treatment in the R6/2 mice. There were however, non significant trends for the treated R6/2 mice to be less affected on some of the measures and there were instances of phenotype progression being delayed in these treated mice. In contrast, we did replicate the protection from striatal atrophy in the R6/2 mice. We also did not observe any beneficial effects of HDACi 4b treatment in the N171-82Q mice. Although the behavioral procedures were replicated and an automated activity assessment was added, there were several unexpected complications in terms of solubility of the drug, CAG repeat length differences and gender differences in progression of the phenotype that could have affected outcomes. Clearly more studies will have to be performed using other methods of delivery as well as assessing effects in more slowly progressing HD models to better evaluate the effects of this HDAC inhibitor. PMID- 23437423 TI - Vascular thoracic outlet in a competitive swimmer: a case report. AB - Thoracic outlet syndrome (TOS) is a well-described condition resulting from compression of the brachial plexus, subclavian artery and/or vein. Though symptoms of pain, numbness, tingling and signs of muscular weakness associated with this condition usually begin insidiously, on rare occasions the presentation is of acute onset and may represent an acute vascular compression. An unusual form of "effort" thrombosis of the subclavian vein may require emergency care in order to ensure controlled clot lysis and thrombus dissolution. Confirmation of subclavian thrombus is obtained by venography and makes use of real time videography to assess for venous flow impairment. Definitive treatment for the underlying cause of this form of TOS is first rib resection and scalenectomy. This case report presents a competitive swimmer who developed an acute onset of limb cyanosis and turgidity during swim training. Awareness of the possibility of acute thrombosis obstructing venous return and producing such signs and symptoms should lead the astute clinician to consider recommending contrast venography to assess the lesion and lead to appropriate medical intervention. PMID- 23437424 TI - Indian Dermatology Online Journal (IDOJ) in 2012 and Beyond. PMID- 23437425 TI - Treatment of nodular scabies with topical tacrolimus. PMID- 23437426 TI - Idiopathic scrotal calcinosis: Is cytological diagnosis enough? PMID- 23437427 TI - Carbamazepine induced severe cutaneous vasculitis. PMID- 23437428 TI - Detection of P53 and Mdm2 in vitiligo. PMID- 23437429 TI - Prevalence of cholinergic urticaria in Indian adults. PMID- 23437430 TI - Polymorphic pityriasis rosea precipitating psoriasis. PMID- 23437431 TI - To the editor: Is this cutaneous angiomyolipoma truly an angiomyolipoma? PMID- 23437432 TI - SkIndia Quiz 8: Multiple subcutaneous swellings around the ears. PMID- 23437433 TI - Recurrent dermatofibrosarcoma protuberans: A continuing problem. PMID- 23437434 TI - ? PMID- 23437436 TI - Proximal humeral fractures: internal fixation. PMID- 23437435 TI - A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders. AB - Metal-ion misregulation and oxidative stress have been linked to the progressive neurological decline associated with multiple neurodegenerative disorders. Transition metal-mediated oxidation of biomolecules via Fenton chemical reactions plays a role in disease progression. Herein we report the synthesis, characterization and antioxidant activity of 2; a pyclen derivative with enhanced antioxidant character. PMID- 23437437 TI - Acquired, non-amyloid related factor X deficiency: review of the literature. PMID- 23437438 TI - Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States. PURPOSE: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV. DATA SOURCES: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV. DATA EXTRACTION: Investigators abstracted and reviewed study details and quality using predefined criteria. DATA SYNTHESIS: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission. LIMITATIONS: Only English language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes. CONCLUSION: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 23437439 TI - Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. AB - BACKGROUND: Multiple treatments are available for chronic hepatitis C virus (HCV) infection. PURPOSE: To compare benefits and harms of antiviral regimens for chronic HCV infection in treatment-naive adults. DATA SOURCES: English-language literature from MEDLINE (1947 to August 2012), the Cochrane Library Database, Embase, Scopus, PsychINFO, and clinical trial registries. STUDY SELECTION: Randomized trials of antiviral treatments and cohort studies examining associations between sustained virologic response (SVR) after therapy and clinical outcomes. DATA EXTRACTION: Several investigators abstracted study details and quality by using predefined criteria. DATA SYNTHESIS: No trial evaluated effectiveness of treatment on long-term clinical outcomes. Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower likelihood of SVR than was pegylated interferon alfa-2a plus ribavirin (absolute difference, 8 percentage points [95% CI, 3 to 14 percentage points]) on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood of SVR than was therapy for 24 weeks, and lower doses of pegylated interferon alfa-2b were less effective than standard doses (2 to 4 fair-quality trials). For genotype 1 infection, fair quality trials found that triple therapy with pegylated interferon, ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likelihood of SVR than was dual therapy (absolute difference, 22 to 31 percentage points). Compared with dual therapy, boceprevir triple therapy increased risk for hematologic adverse events and telaprevir triple therapy increased risk for anemia and rash. A large well-designed cohort study and 18 smaller cohort studies found that an SVR after antiviral therapy was associated with lower risk for all-cause mortality than was no SVR. LIMITATIONS: Trials involved highly selected populations. Observational studies did not always adequately control for confounders. CONCLUSION: SVR rates for genotype 1 infection are higher with triple therapy that includes a protease inhibitor than with standard dual therapy. An SVR after antiviral therapy appears associated with improved clinical outcomes. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 23437440 TI - How does one night of sleep deprivation affect the internal clock? AB - Twelve subjects performed two temporal tasks, one explicit (Experiment 1) and one implicit (Experiment 2) after one night of sleep deprivation and after one night of normal rest. Experiment 1 involved a 1100-ms duration production task, and in Experiment 2 subjects performed a word identification task requiring implicit estimation of vowel duration (around 150 ms). One night of sleep deprivation had the same pattern of effect on explicit timing in the suprasecond range and implicit timing in the millisecond range. Specifically, sleep deprivation induced productions of shorter intervals in the duration production task and estimation of segmental durations as being longer in the word identification task. Both results are consistent with an acceleration of pacemaker rate.Moreover, in both experiments, we found a correlation between the alertness level of participants and the size of the effect. Therefore, sleep deprivation, which physiologically manipulates cortical arousal level, produced similar performance modulation in suprasecond explicit and subsecond implicit tasks suggesting a common mechanism. PMID- 23437441 TI - Poststroke spasticity: Treating to the disability. PMID- 23437442 TI - A qualitative analysis of life course adjustment to multiple morbidity and disability. AB - The accumulation of limitations over the life course requires that women readapt to environmental barriers they encounter over time. The purpose of this qualitative case study was to detail the life experiences associated with living with mobility, cognitive, and sensory loss experienced by a woman and her sister who participated in an ongoing ethnographic study of mobility impairment in women. In-depth interviews were subjected to thematic, life course analysis. A family case study was interpreted as an exemplar for aging with early-onset disability into multiple morbidity, which was described as a series of loss, recovery, and reengagement. Within the case study, the participant suggested that because her functional limitations were not accommodated earlier in life due to societal and family-level disadvantage, these limitations were more difficult to adjust to in later years. PMID- 23437443 TI - Response to letter regarding article, "Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy". PMID- 23437445 TI - Reply to Ricciotti et al.: Evidence for vascular COX isoforms. PMID- 23437444 TI - Reply to Sauter and Eisner: Differences outweigh commonalities in the communication of emotions across human cultures. PMID- 23437446 TI - The safety of postmenopausal testosterone therapy. PMID- 23437448 TI - Breaking news: HRT to prevent chronic conditions. PMID- 23437447 TI - Post-oophorectomy estrogen use and breast cancer risk. PMID- 23437449 TI - DXA vs. QUS to predict fracture risk. PMID- 23437450 TI - History of weight cycling and future weight loss. PMID- 23437451 TI - ECG of the month. Cardiac failure and stroke in a 43-year-old woman. Coarse atrial fibrillation indicating left atrial enlargement and left ventricular hypertrophy with repolarization abnormality. AB - A 43-year-old woman with a long history of heavy cigarette smoking was in good health until she developed fatigue, dyspnea on exertion, and paroxysmal nocturnal dyspnea approximately three months before admission to our hospital. Four weeks before admission, she was admitted to another hospital for the sudden onset of a right hemiparesis. She was noted to be in atrial fibrillation, and cardiac catheterization and angiocardiography revealed triple-vessel coronary arterial disease and moderately severe mitral regurgitation. Because of repeated episodes of paroxysmal nocturnal dyspnea, she was referred to our hospital for cardiac surgery. On admission, an electrocardiogram was recorded (Figure). PMID- 23437452 TI - Ultrasonographic findings in circumscribed choroidal hemangioma after photodynamic therapy. AB - Circumscribed choroidal hemangioma (CCH) is a benign and relatively rare tumor located posteriorly to the equator. The most frequently associated clinical finding is an exudative retinal detachment (ERD). The aim of this work is to describe ultrasonographic findings in eyes diagnosed with CCH + ERD after photodynamic therapy (PDT). Five eyes of five patients diagnosed with CCH (2 men and 3 women; 3 right eyes and 2 left eyes; mean age 50.6 (range 42-63) years) were referred to the Unit of Ocular Oncology. All cases were selected for PDT since all of them showed a macula-off ERD and hence poor visual acuity. The PDT protocol consisted of verteporfin 6 mg/m2 body surface area and exposure to laser light dose at 689 nm at an intensity of 600 mW/cm2 (1 to 3 sessions depending on the persistence of ERD). Ultrasonographic examination was performed by use of the I3-ABD System (posterior segment 10 MHz B-scan and 8 MHz standardized diagnostic A-scan probes, Innovative Imaging Inc., Sacramento, CA, USA). Ultrasonographic findings recorded on the first examination were consistent with those previously described for CCH in the literature. Dimensions of the tumors were very similar in all cases. However, after PDT we detected significant reduction of the height of the tumor and increased reflectivity, without changes in internal structure. Moreover, we detected retinal reattachment in all cases and therefore a slight improvement in visual acuity. Significant changes in ultrasonographic findings can be found after PDT for CCH. PMID- 23437453 TI - Don't think the recovery auditors will disappear. AB - Medicare's Recovery Audit program is under scrutiny from all fronts, but the program is so successful, it's not going to go away, so hospitals need to continue to prepare. Make sure that documentation in the medical record shows that the services provided are medically necessary and reflects the severity of illness and intensity of service. Analyze all your denials and appeal those you think are unjustified, all the way to the administrative law judge level, if necessary. Follow screening criteria for patients with targeted diagnoses and make sure physicians are not overusing observation services. PMID- 23437454 TI - Keep informed about RA focus in your area. PMID- 23437455 TI - CM redesign cuts LOS, readmissions. AB - University Hospitals Case Medical Center in Cleveland revamped its case management process, resulting in drops in length of stay and readmissions. A three-person care management team is assigned to each unit, with each member having a specific focus. The case management team holds rounds each day with the interdisciplinary team, which includes representatives from post-acute providers. An electronic board tracks patients and includes expected length of stay and discharge disposition, ancillary services, and discharge needs. PMID- 23437457 TI - Safe lifting becomes standard practice. PMID- 23437456 TI - Team huddles improve LOS, core measures. AB - When Springfield (OH) Regional Medical Center began daily multidisciplinary team huddles to facilitate patient care, performance on targeted core measures rose and the observed-to-expected length of stay ratio decreased. Case managers and charge nurses on each unit facilitate the daily multidisciplinary huddles during which every patient is discussed. The team uses a series of tools, including huddle logs and referral sheets to track what patients need and who should provide the services. At the huddles, which are at specific times every day, the team reviews each patient, the plan of care and goals, and what needs to happen that day. PMID- 23437458 TI - Pin yourself down to ensure success. PMID- 23437459 TI - Treatments for heart failure. Many therapies can be effective, but care must be individualized. PMID- 23437460 TI - Ask the doctors. I am 72 years old, and have had diabetes and high blood pressure for about 15 years. I thought these problems were pretty well controlled, but I recently learned that my kidney function is declining. My creatinine level is now 2.2 milligrams per deciliter (mg/dL). How serious is this? PMID- 23437461 TI - Ask the doctors. I am a 67-year-old woman with high blood pressure. Two weeks ago, I felt some chest pressure and went to the emergency department. The pain cleared up when they gave me an antacid. My EKG and blood tests were normal. The doctor thought my pain might be due to acid in my esophagus. But when my own doctor sent me for an exercise test, I got chest pain after about five minutes, and the cardiologist said my EKG showed abnormalities that are strongly suggestive of coronary disease. She prescribed a beta blocker and suggested cardiac catheterization. Do you agree with this? PMID- 23437462 TI - When should we treat blood pressure? Lifetime cardiovascular risk now plays a role in the decision. PMID- 23437464 TI - Women: cardiac rehab key to recovery. So why don't more take advantage of it after a heart attack? PMID- 23437463 TI - Carotid stenosis treatments compared. Both surgical and nonsurgical options can prevent stroke. PMID- 23437465 TI - Muscle aches and pains from statin use. Discomfort usually resolves with a lower dose or a different statin. PMID- 23437466 TI - About rhabdomyolysis. PMID- 23437467 TI - New devices compensate for foot drop. Nerve stimulation can help many people walk normally again. PMID- 23437468 TI - Aspirin not effective in some people. Failure to take the drug may be the most common reason. PMID- 23437469 TI - Heart-healthy menu choices now clear. Logo makes it easy to spot low-fat, low calorie entrees. PMID- 23437470 TI - "Smart pill" won't let you forget to take your medications. PMID- 23437471 TI - Fat that's bad for the heart, brain. PMID- 23437472 TI - ER evaluation methods compared. PMID- 23437473 TI - Impact of inactivity assessed. PMID- 23437474 TI - [Current problems associates with "alopecia" and "wigs" for outpatients undergoing cancer therapy]. PMID- 23437475 TI - GLUT-1. PMID- 23437476 TI - Oncologist practice consolidation continues: driven by changes in reimbursement and standards of care, independent community oncology practices continue to dwindle.. PMID- 23437477 TI - Exploring new ways to broaden the reach of molecular tumor testing. PMID- 23437478 TI - Health on hold. But Obama legislation would let them live in U.S. legally. AB - The Obama administration's plan that would give many illegal immigrants a path to stay in the U.S. legally leaves out one thing: federally subsidized access to health insurance coverage. "I think that gives immigrants a mixed message about how welcome they will be," says Sonal Ambegaokar, left, of the National Immigration Law Center. PMID- 23437479 TI - ACA back in spotlight. Immigration reform brings debate on coverage. PMID- 23437481 TI - Payment overhaul. CMS' bundled-payment initiative nears launch. PMID- 23437480 TI - Forging a new path. New law offers incentives to develop antibiotics. PMID- 23437482 TI - 2% Medicare cut looms. Sequester could be hurdle in reform's path. PMID- 23437483 TI - Data battle. UnitedHealth deal is latest move in industry shift. PMID- 23437484 TI - Obstacles ahead. Shared decisionmaking faces roadblocks, despite push, incentives. PMID- 23437485 TI - Round two for ACA? Liberty University case may put health reform law before high court again. PMID- 23437486 TI - Mayo's ultimatum. Clinic wants $600 million in improvements by state. PMID- 23437487 TI - Motive questioned. N. J. hospital pays $12.6 million settlement. PMID- 23437488 TI - A little extra in the fiscal deal. Backroom deals are bad medicine and no way to set payment policy. PMID- 23437489 TI - The overseas patient trap. Systems face language, cultural differences tending to health tourists' needs. PMID- 23437490 TI - ACHE Gold Medal Award. A diverse legacy. Longtime CEO transformed the ACHE. PMID- 23437491 TI - ACHE Gold Medal Award. Selfless leadership. Lerner's healthcare career spans four decades. PMID- 23437492 TI - ACHE Young Healthcare Executive of the Year. Engineering change. Up-and-coming exec focuses on communication. PMID- 23437493 TI - Full disclosure first. Alternative med-mal approaches show promise. PMID- 23437494 TI - Largest professional liability carriers. Ranked by direct premiums written for medical professional liability in the U.S. in 2011. PMID- 23437495 TI - Prioritizing the prevention of HIV/AIDS in African women: a call for action. PMID- 23437497 TI - Knowledge, attitudes and barriers towards prevention of mother-to-child transmission of HIV among women attending antenatal clinics in Uyam District of Zaki-Biam in Benue State, Nigeria. AB - Benue State in north central Nigeria has one of the highest HIV/AIDS prevalence rates of 9.3%, among children and adults aged 13-45 years. To improve the survival of mothers and children and to identify the major challenges in scaling up PMTCT services, a descriptive, study was conducted to assess knowledge, attitudes and barriers to the uptake of PMTCT by 384 women attending antenatal clinics (ANC) in Uyam, Zaki-Biam, a semi-urban area of Benue State. A standard questionnaire was used for data collection. A high number of subjects knew that unprotected sexual intercourse is a risk factor for transmission, with most 281 (73.2%) of them aware that an HIV infected woman could get pregnant; while 275 (71.6%) knew that infection can be transmitted from the mother to her unborn child. Only 214 (55.7%) of the study participants had done the HIV test in pregnancy because of, inadequate VCT centers, issues of stigma and absence of family support including attitudes of staff. Age, parity and socio- economic status, as well as location influenced the responses of respondents. In spite of the increasing public awareness in Nigeria about HIV/AIDS, there still exist gaps as a result of different levels of education and access to information, coupled with lack of trained personnel and adequately equipped health care facilities. To improve survival and probably eliminate HIV/AIDS, the integration of PMTCT into primary health care services in Nigerian communities should be considered. PMID- 23437496 TI - Motivational groups support adherence to antiretroviral therapy and use of risk reduction behaviors in HIV positive Nigerian women: a pilot study. AB - Nigerian women comprise the fastest growing group of persons with AIDS in Africa. Antiretroviral therapy has transformed the course of HIV/AIDS to a treatable, chronic illness worldwide. The purpose of this pilot study was to assess the efficacy of a group intervention using motivational interviewing (MI) to promote adherence to antiretroviral therapy (ART) and use of risk reduction behaviors (RRB) among HIV-infected women in Nigeria. Recruited participants (n=60) were randomly assigned to the motivational group or the health promotion program (HPP) control group. The 6 month follow-up results indicate that, compared to the control group, MI participants reported significantly higher levels of adherence to ART, higher knowledge of HIV, higher use of condoms/protection during sexual encounters and decision-making not to have sex when no protection was available. The MI participants also had fewer mean number of sexual partners. MI in group format shows promise in promoting adherence to ART and use of RRB in HIV-infected Nigerian women. PMID- 23437498 TI - Why some women deliver in health institutions and others do not: a cross sectional study of married women in Ghana, 2008. AB - Existing inequalities in an environment where men wield so much authority can have negative implications for women's reproductive health outcomes. Using a quantitative approach, the study explores the relationship between some selected socioeconomic variables, women's status and choice of place of delivery. All three indicators of status employed by the study were significantly associated with whether a woman had an institutional delivery or not. This association however diminished after controlling for other confounding socio-economic variables. The findings indicate that a woman's status does not act independently to affect her choice of place of delivery but these effects are channelled through some socio-economic variables. Wealth and educational status of the women and their partners emerged predictors of choice of place of delivery. Expansion of economic opportunities for women, as well as female education must be encouraged. In addition, these should not be done in neglect of male education. PMID- 23437499 TI - Physical access to health facilities and contraceptive use in Kenya: evidence from the 2008-2009 Kenya Demographic and Health Survey. AB - The objective of the study was to determine the spatial variation in modern contraceptive use and unmet need for family planning across the counties of Kenya and to examine whether the spatial patterns were associated with inequalities in physical access to health facilities. Data were obtained from the 2008-2009 Kenya Demographic and Health Survey and linked to the location of health facilities in the country. Multivariate logistic regression was used to examine the influence of distance to the nearest health facility and health facility density, in addition to other covariates, on modern contraceptive use and unmet need. Overall, the prevalence of modern contraceptive use and unmet need among women aged 15-49 in Kenya was 42.1% and 19.7% respectively. Among the respondents who lived more than 5 km from the nearest health facility modern contraceptive use was significantly less likely compared to women resident 5 km or less from the nearest health facility. Women from counties with higher health facility density were 53% more likely to use modern contraceptives compared to women in counties with low health facility density. Distance and health facility density in the county were not significantly associated with unmet need. Physical access to health facilities is an important determinant of modern contraceptive use and unmet need in Kenya. Strategies should be developed in underserved counties to mitigate the challenge of distance to health facilities, such as delivering services by outreach and mobile facilities. PMID- 23437500 TI - Community, social group, and individual level correlates of rural Malawian men's and women's reproductive health intentions and practices. AB - Using a sample of 656 men and 930 women from rural Malawi in 2000, the authors examined the association between various individual and community level factors, as well as participation in social groups, and four reproductive health outcomes: intentions to use any contraceptives in the next six months, current use of modem contraceptives, wanting an HIV test, and having had an HIV test. Women in social groups have higher odds of reporting intentions to use contraceptives, wanting an HIV test, and of having had an HIV test than those not in groups. Among men, social group participation is only slightly associated with having had an HIV test. For all, education is positively associated with all four outcomes, and number of children is associated with intentions to use and actual use of contraceptives. At a community level, proximity to a health center or school is positively associated with three outcomes for women and with use of modern contraceptive methods for men. PMID- 23437501 TI - Identifying pregnant women who would adhere to food taboos in a rural community: a community-based study. AB - Poor maternal nutrition, especially in rural settings, adversely affects pregnancy and birth outcomes. In many local communities, pregnant women have food taboos with consequent depletion of vital nutrients. To facilitate early identification and prompt counseling, this study aimed at describing pregnant women who are likely to keep food taboos. Data was collected from 405 pregnant women that attended antenatal care at health facilities in Saki East Local Government of Oyo state, Nigeria. Sociodemographic characteristics of the women were described using means and proportions. Using logistic regression analysis, maternal characteristics significantly associated with adherence to food taboos were identified. The data was analysed using SAS 9.2. Factors associated with food taboos were teen age, primigravidity, low body mass index, lack of formal education, and low monthly family income. Health workers should have a high index of suspicion for food taboos among pregnant women with the identified risk factors. PMID- 23437502 TI - [Are the attitudes associated with the mother and HIV/AIDS responsible for the rise in infant mortality recorded in Cote d'Ivoire in the 1990s?]. AB - Demographic and Health Surveys conducted in the 1990s in Cote d'Ivoire suggest a resurgence of mortality during this period. This article examines the responsibility of mother attitudes and HIV/AIDS pandemic in the increase of mortality recorded. The rise in mortality was discernible between the first and second DHS, so we tried to find out whether there have been, between the two periods, negative changes in child survival factors associated with mother attitudes and HIV/AIDS pandemic. Whether it has to do with antenatal visits, birthing places, mother and child vaccination or breastfeeding, there is an improvement in the practices of women mothers. The HIV-related mortality has certainly increased over the decade but the improvement on the part of infant mortality is not statistically significant between the two observations. PMID- 23437503 TI - Obstructed labour in resource-poor settings: the need for revival of symphysiotomy in Nigeria. AB - Symphysiotomy is an operation in which the fibres of the pubic symphysis are partially divided to allow separation of the joint and thus enlargement of the pelvic dimensions thereby facilitating vaginal delivery of the foetus in the presence of mild to moderate cephalopelvic disproportion. It is performed with local anaesthesia, does not require an operating theatre or advanced surgical skills. It can be a lifesaving procedure for both mother and baby in obstructed labour, especially in rural areas and resource-poor settings of developing countries, where a 24 hours availability of a caesarean section cannot be guaranteed. It is a simple underused technology that can be performed by a graduate doctor or midwife in rural health facilities and hospitals where most of the times, in Nigeria, there are no practicing specialist obstetricians. In rural hospital and in communities where sympysiotomy is still being performed, it is evident that it is preferred to caesarean section because of the socio-cultural desire to achieve a vaginal delivery. This paper highlights our experiences with symphysiotomy in a rural Roman Catholic hospital providing evidence on the safety of symphysiotomy and the need for its revival and reinstatement in the obstetric arsenal in Nigeria and similar countries in sub-Saharan Africa where maternal mortality as a result of prolonged and neglected obstructed labour still occur. PMID- 23437504 TI - Widowers' accounts of maternal mortality among women of low socioeconomic status in Nigeria. AB - The research is based on information collected on 50 deceased Nigerian women of low socioeconomic status in different locations of the country including Lagos, Ibadan, Kaduna, Zaria, Minna, Enugu, and Port-Harcourt among others. They had some common characteristics such as low levels of education, involvement in petty trading and were clients of a microfinance bank as small loan receivers. Primary data were generated mainly through verbal autopsy with widowers employing in depth interviews and key informant interviews. In addition, unobtrusive observation was carried out in these locations to ascertain in some instances the distance between the deceased homes and health facilities patronised by the women. Secondary data were specific to death certificates of the deceased supplied by the widowers. Both ethnographic summaries and content analysis were employed in data analysis to account for contextual differences, especially in a multicultural society like Nigeria. The findings implicated several issues that are taken for granted at the micro-family and macro-society levels. It specifically revealed that small loans alone are not sufficient to empower poor women to make meaningful contributions to their own reproductive health in a patriarchal society like Nigeria. Results also indicated that cultural differences as well as rural-urban dichotomy were not proximate determinants of maternal behaviour; the latter rather finds expression in low socioeconomic status. Consequently, policy relevant recommendations that could contribute to significant maternal mortality reduction were proffered. PMID- 23437505 TI - Emergency caesarean delivery in prolonged obstructed labour as risk factor for obstetric fractures--a case series. AB - Birth fractures predominantly affect the clavicle, humerus or femur. Brachial plexus injury may co-exist with humeral or clavicular fractures. From January 2002 to December 2010, 8 neonates with fractures after caesarean section were treated under the supervision of the first author following obstructed labour and caesarean delivery. The most classical of the cases is a vertex-presenting neonate who was delivered by caesarean section for obstructed labour in a primipara in whom ipsilateral klumpke's palsy and fractures of the clavicle and humerus were confirmed. Literature review did not consider emergency caesarean delivery as one of the predisposing factors for such birth injuries. This case series, in addition to presenting emergency caesarean section as a predisposing factor for birth injuries, offers to suggest a manoeuvre that may reduce severity and rate of birth injuries in caesarean section for obstructed labour in our environment where obstructed labour is still rife. PMID- 23437506 TI - Gender equality and childbirth in a health facility: Nigeria and MDG5. AB - This paper examined how addressing gender equality can lead to reductions in maternal mortality in Nigeria through an increased use of facility delivery. Because the majority of maternal complications cannot be predicted and often arise suddenly during labor, delivery and the immediate postpartum period, childbirth in a health facility is key to reducing maternal mortality. This paper used data from the 2008 Nigeria Demographic and Health Survey (DHS) to examine associations of gender measures on the utilization of facility delivery after controlling for socio-demographic factors. Four gender equality measures were studied: household decision-making, financial decision-making, attitudes towards wife beating, and attitudes regarding a wife's ability to refuse sex. Results found older, more educated, wealthier, urban, and working women were more likely to have a facility delivery than their counterparts. In addition ethnicity was a significant variable indicating the importance of cultural and regional diversity. Notably, after controlling for the socioeconomic variables, two of the gender equality variables were significant: household decision-making and attitudes regarding a wife's ability to refuse sex. In resource-poor settings such as Nigeria, women with more decision-making autonomy are likely better able to advocate for and access a health facility for childbirth. Thus programs and policies that focus on gender in addition to focusing on education and poverty have the potential to reduce maternal mortality even further. PMID- 23437507 TI - Assessment of uterine cavity size and shape: a systematic review addressing relevance to intrauterine procedures and events. AB - Uterine cavity measurement began with evaluation of post-mortem and surgical specimens. It has been extended in vivo by use of mechanical instruments and visualization techniques. This is a systematic review of the range of values for the uterine cavity and the practical implications of these measurements, Following a review of multiple data bases & a QUORUM analysis. Only articles with clearly defined quantitative measurements were included. Mechanical cavity measurements with a variety of instruments gave a mean endometrial cavity length (ECL) of 33.73 mm (18-22.1) and a mean endometrial cavity width (ECW) of 25.1 mm (17.8-32.2) for nulliparae. The values for multiparae were mean ECL 38.6mm(20.61 40.3) and mean ECW 34.9 mm (23.4-53). Imaging measurements for the uterine cavity by hysterography and ultrasound were mean ECL 44.3 mm (29-64) for multiparae and ECL 37 mm for nulliparae. Mean ECW was 28.2 mm (21-33) for nulliparae and 32.1 mm (26-38) for multiparae. There were wide variations due to parity, ethnicity and gestational states. Accurate measurement of intrauterine parameters is valuable for improving and enhancing many intrauterine procedures including IUD insertion, endometrial ablation, embryo placement in IVF and management of spontaneous and therapeutic abortion. PMID- 23437508 TI - Sexual coercion among in-school adolescents in Rwanda: prevalence and correlates of victimization and normative acceptance. AB - Adolescents are particularly vulnerable to sexual coercion, as victim as well as perpetrator. This paper aims to adapt sexual and reproductive health interventions to the reality of young people's sexuality and relationships. This study assesses the prevalence of forced sex, characteristics of victims and norms regarding sexual coercion among Rwandan adolescents. A survey was completed by 285 senior secondary school students and four focus groups were conducted. Of sexually active respondents, 15.5% (95% CI = [15.1 - 15.9]) reported forced sexual intercourse. Sexual victimization was associated with being female and having (had) a concurrent sexual relationship. Acceptance of sexual coercion was associated with importance attached to Rwandan traditions and an interaction term between sex (being male) and alcohol use. Respondents linked concurrency and age disparate relationships to transactional sex, increasing the risk of sexual coercion. Various risk factors were identified. The findings suggest the need for moving towards comprehensive sex education. PMID- 23437510 TI - Status of emergency obstetric care in a local government area in south-south Nigeria. AB - This study assessed the status of the availability and performance of emergency obstetric care (EmOC) in 12 functional public health facilities out of the existing 19 in Gokana Local Government Area of Rivers State in south-south Nigeria, prior to the midwives service scheme (MSS) launch in 2009. No facility qualified as basic EmOC, while one had comprehensive EmOC status. Signal functions that required supply of medical consumables were performed by more facilities than services that required special training, equipment and maintenance. Only two facilities (16.67%) had the minimum requirement of > or =4 midwives for 24-hour EmOC service; while only 2.2% of expected births occurred at the facilities. The poor state of maternal health resources in the study area requires urgent interventions by Local and State Governments for infrastructure upgrade and deployment and training of staff towards attainment of MDG-5. A follow-up evaluation would be required since the commencement of the MSS. PMID- 23437509 TI - Correlates of contraceptive use among Ghanaian women of reproductive age (15-49 years). AB - Though fertility in Ghana has declined from an average of 8 children per woman over the past three decades to 4 per woman in recent times, the current rate of population growth is still unmatched by the requisite economic growth. Recent evidence suggests that the use of contraceptives have increased marginally despite the considerable decline in fertility rate. This paper revisits the determinants of contraceptive use among Ghanaian women, aged 15-49 using the 2008 GDHS. Empirically, the logistic and multinomial logistic regressions are used. Our results indicate that wealth status, level of education, ownership of health insurance, number of surviving children, marital status, location and geographical area of residence, religion and women autonomy are significant correlates of contraceptive use in Ghana. The finding reveals that, women who take health decisions jointly with their partners are more likely to use modern contraceptives as compared to women who take health decisions alone. PMID- 23437511 TI - Pregnancy outcome after cerclage for cervical incompetence at the University of Port Harcourt Teaching Hospital, Port Harcourt. AB - Cervical incompetence is often associated with mid trimester pregnancy losses and preterm labour. cervical cerclage to prevent miscarriage and preterm labour is practiced world wide. The objective of this study was to document the feto maternal outcome following cervical cerclage for cervical incompetence. The study reviewed all case files of pregnant women who had cervical cerclage for cervical incompetence between January 1, 2004 to December 31, 2008, at the University of Port Harcourt Teaching Hospital. The study found an incidence of 0.17% of cervical incompetence among the antenatal population. Following cervical cerclage, miscarriage rate was 9.4%. Preterm delivery occurred in 21.8% while term pregnancy occurred in 68.8% of the women. There is improvement in pregnancy outcome after cervical cerclage for cervical incompetence hence we recommend the insertion for true cases of cervical incompetence. PMID- 23437512 TI - Post-processing strategies for improving local gene expression pattern analysis. AB - This paper proposes a new analytical process highlighted by a soft subspace clustering method, a changing window technique, and a series of post-processing strategies to enhance the identification and characterisation of local gene expression patterns. The proposed method can be conducted in an interactive way, facilitating the exploration and analysis of local gene expression patterns in real applications. Experimental results have shown that the proposed method is effective in identification and characterization of functional gene groups in terms of both local expression similarities and biological coherence of genes in a cluster. PMID- 23437513 TI - Improving robustness of gene ranking by multi-criterion combination with novel gene importance transformation. AB - Feature ranking, which ranks features via their individual importance, is one of the frequently used feature selection techniques. Traditional feature ranking criteria are apt to produce inconsistent ranking results even with light perturbations in training samples when applied to high dimensional and small sized gene expression data, which brings troubles for further studies such as biomarker identification. A widely used strategy for solving the inconsistencies is the multicriterion combination, where score normalisation is crucial. In this paper, three problems in existing methods are first analyzed, and then a new feature importance transformation algorithm based on resampling and permutation is proposed for score normalisation. Experimental studies on four popular gene expression data sets show that the multi-criterion combination based on the proposed score normalisation produces gene rankings with improved robustness. PMID- 23437514 TI - Integrative analysis of time course microarray data and DNA sequence data via log linear models for identifying dynamic transcriptional regulatory networks. AB - Since eukaryotic transcription is regulated by sets of Transcription Factors (TFs) having various transcriptional time delays, identification of temporal combinations of activated TFs is important to reconstruct Transcriptional Regulatory Networks (TRNs). Our methods combine time course microarray data, information on physical binding between the TFs and their targets and the regulatory sequences of genes using a log-linear model to reconstruct dynamic functional TRNs of the yeast cell cycle and human apoptosis. In conclusion, our results suggest that the proposed dynamic motif search method is more effective in reconstructing TRNs than the static motif search method. PMID- 23437515 TI - A novel multi-stage feature selection method for microarray expression data analysis. AB - With the development of genome research, finding method to classify cancer and detect biomarkers efficiently has become a challenging problem. In this paper, a novel multi-stage method for feature selection is proposed which considers all kinds of genes in the original gene set. The method eliminates the irrelevant, noisy and redundant genes and selects a subset of relevant genes at different stages. The proposed method is examined on microarray datasets of Leukemia, Prostate, Colon, Breast, Nervous and DLBCL by different classifiers and the best accuracies of the method in these datasets are 100%, 98.04%, 100%, 89.74%, 100% and 98.28%, respectively. PMID- 23437516 TI - Modelling splice sites with locality-sensitive sequence features. AB - The splice sites are essential for pre-mRNA maturation and crucial for Splice Site Modelling (SSM); however, there are gaps between the splicing signals and the computationally identified sequence features. In this paper, the Locality Sensitive Features (LSFs) are proposed to reduce the gaps by homogenising their contexts. Under the skewness-kurtosis based statistics and data analysis, SSM attributed with LSFs is fulfilled by double-boundary outlier filters. The LSF based SSM had been applied to six model organisms of diverse species; by the accuracy and Receiver Operating Characteristic (ROC) analysis, the promising results show the proposed methodology is versatile and robust for the splice-site classification. It is prospective the LSF-based SSM can serve as a new infrastructure for developing effective splice-site prediction methods and have the potential to be applied to other sequence prediction problems. PMID- 23437517 TI - [Pneumocystis jirovecii: one hundred years of history]. AB - INTRODUCTION: Pneumocystis jirovecii is one of the most important opportunistic pathogens affecting AIDS individuals and immunodepressive patients. In spite of the fact that it was observed one hundred years ago for the first time, many fundamental aspects of its biology and the morbidity it causes are still unknown. OBJECTIVE: this paper was aimed at presenting updating on the main aspects of the history, the epidemiology and the biology of P. jirovecii and the disease it causes. CONCLUSIONS: a number of review articles have been published since the discovery, all of which provide details and novel elements of the microorganism. However, few original papers dealing with this problem have been found in the Spanish literature. PMID- 23437518 TI - [Presumptive identification of Cryptococcus gattii isolated from Terminalia catappa in Monteria city, Cordoba, Colombia]. AB - INTRODUCTION: the members of the Cryptococcus neoformans species complex are responsible for cryptococcosis in animals and humans. Human infection is thought to be acquired by inhalation of airborne propagules from an environmental source; therefore it is greatly important to study their habitat. OBJECTIVE: to determine the ecological relationship of Cryptococcus gattii with Terminalia catappa trees present in urban areas of Monteria city in Colombia. METHODS: a total of 163 Terminalia catappa trees were selected; some samples were taken from the bark, the leaves, the flowers, the fruits of these trees and from the surrounding soil. The yeast was isolated using the Guizotia abyssinica seed agar medium; it was identified thanks to biochemical and morphologic tests whereas the right variety was determined by L-canavanine-glycine-bromothymol blue (CGB), D-proline and D tryptophan tests. RESULTS: there was obtained 9.050 CFU/g isolate of Cryptococcus spp., 5.795 CFU/g of which were presumptively identified as Cryptococcus gattii. The highest percentage of isolates was found in flowers, followed by bark and fruits, presenting small cellular and capsular sizes. These isolates were more frequent in the south of the city, followed by the center zone and the lowest percentage in the northern zone. CONCLUSIONS: these findings confirmed the close relationship of Cryptococcus gattii and Terminalia catappa, being this the first study conducted in Monteria city. These results give us meaningful information for understanding and analyzing the epidemiology of cryptococcosis in Monteria city, Colombia. PMID- 23437519 TI - [Effect of 4B3 monoclonal antibody on the experimental Cryptococcus neoformans infection]. AB - INTRODUCTION: frequent relapses and high lethality of criptococcosis has encouraged the search for new therapeutic strategies. OBJECTIVES: to evaluate the effect of the monoclonal antibody 4B3 on the cryptococcal infection in Balb/c mice. METHODS: the kinetics in serum concentration of the studied monoclonal antibody was determined for intraperitoneal administration (500 microg) by quantitative sandwich ELISA. In order to assess its protective capability, were administered 500 microg of 4B3 and innoculated 2 x 10(22) cells/mL of Cryptococcus neoformans. The survival of mice was recorded and the yeast dissemination to the main target organs was evaluated. Macrophages P338.D1 cell lines were used to measure the effect of the monoclonal antibody 4B3 on the phagocytosis and lysis of the microorganism. RESULTS: the used dose helped to keep high values (38 microg/m) of 4B3 in serum for at least 46 days. It was found that the monoclonal antibody does not give protection, which makes the microorganism dissemination possible, along with the reduction in the survival of mice. Finally, the phagocytosis test showed that 4B3 increased the phagocytic activity of macrophages without any fungicidal effect. CONCLUSIONS: the monoclonal antibody 4B3 stimulates C. neoformans phagocytosis by macrophages without fungicidal effect, thus favoring yeast dissemination and decreasing the survival of mice due to cryptococcal infection PMID- 23437520 TI - [Radiological patterns and final diagnosis of patients presumptive of pulmonary tuberculosis with negative sputum smears]. AB - INTRODUCTION: the diagnosis of pulmonary tuberculosis in sputum smears-negative patients is a challenge for today's medical practice, mostly supported on clinical and radiographic elements. In Hospital Neumologico Benefico Juridico of Havana, there is an expert commission for the sputum smear-negative diagnosis of tuberculosis called CODIBAARNE. OBJECTIVE: to identify the radiological patterns and the final diagnosis of patients submitted to this committee from October 2002 to December 2003. METHODS: a descriptive study was conducted in a sample of patients within the above-mentioned period, who had been studied and followed-up in Hospital Neumologico Benefico Juridico in order to define their final diagnoses under the CODIBAARNE commission recommendation. Data were gathered from the register of patients and from the individual medical histories. RESULTS: the average age of these patients was 68.2 years and 57 % were males. The most frequent symptoms were cough (76 %), general syndrome (70 %) and expectoration (61 %). The mostly seen radiographic patterns were infiltrates, with or without cavitation (44 %) and fibrotic lesions (34 %). The most common diagnoses showed bronchiectasia (26 %), followed by sputum smears-negative pulmonary tuberculosis (24 %). CONCLUSIONS: the results of this research work evinced the importance of the work by the group of experts in CODIBAARNE regarding the sputum smears negative diagnosis of tuberculosis cases. PMID- 23437521 TI - [Evaluation of the immobilization of one HIV-2 gp36 peptide in nitrocellulose membrane]. AB - INTRODUCTION: antigen immobilization in solid supports is used for the development of several immunoassays. One of the first technologies developed was the protein adsorption by direct application to nitrocellulose. OBJECTIVE: to standardize the immobilization of a synthetic peptide of the HIV-2 transmembrane protein gp36 to nitrocellulose support for diagnostic purposes and to evaluate the performance parameters in a group of serum samples with recognized interesting reactivity. METHODS: the peptide was freely immobilized, conjugated to bovine serum albumin (BSA) and to keyhole limpet hemocyanin (KLH) as carrier proteins. Immobilization parameters were analyzed and then, the optimal immobilization alternative was determined. Using the chosen variant, the diagnostic sensitivity and specificity against reference panels of the AIDS Research Laboratory were evaluated. Analytical specificity was evaluated with reactive samples to HIV-1 and HTLV-1. RESULTS: the analysis of the immobilized peptide variants to nitrocellulose membranes showed that the gp36 peptide-BSA was the one that succeeded in setting the greatest differentiation between positive and negative samples. There were observed 100 % sensitivity, 95.2 % diagnostic specificity and 100 % analytical specificity. CONCLUSIONS: the gp36-BSA peptide immobilized on nitrocellulose membranes showed efficacy for the serological diagnosis of HIV-2, which will allow considering this peptide for diagnostic uses in systems with nitrocellulose -based solid phase. PMID- 23437522 TI - [Sequence of viral infection associated to pregnancy in a dengue outbreak in Santiago de Cuba in 2006]. AB - INTRODUCTION: several dengue outbreaks have taken place in Santiago de Cuba province in the last few years, in which pregnant women have been involved. OBJECTIVES: to determine the immunity and to describe the role of dengue infection and its sequence. METHODS: an observational and descriptive study was conducted to characterize dengue immunity in mothers and children after 10 and 12 months of birth and to determine the influence of certain viral infection sequences in pregnant women who suffered this disease during the dengue 3 epidemics in Santiago de Cuba. To this end, serum samples from 25 females tested dengue 3-positive and from children born to them after 10 and 12 months of childbirth were studied. IgG titers and viral infection sequences were determined and analyzed according to the World Health Organization dengue classification criteria. RESULTS: the children did not present with the antibodies and the viral infection sequences associated to mothers; in order of frequency, the same percentage was observed in DEN2/DEN3, DEN1/DEN2/DEN3 (21,74 %); but lower percentage in DEN1/DEN3 (17,39 %). CONCLUSIONS: the children did not develop humoral immunity (IgG) despite some manifestations inherent to the disease. The secondary infections prompted the most serious forms of the disease. PMID- 23437523 TI - [Molecular diagnosis of influenza A(H1N1) 2009 virus and other respiratory viruses during the first pandemic wave in Cuba]. AB - INTRODUCTION: the first pandemic virus of the 21st century - the influenza A (H1N1)/2009 virus-appeared in Mexico in April 2009 after triple reassortment of influenza strains of avian, human and pig origin and from there, it was spread worldwide. With the purpose of facing up to this event, Cuba adopted antipandemic measures including the virology surveillance using all necessary actions. OBJECTIVES: the detection and validation of the entry of the causative agent of pandemic into the country in a fast and timely way, in addition to the definition of involvement of other viruses in the etiology of acute respiratory infections. METHODS: as a result of the lab surveillance, from the 38th to the 42nd epidemiological weeks (September and October, 2009), 1 063 respiratory clinical samples were processed (nasopharyngeal exudates, bronchial aspirates and lung necropsy samples). The highest number of confirmed cases caused by the new virus was detected in this period that represented the first pandemic wave in Cuba. Diagnosis was based on molecular diagnosis algorithm. RESULTS: out of the 1063 samples, 597 (56.0 %) were positive. The pandemic influenza A (H1N1) virus was the most commonly detected etiological agent in 306 suspected cases (51 %) followed by influenza A (H3N2) virus in 228 cases (38 %). Other respiratory viruses were diagnosed in 63 clinical samples (11 %). The pandemic virus was confirmed in 50 pregnant women. Rhinoviruses were identified more frequently in those samples from patients with clinical diagnosis of bronchial pneumonia and broncholitis. Morbidity increased during this period; 225 825 medical consultations were notified due to acute respiratory infections mid-October 2009. CONCLUSIONS: the molecular diagnosis algorithm proved to be sensitive, specific and effective to assure the systematic virological surveillance in our country during the pandemic phase. PMID- 23437524 TI - [Effectiveness of the anti-meningococcal vaccine VA-MENGO-BC in the first year of life of Cuban children, 1997-2008]. AB - INTRODUCTION: meningococcal disease is an important health problem worldwide. Since 1991 the vaccine VA-MENGOC-BC has been used in Cuban under one-year old infants. OBJECTIVE: to evaluate the effectiveness of the vaccine VA-MENGO-BC METHODS: for the evaluation after licensing this vaccine, all the infants affected by meningococcal disease between 1997 and 2008 were studied. RESULTS: a total number of 114 cases were recorded. The annual average incidence was 7.1 per 100 000 infants. The mean vaccinal effectiveness for the period was 84.0 %, ranging from 68 % to 104 %. The frequency of disease in unvaccinated children was 20.2 % (23/114); 79.8 % (91/114) within the vaccination age, but only 75.8 % (69/91) of them had confirmed the immunization date. Only 26.4 % (24/91) had one single dose applied whereas 73.6 % (67/91) had completed their vaccination schedule (2 doses). The meningococcal disease prevailed in the first six months of life, declined afterwards and then started to rise again at 10 and 11 months of age. The meningeal form of clinical presentation predominated (89.5 %); case fatality rate was 7.0 % (8/114), being 4.4 % for meningococcemia and 2,6 % for meningitis. CONCLUSIONS: the vaccine VA-MENGOC-BC effectiveness in infants was satisfactory. It is suggested that further analysis be made by a group of experts on the use of a booster dose. PMID- 23437525 TI - [Cuban advisory work to face the rise of malarial cases in two Haitian departments in April 2010]. AB - INTRODUCTION: malaria is considered to be a serious health problem in Haiti, mainly in the rural zones of the coastal area located at 600 m above the sea level, particularly shallow zones with rice crops. OBJECTIVE: to describe the actions taken in four sites of two Haitian departments to face the rise of the number of malarial cases. METHODS: the advisory work was carried out in three communities located in the West department and one in Nippes department in April 2010. Fever screenings along with sample-taking for thick smear test were performed as well as anti-vector activities including search for breeding sites and thermal treatment in the house and out of it. RESULTS: it was confirmed in this thick smear test that not all the persons presenting with febrile symptoms suffered malaria since low positive values to this disease were obtained. During this study, only Plasmodium falciparum was diagnosed. Out of the 46 breeding sites, 26 were positive to Anopheles albimanus. The impact of insecticidal treatment could not be assessed since the areas did not have preliminary data on this respect. CONCLUSIONS: these results provide the malaria control program with pieces of knowledge about the distribution and control of vectors in addition to emphasizing the need of making an updated stratification of the incidence of the disease that comprises all the aspects of the malaria control program in Haiti. PMID- 23437526 TI - [Effectiveness of insecticidal formulations for the Aedes aegypti adult population control in La Habana, Cuba]. AB - INTRODUCTION: the vector control remains the sole sustainable measure to prevent dengue transmission in which the key role goes to adulticides in case of high rates of infestation by the vector, outbreaks or dengue epidemics. Pyrethroids are the most used whereas organophosphorous chloripirifos has been occasionally used because of the cost. OBJECTIVES: to determine the effectiveness of insecticides in their commercial formulation that is applied today by the National Unit of Anti-Vector Control and Surveillance in Cuba for the control of Ae aegypti adults such as chlorpirifos (Terfos 48 CE) and pyrethroids, lambda cyhalothrin (ICON 2.5 CE) and cypermethrin (Galgotrin 25 CE). METHODS: fifteen Ae. Aegypti strains from the 15 municipalities of La Habana province, collected in 2008, and the Rockefeller reference strain were used. The level of effectiveness of these products against the adult vector was determined through WHO-recommended bioassays. RESULTS: in situ effectiveness bioassays, Terphos 48 CE was the most effective in causing 100 % mortality of all the strains, followed by Icon 2.5 CE and Galgotrin 25 CE which reached 98 % and 100 % mortality rates respectively. CONCLUSIONS: the field tests showed that the insecticides currently in use in the Aedes aegypti eradication program are still highly effective in La Habana province. The combined use of chlorpirifos and pyrethroids are recommended to delay the evolution of resistance to this last group of insecticides. PMID- 23437527 TI - [Optimization of extracting solutions of antibacterial molecules from Cenchritis muricatus (Gastropoda: Littorinidae)]. AB - INTRODUCTION: marine mollusks are natural reservoirs of molecules with therapeutic potential for the treatment of infectious diseases, at a time when many antibiotic-resistant strains are being described. OBJECTIVE: to compare three solutions: 30 % acetic acid, 50 % methanol and saline-acid (NaCl 0.6 mol/L, 1 % HCl) according to their capacities to extract molecules with antimicrobial activity from the marine mollusk Cenchritis muricawus. METHODS: the three extraction solutions were used to process the biological material, and then, the obtained extracts were analyzed in terms of total protein concentration and the bacterial growth inhibition of Staphylococcus aureus and Escherichia coli strains by means of a turbidimetric bioassay using 96 well microplates in Luria-Bertani (LB) culture medium. RESULTS: the highest total protein concentration (7.8 microg/mL) was found in the C. muricatus extract from the saline-acid solution. Additionally, 200 microg/mL of total proteins from the extract caused significant growth inhibition (p< 0.001) of S. aureus (12.64 %) and E. coli (12.1 %) compared to the positive control of growth inhibition using chloramphenicol. CONCLUSIONS: according to these results, the saline-acid solution proved to be more efficient in extracting molecules with antibacterial activity that are likely to be antimicrobial peptides from C. muricatus. PMID- 23437528 TI - [Contributions made by the Cuban advisory work to the entomological surveillance in Haiti]. AB - INTRODUCTION: the earthquake occurred in Haiti in January 2010 led to the worsening of the hygienic, sanitary and environmental conditions and increased the number of breeding sites for disease-borne vectors in the country. OBJECTIVES: to report the first results of the entomological surveillance set by the Cuban advisory group in Haiti after the earthquake. METHODS: the work was carried out in 7 sites located in West department, one of the ten departments of the country; larval sampling was conducted in reservoirs and natural breeding sites based on the methodologies for both. The sampling was weekly in the May October period in 2010. RESULTS: twelve mosquito species were reported in the West department as well as the presence of Triatoma rubrofasciata. The fundamental breeding sites of the three most important mosquito species were identified including Aedes aegypti with water tanks followed by worn car rubbers and small artificial deposits, Anopheles albimanus in rice fields, animal footprints and coastal swampy plains, and Culex quinquefasciatus, one lymphatic phylarosis-borne vector still existing in Haiti, in drains and waste water ditches. CONCLUSIONS: these results are the first ones from this surveillance program after the earthquake and represent valuable information for the decision making at the time of designing a control program to face the occurrence of any epidemics in which these insect vectors might be involved in this department. PMID- 23437529 TI - [Antimalarial activity of hydroalcoholic extract from Bixa orellana L]. AB - INTRODUCTION: Bixa orellana L. is one species used in traditional herb medicine in several continents. Among the medicinal properties attributed to this plant, the antimalarial action has been included. OBJECTIVE: to evaluate in vitro and in vivo antimalarial activity of extract from B. orellana grown in Cuba. METHODS: the antimalarial activity of the hydroalcoholic extract fro Bija seeds was evaluated in vitro against Plasmodium falciparum Ghana strain and in vivo using a model of murine malaria, that is, Balb/c mice infected with Plasmodium berghei ANKA strain. Citotoxicity was determined against MRC-5 human fibroblasts. Additionally, phytochemical composition of the studied extract was preliminarily informed. RESULTS: the extract exhibited IC50 (medium inhibitory concentration) of 11.6 microg/mL, CC50 (medium citotoxic concentration) of 60.2 microg/mL and SI (selectivity index) of 5.1. Subcutaneous administration of the extract at a 500 mg/kg dose caused parasitemia reduction of 50.3 +/- 5.8 % on infected animals compared with that of the controls. Phytochemical screening was consistent with detection of triterpenoids and/or steroids, alkaloids, lactonic compounds, phenols, tanins and flavonoids. CONCLUSIONS: the hydroalcoholic extract from B. orellona seeds grown in Cuba showed in vitro and in vivo moderate antimalarial activity. Bioassay-guided fractioning will allow identifying the molecules responsible for the exhibited extract activity and re-evaluating the potentialities of this extract. PMID- 23437530 TI - [Development, current trend, and challenges of epidemiology in Cuba]. PMID- 23437531 TI - [Contribution of the National Influenza Laboratory to confront the 2009 pandemic influenza in Cuba]. AB - INTRODUCTION: Acute respiratory infections are considered the most important causes of morbidity and mortality around the world. These infections became more significant when associated to epidemics and pandemic events caused by influenza virus. The need for global surveillance of influenza viruses was recognized as early as 1947 and led to the establishment of the World Health Organization (WHO) Global Influenza Surveillance Network (GISN). The Cuban National Influenza Centre (NIC) belongs to this network since 1975. On April 2009, the recognition of a new influenza A (H1N1) of swine origin circulating in humans was identified as the causative agent of the first pandemic in the 21st century declared by the WHO. OBJECTIVE: to carry out surveillance of the new pandemic virus nationwide. METHODS: The Cuban National Influenza Center developed a diagnostic diagram to confirm infection with the pandemic virus in suspected cases. Different PCR assays for typing and subtyping of influenza A virus were used. RESULTS: From April to December 2009, 6 900 clinical respiratory samples were processed by using this diagram, 980 cases were confirmed and notified to the national health authorities and to the Pan American Health Organization. Human rhinoviruses were other important etiologic agents of the frequently detected acute respiratory infections. CONCLUSION: With the national strategy for surveillance at lab, it was possible to effectively monitor the circulation of the influenza viruses and of other respiratory viruses in our country and to alert the national health authorities, with a view to facing up to the pandemic influenza (2009). PMID- 23437532 TI - [Design and implementation of a molecular method for influenza A virus (H1N1) in Cuba]. AB - INTRODUCTION: From March through April of 2009, Mexico notified outbreaks of respiratory illness, due to a new influenza virus of swine origin, which spread over rapidly via human-to-human transmission. The molecular methods currently in use were not suitable because the genome composition based on gene segments of swine, avian and human origin was quite different from the influenza A virus (H1N1) circulating at that time. OBJECTIVE: Based on the published sequences, a set of specific primers for the HA gene was designed to evaluate a new RT-PCR assay. METHODS: The RT-PCR assay processed 3 197 clinical samples from suspected cases of pandemic influenza A (H1N1) infection. RESULTS: The novel optimized method obtained a 262 pb segment, without unspecific reactions. The new method proved to be useful in the diagnosis and subtyping of pandemic HINI influenza virus. The amplified product was verified by nucleotide sequencing, thus confirming the virus. CONCLUSIONS: The introduction of this new assay for the laboratory surveillance of influenza virus strengthens the diagnostic capacity of the National Reference Laboratory. PMID- 23437533 TI - [Cuban strategy for the molecular characterization of the pandemic influenza A virus (H1N1)]. AB - INTRODUCTION: In April 2009, there was identified a variant of the A/H1N1 influenza virus of swine origin, and shortly after the first pandemic in XXI century was declared. OBJECTIVES: To establish a nucleotide sequencing strategy for the differential diagnosis of the seasonal and pandemic influenza A viruses, and to obtain as much molecular information as possible about hemagglutinin and neuraminidase genes in patients with influenza-like illnesses, in those with severe respiratory infection and in patients who died. METHODS: Three sequencing strategies were designed and implemented, which also offered important information about the new virus in Cuba. RESULTS: The third strategy provided the most comprehensive results such as differential diagnosis, the surveillance of the D222G/E mutation in hemagglutinin and Tamiflu-resistant H275Y viral variants. In spite of the fact that the mentioned mutations were not detected, their presence in the Cuban population can not be ignored since these strategies were not designed for this end. It is imperative to design a study to fulfill this objective. CONCLUSIONS: The sequencing strategies in our algorithm allowed the differential diagnosis of the seasonal and the pandemic viruses, and their molecular characterization. PMID- 23437534 TI - [Severe acute respiratory infection in Cuban patients during the influenza A(H1N1) pandemic in Cuba, 2009]. AB - INTRODUCTION: On April 2009, the Mexican health authorities reported increased hospitalization indexes caused by pneumonia with high mortality rates to the Pan American Health Organization (PAHO). The National Epidemiological Surveillance System of Mexico noticed that this increase mainly occurred in the 20-40 year old population. A new type of swine influenza A (H1N1) virus was identified by laboratory studies as the etiological agent of the first pandemic of the 21st century. On April 26 2009, the National Anti-pandemic Plan was activated by the Cuban Ministry of Public Health, and on May 7th, the lab-confirmed index case appeared. An integrated surveillance system with laboratory confirmation was set up. OBJECTIVES: To detect pandemic influenza virus during the pandemic wave. METHODS: The epidemiological weeks 37 to 41 witnessed a rise of the number of sick people seen by the medical services. In this period, the samples taken from patients clinically diagnosed with severe acute respiratory infection were selected for this analysis; they were divided into three groups, that is, 370 children and adults in critical condition, 55 pregnant women in severe condition and 30 fatal cases. The diagnosis of the pandemic virus was performed by Real Time Polymerase Chain Reaction Test (PCR). Other respiratory viruses were tested by conventional PCR. RESULTS: The pandemic influenza virus was detected in 65 children and adults, 20 pregnant women and 9 fatal cases. The seasonal influenza A (H3N2) virus was identified in 81 cases of severe acute respiratory infection covering all age groups, 10 pregnant women and 5 deceased on the basis of real time polymerase chain reaction test. Other respiratory viruses were also monitored by the end-point polymerase chain reaction. CONCLUSIONS: The comprehensive analysis of these results contributes to the national and regional surveillance of respiratory viruses for the improvement of the prevention and control programs of the acute respiratory infections. PMID- 23437535 TI - [Reactogenicity associated to the intradermally administered inactivated poliovirus vaccine with a needle-free injector]. AB - INTRODUCTION: As the goal of poliomyelitis eradication is about to be accomplished, the need for an affordable and appropriate inactivated poliovirus vaccine (IPV) for use in developing countries has become a target for WHO. OBJECTIVE: To evaluate the reactogenicity of the inactivated poliovirus vaccine. METHOD: An experimental-type multicenter study was conducted, as part of a Phase I-II controlled clinical randomized and blinded assay, in 471 healthy infants of both sexes born in July and August 2006 in Camaguey province. The parents of the children who met the inclusion criteria gave their consent in writing. The children received three doses of the inactivated poliovirus vaccine at 6, 10 and 14 weeks after birth. This vaccine came form the Institute of Sera in Denmark and had been approved for use in this assay by the Cuban regularoty authorities, Low 0.1 mL inactivated poliovirus vaccine dose was intradermally administered to the study group A in the anterolateral side of the left thigh using the needle-free injector called Biojector 2000. The usual 0.5 mL dose was intramuscularly administered on the same site using a pre-filled syringe. The adverse events were observed during the first hour, 24, 48, and 72 hours after the immunization, as well as 7 and 30 days afterwards. The pediatrician in charge of the health area evaluated the reactogenicity at first and then the family physician was in charge of observing the adverse events in the remaining period. RESULTS: The 79.6% of children in group A and 75% in group B completed the research protocol. Mild local adverse reactions prevailed, mainly induration, pain and redness at the injection site. CONCLUSION: the Clinical trial proved the safety of the inactivated poliovirus vaccine for intramuscular administration, and also showed the safety of the intradermal route of administration and of the needle-free injector. PMID- 23437536 TI - [Clinical and pathological correlation in fatal dengue cases found in Maracaibo, Venezuela]. AB - INTRODUCTION: Given the importance of dengue in America, it is indispensable to know the cause of death of the infected people and to evaluate the few necropsy studies available. OBJECTIVE: To describe and to analyze the relevant clinical and pathological findings in fatal dengue cases of dengue in a Venezuelan endemic area. METHODS: Eight fatal cases, according to clinical and epidemiological dengue criteria and/or confirmed by complete serological tests were studied after complete clinical necropsy. The tissues were processed by standard histopathological techniques. RESULTS: All these cases showed severe lung disease (diffuse alveolar damage, non cardiogenic pulmonary edema, thromboembolism, bronchopneumonia, pneumonitis, intralveolar hemorrhage). Six presented with pleural or abdominal effusion. Focal hepatic necrosis was found in two cases. The cause of death was related to respiratory failure in six (6) cases secondary to lung disease; two with hypovolemic shock, and one developed liver failure. CONCLUSION: the studied dengue cases showed fatal severe pulmonary compromise leading to death, unlike those reported in other studies of autopsies in The Americas. They also developed multiple organ failure, which in most cases led to death not directly associated to hypovolemic shock. These findings in autopsies will allow designing therapeutic strategies to avoid mortality. PMID- 23437537 TI - [Antimalarial activity and cytotoxicity of hydroalcoholic extracts from six plant species used in Cuban traditional medicine]. AB - INTRODUCTION: Malaria is the most important parasitic disease for global health. Lack of the structural diversity in current antimalarials demands the urgent search for new therapeutic alternatives. The plants have shown their potential to provide effective antimalarials, therefore, a large sample of Cuban medicinal plants is being studied. OBJECTIVES: To evaluate antimalarial activity of extracts from six plant species and to determine their selectivity by meassuring cytotoxicity against human cells. METHODS: Hydroalcoholic extracts from Annona glabra L., Bidens pilosa L., Cecropia peltata L., Curcuma longa L., Hura crepitans L. and Pluchea odorata (L.) Cass. were prepared. Their activity was evaluated in vitro against Plasmodium falciparum and human fibroblasts MRC-5. The mean inhibitory concentration, the mean cytotoxic concentration and the selectivity index were estimated. A preliminary phytochemical screening of the most active extract was made. RESULTS: H. cre-pitans extract was the only one that showed good antiplasmodial activity (mean inhibitory concentration of 5,7 microg/mL) with excellent selectivity (selectivity index of 18,8). Phytochemical screening revealed the presence of phenolic compounds, triterpenoids, alkaloids, quinones, flavonoids and anthocyanidins. CONCLUSIONS: One extract with potent antimalarial activity in vitro was obtained. This result is an incentive to continue studying this vegetal preparation. PMID- 23437538 TI - [Distribution and ecological characteristics of freshwater snails of medical importance in Santiago de Cuba province]. AB - INTRODUCTION: The ability of freshwater snails to serve as intermediary host of parasites responsible for some tropical diseases is well known. OBJECTIVE: A malacological study was carried out in the Santiago de Cuba province in order to determine the distribution of freshwater snails of medical importance and their relation with the main ecosystems. METHOD: Nineteen sites were sampled in the province and the abundance of each of the species was compared to the type of habitat by means of the correspondence analysis. Each site was referred from the geographical viewpoint to determine the distribution patterns. RESULTS: A total amount of 12 freshwater snail species was found and the most abundant were Tarebia granifera, Physa acuta and Pyrgophorus parvulus. Rivers are the main types of ecosystems associated to these species followed by springs and ditches. Fossaria cubensis showed high density in flooded grounds whereas Biomphalaria pallida was the only planorbid species that could coexist with thiarid species. CONCLUSIONS: Due to the species found in this province, the likelihood of possible outbreaks of fasciolosis as well as the introduction of schistosomiasis is considered as high. PMID- 23437539 TI - [Bioecological studies of Aedes (St) aegypti in an urban area with low vector density in Camaguey province]. AB - INTRODUCTION: The control of the breeding sites of mosquitoes of medical importance is essential for the anti-vector fighting programs; however, the efforts made so far have not great enough since the confirmed dengue fever cases gradually increase. OBJECTIVE: To provide information on the main breeding sites of Aedes aegypti in an urban area with low vector density in Camaguey province. METHODS: The urban universe was fully surveyed from January to December 2007. The collection procedure in the positive containers followed the National Vector Control program methodology. The characteristics of each container were written in a customized study form of positive blocks. The representative percentage of each positive container, as well as the proportion of larvae per container were determined. RESULTS: Aedes aegypti formed colonies in 44 different containers, being the artificial reservoirs the predominant ones (97.73%). The majority were permanent, useful and unchangeable. Following the population's criteria, the combination of permanent plus useful is valid in 17 types of containers accounting for 38.36% and contributing 180 positive containers for 81.08% of the total number. The tanks placed on the ground reached 36.03% positivity. CONCLUSIONS: The high number of mosquito-positive tanks demands greater individual responsibility in improving domestic sanitation and thus, the increase of awareness in order to achieve more active community involvement in this regard. The latter together with the strengthening of transectoriality will allow having an impact on the elimination and final disposal of all the useless materials that may serve as possible breeding sites of mosquitoes. PMID- 23437540 TI - [High performance liquid chromatography-validated analytical method for 1% permethrin quantification]. AB - INTRODUCTION: In Cuba, as well as in other countries, Pediculus capitis infestation has increased since the 70's; this is the reason why a program aimed at controlling and preventing this infestation was designed. This program includes quality control studies of the active synthetic pyrethroid Permethrin and its activity at 1% on lice and 5% on scabies. Due to its low toxicity and positive risk/benefit ratio, Permethrin is a pediculicide of choice to decrease Pediculus capitis infestation. OBJECTIVE: To validate an analytical method using high performance liquid chromatography and its application in the quantification of 12 samples from 2 batches of Cuban-made 1% permethrin pediculicidal preparation. METHODS: Linearity, precision and accuracy parameters were determined. Seven calibration standards and working solutions with concentrations ranging from 100 to 15000 microg/mL were prepared. These validation parameters were verified through the correlation coefficient, the variation coefficient and the percentage relative error. RESULTS: The specificity of this method was proved in the chromatograms that showed retention times of 8,8 to 9,2 min for the isomer trans and 10,7 to 11,2 min for the isomer cis. The correlation coefficient for both isomers was higher than 0,99; the variation coefficient was under 3% and the percentage relative error was--3 and 1% for the inter-day and intraday studies, respectively. The mean permethrin concentration in 1% solution batches was estimated at 6 780,14 microg/mL. CONCLUSIONS: The validated method was linear, precise and exact within the range of the studied concentrations. The estimated concentration of permethrin was below the expected rate according to the composition of 1% permethrin solution (9 100-10 900 microg/mL). This method may be useful for the quantification of 1% permethrin solutions in the quality studies of the product sold to the population. PMID- 23437541 TI - [Phenotypic characterization of Aeromonas isolated from patients with acute diarrheal diseases]. AB - INTRODUCTION: The acute diarrheal diseases are one of the main causes of morbidity and mortality in children aged under 5 years and in the general population; this demands a great deal of care in the healthcare services. The situation worsens due to the overuse of antimicrobials and the development of bacterial resistance, being the latter an emerging health problem in different areas of the world. Among the causative microorganisms of acute diarrheal diseases are those of Aeromonas genus, recognized as second risk emerging pathogens. OBJECTIVES: To determine the most frequently isolated Aeromonas species in fecal samples from acute diarrheal patients and their antimicrobial susceptibility. METHODS: The Bauer-Kirby's method allowed identifying the susceptibility to several antimicrobials of 100 isolated samples coming from the provincial hygiene and epidemiology centers during 2007 and 2008. RESULTS: Identification of the species was accomplished in 67% of isolates, being A. caviae (33%) y A. hydrophila (29%) the predominant species. It was demonstrated that 100% of isolates got resistant to at least one of the studied antimicrobials. Drug resistance to cefalotine, sulfonamides and nalidixic acid showed the highest percentages. CONCLUSIONS: Tetracycline and chloramphenicol are recommended as the drugs of choice for treating intestinal infections caused by these microorganisms in Cuba. PMID- 23437542 TI - [Operational impact of the use of insecticidal products on Aedes aegypti larvae in Havana province]. AB - INTRODUCTION: In spite of the huge efforts of the Aedes aegypti eradication program in Cuba, there are still certain infestation indexes favoring the development of outbreaks or epidemics in some regions of the country. Havana province holds a leading position in this negative indicator, in which the use of insecticides plays an important role. OBJECTIVES: To evaluate the impact of the use of insecticides in the development of drug resistance by this species in Havana. METHODS: Fifteen Ae. aegypti strains from the fifteen municipalities of the province were used. They were all collected in 2008. The level of susceptibility to insecticides was measured by means of the WHO-recommended bioassays. RESULTS: Sixty percent of the strains were susceptible to chlorpirifos; more resistance to pyrethroid cypermethrin was observed followed by lambdacyalothrin and cifluthrin. CONCLUSIONS: The insecticide Chlorpirifos is a good candidate to be used with pyrethroids, on a rotational scheme, to delay the development of resistance to pyrethroids in Ae. aegypti vectors in Havana province. PMID- 23437543 TI - [Alteration in superficial anionic charge of erythrocytes and desialated erythrocytes caused by Ascaris lumbricoides]. AB - INTRODUCTION: Sialic acid of the erythrocytes has hemorreologic and hemodynamic importance, so its reduction causes erythrocyte aggregation and low blood flow. OBJECTIVE: To study the effect of A. lumbricoides on the anionic charge of erythrocytes and of desialated erythrocytes, taking the time of contact of the erythrocytes with parasite extracts into account. METHODS: Twenty parasite extracts and Group O erythrocyte suspensions in saline medium (GR) and in bromelin enzymatic medium (GR(b)) were used. The erythrocytes were treated by incubating the globular sediment with the same volume of parasite extracts, at 37 degrees C for 15, 30, 45, 60, 90 and 120 min. There was a control for each treatment interval (erythrocytes without contact with parasite extracts). The polybrene's method was simultaneously applied to the controls, the GR ad the GR(b). Each obtained aggregation was given a scoring. C(exp)CAS[EA) was calculated as the quotient between the treated erythrocytes scoring and the control. RESULTS: the statistical analysis allowed arriving to the conclusion that the time of GR and GR(B) treatment had a highly significant effect on the value of C(exp) CAS[EA]; the median of C(exp) CAS[EA]; was significantly higher for GR than for GR(B); the sialic acid uptake in GR was higher from 90 minutes on, whereas this parameter was lower in G(B) at 15 min; no significant differences were observed for the rest of the treatment times. The results showed that the sialic acid uptake by the parasite depended on the time of treatment and that the parasite extract caused more alteration in the superficial charge of GR(B). CONCLUSIONS: The reduction of sialic acid could be related to thrombosis and anemia in ascariosis. The experience gained allows us to consider that the effect of the parasite may be more significant in diabetic and hypertensive individuals. PMID- 23437544 TI - [Pandemic influenza in Cuba]. PMID- 23437545 TI - [Enzymatic immunoassays for the detection of infectious agents or their products: presentation of some designs and applications]. AB - This paper assessed the impact of the immunoenzymatic assays on the field of the immunochemistry-based analytics for the last 40 years, and on the detection of infectious agents or the products related to their presence and/or pathogenic activity. It also addressed some designs and formats of these immunoassays from electrochemical methods of detection, assays to determine proteolytic microbial activity and their inhibitors as possible therapeutical targets, more sensitive direct triple antibody systems, alternative enzymatic activity detectors, assays for viral serology of minimal determinations to competitive assays for evaluation of vaccinal candidate effectiveness based on selected peptide combinations. Finally, it provided a rapid overview of the near future of this type of immunoassays in the light of the emerging detection analytical technologies. PMID- 23437546 TI - [Algorithms for hospital-acquired infection surveillance in intensive care units]. AB - IINTRODUCTION: the occurrence of nosocomial infection in an intensive care unit is very high and increases the possibilities of the patient's death and the cost of care. OBJECTIVES: to find out and apply diagnosis algorithms for nosocomial infection surveillance at the critical patient care service. METHODS: in 2005, a three-phase research study was carried out in "Cira Garcia" clinics: management and analysis of international and national information on this topic, the preparation of the algorithm, and the application of such algorithm in nosocomial infections surveillance at the progressive care units. RESULTS: three algorithms were found for the most frequent infections and they were used for the nosocomial infection diagnosis for 4 years. CONCLUSIONS: the use of these algorithms is a good supporting method to identify nosocomial infection, which leads to a better and prompt diagnosis and facilitates the involvement of infectious control staff in the individual analysis of each patient. PMID- 23437547 TI - [Enabling intervention for active screening of respiratory symptomatic patients in two municipalities located in the City of Havana province]. AB - OBJECTIVES: to evaluate the feasibility and immediate effect of an enabling intervention to improve the active screening of respiratory symptomatic patients in groups at risk of suffering tuberculosis and the quality of filling in lab records. METHODS: a quasi-experimental-designed intervention study was conducted in two health areas of Boyeros municipality (Salvador Allende polyclinics and Federico Capdevila polyclinics). Two other areas were selected as controls in "10 de Octubre" municipality ("Turcios Lima" polyclinics and "Puente Uceda" polyclinics). Family physicians and nurses were then trained to identify patients with respiratory symptoms in the risk groups during home visits, finally sputum tests were indicated. A new model for lab recording was used. After 2 months, the ratio of detected respiratory symptomatic cases was estimated. The relative risk (95 % CI) was found. The percentage by type of screening, risk group and number of empty, misplaced and wrongly filled in items in the new model was calculated. RESULTS: after the intervention, the capabilities of physicians and nurses for detecting respiratory symptomatic patients in "Salvador Allende" health area was almost 2.5 times higher than before (RR= 2.4320) and in "Federico Capdevila" health area was almost 2 times higher (RR = 1.8112). Over 80 % of this improvement was due to active screening carried out almost completely (90 %) in risk groups. There were no misplaced or wrongly filled data, just empty items under 0.5%. CONCLUSIONS: the enabling intervention proved to be immediate and effective in order to raise the active screening of respiratory symptomatic patients in risk groups and to improve the quality of filling in lab records. PMID- 23437548 TI - [Challenge clinical trial for evaluation of a vaccine candidate strain against cholera]. AB - INTRODUCTION: live attenuated oral Vibrio cholerae Ol El Tor, Ogawa strain 638 has demonstrated to be well tolerated and immunogenic when administrated orally in studies carried out in healthy volunteers. OBJECTIVES: to evaluate the protection against cholera infection in a challenge clinical trial, for the technological and pharmaceutical scale-up of this vaccinal candidate as active ingredient at industrial level. METHODS: a total of 21 healthy volunteers were involved in this trial; the vaccine candidate was administered to 12 of them and the remaining nine were given the placebo. Twenty eight days later, all of them received an infective dose of a V. cholerae virulent strain. RESULTS: diarrheas were observed in 7 out of 9 placebos whereas not a single vaccinated volunteer showed diarrheas. More frequent and intense loose stools were found in the placebo volunteers with O-blood group. All volunteers in he placebo group excreted V. cholerae, but only three (25%) out of the 12 vaccinated volunteers did so. CONCLUSION: in this challenge clinical trial model, the 638 strain proved to protect people against the diarrhea caused by a virulent V. cholerae strain. PMID- 23437549 TI - [Effect of Vimang in HIV/AIDS patients]. AB - INTRODUCTION: the oxidative stress (OS) has been recognized as a co-factor of HIV infection evolution to AIDS condition. OBJECTIVES: to evaluate the possible antioxidant effect and the impact on the functioning of several systems in the body, resulting in the toxicological safety of Vimang use. METHODS: sixty eight HIV-seropositive patients were double-blind randomized in two groups; the first was supplied with Vimang during six months and the other with placebo. Redox condition and the biochemical indexes of the hematological, renal and hepatic functions were measured. Also, dietary intake was assessed through surveys administered for 7 days at the beginning and at the end of the study. RESULTS: there were statistically significant differences between the groups regarding positive change in redox figures in Vimang group compared to those of the placebo group. No significant difference was found either in the evaluated dietary intake indexes or in the biochemical indexes of the renal, hematological and hepatic functions at the end of the study. CONCLUSIONS: Vimang antioxidant effect was shown, without any toxic influence during the six month-study conducted in HIV/AIDS patients. PMID- 23437550 TI - [Pneumonia caused by Rhodococcus equi: clinical and radiological findings in 8 AIDS patients]. AB - INTRODUCTION: the Rhodococcus equi is one bacterium of the order Actinomycetales. It rarely appears in humans, but the HIV/AIDS epidemic has increased the number of cases and the main affected organ is the lung. It causes pneumonia characterized by a slow clinical and radiological progression. OBJECTIVE: to describe the initial radiological alterations from R. equi infection in 8 AIDS patients, the radiological evolution and the clinical and immunological presentation. METHODS: a retrospective descriptive study of radiological pulmonary images from AIDS patients with respiratory infection due to Rhodococcus equi was conducted. RESULTS: these patients presented with high fever (39 degrees C), cough with expectoration and shortness of breath. Homogeneous opacity was the most frequent radiological presentation (62,5% of cases), located predominantly in the lower lobules. The radiological evolution was characterized by opacity with inner cavitation in 4 cases, fibrosis in 4 cases, and one case showed total recovery of lesions. The CD4+ T-cell count was low in all the patients. The evolution ranged from 2 to 33 months. CONCLUSIONS: the R equi pneumonia diagnosis should be borne in mind when dealing with HIV/AIDS patients with compromised immunological condition and breathing process with radiological manifestation of pulmonary consolidation evolving into cavitation, and torpid and prolonged clinical and radiological evolution. PMID- 23437551 TI - [Inhibitory effect of turpentine oil on Aedes aegypti (Diptera:Culicidae) larvae growth]. AB - INTRODUCTION: in the fight for environmental protection, finding out alternative ways to control vectors that are important from the medical viewpoint is a must. Those plants having potent active principles and high chemical stability to act as pesticides can contribute to this end. OBJECTIVE: to evaluate the possible inhibitory effect of photochemically-modified turpentine oil on Aedes aegypti larvae growth. METHODS: Aedes aegypti larvae of an insecticide-sensitive strain from the insect breeding site located in the Institute of Tropical Medicine were used. During a week after the exposure to the lethal dose causing 90% mortality, the mortality indexes of larvae and pupas were recorded as well as the number of emerged adults and their sex in addition to adults stuck to the exuvias. RESULTS: high larval and pupal mortality was observed in the survivors to the lethal dose causing 90% mortality after one week of the exposure; mortality index was 39.46%. Larvae which managed to grow to become adults amounted to 60.54% of the surviving larvae. Female to male ratio was very similar in the control whereas the exposed group showed a higher number of male adults. On estimating the hatching inhibition percentage, it got 36.47%. CONCLUSIONS: the activity of turpentine oil as larvicide and Ae. aegypti growth inhibitor was demonstrated. PMID- 23437552 TI - [Resistance to organophosphorus insecticides found in Aedes aegypti (Diptera: Culicidae) from Santiago de Cuba, 1997-2009]. AB - INTRODUCTION: resistance to organophosphorus insecticides was diagnosed in Aedes aegypti (Linnaeus, 1762) from Santiago de Cuba in 1997 and some of them are still used up to date; hence the need of ascertaining how the insecticidal resistance has changed in recent times, particularly in 2009. OBJECTIVE: to evaluate the resistance to organophosporus insecticides in larvae from Santiago de Cuba collected in 2009, and its variation in comparison with that observed in 1997; and to determine the frequency of occurrence of resistance mechanisms on the basis of high esterase activity and its classification. METHODS: resistance to organophosphorus insecticides such as malathion, pirimiphos, methyl, phenitrotion, phention, temephos and clorpiriphos in larvae by using the WHO recommended methodology. The esterase mechanism was identified through biochemical assays and polyacrylamide gel electrophoresis. RESULTS: larvae from the Santiago de Cuba strain were susceptible to malathion, pirimiphos, methyl and phenitrothion; there was no variation with the results achieved in a Santiago de Cuba strain in 1997, moderate resistance to phenthion and high resistance to temephos and chlorpiriphos were observed. When comparing these results with those of 1997, it was noted that resistance to the three insecticides increased in the 1997-2009 period. In the Santiago de Cuba strain 2009, it was shown that esterase activity was very high at a rate of 0.7. The presence of an amplified type B esterase with relative mobility of 0.95 cm was detected, which did not exist in the reference strain. CONCLUSIONS: resistance to insecticides and its mechanisms are highly variable, even in the same species subjected to various intensities in the insecticidal use, therefore, it is necessary to constantly monitor both aspects at local level in the course of time, with a view to an effective vector control program. PMID- 23437554 TI - [Efficacy of indoor treatment with cypermethrin, lambda-cyhalothrin and chlorpyrifos for the regulation of Aedes aegypti in the City of Havana]. AB - INTRODUCTION: in dengue outbreaks or epidemics, the chemical pesticides play a fundamental role to control disease-borne adult mosquitoes and to support the Vector Control program in Cuba. OBJECTIVES: to find out the effectiveness and the efficiency of insecticidal formulations in use for the control of Aedes aegypti mosquito in three strains from the City of Havana. METHODS: bioassays followed the methodology recommended by the World Health Organization. Efficacy and efficiency were compared in the studied insecticides between the cold spraying and the thermal spraying. A standardization test was applied to verify the nature of each variable; one three-factor ANOVA to see any differences among the mortality means and the Kruskal-Wallis test to find out difference among the mortality values for each type of treatment with respect to the preparation of one liter of mixture (efficiency), for a significance level of p < 0,05. RESULTS: when comparing the mortality figures reached with both types of treatment, it was evinced that there was a highly significant difference between them, the most favourable results corresponded to thermal spraying, which proved the efficacy of this treatment and its efficiency (effectiveness/cost). CONCLUSIONS: there exists a highly significant difference between the formulations, which favors Galgothrin 25 EC. PMID- 23437553 TI - [Effect of pyriproxyfen for the Aedes (S) aegypti control (Diptera: Culicidae) in strains with various degrees of temephos resistance]. AB - INTRODUCTION: the continuous use of the organophosphate temephos for Aedes (Stegomyia) aegypti (Linnaeus, 1762) has prompted the emergence of resistance to this product in several countries. Pyriproxyfen is an analogue of the juvenile hormone recommended by the World Health Organization as one of the alternative regulators of the dengue vector in drinking waters. OBJECTIVES: to evaluate the efficacy of pyriproxyfen in those strains with various degrees of temephos resistance, in order to be used as a possible regulator of Ae. aegypti. METHODS: for this study, two reference Ae. aegypti strains were used, one susceptible and the other resistant to temephos, and three field strains collected in Boyeros, Cotorro and 10 de Octubre municipalities, all of them from the City of Havana province, Cuba. For the temephos and pyriproxyfen evaluation, the WHO recommended bioassays were used. RESULTS: at high concentrations, pyriproxyfen showed larvicidal properties. At 0,01 and 1 ppb concentrations, inhibition of emergence due to increase of pupal mortality and to lesser extent in adults in the process of breaking the pupal exubia was demonstrated. This growth regulator was effective at the same doses in all the strains, regardless of the degree of temephos resistance, being IE50 values within the range for Aedes genus. CONCLUSIONS: according to the results, the effectiveness of pyriproxyfen was not affected by the degree of temephos resistance in the studied strains, and this is a useful tool in the Ae. aegypti control. PMID- 23437555 TI - [Susceptibility to nystatin of oral Candida isolates and its correlation with the response to treatment]. AB - INTRODUCTION: oropharyngeal candidiasis is an early marker of progression to AIDS in H1V-positive patients and an indicator of non-adherence of treatment or possible failure in patients undergoing anti-retroviral therapy. OBJECTIVE: to determine the in vitro susceptibility to nystatin in Candida strains isolated from the oral cavity of HIV-positive patients, and to correlate the results with the response to treatment. METHODS: a study of in vitro susceptibility to nystatin was conducted in 104 oral isolates from 97 HIV/AIDS patients, who participated as volunteers in a clinical trial to evaluate the response to four antifungal drugs. Fifty-eight of the 104 isolates were obtained before starting treatment and the remaining 46 at the end of therapy. Broth microdilution method was performed according to the document M27-A3 of the Clinical and Laboratory Standards Institute. RESULTS: one hundred percent of the strains were susceptible to nystatin, with minimum inhibitory concentration (MIC) values of <16 microg/mL, regardless of the time of isolation and of the drug administered to patients. In the group of patients treated with nystatin, the MIC80 ranges (1-2 microg/mL), geometric mean and cumulative values of the drug against Candida albicans isolates before starting treatment were similar to those obtained against strains recovered at the end. Among the identified species, C. lusitaniae reached the highest absolute MIC value (4 microg/mL). CONCLUSIONS: the correlation between the clinical evolution and the results of in vitro susceptibility tests was good in patients with a favorable outcome; however, it did not allow predicting possible treatment failure. PMID- 23437556 TI - [Community-based survey on knowledge and perceptions about dengue and preventive practice in Lisa municipality, City of Havana province]. AB - INTRODUCTION: the population's knowledge is important to develop participatory processes that support the reduction of Aedes aegypti. OBJECTIVES: to identify sociodemographic factors, knowledge, perceptions and practice in the population of three people's councils in Lisa municipality about Aedes aegypti control and dengue prevention; to determine the association of these sociodemographic factors with the adequate level of knowledge about dengue, and relate the implementation of suitable practice to risk knowledge and perceptions. METHODS: cross-sectional study was conducted in which surveys and an observational guide were applied to a randomized sample of individuals living in the selected areas. Percentages from the people's councils were compared whereas two logistic regression models to set relations among the studied variables were adjusted for. RESULTS: the most cited breeding site for Aedes aegypti was garbage (67.3%), the most referred preventive measure was container covering (90.2%); perception of risk of getting sick was low or non-existent (55%); regarding the visited houses, the most used practices were cleaning of backyards and water tank protection. In the multi-variate analysis, the young people showed better knowledge than people aged over 59 years whereas those people having better knowledge of breeding sites and preventive measures were the ones who followed adequate practice. CONCLUSIONS: it was demonstrated that adequate knowledge on dengue and its vector are related to better implementation of suitable preventive measures in the house; however, specific aspects on breeding sites should be taken into consideration within the educational programs carried out in each locality. PMID- 23437557 TI - Chromoblastomycosis in Santa Catarina state, Brazil. AB - A case of chromoblastomycosis caused by Cladophialophora carrionii is reported. The diabetic and hypertensive patient presented serpiginous and verrucous lesions, with centrifugal evolution. The patient, with a history of disease for 59 years, had not been diagnosed or treated before. Dematiaceous septate hyphal and elliptical conidia were seen on microscopic observations. The isolated fungus was identified on the basis of micro-macromorphologic characteristics. PMID- 23437558 TI - [Cyptococcus gattii isolated from a cheetah (Acinonyx jubatus) in the National Zoo of Cuba]. AB - INTRODUCTION: Cryptoccosis--systemic mycosis caused by Cryptococcus species--has considerably raised its incidence in the last years, mainly associated with the human immunodeficiency virus infection. It has also been described in animals, but rare cases. METHODS: a case of a female cheetah (Acinonyx jubatus) kept in the Nacional Zoo of Havana was presented. The animal came from South Africa. She began losing weight, and suffering asthenia, anorexia and breathing problems with abundant nasal secretion. RESULTS: mycological testing of these secretions disclosed the presence of serotype B Cryptococcus gattii. Because of the origin and captive condition of the animal, it was believed that the infection had been latent for 16 months at least. CONCLUSIONS: up to the present, in Cuba, all clinical Cryptococcus isolates were C. neoformans var. grubii, so it is considered that the infection was caught in the country of origin of the female cheetah. This is the first C. gattii isolate in Cuba from an animal coming from South Africa where this fungus is endemic. PMID- 23437559 TI - Each of us has a role to play in building a better future. PMID- 23437560 TI - Now that the elections are over, ACA implementation moves forward. PMID- 23437561 TI - The ACA and insurance--regulation of a concentrated marketplace. PMID- 23437562 TI - Iowa Congressional delegation opposes rural Medicare rate cuts. PMID- 23437563 TI - The minor minefield: treating teenagers. PMID- 23437564 TI - Community bound: Penn Dental Medicine expanding its reach in West Philly at New Sayre Health Center Clinic. PMID- 23437565 TI - Cross-cultural collaboration. PMID- 23437567 TI - Adhesive prosthodontics. PMID- 23437566 TI - Connecting to the community. PMID- 23437568 TI - Growing a world-class faculty. PMID- 23437569 TI - Oral cancer screening. PMID- 23437570 TI - Facilities update, master plan spotlight. PMID- 23437571 TI - Answering the call to higher education. PMID- 23437572 TI - The final chapters. PMID- 23437573 TI - No, it's not a recording device. PMID- 23437574 TI - Staying upright. PMID- 23437575 TI - A study space for aging in place. PMID- 23437576 TI - Cultivating conversations. PMID- 23437577 TI - Caring for the caregiver. PMID- 23437578 TI - Geriatrician in chief. Interview by Carmen Peota. PMID- 23437579 TI - In the comfort of home. PMID- 23437580 TI - The eye exam. PMID- 23437582 TI - Q&A with MMA President, Dan maddox, M.D. PMID- 23437581 TI - Tackling prescription opioid abuse. PMID- 23437583 TI - What the VA can teach us about geriatric care. AB - The innovation now being demanded by Medicare is creating new opportunities for health care organizations to redesign how they deliver care for elderly people. For many years, the VA Health System has experimented with ways to deliver care more effectively and efficiently. Hospital-based postacute and palliative care and home-based primary care are two examples of successful approaches that non-VA providers should be looking at as they move away from fee-for-service reimbursement and invent new care-delivery models. PMID- 23437584 TI - Using dementia as the organizing principle when caring for patients with dementia and comorbidities. AB - Most patients with dementia have other chronic health concerns as well. Because dementia affects every aspect of a patient's life, its consequences need to be considered in each care decision, including the treatment of comorbid illnesses. In this article, we present a framework for organizing the care of such patients around their dementia, rather than around their other conditions. PMID- 23437585 TI - Empowering older adults to manage chronic conditions and reduce their risk for falls. AB - Chronic diseases and falls are among the major causes of death and disability among people age 65 and older. Often, they can be managed or, in the case of falls, prevented. Studies have shown that programs that teach people to manage their conditions or risk factors can reduce the chance of complications or poor outcomes that can affect their quality of life and independence. This article reminds physicians that older adults should be encouraged to engage in preventing disease and injury and describes two programs that have been shown to help older adults do this: A Matter of Balance for fall prevention and Living Well with Chronic Conditions. PMID- 23437586 TI - Three stories, three outcomes. AB - Physicians who care for older patients may find themselves being asked to make a judgment about whether a person is able to continue driving. Discussing this topic is rarely easy for the physician or the patient. One option for physicians who find themselves in this situation is referring the patient for an evaluation by a driver rehabilitation specialist. This article describes what this entails and how such an evaluation might help clarify whether a patient can safely remain behind the wheel. PMID- 23437587 TI - Facilitating care transitions for older adults. AB - Successful transitions between care settings can reduce the chance of complications for older adults with complex health conditions. Ensuring good transitions involves not only executing a well-thought-out medical plan but also referring patients to support services in the community and attending to the needs and well-being of their caregivers. This article describes why these factors are so important and how physicians can use Minnesota resources to improve care transitions. PMID- 23437588 TI - DollyBelle: a patient's final gift. PMID- 23437589 TI - The AED. PMID- 23437590 TI - Changes to dental Medicaid in Louisiana. PMID- 23437591 TI - The certainty of uncertainty: a time to band together. PMID- 23437592 TI - Dream a little dream with me--a midwinter night's dream. PMID- 23437593 TI - Following footsteps. Q&A with David Fulton Jr. 2013 CDS President. Interview by Walter Lamacki. PMID- 23437594 TI - Don't be numb; do the right thing. PMID- 23437595 TI - Be resolved. PMID- 23437596 TI - West Side Collaborative helps patients overcome barriers to healthcare. PMID- 23437597 TI - How to keep your teeth in your golden years. PMID- 23437598 TI - Penny wise, pound foolish. PMID- 23437599 TI - Wind me up. PMID- 23437600 TI - The next game changer? PMID- 23437601 TI - Toothbrushing alone: no true value for stopping dental caries. PMID- 23437602 TI - Dancing with the devil. PMID- 23437603 TI - Young investigators and translational research. AB - In the December 2012 Journal of the California Dental Association, we displayed the talents of our dental students and their ability to perform basic research on topics ranging from how to improve wound healing to mechanisms for tumor identification and metastasis. The work of these young investigators assures us that future basic dental research will continue to provide a better understanding of oral biology. These clues would be useless without a cadre of dental investigators who can incorporate this information into strategies that can permit us to take better care of our patients. This month, we feature new and young investigators who are interested in translational research. This is the research of turning clinical observations, basic research findings and technological innovations into clinical strategies for taking care of our patients. PMID- 23437604 TI - Characterization of dental anatomy and gingival biotype in Asian populations. AB - Gingival and dental characteristics are risk factors for periodontal problems. With short or fused roots, a decreased periodontium results in some attachment loss, compromising periodontal stability. Similarly, with an increased incidence of thin gingival biotype, inflammatory and traumatic insults may result in gingival recession. Anecdotally, Asian dentitions have been described as having short roots with "thin gingiva". This cross-sectional study will utilize clinical data and radiographic interpretation to ascertain whether this clinical impression is valid. PMID- 23437605 TI - Mathematical filtering minimizes metallic halation of titanium implants in MicroCT images. AB - Microcomputed tomography (MicroCT) images containing titanium implant suffer from x-rays scattering, artifact and the implant surface is critically affected by metallic halation. To improve the metallic halation artifact, a nonlinear Total Variation denoising algorithm such as Split Bregman algorithm was applied to the digital data set of MicroCT images. This study demonstrated that the use of a mathematical filter could successfully reduce metallic halation, facilitating the osseointegration evaluation at the bone implant interface in the reconstructed images. PMID- 23437606 TI - The effect of angulation sensors on implant placement. AB - It is hypothesized that use of an angulation sensor could increase the alignment accuracy of multiple implant osteotomies without requiring the use of guided surgical templates. Therefore, the purpose of this study was to determine if use of such a sensor mounted on a surgical handpiece could improve implant placement. PMID- 23437607 TI - Dig this. PMID- 23437608 TI - Close-up on heart health. PMID- 23437609 TI - Cardiology as a practice focus for NPs & PAs. PMID- 23437610 TI - Workforce volume strives to meet patient demand. PMID- 23437611 TI - Reducing readmission rates. PMID- 23437612 TI - National Salary Report 2012: a big increase for PA salary, but just a nudge for NPs. PMID- 23437613 TI - Therapeutic hypothermia. PMID- 23437614 TI - Diastolic heart failure. PMID- 23437615 TI - Takotsubo cardiomyopathy. PMID- 23437616 TI - An endowed chair in physician assistant studies. PMID- 23437617 TI - Melanoma opportunistic surveillance by physician assistant and medical students: analysis of a novel educational trainer. AB - PURPOSE: The objective was to identify first-year physician assistant (PA) students' and third-year medical students' knowledge, attitudes, and behaviors about melanoma and to assess an educational intervention. METHODS: Thirty first year PA students and 29 third-year medical students (M3) at Northwestern University completed a questionnaire on participants' views of barriers and facilitators to performing melanoma screening. The students were given a pretest with a melanoma education model trainer to identify suspicious lesions, and following an educational intervention, students were given a posttest model trainer assessment. RESULTS: Apart from time constraints (87% PA; 79% M3) and comorbidities (53% PA; 57% M3), lack of training was a frequently reported barrier to performing opportunistic surveillance (27% PA; 31% M3). Commonly reported facilitators included identification of patients at high risk for developing melanoma (60% PA; 69% M3) and skin-examination training to recognize melanoma (67% PA; 55% M3). With the melanoma trainer pretest, 35% of PA students and 27% of M3 students identified all of the melanomas (P = .61). Following educational intervention, 67% of PA students and 10% of M3 students identified all of the melanomas (P<.01). PA student identification of melanoma significantly increased from pretest to posttest (P = .035), while M3 decreased, but not appreciably (P = .063). CONCLUSIONS: Education in melanoma detection may enhance the students' cognitive and technical skills necessary to perform accurate opportunistic surveillance. Although PA and medical students reported the same significant barriers and facilitators to performing skin exams, there was a difference in implementation of skills and in the management decisions. PMID- 23437618 TI - A study of empathy decline in physician assistant students at completion of first didactic year. AB - PURPOSE: This research investigated empathy trends among physician assistant (PA) students through their education and included gender differences and specialty job interest. This research partially replicates similar studies of medical and other health professions students. METHODS: The Jefferson Scale on Physician Empathy (SPE) was administered to PA students three times: (1) during matriculation, (2) near the end of their didactic training and (3) during their clinical education phase. Data were analyzed using both parametric (ANOVA) and nonparametric (binomial) methods. RESULTS: A total of 328 survey responses (270 females, 57 males, and one nonindicator) from the graduating classes of 2009 through 2014 at a northeastern university were collected and analyzed. Reliability for the JSPE was .80 (Cronbach) in this sample. Sixty-two percent had lower median JSPE empathy scores toward the end of their didactic training than at the time of matriculation (P = .0001), while the difference between empathy scores from years two and three was not significant (P = .37). Women were significantly more empathetic (mean = 5.05) at the time of matriculation than men (mean = 4.70, P = .0003), while both genders appeared to lose empathy in a parallel fashion during didactic training (P = .76). There was no association between empathy scores and prospective job category interest. CONCLUSION: These findings illustrate a decline in empathy among both genders during PA training, similar to other health care providers' educations, and support the need for further conversation regarding a role for empathy assessment and curricula in PA education. PMID- 23437619 TI - Level of stress and common coping strategies among physician assistant students. AB - PURPOSE: This study assessed levels of stress and coping strategies in physician assistant (PA) students. METHODS: The study used a descriptive, cross-sectional design. Data were collected through an electronic survey that was sent to all current student members of the Texas Academy of Physician Assistants (N = 560). The Perceived Stress Scale was used to measure level of stress, and the Brief COPE Inventory was used to measure coping strategies. RESULTS: A total of 146 (26.3%) students participated in the study. Most respondents were female, young, single, and Caucasian/non-Hispanic. The mean stress score was 33.3, higher than that reported in the overall general US population. Areas of most concern included feeling nervous and stressed, feeling upset about unexpected happenings, and an inability to control life's irritations and manage personal problems. Self distraction, venting, and self-blame were the most frequently used unhealthy coping strategies. Acceptance, active coping, and emotional support were the most frequently used positive coping strategies. CONCLUSION: The results of this study indicated that students in PA training experience higher levels of stress than the general population in the United States, making healthy coping strategies among PA students particularly important. The results of this study can inform future research, curriculum design, teaching methods, and educational intervention in PA training programs. PMID- 23437620 TI - Exploring the sexual attitudes of physician assistant students: implications for obtaining a sexual history. AB - PURPOSE: This study examined the sexual attitudes of physician assistant (PA) students and assessed their effect on obtaining a sexual history. METHODS: Students enrolled in New York Institute of Technology and Touro College Manhattan Campus PA programs completed the Derogatis Sexual Functioning Inventory-Attitudes Subscale (DSFI-AS). Demographic data included age, gender, ethnicity, marital status, sexual orientation, and yes/no question regarding whether the participant considers him/herself religious. RESULTS: Mean score was 23.3 +/- 14.0 indicating liberal sexual attitudes. Sixty-four percent (n = 114) were liberal, 35.4% (n = 63) neutral, and 0.6% (n = 1) conservative. Mean scores were 23.29 +/- 13.6 for females and 23.33 +/- 15.4 for males (P>.05); 24.8 +/- 13.4 for Caucasians and 18.0 +/- 15.1 for all other ethnicities (P<.05); and 18.9 +/- 13.6 for religious and 28.44 +/- 12.8 for nonreligious participants (P<.05). CONCLUSION: Two factors related significantly with sexual attitudes: ethnicity and relationship with religion. It's imperative that students examine their sexual attitudes and recognize the effect this may have on patient care. PMID- 23437621 TI - An assessment of psychological stress and symptomatology for didactic phase physician assistant students. AB - PURPOSE: The purpose of this study was to assess the amount of psychological stress experienced by didactic phase, physician assistant (PA) students. METHODS: The Symptom Checklist-90-R (SCL-90-R) survey was administered to 81 students in 2011 during the first two didactic phase semesters at two PA programs. Using ANOVA and t-tests, several variables were analyzed for significance. RESULTS: The SCL-90-R results portray that a significant proportion of the students from both programs reported elevated levels of stress during the first and second semester of the didactic year. Although several significant levels were noted throughout this study, it is not known how these scores from PA students would compare to other medical and/or nonmedical graduate students. Additional studies of stress from both medical and nonmedical graduate students would be beneficial for comparison to PA students. PMID- 23437622 TI - Using popular movies and reflections to increase the cultural sensitivity of students. PMID- 23437623 TI - Attendance policies: do they help or hinder adult learning? PMID- 23437624 TI - Achieving balance: healing in native art. AB - It has been my great fortune to have spent this past summer traveling across North America with my husband. We left our home state of New Hampshire in June and, in late July, arrived in the 49th state, Alaska, where we have settled in for the winter. From Manitoulin Island and the shores of Lake Huron to the Black Hills of South Dakota and on through the Canadian Rockies, we traveled through a number of North American Native communities. It is this experience and my recent introduction to Alaskan Native culture and peoples that are the impetus for this feature, where I will explore the historical and re-emerging use of art to promote health and healing in Native communities. PMID- 23437625 TI - Necessity and benefits of physician assistants' participation in international clinical experiences. AB - Several consultation stations have been set up in an unfinished stone building. My team is made up of a Kenyan physician assistant (called clinical officer), a Kenyan medical student, and me, a US physician assistant student. We are huddled around a small worn-out square table. A middle-aged woman and her two children, ages 2 and 6, approach the table. They have traveled 2 miles to the medical camp. The children, covered in dust, are emaciated with protruding abdomens, dry skin, and congested noses. The clinical officer (CO) conducts a brief interview in Swahili, the Kenyan national language. The mother explains that they have been coughing up thick yellow sputum for a week and have no appetite. They've also had diarrhea for a couple of weeks. I examine the children, who are obviously scared. Hot, moist skin. They are both running a fever. I listen to the lungs: reduced lung sounds. The protruding abdomens are rock hard. I report the findings to the team. The CO turns to the Kenyan medical student and me and quizzes us on differential diagnoses with rationale for each. We come up with malaria, pneumonia, TB, and worm infestation. Due to limited resources, medical diagnosis in Kenya relies heavily on history and physical exam. The CO explains that comorbid conditions are probable. Luckily, we have malaria-testing kits at the camp. They test negative for malaria. We decide to treat them for pneumonia. We also offer them a free hot meal, toothbrushes, T-shirts, coloring paper, and crayons. The children manage to smile. The mother is so grateful, she cries. PMID- 23437626 TI - The effect of audience response systems on adult learning: evidence-based rationale and audience response systems implementation guide. PMID- 23437627 TI - The influence of attention, learning, and motivation on visual search. AB - The 59th Annual Nebraska Symposium on Motivation (The Influence of Attention, Learning, and Motivation on Visual Search) took place April 7-8, 2011, on the University of Nebraska-Lincoln campus. The symposium brought together leading scholars who conduct research related to visual search at a variety levels for a series of talks, poster presentations, panel discussions, and numerous additional opportunities for intellectual exchange. The Symposium was also streamed online for the first time in the history of the event, allowing individuals from around the world to view the presentations and submit questions. The present volume is intended to both commemorate the event itself and to allow our speakers additional opportunity to address issues and current research that have since arisen. Each of the speakers (and, in some cases, their graduate students and post docs) has provided a chapter which both summarizes and expands on their original presentations. In this chapter, we sought to a) provide additional context as to how the Symposium came to be, b) discuss why we thought that this was an ideal time to organize a visual search symposium, and c) to briefly address recent trends and potential future directions in the field. We hope you find the volume both enjoyable and informative, and we thank the authors who have contributed a series of engaging chapters. PMID- 23437628 TI - Searching in space and in time. AB - Our conception of attention is intricately linked to limited processing capacity and the consequent requirement to select, in both space and time, what objects and actions will have access to these limited resources. Seminal studies by Treisman (Cognitive Psychology, 12, 97-136, 1980) and Broadbent (Perception and Psychophysics, 42, 105-113, 1987; Raymond et al. Journal of Experimental Psychology: Human Perception and Performance, 18, 849-860, 1992) offered the field tasks for exploring the properties of attention when searching in space and time. After describing the natural history of a search episode we briefly review some of these properties. We end with the question: Is there one attentional "beam" that operates in both space and time to integrate features into objects? We sought an answer by exploring the distribution of errors when the same participant searched for targets presented at the same location with items distributed over time (McLean et al. Quarterly Journal of Experimental Psychology, 35A, 171-186, 1982) and presented all at once with items distributed over space (Snyder Journal of Experimental Psychology; 92, 428-431, 1972). Preliminary results revealed a null correlation between spatial and temporal slippage suggesting separate selection mechanisms in these two domains. PMID- 23437629 TI - Automatic control of visual selection. AB - This paper seeks out to reduce the role of the homunculus, the 'little man in the head' that is still prominent in most psychological theories regarding the control our behaviour. We argue that once engaged in a task (which is a volitional act), visual selection run off more or less in an automatic fashion. We argue that the salience map that drives automatic selection is not only determined by raw physical salience of the objects in the environment but also by the way these objects appear to the person. We provide evidence that priming (feature priming, priming by working memory and reward priming) sharpens the cortical representation of these objects such that these objects appear to be more salient above and beyond their physical salience. We demonstrate that this type of priming is not under volitional control: it occurs even if observers try to volitionally prepare for something else. In other words, looking at red prepares our brain for things that are red even if we volitionally try to prepare for green. PMID- 23437632 TI - Statistical learning and its consequences. AB - Statistical learning refers to an unconscious cognitive process in which repeated patterns, or regularities, are extracted from the sensory environment. In this chapter, I describe what is currently known about statistical learning. First, I classify types of regularities that exist in the visual environment. Second, I introduce a family of experimental paradigms that have been used to study statistical learning in the laboratory. Third, I review a series of behavioral and functional neuroimaging studies that seek to uncover the underlying nature of statistical learning. Finally, I consider ways in which statistical learning may be important for perception, attention, and visual search. The goals of this chapter are thus to highlight the prevalence of regularities, to explain how they are extracted by the mind and brain, and to suggest that the resulting knowledge has widespread consequences for other aspects of cognition. PMID- 23437630 TI - Guidance of visual search by memory and knowledge. AB - To behave intelligently in the world, humans must be able to find objects efficiently within the complex environments they inhabit. A growing proportion of the literature on visual search is devoted to understanding this type of natural search. In the present chapter, I review the literature on visual search through natural scenes, focusing on the role of memory and knowledge in guiding attention to task-relevant objects. PMID- 23437631 TI - Reward and attentional control in visual search. AB - It has long been known that the control of attention in visual search depends both on voluntary, top-down deployment according to context-specific goals, and on involuntary, stimulus-driven capture based on the physical conspicuity of perceptual objects. Recent evidence suggests that pairing target stimuli with reward can modulate the voluntary deployment of attention, but there is little evidence that reward modulates the involuntary deployment of attention to task irrelevant distractors. We report several experiments that investigate the role of reward learning on attentional control. Each experiment involved a training phase and a test phase. In the training phase, different colors were associated with different amounts of monetary reward. In the test phase, color was not task relevant and participants searched for a shape singleton; in most experiments no reward was delivered in the test phase. We first show that attentional capture by physically salient distractors is magnified by a previous association with reward. In subsequent experiments we demonstrate that physically inconspicuous stimuli previously associated with reward capture attention persistently during extinction--even several days after training. Furthermore, vulnerability to attentional capture by high-value stimuli is negatively correlated across individuals with working memory capacity and positively correlated with trait impulsivity. An analysis of intertrial effects reveals that value-driven attentional capture is spatially specific. Finally, when reward is delivered at test contingent on the task-relevant shape feature, recent reward history modulates value-driven attentional capture by the irrelevant color feature. The influence of learned value on attention may provide a useful model of clinical syndromes characterized by similar failures of cognitive control, including addiction, attention-deficit/hyperactivity disorder, and obesity. PMID- 23437633 TI - Overcoming hurdles in translating visual search research between the lab and the field. AB - Research in visual search can be vital to improving performance in careers such as radiology and airport security screening. In these applied, or "field," searches, accuracy is critical, and misses are potentially fatal; however, despite the importance of performing optimally, radiological and airport security searches are nevertheless flawed. Extensive basic research in visual search has revealed cognitive mechanisms responsible for successful visual search as well as a variety of factors that tend to inhibit or improve performance. Ideally, the knowledge gained from such laboratory-based research could be directly applied to field searches, but several obstacles stand in the way of straightforward translation; the tightly controlled visual searches performed in the lab can be drastically different from field searches. For example, they can differ in terms of the nature of the stimuli, the environment in which the search is taking place, and the experience and characteristics of the searchers themselves. The goal of this chapter is to discuss these differences and how they can present hurdles to translating lab-based research to field-based searches. Specifically, most search tasks in the lab entail searching for only one target per trial, and the targets occur relatively frequently, but field searches may contain an unknown and unlimited number of targets, and the occurrence of targets can be rare. Additionally, participants in lab-based search experiments often perform under neutral conditions and have no formal training or experience in search tasks; conversely, career searchers may be influenced by the motivation to perform well or anxiety about missing a target, and they have undergone formal training and accumulated significant experience searching. This chapter discusses recent work that has investigated the impacts of these differences to determine how each factor can influence search performance. Knowledge gained from the scientific exploration of search can be applied to field searches but only when considering and controlling for the differences between lab and field. PMID- 23437635 TI - [House dust mite allergy--living with the invisible roommates]. AB - House dust mites are the most common sources of allergic sensitization, primarily responsible for the occurrence of various clinical forms of respiratory and skin allergies, but also of certain forms of food allergy. There are many various mite species, of which only a small number are constantly or occasionally found in house dust samples. Mites from Pyroglyphidae family, Dermatophagoides pteronyssinus and Dermatophagoides farinae are most frequently responsible for sensitization of susceptible persons. Other less commonly found species may represent individual primary sources of sensitization, or may cause disease symptoms due to cross-reactivity. The exposure to various mite species within different geographical regions accounts for the generation of various sensitization profiles. Knowing these profiles is important for planning rational specific immunotherapy, which greatly determines its efficacy. The aims of this paper are to review the environment conditions that influence mite incidence and the ways their changes can control allergen amounts in patient homes, to review the allergenic content and the significance of cross-reactivity among mite allergens, and finally, to explain the factors that enable the generation of various sensitization profiles. PMID- 23437634 TI - When do I quit? The search termination problem in visual search. AB - In visual search tasks, observers look for targets in displays or scenes containing distracting, non-target items. Most of the research on this topic has concerned the finding of those targets. Search termination is a less thoroughly studied topic. When is it time to abandon the current search? The answer is fairly straight forward when the one and only target has been found (There are my keys.). The problem is more vexed if nothing has been found (When is it time to stop looking for a weapon at the airport checkpoint?) or when the number of targets is unknown (Have we found all the tumors?). This chapter reviews the development of ideas about quitting time in visual search and offers an outline of our current theory. PMID- 23437636 TI - [Risk factors of asymptomatic hypertension on the territory of Posusje Municipality (Bosnia and Herzegovina)]. AB - Arterial hypertension is the leading mortality risk factor. The aim of the study was to assess the rate of asymptomatic hypertension detected in a randomly selected population sample in Posusje Municipality according to the grade of hypertension (mild, moderate or severe) and risk factors. The following risk factors were analyzed: intake of saturated fatty acids, alcohol, tobacco products and black coffee. Asymptomatic hypertension was detected in 532 of 2000 (26.60%) subjects included in the study. In comparison to the rest of the study sample, these 532 subjects reported a statistically significantly higher consumption of saturated fatty acids, alcohol, tobacco products and black coffee. PMID- 23437637 TI - [Correlation between pholcodine and perioperative anaphylaxis]. AB - A large number of individuals experiencing anaphylactic reaction to neuromuscular blocking agents have not previously been in contact with them. The search for a substance inducing sensitization to muscle relaxants has led Norwegian and Swedish scientists to pholcodine, a cough suppressant, which is widely used in Europe and worldwide. Ammonium ion is an epitope common to pholcodine and neuromuscular blocking agents and it is the basis of their cross-reactivity. Based on the results of published studies that pointed to a connection of the use of pholcodine and perioperative anaphylactic reaction, pholcodine was withdrawn from the Norwegian market and subsequent research revealed a reduction of anaphylactic reactions in that country. In its latest report, the European Medicines Agency made a decision not to withdraw pholcodine mixtures from the market but it urged further research with the aim to clarify the cross-reactivity between pholcodine and neuromuscular blocking agents. PMID- 23437638 TI - [House dust mite allergy--how to win?]. AB - Manifestations of house dust mite allergy include perennial allergic rhinitis often accompanied by ocular symptoms, allergic asthma, and somewhat rarer atopic dermatitis. Sensitization to mite tropomyosin may lead to hypersensitivity to certain foodstuffs. Allergic sensitization and development of the disease are connected to the level of allergen exposure, indicating that the patients' home exposure to mite allergens is a useful indicator of their risk. Since the possibility of allergen avoidance is limited, and available pharmacological treatments have just symptomatic effects, the only causative treatment for mite allergy is specific immunotherapy. Its well-documented clinical effects include reduction of symptoms, prevention of the disease severity progression, and prevention of sensitization to new allergens. Immunological parameters show characteristic dynamics during treatment, which is also reflected in gradual reduction of the skin reactivity towards the allergen. Despite ample evidence and a hundred-year use in clinical practice, the efficacy of specific immunotherapy is sometimes still questioned. The aim of this paper is to show that, when properly indicated with due consideration of the person's sensitization profile, it is a very successful treatment method. PMID- 23437639 TI - [Stercoral rectosigmoid colonic perforation with fecal peritonitis]. AB - Chronic constipation can lead to fecal impaction and catastrophic complication such as colonic obstruction, perforation and fecal peritonitis. A case is reported of stercoral perforation of the rectosigmoid with pneumoperitoneum and fecal peritonitis. The patient was admitted for the signs of acute abdomen with pneumoperitoneum diagnosed on native radiological imaging. PMID- 23437640 TI - [Acute abdomen two days after vaginal birth after cesarean section]. AB - A case is presented of puerperal acute abdomen with diffuse peritonitis and paralytic ileus two days after unnoticed complete uterine rupture after VBAC (vaginal birth after cesarean section) and uterine cavity obstetric examination. Explorative laparotomy, intestinal adhesiolysis, uterine revision and sutures, abdominal lavage and drainage were performed. The operation was followed by successful recovery and intact fertility. Medical and forensic aspects are discussed. PMID- 23437641 TI - [Why benzodiazepines are still in wide use?]. AB - The advent of benzodiazepines in the 1960s provided their wide use in neurology and psychiatry. They proved to be myorelaxant and anticonvulsive therapy in neurology; their anxiolytic and hypnotic properties have made them the treatment of choice for insomnia and anxiety problems; they have also been used in alcohol withdrawal and in anesthesia, and for a wide range of treatments in other clinical branches. However, reports giving rise to a prescription controversy including abuse, harmful effects, intoxication and dependence toward addiction appeared soon. On the other hand, the revolutionary appearance of selective serotonin reuptake inhibitors (SSRIs) overshadowed benzodiazepines. According to recommendations of many scientific and professional institutions, the use of benzodiazepines has been gradually excluded or reduced or limited to short-term use. However, clinical experience showed that benzodiazepines are frequently used for long-term treatment, and there are many reasons for this, e.g., prescribing tradition, patient preference, difficulties associated with benzodiazepine withdrawal (even in patients taking low doses) because they have a rapid clinical onset of action, and good efficacy with few initial adverse effects. Moreover, SSRIs as alternative drugs are associated with incomplete therapeutic response and more uncomfortable adverse effects. Some authors therefore point out that the rationale for the shift from benzodiazepines to SSRIs is inappropriate. PMID- 23437642 TI - On temporomandibular disorders. Time trends, associated factors, treatment need and treatment outcome. AB - During the last few decades, and especially during the 1990s, an increase in musculoskeletal pain conditions and stress-related ill-health has been observed in Sweden. At the same time, an improvement in the oral health of the population has been noted. The overall aim of this thesis was to acquire knowledge relating to possible time trends for the presence of temporomandibular disorders (TMD) in the population. A further objective was to study factors that possibly influence the presence of these disorders and the outcome of their treatment. Studies I-III are based on a series of repeated cross-sectional population-based investigations. Three independent samples of 130 individuals in the age groups of 3, 5, 10, 15, 20, 30, 40, 50, 60 and 70 years were randomly selected from the inhabitants of the city of Jonkoping, Sweden in 1983, 1993 and 2003. The total participation rate was 21%, 22% and 29% respectively. The participants were examined using a questionnaire, interview and a clinical examination of the stomatognathic system regarding the presence of symptoms and signs indicative of TMD. Study IV is a retrospective survey of a clinical sample of patients referred to and treated at the Department of Stomatognathic Physiology, The Institute for Postgraduate Dental Education, Jonkoping, in 1995-2002. The overall frequencies of symptoms and the rates for some clinical signs and consequently of an estimated treatment need in adults increased during the study period. In 2003, the prevalence of frequent headache in 20-year-olds, mainly females, had markedly increased. The reports of bruxism among adults increased from 1983 to 2003. Awareness of bruxism and self-perceived health impairment were associated with TMD symptoms and signs. A favourable treatment outcome was observed for the majority of patients with common TMD sub-diagnoses and no strong predictors of treatment outcome were found. In conclusion, the results suggest some time trends towards an increased prevalence in the overall symptoms and some signs indicative of TMD in the Swedish adult population during the time period 1983-2003. A profound understanding of the social determinants of health is recommended when planning public health resources. PMID- 23437643 TI - Special issue on 'Advanced treatment technologies for waste recycling': selected papers from the 'International Conference on Solid Waste-Moving Towards Sustainable Resource Management', 2-6 May 2011, Hong Kong Sar. PMID- 23437644 TI - Study on the combined sewage sludge pyrolysis and gasification process: mass and energy balance. AB - A combined pyrolysis and gasification process for sewage sludge was studied in this paper for the purpose of its safe disposal with energy self-balance. Three sewage sludge samples with different dry basis lower heat values (LHV(db)) were used to evaluate the constraints on this combined process. Those samples were pre dried and then pyrolysed within the temperature range of 400-550 degrees C. Afterwards, the char obtained from pyrolysis was gasified to produce fuel gas. The experimental results showed that the char yield ranged between 37.28 and 53.75 wt% of the dry sludge and it changed with ash content, pyrolysis temperature and LHV(db) of the sewage sludge. The gas from char gasification had a LHV around 5.31-5.65 MJ/Nm3, suggesting it can be utilized to supply energy in the sewage sludge drying and pyrolysis process. It was also found that energy balance in the combined process was affected by the LHV(db) of sewage sludge, moisture content and pyrolysis temperature. Higher LHV(db), lower moisture content and higher pyrolysis temperature benefit energy self-balance. For sewage sludge with a moisture content of 80 wt%, LHV(db) of sewage sludge should be higher than 18 MJ/kg and the pyrolysis temperature should be higher than 450 degrees C to maintain energy self-sufficiency when volatile from the pyrolysis process is the only energy supplier; when the LHV(db) was in the range of 14.65 18 MJ/kg, energy self-balance could be maintained in this combined process with fuel gas from char gasification as a supplementary fuel; auxiliary fuel was always needed if the LHV(db) was lower than 14.65 MJ/kg. PMID- 23437645 TI - Pyrolysis and gasification of landfilled plastic wastes with Ni-Mg-La/Al2O3 catalyst. AB - Pyrolysis and gasification processes were utilized to study the feasibility of producing fuels from landfilled plastic wastes. These wastes were converted in a gasifier at 700-900 degrees C. The equivalence ratio (ER) was varied from 0.4-0.6 with or without addition ofa Ni-Mg-La/Al2O3 catalyst. The pyrolysis and gasification of plastic wastes without catalyst resulted in relatively low H2, CO and other fuel gas products with methane as the major gaseous species. The highest lower heating value (LHV) was obtained at 800 degrees C and for an ER of 0.4, while the maximum cold gas efficiency occurred at 700 degrees C and for an ER of 0.4. The presence of the Ni-Mg-La/Al2O3 catalyst significantly enhanced H2 and CO production as well as increasing the gas energy content to 15.76-19.26 MJ/m3, which is suitable for further usage as quality fuel gas. A higher temperature resulted in more H2 and CO and other product gas yields, while char and liquid (tars) decreased. The maximum gas yield, gas calorific value and cold gas efficiency were achieved when the Ni-Mg-La/Al2O3 catalyst was used at 900 degrees C. In general, addition of prepared catalyst resulted in greater H2, CO and other light hydrocarbon yields from superior conversion of wastes to these gases. Thus, thermochemical treatment of these problematic wastes using pyrolysis and gasification processes is a very attractive alternative for sustainable waste management. PMID- 23437646 TI - Steam reforming of tar model compound using Pd catalyst on alumina tube. AB - Gasification processing of biomass as a renewable energy source generates tar in the product gas. Tar leads to foul-up of the process equipment by corrosion and deposit formation. Catalytic elimination of tars is a crucial step to improve fuel gas quality from the process. In this study, a palladium catalyst on alumina (Pd/Al2O3) was used in steam reforming of benzene as a biomass gasification tar model compound. The reaction was carried out in a laboratory-scale tube reactor made of stainless steel to study the effect of reaction temperature, catalyst loading, quantity of palladium catalyst tubes, steam to carbon ratio (S/C), and residence time on catalytic performance and stability. Pd/Al2O3 showed high efficiency ofbenzene decomposition and enhanced the formation of fuel gas. Hydrogen and carbon conversions increased with reaction temperature. Although the benzene concentration increased from 2000 to 5000 mg/l, the catalytic performance at 600 degrees C and 800 degrees C was similar. 1.0 wt% Pd/Al2O3 showed excellent catalytic activity with the highest hydrogen and carbon conversions of 83% and 81%, respectively at 800 degrees C. This result is attributed to the smooth surface of the palladium, as noted from scanning electron microscopy imaging. An S/C of 2 provided the highest conversion. The addition of catalyst from four and seven tubes did not result in any great difference in terms of benzene cracking efficiency. The fourth cyclic usage of 1.0 wt% Pd/Al2O3 exhibited a higher conversion than that of 0.5 wt%. PMID- 23437647 TI - Utilization of sludge waste from natural rubber manufacturing process as a raw material for clay-ceramic production. AB - The possibility of utilization of the sludge waste obtained from the natural rubber manufacturing process as a raw material for producing clay ceramics was investigated. To prepared clay-based ceramic, the mixtures of traditional clay and sludge waste (10-30 wt%) were milled, uniaxilly pressed and sintered at a temperature between 1000 and 1200 degrees C. The effect of sludge waste on the properties of clay-based ceramic products was examined. The results showed that the amount of sludge waste addition had an effect on both sinterability and properties of the clay ceramics. Up to 30 wt% of sludge waste can be added into the clay ceramics, and the sintered samples showed good properties. PMID- 23437648 TI - Formation of nickel and copper ferrites in ceramics: a potential reaction in the reuse of iron-rich sludge incineration ash. AB - This study investigates potential solid-state reactions for the stabilization of hazardous metals when reusing the incineration ash from chemically enhanced primary treatment (CEPT) sludge to fabricate ceramic products. Nickel and copper were used as examples of hazardous metals, and the iron content in the reaction system was found to play a major role in incorporating these hazardous metals into their ferrite phases (NiFe2O4 and CuFe2O4). The results from three-hour sintering experiments on NiO + Fe2O3 and CuO + Fe2O3 systems clearly demonstrate the potential for initiating metal incorporation mechanisms using an iron containing precursor at attainable ceramic sintering temperatures (above 750 degrees C). Both ferrite phases were examined using a prolonged leaching experiment modified from the widely used toxicity characteristic leaching procedure (TCLP) to evaluate their long-term metal leachability. The leaching results indicate that both the NiFe2O4 and the CuFe2O4 products were significantly superior to their oxide forms in immobilizing hazardous metals. PMID- 23437649 TI - Hydrothermal treatment of incineration fly ash for PCDD/Fs decomposition: the effect of iron addition. AB - The catalytic effect of Fe addition on the decomposition of polychlorinated dibenzo-dioxins and polychlorinated dibenzofurans (PCDD/Fs) contained in municipal solid waste incineration (MSWI) fly ash during the hydrothermal process was investigated. Influencing factors, such as Fe addition mode, reaction time and cooling procedure after reaction, were tested to evaluate their effects. Experimental results indicated that Fe addition in the form of a mixture of ferrous sulphate and ferric sulphate enhanced decomposition of PCDD/Fs contained in the MSWI fly ash, particularly for the decomposition of 2,3,7,8 tetrachlorodibenzo-dioxin and 2,3,7,8-tetrachlorodibenzo-furan under the reaction temperature of 563 K. The decomposition rate of PCDD/Fs reached 90.33% by international toxicity equivalent (I-TEQ) when Fe was added as a mixture of ferrous and ferric sulphates by 5% (wt/wt) with the Fe (III)/Fe (II) ratio being 2; without Fe addition, the decomposition rate of PCDD/Fs was only 46.17% by I TEQ in the same process. Fe addition in the form of ferrous sulphate alone also showed an enhancing effect on PCDD/Fs decomposition, but the associated decomposition rates were relatively lower, suggesting iron oxides formed from the mixture of ferric and ferrous sulphates are more favourable catalysts. At the same time, the cooling procedure after the hydrothermal reaction became more flexible if Fe was added in the form of a mixture of ferric and ferrous sulphates. Although a longer reaction time was helpful to increase decomposition rates of PCDD/Fs, 1 h was proved to be a reasonable time under this condition. PMID- 23437650 TI - Effects of Al-coagulant sludge characteristics on the efficiency of coagulants recovery by acidification. AB - This study evaluated the effects of Al-coagulant sludge characteristics on the efficiency ofcoagulant recovery by acidification with H2SO4. Two sludge characteristics were studied: types of coagulant and textures of the suspended solid in raw water. The coagulant types are aluminium sulphate and polyaluminium chloride (PACl); the textures of the suspended solid are sand-based and clay based. Efficiency of aluminium recovery at a pH of 2 was compared for different sludges obtained from water treatment plants in Taiwan. The results showed that efficiency of aluminium recovery from sludge containing clayey particles was higher than that from sludge containing sandy particles. As for the effect of coagulant types, the aluminium recovery efficiency for sludge using PACl ranged between 77% and 100%, whereas it ranged between 65% and 72% for sludge using aluminium sulphate as the coagulant. This means using PACl as the coagulant could result in higher recovery efficiency of coagulant and be beneficial for water treatment plants where renewable materials and waste reduction as the factors for making decisions regarding plant operations. However, other metals, such as manganese, could be released with aluminium during the acidification process and limit the use of the recovered coagulants. It is suggested that the recovered coagulants be used in wastewater treatment processes. PMID- 23437651 TI - Development of a method for recycling of CRT funnel glass. AB - Finding better solutions to manage and recycle cathode-ray tube (CRT) glass is crucial for reducing the environmental threats due to the disposal of the glass. In this paper, the results of a laboratory study on developing a method for removing lead from crushed funnel glass surface and re-utilizing the treated glass in cement mortar are presented. The results demonstrate that nitric acid at 3-5% concentration levels can be used to remove most of the lead from the crushed funnel glass surface and render it as non-hazardous waste based on toxicity characteristics leaching procedure (TCLP) testing. It is noted that the particle size of glass and number of treatment cycles are significant factors affecting lead extraction. The study further demonstrated that it is feasible to utilize up to 100% of treated funnel glass as a replacement for natural sand for producing cement mortar. PMID- 23437652 TI - Health risk assessment of PCDD/F emissions from municipal solid waste incinerators (MSWIs) in China. AB - The objectives of this study were to determine the environmental impacts of polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (PCDD/Fs) emitted from two typical municipal solid-waste incinerators (MSWIs), named M and L, in China. The main differences between the two MSWIs relate to incineration technologies, treatment capacities, emission standards and meteorological conditions. The distribution of PCDD/Fs in the surrounding ambient air and soils of the MWSIs were monitored and compared. In addition, air dispersion models and health risk assessments were combined to determine the behaviour and transport of PCDD/Fs. The results indicated that higher PCDD/F emission levels resulted in higher concentrations in the surrounding environment. The average PCDD/F levels emitted from the M MSWI was about seven times higher than those emitted from the L MSWI and about 10 times and 2 times higher in air and soils, respectively. The simulation results were similar to the trend of the monitored results. Both the observed and the simulation results suggested that the atmospheric pollution by PCDD/F surrounding the M MSWI was relatively serious; the environmental impact of the L MSWI was not significant. PMID- 23437653 TI - Environmental risk related to specific processes during scrap computer recycling and disposal. AB - The purpose of this work was to achieve a better understanding of the generation of toxic chemicals related to specific processes in scrap computer recycling and disposal, such as thermal recycling of printed circuit boards (PCBs) and the landfilling or dumping of cathode ray tubes (CRTs). Tube furnace pyrolysis was carried out to simulate different thermal treatment conditions for the identification of the by-products and potential environmental risk from thermal recycling ofPCBs. The Toxicity Characteristic Leaching Procedure (TCLP) and a column test were used to study the leaching characteristics of lead from waste CRT glass, which is one of the most important environmental concerns arising from the disposal of e-waste. The results indicate that more attention should be paid to the benzene series when recycling PCBs under thermal conditions, especially for workers without any personal protection equipment. The impact of immersion on the leaching of lead from CRT leaded glass was more effective than the impact of washing only by acid rain. Thus when waste leaded glass has to be stored for some reason, the storage facility should be dry. PMID- 23437654 TI - Transformation of heavy metals and the formation of secondary iron minerals during pig manure bioleaching by the co-inoculation acidophilic thiobacillus. AB - Bioleaching of heavy metals from pig manure using a mixture of harmless iron- and sulfur-oxidizing bacteria in an air-lift reactor was conducted. The transformation of heavy metals and the formation of secondary Fe minerals during bioleaching were also investigated in the present study. The removal efficiencies of Zn, Cu, and Mn from pig manure were 95.1%, 80.9%, and 87.5%, respectively. Zn mainly existed in the form of Fe-Mn oxides in fresh pig manure; most of the pig manure-borne Cu was in organic matter form; Mn existed mainly in Fe-Mn oxides, carbonates, and residual forms. The pig manure can be applied to land more safely after bioleaching because the heavy metals mainly existed in stable forms. The removal efficiencies Zn, Cu, and Mn had good relationships with pH and oxidation reduction potential during bioleaching. A mixture ofjarosite and schwertmannite was found in the bioleached pig manure, which might have an adverse effect on the solubilization efficiency of toxic metals from pig manure. The bioleaching process using a mixture of harmless iron- and sulfur-oxidizing bacteria was shown to be a very feasible technology for the removal of heavy metals from pig manure. PMID- 23437655 TI - In-vessel co-composting of horse stable bedding waste and blood meal at different C/N ratios: process evaluation. AB - Abattoir blood meal is rich in nitrogen and its potential as a co-composting material for horse stable bedding waste was evaluated at two C/N ratios -32 (LBM, low blood meal) and 16 (HBM, high blood meal) - to improve the nutrient contents of the final compost. The mix was composted for 7 days in a 10 tonne/day in vessel composter and cured aerobically. After 56 days ofcomposting, the ammoniacal-N, CO2 evolution rate and C/N ratio of both LBM and HBM were within the guideline values; however, delayed decomposition and lower seed germination index were observed with HBM. In addition, HBM resulted in 84% loss of the initial ammoniacal-N. Almost similar organic decompositions, 62.4% and 59.6% with LBM and HBM, respectively, were achieved. However, a stable compost product can be obtained within 6-7 weeks with LBM, whereas >8 weeks were required for HBM composting. Therefore, co-composting at the C/N ratio of 32 is recommended to achieve odour-free and faster composting. PMID- 23437656 TI - Comparison of different fluorescence spectrum analysis techniques to characterize humification levels of waste-derived dissolved organic matter. AB - In the present work, the humification level of waste-derived dissolved organic matter (DOM) at different waste biostability was investigated, by using fluorescent excitation-emission matrix (EEM) scanning. Different fluorescence spectrum analysis techniques were applied and compared. Experimental results demonstrate that parallel factor (PARAFAC) analysis was sensitive to reflect DOM humification, and the most reasonable to deconstruct DOM compositions, when compared with other spectrum analysis techniques. It suggests applying the DOM EEM-PARAFAC pipeline for rapid estimation of waste biostability. PMID- 23437657 TI - Biodegradation of organics in landfill leachate by immobilized white rot fungi, Trametes versicolor BCC 8725. AB - Immobilized Trametes versicolor BCC 8725 was evaluated for the biodegradation of the organic components of four different types of landfill leachate collected at different time periods and locations from the Nonthaburi landfill site of Thailand in batch treatment. The effects of carbon source, ammonia and organic loading on colour, biochemical oxygen demand (BOD) and chemical oxygen demand (COD) removal, and the reuse of immobilized fungi were investigated. It was found that fungi can remove 78% of colour, reduce BOD by 68% and reduce COD by 57% in leachate within 15 days at optimum conditions. Organic loading and ammonia were the factors that affected the biodegradation. When immobilized T versicolor on polyurethane foam (PUF) was subjected to repeated use for treatment over the course of three cycles, the decolourization efficiency of the first and the second cycle was very similar, whereas the third cycle was about 20% lower than the first cycle under similar conditions. The obtained removal of colour, BOD and COD indicates the effectiveness of fungi for leachate treatment with high organic loading and varied leachate characteristics. PMID- 23437658 TI - Ultrasound imaging techniques in density separation of polyolefin waste. AB - Ultrasound imaging techniques are investigated using a multi-element sensor array for purposes of monitoring and measurement ofpolyolefin waste particles inside the black ferrous liquid ofa magnetic density separator (MDS). A medical ultrasound imaging system with real-time capability was adapted first to assess the potential of imaging technology inside the MDS. An image processing routine was developed to determine the depth distribution of the detected particles as they are carried by the flow in the MDS channel. This real-time information is vital for optimizing the splitter position, which directly influences quality and recovery of the MDS polyolefin products. Despite successes in the laboratory, the medical technology proved unsatisfactory for continuous high-quality image forming in the industrial set-up as it requires regular operator intervention. Therefore, research has been initiated into alternative imaging methods, which are also being investigated in other fields such as non-destructive testing and geophysics. The influence of different ultrasound datasets and related image forming techniques were investigated, for which dedicated algorithms were implemented in Matlab. The main advantages and disadvantages of the different techniques are addressed. It is concluded that the alternative imaging methods may be more robust and deliver higher image quality compared to the commercial medical imager. In particular, sizing of polyolefin particles may improve significantly if the method takes into account the correct ultrasound velocities of both the ferrous liquid and the immersed polyolefin particles. PMID- 23437659 TI - Effects on cement after partial replacement with burned joss paper ash. AB - In the last ten years, as international environmental protection consciousness has increased, the study and applications of green building, green construction materials and energy savings as well as reduction of carbon dioxide have become urgent issues for governments. In Taiwan, joss papers are burned in more than 11,731 registered shrines or temples in traditional Chinese deity or ancestor worship ceremonies during special holidays or occasions. Instead of placing this large amount of burned joss paper ash (BJPA) in landfills, this study proposes recycling BJPA by replacing some cement with calcined BJPA (CBJPA) in mortar specimens. After BJPA samples were calcined at a high kiln temperature, mortar samples were created using CBJPA to replace cement at seven different levels: 0%, 5%, 10%, 15%, 20%, 25% and 30%. Tests like setting time and compressive strength were performed for macro-analyses; scanning electron microscopy-energy dispersive spectroscopy, X-ray diffraction and thermal gravimetric analysis/differential thermal analysis were carried out for the microstructure and chemical composition analyses. The test results showed that the compressive strengths of specimens with different levels of CBJPA replacement were apparently less than those of the control group (0% CBJPA) at all curing times. The compressive strength and setting time both decreased as the fraction of CBJPA in the mortar increased. Furthermore, because the hydration product did not cement and the mortar specimen structure was loose, the expected strength improvement from the pozzolanic reaction provided by the CBJPA was not clearly observed. PMID- 23437660 TI - Isolation and characterization of Streptomyces spp. strains F-6 and F-7 capable of decomposing alkali lignin. AB - Biodegradation and bioconversion of lignin are the result of the combined action of fungi, bacteria and actinomycetes. Through screening from forest soil, two novel isolated actinomycete strains were identified as Streptomyces spp. strains F-6 and F-7 by their morphology, cultural characteristics and high homology to the 16S rRNA gene. Both strains possessed laccase and manganese peroxidase activities. Laccase activity produced by strain F-6 was up to 935.4 U g(-1) dry cell weight. More than 50% of alkali lignin was removed by strains F-6 and F-7 in 12 days of incubation. GC-MS analysis of the biodegraded products showed strain F 6 converted lignin into phenol and broken phenol compounds. The two strains could co-culture with white-rot fungus, and the combined actinonycete-fungus system decomposed alkali lignin effectively. PMID- 23437661 TI - Effect of inorganic carbon on the completely autotrophic nitrogen removal over nitrite (CANON) process in a sequencing batch biofilm reactor. AB - Ammonia-oxidizing bacteria (AOB) and anaerobic ammonia-oxidizing bacteria (AnAOB) are autotrophic microorganisms. Inorganic carbon (IC) is their main carbon source. The effects of IC limitation on AOB and AnAOB in the completely autotrophic nitrogen removal over nitrite (CANON) process in a sequencing batch biofilm reactor (SBBR) were examined. The optimal IC concentration in the influent was investigated. The start-up time of the CANON process from the activated sludge in the SBBR was 80 d under controlled free ammonia (FA) conditions and sufficient IC source. The AOB and AnAOB activities were limited by an IC concentration of 50 mg-C-L(-1) in the influent, whilst the nitrogen loading rate (NLR) was 200 mg-N x L(-1) x d(-1). The experiment on recovering the influent IC showed that AOB and AnAOB activities were affected by the IC limitation, and not by the pH or FA, at 200mg-N x L(-1) x d(-1) NLR and 50mg-C x L(-1) IC in the CANON process. The activities were recovered by increasing the IC concentration in the influent. From an economic point of view, the optimal IC concentration in the influent was 250mg-C x L(-1) at 200mg-N x L(-1) x d(-1) NLR in this CANON system. PMID- 23437662 TI - The competition between flocculent sludge and aerobic granules during the long term operation period of granular sludge sequencing batch reactor. AB - The long-term operational stability of aerobic granular sludge reactor was investigated in this study. It was found that the fraction of flocculent sludge fluctuated from 5 to 35%, even with a settling time of less than 5 minutes and manual discharge of flocculent sludge during a steady state of more than 400 days. Although the microbial community structure of flocculent sludge was similar to that of granular sludge co-existing in the reactor, the specific growth rate, the observed biomass yield and the specific oxygen consumption rate of flocculent sludge were much higher than those of granular sludge with identical microbial community structures. Therefore, the presence offlocculent sludge in the granular sludge reactor is mainly because of the kinetic superiority of flocculent sludge over granular sludge, rather than microbial competition. Increasing mass transfer in the feast period or discharging excess flocculent sludge could enhance the growth of granular sludge and improve the stability of the long-term operation of the granular sludge reactor. PMID- 23437663 TI - Mesophilic anaerobic co-digestion of pulp and paper sludge and food waste for methane production in a fed-batch basis. AB - Co-digestion of pulp and paper sludge (PPS) and food waste (FW) in a batch-fed digestion system was conducted on a laboratory scale. Three reactors named A1, A2, and A3 were tested. PPS and FW mixed at different mass ratios of 1:3, 1:1, and 3:1, respectively, were loaded in the reactors. Bioconversion at high efficiency was obtained in the system. The accumulative methane yield of each reactor was 144mLg(-1)VSfed (A1), 256 mL g(-1) VSfed (A2), and 123 mL g(-1)VSfed (A3). The soluble chemical oxygen demand (COD) removal efficiencies reached 73.2% (Al), 93.9% (A2), and 79.6% (A3). A pH in the range 5.8-8.4 was obtained in the three reactors without adjustment due to the high buffer capacity of the mixing feedstock. No toxicity inhibitions of volatile fatty acids and NH3-N occurred in reactor A2. This study showed that it was good for co-digestion of PPS and FW in a mass ratio of 1:1 for methane production, which resulted in higher methane yield, a greater buffer capacity, a higher organics removal efficiency, and a more stable process. PMID- 23437664 TI - Organic substrates as electron donors in permeable reactive barriers for removal of heavy metals from acid mine drainage. AB - This research was conducted to select suitable natural organic substrates as potential carbon sources for use as electron donors for biological sulphate reduction in a permeable reactive barrier (PRB). A number of organic substrates were assessed through batch and continuous column experiments under anaerobic conditions with acid mine drainage (AMD) obtained from an abandoned lignite coal mine. To keep the heavy metal concentration at a constant level, the AMD was supplemented with heavy metals whenever necessary. Under anaerobic conditions, sulphate-reducing bacteria (SRB) converted sulphate into sulphide using the organic substrates as electron donors. The sulphide that was generated precipitated heavy metals as metal sulphides. Organic substrates, which yielded the highest sulphate reduction in batch tests, were selected for continuous column experiments which lasted over 200 days. A mixture of pig-farm wastewater treatment sludge, rice husk and coconut husk chips yielded the best heavy metal (Fe, Cu, Zn and Mn) removal efficiencies of over 90%. PMID- 23437665 TI - Development of low-cost amine-enriched solid sorbent for CO2 capture. AB - CO2 capture amine-enriched solid sorbent using agricultural wastes, such as bagasse, or industrial wastes, such as mullite, as support materials could provide efficient alternative CO2 reduction due to their low cost and ability to shape into many forms. These amine-enriched solid sorbents were prepared by treatment with monoethanolamine (MEA), diethanolamine, piperazine (PZ), 2-(2 aminoethyl-amino) ethanol (AEEA) and mixtures of these amines. The performance of amine-enriched solid sorbents with various amine compositions was studied in a tubular column at 1 atm and an adsorption temperature of 303 K. The CO2 capture capacities of the amine-enriched solid sorbents were determined by gas chromatography at a desorption temperature of 393 K. Amine-enriched solid sorbents in this study exhibited high performance CO2 capture. The MEA-PZ enriched solid sorbent does have the highest CO2 capture performance of the amine enriched bagasse support-based sorbents, and the results indicate that PZ is the most effective promoter in this study. The CO2 capture performances of solid sorbents in this study were compared with commercial solid sorbents. This study could lead to the development of low-cost solid sorbents for CO2 capture that can be used in many industrial applications. PMID- 23437666 TI - Removal of Cd(II), Cu(II) and Zn(II) from aqueous solutions by live Phanerochaete chrysosporium. AB - Living Phanerochaete chrysosporium mycelia were used to remove heavy metals of Cd(II), Cu(II) and Zn(II) in auqeous solution. The uptake of heavy metal by the mycelia was dependent on the environmental conditions. The optimum biosorption conditions of Cd(II), Cu(II), and Zn(II) were pH 5.5-6.5 at 37 degrees C, and 6 h. Under these conditions, the fungal biosorbent removed Cd(II), Cu(II), and Zn(II) rapidly and efficiently with maximum metal removal capacities of 59.77 mg/g, 74.78 mg/g, and 54.12 mg/g, respectively. The pseudo second-order kinetic model was superior to the pseudo first-order kinetic model, which indicated that the change ofthe surface sorption sites number was proportional to the square ofthe remaining unoccupied surface sites number. Fourier transform infrared (FT IR) spectra indicated that hydroxyl and carboxyl groups were relevant to biosorption. Some crystal particles were found on the surface of the P. chrysosporium under scanning electron microscopy. Energy dispersive X-ray analysis and FT-IR revealed that amino acids and proteins were involved in binding metal ions. The results demonstrated that P. chrysosporium was a good potential biosorbent for adsorbing heavy metals. PMID- 23437667 TI - Effects of soil organic matter and ageing on remediation of diesel-contaminated soil. AB - Bioremediation of diesel-contaminated soil was investigated for the effects of soil organic matter (SOM) and ageing time in two sets of experiments (Batch I and II, respectively). This study examined degradation efficiency in soil artificially contaminated with diesel oil (maximum total petroleum hydrocarbons (TPH) concentration of 9000 mg/kg soil). Batch I data showed that the values of the first-order degradation rate, k, were relatively high in the low-SOM soil batches. The quantity of SOM negatively correlated with the TPH degradation rates and with the total TPH degradation efficiency (%). Introduction of rhamnolipid to the soil proved to be a useful solution to resolve the problem of the residual TPH in the soil with high SOM. In Batch II, the k values decreased with the length of ageing time: 0.0245, 0.0128 and 0.0090 l/d in samples ST0 (freshly contaminated), ST38 (aged for 38 days) and ST101 (aged for 101 days), respectively. The TPH degradation efficiency (%) also decreased along with the ageing time. The research also applied molecular technology to analyse the bacterial community dynamics during the bioremediation course. Multivariate statistics based on terminal-restriction fragment length data indicated: 1) the soils with different SOM resulted in separate bacterial community structures, 2) ageing time created a variety of bacterial communities, 3) the bacterial community dynamics was associated with the hydrocarbon consumption. The SOM content in soils affected the TPH degradation rate and efficiency and the bacterial community structures. Aged soil is more difficult to remediate than freshly contaminated soil, and the resulting bacterial community was less dynamic and showed a lack of succession. PMID- 23437668 TI - Photocatalytic reduction of Cr(VI) from agricultural soil column leachates using zinc oxide under UV light irradiation. AB - The photocatalytic reduction of Cr(VI) from agricultural soil leachates irrigated with Cr(VI)-containing waste hydroponic solution was evaluated in this work. For this purpose, zinc oxide was used as a catalyst under UV irradiation (lambda = 365 nm). The reduction of Cr(VI) was preliminarily evaluated on synthetic solutions with a concentration of 15 mg L(-1) to optimize the catalyst loading and the solution pH and to determine the effect of organic matter. Greater removal of Cr(VI) was observed at pH 7, and the optimum catalyst loading was found to be 2 g L(-1), which achieved an 84% Cr(VI) reduction in 6 h. The influence of dissolved organic matter on the reduction of Cr(VI) was evaluated through the addition of different concentrations of humic acid (HA) to the chromium solution. The removal of Cr(VI) was continuously enhanced as the HA concentration gradually increased from 0 to 14 mg L(-1). The percentage of hexavalent chromium reduction from soil leachates was in the range of 13-99%, and the rate constant was significantly enhanced by the presence of organic compounds in the soil pore water. Thus, a marked synergistic effect between the photocatalytic reduction of Cr(VI) and the organic matter in soil (e.g. humic substances) was observed in real samples and was similar to that observed in the Cr(VI) synthetic solution that contained HA. PMID- 23437669 TI - Influence of leaching conditions on the release kinetics of lead, chromium and nickel from solidified/stabilized cementitious materials. AB - In this work, we investigate, on a laboratory scale, the influence of the leaching conditions on the release of various chemical elements from a cementitious material obtained by solidification of PbO, Ni2O3 and Cr2O3 with blended cement (CEMII-B32.5, according to European Standards). The pH effects on the pollutants release and the composition of the initial pore solution (target elements: chloride, sulfate, sodium, potassium, calcium, lead, chromium and nickel) were assessed through an experimental procedure consisting of two equilibrium leaching tests [the acid neutralization capacity (ANC) and the pore water (PW) tests] and the maximum mobile fraction (MMF) text. Samples of the same material were submitted in parallel to dynamic leaching tests in order to assess the influence of the boundary conditions (instantaneous liquid/solid (L/S) ratio, solution renewal) on the leaching kinetics of the target elements. The comparison criteria were the leachate saturation state, the released cumulative quantities and the leaching flux. Generally, leachate quantities obtained by the ANC, PW and MMF tests were important. However, the lowest released amount was observed for the monolith leaching test, and leachate saturation slowed down the dynamic release. Finally, experimental results highlighted another important parameter: the influence of the liquid/solid contact type on leaching kinetics. PMID- 23437670 TI - Struvite-based fertilizer and its physical and chemical properties. AB - This study describes a method to formulate struvite fine powder into pellets that are easy to spread on agricultural land. To evaluate the quality of produced pellets, some chemical and physical properties commonly measured for fertilizers were tested. The findings indicated that the salt index and heavy metal content ofstruvite pellets were significantly lower than those of commercial NPK fertilizers. In addition, the percentage of nutrient released from struvite pellets after 105 days was in the range of 9.6-23.2, 8.4-26.7 and 11.3-32.6% for nitrogen, phosphorous and magnesium, respectively, which is considerably lower than that of commercial NPK fertilizer. Among different formulations between struvite crystals and binders, starch and bentonite were the most efficient in agglomerating struvite powder, leading to an increase in the crush strength to over the recommended limit of >2.5 kgf for fertilizer hardness. PMID- 23437671 TI - Partial ozonation pre-treatment for sludge solubilization and simultaneous degradation of bisphenol A: quantification studies. AB - Ozonation pre-treatment was investigated for the enhancement of sludge solids and organic matter solubilization and simultaneous degradation of bisphenol A (BPA), an endocrine disruptor compound from wastewater sludge (WWS). The ultrafast method (15 s per sample) used for the analysis of BPA in WWS is based on Laser Diode Thermal Desorption/Atmospheric Pressure Chemical Ionization coupled to tandem Mass Spectrometry. The statistical methods used for optimization studies comprised the response surface method with fractional factorial designs and central composite designs. The ozonation pre-treatment process was carried out with four independent variables, namely WWS solids concentration (15-35 g l(-1)), pH (5-7), ozone dose (5-25 mg g(-1) SS) and ozonation time (10-30 min). It was observed that among all the variables studied, ozone dose had more significantly (probability (p) < 0.001) affected the efficiency of the ozonation pre-treatment by increasing sludge solids (suspended solids (SS) and volatile solids) solubilization and organic matter (soluble chemical oxygen demand and soluble organic carbon) increment and BPA degradation from WWS. During the optimization process, it was found that higher BPA degradation (100%) could be obtained with 24 g l(-1) SS, 6.23 pH with an ozone dose of 26.14 mg g(-1) SS for 16.47 min ozonation time. The higher ozone dose used in this study was observed to be cost effective on the basis of solids and organic matter solubilization and degradation of BPA. PMID- 23437672 TI - Waste polypropylene plastic conversion into liquid hydrocarbon fuel for producing electricity and energies. AB - Thermal degradation of polypropylene (PP) waste plastic is batched process studied for the purpose of converting waste PP into liquid hydrocarbon fuel and useful chemicals. The stainless steel reactor is used for conversion to fuel; this reactor chamber has a diameter of 6 inches, height of 18 inches and a temperature input capacity of 500 degrees C. The temperature of 150-370 degrees C was used for PP conversion into fuel. We have also used 1 kg PP waste plastic for conversion into fuel and HZSM-5 catalyst of 5% by preference was used by total weight of sample. Yield percentages obtained from PP to fuel are 92%, 2% light gas and 6% residue. Experimental finish time was 5.25 hours. By gas chromatograph/mass spectrometry instrumental analysis, the PP to fuel carbon range is found to be C3-C25,and the low sulfur level is detected by the American Society for Testing and Materials (ASTM) test method to be <1.0 ppm. PMID- 23437673 TI - Long term in-line sludge storage in wastewater treatment plants: the potential for phosphorus release. AB - Phosphorus removal in on-site wastewater treatment plants is normally obtained by chemical precipitation. Aluminium-based chemicals are the favoured coagulants as they are not affected by redox potential. On-site wastewater treatment package plants do not have separate sludge treatment facilities, and sludge is normally collected on an annual basis. This can potentially increase the risk of phosphorus release into the water phase, subsequently reducing treatment efficiency. This study aimed to detect release of phosphorus as a result of chemical and biological processes. Variables in the study were time, aluminium dosage and pH. Wastewater sludge was monitored for 46 weeks to investigate the different mechanisms of phosphorus release and the longevity of the aluminium treatment involving varying aluminium dosages. Phosphorus compounds were analysed based on a modified Psenner sequential fractionation method. Both pH and aluminium dosage affect the longevity of the phosphorus retention of chemically precipitated wastewater sludge, where sufficient longevity is obtained with pH control and increased aluminium dosages. Chemical dosages similar to what is considered normal levels are sufficient to retain the phosphorus in the sludge for annual sludge collection intervals. Release of soluble phosphorus was attributed to microbial activity and crystallization of Al-hydroxide complexes. PMID- 23437674 TI - Enhanced bio-methane production from co-digestion of different organic wastes. AB - This paper deals with an experimental study aimed at assessing the effect of mixing different organic wastes on the anaerobic digestion process. Livestock manure and organic solid wastes have been taken into account as substrates to verify if their mixing gives rise to higher methane production rates and lower risk of process failure. Bio-methane potential (BMP) tests have been conducted using the following substrates: buffalo manure (BM), poultry manure (PM), organic fraction of the municipal solid waste (OFMSW), greengrocery waste (GW) and two different mixtures composed of BM and OFMSW. Mixing BM with OFMSW resulted in 12% and 30% higher methane volumes after 30 and 15 days from the test start, respectively. Experimental data have been also used to calibrate and validate a mathematical model previously proposed by the authors, showing its capability to reproduce the synergistic effect on methane production promoted by co-digesting BM and OFSMW. PMID- 23437675 TI - Incorporating biodegradation and advanced oxidation processes in the treatment of spent metalworking fluids. AB - The treatment of spent metalworking fluids (MWFs) is difficult due to their complex and variable composition. Small businesses often struggle to meet increasingly stringent legislation and rising costs as they need to treat this wastewater on site annually over a short period. Larger businesses that treat their wastewater continuously can benefit from the use of biological processes, although new MWFs designed to resist biological activity represent a challenge. A three-stage treatment is generally applied, with the oil phase being removed first, followed by a reduction in COD loading and then polishing of the effluent's quality in the final stage. The performance of advanced oxidation processes (AOPs), which could be of benefit to both types of businesses was studied. After assessing the biodegradability of spent MFW, different AOPs were used (UV/H2O2, photo-Fenton and UV/TiO2) to establish the treatability of this wastewater by hydroxyl radicals (*OH). The interactions of both the chemical and biological treatments were also investigated. The wastewater was found to be readily biodegradable in the Zahn-Wellens test with 69% COD and 74% DOC removal. The UV/TiO2 reactor was found to be the cheapest option achieving a very good COD removal (82% at 20 min retention time and 10 L min(-1) aeration rate). The photo Fenton process was found to be efficient in terms of degradation rate, achieving 84% COD removal (1 M Fe2+, 40 M H2O2, 20.7 J cm(-2), pH 3) and also improving the wastewater's biodegradability. The UV/H202 process was the most effective in removing recalcitrant COD in the post-biological treatment stage. PMID- 23437676 TI - Evaluation of a plant material-based air purifier for removing H2S, NH3 and swine manure odour. AB - A plant material-based air purifier (PMAP) was evaluated for odour removal. Laboratory tests were performed using two identical chambers: one treated by PMAP, and one as the control. Swine manure, hydrogen sulphide (H2S) and ammonia (NH3) were tested as odour sources. The test was also conducted in a swine barn. Air samples were taken from test chambers and two rooms in the pig barn and analysed for H2S, NH3 and odour concentrations. When treated with PMAP, the H2S concentration in the sealed chamber was subject to exponential decay, with the decay constant ranging from 0.59 to 0.70 l/h. The H2S concentration was reduced from 20 to 3 ppm in 3 h and to 0.2 ppm in 7h for H2S produced by chemical reaction, and from 0.4 to 0.02 ppm in 3 h for swine manure as the odour source. When an equal amount of ammonia solution was placed in the two test chambers, the NH3 concentration reached a peak value of 25 ppm in the chamber treated by PMAP, and 43 ppm in the control. The NH3 concentration in the treated chamber was reduced to 5 ppm in 3.5 h but stayed at 37 ppm in the control. The PMAP reduced the NH3 concentration from 38 to 10 ppm when swine manure was used as the odour source. The PMAP was capable of reducing swine odour in both laboratory and in barn conditions. The reduction rate was at least 50%. The results from this research indicate the plant-based materials provide an alternative, environmentally friendly way for odour control. It is also shown that the mode of odour reduction by the PMAP was the removal of odour compounds, in contrast to odour masking, which occurs for most plant materials that have been used for odour control. PMID- 23437677 TI - Other people's lives: reflections on medicine, ethics, and euthanasia. PMID- 23437678 TI - Nutrition and physical activity. Preface. PMID- 23437679 TI - The intersection of adolescent development with eating behaviors and physical activity. PMID- 23437680 TI - Familial influences on adolescents' eating and physical activity behaviors. PMID- 23437681 TI - Determinants of undernutrition and overnutrition among adolescents in developing countries. PMID- 23437682 TI - The truth about vitamin D and adolescent skeletal health. PMID- 23437683 TI - Improving the diets and eating patterns of children and adolescents: how can nutrition education help? PMID- 23437684 TI - Promoting youth physical activity through physical education and after-school programs. PMID- 23437685 TI - Media use and sedentary behavior in adolescents: what do we know, what has been done, and where do we go? PMID- 23437686 TI - Integrating messages from the eating disorders field into obesity prevention. AB - Weight-related problems, including unhealthy weight control behaviors, binge eating, overweight and obesity, and eating disorders, are prevalent in youth. Furthermore, many young people exhibit more than one of these problems. Therefore, it is essential to consider how to simultaneously work toward the prevention of a broad range of weight-related problems in youth. Dieting, body dissatisfaction, weight talk, and weight-related teasing are commonly addressed risk factors within eating disorder prevention interventions, whereas low levels of physical activity and high intakes of foods high in fat and sugar are commonly addressed within interventions aimed at obesity prevention. Empirical data to be presented in this article demonstrate why risk factors such as dieting and body dissatisfaction, which are typically addressed within the eating disorder field, need to also be addressed within the obesity field. Although dieting and body dissatisfaction strongly predict weight gain over time, these findings are not always taken into account in the design of obesity interventions for youth. Possible reasons as to why risk factors such as dieting, body dissatisfaction, and weight stigmatization may be not adequately addressed within interventions addressing obesity are discussed. Suggestions for how physicians and other nonphysician clinicians might link messages from the fields of both eating disorders and obesity into their work with youth are provided. Finally, the potential for work on mindfulness and yoga to decrease risk factors for both eating disorders and obesity are explored. PMID- 23437687 TI - Interventions for treating overweight and obesity in adolescents. PMID- 23437688 TI - Emerging adulthood: a critical age for preventing excess weight gain? PMID- 23437689 TI - Environmental and policy strategies to improve eating, physical activity behaviors, and weight among adolescents. PMID- 23437691 TI - In Alaska, hers is not a unique regret. PMID- 23437692 TI - Bridging the gaps: Alaska's physician community: yesterday, today & tomorrow. PMID- 23437690 TI - Advances in methodologies for assessing dietary intake and physical activity among adolescents. PMID- 23437693 TI - Waxing aesthetic: physician fuses art with medicine. PMID- 23437694 TI - First legacy. Mom & son agree: there's no place like WWAMI. PMID- 23437695 TI - 'It was a wonderful time to be a doctor'. PMID- 23437696 TI - Orthopedic case study. PMID- 23437697 TI - [Health care financing models]. AB - The functioning of health care depends mainly on the level and method of financing. Countries choose between different models. Bismarck's model is financing based mainly on the contributions that are obligatory for employers and employees, decentralized model of managing and contracting services. Beveridge's model is financed mostly from the government taxes, it allows contributing to the cost of benefits for patients and participation by private sector. Residual model is based on the optional and private health insurances, supplemented only by National Health Service. Siemaszko's model in his assumption is based on the financing of benefits by the state budget, provides permanent control of the state and equal access to all the benefits for citizens. Choice of a specific financing model entails certain impact on all of the system's participants. The purpose of this article is to introduce subject of health care financing based on the literature and the authors' own thoughts. PMID- 23437698 TI - [Heart rate recovery after exercise in subjects undergoing cardiologic rehabilitation]. AB - Research indicates that slow heart rate recovery 1-2 minutes after exercise is a predictor of cardiovascular mortality, sudden mortality as well. It is hardly related to myocardial ischemia; most of all, it is related to impaired activities of the parasympathetic system. The purpose of this study was to assess HRR in subjects after a surgical treatment (percutaneous coronary intervention - PCI) of acute coronary syndromes (ACS), undergoing cardiologic rehabilitation. MATERIALS AND METHODS: The study comprised 58 subjects, 42 men and 16 women aged 49-68 (56.8 +/- 7.6) after ACS treated with PCI undergoing cardiologic rehabilitation (stage 2)--group I. The comparative group comprised 34 subjects, 25 men and 9 women aged 46-61 (55.5 +/- 8.9 lat) who were clinically healthy and who underwent a single sub-maximal exercise test--group II. In subjects undergoing rehabilitation, an exercise test was performed twice --before and after stage 2 of rehabilitation. HRR was defined as a difference between the peak heart rate and those after the 1st (HRR1) and 2nd (HRR) minute of recovery. RESULTS: After stationary rehabilitation as a part of stage 2 of cardiologic rehabilitation, HRR2 was 26.3 +/- 10.6/min and was 40.8/min +/- 13.8/min; both these values were not significantly different from values observed in healthy subjects (p > 0.05). Significant increase in HRR1 and HRR2 was observed after the completion of stage 2 of cardiologic rehabilitation in ill subjects (p < 0.05) as compared to initial values. CONCLUSIONS: In subjects after ACS treated with PCI, it is observed that HRR changes back to normal values observed in healthy subjects as a result of underwent cardiologic rehabilitation. HRR should become an important factor in assessing effectiveness of conducted cardiologic rehabilitation. PMID- 23437699 TI - [Difficulties in the diagnosis of the first symptoms of brain tumors prehospital delay diagnosis]. AB - The nervous system tumors pose a current challenge to modern medicine. Diagnosis, established at an early stage of tumor development, increases the chance of the use of radical therapeutic methods, which is associated with better prognosis. The preferred method of treatment of brain tumors is the surgical treatment. Success of this therapy depends on the possibility of the radical removal of neoplastic tissue. The aim of the study was to evaluate the type and duration of clinical symptoms, which were the cause for hospitalization, prehospital diagnostics and possibilities of the use the methods of treatment giving the chance for cure at the time of diagnosis of the neoplastic process within central nervous system. MATERIAL AND METHODS: A retrospective analysis of medical records of 56 patients, hospitalized in 2009-2010 at the Department of Neurology and Epileptology, The Medical Centre of Postgraduate Education in Warsaw. The basis for the diagnosis were the results of two-phase neuroimaging studies. The whole results were analyzed statistically to looking for a correlation between the duration of symptoms prior to hospitalization, their nature and the proposed treatment. RESULTS: Draws attention to the young age of analyzed patients (mean age 67 years). The most common symptoms were disturbances of consciousness or behavioral changes (37% patients), limb weakness and sensory disturbances (37%) and speech disorders (30%). Other, commonly reported nonspecific symptoms were: somnolence, deterioration of everyday functioning, fatigue and malaise. In the group of the 56 patients with confirmed tumor, 14 (25%) were urgently admitted to our Department, 13 (23%) arrived first to the general practitioner practice. Unfortunately, 29 (52%) out of 56 patients did not arrived to the outpatient physician, despite the first discomfort feelings. They got at a later time directly to the hospital emergency room. In most cases the proposed treatment was neurosurgical operation (n = 19, 35%), whereas radiotherapy was suggested to 4 patients (8%), and palliative treatment in the form of radiation therapy to the whole area of the brain (n = 11, 20%) and of the spine (n = 1) to 12 people. We did not find a statistically significant correlation in our study. CONCLUSIONS: Nonspecific symptoms that may be the only manifestation of proliferative disease within the central nervous system, should attract particular oncology attention, otherwise the diagnosis may be delayed. Advancement of the disease at the moment of establishment of the diagnosis does not allow for the use of causal treatment. PMID- 23437700 TI - [Influence of the anti-inflammatory, anti-bacterial and anti-oxidative treatment combined with the dietary supplementation on sperm parameters]. AB - The severe oligospermia and lukocytospermia is diagnosed among 25-40% of the infertile patients despite the absence of any clinical manifestation of the inflammatory process. The white blood cells are the main source of the free oxidative radicals, which can injure the cell membranes and the sperm DNA integrity influencing the reproductive potential of the male gametes. The aim of study was to assess the influence of the anti-inflammatory anti-bacterial and anti-oxidative treatment combined with the dietary supplementation on sperm parameters in the patients with severe oligospermia and lukocytospermia. MATERIALS AND METHODS: 100 patients with a severe oligospermia and leukocytospermia were qualified into the study. The anti-inflammatory anti bacterial and anti-oxidative treatment combined with dietary supplementation was applied for 90 days. The sperm analysis was performed before and after the treatment. RESULTS: The mean volume of sperm samples and spermatozoa concentration were comparable before and after treatment. The leukocyte concentration was significantly lower after the therapy. There were significantly more spermatozoa in the fast and slow forward movement, less spermatozoa without movements and comparable concentration in spermatozoa in slow undirected movement after applied treatment. CONCLUSIONS: The present study demonstrated that the anti-inflammatory, anti-bacterial and anti-oxidative treatment combined with dietary supplementation in the patients with severe oligospermia and lukocytospermia improves the sperm movement parameters and reduces the inflammatory response. Therefore, it might be beneficial to patient suffering from the infertility. PMID- 23437701 TI - [Monocytic parameters in patients with rheumatologic diseases reflect intensity of depressive disorder]. AB - Last years have brought important informations about the changes in white blood cell parameters in patients with depressive disorder and furthermore changes in the levels of cytokine production. The concept of bidirectional communications between the immune system and the central nervous system has been expressed as the 'macrophage theory of depression' and the 'cytokine hypothesis of depression' that described greater expression of monocyte-associated Interleukin-1beta (IL 1beta), Interleukin-1(see text for symbol) (IL-1(see text for symbol)), tumor necrosis factor-alpha (TNF-alpha), Interleukin-6 (IL-6), Interleukin-8 (IL-8) etc., in patients suffering from depression. It was supported by many findings e.g. administration of proinflammatory cytokines in the treatment of cancer and hepatitis C, that induced depressive symptomatology. Generally Depression accompanies a number of illnesses characterized by chronic inflammatory response. The aim of this study was to investigate the association between intensity of depression and blood cells counts in patients attending Rheumatology Department. MATERIALS AND METHODS: Research included 56 patients hospitalized in Department of Rheumatology (Medical University of Bialystok), by the reason of rheumatic arthritis (RA), systemic lupus erythematosus (SLE), ankylosing Spondylitis (AS), systemic scleroderma, Churg-Strauss syndrome (CSS) and psoriatic arthritis (PA). Researched group was presenting by 46 women (mean age 51 years; range 18-73) and 10 men (mean age 50 years; range 27-78). Depressive symptoms were assessed using the Beck Depression Inventory (BDI) and Hamilton Depression Scale (HAM-D). Peripheral blood samples were obtained from all 56 patients for standard blood cell counts. Statistical analysis was performed using Statistica 9.0 pl (Statsoft, Cracov, Poland). Spearman's rank correlation coefficient was used to estimate associations between variables. P-values < 0.05 were considered statistically significant. RESULTS: The mean BDI value was found to be 12 +/- 8 and the mean HAM-D 14 +/- 9. Monocytes ratio significantly correlated with the intensity of depressive symptoms. CONCLUSIONS: Stress and pain increase with illness progression are only fragments of the analyzed problem ground. Although monocytes value remained within the upper limit of normal value, their correlation with depressive symptoms suggests that the serious reason for such a depressive mood state is a high level of monocytes. It indicates on necessity of early diagnosis and treatment of depression associate with chronic proinflammatory diseases. It may be also speculated potential efficiency of an adjunctive treatment with cytokine inhibitors and oxidative stress inhibitory factors in the therapy of depressive disorders. PMID- 23437702 TI - [Assessment of mental status at the drivers of the vehicles after using alcohol or drunk driving]. AB - Alcohol changes the behavior and works toward making behavior carrying a risk, such as driving in the state of intoxication, work at height, using machines requiring full medical fitness, breach of security at work. The aim of the study was to present a preliminary assessment of the mental state of drivers by gender, to driving under the influence of alcohol or in a state of intoxication, who volunteered for the study to the Regional Occupational Health Centre in Kielce and psychological analysis of the type of decisions which the driver received after the testing. MATERIAL AND METHODS: 526 papers were assessed psychological examination of drivers surveyed in 2004, 2007 and 2010 who received a positive psychological judgment of the scheduled date of follow-up examination or negative. In 2012, an additional random sample of 50 drivers who ran a vehicle under the influence of alcohol were assessed using the general health Questionnaire (GHQ-The General Health Questionnaires) David Goldberg. RESULTS: Of the 526 drivers surveyed 3774 due to mental disorders received a favorable ruling or negative term. Psychological judgments of 526 400 were issued to the timing of follow-up examination and negative 126th. The 320 drivers had alcohol dependence syndrome. That 155 was referred to the outpatient alcohol treatment centers facilities located near their place of residence. Only 3 drivers in Group 50 evaluated using a questionnaire GHQ had symptoms of depression. CONCLUSIONS: An important reason for inability to drive are the irregularities observed in psychological tests. In 35% are impaired motor skills, 23% personality disorder, 20% of changes in tests assessing intelligence and memory. There was no significant relationship (p = 0.5583) between gender and the concentration of GGT in the category of normal. PMID- 23437703 TI - [The knowledge about mental disorders and the attitudes towards treatment among students--preliminary results]. AB - Public image of psychiatry and psychiatrists is filled with stigmatizing stereotypes. Psychiatric patients also suffer from stigma. Mental illness is one of the most socially excluding stigmata. The aim of the study was to present state of knowledge about mental disorders among medical students and to assess students' attitudes to psychiatric treatment. MATERIAL AND METHODS: The study involved 60 students from the Medical University of Lodz, a medical faculty (n = 30) and emergency medical services faculty (n = 30). The study used a questionnaire constructed by the authors, consisting of three parts: 1. socio demographic variables, 2. attitudes towards psychiatric treatment, 3. knowledge about mental disorders. RESULTS: According to the majority of respondents (95%) specialization in psychiatry is necessary. Only 40% of respondents know that to hold a first visit to a psychiatrist a referral is not necessary. Over 90% of the students did not treat visiting the psychiatrist as a reason for shame. A small percentage of them would approach this appointment at the instigation (26.6%). Respondents demonstrated a knowledge of the causes of mental disorders, but confirmed the negative stereotypes about aggression of psychiatric patients and electroconvulsive therapy (only 22 students are aware of its use in modem psychiatry). According to the majority of respondents, mental illness does not begin suddenly (78.33%), hereditary factors play a dominant role in their development (48.33%), and stress significantly increases the risk of their occurrence. Only 26 of the respondents did not agree with the finding of increased aggressiveness of psychiatric patients. CONCLUSIONS: The image a mentally ill person in the eyes of medical students does not differ from the stereotypical thinking of the general population. The results of this study suggest necessity of spread the knowledge of psychiatry among medical students. PMID- 23437704 TI - [Beta-blockers usage in cardio-vascular diseases co-existing with COPD]. AB - Chronic obstructive pulmonary disease (COPD) is one of the most frequent chronic diseases. Slightly reversable and progressive decrease in airflow through the airways is characteristic for the disease. It has been brought up last years that COPD course influences not only pulmonary system status but also many co-existing diseases in the eldery, especially cardio-vascular diseases, such as: ischaemic heart disease, hypertension, heart arrythmias, heart infarction. Wide usage and established position in the treatment of cardio-vascular diseases have the antagonists of beta-adrenergic receptors (beta-blockers). The aim of this work was the combination of the studies results quoted in the literature about the usage of beta-blockers in cardiovascular diseases co-existing with COPD. Conclusions. Nowadays there are no unambiguous recommendations for the usage of beta-blocker in patients with COPD and the decision about including them into treatment depends on the individually estimated risk of complications. PMID- 23437705 TI - [CXCL10/IP-10 as a new biomarker for Mycobacterium tuberculosis infection]. AB - In low prevalence countries, where identification and treatment of latent TB infection (LTBI) are basis of national programmes against tuberculosis, the diagnosis is focused mainly on tuberculin skin test (TST) and interferon gamma release assay (IGRA), both of which seem to be imperfect. This is why searches for a new, more specific biomarker for TB infection have been conducted. A promising candidate for the new marker is interferon gamma induced protein (IP 10). IP-10 is a chemokine, which can be detected in increased amounts in patients with active tuberculosis, latent TB infection and in individuals who had contact with an index case. It has been commonly suggested that a simultaneous analysis of IGRA and IP-10 level increases the effectiveness of IGRA, however it is still not certain whether measurement of IP-10 level might help distinguish between the above mentioned forms of tuberculous infection. Hopes are high as the protein is proved to be a good marker for treatment monitoring in adults, though there is no available data on its usefulness in monitoring therapy in paediatric population. More studies are still needed to fully assess the benefits of IP-10 level measurement as a biomarker for tuberculous infection, especially in children. PMID- 23437706 TI - [The role of paracetamol in transition reactions of alpha-nitrogen and oxidative stress in the liver]. AB - Paracetamol (Acetaminophen, PC) is metabolized in liver to N-acetyl-p-benzoquinon imine (NAPQI), that is in turn conjugated by glutathione S-transferase with glutathione. NAPQI inhibits the respiratory chain. It may cause a 90% decrease of ATP concentration in mitochondria of hepatocytes. The oxidation of paracetamol to quinine form can also generate free radicals. Both above mentioned processes, can injure the mitochondria and cells. There have not been found in accessible literature any data dealing with paracetamol influence on the process elimination of the alpha nitrogen in the liver. The ATP concentration decline may lead to disturbances in mitochondrial enzymes. There are discrepant data of the role of free radicals in the mechanism of toxic action of paracetamol. PMID- 23437707 TI - [Diagnostic usefulness of uterine artery Doppler]. AB - Doppler waves present hemodynamic state of vascular bed. This method is used in a diagnostic of pathological states in pregnancy. Basing on the observation of curve shape of uterine artery blood flow, we may conclude about its vascular resistance, wall tension and amount of blood. Several studies confirmed the opportunity of the use of Doppler uterine artery in a diagnosis and prognosis of complicated pregnancies. The incidence of notch in uterine artery blood flow was observed in pregnancies with incomplete trophoblast invasion and inadequate placentation. Many studies confirmed that bilateral notch might be associated with increased likelihood of different pregnancy complications, particularly pregnancy--induced hypertension (PIH) and intrauterine growth restriction (IUGR). The results of the most recent trials include the possibility of the use Ut-PI in a distinguishing of abnormal biochemical, prenatal tests in chromosomal aberrations and different pathological states in pregnancy such as preeclampsia and fetal hypotrophy. PMID- 23437708 TI - [Anti-tumor activity of 1-O-alkylglycerols--the main component of shark liver oil]. AB - Fish oils contain several active compounds that modify cell activity and influence various functions of the human body. Shark liver oils are rich in 1-O alkylglycerols which have strong ability to stimulate human immune system. In this review we discuss findings of the recent studies that showed antitumor properties of 1-O-alkylglycerols derived from fish oils and its effect in adjunctive treatment of several types of cancer. PMID- 23437709 TI - [Diagnostic imaging of the prostate cancer]. AB - Diagnosis of the prostate cancer is based on clinical, biochemical and histological examinations, as well as various imaging techniques. From the last listed group, magnetic resonance imaging (MRI) provides precise identification of focal areas and local staging of the cancer. It improves evaluation of the local extracapsular extension and involvement of regional lymph nodes, which has significant implications for a patient management. MRI, supplemented by dynamic contrast enhanced and diffusion-weighted imaging (DWI), is especially useful in detection of small focal lesions. MRI also plays an important role in the evaluation of a local recurrence and monitoring of the early and late response to treatment. Whole-body MRI should be performed in patients with a disseminated disease. In patients with an increased level of prostate specific antigen (PSA), small lesions, local recurrence and distant metastases, not detected by other imaging techniques, a positron emission tomography (PET) should be also performed. Computed tomography (CT) does not play a significant role in the diagnosis of the primary prostate cancer, however new CT scanners improve the accuracy of prostate cancer staging. Diagnostic imaging is also widely used in the screening process. Transrectal ultrasound (TRUS) examination of the organ is applied to obtain systematic core biopsies for a histological examination. PMID- 23437710 TI - [Anticancer activity of flavonoids]. AB - On the basis of previous in vitro, in vivo and epidemiological studies was found that flavonoids among their many biological and pharmacological properties have a great anticancer potential. High intake of foods rich in these compounds, mainly vegetables and fruits is associated with a low rate of cancer in humans. Flavonoids may act at different stages of carcinogenesis: initiation, promotion and progression. The complex mechanism of antitumor action include: antioxidant activity, carcinogens inactivation, antiproliferation, block of the cell cycle, induction of apoptosis and differentiation, inhibition of angiogenesis and elimination of drug resistance. With multidirectional action in carcinogenesis and targeting its action only on cancer cells, it is suggested that these compounds may give a new perspective of their use in prevention and therapy of cancer. PMID- 23437711 TI - [Varicose veins of lower--how to recognize and treat]. AB - Varicose veins of lower limbs are the most common symptom of chronic venous disorders. They are known for medicine since the Hippocrates time (460-375b.C.), but they were not treated as a serious problem for many years. At present century varicose veins are considered to be not only an esthetic problem, but also a social problem. Scientists from the around world still try to find the best way to treat them. In spite of development the phlebology as a separate science, patients very often don't know where they should ask for help. Usually they are treated by physicians, general practitioners or surgeons. That's why physicians should know very well what to do with patients who suffer from symptoms of chronic venous insufficiency. That's very important also to learn patients, especially with risk factors, how to changed bad habits which promote to development of venous insufficiency and varicose veins. Patients should know how to decrease symptoms of this disease and treat them or how to prevent serious complications. PMID- 23437712 TI - [New insight into medication adherence in chronic skin diseases]. AB - In everyday medical practice, often even carefully designed treatment plan does not bring the expected results. In such cases, it often tums out that the reason of it is lack of patient compliance to doctor's recommendations (non-adherence). This problem affects up to 50% of patients, it may be the result of many factors, such as their socioeconomic status, knowledge, motivation for treatment, and the availability and quality of medical care. The relationship between doctor and patient, the nature of disease, drug prices and the possibility of adverse side effects are also significant. Lack of involvement of patients in the treatment process is particularly evident in chronic diseases that require prolonged and regular treatment. Interpersonal skills of the clinician and a possibility to establish a good relationship between doctor and patient have strong influence on adherence. In the Internet age, patients often gain on their own information about their disease, which can both positively and negatively affect the healing process. For this reason, one of the factors that increase the compliance is a proper education of patients. In addition, the doctor may use several other useful methods to enhance the therapeutic effect. Patient's preference when selecting medicinal preparations, simplifying treatment regimens and accurate information given to patients regarding the use of drugs also have a significant impact in such cases. PMID- 23437713 TI - [Tourism, imported parasitic diseases, and their prevention]. AB - The paper gives the results of observations of 1558 patients before and after tourist travels to tropical countries and 368 individuals visiting the north areas of the Russian Federation. Different conditions (malaria, amebiasis, leishmaniasis, intestinal and tissue helminthiasis, insect bites, venomous fish pricks, medusa burn, tick bites, etc.) were found in 402 persons. Prophylactic immunization included vaccination against hepatitis A and B viruses, meningitis, typhus, yellow fever, tick-borne encephalitis in more than 2500 patients (not including influenza vaccination in the epidemic season). The performed observations reinforce the statement that imported pathology is urgent to Russia and suggest that it is necessary to develop this section of medicine and to set up a network of health care facilities with a necessary therapeutic and diagnostic base to render skilled care to tourists. It is essential to improve medical staff training in travel medicine. PMID- 23437714 TI - [The specific features of imported Plasmodium vivax malaria, Chesson strain type]. AB - The details of imported case of Chesson strain of P. vivax malaria to Russian Federation (Moscow) from border areas between Myanmar and Thailand is given. It might further confirm the expansion of this strain from its original place in the Western Pacific towards other territories in the World, described in various publications. PMID- 23437715 TI - [Toxocariasis in the Republic of Altai. Geoinformation mapping simulation]. AB - Toxocariasis is one of the most important zooanthroponotic natural-focal parasitic diseases in the Republic of Altai. The prevalence of their invasion among the inhabitants of the Republic has increased by more than 7 times. The data of the authors' observations ofToxocara infection in animals (cats, dogs), soil contamination with helminth eggs, and prevalence of human toxocariasis in the Republic of Altai, by considering the results of tests for antibodies against its pathogen in the inhabitants of the region, were automatically processed using geoinformation mapping simulation, which yielded a mapping model to rank the region's area by morbidity rates. The use of up-to-date computers and geo information systems makes it possible to systematize information on this invasion and to see major foci of the disease to reveal the reasons for their assignment to the specific type of the region's landscape. PMID- 23437716 TI - [Epizootiological characteristics of clonorchiasis foci in the Amur River ecosystem in the Jewish autonomic region]. AB - Malacofaunal and ichthyoparasitological studies were conducted in the floodplain river ecosystem in the middle course of the Amur River. The studies covered its channels and tributaries, such as Big and Small Bira, Bidzhan, In, and Vertoprashikha Rivers, in the Birobidzhan, Leninskoye, and Smidovich districts of the Jewish Autonomic Region in the second half of August 2011. It was established that there were biotopes of the mollusk Parafossalurus manchouricus, the first intermediate host of Clonorchis sinensis, in the exosystems of the In, Bira, and Bidzhan Rivers. Sporadic P. manchouricus specimens were found in the Bidzhan channel in the vicinity of its estuary and on the flooded bank of the In River. The bay of the Bira River (the town of Birobidzhan) exhibited a biotope of P. manchouricus with a mollusk population density of 180 to 300 specimens/m2. Seven of 16 examined fish species showed metacercariae of Clonorchis. Among them there were not only Cyprinidae, but also representatives of other families and orders. The two-year-olds of orca-skripuns (Pseudobagrus fulvidraco), orca-whips (Tachysyrus ussuriensis), and Brazhnikov's orsas (Liocassis braschnikowi) were infected with C. sinensis metacercariae. Clonorchis metacercariae were first detected in Amur sleepers (Percottus glehni). This fish species has not been heretofore recorded as the second intermediate host ofC. sinensis. The highest invasion extent for C. sinensis metacercariae was revealed in Amur bitterlings (Rhodeus sericeus) born during the current year. In the biotopes ofdifferent water reservoirs, it changed from 10.0 to 48.0%. In 4 of 6 water reservoirs, Amur bitterlings were found to have larvae of this species of trematodes. The invasion rates were in the range from 1 to 4 metacercariae per fish. Only in individual cases, they were as great as 28 parasitic larvae per fish. PMID- 23437717 TI - [Infection with opistorchis larvae in the fish family cyprinidae in the Ob-Irtysh River basin in the Tyumen region]. AB - Fishes, such as ide (Leuciscus idus), dace (Leuciscus leuciscus), carpbream (Abramis brama), roach (Rutilus rutilus), and muvarica (Alburnus alburnus), with different frequency and rate of invasion and abundance index were infested with larvae of O. felineus, M. bilis, and P. truncatum. There were the highest rates of fish infection with P. truncatum larvae in the subtaiga zone (the south of the region) and with O. felineus metacercariae in the northern subtaiga and taiga zones. In research, experimental, and clinical studies, the nosological entity opisthorchiasis is a parasitic cenosis consisting of 2-3 co-members requiring their specific identification, which allows therapeutic measures to be more effectively implemented among the population of a hyperendemic focus. PMID- 23437718 TI - [Cell mechanisms that control Toxoplasma gondii dissemination in parenteral and oral infection]. PMID- 23437720 TI - [Results of 20-year observations of changes in the size of an Ixodes ricinus (Acari: Ixodes) population and a change in its infection with tick-borne borreliosis pathogens in the north of the Kaluga Region]. AB - The paper shows changes in the size of Ixodes ricinus ticks population and their infection according to the results of their 20-year systematic collections and censuses on the same routes in the Zhukovsky District, Kaluga Region. It has been established that there are always some infected I. ricinus ticks in the season of their activity (April to September). The maximal focal hazard characterized by the highest abundance indices for infected ticks is seen in May-June. This area requires greater attention due to the changes in the regime and borders of the buffer zone of the State Tarusa Complex, a national nature reserve. PMID- 23437719 TI - [DNA diagnosis of blastocystis infection by PCR]. PMID- 23437721 TI - [Immunomodulating effect of an Ixodes persulcatus (Ixodidae) tick salivary gland extract on BALB/c mice lymphocytes in an in vitro system]. AB - The immunomodulating effect of the components of an Ixodes persulcatus (Ixodidae) tick salivary gland extract (SGE) on BALB/c mice lymphocytes was evaluated. SGE of partially engorged ticks at a concentration of 50 microg/ml causes the maximum suppression ofT- and B-lymphocyte subpopulations. SGE of hungry ticks at the same concentration induces the suppression of only CD69+ T cells and TLR-2+ B cells, but produces no suppressive effect on CD69+ B lymphocytes, TLR-2+ T lymphocytes, and TLR-4+ T and B lymphocytes. SGE shows different effects on the synthesis of IFN-gamma and IL-4 by T helper cells. SGE of hungry ticks stimulated the increase of IFN-gamma and IL-4 synthesis by 4.7 and 2.6 times, respectively, as compared to the control. The findings may be of value in studying the pathogenesis of transmissible infections and in designing the vaccines based on tick gland components. PMID- 23437722 TI - [Trend in the emergence of flea imagoes from cocoons in the nests of a mountain gopher (Spermophilus musicus) in the central Caucasian highland natural focus of plague]. AB - The results of observations of a trend in the emergence of flea imagoes from cocoons in the nests of mountain gopher (Spermophilus musicus) (Elbrus region) confirm that the dominant species: Citellophilus tesquorum elbrusensis and Ctenophthalmus golovi golovi have two generations. Emergence of first-generation imagoes from cocoons is recorded in July-August in the nests where the grophers constantly inhabit in May-June. These are brood-rearing and other summer nests and, to a lesser degree, former wintering ones. Hatching of the bulk of second generation flea imagoes is observed in the nests constantly inhabited by grophers in July-August (these are nests made from summer holes and renovable wintering nests). The onset of emergence of second-generation imagoes from cocoons in both flea species is noted in September; some specimens hibernate in the cocoons, by emerging from them next April. PMID- 23437723 TI - [Cardiac involvement in adults with echinococcosis]. AB - Experiments have established that the first target for echinococcus is the liver and lung and that for pathogenic fungi and protozoa is the heart. Adult patients with hepatic hydatid disease complicated by paecilomycosis have been found to have atypical paecilomycosis-associated myocarditis, the treatment of which was developed by the authors, by using antibiotics, fungicides, and homeopathic remedies. PMID- 23437724 TI - [The duration of the residual effect of the insecticide icon and the resistance of the major malaria pathogen vector (Anopheles superpictus Grassi) in Tajikistan to the insecticides used in the Republic]. PMID- 23437725 TI - [The preparation of the salicylanilide MCT-12 and the investigation of its toxicity and anthelmintic activity]. PMID- 23437727 TI - [Parasitic affliction of the vision organs]. PMID- 23437726 TI - [The specific features of the epidemiology and epizootology of dirofilariasis in Rostov-on-Don and the Rostov region]. AB - In the Rostov Region, there have been stable foci of dirofilariasis for a long time (since the 1990s). Two helminth species (Dirofilaria repens, D. immitis) parasitize in definitive hosts. There has been recently a species-specific alteration in the foci, by increasing the proportion of canine D. immitis invasion and mixed invasions associated with the change in weather and climatic conditions and in the species-specific composition of carriers. The smaller number of patients with dirofilariasis is a consequence of the reduced affection of dogs and mosquitos. PMID- 23437728 TI - [A case of imported vivax malaria in Tomsk]. PMID- 23437729 TI - [Rare cases of human fascioliasis]. PMID- 23437730 TI - [Laboratory diagnosis of Blastocystis spp]. PMID- 23437731 TI - Quality and safety. Nicholson argues his case to complete 'unfinished business'. PMID- 23437733 TI - Operating on a different level. Interview by Daloni Carlisle. PMID- 23437734 TI - Haddow, Allwood, and Hunter. The Finnamore F20 competition. PMID- 23437732 TI - 'Powerful' board will reshape top hospitals. Interview by David Nicholson. PMID- 23437735 TI - Commissioning. Still as many questions as answers about CCGs. PMID- 23437736 TI - Commissioning. To authorisation and beyond. PMID- 23437737 TI - Clinical leadership. When in Leeds, do as the Romans did. PMID- 23437738 TI - Legal. Where next for treatment centres? PMID- 23437739 TI - The challenge for hospitals in 2013. Post-Francis climate will create perfect storm of NHS scrutiny. PMID- 23437740 TI - Trusts able to push back FT application dates. PMID- 23437741 TI - Redundancy threat for 3,500 managers. PMID- 23437742 TI - Exclusive. Chiefs express fears over weekend safety. PMID- 23437743 TI - Pension arithmetic. The profitable prize behind the pensions. PMID- 23437744 TI - Opportunities in clinical research. PMID- 23437745 TI - Aspirations of greatness. PMID- 23437746 TI - Performance. Neighbourhood watch may stop another tragedy. PMID- 23437747 TI - Roundtable. Rewriting the script. PMID- 23437748 TI - Acute care. Create a culture of caring for staff. PMID- 23437749 TI - Patient experience. Telling tales could cut complaints. PMID- 23437750 TI - Workforce. Rethinking the road to recovery. PMID- 23437751 TI - Survey finds physicians very wary of doctor ratings. PMID- 23437752 TI - Publicly reported physician ratings: here to stay but not yet ready for prime time. PMID- 23437753 TI - Benchmarking's role in driving performance. PMID- 23437754 TI - Strategies for aligning independent physicians. PMID- 23437755 TI - Storytelling defines your organizational culture. PMID- 23437757 TI - Effects of expanding an ED clinical decision unit. PMID- 23437756 TI - A results-driven risk management program: one surgical group's success story. PMID- 23437758 TI - Strategically using IT resources in health care. PMID- 23437759 TI - The challenges of increasing racial diversity in health care. PMID- 23437760 TI - Popcorn coaching. PMID- 23437761 TI - Health hackers and citizen scientists shake up medical research. PMID- 23437762 TI - Meet the new boss. PMID- 23437763 TI - Editorial comment to coverage of urethroplasty in pediatric hypospadias: randomized comparison between different flaps. PMID- 23437764 TI - Solid-state structural transformations of two Ag(I) supramolecular polymorphs to another polymer upon absorption of HNO3 vapors. AB - Solid-state structural transformation of two polymorphic forms of [Ag(8-HqH)(8 Hq)]n (1alpha and 1beta, where 8-HqH = 8-hydroxyquinoline and 8-Hq(-) = 8 hydroxyquinolate) to {[Ag(8-HqH)2]NO3}n (2) has been observed upon solid-gas reaction of compounds 1alpha and 1beta with HNO3 vapors. Solid-gas reaction of compound 2 with hydrated vapors of NH3 results in the formation of only the 1beta polymorph, while solid-solid reaction of compound 2 with KOH results in the formation of a 1alpha and 1beta mixture with chiral and achiral space groups of P2(1)2(1)2(1) and Pbcn, respectively. PMID- 23437765 TI - Exploration of the meaning of connectedness for older people in long-term care in context of their quality of life: a review and commentary. AB - BACKGROUND: A link between 'quality of life' and 'connectedness' is emerging in the literature. However, there has been little debate on what 'connectedness' means and how it can be fostered in long-term care settings. This review examines the meaning of 'connectedness' in long-term care. AIM: This paper critically examines the meaning of 'connectedness' in the context of its contribution to the quality of life of older people living in long-term care settings. METHOD: Key databases (CINAHL, PsychInfo and Medline) were searched systematically. Fourteen papers and two book chapters met the inclusion criterion of papers exploring 'connectedness for older people in residential care'. CONCLUSIONS: The experience of connectedness for older people in long-term care settings is linked with quality of life and successful ageing. Fundamental prerequisites of connectedness for older people are: self-awareness, meaningful relationships with family and friends, involvement in meaningful activities and connections with wider society. However, barriers to these prerequisites are evident for many residents in long term care settings. IMPLICATIONS FOR PRACTICE: Register and Herman (Advances in Nursing Science, 33, 2010, 53) identify six connections that combine to generate connectedness for older people. These connections are representative of the factors associated with increased quality of life for residents living in long term care settings. The six connections are helpful in identifying areas to focus on when planning person-centred care. PMID- 23437766 TI - Discovery of novel dual inhibitors of the wild-type and the most prevalent drug resistant mutant, S31N, of the M2 proton channel from influenza A virus. AB - Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (44) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections. PMID- 23437767 TI - Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling. AB - Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine exposure model for schizophrenia. PMID- 23437768 TI - Diagnosis of pulmonary tuberculosis in a pastoralist population in Ethiopia: are three sputum specimens needed? AB - OBJECTIVE: To assess the number of sputum specimens necessary for a reliable diagnosis of pulmonary tuberculosis (PTB) in a pastoralist population in Ethiopia. METHOD: Using routine data from Ethiopia, where three sputum specimens are currently recommended for the diagnosis of PTB, we documented, (i) the proportion of persons with suspected, PTB who submitted a first, second and third sputum specimen for smear examination and (ii) the incremental smear-positive yield from the first, to the second and third specimens. RESULTS: Of 505 persons with suspected PTB, 107 (22%) failed to submit three samples. Of 60 patients who submitted three sputum samples with at least one smear-positive sample, the first sputum sample was smear positive in 56 (93%) cases; the second sputum sample was the first to be positive in 3 (5%) cases and in only one case was the third sample the first to be smear positive (additional yield 2%). CONCLUSION: In a pastoralist setting, a reliable diagnosis of PTB can be achieved with two sputum specimens and PTB diagnosis may be adequate with just one sputum specimen. However, if this more radical approach was adopted, ways of increasing diagnostic sensitivity should be explored. PMID- 23437769 TI - Exploring novel KDR inhibitors based on pharmaco-informatics methodology. AB - Kinase-insert domain-containing receptor (KDR) is one of the important mediators of Vascular endothelial growth factor (VEGF) function in endothelial cells. Inhibition of KDR can be therapeutically advantageous for treatment of a number of diseases. The present study focuses on exploring novel KDR inhibitors by means of pharmaco-informatics methodologies. Three-dimensional quantitative structure activity relationship (3D-QSAR) analysis by atom-based pharmacophore mapping over a set of 85 molecules provides a proposition regarding the molecular fingerprint that can be optimized for designing more active inhibitors. The model was statistically validated with Q(2) = 0.865 for training and r(2) = 0.789, Pearson r = 0.903 for test set molecules; r(2)(0.925) by external validation suggests model robustness and indicates it as a strong query for screening any compound library. Virtual screening shows the importance of active site and hinge region residue for interaction with KDR inhibitors. Remarkably the retrieved hits contain a urea backbone, implicating urea derivatives as promising candidate for designing KDR inhibitors. The hydrophobicity of active site, which has until now been overlooked, has been raised into the picture by this study. This can impact on KDR drug development. The study thus quantifies crucial structural requirements necessary for a favourable interaction with the receptor binding site while the cooperative pattern provides important structural clues to chemists for framing potent medicinal agents in future. PMID- 23437770 TI - How are fragments optimized? A retrospective analysis of 145 fragment optimizations. AB - Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipophilicity indices than do X-ray and NMR. These advantageous properties are partially preserved in the optimization since higher affinity starting points allow optimizations better balanced between affinity and physicochemical property improvements. Size independent ligand efficiency (SILE) and lipophilic indices (primarily LELP) were found to be appropriate metrics to monitor optimizations. Small and medium enterprises (SME) produce optimized compounds with better properties than do big pharma companies and universities. It appears that the use of target structural information is a major reason behind this finding. Structure based optimization was also found to dominate successful fragment optimizations that result in clinical candidates. These observations provide optimization guidelines for fragment-based drug discovery programs. PMID- 23437771 TI - Stereodivergent SN2@P reactions of borane oxazaphospholidines: experimental and theoretical studies. AB - The stereodivergent ring-opening of 2-phenyl oxazaphospholidines with alkyl lithium reagents is reported. N-H oxazaphospholidines derived from both (+)-cis-1 amino-2-indanol and (-)-norephedrine provide inversion products in a highly stereoselective process. In contrast, N-Me oxazaphospholidines yield ring-opening products with retention of configuration at the P center, as previously reported by Juge and co-workers. As a result, from a single amino alcohol auxiliary, both enantiomers of key P-stereogenic intermediates could be synthesized. Theoretical studies of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H substrates react in a single step via preferential backside S(N)2@P substitution with inversion at phosphorus. N-methylated substrates react preferentially via a two-step frontside S(N)2@P, yielding a ring-opened product in which the nucleophilic methyl binds to P with retention of configuration. DFT calculations have shown that the BH3 unit is a potent directing group to which the methyl lithium reagent coordinates via Li in all the reactions studied. PMID- 23437773 TI - Comparative study to predict toxic modes of action of phenols from molecular structures. AB - Quantitative structure-activity relationship models for the prediction of mode of toxic action (MOA) of 221 phenols to the ciliated protozoan Tetrahymena pyriformis using atom-based quadratic indices are reported. The phenols represent a variety of MOAs including polar narcotics, weak acid respiratory uncouplers, pro-electrophiles and soft electrophiles. Linear discriminant analysis (LDA), and four machine learning techniques (ML), namely k-nearest neighbours (k-NN), support vector machine (SVM), classification trees (CTs) and artificial neural networks (ANNs), have been used to develop several models with higher accuracies and predictive capabilities for distinguishing between four MOAs. Most of them showed global accuracy of over 90%, and false alarm rate values were below 2.9% for the training set. Cross-validation, complementary subsets and external test set were performed, with good behaviour in all cases. Our models compare favourably with other previously published models, and in general the models obtained with ML techniques show better results than those developed with linear techniques. We developed unsupervised and supervised consensus, and these results were better than our ML models, the results of rule-based approach and other ensemble models previously published. This investigation highlights the merits of ML-based techniques as an alternative to other more traditional methods for modelling MOA. PMID- 23437772 TI - Colloidal aggregation causes inhibition of G protein-coupled receptors. AB - Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field. PMID- 23437774 TI - Voluntary suppression of thoughts is influenced by anxious and ruminative tendencies in healthy volunteers. AB - Replicating thought suppression effects with the Think/No-Think paradigm (TNT) has failed in some studies investigating the phenomenon of below-baseline recall of suppressed stimuli. Attempts have been made to isolate factors that might explain inter-individual differences in suppression performance. Certain personality traits, whether associated with a pathological state or investigated in a community sample, have been shown to interfere with successful thought suppression and might be responsible for some of the negative results obtained in TNT studies. In the present study we investigate the influence of psychometric measures of depression and anxiety in a fairly large sample of healthy volunteers. We show that high brooding and anxious tendencies predict worse suppression performance. While no suppression was shown when investigating the TNT not taking the psychometric measures into account, including these two traits in the analysis resulted in a pattern of below-baseline recall only for low brooders and low anxious participants. We argue that inclusion of variables measuring personality traits is warranted using the TNT and that these variables already exert their influence at minimal levels of variance, significantly improving the interpretability of the results. Future research should therefore cautiously investigate potential confounding personality characteristics before analysing their data. PMID- 23437775 TI - Oxidation of primary amines to oximes with molecular oxygen using 1,1-diphenyl-2 picrylhydrazyl and WO3/Al2O3 as catalysts. AB - The oxidative transformation of primary amines to their corresponding oximes proceeds with high efficiency under molecular oxygen diluted with molecular nitrogen (O2/N2 = 7/93 v/v, 5 MPa) in the presence of the catalysts 1,1-diphenyl 2-picrylhydrazyl (DPPH) and tungusten oxide/alumina (WO3/Al2O3). The method is environmentally benign, because the reaction requires only molecular oxygen as the terminal oxidant and gives water as a side product. Various alicyclic amines and aliphatic amines can be converted to their corresponding oximes in excellent yields. It is noteworthy that the oxidative transformation of primary amines proceeds chemoselectively in the presence of other functional groups. The key step of the present oxidation is a fast electron transfer from the primary amine to DPPH followed by proton transfer to give the alpha-aminoalkyl radical intermediate, which undergoes reaction with molecular oxygen and hydrogen abstraction to give alpha-aminoalkyl hydroperoxide. Subsequent reaction of the peroxide with WO3/Al2O3 gives oximes. The aerobic oxidation of secondary amines gives the corresponding nitrones. Aerobic oxidative transformation of cyclohexylamines to cyclohexanone oximes is important as a method for industrial production of epsilon-caprolactam, a raw material for Nylon 6. PMID- 23437776 TI - Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity. AB - Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that degrades insulin and the amyloid beta-protein and is strongly implicated in the pathogenesis of diabetes and Alzheimer's disease. We recently developed the first effective inhibitors of IDE, peptide hydroxamates that, while highly potent and selective, are relatively large (MW > 740) and difficult to synthesize. We present here a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds. Through the generation of truncated variants, we identified a compound with significantly reduced size (MW = 455.5) that nonetheless retains good potency (ki = 78 +/- 11 nM) and selectivity for IDE. Notably, the potency of these inhibitors was found to vary as much as 60-fold in a substrate-specific manner, an unexpected finding for active site-directed inhibitors. Collectively, our findings demonstrate that potent, small-molecule IDE inhibitors can be developed that, in certain instances, can be highly substrate selective. PMID- 23437777 TI - Novel GNE mutations in autosomal recessive hereditary inclusion body myopathy patients. AB - Hereditary Inclusion Body Myopathy (HIBM, IBM2, MIM:600737) is an autosomal recessive adult onset progressive muscle wasting disorder. It is associated with the degeneration of distal and proximal muscles, while often sparing the quadriceps. The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes the first two committed, rate limiting steps in the biosynthesis of N-acetylneunaminic acid (sialic acid). Affected individuals have been identified with mutations in the GNE gene. In the present study, the GNE coding region of 136 symptomatic patients were sequenced. A total of 41 patients were found to have GNE mutations. Eight novel mutations were discovered among seven patients. Of the eight novel mutations, seven were missense (p.I150V, p.Y186C, p.M265T, p.V315T, p.N317D, p.G669R, and p.S699L) and one was nonsense (p.W495X), all of which span the epimerase, kinase, and allosteric domains of GNE. In one patient, one novel mutation was found in the allosteric region and kinase domain of the GNE gene. Mutations in the allosteric region lead to a different disease, sialuria; however, this particular mutation has not been described in patients with sialuria. The pathological significance of this variation with GNE function remains unknown and further studies are needed to identify its connection with HIBM. These findings further expand the clinical and genetic spectrum of HIBM. PMID- 23437778 TI - Computer use and letter knowledge in pre-school children: a population-based study. AB - AIM: To explore the link between pre-school children's general home computer use and their letter knowledge. METHODS: As part of the Early Language in Victoria Study, a community cohort of 1539 four-year-old children was tested on letter knowledge as well as on non-verbal intelligence, oral language, articulation and phonological awareness. Performance on these measures was examined in relation to parent-questionnaire responses exploring home literacy environment and the amount of time children spent using the computer. RESULTS: A positive correlation between computer use and letter knowledge was found, and this association was still evident after controlling for other cognitive and environmental factors known to predict the development of letter knowledge in young children. CONCLUSIONS: Greater computer use in pre-school children appears to have a positive association with emerging literacy development. Future research needs to examine the nature of that association. PMID- 23437779 TI - Meaning in Life in Emerging Adulthood: A Person-Oriented Approach. AB - The present study investigated naturally occurring profiles based on two dimensions of meaning in life: Presence of Meaning and Search for Meaning. Cluster analysis was used to examine meaning-in-life profiles, and subsequent analyses identified different patterns in psychosocial functioning for each profile. A sample of 8,492 American emerging adults (72.5% women) from 30 colleges and universities completed measures on meaning in life, and positive and negative psychosocial functioning. Results provided support for five meaningful yet distinguishable profiles. A strong generalizability of the cluster solution was found across age, and partial generalizability was found across gender and ethnicity. Furthermore, the five profiles showed specific patterns in relation to positive and negative psychosocial functioning. Specifically, respondents with profiles high on Presence of Meaning showed the most adaptive psychosocial functioning, whereas respondents with profiles where meaning was largely absent showed maladaptive psychosocial functioning. The present study provided additional evidence for prior research concerning the complex relationship between Presence of Meaning and Search for Meaning, and their relation with psychosocial functioning. Our results offer a partial clarification of the nature of the Search for Meaning process by distinguishing between adaptive and maladaptive searching for meaning in life. PMID- 23437780 TI - Usage and impact of an online education tool for preventing sudden unexpected death in infancy. AB - AIM: This paper describes the usage, impact and reach of an online education tool for preventing sudden infant death. METHODS: A 24-slide presentation was formatted for online access. Content was designed for mainstream audiences to align current knowledge, attitudes and actions for a blitz approach to preventing sudden infant death in New Zealand (NZ). The tool was promoted through a network of 'safe sleep' champions across the country and collected basic information on usage, reach and impact. RESULTS: From 3286 completed online sessions between 18 November 2009 and 31 December 2011, there were 2683 (81.7%) with complete data. Average usage was 24.4 completed sessions/week, over a 2-year period, at a cost of NZD1.11 per completed session. Usage reached across regions, ethnic groups and roles. On completion of the course, most rated highly (7-9/9) (68.8%) their 'increased confidence' to discuss infant sleep safety with others. A high increased confidence rating was significantly influenced by spending more time per slide (P < 0.05) and being Maori, Pacific, Asian or 'other' compared with NZ European (P < 0.05). CONCLUSIONS: This simple online education tool achieved its aims of high usage, broad participation and cost-effective impact on increasing confidence to discuss infant sleep safety with others. e-Learning modes should be considered where there is a need to align large numbers of people in a short time with understandings and actions for addressing a specific health issue. PMID- 23437781 TI - A prospective study comparing the sensed R wave in bipolar and extended bipolar configurations: the PropR study. AB - BACKGROUND: Progress in implantable cardiac defibrillator (ICD) technology has allowed for switching the sensing polarity for the detection of ventricular fibrillation (VF). However, whether one sensing polarity confers additional advantage over the other is not known. OBJECTIVES: To determine whether one sensing polarity is superior to the other for the detection of VF. METHODS: Patients were enrolled into a prospective randomized study of sensing of VF and R waves in normal rhythm. Sensing of VF was determined by number of under sensed beats (USB), and time to detection of VF (TDVF). Each patient underwent ICD implantation followed by testing of the ICD. At each induction, patients were randomized to sensing in extended bipolar (EBP) or true bipolar (TBP) configuration. Additionally, R waves were compared at implant and at 1-month follow-up. RESULTS: A total of 50 patients were enrolled into the study. When evaluating the primary endpoint, no difference was found between USB in EBP or TBP configuration; 1.1 +/- 1.2 beats versus 1.3 +/- 1.3 beats; P = NS. Also, no difference was found between TDVF in EBP or TBP configurations; 5.9 +/- 0.6 seconds versus 5.9 +/- 0.6 seconds; P = NS. With regard to the secondary endpoints, there was no difference between R waves in EBP or TBP configurations at the time of implant 10.9 +/- 4.8 mV versus 10.9 +/- 4.8 mV P = NS; or at 1 month follow-up 12.4 +/- 4.7 mV versus 12.0 +/- 5.4 mV P = NS. CONCLUSIONS: There is no difference in the detection of VF between EBP or TBP configurations in patients undergoing ICD implantation. PMID- 23437782 TI - A Neuropsychological Model of Mentally Tough Behavior. AB - Four studies were conducted with two primary objectives: (a) to conceptualize and measure mental toughness from a behavioral perspective and (b) to apply relevant personality theory to the examination of between-person differences in mentally tough behavior. Studies 1 (N = 305 participants from a range of different sports) and 2 (N = 110 high-level cricketers) focused on the development of an informant rated mental toughness questionnaire that assessed individual differences in ability to maintain or enhance performance under pressure from a wide range of stressors. Studies 3 (N = 214) and 4 (N = 196) examined the relationship between reinforcement sensitivities and mentally tough behavior in high-level cricketers. The highest levels of mental toughness reported by coaches occurred when cricketers were sensitive to punishment and insensitive to reward. Study 4 suggested that such players are predisposed to identify threatening stimuli early, which gives them the best possible opportunity to prepare an effective response to the pressurized environments they encounter. The findings show that high-level cricketers who are punishment sensitive, but not reward sensitive, detect threat early and can maintain goal-directed behavior under pressure from a range of different stressors. PMID- 23437783 TI - Types and distribution of congenital heart defects associated with trisomy 21 in Singapore. AB - AIM: Atrioventricular septal defect (AVSD) is widely accepted as the most common type of congenital heart defect in trisomy 21. Most of these studies, however, were conducted in Caucasian communities. The few Asian studies that had been conducted on this subject yielded different results. In the largest study of its kind in Asia, we described the distribution of types of congenital heart defects associated with trisomy 21 in Singapore. METHODS: Five hundred and eighty-eight patients with trisomy 21 born in 1996-2010, and confirmed by karyotyping, were included in the study. The diagnosis of congenital heart defects were made on echocardiography. Variables extracted for analysis were demographics (race and gender) and the types of congenital heart defects. Except for complex cyanotic heart defects, haemodynamically significant lesions were accounted for separately in cases where more than one type of congenital heart defect coexisted in a patient. RESULTS: Ventricular septal defect (VSD) (39.2%) was the most common congenital heart defect associated with trisomy 21 in our study, followed by patent ductus arteriosus (34.3%), secundum atrial septal defect (23.4%) and AVSD (15.6%). This study validates previous smaller Asian studies identifying VSD as the most common cardiac lesion associated with trisomy 21. A high proportion (25.0%) of trisomy 21 patients with tetralogy of Fallot also had AVSDs. Coarctation of the aorta was uncommon. CONCLUSION: VSD was the most common congenital heart defect seen in trisomy 21 in our study. A high proportion (25.0%) of trisomy 21 patients with tetralogy of Fallot also had AVSDs. PMID- 23437784 TI - Five-year economic evaluation of non-melanoma skin cancer surgery at the Costa del Sol Hospital (2006-2010). AB - BACKGROUND: The cost associated with treatment of non-melanoma skin cancer is expected to rise considerably over the coming decades. This important public health problem is therefore expected to have an enormous economic impact for the various public health services. OBJECTIVES: To estimate the cost of the surgical care process of non-melanoma skin cancer at the Costa del Sol Hospital and seek areas to improve its efficiency, using the activity-based costing (ABC) method and the tools designed for decision analysis. SECONDARY OBJECTIVE: To compare the costs for hospitalized patients obtained using the ABC method with the data published by the Spanish Ministry of Health, using the diagnosis-related groups (DRG) classification system. MATERIAL AND METHODS: Retrospective analysis of the cost of non-melanoma skin cancer surgery at the Costa del Sol Hospital. RESULTS: The total estimated cost from 2006 to 2010 was 3 398 540?. Most of the episodes (47.3%) corresponded to minor outpatient surgery. The costs of the episodes varied greatly according to the type of admission: 423? (minor outpatient surgery), 1267? (major outpatient surgery), and 1832? (inpatient surgery). The average cost of an inpatient episode varied significantly depending on the calculation system used (ABC: 2328? vs. DRG: 5674?). CONCLUSIONS: The ABC cost analysis system favours standardization of the care process for these tumours and the detection of areas to improve efficiency. This would enable more reliable economic studies than those obtained using traditional methods, such as the DRG. PMID- 23437785 TI - Differences in the atrial electrophysiological properties between vagal and sympathetic types of atrial fibrillation. AB - INTRODUCTION: Autonomic modulation of the cardiac activity plays an important role in the pathogenesis of atrial fibrillation (AF). The aim of this study was to assess the differences in the atrial electrical and structural properties between patients with vagal and sympathetic AF. METHODS: The study included 30 patients (53 +/- 12 years old, male 26) with frequent attacks of symptomatic paroxysmal AF. All cases underwent 24-hour ambulatory Holter monitoring before the catheter ablation. The onset of AF accompanied with an increased HF component and decreased L/H ratio was designated as a vagal type (group 1, n = 12), whereas a decreased HF component and increased L/H ratio was classified as a sympathetic type (group 2, n = 18). Electrical and structural properties were evaluated during the ablation procedure. RESULTS: All patients had AF originating from PVs. There was a higher incidence of non-PV triggers in group 2 patients than that in group 1 (44% vs 8%, P = 0.04). Group 1 had a higher bipolar peak-to-peak voltage and mean DF of the global left atrium (LA), shorter total activation time, and smaller LA volume than group 2, whereas the electrical and structural properties in the right atrium were similar. After a follow-up of 15 +/- 7 months, there was a lower incidence of AF recurrence in group 1 than that in group 2 (0% vs 28%, P = 0.02). CONCLUSION: There are better electrical properties and a smaller LA volume in patients with vagal-type AF. In contrast, the LA substrate is worse, and coexisting non-PV triggers and recurrence following ablation are more prevalent in patients with the sympathetic-type AF. PMID- 23437786 TI - Full house of fears: evidence that people high in attachment anxiety are more accurate in detecting deceit. AB - Lying is deep-rooted in our nature, as over 90% of all people lie. Laypeople, however, do only slightly better than chance when detecting lies and deceptions. Recently, attachment anxiety was linked with people's hypervigilance toward threat-related cues. Accordingly, we tested whether attachment anxiety predicts people's ability to detect deceit and to play poker-a game that is based on players' ability to detect cheating. In Study 1, 202 participants watched a series of interpersonal interactions that comprised subtle clues to the honesty or dishonesty of the speakers. In Study 2, 58 participants watched clips in which such cues were absent. Participants were asked to decide whether the main characters were honest or dishonest. In Study 3, we asked 35 semiprofessional poker players to participate in a poker tournament, and then we predicted the amount of money won during the game. Results indicated that attachment anxiety, but not other types of anxiety, predicted more accurate detection of deceitful statements (Studies 1-2) and a greater amount of money won during a game of poker (Study 3). Results are discussed in relation to the possible adaptive functions of certain personality characteristics, such as attachment anxiety, often viewed as undesirable. PMID- 23437787 TI - Benefit to decrease esophageal damage using an ablation catheter with increased irrigation channels for pulmonary vein isolation. AB - INTRODUCTION: An ablation catheter has been developed with six additional irrigation channels at the proximal end of the ablating electrode. We investigated the potential improvement of esophageal damage when the number of irrigation channels of the ablation catheter was increased during pulmonary vein isolation (PVI). METHODS: This study included a total of 296 consecutive patients with atrial fibrillation. One hundred forty-eight patients were randomly assigned to receive PVI using an ablation catheter with six distal irrigation channels (6C) and 148 patients to receive PVI using an ablation catheter with 12 distal irrigation channels (12C). The luminal esophageal temperature (LET) was monitored in all patients. RESULTS: A total of 639 radiofrequency energy applications (in 225 out of 296 patients) reached the cut-off temperature. The time for the LET to reach the cut-off temperature was shorter for the 6C than the 12C group, and the 6C group had a higher T max of the LET than the 12C group. Some patients experienced a transient drop in the LET (TDLET) just before the delivery of the energy. The site that caused a TDLET before the energy delivery always reached the cut-off temperature. TDLET was more frequent in the 6C group than in the 12C group. CONCLUSIONS: The LET only showed a small difference between the 6C and 12C groups. In contrast, there may be a lower risk of esophageal injury with the 6C than the 12C if we use TDLET. PMID- 23437788 TI - Metformin in dermatology: an overview. AB - For several decades, metformin has been used as an oral hypoglycaemic agent, where it is the first line of treatment in overweight and obese type 2 diabetic patients. This is because it decreases the hepatic glucose output and acts as an insulin sensitizer by increasing the glucose utilization by muscles and adipocytes. As a result of the improvement in glycaemic control, serum insulin concentrations decline slightly, thus improving hyperinsulinaemia and its signs. In addition, it has been shown that metformin has platelet anti-aggregating and antioxidant effects. These pharmacological properties have allowed metformin to be effective in non-diabetic situations including cutaneous conditions. This is an evidence-based review on the use of metformin in the treatment of skin disorders such as hirsutism, acne, hidradenitis suppurativa, acanthosis nigricans, psoriasis, skin cancer, among others. In addition, cutaneous side effects such as leukocytoclastic vasculitis, bullous pemphigoid, psoriasiform drug eruption, lichen planus and acute alopecia have been associated with metformin use and are discussed in the article. PMID- 23437789 TI - Red grape seed extract improves lipid profiles and decreases oxidized low-density lipoprotein in patients with mild hyperlipidemia. AB - Hyperlipidemia can lead to atherosclerosis by lipoprotein deposition inside the vessel wall and oxidative stress induction that leads to the formation of atherosclerotic plaque. Oxidized low-density lipoprotein particles (Ox-LDL) have a key role in the pathogenesis of atherosclerosis. The lipid-lowering properties and antioxidants of the grape seed can be beneficial in atherosclerosis prevention. We conducted a randomized double-blind placebo-controlled crossover clinical trial. Fifty-two mildly hyperlipidemic individuals were divided into two groups that received either 200 mg/day of the red grape seed extract (RGSE) or placebo for 8 weeks. After an 8-week washout period, the groups were crossed over for another 8 weeks. Lipid profiles and Ox-LDL were measured at the beginning and the end of each phase. RGSE consumption reduced total cholesterol (-10.68+/-26.76 mg/dL, P=.015), LDL cholesterol (-9.66+/-23.92 mg/dL, P=.014), and Ox-LDL ( 5.47+/-12.12 mg/dL, P=.008). While triglyceride and very low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased by RGSE, the changes were not statistically significant. RGSE consumption decreases Ox-LDL and has beneficial effects on lipid profile-consequently decreasing the risk of atherosclerosis and cardiovascular disorders-in mild hyperlipidemic individuals. PMID- 23437790 TI - Antihyperglycemic and antioxidant activity of crocin in streptozotocin-induced diabetic rats. AB - The aim of the present study was to investigate the antihyperglycemic and protective potential of crocin, a pharmacologically active constituent of Crocus sativus L., in streptozotocin-induced diabetic rats. Rats were administered crocin intraperitoneally at doses of 15, 30, and 60 mg/kg of body weight for 6 weeks. The levels of thiobarbituric acid reactive substance (TBARS) and total thiol (SH) groups were measured in the liver and kidney at the end of 6 weeks. Under our experimental conditions, crocin at a dose of 60 mg/kg was found to significantly reduce the blood glucose level in diabetic animals. In addition, there was a significant increase in TBARS levels and decreased total thiol concentrations in the liver and kidney of diabetic animals. Crocin, at doses of 30 and 60 mg/kg, appears to exert an antioxidative activity demonstrated by a lowering of lipid peroxidation levels in these organs. In conclusion, our findings suggest that crocin has the hypoglycemic and antioxidative properties in streptozotocin-induced diabetes and it may be useful in the management of diabetic patients. PMID- 23437791 TI - Pu-erh tea hot-water extract activates Akt and induces insulin-independent glucose transport in rat skeletal muscle. AB - Skeletal muscle is a major organ that is important for whole-body glucose metabolism. We found that when isolated rat epitrochlearis muscle was incubated with a Pu-erh tea hot-water extract (PTE) for 30 min, the rate of 3-O-methyl-D glucose (3MG) transport increased in the absence of insulin. This activation was associated with an increase in Ser(473) phosphorylation of Akt, a signaling intermediary leading to insulin-dependent glucose transport, but not Tyr(458) phosphorylation of phosphoinositide 3-kinase p85, an upstream molecule of Akt. PTE-stimulated 3MG transport was also not accompanied by Thr(172) phosphorylation of the catalytic alpha-subunit of 5'-AMP-activated protein kinase (AMPK). Gallic acid, a water-soluble ingredient in Pu-erh tea, stimulated Akt phosphorylation, but not AMPK phosphorylation. These results suggest that Pu-erh tea potentially promotes skeletal muscle glucose transport at least in part by activating Akt. PMID- 23437792 TI - A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis. AB - BACKGROUND: There is limited information on systemic and biological treatment optimization and transitioning in routine clinical practice. OBJECTIVE: To provide practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis. METHODS: Dermatologists from 33 countries contributed to the Transitioning Therapies programme. Fourteen questions were identified. Answers were drafted based on systematic literature reviews (7/14 questions) and expert opinion (7/14 questions). Using a modified Delphi procedure, dermatologists from 30 countries voted on their level of agreement with each draft answer (scale: 1-9, strong disagreement to strong agreement). Consensus was defined as >=75% of participants scoring within the 7-9 range. RESULTS: Consensus was achieved on the answers to all questions. Recommendations for the use of cyclosporine and methotrexate were agreed. Transitioning from a conventional systemic therapy to a biological agent may be done directly or with an overlap (if transitioning is required because of lack of efficacy) or potentially with a treatment-free interval (if transitioning is required for safety reasons). Combination therapy may be beneficial. Continuous therapy for patients on biologicals is strongly recommended. However, during successful maintenance with biological monotherapy, a dosage reduction may be considered to limit drug exposure, although this may carry the risk of decreased efficacy. Switching biologicals for reasons of efficacy should be done without a washout period, but switching for reasons of safety may require a treatment-free interval. CONCLUSION: This consensus provides practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis, based on literature reviews and the expert opinion of dermatologists from across the globe. PMID- 23437793 TI - Age differences in the use of implantable cardioverter-defibrillators among older patients hospitalized with heart failure. AB - INTRODUCTION: Practice guidelines recommend the use of ICDs in patients with heart failure (HF) and a left ventricular ejection fraction (LVEF) of <= 35% in the absence of contraindications. METHODS AND RESULTS: We performed an analysis of ICD use among patients admitted with HF with LVEF of <= 35% and discharged alive from 251 hospitals participating in the American Heart Association's Get With The Guidelines-HF Program between January 2005 and September 2011. Among 35,772 guideline-eligible patients, 17,639 received an ICD prior to hospitalization (10,886), during hospitalization (4,876), or were discharged with plans to undergo ICD placement after hospitalization (1,877). After adjustment, increasing age was associated with lower ICD use (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.87-0.91 per 5-year increase in age, P < 0.0001). Compared with patient age < 55 years, older age groups >= 65 years were less likely to receive an ICD (P < 0.003). Compared with men in the same age group, women were significantly less likely to receive an ICD; this difference was more marked with increasing age (P value for interaction = 0.006). There was a temporal increase in ICD use (adjusted OR 1.23, 95% CI 1.15-1.31 of ICD use per year) that was similar in each age group (P value for interaction = 0.665). CONCLUSIONS: Eligible older HF patients age >= 65 years were significantly less likely to receive an ICD. With increasing age, women were less likely to receive an ICD than men. ICD use significantly increased over time in all age groups; however, age-related differences in ICD use persisted. PMID- 23437794 TI - Comparison of electroanatomical mapping systems: accuracy in left atrial mapping. AB - BACKGROUND: Current 3D mapping systems have difficulty rendering complex cardiac structures. Different electroanatomical mapping software has been recently developed which uses a mathematical algorithm to improve interpolation between mapped points and delineation of closely spaced structures. This study tested the feasibility and accuracy of this software in comparison to traditional software. METHODS: In vivo 3D impedance-based mapping using a multielectrode catheter with a single geometry point cloud was performed in the left atria and pulmonary veins (PV) in 23 patients undergoing catheter ablation for atrial fibrillation. The maps were analyzed with traditional (NavX, St. Jude Medical, Minnetonka, MN, USA), either with or without multichamber mapping versus St. Jude OneModelTM software and dimensions of cardiac chambers in human studies were compared to preprocedural computed tomographic (CT) or magnetic resonance (MR) scans to determine the relative accuracy of the maps. RESULTS: Maps created by the OneModel software provided greater detail of complex cardiac structures compared to traditional software. Comparison of the left atrial/pulmonary vein electroanatomical maps with the CT and MR scans as reference standard demonstrated significantly less error in measurement of all PV ostial long- and short-axis dimensions, inter-PV distance, and ridge width (left PV to left atrial appendage) with the OneModel versus traditional software (P < 0.001 for all dimensions measured). CONCLUSIONS: The OneModel software produces maps that are more accurate in rendering complex cardiac structures compared to traditional software. PMID- 23437795 TI - Cospeciation vs host-shift speciation: methods for testing, evidence from natural associations and relation to coevolution. AB - Hosts and their symbionts are involved in intimate physiological and ecological interactions. The impact of these interactions on the evolution of each partner depends on the time-scale considered. Short-term dynamics - 'coevolution' in the narrow sense - has been reviewed elsewhere. We focus here on the long-term evolutionary dynamics of cospeciation and speciation following host shifts. Whether hosts and their symbionts speciate in parallel, by cospeciation, or through host shifts, is a key issue in host-symbiont evolution. In this review, we first outline approaches to compare divergence between pairwise associated groups of species, their advantages and pitfalls. We then consider recent insights into the long-term evolution of host-parasite and host-mutualist associations by critically reviewing the literature. We show that convincing cases of cospeciation are rare (7%) and that cophylogenetic methods overestimate the occurrence of such events. Finally, we examine the relationships between short-term coevolutionary dynamics and long-term patterns of diversification in host-symbiont associations. We review theoretical and experimental studies showing that short-term dynamics can foster parasite specialization, but that these events can occur following host shifts and do not necessarily involve cospeciation. Overall, there is now substantial evidence to suggest that coevolutionary dynamics of hosts and parasites do not favor long-term cospeciation. PMID- 23437796 TI - Self-reported sleep quality of patients with atrial fibrillation and the effects of cardioversion on sleep quality. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance encountered in clinical practice and is associated with impaired quality of life. Data from the previous studies have shown that sleep quality (SQ), as a component of life quality, may also deteriorate in patients with AF. However, it remains unclear; we do not know whether SQ improves after sinus rhythm is maintained. Therefore, we aimed to examine the relationship between SQ and AF, as well as the effects of sinus rhythm restoration with direct current cardioversion (DCC) on SQ among patients with persistent AF. METHODS: One hundred fifty-three patients with a diagnosis of nonvalvular AF and 150 age-matched control subjects with sinus rhythm were recruited. SQ was assessed using the Pittsburgh Sleep Quality Index (PSQI). The study was designed with two stages. First, the difference in SQ between AF patients and age-matched controls was examined. Patients with global PSQI scores greater than 5 were defined as "poor sleepers." Thus, a higher global PSQI score indicated worsened SQ. Predictors of poor SQ were also analyzed using a regression model. Second, the effect of rhythm control on SQ was studied in patients with AF who were eligible for DCC. Of the 65 patients with persistent AF, 54 patients with successful cardioversion were followed for 6 months. The remaining 11 patients, whose cardioversion was unsuccessful, were not followed. After 6 months of follow-up, the PSQI scores of patients with sinus rhythm maintenance (n = 39) and patients with AF recurrence (n = 15) were reassessed. Changes in global PSQI scores (baseline vs after 6 months) were analyzed. RESULTS: The PSQI scores were significantly higher in the AF group compared to the control group (9.4 +/- 4.6 vs 5.8 +/- 4.1, P = 0.001, respectively). The prevalence of poor sleepers was significantly higher in the AF group (76%) than in the control group (45%) (P < 0.001 by the chi(2) test). Multivariate logistic regression analysis showed that AF (odds ratio [OR]: 3.36, 95% confidence interval [CI]: 2.00-5.55), age (OR: 1.02, 95% CI: 1.00-1.04), and diabetes mellitus (OR:1.79, 95% CI: 1.03-3.14) were independent predictors of poor SQ. In the second stage, the effect of rhythm control on the SQ of the 54 patients with successful DCC was analyzed. PSQI scores improved significantly between baseline and the 6 months in sinus rhythm maintenance group (8.7 +/- 4.1 vs 7.2 +/- 3.8, P < 0.001, respectively). However, in the AF recurrence group, the change in global PSQI scores between baseline and the sixth month was not statistically significant (9.8 +/- 4.5 vs 9.2 +/- 4.2, P = 0.56, respectively). CONCLUSION: Patients with AF have shorter sleep duration and poor SQ. Maintenance of sinus rhythm after DCC may have a favorable effect on the SQ of patients with AF. Nevertheless, AF is an independent predictor of poor SQ. PMID- 23437797 TI - The Arabidopsis leaf provascular cell transcriptome is enriched in genes with roles in vein patterning. AB - Several classes of genes have been associated, by mutant phenotypes or cell biology, with the formation of vein patterns during early leaf development, including genes for certain transcription factors, auxin transport and response factors, endomembrane traffic components and other signaling pathway components. The majority of these are expressed with spatial and temporal specificity that includes expression in the precursors of vascular cells - provascular (PV) and procambial (PC) cells - suggesting that other PV/PC-specific genes might have roles in vein patterning. We inventoried the PV/PC transcriptome of Arabidopsis leaves using a combination of laser microdissection and microarray expression profiling, and determined the phenotypes of knock-outs of previously uncharacterized PV/PC-specific genes. As examples, we observed vein pattern defects in knock-out lines of KEG and a CCCH zinc finger protein. This strategy of gene discovery, based on the identification of a gene set co-expressed in the same cells during the targeted developmental event, appears to be an efficient means of identifying genes functionally relevant to the event. In the case of vein patterning, this strategy would have identified many or most of the genes previously obtained by labor-intensive screening for pattern-defective mutants. PMID- 23437798 TI - State of the science: does the theory of maternal role attainment apply to African American motherhood? AB - INTRODUCTION: This article reviews the current state of knowledge of the theory of maternal role attainment (MRA) and its relevance in describing African American motherhood. EBSCOhost Research Databases that included PubMed, CINAHL plus, MEDLINE, PsycINFO, SCOPUS, and Web of Science were searched for journal articles that examined maternal identity and MRA. Keyword searches included maternal identity, maternal role attainment, becoming a mother, prenatal attachment, maternal-fetal attachment, and maternal-infant attachment. Inclusion criteria for this review were published journal articles of studies conducted in the United States, with a clear delineation of the theoretical framework of MRA. Journal articles that measured MRA among women with depression or medically fragile infants were excluded. Two hundred and twelve studies were reviewed; 25 studies, published between 1975 and 2007, met the inclusion criteria. Nine articles described the theory of MRA, 11 articles measured variables thought to influence MRA, and 6 articles described maternal-fetal attachment, a construct of MRA. METHODS: Studies were reviewed, categorized, and analyzed to determine current knowledge of how the theory of MRA describes African American motherhood. Categories included studies describing the theoretical framework of maternal identity and MRA, studies measuring key variables thought to impact MRA, and studies measuring maternal-fetal attachment and maternal-infant attachment. RESULTS: The studies were limited by homogenous samples of upper-middle-class white women and low-income, single, African American adolescents. Study results of MRA cannot be generalized to African American women. DISCUSSION: Further research is essential to identify attributes influencing MRA, specifically among larger samples of African American women with demographics similar to that of the white populations that have been included in studies thus far. PMID- 23437799 TI - The quality of life and psychiatric morbidity in patients operated for Arnold Chiari malformation type I. AB - BACKGROUND: There are some case reports that highlight the association of Arnold Chiari malformation (ACM) with psychiatric symptoms. We assessed the association between ACM and psychiatric symptoms and risk factors in terms of psychiatric morbidity and evaluated the quality of life after surgery. METHODS: This study consisted of sixteen patients who underwent decompression operation at the Department of Neurosurgery of Sisli Etfal Hospital. The MINI plus, Short-Form McGill Pain Questionnaire and WHOQOL-BREF-TR were administered to patients. RESULTS: About 43.8% of the patients had a psychiatric disorder. About 50% of the patients had co-existing syringomyelia of which 50% with syringomyelia had a psychiatric disorder. Patients with syringomyelia without any psychiatric disorder had significantly lower scores on physical domain of WHOQOL-BREF-TR (p = 0.02) than the patients without syringomyelia and psychiatric disorder. Subjects with a psychiatric disorder had lower scores on four domains of WHOQOL-BREF-TR. The patients with psychiatric diagnoses had significantly higher scores on affective pain index (p = 0.021) and total pain index (p = 0.037) than the patients without any psychiatric disorder. CONCLUSION: The presence of a psychiatric condition influences not only the physical aspect but also deteriorates the psychological and social relations and environmental aspect. Moreover the presence of a psychiatric disorder increases the perception of pain and causes more discomfort. PMID- 23437800 TI - Cardiometabolic comorbidity in antipsychotic treated patients: need for systematic evaluation and treatment. AB - OBJECTIVE: The aim of the study was to determine the prevalence of cardiometabolic dysregulations and their somatic treatment regimens in a group of psychiatric patients treated with antipsychotics. METHODS: In a naturalistic cohort study, baseline cardiometabolic parameters were measured in 543 outpatients. After one year, a second assessment was performed in 220 patients out of the total sample. In addition, it was investigated whether in patients with somatic comorbidities adequate treatment was prescribed. RESULTS: In this cohort, about half of the patients fulfilled the criteria for metabolic syndrome. Only a limited number of patients, however, received pharmacologic treatment for individual risk factors: About 19% for hypercholesterolemia, 26% for hypertension, and 52% for diabetes. Non-treated patients were significantly younger than treated patients. Follow-up data show that the course of the cardiometabolic parameters can be dynamic. CONCLUSIONS: Cardiometabolic risk factors are highly prevalent in psychiatric patients treated with antipsychotic drugs. Unfortunately, adequate treatment of cardiometabolic comorbidity in these relatively young patients is seriously hampered. Thus, specific guidelines for psychiatric patients have to be developed taking into account the high cardiovascular risk at a relatively young age and potential pharmacokinetic interactions between psychotropics and somatic compounds. Moreover, integration of psychiatric and physical health care systems for patients with mental disorders is urgently needed. PMID- 23437801 TI - Effects of first occasion test experience on longitudinal cognitive change. AB - Effects of additional test experience on longitudinal change in 5 cognitive abilities was examined in a sample of healthy adults ranging from 18 to 80 years of age. Participants receiving experience with parallel versions of the cognitive tests on the first occasion had more positive cognitive change an average of 2.5 years later than participants performing only a single version of the tests on the first occasion. Importantly, these test experience effects were similar in adults of different ages, which implies that retest contributions to cognitive change are comparable among healthy adults between 18 and 80 years of age. PMID- 23437802 TI - Domain differences in the weights of perceptual and conceptual information in children's categorization. AB - Visual appearance is one of the main cues children rely on when categorizing novel objects. In 3 studies, testing 128 3-year-olds and 192 5-year-olds, we investigated how various kinds of information may differentially lead children to overlook visual appearance in their categorization decisions across domains. Participants saw novel animals or artifacts of varying degrees of similarity to target categories and were asked to place them in 1 of 2 categories. Manipulated across studies was the kind of information pitted against visual similarity: internal information (Study 1, both 3- and 5-year-olds), intentional information (Study 2, both 3- and 5-year-olds), or labels (Study 3, only 5-year-olds). Overall, we found that for 5-year-olds, but not so for 3-year-olds, internal information had a stronger effect on the categorization of animals than of artifacts. Intentional information, in turn, had a stronger effect on both age groups' categorization of artifacts than of animals. Labels too had a stronger effect on 5-year-olds' categorization of artifacts than of animals. These findings are consistent with a domain-specific account of categorization, according to which the weight of different kinds of information on categorization decisions depends on children's developing understanding of domains. PMID- 23437803 TI - Selective social learning: new perspectives on learning from others. AB - This special issue was motivated by the recent, wide-ranging interest in the development of children's selective social learning. Human beings have a far reaching dependence on others for information, and the focus of this issue is on the processes by which children selectively and intelligently learn from others. It showcases some of the finest current work in this area and also aims to encourage new lines of investigation and new ways of thinking about how children learn from others. This issue also serves to highlight this new direction in basic research for the broader community of researchers, educators, and practitioners. Research on issues related to the facilitation of social learning has clear relevance to early educational contexts. In addition, by bringing together a varied pool of research on the same general topic, developmental scientists can discern the consistencies and themes that emerge from their collective efforts. The work presented here illustrates the breadth of children's selectivity across ages and domains of development, and it highlights the growing range of methods that can be recruited to investigate selectivity. This new research leads the field to reconsider the various ways in which social information guides learning and calls for novel theoretical accounts of these developments. PMID- 23437804 TI - Pre- and intra-procedural predictors of reverse remodeling after cardiac resynchronization therapy: an MRI study. AB - INTRODUCTION: Response rate after cardiac resynchronization therapy (CRT) remains suboptimal. We sought to identify pre- and intraprocedural predictors of response using MRI. METHODS AND RESULTS: Sixty patients underwent MRI before CRT. Left ventricular (LV) volumes and ejection fraction were assessed on cine images. Intra-LV dyssynchrony was defined as the maximal delay between first peaks of radial wall motion over 20 segments. Myocardial scar extent was quantified using delayed-enhanced MRI. After CRT, the paced LV segment was characterized on preprocedural MRI with respect to presence of scar and mechanical delay, the latter being quantified using time to first peak of wall motion, expressed in percentage of the total LV activation. Echocardiography was performed before and 6 months after CRT to quantify reverse remodeling (RR). Mean RR at 6 months was 30 +/- 29% of baseline LV end-systolic volume. At univariate analysis, RR related to baseline LV end-diastolic and end-systolic volumes (R(2) = 0.101, P = 0.01; R(2) = 0.072, P = 0.04), intra-LV mechanical dyssynchrony (R(2) = 0.351, P < 0.0001), scar extent (R(2) = 0.273, P < 0.0001), and presence of scar at pacing site (R(2) = 0.100, P = 0.01). QRS duration and mechanical delay at pacing site were not found related to RR (R(2) = 0.041, P = 0.12 and R(2) = 0.012, P = 0.4, respectively). At multivariate analysis intra-LV mechanical dyssynchrony, scar extent, and LV end-diastolic volume were independent predictors of RR (R(2) = 0.307, P = 0.001; R(2) = 0.096, P = 0.002, R(2) = 0.078, P = 0.005, respectively). CONCLUSION: Intra-LV dyssynchrony and scar extent are independent predictors of RR after CRT. Scar at pacing site is associated to a lesser response to CRT. Mechanical delay at this site has no impact on the response. PMID- 23437805 TI - Diagnosis, prognosis and awareness of dying in nursing homes: towards the Gold Standard? AB - BACKGROUND: In Western society and increasingly elsewhere, death has become medicalised and 'hospitalised' even when people are enduring deteriorating terminal conditions such as dementia and heart failure. In an attempt to rationalise and dignify the place and manner of death, evidence is emerging that the adoption of end-of-life care pathways and models can improve the experience of the end-of-life care across a range of care settings. Each of these demands skills and knowledge in the assessment and prediction of the dying trajectory. AIM: In this study, we report complexities facing relatives, residents and nursing home staff in the awareness, diagnosis and prediction of the dying trajectory. METHODS: Data were collected and analysed within a broadly qualitative methodology. The contexts were two nursing homes in the Greater Manchester area, each at different stages of implementing 'Gold Standards Framework' approaches to planning end-of-life care with residents and their relatives. From 2008 to 2011 and with appropriate consent, data were collected by a mixture of interviews and participant observation with residents, relatives and staff. Appropriate ethics approvals were sought and given. RESULTS: Key emerging themes were diagnosis and awareness of dying in which there is no substitute for experience. Significant resource is needed to engage staff, residents and relatives/carers with the idea of advance care planning. CONCLUSIONS: Talking to residents and relatives about their feelings and wishes for care at the end of life remains especially difficult, but education and training in key skills and knowledge can engender confidence. Challenges include diagnosing and predicting dying trajectories. IMPLICATIONS FOR PRACTICE: Advance care planning can reduce the distress from and number of inappropriate hospital admissions, but requires determination and consistent application of the approach. This can be very challenging in the face of staff rotation and the unpredictability both of the dying trajectory and the decision-making of some out of hours medical staff. PMID- 23437807 TI - Cryoablation of AVNRT when sustained tachycardia cannot be induced. AB - BACKGROUND: Inducibility of sustained tachycardia is preferred prior to cryoablation for atrioventricular nodal reentrant tachycardia (AVNRT). METHOD: The Pediatric Electrophysiology Database of a single institution was retrospectively reviewed for patients with clinical sustained (>= 30 seconds of symptoms) AVNRT documented by noninvasive means who underwent cryoablation for AVNRT to determine if intermediate-term success with cryoablation for AVNRT can be achieved without inducibility of sustained AVNRT during electrophysiology study (EPS). RESULTS: There were no differences between patients with sustained (>= 30 seconds of tachycardia) AVNRT (N = 67) and patients with nonsustained (ns, >= 3 beats and <30 seconds of tachycardia) AVNRT at EPS (N = 16). Acute success was achieved without PR prolongation in all patients. Although duration of follow up was shorter for the sustained group than the nonsustained group (2.7 +/- 1.6 years vs 3.8 +/- 1.4 years, P = 0.008), recurrence rate was similar (6% vs 6.3%, P = 0.6). In patients with only nonsustained AVNRT at EPS, supportive findings for procedural effectiveness seen: (1) Dual atrioventricular node physiology (DAVNP) was eliminated in 14/14, (2) the fast pathway effective refractory period (FPERP) decreased after ablation in 10/11, (3) sustained slow pathway conduction was eliminated in 8/8 including both patients without discrete DAVNP prior to ablation, and (4) FPERP increased during lesion formation in 10/10. CONCLUSION: Intermediate-term success can be achieved with cryoablation of ns AVNRT. Attention should be paid to supportive indicators of damage to slow pathway. PMID- 23437806 TI - Niche differentiation of ammonia oxidizers and nitrite oxidizers in rice paddy soil. AB - The dynamics of populations and activities of ammonia-oxidizing and nitrite oxidizing microorganisms were investigated in rice microcosms treated with two levels of nitrogen. Different soil compartments (surface, bulk, rhizospheric soil) and roots (young and old roots) were collected at three time points (the panicle initiation, heading and maturity periods) of the season. The population dynamics of bacterial (AOB) and archaeal (AOA) ammonia oxidizers was assayed by determining the abundance (using qPCR) and composition (using T-RFLP and cloning/sequencing) of their amoA genes (coding for a subunit of ammonia monooxygenase), that of nitrite oxidizers (NOB) by quantifying the nxrA gene (coding for a subunit of nitrite oxidase of Nitrobacter spp.) and the 16S rRNA gene of Nitrospira spp. The activity of the nitrifiers was determined by measuring the rates of potential ammonia oxidation and nitrite oxidation and by quantifying the copy numbers of amoA and nxrA transcripts. Potential nitrite oxidation activity was much higher than potential ammonia oxidation activity and was not directly affected by nitrogen amendment demonstrating the importance of ammonia oxidizers as pace makers for nitrite oxidizer populations. Marked differences in the distribution of bacterial and archaeal ammonia oxidizers, and of Nitrobacter-like and Nitrospira-like nitrite oxidizers were found in the different compartments of planted paddy soil indicating niche differentiation. In bulk soil, ammonia-oxidizing bacteria (Nitrosospira and Nitrosomonas) were at low abundance and displayed no activity, but in surface soil their activity and abundance was high. Nitrite oxidation in surface soil was dominated by Nitrospira spp. By contrast, ammonia-oxidizing Thaumarchaeota and Nitrobacter spp. seemed to dominate nitrification in rhizospheric soil and on rice roots. In contrast to soil compartment, the level of N fertilization and the time point of sampling had only little effect on the abundance, composition and activity of the nitrifying communities. The results of our study show that in rice fields population dynamics and activity of nitrifiers is mainly differentiated by the soil compartments rather than by nitrogen amendment or season. PMID- 23437808 TI - Fetus papyraceus: congenital pulmonary anomalies associated with congenital aplasia cutis on the surviving twin. AB - Aplasia cutis congenita (ACC) can be associated with fetus papyraceus. We report here the first case of ACC linked to fetus papyraceus with pulmonary anomalies. At birth, the patient presented with skin lesions of the trunk consisting of well defined, symmetrically distributed, bilateral atrophic ulcerations. Physical examination was otherwise normal. Persistent bronchospasm occurred at the age of 7 months; computed tomography images showed small bilateral pulmonary bullae. At the age of 5 years, skin and pulmonary lesions had not extended. Although the mechanisms of ACC linked to fetus papyraceus are unclear, vascular ischemia is strongly suggested, and could explain the bilateral and symmetric congenital skin and lung aplasia. PMID- 23437809 TI - pi-Conjugated heterotriangulene macrocycles by solution and surface-supported synthesis toward honeycomb networks. AB - A comparative analysis between a solution and a surface-mediated synthesis of heterotriangulene macrocycles is reported. The results show a preferential formation of the pi-conjugated macrocycles on surface due to two-dimensional confinement. The macrocycle prepared on a several hundred milligram scale by solution chemistry was characterized by single-crystal X-ray analysis and was furthermore extended toward next generation honeycomb species. Investigation of the photophysical and electronic properties together with the good thermal stability revealed the potential of MC6 as hole-transport material for organic electronics. PMID- 23437810 TI - Herbivore exclusion drives the evolution of plant competitiveness via increased allelopathy. AB - The 'Evolution of Increased Competitive Ability (EICA)' hypothesis predicts the evolution of plant invasiveness in introduced ranges when plants escape from their natural enemies. So far, the EICA hypothesis has been tested by comparing plant vigor from native and invasive populations, but these studies are confounded by among-population differences in additional environmental factors and/or founder effects. We tested the major prediction of EICA by comparing the competitive ability (CA) of Solidago altissima plants originating from artificial selection plots in which we manipulated directly the exposure to above-ground herbivores. In a common garden experiment, we found an increase in inter specific, but not intra-specific, CA in clones from herbivore exclusion plots relative to control plots. The evolutionary increase in inter-specific CA coincided with the increased production of polyacetylenes, whose major constituent was allelopathic against a heterospecific competitor, Poa pratensis, but not against conspecifics. Our results provide direct evidence that release from herbivory alone can lead to an evolutionary increase in inter-specific CA, which is likely to be mediated by the increased production of allelopathic compounds in S. altissima. PMID- 23437811 TI - The role of skin substitutes in the management of chronic cutaneous wounds. AB - Chronic wounds, including diabetic and venous ulcers, represent disruption of normal healing processes resulting in a pathological state of nonhealing cutaneous inflammation. They place an increasingly significant economic burden on healthcare providers as their prevalence is rising in keeping with an aging population. Current treatment modalities are slow acting and resource intensive. Bioengineered skin substitutes from autogenic, allogenic, or xenogenic sources have emerged as a new and alternative therapeutic option. A range of such products is licensed for clinical use, which differ in terms of structure and cellular content. Placed directly onto a prepared wound bed, skin substitutes may stimulate or accelerate healing by promoting revascularization, cellular migration, and repopulation of wound fields through provision of an appropriate scaffold material to facilitate these processes. Products containing fetal or autologous cells also benefit from early release of bioactive molecules including growth factors and cytokines. To date, limited numbers of randomized controlled trials studying skin substitutes have been published but evidence from case series and case-control studies is encouraging. This review discusses chronic wound biology, the influence that skin substitutes can exert on this environment, the products currently available, and examines the evidence for their use in chronic wound management. PMID- 23437812 TI - Outcomes of planned home births attended by certified nurse-midwives in southeastern Pennsylvania, 1983-2008. AB - INTRODUCTION: In this study, we examined the perinatal outcomes of planned home births over a 25-year period (1983-2008) in a group of primarily Amish women (98%) attended by certified nurse-midwives (CNMs) in southeastern Pennsylvania. METHODS: This was a retrospective, descriptive analysis of data (N = 1836 births) from several CNM practices. Data were abstracted for 25 items, including demographics, labor, and birth. Initially, 2 investigators abstracted 15 records to compare assessments and standardize definitions. Charts were then divided and abstracted individually by one investigator. Several relationships were examined in 2 by 2 tables using the chi-square procedure for the difference in proportions. Maternal and newborn transfers to the hospital were included in the analysis. RESULTS: Of the women who planned home birth for 1836 pregnancies, 1733 of the births occurred at home. Although more than one-third of the women were of high parity (gravida 5-13), rates of postpartum hemorrhage were low (n = 96, 5.5%). There were no maternal deaths. Nearly half of the maternal transfers to the hospital (n = 103, 5.6%) were for ruptured membranes without labor (n = 25, 1.4%) and/or failure to progress (n = 23, 1.3%). The neonatal hospital admission rate also was low (n = 13, 0.75%). Of the 7 (0.4%) early neonatal deaths, all were attributed to lethal congenital anomalies that are common to this population. DISCUSSION: This study is the first to describe the outcomes of planned home births in a primarily Amish population cared for by CNMs. It also adds to the literature on planned home births in the United States and supports the findings from previous studies that women who have home births attended by CNMs have safety profiles equal to or better than profiles of women who had hospital births in similar populations. PMID- 23437813 TI - Predictors of health service use over the palliative care trajectory. AB - BACKGROUND: Health system restructuring coupled with the preference of patients to be cared for at home has altered the setting for the provision of palliative care. Accordingly, there has been emphasis on the provision of home-based palliative care by multidisciplinary teams of health care providers. Evidence suggests that these teams are better able to identify and deal with the needs of patients and their family members. Currently there is a lack of literature examining the predictors of palliative care service use for various professional service categories. OBJECTIVE: The purpose of this study was to examine the predictors of the propensity and intensity of five main health service categories in the last three months of life for home-based palliative care patients. DESIGN: This was a prospective cohort study. The predictors of service use were assessed using a two-part model, which treats the decision to use a service (propensity) and the amount of service use (intensity) as two distinct processes. Propensity was modeled using a logistic regression and intensity was modeled using ordinary least squares regression. RESULTS: The results indicate that each service category emerged with a different set of predictor variables. Common predictors of health service use across service categories were patient age and functional status. The results suggest that a consistent set of predictors across service categories does not exist, and thus the determinants of access to each service category are unique. CONCLUSION: These findings will help case managers, health administrators, and policy decision makers better allocate human resources to palliative patients. PMID- 23437814 TI - C-reactive protein predicts pleurodesis success in malignant pleural effusion patients. PMID- 23437815 TI - RNA interference-mediated depletion of N-ethylmaleimide sensitive fusion protein and synaptosomal associated protein of 25 kDa results in the inhibition of blood feeding of the Gulf Coast tick, Amblyomma maculatum. AB - The signalling pathways in tick salivary glands that control 'sialo-secretome' secretion at the tick-host interface remain elusive; however, this complex process is essential for successful feeding and manipulation of the host haemostatic response. Exocytosis of the sialo-secretome in the salivary glands requires a core of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment proteins (SNAPs) and receptor proteins (SNAREs). SNAREs have been identified as the key components in regulating the sialo-secretome in the salivary gland cells. In this study, we utilized RNA interference to investigate the functional role of two Amblyomma maculatum SNARE complex proteins, AmNSF and AmSNAP-25, in the tick salivary glands during extended blood feeding on the vertebrate host. Knock-down of AmNSF and AmSNAP-25 resulted in death, impaired feeding on the host, lack of engorgement and inhibited oviposition in ticks. Depletion also led to important morphological changes in the collapse of the Golgi apparatus in the salivary gland cells. Our results imply a functional significance of AmNSF and AMSNAP-25 in prolonged tick feeding, and survival on the host. Further characterization of the factors that regulate exocytosis may lead to novel approaches to prevent tick borne diseases. PMID- 23437816 TI - Uncovering phantom shocks in cardiac patients with an implantable cardioverter defibrillator. AB - BACKGROUND: Implantable cardioverter defibrillator recipients sometimes report "phantom shocks" (PSs), defined as a reported shock lacking objective evidence. The aim of this study was to describe the subjective experience of PSs and their psychosocial correlates using a mixed methods approach. METHODS: PS participants were matched on sex and age with individuals who received objective shocks only (OSO). Participants were interviewed and completed measures of posttraumatic stress disorder (PTSD Checklist-Civilian Version), depression and anxiety (Hospital Anxiety and Depression Scale), disease-specific distress (Cardiac Anxiety Questionnaire-CAQ), and social desirability (Socially Desirable Response Set-SDRS). Interviews were analyzed using interpretative phenomenological analysis (IPA). RESULTS: Seventeen male patients participated (PS: n = 9; OSO: n = 8). Three themes emerged from IPA: (1) PS as a somatic experience, (2) the emotional impact of PSs, and (3) searching for meaning. Quantitative analyses showed that both groups exhibited elevated trauma and anxiety levels. Effect size differences (ESD) suggested a medium ESD on depression (P = 0.176, etap (2) = 0.118) and PTSD (avoidance: P = 0.383, etap (2) = 0.055, numbing: P = 0.311, etap (2) = 0.068), and a large ESD on SDRS (P = 0.081, etap (2) = 0.189), where PS participants, comparatively, exhibited elevated levels. A medium ESD was detected on CAQ-fear (P = 0.237, etap (2) = 0.092) where OSO participants exhibited greater heart-focused worry. CONCLUSION: The qualitative and quantitative findings of this mixed method study show convergence in terms of the emotional factors associated with the experience of PSs. PSs are often reported to be indistinguishable from objective shocks, evoking alarm, frustration, and confusion, forcing the individual to face the uncertainties of what to them is a novel and confusing experience. PMID- 23437818 TI - Excluding the presence of left atrial thrombus before pulmonary vein isolation. PMID- 23437819 TI - Biological therapy for Crohn's disease in a liver transplant patient. PMID- 23437820 TI - A rare cause of sensing integrity count in a patient with ICD and dedicated true bipolar lead. PMID- 23437821 TI - Dysfunctions at human intestinal barrier by water-borne protozoan parasites: lessons from cultured human fully differentiated colon cancer cell lines. AB - Some water-borne protozoan parasites induce diseases through their membrane associated functional structures and virulence factors that hijack the host cellular molecules and signalling pathways leading to structural and functional lesions in the intestinal barrier. In this Microreview we analyse the insights on the mechanisms of pathogenesis of Entamoeba intestinalis, Giardia and Cryptosporidium observed in the human colon carcinoma fully differentiated colon cancer cell lines, cell subpopulations and clones expressing the structural and functional characteristics of highly specialized fully differentiated epithelial cells lining the intestinal epithelium and mimicking structurally and functionally an intestinal barrier. PMID- 23437822 TI - Selection of lactic acid bacteria to promote an efficient silage fermentation capable of inhibiting the activity of Aspergillus parasiticus and Fusarium gramineraum and mycotoxin production. AB - AIMS: To select lactic acid bacteria with potential silage inoculant properties. The bio-control activity against mycotoxicogenic fungi and the presence of antibiotics resistance gene were also evaluated. METHODS AND RESULTS: Lactobacillus rhamnosus RC007 and Lactobacillus plantarum RC009 were selected on the basis of growth rate and efficacy in reducing the pH of maize extract medium; therefore, they were evaluated for their bio-control ability against Fusarium graminearum and Aspergillus parasiticus. Studies on lag phase, growth rate and aflatoxin B1 (AFB1) and zearalenone (ZEA) production were carried out in vitro under different regimes of aw (0.95 and 0.99); pH (4 and 6); temperature (25 and 37 degrees C); and oxygen availability (normal and reduced). Lactobacillus rhamnosus RC007 was able to completely inhibit the F. graminearum growth at all assayed conditions, while Lact. plantarum RC009 only did it at pH 4. Both Lactobacillus strains were able to significantly reduce the A. parasiticus growth rate mainly at 0.99 aw . A decrease in ZEA production was observed as result of Lactobacillus strains -F. graminearum interaction; however, the A. parasiticus- Lact. plantarum interaction resulted in an increased AFB1 production. Lactobacillus rhamnosus RC007 proved to have no genes for resistance to the tested antibiotics. CONCLUSIONS: The ability of Lact. rhamnosus RC007 to rapidly drop the pH and to inhibit fungal growth and mycotoxin production and the absence of antibiotic resistance genes shows the potential of its application as inoculant and bio-control agent in animal feed. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated the importance of selecting bacteria for silage inoculants not only for the improvement of silage fermentation but also for their effects on mycotoxicogenic fungi and the resulting mycotoxin production due to the risk that they may involve. PMID- 23437823 TI - Coexistence of congenital giant melanocytic nevus of the scalp with cranial defect, poliosis, and hair loss. AB - Congenital melanocytic nevi (CMN) are pigmented lesions presenting on the skin in approximately 1% of all newborns at or shortly after birth. CMN have been described as being associated with several anomalies, including cranial bone hypertrophy, scoliosis, and spina bifida. This is the first report to describe a giant congenital melanocytic nevus on the scalp associated with cranial involvement, poliosis, and alopecia. PMID- 23437824 TI - Absorption of CO2 and CS2 into the Hofmann-type porous coordination polymer: electrostatic versus dispersion interactions. AB - Absorption of CO2 and CS2 molecules into the Hofmann-type three-dimensional porous coordination polymer (PCP) {Fe(Pz)[Pt(CN)4]}n (Pz = pyrazine) was theoretically explored with the ONIOM(MP2.5 or SCS-MP2:DFT) method, where the M06 2X functional was employed in the DFT calculations. The binding energies of CS2 and CO2 were evaluated to be -17.3 and -5.2 kcal mol(-1), respectively, at the ONIOM(MP2.5:M06-2X) level and -16.9 and -4.4 kcal mol(-1) at the ONIOM(SCS MP2:M06-2X) level. It is concluded that CS2 is strongly absorbed in this PCP but CO2 is only weakly absorbed. The absorption positions of these two molecules are completely different: CO2 is located between two Pt atoms, whereas one S atom of CS2 is located between two Pz ligands and the other S atom is between two Pt atoms. The optimized position of CS2 agrees with the experimentally reported X ray structure. To elucidate the reasons for these differences, we performed an energy decomposition analysis and found that (i) both the large binding energy and the absorption position of CS2 arise from a large dispersion interaction between CS2 and the PCP, (ii) the absorption position of CO2 is mainly determined by the electrostatic interaction between CO2 and the Pt moiety, and (iii) the small binding energy of CO2 comes from the weak dispersion interaction between CO2 and the PCP. Important molecular properties relating to the dispersion and electrostatic interactions, which are useful for understanding and predicting gas absorption into PCPs, are discussed in detail. PMID- 23437825 TI - ORFH79 impairs mitochondrial function via interaction with a subunit of electron transport chain complex III in Honglian cytoplasmic male sterile rice. AB - Cytoplasmic male sterility (CMS) has attracted great interest because of its application in crop breeding. Despite increasing knowledge of CMS, not much is understood about its molecular mechanisms. Previously, orfH79 was cloned and identified as the CMS gene in Honglian rice, but how the ORFH79 protein causes pollen abortion is still unknown. Through bacterial two-hybrid library screening, P61, a subunit of the mitochondrial electron transport chain (ETC) complex III, was selected as a candidate that interacts with ORFH79. Bimolecular fluorescence complementation (BiFC) and coimmunoprecipitation (coIP) assays verified their interaction inside mitochondria. Blue native polyacrylamide gel electrophoresis (BN-PAGE) and western blotting showed ORF79 and P61 colocalized in mitochondrial ETC complex III of CMS lines. Compared with the maintainer line, Yuetai B (YB), a significant decrease of enzyme activity was detected in mitochondrial complex III of the CMS line, Yuetai A (YA), which resulted in decreased ATP concentrations and an increase in the reactive oxygen species (ROS) content. We propose that the CMS protein, ORFH79, can bind to complex III and decrease its enzyme activity through interaction with P61. This defect results in energy production dysfunction and oxidative stress in mitochondria, which may work as retrograde signals that lead to abnormal pollen development. PMID- 23437826 TI - Fusarium keratitis in South India: causative agents, their antifungal susceptibilities and a rapid identification method for the Fusarium solani species complex. AB - Seventy Fusarium isolates derived from human keratomycosis were identified based on partial sequences of the beta-tubulin (beta-TUB) and translation elongation factor 1alpha (EF-1alpha) genes. Most of the isolates were confirmed as members of the F. solani species complex (75.71%), followed by the F. dimerum species complex (8.57%), the F. fujikuroi species complex (8.57%), the F. oxysporum species complex (4.29%) and the F. incarnatum-equiseti species complex (2.86%). A combined phylogenetic tree was estimated including all the 70 isolates. Isolates belonging to different species complexes formed separate clades. In this study, we also report the first isolation of F. napiforme from human keratomycosis. A new method based on a specific EcoRI restriction site in the EF-1alpha gene was developed for the rapid identification of F. solani. In vitro antifungal susceptibilities of the isolates to seven antifungals were determined by broth microdilution method. Terbinafine, natamycin and amphotericin B proved to be the most effective drugs, followed by voriconazole. The minimal inhibitory concentrations of clotrimazole, econazole and itraconazole were generally high (>=64 MUg ml(-1) ). The interactions between the two most effective antifungals (natamycin and terbinafine) were determined by checkerboard microdilution method. Synergism (71.8%) or no interaction (28.2%) was revealed between the two compounds. PMID- 23437827 TI - When will the war end? PMID- 23437830 TI - What's in a name anyway? PMID- 23437829 TI - Isn't that just good medical care? PMID- 23437831 TI - The role of complementary and alternative medicine in children at the end of life. PMID- 23437832 TI - Multisite studies offer a solution to recruitment challenges in palliative care studies. PMID- 23437833 TI - Information provision and patient reported outcomes in patients with metastasized colorectal cancer: results from the PROFILES registry. AB - BACKGROUND: Patients with metastasized colorectal cancer (mCRC) have different information needs compared with patients with nonmetastatic colorectal cancer (CRC). Appropriate information provision leads to better patient reported outcomes for patients with nonmetastatic disease. OBJECTIVE: To measure the perceived level of, and satisfaction with, information received by patients with mCRC as compared with those with nonmetastatic (stage I,II,III) CRC. Also, associations of information provision with health status, anxiety, depression, and illness perceptions were investigated. METHODS: A cross-sectional population based survey was conducted. All CRC patients diagnosed between 2002 and 2007 according to the Eindhoven Cancer Registry (ECR) were selected. Response rate was 75% (n=1159, of which 139 had mCRC). Participants completed questionnaires on information provision (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-INFO25), health status (Short Form-36), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), and illness perceptions (Brief Illness Perception Questionnaire [B-IPQ]). RESULTS: The perceived receipt of information was quite comparable between CRC patients with and without mCRC. Only perceived receipt of treatment information was higher for patients with mCRC (45 versus 37; p<0.01). Sixty percent of the patients with mCRC were satisfied with the amount of received information and almost 30% wanted to receive more information. The perceived receipt of more disease information and information about other services was associated with worse health outcomes, whereas satisfaction with the received information was not associated with health outcomes. CONCLUSION: The findings of this study indicate that some improvements can be made in the provision of information to patients with mCRC. Adequate assessment of information needs of mCRC patients, as well as appropriate responses to these needs by providing the information in an appropriate way could possibly lead to improvements in patient satisfaction. PMID- 23437834 TI - Safe patient handling education in Nepal: a Canadian perspective in creating and conducting training in a developing country. AB - BACKGROUND: Safe patient handling (SPH) and positioning is a worldwide health care issue in both developed and developing countries. It is important for all caregivers and patients but especially for palliative care and oncology patients. While there is a wide breadth of curriculum available in developed countries, little information is available about how to teach SPH and positioning in a developing country where resources are very limited. OBJECTIVE/METHODOLOGY: This article describes the process and recommendations used by a Canadian multidisciplinary health professional team in developing SPH curriculums for palliative care communities in Nepal. Educational materials were developed to teach SPH to a group of health care professionals at a palliative care conference in Bhaktapur, Nepal, in addition to a number of other settings within the Kathmandu Valley area. RESULTS: Current barriers toward future development of SPH in Nepal are defined and discussed. The SPH curriculums that have been created are provided and specific recommendations are outlined. There is a dearth of research to guide SPH education in developing countries. SPH change requires long term support and curriculums that are culturally sensitive and contextually appropriate. PMID- 23437835 TI - AICD: what's in a name? PMID- 23437836 TI - Midwives don't deliver or catch: a humble vocabulary suggestion. PMID- 23437837 TI - Crouching variation revealed. AB - The term 'phenotypic capacitance' was introduced nearly 15 years ago to describe the strain-specific effects of impairing Hsp90, a molecular chaperone, in the fly Drosophila melanogaster (Rutherford & Lindquist 1998). In one genetic background, Hsp90 depletion caused deformed eyes, whereas in other genetic backgrounds, the wings or abdomens or other aspects of morphology were affected. Hsp90 was therefore viewed as acting like a capacitor, allowing genetic differences to build up and to be released at a later time. In the years since, it has been debated whether capacitance is a laboratory curiosity or a major force in evolution. In this issue of Molecular Ecology, Takahashi (2013) presents evidence, from high-resolution morphometric analysis of fly wings, that a large number of other capacitors exist in D. melanogaster, and that the variation they reveal can be quite subtle. His results advance our understanding of capacitance and contribute to a new view of its role in evolutionary adaptation. PMID- 23437838 TI - A cryptic rock-paper-scissors game between Drosophila males. AB - Explaining the maintenance of genetic variation in characters associated with Darwinian fitness is a preoccupation of evolutionary biologists. Spatial or temporal variation in the environment can certainly promote polymorphism, yet even populations of 'model organisms', like fruit flies, kept on invariant protocols for hundreds of generations in the laboratory often show fitness variation that exceeds what would be expected from the input of new mutations alone. Such observations suggest either complexities of selection or of genetic architecture, and offer a powerful tool for the study of mechanisms that promote stable polymorphism. In this issue of Molecular Ecology, Zhang et al. (2013) report examples of nontransitivity in the outcome of postcopulatory sexual selection in the fruit fly, Drosophila, that follow the rules of the popular stalemate-breaking game roshambo - or rock, paper, scissors (RPS). The important feature of RPS is that while each strategy beats one other, it in turn is beaten by the third. Using chromosome extraction lines, the authors confirm earlier findings that the outcome of postcopulatory sexual selection via sperm competition for a male depends, in part, upon the competitor male's genotype. But taking it one step further, they demonstrate the nontransitivities between males required for circular RPS cycles in sperm competition between males, and are able to identify at least four associated loci. Because the postmating phenotype involves hundreds of potentially interacting peptides and receptors, this is an important step to understanding the persistence of variation in a critical component of male fitness. PMID- 23437839 TI - Excluding the presence of left atrial thrombus before pulmonary vein isolation: "primum non nocere"! PMID- 23437840 TI - Identification of Culex complex species using SNP markers based on high resolution melting analysis. AB - Mosquitoes belonging to the Culex pipiens complex are primary vectors for diseases such as West Nile encephalitis, Eastern equine encephalitis, many arboviruses, as well as lymphatic filariases. Despite sharing physiological characteristics, each mosquito species within the Culex complex has unique behavioural and reproductive traits that necessitate a proper method of identification. Unfortunately, morphometric methods of distinguishing members of this complex have failed to yield consistent results, giving rise to the need for molecular methods of identification. In this study, we propose a novel identification method using high-resolution melting (HRM) analysis by examining single-nucleotide polymorphisms in the acetylcholinesterase-2 (ace-2) locus. Our method provides a high confidence for species determination among the three Culex complex mosquitoes. PMID- 23437842 TI - Understanding the reactivity of enol ether radical cations: investigation of anodic four-membered carbon ring formation. AB - The reactivity of enol ether radical cations was investigated in anodic four membered carbon ring formations, advancing the mechanistic understanding of these reactions. The mono-ring-containing aromatic cations were reduced through inter- or intramolecular electron transfer to give mono- or bis-ring-containing compounds, respectively. Small structural changes in the hydrocarbon linkers tethering two aromatic rings exerted a powerful effect on the efficiency of such electron transfer events. PMID- 23437843 TI - Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors. AB - The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6' substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 < 49 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies. PMID- 23437844 TI - Adverse psychological effects and costs associated with waiting for radiofrequency ablation. AB - BACKGROUND: Radiofrequency ablation (RFA) is undertaken as a potentially curative treatment for a variety of heart rhythm disturbances. Previous studies have demonstrated improved quality of life and reduced symptoms after ablation. In many health care environments waiting lists exist for scheduling of procedures. However, the psychological effects of waiting for radiofrequency ablation have not previously been assessed. We hypothesized that waiting for this intervention may be associated with increased psychological morbidity and health care costs. METHODS: Ninety-two patients scheduled for elective RFA completed repeated questionnaires comprising the Medical Outcomes Short Form 36, Hospital Anxiety and Depression Scale, and an in-house questionnaire designed to assess the burden of symptoms related to arrhythmia (arrhythmia-related burden score). Mean scores were generated and compared at time points while waiting, before and after the procedure. Regression analyses were carried out to identify predictors of increased psychological morbidity while waiting and immediately prior to the procedure. Health care costs during the waiting period as a consequence of arrhythmia were quantified. RESULTS: Mean scores for parameters of psychological morbidity worsened during the period of waiting and improved after the procedure. Predictors of adverse effects within the cohort varied according to the time point assessed for each of the measures of psychological morbidity. A conservative estimate of the health care cost incurred while waiting exceeds L 181 per patient. CONCLUSIONS: Waiting for radiofrequency ablation appears to be associated with adverse psychological effects and health care costs. These results may support strategies to reduce waiting times and prioritize resource allocation. PMID- 23437845 TI - Midchildhood acne associated with inhaled corticosteroids: report of two cases and review of the literature. AB - Midchildhood acne has been attributed to a number of causes in the literature, including adrenocortical tumor, hyperandrogenemia due to hypothalamic dysfunction, and contact with greasy topical skin care products. There are only a few case reports of inhaled steroids causing acneiform eruptions, all of which occurred in adults and with symptoms suggesting that the acne resulted from systemic absorption. We present two cases of comedonal and inflammatory midchildhood acne temporally associated with the use of inhaled corticosteroids administered through face masks, implicating a causative relationship between topical steroid exposure and midchildhood acne that does not necessitate systemic absorption. PMID- 23437847 TI - Expert testimony in a child sex abuse case: Translating memory development research. AB - In this paper we describe a custody case that centred on allegations of child sexual abuse. A pair of preschool-aged sisters accused their biological father of various sexual acts, though their allegations were made under problematic conditions and were contradicted by other statements they made. In an affidavit written by one of us (MB), we describe the relevant memory development research in the course of presenting the court with a scientific analysis. We find compelling evidence of multiple risk factors in the way the daughters' recollections were elicited. Although the "ultimate question" of guilt is beyond our purview, our identification of risks was instrumental in the legal system's decision that the children's allegations were not valid. We put this analysis forward as an example of evidence-based testimony in which scientific findings from the memory literature can be used to frame an expert's analysis. PMID- 23437846 TI - Emergency contraception. AB - There have been numerous attempts to control fertility after unprotected sexual intercourse (UPSI). From very bizarre methods like the vaginal application of Coca Cola to the more serious attempts using calcium antagonists influencing fertility parameters in sperm to hormonal methods or intrauterine devices. So far, hormonal methods preventing or delaying ovulation have proved to be the most popular starting with the combination of ethinyl estradiol and levonorgestrel (LNG), known as the Yuzpe regimen. The first dose had to be taken within 72 hours of UPSI, a second one 12 hours later. Later on, LNG alone, at first in a regimen similar to the Yuzpe method (2 * 0.75 mg 12 hours apart) showed to be more successful, eventually resulting in the development of a 1.5 mg LNG pill that combined good efficacy with a high ease of use. Several efficacious and easy to use methods for emergency contraception (EC) are available on the market today with the most widely spread being LNG in a single dose of 1.5 mg (given as one tablet of 1.5 mg or 2 tablets of 0.75 mg each) for administration up to 3 days (according to WHO up to 5 days) after UPSI. Its limitations are the non-optimal efficacy which is decreasing the later the drug is taken and the fact that it is only approved for up to 72 hours after UPSI. This regimen has no effect on the endometrium, corpus luteum function and implantation, is not abortive and don't harm the fetus if accidentally taken in early pregnancy. It has no impact on the rate of ectopic pregnancies. It has become the standard method used up to this day in most countries. Since the mid 1970s copper IUDs have been used for EC, which show a high efficacy. Their disadvantages lie in the fact that EC is considered an off label use for most IUDs (not for the GynFix copper IUD in the European Union) and that they might not be acceptable for every patient. Furthermore IUD-insertion is an invasive procedure and it is required trained providers and sterilized facilities. Mifepristone in the dosages of 10 or 25 mg is used with good results as an emergency contraceptive in China for up to 120 hours after UPSI, but has never received any significant consideration in Western countries. While high doses of mifepristone has an effect on endometrial receptivity and will inhibit ovulation if given in the follicular phase and prevent implantation if given in the early luteal phase, low doses such as 10 mg has no impact on the endometrium. Mifepristone does not increase the rate of ectopic pregnancies. The most recent development is the approval of the selective progesterone receptor modulator ulipristal acetate (UPA) in the dosage of 30 mg for EC up to 5 days after UPSI, combining the safe and easy application of the single dose LNG pill with an even higher efficacy. It has shown to be more efficacious than LNG and can be used for up to 120 hours after UPSI; the difference in efficacy is highest for 0-24 hours, followed by 0-72 hours following UPSI. No VTE has been reported following UPA-administration or any progesterone receptor modulator. No effect on endometrium, corpus luteum function and implantation has been observed with doses used for EC. Independent of the substance it should be noted that, if there is a choice, the intake of an oral emergency contraceptive pill should happen as soon as possible after the risk situation. A pre-existing pregnancy must be excluded. Possible contraindications and drug interactions must be considered according to the individual special product informations. PMID- 23437848 TI - Immunotherapy of allergic diseases using probiotics or recombinant probiotics. AB - Allergic diseases affect up to 30% of the western population, and their prevalence is increasing. Probiotics are able to modulate the mucosal immune response, and clinical trials demonstrated that specific strains, especially lactic acid bacteria (LAB) ones, reduce allergic symptoms. Moreover, the use of recombinant probiotics has been evaluated as possible strategies for the immunotherapy of allergic diseases. The production and delivery of allergens by recombinant LAB in concert with their ability to induce a Th1-type immune response have been shown to be a promising mucosal vaccination strategy in mouse model. The aim of this article is to review the applications of probiotics in allergy immunotherapy with a special focus on recombinant LAB delivering proteins or DNA. PMID- 23437849 TI - Invasive fungal infections in paediatric acute myeloid leukaemia. AB - Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in paediatric acute myeloid leukaemia (AML). This study describes risk factors for IFI and IFI-related sepsis in this population. We conducted a population-based, retrospective cohort study of children with AML in Canada. IFIs during chemotherapy and prior to haematopoietic stem cell transplantation, relapse, persistent disease or death were identified. Risk factors for proven or probable IFI were examined. Among courses complicated by IFI, risk factors for sepsis were also evaluated. There were 341 children with AML included of which 41 (12.0%) experienced 46 different episodes of IFI. Candida species accounted for 23 (50.0%) of IFIs and Aspergillus spp. accounted for 14 (30.4%). Days of broad spectrum antibiotics, days of corticosteroids and neutropenia at start of the course were independently associated with IFI. Only days of fever were independently associated with IFI-related sepsis. Invasive fungal infections occurred in 12.0% of paediatric AML patients. Risk factors for IFI and IFI related sepsis were identified. This knowledge may help to consider targeted strategies. PMID- 23437850 TI - Bruno-like proteins modulate flowering time via 3' UTR-dependent decay of SOC1 mRNA. AB - The Bruno RNA-binding protein (RBP) has been shown to initially repress the translation of oskar mRNA during Drosophila oogenesis and later to be involved in a broad range of RNA regulation. Here, we show that homologous constitutive overexpression of each of two Arabidopsis thaliana Bruno-like genes, AtBRN1 and AtBRN2, delayed the flowering time, while the atbrn1 atbrn2-3 double mutant flowered early and exhibited increased expression of APETALA1 (AP1) and LEAFY (LFY) transcripts. Crossing of 35S::AtBRNs with SOC1 101-D plants demonstrated that 35S::AtBRNs suppress an early-flowering phenotype of SOC1 101-D in which the coding sequence (CDS) with the 3' UTR of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) gene is overexpressed. However, this early-flowering phenotype by SOC1 overexpression was maintained in the plants coexpressing 35S::AtBRNs and 35S::SOC1 without the 3' UTR (-3' UTR). Using yeast three-hybrid, electrophoretic mobility shift, RNA immunoprecipitation, and protoplast transient assays, we found that AtBRNs bind to the 3' UTR of SOC1 RNA and participate in mRNA decay, which was mediated by the distal region of the SOC1 3' UTR. Overall, AtBRNs repress SOC1 activity in a 3' UTR-dependent manner, thereby controlling the flowering time in Arabidopsis. PMID- 23437851 TI - Recovery of self-rated health as a predictor of recurrent ischemic events after first myocardial infarction: a 13-year follow-up. AB - OBJECTIVE: Following the trajectory hypothesis for the validity of self-rated health (SRH), we tested whether subjective recovery of health, that is, return to the same or higher level of SRH after a major health event, independently predicts better long-term prognosis. METHODS: Participants were 640 patients (<= 65 years) admitted to the eight medical centers in central Israel with incident MI in a 1-year period (mean age 54, 17% female). Baseline data were collected within days of the index MI. SRH in the preceding year was assessed at baseline, and current SRH was assessed 3-6 months later. Recurrent ischemic events (recurrent MI, hospitalization with unstable angina pectoris, or cardiac death) were recorded during a mean follow-up of 13 years. RESULTS: A reduced risk of recurrent events was associated with an upward change of one level (e.g., from 3 at T1 to 4 at T2) in SRH (HR = 0.76, 95%CI: 0.69-0.85), controlling for baseline retrospective SRH. Risk was still significantly lower for each unit of improvement after adjusting for sociodemographics, preevent comorbidity, cardiac risk factors, MI severity, and early post-MI events (HR = 0.85, 95% CI 0.75 0.95). CONCLUSIONS: Individuals who perceived themselves 3-6 months after a first MI to be healthier than they had been in the year preceding the MI were more likely to survive event-free throughout the next 13 years, controlling for baseline retrospective SRH and multiple cardiac risk factors. Failure to experience such subjective recovery of one's health is a serious risk factor, which indicates that SRH should be monitored regularly after a MI. PMID- 23437852 TI - Lagged relationships among sleep disturbance, fatigue, and depressed mood during chemotherapy. AB - OBJECTIVE: Recent research suggests that sleep disturbance, fatigue, and depressed mood form a symptom cluster in patients treated with chemotherapy. To date, however, no studies have examined lagged relationships among these symptoms during chemotherapy, a time when symptom variability is high. The aim of the current study was to examine lagged changes among daily symptoms during platinum based chemotherapy. METHOD: Participants were 78 women with gynecologic cancer (mean age 63 years, SD = 11; 91% Caucasian, 97% non-Hispanic). Sleep disturbance was assessed via wrist actigraphy, whereas fatigue and depressed mood were assessed via daily diary in the week after participants' first chemotherapy infusion. Latent change score models (LCS) were used to examine lagged relationships between symptom pairs. RESULTS: High levels of sleep disturbance (i.e., minutes awake at night) were associated with earlier subsequent peaks in fatigue, and high levels of fatigue were associated with higher subsequent levels of depressed mood. CONCLUSIONS: These findings suggest that sleep disturbance, fatigue, and depressed mood occur in a cascade pattern during chemotherapy, in which increases in sleep disturbance contribute to fatigue, which, in turn, contributes to depressed mood. Interventions targeting symptoms early in the cascade, such as sleep disturbance, may provide benefits across multiple downstream symptoms. PMID- 23437853 TI - Social-cognitive theory predictors of exercise behavior in endometrial cancer survivors. AB - OBJECTIVE: This study evaluated whether social-cognitive theory (SCT) variables, as measured by questionnaire and ecological momentary assessment (EMA), predicted exercise in endometrial cancer survivors. METHOD: One hundred posttreatment endometrial cancer survivors received a 6-month home-based exercise intervention. EMAs were conducted by using hand-held computers for 10- to 12-day periods every 2 months. Participants rated morning self-efficacy and positive and negative outcome expectations by using the computer, recorded exercise information in real time and at night, and wore accelerometers. At the midpoint of each assessment period, participants completed SCT questionnaires. Using linear mixed-effects models, the authors tested whether morning SCT variables predicted minutes of exercise that day (Question 1) and whether exercise minutes at time point Tj could be predicted by questionnaire measures of SCT variables from time point Tj 1 (Question 2). RESULTS: Morning self-efficacy significantly predicted that day's exercise minutes (p < .0001). Morning positive outcome expectations were also associated with exercise minutes (p = .0003), but the relationship was attenuated when self-efficacy was included in the model (p = .4032). Morning negative outcome expectations were not associated with exercise minutes. Of the questionnaire measures of SCT variables, only exercise self-efficacy predicted exercise at the next time point (p = .003). CONCLUSIONS: The consistency of the relationship between self-efficacy and exercise minutes over short (same day) and longer (Tj to Tj-1) time periods provides support for a causal relationship. The strength of the relationship between morning self-efficacy and exercise minutes suggest that real-time interventions that target daily variation in self-efficacy may benefit endometrial cancer survivors' exercise adherence. PMID- 23437854 TI - Towards understanding the links between health literacy and physical health. AB - OBJECTIVE: Low health literacy predicts poor health, but the underpinnings of the associations are yet to be understood. This study tested the associations between health literacy and three objective health outcomes in older people and investigated the extent to which general (not health-related) cognition and earlier life-course factors such as childhood cognitive ability, educational level and occupational class accounted for these associations. METHOD: Participants were 730 community-dwelling older people (350 women; mean age 72.50 years, SD = 0.71). Physical fitness (defined by walk time, lung function, and grip strength), body mass index, and count of natural teeth were used as health outcomes. Rapid Estimate of Adult Literacy in Medicine (REALM), Shortened Test of Functional Health Literacy in Adults (S-TOFHLA), and Newest Vital Sign (NVS) were used to measure health literacy. Age 11 and concurrent general cognitive ability, educational level, and occupational social class were used as covariates. RESULTS: Lower REALM, S-TOFHLA and NVS scores were associated with worse scores on all health outcomes (beta = .09 to .17). However, cognitive ability in old age and childhood and educational and occupational levels accounted for the majority of these associations: After adjusting for these covariates, only physical fitness was significantly associated with REALM and S-TOFHLA (beta = .06 and .11). CONCLUSIONS: Low health literacy was associated with poorer health largely because it reflected general cognitive ability, educational and/or occupational levels. These variables plays some role in health beyond their association with the reading and numeracy skills captured by common health literacy measures. PMID- 23437855 TI - Is ignorance bliss? Depression, antidepressants, and the diagnosis of prediabetes and type 2 diabetes. AB - OBJECTIVE: To examine the association between clinically identified and undiagnosed prediabetes and Type 2 diabetes with depression and antidepressant medication use. METHODS: Data come from the National Health and Nutrition Examination Study (2005 and 2007), a population-based cross-sectional survey. Analysis is limited to adults aged 30 and older (n = 3,183, Mean age = 52.1 year). Depression syndrome was measured by the Patient Health Questionnaire-9. Participants were categorized using fasting glucose levels as normoglycemic (glucose <100 mg/dL), undiagnosed prediabetes (glucose 100-125.9), clinically identified prediabetes (glucose 100-125.9 plus clinician diagnosis), undiagnosed Type 2 diabetes (glucose >126), and clinically identified Type 2 diabetes (glucose >126 plus clinician diagnosis or use of antidiabetic medications). Health behaviors included smoking, poor diet, excessive alcohol use, and obesity. Health promotion behaviors included efforts to change diet, lose weight, and increase physical activity. RESULTS: Clinically identified diabetes was associated with 4.3-fold greater odds of depression, but undiagnosed diabetes was not significantly associated with depression. This relationship was more pronounced for prediabetes. Clinically identified diabetes was associated with 1.8-fold greater odds of antidepressant use, but undiagnosed diabetes was not significantly associated with antidepressant use. Health behaviors were not consistently related to depression syndrome. CONCLUSION: The relationship between diabetes status and depression and antidepressant use depends on whether the diabetes has been clinically identified. Findings are consistent with the hypothesis that the relationship between diabetes and depression may be attributable to factors related to disease management. Previous reports linking antidepressants and diabetes may be attributable to clinical ascertainment bias. PMID- 23437856 TI - Assessing social support, companionship, and distress: National Institute of Health (NIH) Toolbox Adult Social Relationship Scales. AB - OBJECTIVE: The quality of our daily social interactions-including perceptions of support, feelings of loneliness, and distress stemming from negative social exchanges-influence physical health and well-being. Despite the importance of social relationships, brief yet precise unidimensional scales that assess key aspects of social relationship quality are lacking. As part of the National Institute of Health (NIH) Toolbox for the Assessment of Neurological and Behavioral Function, we developed brief self-report scales designed to assess aspects of social support, companionship, and social distress across age cohorts. This article details the development and psychometric testing of the adult NIH Toolbox Social Relationship scales. METHODS: Social relationship concepts were selected, and item sets were developed and revised based on expert feedback and literature review. Items were then tested across a community-dwelling U.S. Internet panel sample of adults aged 18 and above (N = 692) using traditional (classic) psychometric methods and item response theory approaches to identify items for inclusion in 5-8 item unidimensional scales. Finally, concurrent validity of the newly developed scales was evaluated with respect to their interrelationships with classic social relationship validation instruments. RESULTS: Results provide support for the internal reliability and concurrent validity of resulting self-report scales assessing Emotional Support, Instrumental Support, Friendship, Loneliness, Perceived Rejection, and Perceived Hostility. CONCLUSION: These brief social relationship scales provide the pragmatic utility and enhanced precision needed to promote future epidemiological and social neuroscience research on the impact of social relationships on physical and emotional health outcomes. PMID- 23437857 TI - Treatment of pediatric obesity using a parent-only approach: a case example. AB - OBJECTIVE: There is a great need for solution-oriented studies and descriptions of interventions for pediatric obesity in real-world settings. This report describes a group-based behavioral parent-only intervention to promote healthier lifestyle habits and reduce weight status in an obese 12-year-old female participant. METHOD: The behavioral parent-only intervention program described was part of a randomized controlled trial that evaluated the impact of 2 behavioral interventions that addressed dietary intake, physical activity, and weight status in overweight and obese youth living in rural settings. Both the child and parent were targeted for behavior change. The intervention included 12 group sessions over 4 months. Behavioral strategies, including self-monitoring, goal setting, performance feedback, reinforcement, stimulus control, and instruction in behavioral parenting strategies were flexibly applied to meet the needs of the family. Assessments were completed at baseline, month-4 posttreatment, and month-10 follow-up. RESULTS: The parent attended 10 of 12 treatment sessions. At follow-up the child had lost 17 pounds and grew 1.7 in. in height. The child also experienced improved quality of dietary intake and a drop in the number of self-reported unhealthy weight control behaviors. The parent experienced no notable decrease or increase in BMI. CONCLUSIONS: The report describes the successful application of a behavioral intervention to address pediatric obesity that uses a parent-only approach. It is hoped that this presentation will facilitate discussion and help encourage further presentations of how the flexible application of evidenced-based interventions can be applied in real-world settings. PMID- 23437858 TI - Atomically dispersed Au-(OH)x species bound on titania catalyze the low temperature water-gas shift reaction. AB - We report a new method for stabilizing appreciable loadings (~1 wt %) of isolated gold atoms on titania and show that these catalyze the low-temperature water-gas shift reaction. The method combines a typical gold deposition/precipitation method with UV irradiation of the titania support suspended in ethanol. Dissociation of H2O on the thus-created Au-O-TiO(x) sites is facile. At higher gold loadings, nanoparticles are formed, but they were shown to add no further activity to the atomically bound gold on titania. Removal of this "excess" gold by sodium cyanide leaching leaves the activity intact and the atomically dispersed gold still bound on titania. The new materials may catalyze a number of other reactions that require oxidized active metal sites. PMID- 23437859 TI - There's madness in their methods--a response to: venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? Proceedings of an Ad Hoc Working Group Meeting. PMID- 23437860 TI - Hierarchical hybrids of carbon nanotubes in amphiphilic poly(ethylene oxide) block-polyaniline through a facile method: from smooth to thorny. AB - A facile approach was developed to synthesize conjugated block copolymer (BCP) poly(ethylene oxide)-b-polyaniline (PEO-PANI). Aldehyde group-terminated PEO was prepared by an esterification reaction of p-formylbenzoic acid and PEO and then reacted with PANI from chemical oxidative polymerization. FT-IR, (1)H NMR, and GPC results indicated that BCPs with different PEO block lengths were successfully synthesized. Moreover, the BCPs were employed to noncovalently modify multiwalled carbon nanotubes (MWNTs) through either the direct or indirect method. In the former method, transmission electron microscopy images showed that a core-shell MWNT@BCP hybrid with a shell thickness of gyration diameter of PEO block (2Rg,PEO) was obtained in 1-methyl-2-pyrrolidone (NMP). These hybrids can be well dispersed in many common solvents and poly(vinyl alcohol) matrix. With the increase of PEO block length, the stability of the MWNT dispersion would be highly improved. Interestingly, in the indirect method where deionized water was added to the NMP solution of BCP/MWNT mixture, the surface of the hybrid micelles encapsulated with MWNTs changed from smooth into hierarchically thorny with the increase of BCP/MWNT weight ratio. In this case, the water contact angle had a minimum value of ~70 degrees at the ratio of 1/8, indicating that the hierarchical thorns followed a Cassie-Baxter regime rather than a Wenzel one. A possible formation mechanism of the unique structure was also proposed. PMID- 23437861 TI - Genome-wide prediction of age at puberty and reproductive longevity in sows. AB - Traditional selection for sow reproductive longevity is ineffective due to low heritability and late expression of the trait. Incorporation of DNA markers into selection programs is potentially a more practical approach for improving sow lifetime productivity. Using a resource population of crossbred gilts, we explored pleiotropic sources of variation that influence age at puberty and reproductive longevity. Of the traits recorded before breeding, only age at puberty significantly affected the probability that females would produce a first parity litter. The genetic variance explained by 1-Mb windows of the sow genome, compared across traits, uncovered regions that influence both age at puberty and lifetime number of parities. Allelic variants of SNPs located on SSC5 (27-28 Mb), SSC8 (36-37 Mb) and SSC12 (1.2-2 Mb) exhibited additive effects and were associated with both early expression of puberty and a greater than average number of lifetime parities. Combined analysis of these SNPs showed that an increase in the number of favorable alleles had positive impact on reproductive longevity, increasing number of parities by up to 1.36. The region located on SSC5 harbors non-synonymous alleles in the arginine vasopressin receptor 1A (AVPR1A) gene, a G-protein-coupled receptor associated with social and reproductive behaviors in voles and humans and a candidate for the observed effects. This region is characterized by high levels of linkage disequilibrium in different lines and could be exploited in marker-assisted selection programs across populations to increase sow reproductive longevity. PMID- 23437862 TI - Transformer-4 version 2.0.1, a free multi-platform software to quickly reformat genotype matrices of any marker type, and archive them in the Demiurge information system. AB - Transformer-4 version 2.0.1 (T4) is a multi-platform freeware programmed in java that can transform a genotype matrix in Excel or XML format into the input formats of one or several of the most commonly used population genetic software, for any possible combination of the populations that the matrix contains. T4 also allows the users to (i) draw allozyme gel interpretations for any number of diploid individuals, and then generate a genotype matrix ready to be used by T4; and (ii) produce basic reports about the data in the matrices. Furthermore, T4 is the only way to optionally submit 'genetic diversity digests' for publication in the Demiurge online information system (http://www.demiurge-project.org). Each such digest undergoes peer-review, and it consists of a geo-referenced data matrix in the tfm4 format plus any ancillary document or hyperlink that the digest authors see fit to include. The complementarity between T4 and Demiurge facilitates a free, safe, permanent, and standardized data archival and analysis system for researchers, and may also be a convenient resource for scientific journals, public administrations, or higher educators. T4 and its converters are freely available (at, respectively, http://www.demiurge-project.org/download_t4 and http://www.demiurge-project.org/converterstore) upon registration in the Demiurge information system (http://demiurge-project.org/register). Users have to click on the link provided on an account validation email, and accept Demiurge's terms of use (see http://www.demiurge-project.org/termsofuse). A thorough user's guide is available within T4. A 3-min promotional video about T4 and Demiurge can be seen at http://vimeo.com/29828406. PMID- 23437863 TI - Reproductive outcomes of HIV seropositive women treated by assisted reproduction. AB - BACKGROUND: Over one million Americans are infected with HIV, and approximately 300,000 are women. Overall health in HIV infected persons has improved, and many seropositive women desire children. This study describes the reproductive outcomes of HIV seropositive women treated by assisted reproduction at our center and compares their clinical results with age-matched HIV seronegative controls. METHODS: From January 1, 1998 to December 31, 2011, 36 HIV seropositive women received treatment with in vitro fertilization (IVF) at a single center. The mean age at start of fertility treatment was 37.7+/-4.8 years. At presentation, 92% of seropositive women were using antiretrovirals and all had undetectable viral loads at time of cycle initiation. Clinical outcomes of seropositive women were compared in a one-to-one ratio to those of randomly selected age-matched seronegative controls undergoing treatment for male factor infertility during the same time period. Comparisons were stratified by age--women less than 35 and greater than 35 years of age. RESULTS: Fifteen treatment cycles resulted in live births (21 infants born without HIV infection). HIV seropositive and seronegative women < 35 years of age had nearly identical IVF clinical outcome parameters, including clinical pregnancy rates and live birth rates. For women 35 years of age or older, baseline serum estradiol levels and live birth rates were significantly lower in HIV seropositive women. CONCLUSIONS: This study demonstrates that the presence of well-controlled HIV infection does not impair fertility treatment in women undergoing IVF. Virally infected women should be encouraged to seek treatment in appropriate cases. PMID- 23437864 TI - Stepwise click functionalization of DNA through a bifunctional azide with a chelating and a nonchelating azido group. AB - A stepwise chemoselective click reaction was performed on nucleosides and oligonucleotides containing 7-octadiynyl-7-deaza-2'-deoxyguanosine and 5 octadiynyl-2'-deoxycytidine with unsymmetrical 2,5-bis(azidomethyl)pyridine using copper(II) acetate. The reaction is selective for the chelating azido group, thereby forming monofunctionalized adducts still carrying the nonchelating azido functionality. The azido-functionalized adduct was applied to a second click reaction, now performed in the presence of reducing agent, to generate cross linked DNA or a pyrene click conjugate. The chelate-controlled stepwise click reaction is applicable to alkynylated nucleosides and oligonucleotides. PMID- 23437865 TI - Fascicular and nonfascicular left ventricular tachycardias in the young: an international multicenter study. AB - INTRODUCTION: The aim of this study was to evaluate the clinical presentation and outcomes of pediatric patients with ventricular tachycardia (VT) originating from left heart structures. METHODS AND RESULTS: This international multicenter retrospective study including 152 patients (age 10.0 +/- 5.1 years, 62% male), divided into those with fascicular VT (85%, 129/152) and nonfascicular LV VT (15%, 23/152). All patients had a normal heart structure or only a minor cardiac abnormality. Adenosine was largely ineffective in both groups (tachycardia termination in 4/74 of fascicular VT and 0/5 of nonfascicular LV VT). In fascicular VT, calcium channel blockers were effective in 80% (74/92); however, when administered orally, there was a 21% (13/62) recurrence rate. In nonfascicular LV VT, a variety of antiarrhythmic therapies were used with no one predominating. Ablation procedures were successful in 71% (72/102) of fascicular VT and 67% (12/18) of nonfascicular LV VT on an intention to treat analysis. Major complications occurred in 5 patients with fascicular VT and 1 patient with nonfascicular LV VT. After a follow-up period of 2 years (1 day to 15 years), 72% of all patients with fascicular VT were off medications with no tachycardia recurrence. One patient died of noncardiac causes. In nonfascicular LV VT, follow up was 3.5 years (0.5-15 years), P = 0.38. A total of 65% of these patients were free from arrhythmias. Two patients died suddenly (P < 0.01). CONCLUSION: The clinical course and outcomes of pediatric patients with fascicular VT and nonfascicular LV VT are varied. Catheter ablation procedures can be curative. PMID- 23437867 TI - Extended-release niacin/laropiprant for lipid management: observational study in clinical practice. AB - AIMS: Patients with dyslipidaemia or hypercholesterolemia carry a substantially increased cardiovascular risk and need optimal treatment of this key risk factor. We aimed to investigate the utilisation, efficacy and tolerability of the single pill combination extended-release niacin/laropiprant 1000 mg/20 mg or 2000 mg /40 mg under conditions of primary care practice. METHODS: The present study was a prospective, non-interventional, observational study involving 885 primary care physicians throughout Germany. Data on adult patients treated with niacin/laropiprant one or two tablets daily within the labelled indication were documented for an average of 23 +/- 7 weeks. The study was registered in the Association of research-based pharmaceutical companies (VFA) database under no. 354. RESULTS: A total of 2359 patients were analysed in the intent-to-treat population (mean age 61.1 years, 67% males) of whom 1917 could be followed up. Background statin therapy was often discontinued and only about 50% of patients received two tables niacin/laropiprant at the end of the study. Individual goal attainment rates as subjectively determined by the investigator were for LDL-C 59.4%, total cholesterol 59.5%, HDL-C 72.8% and TG 51.5%, respectively. Objective (laboratory) goal attainment rates according to NCEP ATP III criteria were lower: LDL-C <100 mg/dl goal was achieved in 17.8%, HDL-C >40 in males or >50 mg/dl in females in 37.9% and TG <150 mg/dl in 18.7%. Totally, 422 adverse events were noted in 231 patients (9.7%), of which 317 were considered drug-related. Flushing occurred in 15%. CONCLUSION: Niacin/laropiprant resulted in beneficial effects on serum lipids and was generally well tolerated. The full potential of the drug combination was not explored by most physicians due to discontinuation of statins and lack of titration of the combination. Overall, treatment effects were consistent with those seen in controlled trials. PMID- 23437866 TI - Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii. AB - Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4 b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a KD of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity. PMID- 23437868 TI - Turning readmission reduction policies into results: some lessons from a multistate initiative to reduce readmissions. AB - Efforts are under way nationally to reduce avoidable hospital readmissions by changing payments to hospitals, but it is unclear how well or how quickly these policy changes will produce widespread reductions in hospital readmissions. To examine some of the challenges to implementing such approaches, the authors analyzed the early experiences of 3 statewide programs to reduce preventable readmissions that began in 2009. Based on interviews with program participants in 2011, the authors identified 3 key obstacles to progress: the difficulty of developing collaborative relationships across care settings, gaps in evidence for effective interventions, and deficits in quality improvement capabilities among some organizations. These findings underscore the uncertainty of success of current readmissions policies and suggest that immediate improvement in readmission rates through a change in reimbursement may be unlikely unless these other obstacles are addressed expeditiously. In particular, cultivation of productive collaboration across care settings will be critical because these kinds of relationships are not well established or naturally occurring in most communities. PMID- 23437869 TI - Assessing gaps in the maternal and child health safety net. AB - The Patient Protection and Affordable Care Act of 2010 proposed sweeping changes to health insurance and health care delivery systems. As a result, local health departments, community health centers, and other safety net providers are expected to play a role in providing access to care for millions of individuals. This study examines the availability of population-based services by local health departments and community health centers in the Midwest/Great Lakes region. For this study, the authors used secondary data on location of community health centers collected by the Health Resources and Services Administration and local health department services delivery from the 2008 National Profile of Local Health Departments. To simultaneously examine the geospatial patterns of service delivery and location of community health centers, the geographic information system shape files of local health department jurisdictions were used to examine prenatal care services. Additionally, the effect of service availability was examined by analyzing the rate of low birth weight births within the service areas of these facilities. Results show large variation in the distribution of community health centers. Additionally, the analysis of local health department services shows that prenatal care services are not available in every jurisdiction. Furthermore, the rates of low birth weight births in these areas are significantly higher than in areas where prenatal care is available. Future studies are needed to examine the relationship between safety net providers as well as their role in improving population health. PMID- 23437870 TI - Childhood lichen sclerosus--a challenge for clinicians. AB - Childhood lichen sclerosus (LS) is a rare and often misdiagnosed inflammatory dermatitis with an unpredictable course. The complications of LS are architectural changes of the vulva; malignant transformation is possible. The objective of our study was to define the background and the long-term course of childhood LS. A registery study identified 44 children with LS treated at Tampere University Hospital, Tampere, Finland, from 1982 to 2010. A questionnaire was sent to the identified patients and 15 responded. The clinical depiction of LS varied significantly. LS was diagnosed in only 16% of the patients at the referring unit. Autoimmune disorders were observed in 6 of the 44 patients. High prevalences of Turner's syndrome (2/44) and kidney disease (2/44) were noted. The majority of the patients were treated with topical corticosteroids. Eight developed architectural changes of the vulva. The questionnaire revealed that three of six patients who were asymptomatic at the end of the registery study follow-up experienced a recurrence of symptoms. None of them were undergoing follow-up. Nine of the 15 patients reported reduced quality of life. Childhood LS is a heterogeneous disease with a remarkable effect on quality of life. The misdiagnosis of childhood LS is common. The association between LS and autoimmune diseases should be noted. The high prevalence of Turner's syndrome raises questions regarding the influence of low estrogen levels on the development of LS. The prognosis cannot be predicted, so long-term follow-up is recommended. New tools for diagnosis and surveillance are needed. PMID- 23437871 TI - NITRILASE1 regulates the exit from proliferation, genome stability and plant development. AB - Nitrilases are highly conserved proteins with catabolic activity but much less understood functions in cell division and apoptosis. To elucidate the biological functions of Arabidopsis NITRILASE1, we characterized its molecular forms, cellular localization and involvement in cell proliferation and plant development. We performed biochemical and mass spectrometry analyses of NITRILASE1 complexes, electron microscopy of nitrilase polymers, imaging of developmental and cellular distribution, silencing and overexpression of nitrilases to study their functions. We found that NITRILASE1 has an intrinsic ability to form filaments. GFP-NITRILASE1 was abundant in proliferating cells, distributed in cytoplasm, in the perinuclear area and associated with microtubules. As cells exited proliferation and entered differentiation, GFP NITRILASE1 became predominantly nuclear. Nitrilase silencing dose-dependently compromised plant growth, led to loss of tissue organization and sustained proliferation. Cytokinesis was frequently aborted, leading to enlarged polyploid cells. In reverse, independently transformed cell lines overexpressing GFP NITRILASE1 showed slow growth and increased rate of programmed cell death. Altogether, our data suggest that NITRILASE1 homologues regulate the exit from cell cycle and entry into differentiation and simultaneously are required for cytokinesis. These functions are essential to maintain normal ploidy, genome stability and tissue organization. PMID- 23437872 TI - Toward an integrated model of executive functioning in children. AB - In this article we review the current status of executive function as a concept, its development, and its assessment during development. Following the review of key issues, we make recommendations for improved conceptualization and definition the precursors to improved models of assessment of executive functioning. PMID- 23437873 TI - Virulence of Curvularia in a murine model. AB - We have evaluated the virulence of two clinically relevant species of Curvularia; Curvularia spicifera and C. hawaiiensis, using an experimental model of disseminated infection in immunocompromised mice. Several inocula were tested over a range 1 * 10(3) -1 * 10(6) colony-forming units/animal. Both species had a similar behaviour, producing a high mortality. Tissue burden and histopathology studies demonstrated that lung was the organ most affected. PMID- 23437874 TI - Non-interacting molecules as innate structural probes in surface plasmon resonance. AB - Determining the structural parameters of a molecular layer remains an unresolved problem in surface plasmon resonance (SPR). Given that molecular form and function are intimately coupled, a breakthrough in this area could be of considerable benefit to the study of protein and/or polymer-decorated material interfaces that are ubiquitous in biology and technology. Here, we describe how noninteracting molecules function as innate structural probes that "feel" the intrinsic exclusion volume of a surface-tethered molecular layer in SPR. Importantly, this is noninvasive and provides a means to bypass the refractive index (RI) constraint that convolutes and hinders SPR thickness measurements. To show proof-of-concept, we use BSA molecules in solution to measure the thicknesses of polyethylene glycol (PEG) molecular brushes as a function of molecular weight. The SPR-acquired brush thicknesses scale with PEG hydrodynamic diameter and are in good agreement with atomic force microscopy force-distance measurements. Theoretical treatments that account for changes in the evanescent field decay length at the metal-dielectric interface indicate that the method is most appropriate for low RI layers with an estimated maximal error of +/-15% in the thickness due to the RI constraint. Such in situ thickness measurements can be easily incorporated into routine SPR binding assays for investigating mesoscopic structure-function correlations of diverse molecular layers (i.e., biointerfaces). PMID- 23437875 TI - Stable hydrogen evolution from CdS-modified CuGaSe2 photoelectrode under visible light irradiation. AB - The photoelectrochemical properties of CuGaSe2 modified by deposition of a thin CdS layer were investigated. The CdS layer formed a p-n junction on the surface of the electrode, improving its photoelectrochemical properties. There was an optimal CdS thickness because of the balance between the charge separation effect and light absorption by CdS. CdS-deposited CuGaSe2 showed high stability under the observed reaction conditions and evolved hydrogen continuously for more than 10 days. PMID- 23437876 TI - Mechanisms of inappropriate defibrillator therapy in a modern cohort of remotely monitored patients. AB - INTRODUCTION: Defibrillator (ICD) technology and monitoring are evolving rapidly. We investigated the mechanisms of inappropriate ICD therapies in a modern cohort of patients followed at our institution via remote monitoring. METHODS: From September 2009 to March 2011, a total of 2,050 ICD patients (19,600 patient months) were remotely followed. All events (shocks and antitachycardia pacing) were adjudicated by arrhythmia specialists. RESULTS: A total of 249 patients received ICD therapy (34% inappropriate therapy). Inappropriate ICD shocks affected 33 (1.6%) patients. There were a total of 249 inappropriate episodes in 85 patients. Supraventricular tachycardia (SVT) with 1:1 atrioventricular association was the predominant mechanism accounting for 133 episodes in 50 patients, followed by atrial fibrillation (97 episodes in 27 patients). T-wave oversensing (16 episodes in five patients), electromagnetic interference (two episodes in two patients), and ectopic beats (one episode in one patient) accounted for a small proportion of events. There were 35 arrhythmic episodes in five patients that could not be classified, all in patients with single-chamber devices. There were no differences in these results by device manufacturer. CONCLUSIONS: Despite many technological advances, inappropriate ICD shocks still occur but at very low rates and SVT with 1:1 atrioventricular association represents their most common mechanism. PMID- 23437877 TI - The challenges of hepatocyte research. PMID- 23437878 TI - The house that Jack built: expanding the concept of plasma cell niches. PMID- 23437879 TI - Galectin-1, immune regulation and liver allograft survival. PMID- 23437880 TI - Molecular analysis of renal allograft biopsies--more than a nice toy for researchers? PMID- 23437881 TI - Minimally invasive robotic kidney transplantation for obese patients previously denied access to transplantation. PMID- 23437883 TI - Fever, dysuria and elevated serum creatinine in a kidney transplant recipient. PMID- 23437884 TI - Pancreas transplantation from donors after circulatory death from the United Kingdom. PMID- 23437885 TI - Correction to "The AJT report". PMID- 23437887 TI - Prey preferences of aquatic insects: potential implications for the regulation of wetland mosquitoes. AB - Wetlands are potential sites for mosquito breeding and are thus important in the context of public health. The use of chemical and microbial controls is constrained in wetlands in view of their potential impact on the diverse biota. Biological control using generalist aquatic insects can be effective, provided a preference for mosquito larvae is exhibited. The mosquito prey preferences of water bugs and larvae of odonate species were evaluated using chironomid larvae, fish fingerlings and tadpoles as alternative prey. Manly's selectivity (alphai ) values with 95% confidence intervals (CIs) were estimated to judge prey preference patterns. Multivariate analysis of variance (manova) and standardized canonical coefficients were used to test the effects of density on prey selectivity. The alphai values indicated a significant preference (P < 0.05) in all of the insect predators tested for mosquito larvae over the alternative prey as a density-dependent function. On a comparative scale, chironomid larvae had the highest impact as alternative prey. In a multiple-prey experiment, predators showed a similar pattern of preference for mosquito larvae over alternative prey, reflecting a significant (P < 0.05) niche overlap. The results suggest that, in a laboratory setting, these insect predators can effectively reduce mosquito density in the presence of multiple alternative prey. PMID- 23437889 TI - Complexation of triptycene-derived macrotricyclic polyether with paraquat derivatives, diquat, and a 2,7-diazapyrenium salt: guest-induced conformational changes of the host. AB - Complexation between a triptycene-derived macrotricyclic polyether containing two dibenzo-[30]-crown-10 cavities and different functionalized paraquat derivatives, diquat, and a 2,7-diazapyrenium salt in both solution and solid state was investigated in detail. It was found that depending on the guests with different terminal functional groups and structures, the macrotricyclic polyether could form 1:1 or 1:2 complexes with the guests in different complexation modes in solution and also in the solid state. Especially, the conformation of the macrotricyclic polyether was efficiently adjusted by the encapsulated guests, which was to some extent similar to substrate-induced fit of enzymes. Moreover, the binding and releasing of the guests in the complexes could be controlled by potassium ions. PMID- 23437888 TI - A NGS approach to the encrusting Mediterranean sponge Crella elegans (Porifera, Demospongiae, Poecilosclerida): transcriptome sequencing, characterization and overview of the gene expression along three life cycle stages. AB - Sponges can be dominant organisms in many marine and freshwater habitats where they play essential ecological roles. They also represent a key group to address important questions in early metazoan evolution. Recent approaches for improving knowledge on sponge biological and ecological functions as well as on animal evolution have focused on the genetic toolkits involved in ecological responses to environmental changes (biotic and abiotic), development and reproduction. These approaches are possible thanks to newly available, massive sequencing technologies-such as the Illumina platform, which facilitate genome and transcriptome sequencing in a cost-effective manner. Here we present the first NGS (next-generation sequencing) approach to understanding the life cycle of an encrusting marine sponge. For this we sequenced libraries of three different life cycle stages of the Mediterranean sponge Crella elegans and generated de novo transcriptome assemblies. Three assemblies were based on sponge tissue of a particular life cycle stage, including non-reproductive tissue, tissue with sperm cysts and tissue with larvae. The fourth assembly pooled the data from all three stages. By aggregating data from all the different life cycle stages we obtained a higher total number of contigs, contigs with blast hit and annotated contigs than from one stage-based assemblies. In that multi-stage assembly we obtained a larger number of the developmental regulatory genes known for metazoans than in any other assembly. We also advance the differential expression of selected genes in the three life cycle stages to explore the potential of RNA-seq for improving knowledge on functional processes along the sponge life cycle. PMID- 23437890 TI - Childhood granulomatous periorificial dermatitis with a good response to oral metronidazole. AB - Childhood granulomatous periorificial dermatitis (CGPD) is a condition included in the spectrum of rosacea and perioral dermatitis that affects prepubescent children. It is characterized by papular eruptions located around the mouth, nose, and eyes that histopathologically show a granulomatous pattern. We report a 9-year-old girl with CGPD who required treatment with an oral antibiotic. Oral metronidazole was administered because of its known efficacy in adult rosacea and its safety in children. The patient responded well to this therapy, showing resolution of the lesions. PMID- 23437891 TI - Pacing inducibility for atrial fibrillation: a test tested? PMID- 23437892 TI - A survey of tobacco dependence treatment guidelines in 121 countries. AB - AIMS: To report progress among Parties to the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in developing national tobacco treatment guidelines in accordance with FCTC Article 14 guideline recommendations. DESIGN: Cross-sectional study. SETTING: Electronic survey from December 2011 to August 2012; participants were asked to complete either an online or attached Microsoft Word questionnaire. PARTICIPANTS: One hundred and sixty-three of the 173 Parties to the FCTC at the time of our survey. MEASUREMENTS: The 51-item questionnaire contained 30 items specifically on guidelines. Questions covered the areas of guidelines writing process, content, key recommendations and other characteristics. FINDINGS: One hundred and twenty one countries (73%) responded. Fifty-three countries (44%) had guidelines, ranging from 75% among high-income countries to 11% among low-income countries. Nearly all guidelines recommended brief advice (93%), intensive specialist support (93%) and medications (96%), while 66% recommended quitlines. Fifty-seven percent had a dissemination strategy, 76% stated funding source and 68% had professional endorsement. CONCLUSION: Fewer than half of the Parties to the WHO FCTC have developed national tobacco treatment guidelines, but, where guidelines exist, they broadly follow FCTC Article 14 guideline recommendations. PMID- 23437894 TI - Glycine metabolism in leaves of Glycine max in 200 and 600-ppm CO2 environments. PMID- 23437893 TI - Synthesis and biological characterization of new aminophosphonates for mitochondrial pH determination by (31)P NMR spectroscopy. AB - A series of mitochondria targeted alpha-aminophosphonates combining a diethoxyphosphoryl group and an alkyl chain-connected triphenylphosphonium bromide tail were designed and synthesized, and their pH-sensitive (31)P NMR properties and biological activities in vitro and in vivo were evaluated. The results showed a number of these mito-aminophosphonates exhibiting pKa values fitting the mitochondrial pH range, short relaxation, and chemical shift parameters compatible with sensitive (31)P NMR detection, and low cytotoxicity on green algae and murine fibroblasts cell cultures. Of these, two selected compounds demonstrated to distribute at NMR detectable levels within the cytosolic and mitochondrial sites following their perfusion to isolated rat livers, with no detrimental effects on cell energetics and aerobic respiration. This study provided a new molecular scaffold for further development of in situ spectroscopic real-time monitoring of mitochondrion/cytosol pH gradients. PMID- 23437895 TI - Sistani population: a different spectrum of beta-thalassemia mutations from other ethnic groups of Iran. AB - This study aimed to characterize the molecular spectrum of beta-thalassemia (beta thal) mutations and evaluate the services available for prenatal diagnosis (PND) among the Sistani population of Iran. Mutations were analyzed with amplification refractory mutation system (ARMS), gap-polymerase chain reaction (gap-PCR), multiplex ligation-dependent probe amplification (MLPA) analysis and direct sequencing. Fetal diagnosis was also confirmed by linkage analysis. Over a 9-year period (2002-2011), 405 at-risk Sistani couples were referred for mutation analysis and/or PND. Of the referred couples, 18.5% had one to three affected children with beta-thal major (beta-TM) and the remainder had no children or were not married. Most of the couples (73.3%) lived in urban areas and the rate of consanguineous marriage was 76.8%. Twenty-one mutations were identified, of which the most frequent ones were IVS-I-5 (G>C) with a frequency of 74.1%, followed by codon 15 G>A (5.0%), codon -88 (C>T) (3.8%), IVS-II-1 (G>A) (3.4%), codons 8/9 (+G) (2.9%) and IVS-I-1 (G>T) (2.7%), which accounted for about 91.9% of the total beta-thal mutations for this region. Furthermore, fetal DNA was obtained from chorionic villus sampling (CVS) for 266 pregnant women and 68 (25.5%) fetuses were diagnosed as affected. In summary, beta-thal mutations are very heterogeneous and significantly different from those found in other parts of Iran and are similar to those of Pakistani and Indian populations. These results could greatly facilitate timely and accurate PND. PMID- 23437896 TI - The Mediterranean red alga Asparagopsis taxiformis has antifungal activity against Aspergillus species. AB - The red algae Asparagopsis taxiformis collected from the Straits of Messina (Italy) were screened for antifungal activity against Aspergillus species. EUCAST methodology was applied and extracts showed antifungal activity against A. fumigatus, A. terreus and A. flavus. The lowest minimum inhibitory concentrations observed were <0.15 mg ml(-1) and the highest were >5 mg ml(-1) for Aspergillus spp. tested. Agar diffusion assays confirmed antifungal activity of A. taxiformis extracts in Aspergillus species. PMID- 23437897 TI - Taking the testing effect beyond the college freshman: benefits for lifelong learning. AB - Formal learning is a lifelong pursuit that does not occur exclusively within universities. Accordingly, methods for improving long-term learning, including the well-established use of testing, should be examined for various ages of learners outside typical university settings to properly assess their usefulness. This study examined testing effects in 60 younger university students aged 18-25, 60 younger community adults aged 18-25, and 60 middle-aged to older community adults aged 55-65 at immediate and longer delays (2-day). All groups similarly benefited from testing at both delays, implying that testing can be a beneficial lifelong learning tool for a diversity of learners. PMID- 23437899 TI - Synergistic effects of encoding strategy and context salience on associative memory in older adults. AB - Older adults' deficits in memory for context and memory for inter-item associations are often assumed to be related, yet typically are examined in separate experiments. The present study combined associative recognition and list discrimination into a single task with conditions that varied in terms of item, pair, and context information, and independently manipulated context salience and encoding strategy between subjects in order to examine their effects on memory for associative information in young and older adults. Older adults' memory for pairs was found to be less affected than that of young adults by manipulations of context and associative information, but the age difference in context effects on pair memory was influenced by an interaction of encoding strategy and context salience. The results provide novel evidence that older adults' deficits in associative memory involve interactions between context and inter-item associations. PMID- 23437898 TI - Demographic predictors of cognitive change in ethnically diverse older persons. AB - The purpose of this study was to evaluate how demographic variables relate to cognitive change and address whether cross-sectional demographic effects on cognitive tests are mirrored in differences in longitudinal trajectories of cognitive decline. We hypothesized that race and ethnicity, education, and language of test administration would relate to cross-sectional status and that the rate of cognitive decline would differ among African Americans, Hispanics, and Caucasians, across levels of educational attainment, and according to linguistic background. Participants were 404 educationally, ethnically, and cognitively diverse older adults enrolled in an ongoing longitudinal study of cognition. Mixed-effects regression analysis was used to measure baseline status and longitudinal change in episodic memory, executive functioning, and semantic memory. Results showed that ethnicity and education were strongly associated with baseline scores, but were, at most, weakly associated with change in cognition over time after accounting for confounding variables. There was evidence that the episodic-memory scores of Spanish-speaking Hispanic participants with limited education underestimated their true abilities in the initial evaluation, which may reflect lack of familiarity with the testing environment. These results- consistent with other reports in the literature--suggest that cross-sectional effects of demographic variables on cognitive-test scores result from differences in life experiences that directly influence test performance and do not indicate greater disease effects on cognition in minorities and those with limited education. PMID- 23437900 TI - Preferences for choice across adulthood: age trajectories and potential mechanisms. AB - Across a variety of decision domains, older adults were found to desire fewer choice options than younger adults, but the age trajectory and underlying mechanisms of these effects remain unknown. The present study examined the pattern and correlates of age differences in choice set size preferences using self-report and behavioral measures. Self-reported choice set size preferences were assessed in a large-scale survey using an adult life span sample (N = 318, ages 18-90 years). A subset of younger and older adults (n = 109) also completed behavioral measures of choice preferences and information seeking. Based on prior research and theorizing on aging and decision making, we tested for a variety of possible covariates, including maximizing and decision-making self-efficacy. Combined results indicated that the age trend of choice set size preferences is linear, gradual, and domain-general. Findings also indicated a significant association between choice preferences and the extent of predecisional information search. Although age differences were evident in both self-report and behavioral measures, they were not explained by any of the covariates tested. We discuss the implications of these findings for research on aging and decision making, as well as public policy. PMID- 23437901 TI - Age-related differences in temporal and spatial dimensions of episodic memory performance before and after hundred days of practice. AB - Normal aging impairs the representation and integration (binding) of spatial and temporal context in episodic memory. We directly compare age differences in episodic memory in relation to processing spatial and temporal context. As part of the COGITO study, 101 younger and 103 older participants trained an object location serial recall task for 100 sessions. Training exacerbated the recall deficit of older relative to younger adults. Younger adults improved in recall performance on both spatial and temporal dimensions. In contrast, older adults improved on the spatial dimension only. Individual differences in pretest performance and change were positively correlated across dimensions among younger adults but negatively related among older adults. We conclude that older adults are impaired at simultaneously processing spatial and temporal context and preferentially process spatial at the expense of temporal context. PMID- 23437902 TI - Colloid interaction energies for physically and chemically heterogeneous porous media. AB - The mean and variance of the colloid interaction energy (Phi*) as a function of separation distance (h) were calculated on physically and/or chemically heterogeneous solid surfaces at the representative elementary area (REA) scale. Nanoscale roughness was demonstrated to have a significant influence on the colloid interaction energy for different ionic strengths. Increasing the roughness height reduced the magnitude of the energy barrier (Phimax*) and the secondary minimum (Phi2min*). Conversely, increasing the fraction of the solid surface with roughness increased the magnitude of Phimax* and Phi2min*. Our results suggest that primary minimum interactions tend to occur in cases where only a portion of the solid surface was covered with roughness (i.e., isolated roughness pillars), but their depths were shallow as a result of Born repulsion. The secondary minimum was strongest on smooth surfaces. The variance in the interaction energy was also a strong function of roughness parameters and h. In particular, the variance tended to increase with the colloid size, the magnitude of Phi*, the height of the roughness, and especially the size (cross-sectional area) of the heterogeneity. Nonzero values of the variance for Phi2min* implied the presence of a tangential component of the adhesive force and a resisting torque that controls immobilization and release for colloids at this location. Heterogeneity reduced the magnitude of Phi* in comparison to the corresponding homogeneous situation. Physical heterogeneity had a greater influence on mean properties of Phi* than similar amounts of chemical heterogeneity, but the largest reduction occurred on surfaces with both physical and chemical heterogeneity. The variance in Phi* tended to be higher for a chemically heterogeneous solid. PMID- 23437903 TI - Use of social stories to improve self-regulation in children with autism spectrum disorders. AB - A multiple baseline across participants design was used to evaluate the effects of Social Stories to help preschool-aged children with characteristics of Autism Spectrum Disorders (ASD) increase their engagement in functional behaviors and use sensory integrative-based strategies to promote self-regulation. Three children, 3-5 years old, from a self-contained preschool classroom were selected to participate in the study. The intervention package included reading individualized Social Stories that discussed desired behaviors and self regulation strategies. The researchers measured the percentage of intervals in which participants engaged in desired behaviors. The frequency of desired behaviors increased for all participants. The use of self-regulation strategies varied across participants. These findings suggest that the intervention was successful in increasing desired behaviors of the three children. Further research is recommended on the effectiveness of embedding sensory integrative strategies into Social Stories. Practitioners may consider the use of Social Stories as a tool to increase independence and encourage self-regulated behaviors in children with characteristics of ASD. PMID- 23437904 TI - Charge photogeneration in donor-acceptor conjugated materials: influence of excess excitation energy and chain length. AB - We investigate the role of excess excitation energy on the nature of photoexcitations in donor-acceptor pi-conjugated materials. We compare the polymer poly(2,6-(4,4-bis(2-ethylhexyl)-4H-cyclopenta[1,2-b;3,4-b']dithiophene) 4,7-benzo[2,1,3]thiadiazole) (PCPDTBT) and a short oligomer with identical constituents at different excitation wavelengths, from the near-infrared up to the ultraviolet spectral region. Ultrafast spectroscopic measurements clearly show an increased polaron pair yield for higher excess energies directly after photoexcitation when compared to the exciton population. This effect, already observable in the polymer, is even more pronounced for the shorter oligomer. Supported by quantum chemical simulations, we show that excitation in high-energy states generates electron and hole wave functions with reduced overlap, which likely act as precursors for the polaron pairs. Interestingly, in the oligomer we observe a lifetime of polaron pairs which is one order of magnitude longer. We suggest that this behavior results from the intermolecular nature of polaron pairs in oligomers. The study excludes the presence of carrier multiplication in these materials and highlights new aspects in the photophysics of donor-acceptor small molecules when compared to polymers. The former are identified as promising materials for efficient organic photovoltaics. PMID- 23437905 TI - Training caregivers: disabilities and dental hygiene. AB - OBJECTIVES: The purpose of the study was to measure the effectiveness of oral health education and training among caregivers. METHODS: Controlled study design. Participants were randomized from the sample n = 30. n = 14 participants in the experimental group and n = 10 in the control group. The experimental group received a lecture and hands-on training in oral hygiene procedures. The control group received a facilitated group discussion. Both groups received a pre-post test. RESULTS: Considering the two groups independently, using a paired t-test, the experimental group, n = 14 had a score difference of 0.0607 (P-value = 0.01) and the control group n = 10, had a score difference of 0.035 (P-value = 0.14). CONCLUSION: This study found that knowledge was improved among caregivers following the implementation of formal oral hygiene training. Although the control group also showed some improvements with the facilitated discussion, the results are not significant to say that both the formal training and the facilitated discussion are equally important in training caregivers effectively. PMID- 23437906 TI - Photodissociation and radiative association of HeH+ in the metastable triplet state. AB - We investigate the photodissociation of HeH(+) in the metastable triplet state as well as its formation through the inverse process, radiative association. In models of astrophysical plasmas, HeH(+) is assumed to be present only in the ground state, and the influence of the triplet state has not been explored. It may be formed by radiative association during collisions between a proton and metastable helium, which are present in significant concentrations in nebulae. The triplet state can also be formed by association of He(+) and H, although this process is less likely to occur. We compute the cross sections and rate coefficients corresponding to the photodissociation of the triplet state by UV photons from a central star using a wave packet method. We show that the photodissociation cross sections depend strongly on the initial vibrational state and that the effects of excited electronic states and nonadiabatic couplings cannot be neglected. We then calculate the cross section and rate coefficient for the radiative association of HeH(+) in the metastable triplet state. PMID- 23437907 TI - Decreased postoperative atrial fibrillation following cardiac transplantation: the significance of autonomic denervation. AB - BACKGROUND: Endocardial ablation approaches targeting the retroatrial cardiac ganglia to treat atrial fibrillation (AF) have been proposed. However, the potential value using this approach is unknown. Disruption of the autonomic inputs with orthotropic heart transplant (OHT) provides a unique opportunity to study the effects of autonomic innervation on AF genesis and maintenance. We hypothesized that due to denervation, the risk of postoperative AF would be lower following OHT compared to surgical maze even though both groups get isolation of the pulmonary veins. METHODS AND RESULTS: We reviewed 155 OHTs (mean age 52 +/- 11 years, 72% males) and used 1:1 age-, sex-, and date-of-surgery-matched two control groups from patients undergoing surgical maze or only coronary artery bypass grafting (CABG). Using conditional logistic regression we compared the odds of AF within 2 weeks following OHT versus controls. Postoperative AF occurred in 10/155 (6.5%) OHT patients. The conditional odds of postoperative AF were lower for OHT as compared to controls (vs maze: odds ratio [OR] 0.27 [95% confidence interval (CI) 0.13-0.57], vs CABG: OR 0.38 [0.17-0.81], P = 0.003; and on additional adjustment for left atrial enlargement, vs maze: OR 0.28 [0.13 0.60], vs CABG: OR 0.14 [0.04-0.47], P = 0.0009). CONCLUSIONS: Risk of postoperative AF is significantly lower with OHT as in comparison to surgical maze. As both surgeries entail isolation of the pulmonary veins but only OHT causes disruption of autonomic innervation, this observation supports a mechanistic role of autonomic nervous system in AF. The benefit of targeting the cardiac autonomic system to treat AF needs further investigation. PMID- 23437908 TI - Species delimitation in Cladonia (Ascomycota): a challenge to the DNA barcoding philosophy. AB - The lichen-forming fungal genus Cladonia is species-rich with approximately 500 described species. The accepted barcode for fungi (ITS rDNA) often fails in identifying Cladonia spp. In order to find other markers that, in combination with the ITS rDNA region can be used for species identification in Cladonia, we studied the loci IGS rDNA, ef1alpha, rpb2 and cox1. A total of 782 sequences from 36 species have been analyzed. PCR amplification success rate, intraspecific and interspecific genetic distance variation, calculated using the K2P model, and the correct identification percentage (PCI) were taken into account to assess possible barcode regions. The marker showing the least intraspecific genetic distance range was cox1, followed by ITS rDNA and ef1alpha. Of the five studied markers only cox1 showed a barcoding gap. The rpb2 locus showed the highest PCI values, but it was the most difficult to amplify. The highest correct identification rates using blast method were obtained with rpb2. PMID- 23437909 TI - Immediate effects of different schedules of somatostatin on portal pressure in patients with liver cirrhosis. AB - WHAT IS KNOWN AND OBJECTIVE: Somatostatin (SST) is used for the treatment of acute variceal bleeding based on its ability to decrease portal pressure and collateral blood flow. To date, no studies have focused on the immediate-early effects (between 1 and 30 min) of SST. The aim of this study was to compare the efficacy of different schedules of SST therapy with placebo on portal pressure in patients with portal hypertension treated with portal-azygous disconnection and to test whether an increase in bolus or infusion dose can improve the clinical efficacy of SST therapy. METHODS: Patients were treated with four different schedules: (a) standard dose (n = 11): one 250 MUg bolus + a continuous infusion of 250 MUg/h; (b) medium dose (n = 10): 500 MUg bolus + a continuous infusion of 250 MUg/h; (c) high dose (n = 10): 250 MUg bolus + a continuous infusion of 500 MUg/h; (d) control (n = 10): an injection of placebo (saline) followed by a placebo infusion. Following SST or placebo administration, portal pressure, central venous pressure (CVP), systemic blood pressure and heart rate (HR) were measured at 1, 3, 5, 7, 10 and 30 min. RESULTS AND DISCUSSION: The three schedules of SST induced a marked, rapid and highly significant decrease in portal pressure. The decline in portal pressure was moderate at 1 min (P < 0.040), achieved a peak effect at 5 min (P < 0.009) and remained decreased at 30 min. The effect of SST on portal pressure was significantly greater than placebo from 1 min after administration. There were no significant differences in portal pressure decrease between the three schedules of SST. The three schedules of SST and the placebo schedule did not induce significant changes in HR, systemic blood pressure and CVP. WHAT IS NEW AND CONCLUSION: This study shows that SST is effective in decreasing portal pressure within 30 min of administration in patients with liver cirrhosis. The clinical schedule used in this study was reasonable and safe. PMID- 23437910 TI - Synthesis, structure, and properties of Ln2Ru3Al15 (Ln = Ce, Gd): comparison with LnRu2Al10 and CeRu4(Al,Si)(15.58). AB - Ln2Ru3Al15 (Ln = Ce, Gd) have been synthesized, and the competition between the growth of Ce2Ru3Al15 and CeRu2Al10 has been studied. The structure of Ce2Ru3Al15 was modified from the previously reported Ce2Ru3Al15 structure, and the structure of Gd2Ru3Al15 was determined for the first time. The magnetic and transport properties of Ln2Ru3Al15 were measured and compared to the properties of LnRu2Al10. Gd2Ru3Al15 orders antiferromagnetically at 21.0 K with a spin reorientation at 4.1 K and has a positive paramagnetic Curie-Weiss temperature of 11.5(17) K, suggesting strong ferromagnetic interactions within the structure. Ce2Ru3Al15 displays two low-temperature magnetic transitions at 3.7 and 3.1 K, the first of which is believed to be an antiferromagnetic ordering, with a thetaN of -7(3) K and a reduced moment of 2.33(4) MUB/mol-Ce. Furthermore, the low temperature magnetic and transport properties display the effects of Kondo screening of the magnetic moments. While structurally related, the properties of Ce2Ru3Al15 do not display the same anomalous features observed in CeRu2Al10. PMID- 23437911 TI - Co-occurrence of cytomegalovirus-induced vanishing bile duct syndrome with papillary stenosis in HIV infection. AB - Jaundice in patients with AIDS can be a result of diverse conditions ranging from opportunistic infections to drug-related hepatotoxicity. With the advent of antiretroviral therapy (ART), the prevalence of AIDS cholangiopathy as a cause of jaundice has decreased; on the other hand, ART-related hepatotoxicity has become one of the commonest causes of jaundice in these patients. AIDS cholangiopathy is a rare condition of extrahepatic biliary obstruction in patients with advanced HIV infection, usually due to opportunistic infections. Vanishing bile duct syndrome (VBDS) is an acquired disorder characterized by progressive destruction and loss of interlobular bile ducts causing intrahepatic cholestasis. Herein, we report co-occurrence of fatal cytomegalovirus (CMV)-induced VBDS along with papillary stenosis, as a component of AIDS cholangiopathy, which to the best of our knowledge has not been documented earlier. This is perhaps the third case of VBDS in a patient with AIDS, and the second in association with CMV infection. VBDS in AIDS has a poor outcome, and liver transplantation may be considered only in a suitable candidate. PMID- 23437912 TI - Bile salt export pump deficiency: A de novo mutation in a child compound heterozygous for ABCB11. Laboratory investigation to study pathogenic role and transmission of two novel ABCB11 mutations. AB - Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal disorders. PFIC type 2 is due to mutation in ABCB11, the gene encoding the bile salt export pump (BSEP) protein. The aim of the study was to describe a child with a de novo mutation in a compound heterozygous for ABCB11 gene. We report a 1.7-year-old girl who presented with pruritus, jaundice and liver dysfunction of PFIC type 2. Immunohistochemistry and molecular analysis are described. Liver biopsy showed micronodular cirrhosis and immunohistochemical staining for BSEP, the protein encoded by ABCB11, displayed a patchy and faint reactivity. Molecular analysis revealed two novel mutations of ABCB11. We give details that one mutation is transmitted by the mother while the second one appears a de novo mutation as mutations or a potential mosaicism were ruled out in the natural father. We further speculate that the ABCB11 mutations do not prevent BSEP glycoprotein to be expressed at the canalicular pole of hepatocytes, but interfere with its ability to export bile salts. As in most instances, mutational analysis is performed following the histochemical demonstration of an undetectable BSEP on liver biopsy specimen. This case stresses that clinical PFIC with an attenuated rather than absent BSEP immunostaining can still be due to ABCB11 mutations presumably encoding a functionally deficient protein. PMID- 23437913 TI - Neuroendocrine differentiation in embryonal type hepatoblastoma. AB - Hepatoblastoma, a malignant tumor which arises occasionally in older children but very rarely in adults, exhibits divergent differentiation with embryonal cells, fetal hepatocytes and immature elements. This report describes an embryonal type hepatoblastoma with neuroendocrine differentiation in a 16-year-old patient, which was diagnosed postoperatively. Clinical and radiologic work-up failed to reveal a primary gastrointestinal malignancy and no primary lesions were detected in any other organ. This feature of hepatoblastoma is considered to be a multidirectional differentiation of the small epithelial or stem cells of the liver. At 2-year follow up, the patient remains symptom-free, with normal laboratory and diagnostic imaging studies, and no recurrent or metastatic disease identified. PMID- 23437914 TI - Ulcerative fungal keratitis in a Brown Swiss cow. AB - An 11-year-old Brown Swiss cow was referred to the Farm Animal Department of the Veterinary Teaching Hospital in Zurich, Switzerland, because of lateral recumbency due to puerperal hemolytic anemia. The animal had developed enophthalmos due to dehydration at the time of presentation. Two days after hospitalization, the cow showed blepharospasm and epiphora of the right eye. Ophthalmic examination of the right eye revealed a fluorescein-positive, paraxial, superficial corneal ulcer with focal edema, and mild superficial neovascularization. White corneal stromal infiltrates were seen at the edges of the ulcer bed. After initial topical treatment with an antibiotic ointment (Neomycin 3.5 mg/g, Bacitracin 250 IU/g) three times a day, an increase in corneal infiltrates was noted on re-examination 2 days later. Several fluorescein negative, punctate, stromal, white opacities were seen dorsal to the ulcer. Cytology demonstrated the presence of fungal hyphae. Topical treatment with 2% miconazole ointment and 0.36% K-EDTA eye drops six times daily and four times daily, respectively, from the second day and continued antibiotics three times daily resolved the clinical symptoms within 6 days. Fungal culture identified the fungal organism as Eurotium amstelodami. PMID- 23437915 TI - Timing of in situ visual information pick-up that differentiates expert and near expert anticipation in a complex motor skill. AB - The timing of visual information pick-up for visual anticipation was examined by comparing the capability of multiple skill groups, expert and near-expert karate athletes and novices, to block attacks using an in situ temporal occlusion paradigm. Participants stood facing a karate opponent and then attempted to block attacks (kicks and punches), whilst their vision of attacks was occluded: (a) prior to onset of opponent motion (O1), (b) after preparatory head movement (O2), and (c) after initiation of the attacking motion (O3). A no occlusion control condition provided complete vision of attacks (O4). Results revealed that expert anticipation was not significantly different to that of near-experts at O1, but was significantly different to the other group across O2-O4. Expert anticipation, however, was significantly above chance across all occlusion conditions, but near experts performed above chance at O3 and O4, whilst novices were better than chance at O4. Unexpectedly, unique evidence was found that expert anticipation could be differentiated from near-expert anticipation in the earliest occlusion condition, where it was found that only experts were capable of using visual information from a static opponent to anticipate and block attacks above chance. The findings further understanding of expert visual anticipation to guide motor skills beyond existing expert-novice comparisons. PMID- 23437916 TI - Acquired epidermodysplasia verruciformis: a comprehensive review and a proposal for treatment. AB - BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by immunologic abnormalities, disseminated human papilloma virus infection, and early development of skin cancers. Acquired forms have been rarely reported and usually occur with immunosuppression. The therapeutic management of the acquired forms is not standardized, and several therapies have been tried, with variable outcomes. OBJECTIVES: To provide updated clinical and experimental information on the treatment of acquired EV. METHODS: A Medline literature search was performed for relevant Medical Subject Heading terms, reviewing publications on strategies for management of acquired EV. We also report a case successfully treated using a combination of photodynamic therapy and oral retinoids. CONCLUSION: Data from the literature show that a standardized approach to this condition is lacking; the combination treatment chosen in our case may be proposed because it led to an excellent clinical outcome and a long-lasting remission. PMID- 23437917 TI - The precision of the hominid timescale estimated by relaxed clock methods. AB - The chronological scenario of the evolution of hominoid primates has been thoroughly investigated since the advent of the molecular clock hypothesis. With the availability of genomic sequences for all hominid genera and other anthropoids, we may have reached the point at which the information from sequence data alone will not provide further evidence for the inference of the hominid evolution timescale. To verify this conjecture, we have compiled a genomic data set for all of the anthropoid genera. Our estimate places the Homo/Pan divergence at approximately 7.4 Ma, the Gorilla lineage divergence at approximately 9.7 Ma, the basal Hominidae divergence at 18.1 Ma and the basal Hominoidea divergence at 20.6 Ma. By inferring the theoretical limit distribution of posterior densities under a Bayesian framework, we show that it is unlikely that lengthier alignments or the availability of new genomic sequences will provide additional information to reduce the uncertainty associated with the divergence time estimates of the four hominid genera. A reduction of this uncertainty will be achieved only by the inclusion of more informative calibration priors. PMID- 23437918 TI - Response to Kute: 'facilitators to national kidney paired donation program'. PMID- 23437919 TI - Probing and controlling photothermal heat generation in plasmonic nanostructures. AB - In the emerging field of thermoplasmonics, Joule heating associated with optically resonant plasmonic structures is exploited to generate nanoscale thermal hotspots. In the present study, new methods for designing and thermally probing thermoplasmonic structures are reported. A general design rationale, based on Babinet's principle, is developed for understanding how the complementary version of ideal electromagnetic antennae can yield efficient nanoscale heat sources with maximized current density. Using this methodology, we show that the diabolo antenna is more suitable for heat generation compared with its more well-known complementary structure, the bow-tie antenna. We also demonstrate that highly localized and enhanced thermal hot spots can be realized by incorporating the diabolo antenna into a plasmonic lens. Using a newly developed thermal microscopy method based on the temperature-dependent photoluminescence lifetime of thin-film thermographic phosphors, we experimentally characterize the thermal response of various antenna and superstructure designs. Data from FDTD simulations and the experimental temperature measurements confirm the validity of the design rationale. The thermal microscopy technique, with its robust sensing method, could overcome some of the drawbacks of current micro/nanoscale temperature measurement schemes. PMID- 23437920 TI - Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction. AB - Nuclear receptor binding to coactivator proteins is an obligate first step in the regulation of gene transcription. Nuclear receptors preferentially bind to an LXXLL peptide motif which is highly conserved throughout the 300 or so natural coactivator proteins. This knowledge has shaped current understanding of this fundamental protein-protein interaction, and continues to inspire the search for new drug therapies. However, sequence specificity beyond the LXXLL motif and the molecular functioning of flanking residues still requires urgent addressing. Here, ribosome display has been used to reassess the estrogen receptor for new and enlarged peptide recognition motifs, leading to the discovery of a potent and highly evolved PXLXXLLXXP binding consensus. Molecular modeling and X-ray crystallography studies have provided the molecular insights on the role of the flanking prolines in priming the length of the alpha-helix and enabling optimal interactions of the alpha-helix dipole and its surrounding amino acids with the surface charge clamp and the receptor activation function 2. These findings represent new structural parameters for modulating the nuclear receptor coactivator interaction based on linear sequences of proteinogenic amino acids and for the design of chemically modified inhibitors. PMID- 23437921 TI - The antimanic-like effect of phenytoin and carbamazepine on methylphenidate induced hyperlocomotion: role of voltage-gated sodium channels. AB - The objective of this study was to verify whether phenytoin modifies methylphenidate-induced hyperlocomotion, an animal model for screening antimanic like drugs, and also evaluate the effect of veratrine, a voltage-gated sodium channel opener, pretreatment on the effect of phenytoin in this model. Carbamazepine was used as a positive control. Methylphenidate (5 mg/kg, s.c.) increased open-field locomotion, and phenytoin (5-10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.) blocked this effect. Veratrine (0.4 mg/kg, s.c.) pretreatment reversed the effects of phenytoin (10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.). Phenytoin (1-50 mg/kg, i.p.) and carbamazepine (10-20 mg/kg i.p.) alone did not change spontaneous locomotor activity. These results indicate that voltage-gated sodium channels play an important role in antimanic-like effects of phenytoin and carbamazepine on psychostimulant-induced hyperlocomotion model. PMID- 23437922 TI - External correlates of the Personality Assessment Inventory higher order structures. AB - This brief report explores the external correlates of 2 higher order structures of the Personality Assessment Inventory (PAI; Morey, 1991, 2007); Hoelzle and Meyer's (2009a, 2009b) PAI Components and Hopwood and Moser's (2011) Internalizing and Externalizing Dimensions. Scores from these higher order structures were correlated with life-event data including education, marital status, employment, suicide attempts, psychiatric hospitalizations, trauma, medical problems, hallucinations, paranoid ideation, drug abuse, alcohol abuse, and arrest. Although some differences were noted, the results showed that both Hoelzle and Meyer's Components and Hopwood and Moser's Dimensions were meaningfully correlated with a wide range of life outcomes in a conceptually consistent manner. Overall, these findings provide support for the utility of these higher order variables. PMID- 23437923 TI - Rethinking stress: the role of mindsets in determining the stress response. AB - This article describes 3 studies that explore the role of mindsets in the context of stress. In Study 1, we present data supporting the reliability and validity of an 8-item instrument, the Stress Mindset Measure (SMM), designed to assess the extent to which an individual believes that the effects of stress are either enhancing or debilitating. In Study 2, we demonstrate that stress mindsets can be altered by watching short, multimedia film clips presenting factual information biased toward defining the nature of stress in 1 of 2 ways (stress-is-enhancing vs. stress-is-debilitating). In Study 3, we demonstrate the effect of stress mindset on physiological and behavioral outcomes, showing that a stress-is enhancing mindset is associated with moderate cortisol reactivity and high desire for feedback under stress. Together, these 3 studies suggest that stress mindset is a distinct and meaningful variable in determining the stress response. PMID- 23437924 TI - "Impulsivity": relations between self-report and behavior. AB - The trait of "impulsivity" is difficult to place within a personality framework due to the many potential pathways to impulsive behavior and the lack of consensus regarding the structure of the trait(s). This lack of consensus also hinders systematic investigation into relations between "impulsivity" and its behavioral manifestations. Undergraduates (Sample 1 N = 507) completed a battery of self-report measures, all purporting to assess trait "impulsivity"; a subset (n = 408) and Sample 2 (N = 388) also completed a retrospective questionnaire about specific behaviors they may have engaged in over the past year, and another subset of Sample 1 agreed to complete (n = 208) and actually completed (n = 152) a 2-week prospective measure of impulsive behaviors. Finally, a subset of Sample 1 (n = 321) and Sample 2 completed an omnibus self-report inventory in a follow up study. Structural equation modeling confirmed a 3-factor structure of what we call impulsigenic traits-traits that are manifested in impulsive behavior. This finding is consistent with previous research and supports the growing consensus that "impulsivity" is a colloquial label attached to a group of distinct traits that have phenotypically similar behavioral manifestations. Each of these impulsigenic traits relates differentially to impulsive behavior and to broad temperamental dimensions. The results also show clear 2-factor structures of both daily and less frequent (yearly/semiyearly) impulsive behaviors. Finally, a unique method of data collection permitted an investigation of relations between the impulsigenic and other personality traits and observed behaviors, demonstrating the predictive utility of personality traits to discrete, in situ behaviors. PMID- 23437925 TI - Sobering stories: narratives of self-redemption predict behavioral change and improved health among recovering alcoholics. AB - The present research examined whether the production of a narrative containing self-redemption (wherein the narrator describes a positive personality change following a negative experience) predicts positive behavioral change. In Study 1, we compared the narratives of alcoholics who had maintained their sobriety for over 4 years with those of alcoholics who had been sober 6 months or less. When describing their last drink, the former were significantly more likely to produce a narrative containing self-redemption than the latter. In Study 2, we examined the relation between the profession of self-redemption and behavioral change using a longitudinal design, by following the newly sober alcoholics from Study 1 over time. Although indistinguishable at initial assessment, newly sober alcoholics whose narratives included self-redemption were substantially more likely to maintain sobriety in the following months, compared to newly sober alcoholics who produced nonredemptive narratives; 83% of the redemptive group maintained sobriety between assessments, compared to 44% of nonredemptive participants. Redemptive participants in Study 2 also demonstrated improved health relative to the nonredemptive group. In both studies, the effects of self redemption on sobriety and health held after controlling for relevant personality traits, alcohol dependence, recovery program involvement, initial physical and mental health, and additional narrative themes. Collectively, these results suggest that the production of a self-redemptive narrative may stimulate prolonged behavioral change and thus indicate a potentially modifiable psychological process that exhibits a major influence on recovery from addiction. PMID- 23437926 TI - Evidence for the involvement of descending pain-inhibitory mechanisms in the antinociceptive effect of hecogenin acetate. AB - Hecogenin is a sapogenin present in the leaves of species from the Agave genus, with a wide spectrum of reported pharmacological activities. The present study was undertaken to evaluate whether hecogenin acetate (1) has antinociceptive properties and to determine its mechanism of action. The nociceptive threshold was evaluated using the tail flick test in mice. Mice motor performance was evaluated in a Rotarod test. By using Fos expression as a marker of neural activation, the involvement of the periaqueductal gray in 1-induced antinociception was evaluated. Intraperitoneal administration of 1 (5-40 mg/kg) produced a dose-dependent increase in the tail flick latency time compared to vehicle-treated group (p < 0.01). Mice treated with 1 (40 mg/kg) did not show motor performance alterations. The antinociception of 1 (40 mg/kg) was prevented by naloxone (nonselective opioid receptor antagonist; 5 mg/kg), CTOP (MU-opioid receptor antagonist; 1 mg/kg), nor-BNI (kappa-opioid receptor antagonist; 0.5 mg/kg), naltrindole (delta-opioid receptor antagonist; 3 mg/kg), or glibenclamide (ATP-sensitive K(+) channel blocker; 2 mg/kg). Systemic administration of 1 (5-40 mg/kg) increased the number of Fos positive cells in the periaqueductal gray. The present study has demonstrated for the first time that 1 produces consistent antinociception mediated by opioid receptors and endogenous analgesic mechanisms. PMID- 23437927 TI - Impact of using a telescoping-support catheter system for left ventricular lead placement on implant success and procedure time of cardiac resynchronization therapy. AB - BACKGROUND: Proper positioning of the left ventricular (LV) lead improves clinical outcomes and survival in patients receiving cardiac resynchronization therapy (CRT). Techniques of LV lead insertion using contrast injection and a telescoping system of delivery catheters to support advancement of the lead into the target branch may allow more efficient, targeted lead placement. We sought to evaluate the impact of an LV lead implant approach using telescoping-support catheters (group TS) on success rate, lead location, and procedural time compared to standard over-the-wire implant techniques (group OTW). METHODS: Four hundred thirty-seven consecutive patients undergoing CRT implantation were divided into group TS (n = 105) or group OTW (n = 332) based upon a review of the operative technique used for LV lead implantation. The primary outcome was success of LV lead implantation at the index procedure. Secondary endpoints included optimal positioning of the LV lead and reduction in procedural fluoroscopy time. RESULTS: Failed LV lead placement was lower (1.9% vs 8.1%, P = 0.02) and optimal lead positioning was achieved more often for group TS than group OTW (87% vs 75%, P = 0.01). In addition, there were significantly shorter fluoroscopy times for group TS versus group OTW (29.6 minutes vs 41.9 minutes, P < 0.01). CONCLUSION: A CRT implant approach using contrast injection and a telescoping-support catheter system results in fewer failed LV lead implants, improved LV lead location, and shorter procedure times. PMID- 23437928 TI - The test of time. PMID- 23437929 TI - Balance of coordination and hydrophobic interaction in the formation of bilayers in metal-coordinated surfactant mixtures. AB - Metal-ligand coordination and hydrophobic interaction are two significant driving forces in the aggregation of mixtures of M(n+) surfactants and alkyldimethylamine oxide (CnDMAO) in aqueous solutions. The coordinated systems exhibit rich aggregation behavior. This study investigated the effect of M(n+) ions (Zn(2+), Ca(2+), Ba(2+), Al(3+), Fe(3+), La(3+), Eu(3+), and Tb(3+)) and hydrophobic chains (hydrocarbon and fluorocarbon) on the formation of metal-coordinated bilayers. We found that fluorocarbon chains and branched hydrocarbon chains are preferable to the corresponding linear hydrocarbon chains for the formation of an Lalpha phase. Moreover, Lalpha phases formed by fluorocarbon chains exhibited higher viscoelasticity than ones formed by the hydrocarbons, and the bilayers formed by branched chains were rather flexible, revealing obvious undulation. The construction of bilayers was also strongly affected by metal ions due to their variable coordination ability with CnDMAO. Our results contribute to the understanding of the formation of metal-coordinated bilayers, which is driven by the interplay of noncovalent forces. PMID- 23437930 TI - Histology of saphenous veins after treatment with the ClariVein(r) device - an ex vivo experiment. AB - BACKGROUND: Endovenous treatment modalities are used increasingly to treat varicose veins. The ClariVein(r) catheter is a new endoluminal mechanico-chemical obliteration technique which can be used without tumescent anesthesia. It is still unclear what changes the mechanical tip of the catheter has on the walls of the vein. PATIENTS AND METHODS: Five great saphenous vein specimens were obtained atraumatically by crossectomy. Then the veins were treated ex vivo with the ClariVein(r) catheter without sclerotherapy. The activated catheter rotating tip (3 500 U/min) was steadily withdrawn at 1-2 mm per second. Subsequently, histological and immunohistochemical investigations of treated (cv) and untreated specimens (plain) were performed. A 4-point score was calculated to compare the results. RESULTS: The mechanical part of the catheter caused a subtle incomplete destruction of the endothelium (endothelium cv: 2.2 vs. plain: 1, p = 0.04). Changes in the media or adventitia were not seen. Immunohistochemical presentation of the endothelium of the intima was demonstrated with antibodies against CD31 (cv: 3.4 vs. plain: 2.8), CD34 (cv: 3.8 vs. plain: 3.2) and factor VIII (cv: 2.2 vs. plain: 1, p = 0,004). CONCLUSIONS: The mechanical part of the ClariVein(r) catheter caused a subtle incomplete destruction of endothelium, which was confirmed histologically and immunohistochemically. The reduced expression of factor VIII in the treated vein could be caused by the release of preformed factor VIII granules due to the minimal mechanical irritation. PMID- 23437932 TI - Microscopic anterior clinoidectomy with micro-rongeurs for a superior projecting paraclinoid internal carotid artery aneurysm: a technical note. AB - Anterior clinoidectomy is an essential manoeuvre for clipping paraclinoid internal carotid artery (ICA) aneurysms. However, the use of a drill or an ultrasonic bone curette in an anterior clinoidectomy involves a high risk for heat or mechanical injury of the superior projecting paraclinoid aneurysm. We report our technique for microscopic anterior clinoidectomy performed only using a micro-rongeur. The case of a superior projecting paraclinoid ICA aneurysm is presented. The anterior clinoid process was removed with our specially crafted micro-rongeurs, while we observed the extradural and intradural routes under a microscope. The aneurysm was completely clipped without any resulting neurological deficits. This technique can be safely used for paraclinoid ICA aneurysms, especially for superiorly projecting aneurysms. PMID- 23437931 TI - BMP-7 attenuates TGF-beta1-induced fibroblast-like differentiation of rat dermal papilla cells. AB - Dermal papilla cells (DPCs) show phenotypic plasticity during wound healing. The multipotency of DPCs is well recognized, but the signaling pathways that regulate the differentiation of these cells into fibroblasts are poorly understood. A preliminary experiment showed that transforming growth factor beta1 (TGF-beta1) can induce DPCs to differentiate into fibroblast-like cells, which suggests that DPCs may be a source of wound-healing fibroblasts. Bone morphogenetic protein-7 (BMP-7), a member of the TGF-beta superfamily, can prevent and reverse fibrosis by counteracting the TGF-beta1-mediated profibrotic effect. To determine whether BMP-7 attenuates the TGF-beta1-induced differentiation of DPCs into fibroblasts, we established an in vitro system for DPC differentiation and recorded the gene expression patterns that distinguished DPCs from fibroblasts. The proportion of fibroblast-like cells was significantly enhanced in DPCs treated with TGF-beta1, as evidenced by immunocytochemistry, flow cytometry, quantitative real-time reverse transcriptase polymerase chain reaction, and Western blot analysis. BMP-7 and TGF-beta1 administration substantially decreased fibroblast-like differentiation, indicating inhibition of TGF-beta1-induced differentiation. The antagonistic BMP-7- and TGF-beta1-activated signaling pathways can be used to promote wound healing or suppress hypertrophic scarring. PMID- 23437933 TI - Uptake and effectiveness of a community pharmacy intervention programme to improve asthma management. AB - WHAT IS KNOWN AND OBJECTIVE: Pharmacists frequently see patients with asthma in the community who have suboptimal management. This study aimed to compare the uptake and effectiveness of pharmacist-initiated mailed and face-to-face interventions for patients whose asthma may not be well managed. METHODS: Seventy one community pharmacies in South Australia, Tasmania and Victoria (Australia) installed a software application that data-mined dispensing records, generating a list of patients who had received six or more asthma reliever inhalers in the preceding 12 months. The pharmacists were randomized, by pharmacy, to perform either a mailed or face-to-face intervention, whereby these patients received educational material and a referral to their general practitioner (GP) for an asthma management review. Matching patients from each pharmacy were also randomly assigned to a control group for 'usual care'. RESULTS AND DISCUSSION: A total of 1483 patients were identified and grouped as follows: 510 (34.4%) mailed intervention, 480 (32.4%) face-to-face intervention and 493 (33.2%) controls. Significantly fewer face-to-face interventions were offered than mailed interventions (66.6% vs. 89.4%, respectively; chi(2) = 64.2, P < 0.0001). There were significant improvements in the preventer-to-reliever ratio after the intervention period (P < 0.0001) in each group. In a per-protocol analysis, the magnitude of improvement in the face-to-face intervention group was greater than in the mailed intervention group. The reverse was true in an intention-to-treat analysis. The improvement in the P : R ratios was mainly due to significant decreases in reliever usage. WHAT IS NEW AND CONCLUSION: Community pharmacy dispensing records can effectively identify patients with suboptimal asthma management, who can then be referred to their GP for review. Time constraints in busy pharmacies may limit the uptake and effectiveness of face-to-face interventions in the 'real world' setting, making mailed interventions an attractive option. PMID- 23437934 TI - Antiferromagnetic spin correlations between corner-shared [FeO5]7- and [FeO6]9- units, in the novel iron-based compound: BaYFeO4. AB - A novel quaternary compound in the Ba-Y-Fe-O phase diagram was synthesized by solid-state reaction and its crystal structure was characterized using powder X ray diffraction. The crystal structure of BaYFeO4 consists of a unique arrangement of Fe(3+) magnetic ions, which is based on alternate corner-shared units of [FeO5](7-) square pyramids and [FeO6](9-) octahedra. This results in the formation of stairwise channels of FeO polyhedra along the b crystallographic axis. The structure is described in an orthorhombic crystal system in the space group Pnma with lattice parameters a = 13.14455(1) A, b = 5.694960(5) A, and c = 10.247630(9) A. The temperature-dependent magnetic susceptibility data reveal two antiferromagnetic (AFM) transitions at 33 and 48 K. An upturn in the magnetic susceptibility data above these transitions is observed, which does not reach its maximum even at 390 K. The field-dependent magnetization data at both 2 and 300 K show a nearly linear dependence and do not exhibit significant hysteresis. Heat capacity measurements between 2 and 200 K reveal only a broad anomaly without any indication of long-range ordering. The latter data set is not in good agreement with the magnetic susceptibility data, which makes it difficult to exactly determine the magnetic ground state of BaYFeO4. Accordingly, a temperature dependent neutron diffraction study is in order, which will enable resolving this issue. The theoretical study of the relative strengths of magnetic exchange interactions along various possible pathways, using extended Huckel spin dimer analysis, shows that only interactions between square pyramidal and octahedral centers are significant, and among them, the intrachannel correlations are stronger than interchannel interactions. This is the first physical property study in such a magnetic ion substructure. PMID- 23437935 TI - Defence responses regulated by jasmonate and delayed senescence caused by ethylene receptor mutation contribute to the tolerance of petunia to Botrytis cinerea. AB - Ethylene and jasmonate (JA) have powerful effects when plants are challenged by pathogens. The inducible promoter-regulated expression of the Arabidopsis ethylene receptor mutant ethylene-insensitive1-1 (etr1-1) causes ethylene insensitivity in petunia. To investigate the molecular mechanisms involved in transgenic petunia responses to Botrytis cinerea related to the ethylene and JA pathways, etr1-1-expressing petunia plants were inoculated with Botrytis cinerea. The induced expression of etr1-1 by a chemical inducer dexamethasone resulted in retarded senescence and reduced disease symptoms on detached leaves and flowers or intact plants. The extent of decreased disease symptoms correlated positively with etr1-1 expression. The JA pathway, independent of the ethylene pathway, activated petunia ethylene response factor (PhERF) expression and consequent defence-related gene expression. These results demonstrate that ethylene induced by biotic stress influences senescence, and that JA in combination with delayed senescence by etr1-1 expression alters tolerance to pathogens. PMID- 23437936 TI - Non-viral gene delivery methods. AB - Gene delivery has attracted increasing interest as a highly promising therapeutic method to treat various diseases, including both genetic and acquired disorders. Viral-vectors based gene delivery can achieve higher transduction efficiency and long-term gene expression, but they may be associated with some shortcomings, such as immunogenicity, carcinogenicity, poor target cell specificity, inability to transfer large size genes and high costs. Non-viral approaches show high potential due to advantages of relative safety, ability to transfer large size gene, less toxicity and easiness for preparation etc. However, the clinical application of non-viral methods is still restricted by some limitations including low transfection efficiency and poor transgene expression. In order to improve gene transfer efficacy, a lot of efforts have been made in the past years, and numerous gene carriers and techniques have been developed. In this review, we summarized the features, drawbacks and prospects of existing and emerging non-viral gene delivery methods. PMID- 23437937 TI - Cell sheet technology for heart failure. AB - Heart failure is a life threatening disorder in worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. This review article provides summary about recent basical and clinical advances about myocardial regeneration induced by bioengineered cardiac tissue. PMID- 23437938 TI - Modular pyridine synthesis from oximes and enals through synergistic copper/iminium catalysis. AB - We describe here a [3+3]-type condensation reaction of O-acetyl ketoximes and alpha,beta-unsaturated aldehydes that is synergistically catalyzed by a copper(I) salt and a secondary ammonium salt (or amine). This redox-neutral reaction allows modular synthesis of a variety of substituted pyridines under mild conditions with tolerance of a broad range of functional groups. The reaction is driven by a merger of iminium catalysis and redox activity of the copper catalyst, which would initially reduce the oxime N-O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediate to the pyridine product. PMID- 23437939 TI - Minimal plus one point designs for testing lack of fit for some sigmoid curve models. AB - D-optimal designs for nonlinear models are often minimally supported. They have been frequently criticized for their inability to test for lack of fit. We construct alternative designs to address this issue for some commonly used sigmoid curves, including logistic, probit, and Gompertz models with two, three, or four parameters. For each model, we compare five nonminimally supported designs in terms of their efficiency, and propose designs that are both statistically efficient and practically convenient for practitioners. PMID- 23437940 TI - An equivalence test for the comparison between a test drug and placebo in human abuse potential studies. AB - Statistical methodologies for human abuse potential studies are rarely evaluated. Human abuse potential studies assess whether test drugs produce positive and negative subjective responses on abuse-related measures using volunteers with histories of recreational drug use. These studies typically have a randomized, double-blind, placebo- and positive-controlled crossover design with at least four treatments: placebo, at least two doses of a test drug, and at least one dose of a positive control drug (a drug with known abuse potential). This article proposes a new test for assessing whether a test drug produces data indicative of abuse potential when compared to placebo. PMID- 23437941 TI - Strength of evidence of noninferiority trials with the two confidence interval method with random margin. AB - This article deals with the dependency(ies) of noninferiority test(s) when the two confidence interval method is employed. There are two different definitions of the two confidence interval method. One of the objectives of this article is to sort out some of the confusion in these two different definitions. In the first definition the two confidence interval method is considered as the fixed margin method that treats a noninferiority margin as a fixed constant after it is determined based on historical data. In this article the method is called the two confidence interval method with fixed margin. The issue of the dependency(ies) of noninferiority test(s) does not occur in this case. In the second definition the two confidence interval method incorporates the uncertainty associated with the estimation for the noninferiority margin. In this article the method is called the two confidence interval method with random margin. The dependency(ies) occurs, because the two confidence interval method(s) with random margin shares the same historical data. In this article we investigate how the dependency(ies) affects the unconditional and conditional across-trial type I error rates. PMID- 23437942 TI - A comparison model for measuring individual agreement. AB - This article proposes a general comparison model for assessing individual agreement of k >= 2 raters evaluating n subjects with m >= 2 replicated readings. Users can explore total-rater agreement relative to intrarater agreement where any subset of the k raters can be selected in the numerator and denominator. Users are also allowed to compare intrarater agreement among selected raters. Based on the ratio of mean squared deviations (MSDs), two comparative agreement indices, total-intra ratio (TIR) and intra-intra ratio (IIR), are proposed. The TIR is a noninferiority assessment such that the differences of individual readings from different raters cannot be inferior by a prespecified margin to the differences of the replicated readings within raters. TIR can be used whether a reference exists or not. The method used by the Food and Drug Administration (FDA) for evaluating individual bioequivalence under relative scale becomes the special case of our approach. The IIR is a classical assessment such that the precision of selected raters can be better than; equal to; or worse than that of other raters. The estimation and statistical inference of TIR and IIR are obtained through GEE methodology. PMID- 23437943 TI - A more powerful test based on ratio distribution for retention noninferiority hypothesis. AB - Rothmann et al. ( 2003 ) proposed a method for the statistical inference of fraction retention noninferiority (NI) hypothesis. A fraction retention hypothesis is defined as a ratio of the new treatment effect verse the control effect in the context of a time to event endpoint. One of the major concerns using this method in the design of an NI trial is that with a limited sample size, the power of the study is usually very low. This makes an NI trial not applicable particularly when using time to event endpoint. To improve power, Wang et al. ( 2006 ) proposed a ratio test based on asymptotic normality theory. Under a strong assumption (equal variance of the NI test statistic under null and alternative hypotheses), the sample size using Wang's test was much smaller than that using Rothmann's test. However, in practice, the assumption of equal variance is generally questionable for an NI trial design. This assumption is removed in the ratio test proposed in this article, which is derived directly from a Cauchy-like ratio distribution. In addition, using this method, the fundamental assumption used in Rothmann's test, that the observed control effect is always positive, that is, the observed hazard ratio for placebo over the control is greater than 1, is no longer necessary. Without assuming equal variance under null and alternative hypotheses, the sample size required for an NI trial can be significantly reduced if using the proposed ratio test for a fraction retention NI hypothesis. PMID- 23437944 TI - Simultaneous confidence intervals of risk differences in stratified paired designs. AB - In stratified matched-pair studies, risk difference between two proportions is one of the most frequently used indices in comparing efficiency between two treatments or diagnostic tests. This article presents five simultaneous confidence intervals and two bootstrap simultaneous confidence intervals for risk differences in stratified matched-pair designs. The proposed confidence intervals are evaluated with respect to their coverage probabilities, expected widths, and ratios of the mesial noncoverage to noncoverage probability. Empirical results show that (1) hybrid simultaneous confidence intervals outperform nonhybrid simultaneous confidence intervals; (2) hybrid simultaneous confidence intervals based on median estimator outperform those based on maximum likelihood estimator; and (3) hybrid simultaneous confidence intervals incorporated with Wilson score and Agresti coull intervals and the bootstrap t-percentile simultaneous interval based on median unbiased estimators behave satisfactorily for small to large sample sizes in the sense that their empirical coverage probabilities are close to the prespecified nominal confidence level, and their ratios of the mesial noncoverage to noncoverage probabilities lie in [0.4,0.6] and are hence recommended. Real examples from clinical studies are used to illustrate the proposed methodologies. PMID- 23437945 TI - The type II error probability of a group sequential test of efficacy and futility, and considerations for power and sample size. AB - For a clinical trial incorporating a group sequential test that allows early stopping for efficacy or futility (GSTEF), the primary hypothesis concerns efficacy. However, the type II error probability of the tests of efficacy is neither specified nor known. The type II error probability of a GSTEF is partitioned into the sum of its component type II error probabilities of futility and efficacy. This partitioning provides transparency, allowing researchers flexibility to set these component error probabilities directly and to know the impact on the total type II error probability and vice versa. This transparency and flexibility should improve the application of GSTEF to clinical trials. PMID- 23437946 TI - Estimating vaccine efficacy under the heterogeneity of vaccine action in a nonrandomly mixing population. AB - Vaccines often have heterogeneous actions because of possible variation in the immune systems of hosts. One must consider such heterogeneity of vaccine action when developing a vaccine efficacy parameter. Addressing this issue the summary model of vaccine action has been proposed in the literature to estimate vaccine efficacy in a randomly mixing population. However, nonrandom mixing is common, particularly in a small-group-mixing population. This article extends the summary model of vaccine action to such a nonrandomly mixing population. The interpretation and estimation of the summary vaccine efficacy were discussed in light of other two models of vaccine action: the leaky and all-or-nothing model. Vaccine efficacy under all models is defined as the relative reduction in transmission probability due to vaccine. Estimation of the transmission probabilities is described based on a deterministic epidemic model of an acute transmitted disease. This article further discusses, based on the above vaccine models, the estimation of vaccination coverage required to control epidemic. Methods are illustrated using data simulated by considering different patterns of mixing and vaccine action. Results confirm that the summary model performs better than other two models when vaccine action is heterogeneous. PMID- 23437947 TI - Evaluation of early efficacy endpoints for proof-of-concept trials. AB - A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost effectiveness is the main concern. PMID- 23437948 TI - Sample size determination for the confidence interval of linear contrast in analysis of covariance. AB - This article provides a way to determine sample size for the confidence interval of the linear contrast of treatment means in analysis of covariance (ANCOVA) without prior knowledge of the actual covariate means and covariate sum of squares, which are modeled as a t statistic. Using the t statistic, one can calculate the appropriate sample size to achieve the desired probability of obtaining a specified width in the confidence interval of the covariate-adjusted linear contrast. PMID- 23437949 TI - Weighted rank tests for noninferiority hypotheses based on paired survival times. AB - Motivated by the design and analysis of a specific type of Phase II cancer clinical trials, we derive in this article a class of weighted rank tests for the testing of noninferiority hypotheses with a prespecified margin based on paired survival times. Monte Carlo simulations are performed to evaluate the performance of the proposed tests. Sample size calculation when these tests are used for the analysis is also discussed. Procedures developed are also applied to a Phase II clinical trial of metastatic breast cancer. PMID- 23437950 TI - Power comparisons for group sequential tests with nonparametric statistics in case of nonproportional hazards. AB - In clinical trials, it is important to set up a design to reach a decision on effectiveness of a drug in treating a disease with the loss of the minimum number of patients. Group sequential designs are very beneficial on this point. However, the proportional hazards assumption must hold to work under a group sequential design properly. A trial running under a group sequential design covers a long time period; therefore, assuming that hazards remain proportional over a long time period is somewhat unrealistic. We should examine and figure out the impact of nonproportional hazards over the hypothesis tests conducted under a group sequential design to set up more reliable designs and decide which test to use in which conditions. In this article, powers of group sequential tests with nonparametric statistics are evaluated under nonproportional hazards by a Monte Carlo simulation study. The simulation study covers different nonproportional hazards scenarios, censoring rates, survival distributions, sample sizes, and tied observations. With this study, we intend to be helpful for clinical trial designers to set up a more reliable group sequential design. PMID- 23437951 TI - A threshold hazard model for estimating serious infection risk following anti tumor necrosis factor therapy in rheumatoid arthritis patients. AB - Over recent years novel biologic agents have been developed for the treatment of rheumatoid arthritis. The most common type of biologic agent in use in the United Kingdom is the anti-tumor necrosis factor inhibitor class. To fully appreciate the potential risks of anti-tumor necrosis factor therapy in patients, knowledge about the baseline hazard (risk pattern) and the characteristics of patients associated with serious infection is important. We propose a nonproportional hazard model for estimating the infection risk, by including the drug exposure history information into the baseline hazard. We found that the infection risk reaches a peak within 1 month after drug exposure starts and then declines steadily for nearly 2 years before stabilizing out. PMID- 23437952 TI - Estimating covariate-adjusted log hazard ratios in randomized clinical trials using cox proportional hazards models and nonparametric randomization based analysis of covariance. AB - In the context of randomized clinical trials with time-to-event outcomes, estimates of covariate-adjusted log hazard ratios for comparing two treatments are obtained via nonparametric analysis of covariance by forcing the difference in means for covariables to zero. The method avoids the assumption of proportional hazards for each of the covariates, and it provides an adjusted analysis for the same population average treatment effect that the unadjusted analysis addresses. It is primarily useful in regulatory clinical trials that require analyses to be specified a priori. To illustrate, the method is applied to a study of lung disease with multivariate time-to-event outcomes. PMID- 23437956 TI - Disruptive viability selection on adult exploratory behaviour in eastern chipmunks. AB - Heterogeneous forces of selection associated with fluctuating environments are recognized as important factors involved in the maintenance of inter-individual phenotypic variance within populations. Consistent behavioural differences over time and across situations (e.g. personality) are increasingly cited as examples of individual variation observed within populations. However, the suggestion that heterogeneous selective pressures target different animal personalities remains largely untested in the wild. In this 5-year study, we investigated the dynamics of viability selection on a personality trait, exploration, in a population of eastern chipmunks (Tamias striatus) experiencing substantial seasonal variations in weather conditions and food availability associated with masting trees. Contrary to our expectations, we found no evidence of fluctuating selection on exploration. Instead, we found strong disruptive viability selection on adult exploration behaviour, independent of seasonal variations. Individuals with either low or high exploration scores were almost twice as likely to survive over a 6-month period compared with individuals with intermediate scores. We found no evidence of viability selection on juvenile exploration. Our results highlight that disruptive selection might play an important role in the maintenance of phenotypic variance of wild populations through its effect on different personality types across temporally varying environmental conditions. PMID- 23437957 TI - Facilitators to national kidney paired donation program. PMID- 23437958 TI - A systematic review of the evidence on the treatment of rapid cycling bipolar disorder. AB - OBJECTIVE: Rapid cycling is associated with longer illness duration and greater illness severity in bipolar disorder. The aim of the present study was to review the existing published randomized trials investigating the effect of treatment on patients with rapid cycling bipolar disorder. METHODS: A MEDLINE search was conducted using combinations of the following key words: bipolar and rapid or rapid-cycling or rapid cycling and randomized. The search was conducted through July 16, 2011, and no conference proceedings were included. RESULTS: The search returned 206 papers and ultimately 25 papers were selected for review. Only six randomized, controlled trials specifically designed to study a rapid cycling population were found. Most data were derived from post hoc analyses of trials that had included rapid cyclers. The literature suggested that: (i) rapid cycling patients perform worse in the follow-up period; (ii) lithium and anticonvulsants have comparable efficacies; (iii) there is inconclusive evidence on the comparative acute or prophylactic efficacy of the combination of anticonvulsants versus anticonvulsant monotherapy; (iv) aripiprazole, olanzapine, and quetiapine are effective against acute bipolar episodes; (v) olanzapine and quetiapine appear to be equally effective to anticonvulsants during acute treatment; (vi) aripiprazole and olanzapine appear promising for the maintenance of response of rapid cyclers; and (vii) there might be an association between antidepressant use and the presence of rapid cycling. CONCLUSION: The literature examining the pharmacological treatment of rapid cycling is still sparse and therefore there is no clear consensus with respect to its optimal pharmacological management. Clinical trials specifically studying rapid cycling are needed in order to unravel the appropriate management of rapid cycling bipolar disorder. PMID- 23437959 TI - Aripiprazole for the treatment of pediatric bipolar I disorder: a 30-week, randomized, placebo-controlled study. AB - OBJECTIVE: To evaluate the long-term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. METHODS: A randomized, double-blind, 30-week, placebo-controlled study of aripiprazole (10 or 30 mg/day) in youths (10-17 years) with bipolar I disorder (manic or mixed) +/ psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving <=26 weeks of double-blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. RESULTS: Of the 210 subjects who entered the 26-week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol-specified last observation carried forward analyses, but not in observed case or mixed-model repeated measures at week 30. Overall time to all-cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children's Global Assessment of Functioning and Clinical Global Impressions-Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. CONCLUSIONS: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms. PMID- 23437960 TI - Treatment of youth with bipolar disorder: long-term versus maintenance. PMID- 23437961 TI - Safety first. PMID- 23437962 TI - The relationship between clinical outcomes and quality of life in first-episode mania: a longitudinal analysis. AB - OBJECTIVES: Despite growing attention to the relationship between bipolar disorder (BD) and quality of life (QoL), there remains a lack of information about QoL in the early stages of BD, and about the course of QoL in people with BD over time. Here, we report on QoL and symptomatic outcomes over a 1.5-year period in a Canadian sample of first-episode mania patients. METHODS: Patients (n = 63) with DSM-IV-TR BD type I recovering from a recent episode of mania were recruited from a university-based hospital setting in Vancouver, BC, Canada and assessed at six monthly intervals for 18 months. In addition to symptomatic and cognitive assessments, two self-report QoL scales [the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Medical Outcomes Study Short Form 36 (SF-36)] were administered. RESULTS: Baseline QoL scores were high, with mean Q-LES-Q scores at 70% of the maximum possible score; QoL continued to show a trend towards improvement over time. Multiple hierarchical regressions were used to explore predictors of QoL over time, finding that: (i) length of illness and severity of depressive symptoms at baseline predicted Q-LES-Q scores at both baseline and six months; (ii) the number of previous depressive episodes and severity of depression at baseline and 12 months all predicted QoL at 12 months; and (iii) only severity of depressive symptoms at 12 months predicted QoL at 18 months. CONCLUSIONS: Our observation that QoL in patients who have recently experienced an episode of mania can be relatively preserved offers hope, both for healthcare providers and for those newly diagnosed. Further, that severity of depressive symptoms even in the early stages of the disease was the consistent predictor of QoL suggests that depressive symptoms need to be aggressively treated to improve QoL. PMID- 23437963 TI - Sociodemographic and clinical features of bipolar disorder patients misdiagnosed with major depressive disorder in China. AB - OBJECTIVES: Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD), which may lead to inappropriate treatment and poor outcomes. This study aimed to compare demographic and clinical features between patients with MDD and those with BD, but being misdiagnosed as MDD, in China. METHODS: A total of 1487 patients diagnosed with MDD were consecutively evaluated in 13 psychiatric hospitals or psychiatric units of general hospitals nationwide in China. The patients' sociodemographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. The Mini International Neuropsychiatric Interview (MINI) was used to establish DSM-IV diagnoses, and identify patients with MDD and those with BD, but being misdiagnosed with MDD. RESULTS: The proportions of BD (all types), bipolar I disorder (BD-I), and bipolar II disorder (BD-II) misdiagnosed as MDD in clinical practice were 20.8%, 7.9%, and 12.8%, respectively. Multiple logistic regression analyses revealed that compared to MDD patients, BD-I was characterized by more atypical depressive features (increased appetite, increased sleep, and weight gain) [odds ratio (OR) = 2.0, 95% confidence interval (CI): 1.2-3.2], more psychotic symptoms (OR = 2.1, 95% CI: 1.3-3.5), more lifetime depressive episodes (OR = 1.1, 95% CI: 1.1-1.2), and earlier age of onset (OR = 0.97, 95% CI: 0.9 0.99); BD-II was characterized by more psychotic symptoms (OR = 2.1, 95% CI: 1.4 3.1) and earlier age of onset (OR = 0.96, 95% CI: 0.9-0.97). In addition, compared to BD-II patients, BD-I patients were characterized by more frequent depressive episodes per year (OR = 3.1, 95% CI: 1.5-6.6). CONCLUSIONS: Depressive episodes in the context of BD-I and BD-II, among those who were misclassified as MDD, present some different clinical features compared to MDD. This finding should be taken into account in guiding diagnostic practices in China. PMID- 23437965 TI - Proteomic analysis of human vitreous associated with idiopathic epiretinal membrane. PMID- 23437964 TI - Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study. AB - OBJECTIVES: Through recent genome-wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage-dependent, L-type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family based association study to determine whether CACNA1C is associated with BP in the Latino population. METHODS: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9-kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family Based Association Test (version 2.0.3) and Haploview (version 4.2) software. RESULTS: An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). CONCLUSIONS: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population. PMID- 23437966 TI - Dynamics and persistence of CYP2D6 inhibition by paroxetine. AB - WHAT IS KNOWN AND OBJECTIVE: Paroxetine is both a substrate and an inhibitor of CYP2D6. The objective of the presented study was to determine the persistence of CYP2D6 inhibition after short term (6 weeks) and long term (18.7 +/- 10.6 weeks) paroxetine treatment. METHODS: Two the studies consisted of 30 depressive/anxiety patients each. In the first study, patients were subdivided into three groups treated with paroxetine (A1), alprazolam (A2) and paroxetine + alprazolam (A3). After 6 weeks, all the patients (A1+A2+A3) were switched to alprazolam treatment; metabolic activity was evaluated at the beginning, after 6 weeks of paroxetine/alprazolam/alprazolam + paroxetine treatment (A1/A2/A3) and 4 weeks after the switch to alprazolam treatment (Week 0, 6, 10). In the second study patients on previous long term paroxetine treatment were subdivided into two groups treated with mirtazapine (B1) or paroxetine (B2); metabolic activity of CYP2D6 was evaluated at the beginning and after 6 weeks of therapy. RESULTS AND DISCUSSION: Metabolic ratio of dextromethorphan to dextrorphan has normalized in all subjects after 4 weeks of paroxetine wash out in the first study. In the second study, 6 weeks after paroxetine discontinuation, restoration of metabolic activity of CYP2D6 was observed in only five of eight originally poor metabolizers. WHAT IS NEW AND CONCLUSION: We conclude that a wash-out period of 4 weeks seems to be sufficient for CYP2D6 disinhibition after short-term paroxetine treatment (6 weeks). On the other hand, treatment with a CYP2D6 substrate less than 6 weeks after long-term paroxetine treatment (18.7 weeks on average) could result in elevated drug plasma levels and occasionally also in drug toxicity. PMID- 23437967 TI - The effect of age of acquisition on older individuals with and without cognitive impairments. AB - The present study compared the effects of age of acquisition (AoA) on object naming across groups of older individuals with cognitive impairments, healthy older controls, and young healthy controls. All participants named a set of 80 pictures, within which both AoA and frequency were manipulated orthogonally. Early-acquired objects were named faster than late-acquired objects across all groups. Response time also declined with age and with cognitive impairment between the groups. The effect of AoA differed across groups, with AoA effects being largest for the older group with cognitive impairments and smallest for the young control group. The present study adds strength to the suggestion that AoA of picture names is one of the factors that influence survival or loss of memories in dementia and cognitive decline, and this could therefore be used as a potential screening test for cognitive impairment disorders in the future. PMID- 23437968 TI - Development of intramolecular vicinal diamination of alkenes: from palladium to bromine catalysis. AB - Palladium catalysis has been instrumental in the development of the intramolecular diamination of alkenes. Reagent combinations of a palladium catalyst and iodosobenzene diacetate or copper(II) salts, respectively, represent the broad applicability and mechanistic variation. Recent work has established alternative copper and bromine catalysts. The occupation with this reaction has also contributed to the development of high oxidation state metal catalysis in alkene difunctionalization and significantly broadened the spectrum of Pd catalyzed C-N bond-forming reactions in general. PMID- 23437970 TI - Recent advances in corneal transplantation for keratoconus. AB - From the rise of modern corneal graft surgery in the late 1950s until recently, corneal transplantation for keratoconus almost exclusively consisted of a full thickness transplant, termed penetrating keratoplasty. This technique involved the removal of all of the layers of the patient's central cornea and replacement with a full-thickness graft. Over approximately the past 20 years, a quiet revolution has occurred with the development of several other types of corneal transplantation surgery for keratoconus. In addition to full thickness grafts, several different types of partial thickness, lamellar grafts, have been developed and are viable alternatives to a full-thickness graft in selected patients. The main aim of these lamellar grafts is to selectively replace the corneal stroma, leaving intact the patient's own Descemet's membrane and endothelial cells, the main target of allograft transplant rejection. In this article, we review the current options with regard to corneal transplantation for keratoconus and review the evidence comparing newer and more established techniques. PMID- 23437969 TI - Fibroblast senescence and squamous cell carcinoma: how wounding therapies could be protective. AB - BACKGROUND: Squamous cell carcinoma (SCC), which has one of the highest incidences of all cancers in the United States, is an age-dependent disease, with the majority of these cancers diagnosed in people age 70 and older. Recent findings have led to a new hypothesis on the pathogenesis of SCC. OBJECTIVES: To evaluate the potential of preventive therapies to reduce the incidence of SCC in at-risk geriatric patients. MATERIALS AND METHODS: Survey of current literature on wounding therapies to prevent SCCs. RESULTS: This new hypothesis of SCC photocarcinogenesis states that senescent fibroblasts accumulate in the dermis, resulting in a reduction in dermal insulin-like growth factor-1 (IGF-1) expression. This lack of IGF-1 expression sensitizes epidermal keratinocytes to fail to suppress ultraviolet light B (UVB)-induced mutations, leading to increased proclivity to photocarcinogenesis. Recent evidence suggests that dermal wounding therapies, specifically dermabrasion and fractionated laser resurfacing, can decrease the proportion of senescent dermal fibroblasts, increase dermal IGF 1 expression, and correct the inappropriate UVB response found in geriatric skin, protecting geriatric keratinocytes from UVB-induced SCC initiation. CONCLUSIONS: In this review, we will discuss the translation of pioneering basic science results implicating commonly used dermal fibroblast rejuvenation procedures as preventative treatments for SCC. PMID- 23437971 TI - Impact of elevated CO2 on tobacco caterpillar, Spodoptera litura on peanut, Arachis hypogea. AB - If the carbon dioxide (CO(2)) concentration in the atmosphere changes in the future, as predicted, it could influence crops and insect pests. The growth and development of the tobacco caterpillar, Spodoptera litura (Fabricius) (Noctuidae: Lepidoptera), reared on peanut (Arachis hypogea L.) foliage grown under elevated CO(2) (550 ppm and 700 ppm) concentrations in open top chambers at Central Research Institute for Dryland Agriculture, Hyderabad, India, were examined in this study. Significantly lower leaf nitrogen, higher carbon, higher relative proportion of carbon to nitrogen and higher polyphenols content expressed in terms of tannic acid equivalents were observed in the peanut foliage grown under elevated CO(2) levels. Substantial influence of elevated CO(2) on S. litura was noticed, such as longer larval duration, higher larval weights, and increased consumption of peanut foliage by S. litura larvae under elevated CO(2) compared with ambient CO(2). Relative consumption rate was significantly higher for S. litura larva fed plants grown at 550 and 700 ppm than for larvae fed plants grown at ambient condition. Decreased efficiency of conversion of ingested food, decreased efficiency of conversion of digested food, and decreased relative growth rate of larvae was observed under elevated CO(2). The present results indicate that elevated CO(2) levels altered the quality of the peanut foliage, resulting in higher consumption, lower digestive efficiency, slower growth, and longer time to pupation (one day more than ambient). PMID- 23437972 TI - Practicability of combined treatment with calcipotriol/betamethasone gel (Daivobet(r) Gel) and improvement of quality of life in patients with psoriasis. AB - BACKGROUND: The successful treatment of psoriasis depends not only on the efficacy of the medication but also on patientsi acceptance and adherence to the prescribed regimen. PATIENTS AND METHODS: In this non-interventional, prospective trial 579 patients with psoriasis were treated once daily with the fixed combination of calcipotriol 50 MUg/g plus betamethasone 0.5 mg/g (Daivobet(r) Gel) for 4 weeks. Comparing the new medication to their previous treatment, patients assessed their quality of life by means of the Dermatology Life Quality Index (DLQI), reported their therapy- associated burden in daily life by the Psoriasis Disability Index (PDI) and assessed how easy the new medication was to employ. Disease severity was rated at the start and end of the study by physicians and patients using a Global Assessment (PGA from 0-5 points) and the Body Surface Area (BSA) assessed by the physicians. RESULTS: Quality of life improved from 8.7 to 3.2 points (p < 0.0001) parallel to a significant decrease of PGA by 39.6% (p < 0.0001) and BSA (72.5% of patients with BSA > 4% before vs. 37.3% after therapy). The application of the study medication was 30% less time consuming and handling associated with significantly higher patient satisfaction. Efficacy and tolerability of Daivobet(r) Gel versus prior treatment were judged "very good" in 85.7% vs. 27.6% of patients. CONCLUSIONS: The study substantiates a significant improvement of the quality of life during therapy with the fixed combination. Patients benefit from the convenience and time-saving as compared to their prior treatment. Thus, Daivobet(r) Gel can be recommended as an effective and well-tolerated treatment which may easily be integrated into daily life of patients with psoriasis. PMID- 23437973 TI - Nicorandil and its associated gastrointestinal side effects. PMID- 23437974 TI - Characterizing ultraviolet germicidal irradiance luminaires. AB - In upper-room ultraviolet germicidal irradiance (UVGI) design, irradiance is an important characteristic, with two opposing dominant dynamics: high-level irradiation on the microorganism and minimum levels of irradiance on human skin and eyes. The use of high-level ray-tracing procedures is followed in establishing radiance and irradiance levels. The main constants in a room influencing these calculations are the spectral and spatial characteristics of the radiation sources in the inter-reflecting surfaces inside the luminaire, as well as the surfaces in the room. The most important characteristic to be determined for the radiation source prior to calculations is its spatial radiant intensity distribution. This characterization is performed using a gonioradiometer. The complexity of the physical construction of the luminaire will determine the extent to which measurements have to be taken. Accurate gonioradiometer readings provide the required radiant intensities in all directions for computer-aided design (CAD), and can also be used to determine the total radiant flux leaving the luminaire, as well as calculating isoirradiance surfaces around the UVGI luminaire. This study will present a laboratory experimental approach to deriving the radiant intensity distribution of a UVGI luminaire. The UVGI luminaire is then characterized in situ, and compared with the gonioradiometric output. PMID- 23437975 TI - Coverage dependent disorder-order transition of 2H-tetraphenylporphyrin on Cu(111). AB - In this study, we investigate the peculiar coverage dependent supramolecular arrangement of 2H-tetraphenylporhpyrin (2HTPP) on Cu(111) with scanning tunneling microscopy at room-temperature. At low coverage, "slow" diffusion of individual 2HTPP molecules along the close-packed atomic rows of the substrate is observed, and no supramolecular ordering occurs. However, at higher coverage, the formation of ordered, checkerboard-like domains is found, with two molecules per unit cell at different distances from the surface. This behavior is attributed to a complex interplay of site specific molecule-substrate interaction, mainly the strong interaction between the iminic N atoms and Cu substrate atoms, with intermolecular T-type and pi-pi interactions. PMID- 23437976 TI - Variations in type III effector repertoires, pathological phenotypes and host range of Xanthomonas citri pv. citri pathotypes. AB - The mechanisms determining the host range of Xanthomonas are still undeciphered, despite much interest in their potential roles in the evolution and emergence of plant pathogenic bacteria. Xanthomonas citri pv. citri (Xci) is an interesting model of host specialization because of its pathogenic variants: pathotype A strains infect a wide range of Rutaceous species, whereas pathotype A*/A(W) strains have a host range restricted to Mexican lime (Citrus aurantifolia) and alemow (Citrus macrophylla). Based on a collection of 55 strains representative of Xci worldwide diversity assessed by amplified fragment length polymorphism (AFLP), we investigated the distribution of type III effectors (T3Es) in relation to host range. We examined the presence of 66 T3Es from xanthomonads in Xci and identified a repertoire of 28 effectors, 26 of which were shared by all Xci strains, whereas two (xopAG and xopC1) were present only in some A*/A(W) strains. We found that xopAG (=avrGf1) was present in all A(W) strains, but also in three A* strains genetically distant from A(W) , and that all xopAG-containing strains induced the hypersensitive response (HR) on grapefruit and sweet orange. The analysis of xopAD and xopAG suggested horizontal transfer between X. citri pv. bilvae, another citrus pathogen, and some Xci strains. A strains were genetically less diverse, induced identical phenotypic responses and possessed indistinguishable T3E repertoires. Conversely, A*/A(W) strains exhibited a wider genetic diversity in which clades correlated with geographical origin and T3E repertoire, but not with pathogenicity, according to T3E deletion experiments. Our data outline the importance of taking into account the heterogeneity of Xci A*/A(W) strains when analysing the mechanisms of host specialization. PMID- 23437977 TI - From rings to crescents: a novel fabrication technique uncovers the transition details. AB - A novel fabrication route is reported for the generation of substrate-supported symmetric and asymmetric metal nanostructures. We combine a colloidal template and angled evaporation to deposit in situ mask materials for subsequent lithographic pattern transfer. The technique is demonstrated for the fabrication of concentric and nonconcentric gold rings and crescents. Optical properties of localized plasmon resonances in such structures are studied by UV-vis-NIR spectroscopy and finite-difference time domain simulations during the transition from rings to crescents revealing the development of strong quadrupolar modes. PMID- 23437979 TI - 1H and 17O NMR relaxometric and computational study on macrocyclic Mn(II) complexes. AB - Herein we report a detailed 1H and 17O relaxometric investigation of Mn(II) complexes with cyclen-based ligands such as 2-(1,4,7,10-tetraazacyclododecan-1 yl)acetic acid (DO1A), 2,2'-(1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetic acid (1,4-DO2A), 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (1,7 DO2A), and 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A). The Mn(II) complex with the heptadentate ligand DO3A does not have inner sphere water molecules (q = 0), and therefore, the metal ion is most likely seven coordinate. The hexadentate DO2A ligand has two isomeric forms: 1,7-DO2A and 1,4 DO2A. The Mn(II) complex with 1,7-DO2A is predominantly six-coordinate (q = 0). In aqueous solutions of [Mn(1,4-DO2A)], a species with one coordinated water molecule (q = 1) prevails largely, whereas a q = 0 form represents only about 10% of the overall population. The Mn(II) complex of the pentadentate ligand DO1A also contains a coordinated water molecule. DFT calculations (B3LYP model) are used to obtain information about the structure of this family of closely related complexes in solution, as well as to determine theoretically the 17O and 1H hyperfine coupling constants responsible for the scalar contribution to 17O and 1H NMR relaxation rates and 17O NMR chemical shifts. These calculations provide 17O A/h values of ca. 40 * 10(6) rad s(-1), in good agreement with experimental data. The [Mn(1,4-DO2A)(H2O)] complex is endowed with a relatively fast water exchange rate (k(ex)298 = 11.3 * 10(8) s(-1)) in comparison to the [Mn(EDTA)(H2O)]2- analogue (k(ex)298 = 4.7 * 10(8) s(-1)), but about 5 times lower than that of the [Mn(DO1A)(H2O)]+ complex (k(ex)298 = 60 * 10(8) s(-1)). The water exchange rate measured for the latter complex represents the highest water exchange rate ever measured for a Mn(II) complex. PMID- 23437978 TI - Pseudomonas aeruginosa biofilm aggravates skin inflammatory response in BALB/c mice in a novel chronic wound model. AB - Chronic wounds are presumed to persist in the inflammatory state, preventing healing. Emerging evidence indicates a clinical impact of bacterial biofilms in soft tissues, including Pseudomonas aeruginosa (PA) biofilms. To further investigate this, we developed a chronic PA biofilm wound infection model in C3H/HeN and BALB/c mice. The chronic wound was established by an injection of seaweed alginate-embedded P. aeruginosa PAO1 beneath a third-degree thermal lesion providing full thickness skin necrosis, as in human chronic wounds. Cultures revealed growth of PA, and both alginate with or without PAO1 generated a polymorphonuclear-dominated inflammation early after infection. However, both at days 4 and 7, there were a more acute polymorphonuclear-dominated and higher degree of inflammation in the PAO1 containing group (p < 0.05). Furthermore, PNA FISH and supplemented DAPI staining showed bacteria organized in clusters, resembling biofilms, and inflammation located adjacent to the PA. The chronic wound infection showed a higher number of PAO1 in the BALB/c mice at day 4 after infection as compared to C3H/HeN mice (p < 0.006). In addition, a higher concentration of interleukin-1beta in the chronic wounds of BALB/c mice was observed at day 7 (p < 0.02), despite a similar number of bacteria in the two mouse strains. The present study succeeded in establishing a chronic PA biofilm infection in mice. The results showed an aggravating impact of local inflammation induced by PA biofilms. In conclusion, our findings indicate that improved infection control of chronic wounds reduces the inflammatory response and may improve healing. PMID- 23437980 TI - Oestrogen, progesterone and oxytocin receptors and COX-2 expression in endometrial biopsy samples from the induction of ovulation to luteolysis in llamas (Lama glama). AB - Endometrial expression of oestrogen (ERalpha), progesterone (PR) and oxytocin receptor (OR) and cyclooxygenase-2 (COX-2) was evaluated from the induction of ovulation to luteolysis in llamas. Ovarian activity was daily assessed by ultrasonography in five females. Ovulation was induced immediately after the detection of an ovulatory follicle by a GnRH injection (Day 0). Endometrial samples were obtained by transcervical biopsies from the left and right horns on day 0 and days 4, 8, 10 and 12 post-GnRH. Blood samples were collected daily for progesterone and estradiol-17beta determinations by RIA. An immunohistochemical technique was used to study receptors population and COX-2 expression which were then evaluated by two independent observers. The expression of ERalpha and PR was highest on day 0 in the luminal epithelium and stroma in association with high plasma estradiol-17beta concentrations. Thereafter, a decrease in ERalpha population was registered on day 4 and a new increase of its expression was observed between days 8 and 12 in those cell types. Conversely, PR population was gradually down-regulated until its lowest expression was reached on day 10 post GnRH in the luminal epithelium. Content of OR was similar throughout the study in all cell types. The expression of COX-2 was highest from day 8 to 12 post-GnRH in the luminal epithelium, in relation to the time of maximal PGF2alpha release. Both steroid receptors populations and COX-2 expression were similar between horns. Meanwhile, OR expression was higher in the right than in the left uterine horn. In summary, this study showed that the loss of endometrium sensitivity to progesterone by days 8-10 post-induction of ovulation and the concomitant increase of COX-2 expression could play a key role in the mechanism of luteolysis and somehow be related to the short corpus luteum lifespan of llamas. PMID- 23437981 TI - Quantitative genetics of costly neonatal sexual size dimorphism in squirrel monkeys (Saimiri boliviensis). AB - Offspring size is often an intimate link between the fitness of parents and offspring. Among mammals, neonate mass is also related to adult levels of dimorphism and intrasexual competitive mating. We describe the sex-specific genetic architecture of neonate mass in captive squirrel monkeys (Saimiri boliviensis), a small Neotropical primate. Best fitting quantitative genetic models show strong maternal genetic effects with little difference between sexes offering limited opportunity for neonatal dimorphism to respond to observed or hypothetical selection. Heritabilities that are approximately zero also imply it is unlikely that neonatal dimorphism can evolve as a correlated response to selection on adult size. However, male mass is also more dependent on maternal condition (age and parity) making dimorphism plastic. Finally, we hypothesize that large maternal genetic effects reflect income breeding and tightly synchronized seasonal reproduction in squirrel monkeys, both of which require strong maternal control of offspring growth and timing of birth. PMID- 23437982 TI - Suicide in prisoners with bipolar disorder and other psychiatric disorders: a systematic review. AB - OBJECTIVES: To examine the risk of suicide and suicide attempts in prisoners with bipolar disorder and other psychiatric disorders compared with prisoners without psychiatric disorders. METHODS: We conducted a systematic review and meta analysis of observational studies comparing suicide outcomes in prisoners with bipolar disorder and other psychiatric disorders to other prisoners. RESULTS: Five studies reported the risk of suicidal outcomes in prisoners with bipolar disorder compared with other prisoners, with a random effects pooled odds ratio of 2.4 (95% confidence interval: 1.6-3.7; I(2) = 0%). This appeared to be lower than the risk of suicidal outcomes for all psychiatric disorders and for depression, specifically, and, in meta-regression, significantly lower (p = 0.03) than for schizophrenia-spectrum disorders. CONCLUSIONS: Although bipolar disorder is associated with suicide and non-fatal suicidal behavior in prisoners, further research is necessary to confirm any associations and mediating mechanisms. PMID- 23437983 TI - The mitogenome of Liobagrus nigricauda (Teleostei, Siluriformes: Amblycipitidae). AB - Liobagrus nigricauda is endemic to the Yangtze River system (Ding 1994, The fishes of Sichuan province. pp. 470-78) and listed as an endangered species (IUCN 2012, Red list of threatened species. http://www.iucnredlist.org ). In this study, the complete mitochondrial genome sequence of L. nigricauda has been obtained with polymerase chain reaction (PCR), which contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a noncoding control region with the total length of 16,512 bp. The gene arrangement and composition are similar to that of other vertebrates. Most of the genes are encoded on heavy strand, except for eight tRNA and ND6 genes. Just like most other vertebrates, the bias against G has a universality in different statistics results. The mitogenome sequence of L. nigricauda would contribute to better understand population genetics and to protect its genetic diversity. PMID- 23437984 TI - Cardiac angiofibroma: a rare primary cardiac tumor. AB - Cardiac angiofibromas are rare tumors. We report a patient with an angiofibroma of the mitral valve and discuss the management of these tumors. PMID- 23437985 TI - Livedoid vasculopathy - current aspects of diagnosis and treatment of cutaneous infarction. AB - Livedoid vasculopathy is a rare, chronic, recurrent disease of the cutaneous microcirculation. Its typical clinical manifestation is a triad which consists of livedo racemosa of the skin, episodic painful ulcerations of the distal aspects of the legs and a healing process leaving small porcelain-white scars called atrophie blanche. As an important result of recent research, livedoid vasculopathy has been defined as a coagulation disorder classified as a vasculopathy different from inflammatory vasculitis. This differentiation adds to the current pathophysiologic understanding and supports the therapeutic rationale with respect to the use of new systemic anticoagulants. The prevention of irreversible residual scarring and the improvement of patientsi quality of life are the main goals in treating cutaneous infarction and require early and consequent treatment. This article presents current knowledge on diagnosing this rare disease and offers practical guidance on its therapy. PMID- 23437986 TI - IR spectroscopy of b4 fragment ions of protonated pentapeptides in the X-H (X = C, N, O) region. AB - The structure of peptide fragments was studied using "action" IR spectroscopy. We report on room temperature IR spectra of b4 fragments of protonated GGGGG, AAAAA, and YGGFL in the X-H (X = C, N, O) stretching region. Experiments were performed with a tandem mass spectrometer combined with a table top tunable laser, and the multiple photon absorption process was assisted using an auxiliary high-power CO2 laser. These experiments provided well-resolved spectra with relatively narrow peaks in the X-H (X = C, N, O) stretching region for the b4 fragments of protonated GGGGG, AAAAA, and YGGFL. The 3200-3700 cm(-1) range of the first two of these spectra are rather similar, and the corresponding peaks can be assigned on the basis of the classical b ion structure that has a linear backbone terminated by the oxazolone ring at the C-terminus and ionizing proton residing on the oxazolone ring nitrogen. The spectrum of the b4 of YGGFL, on the other hand, is different from the two others and is characterized by a band observed near 3238 cm(-1). Similar band positions have recently been reported for one of the four isomers of the b4 of YGGFL studied using double resonance IR/UV technique. As proposed in this study, the IR spectrum of this ion at room temperature can also be assigned to a linear N-terminal amine protonated oxazolone structure. However, an alternative assignment could be proposed because our room temperature IR spectrum of the b4 of YGGFL nicely matches with the predicted IR absorption spectrum of a macrocyclic structure. Because not all experimental IR features are unambiguously assigned on the basis of the available literature structures, further theoretical studies will be required to fully exploit the benefits offered by IR spectroscopy in the X-H (X = C, N, O) stretching region. PMID- 23437987 TI - Impact of body mass index on atrial fibrillation recurrence: a meta-analysis of observational studies. AB - BACKGROUND: Obesity is associated with increased risk of atrial fibrillation (AF). Several trials exploring the impact of elevated body mass index (BMI) on the catheter ablation of AF have been published and yield conflicting results. We thus conducted a meta-analysis to explore the association between elevated BMI and AF recurrence in patients undergoing catheter ablation. METHODS: A systematic review and meta-analysis was performed. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled. RESULTS: Six observational studies including 2,358 patients were included. Of those, four studies were prospective cohort studies, and two were retrospective studies. Elevated BMI increased the risk of AF recurrence compared to normal BMI by 31%, where the difference between the two arms was statistically significant (RR = 1.308, 95% CI: 1.036-1.651, P = 0.02). Compared to normal BMI group, the overweight group had a 27% increased risk of AF recurrence (RR = 1.270, 95% CI 0: 961-1.679, P = 0.093) and the obese group had a significantly increased risk of AF recurrence (RR = 1.378, 95% CI: 1.006-1.887, P = 0.045). When compared to the overweight group, the obese group has a 12% increased risk of AF recurrence (RR = 1.116, 95% CI: 0.866-1.438, P = 0.397). CONCLUSIONS: Elevated BMI is associated significantly with AF recurrence in patients undergoing catheter ablation. There is a graded relationship between elevated BMI and increased risk of AF recurrence. PMID- 23437988 TI - Anterior segment optical coherence tomography in black-on-clear polypseudophakia. PMID- 23437989 TI - Impact of immediate loading on early bone healing at two-piece implants placed in fresh extraction sockets: an experimental study in the beagle dog. AB - OBJECTIVE: To study early bone healing of immediately loaded implants placed in fresh extraction sockets versus immediate implants without occlusal loading in the dog. MATERIALS AND METHODS: A total of 48 implants were placed in the distal sockets of Pm3 and Pm4 in the lower jaw of 12 Beagle dogs immediately after tooth extraction. In the control group, no loading was applied. In the test group, an immediate loading restoration with occlusal contacts was performed. Dogs were sacrificed at 2, 4 and 8 weeks for histological analysis. RESULTS: At the end of the study, there was a 100% implant and prosthesis survival. Similar results for test and control groups were observed for bone-to-implant contact (%) and peri implant bone area. Inter-thread bone area tended to decrease in the control and increase in the test. With respect to ridge alterations, bone resorption was more pronounced on the buccal aspect and was observed in both groups. CONCLUSION: Immediate loading did not impair early stages of bone healing and crestal bone modelling at two-piece implants in fresh extraction sockets in the beagle dog; however, bone resorption occurred in all specimens in both groups. PMID- 23437990 TI - Correction of infraorbital dark circles using collagenase-digested fat cell grafts. AB - BACKGROUND: A number of factors, including visibility of the orbicularis oculi muscle through thin skin, can cause dark circles around the eyes. Fat grafts have been used to augment the lower eyelid skin to correct dark circles, but irregularities caused by leaving visible lumps of the fat can occur. We used collagenase-digested fat cell grafts to correct these deformities. METHODS AND MATERIALS: Fat was aspirated from the medial thigh using the Coleman method. After centrifugation, the middle fat layer was segregated, digested using Clostridium histolyticum-derived type II collagenase, and mixed with Hartman's solution. The grafts were injected into the infradermal layer using blunt 22-G needles. RESULTS: Eighty-two patients were evaluated for improvement using photographic evidence; 55 (67.1%) showed improvement, 23 (28%) showed no difference, and four (4.9%) had worsened from preoperative findings. There were no visible lumps of fat, contour irregularities, or fat necroses. Postoperative edema and ecchymosis were minimal. CONCLUSION: Collagenase-digested fat cell grafts provide another option for correcting dark circles by augmenting thin skin. Further histologic evaluation of the grafted collagenase-digested fat cells is recommended. PMID- 23437991 TI - Selection of soybean pods by the stink bugs, Nezara viridula and Piezodorus guildinii. AB - Different biological parameters of the stink bugs, Nezara viridula L. and Piezodorus guildinii Westwood (Hemiptera: Pentatomidae), are affected by the developmental stage of the soybean (Glycine max Merrill) pods they feed on. These effects of the soybean on the stink bugs could represent a selection pressure leading to the ability of these species to discriminate the phenological stage of soybean pods, and, therefore, to exhibit feeding preferences. We designed three studies: (1) Distant detection of soybean pods through an olfactometer; (2) Free choice tests to evaluate preferences for soybean pods of different developmental stages; (3) No choice tests to study effects of soybean pod development on feeding time and number of probes. Stink bugs showed no differential response to olfactometer arms with or without soybean pods, suggesting an inability to detect soybean volatiles. Free choice tests showed no species effects on pods selection, but significant differences among fifth instar nymphs, adult male, and adult females. Fifth instar nymphs fed more frequently on soybean pods of advanced development stages compared to female adults, despite previous evidence showing poor development of stink bugs fed pods of the same stage. No choice tests showed significant effects of stink bug species, stink bug stage and sex, and soybean pod phenology. N. viridula expressed shorter feeding times and higher numbers of probes than P. guildinii. The highest numbers of probes of both species were observed when they were fed soybean pods in early phenological stages. When placed in direct contact with food, fifth instar nymphs prefered to feed on more developed pods, despite these pods being suboptimal food items. These results suggest that for the ecological time framework of soybean-stink bugs coexistence, around thirty-five years in Argentina, the selection pressure was not enough for stink bugs to evolve food preferences that match their performance on soybean pods of different development stages. PMID- 23437992 TI - Methods used to quit smoking by people with physical disabilities. AB - PURPOSE/OBJECTIVE: People with mobility impairments (MIs) have higher smoking rates than the general population. We evaluated the use of psychosocial and pharmacological methods to quit smoking and readiness to quit smoking in this population in a cross-sectional study. RESEARCH METHOD/DESIGN: Current and former smokers with MIs who needed equipment to ambulate (e.g., cane, wheelchair; n = 152, 53.3% female, 86.2% current smokers) were recruited from the community and interviewed by telephone regarding their lifetime use of various quit methods and readiness to quit smoking. RESULTS: Results indicated that 57.3% reported a quit attempt in the past year, and 62% and 88.4% were planning on quitting in the next 30 days and six months, respectively. A minority of smokers with MIs reported using any type of counseling (5.3%; 3.3% in-person counseling and 2.6% phone counseling) or tablet medication (8.6%); 75% had made a "cold turkey" quit attempt (e.g., without any assistance). 36.8% and 19.7% reported using the nicotine patch and gum, respectively. Regression analyses indicated that greater nicotine dependence was associated with lower use of psychosocial treatments (p < .05), greater education was associated with greater tablet medication use (p = .051), and higher income was associated with both greater nicotine replacement therapy (NRT) and tablet medication use (p < .05). Minorities with MIs were significantly less likely to use NRT than non-Hispanic Whites (p < .05). CONCLUSIONS: Individuals with MIs are motivated to quit smoking but underuse some empirically validated cessation treatment options. PMID- 23437993 TI - Meaning-making following spinal cord injury: Individual differences and within person change. AB - OBJECTIVE: Several studies of people coping with trauma or loss suggest that finding meaning in one's experience predicts better adjustment. However, these studies assume that meaning is a stable individual-difference construct. We assess the temporal stability of searching for and finding meaning in a sample of people with spinal cord injury (SCI), and test the effect of change in searching and finding meaning on depressive affect, subjective well-being (SWB), and perceived growth. METHOD: Sixty-seven adults with SCI were interviewed on 3 occasions over the first 13 months of their injury. RESULTS: Searching for and finding meaning are moderately stable over time. Multilevel analyses indicated that in addition to between-person effects of searching for and finding meaning on depressive symptoms and well-being, there was also evidence of within-person effects of searching for and finding meaning, such that more frequent searching was associated declines in adjustment, whereas increases in found meaning were associated with improved adjustment. Finding meaning, at both the between-person and within-person levels, was associated with greater perceived growth, but such growth was not associated with depressive symptoms or SWB. CONCLUSIONS: The within-person analyses demonstrate that meaning-making is a process that is not necessarily linear yet is important for understanding the process of adaptation for many people coping with SCI. PMID- 23437994 TI - Disability identity: exploring narrative accounts of disability. AB - OBJECTIVE: To review a type of narrative identity, disability identity, which is a potentially important topic concerning the social psychology of disability. Disability identity entails a positive sense of self, feelings of connection to, or solidarity with, the disability community. A coherent disability identity is believed to help individuals adapt to disability, including navigating related social stresses and daily hassles. Attention to disability narratives will enable rehabilitation psychologists to develop detailed theories and plan empirical investigations aimed at exploring the psychosocial applications of disability identity. METHOD: We examined six narratives (e.g., articles, chapters, books, blogs) written by people with disabilities in order to identify excerpts illustrating disability identity. RESULTS: Using themes drawn from disability identity research (i.e., communal attachment, affirmation of disability, self worth, pride, discrimination, personal meaning), we categorized excerpts from the narratives. CONCLUSION: By highlighting positive aspects of disability identity, the study of disability narratives can inform persons with and without disabilities about how individuals live with disabilities. We discuss reasons rehabilitation researchers and practitioners should consider disability identity and narratives in their respective efforts. PMID- 23437995 TI - Acceptance of pain in neurological disorders: associations with functioning and psychosocial well-being. AB - OBJECTIVE: Chronic pain acceptance has been shown to be related to positive adjustment to chronic pain in patients presenting with pain as a primary problem. However, the role of pain acceptance in adjustment to chronic pain secondary to a neurological disorder that is often associated with physical disability has not been determined. The purpose of this study was to examine whether two domains of chronic pain acceptance--activity engagement and pain willingness--predict adjustment to pain, controlling for pain intensity and key demographic and clinical variables in individuals with muscular dystrophy (MD), multiple sclerosis (MS), post-polio syndrome (PPS), or spinal cord injury (SCI). METHOD: Participants were 508 community-dwelling adults with a diagnosis of MD, MS, PPS, or SCI who also endorsed a chronic pain problem. Participants completed self report measures of pain acceptance, quality of life, pain interference, pain intensity, depression, and social role satisfaction. RESULTS: Hierarchical linear regressions indicated that activity engagement predicted lower pain interference and depression, and greater quality of life and social role satisfaction. Pain willingness predicted less pain interference and depression. Together, the two pain acceptance subscales accounted for more variance in outcomes than did self reported pain intensity. CONCLUSIONS: Findings correspond with the broader pain acceptance literature, although activity engagement appears to be a more robust predictor of adjustment than does pain willingness. This research supports the need for future studies to determine the extent to which treatments that increase acceptance result in positive outcomes in persons with chronic pain secondary to neurological disorders. PMID- 23437996 TI - Major depressive disorder and factorial dimensions among individuals with recent onset spinal cord injury. AB - OBJECTIVE: We examine the rates of major depressive disorder, single episode determined by the Inventory to Diagnose Depression (IDD) in a clinical sample of persons with recent-onset spinal cord injury (SCI; <=52 weeks) participating in an inpatient SCI rehabilitation program. We also analyzed the factor structure of the IDD measure in an attempt to replicate the factor structure reported by Frank et al. (1992), and we examined item endorsement patterns. DESIGN: A retrospective chart review was conducted. Participants were 354 individuals (93 women, 261 men) in an inpatient SCI rehabilitation program. RESULTS: Fifteen percent of the sample met criteria for a major depressive disorder (MDD). A higher rate of depression was observed among women. A "dysphoria" factor accounted for 24% of the variance in the final four-factor model. The four-factor solution explained a total of 35.5% of the variance, with an "anhedonia" factor contributing 4.6%, a "sleep" factor contributing 3.5%, and an "appetite" factor contributing 3.5%, respectively. Items assessing symptoms of insomnia, weight loss, worrying about health, and decreased energy had the highest percentage of endorsement to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for clinical significance. CONCLUSIONS: The rate of single episodes of MDD determined by the IDD parallels the rate observed with the Patient Health Questionnaire-9 (PHQ-9). The factor structure of the IDD was similar to that reported by Frank et al. (1992). Information provided by the IDD about the presence and severity of MDD symptoms can inform interventions for persons with SCI. PMID- 23437997 TI - Correlates of health-related quality of life in African American and Caucasian stroke caregivers. AB - OBJECTIVE: Stroke is a leading cause of long-term disability in the United States. Family caregivers are susceptible to negative outcomes as a result of their caregiving role. A stress process model was utilized to identify characteristics of stroke caregivers who are at risk for poor physical and mental health-related quality of life (QOL). RESEARCH METHOD: Individuals who experienced an incident stroke event within the previous year were identified from a larger epidemiologic study of stroke incidence. These stroke survivors were enrolled in the Caring for Adults Recovering from the Effects of Stroke (CARES) study along with their primary family caregivers (N = 146 dyads). Caregivers completed a baseline telephone interview that assessed physical and mental health-related QOL, problems their family members were experiencing, appraisals of those problems, and caregiver resources. RESULTS: Objective stressors, appraisals, and caregiver resources were related to caregiver physical and mental health-related QOL, ps <.05. Objective stressors were found to have a stronger association with caregiver mental health than physical health. Hierarchical regression models showed the relative importance of each category of predictors. In the final models, older age and receiving more support were associated with worse physical health-related QOL whereas African American race and fewer stroke survivor problems were associated with better mental health. CONCLUSIONS: The correlates of health-related QOL identified in this national sample of caregivers can help identify stroke caregivers who are at risk for poor adjustment to the caregiving role and aid in identifying areas that can potentially be intervened upon for these caregivers. PMID- 23437998 TI - Treatment adherence in cognitive processing therapy for combat-related PTSD with history of mild TBI. AB - OBJECTIVE: This retrospective study examined treatment adherence in Cognitive Processing Therapy (CPT) for combat-related posttraumatic stress disorder (PTSD) in Veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) with and without history of mild traumatic brain injury (mTBI). METHOD: Medical record review of consecutive referrals to an outpatient PTSD clinic identified veterans diagnosed with combat-related PTSD who began treatment with CPT. The sample (N = 136) was grouped according to positive (n = 44) and negative (n = 92) mTBI history. Groups were compared in terms of presenting symptoms and treatment adherence. RESULTS: The groups were not different on a pretreatment measure of depression, but self-reported and clinician-rated PTSD symptoms were higher in veterans with history of mTBI. The treatment completion rate was greater than 61% in both groups. The number of sessions attended averaged 9.6 for the PTSD group and 7.9 for the mTBI/PTSD group (p = .05). IMPLICATIONS: Given the lack of marked group differences in treatment adherence, these initial findings suggest that standard CPT for PTSD may be a tolerable treatment for OEF/OIF veterans with a history of PTSD and mTBI as well as veterans with PTSD alone. PMID- 23437999 TI - Meeting physical activity recommendations: self-regulatory efficacy characterizes differential adherence during arthritis flares. AB - PURPOSE: Using social-cognitive theory, we examined whether adults who experienced an arthritis flare and met/did not meet the disease-specific public health recommended dose for physical activity differed in their self-regulatory efficacy beliefs, overall pain, and flare-related factors. RESEARCH METHOD/DESIGN: Adults with arthritis (N = 56; M(age) = 49.41 +/- 11.56 years) participated in this prospective study. RESULTS: Multivariate analysis of variance comparing groups who met or did not meet the recommended dose (n(met) = 24, >= 150 minutes/week vs. n(not met) = 32, < 150 min/week) on efficacy, overall pain, and flare-related factors was significant (p < .01; eta(partial)2 = .28). People meeting the dose had significantly greater self-regulatory efficacy to overcome arthritis barriers (M(met dose) = 7.33 +/- 1.95 vs. M(did not meet dose) = 5.74 +/- 2.08, eta(partial)2 = .14) and to schedule/plan (M(met dose) = 7.27 +/ 1.80 vs. M(did not meet dose) = 5.72 +/- 1.90, eta(partial)2 = .15). Overall pain and flare-related factors did not differ (ps > .05). CONCLUSION/IMPLICATION: During flares, individuals with greater self-regulatory efficacy to manage disease barriers and plan their physical activity were more adherent to disease specific public health activity recommendations. This study was the first to demonstrate differences in social cognitions that characterize adherence to recommended activity among people challenged by arthritis flares. Findings support the theoretical position that self-regulatory efficacy is related to better adherence in the face of challenging disease-related circumstances. The importance of studying individual characteristics of people who succeed in being active despite such obstacles is stressed. PMID- 23438000 TI - Factor structure, reliability, and validity of the Frontal Systems Behavior Scale (FrSBe) in an acute traumatic brain injury population. AB - OBJECTIVE: This study investigated the psychometric properties of the Frontal Systems Behavior Scale (FrSBe) in an acute traumatic brain injury (TBI) population across indices of factor structure, reliability, and validity. METHOD: Data were collected from 101 individuals undergoing acute rehabilitation for moderate and severe TBI both upon emergence from posttraumatic amnesia and at hospital discharge, as well as from their family members or caregivers. RESULTS: Four separate confirmatory factor analyses (CFAs) suggested that the FrSBe's three-factor/three-subscale solution did not fit the data well, and follow-up CFAs employing a one-factor structure similarly yielded poor fit indices. Four exploratory factor analyses (EFAs) failed to produce factor solutions consistent with each other or that resembled the factor solution retained in the EFA during the FrSBe's initial construction. The FrSBe had sufficiently high internal consistency at the total-score and subscale-score levels, good convergent validity with other indices of TBI functioning, and good test-retest reliability in the family administration of the measure, but not in the patient administration. CONCLUSIONS: The FrSBe is an appropriate measure for use in an inpatient TBI population when using the total score and the family administration, though its subscales and patient administration warrant more rigorous examination. PMID- 23438001 TI - Predictors of adherence to home rehabilitation exercises following anterior cruciate ligament reconstruction. AB - OBJECTIVE: Although home exercises are commonly prescribed following anterior cruciate ligament (ACL) reconstruction and are considered important in obtaining successful rehabilitation outcomes, little is known about factors associated with the completion of such exercises. Consequently, this study was designed to identify predictors of adherence to home rehabilitation exercises after ACL surgery. METHOD: Participants (33 women, 58 men) completed indices of athletic identity, neuroticism, optimism, and pessimism before ACL surgery and measures of daily pain, negative mood, stress, and home exercise completion for 42 days postoperatively. RESULTS: Participants reported a high level of adherence to the prescribed regimen. Home exercise completion increased significantly over time as the number of sets of prescribed home exercises declined. Personal factors were not predictive of home exercise completion. Participants completed fewer home exercises on days when they experienced more stress or negative mood. CONCLUSIONS: Day-to-day variations in negative mood and stress may contribute to adherence to prescribed home exercises. PMID- 23438002 TI - Experiences of stigma by association among family members of people with mental illness. AB - OBJECTIVE: To investigate the relationships between public stigma, stigma by association (SBA), psychological distress, perceived closeness, perceived heredity, and the type of family relationship among family members of people with a mental illness. METHOD: In this cross-sectional survey, data from 527 family members of people with a mental illness were analyzed. RESULTS: Perceptions of public stigma were found to be positively related to SBA and SBA correlated with greater psychological distress and less perceived closeness. SBA also mediated relationships between perceived public stigma and psychological distress, and between perceived public stigma and perceived closeness. Further, among participants who reported SBA, immediate family members showed lower levels of perceived closeness than extended family members. Also, the perceived heredity of mental illness was associated with perceptions of public stigma and psychological distress. CONCLUSION: The findings suggest that family members of people with a mental illness could benefit from education on mental illnesses, their treatment, and the extent to which they are hereditary. Additionally, particular attention should be paid to the psychological needs that arise from being a caregiver of someone with a mental illness. PMID- 23438003 TI - Boosting workplace stair utilization: a study of incremental reinforcement. AB - PURPOSE: This study was designed to determine whether engagement in stair taking can be increased in a worksite setting through the provision of an employer sponsored, behavior-based incentive system in which employees (members) accumulate points that can be redeemed for merchandise. METHODS/DESIGN: ChipRewards implemented stair utilization in one employer as a part of a larger health incentive engagement program. Using an AB (baseline-intervention) design, members (N = 216) were observed for 6 months (6.17.10 to 12.14.10 or 129 weekdays after excluding 52 weekend days) before the intervention (baseline) and after 6 months (1.1.11 to 6.30.11 with the same number of weekdays) of implementation. RESULTS: Members were 84% female, 51% Caucasian, 48% African American, 3% Hispanic, and 45 years average age. The number of total stair transactions for all members for all days monitored increased from 5,070 to 38,900, and the average number of stair transactions per day rose from 39 to 301, representing over a 600% increase. The overall cost of incentives for stair utilization was $3,739.30 or $17.55 per member on average. CONCLUSION/IMPLICATIONS: This study supports that stair usage in the workplace is a viable way to increase physical activity. This study adds to existing research that attempted to increase stair utilization through promotion only by adding a behavioral reinforcement strategy. Finally, this study demonstrates that a physical activity among employees at the worksite can be increased with minimal relative cost. PMID- 23438004 TI - Promoting physical activity: fertile ground for rehabilitation psychology. AB - Comments on the article by Schmacher et al. (see record 2013-06066-009). Readers of Rehabilitation Psychology might be surprised, or maybe even alarmed, to find an article on promoting physical activity in able-bodied people between the covers of their latest issue. This commentary contends that this area of research and practice might be one into which rehabilitation psychologists want to venture. Schumacher and coworkers describe a field test (N = 216) of a token system for reinforcing stair taking. The setting was an eight-story office building housing a single company in a midsized city in the southeastern United States. Schumacher et al. report an increase from 39 stair transactions per day by all study participants in the 6 months before implementation of the intervention to 301 transactions in the 6 months after the implementation of the intervention, which represents a 600% increase. The cost of the intervention was only $17 per person. Although replication of these results in a study with additional sources of control would increase confidence in the validity of the findings, the size of the gains in stair taking, the number of participants in the study, the length of the baseline and implementation periods, and the objective measurement of outcome warrant attention. PMID- 23438005 TI - Coping humor and family functioning in parents of children with disabilities. AB - OBJECTIVE: The purpose of this study was to investigate whether coping humor predicted certain measures of family functioning in parents of children with disabilities. METHOD: Seventy-two parents of children diagnosed primarily with autism spectrum disorders and multiple disabilities completed the Coping Humor Scale (CHS) and Family Adaptability and Cohesion Evaluation Scales (FACES IV). The FACES IV measures two major dimensions of family functioning: cohesion and flexibility. The CHS measures the degree to which participants use humor to cope with stressful experiences in their lives. Optimal functioning of the family is theorized to be based on a balanced level of both cohesion and flexibility. In the present study, coping humor was hypothesized to predict balanced cohesion as well as balanced flexibility. The data were analyzed using single and hierarchical linear regression. RESULTS: The results of the regressions indicated that coping humor significantly, albeit weakly, predicted cohesion and flexibility. However, the effects of education level and the number of children in the family also had a significant predictive effect on cohesion and flexibility. CONCLUSIONS: Contributions of the study, limitations, and implications for future research and clinical practice are discussed. PMID- 23438006 TI - The Kennedy Krieger Independence Scales-Spina Bifida Version: a measure of executive components of self-management. AB - PURPOSE/OBJECTIVE: Successful implementation of functional self-care skills depends upon adequate executive functioning; however, many scales assessing adaptive skills do not address the inherent executive burden of these tasks. This omission is especially relevant for individuals with spina bifida, for whom medical self-care tasks impose a significant burden requiring initiation and prospective memory. The Kennedy Krieger Independence Scales-Spina Bifida Version (KKIS-SB) is a caregiver-reported measure designed to address this gap; it assesses skills for managing both typical and spina bifida-related daily self care demands, with a focus on the timely and independent initiation of adaptive skills. RESEARCH METHOD/DESIGN: Parents of 100 youth and young adults with spina bifida completed the KKIS-SB. Exploratory factor analysis and Pearson's correlations were used to assess the factor structure, reliability, and construct validity of the KKIS-SB. RESULTS: The scale demonstrates excellent internal consistency (Cronbach's alpha = .891). Exploratory factor analysis yielded four factors, explaining 65.1% of the total variance. Two primary subscales were created, initiation of routines and prospective memory, which provide meaningful clinical information regarding management of a variety of typical (e.g., get up on time, complete daily hygiene routines on time) and spina bifida-specific self care tasks (e.g., begin self-catheterization on time, perform self-examination for pressure sores). CONCLUSIONS/IMPLICATIONS: Based upon internal consistency estimates and correlations with measures of similar constructs, initial data suggest good preliminary reliability and validity of the KKIS-SB. PMID- 23438007 TI - Evaluating the needs of military and veterans' families in a polytrauma setting. AB - OBJECTIVE: To examine the perceived importance of needs and the extent to which they are met among a sample of family members in an inpatient polytrauma setting. METHOD: The Family Needs Questionnaire was administered to 44 family members of patients at the Polytrauma Rehabilitation Center at McGuire Veterans Affairs Medical Center over a 30-month period. RESULTS: Families rated health information needs as most important and most frequently met. conversely, family members rated emotional support and instrumental support needs as least important and most frequently unmet. CONCLUSION: Preliminary data suggest that the similarity between family needs in military and civilian settings is noteworthy, and provide direction for development of empirically based family intervention models for polytrauma settings. PMID- 23438008 TI - Chronic pain and the interpersonal theory of suicide. AB - OBJECTIVE: Chronic pain is a known risk factor for suicide. To date, however, few studies of people with chronic pain have tested specific predictions about suicidal ideation that are derived from theory. The interpersonal theory of suicide proposes that the psychological constructs of thwarted belongingness and perceived burdensomeness are unique and independent precursors to suicidal ideation. We tested this hypothesis in a clinical sample of patients with chronic pain. METHOD: A total of 303 patients of a chronic pain rehabilitation program completed measures of pain severity, duration, and disability; cognitive affective measures of depression and catastrophizing; and interpersonal measures of relationship distress and self-perceived burden to others. The latter measures were included as indices of the belongingness and burdensomeness constructs. Participants also rated two items pertaining to suicidal ideation. RESULTS: In a multiple regression analysis, both distress in interpersonal relations (beta = 0.12, p = .037) and self-perceived burden to others (beta = 0.25, p < .001) were significant predictors of suicidal ideation, even after adjusting statistically for demographic characteristics, pain severity and duration, functional limitations, catastrophizing, and depression. CONCLUSIONS: These findings suggest that the interpersonal theory is relevant to understanding elevated rates of suicidal ideation among people with chronic pain, and may have broader applicability to other populations with chronic illness or disability. PMID- 23438009 TI - Differential timing of defense-related responses induced by cerato-platanin and cerato-populin, two non-catalytic fungal elicitors. AB - The cerato-platanin (CP) family consists of fungal-secreted proteins involved in various stages of the host-fungus interaction and acting as phytotoxins and elicitors of defense responses. The founder member of this family is CP, a non catalytic protein with a six-stranded double-psibeta-barrel fold. Cerato-populin (Pop1) is an ortholog showing low sequence identity with CP. CP is secreted by Ceratocystis platani, the causal agent of the canker stain of plane. Pop1 is secreted by Ceratocystis populicola, a pathogen of poplar. CP and Pop1 have been suggested to act as PAMPs (pathogen-associated molecular patterns) because they induce phytoalexin synthesis, transcription of defense-related genes, restriction of conidia growth and cell death in various plants. Here, we treated plane leaves with CP or Pop1, and monitored defense responses to define the role of these elicitors in the plant interactions. Both CP and Pop1 were able to induce mitogen activated protein kinases (MAPKs) phosphorylation, production of reactive oxygen species and nitric oxide, and overexpression of defense related genes. The characteristic DNA fragmentation and the cytological features indicate that CP and Pop1 induce cell death by a mechanism of programmed cell death. Therefore, CP and Pop1 can be considered as two novel, non-catalytic fungal PAMPs able to enhance primary defense. Of particular interest is the observation that CP showed faster activity compared to Pop1. The different timing in defense activation could potentially be due to the structural differences between CP and Pop1 (i.e. different hydrophobic index and different helix content) therefore constituting a starting point in unraveling their structure-function relationships. PMID- 23438010 TI - A nonribosomal peptide synthetase mediates siderophore production and virulence in the citrus fungal pathogen Alternaria alternata. AB - Alternaria species produce and excrete dimethyl coprogen siderophores to acquire iron. The Alternaria alternata gene AaNPS6, encoding a polypeptide analogous to fungal nonribosomal peptide synthetases, was found to be required for the production of siderophores and virulence on citrus. Siderophores purified from culture filtrates of the wild-type strain did not induce any phytotoxicity on the leaves of citrus. Fungal strains lacking AaNPS6 produced little or no detectable extracellular siderophores and displayed an increased sensitivity to H2O2, superoxide-generating compounds (KO2 and menadione) and iron depletion. Deltanps6 mutants were also defective for the production of melanin and conidia. The introduction of a wild-type AaNPS6 under the control of its endogenous promoter to a Deltanps6 null mutant at least partially restored siderophore production and virulence to citrus, demonstrating a functional link between iron uptake and fungal pathogenesis. Elevated sensitivity to H2O2, seen for the Deltanps6 null strain could be relieved by exogenous application of ferric iron. The expression of the AaNPS6 gene was highly up-regulated under low-iron conditions and apparently controlled by the redox-responsive yeast transcriptional regulator YAP1. Hence, the maintenance of iron homeostasis via siderophore-mediated iron uptake also plays an important role in resistance to toxic reactive oxygen species (ROS). Our results demonstrate further the critical role of ROS detoxification for the pathogenicity of A. alternata in citrus. PMID- 23438011 TI - Sexual behaviour after antiretroviral therapy initiation in female sex workers and HIV-positive patients from the general population, Cotonou, Benin. AB - From September 2008 to December 2011, we enrolled and followed-up 247 HIV negative, 88 untreated and 32 treated HIV-positive female sex workers (FSWs), as well as 238 untreated and 115 treated HIV-positive patients from the general population (GP) of Cotonou, Benin. We wanted to assess the effect of antiretroviral therapy (ART) on sexual risk-taking in FSWs and patients from the GP. We used multivariate log binomial regression models for repeated measures to compare risky behaviours reported during pre-ART and post-ART visits and we performed linear time-trend analyses to assess changes in condom use in all five groups. At 58.8% of pre-ART and 45.3% of post-ART visits (adjusted p value=0.293), treated FSWs have reported >=16 clients during the last week of work. Inconsistent condom use with clients over the same period decreased by more than 50% (from 20.7 to 10.0%, adjusted p-value=0.082). In treated patients from the GP, inconsistent condom use with regular partners during the last four months was reported at 52.8% of pre-ART and 53.5% of post-ART visits (p=0.778). Reported casual sex was stable (36.8% versus 38.7%, adjusted p-value=0.924). In linear time-trend analyses, there was a significant downward trend in inconsistent condom use at the early stage of the study and stability thereafter in all HIV negative and HIV-positive FSWs. There was no negative alteration in sexual behaviour following ART initiation either inpatients from the GP or in FSWs. The results underscore the key role of concomitant sexual risk-reduction strategies. PMID- 23438013 TI - Wicking in a powder. AB - We investigate the wicking in granular media by considering layers of grains at the surface of a liquid and discuss the critical contact angle below which spontaneous impregnation takes place. This angle is found to be on the order of 55 degrees for monodisperse layers, significantly smaller than 90 degrees , the threshold value for penetrating assemblies of tubes. Owing to geometry, impregnating grains is more demanding than impregnating tubes. We also consider the additional effects of polydispersity and pressure on this wetting transition and discuss the corresponding shift observed for the critical contact angle. PMID- 23438012 TI - Palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides via tert butyl isocyanide insertion. AB - A simple and efficient palladium-catalyzed carbonylative Sonogashira coupling via tert-butyl isocyanide insertion has been developed, which demonstrates the utility of isocyanides in intermolecular C-C bond construction. This methodology provides a novel pathway for the synthesis of alkynyl imines which can undergo simple silica gel catalyzed hydrolysis to afford alkynones. The approach is tolerant of a wide range of substrates and applicable to library synthesis. PMID- 23438014 TI - Relative intermolecular orientation probed via molecular heat transport. AB - In this work, through investigating a series of liquid, glassy, and crystalline samples with ultrafast multiple-mode 2D IR and IR transient absorption methods, we demonstrated that the signal anisotropy of vibrational relaxation-induced heat effects is determined by both relative molecular orientations and molecular rotations. If the relative molecular orientations are randomized or molecular rotations are fast compared to heat transfer, the signal anisotropy of heat effects is zero. If the relative molecular orientations are anisotropic and the molecular rotations are slow, the signal anisotropy of heat effects can be nonzero, which is determined by the relative orientations of the energy source mode and the heat sensor mode within the same molecule and in different molecules. We also demonstrated that the correlation between the anisotropy value of heat signal and the relative molecular orientations can be quantitatively calculated. PMID- 23438015 TI - A natural topological insulator. AB - The earth's crust and outer space are rich sources of technologically relevant materials which have found application in a wide range of fields. Well established examples are diamond, one of the hardest known materials, or graphite as a suitable precursor of graphene. The ongoing drive to discover novel materials useful for (opto)electronic applications has recently drawn strong attention to topological insulators. Here, we report that Kawazulite, a mineral with the approximate composition Bi2(Te,Se)2(Se,S), represents a naturally occurring topological insulator whose electronic properties compete well with those of its synthetic counterparts. Kawazulite flakes with a thickness of a few tens of nanometers were prepared by mechanical exfoliation. They exhibit a low intrinsic bulk doping level and correspondingly a sizable mobility of surface state carriers of more than 1000 cm(2)/(V s) at low temperature. Based on these findings, further minerals which due to their minimized defect densities display even better electronic characteristics may be identified in the future. PMID- 23438016 TI - Crude tonsillectomy and local concepts of illness in Kisoro, Uganda: community perception of gapfura and its treatment. AB - The practice of crude tonsillectomy (CT), performed by traditional healers for a locally defined illness known as gapfura, has become increasingly common in south western Uganda. This study describes perceptions of gapfura and examines the intersection of locally defined and biomedical illness. Kisoro District Hospital (KDH) staff (n=55) were surveyed, with 95% reporting that CT caused death, and 60% estimating that recipients died as a result of the procedure. Surveys of community members (n=737) revealed that 95% were familiar with gapfura as a common illness with variable symptoms; syndrome classification categorised 58% of descriptive responses as 'upper respiratory infection', while 42% suggested more severe diseases. Although only 26% of community respondents told the interviewer that CT was the best treatment, 47% believed the majority of community members use CT and 43% of those treated for gapfura within the past year received CT. The divergent perceptions of community members and allopathic health providers may be rooted in the use of gapfura as an idiom reflecting larger social stressors and CT as a response to this distress. Interventions to curb the practice of CT need to be multifaceted and will involve further anthropologic investigation, public health involvement, and education that encompasses the social context of disease. PMID- 23438017 TI - Gender difference in tooth autotransplantation with complete root formation: a retrospective survey. AB - Gender-related risk factors in the survival of transplanted teeth with complete root formation have not yet been identified. The purpose of this study was to investigate gender differences in tooth autotransplantation at dental clinics. We asked participating dentists to provide information on transplantations they had undertaken from 1 January 1990 to 1931 December 2010. The data were screened to exclude patients who underwent more than one transplantation, smokers or those whose smoking habits were unknown, patients under 30 or who were 70 years old and over, cases where the transplanted teeth had incomplete root formation or multiple roots and those with fewer than 20 present teeth post-operation. We analysed 73 teeth of 73 males (mean age, 47.2 years) and 106 teeth of 106 females (mean age, 45.3 years) in this study. The cumulative survival rate and mean survival time were calculated using the Kaplan-Meier method. The cumulative survival rate for males was 88.3% at the 5-year mark, 64.8% at 10 years and 48.6% at 15 years; for females, it was 97.2% at the 5-year mark, 85.9% at 10 years and 85.9% at 15 years. A log-rank test indicated the difference between males and females to be significant (P = 0.011). There was also a significant difference in the main causes for the loss of transplanted teeth: males lost more transplanted teeth due to attachment loss than females (P < 0.05). These results indicate that males require more attention during the autotransplantation process, particularly at the stage of pre-operation evaluation and that of follow-up maintenance. PMID- 23438018 TI - Recent northward range expansion promotes song evolution in a passerine bird, the Light-vented Bulbul. AB - In common with human speech, song is culturally inherited in oscine passerine birds ('songbirds'). Intraspecific divergence in birdsong, such as development of local dialects, might be an important early step in the speciation process. It is therefore vital to understand how songs diverge, especially in founding populations. The northward expansion of the Light-vented Bulbul Pycnonotus sinensis (J. F. Gmelin, 1789) into north China in the last 30 years provides an excellent opportunity to study birdsong evolution. We compared ~4400 songs from newly established northern populations with ~2900 songs from southern populations to evaluate song divergence after recent expansion. The total pool of syllables and especially song types was considerably smaller in the north than in the south, indicating 'founder effects' in the new population. The ancestral pattern of mosaic song dialects changed into a pattern of wide geographical sharing of a few song types and syllables, likely the result of fewer geographical barriers to 'meme flow', and the recent spread across a large area in the north. Our results suggest that song evolution and vocal trait shifts can arise rapidly after range expansion, and that in the Light-vented Bulbul 'founder effects', geographical isolation, and recent rapid expansions played important roles in the evolution of song dialects. PMID- 23438019 TI - The efficacy of amiodarone-propranolol combination for the management of childhood arrhythmias. AB - BACKGROUND: The aim of this study was to present our data regarding the efficacy and safety of combining amiodarone and propranolol for the management of arrhythmias in infants. METHODS: Children aged between 0 and 18 years who received combination therapy with amiodarone and propranolol for persistent monotherapy resistance tachyarrhythmia between 2007 and 2011 were included in the study. Treatment efficacy and adverse effects were evaluated by review of clinical signs and symptoms, 12-lead electrocardiogram, 24-hour Holter monitorization, liver enzymes, thyroid function tests, chest x-ray, and ophthalmologic examination. RESULTS: A total of 25 patients (15 male and 10 female) were enrolled in this study with a mean age of 17.9 months (0-132) and a mean weight of 8.65 kg (2.2-25). In 18 patients, treatment was started before their first age. Tachyarrhythmia persisted in two patients despite combination therapy, and treatment regimen was changed. Complete control of the arrhythmia was achieved within the first 2 months of combination treatment in 20 patients, whereas in the remaining three patients short attacks of tachycardia who responded to dose increases were controlled beyond 2 months of treatment and no recurrence were observed. Overall, success of amiodarone-propranolol combination treatment was 92%. Mild elevation in thyroid-stimulating hormone level was observed in one patient that required discontinuation of treatment. CONCLUSION: Our results suggest that a combination of amiodarone and propranolol is an effective and safe option for the treatment of persistent arrhythmias in neonates and infants, and may serve as a bridge to ablation therapy in older children. PMID- 23438020 TI - The role of anthocyanin in photoprotection and its relationship with the xanthophyll cycle and the antioxidant system in apple peel depends on the light conditions. AB - The synthesis of anthocyanin, the xanthophyll cycle, the antioxidant system and the production of active oxygen species (AOS) were compared between red and non red apple cultivars, in response to either long-term sunlight exposure (high light intensity) during fruit development, or to exposure of bagged fruits to lower light intensity late in fruit development. During fruit development of red and non-red apples, the xanthophyll cycle pool size decreased much more in red apple peel late in development. With accumulation of AOS induced by long-term sunlight exposure, enhancement of the antioxidant system was found. However, this change became significantly lower in red apple than non-red apple as fruit developed, which might serve to accelerate the anthocyanin synthesis in red apple peel. When, late in fruit development, bagged fruits were exposed to sunlight, the accumulation of AOS was lower in red apple peel than in non-red peel. This could be due to the higher anthocyanin concentration in the red peels. Meanwhile, compared with that in non-red cultivar, the xanthophyll cycle and the antioxidant system in red apple peel were protected first but then down-regulated by its higher anthocyanin concentration during sunlight exposure. In conclusions, red and non-red apples peel possess different photoprotective mechanisms under high light conditions. The relationship between anthocyanin synthesis and the xanthophyll cycle, and the antioxidant system, depends on the light conditions that fruit undergoes. PMID- 23438021 TI - Lanthanide speciation in potential SANEX and GANEX actinide/lanthanide separations using tetra-N-donor extractants. AB - Lanthanide(III) complexes with N-donor extractants, which exhibit the potential for the separation of minor actinides from lanthanides in the management of spent nuclear fuel, have been directly synthesized and characterized in both solution and solid states. Crystal structures of the Pr(3+), Eu(3+), Tb(3+), and Yb(3+) complexes of 2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3 yl)-1,10-phenanthroline (CyMe4-BTPhen) and the Pr(3+), Eu(3+), and Tb(3+) complexes of 6,6'-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3 yl)-2,2'-bypyridine (CyMe4-BTBP) were obtained. The majority of these structures displayed coordination of two of the tetra-N-donor ligands to each Ln(3+) ion, even when in some cases the complexations were performed with equimolar amounts of lanthanide and N-donor ligand. The structures showed that generally the lighter lanthanides had their coordination spheres completed by a bidentate nitrate ion, giving a 2+ charged complex cation, whereas the structures of the heavier lanthanides displayed tricationic complex species with a single water molecule completing their coordination environments. Electronic absorption spectroscopic titrations showed formation of the 1:2 Ln(3+)/L(N4-donor) species (Ln = Pr(3+), Eu(3+), Tb(3+)) in methanol when the N-donor ligand was in excess. When the Ln(3+) ion was in excess, evidence for formation of a 1:1 Ln(3+)/L(N4 donor) complex species was observed. Luminescent lifetime studies of mixtures of Eu(3+) with excess CyMe4-BTBP and CyMe4-BTPhen in methanol indicated that the nitrate-coordinated species is dominant in solution. X-ray absorption spectra of Eu(3+) and Tb(3+) species, formed by extraction from an acidic aqueous phase into an organic solution consisting of excess N-donor extractant in pure cyclohexanone or 30% tri-n-butyl phosphate (TBP) in cyclohexanone, were obtained. The presence of TBP in the organic phase did not alter lanthanide speciation. Extended X-ray absorption fine structure data from these spectra were fitted using chemical models established by crystallography and solution spectroscopy and showed the dominant lanthanide species in the bulk organic phase was a 1:2 Ln(3+)/L(N-donor) species. PMID- 23438022 TI - Wound blotting: a convenient biochemical assessment tool for protein components in exudate of chronic wounds. AB - Because wound exudate includes secreted proteins that affect wound healing, its biochemical analysis is useful for objective assessment of chronic wounds. Wound blotting allows for collection of fresh exudate by attaching a nitrocellulose membrane onto the wound surface. To determine its applicability for several analysis methods and its executability in clinical wound assessment, this study comprised an animal experiment and clinical case reports. In the animal experiment, full-thickness wounds were created on the dorsal skin of mice, and exudate samples were collected daily by a conventional method and by wound blotting. Extremely small but adequate volumes of exudate were collected by wound blotting for subsequent analysis in the animal experiments. Immunostaining showed the concentration and distribution of tumor necrosis factor (TNF) alpha. The activity of alkaline phosphatase was visualized by reaction with chemiluminescent substrate. The TNF distribution analysis indicated three different patterns: wound edge distribution, wound bed distribution, and a mostly negative pattern in both the animal and clinical studies, suggesting association between the TNF distribution pattern and wound healing. Our results indicate that wound blotting is a convenient method for biochemical analysis of exudate and a candidate tool with which to predict the healing/deterioration of chronic ulcers. PMID- 23438023 TI - Leber hereditary optic neuropathy mutations and toxic-genetic optic neuropathy - authors' response. PMID- 23438024 TI - Complete mitochondrial genome of the freshwater sculpin Cottus koreanus (Scorpaeniformes, Cottidae). AB - The complete mitochondrial genome was sequenced from the freshwater sculpin Cottus koreanus. The genome sequence was 16,560 bp in size, and the gene order and contents were identical with those of previously reported fish mitochondrial genomes. Of 13 protein-coding genes (PCGs), 3 genes (CO2, ND4, Cytb) had incomplete stop codons. The base composition of C. koreanus mitogenome showed anti-G bias (13.94% and 12.73%) on the second and third positions of PCGs, respectively. PMID- 23438025 TI - Symptomatic compression of the pulmonary artery by a thymic cyst. PMID- 23438026 TI - Influence of the FecX(R) allele in heterozygous ewes on follicular population and outcomes of IVP and ET using LOPU-derived oocytes. AB - Ewes heterozygous for the FecX(R) allele (R+) in the bone morphogenetic protein 15 (BMP15) gene display increased ovulation rate and prolificacy. Besides this phenotypic advantage, the influence of the FecX(R) allele on follicle number and size, oocyte competence and in vitro production (IVP) remains undefined. With these aims, 8 R+ and 8 wild-type (++) ewes were subjected to 2 laparoscopic ovum pick-up (LOPU) trials (four sessions per trial; two with and two without FSH) and subsequent IVP and fresh embryo transfer. All follicles >3 mm were punctured (n = 1673). Genotype did not significantly affect the number of punctured follicles per ewe and session (10.4 and 10.2 in R+ and ++ untreated ewes, 17.4 and 14.3 in R+ and ++ FSH-treated ewes, respectively), but follicular diameter of R+ ewes was significantly reduced compared with ++ ewes (-0.2 mm in untreated and -0.8 mm in FSH-treated ewes; p < 0.01). R+ ewes showed higher recovery rate and increased numbers of total and suitable cumulus-oocyte complexes for in vitro maturation (IVM). Similar rates of day 8 blastocysts were observed in R+ (36.1%, 147/407) and ++ (32.6%, 100/307) ewes, but the final output of day 8 blastocysts per ewe and session was higher in R+ ewes (+0.75; p < 0.005), without differences in survival rate at birth of the transferred embryos (40.4%, 21/52 vs 36.4%, 16/44, respectively). In conclusion, a higher number of oocytes proven to be competent for in vitro development and embryo survival after transfer are recovered from R+ ewes, despite the lower mean size of their follicles at puncture. PMID- 23438027 TI - Infectious ophthalmology, a neglected field in clinical microbiology. PMID- 23438028 TI - Endophthalmitis. AB - Endophthalmitis means bacterial or fungal infection inside the eye involving the vitreous and/or aqueous humors. Most cases are exogenous and occur after eye surgery, after penetrating ocular trauma, or as an extension of corneal infection. An increasing number of cases are occurring after intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications. Endophthalmitis may also be endogenous, arising from bacteraemic or fungaemic seeding of the eye. The infected eye never serves as a source of bacteraemia or fungaemia, however. The most common pathogens in endophthalmitis vary by category. Coagulase-negative staphylococci are the most common causes of post cataract endophthalmitis, and these bacteria and viridans streptococci cause most cases of post-intravitreal anti-VEGF injection endophthalmitis, Bacillus cereus is a major cause of post-traumatic endophthalmitis, and Staphylococcus aureus and streptococci are important causes of endogenous endophthalmitis associated with endocarditis. In Taiwan and other East Asian nations, Klebsiella pneumoniae causes most cases of endogenous endophthalmitis, in association with liver abscess. Endogenous fungal endophthalmitis in hospitalized patients is usually caused by Candida species, particularly Candida albicans. Acute endophthalmitis is a medical emergency. The most important component of treatment is the intravitreal injection of antibiotics, along with vitrectomy in severe cases. Systemic antibiotics should be used in cases of endogenous endophthalmitis and exogenous fungal endophthalmitis, but their role in exogenous bacterial endophthalmitis is uncertain. Repeated intravitreal injections of antibiotics may be necessary if there is no response to the initial therapy. Many eyes that receive prompt and appropriate treatment will recover useful vision. PMID- 23438030 TI - The identification of culicine mosquitoes in the Shadegan wetland in southwestern Iran. AB - In order to study the culicine mosquito fauna (Diptera: Culicidae: Culicinae) of the Shadegan wetland in southern Khouzestan Province of Iran, sampling was carried out using hand catch, total catch, and New Jersy light traps, from October 2008 to March 2009. A total of 2664 culicine mosquitoes were captured. Three genera and five species were identified, including Culex pipiens L., Cx. tritaeniorhynchus Giles, Cx. sinaiticus Kirkpatrik, Cx. modestus Ficalbi, Ochlerotatus caspius Pallas and a Culiseta species. All of these species, reported for the first time, were from the Shadegan wetland and Khouzestan Province, and some are medically important. PMID- 23438031 TI - Rates of HIV, syphilis, and HCV infections among different demographic groups of female sex workers in Guangxi China: evidence from 2010 national sentinel surveillance data. AB - To examine the prevalence of HIV, syphilis, and hepatitis C virus (HCV) infections by demographic characteristics and identify the subgroups of female sex workers (FSW) who are at a higher risk of the infections. Secondary analysis of the 2010 National Sentinel Surveillance (NSS) data was conducted in the current study. A total of 12,622 FSW recruited from 35 NSS sites in Guangxi, China were included in the analysis. FSW were tested for HIV, syphilis, and HCV. The overall prevalence of HIV, syphilis, and HCV infections were 1.0, 6.1, and 1.0%, respectively. The prevalence of HIV and syphilis infections was significantly higher among women who were 40 years of age or older, worked in small commercial sex venues or on the street, were divorced or widowed, or had no formal schooling. A very high HIV infection prevalence (8.2%) was observed among a small number of cross-border foreign FSW (n=49). The prevalence of HCV infection did not differ by most of the demographic characteristics. Living in other provinces or being a Zhuang-ethnic served as protective factors for HCV. The multivariable analyses confirmed the bivariate results suggesting higher prevalence of HIV and syphilis infections among FSW who were older, divorced or widowed, or had no formal schooling. Future HIV intervention prevention efforts among FSW need to pay particular attention to these women in order to effectively curtail the infections among this most-at-risk population as well as to prevent the further spread of HIV and syphilis to other populations. PMID- 23438032 TI - Evaluation of an oscillometric blood pressure monitor for use in anesthetized sheep. AB - OBJECTIVE: To determine the accuracy of an oscillometric blood pressure monitor in anesthetized sheep. STUDY DESIGN: Prospective study. ANIMALS: Twenty healthy adult sheep, 11 males and nine females, weighing 63.6 +/- 8.6 kg. METHODS: After premedication with buprenorphine or transdermal fentanyl, anesthesia was induced with ketamine-midazolam and maintained with isoflurane and ketamine, 1.2 mg kg( 1) hour(-1), +/- lidocaine, 3 mg kg(-1) hour(-1). Invasive blood pressure measurements were obtained from an auricular arterial catheter and noninvasive measurements were from a cuff on the metatarsus or antebrachium. Simultaneous invasive and noninvasive measurements were recorded over a range (55-111 mmHg) of mean arterial pressures (MAP). Isoflurane concentration was increased to decrease MAP and decreasing the isoflurane concentration and infusing dobutamine achieved higher pressures. Invasive and noninvasive measurements were compared. RESULTS: Correlation (R(2)) was good between the two methods of measurement (average of three consecutive readings) for systolic (SAP) (0.87), diastolic (DAP) (0.86), and mean (0.90) arterial pressures (p < 0.001). Bias +/- SD between noninvasive and invasive measurements for SAP was 3 +/- 8 mmHg, for DAP was -10 +/- 7 mmHg, and MAP was -7 +/- 6 mmHg. There was no significant difference between the average of three measurements and use of the first measurement. Correlations using the first measurement were SAP (0.82), DAP (0.84), and MAP (0.89). Bias +/- SD for SAP was 3 +/-10 mmHg, for DAP was -11 +/- 7 mmHg, and MAP was -7 +/- 6 mmHg. The oscillometric monitor slightly overestimated SAP and underestimated DAP and MAP for both average values and the first reading. CONCLUSIONS AND CLINICAL RELEVANCE: This oscillometric model provided MAP measurements that were acceptable by ACVIM standards. MAP measurements with this monitor were lower than those found with the invasive technique so a clinical diagnosis of hypotension may be made in sheep that are not hypotensive. PMID- 23438033 TI - Synthesis of hexa(furan-2-yl)benzenes and their pi-extended derivatives. AB - The first synthesis of hexa(furan-2-yl)benzene derivatives is described. The RhCl3/i-Pr2NEt-catalyzed cyclotrimerization of di(furan-2-yl)acetylenes was an effective method for constructing hexa(furan-2-yl)benzene derivatives in good yields. Their pi-extended derivatives were also synthesized by Suzuki-Miyaura coupling between hexakis(5-Bpinfuran-2-yl)benzene (Bpin = (pinacolato)boryl) and several aryl iodides. PMID- 23438034 TI - Surface functionality as a means to impact polymer nanoparticle size and structure. AB - When polymeric nanoparticles (NPs) are formed by nanoprecipitation, which is a nucleation-growth process, the control over size requires changing the polymer concentration or solvent composition. Here, we demonstrate that the NP size can be controlled independent of polymer variables by introducing a polyelectrolyte (PE) in the aqueous phase. PEs that exhibit hydrogen bonding (H-bonding) yield a reduction in NP size, whereas PEs that do not possess this characteristic promote the formation of larger NPs. The observed effect can be attributed to the formation of a diffusional barrier around the NP in the form of a dense shell. This principle of controlling NP size is not limited to polymers and can also be employed in the production of lipid NPs. PMID- 23438036 TI - Benzimidazole analogs of (L)-tryptophan are substrates and inhibitors of tryptophan indole lyase from Escherichia coli. AB - Tryptophan indole lyase (TIL), an enzyme found in Escherichia coli and related enterobacteria, produces indole from l-tryptophan (l-Trp). Indole is a signaling molecule in bacteria, affecting biofilm formation, pathogenicity and antibiotic resistance. beta-(Benzimidazol-1-yl)-l-alanine (BZI-Ala), 2-amino-4-(benzimidazol 1-yl)butyric acid (homo-BZI-Ala) and 2-amino-5-(benzimidazol-1-yl)pentanoic acid (bishomo-BZI-Ala) were synthesized and tested as substrates and inhibitors of TIL. BZI-Ala is a good substrate of TIL, with Km = 300 MUm, kcat = 5.6 s(-1) and kcat /Km = 1.9 * 10(4) , similar to l-Trp. BZI-Ala is also a good substrate for H463F mutant TIL, which has very low activity with l-Trp. In contrast, homo-BZI Ala was found to be a potent competitive inhibitor of TIL, with a Ki of 13.4 MUm. However, the higher homolog, bishomo-BZI-Ala, was inactive as an inhibitor of TIL at a concentration of 600 MUm, and is thus a much weaker inhibitor. The reaction of TIL with BZI-Ala was too fast to be observed in the stopped-flow spectrophotometer, and shows an aldimine intermediate in the steady state. However, H463F TIL shows equilibrating mixtures of aldimine and quinonoid complexes in the steady state. The spectra of the reaction of TIL with homo-BZI Ala show a rapidly formed intermediate absorbing at 340 nm, probably a gem diamine, that decays slowly to form a quinonoid complex absorbing at 494 nm. The potent binding of homo-BZI-Ala may be due to it being a 'bi-product' analog of the indole-alpha-aminoacrylate complex. These results demonstrate that an amino acid substrate may be converted to a potent inhibitor of TIL simply by homologation, which may be useful in the design of other potent TIL inhibitors. PMID- 23438035 TI - PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. AB - High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs. PMID- 23438037 TI - Aneurysmal bone cyst in a 21-year-old woman presenting with chronic low back pain in a chiropractic office: a case report. AB - OBJECTIVE: To emphasize the importance of early detection, recognition, appropriate investigation, accurate diagnosis, proper referral, and treatment of an aneurysmal bone cyst (ABC) presenting as chronic low back pain (LBP) in a chiropractic office. CLINICAL FEATURES: A 21-year-old female student presented to the chiropractic office with a 2-year history of severe and progressive LBP. The patient described the LBP as an aching type of pain that was more pronounced during activity and exercises. She also reported weight loss and increased fatigue. INTERVENTION AND OUTCOME: A detailed clinical, physical, and imaging evaluation was performed. A well-defined, expansile, and lytic bone lesion with the appearance of a possible ABC was detected; it involved the left inferior half and posterolateral aspect of the vertebral body of L3. RESULTS: Treatment consisted of an L3 hemivertebrectomy resection en bloc and a vertebral fusion from L2 to L4 with tricortical iliac crest graft. After surgery and recovery, LBP was relieved and the bone lesion did not recur. CONCLUSION: Although uncommon, ABC is an important lesion that can affect the spine. Healthcare providers must be aware that the cause of LBP may extend beyond musculoskeletal dysfunction. It is important to identify an ABC and refer the patient for appropriate evaluation and care. PMID- 23438038 TI - Novel planar-structure electrochemical devices for highly flexible semitransparent power generation/storage sources. AB - Flexible and transparent power sources are highly desirable in realizing next generation all-in-one bendable, implantable, and wearable electronic systems. The developed power sources are either flexible but opaque or semitransparent but lack of flexibility. Therefore, there is increasing recognition of the need for a new concept of electrochemical device structure design that allows both high flexibility and transparency. In this paper, we present a new concept for electrochemical device design--a two-dimensional planar comb-teeth architecture on PET substrate--to achieve both high mechanical flexibility and light transparency. Two types of prototypes--dye-sensitized solar cells and supercapacitors--have been fabricated as planar devices and demonstrated excellent device performance, such as good light transparency, excellent flexibility, outstanding multiple large bending tolerance, light weight, effective prevention of short circuits during bending, and high device integration with up-date microelectronics, compared to conventional sandwich structure devices. Our planar design provides an attractive strategy toward the development of flexible, semitransparent electrochemical devices for fully all-in one elegant and wearable energy management. PMID- 23438039 TI - To target or not to target APRIL in systemic lupus erythematosus: that is the question! AB - Among the cytokines that regulate B-cell homeostasis are the TNF-like ligands B lymphocyte stimulator (BLyS; also B-cell activation factor) and a proliferation inducing ligand (APRIL). BLyS and APRIL share two receptors; that is, B-cell maturation antigen and transmembrane activator and CAML interactor. Therapeutic approaches using biologics are limited for treatment of lupus patients. One previously approved drug is belimumab, which antagonizes the B-cell stimulator BLyS. Atacicept, another biologic inhibiting BLyS and APRIL, was terminated for serious adverse events--raising the question of whether APRIL should be neutralized in autoimmune diseases. PMID- 23438040 TI - Unrecognized intrahepatic cholangiocarcinoma: an analysis of 993 adult cirrhotic liver explants. AB - Liver cirrhosis is a recognized risk factor for intrahepatic cholangiocarcinoma (I-CCa). Small I-CCa nodules might be undiagnosed or misdiagnosed as hepatocellular carcinoma (HCC) in the context of liver cirrhosis. The aim of this study was to determine the prevalence and clinical impact of undetected I-CCa in liver explants of adult cirrhotic patients undergoing liver transplantation (LT). From December 1985 to November 2008, a first LT was performed in 993 adult cirrhotic patients in three French academic Hospitals. All liver explants were analyzed for the presence of nodules. The diagnosis of HCC was made in 331 cases (33.3% of the patients). Similarly, an I-CCa was identified in 10 (1%) patients, with a mean size of 31 +/- 17 mm. The mean age at transplantation was 58.8 yr (range 45 - 66), and all the patients were men. The mean follow-up after LT was 33 months (range 4-52). Post-transplant tumor recurrence was observed in five patients (50%), after a mean delay of 10 months. All five patients died. Malignant recurrence was associated with the presence of venous emboli on liver explants. Our results suggest that unrecognized I-CCa complicating liver cirrhosis is a rare entity, associated with high risk of recurrence and poor prognosis. PMID- 23438041 TI - Reducing the risk of HIV infection during pregnancy among South African women: a randomized controlled trial. AB - Mpumalanga Province, South Africa has one of the highest HIV/AIDS diagnosis rates among pregnant women (~29.4%). This study sought to enhance male involvement in pregnancy to increase HIV disclosure, sexual communication, HIV knowledge and reduce unprotected sex. Participants attending Antenatal Clinics (ANC) completed HIV counseling and testing and were enrolled with male partners (n=239 couples, 478 individuals). Twelve ANCs were randomly assigned to provide a prevention of mother-to-child transmission (PMTCT) intervention or the standard of care, health education sessions plus PMTCT. Participants were assessed at baseline and post intervention (approximately 6-8 weeks post-baseline) on demographics, sexual behavior, HIV-related knowledge, and conflict resolution strategies. Experimental participants increased HIV knowledge, use of negotiation, and decreased intimate partner violence. Additionally, they were more likely to have increased condom use from baseline to post-intervention (OR=5.1, 95% CI=[2.0, 13.3]). Seroconversions in the control condition exceeded experimental (6 vs. 0). HIV serostatus disclosure to partner did not increase over time for men or women within the experimental or control condition. Male involvement in pregnancy may be an important strategy to reduce sexual risk behavior and HIV transmission. Results support the utility of group interventions to enhance communication and HIV knowledge among pregnant couples. PMID- 23438042 TI - Prevalence of macular anatomic abnormalities in high myopia. AB - BACKGROUND AND OBJECTIVE: Macular anatomic abnormalities in high myopia are more frequent in the presence of posterior staphyloma. The objective was to determine the prevalence of foveoschisis, foveal detachment, vascular traction, epiretinal membrane (ERM), and macular hole (MH) in eyes with high myopia by spectral-domain optical coherence tomography. PATIENTS AND METHODS: Prospective, observational study. Eyes with myopia greater than 8 diopters (D) were included. Results were analyzed using chi-square and Student's t tests. RESULTS: The study included 116 eyes of 72 patients. Mean spherical equivalent: -15.04 +/- 5.33 D. Mean axial length: 28.88 +/- 2.31 mm. Foveoschisis was observed in 17 eyes (14.65%), vascular traction in 17 (14.65%), ERM in 13 (11.2%), lamellar MH in two (1.72%), and posterior staphyloma in 41 (35.34%). Presence of foveoschisis, vascular traction, and ERM was more frequent in eyes with posterior staphyloma (P = .0001). CONCLUSION: Macular anatomic abnormalities were observed in 22.41% of eyes with high myopia and in 53.65% of eyes with posterior staphyloma. PMID- 23438043 TI - Subarachnoid pressures and cardiorespiratory parameters during cisternal myelography in isoflurane anaesthetized dogs. AB - OBJECTIVE: To measure subarachnoid pressures, systemic circulatory and respiratory effects, and to calculate cerebral perfusion pressure during cisternal myelography. STUDY DESIGN: Prospective clinical study. ANIMALS: Forty three client owned dogs with clinical signs of spinal disease, weighing 6-56 kg. METHODS: Dogs were premedicated with butorphanol and diazepam intravenously (IV) and anaesthesia was induced with propofol and maintained with isoflurane vaporized in oxygen. Ventilation was spontaneous. Heart and respiratory rates, invasive mean arterial blood pressure (MAP), end tidal carbon dioxide and isoflurane concentration were measured continuously. Initial subarachnoid pressure (SaP0 ) was measured in the cisterna magna with a needle pressure gauge. Iohexol 0.3 mL kg(-1) was injected at a rate of 4.1 mL minute(-1) into the cerebellomedullary cistern. The SaP was recorded during and at 120 seconds after contrast administration. The maximum SaP (SaPmax ) and minimum calculated cerebral perfusion pressure (CPPmin ) were recorded for each case. RESULTS: Prior to contrast injection, mean +/- SD, MAP was 73 +/- 20 mmHg and SaP0 was 10 +/- 3 mmHg. The cerebral perfusion pressure (CPP) was 64 +/- 20 mmHg. The contrast injection increased the SaP0 to 73 +/- 33 mmHg (SaPmax ). After injection, MAP increased to 97 +/- 25 mmHg and the CPP decreased to 14 +/- 34 mmHg. A negative correlation was found between the lowest CPP and body weight (rho = -0.77, p < 0.0001). Nine dogs had bradycardia, apnoea and hypertension, 21 dogs had at least one of these signs. The number of clinical signs showed significant correlation with body weight (rho = -0.68, p < 0.0001), SaPmax (rho = -0.66, p < 0.0001) and CPPmin (rho = -0.73, p < 0.0001). CONCLUSIONS AND CLINICAL RELEVANCE: Cerebral perfusion can severely decrease during cisternal myelography using the standard dose of iohexol. Bradycardia, apnoea and systemic hypertension were associated with decreased CPP. PMID- 23438044 TI - Synthesis of withasomnines and their non-natural analogues from aldehydes and 4 nitro-1-butanol in three steps. AB - Total synthesis of all three pyrazole-based withasomnine alkaloids and selected examples of their non-natural analogs has been achieved from readily available aldehydes and 4-nitro-1-butanol in three steps. Since 4-nitro-1-butanol in turn is prepared in two steps via Michael addition of nitromethane to acrylate followed by borane reduction of the ester group and the key 1,3-dipolar cycloaddition step is carried out with commercially available TMSCHN2, this approach is a very convenient and economical one. PMID- 23438045 TI - Ricinus communis treatment of denture stomatitis in institutionalised elderly. AB - This study compared the effectiveness of Ricinus communis (RC) with Nystatin (NYS) and Miconazole (MIC) in the treatment of institutionalised elderly with denture stomatitis (DS). They (n = 30) were randomly distributed into three groups: MIC, NYS or RC. Clinical and mycological evaluations were performed prior to the use of the antifungal (baseline) and repeated after 15 and 30 days of treatment. The sample was clinically examined for oral mucosal conditions. Standard photographs were taken of the palate, and the oral candidiasis was classified (Newton's criteria). Mycological investigation was performed by swabbing the palatal mucosa, and Candida spp. were quantified by counting the number of colony-forming units (cfu mL-1). The clinical and mycological data were analysed, respectively by Wilcoxon and Student's t-test (alpha = 0.05). Significant improvement in the clinical appearance of DS in the MIC and RC groups was observed between the 1st and 3rd collections (MIC - P = 0.018; RC - P = 0.011) as well as between the 2nd and 3rd collections (MIC - P = 0.018; RC - P = 0.011). Neither groups showed a statistically significant reduction in cfu mL-1 at any time. Although none of the treatments decreased the cfu mL-1, it was concluded that Ricinus communis can improve the clinical condition of denture stomatitis in institutionalised elderly patients, showing similar results to Miconazole. PMID- 23438046 TI - Quantum chemistry aspects of the solvent effects on 3,4-dimethyl-2,5 dihydrothiophen-1,1-dioxide pyrolysis reaction. AB - A theoretical density functional theory (DFT) study was employed to investigate solvent effects on a retro-cheletropic ene reaction. The use of a nonpolar solvent in this retro-ene reaction is desirable to improve the reaction rate. Interactions between 14 different solvents and the reaction mixtures (reactant and transition state) were considered using DFT solvation calculations. These results were used to determine the role of solvents on the rate constants. Theoretical calculations at the B3LYP/6-311++G(d,p) level revealed that in the presence of solvents with low polarity the reaction becomes faster, which is in accordance with experimental data. Transition state-solvent interactions were analyzed by the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. Finally, several correlations between electron densities in bond critical points of the C-S bond and interaction energy as well as vibrational frequencies at the transition state have been investigated. PMID- 23438047 TI - Sequestration of PDC-109 protein by specific antibodies and egg yolk cryoprotects bull spermatozoa. AB - PDC-109, one of the most abundant proteins in bovine seminal plasma, has detrimental effect on spermatozoa in a time- and concentration-dependent manner. Therefore, we hypothesized that sequestration of detrimental protein from ejaculates would be beneficial following cryopreservation of sperm cells. To this aim, we evaluated the effect of sequestration of PDC-109 either by anti-PDC-109 antibodies (Ab) or egg yolk (EY) alone or by the synergistic action of EY + Ab in minimizing cryoinjury to bull spermatozoa. PDC-109 protein was purified by applying two-step chromatography procedures. The purified protein was injected in rabbits to raise antibodies which were isolated using ion-exchange chromatography. After checking the Ab cross-reactivity, they were quantitated and added to ejaculates, either alone or in addition to EY in Tris-glycerol (TG) extender. Thus, ejaculates were processed in extender containing EY + TG (group I), Ab + TG (group II) or EY + Ab + TG (group III). Semen quality parameters (SQPs) viz. viability and acrosome integrity (FITC-PSA), cryoinjury to spermatozoa (chlortetracycline, CTC assay) and in vitro fertility of protein sequestered-semen (zona-penetration assay) were evaluated. A significant (p < 0.05) improvement in post-thaw SQPs as well as in non-capacitated spermatozoa observed at pre-freeze and post-thaw stages of cryopreservation in group III compared with other groups indicated reduction in protein-mediated cryoinjury. From this study, it can be concluded that sequestration of PDC-109 by synergistic action of EY+Ab as compared to either of them alone significantly improve sperm quality and minimize cryoinjury to bull spermatozoa upon storage at ultra-low temperatures. PMID- 23438048 TI - Malaria rapid diagnostic tests in endemic settings. AB - Malaria rapid diagnostic tests (RDTs) are instrument-free tests that provide results within 20 min and can be used by community health workers. RDTs detect antigens produced by the Plasmodium parasite such as Plasmodium falciparum histidine-rich protein-2 (PfHPR2) and Plasmodium lactate dehydrogenase (pLDH). The accuracy of RDTs for the diagnosis of uncomplicated P. falciparum infection is equal or superior to routine microscopy (but inferior to expert microscopy). Sensitivity for Plasmodium vivax is 75-100%; for Plasmodium ovale and Plasmodium malariae, diagnostic performance is poor. Design limitations of RDTs include poor sensitivity at low parasite densities, susceptibility to the prozone effect (PfHRP2-detecting RDTs), false-negative results due to PfHRP2 deficiency in the case of pfhrp2 gene deletions (PfHRP2-detecting RDTs), cross-reactions between Plasmodium antigens and detection antibodies, false-positive results by other infections and susceptibility to heat and humidity. End-user's errors relate to safety, procedure (delayed reading, incorrect sample and buffer volumes) and interpretation (not recognizing invalid test results, disregarding faint test lines). Withholding antimalarial treatment in the case of negative RDT results tends to be infrequent and tendencies towards over-prescription of antibiotics have been noted. Numerous shortcomings in RDT kits' labelling, instructions for use (correctness and readability) and contents have been observed. The World Health Organization and partners actively address quality assurance of RDTs by comparative testing of RDTs, inspections of manufacturing sites, lot testing and training tools but no formal external quality assessment programme of end-user performance exists. Elimination of malaria requires RDTs with lower detection limits, for which nucleic acid amplification tests are under development. PMID- 23438049 TI - Analysis of FOXP3 gene and protein expressions in renal allograft biopsies and their association with graft outcomes. AB - BACKGROUND: The transcription factor FOXP3 is increased in acute renal rejection, but its influence on graft outcomes is unclear. This study correlated FOXP3 with dendritic cells and graft outcomes. METHODS: We assessed 96 kidney transplants undergoing allograft biopsy for cause. FOXP3 mRNA was analyzed by real-time polymerase chain reaction (PCR) and FOXP3 protein and DCsCD83(+) by immunohistochemistry. Graft function and survival were assessed at 5 years post transplantation, as well as by independent predictors of graft loss. RESULTS: Intragraft FOXP3 gene and protein expression were significantly correlated (r = 0.541, p < 0.001). Both FOXP3 mRNA and protein were increased in patients with acute rejection (AR). High expression of FOXP3 mRNA or protein in biopsies did not correlate with clinical variables, but there was a trend to higher positive variation in the glomerular filtration rate (GFR) from biopsy to last follow-up. Patients with FOXP3-mRNA(high) had more DCsCD83(+) in biopsy, but these cells did not associate with AR. Five-year graft survival was not influenced by either FOXP3 mRNA or protein expressions. CONCLUSIONS: FOXP3 mRNA and protein had a good correlation in archival renal graft tissue. Increased FOXP3 expression was found in AR and FOXP3 associated with high numbers of DCs. However, both FOXP3 mRNA and protein was not associated with better allograft outcomes. PMID- 23438050 TI - Under cover of darkness, caterpillars take flight: the immature stages and feeding ecology of the glasswinged butterfly, Oleria baizana in eastern Ecuador. AB - This paper describes the morphology and behavior of the immature stages of Oleria baizana (Haensch) (Lepidoptera: Nymphalidae) from northeastern Ecuador. Brugmansia aurea Lagerh. (Solanales: Solanaceae) is the larval food plant. Eggs are laid singly, off of the host plant in the leaf litter. During the night, larvae climb a food plant seedling and sever a leaf petiole, parachuting with the leaf to the ground where they remain while feeding. Oleria baizana has five larval stadia, and individuals take 77 days to mature from oviposition to adult stage. PMID- 23438051 TI - Sterility testing of apheresis hematopoietic progenitor cell products using an automated blood culture system. AB - BACKGROUND: AABB Standards require monitoring of hematopoietic progenitor cell (HPC) products for microbial contamination. To date, there is no automated blood culture system cleared by the Food and Drug Administration for this application. Our objective was to validate the VersaTREK system (TREK Diagnostic Systems) for sterility testing of apheresis HPC products. STUDY DESIGN AND METHODS: Four aerobic bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mitis, and Bacillus cereus), five anaerobic bacteria (Fusobacterium necrophorum, Clostridium perfringens, Bacteroides fragilis, Prevotella loescheii, and Propionibacterium acnes), and one fungus (Candida albicans) were spiked into apheresis HPC products at concentrations of 10, 10(2) , 10(3) , and 10(4) colony forming units (CFUs)/mL. Aerobic and anaerobic bottles were incubated until positive or for up to 5 days. DNA was simultaneously extracted for polymerase chain reaction amplification of 16S ribosomal RNA (rRNA) gene. RESULTS: All aerobic bacteria grew in both bottles at all concentrations tested within 24 hours, and the time to positivity (TTP) was significantly shorter with aerobic bottles. C. albicans grew in the aerobic media at all concentrations within 30 hours. Anaerobes grew in the anaerobic bottle at all concentrations within 5 days. No bacteria were detected by using 16S rRNA gene amplification at 10(4) CFUs/mL. CONCLUSION: Compared to culture, 16S rRNA gene amplification of HPCs does not improve sensitivity or turnaround time for HPC sterility testing. The VersaTREK system is a reliable tool for detecting microbial contamination of apheresis HPC products with a limit of detection of less than or equal to 10 CFUs/mL. Inclusion of both the aerobic and the anaerobic culture bottles achieves the shortest TTP for all species tested. PMID- 23438052 TI - The complete mitochondrial genome sequence of Sarcocheilichthys nigripinnis (Cypriniformes, Cyprinidae). AB - We determined the complete mitochondrial genome (mitogenome) sequence of Sarcocheilichthys nigripinnis by using long polymerase chain reaction method. The total length of S. nigripinnis mitogenome is 16,680 bp, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs, and a noncoding control region. The overall base composition of S. nigripinnis is 26.36% for T, 26.67% for C, 30.07% for A, and 16.90% for G, with a slight AT bias of 56.43%. PMID- 23438053 TI - Behavioral interventions in patients with an implantable cardioverter defibrillator: lessons learned and where to go from here? AB - BACKGROUND: The implantable cardioverter defibrillator (ICD) is the first-line treatment for primary and secondary prevention of sudden cardiac death. A subgroup of patients experience psychological distress postimplant, and no clear evidence base exists regarding how best to address patients' needs. The aim of this critical review is to provide an overview of behavioral interventions in ICD patients to date, and to delineate directions for future research using lessons learned from the ongoing RISTA and WEBCARE trials. METHODS: We searched the PubMed and PsycInfo databases to identify reports of behavioral trials targeting distress and related factors in ICD patients published between 1980 and April 2012. RESULTS: We identified 17 trials for the review. Generally, compared to usual care, behavioral interventions were associated with reduced anxiety and depression and improved physical functioning, with effect sizes ranging from small to moderate-large (0.10-1.79 for anxiety; 0.23-1.20 for depression). Important limitations were small sample sizes and potential selection bias, hampering generalizability of the results. In addition to a need for larger trials, experiences from the RISTA and WEBCARE trials suggest that intervention trials tailored to the individual patient may be the way forward. CONCLUSIONS: Behavioral interventions show promise with respect to reducing distress in ICD patients. Large-scale intervention trials targeted to the individual needs and preferences of patients are warranted, as a "one size fits all" approach is unlikely to work for all ICD patients. PMID- 23438055 TI - Hydrogen plasma treatment of silicon dioxide for improved silane deposition. AB - We describe a method for plasma cleaning silicon surfaces in a commercial tool that removes adventitious organic contamination and enhances silane deposition. As shown by wetting, ellipsometry, and XPS, hydrogen, oxygen, and argon plasmas effectively clean Si/SiO2 surfaces. However, only hydrogen plasmas appear to enhance subsequent low-pressure chemical vapor deposition of silanes. Chemical differences between the surfaces were confirmed via (i) deposition of two different silanes: octyldimethylmethoxysilane and butyldimethylmethoxysilane, as evidenced by spectroscopic ellipsometry and wetting, and (ii) a principal components analysis (PCA) of TOF-SIMS data taken from the different plasma treated surfaces. AFM shows no increase in surface roughness after H2 or O2 plasma treatment of Si/SiO2. The effects of surface treatment with H2/O2 plasmas in different gas ratios, which should allow greater control of surface chemistry, and the duration of the H2 plasma (complete surface treatment appeared to take place quickly) are also presented. We believe that this work is significant because of the importance of silanes as surface functionalization reagents, and in particular because of the increasing importance of gas phase silane deposition. PMID- 23438054 TI - Randomized controlled trial on collagen/oxidized regenerated cellulose/silver treatment. AB - Collagen/oxidized regenerated cellulose (ORC)/silver therapy has been designed to facilitate wound healing by normalizing the microenvironment and correcting biochemical imbalances in chronic wounds. The aim of this study was to compare collagen/ORC/silver therapy to control (standard treatment). Patients with diabetic foot ulcers were randomized to either collagen/ORC/silver (24) or control treatment (15). Wound area measurements and wound fluid samples were taken weekly. Protease levels were measured in wound fluid samples to investigate differences between responders (>=50% reduction in wound area by week 4) and nonresponders (<50% reduction in wound area by week 4). There were significantly more responders in the collagen/ORC/silver group compared with the control group (79% vs. 43%, p = 0.035). There were significantly fewer withdrawals from the study because of infection in the collagen/ORC/silver group compared with the control group (0% vs. 31%, p = 0.012). The sum of matrix metalloproteinase-9 and elastase concentration was higher in nonresponders compared with responders at baseline (p = 0.0705) and week 4 (p = 0.012). The results suggest that collagen/ORC/silver normalizes the wound microenvironment and protects against infection, resulting in improved wound healing. It was also demonstrated that measuring a combination of proteases may be a more relevant prognostic healing marker than any individual protease alone. PMID- 23438056 TI - Metals and metal derivatives in medicine. AB - Several chemical elements are required by living organisms in addition to the four elements carbon, hydrogen, nitrogen and oxygen usually present in common organic molecules. Many metals (e.g. sodium, potassium, magnesium, calcium, iron, zinc, copper, manganese, chromium, molybdenum and selenium) are known to be required for normal biological functions in humans. Disorders of metal homeostasis and of metal bioavailability, or toxicity caused by metal excess, are responsible for a large number of human diseases. Metals are also extensively used in medicine as therapeutic and/or diagnostic agents. In the past 5000 years, metals such as arsenic, gold and iron have been used to treat a variety of human diseases. Nowadays, an ever-increasing number of metal-based drugs is available. These contain a broad spectrum of metals, many of which are not among those essential for humans, able to target proteins and/or DNA. This mini-review describes metal-containing compounds targeting DNA or proteins currently in use, or designed to be used, as therapeutics against cancer, arthritis, parasitic and other diseases, with a special focus on the available information, often provided by X-ray studies, about their mechanism of action at a molecular level. In addition, an overview of metal complexes used for diagnosing diseases is presented. PMID- 23438057 TI - Biological activities and corresponding SARs of andrographolide and its derivatives. AB - In recent years, pharmaceutical chemists have synthesized large numbers of andrographolide derivatives, which bear important biological activities such as anti-inflammatory, antibacterial, antivirus, antitumor, antidiabetic, and antifeedant. Consequently, corresponding SARs were increasingly obvious. This paper aimed to review all the available literature in this field, highlighting the significant achievements on the structural modification and SARs of andrographolide and its derivatives. PMID- 23438058 TI - Are sleep studies helpful in children with Prader-Willi syndrome prior to commencement of growth hormone therapy? AB - AIMS: To examine sleep study findings in children with Prader-Willi syndrome (PWS) referred for polysomnography (PSG) before commencement of growth hormone (GH) and to evaluate the impact of sleep testing on treatment decisions. METHODS: The sleep unit database was used to identify all cases over an 8-year period (2003-2011). Standard overnight PSG was performed in the sleep laboratory. Obstructive sleep apnoea (OSA) was defined by an obstructive apnoea-hypopnoea index >1/h. Age, symptoms of OSA, tonsillar size and body mass index (BMI) Z score were obtained through chart review. RESULTS: OSA was diagnosed in 15 of 34 (44%) cases identified. Those with OSA were significantly older (P = 0.009) and more likely to have enlarged tonsils (P = 0.05) than those without OSA. There was no difference in BMI Z-score or the presence of symptoms of OSA. GH was deferred in 13 (38%) pending treatment for OSA. CONCLUSIONS: OSA was frequently present in children with PWS referred simply to meet the requirement for PSG before starting GH. OSA was more likely in older children and those with enlarged tonsils. GH treatment was deferred in 38% of cases. This study supports routine performance of PSG prior to GH, regardless of clinical history. PMID- 23438059 TI - Structure of the extracellular domains of human and Xenopus Fn14: implications in the evolution of TWEAK and Fn14 interactions. AB - TWEAK (TNF homologue with weak apoptosis-inducing activity) and Fn14 (fibroblast growth factor-inducible protein 14) are members of the tumor necrosis factor (TNF) ligand and receptor super-families. Having observed that Xenopus Fn14 cross reacts with human TWEAK, despite its relatively low sequence homology to human Fn14, we examined the conservation in tertiary fold and binding interfaces between the two species. Our results, combining NMR solution structure determination, binding assays, extensive site-directed mutagenesis and molecular modeling, reveal that, in addition to the known and previously characterized beta hairpin motif, the helix-loop-helix motif makes an essential contribution to the receptor/ligand binding interface. We further discuss the insight provided by the structural analyses regarding how the cysteine-rich domains of the TNF receptor super-family may have evolved over time. DATABASE: Structural data are available in the Protein Data Bank/BioMagResBank databases under the accession codes 2KMZ, 2KN0 and 2KN1 and 17237, 17247 and 17252. STRUCTURED DIGITAL ABSTRACT: TWEAK binds to hFn14 by surface plasmon resonance (View interaction) xeFn14 binds to TWEAK by enzyme linked immunosorbent assay (View interaction) TWEAK binds to xeFn14 by surface plasmon resonance (View interaction) hFn14 binds to TWEAK by enzyme linked immunosorbent assay (View interaction). PMID- 23438060 TI - Diagnostic potential of hepcidin testing in pediatrics. AB - OBJECTIVES: Hepcidin, a peptide hormone released by hepatocytes into circulation is the main regulator of dietary iron absorption and cellular iron release. Although commercial tests are available, assay harmonization for hepcidin has not been yet reached, making reference intervals and consequent clinical decisions still elusive for each assay and specific population. The aim of this study is to set up hepcidin measurement in pediatric age and to investigate its potential usefulness in the diagnosis and management of iron disorders in children. METHODS: Serum hepcidin was measured by using an automated commercial immunoassay. Reference values were obtained from 86 healthy children. Hepcidin was then evaluated in 52 children with diseases where this hormone was expected to be differently regulated. RESULTS: Hepcidin values were 43.6 ng/mL median; 32 52.7 1-3 q: in males and 36.4 ng/mL median; 28.5-45.7 1-3 q: in females (P = 0.039). Hepcidin was significantly higher in postpubertal normal females than in normal males. Hepcidin resulted up-regulated in anemia of chronic disease of children affected by systemic Juvenile Idiopathic Arthritis and decreased after treatment with anakinra, an anti-interleukin-1 receptor antagonist. In iron deficiency anemia patients on oral iron supplementation and in beta-thalassemia subjects, hepcidin levels were similar to those found in healthy subjects. CONCLUSIONS: This study sets up reference values for pediatric population and shows that in normal controls serum hepcidin react differently to puberty in females vs. males. In addition, it suggests that serum hepcidin may discriminate microcytic inflammatory anemia of Juvenile Idiopathic Arthritis from iron deficiency anemia. Overall these findings may represent a helpful tool for future studies tailored to understand the role of hepcidin in management of iron disorders in children. PMID- 23438061 TI - Automating quantum dot barcode assays using microfluidics and magnetism for the development of a point-of-care device. AB - The impact of detecting multiple infectious diseases simultaneously at point-of care with good sensitivity, specificity, and reproducibility would be enormous for containing the spread of diseases in both resource-limited and rich countries. Many barcoding technologies have been introduced for addressing this need as barcodes can be applied to detecting thousands of genetic and protein biomarkers simultaneously. However, the assay process is not automated and is tedious and requires skilled technicians. Barcoding technology is currently limited to use in resource-rich settings. Here we used magnetism and microfluidics technology to automate the multiple steps in a quantum dot barcode assay. The quantum dot-barcoded microbeads are sequentially (a) introduced into the chip, (b) magnetically moved to a stream containing target molecules, (c) moved back to the original stream containing secondary probes, (d) washed, and (e) finally aligned for detection. The assay requires 20 min, has a limit of detection of 1.2 nM, and can detect genetic targets for HIV, hepatitis B, and syphilis. This study provides a simple strategy to automate the entire barcode assay process and moves barcoding technologies one step closer to point-of-care applications. PMID- 23438062 TI - Quantum yield measurement in a multicolor chromophore solution using a nanocavity. AB - Using our nanocavity-based method for precise determination of the absolute quantum yield values, we measure the quantum yield of each of the three different chromophores types with strongly overlapping absorption spectra in a multicolor solution, which is impossible to do by any other existing technique. By measuring the modification of the radiative rate of the chromophores at different cavity lengths, we extract the quantum yield of CdSe/ZnS semiconductor nanocrystals emitting at three different wavelengths and excited by a single wavelength in the multicolor solution. Using several detection channels, we show that only one measurement is needed for determining the quantum yield values of all the types of chromophores in the sample. The obtained results show a very good agreement with the values commonly observed using other techniques. The nanocavity-based method opens up new opportunities of determining fluorescence quantum yields in complex systems and can be used for a big variety of fluorescence studies where multichromophore samples are involved. PMID- 23438063 TI - Chiral cyclopropenyl ketones: reactive and selective Diels-Alder dienophiles. AB - The synthesis and Diels-Alder reactions of cyclopropenyl ketones are described. Cyclopropenyl ketones are highly reactive dienophiles that can engage a range of cyclic dienes and 2,3-dimethylbutadiene. The strategy of using cyclopropenyl ketones to facilitate Diels-Alder reactions is not limited to products that contain three-membered rings, as reductive opening by SmI2 can be used to produce a product that lacks a cyclopropane but retains a quaternary stereogenic center. PMID- 23438064 TI - Acid-base and electrolyte balance following administration of three crystalloid solutions in dogs undergoing elective orthopaedic surgery. AB - OBJECTIVE: To compare acid-base balance and incidence of hyperchloraemic metabolic acidosis following administration of three crystalloid solutions to dogs undergoing anaesthesia for orthopaedic surgery. STUDY DESIGN: Prospective, randomised, clinical study. ANIMALS: Sixty dogs. METHODS: During a non standardised anaesthetic, 0.9% saline (S), Hartmann's solution (H) or a polyionic glucose-free maintenance solution (M) was administered IV at 10 mL kg(-1) hour( 1) . Venous blood pH, PCO2 , PCV, total protein, urea, sodium, potassium and chloride concentrations were measured at induction of anaesthesia (T0) and after 2 hours of fluid therapy (T2). Base excess (BE), bicarbonate, corrected chloride concentration (corrCl), osmolality, change in plasma volume (PV) and strong ion gap (SIG) were calculated. Changes in variables within groups (1-sample Student's t-test/Wilcoxon signed rank test) and between groups (1-way anova/Kruskal-Wallis) were assessed. Data are presented as median (interquartile range). Significance was set at p < 0.05. RESULTS: No significant differences existed between groups for pH, PCO2 , PCV, total protein, urea, potassium, corrCl, PV and SIG. Potassium significantly increased in all groups. Significant differences existed between groups S and M for BE, sodium, chloride, bicarbonate and osmolality, and between groups H and M for sodium and osmolality. Chloride concentration significantly changed from 116 (114-117) to 117 (116-119) mmol L(-1) in group S, 116 (115-118) to 115 (113-117) mmol L(-1) in group H and 116 (115-118) to 114 (113-118) mmol L(-1) in group M. In groups H and M, sodium and osmolality decreased, and BE and bicarbonate concentration increased significantly. Plasma volume increased by 28 (14-44)%, 25 (5-40)% and 24 (13-33)% in groups S, H and M, respectively. CONCLUSION AND CLINICAL RELEVANCE: Hyperchloraemic metabolic acidosis did not develop after intraoperative 0.9% saline, Hartmann's solution or maintenance solution at 10 mL kg(-1) hour(-1) for 2 hours in dogs undergoing elective orthopaedic surgery. Bicarbonate and BE increased after Hartmann's and maintenance solutions. Increases in potassium concentration were unexplained. PMID- 23438065 TI - Elemental ion release from fixed restorative materials into patient saliva. AB - The objective of this study was to quantitatively investigate the elemental ion release from the fixed gold alloy and ceramic crowns into patient saliva. Twenty patients who participated in the study were divided into two equal groups; 1) full coverage type IV gold crowns and 2) full coverage CAD-CAM-fabricated ceramic crowns. Saliva collection and clinical evaluation of marginal integrity and gingival health were performed before crowns preparation, 3 months and 6 months after crowns placement. Clinical evaluations were conducted using California Dental Association criteria. Collected saliva samples were analysed for element release using inductively coupled plasma mass spectrometer. The zinc, copper, palladium, gold and silver were released from type IV gold crowns into saliva, while the silicon and aluminium were released from ceramic crowns. A clinically significant number of subjects had increased release of zinc from baseline to three-month recall and increased silicon release from baseline to both three month and six-month recalls. For all elements, the subjects' counts for the case of three-month recall to six-month recall were never higher than that of the case of baseline to three-month recall except for palladium. No obvious adverse effects on marginal integrity or gingival health were noticed. Significant increased releases of zinc from cast gold crowns and silicon from CAD-CAM fabricated ceramic crowns into the saliva were evident after 3 months of clinical service. PMID- 23438066 TI - Using cost as a consideration for antiretroviral regimen selection: an example using average wholesale prices. AB - Funding for the AIDS Drug Assistance Program (ADAP) has lagged behind the number of persons needing antiretroviral therapy, leading to waiting lists and reduction of needed treatments and services. This paper demonstrates a method of providing more treatment for the same amount of money by selecting clinically equivalent, but lower-cost drug regimens. Average wholesale prices (AWPs) were used to calculate the annual costs of preferred, alternative, and acceptable regimens. The cost of each regimen was divided into $1,000,000 to determine how many patients could be treated per $1,000,000 that an ADAP had to spend. AWPs for preferred regimens ranged from $25,318 to 35,645 per year. For alternative regimens, the range of annual AWPs was $22,002-$32,335. The range for the acceptable regimens was $19,031-$31,543. The range of person treated per $1,000,000 per year was from 28 to 52. Funding shortages will lead ADAPs to resort to waiting lists or other means of denying appropriate care unless alternative approaches to treatment are sought. Cost conscious selection of regimens where there is no harm to individual patients is one alternative approach. Medical conditions that allow exceptions to lower-cost-based regimens must be developed with the assistance of clinicians. PMID- 23438068 TI - An evaluation of clinical stability criteria to predict hospital course in community-acquired pneumonia. AB - A number of different methods exist to assess clinical stability, a key component of pneumonia management. We compared the prognostic value of different stability criteria through a secondary analysis of the Edinburgh pneumonia study database. We studied four clinical stability criteria (Halm's criteria, the ATS criteria, CURB and 50% or more decrease in C-reactive protein from baseline). Outcomes included 30-day mortality, need for mechanical ventilation or vasopressor support (MV/VS), development of a complicated pneumonia, and a combined outcome of the above. A total of 1079 patients (49.8% male), with a median age of 68 years (IQR 53-80), were included. Ninety-three patients (8.6%) died by day 30, 91 patients (8.4%) required MV/VS and 99 patients (9.2%) developed a complicated pneumonia. Patients with increasing severity of pneumonia on admission, assessed by both CURB-65 and PSI, took a progressively longer time to achieve clinical stability assessed by any method (p < 0.001 for all criteria). Halm's criteria had the highest area under the curve (AUC) for prediction of 30-day mortality (AUC 0.95 (0.94-0.96)), need for MV/VS (AUC 0.96 (0.95-0.97)) and combined adverse outcome (AUC 0.96 (0.95-0.97)). C-reactive protein had the highest area under the curve for complicated pneumonia (AUC 0.96 (0.95-0.97)). Adding C-reactive protein to Halm's criteria increased the area under the curve, but the difference was only statistically significant for complicated pneumonia. All of the criteria performed well in predicting adverse outcomes in patients with pneumonia. Halm's criteria performed best when identifying patients at low risk of complications. PMID- 23438067 TI - The lipid composition and physical properties of the yeast vacuole affect the hemifusion-fusion transition. AB - Yeast vacuole fusion requires the formation of SNARE bundles between membranes. Although the function of vacuolar SNAREs is controlled in part by regulatory lipids, the exact role of the membrane in regulating fusion remains unclear. Because SNAREs are membrane-anchored and transmit the force required for fusion to the bilayer, we hypothesized that the lipid composition and curvature of the membrane aid in controlling fusion. Here, we examined the effect of altering membrane fluidity and curvature on the functionality of fusion-incompetent SNARE mutants that are thought to generate insufficient force to trigger the hemifusion fusion transition. The hemifusion-fusion transition was inhibited by disrupting the 3Q:1R stoichiometry of SNARE bundles with the mutant SNARE Vam7p(Q283R) . Similarly, replacing the transmembrane domain of the syntaxin homolog Vam3p with a lipid anchor allowed hemifusion, but not content mixing. Hemifusion-stalled reactions containing either of the SNARE mutants were stimulated to fuse with chlorpromazine, an amphipathic molecule that alters membrane fluidity and curvature. The activity of mutant SNAREs was also rescued by the overexpression of SNAREs, thus multiplying the force transferred to the membrane. Thus, we conclude that either increasing membrane fluidity, or multiplying SNARE-generated energy restored the fusogenicity of mutant SNAREs that are stalled at hemifusion. We also found that regulatory lipids differentially modulated the complex formation of wild-type SNAREs. Together, these data indicate that the physical properties and the lipid composition of the membrane affect the function of SNAREs in promoting the hemifusion-fusion transition. PMID- 23438070 TI - Large scale computational chemistry modeling of the oxidation of highly oriented pyrolytic graphite. AB - Large scale molecular dynamics (MD) simulations are performed to study the oxidation of highly oriented pyrolytic graphite (HOPG) by hyperthermal atomic oxygen beam (5 eV). Simulations are performed using the ReaxFF classical reactive force field. We present here additional evidence that this method accurately reproduces ab initio derived energies relevant to HOPG oxidation. HOPG is modeled as multilayer graphene and etch-pit formation and evolution is directly simulated through a large number of sequential atomic oxygen collisions. The simulations predict that an oxygen coverage is first established that acts as a precursor to carbon-removal reactions, which ultimately etch wide but shallow pits, as observed in experiments. In quantitative agreement with experiment, the simulations predict the most abundant product species to be O2 (via recombination reactions), followed by CO2, with CO as the least abundant product species. Although recombination occurs all over the graphene sheet, the carbon-removal reactions occur only about the edges of the etch pit. Through isolated defect analysis on small graphene models as well as trajectory analysis performed directly on the predicted etch pit, the activation energies for the dominant reaction mechanisms leading to O2, CO2, and CO product species are determined to be 0.3, 0.52, and 0.67 eV, respectively. Overall, the qualitative and quantitative agreement between MD simulation and experiment is very promising. Thus, the MD simulation approach and C/H/O ReaxFF parametrization may be useful for simulating high-temperature gas interactions with graphitic materials where the microstructure is more complex than HOPG. PMID- 23438069 TI - Mitogen-activated protein kinase p38b interaction with delta class glutathione transferases from the fruit fly, Drosophila melanogaster. AB - Glutathione transferases (GSTs) are a family of multifunctional enzymes involved in xenobiotic biotransformation, drug metabolism, and protection against oxidative damage. The p38b mitogen-activated protein kinase is involved in cellular stress response. This study screened interactions between Drosophila melanogaster Meigen (Diptera: Drosophilidae) Delta class glutathione transferases (DmGSTs) and the D. melanogaster p38b MAPK. Therefore, 12 DmGSTs and p38b kinase were obtained as recombinant proteins. The study showed that DmGSTD8 and DmGSTD11b significantly increased p38b activity toward ATF2 and jun, which are transcription factor substrates. DmGSTD3 and DmGSTD5 moderately increased p38b activity for jun. In addition, GST activity in the presence of p38b was also measured. It was found that p38b affected substrate specificity toward CDNB (1 chloro-2,4-dinitrobenzene) and DCNB (1,2-dichloro-4-nitrobenzene) of several GST isoforms, i.e., DmGSTD2, DmGSTD5, DmGSTD8, and DmGSTD11b. The interaction of a GST and p38b can affect the substrate specificity of either enzyme, which suggests induced conformational changes affecting catalysis. Similar interactions do not occur for all the Delta enzymes and p38b, which suggests that these interactions could be specific. PMID- 23438071 TI - The JR blood group system: identification of alleles that alter expression. AB - BACKGROUND: The ABCG2 gene encodes antigens of the JR blood group system. Red blood cells (RBCs) from individuals homozygous for ABCG2 null alleles are nonreactive with polyclonal and monoclonal anti-Jr(a) . However, some RBCs have been defined as Jr(a+(W) /-) or Jr(a-), particularly when tested with polyclonal anti-Jr(a) . In an effort to resolve these apparent serologic ambiguities, the current study was undertaken. STUDY DESIGN AND METHODS: Hemagglutination of RBCs from two individuals known to express a single copy of functional ABCG2 were compared to RBCs from eight unrelated, previously characterized, Jr(a+(W) /-) donors. Standard polymerase chain reaction-based methods were used to characterize ABCG2 alleles. RESULTS: Two monoclonal anti-Jr(a) clones agglutinated RBCs from the eight Jr(a+(W) /-) study subjects. Two of these subjects were homozygous for a missense ABCG2 change (c.1858A; Asp620Asn). Two were heterozygous for two missense changes; one was c.1858G>A and c.421C>A (Asp620Asn; Gln141Lys), and the other was c.1714A>C and c.421C>A (Ser572Arg; Gln141Lys). The remaining four subjects were heterozygous for c.421C>A (Gln141Lys), and for one of four null alleles. CONCLUSIONS: We have identified three ABCG2 alleles that are newly associated with weakened Jr(a) expression. One of these is novel, the missense allele c.1714A>C (Ser572Arg) and two that have been previously described c.421C>A (rs2231142; Gln141Lys) and c.1858G>A (rs34783571; Asp620Asn). In addition, we found a novel, presumed null allele, c.1017_1019delCTC (Ser340del). PMID- 23438072 TI - Pulmonary hypertension among patients on dialysis and kidney transplant recipients. AB - Pulmonary arterial hypertension (PAH) is a serious cardiac complication among patients with end-stage renal disease (ESRD). We investigated pulmonary hypertension and its associated factors among patients who were on chronic dialysis and kidney transplant recipients. One hundred-eighty patients in three groups of hemodialysis (HD), peritoneal dialysis (PD), and kidney transplant were studied. Demographic and clinical characteristics and echocardiographic findings were evaluated. A multivariable linear regression model was used to find factors associated with pulmonary artery pressure. The mean age of participants was 50.3 +/- 15.5 years and 63.9% were male. We found pulmonary hypertension (mean pulmonary artery pressure >25 mmHg) in 31.6%, 8.3%, and 5% of the patients on HD, PD, and transplant recipients, respectively (p < 0.001). In multivariate analyses, being on HD (B = 5.276, confidence interval [CI] 95%: 1.211-9.341), age (B = -0.319, CI 95%: -0.501 to -0.138), smoking (B = 11.631, CI 95%: 1.847 21.416), systolic cardiac dysfunction (B = 6.313, CI 95%: 3.073-9.554), and diastolic cardiac dysfunction (B = 5.227, CI 95%: 1.176-9.277) were associated with systolic pulmonary artery pressure. These results showed that pulmonary hypertension is a frequent cardiac complication among patients with ESRD, and the type of renal replacement therapy (HD), systolic and diastolic cardiac dysfunction, and smoking are associated with increased pulmonary artery pressure. Further studies with larger sample sizes and also prospective studies are recommended in this regard. PMID- 23438073 TI - Complete mitochondrial genome of Anodontostoma chacunda (Clupeiformes: Clupeidae): genome characterization and phylogenetic consideration. AB - The complete mitochondrial genome sequence of Anodontostoma chacunda was determined in this paper. The genome is 16,772 bp in length and contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 2 noncoding regions. With the exception of ND6 and eight tRNA genes, all other genes are encoded on the heavy strand. Gene organization is similar to that observed in most other vertebrates. Overall base compositions of mitogenome are 27.4% of A, 28.7% of C, 25.1% of T, and 18.8% of G. Phylogenetic analyses using the concatenated nucleotide sequence of 12 protein-coding genes on the heavy strand reveal that genus Anodontostoma is the sister group to the assemblage (Nematalosa, (Clupanodon, Konosirus)) within subfamily Dorosomatinae. PMID- 23438074 TI - Communication between (L)-galactono-1,4-lactone dehydrogenase and cytochrome c. AB - l-galactono-1,4-lactone dehydrogenase (GALDH) catalyzes the terminal step of vitamin C biosynthesis in plant mitochondria. Here we investigated the communication between Arabidopsis thaliana GALDH and its natural electron acceptor cytochrome c (Cc). Using laser-generated radicals we observed the formation and stabilization of the GALDH semiquinone anionic species (GALDHSQ ). GALDHSQ oxidation by Cc exhibited a nonlinear dependence on Cc concentration consistent with a kinetic mechanism involving protein-partner association to form a transient bimolecular complex prior to the electron transfer step. Oxidation of GALDHSQ by Cc was significantly impaired at high ionic strength, revealing the existence of attractive charge-charge interactions between the two reactants. Isothermal titration calorimetry showed that GALDH weakly interacts with both oxidized and reduced Cc. Chemical shift perturbations for (1) H and (15) N nuclei of Cc, arising from the interactions with unlabeled GALDH, were used to map the interacting surface of Cc. For Arabidopsis Cc and yeast Cc, similar residues are involved in the interaction with GALDH. These residues are confined to a single surface surrounding the heme edge. The range of chemical shift perturbations for the physiological Arabidopsis Cc-GALDH complex is larger than that of the non physiological yeast Cc-GALDH complex, indicating that the former complex is more specific. In summary, the results point to a relatively low affinity GALDH-Cc interaction, similar for all partner redox states, involving protein-protein dynamic motions. Evidence is also provided that Cc utilizes a conserved surface surrounding the heme edge for the interaction with GALDH and other redox partners. DATABASE: NMR assignment of the backbone amide resonances of Arabidopsis CcRED has been deposited in BMRB database (BMRB accession number 18828). L-galactono-1,4-lactone dehydrogenase (L-galactono-1,4-lactone: ferricytochrome c oxidoreductase, EC 1.3.2.3). PMID- 23438075 TI - Wenxin Keli suppresses ventricular triggered arrhythmias via selective inhibition of late sodium current. AB - BACKGROUND: Wenxin Keli is a popular Chinese herb extract that approximately five million Asians are currently taking for the treatment of a variety of ventricular arrhythmias. However, its electrophysiological mechanisms remain poorly understood. METHODS AND RESULTS: The concentration-dependent electrophysiological effects of Wenxin Keli were evaluated in the isolated rabbit left ventricular myocytes and wedge preparation. Wenxin Keli selectively inhibited late sodium current (INa) with an IC50 of 3.8 +/- 0.4 mg/mL, which was significantly lower than the IC50 of 10.6 +/- 0.9 mg/mL (n = 6, P < 0.05) for the fast INa. Wenxin Keli produced a small but statistically significant QT prolongation at 0.3 mg/mL, but shortened the QT and Tp-e interval at concentrations >= 1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8 +/- 1.0 ms to 38.3 +/- 1.1 ms (n = 6, P < 0.01) at 3 mg/mL at a basic cycle length of 2,000 ms. However, its effect on the QRS duration exhibited weak use-dependency, that is, QRS remained less changed at increased pacing rates than other classic sodium channel blockers, such as flecainide, quinidine, and lidocaine. On the other hand, Wenxin Keli at 1 3 mg/mL markedly reduced dofetilide-induced QT and Tp-e prolongation by attenuation of its reverse use-dependence and abolished dofetilide-induced early afterdepolarization (EAD) in four of four left ventricular wedge preparations. It also suppressed digoxin-induced delayed after depolarization (DAD) and ventricular tachycardias without changing the positive staircase pattern in contractility at 1-3 mg/mL in a separate experimental series (four of four). CONCLUSIONS: Wenxin Keli suppressed EADs, DADs, and triggered ventricular arrhythmias via selective inhibition of late INa. PMID- 23438076 TI - Nuclear export factor 3 is involved in regulating the expression of TGF-beta3 in an mRNA export activity-independent manner in mouse Sertoli cells. AB - The NXF (nuclear export factor) family members are implicated in the transport of mRNA from the nucleus to the cytoplasm. Recently, some members of the NXF family have been reported to play divergent functional roles, such as post transcriptional regulation, translational control, regulation of mRNA stability and trafficking. However, little is known about the roles of NXF3 in spermatogenesis. In the present study, we found that mouse NXF3, specifically expressed in principal cells in segment II of the caput epididymis, as well as Sertoli cells in the mouse testis, was required to mediate TGF-beta (transforming growth factor beta)-induced down-regulation of Tgfb3/TGF-beta3 mRNA expression and protein secretion in Sertoli cells. In addition, NXF3 was also involved in TGF-beta-induced transcriptional regulation of other genes associated with Sertoli cell maturation and the restructuring of the Sertoli cell BTB (blood testis barrier), such as Gata1 (GATA-binding protein 1), Wt1 (Wilms's tumour homologue 1), Cldn11 (claudin11) and Cdkn1a (cyclin-dependent kinase inhibitor 1A or p21(Cip1)). The transcriptional regulation of NXF3 was mediated through physical interaction with STRAP (serine/threonine kinase receptor-associated protein), where NXF3 inhibited the complex formation among Smad7, STRAP and activated type I TGF-beta receptor. Taken together, our data provide mechanistic insights into the roles of NXF3 in TGF-beta-mediated expression of Tgfb3 and other genes. NXF3 may be implicated in Sertoli cell maturation and the extensive restructuring of the Sertoli cell BTB. PMID- 23438077 TI - Robust ordered cubic mesostructured polymer/silica composite films grown at the air/water interface. AB - Polymer/silica composite films, stable to calcination, were produced using catanionic surfactant mixtures (hexadecyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS)) and polymers (polyethylenimine (PEI) or polyacrylamide (PAAm)) at the air/water interface. Film formation processes were probed by time-resolved neutron reflectivity measurements. Grazing incidence X ray diffraction (GID) measurements indicate that the mesophase geometry of the interfacial films could be controlled to give lamellar, 2D hexagonal, and several cubic phases (Pn3-m, Fm3-m, and Im3-m) by varying the polyelectrolyte molecular weight, polyelectrolyte chemical nature, or the cationic:anionic surfactant molar ratio. On the basis of GID results, a phase diagram for the catanionic surfactant/polyelectrolyte/TMOS film system was drawn. These films can be easily removed from the interface and mesoporous silica films which retain the film geometry can be obtained after calcination; moreover, this film preparation method provides a simple way to impart polymer functionality into the mesostructured silica wall, which means these films have potential applications in a variety of fields such as catalysis, molecular separation, and drug delivery. PMID- 23438078 TI - Apnoea after the 2-month immunisation in extremely preterm infants: what happens with the 4-month immunisation? AB - AIM: To describe the outcome of the 4-month immunisation in a cohort of extremely preterm babies who had clinically significant apnoea after their 2-month immunisation. METHOD: A retrospective audit was conducted from January 2001 to January 2011 at Flinders Medical Centre (FMC). Suspected apnoeic reactions to the 2-month immunisation in preterm infants <=28 weeks + 6 days gestation were identified from the Neonatal Unit database. The medical records of babies with reactions then reviewed. We classified apnoeic reactions using predefined criteria into likely, possible or unlikely. The outcomes for subsequent immunisations were determined either when babies were specifically readmitted to FMC for immunisation and cardiorespiratory monitoring, or from the SA Health Immunisation Unit database. RESULTS: There were 203 extremely preterm babies at FMC over the study period who received their 2-month immunisation as inpatients. Clinically significant apnoea post immunisation occurred in 17 (8.4%) babies (likely in 12 and possible 5). The subsequent (4-month) immunisation was given with inpatient cardiorespiratory monitoring in nine babies (seven with likely and two with possible reactions), and no instability was identified. There were eight babies not readmitted to FMC for the subsequent immunisation. No reported adverse events were recorded on the SA Health Immunisation Unit database for these babies. CONCLUSIONS: Apnoea following the 2-month immunisation in extremely preterm infants is not likely to be repeated with the subsequent immunisation. Prospective surveillance using standardised case definitions and monitoring protocols in this population are required to guide uniform practice. PMID- 23438079 TI - Microfluidic wound bandage: localized oxygen modulation of collagen maturation. AB - Restoring tissue oxygenation has the potential to improve poorly healing wounds with impaired microvasculature. Compared with more established wound therapy using hyperbaric oxygen chambers, topical oxygen therapy has lower cost and better patient comfort, although topical devices have provided inconsistent results. To provide controlled topical oxygen while minimizing moisture loss, a major issue for topical oxygen, we have devised a novel wound bandage based on microfluidic diffusion delivery of oxygen. In addition to modulating oxygen from 0 to 100% in 60 seconds rise time, the microfluidic oxygen bandage provides a conformal seal around the wound. When 100% oxygen is delivered, it penetrates wound tissues as measured in agar phantom and in vivo wounds. Using this microfluidic bandage, we applied the oxygen modulation to 8 mm excisional wounds prepared on diabetic mice. Treatment with the microfluidic bandage demonstrated improved collagen maturity in the wound bed, although only marginal differences were observed in total collagen, microvasculature, and external closure rates. Our results show that proper topical oxygen can improve wound parameters underneath the surface. Because of the ease of fabrication, the oxygen bandage represents an economical yet practical method for oxygen wound research. PMID- 23438080 TI - Expression of Galpha12 predicts progression and prognosis of oral squamous cell carcinomas in Taiwan. AB - BACKGROUND: Expression of Galpha12 is found to be associated with cancer cell proliferation, migration, invasion, and metastasis. METHODS: This study used immunohistochemistry to examine the expression of Galpha12 protein in 100 specimens of oral squamous cell carcinoma (OSCC), 45 specimens of oral epithelial dysplasia (OED), and 36 specimens of normal oral mucosa (NOM). RESULTS: The mean Galpha12 labeling indices (LIs, defined as the percentage of positive cells in total cells) increased significantly from NOM (7 +/- 11%) through OED (21 +/- 20%) to OSCC samples (53 +/- 33%, P < 0.001). The higher mean Galpha12 LI was significantly associated with OSCCs with larger tumor size (P = 0.003), positive lymph node metastasis (P = 0.002), or more advanced clinical stages (P = 0.003). Positive lymph node metastasis (P = 0.039) and Galpha12 LI > 50% (P = 0.009) were identified as independent unfavorable prognosis factors by multivariate analyses with Cox regression model. Moreover, Kaplan-Meier curve showed that OSCC patients with a Galpha12 LI > 50% had a significantly poorer cumulative survival than those with a Galpha12 LI <= 50% (log-rank test, P = 0.009). CONCLUSIONS: Our results showed a stepwise and significant elevation in Galpha12 protein expression from NOM through OED to OSCCs, suggesting that overexpression of Galpha12 protein may be an early event in oral carcinogenesis and may play a pivotal role in oral cancer development. Moreover, the Galpha12 protein can be a biomarker for prediction of the progression of OSCCs and the prognosis of patients with OSCC in Taiwan. PMID- 23438081 TI - Copper-catalyst-controlled site-selective allenylation of ketones and aldehydes with propargyl boronates. AB - A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity. PMID- 23438082 TI - Gender equality and education: Increasing the uptake of HIV testing among married women in Kenya, Zambia and Zimbabwe. AB - Gender equality and education are being promoted as strategies to combat the HIV epidemic in Africa, but few studies have looked at the role of gender equality and education in the uptake of a vital service - HIV testing. This study looks at the associations between education (a key input needed for gender equality) and key gender equality measures (financial decision making and attitudes toward violence) with ever tested for HIV and tested for HIV in the past year. The study focused on currently married women ages between15-24 and 25-34 in three countries - Kenya, Zambia, and Zimbabwe. The data came from the Demographic and Health Surveys. Logistic regression was used to study the role of gender equality and education on the HIV testing outcomes after controlling for both social and biological factors. Results indicated that education had a consistent positive relationship with testing for both age groups, and the associations were always significant for young women aged 15-24 years (p<0.01). The belief that gender based violence is unacceptable was positively associated with testing for women aged 25-34 in all the three countries, although the associations were only significant in Kenya (among women reporting ever being tested: OR 1.58, p<0.00; among women reporting being tested in the past year: OR 1.34, p<0.05) and Zambia (among women reporting ever being tested: OR 1.24, p<0.10; among women reporting being tested in the past year: OR 1.29, p<0.05). High financial decision making was associated with testing for women aged 25-34 in Zimbabwe only (among women reporting ever being tested: OR 1.66, p<0.01). Overall, the findings indicate that the education and the promotion of gender equality are important strategies for increasing uptake of a vital HIV service, and thus are important tools for protecting girls and young women against HIV. PMID- 23438083 TI - A possible anaphylactoid reaction in a cow after intravenous meloxicam. PMID- 23438084 TI - Paul I Korner (1925-2012). PMID- 23438085 TI - Is it too early to declare nitric oxide synthase activity as a novel predictor of stiff vessel walls in atherosclerosis? PMID- 23438086 TI - Investigating temporal patterns of a native bee community in a remnant North American bunchgrass prairie using blue vane traps. AB - Native bees are important ecologically and economically because their role as pollinators fulfills a vital ecosystem service. Pollinators are declining due to various factors, including habitat degradation and destruction. Grasslands, an important habitat for native bees, are particularly vulnerable. One highly imperiled and understudied grassland type in the United States is the Pacific Northwest Bunchgrass Prairie. No studies have examined native bee communities in this prairie type. To fill this gap, the bee fauna of the Zumwalt Prairie, a large, relatively intact remnant of the Pacific Northwest Bunchgrass Prairie, was examined. Native bees were sampled during the summers of 2007 and 2008 in sixteen 40-ha study pastures on a plateau in northeastern Oregon, using a sampling method not previously used in grassland studies-blue vane traps. This grassland habitat contained an abundant and diverse community of native bees that experienced marked seasonal and inter-annual variation, which appears to be related to weather and plant phenology. Temporal variability evident over the entire study area was also reflected at the individual trap level, indicating a consistent response across the spatial scale of the study. These results demonstrate that temporal variability in bee communities can have important implications for long term monitoring protocols. In addition, the blue vane trap method appears to be well-suited for studies of native bees in large expanses of grasslands or other open habitats, and may be a useful tool for monitoring native bee communities in these systems. PMID- 23438087 TI - Evidence for the role of Mycobacterium tuberculosis RecG helicase in DNA repair and recombination. AB - In order to survive and replicate in a variety of stressful conditions during its life cycle, Mycobacterium tuberculosis must possess mechanisms to safeguard the integrity of the genome. Although DNA repair and recombination related genes are thought to play key roles in the repair of damaged DNA in all organisms, so far only a few of them have been functionally characterized in the tubercle bacillus. In this study, we show that M. tuberculosis RecG (MtRecG) expression was induced in response to different genotoxic agents. Strikingly, expression of MtRecG in Escherichia coli ?recG mutant strain provided protection against mitomycin C, methyl methane sulfonate and UV induced cell death. Purified MtRecG exhibited higher binding affinity for the Holliday junction (HJ) compared with a number of canonical recombinational DNA repair intermediates. Notably, although MtRecG binds at the core of the mobile and immobile HJs, and with higher binding affinity for the immobile HJ, branch migration was evident only in the case of the mobile HJ. Furthermore, immobile HJs stimulate MtRecG ATPase activity less efficiently than mobile HJs. In addition to HJ substrates, MtRecG exhibited binding affinity for a variety of branched DNA structures including three-way junctions, replication forks, flap structures, forked duplex and a D-loop structure, but demonstrated strong unwinding activity on replication fork and flap DNA structures. Together, these results support that MtRecG plays an important role in processes related to DNA metabolism under normal as well as stress conditions. PMID- 23438088 TI - Atmospheric oxidation mechanism of phenol initiated by OH radical. AB - The gas-phase oxidation mechanism of phenol initiated by OH radical was investigated using DFT and ab initio calculations. The initiation of the reaction is dominated by OH addition to ortho-position, forming P2, which subsequently combines with O2 at the ipso-position to form P2-1-OO adduct. A concerted HO2 elimination process from P2-1-OO was found to be much faster than the common ring closure to bicyclic intermediates. The HO2 elimination process from P2-1-OO forms 2-hydroxy-3,5-cyclohexadienone (HCH) as the main product and is also responsible for the experimental fact that the rate constants for reaction between P2 and O2 are about 2 orders of magnitude higher than those between other aromatic-OH adducts and O2. It was speculated that HCH would isomerize to catechol, which is thermodynamically more stable than HCH and was the experimentally observed main product, possibly through heterogeneous processes. Reaction of P2 with NO2 proceeded by addition to form P2-n-NO2 (n = 1, 3, 5), followed by HONO elimination from P2-1/3-NO2 to form catechol. The barriers for HONO elimination and catechol formation are below the separate reactants P2 and NO2, being consistent with the experimental observation of catechol in the absence of O2, while H2O elimination from P2-1/3-NO2 to form 2-nitrophenol (2NP) is hindered by high barriers. The most likely pathway for 2NP is the reaction of phenoxy radical and NO2. PMID- 23438089 TI - Synthesis of 1-aminoisoquinolines by gold(III)-mediated domino reactions from 2 alkynylbenzamides and ammonium acetate. AB - A facile synthetic route toward pharmaceutically interesting 1-aminoisoquinoline derivatives by gold(III)-mediated domino reactions is described. This synthetic protocol starts from readily available 2-alkynylbenzamides and ammonium acetate and takes place under mild reaction conditions compatible with a variety of functional groups. A plausible mechanism for the domino process is proposed, supported by the reaction of a possible intermediate, N-(3-phenyl-1H-isochromen-1 ylidene)propan-1-amine. PMID- 23438090 TI - Cluster-randomized trial of a web-assisted tobacco quality improvement intervention of subsequent patient tobacco product use: a National Dental PBRN study. AB - BACKGROUND: Brief clinician delivered advice helps in tobacco cessation efforts. This study assessed the impact of our intervention on instances of advice given to dental patients during visits on tobacco use quit rates 6 months after the intervention. METHODS: The intervention was cluster randomized trial at the dental practice level. Intervention dental practices were provided a longitudinal technology-assisted intervention, oralcancerprevention.org that included a series of interactive educational cases and motivational email cues to remind dental provides to complete guideline-concordant brief behavioral counseling at the point of care. In all dental practices, exit cards were given to the first 100 consecutive patients, in which tobacco users provided contact information for a six month follow-up telephone survey. RESULTS: A total of 564 tobacco using dental patients completed a six month follow-up survey. Among intervention patients, 55% reported receiving advice to quit tobacco, and 39% of control practice patients reported receiving advice to quit tobacco (p < 0.01). Six-month tobacco use quit rates were not significantly between the Intervention (9%) and Control (13%) groups, (p = 0.088). CONCLUSION: Although we increased rates of cessation advice delivered in dental practices, this study shows no evidence that brief advice by dentist's increases long-term abstinence in smokers. TRIAL REGISTRATION: ClinicalTrials.gov NCT00627185. PMID- 23438091 TI - Age-related prognosis of syncope associated with a preexcitation syndrome. AB - BACKGROUND: Syncope in Wolff-Parkinson-White syndrome (WPW) is without relationship with WPW or reveals a poorly tolerated arrhythmia. Electrophysiologic study (EPS) is recommended. The purpose of the study was to evaluate the influence of the patient's age on the causes and prognosis of syncope. METHODS: A total of 98 patients, mean age 35 +/- 18 years, with WPW were admitted for syncope. Note that 29 were aged between 9 and 19 years (mean 15 +/- 3) (children and teenagers/group I), 45 between 20 and 49 years (mean 34 +/- 8) (adults/group II), and 24 between 50 and 70 years (mean 60 +/- 8) (elderly/group III). EPS consisted of atrial pacing and programmed atrial stimulation in control state and after isoproterenol. RESULTS: Potentially malignant form (rapid conduction in accessory pathway >240 beats/min in control state or >300 beats/min after isoproterenol and atrial fibrillation [AF] induction) was more frequent in group I (34%) than in groups II (7%) (P < 0.002) and III (0%) (P < 0.001). Orthodromic atrioventricular reentrant tachycardia (AVRT) and AF were induced as frequently in groups I (59, 34%), II (47, 15.5%), and III (54, 17%). AVRT was induced in all but one patient with malignant form. EPS was as frequently negative in groups I (27.5%), II (44%), and III (37.5%). Natural follow-up (mean 8 +/- 6 years) indicated a favorable prognosis, only related to AVRT induction. Induced AF was without significance. CONCLUSIONS: Data in syncope and WPW syndrome depended on age: electrophysiological malignant form was frequent in children/teenagers, rare in adults, and absent in elderly. AVRT, the main cause of syncope, was as frequent in all ranges of age. AF's induction alone had no significance. Final prognosis was favorable. PMID- 23438092 TI - Risk factors for renal disease and urinary abnormalities in men and women: data from the World Kidney Day in the province of Ferrara, Italy. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide health problem due to its morbidity and mortality, and cost. World Kidney Day (WKD) has been planned to improve disease prevention. The aim of this study was to evaluate CKD risk factors and urinary abnormalities, collected on WKD along several years, in men and women. PATIENTS AND METHODS: Between 2006 and 2012, 1980 subjects, of whom 1012 women, from general population living in Ferrara area, a town in the north east of Italy, were investigated. For each participant age, sex, smoking, hypertensive and diabetic status, body mass index (BMI), waist circumference (WC), and blood pressure (BP) were obtained. Moreover, body shape index (BSI) was calculated. All subjects underwent dipstick urinalysis. RESULTS: Men had higher BMI, WC, and BP than women. Women had higher prevalence of abdominal obesity and higher BSI (0.0951 +/- 0.0105 vs. 0.0920 +/- 0.0071 m(11/6)kg(-2/3)), while men had higher prevalence of overweight. In women, hematuria and leukocyturia were more prevalent (16.9% vs. 12.8%; OR 95%CI 1.161 (1.042-1.294); p = 0.012; 18.5% vs. 7% OR 95%CI 1.538 (1.403-1.676); p < 0.001, respectively), while glycosuria was less frequent (4.2% vs. 8.8% OR 95%CI 0.642 (0.501-0.822); p < 0.001) than in men. Frequency of proteinuria was similar in the two sexes. Venn diagrams indicate a different overlap of urinary abnormalities in the two sexes. CONCLUSIONS: Risk factors for CKD collected during the WKD appear to be different in the two sexes, and urinary abnormalities overlap differently. Data collected during the WKD are related to sex, and women deserve greater attention. PMID- 23438093 TI - Effect of home mechanical in-exsufflation on hospitalisation and life-style in neuromuscular disease: a pilot study. AB - AIM: Mechanical in-exsufflation (MI-E) augments the weakened cough of patients with neuromuscular disease (NMD), clearing secretions and overcoming atelectasis. Little has been published on the impact of MI-E alone on rates of hospitalisation and quality of life (QOL). The aim of this study was to assess the impact of home MI-E on hospital admissions and life-style in children with NMD. METHODS: A retrospective chart review was performed on children using MI-E, including data on the number of admissions to hospital, length of stay and hours of ventilation. A parental survey was used to gather information on the impact of MI-E on life style for the child and family. RESULTS: Ten children with NMD (seven spinal muscular atrophy, two Duchenne muscular dystrophy and one centronuclear myopathy) using MI-E at home were identified. MI-E use commenced at mean age of 8.5 years (range 1.1-16.9) with 1.4 years of use (range 0.3-3.8). MI-E pressures ranged from +/-30 to 40 cmH2 O with no complications reported. There was a significant reduction in hospital days at 6 (P = 0.036) and 12 (P = 0.028) months following commencement of home MI-E compared with the same period preceding MI-E use. The survey highlighted positive benefits of MI-E use, in particular the ability to treat many pulmonary exacerbations at home. CONCLUSIONS: Home MI-E use by children with NMD can reduce hospitalisation and benefit families by maintaining their child at home. PMID- 23438094 TI - Comparison of visually estimated blood loss with direct hemoglobin measurement in multilevel spine surgery. AB - BACKGROUND: Estimates of blood loss in the operating room are typically performed as a visual assessment by providers, despite multiple studies showing this to be inaccurate. Use of a less subjective measurement of blood loss such as direct measurement of the hemoglobin (Hb) mass lost from the surgical field may better quantify surgical bleeding. The objective of this investigation was to compare anesthesiologist estimates of intraoperative blood loss with measured Hb loss. STUDY DESIGN AND METHODS: Sixty patients undergoing posterior spine surgery were enrolled in a prospective, randomized trial comparing intraoperative blood loss using unipolar cautery alone or with use of a bipolar tissue sealant device. Hb concentration and fluid volume were measured from all surgical sponges, suction canisters, and the cell salvage device. Using the volume and concentration of Hb from each solution allowed calculation of Hb mass, which was converted into volume of blood lost and compared with estimates of blood loss documented by the anesthesia team. A single-sample t test of no difference was used to compare estimated with measured blood loss. RESULTS: Mean estimated blood loss exceeded measured blood loss by 246 mL (860 mL vs. 614 mL, p < 0.0001). CONCLUSION: Estimated blood loss exceeded measured blood loss by 40% on average. The likely etiology of this discrepancy relates to the inability to visually determine Hb concentration of sanguineous solutions in suction canisters and surgical sponges. Ramifications of excessive bleeding estimates include unnecessary transfusion and overadministration of intravenous fluids, both of which may have deleterious effects. PMID- 23438096 TI - Analysis of intracellular human immunodeficiency virus (HIV)-1 drug resistance mutations in multi-failed HIV-1-infected patients treated with a salvage regimen: 72-week follow-up. AB - The human immunodeficiency virus (HIV) mutational archive of proviral DNA was monitored during a 72-week follow-up in 20 multidrug-experienced HIV-1-infected patients treated with a darunavir/ritonavir-based salvage therapy. At the beginning of the study, all patients harboured a number of intracellular drug resistance-associated mutations (RAMs) in peripheral blood mononuclear cells. In some patients, a significant fluctuation in the number of RAMs was observed during the observation period. However, all patients, notwithstanding the presence or the fluctuation of intracellular RAMs, showed a persistently undetectable viraemia. The data suggest that the archived resistant viral variants change during suppressive therapy, but that the variants are unable to re-emerge and to affect virological response. PMID- 23438097 TI - Good tolerance to goat's milk in patients with recurrent aphthous ulcers with increased immunoreactivity to cow's milk proteins. AB - BACKGROUND: Recurrent aphthous ulcers (RAU) represent a very common, but poorly understood mucosal disorder. The connection between immunity to cow's milk proteins (CMP) and oral diseases was noted earlier. The goal of this study was to determine the prevalence of the increased levels of serum antibodies to goat's milk proteins (GMP), by enzyme-linked immunosorbent assay (ELISA) test, in subjects who have RAU and proven increased immunity to CMP. METHODS: Fifty subjects with RAU (36 with proven increased immunity to CMP and 14 without this increased immunity) were included in this research. Levels of serum IgA, IgG, and IgE antibodies to the same quantity of the examined antigens were determined by ELISA. The statistical analysis of data was performed by Wilcoxon rank-sum test and Mann-Whitney test. RESULTS: The levels of serum antifresh cow's milk IgA, IgG, and IgE antibodies were significantly higher than the levels of serum antifresh goat's milk, in subjects with RAU with proven increased immunoreactivity to CMP (P = 0.0003; P < 0.0001; P < 0.0001). CONCLUSIONS: These results indicate that patients with RAU with increased immunity to CMP could consider the use of goat's milk as the alternative protein source. PMID- 23438098 TI - Synthesis of N-vinylcarbazoles via dehydrogenative coupling of N-H carbazoles with alkenes under palladium catalysis. AB - The synthesis of N-vinylcarbazoles was achieved by the palladium-catalyzed aza Wacker reaction of N-H carbazoles with styrenes. In this reaction, Markovnikov adducts were exclusively produced. In contrast, the reaction with electron deficient alkenes such as acrylates and acrylamides gave only anti-Markovnikov adducts. PMID- 23438099 TI - Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor involved in all aspects of wound healing. TGF-beta accelerates wound healing, but an excess of its presence at the wound site has been implicated in pathological scar formation. Our group has recently identified CD109, a glycophosphatidylinositol-anchored protein, as a novel TGF-beta coreceptor and inhibitor of TGF-beta signaling in vitro. To determine the effects of CD109 in vivo on wound healing, we generated transgenic mice overexpressing CD109 in the epidermis. In excisional wounds, we show that CD109 transgenic mice display markedly reduced macrophage and neutrophil recruitment, granulation tissue area, and decreased Smad2 and Smad3 phosphorylation, whereas wound closure remains unaffected as compared with wild-type littermates. Futhermore, we demonstrate that the expression of the proinflammatory cytokines interleukin-1alpha and monocyte chemoattractant protein-1, and extracellular matrix components is markedly decreased during wound healing in CD109 transgenic mice. In incisional wounds, CD109 transgenic mice show improved dermal architecture, whereas the tensile strength of the wound remains unchanged. Taken together, our findings demonstrate that CD109 overexpression in the epidermis reduces inflammation and granulation tissue area and improves collagen organization in vivo. PMID- 23438100 TI - Complete mitochondrial genome of the striped grouper Epinephelus latifasciatus (Serranidae, Epinephelinae). AB - The complete mitochondrial genome of the striped grouper Epinephelus latifasciatus is first presented in this study. The total length of E. latifasciatus is 16,389 bp, consisting of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and an A+T-rich control region. The gene order and transcriptional orientation are identical to those of most vertebrates. The total base composition is 28.6% A, 29.1% C, 26.4% T, and 16.0% G, with a slight A+T bias of 55.0%. The dihydrouridine arm of tRNA-Ser2 is replaced with one loop, because of which it cannot be folded into typical cloverleaf secondary structure. The termination-associated sequences and conserved sequence blocks (CSB1-3) are found in the control region. PMID- 23438101 TI - Omega-3 polyunsaturated fatty acids reduce insulin resistance and triglycerides in obese children and adolescents. AB - BACKGROUND: Approximately 50% of obese children are insulin resistant. It has been suggested that pharmacological and nutritional options should be considered to improve the management of insulin resistance (IR). OBJECTIVE: To assess the effect of metformin (Met) or omega-3 (omega-3) polyunsaturated fatty acids (PUFA) on the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index, lipid profile, and body mass index (BMI) of obese children. METHODS: We included 201 obese and insulin-resistant children and adolescents. Ninety-eight of them received 500 mg of Met, and 103 received 1.8 g of omega-3 PUFA for 12 wk. This was an open-label study with assignment of treatment based on which school the child attended. At the baseline and at the end of study, the following parameters were measured: weight, height, waist circumference, blood pressure, insulin, glucose, lipid profile, and HOMA-IR index. There were no lifestyle interventions. RESULTS: At baseline, the age, BMI, and IR in children of both groups were comparable. The treatment assigned for each group was well tolerated. Metabolic changes were adjusted for age, sex, and change in BMI. Concerning the IR profile at the end of intervention, omega-3 significantly decreased the concentrations of glucose and insulin while reducing HOMA-IR values; meanwhile, Met negligibly affected insulin levels. Regarding lipids, Met increased high density lipoprotein cholesterol (HDL-C) and decreased low density lipoprotein cholesterol (LDL-C), but triglycerides were not affected; in contrast, triglycerides were decreased significantly by omega-3. The effects on BMI were marginal under Met but were significant with omega-3. CONCLUSION: The results of this work suggest that omega 3 may be useful as an adjuvant therapy in obese children and adolescents with IR. PMID- 23438102 TI - Giving monoclonal antibodies to healthy volunteers in phase 1 trials: is it safe? AB - Many monoclonal antibodies (MAbs) have been studied in healthy volunteers in phase 1, but few data have been published on the safety of that practice. We aimed to review the available data, and thereby to estimate the risks of participation in phase 1trials of MAbs. We searched PubMed, the ClinicalTrials.gov database and Google, using the search terms 'monoclonal antibody', 'phase 1' and 'healthy volunteers'. We identified 70 completed trials of MAbs in healthy volunteers, but the published data were too sparse to allow confident assessment of the risks of MAbs in healthy volunteers. Our best estimate of risk of a life-threatening adverse event was between 1: 425 and 1: 1700 volunteer-trials, but all such events occurred in a single trial (of TGN1412). In a phase 1trial of a small molecule, the risk of death or a life threatening adverse event appears to be 1: 100,000-1,000,000 volunteer-trials, which is similar to the risk of many ordinary daily activities. Most people would consider that level of risk to be 'minimal' or 'negligible' and, therefore, acceptable. On that basis, the safety record of MAbs in healthy volunteers has been ruined by the TGN1412 disaster. However, that experience is unlikely to be repeated, because of improvements in governance and practice of phase 1trials. If the experience of TGN1412 is disregarded, it seems reasonable to continue using healthy volunteers in phase 1trials of MAbs, provided that there are scientific and medical reasons to conclude that the risk is truly minimal. PMID- 23438104 TI - Hyperthermic overdrive: oxygen delivery does not limit thermal tolerance in Drosophila melanogaster. AB - The causes of thermal tolerance limits in animals are controversial. In many aquatic species, it is thought that the inability to deliver sufficient oxygen at high temperatures is more critical than impairment of molecular functions of the mitochondria. However, terrestrial insects utilize a tracheal system, and the concept of a mismatch between metabolic demand and circulatory performance might not apply to them. Using thermo-limit respirometry, it has been shown earlier in Drosophila melanogaster that CO(2) release rates at temperatures above the upper thermal limit (CT(max)) exceed the rate at CT(max). The nature of this post CT(max), or "post-mortal" peak, is unknown. Either its source is increased aerobic mitochondrial respiration (hyperthermic overdrive), or an anaerobic process such as liberation of stored CO(2) from the hemolymph. The post-mortal peak of CO(2) release was found to be oxygen dependent. As the rate of CO(2) emission is a conservative indicator of rate of O(2) consumption, aerobic flux at the thermal limit is submaximal, which contradicts the theory that oxygen availability limits metabolic activity at high temperatures in insects. Consequently, the tracheal system should be capable of delivering sufficient oxygen for aerobic activity of the mitochondria at and above Ct(max). PMID- 23438103 TI - Psychological consultation in older adult inpatient settings: a qualitative investigation of the impact on staff's daily practice and the mechanisms of change. AB - OBJECTIVES: Psychological consultation is becoming increasingly common within older adult mental health and dementia services. However, there is very little research that examines the impact or effectiveness of this method of working. This study explored how psychological consultation impacted on the daily practice of staff working on mental health and dementia inpatient units. It also examined the mechanisms that enabled this process. METHOD: Given the lack of current literature in this area, an exploratory qualitative design was employed. Ten staff who had received psychological consultation were individually interviewed. Staff comprised qualified and unqualified staff from a range of professions, and worked on older adult mental health or dementia units. Interviews were subject to thematic analysis. RESULTS: Five themes were identified from the analysis: (1) 'It makes you understand the reasons why people are like they are'; (2) 'It depends on the patient or service user'; (3) the importance of visibility and accessibility; (4) impact of psychology consultation on the effectiveness of the team; and (5) impact of psychology consultation on feelings invoked in the workplace. CONCLUSIONS: The findings suggest that psychological consultation impacted on staffs' daily practice in a variety of ways. Psychological consultation also appeared to increase team efficiency. Less positive findings were identified within the dementia setting. Specific recommendations are drawn from the conclusions to further guide clinical psychologists working within teams. Direction for future research in the area of psychological consultation is also suggested. PMID- 23438105 TI - Pyrvinium pamoate does not activate protein kinase CK1, but promotes Akt/PKB down regulation and GSK3 activation. AB - It has been reported that pyrvinium pamoate (PyrPam), an FDA (U.S. Food and Drug Administration)-approved anthelminthic drug, is a potent inhibitor of Wnt signalling by a mechanism which implies the direct activation of protein kinase CK1alpha. In the present paper, we provide data ruling out any direct stimulatory effect of PyrPam on CK1, by showing that the catalytic activity of CK1alpha and those of its isoforms delta and gamma1 are not significantly affected by PyrPam when tested with the aid of specific peptide and protein substrates. Accordingly, cell treatment with PyrPam has no significant effect on the phosphorylation of beta-catenin Ser(45). By contrast, the phosphorylation of beta-catenin Thr(41) is increased upon cell treatment with PyrPam, through a mechanism that implies the upstream dephosphorylation of Akt/PKB (protein kinase B) and of GSK3 (glycogen synthase kinase 3). It can be concluded from the present study that PyrPam is not a bona fide activator of CK1, its perturbation of cell signalling pathways being mediated by a complex mechanism initiated by a fall in Akt phosphorylation whose down-regulation promotes reduced phosphorylation and activation of GSK3. Consistent with this, lysates of cells treated with PyrPam display enhanced protein phosphorylation which is unaffected by CK1 inhibition, while disappearing upon inhibition of GSK3. Our data are consistent with the observation that PyrPam ultimately inhibits Wnt signalling despite its lack of efficacy on CK1. PMID- 23438106 TI - Consequences of membrane topography. AB - The surface of mammalian cells is neither smooth nor flat and cells have several times more plasma membrane than the minimum area required to accommodate their shape. We discuss the biological function of this apparent excess membrane that allows the cells to migrate and undergo shape changes and probably plays a role in signal transduction. Methods for studying membrane folding and topography- atomic force microscopy, scanning ion conductance microscopy, fluorescence polarization microscopy and linear dichroism--are described and evaluated. Membrane folding and topography is frequently ignored when interpreting microscopy data. This has resulted in several misconceptions regarding for instance colocalization, membrane organization and molecular clustering. We suggest simple ways to avoid these pitfalls and invoke Occam's razor--that simple explanations are preferable to complex ones. Topography, i.e. deviations from a smooth surface, should always be ruled out as the cause of anomalous data before other explanations are presented. PMID- 23438107 TI - Reactivity of first-row transition metal monocations (Sc+, Ti+, V+, Zn+) with methyl fluoride: a computational study. AB - The gas-phase reactivity of methyl fluoride with selected first-row transition metal monocations (Sc(+), Ti(+), V(+), and Zn(+)) has been theoretically investigated. Our thermochemical and kinetics study shows that early transition metal cations exhibit a much more active chemistry than the latest transition metal monocation Zn(+). The strong C-F bond in methyl fluorine can be activated by scandium, titanium, and vanadium monocations yielding the metal fluorine cation, MF(+). However, the rate efficiencies vary dramatically along the period 0.73 (Sc), 0.91 (Ti), and 0.028 (V) in agreement with the experimental observation. The kinetics results show the relative importance of the entrance and exit channels, apart from the "inner" bottleneck, to control the global rate constant of these reactions. At the mPW1K/QZVPP level our computed kglobal (at 295 K), 1.99 * 10(-9) cm(3) molecule(-1) s(-1) (Sc(+)), 1.29 * 10(-9) cm(3) molecule(-1) s(-1) (Ti(+)), and 3.46 * 10(-10) cm(3) molecule(-1) s(-1) (V(+)) are in good agreement with the experimental data at the same temperature. For the reaction of Zn(+) and CH3F our predicted value for kouter, at 295 K, 3.79 * 10( 9) cm(3) molecule(-1) s(-1), is in accordance with the capture rate constant. Our study suggests that consideration of the lowest excited states for Ti(+) and V(+) is mandatory to reach agreement between calculations and experimental measurements. PMID- 23438110 TI - Intracranial pressure and cardiopulmonary variables during isoflurane or sevoflurane anesthesia at various minimum alveolar concentration multiples in normocapnic dogs. AB - OBJECTIVE: To compare effects of isoflurane and sevoflurane on intracranial pressure and cardiovascular variables at 1.0, 1.5, and 2.0 times the minimum alveolar concentration (MAC) in mechanically ventilated normocapnic dogs. ANIMALS: 6 healthy male Beagles. PROCEDURES: The individual MAC was determined for each agent with an electrical stimulus. After a minimum of 1 week, anesthetic induction by use of a mask with one of the inhalation anesthetics selected randomly was followed by mechanical ventilation and instrumentation for measurement of intracranial pressure and cardiovascular variables. Heart rate; systolic, mean, and diastolic arterial blood pressures; central venous pressure; mean pulmonary arterial pressure; pulmonary artery occlusion pressure; cardiac output; intracranial pressure (ICP); core body temperature; end-tidal inhalation anesthetic and carbon dioxide concentration; and arterial blood gas values were measured after attaining equilibrium at 1.0, 1.5, and 2.0 MAC of each inhalation anesthetic. Cardiac index, systemic vascular resistance, pulmonary vascular resistance, and cerebral perfusion pressure (CPP) were calculated. RESULTS: Mean ICP did not differ within and between anesthetics at any MAC. Compared with equipotent concentrations of isoflurane, the CPP and mean values for systolic, mean, and diastolic arterial blood pressures were increased at 2.0 MAC for sevoflurane, whereas mean values for mean and diastolic arterial blood pressures and systemic vascular resistance were increased at 1.5 MAC for sevoflurane. CONCLUSIONS AND CLINICAL RELEVANCE: Although ICP was similar in healthy normocapnic dogs, CPP was better maintained during 2.0 MAC for sevoflurane, compared with isoflurane. PMID- 23438111 TI - Pharmacokinetics of meloxicam after intravenous, intramuscular, and oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To compare pharmacokinetics after IV, IM, and oral administration of a single dose of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS: 11 healthy parrots. PROCEDURES: Cohorts of 8 of the 11 birds comprised 3 experimental groups for a crossover study. Pharmacokinetics were determined from plasma concentrations measured via high-performance liquid chromatography after IV, IM, and oral administration of meloxicam at a dose of 1 mg/kg. RESULTS: Initial mean +/- SD plasma concentration of 17.3 +/- 9.0 MUg/mL was measured 5 minutes after IV administration, whereas peak mean concentration was 9.3 +/- 1.8 MUg/mL 15 minutes after IM administration. At 12 hours after administration, mean plasma concentrations for IV (3.7 +/- 2.5 MUg/mL) and IM (3.5 +/- 2.2 MUg/mL) administration were similar. Peak mean plasma concentration (3.5 +/- 1.2 MUg/mL) was detected 6 hours after oral administration. Absolute systemic bioavailability of meloxicam after IM administration was 100% but was lower after oral administration (range, 49% to 75%). Elimination half-lives after IV, IM, and oral administration were similar (15.9 +/- 4.4 hours, 15.1 +/- 7.7 hours, and 15.8 +/- 8.6 hours, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetic data may provide useful information for use of meloxicam in Hispaniolan Amazon parrots. A mean plasma concentration of 3.5 MUg/mL would be expected to provide analgesia in Hispaniolan Amazon parrots; however, individual variation may result in some birds having low plasma meloxicam concentrations after IV, IM, or oral administration. After oral administration, meloxicam concentration slowly reached the target plasma concentration, but that concentration was not sustained in most birds. PMID- 23438112 TI - Comparison of the mechanical characteristics of polymerized caprolactam and monofilament nylon loops constructed in parallel strands or as braided ropes versus cranial cruciate ligaments of cattle. AB - OBJECTIVE: To compare the mechanical characteristics of polymerized caprolactam and monofilament nylon loops with those of the cranial cruciate ligament (CCL) in cattle. SAMPLE: 6 femorotibial joints harvested from 3 cows and suture constructs made from No. 8 polymerized caprolactam, 80-lb test monofilament nylon fishing line, and 450-lb test monofilament nylon fishing line. PROCEDURES: Joints were cleared of soft tissue structures except the CCL, connected to a load frame, and loaded to failure while measuring force and elongation. Synthetic constructs tested in a similar manner included single-stranded and 3-stranded No. 8 polymerized caprolactam, 3- and 6-stranded 80-lb test monofilament nylon fishing line, and 3- and 6-stranded 450-lb test monofilament nylon fishing line. RESULTS: The CCL ruptured at a mean +/- SD force of 4,541 +/- 1,417 N with an elongation of 2.0 +/- 0.3 cm. The tensile strength of 3-stranded 450-lb test monofilament nylon fishing line was similar to that of the CCL, rupturing at loads of 5,310 +/ 369 N (braided strands) and 6,260 +/- 239 N (parallel strands). Elongation was greater for braided constructs. CONCLUSIONS AND CLINICAL RELEVANCE: The 3 stranded cords of 450-lb test monofilament nylon fishing line most closely approximated the strength of the CCL. Marked increases in elongation occur when large-sized materials are constructed in braided configurations, and this elongation would likely not provide stability in CCL-deficient stifle joints. Additional studies are needed to determine whether any of these materials are suitable CCL replacements in cattle. PMID- 23438114 TI - Effects of imidazoline and nonimidazoline alpha-adrenergic agents, including xylazine, medetomidine, yohimbine, tolazoline, and atipamezole, on aggregation of bovine and equine platelets. AB - OBJECTIVE: To investigate effects of various imidazoline and nonimidazoline alpha adrenergic agents on aggregation and antiaggregation of bovine and equine platelets. SAMPLE: Blood samples obtained from 8 healthy adult cattle and 16 healthy adult Thoroughbreds. PROCEDURES: Aggregation and antiaggregation effects of various imidazoline and nonimidazoline alpha-adrenergic agents on bovine and equine platelets were determined via a turbidimetric method. Collagen and ADP were used to initiate aggregation. RESULTS: Adrenaline, noradrenaline, or alpha adrenoceptor agents alone did not induce changes in aggregation of bovine or equine platelets or potentiate ADP- or collagen-induced platelet aggregation. Adrenaline and the alpha(2)-adrenoceptor agonist clonidine had an inhibitory effect on ADP- and collagen-induced aggregation of bovine platelets. The alpha(2) adrenoceptor antagonists phentolamine and yohimbine also inhibited collagen induced aggregation of bovine platelets. Noradrenaline, other alpha-adrenoceptor agonists (xylazine, oxymetazoline, and medetomidine), and alpha-adrenoceptor antagonists (atipamezole, idazoxan, tolazoline, and prazosin) were less effective or completely ineffective in inhibiting ADP- and collagen-induced aggregation of bovine platelets. The imidazoline alpha(2)-adrenoceptor agonist oxymetazoline submaximally inhibited collagen-induced aggregation of equine platelets, and the alpha(2)-adrenoceptor antagonist idazoxan, along with phentolamine and yohimbine, also inhibited collagen-induced aggregation of equine platelets. The imidazoline compound antazoline inhibited both ADP- and collagen-induced aggregation of equine platelets. CONCLUSIONS AND CLINICAL RELEVANCE: Several drugs had effects on aggregation of platelets of cattle and horses, and effective doses of ADP and collagen also differed between species. The alpha(2)-adrenoceptor agonists (xylazine and medetomidine) and antagonists (tolazoline and atipamezole) may be used by bovine and equine practitioners without concern for adverse effects on platelet function and hemostasis. PMID- 23438113 TI - Expression of proteins in serum, synovial fluid, synovial membrane, and articular cartilage samples obtained from dogs with stifle joint osteoarthritis secondary to cranial cruciate ligament disease and dogs without stifle joint arthritis. AB - OBJECTIVE: To identify proteins with differential expression between healthy dogs and dogs with stifle joint osteoarthritis secondary to cranial cruciate ligament (CCL) disease. SAMPLE: Serum and synovial fluid samples obtained from dogs with stifle joint osteoarthritis before (n = 10) and after (8) surgery and control dogs without osteoarthritis (9) and archived synovial membrane and articular cartilage samples obtained from dogs with stifle joint osteoarthritis (5) and dogs without arthritis (5). PROCEDURES: Serum and synovial fluid samples were analyzed via liquid chromatography-tandem mass spectrometry; results were compared against a nonredundant protein database. Expression of complement component 3 in archived tissue samples was determined via immunohistochemical methods. RESULTS: No proteins had significantly different expression between serum samples of control dogs versus those of dogs with stifle joint osteoarthritis. Eleven proteins (complement component 3 precursor, complement factor I precursor, apolipoprotein B-100 precursor, serum paraoxonase and arylesterase 1, zinc-alpha-2-glycoprotein precursor, serum amyloid A, transthyretin precursor, retinol-binding protein 4 precursor, alpha-2 macroglobulin precursor, angiotensinogen precursor, and fibronectin 1 isoform 1 preproprotein) had significantly different expression (> 2.0-fold) between synovial fluid samples obtained before surgery from dogs with stifle joint osteoarthritis versus those obtained from control dogs. Complement component 3 was strongly expressed in all (5/5) synovial membrane samples of dogs with stifle joint osteoarthritis and weakly expressed in 3 of 5 synovial membrane samples of dogs without stifle joint arthritis. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that the complement system and proteins involved in lipid and cholesterol metabolism may have a role in stifle joint osteoarthritis, CCL disease, or both. PMID- 23438115 TI - In vitro effect of pimobendan on platelet aggregation in dogs. AB - OBJECTIVE: To determine whether pimobendan has in vitro antithrombotic properties through inhibition of platelets in canine blood samples. ANIMALS: 10 healthy adult dogs. PROCEDURES: Blood samples were collected from each dog into tubes containing hirudin or sodium citrate. Pimobendan was added to blood samples (final concentration, 0.0, 0.01, 0.1, 1.0, or 10.0MUM) containing hirudin prior to undergoing collagen- and ADP-induced whole blood impedance aggregometry. Plasma thromboxane concentrations were measured after platelet aggregation. Pimobendan was also added to blood samples (0.0, 0.01, or 10.0MUM) containing sodium citrate prior to thromboelastographic evaluation. RESULTS: Compared with findings for 0.0MUM pimobendan, composite platelet aggregation (area under the curve [AUC]) and maximal platelet aggregation (aggregation units [AUs]) at 10.0MUM pimobendan were significantly decreased for collagen-induced aggregation (AUC, 349.7 +/- 58.4 vs 285.1 +/- 72.2; maximal platelet aggregation, 196.2 +/- 25.8 AUs vs 161.5 +/- 38.0 AUs), and the AUC and velocity of aggregation at 10.0MUM pimobendan were significantly decreased for ADP-induced aggregation (AUC, 268.5 +/- 35.1 vs 213.4 +/- 77.2; velocity of aggregation, 15.7 +/- 2.9 AUs/min vs 11.8 +/- 3.5 AUs/min). Pimobendan had no significant effect on plasma thromboxane concentration or thromboelastographic variables, regardless of concentration. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro, pimobendan had an antiplatelet effect in canine blood samples at a concentration 1,000-fold higher than that clinically achievable. These antiplatelet properties do not appear to contribute to the positive clinical profile of the drug in dogs. Pimobendan administration would not appear to confer a risk for bleeding and does not have to be avoided in dogs with thrombocytopenia or those concurrently receiving antiplatelet drugs. PMID- 23438116 TI - Myocardial cytokine expression in dogs with systemic and naturally occurring cardiac diseases. AB - OBJECTIVE: To compare myocardial cytokine expression in dogs with naturally occurring cardiac or systemic diseases and dogs without cardiac or systemic diseases (control dogs) SAMPLE: Myocardial tissue samples from 7 systemic disease affected dogs (SDDs), 7 cardiac disease-affected dogs (CDDs), and 8 control dogs. PROCEDURES: mRNA expression of interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta1, TGF-beta2, TGF-beta3, and growth differentiation factor-15 in myocardial tissue samples obtained from CDDs, SDDs, and control dogs were analyzed via quantitative PCR assays. RESULTS: In control dogs, only mRNA for TNF alpha, TGF-beta1, and TGF-beta3 was detected; concentrations were significantly higher in male than in female dogs. In SDDs and CDDs, all cytokines, growth factors, and growth differentiation factor-15 were expressed. Compared with findings in SDDs, IL-1, IL-6, IL-8, IL-10, TNF-alpha, and IFN-gamma expression was significantly increased in CDDs; specifically, IL-1, IL-8, TNF-alpha, TGF beta1, and TGF-beta3 expression was increased in the atria and IL-8, IL-10, TNF alpha, and IFN-gamma expression was increased in the ventricles of CDDs. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggested that the alterations in cytokine expression in SDDs and CDDs, compared with control dog findings, were a result of inflammatory system activation. The differences in cytokine expression in atria and ventricles between SDDs and CDDs were suggestive of different remodeling processes. A better knowledge of myocardial involvement in SDDs and of immune regulation in CDDs might beneficially affect morbidity and mortality rates and provide new treatment approaches. PMID- 23438117 TI - Contrast-enhanced ultrasonographic evaluation of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism. AB - OBJECTIVE: To assess vascular changes induced by hyperadrenocorticism of hyperplastic adrenal glands in dogs via contrast-enhanced ultrasonography. ANIMALS: 12 dogs with pituitary-dependent hyperadrenocorticism (PDH) and 7 healthy control dogs >= 7 years old. PROCEDURES: Dogs were assigned to the PDH and control groups and to small-breed (n = 6), medium-breed (4), and large-breed (9) subgroups. Contrast-enhanced ultrasonography of both adrenal glands in each dog was performed with IV injections of contrast agent. Time-intensity curves for the adrenal cortex, adrenal medulla, and ipsilateral renal artery of both adrenal glands were generated. Perfusion variables (time to peak [TTP], upslope of wash in phase, and downslope of washout phase) were calculated. RESULTS: Contrast enhanced ultrasonography revealed no qualitative difference between PDH and control groups. Quantitatively, TTPs were longer in the adrenal cortex and adrenal medulla of the PDH group, compared with values for the control group, particularly in the adrenal cortex and adrenal medulla of the small-breed subgroup. Washout downslopes were lower for the renal artery, adrenal cortex, and adrenal medulla of the small-breed subgroup between the PDH and control groups. No other perfusion variables differed between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Contrast-enhanced ultrasonography of the adrenal glands in dogs with PDH revealed a delayed TTP in the adrenal cortex and adrenal medulla, compared with values for control dogs. Contrast-enhanced ultrasonography was able to detect vascular changes induced by hyperadrenocorticism. Further studies are needed to evaluate whether reference ranges for clinically normal dogs and dogs with PDH can be determined and applied in clinical settings. PMID- 23438118 TI - Distribution of 2-deoxy-2-fluoro-d-glucose in the coelom of healthy bald eagles (Haliaeetus leucocephalus). AB - OBJECTIVE: To determine 2-deoxy-2-fluoro (fluorine 18)-d-glucose ((18)FDG) biodistribution in the coelom of bald eagles (Haliaeetus leucocephalus). ANIMALS: 8 healthy adult bald eagles. PROCEDURES: For each eagle, whole-body transmission noncontrast CT, 60-minute dynamic positron emission tomography (PET) of the celomic cavity (immediately after (18)FDG injection), whole-body static PET 60 minutes after (18)FDG injection, and whole-body contrast CT with iohexol were performed. After reconstruction, images were analyzed. Regions of interest were drawn over the ventricular myocardium, liver, spleen, proventriculus, cloaca, kidneys, and lungs on dynamic and static PET images. Standardized uptake values were calculated. RESULTS: Kidneys had the most intense (18)FDG uptake, followed by cloaca and intestinal tract; liver activity was mild and slightly more intense than that of the spleen; proventricular activity was always present, whereas little to no activity was identified in the wall of the ventriculus. Activity in the myocardium was present in all birds but varied in intensity among birds. The lungs had no visibly discernible activity. Mean +/- SD standardized uptake values calculated with representative regions of interest at 60 minutes were as follows: myocardium, 1. 6 +/- 0.2 (transverse plane) and 1.3 +/- 0.3 (sagittal plane); liver, 1.1 +/- 0.1; spleen, 0.9 +/- 0.1; proventriculus, 1.0 +/- 0.1; cloaca, 4.4 +/- 2.7; right kidney, 17.3 +/- 1.0; left kidney, 17.6 +/- 0.3; and right and left lungs (each), 0.3 +/- 0.02. CONCLUSIONS AND CLINICAL RELEVANCE: The study established the biodistribution of (18)FDG in adult eagles, providing a baseline for clinical investigation and future research. PMID- 23438119 TI - Ultrasonographic measurement of the pancreas and pancreatic duct in clinically normal dogs. AB - OBJECTIVE: To obtain ultrasonographic reference values for the thickness of the pancreas and the diameter of the pancreatic duct in clinically normal dogs. ANIMALS: 242 adult dogs with no clinical signs of gastrointestinal tract disease. PROCEDURES: The maximum pancreatic thickness and the diameter of the pancreatic duct were recorded ultrasonographically at the level of the left lobe, body, and right lobe of the pancreas. RESULTS: Mean +/- SD pancreatic thickness measurements were as follows: left lobe, 6.5 +/- 1.7 mm (n = 214); body, 6.3 +/- 1.6 mm (155); and right lobe, 8.1 +/- 1.8 mm (239). The mean pancreatic duct diameter was 0.6 +/- 0.2 mm (n = 42) in the left lobe and 0.7 +/- 0.2 mm (213) in the right lobe. The right pancreatic duct was visible in 213/242 (88.0%) dogs, and the left pancreatic duct was visible in 41/242 (16.9%) dogs. However, the body was visible in only 16/242 (6.6%) dogs. Pancreatic thickness and diameter of the pancreatic duct significantly increased with body weight in all lobes, but age was not correlated with the measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonographic reference values for the pancreas and pancreatic duct of dogs were determined. Results of this study indicated that the pancreatic duct was visible, especially in the right lobe of the pancreas. These values may be useful for the assessment of pancreatic abnormalities, such as chronic pancreatitis and exocrine pancreatic insufficiency. PMID- 23438120 TI - Comparison of acute infection of calves exposed to a high-virulence or low virulence bovine viral diarrhea virus or a HoBi-like virus. AB - OBJECTIVE: To compare acute infection of cattle exposed to a high-virulence (HV) bovine viral diarrhea virus (BVDV), low-virulence (LV) BVDV, or HoBi-like virus. ANIMALS: 24 Holstein bull calves. PROCEDURES: Colostrum-deprived 2- to 4-week-old calves, free of BVDV antigen and antibodies, were allocated into 4 groups (6 calves/group). Calves in 3 groups were exposed to an LV BVDV strain (BVDV2 RS886), an HV BVDV strain (BVDV2-1373), or a HoBi-like virus (D32/00 HoBi), whereas calves in the fourth group were not exposed to a virus but were cohoused with calves exposed to the HoBi-like virus. Circulating WBCs, platelets, rectal temperature, and presence of virus in the blood were monitored. RESULTS: Infection of calves with any of the 3 viruses resulted in reduced numbers of circulating WBCs. Pyrexia was detected in all calves exposed to HV BVDV or LV BVDV but in only 3 of 6 calves exposed to the HoBi-like virus. Diarrhea was observed in 0 of 6 calves exposed to the HoBi-like virus, 2 of 6 calves exposed to the LV BVDV, and 6 of 6 calves exposed to the HV BVDV. The HoBi-like virus was transmitted from acutely infected calves to naive cohorts. CONCLUSIONS AND CLINICAL RELEVANCE: The HoBi-like viruses are an emerging species of pestivirus isolated from water buffalo and cattle in South America, Southeast Asia, and Europe but not from cattle in the United States. Understanding the clinical course of disease caused by HoBi-like pestiviruses will be important for the design of surveillance programs for the United States. PMID- 23438121 TI - Effect of cold compress application on tissue temperature in healthy dogs. AB - OBJECTIVE: To measure the effect of cold compress application on tissue temperature in healthy dogs. ANIMALS: 10 healthy mixed-breed dogs. PROCEDURES: Dogs were sedated with hydromorphone (0.1 mg/kg, IV) and diazepam (0.25 mg/kg, IV). Three 24-gauge thermocouple needles were inserted to a depth of 0.5 (superficial), 1.0 (middle), and 1.5 (deep) cm into a shaved, lumbar, epaxial region to measure tissue temperature. Cold (-16.8 degrees C) compresses were applied with gravity dependence for periods of 5, 10, and 20 minutes. Tissue temperature was recorded before compress application and at intervals for up to 80 minutes after application. Control data were collected while dogs received identical sedation but with no cold compress. RESULTS: Mean temperature associated with 5 minutes of application at the superficial depth was significantly decreased, compared with control temperatures. Application for 10 and 20 minutes significantly reduced the temperature at all depths, compared with controls and 5 minutes of application. Twenty minutes of application significantly decreased temperature at only the middle depth, compared with 10 minutes of application. CONCLUSIONS AND CLINICAL RELEVANCE: With this method of cold treatment, increasing application time from 10 to 20 minutes caused a further significant temperature change at only the middle tissue depth; however, for maximal cooling, the minimum time of application should be 20 minutes. Possible changes in tissue temperature and adverse effects of application > 20 minutes require further evaluation. PMID- 23438122 TI - Effect of warm compress application on tissue temperature in healthy dogs. AB - OBJECTIVE: To measure the effect of warm compress application on tissue temperature in healthy dogs. ANIMALS: 10 healthy mixed-breed dogs. PROCEDURES: Dogs were sedated with hydromorphone (0.1 mg/kg, IV) and diazepam (0.25 mg/kg, IV). Three 24-gauge thermocouple needles were inserted to a depth of 0.5 cm (superficial), 1.0 cm (middle), and 1.5 cm (deep) into a shaved, lumbar, epaxial region to measure tissue temperature. Warm (47 degrees C) compresses were applied with gravity dependence for periods of 5, 10, and 20 minutes. Tissue temperature was recorded before compress application and at intervals for up to 80 minutes after application. Control data were collected while dogs received identical sedation but with no warm compress. RESULTS: Mean temperature associated with 5 minutes of heat application at the superficial, middle, and deep depths was significantly increased, compared with the control temperature. Application for 10 minutes significantly increased the temperature at all depths, compared with 5 minutes of application. Mean temperature associated with 20 minutes of application was not different at the superficial or middle depths, compared with 10 minutes of application. Temperature at the deep depth associated with 10 minutes of application was significantly higher, compared with 20 minutes of application, but all temperature increases at this depth were minimal. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that application of a warm compress should be performed for 10 minutes. Changes in temperature at a tissue depth of 1.5 cm were minimal or not detected. The optimal compress temperature to achieve therapeutic benefits was not determined. PMID- 23438123 TI - Orthotopic model of canine osteosarcoma in athymic rats for evaluation of stereotactic radiotherapy. AB - OBJECTIVE: To develop an orthotopic model of canine osteosarcoma in athymic rats as a model for evaluating the effects of stereotactic radiotherapy (SRT) on osteosarcoma cells. ANIMALS: 26 athymic nude rats. PROCEDURES: 3 experiments were performed. In the first 2 experiments, rats were injected with 1 * 10(6) Abrams canine osteosarcoma cells into the proximal aspect of the tibia (n = 12) or distal aspect of the femur (6). Tumor engraftment and progression were monitored weekly via radiography, luciferase imaging, and measurement of urine pyridinoline concentration for 5 weeks and histologic evaluation after euthanasia. In the third experiment, 8 rats underwent canine osteosarcoma cell injection into the distal aspect of the femur and SRT was administered to the affected area in three 12-Gy fractions delivered on consecutive days (total radiation dose, 36 Gy). Percentage tumor necrosis and urinary pyridinoline concentrations were used to assess local tumor control. The short-term effect of SRT on skin was also evaluated. RESULTS: Tumors developed in 10 of 12 tibial sites and all 14 femoral sites. Administration of SRT to rats with femoral osteosarcoma was feasible and successful. Mean tumor necrosis of 95% was achieved histologically, and minimal adverse skin effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The orthotopic model of canine osteosarcoma in rats developed in this study was suitable for evaluating the effects of local tumor control and can be used in future studies to evaluate optimization of SRT duration, dose, and fractionation schemes. The model could also allow evaluation of other treatments in combination with SRT, such as chemotherapy or bisphosphonate, radioprotectant, or parathyroid hormone treatment. PMID- 23438124 TI - Comparison of efficacy and duration of effect on corneal sensitivity among anesthetic agents following ocular administration in clinically normal horses. AB - OBJECTIVE: To compare efficacy and duration of effect on corneal sensitivity of 0.5% proparacaine hydrochloride, 0.5% bupivacaine hydrochloride, 2% lidocaine hydrochloride, and 2% mepivacaine hydrochloride solutions following ocular administration in clinically normal horses. ANIMALS: 68 clinically normal horses. PROCEDURES: 60 horses were assigned to receive 1 anesthetic agent in 1 eye. For each of another 8 horses, 1 eye was treated with each of the anesthetic agents in random order with a 1-week washout period between treatments. Corneal sensitivity was assessed via corneal touch threshold (CTT) measurements obtained with a Cochet-Bonnet aesthesiometer before and at 1 minute, at 5-minute intervals from 5 to 60 minutes, and at 10-minute intervals from 60 to 90 minutes after application of 0.2 mL of anesthetic agent. General linear mixed models were fitted to the CTT data from each of the 2 experimental groups to assess the effects of the anesthetic agents over time, accounting for repeated observations within individual horses. RESULTS: Corneal sensitivity decreased immediately following topical application of each anesthetic agent; effects persisted for 35 minutes for proparacaine and mepivacaine treatments, 45 minutes for lidocaine treatment, and 60 minutes for bupivacaine treatment. Maximal CTT reduction was achieved following application of bupivacaine or proparacaine solution, whereas mepivacaine solution was least effective. CONCLUSIONS AND CLINICAL RELEVANCE: Ocular application of each evaluated anesthetic agent reduced corneal sensitivity in horses; although 0.5% proparacaine or 2% lidocaine solution appeared to induce adequate short-duration corneal anesthesia, use of 0.5% bupivacaine solution may be more appropriate for procedures requiring longer periods of corneal anesthesia. PMID- 23438125 TI - Effects of route of administration and feeding schedule on pharmacokinetics of robenacoxib in cats. AB - OBJECTIVE: To establish pharmacokinetics of robenacoxib after administration to cats via the IV, SC, and oral routes. ANIMALS: 24 cats. PROCEDURES: In a crossover design, robenacoxib was administered IV, SC, and orally (experiment 1) and orally (experiment 2) to cats with different feeding regimens. Blood robenacoxib concentrations were assayed, with a lower limit of quantification of 3 ng/mL. RESULTS: In experiment 1, geometric mean pharmacokinetic values after IV administration of robenacoxib were as follows: blood clearance, 0.44 L/kg/h; plasma clearance, 0.29 L/kg/h; elimination half-life, 1.49 hours; and volume of distribution at steady state (determined from estimated plasma concentrations), 0.13 L/kg. Mean bioavailability was 69% and median time to maximum concentration (Cmax) was 1 hour for cats after SC administration of robenacoxib, whereas mean bioavailability was 49% and 10% and median time to Cmax was 1 hour and 30 minutes after oral administration to cats after food withholding and after cats were fed their entire ration, respectively. In experiment 2, geometric mean Cmax was 1,159, 1,201, and 692 ng/mL and area under the curve from 0 to infinity was 1,337, 1,383, and 1,069 ng * h/mL following oral administration to cats after food withholding, cats fed one-third of the daily ration, and cats fed the entire daily ration, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: For treatment of acute conditions in cats, it is recommended to administer robenacoxib by IV or SC injection, orally after food withholding, or orally with a small amount of food to obtain optimal bioavailability and Cmax. PMID- 23438126 TI - Plasma matrix metalloproteinase activity in horses after intravenous infusion of lipopolysaccharide and treatment with matrix metalloproteinase inhibitors. AB - OBJECTIVE: To establish an in vivo method for matrix metalloproteinase (MMP)-2 and MMP-9 induction in horses via IV administration of lipopolysaccharide (LPS) and to evaluate the ability of doxycycline, oxytetracycline, flunixin meglumine, and pentoxifylline to inhibit equine MMP-2 and MMP-9 production. ANIMALS: 29 adult horses of various ages and breeds and either sex. PROCEDURES: In part 1, horses received an IV administration of LPS (n = 5) or saline (0.9% NaCl) solution (5). Venous blood samples were collected before and at specified times for 24 hours after infusion. Plasma was harvested and analyzed for MMP-2 and MMP 9 activities via zymography. In part 2, horses received doxycycline (n = 5), oxytetracycline (5), flunixin meglumine (5), or pentoxifylline (4) before and for up to 12 hours after administration of LPS. Plasma was obtained and analyzed, and results were compared with results from the LPS-infused horses of part 1. RESULTS: Administration of LPS significantly increased MMP-2 and MMP-9 activities in the venous circulation of horses. All MMP inhibitors significantly decreased LPS-induced increases in MMP activities but to differing degrees. Pentoxifylline and oxytetracycline appeared to be the most effective MMP-2 and MMP-9 inhibitors, whereas doxycycline and flunixin meglumine were more effective at inhibiting MMP 2 activity than MMP-9 activity. CONCLUSIONS AND CLINICAL RELEVANCE: IV administration of LPS to horses caused increased venous plasma activities of MMP 2 and MMP-9. These MMP activities were reduced by pentoxifylline and oxytetracycline, suggesting that further evaluation of these medications for treatment and prevention of MMP-associated diseases in horses is indicated. PMID- 23438127 TI - Effect of transportation during periods of high ambient temperature on physiologic and behavioral indices of beef heifers. AB - OBJECTIVE: To determine the effect of transportation during periods of high ambient temperature on physiologic and behavioral indices of beef heifers. ANIMALS: 20 heifers (mean body weight, 217.8 kg). PROCEDURES: Ten heifers were transported 518 km when the maximum ambient temperature was >= 32.2 degrees C while the other 10 heifers served as untransported controls. Blood samples were collected from transported heifers at predetermined intervals during the transportation period. For all heifers, body weights, nasal and rectal temperatures, and behavioral indices were measured at predetermined intervals for 3 days after transportation. A week later, the entire process was repeated such that each group was transported twice and served as the control twice. RESULTS: Transported heifers spent more time near the hay feeder on the day of transportation, had lower nasal and rectal temperatures for 24 hours after transportation, and spent more time lying down for 2 days after transportation, compared with those indices for control heifers. Eight hours after transportation, the weight of transported heifers decreased 6%, whereas that of control heifers increased 0.6%. At 48 hours after initiation of transportation, weight, rectal temperature, and time spent at various pen locations did not differ between transported and control heifers. Cortisol concentrations were higher 4 hours after initiation of transportation, compared with those determined just prior to transportation. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated transportation during periods of high ambient temperatures caused transient changes in physiologic and behavioral indices of beef heifers. PMID- 23438129 TI - Effects of conjugated linoleic acids on prostaglandin secretion by bovine endometrial epithelial cells in vitro. AB - OBJECTIVE: To determine the effects of 2 conjugated linoleic acid (CLA) isomers (cis-9, trans-11 and trans-10, cis-12) on synthesis of prostaglandin (PG) E(2) and F(2alpha) and expression of prostaglandin H synthase-2 (PGHS-2) of adult and fetal bovine endometrial epithelial cells in vitro. SAMPLE: Primary cultures of endometrial epithelial cells obtained from 4 adult cows and 4 fetal bovine carcasses. PROCEDURES: Cells were exposed to 0, 50, 100, or 200MUM cis-9, trans 11 or trans-10, cis-12 CLA isomers for 24 hours. Culture media collected before and after 6 hours of stimulation of cells with phorbol 12-myristate 13-acetate were assayed to detect PGE(2) and PGF(2alpha) via ELISA. After stimulation, cells were collected for western blot analysis to quantify PGHS-2. RESULTS: Concentrations of PGF(2alpha) and PGE(2) were significantly lower in culture media of adult and fetal endometrial epithelial cells exposed to any concentration of either CLA than they were in media of cells not exposed to CLAs. The trans-10, cis-12 CLA isomer seemed to decrease PG production more markedly than did the cis-9, trans-11 CLA isomer. Most concentrations of both CLAs significantly reduced culture media PGE(2):PGF(2alpha) concentration ratios of cells. Exposure of cells to CLAs did not affect expression of PGHS-2 protein. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated CLAs significantly decreased PGF(2alpha) and PGE(2) concentrations and PGE(2):PGF(2alpha) concentration ratios for cultures of adult and fetal endometrial epithelial cells with no apparent effect on PGHS-2 expression. Similar effects in cows could have effects on maternal recognition of pregnancy and immune function. PMID- 23438130 TI - Comparison of first-intention healing of carbon dioxide laser, 4.0-MHz radiosurgery, and scalpel incisions in ball pythons (Python regius). AB - OBJECTIVE: To evaluate first-intention healing of CO(2) laser, 4.0-MHz radiowave radiosurgery (RWRS), and scalpel incisions in ball pythons (Python regius). ANIMALS: 6 healthy adult ball pythons. PROCEDURES: A skin biopsy sample was collected, and 2-cm skin incisions (4/modality) were made in each snake under anesthesia and closed with surgical staples on day 0. Incision sites were grossly evaluated and scored daily. One skin biopsy sample per incision type per snake was obtained on days 2, 7, 14, and 30. Necrotic and fibroplastic tissue was measured in histologic sections; samples were assessed and scored for total inflammation, histologic response (based on the measurement of necrotic and fibroplastic tissues and total inflammation score), and other variables. Frequency distributions of gross and histologic variables associated with wound healing were calculated. RESULTS: Gross wound scores were significantly greater (indicating greater separation of wound edges) for laser incisions than for RWRS and scalpel incisions at all evaluated time points. Necrosis was significantly greater in laser and RWRS incisions than in scalpel incision sites on days 2 and 14 and days 2 and 7, respectively; fibroplasia was significantly greater in laser than in scalpel incision sites on day 30. Histologic response scores were significantly lower for scalpel than for other incision modalities on days 2, 14, and 30. CONCLUSIONS AND CLINICAL RELEVANCE: In snakes, skin incisions made with a scalpel generally had less necrotic tissue than did CO(2) laser and RWRS incisions. Comparison of the 3 modalities on the basis of histologic response scores indicated that use of a scalpel was preferable, followed by RWRS and then laser. PMID- 23438131 TI - Effects of right ventricular nonapical pacing on cardiac function: a meta analysis of randomized controlled trials. AB - BACKGROUND: A meta-analysis of randomized controlled trials (RCTs) was conducted to compare the effects of right ventricular nonapical (RVNA) and right ventricular apical (RVA) pacing on cardiac function. METHODS: A systematic literature search was performed using MEDLINE, EMBASE, and the Cochrane Library to identify RCTs comparing RVNA pacing with RVA pacing with follow-up >=2 months. Twenty RCTs involving 1,114 patients were included. RESULTS: Compared with RVA pacing, RVNA (mainly right ventricular septum [RVS]) pacing exhibited not only excellent pacing threshold and R-wave amplitude but also higher impedance. RVNA pacing showed a significant increase in left ventricular ejection fraction (LVEF) at the end of follow-up (weighted mean difference = 3.58, 95% confidence interval = 1.80-5.35), and the effects were observed in the following subgroups: 6-month follow-up, <=12-month follow-up, >12-month follow-up, baseline LVEF <=45%, and baseline LVEF >45%. RVS and RVA pacing significantly differed in improving LVEF (weighted mean difference = 4.82, 95% confidence interval = 2.78-6.87). In addition, RVNA pacing resulted in a narrower QRS duration, a smaller left ventricular end-systolic volume, and a lower New York Heart Association functional class. CONCLUSIONS: This meta-analysis found that RVNA (mainly RVS) pacing exhibited satisfactory long-term lead performance compared with RVA pacing and demonstrated beneficial effects in improving LVEF after the 6-month follow up. Furthermore, it proved superior to RVA pacing in terms of interventricular synchrony and cardiac function. PMID- 23438132 TI - The effect of insulin treatment on Rac1 expression in diabetic kidney. AB - This study was designed to evaluate the renoprotective effect of insulin on diabetic nephropathy through Rac1 inhibition. Twenty Wistar rats were divided into three groups: control (C), diabetic (D), and insulin-treated diabetic (D + I). Diabetes was induced by a single streptozotocin (STZ) injection (45 mg/kg i.p.) in adult male rats. Diabetic animals were treated subcutaneously with insulin (6 U/kg), or saline once a day for 8 weeks. Age-matched control rats received only saline. The kidney tissue samples were analyzed by immunohistochemical staining for Rac1 and cleaved caspase-3 expressions and using the TUNEL method for determining apoptotic cells. Diabetes increased the number of TUNEL (+) cells and cleaved caspase-3 and Rac1 expression levels in kidney. Administration of insulin for 8 weeks reduced Rac1 expression and ameliorated histopathological changes in kidney of STZ-induced diabetes model. These results may suggest that the renoprotective effect of insulin at least partly results from inhibition of Rac1 overexpression. PMID- 23438133 TI - Central venous access device-related infections in patients with haemophilia. AB - AIMS: Fully implantable central venous access devices (CVADs) can offer long-term reliable venous access to facilitate regular factor replacement therapy in haemophilia. However, CVAD-related infection remains a major deterrent to the optimal use of CVAD in this population. This report represents the first review of CVAD use in haemophilia in Australia and aims to examine the rate of complications including CVAD-related infections. METHODS: A retrospective review of medical records was conducted of all haemophilic patients with fully implantable CVADs at the Royal Children's Hospital (RCH), Melbourne, between 1 June 1992 and 30 June 2009. CVAD-related bloodstream infection was defined based on the guidelines from the Centre of Disease Control and Victoria National Nosocomial Infection Surveillance. To further enhance identification of CVAD related infection in this study, a third criterion of 'suspected infection' was added by the authors. RESULTS: Eighty-one CVADs in 56 patients were managed at the RCH during this time period resulting in a combined study period of 94 756 CVAD days. Median age at first CVAD insertion = 2.16 years (range 0.66 to 13.98 years). CVADs were inserted predominantly due to difficult venous access and prophylaxis initiation (70.4%). Median life-span of a CVAD was 1227 days, equivalent to 3.36 years (n = 50; range 0.22 to 9.44 years). Fifty-seven CVAD related infections occurred in 37 CVADs (46.3%) in 29 patients (51.8%). Overall incidence of confirmed CVAD-related bloodstream infection = 0.42 per 1000 CVAD days (95% confidence interval (CI): 0.31 to 0.58 per 1000 CVAD days) and indicate better performance compared with the published benchmark of 0.66 per 1000 CVAD days (0.44 to 0.97 per 1000 CVAD days). The incidence of both confirmed (criteria 1, 2) and suspected (criterion 3) CVAD-related infection is 0.60 per 1000 CVAD days (95% CI: 0.46 to 0.78), which is comparable to the international benchmark. The majority of CVAD-related infections (73.7%) were successfully treated with intravenous antimicrobials without necessitating CVAD removal. Klebsiella pneumoniae was the most common organism found in positive blood cultures. CONCLUSION: CVAD-related infection in this Australian population was comparable to rates described in the medical literature. Ongoing surveillance for infection rates is important to provide an up-to-date assessment of risks associated with CVAD use in this population. PMID- 23438134 TI - Donor cycle and donor segmentation: new tools for improving blood donor management. AB - BACKGROUND AND OBJECTIVES: An adequate donor population is of key importance for the entire blood transfusion chain. For good donor management, a detailed overview of the donor database is therefore imperative. This study offers a new description of the donor cycle related to the donor management process. It also presents the outcomes of a European Project, Donor Management IN Europe (DOMAINE), regarding the segmentation of the donor population into donor types. MATERIALS AND METHODS: Blood establishments (BEs) from 18 European countries, the Thalassaemia International Federation and a representative from the South-Eastern Europe Health Network joined forces in DOMAINE. A questionnaire assessed blood donor management practices and the composition of the donor population using the newly proposed DOMAINE donor segmentation. 48 BEs in 34 European countries were invited to participate. RESULTS: The response rate was high (88%). However, only 14 BEs could deliver data on the composition of their donor population. The data showed large variations and major imbalances in the donor population. In 79% of the countries, inactive donors formed the dominant donor type. Only in 21%, regular donors were the largest subgroup, and in 29%, the proportion of first time donors was higher than the proportion of regular donors. CONCLUSION: Good donor management depends on a thorough insight into the flow of donors through their donor career. Segmentation of the donor database is an essential tool to understand the influx and efflux of donors. The DOMAINE donor segmentation helps BEs in understanding their donor database and to adapt their donor recruitment and retention practices accordingly. Ways to use this new tool are proposed. PMID- 23438135 TI - To smell or not to smell? That is the question! PMID- 23438136 TI - Dry skin in the winter is related to the ceramide profile in the stratum corneum and can be improved by treatment with a Eucalyptus extract. AB - BACKGROUND: Dry skin in the winter has been reported to involve scaling, defects in water holding and barrier functions, and decreased ceramide (CER) levels in the stratum corneum (SC). We previously reported that a Eucalyptus extract promotes CER synthesis in cultured keratinocytes and accelerates the recovery of hydration in a barrier-disrupted model of human skin. AIMS: One of the objectives was to examine the CER profile and its contribution to the relief of dry skin. The other objective was to assess the efficacy of a Eucalyptus extract to treat dry skin. PATIENTS/METHODS: Twenty subjects with dry skin on their legs were assessed and their CER profiles were analyzed using tape-stripping. A moisturizer with a Eucalyptus extract was assessed for its effects on dry skin using a leg regression methodology comprising 28 days of treatment and 14 days of regression. RESULTS: Indicators of dry skin conditions (conductance, dryness, roughness, and scaliness) strongly correlated with the level of CER, CER [NP], and CER[NH]. Treatment with the Eucalyptus extract significantly improved conductance (3 days after regression) and transepidermal water loss (14 days after regression) compared with the placebo. After 28 days of treatment with the Eucalyptus extract, the level of CER in the SC did not increase, but CER [NP] did increase. CONCLUSIONS: These results suggest that not only the level of CER, but also specific CER species strongly contribute to dry skin relief and products that increase those are useful to improve dry skin conditions. PMID- 23438138 TI - Reductions in body measurements promoted by a garment containing ceramic nanoparticles: a 4-month follow-up study. AB - BACKGROUND: Published literature reports significant improvements in pathological conditions, such as pain, blood dyscrasias, and cellulite, after using topical occlusive accessories containing particulate ceramic materials. Recent work reported a reduction in body measurements after 30 days of daily use of high waist undershorts made of synthetic fabrics with embedded ceramic particles. OBJECTIVES: In this study, we investigated whether the use of a garment made with synthetic fibers embedded with powdered ceramic could lead to reductions in body measurements at a longer time span (120 day). METHODS: Thirty-two female volunteers wore clothing containing ceramic powder for at least 8 h a day for 120 days. The efficacy of the treatment was evaluated through anthropometric measurements taken before treatment and after 30, 60, and 120 days of treatment. RESULTS: The experimental data showed a more pronounced reduction in body measurements at the beginning of treatment with a trend of stabilization in measured body circumferences during the final 60 days of the experimental period. CONCLUSIONS: The experimental data showed that the occlusive treatment with a garment composed of ceramic particles promoted reductions in body measurements during a 120-day experimental period. PMID- 23438137 TI - Efficacy of hydroquinone-free skin-lightening cream for photoaging. AB - BACKGROUND: Hyperpigmentation and solar damage remains a difficult problem to treat with topical agents. AIMS: To evaluate a novel skin-lightening complex (SLC) comprising four actives targeting melanin formation at multiple levels, namely disodium glycerophosphate, L-leucine, phenylethyl resorcinol, and undecylenoyl phenylalanine, in an oil-in-water emulsion cream. PATIENTS/METHODS: Skin-lightening complex was evaluated in 80 female subjects of skin types I-III with at least moderate mottled hyperpigmentation. After a wash-out period of 1 month with a sunscreen, the subjects added a cream containing the SLC for 12 weeks twice daily to entire face and continued the sunscreen use. RESULTS: Whereas there was no significant change during the wash-out period, the primary endpoint mottled hyperpigmentation decreased by 32% after the 12-week treatment period with the SLC cream. Secondary endpoints such as severity and number of lentigines, skin tone, and skin brightness also improved. In all, 57% of the subjects showed at least a moderate response, 17% did not improve, and 3% got worse after the treatment. CONCLUSIONS: The SLC cream was well tolerated, in particular when comparing with exfoliating or peeling agent containing skin lightening products. When used with a daily sunscreen, this study confirms that the SLC represents an alternative to hydroquinone, retinoids, and many other skin lightening actives. PMID- 23438139 TI - The effect of a vitamin A palmitate and antioxidant-containing oil-based moisturizer on photodamaged skin of several body sites. AB - BACKGROUND: Cumulative lifetime sun exposure is accepted as having a very important role to play in the expression of the signs of photoaging, which is then superimposed on the intrinsic processes involved in the chronological aging of skin. Many groups have evaluated the effects of emulsion-based products, mostly although not exclusively, on the face using a variety of actives including retinoids and antioxidants. Nevertheless, the effect of a topical anhydrous product on photodamaged skin has not been reported in the literature. AIMS: The objective of this study was to clinically evaluate the effect of a vitamin A palmitate and antioxidant-containing oil-based moisturizer on facial, neck, decolletage, arms, and lower leg body sites. METHODS: In a randomized, controlled and efficacy grader-blinded clinical study conducted over 12 weeks, while at the same time recording the changes in skin condition for a no-treatment group over the same time period, live clinical expert grading of all body sites and also grading of photographs for the face and neck assessed changes in the signs of photodamage was performed for the treatment and no-treatment groups. RESULTS: Compared to the no-treatment group, and to baseline, the oil improved fine lines, coarse wrinkles, mottled pigmentation, uneven skin tone, roughness, firmness, and clarity of the skin on the face and neck and was also shown to improve crepey skin texture, dryness, scaling and roughness on the decolletage, arms and lower legs at the primary end point at 12 weeks (P < 0.001). Moreover, improvements in a variety of parameters were observed as quickly as 2 weeks. In general, the degree of improvement was greatest in the order legs > arms > decolletage > face > neck. CONCLUSIONS: Collectively, these results show the cumulative improvements in the signs of photoaging compared to a no-treatment control group for the oil based antiaging moisturizer for the first time. The differences in the efficacy of the vitamin A palmiate and antioxidant oil-based moisturizer on different body sites probably reflect the differences in likely photodamage. PMID- 23438140 TI - Comparison of noncross-linked and cross-linked hyaluronic acid with regard to efficacy of the proliferative activity of cutaneous fibroblasts and keratinocytes in vitro. AB - BACKGROUND: Intradermal application of hyaluronic acid (HA) in varying chain length and cross-linking density is used routinely for hydrodynamic volume replacement of the extracellular matrix to reduce the clinical effects of aging. OBJECTIVES: In vitro data show that via receptors of the hyaladherin group hyaluronic acid has additionally direct or indirect effects on cells. In the case of native noncross-linked HA, it has been proved that the proliferative and metabolic activity of cutaneous fibroblasts can be increased. The aim of this study was to investigate whether these effects can be proved also for cross linked HA and how these effects can be quantified for different preparations. MATERIALS AND METHODS: The effect on proliferative activity in cultures of native cutaneous fibroblasts and keratinocytes was investigated for noncross-linked HA, for noncross-linked HA with added glycerol, for HA that was stabilized in the carboxyl and hydroxyl groups per inner esterification, and for HA that was chemically cross-linked by 1,4-butanediol-diglycidylether, mixed in small particles in a biphasic compound with native HA, each in different concentrations (0.1, 1.0 and 10.0 mg/mL). RESULTS: HA that was stabilized in the carboxyl and hydroxyl groups per inner esterification induces the strongest proliferative effect on both cell types. Native noncross-linked HA and chemically cross-linked HA show a rather modest proliferative effect and on fibroblasts only, whereas noncross-linked HA with added glycerol in high concentrations provokes a rather antiproliferative effect. CONCLUSIONS: The data show that HA does induce direct effects on cells depending on type and density of the cross-linkage. The practical relevance in terms of a metabolic filler effect needs to be verified in clinical studies. PMID- 23438141 TI - Effect of essential oils, hydrating agents, and ethanol on hair removal efficiency of thioglycolates. AB - BACKGROUND: The required time for hair removal by chemical depilatories has always been a concern and depends on different parameters including permeation into the hair shaft. OBJECTIVES: In an attempt to improve this process, it was decided here to investigate the possibility of decreasing depilation time of thioglycolates, widely used depilatories, using penetration enhancers. METHODS: Urea, sodium dodecyl sulfate, dimethylsulfoxide (DMSO), ethanol (75 and 96%), NaCl, and peppermint and orange oils were used as penetration enhancers, and their effect on depilatory time of thioglycolates, represented as tear resistance time (TRT) of hair shaft under a constant tensile stress, was studied. The effects of temperature and hydration on TRT were also investigated. RESULTS: Results showed that ethanol (75%), DMSO, and peppermint oil (ethanolic solution) were able to significantly reduce TRT up to two times from about 6 to 3.5 min. Other enhancers were not able to change TRT. Results also revealed that increase in temperature from 20 to 37 degrees C reduces TRT by about 4 times. Hydration in boiling water also reduced TRT significantly about 1.5 times. CONCLUSIONS: Present results show that it is possible to reduce depilation time by penetration enhancers. Such improvement can increase users' compliance and might provide other advantages like decreased skin irritation. PMID- 23438142 TI - Short flap rhytidectomy and fractional CO2 laser rejuvenation of the aging face. AB - BACKGROUND: There is currently a high demand for a concurrent system of skin rejuvenation accompanying rhtidectomy. CO2 laser treatment prior to surgical ablative reduction has produced promising results, but the adjunct service of laser treatment at the time of surgery has never been reviewed. OBJECTIVES: Determine the effects of concurrent treatment of rhytides and evidence of aging in the skin with surgical correction followed by fractional CO2 laser application. METHODS: During study time from September 2008 to February 2009 treat patients who have underwent short flap rhytidectomy to the Lutronic eCO2TM fractional laser using the patented "Controlled Chaos Technology." RESULTS: Complications included 2.3% herpes simplex outbreak, 4% persistent erythema past 2 weeks, four cases of prolonged edema to 5 days, one case of impetigo, and no evidence of dyspigmentation. Patient satisfaction data demonstrated no refunds at 12 months. CONCLUSIONS: Combination fractional laser resurfacing with short flap, high-Superficial muscular aponeurotic system rhytidectomy is a safe procedure with excellent patient satisfaction and clinical outcomes. PMID- 23438143 TI - Tranexamic acid: an important adjuvant in the treatment of melasma. AB - This article reviews an old drug tranexamic acid to its new use in the treatment of melasma. Its mechanism of preventing the activation of melanocyte from UV light, hormone and injured kerationcyte through the inhibition of the plasminogen activator system will be explored. The detail usage for such indication and its safety profile will also be thoroughly evaluated. PMID- 23438144 TI - Clinical study of nail changes in vitiligo. AB - Both vitiligo and alopecia areata (AA) are associated together, associated with other autoimmune diseases, and autoimmunity is one of the important theories in their etiology. Nail changes are a known association with AA, thus we hypothesized that nail changes can be found in vitiligo patients. On revising the literature, only two types of nail changes were described in association with vitiligo. Our aim was to study the frequency and types of nail changes among vitiligo patients in comparison with normal healthy volunteers. This multi centric study was carried on 91 patients with vitiligo, as well as 91 normal healthy control subjects who were age- and sex-matched. Nails were examined for changes in nail plates as regards striations, texture, curvature, dystrophy, and pigmentation. The presence or absence of the thumb lunula was also reported. Nail changes were observed in 62 patients (68.1%) and 46 (50.5%) control subjects with a statistically significant difference (P = 0.016). Longitudinal ridging and absent lunula were significantly higher in patients than in the controls (P = 0.001 and 0.037, respectively). Other reported nail abnormalities in the current study included punctate leukonychia, pitting, flag sign, and Terry's nails. Awareness of this association will widen the clinician's perspective to carefully examine the nail changes in vitiligo patients and conversely examine patients with nail changes for vitiligo. PMID- 23438145 TI - A five-patient prospective pilot study of a polycaprolactone based dermal filler for hand rejuvenation. AB - BACKGROUND: Hand rejuvenation is becoming more popular as a complementary procedure to facial treatments. Current options include the relatively invasive lipofilling and the less invasive dermal fillers treatments, of which the latter often is too short lasting. An ideal product would therefore be minimally invasive, however, providing longer lasting results. OBJECTIVES: The objective of this pilot study is to evaluate the safety and efficacy of a polycaprolactone based dermal filler for hand rejuvenation. METHODS: The dorsum of the hands of five subjects was treated with 1.0 mL polycaprolactone based dermal filler per hand. Subjects were seen for follow-up visits after 1, 4, 16, and 24 weeks. RESULTS: The results showed consistent and high patient satisfaction throughout the duration of the study using a Visual Analog Scale. Satisfaction was rated at 82% at 24 weeks and patients were 88% likely to return for repeat treatments on average. On the subject GAIS assessment, all subjects reported an improvement compared to pretreatment throughout the duration of the study. The physicians' GAIS results were very much improved (90%) and much improved (10%) compared to pretreatment throughout the 24 weeks follow-up. CONCLUSIONS: The data of this small pilot suggest that the polycaprolactone based dermal filler is safe, well tolerated and effective for hand rejuvenation, and potentially offers a valuable addition to the current treatment armamentum. Additional studies in a larger patient population should be performed to confirm these findings. PMID- 23438146 TI - Visual attention to and perception of undamaged and damaged versions of natural and colored female hair. AB - Female hair color is thought to influence physical attractiveness, and although there is some evidence for this assertion, research has yet not addressed the question if and how physical damaging affects the perception of female hair color. Here we investigate whether people are sensitive (in terms of visual attention and age, health and attractiveness perception) to subtle differences in hair images of natural and colored hair before and after physical damaging. We tracked the eye-gaze of 50 men and 50 women aged 31-50 years whilst they viewed randomized pairs of images of 20 natural and 20 colored hair tresses, each pair displaying the same tress before and after controlled cuticle damage. The hair images were then rated for perceived health, attractiveness, and age. Undamaged versions of natural and colored hair were perceived as significantly younger, healthier, and more attractive than corresponding damaged versions. Visual attention to images of undamaged colored hair was significantly higher compared with their damaged counterparts, while in natural hair, the opposite pattern was found. We argue that the divergence in visual attention to undamaged colored female hair and damaged natural female hair and associated ratings is due to differences in social perception and discuss the source of apparent visual difference between undamaged and damaged hair. PMID- 23438148 TI - Gold-catalyzed oxidative cyclization of chiral homopropargyl amides: synthesis of enantioenriched gamma-lactams. AB - A gold-catalyzed tandem cycloisomerization/oxidation of homopropargyl amides has been developed, which provides ready access to synthetically useful chiral gamma lactams with excellent ee by combining the chiral tert-butylsulfinimine chemistry and gold catalysis. The utility of this methodology has also been demonstrated in the synthesis of biologically active compound S-MPP and natural product (-) bgugaine. The use of readily available starting materials, a simple procedure, and mild reaction conditions are other significant features of this method. PMID- 23438147 TI - Shifting from glucose diagnosis to the new HbA1c diagnosis reduces the capability of the Finnish Diabetes Risk Score (FINDRISC) to screen for glucose abnormalities within a real-life primary healthcare preventive strategy. AB - BACKGROUND: To investigate differences in the performance of the Finnish Diabetes Risk Score (FINDRISC) as a screening tool for glucose abnormalities after shifting from glucose-based diagnostic criteria to the proposed new hemoglobin (Hb)A1c-based criteria. METHODS: A cross-sectional primary-care study was conducted as the first part of an active real-life lifestyle intervention to prevent type 2 diabetes within a high-risk Spanish Mediterranean population. Individuals without diabetes aged 45-75 years (n = 3,120) were screened using the FINDRISC. Where feasible, a subsequent 2-hour oral glucose tolerance test and HbA1c test were also carried out (n = 1,712). The performance of the risk score was calculated by applying the area under the curve (AUC) for the receiver operating characteristic, using three sets of criteria (2-hour glucose, fasting glucose, HbA1c) and three diagnostic categories (normal, pre-diabetes, diabetes). RESULTS: Defining diabetes by a single HbA1c measurement resulted in a significantly lower diabetes prevalence (3.6%) compared with diabetes defined by 2-hour plasma glucose (9.2%), but was not significantly lower than that obtained using fasting plasma glucose (3.1%). The FINDRISC at a cut-off of 14 had a reasonably high ability to predict diabetes using the diagnostic criteria of 2 hour or fasting glucose (AUC = 0.71) or all glucose abnormalities (AUC = 0.67 and 0.69, respectively). When HbA1c was used as the primary diagnostic criterion, the AUC for diabetes detection dropped to 0.67 (5.6% reduction in comparison with either 2-hour or fasting glucose) and fell to 0.55 for detection of all glucose abnormalities (17.9% and 20.3% reduction, respectively), with a relevant decrease in sensitivity of the risk score. CONCLUSIONS: A shift from glucose-based diagnosis to HbA1c-based diagnosis substantially reduces the ability of the FINDRISC to screen for glucose abnormalities when applied in this real-life primary-care preventive strategy. PMID- 23438149 TI - Salt (sodium chloride) content of retail samples of Nigerian white bread: implications for the daily salt intake of normotensive and hypertensive adults. AB - BACKGROUND: Bread has been identified as a major contributor to the excessive salt (sodium chloride) intake of consumers in many countries, some of which have very high incidences of hypertension and related cardiovascular complications, such as stroke. This has prompted a global rise in interest in the salt content of breads produced and consumed in many other countries. METHODS: The sodium contents of retail samples of 100 brands of Nigerian white bread were determined by photometry with a view to estimating the relative contribution of bread to the recommended daily sodium intake of both normotensive and hypertensive adults in the country. RESULTS: The salt content of the bread samples varied extensively, ranging from 0.51 g per 100 g (0.51%) to 1.8 g per 100 g (1.8%). The average salt content was 1.36 g per 100 g. Based on an estimated consumption of six slices of bread (about 180 g) per meal of bread, this equates to a daily intake of between 0.99 g and 3.33 g of salt from bread alone. This represents between 19.8% and 66.6% of the recommended daily allowance of 5 g for normotensive adults, and between 24.75% and 83.25% of the recommended daily allowance of 4 g for hypertensive adults. CONCLUSIONS: The consumption of some brands of bread by normotensive and hypertensive adults puts them at great risk of exceeding their recommended daily allowance for salt. Thus, there is an urgent need to regulate the amount of salt added to bread. In the interim, compelling bakers to declare the salt content of their products on the packaging could help consumers, especially hypertensive adults, avoid brands with a high salt content. PMID- 23438150 TI - Osteopontin expression is an independent factor for poor survival in oral squamous cell carcinoma: a computer-assisted analysis on TMA sections. AB - INTRODUCTION: Osteopontin (OPN) is non-collagenous extracellular matrix protein involved in various physiological and pathological events, including tumor progression. The aim of this study was to analyze the expression of OPN in normal oral mucosa and oral squamous cell carcinoma (OSCC) and to assess its prognostic significance. METHODS: The expression of OPN was immunohistochemicaly analyzed in 86 OSCC and compared with clinicopathological variable such as tumor size, nodal stage, WHO clinical stage, Ki-67 proliferation index, and patients' outcome. OPN mRNA was analyzed using quantitative real-time PCR and compared with protein OPN expression and clinical outcome in 18 OSCC samples. RESULTS: The expression of OPN protein was found in OSCC tumor cells (t-OPN) and various stromal cells (s OPN). High level of t-OPN expression was associated with higher nodal stage (P = 0.045), higher WHO clinical stage (P = 0.033), and poor clinical outcome (P = 0.022). In multivariate analysis, t-OPN emerged as an adverse independent factor for survival (P = 0.049). Although correlated with t-OPN (P = 0.005), s-OPN was not significantly associated with clinical parameters, including patients' outcome. Also, there was no association between OPN and clinical parameters at the mRNA level. CONCLUSION: OPN is upregulated in tumor and stromal OSCC cells. Tumor cell-derived OPN is involved in tumor progression and can independently predict the clinical outcome. Stromal-derived OPN probably has a different function compared with OPN secreted from tumor cells. PMID- 23438151 TI - Biosynthesis of 9-methylstreptimidone involves a new decarboxylative step for polyketide terminal diene formation. AB - 9-Methylstreptimidone is a glutarimide antibiotic showing antiviral, antifungal, and antitumor activities. Genome scanning, bioinformatics analysis, and gene inactivation experiments reveal a gene cluster responsible for the biosynthesis of 9-methylstreptimidone in Streptomyces himastatinicus. The unveiled machinery features both acyltransferase- and thioesterase-less iterative use of module 5 as well as a branching module for glutarimide generation. Impressively, inactivation of smdK leads to a new carboxylate analogue unveiling a new mechanism for polyketide terminal diene formation. PMID- 23438152 TI - FTO T/A and peroxisome proliferator-activated receptor-gamma Pro12Ala polymorphisms but not ApoA1 -75 are associated with better response to lifestyle intervention in Brazilians at high cardiometabolic risk. AB - BACKGROUND: The role of obesity-related polymorphisms on weight loss and inflammatory responses to interventions is unclear. We investigated associations of certain polymorphisms with response to a lifestyle intervention. METHODS: This 9-month intervention on diet and physical activity included 180 Brazilians at high cardiometabolic risk, genotyped for the fat mass and obesity-associated (FTO) T/A, peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala, and ApoA1 -75G/A polymorphisms. Changes in metabolic and inflammatory variables were analyzed according to these polymorphisms. RESULTS: The intervention resulted in lower energy intake and higher physical activity. Anthropometric measurements, 2-hr plasma glucose, insulin, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) improved significantly for the total sample, and these benefits were similar among genotypes. Only variant allele carriers of FTO T/A decreased fasting plasma glucose after intervention (99.9+/-1.3 to 95.6+/ 1.4 mg/dL, P=0.021). Mean blood pressure reduced after intervention in variant allele carriers of the PPARgamma Pro12Ala (109.4+/-2.1 to 101.3+/-2.1 mmHg, P<0.001). Improvement in lipid variables was not significant after adjustment for medication. Only the reference genotype of PPARgamma Pro12Ala increased apolipoprotein A1 (ApoA1) after intervention (134.3+/-2.4 to 140.6+/-2.3 mg/dL, P<0.001). Only variant allele carriers of FTO reduced C-reactive protein (CRP) concentration (0.366+/-0.031 to 0.286+/-0.029 mg/dL, P=0.023). CONCLUSION: In Brazilian individuals, the FTO T/A polymorphism induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPARgamma Pro12Ala seems to favor a better lipid profile, while the variant allele decreases blood pressure. Our data did not support benefits of the variant allele of ApoA1 -75G/A polymorphism. Further studies are needed to direct lifestyle intervention to subsets of individuals at cardiometabolic risk. PMID- 23438153 TI - Coronary artery calcium screening in persons with metabolic syndrome and diabetes: implications for prevention. AB - Abstract Diabetes and metabolic syndrome are major risk factors for coronary heart disease (CHD). Many patients suffering CHD events are not adequately identified by traditional risk assessment, suggesting the need for early detection of subclinical CHD to identify those at highest risk. Coronary artery calcium (CAC) screening has added utility in categorizing patients with intermediate and high risk of CHD events, and a growing body of evidence suggests its use for CHD risk assessment in persons with metabolic syndrome and diabetes mellitus. These studies demonstrate the presence and extent of CAC to be greater in those with these conditions, compared to those without, and that CHD risk varies greatly according to the extent of CAC both in persons with and without metabolic syndrome and diabetes mellitus. More recently, guidelines regarding the use of CAC screening have been extended to those with diabetes mellitus, helping to further stratify those patients that may benefit from more intensive therapy. This review evaluates the role and possible benefits of CAC screening, with a focus on those with metabolic syndrome and diabetes mellitus for evaluating the risk for CHD. PMID- 23438154 TI - Physical activity in patients with metabolic syndrome: at screening and three years thereafter. AB - BACKGROUND: Metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes. Physical activity can decrease these risks. Many randomized clinical trials to increase physical activity have demonstrated disappointing results, and implementation in daily practice appeared to be difficult. The aim of this study was to investigate whether 3 years of usual care with available guidelines in a primary care setting result in change in physical activity in patients with screen-detected metabolic syndrome. METHODS: After a population-based screening, 473 patients were diagnosed with metabolic syndrome and received advice to increase physical activity. Three years later, they were invited for follow-up. Physical activity was measured by means of the validated SQUASH questionnaire. The primary outcome measure was: % of metabolic syndrome patients that fulfill the Dutch Physical Activity Guideline (DPAG) criterion (30 min of moderately intensive physical activity at least 5 days per week) at screening and follow-up. RESULTS: In the final study population (n=168), the proportion of patients fulfilling the DPAG criterion did not significantly increase between screening (56.0%) and follow-up (60.7%) (P=0.29). Female gender [odds ratio (OR)=3.59; 95% confidence interval (CI) 1.24-10.39] and body mass index (BMI) at baseline (OR=0.82; 95% CI 0.69-0.97) appeared to be independent predictors of increase in physical activity. CONCLUSIONS: In this real-world setting, despite the advice to increase physical activity, the number of metabolic syndrome patients with sufficient physical activity did not significantly increase after 3 years. This finding confirms the need for an intensified approach to achieve an increase in physical activity in this group, with special attention to men and patients with higher BMI values. PMID- 23438155 TI - Association of metabolic risk with longitudinal physical activity and fitness: coronary artery risk development in young adults (CARDIA). AB - BACKGROUND: Despite established relationships between physical activity (PA) or physical fitness (fitness) and metabolic risk, the prospective association is not well understood. The purpose of this study was to determine whether metabolic risk in young adults is associated with 20-year PA or fitness trajectories. METHODS: Young adults were from the Coronary Artery Risk Development in Young Adults (CARDIA) study, baseline ages 18-30 years (n=4161). PA was determined from a self-reported questionnaire administered at baseline and at follow-up exams at years 2, 5, 7, 10, 15, and 20. Fitness (seconds) was estimated from a graded exercise treadmill test at baseline and years 7 and 20. Baseline metabolic risk was calculated using age-adjusted principal components analysis (elevated=top 10% of first factor), for each sex-race group, from mean arterial pressure, glucose, waist circumference, triglycerides, and high-density lipoprotein cholesterol. Repeated measures general linear modeling estimated PA and fitness trajectories over 20 years, separately in sex-race groups, adjusting for age and smoking status. RESULTS: PA was significantly lower among those with elevated metabolic risk compared with normal risk at baseline and each subsequent time point (black and white men, white women; all P<0.0001; black women P=0.27). Significant and consistent results were also found with fitness trajectories for all sex-race groups (P<0.0001). Despite these lower PA and fitness levels at baseline in young adults with elevated metabolic compared with normal risk, 20-year trajectories declined at similar rates. CONCLUSION: Elevated metabolic risk is associated with lower levels of PA and fitness in early adulthood, and these differences persist over 20 years. PMID- 23438156 TI - Metabolic syndrome in normal and complicated pregnancies. AB - BACKGROUND: The aim of our study was to elucidate the association of the metabolic syndrome with the risk of unsuccessful pregnancy. METHODS: This was a retrospective observational study conducted at Markusovszky Teaching Hospital, Szombathely, Hungary, a tertiary health care center. During the study period of 2007-2011 (5 years), 7373 pregnancies were followed. Pregnant women who were suffering from metabolic syndrome in the first trimester of gestation during the study period were compared to all other pregnant women without the syndrome. Retrospectively, 219 (2.9%) patients met the criteria of metabolic syndrome during the first trimester. Our goal was to evaluate the prevalence of the metabolic syndrome in normal pregnancies and in those complicated by either premature birth, or intrauterine growth retardation (IUGR), pregnancy-induced hypertension, and preeclampsia. RESULTS: The rate of preterm birth was 15.2% [32/219 in the metabolic syndrome group vs. 11.1% (p=0.051) in the control group]. Within the affected group, 40 pregnancies were complicated with IUGR (18.4%) versus 3.3%, in the unaffected group (p<0.001). In 58 cases, we observed preeclampsia during pregnancy [26.7% vs. 5.2% (p<0.001)] in the control group. Among the patients affected by the metabolic syndrome, 83 patients (38.2%) had more then one pregnancy complication during pregnancy, and only 59 cases (27.2%) had no adverse events during pregnancy and delivery (p<0.001). CONCLUSIONS: Our study demonstrated a higher rate of complicated pregnancies in association with metabolic syndrome compared to the control group. PMID- 23438157 TI - Empiric evidence for a genetic contribution to predisposition to surgical site infection. AB - The genetics of microbial pathogens have been extensively studied, but there has been little work on human genetic susceptibility to surgical site infection (SSI). We analyzed a large genealogical population database to study the familial contribution to SSI. We analyzed 651 individuals with International Classification of Disease, Ninth Revision codes indicating the presence of SSI. Matched hospital controls were randomly selected from the database based on birth year, sex, and birthplace. The average relatedness of all possible pairs of cases and separately of controls (*1000 sets) was compared empirically. The relative risk (RR) for SSI was estimated by comparing the number of observed affected individuals among the relatives of cases to the number of affected individuals observed among relatives of matched hospital controls. The genealogical index of familiality test for patients with SSI showed significant excess relatedness (p < 0.010); this excess was still observed when close relationships were ignored (p = 0.019). The RR for third-degree relatives of cases was significantly elevated (1.62, p = 0.029). The significant excess relatedness and the significantly elevated RR to distant relatives support a genetic predisposition to acquiring SSI. PMID- 23438158 TI - S100B and schizophrenia. AB - The research for peripheral biological markers of schizophrenia, although abundant, has been unfruitful. In the last 2 decades, the S100B protein has made its own room in this area of research. S100B is a calcium-binding protein that has been proposed as a marker of astrocyte activation and brain dysfunction. Research results on S100B concentrations and schizophrenia clinical diagnosis are very consistent; patients with schizophrenia have higher S100B concentrations than healthy controls. The results regarding schizophrenia subtypes and clinical characteristics are not as conclusive. Age of patients, body mass index, illness duration and age at onset have been found to show no correlation, a positive correlation or a negative correlation with S100B levels. With respect to psychopathology, S100B data are inconclusive. Positive, negative and absence of correlation between S100B concentrations and positive and negative psychopathology have been reported. Methodological biases, such as day/night and seasonal variations, the use of anticoagulants to treat biological samples, the type of analytical technique to measure S100B and the different psychopathological scales to measure schizophrenia symptoms, are some of the factors that should be taken into account when researching into this area in order to reduce the variability of the reported results. The clinical implications of S100B changes in schizophrenia remain to be elucidated. PMID- 23438159 TI - Study of the efficacy and safety of switching from risperidone to paliperidone in elderly patients with schizophrenia. AB - AIM: We investigated the clinical efficacy and safety of switching to paliperidone (PAL) in elderly schizophrenia patients receiving risperidone. METHODS: The subjects were 27 inpatients who had been diagnosed with schizophrenia according to the DSM-IV. The patient's clinical symptoms were assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity of Illness Scale, and their safety was assessed using the Drug-induced Extrapyramidal Symptoms Scale, bodyweight, body mass index, and laboratory tests. We also investigated patient satisfaction using the Drug Attitude Inventory, a subjective outcome measure. RESULTS: No significant differences in clinical symptom improvement efficacy were seen between the PAL switching group and the control group. The mean changes from baseline on the Drug induced Extrapyramidal Symptoms Scale total score, Drug Attitude Inventory score, and prolactin level were significantly greater in the PAL-switching group than in the control group. Furthermore, patients with PAL needed less biperiden, even though they had similar risperidone-equivalent daily dosages to the control group. CONCLUSIONS: The results of this study suggest that switching elderly patients from risperidone to PAL may result in superior safety and patient satisfaction, and may also make it possible to reduce the dosage of biperiden. PMID- 23438160 TI - Wechsler Intelligence Scale for Children 4th edition-Chinese version index scores in Taiwanese children with attention-deficit/hyperactivity disorder. AB - AIM: The Wechsler Intelligence Scale for Children 4th edition-Chinese version (WISC-IV-Chinese) has been in clinical use in Taiwan since 2007. Research is needed to determine how the WISC-IV, modified from its earlier version, will affect its interpretation in clinical practice in a Mandarin-speaking context. METHODS: We attempted to use WISC-IV-Chinese scores to identify the cognitive strengths and weaknesses in 334 Taiwanese children with attention deficit/hyperactivity disorder (ADHD). Comparison of cognitive profiles of WISC IV-Chinese scores between subtypes of ADHD was also performed. RESULTS: The results indicated that the four-factor model of the WISC-IV-Chinese fitted well for Taiwanese children with ADHD. The profiles showed that performance in the index score of the Processing Speed Index was the weakness domain for the Taiwanese children with ADHD, as confirmed by two different kinds of analytic methods. Cognitive profile analysis of ADHD subtypes revealed children with inattentive subtypes to have a greater weakness in processing speed performance. CONCLUSION: The implications of the profiles of the index scores on the WISC-IV Chinese version for Taiwanese children with ADHD were explored. PMID- 23438161 TI - Oxidative stress status in recently abstinent methamphetamine abusers. AB - AIM: Methamphetamine (METH) administration is associated with excessive oxidative stress. It is not known whether the systemic oxidative stress indices would alter during early abstinence in METH abusers with positive urine testing for recent METH exposure. METHODS: Sixty-four non-treatment-seeking METH abusers enrolled from a controlled environment and 60 healthy controls participated in the study. Fasting serum malondialdehyde (MDA) levels and anti-oxidant indices, including superoxide dismutase (SOD) and catalase (CAT) activity, and glutathione (GSH) levels, were measured at baseline and 2 weeks after the first measurement. We compared the differences of these oxidative stress indices between METH abusers and controls and examined the changes of the indices 2 weeks after baseline in the METH group. RESULTS: At baseline, the recently abstinent METH abusers had significantly higher MDA levels, lower SOD activity, and higher CAT activity and GSH levels compared to healthy controls. CAT and GSH values were positively correlated with MDA but negatively correlated with SOD. These oxidative stress indices did not significantly correlate with age, smoking amount, Alcohol Use Disorder Identification Test scores, or METH use variables. After 2 more weeks of abstinence, the indices did not alter nor normalize. CONCLUSION: Compared to controls, we found that METH abusers have persistently higher systemic oxidative stress throughout early abstinence. The compromised SOD as well as elevated CAT activity and GSH levels may act together as a compensatory mechanism to counteract excessive oxidative stress induced by METH. Whether the oxidative stress could improve after a longer period of abstinence needs to be examined in future studies. PMID- 23438162 TI - Sociodemographic determinants of attitudinal barriers in the use of mental health services in Japan: findings from the World Mental Health Japan Survey 2002-2006. AB - AIM: Sociodemographic correlates of Japanese attitudinal barriers to mental health services might be different from previous studies in Western countries, reflecting a different culture. We investigated sociodemographic correlates of attitudinal barriers to mental health services in a community population in Japan, based on data collected in the World Mental Health Survey Japan surveys. METHODS: An interview survey was conducted of a random sample of residents living in 11 communities across Japan during 2002-2006. A total of 1359 participants were analyzed. The variables on attitudinal barriers to mental health services were measured by using the World Health Organization Composite International Diagnostic Interview 3.0. The association between these variables and sociodemographic variables were analyzed by using multiple logistic regressions. RESULTS: Being male was significantly associated with willingness to go for professional help and feeling comfortable to talk with a professional. Compared to the youngest group (20-34 years old), those aged from 35 to 49 years had a significantly lower prevalence of feeling embarrassed about friends knowing about their getting professional help, while the oldest group (aged over 65 years) had a significantly higher prevalence of being embarrassed. Being currently married was significantly associated with higher expectations about mental health services, but it was significantly and negatively associated with willingness to go for professional help. CONCLUSION: These results suggest that demographic patterns of attitudinal barriers to mental health services in Japan are unique, compared with previous studies in Western countries. An anti-stigma campaign may need to consider such country-specific patterns in a particular country. PMID- 23438163 TI - Persistent mental health disturbances during the 10 years after a disaster: four wave longitudinal comparative study. AB - AIM: Although some studies have examined the long-term effects of disasters, very little is known about severe persistent symptoms following disasters. The aim of the present study was to examine persistent mental health problems and to what extent disaster exposure predicts long-term persistent disturbances. METHODS: Following a major disaster, a four-wave study was conducted (surveys 2-3 weeks, 18 months, 4 years and 10 years after the event) that examined severe post traumatic stress disorder (PTSD) symptomatology (Impact of Event Scale), anxiety and depression symptoms and sleeping problems (Symptom Check List-90-R), and use of physician-prescribed tranquilizers. Participants were affected adult Dutch native residents (n = 1083). At wave 2 and 3, a control group participated (n = 694). At wave 1, severity of disaster exposure was examined. Multiple imputation was used to target the problem of missing data across surveys due to non-response such as in the fourth wave (61%). RESULTS: In total, 6.7% (95% confidence interval [CI]: 5.1-8.2) developed persistent PTSD symptoms during the 10 years after the event. For anxiety, depression, sleeping problems these prevalences were 3.8% (95%CI: 2.7-5.0), 6.2% (95%CI: 4.7-7.6) and 4.8% (95%CI: 3.5-6.1) respectively. In total 1.3% (95%CI: 0.6-2.0) used tranquilizers at all waves. Approximately one out of 10 with severe symptoms 2-3 weeks after the event, developed persistent symptoms. Even in the long term, affected residents compared to controls had more often chronic anxiety symptoms and sleeping problems. High disaster exposure independently predicted persistent PTSD symptoms (adjusted odds ratio [adj. OR], 4.20; 95%CI: 2.02-8.74, P < 0.001), anxiety (adj. OR, 3.43; 95%CI: 1.28-9.20, P < 0.01), depression symptoms (adj. OR, 2.95; 95%CI: 1.26 6.93, P < 0.01), and sleeping problems (adj. OR, 3.74; 95%CI: 1.56-8.95, P < 0.001). CONCLUSION: Post-disaster mental health care should (also) target persistent mental health disturbances in the long term, especially PTSD, anxiety, depression symptoms, and sleeping problems. High disaster exposure may be an early marker for risk of persistent symptoms. PMID- 23438164 TI - Frequency and clinical features of suicide attempts in elderly patients in Japan. AB - The objective of this study was to investigate the clinical features of suicide attempts in elderly patients (>=65 years) in Japan. We enrolled 546 patients who attempted suicide and were hospitalized for inpatient treatment. Characteristics were compared between the elderly and non-elderly patients. Compared with the non elderly group, the incidence of mood disorders was significantly higher and the average length of stay in the intensive care unit and the duration of hospitalization were significantly longer in the elderly group. Elderly patients hospitalized for attempted suicide were more likely to have mood disorders than the non-elderly. PMID- 23438165 TI - Association of the BDNF C270T polymorphism with schizophrenia: updated meta analysis. AB - Brain-derived neurotrophic factor (BDNF) has been suggested to play a role in the pathophysiology of schizophrenia. The C270T polymorphism (rs56164415) in the BDNF 5'-non-coding region has been extensively investigated for an association with schizophrenia, but with conflicting results. An updated meta-analysis was therefore performed of 13 case-control association studies (3505 patients and 3992 controls). An association was found between the T allele and schizophrenia. The association was significant in the East Asian population, but not in the Caucasian population. It is suggested that the BDNF C270T polymorphism contributes to schizophrenia susceptibility, especially in East Asian subjects. PMID- 23438166 TI - Text messaging as a new compulsive behavior in a patient with Parkinson's disease. PMID- 23438167 TI - Memantine-associated renal impairment in a patient with Alzheimer's disease. PMID- 23438168 TI - Venlafaxine-related akathisia side-effects and management in a depressed patient. PMID- 23438169 TI - Paliperidone in the treatment of Tourette's syndrome with comorbid schizophrenia. PMID- 23438170 TI - Hashimoto's encephalopathy with hippocampus involvement detected on continuous arterial spin labeling. PMID- 23438171 TI - Manic symptoms associated with pregabalin in a patient with conversion disorder. PMID- 23438172 TI - Successfully treated delirium in an extremely elderly patient by switching from risperidone to ramelteon. PMID- 23438173 TI - Amisulpride-associated acute onset of metabolic syndrome in a schizophrenia patient. PMID- 23438174 TI - The dimensionality of ecological networks. AB - How many dimensions (trait-axes) are required to predict whether two species interact? This unanswered question originated with the idea of ecological niches, and yet bears relevance today for understanding what determines network structure. Here, we analyse a set of 200 ecological networks, including food webs, antagonistic and mutualistic networks, and find that the number of dimensions needed to completely explain all interactions is small ( < 10), with model selection favouring less than five. Using 18 high-quality webs including several species traits, we identify which traits contribute the most to explaining network structure. We show that accounting for a few traits dramatically improves our understanding of the structure of ecological networks. Matching traits for resources and consumers, for example, fruit size and bill gape, are the most successful combinations. These results link ecologically important species attributes to large-scale community structure. PMID- 23438175 TI - Genetic structure of the aphid, Chaetosiphon fragaefolii, and its role as a vector of the Strawberry Yellow Edge Virus to a native strawberry, Fragaria chiloensis in Chile. AB - The monoecious anholocyclical aphid, Chaetosiphon fragaefolii (Cockerell) (Homoptera: Aphididae), was collected on a native strawberry, Fragaria chiloensis (L.) Duchesne (Rosales: Rosaceae) from different sites in Chile. The presence of this aphid was recorded during two consecutive years. F. chiloensis plants were collected from seven natural and cultivated growing areas in central and southern Chile. Aphids were genotyped by cross-species amplification of four microsatellite loci from other aphid species. In addition, the aphid borne virus Strawberry mild yellow edge virus was confirmed in F. chiloensis plants by double antibody sandwich ELISA and RT-PCR. Genetic variability and structure of the aphid populations was assessed from the geo-referenced individuals through AMOVA and a Bayesian assignment test. The presence of C. fragaefolii, during the two year study was detected in only four of the seven sites (Curepto, Contulmo, Chilian and Cucao). Genetic variation among these populations reached 19% of the total variance. When assigning the individuals to groups, these were separated in three genetic clusters geographically disjunct. Of the seven sampled sites, six were positive for the virus by RT-PCR, and five by double-antibody sandwich ELISA . The incidence of the virus ranged from 0-100%. Presence of the virus corresponded with the presence of the aphid in all but two sites (Chilian and Vilches). The greatest incidence of Strawberry mild yellow edge virus was related to the abundance of aphids. On the other hand, sequences of the coat protein gene of the different virus samples did not show correspondence with either the genetic groups of the aphids or the sampling sites. The genetic structure of aphids could suggest that dispersal is mainly through human activities, and the spread to natural areas has not yet occurred on a great scale. PMID- 23438176 TI - A concept analysis of oral hygiene care in dependent older adults. AB - AIM: To report a concept analysis of oral hygiene care. BACKGROUND: Oral hygiene care, as it is provided to older patients in hospital and long-term care settings by nurses and their delegates, has the potential to contribute to the oral health of patients while preventing aspiration pneumonia as well as periodontitis, which itself has been associated with several systemic diseases. However, the state of oral cleanliness in such patients tends to be poor and despite the existence of guidelines, nursing care practices may be inadequate and not reflective of recent advances in knowledge. DESIGN: Concept analysis. DATA SOURCES: A search of electronic databases (2002-2012), use of internet search engines, and hand searching yielded an international data set of 66 research studies, reviews, and practice guidelines. REVIEW METHODS: The concept analysis method of Walker and Avant was used to explore the concept of oral hygiene care in the context of frail older patients. RESULTS: Oral hygiene care involves approaches informed by knowing the patient, inspecting the oral cavity, removing plaque, cleansing the oral tissues, decontaminating the oral cavity, using fluoride products and maintaining oral tissue moisture. Those attributes, along with their antecedents and consequences, form a conceptual framework from which a middle-range theory of nurse-administered oral hygiene care is derived that could be tested, evaluated, modified, and translated into practice. CONCLUSIONS: Clarity around the concept of oral hygiene care as a nursing intervention could enable nurses to impact oral health outcomes and possibly prevent systemic diseases in older patients. PMID- 23438177 TI - Rational engineering of plasticity residues of sesquiterpene synthases from Artemisia annua: product specificity and catalytic efficiency. AB - Most TPSs (terpene synthases) contain plasticity residues that are responsible for diversified terpene products and functional evolution, which provide a potential for improving catalytic efficiency. Artemisinin, a sesquiterpene lactone from Artemisia annua L., is widely used for malaria treatment and progress has been made in engineering the production of artemisinin or its precursors. In the present paper, we report a new sesquiterpene synthase from A. annua, AaBOS (A. annua alpha-bisabolol synthase), which has high sequence identity with AaADS (A. annua amorpha-4,11-diene synthase), a key enzyme in artemisinin biosynthesis. Comparative analysis of the two enzymes by domain swapping and structure-based mutagenesis led to the identification of several plasticity residues, whose alteration changed the product profile of AaBOS to include gamma-humulene as the major product. To elucidate the underlying mechanisms, we solved the crystal structures of AaBOS and a gamma-humulene producing AaBOS mutant (termed AaBOS-M2). Among the plasticity residues, position 399, located in the substrate-binding pocket, is crucial for both enzymes. In AaBOS, substitution of threonine for leucine (AaBOSL339T) is required for gamma humulene production; whereas in AaADS, replacing the threonine residue with serine (AaADST399S) resulted in a substantial increase in the activity of amorpha 4,11-diene production, probably as a result of accelerated product release. The present study demonstrates that substitution of plasticity residues has potential for improving catalytic efficiency of the enzyme. PMID- 23438178 TI - Does productive role occupancy prevent depression among older rural Chinese adults? A latent difference score analysis. AB - OBJECTIVES: Depression has been reported as common among older rural Chinese adults, who often face limited access to healthcare services and resources. Empirical studies conducted in the West have shown beneficial effects of productive engagement on psychological well-being. However, the mechanisms by which engagement in productive activities leads to and results from improved mental health remain unclear. METHOD: Utilizing role enhancement and social resource theories, the present study investigated the relationship between productive role occupancy and depression among older Chinese adults in rural areas over 8 years. Using four waves of data from the Well-Being of Elderly in Anhui Province of China study, we employed bivariate latent different score analysis to examine the temporal sequence of productive role occupancy and depression among 1696 older adults. RESULTS: Findings indicated that trajectories of productive role occupancy and depression rose across the four waves. There is evidence for self-feedback effects in productive role occupancy and depression. Depression had a significant effect on subsequent changes in productive role occupancy (beta = -0.042, p = 0.000), whereas productive role occupancy had no significant effect on subsequent changes in depression. CONCLUSION: The mental well-being of participants worsened over time. Engaging in productive activities had no effect on mental health status, and rural older adults with poor mental health were less likely to engage in productive activities over time. Findings suggest that psychological well-being as a personal resource significantly affects how productively Chinese adults age in late life. PMID- 23438179 TI - Lumican effects in the control of tumour progression and their links with metalloproteinases and integrins. AB - Lumican is a member of the small leucine-rich proteoglycan family. It is present in numerous extracellular matrices of different tissues, such as muscle, cartilage, and cornea. In skin, lumican is present as a glycoprotein. It plays a critical role in collagen fibrillogenesis, as shown by knocking out of its gene in mice. A direct link between lumican expression and melanoma progression and metastasis has been demonstrated. Lumican was shown to impede tumour cell migration and invasion by directly interacting with the alpha2beta1 integrin. In addition, an active sequence of the lumican core protein, called lumcorin, was identified as being responsible for inhibition of melanoma cell migration. Lumican was also shown to exert angiostatic properties by downregulating the proteolytic activity associated with endothelial cell membranes, particularly matrix metalloproteinase (MMP)-14 and MMP-9. Globally, lumican appears to be a potent agent for inhibiting tumour progression rather than tumorigenesis. However, progressive changes in proteoglycans occur in the tumour environment. The complexity and diversity of proteoglycan structure might be responsible for a variety of functions that regulate cell behaviour. Through their core protein and their glycosaminoglycan chains, proteoglycans can interact with growth factors and chemokines. These interactions affect cell signalling, motility, adhesion, growth, and apoptosis. This review summarizes recent data concerning lumican control of tumour progression in different cancers, with a particular focus on its interactions with MMPs and integrins. Its potential therapeutic implications are discussed. PMID- 23438180 TI - Extracellular facile biosynthesis, characterization and stability of gold nanoparticles by Bacillus licheniformis. AB - CONTEXT: The development of a reliable, eco-friendly process for synthesis of gold nanoparticles (AuNPs) has gained impetus in recent years to counter the drawbacks of chemical and physical methods. OBJECTIVE: This study illustrates simple, green synthesis of AuNPs in vitro using cell lysate supernatant (CLS) of non-pathogenic bacteria and to investigate its potential antimicrobial activity. MATERIALS AND METHODS: Gold nanoparticles were synthesized by the reduction of precursor AuCl4- ions using the CLS of Bacillus licheniformis at 37 degrees C upon 24 h of incubation. The nanoparticles were characterized for their morphology, particle size, optical absorption, zeta potential, and stability. Further the antimicrobial activity was assayed using cup-plate method. RESULTS: The process of biosynthesis was extracellular and the gold ions were reduced to stable nanogold of average size 38 nm. However, upon storage of AuNPs for longer duration at room temperature stability was influenced in terms of increase in particle size and decrease in zeta potential with respect to as synthesized nanoparticles. SEM micrographs revealed the spherical shape of AuNPs and EDX analysis confirmed the presence of gold in the sample. Also clear zone of inhibition was observed against Bacilllus subtilis MTCC 8364, Pseudomonas aeruginosa MTCC 7925, and Escherichia coli MTCC 1698 confirming the antimicrobial activity of AuNPs. DISCUSSION: The bioprocess under study was simple and less time consuming as compared to other methods as the need for harvesting AuNPs from within the microbial cells via downstream process will be eliminated. Nanoparticles exhibited good stability even in absence of external stabilizing agents. AuNPs showed good antimicrobial activity against several Gram-negative and Gram-positive pathogenic bacteria. CONCLUSION: The extracellular biosynthesis from CLS may serve as a suitable alternative for large scale synthesis of gold nanoparticles in vitro. The synthesis from lysed bacterial cell strongly suggests that exposure of microbial whole cells to the gold solution for nanoparticle formation is not necessary and that microorganism even in lysed state retained its bioreduction potential. Further the potential of biologically synthesized AuNPs as antimicrobial agents will be of great commercial importance. PMID- 23438181 TI - Biophysical insight into furosemide binding to human serum albumin: a study to unveil its impaired albumin binding in uremia. AB - Exogenous substances like drugs, when absorbed, enter into the circulatory system and bind reversibly and extensively to human serum albumin (HSA). But transport of various drugs like a diuretic, furosemide (FUR), via albumin in uremia is seriously compromised due to accumulation of uremic toxins. The reason behind it is explored by investigating the binding mechanism of FUR to HSA. Isothermal titration calorimetry results show that FUR binds with HSA at high (Kb ~ 10(4)) and low affinity (Kb ~ 10(3)) sites whereas spectroscopic results predict binding at a single site (Kb ~ 10(5)). Thermodynamic analysis shows that the HSA-FUR complex formation occurs via hydrogen bonds and hydrophobic interactions and undergoes slight structural changes, as evident by FTIR and far-UV CD. Further, the lifetime of HSA decreases only marginally and thus the magnitude of energy transfer efficiency is small, as obtained by time-resolved measurements. A displacement experiment predicts that the FUR binds mainly to site I but a new site having lower affinity is also observed, which shares some residues with site II as supported by molecular docking results. Results revealed that in uremia, FUR indirectly competes for Arg410, Lys414, and Ser489 with site II bound uremic toxins and directly competes for site I with site I bound uremic toxins. PMID- 23438182 TI - Use of asymmetric bidirectional catheters with different curvature radius for catheter ablation of cardiac arrhythmias. AB - BACKGROUND: The impact of recently introduced asymmetric bidirectional ablation catheters on procedural parameters and acute success rates of ablation procedures is unknown. METHODS: We retrospectively analyzed data regarding ablations using a novel bidirectional catheter in a tertiary cardiac center and compared these in 1:5 ratio with a control group of procedures matched for age, gender, operator, and ablation type. RESULTS: A total of 50 cases and 250 controls of median age 60 (50-68) years were studied. Structural heart disease was equally prevalent in both groups (39%) while history of previous ablations was more common in the study arm (54% vs 30%, P = 0.001). Most of the ablation cases were for atrial fibrillation (46%), followed by atrial tachycardia (28%), supraventricular tachycardia (12%), and ventricular tachycardia (14%). Median procedure duration was 128 (52-147) minutes with the bidirectional, versus 143 (105-200) minutes with the conventional catheter (P = 0.232), and median fluoroscopy time was 17 (10-34) minutes versus 23 (12-39) minutes, respectively (P = 0.988). There was a trend toward a lower procedure duration for the atrial tachycardia ablations, 89 (52-147) minutes versus 130 (100-210) minutes, P = 0.064. The procedure was successfully completed in 96% of the bidirectional versus 84% of the control cases (P = 0.151). A negative correlation was observed between the relative fluoroscopy duration and the case number (r = -0.312, P = 0.028), reflecting the learning curve for the bidirectional catheter. CONCLUSIONS: The introduction of the bidirectional catheter resulted in no prolongation of procedure parameters and similar success rates, while there was a trend toward a lower procedure duration for atrial tachycardia ablations. PMID- 23438183 TI - Proteomics applied to transfusion plasma: the beginning of the story. AB - 'Safe blood' is and has always been the major concern in transfusion medicine. Plasma can undergo virus inactivation treatments based on physicochemical, photochemical or thermal methodologies for pathogen inactivation. The validation of these treatments is essentially based on clottability assays and clotting factors' titration; however, their impact on plasma proteins at the molecular level has not yet been evaluated. Proteomics appears as particularly adapted to identify, to localize and, consequently, to correlate these modifications to the biological activity change. At the crossroads of biology and analytical sciences, proteomics is the large-scale study of proteins in tissues, physiological fluids or cells at a given moment and in a precise environment. The proteomic strategy is based on a set of methodologies involving separative techniques like mono- and bidimensional gel electrophoresis and chromatography, analytical techniques, especially mass spectrometry, and bioinformatics. Even if plasma has been extensively studied since the very beginning of proteomics, its application to transfusion medicine has just begun. In the first part of this review, we present the principles of proteomics analysis. Then, we propose a state of the art of proteomics applied to plasma analysis. Finally, the use of proteomics for the evaluation of the impact of storage conditions and pathogen inactivation treatments applied to transfusion plasma and for the evaluation of therapeutic protein fractionated is discussed. PMID- 23438184 TI - SGLT2 inhibition: a novel prospective strategy in treatment of diabetes mellitus. AB - The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. PMID- 23438186 TI - Characterization of the role of distinct plasma cell-free DNA species in age associated inflammation and frailty. AB - Plasma cell-free DNA (cf-DNA) has recently emerged as a potential biomarker of aging, reflecting systemic inflammation, and cell death. In addition, it has been suggested that cf-DNA could promote autoinflammation. Because the total cf-DNA pool comprises different cf-DNA species, we quantified the plasma levels of gene coding cf-DNA, Alu repeat cf-DNA, mitochondrial DNA (mtDNA) copy number, and the amounts of unmethylated and total cf-DNAs. We identified the relationships between these cf-DNA species and age-associated inflammation, immunosenescence, and frailty. Additionally, we determined the cf-DNA species-specific transcriptomic signatures in blood mononuclear cells to elucidate the age-linked leukocyte responses to cf-DNA. The study population consisted of n = 144 nonagenarian participants of the Vitality 90+ Study and n = 30 young controls. In the nonagenarians, higher levels of total and unmethylated cf-DNAs were associated with systemic inflammation and increased frailty. The mtDNA copy number was also directly correlated with increased frailty but not with inflammation. None of the cf-DNA species were associated with immunosenescence. The transcriptomic pathway analysis revealed that higher levels of total and unmethylated cf-DNAs were associated with immunoinflammatory activation in the nonagenarians but not in the young controls. The plasma mtDNA appeared to be inert in terms of inflammatory activation in both the nonagenarians and young controls. These data demonstrate that the plasma levels of total and unmethylated cf-DNA and the mtDNA copy number could serve as biomarkers of frailty. In addition, we suggest that circulating self-DNA, assessed as total or unmethylated cf-DNA, might aggravate immunoinflammatory reactivity in very old individuals. PMID- 23438187 TI - Causes of recurrent pneumonia in children in a general hospital. AB - AIM: Because the few previous studies on underlying causes of recurrent pneumonia in children have come from tertiary care referral centres where selection bias may be important, the aim of this study was to examine underlying causes of recurrent pneumonia in children in a general hospital. METHODS: We performed a retrospective chart review in a general hospital of 62 children with recurrent pneumonia over a 7.5 years period. RESULTS: In 19 patients (30.6%), no cause was identified, commonly because favourable natural history obviated the need for a full and invasive diagnostic work-up. Other underlying causes included recurrent aspiration in 16 patients (25.7%), lung disease (airway stenosis, bronchiectasis, middle lobe syndrome or tracheooesophageal fistula) in 10 patients (16.1%) and immune deficiency in 10 patients (16.1%). In contrast to previous studies, asthma was never diagnosed as an underlying cause, but diagnostic confusion between asthma (or recurrent upper respiratory tract infections) and recurrent pneumonia was common. CONCLUSION: The cause of recurrent pneumonia in children remains elusive in almost a third of patients, partly because the favourable natural history consistent with immune system maturation eliminates the need for further diagnostic procedures. Asthma is more likely a differential diagnostic consideration than an underlying cause of recurrent pneumonia in children. A standardised diagnostic guideline is needed to improve knowledge on causes of recurrent pneumonia in children. PMID- 23438185 TI - Increased hippocampal NgR1 signaling machinery in aged rats with deficits of spatial cognition. AB - Myelin-associated inhibitor/NgR1 signaling has important roles in modulation of synaptic plasticity, with demonstrated effects on cognitive function. We have previously demonstrated that NgR1 and its ligands are upregulated in the hippocampus of aged rats with impaired spatial learning and memory, but it is unknown whether increased expression of these proteins indicates a potential increase in pathway signaling because NgR1 requires co-receptors for signal transduction through RhoA. Two co-receptor complexes have been identified to date, comprised of NgR1 and LINGO-1, and either p75 or TROY. In this study, we assessed the expression of LINGO-1, p75 and TROY, and the downstream effector RhoA in mature adult (12 months) and aged (26 months) male Fischer 344/Brown Norway hybrid rats classified as cognitively impaired or cognitively intact by Morris water maze testing. The hippocampal distribution of NgR1 and its co receptors was assessed to determine whether receptor/co-receptor interaction, and therefore signaling through this pathway, is possible. Protein expression of LINGO-1, p75, TROY and RhoA was significantly elevated in cognitively impaired, but not intact, aged rats compared with mature adults, and expression levels correlated significantly with water maze performance. Co-localization of NgR1 with LINGO-1, p75 and TROY was observed in hippocampal neurons of aged, cognitively impaired rats. Further, expression profiles of NgR1 pathway components were demonstrated to classify rats as cognitively intact or cognitively impaired with high accuracy. Together, this suggests that hippocampal induction of this pathway is a conserved phenomenon in cognitive decline that may impair learning and memory by suppressing neuronal plasticity. PMID- 23438188 TI - The effects of platelet gel-released supernatant on human fibroblasts. AB - In recent years, interest in the topical use of platelet gel (PG) to stimulate wound healing has rapidly extended into various clinical applications and specialized fields. Many recent in vitro and in vivo studies have attempted to explain the biological mechanisms involved in PG-induced tissue regeneration/reparation. However, it remains unclear which parameters should be used in clinical applications to obtain satisfactory results in the healing of wounds. Toward this end, the present study focused on understanding the relationship between platelet concentrations and the cellular parameters of the cell types, i.e., fibroblasts, involved in wound healing. Normal human dermal fibroblasts were treated with PG-released supernatant at various concentrations in different assays (proliferation, migration, invasion, and in vitro scratch wound closure) to identify the most effective concentration to promote the fibroblasts' activities. Different concentrations of platelets per microliter in PG have different levels of efficacy in inducing fibroblast activity. The most effective concentration was obtained from PG at a concentration of approximately 0.5-1.5 * 10(6) plt/MUL; higher concentrations were less effective. This study shows that excessively high concentrations of platelets per microliter have an inhibitory effect on the wound healing processes and are, therefore, counterproductive. PMID- 23438189 TI - Predicting ecosystem stability from community composition and biodiversity. AB - As biodiversity is declining at an unprecedented rate, an important current scientific challenge is to understand and predict the consequences of biodiversity loss. Here, we develop a theory that predicts the temporal variability of community biomass from the properties of individual component species in monoculture. Our theory shows that biodiversity stabilises ecosystems through three main mechanisms: (1) asynchrony in species' responses to environmental fluctuations, (2) reduced demographic stochasticity due to overyielding in species mixtures and (3) reduced observation error (including spatial and sampling variability). Parameterised with empirical data from four long-term grassland biodiversity experiments, our prediction explained 22-75% of the observed variability, and captured much of the effect of species richness. Richness stabilised communities mainly by increasing community biomass and reducing the strength of demographic stochasticity. Our approach calls for a re evaluation of the mechanisms explaining the effects of biodiversity on ecosystem stability. PMID- 23438190 TI - Effect of slope and footwear on running economy and kinematics. AB - Lower energy cost of running (Cr) has been reported when wearing minimal (MS) vs traditional shoes (TS) on level terrain, but the effect of slope on this difference is unknown. The aim of this study was to compare Cr, physiological, and kinematic variables from running in MS and TS on different slope conditions. Fourteen men (23.4 +/- 4.4 years; 177.5 +/- 5.2 cm; 69.5 +/- 5.3 kg) ran 14 5-min trials in a randomized sequence at 10 km/h on a treadmill. Subjects ran once wearing MS and once wearing TS on seven slopes, from -8% to +8%. We found that Cr increased with slope gradient (P < 0.01) and was on average 1.3% lower in MS than TS (P < 0.01). However, slope did not influence the Cr difference between MS and TS. In MS, contact times were lower (P < 0.01), flight times (P = 0.01) and step frequencies (P = 0.02) were greater at most slope gradients, and plantar-foot angles - and often ankle plantar-flexion (P = 0.01) - were greater (P < 0.01). The 1.3% difference between footwear identified here most likely stemmed from the difference in shoe mass considering that the Cr difference was independent of slope gradient and that the between-footwear kinematic alterations with slope provided limited explanations. PMID- 23438191 TI - Stereoselective synthesis of spiropiperidines as BACE-1 aspartyl protease inhibitors via late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. AB - A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8 diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey-Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation. PMID- 23438192 TI - New insight into the structure, development, functions and popular disorders of bursa Fabricii. AB - Humoral immune responses in birds, contrary to mammals, depend on the normal functioning of bursa Fabricii. Recent studies have delivered new information about the structure, development and origin of cells that compose the bursa environment. Several viral infections affect bursa, causing lymphocyte depletion or excessive proliferation. This review summarizes data on the development and histology of healthy bursa and introduces some common disorders that affect this organ. PMID- 23438193 TI - Positive correlation of Oct4 and ABCG2 to chemotherapeutic resistance in CD90(+)CD133(+) liver cancer stem cells. AB - Liver cancer is one of the most common tumors worldwide and drug resistance is a major obstacle to successful therapy. The growing data show that cancer stem cells (CSCs), a rare subpopulation of cancer cells, might be an important mechanism of drug resistance. To explore the self-renewal ability and chemotherapy resistance in liver CSCs, we enriched CD90(+)CD133(+) hepatocellular carcinoma (HCC) CSCs using sphere formation, which was accomplished by cultivating HCC CSCs from established HCC cell lines (HepG2 line and Hep3B line). Cell proliferation capacity was detected using colony formation assays, and cell activity was detected using methyl thiazolyl tetrazolium (MTT) assays after doxorubicin treatment. Expression of CD90, CD133, Oct4, and ABCG2 mRNA and protein levels was detected by PCR and western blot, respectively, which showed that these genes were significantly overexpressed in liver CSCs compared to parental cells (p<0.05). Oct4 and ABCG2 are highly expressed in enriched CD90(+)CD133(+) liver CSCs and are closely associated with chemotherapy drug resistance. We postulated that liver CSCs maybe the cause of high recurrence in liver cancer. PMID- 23438194 TI - Direct reprogramming of fibroblasts to myocytes via bacterial injection of MyoD protein. AB - Forced exogenous gene expression has been well characterized as an effective method for directing both cellular differentiation and dedifferentiation. However, transgene expression is not amenable for therapeutic application due to potential insertional mutagenesis. Protein-based techniques provide a safe alternative, but current protein delivery methods are quite limited by labor intensive purification processes, low protein yield, and inefficient intracellular targeting. Such limitations may be overcome by using a naturally occurring bacterial protein injection system, called the type III secretion system (T3SS), which injects bacterial proteins directly into the eukaryotic cell cytoplasm. Using a genetically attenuated strain of Pseudomonas aeruginosa, we have previously described the ability of this system to easily deliver a high quantity of protein to both differentiated and pluripotent cells. MyoD is a key muscle regulatory factor, the overexpression of which is able to induce transdifferentiation of numerous cell types into functional myocytes. Here we demonstrate transient injection of MyoD protein by P. aeruginosa to be sufficient to induce myogenic conversion of mouse embryonic fibroblasts. In addition to clear morphological changes, muscle-specific gene expression has been observed both at mRNA and protein levels. These studies serve as a foundation for the bacterial delivery of transcription factors to efficiently modulate concentration dependent and temporal activation of gene expression that directs cell fate without jeopardizing genomic integrity. PMID- 23438195 TI - The direct renin inhibitor aliskiren improves vascular remodelling in transgenic rats harbouring human renin and angiotensinogen genes. AB - In the present study, we tested the hypothesis that chronic treatment with the direct rennin inhibitor aliskiren improves the remodelling of resistance arteries in dTGR (double-transgenic rats). dTGR (5 weeks) were treated with aliskiren (3 mg/kg of body mass per day) or ramipril (1 mg/kg of body mass per day) for 14 days and compared with age-matched vehicle-treated dTGR. BP (blood pressure) was similarly reduced in both aliskiren-treated and ramipril-treated rats compared with control dTGR (167+/-1 and 169+/-2 mmHg compared with 197+/-4 mmHg respectively; P<0.05). The M/L (media-to-lumen) ratio assessed on pressurized preparations was equally reduced in aliskiren-treated and ramipril-treated rats compared with controls (6.3+/-0.5 and 6.4+/-0.2% compared with 9.8+/-0.4% respectively; P<0.05). Endothelium-dependent and -independent relaxations were similar among the groups. L-NAME (N(G)-nitro-L-arginine methyl ester) significantly reduced acetylcholine-induced dilation in drug-treated dTGR. This effect was significantly more prominent in aliskiren-treated rats. eNOS (endothelial NO synthase) expression showed a 2-fold increase only in aliskiren treated dTGR as compared with controls (P<0.01) and ramipril-treated dTGR (P<0.05). Plasma nitrite, as an index of NO production, was significantly increased in dTGR treated with either aliskiren or ramipril compared with controls. Only aliskiren induced a 2-fold increase in plasma nitrite, which was significantly greater than that induced by ramipril (P<0.05). gp91(phox) expression and ROS (reactive oxygen species) production in aorta were significantly and similarly reduced by both drugs. In conclusion, equieffective hypotensive doses of aliskiren or ramipril reduced the M/L ratio of mesenteric arteries and improved oxidative stress in dTGR. However, only aliskiren increased further NO production in the vasculature. Hence, in dTGR, direct renin inhibition induces favourable effects similar to that induced by ACE (angiotensin-converting enzyme) inhibition in improving vascular remodelling through different mechanisms. PMID- 23438196 TI - Global Collembola on Deception Island. AB - Three new non-indigenous springtail species are recorded in recent collections made on Deception Island, South Shetland Islands, maritime Antarctic: Deuteraphorura (Deuteraphorura) cebennaria (Gisin) (Collembola: Onychiuridae), Mesaphorura macrochaeta Rusek (Tullbergiidae), and Proisotoma minuta Axelson (Isotomidae). One of these, D. (D.) cebennaria, is described. Additionally, two new indigenous species, Mesaphorura macrochaeta Rusek and Proisotoma minuta Axelson, are also recorded. The total number of Collembola species now known from the island is 14, comprised of eight native species and six non-indigenous species. This number of non-indigenous species recorded at Deception Island compares with only a single non-indigenous springtail recorded at any other maritime or continental Antarctic location. The reason underlying this high level of occurrence of non-indigenous species on Deception Island is likely to be a combination of the island's high level of human visitation and the presence of relatively benign terrestrial habitats associated with areas of geothermal activity. Two of the new records represent species recently assessed as being of the highest risk to become invaders in the less extreme environments of the subantarctic, thereby emphasising the importance and urgency of adopting and applying effective biosecurity measures to protect the unique and vulnerable ecosystems of this region. Also documented are the impacts on the soil fauna of the island from human trampling, which drastically reduced densities of both native and non-indigenous species to 1% of the abundance typical of non-trampled sites. PMID- 23438197 TI - Dimensional changes of maxillary sinuses and pharyngeal airway in Class III patients undergoing bimaxillary orthognathic surgery. AB - OBJECTIVE: To evaluate the pharyngeal airway and maxillary sinus volume changes after mandibular setback surgery combined with maxillary advancement and/or impaction surgery. MATERIALS AND METHODS: Seventeen Class III skeletal patients (11 females, 6 males) who required bimaxillary orthognathic surgery were selected. Volumetric measurements were performed using cone beam computed tomography (CBCT) scans preoperatively and 3.9 +/- 0.87 months postoperatively. All the CBCT scans were assessed and analyzed using MIMICS 14.0 software. Preoperative and postoperative volumes of pharyngeal airway and maxillary sinuses and the relationship between the amounts of surgical movement of the jaws and the above volumes were statistically evaluated. RESULTS: The pharyngeal airway area presented no significant change except for the lower and total pharyngeal airway volumes in males, in whom a significant decrease was observed (4196.27 +/- 2061.11 mm(3) and 3375.53 +/- 3624.67 mm(3), respectively). No significant change was observed in the minimal cross-sectional area of the pharyngeal airway. There was a significant decrease in the volume of the maxillary sinuses after the surgery by 3448.09 +/- 3315.56 mm(3). No correlation was found between the amount of skeletal movement and the change in the volume of pharyngeal airway or maxillary sinuses. CONCLUSION: There was a significant decrease only for lower and total pharyngeal airway volumes in males and a significant decrease in the volume of the maxillary sinuses. PMID- 23438198 TI - Receptor-mediated endocytosis across human placenta: emphasis on megalin. AB - Receptor-mediated endocytosis plays an important role in the maternal-fetal transport of various nutrients and drugs across human placenta. Megalin, a 600 kDa endocytic receptor, is expressed in placental syncytiotrophoblasts and is thought to contribute to the transport functions of the placenta. However, the molecular mechanisms involved in megalin-mediated transplacental transport of most substrates have not yet been characterized. Megalin is most extensively expressed on the apical surface of renal proximal tubular epithelial cells, where it is involved in the reabsorption of proteins, vitamins, and polybasic drugs including aminoglycoside (AG) antibiotics. It has been suggested that megalin mediated endocytosis is primarily responsible for accumulation of aminoglycosides (AGs) in the renal proximal tubule, which results in direct cellular injury and death. The role of megalin in the renal uptake and accumulation of aminoglycosides has therefore received much attention. It is not known, however, whether megalin is involved in the maternal-fetal transport of AGs and other commonly used polybasic drugs. Studies designed to characterize the role of megalin in transplacental transport and to understand the molecular mechanisms involved in megalin-mediated endocytosis across human placenta are therefore needed. PMID- 23438199 TI - A case of recurrent episodes of acute renal allograft failure caused by renal pedicle tortion. AB - BACKGROUND: Acute allograft failure which occur intermittently after renal transplantation caused by graft tortion is a very rare entity. We here report highly unusual case of recurrent episodes of acute allograft dysfunction two years after kidney transplantation secondary to ischemic tubular necrosis caused by tortion of renal pedicle due to rotation of the allograft with body movements. CASE PRESENTATION: A 55 year-old male patient with living unrelated kidney transplantation for chronic renal failure caused by autosomal dominant polycystic kidney disease had presented recurrent acute deteriorations in renal functions. All laboratory values were within normal limits except elevated serum creatinine levels, acute tubular necrosis in graft biopsy, and detection of pelvic dilatation in renal ultrasonography from time to time. Changes in axis of graft in nuclear medicine scans taken at different times during the same study made us bring to mind the diagnosis of renal pedicle tortion. Renal blood flow measurements with Doppler ultrasonography in different body positions helped to reach the final diagnosis of mobile kidney right on time. The patient is now well after prompt surgical treatment with nephropexy. DISCUSSION: Unfortunately, tortion of allograft once occurred is associated with very high rate of graft loss due to arterial compromise and infarction and it is very difficult to diagnose without high level of suspicion. We discuss the causes of renal allograft tortion and the measures to prevent its occurrence and the methods to diagnose. PMID- 23438200 TI - Dietary restriction of rodents decreases aging rate without affecting initial mortality rate -- a meta-analysis. AB - Dietary restriction (DR) extends lifespan in multiple species from various taxa. This effect can arise via two distinct but not mutually exclusive ways: a change in aging rate and/or vulnerability to the aging process (i.e. initial mortality rate). When DR affects vulnerability, this lowers mortality instantly, whereas a change in aging rate will gradually lower mortality risk over time. Unraveling how DR extends lifespan is of interest because it may guide toward understanding the mechanism(s) mediating lifespan extension and also has practical implications for the application of DR. We reanalyzed published survival data from 82 pairs of survival curves from DR experiments in rats and mice by fitting Gompertz and also Gompertz-Makeham models. The addition of the Makeham parameter has been reported to improve the estimation of Gompertz parameters. Both models separate initial mortality rate (vulnerability) from an age-dependent increase in mortality (aging rate). We subjected the obtained Gompertz parameters to a meta-analysis. We find that DR reduced aging rate without affecting vulnerability. The latter contrasts with the conclusion of a recent analysis of a largely overlapping data set, and we show how the earlier finding is due to a statistical artifact. Our analysis indicates that the biology underlying the life-extending effect of DR in rodents likely involves attenuated accumulation of damage, which contrasts with the acute effect of DR on mortality reported for Drosophila. Moreover, our findings show that the often-reported correlation between aging rate and vulnerability does not constrain changing aging rate without affecting vulnerability simultaneously. PMID- 23438201 TI - A histological assessment of the Bethesda system for reporting thyroid cytopathology (2010) abnormal categories: a series of 219 consecutive cases. AB - OBJECTIVE: The purposes of this study were to establish the distribution of thyroid lesions that were seen in Hatay (a province of southern Turkey), to review the accuracy of fine needle aspiration cytology (FNAC) in the diagnosis of thyroid nodules and to correlate the FNAC results with the histopathology of the excised specimens, especially in indeterminate cases. METHODS: Data on patient cytology were retrieved by a retrospective search of all thyroid FNAC specimens that had been evaluated at the Department of Pathology, Antakya Public Hospital, Hatay, Turkey between January 2009 and February 2011; 1021 thyroid FNAC samples were reviewed and interpretations were recorded according to the Bethesda system for reporting thyroid cytopathology (TBSRTC). The results of adequate FNAC samples were compared with the histological diagnoses in the cases in which surgery was performed, and the malignancy rates, especially in indeterminate categories, were calculated. RESULTS: Of the 1021 FNAC samples, 697 (68.3%) were benign, 122 (11.9%) were non-diagnostic, 100 (9.8%) were atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 41 (4%) were follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 36 (3.5%) were suspicious for malignancy (SM) and 25 (2.4%) were malignant. In 219 cases, there was follow-up histology. Rates of malignancy were as follows: benign, 0%; AUS/FLUS, 12.7%; FN/SFN, 35.0%; SM, 91.4%; malignant, 100%. CONCLUSIONS: In our study, the cytohistological correlation of benign and malignant lesions was 100%. In the indeterminate categories, we recommend that clinicians should evaluate both the clinical and radiological findings of patients in addition to the FNAC results. PMID- 23438202 TI - Development of the parents' perception of their involvement in their child's tennis activity questionnaire (Q-PPICTA). AB - The purpose of this study was to develop and validate a questionnaire for assessing parents' perception of their involvement in their children's tennis activity (Q-PPICTA). The validation required four successive studies. In study 1, a preliminary version of the questionnaire was formulated after selecting and adapting items taken from existing questionnaires and interviews conducted with the parents of 36 young tennis players. Three factors for measuring parental involvement in sport were identified and retained: emotional, logistic, and informational supports. In study 2, exploratory factor analyses were performed on data collected from 214 parents of tennis players. Results attested the questionnaire's three-factor structure and ascertained its internal consistency. In study 3, a confirmatory factor analysis as well as tests on convergent and discriminant validity were carried out on data gathered from a different sample of 220 parents of tennis players. Statistics confirmed the questionnaire's three factor structure and reliability. In study 4, the questionnaire's external construct validity was compared with another sample consisting of 192 parents and their children. Overall, results underlined satisfactory psychometric properties for the Q-PPICTA. Nevertheless, further studies are required to confirm the questionnaire's accuracy, reliability, and temporal validity. PMID- 23438203 TI - Effect of health professional education on outcomes of chronic obstructive pulmonary disease in primary care: a non-randomized clinical trial. AB - BACKGROUND AND OBJECTIVE: The best strategy to achieve optimal integrated management to patients with chronic obstructive pulmonary disease (COPD) in primary care (PC) is not clear. We aimed to evaluate the effectiveness of an intervention in PC based on an integrated programme, which combines diverse strategies directed at health professionals to improve quality of life and clinical outcomes of their patients with COPD. We compared the outcome with results from standard practice. METHODS: A prospective, multicentre, quasi experimental study and a 12-month follow up was performed. Intervention consisted of an integrated education programme in PC. The main outcome variable was the change in total score of the St. George's Respiratory Questionnaire (SGRQ) at the end of follow up between the control and intervention group. RESULTS: A total of 801 patients participated in the study with a mean age of 70.2 years and a mean FEV1 (% predicted) of 55%. At 1-year follow up, the SGRQ score did not significantly differ. Although the intervention group showed an improvement in dietary, exercise and smoking habits, there was an increase in reported exacerbations and hospital admissions (P < 0.001). CONCLUSIONS: Implementation of an integrated education programme in a PC setting, which combines diverse strategies directed at health professionals, did not achieve the expected changes in quality of life measured by SGRQ at 1-year follow up. Nonetheless, this study observed an improvement in patients' lifestyle choices, even though this did not result in a significant change in the clinical evolution or heath status over 12 months. PMID- 23438205 TI - Impaired tissue regeneration corresponds with altered expression of developmental genes that persists in the metabolic memory state of diabetic zebrafish. AB - As previously reported by our laboratory, streptozocin-induced diabetes mellitus (DM) in adult zebrafish results in an impairment of tissue regeneration as monitored by caudal fin regeneration. Following streptozocin withdrawal, a recovery phase occurs to reestablish euglycemia, via pancreatic beta-cell regeneration. However, DM-associated impaired fin regeneration continues indefinitely in the metabolic memory (MM) state, allowing for subsequent molecular analysis of the underlying mechanisms of MM. This study focuses on elucidating the molecular basis that explains the DM-associated impaired fin regeneration and why it persists into the MM state with the aim of better understanding MM. Using a combination of microarray analysis and bioinformatics approaches, our study found that of the 14,900 transcripts analyzed, aberrant expression of 71 genes relating to tissue developmental and regeneration processes were identified in DM fish and the altered expression of these 71 genes persisted in MM fish. Key regulatory genes of major development and signal transduction pathways were identified among this group of 71. The aberrant expression of key regulatory genes in the DM state that persist into the MM state provides a plausible explanation on how hyperglycemia induced impaired fin regeneration in the adult zebrafish DM/MM model. PMID- 23438206 TI - Measuring the intravitreal mobility of nanomedicines with single-particle tracking microscopy. AB - AIM: To develop a robust assay to evaluate and compare the intravitreal mobility of nanoparticles in the intact vitreous body. MATERIALS & METHODS: Excised bovine eyes were prepared to preserve the fragile structure of the vitreous humor, while permitting high-resolution fluorescence microscopy and single-particle tracking analysis of intravitreally injected nanoparticles. This assay was validated by analyzing polystyrene beads and further employed to evaluate gene nanomedicines composed of poly(amido amine)s and plasmid DNA. RESULTS: The assay was able to distinguish immobilized cationic nanoparticles from mobile PEGylated nanoparticles. PEGylation of the polyplexes resulted in a drastic improvement of their mobility. CONCLUSION: An ex vivo eye model is presented for studying nanoparticle mobility in intact vitreous humor by single-particle tracking microscopy. These results give important guidelines for developing gene- and drug delivery nanomedicines that are compatible with intravitreal administration. PMID- 23438207 TI - Candida albicans endocarditis with giant vegetation from an implantable cardioverter-defibrillator lead. AB - BACKGROUND: Endocarditis is a potentially lethal complication of implantation of a cardioverter-defibrillator (ICD). METHODS: We report the case of a 62-year-old male with candidemia and vegetation from a large implantable ICD lead that could not be extracted percutaneously. The ICD system was completely and successfully removed through pocket re-exploration and sternotomy with cardiopulmonary bypass. RESULTS: Although the patient was considered at high risk from thrombocytopenia, systemic infection, and symptomatic heart failure with a very low ejection fraction, the surgical procedure used to remove his ICD provided a good clinical outcome. CONCLUSION: An early and aggressive combination of surgical and medical therapy is effective for the removal of an ICD causing endocarditis, and reimplantation of the device is safe when guided by principles for preventing infection. PMID- 23438208 TI - Purinoceptor-mediated, capsaicin-resistant excitatory effect of allyl isothiocyanate on neurons of the guinea-pig small intestine. AB - Allyl isothiocyanate (AITC; 200 MUM) caused atropine- and tetrodotoxin-sensitive longitudinal muscle contraction on the guinea-pig small intestine. The response was not influenced by hexamethonium, a functional blockade of capsaicin-sensitive neurons or by antagonists acting at TRPV1 or TRPA1, but was abolished by the P2 purinoceptor antagonist PPADS (50 MUM). It is concluded that cholinergic motoneurons are activated by a purinergic mechanism in the course of the AITC response, independently of capsaicin-sensitive processes or even TRPA1. PMID- 23438209 TI - Accuracy of cough reporting by carers of Indigenous children. AB - AIMS: The study aims to determine the reliability of a 24-h history of reported cough presence and quality (wet/dry) compared with objectively recorded cough, and evaluate factors that may influence cough reporting. METHODS: A digital recorder (ICD-PX720, Sony, Tokyo, Japan) was attached to 47 Indigenous children for 24 h during admission at Royal Darwin Hospital. After recording, carers reported their child's cough details. Cough counts were objectively measured and details of cough reports by carer (cough present/absent, quality wet/dry, cough severity determined by visual analogue scale and verbal category descriptive score) were the main outcomes measured. Other factors examined were: carer's sex, age, education, smoking, carer's cough, parent versus non-parent, respiratory illness in child and mean parent-proxy cough-specific quality of life questionnaire. Data were entered into STATA (V.10, STATA Corp., College Station, TX, USA). Cohen's kappa (kappa) coefficients and Spearman's rank correlation coefficient (rs ) were used for data analysis. RESULTS: Reporting of cough by Indigenous carers (compared with cough monitoring) was slight when a low cough threshold (0.25 coughs/h) was used (kappa = 0.17, 95% CI -0.15, 0.49) and moderate when a higher cough threshold was used (kappa = 0.57, 95% CI 0.28, 0.88). Carers' evaluation of wet cough disagreed with clinician's evaluation (kappa = -0.24, 95% CI -0.58, 0.09). Subjective reporting of cough severity moderately correlated with objective cough rates (rs = 0.41 to 0.44, 95% CI 0.11, 0.67). None of the factors examined was associated with reliability of cough reporting. CONCLUSIONS: The unreliability of reporting of cough highlights the need for community education on the importance of cough to improve health-seeking behaviour for early detection and treatment of respiratory disease. PMID- 23438210 TI - Reply: To PMID 22967227. PMID- 23438211 TI - Lissonota holcocerica Sheng sp.n (Hymenoptera: Ichneumonidae) parasitizing Holcocerus hippophaecolus (Lepidoptera: Cossidae) from China. AB - This paper describes Lissonota holcocerica Sheng sp.n. (Hymenoptera: Ichneumonidae), parasitizing Holcocerus hippophaecolus Hua, Chou, Fang and Chen (Lepidoptera: Cossidae) in Inner Mongolia, Liaoning, and Ningxia, China. The adults of L. holcocerica emerge from a cocoon during the daytime, mostly from 09:00 to 14:00 hr, then start calling and mating, mostly from 08:00 to 12:00 hr. Mating lasts from 15 sec to 15 min. The longevity of males is 5.8 +/- 2.4 days, whereas for females longevity is 7.6 +/- 4.6 days in the field. Nutritional supplements can significantly extend the life span of L. holcocerica. Mated females search for hosts by walking on the base of Hippophae rhamnoides L. (Rosales: Elaeagnaceae) stem infested by Ho. hippophaecolus, vibrating their antennae and tapping while searching the stem for oviposition sites. Parasitized cocoons of Ho. hippophaecolus collected in field were half the size of normal ones or even smaller. PMID- 23438212 TI - In vitro to in vivo extrapolation and physiologically based modeling of cytochrome P450 mediated metabolism in beagle dog gut wall and liver. AB - The beagle dog is a widely used in vivo model to guide clinical formulation development and to explore the potential for food effects. However, the results in dogs are often not directly translatable to humans. Consequently, a physiologically based modeling strategy has been proposed, using the dog as a validation step to verify model assumptions before making predictions in humans. One current weakness in this strategy is the lack of validated tools to incorporate gut wall metabolism into the dog model. In this study, in vitro to in vivo extrapolation factors for CYP2B11 and CYP3A12 mediated metabolism were established based on tissue enzyme abundance data reported earlier. Thereafter, physiologically based modeling of intestinal absorption in beagle dog was conducted in GastroPlus using V(max) and K(m) determined in recombinant enzymes as inputs for metabolic turnover. The predicted fraction of absorbed dose escaping the gut wall metabolism (F(g)) of all five reference compounds studied (domperidone, felodipine, nitrendipine, quinidine, and sildenafil) were within a two-fold range of the value estimated from in vivo data at single dose levels. However, further in vivo studies and analysis of the dose-dependent pharmacokinetics of felodipine and nitrendipine showed that more work is required for robust forecasting of nonlinearities. In conclusion, this study demonstrates an approach for prediction of the gut wall extraction of CYP substrates in the beagle dog, thus enhancing the value of dog studies as a component in a strategy for the prediction of human pharmacokinetics. PMID- 23438213 TI - Age-related variation in reproductive traits in the wandering albatross: evidence for terminal improvement following senescence. AB - The processes driving age-related variation in demographic rates are central to understanding population and evolutionary ecology. An increasing number of studies in wild vertebrates find evidence for improvements in reproductive performance traits in early adulthood, followed by senescent declines in later life. However, life history theory predicts that reproductive investment should increase with age as future survival prospects diminish, and that raised reproductive investment may have associated survival costs. These non-mutually exclusive processes both predict an increase in breeding performance at the terminal breeding attempt. Here, we use a 30-year study of wandering albatrosses (Diomedea exulans) to disentangle the processes underpinning age-related variation in reproduction. Whilst highlighting the importance of breeding experience, we reveal senescent declines in performance are followed by a striking increase in breeding success and a key parental investment trait at the final breeding attempt. PMID- 23438214 TI - Mutation spectrum of dystrophin gene in malaysian patients with Duchenne/Becker muscular dystrophy. AB - We undertook the clinical feature examination and dystrophin analysis using multiplex ligation-dependent probe amplification (MLPA) and direct DNA sequencing of selected exons in a cohort of 35 Malaysian Duchenne/Becker muscular dystrophy (DMD/BMD) patients. We found 27 patients with deletions of one or more exons, 2 patients with one exon duplication, 2 patients with nucleotide deletion, and 4 patients with nonsense mutations (including 1 patient with two nonsense mutations in the same exon). Although most cases showed compliance to the reading frame rule, we found two unrelated DMD patients with an in-frame deletion of the gene. Two novel mutations have been detected in the Dystrophin gene and our results were compatible with other studies where the majority of the mutations (62.8%) are located in the distal hotspot. However, the frequency of the mutations in our patient varied as compared with those found in other populations. PMID- 23438215 TI - Absence of the articular disc in the tasmanian devil temporomandibular joint. AB - The articular disc of the temporomandibular joint is a constant structure in mammals. According to Parsons' report in 1900, however, it is absent in four animals: the armadillo, two kinds of monotremes and the Tasmanian devil. Thereafter, no research was performed to confirm this observation. The aim of this study was to determine by anatomical and histological examination whether the Tasmanian devil has an articular disc in its temporomandibular joint. Six fresh frozen corpses and one dry skull of Tasmanian devils were obtained from the School of Zoology, University of Tasmania. The corpses were dissected and the morphology of the temporomandibular joint was carefully observed by gross anatomical and histological examination. The structure of the temporomandibular joint of the dry skull was examined macroscopically and by micro-computed tomography. In all cases, absence of the articular disc in the Tasmanian devil temporomandibular joint was morphologically confirmed. The surface layer of both the condyle and the glenoid fossa comprised a thick fibrous tissue. Micro computed tomography revealed dense and fine trabecular bone in the condyle. The thick fibrous tissue covering the condyle and high-density trabecular bone in the condyle might play a role in absorption against powerful mastication and heavy loading of the Tasmanian devil temporomandibular joint. PMID- 23438216 TI - Regioselective opening of myo-inositol orthoesters: mechanism and synthetic utility. AB - Acid hydrolysis of myo-inositol 1,3,5-orthoesters, apart from orthoformates, exclusively affords the corresponding 2-O-acyl myo-inositol products via a 1,2 bridged five-membered ring dioxolanylium ion intermediate observed by NMR spectroscopy. These C-2-substituted inositol derivatives provide valuable precursors for rapid and highly efficient routes to 2-O-acyl inositol 1,3,4,5,6 pentakisphosphates and myo-inositol 1,3,4,5,6-pentakisphosphate with biologically interesting and anticancer properties. Deuterium incorporation into the alpha methylene group of such alkyl ester products (2-O-C(O)CD2R), when the analogous alkyl orthoester is treated with deuterated acid, is established utilizing the novel orthoester myo-inositol 1,3,5-orthobutyrate as an example. Such deuterated ester products provide intermediates for deuterium-labeled synthetic analogues. Investigation into this selective formation of 2-O-ester products and the deuterium incorporation is presented with proposed mechanisms from NMR experiments. PMID- 23438217 TI - Acute kidney injury with pigment nephropathy following spider bite: a rarely reported entity in India. AB - Acute kidney injury (AKI) can be seen in tropical regions following bites of various venomous animals and insects. Renal failure is seen most commonly following the bite of spiders of the Loxosceles spp. Dermonecrosis, systemic inflammatory response, hemolysis, rhabdomyolysis, and direct venom-related effects are postulated as causes of AKI. We report a documented case of AKI with pigment nephropathy following the bite of a brown spider from a tropical region which is known to have many venomous animals but has no previous reports of AKI following spider bite. Whether this is due to absence of toxic spider species or underreporting needs to be determined. PMID- 23438218 TI - Physiological aspects of the subcellular localization of glycogen in skeletal muscle. AB - Glucose is stored in skeletal muscle fibers as glycogen, a branched-chain polymer observed in electron microscopy images as roughly spherical particles (known as beta-particles of 10-45 nm in diameter), which are distributed in distinct localizations within the myofibers and are physically associated with metabolic and scaffolding proteins. Although the subcellular localization of glycogen has been recognized for more than 40 years, the physiological role of the distinct localizations has received sparse attention. Recently, however, studies involving stereological, unbiased, quantitative methods have investigated the role and regulation of these distinct deposits of glycogen. In this report, we review the available literature regarding the subcellular localization of glycogen in skeletal muscle as investigated by electron microscopy studies and put this into perspective in terms of the architectural, topological, and dynamic organization of skeletal muscle fibers. In summary, the distribution of glycogen within skeletal muscle fibers has been shown to depend on the fiber phenotype, individual training status, short-term immobilization, and exercise and to influence both muscle contractility and fatigability. Based on all these data, the available literature strongly indicates that the subcellular localization of glycogen has to be taken into consideration to fully understand and appreciate the role and regulation of glycogen metabolism and signaling in skeletal muscle. A full understanding of these phenomena may prove vital in elucidating the mechanisms that integrate basic cellular events with changing glycogen content. PMID- 23438219 TI - A step-defined sedentary lifestyle index: <5000 steps/day. AB - Step counting (using pedometers or accelerometers) is widely accepted by researchers, practitioners, and the general public. Given the mounting evidence of the link between low steps/day and time spent in sedentary behaviours, how few steps/day some populations actually perform, and the growing interest in the potentially deleterious effects of excessive sedentary behaviours on health, an emerging question is "How many steps/day are too few?" This review examines the utility, appropriateness, and limitations of using a reoccurring candidate for a step-defined sedentary lifestyle index: <5000 steps/day. Adults taking <5000 steps/day are more likely to have a lower household income and be female, older, of African-American vs. European-American heritage, a current vs. never smoker, and (or) living with chronic disease and (or) disability. Little is known about how contextual factors (e.g., built environment) foster such low levels of step defined physical activity. Unfavorable indicators of body composition and cardiometabolic risk have been consistently associated with taking <5000 steps/day. The acute transition (3-14 days) of healthy active young people from higher (>10 000) to lower (<5000 or as low as 1500) daily step counts induces reduced insulin sensitivity and glycemic control, increased adiposity, and other negative changes in health parameters. Although few alternative values have been considered, the continued use of <5000 steps/day as a step-defined sedentary lifestyle index for adults is appropriate for researchers and practitioners and for communicating with the general public. There is little evidence to advocate any specific value indicative of a step-defined sedentary lifestyle index in children and adolescents. PMID- 23438220 TI - Patterns of weekday and weekend physical activity in youth in 2 Canadian provinces. AB - Few Canadian children are meeting physical activity (PA) guidelines for optimal growth and health. There is little information describing the patterns of PA among Canadian youth, so it is difficult to determine where the deficits occur. The purpose of this study was to identify subgroups of youth and windows of time characterized by low PA and high sedentary behaviour. We conducted a cross sectional study of 626 youth (aged 10-15 years) in 2 Canadian provinces. The primary exposure variables included geographic setting (rural vs. urban), sex, and days of the week (weekend days vs. weekdays). The primary outcome measures were minutes of light PA, moderate to vigorous physical activity (MVPA), and sedentary behavior, assessed with accelerometry. Compared with weekdays, MVPA was ~30% lower on weekend days (55.8 +/- 23.0 min vs. 38.7 +/- 26.7 min; p < 0.001), whereas light PA was ~15% higher. Significantly more youth achieved an average of >60 min of MVPA on weekdays than on weekend days (46% vs. 22%; p < 0.001). Sex specific differences in MVPA were more pronounced on weekdays than on weekend days (~13 vs ~8 min per day; p < 0.01). Youth in rural settings achieved ~9 fewer minutes of MVPA daily than youth in urban settings (p < 0.001). In youth 10 to 15 years of age, daily MVPA is lower and light PA is higher on weekend days than on weekdays. Girls and students living in rural areas were particularly vulnerable to low levels of MVPA. PMID- 23438221 TI - Dose-dependent responses of myofibrillar protein synthesis with beef ingestion are enhanced with resistance exercise in middle-aged men. AB - Aging impairs the sensitivity of skeletal muscle to anabolic stimuli, such as amino acids and resistance exercise. Beef is a nutrient-rich source of dietary protein capable of stimulating muscle protein synthesis (MPS) rates in older men at rest. To date, the dose-response of myofibrillar protein synthesis to graded ingestion of protein-rich foods, such as beef, has not been determined. We aimed to determine the dose-response of MPS with and without resistance exercise to graded doses of beef ingestion. Thirty-five middle-aged men (59 +/- 2 years) ingested 0 g, 57 g (2 oz; 12 g protein), 113 g (4 oz; 24 g protein), or 170 g (6 oz; 36 g protein) of (15% fat) ground beef (n = 7 per group). Subjects performed a bout of unilateral resistance exercise to allow measurement of the fed state and the fed plus resistance exercise state within each dose. A primed constant infusion of l-[1-(13)C]leucine was initiated to measure leucine oxidation and of l-[ring-(13)C(6)]phenylalanine was initiated to measure myofibrillar MPS. Myofibrillar MPS was increased with ingestion of 170 g of beef to a greater extent than all other doses at rest and after resistance exercise. There was more leucine oxidation with ingestion of 113 g of beef than with 0 g and 57 g, and it increased further after ingestion of 170 g of beef (all p < 0.05). Ingestion of 170 g of beef protein is required to stimulate a rise in myofibrillar MPS over and above that seen with lower doses. An isolated bout of resistance exercise was potent in stimulating myofibrillar MPS, and acted additively with feeding. PMID- 23438204 TI - Protein analysis by shotgun/bottom-up proteomics. PMID- 23438222 TI - Effect of recovery mode on postexercise vagal reactivation in elite synchronized swimmers. AB - This study investigated the effect of whole-body cryostimulation (WBC), contrast water therapy (CWT), active recovery (ACT), and passive condition (PAS) protocols on the parasympathetic reactivation and metabolic parameters of recovery in elite synchronized swimmers who performed 2 simulated competition ballets (B1 and B2) separated by 70 min. After determining maximal oxygen consumption (VO(2max400)) and blood lactate concentrations ([La(-)](b400)) during a 400-m swim trial, 11 swimmers performed 1 protocol per week in randomized order. Heart rate variability (HRV) was measured at rest (PreB1), 5 min after B1 (PostB1), before B2 (PreB2), and 5 min after B2 (PostB2). VO(2peak) was measured at PostB1 and PostB2, and [La(-)](b) was measured at PostB1, PreB2, and PostB2. PostB1 VO(2peak) and VO(2max400) were similar, but PostB1 [La(-)](b) was higher than [La(-)](b400) (p = 0.004). Each ballet caused significant decreases in HRV indices. At PreB2, all HRV indices had returned to PreB1 levels in the CWT, PAS, and ACT protocols, whereas the WBC protocol yielded a 2- to 4-fold increase in vagal-related HRV indices, compared with PreB1. WBC and ACT both increased [La( )](b) recovery, compared with PAS (p = 0.06 and p = 0.04, respectively), and yielded an increased VO(2peak) from B1 to B2; however, it decreased after PAS (+5.4%, +3.4%, and -3.6%; p < 0.01). This study describes the physiological response to repeated maximal work bouts that are highly specific to elite synchronized swimming. In the context of short-term recovery, WBC yields a strong parasympathetic reactivation, and shows similar effectiveness to ACT on the metabolic parameters of recovery and subsequent exercise capacity. PMID- 23438223 TI - Effect of a carbohydrate mouth rinse on simulated cycling time-trial performance commenced in a fed or fasted state. AB - It is presently unclear whether the reported ergogenic effect of a carbohydrate (CHO) mouth rinse on cycling time-trial performance is affected by the acute nutritional status of an individual. Hence, the aim of this study was to investigate the effect of a CHO mouth rinse on a 60-min simulated cycling time trial performance commenced in a fed or fasted state. Twelve competitive male cyclists each completed 4 experimental trials using a double-blinded Latin square design. Two trials were commenced 2 h after a meal that contained 2.5 g.kg(-1) body mass of CHO (FED) and 2 after an overnight fast (FST). Prior to and after every 12.5% of total time during a performance ride, either a 10% maltodextrin (CHO) or a taste-matched placebo (PLB) solution was mouth rinsed for 10 s then immediately expectorated. There were significant main effects for both pre-ride nutritional status (FED vs. FST; p < 0.01) and CHO mouth rinse (CHO vs. PLB; p < 0.01) on power output with an interaction evident between the interventions (p < 0.05). The CHO mouth rinse improved mean power to a greater extent after an overnight fast (282 vs. 273 W, 3.4%; p < 0.01) compared with a fed state (286 vs. 281 W, 1.8%; p < 0.05). We concluded that a CHO mouth rinse improved performance to a greater extent in a fasted compared with a fed state; however, optimal performance was achieved in a fed state with the addition of a CHO mouth rinse. PMID- 23438224 TI - Caffeine ingestion impairs insulin sensitivity in a dose-dependent manner in both men and women. AB - The effects of alkaloid caffeine on insulin sensitivity have been investigated primarily in men, and with a single caffeine dose most commonly of 5-6 mg.kg(-1) of body weight (BW). It is unknown if the effects of caffeine on glucose homeostasis are sex-specific and (or) dose-dependent. This study examined whether caffeine ingestion would disrupt glucose homeostasis in a dose-dependent or threshold manner. It also examined whether sex-specific responses to caffeine exist. It was hypothesized that women would have an exaggerated response to caffeine, and that caffeine would only impair glucose metabolism once a threshold was reached. Twenty-four healthy volunteers (12 males, 12 females) participated in 4 trials, in a crossover, randomized, and double-blind fashion. They ingested caffeine (1, 3, or 5 mg.kg(-1) of BW) or placebo followed, 1 h later, by a 2-h oral glucose tolerance test. Glucose, insulin, C-peptide area under the curve (AUC), and insulin sensitivity index data were fitted to a segmented linear model to determine dose-responses. There were no differences between sexes for any endpoints. Regression slopes were significantly different from zero (p < 0.05) for glucose, insulin, and C-peptide AUCs, with thresholds being no different from zero. Increasing caffeine consumption by 1 mg.kg(-1) of BW increased insulin and C-peptide AUCs by 5.8% and 8.7%, respectively. Despite this exaggerated insulin response, glucose AUC increased by 11.2 mmol per 120 min.L(-1) for each mg.kg(-1) BW consumed. These results showed that caffeine ingestion disrupted insulin sensitivity in a dose-dependent fashion beginning at very low doses (0-1 mg.kg( 1) BW) in both healthy men and women. PMID- 23438225 TI - Oophorectomy hinders antioxidant adaptation promoted by swimming in Wistar rats. AB - Oxidative stress is associated with postmenopause and is also responsible for various metabolic alterations. The redox imbalance observed during ovarian decline can be induced experimentally by bilateral ovariectomy in rats. In addition to hormone replacement, regular moderate physical exercise is indicated to prevent several common postmenopausal diseases. This study aimed to assess the effect of daily swimming on the antioxidant defense system of oophorectomized Wistar rats. Control and oophorectomized groups were submitted to 1 h of daily swimming for 90 days. Levels of lipid peroxidation and glutathione content and the activities of superoxide dismutase enzyme and glutathione peroxidase in erythrocytes, liver, and brain were assessed every 30 days. The control group exhibited lower lipoperoxidation that was associated with a significant increase in superoxide dismutase enzyme activity, glutathione peroxidase activity, and glutathione content in erythrocytes and liver; however, swimming did not cause changes in antioxidant parameters in the brain over time. The oophorectomized group showed no antioxidant adaptation to daily swimming and had greater oxidative damage in the liver and blood. Our results suggest that ovariectomy hinders antioxidant adaptation in Wistar rats submitted to daily swimming. PMID- 23438226 TI - Oxygen uptake kinetics in endurance-trained and untrained postmenopausal women. AB - The rate of adjustment for pulmonary oxygen uptake (tauVO(2p)) is slower in untrained and in older adults. Near-infrared spectroscopy (NIRS) has shed light on potential mechanisms underlying this in young men and women and in older men; however, there is no such data available in older women. The purpose of this study was to gain a better understanding of the mechanisms of slower tauVO(2p) in older women who were either endurance-trained or untrained. Endurance-trained (n = 10; age, 62.6 +/- 1.0 years) and untrained (n = 9; age, 69.1 +/- 2.2 years) older women attended 2 maximal and 2 submaximal (90% of ventilatory threshold) exercise sessions. Oxygen uptake (VO(2)) was measured breath by breath, using a mass spectrometer, and changes in deoxygenated hemoglobin concentration of the vastus lateralis ([HHb]) were measured using NIRS. Heart rate was measured continuously with a 3-lead electrocardiogram. tauVO(2p) was faster in trained (35.1 +/- 5.5 s) than in untrained (57.0 +/- 8.1 s) women. The normalized [HHb] to VO(2) ratio, an indicator of muscle O(2) delivery to O(2) utilization, indicated a smaller overshoot in trained (1.09 +/- 0.1) than in untrained (1.39 +/- 0.1) women. Heart rate data indicated a faster adjustment of heart rate in trained (33.0 +/- 13.0) than in untrained (68.7 +/- 14.1) women. The pairing of VO(2p) data with NIRS-derived [HHb] data indicates that endurance-trained older women likely have better matching of O(2) delivery to O(2) utilization than older untrained women during moderate-intensity exercise, leading to a more rapid adjustment of VO(2p). PMID- 23438227 TI - Effects of varying attentional focus on health-related physical fitness performance. AB - Assessing health-related physical fitness is important for determining health status. However, verbal instructions provided during an assessment generally do not specify direction of attentional focus. This investigation examined the effect of attentional focus on performance outcomes during appraisals of health related physical fitness. Eight females (25.0 +/- 4.0 years) and 8 males (26.3 +/ 3.9 years) completed 7 physical fitness tests of the Canadian Physical Activity, Fitness and Lifestyle Approach (modified Canadian Aerobic Fitness Test, grip strength, push-ups, sit and reach, partial curl-ups, vertical jump, and back extension) on 3 different days, each separated by 1 week. On day 1, no attentional focus was specified. On days 2 and 3, participants were asked to adopt an external focus (instructions focused attention away from the body) or an internal focus (instructions focused attention on the body's movement) in randomized order. Irrespective of sex, adopting an external focus resulted in significantly better performance on all tests when compared with no focus or internal-focus conditions. An internal focus also resulted in performance decrements for grip strength, push-ups, and vertical jump vs. no focus. These results demonstrate that instructing individuals to adopt an external focus provides a performance advantage on appraisals of aerobic and musculoskeletal fitness, whereas an internal focus may hinder performance. In some participants, these scores may convert to a rating of health status that is 1 health benefit zone higher or lower, respectively. This highlights further the importance of formulating verbal instructions that incorporate attentional focus for optimal performance on appraisals of physical fitness. PMID- 23438228 TI - Protective effect of dietary tender cluster beans (Cyamopsis tetragonoloba) in the gastrointestinal tract of experimental rats. AB - In this study, the gastrointestinal protective effect of soluble, dietary fiber rich tender cluster beans, with respect to the activities of antioxidant enzymes and the concentration of antioxidant molecules, was examined in Wistar rats. Dietary intervention with tender cluster beans (15% freeze-dried powder in the diet for 8 weeks) significantly enhanced the activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase, glutathione-S transferase, and GPX) and the concentrations of antioxidant molecules in both gastric and intestinal mucosa. Further, in combination with capsaicin (0.01%), the beneficial effect was even higher. There is a strong indication that tender cluster beans offer a significant gastroprotective effect, and a much greater effect when combined with capsaicin in terms of increased antioxidant status. In a separate study, these dietary components were found to alleviate the diminished activities of antioxidant enzymes and antioxidant molecules in gastric and intestinal mucosa under conditions of ethanol-induced oxidative stress. The gastroprotective effect of the cluster bean was also reflected in its positive effect on gastric mucosal glycoproteins, resulting in a lowering of mucosal injury. Incidentally, the serum and liver also showed an elevated antioxidant status, thus suggesting desirable lowered oxidative stress results when tender cluster beans are consumed. PMID- 23438229 TI - Influence of upper-body exercise order on hormonal responses in trained men. AB - The aim of this study was to examine acute hormonal responses after different sequences of an upper-body resistance-exercise session. Twenty men completed 2 sessions (3 sets; 70% 1-repetition maximum; 2 min passive rest between sets) of the same exercises in opposite sequences (larger to smaller vs. smaller to larger muscle-group exercises). Total testosterone (TT), free testosterone (FT), testosterone/cortisol (T/C) ratio, sex-hormone-binding globulin (SHBG), growth hormone (GH), and cortisol (C) concentrations were measured before and immediately after each sequence. The results indicate that the GH concentration increased after both sessions, but the increase was significantly greater (p < 0.05) after the sequence in which larger muscle-group exercises were performed prior to the smaller muscle-group exercises. No differences were observed between sessions for TT, FT, SHBG, C, or the T/C ratio at baseline or immediately after resistance exercise. These results indicate that performing larger muscle-group exercises first in an upper-body resistance-exercise session leads to a significantly greater GH response. This may have been due to the significantly greater exercise volume accomplished. In summary, the findings of this investigation support the common prescriptive recommendation to perform larger muscle group exercises first during a resistance-exercise session. PMID- 23438230 TI - Oxygen consumption, substrate oxidation, and blood pressure following sprint interval exercise. AB - This study examined the acute effect of sprint interval exercise (SIE) on postexercise oxygen consumption, substrate oxidation, and blood pressure. The participants were 10 healthy males aged 21-27 years. Following overnight fasts, each participant undertook 2 trials in a random balanced order: (i) four 30-s bouts of SIE on a cycle ergometer, separated by 4.5 min of recovery, and (ii) resting (control) in the laboratory for an equivalent period. Time-matched measurements of oxygen consumption, respiratory exchange ratio, and blood pressure were made for 2 h into recovery. Total 2-h oxygen consumption was significantly higher in the SIE than in the control trial (mean +/- SD: CONTROL: 31.9 +/- 6.7 L vs Exercise: 45.5 +/- 6.8 L, p < 0.001). The rate of fat oxidation was 75% higher 2 h after the exercise trial compared with the control trial ( CONTROL: 0.08 +/- 0.05 g.min(-1) vs Exercise: 0.14 +/- 0.06 g.min(-1), p = 0.035). Systolic blood pressure ( CONTROL: 117 +/- 8 mm Hg vs Exercise: 109 +/- 8 mm Hg, p < 0.05) and diastolic blood pressure ( CONTROL: 84 +/- 6 mm Hg vs Exercise: 77 +/- 5 mm Hg, p < 0.05) were significantly lower 2 h after the exercise trial compared with the control trial. These data showed a 42% increase in oxygen consumption (~13.6 L) over 2 h after a single bout of SIE. Moreover, the rate of fat oxidation increased by 75%, whereas blood pressure was reduced by ~8 mm Hg 2 h after SIE. Whether these acute benefits of SIE can translate into long-term changes in body composition and an improvement in vascular health needs investigation. PMID- 23438231 TI - Effect of the SORT1 low-density lipoprotein cholesterol locus is sex-specific in a fit, Canadian young-adult population. AB - The SORT1 locus was originally identified by genome-wide association studies of low-density lipoprotein cholesterol (LDL-C) in adults. Although the effect sizes of this locus are relatively small, we hypothesized that a younger population would show a greater genetic effect because of fewer confounding variables. As such, we investigated the association between the SORT1 locus and LDL-C in a group of healthy young adults. Subjects (n = 122, mean age = 23.2 years) were recruited from the University of Calgary. Lipid measures and genomic DNA were collected from peripheral blood after an overnight fast. Blood pressure, percent body fat (%BF), and maximal oxygen consumption were also measured. Associations between genotype and LDL-C were investigated using linear regression. Nearly one half (42.9%) of the female and 21.7% of the male subjects had a %BF that was above a healthy range. More than one quarter of the subjects had LDL-C values that were considered nonoptimal. Although the association was not significant when both sexes were combined, a significant association was observed between the SORT1 locus (GG: 2.46 +/- 0.11 mmol.L(-1) vs. GT-TT: 2.06 +/- 0.12 mmol.L(-1), p = 0.016) and LDL-C in male subjects, with genotype explaining 3.0% of the variability in LDL-C. A high prevalence of nonoptimal LDL-C exists in this young population even though it is otherwise fit and healthy. A significant association was found between LDL-C and the minor SORT1 allele in male subjects, with an effect size larger than previously reported in older populations. SORT1 is a valuable target for identifying individuals who would most benefit from early interventions to prevent cardiovascular disease. PMID- 23438232 TI - Effect of 10-day forced treadmill training on neurotrophic factors in experimental autoimmune encephalomyelitis. AB - The impact of exercise on disease progression in multiple sclerosis (MS) is unclear. In the present study, we evaluated the clinical effects of forced wheel running on rats induced with experimental autoimmune encephalomyelitis (EAE), a model of MS. Female Lewis rats (n = 40) were randomly assigned to 1 of 4 groups prior to inoculation: EAE exercise (EAE-Ex), EAE sedentary (EAE-Sed), control exercise (Con-Ex), or control sedentary (Con-Sed). Exercise training was composed of forced treadmill running at increasing intensity across 10 consecutive days. No significant differences in clinical disability were observed in the EAE groups at the conclusion of this study. Furthermore, no significant differences in brain mass were observed across groups. Analysis of brain tissue proteins revealed that tumour necrosis factor-alpha (TNF-alpha) concentrations were higher in both EAE groups compared with the control groups (p < 0.05); however, no significant differences were seen between the EAE-Ex and EAE-Sed groups. The Con-Ex group had lower whole-brain TNF-alpha compared with the Con-Sed group (p < 0.05). Nerve growth factor concentrations were greater in the EAE-Ex animals compared with both control groups (p < 0.05 for both). No differences were seen in brain derived neurotrophic factor. Our results indicate that aerobic exercise can modulate the proteins associated with disability in EAE; however, further research is required to understand the total impact of exercise on EAE disability and disease progression. PMID- 23438233 TI - Night and postexercise cardiac autonomic control in functional overreaching. AB - The purpose of this study was to evaluate the effect of a 2-week overload period immediately followed by a 1-week taper period on the autonomic control of heart rate during the night or after exercise cessation. Eleven male endurance athletes increased their usual training volume by 100% for 2 weeks (overload) and decreased it by 50% for 1 week (taper). A maximal graded exercise test and a constant-speed test at 85% of peak treadmill speed, both followed by a 10-min passive recovery period, were performed at baseline and after each period. Heart rate variability was also measured during a 4-h period in the night or during estimated slow-wave sleep. All participants were considered to be overreached based on performance and physiological and psychological criteria. We found a decrease in cardiac parasympathetic control during slow-wave sleep (HFnu = 61.3% +/- 11.7% vs 50.0% +/- 10.1%, p < 0.05) but not during the 4-h period, as well as a faster heart rate recovery following the maximal graded exercise test (tau = 61.8 +/- 14.5 s vs 54.7 +/- 9.0 s, p < 0.05) but not after the constant-speed test, after the overload period. There was a return to baseline for both measures after the taper period. Other indices of cardiac autonomic control were not altered by the overload period. Care should be taken in selecting the most sensitive heart rate measures in the follow-up of athletes, because cardiac autonomic control is not affected uniformly by overload training. PMID- 23438234 TI - Augmentation of the exercise pressor reflex in prehypertension: roles of the muscle metaboreflex and mechanoreflex. AB - This study investigated the hemodynamic mechanisms underlying the exaggerated blood pressure response to muscle contraction in prehypertensive humans and the potential role of skeletal muscle metabo- and mechanoreceptors in this response. To accomplish this, changes in peak mean arterial blood pressure (DeltaMAP), cardiac output, and total peripheral resistance (DeltaTPR) were compared between prehypertensive (n = 23) and normotensive (n = 19) male subjects during 2 min of static contraction (at 50% of maximal tension), 2 min of postexercise muscle ischemia (metaboreflex), and 1 min of passive dorsiflexion of the foot (tendon stretch, mechanoreceptor reflex). These variables were assessed before and during the interventions. Percentage increases from baseline in MAP and TPR in response to the exercise pressor reflex were augmented in the prehypertensives, compared with the normotensives (44% +/- 5% vs. 33% +/- 4% and 34% +/- 15% vs. 2% +/- 8%, respectively) (p < 0.05). Metaboreflex-induced increases in MAP and TPR were also augmented in the prehypertensives (28% +/- 5% vs. 14% +/- 4% and 36% +/- 12% vs. 14% +/- 9%, respectively) (p < 0.05). In response to the mechanoreflex, no differences in the percentage increase in MAP or TPR were seen between groups. The results indicate that the reflex pressor response to static contraction is augmented in prehypertension and suggest that this phenomenon is due, at least in part, to enhanced activation of metaboreceptors. PMID- 23438235 TI - The contribution of energy systems during the upper body Wingate anaerobic test. AB - The purpose of this study was to measure the contribution of the aerobic, anaerobic lactic, and alactic systems during an upper body Wingate Anaerobic test (WAnT). Oxygen uptake and blood lactate were measured before, during, and after the WAnT and body composition analyzed by dual-energy X-ray absorptiometry. The contribution of the energy systems was 11.4% +/- 1.4%, 60.3% +/- 5.6%, and 28.3% +/- 4.9% for the aerobic, anaerobic lactic, and alactic systems, respectively. PMID- 23438236 TI - Resistance exercise order does not determine postexercise delivery of testosterone, growth hormone, and IGF-1 to skeletal muscle. AB - Does resistance exercise order affect hormone availability? Participants performed arm exercise before and after leg exercise. Hormone delivery was estimated by multiplying brachial artery blood flow and hormone concentrations. Blood flow increased after arm (276%) and leg (193%; both p < 0.001) exercise. Testosterone, growth hormone, and insulin-like growth factor 1 showed with distinct delivery patterns between conditions; however (interactions all p < 0.001), net exposure was similar. The anabolic potential of postexercise hormones was not affected by exercise order. PMID- 23438237 TI - Health status and mortality rates of adolescents and young adults in the Brussels Capital Region: differences according to region of origin and migration history. AB - OBJECTIVE: To examine and quantify differences in both self-rated health (SRH) and mortality according to region of origin, migration history and educational level among adolescents and young adults living in the Brussels-Capital Region (BCR). DESIGN: The data consist of the census of 2001 for the BCR linked to death and emigration records for the period of 01/10/2001-01/01/2006. Belgian, Maghreb, Turkish and sub-Saharan African 15-34 year olds are included in the analyses. Odds ratios are calculated for SRH (0 = poor health, 1 = good health) using logistic regression. Age-standardised mortality rates are computed and mortality rate ratios are shown using Poisson regression. RESULTS: There are marked health differences according to region of origin. While Maghrebins and Turks (M/T) feel less healthy, sub-Saharan Africans (SSA) feel healthier than Belgians. Furthermore, there are important differences within nationality groups, with second-generation M/T having a worse health status than the first generation. While first-generation SSA feel a lot healthier than Belgians, there is no difference between second-generation SSA and Belgians. Education plays a marked role in health and mortality differences, especially in young adulthood (25-34 years). Migration history is even more important than region of origin concerning mortality differences. First-generation M/T show lower mortality risks compared to Belgians and second-generation M/T, while the latter show comparable mortality risks as Belgians after controlling for education. CONCLUSION: Important differences are observed according to both region of origin and migration history among adolescents and young adults in the BCR. These differences significantly reduce when accounting for education, suggesting that investing in education is a public-health strategy worth considering. Further research in this area may benefit from taking migration history into account. PMID- 23438238 TI - G16R single nucleotide polymorphism but not haplotypes of the beta(2)-adrenergic receptor gene alters cardiac output in humans. AB - Variation in genes encoding the beta(2)-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with beta(2) mediated vasodilation, but the effect of ADRB2 haplotypes on Q has not been studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise. Only the G16R polymorphism was associated with Q. In carriers of the Arg(16) allele, Q(rest) (resting Q) was 0.4 [95% CI (confidence interval), 0.0-0.7] l/min lower than in G16G homozygotes (P=0.048). During exercise, the increase in Q was by 4.7 (95% CI, 4.3-5.2) l/min per litre increase in pulmonary Vo(2) (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0-0.9) l/min lower in Arg16 carriers (P=0.035). A similar effect size was observed for the Arg16 haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q was 0.5 (CI, 0.0 -1.0) l/min greater in ACE I/I carriers compared with I/D and D/D subjects (P=0.054). In conclusion, the ADRB2 Arg16 allele in humans is associated with a lower Q both at rest and during exercise, overriding the effects of haplotypes. PMID- 23438239 TI - Attentional biases for betel nut cues in heavy and light chewers. AB - The betel nut (Areca catecu) is regarded by the World Health Organization as the fourth most prevalent human carcinogen. Our study aims to investigate whether habitual chewers show bias in their attention toward betel nut usage. In the current study, heavy and light betel nut chewers were instructed to respond to a probe presented immediately after either one of a pair of areca-related picture and non-areca-matched picture. The presentation durations of these pictures were manipulated to investigate attentional biases under awareness threshold (17 ms), in initial orienting (200 ms), and maintenance of attention (2,000 ms). Faster response to the probe replacing the areca-related picture, in comparison with a matched picture, indicated attentional bias. The results showed that neither group showed subliminal attentional biases. Further, heavy chewers, but not light chewers, exhibited supraliminal biases toward betel nut cues in initial orienting of attention and maintained attention. Moreover, attentional bias scores at 2,000 ms were also shown to be positively associated with betel nut craving and dependence. Implications of the current findings are thoroughly discussed in the article. PMID- 23438240 TI - Perceptions of partners' problematic alcohol use affect relationship outcomes beyond partner self-reported drinking: alcohol use in committed romantic relationships. AB - Alcohol use is prevalent among college students, including those who are in committed romantic relationships. Individuals' perceptions of their partner's alcohol use may have significant effects on how they view both their partner and their relationship. The current study examines the effect of one's perception of one's romantic partner's drinking as problematic on one's relationship satisfaction and commitment, and whether this varies as a function of one's partner's drinking. Both partners in romantic heterosexual relationships (N = 78 dyads) completed an online survey assessing alcohol use and problems, relationship satisfaction and commitment, and the perception that their partner's drinking was problematic. Analyses using Actor-Partner Interdependence Models (APIMs) revealed a partner-moderated actor interaction, such that partner self reported drinking significantly moderated the association between the actor's perception of their partner's drinking as problematic and actor relationship outcomes. Results indicated that when partners drank at higher levels, perceiving their drinking as problematic did not have an effect. These individuals were less satisfied regardless of their perceptions. However, when partners drank at lower levels, perceiving their drinking as problematic was negatively associated with relationship outcomes. Furthermore, for alcohol consumption, three-way interactions with gender emerged, indicating that this effect was stronger for males. Results extend the literature on drinking in relationships and on interpersonal perception. Implications and future directions are discussed. PMID- 23438241 TI - Predictors and consequences of pregaming using day- and week-level measurements. AB - Drinking before going to a social event is common in adolescents and young adults and is associated with harmful outcomes, but information collected at the daily level is needed to better examine individual and contextual factors associated with pregaming. The purpose of this study was to investigate the prevalence of pregaming in a diverse sample of college students; demographic differences in rates of pregaming; the degree to which pregaming is associated with higher volume drinking, intoxication, and consequences; and the importance of time-of year and day-of-week. College students (N = 750) at three colleges completed past week surveys throughout their freshman and sophomore years. Pregaming was reported by 3 out of 4 drinkers and occurred on 31% of 12,361 drinking days. Compared with nonpregaming days, participants drank approximately 2 more drinks on pregaming days; this increase accounted for a .040 higher estimated blood alcohol concentration. Using generalized estimating equations, we established that women, racial/ethnic minority students, and first-year students were more likely to pregame on a drinking day than males, non-Hispanic White students, and sophomore students, respectively. Men became more intoxicated on pregaming days and sophomores consumed more alcohol. Pregaming predicted higher positive and higher negative consequences, even after controlling for the number of drinks consumed. Pregaming was more common in the fall semester, in the early weeks of each semester, and on weekends. Prevention efforts targeting first-year students, the early weeks of the semester, and the hours before traditional party times may be effective at reducing this hazardous practice. PMID- 23438242 TI - Selective attention to emotional pictures as a function of gambling motives in problem and nonproblem gamblers. AB - Problem gambling may reflect a maladaptive means of fulfilling specific affect regulation motives, such as enhancing positive affect or coping with negative affect. Research with clinical populations indicates that disorders with prominent affective symptoms are characterized by attentional biases for symptom congruent information. Thus, we assessed whether problem gamblers with enhancement motives for gambling would demonstrate attentional biases for positive emotional information, relative to other types of emotional information, and problem gamblers with coping motives for gambling would demonstrate attentional biases for negative emotional information, compared with other types of emotional information. In addition, we expected motive-congruent biases to be stronger in problem gamblers than nonproblem gamblers. To test these hypotheses, problem and nonproblem gamblers received an emotional orienting task in which neutral, negative, and positive pictorial cues appeared to one side of the computer screen, followed by target words in cued or uncued locations. In a look away condition, participants had to shift attention away from pictures to respond to predominantly uncued targets, whereas in a look-toward condition, they had to orient to pictures to categorize predominantly cued targets. The results revealed motive-congruent orienting biases and disengagement lags for emotional pictures in problem gamblers. The link between motives and affective biases was less apparent in nonproblem gamblers. Results suggest that attentional measures may provide a useful complement to the subjective methodologies that are typically employed in studying problem gamblers. PMID- 23438243 TI - The assessment of protective behavioral strategies: comparing the absolute frequency and contingent frequency response scales. AB - The purpose of the present studies was to examine the effects of response scale on the observed relationships between protective behavioral strategies (PBS) measures and alcohol-related outcomes. We reasoned that an "absolute frequency" scale (stem: "how many times ..."; response scale: 0 times to 11+ times) conflates the frequency of using PBS with the frequency of consuming alcohol; thus, we hypothesized that the use of an absolute frequency response scale would result in positive relationships between types of PBS and alcohol-related outcomes. Alternatively, a "contingent frequency" scale (stem: "When drinking ... how often ..."; response scale: never to always) does not conflate frequency of alcohol use with use of PBS; therefore, we hypothesized that use of a contingent frequency scale would result in negative relationships between use of PBS and alcohol-related outcomes. Two published measures of PBS were used across studies: the Protective Behavioral Strategies Survey (PBSS) and the Strategy Questionnaire (SQ). Across three studies, we demonstrate that when measured using a contingent frequency response scale, PBS measures relate negatively to alcohol-related outcomes in a theoretically consistent manner; however, when PBS measures were measured on an absolute frequency response scale, they were nonsignificantly or positively related to alcohol-related outcomes. We discuss the implications of these findings for the assessment of PBS. PMID- 23438244 TI - Influences of mood variability, negative moods, and depression on adolescent cigarette smoking. AB - Understanding the emotional risk factors for cigarette smoking in adolescence can greatly inform prevention efforts. The current study examined prospective relationships between 3 affective dimensions--negative mood variability, overall negative mood, and depression---affect-related smoking motives, and future smoking patterns among adolescents. The current study expands on prior research by using real-time methods to assess mood and by focusing on a key developmental transition in smoking behavior: the progression from experimentation or low level, infrequent use to higher use. Ninth- and 10th-grade students (N = 461; 55% girls) provided data on cigarette use at a baseline and follow-up 15-month wave, and also provided ecological momentary assessments of negative moods via palmtop computers for 1 week at each wave. Negative mood was examined via the means of negative mood reports at each wave, and mood variability was examined via the intraindividual standard deviations of negative mood reports at each wave. Depressive symptoms and smoking motives were also assessed. Findings supported a complex self-medication model of smoking escalation in adolescence whereby mood smoking relationships differed by affect dimension and gender. For girls, greater negative mood variability at baseline significantly predicted rapid escalation in smoking over time, whereas depressive symptoms and overall negative mood were unrelated to girls' smoking patterns. In contrast, overall negative mood significantly predicted boys' smoking escalation among those with affect-related motives for smoking. Results thus suggest that inconsistent mood-smoking relations in past work may be driven by the complex interrelationships among affect vulnerabilities, gender, and smoking patterns. PMID- 23438245 TI - Alcohol cues, approach bias, and inhibitory control: applying a dual process model of addiction to alcohol sensitivity. AB - Low sensitivity to the acute effects of alcohol is a risk factor for heavy drinking and related problems. However, little research has tested process explanations for such effects. The current study tested the hypothesis that low sensitivity is associated with automatic approach biases for alcohol cues, coupled with deficits inhibiting responses in the presence of such cues. Eighty five participants varying in alcohol sensitivity completed an Alcohol-Approach Avoidance Task and a Cued Go/No-Go Task while event-related potentials were recorded. Low sensitivity (LS) individuals showed evidence of automatic approach tendencies toward alcohol cues in both tasks, and experienced deficits inhibiting prepotent responses cued by alcohol images. Additionally, the event-related potential data indicated that LS individuals experienced more conflict when attempting to inhibit alcohol-cued responses, but not nonalcohol-cued responses, compared with their high-sensitivity counterparts. Together, these data indicate that alcohol cues elicit an approach bias among LS individuals, translating into greater difficulty inhibiting behavioral responses in the presence of such cues, a pattern generally supportive of dual process models of substance use. PMID- 23438247 TI - White and black adolescent females differ in profiles and longitudinal patterns of alcohol, cigarette, and marijuana use. AB - Emerging research suggests that white youth are more likely to show continuity of alcohol use in the year after drinking onset, compared with black youth. Little is known, however, regarding racial differences in year-to-year continuity of alcohol, cigarette, and marijuana use during adolescence, particularly among females, who are at greater risk for certain substance-related harm than males. This study used latent class/transition analysis to identify profiles of past year alcohol, cigarette, and marijuana use at ages 13-17 in a community sample of 1076 adolescent females (57% black, 43% white). Three profiles of past year substance use were identified in separate analyses by race: "no use," "alcohol only," and "polydrug use." Although similar labels describe the profiles, the probability of endorsing use of a particular substance for a given profile differed by race, precluding direct comparison. Latent transition analyses of five annual waves covering ages 13-17 indicated that an intermittent pattern of use (e.g., use in one year, but not the next) was relatively low at all ages among white girls, but among black girls, an intermittent pattern of use began to decline at age 15. Among black girls, conduct problems at age 12 predicted substance using profiles at age 13, whereas among white girls, intentions to use alcohol and cigarettes at age 12 predicted substance using profiles at age 13. Racial differences in girls' substance use profiles suggest the potential utility of culturally tailored interventions that focus on differences in risk for specific substances and relatively distinct early patterns of use. PMID- 23438246 TI - Sexual orientation differences in the relationship between victimization and hazardous drinking among women in the National Alcohol Survey. AB - This study examined relationships between past experiences of victimization (sexual abuse and physical abuse in childhood, sexual abuse and physical abuse in adulthood, and lifetime victimization) and hazardous drinking among sexual minority women compared to exclusively heterosexual women. Data were from 11,169 women responding to sexual identity and sexual behavior questions from three National Alcohol Survey waves: 2000 (n = 3,880), 2005 (n = 3,464), and 2010 (n = 3,825). A hazardous drinking index was constructed from five dichotomous variables (5+ drinking in the past year, drinking two or more drinks daily, drinking to intoxication in the past year, two or more lifetime dependence symptoms, and two or more lifetime drinking-related negative consequences). Exclusively heterosexual women were compared with three groups of sexual minority women: lesbian, bisexual, and women who identified as heterosexual but reported same-sex partners. Each of the sexual minority groups reported significantly higher rates of lifetime victimization (59.1% lesbians, 76% bisexuals, and 64.4% heterosexual women reporting same-sex partners) than exclusively heterosexual women (42.3%). Odds for hazardous drinking among sexual minority women were attenuated when measures of victimization were included in the regression models. Sexual minority groups had significantly higher odds of hazardous drinking, even after controlling for demographic and victimization variables: lesbian (ORadj = 2.0, CI = 1.1-3.9, p < .01; bisexual (ORadj = 1.8, CI = 1.0-3.3, p < .05; heterosexual with same-sex partners (ORadj = 2.7; CI = 1.7-4.3, p < .001). Higher rates of victimization likely contribute to, but do not fully explain, higher rates of hazardous drinking among sexual minority women. PMID- 23438248 TI - Parallel demand-withdraw processes in family therapy for adolescent drug abuse. AB - Isomorphism, or parallel process, occurs in family therapy when patterns of therapist-client interaction replicate problematic interaction patterns within the family. This study investigated parallel demand-withdraw processes in brief strategic family therapy (BSFT) for adolescent drug abuse, hypothesizing that therapist-demand/adolescent-withdraw interaction (TD/AW) cycles observed early in treatment would predict poor adolescent outcomes at follow-up for families who exhibited entrenched parent-demand/adolescent-withdraw interaction (PD/AW) before treatment began. Participants were 91 families who received at least four sessions of BSFT in a multisite clinical trial on adolescent drug abuse (Robbins et al., 2011). Prior to receiving therapy, families completed videotaped family interaction tasks from which trained observers coded PD/AW. Another team of raters coded TD/AW during two early BSFT sessions. The main dependent variable was the number of drug-use days that adolescents reported in timeline follow-back interviews 7 to 12 months after family therapy began. Zero-inflated Poisson regression analyses supported the main hypothesis, showing that PD/AW and TD/AW interacted to predict adolescent drug use at follow-up. For adolescents in high PD/AW families, higher levels of TD/AW predicted significant increases in drug use at follow-up, whereas for low PD/AW families, TD/AW and follow-up drug use were unrelated. Results suggest that attending to parallel demand-withdraw processes in parent-adolescent and therapist-adolescent dyads may be useful in family therapy for substance-using adolescents. PMID- 23438249 TI - Measuring cognitive distortions in pathological gambling: review and meta analyses. AB - There is broad agreement that cognitive distortions are an integral component of the development, maintenance, and treatment of pathological gambling. There is no authoritative catalog of the distortions that are observed more frequently in pathological gamblers than in others, but several instruments have been successfully developed that measure various distortions of interest, which are reviewed. All of the prominent instruments include measures of the illusion of control (perceiving more personal control over events than is warranted), and almost all include measures of gambler's fallacy (the belief that after a string of one event, such as a coin landing heads, an alternative event, such as the coin landing tails, becomes more likely). Beyond these two errors, there is scant consensus on relevant errors, and a wide variety has been studied. Meta-analyses were conducted on differences between PGs and non-PGs in scores on six published instruments that were developed to measure distortions in gamblers. All instruments reveal large effects using Hedge's g statistic, suggesting that the impact of distortions on PG is robust. Several subscales, assigned diverse names by scale authors, can be viewed as reflecting common distortions. Those judged to assess gambler's fallacy show evidence of more robust effects sizes than those that assess illusion of control. It is recommended that future research focus more specifically on the impact of particular distortions on gambling disorders. PMID- 23438251 TI - The impact of internet gambling on gambling problems: a comparison of moderate risk and problem Internet and non-Internet gamblers. AB - Numerous studies have reported higher rates of gambling problems among Internet compared with non-Internet gamblers. However, little research has examined those at risk of developing gambling problems or overall gambling involvement. This study aimed to examine differences between problem and moderate-risk gamblers among Internet and non-Internet gamblers to determine the mechanisms for how Internet gambling may contribute to gambling problems. Australian gamblers (N = 6,682) completed an online survey that included measures of gambling participation, problem gambling severity, and help seeking. Compared with non Internet gamblers, Internet gamblers were younger, engaged in a greater number of gambling activities, and were more likely to bet on sports. These differences were significantly greater for problem than moderate-risk gamblers. Non-Internet gamblers were more likely to gamble on electronic gaming machines, and a significantly higher proportion of problem gamblers participated in this gambling activity. Non-Internet gamblers were more likely to report health and psychological impacts of problem gambling and having sought help for gambling problems. Internet gamblers who experience gambling-related harms appear to represent a somewhat different group from non-Internet problem and moderate-risk gamblers. This has implications for the development of treatment and prevention programs, which are often based on research that does not cater for differences between subgroups of gamblers. PMID- 23438252 TI - Risk behaviors and drug use: a latent class analysis of heavy episodic drinking in first-year college students. AB - Examining individual characteristics may not yield an understanding of the complex array of factors that affect college student alcohol use. Utilizing a latent class analysis, the present study investigated an alcohol and drug use database of first-year college students at 89 U.S. colleges and universities (N = 21,945). These data were collected between December, 2010 and September, 2011. This study identified: (1) classes based on alcohol consumption, alcohol-related behaviors, and past-year use of illegal drugs and nonmedical use of prescriptions medications (NMUPM); (2) demographic covariates of these classes; and (3) differential social norms awareness, perceived harmfulness of illegal drugs and NMUPM, and protective strategies. Four classes were identified: (1) Low Risk Drinking/Low Prevalence Drug Use (Class 1); (2) Lower Intake Drinking/Moderate Prevalence Drug Use (Class 2); (3) Moderate Risk Drinking/Moderate Prevalence Drug Use (Class 3); and (4) High Risk Drinking/High Prevalence Drug Use (Class 4). Classes differed in self-reported typical week drinking, estimated peak blood alcohol content over the past 2 weeks, high-risk alcohol use, negative alcohol related consequences, driving under the influence or riding with drinking drivers, alcohol-related protective behaviors, and past-year substance use. Of particular interest was the identification of a latent class (Class 2) composed primarily of females with a relatively low alcohol intake, but with a high probability of past-year other substance use. This group reported negative alcohol-related consequences despite their relatively low intake. To our knowledge, this is the first latent class analysis of college student alcohol use that includes a drug use indicator and compares social norms awareness, harmfulness perceptions, and alcohol-related protective behaviors between classes. PMID- 23438250 TI - Coping styles and illicit drug use in older adults with HIV/AIDS. AB - The prevalence of HIV infection in older adults is increasing; by 2015, over half of adults living with HIV/AIDS in the United States will be over 50. This study describes the prevalence of drug use and examines psychosocial predictors of drug use in a sample of HIV-infected adults aged 50 and older. Participants were 301 HIV-positive older adults enrolled in a clinical trial of a coping intervention aimed to reduce their depressive symptoms. One-quarter used illicit drugs in the past 60 days (48% any cocaine, 48% weekly marijuana, 44% any other drugs) with an average of 36 days for marijuana and 15 days for cocaine. After controlling for demographics, self-destructive avoidance was positively associated and spiritual coping was negatively associated with drug use. These findings suggest that assessment of drug abuse should be a routine part of care for older patients in HIV clinics. Furthermore, interventions designed to increase spiritual coping and decrease self-destructive avoidance may be particularly efficacious for HIV infected older adults. PMID- 23438253 TI - Do pre-operative knee laxity values influence post-operative ones after anterior cruciate ligament reconstruction? AB - The objective of this study was to verify whether pre-reconstruction laxity condition effects post-reconstruction outcome. A total of 100 patients who underwent navigated Anterior Cruciate Ligament (ACL) reconstruction were included in the study and knee laxity analysed retrospectively. The knee was assessed in six different laxity tests before and after ACL reconstruction, namely antero posterior (AP) and internal-external (IE) at 30 degrees and 90 degrees , and varus-valgus (VV) rotations at 0 degrees and 30 degrees of flexion. For each test, the least square (LS) fitting line based on pre-operative-to-post-operative laxity value was calculated. To what degree the post-operative laxity value is explainable by the corresponding pre-operative condition was evaluated by the LS line slope. Post-operatively, for each single patient, the grade of laxity decreased at any evaluated test. The strongest influence of pre-operative-to-post operative laxity values was found during IE30 and IE90 tests. While AP30 and VV0 tests seem to be those in which the post-reconstruction laxity was barely affected by the pre-surgery condition. The analysis of the global laxity reduction confirms the previous results. Following this hypothesis, our study remarks on the importance of combined lesions to secondary restraints and the importance of fully understanding the residual laxity to optimize the surgical technique. PMID- 23438254 TI - Synthetic pyrethroid effect on blood plasma biomarker enzymes and histological changes in Catla catla. AB - Alpha-cypermethrin is an isoform of cypermethrin; it is an active pyrethroid used extensively to control a wide range of pests in agriculture and animal breeding. In this study four groups of six fish were examined. The first group served as a control in fresh water alone, with no pyrethroid. The second, third and fourth groups were exposed to alpha-cypermethrin for 4, 8 and 96 h respectively. At the end of the each exposure period, the fish were sacrificed, and the required muscle tissues were collected for histological examination. The blood was drawn with heparinized needles and processed for serum enzymatic studies. Serum enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), amylase, acid phosphatase (ACP) and gamma-glutamyl transpeptidase (GGT) were measured at 4, 8 and 96 h. AST enzyme activity was significantly increased at 4 h, whereas ALT and amylase enzyme activities were significantly reduced at all the time points. ACP enzyme activity was significantly reduced at 4 and 8 h, whereas GGT enzyme activity was significantly increased at all the time points. Hepatocyte cytoplasmic vacuolisation and degeneration, rupture of blood vessels, and necrosis was found at all time points. Congestion of blood vessels, bulging, distortion of filaments, erosion and disintegration of blood corpuscles and hyperplasia of epithelium were found in treated gills at 4, 8 and 96 h. Breakdown of muscle fibres, vacuolation and accumulation of lipids and melanin in white muscle were observed in treated fish muscle at 4, 8 and 96 h. PMID- 23438255 TI - The use of transcutaneous electrical nerve stimulation (TENS) in a major cancer center for the treatment of severe cancer-related pain and associated disability. AB - BACKGROUND: Cancer pain is difficult to treat, often requiring a multimodal approach. While medication management remains the mainstay for the treatment of cancer pain, medications are often associated with undesired side effects. Transcutaneous electrical nerve stimulation (TENS) provides a potential adjunctive method for treating cancer pain with minimal side effects. OBJECTIVE: Few studies have been performed evaluating the efficacy of TENS on cancer pain. We sought to examine the usefulness of TENS on all cancer patients and to specifically look at the use of TENS as a goal-directed therapy to improve functionality. DESIGN: Retrospective cohort study. METHODS: Since 2008, patients with chronic cancer pain and on multimodal pain regimens were trialed with TENS. Those patients who showed an improvement in pain symptoms or severity were educated about and provided with a TENS unit for use at home. Pain symptoms and scores were monitored with the visual analog scale (VAS), the numerical rating pain (NRP) scale, and Short-Form McGill Questionnaire at the start of TENS treatment and at 2 months follow-up. RESULTS: TENS proved beneficial in 69.7% of patients over the course of 2 months. In TENS responsive patients, VAS scores decreased by 9.8 on a 0-100 mm scale (P < 0.001), and NRP scores decreased by 0.8 on a 1-10 scale (P < 0.001). LIMITATIONS: Lack of placebo and lack of blinding of physician and patient. CONCLUSIONS: TENS provides a beneficial adjunct for the treatment of cancer pain, especially when utilized as a goal-directed therapy. PMID- 23438256 TI - Post-traumatic stress disorder symptoms after acute lung injury: a 2-year prospective longitudinal study. AB - BACKGROUND: Survivors of critical illnesses often have clinically significant post-traumatic stress disorder (PTSD) symptoms. This study describes the 2-year prevalence and duration of PTSD symptoms after acute lung injury (ALI), and examines patient baseline and critical illness/intensive care-related risk factors. METHOD: This prospective, longitudinal cohort study recruited patients from 13 intensive care units (ICUs) in four hospitals, with follow-up 3, 6, 12 and 24 months after ALI onset. The outcome of interest was an Impact of Events Scale - Revised (IES-R) mean score >=1.6 ('PTSD symptoms'). RESULTS: During the 2 year follow-up, 66/186 patients (35%) had PTSD symptoms, with the greatest prevalence by the 3-month follow-up. Fifty-six patients with post-ALI PTSD symptoms survived to the 24-month follow-up, and 35 (62%) of these had PTSD symptoms at the 24-month follow-up; 50% had taken psychiatric medications and 40% had seen a psychiatrist since hospital discharge. Risk/protective factors for PTSD symptoms were pre-ALI depression [hazard odds ratio (OR) 1.96, 95% confidence interval (CI) 1.06-3.64], ICU length of stay (for a doubling of days, OR 1.39, 95% CI 1.06-1.83), proportion of ICU days with sepsis (per decile, OR 1.08, 95% CI 1.00-1.16), high ICU opiate doses (mean morphine equivalent >=100 mg/day, OR 2.13, 95% CI 1.02-4.42) and proportion of ICU days on opiates (per decile, OR 0.83, 95% CI 0.74-0.94) or corticosteroids (per decile, OR 0.91, 95% CI 0.84-0.99). CONCLUSIONS: PTSD symptoms are common, long-lasting and associated with psychiatric treatment during the first 2 years after ALI. Risk factors include pre-ALI depression, durations of stay and sepsis in the ICU, and administration of high-dose opiates in the ICU. Protective factors include durations of opiate and corticosteroid administration in the ICU. PMID- 23438258 TI - Laser printing of nanoparticle toner enables digital control of micropatterned carbon nanotube growth. AB - Commercialization of materials utilizing patterned carbon nanotube (CNT) forests, such as hierarchical composite structures, dry adhesives, and contact probe arrays, will require catalyst patterning techniques that do not rely on cleanroom photolithography. We demonstrate the large scale patterning of CNT growth catalyst via adaptation of a laser-based electrostatic printing process that uses magnetic ink character recognition (MICR) toner. The MICR toner contains iron oxide nanoparticles that serve as the catalyst for CNT growth, which are printed onto a flexible polymer (polyimide) and then transferred to a rigid substrate (silicon or alumina) under heat and mechanical pressure. Then, the substrate is processed for CNT growth under an atmospheric pressure chemical vapor deposition (CVD) recipe. This process enables digital control of patterned CNT growth via the laser intensity, which controls the CNT density; and via the grayscale level, which controls the pixelation of the image into arrays of micropillars. Moreover, virtually any pattern can be designed using standard software (e.g., MS Word, AutoCAD, etc.) and printed on demand. Using a standard office printer, we realize isolated CNT microstructures as small as 140 MUm and isolated catalyst "pixels" as small as 70 MUm (one grayscale dot) and determine that individual toner microparticles result in features of approximately 5-10 MUm . We demonstrate that grayscale CNT patterns can function as dry adhesives and that large-area catalyst patterns can be printed directly onto metal foils or transferred to ceramic plates. Laser printing therefore shows promise to enable high-speed micropatterning of nanoparticle-containing thin films under ambient conditions, possibly for a wide variety of nanostructures by engineering of toners containing nanoparticles of desired composition, size, and shape. PMID- 23438257 TI - The alarmin HMGB-1 influences healing outcomes in fetal skin wounds. AB - In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar-forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age-related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high-mobility group box-1 (HMGB-1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB 1 compared with E15 keratinocytes. After injury, HMGB-1 was released to a greater extent from keratinocytes at the margin of scar-forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB-1. HMGB-1-injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular HMGB-1 levels influence the quality of healing in cutaneous wounds. PMID- 23438259 TI - Peptic ulceration, Helicobacter pylori seropositivity and chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: We have suggested that chronic inflammation of other foregut derivatives might be associated with airway inflammation and amplification of the response to inhaled stimuli such as cigarette smoke leading to chronic obstructive pulmonary disease (COPD). One of the commonest causes of chronic foregut inflammation is gastritis secondary to Helicobacter Pylori infection. We tested the hypothesis that peptic ulceration and H. Pylori seropositivity are associated with COPD independently of other shared risk factors. METHODS: We reviewed primary care medical records and performed full lung function tests on 329 miners seen over 2 years as part of a compensation scheme. We also performed H. Pylori serology in patients with varying degrees of severity of COPD compared with a matched control population. RESULTS: The prevalence of peptic ulcer disease in the groups classed as normal, chronic bronchitis, mild, moderate and severe COPD was 3.2%, 16.2%, 21.4%, 42.4% and 56.2%, respectively. There was a strong and independent relationship between the presence of peptic ulcer disease and percent of predicted forced expiratory volume in 1 s (-13.3%; 95% confidence interval: 6.7-19.9; P < 0.001) and forced expiratory volume in 1 s/forced vital capacity ratio (-5.06%; 95% confidence interval: 1.8-8.2; P < 0.001). Positive H. pylori serology was present in 54.7% of 58 patients with COPD and 23.5% of 17 controls (P = 0.026). CONCLUSIONS: Our findings suggest a relationship between peptic ulcer disease and COPD that is more that just a shared susceptibility to different environmental stimuli. PMID- 23438260 TI - President's annual state of the academy report. PMID- 23438261 TI - Carbonylation of myofibrillar proteins through the maillard pathway: effect of reducing sugars and reaction temperature. AB - Carbonylation is recognized as one of the most remarkable chemical modifications in oxidized proteins and is generally ascribed to the direct attack of free radicals to basic amino acid residues. The purpose of this work was to investigate the formation of specific carbonyls, alpha-aminoadipic and gamma glutamic semialdehydes (AAS and GGS, respectively), in myofibrillar proteins (MP) through a Maillard-type pathway in the presence of reducing sugars. The present study confirmed the concurrent formation of protein carbonyls and advanced glycation end-products (AGEs) during incubation (80 degrees C/48 h) of MP (4 mg/mL) in the presence of reducing sugars (0.5 M). Copper irons (10 MUM) were found to promote the formation of protein carbonyls, and a specific inhibitor of the Maillard reaction (0.02 M pyridoxamine) blocked the carbonylation process which emphasize the occurrence of a Maillard-type pathway. The Maillard-mediated carbonylation occurred in a range of reducing sugars (0.02-0.5 M) and reaction temperatures (4-110 degrees C) compatible with food systems. Upcoming studies on this topic may contribute further to shed light on the complex interactions between protein oxidation and the Maillard reaction and the impact of the protein damage on food quality and human health. PMID- 23438262 TI - Bolus fluid therapy and sodium homeostasis in paediatric gastroenteritis. AB - AIM: The study aims to assess the risk of developing hyponatraemia when large volume bolus fluid rehydration therapy is administered. METHODS: We conducted a prospective randomised study in a tertiary-care centre emergency department. Participants included children with gastroenteritis and dehydration requiring intravenous rehydration. They were randomised to receive 60 mL/kg (large) or 20 mL/kg (standard) 0.9% saline bolus followed by maintenance 0.9% saline for 3 h. Biochemical tests were performed at baseline and 4 h. The primary outcome measure was the development of hyponatraemia at 4 h. Secondary outcome measures were (i) change in sodium relative to baseline value; (ii) magnitude of decrease among those who experienced a decrease; (iii) risk of hypernatraemia; (iv) correlations between urine parameters and hyponatraemia; and (v) fluid overload. RESULTS: Eighty-four of 224 (38%) participants were hyponatraemic at baseline. At 4 h, 22% (48/217) had a dysnatraemia, and similar numbers of children were hyponatraemic in both groups: large (23% (26/112)) versus standard (21% (22/105)) (P = 0.69). Among initially hyponatraemic children, 63% (30/48) who received large-volume rehydration and 44% (15/34) of those administered standard rehydration were isonatraemic at 4 h (P = 0.10). Overall, children who received 60 mL/kg experienced a larger mean increase (1.6 +/- 2.4 mEq/L vs. 0.9 +/- 2.2 mEq/L; P = 0.04) and were less likely to experience a sodium decrease of >=2 mEq/L (8/112 vs. 17/105; P = 0.04) than those administered 20 mL/kg. CONCLUSIONS: Large-volume bolus rehydration therapy with 0.9% saline is safe. It does not promote the development of hyponatraemia over the short term, but hastens the resolution of baseline hyponatraemia. PMID- 23438263 TI - Microwave-mediated reduction of disulfide bridges with supported (tris(2 carboxyethyl)phosphine) as resin-bound reducing agent. AB - We report on the synthesis and use of a new supported reagent consisting in tris(2-carboxyethyl)phosphine (TCEP) immobilized on hydrophilic PEG based resin beads. Used in conjunction with a 5 min microwave (MW) irradiation, "supported TCEP" reduced disulfide bridges in free thiols in peptides having two or more cysteine residues. Separation of reaction products from reducing agent was easily performed by simple filtration. PMID- 23438264 TI - Designing attractive gamification features for collaborative storytelling websites. AB - Gamification design is considered as the predictor of collaborative storytelling websites' success. Although aforementioned studies have mentioned a broad range of factors that may influence gamification, they neither depicted the actual design features nor relative attractiveness among them. This study aims to identify attractive gamification features for collaborative storytelling websites. We first constructed a hierarchical system structure of gamification design of collaborative storytelling websites and conducted a focus group interview with eighteen frequent users to identify 35gamification features. After that, this study determined the relative attractiveness of these gamification features by administrating an online survey to 6333 collaborative storytelling websites users. The results indicated that the top 10 most attractive gamification features could account for more than 50% of attractiveness among these 35 gamification features. The feature of unpredictable time pressure is important to website users, yet not revealed in previous relevant studies. Implications of the findings were discussed. PMID- 23438265 TI - Prevalence and patterns of sexting among ethnic minority urban high school students. AB - Although sexting among U.S. youth has received much popular media attention, there are only limited data on its prevalence among ethnic minority youth. This study, therefore, specifically examined the prevalence and patterns of sexting (sending and/or receiving a nude or semi-nude picture/video or a sexual text-only message) among a sample of black and Hispanic youth. Data from 1,034 tenth graders from a large, urban school district in southeast Texas were used to calculate the prevalence of sexting by gender-race/ethnicity. Overlap among sexting behaviors was also examined. Electronic surveys were administered via an audio-computer-assisted self-interview on laptop computers. Prevalence estimates were obtained, and chi-square analyses were conducted to compare the distribution of sexting behaviors by gender-race/ethnicity subgroups. More than 20% of students reported sending either a nude or semi-nude picture/video or a sexual text-only message (jointly referred to as a "sext"), and more than 30% reported receiving a sext. Sexts were also frequently shared with unintended recipients. Black males and females reported similar prevalence estimates for sexting behaviors. However, they were more likely than Hispanic males to participate in some sexting behaviors. Hispanic females reported the lowest estimates for sexting behaviors for all gender-race/ethnicity subgroups. Many youth who sent or received a nude or semi-nude picture/video were also likely to have sent or received sexual text-only messages. The results of this study indicate that sexting is prevalent among ethnic minority youth. However, more research is needed to understand the specific context and circumstances around which sexting occurs in this population. PMID- 23438266 TI - Children's perspectives on cyberbullying: insights based on participatory research. AB - Cyberbullying is an emerging problem among youngsters. Although the current body of knowledge about cyberbullying is expanding rapidly, it lacks a more in-depth research approach honoring adolescents' perspectives on the problem. Moreover, very few studies have focused on cyberbullying among elementary school children. The purpose of this study therefore, was to explore children's perspectives on the problem of cyberbullying. A participatory research design was used in which 28 children (aged 11-12 from four elementary schools) actively participated for 6 weeks in weekly scheduled group sessions. In these sessions, different aspects of cyberbullying were discussed using various enabling techniques. Between sessions, the children were given preparation assignments. The research revealed several ambiguities that should be addressed in interventions against cyberbullying. First, it appears difficult for all parties involved to distinguish cyberbullying from innocent pranks. Frequency and intention are key variables, but these are ambiguous in the context of cyberbullying. Second, cyberbullies may have very different motives, not all of which have to do with their relationship with the victim. Third, the expectations children have of the way their parents or teachers will react to incidents of cyberbullying are an obstacle for seeking help. Children are particularly afraid of overreaction and the subsequent loss of their Internet privileges. These results confirm earlier insights from research on cyberbullying, and examine the ambiguities in more detail. In addition, the research demonstrates the usefulness of participatory research to investigate cyberbullying among younger children and demonstrates that the research led to mutual learning. PMID- 23438267 TI - Personality profiles associated with different motivations for playing World of Warcraft. AB - Gamers play massively multiplayer online role-playing games (MMORPGs) for a variety of reasons. For example, some gamers play primarily as a form of socialization, whereas others play to gain a sense of achievement. Past studies have shown that these motives are associated with individual differences such as gender and number of years spent playing online games. What other individual differences might affect why people play MMORPGs? Personality is known to be associated with in-game behaviors, raising the possibility of link between personality and gaming motives. The present study examines the relationship between gamers' Big Five personality traits and their motivations for playing World of Warcraft. Results reveal several links between a player's personality and gaming motivations. For instance, individuals playing to socialize tend to be high on extraversion, agreeableness, neuroticism, and openness, whereas individuals playing to gain a sense of achievement tend to be high on extraversion and neuroticism, but low on agreeableness and conscientiousness. Findings are discussed with respect to previous research on links between personality and motives in other MMORPGs and in terms of how and why the connections between personality and motives may differ across online and offline contexts. PMID- 23438268 TI - The influence of social networking photos on social norms and sexual health behaviors. AB - Two studies tested whether online social networking technologies influence health behavioral social norms, and in turn, personal health behavioral intentions. In Study 1, experimental participants browsed peers' Facebook photos on a college network with a low prevalence of sexually suggestive content. Participants estimated the percentage of their peers who have sex without condoms, and rated their own future intentions to use condoms. Experimental participants, compared to controls who did not view photos, estimated that a larger percentage of their peers use condoms, and indicated a greater intention to use condoms themselves in the future. In Study 2, participants were randomly assigned to view sexually suggestive or nonsexually suggestive Facebook photos, and responded to sexual risk behavioral questions. Compared to participants viewing nonsuggestive photos, those who viewed sexually suggestive Facebook photos estimated that a larger percentage of their peers have unprotected sexual intercourse and sex with strangers and were more likely to report that they themselves would engage in these behaviors. Thus, online social networks can influence perceptions of the peer prevalence of sexual risk behaviors, and can influence users' own intentions with regard to such behaviors. These studies suggest the potential power of social networks to affect health behaviors by altering perceptions of peer norms. PMID- 23438269 TI - Serum concentrations of antibiotics during severe invasive surgery such as esophagectomy for esophageal cancer. AB - This study was performed to confirm the antibiotic regimen during a severe invasive surgery, such as esophagectomy, with a long procedure and a large amount of normal volumes of infusion. Ten patients with esophageal cancer were enrolled in this study, and cefmetazole sodium concentrations in serum were measured during esophagectomy. The ranges of minimum inhibitory concentrations for 90% of isolates of cefmetazole sodium for microorganisms in our institutions for 8 years were investigated. The maximum concentration was 83.9 MUg/mL just after the completion of infusion, and its half-life was 1.5 hours. Serum concentration of cefmetazole sodium was kept above 16 MUg/mL for 4 hours during esophagectomy. It was kept above 32 MUg/mL for 2.5 hours after injection. There are almost no differences in the pharmacokinetics of cefmetazole sodium between common use and during esophagectomy. In addition, additive infusion of antibiotics 4 hours after the first infusion was recommended during esophagectomy. PMID- 23438270 TI - Evaluation of the BISAP score in predicting severity and prognoses of acute pancreatitis in Chinese patients. AB - The present study was to evaluate the accuracy of bedside index for severity in acute pancreatitis (BISAP) in predicting the severity and prognoses of acute pancreatitis (AP) in Chinese patients. Clinical data for 497 patients with AP were analyzed retrospectively to compare BISAP with acute physiology and chronic health evaluation II, Ranson, and computed tomography severity index scores in predicting the severity of AP and the occurrence of pancreatic necrosis, mortality, and organ failure in patients with severe AP (SAP) using the area under the receiver-operating characteristic curve. Of the 497 patients, 396 had mild AP and 101 had SAP. There were significant correlations between the scores of any two systems. BISAP performed similarly to other scoring systems in predicting SAP, as well as pancreatic necrosis, mortality, and organ failure in SAP patients, in terms of the area under the receiver-operating characteristic curve. BISAP score is valuable in predicting the severity of AP and prognoses of SAP in Chinese patients. PMID- 23438271 TI - Diagnostic value of open biopsy for malignant T-cell lymphoma of the liver. AB - A 62-year-old man was referred to our hospital because of pain in the right upper quadrant. Laboratory tests revealed normal levels of tumor markers. Abdominal ultrasonography showed a hypoechoic mass of approximately 9 cm in diameter in the right lobe of the liver. Computed tomography revealed a low-density mass with peripheral enhancement in the posterior segment of the right lobe. Magnetic resonance imaging showed a low-intensity mass on T(1)-weighted images and a high intensity mass on T(2)-weighted images. Abdominal angiography showed enhanced staining only at the periphery of the tumor. An open biopsy was performed and intraoperative examination of frozen sections indicated malignant lymphoma. The histopathologic diagnosis was malignant T-cell lymphoma. After combined chemotherapy, the tumor shrank to 4 cm in diameter. To our knowledge, only 15 cases of malignant T-cell lymphoma have been reported previously. Diagnosis is particularly challenging because this type of tumor has no distinctive imaging characteristics or signs or symptoms. This case emphasizes the need to include malignant T-cell lymphoma in the differential diagnosis and demonstrates the importance of open biopsy in patients with a suspected liver tumor. PMID- 23438272 TI - Giant hepatic hemangioma presenting as gastric outlet obstruction. AB - Hemangioma, a most frequently encountered primary benign tumor of the liver, is generally determined incidentally during the course of radiologic tests for other reasons. Most lesions are less than 3 cm and a significant proportion of patients are asymptomatic, although the size and location of the lesion in some patients may be associated with the onset of symptoms. Pressure on the stomach and duodenum of giant hemagiomas developing in the left lobe of the liver, in particular, may result in the development of abdominal pain, nausea, vomiting, and feeling bloated, which are characteristic of a gastric outlet obstruction. A 42-year-old man presented with findings of gastric outlet obstruction and weight loss as a result of a giant hepatic hemangioma. PMID- 23438273 TI - Surgical site infection and validity of staged surgical procedure in emergent/urgent surgery for ulcerative colitis. AB - Although restorative proctocolectomy is recognized as a standard procedure for ulcerative colitis, infectious complications after surgery cannot be disregarded. The aim of this study was to define predictors of surgical site infection (SSI) in urgent/emergent surgery for ulcerative colitis. We performed prospective SSI surveillance for 90 consecutive patients. Possible risk factors were analyzed by logistic regression analyses. Incidences of incisional SSI (i-SSI) and organ/space SSI were 31.1% and 6.9%, respectively, and increased significantly with higher wound class (P < 0.01). Multivariate analysis showed wound class >=3 as an independent risk factor for i-SSI. In univariate analysis, although the mucous fistula procedure was a risk factor for i-SSI (odds ratio, 3.45; P < 0.01), Hartmann procedure also represented a risk factor for o-SSI (odds ratio, 12.8; P < 0.01). Urgent restorative proctocolectomy for patients without high wound class and emergent total colectomy with mucous fistula for patients with high wound class appear to represent feasible options. PMID- 23438274 TI - The effects of hyperbaric oxygen therapy on experimental colon anastomosis after preoperative chemoradiotherapy. AB - The aim of the present study was to investigate the effect of hyperbaric oxygen therapy (HBOT) on colon anastomosis after chemoradiotherapy (CRT). Sixty female Wistar-Albino rats were divided into 5 groups and underwent left colon resection and end-to-end anastomosis. CRT simulation was performed on 2 sham groups before the anastomosis, and 1 of these groups was administered additional postoperative HBOT. Two groups were administered CRT before the anastomosis, and 1 of them received additional postoperative HBOT. On postoperative day 5, all groups underwent relaparotomy; burst pressure was measured and samples were obtained for histopathologic and biochemical analysis. There was a significant weight loss in the CRT groups and postoperative HBOT had an improving effect. Significantly decreased burst pressure values increased up to the levels of the controls after HBOT. Hydroxyproline levels were elevated in all groups compared to the control group. Hydroxyproline levels decreased with HBOT after CRT. No significant difference was observed between the groups regarding fibrosis formation at the anastomosis site. However, regression was observed in fibrosis in the group receiving HBOT after CRT. Preoperative CRT affected anastomosis and wound healing unfavorably. These unfavorable effects were alleviated by postoperative HBOT. HBOT improved the mechanical and biochemical parameters of colon anastomosis in rats. PMID- 23438275 TI - Fournier gangrene as a manifestation of undiagnosed metastatic perforated colorectal cancer. AB - Abstract Fournier gangrene is a necrotizing soft tissue infection involving the perineum. We present a case of Fournier gangrene as the clinical presentation of perforated metastatic rectal cancer. The patient is a 78-year-old man in a nursing home who presented to our institution with necrosis and ischemia of the scrotum. After wide debridement of necrotic tissue and bilateral orchiectomy, computed tomography was carried out to investigate abnormal findings seen on his chest X-ray, which revealed multiple pulmonary metastases as well as a mass highly suspicious for a perforated rectal mass. Once stable, a diverting colostomy and biopsies of the rectal mass were performed, confirming the presence of a metastatic, poorly differentiated rectal adenocarcinoma. Albeit an unusual etiology of Fournier gangrene, this case highlights the rare but important causes of this deadly condition and teaches us to be cognizant of the variations in the presentation of colorectal cancer. PMID- 23438276 TI - Colorectal cancer with multiple metachronous metastasis achieving complete remission 14 years after surgical resection: report of a case. AB - A 63-year-old man underwent a colectomy for sigmoid colon cancer in 1997. The upper lobe of his left lung and his left adrenal gland were resected because of metachronous metastases, 7 and 10 years after the initial surgery, respectively. Recurrence of metastases to the middle lobe of the right lung and left adrenal gland were sequentially detected in 2007, and a multimodal therapy, consisting of the combination of radiotherapy and chemotherapy, was conducted since 2007. The chemotherapy included drugs such as FOLFOX, FOLFIRI, bevacizumab, capecitabine, and cetuximab. In 2011, the complete response of all metastatic lesions could be achieved, and no recurrence was detected for more than 1 year. In spite of repeated recurrences, by the combination of surgical resection, chemotherapy, and radiotherapy, the complete response could be achieved 14 years after the initial surgical resection, which can be attributed to the development of new treatment modalities and new agents for colorectal cancer. PMID- 23438277 TI - Management of postoperative complications following splenectomy. AB - Complications of post-splenectomy, especially intra-abdominal hemorrhage can be fatal, with delayed or inadequate treatment having a high mortality rate. The objective of this study was to investigate the cause, prompt diagnosis, and outcome of the fatal complications after splenectomy with a focus on early diagnosis and management of hemorrhage after splenectomy. The medical files of patients who underwent splenectomy between January 1990 and March 2011 were reviewed retrospectively. The cause, characteristics, management, and outcome in patients with post-splenectomy hemorrhage were analyzed. Fourteen of 604 patients (1.19%) undergoing splenectomy had intraperitoneal hemorrhage: reoperation was performed in 13 patients, and 3 patients died after reoperation, giving the hospital a mortality rate of 21.43%; whereas, 590 of 604 patients (98%) had no hemorrhage following splenectomy, and the mortality rate (0.34%) in this group was significantly lower (P < 0.001). The complications following splenectomy, including pneumonia pancreatitis, gastric fistula, gastric flatulence, and thrombocytosis, in patients with postoperative hemorrhage were significantly higher than those without hemorrhage (P < 0.001). According to the reasons for splenectomy, 14 patients with post-splenectomy hemorrhage were grouped into two groups: splenic trauma (n = 9, group I) and portal hypertension (n = 5, group II). The median interval between splenectomy and diagnosis of hemorrhage was 15.5 hours (range, 7.25-19.5 hours). No differences were found between groups I and II in terms of incidence of postoperative hemorrhage, time of hemorrhage after splenectomy, volume of hemorrhage, and mortality of hemorrhage, except transfusion. Intra-abdominal hemorrhage after splenectomy is associated with higher hospital mortality rate and complications. Early massive intraperitoneal hemorrhage is often preceded by earlier sentinel bleeding; careful clinical inquiry and ultrasonography are the mainstays of early diagnosis. PMID- 23438278 TI - Minimal invasive treatment of abdominal multiorgan echinococcosis. AB - Hydatid disease is a severe zoonosis, exerting a high economic and social impact through its numerous complications, leading to disabilities, even death. Because of technical developments, especially the increasing experience of surgeons, laparoscopic surgery has been extended so that it can be successfully applied to abdominal hydatid cysts. We present the case of a 16-year-old patient who came to our clinic for upper abdominal pain. The abdominal ultrasonography and computed tomography (CT) showed 2 cyst-like tumors, with hydatid features: one affecting the eighth liver segment and the other located at the upper pole of the spleen. We performed the surgical intervention using a laparoscopic approach, with an uneventful postoperative follow-up and the patient was discharged home on postoperative day 4. The postoperative images at 6 and 12 months showed a decrease in size of the remnant cystic cavities. PMID- 23438279 TI - Epidermal cyst of the breast treated by vacuum-assisted biopsy. AB - A 38-year-old woman presented for evaluation of a firm mass (measuring 20 * 20 mm) in the upper outer quadrant of her left breast. On the basis of the clinical and radiologic findings, we diagnosed a benign breast tumor and scheduled removal by a hand-held vacuum-assisted biopsy device (VABD) under ultrasonographic guidance. Because the first specimen removed from the tumor was white, flaky, and waxy material, we strongly suspected that the lesion was an epidermal cyst. We continued VABD treatment until the tumor was invisible on real-time ultrasonography. Histologic examination demonstrated that the tumor was composed of mature stratified squamous epithelium and laminated layers of keratin, findings consistent with a diagnosis of epidermal cyst. These cysts rarely occur in the breast and are sometimes difficult to distinguish from breast cancer. To our knowledge, this is the first report of an epidermal cyst treated by VABD. PMID- 23438280 TI - Vignette thyroid surgery: a glimpse into its history. AB - At present, physicians and surgeons treating thyroid disorders can rely on highly accurate and precise investigations, modern equipment, and state of the art operating theater to achieve optimum results; however, this was not the case at the beginning of the treatment of thyroid diseases centuries ago. We present a short history of the treatment and understanding of thyroid diseases in the past few decades. Also we present the contributions of the important surgeons who tried to perfect the treatment of thyroid diseases, including surgery, thus making modern day management easier. PMID- 23438281 TI - Risk factors effecting mortality in acute mesenteric ischemia and mortality rates: a single center experience. AB - The objective of this study is to discuss the effective factors on morbidity and mortality in patients who were operated on for acute mesenteric ischemia. Between 2006 and 2011, 95 patients, who underwent emergent surgery for acute mesenteric ischemia, were analyzed retrospectively. The study group consisted of 56 men (58.9%) and 39 women (41.1%), with an average age of 68.4 +/- 14.4 years. Elapsed time between the onset of the symptoms and the surgical operation was less than 24 hours in 47 (49.5%) cases, and more than 24 hours in 48 cases (50.5%) (P < 0.001). Although all of the patients had intestinal necroses, colon involvement was seen in 38 patients, and mortality was higher in this group of patients (P < 0.001). Mortality rate was 42.1%. This was higher in older patients, those with increased leukocyte levels, increased elapsed time to laparotomy, and when the colon was involved. PMID- 23438282 TI - Effects of natural and recombinant hirudin on VEGF expression and random skin flap survival in a venous congested rat model. AB - We aim to investigate the effects of locally injected natural and recombinant hirudin on vascular endothelial growth factor (VEGF) expression and flap survival in venous congested skin flaps using a rat model. A dorsal random skin flap (10 * 3 cm) was prepared on each of 30 Wistar rats to establish a venous congested model. The rats were randomly divided into 2 treatment groups [receiving subcutaneous injection of either natural hirudin (6 U) or recombinant hirudin (6 U)] and a control group, which received subcutaneous injection of physiologic saline. After treatment, skin flap survival rates were calculated. VEGF messenger RNA levels and VEGF-positive vessel density as a marker for VEGF levels were measured in the flaps during and after treatment. The skin flap VEGF messenger RNA levels increased in the natural hirudin-treated group. The VEGF-positive vessel density was increased in all 3 groups. Statistically significant increases of VEGF levels were observed in the natural and recombinant hirudin-treated groups compared with the control group (P < 0.05). The skin flap survival rates were improved in both hirudin treated groups. Natural and recombinant hirudin can increase VEGF expression in random skin flaps, which can potentially improve random skin flap survival in rats through angio genic mechanisms. Our results showed that hirudin treatment led to an increase in VEGF expression in the congested skin flaps. Natural hirudin demonstrated more pronounced effects than recombinant hirudin. Further studies are needed to understand the specific mechanisms. PMID- 23438283 TI - Needleless closed system does not reduce central venous catheter-related bloodstream infection: a retrospective study. AB - The needleless closed system (NCS) has been disseminated in several clinical fields to prevent central venous catheter-related bloodstream infection (CVC RBSI), in place of the conventional Luer cap system (LCS). The purpose of this study is to examine whether NCS is really superior to conventional LCS for prevention of CVC-RBSI. Between May 2002 and December 2008, 1767 patients received CVC in our department. The time interval from insertion to development of CVC-RBSI was compared retrospectively between selected patients who were treated using the conventional LCS (group 1, n = 89, before June 2006) and the NCS (group 2, n = 406, June 2006 and after). Kaplan-Meier analysis revealed no significant difference in the time interval from insertion to development of CVC RBSI between the two groups. NCS does not reduce CVC-RBSI in adult colorectal cancer patients who undergo CVC insertion. PMID- 23438284 TI - Goals for 2013. PMID- 23438285 TI - Histological variations of the glenoid labrum in dogs. AB - As the structure and clinical meaning of the canine glenoid labrum are repeatedly disputed up to now, an anatomical histological description of the structure and its varieties in older dogs is carried out. In this study, 20 shoulder joints are histologically and immunohistologically examined. The glenoid labrum (GL) is composed of up to three different zones: a transition zone composed of fibre cartilage with collagen fibres arranged like a fishnet-like pattern, a zone of circularly leading fibre bundles and a meniscoid fold with synovial coverage. A variable recess exists between the GL and the joint surface. PMID- 23438286 TI - Reply: To PMID 22775341. PMID- 23438287 TI - Role of statins in Alzheimer's disease: a retrospective meta-analysis for commonly investigated clinical parameters in RCTs. AB - This review was conducted to assess the role of statins in the treatment of Alzheimer's disease (AD). We conducted meta-analysis using the randomised controlled trials (RCTs) conducted in patients who suffered from Alzheimer's disease, by conducting searches for RCTs in MEDLINE, EMBASE and Cochrane (up to 2012). An overall of five studies were included and analysed. The evaluation was done for some commonly evaluated clinical parameters like Clinical Global Impression of Change (CGIC), Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale (ADAS-CoG). Statistical evaluation was done as per method described by Neyeloff et al. and forest plots were plotted for each evaluated parameter. MMSE score showed a significant difference in favour of statins. ADAS-CoG and CGIC did not show a significant advantage for statins in comparison to placebo. Highly heterogeneous distribution was seen for MMSE score. Further trials need to be conducted to arrive at more robust results. PMID- 23438288 TI - Real-time microbial adaptive diversification in soil. AB - Bacteria undergo adaptive diversification over a matter of days in test tubes, but the relevance to natural populations remains unclear. Here, we report real time adaptive diversification of the bacterium Pseudomonas fluorescens in its natural environment, soil. Crucially, adaptive diversification was much greater in the absence of the established natural microbial community, suggesting that resident diversity is likely to inhibit, rather than promote, adaptive radiations in natural environments. Rapid diversification is therefore likely to play an important role in the population and community dynamics of microbes in environments where resident communities are perturbed, such as by agriculture, pollution and antibiotics. PMID- 23438290 TI - Working conditions at hospital food service and the development of venous disease of lower limbs. AB - The present study assesses some factors that may influence the development of lower limb venous disease in workers of a hospital food service unit. An Ergonomic analysis of work was carried out at a hospital located in the south of Brazil. As for data collection, the following were used: interviews and body mass index assessment; specific clinical examination to diagnose venous disease, water displacement volumetry of the lower limbs. The activities performed at the workplace were followed by direct observation with image registration, use of pedometers, stopwatches, decibel meter, and digital thermo-hygrometer. It was observed different degrees of venous disease in 78% of the cases investigated. The volumetric variation of the lower limbs was 5.13%, showing the presence of edema. Working in hospital food service is associated with circulatory disorders of lower limbs, such as edema and venous disease. The following risk factors were identified: standing activities at work during a long period of time, high temperature, and humidity and carrying heavy weights. PMID- 23438289 TI - Effect of estrogen on molecular and functional characteristics of the rodent vaginal muscularis. AB - INTRODUCTION: Vaginal atrophy is a consequence of menopause; however, little is known concerning the effect of a decrease in systemic estrogen on vaginal smooth muscle structure and function. As the incidence of pelvic floor disorders increases with age, it is important to determine if estrogen regulates the molecular composition and contractility of the vaginal muscularis. AIM: The goal of this study was to determine the effect of estrogen on molecular and functional characteristics of the vaginal muscularis utilizing a rodent model of surgical menopause. METHODS: Three- to 4-month old Sprague-Dawley rats underwent sham laparotomy (Sham, N = 18) or ovariectomy (Ovx, N = 39). Two weeks following surgery, animals received a subcutaneous osmotic pump containing vehicle (Sham, Ovx) or 17beta-estradiol (Ovx). Animals were euthanized 1 week later, and the proximal vagina was collected for analysis of contractile protein expression and in vitro studies of contractility. Measurements were analyzed using a one-way analysis of variance followed by Tukey's post hoc analysis (alpha = 0.05). MAIN OUTCOME MEASURES: Protein and mRNA transcript expression levels of contractile proteins, in vitro measurements of vaginal contractility. RESULTS: Ovariectomy decreased the expression of carboxyl-terminal myosin heavy chain isoform (SM1) and h-caldesmon and reduced the amplitude of contraction of the vaginal muscularis in response to KCl. Estradiol replacement reversed these changes. No differences were detected in the % vaginal muscularis, mRNA transcript expression of amino-terminal MHC isoforms, l-caldesmon expression, and maximal velocity of shortening. CONCLUSION: Systemic estrogen replacement restores functional and molecular characteristics of the vaginal muscularis of ovariectomized rats. Our results indicate that menopause is associated with changes in the vaginal muscularis, which may contribute to the increased incidence of pelvic floor disorders with age. PMID- 23438291 TI - Serum fetuin-A levels, QT dispersion and P dispersion in dialysis patients. AB - BACKGROUND: This study aims to find association of fetuin-A with serum lipids, QT dispersion (QT-d), and P dispersion (P-d) in dialysis patients. METHODS: Fetuin-A serum levels were assessed in 50 dialysis patients. RESULTS: Serum fetuin-A levels were significantly associated with QT-d (r = 0.289, p = 0.044), P-d (r = 0.39, p = 0.005), total cholesterol (r = 0.526, p = 0.000), low-density lipoprotein cholesterol (LDL-C) (r = 0.456, p = 0.00), triglyceride (r = 0.360, p = 0.011) and highly sensitive C-reactive protein (hsCRP) (r = -0.347, p = 0.030). In step-wise multiple regression analysis including being on hemodialysis (HD), presence of diabetes mellitus (DM), total cholesterol, LDL-C, triglycerides, hsCRP, only total cholesterol (b = 0.419, p = 0.03), and hsCRP (b = -0.316, p = 0.03) proved to be independent predictors of serum fetuin-A levels. QT-d showed a linear correlation with total cholesterol (r = 0.309, p = 0.029), LDL-C (r = 0.304, p = 0.038), P-d (r = 0.390, p = 0.005), and fetuin-A levels (r = 0.289, p = 0.044). In multiple regression analyses, the independent predictor of QT-d was being on HD (b = -0.417, p = 0.004), whereas total cholesterol, LDL-C, presence of DM, serum fetuin-A levels, and P-d had no independent effect on corrected QT (QT-C). Being on HD and age were important determinants of P-d whereas presence of DM, total cholesterol, LDL-C, fetuin-A, and QT-d had no independent effect on P-d. CONCLUSIONS: Lower fetuin-A levels are associated with high hsCRP and low cholesterol levels in dialysis patients. PMID- 23438292 TI - Interactions between multiwall carbon nanotubes and poly(diallyl dimethylammonium) chloride: effect of the presence of a surfactant. AB - The interactions between multiwall carbon nanotubes (MWCNTs) and poly(diallyl dimethylammonium) chloride (PDDA) have been studied in the presence of different ionic and nonionic surfactants, such as sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB), Tween 20, 40, 60, and 80, and Triton X 100. On the basis of scanning electron microscopy (SEM) results, the MWCNT/PDDA sample treated with Triton X-100 has been observed to show good dispersion of nanotubes. This is due to the pi-pi stacking between the benzene ring of Triton X 100 and the hexagonal carbon rings of nanotubes and better coating of PDDA on MWCNTs, as is confirmed by the Raman studies. Energy dispersive X-ray (EDX) spectroscopic data shows the presence of higher oxygen content in the MWCNTs/PDDA/Triton X-100 sample. The maximum upshift in the C1s peak position and down-shift in the N1s peak position for the MWCNTs/PDDA/Triton X-100 sample has been observed from X-ray photoelectron spectroscopy (XPS) results and is due to the intermolecular charge transfer from carbon in MWCNTs to nitrogen in PDDA. The presence and nature of a surfactant in the MWCNTs/PDDA system has been found to affect their interactions. The above results suggest that the MWCNTs/PDDA/Triton X-100 system is suitable as a metal-free electrocatalyst for the oxygen reduction reaction (ORR) in fuel cells. PMID- 23438294 TI - When big brother is watching: goal orientation shapes reactions to electronic monitoring during online training. AB - Web-based training is frequently used by organizations as a convenient and low cost way to teach employees new knowledge and skills. As web-based training is typically unproctored, employees may be held accountable to the organization by computer software that monitors their behaviors. The current study examines how the introduction of electronic performance monitoring may provoke negative emotional reactions and decrease learning among certain types of e-learners. Through motivated action theory and trait activation theory, we examine the role of performance goal orientation when e-learners are exposed to asynchronous and synchronous monitoring. We show that some e-learners are more susceptible than others to evaluation apprehension when they perceive their activities are being monitored electronically. Specifically, e-learners higher in avoid performance goal orientation exhibited increased evaluation apprehension if they believed asynchronous monitoring was present, and they showed decreased skill attainment as a result. E-learners higher on prove performance goal orientation showed greater evaluation apprehension if they believed real-time monitoring was occurring, resulting in decreased skill attainment. PMID- 23438293 TI - Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt sensitive rat. AB - 20-HETE (20-hydroxyeicosatetraenoic acid), a vasoconstrictor metabolite of arachidonic acid formed through the action of CYP4A (cytochrome P450-4A) in vascular smooth muscle cells, has been implicated in the development of hypertension and vascular dysfunction. There have been a number of reports in human subjects demonstrating an association between elevated urinary excretion of 20-HETE and hypertension, as well as increased 20-HETE production and vascular dysfunction. The Dahl SS (salt-sensitive) rat is a genetic model of salt sensitive hypertension that exhibits vascular dysfunction, even when maintained on a normal-salt diet and before the development of hypertension. This mini review highlights our current research on the role of CYP4A and 20-HETE in the vascular dysfunction of the Dahl SS rat. In our studies, the SS rat is compared with the consomic SS-5BN rat, having chromosome 5 from the salt-resistant Brown Norway rat (carrying all CYP4A genes) introgressed on to the SS genetic background. Our laboratory has demonstrated restoration of normal vascular function in the SS rat with inhibition of the CYP4A/20-HETE pathway, suggesting a direct role for this pathway in the vascular dysfunction in this animal model. Our studies have also shown that the SS rat has an up-regulated CYP4A/20-HETE pathway within their cerebral vasculature compared with the SS-5BN consomic rat, which causes endothelial dysfunction through the production of ROS (reactive oxygen species). Our data shows that ROS influences the expression of the CYP4A/20-HETE pathway in the SS rat in a feed-forward mechanism whereby elevated ROS stimulates production of 20-HETE. The presence of this vicious cycle offers a possible explanation for the spiralling effects of elevated 20-HETE on the development of vascular dysfunction in this animal model. PMID- 23438295 TI - Synthesis of penicillenol C1 and of a bis-azide analogue for photoaffinity labeling. AB - Two diasteroisomers of the Penicillium metabolite penicillenol C1 were synthesized for the first time by 3-acylation of an L-threonine-derived tetramic acid with enantiopure 2-methyloct-(6E)-enoic acids. The 5S,6R,9S isomer has NMR spectra and optical rotation identical with those of the natural compound. A bis azide-tagged penicillenol analogue was also synthesized for photoaffinity labeling of target proteins. The photolysis of the bis-azide in the presence of methanol as a protein-mimicking nucleophile led to reaction only of the aryl azide, while leaving the benzyl azide available for pull-downs or the attachment of fluorescent tracers. As a proof of concept, the distribution of this bis-azide tagged tetramic acid in living cells was visualized via a Staudinger ligation between the azide tag and a phosphane fluorophore. PMID- 23438296 TI - The influence of mood on the relation between proactive coping and rehabilitation outcomes. AB - The relationship between proactive coping, mood, and psychological and functional outcomes was examined in a sample of 228 older adults undergoing rehabilitation following joint replacement surgery. Proactive coping is a coping style that is goal oriented and involves approaching stressors as challenges rather than threats. It was hypothesized that older adults who use proactive coping strategies would experience improved psychological and functional outcomes following rehabilitation. Further, it was expected that this relation would be mediated by the experience of positive mood. Support for the proposed mediation model was found, whereby the experience of vigor was found to mediate the effect of proactive coping on outcomes. Theoretical and practical implications of the research findings are discussed in the context of interventions to foster proactive coping in older adults. PMID- 23438297 TI - Anaplastic astrocytomas with abundant Rosenthal fibers in elderly patients: a diagnostic pitfall of high-grade gliomas. AB - To investigate the clinicopathological features of anaplastic astrocytoma (AA) with abundant Rosenthal fibers (RFs), this study assessed four cases of AA (elderly patients; age >= 70 years). Histologically, these tumors were composed of diffusely infiltrating astrocytomas with brightly eosinophilic cytoplasmic granules or cork-screw or beaded bundles. Tumor cells showed pleomorphism, bizarre giant cells, and mitotic activity, but no necrosis. The cytoplasmic granules showed negativity on PAS staining. Immunohistochemically, the tumor cells with cytoplasmic granular cells showed a positive reaction for GFAP. The cytoplasmic eosinophilic granules or bundles were positive for alphaB-crystallin, ubiquitin and HSP27. In addition, tumor cells showed strong cytoplasmic positivity for isocitrate dehydrogenase 1 (IDH1)-R132H protein in all cases. The MIB-l labeling index of these cases ranged from 7% to 10%. In cases 1 and 2, ultrastructurally, the tumor cells had electron-dense, amorphous structures in the cytoplasm and in the processes. These structures were bound to glial intermediate filaments. Based on these microscopic, immunohistochemical and ultrastructural findings, case 1 was diagnosed as AA with abundant, mixed, common type of RFs and miniature (m) RFs, and cases 2,3, and 4 were diagnosed as AA with abundant mRFs. These results indicate that the presence of RFs in astrocytic tumors does not necessarily exclude a diagnosis of high-grade astrocytoma. In addition, AAs with abundant mRFs in elderly patients should be classified as a peculiar variant of AA. PMID- 23438299 TI - MoO2-ordered mesoporous carbon nanocomposite as an anode material for lithium-ion batteries. AB - In the present work, the nanocomposite of MoO2-ordered mesoporous carbon (MoO2 OMC) was synthesized for the first time using a carbon thermal reduction route and the mesoporous carbon as the nanoreactor. The synthesized nanocomposite was characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), N2 adsorption-desorption, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) measurements. Furthermore, this nanocomposite was used as an anode material for Li-ion intercalation and exhibited large reversible capacity, high rate performance, and good cycling stability. For instance, a high reversible capacity of 689 mAh g(-1) can remain after 50 cycles at a current density of 50 mA g(-1). It is worth mentioning that the MoO2-OMC nanocomposite electrode can attain a high reversible capacity of 401 mAh g(-1) at a current density as high as 2 A g(-1). These results might be due to the intrinsic characteristics of nanocomposite, which offered a better accommodation of the strain and volume changes and a shorter path for Li-ion and electron transport, leading to the improved capacity and enhanced rate capability. PMID- 23438298 TI - G-quadruplex folds of the human telomere sequence alter the site reactivity and reaction pathway of guanine oxidation compared to duplex DNA. AB - Telomere shortening occurs during oxidative and inflammatory stress with guanine (G) as the major site of damage. In this work, a comprehensive profile of the sites of oxidation and structures of products observed from G-quadruplex and duplex structures of the human telomere sequence was studied in the G-quadruplex folds (hybrid (K(+)), basket (Na(+)), and propeller (K(+) + 50% CH3CN)) resulting from the sequence 5'-(TAGGGT)4T-3' and in an appropriate duplex containing one telomere repeat. Oxidations with four oxidant systems consisting of riboflavin photosensitization, carbonate radical generation, singlet oxygen, and the copper Fenton-like reaction were analyzed under conditions of low product conversion to determine relative reactivity. The one-electron oxidants damaged the 5'-G in G quadruplexes leading to spiroiminodihydantoin (Sp) and 2,2,4-triamino-2H-oxazol-5 one (Z) as major products as well as 8-oxo-7,8-dihydroguanine (OG) and 5 guanidinohydantoin (Gh) in low relative yields, while oxidation in the duplex context produced damage at the 5'- and middle-Gs of GGG sequences and resulted in Gh being the major product. Addition of the reductant N-acetylcysteine (NAC) to the reaction did not alter the riboflavin-mediated damage sites but decreased Z by 2-fold and increased OG by 5-fold, while not altering the hydantoin ratio. However, NAC completely quenched the CO3(*-) reactions. Singlet oxygen oxidations of the G-quadruplex showed reactivity at all Gs on the exterior faces of G quartets and furnished the product Sp, while no oxidation was observed in the duplex context under these conditions, and addition of NAC had no effect. Because a long telomere sequence would have higher-order structures of G-quadruplexes, studies were also conducted with 5'-(TAGGGT)8-T-3', and it provided oxidation profiles similar to those of the single G-quadruplex. Lastly, Cu(II)/H2O2 mediated oxidations were found to be indiscriminate in the damage patterns, and 5 carboxamido-5-formamido-2-iminohydantoin (2Ih) was found to be a major duplex product, while nearly equal yields of 2Ih and Sp were observed in G-quadruplex contexts. These findings indicate that the nature of the secondary structure of folded DNA greatly alters both the reactivity of G toward oxidative stress as well as the product outcome and suggest that recognition of damage in telomeric sequences by repair enzymes may be profoundly different from that of B-form duplex DNA. PMID- 23438300 TI - Of war and sausages: a case-directed review of infant botulism. AB - Within a 3-month period, two infants presented non-specifically to hospital and rapidly progressed developing flaccid paralysis. Both children were diagnosed with infant botulism. We briefly review these two cases and discuss the diagnostic and management issues involved with this rare childhood disease. PMID- 23438301 TI - Intraforaminal location of thoracolumbar anterior medullary arteries. AB - BACKGROUND: Transforaminal epidural steroid injection (TFESI) is a widely utilized interventional pain technique for radicular pain. Although the six o'clock position of the pedicle in the so-called "safe triangle" has been used as a target location, there have been a number of reported catastrophic complications of this procedure, including paraplegia. The mechanism of this has been attributed to the intravascular injection of steroids. The goal of this study was to examine the intraforaminal location of thoracolumbar medullary arteries which would help guide pain physicians in developing safer techniques and guidelines. METHODS: Twenty-four (24) embalmed cadavers were dissected and examined for the presence and distribution of thoracolumbar anterior medullary arteries. Access to the anterior surface of the spinal cord was made via anterior corpectomy from C2 to S5. Each medullary artery's course was determined by dissection from its origin, the anterior spinal artery, through the intervertebral foramen. The foramen was subsequently opened in the coronal plane, and the intraforaminal location of the artery, its diameter, and its relation to other foraminal structures were examined and measured. RESULTS: In the thoracolumbar foramina (T4-L2), 39 anterior medullary arteries were found, including 23 great medullary arteries (Adamkiewicz artery). One Adamkiewicz artery was found to be located in the left S2 foramen and was not included in the statistical analysis. Of the analyzed 39 anterior medullary arteries, 29 (74%) were located in the upper 1/3 of the foramen, 9 (23%) were located in the middle, and 1 (3%) artery was located in the lower 1/3. In relation to the dorsal root ganglion--ventral root complex, 21 (54%) arteries were located anterosuperiorly, 16 (41%) anteriorly, and 2 (5%) anteroinferiorly. The average intraforaminal artery diameter was 1.20 mm (0.84-1.91 mm). At thoracolumbar levels, the artery is almost always (92% +/- 15%) located anterosuperior to the nerve. At typical thoracic levels, it is less often anterosuperior (38% +/- 19%), but more often anterior to the nerve. CONCLUSIONS: At thoracolumbar levels, if needles were to encounter an artery, they are most likely to do so if placed anterosuperior to the nerve. Encountering an artery anterosuperior to the nerve is less likely at typical thoracic levels, but the likelihood is far from negligible. Pain physicians should be cognizant of this when considering optimal needle placement during transforaminal epidural steroid injections. PMID- 23438303 TI - Specific flexion-related low back pain and sitting: comparison of seated discomfort on two different chairs. AB - No study has examined the effectiveness of prescribing seating modifications according to the individual clinical presentation of people with low back pain (LBP). A dynamic, forward-inclined chair ('Back App') can reduce seated paraspinal muscle activation among pain-free participants. This study examined 21 participants whose LBP was specifically aggravated by prolonged sitting and was eased by standing. Low back discomfort (LBD) and overall body discomfort (OBD) were assessed every 15 min while participants sat for 1 h on both the dynamic, forward-inclined chair and a standard office chair. LBD increased significantly more (p = 0.005) on the standard office chair, with no significant difference (p = 0.178) in OBD between the chairs. The results demonstrate that, in a specific flexion-related subgroup of people with LBP, increased LBD during sitting can be minimised through modifying chair design. Mechanisms that minimise seated discomfort may be of relevance in LBP management, as part of a biopsychosocial management plan. PRACTITIONER SUMMARY: This study examined low back discomfort (LBD) during a typing task among people with low back pain (LBP). Sitting on a dynamic, forward-inclined chair resulted in less seated LBD than sitting on a standard office chair. Further research is required to examine the long-term effectiveness of ergonomics interventions in LBP. PMID- 23438305 TI - Microbial contamination of clinical islet transplant preparations is associated with very low risk of infection. AB - BACKGROUND: Several published studies have analyzed microbial contamination rates of islet products, ranging from 0% to 16%. However, few studies make reference to potential clinical consequences for transplant recipients and possible impact on islet survival. MATERIALS AND METHODS: The current study defines rates of microbiological contamination of islet products under current good manufacturing practice conditions in 164 patients receiving 343 transplants at a single institution. RESULTS: Nineteen (5.5%) islet preparations showed positive microbial growth with a majority (79.4%) due to Gram-positive organisms. The most frequently identified microorganism was coagulase-negative Staphylococcus (nine of 19 [47.3%]), followed by polymicrobial organisms (eight of 19 [42.1%]). No patient developed signs of clinical infection, and there were no hepatic abscesses evident on imaging by ultrasound or magnetic resonance imaging (none of 19 [0%]), despite the use of potent T-depletional induction. Finally, we could not demonstrate any negative impact of microbiological contamination on long-term islet graft survival. CONCLUSIONS: Microbiological contamination of the final islet preparation appears to have little or no effect on patients or on islet survival when appropriate antibiotics are given. However, preparation sterility should be guaranteed at all cost in order maximize patient safety and avoid potential complications in immunosuppressed patients. PMID- 23438304 TI - Routine sensor-augmented pump therapy in type 1 diabetes: the INTERPRET study. AB - BACKGROUND: Sensor-augmented pump (SAP) therapy can improve glycemic control, compared with multiple daily insulin injections or with insulin pump therapy alone, without increasing the risk of hypoglycemia. SUBJECTS AND METHODS: A 12 month observational study in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII), upon the introduction of continuous glucose monitoring (CGM), was conducted in 15 countries (in Europe and in Israel) to document the real-life use of SAP and assess which variables are associated with improvement in type 1 diabetes management. RESULTS: Data from 263 patients (38% male; mean age, 28.0 +/- 15.7 years [range, 1-69 years]; body mass index, 23.3 +/- 4.9 kg/m(2); diabetes duration, 13.9 +/- 10.7 years; CSII duration, 2.6 +/- 3 years) were collected. Baseline mean glycated hemoglobin A1c (HbA1c) was 8.1 +/- 1.4%; 82% had suboptimal HbA1c (>= 7%). The average sensor use for 12 months was 30% (range, 0-94%), and sensor use decreased with time (first 3 months, 37%; last 3 months, 27%). Factors associated with improvement in HbA1c after 12 months in patients with baseline HbA1c >= 7% were high baseline HbA1c (P<0.001), older age group (P<0.001), and more frequent sensor use (P = 0.047). Significantly less hospitalization, increased treatment satisfaction, and reduced fear of hypoglycemia were reported after 12 months of SAP. CONCLUSIONS: This is the largest and longest multicenter prospective observational study providing real-life data on SAP. These results are consistent with those of controlled trials showing the effectiveness of CGM in pump users. PMID- 23438306 TI - 18beta-Glycyrrhetinic acid from licorice root impairs dendritic cells maturation and Th1 immune responses. AB - 18beta-Glycyrrhetinic acid (beta-GA) is a natural triterpenoid compound derived from licorice root. beta-GA has been demonstrated to exert antiviral and antitumor effects. However, the effects of the maturation and immunostimulatory functions of dendritic cells (DCs) remain to be clearly elucidated. In this study, we attempted to determine whether beta-GA could influence DCs surface molecule expression, antigen uptake capacity, cytokine production and capacity to induce T-cell differentiation. The DCs used in this study were derived from murine bone marrow cells, and were used as immature or lipopolysaccharide (LPS) stimulated mature DCs. The DCs were then assessed with regard to surface molecules expression, cytokine production, capacity to induce T-cell differentiation and proliferation. beta-GA was shown to significantly suppress the expression of surface molecules CD80, CD86, major histocompatibility complex (MHC) class I and MHC class II as well as the levels of interleukin-12 production in LPS-stimulated DCs. Moreover, beta-GA-treated DCs showed an impaired induction of the T helper type 1 immune response. These findings provide important understanding of the immunopharmacological functions of beta-GA and have ramifications for the development of therapeutic adjuvants for the treatment of DCs-related acute and chronic diseases. PMID- 23438308 TI - Noble gases in pure lipid membranes. AB - The mechanism of how a noble gas modifies the excitability of nerve cells and how such excitability can be recovered under hyperbaric pressure remains unclear. Here we present a calorimetric study where the melting point depression of pure lipid membranes induced by noble gases and its recovery with a hydrostatic pressure is addressed. A correlation is found between the electric polarizability (alpha) of these gases and their effect on the melting transition of the membranes. These results concur with other findings to support the idea that general anesthesia only depends on the ability of a certain atom or molecule to increase the general disorder of the membrane. PMID- 23438307 TI - Roles of chondroitin sulfate and dermatan sulfate in the formation of a lesion scar and axonal regeneration after traumatic injury of the mouse brain. AB - Dermatan sulfate (DS) is synthesized from chondroitin sulfate (CS) by epimerization of glucuronic acid of CS to yield iduronic acid. In the present study, the role of CS and DS was examined in mice that received transection of nigrostriatal dopaminergic pathway followed by injection of glycosaminoglycan degrading enzymes into the lesion site. Two weeks after injury, fibrotic and glial scars were formed around the lesion, and transected axons did not regenerate beyond the fibrotic scar. Injection of chondroitinase ABC (ChABC), which degrades both CS and DS, completely suppressed the fibrotic scar formation, reduced the glial scar, and promoted the regeneration of dopaminergic axons. Injection of the DS-degrading enzyme chondroitinase B (ChB) also yielded similar results. By contrast, injection of chondroitinase AC (ChAC), a CS-degrading enzyme, did not suppress the fibrotic and glial scar formation, but reduced CS immunoreactivity and promoted the axonal regeneration. Addition of transforming growth factor-beta1 (TGF-beta1) to a co-culture of meningeal fibroblasts and cerebral astrocytes induces a fibrotic scar-like cell cluster. The effect of TGF beta1 on cluster formation was suppressed by treatment with ChABC or ChB, but not by ChAC. TGF-beta1-induced cell cluster repelled neurites of neonatal cerebellar neurons, but addition of ChABC or ChAC suppressed the inhibitory property of clusters on neurite outgrowth. The present study is the first to demonstrate that DS and CS play different functions after brain injury: DS is involved in the lesion scar formation, and CS inhibits axonal regeneration. PMID- 23438309 TI - Isolation and structural determination of triterpenoid glycosides from the aerial parts of alsike clover (Trifolium hybridum L.). AB - Five azukisapogenol glycosides (1-5) have been isolated from the aerial parts of alsike clover (Trifolium hybridum L.), and their structures were elucidated by combined spectroscopic, spectrometric (1D and 2D NMR; HRESIMS, ESI-MS/MS), and chemical methods. Three of them are new compounds and were identified as 3-O-[ alpha-L-arabinopyranosyl(1->2)]-beta-D-glucuronopyranosyl azukisapogenol (1), 3-O [-beta-D-glucuronopyranosyl(1->2)-beta-D-glucuronopyranosyl]-29-O-beta-D glucopyranosyl azukisapogenol (2), and 3-O-[-alpha-L-arabinopyranosyl(1->2)-beta D-glucuronopyranosyl]-29-O-beta-D-glucopyranosyl azukisapogenol (3). The remaining two (4, 5) are known compounds but have not been previously described as saponins constituents of the genus Trifolium . Also, azukisapogenol is reported here as a triterpenoid aglycone for the first time in this genus. Finally, the main chemotaxonomic features that may be recognized as specific of Trifolium species were discussed. PMID- 23438311 TI - Long-term sickness absence in the workplace: causes of sickness absence and their predictors. PMID- 23438312 TI - Water quality indicators: bacteria, coliphages, enteric viruses. AB - Water quality through the presence of pathogenic enteric microorganisms may affect human health. Coliform bacteria, Escherichia coli and coliphages are normally used as indicators of water quality. However, the presence of above mentioned indicators do not always suggest the presence of human enteric viruses. It is important to study human enteric viruses in water. Human enteric viruses can tolerate fluctuating environmental conditions and survive in the environment for long periods of time becoming causal agents of diarrhoeal diseases. Therefore, the potential of human pathogenic viruses as significant indicators of water quality is emerging. Human Adenoviruses and other viruses have been proposed as suitable indices for the effective identification of such organisms of human origin contaminating water systems. This article reports on the recent developments in the management of water quality specifically focusing on human enteric viruses as indicators. PMID- 23438313 TI - Spectrum of nephrotic syndrome in adults: clinicopathological study from a single center in India. AB - BACKGROUND: The etiology of nephrotic syndrome (NS) in adults varies depending on the geographical location and is poorly studied in the Indian subcontinent. METHODS: Patients (>=16 years old) with NS presenting to our center and undergoing a kidney biopsy from April 2010 to September 2012 were included for this study. All biopsies were subjected to light and immunofluorescence microscopy, and electron microscopy in selected cases. The histopathological spectrum was analyzed according to the various clinical parameters. RESULTS: A total of 410 kidney biopsies were included for analysis. Two hundred and thirty seven (57.8%) patients were male and 173 (42.19%) patients were female. The average age at presentation was 33.68 +/- 13.88 years. Among the patients, 88.05% (n = 361) were diagnosed with primary glomerular diseases (PGD) and 11.95% (n = 49) with secondary glomerular diseases (SGD). The most common histological lesions were focal segmental glomerulosclerosis (FSGS) (24.63%) followed by minimal change disease (MCD) (23.9%) and membranous nephropathy (MN) (22.44%). The most common form of SGD was lupus nephritis (LN) (6.58% of all cases). FSGS (28.27%) and MCD (21.96%) were the most common lesions in males and females, respectively. In the age groups of 16-29 years, 30-59 years, and >=60 years, MCD (28.96%), MN (24%), and MN (40.74%) were the most common lesions, respectively, followed by FSGS in all groups (25.68%, 24.5%, and 18.52%, respectively). Among the patients, 27.07% had serum creatinine >=1.5 mg/dL and 28.54% had either macroscopic or microscopic hematuria. CONCLUSIONS: FSGS is increasingly becoming the most common cause of adult NS. This trend in Asia is seen predominantly in countries of the Indian subcontinent. PMID- 23438314 TI - A randomized controlled trial of COMPASS web-based and face-to-face teacher coaching in autism. AB - OBJECTIVE: Most children with autism rely on schools as their primary source of intervention, yet research has suggested that teachers rarely use evidence-based practices. To address the need for improved educational outcomes, a previously tested consultation intervention called the Collaborative Model for Promoting Competence and Success (COMPASS; Ruble, Dalrymple, & McGrew, 2010; Ruble, Dalrymple, & McGrew, 2012) was evaluated in a 2nd randomized controlled trial, with the addition of a web-based group. METHOD: Forty-nine teacher-child dyads were randomized into 1 of 3 groups: (1) a placebo control (PBO) group, (2) COMPASS followed by face-to-face (FF) coaching sessions, and (3) COMPASS followed by web-based (WEB) coaching sessions. Three individualized goals (social, communication, and independence skills) were selected for intervention for each child. The primary outcome of independent ratings of child goal attainment and several process measures (e.g., consultant and teacher fidelity) were evaluated. RESULTS: Using an intent-to-treat approach, findings replicated earlier results with a very large effect size (d = 1.41) for the FF group and a large effect size (d = 1.12) for the WEB group relative to the PBO group. There were no differences in overall change across goal domains between the FF and WEB groups, suggesting the efficacy of videoconferencing technology. CONCLUSIONS: COMPASS is effective and results in improved educational outcomes for young children with autism. Videoconferencing technology, as a scalable tool, has promise for facilitating access to autism specialists and bridging the research-to-practice gap. PMID- 23438315 TI - Uncertainties associated with the reuse of treated hydraulic fracturing wastewater for crop irrigation. PMID- 23438316 TI - Editorial comment to circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: profile comparison. PMID- 23438317 TI - Body shape analyses of large persons in South Korea. AB - Despite the prevalence of obesity and overweight, anthropometric characteristics of large individuals have not been extensively studied. This study investigated body shapes of large persons (Broca index >= 20, BMI >= 25 or WHR>1.0) using stature-normalised body dimensions data from the latest South Korean anthropometric survey. For each sex, a factor analysis was performed on the anthropometric data set to identify the key factors that explain the shape variability; and then, a cluster analysis was conducted on the factor scores data to determine a set of representative body types. The body types were labelled in terms of their distinct shape characteristics and their relative frequencies were computed for each of the four age groups considered: the 10s, 20s-30s, 40s-50s and 60s. The study findings may facilitate creating artefacts that anthropometrically accommodate large individuals, developing digital human models of large persons and designing future ergonomics studies on largeness. PRACTITIONER SUMMARY: This study investigated body shapes of large persons using anthropometric data from South Korea. For each sex, multivariate statistical analyses were conducted to identify the key factors of the body shape variability and determine the representative body types. The study findings may facilitate designing artefacts that anthropometrically accommodate large persons. PMID- 23438318 TI - Structural evolution and the control of defects in atomic layer deposited HfO2 Al2O3 stacked films on GaAs. AB - The structural characteristics and interfacial reactions of bilayered dielectric stacks of 3 nm HfO2/2 nm Al2O3 and 3 nm Al2O3/2 nm HfO2 on GaAs, prepared by atomic layer deposition (ALD), were examined during film growth and the postannealing process. During the postdeposition annealing (PDA) of the Al2O3/HfO2/GaAs structures at 700 degrees C, large amounts of Ga oxides were generated between the Al2O3 and HfO2 films as the result of interfacial reactions between interdiffused oxygen impurities and out-diffused atomic Ga. However, in the case of the HfO2/Al2O3/GaAs structures, the presence of an Al2O3 buffer layer effectively blocked the out-diffusion of atomic Ga, thus suppressing the formation of Ga oxide. Microstructural analyses showed that HfO2 films that were deposited on Al2O3/GaAs had completely crystallized during the PDA process, even at 700 degrees C, because of the Al2O3 diffusion barrier. Capacitance-voltage measurements showed a relatively large frequency dispersion of the Al2O3/HfO2/GaAs structure in accumulation capacitance compared to the HfO2/Al2O3/GaAs structure due to a higher interface state density. Conductance results revealed that the Al2O3 buffer layer on GaAs resulted in a significant reduction in gap states in GaAs. The induced gap state in the Al2O3/HfO2/GaAs structure originated from the out-diffusion of atomic Ga into the HfO2 film. Density functional theory calculations supported this conclusion. PMID- 23438319 TI - Placental weight relative to birthweight in pregnancies with maternal diabetes mellitus. AB - OBJECTIVES: To study the association of maternal diabetes mellitus with placental weight, birthweight and placental weight-to-birthweight ratio. DESIGN: Population based study. SETTING: Medical Birth Registry of Norway. POPULATION: All singleton births in Norway during 1999-2008 (n = 536,997). METHODS: We compared the distribution of placental weight z-scores and placental weight-to-birthweight ratio between pregnancies with and without diabetes. The associations of diabetes with placental weight z-scores were also estimated as odds ratios with and without adjustment for birthweight, maternal age, parity, preeclampsia, smoking and cesarean delivery. MAIN OUTCOME MEASURES: Placental weight, birthweight and placental weight-to-birthweight ratio. RESULTS: Mean placental weight was 736.6 g in diabetic pregnancies and 672.1 g in non-diabetic pregnancies. The corresponding birthweights were 3682.1 g and 3557.0 g. In diabetic pregnancies, 26.2% of the placentas were in the highest decile of placental weight z-score, as compared with 9.7% in non-diabetic pregnancies (p < 0.001). The corresponding figures for being in the highest decile of placental weight-to-birthweight ratio were 18.2 and 9.9% (p < 0.001). The crude odds ratio for having a placenta in the highest decile of placental weight z-score was 3.29 (95% confidence interval 3.14 3.45) in diabetic pregnancies with non-diabetic pregnancies as the reference. After adjustment for birthweight and other variables, the odds ratio was 2.42 (95% confidence interval 2.29-2.56). CONCLUSIONS: In diabetic pregnancies, placental weight as well as placental weight relative to birthweight were higher than in non-diabetic pregnancies. PMID- 23438320 TI - Means and extremes: building variability into community-level climate change experiments. AB - Experimental studies assessing climatic effects on ecological communities have typically applied static warming treatments. Although these studies have been informative, they have usually failed to incorporate either current or predicted future, patterns of variability. Future climates are likely to include extreme events which have greater impacts on ecological systems than changes in means alone. Here, we review the studies which have used experiments to assess impacts of temperature on marine, freshwater and terrestrial communities, and classify them into a set of 'generations' based on how they incorporate variability. The majority of studies have failed to incorporate extreme events. In terrestrial ecosystems in particular, experimental treatments have reduced temperature variability, when most climate models predict increased variability. Marine studies have tended to not concentrate on changes in variability, likely in part because the thermal mass of oceans will moderate variation. In freshwaters, climate change experiments have a much shorter history than in the other ecosystems, and have tended to take a relatively simple approach. We propose a new 'generation' of climate change experiments using down-scaled climate models which incorporate predicted changes in climatic variability, and describe a process for generating data which can be applied as experimental climate change treatments. PMID- 23438321 TI - C-reactive protein versus erythrocyte sedimentation rate, white blood cell count and alkaline phosphatase in diagnosing bacteraemia in bone and joint infections. AB - AIM: Bacteraemia is common in childhood acute bone and joint infections and demands urgent treatment. Blood C-reactive protein (CRP), erythrocyte sedimentation rate and white blood cell count (WBC) are well known and established markers in these infections. Instead, no information is available on serum alkaline phosphatase whose concentration is known to increase in septic conditions. METHODS: In our large prospective treatment trial comprising of 265 children with acute culture-positive bone or joint infection, all these laboratory indices were monitored on admission to hospital. The predictive value to detect bacteraemia was assessed for each of these four indices. RESULTS: In all, 59% of the patients showed bacteraemia. CRP was significantly (P < 0.05) higher among bacteraemic patients, whereas erythrocyte sedimentation rate, white blood cell count and alkaline phosphatase were not. The area under receiver operator characteristic curve for CRP was 0.588 (CI95% 0.524-0.649) and the significance level P (Area = 0.5) was <0.05. CONCLUSION: None of the markers could reliably diagnose bacteraemia. CRP alone was significantly higher among bacteraemic patients. PMID- 23438322 TI - Counterion density profile around charged cylinders: the strong-coupling needle limit. AB - Charged rod-like polymers are not able to bind all their neutralizing counterions: a fraction of them evaporates, while the others are said to be condensed. We study here counterion condensation and its ramifications, both numerically by means of Monte Carlo simulations employing a previously introduced powerful logarithmic sampling of radial coordinates and analytically, with special emphasis on the strong-coupling regime. We focus on the thin rod or needle limit that is naturally reached under strong Coulombic couplings, where the typical intercounterion spacing a' along the rod is much larger than its radius R. This regime is complementary and opposite to the simpler thick rod case where a' ? R. We show that due account of counterion evaporation, a universal phenomenon in the sense that it occurs in the same clothing for both weakly and strongly coupled systems, allows one to obtain excellent agreement between the numerical simulations and the strong-coupling calculations. PMID- 23438323 TI - Hypertensive pregnancy disorders as a risk factor for future cardiovascular and metabolic disorders (Tehran Lipid and Glucose Study). AB - BACKGROUND: Although hypertensive pregnancy disorders (HPD) are common worldwide, there is no consensus regarding their long-term cardiovascular and metabolic consequences. We aimed to ascertain the association between HPD and the development of cardiovascular and metabolic disturbances later in life. MATERIAL AND METHODS: A cohort of 226 women with a history of HPD was selected as the case group, and a group of 226 age- and body-mass-index-matched women, with no history of HPD, was selected as controls. Both groups were selected from among participants of the Tehran Lipid and Glucose Study and were compared for concentrations of metabolic parameters and incidence of hypertension, type 2 diabetes mellitus (T2DM) and dyslipidemia over a follow up of 10 years. RESULTS: Women with a history of HPD, compared with age- and body-mass-index-matched women without such a history, had an increased risk of cardiovascular and metabolic disorders, including a twofold increased risk for hypertension (95% confidence interval [CI]: 1.4-3.2), a threefold increased risk for T2DM (95% CI: 1.8-5.2) and a 1.3-fold increased risk for dyslipidemia (95% CI: 1.2-1.5). CONCLUSIONS: Women with a history of hypertension in pregnancy are at increased risk for subsequent diagnosis of hypertension, dyslipidemia and T2DM later in life. These women may benefit from close monitoring and timely implementation of primary prevention measures of cardiovascular and metabolic risk factors and lifestyle modifications. PMID- 23438324 TI - Fluorescence of diimidazo[1,2-a:2',1'-c]quinoxalinium salts under various conditions. AB - The synthesis and photophysical properties of diimidazo[1,2-a:2',1' c]quinoxalinium salts were examined for different counteranions. The ethyl substituted diimidazo[1,2-a:2',1'-c]quinoxalinium salt with tosylate anion (categolized in ionic liquid) showed good fluorescence (PhiF = 0.77) in organic solvent. The 3,10-diphenyldiimidazo[1,2-a:2',1'-c]quinoxalinium salts showed absorption and fluorescence peaks resembling those of the former diimidazoquinoxaline. The salt also emitted under various conditions such as in organic solvents, water, and even in the solid state, while retaining a good fluorescence quantum yield (PhiF = 0.5-0.8). Furthermore, the fluorescence was quenched efficiently through the introduction of an electron-donating substituent on the alkyl side chain. PMID- 23438325 TI - Rheological bases for empirical rules on shear viscosity of lubrication oils. AB - The shear relaxation spectra of various lubrication oils were measured at 5-205 MHz and 10-70 degrees C, and the variation of the steady-state shear viscosity (eta0) was divided into the contributions of the high-frequency shear modulus (Ginfinity) and relaxation time (tau). The temperature dependence of eta0 was dominated by that of tau. The increase in molecular weight accompanies both increase in tau and decrease in Ginfinity, and the increase in eta0 results from the larger effect of the former. The flexibility of the chain reduced tau, while its effect on Ginfinity was rather small. The introduction of phenyl or cyclohexyl groups enhanced Ginfinity. Oils of larger Ginfinity tend to exhibit a larger temperature dependence of eta0. PMID- 23438326 TI - Polymorphisms in GABRB3 and oral clefting in the Brazilian population. AB - The aim of this study was to evaluate the influence of the gamma-aminobutyric acid receptor type A beta-3 subunit (GABRB3) polymorphisms in patients with nonsyndromic cleft lip and/or palate (NSCL/P). We carried out a structured case control analysis of three GABRB3 polymorphisms (rs4477673, rs6576618, and rs981778) in 229 patients with nonsyndromic cleft lip with or without cleft palate (CL+/-P) and in 314 unaffected controls from Brazil. The polymorphisms were genotyped by the TaqMan 5'-exonuclease allelic discrimination assay, and each sample was independently typed for 40 biallelic short insertion/deletion markers (INDELs) to characterize the genomic ancestry. The genotype distributions of the three polymorphisms were as expected by the Hardy-Weinberg equilibrium test. After adjustment to ancestry contribution, the minor A allele of rs981778 was associated with NSCL/P, but significant results did not persist after Bonferroni correction for multiple tests. Similarly, the haplotype analysis revealed that the CCA haplotype (C allele of rs4477673, C allele of rs6576618, and A allele of rs981778) was correlated with NSCL/P, but this association did not remain statistically significant after Bonferroni correction. With a weak association, our data do not support the hypothesis that the GABRB3 variants are a cause of NSCL/P, but further studies are warranted. PMID- 23438327 TI - Swim therapy reduces mechanical allodynia and thermal hyperalgesia induced by chronic constriction nerve injury in rats. AB - OBJECTIVE: Neuropathic pain is common and often difficult to treat because it generally does not respond well to the currently available pain medications or nerve blocks. Recent studies in both humans and animals have suggested that exercise may induce a transient analgesia and reduce acute pain in normal healthy individuals. We examined whether swim therapy could alleviate neuropathic pain in rats. DESIGN: Rats were trained to swim over a 2-week period in warm water. After the rats were trained, neuropathic pain was induced by constricting the right sciatic nerve, and regular swimming was resumed. The sensitivity of each hind paw was monitored using the Hargreaves test and von Frey test to evaluate the withdrawal response thresholds to heat and touch. RESULTS: The paw ipsilateral to the nerve ligation expressed pain-like behaviors including thermal hyperalgesia and mechanical allodynia. Regular swim therapy sessions significantly reduced the mechanical allodynia and thermal hyperalgesia. Swim therapy had little effect on the withdrawal thresholds for the contralateral paw. In addition, swim therapy alone did not alter the thermal or mechanical thresholds of normal rats. CONCLUSIONS: The results suggest that regular exercise, including swim therapy, may be an effective treatment for neuropathic pain caused by nerve injuries. This study, showing that swim therapy reduces neuropathic pain behavior in rats, provides a scientific rationale for clinicians to test the efficacy of exercise in the management of neuropathic pain. It may prove to be a safe and cost effective therapy in a variety of neuropathic pain states. PMID- 23438328 TI - Systemic inflammation is associated with differential gene expression and airway neutrophilia in asthma. AB - Systemic inflammation is reported to be associated with neutrophilic airway inflammation in asthma, but mechanisms underlying this finding are not well understood. This study aimed to examine the molecular mechanisms of the airway neutrophilia that are associated with systemic inflammation in asthma. Fifty stable nonsmoking adults with asthma had plasma high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) assayed. Subjects with an elevation of both hsCRP and IL-6 were grouped as asthmatics with systemic inflammation, and those with both hsCRP and IL-6 within the normal ranges were grouped as asthmatics without systemic inflammation. Clinical characteristics and sputum inflammatory cell counts were compared between the two groups. Gene expression profiles from sputum were analyzed and altered expression of four genes (CCL8, IL8RA, SELL, and PI3) was confirmed using quantitative PCR. Asthmatics with systemic inflammation (n=18, 36%) had a higher BMI, greater history of cigarette smoking, lower FVC% predicted, and increased sputum neutrophils compared to those without systemic inflammation (n=16, 32%). Microarray analysis identified 449 genes that were significantly altered in sputum between the two groups. Altered genes were involved in IL-1, TNF-alpha/nuclear factor-kappaB, and Kit receptor pathways, and were related to innate immune response, defense and inflammatory response, in particular neutrophilic inflammation. Systemic inflammation was associated with airway neutrophilia in asthma, and was related to a group of differentially expressed genes in the lung involving multiple cytokine pathways. Our findings suggest that targeting systemic inflammation might provide a novel therapeutic strategy for neutrophilic asthma. PMID- 23438329 TI - Rejection sensitivity as a mediator of the impact of childhood exposure to family violence on adult attachment behavior. AB - Substantial evidence indicates a link between exposure to family violence in childhood and troubled social relationships. We draw on attachment and social cognitive theory to formulate a model of the mechanisms underlying this association. The model proposes that early experiences of overt rejection (e.g., physical maltreatment) or covert rejection (e.g., emotional neglect) are internalized as sensitivity to rejection. In this study, we operationalize sensitivity to rejection in social-cognitive terms as a tendency to expect and be concerned about rejection across a range of social situations. We hypothesize that rejection sensitivity mediates the link between exposure to family violence and adult attachment behavior. Data from a survey of 212 undergraduates support this hypothesis and also provide evidence that indicates sensitivity to rejection underlies both avoidant and ambivalent patterns of insecure adult attachment behavior. Overall, the results illustrate the power of a process approach to explaining the developmental sequelae of maltreatment. PMID- 23438330 TI - Orvinols with mixed kappa/mu opioid receptor agonist activity. AB - Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [(35)S]GTPgammaS assay are predictive of the in vivo profile. PMID- 23438331 TI - Incidence rate of symptomatic painless thyroiditis presenting with thyrotoxicosis in Denmark as evaluated by consecutive thyroid scintigraphies. AB - BACKGROUND: Painless thyroiditis (PT) is a transient kind of thyrotoxicosis, with lack of uptake on a thyroid scintigraphy in a non-tender thyroid gland, elevated anti-TPO antibodies, no fever, no history of increased iodine intake, and a normal sedimentation rate. The prevalence of PT varies hugely in the literature. OBJECTIVE: To establish the incidence rate of PT in Denmark as well as to describe the phenotype of PT in more detail. METHODS: Tc-99m pertechnetate scintigraphies were performed over a period of 9.75 years on 6022 consecutive patients (2349 had a thyrotoxic episode), and were divided into high or normal (5528), reduced (300) or lack of uptake (194). Patient records were evaluated: 292 with reduced, and 186 with lack of uptake. As a control measure, 230 consecutive thyrotoxic patients were also analyzed. RESULTS: Based on scintigraphies, 12 patients had PT, 10 with lack of uptake and two with reduced, corresponding to an incidence rate of 0.49/100,000 person years. It was predicted, that only one patient among the newly diagnosed consecutive thyrotoxic cohort had PT. This patient was identified. The prevalence of PT among thyrotoxic patients was 0.51% as evaluated by scintigraphy, and 0.43% among the biochemically thyrotoxic patient cohort. Twenty-five percent had more than one thyrotoxic episode, 75% had at least one subsequent hypothyroid episode, and 33% developed permanent hypothyroidism. CONCLUSIONS: PT presenting with symptomatic thyrotoxicosis is an extremely rare disease in Denmark. Symptomatic PT presents most often with no uptake on a Tc-99m pertechnetate scintigraphy. Clinical follow up is essential. PMID- 23438332 TI - Notes on the implementation of the IREQ model for the assessment of extreme cold environments. AB - This paper has been devoted to the difficulties that practitioners, skilled ergonomists or occupational health experts could find in the assessment of cold environments by means of (insulation required) IREQ model at the base of the (International Standardization Organization) ISO 11079 Standard. The in-depth analysis discussed here has underlined several difficulties about: (a) the graphical calculation of the predicted limit exposures; (b) some differences in both IREQ and (duration limit exposure) DLE values reported in ISO 11079; and (c) some errors and incongruities in the program available online for the assessment of DLEs. These occurrences lead to the systematic overestimation of the DLE that exceed up to 4 h, those obtained by means of the figures reported in the Standard with the consequent unreliable assessment. Such matters justify the need to promote, in the whole scientific community involved in the ergonomics of the thermal environment, an in-depth discussion on the best practice to be followed for the assessment of extreme cold environments by means of IREQ model. PRACTITIONER SUMMARY: Incongruities in IREQ model and errors in the code suggested by ISO 11079 Standard prevent a reliable assessment of cold environments with DLE systematically overestimated. Therefore IREQ model has been theoretically investigated trying to help both neophytes and skilled ergonomists on the best practice to be followed. PMID- 23438336 TI - Evolving story of vitamin D; supplementing vs. implementing new approaches. PMID- 23438337 TI - Oncogenic role of kinesin proteins and targeting kinesin therapy. AB - The kinesin superfamily (KIF) is a group of proteins that share a highly conserved motor domain. Except for some members, many KIF proteins have adenosine triphosphatase activity and microtubule-dependent plus-end motion ability. Kinesins participate in several essential cellular functions, including mitosis, meiosis and the transport of macromolecules. Increasing evidence indicates kinesin proteins play critical roles in the genesis and development of human cancers. Some kinesin proteins are associated with maligancy as well as drug resistance of solid tumor. Thus, targeting KIF therapy seems to be a promising anticancer strategy. Inhibitors of KIF such as kinesin spindle protein (KSP/Eg5) have entered clinical trials for monotherapy or in combination with other drugs, and kinesins other than Eg5 with various potential anticancer target characteristics are also constantly being discovered and studied. Here, we summarize the oncogenic roles of kinesin proteins and potential cancer therapy strategies that target KIF. PMID- 23438338 TI - RNA 3D structure prediction by using a coarse-grained model and experimental data. AB - RNAs form complex secondary and three-dimensional structures, and their biological functions highly rely on their structures and dynamics. Here we developed a general coarse-grained framework for RNA 3D structure prediction. A new, hybrid coarse-grained model that explicitly describes the electrostatics and hydrogen-bond interactions has been constructed based on experimental structural statistics. With the simulated annealing simulation protocol, several RNAs of less than 30-nt were folded to within 4.0 A of the native structures. In addition, with limited restraints on Watson-Crick basepairing based on the data from NMR spectroscopy and small-angle X-ray scattering (SAXS) information, the current model was able to characterize the complex tertiary structures of large size RNAs, such as 5S ribosome and U2/U6 snRNA. We also demonstrated that the pseudoknot structure was better captured when the coordinating Mg(2+) cations and limited basepairing restraints were included. The accuracy of our model has been compared favorably with other RNA structure prediction methods presented in the previous study of RNA-Puzzles. Therefore the coarse-grained model presented here offers a unique approach for accurate prediction and modeling of RNA structures. PMID- 23438340 TI - Adsorption and Aggregation behaviors of tetrasiloxane-tailed gemini surfactants with (EO)m spacers. AB - Adsorption and aggregation behaviors of novel tetrasiloxane-tailed gemini surfactants N,N'-ditetrasiloxane-N,N'-digluconamide oligo ethylene glycol diglycidyl (Si-m-Si, where m is the number of ethylene glycol of 1, 2, and 3) were investigasted using surface tension, bromophenol blue encapsulation, dynamic light scattering (DLS), and transmission electron microscope (TEM) methods. The static surface tension of the aqueous Si-m-Si solutions measured at the critical aggregate concentration (CAC) was observed to be lower than that of traditional hydrocarbon gemini surfactants. This suggests that these newly synthesized gemini surfactants are capable of forming a closely packed monolayer film at the air/aqueous solution interface. With a combination of DLS data, TEM measurements, and bromophenol blue entrapment studies, formations of vesicles in Si-m-Si solutions appear to occur at a concentration well above the CAC. Moreover, the size of vesicles depended on their m values. PMID- 23438341 TI - The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (epsilonPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design. AB - OBJECTIVE: Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. DESIGN: The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI 1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). PATIENTS: A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for >=3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of >=4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. RESULTS: Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. CONCLUSIONS: We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study. PMID- 23438343 TI - Fabrication of microlens arrays by localized hydrolysis in water droplet microreactors. AB - We report a facile self-assembly strategy for fabricating TiO2 microlens arrays by localized hydrolysis of TiCl4 precursor in water droplets. Microcontact printing was used to define hydrophilic areas on a substrate for space resolved hydrolytic reaction. The water droplets served as the templates, reactant, and microreactors. Highly ordered TiO2 microlens arrays could be produced, which exhibit excellent ability to focus light. Because both size and shape of the final TiO2 microlens can be controlled by the printed chemical pattern and the precursor concentration, it is possible to define TiO2 microlens arrays with different imaging properties. This new method shows attractive features of simplicity, low cost, and requires no heating process, hence is suitable for a range of applications. PMID- 23438342 TI - Off-resonance surface-enhanced Raman spectroscopy from gold nanorod suspensions as a function of aspect ratio: not what we thought. AB - Design of nanoparticles for surface-enhanced Raman scattering (SERS) within suspensions is more involved than simply maximizing the local field enhancement. The enhancement at the nanoparticle surface and the extinction of both the incident and scattered light during propagation act in concert to determine the observed signal intensity. Here we explore these critical aspects of signal generation and propagation through experiment and theory. We synthesized gold nanorods of six different aspect ratios in order to obtain longitudinal surface plasmon resonances that incrementally spanned 600-800 nm. The Raman reporter molecule methylene blue was trap-coated near the surface of each nanorod sample, generating SERS spectra, which were used to compare Raman signals. The average number of reporter molecules per nanorod was quantified against known standards using electrospray ionization liquid chromatography mass spectrometry. The magnitude of the observed Raman signal is reported for each aspect ratio along with the attenuation due to extinction in suspension. The highest Raman signal was obtained from the nanorod suspension with a plasmon resonance blue-shifted from the laser excitation wavelength. This finding is in contrast to SERS measurements obtained from molecules dried onto the surface of roughened or patterned metal substrates where the maximum observed signal is near or red shifted from the laser excitation wavelength. We explain these results as a competition between SERS enhancement and extinction, at the excitation and scattered wavelengths, on propagation through the sample. PMID- 23438344 TI - Bronchoscopic evaluation of unexplained recurrent and persistent pneumonia in children. AB - BACKGROUND: Persistent or recurrent pneumonia in children can pose a significant challenge to paediatricians and respiratory physicians. AIM: The aim of this study is to determine the role of flexible bronchoscopy (FB) in evaluation of recurrent or persistent pneumonia that remain otherwise unexplained by non invasive diagnostic tests in children. METHODS: Retrospective evaluation of patients who underwent FB with an indication of recurrent or persistent pneumonia from 1997 to 2011. RESULTS: Among 2600 FB procedures, 434 (17%) were performed with the indication of recurrent or persistent pneumonia. There were 237 (54%) boys. Median age at presentation was 84 months, and median duration of symptoms was 9 months. FB led to specific diagnosis in 33% of the cases. The most common diseases diagnosed by FB were malacia disorders (n: 32, 7%), aspirated foreign body (n: 30, 7%), endobronchial tuberculosis (n: 20, 5%), congenital airway anomalies (n: 14, 3%), mucus plugs (n: 14, 3%), pulmonary haemosiderosis (n: 12, 3%) and middle lobe syndrome (n: 11, 3%). During FB, only 6% of the patients had minor complications such as transient hypoxia, stridor and tachycardia. CONCLUSIONS: In our study, FB proved to be a safe and effective tool in evaluation of children with persistent or recurrent pneumonia. FB is indicated for children with recurrent or persistent pneumonia where the underlying diagnosis remains unclear even after non-invasive diagnostic tests. PMID- 23438335 TI - Sewage reflects the distribution of human faecal Lachnospiraceae. AB - Faecal pollution contains a rich and diverse community of bacteria derived from animals and humans, many of which might serve as alternatives to the traditional enterococci and Escherichia coli faecal indicators. We used massively parallel sequencing (MPS) of the 16S rRNA gene to characterize microbial communities from wastewater treatment plant (WWTP) influent sewage from 12 cities geographically distributed across the USA. We examined members of the Clostridiales, which included the families Clostridiaceae, Lachnospiraceae and Ruminococcaceae for their potential as sewage indicators. Lachnospiraceae was one of the most abundant groups of faecal bacteria in sewage, and several Lachnospiraceae high abundance sewage pyrotags occurred in at least 46 of 48 human faecal samples. Clone libraries targeting Clostridium coccoides (C. coccoides) in sewage samples demonstrated that Lachnospiraceae-annotated V6 pyrotags encompassed the previously reported C. coccoides group. We used oligotyping to profile the genus Blautia within Lachnospiraceae and found oligotypes comprised of 24 entropy components that showed patterns of host specificity. These findings suggest that indicators based on Blautia might have the capacity to discriminate between different faecal pollution sources. Development of source-specific alternative indicators would enhance water quality assessments, which leads to improved ecosystem health and reduced human health risk due to waterborne disease. PMID- 23438345 TI - Monophyletic origin of magnetotaxis and the first magnetosomes. AB - Horizontal gene transfer (HGT), the transfer of genetic material other than by descent, is thought to have played significant roles in the evolution and distribution of genes in prokaryotes. These include those responsible for the ability of motile, aquatic magnetotactic bacteria (MTB) to align and swim along magnetic field lines and the biomineralization of magnetosomes that are responsible for this behaviour. There is some genomic evidence that HGT might be responsible for the distribution of magnetosome genes in different phylogenetic groups of bacteria. For example, in the genomes of a number of MTB, magnetosome genes are present as clusters within a larger structure known as the magnetosome genomic island surrounded by mobile elements such as insertion sequences and transposases as well as tRNA genes. Despite this, there is no strong direct proof of HGT between these organisms. Here we show that a phylogenetic tree based on magnetosome protein amino acid sequences from a number of MTB was congruent with the tree based on the organisms' 16S rRNA gene sequences. This shows that evolution and divergence of these proteins and the 16S rRNA gene occurred similarly. This suggests that magnetotaxis originated monophyletically in the Proteobacteria phylum and implies that the common ancestor of all Proteobacteria was magnetotactic. PMID- 23438346 TI - Impulsive and episodic disorders of aggressive behaviour following traumatic brain injury. AB - BACKGROUND: Aggressive behaviour is a frequent legacy of traumatic brain injury (TBI) and a major obstacle to psychosocial recovery. Aggression can take many forms and there is currently no uniform method of assessment that distinguishes aggressive sub-types in a way that can assist decisions for treatment. REVIEW: This paper attempts to provide a framework that will help distinguish two primary sub-types of aggression following TBI, impulsive and episodic aggression, based on their most prominent clinical characteristics. It is hoped that, by providing a description of the phenomenology associated with each form of aggression, together with an explanation of the probable neuropathology underpinning each sub type, the clinical classification of these two forms of aggression will improve, leading to a commensurate improvement in the choice of treatment interventions, resulting in better psychosocial outcomes. PMID- 23438347 TI - Strengthening neurotrauma care systems in low and middle income countries. AB - PRIMARY OBJECTIVE: To review basic elements to be considered in the development of effective neurotrauma care systems in low- and middle-income countries. Neurotrauma occurs more frequently in developing countries. The survival rate among neurotrauma patients depends in large part on the degree of sophistication of the trauma system. RESEARCH DESIGN: A critical review of the literature was undertaken. RESULTS: In developing countries, there are difficulties in fully integrating the resources for care if the local and regional trauma systems are poorly structured. Factors like inadequate emergency and neurointensive care, low compensation compared with elective procedures or high medico-legal risks may result in a lack of interest from the few available neurosurgeons to be fully integrated in neurotrauma care. Appropriate structuring of trauma systems according to countries needs and their functionality is a key element that would facilitate the optimal use of resources for integral neurotrauma care. CONCLUSIONS: In order to implement an efficient trauma system, organization of low cost resources such as trauma registries and quality control programmes are required. The participation of medical associations in legislative and government processes is also an important factor for the appropriate development and organization of an effective trauma system in under-privileged areas. PMID- 23438348 TI - Evaluation of the patient generated index as a measure of quality-of-life in people with severe traumatic brain injury. AB - OBJECTIVES: Quality-of-life (QoL) measures may be useful in quantifying the personal impact of an acquired brain injury and as an indicator of the effectiveness of service provision. This study investigated the validity of the patient generated index (PGI) as a measure of QoL with a sample of adults who had sustained a severe traumatic brain injury. METHOD: Fifty-five participants with an acquired brain injury were selected from four regional rehabilitation centres. Each participant completed validated questionnaires measuring subjective satisfaction with life, community integration, emotional distress, socially desirable responding and the patient generated index. RESULTS: The criterion related validity of the PGI was demonstrated through a statistically significant positive correlation with life satisfaction. Evidence of construct validity was observed through significant correlations with measures of emotional distress and community integration. Depression had a strong negative association with QoL. Social desirability correlated significantly with both indices of QoL, suggesting that this variable may be treated as a covariate. CONCLUSION: The results offer some preliminary evidence for the validity of the PGI as a measure of QoL in people with severe brain injury. PMID- 23438349 TI - Burnout and coping strategies of polytrauma team members caring for veterans with traumatic brain injury. AB - OBJECTIVE: The aims of this national study were to (1) examine the extent of job burnout among VA Polytrauma team members engaged in the diagnosis and treatment of traumatic brain injury (TBI); and (2) identify their coping strategies for dealing with job-related stress. DESIGN: A cross-sectional sample of 233 VA Polytrauma team members completed the Maslach Burnout Inventory (MBI) and identified strategies for coping with work stress as part of an online survey. RESULTS: VA Polytrauma team members experience moderate levels of emotional exhaustion, but low levels of depersonalization and high levels of personal accomplishment. Moreover, 24% of participants reported high levels of emotional exhaustion, which may be a precursor to job burnout. Participants who reported caring for veterans with TBI >=50% of their time experienced higher levels of emotional exhaustion than those who spent <50% of their time (p <= 0.001). Five major thematic categories related to coping strategies emerged from the data: (1) connecting with others, (2) promoting a healthy lifestyle, (3) pursuing outside interests, (4) managing work environment and (5) maintaining positive thinking. CONCLUSION: Polytrauma team members caring for Veterans with TBI may be at risk for job burnout. PMID- 23438350 TI - Eye movement and online bisection task in unilateral patients with neglect: a new look to the 'gradient effect'. AB - PRIMARY OBJECTIVE: The present study explored the behavioural and eye-movement measures in spatial unilateral neglect in response to a bisection task. RESEARCH DESIGN: Four right neglect patients were considered and compared with 11 control subjects during an online task (segment bisection). METHODS AND PROCEDURES: Eye movements (fixation count and duration) and behavioural responses were monitored during an online bisection task, consisting of unfilled segments (two ending points) to be bisected by subjects. Segment length (six levels) and spatial dislocation (five levels) were modulated to explore a possible 'gradient effect'" (left-to-right) in neglect bias. MAIN OUTCOMES AND RESULTS: Consistent spatial biases were found for both bisection position and eye fixations as a function of segment length (from shorter to longer) and segment spatial dislocation (from right to left). However, only the more eccentric left-positions induced a greater rightward bias in patients, with increasing more right-side bisection and visual right-directed fixations. Also segment length produced significant differences between-groups for behavioural responses, with more right-side bisection for longer segment in patients, and eye movement behaviour, with increased fixation count and duration rightward oriented in response to longer segments. CONCLUSIONS: Although a left-to-right and longer-to-shorter 'continuous-gradient effect' was not supported by the results, an 'extreme left-gradient effect' was suggested and discussed. PMID- 23438351 TI - Early intervention for patients at risk for persisting disability after mild traumatic brain injury: a randomized, controlled study. AB - STUDY OBJECTIVE: To investigate the effect of an early intervention visit in addition to written information and treatment as usual for patients with an estimated high risk for persisting disability after a mild traumatic brain injury (MTBI). RESEARCH DESIGN: Randomized controlled trial. METHODS: One hundred and seventy-three patients, aged 15-70 years with a Glasgow coma scale of 14-15 were included. All received written information about MTBI. Ninety-seven patients who reported three or more symptoms according to the rivermead post-concussion symptoms questionnaire (RPQ) at 10 days after the injury were considered as high risk patients and were randomized to either early visit to a doctor or to treatment as usual (TAU); all patients including the 76 low-risk patients were followed-up at 3 months. Completion rate was 83%. Outcome measures included RPQ and the hospital anxiety and depression scale. RESULTS: RPQ symptoms decreased significantly in both randomized groups, but were not significantly different in the groups at 3 months. At 3 months, anxiety and depression scores did not differ between groups. CONCLUSIONS: An early intervention, offered to patients with an estimated high risk for persisting disability, had no additional effect on symptom level at 3 months after MTBI as compared to TAU. PMID- 23438352 TI - An examination of discharge against medical advice from brain injury inpatient rehabilitation. AB - OBJECTIVE: Discharges against medical advice (DAMA) have been considered predictors of adverse outcomes for patients in acute care and psychiatric hospitals. However, little is known about the profile of patients who discharge AMA admitted to rehabilitation hospitals. The aims of this study were to provide a profile of patients who received inpatient rehabilitation services following a traumatic brain injury (TBI) who discharged AMA and to compare this group with the regular discharge group. RESEARCH DESIGN: Retrospective cohort study. METHODS: Hospital discharge data from two national administrative databases were reviewed for the years 2001-2006. RESULTS: The databases yielded 1559 cases of TBI (average length of stay = 51 days). Of these, 31 (2.0%) had recorded DAMA events: one in 50 patients left rehabilitation against medical advice. Compared to regular discharge (n = 1247), DAMA was significantly associated with unemployment, intentional injury, higher motor functions at admission and shorter length of stay. Known factors for DAMA in acute hospitals, such as male sex, young age and substance abuse history, were not significant. CONCLUSION: Careful screening and assessment of patients who discharge AMA could enable better prevention and management strategies, thus improving health outcomes and enhancing healthcare delivery. PMID- 23438353 TI - 'If I haven't got any smell ... I'm out of work': consequences of olfactory impairment following traumatic brain injury. AB - PRIMARY OBJECTIVE: Although estimates of the incidence of post-traumatic olfactory dysfunction range from 10-66.8%, there has been little research into its functional implications. The objective of this study was to describe the impact of olfactory impairment on daily activities and social participation from the perspective of adults who are living with the impairment. RESEARCH DESIGN: A qualitative research design based on a constructivist grounded theory approach. METHODS AND PROCEDURES: Purposive sampling of five participants with severe traumatic brain injury (TBI) who reported post-injury changes in their olfactory function was utilized. No participant had a pre-injury history of olfactory disturbance. The presence of olfactory disturbance was confirmed using the University of Pennsylvania Smell Identification Test (UPSIT). A semi-structured interview was employed to ascertain the participants' experiences. All interviews were transcribed verbatim and thematic analyses applied. CONCLUSIONS: The themes that emerged demonstrated olfactory dysfunction has significant impact on a range of activities and social roles. PMID- 23438354 TI - Serial monitoring of CO2 reactivity following sport concussion using hypocapnia and hypercapnia. AB - PRIMARY OBJECTIVE: This study examined the effects of mild traumatic brain injury (mTBI) on cerebrovascular reactivity (CVR). RESEARCH DESIGN: A repeated measures design was used to examine serial changes in CVR. METHODS AND PROCEDURES: Twenty subjects who recently suffered a mTBI were subjected to a respiratory challenge consisting of repeated 20 s breath-holds (BH) and hyperventilations (HV). Testing occurred on days 2 (D2), 4 (D4) and 8 (D8) post-injury as well as a baseline (BASE) assessment (after return-to-play). Transcranial Doppler was used to assess mean cerebral blood velocity (vMCA) and expired gas analysis provided end-tidal carbon dioxide (PETCO2) levels. RESULTS: There was no significant difference in resting vMCA across all testing days for mTBI. No significant differences in PETCO2 were found throughout the testing protocol. A significant effect (p < 0.001) of testing day on vMCA was found during BH and HV challenges for mTBI. Post-hoc analysis revealed significant differences (p < 0.05) in vMCA between D2 and the other testing days. CONCLUSIONS: These data suggest that, following mTBI: (1) CVR is not impaired at rest; (2) CVR is impaired in response to respiratory stress; and (3) the impairment may be resolved as early as 4 days post-injury. PMID- 23438355 TI - Effect of neuroprotective therapies (hypothermia and cyclosporine a) on dopamine induced apoptosis in human neuronal SH-SY5Y cells. AB - INTRODUCTION: This study aimed to evaluate the effect of hypothermia and CyA on neuronal survival after induced injury in a neuronal model. METHODS: Human neuroblastoma SH-SY5Y cells were seeded and allowed to grow. To determine whether lower temperatures protect from dopamine-induced apoptosis, cells were treated with dopamine at 100 uM, at 300 uM or without dopamine and incubated at 32 degrees C or 37 degrees C for 24 hours. To assess the effect of CyA, cells were pre-incubated with CyA at 37 degrees C and after dopamine was added. RESULTS: After 24 hours of incubation at 37 degrees C, 100 uM and 300 uM dopamine induced 42% (SD = 21) and 58% (SD = 7.9) apoptotic SH-SY5 cells, respectively. In cultures at 32 degrees C dopamine-induced apoptosis could be reversed by hypothermia [7% (SD = 1.4) and 3.45% (SD = 1.1) for 100 uM and 300 uM, respectively], similar to levels obtained in non-treated cells [2.4% (SD = 1.5)]. Cyclosporine A treatment did not render the expected result, since CyA-pre treated cells and SH-SY5Y cells showed higher levels of apoptosis than those observed with dopamine alone CONCLUSIONS: Hypothermia has a marked protective effect against apoptotic cell death induced by dopamine in a human neuroblastic cell line. The neuroprotective effect of CyA described with other apoptotic cell death stimuli was not demonstrated with our experimental conditions. PMID- 23438356 TI - Delayed neurovascular inflammation after mild traumatic brain injury in rats. AB - INTRODUCTION: Experimental traumatic brain injury (TBI) elicits acute local inflammatory responses, including up-regulation of adhesion molecules and neutrophils in the injured brain. However, in clinical experiences there were at least three types of TBI, which included mild, moderate and severe types, and there would be different neuroinflammatory responses. This study investigated the inflammatory responses after mild TBI in rats. METHODS: Adult male Sprague-Dawley rats (n = 40) were group-housed and injured using an impact method. Motor function was assessed 1-4 days after the injury by using a grip test (Grip strength meter; Singa). Blood samples collected from the rats before the injury and after the injury and the Intercellular adhesion molecule-1 (ICAM-1) level were measured. RESULTS: The ICAM-1 expression from pre-injury to post-injury showed a significantly greater gradual elevation in the rats in the mild-injury group than in the moderate-injury group. The neurological function evaluated with grip test showed no deterioration of neurological function in the mild-injury group but gradual deterioration in the moderate-injury group. CONCLUSION: These findings showed a delayed inflammatory reaction in the mild-injury group without progressive deterioration of neurological function. Therefore, in the moderate injury group, no progression phase was observed. PMID- 23438357 TI - Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer. AB - BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3+ esophagitis and pneumonitis. We present outcomes for the first known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). MATERIAL AND METHODS: Six patients were treated: five concurrently and one sequentially. Five patients received 60-66 CGE in 30-34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. RESULTS: The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis, and no other acute grade 3+ non-hematological toxicities were seen. One patient with a history of pulmonary fibrosis and atrial fibrillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died: two of progressive disease and one after a fall; the latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. CONCLUSION: In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further investigation as a method of reducing the toxicity of CRT. PMID- 23438358 TI - Impaired health-related quality of life after chemoradiotherapy for anal cancer: late effects in a national cohort of 128 survivors. AB - BACKGROUND: Chemoradiotherapy is an effective treatment for anal cancer, yet from follow-up many survivors seem to suffer from late effects. Data of long-term health-related quality of life (HRQOL) in anal cancer survivors are limited, and there is a growing interest in cancer survivorship. MATERIAL AND METHODS: A national cohort of all anal cancer survivors treated with curative chemoradiotherapy in 2000-2007 was invited to a cross-sectional study. Of 199 eligible survivors, 128 (64%) returned the questionnaires, the median time since diagnosis was 66 months. The median age was 61 years and 79% were women. HRQOL was evaluated with EORTC questionnaires QLQ-C30 and QLQ-CR29, and neurotoxicity with the Scale of Chemotherapy-Induced Neurotoxicity. An age- and sex-matched reference group of volunteers (n = 269) not treated for pelvic cancer answered the same questionnaires. Results from QLQ-C30 of the reference group were compared to Norwegian and Dutch normative data. RESULTS: The mean scores of anal cancer survivors were poorer compared to volunteers and normative data. Anal cancer survivors reported significant impairment of function, especially social and role function, compared to the volunteers (difference >= 20 points, p < 0.001). Survivors had markedly increased scores for fatigue, dyspnoea, insomnia and diarrhoea (difference >= 15 points, p < 0.001). The global quality of life was significantly reduced (difference 15 points, p < 0.001). Anal cancer survivors had increased stool frequency, more buttock pain, flatulence, faecal incontinence, impotence (males), dyspareunia and reduced sexual interest (females) (difference >= 15 points, p < 0.001). There was increased frequency of tinnitus in survivors treated with cisplatin-based chemotherapy (p = 0.004). CONCLUSIONS: Survivors after chemoradiotherapy for anal cancer have significant long-term impairment of HRQOL. Reduced social, role and sexual function, and increased diarrhoea, incontinence for gas and stools, and buttock pain were commonly reported. Increased awareness of this may lead to better management of late effects and better care for cancer survivors. PMID- 23438359 TI - Harvest for health gardening intervention feasibility study in cancer survivors. AB - BACKGROUND: Cancer survivors are at increased risk for second malignancies, cardiovascular disease, diabetes, and functional decline. Evidence suggests that a healthful diet and physical activity may reduce the risk of chronic disease and improve health in this population. METHODS: We conducted a feasibility study to evaluate a vegetable gardening intervention that paired 12 adult and child cancer survivors with Master Gardeners to explore effects on fruit and vegetable intake, physical activity, quality-of-life, and physical function. Throughout the year long study period, the survivor-Master Gardener dyads worked together to plan/plant three gardens, harvest/rotate plantings, and troubleshoot/correct problems. Data on diet, physical activity, and quality-of-life were collected via surveys; anthropometrics and physical function were objectively measured. Acceptability of the intervention was assessed with a structured debriefing survey. RESULTS: The gardening intervention was feasible (robust enrollment; minimal attrition) and well-received by cancer survivors and Master Gardeners. Improvement in three of four objective measures of strength, agility, and endurance was observed in 90% of survivors, with the following change scores [median (interquartile range)] noted between baseline and one-year follow-up: hand grip test [+ 4.8 (3.0, 6.7) kg], 2.44 meter Get-Up-and-Go [+ 1.0 (+ 1.8, + 0.2) seconds], 30-second chair stand [+ 3.0 (+ 1.0, 5.0) stands], and six-minute walk [+ 11.6 (6.1, 48.8) meters]. Increases of >= 1 fruit and vegetable serving/day and >= 30 minutes/week of physical activity were observed in 40% and 60%, respectively. CONCLUSION: These preliminary results support the feasibility and acceptability of a mentored gardening intervention and suggest that it may offer a novel and promising strategy to improve fruit and vegetable consumption, physical activity, and physical function in cancer survivors. A larger randomized controlled trial is needed to confirm our results. PMID- 23438360 TI - Treatment decisions and discontinuation of palliative chemotherapy near the end of-life, in relation to socioeconomic variables. AB - During the last decades, the possibilities to prolong survival with chemotherapy even in metastatic disease have increased. Our aim was to study treatment decisions and treatment discontinuation decisions in the proximity of death. METHODS: The medical records of 346 patients with disseminated cancer and a recorded death during 2009 were assessed in relation to demographic and clinical variables and documented treatment decisions were recorded. RESULTS: Palliative chemotherapy was offered in 54% or these cases and generally one or two regimens were administered, before ending treatment. During the last month of life, 32% received treatment and much more often as an oral (instead of intravenous) treatment than in earlier stages (p < 0.001). Younger patients (p = 0.02) and those with young children (p < 0.001) were treated to a higher degree and also closer to death (p = 0.03). Other variables associated with a higher probability of treatment were high education level (p = 0.001), living with a partner (p = 0.001), female gender (p = 0.023) and ethnicity of non-European origin (p = 0.031). In a multivariate analysis, young age and high education remained as independent factors. In 57% of the cases there was no formal documentation of treatment discontinuation or end-of-life discussions with the patient. CONCLUSION: Socioeconomic status (SES) is of importance for the treatment decisions. About half of the patients with disseminated disease receive palliative chemotherapy and of these, about one third are treated even during the last month of life. In a majority of cases, there is no formal documentation of treatment discontinuation or end-of-life discussions. PMID- 23438361 TI - Outside the box. PMID- 23438362 TI - Portable kit for the assessment of gait parameters in daily telerehabilitation. AB - BACKGROUND: When designing a complete process of daily telerehabilitation, it should be borne in mind that patients should be furnished with properly designed methodologies for executing specific motion tasks and the assessment of the relevant parameters. In general, such a process should comprehend three basic elements in both the hospital and the home: (a) instrumented walkways, (b) walking aids or supports, and (c) equipment for the assessment of parameters. The objective, with gait being the focus, of this study was thus to design a simple, portable kit-as an alternative to the complex and expensive instruments currently used-to be easily interfaced or integrated with the instrumented walkways and aids/supports both for self-monitoring while patients are exercising with their own aids and for clinical reporting. MATERIALS AND METHODS: The proposed system is a portable kit that furnishes useful parameters with feedback to both the patient and the trainer/therapist. Capable of being integrated with the most common mechanical tools used in motion rehabilitation (handrail, scales, walkways, etc.), it constantly monitors and quantitatively assesses progress in rehabilitation care. It is composed of one step counter, photo-emitter detectors, one central unit for collecting and processing the telemetrically transmitted data, and a software interface. RESULTS AND DISCUSSION: The system has been successfully validated on 16 subjects at the second level of the Tinetti test in a clinical application for both home and the hospital. The portable kit can be used with different rehabilitation tools and on varying ground rugosity. Advantages include (a) very low cost, when compared with optoelectronic solutions or other portable devices, (b) very high accuracy, also for subjects with imbalance problems, compared with other commercial solutions, and (c) integration (compatibility) with any rehabilitative tool. PMID- 23438363 TI - Structural features of the apelin receptor N-terminal tail and first transmembrane segment implicated in ligand binding and receptor trafficking. AB - G-protein coupled receptors (GPCRs) comprise a large family of membrane proteins with rich functional diversity. Signaling through the apelin receptor (AR or APJ) influences the cardiovascular system, central nervous system and glucose regulation. Pathophysiological involvement of apelin has been shown in atherosclerosis, cancer, human immunodeficiency virus-1 (HIV-1) infection and obesity. Here, we present the high-resolution nuclear magnetic resonance (NMR) spectroscopy-based structure of the N-terminus and first transmembrane (TM) segment of AR (residues 1-55, AR55) in dodecylphosphocholine micelles. AR55 consists of two disrupted helices, spanning residues D14-K25 and A29-R55(1.59). Molecular dynamics (MD) simulations of AR built from a hybrid of experimental NMR and homology model-based restraints allowed validation of the AR55 structure in the context of the full-length receptor in a hydrated bilayer. AR55 structural features were functionally probed using mutagenesis in full-length AR through monitoring of apelin-induced extracellular signal-regulated kinase (ERK) phosphorylation in transiently transfected human embryonic kidney (HEK) 293A cells. Residues E20 and D23 form an extracellular anionic face and interact with lipid headgroups during MD simulations in the absence of ligand, producing an ideal binding site for a cationic apelin ligand proximal to the membrane-water interface, lending credence to membrane-catalyzed apelin-AR binding. In the TM region of AR55, N46(1.50) is central to a disruption in helical character. G42(1.46), G45(1.49) and N46(1.50), which are all involved in the TM helical disruption, are essential for proper trafficking of AR. In summary, we introduce a new correlative NMR spectroscopy and computational biochemistry methodology and demonstrate its utility in providing some of the first high-resolution structural information for a peptide-activated GPCR TM domain. PMID- 23438365 TI - Reply: To PMID 21480836. PMID- 23438364 TI - Properties of membranes derived from the total lipids extracted from the human lens cortex and nucleus. AB - Human lens lipid membranes prepared using a rapid solvent exchange method from the total lipids extracted from the clear lens cortex and nucleus of 41- to 60 year-old donors were investigated using electron paramagnetic resonance spin labeling. Profiles of the phospholipid alkyl-chain order, fluidity, oxygen transport parameter, and hydrophobicity were assessed across coexisting membrane domains. Membranes prepared from the lens cortex and nucleus were found to contain two distinct lipid environments, the bulk phospholipid-cholesterol domain and the cholesterol bilayer domain (CBD). The alkyl chains of phospholipids were strongly ordered at all depths, indicating that the amplitude of the wobbling motion of alkyl chains was small. However, profiles of the membrane fluidity, which explicitly contain time (expressed as the spin-lattice relaxation rate) and depend on the rotational motion of spin labels, show relatively high fluidity of alkyl chains close to the membrane center. Profiles of the oxygen transport parameter and hydrophobicity have a rectangular shape and also indicate a high fluidity and hydrophobicity of the membrane center. The amount of CBD was greater in nuclear membranes than in cortical membranes. The presence of the CBD in lens lipid membranes, which at 37 degrees C showed a permeability coefficient for oxygen about 60% smaller than across a water layer of the same thickness, would be expected to raise the barrier for oxygen transport across the fiber cell membrane. Properties of human membranes are compared with those obtained for membranes made of lipids extracted from cortex and nucleus of porcine and bovine eye lenses. PMID- 23438366 TI - Are left-handed women at increased risk of endometriosis? PMID- 23438367 TI - Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells. AB - Chemotherapy for colorectal cancer has become more complicated and diversified with the appearance of molecular-targeting agents. 5-Fluorouracil (5-FU) has been a mainstay of chemotherapy for colorectal cancer, but it is still unknown whether the combining of 5-FU with novel molecular-targeting agents is effective. Thymidylate synthase (TS) is a direct target of 5-FU, and the low TS level has been generally supposed to sensitize 5-FU's efficacy. We therefore hypothesized that RB-reactivating agents could enhance the efficacy of 5-FU, because the RB reactivating agents could suppress the function of transcription factor E2F of TS gene promoter. We used three RB-reactivating agents, trametinib/GSK1120212 (MEK inhibitor), fenofibrate (PPARalpha agonist), and LY294002 (PI3K inhibitor), with 5-FU against human colon cancer HT-29 and HCT15 cells. Trametinib induced p15 and p27 expression and reduced cyclin D1 levels in HT-29 cells. Fenofibrate also dephosphorlated ERK1/2 and reduced cyclin D1 levels in HT-29 cells. LY294002 induced p27 expression in HCT15 cells. All three agents caused dephosphorylation of RB protein and G1-phase arrest with a reduction of TS expression. As a consequence, the combination of 5-FU with each of the agents resulted in a significant decrease of colony numbers in HT-29 or HCT15 cells. These results suggest "RB-reactivation therapy" using molecular-targeting agents to be a new strategy for 5-FU-based chemotherapy. In particular, we strongly expect trametinib, which was discovered in Japan and was recently submitted to FDA for approval, to be used together with established regimens for colorectal cancer. PMID- 23438368 TI - Renal cell cancer treated with a single-edged sword. AB - Preclinical and early clinical data suggest that antiangiogenic treatments may lead to more aggressive tumors. In this issue of Cell Reports, Blagoev et al. (2013) show that sunitinib, a multikinase inhibitor with antiangiogenic effects, does not worsen the survival of patients with metastatic kidney cancer. PMID- 23438369 TI - A molecular motor, KIF13A, controls anxiety by transporting the serotonin type 1A receptor. AB - Molecular motors are fundamental to neuronal morphogenesis and function. However, the extent to which molecular motors are involved in higher brain functions remains largely unknown. In this study, we show that mice deficient in the kinesin family motor protein KIF13A (Kif13a(-/-) mice) exhibit elevated anxiety related behavioral phenotypes, probably because of a reduction in 5HT(1A) receptor (5HT(1A)R) transport. The cell-surface expression level of the 5HT(1A)R was reduced in KIF13A-knockdown neuroblastoma cells and Kif13a(-/-) hippocampal neurons. Biochemical analysis showed that the forkhead-associated (FHA) domain of KIF13A and an intracellular loop of the 5HT(1A)R are the interface between the motor and cargo vesicles. A minimotor consisting of the motor and FHA domains is able to transport 5HT(1A)R-carrying organelles in in vitro reconstitution assays. Collectively, our results suggest a role for this molecular motor in anxiety control. PMID- 23438370 TI - Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli. AB - The area postrema mediates the hypophagic effect of the pancreatic hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 MUg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 MUg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co localization of amylin-induced c-Fos and CTR (68%), no c-Fos/CTR co-localization occurred after treatment with GLP-1 or the GLP-1R agonist exendin 4 (2 MUg/kg ip). Similarly, LiCl (76 mg/kg ip) or AngII (50 MUg/kg sc) led to c-Fos expression only in CTR negative AP neurons. In conclusion, our findings support a protein-dependent modulation of behavioral and neuronal amylin responsiveness under equicaloric feeding conditions. Amino acids might contribute to the inhibitory effect of diet-derived protein to reduce amylin-induced neuronal AP activation. Neuronal AP responsiveness to GLP-1 is also increased in the fasted state suggesting that diet-derived nutrients may also interfere with AP-mediated GLP-1 effects. Nevertheless, the primary target neurons for amylin appear to be distinct from cells targeted by GLP-1 and by stimuli producing aversion (LiCl) or contributing to blood pressure regulation (AngII) via the AP. Since amylin and GLP-1 analogs are targets for the treatment of obesity, the nutrient-dependent modulation of AP responsiveness might entail implications for such therapeutic approaches. PMID- 23438371 TI - Aromatase regulates aggression in the African cichlid fish Astatotilapia burtoni. AB - The roles of estrogen and androgens in male social behavior are well studied, but little is known about how these hormones contribute to behavior in a social hierarchy. Here we test the role of aromatase, the enzyme that converts testosterone into estradiol, in mediating aggression and reproductive behavior in male Astatotilapia burtoni, an African cichlid fish that displays remarkable plasticity in social behavior. We first measured aromatase expression in subordinate and dominant males in brain regions that regulate social behavior and found that subordinate males have higher aromatase expression than dominant males in the magnocellular and gigantocellular regions of the preoptic area. Next, we functionally tested the role of aromatase in regulating behavior by intraperitoneally injecting dominant males with either saline or fadrozole (FAD), an aromatase inhibitor, and found that FAD treatment decreases aggressive, but not reproductive, behaviors compared to saline controls. To determine the underlying physiological and molecular consequences of FAD treatment, we measured estradiol and testosterone levels from plasma and brain aromatase expression in FAD and saline treated dominant males. We found that estradiol levels decreased and testosterone levels increased in response to FAD treatment. Moreover, FAD treated males had increased aromatase expression in the gigantocellular portion of the POA, possibly a compensatory response. Overall, our results suggest aromatase is a key enzyme that promotes aggression in A. burtoni males through actions in the preoptic area. PMID- 23438372 TI - Neonatal tactile stimulation alleviates the negative effects of neonatal isolation on novel object recognition, sociability and neuroendocrine levels in male adult mandarin voles (Microtus mandarinus). AB - Neonatal isolation results in long-lasting negative alterations to the brain and behavior. Some of these changes include effects on non-spatial learning and memory, sociability and neuroendocrine levels. Theoretically, neonatal tactile stimulation should reverse the impacts of neonatal isolation; however, this remains unknown for changes relating to learning, memory, sociability and hormones in social animals. Using socially monogamous mandarin voles (Microtus mandarinus), the long-lasting effects of these early manipulations on anxiety like behavior, novel object recognition, sociability, and neuroendocrine levels were investigated. Compared with neonatal-isolated males, males subjected to the same manipulation but accompanied with tactile stimulation had heavier body weights across PND4-18 and displayed significantly less anxiety-like behavior in an open field test. In addition, tactile stimulation increased the preference index for novel object recognition reduced by neonatal isolation. Compared with control males, neonatal-isolated males engaged in less body contact with unfamiliar same-sex individuals and this effect was reversed by neonatal tactile stimulation. Tactile stimulation enhanced aggressive behavior in neonatal isolated males and increased the levels of AVP and OT in the paraventricular nucleus (PVN) which were decreased by neonatal isolation. This early manipulation also reduced serum CORT levels that were significantly up-regulated by neonatal isolation in both neonatal and adult offspring. These results indicate that adequate tactile stimulation in early life plays an important role in the prevention of behavioral disturbances induced by neonatal isolation, possibly through the alteration of central OT, AVP and the serum corticosterone levels. PMID- 23438373 TI - Cognitive-behavioral group therapy for youths with anxiety disorders in the community: effectiveness in low and middle income countries. AB - BACKGROUND: Although cognitive-behavioral therapy (CBT) is established as a first line treatment for anxiety disorders in children and adolescents, there is little evidence about the effectiveness of CBT protocols in cases identified in the community in low and middle income countries (LaMICs). AIMS: To evaluate the effectiveness of group CBT protocol for youths with anxiety disorders identified in a community sample in LaMICs. METHOD: A total of 14 sessions of group CBT for youths and 2 concurrent sessions for parents based on Kendall's Coping Cat program were offered. Participants were selected from a cross-sectional community study; 45 subjects fulfilled inclusion criteria and 28 agreed to participate in the open clinical trial. Treatment effectiveness was evaluated with standard clinical, self- and parent-rated measures of anxiety, depression, externalizing symptoms and quality of life (QoL). RESULTS: Twenty youths completed the protocol. All scales showed an improvement of anxiety and reduction in externalizing symptoms over time, with a moderate to large effect size (d = 0.59 to 2.06; p < .05), but not in depressive symptoms or QoL. CONCLUSIONS: Consistent with previous evidence, group CBT is effective in treating anxiety disorders in youths. Results encourage further randomized clinical trials using CBT protocols adapted and developed to be used in LaMICs. PMID- 23438374 TI - Block of the superior cervical ganglion, description of a novel ultrasound-guided technique in human cadavers. AB - OBJECTIVE: Injection of opioids to the superior cervical ganglion (SCG) has been reported to provide pain relief in patients suffering from different kinds of neuropathic facial pain conditions, such as trigeminal neuralgia, postherpetic neuralgia, and atypical facial pain. The classic approach to the SCG is a transoral technique using a so-called "stopper" to prevent accidental carotid artery puncture. The main disadvantage of this technique is that the needle tip is positioned distant from the actual target, possibly impeding successful block of the SCG. A further limitation is that injection of local anesthetics due to potential carotid artery puncture is contraindicated. We hypothesized that the SCG can be identified and blocked using ultrasound imaging, potentially increasing precision of this technique. INTERVENTIONS: In this pilot study, 20 US guided simulated blocks of the SCG were performed in 10 human cadavers in order to determine the accuracy of this novel block technique. After injection of 0.1 mL of dye, the cadavers were dissected to evaluate the needle position and coloring of the SCG. RESULTS: Nineteen of the 20 needle tips were located in or next to the SCG. This corresponded to a simulated block success rate of 95% (95% confidence interval 85-100%). In 17 cases, the SCG was completely colored, and in two cases, the caudal half of the SCG was colored with dye. CONCLUSIONS: The anatomical dissections confirmed that our ultrasound-guided approach to the SCG is accurate. Ultrasound could become an attractive alternative to the "blind" transoral technique of SCG blocks. PMID- 23438375 TI - pH-controlled nanoaggregation in amphiphilic polymer co-networks. AB - Domain formation and control in pH-responsive amphiphilic polymer co-networks are studied theoretically. Two different molecular architectures of the polymer network are considered, depending on whether the pH-sensitive motif is borne by the hydrophobic or the hydrophilic monomer. When the hydrophobic polymer contains acidic groups, such chains form nanometric aggregates at acidic conditions, but they are found in a swollen state at alkaline pH. At intermediate pH, the nanoaggregation behavior of the hydrophobic polymer depends critically on the environment salt concentration. Moreover, our results indicate the presence of microphase separation into domains of swollen and aggregated hydrophobic chains. If the hydrophilic polymer is the ionizable component of the network, the nanoaggregation of hydrophobic monomers is weakly dependent on the pH and salt concentration, and except at very low volume fraction, the aggregate is the most probable conformation of the network in the entire range of pH and salt concentration studied. The two different hydrogels display quantitatively similar swelling transition and apparent pKa, but at the nanoscale, their behavior is qualitatively different. The spatial distribution of electric charge on the network as well as the local density of the different chemical species within the hydrogel can be controlled, as a function of pH and salt concentration, by the molecular architecture of the polymer network. These findings have relevance for applications in biomaterials and nanotechnology, in particular, in the design of oral delivery devices for the administration of hydrophobic drugs. PMID- 23438376 TI - Recent advancements in the treatment of melanoma: part I--understanding melanoma from the inside out! PMID- 23438377 TI - Historical review of melanoma treatment and outcomes. AB - The surgical and medical management of melanoma has changed dramatically since the first description of melanoma as a disease entity more than 200 years ago. Refinement of surgical techniques, including evaluation of optimal surgical margins, utility of elective lymph node dissection, and incorporation of sentinel lymph node mapping as both a prognostic tool and guide for selective lymphadenectomy have lessened surgical morbidity and improved outcomes for early stage and locally advanced melanoma. Astute clinical observations of the integrated roles of the immune system and oncogenic mutations have more recently led to improvements in survival and quality of life for advanced melanoma. Herein, we provide an overview of the most significant surgical and medical milestones in the treatment of melanoma over the past 2 centuries. PMID- 23438378 TI - Melanoma genetics: the other side. AB - Although melanoma has traditionally been regarded as a uniformly fatal malignancy, personalized treatment of this cancer relies on the recognition of its genetic heterogeneity and our ability to pharmacologically target these specific and recurrent changes. Recent advances in the treatment of melanoma have come from the understanding that melanoma is a large family of molecularly distinct diseases. Advances in melanoma genetics and new molecular technology, such as whole-exome and whole-genome sequencing, have lead to unprecedented progress in understanding the key oncogenes and signaling pathways involved in the pathogenesis and progression of melanoma. In addition, we have gained an appreciation for the complexity of such a system with numerous points of cross talk, which has partially impeded our current therapeutic strategies in patients with advanced melanoma. In this review, we focus on the novel discoveries in melanoma genetics and the potential for therapeutic options. PMID- 23438379 TI - Immunology of melanoma. AB - It can be safely said that human melanomas are immunogenic. Virtually all the major principles of "tumor immunology" have been experimentally established in this model. It is now amply clear that melanoma cells display multiple antigens and peptide epitopes that are targetable by the host immune system and that patients with melanoma are capable of responding to these antigens and epitopes serologically as well as through the cell-mediated mechanisms. The immune responses against melanoma are, however, subject to regulation by the regulatory processes within the immune system itself and melanoma cells can resort to overt evasive activities. Indeed, the intrinsic as well as the extrinsic mechanisms within the immune system that are designed to control the magnitude as well as the duration of immune responses at times act as constraints against generating a robust and long-lasting antimelanoma response and melanoma cells are capable of using all the tricks (eg, downregulation of targetable molecules, elaboration of immunosuppressive cytokines) available to living organisms so as to evade immune recognition and destruction. As a result, the immune system often fails to protect the host against melanoma development and progression. The cumulative knowledge over the years on melanoma-associated antigens and epitopes, on methods of immunization, and on technologies for generating melanoma antigen-specific T cells, natural or engineered, have led to the development of immunotherapeutic strategies with "melanoma vaccines" and with T-cell-based adoptive immunotherapy for melanoma. Although these strategies have not been uniformly successful in all cases, durable complete regressions of metastatic melanoma can at times be obtained with active specific immunization or adoptive cell therapy. There is reason for hope that continued research in the field is likely to improve the outcome of melanoma immunotherapy: the ultimate goal of tumor immunology. PMID- 23438381 TI - Vaccines against advanced melanoma. AB - Research shows that cancers are recognized by the immune system but that the immune recognition of tumors does not uniformly result in tumor rejection or regression. Quantitating the success or failure of the immune system in tumor elimination is difficult because we do not really know the total numbers of encounters of the immune system with the tumors. Regardless of that important issue, recognition of the tumor by the immune system implicitly contains the idea of the tumor antigen, which is what is actually recognized. We review the molecular identity of all forms of tumor antigens (antigens with specific mutations, cancer-testis antigens, differentiation antigens, over-expressed antigens) and discuss the use of these multiple forms of antigens in experimental immunotherapy of mouse and human melanoma. These efforts have been uniformly unsuccessful; however, the approaches that have not worked or have somewhat worked have been the source of many new insights into melanoma immunology. From a critical review of the various approaches to vaccine therapy we conclude that individual cancer-specific mutations are truly the only sources of cancer specific antigens, and therefore, the most attractive targets for immunotherapy. PMID- 23438380 TI - Melanocytes, melanocyte stem cells, and melanoma stem cells. AB - Melanocyte stem cells differ greatly from melanoma stem cells; the former provide pigmented cells during normal tissue homeostasis and repair, and the latter play an active role in a lethal form of cancer. These 2 cell types share several features and can be studied by similar methods. Aspects held in common by both melanocyte stem cells and melanoma stem cells include their expression of shared biochemical markers, a system of similar molecular signals necessary for their maintenance, and a requirement for an ideal niche microenvironment for providing these factors. This review provides a perspective of both these cell types and discusses potential models of stem cell growth and propagation. Recent findings provide a strong foundation for the development of new therapeutics directed at isolating and manipulating melanocyte stem cells for tissue engineering or at targeting and eradicating melanoma specifically, while sparing nontumor cells. PMID- 23438383 TI - Targeted therapy in melanoma. AB - Since the discovery of activating mutations in the BRAF oncogene in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. We review the latest developments in our understanding of the role of BRAF/MEK/ERK pathway signaling in melanoma, and the development of inhibitors of this pathway. We also explore alternative mutations seen in melanoma, such as NRAS, KIT, GNAQ, and GNA11, and the drug development that is ongoing based on this biology. Strategies for the management of the vexing clinical problem of BRAF inhibitor resistance, primarily via combination therapy, are outlined. With the recent approval of the BRAF inhibitor vemurafenib for stage IV metastatic melanoma, use of this agent is expanding in the United States. Thus, management of the skin toxicities of this agent, such as squamous cell carcinomas, "acneiform" eruptions, hand-foot syndrome, and panniculitis, will be a growing problem facing dermatologists today. We discuss the toxicities of targeted agents in use for melanoma, in particular the dermatologic effects and the management of these skin toxicities. PMID- 23438384 TI - The adoptive transfer of cultured T cells for patients with metastatic melanoma. AB - T cells have been shown to be capable of rejecting a patient's tumor. Weak responses to current vaccines and the toxicity of exogenously administered cytokines limit the intensity of the T-cell response that can be actively generated in vivo. Adoptive T-cell transfer enhances an intrinsically weak immune response to cancer by activating and expanding tumor reactive T cells in vitro and manipulating the environment of the host at the time of transfer. One can frequently find tumor-reactive T cells in metastatic lesions in patients with melanoma, and expand them in vitro for readministration. When successful, this adoptive cellular immunotherapy has resulted in sustainable curative outcomes. Subsequently, the applicability of adoptive T-cell transfer has been greatly expanded by the development of methods to genetically engineer open-repertoire human T-cells to confer tumor reactivity. This re-direction of T-cell specificity can be achieved by introducing a variety of receptors that ligate tumor associated antigens and then trigger the normal activation mechanism of T cells. Future T-cell engineering will add a new dimension by reprogramming T-cell functions for optimal tumor rejection. The antigens recognized by T cells, the techniques to procure and grow tumor reactive T cells, the conditioning of the recipient to optimize efficacy, and the results of clinical protocols are reviewed herein. PMID- 23438382 TI - Immunomodulatory therapy for melanoma: ipilimumab and beyond. AB - In 2011, the U.S. Food and Drug Administration approved the first new therapy for melanoma in more than a decade, ipilimumab (Yervoy). Ipilimumab is a novel antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a regulatory molecule expressed on activated T cells. Blockade of this important immune checkpoint can lead to durable tumor regression, and phase III studies show an overall survival benefit for patients with advanced melanoma. During the clinical development of ipilimumab, several unique features of this immunotherapy were identified, including the remarkable durability of responses and a distinct side-effects profile. We review the preclinical and clinical development of CTLA 4-blocking antibodies and describe current practices using ipilimumab for the treatment of advanced melanoma. Unique clinical issues related to ipilimumab will be summarized. Lastly, we will briefly preview combination therapies that incorporate ipilimumab and new checkpoint-targeting antibodies currently in clinical development. PMID- 23438385 TI - Gendercide: examining gender-based crimes against women and men. PMID- 23438387 TI - Formation of photoconductive nanowires of tetracene derivative in composite thin film. AB - Nanowires of tetracene dicarboxylic imide disulfide with an N-hexyl substituent (HexylTIDS) were successfully constructed in composite thin film containing poly(3-hexylthiophene) (P3HT). The nanowire structures were investigated by atomic force microscopy and scanning electron microscopy. The photoconductivity of the composite films was evaluated by time-resolved microwave conductivity measurements, revealing that the film containing a 1:1 w/w ratio of HexylTIDS and P3HT exhibited the highest photoconductivity (2.1 * 10(-7) m(2)/(V s)). The intermolecular interactions of HexylTIDS molecules were important in nanowire formation. These results suggest a one-step method for fabricating small-molecule based nanowires in composite films from a blended solution. This type of composite film, and its fabrication method, will be useful for developing organic thin-film photoelectronic devices. PMID- 23438386 TI - Environmental and occupational pesticide exposure and human sperm parameters: a systematic review. AB - Of continuing concern are the associations between environmental or occupational exposures to pesticides and semen quality parameters. Prior research has indicated that there may be associations between exposure to pesticides of a variety of classes and decreased sperm health. The intent of this review was to summarize the most recent evidence related to pesticide exposures and commonly used semen quality parameters, including concentration, motility and morphology. The recent literature was searched for studies published between January 2007 and August 2012 that focused on environmental or occupational pesticide exposures. Included in the review are 17 studies, 15 of which reported significant associations between exposure to pesticides and semen quality indicators. Two studies also investigated the roles genetic polymorphisms may play in the strength or directions of these associations. Specific pesticides targeted for study included dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), and abamectin. Pyrethroids and organophosphates were analyzed as classes of pesticides rather than as individual compounds, primarily due to the limitations of exposure assessment techniques. Overall, a majority of the studies reported significant associations between pesticide exposure and sperm parameters. A decrease in sperm concentration was the most commonly reported finding among all of the pesticide classes investigated. Decreased motility was also associated with exposures to each of the pesticide classes, although these findings were less frequent across studies. An association between pesticide exposure and sperm morphology was less clear, with only two studies reporting an association. The evidence presented in this review continues to support the hypothesis that exposures to pesticides at environmentally or occupationally relevant levels may be associated with decreased sperm health. Future work in this area should focus on associations between specific pesticides or metabolic products and sperm quality parameters. Analysis of effects of varying genetic characteristics, especially in genes related to pesticide metabolism, also needs further attention. PMID- 23438388 TI - A comprehensive molecular phylogeny for the hornbills (Aves: Bucerotidae). AB - The hornbills comprise a group of morphologically and behaviorally distinct Palaeotropical bird species that feature prominently in studies of ecology and conservation biology. Although the monophyly of hornbills is well established, previous phylogenetic hypotheses were based solely on mtDNA and limited sampling of species diversity. We used parsimony, maximum likelihood and Bayesian methods to reconstruct relationships among all 61 extant hornbill species, based on nuclear and mtDNA gene sequences extracted largely from historical samples. The resulting phylogenetic trees closely match vocal variation across the family but conflict with current taxonomic treatments. In particular, they highlight a new arrangement for the six major clades of hornbills and reveal that three groups traditionally treated as genera (Tockus, Aceros, Penelopides) are non monophyletic. In addition, two other genera (Anthracoceros, Ocyceros) were non monophyletic in the mtDNA gene tree. Our findings resolve some longstanding problems in hornbill systematics, including the placement of 'Penelopides exharatus' (embedded in Aceros) and 'Tockus hartlaubi' (sister to Tropicranus albocristatus). We also confirm that an Asiatic lineage (Berenicornis) is sister to a trio of Afrotropical genera (Tropicranus [including 'Tockus hartlaubi'], Ceratogymna, Bycanistes). We present a summary phylogeny as a robust basis for further studies of hornbill ecology, evolution and historical biogeography. PMID- 23438389 TI - Mood states determine the degree of task shielding in dual-task performance. AB - Current models of multitasking assume that dual-task performance and the degree of multitasking are affected by cognitive control strategies. In particular, cognitive control is assumed to regulate the amount of shielding of the prioritised task from crosstalk from the secondary task. We investigated whether and how task shielding is influenced by mood states. Participants were exposed to two short film clips, one inducing high and one inducing low arousal, of either negative or positive content. Negative mood led to stronger shielding of the prioritised task (i.e., less crosstalk) than positive mood, irrespective of arousal. These findings support the assumption that emotional states determine the parameters of cognitive control and play an important role in regulating dual task performance. PMID- 23438390 TI - Words of wisdom: re: big med: restaurant chains have managed to combine quality control, cost control, and innovation. Can health care? PMID- 23438391 TI - Words of wisdom: re: radical prostatectomy versus observation for localized prostate cancer. PMID- 23438392 TI - Words of wisdom: re: radical prostatectomy versus observation for localized prostate cancer. PMID- 23438393 TI - Words of wisdom: re: high-throughput lensfree 3D tracking of human sperms reveals rare statistics of helical trajectories. PMID- 23438394 TI - Words of wisdom: re: prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. PMID- 23438395 TI - Words of wisdom: re: pilot trial of sunitinib therapy in patients with von hippel lindau disease. PMID- 23438396 TI - Regulatory considerations for the approval of analgesic drugs for cattle in the United States. AB - Continuous life-cycle management of veterinary drugs by the Food and Drug Administration Center for Veterinary Medicine (CVM) ensures that safe and effective approved animal drugs are available for use in the United States. This article summarizes basic requirements for the approval of new animal drugs, with a specific focus on the approval of analgesic drugs for use in cattle. CVM encourages drug companies to use innovative approaches to demonstrate the effectiveness of analgesic drugs for cattle. There is an obvious need for continued research into the development of new animal drugs for the control of pain in cattle. PMID- 23438397 TI - A review of analgesic compounds used in food animals in the United States. AB - Extralabel drug use for pain relief in the United States is regulated under the Animal Medicinal Drug Use Clarification Act. Agents that may provide analgesia in livestock include local anesthetics, nonsteroidal antiinflammatory drugs, opioids, alpha2-agonists, and N-methyl-d-aspartate receptor antagonists. The challenges associated with providing pain relief in food animals and the salient pharmacokinetic and pharmacodynamic features of the analgesic compounds that could potentially be used in livestock are reviewed. The potential use of novel agents such as bicarbonate, magnesium, ethanol, and gabapentin to augment analgesia is also discussed. PMID- 23438398 TI - Extralabel use of anesthetic and analgesic compounds in cattle. AB - The need for drugs for sedation, anesthesia, or analgesia in cattle is relatively common in bovine practice. Because almost nothing is specifically approved for anesthesia or analgesia in cattle, the administration of most of these drugs represents extralabel drug use. The primary purpose of this article is to discuss the pharmacokinetics of the main drugs used for sedation, anesthesia, or analgesia in cattle, including information on meat and milk withdrawal where possible. PMID- 23438399 TI - Behavioral responses of cattle to pain and implications for diagnosis, management, and animal welfare. AB - Pain is a subjective experience in humans and livestock and can only be measured indirectly, posing challenges for veterinary practitioners in terms of diagnosis and treatment of bovine pain. In this review, attitudes of citizens, producers, and veterinarians are explored regarding pain and its associations with animal welfare and husbandry procedures. Behavior used to quantify pain in cattle is identified in terms of pain-specific behaviors and general behavioral responses that can be observed during painful procedures or convalescence. Finally, nociception and cognitive tests used for reporting pain in human patients are investigated for application to bovine patients. PMID- 23438400 TI - Remote noninvasive assessment of pain and health status in cattle. AB - Cattle behavior is frequently monitored to determine the health of the animal. This article describes potential benefits and challenges of remotely monitoring cattle behavior with available methodologies. The behavior of interest, labor required, and monitoring expenses must be considered before deciding which remote behavioral monitoring device is appropriate. Monitoring the feeding behavior of an animal over time allows establishment of a baseline against which deviations can be evaluated. Interpretation of multiple behavioral responses as an aggregate indicator of animal wellness status instead of as individual outcomes may be a more accurate measure of true state of pain or wellness. PMID- 23438401 TI - Assessment and management of pain associated with castration in cattle. AB - Validated pain assessment tools are needed to support approval of analgesic compounds to alleviate pain associated with castration. Accelerometers, videography, heart rate variability, electroencephalography, thermography, and plasma neuropeptide measurement to assess behavioral, physiologic, and neuroendocrine changes associated with castration are discussed. Preemptive local and systemic analgesia are also reviewed. Previous studies found that preemptive administration of nonsteroidal antiinflammatory drug (NSAID) and local anesthesia significantly decreased peak serum cortisol concentration after castration. Local anesthesia alone tended to decrease peak cortisol concentrations more than NSAIDs, whereas NSAIDs alone tended to decrease the area under the cortisol-time curve more than local anesthesia alone. PMID- 23438402 TI - Bovine dehorning: assessing pain and providing analgesic management. AB - Dehorning or disbudding in cattle is performed for a variety of reasons using various methods. Pain associated with this procedure has been mostly evaluated through behavioral, physiologic, and neuroendocrine changes following dehorning. Analgesics, including local nerve blockades, anti-inflammatories, and opioids have demonstrated an effective attenuation of the cortisol response. The administration of sedatives with analgesic properties has been indicated in the attenuation of the acute phase of pain associated with dehorning. Following a literature review, this article recommends a multimodal approach to analgesia for dehorning procedures, including the use of a local anesthetic and anti inflammatory and, when possible, a sedative-analgesic. PMID- 23438403 TI - Assessment and management of pain associated with lameness in cattle. AB - Lameness impacts the cattle industry in economic losses and welfare considerations. In addition to production deficits, pain and distress associated with lameness have been documented. The evaluation and prevalence of lame cattle is one of the primary factors in third-party welfare audit programs. To improve earlier detection and treatment of lameness, locomotion scoring systems have been developed for routine use by farm employees. Recommendations for pain management typically include the use of a multimodal therapeutic approach. Similarly, in lame cattle, pain can best be alleviated by implementing a multimodal approach including corrective claw trimming and placement of foot blocks combined with additional benefits provided by analgesic compounds. PMID- 23438404 TI - Prevention and management of surgical pain in cattle. AB - Management of pain continues to be an important consideration in livestock on which surgical procedures are performed. A balance must be achieved between the need to mitigate discomfort and the economic constraints of the production enterprise. Moral and ethical dilemmas have increased among consumers and these concerns have stimulated interest to reexamine the methods used to achieve the shared goals of humane production of safe, affordable animal products for human consumption. This article discusses drug and anesthetic protocols for field surgery of cattle, including nonsteroidal antiinflammatory drugs, opioids, local and regional anesthesia, epidural anesthesia, and electroacupuncture. PMID- 23438405 TI - Assessment and management of pain in small ruminants and camelids. AB - Many disease processes and management procedures of small ruminants have the potential to result in painful or noxious stimuli. There are a variety of medications and interventions that can be used to minimize the long-term consequences of pain in these species. The first portion of this article focuses on the commonly used medications available for pain management of small ruminants and discusses the benefits and side effects to their use. The second portion of the article focuses on the management of pain associated with common diseases or procedures of these species. PMID- 23438406 TI - Chemical restraint and injectable anesthesia of ruminants. AB - The ketamine stun technique provides enhanced patient cooperation when compared with more traditional injectable chemical restraint cocktails. Depending on the dose and route of administration, the ketamine stun also provides a variable degree of systemic analgesia. The ketamine stun technique has been shown to reduce the stress response to castration and dehorning in calves. Anesthesia should be considered for procedures requiring an extended period of immobility or a high level of systemic analgesia. Constant rate infusion techniques, such as double drip or ruminant triple drip, provide a more stable plane of injectable anesthesia than bolus administration techniques. PMID- 23438407 TI - The economics of pain management. AB - Using castration and dehorning as the test base, this article evaluates whether pain management is associated with increased production and whether this motivates producers. The literature supporting increased production parameters is limited. Studies have evaluated short periods and often use few animals. Few studies are repeated and the potential for publication bias is high. There is little evidence that pain management is associated with increased production. This is a concern because survey data suggest producers are partly motivated based on economic factors. The unanswered question is whether economic incentive programs would be greater motivators than increased production. PMID- 23438408 TI - Pain management. PMID- 23438409 TI - Long-range ordering of block copolymer cylinders driven by combining thermal annealing and substrate functionalization. AB - This work presents a new method for forming well-defined nanostructured thin films from self-assembled polystyrene-block-poly(l-lactide) (PS-PLLA) on Si wafers with a functionalized SiO2 surface. Large, well-ordered, perpendicular PLLA cylinders in PS-PLLA thin films can be formed using the functionalized substrate. In contrast to random copolymers, a neutral substrate for the PS and PLLA blocks is formed by functionalizing a substrate with hydroxyl-terminated PS (PS-OH) followed by hydroxyl-terminated PLLA (PLLA-OH). The heterogeneous grafting of PS-OH and PLLA-OH can be substantially alleviated using this two-step functionalization. Accordingly, the surface properties can be fine-tuned by controlling the ratio of grafted PS-OH to PLLA-OH to control the orientation of the PLLA cylinders on the functionalized SiO2. Nevertheless, the orientation that is driven by the neutral substrate is surprisingly limited in that the effective length of orienting cylinders is less than twice the interdomain spacing. Thermal annealing at high temperature can yield a neutral air surface, rendering perpendicular PLLA cylinders that stand sub-micrometers from the air surface. Consequently, the neutral substrate can be used to enable truly film-spanning perpendicular cylinders in films to be fabricated using the high-temperature thermal treatment. In addition, the perpendicular cylinders can be laterally ordered by further increasing the annealing temperature. The ability to create these film-spanning perpendicular cylinders in films with a well-ordered texture and sub-micrometer thickness opens up possible applications in nanotechnology. PMID- 23438410 TI - PTPN22 gene polymorphism (C1858T) is associated with susceptibility to type 1 diabetes: a meta-analysis of 19,495 cases and 25,341 controls. AB - The protein tyrosine phosphatase N22 (PTPN22) gene C1858T polymorphism has been reported to be associated with susceptibility to type 1 diabetes (T1D) in relatively small sample sizes. This study aimed at investigating the pooled association by carrying out a meta-analysis on the published studies. The Medline, EBSCO, and BIOSIS databases were searched to identify eligible studies published in English before June 2012. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). The presence of heterogeneity and publication bias was explored by using meta-regression analysis and Begg's test, respectively. A total of 28 studies were involved in this meta-analysis. Across all populations, significant associations were found between the PTPN22 C1858T polymorphism and susceptibility to T1D under genotypic (TT vs. CC [OR = 3.656, 95% CI: 3.139-4.257], CT vs. CC [OR = 1.968, 95% CI: 1.683-2.300]), recessive (OR = 3.147, 95% CI: 2.704-3.663), and dominant models (OR = 1.957, 95% CI: 1.817 2.108). In ethnicity- and sex-stratified analyses, similar associations were found among Caucasians and within Caucasian male and female strata. The meta analysis results suggest that the PTPN22 C1858T polymorphism was associated with susceptibility to T1D among the Caucasian population, and males who carried the 1858T allele were more susceptible to T1D than females. PMID- 23438411 TI - Effects of a forgiveness intervention for older adults. AB - The authors' aim in the present study was to examine the effects of a brief forgiveness intervention for older adults. The psychoeducational group intervention consists of (a) established core components of previous forgiveness interventions and (b) additional components considering specific needs of older adults. Seventy-eight older adults (mean age 70.1 years) were randomized to a treatment condition or a waiting-list control condition. The intervention reduced the levels of perceived actual transgression painfulness, transgression-related emotions and cognitions, and negative affect. These findings suggest the promise of forgiveness interventions for older adults that help participants clarify and deal with past, present, and future interpersonal transgressions. PMID- 23438412 TI - Financial strain and regional unemployment as barriers to job search self efficacy: a test of social cognitive career theory. AB - Social cognitive career theory (SCCT) emphasizes the potential impact of contextual barriers on vocational self-efficacy, interests, and goals. However, most tests of SCCT to date have focused exclusively on person-level, perceptual barriers rather than objective, macroeconomic barriers that may influence large groups of people. In this study, we examine how the effects of personal experiences with financial strain among a sample of adults who are unemployed are qualified by regional unemployment rates. Results indicated that financial strain has a direct, negative relation with job search self-efficacy, and indirect, negative relations with job search outcome expectations and search goals. These direct and indirect relations are moderated by unemployment rates and are only significant for participants residing in U.S. counties with high unemployment. These findings highlight the importance of taking into account broader contextual influences when studying vocational outcomes and demonstrate the applicability of incorporating macroeconomic barriers and supports into SCCT in future research. PMID- 23438413 TI - Disentangling the link between perceiving a calling and living a calling. AB - Research has suggested there is an important distinction between perceiving a calling and living a calling. With a sample of 542 working adults, the current study examined (a) the degree to which perceiving a calling and living a calling differed according to yearly income and level of educational attainment and (b) potential mediators that may explain the link between perceiving a calling and living a calling. Adults with higher yearly incomes and more education were significantly more likely to endorse living a calling, but no significant group differences were found for perceiving a calling. Additionally, using structural equation modeling, work volition was found to be a significant mediator in the link between perceiving a calling and living a calling, and organizational support was found to be a significant mediator in the link between work volition and living a calling. The strength and significance of these indirect effects were supported by bootstrapping techniques. We suggest that part of the reason people with a calling feel more able to live out that calling is because of increased feelings of control in their career decision making. Implications for research and practice are discussed. PMID- 23438415 TI - Ion release and physical properties of CPP-ACP modified GIC in acid solutions. AB - A new glass-ionomer cement (GIC) (Fuji VIITM EP) includes 3% (w/w) casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) to enhance ion release. OBJECTIVES: To assess this new GIC compared with a GIC without CPP-ACP (Fuji VIITM) with respect to ion release, changes in surface hardness and in mass under a variety of acidic and neutral conditions. METHODS: Eighty blocks of Fuji VIITM (F7) and Fuji VIITM EP (F7EP) were subjected to three acidic solutions (lactic and citric acids pH 5.0, hydrochloric acid pH 2.0) and water (pH 6.9) over a three-day period. Ion release, surface hardness and weight measurements were carried out every 24h. RESULTS: Higher calcium ion release from F7EP was observed under all acidic conditions. Increased inorganic phosphate ion release was observed for F7EP in hydrochloric and citric acids. Fluoride ion release was similar between F7 and F7EP under all conditions but was significantly higher in acids compared with water. After three days there was no significant difference in surface hardness (p>0.05) between the two materials under all conditions except hydrochloric acid. Minimal change in mass was observed for F7 and F7EP in water, lactic and hydrochloric acids, however citric acid caused significantly more mass loss compared with water (p<0.001). CONCLUSION: Incorporation of 3% (w/w) CPP-ACP into F7 enhanced calcium and phosphate ion release, with no significant change in fluoride ion release and no adverse effects on surface hardness or change in mass. CLINICAL SIGNIFICANCE STATEMENT: GICs have the potential to release fluoride ions particularly under acidic conditions associated with dental caries and erosion. A new GIC containing CPP-ACP and fluoride releases not only fluoride ions but also calcium and phosphate ions under acidic conditions which should help to inhibit demineralisation associated with caries and erosion. PMID- 23438414 TI - Anabolic potential of bone mineral in human periosteal fibroblasts using steroid markers of healing. AB - A deproteinized natural cancellous bone mineral (B) was studied in a cell culture model for its anabolic potential using two radiolabelled steroid substrates, 14C testosterone (14C-T) and 14C-4-androstenedione (14C-4-A) independently; in the presence or absence of the anti-androgen finasteride (F) and minocycline (M). Culture medium was assayed for the biologically active metabolite 5 alpha dihydrotestosterone (DHT) a marker of regenerative potential and wound healing. Confluent monolayer cultures of human periosteal fibroblasts were incubated in Eagle's minimum essential medium with each of the substrates 14C-T and 14C-4-A. Incubations were performed with previously established optimal concentrations of B5 (milligrams/ml), M25 (MUg/ml) and F5 (MUg/ml) alone and in combination (n=6) for 24h. The eluent was solvent extracted with ethyl acetate (2 ml x 2) and subjected to TLC in a benzene/acetone solvent system (4:1 v/v) for separation of metabolites; they were quantified using a radioisotope scanner. The yield of DHT was increased over controls in response to B and M with both substrates 14C-T and 14C-4-A by 1.7, 1.8-fold and 1.7, 1.6-fold respectively (n=6; p<0.001; one way ANOVA). Combined incubations of B and M resulted in similar yields. F inhibited DHT yields with both radiolabelled substrates by 2-3-fold (n=6; p<0.001) which was overcome by a combined incubation of F+B to values similar to those of controls (p<0.01). Documented pro-anabolic effects of minocycline were applicable as a standard for confirmation of responses to B. Significant increases in yields of DHT in response to B and M with both substrates indicate their anabolic potential in periosteal fibroblasts with implications for wound healing. PMID- 23438416 TI - Clinical interpretation of a masticatory normative indicator analysis of masticatory function in subjects with different occlusal and prosthodontic status. AB - OBJECTIVES: To analyse the masticatory function of subjects characterised by different occlusal and prosthodontic status. Using Optosil((r)) as a test food, the masticatory normative indicator (MNIOPT) was used to differentiate between sufficient ('normal') and impaired masticatory function. METHODS: Outcomes of occlusal force and masticatory tests were aggregated from three earlier studies dealing with four denture groups and three natural dentition groups. The four denture groups had a complete removable dental prosthesis in the upper jaw, and displayed one of the four following lower jaw prosthodontic rehabilitations: (i) complete removable dental prosthesis on a low mandible; (ii) complete removable dental prosthesis on a higher mandible; (iii) overdenture on natural roots; and (iv) overdenture on dental implants. The three natural dentition groups were: (i) shortened dental arch; (ii) complete dentition in older participants, and (iii) complete dentition in younger participants. All participants were women. They performed the same tests twice, and outcomes were averaged. RESULTS: A MNIOPT value of 3.68 mm was determined from the participants with complete natural dentitions. Applying the MNIOPT to the participants in the denture groups pointed at a considerable chance for impaired masticatory function, except for participants in the overdenture -implants group. The four denture groups compensated for reduced masticatory efficiency by increased number of masticatory cycles and prolonged mastication time until 'swallowing'. Nevertheless, they also 'swallowed' larger particles compared to the complete dentition group. CLINICAL SIGNIFICANCE: For a given patient or for a group of subjects with specific dental conditions, MNI enables to discriminate between a sufficient ('normal') and an impaired masticatory function. PMID- 23438417 TI - The effect of a coupling medium on color and translucency of CAD-CAM ceramics. AB - OBJECTIVES: To evaluate color and translucency of ceramics and the influence of a coupling medium (G - glycerin) on these optical properties, testing the hypothesis that glycerin influences the translucency values regardless the evaluation method. METHODS: Five specimens from A2-shaded ceramics (IPS e.max CAD HT and LT, IPS Empress CAD HT and LT, Paradigm C, and Vita Mark II) were fabricated from ceramic blocks and polished to 1.0 +/- 0.01mm in thickness. A spectrophotometer (Vita Easys hade) was used to measure the CIELAB coordinates and the reflectance value (Y) of specimens placed on white and black backgrounds. The translucency parameter (TP) and the contrast ratio (CR) were calculated. Another spectrophotometer (Lambda 20) was used to measure the direct light transmittance (T%) of the specimens. The color and the CIELAB coordinates were evaluated using the Vita Easy shade on neutral grey background and values were used to calculate difference in color (DeltaE). All evaluations were repeated using G and values were recorded. Data were statistically analyzed using Anova, Tukey and Student's t-test (alpha=0.05) and Pearson's correlation. RESULTS: Although the mean translucency values were significantly different for each method (TP and CR), they were strongly correlated (r2=0.97), even when G was used (r2=0.96). CONCLUSION: The coupling medium significantly influenced the mean values of DeltaE and translucency. CLINICAL SIGNIFICANCE: Color and translucency values cannot be compared if measured using different coupling media (e.g. air and liquid glycerin). PMID- 23438419 TI - Effect of types of luting agent on push-out bond strength of zirconium oxide posts. AB - OBJECTIVE: The aim of this study was to investigate the effect of different luting agents on the bond strength of zirconium oxide posts in root canals after artificial ageing. MATERIAL AND METHODS: Thirty single-rooted extracted teeth were collected. Post spaces were prepared. Custom milled zirconium oxide posts (Cercon, Degudent) were fabricated. Specimens were divided into 3 groups (n=10), according to the luting agents used: group RA, conventional resin luting agent (RelyX ARC); group RU, self-adhesive resin luting agent (RelyX Unicem); and group Z, zinc phosphate luting agent (DeTrey). Specimens were subjected to thermocycling and water storage at 37 degrees C. Specimens were horizontally sectioned into three sections and subjected to a push-out test with 0.5mm/min crosshead speed. The failure mode was assessed by scanning electron microscopy. Data were analysed by using 2-way ANOVA. RESULTS: The following bond strength values were obtained: group RA - 8.89 MPa, group RU - 10.30 MPa and group Z - 9.31 MPa. There was no significant difference in bond strength among the groups (P=0.500). Adhesive failure mode at the cement/post bonded interface was seen in 100%, 66.67% and 83.3% of examined sections in groups RA, RU and Z, respectively. There was no significant difference in bond strength among different root regions (P=0.367). CONCLUSION: The type of luting agent had no significant effect on the push-out bond strength of zirconium oxide posts after artificial ageing. CLINICAL SIGNIFICANCE: Conventional luting agents, such as zinc phosphate cement, seem to provide comparable retention to resin luting agents for cementing custom milled zirconium oxide posts. PMID- 23438418 TI - Reduced wear of enamel with novel fine and nano-scale leucite glass-ceramics. AB - OBJECTIVES: Leucite glass-ceramics used to produce all-ceramic restorations can suffer from brittle fracture and wear the opposing teeth. High strength and fine crystal sized leucite glass-ceramics have recently been reported. The objective of this study is to investigate whether fine and nano-scale leucite glass ceramics with minimal matrix microcracking are associated with a reduction in in vitro tooth wear. METHODS: Human molar cusps (n=12) were wear tested using a Bionix-858 testing machine (300,000 simulated masticatory cycles) against experimental fine crystal sized (FS), nano-scale crystal sized (NS) leucite glass ceramics and a commercial leucite glass-ceramic (Ceramco-3, Dentsply, USA). Wear was imaged using Secondary Electron Imaging (SEI) and quantified using white light profilometry. RESULTS: Both experimental groups were found to produce significantly (p<0.05) less volume and mean-height tooth loss compared to Ceramco 3. The NS group had significantly (p<0.05) less tooth mean-height loss and less combined (tooth and ceramic) loss than the FS group. Increased waviness and damage was observed on the wear surfaces of the Ceramco-3 glass-ceramic disc/tooth group in comparison to the experimental groups. This was also indicated by higher surface roughness values for the Ceramco-3 glass-ceramic disc/tooth group. CONCLUSIONS: Fine and nano-sized leucite glass-ceramics produced a reduction in in vitro tooth wear. The high strength low wear materials of this study may help address the many problems associated with tooth enamel wear and restoration failure. PMID- 23438421 TI - 'Old' and 'new' drugs for the treatment of cancer pain. AB - INTRODUCTION: More than 20 years ago the World Health Organization (WHO) published the booklet 'Cancer Pain Relief', including the fundamentals and clear principles, which was summarized in five simple sentences: 'by mouth', 'by the clock', 'by the ladder', 'for the individual' and 'attention to detail'. Over the years, several modifications to the analgesic ladder have been proposed, as the addition of two further steps, related to the switch of opioid and/or non invasive route of administration, and to the use of invasive approaches, or again the skip of the second step; nevertheless the educational value and benefits related to the worldwide dissemination are of paramount importance. AREAS COVERED: To date, all the guidelines are inspired by the strategy of WHO; below some of the most important international guidelines published in the last two years are compared, particularly as regards the criteria of choice of opioids for moderate/severe pain. EXPERT OPINION: The discussion on the role of the second step of the WHO analgesic ladder is still open. The challenge for new formulations of 'old' opioids will be to better manage cancer pain, with more tailored efficacy and possibly less side effects. PMID- 23438423 TI - Pharmacoeconomic implications of thromboprophylaxis with new oral anticoagulants after total hip or knee replacement in the USA. AB - INTRODUCTION: Adequate thromboprophylaxis after total hip or knee replacement (THR or TKR) is essential to reduce the incidence of venous thromboembolism (VTE) and its associated complications. Although effective, traditional anticoagulants are associated with a considerable economic burden, particularly when used outside the hospital setting. This article explores whether newer oral anticoagulants can reduce costs of VTE prophylaxis and therapy. AREAS COVERED: Cost associated with vitamin K antagonists; indirect costs associated with complicated or inconvenient anticoagulation regimens, non-adherence and associated complications; potential of the newer oral anticoagulants, including direct thrombin inhibitors and direct factor Xa inhibitors, to produce indirect cost savings after THR or TKR through a potential reduction in VTE rates and administration and monitoring costs. EXPERT OPINION: The use of new anticoagulants for VTE prophylaxis after THR or TKR can result in direct and indirect cost savings through improved efficacy by reducing VTE rates and decreased drug administration and monitoring costs compared with traditional anticoagulants. Future research will need to focus on cost analyses driven by clinical outcomes measured on the performance of these agents in actual clinical practice. PMID- 23438422 TI - Kidney stones: an update on current pharmacological management and future directions. AB - INTRODUCTION: Kidney stones are a common problem worldwide with substantial morbidities and economic costs. Medical therapy reduces stone recurrence significantly. Much progress has been made in the last several decades in improving therapy of stone disease. AREAS COVERED: This review discusses i) the effect of medical expulsive therapy on spontaneous stone passage, ii) pharmacotherapy in the prevention of stone recurrence and iii) future directions in the treatment of kidney stone disease. EXPERT OPINION: Fluid intake to promote urine volume of at least 2.5 L each day is essential to prevent stone formation. Dietary recommendations should be adjusted based on individual metabolic abnormalities. Properly dosed thiazide treatment is the standard therapy for calcium stone formers with idiopathic hypercalciuria. Potassium alkali therapy is considered for hypocitraturia, but caution should be taken to prevent potential risk of calcium phosphate stone formation. For absorptive hyperoxaluria, low oxalate diet and increased dietary calcium intake are recommended. Pyridoxine has been shown effective in some cases of primary hyperoxaluria type I. Allopurinol is used in calcium oxalate stone formers with hyperuricosuria. Treatment of cystine stones remains challenging. Tiopronin can be used if urinary alkalinization and adequate fluid intake are insufficient. For struvite stones, complete surgical removal coupled with appropriate antibiotic therapy is necessary. PMID- 23438425 TI - Genetic fate-mapping of tyrosine hydroxylase-expressing cells in the enteric nervous system. AB - BACKGROUND: During development of the enteric nervous system, a subpopulation of enteric neuron precursors transiently expresses catecholaminergic properties. The progeny of these transiently catecholaminergic (TC) cells have not been fully characterized. METHODS: We combined in vivo Cre-lox-based genetic fate-mapping with phenotypic analysis to fate-map enteric neuron subtypes arising from tyrosine hydroxylase (TH)-expressing cells. KEY RESULTS: Less than 3% of the total (Hu(+) ) neurons in the myenteric plexus of the small intestine of adult mice are generated from transiently TH-expressing cells. Around 50% of the neurons generated from transiently TH-expressing cells are calbindin neurons, but their progeny also include calretinin, neurofilament-M, and serotonin neurons. However, only 30% of the serotonin neurons and small subpopulations (<10%) of the calbindin, calretinin, and neurofilament-M neurons are generated from TH expressing cells; only 0.2% of nitric oxide synthase neurons arise from TH expressing cells. CONCLUSIONS & INFERENCES: Transiently, catecholaminergic cells give rise to subpopulations of multiple enteric neuron subtypes, but the majority of each of the neuron subtypes arises from non-TC cells. PMID- 23438427 TI - Spatio-temporal clustering of American Cutaneous Leishmaniasis in a rural municipality of Venezuela. AB - BACKGROUND: American Cutaneous Leishmaniasis (ACL) is an endemic disease in most Latin-American countries and a public health problem. The number of new cases in the world is thought to be about 1.5 million each year. A new epidemiologic pattern has been observed in the last years, in this sense, Geographic Information Systems (GIS) combined with methods of spatial analysis provide powerful new tools for understanding it. STUDY OBJECTIVE: To investigate the spatial and temporal features of American Cutaneous Leishmaniasis, in an area known to be endemic. METHODS: We retrospectively conducted a space-time cluster analysis of incident cases of ACL using cross sectional data recorded from 1348 confirmed cases from 1992 to 2007 in a rural municipality in Venezuela, to test whether the cases were distributed randomly over space and time. We used the space-time permutation scan statistic and GIS. The identified clusters were analyzed for age, sex and job. These allowed us to investigate transmission patterns of ACL without an explicit entomological study. RESULTS: The analysis showed statistically significant space-time clusters of ACL (p-value<0.01). The most likely cluster contained 35.47% of the total cases (n=177) from 1995 to 1998. Four secondary clusters were identified for different periods. There was an indication of ACL cluster spread from the northeast to other points of the municipality. Three transmission patterns (domiciliary, peri-domiciliary and sylvatic environments) were identified along the study area. CONCLUSION: The transmission of ACL has a spatial and temporal pattern in the studied area which is related to a complex cycle where the environment and other factors have a significant influence. PMID- 23438428 TI - Co-circulation of influenza A virus strains and emergence of pandemic via reassortment: the role of cross-immunity. AB - Reassortment is an important evolutionary route for influenza A viruses to generate pandemic strains. The pre-requisite for reassortment to occur is co infection of different influenza virus strains in the same host population. Empirical evidence suggests that co-circulation of influenza A virus strains is common and co-infection in patients has been reported. Whether a novel virus can successfully spread among a host population is determined by its life-history (infectivity and infectious period). It is also well known that different influenza A strains interfere through the immune response of human body cells. The reassortant virus strain generated from co-infections deviates dramatically in antigenic and genetic properties from its parental strains such that human populations have limited immunity against it. We consider a mathematical model which includes two strains of influenza virus within a standard SIR model and integrate life history and cross-immunity into the evolutionary dynamics of influenza virus. We assume that, following primary infection by one strain and recovery, individuals are susceptible to secondary infection by the other strain only but with reduced probability due to cross-immunity. Co-infection is included to examine how life-history and cross-immunity interplay to regulate the co circulation and co-infection of different influenza A virus strains in human populations. Further, we introduce novel strains via reassortment and investigate how the opportunities of a reassortant strain developing into a pandemic are constrained by its life-history and the residual immunity within human populations. We find that though the probability of pandemic emergence via reassortment increases with transmissibility of reassortant strains and the rate of reassortment, the existence of cross-immunity acquired through previous infections or vaccination can greatly constrain pandemic emergence. PMID- 23438426 TI - Evolutionary and molecular analysis of the emergent severe fever with thrombocytopenia syndrome virus. AB - In 2009, a novel Bunyavirus, called severe fever with thrombocytopenia syndrome virus (SFTSV) was identified in the vicinity of Huaiyangshan, China. Clinical symptoms of this zoonotic virus included severe fever, thrombocytopenia, and leukocytopenia, with a mortality rate of ~10%. By the end of 2011 the disease associated with this pathogen had been reported from eleven Chinese provinces and human-to-human transmission suspected. However, current understanding of the evolution and molecular epidemiology of SFTSV before and after its identification is limited. To address this we undertake phylogenetic, evolutionary and structural analyses of all available SFTSV genetic sequences, including a new SFTSV complete genome isolated from a patient from Henan in 2011. Our discovery of a mosaic L segment sequence, which is descended from two major circulating lineages of SFTSV in China, represents the first evidence that homologous recombination plays a role in SFTSV evolution. Selection analyses indicate that negative selection is predominant in SFTSV genes, yet differences in selective forces among genes are consistent between Phlebovirus species. Further analysis reveals structural conservation between SFTSV and Rift Valley fever virus in the residues of their nucleocapsids that are responsible for oligomerisation and RNA binding, suggesting the viruses share similar modes of higher-order assembly. We reconstruct the epidemic history of SFTSV using molecular clock and coalescent based methods, revealing that the extant SFTSV lineages originated 50-150 years ago, and that the viral population experienced a recent growth phase that concurs with and extends the earliest serological reports of SFTSV infection. Taken together, our combined structural and phylogenetic analyses shed light into the evolutionary behaviour of SFTSV in the context of other, better-known, pathogenic Phleboviruses. PMID- 23438429 TI - Nested model reveals potential amplification of an HIV epidemic due to drug resistance. AB - The use of antiretroviral therapy (ART) is the most efficient measure in controlling the HIV epidemic. However, emergence of drug-resistant strains can reduce the potential benefits of ART. The viral dynamics of drug-sensitive and drug-resistant strains at the individual level may play a crucial role in the emergence and spread of drug resistance in a population. We investigate the effect of the viral dynamics within an infected individual on the epidemiological dynamics of HIV using a nested model that links both dynamical levels. A time dependent between-host transmission rate that receives feedback from a model of two-strain virus dynamics within a host is incorporated into an epidemiological model of HIV. We analyze the resulting dynamics of the model and identify model parameters such as time when ART is initiated, fraction of cases treated, and the probability that a patient develops drug resistance, as having the greatest impact on total infection and prevalence of drug resistance. Importantly, for small values of the risk of a patient developing drug resistance, increasing the fraction of cases treated can increase the cumulative number of infected individuals. Such a pattern is the result of the balance between not treating a patient and having future cases still sensitive to treatment, and treating the patient and increasing the chances for future (untreatable) drug-resistant infections. The current modeling framework incorporates important aspects of virus dynamics within a host into an epidemic model. This approach provides useful insights on the drug resistance dynamics of an epidemic of HIV, which may assist in identifying an optimal use of ART. PMID- 23438431 TI - A mathematical model for HIV and hepatitis C co-infection and its assessment from a statistical perspective. AB - The hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are a clear threat for public health, with high prevalences especially in high risk groups such as injecting drug users. People with HIV infection who are also infected by HCV suffer from a more rapid progression to HCV-related liver disease and have an increased risk for cirrhosis and liver cancer. Quantifying the impact of HIV and HCV co-infection is therefore of great importance. We propose a new joint mathematical model accounting for co-infection with the two viruses in the context of injecting drug users (IDUs). Statistical concepts and methods are used to assess the model from a statistical perspective, in order to get further insights in: (i) the comparison and selection of optional model components, (ii) the unknown values of the numerous model parameters, (iii) the parameters to which the model is most 'sensitive' and (iv) the combinations or patterns of values in the high-dimensional parameter space which are most supported by the data. Data from a longitudinal study of heroin users in Italy are used to illustrate the application of the proposed joint model and its statistical assessment. The parameters associated with contact rates (sharing syringes) and the transmission rates per syringe-sharing event are shown to play a major role. PMID- 23438430 TI - Detectable signals of episodic risk effects on acute HIV transmission: strategies for analyzing transmission systems using genetic data. AB - Episodic high-risk sexual behavior is common and can have a profound effect on HIV transmission. In a model of HIV transmission among men who have sex with men (MSM), changing the frequency, duration and contact rates of high-risk episodes can take endemic prevalence from zero to 50% and more than double transmissions during acute HIV infection (AHI). Undirected test and treat could be inefficient in the presence of strong episodic risk effects. Partner services approaches that use a variety of control options will be likely to have better effects under these conditions, but the question remains: What data will reveal if a population is experiencing episodic risk effects? HIV sequence data from Montreal reveals genetic clusters whose size distribution stabilizes over time and reflects the size distribution of acute infection outbreaks (AIOs). Surveillance provides complementary behavioral data. In order to use both types of data efficiently, it is essential to examine aspects of models that affect both the episodic risk effects and the shape of transmission trees. As a demonstration, we use a deterministic compartmental model of episodic risk to explore the determinants of the fraction of transmissions during acute HIV infection (AHI) at the endemic equilibrium. We use a corresponding individual-based model to observe AIO size distributions and patterns of transmission within AIO. Episodic risk parameters determining whether AHI transmission trees had longer chains, more clustered transmissions from single individuals, or different mixes of these were explored. Encouragingly for parameter estimation, AIO size distributions reflected the frequency of transmissions from acute infection across divergent parameter sets. Our results show that episodic risk dynamics influence both the size and duration of acute infection outbreaks, thus providing a possible link between genetic cluster size distributions and episodic risk dynamics. PMID- 23438432 TI - Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. AB - Long noncoding RNAs (lncRNAs) are key regulators of diverse biological processes such as transcriptional regulation, cell growth and differentiation. Previous studies have demonstrated that the lncRNA-ANCR (anti-differentiation ncRNA) is required to maintain the undifferentiated cell state within the epidermis. However, little is known about whether ANCR regulates osteoblast differentiation. In this study, we found that the ANCR expression level is significantly decreased during hFOB1.19 cell differentiation. ANCR-siRNA blocks the expression of endogenous ANCR, resulting in osteoblast differentiation, whereas ANCR overexpression is sufficient to inhibit osteoblast differentiation. We further demonstrated that ANCR is associated with enhancer of zeste homolog 2 (EZH2) and that this association results in the inhibition of both Runx2 expression and subsequent osteoblast differentiation. These data suggest that ANCR is an essential mediator of osteoblast differentiation, thus offering a new target for the development of therapeutic agents to treat bone diseases. PMID- 23438433 TI - Heme oxygenase-2/adiponectin protein-protein interaction in metabolic syndrome. AB - Insulin resistance with adipose tissue dysfunction and dysregulation in the production and secretion of adipokines is one of the hallmarks of metabolic syndrome. We have previously reported that increased levels of the heme oxygenase (HO) system, HO-1/HO-2 results in increased levels of adiponectin. Despite documentation of the existence of the anti-inflammatory axis HO-adiponectin, a possible protein-protein interaction between HO and adiponectin has not been examined. Here, we investigated the existence of protein interactions between HO 2 and adiponectin in the maintenance of adipocyte function during metabolic syndrome by integrating phenotypic and in silico studies. Compared to WT animals, HO-2 null mice displayed an increase in both visceral and subcutaneous fat content and reduced circulating adiponectin levels. The decrease in adiponectin was reversed by upregulation of HO-1. HO-2 depletion was associated with increased adipogenesis in cultured mesenchymal stem cells (MSCs) and decreased adiponectin levels in the culture media. In addition, HO-1 siRNA decreased adiponectin release. HO-2 was found to bind to the monomeric form of adiponectin, according to poses and calculated energies. HO-2-adiponectin interactions were validated by the two-hybrid system assay. In conclusion, protein-protein interactions between HO-2 and adiponectin highlight the role of HO-2 as a molecular chaperone for adiponectin assembly, while HO-1 increases adiponectin levels. Thus, crosstalk between HO-2 and HO-1 could be manipulated in a therapeutic approach to ameliorate the deleterious effects of obesity and the metabolic syndrome. PMID- 23438434 TI - Snail modulates cell metabolism in MDCK cells. AB - Snail, a repressor of E-cadherin gene transcription, induces epithelial-to mesenchymal transition and is involved in tumor progression. Snail also mediates resistance to cell death induced by serum depletion. By contrast, we observed that snail-expressing MDCK (MDCK/snail) cells undergo cell death at a higher rate than control (MDCK/neo) cells in low-glucose medium. Therefore, we investigated whether snail expression influences cell metabolism in MDCK cells. Although gylcolysis was not affected in MDCK/snail cells, they did exhibit reduced pyruvate dehydrogenase (PDH) activity, which controls pyruvate entry into the tricarboxylic acid (TCA) cycle. Indeed, the activity of multiple enzymes involved in the TCA cycle was decreased in MDCK/snail cells, including that of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2), succinate dehydrogenase (SDH), and electron transport Complex II and Complex IV. Consequently, lower ATP content, lower oxygen consumption and increased survival under hypoxic conditions was also observed in MDCK/snail cells compared to MDCK/neo cells. In addition, the expression and promoter activity of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits the activity of PDH, was increased in MDCK/snail cells, while expression levels of glutaminase 2 (GLS2) and ATP-citrate lyase (ACLY), which are involved in glutaminolysis and fatty acid synthesis, were decreased in MDCK/snail cells. These results suggest that snail modulates cell metabolism by altering the expression and activity of key enzymes. This results in enhanced glucose dependency and leads to cell death under low-glucose conditions. On the other hand, the reduced requirements for oxygen and nutrients from the surrounding environment, might confer the resistance to cell death induced by hypoxia and malnutrition. PMID- 23438435 TI - The effect of eicosapentaenoic and docosahexaenoic acid on protein synthesis and breakdown in murine C2C12 myotubes. AB - Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been found to stimulate protein synthesis with little information regarding their effects on protein breakdown. Furthermore whether there are distinct effects of EPA and DHA remains to be established. The aim of the current study was to determine the distinct effects of EPA and DHA on protein synthesis, protein breakdown and signalling pathways in C2C12 myotubes. Fully differentiated C2C12 cells were incubated for 24h with 0.1% ethanol (control), 50 MUM EPA or 50 MUM DHA prior to experimentation. After serum (4h) and amino acid (1h) starvation cells were stimulated with 2 mM L-leucine and protein synthesis measured using (3)H-labelled phenylalanine. Protein breakdown was measured using (3)H-labelled phenylalanine and signalling pathways (Akt, mTOR, p70S6k, 4EBP1, rps6 and FOXO3a) via Western blots. Data revealed that after incubation with EPA protein synthesis was 25% greater (P<0.05) compared to control cells, with no effect of DHA. Protein breakdown was 22% (P<0.05) lower, compared to control cells, after incubation with EPA, with no effect of DHA. Analysis of signalling pathways revealed that both EPA and DHA incubation increased (P<0.05) p70s6k phosphorylation, EPA increased (P<0.05) FOXO3a phosphorylation, with no alteration in other signalling proteins. The current study has demonstrated distinct effects of EPA and DHA on protein metabolism with EPA showing a greater ability to result in skeletal muscle protein accretion. PMID- 23438436 TI - LGR5 and Nanog identify stem cell signature of pancreas beta cells which initiate pancreatic cancer. AB - Pancreas cancer, is the fourth leading cause of cancer death but its cell of origin is controversial. We compared the localization of stem cells in normal and cancerous pancreas using antibodies to the stem cell markers Nanog and LGR5. Here we show, for the first time, that LGR5 is expressed in normal pancreas, exclusively in the islets of Langerhans and it is co-localized, surprisingly, with Nanog and insulin in clusters of beta cells. In cancerous pancreas Nanog and LGR5 are expressed in the remaining islets and in all ductal cancer cells. We observed insulin staining among the ductal cancer cells, but not in metastases. This indicates that the islet's beta cells, expressing LGR5 and Nanog markers are the initiating cells of pancreas cancer, which migrated from the islets to form the ductal cancerous tissue, probably after mutation and de-differentiation. This discovery may facilitate treatment of this devastating cancer. PMID- 23438437 TI - Impaired energy metabolism in a Drosophila model of mitochondrial aconitase deficiency. AB - Aconitase catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle, and its deficiency in humans is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. Here we investigated the effect of gene knockout and knockdown of the mitochondrial aconitase Acon in Drosophila. Acon-knockout flies were homozygous lethal, indicating that Acon is essential for viability. RNA interference-generated Acon knockdown flies exhibited a variety of phenotypes, such as reduced locomotor activity, a shortened lifespan, and increased cell death in the developing brain. Metabolomic analysis revealed that acetyl-CoA, citrate/isocitrate, and cis aconitate were significantly increased, while most metabolites of glycolysis and the TCA cycle were reduced. Reduced triacylglyceride and increased acetyl-CoA suggested that lipids were used as an energy source because of the impaired glycolysis and TCA cycle. The Acon-knockdown model should facilitate further understanding of the pathophysiology of m-aconitase deficiency in humans. PMID- 23438438 TI - Mechanisms involved in suppression of ADAMTS4 expression in synoviocytes by high molecular weight hyaluronic acid. AB - Aggrecan degradation is considered to play a key role in the progression of osteoarthritis (OA). Aggrecanases are members of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, and degrade aggrecan in OA cartilage. The aim of this study was to clarify the mechanisms of expression of ADAMTS4 induced by IL-1beta in human fibroblast-like synoviocyte (HFLS) cells by high molecular weight hyaluronan (HMW-HA), a therapeutic agent used for OA. Monolayer cultures of HFLS cells were incubated with IL-1beta and HMW-HA. In some experiments, cells were pretreated with the CD44 function blocking monoclonal antibody or inhibitors of signaling pathways prior to addition of IL-1beta and HMW-HA. The expressions of ADAMTS4 mRNA and protein were monitored using real-time RT-PCR, Western blotting, and immunofluorescence microscopy. To further determine the role of HMW-HA in IL-1beta-induced ADAMTS4 expression, activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), Akt, and NF-kappaB were analyzed by Western blotting. HMW-HA suppressed ADAMTS4 mRNA and protein expressions induced by IL-1beta. Pretreatment with the anti-CD44 monoclonal antibody recovered the inhibitory effect of HMW-HA on expression of ADAMTS4 mRNA induced by IL-1beta. Western blotting analysis revealed that IL 1beta-induced phosphorylation of p38 MAPK and JNK protein were diminished by HMW HA. Furthermore, inhibition of the p38 MAPK and JNK pathways by chemical inhibitors suppressed ADAMTS4 mRNA expression stimulated by IL-1beta. These results suggest that HMW-HA plays an important role as a regulatory factor in synovial tissue inflammation. PMID- 23438439 TI - INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors. AB - Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5 positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors. PMID- 23438440 TI - A role for TNFalpha in intervertebral disc degeneration: a non-recoverable catabolic shift. AB - This study examines the effect of TNFalpha on whole bovine intervertebral discs in organ culture and its association with changes characteristic of intervertebral disc degeneration (IDD) in order to inform future treatments to mitigate the chronic inflammatory state commonly found with painful IDD. Pro inflammatory cytokines such as TNFalpha contribute to disc pathology and are implicated in the catabolic phenotype associated with painful IDD. Whole bovine discs were cultured to examine cellular (anabolic/catabolic gene expression, cell viability and senescence using beta-galactosidase) and structural (histology and aggrecan degradation) changes in response to TNFalpha treatment. Control or TNFalpha cultures were assessed at 7 and 21 days; the 21 day group also included a recovery group with 7 days TNFalpha followed by 14 days in basal media. TNFalpha induced catabolic and anti-anabolic shifts in the nucleus pulposus (NP) and annulus fibrosus (AF) at 7 days and this persisted until 21 days however cell viability was not affected. Data indicates that TNFalpha increased aggrecan degradation products and suggests increased beta-galactosidase staining at 21 days without any recovery. TNFalpha treatment of whole bovine discs for 7 days induced changes similar to the degeneration processes that occur in human IDD: aggrecan degradation, increased catabolism, pro-inflammatory cytokines and nerve growth factor expression. TNFalpha significantly reduced anabolism in cultured IVDs and a possible mechanism may be associated with cell senescence. Results therefore suggest that successful treatments must promote anabolism and cell proliferation in addition to limiting inflammation. PMID- 23438441 TI - Comparison of two school-based programmes for health behaviour change: the Belo Horizonte Heart Study randomized trial. AB - OBJECTIVE: To assess the efficacy of two school-based programmes to promote students' willingness to engage in lifestyle changes related to eating habits and physical activity behaviours. DESIGN: Elementary school-based health promotion intervention, designed as a multicomponent experimental study, based on a behavioural epidemiological model. SETTING: Nine intervention and eight comparative public and private elementary schools. SUBJECTS: The goal was to determine the impact on the longitudinally assessed outcomes of two programmes that addressed healthy nutrition and active living in a cohort of 2038 children. The evaluations used pre-intervention and follow-up student surveys that were based on the Transtheoretical Model of the stages of behaviour change. RESULTS: In the intervention group, there were significant (P < 0.001) differences between the pre- and post-intervention times in the stages of change, with a reduction in the percentage of children at the pre-contemplation and contemplation stages and increased percentages at the preparation, action and maintenance stages, leading to healthier behaviours in fatty food consumption, fruit and vegetable consumption, physical activity and time spent in sedentary activities. The determinants of the behaviour stage were the intervention programme, the type of school and the presence of motivated teachers. The comparison group did not show significant differences between the pre- and post-intervention times for any of the stages of behaviour. CONCLUSIONS: The intervention programme encouraged the students to make healthy lifestyle choices related to eating habits and physical activity behaviours. PMID- 23438442 TI - Canine herpesvirus-1 ocular diseases of mature dogs. AB - Canine herpesvirus-1 (CHV-1) is an alphaherpesvirus with a host range restricted to canids. Latent CHV-1 infection is endemic in domestic dog populations worldwide. The role of CHV-1 in severe systemic neonatal infections and as an aetiology of infectious infertility and abortion has been appreciated for decades; however, ocular diseases of mature dogs conclusively associated with CHV 1 infection were only recently described. Clinically, CHV-1 infection may produce a diverse range of adnexal and ocular surface lesions in mature dogs, including blepharitis, conjunctivitis, ulcerative keratitis, and nonulcerative keratitis. These conditions can develop during primary or recurrent ocular CHV-1 infection. Recurrent CHV-1 infections associated with reactivation of latent virus may be observed during a variety of situations and in association with numerous different viral reactivation stimuli, including the administration of immunosuppressive pharmaceuticals. The understanding of CHV-1 pathophysiology and ocular infections in mature dogs has expanded rapidly during the past few years, but much remains to be elucidated. As the number of dogs living with chronic immunomodulatory systemic diseases and receiving immunosuppressive therapeutics continues to grow, the clinical importance of CHV-1 ocular infections is also likely to increase. PMID- 23438443 TI - Poor sleep in PCOS; is melatonin the culprit? AB - STUDY QUESTION: Are daily cycles in urinary melatonin and oxidative stress marker levels (8-hydroxydeoxyguanosine) altered in PCOS, and is this associated with changes in sleep quality? SUMMARY ANSWER: There is an association between elevated nighttime melatonin and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, and poor sleep quality in our PCOS study group. WHAT IS KNOWN ALREADY: Women with PCOS are known to have poorer sleep. However, there have been few studies examining the possible association between melatonin levels and sleep quality in women with polycystic ovarian syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: This is a case-control study of PCOS (n = 26) and non-PCOS control (n = 26) subjects recruited from a tertiary gynaecological centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were requested to complete sleep questionnaires for a month. In a subgroup from these cohorts (PCOS, n = 15; controls, n = 18), urine samples were also collected at various time points over a 24-h period. In addition, their sleep patterns and lighting environment were monitored for 3 consecutive days and nights using a wrist-mounted Actiwatch device. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women had significantly elevated night-time urinary levels of the melatonin metabolite 6-sulfatoxymelatonin (aMT6s) and of 8-OHdG (both at P < 0.05), as well as significantly reduced sleep quality (P < 0.05), compared with the controls. LIMITATIONS, REASONS FOR CAUTION: Due to the small sample size of the study, further studies will be required to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Our preliminary work provides a possible new insight into the interactions between melatonin, increased oxidative stress and sleep in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Faculty of Medicine, University of Southampton. PMID- 23438444 TI - Direct real-time monitoring of stage transitions in graphite intercalation compounds. AB - Graphite intercalation compounds (GIC) possess a broad range of unique properties that are not specific to the parent materials. While the stage transition, changing the number of graphene layers sandwiched between the two layers of intercalant, is fundamentally important and has been theoretically addressed, experimental studies revealed only macroscopic parameters. On the microscale, the phenomenon remains elusive up to the present day. Here we monitor directly in real time the stage transitions using a combination of optical microscopy and Raman spectroscopy. These direct observations yield several mechanistic conclusions. While we obtained strong experimental evidence in support of the Daumas-Herold theory, we find that the conventional interpretation of stage transitions as sliding of the existing intercalant domains does not sufficiently capture the actual phenomena. The entire GIC structure transforms considerably during the stage transition. Among other observations, massive wavefront-like perturbations occur on the graphite surface, which we term the tidal wave effect. PMID- 23438445 TI - Mild chronic kidney disease and functional impairment in community-dwelling older adults. AB - BACKGROUND: chronic kidney disease (CKD) has been associated with an increased risk of death and cardiovascular events, but its relationship with non-vascular outcomes, including functional impairment (FI), is less well understood. OBJECTIVE: in this study, we review the association between CKD and FI, adjusting for potential confounders and risk factors, with a primary outcome of impairment in any instrumental ADL (IADL) or basic ADL (BADL). DESIGN: the Cardiovascular Multimorbidity in Primary Care Study (CLARITY) is a cross-sectional study of community-dwelling adults. SETTING: participants were adults living in the West of Ireland attending university-affiliated general practices. SUBJECTS: all participants were adults aged >=50 years living in the community. METHODS: CKD was defined as an estimated glomerular filtration rate (eGFR) <=60 ml/min/1.73 m(2). A standardised self-reported health questionnaire to measure activities of daily living (ADL) was completed by participants. Logistic regression analyses were used to determine the independent association between CKD and FI. RESULTS: a total of 3,499 patients were included with a mean age of 66.2 +/- 10.3 years. 18.0% (n = 630) had CKD (mean eGFR 50.2 +/- 9.2 ml/min/1.73m(2)), 21.9% (n = 138) of which had a diagnosis of CKD documented in medical records. 40.4% (n = 1,413) reported FI and multivariable adjustment showed CKD to be independently associated with FI (OR: 1.43, 1.15-1.78), impairment in IADL (OR: 1.43, 1.15 1.78) and impairment in BADL (OR: 1.39, 1.11-1.75). CONCLUSION: our study shows even mild CKD is associated with FI, independent of age, gender, co-morbidities, traditional vascular risk factors and cardiovascular events. PMID- 23438446 TI - Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry. AB - BACKGROUND: hip fractures are usually caused by a combination of reduced bone mineral density and falls; using antidepressant drugs may affect both of these. OBJECTIVE: we aimed to examine associations between exposure to antidepressant drugs and the risk of hip fracture among older people, and, provided associations found, to estimate the attributable risk of hip fracture. DESIGN: we conducted a nationwide prospective cohort study of the 906,422 people in Norway born before 1945. METHODS: information on all prescriptions of antidepressants dispensed in 2004-10 and all primary hip fractures in 2005-10 was obtained from the Norwegian Prescription Database, and the Norwegian Hip Fracture Registry, respectively. The incidence rates of hip fracture during the time people were exposed and unexposed to antidepressant drugs were compared by calculating the standardised incidence ratio (SIR). RESULTS: altogether 39,938 people (4.4%) experienced a primary hip fracture. The risk of hip fracture was increased for people exposed to any antidepressant [SIR = 1.7, 95% confidence interval (CI) 1.7-1.8]; tricyclic antidepressants (SIR = 1.4, 95% CI: 1.3-1.5); selective serotonin reuptake inhibitors (SSRIs) (SIR = 1.8, 95% CI: 1.7-1.8) and other antidepressants (SIR = 1.6, 95% CI: 1.5-1.7). The risk of hip fracture attributable to exposure to antidepressant drugs was 4.7%. CONCLUSIONS: this study indicated an increased risk of hip fracture among people exposed to antidepressants, especially those with serotonergic properties such as SSRIs. This association needs to be explored further in clinical studies. PMID- 23438447 TI - All eyes on me?! Social anxiety and self-directed perception of eye gaze. AB - To date, only little is known about the self-directed perception and processing of subtle gaze cues in social anxiety that might however contribute to excessive feelings of being looked at by others. Using a web-based approach, participants (n=174) were asked whether or not briefly (300 ms) presented facial expressions modulated in gaze direction (0 degrees , 2 degrees , 4 degrees , 6 degrees , 8 degrees ) and valence (angry, fearful, happy, neutral) were directed at them. The results demonstrate a positive, linear relationship between self-reported social anxiety and stronger self-directed perception of others' gaze directions, particularly for negative (angry, fearful) and neutral expressions. Furthermore, faster responding was found for gaze more clearly directed at socially anxious individuals (0 degrees , 2 degrees , and 4 degrees ) suggesting a tendency to avoid direct gaze. In sum, the results illustrate an altered self-directed perception of subtle gaze cues. The possibly amplifying effects of social stress on biased self-directed perception of eye gaze are discussed. PMID- 23438449 TI - Illusory and veridical mapping of tactile objects in the primary somatosensory and posterior parietal cortex. AB - While several behavioral and neuroscience studies have explored visual, auditory, and cross-modal illusions, information about the phenomenology and neural correlates of somatosensory illusions is meager. By combining psychophysics and somatosensory evoked potentials, we explored in healthy humans the neural correlates of 2 compelling tactuo-proprioceptive illusions, namely Aristotle (1 object touching the contact area between 2 crossed fingers is perceived as 2 lateral objects) and Reverse illusions (2 lateral objects are perceived as 1 between crossed-fingers object). These illusions likely occur because of the tactuo-proprioceptive conflict induced by fingers being crossed in a non-natural posture. We found that different regions in the somatosensory stream exhibit different proneness to the illusions. Early electroencephalographic somatosensory activity (at 20 ms) originating in the primary somatosensory cortex (S1) reflects the phenomenal rather than the physical properties of the stimuli. Notably, later activity (around 200 ms) originating in the posterior parietal cortex is higher when subjects resist the illusions. Thus, while S1 activity is related to illusory perception, PPC acts as a conflict resolver that recodes tactile events from somatotopic to spatiotopic frames of reference and ultimately enables veridical perception. PMID- 23438448 TI - Exemplar selectivity reflects perceptual similarities in the human fusiform cortex. AB - While brain imaging studies emphasized the category selectivity of face-related areas, the underlying mechanisms of our remarkable ability to discriminate between different faces are less understood. Here, we recorded intracranial local field potentials from face-related areas in patients presented with images of faces and objects. A highly significant exemplar tuning within the category of faces was observed in high-Gamma (80-150 Hz) responses. The robustness of this effect was supported by single-trial decoding of face exemplars using a minimal (n = 5) training set. Importantly, exemplar tuning reflected the psychophysical distance between faces but not their low-level features. Our results reveal a neuronal substrate for the establishment of perceptual distance among faces in the human brain. They further imply that face neurons are anatomically grouped according to well-defined functional principles, such as perceptual similarity. PMID- 23438450 TI - Influence of surgically implantable telemetry solutions on in-life and post mortem toxicology endpoints. AB - INTRODUCTION: Understanding the appropriate application of telemetry and other technologies for nonclinical investigation of functional safety issues in the context of ongoing toxicology evaluations is a current industry challenge. One major issue is related to the potential impact of surgical implantation of a telemetry device on contemporarily established measures of drug toxicity, and potential for confounding pathological issues related to the systemic and local response of the experimental animal to the presence of a foreign body. This study was designed to evaluate the potential local and systemic impact of different implanted telemetry devices with varying requisite degrees of surgical complexity on general toxicology study endpoints. METHODS: Sixteen male beagle dogs 1) no surgical instrumentation [n=4], 2) Jacketed External Telemetry (JET) with femoral artery blood pressure implant (PA-C10 LA) [n=4], or 3) fully implantable (DSI-D70 CCTP) devices [n=8], were assigned to experimental groups and evaluated within the context of a standard repeat-dose toxicology design to determine the potential impact of these treatments on routine in-life and post-mortem toxicological endpoints. RESULTS: Device implantation, regardless of the level of invasiveness/complexity was without effect on any in-life safety parameter, including clinical chemistry and hematology, assessed in the experimental design. Histopathological findings were limited to the expected, primarily minimal to mild localized effects characteristic of a foreign body reaction (fibrosis, inflammation) in the area immediately in contact with the body of the transmitter device and associated sites of ECG lead and pressure catheter interface with local tissues. DISCUSSION: This study represents the first definitive evaluation of the influence of variably invasive telemetry device implantation on standardized, essential toxicology endpoints in the context of a simulated repeated dose experimental design. The data suggest that, when carefully evaluated, the local effects of implanted telemetry devices can be managed in the context of a standard Investigational New Drug (IND)-enabling toxicology study. This study provides support for the potential incorporation of unrestrained cardiovascular assessments via implanted or external telemetry into standard multi-dose toxicology studies. PMID- 23438452 TI - Validation of the VitalPACTM Early Warning Score (ViEWS) in acutely ill medical patients attending a resource-poor hospital in sub-Saharan Africa. AB - BACKGROUND: The VitalPACTM Early Warning Score (ViEWS) has an area under the receiver operator characteristic curve (AUROC) for death of acute unselected medical patients within 24h of 88% and the UK National Early Warning Scores is based on it. The score's discrimination has been validated on patients in the developed world, but nothing is known of its performance in resource-poor hospitals. METHODS: ViEWS was validated in 844 acutely ill medical patients admitted to Kitovu Hospital, Masaka, Uganda. RESULTS: The AUROC for death within 24h of admission was 88.6% (95% CI 82.5-94.7%). The inability to walk without help was found to be an additional independent predictor of in-hospital mortality, and ViEWS modified to include it had an AUROC for death within 24h of 91.9% (95% CI 86.5-97.2%). CONCLUSION: The discrimination of ViEWS in a resource poor sub-Saharan Africa hospital is the same as in the developed world. Inability to walk without help was found to be an additional independent predictor of mortality. PMID- 23438451 TI - Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity. AB - Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-alpha levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. PMID- 23438453 TI - The neuroprognostic challenge of post-arrest care. PMID- 23438454 TI - A randomized, cross-over comparison of preference between two reusable insulin pen devices in pen-naive adults with diabetes. AB - OBJECTIVE: To evaluate final preference and ease-of-use attributes of two reusable pen injectors, HPS (HumaPen Savvio) and HPL (HumaPen Luxura), in adults with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 1 day, randomized, two-period crossover, open-label, simulated-injection study in 203 pen-naive subjects (mean age 58.4 years). MAIN OUTCOME MEASURES: Functional and ease-of-use attributes of insulin pen injectors were evaluated using a 16-item survey (7 point scale) where higher scores reflected greater preference and equal scores reflected no preference. The primary objective was final pen preference, with statistical gate-keeping to the ease of detecting an insufficient remaining dose (IRD) of insulin upon dose selection. RESULTS: For final overall pen preference, HPS was chosen by 150 of 203 subjects (73.9%, 95% confidence interval [CI] = 67.3%-79.8%). For the IRD item, 'It is easy to know when there is not enough insulin left in the cartridge for the dose I need before I inject', HPS was preferred by 94 of 107 subjects with a preference (87.9%, 95% CI = 80.1% 93.4%). In 14 of the remaining 15 survey items, 64.3% to 87.7% of subjects with a preference statistically significantly preferred HPS over HPL. To confirm the results, subjects with no preference for either pen, which ranged between 95 and 148, were included in a Bayesian analysis. KEY LIMITATIONS: Injection simulation, use of an unvalidated survey, and office setting which did not allow for direct clinical experience with the devices. CONCLUSIONS: The majority of pen-naive subjects preferred HPS over HPL. For all ease-of-use attributes, the majority of subjects with a preference chose HPS over HPL. Some attributes of both pens were equally acceptable, as many subjects had no preference. PMID- 23438457 TI - Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism. AB - OBJECTIVE: To evaluate the efficacy of initial doses of desoxycorticosterone pivalate (DOCP) that are lower and less expensive than the presently recommended initial dose of 2.2 mg/kg for treating dogs with primary hypoadrenocorticism. METHODS: A retrospective study was performed on 49 dogs with primary hypoadrenocorticism, including 36 with initial DOCP doses less than 2.2 mg/kg. Medical records were reviewed for clinical data. All study dogs were followed up with telephone calls to owners or veterinarians to determine the date of death or last follow-up. Data were analysed to investigate relationships between initial DOCP dose and survival and serum Na, K and their ratio. RESULTS: Regardless of their initial DOCP dose, none of the dogs developed uncontrolled hypoadrenocorticism or severe electrolyte abnormalities or clinical problems that would have made an increase in the DOCP dose necessary. Over time, most dogs had a decrease in their DOCP dose in mg/kg, because of weight gain during treatment. No statistically significant relationships were found between initial DOCP dose and survival or post-treatment serum Na, K or Na : K, with the exception of one statistically significant result that suggested lower efficacy for higher doses. CONCLUSION: Initial DOCP doses less than 2.2 mg/kg may be effective in controlling serum electrolyte concentrations in dogs with primary hypoadrenocorticism without adversely affecting survival. If confirmed by additional research, these findings would enable practitioners to reduce the cost of DOCP treatment by using lower initial doses, potentially saving the lives of dogs that would otherwise be euthanased because of treatment expense. PMID- 23438458 TI - Bioavailability of two L-thyroxine formulations after oral administration to healthy dogs. AB - OBJECTIVE: To describe the pharmacokinetics of two veterinary formulations of L thyroxine available in Australia. METHODS: A two-phase randomised, crossover, open-label trial followed by a third-phase parallel-dosing trial was conducted in 11 healthy dogs with an investigative oral L-thyroxine liquid formulation and a reference tablet formulation. Blood sampling was done at defined intervals and serum total L-thyroxine concentrations were measured by radioimmunoassay. The post-dose concentrations were plotted as a function of time for each period and the relative bioavailability of the two formulations were compared using a general linear model with factors for dog, phase, sequence and formulation. RESULTS: Following oral administration of the reference tablet at the dose of 100 MUg/kg, a maximum plasma concentration of approximately 96.2 nmol/L (baseline endogenous corrected) was reached within 3.77 h. For the investigative liquid preparation at a dose of 50 MUg/kg, the maximum plasma concentration was 60.1 nmol/L (baseline endogenous corrected), which was reached within 3.59 h. CONCLUSION: The geometric mean of the relative bioavailability for the liquid/tablet product was 1.1, which suggests that the relative bioavailability of thyroxine following administration of tablet or liquid formulation is similar. PMID- 23438459 TI - 'Cysticercosis storm' in feedlot cattle in north-west New South Wales. AB - OBJECTIVE: To investigate the cause of an outbreak of bovine cysticercosis (Taenia saginata) infection on a cattle property in north-western New South Wales (NSW). METHODS: Cystic lesions were detected in the muscles of cattle during routine meat inspection at slaughter. These lesions were confirmed to be cysticerci of T. saginata through histology and polymerase chain reaction (PCR). Data on cattle maintenance were obtained through interviews with feedlot owners and staff. A suspect feed supplement was investigated. RESULTS: Between 5 July to 13 December 2010, 390 feedlot cattle from north-western NSW were slaughtered in abattoirs in NSW and Queensland. Of these, 138 animals had been maintained exclusively in feedlot enclosures from 80 to 300 days. Bovine cysticercosis was discovered in 80 cattle (58%, 26 carcasses were condemned). Another 18 cattle spent 24 h in the feedlot before being moved onto pasture and 1 of them was found to be infected. During the 5 months following the initial outbreak, a further 275 cattle were slaughtered; 2 of 51 heifers retained in the feedlot for a further 100 days were infected. None of the 234 animals grazed exclusively on pasture on the property were infected. Bovine cysticercosis was confirmed through examination of histological sections of muscle lesions and PCR using DNA extracted from cysticerci. No eggs of T. saginata were recovered from the feed supplement using a standard flotation method. CONCLUSIONS: The source of infection arose from rations contaminated with human faeces. All possibilities for local contamination were eliminated during the investigation. The suspected source of infection was imported copra meal, which was used as a feed supplement. PMID- 23438460 TI - Ease of moving young calves at different ages. AB - BACKGROUND: Young ('bobby') calves transported to the abattoir in their first week of life have not yet developed natural herding behaviour. The calves are still in a 'hider' phase and naturally spend most of their time lying and sleeping. Anecdotally, calves are easier to handle as they get older, although it is unclear if they are inherently more responsive to a handler. METHODS: This study examined the ease of moving 3-, 5- and 9-11-day-old calves individually through an obstacle course involving a 12 degrees incline, a 11 degrees decline and two 90 degrees turns. RESULTS: There was a significant effect of age on both the total time taken to move through the course (99 vs 86 vs 72s for 3-, 5- and 9 11-day-old calves, respectively; P < 0.05) and the number of interventions by the handler (8.4 vs 7.3 vs 4.8 interventions per calf for 3-, 5- and 9-11-day-old calves, respectively; P < 0.05). CONCLUSION: Ease of herding bobby calves improved with age, although individually handled calves were relatively easy to move regardless of age. PMID- 23438461 TI - Presence of Ureaplasma diversum in the Australian cattle population. AB - In cattle, Ureaplasma diversum has been associated with decreased fertility, granular vulvovaginitis, endometritis, salpingitis and spontaneous abortion in cows and seminal vesiculitis, balanoposthitis and changes in bull sperm. The presence of U. diversum within the Australian cattle population has not been established. One of the aims of this study was to determine if U. diversum was present in Australian cattle, using culture and polymerase chain reaction (PCR), both of which are considered to be gold standards for bacterial identification. Of 100 samples collected from 66 male and 34 female cattle, 15 were positive for U. diversum. Therefore, Australia can no longer be considered free of U. diversum. Further studies should be conducted to ascertain the effects of U. diversum within Australian cattle herds and, if warranted, to investigate prevention, treatment and eradication protocols. PMID- 23438462 TI - Use of ultrasound-guided autologous bone marrow transfer for treatment of suspensory ligament desmitis in 30 race horses (2003-2010). AB - OBJECTIVE: To evaluate the racing performance of horses that underwent ultrasound guided intralesional injection of autologous bone marrow aspirate for treatment of selected forelimb suspensory ligament (body or branch) core lesions. DESIGN: Retrospective cohort study of 13 Standardbred and 17 Thoroughbred race horses. METHODS: Autologous bone marrow aspirated from the sternebrae was injected, under ultrasound guidance, into suspensory ligament core lesions (body or branch). Racing records were reviewed for a comparison of performance before and after surgery. RESULTS: Of the 13 Standardbreds, 9 (69%) had one or more starts within the follow-up period and 9 (69%) had five or more starts. Of the 17 Thoroughbreds, 15 (88%) had one or more starts within the follow-up period and 12 (71%) had five or more starts. Eight Standardbred horses had at least one start both before and after surgery. Earnings per start did not differ significantly between the three starts immediately after surgery compared with the three starts immediately prior to surgery. Thirteen Thoroughbred horses had at least one start both before and after surgery. Earnings per start were less for the three starts immediately after surgery compared with the three starts immediately prior to surgery. CONCLUSIONS AND CLINICAL RELEVANCE: A horse with a core lesion in the branch or body of the suspensory ligament has a good prognosis for return to racing after treatment with intralesional injection of bone marrow aspirate. PMID- 23438463 TI - Hoof conformation and performance in the racing Thoroughbred in Macau. AB - OBJECTIVES: To investigate associations between race performance and hoof-ground angle (HG), pastern-hoof angle (PH) and mediolateral hoof angle (ML) of the left forelimb. METHODS: A total of 1570 starts were recorded from 636 horses, and meetings were equally divided between sand and turf tracks. HG, PH and ML were measured on each starter in a race, over a 3-month period, using a Finnegan hoof gauge (Tallahesse Asia Holdings Ltd, Hong Kong) and digital photographic images. Race performance was recorded as win or place (1st-3rd). RESULTS: There was no association between the probability of winning or placing and gauge HG, photographic HG or photographic ML. There was a significant negative association between PH and the probability of winning on the turf track. On the turf surface, the odds ratio of winning for each 1 degrees decrease in PH was 1.06 (95% confidence interval 1.01-1. 12). There was no association between the probability of winning or placing on the sand track and PH. CONCLUSIONS AND CLINICAL RELEVANCE: Direct measures of hoof conformation (HG and ML) were not related to racehorse performance in Macau. Lower PH was associated with better performance on a turf track. Further investigation into factors affecting PH and why it is related to performance are warranted. This study demonstrated that PH was associated with performance on a turf track. This information may be useful in the management and selection of Thoroughbred racehorses. PMID- 23438464 TI - Role of genetically engineered animals in future food production. AB - Genetically engineered (GE) animals are likely to have an important role in the future in meeting the food demand of a burgeoning global population. There have already been many notable achievements using this technology in livestock, poultry and aquatic species. In particular, the use of RNA interference (RNAi) to produce virus-resistant animals is a rapidly-developing area of research. However, despite the promise of this technology, very few GE animals have been commercialised. This review aims to provide information so that veterinarians and animal health scientists are better able to participate in the debate on GE animals. PMID- 23438466 TI - UDP-glucose pyrophosphorylase is a novel plant cell death regulator. AB - Programmed cell death (PCD) is an essential process that functions in plant organ sculpture, tissue differentiation, nutrient recycling, and defense against pathogen attack. A full understanding of the mechanism of PCD in plants is hindered by the limited identification of protein components of the complex signaling circuitry that underpins this important physiological process. Here we have used Arabidopsis thaliana and fumonisin B1 (FB1) to identify proteins that constitute part of the PCD signaling network. We made an inadvertent, but important observation that exogenous sucrose modulates FB1-induced cell death and identified sucrose-induced genes from publicly available transcriptomic data sets for reverse genetic analyses. Using transfer-DNA gene knockout plants, UDP glucose pyrophosphorylase 1 (UGP1), a sucrose-induced gene, was demonstrated to be a critical factor that regulates FB1-induced PCD. We employed 2D-DiGE to identify proteomic changes preceding PCD after exposure of Arabidopsis to FB1 and used UGP1 knockout plants to refine the analysis and isolate downstream candidate proteins with a putative PCD regulatory function. Our results reveal chloroplasts as the predominantly essential organelles in FB1-induced PCD. Overall, this study reveals a novel function of UGP1 as a cell death regulator and provides candidate proteins likely recruited downstream in the activation of plant PCD. PMID- 23438467 TI - Distinctiveness of social and meta-cognition in schizophrenia across cultures. PMID- 23438468 TI - Sunflecks? PMID- 23438469 TI - Pre-existing immunity to norovirus GII-4 virus-like particles does not impair de novo immune responses to norovirus GII-12 genotype. AB - Noroviruses (NoVs) are one of the leading causes of acute nonbacterial gastroenteritis in humans of all ages. In the 1990s, NoV genotype GII-4 became responsible for the majority of NoV sporadic gastroenteritis cases and outbreaks worldwide. Vaccine development against NoV GII-4 is underway. At the same time, there is concern of new emerging NoV genotypes, such as GII-12, which has been recently associated with increasing numbers of NoV outbreaks worldwide. The specific question is whether type-specific pre-existing immunity to NoV GII-4 might impair cognate immune response induced by new viral infections or vaccines. Using GII-4 and GII-12 virus-like particles, we tested the impact of the immunity generated against NoV GII-4 on de novo antibody responses to GII-12 in mice. We found that pre-existing immunity to NoV GII-4 did not impair de novo immune response to the novel antigen, therefore suggesting lack of original antigenic sin (OAS). PMID- 23438470 TI - Molecular mechanisms underlying the anti-obesity potential of prunetin, an O methylated isoflavone. AB - Prunetin is an O-methylated isoflavone, which is a type of flavonoid. There are a limited number of reports detailing the biological activities of prunetin. Although an anti-inflammatory effect of prunetin has been reported in vitro, to our knowledge, there have been no reports on anti-adipogenic effects of prunetin in obese animals. The aims of this study were to determine whether prunetin suppresses high-fat diet (HFD)-induced adipogenesis in the liver and visceral adipose tissues of mice, and to explore the underlying mechanisms mediating the actions of prunetin. To this end, mice were fed a HFD for 10 weeks to induce obesity, and prunetin (10 MUg/kg or 20 MUg/kg) was administered in the last 3 weeks. Compared to saline-treated mice, mice treated with prunetin showed significantly reduced body weight gain, visceral fat pad weights, and plasma glucose levels. We found that prunetin significantly inhibited the HFD-induced upregulation of the expression of important adipogenic genes (PPARgamma, C/EBPalpha, SREBP, aP2, LPL adiponectin, and leptin), and suppressed HFD-mediated increase in expression of lipid metabolism-related genes (SREBP, PPARgamma, LXR, and HMG-CoA) in the liver tissues. Furthermore, prunetin induced expression of adiponectin receptors 1 and 2 (adipoR1, adipoR2), as well as that of AMP activated protein kinase (AMPK) in the liver and adipose tissue. These results suggest that prunetin mediates anti-obesity/adipogenesis effects by suppressing obesity-related transcription through a feedback mechanism that regulates the expression of adiponectin, adipoR1, adipoR2, and AMPK. PMID- 23438471 TI - The circadian clock circuitry and the AHR signaling pathway in physiology and pathology. AB - Life forms populating the Earth must face environmental challenges to assure individual and species survival. The strategies predisposed to maintain organismal homeostasis and grant selective advantage rely on anticipatory phenomena facing periodic modifications, and compensatory phenomena facing unpredictable changes. Biological processes bringing about these responses are respectively driven by the circadian timing system, a complex of biological oscillators entrained to the environmental light/dark cycle, and by regulatory and metabolic networks that precisely direct the body's adjustments to variations of external conditions and internal milieu. A critical role in organismal homeostatic functions is played by the aryl hydrocarbon receptor (AHR) complex, which senses environmental and endogenous compounds, influences metabolic responses controlling phase I/II gene expression, and modulates vital phenomena such as development, inflammation and adaptive immunity. A physiological cross talk between circadian and AHR signaling pathways has been evidenced. The alteration of AHR signaling pathway deriving from genetic damage with polymorphisms or mutations, or produced by exogenous or endogenous AHR activation, and chronodisruption caused by mismatch between the body's internal clock and geophysical time/social schedules, are capable of triggering pathological mechanisms involved in metabolic, immune-related and neoplastic diseases. On the other hand, the molecular components of the circadian clock circuitry and AHR signaling pathway may represent useful tools for preventive interventions and valuable targets of therapeutic approaches. PMID- 23438472 TI - Impact of animal and management factors on collagen characteristics in beef: a meta-analysis approach. AB - The aim of this paper was to identify pre-slaughter factors that modify total and insoluble collagen contents in bovine muscle to construct a model of collagen dynamics. The meta-analyses were performed with primary data of total (n = 1165) and insoluble (n = 1145) collagen contents from INRA experiments obtained from different muscles in young bulls, cows and steers. According to both the bibliography and meta-analyses, total collagen content and solubility were greatly affected by the muscle (type). Moreover, the pattern of the evolution of collagen characteristics was similar among Longissimus, Semitendinosus and Triceps brachii muscles in young bulls. In cows, collagen contents in the Triceps brachii muscle had delayed dynamics compared with the other muscles. Collagen characteristics differed among breeds because of variation in the maturity of the breed. Similarly, according to the meta-analyses, total and insoluble collagen content evolutions with the degree of maturity (DOM; proportion of adult weight reached at slaughter) were different in dairy and rustic breeds from those of beef breeds, especially in bulls. Although the relationships between collagen content and DOM were quantified in different muscles and sexes, the precision of the fitted equations was not sufficient for prediction. Consequently, relying on the hypotheses raised by the meta-analysis and the literature, an approach to further develop a dynamic mechanistic model of soluble and insoluble collagen content is proposed. PMID- 23438473 TI - Wounds that will not heal: pervasive cellular reprogramming in cancer. AB - There has been an explosion of articles on epithelial-mesenchymal transition and other modes of cellular reprogramming that influence the tumor microenvironment. Many controversies exist and remain to be resolved. The interest of the pathologists in the molecular and functional parallels between wound healing and the developing tumor stroma has its earliest origin in the writings of Rudolph Virchow in the 19(th) century. Since then, most of the focus has been primarily on the dynamics of the extracellular matrix; however, new interest has been redirected toward deciphering and understanding the enigmatic, yet elegant, plasticity of the cellular components of the proliferating epithelia and stroma and how they are reciprocally influenced. Citing several examples from breast cancer research, we will trace how these perspectives have unfolded in the pages of The American Journal of Pathology and other investigative journals during the past century, their impact, and where the field is headed. PMID- 23438475 TI - Monocyte/macrophage MMP-14 modulates cell infiltration and T-cell attraction in contact dermatitis but not in murine wound healing. AB - Monocyte infiltration and subsequent differentiation into macrophages has been shown to be crucial during inflammation. Metalloproteinases are key enzymes in these processes, but the role of MMP-14 remains largely unknown. To address this question, we generated animals with conditional ablation of MMP-14 in the monocyte/macrophage lineage. The knockout (KO) animals (LysM-Cre(+)MMP-14(fl/fl)) were healthy and fertile, and neither skin architecture nor differentiation was altered from the wild type (WT). Full-thickness wounds were induced, and careful analysis of wound closure, granulation tissue formation, and angiogenesis revealed no differences between genotypes. The inflammatory response, monocyte influx, differentiation, and lymphocyte infiltration was also similar in KO and WT animals. Ear swelling after croton oil application was similar in the KO and WT animals. Interestingly, the number of monocytes and macrophages, as well as of T cells, was significantly reduced in KO animals, compared with WT animals. Similarly, both P-selectin and proinflammatory cytokine levels were markedly reduced in KO animals. In vitro, the migratory capacity of isolated KO macrophages was significantly impaired on fibronectin, a substrate of MMP-14. These data point to a role of MMP-14 during transendothelial migration of monocytes and T-cell attraction. PMID- 23438476 TI - Convergent replication of mouse synthetic prion strains. AB - Prion diseases are neurodegenerative disorders characterized by the aberrant folding of endogenous proteins into self-propagating pathogenic conformers. Prion disease can be initiated in animal models by inoculation with amyloid fibrils formed from bacterially derived recombinant prion protein. The synthetic prions that accumulated in infected organisms are structurally distinct from the amyloid preparations used to initiate their formation and change conformationally on repeated passage. To investigate the nature of synthetic prion transformation, we infected mice with a conformationally diverse set of amyloids and serially passaged the resulting prion strains. At each passage, we monitored changes in the biochemical and biological properties of the adapting strain. The physicochemical properties of each synthetic prion strain gradually changed on serial propagation until attaining a common adapted state with shared physicochemical characteristics. These results indicate that synthetic prions can assume multiple intermediate conformations before converging into one conformation optimized for in vivo propagation. PMID- 23438477 TI - Risk factors for pancreatic ductal adenocarcinoma specifically stimulate pancreatic duct glands in mice. AB - Diabetes mellitus type 2 and chronic pancreatitis are regarded as risk factors for pancreatic cancer. Pancreatic duct glands (PDGs) were recently described as a new compartment of the major duct in humans and mice. To evaluate the influence of diabetes and chronic pancreatitis on PDGs, cerulein was injected i.p., repetitively over 10 weeks, in mice exhibiting obesity and a type 2 diabetes-like syndrome (B6.V-Lep(ob/ob)) and in lean littermates. By using 5-bromo-2' deoxyuridine (BrdU), a label-retaining cell population was characterized in PDGs. Cerulein administration led to more BrdU(+) cells in PDGs of obese mice compared with lean mice. The observed increase was specific to PDGs, because BrdU incorporation in cells of the pancreatic duct was not increased. In addition, the expression of distinct tumor markers in PDGs was characterized by Muc5ac, S100P, regenerating islet-derived 3beta, 14-3-3 sigma, and prostate stem cell antigen immunochemistry. Type 2 diabetes-like syndrome, accompanied by chronic pancreatitis, enhanced nuclear localization of S100P. Both risk factors for pancreatic cancer also induced the production of Muc5ac and the nuclear localization of S100P [corrected]. These results demonstrate that diabetes and chronic pancreatitis jointly enhance BrdU incorporation and production of pancreatic cancer-specific proteins in PDGs. The observed alterations suggest that pancreatic tumors might originate from the newly discovered histomorphological structures, called PDGs, which could represent a target for future anticancer therapies. PMID- 23438478 TI - Death-associated protein kinase controls STAT3 activity in intestinal epithelial cells. AB - The TNF-IL-6-STAT3 pathway plays a crucial role in promoting ulcerative colitis associated carcinoma (UCC). To date, the negative regulation of STAT3 is poorly understood. Interestingly, intestinal epithelial cells of UCC in comparison to ulcerative colitis show high expression levels of anti-inflammatory death associated protein kinase (DAPK) and low levels of pSTAT3. Accordingly, epithelial DAPK expression was enhanced in STAT3(IEC-KO) mice. To unravel a possible regulatory mechanism, we used an in vitro TNF-treated intestinal epithelial cell model. We identified a new function of DAPK in suppressing TNF induced STAT3 activation as DAPK siRNA knockdown and treatment with a DAPK inhibitor potentiated STAT3 activation, IL-6 mRNA expression, and secretion. DAPK attenuated STAT3 activity directly by physical interaction shown in three dimensional structural modeling. This model suggests that DAPK-induced conformational changes in the STAT3 dimer masked its nuclear localization signal. Alternatively, pharmacological inactivation of STAT3 led to an increase in DAPK mRNA and protein levels. Chromatin immunoprecipitation showed that STAT3 restricted DAPK expression by promoter binding, thereby reinforcing its own activation by inducing IL-6. This novel negative regulation principle might balance TNF-induced inflammation and seems to play an important role in the inflammation-associated transformation process as confirmed in an AOM+DSS colon carcinogenesis mouse model. DAPK as a negative regulator of STAT3 emerges as therapeutic option in the treatment of ulcerative colitis and UCC. PMID- 23438479 TI - From fixed points to chaos: three models of delayed discrimination. AB - Working memory is a crucial component of most cognitive tasks. Its neuronal mechanisms are still unclear despite intensive experimental and theoretical explorations. Most theoretical models of working memory assume both time invariant neural representations and precise connectivity schemes based on the tuning properties of network neurons. A different, more recent class of models assumes randomly connected neurons that have no tuning to any particular task, and bases task performance purely on adjustment of network readout. Intermediate between these schemes are networks that start out random but are trained by a learning scheme. Experimental studies of a delayed vibrotactile discrimination task indicate that some of the neurons in prefrontal cortex are persistently tuned to the frequency of a remembered stimulus, but the majority exhibit more complex relationships to the stimulus that vary considerably across time. We compare three models, ranging from a highly organized line attractor model to a randomly connected network with chaotic activity, with data recorded during this task. The random network does a surprisingly good job of both performing the task and matching certain aspects of the data. The intermediate model, in which an initially random network is partially trained to perform the working memory task by tuning its recurrent and readout connections, provides a better description, although none of the models matches all features of the data. Our results suggest that prefrontal networks may begin in a random state relative to the task and initially rely on modified readout for task performance. With further training, however, more tuned neurons with less time-varying responses should emerge as the networks become more structured. PMID- 23438480 TI - Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. AB - The spinocerebellar ataxias type 1 (SCA1), 2 (SCA2), 3 (SCA3), 6 (SCA6) and 7 (SCA7) are genetically defined autosomal dominantly inherited progressive cerebellar ataxias (ADCAs). They belong to the group of CAG-repeat or polyglutamine diseases and share pathologically expanded and meiotically unstable glutamine-encoding CAG-repeats at distinct gene loci encoding elongated polyglutamine stretches in the disease proteins. In recent years, progress has been made in the understanding of the pathogenesis of these currently incurable diseases: Identification of underlying genetic mechanisms made it possible to classify the different ADCAs and to define their clinical and pathological features. Furthermore, advances in molecular biology yielded new insights into the physiological and pathophysiological role of the gene products of SCA1, SCA2, SCA3, SCA6 and SCA7 (i.e. ataxin-1, ataxin-2, ataxin-3, alpha-1A subunit of the P/Q type voltage-dependent calcium channel, ataxin-7). In the present review we summarize our current knowledge about the polyglutamine ataxias SCA1, SCA2, SCA3, SCA6 and SCA7 and compare their clinical and electrophysiological features, genetic and molecular biological background, as well as their brain pathologies. Furthermore, we provide an overview of the structure, interactions and functions of the different disease proteins. On the basis of these comprehensive data, similarities, differences and possible disease mechanisms are discussed. PMID- 23438481 TI - The methylarginines NMMA, ADMA, and SDMA are ubiquitous constituents of the main vegetables of human nutrition. AB - Endogenous methylarginines, N(G),N(G)-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), N(G)-N('G)-dimethyl-L-arginine (symmetric dimethylarginine; SDMA), and N(G)-monomethyl-L-arginine (monomethylarginine; NMMA) are supposed to be produced in human body through the methylation of protein arginine residues by protein arginine methyltransferases (PRMT) and released during proteolysis of the methylated proteins. Micromolar concentration of ADMA and NMMA can compete with arginine for nitric oxide synthase (NOS) reducing nitric oxide (NO) formation, whereas SDMA does not. Indeed, increased ADMA and SDMA plasma levels or a decreased arginine/ADMA ratio is related with risk factors for chronic kidney disease and cardiovascular disease. To the best of our knowledge the exogenous presence of methylarginines, like that in fruits and vegetables, has never been described so far. Here, we report the finding that methylarginines are ubiquitous in vegetables which represent an important part of human daily diet. Some of these vegetables contain discrete amounts of ADMA, SDMA, and NMMA. Specifically, among the vegetables examined, soybean, rye, sweet pepper, broad bean, and potato contain the highest ADMA and NMMA mean levels. Our results establish that the three methylarginines, in addition to being produced endogenously, can also be taken daily through the diet in conspicuous amounts. We propose that the contribution of the methylarginines contained in the vegetables of daily diet should be taken into account when the association between vegetable assumption and their levels is evaluated in clinical studies. Furthermore, a comprehensive understanding on the role of the digestive breakdown process and intestinal absorption grade of the methylarginines contained in vegetables is now needed. PMID- 23438483 TI - Association of baseline C-reactive protein and prior anti-tumor necrosis factor therapy with need for weekly dosing during maintenance therapy with adalimumab in patients with moderate to severe Crohn's disease. AB - OBJECTIVE: A post hoc analysis of data from the adalimumab Crohn's disease (CD) maintenance trial (CHARM, NCT00077779), examining the relationship between adalimumab dosing and maintenance of remission and response in subgroups stratified by previous anti-TNF use and baseline CRP. METHODS: All patients received open-label induction (adalimumab: 80 mg, week [wk] 0; 40 mg, wk 2). At wk 4, all patients were randomized to double-blind maintenance adalimumab (40 mg weekly or every other week [eow]) or placebo for 52 weeks. In this analysis, clinical remission (CDAI <150) and clinical response (CR-100) at wk 26 and wk 56 by baseline CRP (high: >= 10 mg/L, or low: <10 mg/L) and prior anti-TNF use were determined for patients with CR-70 at wk 4. RESULTS: Of 498 patients in this analysis, 260 (52.2%) were anti-TNF-naive. For anti-TNF-naive patients, the wk 56 remission rates in the adalimumab groups were significantly greater than placebo (P < 0.05) for both high and low CRP cohorts, with no statistically significant differences between remission rates with eow and weekly dosing within each CRP cohort (high: 52.8% eow, 53.5% weekly; low: 34.7% eow, 41.9% weekly). For anti TNF-exposed patients, wk 56 remission rates were higher than placebo with both eow and weekly dosing within each cohort; weekly dosing in the high CRP cohort and eow dosing in the low CRP cohort achieved statistical significance (P < 0.05). In the high CRP cohort, remission rate with weekly dosing (46.9%) was statistically significantly greater compared with eow dosing (22.5%). There were no significant differences between eow (23.1%) and weekly (37.0%) dosing in the low CRP group. For all subgroups, clinical remission (wk 26) and clinical response (wk 26 and wk 56) patterns were similar to those observed for wk 56 remission. CONCLUSIONS: These subgroup analyses suggest that in patients with moderately to severely active CD, weekly dosing may be most effective in the anti TNF-experienced patients with elevated CRP at baseline. PMID- 23438484 TI - The effect of very brief exposure on experienced fear after in vivo exposure. AB - Two experiments tested the effect of exposure to masked phobic stimuli at a very brief stimulus onset asynchrony on reducing the subjective experience of fear caused by in vivo exposure to a feared object. In the main experiment, 35 spider fearful and 35 non-fearful participants were identified with a questionnaire and a behavioural avoidance test (BAT) with a live tarantula. One week later, they were individually administered one of two continuous series of masked images: spiders or flowers. They engaged in the BAT again immediately thereafter. They provided ratings of subjective fear at the end of each BAT (pre- and post manipulation). Very brief exposure to images of spiders reduced the fearful group's and not the non-fearful group's experience of fear at the end of the BAT. This effect was replicated with another sample of 26 spider-fearful participants from the same population. Theoretical implications are discussed. PMID- 23438482 TI - Proteomic analysis of the NOS2 interactome in human airway epithelial cells. AB - The cytokine-inducible isoform of nitric oxide synthase (NOS2) is constitutively expressed in human respiratory epithelia and is upregulated in inflammatory lung disease. Here, we sought to better define the protein interactions that may be important for NOS2 activity and stability, as well as to identify potential targets of NOS2-derived NO, in the respiratory epithelium. We overexpressed Flag tagged, catalytically-inactive NOS2 in A549 cells and used mass spectrometry to qualitatively identify NOS2 co-immunoprecipitating proteins. Stable isotope labeling of amino acids in cell culture (SILAC) was used to quantify the coordinate effects of cytokine stimulation on NOS2-protein interactions. Multi protein networks dominated the NOS2 interactome, and cytokine-inducible interactions with allosteric activators and with the ubiquitin-proteasome system were correlated with cytokine-dependent increases in NO metabolites and in NOS2 ubiquitination. The ubiquitin ligase scaffolding protein, FBXO45, was identified as a novel, direct NOS2 interactor. Similar to the SPRY domain-containing SOCS box (SPSB) proteins, FBXO45 requires Asn27 in the (23)DINNN(27) motif of NOS2 for its interaction. However, FBXO45 is unique from the SPSBs in that it recruits a distinct E3 ligase complex containing MYCBP2 and SKP1. Collectively, these findings demonstrate the general utility of interaction proteomics for defining new aspects of NOS2 physiology. PMID- 23438485 TI - Ras1CA-upregulated BCPI inhibits cathepsin activity to prevent tissue destruction of the Bombyx posterior silk gland. AB - Using the GAL4/UAS transgenic system established in the silkworm, Bombyx mori, we have previously reported that overexpression of the Ras1(CA) oncogene specifically in the posterior silk gland (PSG) resulted in improved fibroin synthesis, silk yield, and other phenotypic effects. However, the detailed molecular mechanism remains to be fully elucidated. Using 2D-DIGE-MS/MS analyses, we compared the proteomic profiles of PSGs from the wild type (WT) and Ras1(CA) overexpressed silkworms. Among the 24 Ras1(CA)-enhanced proteins, the Bombyx cysteine protease inhibitor (BCPI) was increased 2.4-fold at the protein level and 3.4-fold at the mRNA level. Consistent with the developmental profiles, injection of recombinant BCPI into the WT silkworms at the early wandering stage inhibited cathepsin activity, prevented tissue destruction of the PSG, and delayed pupation. Moreover, injection of small-molecule inhibitors of cathepsin into the WT silkworms prevented PSG destruction and delayed pupation, confirming the role of BCPI in inhibiting cathepsin activity. Furthermore, injection of chemical inhibitors of the Ras downstream effectors into the Ras1(CA) overexpressed and WT silkworms revealed that both Raf-MAPK and PI3K-TORC1 pathways were required for Ras1 to induce bcpi expression. Taken together, we conclude that via the downstream Raf-MAPK and PI3K-TORC1 pathways, Ras1(CA) upregulates bcpi, which inhibits cathepsin activity thus preventing PSG destruction in Bombyx. PMID- 23438486 TI - Isolation, characterization, cloning and expression of an alpha-neurotoxin from the venom of the Mexican coral snake Micrurus laticollaris (Squamata: Elapidae). AB - A new member of short chain alpha-neurotoxic protein family from venom of the Mexican coral snake, Micrurus laticollaris, was characterized. This protein, named MlatA1, possesses 61 amino acids with 8 conserved cysteine residues, sharing 30-91% sequence identity with other fully sequenced Micrurus toxins. MlatA1 (LD50i.v. = 0.064 mg/kg) antagonizes with both fetal and adult nicotinic acetylcholine receptor (nAChR) as well as alpha-7 neuronal nAChR in a dose dependent way. Specific rabbit anti-Mlat serum (titer higher than 18,000) does not show any protective ability against this toxin, nevertheless it was able to recognize protein bands in six out of twelve Micrurus venoms showing the existence of two distinct antigenic groups for alpha-neurotoxins in North American coral snakes species. The MlatA1 gene was cloned and used to produce recombinant toxin (rMlatA1) that was recognized by rabbit anti-native toxin but was depleted of toxic activity. PMID- 23438487 TI - The ever-increasing and -changing demands on the registered dietitian's expertise. PMID- 23438488 TI - Make your point with knowledge, civility, respect. PMID- 23438489 TI - The academy of nutrition and dietetics' public policy priorities overview. PMID- 23438490 TI - Nutritional implications of bariatric surgery and the role of registered dietitians. PMID- 23438492 TI - A qualitative study of nutrition-based initiatives at selected food banks in the feeding America network. AB - Food banks are the foundation of the US emergency food system. Although their primary mission is to alleviate hunger, the rise in obesity and diet-related diseases among food-insecure individuals has led some food bank personnel to actively promote more nutritious products. A qualitative interview approach was used to assess nutrition-related policies and practices among a sample of 20 food banks from the national Feeding America network. Most food bank personnel reported efforts to provide more fresh produce to their communities. Several described nutrition-profiling systems to evaluate the quality of products. Some food banks had implemented nutrition policies to cease distributing low-nutrient products, such as soda and candy; however, these policies were more controversial than other strategies. The obstacles to implementing strong nutrition policies included fear of reducing the total amount of food distributed, discomfort choosing which foods should not be permitted, and concern about jeopardizing relationships with donors and community partners. Empirical research is needed to measure how food bank nutrition policies influence relationships with food donors, the amount of food distributed, the nutritional quality of food distributed, and the contribution of food bank products to the food security and nutritional status of the communities they serve. PMID- 23438491 TI - Long-term dietary intake and nutritional deficiencies following sleeve gastrectomy or Roux-En-Y gastric bypass in a mediterranean population. AB - BACKGROUND: Data on long-term dietary changes and nutritional deficiencies after sleeve gastrectomy (SG) in grade 3 obese patients are scarce. OBJECTIVE: To prospectively compare dietary changes and nutritional deficiencies in grade 3 obese patients 5 years after SG and Roux-en-y gastric bypass (GBP). PARTICIPANTS/SETTING: Three hundred and fifty-five patients who had SG (n=61) or GBP (n=294) (May 2001-December 2006) at a Spanish university hospital. DESIGN: Longitudinal, prospective, observational study. PRIMARY OUTCOMES/STATISTICAL ANALYSES: Changes in energy, macronutrient, and micronutrient intake, and weight loss were analyzed using mixed models for repeated measurements. RESULTS: At the 5-year follow-up visit, the percentage of excess weight loss (P=0.420) and daily energy intake (P=0.826), as well as the proportion of energy from carbohydrates (P=0.303), protein (P=0.600), and fat (P=0.541) did not differ between surgical groups. Energy intake (P=0.004), baseline weight (P<0.001), and time period (P<0.001), but not the proportion of different macronutrients or the type of surgery, independently predicted the percentage excess weight loss over time. After SG or GBP, the mean daily dietary intake of calcium, magnesium, phosphorus, and iron was less than the current recommendations. Despite universal supplementation, the prevalence of nutritional deficiencies was comparable after SG or GBP, with 25-hydroxyvitamin D being the most commonly observed deficiency (SG, 93.3% to 100%; GBP, 90.9% to 85.7%, P=not significant). In an adjusted multivariate regression model, energy intake and lipid intake independently predicted plasma 25(OH)-vitamin D levels. CONCLUSIONS: Data show that SG and GBP are associated with similar long-term weight loss with no differences in terms of dietary intake. Furthermore, data demonstrate that both types of surgeries carry comparable nutritional consequences. PMID- 23438493 TI - Acne: the role of medical nutrition therapy. AB - Acne is a common disease in Westernized nations, particularly among adolescents and young adults. Acne has substantial effects on quality of life, making treatment essential. Medical nutrition therapy as a potential treatment for acne is not new, although the literature examining diet and acne during the past 100 years is mixed. During the late 1800s and early 1900s, diet was commonly used as an adjunct treatment for acne. During the 1960s, however, the diet-acne connection fell out of favor. In recent years, dermatologists and registered dietitians have revisited the idea and become increasingly interested in the role of medical nutrition therapy in acne treatment. This article reviews the history and existing literature examining the association between diet and acne. Although the total number of studies conducted within the past 40 years is relatively small, the growing body of epidemiologic and experimental evidence suggests a relationship between diet and acne. Compared with other dietary factors, more research examines dietary glycemic load. The evidence is more convincing for high glycemic load diets, compared with other dietary factors. To date there are no randomized controlled trials investigating the relationship between frequent dairy or milk consumption and acne. Similarly, the number of research studies examining the relationship between dietary fat and/or n-3 fatty acids is sparse and the evidence is less robust. Taken together, several methodologic limitations need to be addressed, and additional research, preferably randomized controlled trials, is warranted before comprehensive evidence-based guidelines can be established. While dermatologists and registered dietitians continue to debate and research the potential relationship between diet and acne, the best dietary approach is to address each acne patient individually, carefully considering the possibility of dietary counseling. PMID- 23438494 TI - Self-reported dietary intake of youth with recent onset of type 2 diabetes: results from the TODAY study. AB - Despite the widely recognized importance of diet in managing diabetes, few studies have documented usual dietary intake in young people with type 2 diabetes. The objectives of our study were to assess dietary intake among a large, ethnically diverse cohort of young people with type 2 diabetes and compare intake to current recommendations. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is a multicenter randomized clinical trial of 699 youth aged 10 to 17 years. At baseline, following a run-in period that included standard diabetes education, diet was assessed using a food frequency questionnaire between 2004 and 2009. Analysis of variance and nonparametric tests were used to compare mean and median nutrient intakes; logistic regression was used to compare the odds of meeting predefined dietary intake recommendation cutpoints between subgroups of age, sex, and race-ethnicity. Percent of energy from saturated fat was consistently 13% to 14% across all subgroups-substantially exceeding national recommendations. Overall, only 12% of youth met Healthy People 2010 guidelines for intake of <10% of energy from saturated fat and only 1% of youth met American Diabetes Association recommendations for intake of <7% of energy from saturated fat. Dietary intake fell substantially below other Healthy People 2010 targets; only 3% met calcium intake goals, 11% met fruit consumption goals, 5% met vegetable consumption goals, and 67% met grain intake goals. Overall, dietary intake in this large cohort of young people with type 2 diabetes fell substantially short of recommendations, in ways that were consistent by sex, age, and race-ethnicity. The data suggest a critical need for better approaches to improve dietary intake of these young people. PMID- 23438495 TI - Trends in body mass index among Ohio's third-grade children: 2004-2005 to 2009 2010. AB - Substantial variation across states in the prevalence and trends in childhood overweight and obesity indicate a need for state-specific surveillance to make state comparisons to national estimates and identify high-risk populations. The purpose of this study was to examine body mass index (BMI) trends among third grade children in Ohio between the 2004-2005 and 2009-2010 school years and examine changes in prevalence of obesity by specific demographic subgroups. Third grade children (n=33,672) were directly weighed and measured throughout the school years by trained health care professionals. Trends in overweight/obesity (>=85th percentile of BMI by age/sex), obesity (>=95th percentile), and obesity level 2 (>=97th percentile) over five time periods (2004-2005, 2006-2007, 2007 2008, 2008-2009, 2009-2010) were modeled using logistic regression, accounting for the survey design and adjusting for sex, race/ethnicity, National School Lunch Program (NSLP) participation, and age. Differences in these BMI categories were also examined by these subgroups. BMI estimates did not demonstrate a statistically significant trend over the five time periods for overweight/obesity (34% to 36%), obesity (18% to 20%), or obesity level 2 (12% to 14%). However, increases in overweight/obesity prevalence were found in Hispanic children (37.8% vs 53.1%; P<0.01). Decreases in obesity (16.6% vs 14.1%; P=0.02) and obesity level 2 (11.3% vs 9.3%; P=0.02) were found among children not participating in NSLP and residing in suburban counties (obesity [17.3% vs 14.7%; P=0.03] and obesity level 2 [11.8% vs 9.8%; P=0.05]). Finally, decreases in overweight/obesity and obesity level 2 among boys were observed (15% vs 12.9%; P=0.02). Despite no significant overall trends in overweight/obesity, obesity, or obesity level 2 between 2004 and 2010, prevalence changed among specific subgroups. Obesity prevention efforts should be widespread and include special emphasis on groups experiencing increases or no change in prevalence. PMID- 23438499 TI - Is there a diet for "yeast allergy"? PMID- 23438496 TI - Dietary protein-induced increases in urinary calcium are accompanied by similar increases in urinary nitrogen and urinary urea: a controlled clinical trial. AB - To determine the usefulness of urinary urea as an index of dietary protein intake, 10 postmenopausal women were enrolled in and completed a randomized, double-blind, cross-over feeding trial from September 2008 to May 2010 that compared 10 days of a 45-g whey supplement with 10 days of a 45-g maltodextrin control. Urinary nitrogen, urinary calcium, urinary urea, and bone turnover markers were measured at days 0, 7, and 10. Paired sample t tests, Pearson's correlation statistic, and simple linear regression were used to assess differences between treatments and associations among urinary metabolites. Urinary nitrogen/urinary creatinine rose from 12.3+/-1.7 g/g (99.6+/-13.8 mmol/mmol) to 16.8+/-2.2 g/g (135.5+/-17.8 mmol/mmol) with whey supplementation, but did not change with maltodextrin. Whey supplementation caused urinary calcium to rise by 4.76+/-1.84 mg (1.19+/-0.46 mmol) without a change in bone turnover markers. Because our goal was to estimate protein intake from urinary nitrogen/urinary creatinine, we used our data to develop the following equation: protein intake (g/day)=71.221+1.719*(urinary nitrogen, g)/creatinine, g) (R=0.46, R(2)=0.21). As a more rapid and less costly alternative to urinary nitrogen/urinary creatinine, we next determined whether urinary urea could predict protein intake and found that protein intake (g/day)=63.844+1.11*(urinary urea, g/creatinine, g) (R=0.58, R(2)=0.34). These data indicate that urinary urea/urinary creatinine is at least as good a marker of dietary protein intake as urinary nitrogen and is easier to quantitate in nutrition intervention trials. PMID- 23438500 TI - Quantitative analysis of the coverage density of Br- ions on Pd{100} facets and its role in controlling the shape of Pd nanocrystals. AB - We report an approach based on a combination of inductively coupled plasma mass spectrometry and X-ray photoelectron spectroscopy for quantitative analysis of the role played by Br(-) ions in the synthesis of Pd nanocrystals. The Br(-) ions were found to adsorb onto Pd{100} facets selectively with a coverage density of ca. 0.8 ion per surface Pd atom. The chemisorbed Br(-) ions could be removed via desorption at an elevated temperature under reductive conditions. They could also be gradually released from the surface when Pd cubic seeds grew into cuboctahedrons and then octahedrons. On the basis of the coverage density information, we were able to estimate the minimum concentration of Br(-) ions needed for the formation of Pd nanocubes with a specific size. If the concentration of Br(-) ions was below this minimum value, not all of the {100} facets could be stabilized by the capping agent, leading to the formation of nanocubes with truncated corners. The quantitative analysis developed in this study is potentially extendable to other systems involving chemisorbed capping agents. PMID- 23438501 TI - Deficient fear recognition in regular cocaine users is not attributable to elevated impulsivity or conduct disorder prior to cocaine use. AB - We previously reported that regular recreational intranasal cocaine users exhibit impaired recognition of facial expressions of fear compared to occasional cocaine users and cocaine-naive controls. The aim of the present study was to re investigate this phenomenon after controlling for impulsivity, conduct disorder (CD) and anti-social personality disorder (ASPD). We employed a cross-sectional design to compare 31 cocaine-naive participants, 35 occasional cocaine users and 20 regular recreational cocaine users. An emotional facial expression (EFE) task which comprised a male and a female face expressing six basic emotions morphed to differing degrees of emotional intensity was administered together with questionnaires to assess: CD, ASPD and impulsiveness. ASPD was not a significant covariate for EFE performance but impulsiveness and CD were significant covariates. After treating impulsiveness and CD as covariates we again observed a group difference in fear recognition ability attributable to the particularly impaired performance of regular cocaine users. This suggests that, although elevated impulsiveness and CD before the age of 15 years, may predispose a relative inability to recognize facial expressions of fear in adulthood, subsequent regular recreational use of cocaine represents an additional factor that is specifically associated with a selective deficit in fear recognition. PMID- 23438502 TI - Harms and benefits associated with psychoactive drugs: findings of an international survey of active drug users. AB - There have been several recent efforts in the UK and the Netherlands to describe the harms of psychoactive substances based on ratings of either experts or drug users. This study aimed to assess the perceived benefits as well as harms of widely used recreational drugs, both licit and illicit, in an international sample of drug users. The survey was hosted at https://www.internationaldrugsurvey.org/ and was available in three languages. Residents reported their experience of 15 commonly used drugs or drug classes; regular users then rated their harms and benefits. In all, 5791 individuals from over 40 countries completed the survey, although the majority were from English speaking countries. Rankings of drugs differed across 10 categories of perceived benefits. Skunk and herbal cannabis were ranked consistently beneficial, whilst alcohol and tobacco fell below many classified drugs. There was no correlation at all between users' harm ranking of drugs and their classification in schedules of the USA or ABC system in the UK. Prescription analgesics, alcohol and tobacco were ranked within the top 10 most harmful drugs. These findings suggest that neither the UK nor US classification systems act to inform users of the harms of psychoactive substances. It is hoped the results might inform health professionals and educators of what are considered to be both the harms and benefits of psychoactive substances to young people. PMID- 23438503 TI - Systematic review of atomoxetine data in childhood and adolescent attention deficit hyperactivity disorder 2009-2011: focus on clinical efficacy and safety. AB - BACKGROUND: Clinicians obtain critical prescribing knowledge from clinical papers and review articles. This is the first published systematic review of clinical atomoxetine data covering 2009-2011. OBJECTIVE: We aim to update clinicians on current clinical atomoxetine data with specific reference to time of onset of efficacy and maximal efficacy. These data may allow critical analysis of comparative efficacy between atomoxetine and stimulant medications. METHODS: A formal systematic review of atomoxetine data from January 2009-June 2011 was conducted. The search term used was "atomoxetine" in the English language. The search yielded 747 citations from which 106 are clinical data. This paper includes clinical efficacy and safety data and excludes quality-of-life and review papers. RESULTS: Atomoxetine has an onset of action within 4 weeks (possibly within 1 week in subsequent responders) but requires at least 12 weeks for full response to be demonstrated. Treatment-naive cohorts (6-12 weeks) report effect sizes of 0.6-1.3. Using minimum 6-week clinical trial criteria, atomoxetine may demonstrate similar efficacy to methylphenidate comparing reduction in core ADHD symptoms in meta-analysis, although the diversity of the data makes interpretation complex. From epidemiological databases, cardiovascular and suicide-related events were similar to those seen in patients taking methylphenidate. CONCLUSIONS: Incremental response time to atomoxetine should be considered in the design of future comparative efficacy trials. PMID- 23438504 TI - Circulating N-cadherin levels are a negative prognostic indicator in patients with multiple myeloma. AB - N-cadherin (cadherin 2, type 1, N-cadherin (neuronal); CDN2) is a homotypic adhesion molecule that is upregulated in breast, prostate and bladder cancer. Here we investigated the prognostic significance of upregulated N-cadherin expression in multiple myeloma (MM). Our results indicate that N-cadherin protein and gene expression is abnormally increased in trephine biopsies and CD38(++) /CD138(+) plasma cells from MM patients, when compared with those of normal donors. In addition, levels of circulating N-cadherin were elevated in a subset of patients with MM (n = 81; mean: 14.50 ng/ml, range: 0-146.78 ng/ml), relative to age-matched controls (n = 27; mean: 2.66 ng/ml, range: 0-5.96 ng/ml), although this did not reach statistical significance. Notably, patients with abnormally high levels of N-cadherin (>6 ng/ml) had decreased progression-free survival (P = 0.036; hazard ratio: 1.94) and overall survival (P = 0.002; hazard ratio: 3.15), when compared with patients with normal N-cadherin levels (<=6 ng/ml). Furthermore, multivariate analyses revealed that the combination of N-cadherin levels and International Staging System (ISS) was a more powerful prognostic indicator than using ISS alone. Collectively, our studies demonstrate that circulating N-cadherin levels are a viable prognostic marker for high-risk MM patients. PMID- 23438505 TI - Evaluating interventions to improve somatic health in severe mental illness: a systematic review. AB - OBJECTIVE: To present a systematic review of the evaluation of randomized interventions directed toward improving somatic health for patients with severe mental illness (SMI). METHOD: A systematic search in PubMed, Embase, Cinahl, and PsycInfo was performed. The scope of the search was prospective studies for patients aged 18-70, published from January 2000 till June 2011. Randomized interventions directed toward improving somatic health for patients with SMI were selected. We excluded studies on elderly, children, and studies performed before 2000. Information on population, type of intervention, follow-up, outcome measures, and on authors' conclusions were drawn from the original articles. RESULTS: Twenty-two original studies were included, presenting four types of interventions: health education (n = 9), exercise (n = 6), smoking cessation (n = 5), and changes in health care organization (n = 2). To evaluate the effect of these studies 93 different outcome measures were used in 16 categories. CONCLUSION: Many interventions directed toward improving somatic health for patients with SMI have been started. These studies did not apply similar evaluations, and did not use uniform outcome measures of the effect of their interventions. Valuable comparisons on effectiveness are therefore almost impossible. PMID- 23438506 TI - Engaging home health care providers in a fall prevention best practice initiative. AB - This article reports key findings regarding the engagement of home health care providers in the implementation of a fall prevention best practice initiative. Participants were 29 home health care providers from physiotherapy, occupational therapy, and nursing. Each participant completed a self-efficacy for evidence based practice survey, and a smaller subgroup of volunteers participated in focus groups for each discipline individually. Findings suggest home health care providers value the implementation of best practice in everyday care, but may need to be highly involved in the development of best practice initiatives and implementation strategies to foster engagement with the initiative in everyday practice. PMID- 23438507 TI - Willingness to pay for home- and community-based services for seniors in Florida. AB - States are increasingly interested in measuring the benefit of home- and community-based services (HCBS) programs in order to determine if continued provision of HCBS can be justified on a cost-benefit basis. This study attempts to assess the maximum dollar amount HCBS enrollees or eligible applicants are willing to pay as a measure of the value of the services to them. A contingent valuation survey was conducted on a random sample of 409 clients who were enrolled in or waitlisted for HCBS programs in Florida. Based on estimates from a random-effect model, the median and mean willingness to pay amounts are calculated to be $901 and $933 per month per person, respectively, with considerable variation across HCBS programs. The major determinants of willingness to pay include household income and individual functional status. The sizable values for willingness to pay reported in this study suggest that HCBS programs are perceived as a valuable resource for the elderly. PMID- 23438508 TI - Variation in Older Americans Act caregiver service use, unmet hours of care, and independence among Hispanics, African Americans, and Whites. AB - Home- and community-based services (HCBS) are underused by minority seniors and their caregivers, despite greater rates of disability. We examined racial/ethnic variation among 1,749 Hispanics, African Americans, and Whites receiving Older Americans Act Title III caregiver services in 2009. In addition, we identified the volume of services used by caregivers, their unmet hours of respite care, and the relationship between service use and seniors' ability to live independently. Minority caregivers cared for seniors in urban areas who had higher rates of disability, poverty, and Medicaid coverage. Hispanics had the highest rate of unmet hours of care, while caregiver services were less likely to help African Americans remain at home. Minorities sought services through community agencies and were more educated than demographically similar national cohorts. Greater efforts to reach minority caregivers of less educated, disabled seniors in urban areas and through community agencies may reduce unmet needs and support independent living. PMID- 23438509 TI - Home health care with telemonitoring improves health status for older adults with heart failure. AB - Home telemonitoring can augment home health care services during a patient's transition from hospital to home. Home health care agencies commonly use telemonitors for patients with heart failure although studies have shown mixed results in the use of telemonitors to reduce rehospitalizations. This randomized trial investigated if older patients with heart failure admitted to home health care following a hospitalization would have a reduction in rehospitalizations and improved health status if they received telemonitoring. Patients were followed up to 180 days post-discharge from home health care services. Results showed no difference in the time to rehospitalization or emergency visit between those who received telemonitoring versus usual care. Older heart failure patients who received telemonitoring had better health status by home health care discharge than those who received usual care. Therefore, for older adults with heart failure, telemonitoring may be an important adjunct to home health care services to improve health status. PMID- 23438510 TI - Interspecies differences in the empty body chemical composition of domestic animals. AB - Domestication of animals has resulted in phenotypic changes by means of natural and human-directed selection. Body composition is important for farm animals because it reflects the status of energy reserves. Thus, there is the possibility that farm animals as providers of food have been more affected by human-directed selection for body composition than laboratory animals. In this study, an analysis was conducted to determine what similarities and differences in body composition occur between farm and laboratory animals using literature data obtained from seven comparative slaughter studies (n = 136 observations). Farm animals from four species (cattle, goats, pigs and sheep) were all castrated males, whereas laboratory animals from three species (dogs, mice and rats) comprised males and/or females. All animals were fed ad libitum. The allometric equation, Y = aX b , was used to determine the influence of species on the accretion rates of chemical components (Y, kg) relative to the growth of the empty body, fat-free empty body or protein weights (X, kg). There were differences between farm and laboratory animals in terms of the allometric growth coefficients for chemical components relative to the empty BW and fat-free empty BW (P < 0.01); farm animals had more rapid accretion rates of fat (P < 0.01) but laboratory animals had more rapid accretion rates of protein, water and ash (P < 0.01). In contrast, there was no difference in terms of the allometric growth coefficients for protein and water within farm animals (P > 0.2). The allometric growth coefficients for ash weight relative to protein weight for six species except sheep were not different from a value of 1 (P > 0.1), whereas that of sheep was smaller than 1 (P < 0.01). When compared at the same fat content of the empty body, the rate of change in water content (%) per unit change in fat content (%) was not different (P > 0.05) across farm animal species and similar ash-to-protein ratios were obtained except for dogs. The fraction of empty body energy gain retained as fat increased in a curvilinear manner, and there was little variation among farm animals at the same fat content of the empty body. These findings may provide the opportunity to develop a general model to predict empty body composition across farm animal species. In contrast, there were considerable differences of chemical body composition between farm and laboratory animals. PMID- 23438511 TI - Role of Arg403 for thermostability and catalytic activity of rabbit 12/15 lipoxygenase. AB - 12/15-Lipoxygenases (12/15-LOX) have been implicated in inflammatory and hyperproliferative diseases but the numerous aspects of structural biology of these enzymes are far from clear. Early mutagenesis data and structural modeling of enzyme-substrate complexes suggested that Arg403, which is localized at the entrance of the putative substrate binding pocket, might interact with the fatty acid carboxylic group. On the other hand, side-chain of Arg403 is a part of an ionic network with the residues of alpha2-helix, which undergoes pronounced conformation changes upon inhibitor binding. To explore the role of Arg403 for catalysis in more detail we exchanged positively charged Arg403 to neutral Leu and quantified structural and functional consequences of the alteration at the site of mutation using fluorometric techniques. We found that a loss of electrostatic interaction between Arg403 and negatively charged amino acid residues of alpha2-helix has only minor impact on protein folding, but partially destabilized the tertiary structure of the enzyme. We hypothesize that interaction of Arg403 with the substrate's carboxylate might be involved in a complex mechanism triggering conformational changes of the alpha2-helix, which are required for formation of the catalytically competent dimer r12/15-LOX complex at pre-catalytic stages. PMID- 23438512 TI - Phosphotyrosine profiling of NSCLC cells in response to EGF and HGF reveals network specific mediators of invasion. AB - Growth factor signaling is deregulated in cancer and often leads to invasion, yet receptor tyrosine kinase signaling pathways driving invasion under different growth factor conditions are not well understood. To identify specific signaling molecules regulating invasion of A549 non-small cell lung carcinoma (NSCLC) cells downstream of the epidermal growth factor receptor (EGFR) and Met, quantitative site-specific mass spectrometric analysis of tyrosine phosphorylation was performed following epidermal growth factor (EGF) or hepatocyte growth factor (HGF) stimulation, at three different growth factor concentrations and at two time points. Through this analysis, the temporal and concentration dependent phosphorylation profiles were obtained for 131 and 139 sites downstream of EGF and HGF stimulation, respectively. To characterize the effect of these signaling network alterations, we quantified 3D cell migration/invasion through Matrigel. Partial least-squares regression (PLSR) analysis was performed to identify the tyrosine phosphorylation sites most strongly correlated with EGF and/or HGF mediated invasion. Potential common and specific signaling events required for driving invasion downstream of EGFR and Met were identified using either a combined or two independent PLSR models, based on the quantitative EGF or HGF data. Our data highlight the integration and compartmentalization of signaling required for invasion in cancer. PMID- 23438513 TI - Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1. AB - 3K3A-APC is a recombinant analog of activated protein C (APC) which is an endogenous protease with multiple functions in the body. Compared to APC, 3K3A APC has reduced anticoagulant activity but preserved cell signaling activities. In the brain, 3K3A-APC exerts neuroprotective effects after an acute or chronic injury. 3K3A-APC is currently under clinical assessment as a neuroprotective agent following acute ischemic stroke. Whether 3K3A-APC can influence post ischemic neurogenesis and improve neurological outcome by promoting brain repair remains unknown. Here we show that murine 3K3A-APC 0.8mg/kg intraperitoneally given at 12h, 1, 3, 5 and 7 days after permanent distal middle cerebral artery occlusion (dMCAO) in mice compared to vehicle improves significantly sensorimotor and locomotor activity 7 and 14 days after stroke, reduces infarct and edema volumes 7 days after stroke by 43% (P<0.05) and 50% (P<0.05), respectively, increases the number of newly formed neuroblasts in the subventricular zone, corpus callosum and the peri-infarct area 7 days after stroke by 2.2-fold, 2.3 fold and 2.2-fold (P<0.05), respectively, and increases the cortical width index 14 days after stroke by 28% (P<0.05). Functional outcome in 3K3A-APC-treated group, but not in vehicle-treated group, correlated inversely with the reductions in the infarct volume, and positively with the number of neuroblasts migrating in the peri-infarct area and the cortical width index. The effects of 3K3A-APC on neuroprotection, neurogenesis and brain repair were lost in protease activated receptor 1 (PAR1) deficient mice. Thus, late therapy with 3K3A-APC is neuroprotective and promotes stroke-induced neurogenesis and repair through PAR1 in mice. PMID- 23438514 TI - Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease. AB - Krabbe disease is a lethal, demyelinating condition caused by genetic deficiency of galactocerebrosidase (GALC) and resultant accumulation of its cytotoxic substrate, psychosine (galactosylsphingosine), primarily in oligodendrocytes (OLs). Psychosine is generated by galactosylation of sphingosine by UDP galactose:ceramide galactosyltransferase (CGT), a galactosylceramide synthesizing enzyme which is primarily expressed in OLs. The expression of CGT and the synthesis of galactosyl-sphingolipids are associated with the terminal differentiation of OL, but little is known about the participation of endogenous psychosine accumulation in OL differentiation under GALC deficient conditions. In this study, we report that accumulation of endogenous psychosine under GALC deficient Krabbe conditions impedes OL differentiation process both by decreasing the expression of myelin lipids and protein and by inducing the cell death of maturating OLs. The psychosine pathology under GALC deficient conditions involves participation of secretory phospholipase A2 (sPLA2) activation and increase in its metabolites, as evidenced by attenuation of psychosine-induced pathology by treatment with pharmacological inhibitor of sPLA2 7,7-dimethyleicosadienoic acid (DEDA). These observations suggest for potential therapeutic efficacy of sPLA2 inhibitor in Krabbe disease. PMID- 23438515 TI - Frizzled-3a and Wnt-8b genetically interact during forebrain commissural formation in embryonic zebrafish. AB - The commissural plate forms the rostral surface of the embryonic vertebrate forebrain and provides a cellular substrate for forebrain commissural axons. We have previously reported that the Wnt receptor frizzled-3a (fzd3a) restricts the expression of the chemorepulsive guidance ligand slit2 to a discrete domain of neuroepithelial cells in the commissural plate of embryonic zebrafish. Loss of Fzd3a function perturbed slit2 expression and disrupted the formation of glial bridges which guide the formation of forebrain commissures. We now show that Wnt8b is also necessary for anterior commissural formation as well as for patterning of slit2 expression at the midline. Knock down of Wnt8b produced the same phenotype as loss of Fzd3a which suggested that these genes were acting together to regulate axon guidance. Simultaneous sub-threshold knock down of both Fzd3a and Wnt8b led to a greater than additive increase in the penetrance of the mutant phenotype which indicated that these two genes were indeed interacting. We have shown here that Fzd3a/Wnt8b signaling is essential for normal patterning of the commissural plate and that loss-of-function in either receptor or ligand causes Slit2-dependent defects in glial bridge morphology which indirectly attenuated axon midline crossing in the embryonic vertebrate forebrain. PMID- 23438516 TI - To disclose hepatitis C virus infection or not: who decides? PMID- 23438517 TI - Hepatitis C virus-infected resident: end of residency, end of career? PMID- 23438518 TI - Invited commentary. PMID- 23438519 TI - Invited commentary. PMID- 23438520 TI - Invited commentary. PMID- 23438521 TI - Invited commentary. PMID- 23438522 TI - Invited commentary. PMID- 23438523 TI - Long-lasting functional disabilities in patients who recover from coma after cardiac operations. AB - BACKGROUND: Uncertainty regarding the long-term functional outcome of patients who awaken from coma after cardiac operations is difficult for families and physicians and may delay rehabilitation. We studied the long-term functional status of these patients to determine if duration of coma predicted outcome. METHODS: We followed 71 patients who underwent cardiac operations; recovered their ability to respond to verbal commands after coma associated with postoperative stroke, encephalopathy, and/or seizures; and were discharged from the hospital. The Glasgow Outcome Scale Extended (GOSE) was used to assess functional disability 2 to 4 years after discharge. Outcomes were classified as favorable (GOSE scores 7 and 8) and unfavorable (GOSE scores 1-6). RESULTS: Of 71 patients identified, 39 were interviewed, 15 died, 1 refused to be interviewed, and 16 were lost to follow-up. Of the 54 patients with completed GOSE evaluations, only 15 (28%) had favorable outcomes. Among patients with unfavorable outcomes, 15 (28%) died, 14 (26%) survived with moderate disabilities, and 10 (18%) had severe disabilities. Factors associated with unfavorable outcomes were increases in duration of coma (p = 0.007), time in intensive care (p = 0.006), length of hospitalization (p = 0.004), and postoperative serum creatine kinase levels (p = 0.006). Only duration of coma was an independent predictor of unfavorable outcome (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.008-1.537; p = 0.042). Patients with durations of coma greater than 4 days were more likely to have unfavorable outcomes (OR, 5.1; 95% CI, 1.3-21.3; p = 0.02). CONCLUSIONS: Two thirds of comatose patients who survived to discharge after cardiac operations had unfavorable long-term functional outcomes. A longer duration of unconsciousness is a predictor of unfavorable outcome. PMID- 23438524 TI - Invited commentary. PMID- 23438525 TI - Invited commentary. PMID- 23438526 TI - Invited commentary. PMID- 23438527 TI - Invited commentary. PMID- 23438528 TI - Invited commentary. PMID- 23438529 TI - Invited commentary. PMID- 23438530 TI - Invited commentary. PMID- 23438531 TI - Invited commentary. PMID- 23438532 TI - Invited commentary. PMID- 23438533 TI - Successful transapical implantation of an Edwards Sapien valve within an insufficient aortic CoreValve prosthesis: an initial experience. AB - Transcatheter aortic valve implantation (TAVI) has become an emerging alternative for high-risk patients with aortic stenosis unsuitable for surgical intervention. We report the case of a 26-mm Edwards Sapien valve (Edwards Lifesciences, Irvine, CA) implanted into an insufficient 29-mm CoreValve prosthesis (Medtronic Inc, Minneapolis, MN) 1 year after implantation using the transapical approach in a 59 year-old man. Transesophageal echocardiography showed severe paravalvular regurgitation and computed tomography revealed the CoreValve to be located slightly below the aortic annulus with evidence of underdeployment. The balloon expandable Sapien system caused a better expansion of the underdeployed CoreValve and the pericardial skirt adequately covered the leakage. The paravalvular regurgitation disappeared and the patient recovered. PMID- 23438534 TI - Successful surgical removal of a giant interventricular fibroma: surgical approach without ventriculotomy. AB - A 14-month-old boy was transported to our hospital by ambulance because of cardiopulmonary arrest after the sudden onset of convulsions. He was resuscitated and transthoracic echocardiography showed a giant interventricular tumor. The cause of this episode was thought to be ventricular arrhythmias induced by the tumor. At operation, an incision line was confirmed by direct ultrasonography. The heart was incised directly on the interventricular septum. The tumor was carefully dissected and completely removed without entering the ventricular cavity. Histologic analysis revealed a fibroma. The patient's postoperative course was uneventful, and he remains well without episodes of heart failure or ventricular arrhythmia. PMID- 23438535 TI - Rupture of valsalva sinus after aortic root replacement with freestyle stentless bioprosthesis. AB - We report a case of aortic wall rupture in a patient with a Medtronic Freestyle stentless bioprosthesis (Medtronic Inc, Minneapolis, MN) after full root implantation. A 68-year-old man who underwent aortic root replacement with a Freestyle bioprosthesis 12 years prior was found to have a large pseudoaneurysm originating from the ruptured noncoronary porcine aortic sinus. A reoperation for aortic root replacement was successfully performed. Despite excellent durability of porcine aortic root bioprostheses, several cases with a ruptured aortic wall have been reported. Degeneration of the elastic tissue and inflammatory reactions may be the main mechanism of this potentially catastrophic complication. PMID- 23438536 TI - Aortic valve replacement for aortic stenosis caused by alkaptonuria. AB - We report a case of aortic stenosis associated with ochronosis in a 70-year-old man who underwent biologic aortic valve replacement. Intraoperative findings included ochronosis of a severely calcified pigmented aortic valve along with pigmentation of the intima of the aorta. PMID- 23438537 TI - Fulminate heparin-induced thrombocytopenia and surgery with deep hypothermic circulatory arrest using bivalirudin. AB - After on-pump coronary artery bypass graft surgery, a patient had acute heparin induced thrombocytopenia with thoracic arterial and venous thrombus formations. Complex emergency surgery with cardiopulmonary bypass and deep hypothermic circulatory arrest using bivalirudin anticoagulation was performed. PMID- 23438538 TI - Acute left hemothorax as a late complication of an active-fixation pacemaker lead. AB - Perforation and migration of pacemaker electrodes into the pleural cavity is a rare event. We report the clinical course and surgical treatment of massive acute hemothorax resulting from intercostal artery laceration, caused by a retained active-fixation pacing lead implanted 10 months earlier. PMID- 23438539 TI - Idiopathic subglottic stenosis: a familial predisposition. AB - Idiopathic subglottic stenosis is a narrowing of the trachea at the level of the cricoid cartilage of unknown etiology. It is a rare condition for which the real incidence has never been established owing to the difficulty of making the diagnosis. Although there is a female preponderance, no familial cases have been reported in the literature. We describe two pairs of sisters as well as a mother and daughter presenting with idiopathic subglottic stenosis. All known causes of tracheal stenosis were excluded, including prolonged intubation, surgery, autoimmune and inflammatory disorders, infection and gastroesophageal reflux disease. These are the first cases reported in the literature that suggest a genetic predisposition for idiopathic subglottic stenosis. PMID- 23438540 TI - A rare association of pulmonary carcinoid, lymphoma, and sjogren syndrome. AB - Pulmonary carcinoid and pulmonary lymphoma are both rare cancers and are seldom seen together. Cases have been reported of their coexistence in the gastrointestinal tract, but our literature searches only found a single case of their coexistence in the lung. We discuss our case as well as the literature to try to find a connection and explanation for this occurrence. PMID- 23438541 TI - Benign emptying of postpneumonectomy space due to severe dehydration. AB - Causes of benign emptying of the postpneumonectomy space include small bronchopleural fistulas with spontaneous healing and escape of fluid into the chest wall or diaphragm. We present an additional cause: severe dehydration. As postpneumonectomy empyema usually involves drainage of the pleural space, it is important to be aware of this uncommon cause so as to avoid unnecessary instrumentation and contamination of the postpneumonectomy space. PMID- 23438542 TI - Spontaneous esophageal hematoma in a patient with atrial fibrillation. AB - We report a case of a spontaneous esophageal hematoma in an anticoagulated patient with atrial fibrillation previously complicated by a cerebrovascular accident. A multidisciplinary discussion resulted in holding of anticoagulation until the esophageal hematoma resolved. The patient was managed nonoperatively and discharged, but returned with a new neurologic deficit 3 weeks later. Aspirin treatment was resumed. After complete resolution of hematoma on outpatient scans, warfarin treatment was restarted. The challenges of managing an esophageal hematoma in a patient requiring anticoagulation are discussed. PMID- 23438543 TI - Pleomorphic malignant histiocytoma of pulmonary arteries presenting as pulmonary aneurysms. AB - Pulmonary aneurysms and primary neoplasms of the great vessels are very rare entities; pulmonary aneurysms are commonly associated with congenital heart diseases, and less frequently in atherosclerosis, medial cystic necrosis, trauma, infection, and inflammatory processes. Many patients have pulmonary hypertension, most frequently resulting from pulmonary artery sarcomas mimicking pulmonary thromboembolism. Symptoms are vague. In 30% of cases, rupture and death occur, related to pulmonary aneurysms. We present the case of a patient with a diagnosis of pulmonary artery pleomorphic malignant histiocytoma that presented as a right pulmonary aneurysm thrombosis and a contained rupture of a left pulmonary aneurysm. PMID- 23438544 TI - Intrapericardial extralobar pulmonary sequestration in adult. AB - Extralobar pulmonary sequestration is a rare congenital pulmonary malformation compared with its counterpart, intralobar pulmonary sequestration, and occurs less in females. Here we describe a 24-year-old woman who underwent a median sternotomy for resection of an intrapericardial extralobar pulmonary sequestration. At her month follow-up visit, she had recovered well with no complications. PMID- 23438545 TI - Repair of a complex bronchogastric fistula after esophagectomy with biologic mesh. AB - Bronchogastric conduit fistula is a rare and potentially fatal complication after esophagectomy for esophageal cancer. We report a case of a patient transferred to our institution with a complex bronchogastric conduit fistula after a thoracoscopic three-hole esophagectomy for midesophageal squamous cell carcinoma. The defect involved the entire membranous airway of the bronchus intermedius, with a 15-cm dehiscence of the gastric conduit staple line. This was successfully reconstructed with a single-stage repair by use of an Alloderm patch reinforced with an intercostal muscle flap. At postoperative follow-up the patient is doing well and tolerating a regular diet without dysphagia. PMID- 23438546 TI - A rare case of left anterior chest bleeding in a female with takayasu disease. PMID- 23438547 TI - Bronchopericardial fistula after a pulmonary resection. PMID- 23438548 TI - Incidental pulmonary embolus in transit during left ventricular assist device implant. PMID- 23438549 TI - Mitral annulus reconstruction and giant left atrial reduction plasty. AB - We describe a simple and reproducible technique permitting both effective left atrial reduction plasty and safe mitral annulus reconstruction, using a patch of left atrium tissue. In a 64-year-old patient undergoing redo mitral valve replacement for mechanical prosthesis disinsertion, a giant left atrium and extensive calcification of the mitral annulus were noted. This technique permitted a safe mechanical mitral prosthesis re-replacement and a significant reduction of left atrial volume by 70%. PMID- 23438550 TI - Partial anomalous pulmonary venous return in a lung transplant recipient. AB - Partial anomalous pulmonary venous return (PAPVR) is a rare condition in which some of the pulmonary veins empty into the systemic venous system. The presence of PAPVR in a lung transplant recipient may cause technical challenges during transplantation. We present a technique for left atrial reconstruction when faced with a recipient with PAPVR. The patient had a left superior pulmonary vein that emptied into the brachiocephalic vein without a left atrial connection. Because of the discrepancy in size of the 2 donor and the single recipient pulmonary veins, left atrial reconstruction was performed before venous anastomosis. PMID- 23438551 TI - Right lower lobe sleeve resection: bronchial flap to correct caliber disparity. AB - Sleeve resection of the right lower lobe is performed infrequently. Caliber disparity between the truncus intermedius and the middle lobe bronchus is a major problem. We report a case of lung cancer completely resected by sleeve resection of the right lower lobe. A bronchial flap constructed from the distal bronchial end was used for correction of the caliber disparity, and interlobar dissection between the upper and middle lobes effectively reduced the tension on the anastomotic site. These procedures are useful for sleeve resection of the right lower lobe. PMID- 23438552 TI - A novel approach to eliminate cardiac perforation in the nuss procedure. AB - Pectus excavatum is the most common congenital abnormality of the chest wall. It may lead to adverse psychosocial development and preoccupation with a negative body image. The Nuss procedure is a minimally invasive approach for improving these patients' body image. The most dangerous complication is cardiac perforation from the insertion of the introducer. Our technique modifies this procedure to include a small subxiphoid incision and a novel sternal lift system that elevates the sternum. This facilitates the insertion of the introducer and placement of the pectus bar(s), and it reduces the risk of intraoperative cardiac perforation. PMID- 23438553 TI - Artificial chordae or annuloplasty? PMID- 23438554 TI - Extensive endarterectomy, onlay patch, and internal mammary bypass of the left anterior descending coronary artery. PMID- 23438555 TI - Reply: To PMID 22381445. PMID- 23438556 TI - Computed tomography in aid to direct aortic access. PMID- 23438557 TI - Reply: To PMID 22633495. PMID- 23438558 TI - Wall motion, geometry, and outcome after ischemic mitral repair versus replacement. PMID- 23438559 TI - Single cannulation, bilateral brain perfusion. PMID- 23438560 TI - Reply: To PMID 22560261. PMID- 23438561 TI - Brachial artery reactivity testing for preoperative microvascular risk assessment in major thoracic surgery. PMID- 23438562 TI - Reply: To PMID 22571880. PMID- 23438563 TI - High-dose argatroban for heparin-induced thrombocytopenia in a child using a ventricular assist device. AB - A 10-year-old boy who was receiving support from a ventricular assist device (VAD) experienced heparin-induced thrombocytopenia that was successfully treated with high-dose argatroban infusion to attain therapeutic activated partial thromboplastin time in spite of high serum argatroban levels. This case also highlights bolus argatroban dosing for VAD change in the setting of persistent ventricular fibrillation. PMID- 23438564 TI - Long-term use of ventricular assist device as a bridge to recovery in acute fulminant myocarditis. AB - We report the successful long-term use of a left ventricular assist device (Berlin EXCOR) as a bridge to recovery in a patient with fulminant parvovirus B19 myocarditis. The use of this device allowed time for myocardial recovery, avoiding the need for cardiac transplantation. PMID- 23438565 TI - Atrioesophageal fistula after surgical unipolar radiofrequency atrial ablation for atrial fibrillation. AB - Atrial fibrillation is the most common arrhythmia in the United States. Procedural treatment options such as the MAZE procedure and radiofrequency ablation are available with reasonable success rates. However, there are risks inherent to these procedures, with atrioesophageal fistula being a rare but devastating complication. We report a patient with atrioesophageal fistula who presented with neurologic symptoms 20 days after her initial MAZE procedure, followed by a quick decline within 24 hours of presentation. PMID- 23438566 TI - Tracheal resection with patient under local anesthesia and conscious sedation. AB - The authors describe the case of a woman with a 2-year history of dyspnea and stridor caused by a tracheal hamartoma. The patient underwent tracheal resection and end-to-end anastomosis under monitored local anesthesia and conscious sedation, which was achieved by boluses of ketamine and midazolam. Local anesthesia was obtained by the use of stepwise local infiltration of 2% lidocaine and 7.5 mg/mL ropivacaine during the operation. The patient remained awake during the entire procedure, thus permitting the movement of the vocal cords to be monitored. Mechanical ventilation was never required. The postoperative period was uneventful, and the patient did not describe having any discomfort. PMID- 23438567 TI - Video-assisted thoracoscopic surgery for ectopic middle mediastinal thymoma in a patient with myasthenia gravis. AB - We present a rare case of middle mediastinal thymoma with myasthenia gravis. A 51 year-old man presented with right ptosis and muscle weakness, and received a diagnosis of generalized myasthenia gravis. Computed tomography of the chest showed a 20-mm nodule in the middle mediastinum, suggesting a possible ectopic thymoma. He underwent video-assisted thoracoscopic extended thymectomy and resection of the tumor. Histologic examination revealed an ectopic thymoma and ectopic thymic tissue around the tumor. One year after the operation, his condition remains well controlled solely with tacrolimus. Careful preoperative radiologic examination concerning possible ectopic thymoma outside the dissection area of the extended thymectomy is recommended. PMID- 23438568 TI - Thymic and pulmonary mucosa-associated lymphoid tissue lymphomas. AB - A 52-year-old woman with no history of autoimmune disease was found to have a mediastinal tumor and focal airspace opacity in the right lung. Tissue diagnosis was obtained by resection of the mediastinal tumor and open fine needle aspiration of the right pulmonary tissue through a median sternotomy. Histopathologic examination and immunohistochemistry of the thymus tumor and cytologic analysis of the pulmonary tissue were both consistent with mucosa associated lymphoid tissue (MALT) lymphoma. This case suggests that multiorgan MALT lymphoma can also develop in the absence of an autoimmune disease such as Sjogren's syndrome. PMID- 23438569 TI - Recurrence of thymoma in the right atrium arising from the coronary sinus. AB - Invasive thymoma is a malignant tumor of the anterior mediastinum that could have intravenous affinity associated with a high recurrence rate. This report highlights the need of coronary sinus exploration when intraatrial thymoma recurrence is diagnosed. Surgical resection of invaded coronary sinus can be achieved safely with a good result. PMID- 23438570 TI - Reconstruction of extrapericardial rupture of inferior vena cava without cardiopulmonary bypass due to blunt trauma. PMID- 23438571 TI - Use of breast implants to fill postinfarct pneumonectomy cavity in cases of bilateral lung transplantation. PMID- 23438572 TI - Cardioplegia delivery by transcutaneous pigtail catheter in minimally invasive mitral valve operations. AB - For cardioplegia delivery and removing air from the aorta in minimally invasive mitral valve operations, we would like to propose a cost-effective pigtail method. The 8F pigtail punctures the aorta, delivers cardioplegia, and stays in place for removing air from the aorta. We then slide its tip out of the aorta as an accessory drain. With more than 100 successes, we are using it in every case and would like to share it with peer surgeons. PMID- 23438573 TI - Region-specific Etv2 ablation revealed the critical origin of hemogenic capacity from Hox6-positive caudal-lateral primitive mesoderm. AB - Hematopoietic cells (HPCs) develop from hemogenic endothelial cells (ECs), a specialized type of ECs undergoing hematopoietic transition. However, the mesoderm origin for hemogenic ECs or HPCs has not been clarified. To examine the origin for hemogenic mesoderm, we inactivated Etv2, a master regulator for EC/HPC commitment, in specific regions. Region-specific Etv2 ablation in early mesoderm caused local EC differentiation block, resulting in the loss of specific vascular beds without compensatory migration of residual ECs into avascular area. This feature of local EC/HPC differentiation block was correlated to the hemogenic potential of each mesoderm subset. We found that caudal-lateral mesoderm of E7.5 8.5 embryos represent the pre-committed population critical for generating hemogenic ECs. Etv2 ablation in caudal-lateral mesoderm by Hoxb6 Cre or Hoxb6CreER transgene affected vitelline plexus formation and intra-aortic hematopoietic clusters. In differentiated embryonic stem cells, this mesoderm subset marked by Hoxb6-lateral mesoderm promoter showed enriched T lymphopoietic potential among Flk-1(+) cells, which could be regarded as a characteristic for definitive HPCs. These findings indicate that critical mesoderm precursors possibly for definitive type hemogenic ECs are regionally specified in primitive mesoderm, suggesting that Hoxb6(+) caudal-lateral mesoderm represents the critical source of HPCs, which are potentially useful to enrich definitive HPCs from embryonic stem cells. PMID- 23438574 TI - Mortality as an indicator of treatment quality after pertrochanteric fractures in the elderly. AB - BACKGROUND: Fractures in people over the age of 65, especially pertrochanteric fractures of the femur, present a growing medical problem. Surgical treatment of such fractures should be performed in the shortest possible time after the accident. Efforts were made to answer the question what contributes to the reduction in mortality after pertrochanteric fractures. MATERIAL/METHODS: This work presents a comparative analysis of two populations treated surgically due to pertrochanteric fractures at the District Hospital of Orthopedic and Trauma Surgery in Piekary Slaskie during years 1988-1992 and 2005-2008. Patient mortality was used as an indicator of treatment quality. In the first group of 118 patients hospitalized in years 1988-1992, there were 48 deaths reported during 12 months after the surgery. In the second studied population of 244 patients (operated in years 2005-2008), 54 deaths were noted in the 12-month period after the surgery. There was a reduction in mortality from 40.6% to 22.3% over those 15 years. CONCLUSIONS: Introducing mortality as an indicator in the comprehensive assessment of treatment quality will intensify its monitoring in both the hospital as well as the out-of-hospital period of care. It will also reveal the individuality and social importance of geriatric fractures. PMID- 23438582 TI - Preschoolers use emotion in speech to learn new words. AB - Two experiments examined 4- and 5-year-olds' use of vocal affect to learn new words. In Experiment 1 (n = 48), children were presented with two unfamiliar objects, first in their original state and then in an altered state (broken or enhanced). An instruction produced with negative, neutral, or positive affect, directed children to find the referent of a novel word. During the novel noun, eye gaze measures indicated that both 4- and 5-year-olds were more likely to consider an object congruent with vocal affect cues. In Experiment 2, 5-year-olds (n = 15) were asked to extend and generalize their initial mapping to new exemplars. Here, 5-year-olds generalized these newly mapped labels but only when presented with negative vocal affect. PMID- 23438583 TI - Generalization of cue recruitment to non-moving stimuli: location and surface texture contingent biases for 3-D shape perception. AB - Long-lasting perceptual biases can be acquired through training in cue recruitment experiments (e.g. Backus, 2011; Haijiang et al., 2006). Stimuli in previous studies contained motion, so the learning could be explained as an idiosyncrasy in some specific neuronal population such as the middle temporal (MT) area (Harrison & Backus, 2010a). The current study addresses the generality of cue recruitment by testing whether motion is necessary for learning a cue contingent perceptual bias. We tested whether location and a novel cue, surface texture, would be recruited as cues to disambiguate perceptually bistable stationary 3-D shapes. In Experiment 1, stereo and luminance cues were used to disambiguate shape according to location in the visual field, and observers' (N=10) percepts on ambiguous test trials became biased in favor of the contingency during training. This bias lasted into the following day. This result together with previous studies that used moving stimuli suggests that location contingent biases are easily learned by the visual system. In Experiment 2, location was fixed, and instead the new cue to be recruited was a surface texture. Learning did not occur when stimuli were para-foveal, texture was task irrelevant, and disparity was continuously present in training stimuli (N=10). However, learning did occur when stimuli were central, task was texture-relevant, and disparity was transient (N=8). Thus, we show for the first time that an abstract cue, surface texture, can also be learned without motion. PMID- 23438584 TI - Contributions of retinal input and phenomenal representation of a fixation object to the saccadic gap effect. AB - The saccadic "gap effect" refers to a phenomenon whereby saccadic reaction times (SRTs) are shortened by the removal of a visual fixation stimulus prior to target presentation. In the current study, we investigated whether the gap effect was influenced by retinal input of a fixation stimulus, as well as phenomenal permanence and/or expectation of the re-emergence of a fixation stimulus. In Experiment 1, we used an occluded fixation stimulus that was gradually hidden by a moving plate prior to the target presentation, which produced the impression that the fixation stimulus still remained and would reappear from behind the plate. We found that the gap effect was significantly weakened with the occluded fixation stimulus. However, the SRT with the occluded fixation stimulus was still shorter in comparison to when the fixation stimulus physically remained on the screen. In Experiment 2, we investigated whether this effect was due to phenomenal maintenance or expectation of the reappearance of the fixation stimulus; this was achieved by using occluding plates that were an identical color to the background screen, giving the impression of reappearance of the fixation stimulus but not of its maintenance. The result showed that the gap effect was still weakened by the same degree even without phenomenal maintenance of the fixation stimulus. These results suggest that the saccadic gap effect is modulated by both retinal input and subjective expectation of re-emergence of the fixation stimulus. In addition to oculomotor mechanisms, other components, such as attentional mechanisms, likely contribute to facilitation of the subsequent action. PMID- 23438585 TI - Cuscuta europaea plastid apparatus in various developmental stages: localization of THF1 protein. AB - It was generally accepted that Cuscuta europaea is mostly adapted to a parasitic lifestyle with no detectable levels of chlorophylls. We found out relatively high level of chlorophylls (Chls a+b) in young developmental stages of dodder. Significant lowering of Chls (a+b) content and increase of carotenoid concentration was typical only for ontogenetically more developed stages. Lower content of photosynthesis-related proteins involved in Chls biosynthesis and in photosystem formation as well as low photochemical activity of PSII indicate that photosynthesis is not the main activity of C. europaea plastids. Previously, it has been shown in other species that the Thylakoid Formation Protein 1 (THF1) is involved in thylakoid membrane differentiation, plant-fungal and plant-bacterial interactions and in sugar signaling with its preferential localization to plastids. Our immunofluorescence localization studies and analyses of haustorial plasma membrane fractions revealed that in addition to plastids, the THF1 protein localizes also to the plasma membrane and plasmodesmata in developing C. europaea haustorium, most abundantly in the digitate cells of the endophyte primordium. These results are supported by western blot analysis, documenting the highest levels of the THF1 protein in "get together" tissues of dodder and tobacco. Based on the fact that photosynthesis is not a typical process in the C. europaea haustorium and on the extra-plastidial localization pattern of the THF1, our data support rather other functions of this protein in the complex relationship between C. europaea and its host. PMID- 23438587 TI - Broader and deeper. PMID- 23438586 TI - Plant microtubules reorganization under the indirect UV-B exposure and during UV B-induced programmed cell death. AB - The role of microtubules in cellular pathways of UV-B signaling in plants as well as in related structural cell response become into focus of few last publications. As microtubules in plant cell reorient/reorganize (become randomized, fragmented or depolymerized) in a response to direct UV-B exposure, these cytoskeletal components could be involved into UV-B signaling pathways as highly responsive players. In the current addendum, indirect UV-B-induced microtubules reorganization in cells of shielded Arabidopsis thaliana (GFP-MAP4) primary roots and the correspondence of microtubules depolymerization with the typical hallmarks of the programmed cell death in Nicotiana tabacum BY-2 (GFP MBD) cells are discussed. PMID- 23438588 TI - RNF212 marks the spot. PMID- 23438589 TI - Filling in the gaps in cranial suture biology. PMID- 23438595 TI - Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease. AB - Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease. PMID- 23438596 TI - The associations between psychiatric label use and young people's help-seeking preferences: results from an Australian national survey. AB - Aims. Emerging evidence suggests that psychiatric labels may facilitate help seeking in young people. This study examined whether young people's use of accurate labels for five disorders would predict their help-seeking preferences. Methods. Young people's help-seeking intentions were assessed by a national telephone survey of 3021 Australian youths aged 15-25. Respondents were presented with a vignette of a young person portraying depression, depression with suicidal thoughts, psychosis, social phobia or post-traumatic stress disorder (PTSD). They were then asked what they thought was wrong with the person, and where they would go for help if they had a similar problem. Results. Accurate psychiatric label use was associated with a preference to seek help from a general practitioner or mental health specialist. Accurately labelling the psychosis vignette was also associated with a preference to not seek help from family or friends. Conclusions. Findings add to the emerging evidence that accurate psychiatric labelling may facilitate help seeking for various mental disorders in young people, and support the promise of community awareness campaigns designed to improve young people's ability to accurately identify mental disorders. PMID- 23438597 TI - The BCL11A transcription factor directly activates RAG gene expression and V(D)J recombination. AB - Recombination-activating gene 1 protein (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining (VDJ) segment recombination, an essential process for antigen receptor expression and lymphocyte development. The transcription factor BCL11A is required for B cell development, but its molecular function(s) in B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds the RAG1 promoter and Erag enhancer to activate RAG1 and RAG2 transcription in pre-B cells. We employed BCL11A overexpression with recombination substrates in a cultured pre-B cell line as well as Cre recombinase-mediated Bcl11a(lox/lox) deletion in explanted murine pre-B cells to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination. PMID- 23438598 TI - The complex containing Drosophila Myb and RB/E2F2 regulates cytokinesis in a histone H2Av-dependent manner. AB - In Drosophila, mutation of the oncogene Myb reduced the expression of mitotic genes, such as polo and ial, and caused multiple mitotic defects, including disrupted chromosome condensation and abnormal spindles. We now show that binucleate cells, the hallmark phenotype of cytokinesis failure, accumulate in Myb-null ovarian follicle cell and wing disc epithelia. Myb functions as an activator in the generally repressive Drosophila RBF, E2F2, and Myb (dREAM)/Myb MuvB complex. Absence of the dREAM subunit Mip130 or E2F2 suppressed the Myb-null cytokinesis defect. Therefore, we used Myb-null binucleate cells as a quantitative phenotypic readout of transcriptional repression by the dREAM complex. In the absence of Myb, the complex was sensitive to the dose of the subunits E2F2, Mip120, Caf1, and Lin-52 but not Mip130 or Mip40. Surprisingly, reduction of the dose of His2Av/H2A.z also suppressed the Myb-null binucleate cell phenotype, suggesting a novel role for this variant histone in transcriptional repression by the dREAM complex. PMID- 23438599 TI - Fyn regulates adipogenesis by promoting PIKE-A/STAT5a interaction. AB - Fyn is a tyrosine kinase with multiple roles in a variety of cellular processes. Here we report that Fyn is a new kinase involved in adipocyte differentiation. Elevated Fyn protein is detected specifically in the adipocytes of obese mice. Moreover, Fyn expression increases progressively in 3T3-L1 cells during in vitro adipogenesis, which correlates with its kinase activity. Inhibition of Fyn by either genetic or pharmacological manipulation restrains the 3T3-L1 preadipocytes from fully differentiating into mature adipocytes. Mechanistically, Fyn regulates the activity of the adipogenic transcription factor signal transducer and activator of transcription 5a (STAT5a) through enhancing its interaction with the GTPase phosphoinositide 3-kinase enhancer A (PIKE-A). The STAT5a activity is therefore reduced in Fyn- or PIKE-ablated adipose tissues, leading to diminished expression of adipogenic markers and adipocyte differentiation. Our data thus demonstrate a novel functional interaction between Fyn, PIKE-A, and STAT5a in mediating adipogenesis. PMID- 23438600 TI - A weak spliceosome-binding domain of Yju2 functions in the first step and bypasses Prp16 in the second step of splicing. AB - Yju2 is an essential splicing factor required for the first catalytic step after the action of Prp2. We dissected the structure of Yju2 and found that the amino (Yju2-N) and carboxyl (Yju2-C) halves of the protein can be separated and reconstituted for Yju2 function both in vivo and in vitro. Yju2-N has a weak affinity for the spliceosome but functions in promoting the first reaction, with the second reaction being severely impeded. The association of Yju2-N with the spliceosome is stabilized by the presence of Yju2-C at both the precatalytic and postcatalytic stages. Strikingly, Yju2-N supported a low level of the second reaction even in the absence of Prp16. Prp16 is known to mediate destabilization of Yju2 and Cwc25 after the first reaction to allow progression of the second reaction. We propose that in the absence of the C domain, Yju2-N is not stably associated with the spliceosome after lariat formation, and thus bypasses the need for Prp16. We also showed, by UV cross-linking, that Yju2 directly contacts U2 snRNA primarily in the helix II region both pre- and postcatalytically and in the branch-binding region only at the precatalytic stage, suggesting a possible role for Yju2 in positioning the branch point during the first reaction. PMID- 23438601 TI - Rtp1p is a karyopherin-like protein required for RNA polymerase II biogenesis. AB - The assembly and nuclear transport of RNA polymerase II (RNA pol II) are processes that require the participation of many auxiliary factors. In a yeast genetic screen, we identified a previously uncharacterized gene, YMR185w (renamed RTP1), which encodes a protein required for the nuclear import of RNA pol II. Using protein affinity purification coupled to mass spectrometry, we identified interactions between Rtp1p and members of the R2TP complex. Rtp1p also interacts, to a different extent, with several RNA pol II subunits. The pattern of interactions is compatible with a role for Rtp1p as an assembly factor that participates in the formation of the Rpb2/Rpb3 subassembly complex and its binding to the Rpb1p-containing subcomplex. Besides, Rtp1p has a molecular architecture characteristic of karyopherins, composed of HEAT repeats, and is able to interact with phenylalanine-glycine-containing nucleoporins. Our results define Rtp1p as a new component of the RNA pol II biogenesis machinery that plays roles in subunit assembly and likely in transport through the nuclear pore complex. PMID- 23438602 TI - ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break induced checkpoint activation and repair. AB - The RAD51 paralogs XRCC3 and RAD51C have been implicated in homologous recombination (HR) and DNA damage responses. However, the molecular mechanism(s) by which these paralogs regulate HR and DNA damage signaling remains obscure. Here, we show that an SQ motif serine 225 in XRCC3 is phosphorylated by ATR kinase in an ATM signaling pathway. We find that RAD51C but not XRCC2 is essential for XRCC3 phosphorylation, and this modification follows end resection and is specific to S and G2 phases. XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks (DSBs). Notably, in response to DSBs, XRCC3 participates in the intra-S-phase checkpoint following its phosphorylation and in the G2/M checkpoint independently of its phosphorylation. Strikingly, we find that XRCC3 distinctly regulates recovery of stalled and collapsed replication forks such that phosphorylation is required for the HR-mediated recovery of collapsed replication forks but is dispensable for the restart of stalled replication forks. Together, these findings suggest that XRCC3 is a new player in the ATM/ATR-induced DNA damage responses to control checkpoint and HR-mediated repair. PMID- 23438603 TI - The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. AB - Mononuclear cytotrophoblasts of the human placenta proliferate rapidly, subsequently fuse, and differentiate to form multinucleated syncytiotrophoblast with induction of aromatase (hCYP19A1) and chorionic gonadotropin (hCGbeta) expression. Using microarray analysis, we identified members of the miR-17~92 cluster and its paralogs, miR-106a~363 and miR-106b~25, that are significantly downregulated upon syncytiotrophoblast differentiation. Interestingly, miR-19b and miR-106a directly targeted hCYP19A1 expression, while miR-19b also targeted human GCM1 (hGCM1), a transcription factor critical for mouse labyrinthine trophoblast development. Overexpression of these microRNAs (miRNAs) impaired syncytiotrophoblast differentiation. hGCM1 knockdown decreased hCYP19A1 and hCGbeta expression, substantiating its important role in human trophoblast differentiation. Expression of the c-Myc proto-oncogene was increased in proliferating cytotrophoblasts compared to that in differentiated syncytiotrophoblast. Moreover, c-Myc overexpression upregulated miR-17~92 and inhibited hCYP19A1 and hCGbeta expression. Binding of endogenous c-Myc to genomic regions upstream of the miR-17~92 and miR-106a~363 clusters in cytotrophoblasts dramatically decreased upon syncytiotrophoblast differentiation. Intriguingly, we observed higher levels of miR-106a and -19b and lower aromatase and hGCM1 expression in placentas from preeclamptic women than in placentas from gestation matched normotensive women. Our findings reveal that c-Myc-regulated members of the miR-17~92 and miR-106a~363 clusters inhibit trophoblast differentiation by repressing hGCM1 and hCYP19A1 and suggest that aberrant regulation of these miRNAs may contribute to the pathogenesis of preeclampsia. PMID- 23438604 TI - BRG1 is required for formation of senescence-associated heterochromatin foci induced by oncogenic RAS or BRCA1 loss. AB - Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of senescence-associated heterochromatin foci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21(CIP1), and p16(INK4a), but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence. PMID- 23438605 TI - Prognostic value of Angiographic Perfusion Score (APS) following percutaneous interventions in acute coronary syndromes. AB - INTRODUCTION: Identifying reperfusion and predicting post procedure risk is important following Percutaneous Coronary Interventions (PCI). An Angiographic Perfusion Score (APS) combining TIMI flow (TFG) and myocardial perfusion (TMPG) grades before and after PCI can accurately measure both epicardial and myocardial perfusion and predict Major Adverse Cardiac Events (MACE). PATIENTS AND METHODS: APS was calculated in 226 (88 ST elevation Myocardial Infarction (STEMI) and 138 Non STEMI) patients. Maximum score being 12, reperfusion was defined as failed: 0 3, partial: 4-9, and full APS: 10-12. Thirty day MACE were observed. RESULTS: APS identified reperfusion significantly more than TMPG alone (STEMI: 50.6% vs 11.8% (p < 0.001); Non STEMI, early reperfusion: 69.4% vs 52.8% (p < 0.01) and Non STEMI late reperfusion: 38.2% vs 7.8%; (p <= 0.001) respectively. A significantly lower incidence of MACE was observed in the full as compared to the failed APS group (1.8% vs 22.5%) (p < 0.001). No differences were noted between TMPG 0-2 (9.8%, 9.4%, 7.3%, respectively) (p = NS). CONCLUSION: Compared to MPG alone APS detects more low risk reperfused patients, post PCI. PMID- 23438606 TI - The never ending quest for an ideal angiographic surrogate of coronary reperfusion. PMID- 23438607 TI - Circulating microRNAs levels in Chinese heart failure patients caused by dilated cardiomyopathy. AB - BACKGROUND: Previous studies demonstrated dysregulated expression of microRNAs (miRNAs) in the myocardium of patients with dilated cardiomyopathy (DCM). This study investigated levels of miRNAs in the circulation of DCM patients, and the value of miRNAs as biomarkers for DCM. METHODS AND MATERIALS: In 45 DCM patients and 39 age- and sex-matched controls, circulating miR-423-5p, miR-126, miR-361 5p, miR-155, and miR-146a concentrations were measured and correlated to cardiac functional parameters, including left ventricular ejection fraction (LVEF) and N terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: Plasma levels of miR 126 and miR-361-5P did not differ between the DCM and control groups (p = 0.331 and p = 0.784, respectively). Plasma levels of the immunity-associated miRNAs, miR-146a and miR-155, did not differ between the DCM and control groups (p = 0.437 and p = 0.702, respectively). Levels of circulating miR-423-5p were significantly greater in the DCM group (p = 0.003). Further, there was a positive correlation between plasma levels of miR-423-5p and NT-proBNP (r = 0.430, p = 0.003). MiR-423-5p distinguished DCM cases from controls with an area under the curve (AUC) receiver operating characteristic (ROC) curve of 0.674 (95% CI, 0.555 0.793). CONCLUSIONS: Patients with DCM have elevated plasma miR-423-5p levels. The plasma concentration of miR-423-5p was positively correlated with the level of NT-proBNP. Circulating levels of miR-423-5p could be served as a diagnostic biomarker for heart failure caused by DCM. Plasma levels of immunity-associated miR-146a, -155, and -126 were not significantly different between DCM and control groups. PMID- 23438608 TI - Postmyocardial infarction left ventricular dysfunction - assessment and follow up of patients undergoing surgical ventricular restoration by the endoventricular patchplasty. AB - BACKGROUND: Surgical ventricular restoration with endoventricular patchplasty improves left ventricular function and restores left ventricular shape. METHOD: The study included patients who presented with transmural anterior myocardial infarctions between June 2007 and May 2008. Briefly the technique included - coronary revascularization, resection of the endocardial scar, left ventricular reconstruction using an endoventricular synthetic patch. Left ventricular geometric parameters were studied preoperatively, early postoperatively, at 3 and 6 months and statistically analyzed by SPSS 14 software package. RESULTS: The ejection fraction increased from 33.5 +/- 5.02 to 37.77 +/- 7.17 immediate postoperatively. The preoperative left ventricular ejection fraction - a mean of 33.25% (+/-5.02%), increased by 10.3%-11% at the third and fourth follow up respectively after surgical ventricular restoration (p <= 0.001). The left ventricular end systolic volume index improved from a mean of 48.84 +/- 11.37 preoperatively to 24.66 +/- 5.92 postoperatively (p <= 0.001). CONCLUSIONS: Surgical ventricular restoration in our study has clearly demonstrated a positive effect on LV geometry. PMID- 23438609 TI - Drug lag for cardiovascular drug approvals in India compared with the US and EU approvals. AB - OBJECTIVE: Age-standardized burden of cardiovascular diseases is substantially higher in low and middle-income countries than in high-income countries. However, Indian patients are not getting access to the new cardiovascular drugs at the same time as patients in the developed nations. The objective of this study was to assess the drug lag for new cardiovascular drugs in India compared with that in the United States (US) or European Union (EU). METHODS: The information regarding approval of new cardiovascular drugs in the United States, European Union and India between 1999 and 2011 were obtained primarily from the online databases of regulatory agencies. The approval lag was obtained for all new cardiovascular drugs approved in each region, and the median approval lag was calculated for each region. RESULTS: Of the 75 new cardiovascular drugs, 61 (81.33%) were approved in the United States, 65 (86.66%) in the European Union and 56 (74.66%) in India. The US was the first to approve 35 (56.45%) out of the 75 new cardiovascular drugs, the EU was the first to approve 24 (38.71%) and India was the first to approve 3 (4.84%). The median approval lag for India (44.14 months) was substantially higher as compared to the United States (0 month) and European Union (2.99 months). CONCLUSION: This study confirms that there is a substantial drug lag in approval of new cardiovascular drugs in India compared with the United States and European Union. The impact of drug lag on health outcomes remains to be established. PMID- 23438610 TI - Rose Angina Questionnaire: validation with cardiologists' diagnoses to detect coronary heart disease in Bangladesh. AB - AIM/OBJECTIVES: The study aimed to validate the Rose Angina Questionnaire (RAQ) to detect coronary heart disease (CHD) by comparing with cardiologists' diagnoses in Bangladesh. METHODS: Patients aged 40-75 years attending to two cardiac hospitals were diagnosed as either CHD positive or CHD negative by cardiologists. The RAQ was used to reclassify them into CHD positive [RAQ] and CHD negative [RAQ]. FINDINGS: There were 302 CHD positive [cardiologists] and 302 CHD negative [cardiologists] individuals. The RAQ reclassified 194 individuals as CHD positive [RAQ] and 409 individuals as CHD negative [RAQ]. Therefore, the RAQ had 53% sensitivity and 89% specificity. There was no difference in sensitivity and specificity during subgroup analyzes by age and gender; the sensitivity was higher among people from lower socio-economic status. CONCLUSION: The RAQ, having moderate sensitivity but high specificity to detect CHD, can be used to screen individuals at risk of CHD in large-scale epidemiological surveys. PMID- 23438611 TI - Population-based intervention for cardiovascular diseases related knowledge and behaviours in Asian Indian women. AB - BACKGROUND & OBJECTIVES: There is poor knowledge and behaviors regarding chronic diseases related nutritional and lifestyle factors among women in low income countries. To evaluate efficacy of a multilevel population-based intervention in improving knowledge and practices for related factors we performed a study in India. METHODS: Population based study among women 35-70 years was performed in four urban and five rural locations. Stratified sampling was performed and we enrolled 4624 (rural 2616, urban 2008) of eligible 8000 women (58%). Demographic details, medical history, diet, physical activity and anthropometry were recorded and blood hemoglobin, glucose and total cholesterol determined. Knowledge and behaviors regarding diet in chronic diseases were inquired in a randomly selected 100 women at each site (n = 900). A systematic multilevel population based intervention (using posters, handouts, street plays, public lectures, group lectures and focused group discussions) was administered over 6 months at each site. The questionnaire was re-administered at the end in random 100 women (n = 900) and differences determined. Descriptive statistics are reported. Comparison of parameters before and after intervention was assessed using Mann Whitney test. RESULTS: Prevalence (%) of chronic disease related lifestyles and risk factors in rural/urban women, respectively, was illiteracy in 63.6/29.4, smoking/tobacco use 39.3/18.9, high fat intake 93.6/93.4, high salt intake 18.2/12.6, low physical activity 59.5/70.2, overweight/obesity 22.5/45.6, truncal obesity 13.0/44.3, hypertension 31.6/48.2, hypercholesterolemia 13.5/27.7, and diabetes in 4.3/15.1 percent. Composite chronic diseases knowledge at baseline vs after intervention increased significantly in overall (32.0 vs 62.0), rural (29.0 vs 63.5) and urban (39.5 vs 60.5) groups (p < 0.001). Significant increase in knowledge regarding diet in hypertension, diabetes, heart disease and anemia as well as importance of dietary proteins, fats, fibres and fruits was observed (p < 0.001). There was insignificant change in most of the practices regarding intake of low fat, high protein, high fibre diet except sieving the flour which declined significantly (80.1 vs 53.6, p < 0.001). CONCLUSIONS: A short-term multilevel population-wide intervention among women in rural and urban locations in India increased chronic disease knowledge but failed to influence practices. PMID- 23438612 TI - Early impairment of left ventricular function in patients with systemic hypertension: new insights with 2-dimensional speckle tracking echocardiography. AB - BACKGROUND: Two-dimensional strain imaging allows rapid and accurate analysis of regional left ventricular (LV) principal strains in the longitudinal, radial, and circumferential directions. The aim of this study was to assess the ability of subtle differences in LV principal strains to characterize features of subclinical LV dysfunction in patients with systemic hypertension and apparently preserved LV systolic function. METHODS: 2-dimensional echocardiographic (2DE) images of the LV were acquired in apical 4-chamber and parasternal short-axis at the basal, mid, and apical levels in 59 subjects, including 25 healthy controls (33 +/- 4 yrs, 14 male) and 34 patients with systemic hypertension (36 +/- 3 yrs, 24 male). Longitudinal (LS), circumferential (CS) and radial strains (RS) were quantified in an 18-segment model using a novel speckle tracking system (2D Cardiac Performance Analysis, TomTec Imaging System, Munich, Germany). RESULTS: In comparison with normal controls, peak LS was markedly attenuated in the subendocardial and subepicardial regions in patients with systemic hypertension. However, circumferential strain was reduced only in subepicardial region; radial strain was not significantly different in the two groups. The subendocardial-to subepicardial gradient of circumferential deformation correlated with the radial strains in both controls and hypertensive patients (R = 0.87, p < 0.001). CONCLUSIONS: Despite reduced longitudinal shortening, LV wall thickening in patients with systemic hypertension remains unaltered due to relatively preserved circumferential shortening. Characterizing the disparities in LV principal strains reveals the presence of subclinical LV dysfunction and provides unique insights into functional adaptations that maintain global LV ejection fraction in patients with systemic hypertension. PMID- 23438613 TI - Efficacy of post exercise pulsed wave tissue velocity imaging in diagnosing more than 70% coronary artery stenosis. AB - BACKGROUND: To evaluate efficacy of post exercise tissue velocity imaging in diagnosing more than 70% coronary artery stenosis. METHOD: Twenty patients with angiographically proved significant coronary artery disease and 26 healthy controls were evaluated. Pulsed wave tissue velocity imaging was performed at rest and immediately after treadmill stress test. Medial and lateral part of mitral annulus and medial and lateral part of tricuspid annulus were evaluated. RESULT: No change or reduction in systolic annular velocity after exercise at any of the four sites identified patients of significant coronary artery disease with 75% sensitivity and 73% specificity. Rise in the ratio of early diastolic inflow velocity to the corresponding early diastolic annular velocity above the identified site-specific cut-off value had sensitivity of 85% but specificity of 34.6%. A combination of no change or decrease in late diastolic annular velocity and no change or decrease in systolic annular velocity at any of the four sites had sensitivity of 75% and specificity of 88.46%. CONCLUSION: Post exercise tissue velocity imaging can provide a useful, objective parameter for detection of ischemic heart disease on stress testing. PMID- 23438614 TI - Hepatic vascular injury: clinical profile, endovascular management and outcomes. AB - BACKGROUND: Endovascular management using angiographic embolization (AE) has been widely used with success as non operative management (NOM) in blunt hepatic trauma. We, in a tertiary care hospital in North of India, assess our use of endovascular management in patients of blunt and post operative trauma with active hepatic vascular bleeding and unstable hemodynamics in controlling bleeding. METHODS: A retrospective review of inpatients from January 2006 to July 2012 requiring transarterial embolization/stenting for active hepatic vascular bleeding was done. All patients had evidence of ongoing hemorrhage as proved by clinical, laboratory and radiological findings in emergency settings. Angiographic intervention in an interventional suite with ongoing resuscitation was performed following which patients were monitored for morbidity and mortality benefits on intermediate follow up. RESULTS: 10 adults and 3 children underwent AE with polyvinyl alcohol particle (PVA)/soft metal coil whereas 1 adult underwent revascularization with a covered stent for arterial bleeding. The mean age of case series was 36.18 +/- 20.90 years with a mean liver injury computed tomography (CT) grade of 3.8 +/- 0.83 in blunt trauma patients. The mean length of hospital stay was 9.62 +/- 7.83 days and the mean follow up period of the group was 25.25 +/- 21.02 months. All patients showed significant clinical improvement with prompt endovascular management resulting in no procedure related mortality. CONCLUSION: Prompt endovascular management is the modality of choice in comparison to NOM without AE in both pediatric and adult patients with hemodynamically compromised inaccessible intra hepatic vascular trauma. PMID- 23438615 TI - Shorter height is related to lower cardiovascular disease risk - a narrative review. AB - Numerous Western studies have shown a negative correlation between height and cardiovascular disease. However, these correlations do not prove causation. This review provides a variety of studies showing short people have little to no cardiovascular disease. When shorter people are compared to taller people, a number of biological mechanisms evolve favoring shorter people, including reduced telomere shortening, lower atrial fibrillation, higher heart pumping efficiency, lower DNA damage, lower risk of blood clots, lower left ventricular hypertrophy and superior blood parameters. The causes of increased heart disease among shorter people in the developed world are related to lower income, excessive weight, poor diet, lifestyle factors, catch-up growth, childhood illness and poor environmental conditions. For short people in developed countries, the data indicate that a plant-based diet, leanness and regular exercise can substantially reduce the risk of cardiovascular disease. PMID- 23438616 TI - Brucella endocarditis - a series of five case reports. AB - Endocarditis due to brucellosis is considered a rare occurrence involving native, congenital and prosthetic valves. The diagnosis needs high degree of suspicion in culture negative endocarditis especially in those with history of exposure to farm animals. A positive culture in a susceptible patient confirms the diagnosis with 91% sensitivity. An early diagnosis and prompt treatment with appropriate antibiotics can restore the valve structural integrity with minimal damage. Here we present a series of five cases of culture proven Brucella endocarditis (four native valves, one prosthetic valve) and this report discusses the diagnostic and management issues involved. PMID- 23438617 TI - Large free-floating left atrial thrombus with normal mitral valve. AB - Left atrial thrombus in the presence of diseased mitral valve and atrial fibrillation is a well known entity. But it is very rare to occur in the presence of normal mitral valve apparatus. We report the case of a 36 year old female who presented with left atrial ball valve thrombus and normal mitral valve apparatus and underwent surgery. This patient with gangrene of right lower limb came for cardiac evaluation. She had infarct in left middle cerebral artery territory- ten months prior to this admission and was on treatment for infertility. She had atrial fibrillation. Emergency surgery to remove the thrombus should be considered given its potential life threatening embolic nature. PMID- 23438618 TI - Giant cardiac hydatid cyst in the interventricular septum protruding to right ventricular epicardium. AB - Cardiac hydatid cyst is a rare condition, and the location of a hydatid cyst in the interventricular septum is exceptional. A 54-year-old female was admitted to our hospital with complaints of chest pain, shortness of breath and malaise. Transthoracic echocardiography defined a cystic mass lesion of 50 * 59 mm originating from apex of the heart protruding into and compressing the interventricular septum. The cyst was excised surgically and the patient was discharged on the 8th postoperative day without symptoms. In our case, localization of the cystic mass was within interventricular septum which is an uncommon site. It limited both ventricular volumes significantly. In addition, this cyst was extensively protruding to the right ventricular epicardium. PMID- 23438619 TI - Initial presentation with dilated cardiomyopathy in a patient of tuberous sclerosis: a rare case report. AB - A 35-year-old man presented with dilated cardiomyopathy, an unusual association with tuberous sclerosis. Clinical history and examination were consistent with tuberous sclerosis including major features of tuberous sclerosis complex (TSC) like facial angiofibroma, shagreen patch, subependymal nodules, and angiomyolipoma of kidney. The clinical manifestations, pathogenesis and evaluation of tuberous sclerosis are discussed. PMID- 23438620 TI - Anomalous left anterior descending artery from pulmonary artery: an extremely rare coronary anomaly. AB - We report a rare coronary artery anomaly-anomalous origin of the left anterior descending artery from the pulmonary artery in a 40-year-old woman. The uniqueness of this case is the absence of any significant morbidity from this condition in adulthood which is in contrast to other reported cases where patients present with myocardial infarction, congestive heart failure, and sometimes death during the early infantile period.(1). PMID- 23438621 TI - Transcatheter embolization of a giant pancreatic pseudoaneurysm: a tale of two bleeds and one thrombus! AB - Erosion of a peripancreatic artery into the pseudocyst as a result of enzymatic digestion of vessel wall gives rise to a pancreatic pseudoaneurysm (PSA), which is a rare complication seen in patients with chronic pancreatitis.(1) Angiographic embolization as a treatment method for acute hemorrhage from pancreatic PSA has become increasingly popular. Here we report a unique case with bleeding from a giant pancreatic PSA where the single PSA had blood supply originating from the branches of both the celiac artery and superior mesenteric artery. PMID- 23438622 TI - Disappearance of orthostatic hypotension after pacemaker implantation in a patient with a long PR interval. AB - Orthostatic hypotension is the fall in blood pressure when upright and has a high prevalence in elderly population. Diagnostic and therapeutic work-up can be long and difficult. We describe the case of an 81-year-old male patient with long PR interval and episodes of 2:1 atrioventricular block, in whom the implantation of a dual chamber pacemaker led to the disappearance of orthostatic hypotension. The most likely mechanism was an impaired cardiac filling with a short diastolic time due to a very prolonged PR interval, a somewhat "pseudo-pacemaker syndrome". The correction of the first degree AV block with the implantation of the pacemaker and the optimization of the AV delay allowed us to correct the diastolic impairment and to resume a normal response to orthostatism. This case underlies the complex and multifactorial nature of orthostatic hypotension and the importance of a correct diagnosis of correctable causes to treat a very disabling condition. PMID- 23438623 TI - Pseudo-aneurysm of mitral aortic intervalvular fibrosa: two case reports. AB - The fibrous body between the mitral and aortic valve, known as mitral-aortic intervalvular fibrosa (MAIVF) is prone to infection and injury resulting in pseudo-aneurysm formation. Because of its relative rarity, we are far from making any conclusion regarding the natural history and appropriate therapeutic strategy for this condition. We report two cases of this condition with two different and rare etiologies with strikingly different natural courses, providing insight into the natural course and timing of surgery in this rare entity. PMID- 23438624 TI - Giant intrapericardial lipoma: an unusual cause of dyspnoea. AB - The pericardial lipomas are rare benign cardiac tumors. The clinical presentation of these cardiac neoplasms varies according to the site of growth. We describe here a case of massive intrapericardial lipoma leading to severe dyspnea, its diagnostic work up and briefly review the existing literature of this uncommon disorder. The patient underwent successful surgical resection of the tumor with complete alleviation of the symptoms. PMID- 23438625 TI - A composed graft for subclavian artery reconstruction in case of redo surgery for aortic coarctation. AB - We report the case of a 66-year-old woman admitted to the intensive care unit (ICU) for ongoing dyspnea and hemoptoe. She was operated upon in 1979 for aortic coarctation by the interposition of a 14 mm Dacron prosthesis from the left subclavian artery to descending aorta. Clinical evaluation performed over the years was normal with no signs of cardiac failure or prosthesis malfunctioning. The computed tomography scans (CT) showed a progressive increase of the descending aorta diameters and the onset of a pseudo-aneurysm of 50 mm in diameter. Patient was re-operated through a median sternotomy enlarged by a left thoracotomy and intra-operative findings revealed the pseudo-aneurysm originating from a dehiscence of the proximal suture. In order to allow a safe reconstruction of the dilated subclavian artery, a T-shaped composed graft was confectioned and then sutured to the descending aorta and the subclavian artery, respectively. Post-operative course was uneventful and three months CT scan showed a normal position of the composed graft. PMID- 23438626 TI - Incessant ventricular tachycardia due to multiple cardiac rhabdomyomas in an infant with Tuberous Sclerosis. AB - We report a case of incessant ventricular tachycardia managed successfully with medications. The transthoracic echocardiogram showed multiple cardiac rhabdomyomas involving ventricular free wall and outflow tracts. Computerized tomography of brain showed multiple subependymal tubers confirming Tuberous Sclerosis. The follow up assessment showed sinus rhythm and regressing cardiac rhabdomyomas. PMID- 23438627 TI - 'FREEDOM' trial: have the interventional cardiologists lost their freedom? PMID- 23438628 TI - How do I do it? Speckle-tracking echocardiography. PMID- 23438629 TI - Myocardial abscess secondary to staphylococcal septicemia: diagnosis with 3D echocardiography. AB - A 56 years old gentleman with staphylococcal septicemia with metastatic abscesses in spleen and heart. Real time 3D trans thoracic echocardiography could not only confirm the diagnosis of myocardial abscess but also well delineate it and identify adjacent structures. PMID- 23438631 TI - Imaging symptoms and syndromes: similarities and differences between schizophrenia and bipolar disorder. PMID- 23438632 TI - DYX1C1 placed in a molecular context. PMID- 23438633 TI - Complex rare variation and its role in endophenotypic variation in schizophrenia. PMID- 23438635 TI - Amoeba-based computing for traveling salesman problem: long-term correlations between spatially separated individual cells of Physarum polycephalum. AB - A single-celled, multi-nucleated amoeboid organism, a plasmodium of the true slime mold Physarum polycephalum, can perform sophisticated computing by exhibiting complex spatiotemporal oscillatory dynamics while deforming its amorphous body. We previously devised an "amoeba-based computer (ABC)" to quantitatively evaluate the optimization capability of the amoeboid organism in searching for a solution to the traveling salesman problem (TSP) under optical feedback control. In ABC, the organism changes its shape to find a high quality solution (a relatively shorter TSP route) by alternately expanding and contracting its pseudopod-like branches that exhibit local photoavoidance behavior. The quality of the solution serves as a measure of the optimality of which the organism maximizes its global body area (nutrient absorption) while minimizing the risk of being illuminated (exposure to aversive stimuli). ABC found a high quality solution for the 8-city TSP with a high probability. However, it remains unclear whether intracellular communication among the branches of the organism is essential for computing. In this study, we conducted a series of control experiments using two individual cells (two single-celled organisms) to perform parallel searches in the absence of intercellular communication. We found that ABC drastically lost its ability to find a solution when it used two independent individuals. However, interestingly, when two individuals were prepared by dividing one individual, they found a solution for a few tens of minutes. That is, the two divided individuals remained correlated even though they were spatially separated. These results suggest the presence of a long-term memory in the intrinsic dynamics of this organism and its significance in performing sophisticated computing. PMID- 23438634 TI - Temperament moderates associations between exposure to stress and children's externalizing problems. AB - The interaction between a temperament profile (four groups determined by high vs. low resistance to control [unmanageability] and unadaptability [novelty distress]) and family stress in predicting externalizing problems at school in children followed from kindergarten through eighth grade (ages 5-13) was investigated. The sample consisted of 556 families (290 boys). At Time 1 just prior to kindergarten, mothers retrospectively reported on their child's temperament during infancy. Each year, mothers reported stress and teachers reported children's externalizing problems. Temperament profile was tested as a moderator of the stress-externalizing association for various time periods. Results indicated that the combination of high resistance to control and high unadaptability strengthens the stress-externalizing association. Findings are discussed in terms of possible underlying mechanisms. PMID- 23438636 TI - Patterns of nucleotide asymmetries in plant and animal genomes. AB - Symmetry in biology provides many intriguing puzzles to the scientist's mind. Chargaff's second parity rule states a symmetric distribution of oligonucleotides within a single strand of double-stranded DNA. While this rule has been verified in a wide range of microbial genomes, it still awaits explanation. In our study, we inquired into patterns of mono- and trinucleotide intra-strand parity in complex plant genomic sequences that became available during the last few years, and compared these to equally complex animal genomes. The degree and patterns of deviation from Chargaff's second rule were different between plant and animal species. We observed a universal inter-chromosomal homogeneity of mononucleotide skews in coding sequences of plant chromosomes, while the base composition of animal coding sequences differed between chromosomes even within a single species. We also found differences in the base composition of dicot introns in comparison to those of monocots. These genome-wide patterns were limited to genic regions and were not encountered in inter-genic sequences. We discuss the implications of our findings in relation to hypotheses about functional correlations of intra-strand parity which have hitherto been put forward. Furthermore, we propose more recent polyploidization and subsequent homogenization of homoeologues as a possible reason for more homogeneous skew patterns in plants. PMID- 23438637 TI - Codon-anticodon interaction and the genetic code evolution. AB - The evolution of the genetic code, with 20 amino acids encoded from the beginning, is analyzed from the viewpoint of codon-anticodon interaction. Imposing a minimum principle for the interaction, in the framework of the so called crystal basis model of the genetic code, we determine the structure of the anticodons in the ancient, archetypal and early genetic codes, that are all reconciled in a unique frame. Most of our results agree with the generally accepted scheme. PMID- 23438638 TI - Biological complexity, quantum coherent states and the problem of efficient transmission of information inside a cell. AB - The intracellular channel of information transmission was analyzed from the point of view of complexity. The most important steps in the transfer of information within a cell are the folding, transport and recognition of proteins. It was shown that the large number of conformational degrees of freedom that proteins possess can paradoxically lead to an information channel with an exponentially small capacity. To resolve this paradox, a model, which assumes a quantum collective behavior of biologically important molecules, was proposed. Experiments to test the quantum nature of the intracellular transfer of information were also proposed. PMID- 23438639 TI - Journal of social work in end-of-life & palliative care. Editor's introduction. PMID- 23438641 TI - Final journey--walking with Adam at end of life. PMID- 23438642 TI - Psychological aspects of bereavement in adults: preliminary development of the bereavement experiences index. AB - This study's aim was to produce a measure of the cognitive and affective impact of bereavement and to investigate the psychometric properties and potential utility of the measure. Using a mixed correlational and comparative design, the bereavement experiences of widows who had time to anticipate their partner's death were compared with those who had no such time. In the first stage of this two-stage study, seven widows completed semi-structured interviews regarding bereavement-related cognitions and affect. A set of bereavement-related statements was derived and formed the Bereavement Experiences Index (BEI). In the second stage, the BEI and a measure of psychological disturbance were administered to 20 additional widows. Unexpected bereavement led to greater psychological impact than expected loss although longer periods of expectation were positively correlated with higher levels of grief-related social dysfunction symptoms. This preliminary version of the BEI showed potential as a measure of grief responses with predictable links to psychological distress. The findings suggested a relationship between the time available to prepare for a loss and the development of psychological disturbance. PMID- 23438643 TI - Good grief: exploring the dimensionality of grief experiences and social work support. AB - This study explored the dimensionality of grief with a sample (n = 180) of caregivers of deceased loved ones; utilizing a positive grief scale, additional data were collected about perceptions of social worker practice behaviors in end of-life care. Results revealed the presence of both positive and negative aspects of grief. Supportive social work practice behaviors at the end of life were present at least 52.2% of the time and specific practices were analyzed as to their association with positive or negative grief reactions. Results from this study suggest that grief is a multidimensional process and that social work practice behaviors can support positive aspects of grief with clients in all fields of practice. PMID- 23438644 TI - Are children's grief camps effective? AB - Bereavement camps are one form of popular grief intervention for children. A review of the existing literature on child bereavement camps was conducted to examine effectiveness of these camps. An initial database search led to 187 entries. Selection criteria employed resulted in a total of eight studies for an in-depth examination. While camps had differences in their lengths, camper acceptance, restrictions, and theoretical frameworks used; many shared similar camp goals and objectives, activities, and outcome measures. Emerging evidence shows camps are promising venues to help bereaved children develop and build resilience in dealing with loss. PMID- 23438645 TI - Professional and educational needs of hospice and palliative care social workers. AB - In the past decade much growth has occurred in the numbers of patients and families served by hospices and palliative care services. Thus, not surprisingly, these services have also been subject to increasing regulation by governmental and accrediting entities. In order to stay up-to-date in this ever-changing environment and to continue to provide effective interventions, social workers must stay engaged in the professional community and continuing education. In this quantitative study, 1,169 practicing hospice and palliative care social workers provided information about their practice activities and agency characteristics, professional affiliations and certification, and ongoing educational needs. About one-half of respondents carried a caseload of 21-50 and were most engaged in communicating the psychosocial needs of the patient and family to other members of the team and assessing for grief and bereavement issues. The most important educational needs pertained to the psychological and social needs of patients and families and psychosocial interventions. Most were members of professional organizations and three-quarters were members of NASW. Although many were aware of the joint NASW-NHPCO social work hospice specialty certification, few held this certification yet. The results of this survey can be utilized in the design of continuing education programs and advocacy for programmatic and policy change within agencies and the industry. PMID- 23438646 TI - Psychosocial care for the caregivers of primary malignant brain tumor patients. AB - Despite clinical experience that suggests a high burden of care among relatives of individuals with a primary malignant brain tumor (PMBT), little is known about their actual needs. In this study, the caregivers' personal experiences, quality of life, burden of care, and psychological well-being were examined. Fifty-nine percent did not receive any financial aid for home care, 33% had increased risk for psychosomatic problems, 45% had anxiety, and 33% increased depression levels. The caregiver's quality of life was most strongly affected by the burden of care (p < .001) and the patient's mental state (p < .03). To improve the situation, empathetic professionals and an early implementation of palliative care and social work are required. PMID- 23438647 TI - End-of-life care in hematology: update from Australia. AB - The purpose of this article is to provide recent findings on the perceptions and experiences about end-of-life care for individuals with a hematological malignancy. A qualitative design based on a series of open-ended interviews and one focus group was utilized to explore and document the experience of survivorship from the perspective of adult patients diagnosed with a hematological malignancy. Fifty participants (n = 26 male; n = 24 female) were interviewed representing the major hematological diagnostic groups: Multiple Myeloma, Lymphoma, and Leukemia. The interviews and focus group were recorded, transcribed verbatim, coded, and thematically analyzed. The findings presented are from the participants' experiences with end-of-life care. The findings indicated that those fortunate enough to know about the benefits of palliative care are more likely to access palliative care during end-of-life care. However, for many hematology patients there are still problems with timely referrals to the palliative system. Within the context of an Australian research program, the findings provide a useful "snapshot" of current issues for Australian hematology patients and their families. PMID- 23438648 TI - Halogenated phospholipids regulate secretory phospholipase A2 group IIA activity. AB - Secretory phospholipase A2 group IIA (sPLA2-IIA) is an active participant of inflammation. The enzyme destroys bacterial cell wall and induces production of biologically active lipid mediators. It is involved in various pathological processes and high serum content and activity of sPLA2-IIA are associated with adverse cardiovascular events. Study of sPLA2-IIA regulation is of great physiological and clinical importance and is necessary for better understanding of mechanisms underlying inflammation. Another major participant of inflammatory response is the enzyme myeloperoxidase (MPO) which is secreted by neutrophils in the focus of inflammation and catalyzes formation of HOCl and HOBr. Both halogenated (chloro- and bromohydrins) and oxidized lipids are formed due to interaction between HOCl and HOBr with unsaturated bonds of phospholipid acyl chains. Previously we showed that oxidized phospholipids stimulate sPLA2-IIA activity. In this study we examined the effects of chloro- and bromohydrins of 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) on sPLA2-IIA activity. In contrast to POPC, chloro- and bromohydrins of POPC (POPC-Cl and POPC-Br, respectively) were not hydrolyzed by sPLA2-IIA. In addition, phospholipids which are sPLA2-IIA substrates, were not cleaved by the enzyme in the presence of POPC Cl and POPC-Br. Halogenohydrins of POPC prevented the activity of both purified and serum sPLA2-IIA. Blocking effects of POPC-Cl and POPC-Br were abolished by increased concentrations of phospholipid-substrate. These results suggest that halogenated phospholipids formed in MPO-dependent reactions can be considered as a new class of biologically active compounds potentially capable of regulating sPLA2-IIA activity in the areas of inflammation and producing the effects opposite to those of oxidized phospholipids. Control over sPLA2-IIA can be useful in the therapy of diseases involving systemic inflammation. PMID- 23438649 TI - Mapping PARP-1 auto-ADP-ribosylation sites by liquid chromatography-tandem mass spectrometry. AB - We demonstrate a novel method for the identification of poly(ADP-ribose) polymerase-1 (PARP-1) autopoly(ADP-ribosyl)ation sites that is suited to collision induced dissociation (CID) tandem mass spectrometry. By employing phosphodiesterase to remove the majority of the poly(ADP-ribose) (pADPr) modification, we reduce the complexity of tandem mass spectrometric analysis of pADPr-modified tryptic peptides. The simplified ribose-5'-phosphate form of the peptides produce tandem mass spectra by CID that are readily interpreted and enable effective localization of the exact sites of PARP-1-catalyzed poly(ADP ribosyl)ation. In conjunction with a phosphopeptide-like enrichment strategy that captures the ribose-5'-phosphate peptides, we identified eight novel sites of PARP-1 automodification, confirmed the localization of two sites previously reported, and provided evidence for two additional targeted peptides with ambiguous modification site assignments. Given the simplicity of the approach, the method is readily applicable to analysis of complex samples. PMID- 23438650 TI - The myxovirus resistance A (MxA) gene -88G>T single nucleotide polymorphism is associated with prostate cancer. AB - BACKGROUND: Myxovirus (influenza virus) resistance A (MxA) is an interferon stimulated antiviral protein that is required for a complete antiviral response. MxA polymorphism (rs2071430) is located within an Interferon Stimulated Response Element (ISRE) at position -88 in the gene's promoter region, and it has been associated with increased susceptibility to infections and various diseases. In general, the low promoter activity genotype (GG) promotes susceptibility, whereas the high promoter activity genotype (TT) confers protection to Hepatitis C viral infection. MxA's role in prostate cancer is not fully understood. Previous literature has shown that MxA may be a mediator of the effect of IFN on normal and tumor cell motility. MxA may act as a tumor suppressor and the level of expression may be a predictor of metastatic potential. Based on this information, in this study we investigated the association of this functional polymorphism (rs2071430) in MxA with prostate cancer. METHODS: Sample size and power was calculated using the PGA software. Genomic DNA from a controls (n=140) and prostate cancer patients (n=164) were used for genotyping SNP rs2071430 on all samples. Statistical analysis was performed using logistic regression model. RESULTS: A significant association was observed between rs2071430 genotype GG and prostate cancer. Individuals harboring the GG genotype are at an increased risk of prostate cancer. Data stratification reveals that the mutant GT genotype offers either offers some protection against prostate cancer in Caucasians. CONCLUSIONS: MxA SNP rs2071430 GG genotype is significantly associated with prostate cancer irrespective of race. However, data stratification also suggests that the GT genotype is under-represented in Caucasian subjects suggesting its role in protection against prostate cancer in Caucasians. Although MxA is primarily implicated in viral infection, but it may be also be associated with prostate cancer. Recent studies have implicated viral and bacterial infections with increased prostate cancer risk. Expression of the high promoter activity genotype may offer resistance to prostate cancer infection and possibly influence clinical outcomes. PMID- 23438651 TI - Evolutionary robust SNPs reveal the misclassification of Mycobacterium tuberculosis Beijing family strains into sublineages. AB - Genotypic classification in Mycobacterium tuberculosis has greatly contributed to the comprehension of phylogenetic and population genetic relationships. It is, therefore, necessary to verify the robustness of the genetic markers for phylogenetic classification. In this study, we report some examples of homoplasy for two molecular markers, the IS6110 insertion at the NTF region, and a single nucleotide polymorphism (SNP) at locus 909166, through genotyping of 1054 Beijing family strains. Our data revealed that a small fraction of strains traditionally classified into modern sublineages by IS6110 insertion at NTF actually belong to an ancient sublineage. We also proved that the robustness of branches in the evolutionary tree established using the putative homoplasious SNP 909166 is relatively low. Our findings highlight the importance of validating genetic markers used to establish phylogeny, evolution, and phenotypic characteristics. PMID- 23438652 TI - Effect of physical activity on bone strength and body composition in breast cancer premenopausal women during endocrine therapy. AB - BACKGROUND: Breast cancer endocrine therapy (ET) is one of the most basic therapeutic methods in oncology. Well-balanced physical activity exerts positive influence on bone strength (BS) and body composition (BC), which has been confirmed by the clinical research regarding osteoporosis, prevention and treatment alike. Accordingly, in the following study, an attempt was made to assess the selected parameters of young, premenopausal women's clinical state under the influence of breast cancer ET, as well as to define the influence of physical activity on the studied parameters. AIM: The assessment of the influence of aerobic and resistance training (AT and RT) on BS and BC in premenopausal women during breast cancer ET. DESIGN: This was a nonrandomized, prospective clinical study. SETTING AND POPULATION: The study was performed in 41 outpatients in the Greater Poland Cancer Centre. METHODS: The examinations were made with the anthropometric and dual energy X-ray absorptiometry measurements. The examinations were conducted according to the schedule: at the baseline, II-after 6 months of ET, III-after 6 months of AT (in 12 months of ET), IV- after following 6 months AT and RT (18 months of ET). RESULTS: After 6 months of the ET without physical activity the bone mineral density (BMD) in all regions and the hip structure parameters were lower in comparison to the baseline and there was a significant increase in fatty tissue. After 6 months of AT the BMD of all regions was lower than in 6 months ET. An introduction of RT caused the analyzed values of BS parameters to increase. Also a significant growth of lean body mass and free fat body mass was observed and so was an insignificant fall in fat. CONCLUSION: The breast cancer ET is related to the changes in BS and BC in premenopausal women. The introduction of AT caused a slowdown in negative changes in bones, and body fat was reduced. The introduction of RT reversed an adverse tendency for BS and sarcopenia. CLINICAL REHABILITATION IMPACT: The study results show that mixed type physical activity (AT and RT) during breast cancer ET could prevent negative changes, of this treatment, in body build in premenopausal women. PMID- 23438653 TI - Education and training of pain medicine specialists in the United States. AB - Many pain patients present with a complex set of symptoms and comorbidities that defy the acumen of any one specific medical specialty; thus the knowledge and skills of the pain physician must, out of necessity cross specialty borders. The competency that comes from mastering essential skills is accomplished during the pain medicine training. The goal of pain medicine training in the United States is to provide the postgraduate trainee with the exposure to multiple disciplines of medicine, as well as multiple interventions, so that upon completion of training, the pain physician will have the necessary skill set to provide competent, appropriate, comprehensive care for the often medically complicated pain patient. In the United States, many training programs are governed by guidelines that have been established by the Accreditation Council for Graduate Medical Education (ACGME). PMID- 23438654 TI - Safety in pharmacological enhancement of stroke rehabilitation. AB - Pharmacological enhancement of neurorehabilitation is based on the concept of neuroplasticity. Agents with probably unfavourable effects on recovery (e.g. classical antiepileptic drugs, butyrophenones) should be avoided. The findings of experimental studies in animal models, investigations in healthy subjects and the findings of neurophysiological studies indicate that there is scope for benefit from pharmacological enhancement in stroke rehabilitation in the clinical setting - in addition to rehabilitative therapies. Randomized controlled clinical trials have shown benefit of pharmacological enhancement in stroke rehabilitation for some agents. Nevertheless, the clinical evidence regarding benefits of this treatment approach is still considered weak for the following reason: First, the beneficial findings of some studies were not confirmed by others. Second, several studies were limited by small patient populations and narrow inclusion criteria. Third, there were concerns regarding safety of some agents (i.e., piracetam, and amphetamines). Dopaminergic agents, Selective Serotonin-Reuptake-Inhibitors (SSRI) and acetylcholinesterase-inhibitors are promising candidates. Their safety and efficacy should be further investigated; ideally in - sufficiently powered - large randomized controlled trials. PMID- 23438655 TI - Prospective assessment of pain and functional status after percutaneous vertebral body-perforation procedure for treatment of vertebral compression fractures. AB - Percutaneous vertebral body perforation is a new technique for treating painful vertebral compression fractures (VCFs). We prospectively evaluated this treatment in 45 consecutive patients with 63 VCFs treated at our hospital between September and December 2009. In all patients, long-term conservative treatment had failed to achieve pain relief, resulting in reduced changes in activities of daily living (ADL). We evaluated visual analogue scale (VAS) scores for pain before and after vertebral body perforation as well as in the chronic phase, changes in ADL, whether recipients would recommend this treatment, and complications. The mean VAS score improved from 6.9 +/- 1.9 before surgery to 3.6 +/- 2.9 immediately after surgery, and to 2.5 +/- 2.1 at 3 months. ADL was improved in 27 patients, and walking became possible in 16 of 24 patients who had been unable to walk. Nearly two-thirds of patients would strongly recommend this treatment to others. The analgesic effect of vertebral body perforation was significantly lower in patients with than in those without vertebral pseudarthrosis before surgery. Only 1 patient suffered a new fracture during the 3-month period after surgery, but there were no perioperative complications. Vertebral body perforation for painful VCFs can achieve early improvement of ADL due to the analgesic effect in carefully selected patients and is a safe treatment with a low frequency of complications. PMID- 23438656 TI - Incidental detection of thyroid nodules at magnetic resonance imaging of the cervical spine. AB - The incidental detection of thyroid lesions in patients undergoing magnetic resonance (MR) imaging of the cervical spine was prospectively evaluated on 389 MR images. Sagittal images extended from the cranio-cervical junction to the upper thoracic level, and axial images from C3-4 to C7-T1 intervertebral levels. Twenty patients (5.1%) had a total of 26 thyroid nodules. Eighteen patients presented with a single dominant nodule, of whom 2 had a multinodular gland with a single dominant nodule (one had 3 and the other had 5 nodules). Two patients had diffusely enlarged gland without a dominant nodule. The mean size of the nodules was 11.6 mm. One thyroid nodule was detected at the C5-6 intervertebral level, 14 at the C6-7, and 11 at the C7-T1. T(2)-weighted imaging was more useful than T(1)-weighted imaging for the detection of thyroid nodules because of the hyperintense versus isointense appearance of the lesions. Thyroid carcinoma was identified at surgery in one patient. The detection rate was low compared with computed tomography with contrast medium and ultrasonography. Our results suggest that MR imaging has limited value for the detection of thyroid lesions and that the presence of such lesions cannot be denied based only on MR imaging of the cervical spine. However, asymptomatic thyroid lesions, including thyroid cancer, can be identified on MR images of the cervical spine, so we recommend that evaluation of these images should consider such lesions. PMID- 23438657 TI - Shoulder traction device for enhanced conventional fluoroscopy during cervical spine operations. AB - Conventional biplanar fluoroscopic imaging of the cervical spine is commonly used during cervical spinal surgery. We designed an intraoperative traction device to prevent shoulder superimposition on the cervical fluoroscopic imaging. During surgery at the stage of fluoroscopic examination, an operator can apply traction via the traction band of the device. This device is safe and easy to use, and can be preoperatively fitted to patients. Fluoroscopic images obtained with the new traction device were definitely superior compared with images obtained without the traction device. This device may be useful in cases with difficult fluoroscopic imagination of the lower cervical spine. PMID- 23438658 TI - Anterior cervical interbody fusion using polyetheretherketone cage filled with autologous and synthetic bone graft substrates for cervical spondylosis: comparative analysis between PolyBone(r) and iliac bone. AB - Clinical and radiological outcomes of cervical interbody fusion using a polyetheretherketone cage filled with PolyBone((r)) (Kyungwon Medical Co., Ltd., Seoul, Korea), beta-tricalcium phosphate material, and autologous iliac bone were retrospectively compared in 47 patients who underwent anterior cervical discectomy and fusion (ACDF) between January 2007 and April 2008. Of these, 23 received iliac bone grafts and 24 received PolyBone. Numeric rating scale and neck disability index were used for clinical outcome assessments. Cervical radiography was performed immediately postoperatively, and at 1, 3, 6, 12, and 24 months postoperatively. Computed tomography (CT) was performed at 12 and 24 months postoperatively. Change in segmental lordosis, disk height, and fusion were compared at 12 and 24 months postoperatively. Clinical outcomes were similar between both groups. CT and radiography at 12 months showed that fusion had occurred in 22 patients in the iliac bone group and in 19 in the PolyBone recipients. Fusion was also identified in 22 patients in both iliac bone and PolyBone groups at 24 months postoperatively. The clinical outcomes of ACDF using PolyBone and iliac bone were similar, with similar cervical interbody fusion rates at 24 months postoperatively. However, the time taken for fusion was apparently longer in the PolyBone group. PMID- 23438659 TI - Prevalence of spinal meningeal cyst in the sacrum. AB - Spinal meningeal cysts in the sacrum (SMC) are known to be occasionally symptomatic with low back pain as well as leg pain, but no distinct prevalence of this pathological entity including asymptomatic lesions has been described. This prospective study investigated the prevalence of SMCs based on magnetic resonance (MR) myelography in 102 consecutive Japanese women with gynecological problems, who underwent pelvic conventional MR imaging. Ten of 102 patients were suspected of being positive for SMC (9.8%), but pseudo-positive findings were possible. A high probability of positive SMC was found in 7/102 (6.9%). MR myelography was better to detect SMCs than conventional MR imaging. Multiplicity and female preponderance may be other features of SMC. The speculated prevalence of SMCs in Japanese females ranged from 6.9% to 9.8%. PMID- 23438660 TI - Synovial cysts of the lumbar spine--pathological considerations and surgical strategy. AB - Symptomatic lumbar synovial cysts (LSCs) are a rare cause of degenerative narrowing of the spinal canal, with thecal sac or nerve root compression. True synovial cysts have a thick wall lined by synovial cells, containing granulation tissue, numerous histiocytes, and giant cells. In contrast, pseudo-cysts lack specialized epithelium, have a collagenous capsule filled with myxoid material, and may be classified into ganglion cysts, originating from periarticular fibrous tissues, and ligamentous cysts, arising from the ligamentum flavum or even from the posterior longitudinal ligament. Here we present the surgical series of the Chair of Neurosurgery at the University of Cagliari (Italy) including a total of 17 LSCs. Surgical technique consisted of facet sparing excision of LSC, achieved by simple hemilaminectomy/laminectomy, and diagnosis was always confirmed by histological specimen examination, which detected the typical synovial epithelium, the intracystic presence of hemosiderin, histiocytes, and calcifications. Further immunohistochemical investigation revealed positive staining for cytokeratin: CK5, CK6, and AE1/AE3. Clinically, our cohort experienced rapid and complete resolution of symptoms, without perioperative complications, or recurrence of cysts or vertebral instability at a median follow up of 28 months, when the MacNab score was generally excellent. A review of the literature, retrieving articles published from 1973, collected a total of 101 articles concerning all the cases of LSC scientifically described to date. Both clinical and histological findings described in our study support the theory of degenerative microtraumatic pathogenesis of synovial cysts. PMID- 23438661 TI - Transformation from asymptomatic to symptomatic of lower cervical spinal dural arteriovenous fistula. AB - A 60-year-old woman presented with a spinal dural arteriovenous fistula (SDAVF) located in the lower cervical region, which had been asymptomatic for 56 months after the initial detection. She underwent embolization of the SDAVF when she became symptomatic, but her neurological recovery was only partial. Cervical SDAVF is rare but sometimes discovered in an asymptomatic state. The natural history and validity of preventive treatment for asymptomatic SDAVF have not been fully established. Her unfavorable outcome demonstrates the potential advantages of adequate treatment at an early stage even for asymptomatic SDAVF. PMID- 23438662 TI - Spinal dural arteriovenous fistula with lipomyelodysplasia. AB - A 72-year-old man presented with a very rare case of spinal dural arteriovenous fistula (AVF) with lipomyelodysplasia manifesting as progressive paraparesis and bladder dysfunction. Magnetic resonance imaging revealed a spinal lipoma associated with tethered cord and spinal cord swelling with dilated perimedullary veins. Embolization of the spinal dural AVF was successfully performed, and is an optional treatment for coexisting spinal dural AVF and lipomyelocele in adults. PMID- 23438663 TI - Conus medullaris-cauda arteriovenous malformation and Klippel-Trenaunay syndrome: what is the treatment goal? AB - A 29-year-old man with Klippel-Trenaunay syndrome (KTS) presented with a symptomatic conus medullaris-cauda arteriovenous malformation (AVM) manifesting as back and right limb pain, which abruptly worsened with the onset of right limb weakness and urinary retention. He was treated by multisession endovascular embolization resulting in improved neurological status. KTS is a sporadic disease with unknown etiology, but genetic susceptibility may lead to the over-expression of angiogenic factors and increased angiogenesis. KTS may be exceptionally associated with slow-flow spinal AVM, but there is no consensus about the optimal treatment for these symptomatic lesions. Embolization treatment may represent a safe option to minimize complications and possibly improve the neurological status in patients with spinal AVM associated with KTS, if one or both legs are already impaired by hypertrophy or other vascular malformations. Genetic analysis may reveal an underlying angiogenesis change, so closer follow up might be indicated in selected patients. PMID- 23438664 TI - Syringomyelia associated with Paget disease of the skull. AB - A 38-year-old man presented with a rare case of syringomyelia associated with Paget disease of the skull. Syringosubarachnoid (SS) shunting was performed. We speculate that deformation of the skull secondary to Paget disease caused narrowing of the foramen magnum with progressive impairment of the cerebrospinal fluid circulation, which led to syringomyelia and neurological symptoms. SS shunting is safe, effective, and technically simple, so may be a useful initial treatment for syringomyelia associated with Paget disease of the skull. PMID- 23438665 TI - Congenital absence of the lumbar facet joint associated with bilateral spondylolysis of the fifth lumbar vertebra. AB - A 14-year-old boy presented with a rare case of congenital absence of lumbar facet joint manifesting as low back pain. Physical examination showed no neurological or hematologic abnormalities. Radiography revealed absence of a facet joint on the right side of L4-5. Computed tomography and three-dimensional computed tomography revealed absence of the facet joint on the right side of L4-5 and spondylolysis on both sides of L5. Pain subsided after conservative treatment. This is an extremely rare case of congenital absence of lumbar facet joint associated with bilateral spondylolysis. PMID- 23438666 TI - Surgical treatment of scaphocephaly with sinus pericranii. AB - A 1-year-old female was admitted with a subcutaneous, pulsatile soft mass in the midline parietal region, and abnormal head shape. Fundus examination showed papilledema, suggesting elevated intracranial pressure. Radiological findings showed sagittal suture craniosynostosis with sinus pericranii. Magnetic resonance venography showed that the drainage through the sinus pericranii was not essential for the venous outflow from the brain. The patient underwent surgical resection of the sinus pericranii and total cranial remodeling. Ligation of the stalk-like orifice attached to the superior sagittal sinus with resection of the sinus pericranii and total cranial reconstruction were performed concurrently. The postoperative course was uneventful, and her papilledema resolved. No recurrence of the sinus pericranii has occurred for 3 years. This case describes a unique one-staged operation to treat sinus pericranii with sagittal suture craniosynostosis. PMID- 23438667 TI - Atlantoaxial intraspinal juxtafacet cyst. AB - A 69-year-old man presented with progressive paralysis of the right arm and leg with a past history of metastatic rectal cancer. Magnetic resonance imaging showed a cystic mass lesion posterior to the odontoid process. Under a preoperative diagnosis of intradural extramedullary tumor, partial transcondylectomy and C1 hemilaminectomy were performed, and the cyst was removed through a transdural approach, decompressing the medulla oblongata and the cervical spinal cord. The histological diagnosis was juxtafacet cyst (ganglion cyst). An atlantoaxial intraspinal juxtafacet cyst at the level of the odontoid process is extremely rare. In our case, the cyst was removed using a posterior approach, resulting in rapid improvement in symptoms. PMID- 23438668 TI - Thoracolumbar extradural arachnoid cyst--three surgical case reports. AB - Three cases of symptomatic extradural arachnoid cyst were treated by surgery. Total excision of the cyst followed by tight closure of the fistula by suture was achieved in all 3 cases. Surgery improved the neurological deficits but urinary incontinence persisted in all three patients. Obliteration of the fistula is considered to be important at surgery from the etiological perspective of the cyst. There are many surgical options, but surgical removal of the cyst and obliteration of the communication usually leads to prompt improvement in neurological deficits. Instability, malalignment, and worsening scoliosis are well-recognized postoperative complications of excessive laminotomy, but the exposure should be wide enough to cover the cyst completely at the operation. Wide exposure of the entire cyst is preferable to avoid missing the fistula and to identify any adhesions or fistula between the cyst and the dura. Identification of the fistula location based on preoperative imaging studies is also important. PMID- 23438669 TI - Pain catastrophizing changes during the menstrual cycle. AB - Pain catastrophizing is an important predictor of pain intensity and pain-related outcomes. Many studies have shown that the level of this phenomenon is higher in women compared to men. The aim of this study was to investigate whether there is a difference in pain catastrophizing in women during the different phases of their menstrual cycle and whether there is a difference in pain catastrophizing depending on the history of childbirth and dysmenorrhea. A prospective study was conducted among 149 healthy women aged 18-35, with a regular menstrual cycle, 80 of which were nulliparous. The participants filled a sociodemographic questionnaire at the enrollment and the Pain Catastrophizing Scale on the 1st, 12th, and 20th day of the menstrual cycle. Pain catastrophizing scores, including all the subscales, significantly varied throughout the menstrual cycle, being highest on the first day of menstrual cycle and declining subsequently. Pain catastrophizing scores were higher in nulliparous than in parous women. Higher pain catastrophizing scores on the first day of the menstrual cycle were found in dysmehorrhoic women and women who regularly use analgesics for dysmenorrhea. Knowing that pain catastrophizing varies throughout the menstrual cycle may help in creating interventions for pain prevention and treatment in cycling women. PMID- 23438671 TI - HOXB8 expression in ovarian serous carcinoma effusions is associated with shorter survival. AB - OBJECTIVE: HOX proteins are key transcription factors in embryogenesis. HOXB5 and HOXB8 were previously shown to be overexpressed in ovarian/primary peritoneal serous carcinoma compared to breast carcinoma using gene expression arrays. The present study investigated the clinical role of HOXB5 and HOXB8 in advanced-stage (FIGO III-IV) ovarian serous carcinoma. METHODS: HOXB5 and HOXB8 protein expression was analyzed in 286 effusions and 76 patient-matched solid lesions (27 primary carcinomas, 49 metastases) using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. RESULTS: Cytoplasmic HOXB5 protein was detected in 268/286 (94%) effusions. HOXB8 was expressed at both the cytoplasm (252/286; 88%) and nucleus (131/286; 46%) of carcinoma cells. Cytoplasmic HOXB5, cytoplasmic HOXB8 and nuclear HOXB8 were found in 56/76 (74%), 76/76 (100%) and 30/76 (39%) solid lesions, respectively, with significantly higher HOXB5 expression in effusions (p=0.002) and higher cytoplasmic HOXB8 in solid lesions (p<0.001). HOXB5 expression was higher in post chemotherapy disease recurrence effusions compared to pre-chemotherapy effusions tapped at diagnosis (p=0.04). In univariate survival analysis of the effusion cohort, higher expression of cytoplasmic HOXB8 was associated with significantly shorter progression-free survival (p=0.033), whereas higher nuclear HOXB8 expression was associated with significantly shorter overall survival in analysis limited to patients with post-chemotherapy effusions (p=0.036). Neither finding was independent prognostic factor in Cox multivariate analysis. CONCLUSIONS: HOXB5 and HOXB8 are frequently expressed in ovarian serous carcinoma, with anatomic site-related differences for cytoplasmic staining. HOXB5 may be affected by chemotherapy in effusions. HOXB8 expression is associated with shorter survival in metastatic serous carcinoma. PMID- 23438670 TI - A phase II evaluation of gefitinib in the treatment of persistent or recurrent endometrial cancer: a Gynecologic Oncology Group study. AB - BACKGROUND: A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer. METHODS: Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined. RESULTS: Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS >=6 months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed. CONCLUSIONS: This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation. PMID- 23438672 TI - Visfatin, a potential biomarker and prognostic factor for endometrial cancer. AB - OBJECTIVE: Visfatin, a newly discovered adipocytokine, is thought to play a role in the pathogenesis of metabolic-syndrome-related cancers. The aim of this study was to assess the clinical significance of serum levels and tissue expression of visfatin in relation to endometrial cancer (EC). METHODS: A total of 234 EC patients were included in this study. Serum visfatin, metabolic and anthropometric parameters were measured in EC patients and controls. Serum visfatin levels were detected using ELISA. Tissue expression of visfatin was analyzed using immunohistochemistry in tissue microarrays. The correlation between clinicopathological variables and visfatin in EC tissues and the prognostic value of visfatin for overall survival was evaluated. RESULTS: Serum levels of visfatin were significantly higher in EC patients than in controls (P<0.05). In univariate and multivariate logistic regression models, a positive association between EC and serum visfatin, BMI, waist-to-hip ratio, diabetes, and hypertension was evident (P<0.05). Visfatin expression was significantly higher in EC tissue than in normal endometrial tissue (P=0.001). Moreover, serum visfatin levels were significantly positively correlated with tissue expression of visfatin in EC patients (P<0.05). High visfatin expression in EC tissues was significantly associated with advanced FIGO stage (P=0.016) and myometrial invasion >=1/2 (P=0.023). The overall survival rate of EC patients was significantly higher in the group with negative visfatin expression than with positive visfatin expression (P=0.035). CONCLUSIONS: Visfatin is a potential serum biomarker and prognostic factor for EC that may indicate high risk for EC and EC progression. It may also be a novel potential therapeutic target for EC. PMID- 23438673 TI - The balance between human maternal plasma angiotensin II and angiotensin 1-7 levels in early gestation pregnancy is influenced by fetal sex. AB - HYPOTHESIS: There are fetal sex-associated differences in the circulating maternal renin-angiotensin system (RAS) in early pregnancy. METHODS: Plasma prorenin, angiotensin (Ang) II, Ang 1-7 and angiotensin-converting enzyme (ACE) concentrations were measured at 15 weeks' gestation in 131 women with uncomplicated pregnancies from the Adelaide SCOPE cohort. Uterine and umbilical artery Doppler sonography was performed at 20 weeks' gestation. RESULTS: At 15 weeks, women bearing female fetuses had higher maternal Ang II concentrations (p = 0.017) and lower Ang 1-7 to Ang II ratios (p = 0.016) than women bearing males. In women with male fetuses, Ang II positively correlated with birth weight (p = 0.028) and prorenin negatively correlated with placental weight (p = 0.014). Female fetuses had higher umbilical artery resistance indices (p = 0.019) that were related to maternal prorenin concentrations (p = 0.007). CONCLUSIONS: In early human pregnancy, the maternal RAS is influenced by fetal sex. The lower Ang 1-7 to Ang II ratios in women with female fetuses may contribute to the lower maternal peripheral microvascular flow as described previously and the lack of any positive effect of Ang II on fetal growth, as seen in women with male fetuses. PMID- 23438674 TI - Placental mesenchymal dysplasia and fetal renal-hepatic-pancreatic dysplasia: androgenetic-biparental mosaicism and pathogenesis of an autosomal recessive disorder. AB - Androgenetic-biparental mosaicism (ABM) denotes an embryo in which a subset of cells contains a diploid chromosomal complement derived entirely from the father. Such embryos have a high incidence of placental mesenchymal dysplasia (PMD) and paternal imprinting disorders because the androgenetic cells have pangenomic paternal uniparental disomy. Uniparental disomy also poses a theoretical risk for paternally transmitted autosomal recessive disorders, if both chromosomes of each autosomal pair are identical (isodisomy). We present the 1st example of a recessive disorder, renal-hepatic-pancreatic dysplasia, in a pregnancy complicated by PMD and ABM. Androgenetic-biparental mosaicism was demonstrated in fetal DNA, extracted from multiple organs, by quantitative polymerase chain reaction-based methods that detected allelic imbalances at the differentially methylated SNRPN locus (chromosome 15); polymorphic short tandem repeat microsatellite markers located on chromosomes 4, 7, 8, 13, 18, and 21; and single nucleotide polymorphisms on chromosomes 1 and 19. Laser capture microdissection was performed to isolate specific placental and renal cell populations and document selective enrichment of androgenetic cells in the stroma of PMD and the epithelium of renal cysts. Mutational analysis of coding sequences did not reveal any mutations in NPHP3, a ciliopathy gene implicated in some cases of renal hepatic-pancreatic dysplasia. Nonetheless, the fetal phenotype and laser capture data support the model of a paternally transmitted autosomal recessive disorder, which occurred because of ABM. PMID- 23438675 TI - Metabolism and immunity: the old and the new. PMID- 23438676 TI - Bone fracture exacerbates murine ischemic cerebral injury. AB - BACKGROUND: Bone fracture increases alarmins and proinflammatory cytokines in the blood, and provokes macrophage infiltration and proinflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome; however, the impact of bone fracture on stroke outcome remains unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response. METHODS: Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n = 10), infarct volume, neuronal death, and macrophages/microglia infiltration (n = 6-7) were analyzed after 3 days. RESULTS: We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere +/- SD: 30 +/- 7% vs.12 +/- 3%, n = 6, P < 0.001), more severe neurobehavioral dysfunction, and more macrophages/microglia in the periinfarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction. CONCLUSIONS: These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke. PMID- 23438680 TI - Myeloperoxidase deficiency induces MIP-2 production via ERK activation in zymosan stimulated mouse neutrophils. AB - Myeloperoxidase (MPO), a major constituent of neutrophils, catalyzes the production of hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion. We have previously reported that MPO-deficient (MPO(-/-)) neutrophils produce greater amount of macrophage inflammatory protein-2 (MIP-2) in vitro than do wild type when stimulated with zymosan. In this study, we investigated the molecular mechanisms governing the up-regulation of MIP-2 production in the mutant neutrophils. Interestingly, we found that zymosan-induced production of MIP-2 was blocked by pre-treatment with U0126, an inhibitor of mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK), and with BAY11-7082, an inhibitor of nuclear factor (NF)-kappaB. Western blot analysis indicated that U0126 also inhibited the phosphorylation of p65 subunit of NF-kappaB (p65), indicating that MIP-2 was produced via the ERK/NF-kappaB pathway. Intriguingly, we found that ERK1/2, p65, and alpha subunit of inhibitor of kappaB (IkappaBalpha) in the MPO(-/-) neutrophils were phosphorylated more strongly than in the wild type when stimulated with zymosan. Exogenous H2O2 treatment in addition to zymosan stimulation enhanced the phosphorylation of ERK1/2 without affecting the zymosan-induced MIP-2 production. In contrast, exogenous HOCl inhibited the production of MIP-2 as well as IkappaBalpha phosphorylation without affecting ERK activity. The zymosan-induced production of MIP-2 in the wild-type neutrophils was enhanced by pre-treatment of the MPO inhibitor 4-aminobenzoic acid hydrazide. Collectively, these results strongly suggest that both lack of HOCl and accumulation of H2O2 due to MPO deficiency contribute to the up regulation of MIP-2 production in mouse neutrophils stimulated with zymosan. PMID- 23438681 TI - Doing the right thing for one's children: deciding whether to take the genetic test for Huntington's disease as a moral dilemma. AB - This is a qualitative examination of candidates' decision-making in relation to the genetic test for Huntington's disease. Semi-structured interviews were conducted with nine participants who were asked about factors influencing their decision whether to take up predictive genetic testing. Transcripts of interviews were subjected to interpretative phenomenological analysis to elicit emergent themes. A key factor for participants was to do the right thing for their children. Interestingly, this factor presents a moral dilemma to participants and can direct them either towards or away from testing. This article offers a detailed examination of how participants think through this dilemma. PMID- 23438677 TI - Effects of anesthetic isoflurane and desflurane on human cerebrospinal fluid Abeta and tau level. AB - BACKGROUND: Accumulation of beta-amyloid protein (Abeta) and tau protein is the main feature of Alzheimer disease neuropathogenesis. Anesthetic isoflurane, but not desflurane, may increase Abeta levels in vitro and in animals. Therefore, we set out to determine the effects of isoflurane and desflurane on cerebrospinal fluid (CSF) levels of Abeta and tau in humans. METHODS: The participants were assigned into spinal anesthesia (N=35), spinal plus desflurane anesthesia (N=33), or spinal plus isoflurane anesthesia (N=38) group by randomization using computer generated lists. Pre- and postoperative human CSF samples were obtained through an inserted spinal catheter. The levels of Abeta (Abeta40 and Abeta42) and total tau in the CSF were determined. RESULTS: Here, we show that isoflurane, but not desflurane, was associated with an increase in human CSF Abeta40 levels (from 10.90 to 12.41 ng/ml) 24 h after the surgery under anesthesia compared to spinal anesthesia (from 11.59 to 11.08 ng/ml), P=0.022. Desflurane, but not isoflurane, was associated with a decrease in Abeta42 levels 2 h after the surgery under anesthesia (from 0.39 to 0.35 ng/ml) compared to spinal anesthesia (from 0.43 to 0.44 ng/ml), P=0.006. Isoflurane and desflurane did not significantly affect the tau levels in human CSF. CONCLUSIONS: These studies have established a system to study the effects of anesthetics on human biomarkers associated with Alzheimer disease and cognitive dysfunction. These findings have suggested that isoflurane and desflurane may have different effects on human CSF Abeta levels. PMID- 23438682 TI - Prognostic value of neuron specific enolase and IL-10 in ischemic stroke and its correlation with degree of neurological deficit. AB - BACKGROUND: The blood-brain barrier is compromised in stroke patients. The release of neuro-biochemical protein markers, such as Neuron Specific Enolase (NSE) into the circulation may allow the pathophysiology and prognosis of patients with cerebrovascular diseases to be evaluated further. METHOD: Present study aimed to investigate the predictive value of NSE and Interleukin-10 (IL-10) with respect to early neurobehavioral outcome which evaluated by National Institute of Health Stroke Scale (NIHSS). We investigated 100 patients of ischemic stroke and blood samples were taken within first 72 h of stroke onset. NSE and IL-10 were analyzed by commercially available ELISA kits. The neurological status was evaluated by a standardized NIHSS at the time of admission. RESULTS: NSE was significantly increased (17.95+/-4.54 vs 7.48+/-1.51 {ng/ml} p<=0.05) and IL-10 significantly decreased (11.79+/-2.77 vs 15.72+/-2.69 {pg/ml} p<=0.05) in patients when compared with controls. NSE also significantly (r=0.8, p<=0.001) correlated with degree of neurological deficit but IL-10 level in serum did not show any significant correlation with NIHSS score at the time of admission. CONCLUSIONS: Serum concentrations of NSE and IL-10 have a high predictive value for early neurobehavioral outcome after acute stroke. PMID- 23438683 TI - Effects of supercritical fluid extraction pressure on chemical composition, microbial population, polar lipid profile, and microstructure of goat cheese. AB - The consumer trend for healthier food choices and preferences for low-fat products has increased the interest in low-fat cheese and nutraceutical dairy products. However, consumer preference is still for delicious food. Low- and reduced-fat cheeses are not completely accepted because of their unappealing properties compared with full-fat cheeses. The method reported here provides another option to the conventional cheese-making process to obtain lower fat cheese. Using CO(2) as a supercritical fluid offers an alternative to reduce fat in cheese after ripening, while maintaining the initial characteristics and flavor. The aim of this experiment was to evaluate the effect of pressure (10, 20, 30, and 40 * 10(6) Pa) of supercritical CO(2) on the amount of fat extracted, microbial population, polar lipid profile, and microstructure of 2 varieties of goat cheese: Majorero, a protected denomination of origin cheese from Spain, and goat Gouda-type cheese. The amount of fat was reduced 50 to 57% and 48 to 55% for Majorero and goat Gouda-type cheeses, respectively. Higher contents (on a fat basis) of sphingomyelin and phosphatidylcholine were found in Majorero cheese compared with control and goat Gouda-type cheeses. The microbial population was reduced after supercritical fluid extraction in both cheeses, and the lethality was higher as pressure increased in Majorero cheese, most noticeably on lactococcus and lactobacillus bacteria. The Gouda-type cheese did not contain any lactobacilli. Micrographs obtained from confocal laser scanning microscopy showed a more open matrix and whey pockets in the Majorero control cheese. This could explain the ease of extracting fat and reducing the microbial counts in this cheese after treatment with supercritical CO(2). Supercritical fluid extraction with CO(2) has great potential in the dairy industry and in commercial applications. The Majorero cheese obtained after the supercritical fluid extraction treatment was an excellent candidate as a low-fat goat cheese, lower in triglycerides and cholesterol but still with all the health benefits inherent in goat milk. PMID- 23438684 TI - Investigating associations between milk metabolite profiles and milk traits of Holstein cows. AB - In the field of dairy cattle research, it is of great interest to improve the detection and prevention of diseases (e.g., mastitis and ketosis) and monitor specific traits related to the state of health and management. During the standard milk performance test, traditional milk traits are monitored, and quality and quantity are screened. In addition to the standard test, it is also now possible to analyze milk metabolites in a high-throughput manner and to consider them in connection with milk traits to identify functionally important metabolites that can also serve as biomarker candidates. We present a study in which 190 milk metabolites and 14 milk traits of 1,305 Holstein cows on 18 commercial farms were investigated to characterize interrelations of milk metabolites between each other, to milk traits from the milk standard performance test, and to influencing factors such as farm and sire effect (half-sib structure). The effect of influencing factors (e.g., farm) varied among metabolites and traditional milk traits. The investigations of associations between metabolites and milk traits revealed groups of metabolites that show, for example, positive correlations to protein and casein, and negative correlations to lactose and pH. On the other hand, groups of metabolites jointly associated with the investigated milk traits can be identified and functionally discussed. To enable a multivariate investigation, 2 machine learning methods were applied to detect important metabolites that are highly correlated with the investigated traditional milk traits. For somatic cell score, uracil, lactic acid, and 9 other important metabolites were detected. Lactic acid has already been proposed as a biomarker candidate for mastitis in the recent literature. In conclusion, we found sets of metabolites eligible to predict milk traits, enabling the analysis of milk traits from a metabolic perspective and discussion of the possible functional background for some of the detected associations. PMID- 23438685 TI - Short communication: analysis of health and survival in a population of Ontario Holstein heifer calves. AB - The objective of the present study was to investigate health and survival in heifer calves, from 16 farms in southwestern Ontario. Research technicians visited the farms on a weekly schedule for 16 mo, starting in January 2008, and collected blood samples and various measurements to determine the overall health status of the calves. Data of 1,588 Holstein heifer calves from birth until 90 to 120 d of age were analyzed. Initially, a survival analysis was carried out to determine which factors surrounding birth increased a calf's risk of mortality. The factors examined were type of birth, calving ease, season of birth, serum total protein, weight during first week of life, treatment status during first week of life, total number of treatments, and bovine respiratory disease status. In general, calves born in fall (October-December), low serum total protein, low weight, and calves treated for illness during the first week of life, increasing number of treatments, and being treated for bovine respiratory disease all increased a calf's risk of mortality. Genetic parameters for requiring treatment for illness, survival, bovine respiratory disease, other diseases, height, and weight were estimated. Heritabilities for treatment, survival, and diseases were low, ranging from 0.04 to 0.07, and were not significant. Moderate and significant heritabilities were found for height (0.33 to 0.45) and weight (0.24 to 0.44). Treatment and survival to 90 to 120 d of age were favorably correlated, indicating that calves requiring less treatment have a higher survival rate and vice versa. Further, body weight was found to have a tendency of favorable genetic correlation (-0.22 to -0.53) with treatment for diseases, indicating that calves with higher body weight in their first month of life were genetically more resistant to diseases than those with average body weight. Overall, our results show the potential of using data on calfhood disease and survival in future dairy cattle breeding programs. Further investigation and improved data collection are required to determine the full impact of genetics on health and survival in dairy heifer calves. PMID- 23438686 TI - Prognostic relevance of PCI-related myocardial infarction. AB - Procedure-related myocardial infarction (pMI) is directly associated with a coronary revascularization procedure, such as percutaneous coronary intervention (PCI) or CABG surgery. In contrast to spontaneous myocardial infarction (MI), the prognostic relevance of pMI is the subject of ongoing debate. Data from retrospective analyses of large, randomized clinical trials, and large, contemporary cohort studies have several shortcomings that limit their extrapolation to clinical practice. In our opinion, the currently available evidence is insufficient to conclude that pMI during PCI, as currently defined, always has important prognostic implications. Until further evidence is available, we recommend adopting the definition for MI given in the third universal definition of MI, which differentiates between pMI and spontaneous MI. This is important not only for clinical decision-making but also for the interpretation of pMI as a surrogate end point in clinical trials. Further studies are essential to understand the pathophysiology and consequences of pMI. PMID- 23438687 TI - Valvular disease: Lipoprotein(a) link to calcification. PMID- 23438688 TI - Risk factors: High calcium intake linked to cardiac death. PMID- 23438689 TI - Vascular disease: Ramipril improves walking times in patients with PAD. PMID- 23438690 TI - Arrhythmias: beta-blockade in patients with HF and AF. PMID- 23438691 TI - Defects in the DNA mismatch repair system do not contribute to the development of childhood wilms tumors. AB - Wilms tumor is the most common childhood renal malignancy. Most Wilms tumors occur sporadically, whereas a genetic predisposition is described in 9-19% of the Wilms tumor patients. In addition to constitutional aberrations, somatic aberrations in multiple genetic loci such as WT1, WT2 or locus 11p15.5, CTNNB1, WTX, TP53, FBXW7, and MYCN have also been linked to Wilms tumorigenesis. In sporadic Wilms tumors, however, the driving somatic genetic aberrations need to be further unraveled. Therefore, it is necessary to obtain more insight into other underlying mechanisms. Little is known about the role of defects in the DNA mismatch repair system in the etiology of Wilms tumors. To detect mismatch repair deficiency in a full cohort of Wilms tumor patients, we combined immunohistochemistry for the expression of mismatch repair proteins and microsatellite instability (MSI) analysis by a fluorescent multiplex polymerase chain reaction-based assay. Of the 121 Wilms tumor patients treated between 1987 and 2010 in our institution, 100 samples from 97 patients were available for analysis. Nuclear staining for MLH1, MSH2, MSH6, and PMS2 proteins was present in all 100 Wilms tumor samples. No pattern of MSI was found in any of the 100 investigated Wilms tumor samples. The matching results of normal expression of the mismatch repair proteins detected by immunohistochemistry and the absence of MSI by DNA analysis in 100 Wilms tumor samples lead us to conclude that defects in the DNA mismatch repair system do not play a significant role in the development of Wilms tumors. PMID- 23438692 TI - Involvement of the dorsal hippocampal GABA-A receptors in histamine-induced facilitation of memory in the Morris water maze. AB - Several types of learning and memory processes are regulated by the hippocampus which is an important subcortical structure in the mammalians' brain. Previous investigations have shown that different receptor systems in the CA1 region of hippocampus are involved in learning and memory functions. Investigating the possible influence of dorsal hippocampal GABA-A receptors on histamine-induced spatial facilitation in adult male Wistar rats was the focus of the current study. Rats were bilaterally implanted with dorsal hippocampal (CA1) cannulae, recovered from surgery and then trained in Morris water maze (MWM) for 4 consecutive days. A block of four trials was given each day. All drugs were injected into CA1 regions, 5min before training. Pre-training intra-CA1 microinjection of muscimol, a GABA-A receptor agonist, at the dose of 0.01 or 0.02MUg/rat, increased the traveled distance or the escape latency and traveled distance to the hidden platform, respectively, indicating a water maze spatial acquisition impairment. Intra-CA1 administration of bicuculline, a GABA-A receptor antagonist however, significantly decreased the escape latency and traveled distance to the hidden platform, suggesting a spatial learning facilitation. On the other hand, pre-training intra-CA1 microinjection of the subthreshold dose of muscimol plus different doses of histamine (0.025, 0.05 and 0.1MUg/rat) did not alter the histamine response. Meanwhile, the co administration of the ineffective dose of bicuculline together with histamine potentiated the spatial learning. Moreover, bilateral infusion of histamine (0.025, 0.05 and 0.1MUg/rat) by itself, facilitated the spatial learning. Notably, the drug injections had no effect on swimming speed during the MWM training sessions. Our results suggest that the dorsal hippocampal (CA1) GABA-A mechanism(s) may influence the histamine-induced facilitation of spatial acquisition. PMID- 23438693 TI - Mdm2 increases cellular invasiveness by binding to and stabilizing the Slug mRNA. AB - Mdm2 is an oncoprotein that induces the degradation of the tumor suppressor, p53. Here, we show that Mdm2 increases the mRNA levels of Slug by binding to and stabilizing the Slug mRNA. While this effect of Mdm2 was observed in both p53 null and p53-expressing cancer cells, it increased the protein levels of Slug only in the former cells. Mdm2 consistently induced Slug-dependent events, such as decreases in E-cadherin levels and increases in cellular invasiveness, only in p53-null cells. Therefore, the binding of Mdm2 to the Slug mRNA appears to provide a novel mechanism through which Mdm2 promotes tumor progression in a manner independent of the presence of p53. PMID- 23438694 TI - Surface-enhanced Raman scattering chip for femtomolar detection of mercuric ion (II) by ligand exchange. AB - The chemical sensing for the convenient detection of mercuric ion (II) (Hg(2+)) have been widely explored with the use of various sensing materials and techniques. It still remains a challenge to achieve ultrasensitive but simple, rapid, and inexpensive detection to metal ions. Here we report a surface-enhanced Raman scattering (SERS) chip for the femtomolar (fM) detection of Hg(2+) by employing silver-coated gold nanoparticles (Au@Ag NPs) together with an organic ligand. 4,4'-Dipyridyl (Dpy) can control the aggregation of Au@Ag NPs via its dual interacting sites to Ag nanoshells to generate strong Raman hot spots and SERS readouts. However, the presence of Hg(2+) can inhibit the aggregation of Au@Ag NPs by the coordination with Dpy, and as a result the SERS signals of Dpy are quenched. On the basis of these findings, a SERS chip has been fabricated by the assembly of Au@Ag NPs on a piece of silicon wafer and the further modification with Dpy. The exchange of Dpy from the chip into the aqueous Hg(2+) droplet results in the quenching of Raman signals of Dpy, responding to 10 fM Hg(2+) that is about 6 orders of magnitude lower than the limit defined by the U.S. Environmental Protection Agency in drinkable water. Each test using the SERS chip only needs a droplet of 20 MUL sample and is accomplished within ~4 min. The SERS chip has also been applied to the quantification of Hg(2+) in milk, juice, and lake water. PMID- 23438695 TI - Obesity/weight gain and breast cancer risk: findings from the Japan collaborative cohort study for the evaluation of cancer risk. AB - BACKGROUND: We analyzed data from the Japan Collaborative Cohort Study (36 164 women aged 40-79 years at baseline in 1988-1990 with no previous diagnosis of breast cancer and available information on weight and height) to examine the association between baseline body mass index (BMI)/weight gain from age 20 years and breast cancer risk in a non-Western population. METHODS: The participants were followed prospectively from enrollment until 1999-2003 (median follow-up: 12.3 years). During follow-up, breast cancer incidence was mainly confirmed through record linkage to population-based cancer registries. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs for the association between breast cancer risk and body size. RESULTS: In 397 644.1 person-years of follow-up, we identified 234 breast cancer cases. Among postmenopausal women, the adjusted HR increased with BMI, with a significant linear trend (P < 0.0001). Risk was significantly increased among women with a BMI of 24 or higher (HR: 1.50, 95% CI: 1.09-2.08 for BMI of 24-28.9, and 2.13, 1.09-4.16 for BMI >= 29) as compared with women with a BMI of 20 to 23.9. Weight gain after age 20 years and consequent overweight/obesity were combined risk factors for postmenopausal breast cancer risk. This combined effect was stronger among women aged 60 years or older. However, the HRs were not significant in premenopausal women. CONCLUSIONS: Our findings support the hypothesis that weight gain and consequent overweight/obesity are combined risk factors for breast cancer among postmenopausal women, particularly those aged 60 years or older. PMID- 23438696 TI - Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse. AB - Negative symptoms, conceptualized as clinical manifestations of schizophrenia, and subsequently described in other psychiatric disorders, include the loss of normal arousal, drive and affective reactivity. In the field of substance abuse, an interesting analogy can be detected between negative symptoms, in their classical meaning, and the amotivational syndrome (AS), which has been described as a form of chronic cannabis intoxication. AS also shows a close resemblance to the reward deficiency syndrome (RDS) of alcoholics and stimulant abusers, and to the post-withdrawal syndrome (PWS) of detoxified heroin addicts. A variety of substances share a common tropism for the dopaminergic system, leading to a state of hypophoria, which seems to represent a common pathway for chronic substance abusers. In the light of these convergences, a common treatment principle for addictive disorders can be enunciated. This consists in resorting to pro dopaminergic drugs, that are supposed to replace damaged functions and control craving, and in avoiding anti-dopaminergic drugs, that are expected to exacerbate craving and impede the reversal of the reward deficiency. PMID- 23438697 TI - Prevalence and risk factors for the use of restraint in psychiatry: a systematic review. AB - AIM: Despite the poor evidence supporting the use of coercive procedures in psychiatry wards and their "psychological damage" on patients, the practice of restraint is still frequent (6-17%) and varies 10-20 times among centers. METHODS: We searched the PubMed, Embase, and PsychInfo databases for papers published between January 1 1990 and March 31 2010 using the key words "restraint", "constraint", "in-patient" and "psychiatry wards" and the inclusion criteria of adult samples (studies of selected samples such as a specific psychiatric diagnosis other than psychosis, adolescence or the elderly, men/women only, personality disorders and mental retardation were excluded), the English, French, Italian or German languages, and an acute setting. RESULTS: The prevalence of the use of restraint was 3.8-20% (not different from previous data), despite the attempts to reduce the use of restraint. The variables most frequently associated with the use of coercive measures in the 49 studies included in this review were male gender, young adult age classes, foreign ethnicity, schizophrenia, involuntary admission, aggression or trying to abscond, and the presence of male staff. CONCLUSIONS: Coercive measures are still widely used in many countries (albeit to a greater or lesser extent) despite attempts to introduce alternatives (introduction of special protocols and nurses' training courses) in some centers that should really be tested in large-scale multicenter studies in order to verify their efficacy. PMID- 23438698 TI - [New developments on the serotonin hypothesis of depression: shunt of tryptophan]. AB - Since the late 1960s, the serotonin deficiency, as demonstrated in major depression, was related to an increased activity of the liver enzyme tryptophan pyrrolase stimulated by an excess of circulating corticosteroids, which would shift the metabolism of tryptophan from serotonin to kynurenine production. The finding that the kynurenine causes different effects in central nervous system suggested that an up-regulation of the tryptophan-kynurenine pathway determined not only a deficiency of serotonin, but could also play a role in the development of anxiety, psychotic symptoms and cognitive impairment associated with depression. This review aims to evaluate the different hormonal and genetic factors regulating the metabolism of tryptophan via kynurenine, and to highlight how this metabolic pathway may be involved in depression pathogenesis. Rate limiting enzymes of kynurenine formation are two: tryptophan 2,3-dioxygenas (TDO) activated by stress hormones, and indoleamine 2,3-dioxygenase (IDO), activated by proinflammatory cytokines. The increased expression of the genes that produce inflammatory cytokines (interferon-gamma and tumor necrosis factor alpha) would determine a genetic predisposition to develop depression by up-regulating the IDO pathway, while environmental stressors would activate TDO via hormonal activation. Therefore, it can be reasonably assumed that the pathway of tryptophan-kynurenine represents one of the main melting points of the interaction between genetic and environmental factors involved in the pathophysiology of depression, as well as new targets for future antidepressant strategies. PMID- 23438699 TI - [Functional neuroimaging of the amygdala: the response to threatening and phobogenic stimuli]. AB - Recent functional neuroimaging studies show that the amygdala has a central role in threat evaluation, in response to conditioned and unconditioned stimuli, in fear learning and fear extinction. The amygdala is involved in the pathophysiology of phobias and anxiety. In this review we critically examine the main findings of functional neuroimaging studies reporting data on the amygdala. Findings suggest that the response of the amygdala to threatening stimuli is mainly modulated by the infralimbic and prefrontal cortices, which inhibit activation of the amygdala (top-down inhibition), and by the hippocampus, the function of which is related to stimulus learning. The activity of the amygdala is modulated by various factors, like stimulus type and origin, emotion triggered by stimulus perception, and attention. The neural network comprising the amygdala and the frontal cortex is involved not only in top-down inhibition, but also in the emotional perception of facial expressions. This network also includes the thalamic pulvinar, which is densely interconnected with the amygdala, directly or indirectly, and which is activated by emotional face recognition of scary fear. Both top-down inhibition mechanisms and emotional face recognition are altered in anxiety disorders, particularly in specific and social phobia, resulting in reduced amygdalar activity inhibition after anxiety - or fear - inducing stimulus perception. Future functional neuroimaging studies will be able to provide new insights of normal and altered neurophysiology of the amygdala. PMID- 23438700 TI - Cannabis use and violent behaviour: a psychiatric patients cohort study in Southern Italy. AB - An ample volume of research evidence supports the conclusion that drug use/abuse is correlated with violent behavior. Some studies have shown that co-morbidity also appears to be predictive of violent behavior. The research evidence indicates gender differences, while socio-economic and familial factors play a role, too. METHOD: We conducted a retrospective study of the clinical files of four public psychiatric outpatient facilities during five years. The objectives of the research were to identify and analyze relationships between: a) cannabis use/abuse and violent behavior and b) cannabis use/abuse, psychopathology, and violent behavior. The study sample consisted of 1,582 subjects. The data, gathered in a dedicated database, were processed by applying univariate and multivariate analysis models. RESULTS: Subjects who used/abused cannabis showed a high prevalence of violent behavior, Regardless of the type of psychiatric disorder, the use of cannabis appears to be an evident risk factor. Significant correlations also emerged between cannabis use/abuse and the type of violent behavior, especially self-inflicted injury. Evidence also emerged that other factors are implicated. This is consistent with the current literature proposing multi-casual explanations of violent behavior. PMID- 23438701 TI - [Risk of hospitalization among patients with co-occurring psychotic and substance use disorders: a 12-year follow-up]. AB - AIM: The study aims to analyze the impact of substance use disorders (SUD) on the risk of hospitalization among patients affected by psychotic disorders. METHODS: During 1995, the patients consecutively admitted to psychiatric hospitalization or to an outpatient visit, were included in the study. Patients were interviewed by a questionnaire with specific reference to Addiction Severity Index (ASI), in order to assess the presence of SUD. During 2008, for each patient, the retrospective assessment of the days and the number of hospitalizations, due to psychiatric cause between 1996 and 2007, was performed. RESULTS: During 1995, 102 patients were included in the study, 15 patients (14.7%) with a current SUD, 17 patients (16.7%) with a past SUD, and 70 patients (68.6% of the sample) without SUD. The follow-up analysis did not show any statistically significant difference among the three subgroups for what concerns the risk of receiving at least one hospitalization and the risk of involuntary treatment. By contrast, hospitalized patients with current SUD, if compared to hospitalized patients with past SUD or patients without SUD, appeared to have a significantly higher overall number of hospital admissions and days of hospitalization. DISCUSSION: The current SUD group showed, in terms of hospitalizations, worse prognostic profiles than the group without SUD and the group with past SUD. The prominent role of a comprehensive assessment and a therapeutic strategy taking into account the potential negative effect of substance use on the stabilization of psychotic symptoms is therefore confirmed. PMID- 23438702 TI - [Emerging mental disorders in a community sample of young adults in Italy: help seeking in a Generalist Community Mental Health setting]. AB - AIM: Delays in the admission to care of young adults with emerging mental disorders represent one of the current major concern in psychiatry. This delay, often experienced in clinical practice, has several determinants. One of these is "unexpressed help-seeking" that is influenced by cultural and historical backgrounds and by the characteristics of the disorder itself, but most of all by the way community mental health services are developed. The aims are to identify: level of stress and mental unease and main determinants of unexpressed help seeking within a community sample of young adults in a national contest of generalist community mental health model. METHODS: the sample is made up of 3,446 university students. An explorative questionnaire together with SVS (Stress related Valuation Scale) for the assessment of subjective stress and GHQ-12 for the evaluation of mental health status were given. A descriptive analysis was carried out followed by correlations between unexpressed help-seeking variable and other variables. A logistic regression was carried out on the subsample with GHQ-12 >=4 utilizing "non help-seeking" as a dependent variable. RESULTS: 46.8% of the sample had a GHQ-12 >=4 score. The amount of unexpressed help-seeking is equal to 63.6% and ends up being significantly correlated to: male sex, nonresident student, high SVS score, absence of Youth Mental Health Services, distrust manifested in relation to existing Services. CONCLUSIONS: A modification of the Community Mental Health Services in the sense of setting up more appropriate contexts for young users, could lead to a reduction of unexpressed help-seeking. PMID- 23438703 TI - [Diagnostic and therapeutic potential of the Elementary Pragmatic Model]. AB - This article describes the major results obtained from studies with the Elementary Pragmatic Model (EPM) composed by 16 Functions (F). The model has undergone experimentation using the Synthesis and Scission Sentences procedure (SISCI test) described in this paper. In functioning individuals there is a prevailing tendency to "maintain their world" (F3) and to decrease the "empty mind" (F0) and "chaos or impossible to select" (F15). On the contrary, individuals with psychiatric disorders, compared with functioning show a decreased degree of "maintaining their world" (F3), a higher degree of "empty mind" (F0) and of "chaos or impossible to select" (F15). The results are useful for both development of creativity in problem solving in business and for improve treatments to psychiatric disorders. PMID- 23438704 TI - Understanding anxiety disorders: the psychology and the psychopathology of defence mechanisms against threats. AB - The mental defense system plays a central role in ensuring individual and species survival from dangers. The cost of its activation is a decrease in freedom in favour of an increase in safety. Anxiety, fear and panic are the organizing principles of this system: anxiety arising in response to the anticipation of a threat, fear arising in response to external environmental threats and panic arising in response to internal somatic homeostatic threats. beyond the correct identification of the above-mentioned organizing principles, making correct therapeutic choices is linked to the ability to discriminate among physiological, pathological and pathophysiological anxiety phenomena. The intensity of the defense reaction is inadequate in determining that its pathological nature is related to the subjective evaluation of a disproportional reaction between individual resources and the potential threat. Very often, the anxious defensive reaction, which to an external observer seems disproportional, is coherent and adequate relative to the personal experience of the patient, and thus, it is not pathological. PMID- 23438706 TI - A high physical symptom count reduces the effectiveness of treatment for depression, independently of chronic medical conditions. AB - AIM: To assess to what extent a high physical symptom count influences the effect of treatment for major depressive disorder (MDD), and whether or not actual comorbid medical conditions explain this relationship. METHOD: Secondary data analysis on a cluster-randomized trial in primary care, comparing the effectiveness of collaborative care with care as usual (CAU). MDD was measured using the PHQ-9. The Physical Symptoms Questionnaire (PSQ) was filled out at baseline by 115 patients (77.2% of those who entered the trial). Multilevel logistic regression models were used to test whether a high physical symptom count predicted lack of response to treatment, adding interaction terms to test differential effects on collaborative care versus CAU. RESULTS: A high physical symptom count negatively influenced the effect of both collaborative care and care as usual (no interaction). Specifically, a high physical symptom count predicted lack of response in both conditions at 3 (odds ratio=6.8), 6 (OR=4.1), and 9 months follow-up (OR=6.4). This was not explained by chronic physical illness. CONCLUSION: In this RCT, patients with MDD accompanied by a high physical symptom count benefited less from treatment for MDD in primary care, regardless of the type of treatment (either collaborative care or CAU). This was not explained by the presence of comorbid medical conditions. Further research is needed to improve treatment for MDD accompanied by a high physical symptom count, although collaborative care for depression is still more effective than CAU for this group of patients. TRIAL REGISTRATION: Dutch trial register ISRCTN15266438. PMID- 23438707 TI - Multiple symptoms and medically unexplained symptoms--closely related concepts in general practitioners' evaluations. A linked doctor-patient study. AB - OBJECTIVES: Symptoms for which doctors cannot find a clear medical explanation, medically unexplained symptoms (MUS), represent a challenge in medical practice. Recent proposals to define this phenomenon are based on patients' symptom count, without distinguishing between medically explained and unexplained symptoms. We describe how general practitioners (GPs) evaluate multiple and medically unexplained symptoms, and how these dimensions are interconnected. Furthermore, we explore how the number of patient-reported symptoms is associated with the two axes. METHODS: A multi-centre, doctor-patient-linked cross-sectional study in general practice. GPs rated consecutive patients along two 11 point ordinal scales assessing multiple (Multi-scale) and medically unexplained symptoms (MUS scale). Patients completed a questionnaire addressing 38 symptoms experienced during the previous week and 866 linked questionnaires were available for analysis. RESULTS: GPs used the whole range of the scales, rating only a minority of the patients as "0 (not at all)". The two scales were highly correlated (r=0.80), with a quadratically weighted kappa of 0.73, reflecting substantial agreement between the scales. MUS-scores were highest in middle age. There was a tendency that Multi-scores increased with age and that correlations between the scales decreased with age, in both sexes, although partly non-significant. The number of patient-reported symptoms was moderately correlated with the two scales. CONCLUSION: Multisymptomatology captures MUS as a continuous construct to a great degree in GPs' clinical evaluations, although the two cannot be regarded as the same phenomenon. Patient-reported symptoms seem to be a less valid proxy for MUS. PMID- 23438705 TI - Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and mammals interact with pyruvate carboxylase and other acetylated biotin-dependent carboxylases. AB - The biological and enzymatic function of SIRT4 is largely uncharacterized. We show that the Caenorhabditis elegans SIR-2.2 and SIR-2.3 orthologs of SIRT4 are ubiquitously expressed, also localize to mitochondria and function during oxidative stress. Further, we identified conserved interaction with mitochondrial biotin-dependent carboxylases (PC, PCC, MCCC), key enzymes in anaplerosis and ketone body formation. The carboxylases were found acetylated on multiple lysine residues and detailed analysis of mPC suggested that one of these residues, K748ac, might regulate enzymatic activity. Nevertheless, no changes in mPC acetylation levels and enzymatic activity could be detected upon overexpression or loss of functional SIRT4. PMID- 23438708 TI - Inducing symptoms in high symptom reporters via emotional pictures: the interactive effects of valence and arousal. AB - OBJECTIVE: Processing unpleasant emotional cues induces elevated reporting of physical symptoms, especially in people with high habitual symptom reporting. The present study examined the role of valence and arousal of emotional pictorial cues on this effect. METHODS: Female participants (N=45; 21 high/24 low habitual symptom reporters) viewed six series of emotional pictures with a homogeneous affective content: low arousal/positive, high arousal/positive, low arousal/negative, high arousal/negative-disgust, high arousal/negative-threat and neutral. Heart rate (HR) and skin conductance level (SCL) were recorded during picture viewing and a symptom checklist and valence and arousal ratings were completed after each trial. RESULTS: High habitual symptom reporters reported more symptoms than low habitual symptom reporters overall, but this difference was more pronounced when processing unpleasant high arousing cues. No group differences were found on physiological measures for any of the conditions, while perceived valence and arousal both moderated the relationship between habitual symptom reporting and symptom induction. CONCLUSION: These findings show an interactive effect of unpleasantness and high arousal on elevated symptom reporting in high habitual symptom reporters, suggesting that different characteristics of emotional cues contribute to a somatic memory activation process leading to the experience of elevated symptoms. PMID- 23438709 TI - Mindfulness-based cognitive therapy for patients with medically unexplained symptoms: a cost-effectiveness study. AB - OBJECTIVE: Our aim was to assess cost-effectiveness of mindfulness-based cognitive therapy (MBCT) compared with enhanced usual care (EUC) in treating patients with persistent medically unexplained symptoms(MUS). METHODS: A full economic evaluation with a one year time horizon was performed from a societal perspective. Costs were assessed by prospective cost diaries. Health-related Quality of Life was measured using SF-6D. Outcomes were costs per Quality Adjusted Life Year (QALY). Bootstrap simulations were performed to obtain mean costs, QALY scores and incremental cost-effectiveness ratios (ICERs). RESULTS: MBCT participants (n=55) had lower hospital costs and higher mental health care costs than patients who received EUC (n=41). Mean bootstrapped costs for MBCT were ?6269, and ?5617 for EUC (95% uncertainty interval for difference: -?1576; ?2955). QALYs were 0.674 for MBCT and 0.663 for EUC. MBCT was on average more effective and more costly than EUC, resulting in an ICER of ?56,637 per QALY gained. At a willingness to pay of ?80,000 per QALY, the probability that MBCT is cost-effective is 57%. CONCLUSION: Total costs were not statistically significantly different between MBCT and EUC. However, MBCT seemed to cause a shift in the use of health care resources as mental health care costs were higher and hospital care costs lower in the MBCT condition. Due to the higher drop-out in the EUC condition the cost-effectiveness of MBCT might have been underestimated. The shift in health care use might lead to more effective care for patients with persistent MUS. The longer-term impact of MBCT for patients with persistent MUS needs to be further studied. PMID- 23438710 TI - Are media warnings about the adverse health effects of modern life self fulfilling? An experimental study on idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF). AB - OBJECTIVE: Medically unsubstantiated 'intolerances' to foods, chemicals and environmental toxins are common and are frequently discussed in the media. Idiopathic environmental intolerance attributed to electromagnetic fields (IEI EMF) is one such condition and is characterized by symptoms that are attributed to exposure to electromagnetic fields (EMF). In this experiment, we tested whether media reports promote the development of this condition. METHODS: Participants (N=147) were randomly assigned to watch a television report about the adverse health effects of WiFi (n=76) or a control film (n=71). After watching their film, participants received a sham exposure to a WiFi signal (15 min). The principal outcome measure was symptom reports following the sham exposure. Secondary outcomes included worries about the health effects of EMF, attributing symptoms to the sham exposure and increases in perceived sensitivity to EMF. RESULTS: 82 (54%) of the 147 participants reported symptoms which they attributed to the sham exposure. The experimental film increased: EMF related worries (beta=0.19; P=.019); post sham exposure symptoms among participants with high pre-existing anxiety (beta=0.22; P=.008); the likelihood of symptoms being attributed to the sham exposure among people with high anxiety (beta=.31; P=.001); and the likelihood of people who attributed their symptoms to the sham exposure believing themselves to be sensitive to EMF (beta=0.16; P=.049). CONCLUSION: Media reports about the adverse effects of supposedly hazardous substances can increase the likelihood of experiencing symptoms following sham exposure and developing an apparent sensitivity to it. Greater engagement between journalists and scientists is required to counter these negative effects. PMID- 23438711 TI - The influence of age on the distribution of self-rated health, burnout and their associations with psychosocial work conditions. AB - OBJECTIVE: Self-rated health (SRH) and burnout are commonly used health indicators. This study was designed to examine the age-specific patterns of SRH and burnout and their correlations with self-reported disease symptoms, and to investigate the moderating effects of age on the associations of psychosocial work conditions with these two health measures. METHODS: Study subjects were 20,454 male and 16,875 female employees from 2 representative surveys conducted in 2007 and 2010 in Taiwan. SRH was assessed by a single item and burnout was assessed by the general burnout subscale of the Copenhagen Burnout Inventory (CBI). Psychosocial work conditions including working hours, psychological and physical job demands, job control, job insecurity and workplace justice were assessed by a validated questionnaire. RESULTS: Older workers were at higher risk for poor SRH which was correlated with the presence of multiple disease symptoms. In contrast, employees aged 30-40 years had higher burnout which was strongly correlated with emotional disturbance. Among all the examined work factors, low workplace justice was found to be the most predominant predictor for poor SRH and high burnout, and the associations were more profound in younger workers than in older workers. CONCLUSION: SRH and burnout were differentially related to age, and there were evidences of moderating effects of age on the associations between psychosocial work conditions and health. Researchers and health practitioners should pay attention to the influence of age when using the measures of SRH and burnout as indicators to detect health risk in association with adverse psychosocial work conditions. PMID- 23438712 TI - Stress-stimulated volitional coping competencies and depression in multiple sclerosis. AB - OBJECTIVE: The present study examined the relationship between volitional modes of coping (self-regulation, volitional inhibition, and self-control) and depression in individuals with multiple sclerosis. METHODS: A cross-sectional study of 121 participants aged 22-60 years with clinically defined MS who were consecutively admitted to a neurological rehabilitation center during a 23-month period. Correlation analyses and hierarchical regressions were conducted to evaluate the predictive value of volitional competencies (Volitional Components Questionnaire, short form, VCQ-S) on depression (Centre for Epidemiologic Studies Depression Scale, CES-D), while controlling for demographic (age, gender, and education) and certain clinical variables (Expanded Disability Status Scale, EDSS; disease duration; and Modified Fatigue Impact Scale, MFIS). RESULTS: Hierarchical regression analyses of depression revealed a model in which 68% of the variance in the CES-D was explained by daily stress situations (VCQ-S), self regulation (VCQ-S), fatigue (MFIS), and education. However, when the analysis included only participants who had scored above the cut-off of the CES-D (n=42), the VCQ-S factor volitional inhibition seemed to play a more relevant part in depression. In particular, the VCQ-S scales stimulation of self-access, stimulation of volitional inhibition, self-motivation, and emotional perseverance/state orientation after failure appear to be valuable predictors on CES-D. CONCLUSIONS: The results suggest that personality-accentuated volitional coping competencies elicited by daily stressful situations could be a relevant factor for depressive mood states in individuals with MS. However, to clarify the exact relationships of this rather circular framework, longitudinal study designs with objective measurements and a stronger focus on MS-specific stressors are needed. PMID- 23438713 TI - The psychosocial correlates of depressive disorders and suicide risk in people with epilepsy. AB - OBJECTIVE: Despite considerable effort to identify correlates of psychopathology in people with epilepsy (PWE), research has yet to identify consistent predictors. We tested the association between factors predicted by a model of adjustment to illness and psychopathology in PWE. METHODS: In 123 PWE recruited from a tertiary referral centre, we examined the cross-sectional relationship between psychosocial factors (illness representations, coping, self-illness enmeshment and self-efficacy) with depression and suicide risk, while controlling for condition-related and demographic factors. RESULTS: Multivariate analyses confirmed previous findings showing that condition-related and demographic variables did not consistently account for unique variance in depression although employment status was found to be a significant predictor of suicide risk. In multivariate analyses escape-avoidance coping and the illness consequences subscale of the illness representation questionnaire predicted unique variance in both depression and suicide risk. CONCLUSION: The results provided partial support for a model of adjustment to illness. Specifically, those who believed epilepsy was serious and coped through avoidance were more likely to be depressed and report a current level of suicide risk. These results suggest that interventions that target coping strategies and illness representations may be warranted for PWE with psychopathology. PMID- 23438714 TI - Increased risk of hypothyroidism and hyperthyroidism in patients with major depressive disorder: a population-based study. AB - OBJECTIVE: To determine the prevalence and incidence of hypothyroidism, hyperthyroidism, and risk factors in patients with major depressive disorder (MDD). METHODS: The National Health Research Institute provided a database of 1,000,000 random subjects for health service studies. We identified subjects aged >=18 years who had at least 1 service claim during 2005 with a primary diagnosis of MDD or with a primary or secondary diagnosis of hypothyroidism or hyperthyroidism. We also compared the incidence of hypothyroidism and hyperthyroidism among patients with MDD and the general population from 2006 through 2010. RESULTS: The prevalence of hypothyroidism in patients with MDD was higher than that in the general population (1.20% vs. 0.30%; odds ratio, 3.08; 95% confidence interval, 2.35-4.03) in 2005. The prevalence of hyperthyroidism was also higher in patients with MDD than in the general population (2.46% vs. 0.79%; odds ratio, 2.77; 95% confidence interval, 2.29-3.35) in 2005. The annual incidence of hypothyroidism was higher in patients with MDD than that in the general population (0.40% vs. 0.13%; risk ratio, 2.47; 95% confidence interval, 2.00-3.06). The annual incidence of hyperthyroidism was also higher in patients with MDD than that in the general population (0.72% vs. 0.32%; risk ratio, 2.06; 95% confidence interval, 1.75-2.43). CONCLUSIONS: Patients with MDD had a higher prevalence and a higher incidence of hypothyroidism or hyperthyroidism than the general population. Female sex was a risk factor for hypothyroidism and hyperthyroidism in MDD. PMID- 23438715 TI - Time-course of depressive symptoms in patients with heart failure. AB - BACKGROUND: It is unclear how depressive symptoms in patients with heart failure develop over time and whether this trajectory of depressive symptoms is associated with hospital admission and prognosis. AIM: To describe the time course of depressive symptoms and determine the relationship with hospitalisation and mortality. METHOD: Data was analysed using 611 patients with completed CES-D questionnaires at baseline and at 18 months. Data on hospitalisation was collected 18 months after discharge and data on mortality was collected 18 and 36 months post-discharge. RESULTS: A total of 140 (61%) of the 229 patients with depressive symptoms at discharge had recovered from depressive symptoms after 18 months whereas 71 (18%) of the 382 non-depressed developed depressive symptoms and 89 (39%) of the 229 depressed remained depressed. Patients with recently (i.e. during the last 18 months) developed depressive symptoms showed a significantly higher risk for cardiovascular hospitalisation (HR 1.7, 95% CI 1.1 2.6, P=.016). After 36 months, patients with developed depressive symptoms after discharge were at a higher risk of all-cause mortality (HR 2.0, 95% CI 1.2-3.5, P=.012) and there was a trend towards a higher risk of all-cause mortality in patients with ongoing depressive symptoms (HR 1.7, 95% CI 0.98-3.1, P=.056). CONCLUSION: A significant proportion of patients with HF, who were reported depressive symptoms at discharge recovered from depressive symptoms during the following 18 months. However, patients who remained having depressive symptoms or patients who developed depressive symptoms had a worse prognosis. PMID- 23438716 TI - Biological correlates of major depression and generalized anxiety disorder in women with polycystic ovary syndrome. AB - OBJECTIVE: We aimed to compare the levels of serum androgens in women with polycystic ovary syndrome (PCOS) who had a diagnosis of only major depressive disorder (MDD), only generalized anxiety disorder (GAD) or who had no psychiatric disorder, as determined by a structured clinical interview. Another objective of the study was to examine whether an association exists between these psychiatric diagnoses and insulin resistance or body mass index via a comparison among the study groups in terms of these parameters. METHOD: This study was performed between March 2011 and February 2012. A total of 73 patients were included in the study. The study sample consisted of three groups: PCOS patients with only major depressive disorder (n=23), PCOS patients with only generalized anxiety disorder (n=20), and PCOS patients without any diagnosed psychiatric disorders (not diagnosed - ND group, n=30). RESULTS: Significant difference was found among the three groups with regard to the serum levels of 17-OHP and DHEAS. When multiple comparisons were performed among the groups, 17-OHP levels were significantly higher in the MDD group than in the ND group. DHEAS levels were significantly higher in the MDD group and the GAD group than in the ND group. CONCLUSION: The present study suggests that MDD and GAD appear to be associated with higher DHEAS levels. PMID- 23438717 TI - Perceived illness stigma is associated with depression in female patients with systemic lupus erythematosus. AB - OBJECTIVES: 1) To assess the prevalence of depression in a sample of female patients with systemic lupus erythematosus (SLE) 2) To evaluate the association between perceived illness stigma and depression in those patients. METHODS: In a cross-sectional study, 80 female SLE patients were evaluated for the presence of depression and perceived illness stigma. Depression was diagnosed using the Structured Clinical Interview for DSM-IV Axis Iota disorders, clinical version (SCID-I-CV), the severity of the depressive symptoms was evaluated using the Hospital Anxiety and Depression Scale-Depression Subscale (HADS-D), and the stigma of illness was assessed using the Stigma Impact Scale (SIS). RESULTS: The prevalence of depression among female SLE patients was 18.75% (15/80). The perceived illness stigma was higher among the depressed group than among the non depressed group (SIS mean scores were 43.87+/-7.87 and 26.62+/-3.79 respectively P<.001), there was a significant positive correlation between SIS and HAD-D scores (r=0.73, P=.002), and there was a significant association between perceived illness stigma and diagnosis of depression (R(2)=0.53, P=.002, odds ratio=3.2), which increased the severity of depressive symptoms (R(2)=0.64, P<.001). CONCLUSION: This study demonstrates a significant association between illness stigma and depression in female SLE patients which may be important in promoting optimal coping for these women . PMID- 23438718 TI - Coping skills and mental health status in adolescents when a parent has cancer: a multicenter and multi-perspective study. AB - OBJECTIVE: Parental cancer increases the risk of psychosocial problems in adolescents. We investigated the frequency and efficacy of adolescents' coping strategies and relationships between those strategies and mental health status. Age and gender differences regarding coping and mental health were also investigated. METHODS: In total, 214 adolescents from 167 families participated in a cross-sectional, multicenter study. All participants were recruited from standard oncological care. Among the participants, 52% utilized a child-centered intervention program. Adolescents' coping skills were measured using KIDCOPE. Mental health status was rated by adolescents and parents by the SDQ for symptomatology and the KIDSCREEN for well-being. RESULTS: We found that 29% of the adolescents showed emotional and behavioral problems. We found gender differences in mental health status but not in coping. Adolescents used a broad spectrum of coping strategies. Active problem-solving, distraction, acceptance, wishful thinking and seeking social support were the most frequently used coping strategies. The utilization of certain coping skills was mediated by their perceived efficacy. Problem-focused or approach-oriented coping strategies generally are associated with better mental health, while avoidance-oriented coping are associated with worse mental health. Emotion-focused coping was associated with both lower and higher mental health. CONCLUSION: The strategies used by adolescents to cope with parental cancer are associated with their mental health. Problem-solving and approach-oriented coping strategies should be facilitated by psychological interventions regardless of age and gender. Age and gender differences in adolescents' mental health should be further investigated because these differences are not explained by differences in coping strategies. PMID- 23438719 TI - The impact of illness perceptions on sexual functioning in patients with systemic lupus erythematosus. AB - OBJECTIVE: Sexual problems are common in patients with chronic illnesses. However, few studies have investigated problems with sexual functioning in patients with systemic lupus erythematosus (SLE). The present cross-sectional study assessed the influence of SLE on sexual functioning and its associations with illness perceptions and medical and socio-demographic characteristics. METHOD: The study included 106 SLE patients who used at least one immunosuppressive agent to control their SLE. Sexual functioning was measured using the Physical Disability Sexual and Body Esteem and the Medical Impact Scale from the Sexual Functioning Questionnaire. Patients' illness perceptions were assessed using the Brief Illness Perception Questionnaire. RESULTS: 49.1% of patients agreed that their SLE had a negative influence on their sexual functioning. In addition, treatment for SLE seemed to play an important role in the negative impact on sexual functioning. Patients' illness perceptions were more important predictors of sexual functioning than medical and socio demographic characteristics. SLE patients appear to report a lower sexual functioning than patients with other chronic illnesses. CONCLUSION: SLE in general and immunosuppressive treatment for SLE specifically have a negative influence on sexual functioning. Patients' illness perceptions appear to play a more important role in the negative impact on sexual functioning than medical characteristics such as disease activity. The high prevalence of sexual problems highlights the need to more frequently address and aim to improve sexual functioning in patients with SLE. Patients may benefit from methods such as illness perception modification and coping style interventions to reduce their sexual problems. PMID- 23438720 TI - Primary attributions in women suffering fibromyalgia emphasize the perception of a disruptive onset for a long-lasting pain problem. AB - OBJECTIVE: Fibromyalgia (FM) is a chronic musculoskeletal pain disorder characterized by widespread pain. This study focuses on patients' attributions of illness and of symptom onset. METHODS: Semi-structured interviews were conducted with 56 women to elicit patients' views on what triggered their FM. The transcripts of the interviews were analyzed using a classical indexing technique to identify key themes. Content analysis was performed by two independent coders. RESULTS: Primary causal attributions fell into five categories: psychological problems (28 respondents); somatic concerns (N=12); violence/abuse during childhood (N=7), gynaecological/obstetrical problems (N=6), and fatigue (N=3). Patients' attributions were internal and external in the same proportions, more frequently unstable than stable, and more often described uncontrollable than controllable. Participants expressed decrements in self-esteem and feelings such as self-blame or despair; global perceptions of persistent pain and long-lasting problems, evoking chronicity and hopelessness; and low perceived control over their lives as well as beliefs that nothing can be done, thus increasing a feeling of guilt and vulnerability. Patients' narratives emphasized disruptive circumstances surrounding symptom onset. CONCLUSION: Attributions often referred to the psychological dimension of the events surrounding FM onset, even though some of them also had a clear somatic dimension. Many narratives mentioned successive disruptive events and suggested an increasing loss of control. Addressing these illness representations may contribute to tailor the treatment and to help patients gain self-coherency by providing means to understand pain onset but also to guide future behaviours, particularly in terms of adjustment and help-seeking. PMID- 23438721 TI - Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers. AB - BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management (CRM) strategies varies by service provider. Using a registry-based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling (GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi-squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers. PMID- 23438722 TI - Effects of post-exercise recovery in a cold environment on muscle glycogen, PGC 1alpha, and downstream transcription factors. AB - PURPOSE: The purpose of this investigation was to determine the impact of post exercise environmental cold exposure on muscle glycogen, PGC-1alpha, and downstream transcription factors. METHODS: Eight males cycled for 1h and recovered in either 7 degrees C (cold) or 20 degrees C (room temp) environment for 4h. Muscle biopsies were obtained pre, post, and 4h post exercise for the analysis of muscle glycogen and mRNA. During recovery participants consumed 1.8 g kg-1 of body weight of an oral dextrose solution immediately following the post biopsy and 2h into recovery. Blood samples were obtained post exercise and at 30, 60, 120, 150, 180, and 240 min post exercise for the analysis of serum glucose and insulin AUC. RESULTS: Oxygen uptake was lower during room temp than during cold recovery (0.40 +/- 0.05 L x min-1 vs. 0.80 +/- 0.12 L x min-1; p<0.01). There was no effect of temperature on muscle glycogen recovery or glucose AUC. However, insulin AUC was greater during the room temp trial compared to the cold trial (5139 +/- 1412 vs. 4318 +/- 1272, respectively; p=0.025). PGC-1alpha gene expression was higher (p=0.029), but ERRalpha and NRF2 were lower (p=0.019 and p=0.046, respectively) after recovery in the cold. There were no differences in NRF1 (p=.173) or TFAM (p=0.694). CONCLUSIONS: This investigation shows no effect of a cold recovery environment on glycogen re-synthesis but does demonstrate reduced ERRalpha and NRF2 mRNA despite elevations in PGC-1alpha mRNA when recovery post-exercise takes place in a cold environment. PMID- 23438724 TI - Editorial: Are We in Need for Novel Therapeutics in Anxiety Disorders? (Thematic Issue: Non-Antidepressant Long Term Treatment of Anxiety Disorders). PMID- 23438725 TI - Non-Antidepressant Treatment of Generalized Anxiety Disorder. AB - INTRODUCTION: Generalized anxiety disorder (GAD) is a prevalent and very disabling anxiety disorder. First-line medications are antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenalin reuptake inhibitors (SNRIs). However, a substantial number of patients do not reach remission while on antidepressants and they may develop troublesome side effects, which highlights the necessity of new therapeutic options for GAD. METHODS: The purpose of this review is to discuss all non antidepressant treatments studied in GAD. We searched MedLine for English articles published between 1980 and 2012, containing the following keywords: "generalized (or generalised) anxiety disorder" OR "anxiety disorder", AND "drug therapy" OR "herbal medicine". 76 articles were finally selected. RESULTS: Pregabalin is the anticonvulsant with the most robust level of evidence in GAD. It rapidly reduces anxiety, has a safe side effect profile and presents a low potential for abuse. Among antipsychotics, quetiapine is the one of choice in GAD, with similar efficacy to SSRIs in low dosages, yet with lower overall tolerability. Benzodiazepines, buspirone and hydroxyzine are Food and Drugs administration (FDA) approved for GAD and have relatively good evidence of efficacy. Other drugs (betablockers, zolpidem, riluzole, etc.) and natural remedies (e.g. Piper methysticum) could be potential treatment options, yet additional research is warranted. CONCLUSION: Pregabalin and quetiapine are the two most promising non-antidepressant treatments for GAD. PMID- 23438726 TI - Non-Antidepressant Pharmacological Treatment of Obsessive Compulsive Disorder: A Comprehensive Review. AB - INTRODUCTION: Obsessive-compulsive disorder (OCD) is associated with significant morbidity and dysfunction. First-line OCD treatments - serotonin reuptake inhibitors (SRIs), cognitive behavioral therapy (CBT) and their combination - though widely used, are not sufficient in treating resistant cases. This eventually raises the need for finding novel strategies, whether by adding-on drugs or switching to a different psychopharmacological class. The aim of this paper is to present a comprehensive review of non-antidepressant pharmacological treatment that has been evaluated for the management of OCD. MATERIALS AND METHODS: A research has been conducted using MedLine and the following Medical Subject Headings (MeSH) terms were used: Obsessive compulsive disorder AND drug therapy. Articles that conformed to specific inclusion criteria were stratified per drug and per quality of evidence. For each drug, articles having the best level of evidence were retained. RESULTS: Sixty-eight articles were reviewed and presented by drug class as follows: antipsychotics, mood stabilizers, gamma-amino butyric acid (GABA) analogues and GABA reuptake inhibitors, benzodiazepines, glutamatergic agents and other miscellaneous drugs. DISCUSSION: There is substantial collective evidence supporting the use of antipsychotics as an augmentation treatment of resistant OCD patients. Although not always consistent, the following drugs showed some efficacy upon randomized controlled trials: risperidone, olanzapine, quetiapine, aripiprazole, haloperidol, topiramate, pindolol, morphine, ondansetron and celecoxib. The efficacy of glutamatergic agents is promising. Numerous other pharmacological agents have been studied yet the results are inconclusive due to several limitations mainly of methodological nature. PMID- 23438723 TI - Oxidative stress in patients with cardiovascular disease and chronic renal failure. AB - Oxidative response regulates many physiological response in human health, but if not properly regulated it could also lead to a number of deleterious effects. The importance of oxidative stress injury depends on the molecular target, the severity of the stress, and the mechanism by which the oxidative stress is imposed: it has been implicated in several diseases including cancer, neurodegenerative diseases, malaria, rheumatoid arthritis and cardiovascular and kidney disease. Most of the common diseases, such as hypertension, atherosclerosis, heart failure, and renal dysfunction, are associated with vascular functional and structural alterations including endothelial dysfunction, altered contractility, and vascular remodeling. Common to these processes is increased bioavailability of reactive oxygen species (ROS), decreased nitric oxide (NO) levels, and reduced antioxidant capacity. Oxidative processes are up regulated also in patients with chronic renal failure (CRF) and seem to be a cause of elevated risk of morbidity and mortality in these patients. In this review, we highlight the role of oxidative stress in cardiovascular and renal disease. PMID- 23438727 TI - Non-Antidepressant Pharmacologic Long-Term Treatment of Panic Disorder. AB - INTRODUCTION: Panic disorder (PD) is a common anxiety disorder. Despite neurophysiological advances, its pathogenesis is still not well elucidated. Although the recommended pharmacological agents have demonstrated efficacy and a rather acceptable tolerability, yet many patients do not respond fully and still suffer from residual symptoms. There is a need for new pharmacological classes with better tolerability and efficacy, and faster onset of action. The purpose of this review is to illustrate the existing non-antidepressant treatment of PD as well as the recent advances in the treatment of PD. METHODS: 38 articles discussing pharmacological treatment of PD were selected for this review. They were mainly openlabel studies, case-reports and review articles. RESULTS: We reviewed the studies on anticonvulsants, benzodiazepines, gamma amino butyric acid (GABAergic) products, atypical antipsychotics, clonidine, as well as emerging drugs in the treatment of PD such as metabotropic glutamate II agonists, and D-cycloserine. CONCLUSION: Although most of the drugs tested were proven effective and well tolerated, the studies on the nonconventional agents are restricted to open-label trials and case reports. Further studies are required to establish their efficacy and tolerability in the treatment of panic disorder. PMID- 23438728 TI - Non-Antidepressant Long-term Treatment in Post-Traumatic Stress Disorder (PTSD). AB - INTRODUCTION: Post-traumatic stress disorder (PTSD) is a frequent and disabling condition that occurs after exposure to a traumatic event, and Selective Serotonin Reuptake Inhibitors (SSRIs) are considered the first-line treatment approach for this disorder. However, a large proportion of patients remain symptomatic and other pharmacological agents have been investigated, based on the understanding of the underlying biological dysfunctions of PTSD. METHODS: We conducted a review of the literature on the pharmacological options for PTSD other than the antidepressants, using MedLine and Web of Science databases, with search terms including the pharmacologic class of each agent plus PTSD, or pharmacotherapy, or fear conditioning. The literature review covered articles published until august 2012, including reviews and original articles. RESULTS: Agents like antipsychotics, anticonvulsants, benzodiazepines, anti-adrenergic agents, have been studied in randomized clinical trials (RCTs), with general positive results for antipsychotics, especially as adjunct therapy, and for prazosin for sleep-related disturbances. However, one important target for novel medications is the modulation of the fear conditioning process, through the alteration of retrieval/reconsolidation or enhancement of fear extinction. This is traditionally targeted in prolonged exposure therapy, but pre-clinical findings from studies investigating agents like propanolol, clonidine, N-Methyl-D aspartic Acid Receptor (NMDAR) compounds, 3,4-methylenedioxy-N-methylamphetamine (MDMA) and cannabinoids, indicate promising results in affecting the fear conditioning process and thus improving PTSD core symptoms. DISCUSSION: Antipsychotics can be considered a reasonable alternative option to PTSD, with the largest body of evidence for risperidone, even though larger RCTs are warranted. Prazosin is also a promising agent, especially for sleep-related disturbances, while anticonvulsants and benzodiazepines lack empirical support. However, the most promising area for pharmacotherapy in PTSD is the modulation of the fear conditioning process, through agents used in adjunct to exposure therapy. PMID- 23438729 TI - Non-Antidepressant Treatment of Social Anxiety Disorder: A Review. AB - Social anxiety disorder is a debilitating mental illness with eventually serious comorbidities such as major depression and alcohol or substance abuse and dependence. Those comorbidities are much more common when social phobia is left neglected and untreated. It is characterized by excessive fears to one or most social situations (circumscribed versus generalized type). Social phobia has its onset typically in childhood or early adolescence and it is associated with significant functional impairment. Although cognitive behavioral therapy and the selective serotonin reuptake inhibitors are considered the mainstay treatment of this disorder, other psychotropic agents can be of value in the management of this condition. This review discusses the efficacy of beta-bockers, benzodiazepines, anticonvulsants, D-cycloserine, buspirone and atypical antipsychotics in the treatment of social anxiety disorder. PMID- 23438730 TI - Non-Antidepressant Psychopharmacologic Treatment of Specific Phobias. AB - Specific phobias are among the most frequently diagnosed disorders in community with a twelve-month prevalence of 8.7% and a lifetime prevalence of 12.5%. Exposure-based therapies constitute the most effective treatment for this type of anxiety disorders. However, pharmacotherapies can still be considered for patients suffering from specific phobias in case they were non-adherent or resistant to exposure-based therapies or in case this kind of therapies was not accessible for them. Few data support the use of antidepressant in the treatment of specific phobias. A literature search via MedLine has been done in order to review all available studies in the domain of nonantidepressant pharmacotherapy of specific phobias. The importance of benzodiazepines such as diazepam, alprazolam and midazolam resides in the short-term reduction of subjective selfreported fear during the exposure to the feared object or situation. General anesthesia for the treatment of dental phobia does not seem to be efficient unless conducted with the inhalation anesthetic nitrous oxide which seems to be efficient on the short and on the long-term. Beta-adrenergic antagonists have been essayed with conflicting results. Cognitive enhancers such as D-cycloserine, glucocorticoids and yohimbine hydrochloride, seem to be more effective than placebo after a short term period of follow-up in treating specific phobia sympotms. In conclusion, promising efficient pharmacotherapies for specific phobias consists of drugs that enhance the efficacy of exposure-based therapies sessions by reducing anticipating phobia-related fear and/or by enhancing cognition during these sessions. PMID- 23438731 TI - Toward a platform for comprehensive glycan sequencing. AB - From a series of recently published reports, an analytical platform has been proposed for a quantitative and qualitative measure of N- and O-glycosylation, complete with peptide-glycan connectivity and detailed structural understanding. As distant as this may appear, a best methods approach will appear that must move us beyond the cartoon stage of structural understanding. Thus, with this unifying goal in mind, we summarize a series of individually promising first phase protocols of sample preparation (release, purification, and quantification) that remain congruent with a concluding phase (methylation and MS(n)) for documented structural detail. Sequential enzymatic N-glycan and chemical O-glycan release from glycopeptides with intervening solid phase extraction and derivatization will provide for a comparative quantification measure of glycosylation. The O glycan release will be nonreductive and coupled with Michael addition to a pyrazolone analog (1-phenyl-3-methyl-5-pyrazolone) with both the peptide and glycan labeled. The product glycans are stable to methylation and appropriate for sequential disassembly (MS(n)). An application using human serum and cancer samples has been detailed characterizing sLe(x) and comparable valence epitopes. This integrated platform will provide opportunities at variable points to contrast, share, and advance alternative protocols in a collaborative effort that is greatly needed. This integrated platform provides end point opportunities to confirm structural details compiled from synthetic standards and well characterized biologics by MS(n). PMID- 23438732 TI - Predicting physical interactions between protein complexes. AB - Protein complexes enact most biochemical functions in the cell. Dynamic interactions between protein complexes are frequent in many cellular processes. As they are often of a transient nature, they may be difficult to detect using current genome-wide screens. Here, we describe a method to computationally predict physical interactions between protein complexes, applied to both humans and yeast. We integrated manually curated protein complexes and physical protein interaction networks, and we designed a statistical method to identify pairs of protein complexes where the number of protein interactions between a complex pair is due to an actual physical interaction between the complexes. An evaluation against manually curated physical complex-complex interactions in yeast revealed that 50% of these interactions could be predicted in this manner. A community network analysis of the highest scoring pairs revealed a biologically sensible organization of physical complex-complex interactions in the cell. Such analyses of proteomes may serve as a guide to the discovery of novel functional cellular relationships. PMID- 23438734 TI - Mapping the global flow of aluminum: from liquid aluminum to end-use goods. AB - Demand for aluminum in final products has increased 30-fold since 1950 to 45 million tonnes per year, with forecasts predicting this exceptional growth to continue so that demand will reach 2-3 times today's levels by 2050. Aluminum production uses 3.5% of global electricity and causes 1% of global CO2 emissions, while meeting a 50% cut in emissions by 2050 against growing demand would require at least a 75% reduction in CO2 emissions per tonne of aluminum produced--a challenging prospect. In this paper we trace the global flows of aluminum from liquid metal to final products, revealing for the first time a complete map of the aluminum system and providing a basis for future study of the emissions abatement potential of material efficiency. The resulting Sankey diagram also draws attention to two key issues. First, around half of all liquid aluminum (~39 Mt) produced each year never reaches a final product, and a detailed discussion of these high yield losses shows significant opportunities for improvement. Second, aluminum recycling, which avoids the high energy costs and emissions of electrolysis, requires signification "dilution" (~ 8 Mt) and "cascade" (~ 6 Mt) flows of higher aluminum grades to make up for the shortfall in scrap supply and to obtain the desired alloy mix, increasing the energy required for recycling. PMID- 23438733 TI - A classifier based on accurate mass measurements to aid large scale, unbiased glycoproteomics. AB - Determining which glycan moieties occupy specific N-glycosylation sites is a highly challenging analytical task. Arguably, the most common approach involves LC-MS and LC-MS/MS analysis of glycopeptides generated by proteases with high cleavage site specificity; however, the depth achieved by this approach is modest. Nonglycosylated peptides are a major challenge to glycoproteomics, as they are preferentially selected for data-dependent MS/MS due to higher ionization efficiencies and higher stoichiometric levels in moderately complex samples. With the goal of improving glycopeptide coverage, a mass defect classifier was developed that discriminates between peptides and glycopeptides in complex mixtures based on accurate mass measurements of precursor peaks. By using the classifier, glycopeptides that were not fragmented in an initial data dependent acquisition run may be targeted in a subsequent analysis without any prior knowledge of the glycan or protein species present in the mixture. Additionally, from probable glycopeptides that were poorly fragmented, tandem mass spectra may be reacquired using optimal glycopeptide settings. We demonstrate high sensitivity (0.892) and specificity (0.947) based on an in silico dataset spanning >100,000 tryptic entries. Comparable results were obtained using chymotryptic species. Further validation using published data and a fractionated tryptic digest of human urinary proteins was performed, yielding a sensitivity of 0.90 and a specificity of 0.93. Lists of glycopeptides may be generated from an initial proteomics experiment, and we show they may be efficiently targeted using the classifier. Considering the growing availability of high accuracy mass analyzers, this approach represents a simple and broadly applicable means of increasing the depth of MS/MS-based glycoproteomic analyses. PMID- 23438738 TI - Parasites R us: Coronado Biosciences recruits parasitic worms to treat autoimmune disease. PMID- 23438739 TI - Ready, set, cleave: proteases in action. AB - Activity-based probes are small molecules that can be used to monitor enzyme activity by covalently binding to specific residues in the active site. In this issue of Chemistry & Biology, Lu and colleagues developed a specific fluorescent activity-based probe that targets the papain-like cysteine bacterial type III effector protease AvrPphB and used it to demonstrate the regulation of the protease secretion and pathogenesis. PMID- 23438740 TI - Resolving resolvins. AB - In this issue of Chemistry & Biology, Dalli and colleagues report the chemical structures of resolvin D3 (RvD3) and aspirin-triggered RvD3, derived from the omega3-fatty acid docosahexaenoic acid. These compounds have a specific temporal appearance within inflammation resolution and display anti-inflammatory and proresolving properties. Together, the results will help design new resolvin mimetics, potential resolution agonists with anti-inflammatory properties. PMID- 23438741 TI - In search of the missing ligands for TetR family regulators. AB - The TetR family of microbial transcription factors directly control the expression of a diverse range of genes in bacteria by sensing specific ligands. In this issue of Chemistry & and Biology, Cuthbertson and colleagues used phylogenomics to guide the identification of TetR-like protein cognate ligands and revealed a novel inducible antibiotic resistance mechanism. PMID- 23438742 TI - Rheostat-ing mitosis. AB - Ark1, the unique Aurora kinase in Schizosaccharomyces pombe, regulates multiple aspects of mitosis. In this issue of Chemistry & Biology, Kawashima and colleagues report the discovery and validation of a fungal Ark1 inhibitor, which they employ to evaluate the mitotic outputs of endogenous Ark1 signaling. PMID- 23438743 TI - Proteostasis modulators with discriminating taste. AB - Small molecules that perturb protein homeostasis are used as cancer therapeutics and as antibiotics to treat bacterial infections. In a recent issue of Cell, Kannan and colleagues describe an intriguing mechanism that enables ribosome targeted macrolides to selectively remodel the bacterial proteome. This finding suggests the exciting possibility of targeting additional proteostasis regulators in a substrate-selective manner. PMID- 23438744 TI - Developing irreversible inhibitors of the protein kinase cysteinome. AB - Protein kinases are a large family of approximately 530 highly conserved enzymes that transfer a gamma-phosphate group from ATP to a variety of amino acid residues, such as tyrosine, serine, and threonine, that serves as a ubiquitous mechanism for cellular signal transduction. The clinical success of a number of kinase-directed drugs and the frequent observation of disease causing mutations in protein kinases suggest that a large number of kinases may represent therapeutically relevant targets. To date, the majority of clinical and preclinical kinase inhibitors are ATP competitive, noncovalent inhibitors that achieve selectivity through recognition of unique features of particular protein kinases. Recently, there has been renewed interest in the development of irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket. Irreversible kinase inhibitors have a number of potential advantages including prolonged pharmacodynamics, suitability for rational design, high potency, and ability to validate pharmacological specificity through mutation of the reactive cysteine residue. Here, we review recent efforts to develop cysteine-targeted irreversible protein kinase inhibitors and discuss their modes of recognizing the ATP-binding pocket and their biological activity profiles. In addition, we provided an informatics assessment of the potential "kinase cysteinome" and discuss strategies for the efficient development of new covalent inhibitors. PMID- 23438745 TI - Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. AB - Antibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window. PMID- 23438746 TI - A substrate-inspired probe monitors translocation, activation, and subcellular targeting of bacterial type III effector protease AvrPphB. AB - The AvrPphB effector of Pseudomonas syringae is a papain-like protease that is injected into the host plant cell and cleaves specific kinases to disrupt immune signaling. Here, we used the unique substrate specificity of AvrPphB to generate a specific activity-based probe. This probe displays various AvrPphB isoforms in bacterial extracts, upon secretion and inside the host plant. We show that AvrPphB is secreted as a proprotease and that secretion requires the prodomain, but probably does not involve a pH-dependent unfolding mechanism. The prodomain removal is required for the ability of AvrPphB to trigger a hypersensitive cell death in resistant host plants, presumably since processing exposes a hidden acylation site required for subcellular targeting in the host cell. We detected two active isoforms of AvrPphB in planta, of which the major one localizes exclusively to membranes. PMID- 23438747 TI - A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro. AB - Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic alpha proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the delta-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs. PMID- 23438749 TI - Directed evolution of a soluble human IL-17A receptor for the inhibition of psoriasis plaque formation in a mouse model. AB - Interleukin-17 (IL-17) is a T-cell-derived cytokine that promotes inflammatory pathology in autoimmune diseases. Blocking IL-17A interactions with its endogenous IL-17 receptor (IL-17RA) can constitute an important target for therapeutic intervention. Here, we utilized a directed evolution approach to generate soluble IL-17RA mutants that exhibit increased IL-17A binding affinity and thermostability, relative to the wild-type. Human fibroblast cell-based assay and in vivo analysis in mice indicated that two improved IL-17RA mutants efficiently inhibit the secretion of IL-17A-induced proinflammatory cytokines. Analysis of one of these mutants in a psoriasis mouse model showed its efficacy in promoting the recovery of psoriasis plaques. This mutant can be used as a promising drug candidate for the treatment of psoriasis and may be a therapeutic agent for various other autoimmune diseases. PMID- 23438748 TI - Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. AB - Resolvins are a family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids. PMID- 23438750 TI - Catalytic site conformations in human PNP by 19F-NMR and crystallography. AB - Purine nucleoside phosphorylase (PNP) is a target for leukemia, gout, and autoimmune disorders. Dynamic motion of catalytic site loops has been implicated in catalysis, but experimental evidence was lacking. We replaced catalytic site groups His257 or His64 with 6-fluoro-tryptophan (6FW) as site-specific NMR probes. Conformational adjustments in the 6FW-His257-helical and His64-6FW-loop regions were characterized in PNP phosphate-bound enzyme and in complexes with catalytic site ligands, including transition state analogs. Chemical shift and line-shape changes associated with these complexes revealed dynamic coexistence of several conformational states in these regions in phosphate-bound enzyme and altered or single conformations in other complexes. These conformations were also characterized by X-ray crystallography. Specific (19)F-Trp labels and X-ray crystallography provide multidimensional characterization of conformational states for free, catalytic, and inhibited complexes of human PNP. PMID- 23438751 TI - Blood tolerant laccase by directed evolution. AB - High-redox potential laccases are powerful biocatalysts with a wide range of applications in biotechnology. We have converted a thermostable laccase from a white-rot fungus into a blood tolerant laccase. Adapting the fitness of this laccase to the specific composition of human blood (above neutral pH, high chloride concentration) required several generations of directed evolution in a surrogate complex blood medium. Our evolved laccase was tested in both human plasma and blood, displaying catalytic activity while retaining a high redox potential at the T1 copper site. Mutations introduced in the second coordination sphere of the T1 site shifted the pH activity profile and drastically reduced the inhibitory effect of chloride. This proof of concept that laccases can be adapted to function in extreme conditions opens an array of opportunities for implantable nanobiodevices, chemical syntheses, and detoxification. PMID- 23438752 TI - Deglycosylation as a mechanism of inducible antibiotic resistance revealed using a global relational tree for one-component regulators. AB - The ligands that interact with the vast majority of small-molecule binding transcription factors are unknown, a significant gap in our understanding of sensory perception by cells. TetR-family regulators (TFRs) are found in most prokaryotes and are involved in regulating virtually every aspect of prokaryotic life however only a few TFRs have been characterized. We report the application of phylogenomics to the identification of cognate ligands for TFRs. Using phylogenomics we identify a TFR, KijR, that responds to the antibiotic kijanimicin. We go on to show that KijR represses a gene, kijX, which confers resistance to kijanimicin. Finally we show that KijX inactivates kijanimicin by the hydrolytic removal of sugar residues. This is a demonstration of antibiotic resistance by deglycosylation. PMID- 23438753 TI - Recycling of informational units leads to selection of replicators in a prebiotic soup. AB - Prebiotic chemical reactions would have been greatly aided by a process whereby living materials could have been recycled under conditions of limiting resources. Recombination of RNA fragments is a viable means of recycling but has not been demonstrated. Using systems based on the Azoarcus group I intron ribozyme, computational Monte Carlo studies indicate that a moderate level of recycling activity, spontaneous or catalyzed, leads to the most robust selection scenarios. It is interesting that recycling leads to a threshold effect where a dominant species suddenly jumps to fixation. In conjunction, laboratory studies with the Azoarcus ribozyme corroborate these results, showing that mixtures of scrambled and/or deleteriously mutated molecules can recycle their component fragments to generate fully functional recombinase ribozymes. These studies highlight the importance of recombination and recycling jointly in the advent of living systems. PMID- 23438754 TI - Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist. AB - Plasminogen activator inhibitor-1 (PAI-1), a serpin, is the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and thus also an inhibitor of fibrinolysis and tissue remodeling. It is a potential therapeutic target in many pathological conditions, including thrombosis and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1. PMID- 23438755 TI - A chemical biology strategy to analyze rheostat-like protein kinase-dependent regulation. AB - Protein kinases may function more like variable rheostats rather than two-state switches. However, we lack approaches to properly analyze this aspect of kinase dependent regulation. To address this, we develop a strategy in which a kinase inhibitor is identified using genetics-based screens, kinase mutations that confer resistance are characterized, and dose-dependent responses of isogenic drug-sensitive and resistant cells to inhibitor treatments are compared. This approach has the advantage that function of wild-type kinase, rather than mutants, is examined. To develop this approach, we focus on Ark1, the fission yeast member of the conserved Aurora kinase family. Applying this approach reveals that proper chromosome compaction in fission yeast needs high Ark1 activity, while other processes depend on significantly lower activity levels. Our strategy is general and can be used to examine the functions of other molecular rheostats. PMID- 23438756 TI - Discovery of wall teichoic acid inhibitors as potential anti-MRSA beta-lactam combination agents. AB - Innovative strategies are needed to combat drug resistance associated with methicillin-resistant Staphylococcus aureus (MRSA). Here, we investigate the potential of wall teichoic acid (WTA) biosynthesis inhibitors as combination agents to restore beta-lactam efficacy against MRSA. Performing a whole-cell pathway-based screen, we identified a series of WTA inhibitors (WTAIs) targeting the WTA transporter protein, TarG. Whole-genome sequencing of WTAI-resistant isolates across two methicillin-resistant Staphylococci spp. revealed TarG as their common target, as well as a broad assortment of drug-resistant bypass mutants mapping to earlier steps of WTA biosynthesis. Extensive in vitro microbiological analysis and animal infection studies provide strong genetic and pharmacological evidence of the potential effectiveness of WTAIs as anti-MRSA beta-lactam combination agents. This work also highlights the emerging role of whole-genome sequencing in antibiotic mode-of-action and resistance studies. PMID- 23438757 TI - "Function-first" lead discovery: mode of action profiling of natural product libraries using image-based screening. AB - Cytological profiling is a high-content image-based screening technology that provides insight into the mode of action (MOA) for test compounds by directly measuring hundreds of phenotypic cellular features. We have extended this recently reported technology to the mechanistic characterization of unknown natural products libraries for the direct prediction of compound MOAs at the primary screening stage. By analyzing a training set of commercial compounds of known mechanism and comparing these profiles to those obtained from natural product library members, we have successfully annotated extracts based on MOA, dereplicated known compounds based on biological similarity to the training set, and identified and predicted the MOA of a unique family of iron siderophores. Coupled with traditional analytical techniques, cytological profiling provides an avenue for the creation of "function-first" approaches to natural products discovery. PMID- 23438758 TI - Immunotherapy: Oncolytic vaccinia virus shows promise in liver cancer. PMID- 23438759 TI - Surgery for NSCLC in the era of personalized medicine. AB - The discovery in 2004 of activating mutations in the EGFR gene opened the era of personalized medicine in thoracic oncology. Treatment with drugs that target EGFR typically results in dramatic tumour response compared with conventional chemotherapy in patients with non-small-cell lung cancer. Subsequently, newer driver oncogenes such as ALK, ROS1 and RET have been discovered. Nevertheless, surgery has become safer and less invasive in the past 10-15 years. In the era of personalized medicine, thoracic surgeons have to think about their evolving roles. In this article, we discuss four topics relevant to this issue. Firstly, the value of surgical specimens as opposed to biopsy specimens for further understanding tumour biology is discussed. Secondly, extended indication of surgery in the era of targeted therapy is considered. Thirdly, in clinical trials that examine neoadjuvant therapy in patients selected by appropriate biomarkers, the important role of surgeons is highlighted. Finally, the possibility of personalizing the surgical procedure itself according to lung cancer subtypes defined by biomarkers is reviewed. PMID- 23438760 TI - MiR-138 promotes the migration of cultured chicken embryonic hypothalamic cells by targeting reelin. AB - Neuronal network remodeling during critical periods of sensory development might be accompanied by alterations in hypothalamic cell populations. MicroRNAs play a central role in regulating neuronal function, including neural stem cell proliferation, and neuronal migration, maturation and integration into viable circuits by modulating different mRNA targets. Here we investigated the role of miR-138 in cell proliferation and migration in a neuron-enriched hypothalamic cell culture prepared from chicks on embryonic day 16. Ectopic expression of miR 138 enhanced hypothalamic cell migration, but did not affect cell proliferation. As a potential mechanism for miR-138's effect on cell migration, we investigated reelin (Reln) as a direct target of miR-138. Luciferase reporter assay and Ago2 immunoprecipitation experiments confirmed direct binding of miR-138 to the Reln 3'-untranslated region. Ectopic miR-138 abolished Reln levels in hypothalamic cells and enhanced their migration, similar to Reln-antisense DNA. Furthermore, inhibition of Reln expression by miR-138 led to decreased phosphorylation level of the key component of Reln-regulated signaling cascades, Disabled 1. These findings describe miR-138 as a novel regulator of hypothalamic cell migration, acting at least in part via inhibition of Reln expression and leading to the inactivation of Reln signals. PMID- 23438761 TI - Parental influences on 7-9 year olds' physical activity: a conceptual model. AB - OBJECTIVE: Models characterizing parental influence on child and adolescent physical activity (PA) over time are limited. Preschool and Adolescent Models (PM and AM) of PA are available leaving the need to focus on elementary-aged children. We tested current models (PM and AM) with a sample of 7-9 year-olds, and then developed a model appropriate to this specific target population. METHODS: Parent-child dyads completed questionnaires in 2010-2011. All models were assessed using path analysis and model fit indices. RESULTS: For adequate power, 90 families were needed, with 174 dyads participating. PM and AM exhibited poor fit when applied to the study population. A gender-specific model was developed and demonstrated acceptable fit. To develop an acceptable model for this population, constructs from both the PM (i.e. parental perception of child competency) and AM (i.e., child-reported self-efficacy) were used. For boys, self efficacy was a strong predictor of PA, which was influenced by various parental variables. For girls, parental PA demonstrated the greatest strength of association with child PA. CONCLUSION: This new model can be used to promote PA and guide future research/interventions. Future studies, particularly longitudinal designs, are needed to confirm the utility of this model as a bridge between currently available models. PMID- 23438762 TI - Cigarette smoking and alcohol drinking in a representative sample of English school pupils: cross-sectional and longitudinal associations. AB - OBJECTIVE: The aim of our study was to examine cross-sectional and longitudinal associations between cigarette smoking and alcohol drinking, in a representative sample of English pupils. METHOD: Data from 13,635 school pupils in the Longitudinal Study of Young People in England (LSYPE) on usage of cigarettes from 2004 (typical age 14) to 2006 (age 16) and alcohol from 2004 to 2007 (age 17), analyzed with latent growth curve models. RESULTS: The weighted percentage of pupils drinking alcohol increased from 26% at age 14 to 71% by age 17, smoking from 12% to 27% by age 16. Pupils with lower socio-economic status were more likely to smoke but less likely to drink alcohol regularly. Both behaviors were positively correlated at age 14, adjusted for several confounding factors. The rate of increase over time was also positively correlated. CONCLUSION: Cigarette smoking and alcohol drinking are already correlated by age 14, are socio economically patterned, and 'move together' during adolescence. Future studies and interventions should be targeted at a younger age range, to identify early smoking and potentially hazardous alcohol drinking patterns. PMID- 23438763 TI - Impact of pellet thickness on quantitative terahertz spectroscopy of solid samples in a polyethylene matrix. AB - Pellets composed of different weight-percent (wt-%) of lactose within a polyethylene (PE) matrix are used to examine how the physical thickness of solid samples impact analytical measurements performed over terahertz (THz) frequencies when using time-domain THz spectroscopy. Results indicate that the thickness of each pellet depends on the mass and physical properties of the individual components that comprise the pellet. Thickness of mixture pellets depends on the porosity of the individual pellet components. Porosity measurements presented here for PE and lactose give values of 25.6 +/- 0.3 and 14.5 +/- 0.1, respectively, which indicate that more air is trapped within the compressed PE matrix compared to that for lactose. This difference in porosity creates different pellet thicknesses for pellets of the same nominal mass but with different relative amounts of PE and lactose. For this binary matrix, the thickness of each pellet is found to be a linear combination of the compressed densities of the individual components. Analysis of the time-domain THz spectra reveals that thinner samples are confounded by a fringe pattern observed in the frequency-domain spectra. This fringe pattern is created by an etalon corresponding to the air/pellet interfaces for the sample in the optical path. Spectra collected from thicker pellets are confounded by a sloping baseline caused by scattering effects within the pellet matrix. The quantitative impact of pellet thickness is determined by comparing the mean standard error of calibration (MSEC) and mean standard error of prediction (MSEP) for a set of leave-three-out cross validation multivariate calibration models based on the partial least-squares (PLS) algorithm. Results indicate that PLS models are capable of analytical measurements with MSEC and MSEP values between 0.04 and 0.20 wt-%. Analysis of spectral variance captured within the corresponding spectral loadings for each model indicates that spectral variance is lowest for the 300 mg samples where the impact of scattering is minimal under conditions when the sample etalon is nonexistent. PMID- 23438764 TI - Development of three PCR assays for the differentiation between Echinococcus shiquicus, E. granulosus (G1 genotype), and E. multilocularis DNA in the co endemic region of Qinghai-Tibet plateau, China. AB - To investigate echinococcosis in co-endemic regions, three polymerase chain reaction (PCR) assays based on the amplification of a fragment within the NADH dehydrogenase subunit 1 (ND1) mitochondrial gene were optimized for the detection of Echinococcus shiquicus, Echinococcus granulosus G1, and Echinococcus multilocularis DNA derived from parasite tissue or canid fecal samples. Specificity using parasite tissue-derived DNA was found to be 100% except for E. shiquicus primers that faintly detected E. equinus DNA. Sensitivity of the three assays for DNA detection was between 2 and 10 pg. Ethanol precipitation of negative PCR fecal samples was used to eliminate false negatives and served to increase sensitivity as exemplified by an increase in detection from 0% to 89% of E. shiquicus coproDNA using necropsy-positive fox samples. PMID- 23438765 TI - Long-term field performance of biosand filters in the Artibonite Valley, Haiti. AB - A field study assessing the sustainability and efficacy of 55 biosand filters installed during 1999-2010 was conducted in the Artibonite Valley, Haiti during 2011. Twenty-nine filters were still in use. Duration of filter use ranged from < 1 to 12 years. Water quality, microbial analysis, and flow rate were evaluated for each functioning filter. Kaplan-Meier analysis of filter lifespans showed that filter use remained high (> 85%) up to seven years after installation. Several filters were still in use after 12 years, which is longer than documented in any previous study. Filtered water from 25 filters (86%) contained Escherichia coli concentrations of < 10 most probable number of coliforms/100 mL. Recontamination of stored filtered water was negligible. Bacterial removal efficiency was 1.1 log(10). Comparable results from previous studies in the same region and elsewhere show that biosand filter technology continues to be an effective and sustainable water treatment method in developing countries worldwide. PMID- 23438766 TI - Reduction of Aedes aegypti vector competence for dengue virus under large temperature fluctuations. AB - Diurnal temperature fluctuations can fundamentally alter mosquito biology and mosquito-virus interactions in ways that impact pathogen transmission. We investigated the effect of two daily fluctuating temperature profiles on Aedes aegypti vector competence for dengue virus (DENV) serotype-1. A large diurnal temperature range of 18.6 degrees C around a 26 degrees C mean, corresponding with the low DENV transmission season in northwestern Thailand, reduced midgut infection rates and tended to extend the virus extrinsic incubation period. Dissemination was first observed at day 7 under small fluctuations (7.6 degrees C; corresponding with high DENV transmission) and constant control temperature, but not until Day 11 for the large diurnal temperature range. Results indicate that female Ae. aegypti in northwest Thailand are less likely to transmit DENV during the low than high transmission season because of reduced DENV susceptibility and extended virus extrinsic incubation period. Better understanding of DENV transmission dynamics will come with improved knowledge of temperature effects on mosquito-virus interactions. PMID- 23438767 TI - Identification of a novel uncultured Rickettsia species strain (Rickettsia species strain Tselenti) in Cyprus. AB - In a previous study conducted in Cyprus, various spotted fever group Rickettsia species were detected and identified in ticks by molecular analysis. Among them, a partially characterized Rickettsia species was detected in Hyalomma anatolicum excavatum and Rhipicephalus turanicus ticks. We report characterization of this rickettsial strain by using polymerase chain reaction sequencing analysis of partial citrate synthase A, outer membrane protein A, outer membrane protein B, and 17-kD protein genes. We propose a provisional name Rickettsia sp. strain Tselenti for this strain until it is isolated and further characterized. PMID- 23438769 TI - Centrifugal continuous-flow left ventricular assist device in patients with hypertrophic cardiomyopathy: a case series. PMID- 23438768 TI - Insecticide resistance allele frequencies in Anopheles gambiae before and after anti-vector interventions in continental Equatorial Guinea. AB - Anti-malaria interventions that rely on insecticides can be compromised by insecticide-resistance alleles among malaria vectors. We examined frequency changes of resistance alleles at two loci, knockdown resistance (kdr) and acetylcholinesterase-1 (ace-1), which confer resistance to pyrethroids and DDT, and carbamates, respectively. A total of 7,059 Anopheles gambiae sensu stricto mosquitoes were analyzed from multiple sites across continental Equatorial Guinea. A subset of sites included samples collected pre-intervention (2007) and post-intervention (2009-2011). Both L1014S and L1014F resistance alleles were observed in almost all pre-intervention collections. In particular, L1014F was already at substantial frequencies in M form populations (17.6-74.6%), and at high frequencies (> 50%) in all but two S form populations. Comparison before and throughout anti-vector interventions showed drastic increases in L1014F, presumably caused by intensified selection pressure imposed by pyrethroids used in vector control efforts. In light of these findings, inclusion of other insecticide classes in any anti-vector intervention can be considered prudent. PMID- 23438770 TI - Newly designed CRRT membranes for sepsis and SIRS--a pragmatic approach for bedside intensivists summarizing the more recent advances: a systematic structured review. AB - In recent years, after all the attention has been focused on the dose for continuous renal replacement therapy (CRRT) in sepsis and systemic inflammation response syndrome (SIRS), the relatively negative results of all those studies did urge our expectations on new approaches regarding CRRT in sepsis and SIRS. So far, after the failure of the major randomized studies on dose, attention is now drawn to new membranes that could better eliminate massive amounts of unbound mediators in wider spectrum and also in greater magnitude Nevertheless, for septic acute kidney injury, the recommended dose will remain 35 ml/kg/h until the IVOIRE (hIgh VOlume in Intensive Care) study will be published. In this new armamentarium, we have distinguished the first tools that can still be called membranes ranging from AN69 Surface Treated (ST), SEPTEX, polymethylmetacrylate, to Oxiris that can still run with a CRRT device. Polymyxin B is still a kind of membrane although it has a larger surface, but it can run in a hemoperfusion system and is also much more selective. Adsorptive columns and sorbents are not anymore membranes but are seen as cartridges as the surface is extremely huge when compared with that of membranes (more than 500 m). They can still run in a hemoperfusion device. At the very end, we do have apheresis or selective plasma exchange (also very close to sorbents and columns) but we have very few data up to now regarding sepsis. Regarding spectrum, CytoSorb seems to be very promising although it is not able to capture endotoxin and IL-10. Oxiris is also promising as it can capture endotoxin and cytokines. AN69 ST is very powerful to capture numerous cytokines and especially high-mobility group box 1 protein (a very upstream cytokine). Polymethylmetacrylate has also the power to capture endotoxin and numerous other cytokines probably with a larger magnitude than Oxiris although this is not proven. Lastly, high-porosity membranes (Septex) may play a role especially when used in continuous venovenous hemodialysis mode. At the end, if we look for a more enlarged spectrum and a higher magnitude, CytoSorb might be seen as the most promising although not having the ability to fix endotoxin. Future studies will tell us which membrane or sorbent will be most useful in the adjunctive treatment for sepsis. PMID- 23438772 TI - Changes in the functional status measures of heart failure patients with mechanical assist devices. AB - Continuous-flow left ventricular assist devices (cfLVADs) have been proven safe and effective for bridge-to-transplant and destination therapy (DT) in patients with advanced heart failure. However, the fixed pump speed of these devices may lack response to activity and oxygen demand, thereby limiting exercise tolerance. The objective of this observational study was to describe exercise capacity as measured by peak oxygen consumption (peak VO2) that may be expected during support with a cfLVAD. Peak VO2 was measured in patients (mean age: 58.3 +/- 11.7 years; 66.7% ischemic and 33.3% DT) before cfLVAD support (11.2 +/- 3.0 ml/kg/min, n = 25), between 3 and 6 months (12.7 +/- 3.5 ml/kg/min, n = 31), at 1 year (10.7 +/- 2.6 ml/kg/min, n = 16), and longer than 1 year (11.2 +/- 1.7 ml/kg/min, n = 10). There was no statistical improvement in peak VO2 at any time point after implantation. In addition, ventilatory efficiency remained poor after LVAD implantation at all time points. Although studies have shown an increase in survival and patient's quality of life, exercise capacity as measured by cardiopulmonary exercise testing remains low during cfLVAD support. PMID- 23438771 TI - Verification of a computational cardiovascular system model comparing the hemodynamics of a continuous flow to a synchronous valveless pulsatile flow left ventricular assist device. AB - The purpose of this investigation is to use a computational model to compare a synchronized valveless pulsatile left ventricular assist device with continuous flow left ventricular assist devices at the same level of device flow, and to verify the model with in vivo porcine data. A dynamic system model of the human cardiovascular system was developed to simulate the support of a healthy or failing native heart from a continuous flow left ventricular assist device or a synchronous pulsatile valveless dual-piston positive displacement pump. These results were compared with measurements made during in vivo porcine experiments. Results from the simulation model and from the in vivo counterpart show that the pulsatile pump provides higher cardiac output, left ventricular unloading, cardiac pulsatility, and aortic valve flow as compared with the continuous flow model at the same level of support. The dynamic system model developed for this investigation can effectively simulate human cardiovascular support by a synchronous pulsatile or continuous flow ventricular assist device. PMID- 23438773 TI - Mechanistic pathway(s) of acquired von willebrand syndrome with a continuous-flow ventricular assist device: in vitro findings. AB - In patients with a ventricular assist device (VAD), diminished high-molecular weight von Willebrand factor (vWF) multimers may contribute to a bleeding diathesis. The mechanistic pathway(s) of vWF degradation and the role of ADAMTS 13, the vWF-cleaving metalloproteinase, are unknown. The objective of this study was to investigate the molecular mechanisms of VAD-induced vWF impairment in an in vitro system.Simple, mock circulatory loops (n = 4) were developed with a clinically approved, paracorporeal continuous-flow VAD. The loops were primed with anticoagulated, whole bovine blood (750 ml). The VAD was operated at constant blood flow and pressure. Blood samples were drawn at baseline and hourly for 6 hours. vWF multimers and ADAMTS-13 protein were quantified by agarose and polyacrylamide gel electrophoresis with immunoblotting. Plasma platelet factor 4 (PF4), a marker of platelet activation, was quantified via ELISA.Within 120 minutes, high-molecular-weight vWF multimers decreased, and low-molecular-weight multimers increased. Multiple low-molecular-weight vWF fragments emerged (~140, 176, 225, and 310 kDa). Total plasma ADAMTS-13 increased by 13 +/- 3% (p < 0.05). Plasma PF4 increased by 21 +/- 7% (p = 0.05).During VAD support, vWF degradation occurred quickly. Multiple mechanisms were responsible and included vWF cleavage by ADAMTS-13 (140 and 176 kDa fragments), and what may have been mechanical demolition of endogenous plasma vWF (225 kDa fragments) and nascent vWF (225 and 310 kDa fragments) from platelets. A modest increase in plasma ADAMTS-13 from activated platelets may have contributed to this process but was not the major mechanism. Mechanical demolition was likely the dominant process and warrants further evaluation. PMID- 23438774 TI - Ischemic versus nonischemic dilated cardiomyopathy: the implications of heart failure etiology on left ventricular assist device outcomes. AB - The effect of heart failure etiology on outcomes after left ventricular assist device (LVAD) implantation has not been fully investigated. The aim of this study was to compare postoperative survival, incidence of LVAD-related complications, left and right heart catheterizations, and echocardiographic findings in patients with ischemic cardiomyopathy (ICM) and nonischemic dilated cardiomyopathy (NIDCM) who underwent continuous-flow LVAD implantation. A total of 100 patients underwent implantation of a HeartMate II (Thoratec Corp., Pleasanton, CA) or HeartWare (HeartWare Inc., Framingham, MA) LVAD at our institution. Patients were stratified into two groups based on the etiology of heart failure, ICM and NIDCM. We identified 34 (34.0%) patients with ICM and 66 (66.0%) with NIDCM. Patients with ICM were significantly older (59.5 vs. 49.3; p < 0.001) and had higher rates of hypertension (91.2% vs. 84.8%; p = 0.021), chronic renal insufficiency (38.2% vs. 25.8%; p < 0.001), peripheral vascular disease (11.8% vs. 10.6%; p = 0.015), and previous cardiac surgery (58.8% vs. 13.6%; p < 0.001). Survival was similar for both groups with 30 day, 6 month, and 1 year survivals of 94.1%, 85.3%, and 82.4%, respectively, for ICM patients versus 95.5%, 92.4%, and 89.4%, respectively, for NIDCM patients (p = 0.743). Etiology of heart failure was not an independent predictor of survival in multivariate logistic regression analysis (p = 0.505). Post-LVAD complications and improvements in postoperative hemodynamic measurements were also similar for both groups. The etiology of heart failure did not appear to affect postoperative outcomes significantly. PMID- 23438775 TI - Electromagnetic interference of automatic implantable cardioverter defibrillator and HeartWare left ventricular assist device. AB - The use of continuous-flow left ventricular assist devices (LVAD) have markedly improved outcomes in patients with advanced heart failure (HF). The HeartWare LVAD is a miniaturized centrifugal pump implanted within the pericardial space. Implantable cardioverter-defibrillators (ICDs) are susceptible to oversensing of extracardiac signals (electromagnetic interference [EMI]). We report two cases of EMI in patients that received a HeartWare LVAD as destination therapy for advanced HF. The patients were 75 and 78 years old, both with severe ischemic dilated cardiomyopathy (ejection fraction < 0.20) and New York Heart Association class 4 heart failure. Both patients had a St. Jude Medical Unify ICD with a 7 Fr dual coil St. Jude Medical Durata ICD lead. In both patients, the lead location was in the right ventricular apex with an inferior orientation. Both patients experienced immediate ICD therapies after LVAD placement, requiring the tachytherapies to be disabled. ICD programming changes to increase sensitivity and the detection windows were ineffective. Both patients underwent ICD system revision. In one patient, the existing lead was moved to an anteroseptal location that stopped the EMI. In the other patient, the ICD system was changed to allow a separate right ventricular sensing lead in an anteroseptal location and a dual coil ICD lead placed in an apical location, a strategy used to obtain an acceptable defibrillation threshold. The patients have had no subsequent EMI detected on clinical and remote monitoring. Patients with a right ventricular apical ICD lead placement that undergo placement of a HeartWare LVAD are susceptible to EMI and inappropriate ICD therapies. These cases suggest the primary mechanism is proximity of the ICD lead to the device and as such relocation to an anteroseptal location can overcome the problem. These data suggest that all patients that receive a HeartWare LVAD with an ICD should have the device carefully checked at maximum LVAD output to determine if EMI may be present. ASAIO Journal 2013;59:136-139. Key Words: left ventricular assist device, electromagnetic interference, improper ICD shocks, end-stage heart failure. PMID- 23438776 TI - Vibration enhances clearance of solutes with varying molecular weights during in vitro hemodialysis. AB - This proof of concept pilot study was performed to determine whether vibration can increase solute clearance when applied to an in vitro dialysis model. Urea, creatinine, gentamicin, and vancomycin transmembrane clearances were calculated at a blood flow rate of 200 ml/min, dialysate flow rates of 2 and 8 L/hr, and no concurrent ultrafiltration at various vibration intensities. Dialyzer integrity was determined by measuring transmembrane pressure, filter drop pressure, and albumin clearance, and by visually inspecting the dialysate. Comparing the highest vibration modality with no vibration, the median percentage increase in urea, creatinine, gentamicin, and vancomycin clearance was 18% (all p < 0.005). The transmembrane clearance of albumin was negligible for all experiments. When measuring transmembrane pressure and filter drop pressure, no significant differences were found between nonvibration and vibration dialysis. The addition of vibration during dialysis increased transmembrane clearance for solutes with molecular weights of 60-1450 Daltons. PMID- 23438777 TI - Pediatric ECMO outcomes: comparison of centrifugal versus roller blood pumps using propensity score matching. AB - Centrifugal blood pumps are being increasingly utilized in children supported with extracorporeal membrane oxygenation (ECMO). Our aim was to determine if survival and ECMO-related morbidities in children supported with venoarterial (VA) ECMO differed by blood pump type.Children aged less than 18 years who underwent VA ECMO support from 2007 to 2009 and reported to the Extracorporeal Life Support Organization registry were propensity score matched (Greedy 1:1 matching) using pre-ECMO characteristics.A total of 2,656 (centrifugal = 2,231, roller = 425) patients were identified and 548 patients (274 per pump type) were included in the propensity score-matched cohort. Children supported with centrifugal pumps had increased odds of hemolysis (odds ratio [OR], 4.03 95% confidence interval [CI], 2.37-6.87), hyperbilirubinemia (OR, 5.48; 95% CI, 2.62 11.49), need for inotropic support during ECMO (OR, 1.54; 95% CI, 1.09-2.17), metabolic alkalosis (blood pH > 7.6) during ECMO (OR, 3.13; 95% CI, 1.49-6.54), and acute renal failure (OR, 1.61; 95% CI, 1.10-2.39). Survival to hospital discharge did not differ by pump type.In a propensity score-matched cohort of pediatric ECMO patients, children supported with centrifugal pumps had increased odds of ECMO-related complications. There was no difference in survival between groups. PMID- 23438778 TI - Development of a rabbit animal model for miniaturized heart-lung machines. AB - The utilization of a heart-lung machine (HLM) for the correction of congenital heart defects can lead to various complications, which can culminate in multiorgan failure and death. To reduce the considerable risk of complications, we developed a miniaturized, highly integrated HLM (MiniHLM) for use in infants and children. For the purpose of testing the MiniHLM, we developed a new rabbit animal model. In all, surgery was performed on 32 rabbits. In the first series, 13 New Zealand white rabbits were placed on cardiopulmonary bypass (CPB) for 1 hour with the use of an initial version of the MiniHLM. In the second series, we operated on 19 Chinchilla Bastard rabbits using the further developed MiniHLM 02 or the Dideco Kids D100 system. While several adjustments had to be made to the operating protocol in the first series in order to lower the mortality rate, 15 of the 19 rabbits were successfully weaned from the HLM in the second series. Blood tests pertaining to hemolysis and the expression of inflammation were performed. In addition, tissue samples were taken from the right atrial auricle for the purpose of investigating the expression of inflammatory parameters. The newly developed MiniHLM prototype was tested successfully in an animal model in terms of technical function, hemolysis, and the expression of inflammation. On account of the comparability of their blood values, as well as their anatomy, Chinchilla Bastard rabbits serve as excellent models for the testing of CPB and support systems for infants and children that do not require the administration of foreign blood. PMID- 23438779 TI - Avalon(c) bicaval dual-lumen cannula for venovenous extracorporeal membrane oxygenation: survey of cannula use in France. AB - We conducted an epidemiologic survey in France on the use of bicaval dual-lumen cannulas for extracorporeal membrane oxygenation (ECMO). Every service that used the Avalon cannula was contacted. Practitioners answered questions concerning its practical usage and complications that were attributable to its usage. We report data for 52 instances of cannula usage. The primary indication was acute respiratory distress syndrome (ARDS) in 77% of cases. Of all of the patients who required cannulas, 46% died. The maximum flow was 2,175 +/- 556 ml/minute for 20 Fr.-diameter cannulas, 3,207 +/- 653 ml/minute for 23 Fr., 3,963 +/- 729 ml/minute for 27 Fr., and 5,490 +/- 984 ml/minute for 31 Fr. Surgeons placed the cannulas in 52% of cases, intensivists placed the cannulas in 23% of cases, and multidisciplinary teams placed the cannulas in 25% of cases. The mean insertion time was 26 +/- 13 minutes, and insertion was performed under transesophageal electrocardiography (TEE) (67%), transthoracic echocardiography (TTE) (25%), fluoroscopy (4%), or no guidance (4%). The main complication was migration into the right ventricle. Problems with hemolysis were described in 21% of cases. No case of cannula thrombosis was found. No case of infection was reported. Bleeding was noted in 17% of cases. The mean time of use was 8 +/- 7 days. Modifications to the supportive care system were required in 15% of cases. Monitoring was performed by chest x-rays (90%), TTE (42%), and TEE (46%). Five extubations occurred during the support period. Nine patients were mobilized. The use of this cannula yielded satisfactory results. We suggest placing these cannulas using TTE or TEE and recommend the use of large-caliber cannulas in hypoxemic patients. PMID- 23438780 TI - Novel concept for pure diffusive capillary membrane oxygenators: silicone hollow sphere (SiHSp) fibers. AB - The preeminent limitation of silicone membrane oxygenators is the poor gas permeability compared with microporous hollow fiber oxygenators (MHFO). However, the imponderability of plasma leakage, foam formation, and brittleness are all hazards that result in blood trauma formation, hereby limiting the application of MHFO during long-term oxygenation therapies. Here, we introduce a novel type of pure diffusive capillary-form silicone membrane called silicone hollow sphere. Silicone hollow sphere walls embed hollow microspheres into the core. The lodging of such microspheres promotes a higher gas exchange performance (as a result of the reduction of dense material) without altering the total thickness of capillary walls; thereby the demanded mechanical strength for handling is nevertheless conserved. Out of the same silicone material, seven SiHSp fibers with six different design specifications and a control were constructed to define experimentally the appropriate configuration for subsequent production. Each fiber was used in a miniaturized module oxygenator of a constant effective membrane surface area (Amem = 0.02 m) and length (L =183 mm) for a fair evaluation. Modules were investigated in vitro with porcine blood. O2 and CO2 transfer rates weighed 12.6 mlO2/min and 10.4 mlCO2/min, respectively, for one type of SiHSp, comparable with microporous polypropylene (OXYPHAN) exhibiting 14.1 mlO2/min and 13.2 mlCO2/min, respectively, at a maximum blood flow rate (Qmax = 200 ml/min). Silicone hollow sphere fibers show a promising competency to MHFs. They also show an evident dominancy over the conventional silicone fibers, evaluated by the control module, which emphasizes the advantage of this design. PMID- 23438781 TI - Noninvasive analysis of synthetic and decellularized scaffolds for heart valve tissue engineering. AB - Microcomputed tomography (u-CT) is a nondestructive, high-resolution, three dimensional method of analyzing objects. The aim of this study was to evaluate the feasibility of using u-CT as a noninvasive method of evaluation for tissue engineering applications. The polyurethane aortic heart valve scaffold was produced using a spraying technique. Cryopreserved/thawed homograft and biological heart valve were decellularized using a detergent mixture. Human endothelial cells and fibroblasts were derived from saphenous vein segments and were verified by immunocytochemistry. Heart valves were initially seeded with fibroblasts followed by colonization with endothelial cells. Scaffolds were scanned by a u-CT scanner before and after decellularization as well as after cell seeding. Successful colonization was additionally determined by scanning electron microscopy (SEM) and immunohistochemistry (IHC). Microcomputed tomography accurately visualized the complex geometry of heart valves. Moreover, an increase in the total volume and wall thickness as well as a decrease in total surface was demonstrated after seeding. A confluent cell distribution on the heart valves after seeding was confirmed by SEM and IHC. We conclude that u-CT is a new promising noninvasive method for qualitative and quantitative analysis of tissue-engineering processes. PMID- 23438782 TI - Total artificial heart support with two continuous-flow ventricular assist devices in a patient with an infiltrating cardiac sarcoma. AB - Primary cardiac sarcoma is normally fatal, but cardiac replacement may provide some hope for long-term survival. A 38 year-old man with cardiac sarcoma, involving the interventricular septum and posterior wall with intermittent mitral obstruction, underwent implantation of two HeartMate II ventricular assist devices for total artificial heart support. After cardiectomy, the HeartMate sewing rings were sewn to the right neoatrium and the left atrial remnants. After the outflow grafts were sewn end to end to the pulmonary artery and aorta, the two drivelines were externalized through the abdominal wall, and perfusion started. The postoperative course was complicated by respiratory and renal dysfunction, which resolved. After 6 months of support, the patient has normal organ function and is ambulatory. Follow-up oncologic evaluation of positron emission tomography-computed tomography scan is negative. PMID- 23438783 TI - Spontaneous endogenous microbubbles in a child with Berlin heart ventricular assist device. AB - We report the case of an 11-year-old boy with familial dilated cardiomyopathy on biventricular assist devices (Berlin Heart EXCOR) who was found to have spontaneous endogenous microbubbles in the left ventricular (LV) cavity on routine echocardiogram. Although no major sequelae resulted from the presence of these microbubbles, it did however lead to several noninvasive investigations. To our knowledge, this is a novel observation of spontaneous endogenous microbubbles in a patient with a Berlin Heart. The unknown clinical significance of this phenomenon highlights the need for further studies. PMID- 23438784 TI - Centrifugal continuous-flow left ventricular assist device in patients with hypertrophic cardiomyopathy: a case series. AB - Left ventricular assist device (LVAD) therapy has been used primarily in patients with end-stage dilated cardiomyopathy (DCM), and patients with hypertrophic cardiomyopathy (HCM) are generally excluded. We compared outcomes in 3 HCM patients with 36 DCM patients. While HCM patients had smaller left ventricular end-diastolic dimensions, average pump flows for the two groups were similar. All patients had marked improvement in mean pulmonary arterial pressures and cardiac index at 5 months. This analysis shows that patients with end-stage heart failure resulting from HCM do benefit from centrifugal cfLVAD therapy in the short to medium term. PMID- 23438785 TI - Complex HeartMate II infection treated with pump exchange to HeartWare HVAD. AB - Left ventricular assist device (LVAD) infections continue to present a serious challenge in both the destination therapy and the bridge to transplant patient populations. As devices are supporting patients longer due to increased durability, infections can evolve and worsen over time. Complex infections, resistant to standard pharmacologic management, require a more aggressive approach to treatment. A series of patients supported by HeartMate II (HMII) LVADs, treated for multidrug resistant complex driveline infections, failed antibiotic therapy and then underwent device exchange. In each case, the HMII device was exchanged for a HeartWare HVAD as we felt its small size and flexible driveline were advantageous properties when dealing with patients with a complex driveline or pump infection. PMID- 23438786 TI - D-ribose ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice. AB - Cisplatin is one of the most potent chemotherapeutic anticancer drugs, but it can produce side effects such as nephrotoxicity. Inflammatory cytokines, chemokines and adhesion molecules have important roles in the pathogenesis of cisplatin induced nephrotoxicity. D-Ribose is a naturally occurring five-carbon monosaccharide that is found in all living cells, and has anti-inflammatory effects in renal ischemia/reperfusion injury. The purpose of this study was to determine the protective effects of D-ribose on cisplatin-induced nephrotoxicity. Forty-eight mice were randomly divided into four groups: control, cisplatin, cisplatin + ribose, and ribose. Mice were given cisplatin (20 mg/kg body weight, intraperitoneally) with or without D-ribose (400 mg/kg body weight, intraperitoneally, immediately after cisplatin injection). At 72 h after cisplatin injection, we measured serum and renal tumor necrosis factor (TNF) alpha and renal monocyte chemoattractant protein (MCP)-1 concentrations by enzyme linked immunosorbent assay; renal expression of intercellular adhesion molecule (ICAM)-1 mRNA by real-time polymerase chain reaction; serum blood urea nitrogen and creatinine; and histological changes. Cisplatin increased serum and renal TNF-alpha concentrations, renal MCP-1 concentration, and renal ICAM-1 mRNA expression. Treatment with D-ribose attenuated the increase in serum and renal TNF-alpha concentrations, renal MCP-1 concentration, and renal ICAM-1 mRNA expression. Consequently, cisplatin-induced renal dysfunction and renal tubular necrosis were attenuated by D-ribose treatment. This is believed to be the first time that protective effects of D-ribose on cisplatin-induced nephrotoxicity via inhibition of inflammatory reactions have been investigated. Thus, D-ribose may become a new therapeutic candidate for the treatment of cisplatin-induced nephrotoxicity. PMID- 23438787 TI - Anomalies and variant anatomy of the aorta and the supra-aortic vessels: additional challenges met by hybrid procedures. AB - INTRODUCTION: Endovascular or hybrid approach to the aortic arch aneurysms is nowadays an appealing solution for selected patients. Aim of this retrospective study is to evaluate the technical and clinical success recorded in complex anatomical settings of endografting. METHODS: Between December 2004 and December 2008, 73 patients were treated with a stent-graft for thoracic aorta aneurysms at our Vascular and Endovascular Surgery center, or in other Italian Centers by our Vascular Surgeon as Proctor. The aortic arch was involved in 31 cases. Four cases of bovine arch, three aberrant right subclavian artery and one case of isolated origin of all the supra-aortic trunks (6 vessels) were recorded. Technical success, procedural planning time and procedural time, stroke and paraplegia incidences were analyzed in terms of difference between "normal" or "complex" arches. RESULTS: Technical success was achieved in all cases. Complex anatomy of the arch and the supra-aortic trunks increased the technical difficulty of endovascular exclusion of the aneurysm and required more often complex debranching of the supra-aortic vessel necessary to obtain an adequate landing zone and to preserve the brain and spinal cord perfusion. We observed one stroke in complex arches procedures and two strokes (one of them fatal) in normal arch procedures. No cases of paraplegia were observed. CONCLUSIONS: In our experience complex anatomy of the arch did not represent a predictive factor in term of peri procedural major neurological adverse events. PMID- 23438788 TI - Antitussive effects of nasal thymol challenges in healthy volunteers. AB - Eighteen healthy volunteers with normal lung function were tested for cough. Before and after nasal administration of thymol (0.025 ml, 10(-3) M) into both nostrils, urge-to-cough, cough threshold, cumulative and total count of coughs per provocation were estimated during standardized and validated capsaicin cough challenge. Nasal thymol challenges induced pleasant olfactory sensation and in 6 out of the 18 subjects also mild cooling sensation. Cough threshold was not influenced when compared with intranasal saline and vehicle challenges (12.5 vs. 13.2 vs. 10.2 MUM of capsaicin to induce two or more coughs (C2), respectively), but the total count of coughs after nasal thymol challenge was significantly lower than that obtained after saline or vehicle (19 vs. 20 vs. 14 coughs/provocation, respectively; p<0.05). Importantly, subjects did not report the urge to cough, which appeared to correspond to C2. We conclude that the modulation of cough by thymol is mostly of olfactory origin. PMID- 23438789 TI - Physical development in children and adolescents with bronchial asthma. AB - Bronchial asthma is the most common chronic disease in children of developmental age. Data from the auxological literature indicate that children with disturbances in growth may also suffer from atopic disorders. The aim of the present study was to evaluate somatic growth in children with bronchial asthma using anthropological methods. The study was carried out using anthropometric measurements and information on the severity and course of the disease on 261 children with bronchial asthma. Mean body height was lower than in healthy peers and about 5% of subjects were short. Mean BMI and skinfold thicknesses were significantly higher and lean body mass was lower in the study group. Seventeen percent of the children were overweight or obese, and 8% were underweight. Body build was more robust in the girls examined. Longitudinal studies will help determine to what degree the disease itself directly affects physical development, and to what degree treatment does. PMID- 23438790 TI - Neonatal toxicity following maternal citalopram treatment. AB - Late gestational exposure to citalopram, may be associated with a neonatal toxicity syndrome with immediate onset at birth or soon after birth and sometimes may be mistaken for neonatal withdrawal syndrome. A 3860 g infant was delivered at 40 weeks gestation. The mother had been taking citalopram 20 mg/day until the day of delivery. Fifteen minutes after birth, the baby became hypertonic. Neonatal serotonin toxicity due to citalopram seems the most likely mechanism, though an important differential diagnosis is a citalopram withdrawal syndrome. We suggest the hypothesis that neonatal withdrawal syndrome may follow citalopram serotonin toxicity. PMID- 23438791 TI - The immune environment of paediatric solid malignancies: evidence from an immunohistochemical study of clinical cases. AB - Childhood malignancies are relatively poorly studied in terms of tumour/host interaction. Using tissue arrays of childhood cancers, we analysed immunohistochemical staining for CD68, CD3 and FOXP3 to evaluate infiltration of myeloid cells, lymphocytes and regulatory T cells. Staining for phosphorylated STAT3 was performed in a subset. The majority of paediatric tumours demonstrated a marked infiltration of CD68+ myeloid cells but, with the exception of neuroblastoma, most showed only sparse infiltration of CD3+/ FOXP3- cells. There was evidence for activation of STAT3 in pPNET (50%), ependymoma (45%) and undifferentiated sarcoma (38%), but it was rarely activated in other tumours. PMID- 23438792 TI - Bronchogenic/foregut cyst of the ileal mesentery in a child mimicking ovarian mass. AB - Intraabdominal bronchogenic cysts, a type of foregut cyst, are very rare. We report a case in a 12-year-old female who presented with severe abdominal pain and, in radiology workup, a cystic lesion that mimicked ovarian mass. PMID- 23438793 TI - The diagnostic value of p27 in comparison to p57 in differentiation between different gestational trophoblastic diseases. AB - The histologic features that permit the identification of complete mole (CM) and partial mole (PM) as well as hydropic abortion (HA) may be overlapping. The cyclin-dependent kinase inhibitor p57Kip2 protein (p57) has been included among the paternally imprinted genes in humans that commonly used for diagnosis of CM. P27 is one of the cell-cycle controlling molecules that may be involved in the proliferation, differentiation and oncogenesis of trophoblastic cells. The current study tried to test the diagnostic validity of several histopathological parameters together with p57 and p27 immunostaining in differentiation between different gestational trophoblastic diseases. The current study was carried out on 13 cases product of conception, 13 cases PM, 25 cases CM and 8 cases choriocarcinoma. Maximal villous diameter at 1.5 mm cut-off point was found to be the most reliable factor in discrimination between PM and product of conception followed by presence of villous cistern, p57 expression by extravillous cytotrophoblasts at 1.5% cut-off point and p27 expression by villous cytotrophoblasts at 25% cut-off point. P27 expression by stromal cells and total trophoblastic population at 7.5% cut-off point could discriminate between PM and CM. P57 and p27 are co-parallely expressed in non-molar as well as partial molar gestations, but they did not show this coordination in choriocarcinoma. This study demonstrated diagnostic values for several cut-off points for p57 and p27 in discrimination between different categories of gestational trophoblastic diseases. The co-expression of p27 and p57 by extravillous cytotrophoblasts and their positive correlation in non-molar gestations may indicate its suppressive role on the proliferation of these cells to provide them the capacity for differentiation and invasion. PMID- 23438794 TI - Terminal deletion 2q37.3 in a patient with Klippel-Trenaunay-Weber syndrome. AB - Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital disorder, characterized by capillary, venous and lymphatic vascular malformations in association with bone and soft tissue hypertrophy. We report a KTWS patient with extensive hemangiomatosis of the right lower limb, trunk and upper limbs; bone and soft tissue hypertrophy of upper limbs, scapular girdle and right lower limb; and muscle atrophy on left lower limb with marked body asymmetry, scoliosis and toe malformations. These pathological features are associated with moderate mental retardation, mild renal and hepatic abnormalities. We identified by array CGH (Comparative Genomic Hybridization) a submicroscopic deletion 2q37.3 that could be related to impaired cognitive function. To our knowledge this is the first reported 2q37.3 microdeletion in a patient with KTWS. PMID- 23438795 TI - Gender and associated skeletal abnormalities in fetuses with neural tube defects. AB - OBJECTIVE: To determine the association between gender and skeletal defects in fetuses with NTDs. METHODS: 150 NTD fetuses have been examined in three years' course (01.2006-01.2009) in the Clinic of Fetopathology at the Center for Maternity and Neonatology, Tunis. RESULTS: The most common gender associated anomalies for males are cleft palate, anomalies in the form and attachment of the outer ear and the agenesis of corpus callosum. For women, they are distortions of the spine and "frog" face. CONCLUSION: The proven associations in the study are important indicators in the purposeful search for NTDs in early prenatal ultrasound diagnosis. PMID- 23438796 TI - U(VI) bioreduction with emulsified vegetable oil as the electron donor--model application to a field test. AB - We amended a shallow fast-flowing uranium (U) contaminated aquifer with emulsified vegetable oil (EVO) and subsequently monitored the biogeochemical responses for over a year. Using a biogeochemical model developed in a companion article (Tang et al., Environ. Sci. Technol.2013, doi: 10.1021/es304641b) based on microcosm tests, we simulated geochemical and microbial dynamics in the field test during and after the 2-h EVO injection. When the lab-determined parameters were applied in the field-scale simulation, the estimated rate coefficient for EVO hydrolysis in the field was about 1 order of magnitude greater than that in the microcosms. Model results suggested that precipitation of long-chain fatty acids, produced from EVO hydrolysis, with Ca in the aquifer created a secondary long-term electron donor source. The model predicted substantial accumulation of denitrifying and sulfate-reducing bacteria, and U(IV) precipitates. The accumulation was greatest near the injection wells and along the lateral boundaries of the treatment zone where electron donors mixed with electron acceptors in the groundwater. While electron acceptors such as sulfate were generally considered to compete with U(VI) for electrons, this work highlighted their role in providing electron acceptors for microorganisms to degrade complex substrates thereby enhancing U(VI) reduction and immobilization. PMID- 23438797 TI - Respiratory rate as a predictor of weaning failure from mechanical ventilation. AB - BACKGROUND AND OBJECTIVE: There is not an ideal predictor of weaning from mechanical ventilation (MV). In a large meta-analysis, despite methodological limitations, respiratory rate (RR) was considered a promising predictor. The aim of this study was to evaluate RR as a predictor of weaning failure from MV. METHODS: We prospectively evaluated 166 patients scheduled for weaning from MV. RR and other essential criteria for weaning were evaluated at an early stage of screening. Patients who met the essential screening criteria for weaning underwent spontaneous breathing trial. RR was compared with the following outcomes: weaning success/failure or extubation failure. RESULTS: Weaning success was present in 76.5% and weaning failure in 17.5% of patients. There were 6% of reintubations. The predictive power for RR weaning failure, RR best cut-off point > 24 breaths per minute (rpm), was: sensitivity 100%, specificity 85%, and accuracy 88% (ROC curve, p<0.0001). Of the patients with weaning failure, 100% were identified by RR during screening (RR cut-off > 24 rpm). There were 15% false positives, weaning successes with RR > 24 rpm. CONCLUSION: RR was an effective predictor of weaning failure. The best cut-off point was RR > 24 rpm, which differed from those reported in the literature (35 and 38 rpm). Only 6% of patients were reintubated, but RR or other weaning criteria did not identify them. PMID- 23438798 TI - Malignant hyperthermia in Brazil: analysis of hotline activity in 2009. AB - BACKGROUND AND OBJECTIVES: Malignant hyperthermia (MH) is a pharmacogenetic disease that causes abnormal hypermetabolic reaction to halogenated anesthetics and/or depolarizing muscle relaxants. In Brazil, there is a hotline telephone service for MH since 1991, available 24 hours a day in Sao Paulo. This article analyzes the activity of the Brazilian hotline service for MH in 2009. METHODS: Prospective analysis of all phone calls made to the Brazilian hotline service for MH from January to December 2009. RESULTS: Twenty-two phone calls were received: 21 from the South/Southeast region of Brazil and one from the North region. Fifteen calls were requests for general information about MH. Seven were about suspected MH acute episodes, two of which were not considered as MH. In five episodes compatible with MH, all patients received halogenated volatile anesthetics (2, isoflurane; 3, sevoflurane) and one also used succinylcholine; there were four men and one woman, with a mean age of 18 years (2-27). The problems described in the five MH episodes were tachycardia (5), increased expired carbon dioxide (4), hyperthermia (3), acidemia (1), rhabdomyolysis (1), and myoglobinuria (1). One patient received dantrolene. All five patients with MH episodes were follow-up in the intensive care unit and recovered without sequelae. Susceptibility to MH was later confirmed in two patients by in vitro muscle contracture test. CONCLUSIONS: The number of calls per year in the Brazilian hotline service for MH is still low. The characteristics of MH episode were similar to those reported in other countries. The knowledge of MH in Brazil needs to be increased. PMID- 23438799 TI - Volume replacement therapy during hip arthroplasty using hydroxyethyl starch (130/0.4) compared to lactated Ringer decreases allogeneic blood transfusion and postoperative infection. AB - BACKGROUND AND OBJECTIVES: Hydroxyethyl starch (HES) 130/0.4 is considered an effective plasma expander when compared to crystalloids. There is controversy around its superiority regarding hemodynamic optimization and about possible detrimental effects on coagulation. The aim of this study was to compare the effects of HES 130/0.4 to lactated Ringer solution during hip arthroplasty in adult patients under spinal anesthesia regarding intraoperative bleeding, hemodynamic parameters, coagulation profile, transfusion requirements and clinical outcomes. METHODS: In this randomized, controlled trial, 48 patients scheduled for hip arthroplasty with spinal anesthesia were randomized into two groups: 24 patients were allocated to receive a preload of 15 mL.kg(-1) of HES 130/0.4 and 24 patients received a preload of 30 mL.kg(-1) lactated Ringer solution before surgery. Hemodynamic measurements, hemoglobin concentrations, biochemical parameters and coagulation tests were evaluated in three periods during surgical procedure. Patients received medical follow-up during their hospital stay and up to postoperative 30 days. Primary outcome was the requirement of red blood cell transfusion between groups during hospital stay. Secondary outcome were hemodynamic parameters, length of hospital stay, mortality and occurrence of clinical postoperative complications. RESULTS: Red blood cell transfusion was required in 17% of patients in the HES group and in 46% in the Ringer group (p = .029). Postoperative infections were more frequently observed in the Ringer group (17%) compared to the HES group (0), p = .037. There were no significant differences between groups in mortality, hospital length of stay and clinical complications other than infection. CONCLUSIONS: During hip arthroplasty, patients treated with hypervolemic hemodilution with hydroxyethyl starch 130/0.4 required less transfusion and presented lower infection rate compared to patients who received lactated Ringer. PMID- 23438800 TI - Selective suprascapular and axillary nerve block provides adequate analgesia and minimal motor block. Comparison with interscalene block. AB - BACKGROUND AND OBJECTIVE: Shoulder arthroscopic surgeries evolve with intense postoperative pain. Several analgesic techniques have been advocated. The aim of this study was to compare suprascapular and axillary nerve blocks in shoulder arthroscopy using the interscalene approach to brachial plexus blockade. METHODS: According to the technique used, sixty-eight patients were allocated into two groups: interscalene group (IG, n=34) and selective group (SG, n=34), with neurostimulation approach used for both techniques. After appropriate motor response, IG received 30 mL of 0.33% levobupivacaine in 50% enantiomeric excess with adrenalin 1:200,000. After motor response of suprascapular and axillary nerves, SG received 15 mL of the same substance on each nerve. General anesthesia was then administered. Variables assessed were time to perform the blocks, analgesia, opioid consumption, motor block, cardiovascular stability, patient satisfaction and acceptability. RESULTS: Time for interscalene blockade was significantly shorter than for selective blockade. Analgesia was significantly higher in the immediate postoperative period in IG and in the late postoperative period in SG. Morphine consumption was significantly higher in the first hour in SG. Motor block was significantly lower in SG. There was no difference between groups regarding cardiocirculatory stability and patient satisfaction and acceptability. Failure occurred in IG (1) and SG (2). CONCLUSIONS: Both techniques are safe, effective, and with the same degree of satisfaction and acceptability. The selective blockade of both nerves showed satisfactory analgesia, with the advantage of providing motor block restricted to the shoulder. PMID- 23438801 TI - Pharmacodynamic evaluation and physical/chemical analysis of two formulations of propofol used in target-controlled infusion. AB - BACKGROUND AND OBJECTIVES: There are several formulations of propofol available to the anesthesiologist for clinical use. The aim of this study was to analyze the physicochemical properties, pharmacodynamic effect, and pharmaceutical and clinical equivalence of the reference drug propofol as well as a similar formulation. METHOD: Sixteen volunteers were enrolled in this randomized, double blind, and paired study of Diprivan and Propovan formulations. Formulations were given as target-controlled infusion with target concentration of 3.0 MUg.mL(-1) for 15 minutes. Variables studied were the area under the curve (AUC) of the bispectral index (BIS) graph regarding time, minimum BIS reached and time to reach it, and recovery time. The two formulations were sent to analysis of particle size of lipid emulsion, surface potential, and active principle quantification. RESULTS: There was no difference between the formulations when comparing AUC, minimum BIS reached and time to reach it. The similar formulation recovery time was lower compared to the reference formulation (eight and 10 min, respectively, p=0.014). Mean particle size of lipid emulsion, surface potential, and active ingredient quantification were similar for both formulations. CONCLUSION: There was no clinically significant difference between the use of propofol, reference Diprivan, and the similar Propovan during infusion. However, the recovery time was longer with the reference drug. Although analysis of both formulations studied show similar results regarding its physicochemical characterization, further studies should be conducted to justify this difference. PMID- 23438802 TI - Three-year evaluation of nosocomial infection rates of the ICU. AB - BACKGROUND AND OBJECTIVES: Evaluating the incidence of nosocomial and invasive device-related infections enables the comparison of the health care associated infection (HAI) between the intensive care units of different hospitals and different units in the same hospital. MATERIAL AND METHODS: A retrospective surveillance study was performed to identify nosocomial infections, device related infections rates, and causal agents from January 2007 through December 2010 in the Anesthesiology Intensive care unit (ICU). HAI were defined according to the CDC (Centers for Disease Control and Prevention) criteria, and invasive device-related infections were defined according to National Nosocomial Infection Surveillance System (NNIS) criteria. RESULTS: During a two-year period, 939 patients were analyzed throughout a total of 7,892 patient-days. The rates of HAI were 53% in 2007, 29.15% in 2008, 28.85% in 2009 while 16.62% in 2010. Most common HAI was blood stream infection. The rate of soft tissue and skin infection was the second most common. Overall, the most common agents were Gram(-) 56.68%, Gram(+) 31.02% and Candida spp 12.3% among patients with nosocomial infections. CONCLUSIONS: The incidence of HAI in the ICU of our hospital was high, compared to the Turkish overall rates obtained at the Refik Saydam Center in 2007. When the rates of device-related infections between 2007 and 2008 were compared, they were higher in 2007. The rates of device-related infections were diminished in 2008 to below-national mean rates by infection control measures. Since the rate of urinary catheter-related infections are still high, we should exert continuous efforts for infection control. PMID- 23438803 TI - Ropivacaine, articaine or combination of ropivacaine and articaine for epidural anesthesia in cesarean section: a randomized, prospective, double-blinded study. AB - BACKGROUND AND OBJECTIVES: Initiation of epidural anesthesia with long-lasting local anesthetics consumes a significant amount of time, which could be problematic in busy obstetric anesthesia suites. We have hypothesized that a combination of articaine and ropivacaine provides faster onset and even an early recovery of sensory-motor block characteristics. METHODS: Sixty term parturients scheduled to have elective cesarean section were randomly allocated into three groups to receive either 20 mL 2% articaine (Group A), 10 mL 2% articaine + 10 mL 0.75% ropivacaine (Group AR) or 20 mL 0.75% ropivacaine (Group R) via lumbar epidural catheter. The onset time of sensory block to T10, T6 and maximum sensory block level, time to two segments regression from maximum sensory block level, onset time and duration of motor block were all recorded. Intraoperative and postoperative additional analgesic requirements were also recorded. RESULTS: Demographic data were similar. The onset times of sensorial block to T10 and T6 were significantly shorter in Groups A and AR in comparison with Group R (p<0.05). The onset times of motor block were similar in all groups, but a more intense motor block was observed in Group R (p<0.05). Two segments regression time and motor block durations were significantly shorter in Groups A and AR in comparison with Group R (p<0.05). Intraoperative supplementary analgesic requirements were higher in Group A than in the other two groups (p<0.05). CONCLUSION: A combination of 2% articaine and 0.75% ropivacaine for epidural anesthesia in a cesarean section should be preferred over epidural 0.75% ropivacaine alone. PMID- 23438804 TI - Hemostatic resuscitation in traumatic hemorrhagic shock: case report. AB - BACKGROUND AND OBJECTIVES: The aim of this paper is to report a case in which the damage control resuscitation (DCR) approach was successfully used to promote hemostatic resuscitation in a polytraumatized patient with severe hemorrhagic shock. CASE REPORT: Female patient, 32 years of age, with severe hemorrhagic shock due to polytrauma with hip fracture, who developed acidosis, coagulopathy, and hypothermia. During fluid resuscitation, the patient received blood products transfusion of fresh frozen plasma/packed red blood cells/platelet concentrate at a ratio of 1:1:1 and evolved intraoperatively with improvement in perfusion parameters without requiring vasoactive drugs. At the end of the operation, the patient was taken to the intensive care unit and discharged on the seventh postoperative day. CONCLUSION: The ideal management of traumatic hemorrhagic shock is not yet established, but the rapid control of bleeding and perfusion recovery and well-defined therapeutic protocols are fundamental to prevent progression of coagulopathy and refractory shock. PMID- 23438805 TI - Bronchial injury and pneumothorax after reintubation using an airway exchange catheter. AB - BACKGROUND AND OBJECTIVES: We report a case of pneumothorax caused by a bronchial perforation during a reintubation using an airway exchange catheter (AEC) in a patient with a head and neck cancer. CASE REPORT: A 53 year old man with oropharynx carcinoma was admitted to ICU for severe pneumonia and severe acute respiratory distress syndrome (ARDS). The patient was recognized as a difficult to-intubate patient and an endotracheal tube (ETT) was inserted through a bronchoscope. After one week of treatment, it was observed an endotracheal cuff perforation. Exchanging the endotracheal tube was necessary to achieve satisfactory pulmonary ventilation. An AEC Cook 14 was used to perform the reintubation. After reintubation, the patient presented a worsening in oxygen saturation and a chest radiography (CXR) revealed a large pneumothorax. A chest tube was inserted and we observed immediate improvement in oxygen saturation. A repeat CXR confirmed correct positioning of the chest tube and reexpansion of the right lung. A bronchoscopy performed showed a posterior laceration in the right main bronchus. The patient was extubated the following day. After four days, the chest tube was removed. A CXR performed a day after chest tube removal revealed a small right upper pneumothorax, but the patient remained asymptomatic. CONCLUSIONS: Airway exchange catheter is a valuable tool to handle with difficult to-intubate patients. Although the physicians generally focus their attention in avoid barotrauma - caused by oxygen supplement or jet ventilation through AEC - concern for insertion technique can minimize life threatening complications and increase the safety of AEC. PMID- 23438806 TI - Use of sugammadex in Strumpell-Lorrain disease: a report of two cases. AB - CONTENT: Strumpell-Lorrain disease - or familial spastic paraplegia (FSP) - is a rare hereditary neurological disorder, mainly characterized by variable degrees of stiffness and weakening of the muscles, with cognitive impairment, deafness, and ataxia in the more severe cases. We describe two female siblings with FSP programmed for cholecystectomy and subtotal colectomy, respectively, and also how we dealt with the anesthetic management in both cases and review the literature on this disease in relation to anesthesia. PMID- 23438807 TI - Anesthetics, cerebral protection and preconditioning. AB - BACKGROUND AND OBJECTIVES: Several studies demonstrate that cerebral preconditioning is a protective mechanism against a stressful situation. Preconditioning determinants are described, as well as the neuroprotection provided by anesthetic and non-anesthetics agents. CONTENT: Review based on the main articles addressing the pathophysiology of ischemia-reperfusion and neuronal injury and pharmacological and non-pharmacological factors (inflammation, glycemia, and temperature) related to the change in response to ischemia reperfusion, in addition to neuroprotection induced by anesthetic use. CONCLUSIONS: The brain has the ability to protect itself against ischemia when stimulated. The elucidation of this mechanism enables the application of preconditioning inducing substances (some anesthetics), other drugs, and non pharmacological measures, such as hypothermia, aimed at inducing tolerance to ischemic lesions. PMID- 23438808 TI - Neurotoxic effects of intrathecal magnesium sulphate. AB - BACKGROUND AND OBJECTIVES: To assess the potential neurotoxic effects at the ultrastructural level of magnesium sulfate administered intrathecally as a single or multi-dose. METHODS: Our study was conducted with 24 Sprague-Dawley rats that weighed 250-300 g. After a 4-hour fast, the rats were given 10 mg.kg(-1) xylazine chloride intraperitoneal and then randomly allocated into three groups. Group I (n=8) received 0.9% normal saline, Group II (n = 8) was given one intrathecal injection of 0.02 mL of 15% magnesium sulphate, and Group III (n = 8) was given 0.02 mL of 15% magnesium sulphate once a day for seven days. The injections were given within 0.40 * 50 mm from the lumbar area. After seven days, the animals were sacrificed under anesthesia with an aortic injection of 10% formaldehyde and their tissues were fixed. The medulla spinalis was then examined and histopathologically evaluated under an electron microscope. The Kruskal-Wallis test was used for statistical evaluation. A value of p < .05 was considered to be statistically significant. RESULTS: Significant neurodegeneration was detected in rats given single or repeated magnesium sulphate injections compared to the control group. The histopathological evaluation score of this group was also high. CONCLUSIONS: Based on electron microscopic examination, we found that intrathecal magnesium sulphate administration induced neurodegeneration. PMID- 23438809 TI - Pain management in burn patients. AB - BACKGROUND AND OBJECTIVES: Despite advances, inappropriate analgesic treatment for burn patients is still seen. The objective of this review was to collect data on pain management in burn patients. CONTENT: We reviewed the mechanisms of pain, burn patient assessment, as well as pharmacological and non-pharmacological treatment. CONCLUSION: Pain management in burn patients is still a challenge for the multidisciplinary team. Frequent and continuous evaluation of the patient's response is very important due to the various stages that the hospitalized burn patient goes through, as well as a combination therapy with analgesic and non pharmacological measures. Understanding the complexity of the pathophysiological, psychological, and biochemical changes a burn patient presents is the first step to achieve success in analgesic management. PMID- 23438810 TI - Anesthetic management of a patient with Brugada syndrome - the use of sugammadex in major abdominal surgery. PMID- 23438811 TI - Precipitation in Gallipoli: sugammadex / amiodarone & sugammadex / dobutamine & sugammadex / protamine. PMID- 23438813 TI - Spatial information dynamics during early zebrafish development. AB - During development inherited information directs growth and specifies the complex spatial organization of cells and molecules. Here we show that a new information metric, the k-space information (kSI), captures the growth and emergence of spatial organization in a developing embryo. Using zebrafish as a model, we quantify the rate of development over the first 24h and demonstrate that important developmental landmarks are associated with well-defined transitions in information dynamics. The rate of development during this time is highest immediately before and after gastrulation, as well early in the segmentation period. We also find that the majority of the information arises from spatial correlations on the length scale of 20-80 MUm, but there are contributions from many length scales that change over time. A comparison of the information dynamics in the maternal-zygotic one-eyed pinhead mutant, which is defective in mesoderm induction, with the wild-type embryo shows that the information dynamics diverge near the onset of gastrulation. Subsequently the mutant lacks a peak in the information dynamics that appears to be associated with the formation of trunk somites in the wild-type embryo. These findings provide a common and objective basis by which to quantify spatial organization, compare mutants and quantify developmental dynamics. The kSI can also be applied to any form of developmental data of arbitrary dimensions, and it offers a broad conceptual framework with which to organize the large amounts of data emerging from various sources. PMID- 23438812 TI - Time course of Keap1-Nrf2 pathway expression after experimental intracerebral haemorrhage: correlation with brain oedema and neurological deficit. AB - Oxidative stress (OS) is involved in the progression of intracerebral haemorrhage (ICH)-induced secondary brain injury. The pathway involving Kelch-like ECH associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is currently recognised as the major endogenous regulatory system against oxidative injury. Although its beneficial role has been described for ICH, the time course of Keap1-Nrf2 pathway expression, the activity of downstream antioxidative enzymes, and the association with brain oedema and neurological deficits have not been fully investigated. In this study, we investigated the temporal changes in expression of Keap1, Nrf2, and their downstream antioxidative proteins in the ICH rat brain. We additionally quantified the relationship between these gene and protein changes with brain water content and neurological behaviour scores. After blood infusion, Keap1 showed decreased expression starting at 8 h, whereas Nrf2 began to show a significant increase at 2 h with a peak at 24 h. Keap1 and Nrf2 are chiefly expressed in neuronal cells but not in glial cells. The downstream antioxidative enzymes such as haemeoxygenase-1 (HO 1), glutathione (GSH), thioredoxin (TRX), and glutathione-S-transferase (GST alpha1) increased to different degrees during the early stages of ICH. Among these enzymes, HO-1 showed a significant time-dependent increase starting 8 h after ICH. In addition, there was a positive correlation between the HO-1 level and brain water content. In combination, these results suggest that activation of the Keap1-Nrf2 pathway may play an important endogenous neuroprotective role during OS after ICH. Because HO-1 expression is temporally associated with brain oedema - reflective of the severity of brain injury - it may be used as a biomarker of haeme-mediated oxidative damage after ICH. PMID- 23438814 TI - Pitx genes are redeployed in adult myogenesis where they can act to promote myogenic differentiation in muscle satellite cells. AB - Skeletal muscle retains a resident stem cell population called satellite cells. Although mitotically quiescent in mature muscle, satellite cells can be activated to produce myoblast progeny to generate myonuclei for skeletal muscle homoeostasis, hypertrophy and repair. Regulation of satellite cell function in adult requires redeployment of many of the regulatory networks fundamental to developmental myogenesis. Involved in such control of muscle stem cell fate in embryos are members of the Pitx gene family of bicoid-class homeodomain proteins. Here, we investigated the expression and function of all three Pitx genes in muscle satellite cells of adult mice. Endogenous Pitx1 was undetectable, whilst Pitx2a, Pitx2b and Pitx2c were at low levels in proliferating satellite cells, but increased during the early stages of myogenic differentiation. By contrast, proliferating satellite cells expressed robust amounts of Pitx3, with levels then decreasing as cells differentiated, although Pitx3 remained expressed in unfused myoblasts. To examine the role of Pitx genes in satellite cell function, retroviral-mediated expression of Pitx1, all Pitx2 isoforms or Pitx3, was used. Constitutive expression of any Pitx isoform suppressed satellite cell proliferation, with the cells undergoing enhanced myogenic differentiation. Conversely, myogenic differentiation into multinucleated myotubes was decreased when Pitx2 or Pitx3 levels were reduced using siRNA. Together, our results show that Pitx genes play a role in regulating satellite cell function during myogenesis in adult. PMID- 23438815 TI - Canonical terminal patterning is an evolutionary novelty. AB - Patterning of the terminal regions of the Drosophila embryo is achieved by an exquisitely regulated signal that passes between the follicle cells of the ovary, and the developing embryo. This pathway, however, is missing or modified in other insects. Here we trace the evolution of this pathway by examining the origins and expression of its components. The three core components of this pathway: trunk, torso and torso-like have different evolutionary histories and have been assembled step-wise to form the canonical terminal patterning pathway of Drosophila and Tribolium. Trunk, torso and a gene unrelated to terminal patterning, prothoraciotrophic hormone (PTTH), show an intimately linked evolutionary history, with every holometabolous insect, except the honeybee, possessing both PTTH and torso genes. Trunk is more restricted in its phylogenetic distribution, present only in the Diptera and Tribolium and, surprisingly, in the chelicerate Ixodes scapularis, raising the possibility that trunk and torso evolved earlier than previously thought. In Drosophila torso-like restricts the activation of the terminal patterning pathway to the poles of the embryo. Torso-like evolved in the pan-crustacean lineage, but based on expression of components of the canonical terminal patterning system in the hemimetabolous insect Acyrthosiphon pisum and the holometabolous insect Apis mellifera, we find that the canonical terminal-patterning system is not active in these insects. We therefore propose that the ancestral function of torso-like is unrelated to terminal patterning and that torso-like has become co-opted into terminal patterning in the lineage leading to Coleoptera and Diptera. We also show that this co-option has not resulted in changes to the molecular function of this protein. Torso-like from the pea aphid, honeybee and Drosophila, despite being expressed in different patterns, are functionally equivalent. We propose that co option of torso-like into restricting the activity of trunk and torso facilitated the final step in the evolution of this pathway; the capture of transcriptional control of target genes such as tailless and huckebein by this complex and novel patterning pathway. PMID- 23438816 TI - Appetitive associative olfactory learning in Drosophila larvae. AB - In the following we describe the methodological details of appetitive associative olfactory learning in Drosophila larvae. The setup, in combination with genetic interference, provides a handle to analyze the neuronal and molecular fundamentals of specifically associative learning in a simple larval brain. Organisms can use past experience to adjust present behavior. Such acquisition of behavioral potential can be defined as learning, and the physical bases of these potentials as memory traces. Neuroscientists try to understand how these processes are organized in terms of molecular and neuronal changes in the brain by using a variety of methods in model organisms ranging from insects to vertebrates. For such endeavors it is helpful to use model systems that are simple and experimentally accessible. The Drosophila larva has turned out to satisfy these demands based on the availability of robust behavioral assays, the existence of a variety of transgenic techniques and the elementary organization of the nervous system comprising only about 10,000 neurons (albeit with some concessions: cognitive limitations, few behavioral options, and richness of experience questionable). Drosophila larvae can form associations between odors and appetitive gustatory reinforcement like sugar. In a standard assay, established in the lab of B. Gerber, animals receive a two-odor reciprocal training: A first group of larvae is exposed to an odor A together with a gustatory reinforcer (sugar reward) and is subsequently exposed to an odor B without reinforcement. Meanwhile a second group of larvae receives reciprocal training while experiencing odor A without reinforcement and subsequently being exposed to odor B with reinforcement (sugar reward). In the following both groups are tested for their preference between the two odors. Relatively higher preferences for the rewarded odor reflect associative learning--presented as a performance index (PI). The conclusion regarding the associative nature of the performance index is compelling, because apart from the contingency between odors and tastants, other parameters, such as odor and reward exposure, passage of time and handling do not differ between the two groups. PMID- 23438817 TI - Mitochondrial ROS fire up T cell activation. AB - Metabolic reprogramming has emerged as an important feature of immune cell activation. Two new studies, including Sena et al. (2013) in this issue of Immunity, identify mitochondrial reactive oxygen species (ROS) arising from metabolic reprogramming as signaling molecules in T cell activation. PMID- 23438818 TI - Interleukin-1 receptor 2 keeps the lid on interleukin-1alpha. AB - The molecular mechanisms that regulate functional activation of IL-1alpha remain elusive. In this issue of Immunity, Zheng et al. (2013) describe a molecular system implicating interleukin-1 receptor-2 (IL-1R2) as a principal cytosolic factor that controls functional IL-1alpha activation during necrosis. PMID- 23438819 TI - Applying pressure on macrophages. AB - In this issue of Immunity, Cortez-Retamozo et al. (2013) demonstrate that the increased production of angiotensin II in tumor-bearing mice induces the expansion of macrophage progenitors and the supply of macrophages. PMID- 23438820 TI - One bug or another: promiscuous T cells form lifelong memory. AB - As humans age, their T cell repertoire becomes dominated by cells exhibiting "memory" characteristics. In this issue of Immunity, Su et al. (2013) demonstrate that a large percentage of virus-specific CD4(+) T cells also exhibit a memory phenotype in unexposed adults. PMID- 23438821 TI - Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. AB - Regulated necrosis, termed necroptosis, is negatively regulated by caspase-8 and is dependent on the kinase activity of RIPK1 and RIPK3. Necroptosis leads to rapid plasma membrane permeabilization and to the release of cell contents and exposure of damage-associated molecular patterns (DAMPs). We are only beginning to identify the necroptotic DAMPs, their modifications, and their potential role in the regulation of inflammation. In this review, we discuss the physiological relevance of necroptosis and its role in the modulation of inflammation. For example, during viral infection, RIPK3-mediated necroptosis acts as a backup mechanism to clear pathogens. Necroptosis is also involved in apparently immunologically silent maintenance of T cell homeostasis. In contrast, the induction of necroptosis in skin, intestine, systemic inflammatory response syndrome, and ischemia reperfusion injury provoke a strong inflammatory response, which might be triggered by emission of DAMPs from necroptotic cells, showing the detrimental side of necroptosis. PMID- 23438822 TI - Chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific T cell immunity. AB - Resolution of acute and chronic viral infections requires activation of innate cells to initiate and maintain adaptive immune responses. Here we report that infection with acute Armstrong (ARM) or chronic Clone 13 (C13) strains of lymphocytic choriomeningitis virus (LCMV) led to two distinct phases of innate immune response. During the first 72 hr of infection, dendritic cells upregulated activation markers and stimulated antiviral CD8(+) T cells, independent of viral strain. Seven days after infection, there was an increase in Ly6C(hi) monocytic and Gr-1(hi) neutrophilic cells in lymphoid organs and blood. This expansion in cell numbers was enhanced and sustained in C13 infection, whereas it occurred only transiently with ARM infection. These cells resembled myeloid-derived suppressor cells and potently suppressed T cell proliferation. The reduction of monocytic cells in Ccr2(-/-) mice or after Gr-1 antibody depletion enhanced antiviral T cell function. Thus, innate cells have an important immunomodulatory role throughout chronic infection. PMID- 23438823 TI - The E3-ligase TRIM family of proteins regulates signaling pathways triggered by innate immune pattern-recognition receptors. AB - Innate immunity conferred by the type I interferon is critical for antiviral defense. To date only a limited number of tripartite motif (TRIM) proteins have been implicated in modulation of innate immunity and anti-microbial activity. Here we report the complementary DNA cloning and systematic analysis of all known 75 human TRIMs. We demonstrate that roughly half of the 75 TRIM-family members enhanced the innate immune response and that they do this at multiple levels in signaling pathways. Moreover, messenger RNA levels and localization of most of these TRIMs were found to be altered during viral infection, suggesting that their regulatory activities are highly controlled at both pre- and posttranscriptional levels. Taken together, our data demonstrate a very considerable dedication of this large protein family to the positive regulation of the antiviral response, which supports the notion that this family of proteins evolved as a component of innate immunity. PMID- 23438824 TI - Cinnamaldehyde-induced apoptosis in human hepatoma PLC/PRF/5 cells involves the mitochondrial death pathway and is sensitive to inhibition by cyclosporin A and z VAD-fmk. AB - Cinnamaldehyde (CIN) has been shown to exert chemopreventive activity against several types of human cancer cells. We previously reported that CIN induced apoptosis of human hepatoma PLC/PRF/5 cells and this effect was associated with activation of the pro-apoptotic Bcl-2 family of proteins and the MAPK cascade. To further clarify the underlying mechanism of CIN-induced apoptosis, we examined in this study its relationship with the mitochondrial death pathway using the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (CsA), and the general caspase inhibitor, z-VAD-fmk. Results indicated that CIN-induced apoptosis involved enhanced ROS generation, disruption of mitochondrial potential, and the mitochondrial release of cytochrome c and Smac/DIABLO into the cytosol, which in turn promoted caspase-3 to its active form and the subsequent cleavage of PARP. Treatment with CIN also downregulated protein levels of the anti-apoptotic factors XIAP and Bcl-2 with concomitant accumulation of the pro apoptotic Bax in a timedependent manner. These mitochondria-related apoptotic effects induced by CIN were however blocked by CsA and z-VAD-fmk pretreatments, which prevented cells from undergoing programmed cell death triggered by CIN. Furthermore, the increase of Bax and decrease of Bcl-2 and XIAP protein expression due to CIN treatment were also reversely modulated by the two inhibitors. Taken together, these results suggested that CIN is an apoptotic inducer that acts on the mitochondrial death pathway in PLC/PRF/5 cells and its effect could be blocked by CsA and z-VAD-fmk. PMID- 23438825 TI - Synthesis and biological evaluation of diaryl ether linked DC-81 conjugates as potential antitumor agents. AB - A series of new diaryl ether linked pyrrolobenzodiazepine (PBD) conjugates (4a-i, 5a-i and 6a-f) was synthesized and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. These conjugates exhibited significant anticancer activity with GI50 values in the range of 0.1-3.88 MUM. Some of the potent conjugates (4b, 4h, 5h, 6b, 6c and 6e) were further investigated on cell cycle distribution. FACS analysis showed the accumulation of cells in G0 phase indicating the apoptosis inducing nature of these conjugates. Moreover, compound 6b caused a decrease in the mitochondrial membrane potential, which indicates the apoptotic nature of the compound through mitochondrial mediated pathway. Further conjugates 4b, 4h and 6b induce the activation of caspase and PARP proteins, followed by apoptotic cell death in MCF7 cell line. PMID- 23438826 TI - Natural compounds with cell growth inhibitory activity in human tumor cell lines. AB - Twenty six compounds (coumarins, flavonoids and alkaloids) were evaluated for their ability to inhibit the growth of three human tumor cell lines: breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and melanoma (A375 C5). Three of them [3-hydroxyflavone (6), 2'-hydroxy-3,4,4',5,6' pentamethoxychalcone (11), Siderin (20)] were very potent in inhibiting all human tumor cell lines tested. The structure / activity relationship is discussed. PMID- 23438827 TI - Myricetin induces apoptosis in HepG2 cells through Akt/p70S6K/bad signaling and mitochondrial apoptotic pathway. AB - The present investigation was undertaken to gain insight into the molecular mechanism by which myricetin induces apoptosis in human hepatocarcinoma HepG2 cells. Myricetin caused the disruption of mitochondrial membrane potential in a dose-dependent manner. Moreover, myricetin triggered translocation of the pro apoptotic protein Bax to the mitochondria, downregulation of anti-apoptotic Bcl-2 expression and upregulated the expression of pro-apoptotic protein Bad in the mitochondria. The present study also showed that myricetin promoted the release of cytochrome C from mitochondria into the cytosol followed by an increase in the proteolytic activation of caspase-3 and the concomitant degradation of PARP protein. Additionally, western blot analysis showed that the Akt/p70s6k1 pathway was inhibited in myricetin-treated HepG2 cells, accordingly the phosphorylation of Bad at Ser136 was downregulated. Collectively, these findings indicate that myricetin induced apoptosis in HepG2 cell through mitochondria apoptotic pathway and Akt/p70s6k1/Bad signaling. Present results provide new information on the possible mechanisms for the anti-cancer activity of myricetin. PMID- 23438829 TI - Plant-Derived Secondary Metabolites as Anticancer Agents. PMID- 23438828 TI - Recent development in targeting PI3K-Akt-mTOR signaling for anticancer therapeutic strategies. AB - Cancer is a diverse class of diseases which differ widely in their cause and biology. The aberrant behavior of cancer reflects up regulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Phosphoinositide-3 kinase(PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway controls various biological processes that are important for normal functioning of the cell via cell cycle progression, survival, migration, transcription, translation and metabolism. However, PI3K signaling pathway is dysregulated almost in all cancers which is due to the amplification and genetic mutation of PI3K gene, encoding catalytic and regulatory subunit of PI3K isoforms. The current review focuses on the structural features of various PI3K isoforms including Akt and mTOR and their inhibition using specific small molecule inhibitors in an attempt to achieve an attractive target for cancer prevention and chemotherapy. PMID- 23438830 TI - Oncogenic MicroRNA-27a is a target for genistein in ovarian cancer cells. AB - MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention. However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In this study, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile, transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found that treatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellular mechanistic studies revealed that genistein down-regulated miR 27a expression, which was accompanied by significantly increased expression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an important role in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growth and migration, offering novel insights into the mechanisms of genistein therapeutic actions. PMID- 23438831 TI - Microtubule-targeting Anticancer Agents from Marine Natural Source. AB - The effective novel therapeutics is urgently needed due to the increasing incidence of malignant cancers and drug multi-resistance. It is particularly imperative to find efficacious and specific anticancer agents. Microtubule targeting drugs are among the most commonly prescribed agents in the combat against cancer. Natural products and their derivatives have historically been invaluable as a source of pharmaceutical leads and therapeutic agents. In particular, marine natural products (MNPs) have demonstrated exceptional potency and potential as anticancer agents. Drug discovery from MNPs provides new pathway and ideas to find original anticancer agents, and enjoys a renaissance in the past few years. In this review, nine classes of typical MNPs are summarized, including novel compounds with diverse structures. Most bioactive marine compounds from different organism include invertebrate animals, algae, fungi and bacteria are concluded. PMID- 23438833 TI - Diabetes: Blocking RANKL signalling might prevent T2DM. PMID- 23438832 TI - Changes in pituitary function with ageing and implications for patient care. AB - The pituitary gland has a role in puberty, reproduction, stress-adaptive responses, sodium and water balance, uterine contractions, lactation, thyroid function, growth, body composition and skin pigmentation. Ageing is marked by initially subtle erosion of physiological signalling mechanisms, resulting in lower incremental secretory-burst amplitude, more disorderly patterns of pituitary hormone release and blunted 24 h rhythmic secretion. Almost all pituitary hormones are altered by ageing in humans, often in a manner dependent on sex, body composition, stress, comorbidity, intercurrent illness, medication use, physical frailty, caloric intake, immune status, level of exercise, and neurocognitive decline. The aim of this article is to critically discuss the mechanisms mediating clinical facets of changes in the hypothalamic-pituitary axis during ageing, and the extent to which confounding factors operate to obscure ageing-related effects. PMID- 23438834 TI - Thyroid dysfunction in the elderly. AB - Thyroid dysfunction is common in the general population, and mild or subclinical forms can be present in more than 10% of individuals aged >80 years. The diagnosis of abnormal thyroid hormone concentrations in people aged >60 years poses a challenge, as the clinical presentation of thyroid dysfunction is usually nonspecific, and ageing is associated with a number of physiological changes that can affect thyroid function test results. Furthermore, the presence of acute or chronic nonthyroidal illnesses and the use of medications that interfere with thyroid function tests are common confounders in the determination of thyroid status in the elderly. Early diagnosis and treatment of overt thyroid dysfunction is crucial in this population in view of the marked effects of abnormal circulating thyroid hormone levels on a number of organ systems, including the heart, the skeleton and the neurological system. The clinical significance of mild thyroid overactivity and underactivity remains uncertain, and the need for treatment of subclinical thyroid dysfunction is much debated. A number of large epidemiological studies have identified associations between mild thyroid dysfunction and short-term as well as long-term adverse outcomes, and a small but increasing number of randomized controlled intervention studies have been reported. Guidelines recommend treatment of thyroid dysfunction on the basis of the degree of abnormal serum TSH concentrations, patient age and associated comorbidities. This Review describes the current evidence on the prevalence, diagnosis, management and long-term consequences of thyroid dysfunction in the elderly. PMID- 23438836 TI - Diabetes: T2DM--will tertiary prevention solve the problem? PMID- 23438840 TI - Obesity: Teaching an old drug new tricks--amlexanox targets inflammation to improve metabolic dysfunction. PMID- 23438835 TI - Oxidative stress and the ageing endocrine system. AB - Ageing is a process characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-related diseases and death. Several hundred theories have attempted to explain this phenomenon. One of the most popular is the 'oxidative stress theory', originally termed the 'free radical theory'. The endocrine system seems to have a role in the modulation of oxidative stress; however, much less is known about the role that oxidative stress might have in the ageing of the endocrine system and the induction of age-related endocrine diseases. This Review outlines the interactions between hormones and oxidative metabolism and the potential effects of oxidative stress on ageing of endocrine organs. Many different mechanisms that link oxidative stress and ageing are discussed, all of which converge on the induction or regulation of inflammation. All these mechanisms, including cell senescence, mitochondrial dysfunction and microRNA dysregulation, as well as inflammation itself, could be targets of future studies aimed at clarifying the effects of oxidative stress on ageing of endocrine glands. PMID- 23438839 TI - Neurosteroids as regenerative agents in the brain: therapeutic implications. AB - Regenerative therapeutics hold the promise of self-renewal and repair. Ageing and age-associated neurodegenerative diseases are marked by a decline in self-renewal and repair, but a capacity for regeneration is retained. The challenge faced by researchers developing molecular therapeutics to promote self-renewal in the nervous system is to activate regenerative and repair pathways often in the context of progressive degeneration. Neurosteroids regulate both regeneration and repair systems in the brain, and among this class of molecules, allopregnanolone has been broadly investigated for its role to promote regeneration in both the central and peripheral nervous systems. In the brain, allopregnanolone induced generation and survival of new neurons in the hippocampus of both aged mice and mice with Alzheimer disease, accompanied by restoration of associative learning and memory function. In the brain of mice with Alzheimer disease, allopregnanolone increased liver X receptor and pregnane X receptor expression, reduced amyloid-beta and microglial activation, and increased markers of myelin and white matter generation. Therapeutic windows for efficacy of allopregnanolone were evident in the brains of mice with both normal ageing and Alzheimer disease. Allopregnanolone dose and a regenerative treatment regimen of intermittent allopregnanolone exposure were determining factors regulating therapeutic efficacy. Allopregnanolone serves as proof of concept for therapeutics that target endogenous regeneration, windows of therapeutic opportunity for regeneration, and critical system biology factors that will determine the efficacy of regeneration. PMID- 23438842 TI - Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia. AB - Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist. PMID- 23438843 TI - Large-scale capture of peptides containing reversibly oxidized cysteines by thiol disulfide exchange applied to the myocardial redox proteome. AB - Redox regulation is emerging as an important post-translational modification in cell signaling and pathogenesis. Cysteine (Cys) is the most redox active of the commonly coded amino acids and is thus an important target for redox-based modifications. Reactions that oxidize the Cys sulfur atom to low oxidation states (e.g., disulfide) are reversible, while further reactions to higher oxidation states (e.g., sulfonic acid) may be irreversible under biological conditions. Reversible modifications are particularly interesting as they mediate redox signaling and regulation of proteins under physiological conditions and during adaptation to oxidant stress. An enrichment method that relied on rapid and specific alkylation of free Cys, followed by thiol-based reduction and resin capture by thiol-disulfide exchange chemistry was applied to isolate reversibly modified Cys-containing peptides. Chromatographic conditions were optimized to provide increased specificity by removal of noncovalent interactions. The technique was highly efficient, based on near equimolar reactions with the resin, reproducible and linear for peptide elution, as quantified by label-free mass spectrometry. The method was applied to a complex protein lysate generated from rat myocardial tissue and 6559 unique Cys-containing peptides from 2694 proteins were identified. Comparison with the rat database and previous studies showed effective enrichment of proteins modified by S-nitrosylation, disulfide formation, and Cys-sulfenic acid. Analysis of amino acid sequence features indicated a preference for acidic residues and increased hydrophilicity in the regions immediately up- or downstream of the reactive Cys. This technique is ideally suited for the enrichment and profiling of reversible Cys modifications on a proteome-wide scale. PMID- 23438845 TI - Tools for decision-making in older cancer patients. Role of the comprehensive geriatric assessment. AB - Approximately 60% of cancer incidence and 70% of cancer mortality occurs in individuals older than 65 years. The optimal approach to cancer therapy in older adults is often unclear. Historically, advanced age has been an exclusion criterion in clinical cancer trials, and older adults have been consistently underrepresented. As a result, there is a lack of information about treatment efficacy and tolerability in this population. Comprehensive Geriatric Assessment (CGA) is one of the most useful tools for the oncologist to make decisions related to older patients diagnosed with cancer. This tool has proved to be very useful to detect many deficits, tolerance to chemotherapy and survival in such patients. In this review, we analyze the role of CGA in decision making in geriatric oncology. PMID- 23438844 TI - MiR-138 and MiR-135 directly target focal adhesion kinase, inhibit cell invasion, and increase sensitivity to chemotherapy in cancer cells. AB - Focal Adhesion Kinase is a 125 kDa non-receptor kinase and overexpressed in many types of tumors. Recently, short noncoding RNAs, called microRNAs have been discovered as regulators of gene expression mainly through binding to the untranslated region (UTR) of mRNA. In this report we show that MiR-138 and MiR 135 down-regulated FAK expression in cancer cells. MiR-138 and MiR-135 inhibited FAK protein expression in different cancer cell lines. The computer analysis of 3'FAK-untranslated region (FAKUTR) identified one conserved MiR-138 binding site (CACCAGCA) at positions 3514-3521 and one conserved MiR-135 (AAGCCAU) binding site at positions 4278-4284 in the FAK-UTR. By a dual-luciferase assay we demonstrate that MiR-138 and MiR-135 directly bound the FAK untranslated region using FAK-UTR-Target (FAK-UTR) luciferase plasmid and inhibited its luciferase activity. The sitedirected mutagenesis of the MiR-138 and MiR-135 binding sites in the FAK-UTR abrogated MiR-138 and MiR-135-directed inhibition of FAK-UTR. Real time PCR demonstrated that cells transfected with MiR-138 and MiR-135 expressed decreased FAK mRNA levels. Moreover, stable expression of MiR-138 and MiR-135 in 293 and HeLa cells decreased cell invasion and increased sensitivity to 5- fluorouracil (5-FU), FAK inhibitor, Y15, and doxorubicin. In addition, MiR-138 significantly decreased 293 xenograft tumor growth in vivo. This is the first report on regulation of FAK expression by MiR-135 and MiR138 that affected invasion, drug sensitivity, and tumor growth in cancer cells, which is important to the development of FAK-targeted therapeutics and understanding their novel regulations and functions. PMID- 23438846 TI - Targeted anti-HER2 cancer therapy in elderly women diagnosed with breast cancer. AB - Trastuzumab or lapatinib treatment with chemotherapy or hormonotherapy are the gold standard treatments for human epidermal growth factor receptor 2 (HER2) positive breast cancer (early breast cancer or metastatic breast cancer). Older patients have been largely underrepresented in clinical trials, and few data on trastuzumab or lapatinib efficacy and toxicity have been reported for this subgroup. This article has reviewed the main articles that have analyzed these items. PMID- 23438847 TI - Efficient generation of induced pluripotent stem cells from human bone marrow mesenchymal stem cells. AB - Ectopic expression of defined sets of genetic factors can reprogramme somatic cells to induced pluripotent stem cells (iPSCs) that closely resemble embryonic stem cells. However, the low reprogramming efficiency is a significant handicap for mechanistic studies and potential clinical application. In this study, we used human bone marrow-derived mesenchymal stem cells (hBMMSCs) as target cells for reprogramming and investigated efficient iPSC generation from hBMMSCs using the compounds of p53 siRNA, valproic acid (VPA) and vitamin C (Vc) with four transcription factors OCT4, SOX2, KLF4, and c-MYC (compound induction system). The synergetic mechanism of the compounds was studied. Our results showed that the compound induction system could efficiently reprogramme hBMMSCs to iPSCs. hBMMSC-derived iPSC populations expressed pluripotent markers and had multi potential to differentiate into three germ layer-derived cells. p53 siRNA, VPA and Vc had a synergetic effect on cell reprogramming and the combinatorial use of these substances greatly improved the efficiency of iPSC generation by suppressing the expression of p53, decreasing cell apoptosis, up-regulating the expression of the pluripotent gene OCT4 and modifying the cell cycle. Therefore, our study highlights a straightforward method for improving the speed and efficiency of iPSC generation and provides versatile tools for investigating early developmental processes such as haemopoiesis and relevant diseases. In addition, this study provides a paradigm for the combinatorial use of genetic factors and molecules to improve the efficiency of iPSC generation. PMID- 23438848 TI - Paraoxonase-1 (PON1) status in pancreatic cancer: relation to clinical parameters. AB - Human paraoxonase 1 (PON1) has been shown to decrease the level of systemic oxidative stress, which is thought to contribute to cancer development. The aim of this study was to examine the interrelationships between PON1 status and some clinical characteristics in patients with pancreatic cancer (PC). A group of 73 consecutive patients with PC (stage II-IV) and 73 control subjects were examined. Laboratory studies included five polymorphisms of the PON1 gene (L55M, Q192R, 108C/T, -126C/T, and -162A/G), PON1 arylesterase (PON1-A) and lactonase (PON1-L) activities, as well as some markers of protein metabolism, insulin resistance, and oxidative stress. In comparison with the control group, no difference in the distribution of the PON1 polymorphisms was found in cancer patients, both arylesterase and lactonase activities being significantly lower (-33, -47 %, respectively, both P < 0.001). There was neither statistically significant association of PON1 polymorphisms with tumour stages nor with diabetes mellitus connected with PC. The genotype distribution of L55M and -108C/T differed only in a subgroup of patients presenting clinically relevant malnutrition (chi2 = 6.50, 6.25, respectively, both P < 0.05). In the PC group, PON1-A and PON1-L activities correlated with Nutritional Risk Index (r = 0.351, 0.409, respectively, both P < 0.01), PON1-L with mid-arm muscle circumference (r = 0.328, P < 0.05), and PON1-A and PON1-L with serum albumin (r = 0.352, 0.391 respectively, both < 0.01). Our results suggest that PON1 plays an important role in PC, especially in cancer associated malnutrition. PMID- 23438849 TI - Recombinant probiotic therapy in experimental colitis in mice. AB - Recently, high interest has been attracted to the research of inflammatory bowel diseases (IBD). Recombinant probiotic bacteria may represent an interesting way to influence the course of IBD. Their benefits include cheap and simple production and easy manipulation of the genetic material. Several gene therapy and probiotic approaches already showed promising results in the past. The aim of this study was to test the probiotic potential of IL-10-expressing Escherichia coli Nissle 1917 in a mouse model of IBD and to compare it with control bacterial strains. The dextran sulphate sodium (DSS) model of colitis was examined for this purpose. Animals received control probiotic bacteria or modified probiotics (expressing IL-10) via gastric gavage. Body weight, stool consistency, food and water consumption were monitored. At the end of the experiment, the parameters of inflammation, oxidative stress and carbonyl stress were analysed in the samples and statistical analysis was performed. We prepared an anti-inflammatory probiotic Escherichia coli strain that we designated Nissle 1917/pMEC-IL10 and proved its anti-inflammatory properties, which are similar to those of the control probiotic strains Nissle 1917 and Lactococcus lactis/pMEC-IL10 in vivo. The probiotic therapy was successful according to several parameters, including colon length, and oxidative and carbonyl stress. Bacterially produced IL-10 was detected in the plasma. The potential of bacterial anti-inflammatory therapy of IBD using modified probiotics was outlined. The results opened a way for upcoming studies using modified probiotics for therapy of systemic diseases. PMID- 23438850 TI - Methylation analysis of tumour suppressor genes in ovarian cancer using MS-MLPA. AB - Epigenetic changes are considered to be a frequent event during tumour development. Hypermethylation of promoter CpG islands represents an alternative mechanism for inactivation of tumour suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. The aim of this study was to investigate promoter methylation of specific genes in ovarian cancer by comparison with normal ovarian tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to compare the methylation status of 69 tissue samples of ovarian cancer with 40 control samples. Using a 15% cut-off for methylation, we observed significantly higher methylation in genes MGMT, PAX5, CDH13, WT1, THBS1, GATA5 in the ovarian cancer group, while in the ESR1 gene we observed significantly higher methylation in the control group compared with the ovarian cancer group. These findings could potentially be used in screening of ovarian cancer and may have implications for future chemotherapy based on epigenetic changes. PMID- 23438851 TI - Female serum immunoglobulins G, A, E and their immunological reactions to seminal fluid antigens. AB - One in five couples of reproductive age has been diagnosed with infertility. Some diagnoses indicate an immunological basis for this disorder. Female immune infertility may be caused by iso-immunization by seminal components. We focused on the characterization of seminal proteins to illustrate the IgG, IgA and IgE immune responses of 31 infertile women. The biochemical characterization was performed by one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis and isoelectric focusing, both of which were followed by immunoblotting analyses. IgG mainly recognized the antigens with relative molecular masses (Mr) 95 and 183 kDa and isoelectric points ranging from 6.9 to 7.0. The immunodominant antigens recognized by IgA had the Mr of 35 kDa and isoelectric points ranging from 6.2 to 7.2. The reactivity of IgE was not confirmed within our group of patients. The seminal IgG- and IgA -binding patterns were analysed immunochemically to determine the characteristics of possible seminal proteins associated with female immune infertility. PMID- 23438852 TI - Acute pancreatitis is associated with Ser608Leu iNOS polymorphism. AB - Acute pancreatitis is an initially localized inflammation of the pancreatic gland. The precise mechanisms by which aetiological factors induce acute pancreatitis are not yet known, but when initiated, common inflammatory pathways seem to be involved, with cytokines being their components of major importance. The inducible nitric oxide synthase gene (iNOS) encodes an enzyme involved in the pathway of reactive oxygen species and induced in response to infection, cytokines. iNOS is capable of generating large quantities of nitric oxide produced during inflammation. The objective of this study was to investigate the association between acute pancreatitis risk and iNOS polymorphisms. The studied single-nucleotide polymorphisms (SNPs) were Ser608Leu, resulting in an amino acid substitution, and 1173C/T and 954G/C, both in the gene promoter region that is linked to increased enzyme expression, leading to higher NO production. The genotypes for the three SNPs were determined in 93 patients with acute pancreatitis and 60 controls without pancreatitis or cancer that were matched for age and gender. Data analysis was done by conditional logistic regression. It was found that the Ser608Leu polymorphism was more frequent among cases with acute pancreatitis compared to controls (OR = 2.88; 95% CI: 1.49-5.57; P = 0.002), although no individually statistically significant associations for the other SNPs studied were detected. We suggest that iNOS Ser608Leu can be used as a marker to define the risk of acute pancreatitis. PMID- 23438853 TI - Is the pain-reducing effect of opioid medication reliable? A psychophysical study of morphine and pentazocine analgesia. AB - A number of laboratory studies have confirmed the efficacy of opioid medication in reducing pain generated by a number of psychophysical modalities. However, one implicit assumption of clinical and experimental pain testing of analgesics is that the analgesic response is stable and will be comparable across repeated administrations. In the current study, the repeatability of opioid analgesia was assessed in a randomized, double-blinded study using 3 psychophysical pain modalities (e.g., thermal, pressure, and ischemic) over 4 medication sessions (2 with active drug, 2 with placebo). Psychophysical responses were evaluated before and after intravenous administration of either morphine (0.08mg/kg; n=52) or pentazocine (0.5mg/kg; n=49). To determine the ability of a drug to reduce pain, 4 analytic methods (i.e., absolute change, percent change, ratio, and residualized change scores) were calculated to generate separate analgesic index scores for each measure and drug condition. All analgesic index scores demonstrated a greater analgesic response compared to saline for both medications, but stability (i.e., test-retest correlations) of the opioid analgesic indices depended on the pain measurement. Ischemic pain outcomes were moderately stable across sessions for both opioid medications; however, heat and pressure analgesic index scores were moderately stable for only morphine and pentazocine, respectively. Finally, within stimulus modalities, analgesic index scores were highly correlated with each other, suggesting that the different methods for computing analgesic responses provided comparable results. These results suggest that analgesic measures are able to distinguish between active drugs. In addition, analgesic responses to morphine and pentazocine demonstrate at least moderate reliability. PMID- 23438854 TI - The coming age of complete, accurate, and ubiquitous proteomes. AB - High-resolution mass spectrometry (MS)-based proteomics has progressed tremendously over the years. For model organisms like yeast, we can now quantify complete proteomes in just a few hours. Developments discussed in this Perspective will soon enable complete proteome analysis of mammalian cells, as well, with profound impact on biology and biomedicine. PMID- 23438855 TI - The Colossus of ubiquitylation: decrypting a cellular code. AB - Ubiquitylation is an essential posttranslational modification that can regulate the stability, activity, and localization of thousands of proteins. The reversible attachment of ubiquitin as well as interpretation of the ubiquitin signal depends on dynamic protein networks that are challenging to analyze. In this perspective, we discuss tools of the trade that have recently been developed to dissect mechanisms of ubiquitin-dependent signaling, thereby revealing the critical features of an important cellular code. PMID- 23438856 TI - The "Observer Effect" in genome-wide surveys of protein-RNA interactions. AB - Recent technological advances have spurred genome-wide studies that afford insights into ribonucleoprotein biology and transcript regulation on an unprecedented scale. Here we review techniques currently used to obtain genome wide profiles of RNA-protein interactions in living cells. We highlight recent studies of the mRNA-bound proteome and address pitfalls inherent in such investigations. PMID- 23438858 TI - O-GlcNAcylation and 5-methylcytosine oxidation: an unexpected association between OGT and TETs. AB - Three recent studies, including one in this issue of Molecular Cell, document unexpected physical and functional interactions between two unrelated enzymes: OGT, which transfers O-GlcNAc to serine/threonine residues of numerous cellular proteins, and TET-family dioxygenases, which successively oxidize 5 methylcytosine in DNA. PMID- 23438859 TI - Painting by numbers: increasing the parts list for chromatin domains. AB - In this issue of Molecular Cell, van Bemmel and colleagues (2013) report the genome-wide mapping of 42 novel chromatin factors, systematically identifying new components of the various chromatin domains present in fly cells. PMID- 23438857 TI - New insights from existing sequence data: generating breakthroughs without a pipette. AB - With the rapidly declining cost of data generation and the accumulation of massive data sets, molecular biology is entering an era in which incisive analysis of existing data will play an increasingly prominent role in the discovery of new biological phenomena and the elucidation of molecular mechanisms. Here, we discuss resources of publicly available sequencing data most useful for interrogating the mechanisms of gene expression. Existing next generation sequence data sets, however, come with significant challenges in the form of technical and bioinformatic artifacts, which we discuss in detail. We also recount several breakthroughs made largely through the analysis of existing data, primarily in the RNA field. PMID- 23438860 TI - A network model of the molecular organization of chromatin in Drosophila. AB - Chromatin governs gene regulation and genome maintenance, yet a substantial fraction of the chromatin proteome is still unexplored. Moreover, a global model of the chromatin protein network is lacking. By screening >100 candidates we identify 42 Drosophila proteins that were not previously associated with chromatin, which all display specific genomic binding patterns. Bayesian network modeling of the binding profiles of these and 70 known chromatin components yields a detailed blueprint of the in vivo chromatin protein network. We demonstrate functional compartmentalization of this network, and predict functions for most of the previously unknown chromatin proteins, including roles in DNA replication and repair, and gene activation and repression. PMID- 23438861 TI - Murine fetal echocardiography. AB - Transgenic mice displaying abnormalities in cardiac development and function represent a powerful tool for the understanding the molecular mechanisms underlying both normal cardiovascular function and the pathophysiological basis of human cardiovascular disease. Fetal and perinatal death is a common feature when studying genetic alterations affecting cardiac development. In order to study the role of genetic or pharmacologic alterations in the early development of cardiac function, ultrasound imaging of the live fetus has become an important tool for early recognition of abnormalities and longitudinal follow-up. Noninvasive ultrasound imaging is an ideal method for detecting and studying congenital malformations and the impact on cardiac function prior to death. It allows early recognition of abnormalities in the living fetus and the progression of disease can be followed in utero with longitudinal studies. Until recently, imaging of fetal mouse hearts frequently involved invasive methods. The fetus had to be sacrificed to perform magnetic resonance microscopy and electron microscopy or surgically delivered for transillumination microscopy. An application of high frequency probes with conventional 2-D and pulsed-wave Doppler imaging has been shown to provide measurements of cardiac contraction and heart rates during embryonic development with databases of normal developmental changes now available. M-mode imaging further provides important functional data, although, the proper imaging planes are often difficult to obtain. High-frequency ultrasound imaging of the fetus has improved 2-D resolution and can provide excellent information on the early development of cardiac structures. PMID- 23438863 TI - Degradation profile and preliminary clinical testing of a resorbable device for ligation of blood vessels. AB - A resorbable device for ligation of blood vessels was developed and tested in vitro to reveal the degradation profile of the device and to predict the clinical performance in terms of adequate mechanical support during a healing period of 1week. In addition, preliminary clinical testing was performed that showed complete hemostasis and good tissue grip of renal arteries in five pigs. The device was made by injection molding of poly(glycolide-co-trimethylene carbonate) triblock copolymer, and it consisted of a case with a locking mechanism connected to a partly perforated flexible band. A hydrolytic degradation study was carried out for 7, 30 and 60days in water and buffer medium, following the changes in mass, water absorption, pH and mechanical properties. A new rapid matrix-free laser desorption ionization-mass spectrometry (LDI-MS) method was developed for direct screening of degradation products released into the degradation medium. The combination of LDI-MS and electrospray ionization-mass spectrometry analyses enabled the comparison of the degradation product patterns in water and buffer medium. The identified degradation products were rich in trimethylene carbonate units, indicating preferential hydrolysis of amorphous regions where trimethylene units are located. The crystallinity of the material was doubled after 60days of hydrolysis, additionally confirming the preferential hydrolysis of trimethylene carbonate units and the enrichment of glycolide units in the remaining solid matrix. The mechanical performance of the perforated band was followed for the first week of hydrolysis and the results suggest that sufficient strength is retained during the healing time of the blood vessels. PMID- 23438862 TI - Mechanical properties of bioactive glass (13-93) scaffolds fabricated by robotic deposition for structural bone repair. AB - There is a need to develop synthetic scaffolds to repair large defects in load bearing bones. Bioactive glasses have attractive properties as a scaffold material for bone repair, but data on their mechanical properties are limited. The objective of the present study was to comprehensively evaluate the mechanical properties of strong porous scaffolds of silicate 13-93 bioactive glass fabricated by robocasting. As-fabricated scaffolds with a grid-like microstructure (porosity 47%, filament diameter 330MUm, pore width 300MUm) were tested in compressive and flexural loading to determine their strength, elastic modulus, Weibull modulus, fatigue resistance, and fracture toughness. Scaffolds were also tested in compression after they were immersed in simulated body fluid (SBF) in vitro or implanted in a rat subcutaneous model in vivo. As fabricated, the scaffolds had a strength of 86+/-9MPa, elastic modulus of 13+/-2GPa, and a Weibull modulus of 12 when tested in compression. In flexural loading the strength, elastic modulus, and Weibull modulus were 11+/-3MPa, 13+/-2GPa, and 6, respectively. In compression, the as-fabricated scaffolds had a mean fatigue life of ~10(6) cycles when tested in air at room temperature or in phosphate-buffered saline at 37 degrees C under cyclic stresses of 1-10 or 2-20MPa. The compressive strength of the scaffolds decreased markedly during the first 2weeks of immersion in SBF or implantation in vivo, but more slowly thereafter. The brittle mechanical response of the scaffolds in vitro changed to an elasto-plastic response after implantation for longer than 2-4weeks in vivo. In addition to providing critically needed data for designing bioactive glass scaffolds, the results are promising for the application of these strong porous scaffolds in loaded bone repair. PMID- 23438864 TI - SOULAGE-TAVIE: development and validation of a virtual nursing intervention to promote self-management of postoperative pain after cardiac surgery. AB - This article is the report of the development and validation of a tailored Web based intervention for postoperative pain self-management in adults who underwent cardiac surgery. The development of SOULAGE-TAVIE included four main phases: (1) identification of a clinical problem, (2) outline design, (3) clinical operationalization, and (4) production. The validation of the intervention's feasibility and acceptability was made through pilot testing with 30 patients expecting cardiac surgery over 4 months in 2010. SOULAGE-TAVIE consists of a 30 minute computer-tailored preoperative educational session about postoperative pain management. Activities and information were tailored according to a predetermined profile. Two short reinforcements were provided in person postoperatively. Ninety-six percent of participants agreed that the strategies proposed responded to their needs. An iterative process among various sources of knowledge gave place to an innovative approach to preoperative education. Pilot testing provided preliminary support for the acceptability and feasibility of a tailored Web-based intervention. Patient empowerment is complementary yet crucial in the current context of care and may contribute to improved pain relief. The use of information technologies can increase personalization and accessibility to health education in a complex environment of care. PMID- 23438865 TI - Using the Omaha System to describe health problems, interventions, and outcomes in home care in Istanbul, Turkey: a student informatics research experience. AB - Preparing nursing students to achieve informatics competencies is essential in today's information-intensive healthcare delivery systems. This study aimed to provide hands-on informatics experience to nursing students and to identify the frequency and type of home care clients' health problems, nursing interventions, and outcomes using a standardized nursing terminology, the Omaha System. Data were collected by 159 nursing students on home visits to 598 clients, who received 8657 interventions from students and faculty for 2267 problems, in addition to the services provided by the home care centers. Skin, neuromusculoskelatal function, personal care, nutrition, and urinary function were the most common problems. The most common intervention category was teaching, guidance, and counseling (47%), followed by treatments and procedures (22%), surveillance (22%), and case management (9%). Outcomes evaluation showed significant improvement in 97.5% of the identified problems. Students gained informatics experience in the use of a standardized nursing language in electronic health records, data management, and use of nursing data at the basic practice level. This study demonstrated that the Omaha System was a useful data collection tool for evaluating problems, interventions, and outcomes in home care and a positive teaching and learning tool for baccalaureate nursing education. PMID- 23438866 TI - New media simulation stories in nursing education: a quasi-experimental study exploring learning outcomes. AB - New media simulation stories are short multimedia presentations that combine simulation, digital technology, and story branching to depict a variety of healthcare-related scenarios. The purpose of this study was to explore whether learning outcomes were enhanced if students viewed the results of both correct and incorrect nursing actions demonstrated through new media simulation stories. A convenience sample of 109 undergraduate nursing students in a family-centered maternity course participated in the study. Study findings suggests that students who viewed both correct and incorrect depictions of maternity nursing actions scored better on tests than did those students who viewed only correct nursing actions. PMID- 23438867 TI - Effect of information and communication technology on nursing performance. AB - The aim of this study was to investigate the influence of information and communication technology use and skills on nursing performance. Questionnaires were prepared relating to using the technology, practical skills in utilizing information, the Six-Dimension Scale of Nursing Performance, and demographics. In all, 556 nurses took part (response rate, 72.6%). A two-way analysis of variance was used to determine the influence of years of nursing experience on the relationship between nursing performance and information and communication technology use. The results showed that the group possessing high technological skills had greater nursing ability than the group with low skills; the level of nursing performance improved with years of experience in the former group, but not in the latter group. Regarding information and communication technology use, the results showed that nursing performance improved among participants who used computers for sending and receiving e-mails, but it decreased for those who used cell phones for e-mail. The results suggest that nursing performance may be negatively affected if information and communication technology are inappropriately used. Informatics education should therefore be provided for all nurses, and it should include information use relating to cell phones and computers. PMID- 23438868 TI - Evolution: A matter of balance. PMID- 23438869 TI - Synthetic biology: A circuit to remember. PMID- 23438870 TI - Response to Sul and Eskin. PMID- 23438871 TI - Mixed models can correct for population structure for genomic regions under selection. PMID- 23438872 TI - High fatty acids modulate P2X(7) expression and IL-6 release via the p38 MAPK pathway in PC12 cells. AB - Diabetic neuropathy (DNP) is the most common chronic complication of diabetes. Elevated free fatty acids (FFAs) have been recently recognized as a major cause of nervous system damage in diabetes. P2X receptors play a primary role in regulation of neuronal interleukin (IL)-6 release, which is of paramount relevance to the functional changes of nerve system. The present study aimed to investigate the effects of high FFAs on the P2X7 expression and IL-6 release in PC12 cells. High FFAs induced P2X7 expression and IL-6 release significantly in PC12 cells. Moreover, high FFAs enhanced ATP or BzATP-induced Ca(2+) signals in PC12 cells. Inhibition of P2X7 by transfection with P2X7-siRNA or co-culture with BBG (a specific P2X7 inhibitor) at high concentrations of FFAs decreased ATP or BzATP-promoted Ca(2+) signals and IL-6 release in PC12 cells. High FFAs induced the phosphorylation of p38 in PC12 cells. Blockade of p38 pathways by SB-203580 inhibited P2X7 up-expression, ATP or BzATP-evoked [Ca(2+)]i rises as well as IL-6 release in PC12 cells exposed to high FFAs. Therefore, high concentrations of FFAs increased the expression of P2X7 in PC12 cells via activation of p38 mitogen activated protein kinase (MAPK) signaling pathway, which contributed to P2X7 mediated IL-6 release from PC12 cells. PMID- 23438873 TI - Antioxidants and cataract. AB - The major causes for cataract formation are free radicals, and these free radicals are neutralized by the presence of endogenous antioxidants in the eye. Using xenobiotics, it has been confirmed that free radicals mediate the formation of cataract. Two cataract model-selenite model and the diabetic cataract model have been developed to study the pathophysiology of cataract formation due to free radicals and the role of antioxidants during the process of cataractogenesis. This review focuses on natural compounds with antioxidant properties that could actually be applied as an interventional strategy on a large scale and are also relatively inexpensive. A brief overview of plants with antioxidant properties that in addition possess potential anti-cataract properties has been discussed. In addition to plants, three natural compounds (curcumin, vitamin C and vitamin E), on which a lot of data exist showing anti cataract and antioxidant activities, have also been discussed. These antioxidants can be supplemented in the diet for a better defence against free radicals. Studies on vitamin C and vitamin E have proved that they are capable of preventing lipid peroxidation, thereby preventing the generation of free radicals, but their efficacy as anti-cataract agent is questionable. Unlike vitamins C and E, curcumin is well established as an anti-cataract agent, but the issue of curcumin bioavailability is yet to be addressed. Nanotechnology proves to be a promising area in increasing the curcumin bioavailability, but still a lot more research needs to be done before the use of curcumin as an effective anti-cataract agent for humans. PMID- 23438876 TI - Genome-wide studies in pharmacogenomics: harnessing the power of extreme phenotypes. PMID- 23438875 TI - Bis-N-norgliovictin, a small-molecule compound from marine fungus, inhibits LPS induced inflammation in macrophages and improves survival in sepsis. AB - Sepsis is a highly lethal disorder characterized by systemic inflammation, and Toll-like receptor 4 (TLR4) in macrophages plays a crucial role in modulating innate immune response and outcome of sepsis. During the screening of natural products against inflammation, we identified bis-N-norgliovictin, a small molecule compound isolated from marine-derived fungus, significantly inhibited lipopolysaccharide (LPS, ligand of TLR4)-induced tumor necrosis factor-alpha (TNF alpha) production in RAW264.7 cells. In this study, we evaluated the effect of bis-N-norgliovictin on TLR4-mediated inflammation in mouse macrophages and LPS induced sepsis model. In RAW264.7 and mouse peritoneal macrophages, bis-N norgliovictin dose-dependently inhibited LPS-induced production of TNF-alpha, interleukin-6 (IL-6), interferon-beta (IFN-beta) and monocyte chemoattractant protein (MCP-1), but without suppressing cell viability. The anti-inflammatory effect was attributed to the down-regulation of TLR4-triggered myeloid differentiation primary response protein 88 (MyD88)-dependent and TIR-containing adapter inducing interferon-beta (TRIF)-dependent signaling pathways, including p38 and c-Jun N-terminal kinase (JNK) of mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3) cascades. Importantly, bis-N-norgliovictin also protected mice against LPS induced endotoxic shock. Intravenous injection of bis-N-norgliovictin 1h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-6, MCP-1 and IL-10, attenuated liver and lung injury and diminished M1 macrophage polarization in liver. Our results demonstrate that bis-N norgliovictin exhibit potent anti-inflammatory effect both in vitro and in vivo. These findings suggest that bis-N-norgliovictin can be a useful therapeutic candidate for the treatment of sepsis and other inflammatory diseases. PMID- 23438874 TI - Effects of cholinesterase inhibitors and serotonin-1A receptor agonists on morphine-induced ventilatory depression and antinociception in rats. AB - Ventilatory depression is a serious side-effect of opioid analgesics. Naloxone, an antagonist of opioid receptors, eliminates not only ventilatory depression but also analgesic effect of opioids. Pharmacological dissociation of adverse reactions from the main action is important clinically and basically. Cholinergic and serotonergic mechanisms are suggested to counteract the opioid-induced ventilatory disturbances, but their influence on analgesia is still controversial. The present study evaluated the effects of cholinesterase inhibitors and serotonin-1A (5-HT1A) receptor agonists on morphine (1.0mg/kg, i.v.)-induced ventilatory depression and analgesia in rats. In anesthetized animals, spontaneous ventilation and hind leg withdrawal reflexes against nociceptive thermal stimuli were measured simultaneously. Physostigmine (0.1 and 0.2mg/kg, i.v.) and donepezil (0.5 and 1.0mg/kg, i.v.) relieved the morphine induced ventilatory depression and enhanced its antinociception. On the other hand, (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.03 and 0.1mg/kg, i.v.) and buspirone (0.1 and 0.3mg/kg, i.v.) did not influence antinociception of morphine while they restored the decreased ventilation. In unanesthetized animals, hypercapnic ventilatory response was measured by using whole-body plethysmography. Physostigmine (0.3mg/kg, i.p.), donepezil (1.0mg/kg, i.p.), 8-OH-DPAT (0.3mg/kg, i.p.) and buspirone (3.0mg/kg, i.p.) all recovered the morphine (10mg/kg, i.p.)-induced depression of hypercapnic ventilatory response. The present study suggests that activation of cholinergic or serotonergic (5-HT1A) mechanisms may be a useful therapeutic approach for morphine-induced ventilatory depression without loss of its analgesic action. PMID- 23438877 TI - Predictive ability of direct-to-consumer pharmacogenetic testing: when is lack of evidence really lack of evidence? PMID- 23438878 TI - Whole-genome sequencing in pharmacogenetics. PMID- 23438879 TI - The patient-centric translational health record. PMID- 23438882 TI - Interview: a discussion on genome-wide associations in pharmacogenomics. PMID- 23438881 TI - Highlights from the latest pharmacogenomic genome-wide association studies. PMID- 23438883 TI - Ask the experts: pharmacogenomics and genome-wide association studies. PMID- 23438884 TI - Estimating heritability in pharmacogenetic studies. AB - AIM: This article aims to evaluate the performance of a recent method to estimate heritability of continuous and binary traits, specifically in the context of pharmacogenetic studies. MATERIALS & METHODS: The approach to be evaluated was designed to estimate heritability in large-scale disease studies. Extensive simulation studies designed to emulate common scenarios seen in pharmacogenetic studies were performed to elucidate the potential utility of this approach outside of disease genetics. The simulations cover continuous and binary traits with small-to-moderate heritability values across a variety of samples sizes in genome-wide, as well as candidate gene, settings. RESULTS: On a genome-wide scale, a combination of relatively large sample sizes (i.e., n >= 1000) and at least moderate underlying heritability (i.e., >= 0.25) are needed in order to attain reasonable statistical power. However, in candidate gene studies, reasonable power can be attained across a more broad range of scenarios. CONCLUSION: Our simulation studies show that the proposed approach has clear utility in the context of pharmacogenetic studies, especially in candidate gene settings, and provides novel supplementary information that can be used to inform decision-making in the pharmaceutical industry. PMID- 23438885 TI - Two algorithms for biospecimen comparison and differentiation using SNP genotypes. AB - AIMS: Biobanks are frequently required to verify specimen relationships. We present two algorithms to compare SNP genotype patterns that provide an objective, high-throughput tool for verification. METHODS: The first algorithm allows for comparison of all holdings within a biobank, and is well suited to construct sample relationships de novo for comparison with assumed relationships. The second algorithm is tailored to oncology, and allows one to confirm that paired DNAs from malignant and normal tissues are from the same individual in the presence of copy number variations. To evaluate both algorithms, we used an internal training data set (n = 1504) and an external validation data set (n = 1457). RESULTS: In comparison with the results from manual review and a priori knowledge of patient relationships, we identified no errors in interpreting sample relationships within our validation data set. CONCLUSION: We provide an efficient and objective method of automated data analysis that is currently lacking for establishing and verifying specimen relationships in biobanks. PMID- 23438887 TI - Beyond the clinic: 'direct-to-consumer' genomic profiling services and pharmacogenomics. AB - This article provides an overview of commercial pharmacogenetics and pharmacogenomics testing services offered online. The concept of 'beyond-the clinic' (BTC) genomic testing is introduced to refer to the variety of formats in which these tests are offered and a typology of BTC models is developed. The authors review such models in relation to tests for individual drug response that are currently on offer. In conclusion, the authors argue that the evolving BTC domain provides opportunities for the pioneering of integrated data repositories, whose gatekeepers are patients or citizens. The authors anticipate that such developments will benefit pharmacogenomics sooner than other areas of medical practice. PMID- 23438886 TI - From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies. AB - BACKGROUND: Genome-wide association studies (GWAS) have had limited success when applied to complex diseases. Analyzing SNPs individually requires several large studies to integrate the often divergent results. In the presence of epistasis, multivariate approaches based on the linear model (including stepwise logistic regression) often have low sensitivity and generate an abundance of artifacts. METHODS: Recent advances in distributed and parallel processing spurred methodological advances in nonparametric statistics. U-statistics for structured multivariate data (uStat) are not confounded by unrealistic assumptions (e.g., linearity, independence). RESULTS: By incorporating knowledge about relationships between SNPs, uGWAS (GWAS based on uStat) can identify clusters of genes around biologically relevant pathways and pinpoint functionally relevant regions within these genes. CONCLUSION: With this computational biostatistics approach increasing power and guarding against artifacts, personalized medicine and comparative effectiveness will advance while subgroup analyses of Phase III trials can now suggest risk factors for adverse events and novel directions for drug development. PMID- 23438888 TI - Rare-variant genome-wide association studies: a new frontier in genetic analysis of complex traits. AB - Genome-wide association studies have, in the last few years, identified thousands of common genetic variants associated with common complex traits and diseases, implicating many genes not previously known to be involved in the biology of those traits. However, these variants have so far explained little of the population variance in trait values or disease susceptibility. As large-scale genome sequencing efforts have revealed the extent of genetic variation at the low end of the frequency range in human populations, the effects of rare variants have been proposed as an explanation of the 'missing genetic variance.' Improved technologies for genotyping rare variants, including inexpensive whole-genome and whole-exome sequencing and rare-variant genotyping chips, coupled with novel analytical methods, are making genome-wide scans for the effects of rare variants possible, and seem likely to usher in a new era in the genetic analysis of complex traits. PMID- 23438889 TI - Pharmacogenetics of disease-modifying antirheumatic drugs in rheumatoid arthritis: towards personalized medicine. AB - Rheumatoid arthritis is a disease showing considerable heterogeneity in all its aspects, including response to therapy. The efficacy of disease-modifying antirheumatic drugs (DMARDs), with or without biological activity, has been unambiguously established. DMARDs improve the symptoms associated with the disease, and, even more importantly, are capable of stagnating the joint damage associated with the disease. Nonetheless, a considerable proportion of patients fail to achieve an adequate response and/or experience toxicity. This variability in treatment response between individuals has given rise to an extensive search for prognostic markers in order to personalize and optimize therapy in rheumatoid arthritis patients. Pharmacogenetics, the study of genetic variation underlying differential responses to drugs, is a rapidly progressing field in rheumatology that might enable personalized therapy in rheumatic diseases. This review will summarize the pharmacogenetics of commonly used synthetic and biological DMARDs. PMID- 23438891 TI - Alliances against depression - A community based approach to target depression and to prevent suicidal behaviour. AB - Depressive disorders as well as fatal and non-fatal suicidal behaviour continue to be important mental health issues. Because of the close relation between depression and suicidal behaviour, it is likely that preventive actions improving care and optimising treatment for depressed patients result in a reduction of suicidal acts. This was shown in the Nuremberg Alliance against Depression, a two year four-level community based intervention program associated with a 24% reduction of suicidal acts (completed and attempted suicides combined) compared to a baseline year and a control region. Serving as a model project, this approach has up to now been adopted in more than 100 regions in Germany and Europe. Within the suicide prevention project OSPI-Europe, the four-level approach was optimized and further implemented and evaluated in different European regions. PMID- 23438892 TI - From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. AB - We revisit our hypothesis that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntarily drug use to habitual, and ultimately compulsive drug use. We especially focus on the transitions in striatal control over drug seeking behaviour that underlie these transitions since functional heterogeneity of the striatum was a key area of Ann Kelley's research interests and one in which she made enormous contributions. We also discuss the hypothesis in light of recent data that the emergence of a compulsive drug seeking habit both reflects a shift to dorsal striatal control over behaviour and impaired prefontal cortical inhibitory control mechanisms. We further discuss aspects of the vulnerability to compulsive drug use and in particular the impact of impulsivity. In writing this review we acknowledge the untimely death of an outstanding scientist and a dear personal friend. PMID- 23438895 TI - A new era in the study of individual differences in drug metabolism and pharmacokinetics. PMID- 23438896 TI - Clinical impact and evidence of pharmacokinetic change by genetic polymorphism. PMID- 23438894 TI - PGC-1alpha regulates hepatic hepcidin expression and iron homeostasis in response to inflammation. AB - Systemic iron homeostasis is finely regulated by the liver through synthesis of the peptide hormone hepcidin (HAMP), which plays an important role in duodenal iron absorption and macrophage iron release. Clinical investigations have shown that chronic and low-grade inflammation leads to the increase of serum HAMP levels and the development of various diseases such as anemia of inflammation. However, gaps remain to fully elucidate the mechanism linking inflammation and iron dysregulation. Here we show that although inflammatory stimuli increase hepatic HAMP expression and cause systemic iron deficiency in mice, they inhibit the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a transcriptional coactivator actively involved in metabolic regulation. Liver-specific overexpression of PGC-1alpha antagonizes lipopolysaccharide-induced HAMP expression and alleviates various pathophysiological changes similar to anemia of inflammation. Consistently, overexpression of PGC-1alpha in HepG2 or HuH7 cells also suppresses HAMP expression and reduces iron accumulation. In contrast, knockdown of PGC-1alpha exaggerates LPS-induced HAMP expression and iron dysregulation. At the molecular level, PGC-1alpha suppresses HAMP transcription via the interaction with hepatocyte nuclear factor 4alpha. In addition, PGC-1alpha is present near hepatocyte nuclear factor 4alpha-binding site on the proximal HAMP promoter and turns the chromatin structure into an inactive state. Our data suggest a critical role for PGC-1alpha in the regulation of hepatic HAMP expression and iron homeostasis under inflammatory circumstances. PMID- 23438898 TI - Aortic dissection. PMID- 23438899 TI - Enhanced performance of NaOH-modified Pt/TiO2 toward room temperature selective oxidation of formaldehyde. AB - Pt/TiO(2) catalysts with various Pt loadings (0.05-2 wt %) were prepared by a combined NaOH-assisted impregnation of titania with Pt precursor and NaBH(4) reduction. The thermal catalytic activity was evaluated toward catalytic decomposition of formaldehyde (HCHO) vapor in the presence of toluene under ambient conditions. HCHO could be selectively oxidized into CO(2) and H(2)O over Pt/TiO(2) catalysts and toluene had no change. Pt/TiO(2) catalysts prepared with the assistance of NaOH showed higher HCHO oxidation activity than those without NaOH due to the introduction of additional surface hydroxyl groups, the enhanced adsorption capacity toward HCHO, and larger mesopores and macropores facilitating diffusion and transport of reactants and products. The as-prepared Pt/TiO(2) catalysts with an optimal Pt loading of 1 wt % exhibited high catalytic stability. Considering the versatile combination of noble-metal nanoparticles and supports, this work will provide new insights to the design of high-performance catalysts for indoor air purification. PMID- 23438900 TI - Live-cell analysis of plant reproduction: live-cell imaging, optical manipulation, and advanced microscopy technologies. AB - Sexual reproduction ensures propagation of species and enhances genetic diversity within populations. In flowering plants, sexual reproduction requires complicated and multi-step cell-to-cell communications among male and female cells. However, the confined nature of plant reproduction processes, which occur in the female reproductive organs and several cell layers of the pistil, limits our ability to observe these events in vivo. In this review, we discuss recent live-cell imaging in in vitro systems and the optical manipulation techniques that are used to capture the dynamic mechanisms representing molecular and cellular communications in sexual plant reproduction. PMID- 23438901 TI - Super-resolution scanning patch clamp reveals clustering of functional ion channels in adult ventricular myocyte. AB - RATIONALE: Compartmentation of ion channels on the cardiomyocyte surface is important for electric propagation and electromechanical coupling. The specialized T-tubule and costameric structures facilitate spatial coupling of various ion channels and receptors. Existing methods such as immunofluorescence and patch clamp techniques are limited in their ability to localize functional ion channels. As such, a correlation between channel protein location and channel function remains incomplete. OBJECTIVE: To validate a method that permits routine imaging of the topography of a live cardiomyocyte and study clustering of functional ion channels from a specific microdomain. METHODS AND RESULTS: We used scanning ion conductance microscopy and conventional cell-attached patch clamp with a software modification that allows controlled increase of pipette tip diameter. The sharp nanopipette used for topography scan was modified into a larger patch pipette that could be positioned with nanoscale precision to a specific site of interest (crest, groove, or T-tubules of cardiomyocytes) and sealed to the membrane for cell-attached recording of ion channels. Using this method, we significantly increased the probability of detecting activity of L type calcium channels in the T-tubules of ventricular cardiomyocytes. We also demonstrated that active sodium channels do not distribute homogenously on the sarcolemma instead, they segregate into clusters of various densities, most crowded in the crest region, that are surrounded by areas virtually free of functional sodium channels. CONCLUSIONS: Our new method substantially increases the throughput of recording location-specific functional ion channels on the cardiomyocyte sarcolemma, thereby allowing characterization of ion channels in relation to the microdomain where they reside. PMID- 23438893 TI - Individual variation in resisting temptation: implications for addiction. AB - When exposed to the sights, sounds, smells and/or places that have been associated with rewards, such as food or drugs, some individuals have difficulty resisting the temptation to seek out and consume them. Others have less difficulty restraining themselves. Thus, Pavlovian reward cues may motivate maladaptive patterns of behavior to a greater extent in some individuals than in others. We are just beginning to understand the factors underlying individual differences in the extent to which reward cues acquire powerful motivational properties, and therefore, the ability to act as incentive stimuli. Here we review converging evidence from studies in both human and non-human animals suggesting that a subset of individuals are more "cue reactive", in that certain reward cues are more likely to attract these individuals to them and motivate actions to get them. We suggest that those individuals for whom Pavlovian reward cues become especially powerful incentives may be more vulnerable to impulse control disorders, such as binge eating and addiction. PMID- 23438902 TI - Glycomic profiling of tissue sections by LC-MS. AB - Because routine preparation of glycan samples involves multiple reaction and cleaning steps at which sample loss occurs, glycan analysis is typically performed using large tissue samples. This type of analysis yields no detailed molecular spatial information and requires special care to maintain proper storage and shipping conditions. We describe here a new glycan sample preparation protocol using minimized sample preparation steps and optimized procedures. Tissue sections and spotted samples first undergo on-surface enzymatic digestion to release N-glycans. The released glycans are then reduced and permethylated prior to online purification and LC-electrospray ionization (ESI)-MS analysis. The efficiency of this protocol was initially evaluated using model glycoproteins and human blood serum (HBS) spotted on glass or Teflon slides. The new protocol permitted the detection of permethylated N-glycans derived from 10 ng RNase B. On the other hand, 66 N-glycans were identified when injecting the equivalent of permethylated glycans derived from a 0.1-MUL aliquot of HBS. On-tissue enzymatic digestion of nude mouse brain tissue permitted the detection of 43 N-glycans. The relative peak areas of these 43 glycans were comparable to those from a C57BL/6 mouse reported by the Consortium for Functional Glycomics (CFG). However, the sample size analyzed in the protocol described here was substantially smaller than for the routine method (submicrogram vs mg). The on-tissue N-glycan profiling method permits high sensitivity and reproducibility and can be widely applied to assess the spatial distribution of glycans associated with tissue sections, and may be correlated with immunoflourescence imaging when adjacent tissue sections are analyzed. PMID- 23438904 TI - Gender disparity in pediatric diseases. AB - Sex/gender differences in terms of incidence, prevalence, age at onset and severity have been documented for several complex adulthood diseases. However, several pediatric diseases also displayed a gender disparity. Unfortunately, epidemiologic studies investigating gender disparity in pediatric age show dissimilar results often depending on the spatial and temporal issues, to considerable regional environmental variations, to social conditions or to infectious agent virulence. Anyway, studies over time showed that gender disparity in childhood mortality and morbidity may be narrow in some pathological conditions whereas in other severe diseases, e.g. sepsis, some cancers and some immune disorders, the disproportion was found as significant. In this work we briefly review literature data dealing with sex/gender differences in morbidity and mortality observed during the pediatric age. In particular, communicable and non-communicable diseases, including cancer, have been considered. The possible mechanisms underlining these differences, e.g. hormonal and epigenetic, are also discussed. The analysis of literature available as concerns pediatric age seems to underline that gender differences start very early in human beings and that hormones as well as gene expression in XX and XY cells can play a role. A reappraisal of the gender issue in pediatric research could thus be pivotal: it might contribute to the improvement of diagnostic and therapeutic strategies as well as to the improvement of the appropriateness of the cures. PMID- 23438903 TI - The LIM protein fhlA is essential for heart chamber development in zebrafish embryos. AB - Four-and-a-half LIM proteins FHL1-3 play important roles in cardiovascular pathophysiology. However, their roles in heart development remain unclear. Here, we report that fhlA, the zebrafish homolog of human FHL1, was found to be expressed around the 22-somite stage. After 24 hpf, expression was restricted to the heart. fhlA knockdown caused an enlarged cardiac chamber phenotype with up regulated expression of the cardiac markers, but fhlA overexpression reduced the sizes of the cardiac chambers and down-regulated expression of the markers. The morphology associated with the cmlc2, amhc, and vmhc expression patterns at the 22 somite and 24 hpf stages included a broadened domain in embryos lacking fhlA and a smaller domain in embryos overexpressing fhlA. The changes in the sizes of the chambers were attributed to the changes in the number of ventricular and atrial cells. Loss of fhlA caused a longer heart period and pause between heartbeats in M-modes than in controls, but fhlA overexpression caused shorter systolic and diastolic intervals. Abnormal cardiac chambers and physiological function were found to be largely rescued. We also showed the expression of fhlA in the heart to be increased by retinoic acid (RA) and decreased by the RA synthase inhibitor DEAB. Both fhlA and RA signaling caused a phenotype characterized by the morphological alterations in the chamber sizes, suggesting that the role of fhlA in heart development is probably regulated by RA signaling. Taken together, these results showed that fhlA regulates the size of the heart chamber by reducing the number of cardiac cells. PMID- 23438912 TI - Training tomorrow's medical education leaders: creating a general pediatric master educator fellowship. PMID- 23438913 TI - 50 years ago in the Journal of Pediatrics: encephalographic changes in celiac disease. PMID- 23438914 TI - 50 years ago in the Journal of Pediatrics: the respiratory manifestations of systemic Haemophilus influenzae infection. PMID- 23438915 TI - 50 years ago in the Journal of Pediatrics: the clinical behavior of the newly born: I. the term baby. PMID- 23438916 TI - 50 years ago in the Journal of Pediatrics: social factors in relation to participation in follow-up care of rheumatic fever. PMID- 23438917 TI - 50 years ago in the Journal of Pediatrics: cat-scratch disease with encephalopathy. PMID- 23438918 TI - 50 years ago in the Journal of Pediatrics: clinical and serologic observations in patients with juvenile rheumatoid arthritis and their relatives. PMID- 23438919 TI - Exercise demonstrates a dose-response effect on insulin resistance, fatness, and visceral fat. PMID- 23438920 TI - Tight glucose control (with frequent episodes of hypoglycemia) among children admitted to the pediatric intensive care unit, does not affect neurocognitive development. PMID- 23438921 TI - Inhaled steroid controller-medication use in childhood has a negative effect on final adult height. PMID- 23438922 TI - Online program improves parenting skills and decreases early-childhood disruptive behavior. PMID- 23438923 TI - A school-based behavioral intervention program demonstrates improvement in individual student behavior. PMID- 23438924 TI - Children with "chronic wet cough" (presumed protracted bacterial bronchitis) respond to 14 days of amoxicillin clavulanate. PMID- 23438925 TI - Clinical prediction rule identifies children at low risk for appendicitis. PMID- 23438926 TI - Removing dietary liquid calories prevents accelerated body mass index increase. PMID- 23438927 TI - A strategic pediatric alliance for the future health of children in Europe. PMID- 23438928 TI - Resistant hypertension. PMID- 23438929 TI - Renin inhibition reverses renal disease in transgenic mice by shifting the balance between profibrotic and antifibrotic agents. AB - Aliskiren, a direct renin inhibitor, is a novel antihypertensive drug. To study whether aliskiren can reverse chronic kidney disease, we administered it to renin transgenic mice, a strain characterized by elevated blood pressure and a slow decline of renal function, mimicking well the progression of hypertensive chronic kidney disease. Ten-month-old transgenic mice were treated either with aliskiren or placebo for 28 days. Age-matched wild-type mice treated or not with aliskiren were considered as normotensive controls. Aliskiren reduced blood pressure to wild-type levels from as early as day 14. Proteinuria and cardiac hypertrophy and fibrosis were also normalized. Renal interstitial fibrosis and inflammation were significantly ameliorated in aliskiren-treated mice (shown by the decrease of proinflammatory and profibrotic markers), and the phenotypes of tubular epithelial cells and podocytes were restored as evidenced by the reappearance of cellular proteins characteristic of normal phenotype of these cells. Profibrotic p38 and Erk mitogen-activated protein kinases were highly activated in placebo treated transgenic animals. Aliskiren treatment cancelled this activation. This nephroprotection was not attributed to the antihypertensive activity of aliskiren, because blood pressure normalization after treatment with hydralazine failed to induce the regression of renal fibrosis. Direct inhibition of renin can restore renal function and structure in aged hypertensive animals with existing proteinuria. This finding suggests that, in addition to antihypertensive action, aliskiren can be also used to treat chronic kidney disease. PMID- 23438930 TI - Optogenetic stimulation of c1 and retrotrapezoid nucleus neurons causes sleep state-dependent cardiorespiratory stimulation and arousal in rats. AB - C1 catecholaminergic neurons and neurons of the retrotrapezoid nucleus are integrative nodes within the brain stem network regulating cardiorespiratory reflexes elicited by hypoxia and hypercapnia, stimuli that also produce arousal from sleep. In the present study, Channelrhodopsin-2 was selectively introduced into these neurons with a lentiviral vector to determine whether their selective activation also produces arousal in sleeping rats. Sleep stages were identified from electroencephalographic and neck muscle electromyographic recordings. Breathing was measured using unrestrained whole body plethysmography and blood pressure by telemetry. During nonrapid eye movement sleep, unilateral photostimulation of the C1 region caused arousal in 83.0+/-14.7% of trials and immediate and intense cardiorespiratory activation. Arousal during photostimulation was also observed during rapid eye movement sleep (41.9+/-5.6% of trials), but less reliably than during nonrapid eye movement sleep. The cardiorespiratory responses elicited by photostimulation were dramatically smaller during rapid eye movement sleep than nonrapid eye movement sleep or wakefulness. Systemic alpha1-adrenoreceptor blockade reduced the cardiorespiratory effects of photostimulation but had no effect on the arousal caused by photostimulation during nonrapid eye movement sleep. Postmortem histology showed that neurons expressing Channelrhodopsin 2-mCherry were predominantly catecholaminergic (81%). These results show that selective activation of C1 and retrotrapezoid nucleus neurons produces state-dependent arousal and cardiorespiratory stimulation. These neurons, which are powerfully activated by chemoreceptor stimulation, may contribute to the sleep disruption associated with obstructive sleep apnea. PMID- 23438931 TI - Relationships between selected gene polymorphisms and blood pressure sensitivity to weight loss in elderly persons with hypertension. AB - Salt sensitivity, the heterogeneity in the response of blood pressure (BP) to alterations in sodium intake, has been studied extensively, whereas weight sensitivity, the heterogeneity in BP response to weight change, has received scant attention. We examined the relationship of 21 gene polymorphisms previously found to be associated with hypertension, diabetes mellitus, or obesity, with weight sensitivity in the Trial of Nonpharmacologic Interventions in the Elderly, where participants with hypertension were randomized to receive intensive dietary intervention of sodium reduction, weight loss, both, or attention control, whereas pharmacological therapy was kept constant. After correcting for multiplicity, we identified significant associations of 3 polymorphisms with weight sensitivity of systolic BP (rs4646994, rs2820037, and rs1800629) and 3 polymorphisms for diastolic BP (rs4646994, rs2820037, and rs5744292). A recursive partitioning algorithm selected the combination of rs4646994, rs1800629, rs1982073, and rs1800896 as the set associated with the highest weight sensitivity. Polymorphisms related to hypertension, obesity, and diabetes mellitus are associated with weight sensitivity of BP. PMID- 23438932 TI - Effect of nifedipine versus telmisartan on prevention of atrial fibrillation recurrence in hypertensive patients. AB - It is controversial whether angiotensin II receptor blockers provide better protection than calcium antagonists against atrial fibrillation (AF) recurrence in hypertensive patients. This study was designed to compare the effect of nifedipine- and telmisartan-based antihypertensive treatments for preventing AF recurrence in hypertensive patients with paroxysmal AF. A total of 149 hypertensive patients with paroxysmal AF were randomized to nifedipine- or telmisartan-based antihypertensive treatment groups. The target blood pressure (BP) was <130/80 mm Hg. Clinic BP, ECG, Holter monitoring, and echocardiography were followed up for 2 years. The primary end point was the incidence of overall and persistent AF recurrence. During follow-up, there was no statistical difference in the rate of patients lowering to target BP between both groups, whereas nifedipine group had slightly better BP control but similar heart rate control at 24 months. The incidence of AF recurrence was similar in both groups (nifedipine versus telmisartan: 58.7% versus 55.4%; P=0.742), and Kaplan-Meier analysis showed no significant difference in the freedom from AF recurrence (log rank test; P=0.48). However, the rate of developing persistent AF in telmisartan group was lower than that in nifedipine group (5.4% versus 16.0%; P=0.035). Patients in telmisartan group had lower values of left atrial diameter, left atrial volume index, and left ventricular mass index at the end of follow-up. The effects of telmisartan in preventing AF recurrences in hypertensive patients with paroxysmal AF after intensive lowering BP is similar to that of nifedipine, but telmisartan has more potent effects on preventing progression to persistent AF. PMID- 23438933 TI - Investing in high blood pressure research: a national institutes of health perspective. PMID- 23438934 TI - Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension. AB - Blood-borne angiotensin II (ANG II) can upregulate p44/42 mitogen-activated protein kinase (MAPK) signaling and ANG II type-1 receptors in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center. We tested the hypothesis that brain p44/42 MAPK signaling contributes to the development of ANG II-induced hypertension. The ANG II infusion (120 ng/kg per min, subcutaneously) induced increases in phosphorylated p44/42 MAPK and ANG II type-1 receptors in the PVN after 1 week, before the onset of hypertension, that were sustained as hypertension developed during a 2- or 3-week infusion protocol. Bilateral PVN microinjections of small interfering RNAs for p44/42 MAPK, at the onset of the ANG II infusion or 1 week later, prevented the early increase in p44/42 MAPK activity. The early treatment normalized ANG II type-1 receptor expression in the PVN and attenuated the hypertensive response to the 2-week infusion of ANG II. The later small interfering RNA microinjections had a transient effect on ANG II type-1 receptor expression in PVN and no effect on the hypertensive response to the 3-week infusion of ANG II. The early treatment also normalized the pressure response to ganglionic blockade. The ANG II infusion induced increases in mRNA for proinflammatory cytokines that were not affected by either small interfering RNA treatment. These results suggest that the full expression of ANG II-induced hypertension depends on p44/42 MAPK-mediated effects. A potential role for p44/42 MAPK in modulating the ANG II-induced central inflammatory response might also be considered. MAPK signaling in PVN may be a novel target for early intervention in the progression of ANG II-dependent hypertension. PMID- 23438935 TI - Changes in subendocardial viability ratio with acute high-altitude exposure and protective role of acetazolamide. AB - High-altitude tourism is increasingly frequent, involving also subjects with manifest or subclinical coronary artery disease. Little is known, however, on the effects of altitude exposure on factors affecting coronary perfusion. The aim of our study was to assess myocardial oxygen supply/demand ratio in healthy subjects during acute exposure at high altitude and to evaluate the effect of acetazolamide on this parameter. Forty-four subjects (21 men, age range: 24-59 years) were randomized to double-blind acetazolamide 250 mg bid or placebo. Subendocardial viability ratio and oxygen supply/demand ratio were estimated on carotid artery by means of a validated PulsePen tonometer, at sea level, before and after treatment, and after acute and more prolonged exposure to high altitude (4559 m). On arrival at high altitude, subendocardial viability ratio was reduced in both placebo (from 1.63+/-0.15 to 1.18+/-0.17; P<0.001) and acetazolamide (from 1.68+/-0.25 to 1.35+/-0.18; P<0.001) groups. Subendocardial viability ratio returned to sea level values (1.65+/-0.24) after 3 days at high altitude under acetazolamide but remained lower than at sea level under placebo (1.42+/-0.22; P<0.005 versus baseline). At high altitude, oxygen supply/demand ratio fell both under placebo (from 29.6+/-4.0 to 17.3+/-3.0; P<0.001) and acetazolamide (from 32.1+/-7.0 to 22.3+/-4.6; P<0.001), its values remaining always higher (P<0.001) on acetazolamide. Administration of acetazolamide may, thus, antagonize the reduction in subendocardial oxygen supply triggered by exposure to hypobaric hypoxia. Further studies involving also subjects with known or subclinical coronary artery disease are needed to confirm a protective action of acetazolamide on myocardial viability under high-altitude exposure. PMID- 23438936 TI - Pathophysiological relevance of aldehydic protein modifications. AB - There is growing body of evidence that oxidative stress, i.e. excess in production of reactive oxygen species, can lead to covalent modification of proteins with bioactive aldehydes that are mostly produced under lipid peroxidation of polyunsaturated fatty acids. Thus generated reactive aldehydes are considered as second messengers of free radicals because they react with major bioactive macromolecules, in particular with various humoral and cellular proteins changing their structure and functions. Therefore, the aldehydic-protein adducts, in particular those involving 4-hydroxy-2-nonenal, malondialdehyde and acrolein can be valuable biomarkers of numerous pathophysiological processes. The development of immunochemical methods is increasing the possibilities to study such non-enzymatic protein modifications, on the one hand, while on the other hand the increase of knowledge on bioactivities of the aldehydes and their protein adducts might lead to better prevention, diagnosis and treatments of pathophysiological processes associated with lipid peroxidation and oxidative stress in general. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23438937 TI - Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine. AB - OBJECTIVE: Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo. DESIGN: Multicentre, parallel-group, double-blind placebo controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up. SETTING: Nine English old-age psychiatry services. PARTICIPANTS: A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+. EXCLUSIONS: clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer. INTERVENTIONS: (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily. MAIN OUTCOME MEASURES: OUTCOME: CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed. RESULTS: Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine). OUTCOME: Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112). HARMS: Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group. CONCLUSIONS: This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results. PMID- 23438938 TI - Identification of signals that facilitate isoform specific nucleolar localization of myosin IC. AB - Myosin IC is a single headed member of the myosin superfamily that localizes to the cytoplasm and the nucleus, where it is involved in transcription by RNA polymerases I and II, intranuclear transport, and nuclear export. In mammalian cells, three isoforms of myosin IC are expressed that differ only in the addition of short isoform-specific N-terminal peptides. Despite the high sequence homology, the isoforms show differences in cellular distribution, in localization to nuclear substructures, and in their interaction with nuclear proteins through yet unknown mechanisms. In this study, we used EGFP-fusion constructs that express truncated or mutated versions of myosin IC isoforms to detect regions that are involved in isoform-specific localization. We identified two nucleolar localization signals (NoLS). One NoLS is located in the myosin IC isoform B specific N-terminal peptide, the second NoLS is located upstream of the neck region within the head domain. We demonstrate that both NoLS are functional and necessary for nucleolar localization of specifically myosin IC isoform B. Our data provide a first mechanistic explanation for the observed functional differences between the myosin IC isoforms and are an important step toward our understanding of the underlying mechanisms that regulate the various and distinct functions of myosin IC isoforms. PMID- 23438939 TI - Metastasis: New insights into organ-specific extravasation and metastatic niches. AB - The appearance of clinically detectable metastases is the end-point of a complex set of biological processes only few cancer cells are capable to complete. Metastatic colonization comprises the most inefficient metastatic steps as it requires a fine-tuned crosstalk between the disseminated cancer (stem) cells and their host microenvironment. The origin of the cancer cell and its intrinsic properties are factors that together with the organ microenvironment and circulation patterns determine the site of metastatic spread, the dormancy period and the extent of metastasis formation. Recent advances provide novel insights into the molecular components required for organ-specific infiltration, the composition of growth-supportive metastatic niches in different tissues and the cancer cell-niche crosstalk. PMID- 23438940 TI - Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation. AB - Formation of the neural tube is the morphological hallmark for development of the embryonic central nervous system (CNS). Therefore, neural tube development is a crucial step in the neurulation process. Slit/Robo signaling was initially identified as a chemo-repellent that regulated axon growth cone elongation, but its role in controlling neural tube development is currently unknown. To address this issue, we investigated Slit/Robo1 signaling in the development of chick neCollege of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH, UKural tube and transgenic mice over-expressing Slit2. We disrupted Slit/Robo1 signaling by injecting R5 monoclonal antibodies into HH10 neural tubes to block the Robo1 receptor. This inhibited the normal development of the ventral body curvature and caused the spinal cord to curl up into a S-shape. Next, Slit/Robo1 signaling on one half-side of the chick embryo neural tube was disturbed by electroporation in ovo. We found that the morphology of the neural tube was dramatically abnormal after we interfered with Slit/Robo1 signaling. Furthermore, we established that silencing Robo1 inhibited cell proliferation while over expressing Robo1 enhanced cell proliferation. We also investigated the effects of altering Slit/Robo1 expression on Sonic Hedgehog (Shh) and Pax7 expression in the developing neural tube. We demonstrated that over-expressing Robo1 down-regulated Shh expression in the ventral neural tube and resulted in the production of fewer HNK-1(+) migrating neural crest cells (NCCs). In addition, Robo1 over-expression enhanced Pax7 expression in the dorsal neural tube and increased the number of Slug(+) pre-migratory NCCs. Conversely, silencing Robo1 expression resulted in an enhanced Shh expression and more HNK-1(+) migrating NCCs but reduced Pax7 expression and fewer Slug(+) pre-migratory NCCs were observed. In conclusion, we propose that Slit/Robo1 signaling is involved in regulating neural tube development by tightly coordinating cell proliferation and differentiation during neurulation. PMID- 23438941 TI - The fouling hydroid Ectopleura larynx: a lack of effect of next generation antifouling technologies. AB - The hydroid Ectopleura larynx is one of the main fouling organisms on salmon aquaculture cages in Norway; this study investigated novel surface materials and microtopographies to deter its settlement. The settlement preferences of hydroid larvae for 12 materials with wettabilities ranging from hydrophobic (54 degrees ) to hydrophilic (112 degrees ) were tested in a no-choice bioassay. Although settlement differed between materials, with the highest average settlement on polytetrafluoroethylene (95%) and the lowest on untreated polyurethane (53%), no trend regarding the tested wettabilities could be found and none of the tested materials was able to reduce average settlement below 50%. Furthermore, nine high density polyethylene (HDPE, 100-600 MUm microtopographies) and seven polydimethylsiloxane (PDMS; 40-400 MUm microtopographies) microtextured surfaces were tested. There was no systematic effect of microtopography on the settlement of E. larynx larvae. However, there was a preference for settlement in channels on PDMS microtopographies between 80 and 300 MUm. Similarly, there were no preferences for any of the examined microtopographies in a 12-day field test using PDMS surfaces at a commercial fish farm. The study indicated that neither surface wettability (hydrophilicity-phobicity) nor microtopographies were effective at deterring the settlement of the hydroid E. larynx. The high plasticity of the aboral pole and the hydrorhiza of the hydroids may explain settlement even under unfavourable conditions, highlighting the successful colonisation traits of this dominant biofouling species. PMID- 23438942 TI - Half Z-plasty, band release, and cavity filling for correction of inverted nipple. AB - The aim of this study was to describe another technique using a half Z-plasty, band release, and cavity filling to correct challenging inverted nipples. In five nipples of three adult Korean female cadavers, the tensile strength of the lactiferous duct was measured. A half Z-plasty was designed below the nipple on the areola using a vertical long axis of 30 degrees , 45 degrees , and 60 degrees for one flap and another of 90 degrees with 15 silicone-made nipple protectors. In six inverted nipples of three women, a half Z-plasty, band release, and cavity filling was performed. The mean breaking strength of each lactiferous was 4.7 +/- 2.3 N. The sum of the forces to break three ducts was 14.1 +/- 6.5 N. The mean angle change of the nipple projection of the silicone model was 7.2 degrees +/- 0.3 degrees , 9.4 degrees +/- 0.5 degrees , and 13.4 degrees +/- 0.5 degrees , respectively, in the 30 degrees , 45 degrees , and 60 degrees flap. In all three nipples operated on, sufficient eversion of the nipples was satisfactorily obtained postoperatively. Releasing the inverted nipple was performed by severing the underlying tight fibrous tissue bands and canaliculi. The support of the nipple was maintained by propping and obliterating the dead space. This procedure was carried out through a half Z-plasty incision below the nipple on the areola. PMID- 23438943 TI - Association between the methionine synthase A2756G polymorphism and neural tube defect risk: a meta-analysis. AB - Many studies have accessed the association between methionine synthase (MTR) A2756G polymorphism and neural tube defect (NTD). However, the conclusions are inconsistent. Our study aimed to clarify the nature of the genetic risks contributed by this polymorphism for NTD using meta-analysis. We searched electronic literature from the PubMed, EMBASE, and Medline databases, from which 10 articles were selected according to the inclusion criteria. The meta-analysis was conducted in 3 groups, namely, NTD patients, mothers with NTD offspring and fathers with NTD offspring. Pooled odds ratios (ORs) and 95% confidence intervals were used to evaluate the strength of the association and the result was corrected by multiple testing. To sum up, no associations between the MTR A2756G polymorphism and NTD risk were found among the 3 groups in all genetic models. However, as their sample size is not large enough, this result needs further research. PMID- 23438944 TI - A prospective analysis of invasive candidiasis following cardiac surgery: severity markers are predictive. AB - AIM: Invasive Candida infections (ICI) in intensive care unit (ICU) patients are associated with high mortality. A 2-year prospective study was performed to improve clinical decision making in long-term ICU patients after cardiac surgery. METHODS: Demographic, clinical and physiological data, the incidence of ICI and Candida colonisation scores were analysed. To assess severity of illness the new simplified acute physiology score (SAPS II score), the European system for cardiac operative risk evaluation (EuroSCORE) and the sequential organ failure assessment (SOFA) score were calculated. To define independent risk factors univariate and multivariate Cox-regression analyses with time-dependent covariates were calculated. RESULTS: One hundred and sixty-nine cardiac surgery patients with ICU admittance >= 4 days out of 513 admittances were enrolled. Ten patients had proven ICI. In the multivariate analysis the SOFA score (HR = 1.29, p = 0.009) was associated with proven ICI. In 71 patients receiving empiric antifungal therapy for presumptive but unproven ICI the SOFA score (HR = 1.18, p = 0.029) and corrected Candida colonisation index (HR 11.08; p = 0.030) were significantly associated to ICI. Neither SAPS II score nor EuroScore were associated with ICI in either patient group. The mortality rate of patients receiving empiric antifungal therapy was significantly lower compared to that of patients with proven ICI (36.6% vs. 80%, respectively). CONCLUSION: Time associated SOFA score assessing acute organ failure was the only independent risk factor for proven ICI. Cardiovascular procedures did not confer risk to develop ICI. Empiric antifungal therapy may be warranted in severely ill cardiac surgery patients. PMID- 23438945 TI - The antihepatic fibrotic effects of fluorofenidone via MAPK signalling pathways. AB - BACKGROUND: Fluorofenidone (AKF-PD) is a novel pyridone agent. The purpose of this study is to investigate the inhibitory effects of AKF-PD on dimethylnitrosamine (DMN)-induced liver fibrosis in rats and the involved molecular mechanism related to hepatic stellate cells (HSCs). MATERIALS AND METHODS: Wistar rats were randomly divided into normal control, DMN, DMN/AKF-PD treatment and DMN/pirfenidone (PFD) treatment groups. AKF-PD and PFD treatments were, respectively, performed for two activated HSCs lines, rat CFSC-2G and human LX2. The cell proliferation was analysed by MTT. The expression of collagen I was determined by immunohistochemical staining and real-time RT-PCR. The expression of alpha-smooth muscle actin (alpha-SMA), tissue inhibitor of metalloproteinases 1 (TIMP-1), extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected by real-time RT-PCR and/or Western blot. RESULTS: AKF-PD significantly reduced PDGF BB-induced proliferation and activation of HSCs, as determined by reducing protein expression of alpha-SMA and TIMP-1. AKF-PD treatment attenuated PDGF-BB induced upregulation of phosphorylation of ERK1/2, p38 and JNK. In fibrotic rat liver, AKF-PD reduced the degree of liver injury and hepatic fibrosis, which was associated with reduced the expression of collagen I, alpha-SMA, TIMP-1 at both mRNA and protein levels. CONCLUSION: AKF-PD treatment inhibits the progression of hepatic fibrosis by suppressing HSCs proliferation and activation via MAPK signalling pathway. PMID- 23438946 TI - Effect of CYP3A5*3 polymorphism on pharmacokinetic drug interaction between tacrolimus and amlodipine. AB - The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0 fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC0 infinity of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine. PMID- 23438948 TI - Liver: Size matters: effects of reduced paracetamol pack sizes in England and Wales. PMID- 23438949 TI - IBD: Fertilizing the gut: host-derived nitrate contributes to Escherichia coli bloom in colitis. PMID- 23438947 TI - Extrinsic primary afferent signalling in the gut. AB - Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that just five structurally distinct types of sensory endings are present in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular-mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators. Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders. PMID- 23438951 TI - Direct anti-atherosclerotic therapy; development of natural anti-atherosclerotic drugs preventing cellular cholesterol retention. AB - The results of numerous clinical trials with statins and other drugs have demonstrated the principal possibility of the prevention and regression of atherosclerosis by pharmacotherapy. This review describes the use of cultured human arterial cells for the mass screening of anti-atherosclerotic substances, the investigation of the mechanisms responsible for their atherosclerosis-related effects, and the optimization of anti-atherosclerotic and anti-atherogenic drug and dietary therapies. Natural products can be considered promising drugs for anti-atherosclerotic therapy. Our basic studies have shown that cellular lipidosis is the principal event in the genesis of atherosclerotic lesions. Using cellular models and natural products, we have developed an approach to prevent lipid accumulation in arterial cells. Based on our knowledge of atherosclerosis, we developed drugs that possess direct anti-atherosclerotic activity. Two-year treatment with allicor (garlic powder) has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Inflaminat (calendula, elder, and violet), which possesses anti-cytokine activity, has been shown to cause the regression of carotid atherosclerosis following the treatment of asymptomatic men for one year. The phytoestrogen-rich drug karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, beta-carotene, alpha-tocopherol, and ascorbic acid) prevents the development of carotid atherosclerosis in postmenopausal women. Thus, our basic findings were successfully translated into clinical practice. Because of this translation, a novel approach to antiatherosclerotic therapy was developed. Our clinical trial confirmed the efficacy of both the novel approach and the novel drugs. PMID- 23438950 TI - Endothelin-1 induced middle cerebral artery occlusion model for ischemic stroke with laser Doppler flowmetry guidance in rat. AB - Stroke is the number one cause of disability and third leading cause of death in the world, costing an estimated $70 billion in the United States in 2009. Several models of cerebral ischemia have been developed to mimic the human condition of stroke. It has been suggested that up to 80% of all strokes result from ischemic damage in the middle cerebral artery (MCA) area. In the early 1990s, endothelin-1 (ET-1) was used to induce ischemia by applying it directly adjacent to the surface of the MCA after craniotomy. Later, this model was modified by using a stereotaxic injection of ET-1 adjacent to the MCA to produce focal cerebral ischemia. The main advantages of this model include the ability to perform the procedure quickly, the ability to control artery constriction by altering the dose of ET-1 delivered, no need to manipulate the extracranial vessels supplying blood to the brain as well as gradual reperfusion rates that more closely mimics the reperfusion in humans. On the other hand, the ET-1 model has disadvantages that include the need for a craniotomy, as well as higher variability in stroke volume. This variability can be reduced with the use of laser Doppler flowmetry (LDF) to verify cerebral ischemia during ET-1 infusion. Factors that affect stroke variability include precision of infusion and the batch of the ET-1 used. Another important consideration is that although reperfusion is a common occurrence in human stroke, the duration of occlusion for ET-1 induced MCAO may not closely mimic that of human stroke where many patients have partial reperfusion over a period of hours to days following occlusion. This protocol will describe in detail the ET-1 induced MCAO model for ischemic stroke in rats. It will also draw attention to special considerations and potential drawbacks throughout the procedure. PMID- 23438952 TI - T cell-based therapies for atherosclerosis. AB - Cardiovascular diseases (CVDs), largely due to atherosclerosis, are the major causes of death in today's world. Atherosclerosis is a chronic inflammatory condition initiated by retention and accumulation of cholesterol-containing lipoproteins, in particular low-density lipoprotein (LDL), in the artery wall. This initiates pathological responses of immune cells that lead to atherosclerotic plaque formation. T cells are present during all stages of the disease, and play an essential role in the initiation and progression of plaques. Whereas most T effector cell responses have been suggested to aggravate atherosclerosis, regulatory T cells (Tregs) have been shown to limit inflammation and inhibit the formation of lesions. In addition to their effects on the local pathological process, T cells and their released mediators modulate systemic lipid metabolism and can increase risk of CVDs. Such knowledge on the pathological and protective function of these cells has led to significant advances in the field. This review examines experimental and pre-clinical studies approaching the manipulation of cellular immunity in atherosclerosis. Modulation of T cells responses by vaccination, antibody therapies, dendritic cell based therapies, and using amino acid-derived metabolites have shown benefits against atherosclerotic plaque progression in animal models. The clinical benefit of T cell-based therapies in humans still requires further investigation. PMID- 23438953 TI - Taking risk prediction to the next level. Advances in biomarker research for atherosclerosis. AB - Advances in risk prediction are necessary to stem the tide of the increasing incidence of global cardiovascular disease. Newly discovered biomarkers are needed for primary and secondary prevention and will undoubtedly play a major role in drug development programs and monitoring of treatment efficacy. The combination of improved -omics technologies and the investigation of relatively untapped sources of biomarkers will likely result in risk algorithms that will add value on top of the traditional risk factors. New sources of biomarkers are being explored with encouraging results. These include microvesicles, microRNAs, circulating cells and atherosclerotic plaques. We will review these sources for their potential for new biomarkers. Furthermore, the major impact of advances in genetics on risk prediction and biomarker development programs will be discussed. PMID- 23438954 TI - Fluid-phase pinocytosis of LDL by macrophages: a novel target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. AB - Circulating low-density lipoprotein (LDL) that enters the blood vessel wall is the main source of cholesterol that accumulates within atherosclerotic plaques. Much of the deposited cholesterol accumulates within plaque macrophages converting these macrophages into cholesterol-rich foamy looking cells. Cholesterol accumulation in macrophages contributes to cholesterol retention within the vessel wall, and promotes vessel wall inflammation and thrombogenicity. Thus, how macrophages accumulate cholesterol and become foam cells has been the subject of intense investigation. It is generally believed that macrophages accumulate cholesterol only through scavenger receptor-mediated uptake of modified LDL. However, an alternative mechanism for macrophage foam cell formation that does not depend on LDL modification or macrophage receptors has been elucidated. By this alternative mechanism, macrophages show receptor independent uptake of unmodified native LDL that is mediated by fluid-phase pinocytosis. In receptor-independent, fluid-phase pinocytosis, macrophages take up LDL as part of the fluid that they ingest during micropinocytosis within small vesicles called micropinosomes, and by macropinocytosis within larger vacuoles called macropinosomes. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. Fluid phase pinocytosis of LDL is a plausible mechanism that can explain how macrophages accumulate cholesterol and become disease-causing foam cells. Fluid phase pinocytosis of LDL is a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis. Recent studies show that phosphoinositide 3-kinase (PI3K), liver X receptors (LXRs), the macrophage colony stimulating factor (M-CSF) receptor, and protein kinase C (PKC) mediate macrophage macropinocytosis of LDL, and thus, these may be relevant targets to inhibit macrophage cholesterol accumulation in atherosclerosis. PMID- 23438955 TI - Mitochondrial mutations in atherosclerosis: new solutions in research and possible clinical applications. AB - Cardiovascular diseases are the leading causes of morbidity and mortality in many industrialized societies. Atherosclerosis is the major risk factor for the development of cardiovascular disease based on arterial endothelial dysfunction caused by the impairment of endothelial-dependent dilation. Atherosclerosis is a complex vascular disease resulted from the harmful interactions between genetic and environmental factors. There is a growing body of evidence in support of a non-redundant role of mitochondrial factors in the pathogenesis of atherosclerosis. Impaired mitochondrial function and structural and qualitative changes in mitochondrial components such as mitochondrial DNA (mtDNA) may be directly involved in the development of multiple atherogenic mechanisms including advanced oxidative stress, abnormalities in glucose and fat metabolism, and altered energy homeostasis. Recent findings showed that the heteroplasmy level of some somatic mtDNA is associated with coronary atherosclerosis. Although this field should further widely elaborated, heteroplasmic mtDNA mutations could represent a new promising molecular biomarker of genetic susceptibility to atherosclerosis and related pathologic conditions. In this review, we critically consider the contribution of mitochondria-related factors to the pathogenesis of the arterial vascular pathology. PMID- 23438956 TI - Blood atherogenicity as a target for anti-atherosclerotic therapy. AB - Atherogenicity of serum taken from patients with coronary heart disease (CHD) is the ability to induce cholesterol deposition in cultured cells, such as vascular smooth muscle cells (VSMCs) from human aortic intima or blood-derived monocytes/macrophages. The discovery of this phenomenon evoked the series of studies of serum components responsible for atherogenic effects, especially serum lipoproteins. A fraction of circulating negatively charged low density lipoproteins (LDL) enriched with disialylated LDL was found in the blood CHD patients. This LDL fraction was prone to multiple modifications including desialylation and oxidation, and had advanced immunogenic and atherogenic properties, resulting in cholesterol accumulation in cultured intimal VSMCs and formation of circulating immune complexes in blood. The analysis of this proatherogenic LDL helped to understand the mechanisms of subclinical stages of atherogenesis, and pointed out the presence of individual susceptibility to atherosclerosis in humans. The practical application of serum atherogenicity phenomenon is the development of cell-based models for the assessment of cardiovascular drugs. The suitability of these models in pharmacological research was supported by the results of atherosclerosis regression studies, evaluation of antiatherogenic properties of various classes of cardiovascular drugs, and elucidating the ways for further development of drugs for direct anti atherosclerotic therapy. PMID- 23438957 TI - Potential use of dendritic cells for anti-atherosclerotic therapy. AB - The chronic inflammatory nature of atherosclerosis is nowadays widely accepted. Dendritic cells (DCs) are likely to play a crucial role in directing innate and adaptive immunity against altered (self-)antigens, such as oxidized low density lipoproteins (oxLDL). DCs are found in early lesions and their numbers become even higher when the lesion progresses. DCs are most abundant in areas of neovascularization where they are often found near T cells. All stages from precursors to fully mature DCs are present in human plaques. Treatment of atherosclerosis is currently based on reducing risk factors, e.g. by use of statins and beta-blockers. Some of these pharmacological agents also show anti inflammatory properties and consequently can affect DC function. Yet, many patients remain at risk for acute coronary events, and new therapies to treat atherosclerosis are needed. One therapeutic strategy is based on isolation of patient's DCs that are then pulsed with appropriate antigen(s) ex vivo, e.g. (immunogenic components of) oxLDL or total extract of atherosclerotic plaque tissue, and returned to the blood stream. Other approaches to ensure immune protection include generation of tolerogenic DCs, or using DCs to deplete detrimental Th1 or Th17 cells. However, the future lies in direct targeting of DCs by manipulating functions of different DC subsets. Therefore, it would be useful to isolate plaque-resident DCs to be able to identify unique antigen(s) on their surface. The challenge is to selectively identify regulatory molecules and novel therapies to inhibit DC migration and function during atherogenesis, without affecting normal DC function under physiological conditions. PMID- 23438958 TI - Emerging anti-inflammatory therapies for atherosclerosis. AB - Atherosclerosis remains one of the main causes of cardiovascular disease, which is the leading cause of death worldwide. It is now accepted that atherosclerosis is an inflammatory, dynamic and complex disease involving multiple cell types, and many antiinflammatory strategies have recently emerged as potential therapeutic approaches for atherosclerotic disease. In this review, we discuss the most recent progress in the development of anti-inflammatory strategies. We highlight the beneficial effects of potent antiinflammatory drugs, including recently developed biologics, and we describe diverse emerging approaches that target inflammatory processes involved in atherosclerosis including tumor necrosis factor antagonists, anti-interleukins, viral-derived serpins, P-selectin inhibition and leukotriene synthesis inhibition. PMID- 23438959 TI - Novel monocyte biomarkers of atherogenic conditions. AB - Hidden low grade inflammation underlines various cardio-metabolic diseases. This type of inflammation is triggered by abnormal reaction to unwanted self products or deregulation of cellular response to cytokines. In the case of atherosclerosis hidden inflammation is induced by modified lipoproteins and develops under control of different cytokines including IL-4 and TGFbeta. The key innate immune cells reacting on these factors are monocytes and macrophages. It is well established that monocytes represent a heterogeneous cell population that easily reacts to pathologic changes in the organism. The best studied marker which expression on monocytes is changed in inflammatory conditions is CD16. Although this marker was shown to be associated with various pathologic conditions its specificity is highly questionable. There is an urgent need of identification of new monocyte-expressed biomarkers that may help not only to detect hidden inflammation but also to determine its type. Our analysis of type 2 activation of human monocytes resulted in identification of 3 novel biomarkers for hidden type 2 inflammation. These include stabilin-1, FOXQ1 and IL17RB. These markers are expressed by monocytes/macrophages under stimulation with IL-4 or its combination with TGFbeta - 2 cytokines playing important role in atherogenesis. Stabilin-1 was demonstrated on the monocytes in patients with hyperholisterolemia and in macrophages within atherosclerotic lesions. Association of FoxQ1 and IL17RB with atherosclerosis can be deduced from published data but requires experimental confirmation. Functions of all three proteins suggest that they are not only diagnostic markers, but also involved in atherogenesis and can be used as targets for novel therapeutic approaches. PMID- 23438960 TI - Naoxintong protects against atherosclerosis through lipid-lowering and inhibiting maturation of dendritic cells in LDL receptor knockout mice fed a high-fat diet. AB - Naoxintong (NXT), a Chinese Materia Medica standardized product, extracted from 16 various kinds of Chinese traditional herbal medicines including Salvia miltiorrhiza, Angelica sinennsis, Astragali Radix, is clinically effective in treating atherosclerosisrelated diseases. Here, we tested the hypothesis that the anti-atherosclerosis effects of NXT might be mediated by suppressing maturation of dendritic cells (DCs) in a mice model of atherosclerosis. LDLR(-/-) mice fed a high-fat diet were treated with placebo, NXT (0.7 g/kg/d, oral diet) or simvastatin (100mg/kg/d, oral diet) for 8 weeks, respectively. NXT treatment significantly reduced plasma triglyceride (112 +/- 18 mg/dl vs. 192 +/- 68 mg/dl, P<0.05) and total cholesterol (944 +/- 158 mg/dl vs. 1387 +/- 208 mg/dl, P<0.05) compared to placebo treatment. Vascular lesions were significantly smaller and macrophage content and amount of DCs in plaques were significantly less in NXT and simvastatin groups than in placebo group (all P<0.05). In addition, expressions of splenic DC membrane molecules (CD40, CD86 and CD80) and the plasma level of IL-12p70 were significantly lower in NXT and simvastatin groups than in placebo group. In conclusion, NXT protects against atherosclerosis through lipid lowering and inhibiting DCs maturation in this mice model of atherosclerosis. PMID- 23438962 TI - Cyclophilins in atherosclerosis: a new therapeutic target? AB - Atherosclerosis is a chronic disease with a significant inflammatory component. Recent studies indicate a role of extracellular cyclophilins as contributors to endothelial inflammation and pathogenesis of atherosclerosis. In this article, we review current literature on pro-inflammatory activities of extracellular cyclophilins and discuss possible approaches to selectively target this novel proinflammatory factor. PMID- 23438961 TI - Importance of receptor-targeted systems in the battle against atherosclerosis. AB - Atherosclerosis is the leading cause of death in the Western World and has been for decades a field of intense research. Yet, while there is a rich and diverse literature describing in detail the players and mechanisms involved in this complex disease in cell and animal models, we remain today with virtually no reliable markers for early diagnosis and targeted treatments options. This review is centered upon the latter. We summarize the latest studies focused on detecting endothelial dysfunction during the early stages of atherosclerosis, when the disease is asymptomatic and describe strategies recently proposed to image and target advanced plaque. PMID- 23438963 TI - The complementary roles of imaging and 'omics' for future anti-atherosclerotic drug development. AB - With the rising global incidence and burden of atherosclerotic disease, there is a need to identify new molecular targets that may not only serve as biomarkers of clinical risk, but also therapeutic targets. The efficiency of drug-development processes needs to improve in order to allocate finite resources towards the evaluation of the most promising compounds. Atherosclerosis imaging provides key information regarding mechanistic efficacy of novel compounds, as an intermediary endpoint, prior to the consideration of embarking upon a large-scale, multi center randomized placebo-controlled trial. Coronary intravascular ultrasonography and B-mode sonography of carotid intima-media thickness will continue to play an important role in evaluating the efficacy of novel anti atherosclerotic compounds. Functional, molecular imaging of atherosclerotic plaque is emerging as an exciting experimental tool, allowing for an even greater understanding of processes that drive the progression and instability of atherosclerotic disease. However, given the complexity and heterogeneity of biological systems, a global, non-targeted, systems biological approach to biomarker discovery is likely to yield the discovery of novel molecular footprints of disease. As such, metabolomic and lipidomic approaches will elucidate metabolite signatures of interest for biomarker evaluation, for clinical risk prediction, as well as safety and toxicity of experimental treatment compounds. Imaging studies will remain important for evaluating novel therapeutic strategies gleaned from omics-based discoveries, as well acting as a triage to further undertake large-scale clinical evaluation of these promising therapeutic strategies. These approaches will provide an opportunity to better understand atherosclerosis, its complications and effective treatments across multiple ethnic populations worldwide. PMID- 23438964 TI - Dendritic cells in atherosclerosis. AB - It is recognized that the development of atherosclerosis involves many elements of an inflammatory process, involving components of both the innate and adaptive immune systems. The presence and roles of macrophages and T-cells in atherogenesis are well-established. More recently dendritic cells have been identified in the vasculature and in atherosclerotic lesions. This review summarises our current understanding of the roles of dendritic cells in the development and regression of atherosclerosis. PMID- 23438965 TI - Novel targets and biomarkers for anti-atherosclerotic therapy. PMID- 23438966 TI - Treatment and control of scabies. AB - PURPOSE OF REVIEW: The treatment of individual patients with scabies and its control in institutional and community settings remains challenging, with relatively few treatment choices available. In this review, evidence of the efficacy of available treatments will be discussed, and possible emerging drug resistance and new therapeutic directions outlined. RECENT FINDINGS: Although there has been attention on the use of ivermectin for the treatment of ordinary scabies and for mass drug administration, evidence supporting its superiority for both indications over alternative treatment is inconclusive. This is particularly true in light of several case reports of drug resistance in human and veterinary settings when the drug has been intensively used. When used correctly, topical agents such as permethrin and benzyl benzoate are effective. Little research on the development of new and more effective acaricides suitable for human use is underway. While the in-vitro acaricidal properties of several natural products have been documented, these are yet to be evaluated in animal studies or clinical trials. SUMMARY: When properly administered, chemotherapy for scabies remains effective in most situations. However, with reports of drug resistance increasing and with the need for therapies suitable for use in interventions to control community outbreaks, there is a need to develop new therapies. PMID- 23438967 TI - Kinetics of N-nitrosopiperazine formation from nitrite and piperazine in CO2 capture. AB - Piperazine (PZ) is an efficient amine for carbon capture systems, but it can form N-nitrosopiperazine (MNPZ), a carcinogen, from nitrogen oxides (NO(x)) in flue gas from coal or natural gas combustion. The reaction of nitrite with PZ was studied in 0.1 to 5 mol/dm(3) PZ with 0.001 to 0.8 mol CO2/mol PZ at 50 to 135 degrees C. The reaction forming MNPZ is first order in nitrite, piperazine carbamate species, and hydronium ion. The activation energy is 84 +/- 2 kJ/mol with a rate constant of 8.5 * 10(3) +/- 1.4 * 10(3) dm(6) mol(-2) s(-1) at 100 degrees C. The proposed mechanism involves protonation of the carbamate species, nucleophilic attack of the carbamic acid, and formation of bicarbonate and MNPZ. These kinetics and mechanism will be useful in identifying inhibitors and other strategies to reduce nitrosamine accumulation in CO2 capture by scrubbing with PZ or other amines. PMID- 23438968 TI - Current developments of coumarin compounds in medicinal chemistry. AB - Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarinbased medicinal chemistry are also presented. PMID- 23438969 TI - Detection of protein palmitoylation in cultured hippocampal neurons by immunoprecipitation and acyl-biotin exchange (ABE). AB - Palmitoylation is a post-translational lipid modification involving the attachment of a 16-carbon saturated fatty acid, palmitate, to cysteine residues of substrate proteins through a labile thioester bond [reviewed in]. Palmitoylation of a substrate protein increases its hydrophobicity, and typically facilitates its trafficking toward cellular membranes. Recent studies have shown palmitoylation to be one of the most common lipid modifications in neurons, suggesting that palmitate turnover is an important mechanism by which these cells regulate the targeting and trafficking of proteins. The identification and detection of palmitoylated substrates can therefore better our understanding of protein trafficking in neurons. Detection of protein palmitoylation in the past has been technically hindered due to the lack of a consensus sequence among substrate proteins, and the reliance on metabolic labeling of palmitoyl-proteins with (3)H-palmitate, a time-consuming biochemical assay with low sensitivity. Development of the Acyl-Biotin Exchange (ABE) assay enables more rapid and high sensitivity detection of palmitoylated proteins, and is optimal for measuring the dynamic turnover of palmitate on neuronal proteins. The ABE assay is comprised of three biochemical steps (Figure 1): 1) irreversible blockade of unmodified cysteine thiol groups using N-ethylmaliemide (NEM), 2) specific cleavage and unmasking of the palmitoylated cysteine's thiol group by hydroxylamine (HAM), and 3) selective labeling of the palmitoylated cysteine using a thiol-reactive biotinylation reagent, biotin-BMCC. Purification of the thiol-biotinylated proteins following the ABE steps has differed, depending on the overall goal of the experiment. Here, we describe a method to purify a palmitoylated protein of interest in primary hippocampal neurons by an initial immunoprecipitation (IP) step using an antibody directed against the protein, followed by the ABE assay and western blotting to directly measure palmitoylation levels of that protein, which is termed the IP-ABE assay. Low-density cultures of embryonic rat hippocampal neurons have been widely used to study the localization, function, and trafficking of neuronal proteins, making them ideally suited for studying neuronal protein palmitoylation using the IP-ABE assay. The IP-ABE assay mainly requires standard IP and western blotting reagents, and is only limited by the availability of antibodies against the target substrate. This assay can easily be adapted for the purification and detection of transfected palmitoylated proteins in heterologous cell cultures, primary neuronal cultures derived from various brain tissues of both mouse and rat, and even primary brain tissue itself. PMID- 23438970 TI - Revision extension to the pelvis versus primary spinopelvic instrumentation in adult deformity: comparison of clinical outcomes and complications. AB - OBJECTIVE: To evaluate the outcomes and complications of patients with adult spinal deformity treated in a primary versus revision fashion with long fusions to the sacropelvis. METHODS: A retrospective review was performed of a multicenter consecutive series of patients with adult spinal deformity requiring fusion to the sacropelvis, either primarily or as revision, with minimum 2-year follow-up. Clinical (Scoliosis Research Society [SRS] 22 questionnaire) and radiographic parameters (including sagittal vertical axis [SVA], coronal Cobb angle, lumbar lordosis, and thoracic kyphosis) were compared between the groups. RESULTS: There were 63 patients who met inclusion criteria; mean patient age was 51.9 years, and mean follow-up was 43 months. Patients requiring primary fusion were older (58.0 years vs. 49.5 years, P=0.01) and at baseline had a lower SVA (2.1 cm vs. 6.8 cm, P=0.01) and greater thoracolumbar Cobb angle (51.2 degrees vs. 36.5 degrees, P=0.003). At last follow-up, patients undergoing primary fusion and patients undergoing revision treatment had similar SVA (2.9 cm vs. 1.8 cm, P=0.32) and lumbar lordosis (-42.3 degrees vs. -43.4 degrees, P=0.82); patients undergoing revision treatment had more favorable SRS 22 scores (3.65 vs. 3.14, P=0.005). There was no statistical difference in complication rates between the groups (44.4% vs. 35%, P=0.68). CONCLUSIONS: Patients requiring revision extension of instrumentation to the pelvis can be treated with the same expectation of radiographic and clinical success as patients treated primarily with fusion to the sacropelvis. The complication rate for the revision procedure is not insignificant and may be similar to a primary procedure that includes pelvic fixation. PMID- 23438971 TI - Intraoperative coregistration of magnetic resonance imaging, positron emission tomography, and electrocorticographic data for neocortical lesional epilepsies may improve the localization of the epileptogenic focus: a pilot study. AB - OBJECTIVE: To objectively mark out abnormal areas of magnetic resonance imaging (MRI), positron emission tomography (PET), and electrocorticography (ECoG) using neuronavigation so as to 1) enhance the accuracy of margins of the epileptogenic zone and 2) understand the relationships of all the three modalities with each other. METHODS: A prospective study was conducted of 37 patients with intractable epilepsy due to lesional, neocortical pathologies from noneloquent areas. Prior to surgery, fusion and transfer of MRI and PET images onto a neuronavigation system was performed. At surgery, this was correlated to intraoperative ECoG using the electrode as referential points. An objective score was created for every electrode point that was correlated with MRI and PET abnormality at the point. The extent of surgical resection was mapped out using these data. RESULTS: From a total of the data recorded from 1280 electrode points, 23.5% were located over the lesion. In addition, over the lesions, 93% of PET and 66% of ECoG points were abnormal. Over the perilesional areas, 43% of PET and 45% of ECoG points were abnormal. Using these data for surgery, both lesional and perileisonal areas were resected; 33/37 patients had good outcome (25 Engel I, 8 Engel II) (mean follow-up: 23.6 +/- 3.2 months; range 18-31 months). CONCLUSION: Multimodal imaging and ECoG using this method seems to provide a better objective localization of the epileptogenic foci. PMID- 23438972 TI - Anaemia management and mortality risk in chronic kidney disease. AB - Renal anaemia is a frequent complication in patients with chronic kidney disease (CKD). Severe anaemia (haemoglobin <90 g/l) is associated with increased risks of mortality and cardiac complications, such as left ventricular hypertrophy and cardiovascular disease, and impaired quality of life. Randomized controlled trials have tested the hypothesis that increasing haemoglobin level using erythropoiesis-stimulating agents (ESAs) lowers these risks and improves quality of life. Use of ESAs to normalize haemoglobin levels (to >=130 g/l) versus the partial correction of anaemia (to haemoglobin levels of 90-110 g/l) has repeatedly been shown to have no cardiac benefit and to be associated with no incremental improvement in outcomes and quality of life (except fatigue), but has been shown to be associated with an increased risk of cardiovascular events and death. Use of more-intense iron dosing has been proposed in order to reduce ESA dosing but liberal intravenous iron therapy is also associated with complications, and its long-term safety has not yet been adequately investigated. For patients with CKD on dialysis, US medication labels recommend administering ESAs at doses sufficient to avoid transfusions, whereas European and Canadian labels recommend targeting haemoglobin levels of 100-120 g/l and 110-120 g/l, respectively. Treatment of anaemia to haemoglobin levels of 90-110 g/l in patients with CKD accomplishes what we want--a reduced need for transfusions and possible reductions in fatigue, while avoiding high doses of ESA or iron in order to achieve a specific haemoglobin goal. PMID- 23438974 TI - APOL1 variants and kidney disease in people of recent African ancestry. AB - Coding variants within the APOL1 gene have been associated with kidney disease, explaining an association that was previously attributed to variants within the neighbouring MYH9 gene. To better define the role of APOL1 in causing kidney disease in individuals of African ancestry, we performed an extensive survey of the common variation in the region surrounding the APOL1 gene, as seen through the lens of the 1000 Genomes Project. Arguing by exclusion, it is reasonable to conclude that the putative APOL1 causal variants are not proxies for any other variants with more direct roles in kidney disease. Our statistical argument is in part made possible by the exceptionally young age of the APOL1 coding variants coupled with the unusually high rate of genetic recombination surrounding this gene. Although no biological evidence currently exists for the causality of APOL1 variants with kidney disease, our statistical reasoning provides a strong case for causality, and a region to target in future functional studies. PMID- 23438975 TI - Editorial: welcome to our Recent Patents on Biotechnology Special Edition on skeletal muscle diseases! PMID- 23438976 TI - Comment on "regulatory FOCUS surface water models fail to predict insecticide concentrations in the field; Environ. Sci. Technol. 2012, 46, 8397-8404". PMID- 23438977 TI - Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor. AB - The familial transthyretin (TTR) amyloidosis (FTA) demonstrates variable penetrance of clinical features associated with mutations in the plasma thyroid hormone-binding protein TTR gene. The purpose of this study was to assess the ocular features, to analyze vitreous and serum vascular endothelial growth factor (VEGF) levels, and to identify the genetic defect in a Chinese family with TTR FTA. The pedigree of interest was a three-generation family with eleven members. The primary ocular signs were vitreous opacities, beginning from the third or fourth decade, accompanied by retinal vasculitis, hemorrhages, and widespread pinpoint deposits in the peripheral retina. Two patients underwent vitrectomy with marked improvement of visual acuity postoperatively. Vitreous and serum samples for VEGF were analyzed with an enzyme-linked immunosorbent assay (ELISA). Forty-eight healthy adult volunteers were enrolled as a control group for the analysis of serum VEGF. Eight subjects who underwent vitrectomy for a macular epiretinal membrane or macular hole were enrolled as control for the analysis of vitreous VEGF. Both serum and vitreous VEGF levels of patients were raised compared to that of controls. Venous blood was collected from family members and the genomic DNA was extracted. All exons and exon-intron boundaries of the TTR gene were sequenced. A previously-described pathogenic transversion in exon 2 (c.G106C, p.Ala36Pro) was identified. Within this family eight individuals were confirmed as affected. In conclusion, a Chinese family with TTR Ala36Pro associated FTA is characterized by early ocular involvement. Widespread pinpoint lesions indicate RPE lesions caused by TTR deposition. FTA is associated with increased VEGF levels, both in serum and vitreous. PMID- 23438973 TI - Vasopressin: a novel target for the prevention and retardation of kidney disease? AB - After several decades during which little attention was paid to vasopressin and/or urine concentration in clinical practice, interest in vasopressin has renewed with the availability of new, potent, orally active vasopressin-receptor antagonists--the vaptans--and with the results of epidemiological studies evaluating copeptin (a surrogate marker of vasopressin) in large population-based cohorts. Several experimental studies in rats and mice had previously shown that vasopressin, acting via vasopressin V2 antidiuretic receptors, contributes to the progression of chronic kidney disease; in particular, to autosomal dominant polycystic kidney disease. New epidemiological studies now suggest a role for vasopressin in the pathogenesis of diabetes mellitus and metabolic disorders via activation of hepatic V1a and/or pancreatic islet V1b receptors. The first part of this Review describes the adverse effects of vasopressin, as revealed by clinical and experimental studies in kidney diseases, hypertension, diabetes and the metabolic syndrome. The second part provides insights into vasopressin physiology and pathophysiology that may be relevant to the understanding of these adverse effects and that are linked to the excretion of concentrated nitrogen wastes and associated hyperfiltration. Collectively, the studies reviewed here suggest that more attention should be given to the vasopressin-thirst-urine concentration axis in clinical investigations and in patient care. Whether selective blockade of the different vasopressin receptors may provide therapeutic benefits beyond their present indication in hyponatraemia requires new clinical trials. PMID- 23438979 TI - Ultra-small NLC for improved dermal delivery of coenyzme Q10. AB - Coenzyme Q10 (CoQ10) acts as an antioxidant in the skin and is frequently contained in anti-aging products. In previous studies, it could be shown that nano-structured lipid carriers (NLC) with a size of about 230 nm are beneficial for the dermal delivery of CoQ10. They increased Q10 skin penetration when compared to equally sized nanoemulsion. In this study, ultra-small NLC were prepared with even smaller mean particles sizes of around 80 nm. The influence of this decrease of particle size was investigated in terms of skin permeation and penetration as well as physicochemical stability of the NLC. Improved dermal delivery of CoQ10 by ultra-small NLC could be achieved. PMID- 23438980 TI - Here and now: my perspective. AB - In this paper the author describes her particular perspective in doing analytic work. She stresses working in the here and now. For example, making interpretations that grow out of what the patient says or does in the sessions, keeping the patient's history in mind, but not letting it lead interpretations. The analysis tries to understand why something is being said now, in this way, and what impact it may have or be designed to have in the analytic relationship. The term 'here' refers to what is going on between patient and analyst in the room while not leaving out the patient's immediate reality in the outside world, his everyday life. The word 'now' implies awareness of time that is not just of the past and future but of the patient's situation at the moment in analysis, which is constantly shifting.The author believes that by working primarily in the present the patient will feel more anchored, both patient and analyst can observe what is going on, for example how anxiety arises or decreases, how defences are mobilised or lessen. Both analyst and patient experience movement and change rather than relying on more theoretical explanations. PMID- 23438978 TI - Hemolytic and pharmacokinetic studies of liposomal and particulate amphotericin B formulations. AB - Amphotericin B (AmB) is a very effective antifungal and antiparasitic drug with a narrow therapeutic window. To improve its efficacy/toxicity balance, new controlled release formulations have been developed based on different encapsulation systems, aggregation states and particle sizes modifications. The kinetics of the hemolytic process was studied not only to characterize the toxicity of different formulations but also as an indicator of drug release. Pharmacokinetic studies in beagle dogs were carried out with those formulations that exhibited the least hemolytic toxicity: liposomal formulation (AmBisome), poly-aggregated AmB and encapsulated particulate AmB formulation. A novel poly aggregated AmB formulation proved to be comparable in terms of low hemolytic activity with the marketed gold standard formulation: AmBisome. Its pharmacokinetic profile, characterized by a smaller area under the curve and larger volume of distribution, was markedly different from AmBisome, resulting in a cost-effective alternative for the treatment of leishmaniasis which can enhance the AmB passive target by the uptake by the cells of the reticulo-endothelial system. Effects of different variables such as type of formulation, dose, microencapsulation, anesthesia and dog's healthy state on AmB pharmacokinetics were studied. PMID- 23438981 TI - Where is here? When is now? AB - With a Kleinian perspective influenced by Betty Joseph, the author describes the distinctive 'here and now' of a psychoanalysis as the place and the time of the patient's inner subjective world as it emerges in the work of patient and analyst. This psychoanalytic 'here' and 'now' is examined with clinical material from the analysis of Mr X; first, with an account of the way his analysis begins and then through a detailed session five years later.The author identifies Mr X's problems with place and time, and how these change over the course of the analysis. He moves from sequestered dyadic relationships towards an Oedipal and family space, and from disconnection and timelessness to acquiring a sense of duration, of being in the present with a past and a future - all of which, the paper aims to show, has implications for technique. PMID- 23438982 TI - Black client, white therapist: working with race in psychoanalytic psychotherapy in South Africa. AB - In post-apartheid South Africa we speak about race extensively. It permeates our workplace, weaves a thread through the fabric of our professional and personal lives, as well as our private conversations and public interactions with others. From within psychoanalytic theory, the thread weaves through the unknown content of our racialized unconscious. When there is a focus on race in the South African psychoanalytic context it largely takes the form of the struggle to articulate the complexities of working with difference, as Swartz notes, or the struggle to map out issues of race. Such struggles are not localized in South Africa, but strongly reflect a much broader struggle within the global psychoanalytic community, as mirrored in the expanding focus on race. Although the consulting rooms seem far removed from the ongoing political tensions that have recently emerged in South Africa, psychoanalytic psychotherapy remains a space of meaningful engagement with the other, and where the therapeutic dyad is one of racial difference it permits an encounter with our racialized unconscious. This article seeks to document the experience of my black client and my white response to her racial pain and struggle; in doing so, I describe the racial 'contact' between us and within us that triggers a racialized transference and countertransference dynamic, which contains the space for racial healing for both of us. PMID- 23438983 TI - Projective identification in Othello and Verdi's Otello. AB - In this paper I explore how projective identification is depicted in Shakespeare's Othello (1603-4 [2006]) and in Verdi's Otello (1887). Both the play and the opera can be seen as studies in projection - in the evacuation into others of feelings that the subject finds unbearable, such as envious and jealous exclusion or unbearable sexual excitement. The essential issue is the same in both the play and the opera, which is that the very sight of love between Othello and Desdemona, or of contentment in anyone's mind, drives Iago mad with envy and jealousy, which he has to expel and project into others, particularly into Othello, who is susceptible to this attack because of his own narcissistic vulnerability. I take two episodes, which appear in both the play and the opera, to explore in detail how projective identification is represented both verbally and musically. I suggest that music, and words used musically, are particularly suited to conveying complex inter- and intra-personal processes such as projective identification. PMID- 23438984 TI - Name-changes in post-war France: the traumatic experiences of the Shoah and its consequences on the second and third generation with reference to the example of name-changes. AB - Starting from our collective initiative to work on the theme of 'The strength of the name', which has given rise both to a conference as well as a documentary called: And their name, they have changed it, I have sought to draw attention in this article to the difference between proper names, patronymic names, and the so called Name-of-the-father. Pronouncing names involves designating the languages of names, which also refer to the accents of names, since I have proposed the idea that each name is evocative of a language, and that changing it also modifies the language of the name. I have approached the question of the name by considering cases of name-changes, essential with regard to Ashkenazi Jewish families who changed their name after the Shoah, along with the trauma that numerous Jewish families suffered after the war. French jurisprudence does not permit reversion to the original name, once it has been changed to a more French sounding name, owing to the immutability of the name and the foreign sound of the names of origin. PMID- 23438985 TI - Playing the game the child allots. AB - This paper explores the relationship between play and interpretative verbalization in child analysis. Through examination of a clinical case, the paper distinguishes between two different modes of interpretative interventions in play. It is the contention of the paper that the analyst's capacity to tolerate tension and respond to the roles the child assigns him widens the area of play, facilitating a space for thinking through. Interpretation is formulated in two distinct ways: (a) interpreting from the context of the roles the analyst assumes within play, respecting the games and facilitating the patient's understanding; (b) interpreting at a distance from play, on the one hand distinguishing the area of play, and on the other hand analyzing that which occurs verbally and non-verbally. PMID- 23438986 TI - The analyst's work. PMID- 23438987 TI - Learning to ride the horse: the back and forth of an analytic treatment and setting - the case of Raquel. PMID- 23438988 TI - Comments on the case of Raquel. PMID- 23438989 TI - Comments on the case of Raquel. PMID- 23438990 TI - On Winnicott's clinical innovations in the analysis of adults: responses to the controversy. PMID- 23438991 TI - Response by Michael Eigen. PMID- 23438992 TI - Response by Jan Abram. PMID- 23438993 TI - Response by Vincenzo Bonaminio. PMID- 23438994 TI - Response by Charles Hanly. PMID- 23438995 TI - Response by Daniel Widlocher. PMID- 23438996 TI - An introduction to the work of Andre Green. PMID- 23438997 TI - Andre Green 1927-2012: an artisan of the future. PMID- 23438998 TI - Andre Green (12 March 1927-22 January 2012). PMID- 23439000 TI - Congenital and acquired bleeding disorders: the right factor for the right patient. PMID- 23439001 TI - CorifactTM/Fibrogammin(r) P in the prophylactic treatment of hereditary factor XIII deficiency: results of a prospective, multicenter, open-label study. AB - Factor XIII (FXIII) deficiency is an extremely rare congenital condition that is associated with a high risk of potentially life-threatening intracranial hemorrhage, poor wound healing, spontaneous abortion, and a life-long tendency towards spontaneous bleeding and severe bleeding after trauma or surgery. Routine prophylaxis with FXIII concentrate is recommended in all individuals with FXIII levels <1 IU/dL from the time of diagnosis, and in some severely affected patients with FXIII levels of 1-4 IU/dL. Fibrogammin(r) P is a highly purified, pasteurized, plasma-derived concentrate that has been available in Europe and other countries since 1993 and has recently been approved as CorifactTM in the USA. To support the US registration of CorifactTM, a 52-week, prospective, multicenter, open-label study was conducted in 41 patients (mean age 19 years; range <1-42 years) with congenital FXIII deficiency. CorifactTM/Fibrogammin(r) P was administered intravenously at an initial dose of 40 IU/kg every 4 weeks, with dosing adjusted to maintain a trough FXIII activity level of 5-20%. No spontaneous bleeding episodes requiring FXIII treatment were reported during the study (primary endpoint). Preoperative use of CorifactTM/Fibrogammin(r) P successfully prevented postoperative bleeding in two surgeries. CorifactTM/Fibrogammin(r) P was well tolerated during a total exposure of ~ 455 subject-months. No patient withdrew from treatment, and there were no reports of virus transmission or thromboembolism-related events. This study adds to the wealth of data gained from clinical trials and almost 20 years of clinical use confirming that CorifactTM/Fibrogammin(r) P is an effective and well-tolerated prophylactic treatment for congenital FXIII deficiency. PMID- 23439002 TI - Severe bleeding in surgical and trauma patients: the role of fibrinogen replacement therapy. AB - Fibrinogen is in a central position in the coagulation system, playing an important role in platelet aggregation and establishing the fibrin network. Fibrinogen is also the first coagulation factor to become critically low during surgery and after major trauma. Hemostatic support has traditionally involved using transfusion of allogeneic blood products, including fresh frozen plasma; however, there is a lack of conclusive evidence supporting the clinical effectiveness of fresh frozen plasma in these situations. Early, targeted fibrinogen substitution may be preferable in terms of speed of administration and clinical effectiveness, with recent studies adding to the weight of evidence demonstrating the potential to significantly reduce blood loss and transfusion requirements in surgical and severe trauma patients with this approach. The availability of point-of-care testing using viscoelastic techniques to guide fibrinogen substitution has enabled the development of transfusion algorithms that lead to individualized, goal-directed, and targeted use of fibrinogen concentrates to improve clinical outcomes. Fibrinogen replacement has become the standard-of-care in several major surgical centers in Europe and is recommended in current European trauma treatment guidelines. Future prospective studies will help to establish the critical threshold and target levels for fibrinogen substitution in different acute-care situations and should encourage more widespread use of this rational and effective approach to the treatment of bleeding-induced coagulopathies. PMID- 23439003 TI - Diagnosis and treatment of acquired von Willebrand syndrome. AB - Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that is characterized by structural or functional alterations in von Willebrand factor (VWF) caused by a range of lymphoproliferative, myeloproliferative, cardiovascular, autoimmune, and other disorders. The pathogenic mechanisms responsible for the VWF abnormalities depend on the underlying condition, but include clearance due to binding of paraproteins, inhibition of VWF, adsorption to the surface of platelets, increased fluid shear stress, and resultant proteolysis or, more rarely, decreased synthesis. The diagnosis and treatment of AVWS are complicated by the need for multiple laboratory tests and the management of bleeding risk in a typically elderly population with serious underlying conditions that predispose towards thrombosis. Recently developed diagnostic algorithms, based on standard laboratory assays, may assist clinicians with the diagnostic workup and help differentiate between AVWS and von Willebrand disease (VWD) types 1 and 2. AVWS should be considered in all patients with new-onset bleeding whenever laboratory findings suggest VWD, particularly in the presence of an AVWS-associated disorder. AVWS testing is also recommended prior to surgery or an intervention with a high risk of bleeding in any individual with an AVWS associated disorder. Treatment of the underlying condition using immunosuppressants, surgery, or chemotherapy, can lead to remission of AVWS in some individuals and should always be considered. Strategies to prevent and/or treat bleeding episodes should also be in place, including the use of VWF containing factor VIII concentrates, desmopressin and tranexamic acid. Treatment success will depend largely on the underlying pathogenesis of the disorder. PMID- 23439004 TI - Epidemiology and treatment of congenital fibrinogen deficiency. AB - Congenital fibrinogen deficiency is a rare bleeding disorder, affecting either the quantity (afibrinogenemia, hypofibrinogenemia) or quality (dysfibrinogenemia) of circulating fibrinogen. There is a strong association between fibrinogen activity levels and clinical bleeding severity. Patients with afibrinogenemia experience frequent, often severe, spontaneous bleeds into the muscles and joints and are at significant risk of intracranial hemorrhage. Patients with hypofibrinogenemia are usually asymptomatic; however, they are vulnerable to bleeding after trauma. Dysfibrinogenemia is associated with both spontaneous bleeding and a relatively high risk of thrombosis. Fibrinogen replacement therapy is effective in treating bleeding episodes in congenital fibrinogen deficiency. Fibrinogen concentrates are the preferred treatment option and guidelines now exist for their on-demand use and to manage surgery. Prophylaxis may benefit patients with afibrinogenemia and others with a severe bleeding tendency. The dose and frequency of administration should be adjusted to maintain a fibrinogen activity level >0.5-1.0 g/L. Pregnant women with afibrinogenemia require prophylactic factor replacement as early as possible during pregnancy, continuing throughout pregnancy, and after the birth. Fibrinogen replacement should also be considered in pregnant women with other fibrinogen deficiencies. The risk of thrombosis presents an additional management challenge in these patients, often necessitating the concurrent use of anticoagulants and fibrinogen. Although basic guidelines have been developed, further studies are needed to help optimize treatment in different patient groups under different clinical circumstances and to improve our understanding of thrombotic events. PMID- 23439005 TI - Antiseptic cyclodextrin-functionalized hydrogels and gauzes for loading and delivery of benzalkonium chloride. AB - Prevention and management of wound infections receive a lot of attention, since the presence of micro-organisms interferes with the wound-healing process. The aim of this work was to use cyclodextrins (CDs) to endow hydrogels and gauzes with the ability to take up antiseptics and sustain their delivery for several hours. Benzalkonium chloride (BzCl) can form inclusion complexes with cross linked CDs that regulate the release through an affinity-driven mechanism. Grafting of CDs to cotton gauzes using citric acid as the linker, at 190 degrees C and for 15 min, led to grafting yields of about 148%, much larger than those obtained at 180 degrees C or with shorter reaction times. Microbiological tests revealed that the BzCl-loaded networks can inhibit the growth of Staphylococcus epidermidis and Escherichia coli both on agar plates and in liquid medium. Furthermore, the antiseptic-loaded gauzes were able to inhibit biofilm formation by Staphylococcus aureus RN1HG pMV158GFP when applied in early stages of biofilm formation and could reduce the number of living cells in preformed biofilms grown in a chronic wound biofilm model. These findings highlight the role of CDs as main components of hydrogels and gauzes for the efficient delivery of antiseptics. PMID- 23439006 TI - Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti tumor immunity. AB - Despite the powerful aspects of immune reactions, most often tumor cells are able to evade immune recognition and destruction. Cosignaling molecules from the B7/CD28 and TNF/TNFR superfamilies emerge as novel targets in immunotherapy. Upregulation of coinhibitory molecules by the tumor cells or tumor-infiltrating lymphocytes clearly attenuates T-cell responses against cancer and appears to be a mechanism exerted by the tumor to escape immune response. Today, a variety of coinhibitory molecules, including CTLA-4 and PD1 have been implicated in immune escape of cancer cells. Antagonist antibodies are developed to overcome immune evasion and until now anti-CTLA-4 and anti-PD1 antibodies have been tested in clinical trials with encouraging results. Here we summarize the recent advances made on PD1/PD1 ligands expression in cancer and we discuss about another couple of inhibitory molecules, BTLA and its ligand HVEM and their potential role in immune escape. Such information may provide novel therapeutic targets to reverse tumor-induced T-cell dysfunction in patients with advanced cancers. PMID- 23439008 TI - Effects of thyroxin (T4) and activin A on in vitro growth of preantral follicles in domestic cats. AB - Preantral follicle culture is a promising technique for rescuing gametes from endangered animals that die abruptly. The objective was to determine effects of thyroxin (T(4)) and activin A on in vitro growth and morphology of preantral feline ovarian follicles. Preantral follicles (86.3 +/- 18.7 MUm) were isolated from fresh ovaries of domestic cats. Healthy follicles were cultured individually for 14 days in 20-MUL microdrops of M199 supplemented with 0.23 mmol/L sodium pyruvate, 2 mmol/L L-glutamine, 12.5 mmol/L HEPES, 0.3% (wt/vol) BSA, 1% (vol/vol) insulin-transferrin-selenite solution, 100 IU/mL penicillin, 0.1 mg/mL streptomycin, 1.0 mIU/mL growth hormone, 2.13 MUg/mL FSH, and 10 ng/mL insulin like growth factor I. The effect of various concentrations of T(4) (0.5, 1.0, or 2.0 MUg/mL) or activin A (10, 100, or 200 ng/mL) on follicle growth and follicular integrity were assessed. Follicle diameter was measured on Days 0, 3, 7, and 14 of culture. Follicle morphology was characterized based on granulosa cell proliferation, dissociation of somatic cells, and detachment of oocytes from follicles. On Day 14, follicles were assessed for viability using ethidium homodimer-1 staining. In the control sample, diameters of follicles increased from initial sizes on Day 3, and peaked on Day 7. This pattern was also observed in both T(4)- and activin A-treated follicles. On Day 7, diameters and diameter gains of follicles treated with 10 ng/mL (mean +/- SEM; 170.8 +/- 7.6 and 35.9 +/ 5.1 MUm, respectively) and 200 ng/mL activin A (165.2 +/- 10.4 and 32.8 +/- 5.5 MUm, respectively) were larger than those of the control follicles (P < 0.05). Furthermore, 10 ng/mL activin A increased percentage of viable follicles on Day 14 (46.9% viable; P < 0.05). Follicles treated with activin A had rapid granulosa cell proliferation until Day 7. In conclusion, activin A promoted growth of preantral feline follicles and supported follicle viability during a 14-day culture, whereas T(4) supplementation had no beneficial effects. PMID- 23439007 TI - PKCalpha and PKCbeta cooperate functionally in CD3-induced de novo IL-2 mRNA transcription. AB - The physiological functions of PKCalpha and PKCtheta isotypes downstream of the antigen receptor have been defined in CD3(+) T cells. In contrast, no function of the second conventional PKC member, PKCbeta, has been described yet in T cell antigen receptor signalling. To investigate the hypothesis that both conventional PKCalpha and PKCbeta isotypes may have overlapping functions in T cell activation signalling, we generated mice that lacked the genes for both isotypes. We found that PKCalpha(-/-)/beta(-/-) animals are viable, live normal life spans and display normal T cell development. However, these animals possess additive defects in T cell responses in comparison to animals that carry single mutations in these genes. Our studies demonstrate that the activities of PKCalpha and PKCbeta converge to regulate IL-2 cytokine responses in anti-CD3 stimulated primary mouse T cells. Here, we present genetic evidence that PKCalpha and PKCbeta cooperate in IL-2 transcriptional transactivation in primary mouse T cells independently of the actions of PKCtheta. PMID- 23439009 TI - Analysis of the solvent accessibility of cysteine residues on Maize rayado fino virus virus-like particles produced in Nicotiana benthamiana plants and cross linking of peptides to VLPs. AB - Mimicking and exploiting virus properties and physicochemical and physical characteristics holds promise to provide solutions to some of the world's most pressing challenges. The sheer range and types of viruses coupled with their intriguing properties potentially give endless opportunities for applications in virus-based technologies. Viruses have the ability to self- assemble into particles with discrete shape and size, specificity of symmetry, polyvalence, and stable properties under a wide range of temperature and pH conditions. Not surprisingly, with such a remarkable range of properties, viruses are proposed for use in biomaterials, vaccines, electronic materials, chemical tools, and molecular electronic containers. In order to utilize viruses in nanotechnology, they must be modified from their natural forms to impart new functions. This challenging process can be performed through several mechanisms including genetic modification of the viral genome and chemically attaching foreign or desired molecules to the virus particle reactive groups. The ability to modify a virus primarily depends upon the physiochemical and physical properties of the virus. In addition, the genetic or physiochemical modifications need to be performed without adversely affecting the virus native structure and virus function. Maize rayado fino virus (MRFV) coat proteins self-assemble in Escherichia coli producing stable and empty VLPs that are stabilized by protein-protein interactions and that can be used in virus-based technologies applications. VLPs produced in tobacco plants were examined as a scaffold on which a variety of peptides can be covalently displayed. Here, we describe the steps to 1) determine which of the solvent-accessible cysteines in a virus capsid are available for modification, and 2) bioconjugate peptides to the modified capsids. By using native or mutationally-inserted amino acid residues and standard coupling technologies, a wide variety of materials have been displayed on the surface of plant viruses such as, Brome mosaic virus, Carnation mottle virus, Cowpea chlorotic mottle virus, Tobacco mosaic virus, Turnip yellow mosaic virus, and MRFV. PMID- 23439010 TI - Calorimetric studies of ligands binding to glutathione S-transferase from the malarial parasite Plasmodium falciparum. AB - Glutathione S-transferase, from the malarial parasite Plasmodium falciparum (PfGST), exerts a protective role in the organism and is thus considered an interesting target for antimalarial drug development. In contrast to other GSTs, it is present in solution as a tetramer and a dimer in equilibrium, which is induced by glutathione (GSH). These properties prevent a calorimetric titration from being conducted upon binding of ligands to this protein's G-site. Thermodynamic characterization can be an optimal strategy for antimalarial drug development, and isothermal titration calorimetry (ITC) is the only technique that allows the separation of the binding energy into both enthalpic and entropic contributions. This information facilitates an understanding of the changes in the drugs' substituents, improving their affinity and specificity. In this study, we have applied a nontypical ITC procedure, based on the dissociation of the ligand-protein complex, to calorimetrically study the binding of the GSH substrate, and the glutathione sulfonate competitive inhibitor, to dimeric PfGST over a temperature range of 15-37 degrees C. The optimal experimental conditions for applying this procedure have been optimized by studying the dimer to tetramer conversion using size exclusion chromatography. The binding of these ligands to dimeric PfGST is noncooperative, the affinity of glutathione sulfonate being approximately 2 orders of magnitude higher than that of its natural substrate GSH. The binding of both ligands is enthalpically favorable and entropically unfavorable at all the studied temperatures. These results demonstrate that, although PfGST presents differences when compared to other known GSTs, these ligands bind to its dimeric form with a similar affinity and energetic balance. However, in contrast to that of other GSTs, the binding of GSH to protein, in the absence of the ligand, is slow. PMID- 23439012 TI - Echocardiography in the perioperative decision making of patients with aortic stenosis. AB - The perioperative management of patients with aortic stenosis is influenced by preoperative echocardiographic findings. This paper explains how to read and interpret key echocardiografic findings and suggests how to optimize monitoring and pharmacological treatment of patients with aortic stenosis undergoing cardiac or non-cardiac surgery. PMID- 23439014 TI - Response to: Preoperative cardiac evaluation in proximal femur fractures and its effects on the surgical outcome. PMID- 23439015 TI - Production of sulfate radical from peroxymonosulfate induced by a magnetically separable CuFe2O4 spinel in water: efficiency, stability, and mechanism. AB - A simple, nonhazardous, efficient and low energy-consuming process is desirable to generate powerful radicals from peroxymonosulfate (PMS) for recalcitrant pollutant removal. In this work, the production of radical species from PMS induced by a magnetic CuFe(2)O(4) spinel was studied. Iopromide, a recalcitrant model pollutant, was used to investigate the efficiency of this process. CuFe(2)O(4) showed higher activity and 30 times lower Cu(2+) leaching (1.5 MUg L( 1) per 100 mg L(-1)) than a well-crystallized CuO at the same dosage. CuFe(2)O(4) maintained its activity and crystallinity during repeated batch experiments. In comparison, the activity of CuO declined significantly, which was ascribed to the deterioration in its degree of crystallinity. The efficiency of the PMS/CuFe(2)O(4) was highest at neutral pH and decreased at acidic and alkaline pHs. Sulfate radical was the primary radical species responsible for the iopromide degradation. On the basis of the stoichiometry of oxalate degradation in the PMS/CuFe(2)O(4), the radical production yield from PMS was determined to be near 1 mol/mol. The PMS decomposition involved an inner-sphere complexation with the oxide's surface Cu(II) sites. In situ characterization of the oxide surface with ATR-FTIR and Raman during the PMS decomposition suggested that surface Cu(II)-Cu(III)-Cu(II) redox cycle was responsible for the efficient sulfate radical generation from PMS. PMID- 23439016 TI - Interstitial laser-induced thermotherapy of the lung: evaluation of the influence of ablation continuity on ablation size in a swine model. AB - The purpose of this study was to assess the relationship between size and the continuity of energy application in interstitial laser-induced thermotherapy. Percutaneous computed tomography-guided laser ablation (30 W, 600 nm diode) of the lung was performed in 7 Yorkshire pigs; a total of 42 ablation zones were created. Twenty ablations were performed using a continuous cycle of 2 min (protocol A) and 22 ablations were performed using 4 intermittent cycles with a duration of 1 min for each cycle interrupted by a 10-s stop between the cycles (protocol B). The lung was harvested immediately after euthanasia for gross pathology and histopathologic evaluation. Statistical analysis was performed using the Student t test and the Spearman correlation coefficient. Laser ablation resulted in complete necrosis of variable size of lung. The mean ablation zone dimensions (+/-SD) were 1.9 (+/-0.4) cm * 1.4 (+/-0.3) cm for protocol A and 2.2 (+/-0.5) cm * 1.4 (+/-0.4) cm for protocol B. The size of the necrosis is not significantly different when comparing a continuous 2-min ablation to a 4-cycle intermittent ablation for 1 min each cycle interrupted by a 10-s stop between the cycles (P = 0.98 and 0.53, respectively). PMID- 23439017 TI - Cardiovascular imaging: new directions in an evolving landscape. PMID- 23439018 TI - Imaging heart failure: current and future applications. AB - A variety of cardiac imaging tests are used to help manage patients with heart failure (HF). This article reviews current and future HF applications for the major noninvasive imaging modalities: transthoracic echocardiography (TTE), single-photon emission computed tomography (SPECT), positron emission tomography (PET), cardiovascular magnetic resonance (CMR), and computed tomography (CT). TTE is the primary imaging test used in the evaluation of patients with HF, given its widespread availability and reliability in assessing cardiac structure and function. Recent developments in myocardial strain, 3-dimensional TTE, and echo contrast appear to offer superior diagnostic and prognostic information. SPECT imaging is a common method employed to detect ischemia and viability in patients with HF; however, PET offers higher diagnostic accuracy for both. Ongoing study of sympathetic and molecular imaging techniques may enable early disease detection, better risk stratification, and ultimately targeted treatment interventions. CMR provides high-quality information on cardiac structure and function and allows the characterization of myocardial tissue. Myocardial late gadolinium enhancement allows the determination of HF etiology and may predict patient outcomes and treatment response. Cardiac CT has become a reliable means for detecting coronary artery disease, and recent advances have enabled concurrent myocardial function, perfusion, and scar analyses. Overall, available imaging methods provide reliable measures of cardiac performance in HF, and recent advances will allow detection of subclinical disease. More data are needed demonstrating the specific clinical value of imaging methods and particularly subclinical disease detection in large-scale, clinical settings. PMID- 23439019 TI - The prognostic role of late gadolinium enhancement magnetic resonance imaging in patients with cardiomyopathy. AB - Cardiovascular magnetic resonance imaging (CMRI) is currently considered part of standard care at many academic centres for the evaluation of patients with ischemic or nonischemic cardiomyopathy. While CMRI provides unparalleled diagnostic versatility for the assessment of myocardial function, perfusion, and tissue health, evidence supporting its prognostic value for the prediction of important cardiovascular events is now emerging. Given the low specificity of currently available clinical markers in patients with cardiomyopathy, more-robust biomarkers aimed at identifying those at high risk of sudden cardiac death and other relevant outcomes are desirable. Late gadolinium enhancement (LGE) CMRI offers the novel capacity to quantify the burden of myocardial fibrosis, a common pathophysiological end point of most cardiomyopathy states. As such, it has the potential to be a robust and ubiquitous marker of cardiovascular events related to the presence of advanced tissue disease. This review paper focuses on the evidence to date supporting LGE imaging as a tool for the prediction of future cardiovascular events in patients with ischemic and nonischemic cardiomyopathy. PMID- 23439020 TI - Standards for provision and accreditation of echocardiography in Ontario. AB - In March of 2010, the Ontario Ministry of Health and Long-term Care and Ontario Medical Association jointly commissioned a Working Group to make recommendations regarding the provision and accreditation of echocardiographic services in Ontario. That commission undertook a process to examine all aspects of the provision, reporting and interpretation of echocardiographic examinations, including the echocardiographic examination itself, facilities, equipment, reporting, indications, and qualifications of personnel involved in the acquisition and interpretation of studies. The result was development of a set of 54 performance standards and a process for accreditation of echocardiographic facilities, initially on a voluntary basis, but leading to a process of mandatory accreditation. This article, and its accompanying Supplemental Material, outline the mandate, process undertaken, standards developed, and accreditation process recommended. PMID- 23439021 TI - Myocardial viability: whom, what, why, which, and how? AB - Viability imaging might be useful to guide decisions for revascularization in patients with ischemic cardiomyopathy. Recent trial results raise important points for clinicians regarding which modalities to use and in which patients. We discuss the modalities currently used in clinical practice. We suggest that testing be reserved for complex patients in whom the risks and potential benefits from revascularization are highest, and emphasize that the results of viability testing are not the only determinant of potential outcome benefit, and should not be viewed in isolation but as an objective adjunct to decision making. PMID- 23439022 TI - Regulation of retroviral polyadenylation. AB - Cellular and viral preRNAs are extensively cotranscriptionally modified. These modifications include the processing of the 3' end. Most preRNAs are polyadenylated, which is required for nuclear export, RNA stability, and efficient translation. Integrated retroviral genomes are flanked by 3' and 5' long terminal repeats (LTRs). Both LTRs are identical on the nucleotide level, but 3' processing has to be limited to the 3'LTR. Otherwise, polyadenylation at the 5'LTR would result in prematurely terminated, noncoding viral RNAs. Retroviruses have developed a variety of different mechanisms to restrict polyadenylation to the 3'LTR, although the overall structure of the LTRs is similar among all retroviruses. In general, these mechanisms can be divided into three main groups: (1) activation of polyadenylation only at the 3' end by encoding the essential polyadenylation signal in the unique 3 region; (2) suppression of polyadenylation at the 5'LTR by downstream elements such as the major splice donor; and (3) the usage of weak polyadenylation sites, which results in some premature polyadenylated noncoding RNAs and in read-through transcripts at the 3'LTR. All these mechanisms exhibit intrinsic problems, and retroviruses have evolved additional regulatory elements to promote polyadenylation at the 3'LTR only. In this review, we describe the molecular regulation of retroviral polyadenylation and highlight the different mechanisms used for polyadenylation control. PMID- 23439023 TI - Open questions about giant viruses. AB - The recent discovery of giant viruses exhibiting double-stranded DNA genomes larger than a million base pairs, encoding more than a thousand proteins and packed in near micron-sized icosahedral particles, opened a new and unexpected chapter in virology. As of today, these giant viruses and their closest relatives of lesser dimensions infect unicellular eukaryotes found in aquatic environments, but belonging to a wide diversity of early branching phyla. This broad phylogenetic distribution of hosts is consistent with the hypothesis that giant viruses originated prior to the radiation of the eukaryotic domain and/or might have been involved in the partition of nuclear versus cytoplasmic functions in ancestral cells. The distinctive features of the known giant viruses, in particular the recurrent presence of components of the translation apparatus in their proteome, raise a number of fundamental questions about their origin, their mode of evolution, and the relationship they may entertain with other dsDNA viruses, the genome size of which exhibits the widest distribution among all biological entities, from less than 5 kb to more than 1.25 Mb (a ratio of 1:250). At a more conceptual level, the convergence between the discovery of increasingly reduced parasitic cellular organisms and that of giant viruses exhibiting a widening array of cellular-like functions may ultimately abolish the historical discontinuity between the viral and the cellular world. PMID- 23439024 TI - Assembly and budding of negative-strand RNA viruses. AB - Assembly of negative-strand RNA viruses occurs by budding from host plasma membranes. The budding process involves association of the viral core or nucleocapsid with a region of cellular membrane that will become the virus budding site, which contains the envelope glycoproteins and matrix protein. This region of membrane then buds out and pinches off to become the virus envelope. This review will address the questions of what are the mechanisms that bring the nucleocapsid and envelope glycoproteins together to form the virus budding site, and how does this lead to release of progeny virions? Recent evidence supports the idea that viral envelope glycoproteins and matrix proteins are organized into membrane microdomains that coalesce to form virus budding sites. There has also been substantial progress in understanding the last step in virus release, referred to as the "late budding function," which often involves host proteins of the vacuolar protein sorting apparatus. Key questions are raised as to the mechanism of the initial steps in formation of virus budding sites: How are membrane microdomains brought together and how are nucleocapsids selected for incorporation into these budding sites, particularly in the case of viruses for which genome RNA sequences are important for envelopment of nucleocapsids? PMID- 23439025 TI - Arthropod-borne flaviviruses and RNA interference: seeking new approaches for antiviral therapy. AB - Flaviviruses are the most prevalent arthropod-borne viruses worldwide, and nearly half of the 70 Flavivirus members identified are human pathogens. Despite the huge clinical impact of flaviviruses, there is no specific human antiviral therapy available to treat infection with any of the flaviviruses. Therefore, there is a continued search for novel therapies, and this review describes the current knowledge on the usage of RNA interference (RNAi) in combating flavivirus infections. RNAi is a process of sequence-specific gene silencing triggered by double-stranded RNA. Antiviral RNAi strategies against arthropod-borne flaviviruses have been reported and although several hurdles must be overcome to employ this technology in clinical applications, they potentially represent a new therapeutic tool. PMID- 23439026 TI - Histological evidence for muscle insertion in extant amniote femora: implications for muscle reconstruction in fossils. AB - Since the 19th century, identification of muscle attachment sites on bones has been important for muscle reconstructions, especially in fossil tetrapods, and therefore has been the subject of numerous biological and paleontological studies. At the microscopic level, in histological thin sections, the only features that can be used reliably for identifying tendon-bone or muscle-tendon bone interactions are Sharpey's fibers. Muscles, however, do not only attach to the bone indirectly with tendons, but also directly. Previous studies failed to provide new indicators for muscle attachment, or to address the question of whether muscles with direct attachment can be identified histologically. However, histological identification of direct muscle attachments is important because these attachments do not leave visible marks (e.g. scars and rugosities) on the bone surface. We dissected the right hind limb and mapped the muscle attachment sites on the femur of one rabbit (Oryctolagus cuniculus), one Alligator mississippiensis, and one turkey (Meleagris cuniculus). We then extracted the femur and prepared four histological thin sections for the rabbit and the turkey and five histological thin sections for the alligator. Sharpey's fibers, vascular canal orientation, and a frayed periosteal margin can be indicators for indirect but also direct muscle attachment. Sharpey's fibers can be oriented to the cutting plane of the thin section at high angles, and two Sharpey's fibers orientations can occur in one area, possibly indicating a secondary force axis. However, only about 60% of mapped muscle attachment sites could be detected in thin sections, and frequently histological features suggestive of muscle attachment occurred outside mapped sites. While these insights should improve our ability to successfully identify and reconstruct muscles in extinct species, they also show the limitations of this approach. PMID- 23439027 TI - Experimental human pneumococcal carriage. AB - Experimental human pneumococcal carriage (EHPC) is scientifically important because nasopharyngeal carriage of Streptococcus pneumoniae is both the major source of transmission and the prerequisite of invasive disease. A model of carriage will allow accurate determination of the immunological correlates of protection, the immunizing effect of carriage and the effect of host pressure on the pathogen in the nasopharyngeal niche. Further, methods of carriage detection useful in epidemiologic studies, including vaccine studies, can be compared. AIM: We aim to develop an EHPC platform that is a safe and useful reproducible method that could be used to down-select candidate novel pneumococcal vaccines with prevention of carriage as a surrogate of vaccine induced immunity. It will work towards testing of candidate vaccines and descriptions of the mechanisms underlying EHPC and vaccine protection from carriage. Current conjugate vaccines against pneumococcus protect children from invasive disease although new vaccines are urgently needed as the current vaccine does not confer optimal protection against non-bacteraemic pneumonia and there has been evidence of serotype replacement with non-vaccine serotypes. METHOD: We inoculate with S. pneumoniae suspended in 100 MUl of saline. Safety is a major factor in the development of the EHPC model and is achieved through intensive volunteer screening and monitoring. A safety committee consisting of clinicians and scientists that are independent from the study provides objective feedback on a weekly basis. The bacterial inoculum is standardized and requires that no animal products are inoculated into volunteers (vegetable-based media and saline). The doses required for colonization (10(4)-10(5)) are much lower than those used in animal models (10(7)). Detecting pneumococcal carriage is enhanced by a high volume (ideally > 10 ml) nasal wash that is relatively mucus free. This protocol will deal with the most important parts of the protocol in turn. These are (a) volunteer selection, (b) pneumococcal inoculum preparation, (c) inoculation, (d) follow-up and (e) carriage detection. RESULTS: Our current protocol has been safe in over 100 volunteers at a range of doses using two different bacterial serotypes. A dose ranging study using S. pneumoniae 6B and 23F is currently being conducted to determine the optimal inoculation dose for 50% carriage. A predicted 50% rate of carriage will allow the EHPC model to have high sensitivity for vaccine efficacy with small study numbers. PMID- 23439028 TI - Prolonged high frequency electrical stimulation is lethal to motor axons of mice heterozygously deficient for the myelin protein P0 gene. AB - The relationship between dysmyelination and the progression of neuropathy in Charcot-Marie-Tooth (CMT) hereditary polyneuropathy is unclear. Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) are indistinguishable from wild-type (WT) at birth and then develop a slowly progressing demyelinating neuropathy reminiscent of CMT Type 1b. Accumulating evidence suggests that impulse conduction can become lethal to acutely demyelinated central and peripheral axons. Here we investigated the vulnerability of motor axons to long-lasting, high-frequency repetitive stimulation (RS) in P0+/- mice as compared to WT littermates at 7, 12, and 20 months of age. RS was carried out in interrupted trains of 200 Hz trains for 3h. Tibial nerves were stimulated at the ankle while the evoked compound muscle action potentials (CMAPs) and the ascending compound nerve action potentials (CNAPs) were recorded from plantar muscles and the sciatic nerve, respectively. In 7-month old mice, there was recovery of CMAP and CNAP following RS. When mice were about one year old, electrophysiological recovery following RS was incomplete and in P0+/- also associated with morphological signs of partial Wallerian degeneration. The effect of RS was larger in P0+/- as compared to age-matched WT. When mice were about 2 years old, the effect was stronger and became similar between WT and P0+/-. RS was followed by a transient hyperpolarization, which decreased with age and was smaller in P0+/- than in WT. Our data suggest that both aging and the dysmyelinating disease process may contribute to the susceptibility to activity induced axonal degeneration. It is possible that in aging mice and in P0+/- there is inadequate energy-dependent Na(+)/K(+) pumping, as indicated by the reduced post-stimulation hyperpolarization, which may lead to a lethal Na(+) overload in some axons. PMID- 23439029 TI - The anti-arthritic effects of Aconitum vilmorinianum, a folk herbal medicine in Southwestern China. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aconiti Radix (AC) and Aconiti Kusnezoffii Radix (AK) are two traditional Chinese medicines commonly used to treat joint pain and arthritis. In Southwestern China, Huangcaowu (AV), the root of Aconitum vilmorinianum Kom., has long been used as a local substitute for these herbs for analgesia and anti-inflammation. However, its anti-arthritic effects have not been investigated. AIM OF STUDY: To investigate the anti-arthritic effects of Huangcaowu (AV). MATERIALS AND METHODS: Mono-arthritis in SD rats was induced by unilateral intra-articular injection of Freund's complete adjuvant. Physiological saline was injected in the contralateral knee. Seventy five percent ethanol extracts of AV (10 mg/kg/day and 100 mg/kg/day), AC (100 mg/kg/day) and AK (100 mg/kg/day) were administered to rats by oral gavage for 14 consecutive days (Day 6 to Day 7) while arthritis was induced at the seventh day (Day 0). The anti arthritic effects of the herbs were assessed by measuring allodynia, swelling, hyperaemia and the vascular permeability of the knee joints. RESULTS: AV (10 mg/kg/day and 100 mg/kg/day), AC (100 mg/kg/day) and AK (100 mg/kg/day) suppressed joint allodynia. AV (10 mg/kg/day and 100 mg/kg/day) and AK (100 mg/kg/day) significantly reduced join swelling and hyperaemia while AC (100 mg/kg/day) did not. AV (100 mg/kg/day) attenuated vascular permeability while AC (100 mg/kg/day) and AK (100 mg/kg/day) showed no improvement. CONCLUSIONS: Huangcaowu (AV) significantly improved allodynia, swelling, hyperaemia and vascular permeability in arthritic knee joints. It showed the highest anti arthritic effects among the three tested Aconitum herbs. PMID- 23439030 TI - Tyrosinase modulation by five Rwandese herbal medicines traditionally used for skin treatment. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional herbal medicines provide an interesting, largely unexplored source for the development of potential new drugs and skin-care cosmetics. Some herbal extracts are known to be inhibitors of melanin formation, sometimes more potent than the classical inhibitors, hydroquinone/arbutin or kojic acid, and are not associated with melanocytes cytotoxicity or mutagenicity. Such plants are used in traditional medicine in many countries, particularly in Africa, for skin lightening. AIM OF THE STUDY: To evaluate in vitro the ability of Rwandese medicinal plants, traditionally used for the treatment of skin (discoloration and attenuation of discolored spots), to modulate pigmentation and tyrosinase activity. MATERIALS AND METHODS: Based on an ethnopharmacological survey, five herbs [Brillantaisia cicatricosa Lindau (Acanthaceae), Chenopodium ugandae (Aellen) Aellen (Chenopodiaceae), Dolichopentas longiflora Oliv. (Rubiaceae), Protea madiensis Oliv. (Proteaceae) and Sesamum angolense Welw. (Pedaliaceae)] were selected. Twenty-seven extracts, obtained by treating the herbs with increasing polarities solvents, were investigated for their effects on cell viability (MTT test) and on pigmentation: inhibition of the enzyme tyrosinase (colorimetry of reaction products, measurement of enzyme activity, TLC-autography; studies on crude cellular extracts obtained from normal melanocytes and on a mushroom tyrosinase) and measurement of melanogenesis by human melanoma cells. RESULTS: None of the tested plant extracts were cytotoxic on tested human melanoma cell lines, except for Dolichopentas longiflora (IC50 of leaves n-hexane extract, 4MUg/ml for MM028 and 4.5MUg/ml for MM001; IC50 of roots ethyl acetate extract, 0.8MUg/ml for MM028 and 3.9MUg/ml for MM001). Almost all extracts inhibited melanogenesis in a melanoma whole cells overall pigmentation assay, a model reflecting the entire cycle of melanogenesis. All the Protea madiensis extracts quite strongly inhibited melanogenesis and, surprisingly, one of the Dolichopentas longiflora leaves extracts was found to increase melanogenesis. These results were confirmed by the modulation of pigmentation reactions by crude cellular extracts obtained from normal melanocytes; interestingly, one of the extracts (Dolichopentas longiflora ethyl acetate extract) is even more active (61% at 500MUg/ml) than kojic acid (<3% at 142MUg/ml and 68% at 1421MUg/ml). In a mushroom tyrosinase inhibition assay, data obtained on some extracts fairly agree with pigmentation inhibition measured on melanocytes proteins as, for example, the methanol extract of Protea madiensis. While a few others extract display discording data, this probably reflects either differences between human and mushroom tyrosinase, interference with melanocytes enzymes at later steps than tyrosinase or the simultaneous presence of compounds with conflicting activities in a given extract. CONCLUSIONS: Ethnopharmacological data represent an efficient approach to discover active herbs. Some of the selected medicinal plants clearly show potent tyrosinase inhibitions while one extract significantly increases cell pigmentation; one extract contains potent growth melanocytes inhibitors. PMID- 23439031 TI - A polyphenol-rich extract from Chaenomeles sinensis (Chinese quince) inhibits influenza A virus infection by preventing primary transcription in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruits of Chaenomeles sinensis Koehne (Chinese quince) are distributed throughout China and Japan. It has traditionally been known to have a therapeutic effect against respiratory symptoms caused by infectious diseases. AIM OF THE STUDY: The polyphenol-rich extract, CSD3, from Chaenomeles sinensis has previously been shown to neutralize influenza virus infectivity. The aim of this study was to clarify which step(s) in the replication cycle in vitro were inhibited. MATERIALS AND METHODS: We examined cell-binding, hemagglutination and hemolytic activities and infectivity of A/Udorn/72(H3N2) virus after pre-treatment with CSD3. We also investigated the time course of synthesis for viral mRNA, cRNA, and vRNA in Madin-Darby canine kidney epithelial cells (MDCK) cells infected with CSD3-treated virus. Finally, we studied the effect of CSD3-treatment on the ultrastructure of the influenza virion. RESULTS: Pre-treatment with CSD3 mildly reduced cell-binding, hemagglutination and hemolytic activities. These activities were reduced by 70% to be equivalent to 30% of the control at 1MUg/ml. CSD3 severely reduced infectivity to 1% of the control at 1MUg/ml. Primary transcription in MDCK cells infected with CSD3 (1MUg/ml)-treated virus was decreased to about 1% of that in cells infected with mock-treated virus. Synthesis of viral cRNA, vRNA and secondary mRNA was also severely decreased. Electron microscopy revealed that the integrity of the virus envelope was damaged by CSD3 and was permeable to uranyl acetate. CONCLUSIONS: The main target step(s) of CSD3 in the replication cycle is after cell-binding but before or at primary transcription. Involvement of the increased permeability of virus envelope as the inhibition mechanism was proposed. CSD3 could be useful in preventing influenza virus infection, and be employed as a lozenge or mouthwash for daily use. PMID- 23439032 TI - Development of a recombinant N-Gp5c fusion protein-based ELISA for detection of antibodies to porcine reproductive and respiratory syndrome virus. AB - The recent dramatic increase in reported cases of porcine reproductive and respiratory syndrome (PRRS) in pig farms is a potential threat to the global swine industry, and thus, detecting PRRS virus (PRRSV) in pig herds is essential to help control the spread of PRRS. IDEXX HerdChekTM PRRS, a commercially available indirect enzyme-linked immunosorbent assay (iELISA), is the industry standard for detection of antibodies against PRRSV. In the present study, an effective iELISA for detection of PRRSV antibodies was developed using a recombinant fusion protein N-Gp5c (rN5c, a combination of the nucleocapsid protein and the C-terminal 78 aa of Gp5) produced in Escherichia coli. This assay was validated by comparison with an immunofluorescent assay and IDEXX-ELISA. The diagnostic specificity, sensitivity, and accuracy of the rN5c-iELISA method were 94.8, 95.6, and 95.1%, respectively. Cross-reactivity assays demonstrated that iELISA was PRRSV-specific. Repeatability tests revealed that the coefficients of variation of positive sera within and between runs were less than 13 and 22%, respectively. The rN5c-iELISA is simpler to produce and perform, time-saving, and suitable for large scale surveys of PRRSV infection at lower cost. PMID- 23439034 TI - Rheumatoid arthritis: TNF disables TREG-cell function through FOXP3 modification. PMID- 23439033 TI - Orthogonal patterning of multiple biomolecules using an organic fluorinated resist and imprint lithography. AB - The ability to spatially deposit multiple biomolecules onto a single surface with high-resolution while retaining biomolecule stability and integrity is critical to the development of micro- and nanoscale biodevices. While conventional lithographic patterning methods are attractive for this application, they typically require the use of UV exposure and/or harsh solvents and imaging materials, which may be damaging to fragile biomolecules. Here, we report the development of a new patterning process based on a fluorinated patterning material that is soluble in hydrofluoroether solvents, which we show to be benign to biomolecules, including proteins and DNA. We demonstrate the implementation of these materials into an orthogonal processing system for patterning multibiomolecule arrays by imprint lithography at room temperature. We further showcase this method's capacity for fabricating patterns of receptor-specific ligands for fundamental cell studies. PMID- 23439035 TI - The ascent of acetylation in the epigenetics of rheumatoid arthritis. AB - Genome-wide association studies have shown that genetic polymorphisms make a substantial but incomplete contribution to the risk of developing rheumatoid arthritis (RA). Efforts to understand the nongenetic contributions to RA disease susceptibility have recently focused on the study of epigenetic mechanisms, namely modifications of DNA and histones, which are subject to environmental influences and regulate gene expression. A surprising theme emerging from studies of the enzymes responsible for these epigenetic modifications, particularly histone deacetylases, is that they regulate inflammatory activation of cell populations relevant to RA through independent, direct, and dynamic interactions with nonhistone proteins. Herein, we highlight studies, the findings of which collectively suggest that revisiting the original definition of epigenetics, conceived some 70 years ago, might advance our interpretation of DNA and histone modifications with regard to gene expression and clinical outcome in RA. Such an approach could also facilitate the development of strategies to target these epigenetic modifications in the clinic. PMID- 23439036 TI - Influence of limestone characteristics on mercury re-emission in WFGD systems. AB - This work evaluates the influence of the effect of the properties of limestones on their reactivity and the re-emission of mercury under typical wet scrubber conditions. The influence of the composition, particle size, and porosity of limestones on their reactivity and the effect of sorbent concentration, pH, redox potential, and the sulphite and iron content of the slurry on Hg(0) re-emission was assessed. A small particle size, a high porosity and a low magnesium content increased the high reactivity of the limestones. Moreover, it was found that the higher the reactivity of the sample the greater the amount of mercury captured in the scrubber. Although sulphite ions did not cause the re-emission of mercury from the suspensions of the gypsums, the limestones enriched in iron increased Hg(0) re-emission under low oxygen conditions. It was observed that the low pH values of the gypsum suspensions favored the cocapture of mercury because Fe(2+) formation was avoided. The partitioning of the mercury in the byproducts of the scrubber depended on the impurities of the limestones rather than on their particle size. No leaching of mercury from the gypsum samples occurred suggesting that mercury was either tightly bound to the impurities of the limestone or was transformed into insoluble mercury species. PMID- 23439037 TI - The corrosion behaviour of galvanized steel in cooling tower water containing a biocide and a corrosion inhibitor. AB - The corrosion behaviour of galvanized steel in cooling tower water containing a biocide and a corrosion inhibitor was investigated over a 10-month period in a hotel. Planktonic and sessile numbers of sulphate reducing bacteria (SRB) and heterotrophic bacteria were monitored. The corrosion rate was determined by the weight loss method. The corrosion products were analyzed by energy dispersive X ray spectroscopy and X-ray diffraction. A mineralized, heterogeneous biofilm was observed on the coupons. Although a biocide and a corrosion inhibitor were regularly added to the cooling water, the results showed that microorganisms, such as SRB in the mixed species biofilm, caused corrosion of galvanized steel. It was observed that Zn layers on the test coupons were completely depleted after 3 months. The Fe concentrations in the biofilm showed significant correlations with the weight loss and carbohydrate concentration (respectively, p < 0.01 and p < 0.01). PMID- 23439038 TI - AAE and AAPD symposium overview: Contemporary management of traumatic injuries to the permanent dentition. PMID- 23439039 TI - Pulp and periradicular testing. AB - Pulp and periradicular testing is crucial to the initial trauma evaluation and to subsequent monitoring of the traumatized teeth and supporting structures. An accurate diagnosis serves as the basis for therapeutic intervention and helps to ensure that destruction of the dental structures will be minimized and function will be regained. The purpose of this review is to present the current best evidence for accurate diagnostic testing of the pulp and periapex of traumatized teeth. Five databases were searched for literature pertaining to pulpal testing and trauma. Widely recognized textbooks were also consulted. Currently used pulp vitality testing is constrained by its subjective character and by the fact that it is a measure of neuronal status and not true pulpal viability. Tests that measure tissue perfusion more accurately reflect pulpal vitality, but they are not available commercially. This review discusses the specificity, sensitivity, and accuracy of commonly used tests, with emphasis on the applicability of certain tests to specific patient presentations in trauma. Factors that influence test selection are discussed, and specific recommendations are made on the basis of best evidence. Although differences exist between the various studies as to the accuracy of commonly used pulpal and periradicular tests, most of these have acceptable predictive value. Pulpal and periradicular tests in the trauma patient should be used in conjunction with clinical and radiographic observations to arrive at a diagnosis and treatment plan. PMID- 23439040 TI - Epidemiology of traumatic dental injuries. AB - The oral region comprises 1% of the total body area, yet it accounts for 5% of all bodily injuries. In preschool children, oral injuries make up as much as 17% of all bodily injuries. The incidence of traumatic dental injuries is 1%-3%, and the prevalence is steady at 20%-30%. The annual cost of treatment is US $2-$5 million per 1 million inhabitants. Etiologic factors vary between countries and with age groups. Important public health implications such as how to best organize emergency dental care and how to prevent dental injuries, decrease cost, and increase lay knowledge are important factors needed to change epidemiologic data toward more favorable figures in the future. PMID- 23439041 TI - Contemporary management of horizontal root fractures to the permanent dentition: diagnosis--radiologic assessment to include cone-beam computed tomography. AB - Historically, obtaining several periapical radiographs has been recommended to diagnose horizontal root fractures. Assessing the 3-dimensional orientation of a fracture is correlated to treatment and outcome. However, conventional radiography yields only limited information for accurate diagnosis. Cone-beam computed tomography (CBCT) is a relatively new and useful technology, which provides an auxiliary imaging modality to supplement conventional radiography for evaluating horizontal root fractures. Despite the increasing application of this technology as well as a growing body of evidence supporting its value in diagnosing horizontal root fractures, there are no specific guidelines for its use. This article aimed to provide such preliminary guidelines for cases of suspected horizontal root fracture as a result of trauma. From a database search it was concluded that CBCT is most useful in cases in which conventional radiography yields inconclusive results or shows a fracture in the middle third of a root. In such cases CBCT may rule out false negatives, ie, a suspected root fracture not visualized with conventional radiography. For a root fracture in the middle third, CBCT may rule out or confirm an oblique course of fracture involving the cervical third in the labiolingual dimension. Although there are considerable advantages when CBCT is included in the assessment of horizontal root fracture and its possible sequelae, more experimental and clinical studies are warranted to determine the exact impact on outcomes. PMID- 23439042 TI - Treatment options: apexogenesis and apexification. AB - This article will describe requirements for case selection and review the procedures for apexogenesis and apexification in immature permanent teeth. Nonclinical and clinical data will be presented to support the recommendations, and outcomes will be presented from clinical studies. The dental pulp is an ectomesenchymally derived connective tissue with certain unique properties such as being encased in hard tissues, which limits its collateral circulation. The pulp provides a matrix for binding of its cells and provides support allowing communication between the cells. In addition to immune cells, the dental pulp contains odontoblasts, which are specialized cells capable of producing dentin. In the absence of a vital pulp, dentin deposition is arrested. When an immature tooth is affected by caries or trauma, the pulp requires proper management according to the degree of inflammation and its vitality. Maintenance of pulp vitality will allow continued root development along the entire root length. If the pulp is irreversibly inflamed or necrotic, root-end closure procedures are required when the apex has not fully formed. PMID- 23439044 TI - Considerations for regeneration procedures. AB - When pulp tissue becomes necrotic in immature teeth, the prognosis of the teeth is compromised. Disinfection of the root(s) presents several challenges including difficulties in cleaning and shaping large canals with open apices, obturation of canals with open apices, and potential root fractures caused by thin and/or weakened root walls. Regenerative endodontic procedures may increase the prognosis of the compromised immature tooth by re-establishment of a functional pulp tissue that fosters continued root development and immune competency. This article reviews the literature related to and discuss considerations for regenerative endodontic procedures and how these procedures may increase the prognosis for immature teeth with necrotic pulp tissue. PMID- 23439045 TI - Root fortification. AB - An incompletely formed tooth is left with thin dentin walls and experiences a higher incidence of cervical root fracture that reduces the long-term overall prognosis of the tooth. Faced with these situations, clinicians have attempted to use various restorative methods to reinforce the remaining root. Various techniques have been reported, and the scientific evidence for each has been reviewed. The biomechanical considerations of reinforcing a weakened root are also reviewed, and the most current information about failure analysis, fracture characteristics of natural dentin, and in vitro test configurations used have been considered. In light of these additional considerations, some recommendations for future understanding of this complex problem have been proposed. PMID- 23439043 TI - Treatment options: biological basis of regenerative endodontic procedures. AB - Dental trauma occurs frequently in children and often can lead to pulpal necrosis. The occurrence of pulpal necrosis in the permanent but immature tooth represents a challenging clinical situation because the thin and often short roots increase the risk of subsequent fracture. Current approaches for treating the traumatized immature tooth with pulpal necrosis do not reliably achieve the desired clinical outcomes, consisting of healing of apical periodontitis, promotion of continued root development, and restoration of the functional competence of pulpal tissue. An optimal approach for treating the immature permanent tooth with a necrotic pulp would be to regenerate functional pulpal tissue. This review summarizes the current literature supporting a biological rationale for considering regenerative endodontic treatment procedures in treating the immature permanent tooth with pulp necrosis. PMID- 23439046 TI - Dental trauma guidelines. AB - Guidelines have been developed for management of numerous medical and dental conditions. If carefully developed and based on best available evidence, they serve a very useful purpose in giving information in dealing with health problems to health care providers as well as patients. The history of trauma guidelines is quite limited, but the American Association of Endodontists has been involved since the 1980s. In recent years, the International Association of Dental Traumatology has developed guidelines for management of traumatic dental injuries, with input from specialists in all relevant disciplines of dentistry. These guidelines, first developed and published in 2001 and updated twice since then, have been accepted as reliable recommendations for the urgent care of traumatic dental injuries; the most recent trauma guidelines were completed by the International Association of Dental Traumatology and published in 2012. The application of these guidelines is to provide both patients and practitioners with the best available information about management of such injuries. As with most guidelines, there are limitations that are primarily related to the level of evidence available, which is low. However, they are useful and, when followed, can lead to better outcomes than when no guidelines are used. PMID- 23439047 TI - Outcomes. AB - Outcomes encompass multiple factors, not just success and failure. They include other considerations such as being workable and profitable to the dentist and safe and acceptable to the patient. The more biological outcomes are most frequently measured. These measurements are on a scale from least to most predictable outcomes of treatment by the dentist, as shown on the evidence pyramid. Impact trauma is an example of a general scarcity of high-level evidence with treatment because of the nature and individuality of the injuries and the difficulty (or impossibility) of designing controlled clinical trials in humans. Much of the evidence is cohort (retrospective or observational studies), case reports, animal studies, and "expert" opinion. Thus, guidelines are largely based on lower levels of evidence. Nonetheless, the current guidelines provide the clinician with the best evidence that is available. The best opportunity for randomized controlled trials is in prevention. Specifically, mouthguard design and usage can be subjected to higher levels of controlled research. Revitalization and regeneration are relatively new procedures. To date, there is a lack of high levels of evidence to be able to substantiate whether these are clinically feasible to become a routine in practice. PMID- 23439048 TI - Ridge preservation/decoronation. AB - Dentoalveolar ankylosis of a tooth is a serious complication in growing individuals. The ankylosed root is continuously resorbed and replaced by bone, and an infraposition of the damaged tooth will develop. The normal alveolar development will be disrupted in this way, and prosthetic treatment will be compromised. Therefore, an ankylosed tooth should be removed before future orthodontic and/or prosthetic therapy is jeopardized. This article will present a method, decoronation, to remove an ankylosed tooth in such a way that the alveolar ridge is preserved and give guidelines for the timing to intervene. The decoronation method is described, and a possible explanation for the favorable outcome is discussed. Different aids to decide the time for intervention are presented. The alveolar ridge was maintained in buccal/palatinal direction, and the bone level increased after decoronation in patients treated before or during pubertal growth periods. The bone level also increased in those treated after this period but not at the same rate, and in a few patients it was unchanged. The clinical finding that decoronation can maintain or reestablish normal alveolar conditions is important for successful implant insertion later. PMID- 23439049 TI - Management of child patient behavior: quality of care, fear and anxiety, and the child patient. AB - Behavior management is a key component when providing dental care to children who have suffered traumatic dental injuries. This article reviews the current status of behavior management including basic communication techniques and advanced techniques used by pediatric dentists. Emphasis is given to oral and inhalation sedation when treating children at initial visits status post dental injury. Little is known about the use of pharmacologic agents in managing young but behaviorally challenging patients who have suffered dental trauma. Future care involving sedation and specialized endodontic procedures of these young patients through collaborative efforts between endodontists and pediatric dentists seems promising and should be pursued. PMID- 23439050 TI - Orthodontic procedures after trauma. AB - This review considers oral trauma and its relationship to orthodontics with respect to prevention and primary, secondary, and tertiary care. The level of evidence is not high in regard to this topic, but recommendable approaches to trauma at each stage are discussed on the basis of available literature and published guidelines. Simplified biomechanics are presented to aid treatment. PMID- 23439051 TI - Evidence-based review of prevention of dental injuries. AB - Despite efforts in reducing the number of dental traumas, most current studies indicate that the incidence of dental trauma remains unchanged and is at a relatively high level for children and young adults. When reviewing the literature on prevention, it is clear that until now the main focus has been on making and promoting mouthguards. The majority of the published studies on mouthguards have focused on materials used and how those behave and protect in vitro. The few epidemiologic studies that have been published on the possible protectiveness of the mouthguards in vivo are mostly of low level of evidence, and even those studies do not all agree on how much they actually protect the dentition. To compound the problem is the fact that the proportional ratio of dental trauma in organized sports is low compared with injuries that occur during children's play or leisure activities. It could be argued that the best strategic measure for preventing dental and oral injuries is education on both how to avoid them and what to do if an injury occurs. The demand of evidence-based dentistry and medicine calls for large prospective studies with randomized intervention to investigate the actual protection of mouthguards and faceguards. In addition, more emphasis should be placed on which is the best and most constructive way to educate youngsters and teenagers on how to avoid traumatic injuries to their teeth by using contemporary means like the Internet and apps. PMID- 23439052 TI - Rapid physical assessment of the injured child. AB - Traumatic injuries that involve the dentition and maxillofacial region may occur as isolated events in pediatric patients but are often associated with multisystem injuries and traumatic brain injuries. The primary trauma survey serves to identify and treat life-threatening injuries. The secondary trauma survey is a complete examination of the patient after the stabilization of physiological parameters. Frequent neurologic and physical assessments of the injured child are crucial to preventing deterioration. The role of the dental professional is to identify and refer for medical evaluation patients who present with concerning neurologic signs and symptoms after traumatic injuries to the maxillofacial region. PMID- 23439053 TI - Mast cells and IgE: from history to today. AB - Role of mast cells in allergy had remained undetermined until the discovery of IgE in 1966. Then, IgE purified from many Liters of plasma, which had been donated from a patient with fatal myeloma, was distributed to researchers all over the world, and thus accelerated exploring the mechanisms involved in allergic reactions, particularly about the role of mast cells and basophils in the IgE-mediated reactions. Identification of mast cells as a progeny of a bone marrow hematopoietic stem cell in 1977 led us to successful in vitro culture of human mast cells. Along with the development of molecular biological techniques, the structure of the high affinity IgE receptor (FcepsilonRI) was determined in 1989. These findings and subsequent investigations brought deeper understanding of IgE-mediated allergic diseases in the past half century, especially where mast cells are involved. We have now even obtained the information about whole genome expression of FcepsilonRI-dependently activated mast cells. In sharp contrast to our comprehension of allergic diseases where IgE and mast cells are involved, the mechanisms involved in non-IgE-mediated allergic diseases or non-IgE-mediated phase of IgE-mediated diseases are almost left unsolved and are waiting for devoted investigators to reveal it. PMID- 23439054 TI - Role of interleukin-33 in innate-type immune cells in allergy. AB - Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is preferentially and constitutively expressed in epithelial cells, and it is especially localized in the cells' nucleus. The nuclear IL-33 is released by necrotic cells after tissue injury and/or trauma, and subsequently provokes local inflammation as an alarmin, like high-mobility group box protein-1 (HMGB-1) and IL-1alpha. IL-33 mainly activates Th2 cells and such innate-type immune cells as mast cells, basophils, eosinophils and natural helper cells that express IL-33R (a heterodimer of IL-1 receptor-like 1 [IL-1RL1; also called ST2, T1, Der4, fit-1] and IL-1 receptor accessory protein [IL-1RAcP]). That activation causes the cells to produce Th2 cytokines, which contribute to host defense against nematodes. On the other hand, excessive and/or inappropriate production of IL-33 is also considered to be involved in the development of such disorders as allergy. In this review, we summarize current knowledge regarding the pathogenic roles of IL 33 in the development of allergic inflammation by focusing on its effects on innate-type immune cells. PMID- 23439055 TI - Genome-wide association studies of allergic diseases. AB - Allergic diseases are complex diseases caused by a combination of genetic and environmental factors. To determine the genetic components of these diseases and to discover the genes and cellular pathways underlying them, a large number of genetic studies have been conducted. Progress in genetics enables us to conduct genome-wide association studies (GWASs), which is a comprehensive and unbiased approach to identify susceptibility loci for multifactorial diseases. Recent GWASs have convincingly detected a large number of loci associated with allergic diseases. Candidate genes in the susceptibility loci suggest roles for epithelial barrier functions, innate-adaptive immunity, IL-1 family signaling, regulatory T cells and the vitamin D pathway in the pathogenesis of allergic diseases. Interestingly, the IL1RL1, HLA, IL13 and C11orf30 regions are overlapping susceptibility loci among atopic dermatitis and asthma or allergic rhinitis. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWASs improve our understanding of the pathophysiology of human allergic diseases and contribute to the development of better treatment and preventive strategies. PMID- 23439056 TI - Gender and chronic tinnitus: differences in tinnitus-related distress depend on age and duration of tinnitus. AB - OBJECTIVE: Conflicting data about the role of gender in tinnitus distress exist in the literature. In addition, little is known about gender differences regarding age and duration of tinnitus. Tinnitus was shown to be related to stress and impairment of coping, sense of coherence, and personal resources. There are known differences in the aforementioned psychological parameters between man and women or among different age groups. The authors hypothesized that this may also be true for patients with chronic tinnitus in addition to gender- and age-related differences in tinnitus annoyance. Therefore, using a large number of patients with chronic tinnitus, the authors analyzed pretherapeutic scores of tinnitus annoyance, perceived stress, proactive coping strategies, sense of coherence, and personal resources in addition to hearing loss and tinnitus pitch and loudness in respect to gender and age of the patients as well as duration of tinnitus. DESIGN: The study group included 607 female and 573 male patients who reported tinnitus for longer than 3 months. The age of the patients ranged from 17 to 81 years in both gender groups. Pretherapeutic scores of tinnitus annoyance, perceived stress, proactive coping strategies, sense of coherence, and personal resources as well as the degree of hearing loss and tinnitus pitch and loudness were analyzed. RESULTS: Irrespective of age and tinnitus duration, women were more annoyed by tinnitus and perceived more stress than men did. In addition, women scored lower than men in proactive coping, sense of coherence, and personal resources but had lower levels of hearing loss and tinnitus loudness than men did. The differences were small, but statistically significant. Analysis of three age groups revealed significant differences between older female and male patients. Tinnitus annoyance was stronger in the middle-age groups of women and men (45-59 years of age) than in younger patients and decreased again in older men (>=60 years of age), but not in older women. Women, but not men, had cognitive distress scores that progressed with age. Older women (>=60 years of age) reported more sleep disturbances than older men. Women had more somatic complaints and coped less efficiently than men, except for younger patients (<45 years of age). The scores of perceived stress decreased whereas scores of sense of coherence and self-efficacy increased in older men and women (>=60 years of age). However, women scored worse than men did in this age group. Hearing loss was found to be correlated with tinnitus loudness and age in both gender groups. The duration of tinnitus affected subjective hearing problems, intrusiveness of tinnitus, and proactive coping. This association was in part age-dependent. CONCLUSIONS: The authors found gender differences regarding tinnitus-related distress in patients with chronic tinnitus; however, these differences depended on age and in part on duration of tinnitus. Addressing these differences could result in improved, tailored therapy approaches. For instance, applying physical exercise and relaxation techniques could be of special help for older women to reduce their somatic complaints and sleep disturbances. Similarly, cognitive behavioral therapy could reduce their cognitive distress. Therapy for younger patients should in particular include stress management. PMID- 23439057 TI - Editorial issue 1 2013: evidence for the future. PMID- 23439060 TI - Mucinous neoplasms of the appendix: a current comprehensive clinicopathologic and imaging review. AB - Mucinous neoplasms of the appendix are a heterogeneous group of neoplasms ranging from simple mucoceles to complex pseudomyxoma peritonei. Considerable controversy exists on their pathologic classification and nomenclature. Clear understanding of the histopathologic diversity of these neoplasms helps in establishing proper communication between the radiologist, the pathologist and the surgeon. In this article, we present a brief discussion of the current taxonomy and nomenclature of mucinous neoplasms of the appendix followed by a review of their imaging features. Important points including the significance of identifying extra appendiceal mucin at imaging, the new classification of pseudomyxoma peritonei into low- and high-grade varieties and the significance of simultaneous ovarian and appendiceal neoplasms are highlighted. PMID- 23439061 TI - A pilot study on the use of injection lipolysis in visceral adipose tissues. AB - BACKGROUND: Intraperitoneal fat, also known as visceral adipose tissue (VAT), poses significant metabolic risks. Reduction of this fat is functionally and aesthetically desirable. Since surgical reduction has serious risks, a noninvasive method for reduction of this fat would have important clinical benefits. OBJECTIVE: The authors evaluate the reduction in VAT in an animal model using injection lipolysis. METHODS: Phosphatidylcholine was injected in half of the omentum of 16 dogs (weight 30-40 kg) by surgical laparotomy. The dogs' vital signs were followed postoperatively. A second laparotomy was performed at 2 weeks (n = 10), 4 weeks (n = 4), or 6 weeks (n = 2). Reduction of fat in the injected side was assessed by comparing with the control side. Specimens of the injected and the control sides were examined microscopically. Intraperitoneal cultures were also obtained. RESULTS: There was a major reduction in the amount of fat in all 16 dogs. No intraperitoneal abscesses, collections, or adhesions developed, and there was no injury to any intra-abdominal organs. Microscopic examination showed significant fat loss and lysis of fat cells with cellular infiltrate formed of predominantly macrophages, with fibrosis developing in the 6-week specimens. No bacterial or fungal growth was observed on the cultures. The dogs' vital signs showed no significant variation from the preoperative baseline. CONCLUSIONS: Injection lipolysis is effective and safe in reducing VAT in dogs. Further studies are needed to prove its efficacy and safety in humans and refine its indications and method of injection. PMID- 23439062 TI - A multi-institutional perspective of complication rates for elective nonreconstructive breast surgery: an analysis of NSQIP data from 2006 to 2010. AB - BACKGROUND: As elective nonreconstructive breast surgery increases in popularity, there is greater demand for accurate multi-institutional data on minor and major postoperative complications. OBJECTIVE: The authors utilized a multi institutional database to compare 30-day morbidities and reoperation rates among the different types of elective nonreconstructive breast surgery. METHODS: Patients in the National Surgical Quality Improvement Program (NSQIP) participant use file who underwent elective nonreconstructive breast surgery between 2006 and 2010 were identified. Twenty defined morbidities were compared among mastopexy, reduction mammaplasty, and augmentation mammaplasty patients using analysis of variance and chi(2) tests for continuous variables and categorical variables, respectively. Logistic regression modeling was employed to identify preoperative risk factors for complications. RESULTS: Of the 3612 patients identified, 380 underwent mastopexy, 2507 underwent reduction mammaplasty, and 725 underwent augmentation mammaplasty. Complication rates were low in all cohorts, and patients undergoing augmentation mammaplasty had the lowest overall complication rate compared with mastopexy and reduction mammaplasty (1.24%, 2.37%, and 4.47%). Patients undergoing reduction mammaplasty had a modestly elevated incidence of overall morbidity, superficial surgical site infections, and wound disruptions (P < .05). Moreover, 30-day reoperation rates for mastopexy, reduction mammaplasty, and augmentation mammaplasty were low (1.58%, 2.07%, and 0.97%), as were the rates of life-threatening complications (0%, 0.16%, and 0%). One death was observed for all 3612 procedures (0.03%). CONCLUSIONS: Elective breast surgery is a safe procedure with an extremely low incidence of life-threatening complications and mortality. Comprehensive data collated from the NSQIP initiative add to the literature, and the findings of this multi-institutional study may help further guide patient education and expectations on potentially deleterious outcomes. PMID- 23439064 TI - Efficacy of acellular dermal matrices in revisionary aesthetic breast surgery: a 6-year experience. AB - BACKGROUND: Augmentation mammaplasty and augmentation mastopexy are associated with a substantial primary and secondary revision rate. Capsular contracture (CC), implant malposition, ptosis, asymmetry, and rippling are the main reasons for revisionary surgery in these patients. Traditional corrective techniques have not been completely reliable in preventing or treating these complications. Recently, acellular dermal matrices (ADM) have been used to assist with revisionary surgery with promising results. OBJECTIVE: The authors review their 6 year experience using ADM for revisionary surgery in aesthetic patients and evaluate long-term outcomes with this approach. METHODS: Patients who underwent revisionary breast augmentation or augmentation mastopexy with ADM in conjunction with standard techniques over a 6-year period between October 2005 and December 2011 were retrospectively reviewed. Only patients with at least 1 year of follow up were included in the analysis. RESULTS: A total of 197 revisions were performed (197 patients). Reasons for revision included CC (61.8%), implant malposition (31.2%), rippling (4.8%), ptosis (4.8%), implant exposure (1.6%), and breast wound (0.5%). The mean +/- SD follow-up period was 3.1 +/- 1.1 years (range, 0.1-6.1 years). The complication rate was 4.8%, including Baker grade III/IV CC (1.6%), infection (1.6%), implant malposition (0.5%), hematoma (0.5%), and seroma (0.5%). Most (98%) revisions were successful, with no recurrence of the presenting complaint. CONCLUSIONS: The use of ADM in conjunction with standard techniques for the reinforcement of weak tissue in revision augmentation and augmentation mastopexy patients appears to be effective. PMID- 23439063 TI - Metabolic and structural effects of phosphatidylcholine and deoxycholate injections on subcutaneous fat: a randomized, controlled trial. AB - BACKGROUND: Phosphatidylcholine and deoxycholate (PC-DC) injections are a popular nonsurgical method to eliminate unwanted fat. The safety and efficacy of this approach is uncertain. OBJECTIVE: The authors evaluate the effects of PC-DC treatments on body composition, adipocyte function, and mechanisms responsible for fat loss. METHODS: This randomized, open-label study enrolled 13 women with a body mass index (BMI) <=30 kg/m(2) and lower abdominal subcutaneous fat suitable for small-volume liposuction. Patients were randomized by the final digit of their Social Security numbers and received between 2 and 4 PC-DC treatments, spaced 8 weeks apart. One side below the umbilicus was injected with PC-DC. The contralateral, control side received no treatment. Adipose tissue biopsies were performed on the treated side at baseline, 1 week after the first treatment, and 8 weeks after the final treatment. The primary outcome was change in adipose tissue thickness at baseline and 8 weeks after the final treatment. RESULTS: Seven women completed the study. Treatment with PC-DC significantly reduced the thickness of the anterior subcutaneous abdominal fat (P = .004). Adipose tissue showed rapid increases in crown-like structures, macrophage infiltration, and reduced expression of leptin, hormone-sensitive lipase, adipose tissue triglyceride lipase, and CD36. Plasma C-reactive protein, lipid profile, and plasma glucose concentrations were unchanged. CONCLUSIONS: PC-DC injections can effectively reduce abdominal fat volume and thickness by inducing adipocyte necrosis. These treatments do not appear to increase circulating markers of inflammation or affect glucose and lipid metabolism. PMID- 23439065 TI - The effects of transanal irrigation as a stepwise bowel management program on the quality of life of children with spina bifida and their caregivers. AB - STUDY DESIGN: Experimental, prospective study. OBJECTIVES: Fecal incontinence and constipation affect the quality of life (QOL) of children with spina bifida and their caregivers. We evaluated the clinical efficacy of a stepwise bowel management program on QOL for children with spina bifida and their caregivers. SETTING: Republic of Korea. METHODS: Between December 2010 and April 2011, 53 children with constipation, fecal incontinence or both underwent a stepwise bowel management program at our spina bifida clinic. The children and their caregivers were evaluated before and after this program using a self-administered questionnaire. RESULTS: Among the children, 11.3% received only oral laxatives and controlled well, 88.7% received transanal irrigation. After this program, the mean number of episodes of fecal incontinence per week, number of diaper changes and total time for bowel care decreased from 6.9 to 0.5 (P=0.004), from 1.6 to 0.2 (P=0.001) and from 27 to 15.9 min (P=0.003), respectively. Caregivers and children were able to leave their houses more often (P=0.006), and caregivers' bothersomeness, anxiety and depression due to bowel care decreased (P<0.001). Factors related to family relationships (P=0.265) and financial impact (P=0.071) improved, but not significantly. CONCLUSIONS: We observed significant improvement in defecation symptoms and QOL scores of spina bifida patients who underwent this program. We recommend that this simple therapeutic method be considered as a safe and valid choice for the treatment of chronic constipation and fecal incontinence. PMID- 23439066 TI - Rehabilitation of persons with spinal cord injury in Afghanistan: some recommendations. PMID- 23439067 TI - The prevalence and impact of age and gender on rehabilitation outcomes in spinal cord injury in India: a retrospective pilot study. AB - STUDY DESIGN: Retrospective, 1 year case series. OBJECTIVES: To analyze the relationship between gender, age, injury-related variables and rehabilitation outcomes in patients with spinal cord injury (SCI). SETTING: Tertiary Rehabilitation Center, Inpatient rehabilitation unit, India. METHODS: The data from a series of SCI cases were analyzed. Each case was followed from admission into the hospital until their discharge. Patients were described according to age, gender, etiology of SCI, neurological classification, medical complications, American spinal injury association (ASIA) classification, length of rehabilitation stay and spinal cord independence measure (SCIM). RESULTS: Forty seven new SCI cases, 37 (78.7%) male and 10 (21.3%) female patients, were reported over a 1-year period during 2009-2010. Male patients were younger than the female ones, but the difference was not statistically significant. There was no statistically significant relationship between age or gender, and the following SCI variables: ASIA classification, neurological classification, SCI complications and length of stay (P>0.05). Traumatic etiology and Pott's disease was found be related with gender (P<0.05). There was no statistically significant relationship between age or gender and SCIM score at admission or discharge (P>0.05). CONCLUSION: Age and gender are not significantly related to outcomes of rehabilitation or characteristics of SCI in this sample. Further research is needed to confirm the generalizability of these findings and to identify which factors contribute more strongly to SCI rehabilitation outcomes. PMID- 23439068 TI - The global map for traumatic spinal cord injury epidemiology: update 2011, global incidence rate. AB - STUDY DESIGN: Literature review. OBJECTIVES: Update the global maps for traumatic spinal cord injury (TSCI) and incorporate methods for extrapolating incidence data. SETTING: An initiative of the International Spinal Cord Society (ISCoS) Prevention Committee. METHODS: A search of Medline/Embase was performed (1959 Jun/30/2011). Enhancement of data-quality 'zones' including individual data ranking as well as integrating regression techniques to provide a platform for continued regional and global estimates. RESULTS: A global-incident rate (2007) is estimated at 23 TSCI cases per million (179,312 cases per annum). Regional data are available from North America (40 per million), Western Europe (16 per million) and Australia (15 per million). Extrapolated regional data are available for Asia-Central (25 per million), Asia-South (21 per million), Caribbean (19 per million), Latin America, Andean (19 per million), Latin America, Central (24 per million), Latin America-Southern (25 per million), Sub-Saharan Africa-Central (29 per million), Sub-Saharan Africa-East (21 per million). DISCUSSION: It is estimated that globally in 2007, there would have been between 133 and 226 thousand incident cases of TSCI from accidents and violence. The proportion of TSCI from land transport is decreasing/stable in developed but increasing in developing countries due to trends in transport mode (transition to motorised transport), poor infrastructure and regulatory challenges. TSCIs from low falls in the elderly are increasing in developed countries with ageing populations. In some developing countries low falls, resulting in TSCI occur while carrying heavy loads on the head in young people. In developing countries high-falls feature, commonly from trees, balconies, flat roofs and construction sites. TSCI is also due to crush-injuries, diving and violence. CONCLUSION: The online global maps now inform an extrapolative statistical model, which estimates incidence for areas with insufficient TSCI data. The accuracy of this methodology will be improved through the use of prospective, standardised-data registries. PMID- 23439069 TI - Optimized system for cerebral perfusion monitoring in the rat stroke model of intraluminal middle cerebral artery occlusion. AB - The translational potential of pre-clinical stroke research depends on the accuracy of experimental modeling. Cerebral perfusion monitoring in animal models of acute ischemic stroke allows to confirm successful arterial occlusion and exclude subarachnoid hemorrhage. Cerebral perfusion monitoring can also be used to study intracranial collateral circulation, which is emerging as a powerful determinant of stroke outcome and a possible therapeutic target. Despite a recognized role of Laser Doppler perfusion monitoring as part of the current guidelines for experimental cerebral ischemia, a number of technical difficulties exist that limit its widespread use. One of the major issues is obtaining a secure and prolonged attachment of a deep-penetration Laser Doppler probe to the animal skull. In this video, we show our optimized system for cerebral perfusion monitoring during transient middle cerebral artery occlusion by intraluminal filament in the rat. We developed in-house a simple method to obtain a custom made holder for twin-fibre (deep-penetration) Laser Doppler probes, which allow multi-site monitoring if needed. A continuous and prolonged monitoring of cerebral perfusion could easily be obtained over the intact skull. PMID- 23439070 TI - Phosphatidic acid metabolism in rat liver cell nuclei. AB - The aim of the present research was to analyze the pathways for phosphatidic acid metabolism in purified nuclei from liver. Lipid phosphate phosphatase, diacylglycerol lipase, monoacylglycerol lipase and PA-phospholipase type A activities were detected. The presence of lysophosphatidic acid significantly reduced DAG production while sphingosine 1-phoshate and ceramide 1-phosphate reduced MAG formation from PA. Using different enzymatic modulators (detergents and ions) an increase in the PA metabolism by phospholipase type A was observed. Our findings evidence an active PA metabolism in purified liver nuclei which generates important lipid second messengers, and which could thus be involved in nuclear processes such as gene transcription. PMID- 23439072 TI - The new black bag, Arrowsmith, and giving. PMID- 23439073 TI - Quality in echocardiography: does it make a difference? PMID- 23439071 TI - American Society of Echocardiography: Remote Echocardiography with Web-Based Assessments for Referrals at a Distance (ASE-REWARD) Study. AB - BACKGROUND: Developing countries face the dual burden of high rates of cardiovascular disease and barriers in accessing diagnostic and referral programs. The aim of this study was to test the feasibility of performing focused echocardiographic studies with long-distance Web-based assessments of recorded images for facilitating care of patients with cardiovascular disease. METHODS: Subjects were recruited using newspaper advertisements and were prescreened by paramedical workers during a community event in rural north India. Focused echocardiographic studies were performed by nine sonographers using pocket-sized or handheld devices; the scans were uploaded on a Web-based viewing system for remote worldwide interpretation by 75 physicians. RESULTS: A total of 1,023 studies were interpreted at a median time of 11:44 hours. Of the 1,021 interpretable scans, 207 (20.3%) had minor and 170 (16.7%) had major abnormalities. Left ventricular systolic dysfunction was the most frequent major abnormality (45.9%), followed by valvular (32.9%) and congenital (13.5%) defects. There was excellent agreement in assessing valvular lesions (kappa = 0.85), whereas the on-site readings were frequently modified by expert reviewers for left ventricular function and hypertrophy (kappa = 0.40 and 0.29, respectively). Six-month telephone follow-up in 71 subjects (41%) with major abnormalities revealed that 57 (80.3%) had improvement in symptoms, 11 (15.5%) experienced worsening symptoms, and three died. CONCLUSIONS: This study demonstrates the feasibility of performing sonographer-driven focused echocardiographic studies for identifying the burden of structural heart disease in a community. Remote assessment of echocardiograms using a cloud-computing environment may be helpful in expediting care in remote areas. PMID- 23439074 TI - Depressed myocardial blood flow reserve in nonischemic dilated cardiomyopathy: findings and explanations. PMID- 23439076 TI - Running a hybrid lab--a technologist's and manager's perspective. PMID- 23439075 TI - ASE-global health and our foundation. PMID- 23439078 TI - Does microsecond sugar ring flexing encode 3D-shape and bioactivity in the heparanome? AB - The biological information encoded in carbohydrate sequences dwarfs that of proteins and nucleic acids. Deciphering structure-function relationships in heparin and heparan sulfate (the heparanome) is further compounded by extreme sequence diversity, experimental difficulties, and the computational cost of rigorous modeling. Here we perform unbiased microsecond dynamics simulations of 11 heparanome oligosaccharides (55 microseconds total) to investigate the effect of sequence on 3D-structure and to underpin a coarse-grained model that is consistent with long-time scale experimentally validated atomic motions in water. Pyranose ring flexing (puckering) in 2-O-sulfo-alpha-l-iduronic acid, which underlies heparin-mediated anticoagulation, was modulated by polymerization (chain position and adjacent residues), which is supported by previous experiments. Furthermore, in coarse-grained simulations, inclusion of puckering was essential to predict macroscopic hydrodynamic properties of heparan sulfate chains containing hundreds of monosaccharaides. Our structural findings and model enable rational molecular design, and we propose that, in the heparanome, puckering, polymer 3D-shape, and bioactivity are inextricably linked. PMID- 23439079 TI - Hemodynamic goal-directed therapy. A review. AB - Patients can show arterial pressure and cardiac index within the normal range and still be in circulatory shock if oxygen and metabolic demand is increased or blood flow distribution is altered.Lactate is produced in anaerobic environment to preserve cellular integrity and physicians use its blood concentration value as a reliable marker of tissue hypoxia and energy failure.The authors review the recent literature on the importance of mixed venous oxygen saturation (SvO(2)) as an early sign of inadequate DO(2) that precede the lactate production. PMID- 23439081 TI - Ruthenium(II) complexes bearing a naphthalimide fragment: a modular dye platform for the dye-sensitized solar cell. AB - Cycloruthenated complexes of the type [Ru(II)(N^N)2(C^N)](+) (N^N = substituted 2,2'-bipyridine; C^N = substituted 3-(2'-pyridyl)-1,8-naphthalimide ligand) are shown to generate high power conversion efficiencies (PCEs) in the dye-sensitized solar cell (DSSC). It is shown that substitution of the pyridine ring of the C^N ligand with conjugated groups can enhance molar absorption extinction coefficients, while the electron density imparted on the metal center is alleviated by the 1,8-naphthalimide fragment. This latter feature maintains a Ru(III)/Ru(II) redox couple more positive than 0.8 V versus NHE, thereby accommodating regeneration of the oxidized dye by an iodide-based redox mediator. This dye platform can consequently be modulated at various sites to enhance light absorption and suppress recombination between the redox mediator and the TiO2 surface without compromising dye regeneration, thereby maintaining device PCEs as high as 7%. We also introduce a new phosphine-based coadsorbent, bis(2 ethylhexyl)phosphinic acid (BEPA), which is significantly easier to synthesize than the widely used bis(3,3-dimethylbutyl)phosphinic acid (DINHOP) while also facilitating high dye loading. PMID- 23439080 TI - Prenatal maternal anxiety predicts reduced adaptive immunity in infants. AB - Prenatal anxiety has been linked with altered immune function in offspring in animal studies, but the relevance for human health is unknown. We examined prenatal maternal anxiety as a predictor of adaptive immunity in infants at 2 and 6 months of age as part of a prospective longitudinal study. The humoral immune response to hepatitis B vaccine was assessed at 2 months (n=80) and 6 months (n=76) of age. Prenatal anxiety predicted lower hepatitis B antibody titers at 6 months of age independent of obstetric and socio-demographic covariates; the effects were limited to those infants who had not completed the 3-dose vaccine series (for transformed titer values, r=-.36, p<.05). Cell-mediated immune responses at 2 (n=56) and 6 (n=54) months of age were examined by ELISpot assays for interferon(IFN)-gamma, interleukin(IL)-2, and IL-4 responder cell frequencies to three antigens: hepatitis B surface antigen, tetanus toxoid, and phytohaemagglutinin (PHA). Prenatal maternal anxiety was associated with reduced IFN-gamma and increased IL-4 responder cell frequencies at 6 months of age, independent of obstetric and socio-demographic covariates. No effect of prenatal anxiety was found on adaptive immunity at 2 months of age. The findings provide the first demonstration in humans that prenatal anxiety alters adaptive immunity in the infant. PMID- 23439083 TI - Antiviral strategies combining antiretroviral drugs with RNAi-mediated attack on HIV-1 and cellular co-factors. AB - To improve the care of HIV-1/AIDS patients there is a critical need to develop tools capable of blocking viral evolution and circumventing therapy-associated problems. An emerging solution is gene therapy either as a stand-alone approach or as an adjuvant to pharmacological drug regimens. Combinatorial RNAi by multiplexing antiviral RNAi inhibitors through vector-mediated delivery has recently shown significant superiority over conventional mono-therapies. Viral as well as cellular co-factor targets have been identified, but they are generally attacked separately. Here, we hypothesized that a mixture of shRNAs directed against highly conserved viral RNA sequences and the mRNAs of cellular components that are involved in HIV replication could restrict mutational escape by enhanced synergistic inhibition. We screened for potent silencer cocktails blending inhibitors acting scattered along the viral replication cycle. The results show enhanced and extended suppression of viral replication for some combinations. To further explore the power of combinatorial approaches, we tested the influence of RNAi-mediated knockdown on the activity of conventional antiretroviral drugs (fusion, RT, integrase and protease inhibitors). We compared the fold-change in IC50 (FCIC50) of these drugs in cell lines stably expressing anti-HIV and anti host shRNAs and measured increased values that are up by several logs for some combinations. We show that high levels of additivity and synergy can be obtained by combining gene therapy with conventional drugs. These results support the idea to validate the therapeutic potential of this anti-HIV approach in appropriate in vivo models. PMID- 23439082 TI - Why is eczema herpeticum unexpectedly rare? AB - Atopic dermatitis (AD) is the most common chronic inflammatory skin disease of humans, affecting approximately 17% of children. AD patients are especially susceptible to cutaneous bacterial and viral infections, and may develop severe or fatal herpes simplex virus (HSV) infection (eczema herpeticum, EH), requiring intensive antiviral therapy. However, even though a majority of adults show serologic evidence of previous HSV exposure, EH occurs in less than 3% of AD patients. The unexpected rarity of AD patients with EH (ADEH+) suggests that multiple host factors play a role in the clinical expression of this complex phenotype. Recent studies comparing ADEH+ versus ADEH- patients reveal that patients prone to ADEH+ have more severe AD skin disease, biomarkers associated with Th2 helper cell responses (reduced interferon levels, circulating eosinophil counts, increased serum IgE and allergen sensitization) and decreased epidermal expression of filaggrin and antimicrobial peptides. ADEH+ subjects are also more likely to have a history of food allergy or asthma, early onset of AD and a history of other cutaneous infections with Staphylococcus aureus or molluscum contagiosum. PMID- 23439085 TI - Strengthening global action against poor quality drugs. PMID- 23439086 TI - The threat of lung cancer in European women. PMID- 23439084 TI - Nanomechanical properties of mineralised collagen microfibrils based on finite elements method: biomechanical role of cross-links. AB - Hierarchical structures in bio-composites such as bone tissue have many scales or levels and synergic interactions between the different levels. They also have a highly complex architecture in order to fulfil their biological and mechanical functions. In this study, a new three-dimensional (3D) model based on the finite elements (FEs) method was used to model the relationship between the hierarchical structure and the properties of the constituents at the sub-structure scale (mineralised collagen microfibrils) and to investigate their apparent nanomechanical properties. The results of the proposed FE simulations show that the elastic properties of microfibrils depend on different factors such as the number of cross-links, the mechanical properties and the volume fraction of phases. The results obtained under compression loading at a small deformation < 2% show that the microfibrils have a Young's modulus (Ef) ranging from 0.4 to 1.16 GPa and a Poisson's ratio ranging from 0.26 to 0.3. These results are in excellent agreement with experimental data (X-ray, AFM and MEMS) and molecular simulations. PMID- 23439087 TI - How and when to help children cope with trauma? PMID- 23439088 TI - A manifesto for maternal health post-2015. PMID- 23439089 TI - CABG or stents in coronary artery disease: end of the debate? PMID- 23439091 TI - Carissa Etienne: taking the reins at PAHO. PMID- 23439092 TI - Gabapentin for refractory chronic cough. PMID- 23439093 TI - Gabapentin for refractory chronic cough. PMID- 23439094 TI - Gabapentin for refractory chronic cough. PMID- 23439095 TI - Gabapentin for refractory chronic cough - Authors' reply. PMID- 23439096 TI - Resistance to second-line drugs in multidrug-resistant tuberculosis. PMID- 23439097 TI - Resistance to second-line drugs in multidrug-resistant tuberculosis. PMID- 23439098 TI - Maternal underweight and child growth and development. PMID- 23439099 TI - Resistance to second-line drugs in multidrug-resistant tuberculosis - Authors' reply. PMID- 23439100 TI - Maternal underweight and child growth and development - Authors' reply. PMID- 23439101 TI - UNITAID can address HCV/HIV co-infection. PMID- 23439102 TI - Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow up of the randomised, clinical SYNTAX trial. AB - BACKGROUND: We report the 5-year results of the SYNTAX trial, which compared coronary artery bypass graft surgery (CABG) with percutaneous coronary intervention (PCI) for the treatment of patients with left main coronary disease or three-vessel disease, to confirm findings at 1 and 3 years. METHODS: The randomised, clinical SYNTAX trial with nested registries took place in 85 centres in the USA and Europe. A cardiac surgeon and interventional cardiologist at each centre assessed consecutive patients with de-novo three-vessel disease or left main coronary disease to determine suitability for study treatments. Eligible patients suitable for either treatment were randomly assigned (1:1) by an interactive voice response system to either PCI with a first-generation paclitaxel-eluting stent or to CABG. Patients suitable for only one treatment option were entered into either the PCI-only or CABG-only registries. We analysed a composite rate of major adverse cardiac and cerebrovascular events (MACCE) at 5 year follow-up by Kaplan-Meier analysis on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00114972. FINDINGS: 1800 patients were randomly assigned to CABG (n=897) or PCI (n=903). More patients who were assigned to CABG withdrew consent than did those assigned to PCI (50 vs 11). After 5 years' follow-up, Kaplan-Meier estimates of MACCE were 26.9% in the CABG group and 37.3% in the PCI group (p<0.0001). Estimates of myocardial infarction (3.8% in the CABG group vs 9.7% in the PCI group; p<0.0001) and repeat revascularisation (13.7%vs 25.9%; p<0.0001) were significantly increased with PCI versus CABG. All-cause death (11.4% in the CABG group vs 13.9% in the PCI group; p=0.10) and stroke (3.7%vs 2.4%; p=0.09) were not significantly different between groups. 28.6% of patients in the CABG group with low SYNTAX scores had MACCE versus 32.1% of patients in the PCI group (p=0.43) and 31.0% in the CABG group with left main coronary disease had MACCE versus 36.9% in the PCI group (p=0.12); however, in patients with intermediate or high SYNTAX scores, MACCE was significantly increased with PCI (intermediate score, 25.8% of the CABG group vs 36.0% of the PCI group; p=0.008; high score, 26.8%vs 44.0%; p<0.0001). INTERPRETATION: CABG should remain the standard of care for patients with complex lesions (high or intermediate SYNTAX scores). For patients with less complex disease (low SYNTAX scores) or left main coronary disease (low or intermediate SYNTAX scores), PCI is an acceptable alternative. All patients with complex multivessel coronary artery disease should be reviewed and discussed by both a cardiac surgeon and interventional cardiologist to reach consensus on optimum treatment. FUNDING: Boston Scientific. PMID- 23439104 TI - Ogilvie's syndrome in severe dengue. PMID- 23439103 TI - Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. AB - BACKGROUND: The anatomical SYNTAX score is advocated in European and US guidelines as an instrument to help clinicians decide the optimum revascularisation method in patients with complex coronary artery disease. The absence of an individualised approach and of clinical variables to guide decision making between coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) are limitations of the SYNTAX score. SYNTAX score II aimed to overcome these limitations. METHODS: SYNTAX score II was developed by applying a Cox proportional hazards model to results of the randomised all comers SYNTAX trial (n=1800). Baseline features with strong associations to 4-year mortality in either the CABG or the PCI settings (interactions), or in both (predictive accuracy), were added to the anatomical SYNTAX score. Comparisons of 4-year mortality predictions between CABG and PCI were made for each patient. Discriminatory performance was quantified by concordance statistics and internally validated with bootstrap resampling. External validation was done in the multinational all comers DELTA registry (n=2891), a heterogeneous population that included patients with three-vessel disease (26%) or complex coronary artery disease (anatomical SYNTAX score >=33, 30%) who underwent CABG or PCI. The SYNTAX trial is registered with ClinicalTrials.gov, number NCT00114972. FINDINGS: SYNTAX score II contained eight predictors: anatomical SYNTAX score, age, creatinine clearance, left ventricular ejection fraction (LVEF), presence of unprotected left main coronary artery (ULMCA) disease, peripheral vascular disease, female sex, and chronic obstructive pulmonary disease (COPD). SYNTAX score II significantly predicted a difference in 4-year mortality between patients undergoing CABG and those undergoing PCI (p(interaction) 0.0037). To achieve similar 4-year mortality after CABG or PCI, younger patients, women, and patients with reduced LVEF required lower anatomical SYNTAX scores, whereas older patients, patients with ULMCA disease, and those with COPD, required higher anatomical SYNTAX scores. Presence of diabetes was not important for decision making between CABG and PCI (p(interaction) 0.67). SYNTAX score II discriminated well in all patients who underwent CABG or PCI, with concordance indices for internal (SYNTAX trial) validation of 0.725 and for external (DELTA registry) validation of 0.716, which were substantially higher than for the anatomical SYNTAX score alone (concordance indices of 0.567 and 0.612, respectively). A nomogram was constructed that allowed for an accurate individualised prediction of 4-year mortality in patients proposing to undergo CABG or PCI. INTERPRETATION: Long-term (4-year) mortality in patients with complex coronary artery disease can be well predicted by a combination of anatomical and clinical factors in SYNTAX score II. SYNTAX score II can better guide decision making between CABG and PCI than the original anatomical SYNTAX score. FUNDING: Boston Scientific Corporation. PMID- 23439105 TI - Paradoxical effect of supplementary progesterone between Day 3 and Day 7 on corpus luteum function and conceptus development in cattle. AB - The aim of the present study was to investigate the effect of short-term progesterone (P4) supplementation during the early metoestrous period on circulating P4 concentrations and conceptus development in cattle. The oestrous cycles of cross-bred beef heifers were synchronised using a 7-day P4-releasing intravaginal device (PRID(r) Delta; 1.55 g P4) treatment with administration of a prostaglandin F(2alpha) analogue (Enzaprost; CEVA Sante Animale) the day before PRID(r) Delta removal. Only those heifers recorded in standing oestrus (Day 0) were used. In Experiment 1, heifers were randomly assigned to one of five groups: (1) control: no treatment; (2) placebo: insertion of a blank device (no P4) from Day 3 to Day 7; (3) insertion of a PRID(r) Delta from Day 3 to Day 7; (4) insertion of a PRID(r) Delta from Day 3 to Day 5; or (5) insertion of a PRID(r) Delta from Day 5 to Day 7. In vitro-produced blastocysts were transferred to each heifer in Groups 2-5 on Day 7 (n=10 blastocysts per heifer) and conceptuses were recovered when heifers were killed on Day 14. Based on the outcome of Experiment 1, in Experiment 2 heifers were artificially inseminated at oestrus and randomly assigned to one of three treatment groups: (1) placebo; (2) PRID from Day 3 to Day 5; or (3) PRID from Day 3 to Day 7. All heifers were killed on Day 16 and recovered conceptuses were incubated in synthetic oviducal fluid medium for 24 h; spent media and uterine flushes were analysed for interferon-tau (IFNT). In both experiments, daily blood samples were taken to determined serum P4 concentrations. Data were analysed using the PROC MIXED procedure of SAS (SAS Institute, Cary, NC, USA). Insertion of a PRID resulted in an increase (P<0.05) in serum P4 that declined following removal. In Experiment 1, P4 supplementation from Day 3 to Day 5 (17.0+/-1.4 mm) or Day 3 to Day 7 (11.3+/-2.3 mm) increased conceptus length compared with placebo (2.1+/-1.8 mm). Serum P4 was significantly lower from Day 9 to Day 14 (P<0.05) and the weight of the Day 14 corpus luteum (CL) was lower in the PRID Day 3-7 group than the placebo or control groups. In Experiment 2, supplementation from Day 3 to Day 5 (94.0+/-18.8 mm) or Day 3 to Day 7 (143.6+/-20.6 mm) increased conceptus length on Day 16 compared with placebo (50.3+/-17.4 mm). Serum P4 was significantly lower in the two supplemented groups following PRID removal compared with placebo (P<0.05) and was associated with a lower CL weight in the Day 3-7 group. Conceptus length was strongly correlated with the IFNT concentration in the uterine flush (r=0.58; P=0.011) and spent culture medium (r=0.68; P<0.002). The findings of the present study highlight the somewhat paradoxical effects of P4 supplementation when given in the early metoestrous period in terms of its positive effect on conceptus development and its potentially negative effects on CL lifespan. PMID- 23439106 TI - Characterisation of a monoclonal antibody detecting Atlantic salmon endothelial and red blood cells, and its association with the infectious salmon anaemia virus cell receptor. AB - Endothelial cells (ECs) line the luminal surfaces of the cardiovascular system and play an important role in cardiovascular functions such as regulation of haemostasis and vasomotor tone. A number of fish and mammalian viruses target these cells in the course of their infection. Infectious salmon anaemia virus (ISAV) attacks ECs and red blood cells (RBCs) of farmed Atlantic salmon (Salmo salar L.), producing the severe disease of infectious salmon anaemia (ISA). The investigation of ISA has up to now been hampered by the lack of a functional marker for ECs in Atlantic salmon in situ. In this study, we report the characterisation and use of a novel monoclonal antibody (MAb) detecting Atlantic salmon ECs (e.g. vessel endothelium, endocardial cells and scavenger ECs) and RBCs. The antibody can be used with immunohistochemistry, IFAT and on Western blots. It appears that the epitope recognised by the antibody is associated with the ISAV cellular receptor. Besides being a tool to identify ECs in situ, it could be useful in further studies of the pathogenicity of ISA. Finally, the detection of an epitope shared by ECs and RBCs agrees with recent findings that these cells share a common origin, thus the MAb can potentially be used to study the ontogeny of these cells in Atlantic salmon. PMID- 23439107 TI - Characterizing bone tunnel placement in medial ulnar collateral ligament reconstruction using patient-specific 3-dimensional computed tomography modeling. AB - BACKGROUND: Medial ulnar collateral ligament (MUCL) reconstruction is successful in restoring valgus elbow stability, but variability in bone tunnel characteristics exists among surgical techniques. HYPOTHESIS: Tunnel parameters such as diameter, drill angle, and starting location in MUCL reconstruction affect tunnel length and bone bridge size between tunnels. STUDY DESIGN: Descriptive laboratory study. METHODS: Three-dimensional models were created from elbow computed tomography scans of 10 throwing athletes and analyzed using Mimics (Materialise) software. The MUCL reconstructions were simulated on each elbow with 3 techniques: Jobe, humeral docking, and DANE TJ. Humeral central tunnels were modified by diameter, medial-lateral epicondylar starting point, and angle with respect to the humeral axis. Ulnar tunnels were varied by diameter and angle with respect to the ulnar axis. Humeral tunnel length, humeral and ulnar bone bridge sizes, and ulnar tunnel aperture and distance from the articular surface of the olecranon were measured. Comparisons were made using 1- and 2-way analysis of variance and Student-Newman-Keuls multiple comparison tests. RESULTS: Mean central humeral tunnel length varied significantly by starting point and angulation of the tunnel both in sagittal and coronal planes, ranging from 14.2 +/- 2.3 mm to 25.5 +/- 4.3 mm (P < .05). Mean bone bridge size between humeral exit tunnels ranged from 9.0 +/- 2.5 mm to 15.1 +/- 3.1 mm, varying by central humeral tunnel orientation and exit tunnel diameter (P < .05). Bone bridge size between ulnar tunnels with the Jobe and docking techniques averaged 6.7 +/- 0.9 mm (3.2-mm tunnels) and 6.4 +/- 0.8 mm (3.5-mm tunnels), respectively. Angle of ulnar tunnels affected distance from the articular surface with the Jobe and docking techniques (P < .0001) and affected tunnel aperture size with the interference screw technique (P < .0001). CONCLUSION: Humeral and ulnar tunnel angles, starting points, and diameters affect tunnel length, distance from the articular surface, and bone bridge size in MUCL reconstructions. Maximal humeral tunnel length is achieved by starting central or lateral to the midpoint of the epicondyle, angulated 30 degrees to the humeral axis in the sagittal plane and 15 degrees in the coronal plane. A reasonable goal tunnel depth should range from 15 to 20 mm. Ulnar tunnels should be placed on the anterior and posterior aspects of the sublime tubercle, directed away from the joint to minimize the likelihood of breaching the articular cartilage. A bone bridge of 6 to 8 mm between these tunnels can be reasonably achieved. Tunnels with the ulnar interference screw fixation technique should also be directed away from the joint but at an angle more perpendicular than 45 degrees to minimize tunnel aperture size. Regardless of angle of the tunnel drilled for the ulnar interference screw employed in the DANE TJ technique, the tunnel length is sufficient to fully contain a 15-mm screw. CLINICAL RELEVANCE: Computer models can guide MUCL reconstruction technique by indicating tunnel placement for maximizing the bone bridge and tunnel length. PMID- 23439108 TI - Imaging findings in recurrent extramedullary leukaemias. AB - Acute leukaemias are relatively common malignancies. Treatment has advanced significantly in the recent past and there has been improved patient survival. This improved initial response is leading to an increasing number of cases of relapse. Extramedullary relapse occurs in a wide variety of locations with varying presentations, imaging findings and differentials. The pathophysiology and clinical course of recurrent extramedullary myeloid and lymphocytic leukaemias are reviewed in this article. The wide variety of imaging findings associated with many important sites of recurrence and the associated differential diagnosis are discussed and illustrated. PMID- 23439109 TI - Interlimb coordination during a cooperative bimanual object manipulation task. AB - This experiment examined asymmetries in the execution of an object manipulation task that requires the coordinated use of both hands. To this end, twenty right hand-dominant participants performed a bimanual object manipulation task, which required that they reach for and grasp two objects located on a tabletop, fit the two objects through a hole in a horizontally or vertically oriented fitting board, and then rotate the objects 180 degrees to produce a "beep" tone. Overall, the two hands were highly synchronized at the start, but not at end, of each movement phase. The decrease in interlimb coupling at later stages of the movement phase was primarily driven by the shorter movement time values for the dominant right hand. In addition, degree of left object rotation was greater than the right object, irrespective of board orientation. In sum, the results suggest that manual asymmetries and role assignment are not hardwired constraints, but depend on the overall task constraints and the manner in which the task is conceptualized. PMID- 23439110 TI - A photometric high-throughput method for identification of electrochemically active bacteria using a WO3 nanocluster probe. AB - Electrochemically active bacteria (EAB) are ubiquitous in environment and have important application in the fields of biogeochemistry, environment, microbiology and bioenergy. However, rapid and sensitive methods for EAB identification and evaluation of their extracellular electron transfer ability are still lacking. Herein we report a novel photometric method for visual detection of EAB by using an electrochromic material, WO(3) nanoclusters, as the probe. This method allowed a rapid identification of EAB within 5 min and a quantitative evaluation of their extracellular electron transfer abilities. In addition, it was also successfully applied for isolation of EAB from environmental samples. Attributed to its rapidness, high reliability, easy operation and low cost, this method has high potential for practical implementation of EAB detection and investigations. PMID- 23439111 TI - Procedural competency of gastroenterology trainees: from apprenticeship to milestones. PMID- 23439112 TI - RANTing about C9orf72. AB - A noncoding repeat expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. In this issue of Neuron, Ash et al. (2013) show that despite being noncoding the repeats are translated, leading to widespread neuronal aggregates of the translated proteins. PMID- 23439113 TI - Is instability good for the brain? AB - In this issue of Neuron, Nahm et al. (2013) examine the Drosophila ortholog of spartin, the human gene mutated in a form of hereditary spastic paraplegia. Spartin inhibits BMP signaling and upregulation of BMP signaling may increase microtubule stability and neurodegeneration. PMID- 23439114 TI - Broadening roles for FMRP: big news for big potassium (BK) channels. AB - FMRP is an RNA-binding protein that negatively regulates translation and which is lost in fragile X syndrome. In this issue of Neuron, Deng et al. (2013) demonstrate a novel translation-independent function for FMRP as a regulator of presynaptic BK channels that modulate the dynamics of neurotransmitter release. PMID- 23439115 TI - Prefrontal NMDA receptors and cognition: working 2B remembered. AB - Cortical neurons use glutamate as a primary neurotransmitter, yet the mechanism through which glutamate receptors regulate higher order cognitive functions is unclear. In this issue of Neuron, Wang et al. (2013) report a previously uncharacterized role for NMDA NR2B receptors in driving mnemonic-related activity of prefrontal neurons. PMID- 23439117 TI - Visceral influences on brain and behavior. AB - Mental processes and their neural substrates are intimately linked to the homeostatic control of internal bodily state. There are a set of distinct interoceptive pathways that directly and indirectly influence brain functions. The anatomical organization of these pathways and the psychological/behavioral expressions of their influence appear along discrete, evolutionarily conserved dimensions that are tractable to a mechanistic understanding. Here, we review the role of these pathways as sources of biases to perception, cognition, emotion, and behavior and arguably the dynamic basis to the concept of self. PMID- 23439116 TI - "Seq-ing" insights into the epigenetics of neuronal gene regulation. AB - The epigenetic control of neuronal gene expression patterns has emerged as an underlying regulatory mechanism for neuronal function, identity, and plasticity, in which short- to long-lasting adaptation is required to dynamically respond and process external stimuli. To achieve a comprehensive understanding of the physiology and pathology of the brain, it becomes essential to understand the mechanisms that regulate the epigenome and transcriptome in neurons. Here, we review recent advances in the study of regulated neuronal gene expression, which are dramatically expanding as a result of the development of new and powerful contemporary methodologies, based on next-generation sequencing. This flood of new information has already transformed our understanding of many biological processes and is now driving discoveries elucidating the molecular mechanisms of brain function in cognition, behavior, and disease and may also inform the study of neuronal identity, diversity, and neuronal reprogramming. PMID- 23439118 TI - mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons. AB - Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyperexcitability, and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA-approved inhibitor both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes. PMID- 23439119 TI - Interaxonal interaction defines tiled presynaptic innervation in C. elegans. AB - VIDEO ABSTRACT: Cellular interactions between neighboring axons are essential for global topographic map formation. Here we show that axonal interactions also precisely instruct the location of synapses. Motoneurons form en passant synapses in Caenorhabditis elegans. Although axons from the same neuron class significantly overlap, each neuron innervates a unique and tiled segment of the muscle field by restricting its synapses to a distinct subaxonal domain-a phenomenon we term synaptic tiling. Using DA8 and DA9 motoneurons, we found that the synaptic tiling requires the PlexinA4 homolog, PLX-1, and two transmembrane semaphorins. In the plexin or semaphorin mutants, synaptic domains from both neurons expand and overlap with each other without guidance defects. In a semaphorin-dependent manner, PLX-1 is concentrated at the synapse-free axonal segment, delineating the tiling border. Furthermore, plexin inhibits presynapse formation by suppressing synaptic F-actin through its cytoplasmic GTPase activating protein (GAP) domain. Hence, contact-dependent, intra-axonal plexin signaling specifies synaptic circuits by inhibiting synapse formation at the subcellular loci. PMID- 23439120 TI - TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. AB - The capsaicin receptor, TRPV1, is regulated by phosphatidylinositol-4,5 bisphosphate (PIP(2)), although the precise nature of this effect (i.e., positive or negative) remains controversial. Here, we reconstitute purified TRPV1 into artificial liposomes, where it is gated robustly by capsaicin, protons, spider toxins, and, notably, heat, demonstrating intrinsic sensitivity of the channel to both chemical and thermal stimuli. TRPV1 is fully functional in the absence of phosphoinositides, arguing against their proposed obligatory role in channel activation. Rather, introduction of various phosphoinositides, including PIP(2), PI4P, and phosphatidylinositol, inhibits TRPV1, supporting a model whereby phosphoinositide turnover contributes to thermal hyperalgesia by disinhibiting the channel. Using an orthogonal chemical strategy, we show that association of the TRPV1 C terminus with the bilayer modulates channel gating, consistent with phylogenetic data implicating this domain as a key regulatory site for tuning stimulus sensitivity. Beyond TRPV1, these findings are relevant to understanding how membrane lipids modulate other "receptor-operated" TRP channels. PMID- 23439121 TI - Spartin regulates synaptic growth and neuronal survival by inhibiting BMP mediated microtubule stabilization. AB - Troyer syndrome is a hereditary spastic paraplegia caused by human spartin (SPG20) gene mutations. We have generated a Drosophila disease model showing that Spartin functions presynaptically with endocytic adaptor Eps15 to regulate synaptic growth and function. Spartin inhibits bone morphogenetic protein (BMP) signaling by promoting endocytic degradation of BMP receptor wishful thinking (Wit). Drosophila fragile X mental retardation protein (dFMRP) and Futsch/MAP1B are downstream effectors of Spartin and BMP signaling in regulating microtubule stability and synaptic growth. Loss of Spartin or elevation of BMP signaling induces age-dependent progressive defects resembling hereditary spastic paraplegias, including motor dysfunction and brain neurodegeneration. Null spartin phenotypes are prevented by administration of the microtubule destabilizing drug vinblastine. Together, these results demonstrate that Spartin regulates both synaptic development and neuronal survival by controlling microtubule stability via the BMP-dFMRP-Futsch pathway, suggesting that impaired regulation of microtubule stability is a core pathogenic component in Troyer syndrome. PMID- 23439122 TI - FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. AB - Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory beta4 subunits. Information theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology. PMID- 23439123 TI - Enhanced intrinsic excitability in basket cells maintains excitatory-inhibitory balance in hippocampal circuits. AB - The dynamics of inhibitory circuits in the cortex is thought to rely mainly on synaptic modifications. We challenge this view by showing that hippocampal parvalbumin-positive basket cells (PV-BCs) of the CA1 region express long-term (>30 min) potentiation of intrinsic neuronal excitability (LTP-IE(PV-BC)) upon brief repetitive stimulation of the Schaffer collaterals. LTP-IE(PV-BC) is induced by synaptic activation of metabotropic glutamate receptor subtype 5 (mGluR5) and mediated by the downregulation of Kv1 channel activity. LTP-IE(PV BC) promotes spiking activity at the gamma frequency (~35 Hz) and facilitates recruitment of PV-BCs to balance synaptic and intrinsic excitation in pyramidal neurons. In conclusion, activity-dependent modulation of intrinsic neuronal excitability in PV-BCs maintains excitatory-inhibitory balance and thus plays a major role in the dynamics of hippocampal circuits. PMID- 23439124 TI - A cholinergic mechanism for reward timing within primary visual cortex. AB - Neurons in rodent primary visual cortex (V1) relate operantly conditioned stimulus-reward intervals with modulated patterns of spiking output, but little is known about the locus or mechanism of this plasticity. Here we show that cholinergic basal forebrain projections to V1 are necessary for the neural acquisition, but not the expression, of reward timing in the visual cortex of awake, behaving animals. We then mimic reward timing in vitro by pairing white matter stimulation with muscarinic receptor activation at a fixed interval and show that this protocol results in the prolongation of electrically evoked spike train durations out to the conditioned interval. Together, these data suggest that V1 possesses the circuitry and plasticity to support reward time prediction learning and the cholinergic system serves as an important reinforcement signal which, in vivo, conveys to the cortex the outcome of behavior. PMID- 23439125 TI - NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. AB - Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPARs) contributed background depolarization to sustain network firing. In contrast, many Response cells were sensitive to AMPAR blockade and increased firing after systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer's disease profoundly impair cognition. PMID- 23439126 TI - The spectrotemporal filter mechanism of auditory selective attention. AB - Although we have convincing evidence that attention to auditory stimuli modulates neuronal responses at or before the level of primary auditory cortex (A1), the underlying physiological mechanisms are unknown. We found that attending to rhythmic auditory streams resulted in the entrainment of ongoing oscillatory activity reflecting rhythmic excitability fluctuations in A1. Strikingly, although the rhythm of the entrained oscillations in A1 neuronal ensembles reflected the temporal structure of the attended stream, the phase depended on the attended frequency content. Counter-phase entrainment across differently tuned A1 regions resulted in both the amplification and sharpening of responses at attended time points, in essence acting as a spectrotemporal filter mechanism. Our data suggest that selective attention generates a dynamically evolving model of attended auditory stimulus streams in the form of modulatory subthreshold oscillations across tonotopically organized neuronal ensembles in A1 that enhances the representation of attended stimuli. PMID- 23439128 TI - Alteration of visual perception prior to microsaccades. AB - Gaze fixation is an active process, with the incessant occurrence of tiny eye movements, including microsaccades. While the retinal consequences of microsaccades may be presumed minimal because of their minute size, a significant perceptual consequence of these movements can also stem from active extraretinal mechanisms associated with corollaries of their motor generation. Here I show that prior to microsaccade onset, spatial perception is altered in a very specific manner: foveal stimuli are erroneously perceived as more eccentric, whereas peripheral stimuli are rendered more foveal. The mechanism for this perceptual "compression of space" is consistent with a spatially specific gain modulation of visual representations caused by the upcoming eye movements, as is hypothesized to happen for much larger saccades. I then demonstrate that this perimicrosaccadic perceptual alteration has at least one important functional consequence: it mediates visual-performance alterations similar to ones classically attributed to the cognitive process of covert visual attention. PMID- 23439127 TI - gamma and the coordination of spiking activity in early visual cortex. AB - Gamma components of the local field potential (LFP) are elevated during cognitive and perceptual processes. It has been suggested that gamma power indicates the strength of neuronal population synchrony, which influences the relaying of signals between cortical areas. However, the relationship between coordinated spiking activity and gamma remains unclear, and the influence on corticocortical signaling largely untested. We investigated these issues by recording from neuronal populations in areas V1 and V2 of anesthetized macaque monkeys. We found that visual stimuli that induce a strong, coherent gamma rhythm result in enhanced pairwise and higher-order V1 synchrony. This is associated with stronger coupling of V1-V2 spiking activity, in a retinotopically specific manner. Coupling is more strongly related to the gamma modulation of V1 firing than to the downstream V2 rhythm. Our results thus show that elevated gamma power is associated with stronger coordination of spiking activity both within and between cortical areas. PMID- 23439129 TI - Functional differentiation of memory retrieval network in macaque posterior parietal cortex. AB - Human fMRI studies revealed involvement of the posterior parietal cortex (PPC) during memory retrieval. However, corresponding memory-related regions in macaque PPC have not been established. In this monkey fMRI study, comparisons of cortical activity during correct recognition of previously seen items and rejection of unseen items revealed two major PPC activation sites that were differentially characterized by a serial probe recognition paradigm: area PG/PGOp in inferior parietal lobule, along with the hippocampus, was more active for initial item retrieval, while area PEa/DIP in intraparietal sulcus was for the last item. Effective connectivity analyses revealed that connectivity from hippocampus to PG/PGOp, but not to PEa/DIP, increased during initial item retrieval. The two parietal areas with differential serial probe recognition profiles were embedded in two different subnetworks of the brain-wide retrieval-related regions. These functional dissociations in the macaque PPC imply the functional correspondence of retrieval-related PPC networks in macaques and humans. PMID- 23439130 TI - Vertical T-maze choice assay for arthropod response to odorants. AB - Given the economic importance of insects and arachnids as pests of agricultural crops, urban environments or as vectors of plant and human diseases, various technologies are being developed as control tools. A subset of these tools focuses on modifying the behavior of arthropods by attraction or repulsion. Therefore, arthropods are often the focus of behavioral investigations. Various tools have been developed to measure arthropod behavior, including wind tunnels, flight mills, servospheres, and various types of olfactometers. The purpose of these tools is to measure insect or arachnid response to visual or more often olfactory cues. The vertical T-maze olfactometer described here measures choices performed by insects in response to attractants or repellents. It is a high throughput assay device that takes advantage of the positive phototaxis (attraction to light) and negative geotaxis (tendency to walk or fly upward) exhibited by many arthropods. The olfactometer consists of a 30 cm glass tube that is divided in half with a Teflon strip forming a T-maze. Each half serves as an arm of the olfactometer enabling the test subjects to make a choice between two potential odor fields in assays involving attractants. In assays involving repellents, lack of normal response to known attractants can also be measured as a third variable. PMID- 23439131 TI - Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels. AB - Droplet microfluidic technology is applied for the high-throughput synthesis via Michael-type addition of reactive, micrometer-sized poly(ethylene glycol) (PEG) hydrogels ("microgels") with precisely controlled dimension and physicochemical properties. A versatile chemical scheme is used to modify the reactive PEG microgels with tethered biomolecules to tune their bioactive properties for the bioreactor culture and manipulation of various (stem) cell types. PMID- 23439132 TI - Electrochemical and spectroscopic investigation of Ln3+ (Ln = Sm, Eu, and Yb) solvation in bis(trifluoromethylsulfonyl)imide-based ionic liquids and coordination by N,N,N',N'-tetraoctyl-3-oxa-pentane diamide (TODGA) and chloride. AB - The electrochemistry and electronic absorption spectroscopy of samarium, europium, and ytterbium were investigated in the 1-(1-butyl)trimethylammonium bis(trifluoromethylsulfonyl)imide (BuMe3NTf2N) and 1-butyl-3-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (BuMePyroTf2N) ionic liquids and in these solvents containing the neutral tridentate ligand N,N,N',N'-tetraoctyl-3-oxo pentane diamide (TODGA) and the anionic hard ligand chloride. Lanthanide ions were introduced into the ionic liquids by controlled potential oxidation of the respective metals to yield solutions containing Eu(2+), Sm(3+), and Yb(3+), and it was possible to cycle between Eu(2+) and Eu(3+) as well as Yb(3+) and Yb(2+) using controlled potential electrolysis. Electronic absorption spectroscopy suggested that the Ln(3+) species are weakly solvated by Tf2N(-) anions as [Ln(Tf2N)x]((x-3)-) in the neat ILs. The quasireversible Ln(3+/2+) couples of all three elements were readily accessible in these ILs, but Sm(2+) was only stable on the voltammetric time scale. Addition of TODGA to [Ln(Tf2N)x]((x-3)-) solutions produces 3:1 complexes with Eu(3+) and Sm(3+) but only a 2:1 complex with the smaller Yb(3+) ion. Depending on the temperature, addition of Cl(-) to solutions of [Ln(Tf2N)x]((x-3)-) induces precipitation of LnCl3(s) when the mole ratio mCl(-)/mLn(3+) ~ 3. However, when mCl(-)/mLn(3+) > 3, these precipitates redissolve to form the octahedral chloride complexes, [LnCl6](3-). PMID- 23439133 TI - The effect of forced growth of cells into 3D spheres using low attachment surfaces on the acquisition of stemness properties. AB - Embryonic stem cells (ESCs) and neural progenitor cells form three-dimensional (3D) colonies or spheres in vitro, and 3D sphere is reported to help maintaining the stemness of stem cells, but the effect of 3D sphere formation on cell reprogramming remains unknown. Here we examined whether 3D sphere culture have any impact on the differentiated cells. We cultured bladder cancer cell RT4 and non-cancerous cell HEK293 on the low attachment dishes coated with soft agarose. When grown on this low attachment dish, cells spontaneously aggregated to form 3D spheres. Data showed that 3D sphere formation promoted the expression of reprogramming factors. Sphere formation of RT4 cells induced cancer stem cell characteristics including higher SP cell percentage, higher metastasis ability and higher tumorigenicity. HEK293 spheres showed upregulation of kidney progenitor cell markers and partially acquired characteristics of ESCs including upregulation of alkaline phosphatase activity, ES cell markers, three germ layer markers and tumorigenicity. The findings suggested that forced growth into 3D spheres by the low attachment surface could induce cells to acquire stemness properties. PMID- 23439134 TI - Osteogenic activity and antibacterial effects on titanium surfaces modified with Zn-incorporated nanotube arrays. AB - Titanium implants having enhanced osteogenic activity and antibacterial property are highly desirable for the prevention of implant associated infection and promotion of osseointegration. In this study, coatings containing titania nanotubes (NTs) incorporated with zinc (NT-Zn) are produced on Ti implants by anodization and hydrothermal treatment in Zn containing solutions. The amount of incorporated Zn can be adjusted by varying the structural parameters such as the nanotube diameter and length as well as hydrothermal treatment time. The suitable NT-Zn coatings with good intrinsic antibacterial properties can prevent post operation infection. Excellent osteogenesis inducing ability in the absence of extraneous osteogenic supplements is demonstrated and the ERK1/2 signaling is found to be involved. The NT-Zn structure which is simple, stable, and easy to produce and scale up has immense potential in bone implant applications. PMID- 23439138 TI - The Gulf War depleted uranium cohort at 20 years: bioassay results and novel approaches to fragment surveillance. AB - During the 1991 GulfWar, U.S. service members were exposed to depleted uranium (DU) through friendly-fire incidents involving DU munitions and vehicles protected by DU armor. Routes of exposure to DU involved inhalation of soluble and insoluble DU oxide particles, wound contamination, and retained embedded DU metal fragments that continue to oxidize in situ and release DU to the systemic circulation. A biennial health surveillance program established for this group of Veterans by the U.S. Department of Veterans Affairs has shown continuously elevated urine DU concentrations in the subset of veterans with embedded fragments for over 20 years. While the 2011 assessment was comprehensive, few clinically significant U-related health effects were observed. This report is focused on health outcomes associated with two primary target organs of concern for long term effects of this combat-related exposure to DU. Renal biomarkers showed minimal DU-related effects on proximal tubule function and cytotoxicity, but significant biomarker results were observed when urine concentrations of multiple metals also found in fragments were examined together. Pulmonary tests and questionnaire results indicate that pulmonary function after 20 y remains within the clinical normal range. Imaging of DU embedded fragment-associated tissue for signs of inflammatory or proliferative reactions possibly associated with foreign body transformation or with local alpha emissions from DU was also conducted using PET-CT and ultrasound. These imaging tools may be helpful in guiding decisions regarding removal of fragments. PMID- 23439139 TI - Robust technique using an imaging plate to detect environmental radioactivity. AB - The Fukushima Daiichi Nuclear Power Plant was severely damaged by the Great East Japan Earthquake on 11 March 2011. Consequently, a large amount of radioactive material was accidentally released. Recently, the focus has been on quantification of environmental radioactive material. However, conventional techniques require complicated and expensive measurement equipment. In this research, the authors developed a simple method to detect environmental radioactive material with an imaging plate (IP). Two specific measurement subjects were targeted: measurements for the depth distribution of radioactive material in soil and surface contamination of a building roof. For the measurement of depth distribution of radioactive material in soil, the authors ascertained that the concentration of environmental radioactivity was highest at 5 cm below the surface, and it decreased with depth. For the measurement of surface contamination of the building roof, the authors created a contamination map of the building roof. The detector developed could contact the ground directly, and unlike other survey meters, it was not influenced by peripheral radioactivity. In this study, the authors verified the feasibility of measurement of environmental radioactivity with an IP. Although the measured values of the IP were relative, further work is planned to perform evaluations of absolute quantities of radioactive material. PMID- 23439140 TI - Mayak Worker Dosimetry System 2008 (MWDS-2008): assessment of internal dose from measurement results of plutonium activity in urine. AB - A new modification of the prior human lung compartment plutonium model, Doses 2005, has been described. The modified model was named "Mayak Worker Dosimetry System-2008" (MWDS-2008). In contrast to earlier models developed for workers at the Mayak Production Association (Mayak PA), the new model more correctly describes plutonium biokinetics and metabolism in pulmonary lymph nodes. The MWDS 2008 also provides two sets of doses estimates: one based on bioassay data and the other based on autopsy data, where available. The algorithm of internal dose calculation from autopsy data will be described in a separate paper. Results of comparative analyses of Doses-2005 and MWDS-2008 are provided. Perspectives on the further development of plutonium dosimetry are discussed. PMID- 23439141 TI - Characterization of MOSFET detectors for in vivo dosimetry in interventional radiology and for dose reconstruction in case of overexposure. AB - As MOSFET (Metal Oxide Semiconductor Field Effect Transistor) detectors allow dose measurements in real time, the interest in these dosimeters is growing. The aim of this study was to investigate the dosimetric properties of commercially available TN-502RD-H MOSFET silicon detectors (Best Medical Canada, Ottawa, Canada) in order to use them for in vivo dosimetry in interventional radiology and for dose reconstruction in case of overexposure. Reproducibility of the measurements, dose rate dependence, and dose response of the MOSFET detectors have been studied with a Co source. Influence of the dose rate, frequency, and pulse duration on MOSFET responses has also been studied in pulsed x-ray fields. Finally, in order to validate the integrated dose given by MOSFET detectors, MOSFETs and TLDs (LiF:Mg,Cu,P) were fixed on an Alderson-Rando phantom in the conditions of an interventional neuroradiology procedure, and their responses have been compared. The results of this study show the suitability of MOSFET detectors for in vivo dosimetry in interventional radiology and for dose reconstruction in case of accident, provided a well-corrected energy dependence, a pulse duration equal to or higher than 10 ms, and an optimized contact between the detector and the skin of the patient are achieved. PMID- 23439142 TI - UV emissions from artificial tanning devices and their compliance with the European technical standard. AB - Use of ultraviolet radiation-emitting tanning devices has been classified as "carcinogenic to humans" (group 1) by the International Agency for Research on Cancer. Following this classification, the knowledge of typical ultraviolet emission levels from tanning devices can be of interest for evaluating their impact on health. In this work, the results of an extensive measurement campaign on artificial tanning appliances are presented. Ultraviolet emissions from 94 tanning appliances produced by 15 different manufacturers were characterized by onsite spectroradiometric measurements. The measured radiometric quantities were compared with reference values fixed in the European technical standard EN 60335 2-27 "Household and similar electrical appliances-Safety. Part 2: Particular requirements for appliances for skin exposure to ultraviolet and infrared radiation." Measurement results indicate that 88% of the examined appliances had ultraviolet emissions not compliant with the technical standard. Among the considered appliances, tanning devices equipped with low pressure lamps showed higher ultraviolet levels of effective irradiance and less compliance with standard requirements. In particular, UV emissions from 100% of low pressure appliances and from 78% of high pressure appliances exceeded the irradiance limit of 0.3 Wm set by the European technical standard. PMID- 23439143 TI - Application of Bayesian inference to the bioassay data from long-term follow-up of two refractory PuO2 inhalation cases. AB - The dominant contribution to the uncertainty in internal dose assessment can often be explained by the uncertainty in the biokinetic model structure and parameters. The International Commission on Radiological Protection (ICRP) is currently updating its biokinetic models, including the Human Respiratory Tract Model (HRTM). Gregoratto et al. (2010) proposed a physiologically-based particle transport model that simplifies significantly the representation of particle clearance from the alveolar interstitial region. Bayesian inference using the Weighted Likelihood Monte-Carlo Sampling (WeLMoS) method is applied to the bioassay and autopsy data from the U.S. Transuranium and Uranium Registries' (USTUR) tissue donors 0202 and 0407 exposed to "high fired," refractory PuO2 aerosols in order to examine the applicability of the revised model and to estimate the uncertainties in model parameters and the lung doses as expressed by the posterior probability distributions. It is demonstrated that, with appropriate adjustments, the Gregoratto et al. particle transport model can describe situations involving exposure to highly insoluble particles. Significant differences are observed in particle clearance pattern characteristics to these two individuals' respiratory systems. The respiratory tract of registrant 0202 was most likely compromised by his prior occupational exposure to coal dust, smoking habit, and chronic obstructive pulmonary disease, while donor 0407 was a non-smoker and had no prior history of lung disorder. However, the central values of the particle transport parameter posterior distributions for both cases are found to be still within the 68% probability range for the inter-subject variability derived by Gregoratto et al. PuO2 particles produced by the plutonium fire were extremely insoluble, with about 99% absorbed into blood at a rate of approximately 4.8 * 10 d (Case 0202) and 5.1 * 10 d (Case 0202). When considering this type of plutonium material, doses to other body organs are small in comparison to those to tissues of the respiratory tract. More than 95% of the total committed weighted equivalent dose is contributed by the lungs. PMID- 23439144 TI - Monte Carlo simulation of in vivo measurement of the most suitable knee position for the optimal measurement of activity. AB - A new computational model has been developed using the Monte Carlo (MC) technique to simulate in vivo measurements with the objective of understanding the most precise measurement location with respect to quantifying the activity of Am in the bones. To benchmark the model, in vivo measurements were performed on the U.S. Transuranium and Uranium Registries (USTUR) case 0846 leg. Front and lateral measurements of the knee of the USTUR case 0846 leg in a bent position and the same measurements with the leg in a straight position using a HP(Ge) detector were completed. Experimental results concluded that the front measurement of the knee in a bent leg position gave the highest count rate, which is an indication of optimal detection efficiency. Therefore, this geometry and knee-detector position were considered as the most appropriate position for knee monitoring. A computational model using MCNPX version 2.6.0 was used to simulate the experimental measurements by using a leg voxel phantom. The mean value and standard deviation (SD) of peak efficiency due to an isotropic 59.5-keV photon from Am were calculated in four different counting geometries. An extra sum of squares F-test was performed on the mean values of the simulated detection efficiencies. The p-value obtained from this statistical test indicates that the differences among the mean values for different counting geometries were significant. These results suggest that the front measurement of a knee in a bent leg position is the optimal counting geometry for in vivo measurement of Am deposited in the bones. The computational model was validated through comparison of the measured and simulated detection efficiencies. It was observed that there is no difference at the 0.1 significant levels between the simulated and measured detection efficiencies in assessment of Am within the bones. PMID- 23439145 TI - Patient release criteria for low dose rate brachytherapy implants. AB - A lack of consensus regarding a model governing the release of patients following sealed source brachytherapy has led to a set of patient release policies that vary from institution to institution. The U.S. Nuclear Regulatory Commission has issued regulatory guidance on patient release in NUREG 1556, Volume 9, Rev. 2, Appendix U, which allows calculation of release limits following implant brachytherapy. While the formalism presented in NUREG is meaningful for the calculation of release limits in the context of relatively high energy gamma emitters, it does not estimate accurately the effective dose equivalent for the common low dose rate brachytherapy sources Cs, I, and Pd. NUREG 1556 states that patient release may be based on patient-specific calculations as long as the calculation is documented. This work is intended to provide a format for patient specific calculations to be used for the consideration of patients' release following the implantation of certain low dose rate brachytherapy isotopes. PMID- 23439146 TI - Risk-based containment and air monitoring criteria for work with dispersible radioactive materials. AB - This paper presents readily understood, technically defensible, risk-based containment and air monitoring criteria, which are developed from fundamental physical principles. The key for the development of each criterion was the use of a calculational de minimis level, in this case chosen to be 100 mrem (or 40 DAC h). Examples are provided that demonstrate the effective use of each criterion. Comparison to other often used criteria is provided. PMID- 23439147 TI - Greek dose reference levels in pediatric pelvis computed tomography examinations. AB - The fact that children do undergo computed tomography (CT) examinations similar to those for adults adults has been a research issue, especially since the former are exposed to greater risk levels (developing stochastic late effects, such as cancer) due to their increased radiosensitivity compared to the latter. In a previous research paper (), the values of dose levels were recorded, analyzed, and compared with the reference values for groups of 0, 1, 5 and 10 y-old children for the regions of head, chest, and abdomen. In this paper, the same age group has been considered for measuring dose levels of the pelvic region. Scanning the pelvic region has been one of the most important CT examination procedures, in which unfortunately part of the lower abdomen region is included without adapting any pediatric protocols. Furthermore, the study determines whether the adjustment of the scanning parameters results in any possible reduction in the radiation dose levels to which the patient is being exposed during the examination. The present work also includes the Greek reference levels for the pelvic CT examination for the 5- and 10-y-old children that have been used for comparison against the European ones. PMID- 23439148 TI - Uptake of 131I in households of thyroid cancer patients. AB - Fifty persons and pets living with thyroid cancer patients who were treated with large administered activities of I have been surveyed to ascertain their uptake of radioiodine from the domestic environment. All patients had been hospitalized for one night after the therapeutic administration, and the thyroids of the cohabitants were assayed 3-10 d after the patients returned home. Seven of the assays were positive for I in the thyroid gland. The transmitted quantities absorbed by the cohabitants were all less than 10 of the patients' burdens at discharge. PMID- 23439149 TI - Incorrect interpretation of moving-filter continuous particulate air monitor responses. AB - The graphs supplied by the vendors of moving-filter continuous particulate air monitors (CPAMs) in their sales literature show linear curves on a log-log scale, with net count rate on one axis and concentration on the other. The implication is that the monitor user is to read the concentration from the graph, given an observed net count rate, at any time. For the nominal filter speeds commonly used for these monitors, using the graph in this way is incorrect. The graphs do not state the limitations of the calculation: (1) the nuclide measured must be long lived; (2) the concentration of that nuclide in the sampled air must remain constant; and (3) the reading of the net count rate must be obtained after a specific time, called the "transit time." This time is typically on the order of several hours. Reading the net count rate at any time earlier than this will result in an incorrect concentration estimate. Given that a major purpose of a CPAM is to alert plant personnel to a change in airborne radioactivity concentrations, by definition when this happens the concentration is not constant. Thus, using the supplied curves will result in an incorrect estimate of that concentration. The solution is to use instead a fixed-filter CPAM and a previously-published quantitative method. With this approach, there is no need to attempt to estimate a concentration, much less to assume that it is constant over long periods of time or that it can only change in a stair-step manner. With this alternative to a moving-filter CPAM, a signal proportional to the time-integrated worker intake can be generated continuously for any time-varying air concentration, including the sums-of-exponentials shapes expected during transient events in compartmental systems. PMID- 23439153 TI - Multiple causes of collaborative inhibition in memory for categorised word lists. AB - Collaborative inhibition is the finding that collaborative groups recall less information than nominal groups (the combined output of an equal number of individuals). The retrieval strategy disruption explanation of collaborative inhibition argues that individuals' idiosyncratic retrieval strategies are disrupted by hearing the contributions of others. In a series of studies, we investigated the role of retrieval interference and other cognitive explanations of collaborative inhibition. We asked collaborative and nominal dyads to recall lists of categorised words. We found that collaborative inhibition results from retrieval strategy disruption and from other factors. Collaborative dyads displayed more limited exploration than nominal dyads: They sampled from fewer categories and, thus, recalled fewer words. Collaborative dyads have different goals than nominal dyads, particularly limiting errors which may also reduce correct recall. We also found that the time period of recall contributes to collaborative inhibition because collaborative dyads recall fewer words early in the retrieval period but more words later than nominal dyads. In addition, we found instances of collaborative advantages such that collaborative dyads made fewer errors and demonstrated more recall organisation than nominal dyads. PMID- 23439154 TI - (Analytical) accuracy of blood glucose meters and patients: how do they come together? PMID- 23439155 TI - Detection of trace glucose on the surface of a semipermeable membrane using a fluorescently labeled glucose-binding protein: a promising approach to noninvasive glucose monitoring. AB - BACKGROUND: Our motivation for this study was to develop a noninvasive glucose sensor for low birth weight neonates. We hypothesized that the underdeveloped skin of neonates will allow for the diffusion of glucose to the surface where it can be sampled noninvasively. On further study, we found that measurable amounts of glucose can also be collected on the skin of adults. METHOD: Cellulose acetate dialysis membrane was used as surrogate for preterm neonatal skin. Glucose on the surface was collected by saline-moistened swabs and analyzed with glucose-binding protein (GBP). The saline-moistened swab was also tested in the neonatal intensive care unit. Saline was directly applied on adult skin and collected for analysis with two methods: GBP and high-performance anion-exchange chromatography (HPAEC). RESULTS: The amount of glucose on the membrane surface was found (1) to accumulate with time but gradually level off, (2) to be proportional to the swab dwell time, and (3) the concentration of the glucose solution on the opposite side of the membrane. The swab, however, failed to absorb glucose on neonatal skin. On direct application of saline onto adult skin, we were able to measure by HPAEC and GBP the amount of glucose collected on the surface. Blood glucose appears to track transdermal glucose levels. CONCLUSIONS: We were able to measure trace amounts of glucose on the skin surface that appear to follow blood glucose levels. The present results show modest correlation with blood glucose. Nonetheless, this method may present a noninvasive alternative to tracking glucose trends. PMID- 23439156 TI - First clinical evaluation of a new percutaneous optical fiber glucose sensor for continuous glucose monitoring in diabetes. AB - BACKGROUND: This article describes a new fiber-coupled, percutaneous fluorescent continuous glucose monitoring (CGM) system that has shown 14 days of functionality in a human clinical trial. METHOD: The new optical CGM system (FiberSense) consists of a transdermal polymer optical fiber containing a biochemical glucose sensor and a small fluorescence photometer optically coupled to the fiber. The glucose-sensitive optical fiber was implanted in abdominal and upper-arm subcutaneous tissue of six diabetes patients and remained there for up to 14 days. The performance of the system was monitored during six visits to the study center during the trial. Blood glucose changes were induced by oral carbohydrate intake and insulin injections, and capillary blood glucose samples were obtained from the finger tip. The data were analyzed using linear regression and the consensus error grid analysis. RESULTS: The FiberSense worn at the upper arm exhibited excellent results during 14 wearing days, with an overall mean absolute relative difference (MARD) of 8.3% and 94.6% of the data in zone A of the consensus error grid. At the abdominal application site, FiberSense resulted in a MARD of 11.4 %, with 93.8% of the data in zone A. CONCLUSIONS: The FiberSense CGM system provided consistent, reliable measurements of subcutaneous glucose levels in human clinical trial patients with diabetes for up to 14 days. PMID- 23439157 TI - Blood glucose self-monitoring with a long-term subconjunctival glucose sensor. AB - BACKGROUND: To evaluate the feasibility of an implantable subconjunctival glucose monitoring system (SGMS) for long-term glucose monitoring, we investigated the in vivo performance of the system. METHOD: The SGMS consists of an implantable ocular mini implant (OMI) and a handheld fluorescence photometer. A clinical study was performed on 47 diabetes patients split into two cohorts. Two different types of OMI were used, with and without a biocompatible surface coating. Duration of the study was 1 year. Correlation between capillary blood glucose and SGMS-derived interstitial fluid glucose was investigated during the first 6 months of the study. RESULTS: Both OMI types were tolerated well in the eyes of the patients. At the beginning of the study, the SGMS of both cohorts revealed a high accuracy with mean absolute relative difference (MARD) values of 7-12%. The performance of the uncoated OMIs deteriorated within 3 months of wearing time, exhibiting a MARD value of 20%. The performance of the surface-coated OMIs was preserved longer. Glucose correlation measurement with reasonable results (MARD of 14%) could be performed for up to 6 months of wear. CONCLUSIONS: The biocompatible surface coating on the OMIs enabled a longer duration of action of up to 6 months compared with 3 months for uncoated implants in a clinical trial. PMID- 23439158 TI - Acute in vivo performance evaluation of the fluorescence affinity sensor in the intravascular and interstitial space in Swine. AB - OBJECTIVE: We assessed and compared the performance levels of a fiber-coupled fluorescence affinity sensor (FAS) for glucose detection in the intradermal tissue and intravascular bed during glucose clamping and insulin administration in a large animal model. RESEARCH DESIGN AND METHODS: The FAS (BioTex Inc., Houston, TX) was implanted in interstitial tissue and in the intravenous space in nondiabetic, anesthetized pigs over 6-7 h. For intradermal assessment, a needle type FAS was implanted in the upper back using a hypodermic needle. For intravenous assessment, the FAS was inserted through a catheter into the femoral artery and vein. Blood glucose changes were induced by infusion of dextrose and insulin through a catheterized ear or jugular vein. RESULTS: Based on retrospective analysis, the mean absolute relative error (MARE) of the sensor in blood and interstitial tissue was 11.9% [standard deviation (SD) = +/- 9.6%] and 23.8% (SD = +/- 19.4%), respectively. When excluding data sets from sensors that were affected by exogenous insulin, the MARE for those sensors tested in interstitial tissue was reduced to 16.3% (SD = +/- 12.5%). CONCLUSIONS: The study demonstrated that the performance level of the FAS device implanted in interstitial tissue and blood can be very high. However, under certain circumstances, exogenous insulin caused the glucose concentration in interstitial tissue to be lower than in blood, which resulted in an overall lower level of accuracy of the FAS device. How significant this physiological effect is in insulin-treated persons with diabetes remains to be seen. In contrast, the level of accuracy of the FAS device in blood was very high because of high mass transfer conditions in blood. While the use of the FAS in both body sites will need further validation, its application in critically ill patients looks particularly promising. PMID- 23439159 TI - Harnessing a nanostructured fluorescence energy transfer sensor for quick detection of extremely small amounts of glucose. AB - Fluorescence technique is one of the major solutions for achieving the continuous and noninvasive glucose sensor for diabetes. In this article, a highly sensitive nanostructured sensor is developed to detect extremely small amounts of aqueous glucose by applying fluorescence energy transfer (FRET). A one-pot method is applied to produce the dextran-fluorescein isothiocyanate (FITC)-conjugating mesoporous silica nanoparticles (MSNs), which afterward interact with the tetramethylrhodamine isothiocyanate (TRITC)-labeled concanavalin A (Con A) to form the FRET nanoparticles (FITC-dextran-Con A-TRITC@MSNs). The nanostructured glucose sensor is then formed via the self-assembly of the FRET nanoparticles on a transparent, flexible, and biocompatible substrate, e.g., poly(dimethylsiloxane). Our results indicate the diameter of the MSNs is 60 +/- 5 nm. The difference in the images before and after adding 20 MUl of glucose (0.10 mmol/liter) on the FRET sensor can be detected in less than 2 min by the laser confocal laser scanning microscope. The correlation between the ratio of fluorescence intensity, I(donor)/I(acceptor), of the FRET sensor and the concentration of aqueous glucose in the range of 0.04-4 mmol/liter has been investigated; a linear relationship is found. Furthermore, the durability of the nanostructured FRET sensor is evaluated for 5 days. In addition, the recorded images can be converted to digital images by obtaining the pixels from the resulting matrix using Matlab image processing functions. We have also studied the in vitro cytotoxicity of the device. The nanostructured FRET sensor may provide an alternative method to help patients manage the disease continuously. PMID- 23439160 TI - Gel encapsulation of glucose nanosensors for prolonged in vivo lifetime. AB - BACKGROUND: Fluorescent glucose-sensitive nanosensors have previously been used in vivo to track glucose concentration changes in interstitial fluid. However, this technology was limited because of loss of fluorescence intensity due to particle diffusion from the injection site. In this study, we encapsulated the nanosensors into injectable gels to mitigate nanosensor migration in vivo. METHODS: Glucose-sensitive nanosensors were encapsulated in two different commercially available gelling agents: gel 1 and gel 2. Multiple formulations of each gel were assessed in vitro for their nanosensor encapsulation efficiency, permeability to glucose, and nanosensor retention over time. The optimal formulation for each gel, as determined from the in vitro assessment, was then tested in mice, and the lifetime of the encapsulated nanosensors was compared with controls of nanosensors without gel. RESULTS: Five gel formulations had encapsulation efficiencies of the nanosensors greater than 90%. Additionally, they retained up to 20% and 40% of the nanosensors over 24 h for gel 1 and gel 2, respectively. In vivo, both gels prevented diffusion of glucose nanosensors at least three times greater than the controls. CONCLUSIONS: Encapsulating glucose nanosensors in two injectable gels prolonged nanosensor lifetime in vivo; however, the lifetime must still be increased further to be applicable for diabetes monitoring. PMID- 23439161 TI - Fluorescence intensity- and lifetime-based glucose sensing using glucose/galactose-binding protein. AB - We review progress in our laboratories toward developing in vivo glucose sensors for diabetes that are based on fluorescence labeling of glucose/galactose-binding protein. Measurement strategies have included both monitoring glucose-induced changes in fluorescence resonance energy transfer and labeling with the environmentally sensitive fluorophore, badan. Measuring fluorescence lifetime rather than intensity has particular potential advantages for in vivo sensing. A prototype fiber-optic-based glucose sensor using this technology is being tested. PMID- 23439162 TI - Single-walled carbon nanotube-based near-infrared optical glucose sensors toward in vivo continuous glucose monitoring. AB - This article reviews research efforts on developing single-walled carbon nanotube (SWNT)-based near-infrared (NIR) optical glucose sensors toward long-term in vivo continuous glucose monitoring (CGM). We first discuss the unique optical properties of SWNTs and compare SWNTs with traditional organic and nanoparticle fluorophores regarding in vivo glucose-sensing applications. We then present our development of SWNT-based glucose sensors that use glucose-binding proteins and boronic acids as a high-affinity molecular receptor for glucose and transduce binding events on the receptors to modulate SWNT fluorescence. Finally, we discuss opportunities and challenges in translating the emerging technology of SWNT-based NIR optical glucose sensors into in vivo CGM for practical clinical use. PMID- 23439163 TI - Minding the gaps in continuous glucose monitoring: a method to repair gaps to achieve more accurate glucometrics. AB - Estimation of glycemic variability requires frequent measures of glucose and is greatly aided by continuous glucose monitoring (CGM); however, under real-world conditions, missing data or "gaps" of >= 10 minutes can occur in CGM data, affecting the reliability of certain estimates. Thus, we determined the magnitude of the gap problem as observed in a cohort of patients with type 2 diabetes and demonstrated an approach to fill the gaps. The approach takes the difference between readings before and after a gap and distributes the difference equally across the number of missing readings, as determined by the sensor's setting for reading frequency. The approach is easy to implement, conservative, and improves estimation of variability measures that reference time, namely, mean of daily differences and continuous overlapping net glycemic action. PMID- 23439164 TI - Hypoglycemia-associated electroencephalogram and electrocardiogram changes appear simultaneously. AB - BACKGROUND: Tight glycemic control in type 1 diabetes mellitus (T1DM) may be accomplished only if severe hypoglycemia can be prevented. Biosensor alarms based on the body's reactions to hypoglycemia have been suggested. In the present study, we analyzed three lead electrocardiogram (ECG) and single-channel electroencephalogram (EEG) in T1DM patients during hypoglycemia. MATERIALS AND METHODS: Electrocardiogram and EEG recordings during insulin-induced hypoglycemia in nine patients were used to assess the presence of ECG changes by heart rate, and estimates of QT interval (QTc) and time from top of T wave to end of T wave corrected for heartbeat interval and EEG changes by extraction of the power of the signal in the delta, theta, and alpha bands. These six features were assessed continuously to determine the time between changes and severe hypoglycemia. RESULTS: QT interval changes and EEG theta power changes were detected in six and eight out of nine subjects, respectively. Rate of false positive calculations was one out of nine subjects for QTc and none for EEG theta power. Detection time medians (i.e., time from significant changes to termination of experiments) was 13 and 8 min for the EEG theta power and QTc feature, respectively, with no significant difference (p = .25). CONCLUSIONS: Severe hypoglycemia is preceded by changes in both ECG and EEG features in most cases. Electroencephalogram theta power may be superior with respect to timing, sensitivity, and specificity of severe hypoglycemia detection. A multiparameter algorithm that combines data from different biosensors might be considered. PMID- 23439165 TI - A novel fasting blood test for insulin resistance and prediabetes. AB - BACKGROUND: Insulin resistance (IR) can precede the dysglycemic states of prediabetes and type 2 diabetes mellitus (T2DM) by a number of years and is an early marker of risk for metabolic and cardiovascular disease. There is an unmet need for a simple method to measure IR that can be used for routine screening, prospective study, risk assessment, and therapeutic monitoring. We have reported several metabolites whose fasting plasma levels correlated with insulin sensitivity. These metabolites were used in the development of a novel test for IR and prediabetes. METHODS: Data from the Relationship between Insulin Sensitivity and Cardiovascular Disease Study were used in an iterative process of algorithm development to define the best combination of metabolites for predicting the M value derived from the hyperinsulinemic euglycemic clamp, the gold standard measure of IR. Subjects were divided into a training set and a test set for algorithm development and validation. The resulting calculated M score, M(Q), was utilized to predict IR and the risk of progressing from normal glucose tolerance to impaired glucose tolerance (IGT) over a 3 year period. RESULTS: M(Q) correlated with actual M values, with an r value of 0.66. In addition, the test detects IR and predicts 3 year IGT progression with areas under the curve of 0.79 and 0.70, respectively, outperforming other simple measures such as fasting insulin, fasting glucose, homeostatic model assessment of IR, or body mass index. CONCLUSIONS: The result, Quantose(TM), is a simple test for IR based on a single fasting blood sample and may have value as an early indicator of risk for the development of prediabetes and T2DM. PMID- 23439166 TI - Gender differences in diabetes self-management: a mixed-methods analysis of a mobile health intervention for inner-city Latino patients. AB - BACKGROUND: The benefit of mobile health (mHealth) on diabetes management among low-income, inner-city patients is largely unknown, particularly for Latino patients. TExT-MED (Trial to Examine Text Message for Emergency Department Patients with Diabetes) is a text message-based program designed to improve disease knowledge, self-efficacy, and glycemic control among low-income, inner city Latinos. In phase I, 23 patients participated in an acceptability and feasibility study. Contrary to our model, there was no increase in knowledge despite increases in self-efficacy and healthy behaviors. In phase II, we performed a mixed-methods analysis to understand how TExT-MED achieved these seemingly contradictory findings. METHOD: We performed a qualitative analysis of focus groups with patients from phase I. We explored patients' receipt of health information from TExT-MED and other information sources. We used these qualitative findings to perform a mixed-methods analysis of the outcomes from phase I, reanalyzing the quantitative measures of self-efficacy, diabetes knowledge, and healthy behaviors. RESULTS: We conducted two focus groups, one in English and one in Spanish. Through qualitative analysis, we found gender differences in information sources, dietary self-efficacy, and desired educational content. Applying this knowledge, we re-stratified phase I outcomes by gender and found differential changes in diabetes knowledge, self-efficacy, and behaviors. Men had increased self-efficacy while women showed increased knowledge. CONCLUSIONS: The efficacy of mHealth on diabetes management was affected by gender. Specifically, men and women differ in their dietary self efficacy, information sources, and desired topics in future mHealth interventions. To achieve maximal impact, future mHealth interventions should be mindful of this gender difference. PMID- 23439167 TI - Changing prescribing patterns of type 2 diabetes medications from 2002-2010: an electronic health record-based evaluation. AB - BACKGROUND: The implementation of electronic health records (EHRs) may support evaluations of health care delivery, such as the prescription of newly approved medications, to adults with diabetes. We aimed to evaluate prescribing patterns of thiazolidinediones and novel glucose-lowering drug classes using electronic prescribing data contained in an outpatient EHR from 2002-2010. METHODS: We identified adults with type 2 diabetes seen from 2002-2010 who were newly prescribed rosiglitazone (ROSI), pioglitazone (PIO), or a novel glucose-lowering drug class (other). The annual number of new prescriptions and their relative percentages (per 1000 patients) were calculated. RESULTS: From 2002-2010, 6209 patients with type 2 diabetes were newly prescribed 8858 eligible medications. In 2006, ROSI and PIO accounted for 44% and 37% of new prescriptions, respectively. After 2007, the relative percentage of new ROSI prescriptions declined more rapidly than PIO prescriptions, falling to 7% and 47% of peak levels, respectively, by 2010. By 2010, the relative percentages of new ROSI, PIO, and other prescriptions were 2%, 18%, and 80%, respectively. CONCLUSIONS: Evaluations of EHR data represent a cost-effective method for evaluating diabetes medications with new Food and Drug Administration warnings or indications. Validation of demographic and clinical data will expand the scope of EHR-based evaluations of health care delivery and outcomes for adults with diabetes. PMID- 23439168 TI - Stepwise self-titration of oral glucose-lowering medication using a mobile telephone-based telehealth platform in type 2 diabetes: a feasibility trial in primary care. AB - BACKGROUND: Telehealth-supported clinical interventions may improve diabetes self management. We explored the feasibility of stepwise self-titration of oral glucose-lowering medication guided by a mobile telephone-based telehealth platform for improving glycemic control in type 2 diabetes. METHODS: We recruited 14 type 2 diabetes patients to a one-year feasibility study with 1:1 randomization. Intervention group patients followed a stepwise treatment plan for titration of oral glucose-lowering medication with self-monitoring of glycemia using real-time graphical feedback on a mobile telephone and remote nurse monitoring using a Web-based tool. We carried out an interim analysis at 6 months. RESULTS: We screened 3476 type 2 diabetes patients; 94% of the ineligible did not meet the eligibility criteria for hemoglobin A1c (HbA1c) or current treatment. Mean (standard deviation) patient age at baseline was 58 (11) years, HbA1c was 65 (12) mmol/mol (8.1% [1.1%]), body mass index was 32.9 (6.4) kg/m2, median [interquartile range (IQR)] diabetes duration was 2.6 (0.6 to 4.7) years, and 10 (71%) were men. The median (IQR) change in HbA1c from baseline to six months was -10 (-21 to 3) mmol/mol (-0.9% [-1.9% to 0%]) in the intervention group and -5 (-13 to 6) mmol/mol (-0.5% [-1.2% to 0.6%]) in the control group. Six out of seven intervention group patients and four out of seven control group patients changed their oral glucose-lowering medication (p = .24). CONCLUSIONS: Self-titration of oral glucose-lowering medication in type 2 diabetes with self monitoring and remote monitoring of glycemia is feasible, and further studies using adapted recruitment strategies are required to evaluate whether it improves clinical outcomes. PMID- 23439169 TI - Professional continuous glucose monitoring in subjects with type 1 diabetes: retrospective hypoglycemia detection. AB - BACKGROUND: An important task in diabetes management is detection of hypoglycemia. Professional continuous glucose monitoring (CGM), which produces a glucose reading every 5 min, is a powerful tool for retrospective identification of unrecognized hypoglycemia. Unfortunately, CGM devices tend to be inaccurate, especially in the hypoglycemic range, which limits their applicability for hypoglycemia detection. The objective of this study was to develop an automated pattern recognition algorithm to detect hypoglycemic events in retrospective, professional CGM. METHOD: Continuous glucose monitoring and plasma glucose (PG) readings were obtained from 17 data sets of 10 type 1 diabetes patients undergoing insulin-induced hypoglycemia. The CGM readings were automatically classified into a hypoglycemic group and a nonhypoglycemic group on the basis of different features from CGM readings and insulin injection. The classification was evaluated by comparing the automated classification with PG using sample based and event-based sensitivity and specificity measures. RESULTS: With an event-based sensitivity of 100%, the algorithm produced only one false hypoglycemia detection. The sample-based sensitivity and specificity levels were 78% and 96%, respectively. CONCLUSIONS: The automated pattern recognition algorithm provides a new approach for detecting unrecognized hypoglycemic events in professional CGM data. The tool may assist physicians and diabetologists in conducting a more thorough evaluation of the diabetes patient's glycemic control and in initiating necessary measures for improving glycemic control. PMID- 23439170 TI - Performance variability of seven commonly used self-monitoring of blood glucose systems: clinical considerations for patients and providers. AB - BACKGROUND: Blood glucose data are frequently used in clinical decision making, thus it is critical that self-monitoring of blood glucose (SMBG) systems consistently provide accurate results. Concerns about SMBG accuracy have prompted the development of newly proposed International Organization for Standardization (ISO) standards: >= 95% of individual glucose results shall fall within +/- 15 mg/dl of the results of the manufacturer's reference procedure at glucose concentrations <100 mg/dl and within +/- 15% for values >= 100 mg/dl. We evaluated seven marketed systems against the current and proposed ISO criteria (criterion A). METHOD: Capillary blood samples were collected from 100 subjects and tested on seven systems: Accu-Chek Aviva Plus, Advocate Redi-Code, Element, Embrace, Prodigy Voice, TRUEbalance, and WaveSense Presto. Results were compared with manufacturer's documented reference system, YSI or perchloric acid hexokinase; three different strip lots from each system were tested on each subject, in duplicate. RESULTS: Compared against current ISO criteria (>= 95% within +/- 15 mg/dl for values <75 mg/dl and +/- 20% for values >= 75 mg/dl) the Accu-Chek Aviva Plus, Element, and WaveSense Presto systems met accuracy criteria. However, only the Accu-Chek Aviva Plus met the proposed ISO criteria (criterion A) in all three lots. The other six systems failed to meet the criteria in at least two of the three lots, showing lot-to-lot variability, high/low bias, and variations due to hematocrit. CONCLUSIONS: Inaccurate SMBG readings can potentially adversely impact clinical decision making and outcomes. Clinicians can reduce controllable variables by prescribing accurate SMBG systems. Adherence to the proposed ISO criteria should enhance patient safety by improving the accuracy of SMBG systems. PMID- 23439171 TI - Variability of blood glucose meters for patient self-testing: analysis of the article by Brazg and coauthors. AB - The article by Brzag and coauthors in this issue of Journal of Diabetes Science and Technology reports a competitive accuracy performance study for a branded meter in comparison with six low-cost meters currently available in the United States. It highlights several important topics: (1) the need for more stringent post-marketing requirements for blood glucose meters after launch and (2) low cost meters use older technologies and their manufacturers do not usually seriously invest in new technology or constant quality assurance efforts. This may explain the study results, which show superior performance of the branded meter. Finally, the article pinpoints to the "quality versus price" dilemma faced by the prescribing physician and their patients in daily routine, which may be additionally aggravated by budget constraints and prescription rules in reimbursed markets. PMID- 23439172 TI - Self-adjustment of insulin dose using graphically depicted self-monitoring of blood glucose measurements in patients with type 1 diabetes mellitus. AB - BACKGROUND: There is a need for patients to be able to adjust their insulin doses accurately and independently during continuous subcutaneous insulin infusion (CSII) therapy in order to avoid glycemic excursions and improve glycemic control. Use of new technology has the potential to aid patients in visualizing their circadian patterns and improving their understanding of data provided by self-monitored blood glucose (SMBG) measurements. METHODS: A 24-week crossover study was performed in 25 patients with type 1 diabetes mellitus using CSII and SMBG. Patients were randomized either to entering blood glucose data into handwritten logbooks or to using the Accu-Chek SmartPix information management system (IMS) coupled with instructions from a training manual to aid interpretation of the IMS readings. Patients analyzed these chart readings every 2 weeks, and outpatient visits were scheduled for both arms every 6 weeks. RESULTS: There was a significantly lower mean overall blood glucose level with the IMS compared with use of a logbook (139 +/- 16.2 versus 150 +/- 19.8 mg/dl; Delta = 10.8 mg/dl; p < .01), and a significantly higher proportion of blood glucose values was in the target range compared with use of a logbook (43.6% versus 38.5%; p < .001). Hypoglycemic events were also significantly lower with the IMS compared with logbooks (3.7 fewer events/6 weeks; p < .05). There was no significant difference between groups in the daily frequency of SMBG measurements. CONCLUSIONS: The use of an IMS, coupled with an easily understood training manual, enables patients to improve glycemic control by performing accurate and timely self-adjustments to their insulin regimens. PMID- 23439173 TI - Automated glycemic pattern analysis can improve health care professional efficiency and accuracy. AB - BACKGROUND: Health care professionals (HCPs) routinely review handwritten blood glucose (BG) logbooks during office visits of patients with diabetes. METHOD: In this study, 64 HCPs were asked to assess glycemic patterns and estimate BG averages in six simulated handwritten logbooks. The HCPs then reviewed the pattern logs and averages in six OneTouch(r) VerioTMIQ meters containing corresponding data sets. RESULTS: The average time needed for pattern review was 7.3 min for handwritten logbooks versus 0.9 min using the meter. The total error rate for logbook pattern identification was 43.0% compared with the meter. The mean percentage deviation between HCP estimates of 30-day BG averages and actual values was 14.5%. CONCLUSIONS: The meter is associated with faster and more accurate pattern analysis compared with handwritten logbooks. PMID- 23439174 TI - Automated glycemic pattern analysis: overcoming diabetes clinical inertia. AB - The OneTouch(r) VerioTM IQ Meter with PatternAlertTM Technology has been approved by the U.S. Food and Drug Administration as the first self-glucose monitor that can automatically determine glycemic patterns [high and low pre-meal blood glucose (BG)] for health care providers (HCPs) and patients. In this issue of Journal of Diabetes Science and Technology, Katz and coauthors demonstrate that this device was more accurate and quicker in detecting abnormal glucose patterns than the review by HCPs of 30-day handwritten BG logs and that its interpretations were positively accepted by the HCPs. Continued development of automated pattern analysis and decision-support software to overcome the "data overload" associated with intensive glucose monitoring and diabetes management will reduce clinical inertia and could dramatically improve diabetes outcomes. PMID- 23439175 TI - Determination of hematocrit interference in blood samples derived from patients with different blood glucose concentrations. AB - BACKGROUND: We performed a blood glucose meter hematocrit (HCT) interference test with lower sample manipulation requirements by using blood samples from patients with different blood glucose (BG) levels. METHODS: Blood from five patients with different BG levels (2.8, 5.6, 8.3, 13.9, 19.4 mmol/liter) was manipulated to contain five different HCT concentrations (35/40/45/50/55%). Each sample was measured three times in parallel with 14 BG testing devices (reference method: YSI 2300 STAT PlusTM Glucose Analyzer). The largest mean deviations in both directions from the reference method (normalized to 100% at 45% HCT) were added as a measure for hematocrit interference factor (HIF). A HIF >10% was considered to represent clinically relevant HCT interference. RESULTS: Few devices showed no clinically relevant HCT interference at high/low BG levels: BGStar(r) (7.2%, 7.3%), iBGStar(r) (9.0%, 8.6%), Contour(r) (10.0%, 4.6%), OneTouch(r) VerioTM 2 (10.0%, 5.2%), and GlucoMen(r) LX (7.2%, 5.1%). Other devices showed interference at one or both glucose ranges: ACCU-CHEK(r) Aviva (12.6%, 10.7%), Aviva Nano (7.2%, 10.5%), Breeze2 (3.6%, 30.2%), GlucoCard G+ (12.6%, 7.0%), OneTouch(r) Ultra(r)2 (12.6%, 25.6%), FreeStyle Freedom Lite(r) (9.0%, 11.0%), Precision Xceed (16.2%, 15.3%), and MediTouch(r) (19.8%, 28.0%). The deviations in all devices were less pronounced in the HCT range of 35-50%. CONCLUSIONS: The results of this trial with less sample manipulation (HCT only) confirmed previous examinations with HCT and glucose manipulation. The same devices showed HCT stability as previously observed. Artificial sample manipulation may be less crucial than expected when evaluating HCT interference. PMID- 23439176 TI - Hematocrit interference of blood glucose meters for patient self-measurement. AB - BACKGROUND: Abnormal hematocrit levels may interfere with glucose readings of patient self-assessment blood glucose (BG) meters. The aim of this laboratory investigation was to assess the potential influence of hematocrit variations on a variety of BG meters applying different measurement technologies. METHODS: Venous heparinized blood was manipulated to contain three different BG concentrations (50-90, 120-180, and 280-350 mg/dl) and five different hematocrit levels (25%, 35%, 45%, 55%, and 65%). After careful oxygenation to normal blood oxygen pressure (65-100 mmHg), each sample was measured (eight times) with the following devices: Accu-Chek(r) Aviva Nano and Active, Breeze(r)2 and Contour(r), FreeStyle Freedom Lite(r), GlucoDr. autoTM, Glucofix(r) mio Plus, GlucoLabTM, GlucoMen(r) LX Plus, Nova Max(r) Link, Nova Max(r) Plus, OneTouch(r) Ultra(r)2 and Verio(r), On Call(r) Plus and Platinum, Optium Xceed(r), Precision Xceed(r), and TaiDoc Fora TD-4227. A YSI 2300 STAT PlusTM glucose analyzer served as reference method. Stability to hematocrit influence was assumed, with <10% mean glucose result bias between the highest and lowest hematocrit levels. RESULTS: Six of the investigated meters showed a stable performance in this investigation: Accu-Chek Active (7%), Glucofix mio Plus (5%), GlucoMen LX Plus (4%), Nova Max Plus (4%), Nova Max Link (7%), and OneTouch Verio (3%). All other meters failed this hematocrit interference test, with FreeStyle Freedom Lite (11%), and On Call Platinum (12%) being the better devices and On Call Plus (68%), GlucoLab (51%), TaiDoc Fora TD-4227 (39%), and Breeze 2 (38%) showing the worst performance. CONCLUSIONS: Hematocrit may affect BG meter performance in daily routine. In case of interference, low hematocrit values (<35%) result in too high readings. Our results encourage use of meters that are not affected by hematocrit interference. PMID- 23439177 TI - Within-individual hematocrit variations and self-monitoring of blood glucose. AB - Many self-monitoring of blood glucose (SMBG) systems have generated artefactually increased glucose results in low-hematocrit patients (e.g., intensive care unit and renal failure patients); conversely, these devices could produce artefactually decreased glucose results in high-hematocrit patients (e.g., neonates). The introduction of hematocrit-independent SMBG systems permits more accurate testing in anemic or polycythemic individuals. In this issue of Journal of Diabetes Science and Technology, Ramljak and coauthors have created glucose bias graphs for 19 common SMBG devices and declared certain systems to be optimally accurate because of insensitivity to hematocrit variation over a broad hematocrit range. Luckily, the average within-individual variation of hematocrit is low (between 2.9 and 3.3%). As such, a larger spectrum of SMBG devices can be regarded as optimally hematocrit independent. PMID- 23439178 TI - Multilevel model of type 1 diabetes mellitus patients for model-based glucose controllers. AB - BACKGROUND: Glucose homeostasis is the result of complex interactions across different biological levels. This multilevel characteristic should be considered when analyzing and designing closed-loop glucose control algorithms. Classic control schemes use only a pharmacokinetic-pharmacodynamic (PKPD) perspective to describe the gluco-regulatory system. METHODS: A multilevel model combining a PKPD model with an insulin signaling model is proposed for patients with type 1 diabetes mellitus T1DM (T1DM). The PKPD Dalla Man model for T1DM is expanded to include an intracellular level involving insulin signaling to control glucose uptake through glucose transporter type 4 (GLUT4) translocation. A model-based controller is then designed and used as an example to illustrate the feasibility of the proposal. RESULTS: Two significant results were obtained for the controller explicitly utilizing multilevel information. No hypo-glycemic events were registered and an excellent performance for interpatient variability was achieved. Controller performance was evaluated using two indexes. The glucose was kept inside the range (70-180) mg/dl more than 99% of the time, and the intrapatient variability measured using control variability grid analysis was solid with 90% of the population inside the target zone. CONCLUSIONS: Multilevel models open new possibilities for designing glucose control algorithms. They allow controllers to take into account variables that have a strong influence on glucose homeostasis. A model-based controller was used for demonstrating how improved knowledge of the multilevel nature of diabetes increases the robustness and performance of glucose control algorithms. Using the proposed multi-level approach, a reduction of the hypoglycemic risk and robust behaviour for intrapatient variability was demonstrated. PMID- 23439179 TI - Hypoglycemia early alarm systems based on recursive autoregressive partial least squares models. AB - BACKGROUND: Hypoglycemia caused by intensive insulin therapy is a major challenge for artificial pancreas systems. Early detection and prevention of potential hypoglycemia are essential for the acceptance of fully automated artificial pancreas systems. Many of the proposed alarm systems are based on interpretation of recent values or trends in glucose values. In the present study, subject specific linear models are introduced to capture glucose variations and predict future blood glucose concentrations. These models can be used in early alarm systems of potential hypoglycemia. METHOD: A recursive autoregressive partial least squares (RARPLS) algorithm is used to model the continuous glucose monitoring sensor data and predict future glucose concentrations for use in hypoglycemia alarm systems. The partial least squares models constructed are updated recursively at each sampling step with a moving window. An early hypoglycemia alarm algorithm using these models is proposed and evaluated. RESULTS: Glucose prediction models based on real-time filtered data has a root mean squared error of 7.79 and a sum of squares of glucose prediction error of 7.35% for six-step-ahead (30 min) glucose predictions. The early alarm systems based on RARPLS shows good performance. A sensitivity of 86% and a false alarm rate of 0.42 false positive/day are obtained for the early alarm system based on six-step-ahead predicted glucose values with an average early detection time of 25.25 min. CONCLUSIONS: The RARPLS models developed provide satisfactory glucose prediction with relatively smaller error than other proposed algorithms and are good candidates to forecast and warn about potential hypoglycemia unless preventive action is taken far in advance. PMID- 23439180 TI - In silico evaluation of an artificial pancreas combining exogenous ultrafast acting technosphere insulin with zone model predictive control. AB - BACKGROUND: Because of the slow pharmacokinetics of subcutaneous (SC) insulin, avoiding postprandial hyperglycemia has been a major challenge for an artificial pancreas (AP) using SC insulin without a meal announcement. METHODS: A semiautomated AP with Technosphere(r) Insulin (TI; MannKind Corporation, Valencia, CA) was designed to combine pulmonary and SC insulin. Manual inhalation of 10 U ultrafast-absorbing TI at mealtime delivers the first, or cephalic, phase of insulin, and an SC insulin pump controlled by zone model predictive controller delivers second-phase and basal insulin. This AP design was evaluated on 100 in silico subjects from the University of Virginia/Padova metabolic simulator using a protocol of two 50 g carbohydrate (CHO) meals and two 15 g CHO snacks. RESULTS: Simulation analysis shows that the semiautomated AP with TI provides 32% and 16% more time in the controller target zone (80-140 mg/dl) during the 4 h postprandial period, with 39 and 20 mg/dl lower postprandial blood glucose peak on average than the pure feedback AP and the AP with manual feed-forward SC bolus, respectively. No severe hypoglycemia (<50 mg/dl) was observed in any cases. CONCLUSIONS: The semiautomated AP with TI provides maximum time in the clinically accepted region when compared with pure feedback AP and AP with manual feed-forward SC bolus. Furthermore, the semiautomated AP with TI provides a flexible operation (optional TI inhalation) with minimal user interaction, where the controller design can be tailored to specific user needs and abilities to interact with the device. PMID- 23439181 TI - Insulin depot formation in subcutaneoue tissue. AB - BACKGROUND: The size and geometry of an insulin depot that is formed during subcutaneous administration by an insulin pump is evaluated. A novel method is used to visualize accurately the depot formation for small volumes of insulin (of the order of 10-100 ul) at a given point in time. Conventional visualization methods such as magnetic resonance imaging are unable to provide such accurate measurements because of their coarse imaging resolution and long measurement time. METHODS: The described method consists of subcutaneously infusing dyed insulin into porcine tissue and subsequently shock freezing it with liquid nitrogen. The frozen sample is then sliced into thin layers using a cryomicrotome. A digital image of each layer is taken and then processed with proprietary software, which identifies the dyed areas on each layer and reconstructs a three-dimensional model of the insulin depot with a planar resolution of 30 * 30 um(2) and a depth resolution of 100 um. Since this process is not viable for living organisms, porcine tissue was used immediately following slaughter of the animal. RESULTS: To date, it is most often assumed that the insulin depot takes the shape of a sphere around the tip of the cannula (e.g., 50 ul insulin equates to a spherical radius of 2.3 mm). However, in practice, such a depot form is never observed. Instead, the insulin depot initially spreads laterally (i.e., parallel) to the skin surface and in the collagen matrix that binds the adipose cells together. The depot outreach increases with larger infused volumes, e.g., maximum outreach measured at 5.0/5.7/7.1 mm (quartiles, n = 17) for 50 ul of infused insulin. Beyond a given infused volume (approximately 100 ul), the insulin also starts to spread perpendicular to the skin surface. CONCLUSIONS: It is concluded that formation of the insulin depot depends on the opening of channels at the boundaries between adipose cells. Hence the insulin follows a path of least resistance and depot formation is determined by the local structure of the subcutaneous tissue. PMID- 23439182 TI - Technical challenges and clinical outcomes of using a closed-loop glycemic control system in the hospital. AB - According to large randomized trials, results suggest that maintaining normoglycemia postoperatively through tight glycemic control (TGC) and intensive insulin therapy (IIT) can improve surgical outcomes as well as reduce mortality and morbidity in critically ill patients. However, trials examining the effects of TGC have had conflicting results. Systematic reviews and meta-analyses have also led to differing conclusions. The main reason these clinical trials and meta analyses show negative results for TGC is the high incidence of hypoglycemia induced by IIT. This could not be prevented because there is no reliable technique that can avoid this condition during IIT. The development of accurate, continuous blood glucose monitoring devices and closed-loop systems for computer assisted blood glucose control in the intensive care unit (ICU) will probably help avoid hypoglycemia in these situations. The STG closed-loop glycemic control system was introduced to our department to be used and evaluated for strict serum glucose control with no hypoglycemic episodes during IIT in the surgical ICU, to reduce the workload of ICU nurses, and to decrease incidents related to the management of blood glucose levels according to manual conventional venous infusion insulin therapy. The goal of our team was to use the STG closed-loop glycemic control system for perioperative TGC in surgical patients to solve the complications of IIT and reduce risk of hypoglycemia. The challenge at our hospital demonstrated that the STG closed-loop glycemic control system can be expected to achieve TGC with no occurrence of hypoglycemia induced by IIT after surgery. PMID- 23439183 TI - Mobile applications for diabetes self-management: status and potential. AB - BACKGROUND: Advancements in smartphone technology coupled with the proliferation of data connectivity has resulted in increased interest and unprecedented growth in mobile applications for diabetes self-management. The objective of this article is to determine, in a systematic review, whether diabetes applications have been helping patients with type 1 or type 2 diabetes self-manage their condition and to identify issues necessary for large-scale adoption of such interventions. METHODS: The review covers commercial applications available on the Apple App Store (as a representative of commercially available applications) and articles published in relevant databases covering a period from January 1995 to August 2012. The review included all applications supporting any diabetes self management task where the patient is the primary actor. RESULTS: Available applications support self-management tasks such as physical exercise, insulin dosage or medication, blood glucose testing, and diet. Other support tasks considered include decision support, notification/alert, tagging of input data, and integration with social media. The review points to the potential for mobile applications to have a positive impact on diabetes self-management. Analysis indicates that application usage is associated with improved attitudes favorable to diabetes self-management. Limitations of the applications include lack of personalized feedback; usability issues, particularly the ease of data entry; and integration with patients and electronic health records. CONCLUSIONS: Research into the adoption and use of user-centered and sociotechnical design principles is needed to improve usability, perceived usefulness, and, ultimately, adoption of the technology. Proliferation and efficacy of interventions involving mobile applications will benefit from a holistic approach that takes into account patients' expectations and providers' needs. PMID- 23439185 TI - Use of structured self-monitoring of blood glucose improves glycemic control in real-world clinical practice: findings from a multinational and retrospectively controlled trial. PMID- 23439184 TI - Associations of youth and parent weight status with reported versus predicted daily energy intake and hemoglobin A1c in youth with type 1 diabetes mellitus. AB - BACKGROUND: The epidemic of overweight/obesity affects youth with type 1 diabetes mellitus (T1DM) and their families. In youth with T1DM and their parents, we examined weight status with reported and expected energy intake and with youth hemoglobin A1c (HbA1c). METHODS: In 243 youth (48% female, 13 +/- 3 years) and their parents (84% female, 45 +/- 6 years), we assessed body mass index (BMI), prevalence of overweight/obesity, reported energy intake (REI), and youth glycemic control (HbA1c). The REI was compared with predicted daily energy requirements (DER; based on age, weight, sex, and physical activity). RESULTS: Youth had diabetes duration of 6.3 +/- 3.4 years and HbA1c of 8.5% +/- 1.3%; 69% used insulin pump therapy. Overweight and obesity affected 23% and 11% of youth and 30% and 24% of parents, respectively. Youth and parent BMI (r = 0.38; p < .001) and weight status (overweight/obese; p < .001) were significantly associated. The ratio of REI:DER was significantly lower in overweight/obese compared with underweight/normal weight parents (1.0 +/- 0.4 versus 1.2 +/- 0.5; p = .001) but did not differ among youth by weight status. Both youth and parent BMI were positively correlated with youth HbA1c (r = 0.14, p = .02; r = 0.16, p = .01, respectively). Hemoglobin A1c tended to be higher in obese than in overweight and normal weight youth (mean +/- standard deviation [SD] 8.4 +/- 1.4, 8.4 +/- 1.3, and 8.8 +/- 1.0, respectively; p = .06) and was significantly higher in youth whose parents were obese versus overweight or underweight/normal weight (mean +/- SD 8.2 +/- 1.2, 8.5 +/- 1.4, and 8.9 +/- 1.5, respectively; p < .001). CONCLUSIONS: Similar to the general population, overweight and obesity are prevalent among families of youth with T1DM. Weight status appears to influence self-REI in parents and glycemic control in youth with T1DM, suggesting the need for family-based dietary interventions. PMID- 23439186 TI - Information and communications technology-supported diabetes prevention and self care management: experiences from the EMOTIONAAL project in Finland. PMID- 23439187 TI - Glycemic variability measures in a group of subjects with type 1 diabetes and repeated severe and non-severe hypoglycemia. PMID- 23439188 TI - Grape seed procyanidin extract reduces the endotoxic effects induced by lipopolysaccharide in rats. AB - Acute inflammation is a response to injury, infection, tissue damage, or shock. Bacterial lipopolysaccharide (LPS) is an endotoxin implicated in triggering sepsis and septic shock, and LPS promotes the inflammatory response, resulting in the secretion of proinflammatory and anti-inflammatory cytokines such as the interleukins (IL-6, IL-1beta, and IL-10) and tumor necrosis factor-alpha by the immune cells. Furthermore, nitric oxide and reactive oxygen species levels increase rapidly, which is partially due to the activation of inducible nitric oxide synthase in several tissues in response to inflammatory stimuli. Previous studies have shown that procyanidins, polyphenols present in foods such as apples, grapes, cocoa, and berries, have several beneficial properties against inflammation and oxidative stress using several in vitro and in vivo models. In this study, the anti-inflammatory and antioxidant effects of two physiological doses and two pharmaceutical doses of grape seed procyanidin extract (GSPE) were analyzed using a rat model of septic shock by the intraperitoneal injection of LPS derived from Escherichia coli. The high nutritional (75mg/kg/day) and the high pharmacological doses (200mg/kg/day) of GSPE showed anti-inflammatory effects by decreasing the proinflammatory marker NOx in the plasma, red blood cells, spleen, and liver. Moreover, the high pharmacological dose also downregulated the genes Il-6 and iNos; and the high nutritional dose decreased the glutathione ratio (GSSG/total glutathione), further illustrating the antioxidant capability of GSPE. In conclusion, several doses of GSPE can alleviate acute inflammation triggered by LPS in rats at the systemic and local levels when administered for as few as 15 days before the injection of endotoxin. PMID- 23439189 TI - Moving from evidence to care: ethical responsibility of health professionals in responding to sexual assault. PMID- 23439190 TI - Can virtue prevail? Safeguarding integrity in medicine and science. PMID- 23439191 TI - Questions of ethics in public health policy. PMID- 23439192 TI - Conference report. PMID- 23439193 TI - Antibiotic use and resistance: perceptions and ethical challenges among doctors, pharmacists and the public in Vellore, South India. AB - Inappropriate antibiotic use and resistance are major public health challenges. Interventional strategies require ascertaining the perceptions of major stakeholders and documenting the challenges to changing practice. Towards this aim, a qualitative study was conducted in Vellore, South India, using focus group discussions among doctors, pharmacists and public. There were eight groups with six to eight participants each. The themes explored were: understanding of infections, antibiotics and resistance; practices and pressure driving antibiotic use; and strategies for appropriate use. Data were transcribed, analysed, verified and a summary prepared with salient features and quotations. It was found that the public had minimal awareness of resistance, antibiotics and infections. They wanted symptomatic relief. Doctors reported prescribing antibiotics for perceived patient expectations and quick recovery. Business concerns contributed to antibiotics sales among pharmacists. Pharmaceutical industry incentives and healthcare provider competition were the main ethical challenges. Suggested interventional strategies by the participants included creating public awareness, better healthcare provider communication, improved diagnostic support, strict implementation of guidelines, continuing education, and strengthening of regulations. Perceived patient benefit, unrestricted autonomy and business-cum-industry pressures are promoting inappropriate use of antibiotics. Strategies improving responsible use will help preserve their effectiveness, and provide distributive justice and benefit for future generations. PMID- 23439194 TI - Web-based medical facilitators in medical tourism: the third party in decision making. AB - The emergence of web-based medical tourism facilitators (MTFs) has added a new dimension to the phenomenon of cross-border travel. These facilitators are crucial connectors between foreign patients and host countries. They help patients navigate countries, doctors and specialties. However, little attention has been paid to the authenticity of information displayed on the facilitators' web portals, and whether they follow ethical guidelines and standards. This paper analyses the available information on MTF portals from an ethics perspective. It compares 208 facilitators across 47 countries for the services offered. Data were collected from the databases of the Medical Tourism Association and World Medical Resources. India was the most common destination country linked to 81 facilitators. The five countries with the maximum number of facilitators were the USA, the UK, India, Canada and Poland. This paper identifies concerns regarding the information displayed about patients' safety, and the maintenance of confidentiality. There is a need to develop ethical standards for this field. PMID- 23439195 TI - Use of the WOMAC questionnaire in Mumbai and the challenges of translation and cross cultural adaptation. AB - Patient-reported outcome measures (PROMs) are disease specific questionnaires that are being increasingly used in clinical practice and research. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), is a widely used PROM in patients with hip or knee osteoarthritis. A validated WOMAC was used by us, and significant challenges were faced in administering it as several questions did not have a cultural connect. Functionally equivalent items in the Indian context had then to be used to complete the score. With greater emphasis today on the use of patient-reported outcome measures, and with data from multi centric studies being pooled, cross-cultural adaptation becomes very important if the pooled data are to be really relevant. In India, with several languages being spoken, and a significant proportion of the population being illiterate, the physician and/ or the impartial witness must provide considerable explanation without attempting to influence the response. The key to the effective and correct use of PROMs thus lies not just in translation, but also in a stepwise validation of the questionnaire, and modification in the context of the country where it is used. Scores like WOMAC are often primary efficacy endpoints in clinical trials; are gaining greater importance to support label claims; have ethical implications, and directly impact regulatory decision making and thus, eventually, evidence-based practice. PMID- 23439196 TI - Informed consent, privacy and confidentiality practised by doctors of a tertiary care hospital in a developing country. AB - BACKGROUND: This aim of this study was to assess the degree to which the doctors of a public sector hospital in Karachi adhere to medical ethics during their consultations. MATERIAL AND METHODS: A cross-sectional study was conducted in Civil Hospital, Karachi, Pakistan, during April-June 2010. 337 patients from Out Patients Departments (OPDs) and wards were recruited through consecutive sampling. A pre-tested structured questionnaire was administered to the participants and they were asked about their demographic profile, and their doctor's practices regarding obtaining informed consent, respecting privacy and confidentiality, and treatment modalities. Written informed consent was taken from all the participants. Data was analysed using SPSS version 16.0, and a p value of < 0.05 was considered as statistically significant. RESULTS: The mean age of the study population was 38.4 +/- 15.0 years. There was an equal ratio of males and females. Our study showed that informed consent was obtained from 66.4% of patients. 56.9% of patients responded that they were not informed about the side effects of the prescribed medicines. 74% females were satisfied with the privacy maintained during the consultation. 64.8% were assured of the confidentiality of their information. Regarding advertisement by doctors, 46.5% of patients said it should be done. CONCLUSION: There has been a marked improvement as compared with the previous practices of biomedical ethics by the doctors of this public sector hospital. However, awareness sessions should be conducted to update / improve the knowledge of ethics among doctors to help them translate their knowledge into practice. PMID- 23439197 TI - Induction of a massacre: the conduct and legacy of Accused no 37. PMID- 23439198 TI - Gender bending, gender testing: reflections on the Pinki Pramanik case. PMID- 23439199 TI - Sex verification tests: ethical, legal and social aspects. PMID- 23439200 TI - Developing and sustaining a medical humanities program at KIST Medical College, Nepal. AB - The author conducted a voluntary Medical Humanities (MH) module at Pokhara, Nepal, in 2007 as a curriculum innovation project for a fellowship in health sciences education. He conducted a module for faculty members at KIST Medical College (KISTMC), Lalitpur, Nepal, in 2008. The modules used literature excerpts, case scenarios, role-plays, paintings and group activities to explore different aspects of MH. The module for faculty members had the objectives of introducing faculty to MH and also creating facilitators for the student modules. For the last four years the author has been facilitating an MH module for first-year medical students at KISTMC. The activity-based modules were conducted in small groups. Participant views about the modules were positive. MH has a number of benefits in medical education and should be strongly considered for inclusion by medical schools in developing countries. MH modules should be creative, fun and taken forward by interested faculty members. PMID- 23439201 TI - Putting the humanities back into medicine: some suggestions. AB - The practice of medicine is an art as well as a science. As doctors diagnose illness and treat patients day after day, they constantly interweave the social, psychological, ethical and scientific aspects of clinical practice. However, the humanistic values necessary for this approach are generally perceived to be lacking in today's medical practice. The Medical Council of India (MCI) believes that a course in medical humanities can help students cultivate a humane attitude towards their patients, as well as give them the knowledge and skills to deal with the complex challenges they will face as they practise medicine. The new Graduate Medical Regulations being formulated by the MCI provide time for teaching this aspect of medical practice. This paper contains some suggestions for the implementation of a medical humanities course in medical colleges. PMID- 23439202 TI - Do we need notification of tuberculosis? A public health perspective. AB - Several instances of tuberculosis (TB) resistant to most drugs were reported in Mumbai in January 2012. Eventually, the Government of India declared TB to be a notifiable disease. This paper looks at the utility of notification and the ethical issues posed by it from a public health practice perspective. The paper argues that notification of TB in the absence of regulation of diagnostic practices, rational use of anti-TB medicines and availability of diagnostic and treatment facilities for drug-resistant TB will pose more ethical problems rather than provide solutions by way of adequate and rational treatment to patients. PMID- 23439203 TI - Moral consensus theory: paradigm cases of abortion and orthothanasia in Brazil. AB - Bioethics is a relatively new way of thinking about relationships in medical practice. It enables reflection on ethical conflicts, and opens up management options without dictating rules. Despite this historical context, medical ethics has been sidelined in the course of the development of bioethics. Bioethical reflection does not automatically result in changes to conflict resolution in daily doctor-patient relationships. However, these reflections are important because they promote the search for a "moral consensus" that establishes new ethical rules for day-to-day medical practice. We suggest that there is no conflict between bioethics and medical ethics; rather, these areas interact to establish new standards of behaviour among physicians. The legalisation of orthothanasia in Brazil is one example of how this theory of moral consensus might operate. On the other hand, the legal battle on abortion illustrates how the law cannot change without such a moral consensus. PMID- 23439204 TI - Of poor patients and callous doctors. PMID- 23439205 TI - The ethics of disability language. PMID- 23439206 TI - After supersession of The Medical Council of India. PMID- 23439207 TI - Disability-selective abortion: denying human rights to make a "perfect world"? PMID- 23439208 TI - Surreptitious use of disulfiram. PMID- 23439209 TI - What's in a name? Anomalies in medical degrees. PMID- 23439210 TI - Identification and characterisation of regional variations in the material properties of ureter according to microstructure. AB - There are few previous studies on the elastic properties of ureter and most have been limited to essentially one-dimensional deformation measurements. The object of this study was, therefore, to identify regional variations in the multiaxial behaviour of rabbit ureter, subjected to in vitro inflation/extension testing under a physiological range of intraluminal pressures and longitudinal forces. A microstructure-motivated material model (via two- and four-fibre families in turn for elastin and collagen) was implemented and its capacity to mathematically characterise the experimental data contrasted favourably with that of the well established phenomenological models, but it was compromised by parameter covariance. Extensive optimisation studies confirmed that the reduced model without contribution to the elastin and circumferential-fibre (collagen) families characterised the data equally well without over-parameterisation. In view of the fitted parameters, the ureteral tissue was stiffer longitudinally, justified by the preferential alignment of collagen along that axis and the lower ureter was stiffer than the upper ureter, justified by the histological observation of a thickest lamina propria, i.e. of highest collagen content, there. The lower ureter was less anisotropic than the upper ureter, possessing a comparatively larger amount of diagonally arranged collagen fibres in tunica mucosa, while having the usual amounts of longitudinally arranged fibres in tunica adventitia and of circumferentially arranged fibres in tunica muscularis. The present data may be used as inputs to mathematical models of the ureter, assessing regional and intramural stress distributions, through which it is hoped that an improved appreciation of ureteral function may be attained in both health and disease. PMID- 23439212 TI - Vasopressin and terlipressin in neonates and children with refractory septic shock. AB - Vasopressin and its analogue terlipressin are potent vasopressors which have been recently proposed in the treatment of catecholamine-resistant septic shock. We review the physiology, metabolism and pharmacology of vasopressin and terlipressin, as well as the available data on their efficacy and safety in neonates and children with septic shock. In adults, vasopressin deficiency can contribute to refractory shock states associated with sepsis. Differently, in children with septic shock vasopressin levels may be normal or even augmented. Nevertheless, low doses of vasopressin and terlipressin seem to have the potential to restore vasomotor tone in conditions refractory to catecholamines, improving organ perfusion with preservation of renal blood flow, while decreasing catecholamine requirements. Vasopressin and terlipressin produce vasoconstriction via stimulation of V1-receptors. In particular, terlipressin has a higher selectivity for V1-receptors and a longer half-life when compared to vasopressin, allowing for intermittent bolus doses. However, the pharmacology of vasopressin/terlipressin in newborns and children has not been sufficiently investigated and data on potential short and long-term adverse effects are still lacking. Further clinical, pharmacokinetic and pharmacodynamic studies are needed to better define the role of vasopressin and terlipressin in septic shock, as well as to prove their effectiveness and safety in infants and children. PMID- 23439211 TI - Astrocytes inhibit microglial surface expression of dendritic cell-related co stimulatory molecules through a contact-mediated process. AB - Murine microglia cultured in isolation were treated sequentially with granulocyte/monocyte colony-stimulating factor (GM-CSF) (5 days) and lipopolysaccharide (LPS) (2 days) to elicit a mature dendritic cell-like (DC like) phenotype. Examined by flow cytometry microglia thus isolated show high surface expression of CD11c together with the co-stimulatory molecules CD40, CD80, and CD86 that are necessary for T-cell activation. In contrast, microglia co-cultured with astrocytes fail to achieve a mature DC-like phenotype. Contact with the astrocytic environment is necessary for the inhibition. Failure was not because of a more rapid degradation of protein. Bone marrow-derived cells, like microglia, were prevented by astrocytes from attaining a mature DC phenotype. Although GM-CSF pre-treatment substantially increases mRNA of co-stimulatory molecules and major histocompatibility complex (MHC) Class II in isolated microglia, co-cultured microglia await treatment with LPS to up-regulate them. In contrast, western blot and immunocytochemical analysis revealed that it is not a failure of transcription or translation, nor is it a more rapid degradation of mRNA that is responsible for the low surface expression; rather microglia co cultured with astrocytes produce mRNA and protein but do not traffic the protein onto the cell surface. PMID- 23439214 TI - Association between nonalcoholic fatty liver disease and coronary artery disease complexity in patients with acute coronary syndrome: a pilot study. AB - Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with acute coronary syndrome (ACS). We assessed the association between NAFLD and SYNTAX Score (SS) in patients with ACS. Eighty consecutive patients with ACS were enrolled. Patients were evaluated using ultrasound to detect NAFLD and hepatosteatosis stage. The prevalence of NAFLD was 81.2%; median SS was 15. The SS was significantly higher in patients with NAFLD (18 +/- 8 vs. 11 +/- 5, P = .001). Univariate analysis showed that the stage of NAFLD correlated with SS (r = .6, P < .001). In multivariate binary logistic analysis, increased age (odds ratio [OR], 1.05; 95% confidence interval [CI],1.00-1.10) and presence of NAFLD (OR, 13.20; 95% CI, 2.52-69.15) were independent factors associated with supramedian SS. In conclusion, among patients with ACS, those with NAFLD have more complex CAD as assessed by SS. PMID- 23439215 TI - Task-dependent interactions between dopamine D2 receptor polymorphisms and L-DOPA in patients with Parkinson's disease. AB - Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning. In the current study, we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with L-DOPA during motor tasks in patients with Parkinson's disease (PD). Forty-five PD patients were genotyped for the DRD2 polymorphism (rs 1076560, G>T). Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF L-DOPA states. For motor sequence learning, DRD2 genotype mediated L-DOPA effects such that L-DOPA associated improvements were only observed in the minor T allele carriers (associated with lower D2 receptor availability, t10=-2.71, p=0.022), whereas G homozygotes showed no performance change with L-DOPA. For the grooved pegboard test, performance improved with L-DOPA independent of patients' DRD2 genotype. Collectively these results demonstrate that common DRD2 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals. PMID- 23439217 TI - Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats. AB - Exercise and environmental enrichment are behavioural interventions that have been shown to improve learning and increase neurogenesis in rodents, possibly via neurotrophin-mediated mechanisms. However, many enrichment protocols incorporate exercise, which can itself be viewed as a source of cognitive stimulation in animals housed in standard laboratory conditions. In this experiment we investigate the effect of each intervention separately and in combination on object recognition memory, and analyse associated changes in the dentate gyrus: specifically, in BDNF expression and cell division. We show that both exercise and enrichment improve object recognition memory, but that BDNF mRNA expression and cell proliferation in the dentate gyrus of the hippocampus increase only in exercised rats. These results are in general agreement with recent studies suggesting that the exercise component is the major neurogenic and neurotrophic stimulus in environmental enrichment protocols. We add to the expanding literature several novel aspects including the finding that enrichment in the absence of exercise can improve object recognition memory, probably via mechanisms that are independent of BDNF upregulation and neurogenesis in the dentate gyrus. PMID- 23439221 TI - How micron-sized dust particles determine the chemistry of our Universe. AB - In the environments where stars and planets form, about one percent of the mass is in the form of micro-meter sized particles known as dust. However small and insignificant these dust grains may seem, they are responsible for the production of the simplest (H(2)) to the most complex (amino-acids) molecules observed in our Universe. Dust particles are recognized as powerful nano-factories that produce chemical species. However, the mechanism that converts species on dust to gas species remains elusive. Here we report experimental evidence that species forming on interstellar dust analogs can be directly released into the gas. This process, entitled chemical desorption (fig. 1), can dominate over the chemistry due to the gas phase by more than ten orders of magnitude. It also determines which species remain on the surface and are available to participate in the subsequent complex chemistry that forms the molecules necessary for the emergence of life. PMID- 23439216 TI - Participation of the nociceptin/orphanin FQ receptor in ethanol-mediated locomotor activation and ethanol intake in preweanling rats. AB - Activation of nociceptin/orphanin FQ (NOP) receptors seems to attenuate ethanol induced reinforcement in adult rodents. Since early ethanol exposure results in later increased responsiveness to ethanol, it is important to analyze NOP receptor modulation of ethanol-related behaviors during early ontogeny. By measuring NOP involvement in ethanol intake and ethanol-induced locomotor activation, we analyzed the specific participation of NOP receptors on these ethanol-related behaviors in two-week-old rats. In each experiment animals were pre-treated with the endogenous ligand for this receptor (nociceptin/orphanin FQ at 0.0, 0.5, 1.0 or 2.0 MUg) or a selective NOP antagonist (J-113397 at 0.0, 0.5, 2.0 or 5.0 mg/kg). Results indicated that activation of the nociceptin receptor system had no effect on ethanol or water intake, while blockade of the NOP receptor has an unspecific effect on consummatory behavior: J-113397 increased ethanol (at a dose of 0.5 mg/kg) and water intake (at 0.5 and 5.0 mg/kg). Ethanol mediated locomotor stimulation was attenuated by activation of the NOP system (nociceptin at 1.0 and 2.0 MUg). Nociceptin had no effect on basal locomotor activity. Blockade of NOP receptors did not modify ethanol-induced locomotor activation. Contrary to what has been reported for adult rodents, nociceptin failed to suppress intake of ethanol in infants. Attenuation of ethanol-induced stimulation by activation of NOP receptor system suggests an early role of this receptor in this ethanol-related behavior. PMID- 23439222 TI - Quality improvement in cardiac critical care. AB - Our quality improvement program began in 2004 to improve cardiac surgery outcomes. Early tracheal extubation in the cardiovascular intensive unit was utilized as a multidisciplinary driver for the quality improvement program. Continuous improvement in the rate of early extubation to drive multidisciplinary quality improvement in cardiac critical care correlated with decreased mortality, morbidity, and improved operational efficiency. Supportive educational efforts included, but were not limited to, principles of change, trust, competing values, crew resource management, evidence based medicine, and quality improvement. PMID- 23439224 TI - Arterial pCO2 changes during thoracoscopic surgery with CO2 insufflation and one lung ventilation. AB - INTRODUCTION: The respiratory effects (changes in pH and PaCO(2)) of carbon dioxide insufflation in thoracoscopic surgery in adult patients with pulmonary disease were not documented previously. METHODS: In this observational study 21 patients scheduled for elective thoracoscopic surgery with one lung ventilation using a double lumen tube and intraoperative carbon dioxide insufflation were studied. Arterial blood gas findings were correlated with demographic and intraoperative variables. RESULTS: When compared to baseline (10-15 minutes of one lung ventilation before carbon dioxide insufflation), carbon dioxide insufflation lowered the pH, 7.31+/-0.08 vs 7.40+/-0.05 (p<0.001) caused increased PaCO(2), 53+/-12 vs 42+/-6.0 (p<0.001) at 40-60 minutes after carbon dioxide insufflation. These derangements in arterial blood gases persisted in the post-anesthetic care unit with pH 7.33+/-0.04 vs 7.40+/-0.05 (p<0.001) and PaCO(2) 51+/-6.7 vs 42+/-6.0 (p<0.001). Moderate hypercarbia defined as PaCO(2) >50 mmHg, developed in 12 of 21 patients (57%) and was associated to lower FEV1/FVC ratios 60+/-21 vs 81+/-3%, older age 69+/-9 vs 56+/-17 years, and history of smoking, 43 +/- 30 vs 16+/-21 pack years, p<0.05. CONCLUSIONS: Intrathoracic carbon dioxide insufflation causes significant derangements in pH and PaCO(2) which is worse in patients with lower FEV1/FVC, increased age and smoking history. PMID- 23439223 TI - Post-partum variation in the expression of paternal care is unrelated to urinary steroid metabolites in marmoset fathers. AB - The organization and activation of maternal care are known to be highly regulated by hormones and there is growing evidence that expression of paternal care is also related to endocrine substrates. We examined the relationship between paternal behavior and steroid hormones in marmoset fathers (Callithrix geoffroyi) and evaluated whether hormone-paternal behavior relationships were altered by previous offspring-care experience in males. Based on previous findings, we predicted that testosterone, estradiol, and cortisol would decrease following the birth of offspring and would be lowest during the period of maximal infant carrying. Furthermore, we predicted that post-partum changes in carrying effort and hormone levels would be influenced by the level of offspring-care experience. Carrying effort and other paternal care behaviors underwent temporal changes over the post-partum period, but these patterns were not related to variation in hormone concentrations over the same period. There was a limited effect of offspring-care experience on hormone concentrations, but experience was found to play a role in the expression of paternal care, with experienced fathers engaging in significantly more infant allogrooming than inexperienced fathers. Furthermore, inexperienced fathers increased the frequency of food sharing in response to infant begging across the post-partum period, while experienced fathers displayed consistently low levels. We posit that a combination of experiential factors and an increased role for alloparents in offspring-care led to these changes. However, it appears that hormonal changes may not influence paternal responsiveness in white-faced marmoset fathers and that hormone-paternal behavior relationships are not critically dependent on a male's previous offspring-care experience. PMID- 23439225 TI - Decrease of GSK3beta phosphorylation in the rat nucleus accumbens core enhances cocaine-induced hyper-locomotor activity. AB - Glycogen synthase kinase 3beta (GSK3beta), which is abundantly present in the brain, is known to contribute to psychomotor stimulant-induced locomotor behaviors. However, most studies have been focused in showing that GSK3beta is able to attenuate psychomotor stimulants-induced hyperactivity by increasing its phosphorylation levels in the nucleus accumbens (NAcc). So, here we examined in the opposite direction about the effects of decreased phosphorylation of GSK3beta in the NAcc core on both basal and cocaine-induced locomotor activity by a bilateral microinjection into this site of an artificially synthesized peptide, S9 (0.5 or 5.0 MUg/MUL), which contains sequences around N-terminal serine 9 residue of GSK3beta. We found that decreased levels of GSK3beta phosphorylation in the NAcc core enhance cocaine-induced hyper-locomotor activity, while leaving basal locomotor activity unchanged. This is the first demonstration, to our knowledge, that the selective decrease of GSK3beta phosphorylation levels in the NAcc core may contribute positively to cocaine-induced locomotor activity, while this is not sufficient for the generation of locomotor behavior by itself without cocaine. Taken together, these findings importantly suggest that GSK3beta may need other molecular targets which are co-activated (or deactivated) by psychomotor stimulants like cocaine to contribute to generation of locomotor behaviors. PMID- 23439226 TI - Examining the long-term stability of overgeneral autobiographical memory. AB - Overgeneral autobiographical memory (OGM) is a proposed trait-marker for vulnerability to depression, but relatively little work has examined its long term stability. This study investigated the stability of OGM over several years in 271 late adolescents and young adults participating in a larger longitudinal study of risk for emotional disorders. The Autobiographical Memory Test (AMT) was administered twice, with test-retest intervals ranging from approximately 3 to 6 years. There was evidence of significant but modest stability in OGM over several years. Specifically, Spearman rank correlations (rhos) between the proportions of specific and categoric memories generated on the two AMTs were .31 and .32, respectively. We did not find evidence that the stability of OGM was moderated by the length of the test-retest interval. Furthermore, the stability coefficients for OGM for individuals with and without a lifetime history of major depressive disorder (MDD) were relatively similar in magnitude and not significantly different from one another (rhos=.34 and .42 for the proportions of specific and categoric memories for those with a history of MDD; rhos=.31 for both the proportions of specific and categoric memories for those without a history of MDD). Implications for the conceptualisation of OGM are discussed. PMID- 23439227 TI - Efficacy of inhaled iloprost in the management of pulmonary hypertension after cardiopulmonary bypass in infants undergoing congenital heart surgery. A case series of 31 patients. AB - INTRODUCTION: Reactive pulmonary hypertension is frequent in children with high pulmonary flow and pressure. Inhaled iloprost and nitric oxide are the only substances approved as selective pulmonary vasodilators, but data about the effectiveness and safety of inhaled iloprost during cardiac surgery in infants and children are limited. METHODS: We retrospectively analysed the effects of inhaled iloprost after cardiopulmonary bypass weaning on the ratio of mean pulmonary artery to mean arterial pressure. The effectiveness of the inhalation set up was tested in an in vitro study. RESULTS: Thirty-one patients received inhaled iloprost during surgery. The clinically used inhalation set up for inhaled iloprost delivered 20% to 30% (500 to 750 ng * kg-1) of the nebulizer dose and caused a decrease in the ratio of mean pulmonary artery to mean arterial pressure from 0.6+/-0.2 to 0.4+/-0.1 and 0.4+/-0.1 (30 and 60 minutes after)p <0.05. In eleven (35%) patients norepinephrine infusion was started. CONCLUSION: Our data suggest that a single dose of inhaled iloprost significantly decreases the ratio of mean pulmonary artery to mean arterial pressure for at least 60 min. Vasopressor support may be indicated to avoid systemic hypotension. The filled dose in the nebulizer should be high enough to compensate for the high depletion rate of the pediatric inhalation system. However, our study allows no final decision about beneficial or detrimental effects of the off label use of inhaled iloprost to reduce pulmonary artery pressure during congenital heart surgery. PMID- 23439228 TI - That which does not degrade you makes you stronger: infectivity of poliovirus depends on vesicle acidification. AB - Several years ago, an explosion of research into pathogens and autophagy showed that viruses have a wide variety of relationships to this conserved homeostatic pathway. Often, autophagy acts as a host defense mechanism, degrading viruses before they can escape the host cell, and, as such, autophagy is suppressed or avoided by those viruses. A subset of viruses, however, induces and subverts the autophagic machinery to promote their own replication. Many of these viruses inhibit the degradative step in the autophagic pathway, presumably to prevent degradation of cytosolic virions before they exit the cell. Recently, we published a study showing that poliovirus (PV), a well-studied model virus, induces true autophagic degradation. The remainder of our study provided surprising clues about the role of autophagy in promoting virus production. The purpose of this punctum is to discuss the significance of our findings to a general understanding of the autophagic pathway and its relationship to a common class of cellular pathogens. PMID- 23439229 TI - Attitudes towards the use and disposal of unused medications in two European Countries. PMID- 23439232 TI - Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. AB - Clostridium difficile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratified depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mild-to moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classification of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI. PMID- 23439233 TI - Isolation, identification and antimicrobial activity of propolis-associated fungi. AB - Propolis is a natural product widely known for its medicinal properties. In this work, fungi present on propolis samples were isolated, identified and tested for the production of antimicrobial metabolites. Twenty-two fungal isolates were obtained, some of which were identified as Alternaria alternata, Aspergillus flavus, Bipolaris hawaiiensis, Fusarium merismoides, Lasiodiplodia theobromae, Penicillium citrinum, Penicillium crustosum, Penicillium janthinellum, Penicillium purpurogenum, Pestalotiopsis palustris, Tetracoccosporium paxianum and Trichoderma koningii. These fungi were grown in liquid media to obtain crude extracts that were evaluated for their antibiotic activity against pathogenic bacteria, yeast and Cladosporium cladosporioides and A. flavus. The most active extract was obtained from L. theobromae (minimum inhibitory concentration = 64 MUg/mL against Listeria monocitogenes). Some extracts showed to be more active than the positive control in the inhibition of Staphylococcus aureus and L. monocitogenes. Therefore, propolis is a promising source of fungi, which produces active agents against relevant food poisoning bacteria and crop-associated fungi. PMID- 23439235 TI - Barrett's esophagus: evolutionary insights from genomics. PMID- 23439234 TI - A rare but unique tumor in the esophagus. Primary esophageal melanoma. PMID- 23439236 TI - Bibliometrics of the top 100 clinical articles in digestive disease. PMID- 23439237 TI - An unusual cause of Dysphagia. Double aortic arch. PMID- 23439238 TI - High transvalvular pressure gradients on intraoperative transesophageal echocardiography after aortic valve replacement: what does it mean? AB - Intraoperative transesophageal echocardiography is now used routinely during aortic valve replacement, allowing immediate evaluation of replaced or repaired valves. It is well recognised that high transvalvular pressure gradients can be detected immediately after implantation of a prosthetic aortic valve which may be due to multifactorial confounding variables, including functional phenomena, pressure recovery and prosthesis-patient mismatch. This review article explores the variety of methods available for assessing prosthetic aortic valve function and considers causative factors which may contribute to high transvalvular gradients in an attempt to determine whether a physical problem with the valve exists, or whether the valve is functioning normally. PMID- 23439239 TI - Antibiotic-induced modifications of the stiffness of bacterial membranes. AB - In the latest years the importance of high resolution analysis of the microbial cell surface has been increasingly recognized. Indeed, in order to better understand bacterial physiology and achieve rapid diagnostic and treatment techniques, a thorough investigation of the surface modifications induced on bacteria by different environmental conditions or drugs is essential. Several instruments are nowadays available to observe at high resolution specific properties of microscopic samples. Among these, AFM can routinely study single cells in physiological conditions, measuring the mechanical properties of their membrane at a nanometric scale (force volume). Such analyses, coupled with high resolution investigation of their morphological properties, are increasingly used to characterize the state of single cells. In this work we exploit such technique to characterize bacterial systems. We have performed an analysis of the mechanical properties of bacteria (Escherichia coli) exposed to different conditions. Such measurements were performed on living bacteria, by changing in real-time the liquid environment: standard phosphate buffered saline, antibiotic (ampicillin) in PBS and growth medium. In particular we have focused on the determination of the membrane stiffness modifications induced by these solutions, in particular between stationary and replicating phases and what is the effect of the antibiotic on the bacterial structure. PMID- 23439241 TI - pH-gradient PAMPA-based in vitro model assay for drug-induced phospholipidosis in early stage of drug discovery. AB - In the present study we validated a widely used, high-throughput in vitro permeability model (PAMPA) to be used at the early stage of drug discovery for the phospholipidosis (PLD) prediction of drug-like compounds. Regarding the mechanism of action of PLD, our pH-gradient PAMPA system is the first noncell based model to mimic one-way transport of cationic amphiphilic drugs (CADs) from cytosol to the lysosome. Moreover, due to the fact that PLD can mainly occur in lung, liver, brain, kidney and heart, we have used similar commercially available original tissue-derived lipid fractions (heart, liver, brain), and in the case mimicking membrane of kidney and lung tissue we prepared tissue-mimetic artificial lipid mixtures in house. Metabolism of a drug can change the degree of PLD depending on the physicochemical properties of metabolites and the rate of metabolism. Our data from 57 drugs and 4 metabolites of earlier and 2 metabolites of newly recognized outliers (phenacetin and bupropion) using our pH-gradient PAMPA system show a good correlation with in vivo PLD data. Moreover, predictive ability of our best system, the lung specific pH-gradient PAMPA model was significantly better than widely used in silico models and it was also slightly better than that of the known noncell based models on our selection of compounds. Our pH-gradient PAMPA systems therefore offer mechanistically alternative, accurate and cost-effective screening tools for the early prediction of PLD potential of drug-like compounds. PMID- 23439240 TI - Definition of formulation design space, in vitro bioactivity and in vivo biodistribution for hydrophilic drug loaded PLGA/PEO-PPO-PEO nanoparticles using OFAT experiments. AB - Modified nanoprecipitation method was used for improved incorporation of hydrophilic drug (irinotecan hydrochloride) into the PLGA/PEO-PPO-PEO blended and blended/adsorbed nanoparticles. One factor at a time (OFAT) variation experiments were conducted in order to determine key formulation factors (concentration and volume of drug solution, evaporation rate and PLGA/PEO-PPO-PEO ratio) influencing nanoparticle properties (particle size and size distribution, encapsulation efficiency, drug content, zeta potential, drug dissolution rate, as well as protein binding capacity). The insight into in vivo behavior of prepared nanoparticles and their potential for effective anticancer treatment was gained by performing biodistribution and cell culture studies as part of OFAT experiments. The mean particle size, mainly dependent upon PLGA/PEO-PPO-PEO ratio, was in the range of 112-125 nm, with narrow unimodal distribution (PDI~0.1). Encapsulation efficiency (32-63%) was impacted by evaporation rate and PLGA/PEO-PPO-PEO ratio. Drug content (0.2-1.51%) and controlled release properties were related to the influence of all tested formulation factors. Structural information for the studied nanoparticles was obtained using DSC and FT-IR spectroscopy. Zeta potential values indicated that presence of PEO-PPO-PEO in the formulations shielded the high surface negative charge of PLGA. PEO-PPO PEO surface coverage of PLGA/PEO-PPO-PEO blended as well as blended/adsorbed nanoparticles depended upon amount of used PEO-PPO-PEO during preparation procedure and was related to the protein resistant characteristics of nanoparticles. Results from in vivo studies evidenced prolonged blood circulation time of the prepared nanoparticles, while cell culture studies indicated higher in vitro bioefficacy compared to free drug. Performed experiments defined possible design space and justified further optimization of formulation using experimental design studies. PMID- 23439242 TI - Interactive effect of reduced pollen availability and Varroa destructor infestation limits growth and protein content of young honey bees. AB - Varroa destructor in combination with one or more stressors, such as low food availability or chemical exposure, is considered to be one of the main causes for honey bee colony losses. We examined the interactive effect of pollen availability on the protein content and body weight of young bees that emerged with and without V. destructor infestation. With reduced pollen availability, and the coherent reduced nutritional protein, we expected that V. destructor infestation during the pupal stage would have a larger negative effect on bee development than without infestation. Moreover, when raised with ample pollen available after emergence, infested pupae were expected not to be able to compensate for early losses due to V. destructor. We found that both V. destructor infestation and reduced pollen availability reduced body weight, abdominal protein level, and increased the head to abdomen protein ratio. The availability of pollen did indeed not result in compensation for reduced mass and protein content caused by V. destructor infestation in young bees after 1 week of their adult life. Both V. destructor and nutrition are top concerns for those studying honey bee health and this study demonstrates that both have substantial effects on young bees and that ample available pollen cannot compensate for reduced mass and protein content caused by V. destructor parasitism. PMID- 23439243 TI - AA amyloid nephropathy with predominant vascular deposition in Crohn's disease. AB - A 44-year-old man with a 17-year history of Crohn's disease (CD) was referred to our nephrology department on suspicion of drug-induced nephrotoxicity. Over the preceding 18 months, he had slowly progressive renal insufficiency with slight urinary abnormalities. His disease activity had been well controlled up to that point with 5-aminosalicylic acid and azathiopurine. Laboratory examination revealed slight proteinuria without hematuria and an elevated serum creatinine level of 1.4 mg/dl. Pathological examination revealed amyloid A (AA) deposition in the kidney, predominantly in the arterial and arteriolar walls with little to none in the glomerular capillaries. AA amyloidosis is typically accompanied by glomerular amyloid deposition and massive proteinuria. In the present case, however, vascular amyloid deposition was predominant, and the renal function was deteriorated with slight urinary abnormalities. The present case confirmed the importance of conducting a definitive pathological diagnosis of renal insufficiency in CD patients. PMID- 23439244 TI - A patient with persistent renal AL amyloid deposition after clinical remission by HDM/SCT therapy. AB - A 62-year-old female patient was admitted to our hospital for evaluation of nephrotic syndrome. Monoclonal gammopathy (IgG lambda type) and urinary Bence Jones proteins were detected in the serum and urine by the immunofixation method. The initial renal biopsy revealed amyloid deposition in mesangial area, glomerular capillary walls and arterioles by Congo-red staining, and amyloid fibers were detected by electron microscopy. On the bone marrow test, plasma cells accounted for 8.6%. Based on these findings, we diagnosed as AL amyloidosis associated with multiple myeloma. We treated her by high-dose intravenous injection therapy of melphalan combined with autologous peripheral blood stem cell transplantation. She achieved complete hematologic response 27 months later, however. Urine M-protein disappeared 2 months after treatment, and proteinuria slowly disappeared 17 months after treatment. On the other hand, amyloid fibers remained in renal biopsied tissues at 17 and 53 months after therapy. Electron microscopic examination also revealed the similar amyloid fibers in glomeruli. These findings suggest that, in this case, immunoglobulin light chains may cause directly and/or indirectly glomerular epithelial injury and nephrotic range proteinuria rather than via amyloid fiber formation. PMID- 23439245 TI - A purpose-built simulator for percutaneous ultrasound-guided renal biopsy. AB - AIMS: To construct a simple and affordable simulator for ultrasoundguided percutaneous renal biopsy. MATERIAL AND METHODS: The kidney biopsy phantom was constructed by embedding a porcine kidney in gelatine. Silicon carbide and aluminium oxide were used as scattering particles in order to mimic the ultrasound appearance of human tissues. Two porcine ribs were also embedded. A latex sheet was placed over the top of the gel layer to resemble skin. The simulator was used and feedback from participants obtained during a renal ultrasound course with an international audience of middle-grade trainees from adult and pediatric nephrology, many of whom had never done a renal biopsy. Biopsy was carried out a single-use biopsy gun. RESULTS: All participants were able to perform a biopsy and obtain a satisfactory sample. All trainees felt that our simulator was very realistic. 94% of participants agreed that the simulator would help to allay their fears in relation to renal biopsy The total cost of the simulator was around L 50,- for consumables per simulator. CONCLUSIONS: We describe a purpose-built and affordable simulator for percutaneous ultrasound guided renal biopsy. We suggest that others evaluate our simulator used as part of a structured approach to teach this important procedure. PMID- 23439246 TI - Fluid responsiveness and right ventricular function in cardiac surgical patients. A multicenter study. AB - INTRODUCTION: We investigated fluid responsiveness in a population of patients undergoing coronary artery revascularization, with respect to their right ventricular ejection fraction. MATERIALS AND METHODS: This was a multicenter trial involving 11 cardiac surgical Institutions and 65 patients undergoing elective coronary artery revascularization. Hemodynamic parameters were measured before and after volume expansion using a modified pulmonary artery catheter and transesophageal echocardiographic monitoring. Patients demonstrating an increase of stroke volume >20% after volume expansion were considered as responders. Volume expansion with 7 ml/kg of plasma expander was performed when required on a clinical basis. RESULTS: In the overall population, only the change in aortic blood velocity (cut-off 13%) was a predictor of fluid responsiveness. In patients with a reduced (<0.3) right ventricular ejection fraction only the value of mean pulmonary arterial pressure was predictive of fluid responsiveness (cut-off 18 mmHg). Patients with right ventricular ejection fraction >=0.3 demonstrated three predictors: changes in aortic blood velocity (cut-off 15%), right ventricular end diastolic volume index (cut-off 80 ml/m(2)), and left ventricular end diastolic area index (cut-off 9 cm(2)/m(2)). CONCLUSIONS: When right ventricular systolic function is depressed, the right ventricle inability to fill the left chambers results in a lack of the left-sided responsiveness predictors. When the right ventricular systolic function is preserved, all the classical fluid responsiveness predictors are confirmed. Right ventricular function is therefore to be always considered when addressing the problem of fluid responsiveness. PMID- 23439247 TI - TECPR2: a new autophagy link for neurodegeneration. AB - Autophagy dysfunction has been implicated in a group of progressive neurodegenerative diseases, and has been reported to play a major role in the pathogenesis of these disorders. We have recently reported a recessive mutation in TECPR2, an autophagy-implicated WD repeat-containing protein, in five individuals with a novel form of monogenic hereditary spastic paraparesis (HSP). We found that diseased skin fibroblasts had a decreased accumulation of the autophagy-initiation protein MAP1LC3B/LC3B, and an attenuated delivery of both LC3B and the cargo-recruiting protein SQSTM1/p62 to the lysosome where they are subject to degradation. The discovered TECPR2 mutation reveals for the first time a role for aberrant autophagy in a major class of Mendelian neurodegenerative diseases, and suggests mechanisms by which impaired autophagy may impinge on a broader scope of neurodegeneration. PMID- 23439248 TI - Ratio of Abeta42/P-tau181p in CSF is associated with aberrant default mode network in AD. AB - The default mode network (DMN) is particularly relevant to Alzheimer's disease (AD) since its structures are vulnerable to deposition of amyloid. Decreased levels of beta-amyloid(1-42) (Abeta42) and increased total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau(181p)) in cerebrospinal fluid (CSF) have been established as valid biomarkers for the diagnosis and prognosis of AD. However, the relationship between CSF biomarkers and change in the DMN is still unknown. In this study we investigated the correlation between the functional connectivity within the DMN and the ratio of Abeta42/P-tau(181p) in the CSF. We found that the ratio of Abeta42/P-tau(181p) was moderately positively correlated with the functional connectivity within the DMN in the left precuneus/cuneus. This finding implicates that the brain functional connectivity within DMN is affected by pathological changes at early stage in AD. This may provide a better understanding of AD pathology progression and improve AD diagnosis. PMID- 23439249 TI - Design of stapled alpha-helical peptides to specifically activate Wnt/beta catenin signaling. PMID- 23439250 TI - Dual suppressive effect of MTORC1 on autophagy: tame the dragon by shackling both the head and the tail. AB - The lysosome is a key subcellular organelle that receives and degrades macromolecules from endocytic, secretory and autophagic pathways. Lysosomal function is thus critical for an efficient autophagic process. However, the molecular mechanisms mediating lysosomal function upon autophagic induction are largely unknown. Our laboratory recently discovered that upon autophagy activation, the lysosome is activated, and this functional activation is dependent on MTORC1 suppression, suggesting that MTORC1 exerts a suppressive effect on lysosomal function. Therefore, data from our study demonstrate that MTORC1 exerts a dual inhibitory effect on autophagy, blocking autophagy not only at the initiation stage via suppression of the ULK1 complex, but also at the degradation stage via inhibition of lysosomal function. We think that understanding the negative regulatory effect of MTORC1 on lysosomal function expands the functional scope of MTORC1 in autophagy regulation, and offers new clues for developing novel interventional strategies in autophagy- and lysosome related diseases. PMID- 23439252 TI - Preoperative characterization of indeterminate large adrenal masses with dual tracer PET-CT using fluorine-18 fluorodeoxyglucose and gallium-68-DOTANOC: initial results. AB - PURPOSE: We aimed to evaluate the usefulness of dual tracer positron emission tomography-computed tomography (PET-CT) with flourine-18 fluorodeoxyglucose (18F FDG) and gallium-68 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1 NaI3-octreotide (68Ga-DOTANOC) in preoperative characterization of large indeterminate adrenal masses. MATERIALS AND METHODS: Ten patients (four males, six females; median age, 35 years) with indeterminate, large (>=4 cm) adrenal masses were included in this prospective study. All patients underwent both 18F FDG PET-CT and 68Ga-DOTANOC PET-CT within one week. Images were evaluated both visually and semi-quantitatively, with standardized uptake value (SUVmax) and SUVratio (SUVmax) of tumor/SUVmax) of mediastinum). Based on differential uptake pattern on 18F-FDG and 68Ga-DOTANOC, lesions were classified as cortical (18F FDG>68Ga-DOTANOC), medullary (68Ga-DOTANOC>18F-FDG), or indeterminate (18F FDG=68Ga-DOTANOC). Histopathology was taken as reference standard. Receiver operating characteristic (ROC) analysis was performed to find a cut-off of SUVmax) and SUVratio to differentiate cortical and medullary lesions. RESULTS: On histopathology, eight lesions were adrenocortical carcinomas, one was benign pheochromocytoma, and one was malignant pheochromocytoma. Visually, 18F-FDG PET CT was positive in all ten lesions, while 68Ga-DOTANOC PET-CT was positive in two, both of which were pheochromocytomas. On SUVmax) based analysis, nine lesions were cortical and one was medullary. On ROC analysis, a SUVmax) cut-off of > 2.3 was obtained for 18F-FDG PET-CT and 3.6 for 68Ga-DOTANOC PET-CT for differentiating adrenal cortical and medullary lesions. The cut-off for SUVratio was 4.5 on 18F-FDG PET-CT and 11.1 on 68Ga-DOTANOC PET-CT. CONCLUSION: These preliminary results demonstrate that dual tracer PET-CT using 18F-FDG and 68Ga DOTANOC could be informative in the preoperative characterization of large indeterminate adrenal masses. PMID- 23439251 TI - A chimerical phagocytosis model reveals the recruitment by Sertoli cells of autophagy for the degradation of ingested illegitimate substrates. AB - Phagocytosis and autophagy are typically dedicated to degradation of substrates of extrinsic and intrinsic origins respectively. Although overlaps between phagocytosis and autophagy were reported, the use of autophagy for ingested substrate degradation by nonprofessional phagocytes has not been described. Blood separated tissues use their tissue-specific nonprofessional phagocytes for homeostatic phagocytosis. In the testis, Sertoli cells phagocytose spermatid residual bodies produced during germ cell differentiation. In the retina, pigmented epithelium phagocytoses shed photoreceptor tips produced during photoreceptor renewal. Spermatid residual bodies and shed photoreceptor tips are phosphatidylserine-exposing substrates. Activation of the tyrosine kinase receptor MERTK, which is implicated in phagocytosis of phosphatidylserine exposing substrates, is a common feature of Sertoli and retinal pigmented epithelial cell phagocytosis. The major aim of our study was to investigate to what extent phagocytosis by Sertoli cells may be tissue specific. We analyzed in Sertoli cell cultures that were exposed to either spermatid residual bodies (legitimate substrates) or retina photoreceptor outer segments (illegitimate substrates) the course of the main phagocytosis stages. We show that whereas substrate binding and ingestion stages occur similarly for legitimate or illegitimate substrates, the degradation of illegitimate but not of legitimate substrates triggers autophagy as evidenced by the formation of double-membrane wrapping, MAP1LC3A-II/LC3-II clustering, SQSTM1/p62 degradation, and by marked changes in ATG5, ATG9 and BECN1/Beclin 1 protein expression profiles. The recruitment by nonprofessional phagocytes of autophagy for the degradation of ingested cell-derived substrates is a novel feature that may be of major importance for fundamentals of both apoptotic substrate clearance and tissue homeostasis. PMID- 23439253 TI - Imaging findings of renal toxicity in patients on chronic lithium therapy. AB - Lithium salts are the mainstay of treatment of bipolar disorder. However, the therapeutic index of lithium is narrow, and severe side effects may be seen. Nephrotoxicity is the most important side effect, which may progress to chronic renal failure. In this pictorial essay, we present ultrasonography, computed tomography, and magnetic resonance imaging findings of renal toxicity secondary to chronic lithium use. We believe that imaging could be extremely helpful for the evaluation of renal toxicity and may even detect preclinical stages of renal parenchymal injury. A combination of different imaging modalities may help clarify findings detected on one modality. PMID- 23439254 TI - Flow diverter as a rescue therapy for a complicated basilar angioplasty. AB - Intracranial atherosclerotic disease is a major cause of ischemic stroke. Stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis was terminated prematurely due to a high stroke and death rate in patients randomized for intracranial stent placement. However, for some patients, angioplasty and/or stent placement remains the best approach. Flow diverters (FDs) are designed to produce a hemodynamic flow diversion by constituting a laminar flow pattern in the parent artery and are mainly used in non-ruptured complex wide-neck aneurysms as well as in ruptured aneurysms. Herein, we present a case where an FD was used in a complicated angioplasty for basilar artery atherosclerosis. A 72-year-old female patient was admitted to our hospital with left side weakness and vertigo. Her diffusion magnetic resonance imaging and magnetic resonance angiography showed right-sided pontine and left sided occipital acute infarcts with left-sided pontine and right-sided occipital chronic infarcted areas and preocclusive mid-basilar stenosis. The patient was under supervised medical treatment. Despite chronic brain stem and occipital infarcts her modified Rankin Scale was 2. Diagnostic angiography showed no posterior communicating arteries and no pial-pial collaterals and a critical mid basilar artery stenosis. We decided to perform intracranial angioplasty to increase the perfusion of posterior circulation and reduce the risk of additional embolic infarcts. Angioplasty was complicated with dissection and vessel perforation. We used an FD for rescue therapy to avoid rebleeding. The patient was discharged with good clinical and angiographic results. PMID- 23439255 TI - Endovascular treatment of surgically implanted arterial graft thrombosis by using manual aspiration thrombectomy. AB - The purpose of this study was to present our experience with guiding catheters in manual aspiration thrombectomy of occluded infra-aortic bypass grafts. This material was designed as a guiding catheter but was also used for thrombus aspiration. Six consecutive patients (all male; mean age, 61.0+/-5.7 years; range, 54-68 years) who underwent manual aspiration thrombectomy at the discretion of the operator for infra-aortic bypass graft thrombosis between 2002 and 2010 were retrospectively reviewed. The angiographic success described as either stenosis or residual thrombus less than 30% was 67%. Primary patency was 50%, and secondary patency was 66.7%. Additional stents were needed in four lesions of three patients. Manual aspiration thrombectomy is intended to remove both soft acute blood clots and hard organized embolic and thrombotic obstructions. Manual aspiration thrombectomy appears to be a safe and effective method for treating delayed graft thrombosis. This method provides an alternative to surgical thrombectomy, especially for patients who are not good candidates for the surgery. PMID- 23439256 TI - Subtypes of renal cell carcinoma: MRI and pathological features. AB - Renal cell carcinoma (RCC) is the most common malignant tumor involving the kidney. Determining the subtypes of renal cell carcinoma is among the major goals of preoperative radiological work-up. Among all modalities, magnetic resonance imaging (MRI) has several advantages, such as inherent soft tissue contrast, detection of lipid and blood products, and excellent sensitivity to detect small amounts of intravenous contrast, which facilitate the discrimination of subtypes of RCC. In this article, we review MRI and pathological features used for determining the main histologic subtypes of RCC, including clear cell, papillary, collecting duct, chromophobe, multilocular cystic, and unclassified RCC. PMID- 23439257 TI - Intrathoracic gossypiboma: a diagnostic challenge. PMID- 23439258 TI - Eyewitness testimony in the Lockerbie bombing case. AB - It was in 1988 that a Pan Am flight blew up over Lockerbie, Scotland, killing 270 people. A Libyan named Al-Megrahi was convicted of the crime. His conviction was based in large part on the testimony of a single eyewitness, a shopkeeper who identified him as the person who had purchased clothing allegedly packed in the suitcase that contained the explosives that blew up the plane. But careful analysis of the eyewitness evidence leads to suspicions about the accuracy of the evidence. This analysis was presented to the Scottish Criminal Cases Review Commission which concluded that the conviction might have been a miscarriage of justice. PMID- 23439260 TI - Improvement of ischemic cholangiopathy in three patients with hereditary hemorrhagic telangiectasia following treatment with bevacizumab. AB - The ischemic biliary phenotype of hereditary hemorrhagic telangiectasia (HHT) is rare but distinct, with progressive biliary tree ischemia usually resulting in an irreversible secondary sclerosing cholangiopathy. When clinically severe, liver transplant is often indicated. We report three patients with marked HHT associated biliary disease, in whom prolonged anti-vascular endothelial growth factor therapy (bevacizumab) notably reversed imaging evidence of biliary disease and clinically obviated need for liver transplantation during the first year of follow-up. PMID- 23439259 TI - A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment. AB - BACKGROUND & AIMS: MK-7009 (vaniprevir) is a non-covalent competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease. This report presents the primary analysis results (safety and sustained viral response) of a phase 2b study of MK 7009 given in combination with peginterferon (PegIFN) alfa2a 180 MUg weekly and ribavirin (RBV) 1000-1200 mg/day, for 24-48 weeks to non-cirrhotic patients who have failed previous PegIFN and RBV treatment. METHODS: We present results of a randomized, placebo-controlled, double-blind study of MK-7009 administered for 24 48 weeks in combination with PegIFN and RBV in 4 regimens to at least 40 patients per arm. Stratification by prior response to PegIFN and RBV was as follows: null response, partial response, breakthrough and relapse. HCV RNA was determined by Roche Cobas Taqman with a lower limit of detection (LLoD) of 10 IU/ml and a lower limit of quantification (LLoQ) of 25 IU/ml. RESULTS: SVR24 in patients on MK 7009+PegIFN and ribavirin (P/R) was statistically superior to placebo+P/R in all treatment groups (p<0.001). MK-7009 at 300 mg b.i.d. and 600 mg b.i.d. is generally well tolerated for use for up to 48 weeks of therapy. Patients in MK 7009 regimens had higher rates of gastrointestinal adverse events as compared to control (mostly mild to moderate). There were no significant differences in rates of anemia and rash between the MK-7009 regimens and control. CONCLUSIONS: In conclusion, patients treated with MK-7009 plus P/R experienced significant improvement in SVR compared to P/R control in a population of GT 1 experienced patients. PMID- 23439261 TI - The liver diseases of lipodystrophy: the long-term effect of leptin treatment. AB - BACKGROUND & AIMS: Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. METHODS: This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N=50) and after leptin replacement (N=27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy. RESULTS: In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 +/- 3.7 months (mean +/- SE, p=0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p<0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. CONCLUSIONS: The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients. PMID- 23439262 TI - A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1. AB - BACKGROUND & AIMS: ABT-450 (combined with low-dose ritonavir, ABT-450/r) is a potent HCV NS3 protease inhibitor, and ABT-072 is a non-nucleoside NS5B polymerase inhibitor. The goal of this study was to evaluate the safety, tolerability, and efficacy of the peginterferon-free combination of ABT-450/r and ABT-072 with ribavirin in treatment-naive patients with IL28B CC genotype, infected with HCV genotype 1. METHODS: This was a phase 2a, multicenter, open label, single-arm study in 11 treatment-naive, non-cirrhotic HCV GT1-infected patients with IL28B rs12979860 genotype CC. Patients received ABT-450/r 150/100 mg once daily and ABT-072 400 mg once daily with weight-based ribavirin 1000-1200 mg/day dosed twice daily for 12 weeks. RESULTS: Eight (73%) patients were male, 9 (82%) were Caucasian (including 3 who self-identified as Hispanic); mean baseline HCV RNA was 6.9 log10 IU/ml (range 6.5-7.3 log10 IU/ml). All 11 patients completed 12 weeks of treatment and maintained HCV RNA <25 IU/ml from weeks 4 through 12 of treatment. Ten patients (91%) achieved sustained virologic response 24 weeks post-treatment, with a second patient relapsing 36 weeks post-treatment. There were no deaths, serious or severe adverse events, or premature discontinuations. Adverse events were mostly mild and the most frequent were headache, fatigue, nausea, and dry skin. CONCLUSIONS: A 12-week regimen of ABT 450/r and ABT-072 with ribavirin was well tolerated with 9/11 patients achieving sustained virologic response through 36 weeks of post-treatment observation. These findings suggest that peginterferon-free regimens may have the potential to cure a high proportion of HCV genotype 1-infected patients. PMID- 23439263 TI - Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. AB - BACKGROUND & AIMS: Acute liver failure (ALF) is a rapidly progressive critical illness with high mortality. Complex intensive care unit (ICU) protocols and emergency liver transplantation (ELT) are now often available, but rarity and severity of illness have limited its study and evidence-base for care. We reviewed patients treated over a 35-year period at a specialist high-volume ICU, quantifying changes in disease aetiology, severity and evolution of ICU support and ELT use and outcome. METHODS: Review of adult patients admitted during the period 1973-2008, with acute liver dysfunction and coagulopathy with overt hepatic encephalopathy (ALF) and those without (acute liver injury; ALI). RESULTS: 3305 patients fulfilled inclusion criteria, 2095 with ALF. Overall hospital survival increased from 30% in 1973-78 to 76% in 2004-08; in ALF from 17% to 62% (both p<0.0001). In ALF patients treated without ELT, survival rose from 17% to 48% (p<0.0001); in those undergoing ELT (n=387) from 56% in 1984-88 to 86% in 2004-08 (p<0.01). Coincident with drug sales-restriction, paracetamol related admissions fell significantly. Viral admissions fell from 56% to 17% of non-paracetamol cases (p<0.0001). Admission markers of liver injury severity fell significantly and the proportion of patients with intracranial hypertension (ICH) fell from 76% in 1984-88 to 20% in 2004-08 (p<0.0001). In those with ICH, mortality fell from 95% to 55% (p<0.0001). CONCLUSIONS: The nature and outcome of ALF have transformed over 35 years, with major improvements in survival and a fall in prevalence of cerebral oedema and ICH, likely consequent upon earlier illness recognition, improved ICU care, and use of ELT. PMID- 23439264 TI - First report of the protozoan parasite Perkinsus marinus in South America, infecting mangrove oysters Crassostrea rhizophorae from the Paraiba River (NE, Brazil). AB - The present work aimed to study the infection by Perkinsus sp. in the mangrove oysters Crassostrea rhizophorae from the estuary of the Paraiba River (Paraiba State, Brazil). Perkinsosis was detected by incubation of oyster gill pieces in Ray's fluid thioglycollate medium. The monthly prevalence values were all above 70%, thus infection was not likely to be a transient event. Perkinsus sp. parasites isolated from eight oysters were propagated in vitro. PCR-RFLP analysis of in vitro cultured cells as well as the sequences of the rDNA ITS region allowed the identification of the in vitro propagated parasites as Perkinsus marinus. Phylogenetic analyses using rDNA ITS region sequences strongly supported the Perkinsus sp. from Paraiba in a monophyletic group with P. marinus. Thus, the results confirmed the species affiliation of Paraiba Perkinsus sp. as P. marinus. This is the first report of P. marinus in Brazil and South America and the first report of P. marinus naturally infecting C. rhizophorae. PMID- 23439265 TI - Reproduction-related effects of green alga Coccomyxa sp. infestation in the horse mussel Modiolus modiolus. AB - The effects of Coccomyxa sp. infestation on the reproductive characteristics of the horse mussel Modiolus modiolus from the north-western Pacific (Peter the Great Bay, Sea of Japan) are demonstrated in this study. The mussels were collected monthly from May to September of 2009, and the prevalence of females and males with green tissues was 39% and 47%, respectively. Overall, the green alga infection caused a mild effect on gametogenesis in the horse mussel. The dynamics of gonad development in the healthy and infected mussels during the study period was generally similar, with the spawning being partial and occurring from the beginning of June to the first half of September; total spawning was recorded at the end of this period. However, several negative reproduction related effects of the green alga infestation were observed, i.e., general gonadal underdevelopment, which was apparent from significant decrease in the acinus areas of the ovaries and testes and an increase in the connective tissue layer between the acini, a delay in some stages of the reproductive cycle and production of decreased number of spermatozoa and large vitellogenic oocytes, especially in the early spawning period (June). All of these results suggest a reduced reproductive output for the infected mussels. PMID- 23439266 TI - Occupational exposures and the development of new-onset asthma: a population based cohort study from the ages of 13 to 44 years. AB - OBJECTIVE: To evaluate the risk of asthma associated with occupational exposures in a population-based cohort. METHODS: The risk of asthma was analyzed in 792 subjects who were asthma free at the age of 13 years. Occupational histories were obtained from subjects at the age of 44 years and occupational exposures determined with an asthma-specific job exposure matrix. Cumulative exposure to latex and risk of asthma was examined using Cox proportional hazards regression. RESULTS: Development of asthma was modestly related to exposure at any time to high molecular weight latex (odds ratio, 1.4; 95% confidence interval, 0.9-2.3). Cumulative latex exposure of 6 to 15 years was associated with a hazard ratio of 1.6 for the development of asthma and after 16 years increased to 2.65 (95% confidence interval, 1.28-5.47). CONCLUSION: There is a significant association between cumulative occupational exposure to latex and new-onset asthma. PMID- 23439267 TI - Modifiable health risks and illness absence from work: evidence from the panel study of income dynamics. AB - OBJECTIVE: Modifiable health risks such as smoking, exercise, and body weight have been linked to illness absence from work. This suggests that employers could improve their productivity if their workers adopted healthier lifestyles, but methodological concerns regarding selection bias and omitted variables remain. METHODS: We use a first-difference model of changes in health behaviors and illness- and family-related absence from work among a nationally representative, longitudinal panel of employed individuals. RESULTS: Workers who lost weight or increased their frequency of light exercise also saw their illness absences decrease over a 2-year period. Some, but not all, of the relationship is mediated by the change in health status. No such decrease was observed for family-related absences. CONCLUSION: The findings are consistent with the proposition that both employers and employees could benefit from efforts to support better health habits. PMID- 23439268 TI - Patient-reported depression severity measured by the PHQ-9 and impact on work productivity: results from a survey of full-time employees in the United States. AB - OBJECTIVE: To examine the burden of depression on work productivity. METHODS: Full-time employees with diagnosed depression were surveyed using the Patient Health Questionnaire for depression severity, and the Health and Work Performance Questionnaire and Work Productivity and Activity Impairment (WPAI) questionnaire for absenteeism and presenteeism. RESULTS: Of the 1051 employees with depression, 40.3% had no depressive symptoms at the time of the survey, 30.4% had mild depression, 15.8% had moderate depression, 7.8% had moderately severe depression, and 5.8% had severe depression. All levels of depression were associated with decreased work productivity. Presenteeism was positively associated with severity of depression (Health and Work Performance Questionnaire, P < 0.0001; WPAI, P < 0.0001). Absenteeism was significantly positively associated with severity of depression using the WPAI. CONCLUSIONS: Decreased overall productivity was seen at all levels of depression, and as severity increased, presenteeism and absenteeism worsened. PMID- 23439269 TI - Association of aryl hydrocarbon receptor gene polymorphism with the neurobehavioral function and autonomic nervous system function changes induced by benzo[a]pyrene exposure in coke oven workers. AB - OBJECTIVE: To analyze the association of aryl hydrocarbon receptor (AhR) gene polymorphism and the neurotoxicity induced by benzo[a]pyrene (B[a]P) in coke oven workers. METHODS: Subjects, 214 coke oven workers and 81 controls, were detected for neurobehavioral function and autonomic nervous system (ANS) function. Airborne B[a]P concentration, urinary 1-hydroxypyrene level, and AhR gene polymorphisms were determined and analyzed for their association with B[a]P neurotoxicity. RESULTS: Neurobehavioral function and ANS function were significantly decreased and dependent on B[a]P dose. The AhR GG, GA, and AA genotypes in G1661A fitted the Hardy-Weinberg equation, whereas C1549T and G1708A gene mutants were not detected. Indices indicating neurotoxicity showed no significant difference among individuals with AA, GG, or GA genotype except for the confusion-bewilderment (P > 0.05). CONCLUSION: The AhR gene polymorphism is not thought to correlate with B[a]P neurotoxicity among coke oven workers. PMID- 23439270 TI - The association of technology in a workplace wellness program with health risk factor reduction. AB - OBJECTIVE: Determine whether there is a relationship between level of engagement in workplace wellness programs and population/individual health risk reductions. METHODS: A total of 7804 employees from 15 employers completed health risk appraisal and laboratory testing at baseline and again after 2 years of participating in their personalized prevention plan. Population and individual health risk transitions were analyzed across the population, as well as by stage of engagement. RESULTS: Of those individuals who started in a high risk category at baseline, 46% moved down to medium risk and 19% moved down to low risk category after 2 years on their prevention plan. In the group that only engaged through the Web-based technology, 24% reduced their health risks (P < 0.0001). CONCLUSIONS: Engaging technology and interactive Web-based tools can empower individuals to be more proactive about their health and reduce their health risks. PMID- 23439271 TI - Michigan work-related amputations, 2008. AB - BACKGROUND: Michigan's work-related amputation surveillance system quantifies and characterizes occupational amputations and facilitates remediation of workplace hazards. OBJECTIVE: To identify and mitigate the hazards that cause amputations, to facilitate workplace investigations, and, ultimately, to significantly reduce the incidence of serious injury. METHODS: Data were abstracted from medical records of patients treated for work-related amputations at Michigan hospitals in 2008 and linked to workers' compensation claims data. Incidents occurring at specific high-risk industries were referred to the Michigan Occupational Safety and Health Administration for potential worksite inspection. RESULTS: A total of 616 Michigan residents sustained a work-related amputation (13.6/100,000 workers). Rates were highest for men, workers aged 20 to 24 years, and those in paper and wood product manufacturing. The Michigan Occupational Safety and Health Administration conducted 39 enforcement inspections in response to specific amputations. CONCLUSIONS: The surveillance system identified more than twice the number of work-related amputations as estimated by the Bureau of Labor Statistics (N = 250) in 2008 and was the impetus for many worksite inspections that otherwise may not have occurred. PMID- 23439272 TI - The impact of various work schedules on sleep complaints and minor accidents during work or leisure time: evidence from a national survey. AB - OBJECTIVE: To explore the prevalence of insomnia symptoms and excessive daytime sleepiness (EDS) in different work schedules and the impact of shift schedules on the risk of minor accidents during work or leisure time. METHODS: Using the data from Taiwan Social Development Trend Survey in 2005 (n = 18,794), insomnia symptoms, EDS, and minor accidents were analyzed using descriptive statistics and multivariable logistic regression model. RESULTS: The evening-to-night group had significantly higher prevalence rates of insomnia symptoms. Higher prevalence rate of EDS was presented in both day-to-evening and evening-to-night groups. Adjusting for confounders, the day-to-evening shift had a higher odds ratio of minor accidents as compared with the fixed daytime workers. CONCLUSIONS: Extended shift workers tend to experience insomnia symptoms and EDS and have an increased likelihood of minor accidents. PMID- 23439273 TI - Temporal and energetic characteristics of behavior predicting long-term job strain, job demands, and job control: a population-based study. AB - OBJECTIVE: To examine whether temporal and energetic characteristics of behavior contribute to perceived job strain and its components. METHODS: There were 611 participants (273 men) aged 30 to 45 years. Temperament traits were measured by Strelau's Formal Characteristics of Behavior-Temperament Inventory in 1997 and 2001. Job characteristics, education, and occupation were reported in 2001 and 2007. RESULTS: We found that higher emotional reactivity and perseveration, and lower briskness, endurance, and activity, predicted higher long-term perceived job strain in men and women. Higher job demands were predicted by lower endurance, higher emotional reactivity, and higher perseveration. Higher long term job control was predicted by higher briskness, endurance, activity, and lower perseveration and emotional reactivity. CONCLUSIONS: Being emotionally highly reactive and having a persevering temperament may increase the likelihood of high job strain, whereas having a brisk, enduring, and active temperament may decrease it. PMID- 23439274 TI - A cost-effectiveness and return-on-investment analysis of a worksite vitality intervention among older hospital workers: results of a randomized controlled trial. AB - OBJECTIVE: To conduct a cost-effectiveness and return-on-investment analysis comparing a worksite vitality intervention with usual care. METHODS: A total of 730 older hospital workers were randomized to the intervention or control group. The 6-month intervention consisted of yoga and aerobic exercising, coaching, and fruit. At baseline, and 6 and 12 months, general vitality, work-related vitality, and need for recovery were determined. Cost data were collected on a 3-monthly basis. The cost-effectiveness analysis was performed from the societal perspective and the return-on-investment analysis from the employer's perspective using bootstrapping techniques. RESULTS: No significant differences in costs and effects were observed. Incremental cost-effectiveness ratios in terms of general vitality (range, 0 to 100), work-related vitality (range, 0 to 6), and need for recovery (range, 0 to 100) were, respectively, ?280, ?7506, and ?258 per point improvement. Per euro invested, ?2.21 was lost. CONCLUSIONS: The intervention was neither cost-effective nor cost-saving. PMID- 23439275 TI - Cerebral oximetry in cardiac and major vascular surgery. AB - We describe the development and current applications of cerebral oximetry (based on near-infrared reflectance spectroscopy) that can be used during cardiac and major vascular surgery to determined brain tissue oxygen saturation. There are presently three cerebral oximetry devices with FDA approval in the United States to measure and monitor cerebral tissue oxygen saturation. 1. INVOS (Somanetics Corporation, Troy, MI - recently COVIDIEN, Boulder, CO); FORE-SIGHT (CAS Medical Systems, Inc. Branford, CT); EQUANOX (Nonin Medical Inc.Minnesota, MN). All devices are portable, non-invasive and easy to use in operating room and intensive care unit. The data provided in these communication may provided information for improvement of perioperative neuromonitoring techniques, and may be crucial in the design of future clinical trials. PMID- 23439276 TI - Current state of the reimplantation technique (DAVID Operation): surgical details and results. AB - Valve-sparing operations are becoming more and more popular because they allow a repair of the native aortic valve and a replacement of the diseased aortic root and the ascending aorta. Previously these patients were treated with a valved conduit and needed anticoagulation with warfarin if a mechanical valve was used or were left with uncertain long-term durability if a biological valve was used. There are two different types of valve-sparing operations available (reimplantation and remodeling technique). Of these two techniques, the reimplantation technique has several advantages but is also technically more demanding. Therefore this paper describes surgical details of the reimplantation technique and the potential pitfalls as well as some results. PMID- 23439277 TI - Mannose binding lectin (mbl2) haplotype frequencies in solid organ transplant patients and correlation with MBL protein levels--evaluation of complement mediated effector pathway deficiency. AB - Mannose-binding lectin (MBL) is a protein critical in activating complement. Patients with wild-type and variant mbl2 genotypes have high or low concentrations of MBL protein, which is known to increase susceptibility to transplant rejection or infection, respectively. Our objective was to determine mbl2 genotype frequencies in future solid organ transplant recipients in order to optimize their induction and maintenance immunosuppressive therapies, and to provide MBL reference data for this unique population. We genotyped 1687 patients, and concurrently measured protein in 807 of them, during 2010-2011. Frequencies of the structural allele SNPs in our population were similar to those of other studied populations; however, Black patients with the same intermediate and deficient mbl2 genotypes as Caucasians produced significantly lower levels of MBL protein; therefore, within this population more genotypes should be considered MBL-deficient. Overall, the most critical parameter in determining serum MBL protein concentration was genotype, which was independent of other factors including ethnicity, gender, or diseased native organ type. PMID- 23439278 TI - Coronary artery surgery: now and in the next decade. AB - In coronary artery surgery the superiority of the internal mammary artery graft in 10-year survival was documented in 1986. In 1999 it was demonstrated that death, reoperation and percutaneous transluminary coronary angioplasty were more frequent in patients undergoing single rather than bilateral internal mammary artery grafting. Today coronary artery bypass grafting surgery is challenged by the success story of modern interventional cardiology. The Syntax Study, however, clearly underlined the better outcome for patients with triple-vessel and/or left main disease undergoing coronary artery bypass grafting in terms of repeat revascularization. Another point of ongoing discussion is the comparison between on-pump and off-pump coronary artery revascularization techniques. Even if mixed results exists in the literature, in experienced hands the combination of aortic no-touch and total arterial revascularization, probably leads to the superiority in off pump coronary artery bypass grafting in terms of significantly decreased rates of mortality, stroke, major adverse cardiac and cerebral vascular events. Coronary artery surgery in the next decade will be influenced by the further progression of minimally invasive surgical principles and by a variety of other factors. The role of robotics and hybrid surgery has yet to be defined. Alternatives within surgery will not only need to move to a less disruptive strategy (e.g. from on-pump to off-pump bypass) but also have to secure sustained innovation, as we can be sure that the current coronary artery bypass grafting activity will change substantially. PMID- 23439279 TI - Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. AB - Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS. PMID- 23439280 TI - Impact of simulated microgravity on the normal developmental time line of an animal-bacteria symbiosis. AB - The microgravity environment during space flight imposes numerous adverse effects on animal and microbial physiology. It is unclear, however, how microgravity impacts those cellular interactions between mutualistic microbes and their hosts. Here, we used the symbiosis between the host squid Euprymna scolopes and its luminescent bacterium Vibrio fischeri as a model system. We examined the impact of simulated microgravity on the timeline of bacteria-induced development in the host light organ, the site of the symbiosis. To simulate the microgravity environment, host squid and symbiosis-competent bacteria were incubated together in high-aspect ratio rotating wall vessel bioreactors and examined throughout the early stages of the bacteria-induced morphogenesis. The host innate immune response was suppressed under simulated microgravity; however, there was an acceleration of bacteria-induced apoptosis and regression in the host tissues. These results suggest that the space flight environment may alter the cellular interactions between animal hosts and their natural healthy microbiome. PMID- 23439281 TI - Alteration in respiratory physiology in obesity for anesthesia-critical care physician. AB - Obesity is known to be a major risk factor of a whole range of cardiovascular, metabolic and respiratory disorders. The pattern of regional fat distribution plays an important role in the pre-disposition of obese subjects to respiratory complications. Obesity is responsible for important changes in respiratory function both during spontaneous breathing as well as during general anesthesia and mechanical ventilation. The most characteristic abnormalities consist of decreased functional residual capacity, reduced expiratory reserve volume, decreased compliance and increased resistance of the respiratory system. Breathing at low lung volume promotes airway closure in the dependent lung zones with consequent gas exchange abnormalities even though lung carbon monoxide diffusing capacity is normal or increased. Weight loss can reduce many of the alterations in pulmonary function related to obesity. PMID- 23439283 TI - Institutional response to FDA warning on aprotinin and impact on outcomes. AB - INTRODUCTION: New evidence of potential risks of aprotinin in 2006 generated public concern about a previously approved drug that was routinely used. In response, we assembled a team of experts within the institution to form guidelines for the appropriate use of aprotinin in cardiac surgery. We report the basis for the guidelines, their implementation, follow-up and resulting patterns of change in aprotinin use. METHODS: We proposed a three-tier system for aprotinin use, according to risk of bleeding and transfusion, and evidence of benefit of aprotinin. Specific recommendations were made with regard to discussion with the patient and documentation regarding aprotinin use and options for patients who refuse the drug. Guidelines were disseminated and accessible on all anesthesia workstations. Aprotinin use was compared before and after institution of guidelines in equivalent categories. RESULTS: Aprotinin was used in 58.5% (469/802) of cases from March 2005 to January 2006. Following institution of guidelines from March 2006 to January 2007, aprotinin was used in 19.7% (151/767) cases representing a 67.8% reduction in usage. In the subset of groups with large reductions in aprotinin use (pre- 82%, n=239; post-guidelines 17%, n=241) there was a significant decrease in acute kidney injury (%?Cr 43.8 vs. 31.7%, p=0.05). CONCLUSIONS: In response to new data and regulatory guidelines, we formulated guidelines based on expert review of data. We reduced aprotinin use, but more importantly, introduced an evidence-based approach to the use of aprotinin, consistent with regulatory guidelines. This model of guideline implementation can be useful in similar scenarios. PMID- 23439282 TI - Hybrid reduced graph for SAR studies. AB - The purpose of this work is the definition and evaluation of both atomic and local new hybrid indices. Inspired by the Refractotopological State Index for Atoms, the new atomic indices are theoretically supported by graph theory principles. The local indices, named Descriptor Centres (DCs), are obtained from the sum of the atomic values of the atoms in the selected group. Different classifiers were used for structure-activity relationship (SAR) studies, including multilayer perceptron (MLP), support vector machines (SVM) and meta classifiers. Prediction with SVM and MLP was around 60%, but the best result was obtained with the meta-classifiers, bagging, decorate and others, with more than 92% accurate prediction. These new hybrid descriptors derived from the Refractotopological State Index for Atoms show a low mutual correlation coefficient. The same behaviour is found in the analogously defined Descriptors Centres. The best results are obtained with the inclusion of the distance between DCs with the use of meta-classifiers. PMID- 23439284 TI - Multivessel coronary artery disease: atheroma progression and dynamic component. AB - Multivessel or multisegment spasm in patients with known widespread coronary atherosclerotic disease is an infrequent occurrence. We describe a prolonged spasm of both the left main and the left anterior descending artery in a patient with chronic effort angina and multivessel coronary artery disease, who previously underwent percutaneous coronary intervention and drug eluting stents implantation. The patient complained of episodes of angina and palpitations, mainly at rest. Exercise stress test resulted positive in therapeutic wash-out. Coronary angiography was performed which showed: 80% stenosis in the proximal segment of the Left Main (LM) and the mid Left Anterior Descending artery (LAD), 90% stenosis of the Posterior Descending Artery (PDA); there was no angiographic evidence of instent restenosis in the previously stented segments. Coronary Artery By-pass Graft (CABG) was proposed, but the patient refused surgery. Reperfusion strategy included coronary angioplasty of the LM and the LAD. Before the procedure, in the presence of ischemic EKG changes, nitrates were infused in the left coronary artery with resolution of both the LM and LAD stenoses. However, intracoronary nitrates in the right coronary artery did not resolve the PDA stenosis. The patient underwent angioplasty and stenting of the PDA alone. Selective spasm involving two anatomically different segments is rare. The left main location is critical since it can lead to unnecessary coronary artery by pass. Intracoronary nitrates should be administered before invasive strategies are advised. PMID- 23439285 TI - Characterisation of avian Pasteurella multocida strains with PCR-RFLP analysis of the ompH gene. AB - The 16 somatic serotype type strains and 60 field isolates of Pasteurella multocida, representing various avian species and geographic regions in Hungary, were characterised by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis of the ompH gene with DraI restriction endonuclease. The type strains yielded eight different (I-VIII) profiles. Strains whose PCR fragment was uncut by DraI (profile IV) could be differentiated with HindIII and PvuII restriction endonucleases. Five of the eight PCR-RFLP profiles (I, III, V, VI and VII) were detected among the field strains. Only a correlation of limited strength was found between the classical somatic serotypes and the PCR-RFLP profiles. However, the results confirmed that molecular methods could confidently distinguish serotype A:1 strains from the other serotypes. Moreover, the specific relationship between somatic serotypes and PCR-RFLP types among isolates from turkey raises the possibility of the existence of host-specific clones within the P. multocida population. PMID- 23439286 TI - Magnetic resonance imaging and brainstem auditory evoked responses in the diagnosis of cerebellar cortical degeneration in american staffordshire terriers. AB - The aim of the study was to determine the diagnostic usefulness of magnetic resonance imaging (MRI) and brainstem auditory evoked responses (BAER) in dogs suspected of having cerebellar cortical degeneration (CCD). In the years 2009 2011, six dogs with suspected CCD were examined. Both MRI and BAER examinations revealed abnormalities in all dogs (100%). By MRI, T2-weighted midsagittal images revealed an increased amount of cerebrospinal fluid (CSF) surrounding the cerebellum within the sulci of the folia in all dogs (100%). In 4 out of the 6 dogs (66.66%), cerebellar hypoplasia was more visible in the region of the dorsal cerebellar lobules. In 5 out of the 6 dogs (83.33%), the fourth ventricle was enlarged. In our studies, the brain to cerebellum ratio evaluated on the midsagittal image was 11.93%, in comparison to 14.9% in normal dogs. By BAER examination, the amplitude of the first and second waves was diminished and III-V interlatency was prolonged in 5 out of the 6 dogs (83.33%). In one out of the 6 dogs (16.67%), only the III-V interlatency was prolonged. In one dog (16.67%), somato-nervous deafness in the left ear was detected, whereas in the right ear the III-V interlatency was prolonged. MRI of the cerebellum is a reliable method for the antemortem diagnosis of CCD in American Staffordshire terriers, as is BAER examination. BAER is an objective diagnostic tool, which - along with other diagnostic modalities - can be helpful in the assessment, management and follow up of dogs with cerebellar abiotrophy. It proved to be useful in determining the severity of neurological lesions in comparison to MRI findings, as well as in assessing the prognosis. PMID- 23439287 TI - Comparison of traditional and sensor-based electronic stethoscopes in beagle dogs. AB - The objective of this study was to compare the auscultatory findings using traditional and electronic sensor-based stethoscopes. Thirty-three adult healthy Beagles (20 females, 13 males, mean age: 4.8 years, range 1.4-8 years) were auscultated by four investigators with different experiences (INVEST-1, -2, -3 and -4) independently with both stethoscopes. Final cardiological diagnoses were established by echocardiography. Mitral murmurs were heard with both stethoscopes by all investigators and echocardiography revealed mild mitral valve insufficiency in 7 dogs (21%, 4 females, 3 males). The statistical sensitivity (Se) in recognising cardiac murmurs proved to be 82% using the traditional stethoscope and 75% using the electronic one in the mean of the four examiners, whilst statistical specificity (Sp) was 99% by the traditional and 100% by the electronic stethoscope. The means of the auscultatory sensitivity differences between the two stethoscopes were 0.36 on the left and 0.59 on the right hemithorax, demonstrating an advantage for the electronic stethoscope being more obvious above the right hemithorax (P = 0.0340). The electronic stethoscope proved to be superior to the traditional one in excluding cardiac murmurs and especially in auscultation over the right hemithorax. Mitral valve disease was relatively common in this clinically healthy research Beagle population. PMID- 23439288 TI - Molecular identification and phylogenetic characterisation of Thelohanellus kitauei - short communication. AB - Thelohanellus kitauei was isolated from the koi Cyprinus carpio haematopterus, and the 18S rRNA gene of T. kitauei was amplified by optimised nested-PCR. The PCR product was sequenced and compared with other 18S rRNA genes of Thelohanellus species to investigate the relationships between their host specificities and infection sites. Based on the 18S rRNA sequences, T. kitauei is most closely related to T. hovorkai (which can infect the intestine). Phylogenetic analysis revealed that T. kitauei was clustered with other Thelohanellus spp. infecting Cyprininae. The present study suggests that the infection site and the host specificity (subfamily level) are reflected in the genetic relationships among Thelohanellus species. PMID- 23439289 TI - Histopathological changes caused by the nymph stage of Linguatula serrata in the mesenteric lymph nodes of goats. AB - Linguatula serrata (Frohlich, 1789) is a ubiquitous parasite species belonging to pentastomids, which has been reported frequently from domestic herbivores of Iran. This study was carried out to elucidate the pathological changes caused by the nymphal stage of L. serrata in the mesenteric lymph nodes (MLNs) of goats. Jejunal and ileal MLNs of slaughtered goats infected with L. serrata were collected and fixed in 10% neutral formal saline. Histopathological changes included follicular necrosis accompanied by a loss of lymphocytes and oedematous cystlike spaces. Granulomatous lesions were formed by mononuclear cell infiltration and necrotic tissue. Some lymphocytes were apoptotic with chromatolysis. A more frequent vascular abnormality was vasculitis. These findings show that larval migration is the main factor to initiate trauma and cause irritation in the MLNs of goats. Since goats are habitual intermediate hosts in Iran, rigorous inspection of the MLNs of slaughtered goats is recommended in order to decrease the chance of human infection through the consumption of raw visceral organs of goats. PMID- 23439290 TI - Molecular evidence of Ehrlichia canis and Rickettsia massiliae in ixodid ticks of carnivores from South Hungary. AB - To monitor the emergence of thermophilic, Mediterranean ixodid tick species and tick-borne pathogens in southern Hungary, 348 ticks were collected from shepherd dogs, red foxes and golden jackals during the summer of 2011. Golden jackals shared tick species with both the dog and the red fox in the region. Dermacentor nymphs were collected exclusively from dogs, and the sequence identification of these ticks indicated that dogs are preferred hosts of both D. reticulatus and D. marginatus nymphs, unlike previously reported. Subadults of three ixodid species were selected for reverse line blot hybridisation (RLB) analysis to screen their vector potential for 40 pathogens/groups. Results were negative for Anaplasma, Babesia and Theileria spp. Investigation of D. marginatus nymphs revealed the presence of Ehrlichia canis, Rickettsia massiliae and Borrelia afzelii for the first time in this tick species. These findings broaden the range of those tick borne agents, which are typically transmitted by Rhipicephalus sanguineus, but may also have Dermacentor spp. as potential or alternative vectors. Ehrlichiacanis was also newly detected in Ixodes canisuga larvae from red foxes. In absence of transovarial transmission in ticks this implies that Eurasian red foxes may play a reservoir role in the epidemiology of canine ehrlichiosis. PMID- 23439291 TI - Granulomatous pneumonia and hepatitis associated with Providencia rettgeri infection in a crocodile monitor lizard (Varanus salvadorii). AB - The present report describes a case of granulomatous pneumonia and hepatitis in a male crocodile monitor lizard (Varanus salvadorii). During the necropsy of the monitor lizard, multifocal to coalescing pale yellow lesions were observed in both lung lobes, as well as similar, though milder, changes in the liver, and an ulcerative lesion on the food pad of the right hindlimb. Histopathologically, the presence of multiple necrotising, chronic granulomas containing bacterial clumps were observed in the parenchyma of the lung and the liver. By microbiological examination of the pathologically altered lung tissues, Providencia rettgeri was identified. Altogether, our findings indicate that the bacterial infection resulting in extensive chronic necrotising granulomatous inflammation was the primary cause of the reptile's death. To our knowledge, this is the first report of Providencia rettgeri-associated granulomatous pneumonia and hepatitis in the monitor lizard. PMID- 23439292 TI - Influence of rumen-protected choline on liver composition and blood variables indicating energy balance in periparturient dairy cows. AB - Rumen-protected choline (RPC) was evaluated for effects on the lipid and glycogen content of the liver and metabolic variables in the blood plasma of dairy cows. Thirty-two Holstein cows were allocated into two groups (RPC group with RPC supplementation and control group without RPC supplementation) 28 days before the expected calving. Cows were fed the experimental diet from 21 days before calving until day 60 of lactation. The diet of the RPC group was supplemented with 100 g/day of RPC from 21 days prepartum until calving and 200 g/day of RPC for 60 days postpartum, providing 25 and 50 g of choline, respectively. Liver samples were taken by percutaneous needle biopsy, then analysed for total lipid (TLl), triglyceride (TGl) and glycogen (GLYl) contents on days -21, +7, +35 and +60 relative to calving. Blood was collected on the same sampling days and 21 days after calving. Glucose, non-esterified fatty acid (NEFA), beta-hydroxybutyrate (BHBA), triglyceride (TGp), total cholesterol (TCh), urea, ammonia and aspartate aminotransferase (AST) were determined from blood samples. The TLl and TGl contents were 25.0 +/- 4.3 g and 25.3 +/- 3.8 g per kg wet weight (mean +/- SEM), respectively, lower in the RPC group than in the control animals. No significant differences were observed in the GLYl concentrations between the two groups. However, a lower TGl: GLYl ratio was shown in the liver of cows fed the RPC diet as compared to the controls. RPC supplementation decreased BHBA while increasing TGp concentrations were shown in the blood of cows fed the RPC diet, possibly as a consequence of improved lipoprotein synthesis in, and triglyceride excretion from, the liver, together with a reduced rate of ketogenesis. PMID- 23439293 TI - Milk production, raw milk quality and fertility of dromedary camels (Camelus Dromedarius) under intensive management. AB - In many arid countries, dromedaries play an important role as a milk source in rural areas. However, the milk and meat production potential of this species is not well understood and documented. A large-scale camel dairy farm was established in 2006 in the United Arab Emirates. This study summarises the most important data on milk production, raw milk quality and reproductive efficiency collected on this farm during the first three years of operation. The average daily milk production, the mean length of lactation and the mean total milk production per lactation of 174 dromedaries were 6.0 +/- 0.12 kg (+/- SEM), 586 +/- 11.0 days (+/- SEM) and 3314 +/- 98.5 kg (+/- SEM), respectively. The lactation curve reached its peak during the 4th month after parturition (mean +/- SEM, 8.9 +/- 0.04 kg), then it declined gradually, falling to 50% of the maximum by the 16th month postpartum (mean +/- SEM, 4.3 +/- 0.06 kg). Milking three times a day did not increase daily milk production compared to two times milking. Mean total viable bacterial count (TVC) and mean somatic cell count (SCC, +/- SEM) of bulk raw camel milk were 4,403 +/- 94 CFU/cm3 and 392,602 +/- 5,999 cells/cm3 for a one-year period, respectively. There was a significant difference among months (P < 0.001). Coliform count was < 10 CFU/cm3 in most cases (96.5%). The average (+/- SEM) fat, protein, lactose, total solids (TS) and solid-non-fat (SNF) concentrations of individual milk samples were 2.51 +/- 0.03%, 2.60 +/- 0.01%, 4.03 +/- 0.03%, 9.98 +/- 0.03% and 7.56 +/- 0.03%, respectively. Lactation period, average daily milk production and morning vs. evening milking significantly influenced milk chemical composition. For the 470 camels in the breeding programme, end-of-season pregnancy rate and birth rate were 87.0% and 82.6%, respectively, after natural mating. We have demonstrated that sustainable milk production is possible from a traditional species, the dromedary camel, under an intensive management system. PMID- 23439294 TI - Daidzein affects steroidogenesis and oestrogen receptor expression in medium ovarian follicles of pigs. AB - Daidzein, a phytoestrogen present in soybean products used in swine feed, has been demonstrated to affect both reproductive and endocrine functions. The aims of this study were to examine the in vitro effects of daidzein on (1) progesterone (P4) and oestradiol (E2) secretion by porcine luteinised granulosa cells harvested from medium follicles, and (2) the mRNA and protein expression of oestrogen receptors alpha and beta (ERalpha and ERbeta) in these cells. The influence of E2 on P4 secretion and ERalpha and ERbeta expression in the granulosa cells of pigs was also investigated. It was found that daidzein inhibited progesterone secretion by luteinised granulosa cells isolated from medium follicles. In contrast, E2 did not affect progesterone production by these cells. Moreover, daidzein did not alter the granulosal secretion of E2. Both daidzein and E2 decreased mRNA expression of ERalpha in the cells examined. The expression of ERbeta mRNA was not affected by daidzein but was inhibited by E2. ERalpha protein was not detected while ERbeta protein was found in the nuclei of the cells. Daidzein and E2 upregulated the expression of ERbeta protein in the cells. In summary, the phytoestrogen daidzein directly affected the porcine ovary by inhibiting progesterone production and increasing ERbeta protein expression. Daidzein-induced changes in follicular steroidogenesis and granulosal sensitivity to oestrogens may disturb reproductive processes in pigs. PMID- 23439295 TI - Differential expression of GDF9, TGFB1, TGFB2 and TGFB3 in porcine oocytes isolated from follicles of different size before and after culture in vitro. AB - The TGFB superfamily genes are involved in several important cell functions, including proliferation and differentiation, and the role of the expression of these genes in growth and development of theca and granulosa cells is well recognised. However, the dependence between the stage of oocyte maturation or follicular size and the expression of these genes in pigs is still not entirely known. This study was aimed at investigating the expression pattern of GDF9, TGFB1, TGFB2 and TGFB3 in porcine oocytes before and after in vitro maturation (IVM) as well as in oocytes collected from follicles of different sizes. RQ-PCR was performed to analyse the expression of GDF9, TGFB1, TGFB2 and TGFB3 in oocytes before and after IVM (oocytes cultured for 44 h in TCM-199), isolated from large (> 5 mm), medium (3-5 mm) and small (< 3 mm) follicles collected from ovaries of 28 puberal crossbred Landrace gilts after slaughter. We found an increased expression of both TGFB1 and TGFB2 in oocytes before IVM collected from large as compared to medium and small follicles (P < 0.05, P < 0.001, P < 0.01, P < 0.05, respectively). In these groups of oocytes we did not observe differences in GDF9 and TGFB3 mRNA levels. However, after IVM, GDF9 protein distribution in oocytes was significantly higher in large and medium follicles as compared to small ones (P < 0.01, P < 0.001, respectively). Moreover, an increased TGFB1, TGFB2 and TGFB3 proteins pattern was observed in oocytes of large compared to small follicles. The highest GDF9 and TGFB1 mRNA levels were found in oocytes after IVM compared to those before IVM. Based on our study we can suppose that the distribution pattern of TGFB superfamily genes is associated with the stage of maturation of porcine oocytes and the follicle size. Furthermore, GDF9 and TGFB1 may serve as molecular markers of the develop-mental potential of porcine oocytes. The confocal microscopic observation revealed that TGFB1 and TGFB3 were translocated between the zona and the cytoplasm of oocytes, depending on the stage of maturation and follicle size. PMID- 23439296 TI - Use of retinyl acetate, retinoic acid and insulin-like growth factor-I (IGF-I) to enhance goat embryo production. AB - Experiments were carried out to investigate the beneficial effects of retinyl acetate (RAc) and retinoic acid (RA) on goat oocyte maturation as well as the effects of insulin-like growth factor-I (IGF-I), RAc and RA during embryo culture under chemically defined conditions. In Experiment 1, in vitro maturation (IVM) was performed in a chemically defined basic maturation medium (bMM) supplemented with 0.3 MUM RAc or 0.5 MUM RA. Presumptive zygotes and embryos (2-4 cells) were cultured in droplets of potassium simplex optimised medium (KSOM); however, none of the embryos reached the blastocyst stage. In Experiment 2, oocytes were matured in bMM + RAc or bMM + RA. Presumptive zygotes and 2- to 4-cell embryos were placed in fresh KSOM droplets supplemented with RAc, RA, IGF-I, RAc+IGF-I or RA+IGF-I. In Experiment 1, addition of RAc and RA to bMM increased (P < 0.05) the proportion of 2- to 4-cell embryos reaching the morula stage as compared to the control. In Experiment 2, supplementation of embryo culture media with retinoids and IGF-I increased (P < 0.05) the proportion of 2- to 4-cell stage embryos developing to the morula and blastocyst stage. Our data demonstrate that goat embryo production in chemically defined media could be improved by exogenous RAc or RA and by the interaction between retinoids and IGF-I, and that goat embryos can be produced in vitro from oocytes following protocols similar to those currently used for cattle. PMID- 23439297 TI - Emergence and characterisation of pandemic H1N1 influenza viruses in Hungarian swine herds. AB - In 2010, two novel porcine H1N1 influenza viruses were isolated from pigs with influenza-like illness in Hungarian swine herds. Sequence and phylogenetic analysis of these strains revealed that they shared molecular features with the pandemic H1N1 influenza virus strains, which emerged globally during 2009. The PB2, HA and NA genes contained unique amino acid changes compared to the available new H1N1 influenza virus sequences of pig origin. Furthermore, the investigated strains could be separated with respect to parallel amino acid substitutions affecting the polymerase genes (PB2, PB1 and PA) and the nucleoprotein (NP) gene, supporting the proposed complementarities between these proteins, all required for the viral fitness. Molecular characterisation of two Hungarian human pandemic H1N1 isolates was also performed, so that we could compare contemporaneous strains of different host species origins. Shared molecular motifs in various genes of animal and human influenza strains suggested that the Hungarian porcine strains could have originated from humans through direct interspecies transmission. This study is among the few that support the natural human-to-pig transmission of the pandemic H1N1 influenza virus. PMID- 23439298 TI - Molecular and genetic characteristics of small ruminant lentiviruses in Slovenia. AB - Small ruminant lentiviruses (SRLV) are spread throughout the world, including Slovenia, where the first evidence of caprine arthritis encephalitis virus (CAEV) infection was found in 1996. This study was conducted to investigate the molecular and genetic characteristics of SRLV infection in Slovenia in order to classify our strains in relation to other known SRLV strains worldwide as well as to establish molecular techniques in concordance with serology. In this study, 340 goats and sheep were tested. Serological examination revealed that 57% of the goats and only 14% of the sheep were seropositive. The results of this study also show that the polymerase chain reaction (PCR) used in this study is less reliable than ELISA, with only 60.6% of the seropositive animals being PCR positive. Thirty-eight nucleotide sequences of the gag region encoding the matrix protein were determined and compared to sequences derived from the GenBank, revealing that Slovenian SRLV strains belong to sequence groups A and B, being maedivisna virus (MVV) and CAEV-like, respectively. In one goat herd, the presence of more than one genotype was confirmed and the majority of goat SRLV sequences were more closely related to MVV than to CAEV prototype strains. PMID- 23439299 TI - Model of haplotype and phenotype in the evolution of a duplicated autoregulatory activator. AB - Gene duplication is believed to play a major role in the evolution of genomic complexity. The presence of a duplicate frees a gene from the constraint of natural selection, leading to its loss of function or the gain of a novel one. Alternately, a pleiotropic gene might partition its functions among its duplicates, thus preserving both copies. Such arguments invoking duplication for novelty or specialisation are not qualitatively true of diploid genotypes, but only of haplotypes. In this paper, we study the consequences of regulatory interactions in diploid genotypes and explore how the context of allelic interactions gives rise to dynamical phenotypes that enable duplicate genes to spread in a population. The regulatory network we study is that of a single autoregulatory activator gene, and the two copies of the gene diverge either as alleles in a diploid species or as duplicates in haploids. These differences are in their transcriptional ability-either via alterations to its activating domain, or to its cis-regulatory binding repertoire. When cis-regulatory changes are introduced that partition multiple regulatory triggers among the duplicates, it is shown that mutually exclusive expression states of the duplicates that emerge are accompanied by a back-up facility: when a highly expressed gene is deleted, the previously unexpressed duplicate copy compensates for it. The diploid version of the regulatory network model can account for allele-specific expression variants, and a model of inheritance of the haplotype network enables us to trace the evolutionary consequence of heterozygous phenotypes. This is modelled for the variations in the activating domain of one copy, whereby stable as well as transiently bursting oscillations ensue in single cells. The evolutionary model shows that these phenotypic states accessible to a diploid, heterozygous genotype enable the spread of a duplicated haplotype. PMID- 23439300 TI - Thalamic deep brain stimulation for orthostatic tremor. AB - BACKGROUND: Orthostatic tremor is an uncommon disorder manifest by high frequency, low amplitude leg tremor upon weight bearing. Treatment with oral tremor agents is inconsistent and usually not satisfactory. METHODS: We implanted bilateral ventralis intermedius nuclei deep brain stimulators into an 82-year-old male with refractory orthostatic tremor. RESULTS: The patient had a marked subjective and objective improvement in leg and arm tremor, mainly manifested by an improved ability to stand. DISCUSSION: Bilateral thalamic deep brain stimulation may be considered in refractory cases of orthostatic tremor. PMID- 23439301 TI - Autoantibodies and autoimmune disease during treatment of children with chronic hepatitis C. AB - OBJECTIVES: Autoantibodies were studied in a well-characterized cohort of children with chronic hepatitis C during treatment with pegylated interferon and ribavirin to assess the relation with treatment and development of autoimmune disease. METHODS: : A total of 114 children (5-17 years), screened for the presence of high-titer autoantibodies, were randomized to pegylated interferon with or without ribavirin. Anti-nuclear, anti-liver-kidney-microsomal, anti thyroglobulin, anti-thyroid peroxidase, insulin, anti-glutamic acid decarboxylase (GAD) antibodies were measured after trial completion using frozen sera. RESULTS: At baseline, 19% had autoantibodies: anti-nuclear antibodies (8%), anti-liver kidney-microsomal antibodies (4%), and glutamic acid decarboxylase antibodies (4%). At 24 and 72 weeks (24 weeks after treatment completion), 23% and 26% had autoantibodies (P=0.50, 0.48 compared with baseline). One child developed diabetes and 2 hypothyroidism during treatment; none developed autoimmune hepatitis. At 24 weeks, the incidence of flu-like symptoms, gastrointestinal symptoms, and headaches was 42%, 8% and 19% in those with autoantibodies versus 52%, 17%, and 26% in those without (P=0.18, 0.36, and 0.20, respectively). In children with negative hepatitis C virus polymerase chain reaction at 24 weeks, there was no difference in the rate of early virologic response/sustained virologic response, respectively, in those with autoantibodies 76%/69% vs 58%/65% in those without (P=0.48). CONCLUSIONS: Despite screening, we found autoantibodies commonly at baseline, during treatment for chronic hepatitis C and after. The presence of antibodies did not correlate with viral response, adverse effects, or autoimmune hepatitis. Neither screening nor archived samples assayed for thyroid and diabetes-related antibodies identified the 3 subjects who developed overt autoimmune disease, diabetes (1), and hypothyroidism (2). PMID- 23439302 TI - The actin-polymerizing activity of SipA is not essential for Salmonella enterica serovar Typhimurium-induced mucosal inflammation. AB - Salmonella enterica serovar Typhimurium depends on type III secretion systems to inject effector proteins into host cells to promote bacterial invasion and to induce intestinal inflammation. SipA, a type III effector, is known to play important roles in both the invasion and the elicitation of intestinal inflammation. The actin-modulating activity of SipA has been shown to promote Salmonella entry into epithelial cells. To investigate whether the actin modulating activity of SipA is required for its ability to induce an inflammatory response in vivo, we generated the SipA(K635A E637W) mutant, which is deficient in actin-modulating activity. Salmonella strains expressing the chromosomal SipA(K635A E637W) point mutation had reduced invasion abilities but still caused colitis similar to that caused by the wild-type strain in a mouse model of infection. Our data indicate that the SipA actin-polymerizing activity is not essential for the SipA-induced inflammatory response in the mouse model of infection. PMID- 23439303 TI - Virulence of the Shiga toxin type 2-expressing Escherichia coli O104:H4 German outbreak isolate in two animal models. AB - In May 2011, a large food-borne outbreak was traced to an unusual O104:H4 enteroaggregative Escherichia coli (EAEC) strain that produced Shiga toxin (Stx) type 2 (Stx2). We developed a mouse model to study the pathogenesis and treatment for this strain and examined the virulence of the isolate for Dutch belted rabbits. O104:H4 strain C227-11 was gavaged into C57BL/6 mice at 10(9) to 10(11) CFU/animal. The infected animals were then given water with ampicillin (Amp; 5 g/liter) ad libitum. The C227-11-infected, Amp-treated C57BL/6 mice exhibited both morbidity and mortality. Kidneys from mice infected with C227-11 showed acute tubular necrosis, a finding seen in mice infected with typical Stx producing E. coli. We provided anti-Stx2 antibody after infection and found that all of the antibody-treated mice gained more weight than untreated mice and, in another study, that all of the antibody-treated animals lived, whereas 3/8 phosphate-buffered saline-treated mice died. We further compared the pathogenesis of C227-11 with that of an Stx-negative (Stx(-)) O104:H4 isolate, C734-09, and an Stx2(-) phage-cured derivative of C227-11. Whereas C227-11-infected animals lost weight or gained less weight over the course of infection and died, mice infected with either of the Stx(-) isolates did not lose weight and only one mouse died. When the Stx-positive (Stx(+)) and Stx2(-) O104:H4 strains were compared in rabbits, greater morbidity and mortality were observed in rabbits infected with the Stx2(+) isolates than the Stx2(-) isolates. In conclusion, we describe two animal models for EAEC pathogenesis, and these studies show that Stx2 is responsible for most of the virulence observed in C227-11-infected mice and rabbits. PMID- 23439304 TI - Vitamin D regulation of OX40 ligand in immune responses to Aspergillus fumigatus. AB - OX40 ligand (OX40L) is a costimulatory molecule involved in Th2 allergic responses. It has been shown that vitamin D deficiency is associated with increased OX40L expression in peripheral CD11c(+) cells and controls Th2 responses to Aspergillus fumigatus in vitro in cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA). To investigate if vitamin D deficiency regulated OX40L and Th2 responses in vivo, we examined the effect of nutritional vitamin D deficiency on costimulatory molecules in CD11c(+) cells and A. fumigatus-induced Th2 responses. Vitamin D-deficient mice showed increased expression of OX40L on lung CD11c(+) cells, and OX40L was critical for enhanced Th2 responses to A. fumigatus in vivo. In in vitro assays, vitamin D treatment led to vitamin D receptor (VDR) binding in the promoter region of OX40L and significantly decreased the promoter activity of the OX40L promoter. In addition, vitamin D altered NF-kappaB p50 binding in the OX40L promoter that may be responsible for repression of OX40L expression. These data show that vitamin D can act directly on OX40L, which impacts Th2 responses and supports the therapeutic use of vitamin D in diseases regulated by OX40L. PMID- 23439305 TI - A double mutant heat-labile toxin from Escherichia coli, LT(R192G/L211A), is an effective mucosal adjuvant for vaccination against Helicobacter pylori infection. AB - Helicobacter pylori infection in the stomach is a common cause of peptic ulcer disease and is a strong risk factor for the development of gastric adenocarcinoma, yet no effective vaccine against H. pylori infection is available to date. In mice, mucosal vaccination with H. pylori antigens when given together with cholera toxin (CT) adjuvant, but not without adjuvant, can induce protective immune responses against H. pylori infection. However, the toxicity of CT precludes its use as a mucosal adjuvant in humans. We evaluated a recently developed, essentially nontoxic double mutant Escherichia coli heat-labile toxin, LT(R192G/L211A) (dmLT), as a mucosal adjuvant in an experimental H. pylori vaccine and compared it to CT in promoting immune responses and protection against H. pylori infection in mice. Immunization via the sublingual or intragastric route with H. pylori lysate antigens and dmLT resulted in a significant decrease in bacterial load after challenge compared to that in unimmunized infection controls and to the same extent as when using CT as an adjuvant. Cellular immune responses in the sublingually immunized mice known to correlate with protection were also fully comparable when using dmLT and CT as adjuvants, resulting in enhanced in vitro proliferative and cytokine responses from spleen and mesenteric lymph node cells to H. pylori antigens. Our results suggest that dmLT is an attractive adjuvant for inclusion in a mucosal vaccine against H. pylori infection. PMID- 23439306 TI - A heterologous prime-boost vaccination strategy comprising the Francisella tularensis live vaccine strain capB mutant and recombinant attenuated Listeria monocytogenes expressing F. tularensis IglC induces potent protective immunity in mice against virulent F. tularensis aerosol challenge. AB - Francisella tularensis, the causative agent of tularemia, is a category A bioterrorism agent. A vaccine that is safer and more effective than the currently available unlicensed F. tularensis live vaccine strain (LVS) is needed to protect against intentional release of aerosolized F. tularensis, the most dangerous type of exposure. In this study, we employed a heterologous prime-boost vaccination strategy comprising intradermally administered LVS DeltacapB (highly attenuated capB-deficient LVS mutant) as the primer vaccine and rLm/iglC (recombinant attenuated Listeria monocytogenes expressing the F. tularensis immunoprotective antigen IglC) as the booster vaccine. Boosting LVS DeltacapB-primed mice with rLm/iglC significantly enhanced T cell immunity; their splenic T cells secreted significantly more gamma interferon (IFN-gamma) and had significantly more cytokine (IFN-gamma and/or tumor necrosis factor [TNF] and/or interleukin-2 [IL 2])-producing CD4(+) and CD8(+) T cells upon in vitro IglC stimulation. Importantly, mice primed with LVS DeltacapB or rLVS DeltacapB/IglC, boosted with rLm/iglC, and subsequently challenged with 10 50% lethal doses (LD50) of aerosolized highly virulent F. tularensis Schu S4 had a significantly higher survival rate and mean survival time than mice immunized with only LVS DeltacapB (P < 0.0001); moreover, compared with mice immunized once with LVS, primed boosted mice had a higher survival rate (75% versus 62.5%) and mean survival time during the first 21 days postchallenge (19 and 20 days for mice boosted after being primed with LVS DeltacapB and rLVS DeltacapB/IglC, respectively, versus 17 days for mice immunized with LVS) and maintained their weight significantly better (P < 0.01). Thus, the LVS DeltacapB-rLm/iglC prime-boost vaccination strategy holds substantial promise for a vaccine that is safer and at least as potent as LVS. PMID- 23439307 TI - Staphylococcus aureus SasA is responsible for binding to the salivary agglutinin gp340, derived from human saliva. AB - Staphylococcus aureus is a major human pathogen that can colonize the nasal cavity, skin, intestine, and oral cavity as a commensal bacterium. gp340, also known as DMBT1 (deleted in malignant brain tumors 1), is associated with epithelial differentiation and innate immunity. In the oral cavity, gp340 induces salivary aggregation with several oral bacteria and promotes bacterial adhesion to tissues such as the teeth and mucosa. S. aureus is often isolated from the oral cavity, but the mechanism underlying its persistence in the oral cavity remains unclear. In this study, we investigated the interaction between S. aureus and gp340 and found that S. aureus interacts with saliva- and gp340-coated resin. We then identified the S. aureus factor(s) responsible for binding to gp340. The cell surface protein SasA, which is rich in basic amino acids (BR domain) at the N terminus, was responsible for binding to gp340. Inactivation of the sasA gene resulted in a significant decrease in S. aureus binding to gp340-coated resin. Also, recombinant SasA protein (rSasA) showed binding affinity to gp340, which was inhibited by the addition of N-acetylneuraminic acid. Surface plasmon resonance analysis showed that rSasA significantly bound to the NeuAcalpha(2 3)Galbeta(1-4)GlcNAc structure. These results indicate that SasA is responsible for binding to gp340 via the N-acetylneuraminic acid moiety. PMID- 23439308 TI - Porphyromonas gingivalis infection-associated periodontal bone resorption is dependent on receptor activator of NF-kappaB ligand. AB - Porphyromonas gingivalis is one of the oral microorganisms associated with human chronic periodontitis. The purpose of this study is to determine the role of the receptor activator of nuclear factor-kappaB ligand (RANKL) in P. gingivalis infection-associated periodontal bone resorption. Inbred female Rowett rats were infected orally on four consecutive days (days 0 to 3) with 1 * 10(9) P. gingivalis bacteria (strain ATCC 33277). Separate groups of rats also received an injection of anti-RANKL antibody, osteoprotegerin fusion protein (OPG-Fc), or a control fusion protein (L6-Fc) into gingival papillae in addition to P. gingivalis infection. Robust serum IgG and salivary IgA antibody (P < 0.01) and T cell proliferation (P < 0.05) responses to P. gingivalis were detected at day 7 and peaked at day 28 in P. gingivalis-infected rats. Both the concentration of soluble RANKL (sRANKL) in rat gingival tissues (P < 0.01) and periodontal bone resorption (P < 0.05) were significantly elevated at day 28 in the P. gingivalis infected group compared to levels in the uninfected group. Correspondingly, RANKL expressing T and B cells in rat gingival tissues were significantly increased at day 28 in the P. gingivalis-infected group compared to the levels in the uninfected group (P < 0.01). Injection of anti-RANKL antibody (P < 0.05) or OPG Fc (P < 0.01), but not L6-Fc, into rat gingival papillae after P. gingivalis infection resulted in significantly reduced periodontal bone resorption. This study suggests that P. gingivalis infection-associated periodontal bone resorption is RANKL dependent and is accompanied by increased local infiltration of RANKL-expressing T and B cells. PMID- 23439309 TI - Role of Toll-like receptor 9 signaling in experimental Leishmania braziliensis infection. AB - Infection with Leishmania braziliensis causes cutaneous or mucocutaneous leishmaniasis in humans. Toll-like receptor 9 (TLR9) expression has been found in granulomas of lesions in L. braziliensis-infected individuals. L. braziliensis inoculation in mice induces very small lesions that are self-healing, whereas deficiency in the TLR adaptor molecule, MyD88, renders mice susceptible to infection. The TLR involved has not been identified, prompting us to investigate if TLR9 triggering by the parasite contributes to the strong resistance to infection observed in L. braziliensis-inoculated mice. The parasites activated wild-type (WT) dendritic cells (DCs) in vitro but not DCs derived from TLR9(-/-) mice. TLR9(-/-) mice inoculated with L. braziliensis exhibited a transient susceptibility characterized by increased lesion size and parasite burden compared to those of WT mice. Surprisingly, elevated levels of gamma interferon (IFN-gamma) were measured at the site of infection and in draining lymph node T cells of TLR9(-/-) mice at the peak of susceptibility, suggesting that unlike observations in vitro, the parasite could induce DC activation leading to the development of Th1 cells in the absence of TLR9 expression. Taken together, these data show that TLR9 signaling is important for the early control of lesion development and parasite burden but is dispensable for the differentiation of Th1 cells secreting IFN-gamma, and the high levels of this cytokine are not sufficient to control early parasite replication following L. braziliensis infection. PMID- 23439311 TI - A rare case of elbow dislocation associated with unrecognized fracture of medial epicondyle and delayed ulnar neuropathy in pediatric age. PMID- 23439310 TI - Humanized mice, a new model to study the influence of drug treatment on neonatal sepsis. AB - Bacterial infection with group B Streptococcus (GBS) represents a prominent threat to neonates and fetuses in the Western world, causing severe organ damage and even death. To improve current therapeutic strategies and to investigate new approaches, an appropriate in vivo model to study the immune response of a human immune system is needed. Therefore, we introduced humanized mice as a new model for GBS-induced sepsis. Humanized mice feature deficiencies similar to those found in neonates, such as lower immunoglobulin levels and myeloid cell dysfunction. Due to the husbandry in specific-pathogen-free (SPF) facilities, the human immune cells in these mice also exhibit a naive phenotype which mimics the conditions in fetuses/neonates. Following infection, cytokine release and leukocyte trafficking from the bone marrow to the lymphoid organ (spleen) and into the peritoneum (site of infection) as well as bacterial spreading and clearance were traceable in the humanized mice. Furthermore, we investigated the effects of betamethasone and indomethacin treatment using this novel sepsis model. Although both drugs are commonly used in perinatal care, little is known about their effects on the neonatal immune system. Treatment of infected humanized mice not only induced the reduction of human leukocytes in the spleen but also increased the bacterial load in all analyzed organs, including the brain, which did not show infiltration of live GBS in untreated controls. These studies demonstrate the utility of the humanized mice as a new model to study an immature human immune response during bacterial infection and allow the investigation of side effects induced by various treatments. PMID- 23439312 TI - Screening for action tremor in epidemiological field surveys: assessing the reliability of a semi-quantitative, visual, template-based scale for rating hand drawn spirals. AB - BACKGROUND: Population-based epidemiological studies of essential and other tremors have need of a rapid yet accurate means to assess tremor, especially mild tremors. Handwriting is often affected by tremor, and a hand-drawn spiral can provide investigators with objective rather than self-reported data. We present a semi-quantitative, ordinal scale to rate hand-drawn spirals. The scale, which includes values for mild tremor, is accompanied by photographic examples of spirals of each rating, providing a visual template for guidance. METHODS: This study, conducted within the framework of a population-based epidemiological study of 5,000 individuals aged 60 and older in Shanghai, asked enrollees to draw an Archimedes spiral with each hand. Spirals were rated using an ordinal scale (0, 0.5, 1, 1.5, 2, and 3). Three raters rated an initial set of 548 spirals. Four raters rated a subsequent set of 200 spirals using a visual template for guidance. RESULTS: Initial agreement (548 spirals) was good (r values ranged from 0.49 to 0.62, all p<0.001). Subsequent agreement (200 spirals and using visual template) improved (r values ranged from 0.67 to -0.91, all p<0.001). DISCUSSION: This tool will be useful to researchers who are attempting to rapidly assess action tremor in their field surveys. PMID- 23439314 TI - Coordinate PI3K pathway and Bcl-2 family disruption in AML. PMID- 23439313 TI - Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy. AB - Temporal lobe epilepsy alters adult neurogenesis. Existing experimental evidence is mainly from chronic models induced by an initial prolonged status epilepticus associated with substantial cell death. In these models, neurogenesis increases after status epilepticus. To test whether status epilepticus is necessary for this increase, we examined precursor cell proliferation and neurogenesis after the onset of spontaneous seizures in a model of temporal lobe epilepsy induced by unilateral intrahippocampal injection of tetanus toxin, which does not cause status or, in most cases, detectable neuronal loss. We found a 4.5 times increase in BrdU labeling (estimating precursor cells proliferating during the 2nd week after injection of toxin and surviving at least up to 7days) in dentate gyri of both injected and contralateral hippocampi of epileptic rats. Radiotelemetry revealed that the rats experienced 112+/-24 seizures, lasting 88+/-11s each, over a period of 8.6+/-1.3days from the first electrographic seizure. On the first day of seizures, their duration was a median of 103s, and the median interictal period was 23min, confirming the absence of experimentally defined status epilepticus. The total increase in cell proliferation/survival was due to significant population expansions of: radial glial-like precursor cells (type I; 7.2*), non-radial type II/III neural precursors in the dentate gyrus stem cell niche (5.6*), and doublecortin-expressing neuroblasts (5.1*). We conclude that repeated spontaneous brief temporal lobe seizures are sufficient to promote increased hippocampal neurogenesis in the absence of status epilepticus. PMID- 23439315 TI - Not guilty by reason of epilepsy. Post-ictal delirium and psychosis resulting in violent offending. PMID- 23439316 TI - Can oestrogen use prevent the onset of psychosis? PMID- 23439317 TI - Multicenter Phase II Study of a New Effective S-1 and Irinotecan Combination Schedule in Patients with Unresectable Metastatic or Recurrent Colorectal Cancer. AB - INTRODUCTION: This multicenter phase II study determined the efficacy and safety of new daily oral S-1 and weekly irinotecan (CPT-11) combination schedule in patients with previously untreated advanced or recurrent colorectal cancer. PATIENTS AND METHODS: Patients received first-line chemotherapy comprising S-1 80 mg/m(2)/day given on days 3 to 7, 10 to 14, and 17 to 21 and 60 mg/m(2) CPT-11 administered intravenously on days 1, 8, and 15 of a 28-day cycle. RESULTS: A total of 45 eligible patients were enrolled in this study. The overall response rate was 48.9%. Median progression-free survival and median overall survival was 8.1 months and 20.9 months, respectively. The rates of grade 3 or 4 toxicity were as follows: neutropenia, 8.9%; anemia, 4.4%; anorexia, 6.7%; and diarrhea, 6.7%. CONCLUSIONS: This new S-1 and irinotecan combination schedule appeared to be an effective, well-tolerated, and convenient regimen in patients with advanced colorectal cancer as compared with conventional regimens such as FOLFIRI and IRIS. PMID- 23439318 TI - Defect induced electronic structure of uranofullerene. AB - The interaction between the inner atoms/cluster and the outer fullerene cage is the source of various novel properties of endohedral metallofullerenes. Herein, we introduce an adatom-type spin polarization defect on the surface of a typical endohedral stable U(2)@C(60) to predict the associated structure and electronic properties of U(2)@C(61) based on the density functional theory method. We found that defect induces obvious changes in the electronic structure of this metallofullerene. More interestingly, the ground state of U(2)@C(61) is nonet spin in contrast to the septet of U(2)@C(60). Electronic structure analysis shows that the inner U atoms and the C ad-atom on the surface of the cage contribute together to this spin state, which is brought about by a ferromagnetic coupling between the spin of the unpaired electrons of the U atoms and the C ad-atom. This discovery may provide a possible approach to adapt the electronic structure properties of endohedral metallofullerenes. PMID- 23439319 TI - Anopheles gambiae, Anoga-HrTH hormone, free and bound structure--a nuclear magnetic resonance experiment. AB - The spread of malaria by the female mosquito, Anopheles gambiae, is dependent, amongst other things, on its ability to fly. This in turn, is dependent on the adipokinetic hormone, Anoga-HrTH (pGlu-Leu-Thr-Phe-Thr-Pro-Ala-Trp-NH2). No crystal structure of this important neuropeptide is available and hence NMR restrained molecular dynamics was used to investigate its conformational space in aqueous solution and when bound to a membrane surface. The results showed that Anoga-HrTH has an almost cyclic conformation that is stabilized by a hydrogen bond between the C-terminus and Thr3. Upon docking of the agonist to its receptor, this H-bond is broken and the molecule adopts a more extended structure. Preliminary AKHR docking calculations give the free energy of binding to be -47.30 kJ/mol. There is a close correspondence between the structure of the docked ligand and literature structure-activity studies. Information about the 3D structure and binding mode of Anoga-HrTH to its receptor is vital for the design of suitable mimetics which can act as insecticides. PMID- 23439320 TI - Exposure to chronic isolation modulates receptors mRNAs for oxytocin and vasopressin in the hypothalamus and heart. AB - The goal of our study was to explore the effect of social isolation stress of varying durations on the plasma oxytocin (OT), messenger ribonucleic acid (mRNA) for oxytocin receptor (OTR), plasma arginine vasopressin (AVP) and mRNA for V1a receptor of AVP (V1aR) expression in the hypothalamus and heart of socially monogamous female and male prairie voles (Microtus ochrogaster). Continuous isolation for 4 weeks (chronic isolation) increased plasma OT level in females, but not in males. One hour of isolation every day for 4 weeks (repeated isolation) was followed by a significant increase in plasma AVP level. Chronic isolation, but not repeated isolation, significantly decreased OTR mRNA in the hypothalamus and heart in both sexes. Chronic isolation significantly decreased cardiac V1aR mRNA, but no effect on hypothalamic V1aR mRNA expression. We did not find a gender difference within repeated social isolation groups. The results of the present study reveal that although chronic social isolation can down-regulate gene expression for the OTR in both sexes, the release of the OT peptide was increased after chronic isolation only in females, possibly somewhat protecting females from the negative consequences of isolation. In both sexes repeated, but not chronic, isolation increased plasma AVP, which could be permissive for mobilization and thus adaptive in response to a repeated stressor. The differential effects of isolation on OT and AVP systems may help in understanding mechanisms through social interactions can be protective against emotional and cardiovascular disorders. PMID- 23439322 TI - Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection. AB - Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7+/ 7.3 kg m(-2)), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity. PMID- 23439321 TI - Holding a grudge: persisting anti-phage CRISPR immunity in multiple human gut microbiomes. AB - The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated) system of bacteria and archaea constitutes a mechanism of acquired adaptive immunity against phages, which is based on genome-encoded markers of previously infecting phage sequences ("spacers"). As a repository of phage sequences, these spacers make the system particularly suitable for elucidating phage-bacteria interactions in metagenomic studies. Recent metagenomic analyses of CRISPRs associated with the human microbiome intriguingly revealed conserved "memory spacers" shared by bacteria in multiple unrelated, geographically separated individuals. Here, we discuss possible avenues for explaining this phenomenon by integrating insights from CRISPR biology and phage bacteria ecology, with a special focus on the human gut. We further explore the growing body of evidence for the role of CRISPR/Cas in regulating the interplay between bacteria and lysogenic phages, which may be intimately related to the presence of memory spacers and sheds new light on the multifaceted biological and ecological modes of action of CRISPR/Cas. PMID- 23439323 TI - Perinatal implications of motor vehicle accident trauma during pregnancy: identifying populations at risk. AB - OBJECTIVE: The purpose of this study was to examine the association between restraint use, race, and perinatal outcome after motor vehicle accidents (MVAs) during pregnancy. STUDY DESIGN: The Duke Trauma Registry and medical records were searched for information on pregnant women at >14 weeks' gestation who were involved in an MVA and who received care through the Emergency Department and the Obstetric Units. Between January 1994 and December 31, 2010, 126 women were identified. Variables that were collected included type of trauma, gestational age at presentation, and delivery outcomes. A prognostic study was performed that evaluated the associations between maternal demographics, details of the accident that included restraint use, and maternal treatment that was related to the accident in relationship to perinatal outcome. RESULTS: There was no difference in the mean age or median gravidity or parity by race among pregnant women who were cared for after an MVA. There was no difference in mean age or racial distribution between women who were restrained compared with women who were unrestrained; unrestrained women were more likely to be nulliparous. Unrestrained women were more likely to require nonobstetric surgery that was related to the trauma. The overall rate of placental abruption was 6%. There were 6 intrauterine fetal deaths, 3 each in the unrestrained (25%) and restrained groups (3.5%; P = .018). Airbags deployed in 17 accidents. Among the 7 women with placenta abruption, 4 women (57%) experienced air bag deployment. CONCLUSION: Lack of restraint use during pregnancy is associated with an increased risk of fetal death. PMID- 23439324 TI - More research, more responsibility: the expansion of duty to warn in cancer patients considering fertility preservation. AB - Reproductive technology is advancing at a steadfast pace. Researchers are successfully refining options for fertility preservation, to the benefit of the cancer community. Research has consistently shown cancer patients and survivors desire to have risks to fertility and preservation options disclosed, and major campaigns have been undertaken to refer these patients to fertility specialists. However, the decision to pursue fertility preservation is not an isolated judgment. A variety of future decisions may arise for the individual or couple, choices that may not have been relayed during the initial decision-making process. Future decisions include the length of time to continue to store frozen gametes, donating banked gametes to infertile couples, and whether embryos created with one partner would be accepted by a new partner. It is important to continue the advancement of fertility preservation not only in the scientific milieu, but also in addressing a patient's preparedness for long-term decision making. PMID- 23439325 TI - Implications of intrauterine protein malnutrition on prostate growth, maturation and aging. AB - AIMS: Maternal malnutrition by low protein diet is associated with an increased incidence of metabolic disorders and decreased male fertility in adult life. This study aimed to assess the impact of maternal protein malnutrition (MPM) on prostate growth, tissue organization and lesion incidence with aging. MAIN METHODS: Wistar rat dams were distributed into two groups, which were control (NP; fed a normal diet containing 17% protein) or a restricted protein diet (RP, fed a diet containing 6% protein) during gestation. After delivery all mothers and offspring received a normal diet. Biometrical parameters, hormonal levels and prostates were harvested at post-natal days (PND) 30, 120 and 360. KEY FINDINGS: MPM promoted low birth weight, decreased ano-genital distance (AGD) and reduced androgen plasma levels of male pups. Prostatic lobes from RP groups presented reduced glandular weight, epithelial cell height and alveolar diameter. The epithelial cell proliferation and collagen deposition were increased in RP group. Incidences of epithelial dysplasia and prostatitis were higher in the RP offspring than in the NP offspring at PND360. SIGNIFICANCE: Our findings show that MPM delays prostate development, growth and maturation until adulthood, probably as a result of low testosterone stimuli. The higher incidence of cellular dysplasia and prostatitis suggests that MPM increases prostate susceptibility to diseases with aging. PMID- 23439326 TI - Hemin, heme oxygenase-1 inducer, attenuates immobilization-induced skeletal muscle atrophy in mice. AB - AIMS: The present study examined the effect of the heme oxygenase (HO)-1 inducer hemin on skeletal muscle atrophy induced by single limb immobilization in mice. MAIN METHODS: Immobilization was conducted in the left hindlimb of C57BL/6 mice for 1 week and the right hindlimb was used as a control. Hemin (30 mg/kg) was administered intraperitoneally once a day during the immobilization period. Gastrocnemius muscles were used for analysis. Muscle weight was measured to quantify degree of atrophy, and exhaustion treadmill test was performed to assess muscle function. KEY FINDINGS: Immobilization increased HO-1 protein levels in skeletal muscle, which was further increased by hemin treatment. Immobilization induced weight loss and a functional reduction in skeletal muscle, which were attenuated by hemin treatment. Gene expression and protein levels of MuRF1 and atrogin-1 were increased by immobilization and hemin treatment attenuated the increment. The phosphorylation of mTOR and p70S6k was decreased by immobilization in skeletal muscle and hemin had no effect on mTOR and p70S6k phosphorylation. Gene expression of the antioxidants superoxide dismutase and glutathione peroxidase 1 in skeletal muscle was reduced by immobilization and hemin treatment recovered the reduction. Immobilization increased levels of carbonylated protein and nitrotyrosine in skeletal muscle, which was reversed by hemin treatment. Gene expression of inflammatory cytokines was increased by immobilization and was normalized as a result of hemin treatment. SIGNIFICANCE: These results suggest that hemin attenuates immobilization-induced skeletal muscle atrophy through the suppression of protein degradation via its anti-oxidant and anti-inflammatory properties. PMID- 23439327 TI - Uncovering the neuroenteric-pulmonary axis: vagal nerve stimulation prevents acute lung injury following hemorrhagic shock. AB - AIMS: Trauma/hemorrhagic shock (T/HS) induced gut injury is known to initiate a systemic inflammatory response which can lead to secondary lung injury. We have shown that vagal nerve stimulation (VNS) protects intestinal epithelial integrity after a severe burn insult. We hypothesize that VNS will protect the lung from injury following T/HS by preventing intestinal barrier failure. MAIN METHODS: Male Balb/c mice were subjected to a T/HS model with and without cervical VNS. Intestinal injury was evaluated by measuring changes in gut barrier function and tight junction protein localization. Lung injury was evaluated using histology and markers of lung inflammation. Using NF-kB-luciferase (NF-kB-luc) transgenic mice, NF-kb-DNA binding was measured by photon emission analysis at 4 after injury. KEY FINDINGS: T/HS is associated gut injury characterized by histologic injury, increased epithelial permeability, and altered localization of gut tight junction proteins. Cervical VNS prevented the T/HS-induced changes in gut barrier integrity. Gut injury after T/HS was associated with acute lung injury at 24 h characterized by histologic injury, increased number of MPO positive stained cells and MPO enzymatic activity, and increased ICAM-1 expression in lung endothelium. VNS decreased T/HS-induced lung injury with a marked decrease in lung inflammation compared to T/HS alone. Lungs harvested from NF-kB-luc mice at 4h post VNS+T/HS demonstrated decreased DNA binding of NF-kB compared to T/HS alone as measured by changes in bioluminescence. SIGNIFICANCE: VNS is effective in protecting against acute lung injury caused by hemorrhagic shock through its ability to prevent gut barrier dysfunction. PMID- 23439328 TI - Left diaphragmatic hernia after pneumonectomy. AB - Patients undergoing pneumonectomy can suffer by cardiovascular and respiratory postoperative complications that can affect patient's outcome by increasing morbidity and mortality. We describe a diaphragmatic hernia occurring after pneumonectomy. with late presentation and with epidural analgesia confusing the scenario suggesting that anesthesiologists should remain aware on this complication even in the late post operative period. PMID- 23439329 TI - Test-retest reliability, criterion-related validity, and minimal detectable change of the Illinois agility test in male team sport athletes. AB - The purposes of this study were first to assess the reliability and criterion related validity of the Illinois change of direction (COD) Illinois Agility Test (IAGT) and second to determine whether a relationship with power and speed exists. A total of 105 male team sport athletes participated in this investigation. Repeat measurements in 89 subjects out of the 105 were performed to assess the test-retest reliability and the 95% confidence interval (CI) of the difference in the score between paired observations (minimal detectable change [MDC]95) of the COD IAGT. The intraclass correlation coefficient and the SEM values for the COD IAGT test were 0.96 (95% CI, 0.85-0.98) and 0.19 seconds, respectively. The smallest worthwhile change (0.20 seconds) for the IAGT was greater than its SEM (0.19 seconds). The MDC95 value for the IAGT was 0.52 seconds. Criterion-related validity of the COD IAGT was assessed in the 105 subjects. They performed the COD IAGT and the T-test. Both tests were significantly correlated (r = 0.31 [95% CI, 0.24-0.39]; p < 0.05). The correlation between COD IAGT, acceleration, straight speed, and leg power was analyzed in all the 105 subjects. Pearson moment correlation revealed no association between acceleration and the COD IAGT. However, significant correlations were observed between the COD IAGT and leg power (r = -0.39 [95% CI, -0.26 to -0.44]; p < 0.05), and speed (r = 0.42 [95% CI, 0.37-0.51]; p < 0.05). When controlling for speed with partial correlation, the significant relationship between the COD IAGT and leg power disappeared. In conclusion, the COD IAGT seems to be a reliable and valid test, whose performance is significantly related to speed rather than to acceleration and leg power. PMID- 23439330 TI - Performance factors in women's team handball: physical and physiological aspects- a review. AB - Team handball is an Olympic sport played professionally in many European countries. Nevertheless, a scientific knowledge regarding women's elite team handball demands is limited. Thus, the purpose of this article was to review a series of studies (n = 33) on physical characteristics, physiological attributes, physical attributes, throwing velocity, and on-court performances of women's team handball players. Such empirical and practical information is essential to design and implement successful short-term and long-term training programs for women's team handball players. Our review revealed that (a) players that have a higher skill level are taller and have a higher fat-free mass; (b) players who are more aerobically resistant are at an advantage in international level women team handball; (c) strength and power exercises should be emphasized in conditioning programs, because they are associated with both sprint performance and throwing velocity; (d) speed drills should also be implemented in conditioning programs but after a decrease in physical training volume; (e) a time-motion analysis is an effective method of quantifying the demands of team handball and provides a conceptual framework for the specific physical preparation of players. According to our results, there are only few studies on on-court performance and time motion analysis for women's team handball players, especially concerning acceleration profiles. More studies are needed to examine the effectiveness of different training programs of women's team handball players' physiological and physical attributes. PMID- 23439331 TI - Collegiate and high school athlete neck strength in neutral and rotated postures. AB - A knowledge of neck strength is important for developing conditioning protocols and for evaluating the relationship between neck strength and head and neck injury, but very few studies have examined neck strength in relationship to athletic participation. The purpose of this study was to quantify isometric neck strength in collegiate and high school athletes. We hypothesized that (a) male athletes would have significantly greater neck strength than females; (b) collegiate athletes would be significantly stronger than high school athletes; and (c) neck strength would vary significantly with head posture. A total of 149 subjects participated (77 men and 72 women; 90 college and 59 high school level). Flexion, extension, and lateral flexion neck strength were measured in neutral and rotated head and neck postures. Neck strength varied significantly according to participants' sex, age, and posture (p < 0.05). Male college students were stronger than those in all other groups (female college students, male high school students, and female high school students). The average female neck strength was 61, 54, and 56% of the average male neck strength for extension, flexion, and lateral flexion, respectively. High school athletes' neck strength was 75, 68, and 65% of collegiate athletes' neck strength for extension, flexion, and lateral flexion, respectively. On average, neck strength was the greatest for extension compared with other force directions. The subjects showed large variation in neck strength with posture, but in general, there were no consistent trends among the subjects. This finding suggests that those whose neck strength was considerably lower in nonneutral postures may consider training to increase strength in rotated postures. These data provide important baseline information for future studies evaluating injury risk or training protocols. PMID- 23439332 TI - Towards standardization of the nomenclature of resistance training exercises. AB - There is a disagreement surrounding the names of resistance training exercises. The purpose of this study was to survey different professionals regarding the nomenclature of resistance training exercises. Two hundred five participants volunteered for the study, of which, 64.9 % were male. Participants self identified as either certified athletic trainer (22.4%), academic (18.5%), strength and conditioning coach (25.9%), personal trainer (15.6%), or clinician (17.6%). Participants were asked to name 10 resistance training exercises as depicted by pictures. A chi2 for exercise name by current profession analysis was used to analyze frequency differences. All exercises in the survey yielded inconsistent terminology primarily related to the responders' profession and 3 items in their naming patterns as follows: specification, equipment, and exercise. These results reveal a need to establish consistent naming pattern guidelines for resistance training exercises. The use of a consistent naming pattern may provide direction and clarity when working with athletes and clients in a strength training environment. We suggest a "specification, equipment, exercise" (e.g., 1 arm dumbbell row) naming pattern be used when naming resistance training exercises. PMID- 23439333 TI - Changes in jump, sprint, and coordinative performances after a senior soccer match. AB - This study aimed to verify the short-term after effects of a soccer match on senior players' all-out and interlimb coordination performances. Right before (prematch) and after (postmatch) a match, 10 senior (52.3 +/- 10.2 years) male soccer players were administered jump (countermovement jump [CMJ]; repeated jump [RJ]), sprint (10 m and 10 m while dribbling the ball [10 mDB]), in-phase (IP) and antiphase (AP) interlimb coordination (synchronized hand and foot flexions and extensions at 80, 120, 180 bpm). Heart rate (HR) responses and subjective rating of perceived exertion (RPE) and rating of muscle pain (RMP) were used to evaluate the intensity of the friendly match. During the match, HR >85% of individual HRmax occurred for 50% of playing time. Subjective ratings at the end of the match were 12.9 +/- 2.2 pt and 2.7 +/- 2.2 pt for RPE and RMP, respectively. Postmatch CMJ, 10 m, 10 mDB, AP, IP 80 bpm, and IP 120 bpm performances did not show any difference with respect to prematch values, whereas improvements (p < 0.05) in RJ (prematch: 17.4 +/- 3.9 cm; postmatch: 19.3 +/- 4.8 cm) and IP 180 bpm (prematch: 30.4 +/- 15.1 second; postmatch: 50.3 +/- 18.9 second) emerged. These findings indicate that senior soccer players are able to cope with the high demands of match play and suggest that an acute bout of intense exercise has an arousing effect that counteracts fatigue effects and facilitates the performance of old trained individuals on complex motor behaviors relying on central executive control. In considering that players consider soccer as highly motivating, with advancing years this sport could help players in preserving high mental and physical functions and maintaining active engagement in life through social interactions. PMID- 23439334 TI - Crossfit-based high-intensity power training improves maximal aerobic fitness and body composition. AB - The purpose of this study was to examine the effects of a crossfit-based high intensity power training (HIPT) program on aerobic fitness and body composition. Healthy subjects of both genders (23 men, 20 women) spanning all levels of aerobic fitness and body composition completed 10 weeks of HIPT consisting of lifts such as the squat, deadlift, clean, snatch, and overhead press performed as quickly as possible. Additionally, this crossfit-based HIPT program included skill work for the improvement of traditional Olympic lifts and selected gymnastic exercises. Body fat percentage was estimated using whole-body plethysmography, and maximal aerobic capacity (VO2max) was measured by analyzing expired gasses during a Bruce protocol maximal graded treadmill test. These variables were measured again after 10 weeks of training and compared for significant changes using a paired t-test. Results showed significant (p < 0.05) improvements of VO2max in men (43.10 +/- 1.40 to 48.96 +/- 1.42 ml . kg . min) and women (35.98 +/- 1.60 to 40.22 +/- 1.62 ml . kg . min) and decreased body fat percentage in men (22.2 +/- 1.3 to 18.0 +/- 1.3) and women (26.6 +/- 2.0 to 23.2 +/- 2.0). These improvements were significant across all levels of initial fitness. Significant correlations between absolute oxygen consumption and oxygen consumption relative to body weight was found in both men (r = 0.83, p < 0.001) and women (r = 0.94, p < 0.001), indicating that HIPT improved VO2max scaled to body weight independent of changes to body composition. Our data show that HIPT significantly improves VO2max and body composition in subjects of both genders across all levels of fitness. PMID- 23439335 TI - The role of neural tension in stretch-induced strength loss. AB - The purpose of this study was to determine if neural tension during passive stretching affected subsequent strength loss. Eleven healthy subjects (10 men, 1 woman; age 34 +/- 12 years) performed maximal isometric hamstring contractions at 100 degrees , 80 degrees , 60 degrees , and 40 degrees knee flexion before and after five 1-minute hamstring stretches performed in either a spinal neutral position or a neural tension position. One leg was stretched in the neutral position and the other in the neural tension position. Hamstring electromyography (EMG) activity was recorded during all contractions and stretches. Passive resistance to stretch was reduced by 11% after stretching (p < 0.01; no difference between neutral or neural tension stretches p = 0.41). Stretch-induced strength loss was apparent after neural tension stretches (12%, p < 0.01) but not after neutral stretches (5%, p = 0.09). There was a rightward shift in the angle torque curve after neutral stretches (strength loss on ascending limb, strength gain on descending limb, p < 0.01). This effect was not apparent after neural tension stretches (p = 0.43). Stretching did not affect EMG activity during isometric contractions (<2% decline p = 0.58; no difference between neutral and neural tension, p = 0.86). Hamstring stretching with the spine in a neutral position did not result in a significant strength loss but shifted the length tension relationship such that strength was decreased at short muscle lengths and increased at long muscle lengths. Hamstring stretching with increased neural tension resulted in strength loss with no associated shift in the length-tension relationship. PMID- 23439336 TI - Dehydration and acute weight gain in mixed martial arts fighters before competition. AB - The purpose of this study was to characterize the magnitude of acute weight gain (AWG) and dehydration in mixed martial arts (MMA) fighters before competition. Urinary measures of hydration status and body mass were determined approximately 24 hours before and then again approximately 2 hours before competition in 40 MMA fighters (mean +/- SE, age: 25.2 +/- 0.65 years, height: 1.77 +/- 0.01 m, body mass: 75.8 +/- 1.5 kg). The AWG was defined as the amount of body weight the fighters gained in the approximately 22-hour period between the official weigh-in and the actual competition. On average, the MMA fighters gained 3.40 +/- 2.2 kg or 4.4% of their body weight in the approximately 22-hour period before competition. Urine specific gravity significantly decreased (p < 0.001) from 1.028 +/- 0.001 to 1.020 +/- 0.001 during the approximately 22-hour rehydration period. Results demonstrated that 39% of the MMA fighters presented with a Usg of >1.021 immediately before competition indicating significant or serious dehydration. The MMA fighters undergo significant dehydration and fluctuations in body mass (4.4% avg.) in the 24-hour period before competition. Urinary measures of hydration status indicate that a significant proportion of MMA fighters are not successfully rehydrating before competition and subsequently are competing in a dehydrated state. Weight management guidelines to prevent acute dehydration in MMA fighters are warranted to prevent unnecessary adverse health events secondary to dehydration. PMID- 23439337 TI - An individualized longitudinal approach to monitoring the dynamics of growth and fitness development in adolescent athletes. AB - This study evaluated the development of anthropometric and fitness characteristics of 3 individual adolescent junior rugby league players and compared their characteristics with a cross-sectional population matched by age and skill level. Cross-sectional anthropometric and fitness assessments were conducted on 1,172 players selected to the Rugby Football League's talent development program (i.e., the Player Performance Pathway) between 2005 and 2008. Three players of differing relative age, maturational status, and playing position were measured and tracked once per year on 3 occasions (Under 13s, 14s, 15s age categories) and compared against the cross-sectional population. Results demonstrated that the later maturing players increased height (player 1 = 9.2%; player 2 = 7.8%) and a number of fitness characteristics (e.g., 60-m speed-player 1 = -14.9%; player 2 = -9.9%) more than the earlier maturing player (player 3 Height = 2.0%, 60-m sprint = -0.7%) over the 2-year period. The variation in the development of anthropometric and fitness characteristics between the 3 players highlights the importance of longitudinally monitoring individual characteristics during adolescence to assess the dynamic changes in growth, maturation, and fitness. Findings showcase the limitations of short-term performance assessments at one-off time points within annual-age categories, instead of advocating individual development and progression tracking without deselection. Coaches should consider using an individual approach, comparing data with population averages, to assist in the prescription of appropriate training and lifestyle interventions to aid the development of junior athletes. PMID- 23439338 TI - Global positioning system watches for estimating energy expenditure. AB - Global positioning system (GPS) watches have been introduced commercially, converting frequent measurements of time, location, speed (pace), and elevation into energy expenditure (EE) estimates. The purpose of this study was to compare EE estimates of 4 different GPS watches (Forerunner, Suunto, Polar, Adeo), at various walking speeds, with EE estimate from a triaxial accelerometer (RT3), which was used as a reference measure in this study. Sixteen healthy young adults completed the study. Participants wore 4 different GPS watches and an RT3 accelerometer and walked at 6-minute intervals on an outdoor track at 3 speeds (3, 5, and 7 km/hr). The statistical significance of differences in EE between the 3 watches was assessed using linear contrasts of the coefficients from the overall model. Reliability across trials for a given device was assessed using intraclass correlation coefficients as estimated in the mixed model. The GPS watches demonstrated lower reliability (intraclass correlation coefficient) across trials when compared with the RT3, particularly at the higher speed, 7 km/hr. Three GPS watches (Forerunner, Polar, and Suunto) significantly and consistently underestimated EE compared with the reference EE given by the RT3 accelerometer (average mean difference: Garmin, -50.5%; Polar, -41.7%; and Suunto, -41.7%; all p < 0.001). Results suggested that caution should be exercised when using commercial GPS watches to estimate EE in athletes during field-based testing and training. PMID- 23439339 TI - Effect of kinesio taping on jumping and balance in athletes: a crossover randomized controlled trial. AB - The purpose of this crossover randomized controlled trial was to verify the effect of Kinesio Taping (KT) applied to the triceps surae with the aim to improve muscle performance during vertical jump (VJ), horizontal jump (HJ), and dynamic balance (DB) in healthy college athletes. The participants were 20 athletes (11 men) who competed in 4 different sports modalities (track and field, handball, volleyball, and soccer). Participants had a mean age of 22.3 +/- 3.3 years, mean height of 1.74 +/- 0.08 m, and mean body mass of 67.8 +/- 10.1 kg. The intervention consisted of applying KT from the origin of the triceps surae to its insertion with the purpose of increasing muscle performance, and the placebo consisted of applying tape with nonelastic properties. There were no significant differences between KT and placebo conditions for height (m) in VJ (KT, 0.18 +/- 0.06; placebo, 0.17 +/- 0.06; p = 0.14), distance (m) in HJ (KT, 1.48 +/- 0.3; placebo, 1.47 +/- 0.3; p = 0.40), and DB in distance reached (m) in the star excursion balance test, normalized by lower limb length (anterior: KT, 90.0 +/- 6.7; placebo, 89.5 +/- 7.5; p = 0.56; posterolateral: KT, 92.5 +/- 7.5; placebo, 93.2 +/- 5.8; p = 0.52; posteromedial: KT, 98.3 +/- 6.7; placebo, 98.7 +/- 7.4; p = 0.69). The KT technique was not found to be useful in improving performance in some sports-related movements in healthy college athletes; therefore, KT applied to the triceps surae should not be considered by athletes when the sole reason of the application is to increase performance during jumping and balance. PMID- 23439340 TI - Measuring lateral shuffle and side cut performance. AB - Lateral shuffle and side cut (SSC) movements are defensive basketball movements where movement speed is critical to performance. The purpose of this study was to compare SSC data obtained using timing lights with motion capture system data and to determine the most appropriate method for measuring SSC performance. Shuffle time data were recorded using both timing lights and a motion capture system while 9 male subjects performed 2 different SSC movement sets, with and without controlling for arm movements, which may influence performance times. Shuffle and side cut times and SSC displacements were used to calculate mean shuffle velocity for each trial. The SEs for the motion capture system were estimated for SSC times (+/- 4.2 milliseconds; ~0.24% of mean shuffle time) and velocities (+/- 5.5 mm . s; ~0.24% of mean shuffle velocity), respectively, indicating high levels of precision. Timing light movement time variability was significantly higher during the uncontrolled (SD = 42 milliseconds) when compared with the controlled (SD = 9 milliseconds, p < 0.001) condition, indicating a significant reduction in variability by controlling non-performance-related variability such as arm movement. A significant positive correlation was found between SSC time and SSC displacement (r = 0.42) indicating that performance times were dependent on displacement. Furthermore, the variance in motion-captured SSC velocity was significantly smaller than the variance in velocity determined using timing lights (p < 0.05). We concluded that motion-captured SSC velocity data reduced systematic errors and non-performance-related movement variability and, therefore, was better able to reflect true performance. As true performance variability in human movement provides important information, the presented method for calculating SSC velocity in this study is recommended for assessing SSC performance. PMID- 23439341 TI - Running demands and heart rate response in rugby union referees. AB - The aim of this study was to examine the match physical demands and exercise intensity associated with men rugby union refereeing using global positioning system technology. Ten male rugby union referees (age, 37.1 +/- 5.9 years; body mass, 83.7 +/- 4.8 kg; height, 175.5 +/- 6.2 cm) were analyzed 2-4 times during a total of 30 national level matches. The average total distance covered by the referees throughout the game was 6,322.2 +/- 564.9 m. As a percentage of total distance, 37.3% (2,356.9 +/- 291.3 m) was spent walking, 24.1% (1,524.4 +/- 229.4 m) jogging, 10.4% (656.2 +/- 130.7 m) running at low intensity, 17.6% (1,110.3 +/ 212.2 m) at medium intensity, 5.5% (347.1 +/- 27.1 m) at high intensity, and 5.2% (328.1 +/- 230.3 m) at sprint. A significant decrease (p < 0.05) in running performance was observed between the first and the second halves in the last 3 speed zones. When the total distance traveled during consecutive 10-minute periods was compared, there was a significantly greater distance covered in the first 10 minutes of the game (876.3 +/- 163 m) compared with 50-60 minutes (679.8 +/- 117.6 m), 60-70 minutes (713.03 +/- 122.3 m), and 70-80 minutes (694.2 +/- 125.7 m; all p < 0.05). The average heart rate responses were similar (p > 0.05) in the first (157 +/- 7 b . min; 85% HRmax) and second half (155 +/- 7 b . min; 84% HRmax). This study provides evidence of reduced high-intensity running toward the end of the game. These findings offer important information to design better training strategies adapted to the requirements and demands of rugby union refereeing. PMID- 23439342 TI - Analysis of specific speed testing for cricketers. AB - A characteristic of cricket sprints, which may require specific assessment, is that players carry a bat when running between the wickets. This study analyzed the relationships between general and specific cricket speed tests, which included 30-m sprint (0- to 5-, 0- to 10-, 0- to 30-m intervals; general); 505 change-of-direction speed test with left and right foot turns (general); 17.68-m sprint without and with (WB) a cricket bat (0- to 5-, 0- to 17.68-m intervals; specific); and run-a-three (specific). Seventeen male cricketers (age = 24.4 +/- 5.0 years; height = 1.84 +/- 0.06 m; mass = 86.9 +/- 13.9 kg) completed the tests, which were correlated (p < 0.05) to determine if they assessed different physical qualities. The subjects were also split into faster and slower groups based on the 17.68-m WB sprint time. A 1-way analysis of variance ascertained between-group differences in the tests (p < 0.05). The 17.68-m WB sprint correlated with the 0- to 10- and 0- to 30-m sprint intervals (r = 0.63-0.78) but not with the 0- to 5-m interval. The run-a-three correlated with the 505 and 17.68-m WB sprint (r = 0.62-0.90) but not with the 0- to 5-m interval. Poor relationships between the 0- to 5-m interval and cricket-specific tests may be because of the bat inclusion, as the sprints with a bat began with the subject ahead of the start line, and bat placed behind it. Furthermore, although the 17.68-m WB sprint and run-a-three differentiated faster and slower subjects, the 0- to 5-m sprint interval, and left foot 505, did not. The results indicated the necessity for cricket-specific speed testing. The 17.68-m WB sprint and run-a three are potentially valuable tests for assessing cricket-specific speed. A bat should be incorporated when testing the running between the wickets ability. PMID- 23439343 TI - Acute effect of proprioceptive neuromuscular facilitation stretching on the number of repetitions performed during a multiple set resistance exercise protocol. AB - It has been proposed that fatigue during strength exercise is negatively influenced by prior proprioceptive neuromuscular facilitation (PNF) stretching. However, it is possible that the effects of PNF on muscle endurance are affected by stretching duration. This study investigated the influence of PNF on the number of repetitions of the leg curl exercise performed with multiple sets and submaximal load. Nineteen men (age 25 +/- 1 years, weight 75.8 +/- 4.2 kg, height 178.1 +/- 3.8 cm, 10-repetition maximum [RM] 78.3 +/- 6.9 kg) performed 4 sets of leg curl with 10RM load with and without previous PNF (3 sets of hip flexion either with knees extended or flexed, duration ~2.5 minutes). The total number of repetitions decreased along sets in both situations (38.6% in control and 41.0% in PNF sessions, p < 0.001). However, no difference between control and PNF was detected for the number of repetitions in each set (first set, p = 0.330; second set, p = 0.072; third set, p = 0.061; fourth set, p = 0.150). In conclusion, the number of repetitions performed in multiple sets of the leg curl was not decreased by prior PNF stretching. Therefore, it appears that a moderate level of PNF could be used before resistance exercise with a minimal negative effect. PMID- 23439344 TI - The influence of training and mental skills preparation on injury incidence and performance in marathon runners. AB - There has been a considerable increase in the number of participants running marathons over the past several years. The 26.2-mile race requires physical and mental stamina to successfully complete it. However, studies have not investigated how running and mental skills preparation influence injury and performance. The purpose of our study was to describe the training and mental skills preparation of a typical group of runners as they began a marathon training program, assess the influence of training and mental skills preparation on injury incidence, and examine how training and mental skills preparation influence marathon performance. Healthy adults (N = 1,957) participating in an 18 week training program for a fall 2011 marathon were recruited for the study. One hundred twenty-five runners enrolled and received 4 surveys: pretraining, 6 weeks, 12 weeks, posttraining. The pretraining survey asked training and mental skills preparation questions. The 6- and 12-week surveys asked about injury incidence. The posttraining survey asked about injury incidence and marathon performance. Tempo runs during training preparation had a significant positive relationship to injury incidence in the 6-week survey (rho[93] = 0.26, p = 0.01). The runners who reported incorporating tempo and interval runs, running more miles per week, and running more days per week in their training preparation ran significantly faster than did those reporting less tempo and interval runs, miles per week, and days per week (p <= 0.05). Mental skills preparation did not influence injury incidence or marathon performance. To prevent injury, and maximize performance, while marathon training, it is important that coaches and runners ensure that a solid foundation of running fitness and experience exists, followed by gradually building volume, and then strategically incorporating runs of various speeds and distances. PMID- 23439345 TI - Effects of pre-exercise, endurance, and recovery designer sports drinks on performance during tennis tournament simulation. AB - Sports drinks are often used before, during, and after tennis tournaments, but their ability to influence physiological and psychological variables and the characteristics of tennis match play remains uncertain. The objective of this study was to evaluate the impact of ingesting specially formulated pre-exercise, endurance, and recovery sports drinks on glycemia and performance indices during a simulated tennis tournament. Eight well-trained male tennis players performed two 3-match round-robin tennis tournaments although ingesting sports drinks (SPDs) or placebos (PLAs) before, during, and after each match (crossover study design). Before the first tournament, match and drink order were randomized (SPDs or PLAs first) and players were placed under controlled nutritional and hydration conditions. Glycemia, heart rate response, rate of perceived exertion, and notational/match analysis were assessed during each match. Sports drinks maintained higher glycemia levels during match 2 and 3 of the tennis tournament compared with PLAs (p < 0.01). Moreover, higher mean heart rates (p < 0.01) and stroke frequencies (p < 0.01) concomitantly with lower rates of perceived exertion (p < 0.01) were recorded throughout the duration of the tournament, when players used the SPDs. During a 3-match tennis tournament, SPDs allow higher stroke frequency during play, with decreased rates of perceived exertion. PMID- 23439346 TI - A comparison of strength and stretch interventions on active and passive ranges of movement in dancers: a randomized controlled trial. AB - The majority of stretching interventional research has focused on the development of a muscle's passive range of movement (PROM). Active range of movement (AROM) refers to the functional range of movement (ROM) available to the participant and provides a better insight into the relationship between muscular antagonistic pairings. The purpose of this study was to assess the effect of 3 strengthening or stretching interventions on hip and lower limb active (AROM) and passive (PROM) ranges of movement. Thirty-nine female dance students (17 +/- 0.52 years; 61.7 +/- 8.48 kg; 164.4 +/- 5.49 cm) volunteered. They were randomly divided into 3 groups, strength training (n = 11); low-intensity stretching (n = 13); moderate intensity or high-intensity stretching (n = 11). Four dancers withdrew during the study. All groups carried out a 6-week intervention. The strength training group focused on end of range hip flexor strength; the low-intensity and moderate intensity stretch group carried out a series of stretches at 3/10 and 8/10 perceived exertion, respectively. Active range of movement and PROM were measured preintervention and postintervention using 2-d video analysis. Repeated measures analysis indicated that although all 3 groups improved their PROM during the experimental period (range increase: 9-200 p < 0.01), no significant differences were found between the groups. For AROM, both the strength training and the low intensity stretch groups revealed significant improvements in ROM (range increase: 20-300) compared with the moderate-intensity or high-intensity stretch group (p < 0.01). The present data show that interventions based on strengthening agonist muscles or decreasing the resistance of antagonist muscles through low intensity stretching are beneficial in the development of both active and passive ranges of movement and provide functional training techniques that are often over looked in favor of the more conservative moderate-intensity stretching programs. PMID- 23439347 TI - Validity of Lactate Thresholds in Inline Speed Skating. AB - Lactate thresholds are commonly used as estimates of the highest workload where lactate production and elimination are in equilibrium (maximum lactate steady state [MLSS]). However, because of the high static load on propulsive muscles, lactate kinetics in inline speed skating may differ significantly from other endurance exercise modes. Therefore, the discipline-specific validity of lactate thresholds has to be verified. Sixteen competitive inline-speed skaters (age: 30 +/- 10 years; training per week: 10 +/- 4 hours) completed an exhaustive stepwise incremental exercise test (start 24 km.h, step duration 3 minutes, increment 2 km.h) to determine individual anaerobic threshold (IAT) and the workload corresponding to a blood lactate concentration of 4 mmol.L (LT4) and 2-5 continuous load tests of (up to) 30 minutes to determine MLSS. The IAT and LT4 correlated significantly with MLSS, and the mean differences were almost negligible (MLSS 29.5 +/- 2.5 km.h; IAT 29.2 +/- 2.0 km.h; LT4 29.6 +/- 2.3 km.h; p > 0.1 for all differences). However, the variability of differences was considerable resulting in 95% limits of agreement in the upper range of values known from other endurance disciplines (2.6 km.h [8.8%] for IAT and 3.1 km.h [10.3%] for LT4). Consequently, IAT and LT4 may be considered as valid estimates of the MLSS in inline speed skating, but verification by means of a constant load test should be considered in cases of doubt or when optimal accuracy is needed (e.g., in elite athletes or scientific studies). PMID- 23439348 TI - Decision-making accuracy in reactive agility: quantifying the cost of poor decisions. AB - Decision-making accuracy and the time cost of incorrect responses was compared between higher- (n = 14) and lower-standard (n = 14) Australian footballers during reactive agility tasks incorporating feint and nonfeint scenarios. Accuracy was assessed as whether the subject turned in the correct direction to each stimulus. With skill groups pooled, decision accuracy at the first (or only) stimulus (decision time 1) was 94 +/- 7%, and it decreased to 83 +/- 20% for the second stimulus (decision time 2; p = 0.01; d = 0.69). However, with skill groups separated, decision accuracy was similar between groups at decision time 1 (higher 95 +/- 6% vs. lower 92 +/- 7%; p = 0.6; d = 0.42), somewhat better in the higher-standard group at decision time 2 (88 +/- 22% vs. 78 +/- 17%; p = 0.08; d = 0.50). But the decrease in accuracy from decision time 1 to 2 was significant in the lower-standard group only (92 +/- 7% to 78 +/- 17%; p = 0.02; d = 1.04). However, with skill groups pooled but agility times examined exclusively in trials involving correct or incorrect decisions, incorrect decisions at decision time 1 during feint trials resulted in a shorter agility time (1.73 +/- 0.24 seconds vs. 2.03 +/- 0.39 seconds; p = 0.008; d = 0.92), whereas agility time was significantly longer in feint (incorrect at decision time 2 only; 2.65 +/- 0.41 seconds vs. 1.97 +/- 0.36 seconds; p < 0.001; d = 1.76) and nonfeint trials (1.64 +/- 0.13 seconds vs. 1.51 +/- 0.10 seconds; p = 0.001; d = 1.13). Therefore, although decision-making errors typically worsen reactive agility performance, successful anticipation of a feint can produce performance improvements. Furthermore, higher-standard footballers are less susceptible to such feints, perhaps because of superior anticipation. Training to improve decision-making accuracy, particularly involving feint movements, may therefore principally benefit lesser-skilled players and should be practiced regularly. PMID- 23439349 TI - More complicated than it looks: the vagaries of calculating intra-abdominal pressure. AB - Activities thought to induce high intra-abdominal pressure (IAP), such as lifting weights, are restricted in women with pelvic floor disorders. Standardized procedures to assess IAP during activity are lacking and typically only focus on maximal IAP variably defined. Our intent in this methods article is to establish the best strategies for calculating maximal IAP and to add area under the curve and first moment of the area as potentially useful measures in understanding biologic effects of IAP. Thirteen women completed a range of activities while wearing an intravaginal pressure transducer. We first analyzed various strategies heuristically using data from 3 women. The measure that seemed to best represent maximal IAP was an average of the 3, 5, or 10 highest values, depending on activity, determined using a top-down approach, with peaks at least 1 second apart using algorithms written for Matlab computer software, we then compared this strategy with others commonly reported in the literature quantitatively using data from 10 additional volunteers. Maximal IAP calculated using the top down approach differed for some, but not all, activities compared with the single highest peak or to averaging all peaks. We also calculated area under the curve, which allows for a time component, and first moment of the area, which maintains the time component while weighing pressure amplitude. We validated methods of assessing IAP using computer-generated sine waves. We offer standardized methods for assessing maximal area under the curve and first moment of the area for IAP to improve future reporting and application of this clinically relevant measure in exercise science. PMID- 23439350 TI - In-hospital outcomes of pedicled bilateral internal mammary artery use in diabetic and nondiabetic patients undergoing off-pump coronary artery bypass grafting: single-surgeon, single-center experience. AB - OBJECTIVE: A common perception is that use of pedicled bilateral internal mammary arteries (BIMA) increases the risk of sternal wound complications in diabetic patients undergoing coronary artery bypass grafting (CABG). The purpose of this study was to compare the in-hospital outcomes of CABG using pedicled BIMA in diabetic and nondiabetic patients. METHODS: From September 1998 to September 2010, 390 consecutive diabetic patients and 519 nondiabetic patients underwent isolated off-pump CABG using pedicled BIMA. The 2 groups had comparable preoperative demographics except for a higher prevalence of acute myocardial infarction (18.9% versus 6.1%, P = .01), peripheral vascular disease (17.2% versus 2.7%, P = .001), an ejection fraction <30% (17.7% versus 8.5%, P = .02), and chronic renal failure (4.5% versus 0.9%, P = .01) in the diabetic patients. RESULTS: The operative mortality rate of the diabetic patients was comparable to that of the nondiabetic patients (2.8% versus 2.1%, P = .87). The in-hospital outcomes, including occurrence of superficial and deep sternal wound infections, were similar except for an increased occurrence of wound infection at the vein harvest site (6.6% versus 1.1%, P = .04) and a need for hemofiltration (11.8% versus 2.1%, P = .02) in the diabetic patients. CONCLUSIONS: Pedicled BIMA use is associated with comparable incidences of sternal wound complications and other outcomes in diabetic patients and nondiabetic patients. Strict perioperative glycemic control, adherence to meticulous closure technique, and postoperative management of surgical wounds can make pedicled BIMA use a default strategy for diabetic patients. PMID- 23439351 TI - Concomitant off-pump coronary artery bypass grafting results in improved in hospital outcomes for patients with ischemic mitral regurgitation undergoing surgery. AB - OBJECTIVE: Surgical management of ischemic mitral regurgitation (IMR) has primarily consisted of revascularization with or without the addition of mitral valve repair or replacement. We hypothesize that performing off-pump coronary artery bypass (OPCAB) grafting before fixing MR improves in-hospital outcomes for patients with IMR undergoing surgery. METHODS: From January 2000 through December 2010, a total of 96 consecutive patients with moderate or severe IMR, as determined by preoperative echocardiography, underwent on-pump coronary artery bypass grafting (CABG) (n = 66) or OPCAB (n = 30) revascularization with concomitant mitral valve repair or replacement. A retrospective analysis of a prospectively collected cardiac surgery database (PATS; Dendrite Clinical Systems, Oxford, UK) was performed. In addition, medical notes and charts were reviewed for all study patients. RESULTS: The 2 groups had similar preoperative demographic and EuroSCORE risk-stratification characteristics. The operative mortality rate for the entire cohort was 9.4%. Patients who underwent OPCAB grafting had a lower operative mortality than those who underwent CABG (3.3% versus 12.1%; P = .006). The mean +/-SD cardiopulmonary bypass time (82.7 +/- 34.7 minutes versus 160.7 +/- 45.2 minutes; P < .001) and cross-clamp time (49.0 +/- 22.4 minutes versus 103.4 +/- 39.5 minutes; P < .001) were significantly shorter in the off-pump group than in the on-pump group. The OPCAB group also had significantly less in-hospital morbidity and shorter stays in the intensive care unit and the hospital. CONCLUSION: Our analysis shows that OPCAB grafting (compared with conventional CABG) before repairing MR is associated with favorable in-hospital outcomes for patients undergoing surgery for IMR. PMID- 23439352 TI - Mitral paravalvular leak: caution in percutaneous occluder device deployment. AB - A frail 70-year-old woman presented with symptomatic mitral paravalvular leak 2 months after undergoing a double valve replacement for mixed mitral and aortic valve disease. There was no evidence of prosthetic valve endocarditis. Percutaneous closure of the paravalvular leak was attempted as an alternative to a high-risk surgical procedure. This therapy was successful in reducing the regurgitation but resulted in severe intravascular hemolysis and acute renal failure requiring hemodialysis.The development of new hemolysis and acute renal failure directed our attention to the Amplatzer device as a possible etiology for these complications. The assumption that her kidney injury was recent and likely reversible compelled us to think of the surgical method as a definitive option. A re-operative surgery was performed, which included retrieval of the occluder devices, pericardial patch repair, and re-replacement using a new biological prosthesis. The patient's urine output gradually improved, and the patient was dismissed with normal renal function.We present this case as an unusual complication of percutaneous device closure. It also highlights the reversible nature of acute renal failure due to intravascular hemolysis and demonstrates the importance of early surgical intervention for this condition. PMID- 23439353 TI - Repair of aortic regurgitation due to Takayasu arteritis. AB - BACKGROUND: Prosthetic valve detachment after aortic valve replacement and pseudoaneurysm formation are the most important postoperative complications in patients with Takayasu arteritis with aortic regurgitation. We reviewed our experience of surgical treatment of aortic regurgitation in patients with Takayasu disease. METHODS: Between November 1997 and September 2011, 11 patients (4 women and 7 men) with Takayasu arteritis with aortic regurgitation underwent surgical treatment. The age of the patients ranged from 26 to 56 years (mean, 40 +/- 9 years). Primary isolated aortic valve replacement was performed in 1 patient, David procedure in 1 patient, Wheat procedure in 1 patient, Bentall procedure in 2 patients, and Cabrol procedure in 6 patients (including 2 patients who underwent primary aortic valve replacement in other hospitals before being admitted to our surgical team). RESULTS: There was no in-hospital death. All patients had an uneventful recovery during the postoperative course and were discharged. Prosthetic valve detachment, pseudoaneurysm formation at the suture line, and dilatation of the ascending aorta were not found in patients with composite aortic root replacement during a mean follow-up of 98 +/- 45 months. One patient died during follow-up. CONCLUSION: Valve detachment after composite aortic root replacement was not observed in patients with Takayasu disease with aortic regurgitation. Satisfactory surgical outcomes were obtained using composite aortic root replacement. However, close follow-up was needed to assess the effectiveness of the Cabrol procedure in patients with Takayasu disease with aortic regurgitation. PMID- 23439354 TI - Long-term right ventricular assist device support for congenitally corrected transposition of the great arteries. AB - With congenitally corrected transposition of the great arteries, the right ventricle (RV) supports the systemic circulation. These patients have an increased risk of developing heart failure. Implantation of a ventricular assist device may be the only therapeutic option for patients who are not transplantation candidates. The technical aspects of implanting a mechanical device into the RV have not been well described, however. We describe our experience with one such case and describe our operative strategy in obtaining optimal placement of the inflow cannula. PMID- 23439355 TI - Results of additional pulsatile pulmonary blood flow with bidirectional glenn cavopulmonary anastomosis: positive effect on main pulmonary artery growth and less need for fontan conversion. AB - BACKGROUND: Additional antegrade pulsatile pulmonary blood flow obtained by leaving the main pulmonary artery patent during bidirectional cavopulmonary shunt has been shown to give additional benefits to the bidirectional Glenn cavopulmonary anastomosis. We retrospectively evaluated our 20-patient pulsatile Glenn series in order to find out whether these salutary effects were valid or not. METHODS: Between June 2007 and November 2011, 20 patients (11 girls and 9 boys) with single-ventricle physiology underwent bidirectional cavopulmonary anastomosis. The additional source of blood flow was through the unligated main pulmonary artery in all patients. A retrospective review of our surgical experience was performed focusing on the role of additional pulmonary flow. Medical records and perioperational and postoperative follow-up data including clinical outcomes were retrospectively retrieved and analyzed. RESULTS: Two patients died in the early postoperative period. One patient died in the follow up period. Mean follow-up time was 23.9 +/- 15.7 months. No superior vena cava syndrome and no increase in pulmonary vascular resistance were observed. Improvement of partial oxygen pressure after pulsatile Glenn has been shown in all patients (P = .00). At a mean interval of 22.9 months, main pulmonary artery size continued to increase after pulsatile Glenn cavopulmonary anastomosis (P = .028). Only 1 patient was converted to Fontan type circulation after pulsatile Glenn cavopulmonary anastomosis. CONCLUSIONS: The pulsatile cavopulmonary shunt is a useful procedure in the early and intermediate term management of patients with a functional univentricular heart. It improves partial oxygen pressure and the impact of pulsatility on the main pulmonary artery. PMID- 23439356 TI - An intramural left main coronary artery with a left sinus of valsalva aneurysm: a unique combination of congenital anomalies. AB - The congenital anomaly of an intramural left main coronary artery arising in the anatomically correct aortic sinus is very infrequent. Aneurysms involving the sinus of Valsalva rarely arise from the left aortic sinus. We present the clinical features and surgical correction of this rare anomaly along with a short discussion of these congenital malformations. PMID- 23439358 TI - An unusual cause of shortness of breath: hamman syndrome. PMID- 23439357 TI - Combined treatment of ulinastatin and tranexamic acid provides beneficial effects by inhibiting inflammatory and fibrinolytic response in patients undergoing heart valve replacement surgery. AB - OBJECTIVE: To investigate the effect of ulinastatin and tranexamic acid administered alone or in combination on inflammatory cytokines and fibrinolytic system in patients undergoing heart valve replacement surgery during cardiopulmonary bypass (CPB). BACKGROUND: CPB-induced fibrinolytic hyperfunction and systemic inflammatory response syndrome (SIRS) are the leading causes responsible for the occurrence of postsurgical complications such as postsurgical cardiac insufficiency and lung injury, which may lead to an increase in postsurgical bleeding, prolongation of hospital stay, and increased costs. METHODS: One hundred twenty patients undergoing heart valve replacement surgery during CPB were randomly assigned into 4 groups of 30 patients each: blank control group (Group C), tranexamic acid group (Group T), ulinastatin group (Group U), and tranexamic acid-ulinastatin combination group (Group D). Physiological saline, tranexamic acid, ulinastatin, and a combination of tranexamic acid and ulinastatin were given to each group, respectively. Arterial blood was collected from the radial artery at 4 time points: after induction of anesthesia (T1), unclamping the ascending aorta (T2), and at 1 hour (T3) and 24 hours (T4) after CPB. The levels of plasma tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL-6), neutrophil elastase (NE), and the concentrations of tissue plasminogen activator (t-PA) and alpha2-antiplasmin (alpha2-AP) were detected. The changes in the volume of pericardial mediastinal drainage after surgery were observed and recorded. RESULTS: The plasma TNF-alpha, IL-6, and NE levels significantly increased in patients from all 4 groups at time points of T2, T3, and T4 in comparison to those before CPB (P < .05), and the plasma TNF alpha and IL-6 levels in groups U and D were significantly lower than those in the other 2 groups (P < .05). The plasma t-PA, alpha2-AP, and D-dimer concentrations significantly increased in patients from all 4 groups at T2 and T3 compared with those before CPB (P < .05), and the plasma t-PA and D-dimer concentrations were significantly lower in groups T and D than those in groups U and C (P < .05) at T2 and T3. The plasma alpha2-AP concentrations in groups T and D were significantly higher than those in Group C at T3 (P < .05). The volumes of pericardial mediastinal drainage per body surface area were significantly lower in groups T and D than those in Group C 6 hours after the surgery (P < .05). CONCLUSIONS: Ulinastatin inhibits the release of inflammatory medium and reduces the inflammatory response during CPB. Tranexamic acid can effectively inhibit the fibrinolytic hyperfunction caused by CPB and thus decreases postsurgical bleeding. In addition, it exhibits a minor anti-inflammatory response. As a consequence, a combined treatment of ulinastatin and tranexamic acid reduces postsurgical bleeding and shortens postoperative hospital stay in patients undergoing heart valve replacement surgery. PMID- 23439359 TI - Cardiac tamponade due to left ventricular pseudoaneurysm after aortic valve replacement. AB - Left ventricular outflow tract pseudoaneurysm is a rare but a potentially lethal complication, mainly after aortic root endocarditis or surgery. Usually, it originates from a dehiscence in the mitral-aortic intervalvular fibrosa and arises posteriorly to the aortic root. We report a rare case of a patient with cardiac tamponade due to left ventricular pseudoaneurysm after aortic valve replacement. The subsequent surgical resection was performed successfully. PMID- 23439361 TI - Left ventricular myxoma producing cardiac failure. AB - INTRODUCTION: Seventy-five percent of primary cardiac tumors are benign, and most are myxomas. Seventy-five percent of myxomas originate from the left atrium, and 2.5% arise from the left ventricle. Heart failure is a rare complication of myxoma. CASE: A 54-year-old male patient with chronic obstructive pulmonary disease was admitted to the pulmonology department with a diagnosis of pneumonia and congestive heart failure during hospitalization. An echocardiography evaluation revealed a mobile mass (3.3 cm X 1.2 cm) in the left ventricle. The measured ejection fraction was 22%. Transthoracic and transesophageal echocardiography and magnetic resonance imaging examinations confirmed the presence of a myxoma in the left ventricle. The myxoma was a hanging mass with a stalk on the interventricular septum near the anterior mitral valve annulus. We visualized the gelatinous fragile mass on the septum; we then extracted the myxoma via a transaortic approach with the patient on cardiopulmonary bypass. The patient was discharged 10 days after surgery. DISCUSSION: Myxoma is treated by early surgical resection because of the potential for serious complications. Left ventricular myxomas have been reported to lead to a silent heart failure. This case is important because of its location and the patient's resultant heart failure. PMID- 23439362 TI - Influence of type of aortic valve prosthesis on coronary blood flow velocity. AB - BACKGROUND: Severe aortic valve stenosis is associated with high resting and reduced hyperemic coronary blood flow. Coronary blood flow increases after aortic valve replacement (AVR); however, the increase depends on the type of prosthesis used. The present study investigates the influence of type of aortic valve prosthesis on coronary blood flow velocity. METHODS: The blood flow velocity in the left anterior descending coronary artery (LAD) and the right coronary artery (RCA) was measured intraoperatively before and after AVR with a stentless bioprosthesis (Sorin Freedom Solo; n = 11) or a bileaflet mechanical prosthesis (St. Jude Medical Regent; n = 11). Measurements were made with an X-Plore epicardial Doppler probe (Medistim, Oslo, Norway) following induction of hyperemia with an adenosine infusion. Preoperative and postoperative echocardiography evaluations were used to assess valvular and ventricular function. Velocity time integrals (VTI) were measured from the Doppler signals and used to calculate the proportion of systolic VTI (SF), diastolic VTI (DF), and normalized systolic coronary blood flow velocities (NSF) and normalized diastolic coronary blood flow velocities (NDF). RESULTS: The systolic proportion of the LAD VTI increased after AVR with the St. Jude Medical Regent prosthesis, which produced higher LAD SF and NSF values than the Sorin Freedom Solo prosthesis (SF, 0.41 +/- 0.09 versus 0.29 +/- 0.13 [P = .04]; NSF, 0.88 +/- 0.24 versus 0.55 +/- 0.17 [P = .01]). No significant changes in the LAD velocity profile were noted after valve replacement with the Sorin Freedom Solo, despite a significant reduction in transvalvular gradient and an increase in the effective orifice area. AVR had no effect on the RCA flow velocity profile. CONCLUSION: The coronary flow velocity profile in the LAD was significantly influenced by the type of aortic valve prosthesis used. The differences in the LAD velocity profile probably reflect differences in valve design and the systolic transvalvular flow pattern. PMID- 23439360 TI - Reverse subclavian flap repair and maintenance of antegrade blood flow within the left subclavian artery in neonates with aortic coarctation and distal arch hypoplasia. AB - Surgical palliation for aortic coarctation with aortic arch hypoplasia in neonates and infants has been used in the clinic as the most beneficial treatment for this disorder. This technique allows the correction of aortic coarctation by the use of "extended" anastomosis without cardiopulmonary bypass, which expands the hypoplastic distal aortic arch via the use of a reverse subclavian flap repair. This technique maintains antegrade blood flow within the left subclavian artery. PMID- 23439367 TI - Nutrition in CKD: Songgaar | Burungaar. PMID- 23439365 TI - IDX184 in combination with pegylated interferon-alpha2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C. AB - BACKGROUND: IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase. METHODS: This randomized, double-blind, placebo controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-alpha2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA>=5 log10 IU/ml, alanine aminotransferase <=3* upper limit of normal and compensated liver disease were dosed. Sequential cohorts of 20 patients, randomized 16:4 (active:placebo), received IDX184 for 14 days at rising daily doses of 50, 100, 150 or 200 mg in combination with P/R for 14 days. RESULTS: At the end of triple dosing, HCV RNA changes from baseline (mean +/-sd log10) and proportion of patients achieving undetectable viral load (<15 IU/ml) based on the efficacy-evaluable population were -2.7 +/-1.3 (13%), -4.0 +/-1.7 (50%), -4.2 +/-1.9 (50%), -4.1 +/-1.2 (40%), -4.3 +/-1.5 (29%) and -3.7 +/-1.2 (25%) for the 50 mg once daily, 50 mg twice daily, 100 mg once daily, 150 mg once daily, 100 mg twice daily and 200 mg once daily IDX184 doses, respectively. P/R alone resulted in a reduction of -1.5 +/-1.3 log10 with only 6% of patients with undetectable viral load. Patients with genotypes-1a or -1b responded similarly. No viral breakthrough or resistance associated with IDX184 was observed. Anti-HCV activity of IDX184 correlated with plasma exposure of its nucleoside metabolite 2'-methylguanosine. Most adverse events were mild or moderate in severity and were consistent with those associated with P/R. The most common adverse events were fatigue and headache. CONCLUSIONS: IDX184 in combination with P/R for 14 days was well tolerated and demonstrated greater antiviral activity with more patients achieving undetectable viral load than P/R. PMID- 23439364 TI - ELAV proteins along evolution: back to the nucleus? AB - The complex interplay of post-transcriptional regulatory mechanisms mediated by RNA-binding proteins (RBP) at different steps of RNA metabolism is pivotal for the development of the nervous system and the maintenance of adult brain activities. In this review, we will focus on the highly conserved ELAV gene family encoding for neuronal-specific RBPs which are necessary for proper neuronal differentiation and important for synaptic plasticity process. In the evolution from Drosophila to man, ELAV proteins seem to have changed their biological functions in relation to their different subcellular localization. While in Drosophila, they are localized in the nuclear compartment of neuronal cells and regulate splicing and polyadenylation, in mammals, the neuronal ELAV proteins are mainly present in the cytoplasm where they participate in regulating mRNA target stability, translation and transport into neurites. However, recent data indicate that the mammalian ELAV RBPs also have nuclear activities, similarly to their fly counterpart, being them able to continuously shuttle between the cytoplasm and the nucleus. Here, we will review and comment on all the biological functions associated with neuronal ELAV proteins along evolution and will show that the post-transcriptional regulatory network mediated by these RBPs in the brain is highly complex and only at an initial stage of being fully understood. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'. PMID- 23439366 TI - CRISPR-Cas: evolution of an RNA-based adaptive immunity system in prokaryotes. AB - The CRISPR-Cas (clustered regularly interspaced short palindromic repeats, CRISPR associated genes) is an adaptive immunity system in bacteria and archaea that functions via a distinct self-non-self recognition mechanism that is partially analogous to the mechanism of eukaryotic RNA interference (RNAi). The CRISPR-Cas system incorporates fragments of virus or plasmid DNA into the CRISPR repeat cassettes and employs the processed transcripts of these spacers as guide RNAs to cleave the cognate foreign DNA or RNA. The Cas proteins, however, are not homologous to the proteins involved in RNAi and comprise numerous, highly diverged families. The majority of the Cas proteins contain diverse variants of the RNA recognition motif (RRM), a widespread RNA-binding domain. Despite the fast evolution that is typical of the cas genes, the presence of diverse versions of the RRM in most Cas proteins provides for a simple scenario for the evolution of the three distinct types of CRISPR-cas systems. In addition to several proteins that are directly implicated in the immune response, the cas genes encode a variety of proteins that are homologous to prokaryotic toxins that typically possess nuclease activity. The predicted toxins associated with CRISPR Cas systems include the essential Cas2 protein, proteins of COG1517 that, in addition to a ligand-binding domain and a helix-turn-helix domain, typically contain different nuclease domains and several other predicted nucleases. The tight association of the CRISPR-Cas immunity systems with predicted toxins that, upon activation, would induce dormancy or cell death suggests that adaptive immunity and dormancy/suicide response are functionally coupled. Such coupling could manifest in the persistence state being induced and potentially providing conditions for more effective action of the immune system or in cell death being triggered when immunity fails. PMID- 23439368 TI - Acute kidney injury: global health alert. PMID- 23439369 TI - Bon appetit: time to eat for better kidney health. PMID- 23439370 TI - Direct and indirect effects of obesity on the kidney. AB - Over the last few decades, much of the world has experienced an epidemic of obesity. In the year 2008, 1.4 billion people worldwide were overweight, and 500 million were obese. Even more alarming is a fact that in the year 2010, 40 million children under the age of 5 years were overweight or obese. In the same time period, the incidence of CKD has also increased worldwide. Obesity has been recognized as a driving force of another global epidemic-diabetes, the leading cause of ESRD. Recent studies are confirming that in addition to risk associated with diabetes per se, increased body mass index is independently linked to increased risk for various kidney disorders, prominently CKD, but also renal cell carcinoma and nephrolithiasis. The purpose of this article is to review current knowledge regarding adverse effects of obesity on the kidney. PMID- 23439371 TI - Obesity in patients undergoing dialysis and kidney transplantation. AB - Obesity poses a major challenge for nephrologists and patients alike, and its prevalence among patients with kidney disease is increasing at least as fast as in the general population. Although the body mass index (BMI) is the most commonly used measurement of excess adiposity, it has important limitations that can be ameliorated by incorporating other markers of body composition. The influence of obesity on outcomes in patients undergoing dialysis and kidney transplantation is of great interest. Although the preponderance of epidemiologic data suggests that, at least in patients undergoing dialysis, obesity has a neutral or protective effect on mortality, although this has not been confirmed in interventional studies needed to establish causality. The effect of obesity on other important outcomes such as quality of life has yet to be determined, and much less information on obesity and outcomes is available in the kidney transplantation population. Similarly, research on the optimal strategies and effects of weight loss in dialysis and kidney transplantation patients is at a nascent stage. PMID- 23439372 TI - Dietary patterns, calories, and kidney disease. AB - Specific nutritional factors that mediate obesity or CKD remain very difficult to quantify in any population. That being said, several macronutrients, including protein intake, have been examined as risk factors for CKD progression. Given the correlation of micro- and macronutrients within a particular diet and the consistency of an individual's dietary habits over time for most individuals, dietary patterns may have a greater impact on CKD risk and progression. This review focuses on dietary patterns and their association with CKD. To date, studies examining dietary patterns and CKD risk remain very limited, and more studies are needed. However, the follow-up period may need to be fairly long to detect any association. Caloric intake itself may also affect CKD risk. This may be due to the influence of caloric intake on sirtuin1, which modulates adiponectin gene expression and nitric oxide bioavailability. PMID- 23439375 TI - Dietary sugar and artificial sweetener intake and chronic kidney disease: a review. AB - Sugar consumption, especially in the form of fructose, has been hypothesized to cause kidney disease. This review provides an overview of the epidemiologic evidence that sugar consumption increases CKD risk. Research supports a causal role of sugar in several kidney disease risk factors, including increasing serum uric acid levels, diabetes, and obesity. Sugar may also harm the kidney via other mechanisms. There is no evidence that sucrose is any safer for the kidney than high fructose corn syrup (HFCS) because both are similar in composition. To date, 5 epidemiologic studies have directly evaluated the relationship between sugar consumption (in the form of sugar-sweetened beverages) and CKD. Although most studies suggest that the risk of CKD is elevated among consumers of sugar sweetened beverages, only 2 studies report statistically significant associations. Three studies have also examined diet soda consumption, with two reporting positive and significant associations. Confounding by unmeasured lifestyle factors may play a role in the positive results whereas poor measurement of sugar and artificial sweetener intake could explain null results. Nevertheless, the hypothesis that sugar causes kidney disease remains plausible, and alternative research designs may be needed. PMID- 23439373 TI - Dietary acid load: a novel nutritional target in chronic kidney disease? AB - Nonvolatile acid is produced from the metabolism of organic sulfur in dietary protein and the production of organic anions during the combustion of neutral foods. Organic anion salts that are found primarily in plant foods are directly absorbed in the gastrointestinal tract and yield bicarbonate. The difference between endogenously produced nonvolatile acid and absorbed alkali precursors yields the dietary acid load, technically known as the net endogenous acid production, and must be excreted by the kidney to maintain acid-base balance. Although typically 1 mEq/kg/day, dietary acid load is lower with greater intake of fruits and vegetables. In the setting of CKD, a high dietary acid load invokes adaptive mechanisms to increase acid excretion despite reduced nephron number, such as increased per nephron ammoniagenesis and augmented distal acid excretion mediated by the renin-angiotensin system and endothelin-1. These adaptations may promote kidney injury. Additionally, high dietary acid loads produce low-grade, subclinical acidosis that may result in bone and muscle loss. Early studies suggest that lowering the dietary acid load can improve subclinical acidosis, preserve bone and muscle, and slow the decline of glomerular filtration rate in animal models and humans. Studies focusing on hard clinical outcomes are needed. PMID- 23439374 TI - Sodium- and phosphorus-based food additives: persistent but surmountable hurdles in the management of nutrition in chronic kidney disease. AB - Sodium- and phosphorus-based food additives are among the most commonly consumed nutrients in the world. This is because both have diverse applications in processed food manufacturing, leading to their widespread use by the food industry. Since most foods are naturally low in salt, sodium additives almost completely account for the excessive consumption of sodium throughout the world. Similarly, phosphorus additives represent a major and "hidden" phosphorus load in modern diets. These factors pose a major barrier to successfully lowering sodium or phosphorus intake in patients with CKD. As such, any serious effort to reduce sodium or phosphorus consumption will require reductions in the use of these additives by the food industry. The current regulatory environment governing the use of food additives does not favor this goal, however, in large part because these additives have historically been classified as generally safe for public consumption. To overcome these barriers, coordinated efforts will be needed to demonstrate that high intake of these additives is not safe for public consumption and as such should be subject to greater regulatory scrutiny. PMID- 23439376 TI - Optimum nutrition for kidney stone disease. AB - We summarize the data regarding the associations of individual dietary components with kidney stones and the effects on 24-hour urinary profiles. The therapeutic recommendations for stone prevention that result from these studies are applied where possible to stones of specific composition. Idiopathic calcium oxalate stone-formers are advised to reduce ingestion of animal protein, oxalate, and sodium while maintaining intake of 800 to 1200 mg of calcium and increasing consumption of citrate and potassium. There are few data regarding dietary therapy of calcium phosphate stones. Whether the inhibitory effect of citrate sufficiently counteracts increasing urine pH to justify more intake of potassium and citrate is not clear. Reduction of sodium intake to decrease urinary calcium excretion would also be expected to decrease calcium phosphate stone recurrence. Conversely, the most important urine variable in the causation of uric acid stones is low urine pH, linked to insulin resistance as a component of obesity and the metabolic syndrome. The mainstay of therapy is weight loss and urinary alkalinization provided by a more vegetarian diet. Reduction in animal protein intake will reduce purine ingestion and uric acid excretion. For cystine stones, restriction of animal protein is associated with reduction in intake of the cystine precursor methionine as well as cystine. Reduction of urine sodium results in less urine cystine. Ingestion of vegetables high in organic anion content, such as citrate and malate, should be associated with higher urine pH and fewer stones because the amino acid cystine is soluble in more alkaline urine. Because of their infectious origin, diet has no definitive role for struvite stones except for avoiding urinary alkalinization, which may worsen their development. PMID- 23439377 TI - Optimal nutrition for predialysis chronic kidney disease. AB - Diet potentially plays a major role in the progression and complications of predialysis CKD. Moderate protein consumption along with a diet low in sodium might slow kidney disease progression. Increasing vegetable protein intake might decrease serum phosphorus, uremic toxins, and kidney damage. Because obesity might be an important factor in the increasing prevalence of CKD, dietary strategies targeting obesity might also benefit CKD progression. In those with more advanced CKD, dietary calcium and phosphorus restriction could minimize vascular calcification. Dietary fiber and vitamin D supplementation might also be important to decrease inflammation in CKD. PMID- 23439379 TI - Nutrition and the kidney: recommendations for peritoneal dialysis. AB - Protein energy wasting (PEW) is highly prevalent in peritoneal dialysis (PD) and is associated with poor outcomes, including hospitalization and mortality. Recognizing and diagnosing PEW in PD is important; although studies are limited, there are interventions that may be associated with improved outcomes. In this review of nutritional aspects of PD, we highlight some of the important causes of PEW and explore the current diagnostic tools that are used to assess PEW. Finally, we discuss the established and experimental therapies for PEW in PD. PMID- 23439378 TI - Optimal nutrition in hemodialysis patients. AB - Protein-energy wasting (PEW) is highly prevalent in patients undergoing maintenance hemodialysis (MHD). It is important to note that there is a robust association between the extent of PEW and the risk of hospitalization and death in these patients, regardless of the nutritional marker used. The multiple etiologies of PEW in advanced kidney disease are still being elucidated. Apart from the multiple mechanisms that might lead to PEW, it appears that the common pathway for all of the derangements is related to exaggerated protein degradation along with decreased protein synthesis. The hemodialysis procedure per se is an important contributor to this process. Metabolic and hormonal derangements such as acidosis, inflammation, and resistance to anabolic properties of insulin resistance and growth hormone are all implicated for the development of PEW in MHD patients. Appropriate management of MHD patients at risk for PEW requires a comprehensive combination of strategies to diminish protein and energy depletion and to institute therapies that will avoid further losses. The mainstay of nutritional treatment in MHD patients is provision of an adequate amount of protein and energy, using oral supplementation as needed. Intradialytic parenteral nutrition should be attempted in patients who cannot efficiently use the gastrointestinal tract. Other anabolic strategies such as exercise, anabolic hormones, anti-inflammatory therapies, and appetite stimulants can be considered as complementary therapies in suitable patients. PMID- 23439380 TI - Stented bioprostheses in aortic position. AB - INTRODUCTION: Biological stented prostheses are currently the main type of prosthetic valve used for aortic valve replacement. The ratio of bioprotheses to mechanical prostheses has switched in the last 15 years; the percentage of biological prostheses implanted has risen from 30 % to 85 %. Moreover the total number of implanted stented bioprostheses remained stable over the last years despite competing procedures like stentless prostheses or transcatheter aortic valve implantation. METHODS: A literature search of all published aortic valve replacement studies was performed from January 2000 through May 2012. RESULTS: The recommendations guiding the type of heart valve replacement have been revised in recent years. Of particular interest are the new generation of biological prostheses with extended durability, a decrease in mortality of reoperation and an increase in life expectancy. Comorbidities such as chronic renal insufficiency or chronic atrial fibrillation are no longer contraindications to bioprostheses. CONCLUSION: Overall, even in face of more innovative biological alternatives the implantation of stented bioprostheses is still a very interesting option and represents actually the most frequent valve implantation technique for aortic stenosis. PMID- 23439381 TI - High-resolution identification of human adiponectin oligomers and regulation by pioglitazone in type 2 diabetic patients. AB - Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, and cardiac protective actions. It homo-oligomerizes into trimers, hexamers, and higher molecular weight (HMW) species, which are not fully characterized. We describe high-resolution separation of adiponectin oligomers under native conditions in polyacrylamide gel coupled with methods for producing standards to provide facile and accurate identification of the oligomers. Using these procedures, adiponectin trimers in human and rodent plasma were found to migrate as two distinct populations. Distributions of these two populations are linearly proportional in plasma from type 2 diabetic patients before (R(2)=0.903, P<0.001) and after (R(2)=0.960, P<0.0001) 12weeks of treatment with pioglitazone as well as from control subjects (R(2)=0.891, P<0.0001). In addition, HMW adiponectin could be separated into three distinct oligomers: nonamer (9mer), dodecamer (12mer), and the previously characterized octadecamer (18mer). Plasma concentrations of all oligomers increased on pioglitazone treatment, with the largest fold increase being observed in 9mers and 12mers compared with baseline. Increasing concentrations of adiponectin during oligomerization in vitro led to a disproportionate increase in 18mers. The difference between in vivo and in vitro observations suggests that higher total adiponectin protein concentration contributes to pioglitazone's ability to enhance HMW adiponectin levels, but additional factors likely affect oligomer assembly or turnover independently. PMID- 23439382 TI - Cyclization tag for the detection and facile purification of backbone-cyclized proteins. AB - Backbone-cyclized proteins, with their characteristic stability toward denaturants such as heat and chemicals, are becoming increasingly significant in many applications. Intein-mediated protein cyclization is the most efficient and frequently used method of choice and has been successfully applied to various targets, achieving stable proteins. However, the detection and isolation of the cyclic protein from the linear one after cyclization is very difficult because the backbone-cyclized protein and the linear one (a by-product formed during the cyclization reaction), which originated from the same molecule, are almost identical in terms of their size. Thus, we first developed a split c-myc tag system; the active c-myc tag was formed only in the backbone-cyclized protein and not in the linear by-product from the inactive precursor, and this helps both the detection and purification of the backbone-cyclized proteins. This tag system, which we called a cyclization tag, was further engineered in its sequence to develop an engineered c-myc (e-myc) tag with enhanced efficiency in the backbone cyclization reaction while keeping its specificity toward the commercial antibody intact. Using two different proteins as models, we show that the cyclization tag developed here can be used as a specific tag for the backbone-cyclized protein, thereby facilitating detection and purification. PMID- 23439384 TI - Expression and differential response to haloperidol treatment of Cyclon/CCDC86 mRNA in schizophrenia patients. AB - A gene known as Cyclon (cytokine-induced protein with coiled-coil domain) or CCDC86 (coiled-coil domain-containing protein 86) is known for its expression in leukocytes in mice, where it regulates the immune response. We investigated whether Cyclon/CCDC68 is expressed in leukocytes of schizophrenia patients and whether it might be used as a biological marker for the disease endophenotype segregation. We examined the level of mRNA of Cyclon/CCDC68 in white blood cells obtained from schizophrenia patients in relapse and remission as well as in healthy controls. The mRNA of Cyclon/CCDC68 was expressed by white blood cells of both schizophrenia patients and healthy controls. There was a dichotomous change in the levels of Cyclon/CCDC68 of relapsed patients before and after treatment. High Cyclon/CCDC68 levels were associated with a recent disease and presence of psychotic symptoms, while low levels were associated with a long duration of the disease and an absence of psychotic symptoms. These data indicate that Cyclon/CCDC68 levels correlate with the clinical presentation of relapsed schizophrenia. Cyclon/CCDC68 might be involved in the immune system disturbances observed in schizophrenia. PMID- 23439383 TI - Long-term potentiation: peeling the onion. AB - Since the discovery of long-term potentiation (LTP), thousands of papers have been published on this phenomenon. With this massive amount of information, it is often difficult, especially for someone not directly involved in the field, not to be overwhelmed. The goal of this review is to peel away as many layers as possible, and probe the core properties of LTP. We would argue that the many dozens of proteins that have been implicated in the phenomenon are not essential, but rather modulate, often in indirect ways, the threshold and/or magnitude of LTP. What is required is NMDA receptor activation followed by CaMKII activation. The consequence of CaMKII activation is the rapid recruitment of AMPA receptors to the synapse. This recruitment is independent of AMPA receptor subunit type, but absolutely requires an adequate pool of surface receptors. An important unresolved issue is how exactly CaMKII activation leads to modifications in the PSD to allow rapid enrichment. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID- 23439385 TI - Docosahexaenoic acid and tetracyclines as promising neuroprotective compounds with poly(ADP-ribose) polymerase inhibitory activities for oxidative/genotoxic stress treatment. AB - The human genome is exposed to oxidative/genotoxic stress by several endogenous and exogenous compounds. These events evoke DNA damage and activate poly(ADP ribose) polymerase-1 (PARP-1), the key enzyme involved in DNA repair. The massive stress and over-activation of this DNA-bound enzyme can be responsible for an energy crisis and neuronal death. The last data indicated that product of PARP-1, i.e. poly(ADP-ribose) (PAR), acts as a signalling molecule and plays a significant role in nucleus-mitochondria cross-talk. PAR translocated to the mitochondria can be involved in mitochondrial permeability, the release of an apoptosis-inducing factor (AIF). Its translocation into the nucleus leads to chromatin condensation, fragmentation and cell death. The exact mechanism of this novel death pathway has not yet fully been understood. In this study the relationship between AIF and PARP/PAR in death signalling in the neuronal cell line (HT22) subjected to oxidative/genotoxic stress evoked by N-methyl-N'-nitro-N nitrosoguanidine (MNNG) was explored. The neuroprotective influence of docosahexaenoic acid (DHA), major dietary omega-3 long-chain polyunsaturated fatty acids as well as the action of tetracyclines, the novel suppressors of PARP 1, were examined. The effect of these all compounds was compared with specific PARP-1 inhibitors. The oxidative/genotoxic stress evoked by MNNG enhanced the level of PAR in a time-dependent manner with a concomitant significant decrease in the mitochondrial AIF protein level. Moreover, the down-regulation of the anti apoptotic proteins (Bcl-2 and Bcl-xL) and the up-regulation of the Bax pro apoptotic protein were presented. In these conditions massive HT22 cell death was observed. Both PARP-1 inhibitors: 3-aminobenzamide (3-AB) and PJ 34, tetracycline: doxocycline and minocycline, as well as DHA protected the cells against PAR formation and AIF translocation. Moreover, all of these compounds enhanced Bcl-xL gene expression and protected the cells against MNNG-induced death. Our data show that both DHA and tetracyclines offer a novel neuroprotective strategy for oxidative/genotoxic stress treatment. PMID- 23439386 TI - Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice. AB - d-Serine, an endogenous co-agonist of the N-methyl-d-aspartate (NMDA) receptor is synthesized from l-serine by serine racemase (SRR). A previous study of Srr knockout (Srr-KO) mice showed that levels of d-serine in forebrain regions, such as frontal cortex, hippocampus, and striatum, but not cerebellum, of mutant mice are significantly lower than those of wild-type (WT) mice, suggesting that SRR is responsible for d-serine production in the forebrain. In this study, we attempted to determine whether SRR affects the level of other amino acids in brain tissue. We found that tissue levels of d-aspartic acid in the forebrains (frontal cortex, hippocampus and striatum) of Srr-KO mice were significantly lower than in WT mice, whereas levels of d-aspartic acid in the cerebellum were not altered. Levels of d-alanine, l-alanine, l-aspartic acid, taurine, asparagine, arginine, threonine, gamma-amino butyric acid (GABA) and methionine, remained the same in frontal cortex, hippocampus, striatum and cerebellum of WT and mutant mice. Furthermore, no differences in d-aspartate oxidase (DDO) activity were detected in the forebrains of WT and Srr-KO mice. These results suggest that SRR and/or d serine may be involved in the production of d-aspartic acid in mouse forebrains, although further detailed studies will be necessary to confirm this finding. PMID- 23439387 TI - Activities of a medical emergency team twenty years after its introduction. AB - INTRODUCTION: We describe and quantify the wide range of activities that a mature Medical Emergency Team can progressively perform. METHODS: The activities performed by a Medical Emergency Team 20 years after its introduction were prospectively collected during 105 consecutive days. RESULTS: The main activity was focused on the follow-up visits to previously treated critically ill patients (mean 7.5 visits/die in working days, 5.1 in the others). A large amount of other scheduled or unscheduled activities (like sedation or analgesia for diagnostic procedures, central venous line placement, phone consultation regarding critical care aspects of treatments) were performed: on average, 7.3 side-activities/die in working days and 5.2 in the others. First consultations in patients not previously seen were on average 3.1/die on working days, 2.4 in the others. Cardiac arrest accounted for 27 (9%) of first time visits. CONCLUSIONS: A Medical Emergency Team can progressively perform many kinds of activities. An evaluation limited to the reduction of in-hospital cardiac arrests or a too early assessment may underestimate its beneficial effects on the Hospital complexity. PMID- 23439388 TI - Clinical results of implanted tissue engineered heart valves. AB - Since the first heterotopic implantation of a biological heart valve in 1955 by Murray, bioprostheses have been steadily improved. For allografts different methods have been evaluated and modified to stabilize and preserve the available tissue. Xenografts were fixed to cross-link the connective tissue as well as prevent immunogenic reactions. Nevertheless, gluteraldehyde fixation leads to structural deterioration, which could only be partially reduced by different kinds of anti-mineralization treatment. Due to preservation and fixation, allografts and xenografts become non-viable bioprostheses with a lack of remodelling, regeneration and growth. Tissue engineering is a possible key to overcome these disadvantages as it will provide living tissue with remodelling, regeneration and growth potential. This overview will look at the key points to provide such tissue engineered heart valves by creating an appropriate scaffold where cells can grow, either in vitro or in vivo and remodel a neo-scaffold which will lead to a functional autologous heart valve, and show initial clinical results. PMID- 23439389 TI - Brain response to affective pictures in the chimpanzee. AB - Advancement of non-invasive brain imaging techniques has allowed us to examine details of neural activities involved in affective processing in humans; however, no comparative data are available for chimpanzees, the closest living relatives of humans. In the present study, we measured event-related brain potentials in a fully awake adult chimpanzee as she looked at affective and neutral pictures. The results revealed a differential brain potential appearing 210 ms after presentation of an affective picture, a pattern similar to that in humans. This suggests that at least a part of the affective process is similar between humans and chimpanzees. The results have implications for the evolutionary foundations of emotional phenomena, such as emotional contagion and empathy. PMID- 23439390 TI - The expression of cytoskeletal proteins in kidney specimens of children with primary focal segmental glomerulosclerosis. AB - Several studies have evaluated cytoskeletal proteins as prognostic factors for some types of nephrotic syndrome. However, studies concerning children with FSGS are scarce. This study was done to evaluate the glomerular, tubular, and interstitial expression of vimentin, desmin, and alpha smooth muscle actin (alpha SMA) in kidney specimens of children with FSGS. Clinical and histologic data of 31 children with FSGS were reviewed. Thirty one formalin-fixed, paraffin-embedded kidney biopsy sections (3 MUm) were selected for immunohistochemical staining. Double immunohistochemistry using a microwave-based two-color staining was applied. The mean age at onset in male and female was 56.3 +/- 41.4 and 78.0 +/- 60.4 months, respectively. The duration of follow-up was 46.3 +/- 56.5 months. Interstitial fibrosis and tubular atrophy were reported in 42% and 54% of the patients, respectively. The latest evaluated mean blood pressure was significantly correlated with the expression of both vimentin and alpha-SMA in the interstitium (P < 0.05). However, we were not able to demonstrate any cytoskeletal protein expression as an independent predictor for renal survival. Further studies with larger sample size and longer follow-up periods are warranted to investigate the prognostic values of other histopathologic features in pediatrics with FSGS. PMID- 23439391 TI - Topical rapamycin (sirolimus) for facial angiofibromas. AB - Rapamycin (sirolimus) is a fungal fermentation product that inhibits the proper functioning of a serine/threonine protein kinase in mammalian cells eponymously named mammalian target of rapamycin, or mTOR. Rapamycin is a novel class of anticancer and immunosuppressant drugs targeting the proteins at molecular level. Rapamycin (sirolimus) is routinely incorporated in drug-eluting stents used for cardiac angioplasty. In recent years, rapamycin was found to be efficacious in managing the symptom complex of tuberous sclerosis, i.e. renal angiomyolipoma, giant cell astrocytoma and pulmonary lymphangiomyomatosis. Various investigators have also proved that topically applied rapamycin causes regression of facial angiofibromas, giving better cosmetic results. PMID- 23439392 TI - Merkel cell polyomavirus-positive Merkel cell carcinoma cells do not require expression of the viral small T antigen. AB - Increasing evidence suggests that Merkel cell carcinoma (MCC) is caused by the Merkel cell polyomavirus (MCV). The viral sequence encodes for two potential oncoproteins, i.e., the small T antigen (sT) and the large T antigen (LT). Indeed, sT has recently been shown to bear transforming activity. Here, we confirm this observation by demonstrating focus formation upon expression of MCV sT in NIH3T3 fibroblasts. On the other hand, however, we provide evidence that established MCC cells do not require sT for growth and survival. Silencing of sT protein expression by two different sT-specific short hairpin RNAs (shRNAs) leads to variable degrees of growth retardation in MCV-positive MCC cell lines. However, these effects are not sT specific, as proliferation of MCV-negative cell lines is similarly affected by these sT shRNAs. Furthermore, ectopic expression of shRNA-insensitive sT does not revert the growth inhibition implicated by sT silencing. Finally, the unambiguous and specific growth inhibition induced by means of an shRNA targeting both T antigens, can be completely rescued by ectopic expression of LT alone, thus demonstrating a dispensable role of sT. Altogether, our results indicate that MCV LT is more relevant in maintaining the proliferation and survival of established MCC cell lines. PMID- 23439394 TI - Vascular endothelial growth factor-d modulates caliber and function of initial lymphatics in the dermis. AB - The lymphatic vasculature is important for skin biology as it maintains dermal fluid homeostasis. However, the molecular determinants of the form and function of the lymphatic vasculature in skin are poorly understood. Here, we explore the role of vascular endothelial growth factor-d (Vegf-d), a lymphangiogenic glycoprotein, in determining the form and function of the dermal lymphatic network, using Vegf-d-deficient mice. Initial lymphatic vessels in adult Vegf-d deficient mice were significantly smaller than wild-type but collecting lymphatics were unaltered. The uptake/transport of dextran in initial lymphatics of Vegf-d-deficient mice was far less efficient, indicating compromised function of these vessels. The role of Vegf-d in modulating initial lymphatics was further supported by delivery of Vegf-d in skin of wild-type mice, which promoted enlargement of these vessels. Vegf-d-deficient mice were subjected to cutaneous wounding to challenge lymphatic function: the resulting wound epithelium was highly edematous and thicker, reflecting inadequate lymphatic drainage. Unexpectedly, myofibroblasts were more abundant in Vegf-d-deficient wounds leading to faster wound closure, but resorption of granulation tissue was compromised suggesting poorer-quality healing. Our findings demonstrate that Vegf d deficiency alters the caliber of initial lymphatics in the dermis leading to reduced functional capacity. PMID- 23439393 TI - Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with a pemphigus mAb. AB - We determined the feasibility of using an anti-desmoglein (Dsg) mAb, Px44, to deliver a biologically active protein to keratinocytes. Recombinantly produced Px44-green fluorescent protein (GFP) injected into mice and skin organ culture delivered GFP to the cell surface of keratinocytes. We replaced GFP with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to produce Px44-TRAIL. We chose TRAIL as a biological model because it inhibits activated lymphocytes and causes apoptosis of hyperproliferative keratinocytes, features of various skin diseases. Px44-TRAIL formed a trimer, the biologically active form of TRAIL. Standard assays of TRAIL activity showed that Px44-TRAIL caused apoptosis of Jurkat cells and inhibited IFN-gamma production by activated CD4+ T cells. Enzyme linked immunoassay with Px44-TRAIL showed delivery of TRAIL to Dsg. Immunofluorescence with Px44-TRAIL incubated on skin sections and cultured keratinocytes or injected into mouse skin, human organ culture, or human xenografts detected TRAIL on keratinocytes. Px44-TRAIL caused apoptosis of the hyperproliferative, but not differentiating, cultured keratinocytes through binding to Dsg3. Foldon, a small trimerization domain, cloned into Px44-TRAIL maintained its stability and biological activity at 37 degrees C for at least 48 hours. These data suggest that such targeted therapy is feasible and may be useful for hyperproliferative and inflamed skin diseases. PMID- 23439395 TI - Frizzled6 deficiency disrupts the differentiation process of nail development. AB - Nails protect the soft tissue of the tips of digits. The molecular mechanism of nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 (Fzd6), that is mutated in a human autosomal recessive nail dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6(-/-) mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation-related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6(-/-) mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of nail/claw formation. PMID- 23439396 TI - The NEDICES Study: Recent Advances in the Understanding of the Epidemiology of Essential Tremor. AB - BACKGROUND: Essential tremor (ET) is the most common tremor disorder. ET has classically been viewed as a benign monosymptomatic condition. Yet over the past 10 years, a growing body of evidence indicates that this is a progressive condition that is clinically heterogeneous, and may be associated with a variety of different features. Large epidemiological studies such as the Neurological Disorders of Central Spain (NEDICES), a longitudinal, population-based survey, have contributed significantly to the changing view of the disease. Our aim is to review some of the main results of NEDICES within the larger framework of the epidemiology of ET. METHODS: Data for this review were gathered from all our articles published up to October 2011 regarding NEDICES study and "Essential Tremor". RESULTS: We have published 18 articles up to October 2011. The prevalence, incidence, and mortality of ET were analyzed in this cohort. In addition, ET was found to be associated with increased frailty and low morale, as well as with a series of non-motor manifestations, including cognitive deficits, mild cognitive impairment, dementia, depressive symptoms, and hearing impairment. Finally, the link between ET and Parkinson's disease (PD) was formally quantified in the NEDICES study, which demonstrated that the risk of developing incident PD was 4.3 times higher in prevalent ET cases than in age-matched controls without ET. CONCLUSIONS: This review highlights the contributions of NEDICES towards the advancement of current knowledge of the epidemiology and clinical features of ET, and emphasizes the importance of population-based studies towards the understanding of complex, ageing-related diseases. PMID- 23439397 TI - Encephalopathy, hypoglycemia, and flailing extremities: a case of bilateral chorea-ballism associated with diabetic ketoacidosis. AB - BACKGROUND: Hypo/hyperglycemia is a known cause of chorea and hemiballism. The temporallobes, hippocampus, basal ganglia, and substantia nigra are most susceptible to hypoglycemic changes. METHODS: We present a caseof bilateral chorea and bi-ballism accompanied by encephalopathyin the setting of severe hypoglycemia and diabetic ketoacidosis. The patient had brain MRI changes involving both caudate nuclei, temporal lobes, and hippocampi. DISCUSSION: This case demonstrates the basal ganglia's vulnerability to hypoglycemia and the need for cautious evaluation of involuntary movements when they occur in the setting of encephalopathy. PMID- 23439398 TI - Humoral immune response of the small-spotted catshark, Scyliorhinus canicula. AB - Cartilaginous fishes are the oldest group in which an adaptive immune system based on immunoglobulin-superfamily members is found. This manuscript compares humoral immune function in small-spotted catshark (Scyliorhinus canicula) with that described for spiny dogfish (Squalus acanthias), another member of the Squalomorphi superorder, and nurse shark, the model for humoral immunity in elasmobranchs and a member of the Galeomorphi superorder. Although small-spotted catshark and nurse shark are separated by over 200 million years we found that immunoglobulin isoforms are well conserved between the two species. However, the plasma protein profile of small-spotted catshark was most similar to that of spiny dogfish, with low levels of pentameric IgM, and IgNAR present as a multimer in plasma rather than a monomer. We show that an antigen-specific monomeric IgM response, with a profile similar to that described previously for nurse sharks, can be raised in small-spotted catshark. Lacking polyclonal or monoclonal antibody reagents for detecting catshark IgNAR we investigated phage-display and recombinant Fc-fusion protein expression as alternative methods to look for an antigen-specific response for this isotype. However, we could find no evidence of an antigen-specific IgNAR in the animals tested using either of these techniques. Thus, unlike nurse sharks where antigen-specific monomeric IgM and IgNAR appear together, it seems there may be a temporal or complete 'uncoupling' of these isotypes during a humoral response in the small-spotted catshark. PMID- 23439399 TI - Temperature-induced transcription of inflammatory mediators and the influence of Hsp70 following LPS stimulation of southern bluefin tuna peripheral blood leukocytes and kidney homogenates. AB - Temperature is known to influence inflammatory signalling in mammals, but far less understood in fish. The aim of the present study was to explore the potential effects of temperature on innate immune signalling in head kidney and leukocyte populations of the economically important southern bluefin tuna through the identification and utilization of gene expression targets in vitro. Here, we identified the mRNA sequences of five potential inflammatory mediators - TNFalpha (1 and 2), IL-1beta, IL-8, and Cox2 - and demonstrate induction of four - TNFalpha (2), IL-1beta, IL-8, and Cox2 - following LPS stimulation of both peripheral blood leukocytes and head kidney homogenates in vitro by real-time quantitative PCR. Comparison of transcriptional expression in cultures held at 18 and 25 degrees C (both within the presumed natural temperature range of this heterothermic species) showed accelerated transcription of cytokines TNFalpha, IL 1beta and IL-8 following LPS stimulation at 25 degrees C in both tissue types. Peak induction reached comparable levels for each transcript at both temperatures during the 24 h test period with only limited (if any) protraction in expression resulting from cold temperature (18 degrees C) incubation. Partial mRNA sequences were also identified for both the constitutively expressed and heat inducible chaperone proteins Hsc70 and Hsp70, and 24 h incubation at 25 degrees C was sufficient to induce Hsp70 transcription in leukocyte but not in head kidney cell populations. Taken together these findings suggest that temperature exerts influence in the timing but not the degree of an innate inflammatory response in bluefin tuna and that different cell populations have differential responsiveness to heat shock in this heterothermic species. Further, LPS stimulation failed to induce Hsp70 at either incubation temperature in leukocytes; whereas 25 degrees C incubation caused Hsp70 up-regulation in leukocytes with or without the presence of LPS. This suggests that Hsp70 does not play a direct role in immune responsiveness for this species and that an environmental temperature of 25 degrees C in excess of 24 h initiates a cellular stress response in blood cells of this organism. Lastly, a strong correlation between Hsp70 and IL-8 transcriptional expression was observed following LPS/heat shock stimulation of leukocytes and five potential heat shock response elements were subsequently identified on the gene promoter region of IL-8 indicating that heat shock co-activation of this chemokine previously identified in mammals is also likely present in fish. PMID- 23439400 TI - Bystander-initiated chest compression-only CPR is better than standard CPR in out of-hospital cardiac arrest. AB - INTRODUCTION: Out-of-hospital cardiac arrest has a low survival rate to hospital discharge. Recent studies compared a simplified form of CPR, based on chest compression alone versus standard CPR including ventilation. We performed systematic review and meta-analysis of randomized controlled trials, focusing on survival at hospital discharge. METHODS: We extensively searched the published literature on out-of hospital CPR for non traumatic cardiac arrest in different databases. RESULTS: We identified only three randomized trials on this topic, including witnessed and not-witnessed cardiac arrests. When pooling them together with a meta-analytic approach, we found that there is already clinical and statistical evidence to support the superiority of the compression-only CPR in terms of survival at hospital discharge, as 211/1842 (11.5%) patients in the chest compression alone group versus 178/1895 (9.4%) in the standard CPR group were alive at hospital discharge: odds ratio from both Peto and DerSimonian-Laird methods =0.80 (95% confidence interval 0.65-0.99), p for effect =0.04, p for heterogeneity =0.69, inconsistency =0%). CONCLUSIONS: Available evidence strongly support the superiority of bystander compression-only CPR. Reasons for the best efficacy of chest compression-only CPR include a better willingness to start CPR by bystanders, the low quality of mouth-to-mouth ventilation and a detrimental effect of too long interruptions of chest compressions during ventilation. Based on our findings, compression-only CPR should be recommended as the preferred CPR technique performed by untrained bystander. PMID- 23439401 TI - Design of an expert system for mitigating trace element toxicity in cancer risk management. AB - Cancer risk management involves obliterating excess concentration of cancer causing trace elements by the natural immune system and hence intake of nutritious diet is of paramount importance. Human diet should consist of essential macronutrients that have to be consumed in large quantities and trace elements are to be consumed in very little amount. As some of these trace elements are causative factors for various types of cancer and build up at the expense of macronutrients, cancer risk management of these trace elements should be based on their initial concentration in the blood of each individual and not on their tolerable upper intake level. We propose an information theory based Expert System (ES) for estimating the lowest limit of toxicity association between the trace elements and the macronutrients. Such an estimate would enable the physician to prescribe required medication containing the macronutrients to annul the toxicity of cancer risk trace elements. The lowest limit of toxicity association is achieved by minimizing the correlated information of the concentration correlation matrix using the concept of Mutual Information (MI) and an algorithm based on a Technique of Determinant Inequalities (TDI) developed by the authors. The novelty of our ES is that it provides the lowest limit of toxicity profile for all trace elements in the blood not restricted to a group of compounds having similar structure. We demonstrate the superiority our algorithm over Principal Component Analysis in mitigating trace element toxicity in blood samples. PMID- 23439402 TI - Intensive insulin therapy to maintain normoglycemia after cardiac surgery. AB - Drugs used in the perioperative period could have an effect on survival as recently pointed out by an international consensus conference on the reduction in mortality in cardiac anesthesia and intensive care. Insulin infusion to achieve a strict glycemic control is the best example of how an ancillary (i.e. non surgical) drug/technique/strategy might influence survival rates in patients undergoing cardiac surgery. The author of this "expert opinion" presents her insights into the use of insulin in this setting and suggest that based on available evidence based medicine, insulin infusion, titrated to "normoglycemia" is a complex intervention, that not only requires the simple administration of a "drug", the hormone insulin, but also needs tools and skills to accurately measure and control blood glucose to achieve normoglycemia while avoiding hypoglycemia and large glucose fluctuations. PMID- 23439403 TI - Remifentanil to treat hypertension in overweight patients during a fentanyl-based cardiac anesthesia A case series. AB - Cardiac surgery is associated with intense nociceptive and autonomic stimulation especially during sternotomy and aortic root dissection and moderate-to-high dose opioids are required to blunt the hemodynamic and neuroendocrine response to this kind of procedures. However, episodes of unwanted sympathetic activation leading to intraoperative hypertension are not always preventable with a fentanyl-based anesthesia regimen and antihypertensive drugs without anesthetic properties are added to obtain hemodynamic stability. We report on five cardiac surgical cases in which intraoperative hypertension unresponsive to incremental doses of fentanyl was successfully treated adding a remifentanil target-controlled infusion instead of a non-anesthetic vasoactive drug. This approach could help to avoid the dilemma: when should we stop adding anesthetics and switch to antihypertensive drugs in cardiac surgery? PMID- 23439404 TI - The role of microRNAs in neural stem cells and neurogenesis. AB - Neural stem cells give rise to neurons through the process of neurogenesis, which includes neural stem cell proliferation, fate determination of new neurons, as well as the new neuron's migration, maturation and integration. Currently, neurogenesis is divided into two phases: embryonic and adult phases. Embryonic neurogenesis occurs at high levels to form the central nervous system. Adult neurogenesis has been consistently identified only in restricted regions and occurs at low levels. As the basic process for embryonic neurodevelopment and adult brain maintenance, neurogenesis is tightly regulated by many factors and pathways. MicroRNA, short non-coding RNA that regulates gene expression at the post-transcriptional level, appears to be involved in multiple steps of neurogenesis. This review summarizes the emerging role of microRNAs in regulating embryonic and adult neurogenesis, with a particular emphasis on the proliferation and differentiation of neural stem cells. PMID- 23439405 TI - Genetically modified pig models for human diseases. AB - Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies. Although genetically modified mice have been widely used to model human diseases, some of these mouse models do not replicate important disease symptoms or pathology. Pigs are more similar to humans than mice in anatomy, physiology, and genome. Thus, pigs are considered to be better animal models to mimic some human diseases. This review describes genetically modified pigs that have been used to model various diseases including neurological, cardiovascular, and diabetic disorders. We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases. PMID- 23439406 TI - Identification of the RNAs for transcription factor Mitf as a component of the Balbiani body. AB - Balbiani body (BB) is a large distinctive organelle aggregate uniquely present in developing oocytes of diverse animal species. BB is thought as a stage-specific structure that resembles germ plasm, the cytoplasmic organelle of germ cells. The role and function of BB have remained speculative because of a highly dynamic structure and a lack of genetic and molecular data. BB has been found to contain proteins and RNAs, none of them--except the zebrafish foxH1 RNA, is or encodes a transcription factor. Here we report in the fish medaka (Oryzias latipes) that RNAs encoding microphthalmia-associated transcription factor (Mitf) are prominent components of the BB. By fluorescence in situ hybridization on ovarian section, we revealed that the transcripts of both mitf1 and mitf2 genes concentrated in the BB, in which they co-localized with the dazl RNA, a definitive BB marker highly conserved in vertebrates. Therefore, the mitf product may play dual roles in germ gene transcription and BB formation and/or function in this organism. Our data provide the second evidence that the RNA of a transcription factor can be a prominent component of the BB in a vertebrate. PMID- 23439408 TI - Cloning of Ln gene through combined approach of map-based cloning and association study in soybean. PMID- 23439407 TI - Dual effects of IL-1 overactivity on the immune system in a mouse model of arthritis due to deficiency of IL-1 receptor antagonist. AB - Previous studies have revealed the significance of cytokine interleukin 1 (IL-1) in the onset and progression of rheumatoid arthritis (RA). The precise molecular mechanisms related to IL-1 underlying RA is still elusive. We conducted a whole genome-wide transcriptomal comparison of wild-type (WT) and arthritis-prone IL-1 receptor antagonist (IL-1rn) deficient BALB/c mice to address this issue. To refine our search efforts, gene expression profiling was also performed on paired wild-type and arthritis-resistant IL-1rn deficient DBA/1 mice as internal controls when identifying causative arthritis candidate genes. Two hundred and fifteen transcripts were found to be dysregulated greater than or equal to 2-fold in the diseased mice. The altered transcriptome in BALB/c mice revealed increased myeloid cell activities and impaired lymphocyte functionality, suggesting dual regulatory effects of IL-1 hyperactivity on immunological changes associated with arthritis development. Phase-specific gene expression changes were identified, such as early increase and late decrease of heat shock protein coding genes. Moreover, common gene expression changes were also observed, especially the upregulation of paired Ig-like receptor A (Pira) in both early and late phases of arthritis. Real-time PCR was performed to validate the expression of Pira and an intervention experiment with a major histocompatibility complex (MHC) class I inhibitor (brefeldin A) was carried out to investigate the role of suppressing Pira activity. We conclude that global pattern changes of common and distinct gene expressions may represent novel opportunities for better control of RA through early diagnosis and development of alternative therapeutic strategies. PMID- 23439409 TI - Difficulties in functioning 1 year after injury: the role of preinjury sociodemographic and health characteristics, health care and injury-related factors. AB - OBJECTIVE: To identify the role of preinjury sociodemographic and health characteristics, injury and injury-related health care characteristics in determining functional outcomes 12 months after injury. DESIGN: Prospective cohort study involving 1-year follow-up. SETTING: Community. PARTICIPANTS: Study participants (N=2282; age range, 18-64y inclusive) were those in the Prospective Outcomes of Injury Study who completed the 12-month interview. The original cohort of 2856 were injured and registered with New Zealand's national no-fault injury insurance agency. With the exception of injury and hospitalization, information on predictors and outcomes was obtained directly from the participants, primarily by telephone interviews, approximately 3 and 12 months after their injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The functional outcomes of interest were the 5 dimensions of the EQ-5D plus a cognitive dimension. Our multivariate analyses included adjustment for preinjury EQ-5D status and time between injury and the 12-month interview. RESULTS: Substantial portions of participants continued to have adverse outcomes, especially pain/discomfort, 12 months after their injury. The significance of factors varied by outcome. Factors adversely associated with at least 3 of the 6 outcomes were preinjury EQ-5D status, being female, aged 45 to 64 years, inadequate household income, preinjury disability, 2 or more prior chronic illnesses, smoking regularly, dislocation or sprains to the spine or upper extremities, and having a relatively severe injury. CONCLUSIONS: A range of preinjury sociodemographic and health characteristics are associated with several adverse functional outcomes 1 year after injury, independent of the nature and severity of injury. The latter, however, also have independent effects on the outcomes. PMID- 23439410 TI - Effect of psychological interventions on depressive symptoms in long-term rehabilitation after an acquired brain injury: a systematic review and meta analysis. AB - OBJECTIVE: To summarize empirical studies on the effectiveness of psychological interventions in long-term rehabilitation after an acquired brain injury (ABI) in reducing depressive symptoms. DATA SOURCES: A systematic literature search was conducted on MEDLINE, PsycINFO, Embase, and CINAHL to identify articles published between January 1990 and October 2011. Search terms included the 3 concepts (1) "brain injur*" or "stroke," (2) "psychotherap*" or "therapy" or "intervention" or "rehabilitation," and (3) "depress*." STUDY SELECTION: Studies evaluating psychological interventions in patients after ABI were included. Time since injury was on average more than 1 year. Trials reported data on validated depression questionnaires before and after the psychological intervention. DATA EXTRACTION: Two independent reviewers extracted information from the sample, the intervention, and the outcome of the included studies and calculated effect sizes (ESs) from depression questionnaires. Thirteen studies were included in a pre post analysis. Seven studies were eligible for a meta-analysis of ESs in active interventions and control conditions. DATA SYNTHESIS: Pre-post ESs were significant in 4 of 13 studies. The overall ES of .69 (95% confidence interval [CI], .29-1.09) suggests a medium effectiveness of psychological interventions on depressive symptoms compared with control conditions. Moderator analysis of the number of sessions and adequate randomization procedure did not show significant ES differences between strata. Studies with adequate randomization did not, however, suggest the effectiveness of psychological interventions on depressive symptoms after ABI. CONCLUSIONS: Psychological interventions are a promising treatment option for depressive symptoms in long-term rehabilitation after ABI. Since only a few adequately randomized controlled trials (RCTs) exist, more RCTs are required to confirm this initial finding. PMID- 23439411 TI - Impact of heart transplantation in infancy and adolescence on quality of life and compliance. AB - INTRODUCTION: Young patients who undergo heart transplantation in their early childhood or adolescence are confronted with typical developmental problems, which affect their specific adjustment to heart transplantation. This study aims at evaluating patients' health related quality of life and at determining the degree and sources of non-compliant behavior with its somatic and psychosocial consequences. METHODS: The study sample consists of 38 patients, who received heart transplantation between the age of 1 and 18 and are now between 16 and 34 years old. All participants received self-rating instruments: The Short-Form Health Survey (SF-36), Giessen Subjective Complaints List (GBB), Medication Experience Scale for Immunosuppressants (MESI), and Health Questionnaire for Children and Young People (KIDSCREEN-27). Patient's scores were compared to the scores of the specific norm sample. Further assessment was done by semi structured interviews directed at psychosocial outcome, compliance, relationship to family and peer-group and integration into the work environment. RESULTS: In comparison to healthy controls the patients showed a significantly reduced quality of life (SF-36) in all psychological and nearly all somatic domains. Patients emphasized a very close and satisfying relationship to their parents and pronounced overall social support. Almost 50% of the patients reported some reduced medical compliance and 20% are to be seen as a high risk group for noncompliance, simultaneously characterized by poor physical and mental status. CONCLUSION: Young adult transplant patients are to be carefully evaluated for psychosocial risks to avoid noncompliance and reduced quality of life in long term follow up. PMID- 23439412 TI - Reliability of Tanner staging performed by orthopedic sports medicine surgeons. AB - PURPOSE: The treatment of anterior cruciate ligament (ACL) tears in children is controversial because of the potential injury to the growth plate resulting from traditional transphyseal surgery. Some authors recommend Tanner staging as a method to determine the patient's maturity to decide between physeal-sparing or transphyseal surgery. This study examines the accuracy and interobserver and intraobserver reliabilities of Tanner staging performed by orthopedic surgeons. METHODS: Twenty-eight photographs representing Tanner stages 1-5 were obtained from a pediatric endocrinologist. Four sports medicine orthopedic surgeons received a tutorial on Tanner staging and independently graded the photographs twice, with a 1-month interval between grading exams. The endocrinologist's grade was considered correct. Intraobserver and interobserver reliabilities were determined. RESULTS: The overall average correct scores were as follows: 53% correct Tanner stages on exam 1 and 59% correct on exam 2. The average results for specific Tanner stages were as follows: Tanner stage 1 = 62% correct on exam 1, 83% on exam 2; Tanner stage 2 = 60%/65%; Tanner stage 3 = 60%/46%; Tanner stage 4 = 45%/55%; and Tanner stage 5 = 50%/45%. Per examiner, correct grading was as follows: examiner 1 = 39% on exam 1 and 35% on exam 2; examiner 2 = 67%/82%; examiner 3 = 50%/42%; and examiner 4 = 67%/75%. When comparing the grading between exams 1 and 2, examiner 1 changed five answers from correct to incorrect; four answers from incorrect to correct; and two answers from incorrect to a different incorrect choice; examiner 2, three/seven/zero; examiner 3, six/four/one; and examiner 4, two/four/zero. CONCLUSIONS: Preoperative Tanner staging performed by orthopedic surgeons is unreliable with large intraobserver and interobserver variabilities. Therefore, relying on Tanner staging as a method to guide decision making for surgery in skeletally immature patients with ACL tears may lead to inadvertent growth plate injury. PMID- 23439413 TI - Validity of ActiGraph child-specific equations during various physical activities. AB - PURPOSE: The purpose of this study was to examine the validity of seven child specific ActiGraph prediction equations/cut points (Crouter vector magnitude two regression model [Cvm2RM], Crouter vertical axis two-regression model [Cva2RM], Freedson child equation, Treuth equation, Trost equation, Puyau equation, and Evenson equation) for estimating energy expenditure and time spent in sedentary behaviors, light physical activity (LPA), moderate physical activity (MPA), and vigorous physical activity (VPA). METHODS: Forty boys and 32 girls (mean +/- SD; age = 12 +/- 0.8 yr) participated in the study. Participants performed eight structured activities and approximately 2 h of free-living activity. Activity data were collected using an ActiGraph GT3X+, positioned on the right hip, and energy expenditure (MET(RMR); activity VO(2) divided by resting VO(2)) was measured using a Cosmed K4b(2). ActiGraph prediction equations were compared against the Cosmed for MET(RMR) and time spent in sedentary behaviors, LPA, MPA, VPA, and moderate and vigorous physical activity. RESULTS: For the structured activities, all prediction methods were significantly different from measured MET(RMR) for three activities or more (P < 0.05); however, all provided close estimates of MET(RMR) during walking. On average, participants were monitored for 95.0 +/- 36.5 min during the free-living measurement. The Cvm2RM and the Puyau methods were within 0.9 MET(RMR) of measured free-living MET(RMR) (P > 0.05); all other methods significantly underestimated measured MET(RMR) (P < 0.05). The Cva2RM was within 9.7 min of measured time spent in sedentary behaviors, LPA, MPA, and moderate and vigorous physical activity, which was the best of the methods examined. All prediction equations underestimated VPA by 6.0-13.6 min. CONCLUSION: Compared with the Cosmed, the Cvm2RM and the Puyau methods provided the best estimate of MET(RMR) and the Cva2RM provided the closest estimate of time spent in each intensity category during the free-living measurement. Lastly, all prediction methods had large individual prediction errors. PMID- 23439414 TI - Walking objectively measured: classifying accelerometer data with GPS and travel diaries. AB - PURPOSE: This study developed and tested an algorithm to classify accelerometer data as walking or nonwalking using either GPS or travel diary data within a large sample of adults under free-living conditions. METHODS: Participants wore an accelerometer and a GPS unit and concurrently completed a travel diary for seven consecutive days. Physical activity (PA) bouts were identified using accelerometry count sequences. PA bouts were then classified as walking or nonwalking based on a decision-tree algorithm consisting of seven classification scenarios. Algorithm reliability was examined relative to two independent analysts' classification of a 100-bout verification sample. The algorithm was then applied to the entire set of PA bouts. RESULTS: The 706 participants' (mean age = 51 yr, 62% female, 80% non-Hispanic white, 70% college graduate or higher) yielded 4702 person-days of data and had a total of 13,971 PA bouts. The algorithm showed a mean agreement of 95% with the independent analysts. It classified PA into 8170 walking bouts (58.5 %) and 5337 nonwalking bouts (38.2%); 464 bouts (3.3%) were not classified for lack of GPS and diary data. Nearly 70% of the walking bouts and 68% of the nonwalking bouts were classified using only the objective accelerometer and GPS data. Travel diary data helped classify 30% of all bouts with no GPS data. The mean +/- SD duration of PA bouts classified as walking was 15.2 +/- 12.9 min. On average, participants had 1.7 walking bouts and 25.4 total walking minutes per day. CONCLUSIONS: GPS and travel diary information can be helpful in classifying most accelerometer-derived PA bouts into walking or nonwalking behavior. PMID- 23439415 TI - Impact on hemostatic parameters of interrupting sitting with intermittent activity. AB - INTRODUCTION: Excessive sitting has been associated with an elevated risk of vascular conditions, particularly venous thrombosis. Interrupting sitting time with intermittent physical activity can reduce venous stasis; however, impacts on other aspects of thrombogenesis are less understood. PURPOSE: To examine the effects of interrupting sitting time on blood coagulation and blood volume parameters in sedentary, middle-age, overweight/obese adults (11 men and 8 women; age = 53.8 +/- 4.9 yr, body mass index = 31.2 +/- 4.1 kg . m(-2); mean +/- SD). METHODS: The randomized three-period, three-treatment acute crossover trial consisted of uninterrupted sitting and sitting interrupted by 2-min bouts of either light- or moderate-intensity treadmill walking every 20 min. In each trial condition, blood samples were collected at baseline before the consumption of a standardized meal (-2 h) and postintervention (5 h). RESULTS: Plasma fibrinogen increased from baseline with uninterrupted sitting (0.24 g . L(-2), 95% confidence interval = 0.13-0.34, P < 0.001). Light-intensity but not moderate intensity activity breaks attenuated the increase by 0.17 g . L(-1) (95% confidence interval = 0.01-0.32, P < 0.05). There were no between-condition differences in prothrombin time, activated partial thromboplastin time, von Willebrand factor, D-dimer, or platelet count. Uninterrupted sitting reduced plasma volume and increased hematocrit, hemoglobin, and red blood cell count; effects attenuated by both light- and moderate-intensity breaks (P < 0.05). White blood cell count increased with uninterrupted sitting and further increased with moderate-intensity breaks. Mean platelet volume increased with moderate-intensity but not light-intensity breaks or uninterrupted sitting. CONCLUSION: Uninterrupted sitting increased fibrinogen and reduced plasma volume, with associated increases in hemoglobin and hematocrit. Activity breaks attenuated these responses, indicative of an ameliorating influence on the procoagulant effects of uninterrupted sitting. PMID- 23439417 TI - Foot bone marrow edema after a 10-wk transition to minimalist running shoes. AB - PURPOSE: Minimalist running shoes are becoming a more popular choice for runners in the past few years. However, there is little conclusive evidence about the advantages or disadvantages of running in these shoes. Although performance benefits may exist, injury may also occur from the added stress of running without the benefit of cushioning under the foot. Bone marrow edema can be a manifestation of added stress on the foot. This study measured bone marrow edema in runners' feet before and after a 10-wk period of transitioning from traditional to minimalist running shoes. METHODS: Thirty-six experienced recreational runners underwent magnetic resonance imaging (MRI) before and after a 10-wk period. Seventeen subjects were in the control group (ran in their traditional shoes only for 10 wk), whereas the other 19 were in the experimental group (gradually transitioned to Vibram FiveFinger running shoes for 10 wk). The severity of the bone marrow edema was scored on a range of 0-4 (0 = no bone marrow edema, 4 = edema in more than 50% of the length of the bone). A score of 4 represented a stress fracture. RESULTS: Pretraining MRI scores were not statistically different between the groups. The posttraining MRI scores showed that more subjects in the Vibram group (10 of 19) showed increases in bone marrow edema in at least one bone after 10 wk of running than that in the control group (P = 0.009). CONCLUSION: Runners interested in transitioning to minimalist running shoes, such as Vibram FiveFingers, should transition very slowly and gradually to avoid potential stress injury in the foot. PMID- 23439416 TI - Physical activity and sedentary behaviors in postpartum Latinas: Madres para la Salud. AB - PURPOSE: To describe the physical activity (PA) and sedentary behaviors of postpartum Latinas who are overweight or obese before initiating Madres para la Salud, a social support-mediated walking intervention to promote postpartum weight loss. METHODS: One hundred thirty-nine postpartum women (13.6 +/- 7.7 wk since childbirth, age = 28.3 +/- 5.6 yr, BMI = 29.7 +/- 3.5 kg . m(-2); mean +/- SD), recruited from organizations serving Latino residents in the Phoenix, Arizona, area completed the Stanford Brief Activity Survey and concurrently wore an accelerometer (ActiGraph) and a pedometer for 7 d and kept a PA record. RESULTS: Most were classified as inactive and lightly active on the Stanford Brief Activity Survey (51% inactive, 37% light, 11% moderate). Most time was spent in sedentary (512.0 +/- 169.9 min . d(-1)) and light-intensity PA (242.4 +/ 51.4 min . d(-1)) with less time in moderate-intensity lifestyle (78.3 +/- 39.9 min . d(-1)), moderate-intensity walking (16.6 +/- 14.4 min . d(-1)), and vigorous-intensity PA (0.34 +/- 1.5 min . d(-1)). Pedometer steps per day were low (total = 4973 +/- 2202 steps, aerobic = 412 +/- 774 steps), with most participants rated as sedentary (61%) or low active (28.1%). Consistent with objective PA measures, PA records showed more time spent in light-intensity PA such as home care, cooking, child care and self-care tasks, occupation, religious events, and watching television. CONCLUSION: By and large, the postpartum Latinas enrolled spent most of their day in low-intensity activity levels with little time spent in health-enhancing PA levels/behaviors. This demographic should be the focus of PA interventions to increase PA to health-enhancing levels. PMID- 23439418 TI - Effects of eccentrically and concentrically biased training on mouse muscle phenotype. AB - INTRODUCTION: The molecular adaptations specifically induced by different muscle contraction types have only been partially elucidated. We previously demonstrated that eccentric contractions in human quadriceps elicited proteome modifications that suggest a muscle fiber typology adaptation. We address this question in a more systematic way by examining here the effects of different running modes on the mouse muscle proteome and the muscle fiber typology. METHODS: Male adult mice (C57BL6) were randomly divided into downhill running (DHR) (quadricipital eccentrically biased contractions), uphill running (UHR) (quadricipital concentrically biased contractions), and untrained control (CONT) groups. Running groups performed five training sessions on an inclined treadmill for 75 to 135 min . d(-1), and the quadriceps muscles were dissected 96 h after the last session. Muscle protein extracts of DHR and UHR groups (n = 4/group) were subjected to a two-dimensional difference in gel electrophoresis (2D-DIGE) analysis coupled with mass spectrometry. The assessment of fiber type, size, and number was performed on the rectus femoris of the three groups (n = 6/group) using myosin heavy chain immunohistochemistry. RESULTS: In the proteomic analysis, eight spots identified as the fast myosin heavy chain isoforms exhibited a lower abundance in DHR compared with UHR (P < 0.05, t-test). In contrast, adenosine triphosphate (ATP) synthase subunit alpha and tubulin beta were more expressed in DHR (P < 0.05). A significant higher proportion of Type I and IIa fibers was found for DHR compared with UHR or CONT groups (P < 0.05, one way ANOVA). CONCLUSIONS: Our data suggest that the eccentrically biased contractions in mice induced specific adaptations in protein expression and muscle fiber composition, which may reflect a more oxidative muscle phenotype. The differences in stress placed on the muscle between both trainings may be responsible for some unique adaptations resulting from the eccentrically biased training. PMID- 23439419 TI - Acute ankle sprain in a mouse model. AB - INTRODUCTION: Ankle sprains remain the most common orthopedic pathology. Conducting long-term studies in humans is difficult and costly, so the long-term consequences of an ankle sprain are not entirely known. PURPOSE: The objective of this study is to develop and test a mechanical ankle instability model in mice. METHODS: Thirty male mice (CBA/2J) were randomly placed into one of three groups: the transected calcaneal fibular ligament (CFL) group, the transected anterior talofibular ligament (ATFL)/CFL group, and a SHAM group. Three days after surgery, all of the mice were individually housed in a cage containing a solid surface running wheel, and daily running wheel measurements were recorded. Before and after surgery, measures of balance and gait were measured on all mice for 4 wk. RESULTS: The mice in the ATFL/CFL group had significantly decreased duration (P = 0.0239), distance (P = 0.013), and speed (P = 0.003) compared with the SHAM group during week 1. During weeks 2 and 3, the ATFL/CFL group had significantly less distance (P = 0.0001) and duration (P = 0.002) compared with the SHAM and CFL-only group. The transection of the lateral ankle ligaments did affect the number of slips experienced during the balance test. The ATFL/CFL group had greater slips at 1 and 4 wk postsurgery (P = 0.05), whereas the CFL-only group had greater slips at 3 d and 1 wk postsurgery (P = 0.05). Relative to the SHAM group, the ATFL/CFL group and CFL-only group had smaller right-stride lengths (involved limb) at 3 d postsurgery (P = 0.05). The ATFL/CFL group also had smaller right-side stride lengths at 1 and 4 wk postsurgery (P = 0.05). CONCLUSIONS: The results of this study indicate that a mouse model can be used to induce mechanical instability in the ankle. PMID- 23439420 TI - Continued sedentariness, change in sitting time, and mortality in older adults. AB - PURPOSE: Prolonged sitting time (ST) is associated with higher mortality. However, previous studies used only a single measure of ST at baseline, so they could not directly assess the effect of continued exposure to high ST, or of changes in ST, on mortality. We prospectively assessed the association of continued sedentariness and of changes in ST for 2 yr with subsequent long-term all-cause mortality. METHODS: This study was based on a prospective cohort of 2635 persons representative of the Spanish population 60 yr and older. ST was self-reported in 2001 and 2003. The median of ST was used as the cutoff to define excessive ST. Individuals were classified as consistently sedentary (> median in 2001 and 2003), newly sedentary (<= median in 2001 and > median in 2003), formerly sedentary (> median in 2001 and <= median in 2003), and consistently nonsedentary (<= median in 2001 and 2003). The association of ST in the period 2001-2003 with all-cause mortality from 2003 through 2011 was assessed with Cox regression and adjusted for the main confounders, including physical activity. RESULTS: Among the study participants, 846 died between 2003 and 2011. Compared with persons who were consistently sedentary, the hazard ratios (95% confidence interval) for mortality were 0.91 (0.76-1.10) in those who were newly sedentary, 0.86 (0.70-1.05) in formerly sedentary individuals, and 0.75 (0.62-0.90) in those who remained consistently nonsedentary. The results were similar across strata defined according to obesity, morbidity, functional limitations, or meeting recommendations for physical activity. CONCLUSION: Compared with older adults who were consistently sedentary during 2 yr, consistently nonsedentary individuals showed reduced all-cause mortality. Individuals who changed ST experienced an intermediate reduction in mortality. PMID- 23439421 TI - Caffeine ingestion and cycling power output in a low or normal muscle glycogen state. AB - PURPOSE: Commencing selected workouts with low muscle glycogen availability augments several markers of training adaptation compared with undertaking the same sessions with normal glycogen content. However, low glycogen availability reduces the capacity to perform high-intensity (>85% of peak aerobic power (VO2 peak)) endurance exercise. We determined whether a low dose of caffeine could partially rescue the reduction in maximal self-selected power output observed when individuals commenced high-intensity interval training with low (LOW) compared with normal (NORM) glycogen availability. METHODS: Twelve endurance trained cyclists/triathletes performed four experimental trials using a double blind Latin square design. Muscle glycogen content was manipulated via exercise diet interventions so that two experimental trials were commenced with LOW and two with NORM muscle glycogen availability. Sixty minutes before an experimental trial, subjects ingested a capsule containing anhydrous caffeine (CAFF, 3 mg . kg(-1) body mass) or placebo (PLBO). Instantaneous power output was measured throughout high-intensity interval training (8 * 5-min bouts at maximum self selected intensity with 1-min recovery). RESULTS: There were significant main effects for both preexercise glycogen content and caffeine ingestion on power output. LOW reduced power output by approximately 8% compared with NORM (P < 0.01), whereas caffeine increased power output by 2.8% and 3.5% for NORM and LOW, respectively, (P < 0.01). CONCLUSION: We conclude that caffeine enhanced power output independently of muscle glycogen concentration but could not fully restore power output to levels commensurate with that when subjects commenced exercise with normal glycogen availability. However, the reported increase in power output does provide a likely performance benefit and may provide a means to further enhance the already augmented training response observed when selected sessions are commenced with reduced muscle glycogen availability. PMID- 23439424 TI - Comparison of aerobic exercise intensity prescription methods in breast cancer. AB - INTRODUCTION: Exercise plays an important role in cancer rehabilitation, but a precise prescription of exercise intensity is required to maximize the benefits of this intervention. It is unknown whether different methods of prescribing aerobic exercise intensity achieve the same intensity. Breast cancer treatments may alter exercise response and thereby may affect the accuracy of these methods. PURPOSE: The purpose of this study was to compare the accuracy and achieved intensity of four common methods of prescribing exercise intensity within and between breast cancer patients recently finished chemotherapy (n = 10), survivors finished treatment (n = 10), and healthy controls (n = 10). METHODS: The methods compared were as follows: the American College of Sports Medicine's metabolic equation for treadmill walking (METW), heart rate reserve (HRR), direct heart rate (DIRECT HR), and RPE. The methods were used to prescribe 60% oxygen consumption reserve (VO2R) in four randomly assigned 10-min periods of treadmill walking with expired gas collection to evaluate 1) achieved intensity (measured % VO2R) and 2) accuracy (defined as: [60% VO2R-achieved intensity]). RESULTS: The accuracy of the methods was not equivalent across groups (P = 0.04). HRR and METW did not differ across groups and were most accurate in patients. HRR, METW, and DIRECT HR were all more accurate than RPE in survivors (P <= 0.01). RPE was the least accurate in all groups. The accuracy of DIRECT HR was much lower in patients than that in survivors and controls (P <= 0.01). CONCLUSIONS: The four methods of exercise intensity prescription varied in accuracy in prescribing 60% VO2R and did not achieve equivalent exercise intensities within breast cancer patients, survivors, and healthy controls. HRR and METW were the most accurate methods for exercise intensity prescription in breast cancer patients and survivors. PMID- 23439422 TI - Changes in physical activity and body composition in postmenopausal women over time. AB - PURPOSE: Higher physical activity (PA) has been associated with greater attenuation of body fat gain and preservation of lean mass across the lifespan. These analyses aimed to determine relationships of change in PA to changes in fat and lean body mass in a longitudinal prospective study of postmenopausal women. METHODS: Among 11,491 women enrolled at three Women's Health Initiative clinical centers who were selected to undergo dual-energy x-ray absorptiometry, 8352 had baseline body composition measurements, with at least one repeated measure at years 1, 3, and 6. PA data were obtained by self-report at baseline and 3 and 6 yr of follow-up. Time-varying PA effect on change in lean and fat mass during the 6-yr study period for age groups (50-59 yr, 60-69 yr, and 70-79 yr) was estimated using mixed effects linear regression. RESULTS: Baseline PA and body composition differed significantly among the three age groups. The association of change in fat mass from baseline and time-varying PA differed across the three age groups (P = 0.0006). In women age 50-59 yr, gain in fat mass from baseline was attenuated with higher levels of PA. Women age 70-79 yr lost fat mass at all PA levels. In contrast, change in lean mass from baseline and time-varying PA did not differ by age group (P = 0.1935). CONCLUSIONS: The association between PA and change in fat mass varies by age group, with younger, but not older, women benefiting from higher levels of aerobic PA. Higher levels of aerobic activity are not associated with changes in lean mass, which tends to decrease in older women regardless of activity level. Greater attention to resistance training exercises may be needed to prevent lean mass loss as women age. PMID- 23439425 TI - Genetic predisposition scores associate with muscular strength, size, and trainability. AB - INTRODUCTION: The number of studies trying to identify genetic sequence variation related to muscular phenotypes has increased enormously. The aim of this study was to identify the role of a genetic predisposition score (GPS) based on earlier identified gene variants for different muscular endophenotypes to explain the individual differences in muscular fitness characteristics and the response to training in patients with coronary artery disease. METHODS: Two hundred and sixty coronary artery disease patients followed a standard ambulatory, 3-month supervised training program for cardiac patients. Maximal knee extension strength (KES) and rectus femoris diameter were measured at baseline and after rehabilitation. Sixty-five single nucleotide polymorphisms (SNP) in 30 genes were selected based on genotype-phenotype association literature. Backward regression analysis revealed subsets of SNP associated with the different phenotypes. GPS were constructed for all sets of SNP by adding up the strength-increasing alleles. General linear models and multiple stepwise regression analysis were used to test the explained variance of the GPS in baseline and strength responses. Receiver operating characteristic curve analyses were performed to discriminate between high- and low-responder status. RESULTS: GPS were significantly associated with the rectus femoris diameter (P < 0.01) and its response (P < 0.0001), the isometric KES (P < 0.05) and its response (P < 0.01), the isokinetic KES at 60 degrees . s (P < 0.05) and 180 degrees . s (P < 0.001) and their responses to training (P < 0.0001), and the isokinetic KES endurance (P < 0.001) and its change after training (P < 0.0001). The GPS was shown as an independent determinant in baseline and response phenotypes with partial explained variance up to 23%. Receiver operating characteristic analysis showed a significant discriminating accuracy of the models, including the GPS for responses to training, with areas under the curve ranging from 0.62 to 0.85. CONCLUSION: GPS for muscular phenotypes showed to be associated with baseline KES, muscle diameter, and the response to training in cardiac rehabilitation patients. PMID- 23439426 TI - Immediate effect of exercise on achilles tendon properties: systematic review. AB - INTRODUCTION: Understanding the mechanical and morphological adaptation of the Achilles tendon (AT) in response to acute exercise could have important implications for athletic performance, injury prevention, and rehabilitation. The purpose of this study was to conduct a systematic review and critical evaluation of the literature to determine the immediate effect of a single bout of exercise on the mechanical and morphological properties of the AT in vivo. METHODS: Five electronic research databases were systematically searched for intervention-based studies reporting mechanical and morphological properties of the AT after a single bout of exercise. RESULTS: Searches revealed 3292 possible articles; 21 met the inclusion criteria. There is evidence that maximal isometric contractions and prolonged static stretching (>5 min) of the triceps surae complex cause an immediate decrease in AT stiffness, whereas prolonged running and hopping have minimal effect. Limited but consistent evidence exists, indicating that AT hysteresis is reduced after prolonged static stretching. Consistent evidence supports a reduction in free AT diameter (anterior-posterior) after dynamic ankle exercise, and this change appears most pronounced in the healthy tendon and after eccentric exercise. CONCLUSIONS: The mechanical and morphological properties of the AT in vivo are affected by acute exercise in a mode- and dose-dependent manner. Transient changes in AT stiffness, hysteresis, and diameter after unaccustomed exercise modes and doses may expose the tendon to increased risk of strain injury and impact on the mechanical function of the triceps surae muscle tendon unit. PMID- 23439427 TI - Meal and beta-alanine coingestion enhances muscle carnosine loading. AB - INTRODUCTION: Beta-alanine (BA) is a popular ergogenic supplement because it can induce muscle carnosine loading. We hypothesize that, by analogy with creatine supplementation, 1) an inverse relationship between urinary excretion and muscle loading is present, and 2) the latter is stimulated by carbohydrate- and protein induced insulin action. METHODS: In study A, the effect of a 5-wk slow-release BA (SRBA) supplementation (4.8 g . d(-1)) on whole body BA retention was determined in seven men. We further determined whether the coingestion of carbohydrates and proteins with SRBA would improve retention. In study B (34 subjects), we explored the effect of meal timing on muscle carnosine loading (3.2 g . d(-1) during 6-7 wk). One group received pure BA (PBA) in between the meals; the other received PBA at the start of the meals, to explore the effect of meal-induced insulin release. Further, we compared with a third group receiving SRBA at the start of the meals. RESULTS AND CONCLUSION: Orally ingested SRBA has a very high whole body retention (97%-98%) that is not declining throughout the 5-wk supplementation period, nor is it influenced by the coingestion of macronutrients. Thus, a very small portion (1%-2%) is lost through urinary excretion, and equally only a small portion is incorporated into muscle carnosine (~ 3%), indicating that most ingested BA is metabolized (possibly through oxidation). Second, in soleus muscles, the efficiency of carnosine loading is significantly higher when PBA is coingested with a meal (+64%) compared with in between the meals (+41%), suggesting that insulin stimulates muscle carnosine loading. Finally, the chronic supplementation of SRBA versus PBA seems equally effective. PMID- 23439429 TI - The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS). AB - In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing. PMID- 23439428 TI - Resveratrol activates SIRT1 in a Lamin A-dependent manner. AB - Human sirtuin1 (SIRT1), the closest homolog of the yeast sir2 protein, functions as an NAD+-dependent histone and non-histone protein deacetylase in several cellular processes, like energy metabolism, stress responses, aging, etc. In our recent study, we have shown that lamin A (a major nuclear matrix protein) directly binds with and activates SIRT1. Resveratrol, a natural phenol, has long been known as an activator of SIRT1. However, resveratrol's direct activation of SIRT1 has been refuted several times. In our study, we have provided a mechanistic explanation to this question, and have shown that resveratrol activates SIRT1 by increasing its binding with lamin A, thus aiding in the nuclear matrix (NM) localization of SIRT1. We have also shown that rescue of adult stem cell (ASC) decline in laminopathy-based premature aging mice by resveratrol is SIRT1-dependent. Further, resveratrol's ameliorating effects on progeria and its capacity to extend lifespan in progeria mice has been established. Here we have summarized these findings and their probable implications on other aspects, like chromatin remodeling, stem cell therapy, DNA damage responses, etc. PMID- 23439430 TI - Nigerian clinical level medical students' knowledge of dental specialty. AB - BACKGROUND: The roles of physicians in oral healthcare delivery are very important due to the unequal distribution of the low oral health manpower as well as the lack of awareness of patients concerning the treatment of oral health problems by dentists in Nigeria. AIM: To assess the Nigerian clinical level medical students' knowledge of dental problems and conditions in relation to the dental specialty that treat them. SUBJECTS AND METHODS: This questionnaire-based cross-sectional study of clinical level medical students of University of Benin, Benin City, Nigeria, was conducted between May and June, 2010. The knowledge of the students was graded as good (16-20), fair (8-15), and poor (<8). RESULTS: Out of the 350 questionnaires distributed, 279 were filled and returned giving an overall response rate of 79.7% (279/350). Of these, 47.0% (131/279), 50.2% (140/279), and 2.8% (8/279) of respondents showed poor, fair and good knowledge respectively. The trend showed a statistically significant increase in the mean level of knowledge of dental specialty with an ascent in the clinical level (P = 0.01). CONCLUSION: The level of knowledge of dental specialty in this survey was suboptimal and varied with different specialties which may have adverse implication in future patient care. The variation in the level of knowledge with different clinical level suggested gain in knowledge about dental specialty mainly through nonformal means among medical students. PMID- 23439431 TI - Characterization of induced neural progenitors from skin fibroblasts by a novel combination of defined factors. AB - Recent reports have demonstrated that somatic cells can be directly converted to other differentiated cell types through ectopic expression of sets of transcription factors, directly avoiding the transition through a pluripotent state. Our previous experiments generated induced neural progenitor-like cells (iNPCs) by a novel combination of five transcription factors (Sox2, Brn2, TLX, Bmi1 and c-Myc). Here we demonstrated that the iNPCs not only possess NPC specific marker genes, but also have qualities of primary brain-derived NPCs (WT NPCs), including tripotent differentiation potential, mature neuron differentiation capability and synapse formation. Importantly, the mature neurons derived from iNPCs exhibit significant physiological properties, such as potassium channel activity and generation of action potential-like spikes. These results suggest that directly reprogrammed iNPCs closely resemble WT-NPCs, which may suggest an alternative strategy to overcome the restricted proliferative and lineage potential of induced neurons (iNCs) and broaden applications of cell therapy in the treatment of neurodegenerative disorders. PMID- 23439432 TI - Blockade of Smad signaling by 3'-deoxyadenosine: a mechanism for its anti fibrotic potential. AB - Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3'-Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3' deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3'-deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3' deoxyadenosine on the expression of collagens triggered by transforming growth factor-beta (TGF-beta1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3'-deoxyadenosine suppressed expression of collagens induced by TGF-beta1 and BMP 4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-beta/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3'-Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2alpha-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3'-deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and alpha-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3'-deoxyadenosine interferes with the TGF-beta and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3'-Deoxyadenosine may be useful for therapeutic intervention in various TGF-beta-related fibrotic disorders. PMID- 23439434 TI - CXCL5 stimulation of RANK ligand expression in Paget's disease of bone. AB - Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2 3% of the population over 55 years of age. PDB is marked by highly localized areas of bone turnover with increased osteoclast activity. Evidence suggests a functional role for measles virus nucleocapsid protein (MVNP) in the pathogenesis of PDB. In the present study, we identified elevated levels (~ 180-fold) of CXCL5 mRNA expression in bone marrow cells from patients with PDB compared with that in normal subjects. In addition, CXCL5 levels are increased (five-fold) in serum samples from patients with PDB. Furthermore, MVNP transduction in human bone marrow monocytes significantly increased CXCL5 mRNA expression. Real-time PCR analysis showed that CXCL5 stimulation increased (6.8-fold) RANKL mRNA expression in normal human bone marrow-derived stromal (SAKA-T) cells. Moreover, CXCL5 increased (5.2-fold) CXCR1 receptor expression in these cells. We further showed that CXCL5 treatment elevated the expression levels of phospho-ERK1/2 and phospho p38. CXCL5 also significantly increased phosphorylation of CREB (cAMP response element-binding) in bone marrow stromal/preosteoblast cells. Chromatin immuneprecipitation (ChIP) assay confirmed phospho-CREB binding to RANKL gene promoter region. Further, the suppression of p-CREB expression by the inhibitors of ERK1/2, p38 and PKA significantly decreased CXCL5 stimulation of hRANKL gene promoter activity. Thus, our results suggest that CREB is a downstream effector of CXCL5 signaling and that increased levels of CXCL5 contribute to enhanced levels of RANKL expression in PDB. PMID- 23439433 TI - PI3K p110gamma overexpression in idiopathic pulmonary fibrosis lung tissue and fibroblast cells: in vitro effects of its inhibition. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease whose molecular pathogenesis remains unclear. In a recent paper, we demonstrated a key role for the PI3K pathway in both proliferation and differentiation into myofibroblasts of normal human lung fibroblasts treated with TGF-beta. In this research, we assessed the expression of class I PI3K p110 isoforms in IPF lung tissue as well as in tissue-derived fibroblast cell lines. Moreover, we investigated the in vitro effects of the selective inhibition of p110 isoforms on IPF fibroblast proliferation and fibrogenic activity. IHC was performed on normal and IPF lung tissue. Expression levels of PI3K p110 isoforms were evaluated by western blot and flow cytometry analysis. Fibroblast cell lines were established from both normal and IPF tissue and the effects of selective pharmacological inhibition as well as specific gene silencing by small interfering RNAs were studied in vitro. No significant differences between normal and IPF tissue/tissue derived fibroblasts were observed for the expression of PI3K p110 alpha, beta and delta isoforms whereas p110gamma was more greatly expressed in both IPF lung homogenates and ex vivo fibroblast cell lines. Myofibroblasts and bronchiolar basal cells in IPF lungs exhibited strong immunoreactivity for p110gamma. Positive staining for the markers of proliferation proliferating cell nuclear antigen and cyclin D1 was also shown in cells of fibrolastic foci. Furthermore, both p110gamma pharmacological inhibition and gene silencing were able to significantly inhibit proliferation rate as well as alpha-SMA expression in IPF fibroblasts. Our data suggest that PI3K p110gamma isoform may have an important role in the etio-pathology of IPF and can be a specific pharmacological target. PMID- 23439435 TI - Inhalant dependence: data from a tertiary care center in South India. AB - BACKGROUND: This study aims to understand the sociodemographic and clinical profile of inhalant abusers seeking treatment from a tertiary care psychiatric hospital in South India. MATERIALS AND METHODS: The clinical charts of patients who utilized the psychiatric services of a tertiary care center in India for over 10 years were examined for the study. RESULTS: The sample had an urban predominance, was mostly unemployed, and was all male. Most of them had an adolescent age of onset of inhalant use (mean - 16.23 years). All patients reported the use of volatile solvents as inhalants. One other substance dependence was identified in more than half of the sample. The psychiatric comorbidity included psychosis and depression. A comparison was made between patients who presented with inhalant dependence only (I) and inhalant-dependent individuals who also used other psychoactive substances apart from nicotine (IP). The inhalant-only group (I) had an earlier mean age at onset of substance use as compared to the IP group. All patients in the I group reported withdrawal symptoms compared to 77% of patients in the (IP) group (P=0.048). The IP group reported a significantly higher occurrence of aggression (54.5 vs. 19%, P=0.02), externalizing symptoms (77.3 vs. 42.9%, P=0.03), and attention-deficit hyperactivity disorder (ADHD) (50 vs. 14.3%, P=0.02). CONCLUSION: Inhalant dependence is a serious health problem in adolescent subjects and is associated with high comorbidity of other substance dependence, psychiatric disorder, and externalizing spectrum disorder. There is a need for community-based prospective studies in this area from India. PMID- 23439436 TI - The effect of pranayama on test anxiety and test performance. AB - OBJECTIVES: In an educational setting, anxiety is often experienced by students when taking a test; which is called 'test anxiety'. This study intends to investigate the effect of doing pranayama on test anxiety and test performance. MATERIALS AND METHODS: The participants consisted of 107 MA students who were randomly assigned to the control and experimental groups. The students of the experimental group practiced pranayama for one full semester. Sarason's (1980) test anxiety scale was given to both the control and experimental groups in the final session, before taking the examination. RESULTS: After practicing pranayama, only 33% of the participants of the experimental group experienced high test anxiety, while this percentage was nearly twice in the control group (66.7%). Furthermore, the result of the t-test for test anxiety and test performance showed that the students of the experimental group had significantly lower mean test anxiety scores (M = 16.00) as compared to the students of the control group (M = 19.31). Also, the test performance scores of the experimental group were higher when compared with the control group. There was a negative correlation between the final test performance and test anxiety (r = -.204, P < .05). CONCLUSIONS: Pranayama seems to have a significant positive effect on test anxiety and test performance. It could be used as an important technique by students prior to their examinations, to reduce their test anxiety and increase their test performance. PMID- 23439437 TI - Editorial: molecular endocrinology articles in the spotlight for March 2013. PMID- 23439439 TI - Treatment of a giant ascending aortic pseudoaneurysm presenting as a presternal pulsatile protrusion almost perforating through the skin. AB - Aortic pseudoaneurysms have the potential for eroding bony structures in the chest, including the sternum, over time. Here, we report the case of a 54-year old woman with a giant pseudoaneurysm of the ascending aorta, 19 years after aortic root (mechanical conduit) and hemiarch replacement. The patient presented to her primary-care physician with a pulsatile presternal subcutaneous protrusion in the midline of her median sternotomy scar. We performed a challenging midline resternotomy after the establishment of a surgical safety net for cerebral and visceral organ protection followed by a supracoronary ascending and hemiarch replacement including a reinsertion of the coronary ostia employing selective antegrade cerebral perfusion and mild systemic hypothermic circulatory arrest. We discuss here the specific surgical considerations of this case. PMID- 23439440 TI - Late outcomes for the surgical management of absent pulmonary valve syndrome in infants. AB - OBJECTIVES: Absent pulmonary valve syndrome (APVS) is a rare cardiac malformation that is usually associated with aneurysmal dilatation of pulmonary arteries and respiratory distress. The surgical mortality of neonates and infants with APVS has decreased tremendously, from 60% in 1980s to 10-20% recently. This study retrospectively reviews surgical outcomes of our 10-year experience in patients with APVS. METHODS: From 2002 to 2012, 42 patients with APVS underwent surgical correction. Thirty-seven patients had APVS as a variant of tetralogy of Fallot, 4 with double outlet right ventricle and 1 with ventricular septal defect. Respiratory distress was present in 12 infants. Four patients needed continuous positive airway pressure and 5 required intubation with mechanical ventilation before surgery. RESULTS: There was no hospital death and 3 late deaths. The mean follow-up time was 62.71 +/- 34.31 months. Significant differences were found in the duration of postoperative ventilation between patients with or without respiratory distress (P = 0.009) and patients with left or right aortic arch (P = 0.012). The Kaplan-Meier curve indicated that overall survival at 5 and 10 years was 92.4%. The survival rates between patients with or without respiratory distress were 72.7 and 100%, respectively (P = 0.003). Overall mortality was associated with longer cardiopulmonary bypass time (P = 0.004) and lower weight at operation (P = 0.042). There were no significant differences in survival and postoperative data such as the duration of ventilation or intensive care unit stay and New York Heart Association class among the three methods of right ventricular outflow tract (RVOT) reconstruction. CONCLUSIONS: Surgical treatment of APVS has got favourable outcomes in terms of mortality and reoperation rate. Different methods of RVOT reconstruction do not affect the surgical outcome. Patients required long-term follow-up for postoperative respiratory complications secondary to persistent bronchomalacia. PMID- 23439441 TI - Routine postoperative chest X-ray is unnecessary following the Nuss procedure for pectus excavatum. AB - OBJECTIVES: Pneumothorax is the most common complication after the Nuss procedure for pectus excavatum. The majority of pneumothoraces are small, and the patients have no symptoms. The aim of this study was to evaluate the necessity for routine chest X-ray immediately after surgery. METHODS: Group I consists of 644 patients who were operated on with a Nuss procedure for pectus excavatum between 2001 and 2009 (85% male, median age 16 [range 7-48 years]) at Aarhus University Hospital. The standard procedure included chest X-ray immediately after surgery and before discharge. Group II consists of 294 patients (88% male, median age 16 [range 11 54 years]) who had a Nuss procedure in the period January 2011 to October 2012, where the standard procedure only included chest X-ray before discharge. RESULTS: In Group I, pneumothorax was found on the chest X-ray obtained immediately after surgery in 333 (52%) patients. Fifteen (4.5%) were treated with chest-tube drainage. Six of these patients had no symptoms, but a 2- to 3-cm pneumothorax, 2 had progression of the pneumothorax and 7 had respiratory symptoms. The median size of those drained was 3 (range 2-6 cm). At the normal 6-week control, no pneumothorax remained. Group II: Among the 294 patients, 1 (0.3%) had a chest tube. CONCLUSIONS: Only patients with respiratory symptoms after the Nuss procedure need a chest X-ray. A routine chest X-ray can be limited to the time of discharge where the position of the bar(s) is also checked. PMID- 23439442 TI - Intraoperative occurrence of a pneumopericardium during double-lung transplantation. AB - Pneumopericardium is rare and has been reported secondary to chest trauma. We report a case of tension pneumopericardium occurring during double-lung transplantation, where intraoperative transoesophageal echocardiography first showed a hypokinetic left ventricle and a few minutes later a compression of its anterolateral portion due to pneumopericardium. Although the pericardium was opened, left ventricular function remained depressed, necessitating extracorporeal membrane oxygenation, which was withdrawn after 48 h of assistance when left ventricular function had recovered. The patient was extubated on the seventh postoperative day but died of multiorgan failure on the 64 th postoperative day. PMID- 23439443 TI - Quantitative evaluation of deep and shallow tissue layers' contribution to fNIRS signal using multi-distance optodes and independent component analysis. AB - To quantify the effect of absorption changes in the deep tissue (cerebral) and shallow tissue (scalp, skin) layers on functional near-infrared spectroscopy (fNIRS) signals, a method using multi-distance (MD) optodes and independent component analysis (ICA), referred to as the MD-ICA method, is proposed. In previous studies, when the signal from the shallow tissue layer (shallow signal) needs to be eliminated, it was often assumed that the shallow signal had no correlation with the signal from the deep tissue layer (deep signal). In this study, no relationship between the waveforms of deep and shallow signals is assumed, and instead, it is assumed that both signals are linear combinations of multiple signal sources, which allows the inclusion of a "shared component" (such as systemic signals) that is contained in both layers. The method also assumes that the partial optical path length of the shallow layer does not change, whereas that of the deep layer linearly increases along with the increase of the source-detector (S-D) distance. Deep- and shallow-layer contribution ratios of each independent component (IC) are calculated using the dependence of the weight of each IC on the S-D distance. Reconstruction of deep- and shallow-layer signals are performed by the sum of ICs weighted by the deep and shallow contribution ratio. Experimental validation of the principle of this technique was conducted using a dynamic phantom with two absorbing layers. Results showed that our method is effective for evaluating deep-layer contributions even if there are high correlations between deep and shallow signals. Next, we applied the method to fNIRS signals obtained on a human head with 5-, 15-, and 30-mm S-D distances during a verbal fluency task, a verbal working memory task (prefrontal area), a finger tapping task (motor area), and a tetrametric visual checker-board task (occipital area) and then estimated the deep-layer contribution ratio. To evaluate the signal separation performance of our method, we used the correlation coefficients of a laser-Doppler flowmetry (LDF) signal and a nearest 5-mm S-D distance channel signal with the shallow signal. We demonstrated that the shallow signals have a higher temporal correlation with the LDF signals and with the 5-mm S-D distance channel than the deep signals. These results show the MD-ICA method can discriminate between deep and shallow signals. PMID- 23439444 TI - HDL's protein cargo: friend or foe in cardioprotection? PMID- 23439445 TI - Gone fishing (for silent atrial fibrillation). PMID- 23439447 TI - Surgical management of obesity and the relationship to cardiovascular disease. PMID- 23439446 TI - Titin is a major human disease gene. PMID- 23439448 TI - Coronary artery embolization after successful surgical ablation of atrial fibrillation. PMID- 23439449 TI - Threatening internal carotid artery floating thrombus: left middle cerebral artery stroke in a patient with lymphoma. PMID- 23439451 TI - IPS multicentric study: Antidepressant prescription patterns. AB - BACKGROUND: There are very few studies from India which have evaluated the prescription pattern for antidepressants by psychiatrists for treatment of depression. AIM: To study the psychotropic prescription patterns of patients with first episode depression from diverse settings including teaching institutions in public and private sectors and even privately run psychiatric clinics. MATERIALS AND METHODS: Prescription data of 706 patients with first episode depression, who participated in the IPS multicentric study, were evaluated. RESULTS: Escitalopram was the most commonly prescribed antidepressant, comprising 40% of the total prescriptions. This was followed by sertraline (17.6%) and fluoxetine (16.3%). In total, selective serotonin reuptake inhibitors (SSRIs) formed 79.2% of all the prescriptions. Tricyclic antidepressants formed a small part (15.15%) of total prescriptions, with imipramine being the most commonly used tricyclic antidepressant. Serotonin-norepinephrine reuptake inhibitors (venlafaxine, desvenlafaxine and duloxetine) were prescribed to 11.3% of patients with equal share of venlafaxine and duloxetine. About one-sixth (N=104; 14.7%) of the patients were prescribed more than one antidepressant. Nearly three-fourth of the patients (N=523; 74.1%) were prescribed a benzodiazepine, with clonazepam being the most preferred agent, prescribed to nearly half of the participants (49%) and formed nearly two-third of the total benzodiazepine prescriptions (346 out of 523). CONCLUSION: Escitalopram is the most commonly prescribed antidepressant and SSRIs are the most commonly prescribed class of antidepressants. Poly pharmacy in the form of concomitant use of two antidepressants is practiced infrequently. However, benzodiazepines are used quite frequently as the co-prescription. PMID- 23439452 TI - Evaporation of freely suspended single droplets: experimental, theoretical and computational simulations. AB - Evaporation is ubiquitous in nature. This process influences the climate, the formation of clouds, transpiration in plants, the survival of arctic organisms, the efficiency of car engines, the structure of dried materials and many other phenomena. Recent experiments discovered two novel mechanisms accompanying evaporation: temperature discontinuity at the liquid-vapour interface during evaporation and equilibration of pressures in the whole system during evaporation. None of these effects has been predicted previously by existing theories despite the fact that after 130 years of investigation the theory of evaporation was believed to be mature. These two effects call for reanalysis of existing experimental data and such is the goal of this review. In this article we analyse the experimental and the computational simulation data on the droplet evaporation of several different systems: water into its own vapour, water into the air, diethylene glycol into nitrogen and argon into its own vapour. We show that the temperature discontinuity at the liquid-vapour interface discovered by Fang and Ward (1999 Phys. Rev. E 59 417-28) is a rule rather than an exception. We show in computer simulations for a single-component system (argon) that this discontinuity is due to the constraint of momentum/pressure equilibrium during evaporation. For high vapour pressure the temperature is continuous across the liquid-vapour interface, while for small vapour pressures the temperature is discontinuous. The temperature jump at the interface is inversely proportional to the vapour density close to the interface. We have also found that all analysed data are described by the following equation: da/dt = P(1)/(a + P(2)), where a is the radius of the evaporating droplet, t is time and P(1) and P(2) are two parameters. P(1) = -lambdaDeltaT/(q(eff)rho(L)), where lambda is the thermal conductivity coefficient in the vapour at the interface, DeltaT is the temperature difference between the liquid droplet and the vapour far from the interface, q(eff) is the enthalpy of evaporation per unit mass and rho(L) is the liquid density. The P(2) parameter is the kinetic correction proportional to the evaporation coefficient. P(2) = 0 only in the absence of temperature discontinuity at the interface. We discuss various models and problems in the determination of the evaporation coefficient and discuss evaporation scenarios in the case of single- and multi-component systems. PMID- 23439453 TI - The evaluation of sources of knowledge underlying different conceptual categories. AB - According to the "embodied cognition" theory and the "sensory-motor model of semantic knowledge": (a) concepts are represented in the brain in the same format in which they are constructed by the sensory-motor system and (b) various conceptual categories differ according to the weight of different kinds of information in their representation. In this study, we tried to check the second assumption by asking normal elderly subjects to subjectively evaluate the role of various perceptual, motor and language-mediated sources of knowledge in the construction of different semantic categories. Our first aim was to rate the influence of different sources of knowledge in the representation of animals, plant life and artifact categories, rather than in living and non-living beings, as many previous studies on this subject have done. We also tried to check the influence of age and stimulus modality on these evaluations of the "sources of knowledge" underlying different conceptual categories. The influence of age was checked by comparing results obtained in our group of elderly subjects with those obtained in a previous study, conducted with a similar methodology on a sample of young students. And the influence of stimulus modality was assessed by presenting the stimuli in the verbal modality to 50 subjects and in the pictorial modality to 50 other subjects. The distinction between "animals" and "plant life" in the "living" categories was confirmed by analyzing their prevalent sources of knowledge and by a cluster analysis, which allowed us to distinguish "plant life" items from animals. Furthermore, results of the study showed: (a) that our subjects considered the visual modality as the main source of knowledge for all categories taken into account; and (b) that in biological categories the next most important source of information was represented by other perceptual modalities, whereas in artifacts it was represented by the actions performed with them. Finally, age and stimulus modality did not significantly influence judgment of relevance of the sources of knowledge involved in the construction of different conceptual categories. PMID- 23439454 TI - Design and evaluation of microemulsion gel system of nadifloxacin. AB - Topical microemulsion systems for the antiacne agent, nadifloxacin were designed and developed to overcome the problems associated with the cutaneous delivery due to poor water solubility. The solubility of nadifloxacin in oils, surfactants and cosurfactants was evaluated to screen the components of the microemulsion. Various surfactants and cosurfactants were screened for their ability to emulsify the selected oily phase. The pseudoternary diagrams were constructed to identify the area of microemulsion existence. The influence of k(m) (surfactant/cosurfactant) ratio on the microemulsion existence region was determined and optimum systems were designed. The systems were assessed for drug loading efficiency and characterised for optical birefringence, pH and refractive index, robustness to dilution, globule size, drug content and thermodynamic stability. Optimised microemulsion systems were formulated into gel form and evaluated for viscosity, spreadability, drug content, ex vivo skin permeation and antibacterial activity. The maximum solubility of nadifloxacin in the microemulsion system was found to be 0.25%. The nadifloxacin microemulsions had a small and uniform globule size (67.3-121.23 nm). The stability results revealed that all formulations showed a stable globule size and the polydispersity index under stress conditions. Incorporation of nadifloxacin in microemulsion gel increased the ex vivo skin permeation and antibacterial activity when compared to marketed cream. PMID- 23439455 TI - Spinal Tuberculosis (Pott's disease) Mimicking Paravertebral Malignant Tumor in a Child Presenting with Spinal Cord Compression. AB - Paravertebral tumors may interfere with the radiological and clinical features of spinal tuberculosis. We report a case of a 3-year-old boy with spinal tuberculosis who was initially misdiagnosed as having a paraspinal tumor. The diagnosis of tuberculosis was made on the basis of intraoperative findings and confirmed by histopathology. This case highlights the importance of awareness of the different radiographic features of spinal tuberculosis, which can mimic a spinal malignancy. In order to avoid delayed diagnosis, pediatricians and radiologists must be aware of spinal tuberculosis, which may interfere with other clinical conditions. PMID- 23439456 TI - Embedding time-limited laboratory orders within computerized provider order entry reduces laboratory utilization. AB - OBJECTIVES: To test the hypothesis that limits on repeating laboratory studies within computerized provider order entry decrease laboratory utilization. DESIGN: Cohort study with historical controls. SETTING: A 20-bed PICU in a freestanding, quaternary care, academic children's hospital. PATIENTS: This study included all patients admitted to the pediatric ICU between January 1, 2008, and December 31, 2009. A total of 818 discharges were evaluated prior to the intervention (January 1, 2008, through December 31, 2008) and 1,021 patient discharges were evaluated postintervention (January 1, 2009, through December 31, 2009). INTERVENTION: A computerized provider order entry rule limited the ability to schedule repeating complete blood cell counts, chemistry, and coagulation studies to a 24-hour interval in the future. The time limit was designed to ensure daily evaluation of the utility of each test. MEASUREMENTS AND MAIN RESULTS: Initial analysis with t tests showed significant decreases in tests per patient day in the postintervention period (complete blood cell counts: 1.5 +/- 0.1 to 1.0 +/- 0.1; chemistry: 10.6 +/- 0.9 to 6.9 +/- 0.6; coagulation: 3.3 +/- 0.4 to 1.7 +/- 0.2; p < 0.01, all variables vs. preintervention period). Even after incorporating a trend toward decreasing laboratory utilization in the preintervention period into our regression analysis, the intervention decreased complete blood cell counts (p = 0.007), chemistry (p = 0.049), and coagulation (p = 0.001) tests per patient day. CONCLUSIONS: Limits on laboratory orders within the context of computerized provider order entry decreased laboratory utilization without adverse affects on mortality or length of stay. Broader application of this strategy might decrease costs, the incidence of iatrogenic anemia, and catheter-associated bloodstream infections. PMID- 23439457 TI - Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study. AB - OBJECTIVES: To describe the frequency and nature of premedications used prior to neonatal endotracheal intubation; to confront observed practice with current recommendations; and to identify risk factors for the absence of premedication. DESIGN, SETTING, AND PATIENTS: Data concerning intubations were collected prospectively at the bedside as part of an observational study collecting around the-clock data on all painful or stressful procedures performed in neonates during the first 14 days of their admission to 13 tertiary care units in the region of Paris, France, between 2005 and 2006. INTERVENTION: Observational study. MEASUREMENTS AND MAIN RESULTS: Specific premedication prior to endotracheal intubation was assessed. Ninety one intubations carried out on the same number of patients were analyzed. The specific premedication rate was 56% and included mostly opioids (67%) and midazolam (53%). Compared with recent guidance from the American Academy of Pediatrics, used premedications could be classified as "preferred" (12%), "acceptable" (18%), "not recommended" (27%), and "not described" (43%). In univariate analysis, infants without a specific premedication compared with others were younger at the time of intubation (median age: 0.7 vs. 2.0 days), displayed significantly more frequent spontaneous breathing at the time of intubation (31% vs. 12%) and a higher percentage of analgesia for all other painful procedures (median values: 16% vs. 6%). In multivariate analysis, no factor remained statistically significant. CONCLUSIONS: Premedication use prior to neonatal intubation was not systematically used and when used it was most frequently inconsistent with recent recommendations. No patient- or center-related independent risk factor for the absence of premedication was identified in this study. PMID- 23439458 TI - Postoperative respiratory failure in children with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals: a pilot study. AB - OBJECTIVE: Children with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals (TOF/PA/MAPCAs), who undergo unifocalization surgery are at risk for prolonged postoperative respiratory failure. We sought to identify risk factors that are associated with prolonged mechanical ventilation in this population. DESIGN: We collected preoperative and operative data from medical records and postoperative data prospectively. Mechanical ventilation beyond postoperative day 5, which was greater than the 50th percentile for the subjects enrolled, was considered prolonged. Risk factors were analyzed using multiple logistic regression, independent samples t test, Fisher's exact test, and Kruskal-Wallis test. Enrollment occurred over a 20-month period between May 2009 and January 2011. SETTING: Lucile Packard Children's Hospital (Palo Alto, CA). PATIENTS: All patients with TOF/PA/MAPCAs presenting for unifocalization or pulmonary artery revision procedures were eligible, including those with additional structural cardiac abnormalities requiring surgical intervention. We excluded patients with single-ventricle cardiac anatomy and preoperative respiratory failure or infection. MEASUREMENTS AND MAIN RESULTS: We enrolled 35 consecutive patients undergoing 37 procedures over the study period. One patient was excluded for single-ventricle anatomy. There were 12 cases (32%) of prolonged mechanical ventilation. Delayed sternal closure was the only risk factor associated with prolonged mechanical ventilation (p = 0.01). Age, weight, cardiopulmonary bypass time, 22q11 microdeletion, postoperative fluid balance, bronchospasm, and nonrespiratory infection were not significantly associated with prolonged mechanical ventilation. Respiratory complications occurred in both groups, and patients with pneumonia were more likely to have a prolonged course (p = 0.03). There was no significant association between the type of surgery performed and duration of mechanical ventilation. CONCLUSIONS: Prolonged postoperative respiratory failure in children undergoing surgery for TOF/PA/MAPCAs was independently associated with delayed sternal closure. Respiratory complications occur after unifocalization surgery, and pneumonia is associated with prolonged mechanical ventilation. Our pilot study suggests that clinical features common in this patient population, such as bronchospasm and 22q11 microdeletion, were not associated with more postoperative respiratory failure. PMID- 23439459 TI - Severe hemorrhagic coagulopathy with hemophagocytic lymphohistiocytosis secondary to Epstein-Barr virus-associated T-cell lymphoproliferative disorder. AB - OBJECTIVE: We describe the coagulopathy and hemorrhagic complications associated with fulminant, secondary hemophagocytic lymphohistiocytosis in a cohort of patients with Epstein-Barr virus-associated T-cell lymphoproliferative disorder. PATIENTS AND METHODS: Institutional Review Board-approved retrospective review of all patients at our children's hospital over 3 years (2008-2010) with hemophagocytic lymphohistiocytosis secondary to acute Epstein-Barr virus associated T-cell lymphoproliferative disorder. RESULTS: Four males (2, 3, 17, and 20 yr old) presented with fever, hepatosplenomegaly, and pancytopenia with elevated serum ferritin, and all met clinical and laboratory criteria for secondary hemophagocytic lymphohistiocytosis. d-dimer on admission was elevated in all patients and remained extremely elevated during hospitalization, while the median prothrombin and activated partial thromboplastin times as well as fibrinogen were all in the normal range. Within a few weeks to months following admission, all patients developed multiorgan system failure with episodes of severe, life-threatening hemorrhage; in all four patients, hemorrhage was not associated with a nadir in platelet count. There were no survivors beyond 4 months from diagnosis. CONCLUSIONS: A coagulopathy characterized by persistent, extreme elevations in plasma d-dimer and severe, life-threatening hemorrhage was noted in association with hemophagocytic lymphohistiocytosis secondary to Epstein Barr virus-associated T-cell lymphoproliferative disorder. We speculate that this coagulopathy is a marker of severe hemophagocytic lymphohistiocytosis in this setting. PMID- 23439460 TI - Risk factors and outcomes of unplanned PICU postoperative admissions: a nested case-control study. AB - BACKGROUND: Although unplanned postoperative admission to PICUs (unplanned intensive care admission [UIA]) is uncommon, it might be associated with increased costs, morbidity, and mortality. However, detailed knowledge of risk factors and outcomes after UIA in children is still lacking. OBJECTIVES: To determine prevalence, risk factors, and outcomes of UIA patients compared with non-UIA patients. DESIGN: Case-control study. SETTING: A tertiary university affiliated hospital. PATIENTS: All postoperative children admitted to the PICU were monitored for UIA. About 28 cases and 88 controls were included. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: The overall prevalence of UIA was 2.6%. About 28 patients (24.1%) of 116 had unplanned admission. Multiple logistic regression revealed that factors predicting UIA were airway abnormality (odds ratio 16.2, 95% confidence interval 2.65-99.6), anesthetic factors (odds ratio 5.8, 95% confidence interval 1.06-32.2), and hypoxia intraoperative (odds ratio 7.4, 95% confidence interval 1.21-46.24). Procedures on abdomen, emergency surgery, combined anesthesia, and occurrence of intraoperative adverse events were also risk factors for an UIA. Patients with UIA had longer duration of mechanical ventilation than non-UIA patients (4.5 vs. 2 days, p = 0.01), but there were no differences in length of PICU and hospital stays. Preventable adverse events were detected in 25% of UIA children. CONCLUSIONS: Airway abnormality, anesthetic factors, and hypoxia intraoperative were risk factors associated with UIA. Although preventable events contribute significantly to unplanned PICU admissions, they constitute a room of opportunity in quality improvement programs. PMID- 23439462 TI - Comparison of nasal continuous positive airway pressure delivered by seven ventilators using simulated neonatal breathing. AB - OBJECTIVES: Nasal continuous positive airway pressure (NCPAP) is an established treatment for respiratory distress in neonates. Most modern ventilators are able to provide NCPAP. There have been no large studies examining the properties of NCPAP delivered by ventilators. The aim of this study was to compare pressure stability and imposed work of breathing (iWOB) for NCPAP delivered by ventilators using simulated neonatal breathing. DESIGN: Experimental in vitro study. SETTING: Research laboratory in Sweden. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Neonatal breathing was simulated using a mechanical lung simulator. Seven ventilators were tested at different CPAP levels using two breath profiles. Pressure stability and iWOB were determined. Results from three ventilators revealed that they provided a slight pressure support. For these ventilators, iWOB could not be calculated. There were large differences in pressure stability and iWOB between the tested ventilators. For simulations using the 3.4-kg breath profile, the pressure swings around the mean pressure were more than five times greater, and iWOB more than four times higher, for the system with the highest measured values compared with the system with the lowest. Overall, the Fabian ventilator was the most pressure stable system. Evita XL and SERVO-i were found more pressure stable than Fabian in some simulations. The results for iWOB were in accordance with pressure stability for systems that allowed determination of this variable. CONCLUSIONS: Some of the tested ventilators unexpectedly provided a minor degree of pressure support. In terms of pressure stability, we have not found any advantages of ventilators as a group compared with Bubble CPAP, Neopuff, and variable flow generators that were tested in our previous study. The variation between individual systems is great within both categories. The clinical importance of these findings needs further investigation. PMID- 23439461 TI - Hypothermia decreases cerebrospinal fluid asymmetric dimethylarginine levels in children with traumatic brain injury. AB - OBJECTIVES: Pathological increases in asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, have been implicated in endothelial dysfunction and vascular diseases. Reduced nitric oxide early after traumatic brain injury may contribute to hypoperfusion. Currently, methods to quantify asymmetric dimethylarginine in the cerebrospinal fluid have not been fully explored. We aimed to develop and validate a method to determine asymmetric dimethylarginine in the cerebrospinal fluid of a pediatric traumatic brain injury population and to use this method to assess the effects of 1) traumatic brain injury and 2) therapeutic hypothermia on this mediator. DESIGN, SETTING, AND PATIENTS: An ancillary study to a prospective, phase II randomized clinical trial of early hypothermia in a tertiary care pediatric intensive care unit for children with Traumatic brain injury admitted to Children's Hospital of Pittsburgh. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A UPLC-MS/MS method was developed and validated to quantitate asymmetric dimethylarginine. A total of 56 samples collected over 3 days with injury onset were analyzed from the cerebrospinal fluid of consented therapeutic hypothermia (n = 9) and normothermia (n = 10) children. Children undergoing diagnostic lumbar puncture (n = 5) were enrolled as controls. Asymmetric dimethylarginine was present at a quantifiable level in all samples. Mean asymmetric dimethylarginine levels were significantly increased in normothermic Traumatic brain injury children compared with that in control (0.19 +/- 0.08 umol/L and 0.11 +/- 0.02 umol/L, respectively, p = 0.01), and hypothermic children had significantly reduced mean asymmetric dimethylarginine levels (0.11 +/- 0.05 umol/L) vs. normothermic (p = 0.03) measured on day 3. Patient demographics including age, gender, and nitric oxide levels (measured as nitrite and nitrate using liquid chromatography coupled with Griess reaction) did not significantly differ between normothermia and hypothermia groups. Also, nitric oxide levels did not correlate with asymmetric dimethylarginine concentrations. CONCLUSIONS: Asymmetric dimethylarginine levels were significantly increased in the cerebrospinal fluid of traumatic brain injury children. Early hypothermia attenuated this increase. The implications of attenuated asymmetric dimethylarginine on nitric oxide synthases activity and regional cerebral blood flow after traumatic brain injury by therapeutic hypothermia deserve future study. PMID- 23439464 TI - Acute lung injury in children--kids really aren't just "little adults". AB - OBJECTIVE: To describe the planned aims and methodology of the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Consensus conference of experts in pediatric acute lung injury. METHODS: A panel of 26 experts in pediatric acute lung injury will meet over the course of one year to develop a better taxonomy to define pediatric acute lung injury, specifically predisposing factors, etiology, and pathophysiology. A modified Delphi approach that emphasizes strong professional agreement will be utilized. RESULTS: The Pediatric Acute Lung Injury Consensus Conference will aim for consensus development on the following topics related to pediatric acute lung injury: 1) definition, incidence, and epidemiology; 2) comorbidities and severity; 3) ventilatory support; 4) pulmonary specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive support and ventilation; 8) extracorporeal support; and 9) morbidity and long-term outcomes. CONCLUSIONS: The importance of this effort for improving care and guiding future research in pediatric acute lung injury is clear. Despite the many epidemiologic, interventional, and outcome studies undertaken by pediatric intensivists worldwide, our understanding of this disease process is limited, and morbidity and mortality remain unacceptably high. By consolidating the knowledge and expertise of the leaders of the field of pediatric acute lung injury, we hope to develop a framework for future progress. PMID- 23439463 TI - Pediatric Risk, Injury, Failure, Loss, End-Stage renal disease score identifies acute kidney injury and predicts mortality in critically ill children: a prospective study. AB - OBJECTIVES: To determine whether Pediatric Risk, Injury, Failure, Loss, End-Stage renal disease (pRIFLE) criteria serve to characterize the pattern of acute kidney injury in critically ill pediatric patients. To identify if pRIFLE score will predict morbidity and mortality in our patient's cohort. DESIGN: Prospective cohort. SETTING: Multidisciplinary, tertiary care, ten-bed PICU. PATIENTS: A total of 266 patients admitted to PICU from November 2009 to November 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The incidence of acute kidney injury in the PICU was 27.4%, of which 83.5% presented within 72 hours of admission to the PICU. Patients with acute kidney injury were younger; weighed less; were more likely to be on fluid overload greater than or equal to 10%; and were more likely to be on inotropic support, diuretics, or aminoglycosides. No difference in gender, use of other nephrotoxins, or mechanical ventilation was observed. Fluid overload greater than or equal to 10% was an independent predictor of morbidity and mortality. In multivariate analysis, acute kidney injury and failure categories, as defined by pRIFLE, predicted mortality, hospital length of stay, and PICU length of stay. CONCLUSIONS: In this cohort of critically ill pediatric patients, acute kidney injury identified by pRIFLE and fluid overload greater than or equal to 10% predicted increased morbidity and mortality. Implementation of pRIFLE scoring and close monitoring of fluid overload upon admission may help develop early interventions to prevent and treat acute kidney injury in critically ill children. PMID- 23439465 TI - The impact of postintubation chest radiograph during pediatric and neonatal critical care transport. AB - OBJECTIVES: Tracheal intubation is necessary in the setting of pediatric/neonatal critical care transport but information regarding usefulness and efficiency of a confirmatory postintubation chest radiograph is limited. We hypothesize that routine postintubation chest radiograph to confirm tracheal tube position is not informative and can be eliminated to improve efficiency without compromising safety in transport. DESIGN: This was a prospective observational study. The primary study outcome was the rate of tracheal tube repositioning after postintubation chest radiograph and the secondary outcome was the on-scene time. Additional data obtained included the initial accuracy of tracheal tube depth based on Pediatric Advanced Life Support and Neonatal Resuscitation Program guidelines. SETTING: A children's hospital-based pediatric/neonatal critical care transport team in northeastern Ohio. PATIENTS: All pediatric/neonatal patients intubated by the transport team during the 18-month study period (January 2009 July 2010). MEASUREMENTS AND MAIN RESULTS: There were 77 patients enrolled (43 pediatric, 34 neonatal). A postintubation chest radiograph was obtained 85.7% of the time and showed tracheal tube malposition in 47% of cases. No difference was seen in the rate of malpositioned tracheal tubes in the neonatal group compared with pediatric group (51.7% vs. 43.2%, p = 0.54). The calculated tracheal tube depth based on the Neonatal Resuscitation Program and Pediatric Advanced Life Support guidelines was correct in 50% of the neonates and 41.9% of the pediatric patients. In patients with appropriate initial tracheal tube depth by calculations, the tracheal tube was repositioned at similar rates after postintubation chest radiograph in both neonatal and pediatric patients (50% vs. 41.9%, p = 0.48). When comparing mean onscene times for patients with/without a postintubation chest radiograph, the neonatal patients saved 33 minutes on average when no chest radiograph was obtained (mean +/- sd: 60.6 +/- 35.8 min vs. 93.8 +/- 23.8 min, p = 0.01). There was no statistical difference in on-scene time for pediatric patients whether they did or did not receive a postintubation chest radiograph. CONCLUSIONS: Although postintubation chest radiographs may extend the overall on-scene transport times in select patients, our data show that the postintubation chest radiographs remain informative in pediatric/neonatal critical care specialty transport and should be obtained when feasible. PMID- 23439466 TI - Volatile anesthetic rescue therapy in children with acute asthma: innovative but costly or just costly?. AB - OBJECTIVES: To describe volatile anesthesia (VA) use for pediatric asthma, including complications and outcomes. DESIGN: Retrospective cohort study. SETTING: Children's hospitals contributing to the Pediatric Health Information System between 2004-2008. PATIENTS: Children 2-18 years old with a primary diagnosis code for asthma supported with mechanical ventilation. INTERVENTION: Those treated with VA were compared to those not treated with VA or extracorporeal membrane oxygenation. Hospital VA use was grouped as none, <5%, 5 10% and >10% among intubated children. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred and fifty-eight patients received mechanical ventilation at 40 hospitals for asthma: 47 (3%) received VA treatment at 11 (28%) hospitals. Those receiving a VA were significantly less likely to receive inhaled b agonists, ipratropium bromide, and heliox, but more likely to receive neuromuscular blocking agents than patients treated without VA. Length of mechanical ventilation, hospital stay (length of stay [LOS]) and charges were significantly greater for those treated with VA. Aspiration was more common but death and air leak did not differ. Patients at hospitals with VA use >10% were significantly less likely to receive inhaled b agonist, ipratropium bromide, methylxanthines, and heliox, but more likely to receive systemic b agonist, neuromuscular blocking agents compared to those treated at hospitals not using VA. LOS, duration of ventilation, and hospital charges were significantly greater for patients treated at centers with high VA use. CONCLUSIONS: Mortality does not differ between centers that use VA or not. Patients treated at centers with high VA use had significantly increased hospital charges and increased LOS. PMID- 23439467 TI - Acute kidney injury based on corrected serum creatinine is associated with increased morbidity in children following the arterial switch operation. AB - BACKGROUND AND OBJECTIVES: Evaluate risk factors for and impact of acute kidney injury on children following the arterial switch operation. DESIGN: Single-center retrospective chart review. SETTING: A tertiary children's hospital. PATIENTS: A total of 92 patients receiving the arterial switch operation from 1997 to 2008 at severe acute kidney injury was defined as a 100% serum creatinine rise over baseline. RESULTS: Of 92 patients, 18 (20%) developed severe acute kidney injury. Neither patient age or weight nor cardiopulmonary bypass time correlated with the development of acute kidney injury. Acute kidney injury was associated with the following: higher postoperative day 1 (POD1) fluid balance, higher inotrope scores (POD1 and POD2), and longer: postoperative ICU length of stay (p = 0.005), overall ICU length of stay (p = 0.05), and postoperative hospital length of stay (p = 0.006). The time to peak creatinine for acute kidney injury patients was between POD1 and POD2. Correction of serum creatinine for fluid balance increased the population defined as severe acute kidney injury and strengthened the association of acute kidney injury with postoperative morbidity. CONCLUSIONS: Acute kidney injury following the arterial switch operation is associated with increased morbidity. In this single center, single population, and homogenous cohort of patients, the development of acute kidney injury was not correlated with age, size, or cardiopulmonary bypass time, but was still associated with prolonged duration of ventilation and hospitalization. Notably, the failure to correct serum creatinine for fluid balance underestimates the prevalence and impact of acute kidney injury. PMID- 23439468 TI - Noninvasive transcutaneous Doppler ultrasound-derived hemodynamic reference ranges in Chinese adolescents. AB - OBJECTIVES: The ultrasonic cardiac output monitor is a noninvasive, quantitative method for measuring and monitoring cardiovascular hemodynamic parameters in patients. The aims of this study were first to establish reference ranges for cardiovascular indices measured by the ultrasonic cardiac output monitor in Chinese children aged 12-18 yr, second to assess the interobserver reliability of the method, and third to compare these ranges with a Caucasian group from Australia. DESIGN, SETTING, AND SUBJECTS: This was a population-based cross sectional cohort study of Chinese adolescents 12-18 years old, performed in secondary schools in Hong Kong. INTERVENTIONS: Ultrasonic cardiac output monitor scans were performed on each subject to measure stroke volume, cardiac output, and systemic vascular resistance together with standard oscillometric measurement of blood pressure and heart rate. Ultrasonic cardiac output monitor parameters were also standardized by deriving body surface area referenced indices. Normal ranges were defined as lying within two standard deviations on either side of the mean. To assess interobserver variability, a second, blinded operator repeated 17% of scans. MEASUREMENTS AND MAIN RESULTS: A total of 590 Chinese adolescents (49% boys) were scanned. Normal ranges for cardiac output, cardiac index, stroke volume, stroke volume index, stroke volume resistance, and systemic vascular resistance index are presented. Males had a significantly higher mean stroke volume, cardiac output, and systemic vascular resistance index compared with females (p < 0.05), but no significant differences were found for the indexed values. When compared with a group of 31 Australian Caucasian adolescents (71% boys), Chinese adolescents have a significantly lower cardiac output and stroke volume (p <0.05), but these differences disappeared when adjusted for body surface area (i.e., stroke volume index, cardiac index, and systemic vascular resistance index). Interobserver variability of ultrasonic cardiac output monitor derived stroke volume showed a coefficient of variation of 10.2%, a correlation coefficient of 0.90 (95% confidence interval 0.85-0.93), while Bland-Altman analysis showed a mean bias of 1.5% (95% limits of agreement were -19.9% to 23.0%). CONCLUSIONS: This study presents normal values for cardiovascular indices in Chinese adolescents using the ultrasonic cardiac output monitor. When referenced to body surface area, the differences between Caucasians and Chinese were insignificant. PMID- 23439469 TI - Aminoterminal pro-B-type natriuretic peptide: heart or lung disease in the neonate?. AB - OBJECTIVES: B-type natriuretic peptides have been shown to enable differentiation between heart and lung diseases in adults and children. In neonates, the role of natriuretic peptides for diagnosis of congenital heart defect (CHD) is not yet ascertained. The purpose of this single-center prospective study was to investigate aminoterminal B-type natriuretic peptide concentrations and their time courses during the first 5 days of life in neonates with CHD compared with neonates with respiratory distress. DESIGN: Single-center prospective study. SETTING: Tertiary-care neonatal ICU. PATIENTS: Aminoterminal B-type natriuretic peptide levels of 40 neonates with arterial duct-dependent CHD and of 40 neonates with respiratory distress without CHD were analyzed on the first, second, third, and fifth day of life. MAIN RESULTS: Mean aminoterminal B-type natriuretic peptide concentrations in the CHD group were significantly higher on the second (14191 vs. 4872 pg/mL), third (17790 vs. 3524 pg/mL), and fifth day (17015 vs. 4044 pg/mL), but not on the first day of life. Repeated measurements analysis of variance revealed a significantly different time course of aminoterminal B-type natriuretic peptide concentrations between the two groups. CONCLUSIONS: On the first day of life, aminoterminal B-type natriuretic peptide cannot differentiate between CHD and respiratory distress without CHD in the neonate. From the second day onwards, aminoterminal B-type natriuretic peptide in neonates with CHD shows higher values and a different time course and enables differentiation between CHD and respiratory distress due to other than cardiac reasons. PMID- 23439470 TI - Aberrant regulation of the integrin very late antigen-4 in systemic lupus erythematosus. AB - Integrin very late antigen-4 (VLA4) is induced during inflammation and can regulate monocyte migration. It has been implicated in atherogenesis, a significant concern in systemic lupus erythematosus (SLE). The aim of this study was to define VLA4 expression in SLE monocytes. Flow cytometry, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry staining with confocal microscopy were used to evaluate VLA4 expression in SLE patients and controls. We found elevated expression of VLA4 in SLE patients with significantly increased VLA4 staining intracellularly compared to control. Exposure of control monocytes to SLE sera or immune complexes led to increased intracellular expression, and immune complexes were capable of driving redistribution of surface VLA4 to the cytoplasm. Therefore, VLA4 was found to be subject to complex regulation with SLE sera driving both RNA expression and redistribution of protein. Stimulation of SLE monocytes with a VLA4 ligand induced significant TNFalpha expression, confirming a functional effect. This behavior may contribute to increased atherosclerosis and monocyte infiltrates in end organs. PMID- 23439471 TI - Systemic lupus erythematosus with cytophagic histiocytic panniculitis successfully treated with high-dose glucocorticoids and cyclosporine A. AB - A 37-year-old male with systemic lupus erythematosus (SLE) presented with high fever, subcutaneous indurations, anemia, thrombocytopenia, elevated liver enzymes and hyperferritinemia. Skin biopsy revealed hemophagocytic histiocytes in the adipose tissues. The patient was diagnosed with SLE with cytophagic histiocytic panniculitis (CHP). Treatment with high-dose glucocorticoids and cyclosporine A induced remission of SLE and CHP. CHP is generally a systemic disorder affecting subcutaneous adipose tissues with a high mortality rate. However, based on the present and previously reported cases, we believe that intensive immunosuppression can ameliorate CHP that occurs as a skin manifestation of SLE. PMID- 23439472 TI - Coincidence of granulomatosis and polyangiitis with atypical clinical manifestation and antiphospholipid syndrome. AB - Granulomatosis and angiitis (GPA) is a multisystemic disease characterized by a granulomatous inflammation, tissue necrosis, and vasculitis of small and medium sized blood vessels. Although the disease has a predilection for the upper respiratory tract, lungs, and kidneys, any organ system may be affected. Here, we present a case of generalized GPA manifested initially by necrotizing isolated parotitis and later by pulmonary-renal syndrome. Simultaneously with pulmonary hemorrhage, our patient developed an antiphospholipid syndrome (APS) presenting with deep vein thrombosis and strongly positive lupus anticoagulant. To the best of our knowledge the coincidence of parotitis and pulmonary-renal syndrome due to GPA and APS has never been reported previously. Concomitant venous thromboembolism may be life-threatening in a patient with GPA. Early diagnosis and institution of the proper therapy are critical in order to prevent organ damage. PMID- 23439473 TI - Efficacy of low-dose intravenous cyclophosphamide in systemic lupus erythematosus presenting with Guillain-Barre syndrome-like acute axonal neuropathies: report of two cases. AB - There are few cases of Guillain-Barre syndrome (GBS), particularly of atypical variants, occurring in association with systemic lupus erythematous (SLE). Reports addressing a specific therapy thus remain almost anecdotal. It is therefore challenging to determine the treatment that is best suited for this subset of patients, especially if initial conventional therapy for GBS fails. We present two cases of GBS-like acute axonal neuropathies, one with acute motor axonal neuropathy (AMAN), and another with acute motor sensory axonal neuropathy (AMSAN), presenting early in the course of SLE. The first case failed to respond to therapy with intravenous immunoglobulins (IVIG) and plasmapheresis, but achieved a favorable outcome when high-dose glucocorticoids along with low-dose intravenous (IV) cyclophosphamide pulses were given. The second case responded favorably to high-dose glucocorticoids, IVIG, and low-dose IV cyclophosphamide pulses. Both patients have remained in clinical remission and without neurologic sequelae after 10 and three years of follow-up, respectively. PMID- 23439474 TI - Electroconvulsive therapy (ECT) for catatonia: delay may be risky. PMID- 23439477 TI - Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection? AB - Fructose is a simple sugar present in honey and fruit, but can also exist as a polymer (fructans) in pasture grasses. Mammals are unable to metabolize fructans, but certain gram positive bacteria contain fructanases and can convert fructans to fructose in the gut. Recent studies suggest that fructose generated from bacteria, or directly obtained from the diet, can induce both increased intestinal permeability and features of metabolic syndrome, especially the development of insulin resistance. The development of insulin resistance is driven in part by the metabolism of fructose by fructokinase C in the liver, which results in oxidative stress in the hepatocyte. Similarly, the metabolism of fructose in the small bowel by intestinal fructokinase may lead to increased intestinal permeability and endotoxemia. While speculative, these observations raise the possibility that the mechanism by which fructans induce laminitis could involve intestinal and hepatic fructokinase. Further studies are indicated to determine the role of fructanases, fructose and fructokinase in equine metabolic syndrome and laminitis. PMID- 23439478 TI - Potential for preventive effects of cocoa and cocoa polyphenols in cancer. AB - Prevention of cancer through the diet is receiving increasing interest, and cocoa because of its polyphenolic compounds has become an important potential chemopreventive and therapeutic natural agent. Cocoa and its main polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. Cocoa flavonoids have been demonstrated to influence several important biological functions in vitro and in vivo by their free radical scavenging ability or through the regulation of signal transduction pathways to stimulate apoptosis and to inhibit inflammation, cellular proliferation, apoptosis, angiogenesis and metastasis. Nevertheless, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of the potential chemopreventive activity of cocoa and its polyphenolic components by summarizing cell culture and animal models studies, as well as interventional and epidemiological studies on humans. PMID- 23439479 TI - Biosafety and antioxidant effects of a beverage containing silymarin and arginine. A pilot, human intervention cross-over trial. AB - The study objective was to investigate the potential of a beverage containing silymarin and L-arginine to alter basic physiological and urodynamic parameters in 22 normal healthy men aged 38-59 years. The volunteers drank 500 ml/day beverage without silymarin and L-arginine for 10 days followed, after a 7-day washout period, by the beverage with 400mg silymarin and 295 mg L-arginine for 10 days. Blood and urine samples were collected on days 0, 10 and 27. The beverages were well-tolerated with no adverse effects. Most of the biochemical, hematological and urodynamic parameters remained unchanged. Total antioxidant capacity, total level of antioxidants, lipoperoxidation products (malondialdehyde), advanced oxidation products of proteins in plasma and glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase levels in erythrocytes were not influenced. Serum gamma-glutamyl transferase, malondialdehyde level and activity of glutathione S-transferase in erythrocytes were lowered at day 27 and the concentration of total plasma SH groups was higher on day 10. Using an ex vivo system, we found that silymarin/silybin at 10-100 MUM is able to adsorb onto human erythrocytes and the complexes displayed antioxidant properties as studied using ex situ square-wave voltammetry. The trial showed that silymarin in vivo may protect erythrocytes against oxidative damage. PMID- 23439480 TI - Ghrelin inhibits sodium metabisulfite induced oxidative stress and apoptosis in rat gastric mucosa. AB - This study aimed to investigate the effect of ghrelin administration on sulfite induced oxidative and apoptotic changes in rat gastric mucosa. Forty male albino Wistar rats were randomized into control (C), sodium metabisulfite (Na2S2O5) treated (S), ghrelin treated (G) and, Na2S2O5+ghrelin treated (SG) groups. Sodium metabisulfite (100 mg/kg/day) was given by gastric gavage and, ghrelin (20 MUg/kg/day) was given intraperitoneally for 5 weeks. Plasma-S-sulfonate level was increased in S and SG groups. Na2S2O5 administration significantly elevated total oxidant status (TOS) levels while depleting total antioxidant status (TAS) levels in gastric mucosa. Ghrelin significantly decreased gastric TOS levels in the SG group compared with the S group. Additionally, TAS levels were found to be higher in SG group in reference to S group. Na2S2O5 administration also markedly increased the number of apoptotic cells, cleaved caspase-3 and PAR expression (PARP activity indicator) and, decreased Ki67 expression (cell proliferation index) in gastric mucosal cells. Ghrelin treatment decreased the number apoptotic cells, cytochrome C release, PAR and, caspase-3 expressions while increasing Ki67 expression in gastric mucosa exposed to Na2S2O5. In conclusion, we suggest that ghrelin treatment might ameliorate ingested-Na2S2O5 induced gastric mucosal injury stemming from apoptosis and oxidative stress in rats. PMID- 23439481 TI - Risk assessment scenarios of children's exposure to aflatoxin M1 residues in different milk types from the Greek market. AB - Occurrence of aflatoxin M1 (AFM1) was determined in 196 milk samples (conventional, organic and kids milk) from the Greek market during November 2009 to June 2010. AFM1 content was analyzed using an Enzyme-Linked Immunosorbent Assay (ELISA) commercial kit. Aflatoxin M1 was detected in 46.5% of the samples. 46.5% of the samples were found positive for AFM1. The most frequent range of detection was between 5 and 10 ng/l. Based on the EU regulation only 2 milk samples presented AFM1 levels higher than the maximum residue limits. Two different scenarios were used for the determination of hazard index: (a) scenario 1 using only positive (detected AFM1) samples and (b) scenario 2 when missing values where imputed with Limit of Detection (LOD) divided by 2. Significant statistical differences between different milk categories were presented only when the results were imputed with LOD/2 values. Exposure assessment scenarios were developed for ages 1, 3, 5, 7 and 12 and their respective estimated weights and daily milk consumption. Under the worst-case scenario all milk types presented a Hazard Index (HI) less than one. The highest HI values appear in the ages of 1-3. PMID- 23439484 TI - Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder. PMID- 23439483 TI - Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system. AB - Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in individuals from diverse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders. PMID- 23439482 TI - The vascular depression hypothesis: mechanisms linking vascular disease with depression. AB - The 'Vascular Depression' hypothesis posits that cerebrovascular disease may predispose, precipitate or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between LLD, vascular risk factors and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in LLD, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor, influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression, but also provide guidance on the potential repurposing of pharmacological agents that may improve LLD outcomes. PMID- 23439485 TI - Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways. AB - Glycogen synthase kinase 3 (GSK3), a prominent enzyme in carbohydrate metabolism, also has a major role in brain function. It is physiologically regulated by the kinase Akt, which phosphorylates GSK3 to inhibit catalytic activity. Inositol hexakisphosphate-1 (IP6K1) generates the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP7), which physiologically inhibits Akt leading to enhanced GSK3 activity. We report that IP6K1 binds and stimulates GSK3 enzymatic activity in a non-catalytic fashion. Physiological relevance is evident in the inhibition of GSK3 activity in the brains of IP6K1-deleted mice. Behavioral alterations of IP6K1 knockout mice resemble those of GSK3 mutants. Accordingly, modulation of IP6K1-GSK3beta interaction may exert beneficial effects in psychiatric disorders involving GSK3. PMID- 23439486 TI - Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study. AB - In a recent human positron emission tomography (PET) study we demonstrated the ability to detect amphetamine-induced dopamine (DA) release in the prefrontal cortex as a reduction in the binding of the DA D(2/3) radioligand [(11)C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [(11)C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate DA concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced DA release and [(11)C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg kg(-1), 0.5 mg kg(-1) and 1.0 mg kg(-1)). Amphetamine led to a significant dose dependent increase in dialysate (0.3 mg kg(-1): 999+/-287%; 0.5 mg kg(-1): 1320+/ 432%; 1.0 mg kg(-1): 2355+/-1026%) as measured with microdialysis and decrease in [(11)C]FLB 457 binding potential (BP(ND), 0.3 mg kg(-1): -6+/-6%; 0.5 mg kg(-1): 16+/-4%; 1.0 mg kg(-1): -24+/-2%) as measured with PET. The relationship between amphetamine-induced peak DeltaDA and Delta[(11)C]FLB 457 BP(ND) in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate DA release is correlated with the magnitude of the reduction in [(11)C]FLB 457 BP(ND) in the frontal cortex. The use of the [(11)C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical DA release in neuropsychiatric disorders such as schizophrenia and addiction. PMID- 23439488 TI - Management of sterno-mediastinitis. AB - With an incidence rate of 1-4%, mediastinitis following cardiac surgery is a rarely occurring complication, but may show a mortality rate of up to 50%. Risk factors for sternal instability are insulin-dependent diabetes mellitus, obesity, immunosuppressed state, chronic obstructive pulmonary disease, osteoporosis, history of radiation, renal failure, body height, smoking and nutritional state. The aim of this paper is to show an overview of this clinical picture, present the risk factors and elucidate the therapy options chronologically. As a result of interdisciplinary cooperation, a therapy concept has developed which is adapted to the patient individually. Therapy begins with the simplest measures and, if deemed necessary, this is then escalated step by step. The aim of the treatment is to bring the infection under control, which requires radical surgical debridement, removal of infected and necrotic tissue, removal of all foreign bodies (including wires and osteosynthesis material) and the removal of all infected, necrotic osseous material if necessary followed by vacuum-assisted closure therapy. The reconstruction of defects of the anterior chest wall is achievable using different muscle flaps. Mostly the muscle pectoralis major is used unilaterally or bilaterally with or without disinsertion of the tendon. Other options are the omental flap, the muscle latissimus dorsi flap or the muscle rectus abdominis flap. A combined approach comprising surgical debridement, short-term vacuum therapy and subsequent myoplastic coverage has proved successful and can be carried out with a high standard of safety. PMID- 23439489 TI - Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas. AB - Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel. PMID- 23439490 TI - The influence of heel height on vertical ground reaction force during landing tasks in recreationally active and athletic collegiate females. AB - PURPOSE: To determine if heel height alters vertical ground reaction forces (vGRF) when landing from a forward hop or drop landing. BACKGROUND: Increased vGRF during landing are theorized to increase ACL injury risk in female athletes. METHODS: Fifty collegiate females performed two single-limb landing tasks while wearing heel lifts of three different sizes (0, 12 & 24 mm) attached to the bottom of a athletic shoe. Using a force plate, peak vGRF at landing was examined. Repeated measures ANOVAs were used to determine the influence of heel height on the dependent measures. RESULTS: Forward hop task- Peak vGRF (normalized for body mass) with 0 mm, 12 mm, and 24 mm lifts were 2.613+/-0.498, 2.616+/-0.497 and 2.495+/-0.518% BW, respectively. Significant differences were noted between 0 and 24 mm lift (p<.001) and 12 and 24 mm lifts (p=.004), but not between the 0 and 12 mm conditions (p=.927). Jump-landing task- No significant differences were found in peak vGRF (p=.192) between any of the heel lift conditions. CONCLUSIONS: The addition of a 24 mm heel lift to the bottom of a sneaker significantly alters peak vGRF upon landing from a unilateral forward hop but not from a jumping maneuver. PMID- 23439491 TI - Aplastic anemia and membranous nephropathy induced by intravenous mercury. AB - Self-injection of mercury can be life-threatening. We report a case of attempted suicide by self-intravenous injection of elemental mercury. The patient suffered from two side effects : membranous nephropathy and aplastic anemia. She was treated and the systemic effects of mercury were reversed after 4 years. The toxicology of mercury, mechanisms of renal and systemic toxicities, and the various therapeutic measures for mercury poisoning are discussed. PMID- 23439487 TI - In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise. AB - New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations. PMID- 23439493 TI - Femtosecond-laser ablation dynamics of dielectrics: basics and applications for thin films. AB - Laser ablation of dielectrics by ultrashort laser pulses is reviewed. The basic interaction between ultrashort light pulses and the dielectric material is described, and different approaches to the modeling of the femtosecond ablation dynamics are reviewed. Material excitation by ultrashort laser pulses is induced by a combination of strong-field excitation (multi-photon and tunnel excitation), collisional excitation (potentially leading to an avalanche process), and absorption in the plasma consisting of the electrons excited to the conduction band. It is discussed how these excitation processes can be described by various rate-equation models in combination with different descriptions of the excited electrons. The optical properties of the highly excited dielectric undergo a rapid change during the laser pulse, which must be included in a detailed modeling of the excitations. The material ejected from the dielectric following the femtosecond-laser excitation can potentially be used for thin-film deposition. The deposition rate is typically much smaller than that for nanosecond lasers, but film production by femtosecond lasers does possess several attractive features. First, the strong-field excitation makes it possible to produce films of materials that are transparent to the laser light. Second, the highly localized excitation reduces the emission of larger material particulates. Third, lasers with ultrashort pulses are shown to be particularly useful tools for the production of nanocluster films. The important question of the film stoichiometry relative to that of the target will be thoroughly discussed in relation to the films reported in the literature. PMID- 23439492 TI - CDCP1 regulates the function of MT1-MMP and invadopodia-mediated invasion of cancer cells. AB - Complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein 1 (CDCP1) is a transmembrane protein that regulates anchorage-independent growth and cancer cell migration and invasion. Expression of CDCP1 is detected in a number of cancer cell lines and tissues and is closely correlated with poor prognosis. Invadopodia are actin-based protrusions on the surface of invasive cancer cells that promote the degradation of the extracellular matrix (ECM) via localized proteolysis, which is mainly mediated by membrane type 1 matrix metalloproteinase (MT1-MMP). MT1-MMP is accumulated at invadopodia by targeted delivery via membrane trafficking. The present study shows that CDCP1 is required for ECM degradation by invadopodia in human breast cancer and melanoma cells. CDCP1 localized to caveolin-1-containing vesicular structures and lipid rafts and was detected in close proximity to invadopodia. Further biochemical analysis revealed that substantial amounts of CDCP1 existed in the Triton X-100 insoluble lipid raft fraction. CDCP1 was coimmunoprecipitated with MT1-MMP and colocalized with MT1 MMP at the vesicular structures. The siRNA-mediated knockdown of the CDCP1 expression markedly inhibited MT1-MMP-dependent ECM degradation and Matrigel invasion and reduced the accumulation of MT1-MMP at invadopodia, as shown by immunofluorescence analysis. These results indicate that CDCP1 is an essential regulator of the trafficking and function of MT1-MMP- and invadopodia-mediated invasion of cancer cells. PMID- 23439494 TI - Treatment of acute septic arthritis. AB - Acute septic arthritis is a rare, but potentially devastating disease. The treatment is initiated intravenously, but can be safely switched to oral after 2 4 days providing large doses of a well-absorbing antibiotic and, for time dependent antibiotics, 4 times-a-day administration are used. Empiric treatment should always cover Staphylococcus aureus and common respiratory pathogens, whereas Kingella kingae and Salmonella are important only regionally. Studies conducted by our group have shown that a total course of 10 days may suffice for previously healthy children in a Western setting. Treatment of neonates, patients with immunodeficiency or cases caused by methicillin-resistant S. aureus, may deserve a different approach. PMID- 23439495 TI - Multifocal choroiditis following simultaneous hepatitis A, typhoid, and yellow fever vaccination. AB - The paper describes the first reported case of multifocal choroiditis following simultaneous hepatitis-A, typhoid, and yellow fever vaccinations. A 33-year-old male developed sudden onset of flashing lights and floaters in his right eye 3 weeks following hepatitis A, typhoid, and yellow fever vaccinations. Fundus examination and angiography confirmed the presence of multiple peripheral chorioretinal lesions. These lesions demonstrated characteristic morphologic changes over a period of 8 weeks which were consistent with a diagnosis of self resolving multifocal choroiditis. Vaccine-induced intraocular inflammation has been described infrequently. We demonstrate the first case of self-resolving multifocal choroiditis following simultaneous administration of hepatitis A, yellow fever, and typhoid immunizations. PMID- 23439496 TI - Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. AB - RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV. PMID- 23439497 TI - A double-switch vector system positively regulates transgene expression by endogenous microRNA expression (miR-ON vector). AB - To better understand and exploit microRNA (miR) regulation, a more precise characterization of miR expression patterns within a tissue or a lineage during development, differentiation, and homeostasis is needed. We previously showed that lentiviral vectors (LV) can be made responsive to miR to stringently control transgene expression as well as to report miR activity "live" and at the single cell level. Although very useful, this approach reports miR activity by transgene suppression, hampering the direct identification and selection of miR-expressing cells. Here, we describe a strategy to couple transgene expression to the activity of the miR of interest. To this aim, we generated LV encoding two in series OFF switches: a transcriptional repressor tagged with miR target sequences and a reporter cassette under the control of the repressor. Reporter expression is ON only when the miR is active and represses translation of the transcriptional repressor. We successfully applied this design to different types of repressors, multiple gene encoding vectors and delivered the system either by two separate or a self-contained vector. We demonstrated its performance by live monitoring of two miRs in different stages of human primary hematopoietic stem/progenitor cell differentiation in vivo. Further applications of this approach include imaging of rare miR-expressing cells and positive regulation of a therapeutic or selector gene in target cells identified by the expression of selected miRs. PMID- 23439498 TI - Application of mutated miR-206 target sites enables skeletal muscle-specific silencing of transgene expression of cardiotropic AAV9 vectors. AB - Insertion of completely complementary microRNA (miR) target sites (miRTS) into a transgene has been shown to be a valuable approach to specifically repress transgene expression in non-targeted tissues. miR-122TS have been successfully used to silence transgene expression in the liver following systemic application of cardiotropic adeno-associated virus (AAV) 9 vectors. For miR-206-mediated skeletal muscle-specific silencing of miR-206TS-bearing AAV9 vectors, however, we found this approach failed due to the expression of another member (miR-1) of the same miR family in heart tissue, the intended target. We introduced single nucleotide substitutions into the miR-206TS and searched for those which prevented miR-1-mediated cardiac repression. Several mutated miR-206TS (m206TS), in particular m206TS-3G, were resistant to miR-1, but remained fully sensitive to miR-206. All these variants had mismatches in the seed region of the miR/m206TS duplex in common. Furthermore, we found that some m206TS, containing mismatches within the seed region or within the 3' portion of the miR-206, even enhanced the miR-206- mediated transgene repression. In vivo expression of m206TS-3G- and miR 122TS-containing transgene of systemically applied AAV9 vectors was strongly repressed in both skeletal muscle and the liver but remained high in the heart. Thus, site-directed mutagenesis of miRTS provides a new strategy to differentiate transgene de-targeting of related miRs. PMID- 23439499 TI - A rationally designed A34R mutant oncolytic poxvirus: improved efficacy in peritoneal carcinomatosis. AB - Oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. It has been shown that a single point mutation in the A34R gene resulted in the production of more total progeny virus and more extracellular enveloped virus (EEV), a form that can be immune-evasive and with enhanced spread. We have genetically engineered a new oncolytic poxvirus (designated vA34R) by incorporating this mutated A34R gene into a viral backbone (vvDD) which was designed for tumor-selective replication. This rationally designed virus can evade neutralization from antipoxvirus antibodies and is highly cytotoxic to cancer cells. It demonstrates improved spread and increased replication within the peritoneal cavity resulting in improved antitumor effects in a peritoneal carcinomatosis (PC) model of MC38 colon cancer. Impressively, after carrier cell-mediated delivery in the preimmunized host, vA34R displayed high replication in tumor nodules yet low accumulation in normal tissues thus enhancing the therapeutic index leading to 70% long-term cures. These results demonstrate that vA34R gains an enhanced therapeutic index for PC via immune evasion, increased spread, and production of more progeny virus. Thus, vA34R may be a potent oncolytic virus (OV) for patients with PC, even after prior exposure to vaccinia virus (VV). PMID- 23439500 TI - Myoblasts and embryonic stem cells differentially engraft in a mouse model of genetic dilated cardiomyopathy. AB - The functional and architectural benefits of embryonic stem cells (ESC) and myoblasts (Mb) transplantations into infarcted myocardium have been investigated extensively. Whereas ESC repopulated fibrotic areas and contributed to myocardial regeneration, Mb exerted their effects through paracrine secretions and scar remodeling. This therapeutic perspective, however, has been less explored in the setting of nonischemic dilated cardiomyopathies (DCMs). Our aim was to compare the integration and functional efficacy of ESC committed to cardiac fate by bone morphogenic protein 2 (BMP-2) pretreatment and Mb used as gold standard following their transplantation into the myocardium of a mouse model of laminopathy exhibiting a progressive and lethal DCM. After 4 and 8 weeks of transplantation, stabilization was observed in Mb-transplanted mice (P = 0.008) but not in groups of ESC-transplanted or medium-injected animals, where the left ventricular fractional shortening (LVFS) decreased by 32 +/- 8% and 41 +/- 8% respectively. Engrafted differentiated cells were consistently detected in myocardia of mice receiving Mb, whereas few or no cells were detected in the hearts of mice receiving ESC, except in two cases where teratomas were formed. These data suggest that committed ESC fail to integrate in DCM where scar tissue is absent to provide the appropriate niche, whereas the functional benefits of Mb transplantation might extend to nonischemic cardiomyopathy. PMID- 23439501 TI - siRNA targeting Hes5 augments hair cell regeneration in aminoglycoside-damaged mouse utricle. AB - Notch signaling is active during the development of mosaic epithelial sheets and during their turnover and regeneration. After the loss of hair cells in the mosaic sheet of the vestibular sensory epithelium, new hair cells can be spontaneously generated by transdifferentiation of supporting cells. This regenerative process involves downregulation of the Hes5 gene and is known to be limited and incomplete, especially when the lesion is severe. Here, we test whether further downregulation of Hes5 gene accomplished by the use of siRNA after a severe lesion induced by an aminoglycoside in the mouse utricle can enhance the transdifferentiation of supporting cells and lead to the increased production of new hair cells. We demonstrate that Hes5 levels in the utricle decreased after the application of siRNA and that the number of hair cells in these utricles was significantly larger than following control treatment. The data suggest that siRNA technology may be useful for inducing repair and regeneration in the inner ear and that the Notch signaling pathway is a potentially useful target for specific gene expression inhibition. PMID- 23439503 TI - Chronic graft-versus-host disease: disease biology and novel therapeutic strategies. AB - Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Chronic GVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases. Standard treatment is 1-2mg/kg/day of prednisone or an equivalent dose of methylprednisolone, with continued administration of a calcineurin inhibitor for steroid sparing. However, the prognosis of steroid-refractory chronic GVHD remains poor. Classically, chronic GVHD was said to involve predominantly Th2 responses. We are now faced with a more complex picture, involving possible roles for thymic dysfunction, transforming growth factor-beta (TGF-beta) and platelet derived growth factor (PDGF), B cells and autoantibodies, and Th1/Th2/Th17 cytokines, as well as regulatory T cells (Tregs), in chronic GVHD. More detailed research on the pathophysiology of chronic GVHD may facilitate the establishment of novel strategies for its prevention and treatment. PMID- 23439504 TI - Phospholipase C produced by Clostridium botulinum types C and D: comparison of gene, enzymatic, and biological activities with those of Clostridium perfringens alpha-toxin. AB - Clostridium botulinum type C and D strains recently have been found to produce PLC on egg yolk agar plates. To characterize the gene, enzymatic and biological activities of C. botulinum PLCs (Cb-PLCs), the cb-plc genes from 8 strains were sequenced, and 1 representative gene was cloned and expressed as a recombinant protein. The enzymatic and hemolytic activities of the recombinant Cb-PLC were measured and compared with those of the Clostridium perfringens alpha-toxin. Each of the eight cb-plc genes encoded a 399 amino acid residue protein preceded by a 27 residue signal peptide. The protein consists of 2 domains, the N- and C domains, and the overall amino acid sequence identity between Cb-PLC and alpha toxin was greater than 50%, suggesting that Cb-PLC is homologous to the alpha toxin. The key residues in the N-domain were conserved, whereas those in the C domain which are important in membrane interaction were different than in the alpha-toxin. As expected, Cb-PLC could hydrolyze egg yolk phospholipid, p nitrophenylphosphorylcholine, and sphingomyelin, and also exhibited hemolytic activity;however, its activities were about 4- to over 200-fold lower than those of alpha-toxin. Although Cb-PLC showed weak enzymatic and biological activities, it is speculated that Cb-PLC might play a role in the pathogenicity of botulism or for bacterial survival. PMID- 23439502 TI - Baculovirus: an insect-derived vector for diverse gene transfer applications. AB - Insect-derived baculoviruses have emerged as versatile and safe workhorses of biotechnology. Baculovirus expression vectors (BEVs) have been applied widely for crop and forest protection, as well as safe tools for recombinant protein production in insect cells. However, BEVs ability to efficiently transduce noninsect cells is still relatively poorly recognized despite the fact that efficient baculovirus-mediated in vitro and ex vivo gene delivery into dormant and dividing vertebrate cells of diverse origin has been described convincingly by many authors. Preliminary proof of therapeutic potential has also been established in preclinical studies. This review summarizes the advantages and current status of baculovirus-mediated gene delivery. Stem cell transduction, preclinical animal studies, tissue engineering, vaccination, cancer gene therapy, viral vector production, and drug discovery are covered. PMID- 23439505 TI - Silenced expression of NFKBIA in lung adenocarcinoma patients with a never smoking history. AB - Nuclear factor of kappa-light polypeptide gene enhancer in B cells inhibitor alpha (NFKBIA), which is a tumor suppressor gene, was found to be silenced in lung adenocarcinomas. We examined NFKBIA expression, mutations in the EGFR and K ras genes, and EML4-ALK fusion in 101 resected lung adenocarcinoma samples from never-smokers. NFKBIA expression was evaluated using immunohistochemistry. NFKBIA expression was negative in 16 of the 101 samples (15.8%). EGFR and K-ras mutations and EML4-ALK fusion were detected in 61 (60.5%), 1 (1.0%), and 2 (2.0%) of the 101 samples, respectively, in a completely mutually exclusive manner. Negative NFKBIA expression was observed significantly more frequently among the tumors with none of the three genetic alterations compared to those with such alterations (p = 0.009). In addition, negative NFKBIA expression was significantly more frequent among the EGFR-wild type samples compared to the EGFR mutant samples (p = 0.013). In conclusion, NFKBIA expression was silenced in adenocarcinomas without EGFR/K-ras mutations or EML4-ALK fusion, suggesting that the silencing of NFKBIA may play an important role in the carcinogenesis of adenocarcinomas independent of EGFR/K-ras mutations or EML4-ALK fusion. PMID- 23439506 TI - Shift work and diabetes mellitus among male workers in Japan: does the intensity of shift work matter? AB - The purpose of this study was to examine the association between shift work and diabetes mellitus by separating shift workers according to the intensity of their shift work (seasonal shift work and continuous shift work). Between May and October 2009, we collected data from annual health checkups and questionnaires at a manufacturing company in Shizuoka, Japan. Questionnaires were returned by 1,601 workers (response rate: 96.2%, men/women = 1,314/287). Diabetes mellitus was defined as hemoglobin A1c >= 6.5% and fasting blood sugar >= 126 mg/dl. After exclusions, which included all the women and clerical workers because they did not work in shifts, we analyzed 475 skilled male workers. After adjusting for age, smoking status, frequency of alcohol consumption, and cohabitation status, odds ratios for diabetes mellitus were 0.98 (95% confidence interval [CI]: 0.28 4.81) and 2.10 (95% CI: 0.77-5.71) among seasonal shift workers and continuous shift workers, respectively, compared with non-shift workers. In an age stratified analysis (<45 years vs. >=45 years), the association between continuous shift work and diabetes mellitus was more pronounced among older participants. Compared with non-shift workers, the risk of diabetes mellitus was increased among continuous shift workers, whereas its effect is limited among seasonal shift workers. PMID- 23439507 TI - Multiple regression analysis for grading and prognosis of cubital tunnel syndrome: assessment of Akahori's classification. AB - The purpose of this study was to quantitatively evaluate Akahori's preoperative classification of cubital tunnel syndrome. We analyzed the results for 57 elbows that were treated by a simple decompression procedure from 1997 to 2004. The relationship between each item of Akahori's preoperative classification and clinical stage was investigated based on the parameter distribution. We evaluated Akahori's classification system using multiple regression analysis, and investigated the association between the stage and treatment results. The usefulness of the regression equation was evaluated by analysis of variance of the expected and observed scores. In the parameter distribution, each item of Akahori's classification was mostly associated with the stage, but it was difficult to judge the severity of palsy. In the mathematical evaluation, the most effective item in determining the stage was sensory conduction velocity. It was demonstrated that the established regression equation was highly reliable (R = 0.922). Akahori's preoperative classification can also be used in postoperative classification, and this classification was correlated with postoperative prognosis. Our results indicate that Akahori's preoperative classification is a suitable system. It is reliable, reproducible and well-correlated with the postoperative prognosis. In addition, the established prediction formula is useful to reduce the diagnostic complexity of Akahori's classification. PMID- 23439508 TI - A prospective study of long-term outcomes in female patients with nonalcoholic steatohepatitis using age- and body mass index-matched cohorts. AB - In patients with nonalcoholic steatohepatitis (NASH), the prevalence of cirrhosis is higher among women than men, and hepatocellular carcinoma (HCC) develops mainly in the cirrhotic stage among women. However, the long-term outcomes in female patients with NASH have not been fully elucidated, and age, gender and BMI were not simultaneously adjusted in previous studies on the prognosis of NASH. To elucidate the outcomes in female patients with NASH, we prospectively compared NASH patients with advanced fibrosis (advanced NASH) with hepatitis C virus related advanced fibrosis (advanced CHC) patients and NASH patients with mild fibrosis (mild NASH) using study cohorts that were adjusted for body mass index (BMI) in addition to age. The median follow-up period was 92.5 months. Liver related complication-free survival was significantly reduced in the advanced NASH group compared to the mild NASH group. No liver-related complications developed in the mild NASH group. The overall survival, liver-related complication- and cardiovascular/cerebrovascular disease-free survival were not significantly different between the advanced NASH and CHC groups. Female patients with NASH and advanced fibrosis may have a less favorable prognosis for liver-related complications than the matched cohorts with NASH and mild fibrosis, but may have a similar prognosis to the matched cohorts with CHC. PMID- 23439509 TI - Severe gummy smile with class II malocclusion treated with LeFort I osteotomy combined with horseshoe osteotomy and intraoral vertical ramus osteotomy. AB - In this article, we report the successful surgical treatment of a patient, 34 years of age, who had a severe gummy smile and a class II malocclusion. The patient had an 11-mm gingival exposure during full smile and a convex profile. A LeFort I osteotomy combined with a horseshoe osteotomy was used for the superior repositioning of the maxilla;then, an intraoral vertical ramus osteotomy (IVRO) and genioplasty were performed for mandibular advancement. The maxilla was acceptably impacted 8mm at the first incisor and 5mm at the first molar. Both the occlusion and facial appearance were significantly improved by this surgical orthodontic treatment. Our results suggest that the combination of a horseshoe osteotomy with a LeFort I osteotomy is a useful technique for reliable superior repositioning of the maxilla. PMID- 23439510 TI - Papillary thyroid carcinoma arising from a median ectopic thyroid with no thyroglossal duct remnant. AB - Thyroid carcinomas arising from ectopic thyroid tissue are uncommon;most of them arise from thyroid tissue in thyroglossal cysts. A rare case of a 66-year-old woman with papillary thyroid carcinoma arising from median ectopic thyroid tissue lacking a thyroglossal duct remnant is reported. The tumor was resected by Sistrunk's procedure, and the patient's postoperative course was good. PMID- 23439511 TI - Histological analysis of failed cartilage repair after marrow stimulation for the treatment of large cartilage defect in medial compartmental osteoarthritis of the knee. AB - Bone marrow-stimulating techniques such as microfracture and subchondral drilling are valuable treatments for full-thickness cartilage defects. However, marrow stimulation-derived reparative tissues are not histologically well-documented in human osteoarthritis. We retrospectively investigated cartilage repairs after marrow stimulation for the treatment of large cartilage defects in osteoarthritic knees. Tissues were obtained from patients who underwent total knee arthroplasty (TKA) after arthroscopic marrow stimulation in medial compartmental osteoarthritis. Clinical findings and cartilage repair were assessed. Sections of medial femoral condyles were histologically investigated by safranin O staining and anti-type II collagen antibody. Marrow stimulation decreased the knee pain in the short term. However, varus leg alignment gradually progressed, and TKA conversions were required. The grade of cartilage repair was not improved. Marrow stimulations resulted in insufficient cartilage regeneration on medial femoral condyles. Safranin O-stained proteoglycans and type II collagen were observed in the deep zone of marrow-stimulated holes. This study demonstrated that marrow stimulation resulted in failed cartilage repair for the treatment of large cartilage defects in osteoarthritic knees. Our results suggest that arthroscopic marrow stimulation might not improve clinical symptoms for the long term in patients suffering large osteoarthritic cartilage defects. PMID- 23439512 TI - Increasing cardiopulmonary resuscitation provision in communities with low bystander cardiopulmonary resuscitation rates: a science advisory from the American Heart Association for healthcare providers, policymakers, public health departments, and community leaders. PMID- 23439513 TI - Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias: long-term outcome after ablation. AB - BACKGROUND: We investigated the impact of catheter ablation on ventricular tachycardia (VT) recurrence and survival in a large number of patients with structural heart disease treated in the setting of a dedicated multiskilled unit. METHODS AND RESULTS: Since January 2007, we have implemented a multidisciplinary model, aiming for a comprehensive management of VT patients. Programmed ventricular stimulation was used to assess acute outcome. Primary end points were VT recurrence and the occurrence of cardiac and sudden cardiac death. Overall, 528 patients were treated by ablation (634 procedures; 1-4 procedures per patient). Among 482 tested with programmed ventricular stimulation after the last procedure, a class A result (noninducibility of any VT) was obtained in 371 patients (77%), class B (inducibility of nondocumented VT) in 12.4%, and class C (inducibility of index VT) in 10.6%. After a median follow-up time of 26 months, VT recurred in 164 (34.1%) of 472 patients. VT recurrence was documented in 28.6% of patients with a class A result versus 39.6% of patients with class B and 66.7% with class C result (log-rank P<0.001). The incidence of cardiac mortality was lower in class A patients than in those with class B and class C (8.4% versus 18.5% versus 22%, respectively; log-rank P=0.002). On the basis of multivariate analysis, postprocedural inducibility of index VT was independently associated both with VT recurrence (hazard ratio, 4.030; P<0.001) and with cardiac mortality (hazard ratio, 2.099; P=0.04). CONCLUSIONS: Within a dedicated VT unit, catheter ablation prevents long-term VT recurrences, which may favorably affect survival in a large number of patients who have VT. PMID- 23439514 TI - The impact of socio-economic status on self-rated health: study of 29 countries using European social surveys (2002-2008). AB - Studies show that the association between socio-economic status (SES) and self rated health (SRH) varies in different countries, however there are not many country-comparisons that examine this relationship over time. The objective of the present study is to determine the effect of three SES measures on SRH in 29 countries according to findings in European Social Surveys (2002-2008), in order to study how socio-economic inequalities can vary our subjective state of health. In line with previous studies, income inequalities seem to be greater not only in Anglo-Saxon and Scandinavian countries, but especially in Eastern European countries. The impact of education is greater in Southern countries, and this effect is similar in Eastern and Scandinavian countries, although occupational status does not produce significant differences in southern countries. This study shows the general relevance of socio-educational factors on SRH. Individual economic conditions are obviously a basic factor contributing to a good state of health, but education could be even more relevant to preserve it. In this sense, policies should not only aim at reducing income inequalities, but should also further the education of people who are in risk of social exclusion. PMID- 23439516 TI - Cardiac protection by volatile anesthetics in non-cardiac surgery? A meta analysis of randomized controlled studies on clinically relevant endpoints. AB - INTRODUCTION: Volatile anesthetics improve post-ischemic recovery. A meta analysis suggested that the cardioprotective properties of desflurane and sevoflurane could reduce mortality and cardiac morbidity in cardiac surgery. Recent American College of Cardiology / American Heart Association Guidelines recommended volatile anesthetic agents during non-cardiac surgery for the maintenance of general anesthesia in patients at risk for myocardial infarction but whether these cardioprotective properties exist in non-cardiac surgery settings is controversial. We therefore performed a meta-analysis of randomized studies to investigate this issue. METHODS: Two investigators independently searched PubMed. Inclusion criteria were random allocation to treatment, comparison of a total intravenous anesthesia regimen vs an anesthesia plan including desflurane or sevoflurane, performed on adult patients undergoing non cardiac surgery. The primary endpoints were the incidence of perioperative myocardial infarction and death. RESULTS: A total of 6219 patients from 79 randomized trials were identified. No myocardial infarctions or deaths were reported in any of the studies we examined. CONCLUSIONS: This meta-analysis highlights a weakness in the literature and the results can be used to design future studies: the cardioprotective properties of desflurane and sevoflurane have never been studied in noncardiac surgery. No randomized study, among those which compared desflurane or sevoflurane to intravenous anesthetics, has addressed major outcomes such as myocardial infarction or mortality. Large, multicentre, randomized clinical trials including patients undergoing high-risk non-cardiac surgery and reporting clinically relevant outcomes such as myocardial infarction and mortality are needed. PMID- 23439515 TI - Relationships between heavy metal concentrations in roadside topsoil and distance to road edge based on field observations in the Qinghai-Tibet Plateau, China. AB - This study investigated the spatial distribution of copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb), chromium (Cr), cobalt (Co), nickel (Ni) and arsenic (As) in roadside topsoil in the Qinghai-Tibet Plateau and evaluated the potential environmental risks of these roadside heavy metals due to traffic emissions. A total of 120 topsoil samples were collected along five road segments in the Qinghai-Tibet Plateau. The nonlinear regression method was used to formulize the relationship between the metal concentrations in roadside soils and roadside distance. The Hakanson potential ecological risk index method was applied to assess the degrees of heavy metal contaminations. The regression results showed that both of the heavy metals' concentrations and their ecological risk indices decreased exponentially with the increase of roadside distance. The large R square values of the regression models indicate that the exponential regression method can suitably describe the relationship between heavy metal accumulation and roadside distance. For the entire study region, there was a moderate level of potential ecological risk within a 10 m roadside distance. However, Cd was the only prominent heavy metal which posed potential hazard to the local soil ecosystem. Overall, the rank of risk contribution to the local environments among the eight heavy metals was Cd > As > Ni > Pb > Cu > Co > Zn > Cr. Considering that Cd is a more hazardous heavy metal than other elements for public health, the local government should pay special attention to this traffic-related environmental issue. PMID- 23439533 TI - Epidural hematoma after minor trauma on patient with biparietal osteodystrophy. AB - Thinning of parietal bone bilaterally is extremely rare but well known phenomenon. Approximate prevalence is 0.4-0.5% according to radiological scans, case reports and anthropologic researches. Even though biparietal osteodystrophy occurs mostly in over 60-year-old women, it shows no special association with race or geographical area tendency. Current definition was changed by understanding that is a pathological situation, not an anatomical variety or result of growing old in time. Biparietal osteodystrophy may have an unusual presentation and treatment still remains unclear. We aim to present a patient with biparietal osteodystrophy associated with minor head trauma that caused parietal fracture and epidural hematoma underneath. PMID- 23439534 TI - [Biomaterials and technologies for vascular grafts: from bench to bedside]. AB - Peripheral artery disease and related revascularization procedures are increasing, due to the aging population and growing incidence of diabetes mellitus. Up to now, autologous saphenous vein is the conduit of choice for peripheral by-pass. Synthetic vascular graft in polyethylene terephthalate (Dacron(r)) and expanded polytetrafluoroethylene (ePTFE) are used if vein access cannot be obtained. These synthetic grafts are successfully used to replace large diameter vessels, but they fail in small diameters (<6 mm) such as for infragenicular by-pass. Reasons for failure are early thrombosis and late intimal hyperplasia. Novel small-diameter vascular grafts with an acceptable clinical outcome are therefore needed. Here, the main materials and technologies for the manufacturing of vascular grafts and the pathway from bench to bedside are discussed . PMID- 23439535 TI - [Adolescents with cancer: the "Youth Project" at the Istituto Nazionale Tumori in Milan]. AB - Adolescents with cancer are a particular group of patients who are less likely to gain access to optimal cancer services at comprehensive cancer Centers: many studies suggest adolescents fare less well than children with the same disease. The paper describes the key issues of the "Youth Project" of the Pediatric Oncology Unit IRCCS Fondazione Istituto Nazionale Tumori in Milan, dedicated to adolescents (over 15 years old) and young adults (up to 25 years old) with solid tumors. This project is a possible clinical and organizational model to address the unique needs of patients in this age group and for bridge the gap in access to care and in recruitment in clinical trials, in clinical and psycho-social management and in curves of healing. The paper also describes the activity of the Adolescent Commission established by the Italian Pediatric Hematology Oncology (AIEOP). PMID- 23439536 TI - [Alcoholic liver disease and liver transplantation]. AB - Alcoholic liver disease (ALD) is the second most common diagnosis among patients undergoing liver transplantation (LT) in Europe and in the United States. The outcome of patients transplanted for ALD is at least as good as that for most other diagnoses and better than that for hepatitis C virus. In case of severe acute alcoholic hepatitis (AAH) non-responders to medical therapy, the reason for denying LT is that it requires abstinence from alcohol for six months before consideration for a transplant. A strict application of a period of abstinence as a policy for transplant eligibility is unfair to non-responder patients, as most of them will have died prior to the end of the six-month sober period. In our opinion, in severe AAH subjects with a good social support, with the frequency of self-help groups (alcoholics anonymous or association of clubs of alcoholics in treatment), with the frequency of Alcohol Unit and without severe psychotic or personality disorders, the lack of pre-LT abstinence alone should not be a barrier against being listed. PMID- 23439537 TI - [Implementation of diagnostic accuracy for COPD (ABC Project): evaluation of a guide-line in territorial clinical practice]. AB - In Italian Territory Medicine there is no consolidated habitude, by Family General Practicioners and Paediatricians, to use Guidelines for diagnosis and management of diseases. Therefore, 19 General Practicioners, organized in a cooperative group, have identified a guideline on COPD, a disease often underdiagnosed and inappropriately treated, and verified, over 3 years of application, if it is possible, in clinical practice, to modify diagnostic therapeutic habitudes. The results - even inferior to expectations for most of the indicators used - showed an increase in the number of cases diagnosed as COPD, possibly linked to a greater use of spirometry and chest Rx. PMID- 23439538 TI - [Bone metabolism, renal function and immune structure in prostate cancer. Our experience]. AB - Relation studies between bone and immune system converge in recent years in osteoimmunology chapter. It has been suggested that prostate cancer cells may alter bone homeostasis, renal function and the immune system. The aim of this paper is to evaluate bone metabolism, renal function and immune process in prostate cancer patients versus control. Patients with prostate malignancy and bone metastases showed a condition of hypocalcemia and hypophosphatemia associated with increased bone anabolism and lymphopenia, suggesting a possible correlation between bone metabolism and immune context in prostate cancer. PMID- 23439540 TI - [Medical cinema]. PMID- 23439539 TI - [Role of vitamin D in the pathogenesis of chronic kidney disease]. AB - Chronic kidney disease (CKD) is a relevant health problem due to its worldwide increasing prevalence and the morbidity and mortality linked to its complications. Since the early stages of CKD, although patients are completely asymptomatic, important mineral homeostasis disorders occur. These disorders, involving serum levels of calcium, phosphorus, parathyroid hormone, and vitamin D, have a striking impact on patient prognosis as they affect the cardiovascular system. The new term of Chronic Kidney Disease-Mineral Bone Disease (CKD-MBD) was introduced to label bone disease during CKD as a systemic disorder tightly linked to cardiovascular calcifications and disabilities. Vitamin D deficiency has a main role in the pathogenesis of CKD-MBD, throughout the pleiotropic actions of this hormone. Vitamin D receptors (VDRs) are ubiquitous and their activation has shown protective effects against secondary hyperparathyroidism development and anti-hypertensive, anti-inflammatory, anti-fibrotic, immunomodulating, anti proliferative, anti-diabetic and anti-proteinuric properties. These mechanisms explain, at least in part, vitamin D status influence in avoiding and delaying cardiovascular disease and CKD progression. These findings strongly support the importance of an early diagnosis of mineral homeostasis disorders in CKD and the need for correction of vitamin D deficiency to prevent related disabilities and major events. PMID- 23439541 TI - A taxonomy of psychology standards and training, and their relevance for psychiatrists. AB - OBJECTIVE: The aim of the article is to describe the current standards for psychology registration and pathways to training that operate in Australia today, to compare these with international requirements, and to discuss how they relate to the work and training of psychiatrists. CONCLUSION: The standards and training for practice in psychology involve multiple pathways that are not straightforward for the public or other health practitioners to understand. Most developed nations other than Australia require higher entry requirements into the profession. New national standards set by the Psychology Board of Australia, such as endorsed areas of practice, will lead to greater consistency in standards and make the task of referring to psychologists with the appropriate competencies more straightforward, allowing for greater collaboration between clinical psychology and psychiatry practitioners. PMID- 23439542 TI - Use of serotonergic antidepressants and St John's wort in older Australians: a population-based cohort study. AB - OBJECTIVE: The study investigated the use of serotonergic antidepressants (SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin-norepinephrine reuptake inhibitors) and St John's wort in a large NSW-based community sample, and sought to identify a potentially dangerous concomitant use of these medications. METHODS: Cross-sectional data from 266,848 participants from the '45 and Up' study were used. The questionnaire captures self-reported treatment for depression or anxiety and antidepressant medications in the last four weeks. RESULTS: 5.8% of participants received treatment for depression or anxiety, with 4.7% taking an SSRI and 1.3% an SNRI. St John's wort was taken by 0.3% of the participants. Use of SSRIs and SNRIs was reported more frequently by females than males (respectively, 64.1% vs 35.9%, 66.9% vs 33.1%). The gender difference was even more pronounced for St John's wort (75.6% vs. 24.4%). Use of antidepressants decreased after the age of 65 years. One hundred and forty people reported concurrent use of an SSRI and an SNRI, and 11 people of an SSRI with St John's wort. CONCLUSIONS: Around 7% of the study population aged 45-65 years reported the use of SSRIs or SNRIs, decreasing to 5% above 70 years of age. It is of concern that some individuals used an SSRI concurrently with St John's wort. PMID- 23439543 TI - Psychiatric symptoms associated with the mental health defence for serious violent offences in Queensland. AB - OBJECTIVE: The purpose of this study was to examine which psychiatric symptoms were associated with a defence of unsoundness of mind for serious violent offences. METHOD: The study included psychiatric reports provided by forensic psychiatrists from the High Secure Inpatient Service for patients found to have a mental health defence by the Mental Health Court between June 2004 and June 2009. RESULTS: The defence of unsoundness of mind was invariably associated with psychotic symptoms. All reports concluded that the patient was deprived of knowledge of the wrongfulness of the act. Patients found to be additionally deprived of the capacity to understand their actions suffered delusional beliefs about the identity of the victim. The symptoms that resulted in a small number of patients being considered deprived of the capacity to control their actions were mixed, but approximately a third suffered passivity phenomena. CONCLUSIONS: Psychiatrists should be specific about how the patient's symptoms link to any deprivation of capacity. Report writers could comment upon the presence or absence of Axis II conditions and the likely impact of any substances in the patient's system at the time of the offence. PMID- 23439544 TI - The Mood Assessment Program is now on the Australian map. AB - OBJECTIVE: To report on the wide uptake and utility of the freely available Mood Assessment Program (MAP) since its introduction as a tool to assist diagnosis and management of mood disorders. METHOD: By mid-2012, some 16,000 patients had completed the MAP. We analyse data derived from such a sample. RESULTS: The majority of patients utilizing this service were referred by general practitioners, psychologists and psychiatrists from within New South Wales (NSW). The great majority across age bands found the MAP easy to complete and judged that it covers issues relating to their mood disorder very well or completely. CONCLUSION: The MAP is available for use Australia-wide with ready referral access for patients of mental health practitioners in general practice, psychiatry, psychology and social work. The online availability of the service makes it ideal for use in areas where access to health services is limited. PMID- 23439545 TI - Gustav Mahler as Freud's patient: a note on possible obstacles to communication and understanding. AB - OBJECTIVE: This article examines the meeting between Gustav Mahler and Sigmund Freud from a perspective that takes into account possible obstacles to their interaction. CONCLUSIONS: Mahler consulted Freud in the context of a marital crisis in 1910. While it appears that a meeting between the two men had some positive effects on Mahler, its long-term impact will never be known because Mahler died only eight months later. This consultation is first examined in the light of a number of its implications and questions for contemporary psychotherapy. The fact that Freud was unable to appreciate music did not seem to interfere with a very focused, ultra-brief intervention for the patient completely devoted to music. On the other hand, Mahler's series of death-related traumas, a life-long preoccupation with death and fear of death, were apparently unnoticed by Freud, who neglected fear of death as an important intrapsychic force and provided an explanation to Mahler that was in accordance with his theories. The article concludes with a comment on the speculation about the link between creativity on one hand and unsatisfied libido and psychological conflicts on the other. PMID- 23439546 TI - Echocardiographic monitoring for clozapine cardiac toxicity: lessons from real world experience. AB - OBJECTIVE: We aimed to identify the baseline prevalence of cardiac dysfunction in patients commencing clozapine, assess adherence with echocardiographic monitoring recommendations, and evaluate the utility and cost of echocardiographic monitoring for the development of clozapine-associated myocarditis and cardiomyopathy. METHODS: A retrospective longitudinal cohort study was undertaken of 159 consecutive patients from a major tertiary centre commencing clozapine in the period January 2002 to July 2009. RESULTS: Some 73% of patients had a baseline study, and 11% had a six-month follow-up study. Nine patients had abnormal left ventricular function at baseline. Myocarditis was identified in three patients, with all cases occurring within the first month of treatment and suspected on clinical grounds before an echocardiogram was performed. One case of possible cardiomyopathy was identified. The cost of echocardiographic screening in the first year of treatment was estimated at $AUD 209,356 per case of cardiomyopathy detected. CONCLUSION: The prevalence of cardiac dysfunction in patients commencing clozapine is high, and there are challenges in adhering with the recommended protocol for monitoring. Routine echocardiography is not useful in the detection of clozapine-associated myocarditis. Although cardiomyopathy may be identified, it is rare and associated with significant cost. Recommendations for routine echocardiographic monitoring should be re-examined. PMID- 23439547 TI - Expression and Genetic Analysis of MicroRNAs Involved in Multiple Sclerosis. AB - Evidence underlines the importance of microRNAs (miRNAs) in the pathogenesis of multiple sclerosis (MS). Based on the fact that miRNAs are present in human biological fluids, we previously showed that miR-223, miR-23a and miR-15b levels were downregulated in the sera of MS patients versus controls. Here, the expression levels of these candidate miRNAs were determined in peripheral blood mononuclear cells (PBMCs) and the serum of MS patients, in addition to three genotyped single nucleotide polymorphisms (SNPs). Mapping in the genomic regions of miR-223, miR-23a and miR-15b genes, 399 cases and 420 controls were tested. Expression levels of miR-223 and miR-23a were altered in PBMCs from MS patients versus controls. Conversely, there were no differences in the expression levels of miR-15b. A significantly decreased genotypic frequency of miR-223 rs1044165 T/T genotype was observed in MS patients. Moreover, the allelic frequency of miR 23a rs3745453 C allele was significantly increased in patients versus controls. In contrast, there were no differences in the distribution of miR-15b SNP. In conclusion, our results suggest that miR-223 and miR-23a could play a role in the pathogenesis of MS. Moreover, miR-223 rs1044165 polymorphism likely acts as a protective factor, while miR-23a rs3745453 variant seems to act as a risk factor for MS. PMID- 23439548 TI - Different Forms of Selenoprotein M Differentially Affect Abeta Aggregation and ROS Generation. AB - Selenoprotein M (SelM), one of the executants of selenium in vivo, is highly expressed in human brain and most probably involved in antioxidation, neuroprotection, and intracellular calcium regulation, which are the key factors for preventing the onset and progression of Alzheimer's disease (AD). In this paper, human SelM was successfully overexpressed in human embryonic kidney cells HEK293T. Sodium selenite (Na(2)SeO(3) 0.5 MUmol/L) increased the expression of full-length SelM and inhibited the expression of truncated SelM. The full-length SelM exhibited higher antioxidant activity than its selenocysteine-to-cysteine mutation form SelM', whereas the truncated SelM had an adverse effect that increased the oxidative stress level of cells. When beta-amyloid (Abeta(42), an AD relevant peptide) was cotransfected with the empty expression vector, SelM, or SelM' under the induction of 0.5 MUmol/L Na(2)SeO(3), the intracellular Abeta(42) aggregation rates were detected to be 57.9% +/- 5.5%, or 22.3% +/- 2.6%, or 26.3% +/- 2.1%, respectively, showing the inhibitory effects on Abeta aggregation by the full-length SelM and SelM'. Meanwhile, the intumescentia of mitochondria caused by Abeta(42) transfection was significantly mitigated by the cotransfection of SelM or SelM' with Abeta(42) under the induction of 0.5 MUmol/L Na(2)SeO(3). On the contrary, cotransfection of SelM and Abeta(42) without the induction of Na(2)SeO(3) increased Abeta(42) aggregation rate to 65.1% +/- 3.2%, and it could not inhibit the Abeta-induced intumescent mitochondria. In conclusion, full-length SelM and SelMc might prevent Abeta aggregation by resisting oxidative stress generated during the formation of Abeta oligomers in cells. PMID- 23439549 TI - Ribosomal Initiation Complex Assembly within the Wild-Strain of Coxsackievirus B3 and Live-Attenuated Sabin3-like IRESes during the Initiation of Translation. AB - Coxsackievirus B3 (CVB3) is an enterovirus of the family of Picornaviridae. The Group B coxsackieviruses include six serotypes (B1 to B6) that cause a variety of human diseases, including myocarditis, meningitis, and diabetes. Among the group B, the B3 strain is mostly studied for its cardiovirulence and its ability to cause acute and persistent infections. Translation initiation of CVB3 RNA has been shown to be mediated by a highly ordered structure of the 5'-untranslated region (5'UTR), which harbors an internal ribosome entry site (IRES). Translation initiation is a complex process in which initiator tRNA, 40S and 60S ribosomal subunits are assembled by eukaryotic initiation factors (eIFs) into an 80S ribosome at the initiation codon of the mRNA. We have previously addressed the question of whether the attenuating mutations of domain V of the poliovirus IRES were specific for a given genomic context or whether they could be transposed and extrapolated to a genomic related virus, i.e., CVB3 wild-type strain. In this context, we have described that Sabin3-like mutation (U473->C) introduced in CVB3 genome led to a defective mutant with a serious reduction in translation efficiency. In this study, we analyzed the efficiency of formation of ribosomal initiation complexes 48S and 80S through 10%-30% and 10%-50% sucrose gradients using rabbit reticulocyte lysates (RRLs) and stage-specific translation inhibitors: 5'-Guanylyl-imidodiphosphate (GMP-PNP) and Cycloheximide (CHX), respectively. We demonstrated that the interaction of 48S and 80S ribosomal complexes within the mutant CVB3 RNA was abolished compared with the wild-type RNA by ribosome assembly analysis. Taken together, it is possible that the mutant RNA was unable to interact with some trans-acting factors critical for enhanced IRES function. PMID- 23439550 TI - The apolipoprotein m-sphingosine-1-phosphate axis: biological relevance in lipoprotein metabolism, lipid disorders and atherosclerosis. AB - Apolipoprotein M (apoM) is a plasma apolipoprotein that mainly associates with high-density lipoproteins. Hence, most studies on apoM so far have investigated its effect on and association with lipid metabolism and atherosclerosis. The insight into apoM biology recently took a major turn. ApoM was identified as a carrier of the bioactive lipid sphingosine-1-phosphate (S1P). S1P activates five different G-protein-coupled receptors, known as the S1P-receptors 1-5 and, hence, affects a wide range of biological processes, such as lymphocyte trafficking, angiogenesis, wound repair and even virus suppression and cancer. The ability of apoM to bind S1P is due to a lipophilic binding pocket within the lipocalin structure of the apoM molecule. Mice overexpressing apoM have increased plasma S1P concentrations, whereas apoM-deficient mice have decreased S1P levels. ApoM S1P is able to activate the S1P-receptor-1, affecting the function of endothelial cells, and apoM-deficient mice display impaired endothelial permeability in the lung. This review will focus on the putative biological roles of the new apoM-S1P axis in relation to lipoprotein metabolism, lipid disorders and atherosclerosis. PMID- 23439551 TI - Characterization of the Expression Profile and Genetic Polymorphism of the Cellular Retinol-Binding Protein (CRBP IV) Gene in Erlang Mountainous Chickens. AB - In this study, we cloned the coding sequence of chicken CRBP IV, quantified the mRNA expression in Erlang Mountainous Chickens, and investigated a polymorphism in this gene and its association with egg production traits among 349 individuals. The cloned fragment contained a 384 bp open reading frame, which encoded a predicted protein of 127 amino acids and was highly conserved among species. Expression of CRBP IV mRNA was detected in all eight tissues (small intestine, heart, liver, kidney, oviduct, ovary, pituitary, and hypothalamus) at different ages (12, 24, 32 and 45 w). High expression was found in small intestine, pituitary, kidney and liver, whereas it was low in the heart (p < 0.05). The CRBP IV mRNA levels changed with age in the various tissues, and were highly expressed in all tissues at 32 w, except for the heart. We identified one nucleotide substitution (c. 826T>C) in the second exon, which caused an amino acid change (p. S49L). Genotypes (TT, TC and CC) had significant effects on the age at first egg (AFE), total eggs for 300 days (TE300) and highest continuous laying days (HCLD). The CC genotype would be genetically advantageous to improve egg production traits due to earlier AFE, more TE300, and longer HCLD. PMID- 23439552 TI - Synthesis and structural characterization of substituted 2-phenacylbenzoxazoles. AB - 1H and 13C NMR spectra of eleven 2-phenacylbenzoxazoles (ketimine form) show that their CDCl(3)-solutions contains also (Z)-2-(benzo[d]oxazol-2-yl)-1 phenylethenols (enolimine form). Intramolecular hydrogen bonding in the latter tautomer was found to be significantly weaker than that one in respective (Z)-2 (2-hydroxy-2-phenylvinyl)pyridines. Integrals of the 1H NMR signals were used to evaluate the molar ratio of the tautomers. Strong electron-donating substituents were found to stabilize the ketimine tautomer. pK(T) (negative logarithm of the equilibrium constant, K(T) = [ketimine]/[enolimine]) was found to be linearly dependent on the Hammett substituent constant sigma. The results of the MP2 ab initio calculations reveal enolimine including an intramolecular OH...N hydrogen bond to be the most stable form both with electron-donor and electron-acceptor substituents. The stability of ketimines is an intermediate of those found for enolimines and enaminones i.e., (E)-2-(benzo[d]oxazol-2(3H)-ylidene)-1 phenylethanones. 13C CPMAS NMR spectral data reveal that in the crystalline state the ketimine tautomer is predominant in p-NMe(2) substituted congener. On the other hand, enolimine forms were detected there when the substituent has less electron-donating character or when it is an electron-acceptor by character. PMID- 23439553 TI - A Steroidal Saponin from Ophiopogon japonicus Extends the Lifespan of Yeast via the Pathway Involved in SOD and UTH1. AB - Nolinospiroside F is a steroidal saponin isolated from Ophiopogon japonicus (O. japonicus). In this study, we found that nolinospiroside F significantly extends the replicative lifespan of K6001 yeast at doses of 1, 3 and 10 MUM, indicating that it has an anti-aging effect. This may be attributed to its anti-oxidative effect, as nolinospiroside F could increase yeast survival under oxidative stress conditions and decrease the level of malondialdehyde (MDA), an oxidative stress biomarker. It could also increase anti-oxidative stress genes, SOD1 and SOD2, expression, and the activity of superoxide dismutase (SOD). It increase the activity of SIRT1, an upstream inducer of SOD2 expression. In sod1 and sod2 mutant yeast strains, nolinospiroside F failed to extend their replicative lifespan. These results indicate that SOD participates in the anti-aging effect of nolinospiroside F. Furthermore, nolinospiroside F inhibited the expression of UTH1, a yeast-aging gene that is involved in the oxidative stress of yeast, and failed to extend the replicative lifespan of uth1 or skn7 mutant yeast cells. SKN7 is the transcriptional activator of UTH1. We also demonstrate that SOD and UTH1 regulate each other's expression. Together, these results suggest that SOD and UTH1 genes are required for and play interactive roles in nolinospiroside F mediated yeast lifespan extension. PMID- 23439555 TI - Molecular self-assembly at metal-electrolyte interfaces. AB - The self-assembly of molecular layers has become an important strategy in modern design of functional materials. However, in particular, large organic molecules may no longer be sufficiently volatile to be deposited by vapor deposition. In this case, deposition from solution may be a promising route; in ionic form, these molecules may even be soluble in water. In this contribution, we present and discuss results on the electrochemical deposition of viologen- and porphyrin molecules as well as their co-adsorption on chloride modified Cu(100) and Cu(111) single crystal electrode surfaces from aqueous acidic solutions. Using in situ techniques like cyclic voltametry and high resolution scanning tunneling microscopy, as well as ex-situ photoelectron spectroscopy data the highly ordered self-assembled organic layers are characterized with respect to their electrochemical behavior, lateral order and inner conformation as well as phase transitions thereof as a function of their redox-state and the symmetry of the substrate. As a result, detailed structure models are derived and are discussed in terms of the prevailing interactions. PMID- 23439554 TI - From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals, probably triggered by common environmental factors. Human leukocyte antigen (HLA) loci were early shown to confer the strongest genetic associations in MS. Now, more than 50 non-HLA MS susceptibility loci are identified, of which the majority are located in immune-regulatory genes. Single nucleotide polymorphisms (SNPs) in the C-type lectin-like domain family 16A (CLEC16A) gene were among the first non-HLA genetic variants that were confirmed to be associated with MS. Fine-mapping has indicated a primary association in MS and also other autoimmune diseases to intronic CLEC16A SNPs. Here, we review the identification of MS susceptibility variants in the CLEC16A gene region, functional studies of the CLEC16A molecule and the recent progress in understanding the implications thereof for MS development. This may serve as an example of the importance for further molecular investigation of the loci identified in genetic studies, with the aim to translate this knowledge into the clinic. PMID- 23439556 TI - Molecular Analysis of RNA-RNA Interactions between 5' and 3' Untranslated Regions during the Initiation of Translation of a Cardiovirulent and a Live Attenuated Coxsackievirus B3 Strains. AB - Coxsackievirus B3 (CVB3) is a causative agent of viral myocarditis, meningitis and pancreatitis. CVB3 overcome their host cells by usurping the translation machinery to benefit viral gene expression. This is accomplished through alternative translation initiation in a cap independent manner at the viral internal ribosomal entry site. The 5' untranslated region (5'UTR) of CVB3 genomic RNA is highly structured. It is the site of multiple RNA-protein and RNA-RNA interactions and it plays a critical role during translation initiation. Similar to the 5'UTR, CVB3 3' untranslated region (3'UTR) also contains secondary structural elements consisting of three stem-loops followed by a poly (A) tail sequence. Long-range RNA-RNA interactions between 5' and 3' ends of some viral genomes have been observed. Because of their dual role in translation and replication, the 5' and 3'UTRs represent promising candidates for the study of CVB3 cardiovirulence. Taking into account that efficient initiation of mRNA translation depends on a temporally and spatially orchestrated sequence of protein-protein, protein-RNA and RNA-RNA interactions, and that, at present, little is known about RNA-RNA interactions between CVB3 5' and 3'UTRs, we aimed in the present study, to assess a possible RNA-RNA interaction between 5' and 3'UTRs during the initiation of translation of a wild-type and a previously characterized mutant (Sabin3-like) CVB3 strains and to investigate the effect of the Sabin3-like mutation on these potential interactions. For this purpose, "Electrophoretic Mobility Shift" assays were carried out. Data obtained did not show any RNA-RNA direct interactions between the 5'- and 3'- ends. Therefore, we can suggest that the possible mechanism by which 3'UTR enhances CVB3 IRES activity may be by bridging the 5' to the 3' end through RNA-protein interaction and not through RNA-RNA direct contact. However, these findings need to be confirmed by carrying out further experiments. PMID- 23439557 TI - Cesium Inhibits Plant Growth through Jasmonate Signaling in Arabidopsis thaliana. AB - It has been suggested that cesium is absorbed from the soil through potassium uptake machineries in plants; however, not much is known about perception mechanism and downstream response. Here, we report that the jasmonate pathway is required in plant response to cesium. Jasmonate biosynthesis mutant aos and jasmonate-insensitive mutant coi1-16 show clear resistance to root growth inhibition caused by cesium. However, the potassium and cesium contents in these mutants are comparable to wild-type plants, indicating that jasmonate biosynthesis and signaling are not involved in cesium uptake, but involved in cesium perception. Cesium induces expression of a high-affinity potassium transporter gene HAK5 and reduces potassium content in the plant body, suggesting a competitive nature of potassium and cesium uptake in plants. It has also been found that cesium-induced HAK5 expression is antagonized by exogenous application of methyl-jasmonate. Taken together, it has been indicated that cesium inhibits plant growth via induction of the jasmonate pathway and likely modifies potassium uptake machineries. PMID- 23439558 TI - Chromatin accessibility at a STAT3 target site is altered prior to astrocyte differentiation. AB - DNA demethylation of astrocyte-specific gene promoters and STAT3 activation in neural precursor cells (NPCs) are essential for astrogliogenesis in the developing brain. To date, it remains unclear whether DNA methylation is the sole epigenetic determinant responsible for suppressing astrocyte-specific genes. Here, we used mouse embryonic stem cells (TKO ESCs) that lacked all 3 DNA methyltransferase genes, Dnmt1, Dnmt3a, and Dnmt3b, and thereby exhibit complete demethylation of the astrocyte-specific glial fibrillary acidic protein (Gfap) gene promoter. We found that although the Gfap promoter was demethylated, STAT3 failed to bind to its cognate element to induce Gfap transcription, whereas it induced transcription of a different target gene, Socs3. Moreover, although the Gfap promoter region containing the STAT3-binding site (GSBS) is enriched with transcription-repressive histone modifications, such as methylation of H3 at lysine 9 (H3K9me3) and H3K27me3, the reduction of these modifications in TKO ESCs was not sufficient for binding of STAT3 at GSBS. Furthermore, GSBS was digested by micrococcal nuclease in late-gestational NPCs that express GFAP upon LIF stimulation, but not in cells that show no expression of GFAP even in the presence of LIF, indicating that STAT3 can access GSBS in the former cells. We further showed that expression of NF-1A, which is known to potentiate differentiation of mid-gestational NPCs into astrocytes, increased its accessibility. Taken together, our results suggest that chromatin accessibility of GSBS plays a critical role in the regulation of Gfap expression. PMID- 23439559 TI - Palliative care in India: current progress and future needs. AB - Despite its limited coverage, palliative care has been present in India for about 20 years. Obstacles in the growth of palliative care in India are too many and not only include factors like population density, poverty, geographical diversity, restrictive policies regarding opioid prescription, workforce development at base level, but also limited national palliative care policy and lack of institutional interest in palliative care. Nonetheless we have reasons to be proud in that we have overcome several hurdles and last two decades have seen palpable changes in the mindset of health care providers and policy makers with respect to need of palliative care in India. Systematic and continuous education for medical staff is mandatory, and a major break-through for achieving this purpose would be to increase the number of courses and faculties in palliative medicine at most universities. PMID- 23439560 TI - Factor structure of indices of the second derivative of the finger photoplethysmogram with metabolic components and other cardiovascular risk indicators. AB - BACKGROUND: The second derivative of the finger photoplethysmogram (SDPTG) is an indicator of arterial stiffness. The present study was conducted to clarify the factor structure of indices of the SDPTG in combination with components of the metabolic syndrome (MetS), to elucidate the significance of the SDPTG among various cardiovascular risk factors. METHODS: The SDPTG was determined in the second forefinger of the left hand in 1,055 male workers (mean age, 44.2+/-6.4 years). Among 4 waves of SDPTG components, the ratios of the height of the "a" wave to that of the "b" and "d" waves were expressed as b/a and d/a, and used as SDPTG indices for the analysis. RESULTS: Principal axis factoring analysis was conducted using age, SDPTG indices, components of MetS, and the serum levels of C reactive protein (CRP) and uric acid. Three factors were extracted, and the SDPTG indices were categorized in combination with age as the third factor. Metabolic components and the SDPTG indices were independently categorized. These three factors explained 44.4% of the total variation. Multiple logistic regression analysis revealed age, d/a, serum uric acid, serum CRP, and regular exercise as independent determinants of the risk of MetS. The odds ratios (95% confidence intervals) were 1.08 (1.04 to 1.11), 0.10 (0.01 to 0.73), 1.24 (1.06 to 1.44), 3.59 (2.37 to 5.42), and 0.48 (0.28 to 0.82), respectively. CONCLUSION: The SDPTG indices were categorized in combination with age, and they differed in characteristics from components of MetS or inflammatory markers. In addition, this cross-sectional study also revealed decrease of the d/a as a risk factor for the development of MetS. PMID- 23439562 TI - Cytotoxic and antimalarial amaryllidaceae alkaloids from the bulbs of Lycoris radiata. AB - Phytochemical investigation of the 80% ethanol extract of the bulbs of Lycoris radiata resulted in the isolation of five new Amaryllidaceae alkaloids: (+)-5,6 dehydrolycorine (1), (+)-3alpha,6beta-diacetyl-bulbispermine (2), (+)-3alpha hydroxy-6beta-acetyl- bulbispermine (3), (+)-8,9-methylenedioxylhomolycorine-N oxide (5), and 5,6-dihydro-5- methyl-2-hydroxyphenanthridine (7), together with two known compounds, (+)-3alpha-methoxy- 6beta-acetylbulbispermine (4) and (+) homolycorine- N-oxide (6). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. Alkaloid 1 showed potent cytotoxicity against astrocytoma and glioma cell lines (CCF-STTG1, CHG-5, SHG-44, and U251), as well as HL-60, SMMC-7721, and W480 cell lines with IC(50) values of 9.4-11.6 MUM. Additonally, compound 1 exhibited antimalarial activity with IC(50) values of 2.3 MUM for D-6 strain and 1.9 MUM for W-2 strain of Plasmodium falciparum. PMID- 23439561 TI - NADPH oxidase NOX5-S and nuclear factor kappaB1 mediate acid-induced microsomal prostaglandin E synthase-1 expression in Barrett's esophageal adenocarcinoma cells. AB - The mechanisms of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not known. Cycloxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis. We have shown that COX-2 mediates acid-induced PGE2 production. The prostaglandin E synthase (PGES) responsible for acid-induced PGE2 production in BE, however, is not known. We found that microsomal PGES1 (mPGES1), mPGES2, and cytosolic PGES (cPGES) were present in FLO EA cells. Pulsed acid treatment significantly increased mPGES1 mRNA and protein levels but had little or no effect on mPGES2 or cPGES mRNA. Knockdown of mPGES1 by mPGES1 small interfering RNA (siRNA) blocked acid-induced increase in PGE2 production and thymidine incorporation. Knockdown of NADPH oxidase, NOX5-S, a variant lacking calcium-binding domains, by NOX5 siRNA significantly inhibited acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Overexpression of NOX5-S significantly increased the luciferase activity in FLO cells transfected with a nuclear factor kappaB (NF-kappaB) in vivo activation reporter plasmid pNF-kappaB Luc. Knockdown of NF-kappaB1 p50 by p50 siRNA significantly decreased acid induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Two novel NF-kappaB binding elements, GGAGTCTCCC and CGGGACACCC, were identified in the mPGES1 gene promoter. We conclude that mPGES1 mediates acid induced increase in PGE2 production and cell proliferation. Acid-induced mPGES1 expression depends on activation of NOX5-S and NF-kappaB1 p50. Microsomal PGES1 may be a potential target to prevent or treat EA. PMID- 23439563 TI - An improved HPLC method with the aid of a chemometric protocol: simultaneous determination of atorvastatin and its metabolites in plasma. AB - The aim of the present study was to optimize a chromatographic method for the analysis of atorvastatin (acid and lactone forms), ortho- and para hydroxyatorvastatin by using an experimental design approach. Optimization experiments were conducted through a process of screening and optimization. The purpose of a screening design is to identify the factors that have significant effects on the selected chromatographic responses, and for this purpose a full 23 factorial design was used. The location of the true optimum was established by applying Derringer's desirability function, which provides simultaneously optimization of all seven responses. The ranges of the independent variables used for the optimization were content of acetonitrile in mobile phase (60-70%), temperature of column (30-40 degrees C) and flow rate (0.8-1.2 mL min-1). The influences of these independent variables were evaluated for the output responses: retention time of first peak (p-hydroxyatorvastatin) and of last peak (atorvastatin, lactone form), symmetries of all four peaks and relative retention time of p-hydroxyatorvastatin. The primary goal of this investigation was establishing a new simple and sensitive method that could be used in analysis of biological samples. The method was validated and successfully applied for determination of atorvastatin (acid and lactone forms) and its metabolites in plasma. PMID- 23439565 TI - Synthesis, characterization and microwave-promoted catalytic activity of novel N phenylbenzimidazolium salts in Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions under mild conditions. AB - A number of novel benzimidazolium salts having aryl substituents such as N phenyl, 4-chlorophenyl and various alkyl substituents were synthesized. Their microwave-assisted catalytic activities were evaluated in Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions using a catalytic system consisting of Pd(OAc)(2)/K(2)CO(3) in DMF/H(2)O under mild reaction conditions with consistent high yields, except those of 2-bromopyridine. PMID- 23439564 TI - Anti-inflammatory and anti-allergic activities of Pentaherb formula, Moutan Cortex (Danpi) and gallic acid. AB - Pentaherb formula (PHF) has been proven to improve the quality of life of children with atopic dermatitis without side effects. The aim of this study was to elucidate the potential anti-inflammatory and anti-allergic activities of PHF, Moutan Cortex (Danpi/DP) and gallic acid (GA) using human basophils (KU812 cells), which are crucial effector cells in allergic inflammation. PHF, DP and GA could significantly suppress the expression of allergic inflammatory cytokine IL 33-upregulated intercellular adhesion molecule (ICAM)-1, and the release of chemokines CCL2, CCL5, CXCL8 and inflammatory cytokine IL-6 from KU812 cells (all p < 0.05). With the combined use of dexamethasone (0.01 MUg/mL) and GA (10 MUg/mL), the suppression of ICAM-1 expression and CCL5 and IL-6 release of IL-33 activated KU812 cells were significantly greater than the use of GA alone (all p < 0.05). The suppression of the IL-33-induced activation of intracellular signalling molecules p38 mitogen activated protein kinase, nuclear factor-kB and c-Jun amino-terminal kinase in GA-treated KU812 cells could be the underlying mechanism for the suppression on ICAM-1, chemokines and cytokines. The combined use of dexamethasone with the natural products PHF or DP or GA might therefore enhance the development of a novel therapeutic modality for allergic inflammatory diseases with high potency and fewer side effects. PMID- 23439566 TI - Quinone derivatives from the rhizomes of Acorus gramineus and their biological activities. AB - A further phytochemical investigation of the rhizomes of Acorus gramineus afforded three new quinone derivatives (1-3), together with two known compounds (4 and 5). The identification and structural elucidation of these new compounds were based on 1D and 2D NMR (COSY, HMQC, HMBC and NOESY) and MS data. The absolute configurations were established on the basis of their circular dichroism (CD) data. To investigate the anti-neuroinflammatory effects of the isolated compounds (1-5), the nitric oxide (NO) production was evaluated in the lipopolysaccharide-activated microglia cell line, BV-2. Compounds (1-5) were also tested for their cytotoxicity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) in vitro by using the SRB assay. PMID- 23439568 TI - Cell phones: the psychosocial risks. AB - Cell phones are a relatively novel and evolving technology. While the potential benefits of this technology continue to emerge, so do the potential psychosocial risks. For example, one psychosocial risk is user stress, which appears to be related to feeling compelled to promptly respond to cell-phone activity in order to maintain spontaneity and access with others. Other potential psychosocial risks include disruptions in sleep; the user's risk of exposure to cyberbullying, particularly the unwanted exposure of photographs and/or videos of the victim; and overuse, particularly among adolescents. With regard to the latter phenomenon, the boundaries among overuse, misuse, dependence, and addiction are not scientifically clear. Therefore, while cell phones are a convenient and expedient technology, they are not without their potential psychosocial hazards. PMID- 23439567 TI - Fragile x-associated tremor ataxia syndrome: the expanding clinical picture, pathophysiology, epidemiology, and update on treatment. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder characterized by kinetic tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. This disorder occurs in both males and females, frequently in families with children who have fragile X syndrome. The clinical features of this disorder, both classic and newly described, are summarized in this paper. In screening studies, fragile X mental retardation 1 (FMR1) gene premutation (55-200 CGG) expansions are most frequently seen in men with ataxia who have tested negative for spinocerebellar ataxias. Since the original description, the classic FXTAS phenotype has now been reported in females and in carriers of smaller (45-54 CGG) and larger (>200 CGG) expansions in FMR1. Premutation carriers may present with a Parkinson disease phenotype or hypotension, rather than with tremor and/or ataxia. Parkinsonism and gait ataxia may also be seen in individuals with gray zone (41-54 CGG) expansions. Studies regarding medication to treat the symptoms in FXTAS are few in number and suggest that medications targeted to specific symptoms, such as kinetic tremor or gait ataxia, may be most beneficial. Great progress has been made in regards to FXTAS research, likely given the readily available gene test and the screening of multiple family members, including parents and grandparents, of fragile X syndrome children. Expansion of genotypes and phenotypes in the disorder may suggest that a broader disease definition might be necessary in the future. PMID- 23439569 TI - Sequence-specific electron injection into DNA from an intermolecular electron donor. AB - Electron transfer in DNA has been intensively studied to elucidate its biological roles and for applications in bottom-up DNA nanotechnology. Recently, mechanisms of electron transfer to DNA have been investigated; however, most of the systems designed are intramolecular. Here, we synthesized pyrene-conjugated pyrrole imidazole polyamides (PPIs) to achieve sequence-specific electron injection into DNA in an intermolecular fashion. Electron injection from PPIs into DNA was detected using 5-bromouracil as an electron acceptor. Twelve different 5 bromouracil-containing oligomers were synthesized to examine the electron injection ability of PPI. Product analysis demonstrated that the electron transfer from PPIs was localized in a range of 8 bp from the binding site of the PPIs. These results demonstrate that PPIs can be a useful tool for sequence specific electron injection. PMID- 23439570 TI - Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells. AB - Skeletal muscle is a major site for glucose metabolism and its injury by cytokines can induce insulin resistance leading to type 2 diabetes. It has been suggested that quercetin may act as an anti-diabetic agent, however, the effects of quercetin on insulin resistance in skeletal muscle remain unknown. We aimed to investigate the role of quercetin and its glycoside, quercitrin in tumor necrosis factor-alpha (TNF-alpha) induced C2C12 skeletal muscle cell impairment. Quercetin, but not quercitrin moderately attenuated the effects of TNF-alpha and enhanced the basal and insulin stimulated uptake of glucose in a dose-dependent manner via the activation of the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways. Furthermore, the underlying mechanism also involved the suppression of nuclear factor-kappaB (NF-kappaB) signaling and the nitric oxide (NO)/inducible nitric oxide synthase (iNOS) system, downstream of AMPK transduction. In summary, quercetin exhibited its effect of improving glucose uptake and insulin sensitivity in skeletal muscle cells via the two independent signaling pathways of Akt and AMPK, and can be developed as a potential anti diabetic agent. PMID- 23439571 TI - Migraine with aura: a predictor of patent foramen ovale in children and adolescents. AB - BACKGROUND: The prevalence of patent foramen ovale (PFO) is higher among adult migraine patients. The purpose of this study was to determine the frequency of PFO in children and adolescent migraine patients. METHODS AND RESULTS: A total of 32 patients with migraine (divided into two subgroups, the migraine with aura subgroup and the migraine without aura subgroup) and 31 normal control subjects were enrolled in this study. All of the participants underwent transthoracic echocardiography with an agitated saline test. We compared the prevalence of PFO and the severity of right-to-left shunt (RLS) in each group. No statistical difference in age and sex ratio was observed in either group. The prevalence of PFO was higher in the migraine group than in the control group, but without statistical significance (46.9% vs. 25.8%, P = 0.084). The prevalence of PFO was significantly higher in the migraine with aura subgroup than in the migraine without aura subgroup ( P = 0.031) and the normal control group ( P = 0.0074). Migraine with aura was the only significant factor showing an association with PFO (<0.01). RLS size did not have an influence on migraine. CONCLUSIONS: Considering the significantly high prevalence of PFO in pediatric migraine with aura patients, migraine with aura is a clear predictor of PFO among children and adolescents. PMID- 23439572 TI - Altered pain perception in children with chronic tension-type headache: is this a sign of central sensitisation? AB - AIM: The aim of this article is to investigate if children (7-17 years) with frequent episodic tension-type headache (FETTH) or chronic TTH (CTTH) have an altered pain perception compared to healthy controls. METHODS: We applied a pressure of five increasing intensities to m. trapezius and m. temporalis with a Somedic Algometer II. Visual analogue scale-score was rated and area under the curve (AUC) calculated. An average AUC in each person was used as an outcome variable in further univariate multiple linear regression analysis because factor analysis showed that AUC represents only one dimension underlying both muscles. RESULTS: Participants included 22 children with FETTH, 36 children with CTTH and 57 controls. The CTTH group had a significantly higher AUC compared to the control group ( P < 0.001). The FETTH group represented an intermediate state. AUC did not change with increasing age, headache years, headache intensity, headache frequency or sex. CONCLUSION: Children with CTTH show significantly increased pain sensitivity in a range of pressures compared to the FETTH group and the controls. Since AUC in m. trapezius and m. temporalis represents only one general latent tenderness, it might indicate that the altered pain perception is mainly due to central sensitisation. PMID- 23439573 TI - Dream-enacting behaviour is associated with impaired sleep and severe headache related disability in migraine patients. AB - BACKGROUND: Sleep disorders, nightmares and visual hallucinations have been reported in migraine patients, which may suggest the involvement of rapid eye movement (REM) sleep regulation in migraine. However, the relationship between migraine and REM sleep behaviour disorder (RBD) remains unclear. METHODS: To investigate the clinical correlates of dream-enacting behaviours (DEB) in migraine patients, we assessed episodic migraine patients ( N = 161, mean age 33.1 years) and headache-free control subjects ( N = 140, mean age 33.1 years) under 50 years of age in a cross-sectional, case-control study. The Japanese version of the RBD screening questionnaire was used, and subjects scoring 5 or higher were defined as having DEB. RESULTS: A significantly increased frequency of DEB was observed in migraine patients compared to controls (24.2% vs. 14.3%). Migraine patients with DEB presented higher scores on the Migraine Disability Assessment and Pittsburgh Sleep Quality Index and an increased rate of smoking compared to those without DEB. Duration of migraine and headache frequency and intensity were not different between migraine patients with or without DEB. CONCLUSION: DEB was associated with impaired sleep and severe headache-related disability in migraine patients and may reflect brainstem dysfunction and increased brain excitability in migraine patients. PMID- 23439574 TI - Functional and effective connectivity in EEG alpha and beta bands during intermittent flash stimulation in migraine with and without aura. AB - OBJECTIVES: This research was a case-control study to evaluate functional and effective connectivity patterns in ongoing electroencephalography (EEG) under repetitive photic stimulation in the interictal phase of migraine patients with and without aura compared to nonmigraine controls. METHODS: EEG was recorded by six scalp electrodes from 19 migraine without aura patients (MO), 19 migraine with aura patients (MA) and 11 healthy subjects (control group (N)). Flash stimuli were presented at 9-27 Hz frequencies. Phase synchronization after Hilbert transform and Granger causality were evaluated filtering the EEG in alpha and beta bands. RESULTS: Phase synchronization increased in alpha band in MO, and decreased in beta band in MA, with respect to controls. The intensity of directed interactions in beta band, revealed by Granger causality, increased in MA compared to both MO patients and controls. DISCUSSION: There were clear differences in ongoing EEG under visual stimulation, which emerged between the two forms of migraine, probably subtended by increased cortical activation in migraine with aura, and compensatory phenomena of reduced connectivity and functional networks segregation, occurring in patients not experiencing aura symptoms. Further investigation may confirm whether the clinical manifestation of aura symptoms is subtended by a peculiar neuronal connectivity pattern. PMID- 23439575 TI - Clinical assessment of the effect of tetrabenazine on functional scales in huntington disease: a pilot open label study. AB - BACKGROUND: Tetrabenazine is a monoamine depleter with a well-documented effect against chorea associated with Huntington disease (HD). There is a paucity of data about how reduction in chorea relates to better performance on motor, gait, cognitive, and psychiatric assessments. METHODS: We designed an open label tetrabenazine withdrawal study to test performance using validated scales. The following instruments were used to assess cognitive, behavioral, and motor function in 10 patients with documented HD: The Montreal Cognitive Assessment, Beck Depression Inventory II, Dynamic Gait Index (DGI), Jebsen Hand Test, Timed 25-foot walk, Berg Balance Test (BBT), QuickDASH, and the Unified Huntington Disease Rating Scale (UHDRS) Motor, Stroop Color Word, Behavioral Assessment, Functional Checklist, and Independence Scale. RESULTS: Subjects performed significantly better while on tetrabenazine as measured by the DGI (p = 0.041), BBT (p = 0.007), and the UHDRS Total Motor (p = 0.009), Maximum Chorea (p = 0.005), and Stroop Color-Word tests (p = 0.028). DISCUSSION: This pilot study demonstrates tetrabenazine's potential effects beyond improvement in chorea. PMID- 23439576 TI - Transcatheter aortic valve replacement in high risk patients with different anaesthetic techniques. AB - INTRODUCTION: Percutaneous retrograde transfemoral or transsubclavian aortic valve replacement is a minimally invasive method of aortic valve replacement in elderly and high-risk patients with symptomatic aortic stenosis considered too fragile to go through conventional heart surgery. The purpose of this study was to compare two different anaesthetic techniques for percutaneous retrograde transfemoral or transsubclavian aortic valve replacement in terms of anaesthetic depth, hemodynamic stability and need for vasoactive drugs. METHODS: Forty-eight elderly or high risk patients, two third of them in their eighties, were scheduled for percutaneous retrograde transfemoral or transsubclavian aortic valve replacement. Anaesthetic induction was standardized, but anaesthesia was afterwards maintained alternately with either propofol infusion or sevoflurane. Need for vasoactive drugs was recorded and anaesthetic depth was estimated from acoustic evoked potential measuring and clinical observation. RESULTS: Twenty eight percent of the patients in the sevoflurane group and 30% of the patients in the propofol group required vasoactive therapy (P=0.84). Forty-four percent of the patients in the sevoflurane group and 57% of the patients in the propofol group had episodes of superficial anaesthesia recorded(P=0.38). CONCLUSIONS: We found no significant difference in the use of vasoactive drugs or in anaesthetic depth between propofol and sevoflurane anaesthesia. Both can be recommended for percutaneous aortic valve replacement. PMID- 23439577 TI - Fatigue heralding multiple sclerosis. AB - BACKGROUND: Fatigue is a common symptom in multiple sclerosis (MS) and is an important determinant of overall well-being and disability. OBJECTIVE: To assess the frequency with which fatigue precedes the diagnosis of MS using a retrospective database analysis. METHODS: Between January 1, 2003 and September 30, 2008, patients diagnosed with fatigue with and without fatigue-related medications within a 3-year period prior to newly diagnosed MS were identified from the MarketScan Databases. All statistical analysis was performed using SAS. RESULTS: Of the 16,976 patients with MS in the overall population, 5305 (31.3%) were newly diagnosed with MS and had three years of continuous healthcare coverage prior to MS diagnosis. Of these patients, 1534 (28.9%) were labeled with chronic fatigue syndrome (ICD9-780.71) or malaise or fatigue (ICD9-780.79) prior to the diagnosis of MS. One-third of these patients were labeled with fatigue one to two years before the diagnosis; 30.8% were diagnosed only with fatigue and had no other MS symptoms prior to their MS diagnosis. Among the patients diagnosed with fatigue, 10.4% were also prescribed medication for fatigue. CONCLUSION: This study demonstrates that fatigue may herald MS, often by years. A careful history for transient neurological symptoms and a physical examination is warranted in any patient presenting with fatigue. PMID- 23439578 TI - Natalizumab treatment decreases serum IgM and IgG levels in multiple sclerosis patients. AB - BACKGROUND: Treatment with natalizumab, a humanized monoclonal antibody against alpha4beta1 integrin, is associated with an increase in lymphoid progenitor cells and B cells in peripheral blood. OBJECTIVE: The objective of this study was to examine the impact of natalizumab therapy on serum levels of total IgG, IgA and IgM in patients with multiple sclerosis (MS). METHODS: In two independent cross sectional patient cohorts, serum levels of IgG, IgA and IgM were compared between patients treated with natalizumab and those not receiving natalizumab. Further, serum levels of IgG, IgA and IgM before and during natalizumab treatment were compared in two longitudinal patient cohorts. RESULTS: In patients treated with natalizumab, serum IgM and IgG levels were significantly lower compared with therapy naive patients (p<0.0001). IgM levels significantly decreased after initiation of natalizumab treatment in both longitudinal patient cohorts (p<0.01). Moreover, patients treated with natalizumab showed a time-dependent decrease in IgM levels during the first 2 years of treatment. CONCLUSION: Natalizumab treatment leads to a significant decrease in serum IgM and IgG levels in patients with MS. IgM levels decrease with treatment duration during the first 2 years of treatment. These findings might support the hypothesis that natalizumab interferes with homing of B cells, possibly leading to impaired differentiation into plasma cells and subsequently disturbed immunoglobulin synthesis. PMID- 23439579 TI - Learning and cognitive fatigue trajectories in multiple sclerosis defined using a burst measurement design. AB - BACKGROUND: Compromised learning and cognitive fatigue are critical clinical features in multiple sclerosis. OBJECTIVES: This study was designed to determine the effect of repeated exposures within and across study visits on performance measures of learning and cognitive fatigue in relapsing-remitting multiple sclerosis (RRMS). METHODS: Thirty patients with RRMS and 30 controls were recruited. Using a burst measurement design (i.e. repeated assessments within and across study visits) the oral version of the Symbol Digit Modalities Test (SDMT) was administered three times during the baseline and two consecutive monthly follow-up visits for a total of nine test administrations. Learning was assessed within and across study visits whereas cognitive fatigue was assessed during the course of each test administration that was divided into three 30-second intervals. RESULTS: Linear mixed-effect models revealed compromised learning within (95% CI: 2.6355 to 3.9867) and across (95% CI: 1.3250 to 3.1861) visits and worse cognitive fatigue (95% CI: -2.1761 to -0.1720) in patients with RRMS compared with controls. Among patients with RRMS, worse self-rated cognitive dysfunction predicted poor learning within (95% CI: -0.1112 to -0.0020) and across (95% CI: -0.0724 to -0.0106) visits. CONCLUSIONS: Burst design is optimal to study learning and cognitive fatigue. This methodology, using the SDMT or other time-efficient tests as outcome measures, can be successfully implemented in longitudinal studies and clinical trials. PMID- 23439580 TI - Mycobacterium avium subsp. paratuberculosis and multiple sclerosis in Sardinian patients: epidemiology and clinical features. AB - BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) is an infectious factor recently found in association with multiple sclerosis (MS) in Sardinia. OBJECTIVES: The objectives of this study were to confirm this association and evaluate its role in clinical features. METHODS: A total of 436 patients and 264 healthy controls (HCs) were included. We examined the blood of each individual for MAPDNA and MAP2694 antibodies using IS900-specific PCR and ELISA, respectively. Differences in MAP presence between the MS group and HCs were evaluated. In MS patients, we considered: gender, age, age at onset, duration of disease, course, EDSS, therapy, relapse/steroids at study time, and oligoclonal bands (OBs). RESULTS: MAPDNA and MAP2694 antibodies were detected in 68 MS and six HCs (p = 1.14 * 10(-11)), and 123 MS and 10 HCs (p = 2.59 * 10( 23)), respectively. OBs were found with reduced frequency in MAP-positive patients (OR = 0.52; p = 0.02). MAP2694 antibodies were detected more in patients receiving MS treatments (OR = 2.26; p = 0.01), and MAPDNA in subjects on steroids (OR = 2.65; p = 0.02). CONCLUSION: Our study confirmed the association of MAP and MS in Sardinia. The low OB frequency in MAP patients suggests a peripheral role as a trigger in autoimmunity. MAP positivity might be influenced by steroids and MS therapy. Studies in other populations are needed to confirm the role of MAP in MS. PMID- 23439581 TI - Expression of cathepsins S and D signals a distinctive biochemical trait in CD34+ hematopoietic stem cells of relapsing-remitting multiple sclerosis patients. AB - BACKGROUND: The elucidation of mechanistic aspects of relapsing-remitting multiple sclerosis (RRMS) pathogenesis may offer valuable insights into diagnostic decisions and medical treatment. RESULTS: Two lysosomal proteases, cathepsins S and D (CatS and CatD), display an exclusive pattern of expression in CD34(+) hematopoietic stem cells (HSCs) from peripheral blood of acute MS (A-MS) patients (n = 20). While both enzymes normally exist as precursor forms in the HSCs of healthy individuals (n = 30), the same cells from A-MS patients consistently exhibit mature enzymes. Further, mature cathepsins are expressed at lower rates in stable MS subjects (S-MS, n = 15) and revert to precursor proteins after interferon-beta1a treatment (n = 5). Mature CatD and CatS were induced in HSCs of healthy donors that were either co-cultured with PBMCs of A-MS patients or exposed to their plasma, suggesting a functional involvement of soluble agents. Following HSC exposure to several cytokines known to be implicated in MS, and based on relative cytokine levels displayed in A-MS, S-MS and control individuals, we identified IL-16 as a specific cell signaling factor associated with cathepsin processing. CONCLUSIONS: These data point to an evident correlation between CatS and CatD expression and MS clinical stage, and define a biochemical trait in HSCs with functional, medical, and diagnostic relevance. PMID- 23439582 TI - Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis. AB - BACKGROUND: There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways. OBJECTIVE: The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity. METHODS: We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice. RESULTS: Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms. CONCLUSIONS: Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process. PMID- 23439583 TI - Effects of Internet popular opinion leaders (iPOL) among Internet-using men who have sex with men. AB - BACKGROUND: The Internet has become a popular venue for facilitating sex networking for men who have sex with men (MSM). OBJECTIVE: The study aimed to evaluate the effectiveness of Internet popular opinion leaders (iPOL) in disseminating information about the human immunodeficiency virus (HIV), increasing the frequency of HIV testing, and reducing risky behaviors among MSM in Taiwan. METHODS: A quasi-experimental study with a nonequivalent control website for comparison was used to estimate the effectiveness of iPOL. A community-level intervention, iPOL, was conducted at the Facebook social networking website and at top1069 as a control. The iPOLs actively disseminated HIV-related information via the platform of Internet opinion leaders and AIDS information center, and discussed and responded to questions or replied to Internet-using MSM. RESULTS: A total of 369 iPOLs posted 432 articles and 503 replies to others, influencing 959,088 persons on Facebook. A total of 1037 MSM, 552 (53.23%) from an intervention website and 485 (46.76%) from a control website, participated in the follow-up study survey (response rate 96%). At the 6 month follow-up after the intervention was conducted, MSM who visited the intervention website were more likely to receive HIV-related information (25.49% versus 10.47%, P<.001), discuss HIV issues with others (41.88% versus 23.79%, P<.001), review articles about HIV (90.58% versus 79.73%, P<.001), and be asked about or discuss HIV-related questions (51.11% versus 31.78%, P<.001) than those on the control website. In addition, MSM were more likely to have HIV tests within 6 months (43.89% versus 22.31%, P<.001) and consistently use condoms during anal sex with online sex partners than those using the control website (34.15% versus 26.19%, P=.004). CONCLUSIONS: The study showed the feasibility and effectiveness of the iPOL intervention as an online HIV prevention program. These findings underscore the importance of disseminating HIV information online, as well as the challenges inherent in the efforts of iPOL to reduce HIV-related risky behaviors among Internet-using MSM. PMID- 23439584 TI - Effect of a peroxynitrite scavenger, a manganese-porphyrin compound on airway remodeling in a murine asthma. AB - Airway remodeling, pathological changes in the lung structure, is a characteristic feature of chronic asthma. The changes include bronchial epithelial hyperplasia and hypertrophy, excess production of mucus, and fibroblast proliferation in the lung. On the other hand, it has been known that both nitric oxide and superoxide anion are increased in exhaled air of asthmatic patients. These molecules react with each other forming a powerful oxidant, peroxynitrite. In this study, effect of a peroxynitrite scavenger, a metalloporphyrin compound, [tetrakis(4 carboxylatophenyl)porphyrinato]manganese(III) (MnTBAP) on multiple antigen challenge-induced airway remodeling was evaluated in mice. When sensitized BALB/c mice were intratracheally challenged with an antigen, ovalbumin, for 3 times, bronchial epithelial thickening and mucus accumulation in the epithelium were histologically observed. Daily treatment with MnTBAP (3, 10 mg/kg/time/twice a day, intraperitoneally (i.p.)) dose-dependently suppressed both the epithelial thickening and mucus accumulation in the epithelium. On the other hand, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining revealed that the multiple antigen challenges increased the number of apoptotic cells in the bronchial epithelium. The increase in apoptotic cells was also effectively suppressed by the treatment with MnTBAP. Taken together, it was suggested that peroxynitrite could be involved in the formation of epithelial hyperplasia associated with the mucus accumulation through induction of apoptosis of the epithelial cells. Thus, peroxynitrite can be a target molecule for development of new pharmacotherapy for asthma. PMID- 23439585 TI - Altered folate receptor 2 expression in uraemic patients on haemodialysis: implications for folate resistance. AB - BACKGROUND: Folate therapy reduces, but does not normalize homocysteine (Hcy) levels, frequently elevated in chronic kidney disease (CKD). The mechanisms of this folate resistance are unknown. Cellular acquisition of folate is mediated by folate receptors (FRs), whose expression is also modulated by folate status, through an Hcy-dependent regulation mechanism involving heterogeneous nuclear ribonucleoprotein-E1 (hnRNP-E1). Our objective was to evaluate whether an alteration of the FR2 (the form present in nucleated blood cells) expression is present in CKD patients on haemodialysis (HD), and its susceptibility to folate treatment. METHODS: A population of chronic uraemic patients on HD was enrolled, along with a control group, and studies on FR2 receptor expression and related items were performed in plasma and mononuclear cells from peripheral blood. A subgroup of patients was treated with methyltetrahydrofolate for 1 month. RESULTS: In HD, there was a significant reduction in FR2 protein expression compared with controls, not correlated with Hcy concentrations, while its mRNA levels were significantly increased. After folate treatment, there was a significant mRNA decrease, in the absence of significant changes in receptor protein expression. hnRNP-E1 gene and protein expression levels increased pre treatment, while decreased post-treatment. CONCLUSIONS: In HD, FR2 expression is altered in peripheral mononuclear cells, since its levels are decreased and are not responsive to variations in Hcy concentration, while the intracellular machinery (receptor mRNA and hnRNP-E1), possibly triggering its regulation, is conserved. These findings provide insight into the mechanisms of folate resistance in uraemia. PMID- 23439586 TI - Mineralocorticoid-receptor signalling in vascular smooth muscle. AB - Human data suggest that eplerenone and spironolactone lowers blood pressure by mechanisms independent of the distal tubule. Now, a novel inducible conditional knockout model of the mineralocorticoid receptor (MR) in vascular smooth muscle cells (VSMCs) brings out understanding further. PMID- 23439587 TI - Management of thoracoabdominal aortic aneurysms. AB - Conventional treatment of thoracoabdominal aortic aneurysms (TAAAs) consists of graft replacement with reattachment of the main aortic branches. Over the past 20 years a multimodal approach has gradually evolved to reduce the trauma of surgery by maximizing organ protection, allowing experienced surgical Centers to have better outcomes than previously reported. However, mortality and morbidity associated to TAAA open repair remain significant. Hybrid repair, consisting of open aortic debranching and revascularization followed by endovascular exclusion of the aneurysm, may extend the indications of TAAA repair to high-risk patients that cannot benefit from surgery, however results are still under evaluation. Aim of this paper is to illustrate the management and results of thoracoabdominal aortic aneurysms surgery with open techniques of organ protection and hybrid approach in our Center. PMID- 23439588 TI - Clinical outcome, and survival between primary percutaneous coronary intervention versus fibrinolysis in patients older than 60 years with acute myocardial infarction. AB - OBJECTIVE: The aim of the present study was to compare the short-term and 6-month clinical outcome, and survival in patients older than 60 years with ST-elevation myocardial infarction randomized to either primary percutaneous coronary intervention (PPCI) or thrombolysis. MATERIALS AND METHODS: 82 patients with STEMI older than 60 years were randomized to either primary PCI or thrombolysis from September 2006 to August 2008. Angiograms were reviewed by two interventionalists not involved in the study. Patients randomized to primary PCI received Aspirin and 600 mg Clopidogrel. Heparin was administered in conjunction with PCI. Patients randomized to thrombolysis received Aspirin followed by streptokinase infusion for one hour. Rescue PCI was considered if there was ongoing pain and ST-segment resolution was <50% at 90 min. after initiation of thrombolysis or chest pain recurred with ST-segment elevation within 24 hours. All patients were followed up for 6 months. End points were reinfarction and cardiac death using competing-risks regression estimation. RESULTS: The mean time from hospital admission to start of streptokinase infusion was 31 +/- 15 min and door to balloon time was 70 +/- 25 min. There was no significant difference between the groups in the number of deaths and reinfarctions at 6 months. As expected, the fibrinolysis group had a higher rate of revascularization and heart failure. CONCLUSION: The higher rates of heart failure and need for revascularization in the fibrinolysis group reinforces benefits of PPCI in patients older than 60 years. PPCI in those who are 60 years and above with AMI is safe and cost effective. PMID- 23439589 TI - Kainate receptors: multiple roles in neuronal plasticity. AB - Ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA)- and AMPA-type, as well as metabotropic glutamate receptors have been extensively invoked in plasticity. Until relatively recently, however, kainate-type receptors (KARs) had been the most elusive to study because of the lack of appropriate pharmacological tools to specifically address their roles. With the development of selective glutamate receptor antagonists, and knockout mice with specific KAR subunits deleted, the functions of KARs in neuromodulation and synaptic transmission, together with their involvement in some types of plasticity, have been extensively probed in the central nervous system. In this review, we summarize the findings related to the roles of KARs in short- and long-term forms of plasticity, primarily in the hippocampus, where KAR function and synaptic plasticity have received avid attention. PMID- 23439590 TI - An evaluation of factors influencing feeding in babies with a cleft palate with and without a cleft lip. AB - The objective of this article was to determine the impact of different bottles and teats for feeding babies with a cleft palate (with and without a cleft lip) on weight velocity, feeding behaviour, and maternal self-esteem. A mixed methods study incorporating the use of diaries to record feeding patterns of babies and levels of professional support received was used. Growth was assessed by converting weights into standard deviation scores and using the differences to express weight velocity over a six-week period. Visual analogue scales were used to assess mothers' perceptions of their children and themselves. The Edinburgh Postnatal Depression Score (EPDS) was used to identify maternal depression. The study demonstrated that the most significant effect on weight was determined by cleft type. Babies with isolated clefts of the hard and soft palate experienced greater feeding problems and suffered the biggest weight losses. This remained significant independently of the type of bottle/teat used. Poor weight gain was also associated with a mother's low perception of herself and her child, and her tendency towards depression. The study highlights the importance of the early assessment of babies' feeding skills and regular follow-up and support from trained and experienced nurse specialists. PMID- 23439591 TI - Evaluation of breastfeeding promotion, support, and knowledge of benefits on breastfeeding outcomes. AB - We examined how prenatal exposure to breastfeeding information from various media sources, maternal knowledge of benefits, family and clinician support, and peer practices influence breastfeeding outcomes in early infancy. Initiation of breastfeeding, any breastfeeding at two months, and exclusivity of breastfeeding at two months were examined in a cohort of US women using data from the Infant Feeding Practices Study II. Descriptive statistics, chi-square analyses and logistic regression were conducted. Approximately 85 percent of the women initiated breastfeeding. At two months, 63.8 percent continued breastfeeding, while only 38.1 percent breastfed exclusively. Mothers with greater knowledge about breastfeeding benefits were 11.2 (95% CI: 6.87-18.45) times more likely to initiate breastfeeding and 5.62 (95% CI: 4.19-7.54) times more likely to breastfeed at two months than those with lower levels of knowledge. Women whose families prenatally supported exclusive breastfeeding were 8.21(5.12-13.2) times more likely to initiate and continue breastfeeding (OR 3.21, 95% CI: 2.51-4.11). Clinicians who supported breastfeeding only also increased the odds of a woman initiating breastfeeding (OR 1.95, 95% CI: 1.31-2.88). Interventions to increase maternal knowledge of breastfeeding benefits and family and clinician support of breastfeeding in the prenatal period may help increase breastfeeding rates. The encouragement of breastfeeding needs to be a priority among health care providers to improve the health of mothers and infants. PMID- 23439592 TI - Identification of high-risk Brugada syndrome patients by combined analysis of late potential and T-wave amplitude variability on ambulatory electrocardiograms. AB - BACKGROUND: Risk stratification is important in the management of Brugada syndrome (BrS). Late potentials (LPs) and T-wave amplitude variability (TAV) in high-resolution ambulatory electrocardiography (ECG) were retrospectively investigated. METHODS AND RESULTS: One hundred and twenty-seven patients diagnosed with BrS on 12-lead ECG were classified into 3 groups: documented ventricular fibrillation (VF)/asystole (n=19), episodes of syncope alone (n=30), and asymptomatic (n=78). Healthy volunteers were enrolled as controls (n=25). In the BrS patients, LPs showed appreciable circadian periodicity; filtered QRS duration (fQRS) and duration of the terminal low-amplitude signal <40 MUV (LAS40) increased, whereas root mean square voltage of the terminal 40 ms of the fQRS (RMS40) decreased at night compared with the day. TAV did not have such a circadian periodicity. LP-positive incidence (night-time) and peak TAV were as follows: VF/asystole>syncope/asymptomatic>control (P<0.001). VF/asystole was discriminated from control at a ratio of 81-84% by night-time LPs (fQRS >116 ms, LAS40 >35 ms, RMS40 <25 MUV) or peak TAV (>54 MUV); VF/asystole was discriminated from syncope/asymptomatic at a ratio of 60-69%, by night-time LPs (fQRS >122 ms, LAS40 >42 ms, RMS40 <18MUV) or peak TAV (>58 MUV). Combined analysis of LPs and peak TAV increased the discriminant ratio up to 93% and 77%, respectively. CONCLUSIONS: Analysis of both LPs and TAV (taking circadian periodicity into account) is useful in identification of high-risk BrS patients. PMID- 23439593 TI - How much eye care services do Asian populations need? Projection from the Singapore Epidemiology of Eye Disease (SEED) study. AB - PURPOSE: We quantified and measured the needs for specific eye care services, including refractive services (RS), annual eye examination services (AES), cataract surgery services (CSS), and low vision services (LVS) in urban adult populations in Asia. METHODS: We conducted three population-based studies of Singapore-resident Chinese, Malays, and Indians aged >=40 years to measure the proportion of people who needed specific eye care services. RESULTS: Our data included 3353 Chinese, 3280 Malays, and 3400 Indians (participation rate 73.6%). Overall, approximately 70% of the populations needed eye care services and more than 30% had more than one need. The age-standardized proportion of people who need RS, AES, CSS, and LVS were 65.3%, 22.4%, 12.5%, and 0.5%, respectively, in Chinese. These figures were 49.6%, 33.6%, 11.0%, and 0.7%, respectively, in Malays, and 55.6%, 40.0%, 13.4%, and 0.8%, respectively, in Indians. With demographic change, our projection showed that the number of adults needing eye care services in urban Asia will grow from 437 million in 2010 to 827 million in 2030. Diabetes was a major cause of AES and a significant predictor for CSS, whereas higher blood pressure was a predictor for AES. CONCLUSIONS: The needs for eye care services in an urban setting in Asia is high, particularly the needs for RS, AES, and CSS. The high prevalences of diabetes and hypertension are the driving factors underlying these needs. The burden of providing such eye care services highlights the need for new strategies for improvements in primary care and capacity building for eye care professionals other than ophthalmologists. PMID- 23439594 TI - Susceptibility of streptozotocin-induced diabetic rat retinal function and ocular blood flow to acute intraocular pressure challenge. AB - PURPOSE: To consider the hypothesis that streptozotocin (STZ)-induced hyperglycemia renders rat retinal function and ocular blood flow more susceptible to acute IOP challenge. METHODS: Retinal function (electroretinogram [ERG]) was measured during acute IOP challenge (10100 mm Hg, increments of 5 mm Hg, 3 minutes per step, vitreal cannulation) in adult Long-Evans rats (6 weeks old; citrate: n = 6, STZ: n = 10) 4 weeks after citrate buffer or STZ (65 mg/kg, blood glucose >15 mM) injection. At each IOP, dim and bright flash (-4.56, -1.72 log cd x s x m(-2)) ERG responses were recorded to measure inner retinal and ON-bipolar cell function, respectively. Ocular blood flow (laser Doppler flowmetry; citrate: n = 6, STZ: n = 10) was also measured during acute IOP challenge. Retinas were isolated for quantitative PCR analysis of nitric oxide synthase mRNA expression (endothelial, eNos; inducible, iNos; neuronal, nNos). RESULTS: STZ-induced diabetes increased the susceptibility of inner retinal (IOP at 50% response, 60.1, CI: 57.0-62.0 mm Hg versus citrate: 67.5, CI: 62.1-72.4 mm Hg) and ON bipolar cell function (STZ: 60.3, CI: 58.0-62.8 mm Hg versus citrate: 65.1, CI: 61.9-68.6 mm Hg) and ocular blood flow (43.9, CI: 40.8-46.8 versus citrate: 53.4, CI: 50.7-56.1 mm Hg) to IOP challenge. Citrate eyes showed elevated eNos mRNA (+49.7%) after IOP stress, an effect not found in STZ-diabetic eyes (-5.7%, P < 0.03). No difference was observed for iNos or nNos (P > 0.05) following IOP elevation. CONCLUSIONS: STZ-induced diabetes increased functional susceptibility during acute IOP challenge. This functional vulnerability is associated with a reduced capacity for diabetic eyes to upregulate eNos expression and to autoregulate blood flow in response to stress. PMID- 23439595 TI - Involvement of SDF1a and STAT3 in granulocyte colony-stimulating factor rescues optic ischemia-induced retinal function loss by mobilizing hematopoietic stem cells. AB - PURPOSE: Granulocyte colony-stimulating factor (G-CSF) has been applied clinically for several years. In this study, we used G-CSF to induce the mobilization of hematopoietic progenitor cells into peripheral blood in an ischemia-induced retinal degeneration model. METHODS: Male Sprague-Dawley rats received G-CSF treatment for 5 days following optic ligation. Histologic and functional evaluations were performed and results were compared with those from untreated rats. Real-time PCR, Western blotting, and immunohistochemical analyses were used to evaluate the expression of retinal cell markers and other substances. RESULTS: Retinal histology showed that transient optic ligation induced retinal cell loss. Postischemia, animals that received G-CSF treatment had a higher retinal cell survival rate than that of control animals. Analysis of apoptosis showed that retinas from G-CSF-treated animals exhibited fewer apoptotic cells than those from control retinas. Immunoblotting analyses indicated the presence of greater numbers of CD34-, but less chemokine receptor type 4 (CXCR4)-, and stromal cell-derived factor 1 alpha (SDF1alpha)-positive cells in the G-CSF-treated ischemic retinas than in ischemic retinas without treatment 14 days after ischemia. The ischemic retinas from G-CSF-treated animals displayed upregulated Thy1 and opsin expression compared with the retinas from untreated animals. Electroretinography indicated superior retinal function in animals treated with G-CSF than in untreated animals postischemia, and that STAT3 might play an important role. CONCLUSIONS: Our results suggest that G-CSF reduces optic ischemia-induced retinal cell loss, possibly through STAT3-regulated mobilization of hematopoietic progenitor cells to the retina. PMID- 23439596 TI - Role of nitric oxide in optic nerve head blood flow regulation during isometric exercise in healthy humans. AB - PURPOSE: We determined whether administration of a nitric oxide synthase (NOS) inhibitor alters optic nerve head blood flow (ONHBF) regulation during isometric exercise in healthy subjects. METHODS: Our study was done in a randomized, placebo-controlled, double-masked, three-way crossover design. A total of 18 healthy subjects was randomized to receive either placebo, phenylephrine, or an inhibitor of NOS (L-NMMA) on three different study days. ONHBF was measured with laser Doppler flowmetry while the study participants performed isometric exercise (squatting). This was done before drug administration and during infusion of the study drugs. Mean arterial pressure (MAP) and IOP were measured noninvasively, and ocular perfusion pressure (OPP) was calculated as 2/3 MAP - IOP. RESULTS: The response in ONHBF to isometric exercise was less pronounced than the response in OPP, indicating for some autoregulatory capacity in the ONH. Administration of L NMMA significantly decreased ONHBF at rest (P < 0.01). In contrast, inhibition of NOS did not alter the pressure-flow relationship in the ONH during an experimental increase in OPP compared to phenylephrine and placebo (P = 0.37 between groups). CONCLUSIONS: The data of our study support previous findings that ONHBF is autoregulated during an experimental increase in OPP. Nitric oxide has an important role in basal ONHBF regulation, but seems not to be involved in the autoregulatory response during an increase in OPP induced by isometric exercise. (ClinicalTrials.gov number, NCT00806741.). PMID- 23439597 TI - Influence of the eye-tracking-based follow-up function in retinal nerve fiber layer thickness using fourier-domain optical coherence tomography. AB - PURPOSE: To evaluate the eye-tracking-based follow-up (EBF) function in the reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained with Fourier-domain optical coherence tomography (Fd-OCT). METHODS: Thirty healthy subjects were imaged on an Fd-OCT device at the same visit by two examiners. Peripapillary circular scans in "high-speed" (HS) mode with the "automatic real time" (ART) set at 16 and in "high-resolution" (HR) mode with the ART off were obtained without and with the EBF function activated. RESULTS: Mean (+/- SD) global RNFL thickness was 105.1 (+/- 9.5) MUm on HS mode and 105.4 (+/- 9.6) MUm on HR mode. Interobserver analysis for global RNFL thickness revealed an intraclass correlation coefficient (ICC) greater than or equal to 0.96 for all but the HR mode without the use of EBF function (ICC = 0.73). Intraobserver analysis for global RNFL thickness revealed an ICC greater than 0.98 for all but the HR mode without the use of EBF function (ICC = 0.86). The interobserver and intraobserver analyses revealed the lowest ICC values for the temporal region on both HS and HR modes. Higher ICC values were obtained with the HS mode and when the EBF function was activated, particularly when using the HR mode. CONCLUSIONS: The EBF function had no influence in the reproducibility of the global peripapillary RNFL thickness measurements in healthy subjects on HS mode with ART on. However, reproducibility of the global RNFL thickness measurements on HR mode as well as of the temporal and temporal superior regions in both HS and HR modes was greater with the EBF function. PMID- 23439598 TI - Relating retinal nerve fiber layer thickness and functional estimates of ganglion cell sampling density in healthy eyes and in early glaucoma. AB - PURPOSE: To investigate the relationship between retinal nerve fiber layer (RNFL) thickness and peripheral grating resolution acuity (PGRA) as well as differential light sensitivity (DLS) in healthy subjects and patients with early glaucoma. The agreement between estimates of retinal ganglion cell (GC) density from each functional test is explored. METHODS: PGRA was measured in 24 patients with early glaucoma (mean deviation [MD] > -8 dB) and 26 healthy subjects using achromatic Gabor stimuli in 4 diagonal visual field locations at 10 degrees eccentricity. DLS for a Goldmann size III equivalent was obtained from individual spatial summation functions and expressed in Humphrey Field Analyzer-equivalent decibel values. RNFL thickness was measured around the optic nerve head using Zeiss Stratus optical coherence tomography and related to functional measures using a retinotopic map. Functional GC density was estimated using structure/function models for both tests. Passing-Bablok regression was used to investigate the structure/function relationships. RESULTS: A positive and statistically significant association was found between PGRA and RNFL thickness, and separately between DLS and RNFL thickness, for combined glaucoma and healthy data (both P < 0.05). The slope of the structure/function association in healthy subjects was not significantly different to that in glaucoma patients using either functional measure (both P > 0.05). Agreement between estimates of GC density from psychophysical data was moderate. CONCLUSIONS: The relationship between PGRA and RNFL thickness is at least as great in magnitude as that between DLS and RNFL thickness; a significant structure/function association is also observed in healthy subjects alone. PMID- 23439599 TI - The comparative histologic effects of subthreshold 532- and 810-nm diode micropulse laser on the retina. AB - PURPOSE: Therapeutic retinal laser photocoagulation can damage the neurosensory retina and cause iatrogenic visual impairment. Subthreshold micropulse photocoagulation may decrease this risk by selective tissue treatment. The aim of this study was to compare subthreshold 810-nm diode micropulse laser and subthreshold 532-nm micropulse laser on the retina by histologic examination and differential protein expression. METHODS: Fourteen Dutch-belted rabbits received subthreshold 810-nm diode micropulse laser photocoagulation in their right eye and subthreshold 532-nm micropulse laser photocoagulation in their left eye. Histology and immunohistochemical detection of stromal cell-derived factor-1 (SDF 1), beta-actin, vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), and insulin-like growth factor 1 (IGF-1) were analyzed 12 hours, 3 days, 14 days, and 28 days post-laser photocoagulation. RESULTS: Histologically, all time points produced a similar degree of retinal disruption in both wavelengths. Immunohistochemically, SDF-1 expression was greatest at the 12-hour time point and decreased thereafter. SDF-1, VEGF, and beta-actin up regulation was detected at early time points in both the 810- and 532-nm micropulse laser-treated animals. CONCLUSIONS: Subthreshold micropulse retinal laser photocoagulation caused equivalent histologic changes from both 532- and 810-nm diode lasers. Differential protein expression was not evident between the different laser conditions. PMID- 23439600 TI - Measuring the effect of pars plana vitrectomy on vitreous oxygenation using magnetic resonance imaging. AB - PURPOSE: To study the effect of pars plana vitrectomy (PPV) on vitreous oxygenation (pO2) using magnetic resonance imaging (MRI). METHODS: Patients due to undergo PPV for either macular hole or epiretinal membrane were recruited. MRI scanning was performed 1 week before and at least 3 months after PPV. MRI T1 mapping was performed using an inversion recovery-true fast imaging with steady state precession (TrueFISP) sequence at several inversion times, from a single slice positioned through the center of both eyes in the axial oblique plane. Additional phantom data were measured in porcine vitreous, to define the relationships between T1 relaxation times and balanced salt solution (BSS), to simulate human vitreous and aqueous, respectively, for a suitable pO2 range (5-70 mm Hg). Pre-PPV pO2 was also measured intraoperatively using a polarographic oxygen probe. RESULTS: Eleven participants (age range 59-84) were recruited; two declined the post-PPV scan. Corrected T1 times indicated that the mean (+/-SD) pO2 increased significantly following PPV, from 13.2 +/- 5.8 to 34.5 +/- 8.0 mm Hg (P < 0.001). In the nonsurgical (control) eye, pO2 did not change significantly from the first to second MRI scan (13.7 +/- 7.8 vs. 16.3 +/- 8.7 mm Hg, P = 0.239). Mean pO2 measured intraoperatively was 7.2 +/- 0.6 mm Hg (n = 10). CONCLUSIONS: These results confirm that vitrectomy substantially increases vitreous pO2. MRI is a noninvasive technique that can be used to study vitreous oxygenation in both vitrectomized and nonvitrectomized eyes. PMID- 23439601 TI - Retinal damage profiles and neuronal effects of laser treatment: comparison of a conventional photocoagulator and a novel 3-nanosecond pulse laser. AB - PURPOSE: To determine detailed effects to retinal cells and, in particular, neurons following laser photocoagulation using a conventional 532 nm Nd:YAG continuous wave (CW) laser. Furthermore, to determine whether a novel 3 ns pulse laser (retinal regeneration therapy; 2RT) could specifically ablate retinal pigment epithelium (RPE) cells without causing collateral damage to other retinal cells. METHODS: Adult Dark Agouti (DA) rats were separated into four groups: control, CW laser (12.7 J/cm(2)/pulse, 100 ms pulse duration), or 3 ns pulse 2RT laser at one of two energy settings ("High," 2RT-H, 163 mJ/cm(2)/pulse; "Low," 2RT-L, 109 mJ/cm(2)/pulse). Animals were treated and killed after 6 hours to 7 days, and retina/RPE was analyzed by histologic assessment, Western blot, polymerase chain reaction, and immunohistochemistry. RESULTS: Both lasers caused focal loss of RPE cells with no destruction of Bruch's membrane; RPE cells were present at lesion sites again within 7 days of treatments. CW and 2RT-H treatments caused extensive and moderate damage, respectively, to the outer retina. There were no obvious effects to horizontal, amacrine, or ganglion cells, as defined by immunolabeling, but an activation of PKCalpha within bipolar cells was noted. There was little discernible damage to any cells other than the RPE with the 2RT-L treatment. CONCLUSIONS: Conventional laser photocoagulation caused death of RPE cells with associated widespread damage to the outer retina but little influence on the inner retina. The novel 3 ns 2RT laser, however, was able to selectively kill RPE cells without causing collateral damage to photoreceptors. Potential benefits of this laser for clinical treatment of diabetic macular edema are discussed. PMID- 23439602 TI - Epithelial membrane protein 2 controls VEGF expression in ARPE-19 cells. AB - PURPOSE: VEGF production by RPE cells has been shown to be important in regulating aberrant angiogenesis in the retina, which is responsible for multiple types of ocular pathology. EMP2 is highly expressed in the RPE and has been shown to regulate FAK activation, which is implicated in VEGF expression in other cell lines. The purpose of this study was to determine whether EMP2 regulates VEGF expression in the RPE cell line, ARPE-19. METHODS: ARPE-19 cells were engineered to overexpress EMP2. EMP2 siRNA was used to decrease EMP2 expression. The small molecule inhibitor PP2 was used to inhibit FAK activation. VEGF levels were measured by Western blot and ELISA. Functional differences in secreted VEGF were assayed using HUVEC migration. RESULTS: VEGF expression levels correlated with levels of EMP2. An increase of VEGF by 150% was observed in EMP2 overexpressing cells as compared with ARPE-19 cells. Concordantly, EMP2 knockdown resulted in a 57% decrease in VEGF expression. HUVEC migration (P = 0.01) and vessel tube formation (P < 0.01) were significantly increased when exposed to cell culture supernatants from EMP2 overexpressing cells. CONCLUSIONS: This study establishes a novel connection between EMP2 and VEGF and may reflect either a direct effect through the tetraspan web or an indirect change through FAK activation. This connection is functionally significant. In addition to the direct use of anti VEGF antibodies, modulation of EMP2 with impact on VEGF is potentially a distinct therapeutic target for the treatment of neovascularization associated with retinal diseases that involve pathologic angiogenesis. PMID- 23439603 TI - Glial cell and inflammatory responses to retinal laser treatment: comparison of a conventional photocoagulator and a novel, 3-nanosecond pulse laser. AB - PURPOSE: Retinal laser photocoagulation represents a major treatment strategy for the management of diabetic macular edema (DME). However, the thermal nature of this procedure defines that collateral tissue injury result, meaning that it cannot be used near the fovea centralis. We studied inflammatory and glial responses resulting from treatment of rats with a conventional laser and with a novel short-duration, nonthermal laser (retinal regeneration therapy [2RT]) at clinically relevant energy levels. METHODS: Pigmented Dark Agouti rats were treated with either a conventional thermal continuous wave (CW; 532-nm, 100-ms pulse duration) or a short-pulse (2RT; 532-nm, Q-switched, 3-ns pulse) laser. Settings were at visible threshold for the CW laser (12.7 J/cm(2)/pulse) and at supra- and subvisible thresholds for the 2RT laser ("high," 2RT-H, 163 mJ/cm(2)/pulse; "low," 2RT-L, 109 mJ/cm(2)/pulse). Rats were killed at various subsequent time points. Samples were processed for histology, immunohistochemistry, RT-PCR, and Western blotting. RESULTS: The CW laser caused outer retinal lesions that were associated with photoreceptor death, astrocyte and Muller cell activation, and infiltration of macrophages and neutrophils. Furthermore, inflammatory cytokines, heat shock proteins, endogenous trophic factors, and matrix metalloproteinases were induced. In comparison, all of these changes were drastically attenuated when the 2RT laser was used, particularly at the subthreshold setting. CONCLUSIONS: The conventional laser produced marked retinal damage and cellular responses consistent with an inflammatory response to thermal injury. In contrast, the 2RT laser produced negligible retinal damage and cellular responses at clinically relevant settings. These results may have important implications for the treatment of retinal disease. PMID- 23439604 TI - Effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity in Japanese dyslipidemic patients, with exploratory analysis of a PLA2G7 gene polymorphism of Val279Phe. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. METHODS AND RESULTS: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40 mg (n=28), 80 mg (n=28), or 16 0mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. CONCLUSIONS: Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA2. PMID- 23439605 TI - The future of heart valve banking and of homografts: perspective from the Deutsches Herzzentrum Berlin. AB - Ever since the early days of homograft implantation in 1956, and the introduction into clinical practice by Ross and Barrat Boyes, homograft heart valves have proven to have many advantages. Its disadvantages became evident during long-term follow up. Factors, such as donor and recipient morbidity, tissue banking techniques, and the often complex surgical technique required to implant, are of great influence on the long term results. Because of European Directives, legally binding quality assurance regulations have been introduced in homograft banks. However, still not all processing methods have been scientifically sub-structured on their effects on the final product and its durability. The donor shortage has stimulated researchers and industries to develop and improve mechanical and biological valve substitutes such as the stentless bioprostheses. In general, candidates for homograft valve implantation include patients with: endocarditis, congenital defects and women who wish to become pregnant. For each category of patients different implantation techniques are required. The results of homograft banking and homograft transplantation in the German Heart Institute Berlin are satisfactory. Freedom of re-infection rate after homograft implantation is 91.9% +/- 3.6% after 15 years. Current developments show an increased interest in tissue engineered as well as in de- and re-cellularization of heart valve homografts. The advantages and disadvantages of the several processing techniques have not yet been proven in long term clinical results. For homograft bankers these developments pose as a challenge to join forces and to initiate cooperate projects aimed at scientific and organizational development. PMID- 23439606 TI - Effects of aerobic exercise training on psychosocial status and serum uric Acid in men with essential hypertension: a randomized controlled trial. AB - BACKGROUND: Chronic psychosocial stress and serum uric acid (SUA) level have been implicated in the etiology and cardiovascular events risk factors in hypertension. Studies have reported significant benefit of exercise in the overall management of hypertension. However, studies on the effect of exercise on psychosocial stress and SUA in the management of hypertension seem scanty. AIM: The aim of this study was to determine the effect of continuous training program on SUA and psychosocial status of black African (Nigerian) population with hypertension. SUBJECTS AND METHODS: Age-matched randomized controlled trial was used; subjects with diagnosis of hypertension attending the hypertensive clinic of Murtala Muhammed Specialist Hospital (MMSH), Kano, Nigeria form the population for the study. Two hundred and seventeen subjects with mild to moderate (systolic blood pressure (SBP) between 140 and180 and diastolic blood pressure (DBP) between 90 and 109 mmHg) essential hypertension were grouped into continuous (112) and control groups (105). The continuous group involved in an 8 weeks continuous training (60%-79% HR max) of between 45 and 60 min, 3 times per week, while the controls group remain sedentary. SBP, DBP, SUA, VO(2) max and psychosocial status were assessed. Student t-test and Pearson correlation test were used in data analysis. RESULTS: The study revealed significant beneficial effect of continuous training programs on VO(2) max, SBP, DBP, SUA, and psychosocial status (P < 0.05). Psychosocial status and SUA was significantly and positively and negatively correlated respectively with VO(2) max at P < 0.01. CONCLUSIONS: This study concludes and supports the recommendations of moderate intensity (continuous) training program in blood pressure reduction, SUA and psychosocial stress management in hypertension. PMID- 23439607 TI - Meta-analyses of diagnostic tests in infectious diseases: how helpful are they in the intensive care setting? AB - In acute-care settings timely and accurate diagnostic tools are critical for patient treatment decisions and outcomes. This review provides an up-to-date look at the meta-analyses of diagnostic test for infections in the ICU setting. There have been 3 meta-analyses investigating the value of procalcitonin as diagnostic marker of sepsis: overall, the performance of procalcitonin test was found moderate-good. Two meta-analyses evaluated methods for diagnosing intravascular device-related bloodstream infections. In general, quantitative catheter segment culture and paired quantitative blood culture showed reliable diagnostic yield, though significant heterogeneity was observed among studies. Criteria of diagnosing VAP in the intensive care unit has been evaluated in 3 systematic reviews. Overall, the cumulative results cast doubts about the usefulness of bacteriological data and quantitative cultures in the diagnosis of VAP; moreover, 2 of these meta-analyses concluded that invasive strategies for VAP diagnosis do not affect mortality. PMID- 23439608 TI - QTL mapping of genes controlling plasma insulin and leptin concentrations: metabolic effect of obesity QTLs identified in an F2 intercross between C57BL/6J and DDD.Cg-A(y) inbred mice. AB - DDD.Cg-A(y) female mice developed massive obesity as compared with B6.Cg-A(y) female mice. We previously identified quantitative trait loci (QTLs) for obesity on chromosomes 1, 6, 9 and 17 in F2 female mice, including F2A(y) (F2 mice with the A(y) allele) and F2 non- A(y) mice (F2 mice without the A(y) allele), produced by crossing C57BL/6J and DDD.Cg-A(y) strains. We here addressed the question whether the obesity QTLs share genetic bases with putative QTLs for plasma glucose, insulin and leptin concentrations. We performed QTL analyses for the first principal component (PC1) extracted from these metabolic measurements to identify the genes that contributed to the comprehensive evaluation of metabolic traits. By single QTL scans, we identified two significant QTLs for insulin concentration on chromosomes 6 and 12, three for leptin concentration on chromosomes 1, 6 and 17, and five for PC1 on chromosomes 1, 6, 12 (two loci) and 17. Although insulin and leptin concentrations and PC1 were not normally distributed in combined F2 mice, results of single QTL scans by parametric and non-parametric methods were very similar. Therefore, QTL scan by the parametric method was performed with the agouti locus genotype as a covariate. A significant QTL * covariate interaction was found for PC1 on chromosome 9. All obesity QTLs had significant metabolic effects. Thus, obesity- and diabetes-related traits in DDD.Cg-A(y) mice were largely controlled by QTLs on chromosomes 1, 6, 9, 12 and 17. PMID- 23439609 TI - In vivo kinematics of the talocrural and subtalar joints with functional ankle instability during weight-bearing ankle internal rotation: a pilot study. AB - Functional ankle instability (FAI) may involve abnormal kinematics. However, reliable quantitative data for kinematics of FAI have not been reported. The objective of this study was to determine if the abnormal kinematics exist in the talocrural and subtalar joints in patients with FAI. Five male subjects with unilateral FAI (a mean age of 33.4 +/- 13.2 years) were enrolled. All subjects were examined with stress radiography and found to have no mechanical ankle instability (MAI). Lateral radiography at weight-bearing ankle internal rotation of 0 degrees and 20 degrees was taken with the ankle at 30 degrees dorsiflexion and 30 degrees plantar flexion. Patients underwent computed tomography scan at 1.0 mm slice pitch spanning distal one third of the lower leg and the distal end of the calcaneus. Three-dimensional (3D) kinematics of the talocrural and subtalar joints as well as the ankle joint complex (AJC) were determined using a 3D-to-2D registration technique using a 3D-to-2D registration technique with 3D bone models and plain radiography. FAI joints in ankle dorsiflexion demonstrated significantly greater subtalar internal rotation from 0 degrees to 20 degrees internal rotation. No statistical differences in plantar flexion were detected in talocrural, subtalar or ankle joint complex kinematics between the FAI and contralateral healthy joints. During ankle internal rotation in dorsiflexion, FAI joints demonstrated greater subtalar internal rotation. The FAI joints without mechanical instability presented abnormal kinematics. This suggests that abnormal kinematics of the FAI joints may contribute to chronic instability. FAI joints may involve unrecognized abnormal subtalar kinematics during internal rotation in ankle dorsiflexion which may contribute to chronic instability and frequent feelings of instability. PMID- 23439610 TI - Fifth toe deformities: overlapping and underlapping toe. AB - Overlapping fifth toe is thought to be a congenital deformity characterized by the proximal phalanx dorsally subluxating and adducting on the fifth metatarsophalangeal joint. Overlapping fifth toes may present as asymptomatic figments of parental concern, but not infrequently this deformity may be painful and disabling in both the pediatric and adult population. Pediatric overlapping fifth toe often corrects with normal ambulation and physicians only need to intervene if symptomatic deformity persists. Nonoperative optimization with strapping, splinting, and shoe modification would be reasonable first-line treatments. Surgical intervention including osteoclysis, percutaneous tenotomy, capsulotomy, syndacilization, tissue rearrangements, tendon transfers, phalangectomy, and toe amputation are indicated only after optimization of less invasive measures. Underlapping fifth toe (or "curly" toe) deformity is also felt to be congenital. In most cases, underlapping fifth toes are noticed by parents and family members early in infancy. The proximal phalanx in underlapping toes is typically in varus at the metatarsophalangeal joint with flexion. It is not uncommon for a rotational malalignment to be present (supination/pronation) as judged by the nailbeds. Similar to overlapping toes, pediatric underlappers commonly correct with reassurance and benign neglect up to age 6. Intervention is warranted in the setting of persistent pain and footwear difficulty. Accommodative shoes, absorbing cushions, and functional modification are the mainstays of nonoperative management. Operative intervention may consist of osteoclysis, percutaneous flexor tenotomy, capsulotomy, tissue rearrangements, tendon transfers, removal of symptomatic spurs, osteotomies, and amputation. After exhaustive review of the published literature, it is clear that fifth toe deformities (whether overlapping or underlapping) have not been extensively studied. No gold standard approach exists in treatment. Prospective research using larger numbers of patients with detailed outcome metrics are needed. Surgeons should carefully tailor surgical intervention to patient specific pathology. LEVELS OF EVIDENCE: Expert Opinion, Level V. PMID- 23439611 TI - Biomechanical evaluation of mini-fragment hardware for supination external rotation fractures of the distal fibula. AB - BACKGROUND: Supination external rotation distal fibula fractures are common, requiring fixation when associated with talar displacement. Subcutaneous distal fibula hardware may become painful, necessitating operative removal. We hypothesize that mini-fragment and small-fragment constructs will demonstrate similar biomechanical stability. METHODS: A biomechanical comparison was performed in synthetic osteoporotic sawbones. The first arm compared two 2.4-mm lag screws with one 3.5-mm lag screw for fixation of a simulated supination external rotation distal fibula fracture. The second arm compared a 2.4-mm plate screw construct with a 3.5-mm lag screw and one-third tubular neutralization plate. During torsional testing, torque and displacement were recorded, and stiffness and peak torque were determined. RESULTS: Differences in mean stiffness and mean load at failure were not statistically significant with lag screw-only fixation. The 3.5-mm plate-screw construct outperformed the 2.4-mm plate-screw construct, but neither mean stiffness nor mean load at failure were statistically significantly different. Dynamic testing also demonstrated similar results. CONCLUSION: Our data suggest that isolated 2.4-mm screws function similarly to one 3.5-mm screw. Although the 3.5-mm plate-screw construct was stiffer, mean load at failure was equivalent for the 2 constructs. These data provide biomechanical evidence to support further investigation in the use of mini fragment hardware for distal fibula fracture fixation. LEVELS OF EVIDENCE: Therapeutic, Level V. PMID- 23439612 TI - Pseudolaric acid B-induced autophagy contributes to senescence via enhancement of ROS generation and mitochondrial dysfunction in murine fibrosarcoma L929 cells. AB - Pseudolaric acid B (PAB) is the primary biologically active compound isolated from the root bark of P. kaempferi Gordon. Our previous study demonstrated that PAB induced mitotic catastrophe in L929 cells and indicated that only a small percentage (12%) of the cells undergoing mitotic catastrophe displayed an apoptotic phenotype after PAB treatment for 72 h. In this study, we found that a minority of the cells undergoing mitotic catastrophe ended in apoptosis, and a majority of them entered a period of senescence. Further data confirmed that PAB induced autophagy, reactive oxygen species (ROS) generation, and mitochondrial dysfunction in L929 cells. Subsequently, we found that autophagy inhibitors significantly delayed the senescence process, indicating that autophagy facilitated senescence. Moreover, ROS scavenger significantly decreased the autophagic level and improved mitochondrial function. Additionally, autophagy inhibitors effectively reduced ROS levels and ameliorated mitochondrial function. In conclusion, autophagy promoted senescence via enhancement of ROS generation and mitochondrial dysfunction in PAB-treated L929 cells. PMID- 23439613 TI - Cognitive dysfunction in patients with renal failure requiring hemodialysis. AB - BACKGROUND AND OBJECTIVES: Renal failure patients show significant impairment on measures of attention and memory, and consistently perform significantly better on neuropsychological measures of memory and attention, approximately 24 hours after hemodialysis treatment. The objectives are to determine the cognitive dysfunction in patients with renal failure requiring hemodialysis. MATERIALS AND METHODS: A total of 60 subjects comprising of 30 renal failure patients and 30 controls were recruited. The sample was matched for age, sex, and socioeconomic status. The tools used were the Standardized Mini-Mental State Examination and the Brief Cognitive Rating Scale. RESULTS: The patients showed high cognitive dysfunction in the pre-dialysis group, in all the five dimensions (concentration, recent memory, past memory, orientation and functioning, and self-care), and the least in the 24-hour post dialysis group. This difference was found to be statistically significant (P=0.001). CONCLUSION: Patients with renal failure exhibited pronounced cognitive impairment and these functions significantly improved after the introduction of hemodialysis. PMID- 23439614 TI - A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding. AB - Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic iron overload. Deferasirox is a chelator used clinically for iron overload, but also is cytotoxic to cells in culture. In order to test whether a prodrug version of deferasirox could minimize its cytotoxicity but retain its protective properties against iron-induced oxidative damage, we synthesized a prochelator that contains a self-immolative boronic ester masking group that is removed upon exposure to hydrogen peroxide to release the bis hydroxyphenyltriazole ligand deferasirox. We present here the synthesis and characterization of this triazole-based, self-immolative prochelator: TIP (4-(5 (2-((4-boronobenzyl)oxy)phenyl)-3-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid). TIP does not coordinate to Fe(3+) and shows only weak affinity for Cu(2+) or Zn(2+), in stark contrast to deferasirox, which avidly binds all three metal ions. TIP converts efficiently in vitro upon reaction with hydrogen peroxide to deferasirox. In cell culture, TIP protects retinal pigment epithelial cells from death induced by hydrogen peroxide; however, TIP itself is more cytotoxic than deferasirox in unstressed cells. These results imply that the cytotoxicity of deferasirox may not derive exclusively from its iron withholding properties. PMID- 23439615 TI - U.S. Policies for school health education: opportunities for advocacy at the local, state, and national levels. AB - Children in K-12 settings comprise roughly one fifth of the population of the United States and are a cohort that has long drawn the interest of health educators. Early education and prevention efforts reduce human suffering, contribute to preparation for classroom learning, affect long-term health, and contain health costs due to preventable diseases. Despite the possible positive impact of a comprehensive approach, no broad-based federal legislation mandates regular school health education. Instead, the current state of school health education policy is a cobbled-together set of policies subsumed under existing laws. The purpose of this article is to provide information about the key legislation that is being used to promote school health education in the United States. Furthermore, the authors suggest opportunities for lobbying for the continuance of existing legislation and advocating for state and local operationalization of these policies. Finally, health educators are rallied to consider raising the issue of advocating for a more complete legislative strategy for school health education. PMID- 23439616 TI - Human chorionic gonadotropin (hCG) in the secretome of cultured embryos: hyperglycosylated hCG and hCG-free beta subunit are potential markers for infertility management and treatment. AB - Human chorionic gonadotropin (hCG) is produced by trophoblast cells throughout pregnancy, and gene expression studies have indicated that hCG-beta subunit (hCGbeta) expression is active at the 2 blastomere stage. Here, we investigated the qualitative hCG output of developing embryos in culture and hCG isoforms expressed in the secretome as a novel sensitive method for detecting hCG. Culture media was collected from the culture plates of 118 embryos in culture (including controls and embryos at different stages of culture) from 16 patients undergoing routine fertility treatment. The hCGbeta was detectable in media from 2 pronuclear (2PN) stage embryos through to the blastocyst stage. The hCGbeta was absent in 1PN and arrested embryos as well as all media controls. Prior to hatching, hyperglycosylated hCG (hCGh) was observed selectively in 3PN embryos, but after hatching, along with hCG, became the dominant hCG molecule observed. We have reported at the 2PN stage the earliest evidence of hCGbeta expression in embryos. There is a suggestion this may be indicative of quality in early embryos, and hCGh seen at the pronuclear stage may suggest triploid abnormality. The dominance of hCG, and hCGh expression, seen after blastocyst hatching may be indicative of potential implantation success. Thus, hCG isoforms have potential roles as biomarkers of embryo viability for embryo/blastocyst transfer. PMID- 23439617 TI - Improving the objective quality of large-scale clinical trials for women with heavy menstrual bleeding: experience from 2 multi-center, randomized trials. AB - This study demonstrates a robust and thorough trial design leading to accurate and objective data collection. We recommend that future studies investigating heavy menstrual bleeding (HMB) should follow, and improve upon, this rigorous approach to menstrual trial data collection, not only to validate clinical results but also to improve the techniques used to acquire these results. We propose that the state-of-the-art methodology described here be used as the basis for new guidelines for the implementation of clinical trials in the area of HMB. PMID- 23439618 TI - Postnatal metabolic and reproductive consequences of fetal and neonatal exposure to the smoking cessation drug bupropion. AB - INTRODUCTION: In all, 10% to 20% of all pregnant women smoke despite intentions to quit. Smoking cessation drugs such as nicotine replacement therapy (NRT) and bupropion are recommended for pregnant women. Our observation that developmental exposure to nicotine adversely affects metabolic and reproductive outcomes in rats has raised concerns about NRT's safety during pregnancy. Conversely, the effect of bupropion has not been reported. OBJECTIVE: The goal of this study was to examine the effect of fetal and neonatal exposure to bupropion on postnatal metabolic and reproductive outcomes. METHODS: Dams (N = 5/group) were exposed to saline or bupropion (5 or 10 mg/kg per d) for 2 weeks prior to mating until weaning. We assessed weight, adiposity, and glucose homeostasis in all offspring until 26 weeks of age. Onset of puberty, fertility, and pregnancy outcomes in the female offspring were also assessed. RESULTS: Fetal and neonatal exposure to bupropion did not cause metabolic derangement in the offspring despite a significant decrease in birth weight in the offspring of dams treated with 10/mg/kg per d bupropion (5.9 +/- 0.2 g vs control 6.7 +/- 0.2 g; P = .02). Moreover, with the exception of accelerated pubertal onset in F1 and F2 offspring, bupropion administration to pregnant dams had no impact on fertility or pregnancy outcomes for either the dam or the female offspring. CONCLUSION: Fetal and neonatal exposure to the smoking cessation drug bupropion, unlike NRT, does not appear to adversely affect metabolic outcomes or the fertility of the female offspring. However, bupropion does appear to alter pubertal onset through an as yet unknown mechanism. PMID- 23439619 TI - Circulating levels of neutrophil gelatinase-associated lipocalin (NGAL) correlate with the presence and severity of preeclampsia. AB - OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a reliable marker of acute renal injury and is produced at the maternal-fetal interface but its role in preeclampsia has not been systematically examined. This study investigated whether plasma NGAL concentrations changed in patients with preeclampsia at diagnosis compared to normotensive controls. STUDY DESIGN: A case control study was performed. Plasma was collected from women with preeclampsia and normotensive controls matched for age, gestational age, and body mass index. Plasma NGAL concentrations were measured by specific enzyme-linked immunosorbent assay. RESULTS: Patients with preeclampsia had significantly higher NGAL concentrations than controls (median [range]: 203.8 ng/mL [66.1-575.4] vs. 122.8 ng/mL [7.0-669.7]; P = .047). In subgroup analysis, patients with severe preeclampsia had significantly higher NGAL concentrations than those with mild preeclampsia. Plasma NGAL concentrations were positively correlated with the amount of proteinuria in women with preeclampsia (P = .003). CONCLUSIONS: Plasma NGAL concentrations were significantly elevated in women with preeclampsia versus normotensive controls, and concentrations appear to be associated with the severity of the disease. PMID- 23439620 TI - The effect of socioeconomic status on access to primary care: an audit study. AB - BACKGROUND: Health care office staff and providers may discriminate against people of low socioeconomic status, even in the absence of economic incentives to do so. We sought to determine whether socioeconomic status affects the response a patient receives when seeking a primary care appointment. METHODS: In a single unannounced telephone call to a random sample of family physicians and general practices (n = 375) in Toronto, Ontario, a male and a female researcher each played the role of a patient seeking a primary care physician. Callers followed a script suggesting either high (i.e., bank employee transferred to the city) or low (i.e., recipient of social assistance) socioeconomic status, and either the presence or absence of chronic health conditions (diabetes and low back pain). We randomized the characteristics of the caller for each office. Our primary outcome was whether the caller was offered an appointment. RESULTS: The proportion of calls resulting in an appointment being offered was significantly higher when the callers presented themselves as having high socioeconomic status than when they presented as having low socioeconomic status (22.6% v.14.3%, p = 0.04) and when the callers stated the presence of chronic health conditions than when they did not (23.5% v. 12.8%, p = 0.008). In a model adjusted for all independent variables significant at a p value of 0.10 or less (presence of chronic health conditions, time since graduation from medical school and membership in the College of Family Physicians of Canada), high socioeconomic status was associated with an odds ratio of 1.78 (95% confidence interval 1.02-3.08) for the offer of an appointment. Socioeconomic status and chronic health conditions had independent effects on the likelihood of obtaining an appointment. INTERPRETATION: Within a universal health insurance system in which physician reimbursement is unaffected by patients' socioeconomic status, people presenting themselves as having high socioeconomic status received preferential access to primary care over those presenting themselves as having low socioeconomic status. PMID- 23439621 TI - Canadian prisoner health complaints system better than that in United States, but still spotty. PMID- 23439622 TI - Scrutiny of Diane-35 due to potential dangers of off-label prescribing. PMID- 23439623 TI - Neurocognitive and psychiatric changes as the initial presentation of neurosyphilis. PMID- 23439624 TI - Admitting mistakes: ethics says yes, instinct says no. PMID- 23439626 TI - Breastfeeding unfriendly in Canada? PMID- 23439627 TI - Canada lags on transparency of industry-doctor relationships. PMID- 23439628 TI - Mental health awareness campaign exposes challenges in combatting stigma. PMID- 23439630 TI - Effects of yoga practice on acumeridian energies: Variance reduction implies benefits for regulation. AB - BACKGROUND AND OBJECTIVE: This paper concerns mechanisms responsible for the efficacy of yoga medicine, traditionally attributed to the enlivenment of prana. Our strategy was to investigate levels of Qi in acupuncture meridians, since Qi is usually considered equivalent to prana. MATERIALS AND METHODS: Electrodermal measurements at acumeridian endpoints (Tsing points) were made on 32 healthy individuals, pre and post 3 weeks yoga lifestyle program using AcuGraph 3 (an instrument in wide use). A previous study found that inherent errors prevent AcuGraph from precisely evaluating Qi energies in single meridians, so group results are reported: (a) Energy levels, (b) energy stability, and (c) energy balance between (i) Yin/Yang meridians, (ii) upper and lower, and (iii) left and right regions of the body. RESULTS: Significant improvements were observed in all but energy stability, supporting the ideas that yoga enlivens prana, and that balance in meridians constitutes health. For balance variables, the study observed shifts toward normal at both ends of variable distributions, reducing standard deviations: post-intervention percentages of subjects with values in the 'healthy' range increased. CONCLUSION: Yoga improved regulation of Qi levels in acumeridian meridians as well as increasing them. PMID- 23439629 TI - Effectiveness of strengthened stimulation during acupuncture for the treatment of Bell palsy: a randomized controlled trial. AB - BACKGROUND: The traditional Chinese theory of acupuncture emphasizes that the intensity of acupuncture must reach a threshold to generate de qi, which is necessary to achieve the best therapeutic effect. De qi is an internal compound sensation of soreness, tingling, fullness, aching, cool, warmth and heaviness, and a radiating sensation at and around the acupoints. However, the notion that de qi must be achieved for maximum benefit has not been confirmed by modern scientific evidence. METHODS: We performed a prospective multicentre randomized controlled trial involving patients with Bell palsy. Patients were randomly assigned to the de qi (n = 167) or control (n = 171) group. Both groups received acupuncture: in the de qi group, the needles were manipulated manually until de qi was reached, whereas in the control group, the needles were inserted without any manipulation. All patients received prednisone as a basic treatment. The primary outcome was facial nerve function at month 6. We also assessed disability and quality of life 6 months after randomization. RESULTS: After 6 months, patients in the de qi group had better facial function (adjusted odds ratio [OR] 4.16, 95% confidence interval [CI] 2.23-7.78), better disability assessment (differences of least squares means 9.80, 95% CI 6.29-13.30) and better quality of life (differences of least squares means 29.86, 95% CI 22.33-37.38). Logistic regression analysis showed a positive effect of the de qi score on facial-nerve function (adjusted OR 1.07, 95% CI 1.04-1.09). INTERPRETATION: Among patients with Bell palsy, acupuncture with strong stimulation that elicited de qi had a greater therapeutic effect, and stronger intensity of de qi was associated with the better therapeutic effects. TRIAL REGISTRATION: Clinicaltrials.gov no. NCT00685789. PMID- 23439631 TI - Cutaneous malignant melanoma incidence rates in Norway. AB - AIMS: The incidence rates of cutaneous malignant melanoma (CMM) increase throughout the world, in spite of introduction of strategies for prevention. However, a decrease in incidence rates is observed in some countries. If the reason for this could be found, it might be useful to transfer the knowledge to other fields of medicine. METHODS: CMM age-standardized incidence rates in different age groups in Norway were obtained from NORDCAN for the years 1970-1989 and 1990-2009. RESULTS: Until 1990, the CMM rates increased, but after that time a stabilization or a decrease was observed for young age groups (15-54 years old), while in older generations (>55 years old) the rates continued to increase. CONCLUSIONS: The decreasing CMM pattern in young age groups may be due to changing patterns to sunlight in sunbathing and use of sunbeds. PMID- 23439632 TI - Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. AB - OBJECTIVE: To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on beta-cell function and body composition. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 +/- 1%) and moderate obesity (BMI 36 +/- 2 kg/m(2)) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of beta-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months. RESULTS: Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 +/- 1.2% for gastric bypass, 7.1 +/- 0.8% for sleeve gastrectomy, and 8.4 +/- 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy ( 16 vs. -10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. beta-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, beta cell function inversely correlated with truncal fat and prandial free fatty acid levels. CONCLUSIONS: Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic beta-cell function and reduces truncal fat, thus reversing the core defects in diabetes. PMID- 23439633 TI - The antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4 (trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain. AB - Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4 (trifluoromethyl)benzyl]-menadione are "subversive substrates." These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III) protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates. PMID- 23439634 TI - Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases. AB - Although beta-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram negative bacteria has been eroded due to the emergence and spread of beta lactamase enzymes that are not affected by currently marketed beta-lactam/beta lactamase inhibitor combinations. Avibactam is a novel, covalent, non-beta-lactam beta-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime. In vitro studies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D beta-lactamases. Here we describe the structures of two clinically important beta-lactamase enzymes bound to avibactam, the class A CTX-M 15 extended-spectrum beta-lactamase and the class C Pseudomonas aeruginosa AmpC beta-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis. PMID- 23439635 TI - Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae. AB - Ertapenem plus doripenem or meropenem were given in three patients suffering from pandrug-resistant, KPC-2-positive Klebsiella pneumoniae bacteremia (2 patients) and urinary tract infection (1 patient), respectively. All responded successfully, without relapse at follow-up. The results obtained should probably be attributed to ertapenem's increased affinity for the carbapenemases hindering doripenem/meropenem degradation in the environment of the microorganism. PMID- 23439636 TI - Inoculum effect on the efficacies of amoxicillin-clavulanate, piperacillin tazobactam, and imipenem against extended-spectrum beta-lactamase (ESBL) producing and non-ESBL-producing Escherichia coli in an experimental murine sepsis model. AB - Escherichia coli is commonly involved in infections with a heavy bacterial burden. Piperacillin-tazobactam and carbapenems are among the recommended empirical treatments for health care-associated complicated intra-abdominal infections. In contrast to amoxicillin-clavulanate, both have reduced in vitro activity in the presence of high concentrations of extended-spectrum beta lactamase (ESBL)-producing and non-ESBL-producing E. coli bacteria. Our goal was to compare the efficacy of these antimicrobials against different concentrations of two clinical E. coli strains, one an ESBL-producer and the other a non-ESBL producer, in a murine sepsis model. An experimental sepsis model {~5.5 log10 CFU/g [low inoculum concentration (LI)] or ~7.5 log(10) CFU/g [high inoculum concentration (HI)]} using E. coli strains ATCC 25922 (non-ESBL producer) and Ec1062 (CTX-M-14 producer), which are susceptible to the three antimicrobials, was used. Amoxicillin-clavulanate (50/12.5 mg/kg given intramuscularly [i.m.]), piperacillin-tazobactam (25/3.125 mg/kg given intraperitoneally [i.p.]), and imipenem (30 mg/kg i.m.) were used. Piperacillin-tazobactam and imipenem reduced spleen ATCC 25922 strain concentrations (-2.53 and -2.14 log10 CFU/g [P < 0.05, respectively]) in the HI versus LI groups, while amoxicillin-clavulanate maintained its efficacy (-1.01 log10 CFU/g [no statistically significant difference]). Regarding the Ec1062 strain, the antimicrobials showed lower efficacy in the HI than in the LI groups: -0.73, -1.89, and -1.62 log10 CFU/g (P < 0.05, for piperacillin-tazobactam, imipenem, and amoxicillin-clavulanate, respectively, although imipenem and amoxicillin-clavulanate were more efficacious than piperacillin-tazobactam). An adapted imipenem treatment (based on the time for which the serum drug concentration remained above the MIC obtained with a HI of the ATCC 25922 strain) improved its efficacy to -1.67 log10 CFU/g (P < 0.05). These results suggest that amoxicillin-clavulanate could be an alternative to imipenem treatment of infections caused by ESBL- and non-ESBL-producing E. coli strains in patients with therapeutic failure with piperacillin-tazobactam. PMID- 23439637 TI - Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose. AB - Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h * WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h * WT(kg)(0.75); central volume of distribution (V), 1.97 liters * WT (kg); and peripheral V, 17.9 liters * WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 MUg/ml for this group of Ureaplasma isolates for >= 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined. PMID- 23439638 TI - OXA-235, a novel class D beta-lactamase involved in resistance to carbapenems in Acinetobacter baumannii. AB - We investigated the mechanism of carbapenem resistance in 10 Acinetobacter baumannii strains isolated from the United States and Mexico between 2005 and 2009. The detection of known metallo-beta-lactamase or carbapenem-hydrolyzing oxacillinase (OXA) genes by PCR was negative. The presence of plasmid-encoded carbapenem resistance genes was investigated by transformation of A. baumannii ATCC 17978. Shotgun cloning experiments and sequencing were performed, followed by the expression of a novel beta-lactamase in A. baumannii. Three novel OXA enzymes were identified, OXA-235 in 8 isolates and the amino acid variants OXA 236 (Glu173-Val) and OXA-237 (Asp208-Gly) in 1 isolate each. The deduced amino acid sequences shared 85% identity with OXA-134, 54% to 57% identities with the acquired OXA-23, OXA-24, OXA-58, and OXA-143, and 56% identity with the intrinsic OXA-51 and, thus, represent a novel subclass of OXA. The expression of OXA-235 in A. baumannii led to reduced carbapenem susceptibility, while cephalosporin MICs were unaffected. Genetic analysis revealed that blaOXA-235, blaOXA-236, and blaOXA-237 were bracketed between two ISAba1 insertion sequences. In addition, the presence of these acquired beta-lactamase genes might result from a transposition-mediated mechanism. This highlights the propensity of A. baumannii to acquire multiple carbapenem resistance determinants. PMID- 23439639 TI - Evidence for recent acquisition and successful transmission of bla(CTX-M-15) in Salmonella enterica in South Korea. AB - We identified two distinct bla(CTX-M)-bearing and five distinct bla(CMY-2) bearing genetic structures located on plasmids from Salmonella enterica and Escherichia coli isolates (n = 35) collected from chickens in South Korea. All Salmonella plasmids shared a common replicon, bla(CTX-M-15) transposon, and core resistance phenotype, while E. coli bla(CTX-M-15) plasmids included four distinct replicons. PMID- 23439640 TI - Population pharmacokinetic analysis of colistin in burn patients. AB - Colistin is increasingly used as a salvage therapy for nosocomial infections caused by multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data for colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients. Fifty patients with burns ranging from 4% to 85% of total body surface area who had been treated with colistimethate sodium (CMS) were studied. CMS, which is hydrolyzed in vivo to an active metabolite, was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, v. 6.2). A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance for the relative fraction of CMS converted into colistin and the presence of edema for the turnover rate constant of CMS converted into colistin. A steady-state 24-h area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Relative to previous studies with critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter, and continuous renal replacement therapy was not a significant covariate for any PK parameters. PMID- 23439641 TI - Zafirlukast inhibits complexation of Lsr2 with DNA and growth of Mycobacterium tuberculosis. AB - The mycobacterial nucleoid-associated protein Lsr2 is a DNA-bridging protein that plays a role in condensation and structural organization of the genome and acts as a global repressor of gene transcription. Here we describe experiments demonstrating that zafirlukast inhibits the complexation between Lsr2 and DNA in vitro. Zafirlukast is shown to inhibit growth in two different species of mycobacteria tested but exhibits no growth inhibition of Escherichia coli. The Lsr2 inhibitory activity is reflected in vivo as determined by monitoring of transcription levels in Mycobacterium tuberculosis. These data suggest that zafirlukast inhibits Lsr2 function in vivo, promoting dysregulation of the expression of an array of genes typically bound by Lsr2 and hindering growth. Since zafirlukast likely operates by a mechanism distinct from current M. tuberculosis drugs and is currently used as a prophylactic treatment for asthma, it offers an intriguing lead for development of new treatments for tuberculosis. PMID- 23439642 TI - Rapid emergence of echinocandin resistance during Candida kefyr fungemia treatment with caspofungin. AB - Echinocandin drugs are widely used for the treatment of candidemia. Resistance is considered rare, and only a few cases of breakthrough candidiasis in patients receiving echinocandin have been reported worldwide. We report here for the first time a Candida kefyr isolate that acquired echinocandin resistance very rapidly after the initiation of caspofungin treatment for candidemia. We characterized the FKS gene mutation responsible for the resistance via the comparison of isolates sampled before and during treatment. PMID- 23439643 TI - Favorable outcome of neonatal cerebrospinal fluid shunt-associated Candida meningitis with caspofungin. AB - Invasive Candida infections associated with medical devices are very difficult to cure without device removal. We present a case of neonatal cerebrospinal fluid shunt-associated Candida meningitis, in which removal of the device was precluded, that was successfully treated with caspofungin. Pharmacokinetic assessment of caspofungin concentrations in cerebrospinal fluid showed that exposure was adequate in the presence of a high systemic exposure. In complex cases of neonatal Candida infections involving medical devices, the addition of caspofungin might be beneficial. PMID- 23439644 TI - Life events, social support, coping strategies, and quality of life in attempted suicide: A case-control study. AB - BACKGROUND: Though deliberate self-harm encompasses a wide variety of medical and social disciplines some of the important psychosocial variable such as life events, social support, coping strategies, and quality of life have not yet been explored in depth in India. AIMS: The aim was to analyze and compare the type and severity of life events, coping strategies, social support, and quality of life of suicide attempters versus matched normal controls, and to identify the risk factors leading to suicide. MATERIALS AND METHODS: A total of 50 consecutive suicide attempters were compared with same number of age, sex, and martial status matched healthy controls using Presumptive Stressful Life Events Scale, Social Support Questionnaire, AECOM Coping Style Scale, and WHO QOL-Bref. RESULTS: Attempters experienced significantly more life events especially untoward events whereas the control group experienced more desirable and impersonal life events. Social support, positive coping, and of QOL were significantly lower in attempters. Among all risk factors desirable life events, good education, and good social support were protective against suicide. CONCLUSION: Suicide attempters were differentiated from healthy controls based on more stressful life events, lower social support, less healthy coping, and poor QOL. Positive life events, good education, and good social support were protective factors against suicide. However, it is difficult to pinpoint a single factor responsible for suicidal behavior. It is the complex interplay of various interrelated factors and the resultant buffering effect, which is protecting the individual against deliberate self-harm. PMID- 23439645 TI - Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. AB - The release of humoral factors between cancer cells and the microenvironmental cells is critical for metastasis; however, the roles of secreted miRNAs in non cell autonomous cancer progression against microenvironmental cells remain largely unknown. Here, we demonstrate that the neutral sphyngomyelinase 2 (nSMase2) regulates exosomal microRNA (miRNA) secretion and promotes angiogenesis within the tumor microenvironment as well as metastasis. We demonstrate a requirement for nSMase2-mediated cancer cell exosomal miRNAs in the regulation of metastasis through the induction of angiogenesis in inoculated tumors. In addition, miR-210, released by metastatic cancer cells, was shown to transport to endothelial cells and suppress the expression of specific target genes, which resulted in enhanced angiogenesis. These findings suggest that the horizontal transfer of exosomal miRNAs from cancer cells can dictate the microenviromental niche for the benefit of the cancer cell, like "on demand system" for cancer cells. PMID- 23439646 TI - Light-dark adaptation of channelrhodopsin C128T mutant. AB - Channelrhodopsins are microbial type rhodopsins that operate as light-gated ion channels. Largely prolonged lifetimes of the conducting state of channelrhodopsin 2 may be achieved by mutations of crucial single amino acids, i.e. cysteine 128. Such mutants are of great scientific interest in the field of neurophysiology because they allow neurons to be switched on and off on demand (step function rhodopsins). Due to their slow photocycle, structural alterations of these proteins can be studied by vibrational spectroscopy in more detail than possible with wild type. Here, we present spectroscopic evidence that the photocycle of the C128T mutant involves three different dark-adapted states that are populated according to the wavelength and duration of the preceding illumination. Our results suggest an important role of multiphoton reactions and the previously described side reaction for dark state regeneration. Structural changes that cause formation and depletion of the assumed ion conducting state P520 are only small and follow larger changes that occur early and late in the photocycle, respectively. They require only minor structural rearrangements of amino acids near the retinal binding pocket and are triggered by all-trans/13-cis retinal isomerization, although additional isomerizations are also involved in the photocycle. We will discuss an extended photocycle model of this mutant on the basis of spectroscopic and electrophysiological data. PMID- 23439647 TI - Interaction of constitutive photomorphogenesis 1 protein with protein-tyrosine phosphatase 1B suppresses protein-tyrosine phosphatase 1B activity and enhances insulin signaling. AB - Recent studies reveal that COP1 suppresses the expression of gluconeogenetic genes and prohibits hepatic glucose production. To get more insight into COP1 in hepatic cells, we examined the impact of COP1 on insulin-responsive genes and insulin signaling. We found that COP1 increased the responsiveness of insulin modulated genes to insulin in that it promoted the expression of insulin-induced genes and inhibited that of insulin-suppressed genes and that COP1 enhanced insulin signaling as it promoted phosphorylation of Akt and ERK as well as tyrosine phosphorylation of IRbeta induced by insulin. To delineate the mechanism under which COP1 modulates insulin signaling, we examined the possibility that COP1 modulates the activity of PTP1B, the major insulin receptor tyrosine phosphatase. The results indicated that COP1 physically interacted with PTP1B and suppressed PTP1B phosphatase activity as well as the association of PTP1B with IRbeta. We suggest that COP1 is a positive regulator of hepatic insulin signaling. PMID- 23439648 TI - Biochemical and biophysical characterization of the sialyl-/hexosyltransferase synthesizing the meningococcal serogroup W135 heteropolysaccharide capsule. AB - Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis and sepsis. Crucial virulence determinants of pathogenic Nm strains are the polysaccharide capsules that support invasion by hindering complement attack. In NmW-135 and NmY the capsules are built from the repeating units (-> 6)-alpha-D Gal-(1 -> 4)-alpha-Neu5Ac-(2 ->)n and (-> 6)-alpha-D-Glc-(1 -> 4)-alpha-Neu5Ac-(2 ->)n, respectively. These unusual heteropolymers represent unique examples of a conjugation between sialic acid and hexosyl-sugars in a polymer chain. Moreover, despite the various catalytic strategies needed for sialic acid and hexose transfer, single enzymes (SiaDW-135/Y) have been identified to form these heteropolymers. Here we used SiaDW-135 as a model system to delineate structure function relationships. In size exclusion chromatography active SiaDW-135 migrated as a monomer. Fold recognition programs suggested two separate glycosyltransferase domains, both containing a GT-B-fold. Based on conserved motifs predicted folds could be classified as a hexosyl- and sialyltransferase. To analyze enzyme properties and interplay of the two identified glycosyltransferase domains, saturation transfer difference NMR and mutational studies were carried out. Simultaneous and independent binding of UDP-Gal and CMP Sia was seen in the absence of an acceptor as well as when the catalytic cycle was allowed to proceed. Enzyme variants with only one functionality were generated by site-directed mutagenesis and shown to complement each other in trans when combined in an in vitro test system. Together the data strongly suggests that SiaDW-135 has evolved by fusion of two independent ancestral genes encoding sialyl- and galactosyltransferase activity. PMID- 23439649 TI - E6AP/UBE3A ubiquitin ligase harbors two E2~ubiquitin binding sites. AB - By exploiting (125)I-polyubiquitin chain formation as a functional readout of enzyme activity, we have quantitatively examined the mechanism of human E6AP/UBE3A for the first time. Initial rate studies identify UbcH7 as the cognate E2 carrier protein for E6AP, although related Ubc5 isoforms and the ISG15 specific UbcH8 paralog also support E6AP with reduced efficacy due to impaired binding and catalytic competence. Initial rates of polyubiquitin chain formation displayed hyperbolic kinetics with respect to UbcH7 concentration (K(m) = 57.6 +/ 5.7 nM and kcat = 0.032 +/- 0.001 s(-1)) and substrate inhibition above 2 MUM. Competitive inhibition by an isosteric UbcH7C86S-ubiquitin oxyester substrate analog (K(i) = 64 +/- 18 nM) demonstrates that Km reflects intrinsic substrate affinity. In contrast, noncompetitive inhibition by a UbcH7C86A product analog (K(i) = 7 +/- 0.7 MUM) and substrate inhibition at high concentrations require two functionally distinct E2~ubiquitin substrate binding sites. The kinetics of polyubiquitin chain formation reflect binding at a cryptic Site 1 not previously recognized that catalyzes E6AP~ubiquitin thioester formation. Subsequent binding of E2~ubiquitin at the canonical Site 2 present in the extant crystal structure is responsible for polyubiquitin chain elongation. Other rate studies show that the conserved -4 Phe(849) residue is required for polyubiquitin chain formation rather than target protein conjugation as originally suggested. The present studies unambiguously preclude earlier models for the mechanism of Hect domain catalyzed conjugation through the canonical binding site suggested by the crystal structure and define a novel two-step mechanism for formation of the polyubiquitin degradation signal. PMID- 23439650 TI - The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model. AB - A critical step in the induction of adaptive mucosal immunity is antigen transcytosis, in which luminal antigens are transported to organized lymphoid tissues across the follicle-associated epithelium (FAE) of Peyer's patches. However, virtually nothing is known about intracellular signaling proteins and transcription factors that regulate apical-to-basolateral transcytosis. The FAE can transcytose a variety of luminal contents, including inert particles, in the absence of specific opsonins. Furthermore, it expresses receptors for secretory immunoglobulin A (SIgA), the main antibody in mucosal secretions, and uses them to efficiently transcytose SIgA-opsonized particles present in the lumen. Using a human FAE model, we show that the tyrosine kinase HCK regulates apical-to basolateral transcytosis of non-opsonized and SIgA-opsonized particles. We also show that, in cultured intestinal epithelial cells, ectopic expression of the transcription factor SPIB or EHF is sufficient to activate HCK-dependent apical to-basolateral transcytosis of these particles. Our results provide the first molecular insights into the intracellular regulation of antigen sampling at mucosal surfaces. PMID- 23439651 TI - Proliferation rate of somatic cells affects reprogramming efficiency. AB - The discovery of induced pluripotent stem (iPS) cells provides not only new approaches for cell replacement therapy, but also new ways for drug screening. However, the undefined mechanism and relatively low efficiency of reprogramming have limited the application of iPS cells. In an attempt to further optimize the reprogramming condition, we unexpectedly observed that removing c-Myc from the Oct-4, Sox-2, Klf-4, and c-Myc (OSKM) combination greatly enhanced the generation of iPS cells. The iPS cells generated without c-Myc attained salient pluripotent characteristics and were capable of producing full-term mice through tetraploid complementation. We observed that forced expression of c-Myc induced the expression of many genes involved in cell cycle control and a hyperproliferation state of the mouse embryonic fibroblasts during the early stage of reprogramming. This enhanced proliferation of mouse embryonic fibroblasts correlated negatively to the overall reprogramming efficiency. By applying small molecule inhibitors of cell proliferation at the early stage of reprogramming, we were able to improve the efficiency of iPS cell generation mediated by OSKM. Our data demonstrated that the proliferation rate of the somatic cell plays critical roles in reprogramming. Slowing down the proliferation of the original cells might be beneficial to the induction of iPS cells. PMID- 23439652 TI - Zinc deficiency impacts CO2 assimilation and disrupts copper homeostasis in Chlamydomonas reinhardtii. AB - Zinc is an essential nutrient because of its role in catalysis and in protein stabilization, but excess zinc is deleterious. We distinguished four nutritional zinc states in the alga Chlamydomonas reinhardtii: toxic, replete, deficient, and limited. Growth is inhibited in zinc-limited and zinc-toxic cells relative to zinc-replete cells, whereas zinc deficiency is visually asymptomatic but distinguished by the accumulation of transcripts encoding ZIP family transporters. To identify targets of zinc deficiency and mechanisms of zinc acclimation, we used RNA-seq to probe zinc nutrition-responsive changes in gene expression. We identified genes encoding zinc-handling components, including ZIP family transporters and candidate chaperones. Additionally, we noted an impact on two other regulatory pathways, the carbon-concentrating mechanism (CCM) and the nutritional copper regulon. Targets of transcription factor Ccm1 and various CAH genes are up-regulated in zinc deficiency, probably due to reduced carbonic anhydrase activity, validated by quantitative proteomics and immunoblot analysis of Cah1, Cah3, and Cah4. Chlamydomonas is therefore not able to grow photoautotrophically in zinc-limiting conditions, but supplementation with 1% CO2 restores growth to wild-type rates, suggesting that the inability to maintain CCM is a major consequence of zinc limitation. The Crr1 regulon responds to copper limitation and is turned on in zinc deficiency, and Crr1 is required for growth in zinc-limiting conditions. Zinc-deficient cells are functionally copper deficient, although they hyperaccumulate copper up to 50-fold over normal levels. We suggest that zinc-deficient cells sequester copper in a biounavailable form, perhaps to prevent mismetallation of critical zinc sites. PMID- 23439654 TI - Genetics for the ophthalmologist. AB - The eye has played a major role in human genomics including gene therapy. It is the fourth most common organ system after integument (skin, hair and nails), nervous system, and musculoskeletal system to be involved in genetic disorders. The eye is involved in single gene disorders and those caused by multifactorial etiology. Retinoblastoma was the first human cancer gene to be cloned. Leber hereditary optic neuropathy was the first mitochondrial disorder described. X Linked red-green color deficiency was the first X-linked disorder described. The eye, unlike any other body organ, allows directly visualization of genetic phenomena such as skewed X-inactivation in the fundus of a female carrier of ocular albinism. Basic concepts of genetics and their application to clinical ophthalmological practice are important not only in making a precise diagnosis and appropriate referral, but also in management and genetic counseling. PMID- 23439653 TI - Constitutive internalization of the leucine-rich G protein-coupled receptor-5 (LGR5) to the trans-Golgi network. AB - LGR5 is a Wnt pathway associated G protein-coupled receptor (GPCR) that serves as a molecular determinant of stem cells in numerous tissues including the intestine, stomach, hair follicle, eye, and mammary gland. Despite its importance as a marker for this critical niche, little is known about LGR5 signaling nor the biochemical mechanisms and receptor determinants that regulate LGR5 membrane expression and intracellular trafficking. Most importantly, in cells LGR5 is predominantly intracellular, yet the mechanisms underlying this behavior have not been determined. In this work we elucidate a precise trafficking program for LGR5 and identify the motif at its C terminus that is responsible for the observed constitutive internalization. We show that this process is dependent upon dynamin GTPase activity and find that wild-type full-length LGR5 rapidly internalizes into EEA1- and Rab5-positive endosomes. However, LGR5 fails to rapidly recycle to the plasmid membrane through Rab4-positive vesicles, as is common for other GPCRs. Rather, internalized LGR5 transits through Rab7- and Rab9-positive vesicles, co-localizes in vesicles with Vps26, a retromer complex component that regulates retrograde trafficking to the trans-Golgi network (TGN) and reaches a steady-state distribution in the TGN within 2 h. Using mutagenesis, particularly of putative phosphorylation sites, we show that the amino acid pair, serine 861 and 864, is the principal C-tail determinant that mediates LGR5 constitutive internalization. The constitutive internalization of LGR5 to the TGN suggests the existence of novel biochemical roles for its Wnt pathway related, but ill defined signaling program. PMID- 23439655 TI - Determination of 17 beta-Estradiol in Rabbit Plasma by Gas Chromatography with Flame Ionization Detection. AB - This article describes gas chromatography-flame ionization detection method for determination of 17 beta-estradiol in rabbit plasma. 17 beta-estradiol and internal standard progesterone were extracted from plasma using liquid-liquid extraction method. Linearity was found between 0.25 and 20 MUg/ml (r(2)=0.994) for plasma samples. Intra-day and inter-day precision, expressed as the relative standard deviation were less than 5.5%, and accuracy (relative error) was less than 3.5%. The mean recovery of 17 beta-estradiol samples was 94.4%. The limits of detection and quantification of method for plasma samples were 0.10 MUg/ml and 0.15 MUg/ml, respectively. Also, clinically used other 10 drugs were investigated to check for potential interferences and the method was successfully applied to the determination of 17 beta-estradiol in New Zealand white rabbits. PMID- 23439656 TI - Integrating dietary supplements into cancer care. AB - Many studies confirm that a majority of patients undergoing cancer therapy use self-selected forms of complementary therapies, mainly dietary supplements. Unfortunately, patients often do not report their use of supplements to their providers. The failure of physicians to communicate effectively with patients on this use may result in a loss of trust within the therapeutic relationship and in the selection by patients of harmful, useless, or ineffective and costly nonconventional therapies when effective integrative interventions may exist. Poor communication may also lead to diminishment of patient autonomy and self efficacy and thereby interfere with the healing response. To be open to the patient's perspective, and sensitive to his or her need for autonomy and empowerment, physicians may need a shift in their own perspectives. Perhaps the optimal approach is to discuss both the facts and the uncertainty with the patient, in order to reach a mutually informed decision. Today's informed patients truly value physicians who appreciate them as equal participants in making their own health care choices. To reach a mutually informed decision about the use of these supplements, the Clinical Practice Committee of The Society of Integrative Oncology undertook the challenge of providing basic information to physicians who wish to discuss these issues with their patients. A list of leading supplements that have the best suggestions of benefit was constructed by leading researchers and clinicians who have experience in using these supplements. This list includes curcumin, glutamine, vitamin D, Maitake mushrooms, fish oil, green tea, milk thistle, Astragalus, melatonin, and probiotics. The list includes basic information on each supplement, such as evidence on effectiveness and clinical trials, adverse effects, and interactions with medications. The information was constructed to provide an up-to-date base of knowledge, so that physicians and other health care providers would be aware of the supplements and be able to discuss realistic expectations and potential benefits and risks. PMID- 23439657 TI - Black cohosh and breast cancer: a systematic review. AB - BACKGROUND: Many women use black cohosh as a natural treatment for menopausal symptoms. However, controversy exists around safety in breast cancer, because of its purported estrogenic activity. We conducted a systematic review of black cohosh use in women with or at risk of breast cancer. METHODS: We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to July 2012 and October 2012 for human interventional or observational data pertaining to the safety and efficacy of black cohosh in patients with or at risk of breast cancer, including an assessment of the effect of black cohosh on estrogen responsive tissues. RESULTS: Of 450 records, we included 26 articles: 14 randomized controlled trials, 7 uncontrolled trials, and 5 observational studies.The evidence on efficacy for ho t flashes is divided, with some benefits seen when compared with baseline, but not when compared with placebo. Two observational studies found no association between black cohosh and risk of breast cancer, whereas 2 studies reported significant reductions in risk of primary breast cancer among postmenopausal women (adjusted odds ratio = 0.47, 95% confidence interval = 0.27-0.82), and risk of recurrence (adjusted hazard ratio = 0.75, 95% confidence interval = 0.63-0.89). Seventeen trials showed no significant impact on circulating hormone levels or proliferation in estrogen responsive tissues. CONCLUSIONS: Current evidence does not support an association between black cohosh and increased risk of breast cancer. There is a lack of evidence supporting the efficacy of black cohosh for reduction of hot flashes in breast cancer patients. Given conflicting but promising results, and apparent safety, further research is warranted. PMID- 23439658 TI - Neither heavy nor light load resistance exercise acutely exacerbates lymphedema in breast cancer survivor. AB - Resistance exercise has great potential to aid in the management of breast cancer related lymphedema (BCRL), but little is known regarding the acute response of performing resistance exercises with the affected limb. PURPOSE: To examine the acute impact of upper body resistance exercise on the amount of swelling and severity of symptoms in women with BCRL and to compare these effects between resistance exercise involving high and low loads (heavier vs lighter weights). METHODS: Seventeen women aged 61 +/- 9 years with mild to severe BCRL participated in this study. Participants completed a high load (6-8 repetition maximum) and low load (15-20 repetition maximum) exercise session consisting of 2 sets of 5 upper body resistance exercises in a randomized order separated by a 10 to 12-day wash-out period. The extent of swelling was assessed using bioimpedance spectroscopy, dual-energy x-ray absorptiometry, and arm circumference measurements. The severity symptoms were assessed using the visual analogue scale (pain, heaviness, and tightness) and a modified Brief Pain Inventory. Measurements were taken pre-exercise, immediately post-exercise, 24 hours post-exercise, and 72 hours post-exercise. RESULTS: No changes in the extent of swelling or the severity of symptoms were observed between pre-exercise and immediately post-exercise, 24 hours post-exercise, or 72 hours post-exercise. No differences in the response to the high or low load exercise were observed. CONCLUSIONS: Upper body resistance exercise does not acutely increase swelling or feelings of discomfort/pain, heaviness tightness in the affected limb of BCRL patients when performed at either high or low loads. PMID- 23439659 TI - Neuromodulation of cancer pain. AB - Managing cancer-related chronic pain is challenging to health care professionals as well as cancer patients and survivors. The management of cancer-related pain has largely consisted of pharmacological treatments, which has caused researchers to focus on neurotransmitter activity as a mediator of patients' perception of pain rather than the electrical activity during neurobiological processes of cancer-related pain. Consequently, brain-based pain treatment has focused mainly on neurotransmitters and not electrical neuromodulation. Neuroimaging research has revealed that brain activity is associated with patients' perceptions of symptoms across various diagnoses. The brain modulates internally generated neural activity and adjusts perceptions according to sensory input from the peripheral nervous system. Cancer-related pain may result not only from changes in the peripheral nervous system but also from changes in cortical activity over time. Thus, cortical reorganization by way of the brain's natural, plastic ability (neuroplasticity) may be used to manage pain symptoms. Physical and psychological distress could be modulated by giving patients tools to regulate neural activity in symptom-specific regions of interest. Initial research in nononcology populations suggests that encouraging neuroplasticity through a learning paradigm can be a useful technique to help treat chronic pain. Here we review evidence that indicates a measurable link between brain activity and patient-reported psychological and physical distress. We also summarize findings regarding both the neuroelectrical and neuroanatomical experience of symptoms, review research examining the mechanisms of the brain's ability to modify its own activity, and propose a brain-computer interface as a learning paradigm to augment neuroplasticity for pain management. PMID- 23439660 TI - Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by oxycodone. AB - Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of oxycodone administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone). Neither oxycodone nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats and demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with oxycodone. PMID- 23439661 TI - Disposition and metabolism of GSK2251052 in humans: a novel boron-containing antibiotic. AB - (S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [14C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite. PMID- 23439662 TI - Metabolism of bis(4-fluorobenzyl)trisulfide and its formation of hemoglobin adduct in rat erythrocytes. AB - Bis(4-fluorobenzyl)trisulfide (BFBTS) is a promising new antitumor agent under investigation. It was metabolized rapidly in vivo in rat, but the metabolic fate and primary site of metabolism have not been clarified. In this study, we investigated the role of blood in the metabolism of BFBTS and compared the BFBTS metabolic potencies in whole blood, plasma, and red blood cells (RBCs) in vitro. Three major metabolites of BFBTS [bis(4-fluorobenzyl)disulfide, para-fluorobenzyl mercaptan, and para-fluorobenzoic acid] were detected in RBCs and whole blood. Significant metabolism of BFBTS was observed in RBCs that were identified as the primary site of BFBTS metabolism. Thiols, including endogenous thiols and hemoglobin, were proven to be the critical factor in BFBTS metabolism. S Fluorobenzylmercaptocysteine Hb (hemoglobin) adducts were characterized in vitro at BFBTS concentration of 250 MUM and higher, whereas such Hb adducts were not detected in RBCs from Sprague-Dawley rats receiving a single intravenous injection of BFBTS at a high dose of 50 mg/kg. Liquid chromatography-tandem mass spectrometry results revealed that adduction induced by BFBTS was prone to take place at Cys125 of globin beta chains. Otherwise, glutathionylation of Hb was also observed that may be attributed to the oxidative effect of BFBTS. In summary, BFBTS was unstable when it met with thiols, and RBCs were the main site of BFBTS metabolism. Hb adducts induced by BFBTS could be detected in vitro at high concentration but not in vivo even at high dose. PMID- 23439663 TI - Late onset CNS immune reconstitution inflammatory syndrome in an immunocompetent patient. AB - Immune reconstitution inflammatory syndrome (IRIS) refers to the presence of paradoxical clinical deterioration attributable to immune system recovery during highly active antiretroviral therapy (HAART). We present an immunocompetent patient with multifocal leukoencephalopathy on HAART, with central nervous system (CNS) IRIS pathology of unknown infectious etiology. CNS IRIS pathology should be suspected in patients on longstanding HAART without immune reconstitution, presenting with unexplained leukoencephalopathy. PMID- 23439664 TI - Elevated expression of hepcidin post-renal ischemia reperfusion injury. PMID- 23439665 TI - Klf7 modulates the differentiation and proliferation of chicken preadipocyte. AB - Kruppel-like factor 7 (Klf7) has been extensively studied in the mammalian species, but its function in avian species is unclear. The objective of this study was to reveal the function of chicken Klf7 (Gallus gallus Klf7, gKlf7) in adipogenesis. The results of real-time reverse transcription polymerase chain reaction demonstrated that the relative mRNA level of chicken Klf7 (gKlf7/gbeta Actin) in the abdominal adipose tissue was significantly associated with the abdominal fat content and the age of broilers (P < 0.05), and gKlf7 was more highly expressed in preadipocytes than in mature adipocytes (P < 0.05). In addition, Oil red O staining showed that gKlf7 inhibited chicken preadipocyte differentiation, and MTT assay indicated that gKlf7 overexpression promoted preadipocyte proliferation. Additionally, luciferase assays showed that gKlf7 overexpression suppressed the chicken CCAAT/enhancer-binding protein alpha (C/ebpalpha), fatty acid synthase (Fasn), and lipoprotein lipase (Lpl) promoter activities (P < 0.05), and gKlf7 knockdown increased the chicken peroxisome proliferator-activated receptor gamma (Ppargamma), C/ebpalpha and fatty acid binding protein 4 (Fabp4) promoter activities (P < 0.05). Together, our study demonstrated that chicken Klf7 inhibits preadipocyte differentiation and promotes preadipocyte proliferation. PMID- 23439666 TI - Molecular mechanisms of neurodegeneration mediated by dysfunctional subcellular organelles in transmissible spongiform encephalopathies. AB - Transmissible spongiform encephalopathies refer to a group of infectious neurodegenerative diseases with an entirely novel mechanism of transmission and pathophysiology including synaptic damage, dendritic atrophy, vacuolization, and microglial activation. Extensive neuronal loss is the main cause of chronic brain deterioration and fatal outcome of prion diseases. As the final outcome of pathological alterations, neuronal death is a prominent feature of all prion diseases. The mechanisms responsible for prion diseases are not well understood. A more comprehensive understanding of the molecular basis of neuronal damage is essential for the development of an effective therapy for transmissible spongiform encephalopathies and other neurodegenerative diseases sharing similar features. Here, we review the molecular mechanisms of mitochondrial dysfunction and endoplasmic reticulum stress-mediated neuronal death, which play crucial roles in the pathogenisis of prion diseases. PMID- 23439667 TI - Oxygen speciation in upgraded fast pyrolysis bio-oils by comprehensive two dimensional gas chromatography. AB - Biomass fast pyrolysis is considered as a promising route to produce liquid for the transportation field from a renewable resource. However, the derived bio-oils are mainly oxygenated (45-50%w/w O on a wet basis) and contain almost no hydrocarbons. Therefore, upgrading is necessary to obtain a liquid with lower oxygen content and characterization of oxygenated compounds in these products is essential to assist conversion reactions. For this purpose, comprehensive two dimensional gas chromatography (GC * GC) can be investigated. Oxygen speciation in such matrices is hampered by the large diversity of oxygenated families and the complexity of the hydrocarbon matrix. Moreover, response factors must be taken into account for oxygenate quantification as the Flame Ionisation Detector (FID) response varies when a molecule contains heteroatoms. To conclude, no distillation cuts were accessible and the analysis had to cover a large range of boiling points (30-630 degrees C). To take up this analytical challenge, a thorough optimization approach was developed. In fact, four GC * GC column sets were investigated to separate oxygenated compounds from the hydrocarbon matrix. Both model mixtures and the upgraded biomass flash pyrolysis oil were injected using GC * GC-FID to reach a suitable chromatographic separation. The advantages and drawbacks of each column combination for oxygen speciation in upgraded bio oils are highlighted in this study. Among the four sets, an original polar * semi polar column combination was selected and enabled the identification by GC * GC ToF/MS of more than 40 compounds belonging to eight chemical families: ketones, furans, alcohols, phenols, carboxylic acids, guaiacols, anisols, and esters. For quantification purpose, the GC * GC-FID chromatogram was divided into more than 60 blobs corresponding to the previously identified analyte and hydrocarbon zones. A database associating each blob to a molecule and its specific response factor (determined by standards injection at different concentrations) was created. A detailed molecular quantification by GC * GC-FID was therefore accessible after integration of the corrected normalized areas. This paper aims to present a detail level in terms of characterization of oxygenated compounds in upgraded bio-oils which to our knowledge has never been reached so far. It is based on an original column set selection and an extremely accurate quantification procedure. PMID- 23439668 TI - Linguistic validation of the Greek M.D. Anderson Symptom Inventory - Head and Neck Module. AB - BACKGROUND: Our goal is to linguistically validate the Greek translation of the M.D. Anderson Symptom Inventory Index - Head and Neck Module. PATIENTS & METHODS: Following forward and backward translation of the previously validated head and neck cancer specific items of the English MDASI-HN into Greek (G-MDASI HN), it was administered along with a cognitive debriefing to head and neck cancer patients able to read and understand Greek. Individual and group responses are presented using descriptive statistics. RESULTS: From 02/2009 through 06/2009 30 subjects with head and neck cancer completed the G-MDASI-HN followed by completion of the accompanying cognitive debriefing. Ninety-eight percent of the individual G-MDASI-HN items were completed. "Voice" item was not completed by 5 patients. Average time to complete the G-MDASI-HN was 13.3 minutes. Average ease of completion was rated at 1.21 on a 0 to 10 scale with "0" being "very easy" and "10" being "very hard". Only 10% of patients reported trouble completing any item, namely "distress" and "numbness". CONCLUSIONS: The Greek MDASI-HN is linguistically valid and a patient-reported instrument that can be used both in outcomes research and as a clinical tool. PMID- 23439669 TI - Acute and chronic thoracic aortic disease: surgical considerations. AB - Acute thoracic aortic aneurysm is one of the most life-threatening vascular disorders recognized to date. The majority of these aortic ruptures rapidly end in mortality, with 50% of patients suffering death before reaching the hospital. Thus, acute management through surgical intervention is often indicated, especially in cases of ascending aortic rupture. Physical examination is critical in making the diagnosis, as clinical signs and symptoms often vary depending on the location of the dissection. Clinicians should have a low threshold for including thoracic aortic dissection in their differential diagnosis, especially when a patient presents with acute onset chest or back pain. In this report, we discuss the different categories of aortic dissections and the current treatment modalities for each. These include endovascular aortic repair, which has become a viable treatment modality in certain cases of type B dissection. Offering a less invasive approach, the technique known as thoracic endovascular repair currently affords a treatment option to a patient population who would have otherwise been deemed non-surgical candidates. Hybrid thoracic endovascular aortic repair has also become a pertinent surgical technique, and successful outcomes have been demonstrated when it is employed to repair ascending aortic aneurysms. We also describe our Acute Aortic Treatment Center, a rapid multicentric triage system for the management of acute aortic pathologies, which has resulted in significant improvements in patient outcomes. PMID- 23439670 TI - Cerebral venous sinus thrombosis in children with nephrotic syndrome. AB - Nephrotic syndrome in infancy and childhood can be associated with thromboembolic complications. We describe two cases of nephrotic syndrome who presented with non specific findings. Magnetic resonance imaging brain with magnetic resonance venography showed thrombosis of multiple venous sinuses. Patients were successfully treated with anticoagulants and there was complete resolution of thrombosis on repeat imaging. PMID- 23439671 TI - Preeclampsia, gestational hypertension and subsequent hypothyroidism. AB - OBJECTIVES: To evaluate the effect of preeclampsia (PE) and gestational hypertension (GH) on subsequent hypothyroidism. Recent studies suggest that women with PE have increased risk for reduced thyroid function, but the association between PE and GH with overt hypothyroidism has not been examined. STUDY DESIGN: Two prospective population-based cohort studies, the Northern Finland Birth Cohorts 1966 and 1986, followed women who had PE (N=955), GH (N=1449) or were normotensive (N=13531) during pregnancy. Finnish national registers were used to confirm subsequent hypothyroidism. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) estimated hypothyroidism risk when comparing women with PE or GH with normotensive women. MAIN OUTCOME MEASURES: Primary hypothyroidism during follow-up of 20-40 years. RESULTS: The subsequent prevalence of hypothyroidism was higher among women with PE (4.0%) and GH (4.5%) compared with normotensive women (3.5%), but the risk increase was not significant (aHR for PE 1.13, 95%CI 0.80-1.59 and aHR for GH 1.11, 95%CI 0.85 1.45). Subgroup analysis among nulliparous women revealed a significant association between late PE and subsequent hypothyroidism (aHR 1.82, 95%CI 1.04 3.19). Early or recurrent PE were not associated with hypothyroidism (aHR 0.93, 95%CI 0.46-1.81 and aHR 1.35, 95%CI 0.63-2.88, respectively). CONCLUSIONS: Overall, PE or GH during pregnancy was not significantly associated with subsequent hypothyroidism in Finnish women after 20-40 years of follow-up. However, late PE in nulliparous women was associated with a 1.8-fold increased risk of subsequent hypothyroidism, a finding that merits further study in other populations. PMID- 23439672 TI - Immediate effects of cryotherapy on static and dynamic balance. AB - PURPOSE/BACKGROUND: Cryotherapy is commonly used in physical therapy with many known benefits; however several investigations have reported decreased functional performance following therapeutic application thereof. The purpose of this study was to determine the effect of cryotherapy applied to the ankle on static and dynamic standing balance. It was hypothesized that balance would be decreased after cryotherapy application. METHODS: Twenty individuals (aged 18 to 40 years) participated in this research project. Each participant was tested under two conditions: an experimental condition where subjects received ice water immersion of the foot and ankle for 15 minutes immediately before balance testing and a control condition completed at room temperature. A Biodex(r) Balance System was used to quantify balance using anterior/posterior (AP), medial/lateral (ML), and overall balance indices. Paired t-tests were used to compare the balance indices for the two conditions with alpha set at 0.05 a priori. Effect size was also calculated to account for the multiple comparisons made. RESULTS: The static balance indices did not display statistically significant differences between the post-cryotherapy and the control conditions with low effect sizes. Dynamic ML indices significantly increased following the cryotherapy application compared to the control exhibiting a moderate effect size indicating decreased balance following cryotherapy application. No differences were noted between experimental and control conditions for the dynamic AP or overall balance indices while a small effect size was noted for both. CONCLUSIONS: The results suggest that cryotherapy to the ankle has a negative effect on the ML component of dynamic balance following ice water immersion. CLINICAL RELEVANCE: Immediate return to play following cryotherapy application is cautioned given the decreased dynamic ML balance and potential for increased injury risk. LEVEL OF EVIDENCE: 3b Case control study. PMID- 23439673 TI - Patients selection for awake neurosurgery. AB - BACKGROUND: Based upon the surgical location and indication, including redundant regions, eloquent areas, deep brain stimulation, and epilepsy foci, some patients will benefit from an awake craniotomy, which allows completion of neurocognitive testing during the intra-operative period. This paper suggests patient selection criteria through a new decision algorithm. METHODS: We completed a retrospective chart review at Tampa General Hospital after IRB approval; data were obtained concerning total number of craniotomies, indications, and problems experienced for selection of awake vs. general anesthetic techniques. RESULTS: A total of 397 craniotomies were performed during the two years 2005 and 2006: among those 79 patients received an awake craniotomy (20%). We have utilized a sedation sequence which includes dexmedetomidine, propofol and LMA placement. A skull block is then performed to anesthetize pin placement, and desflurane and remifentanil are used for maintenance until the dural incision. At this time the inhalation agent is stopped and the LMA is removed while breathing spontaneously: the patient remains sedated on dexmedetomidine and remifentanil for the duration of the operation and can communicate effectively if closely coached. Analysis of all patient data led us to a decision tree to guide the surgeon and anesthesiologist in selecting the awake patients. DISCUSSION: We describe the sequence of steps and anesthetic agents which has proved successful for our group. Finally, the use of the proposed decision algorithm simplifies preoperative anesthetic selection and prevents erroneous assignment of inappropriate patients to an awake technique. PMID- 23439674 TI - Evidence based practice of chronic pain. AB - The patients with chronic pain are increasingly reporting to the physicians for its management. Chronic pain are associated with head, neck and shoulder pain, spinal pain, pain in the joints and extremities, complex regional pain syndrome and phantom pain. The chronic pain is being managed worldwide. The different specialty of medicine is producing a lot of evidence through the published literature but the same is not being published in the field of chronic pain management. Though some evidence is being reported as to different aspects of pain management from different parts of the world but same is lacking from Indian subcontinent. This is in contrast to much done clinical work in this field as well. We present here the available evidence in relation to chronic pain management. PMID- 23439675 TI - Positional torticollis while lying on side. AB - BACKGROUND: Spasmodic torticollis refers to involuntary dystonic movements of the head that may be associated with certain body and neck positions. The pathophysiology of dystonia is not fully known. CASE REPORT: We report a case of torticollis that was unusual in the sense that it occurred only when the patient was lying on one side. DISCUSSION: The cause of the cervical dystonia in this patient was unclear and the positional nature of the movements was unusual. PMID- 23439676 TI - Increasing prevalence of type 2 diabetes in a rural bangladeshi population: a population based study for 10 years. AB - BACKGROUND: To observe changes in the prevalence of type 2 diabetes mellitus (DM) and impaired fasting glucose (IFG) and its associated risk factors in a rural Bangladeshi population over a 10-year period. METHODS: Three cross-sectional studies were undertaken in a rural community (aged >=20 years) in 1999, 2004, and 2009. Structured questionnaires including sociodemographic parameters, anthropometric measurements, blood pressure, and blood glucose values were recorded. DM and IFG were diagnosed using 1999 World Health Organization criteria. RESULTS: Age standardized prevalence of DM increased significantly (P<0.001) from 1999 to 2009 (2.3%, 6.8%, and 7.9% in 1999, 2004, and 2009, respectively). The prevalence of IFG increased significantly (P=0.011) from 4.6% to 5.8% between 1999 and 2004 but then decreased from 5.8% to 5.3% during 2004 to 2009. Significant linear trends were shown in both sexes for general and central obesity as indicated by body mass index, waist circumference, and waist hip ratio (WHR). Increasing age and systolic blood pressure were significant risk factors for DM in all three studies. WHR for males was also significantly associated with the risk of DM in all three studies. WHR for females was only significantly associated with DM in 2009. CONCLUSION: A significant rise in the prevalence of DM was observed in this population over 10 years. This increase was seen in both sexes, and in all age groups. A significant increase in the prevalence of the associated risk factors of general and central obesity was observed in both sexes. PMID- 23439677 TI - Burr Hole Drainage : Could Be Another Treatment Option for Cerebrospinal Fluid Leakage after Unidentified Dural Tear during Spinal Surgery? AB - Authors report a rare case of acute intracranial subdural and intraventricular hemorrhage that were caused by intracranial hypotension resulted from cerebrospinal fluid leakage through an unidentified dural tear site during spinal surgery. The initial brain computed tomography image showed acute hemorrhages combined with preexisting asymptomatic chronic subdural hemorrhage. One burr hole was made over the right parietal skull to drain intracranial hemorrhages and subsequent drainage of cerebrospinal fluid induced by closure of the durotomy site. Among various methods to treat cerebrospinal fluid leakage through unidentified dural injury site, primary repair and spinal subarachnoid drainage are well known treatment options. The brain imaging study to diagnose intracranial hemorrhage should be taken before selecting the treatment method, especially for spinal subarachnoid drainage. Similar mechanism to its spinal counterpart, cranial cerebrospinal fluid drainage has not been mentioned in previous article and could be another treatment option to seal off an unidentified dural tear in particular case of drainage of intracranial hemorrhage is needed. PMID- 23439678 TI - The Use of Hypothermia Therapy in Traumatic Ischemic / Reperfusional Brain Injury: Review of the Literatures. AB - Therapeutic mild hypothermia has been used widely in brain injury. It has evaluated in numerous clinical trials, and there is strong evidence for the use of hypothermia in treating patients with several types of ischemic / reperfusional (I/R) injuries, examples being cardiac arrest and neonatal hypoxic ischemic encephalopathy.In spite of many basic research projects demonstrating effectiveness, therapeutic hypothermia has not been proven effective for the heterogeneous group of traumatic brain injury patients in multicenter clinical trials. In the latest clinical trial, however, researchers were able to demonstrate the significant beneficial effects of hypothermia in one specific group; patients with mass evacuated lesions. This suggested that mild therapeutic hypothermia might be effective for I/R related traumatic brain injury.In this article we have reviewed much of the previous literature concerning the mechanisms of I/R injury to the protective effects of mild therapeutic hypothermia. PMID- 23439679 TI - Both endonucleolytic and exonucleolytic cleavage mediate ITS1 removal during human ribosomal RNA processing. AB - Human ribosome production is up-regulated during tumorogenesis and is defective in many genetic diseases (ribosomopathies). We have undertaken a detailed analysis of human precursor ribosomal RNA (pre-rRNA) processing because surprisingly little is known about this important pathway. Processing in internal transcribed spacer 1 (ITS1) is a key step that separates the rRNA components of the large and small ribosomal subunits. We report that this was initiated by endonuclease cleavage, which required large subunit biogenesis factors. This was followed by 3' to 5' exonucleolytic processing by RRP6 and the exosome, an enzyme complex not previously linked to ITS1 removal. In contrast, RNA interference mediated knockdown of the endoribonuclease MRP did not result in a clear defect in ITS1 processing. Despite the apparently high evolutionary conservation of the pre-rRNA processing pathway and ribosome synthesis factors, each of these features of human ITS1 processing is distinct from those in budding yeast. These results also provide significant insight into the links between ribosomopathies and ribosome production in human cells. PMID- 23439680 TI - The WD40 protein Morg1 facilitates Par6-aPKC binding to Crb3 for apical identity in epithelial cells. AB - Formation of apico-basal polarity in epithelial cells is crucial for both morphogenesis (e.g., cyst formation) and function (e.g., tight junction development). Atypical protein kinase C (aPKC), complexed with Par6, is considered to translocate to the apical membrane and function in epithelial cell polarization. However, the mechanism for translocation of the Par6-aPKC complex has remained largely unknown. Here, we show that the WD40 protein Morg1 (mitogen activated protein kinase organizer 1) directly binds to Par6 and thus facilitates apical targeting of Par6-aPKC in Madin-Darby canine kidney epithelial cells. Morg1 also interacts with the apical transmembrane protein Crumbs3 to promote Par6-aPKC binding to Crumbs3, which is reinforced with the apically localized small GTPase Cdc42. Depletion of Morg1 disrupted both tight junction development in monolayer culture and cyst formation in three-dimensional culture; apico-basal polarity was notably restored by forced targeting of aPKC to the apical surface. Thus, Par6-aPKC recruitment to the premature apical membrane appears to be required for definition of apical identity of epithelial cells. PMID- 23439681 TI - Arp2/3 complex ATP hydrolysis promotes lamellipodial actin network disassembly but is dispensable for assembly. AB - We examined the role of ATP hydrolysis by the Arp2/3 complex in building the leading edge of a cell by studying the effects of hydrolysis defects on the behavior of the complex in the lamellipodial actin network of Drosophila S2 cells and in a reconstituted, in vitro, actin-based motility system. In S2 cells, nonhydrolyzing Arp2 and Arp3 subunits expanded and delayed disassembly of lamellipodial actin networks and the effect of mutant subunits was additive. Arp2 and Arp3 ATP hydrolysis mutants remained in lamellipodial networks longer and traveled greater distances from the plasma membrane, even in networks still containing wild-type Arp2/3 complex. In vitro, wild-type and ATP hydrolysis mutant Arp2/3 complexes each nucleated actin and built similar dendritic networks. However, networks constructed with Arp2/3 hydrolysis-defective mutants were more resistant to disassembly by cofilin. Our results indicate that ATP hydrolysis on both Arp2 and Arp3 contributes to dissociation of the complex from the actin network but is not strictly necessary for lamellipodial network disassembly. PMID- 23439682 TI - Sequential actin-based pushing forces drive meiosis I chromosome migration and symmetry breaking in oocytes. AB - Polar body extrusion during oocyte maturation is critically dependent on asymmetric positioning of the meiotic spindle, which is established through migration of the meiosis I (MI) spindle/chromosomes from the oocyte interior to a subcortical location. In this study, we show that MI chromosome migration is biphasic and driven by consecutive actin-based pushing forces regulated by two actin nucleators, Fmn2, a formin family protein, and the Arp2/3 complex. Fmn2 was recruited to endoplasmic reticulum structures surrounding the MI spindle, where it nucleated actin filaments to initiate an initially slow and poorly directed motion of the spindle away from the cell center. A fast and highly directed second migration phase was driven by actin-mediated cytoplasmic streaming and occurred as the chromosomes reach a sufficient proximity to the cortex to activate the Arp2/3 complex. We propose that decisive symmetry breaking in mouse oocytes results from Fmn2-mediated perturbation of spindle position and the positive feedback loop between chromosome signal-induced Arp2/3 activation and Arp2/3-orchestrated cytoplasmic streaming that transports the chromosomes. PMID- 23439684 TI - Statistical challenges in systematic evidence generation through analysis of observational healthcare data networks. AB - Observational healthcare databases offer significant potential for generating evidence about the effects of medical products. Recent US and international efforts attempt to coordinate analysis activities across observational data networks for active drug safety surveillance and comparative effectiveness research. Several statistical challenges exist that require further research to inform the appropriate use of observational data for identifying and evaluating temporal relationships between medical product exposures and outcomes. This review highlights current work across the areas of data quality, methods development, and performance evaluation that promise to contribute to our understanding of best practices for observational analyses moving forward. PMID- 23439683 TI - Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. AB - The nuclear lamina consists of A- and B-type lamins. Mutations in LMNA cause many human diseases, including progeria, a premature aging syndrome, whereas LMNB1 duplication causes adult-onset autosomal dominant leukodystrophy (ADLD). LMNB1 is reduced in cells from progeria patients, but the significance of this reduction is unclear. In this paper, we show that LMNB1 protein levels decline in senescent human dermal fibroblasts and keratinocytes, mediated by reduced transcription and inhibition of LMNB1 messenger ribonucleic acid (RNA) translation by miRNA-23a. This reduction is also observed in chronologically aged human skin tissue. To determine whether altered LMNB1 levels cause senescence, we either increased or reduced LMNB1. Both LMNB1 depletion and overexpression inhibited proliferation, but only LMNB1 overexpression induced senescence, which was prevented by telomerase expression or inactivation of p53. This phenotype was exacerbated by a simultaneous reduction of LMNA/C. Our results demonstrate that altering LMNB1 levels inhibits proliferation and are relevant to understanding the molecular pathology of ADLD. PMID- 23439685 TI - Orthostatic tremor responds to bilateral thalamic deep brain stimulation. AB - BACKGROUND: Orthostatic tremor (OT) is a disabling movement disorder manifested by postural and gait disturbance. Primarily a condition of elderly people, it can be progressive in up to 15% of patients. The primary treatments are medications that are often ineffective. CASE REPORT: A 75-year-old male presented with a 10 year history of progressive and disabling OT. He had tried various medications without significant benefits. He underwent bilateral thalamic Vim deep brain stimulation (DBS). At 30-month follow-up, he has had continued significant improvement of his OT. DISCUSSION: Bilateral thalamic DBS may be a viable option for medically refractory OT. PMID- 23439686 TI - Is high-resolution ultrasonography suitable for the detection of temporomandibular joint involvement in children with juvenile idiopathic arthritis? AB - OBJECTIVES: The purpose of this study was to determine the potential of high resolution ultrasonography for the detection of temporomandibular joint (TMJ) changes in children with juvenile idiopathic arthritis (JIA). METHODS: We investigated prospectively 20 children (17 female and 3 male; mean age 11.06 years, standard deviation 3.43 years) with TMJ disorders caused by JIA, over a period of 16 months. Using a 12 MHz array transducer, four images in each TMJ (160 images) were acquired. Each image was analysed with regard to five different aspects (condylar erosion, thickness of the condylar disc, synovial thickness, joint effusion and enlargement of the intra-articular space). RESULTS: Diagnosis of JIA was ensured for every child and involvement of the TMJ was proven by MRI. Overall 287 changes (35.9%) were detected by using high-resolution ultrasonography. On 124 images (77.5%) condylar erosions were diagnosed; on 55 images (34.4%) synovial thickness was abnormal; on 48 images (30%) we could see higher thickness of the condylar disc; on 40 images (25%) irregularities of the bony surface were detected; and on 20 images (12.5%) we found joint effusion. CONCLUSION: High-resolution ultrasonography could be a sufficient diagnostic method, especially for the detection of condylar involvement in children with JIA, even if not all parts of the TMJ are visible for ultrasonography. High resolution ultrasonography is a valuable tool in particular situations: (i) when MRI examination is not available; (ii) when children fear MRI examination; (iii) in more advanced stages of JIA; and (iv) for monitoring the progression of TMJ involvement and response of therapy. PMID- 23439687 TI - A questionnaire study to investigate custom and practice of imaging methods for the anterior region of the mandible prior to dental implant placement. AB - OBJECTIVES: To investigate the custom and practice of private dental implant practitioners in the north-west of England when planning imaging methods prior to implant placement in the symphyseal region of the edentulous mandible. To gain an understanding of decision-making when prescribing imaging methods. METHODS: A web based questionnaire presented two realistic clinical scenarios. Both were of edentulous patients for whom implant-retained lower complete dentures were planned. A mixed mode survey methodology was employed. RESULTS: 169 dentists were surveyed with an 80% response rate. The results showed no agreement on prescription of imaging methods. Those in the 0-10 years qualified group were significantly associated with the prescription of three-dimensional (3D) imaging. Implant practitioners who place more than 100 implants per year were significantly associated with the non-use of imaging guides and prescription of the same view for both cases. The sample as a whole, however, changed their prescription according to the case difficulty. Those who have a cone beam CT machine available were more likely to use 3D imaging regardless of the difficulty of the case. CONCLUSIONS: Existing guidelines are open to interpretation and could be construed to support a range of imaging choices. Training in dental implantology may leave dentists to make their own judgements about selection criteria. The idiosyncratic nature of independent dental practice may be an important factor in the chaotic pattern of prescriptions. There is a need for widely disseminated, evidence-based selection criteria for imaging prior to dental implantology which are clear and specific. PMID- 23439688 TI - Analysing penal innovation. PMID- 23439690 TI - Endovascular treatment of descending thoracic aneurysms. AB - INTRODUCTION: Current strategies for repair of descending thoracic aortic aneurysms consist of open repair with surgical graft replacement or thoracic endovascular aortic repair. We review and update our overall experience in aortic thoracic diseases and specifically analyzed our outcomes with thoracic endovascular aortic repair in patients with descending thoracic aortic aneurysms. METHODS: From 1993 to present a total of 1144 patients were treated in our Center for pathology involving the thoracic aorta. Since 1998, 322 patients underwent thoracic endovascular aortic repair, and among this group, in 188 cases the descending aorta was involved. In 74% of patients treated for a descending thoracic aortic lesion, a degenerative aneurysm was observed. RESULTS: In patients with descending thoracic aortic aneurysms receiving thoracic endovascular aortic repair, our technical success rate, i.e. deployment of endograft with complete exclusion of the lesion/minimal endoleak, was 99.5% (one case required emergent open conversion) with a perioperative mortality of 2.6% (five patients). The rate of spinal cord ischemia, manifesting either as paraplegia or paraparesis, was 4.7%. Delayed onset spinal cord ischemia ameliorated with adequate arterial pressure and cerebrospinal fluid drainage. CONCLUSIONS: Our experience of selected patients undergoing thoracic endovascular aortic repair of descending thoracic aorta aneurysms is satisfactory with very low mortality and morbidity. A large use of thoracic endovascular aortic repair is foreseen in the next future. PMID- 23439689 TI - Early life influences on the development of chronic obstructive pulmonary disease. AB - There is increasing evidence that chronic obstructive pulmonary disease (COPD) is not simply a disease of old age that is largely restricted to heavy smokers, but may be associated with insults to the developing lung during foetal life and the first few years of postnatal life, when lung growth and development are rapid. A better understanding of the long-term effects of early life factors, such as intrauterine growth restriction, prenatal and postnatal exposure to tobacco smoke and other pollutants, preterm delivery and childhood respiratory illnesses, on the subsequent development of chronic respiratory disease is imperative if appropriate preventive and management strategies to reduce the burden of COPD are to be developed. The extent to which insults to the developing lung are associated with increased risk of COPD in later life depends on the underlying cause, timing and severity of such derangements. Suboptimal conditions in utero result in aberrations of lung development such that affected individuals are born with reduced lung function, which tends to remain diminished throughout life, thereby increasing the risk both of wheezing disorders during childhood and subsequent COPD in genetically susceptible individuals. If the current trend towards the ever-increasing incidence of COPD is to be reversed, it is essential to minimize risks to the developing lung by improvements in antenatal and neonatal care, and to reduce prenatal and postnatal exposures to environmental pollutants, including passive tobacco smoke. Furthermore, adult physicians need to recognize that lung disease is potentially associated with early life insults and provide better education regarding diet, exercise and avoidance of smoking to preserve precious reserves of lung function in susceptible adults. This review focuses on factors that adversely influence lung development in utero and during the first 5 years of life, thereby predisposing to subsequent COPD. PMID- 23439693 TI - Study of mitral valve in human cadaveric hearts. AB - OBJECTIVES: The mitral valve is a complex structure that is altered by disease states. The classical image of the mitral valve is a bicuspid valve with two leaflets and two papillary muscles. The reason for the present study is to study the morphology and morphometry of the mitral valve. MATERIALS AND METHODS: This study was carried out on 116 human cadaveric hearts. Hearts were opened along the left border through the atrioventricular valve. The diameter and circumference of the annulus was measured and the number of valve leaflets was observed. RESULTS: The mean annular diameter was 2.22 cm. The mean circumference of mitral valve annulus was 9.12 cm. The standard description of the mitral valve is bicuspid. In the present study, we found the number of cusps to be variable, from monocuspid to hexacuspid and classified them accordingly. CONCLUSIONS: The mitral valve is not always a bicuspid valve. The number of cusps varies greatly. An increase in the number of the cusp and their improper approximation most likely causes various valvular disorders. PMID- 23439691 TI - Radioiodination of an endotoxin.MD-2 complex generates a novel sensitive, high affinity ligand for TLR4. AB - A purified complex of metabolically labeled [(3)H]lipooligosaccharide (LOS) and recombinant human myeloid differentiation factor 2 (MD-2), [(3)H]LOS.MD-2, has been used to demonstrate pM affinity binding interactions with soluble TLR4 ectodomain (TLR4ecd). For measurement of the binding parameters of membrane-bound TLR4, we took advantage of the stability of endotoxin.MD-2 and tyrosine(s) present on the surface of MD-2 to radioiodinate LOS.MD-2. Radioiodinated LOS.MD-2 generated a reagent with an estimated 1:1 molar ratio of [(125)I] to sMD-2 with 20-fold higher specific radioactivity and TLR4-activating properties comparable to metabolically-labeled LOS.MD-2. LOS.MD-2[(125)I] and [(3)H]LOS.MD-2 have similar affinities for soluble (FLAG) TLR4ecd and for membrane-bound TLR4 in HEK293T/TLR4 cells. In a similar dose-dependent manner, sMD-2 and LOS.MD-2 inhibit LOS.MD-2[(125)I] binding to TLR4 indicating the pM affinity binding of LOS.MD-2[(125)I] is agonist-independent. LOS.MD-2[(125)I] allowed measurement of low levels of cell-surface human or murine TLR4 expressed by stable cell lines (2000-3000 sites/cell) and quantitatively measures low levels of 'MD-2-free' TLR4 (est. 250 molecules/cell) in cells co-expressing TLR4 and MD-2. Occupation of 50 100 TLR4/cell by LOS.MD-2 is sufficient to trigger measurable TLR4-dependent cell activation. LOS.MD-2[(125)I] provides a powerful reagent to measure quantitatively functional human and murine cell-surface TLR4, including in cells where surface TLR4 is potentially functionally significant but not detectable by other methods. PMID- 23439692 TI - Challenges and success of recruiting and retention for a culturally tailored diabetes prevention program for adults of Mexican descent. AB - PURPOSE: The purpose of this article is to describe methods used to recruit and retain high-risk, Spanish-speaking adults of Mexican origin in a randomized clinical trial that adapts Diabetes Prevention Program (DPP) content into a community-based, culturally tailored intervention. METHODS: Multiple passive and active recruitment strategies were analyzed for effectiveness in reaching the recruitment goal. Of 91 potential participants assessed for eligibility, 58 participated in the study, with 38 in the intervention and 20 in the attention control group. The American diabetes association risk assessment questionnaire, body mass index, and casual capillary blood glucose measures were used to determine eligibility. RESULTS: The recruitment goal of 50 individuals was met. Healthy living diabetes prevention presentations conducted at churches were the most successful recruiting strategy. The retention goal of 20 individuals was met for the intervention group. Weekly reminder calls were made by the promotora to each intervention participant, and homework assignments were successful in facilitating participant engagement. CONCLUSIONS: A community advisory board made significant and crucial contributions to the recruitment strategies and refinement of the intervention. RESULTS: support the feasibility of adapting the DPP into a community-based intervention for reaching adults of Mexican origin at high risk for developing diabetes. PMID- 23439694 TI - The transaortic approach for transcatheter aortic valve implantation: a valid alternative to the transapical access in patients with no peripheral vascular option. A single center experience. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) in patients with poor peripheral vessels still remains problematic, as the transapical approach is not always feasible and is sometimes associated with myocardial damage, bleeding, post-procedural chest pain and pleural effusion. In order to address these issues, we adopted the recently introduced transaortic (TAo) approach. The purpose of this study was to evaluate the efficacy and safety of the TAo-TAVI approach using both the Sapien XT and the CoreValve according to VARC criteria. METHODS: Of 492 patients (October 2006 to February 2012), TAo-TAVI was performed in 94 consecutive patients with unfavourable peripheral access between January 2011 and February 2012. Aortic root condition, valve anatomy and annulus size were carefully assessed by multidetector computed tomography (MDCT) for possible TAo-TAVI. The aorta was exposed through an inverted 'T' manubriotomy. After retrograde guidewire crossing of the aortic valve, sheath insertion allowed device positioning and deployment subsequent to balloon valvuloplasty. RESULTS: Mean age was 84.1 +/- 5.4 years (67-96) and logistic EuroSCORE 17.6 +/- 10.2%. The Sapien XT was used in 88.3% and the CoreValve in 11.7% of patients. Full sternotomy allowed concomitant complete off-pump revascularization (2-4 grafts) in 11 patients. Device success rate was 92.6%. Paravalvular leak >=2/4 was observed in 7.4%. Conversion to open chest surgery was required in 5.3% (3 aortic dissections, 1 valve migration and 1 left main occlusion). Three cerebrovascular accidents (2 transient ischaemia and 1 delayed stroke) were noted. Transfusion >=4 units was performed in 12 patients (12.8%). Intensive care unit (ICU) and total hospital stay were 4.9 +/- 5.0 and 12.2 +/- 6.2 days, respectively. Thirty day mortality and combined safety endpoint were reported in 7.4 and 16.0%, respectively. CONCLUSIONS: The TAo approach for both Sapien XT and CoreValve implantation can be used with satisfactory clinical outcome and an acceptable risk. This access route could prove a valid alternative to the transapical approach. PMID- 23439695 TI - Editorial comment: Selective sinus repair in acute type A dissection. PMID- 23439696 TI - Benzopyrene serum concentration after endovenous laser ablation of the great saphenous vein. AB - BACKGROUND: During endovenous laser ablation (EVLA) of the great saphenous vein, patients often involuntarily mention an uncomfortable "burnt" smell and taste. When applying intense heat to proteins and carbohydrates, it is inevitable that polycyclic aromatic hydrocarbons (PAHs) are formed. This group of PAH includes the human carcinogen benzo[a]pyrene (B[a]P). This study determined the serum concentration of B[a]P just before and after EVLA. METHODS: A total of 20 patients were included. The B[a]P serum concentration was determined just before and directly after EVLA. RESULTS: In 18 patients, B[a]P was determined before and after EVLA. In 2 patients, EVLA was not possible. In this study, no elevated serum concentration of B[a]P was found before and after EVLA. CONCLUSION: It remains to be established which heat products cause the burnt smell and taste sensation in patients during EVLA. Further research is needed to determine whether EVLA can be considered as a safe procedure. PMID- 23439697 TI - Percutaneous aortic valve implantation: the anesthesiologist perspective. AB - Percutaneous aortic valve implantation is an emergent technique alternative to surgical aortic valve replacement in high risk patients with aortic stenosis. Percutaneous aortic valve implantation techniques are undergoing rapid development and currently represent a dynamic field of research. Perioperative optimal strategies keep on evolving too. At a review of the literature, only three previous papers on Pubmed focused specifically on anesthesiological challenges of percutaneous aortic valve implantation. In one of them our first 6 months experience was reported. In this new paper we describe the anesthesiological management of percutaneous aortic valve implantation at our Centre, reporting the results of our implantation program from November 2007 to February 2009. PMID- 23439699 TI - Sudden cardiac arrest in a marathon runner. A case report. AB - Sudden cardiac death is a rare condition resulting from undetected cardiac abnormalities in athletes and non-athletes. Participant screening, immediate and advanced medical management can probably reduce mortality and ameliorate outcomes. In recent years, extracorporeal membrane oxygenation has emerged as a valuable therapeutic option in patients experiencing refractory cardiac arrest as a bridge to different types of outcome, including recovery, heart transplantation or ventricular assist device and organ donations. In this report we describe a case of a sudden cardiac arrest in a marathon runner treated with extracorporeal membrane oxygenation. PMID- 23439698 TI - Gonadal- and sex-chromosome-dependent sex differences in the circadian system. AB - Compelling reasons to study the role of sex in the circadian system include the higher rates of sleep disorders in women than in men and evidence that sex steroids modulate circadian control of locomotor activity. To address the issue of sex differences in the circadian system, we examined daily and circadian rhythms in wheel-running activity, electrical activity within the suprachiasmatic nucleus, and PER2::LUC-driven bioluminescence of gonadally-intact adult male and female C57BL/6J mice. We observed greater precision of activity onset in 12-hour light, 12-hour dark cycle for male mice, longer activity duration in 24 hours of constant darkness for female mice, and phase-delayed PER2::LUC bioluminescence rhythm in female pituitary and liver. Next, in order to investigate whether sex differences in behavior are sex chromosome or gonadal sex dependent, we used the 4 core genotypes (FCG) mouse model, in which sex chromosome complement is independent of gonadal phenotype. Gonadal males had more androgen receptor expression in the suprachiasmatic nucleus and behaviorally reduced photic phase shift response compared with gonadal female FCG mice. Removal of circulating gonadal hormones in adults, to test activational vs organizational effects of sex revealed that XX animals have longer activity duration than XY animals regardless of gonadal phenotype. Additionally, we observed that the activational effects of gonadal hormones were more important for regulating activity levels in gonadal male mice than in gonadal female FCG mice. Taken together, sex differences in the circadian rhythms of activity, neuronal physiology, and gene expression were subtle but provide important clues for understanding the pathophysiology of the circadian system. PMID- 23439700 TI - Juan Valverde de Hamusco's unauthorized reproduction of a brain dissection by Andreas Vesalius. AB - OBJECTIVE: The objective of the present work is to examine images of the brain dissection by Flemish-born anatomist Andreas Vesalius (1514-1564) as originally represented in the Fabrica (1543), and later copied without Vesalius' permission by Spanish anatomist Juan Valverde de Hamusco (c1525-c1587) in Historia de la composicion del cuerpo humano (1556). METHODS: Illustrations of the brain dissection in the Fabrica were obtained in digital form, resized, and arranged in a comparable montage to that presented by Valverde. Computer manipulations were used to assess image correspondence. RESULTS: The Valverde illustrations are approximately half the size and are mirror images of those in the Fabrica, but otherwise show the same dissection stages, and identical transverse brain levels and structures. The Valverde illustrations lack shadowing and show minor variations in perspective and fine details (e.g., branching pattern of the middle meningeal artery) from those in the Fabrica. CONCLUSION: Craftsmen under the direction of Valverde copied the woodcut prints in the Fabrica in close but approximate form by freehand engraving onto copper plates. Differences in the sizes of the images, and in perspective and fine detail, preclude direct tracing of images as the means of copying. Because engravings are in effect "flipped over" to make further prints, subsequent prints made from Valverde's copperplate engravings are mirror images of the prints in Vesalius' Fabrica. PMID- 23439702 TI - Isolated ocular flutter. PMID- 23439701 TI - Diffusion tensor imaging in parkinsonian syndromes: a systematic review and meta analysis. AB - OBJECTIVES: We performed a systematic review to assess alterations in measures of diffusion tensor imaging (DTI) in parkinsonian syndromes, exploring the potential role of DTI in diagnosis and as a candidate biomarker. METHODS: We searched EMBASE and Medline databases for DTI studies comparing parkinsonian syndromes or related dementias with controls or another defined parkinsonian syndrome. Key details for each study regarding participants, imaging methods, and results were extracted. Estimates were pooled, where appropriate, by random-effects meta analysis. RESULTS: Of 333 results, we identified 43 studies suitable for inclusion (958 patients, 764 controls). DTI measures detected alterations in all parkinsonian syndromes, with distribution varying differentially with disease type. Nine studies were included in a meta-analysis of the substantia nigra in Parkinson disease. A notable effect size was found for lowered fractional anisotropy in the substantia nigra for patients with Parkinson disease vs controls (-0.639, 95% confidence interval -0.860 to -0.417, p < 0.0001). CONCLUSION: DTI may be a promising biomarker in parkinsonian syndromes and have a future role in differential diagnosis. Larger cohort studies are required to investigate some encouraging preliminary findings. Given the complexity of the parkinsonian syndromes, it is likely that any potential DTI biomarker would be used in combination with other relevant biomarkers. PMID- 23439703 TI - Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. PMID- 23439704 TI - Trick or treat? Showing patients with functional (psychogenic) motor symptoms their physical signs. PMID- 23439705 TI - Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards subcommittee of the American Academy of Neurology and the American Headache Society. AB - Peer Carsten Tfelt-Hansen, Glostrup, Denmark: According to the recent American Academy of Neurology (AAN) guideline update, a drug can be recommended as possibly effective for migraine prevention if it had demonstrated efficacy in one Class II study.(1) Eight drugs are recommended as possibly effective,(1) and there are several drugs for which I would question the evidence. Due to space limitations, I have chosen just one example. PMID- 23439706 TI - Clinical reasoning: a 56-year-old man with progressive spasticity. PMID- 23439707 TI - Pearls and oy-sters: small but consequential: intracerebral hemorrhage caused by lenticulostriate artery aneurysm. PMID- 23439709 TI - Teaching NeuroImages: lipoid proteinosis (Urbach-Wiethe disease): typical findings in this rare genodermatosis. PMID- 23439708 TI - Teaching NeuroImages: Wernicke encephalopathy: diagnostically deceptive but treatable. PMID- 23439710 TI - Teaching NeuroImages: gelsolin-related amyloidosis: a rare cause of progressive facial diparesis. PMID- 23439711 TI - Trigeminal nerve stimulator: a new treatment for seizures? PMID- 23439712 TI - A comparative review of canine and human rhabdomyosarcoma with emphasis on classification and pathogenesis. AB - Rhabdomyosarcomas are a diverse group of malignant mesenchymal neoplasms exhibiting variable levels of differentiation toward skeletal myocytes. Neoplastic cells may resemble relatively undifferentiated myoblasts, satellite cells, or more differentiated elongated spindle cells and multicellular myotubes. In veterinary medicine, classification into subtypes and variants is based on an outdated system derived from human pathology and is solely based on histologic characteristics. In contrast, classification of human rhabdomyosarcoma is based on histologic, immunohistochemical, and molecular diagnostic techniques, and subclassification has clinical and prognostic relevance. Relevance of tumor subtyping has not been established in veterinary medicine. Recent discoveries of components of the molecular pathogenesis and genomes of human rhabdomyosarcomas have led to new diagnostic techniques and revisions of the human classification system. The current classification system in veterinary medicine is reviewed in light of these changes. Diagnosis of rhabdomyosarcoma using histopathology, electron microscopy, and the clinical aspects of human and canine rhabdomyosarcomas is compared. The clinical features and biologic behavior of canine rhabdomyosarcomas are compared with canine soft tissue sarcomas. PMID- 23439713 TI - Challenges in diagnosing a metabolic disorder: error of pyruvate metabolism or drug induced? AB - Certain drugs are known to cause metabolic changes resulting in altered metabolic profiles. We report here a case where a combination of antiepileptic drugs resulted in a profile that mimicked a metabolic disorder. A 16month-old female child on antiepileptic drugs (valproate and topiramate) was suspected to have the inherited metabolic disorder, dihydrolipoamide dehydrogenase deficiency, based on clinical symptoms and metabolic profile showing hyperalaninemia, elevated branched-chain amino acids, and lactate-pyruvate ratio. Suspecting that the observed metabolic changes could have also arised from medication, current medication was weaned off and replaced with levetiracetam, clonazepam, and levocarnitine (supportive therapy). Metabolic profiling conducted after 47 days showed normal alanine, branched-chain amino acids, ornithine, and lactate pyruvate ratio, suggesting that the earlier abnormalities could have been medication induced. We stress that metabolic changes resulting from chronic medication should be considered while interpreting a positive result when investigating an inherited metabolic disorder. PMID- 23439714 TI - Pilocytic astrocytoma: a disease with evolving molecular heterogeneity. AB - Pilocytic astrocytoma, the most common pediatric brain tumor, is a clinically and molecularly heterogeneous disease that occurs most often in the cerebellum and hypothalamic and chiasmatic regions. Classically, pilocytic astrocytomas are driven by the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Recently described genetic aberrations involving this pathway are critical for tumorigenesis. Tandem duplication of 7q34 encodes BRAF and produces several KIAA1549-BRAF novel oncogenic fusions. Activating point mutations of BRAF, such as BRAF (V600E), also lead to pilocytic astrocytoma. Loss of the NF1 gene allows hyperactivation of the oncogene KRAS. In this review, we discuss the current understanding of the novel molecular aberrations described in pilocytic astrocytomas and their clinical relevance for prognosis and treatment. The prognostic indications of these aberrations are discussed with regard to tumor location, tumor pathology, and patient age. A better understanding of the evolving molecular heterogeneity of pilocytic astrocytomas offers hope for developing molecularly targeted therapeutic armamentariums. PMID- 23439715 TI - Bilateral periventricular nodular heterotopia with megalencephaly: a case report. AB - Bilateral periventricular nodular heterotopia is a neuronal migration disorder characterized by gray matter cellular rests in the periventricular regions. Megalencephaly has not been reported in children with bilateral periventricular nodular heterotopia. No other disorder with a similar phenotype has been reported. Here we report the case of a 5-year-old Japanese boy with bilateral periventricular nodular heterotopia and megalencephaly. Relative macrocephaly was evident at birth, and bilateral periventricular nodular heterotopia and megalencephaly were noted on magnetic resonance imaging (MRI). However, no hydrocephalus or indication of cerebral cortical dysplasia was seen. A mild intellectual disability was present, but the patient had no history of seizures. Genetic analysis revealed no mutation on the capillary sequences for FLNA, and no pathogenic abnormalities were evident on array comparative genomic hybridization. This case could represent a new disease entity: bilateral periventricular nodular heterotopia with megalencephaly. PMID- 23439716 TI - Pattern and determinants of antenatal booking at abakaliki southeast Nigeria. AB - BACKGROUND: Antenatal care is one of the pillars of SAFE Motherhood Initiative aimed at preventing adverse pregnancy outcome. Early antenatal booking is recommended for this benefit. AIM: The objective of this study was to determine the antenatal booking pattern of pregnant women and its determinants. SUBJECTS AND METHODS: A cross-sectional survey of pregnant women attending the antenatal booking clinic at Federal Medical Centre Abakaliki Ebonyi State between April 6, 2011 to August 5, 2011 was undertaken. Epi info 2008 version was used for analysis. RESULTS: The mean age of the respondents was 27.46 (5.81) years and the mean gestational age at booking was 24.33 (5.52) weeks. A total of 83.1% (286/344) of the pregnant women booked after the first trimester while the remaining 16.9% (56/344) booked early. Socio-biological variables and past obstetrics history did not contribute significantly to the gestational age at booking while sickness in index pregnancy, personal wishes, and financial constraint were statistically significant reasons given for seeking antenatal care. Majority of the pregnant women 37.2% (128/344) suggested that the second trimester was the ideal gestational age for booking while 18.3% (63/344) did not know the ideal gestational age for booking. Most pregnant women 81.1% (279/344) knew the benefits of early antenatal care even though they booked late 83.1% (286/344). CONCLUSION: Most pregnant women access antenatal care late at Abakaliki because of misconception and poverty. Health education and subsidization of cost of medical services will help in reversing the trend of late antenatal booking. PMID- 23439717 TI - Analgesia for thoracic surgery: the role of paravertebral block. AB - An appropriate post operative analgesia after thoracotomies is mandatory to improve the patient's outcome, reduce complications rate, morbidity, hospital cost and length of stay. In this paper we review the evidences regarding the use of paravertebral block for thoracic surgery. In particular we examine the effect of paravertebral block compared to the other technique in four major issues: analgesia, complications rate, postoperative pulmonary function and transition from acute to chronic pain. We conclude that paravertebral block is superior to intravenous analgesia in providing pain control and preserving postoperative pulmonary function while it is equal to thoracic epidural analgesia regarding this two issues. Paravertebral block has a better safety profile when compared to intravenous and thoracic epidural analgesia. Its effect on chronic pain incidence still needs further studies. PMID- 23439718 TI - Regeneration of condyle with a functional appliance. AB - Condylar regeneration with the use of functional appliances after condylectomy has been validated. However, the process during treatment remains unclear. In this study, we evaluated the condylar regeneration process and then examined mandibular growth and masticatory muscle activity after regeneration in growing rats. Seventy-five male Wistar rats aged 4 weeks were equally divided into 3 groups: unilateral condylectomy group, unilateral condylectomy + appliance group, or control group. The use of a functional appliance following condylectomy promoted mandibular growth and regeneration of the condyle 1 week after condylectomy. Condyle regeneration showing normal morphology was finally achieved 8 weeks after condylectomy. Asymmetrical masticatory muscle activity was observed after condylectomy. However, the use of a functional appliance produced symmetrical masticatory muscle activity. These results indicate a favorable regeneration process in the condylectomized area due to the use of a functional appliance. In addition, due to condylar regeneration, symmetrical masticatory muscle activity was achieved. PMID- 23439719 TI - Clinical perspectives on human genetic screening to prevent nevirapine toxicity. AB - Nevirapine is one of the most extensively prescribed antiretroviral drugs worldwide. However, a concern is increased risk for severe toxicity when antiretroviral-naive individuals with higher CD4 T-cell counts initiate nevirapine-containing regimens. Several genetic variants are associated with nevirapine toxicities. The authors used data from a previous study to anticipate potential consequences of genetic screening to prevent nevirapine adverse events. That study enrolled cohorts of African, Asian and European descent in 11 countries, including 276 patients who had experienced severe cutaneous and/or hepatic adverse events with nevirapine-containing regimens and 587 matched nevirapine-tolerant controls. Associations were identified with HLA-Cw*04, HLA B*35, HLA-DRB*01 and CYP2B6 516G>T (rs3745274); however, positive predictive values for these genetic markers were low, and most nevirapine-associated adverse events occurred in patients without these markers. Unless better genetic predictors are identified, nevirapine toxicity is best avoided by continuing to follow current prescribing guidelines that are based largely on CD4 T-cell criteria. PMID- 23439720 TI - Reasons for Substance Use: A Comparative Study of Alcohol Use in Tribals and Non tribals. AB - BACKGROUND: Consumption of alcohol has been attributed to different reasons by consumers. Attitude and knowledge about the substance and addiction can be influenced by the cultural background of the individual. The tribal population, where alcohol intake is culturally accepted, can have different beliefs and attributes causing one to take alcohol. This study attempts to examine the reasons for alcohol intake and the belief about addiction and their effect on the severity of addiction in people with a different ethnic background. MATERIALS AND METHODS: The study was conducted at a Psychiatric institute with a cross sectional design. The study population included patients hailing from the Jharkhand state, twenty each, belonging to tribal and non-tribal communities. Patients fulfilling the ICD 10 diagnostic criteria of mental and behavioral disorders due to the alcohol dependence syndrome, with active dependence, were taken, excluding those having any comorbidity or complications. The subjects were assessed with specially designed Sociodemographic-Clinical Performa, modified version of Reasons for Substance Use scale, Addiction Belief scale, and the Alcohol Dependence scale. STATISTICAL ANALYSIS AND RESULTS: A significantly high number of tribals cited reasons associated with social enhancement and coping with distressing emotions rather than individual enhancement, as a reason for consuming alcohol. Addiction was severe in those consuming alcohol to cope with distressing emotions. Belief in the free-will model was noted to be stronger across the cultures, without any correlation with the reason for intake. This cross-sectional study design, which was based on patients, cannot be easily generalized to the community. CONCLUSION: [corrected] Societal acceptance and pressure as well as high emotional problems appears to be the major etiology leading to higher prevalce of substance depedence in tribals. Primary prevention should be planned to fit the needs of the ethnics. PMID- 23439721 TI - Clinical and radiological comparison of femur and fibular allografts for the treatment of cervical degenerative disc diseases. AB - OBJECTIVE: This consecutive retrospective study was designed to analyze and to compare the efficacy and outcomes of anterior cervical discectomy and fusion (ACDF) using a fibular and femur allograft with anterior cervical plating. METHODS: A total of 88 consecutive patients suffering from cervical degenerative disc disease (DDD) who were treated with ACDF from September 2007 to August 2010 were enrolled in this study. Thirty-seven patients (58 segments) underwent anterior interbody fusion with a femur allograft, and 51 patients (64 segments) were treated with a fibular allograft. The mean follow-up period was 16.0 (range, 12-25) months in the femur group and 19.5 (range, 14-39) months in the fibular group. Cage fracture and breakage, subsidence rate, fusion rate, segmental angle and height and disc height were assessed by using radiography. Clinical outcomes were assessed using a visual analog scale and neck disability index. RESULTS: At 12 months postoperatively, cage fracture and breakage had occurred in 3.4% (2/58) and 7.4% (4/58) of the patients in the femur group, respectively, and 21.9% (14/64) and 31.3% (20/64) of the patients in the fibular group, respectively (p<0.05). Subsidence was noted in 43.1% (25/58) of the femur group and in 50.5% (32/64) of the fibular group. No difference in improvements in the clinical outcome between the two groups was observed. CONCLUSION: The femur allograft showed good results in subsidence and radiologic parameters, and sustained the original cage shape more effectively than the fibular allograft. The present study suggests that the femur allograft may be a good choice as a fusion substitute for the treatment of cervical DDD. PMID- 23439722 TI - Visual outcome and impact on quality of life after surgeries differ in children operated for unilateral and bilateral cataract (Pune study 2011). AB - BACKGROUND: We compared vision and quality of life (VQL) of children aged 5-15 years and operated for unilateral and bilateral cataract between 2008 and 2010 in western India. MATERIALS AND METHODS: In this cohort study, ophthalmologists assessed vision, anterior and posterior segment of eyes with cataract. Children completed a functional vision questionnaire (LVP-FVQ). Follow up at 6 months after surgery included the best corrected visual acuity (BCVA), FVQ and eye assessment. The improvement of BCVA and quality of life were compared in group of unilateral and bilateral cataract. RESULT: A total of 20 (70%) bilateral and 7 (39%) unilateral cataract were operated within 1 month of detection. All 48 eyes with bilateral cataract were congenital and 12 (67%) unilateral cataract were traumatic. Among bilateral group, 27 eyes [56.2% (95% confidence interval (CI) 44.4-72.2)] and in unilateral group 11 eyes [61.1% (95% CI 38.6-83.6)] had vision >= 20/60 at 6 months follow up. The visual gain was significantly higher in children who were operated between 1 month and 1 year of detection (adjusted Odds ratio (OR) = 15.6 P = 0.03). Positive impact on VQL in bilateral group was noted in 50%, 27%, and 13% children for subscale of distant vision, near vision, and field of vision, respectively. There was positive impact in these subscales among children with unilateral cataract. Thirty percent eyes with bilateral cataract and 22% of eyes with unilateral cataract improved their vision. Surgery within 1 month of cataract was significant predictor of improved vision (OR = 16.6 P = 0.02). CONCLUSION: Vision and VQL improved in children with unilateral and bilateral cataract. However, it was better 6 months following surgery in children with bilateral cataract than in children with unilateral cataract. PMID- 23439723 TI - New type of left ventricular rupture during redo mitral valve replacement. A case report. AB - We report the case of a 41 years old woman who presented with massive bleeding after redo mitral valve replacement. A Left ventricular rupture, different from the three known types of wall rupture was hardly identified and controlled with extreme difficulty. The patient died eight days postoperatively due to disseminated intravascular coagulopathy. Retrospective analysis of the Echocardiographic examination was highly suggestive of abnormal position of the previously implanted mitral valve bioprosthesis with left ventricular outflow tract obstruction and weakness of the posterior wall of the left ventricular outflow tract. PMID- 23439724 TI - Evaluating the McDonald's business model for HIV prevention among truckers to improve program coverage and service utilization in India, 2004-2010. AB - BACKGROUND: This study describes the experiences and results of a large-scale human immunodeficiency virus (HIV) prevention intervention for long-distance truck drivers operating on the national highways of India. METHODS: The intervention for long-distance truckers started in 2004 across 34 trans-shipment locations. However, due to poor coverage and utilization of services by truckers in the initial 18-month period, the intervention was redesigned to focus on only 17 trans-shipment locations. The redesigned intervention model was based on the McDonald's business franchise model where the focus is on optimal placement of services, supported with branding and standardization of services offered, and a surround sound communication approach. Program output indicators were assessed using program monitoring data over 7 years (2004-2010) and two rounds of cross sectional behavioral surveys conducted in January 2008 (n = 1402) and July 2009 (n = 1407). RESULTS: The number of truckers contacted per month per site increased from 374 in 2004 to 4327 in 2010. Analysis of survey data showed a seven-fold increase in clinic visits in the past 12 months from 2008 to 2009 (21% versus 63%, P < 0.001). A significant increase was also observed in the percentage of truckers who watched street plays (10% to 56%, P < 0.001), and participated in health exhibitions (6% to 35%, P < 0.001). Furthermore, an increase from round 1 to round 2 was observed in the percentage who received condoms (13% to 22%, P < 0.001), and attended one-one counseling (15% to 21%, P < 0.01). Treatment-seeking from program clinics for symptoms related to sexually transmitted infections increased six-fold during this period (16% versus 50%, P < 0.001). CONCLUSION: Adoption of a business model for HIV prevention helped to increase program coverage and service utilization among long-distance truckers. Implementing HIV prevention programs in a highly mobile population such as truckers, in a limited number of high-impact locations, supported by branding of services, could help in saturating coverage and optimum utilization of available resources. PMID- 23439726 TI - Solubility Prediction of Satranidazole in Aqueous N,N-dimethylformamide Mixtures Using Extended Hildebrand Solubility Approach. AB - The solubility of satranidazole in several water-N,N-dimethylformamide mixtures was analysed in terms of solute-solvent interactions and data were treated on the basis of extended Hildebrand solubility approach. The solubility profile of satranidazole in water-N,N-dimethylformamide mixtures shows a curve with a solubility maxima well above the ideal solubility of drug. This is attributed to solvation of the drug with the water-N,N-dimethylformamide mixture, and indicates that the solute-solvent interaction energy (W) is larger than the geometric mean (delta(1)delta(2)) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy (W) is obtained. In this case, the energy term is regressed against a polynomial in delta(1) of the binary solvent mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the mole fraction solubility of satranidazole in the studied mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design. PMID- 23439725 TI - Effects of 6-week whole body vibration training on the reflex response of the ankle muscles: a randomized controlled trial. AB - BACKGROUND: The ligament sprain of the lateral ankle is the most frequent injury that occurs when participating in sports. Whole body vibration (WBV) is a training method that has been recently introduced as a rehabilitative tool for treatment of athletes. It has been hypothesized that the transmission of mechanical oscillations from the vibrating platform may lead to physiological changes in muscle spindles, joint mechanoreceptors, as well as improve balance. PURPOSE: [corrected] The aim of this study was to assess the effects of a 6-week WBV training program on the reflex response mechanism of the peroneus longus (PL), peroneus brevis (PB) and anterior tibialis (AT) muscles in ankle inversion at 30o from horizontal, in a static position. METHODS: This study was a single blinded and randomized controlled trial. Forty-four healthy, physically active participants were randomly split into two groups: the experimental group (n = 26) (the WBV training) and control group (n = 18). Reaction time (RT), maximum electromyographic (EMG) peak (peak EMG), time to the maximum peak EMG (peak EMG time) and reflex electrical activity of all the muscles were assessed before and after the WBV training through surface EMG. RESULTS: After 6-weeks WBV training, there were no significant changes in the variables analysed for all the muscles involved. CONCLUSION: A 6-week WBV training does not improve the reflex response mechanism of the lateral stabilizing muscles of the ankle. LEVEL OF EVIDENCE: 1b. PMID- 23439727 TI - Use of recombinant activated factor VII for bleeding following resection of mediastinal angiosarcoma. AB - Sarcomatous lesions of the mediastinum usually present as aggressive and multicentre masses often attached to adjoining structures including heart and lungs. A forty one year male diagnosed with sarcomatous lesion in mediastinum presented for biopsy through midsternotomy later confirmed as angiosarcoma on histopathology. Patient bled excessively after surgery and required reopening of the chest. However, bleeding could not be controlled with reopening, blood products and packing of the mediastinal cavity. Bleeding could only be controlled by using recombinant activated factor VII as rescue therapy without any adverse effects. PMID- 23439728 TI - Impact of co-morbid attention-deficit/hyperactivity disorder on self-perceived health-related quality-of-life of children with specific learning disability. AB - BACKGROUND: About 12-24% of children with specific learning disability (SpLD) have co-occurring attention-deficit/hyperactivity disorder (ADHD). According to "parent-proxy reports", co-occurring "untreated" ADHD adversely impacts the health-related quality of life (HRQoL) of children with newly diagnosed SpLD, especially in their psychosocial functioning. AIMS: To analyze the impact of "untreated" co-occurring ADHD on the "self-perceived" HRQoL of children with "newly diagnosed" SpLD. SETTING AND DESIGN: Cross-sectional questionnaire-based study in a learning disability clinic situated in a medical college. MATERIALS AND METHODS: From February 2008 to December 2008, 136 consecutive children newly diagnosed as having "SpLD with co-occurring ADHD (SpLD/ADHD)" or "SpLD only" were enrolled. The DISABKIDS chronic generic module (DCGM-37-S (V31)) instrument was used to measure their HRQoL. DCGM-37-S (V31) mean facet and total scores were computed for "SpLD/ADHD" and "SpLD only" children groups and compared using independent samples t-test. RESULTS: HRQoL of "SpLD/ADHD" children was significantly better in limitation facet (mean difference: 8.20; 95% confidence interval (CI): 1.75-15.29; P=0.024). Although not statistically significant, the HRQoL of "SpLD/ADHD" children was better in independence, emotion, social inclusion and social exclusion facets; and in total score. CONCLUSIONS: "SpLD/ADHD" children perceive their physical functioning to be significantly better. Also their perceptions of their psychosocial functioning are better. Contrary to parent-proxy reports, co-occurring "untreated" ADHD does not adversely impact the self-perceived HRQoL of children with "newly diagnosed" SpLD. PMID- 23439729 TI - A transient auditory signal shifts the perceived offset position of a moving visual object. AB - Information received from different sensory modalities profoundly influences human perception. For example, changes in the auditory flutter rate induce changes in the apparent flicker rate of a flashing light (Shipley, 1964). In the present study, we investigated whether auditory information would affect the perceived offset position of a moving object. In Experiment 1, a visual object moved toward the center of the computer screen and disappeared abruptly. A transient auditory signal was presented at different times relative to the moment when the object disappeared. The results showed that if the auditory signal was presented before the abrupt offset of the moving object, the perceived final position was shifted backward, implying that the perceived visual offset position was affected by the transient auditory information. In Experiment 2, we presented the transient auditory signal to either the left or the right ear. The results showed that the perceived visual offset shifted backward more strongly when the auditory signal was presented to the same side from which the moving object originated. In Experiment 3, we found that the perceived timing of the visual offset was not affected by the spatial relation between the auditory signal and the visual offset. The present results are interpreted as indicating that an auditory signal may influence the offset position of a moving object through both spatial and temporal processes. PMID- 23439730 TI - Diagnostic Accuracy of 64-Slice MDCT Coronary Angiography for the Assessment of Coronary Artery Disease in Korean Patients with Type 2 Diabetes. AB - BACKGROUND: A 64-slice multidetector computed tomography (MDCT) is well known to be a useful noninvasive form of angiography for the general population, but not for certain patients with diabetes. The aim of this study was to investigate the diagnostic accuracy and usefulness of 64-slice MDCT coronary angiography for detecting coronary artery disease in Korean patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 240 patients were included, 74 of whom had type 2 diabetes (M:F=40:33; 41.8+/-9.5 years). We compared significant coronary stenosis (>50% luminal narrowing) in MDCT with invasive coronary angiography (ICA) by segment, artery, and patient. We also evaluated the influence of obesity and coronary calcium score on MDCT accuracy. RESULTS: Of the 4,064 coronary segments studied, 4,062 segments (T2DM=1,109) were assessed quantitatively by both MDCT and ICA, and 706 segments (T2DM=226) were detected as a significant lesion by ICA in all patients. Sensitivity, specificity, as well as positive and negative predictive values for the presence of significant stenosis in T2DM were: by segment, 89.4%, 96.4%, 85.8%, and 97.4%, respectively; by artery (n=222), 95.1%, 92.9%, 94.4%, and 93.8%, respectively; by patients (n=74), 98.4%, 100.0%, 98.4%, and 90.0%, respectively. Regardless of presence of diabetes, there was no significant difference in diagnostic accuracy. Obesity (>=25 kg/m(2)) and coronary calcium score did not also affect the diagnostic accuracy of MDCT. CONCLUSION: The 64-slice MDCT coronary angiography was found to have similar diagnostic accuracy with ICA, regardless of diabetes. These results suggest MDCT may be helpful to reduce unnecessary invasive studies for patients with diabetes. PMID- 23439731 TI - Cerebellar pathology of a dual clinical diagnosis: patients with essential tremor and dystonia. AB - BACKGROUND: Clinical studies have implicated the cerebellum in the pathogenesis of essential tremor (ET), and recent postmortem studies have identified structural changes in the ET cerebellum. While the basal ganglia have traditionally been implicated in dystonia, cerebellar involvement has been suggested as well, and a recent study showed Purkinje cell (PC) loss. We conducted a detailed postmortem examination of the brain in four individuals with clinical diagnoses of ET and dystonia, and hypothesized that pathological changes in the cerebellum would be greater in these four ET cases than in published ET cases without dystonia. METHODS: After a complete neuropathological assessment, a standard parasagittal neocerebellar tissue block was harvested in each brain. One 7-um thick section was stained with luxol fast blue/hematoxylin and eosin, and one section with the Bielschowsky method. We quantified PCs, torpedoes, heterotopic PCs, PC dendritic swellings, and basket cell changes. RESULTS: Two ET+dystonia cases had more microscopic changes in the cerebellum than published ET cases; the other two cases had similar changes to published ET cases. DISCUSSION: This is the first report that uses human autopsy tissue to study patients with both ET and dystonia. The findings were heterogeneous. Additional studies, with larger samples, are needed. PMID- 23439732 TI - Stentless aortic valves. Current aspects. AB - The design of stentless valve prostheses is intended to achieve a more physiological flow pattern and superior hemodynamics in comparison to stented valves. First - generation stentless bioprosthesis were the Prima valve, the Freestyle valve and the Toronto stentless porcine valve. The second generation of stentless valves, as the Super stentless aortic porcine valve, need only one suture line. The Sorin Pericarbon Freedom and the Equine 3F heart Valve belong to the third generation of stentless valve pericardial bioprostheses. A stentless valve to replace a full root can be implanted by several surgical techniques: complete or modified subcoronary, root inclusion and full root. The full root technique is accompanied by the lowest incidence of patient-prothesis mismatch. Our own clinical experience reflects more than 3000 stentless valve implantations since April 1996. Randomized study trials showed a hemodynamic advantage for stentless valves, but several could not reach a significant level. Also reported was a significant advantage of stentless bioprostheses concerning transvalvular gradients, effective valve area and quicker regression of the left ventricular mass 6 months after the operation, but at 12 months. Advantages are obvious in patients with a decreased left ventricle ejection fraction of less than 50% and in smaller implanted valve size, concomitant aortic root pathology (e.g. dissection) and aortic valve endocarditis. A survival advantage for stentless bioprostheses in comparison to stented ones has been reported by all studies in the literature. Stentless valves enrich the surgical armamentarium. Time will define the place of stentless valves in the future. PMID- 23439733 TI - Cardiovascular tissue banking in Europe. AB - INTRODUCTION: In the past 50 years, human cardiovascular tissue allografts, also called homografts, have been implanted into patients with different valvular diseases. The use of these allografts and the number of cardiovascular tissue banks and their respective techniques increased. We conducted a survey to establish the quantity of allografts processed, and issued by, European tissue banks. The survey also included the collection of other relevant statistics. METHODS: In 2011, the Foundation of European Tissue Banks collected data from 19 different cardiovascular tissue banks in 11 European countries. RESULTS: From 2007 to 2010 the data show a decrease in the number of hearts received, from 1700 to 1640 in 18 tissue banks; the average number of hearts received for cardiovascular tissue processing decreased from 113 to 91. The number of heart valves issued for transplantation increased from 1272 in 2007 to 1486 in 2010. The average rate of discard because of microbiological contamination was 20.7%, while 4.2% of the grafts were not used because of positive serology. Half of the tissue banks issued arterial grafts, while 3 banks also issued veins and pericardium. An overview of decontamination methods shows considerable methodological differencesbetween 17 cardiovascular tissue banks. CONCLUSIONS: From the experience in Europe, it can be concluded that cardiovascular tissue banks have an established place in the domain of cardiovascular surgery. The statistics show fluctuating data concerning the demand for human cardiovascular allografts and methodological questions. There is room for growth and improvement with respect to validation of decontamination methods. PMID- 23439734 TI - Common mutation underlying primary hyperoxaluria type1 in three Indian children. AB - Primary hyperoxaluria is an autosomal recessive disorder caused by deficiency of alanine-glyoxylate aminotransferase, which is encoded by the AGXT gene. We report three Indian children with primary hyperoxaluria type1 having a common mutation in this gene. All patients had evidence of chronic kidney disease at the time of diagnosis, with subsequent progression to end-stage renal disease. The detection of an identical mutation in the AGXT gene suggests that specific genetic screening for this mutation may be useful when considering the diagnosis of primary hyperoxaluria type1. PMID- 23439735 TI - Most Care®: a minimally invasive system for hemodynamic monitoring powered by the Pressure Recording Analytical Method (PRAM). AB - Invasive hemodynamic monitoring is a cornerstone of the care of critically ill and hemodynamically unstable patients in both intensive care units and operating rooms. The assessment of cardiac output by means of the pulmonary artery catheter has been considered the clinical gold standard. Nevertheless, several concerns have been raised regarding its invasiveness, usefulness, and associated complica tions. These disadvantages have led to the development, during the last years, of a number of less invasive technologies for cardiac output determination. Among them, those based on the analysis of a peripheral arterial waveform have become commonly used. Most Care((r)) is a minimally invasive arterial pressure based monitor powered by the Pressure Recording Analytical Method (PRAM), the only algorithm that does not require prior calibration or pre-calculated parameters and which is based of flow. PRAM provides the measurement of the main factors of hemodynamics, such as systemic blood pressures, stroke volume, cardiac output, and vascular resistances. Moreover, dynamic indices of fluid responsiveness are continuously displayed. In the present paper, we reviewed the current literature focusing on advantages and limitations of PRAM. PMID- 23439736 TI - Reducing psychological distress and obesity through Yoga practice. AB - BACKGROUND: Yoga practice has been effectively prescribed in conjunction with other medical and yogic procedures in the management of severe psychosomatic diseases, including cancer, bronchial asthma, colitis, peptic and ulcer. It improves strength and flexibility, and may help control physiological variables such as blood pressure, lipids, respiration, heart rate, and metabolic rate to improve overall exercise capacity. AIM OF THE STUDY: The aim of this study is to evaluate the effects of Yogic Practice on anxiety/depression associated with obesity. MATERIALS AND METHODS: Patients were recruited from the Department of Physiology, C.S.M. Medical University (erstwhile KGMU), Lucknow, Uttar Pradesh, India. A total of 272 subjects were divided into two groups: 1) group of 205 subjects (with yogic practice) and 2) a control group of 67 subjects (with aerobic exercise). Assessment of anxiety and depression were done by Hamilton Rating Scale. RESULT: This study supports yoga as an effective tool with no diet restriction to improve anxiety and depression symptoms as well as obesity in obese subjects CONCLUSION: Incorporating yogic asana in the treatment protocol of patients suffering from anxiety and depression may prove beneficial in the long run. PMID- 23439737 TI - High volumes of intravenous fluid during cardiac surgery are associated with increased mortality. AB - INTRODUCTION: Positive fluid balance during abdominal surgery has been associated with increased morbidity. We hypothesized that administration of large volumes of intravenous fluids in cardiac surgery is associated with increased mortality. METHODS: Retrospective analysis of data on 1358 patients who underwent cardiac surgery from 2001 to 2005 at two major hospitals in Western New York. Patients were divided in to those who received intravenous fluids above the median volume (3.9 L) and those who received less than the median volume of intra-operative fluid. Acute Kidney Injury Network criteria based on serum creatinine were used to define Acute Kidney injury. RESULTS: Logistic regression and Cox-proportional models showed increased 90 day mortality (HR -2.8, 95% CI -1.16-7.01) in those patients who received greater than the median volume of intravenous during cardiac surgery. This was confirmed with propensity score analysis. Furthermore, the marginal effects analysis revealed that after about 4.0 liters of intravenous fluid, the survival probability falls significantly in cardiac surgery patients. CONCLUSIONS: Administration of large volumes of intra-operative intravenous fluid is independently associated with an increase in 90 day mortality in cardiac surgery. PMID- 23439738 TI - Spatial Discrimination Threshold Abnormalities are not Detected in a Pilot Study of DYT6 Dystonia Mutation Carriers. AB - BACKGROUND: Spatial discrimination thresholds (SDTs) assess somatosensory integration, and provide a window into better understanding the pathophysiology of dystonia. They are abnormal in some focal dystonias, but normal in DYT1 dystonia. It is unknown whether SDTs are altered in DYT6 gene mutation carriers (C). METHODS: SDTs were assessed in 17 DYT6 C (including eight manifesting carriers), 15 DYT1 C (including seven manifesting carriers) and 34 controls, using a standardized grating orientation task. Subjects were asked to recognize the orientation of Johnson-Van Boven-Philips (JVP) dome gratings on either index fingertip until 40% or more answers were incorrect. SDTs between indexes were calculated and averaged, with a final SDT assigned to each subject, and tertiles for control SDTs were constructed. RESULTS: SDTs of DYT6 C or DYT1 C were comparable to those of controls, and not more likely to be in the worst tertile (p = 0.8 for DYT6 C vs. controls and p = 1.0 for DYT1 C vs. controls). This was independent of gene expression. DISCUSSION: DYT6 carriers do not have impaired SDTs with the JVP dome paradigm. The normal SDT pattern thus suggests shared sensory physiologic patterns with DYT1 dystonia. PMID- 23439739 TI - Stillbirth rate in a teaching hospital in South-eastern Nigeria: a silent tragedy. AB - BACKGROUND: Stillbirths often are not seen as a major public health problem, for despite increasing attention and investment on maternal, neonatal, and child health, stillbirths remain invisible. AIM: The objective of this study was to determine the stillbirth rate at the Imo State University Teaching Hospital, Orlu. SUBJECTS AND METHODS: Analysis of the case records of stillbirths that occurred in the institution over a 5-year period from 1(st) July 2005 to 30(th) June 2010 was made. Data retrieved was analyzed for age of the women, parity, presumptive risk factor for the stillbirth, and booking status of the women. Also, the total births during the period of study were obtained. A P-value of <0.05 is said to be significant at confidence level of 95% (95/100). RESULTS: There were a total of 1,142 deliveries within the study period, out of which 206 resulted in stillbirths. This gave an institutional stillbirth rate of 18% (180/1000 deliveries). One-hundred and fifty-five 75.2% (155/206) of the stillbirths were macerated stillbirth. The age range of the women was 15-44 years. The modal age was 31 years. The age group of 26-30 years had the highest prevalence rate of stillbirths of 79 (38.3%, 79/206), while age group of more than 40 years contributed the least with four stillbirths 4 (1.9%, 4/206). CONCLUSION: The stillbirth rate at the institution is too high and efforts must be made to reduce it. PMID- 23439740 TI - Atrial Fibrillation and Early Clinical Outcomes After Mitral Valve Surgery in Patients with Rheumatic vs. Non-Rheumatic Mitral Stenosis. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia after open heart surgery that can lead to early morbidity and mortality following operation. Mitral stenosis (MS) is a structural abnormality of the mitral valve apparatus that can be resulted from previous rheumatic fever or non-rheumatic fever such as congenital mitral stenosis, malignant carcinoid disease etc. This study was designed to test the hypothesis that type of mitral stenosis can affect the incidence, duration and frequency of AF post mitral valve replacement. MATERIALS AND METHODS: We selected fifty patients with rheumatic mitral stenosis and 50 patients with non-rheumatic mitral stenosis who were candidates for mitral valve replacement (MVR) surgery. Pre-operative tests such as CRP, ESR, CBC, UA, ANA, APL (IgM, IgG), ANCA, RF were performed on participants' samples and the type of mitral stenosis, rheumatic or non-rheumatic, was determined clinically. Early post-operative complications such as infection, bleeding, vomiting, renal and respiratory dysfunction etc., were recorded. All patients underwent holter monitoring after being out of ICU to the time of discharge. RESULTS: The mean age of patients was 48.56 +/- 17.64 years. 57 cases (57%) were male, and 43 cases (43%) were female. Post-operative AF occurred in 14 cases (14%); 3 cases (6%) in non-rheumatic mitral stenosis group, and 11 cases (22%) in the rheumatic mitral stenosis group. There was a significant relationship between the incidence of AF and type of mitral stenosis (P = 0.02). Renal dysfunction after MVR was higher in rheumatic MS group than in non-rheumatic MS group (P = 0.026). There was no relationship between the type of mitral stenosis (rheumatic or non-rheumatic) and early mortality after mitral valve replacement (P = 0.8). CONCLUSION: We concluded that the type of mitral stenosis affect post-operative outcomes, especially the incidence of atrial fibrillation and some complications after mitral valve replacement. PMID- 23439741 TI - Pain with no cause! Nurses' perception. AB - CONTEXT: Nurses are called upon to assess chronic pain in health settings and their perceptions about chronic pain are likely to influence the pain assessment and pain relief. SETTINGS AND DESIGN: This survey as a part of chronic pain education workshop was conducted at National Institute of Mental Health and Neurosciences, Bangalore, India, by pain education group. Here we present the observations collected during the workshop on chronic pain held for nurses. MATERIALS AND METHODS: A semiqualitative method was used to survey the perceptions about chronic pain among nurses. The survey form consisted of 28 statements about chronic pain with options of agree and disagree to be marked prepared by the pain education group. STATISTICAL ANALYSIS USED: The data were computed and frequency distribution of different statements was derived. RESULTS: The total number of participants was 44. Two-thirds of the nurses had good knowledge about pain behaviors. About 70% of the nurses reported that severity of pain to be assessed by observing patient's behavior and felt that if a house wife complains of pain it is to avoid work. Only 11% of the nurses provided correct responses related to discussion on pain being psychological; 90% had poor knowledge about pain communication on pain to be treated only for the underlying cause. CONCLUSIONS: These observations highlight the fact that inadequacies in knowledge about chronic pain exist among nurses; the main areas include pain communication and pain treatments. It is important to include proper pain curriculum and training for chronic pain assessment and management. PMID- 23439742 TI - Hydrogen/Deuterium Exchange Reflects Binding of Human Centrin 2 to Ca(2+) and Xeroderma Pigmentosum Group C Peptide: An Example of EX1 Kinetics. AB - Xeroderma pigmentosum (XP) is a genetic disease affecting 1 in 10,000-100,000 and predisposes people to early-age skin cancer, a disease that is increasing. Those with XP have decreased ability to repair UV-induced DNA damage, leading to increased susceptibility of cancerous non-melanomas and melanomas. A vital, heterotrimeric protein complex is linked to the nucleotide excision repair pathway for the damaged DNA. The complex consists of XPC protein, human centrin 2, and RAD23B. One of the members, human centrin 2, is a ubiquitous, acidic, Ca(2+)-binding protein belonging to the calmodulin superfamily. The XPC protein contains a sequence motif specific for binding to human centrin 2. We report here the Ca(2+)-binding properties of human centrin 2 and its interaction with the XPC peptide motif. We utilized a region-specific H/D exchange protocol to localize the interaction of the XPC peptide with the C-terminal domain of centrin, the binding of which is different than that of calmodulin complexes. The binding dynamics of human centrin 2 to the XPC peptide in the absence and presence of Ca(2+) are revealed by the observation of EX1 H/D exchange regime, indicating that a locally unfolded population exists in solution and undergoes fast H/D exchange. PMID- 23439743 TI - Effects of Stigmatization on Gay Men Living with HIV/AIDS in a Central-Eastern European Context: A Qualitative Analysis from Hungary. AB - This qualitative study highlights the social dynamics affecting people living with HIV (PLH) in Hungary and in the Central-Eastern European region. The study focused on the special needs and concerns of men living with HIV/AIDS as well as changes in their social relationships and institutional support provision, coping strategies and patterns of social functioning, especially in the context of social stigmatization. Consistent with international qualitative research findings in the field of HIV/AIDS prevention, the present study contributes to a fuller understanding of relationship between sexual behavior, HIV/AIDS related risks and risk perceptions as well as homosexuality-and HIV/AIDS stigma-related social exclusion in a previously under-researched socio-cultural setting. The findings of our study point to several barriers to effective HIV prevention, which should be overcome to improve the present situation by lessening the adverse effects of HIV/AIDS-and homosexuality-related stigma within the gay community, the general population and especially among service providers. One of the main barriers is the lack of public health programs specifically targeting MSM in Hungary, where the predominant mode of HIV transmission remains sex between men. PMID- 23439745 TI - Sutureless large incision cataract extraction: Indications and results from two teaching hospital eye departments in the United Kingdom. AB - OBJECTIVE: To highlight the role of Sutureless Large Incision Cataract Extraction (SLICE) in the United Kingdom for the treatment of cataracts at high risk for intra- or postoperative complications. SETTING: Two University Hospitals in the United Kingdom MATERIALS AND METHODS: Retrospective case note review of planned SLICE performed over a 12-month period. RESULTS: SLICE was performed on 11 eyes of 11 patients (mean age, 79 years) having preoperative vision of hand motions (10 eyes) with very dense or mobile cataracts and high risk for phacoemulsification. Mean follow up was 12 weeks, with no operative or postoperative complications. Nine patients (without ocular or systemic comorbidity) achieved best corrected vision of 0.3 LogMAR (20/40) or better. CONCLUSIONS: SLICE is safe and effective for dense or mobile cataracts and can play a role in patients where conventional phacoemulsification carries higher risks of complications. PMID- 23439744 TI - Sitagliptin as add-on therapy in insulin deficiency: biomarkers of therapeutic efficacy respond differently in type 1 and type 2 diabetes. AB - BACKGROUND: Sitagliptin has been proven to be effective and safe as add-on to insulin in adult patients with type 2 diabetes and absolute insulin deficiency. Recently, it has been suggested to extend the use of dipeptidyl-peptidase-4 inhibitors to type 1 diabetes. The aim of this study was to evaluate and compare the effects of a long-term, fixed-dose combination of sitagliptin and metformin as add-on to insulin on body mass index, fasting plasma glucose, fructosamine, HbA(1c), lipids, and daily dose of insulin in both type 1 diabetes and insulin treated type 2 diabetes. METHODS: We recruited 25 patients with type 1 diabetes (mean age 51 +/- 10 years, mean disease duration 26 +/- 13 years) and 31 insulin treated type 2 diabetic patients (mean age 66 +/- 8 years, mean disease duration 19 +/- 9 years), who received sitagliptin with metformin as a fixed-dose combination (50/1000 mg once or twice daily) or sitagliptin (100 mg once daily, if intolerant to metformin) in addition to ongoing insulin therapy for 46 +/- 19 weeks and 56 +/- 14 weeks, respectively. RESULTS: After 21 +/- 9 weeks, patients with type 1 diabetes had a significantly lower body mass index, fasting plasma glucose, fructosamine, HbA(1c), and daily insulin requirement. After 49 +/- 17 weeks, they maintained their weight loss and total daily insulin dose and showed a significant reduction in low-density lipoprotein cholesterol levels, whereas their HbA(1c) had returned to baseline values. In patients with type 2 diabetes, long-term treatment remained weight-neutral but had persistent beneficial effects on short-term, intermediate-term, and long-term biomarkers of metabolic control, as well as on low-density lipoprotein cholesterol levels and insulin requirement. CONCLUSION: Clinical outcomes differed according to type of diabetes in terms of quality and over time. In type 2 diabetes, the combination therapy significantly improved metabolic control and the lipid profile, and decreased insulin requirements, even in the absence of clinically significant weight loss. In type 1 diabetes, the combined therapy only temporarily improved metabolic control, but significantly decreased body weight, low-density lipoprotein cholesterol levels, and insulin requirements. PMID- 23439746 TI - Metabolic syndrome in patients with severe mental illness undergoing psychiatric rehabilitation receiving high dose antipsychotic medication. AB - BACKGROUND: To review evidence of chronic antipsychotic medication and the association with metabolic syndrome in mentally ill patients. This evidence was used to analyse a cohort of patients with severe mental illness and to deduce a correlation between the prevalence of metabolic syndrome and their dose regimens. MATERIALS AND METHODS: Twenty-four male patients undergoing Psychiatric rehabilitation underwent a review of current medication and assessment of risk factors for metabolic syndrome. Assessment criteria was based upon National Cholesterol Education Programme expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III) (NCEP ATP III) criteria, incorporating waist circumference, raised triglycerides, reduced high density lipoprotein, raised blood pressure and fasting blood glucose. PubMed, Nature and Science Direct databases have been used to compile the medical and scientific background on metabolic syndrome and antipsychotic medication and the effect on patients particularly on high dose. RESULTS: Out of 24 patients, 10 patients (41.7%) were receiving high dose antipsychotics (HDA) and four were on maximum dosage limits of 100%. 8.3% (2/24) patients were receiving only one first generation antipsychotics (FGA), 37.5% (9/24) patients were receiving only one second generation antipsychotic (SGA), 45.8% patients (11/24) were receiving two or more SGA only, and only one patient was receiving two or more FGA. One patient was receiving a combination of FGA and SGA. PRN ("as needed") therapy was not included in this study as their usage was limited. Clozapine was mostly prescribed in these patients (10/24, 41.6%). Four out of the 24 patients refused blood tests therefore were excluded from the following results. In the patients evaluated, 55% (11/20) had confirmed metabolic syndrome. In these patients with metabolic syndrome, 45.4% (5/11) were on HDA and 27.3% (3/11) were on maximum British National Formulary (BNF) limits of 100% of dosage. Four out of the nine remaining patients not diagnosed with metabolic syndrome were on HDA. CONCLUSIONS: Evidence supports the association between antipsychotic medication and metabolic syndrome. The data extrapolated from this cohort of mentally ill patients demonstrates that there is an increase in risk factors for metabolic syndrome and weight gain in the majority of patients on antipsychotic medication. The data however does not support any further predisposition to metabolic syndrome in these patients taking HDA. It also cannot be assumed antipsychotic medication is independently associated with the prevalence of these abnormalities. PMID- 23439747 TI - Clinical trials of cancer cachexia therapy, now and hereafter. PMID- 23439748 TI - Cancer of unknown primary or unrecognized adnexal skin primary carcinoma? Limitations of gene expression profiling diagnosis. PMID- 23439749 TI - If at first you don't succeed: stem-cell transplantation for acute myeloid leukemia after first relapse. PMID- 23439750 TI - Dexrazoxane prevention of anthracycline cardiomyopathy. PMID- 23439751 TI - Cancer of unknown primary origin: using ancillary techniques with caution. PMID- 23439752 TI - Acute myeloid leukemia in first remission: to choose transplantation or not? AB - A 42-year-old woman presented with bruising and fatigue. Her WBC count was 10,370/MUL, with a differential showing 5% polys, 5% monos, 10% lymphocytes, and 80% myeloid-appearing blasts, some of which contained Auer rods (Fig 1). Bone marrow examination revealed 90% infiltration with myeloid-appearing blasts, and flow cytometry analysis confirmed the diagnosis of acute myeloid leukemia (AML) with expression of CD33, CD13, and CD117. Cytogenetics revealed a normal female karyotype; molecular testing for NPM1, FLT3-ITD, and CEBPalphamutations revealed wild-type status for each gene. The patient received induction therapy with daunorubicin 90 mg/m(2) per day for 3 days and continuous-infusion cytarabine 100 mg/m(2) per day for 7 days. After an induction course complicated by Gram negative bacterial sepsis, her counts recovered by day 32, and bone marrow examination 6 weeks after diagnosis showed a complete remission. One week later she feels well and has normal physical and laboratory examinations. She is an only child (but has a common HLA type) and presents for discussion of postremission therapy options. PMID- 23439754 TI - Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. AB - PURPOSE: The aims of this study were to quantify the prospects of salvage treatment of patients who did not undergo transplantation in first complete remission (CR1) and to assess the contribution of allograft in second complete remission (CR2) with respect to major risk groups. This evaluation can inform the decision whether to offer a transplant in CR1. PATIENTS AND METHODS: Of 8,909 patients who entered the Medical Research Council AML10, AML12, and AML15 trials, 1,271 of 3,919 patients age 16 to 49 years who did not receive a transplant in CR1 relapsed. Of these patients, 19% are alive beyond 5 years compared with 7% of patients who relapsed after an allograft in CR1. Overall survival and the contribution of a transplant in CR2 were assessed overall and by cytogenetic risk group by using Mantel-Byar analysis. RESULTS: Fifty-five percent of patients who relapsed entered CR2. This percentage varied by risk group as follows: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5 year survivals of 32%, 17%, 7%, and 23%, respectively. Sixty-seven percent of remitters received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% v 16%). A more stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup. CONCLUSION: Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants. PMID- 23439753 TI - Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of vater. AB - PURPOSE: Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. PATIENTS AND METHODS: We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. RESULTS: Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P < .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. CONCLUSION: Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design. PMID- 23439755 TI - Rare case of hairy cell leukemia with brain parenchymal involvement: a diagnostic dilemma. PMID- 23439756 TI - Temporal trends in mortality from diseases of the circulatory system after treatment for Hodgkin lymphoma: a population-based cohort study in Sweden (1973 to 2006). AB - PURPOSE: Hodgkin lymphoma (HL) survival in Sweden has improved dramatically over the last 40 years, but little is known about the extent to which efforts aimed at reducing long-term treatment-related mortality have contributed to the improved prognosis. METHODS: We used population-based data from Sweden to estimate the contribution of treatment-related mortality caused by diseases of the circulatory system (DCS) to temporal trends in excess HL mortality among 5,462 patients diagnosed at ages 19 to 80 between 1973 and 2006. Flexible parametric survival models were used to estimate excess mortality. In addition, we used recent advances in statistical methodology to estimate excess mortality in the presence of competing causes of death. RESULTS: Excess DCS mortality within 20 years after diagnosis has decreased continually since the mid-1980s and is expected to further decrease among patients diagnosed in the modern era. Age at diagnosis and sex were important predictors for excess DCS mortality, with advanced age and male sex being associated with higher excess DCS mortality. However, when accounting for competing causes of death, we found that excess DCS mortality constitutes a relatively small proportion of the overall mortality among patients with HL in Sweden. CONCLUSION: Excess DCS mortality is no longer a common source of mortality among Swedish patients with HL. The main causes of death among long term survivors today are causes other than HL, although other (non-DCS) excess mortality also persists for as long as 20 years after diagnosis, particularly among older patients. PMID- 23439757 TI - High-grade KIT-negative sarcoma of the small bowel in a patient with chronic myeloid leukemia receiving long-term tyrosine kinase inhibitors. PMID- 23439758 TI - Paradoxical immune reconstitution inflammatory syndrome associated with rituximab containing regimen in a patient with lymphoma. PMID- 23439760 TI - Changes in electromyography and F wave responses in two cats with presumed local tetanus: implications for diagnosis and prognosis. AB - Two cases of focal tetanus in the cat are described. Clinical findings included severe muscular spasms of the pelvic limbs in one cat, and involvement of the thoracic limbs and muscles of the neck and face in the other. Electromyography in both cats showed spontaneous activity characterised by the presence of motor unit potentials. F waves, never previously reported in focal tetanus in animals, showed significantly increased F/M amplitude ratio in both cats and increased F wave duration in one cat. The electrodiagnostic findings provided relevant diagnostic and, possibly, prognostic information. PMID- 23439759 TI - Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. AB - PURPOSE: Prior studies have suggested that melatonin, a frequently used integrative medicine, can attenuate weight loss, anorexia, and fatigue in patients with cancer. These studies were limited by a lack of blinding and absence of placebo controls. The primary purpose of this study was to compare melatonin with placebo for appetite improvement in patients with cancer cachexia. PATIENTS AND METHODS: We performed a randomized, double-blind, 28-day trial of melatonin 20 mg versus placebo in patients with advanced lung or GI cancer, appetite scores >= 4 on a 0 to 10 scale (10 = worst appetite), and history of weight loss >= 5%. Assessments included weight, symptoms by the Edmonton Symptom Assessment Scale, and quality of life by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Differences between groups from baseline to day 28 were analyzed using one-sided, two-sample t tests or Wilcoxon two-sample tests. Interim analysis halfway through the trial had a Lan-DeMets monitoring boundary with an O'Brien-Fleming stopping rule. Decision boundaries were to accept the null hypothesis of futility if the test statistic z < 0.39 (P >= .348) and reject the null hypothesis if z > 2.54 (P <= .0056). RESULTS: After interim analysis of 48 patients, the study was closed for futility. There were no significant differences between groups for appetite (P = .78) or other symptoms, weight (P = .17), FAACT score (P = .95), toxicity, or survival from baseline to day 28. CONCLUSION: In cachectic patients with advanced cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo. PMID- 23439761 TI - Iodine concentration in commercial cat foods from three regions of the USA, 2008 2009. AB - Fluctuations in iodine concentration in food have been suggested as one risk factor for the development of feline hyperthyroidism, an epidemic disease first described in 1979. Three international studies have examined iodine concentrations of commercial cat foods. The iodine concentration of 112 commercial cat foods from across the USA was measured, and the daily iodine intake by hypothetical 4.5 kg adult cats or 1.4 kg kittens calculated in this descriptive epidemiologic study to examine differences in feline iodine intake due to (i) geographical source of foods, (ii) packaging type, (iii) brand-to brand variation, (iv) form of iodine supplementation, (v) types and numbers of seafood ingredients and (vi) kitten and 'therapeutic' diets. Dramatic variation among canned foods (resulting in ingestion of approximately 49-9639 MUg iodine/day) suggests that the disparity in iodine concentrations may lead to development of nodular hyperplasia and, later, clinical hyperthyroidism, if cats consume diets that are at first iodine-deficient and later contain excessive iodine. Manufacturers are encouraged to ensure adequate iodine supplementation across all products and areas of the USA. PMID- 23439764 TI - Total phenolics and total flavonoids in selected Indian medicinal plants. AB - Plant phenolics and flavonoids have a powerful biological activity, which outlines the necessity of their determination. The phenolics and flavonoids content of 20 medicinal plants were determined in the present investigation. The phenolic content was determined by using Folin-Ciocalteu assay. The total flavonoids were measured spectrophotometrically by using the aluminium chloride colorimetric assay. The results showed that the family Mimosaceae is the richest source of phenolics, (Acacia nilotica: 80.63 mg gallic acid equivalents, Acacia catechu 78.12 mg gallic acid equivalents, Albizia lebbeck 66.23 mg gallic acid equivalents). The highest total flavonoid content was revealed in Senna tora which belongs to the family Caesalpiniaceae. The present study also shows the ratio of flavonoids to the phenolics in each sample for their specificity. PMID- 23439763 TI - The Role of Biomarkers for Diagnosis of and Therapeutic Decisions Related to Invasive Aspergillosis in Children. AB - Invasive aspergillosis (IA) is a feared opportunistic infection for many immuncompromised children resulting in significant morbidity and mortality. Timely diagnosis based on traditional testing modalities and clinical evaluation has proven to be challenging. Assays designed to measure IA biomarkers such as galactomannan (GM) and beta-D-glucan (BG) represent a potential significant improvement in the ability to diagnose pediatric IA. However, as with any new diagnostic tool, clinicians need to be aware of the operating characteristics of these assays in order to apply them in the appropriate settings. Published adult and pediatric data regarding GM and BG testing are reviewed and guidance regarding the appropriate utility of these assays in children is offered. PMID- 23439762 TI - Regulation of ca(2+) signaling in pulmonary hypertension. AB - Understanding the cellular and molecular mechanisms involved in the development and progression of pulmonary hypertension (PH) remains imperative if we are to successfully improve the quality of life and life span of patients with the disease. A whole plethora of mechanisms are associated with the development and progression of PH. Such complexity makes it difficult to isolate one particular pathway to target clinically. Changes in intracellular free calcium concentration, the most common intracellular second messenger, can have significant impact in defining the pathogenic mechanisms leading to its development and persistence. Signaling pathways leading to the elevation of [Ca(2+)](cyt) contribute to pulmonary vasoconstriction, excessive proliferation of smooth muscle cells and ultimately pulmonary vascular remodeling. This current review serves to summarize the some of the most recent advances in the regulation of calcium during pulmonary hypertension. PMID- 23439765 TI - Psychiatric morbidity in patients with transverse myelitis and stroke: A comparison. AB - BACKGROUND: Psychiatric morbidity may be highly prevalent in transverse myelitis (TM), but data on this aspect are limited. AIM: To assess psychiatric morbidity in a clinical sample of patients with idiopathic TM compared to patients with a recent stroke. MATERIALS AND METHODS: Consecutive patients with idiopathic TM and stroke (30 each) underwent two-stage screening with the General Health Questionnaire-12 (GHQ-12) and Structured Clinical Interview for Axis I DSM-IV Disorders - Clinician Version (SCID I-CV), and ratings of depression, disability levels, and cognitive impairment. RESULTS: Seventy percent of the patients with TM scored above the cut-off on the GHQ; 30% had a positive diagnosis of a psychiatric disorder. Major depression (17%) was the commonest psychiatric disorder. Mini-Mental State Examination (MMSE) scores indicated cognitive impairment in 23% of patients with TM. Higher GHQ-12 scores were associated with greater disability. These results were similar to those obtained among patients with stroke. CONCLUSION: A high prevalence of psychological distress and psychiatric morbidity was found in idiopathic TM. This morbidity was associated with greater disability. PMID- 23439766 TI - Onset of pulmonary stenosis after arterial switch operation for transposition of great arteries with intact ventricular septum. AB - INTRODUCTION: Pulmonary stenosis remains the most frequent complication and cause of reintervention after the arterial switch operation for transposition of the great arteries We investigated the onset, incidence, and outcome of pulmonary stenosis after arterial switch operation in neonates with transposition of the great arteries and intact ventricular septum. METHODS: Arterial switch operation using Lecompte maneuver was performed in 222 neonates with transposition of great arteries and intact ventricular septum. Complete medical records with serial echocardiograms were available for 174 (73%) patients and were reviewed for incidence of postoperative pulmonary stenosis defined as a thickened and doming pulmonary valve and/or a pressure gradient of >25 mmHg. RESULTS: During a mean follow-up of 14.4 +/- 0.54 years, 31 children developed pulmonary stenosis. Onset of significant stenosis occurred as early as 30 days and as late as 10 years after arterial switch operation. Uncomplicated interventional balloon/stent angioplasty was performed in 11 patients with supravalvular stenosis (mean pressure gradients of 65 mmHg). Severe restenosis occurred in these patients post angioplasty (range 2-7 years). In other 10 patientseither patch enlargement of the area involved or angioplasty were performed. Freedom from intervention was 68.6+/-8.7% at 1 year and 42.8.1+/-9.5% at 15 years and onwards. CONCLUSION: Over time, pulmonary stenosis developed after arterial switch operation. Balloon angioplasty for supravalvular pulmonary stenosis could be the initial treatment of choice owing to the high success rate. Surgical intervention is offered to those with pulmonary valve stenosis having pressure gradients of >50 mmHg, and for re-stenosis after intervention/stent implantation. PMID- 23439767 TI - High-sensitivity C-reactive protein (hs-CRP) and tumor necrotizing factor-alpha (TNF-alpha) after on- and off- pump coronary artery bypass grafting. AB - INTRODUCTION: Coronary artery bypass grafting (CABG) is one of the most frequently performed operations around the world. The aim of this study is to evaluate high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor alpha (TNF-alpha) differences between on-pump and off-pump coronary surgery. METHODS: In this prospective study, 90 patients with coronary artery disease referred for CABG were enrolled from July 2006-November 2007. Levels of hs-CRP and TNF-alpha were measured by ELISA using commercial kits RESULTS: hs-CRP levels significantly (p<0.001) increase after CABG. But no difference between off-pump and on-pump groups was noted for hs-CRP and TNF-alpha levels (p=0.4, p=0.8). CONCLUSIONS: There was no difference in high-sensitivity C-reactive protein (hs CRP) and TNF-alpha between on-pump and off-pump CABG surgery. PMID- 23439768 TI - Ross procedure. AB - INTRODUCTION: In 1967 Donald Ross introduced the subcoronary Ross procedure consisting of transplantation of the autologous pulmonary valve into aortic position. We describe our 15-year experience in Ross procedures. METHODS: 576 subcoronary operations have been performed (436 male and 140 female patients); the mean age was 45+/-11.9 years. (range, 13 to 70 years). The mean follow-up was 7+/-4.2 years (range, 0 to 16 years). There were 4597 patient years at follow-up with a clinical completeness of 95% and echo completeness of 91%. RESULTS: There were two operative deaths (0.3%) and 31 patients with reoperation. The survival is similar to that of the normal population and the freedom from allo- and autograft reoperation is 87% at 15 years. Autograft regurgitation at last examination was grade 0 in 40%, trace in 54%, grade I in 19%, grade II in 4% and grade III in 0.4%; the pressure gradient was smaller than 5 mmHg in 57% and between 5 and 10 mmHg in 24%. Only 6% had a transvalvular pressure gradient of more than 10 mmHg. DISCUSSION: After 15 years of experience it can be concluded that the subcoronary technique provides near normal survival in adult patients, with excellent hemodynamics and acceptable rate of reoperations. PMID- 23439769 TI - White matter hyperintensity burden on magnetic resonance imaging in essential tremor. AB - BACKGROUND: Whereas structural abnormalities in the cerebellum have been associated with essential tremor (ET), the contribution of vascular disease via white matter hyperintensities (WMHs) and strokes has not been examined. In this study, we have explored these potential associations and hypothesized that ET would be associated with greater overall WMH volume, greater cerebellar WMH volume, and greater infarct presence. METHODS: In a cross-sectional magnetic resonance imaging (MRI) study of 540 community-dwelling elderly persons in northern Manhattan, New York, brain measures of total WMH volume and regional WMH volume were derived from T(2)-weighted fluid attenuated inverse recovery-weighted MR images. The presence of cerebral infarcts on MRI was determined as well. RESULTS: Total WMH volume was greater among 33 ET cases than 507 controls in both univariate (OR = 1.41, p = 0.038) and fully adjusted analyses (OR = 1.44, p = 0.03). Cerebellar WMH volume was associated with marginally increased odds of ET in a univariate model (OR = 1.52, p = 0.11) and significantly increased odds in a fully adjusted multivariate model (OR = 1.74, p = 0.049). Temporal lobe WMH volume was associated with significantly increased odds of ET in both univariate (OR = 3.36, p<0.001) and fully adjusted models (OR = 3.73, p<0.001). Large strokes were significantly more common in cases than in controls in unadjusted analyses (OR = 3.04, p = 0.02) and marginally in adjusted analyses (OR = 2.56 2.57, p = 0.045-0.056). The distribution of strokes did not differ by diagnosis. DISCUSSION: MRI data in this study indicated that ET was associated with greater total WMH volume, greater cerebellar WMH volume and possibly more strokes. Cerebrovascular disease could play a role in the development of ET. PMID- 23439770 TI - The acute effects of two passive stretch maneuvers on pectoralis minor length and scapular kinematics among collegiate swimmers. AB - PURPOSE/BACKGROUND: To compare the acute effects of two passive stretches on pectoralis minor length and scapular kinematics among a group of collegiate swimmers. METHODS: The study was a descriptive design with repeated measures. All procedures were conducted in a biomechanics laboratory and collegiate swimming facility. Fifty asymptomatic shoulders from 29 NCAA swimmers were used (15 control shoulders, 17 focused stretch shoulders, 18 gross stretch shoulders). Pre and post-test linear pectoralis minor length, as well as scapular kinematics (upward/downward rotation, external/internal rotation, anterior/posterior tilt) were measured as dependent variables. Pectoralis minor length was measured using a standard tape measure and three-dimensional scapular kinematics were measured using an electromagnetic capture system. RESULTS: The gross stretch shoulders had a significant increase in pectoralis minor length compared to the control shoulders (P=.007). There were no other significant changes in length for either the focused stretch or control shoulders (P>.07). No statistically significant (P>.08) differences for all three scapular kinematic variables were found among any of the three groups (P>.08). CONCLUSIONS: Our results revealed no acute improvements of scapular upward rotation, external rotation, or posterior tilt after the application of either passive stretch maneuver to the pectoralis minor muscle. LEVEL OF EVIDENCE: 2b. PMID- 23439771 TI - Increased selenoprotein p levels in subjects with visceral obesity and nonalcoholic Fatty liver disease. AB - BACKGROUND: Selenoprotein P (SeP) has recently been reported as a novel hepatokine that regulates insulin resistance and systemic energy metabolism in rodents and humans. We explored the associations among SeP, visceral obesity, and nonalcoholic fatty liver disease (NAFLD). METHODS: We examined serum SeP concentrations in subjects with increased visceral fat area (VFA) or liver fat accumulation measured with computed tomography. Our study subjects included 120 nondiabetic individuals selected from participants of the Korean Sarcopenic Obesity Study. In addition, we evaluated the relationship between SeP and cardiometabolic risk factors, including homeostasis model of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hsCRP), adiponectin values, and brachial-ankle pulse wave velocity (baPWV). RESULTS: Subjects with NAFLD showed increased levels of HOMA-IR, hsCRP, VFA, and several components of metabolic syndrome and decreased levels of adiponectin and high density lipoprotein cholesterol than those of controls. Serum SeP levels were positively correlated with VFA, hsCRP, and baPWV and negatively correlated with the liver attenuation index. Not only subjects with visceral obesity but also those with NAFLD exhibited significantly increased SeP levels (P<0.001). In multiple logistic regression analysis, the subjects in the highest SeP tertile showed a higher risk for NAFLD than those in the lowest SeP tertile, even after adjusting for potential confounding factors (odds ratio, 7.48; 95% confidence interval, 1.72 to 32.60; P=0.007). CONCLUSION: Circulating SeP levels were increased in subjects with NAFLD as well as in those with visceral obesity and may be a novel biomarker for NAFLD. PMID- 23439772 TI - Pexelizumab and survival in cardiac surgery. AB - A recent international consensus conference on the reduction in mortality in cardiac anesthesia and intensive care included pexelizumab, a recombinant monoclonal antibody to the component 5 of the complement system, among the ancillary (i.e. non-surgical) drugs/techniques/strategies that might influence survival rates in patients undergoing cardiac surgery. The consensus conferences state that "A subgroup analysis of a meta-analysis of randomized controlled trials suggested that pexelizumab might reduce mortality (longest follow up available, up to 6 months) in patients undergoing coronary artery bypass grafting. Pexelizumab was not included among the most important topics of the consensus conference as it was the only topic that did not receive a sufficient percentage of votes from the audience (32% at the first round and 35% at the second round). Pexelizumab is no longer on the market, however, the concept of reducing the generalized inflammatory process accompanying cardiopulmonary bypass deserves further investigation. PMID- 23439774 TI - Tricuspid valve surgery. AB - INTRODUCTION: The tricuspid valve has been taken as a non-critical valve in terms of acute or late mortality in a number of conditions. Tricuspid functional regurgitation is a cause of late operations with an increased morbidity. A number of techniques have been described and used in clinical practice in the past forty years and include simple suture techniques and the use of support for annuloplasty with the use of different types of prosthetic rings. The experience accumulated over the years indicates that tricuspid annuloplasty is mandatory to improve late results, which are superior, in general, to replacement of the valve. METHODS: The role of echocardiography in defining surgical planning, intraoperative results and follow-up is reviewed as echocardiography is a fundamental tool in cardiac surgery. Surgery for isolated lesions of the tricuspid valve has not received much attention and herein we report the results of the follow-up of a limited series of patients undergoing isolated tricuspid surgery. RESULTS: The correlation between echocardiographic measurements and surgical measurements was confirmed and was helpful at the time of the confirmation of repair (r=0.53). Forty-seven patients (18 repair, 29 replacement) underwent isolated surgery. Results of isolated tricuspid repair seemed to be superior when compared to those of tricuspid replacement. Survival was 20.7% for tricuspid valve replacement (N=18) and 50% for tricuspid valve repair (N=29) (p=0.04). Freedom from reoperation was 94.4+/-5.4% for repair and 67.3+/-12.1% for replacement (p= 0.0011). CONCLUSIONS: The tricuspid valve continues to be a surgical challenge. PMID- 23439775 TI - Where are italian anesthesiologists and intensive care specialists publishing? A quantitative analysis of publication activity. AB - INTRODUCTION: With the continuing worldwide shortage of anesthesiologists, the demands of clinical duties allow very little time for research activities. Every dedicated biomedical center should provide doctors and scientists with the proper environment to facilitate education, clinical practice and research activities and promote publication in international peer-review journals. METHODS: In this observational study, the Scopus database was searched for publications ( 2004 2009 ) to identify the most prolific authors among Italian anesthesiologists and intensive care specialists working in Italy. We then identified the journals that most frequently hosted Italian writers. RESULTS: The top 20 authors published between 30 and 76 papers each (mean 51) in the last 5 years. Intensive Care Medicine (112 papers, 14%), Minerva Anestesiologica (92 papers, 11%), Critical Care Medicine (55 papers, 7%), Journal of Cardiothoracic and Vascular Anesthesia (32 papers, 4%), and European Journal of Anesthesiology (32 papers, 4%) most frequently hosted Italian authors. DISCUSSION: Despite its obvious limitations such as the choice of a single database (Scopus), the absence of important qualitative indicators (e.g. impact factor, citation index), the inclusion of any type of publication (a letter to the editor or reviews counted like a randomized controlled study) and the possible exclusion of important scholars, this is the most up-to-date and comprehensive attempt to perform a quantitative analysis of publishing in Italy. Each of the 20 indexed Journals that most frequently hosted Italian authors only accepts manuscripts in English and has impact factor. PMID- 23439773 TI - The Genome of Nitrospina gracilis Illuminates the Metabolism and Evolution of the Major Marine Nitrite Oxidizer. AB - In marine systems, nitrate is the major reservoir of inorganic fixed nitrogen. The only known biological nitrate-forming reaction is nitrite oxidation, but despite its importance, our knowledge of the organisms catalyzing this key process in the marine N-cycle is very limited. The most frequently encountered marine NOB are related to Nitrospina gracilis, an aerobic chemolithoautotrophic bacterium isolated from ocean surface waters. To date, limited physiological and genomic data for this organism were available and its phylogenetic affiliation was uncertain. In this study, the draft genome sequence of N. gracilis strain 3/211 was obtained. Unexpectedly for an aerobic organism, N. gracilis lacks classical reactive oxygen defense mechanisms and uses the reductive tricarboxylic acid cycle for carbon fixation. These features indicate microaerophilic ancestry and are consistent with the presence of Nitrospina in marine oxygen minimum zones. Fixed carbon is stored intracellularly as glycogen, but genes for utilizing external organic carbon sources were not identified. N. gracilis also contains a full gene set for oxidative phosphorylation with oxygen as terminal electron acceptor and for reverse electron transport from nitrite to NADH. A novel variation of complex I may catalyze the required reverse electron flow to low-potential ferredoxin. Interestingly, comparative genomics indicated a strong evolutionary link between Nitrospina, the nitrite-oxidizing genus Nitrospira, and anaerobic ammonium oxidizers, apparently including the horizontal transfer of a periplasmically oriented nitrite oxidoreductase and other key genes for nitrite oxidation at an early evolutionary stage. Further, detailed phylogenetic analyses using concatenated marker genes provided evidence that Nitrospina forms a novel bacterial phylum, for which we propose the name Nitrospinae. PMID- 23439776 TI - Gender-related variation in the clinical presentation and outcomes of critical limb ischemia. AB - Critical limb ischemia (CLI) is a major cause of limb loss and mortality among patients with advanced peripheral artery disease. Our objective was to evaluate the gender-specific differences in patient characteristics and clinical outcomes among patients with CLI. We performed a retrospective analysis of 97 women and 122 men presenting with CLI who underwent angiography from 2006 to 2010. Baseline demographics, procedural details, and lesion characteristics were assessed for each patient. Kaplan-Meier analysis was used to assess long-term patient and lesion-level outcomes. Cox proportional hazard modeling was used to evaluate the relationship between gender and major adverse cardiovascular events (MACE). Compared to men, women were less likely to have a history of coronary artery disease (39% vs 54%, p = 0.02) or diabetes (57% vs 70%, p = 0.05) but had similar baseline medical therapy. At angiography, women were more likely to have significant femoropopliteal (77% vs 67%, p = 0.02) and multi-level infrainguinal disease (63% vs 51%, p = 0.02). Women were also more likely to undergo multi vessel percutaneous intervention (69% vs 55%, p = 0.05), but had similar rates of limb salvage after percutaneous intervention or surgical bypass (HR 0.94 [95% CI 0.45-1.94], p = 0.9). During follow-up, women had higher rates of subsequent major adverse cardiovascular events (HR 1.63 [95% CI 1.01-2.63], p = 0.04). In conclusion, women with CLI are more likely to present with femoropopliteal and multi-level infrainguinal disease. Despite similar rates of limb salvage, women with CLI have an increased rate of subsequent major adverse cardiovascular events. PMID- 23439777 TI - Isolated pharmaco-mechanical thrombectomy (IPMT) for the endovascular treatment of acute axillofemoral graft occlusion. AB - Since the long-term patency of axillofemoral (AXF) grafts is inferior to aorto bifemoral (ABF) grafts, limb salvage procedures are crucial in this group of patients. Emerging endovascular devices have helped in the successful restoration of flow for acute limb ischemia in both native arteries as well as bypass grafts. One such device, the Trellis thrombectomy system is being used more frequently in this setting. The device has previously been used in veins, native arteries, and rarely in aortofemoral grafts. We present its first successful use for the treatment of occluded AXF bypass graft. The use of this device helped to isolate the treatment zone in the occluded graft, which allowed the use of a lower dose of thrombolytics, less systemic release of thrombolytics, and less distal embolization. Resolution of extensive clot burden was achieved and, with subsequent stenting of the graft at the distal anastomotic site, arterial flow to the leg through the AXF graft was restored and a revision surgery was avoided. PMID- 23439778 TI - Inferior vena cava thrombosis: a review of current practice. AB - Inferior vena cava (IVC) thrombosis remains under-recognised as it is often not pursued as a primary diagnosis. The aetiology of IVC thrombosis can be divided into congenital versus acquired, with all aetiological factors found among Virchow's triad of stasis, injury and hypercoagulability. Signs and symptoms are related to aetiology and range from no symptoms to cardiovascular collapse. Painful lower limb swelling combined with lower back pain, pyrexia, dilatation of cutaneous abdominal wall veins and a concurrent rise in inflammatory markers are suggestive of IVC thrombosis. Following initial lower limb venous duplex, magnetic resonance imaging (MRI) is the optimal non-invasive imaging tool. Aetiology directs treatment, which ranges from anticoagulation and lower limb compression to open surgery, with endovascular therapies increasingly favoured. The objective of this review is to assess current literature on the aetiology, presentation, investigation, treatment, prognosis and other factors pertaining to IVC thrombosis. PMID- 23439779 TI - Disseminated candidiasis 18 years after renal transplantation. AB - Although mucocutaneous candidiasis is a common infection in renal transplant recipients, disseminated candidiasis is rare. Candida pnemonia causing miliary mottling on X-ray chest with the central nervous system involvement is still rarer. We report an unusual case with disseminated candidiasis that presented 18 years after renal transplantation and improved on conventional antifungal therapy; the relevant literature is reviewed. PMID- 23439780 TI - Body surface area as a key determinant of aortic root and arch dimensions in a population-based study. AB - The associations between the aortic dimensions (of the aortic sinus, aortic annulus and aortic arch) and physiological variables have not been established in the Chinese population. The present study examined the associations among physiological variables to determine the aortic root and arch dimensions echocardiographically. The diameters of the aortic sinus, annulus and arch were measured in 1,010 subjects via 2-D echocardiography with a 3.5-MHz transducer in a trans-thoracic position. The images of the aortic sinus and aortic annulus were obtained from a standard parasternal long-axis view. The maximum diameter of the valve orifice was measured at the end of systole. The aortic arch dimension was visualized in the long-axis using a suprasternal notch window and the maximum transverse diameter was measured. Epidata 3.0, Excel 2007 and SPSS version 17.0 were used to collect and analyze the data. A total of 1,010 subjects were enrolled. The mean age was 55.0+/-17.0 years (range of 18 to 90 years). The body surface area (BSA) was the best predictor of all the studied physiological variables and may be used to predict aortic sinus, annulus and arch dimensions independently (r=0.54, 0.37 and 0.39, respectively). Gender, blood pressure, age and BSA are significant predictors of the aortic dimensions. Of these, BSA was the best predictor. PMID- 23439782 TI - Functional vs. Strength training in adults: specific needs define the best intervention. AB - BACKGROUND/PURPOSE: Studies that have aimed to compare different strategies to improve functional capacity have produced controversial results. Furthermore, such studies have focused solely on dependent individuals. In contrast, the present study aimed to compare traditional training to functional training for independent individuals. The purpose of this study was to compare traditional training to functional training in healthy and independent middle-aged adults (40 60 years old) and elderly subjects (older than 60 years old). METHODS: One hundred and one subjects (54.75 +/- 8.84 years) were divided into two groups that each performed 24 sessions of a training protocol twice per week. The subjects were assessed using quantitative (Y-Balance Test) and qualitative methods (Functional Movement ScreenTM). The individuals were compared by observing changes between pretest and posttest according to their intervention group, sex and age. RESULTS: When the entire sample was considered, the results showed that there were no differences in improvement between the training protocols. However, when specific groups were analyzed, functional training was less effective for women compared to men in the same group (Z=-2.598; p=0.009; effect size=0.43) and compared to women in the conventional group (Z=-2.704; p=0.007; effect size=0.41). CONCLUSIONS: There were no differences between the two protocols in their ability to improve functional capacity as measured by the two chosen outcome measures. However, each subject's condition before the intervention must be considered. Some individuals may require additional basic training or specific training. In the current study, the women may have needed to improve their basic capabilities before practicing more specific training protocols. LEVEL OF EVIDENCE: 2b. This is a pre- and post-intervention analysis using within-group and between-groups comparisons. PMID- 23439781 TI - Vulnerable plaque: from bench to bedside; local pacification versus systemic therapy. AB - Critical coronary stenoses accounts for a small proportion of acute coronary syndromes and sudden death. The majority are caused by coronary thromboses that arise from a nonangiographically obstructive atheroma. Recent developments in noninvasive imaging of so-called vulnerable plaques created opportunities to direct treatment to prevent morbidity and mortality associated with these high risk lesions. This review covers therapy employed in the past, present, and potentially in the future as the natural history of plaque assessment unfolds. PMID- 23439783 TI - Prevalence of fatigue among cancer patients receiving various anticancer therapies and its impact on quality of life: a cross-sectional study. AB - BACKGROUND: Fatigue is disabling and continuous phenomenon in cancer patients during and after various anticancer treatments which can continue for many years after treatment and definitely it has profound effect on Quality of Life (QOL). However, determining its severity is still underestimated among the cancer patients and also very few studies in the literature exist reporting on Cancer Related Fatigue (CRF) among Indian population. AIMS: To find out the prevalence of rate of fatigue in cancer patient receiving various anti cancer therapies. To find out the relative impact of fatigue on QOL. MATERIALS AND METHODS: This cross sectional observational study included a total 121 cancer patients receiving radiotherapy, chemotherapy, and concurrent chemo-radiation with the age group of above 15 years who fulfilled the inclusion and exclusion criteria. All the patients were assessed for severity of fatigue using Brief Fatigue Inventory (BFI) and for QOL using FACT-G scale while they were receiving the anticancer therapies as an in-patient in the regional cancer centers in Madhya Pradesh, India. RESULTS: The severe fatigue was more prevalent in chemotherapy [58/59 (98.30%)], and concurrent chemo-radiation (33/42 (78.57%)) as compared to radiotherapy (Moderate-9/20 (45%) and Severe-9/20 (45%)). Moderate correlations were exhibited between fatigue due to radiotherapy and QOL (r = -0.71, P < 0.01), whereas weak correlation was found between fatigue due to chemotherapy and concurrent chemo-radiation (r = -0.361, P < 0.01 and r = -0.453, P < 0.01, respectively). CONCLUSION: Severity of fatigue was found more after chemotherapy and concurrent chemo-radiation therapy while impact on QOL was more after the radiotherapy. PMID- 23439784 TI - Intra-articular methotrexate associated to lipid nanoemulsions: anti-inflammatory effect upon antigen-induced arthritis. AB - OBJECTIVE: Commercial methotrexate formulations (MTX) have poor anti-inflammatory action for intra-articular treatment of rheumatoid arthritis. Our aim was to investigate whether an association between methotrexate and lipidic nanoemulsions (LDE) could improve MTX intra-articular action. METHODS: For its association to LDE, MTX was previously esterified with dodecyl bromide. LDE-MTX was prepared by high pressure homogenization. Antigen-induced arthritis (AIA) was achieved in rabbits sensitized with methylated bovine serum albumin, and the rabbits were subsequently intra-articularly injected with the antigen. Twenty-four hours after AIA induction, groups of four to nine rabbits were intra-articularly injected with increasing doses (0.0625-0.5 MUmol/kg) of LDE-MTX, and were compared to treatment with 0.5 MUmol/kg commercial MTX, LDE alone, and saline (controls). Synovial fluid was collected 48 hours after AIA induction for analysis of protein leakage and cell content. Synovial membranes were collected for histopathology. Uptake of LDE labeled with (3)H-cholesteryl ether by the synovial tissue was also determined. RESULTS: Uptake of radioactive LDE by arthritic joints was 2.5-fold greater than by normal joints. Treatment with intra-articular LDE-MTX elicited a clear dose response pattern by reducing the synovial leukocyte infiltrate (P = 0.004) and protein leakage (P = 0.032) when compared with arthritic non-treated joints. In contrast, the intra-articular injection of commercial MTX and LDE did not reduce leukocyte infiltrate or protein leakage. Toxicity to treatment was not observed in any of the animals. CONCLUSION: The association between LDE and MTX presented a marked anti-inflammatory effect that was absent after intra-articular commercial MTX treatment. Therefore, the new formulation is a candidate for future clinical studies. PMID- 23439785 TI - The motor cortex: a network tuned to 7-14 Hz. AB - The neocortex or six layer cortex consists of at least 52 cytoarchitectonically distinct areas in humans, and similar areas can be distinguished in rodents. Each of these areas has a defining set of extrinsic connections, identifiable functional roles, a distinct laminar arrangement, etc. Thus, neocortex is extensively subdivided into areas of anatomical and functional specialization, but less is known about the specialization of cellular and network physiology across areas. The motor cortex appears to have a distinct propensity to oscillate in the 7-14 Hz frequency range. Augmenting responses, normal mu and beta oscillations, and abnormal oscillations or after discharges caused by enhancing excitation or suppressing inhibition are all expressed around this frequency range. The substrate for this activity may be an excitatory network that is unique to the motor cortex or that is more strongly suppressed in other areas, such as somatosensory cortex. Interestingly, augmenting responses are dependent on behavioral state. They are abolished during behavioral arousal. Here, I briefly review this evidence. PMID- 23439786 TI - Liquid Flooded Flow-Focusing Microfluidic Device for in situ Generation of Monodisperse Microbubbles. AB - Current microbubble-based ultrasound contrast agents are administered intravenously resulting in large losses of contrast agent, systemic distribution, and strict requirements for microbubble longevity and diameter size. Instead we propose in situ production of microbubbles directly within the vasculature to avoid these limitations. Flow focusing microfluidic devices (FFMDs) are a promising technology for enabling in situ production as they can produce microbubbles with precisely controlled diameters in real-time. While the microfluidic chips are small, the addition of inlets and interconnects to supply the gas and liquid phase greatly increases the footprint of these devices preventing the miniaturization of FFMDs to sizes compatible with medium and small vessels. To overcome this challenge, we introduce a new method for supplying the liquid (shell) phase to an FFMD that eliminates bulky interconnects. A pressurized liquid-filled chamber is coupled to the liquid inlets of an FFMD, which we term a flooded FFMD. The microbubble diameter and production rate of flooded FFMDs were measured optically over a range of gas pressures and liquid flow rates. The smallest FFMD manufactured measured 14.5 * 2.8 * 2.3 mm. A minimum microbubble diameter of 8.1 +/- 0.3 MUm was achieved at a production rate of 450,000 microbubbles/s (MB/s). This represents a significant improvement with respect to any previously reported result. The flooded design also simplifies parallelization and production rates of up to 670,000 MB/s were achieved using a parallelized version of the flooded FFMD. In addition, an intravascular ultrasound (IVUS) catheter was coupled to the flooded FFMD to produce an integrated ultrasound contrast imaging device. B-mode and IVUS images of microbubbles produced from a flooded FFMD in a gelatin phantom vessel were acquired to demonstrate the potential of in situ microbubble production and real time imaging. Microbubble production rates of 222,000 MB/s from a flooded FFMD within the vessel lumen provided a 23 dB increase in B-mode contrast. Overall, the flooded design is a critical contribution towards the long- term goal of utilizing in situ produced microbubbles for contrast enhanced ultrasound imaging of, and drug delivery to, the vasculature. PMID- 23439787 TI - Takayasu's Arteritis in a Patient with Sydenham's Chorea: is There an Association? AB - BACKGROUND: Takayasu's arteritis (TA) has been associated with many conditions. Herein described is a case of TA in a patient with rheumatic fever complicated with Sydenham's chorea. CASE REPORT: A 17-year-old female presented at age 6 with rheumatic fever followed by chorea a month later. At the age of 16, she developed a blood pressure discrepancy between the arms and faint pulses. Computed tomography angiography revealed diffuse aortic involvement and narrowing of the arteries. DISCUSSION: The presence of rheumatic fever and Sydenham's chorea in TA raises the possibility of an immunological basis for the pathogenesis of the disease. PMID- 23439788 TI - In vitro Studies of Antimicrobial Activity of Crude Extracts of the Indian Grasses Dhaman (Cenchrus ciliaris) and Kala-Dhaman (Cenchrus setigerus). AB - The aim of present study was to investigate the antimicrobial activity of Cenchrus ciliaris and Cenchrus setigerus extracts in order to use it as a possible source for new antimicrobial substances against important human pathogens. Crude extracts of the stem of Cenchrus ciliaris and Cenchrus setigerus were evaluated against some medically important pathogens viz. Escherichia coli, Raoultella planticola, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Enterobacter aerogenes, Candida albicans and Aspergillus flavus. The dried and powdered stems were successively extracted with hexane, toluene, isopropyl alcohol, acetone and ethanol using soxhlet assembly. The antimicrobial activity assay was done by both disc diffusion and serial dilution methods. Isopropyl alcohol extract of Cenchrus setigerus showed highest activity against Escherichia coli. The test pathogens were more sensitive to the isopropyl alcohol, acetone and ethanol extracts than to the hexane and toluene extracts except against Bacillus subtilis. Result reveals that the most bioactive compound was cycloleucolenol-9,19-cycloergost-24 (28)-en-3-ol, 4, 14-dimethyl acetate in both the species of Cenchrus grass, (19.15%) in isopropanol extract of Cenchrus setigerus whereas, (14.03%) in acetone extract of Cenchrus ciliaris. PMID- 23439789 TI - B-type natriuretic peptide as a predictor of outcome in a general intensive care unit. AB - BACKGROUND: B-type natriuretic peptide is a hormone secreted by the heart in response to ventricular wall stress. Increased B-type natriuretic peptide plasma levels are also found as a consequence of noncardiac conditions including sepsis, surgery-induced systemic inflammatory response syndrome and kidney failure. Since these conditions are common in general intensive care unit patients, we hypothesized that B-type natriuretic peptide could be a helpful marker in predicting outcome in this setting. METHODS: We measured plasma B-type natriuretic peptide concentrations in 228 patients at admission to our general intensive care unit. The primary aim of the study was to investigate the relationship between B-type natriuretic peptide and hospital mortality. The secondary aim of the study was to investigate the association between B-type natriuretic peptide and severity of disease, quantified by the Simplified Acute Physiology Score II. RESULTS: Logistic regression revealed a positive association between B-type natriuretic peptide level and in-hospital death (OR= 1.59; 95% CI 1.30 to 1.95; p<0.0001) and a Cox proportional hazards regression model showed that B-type natriuretic peptide was significantly associated with the risk of death (HR=1.27; 95% CI 1.11 to 1.46; p=0.0005). B-type natriuretic peptide was higher in patients who died in the hospital than in those who survived (371.20 pg/ml vs. 127.10 pg/ml; p<0.0001). There was a positive correlation between B type natriuretic peptide and Simplified Acute Physiology Score II (r=0.50; 95% CI 0.40 to 0.59; p<0.0001). DISCUSSION: B-type natriuretic peptide on admission is an independent prognostic marker of outcome in an unselected cohort of critically ill patients. PMID- 23439790 TI - Ranibizumab in patients with dense cataract and proliferative diabetic retinopathy with rubeosis. AB - BACKGROUND: To evaluate the safety of ranibizumab as a surgical adjunct during cataract surgery in patients with proliferative diabetic retinopathy (PDR) with rubeosis, and to evaluate the efficacy and adverse effects of ranibizumab in treating PDR with rubeosis. MATERIALS AND METHODS: Three intravitreal injections of 0.5 mg ranibizumab were administered on day-1, months-1 and -2 with cataract surgery 6-16 days after first injection. Retreatments with ranibizumab injections and pan-retinal photocoagulation (PRP) were given if recurrence or persistence of PDR was noted between months-3 and -11. Safety observation visits occurred at months-12, -18 and -24. Primary end points were incidence and severity of adverse events (AEs) that were related to both cataract surgery and treatment of PDR with rubeosis through month -12. RESULTS: Of six patients screened, four (mean age 61.3 years) were enrolled. No AEs were noted with either cataract surgery or treatment of PDR. Neovascularization of iris (NVI) promptly regressed by 4 days after first ranibizumab injection, prior to cataract surgery in three of four patients (one had significantly regressed NVI by post-injection day-3 visit); NVI was not noted in any patient at 2 weeks after first ranibizumab injection. Recurrence of rubeosis or NVA after 3 monthly injections was not observed in any. At month-12, PDR was not present when assessed clinically and by fluorescein angiogram (FA). Only one patient developed neovascularization of disc and neovascularization elsewhere and required retreatments at months-5 and -9. CONCLUSIONS: Multiple intravitreal injections of ranibizumab may be a safe, effective treatment adjunct for PDR and diabetes-related rubeosis. PMID- 23439791 TI - Diagnosis, prevention and management of postoperative pulmonary edema. AB - Postoperative pulmonary edema is a well-known postoperative complication caused as a result of numerous etiological factors which can be easily detected by a careful surveillance during postoperative period. However, there are no preoperative and intraoperative criteria which can successfully establish the possibilities for development of postoperative pulmonary edema. The aims were to review the possible etiologic and diagnostic challenges in timely detection of postoperative pulmonary edema and to discuss the various management strategies for prevention of this postoperative complication so as to decrease morbidity and mortality. The various search engines for preparation of this manuscript were used which included Entrez (including Pubmed and Pubmed Central), NIH.gov, Medknow.com, Medscape.com, WebMD.com, Scopus, Science Direct, MedHelp.org, yahoo.com and google.com. Manual search was carried out and various text books and journals of anesthesia and critical care medicine were also searched. From the information gathered, it was observed that postoperative cardiogenic pulmonary edema in patients with serious cardiovascular diseases is most common followed by noncardiogenic pulmonary edema which can be due to fluid overload in the postoperative period or it can be negative pressure pulmonary edema (NPPE). NPPE is an important clinical entity in immediate post-extubation period and occurs due to acute upper airway obstruction and creation of acute negative intrathoracic pressure. NPPE carries a good prognosis if promptly diagnosed and appropriately treated with or without mechanical ventilation. PMID- 23439792 TI - Cerebellar Ataxia from Multiple Potential Causes: Hypothyroidism, Hashimoto's Thyroiditis, Thalamic Stimulation, and Essential Tremor. AB - BACKGROUND: Both hypothyroidism and Hashimoto's thyroiditis (HT) can rarely be associated with cerebellar ataxia. Severe essential tremor (ET) as well as bilateral thalamic deep brain stimulation (DBS) may lead to subtle cerebellar signs. CASE REPORT: We report a 74-year-old male with hypothyroidism and a 20 year history of ET who developed cerebellar ataxia after bilateral thalamic DBS. Extensive workup revealed elevated thyroid stimulating hormone and thyroperoxidase antibody titers confirming the diagnosis of HT. DISCUSSION: Our case demonstrates multiple possible causes of cerebellar ataxia in a patient, including hypothyroidism, HT, chronic ET, and bilateral thalamic DBS. Counseling of patients may be appropriate when multiple risk factors for cerebellar ataxia coexist in one individual. PMID- 23439793 TI - Perioperative management of antiplatelet therapy in patients with drug-eluting stents. AB - Significant advancements in percutaneous treatment of coronary artery disease have been achieved with the introduction of bare metal stents. They have two major drawbacks: acute/subacute stent thrombosis, successfully managed with antiplatelet therapy immediately after stent implantation; and in-stent restenosis, prevention of which has been achieved with the development of drug eluting stents. Drug-eluting stents have become preferred therapy for patients undergoing coronary artery intervention, though reports of late stent thrombosis have led to uncertainty about the duration of antiplatelet therapy after drug eluting stents placement. Much controversy remains regarding perioperative management of patients with these devices, presenting for surgery or other invasive procedures. The purpose of this review is to provide an overview of the changing culture of coronary artery stenting, in addition to discussing perioperative management strategies and controversies surrounding coronary stents and antiplatelet therapy. A comprehensive literature search of MEDLINE was conducted using as keywords: antiplatelet therapy, non-coronary surgery, drug eluting stents, and stent thrombosis. There is no definite standard of care for the perioperative management of drug-eluting stents in patients with drug-eluting stents. However, there is a growing understanding of the importance of continuation of drug-eluting stents in the perioperative period in order to prevent stent thrombosis along with a concern about the possibility of increased bleeding. Appropriate timing of surgery after coronary artery stenting, team approach to the perioperative management of such patients with involvement of cardiologist, anesthesiologist, and surgeon, and development of an individual plan for each patient, weighing that patient's risk of thrombosis vs the risk of bleeding, could improve patient safety and optimize outcome. PMID- 23439794 TI - Influence of aspirin on pilocarpine-induced epilepsy in mice. AB - Aspirin (acetylsalicylic acid) is one of the most widely used therapeutic agents based on its pharmacological actions, including anti-inflammatory, analgesic, anti-pyretic, and anti-thrombotic effects. In this study, we investigated the effects of aspirin on seizure susceptibility and hippocampal neuropathology following pilocarpine-induced status epilepticus (SE). SE was induced by pilocarpine hydrochloride (280 mg/kg, i.p.) administration in C57BL/6 mice (aged 8 weeks). Aspirin was administered daily (15 mg/kg or 150 mg/kg, i.p.) for 10 days starting 3 days before SE, continuing until 6 days after SE. After pilocarpine injection, SE onset time and mortality were recorded. Neuronal cell death was examined using cresyl violet and Fluoro-Jade staining, and glial responses were observed 7 days post SE using immunohistochemistry. In the aspirin treated group, the onset time of SE was significantly shortened and mortality was markedly increased compared to the control group. However, in this study, aspirin treatment did not affect SE-induced neuronal cell death or astroglial and microglial responses in the hippocampus. In conclusion, these results suggest that the safety of aspirin should be reevaluated in some patients, especially with neurological disorders such as temporal lobe epilepsy. PMID- 23439795 TI - Can timing of tracheal extubation predict improved outcomes after cardiac surgery? AB - INTRODUCTION: Early tracheal extubation is a common goal after cardiac surgery. Our study aims to examine whether timing of tracheal extubation predicts improved postoperative outcomes and late survival after cardiac surgery. We also evaluated the optimal timing of extubation and its association with better postoperative outcomes. METHODS: Between 2002 and 2006, 1164 patients underwent early tracheal extubation (<6 hours after surgery) and 1571 had conventional extubation (>6 hours after surgery). Propensity score adjustment and multivariable logistic regression analysis were used to adjust for imbalances in the patients' preoperative characteristics. Receiver operating characteristic curves (ROC) were used to identify the best timing of extubation and improved postoperative outcomes. Cox regression analysis was used to identify whether early extubation is a risk factor for decreased late mortality. RESULTS: Results - Early extubation was associated with lower propensity score-adjusted rate of operative mortality (Odds Ratio =0.55, 95% Confidence Intervals =0.31-0.98, p=0.043). Extubation within 9 hours emerged as the best predictor of improved postoperative morbidity and mortality (sensitivity =85.5%, specificity =52.7%, accuracy =64.5%). Early extubation also predicted decreased late mortality (Hazard Ratio =0.45, 95% Confidence Intervals 0.31-0.67, p<0.001). CONCLUSIONS: Early extubation may predict improved outcomes after cardiac surgery. Extubation within 9 hours after surgery was the best predictor of uncomplicated recovery after cardiac surgery. Those patients intubated longer than 16 hours have a poorer postoperative prognosis. Early extubation predicts prolonged survival up to 16 months after surgery. PMID- 23439796 TI - Chronic idiopathic neutrophilia in a smoker, relieved after smoking cessation with the use of electronic cigarette: a case report. AB - INTRODUCTION: Smoking is a major risk factor for a variety of diseases. Electronic cigarettes are battery-operated devices that deliver nicotine to the lungs by evaporation of a liquid. Chronic idiopathic neutrophilia is a condition characterized by elevated white blood cell and neutrophil counts without any underlying disease; smoking has been implicated as a potential cause. CASE PRESENTATION: A male Caucasian patient, born in 1977, presented in September 2005 with asymptomatic elevation of white blood cell and neutrophil count, and mildly elevated C-reactive protein levels. He was a smoker since 1996 and was treated with 20 mg/day of simvastatin since 2003 due to hyperlipidemia. Clinical examination, and laboratory and imaging investigations ruled out any infectious, haematological, rheumatological, or endocrine conditions. He was followed-up regularly and was advised to stop smoking. He had 2 unsuccessful attempts to quit smoking; one was unassisted and the second was performed with the use of both varenicline and nicotine replacement therapy (patches). During the subsequent 6.5 years, his leukocyte and C-reactive protein levels were repeatedly elevated; the condition was consistent with chronic idiopathic neutrophilia. In February 2012, he started using electronic cigarettes and he managed to quit smoking within 10 days. After 6 months, laboratory examination showed normalized leukocyte count and C-reactive protein levels, confirmed immediately by a second laboratory and by repeated tests after 1 and 2 months. CONCLUSION: Smoking cessation with the use of electronic cigarette led to reversal of chronic idiopathic neutrophilia. The daily use of electronic cigarette may help preserve the beneficial effects of smoking cessation. PMID- 23439797 TI - Mobile pedunculated left ventricular masses in a man with recurrent emboli. AB - A 51-year-old man was found to have left ventricular masses by transthoracic echocardiography, one attached to the posterior wall of the left ventricle and another attached to the anterolateral wall of the left ventricle. He had several events of systemic embolization over the last few weeks. Surgical excision was recommended to avoid further embolization. The patient underwent successful resection of the left ventricular masses under cardiopulmonary bypass through the left atrial and transverse aortotomy approach. Histopathologic exam was diagnostic for organized thrombi. PMID- 23439798 TI - A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. AB - CONTEXT: Stress is a state of mental or emotional strain or tension, which can lead to underperformance and adverse clinical conditions. Adaptogens are herbs that help in combating stress. Ayurvedic classical texts, animal studies and clinical studies describe Ashwagandha as a safe and effective adaptogen. AIMS: The aim of the study was to evaluate the safety and efficacy of a high concentration full-spectrum extract of Ashwagandha roots in reducing stress and anxiety and in improving the general well-being of adults who were under stress. SETTINGS AND DESIGN: Single center, prospective, double-blind, randomized, placebo-controlled trial. MATERIALS AND METHODS: A total of 64 subjects with a history of chronic stress were enrolled into the study after performing relevant clinical examinations and laboratory tests. These included a measurement of serum cortisol, and assessing their scores on standard stress-assessment questionnaires. They were randomized to either the placebo control group or the study drug treatment group, and were asked to take one capsule twice a day for a period of 60 days. In the study drug treatment group, each capsule contained 300 mg of high-concentration full-spectrum extract from the root of the Ashwagandha plant. During the treatment period (on Day 15, Day 30 and Day 45), a follow-up telephone call was made to all subjects to check for treatment compliance and to note any adverse reactions. Final safety and efficacy assessments were done on Day 60. STATISTICAL ANALYSIS: t-test, Mann-Whitney test. RESULTS: The treatment group that was given the high-concentration full-spectrum Ashwagandha root extract exhibited a significant reduction (P<0.0001) in scores on all the stress assessment scales on Day 60, relative to the placebo group. The serum cortisol levels were substantially reduced (P=0.0006) in the Ashwagandha group, relative to the placebo group. The adverse effects were mild in nature and were comparable in both the groups. No serious adverse events were reported. CONCLUSION: The findings of this study suggest that a high-concentration full-spectrum Ashwagandha root extract safely and effectively improves an individual's resistance towards stress and thereby improves self-assessed quality of life. PMID- 23439799 TI - A preliminary clinical evaluation of external snehan and asanas in the patients of sciatica. AB - Lower back pain radiating to either on one leg or both legs along the course of sciatic nerve is a common ailment in the clinical practice, this type of peculiar symptomatology is termed as "Sciatica" in modern medicine. The medical treatment is unsatisfactory for both the patient and the neurosurgeons, as the surgical treatment has its own hazards and the cost of the surgical procedure and medical treatment is prohibitory to most of the Indian patients. Hence, most of the patients present themselves to the practitioners of Indian medicines like Ayurveda and yoga. This study was designed to evaluate the preliminary clinical effects of Bahya Snehan and Asanas in the patients of sciatica. This was a prospective randomized active control trial. A total of 60 participants showing classical symptoms of Sciatica between 18 and 65 years of age were randomly assigned to receive Ayurvedic or Yogic measure. One group received Snehan (external) with Bhujang and Shalabh Asana while another group received Bhujang and Salabh Asana only. Both groups practiced supervised intervention for 4 weeks. The signs and symptoms like Katishool (pain), tenderness, Stambha (rigidity), difficulty in walking, pain on bending forward were graded and interpreted at the end of the trail Significant improvement was observed in both groups before and after external Snehan with Bhujang and Shalabh Asana and in another group Bhujang and Salabh Asana only. CONCLUSIONS: Both groups, one with Snehan with asanas and the second with asanas only showed significant improvement in the patients of sciatica (Gridhrasi). PMID- 23439800 TI - Interactions with heterospecific males do not affect how female Mesocricetus hamsters respond to conspecific males. AB - Reproductive interference includes any interspecific interaction that reduces the fitness of one or both species involved. There are several types of reproductive interference, but they normally involve the direct cost of interacting or mating with heterospecifics. An indirect cost of interacting with heterospecific individuals is a consequent reduction in successful interactions with conspecifics. We tested the hypothesis that being aggressive towards a heterospecific individual will diminish sexual responses towards conspecifics in later encounters. We used two species of Mesocricetus hamsters (Syrian and Turkish hamsters), whose interspecific interactions have previously been determined. We exposed or both exposed and paired Syrian hamster females with a conspecific or a heterospecific male. Five minutes later, we paired all females with a conspecific male and measured the latency to lordosis, the duration of lordosis and any incidence of aggression. We found that (1) interactions with heterospecific males did not affect how females responded to conspecific males in later encounters and (2) previous pairing of female subjects with either conspecific or heterospecific males promoted a faster sexual response by females in subsequent interactions with conspecific males. Thus, aggressive interactions of Syrian hamster females with heterospecific males, contrary to our initial hypothesis, had a positive effect on subsequent interactions with conspecific males. PMID- 23439801 TI - A study on professional stress, depression and alcohol use among Indian IT professionals. AB - BACKGROUND: Stress has touched almost all professions posing threat to mental and physical health. India being the Information Technology (IT) hub with lakhs involved as IT Professionals, there is a need to assess prevalence of professional stress, depression and problem alcohol use and understand their association. OBJECTIVES: (1) To screen for the prevalence of professional stress, risk for depression and harmful alcohol use among software engineers. (2) To study the association between professional stress, risk for depression and harmful alcohol use. MATERIALS AND METHODS: This is a cross-sectional online study conducted using screeing questionnaires like professional life stress scale, centre for epidemiological studies depression scale and alcohol use disorders identification test. This study was conducted specifically on professionals working in an IT firm with the designation of a software engineer. RESULTS: A total of 129 subjects participated in the study. 51.2% of the study sample was found to be professionally stressed at the time of the interview. 43.4% of the study population were found to be at risk for developing depression. 68.2% of those who were professionally stressed were at risk for developing depression compared with only 17.5% of those who were not professionally stressed. Odds ratio revealed that subjects who were professionally stressed had 10 times higher risk for developing depression compared to those who were not professionally stressed. Subjects who were professionally stressed had 5.9 times higher prevalence of harmful alcohol use compared to those who were not professionally stressed. Subjects who were at risk for developing depression had 4.1 times higher prevalence of harmful alcohol use compared with those who were not at risk for developing depression. CONCLUSION: Such higher rates of professional stress, risk for developing depression and harmful alcohol use among software engineers could hinder the progress of IT development and also significantly increase the incidence of psychiatric disorders. PMID- 23439802 TI - Predictive clinical parameters and glycemic efficacy of vildagliptin treatment in korean subjects with type 2 diabetes. AB - BACKGROUND: The aims of this study are to investigate the glycemic efficacy and predictive parameters of vildagliptin therapy in Korean subjects with type 2 diabetes. METHODS: In this retrospective study, we retrieved data for subjects who were on twice-daily 50 mg vildagliptin for at least 6 months, and classified the subjects into five treatment groups. In three of the groups, we added vildagliptin to their existing medication regimen; in the other two groups, we replaced one of their existing medications with vildagliptin. We then analyzed the changes in glucose parameters and clinical characteristics. RESULTS: Ultimately, 327 subjects were analyzed in this study. Vildagliptin significantly improved hemoglobin A1c (HbA1c) levels over 6 months. The changes in HbA1c levels (DeltaHbA1c) at month 6 were -2.24% (P=0.000), -0.77% (P=0.000), -0.80% (P=0.001), -0.61% (P=0.000), and -0.34% (P=0.025) for groups 1, 2, 3, 4, and 5, respectively, with significance. We also found significant decrements in fasting plasma glucose levels in groups 1, 2, 3, and 4 (P<0.05). Of the variables, initial HbA1c levels (P=0.032) and history of sulfonylurea use (P=0.026) were independently associated with responsiveness to vildagliptin treatment. CONCLUSION: Vildagliptin was effective when it was used in subjects with poor glycemic control. It controlled fasting plasma glucose levels as well as sulfonylurea treatment in Korean type 2 diabetic subjects. PMID- 23439803 TI - Role of continuous positive airway pressure to the non-ventilated lung during one lung ventilation with low tidal volumes. AB - INTRODUCTION: In multiple study populations large tidal volumes (8 - 12 ml/kg) have deleterious effects on lung function in multiple study populations. The accepted approach to hypoxemia during one-lung ventilation is the application of continuous positive airway pressure to the non-ventilated lung first, followed by application of positive end-expiratory pressure to the ventilated lung. To our knowledge the effectiveness of positive end-expiratory pressure or continuous positive airway pressure on maintaining PaO(2) with one-lung ventilation was not studied with smaller tidal volume (6ml/kg) ventilation. Our objective was to compare continuous positive airway pressure of 5 cm H(2)O or positive end expiratory pressure of 5 cm H(2)O during small tidal volume one-lung ventilation. METHODS: Thirty patients undergoing elective, open thoracotomy with one-lung ventilation were randomized to continuous positive airway pressure or positive end-expiratory pressure and then crossed over to the other modality. RESULTS: There was a statistically significant higher PaO(2) (141+/-81.6 vs 112+/-48.7, p = 0.047) with continuous positive airway pressure than positive end-expiratory pressure while on one-lung ventilation. Two patients desaturated requiring 100% O(2) with both positive end-expiratory pressure and continuous positive airway pressure. On two occasions the surgeon requested the continuous positive airway pressure be discontinued due to lung inflation. CONCLUSION: The use of continuous positive airway pressure of 5 cm H(2)O to the non-ventilated lung while using small tidal volumes for one-lung ventilation improved PaO(2) when compared with positive end-expiratory pressure of 5 cm H(2)O to the ventilated lung. PMID- 23439804 TI - Objective Evaluation of Overactive Bladder: Which Surveys Should I Use? AB - Overactive bladder (OAB) is a common condition that affects many adults, and prevalence increases with age in both men and women. It is characterized by symptoms of urinary frequency and urgency with or without urge incontinence in the absence of another proven etiology. As a diagnosis based solely on urinary symptoms, proper evaluation of OAB often depends on the use of psychometrically validated questionnaires to assess symptom severity and degree of bother. General urinary assessment forms can evaluate many urinary symptoms while modular questionnaires can focus on the most bothersome complaints. Many questionnaires have been formulated and validated to achieve these goals. Currently, the ideal questionnaire does not exist. This review attempts to outline the range of questionnaires available to the clinician to assist in evaluating symptoms as well as degree of impact on quality of life. PMID- 23439805 TI - Type 3 renal tubular acidosis. AB - Renal tubular acidosis (RTA) is a group of transport defects in the reabsorption of bicarbonate, the excretion of hydrogen ion (H(+)), or both, resulting in systemic acidosis and hypokalemia with a normal glomerular filtration rate. Although isolated proximal (type 2) or distal (type 1) tubular pathologies are well characterized, a combined pathology leading to type 3 RTA is very rare. Here, we report a case of type 3 RTA, using an algorithmic approach to classify a scenario of hypokalemic metabolic acidosis in the setting of episodic flaccid paralysis. PMID- 23439806 TI - Bullet embolisation from injured inferior cava vein to the right ventricle. AB - Gunshot injuries of the human body challenge surgical teams in the emergency department. Since such injuries do not follow any rule, every patient should be considered a special case. Our case, of bullet embolism from injured inferior cava vein to the right heart ventricle is a rare one. Such cases make us be more alert for diagnosis and treatment of this kind of injury. Well equipped hospitals and experienced medical teams are necessary for successful outcome. PMID- 23439809 TI - Development of a physical performance assessment checklist for athletes who sustained a lower extremity injury in preparation for return to sport: a delphi study. AB - PURPOSE/BACKGROUND: To develop a consensus on the critical constructs necessary to be included in a physical performance assessment checklist (PPAC) to assess an athlete's ability for return to sport following a lower extremity injury. METHODS: The study used a 3-round Delphi method to finalize the PPAI originally developed by a panel of experts. Fourteen Delphi representative sample participants were randomly derived from the authors of peer-reviewed publications of lower extremity injuries. Nine participants completed all 3 rounds. RESULTS: Throughout the 3 rounds, the 10 initial constructs were modified and revised to produce the finalized PPAC consisting of 12 constructs necessary to consider for an athlete's return to sport after a lower extremity injury. CONCLUSIONS: This instrument can be used as a checklist to advocate for prospective batteries of physical performance tests to incorporate the elements identified by this study. LEVEL OF EVIDENCE: 5. PMID- 23439810 TI - Anesthesia and analgesia case reports. PMID- 23439811 TI - Combined spinal epidural or traditional epidural technique: who wins? PMID- 23439812 TI - Transcatheter aortic valve replacement: an encounter with innovation in the field of cardiothoracic anesthesiology. PMID- 23439813 TI - Scientific fraud: impact of Fujii's data on our current knowledge and practice for the management of postoperative nausea and vomiting. PMID- 23439814 TI - A different perspective on anesthetics and climate change. PMID- 23439815 TI - Importance of education in interpretation of alarms. PMID- 23439816 TI - The impact of portopulmonary hypertension on intraoperative right ventricular function of living donor liver transplant recipients. PMID- 23439817 TI - Nonsustained ventricular tachycardia resolving under general anesthesia: a case presentation. PMID- 23439818 TI - Editor's note: notices of retractions. PMID- 23439821 TI - Prevention of postoperative nausea and vomiting with a combination of granisetron and droperidol. Anesth Analg 1998;86:613-6. Retraction. PMID- 23439822 TI - The effects of milrinone and its mechanism in the fatigued diaphragm in dogs: Anesth Analg 1998;87:1077-82. Retraction. PMID- 23439823 TI - Prophylactic oral antiemetics for preventing postoperative nausea and vomiting: granisetron versus domperidone. Anesth Analg 1998;87:1404-7. Retraction. PMID- 23439824 TI - A granisetron-droperidol combination prevents postoperative vomiting in children. Anesth Analg 1998;87:761-5. Retraction. PMID- 23439825 TI - Preoperative oral antiemetics for reducing postoperative vomiting after tonsillectomy in children: granisetron versus perphenazine. Anesth Analg 1999;88:1298-301. Retraction. PMID- 23439826 TI - Granisetron/dexamethasone combination for reducing nausea and vomiting during and after spinal anesthesia for cesarean section. Anesth Analg 1999;88:1346-50. Retraction. PMID- 23439827 TI - Propofol decreases diaphragmatic contractility in dogs. Anesth Analg 1999;89:1557 60. Retraction. PMID- 23439829 TI - The effect of olprinone compared with milrinone on diaphragmatic muscle function in dogs. Anesth Analg 1999;89:781-5. Retraction. PMID- 23439828 TI - Comparison of ramosetron and granisetron for preventing postoperative nausea and vomiting after gynecologic surgery. Anesth Analg 1999;89:476-9. Retraction. PMID- 23439830 TI - Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery. Anesth Analg 2000;90:472-5. Retraction. PMID- 23439831 TI - The effect of sedative drugs on diaphragmatic contractility in dogs: propofol versus midazolam. Anesth Analg 2000;91:1035-7. Retraction. PMID- 23439832 TI - Dose-response characteristics of midazolam for reducing diaphragmatic contractility. Anesth Analg 2001;92:1590-3. Retraction. PMID- 23439833 TI - Colforsin daropate improves contractility in fatigued canine diaphragm. Anesth Analg 2001;92:762-6. Retraction. PMID- 23439835 TI - The dose-related efficacy of diltiazem for enhancing diaphragmatic fatigability in dogs. Anesth Analg 2002;95:129-32. Retraction. PMID- 23439834 TI - The dose-range effects of propofol on the contractility of fatigued diaphragm in dogs. Anesth Analg 2001;93:1194-8. Retraction. PMID- 23439836 TI - Flumazenil recovers diaphragm muscle dysfunction caused by midazolam in dogs. Anesth Analg 2002;95:944-7. Retraction. PMID- 23439837 TI - The effect of inhaled colforsin daropate on contractility of fatigued diaphragm in dogs. Anesth Analg 2003;96:1032-4. Retraction. PMID- 23439838 TI - Midazolam-induced muscle dysfunction and its recovery in fatigued diaphragm in dogs. Anesth Analg 2003;97:755-8. Retraction. PMID- 23439839 TI - The recovery profile of reduced diaphragmatic contractility induced by propofol in dogs. Anesth Analg 2004;99:113-6. Retraction. PMID- 23439840 TI - The effects of different dobutamine infusion rates on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs. Anesth Analg 2007;105:1379-84. Retraction. PMID- 23439841 TI - Quality of life outcomes in patients living with stoma. AB - BACKGROUND: Despite efforts to maintain the intestinal tissue and treat gastrointestinal disease, a large number of patients undergo ostomy surgery each year. Using stoma reduces the patient's quality of life (QOL) greatly. Although there are approximately 3000 patients in Iran; there is little information about the impact of stoma on their QOL. AIMS: The study aims to evaluate QOL of stoma patients using a special measurement tool. SETTINGS AND DESIGN: This survey was a cross-sectional study that was conducted on 102 random samples of stoma patients. MATERIALS AND METHODS: The City of Hope Quality of Life-Ostomy Questionnaire was used for collecting demographic and clinical information and evaluating QOL. STATISTICAL ANALYSIS USED: Univariate and multiple regression analyses were performed to identify predictors of QOL. RESULTS: The mean score for the overall QOL for stoma patients was 7.48 +/- 0.9. 70% of patients were dissatisfied with sexual activities. More than half of them reported feelings of depression following stoma surgery. Univariate analysis indicated that factors such as the type of ostomy (temporary/permanent), the underlying disease that had led to the stoma, depression, problem with location of ostomy, and change in clothing style had significant effects on overall QOL and its subscales (P < 0.05). The results of the regression analyses showed that only depression and problem with the location of ostomy were statistically significant in predicting patients' QOL and its subscales (P < 0.05). CONCLUSIONS: The findings demonstrated that living with stoma influences the overall aspect of QOL. Education for the patients and their families is important for improving the stoma patients' QOL. Sexual and psychological consultation may also improve patients' QOL. PMID- 23439842 TI - Liposomes and nanotechnology in drug development: focus on ocular targets. AB - Poor drug delivery to lesions in patients' eyes is a major obstacle to the treatment of ocular diseases. The accessibility of these areas to drugs is highly restricted by the presence of barriers, including the corneal barrier, aqueous barrier, and the inner and outer blood-retinal barriers. In particular, the posterior segment is difficult to reach for drugs because of its structural peculiarities. This review discusses various barriers to drug delivery and provides comprehensive information for designing nanoparticle-mediated drug delivery systems for the treatment of ocular diseases. Nanoparticles can be designed to improve penetration, controlled release, and drug targeting. As highlighted in this review, the therapeutic efficacy of drugs in ocular diseases has been reported to be enhanced by the use of nanoparticles such as liposomes, micro/nanospheres, microemulsions, and dendrimers. Our recent data show that intravitreal injection of targeted liposomes encapsulating an angiogenesis inhibitor caused significantly greater suppression of choroidal neovascularization than did the injection of free drug. Recent progress in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising approach for advanced therapy of ocular diseases. PMID- 23439843 TI - SPG11 Presenting with Tremor. AB - BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurological diseases, which typically present with progressive lower extremity weakness and spasticity causing progressive walking difficulties. Complicating neurological or extraneurological features may be present. CASE REPORT: We describe a 19-year-old male who was referred because of an action tremor of the hands; he later developed walking difficulties. Callosal atrophy was present on his cerebral magnetic resonance imaging scan, prompting genetic testing for SPG11, which revealed homozygous mutations. DISCUSSION: The clinical features, differential diagnosis and management of SPG11, the most common form of autosomal recessive complicated HSP with a thin corpus callosum are discussed. PMID- 23439844 TI - Constituents of Artemisia gmelinii Weber ex Stechm. from Uttarakhand Himalaya: A Source of Artemisia Ketone. AB - The essential oils isolated from the aerial parts of two different populations of Artemisia gmelinii growing in Uttarakhand Himalaya region were analysed by gas chromatography and gas chromatography/mass spectrometry (GC-MS) in order to determine the variation of concentration in their constituents. Artemisia ketone was detected as a major constituent in both the populations i.e., Niti valley and Jhelum samples. Niti oil was found to have considerably greater amounts of artemesia ketone (53.34%) followed by alpha-thujone (9.91%) and 1,8-cineole (6.57%), Similarly, the first major compound in Jhelum oil was artemesia ketone (40.87%), whereas ar-curcumene (8.54%) was identified as a second major compound followed by alpha-thujone (4.04%). Artemisia ketone can be useful for perfumery and fragrance to introduce new and interesting herbaceous notes. PMID- 23439845 TI - The Role of Parenting in Alcohol and Tobacco Use Among Latino Adolescents. AB - Parents can impact adolescent substance use, but it is unclear which substances are most affected. This study compared associations between parenting behaviors and alcohol and tobacco use to see if parenting was equally related to both behaviors. Alcohol and tobacco use data were collected from 252 Latino adolescents living along the San Diego-Tijuana border. Logistic regression was used to test parenting behaviors' impact. Parenting was protective against alcohol use, but not related to tobacco use. Substance using peers affected both alcohol and tobacco use. Alcohol prevention efforts among Latino adolescents should target parenting behaviors. PMID- 23439846 TI - PANDA: a pipeline toolbox for analyzing brain diffusion images. AB - Diffusion magnetic resonance imaging (dMRI) is widely used in both scientific research and clinical practice in in-vivo studies of the human brain. While a number of post-processing packages have been developed, fully automated processing of dMRI datasets remains challenging. Here, we developed a MATLAB toolbox named "Pipeline for Analyzing braiN Diffusion imAges" (PANDA) for fully automated processing of brain diffusion images. The processing modules of a few established packages, including FMRIB Software Library (FSL), Pipeline System for Octave and Matlab (PSOM), Diffusion Toolkit and MRIcron, were employed in PANDA. Using any number of raw dMRI datasets from different subjects, in either DICOM or NIfTI format, PANDA can automatically perform a series of steps to process DICOM/NIfTI to diffusion metrics [e.g., fractional anisotropy (FA) and mean diffusivity (MD)] that are ready for statistical analysis at the voxel-level, the atlas-level and the Tract-Based Spatial Statistics (TBSS)-level and can finish the construction of anatomical brain networks for all subjects. In particular, PANDA can process different subjects in parallel, using multiple cores either in a single computer or in a distributed computing environment, thus greatly reducing the time cost when dealing with a large number of datasets. In addition, PANDA has a friendly graphical user interface (GUI), allowing the user to be interactive and to adjust the input/output settings, as well as the processing parameters. As an open-source package, PANDA is freely available at http://www.nitrc.org/projects/panda/. This novel toolbox is expected to substantially simplify the image processing of dMRI datasets and facilitate human structural connectome studies. PMID- 23439847 TI - The impact of extensive clonal growth on fine-scale mating patterns: a full paternity analysis of a lily-of-the-valley population (Convallaria majalis). AB - BACKGROUND AND AIMS: The combination of clonality and a mating system promoting outcrossing is considered advantageous because outcrossing avoids the fitness costs of selfing within clones (geitonogamy) while clonality assures local persistence and increases floral display. The spatial spread of genetically identical plants (ramets) may, however, also decrease paternal diversity (the number of sires fertilizing a given dam) and fertility, particularly towards the centre of large clumped clones. This study aimed to quantify the impact of extensive clonal growth on fine-scale paternity patterns in a population of the allogamous Convallaria majalis. METHODS: A full analysis of paternity was performed by genotyping all flowering individuals and all viable seeds produced during a single season using AFLP. Mating patterns were examined and the spatial position of ramets was related to the extent of multiple paternity, fruiting success and seed production. KEY RESULTS: The overall outcrossing rate was high (91 %) and pollen flow into the population was considerable (27 %). Despite extensive clonal growth, multiple paternity was relatively common (the fraction of siblings sharing the same father was 0.53 within ramets). The diversity of offspring collected from reproductive ramets surrounded by genetically identical inflorescences was as high as among offspring collected from ramets surrounded by distinct genets. There was no significant relationship between the similarity of the pollen load received by two ramets and the distance between them. Neither the distance of ramets with respect to distinct genets nor the distance to the genet centre significantly affected fruiting success or seed production. CONCLUSIONS: Random mating and considerable pollen inflow most probably implied that pollen dispersal distances were sufficiently high to mitigate local mate scarcity despite extensive clonal spread. The data provide no evidence for the intrusion of clonal growth on fine-scale plant mating patterns. PMID- 23439848 TI - Preoperative IABP in high risk patients undergoing CABG. AB - A recent international consensus conference on the reduction in mortality in cardiac anesthesia and intensive care included intraoperative aortic balloon pump among the ancillary (i.e. non-surgical) drugs/techniques/strategies that might influence survival rates in patients undergoing cardiac surgery. The consensus conferences state that "Pre-operative intraoperative aortic balloon pump might reduce 30-day mortality in elective high risk patients undergoing coronary artery bypass surgery unless specifically contraindicated". The authors of this "expert opinion" presents their insights into the use of the preoperative intraoperative aortic balloon pump and conclude that based on available limited randomized controlled trials and clinical experience preoperative intraoperative aortic balloon pump saves lives in unstable patients. PMID- 23439849 TI - Prevalence of restless leg syndrome in subjects with depressive disorder. AB - BACKGROUND: Restless legs syndrome (RLS) is known to be associated with depression. We hypothesized that RLS in depression is linked to the severity, duration, and frequency of depressive episodes. MATERIALS AND METHODS: Subjects fulfilling DSM-IV-TR criteria of depressive disorders were included in this study after seeking informed consent. Using structured interview of MINI-Plus their demographic data and history were recorded. Severity of depression was assessed with the help of HAM-D. Insomnia was diagnosed following ICSD-2 criteria. RLS was diagnosed according to IRLSSG criteria. Descriptive statistics, Chi-square test, independent sample t test and MANOVA were computed with the help of SPSS v 17.0. RESULTS: RLS was reported by 31.48% of sample. There was no gender difference in prevalence of RLS (X(2) =0.46; P=0.33). There was no difference in the age , total duration of depressive illness and number of depressive episodes between RLS and non-RLS groups (F=0.44; P=0.77; Wilk's Lambda=0.96). The HAM-D score was higher in the non-RLS group (P=0.03). Onset of RLS symptoms was not related to onset of depressive symptoms. CONCLUSION: RLS is prevalent in depressive disorder. However, onset of RLS is unrelated to age and number or duration of depressive disorders. PMID- 23439850 TI - Examining the motor phenotype of patients with both essential tremor and Parkinson's disease. AB - BACKGROUND: The subset of patients with essential tremor (ET) that develops Parkinson's disease (PD) has not been fully clinically characterized. METHODS: Motor features were retrospectively reviewed in 18 ET patients who developed PD (ET->PD), 20 ET and 30 PD patients with similar ages and disease durations. RESULTS: Fewer ET->PD than ET patients had widespread postural and/or action tremor (2/17 [11.8%] vs. 11/17 [64.7%]; p = 0.001) and marginally fewer had cerebellar signs (1/15 [6.7%] vs. 6/18 [33.3%], p = 0.06). ET->PD patients required fewer ET medications than did their counterparts with ET (p = 0.001). ET >PD patients and PD patients did not differ in UPDRS, Hoehn and Yahr, or Schwab and England scores (each p>=0.14). DISCUSSION: ET patients who develop PD may have distinct pre-PD motor features compared to their counterparts with ET who do not develop co-existing PD. Prospective studies are needed to evaluate the predictive value of these clinical features for the emergence of PD. PMID- 23439851 TI - Cardiac anesthesia and surgery in geriatric patients: epidemiology, current surgical outcomes, and future directions. AB - The mean life expectancy of the population of the United States is projected to increase from 78.3 years at present to over 81 years in 2025, with a concomitant increase in the percentage of the population over the age of 75 years. Elderly patients are more likely to present with valvular and coronary artery disease than younger patients, and as better perioperative management contributes to improving post-operative outcomes and lower referral thresholds, very elderly patients form an increasingly large proportion of the cardiac surgical population. This article summarizes the impact of age-related pathophysiologic changes on patients' response to cardiac surgery and anesthesia, outlines useful perioperative strategies in this age group, and reviews the literature on outcomes after valvular and coronary in elderly patients. PMID- 23439852 TI - Spontaneous coronary artery dissection: case report and review of literature. AB - Spontaneous coronary artery dissection (SCAD) is an unusual cause of acute coronary syndrome or sudden cardiac death. SCAD has most frequently been described as presenting as an acute coronary syndrome in females during the peripartum period. It may also be associated with autoimmune and collagen vascular diseases, Marfan's syndrome, chest trauma, and intense physical exercise. The most common presentation of SCAD is the acute onset of severe chest pain associated with autonomic symptoms. This condition has a high mortality rate if not identified and treated promptly. Here, we present a case of SCAD presenting with stroke, followed by a brief review. PMID- 23439853 TI - Comparison of intravitreal bevacizumab, intravitreal triamcinolone acetonide, and macular grid augmentation in refractory diffuse diabetic macular edema: A prospective, randomized study. AB - BACKGROUND: In spite of laser being the gold standard treatment for Diabetic Macular edema (DME), some patients do not respond to laser. Various treatment modalities are being tried in the management of refractory diffuse DME (DDME). PURPOSE: To compare the efficacy of intravitreal bevacizumab (IVB), intravitreal triamcinolone acetonide (IVTA), and macular grid augmentation in the management of refractory DDME. SETTINGS AND DESIGN: Prospective randomized study in a tertiary eye care center. MATERIALS AND METHODS: SIXTY PATIENTS WITH REFRACTORY DDME WERE RANDOMLY ASSIGNED TO THREE GROUPS: Group 1 received IVB (1.25 mg/0.05 ml), Group 2 received IVTA (4 mg/0.1ml), and Group 3 underwent laser augmentation. Primary outcome measures were best corrected visual acuity (BCVA) and central macular thickness (CMT) at the end of 6 months. STATISTICS: Analysis was performed using SPSS 14.0 RESULTS: Group 1 and 2 showed significant improvement in mean BCVA from 20/160 at baseline to 20/80 and from 20/125 to 20/63, respectively, at 6 months (P < 0.05). These groups also showed a significant reduction in the mean CMT from 457 +/- 151 MU at baseline to 316 +/- 136 MU and from 394 +/- 61 MU to 261 +/- 85 MU, respectively, at 6 months (P < 0.05). Group 3 showed only small improvement in mean BCVA from 20/100 to 20/80 (P = 1.0) while mean CMT increased from 358 +/- 89 MU at baseline to 395 +/- 127 MU at 6 months (P = 0.191). Eight (40%) eyes in Group 2 had intraocular pressure (IOP) rise and 10 (50%) eyes developed cataract. CONCLUSIONS: Both IVB and IVTA may be effective in the treatment of refractory DDME compared with macular grid augmentation. IVTA may be associated with side effects such as IOP rise and cataract formation. PMID- 23439854 TI - Mindfulness-based cognitive behavior therapy in patients with anxiety disorders: a case series. AB - The present study is aimed at evaluating the effectiveness of a Mindfulness-Based Cognitive Behavior Therapy (MBCBT) for reducing cognitive and somatic anxiety and modifying dysfunctional cognitions in patients with anxiety disorders. A single case design with pre- and post-assessment was adopted. Four patients meeting the specified inclusion and exclusion criteria were recruited for the study. Three patients received a primary diagnosis of generalized anxiety disorder (GAD), while the fourth patient was diagnosed with Panic Disorder. Patients were assessed on the Cognitive and Somatic Anxiety Questionnaire (CSAQ), Penn State Worry Questionnaire (PSWQ), Hamilton's Anxiety Inventory (HAM-A), and Dysfunctional Attitudes Scale. The therapeutic program consisted of education regarding nature of anxiety, training in different versions of mindfulness meditation, cognitive restructuring, and strategies to handle worry, such as, worry postponement, worry exposure, and problem solving. A total of 23 sessions over four to six weeks were conducted for each patient. The findings of the study are discussed in light of the available research, and implications and limitations are highlighted along with suggestions for future research. PMID- 23439855 TI - Ischemic stroke and neuroprotection. AB - Stroke is a major cause of morbidity and mortality in both developed and developing countries of the world. Greater understanding of the pathophysiology of neuronal damage in ischemic stroke has generated interest in neuroprotection as a management strategy. This paper aims to review the current concept and place of neuroprotection in ischemic stroke. An extensive search of all materials related to the topic was made using library sources including Pubmed and Medline searches. Current research findings were also included. The findings are as presented. Neuroprotection is an increasingly recognized management strategy in ischemic stroke that promises to assist clinicians in reducing stroke mortality rates and improving the quality of life of survivors. PMID- 23439856 TI - Effects of yoga on functional capacity and well being. AB - Yoga has proven beneficial effects on various health domains including musculoskeletal conditions, cardiopulmonary conditions through the practice of asana and pranayamas as well as on mental health, as it is known to enhance the body-and mind coordination. There is paucity of data on the effect of yoga on functional capacity in literature using 6 min walk test. The present study aims to look at the effect of yoga on 6-min walked distance, rating of perceived exertion (RPE), recovery time following the walk and state of well being. This is a hospital-based longitudinal study where 30 physiotherapy students of the age group 18 - 22 years of either sex were enrolled. Subjects having musculoskeletal problems, cardio respiratory disease and those who were not willing to volunteer were excluded They received Yoga intervention in form of Yogic practices which included a combination of asanas, pranayamas and omkar chanting for 1 h for 30 sessions. A baseline 6-min walk test was conducted on subjects and the 6-min walked distance, rating of perceived exertion (RPE) on modified Borg's scale were recorded. The baseline state of well-being was noted using the Warwick- Edinburgh mental well-being scale and similar recording was done post intervention after 30 sessions. Of the 30 subjects, there were no drop outs as these were committed college students. Of them, 24 were females and 6 were males with a mean age of 21.5 years SD 2.38. Statistically significant improvements were observed in 6-min walk distance (P value = 0.000), RPE (P value < 0.000), recovery time (P value < 0.000) and sense of well being score (P value < 0.000). Yoga practices are beneficial in improving the functional capacity in young healthy adults. Yoga can very well be incorporated in medical practice for increasing the patient's functional capacity, for those who have limitations in performing aerobic training due to various health reasons. The improved state of well being motivates the patients to adhere to yogic practices. PMID- 23439857 TI - A quantitative evaluation of fluid leakage around a polyvinyl chloride tapered endotracheal tube cuff using an in-vitro model. AB - INTRODUCTION: This study was designed to quantitatively evaluate the sealing effect of a polyvinyl chloride tapered endotracheal tube cuff and to compare the tapered cuff with cylindrical endotracheal tube cuffs using an in vitro viscous fluid model. METHODS: Five types of 8.0 mm inner diameter endotracheal tubes (TaperGuard, PortexSacett, PortexSoftseal, Sheridan HVT, Sheridan CF) were fixed in vertically placed 20mm internal diameter acrylic tubes. The cuffs were inflated to 25 mmHg pressure and water was added to the top of the cuff. The amount of water leaking around the cuff at five minutes was measured. Afterwards a viscous fluid was poured above the cuff and the amount of fluid passing around the cuff at five minutes and four hours was measured. Each determination was repeated five times and the data analyzed. RESULTS: The median (range) amount (ml) of dyed water passing around the cuff at 5 minutes was TaperGuard tube 0 (0 0.2), PortexSacett 81.1 (44.6-107.9), PortexSoftseal 95.4 (91.4-113.7), Sheridan HVT 46.5 (32.7-74.6) and Sheridan CF 52.6 (31.9-62.2), suggesting that TaperGuard significantly (P<0.05) reduced fluid leakage. The viscous fluid leakage at 5 minutes was not significantly different among the groups while the amount of leaked viscous fluid at 4 hours was 0.2 (0-1.1) for the TaperGuard, 57.6 (11.9 117.4) for the PortexSacett, 23.2 (13.8-33.0) for the PortexSoftseal, 5.5 (2.7 15.4) for the Sheridan HVT and 5.6 (1.8-7.9) for the Sheridan CF. CONCLUSION: An endotracheal tube with a tapered polyvinyl chloride cuff had significantly less fluid leakage compared to four tubes with cylindrical cuffs. PMID- 23439858 TI - Cellular aggregation is a key parameter associated with long term variability in paclitaxel accumulation in Taxus suspension cultures. AB - Plant cell cultures provide a renewable source for synthesis and supply of commercially valuable plant-derived products, particularly for secondary metabolites. However, instability in product yields over multiple passages has hampered the efficient and sustainable use of this technology. Paclitaxel accumulation in Taxus cell suspension culture was quantified over multiple passages and correlated to mean aggregate size, extracellular sugar level, ploidy, and cell cycle distribution. Paclitaxel levels varied approximately 6.9 fold over the six-month timeframe investigated. Of all of the parameters examined, only mean aggregate size correlated with paclitaxel accumulation, where a significant negative correlation (r = - 0.75, p < 0.01) was observed. These results demonstrate the relevance of measuring, and potentially controlling, aggregate size during long term culture passages, particularly for plant suspensions where industrially relevant secondary metabolites are not pigmented to enable rapid culture selection. PMID- 23439860 TI - Anatomical variability of the anterolateral thigh flap perforators between sexes: a cadaveric study. AB - BACKGROUND: Anterolateral thigh flap (ALTF) has gain popularity as a workhorse flap in the management of simple as well as complex tissue defects. The purpose of this study was to investigate the differences in ALTF's perforators' location in male and female human cadavers. METHODS: The study involved 30 fresh human cadavers of both sexes. A total of 60 flaps were examined. The flaps were raised as originally designed. After location of vessels, the distance from the anterior superior iliac spine (ASIS) to subsequent perforators was measured. Also, the kind of the perforator, its diameter and origin were marked. Perforators were designated according to Yu's classification (A, B, and C). The perforators were divided into thin (<0.5 mm), medium (0.5-1 mm), and thick (>1 mm). Ratio of the ASIS-patella distance to the distance of a given perforator from the ASIS (AP rate) was calculated. RESULTS: The mean AP rate (perforator location) was different in both sexes. Mean AP rate in men was calculated as 0.498 +/- 0.117, and in women, 0.559 +/- 0.114. Differences in AP rate between female and male were statistically significant (t = -3.144; p < 0.002). Mean flap thickness was 3.65 cm in women and 1.17 cm in men (t = -14.444; p < 0.00001). In men, 63 perforators originated from descending branch, and seven perforators originated from oblique branch. In women, there were 67 and one, respectively. CONCLUSIONS: In men, perforators are located closer to the ASIS in comparison to women. Clinically significant perforators (Phi > 0.5 mm), in majority of cases, occur in A and B positions. Thickness of the flap was higher in women. The oblique branch was more common in men. PMID- 23439859 TI - Comparison of ectopic gene expression methods in rat neural stem cells. AB - Neural stem cells (NSCs) have the ability to proliferate and differentiate into various types of cells that compose the nervous system. To study functions of genes in stem cell biology, genes or siRNAs need to be transfected. However, it is difficult to transfect ectopic genes into NSCs. Thus to identify the suitable method to achieve high transfection efficiency, we compared lipid transfection, electroporation, nucleofection and retroviral transduction. Among the methods that we tested, we found that nucleofection and retroviral transduction showed significantly increased transfection efficiency. In addition, with retroviral transduction of Ngn2 that is known to induce neurogenesis in various types of cells, we observed facilitated final cell division in rat NSCs. These data suggest that nucleofection and retroviral transduction provide high efficiency of gene delivery system to study functions of genes in rat NSCs. PMID- 23439861 TI - Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. AB - BACKGROUND: Ipilimumab is a recently approved immunotherapy that has demonstrated an improvement in the overall survival (OS) of patients with metastatic melanoma. We report a single-institution experience in patients treated in a compassionate use program. PATIENTS AND METHODS: In this prospective study, patients were treated between June 2010 and September 2011. Inclusion criteria were a diagnosis of unresectable stage III or IV melanoma, at least one previous line of chemotherapy, and survival 12 weeks after the first perfusion. Four courses of ipilimumab were administered at a dose of 3 mg/kg every 3 weeks. RESULTS: Seventy three patients were included. Median OS was 9.1 months (95% CI 6.4-11.3) from the start of ipilimumab. Immune-related adverse events were observed in 45 patients (62%), including 19 grade 3-4 events (26%). No drug-related death occurred. A lymphocyte count >1000/mm(3) at the start of the second course and an increase in the eosinophil count >100/mm(3) between the first and second infusions were correlated with an improved OS. CONCLUSION: Ipilimumab toxic effect is manageable in real life. Biological data such as lymphocyte and eosinophil counts at the time of the second ipilimumab infusion appear to be early markers associated with better OS. PMID- 23439862 TI - The rough guide to systematic reviews and meta-analyses. AB - The hierarchy of evidence based medicine postulates that systematic reviews of homogenous randomized trials represent one of the uppermost levels of clinical evidence. Indeed, the current overwhelming role of systematic reviews, meta analyses and meta-regression analyses in evidence based heath care calls for a thorough knowledge of the pros and cons of these study designs, even for the busy clinician. Despite this sore need, few succinct but thorough resources are available to guide users or would-be authors of systematic reviews. This article provides a rough guide to reading and, summarily, designing and conducting systematic reviews and meta-analyses. PMID- 23439863 TI - Space-valence priming with subliminal and supraliminal words. AB - To date it is unclear whether (1) awareness-independent non-evaluative semantic processes influence affective semantics and whether (2) awareness-independent affective semantics influence non-evaluative semantic processing. In the current study, we investigated these questions with the help of subliminal (masked) primes and visible targets in a space-valence across-category congruence effect. In line with (1), we found that subliminal space prime words influenced valence classification of supraliminal target words (Experiment 1): classifications were faster with a congruent prime (e.g., the prime "up" before the target "happy") than with an incongruent prime (e.g., the prime "up" before the target "sad"). In contrast to (2), no influence of subliminal valence primes on the classification of supraliminal space targets into up- and down-words was found (Experiment 2). Control conditions showed that standard masked response priming effects were found with both subliminal prime types, and that an across-category congruence effect was also found with supraliminal valence primes and spatial target words. The final Experiment 3 confirmed that the across-category congruence effect indeed reflected priming of target categorization of a relevant meaning category. Together, the data jointly confirmed prediction (1) that awareness-independent non-evaluative semantic priming influences valence judgments. PMID- 23439864 TI - Transfer of doxazosin into breast milk. AB - To the best of our knowledge, there have been no published studies of doxazosin transfer into human milk. In rats, milk concentrations twentyfold higher than in plasma have been reported. Based on these animal data, some references advise to avoid breastfeeding during doxazosin therapy. However, the physicochemical properties of doxazosin suggest low transfer into human milk. A 37-year-old breastfeeding woman who was administered doxazosin 4 mg daily for 2 doses was studied. Doxazosin concentrations in milk and plasma were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The milk/plasma area under the concentration-time curve (AUC0-18 hours) ratio was 0.1. This finding is consistent with what could be predicted based on the physicochemical properties of doxazosin. The average and maximum milk concentrations were 2.9 and 4.2 ug/L. These values correspond to estimated relative infant doses of 0.06% and 0.09%, respectively, assuming standard infant milk intake. These values are well below the generally accepted cutoff of 10% for predicting safety during breastfeeding. A low relative infant dose of < 0.1% suggests that maternal doxazosin therapy may be compatible with breastfeeding after careful individual risk-benefit analysis. PMID- 23439865 TI - Predictors and consequences of in-hospital formula supplementation for healthy breastfeeding newborns. AB - BACKGROUND: Although exclusive breastfeeding is recommended for the first 6 months, the use of breast milk substitutes is widespread around the world. OBJECTIVES: To describe the patterns of infant formula supplementation among healthy breastfeeding newborns, to identify factors contributing to in-hospital formula supplementation, and to assess the dose-response relationship between the amount of in-hospital formula supplementation and the duration of any breastfeeding. METHODS: A sample of 1246 breastfeeding mother-infant pairs was recruited from 4 public hospitals in Hong Kong and followed prospectively for 12 months or until weaned. Multiple logistic regression analysis was used to examine factors associated with in-hospital supplementation. Cox regression analysis was used to explore the impact of in-hospital supplementation on breastfeeding duration. RESULTS: Of the total, 82.5% of newborns were supplemented in the hospital; one-half received formula within 5 hours of birth. Assisted vaginal delivery (odds ratio [OR] = 2.06, 95% confidence interval [CI] 1.03, 4.15), cesarean section (OR = 3.45, 95% CI 1.75, 6.80), and higher birth weight (OR = 1.56, 95% CI 1.12, 2.18) were positively associated with in-hospital formula supplementation, whereas initiating breastfeeding in the delivery room (OR = 0.55, 95% CI 0.33, 0.89) was associated with decreased likelihood of in-hospital supplementation. Any infant formula in the first 48 hours was associated with a shorter duration of breastfeeding (hazard ratio [HR] = 1.51, 95% CI 1.27, 1.80), but there was no dose-response effect. CONCLUSION: In-hospital formula supplementation is common in Hong Kong hospitals and appears to be detrimental to breastfeeding duration. Continued efforts should be made to avoid the provision of infant formula to breastfeeding babies while in the hospital unless medically indicated. PMID- 23439866 TI - Cardiac resynchronization therapy-defibrillator improves long-term survival compared with cardiac resynchronization therapy-pacemaker in patients with a class IA indication for cardiac resynchronization therapy: data from the Contak Italian Registry. AB - AIMS: In candidates for cardiac resynchronization therapy (CRT), the choice between pacemaker (CRT-P) and defibrillator (CRT-D) implantation is still debated. We compared the long-term prognosis of patients who received CRT-D or CRT-P according to class IA recommendations of the European Society of Cardiology (ESC) and who were enrolled in a multicentre prospective registry. METHODS AND RESULTS: A total of 620 heart failure patients underwent successful implantation of a CRT device and were enrolled in the Contak Italian Registry. This analysis included 266 patients who received a CRT-D and 108 who received a CRT-P according to class IA ESC indications. Their survival status was verified after a median follow-up of 55 months. During follow-up, 73 CRT-D and 44 CRT-P patients died (rate 6.6 vs. 10.4%/year; log-rank test, P = 0.020). Patients receiving CRT-P were predominantly older, female, had no history of life-threatening ventricular arrhythmias, and more frequently presented non-ischaemic aetiology of heart failure, longer QRS durations, and worse renal function. However, the only independent predictor of death from any cause was the use of CRT-P (hazard ratio, 1.97; 95% confidence interval, 1.21-3.16; P = 0.007). CONCLUSION: The implantation of CRT-D, rather than CRT-P, may be preferable in patients presenting with current class IA ESC indications for CRT. Indeed, CRT-D resulted in greater long-term survival and was independently associated with a better prognosis. PMID- 23439867 TI - Tachycardia detection performance of implantable loop recorders: results from a large 'real-life' patient cohort and patients with induced ventricular arrhythmias. AB - AIMS: Implantable loop recorders (ILRs) are valuable for diagnosing arrhythmias. We evaluated tachycardia detection performance of the Medtronic Reveal((r)) ILR with FullViewTM Software. METHODS AND RESULTS: The rate of occurrence of tachycardia detection [supraventricular tachycardia, ventricular tachycardia (VT), and ventricular fibrillation (VF)] and the percentage of appropriately detected tachycardias were determined from all 2190 ILR patients that transmitted to CareLink over a 4-month period (total follow-up = 135.6 patient-years). All 1909 tachycardia episodes were reviewed. Episodes with actual heart rate above the programmed tachycardia detection rate were classified as appropriate. Sensitivity to detect true ventricular arrhythmias was assessed in another group of 215 patients undergoing implantable cardioverter defibrillator (ICD) implant testing. Skin electrodes represented ILR electrodes. Induced VF (404 episodes) and VT (93 episodes) were processed by an emulation of FullView Software. Generalized estimation equation analysis adjusted for multiple episodes per patient. In the CareLink cohort, 68.7% (63.9% adjusted) of detected episodes had tachycardia above the detection rate. Of 1642 episodes detected in the VT zone (12.1 episodes/patient-year), 78.8% (79.0% adjusted) had tachycardia above the detection rate. Of 267 episodes detected in the fast VT zone (1.9 episodes/patient-year), 6.7% (9.4% adjusted) had tachycardia above the detection rate. Twelve true VT/VF episodes were observed in 10 patients. In the ICD patient cohort, 95.9% (96.5% adjusted) of induced VT/VF segments were correctly detected at nominal rate cutoffs. When VT detection was set to 130 b.p.m. (to include the slowest VT), 99.0% (99.3% adjusted) were correctly detected. CONCLUSION: The majority (63.9%) of detected tachycardias contained true tachycardia. Sensitivity to detect induced VT/VF was 99.3%. PMID- 23439869 TI - Assessing families of adult type 2 diabetic populations. PMID- 23439868 TI - Cardiac pacing in paediatric patients with congenital heart defects: transvenous or epicardial? AB - AIMS: Cardiac pacing is a difficult technique in children, particularly in patients with congenital heart defects (CHDs). Few studies to date have addressed this topic. METHODS AND RESULTS: We performed a retrospective analysis of the results of a single centre. Between 1982 and 2008, 287 patients with CHD, median age of 5 years (25-75%, 1-11) underwent cardiac pacing for sinus node dysfunction (SND) and atrioventricular block (AVB); 97% of patients underwent at least one heart surgery. Endocardial systems (Endo) were implanted in 117 patients, epicardial systems (Epi) in 170, with 595 leads (228 Endo, 367 Epi). Endocardial systems showed a significantly older age group with more frequent SND; Epi a younger age group, with more frequent AVB, greater number of surgical interventions. Perioperative complications were mortality 0.6% (Epi), pericardial effusion 0.6% (Epi), and haemothorax 3.4% (Endo). The median follow-up is 5 (2 10) years: the pacing system failed in 29% of patients, 13% Endo, and 40% Epi (P < 0.0001). Multivariate analysis showed a significantly higher risk of failure for Epi, a lower implant age, greater the number of leads implanted. The risk of malfunction of the leads increases significantly for Epi and the younger age when implanted. The steroid-eluting leads have a lower risk of malfunction (P = 0.05), steroid-eluting Endo leads provide significantly better outcomes than Epi. CONCLUSION: Cardiac pacing in paediatric patients with CHD shows satisfactory results in the long term. Endocardial systems show significantly better results than Epi systems. A younger age when implanted is a risk factor for complications at follow-up. PMID- 23439870 TI - Catalyst-free growth of nanocrystalline graphene/graphite patterns from photoresist. AB - Catalyst-free growth of a nanocrystalline few-layer graphene (or graphite) film from photoresist on variable substrates was demonstrated. The thickness of the film can be easily controlled from 1 nm to hundreds of nanometers. With this method, graphene/graphite patterns with different thicknesses have been designed for integrated electronics. PMID- 23439871 TI - Recruitment and Retention for Community-Based eHealth Interventions with Populations of Low Socioeconomic Position: Strategies and Challenges. AB - Given persistent communication inequalities, it is important to develop interventions to improve Internet and health literacy among underserved populations. These goals drove the Click to Connect (C2C) project, a community based eHealth intervention that provided novice computer users of low socioeconomic position (SEP) with broadband Internet access, training classes, a Web portal, and technical support. In this paper, we describe the strategies used to recruit and retain this population, the budgetary implications of such strategies, and the challenges and successes we encountered. Results suggest that personal contact between study staff and participants and provision of in-depth technical support were central to successful recruitment and retention. Such investments are essential to realize the promise of eHealth with underserved populations. PMID- 23439872 TI - Strain-dependent dysregulation of one-carbon metabolism in male mice is associated with choline- and folate-deficient diet-induced liver injury. AB - Dysregulation of one-carbon metabolism-related metabolic processes is a major contributor to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). It is well established that genetic and gender-specific variations in one-carbon metabolism contribute to the vulnerability to NAFLD in humans. To examine the role of one-carbon metabolism dysregulation in the pathogenesis and individual susceptibility to NAFLD, we used a "population-based" mouse model where male mice from 7 inbred were fed a choline- and folate-deficient (CFD) diet for 12 wk. Strain-dependent down-regulation of several key one-carbon metabolism genes, including methionine adenosyltransferase 1alpha (Mat1a), cystathionine-beta synthase (Cbs), methylenetetrahydrofolate reductase (Mthfr), adenosyl homocysteinase (Ahcy), and methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), was observed. These changes were strongly associated with interstrain variability in liver injury (steatosis, necrosis, inflammation, and activation of fibrogenesis) and hyperhomocysteinemia. Mechanistically, the decreased expression of Mat1a, Ahcy, and Mthfd1 was linked to a reduced level and promoter binding of transcription factor CCAAT/enhancer binding protein beta (CEBPbeta), which directly regulates their transcription. The strain specificity of diet-induced dysregulation of one-carbon metabolism suggests that interstrain variation in the regulation of one-carbon metabolism may contribute to the differential vulnerability to NFLD and that correcting the imbalance may be considered as preventive and treatment strategies for NAFLD. PMID- 23439873 TI - Double ANCA-positive vasculitis in a patient with infective endocarditis. AB - The most common pattern of renal involvement in infective endocarditis is infection-associated glomerulonephritis. Due to clinical symptoms and signs that overlap with vasculitis, the diagnosis of infective endocarditis may be delayed. The unusual combination of reduced complement with positive antineutrophil cytoplasmic antibody should raise the suspicion of infections such as infective endocarditis. PMID- 23439874 TI - A new method for managing emergency calls. AB - Available methods for managing territorial medical emergencies are nowadays very effective. Nevertheless, resources are limited, and such methods are far from being perfect. It could be difficult, sometimes, to ensure adequate and prompt medical care to the community when emergency is taking place in such short times as those recommended for cardiocirculatory arrest or a trauma. The major intent of this project is to implement some drawbacks of the current management of medical rescue on the territory improving overall response times to emergencies and providing the delivery of qualified pre-hospital patient care. This may include (but not be limited to) the institution of a database, on a voluntary basis, for trained personnel. Such database should include resuscitation specialists, physicians, but also anyone who has undergone recognized training. Upon receiving a medical emergency call, an off-duty operator can be selected from the database (in a cooperative, non-competitive manner with the dedicated emergency services), based on current position of his/her cellular phone and his/her training profile. Finally, the operator who is both closest to and best prepared for the emergency is contacted via cellular phone. If the operator is available he/she can precede or join the mobile unit on site, managing the emergency according to his/her profile, possibly in cooperation with the ambulance personnel and even up to hospital admission. PMID- 23439875 TI - A citrus waste-based biorefinery as a source of renewable energy: technical advances and analysis of engineering challenges. AB - An assessment of recent technical advances on pretreatment processes and its effects on enzymatic hydrolysis as the main steps of a proposed citrus processing waste (CPW) biorefinery is presented. Engineering challenges and relevant gaps in scientific and technical information for reliable design, modeling and scale up of a CPW biorefinery are also discussed. Some integrated physico-chemical pretreatments are proposed for testing for CPW, including high speed knife grinding and simultaneous caustic addition. These new proposed processes and the effect of parameters such as particle size, surface area and morphology, pore volume and chemical composition of the diverse fractions resulting from pretreatment and enzymatic hydrolysis need to be evaluated and compared for pretreated and untreated samples of grapefruit processing waste. This assessment suggests the potential for filling the data gaps, and preliminary results demonstrate that the reduction of particle size and the increased surface area for the CPW will result in higher reaction rates and monosaccharide yields for the pretreated waste material. PMID- 23439876 TI - Selective flotation of PVC using gelatin and lignin alkali. AB - Recycling has become one of the most important issues as a result of increasing waste mass in present day. This is especially important for polymer wastes as they are hard to degenerate in nature. Today, most of the practical methods used for the recycling of waste mass, such as hand sorting, gravity separation, etc., cannot be performed successfully owing to close densities of polymers. Froth flotation can be used successfully and economically for this purpose. The main objective of this study was to investigate the effect of plasticizer reagents and the success of froth flotation at plastic recycling. In this study, lignin alkali and gelatin were used as plasticizer reagents. The effect of these reagents was searched with the parameters of pH, concentration, conditioning and flotation time. In the case of post-consumed polyethylene terephthalate and polyvinyl chloride (PVC), 98.9% purity of PVC was obtained at optimum conditions. PMID- 23439877 TI - Economic and employment potential in textile waste management of Faisalabad. AB - The aim of this study is to characterize the waste from the textile industry, to identify the sources and types of waste generation and to find out the economic and employment potential in this sector. Textile waste, its management, and the economic and employment potential in this sector are unrevealed facts in developing countries such as Pakistan. The textile industry is ranked first in export earning in Pakistan. Textile export of yarn and cloth from Faisalabad is US$3 billion per year. On average 161 325 people are employed in the textile sector in Faisalabad, of which 11 860 are involved in solid waste handling and management. The textile industries generate solid wastes such as fibre, metal, plastic and paper waste. A total of 794 209 kg day(-1) (289 886 285 kg year(-1)) solid waste is produced from this sector and purchased by cotton waste junkshop owners at US$125 027 day(-1) (US$45 634 855 year(-1)). Only pre-consumer textile waste is considered. Interestingly no waste is sent to landfill. The waste is first segregated into different categories/ types by hand and then weighed. Cotton waste is sold to brick kilns where it is used as an alternative fuel as it is cheaper than wood/coal. Iron scrap is sold in the junk market from where it is resold to recycling industries. Paper waste is recycled, minimizing the virgin material used for producing new paper products. Iron and plastic drums are returned to the chemical industries for refilling, thus decreasing the cost of dyes and decreasing the demand for new drums. Cutting rags are used for making different things such as ropes and underlay, it is also shredded and used as fillings for pillows and mattresses, thus improving waste management, reducing cost and minimizing the need for virgin material. As no system of quality control and no monitoring of subsequent products exist there is a need to carry out quality control and monitoring. PMID- 23439878 TI - Social determinants of quality of elderly life in a rural setting of India. AB - OBJECTIVE: The aim of this study is to understand the social determinants of quality of elderly life in rural central India and describe their perspectives on various issues related to their quality of life. MATERIALS AND METHODS: It was a community-based mixed-methods study in which quantitative (survey) method was followed by qualitative (Focus Group Discussion, FGD). The study was done in field practice area of a Rural Health Training Centre. We decided to interview all the elderly (>60 years) in two feasibly selected wards of village Anji by using the "WHO-Quality of Life (WHOQOL)-brief questionnaire." We used WHOQOL syntax for the calculation of mean values of four domains. Following survey, four FGDs were carried out. RESULTS: The determinants of perceived physical health, amenable for intervention were their currently working status, not being neglected by the family, and involvement in social activities. The determinants for psychological support were health insurance, and their current working status. The determinants for social relations were membership in social group and their present working status. The determinants for perceived environment were membership in social groups and relationship with the family members. In qualitative research, factors such as active life, social activity, spirituality, health care, involvement in decision making, and welfare schemes by the Government were found to contribute to better quality of elderly life. Problems or conflicts in family environment, lack of shelter and financial security, overtapped resources, and gender bias add to negative feelings in old age life. CONCLUSIONS: There is a need for intervention at social and family level for elderly friendly environment at home and community level. PMID- 23439879 TI - Phenolic Content, Antioxidant Activity, Antibacterial Activity and Phytochemical Composition of Garcinia lancifolia. AB - Garcinia lancifolia (Clusiaceae) is an unexplored medicinal plant used as stomachic, diuretic and its fruit is used to cure dysentery and diarrhoea. The acidic fruits are used to prepare juice, pickle and curries. The phytochemical analysis of different extracts of G. lancifolia leaf, stem and fruit revealed the presence of tannins, saponins, flavonoids, terpenoids, alkaloids and cardiac glycosides. The high phenolic content was observed in the methanol extract of leaf followed by methanol extract of stem and dichloromethane extract of leaf. The G. lancifolia fruit juice exhibited high antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Micrococcus luteus, Streptococcus mutans, Bacillus mycoides and Bacillus subtilis. The methanol extract of fruit pulp was also very effective against Gram-positive bacteria when compared with Gram-negative bacteria. The radical scavenging activity of 1,1-diphenyl-2 picrylhydrazyl was highest in fruit juice followed by methanol extract of leaf and stem. All extracts showed concentration-dependent increase in the antioxidant activity. PMID- 23439880 TI - Soluble ST2 as a Diagnostic and Prognostic Marker for Acute Heart Failure Syndromes. AB - OBJECTIVES: We investigated the association of sST2 with diagnostic and prognostic outcomes and assessed whether it aids B-natriuretic peptide (BNP) in diagnosing and predicting outcomes in emergency department (ED) patients with suspected AHFS. METHODS: We recruited patients who presented to the ED of 3 tertiary hospitals with signs or symptoms of AHFS and met modified Framingham criteria for AHFS. Outcome measures were a final diagnosis of AHFS and 5-and 30 day adverse events. RESULTS: In the 295 subjects with sST2 available, the median sST2 was 0.20 ng/ml (IQR=0.10, 0.34). Although unadjusted analyses indicated sST2 was significantly associated with the diagnosis of AHFS (p=0.02), this was not so in the adjusted analysis (p=0.33). Moderately low diagnostic utility was noted with an AUC of 0.62 (95% CI=0.56, 0.69). Similar sST2 test characteristics were seen when BNP was restricted between 100 and 500 pg/ml. While sST2 was associated with AHFS readmission at 30-days (p=0.04), in the adjusted analyses it was not associated with adverse events. CONCLUSION: In patients with signs or symptoms of AHFS, unadjusted analyses indicated that sST2 was significantly associated with the diagnosis of AHFS and with 30-day AHFS recidivism. However, the associations did not carry over to adjusted analyses, and sST2 did not add significant information with regard to explaining the diagnostic and prognostic variability of BNP. PMID- 23439881 TI - Do women requesting only contraception find attendance at an integrated sexual health clinic more stigmatizing than attendance at a family planning-only clinic? AB - PURPOSE: Both sexually transmitted infections and the genitourinary medicine clinics that patients attend for management of sexually transmitted infections are stigmatized by patients' perceptions. The aim of this study was to assess whether women requesting contraception only find attendance at an integrated sexual health clinic (ISHC) more stigmatizing than attendance at a family planning (FP)-only clinic. PATIENTS AND METHODS: Women requesting contraception only were asked to complete a stigma assessment questionnaire in the waiting room of the clinic they attended. Ease of understanding was assessed for each item of the questionnaire prior to commencement of the survey. The questionnaire was given to women attending either an ISHC or a FP-only clinic. RESULTS: One hundred questionnaires that fulfilled the inclusion criteria were returned. The users of FP-only services were generally older than the users of ISHCs and were more likely than the users of ISHCs to classify themselves as UK white. Stigma perception was significantly higher for the ISHC than the FP-only clinic. CONCLUSION: The results of this research indicate that among women who request contraception only, perceived stigma is higher when they attend an ISHC than when they attend a FP-only clinic. As this survey only enrolled clinic users, the authors were unable to assess whether integration generates sufficient stigma to deter some women from accessing contraception from integrated services. Of all stigma-related issues, disclosure concerns are likely to be the most important to the service user. Stigma is not an issue of overriding concern for most service users. PMID- 23439882 TI - LINGO-1 and Neurodegeneration: Pathophysiologic Clues for Essential Tremor. AB - Essential tremor (ET), one of the most common adult-onset movement disorders, has been associated with cerebellar Purkinje cell degeneration and formation of brainstem Lewy bodies. Recent findings suggest that genetic variants of the leucine-rich repeat and Ig domain containing 1 (LINGO-1) gene could be risk factors for ET. The LINGO-1 protein contains both leucine-rich repeat (LRR) and immunoglobulin (Ig)-like domains in its extracellular region, as well as a transmembrane domain and a short cytoplasmic tail. LINGO-1 can form a ternary complex with Nogo-66 receptor (NgR1) and p75. Binding of LINGO-1 with NgR1 can activate the NgR1 signaling pathway, leading to inhibition of oligodendrocyte differentiation and myelination in the central nervous system. LINGO-1 has also been found to bind with epidermal growth factor receptor (EGFR) and induce downregulation of the activity of EGFR-PI3K-Akt signaling, which might decrease Purkinje cell survival. Therefore, it is possible that genetic variants of LINGO 1, either alone or in combination with other genetic or environmental factors, act to increase LINGO-1 expression levels in Purkinje cells and confer a risk to Purkinje cell survival in the cerebellum.Here, we provide a concise summary of the link between LINGO-1 and neurodegeneration and discuss various hypotheses as to how this could be potentially relevant to ET pathogenesis. PMID- 23439883 TI - A prospective cohort study on the role of nonspecialist staff in preventing relapses and improving clinic attendance of patients with schizophrenia. AB - BACKGROUND: The Sri Lankan government employs graduates from local universities (trained in nonpsychiatry disciplines) as Mental Health Development Officers (MHDOs) to fulfill the role of a psychiatric social worker. MATERIALS AND METHODS: This was a prospective interventional cohort study on preventing relapses of schizophrenia by active involvement of MHDOs. The intervention (randomly selected) and control groups each had 25 follow-up patients with schizophrenia (1:1 match for sex, ethnicity, age, and duration of illness). The intervention was to develop a close liaison with the patient/family and build an individualized client oriented follow-up through the MHDOs. The follow-up period was 1 year. RESULTS: The intervention group had better clinic attendance, less relapses, and defaults. The number needed to follow-up to avert a relapse or a default was 12.5 and 5 respectively. CONCLUSIONS: Low-cost strategies involving nonspecialist staff can reduce relapses and defaults in patients with schizophrenia. PMID- 23439885 TI - Mirror movements in essential tremor: prevalence and relationship to mini-mental status test scores. AB - BACKGROUND: Mirror movements (MM) are mirror reversals of contralateral, voluntary alternating or repetitive limb movements. MM have been described in age related neurological diseases, including essential tremor (ET). MM could represent a motor release sign. Cognitive dysfunction (especially executive dysfunction) and dementia have also been reported among ET patients. It is conceivable that MM and cognitive dysfunction in ET arise from the same underlying anatomical or physiological substrate. Hence, the underlying clinical question is whether MM are a simple and easily elicited motor marker for incipient cognitive change or dementia in ET? Identifying such a marker would have value to clinicians, and we are unaware of prior studies that have assessed this issue. METHODS: The Folstein Mini-Mental State Exam (FMMSE) and the Modified Mini-Mental Status Examination (mMMSE) were administered to 148 ET cases enrolled in a cross-sectional clinical study. RESULTS: MM were present in 115 out of 148 (77.7%) ET cases. In analyses that considered age, there were no differences in FMMSE or mMMSE scores between participants with vs. without MMs (all p values >0.05). DISCUSSION: These data suggest that MM, while present in a considerable number of ET cases, would not be a useful motor marker for incipient cognitive change in ET cases. PMID- 23439884 TI - Major themes for 2010 in cardiothoracic and vascular anesthesia. AB - Significant variability in transfusion practice persists despite guidelines. Although the lysine analogues are effective antifibrinolytics, safety concerns exist with high doses tranexamic acid. Despite recombinant activated factor VII promising results in massive bleeding after cardiac surgery, it significantly increases arterial thromboembolic risk. Aortic valve repair may evolve to standard of care. Transcatheter aortic valve implantation is an established therapy for aortic stenosis. The cardiovascular anesthesiologist features prominently in the new guidelines for thoracic aortic disease. Although intense angiotensin blockade improves outcomes in heart failure, it might aggravate the maintenance of perioperative systemic vascular tone. Ultrafiltration is an alternative to diuresis for volume overload in heart failure. Management of heart failure titrated to brain natriuretic peptide activity reduces mortality. A major surgical advance has been the significant outcome improvement achieved with continuous-flow left ventricular assist devices. Advanced liver disease is a significant predictor for perioperative bleeding, transfusion and mortality after ventricular assist device insertion. Acquired von Willebrand syndrome is not only common in patients with these devices but often aggravating bleeding and transfusion in this setting. Metabolic myocardial modulation with perhexilene significantly enhances effort tolerance in hypertrophic cardiomyopathy. A landmark report has highlighted future priorities in this disease. Pediatric cardiac surgical trials have revealed the importance of perioperative cerebral oxygen saturation monitoring and the Sano shunt. Advances in pediatric-specific ventricular assist devices will likely revolutionize pediatric heart failure. Recent reports have highlighted the priorities for future perioperative trials and for training models in pediatric cardiac anesthesia. PMID- 23439886 TI - Numerical Poisson-Boltzmann Model for Continuum Membrane Systems. AB - Membrane protein systems are important computational research topics due to their roles in rational drug design. In this study, we developed a continuum membrane model utilizing a level set formulation under the numerical Poisson-Boltzmann framework within the AMBER molecular mechanics suite for applications such as protein-ligand binding affinity and docking pose predictions. Two numerical solvers were adapted for periodic systems to alleviate possible edge effects. Validation on systems ranging from organic molecules to membrane proteins up to 200 residues, demonstrated good numerical properties. This lays foundations for sophisticated models with variable dielectric treatments and second-order accurate modeling of solvation interactions. PMID- 23439887 TI - Periferic intravenous infusion of fenoldopam through an elastomeric pump. AB - INTRODUCTION: Fenoldopam has been used to protect renal function in critically ill patients and in those undergoing major surgery, where a possible damage of kidney is expected. Numerous randomized studies and meta-analysis demonstrated the efficacy of fenoldopam in this setting. We performed this study to demonstrate the feasibility of administering fenoldopam, trough an elastomeric pump connected to a peripheral vein, to patients undergoing nephron sparing surgery. MATERIALS AND METHODS: Twenty consecutive patients, ASA physical status class I-III, undergoing laparoscopic or laparotomic renal tumorectomy were enrolled. Fenoldopam was infused trough an elastomeric pump at a fixed dosage of 0.1 mcg/kg/min, obtained after diluting the drug with saline solution according to the weight of the patient. We injected the drug trough a peripheral vein from the induction of anaesthesia for 48 hours after the end of surgery. RESULTS: The infusion of fenoldopam did not modify the haemodynamic parameters. We did not find episodes of hypotension and only in three patients we registered episodes of tachycardia, not requiring the suspension of the infusion. No other side-effect was noted. CONCLUSIONS: The administration of fenoldopam, trough an elastomeric pump, in patients undergoing renal tumorectomy is feasible through a peripheral vein access. PMID- 23439888 TI - Transcanalicular laser dacryocystorhinostomy using low energy 810 nm diode laser. AB - BACKGROUND: Hypertrophic scarring may be a cause of failure after transcanalicular laser dacryocystorhinostomy (DCR) surgery. This hypertrophic scarring results from tissue charring and excessive coagulation, which may be caused by the high laser energy. We have evaluated the use of low energy settings to prevent hypertrophic scarring, for a successful outcome. AIMS: To perform and evaluate transcanalicular laser DCR using low energy 810 nm diode laser. DESIGN: Interventional, non-comparative, case series. MATERIALS AND METHODS: Patients with nasolacrimal duct obstruction and chronic dacryocystitis, who needed DCR, and were fit for surgery under local anesthesia, were recruited to undergo transcanalicular laser DCR using a 810 nm diode laser. The outcome was measured by the patency of the lacrimal passage, as indicated by the relief in the symptoms and the patency on syringing at the last follow-up. The surgical time and surgical complications were noted. STATISTICAL ANALYSIS USED: Descriptive analysis. RESULTS: The study included 94 patients. The average age was 30.1 years (range 15 - 69 years). Seventy (74.4%) patients were female. Eight patients had failed external DCR. Per-operative patency of the passage was obtained in all the patients. Average surgical time was seven minutes (5 - 18 minutes). At the end of the study period of one year, a successful outcome was seen in 85 patients (90.5%). There were eight patients of previous failed DCR surgeries, and six of them achieved a cure at the end of follow-up. CONCLUSIONS: Transcanalicular Laser DCR can be safely performed using a low power 810 nm diode laser. The surgery is elegant, minimally invasive, allows fast rehabilitation, and has an excellent success rate. PMID- 23439889 TI - Efficient neocentromere formation is suppressed by gene conversion to maintain centromere function at native physical chromosomal loci in Candida albicans. AB - CENPA/Cse4 assembles centromeric chromatin on diverse DNA. CENPA chromatin is epigenetically propagated on unique and different centromere DNA sequences in a pathogenic yeast Candida albicans. Formation of neocentromeres on DNA, nonhomologous to native centromeres, indicates a role of non-DNA sequence determinants in CENPA deposition. Neocentromeres have been shown to form at multiple loci in C. albicans when a native centromere was deleted. However, the process of site selection for CENPA deposition on native or neocentromeres in the absence of defined DNA sequences remains elusive. By systematic deletion of CENPA chromatin-containing regions of variable length of different chromosomes, followed by mapping of neocentromere loci in C. albicans and its related species Candida dubliniensis, which share similar centromere properties, we demonstrate that the chromosomal location is an evolutionarily conserved primary determinant of CENPA deposition. Neocentromeres on the altered chromosome are always formed close to the site which was once occupied by the native centromere. Interestingly, repositioning of CENPA chromatin from the neocentromere to the native centromere occurs by gene conversion in C. albicans. PMID- 23439890 TI - Marriage and the well-being of children. AB - Children's well-being has become the focal consideration in legal and public policy debates regarding same-sex marriage. In this article, we critically examine and rebut the central moral argument made by opponents of same-sex marriage: that the state should not license any domestic arrangement other than "traditional marriage" because doing so would be detrimental to children's well being. Although many have challenged the empirical premise that children raised by same-sex couples fare worse than children in other arrangements, we focus primarily on the normative premises for exclusively licensing traditional (that is, monogamous, heterosexual) marriage. We argue that even if the empirical support for its claims was strong, the argument is morally insufficient for denying state recognition to other types of relationships. Importantly, we affirm the state's vital role in promoting children's well-being. We question, however, the approach of delegitimizing certain relationships as a means to that end. Instead, we argue, the state should encourage and support individuals who want to care for children, presume that any couple or individual is capable of adequate child-rearing, and ensure that all adults who are raising children (whether married or not) have the material resources and support necessary to be good parents. Such a policy would (1) set a reasonable minimal threshold for state recognition, (2) be vigilant in identifying cases falling below this threshold, and then (3) either assist or disqualify underperforming arrangements. It would also, appropriately, decouple arguments about legitimate and illegitimate types of relationships from arguments about what is best for children. PMID- 23439891 TI - Prenatal substance abuse: short- and long-term effects on the exposed fetus. AB - Prenatal substance abuse continues to be a significant problem in this country and poses important health risks for the developing fetus. The primary care pediatrician's role in addressing prenatal substance exposure includes prevention, identification of exposure, recognition of medical issues for the exposed newborn infant, protection of the infant, and follow-up of the exposed infant. This report will provide information for the most common drugs involved in prenatal exposure: nicotine, alcohol, marijuana, opiates, cocaine, and methamphetamine. PMID- 23439892 TI - Chest compression quality over time in pediatric resuscitations. AB - BACKGROUND: Chest compression (CC) quality deteriorates with time in adults, possibly because of rescuer fatigue. Little data exist on compression quality in children or on work done to perform compressions in general. We hypothesized that compression quality, work, and rescuer fatigue would differ in child versus adult manikin models. METHODS: This was a prospective randomized crossover study of 45 in-hospital rescuers performing 10 minutes of single-rescuer continuous compressions on each manikin. An accelerometer recorded compression quality measures over 30-second epochs. Work and power were calculated from recorded force data. A modified visual analogue scale measured fatigue. Data were analyzed by using linear mixed-effects models and Cox regression analysis. RESULTS: A total of 88 484 compression cycles were analyzed. Percent adequate CCs/epoch (rate >= 100/minute, depth >= 38 mm) fell over 10 minutes (child: from 85.1% to 24.6%, adult: from 86.3% to 35.3%; P = .15) and were <70% in both by 2 minutes. Peak work per compression cycle was 13.1 J in the child and 14.3 J in the adult (P = .06; difference, 1.2 J; 95% confidence interval, -0.05 to 2.5). Peak power output was 144.1 W in the child and 166.5 W in the adult (P < .001; difference, 22.4 W, 95% confidence interval, 9.8-35.0). CONCLUSIONS: CC quality deteriorates similarly in child and adult manikin models. Peak work per compression cycle is comparable in both. Peak power output is analogous to that generated during intense exercise such as running. CC providers should switch every 2 minutes as recommended by current guidelines. PMID- 23439893 TI - Low-dose heparin use and the patency of peripheral IV catheters in children: a systematic review. AB - OBJECTIVE: To assess evidence from randomized controlled trials (RCTs) on the efficacy of low-dose heparin for prolonging patency of peripheral intravenous (PIV) catheters in the pediatric population. METHODS: We searched Medline, Embase, CINAHL, and Cochrane Central Register of Controlled Trials to identify studies up to June 6, 2012. Additional citations were retrieved from the bibliography of selected articles. The eligible studies were RCTs of low-dose heparin used in PIV catheters as compared with control and measured any one of the following outcomes: duration of catheter patency, infusion failure rates, or phlebitis. Data were extracted by 1 reviewer by using a standardized form and checked for accuracy by a second reviewer. Discrepancies were resolved by consensus. RESULTS: Thirteen RCTs were identified (3 RCTs of continuous infusion and 10 RCTs of intermittent flush). Catheters using heparin had longer patency (mean difference [95% confidence interval]: 26.51 hours [2.37 to 50.65], P < .001, for the infusion studies and 2.82 hours [-0.04 to 5.67], P = .05, for intermittent flush studies). Heparin usage also resulted in a lower rate of infusion failure (rate ratio [95% confidence interval]: 0.78 [0.62 to 0.99], P = .04, for the infusion studies and 0.88 [0.72 to 1.09], P = .25, for intermittent flush studies). Lower phlebitis rates were also observed with heparin usage; however, the results did not reach significance. There was no increase in heparin related side effects noted. CONCLUSIONS: Low-dose heparin as continuous infusion in PIV catheters resulted in clinically significant benefits in terms of catheter patency and fewer episodes of infusion failures. Heparin's use in intermittent flush solutions showed minimal benefits. PMID- 23439895 TI - Maternal alcohol use and sudden infant death syndrome and infant mortality excluding SIDS. AB - BACKGROUND: Improvements in the rate of infant mortality (death in first year of life) have not occurred in recent years. This study investigates the association between maternal alcohol-use disorder and sudden infant death syndrome (SIDS) and infant mortality not classified as SIDS using linked, population-based health and mortality data. METHODS: Exposed mothers were identified through the presence of an International Classification of Diseases 9/10 alcohol diagnosis, a proxy for alcohol-use disorder, recorded on health, mental health, and/or drug and alcohol datasets (1983-2005). Comparison mothers without an alcohol diagnosis were frequency matched to exposed mothers on maternal age within maternal race and year of birth of their children. All offspring with their birth recorded on the Midwives Notification System compose the exposed (n = 21 841) and comparison (n = 56 054) cohorts. Cases of SIDS (n = 303) and infant mortality excluding SIDS (n = 598) were identified through linkage with the Western Australian Mortality Register. Analyses were conducted by using Cox regression and results presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: The highest risk of SIDS occurred when a maternal alcohol diagnosis was recorded during pregnancy (aHR 6.92, 95% CI 4.02-11.90) or within 1 year postpregnancy (aHR 8.61, 95% CI 5.04-14.69). An alcohol diagnosis recorded during pregnancy more than doubled the risk of infant deaths (excluding SIDS) (aHR 2.35, 95% CI 1.45-3.83). Maternal alcohol-use disorder is attributable for at least 16.41% (95% CI 9.73%-23.69%) of SIDS and 3.40% (95% CI 2.28%-4.67%) of infant deaths not classified as SIDS. CONCLUSIONS: Maternal alcohol-use disorder is a significant risk factor for SIDS and infant mortality excluding SIDS. PMID- 23439896 TI - Oral health care for children with developmental disabilities. AB - Children with developmental disabilities often have unmet complex health care needs as well as significant physical and cognitive limitations. Children with more severe conditions and from low-income families are particularly at risk with high dental needs and poor access to care. In addition, children with developmental disabilities are living longer, requiring continued oral health care. This clinical report describes the effect that poor oral health has on children with developmental disabilities as well as the importance of partnerships between the pediatric medical and dental homes. Basic knowledge of the oral health risk factors affecting children with developmental disabilities is provided. Pediatricians may use the report to guide their incorporation of oral health assessments and education into their well-child examinations for children with developmental disabilities. This report has medical, legal, educational, and operational implications for practicing pediatricians. PMID- 23439898 TI - Computer-generated reminders and quality of pediatric HIV care in a resource limited setting. AB - OBJECTIVES: To evaluate the impact of clinician-targeted computer-generated reminders on compliance with HIV care guidelines in a resource-limited setting. METHODS: We conducted this randomized, controlled trial in an HIV referral clinic in Kenya caring for HIV-infected and HIV-exposed children (<14 years of age). For children randomly assigned to the intervention group, printed patient summaries containing computer-generated patient-specific reminders for overdue care recommendations were provided to the clinician at the time of the child's clinic visit. For children in the control group, clinicians received the summaries, but no computer-generated reminders. We compared differences between the intervention and control groups in completion of overdue tasks, including HIV testing, laboratory monitoring, initiating antiretroviral therapy, and making referrals. RESULTS: During the 5-month study period, 1611 patients (49% female, 70% HIV infected) were eligible to receive at least 1 computer-generated reminder (ie, had an overdue clinical task). We observed a fourfold increase in the completion of overdue clinical tasks when reminders were availed to providers over the course of the study (68% intervention vs 18% control, P < .001). Orders also occurred earlier for the intervention group (77 days, SD 2.4 days) compared with the control group (104 days, SD 1.2 days) (P < .001). Response rates to reminders varied significantly by type of reminder and between clinicians. CONCLUSIONS: Clinician-targeted, computer-generated clinical reminders are associated with a significant increase in completion of overdue clinical tasks for HIV-infected and exposed children in a resource-limited setting. PMID- 23439899 TI - Trends in resource utilization for hospitalized children with skin and soft tissue infections. AB - OBJECTIVE: To describe trends in national resource utilization for pediatric skin and soft tissue infection (SSTI) hospitalizations. METHODS: This was a cross sectional analysis of hospital discharges from 1997 to 2009 within the Healthcare Cost and Utilization Project Kids' Inpatient Database for children with isolated SSTIs. Outcomes examined included patient and hospital characteristics, number of hospitalizations, and resource utilization including length of stay (LOS), hospital charges, and performance of incision and drainage (I&D). Trends in resource utilization were assessed by using linear regression in a merged data set with survey year as the primary independent variable. Multivariate logistic regression was conducted for 2009 data to assess factors associated with increased I&D. RESULTS: The weighted proportion of SSTI hospitalizations among all hospitalizations doubled (0.46% vs 1.01%) from 1997 to 2009. During the same period, patient demographic trends included a shift to increased hospitalizations in infant and preschool-age groups as well as publicly insured children. Mean LOS decreased from 3.11 to 2.71 days. Increased resource utilization included changes in mean charges from $6722 to $11 534 per hospitalization and a twofold increase in I&D (21% to 44%). Factors associated with I&D include young age, African American race, female gender, publicly or uninsured children, and southern region of the United States. CONCLUSIONS: SSTI is responsible for an emerging increase in health services utilization. Additional study is warranted to identify interventions that may effectively address this public health burden. PMID- 23439900 TI - Stronger laws are needed to protect teens from indoor tanning. PMID- 23439901 TI - Interns' success with clinical procedures in infants after simulation training. AB - BACKGROUND AND OBJECTIVE: Simulation-based medical education (SBME) is used to teach residents. However, few studies have evaluated its clinical impact. The goal of this study was to evaluate the impact of an SBME session on pediatric interns' clinical procedural success. METHODS: This randomized trial was conducted at 10 academic medical centers. Interns were surveyed on infant lumbar puncture (ILP) and child intravenous line placement (CIV) knowledge and watched audiovisual expert modeling of both procedures. Participants were randomized to SBME mastery learning for ILP or CIV and for 6 succeeding months reported clinical performance for both procedures. ILP success was defined as obtaining a sample on the first attempt with <1000 red blood cells per high-power field or fluid described as clear. CIV success was defined as placement of a functioning catheter on the first try. Each group served as the control group for the procedure for which they did not receive the intervention. RESULTS: Two-hundred interns participated (104 in the ILP group and 96 in the CIV group). Together, they reported 409 procedures. ILP success rates were 34% (31 of 91) for interns who received ILP mastery learning and 34% (25 of 73) for controls (difference: 0.2% [95% confidence interval: -0.1 to 0.1]). The CIV success rate was 54% (62 of 115) for interns who received CIV mastery learning compared with 50% (58 of 115) for controls (difference: 3% [95% confidence interval: -10 to 17]). CONCLUSIONS: Participation in a single SBME mastery learning session was insufficient to affect pediatric interns' subsequent procedural success. PMID- 23439902 TI - Associations of food stamp participation with dietary quality and obesity in children. AB - OBJECTIVE: To determine if obesity and dietary quality in low-income children differed by participation in the Supplemental Nutrition Assistance Program (SNAP), formerly the Food Stamp Program. METHODS: The study population included 5193 children aged 4 to 19 with household incomes <=130% of the federal poverty level from the 1999-2008 NHANES. Diet was measured by using 24-hour recalls. RESULTS: Among low-income US children, 28% resided in households currently receiving SNAP benefits. After adjusting for sociodemographic differences, SNAP participation was not associated with a higher rate of childhood obesity (odds ratio = 1.11, 95% confidence interval [CI]: 0.71-1.74). Both SNAP participants and low-income nonparticipants were below national recommendations for whole grains, fruits, vegetables, fish, and potassium, while exceeding recommended limits for processed meat, sugar-sweetened beverages, saturated fat, and sodium. Zero percent of low-income children met at least 7 of 10 dietary recommendations. After multivariate adjustment, compared with nonparticipants, SNAP participants consumed 43% more sugar-sweetened beverages (95% CI: 8%-89%), 47% more high-fat dairy (95% CI: 7%, 101%), and 44% more processed meats (95% CI: 9%-91%), but 19% fewer nuts, seeds, and legumes (95% CI: -35% to 0%). In part due to these differences, intakes of calcium, iron, and folate were significantly higher among SNAP participants. Significant differences by SNAP participation were not evident in total energy, macronutrients, Healthy Eating Index 2005 scores, or Alternate Healthy Eating Index scores. CONCLUSIONS: The diets of low-income children are far from meeting national dietary recommendations. Policy changes should be considered to restructure SNAP to improve children's health. PMID- 23439903 TI - Increased length of stay and costs associated with weekend admissions for failure to thrive. AB - OBJECTIVE: To evaluate whether admission day of the week affects the length of stay (LOS) and health care costs for failure to thrive (FTT) admissions. METHODS: Administrative data were obtained for all children aged <2 years (N = 23 332) with a primary admission diagnosis of FTT from 2003-2011 from 42 freestanding US hospitals. Demographic characteristics, day of admission, LOS, costs per stay, number of discharge diagnoses, primary discharge diagnoses, primary procedure code, number of radiologic and laboratory units billed during admission were obtained for each admission. Linear regression and zero-truncated Poisson regression were used for analysis. RESULTS: Weekend admission was significantly correlated with increased LOS and increased average cost (P < .002). This finding was also true for children with both admission and discharge diagnoses of FTT (P < .001). The number of procedures for children admitted on the weekend was not significantly different compared with children admitted on the weekdays (incident rate ratio [IRR]:1.04 [95% confidence interval (CI): 0.99-1.09]). However, weekend admissions did have more radiologic studies (IRR: 1.13 [95% CI: 1.10 1.16]) and laboratory tests (IRR: 1.39 [95% CI: 1.38-1.40]) performed. If one half of weekend admissions in 2010 with both admission and discharge diagnoses of FTT were converted to Monday admissions, total savings in health care dollars for 2010 would be $534, 145. CONCLUSIONS: Scheduled FTT admissions on weekends increased LOS and health care costs compared with weekday admissions of similar levels of complexity. Reduction in planned weekend admissions for FTT could significantly reduce health care costs. PMID- 23439904 TI - Screening for hypertension in children and adolescents to prevent cardiovascular disease. AB - BACKGROUND AND OBJECTIVE: The prevalence of hypertension is increasing in children, and may persist into adulthood. This systematic review was conducted for the US Preventive Services Task Force recommendation on the effectiveness of screening asymptomatic children and adolescents for hypertension in order to prevent cardiovascular disease. METHODS: Eligible studies were identified from Medline and the Cochrane Library (through July 2012). We included trials and controlled observational studies in asymptomatic children and adolescents on the effectiveness and harms of screening and treatment, as well as accuracy of blood pressure measurement. One author extracted study characteristics and results, which were checked for accuracy by a second author. RESULTS: No studies evaluated the effects of screening for hypertension on health outcomes. Two studies of screening tests for elevated blood pressure reported moderate sensitivities (0.65, 0.72) and specificities (0.75, 0.92). Sensitivities and specificities of child hypertension for the later presence of adult hypertension (7 studies) were wide ranging (0-0.63 and 0.77-1.0, respectively), and associations between child hypertension and carotid intima media thickening and proteinuria in young adults (3 studies) were inconsistent. Seven studies reported that drug interventions effectively lowered blood pressure in adolescents over short follow-up periods. No serious treatment-related adverse effects were reported. CONCLUSIONS: There is no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults. Additional studies are needed to improve diagnosis and risk stratification of children with elevated blood pressure and to quantify risks and benefits of interventions. PMID- 23439905 TI - Different guidelines for imaging after first UTI in febrile infants: yield, cost, and radiation. AB - OBJECTIVE: To evaluate the yield, economic, and radiation costs of 5 diagnostic algorithms compared with a protocol where all tests are performed (ultrasonography scan, cystography, and late technetium(99)dimercaptosuccinic acid scan) in children after the first febrile urinary tract infections. METHODS: A total of 304 children, 2 to 36 months of age, who completed the diagnostic follow-up (ultrasonography, cystourethrography, and acute and late technetium(99)dimercaptosuccinic acid scans) of a randomized controlled trial (Italian Renal Infection Study 1) were eligible. The guidelines applied to this cohort in a retrospective simulation were: Melbourne Royal Children's Hospital, National Institute of Clinical Excellence (NICE), top down approach, American Academy of Pediatrics (AAP), and Italian Society of Pediatric Nephrology. Primary outcomes were the yield of abnormal tests for each diagnostic protocol; secondary outcomes were the economic and radiation costs. RESULTS: Vesicoureteral reflux (VUR) was identified in 66 (22%) children and a parenchymal scarring was identified in 45 (15%). For detection of VUR (47/66) and scarring (45/45), the top down approach showed the highest sensitivity (76% and 100%, respectively) but also the highest economic and radiation costs (?52 268. 624 mSv). NICE (19/66) and AAP (18/66) had the highest specificities for VUR (90%) and the Italian Society of Pediatric Nephrology had the highest specificity (20/45) for scars (86%). NICE would have been the least costly (?26 838) and AAP would have resulted in the least radiation exposure (42 mSv). CONCLUSIONS: There is no ideal diagnostic protocol following a first febrile urinary tract infection. An aggressive protocol has a high sensitivity for detecting VUR and scarring but carries high financial and radiation costs with questionable benefit. PMID- 23439906 TI - Growth outcomes of weight faltering in infancy in ALSPAC. AB - OBJECTIVE: The goal of this study was to investigate growth outcomes in term infants with weight faltering. METHODS: Conditional weight gain was calculated on term infants from the Avon Longitudinal Study of Parents and Children. Cases of weight faltering were infants with a conditional weight gain below the fifth centile. Outcome growth measurements included weight and length/height (from 9 months to 13 years), BMI, mid-arm circumference, and waist circumference (at 7, 10, and 13 years). RESULTS: Weight data were available on 11 499 infants; 507 had "early" weight faltering (before 8 weeks), and 480 had "late" weight faltering (between 8 weeks and 9 months). The early group showed enhanced weight gain from 8 weeks until 2 years, then gained weight at the same rate as the controls. Gain in height was proportionally slower than gain in weight through childhood. By 13 years, they had BMI, mid-arm circumference, and waist circumference similar to the controls. The late group showed steady weight gain throughout childhood; enhanced weight gain compared with the controls only occurred between 7 and 10 years. Gain in height was proportional to gain in weight. This group remained considerably lighter and shorter than the controls up to the age of 13 years. CONCLUSIONS: Children with weight faltering before 8 weeks showed a different pattern of "catch-up" to those with weight faltering later in infancy. By 13 years, the anthropometric profile of the 2 groups was within population norms. PMID- 23439907 TI - Facial dysmorphism across the fetal alcohol spectrum. AB - OBJECTIVE: Classic facial characteristics of fetal alcohol syndrome (FAS) are shortened palpebral fissures, smooth philtrum, and thin upper vermillion. We aim to help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially among nonsyndromal heavily exposed (HE) individuals without classic facial characteristics. METHODS: Of 192 Cape Coloured children recruited, 69 were born to women who reported abstaining from alcohol during pregnancy. According to multifaceted criteria, the remainder were allocated clinically to the FAS (n = 22), partial FAS (n = 26) or nonsyndromal HE (n = 75) categories. We used dense surface modeling and signature analyses of 3-dimensional facial photographs to determine agreement between clinical categorization and classifications induced from face shape alone, to visualize facial differences, and to consider predictive links between face shape and neurobehavior. RESULTS: Face classification achieved significant agreement with clinical categories for discrimination of nonexposed from FAS alone (face: 0.97-1.00; profile: 0.92) or with the addition of partial FAS (face: 0.90; profile: 0.92). Visualizations of face signatures delineated dysmorphism across the fetal alcohol spectrum and in half of the nonsyndromal HE category face signature graphs detected facial characteristics consistent with prenatal alcohol exposure. This subgroup performed less well on IQ and learning tests than did nonsyndromal subjects without classic facial characteristics. CONCLUSIONS: Heat maps and morphing visualizations of face signatures may help clinicians detect facial dysmorphism across the fetal alcohol spectrum. Face signature graphs show potential for identifying nonsyndromal heavily exposed children who lack the classic facial phenotype but have cognitive impairment. PMID- 23439909 TI - The diagnosis and management of acute otitis media. AB - This evidence-based clinical practice guideline is a revision of the 2004 acute otitis media (AOM) guideline from the American Academy of Pediatrics (AAP) and American Academy of Family Physicians. It provides recommendations to primary care clinicians for the management of children from 6 months through 12 years of age with uncomplicated AOM. In 2009, the AAP convened a committee composed of primary care physicians and experts in the fields of pediatrics, family practice, otolaryngology, epidemiology, infectious disease, emergency medicine, and guideline methodology. The subcommittee partnered with the Agency for Healthcare Research and Quality and the Southern California Evidence-Based Practice Center to develop a comprehensive review of the new literature related to AOM since the initial evidence report of 2000. The resulting evidence report and other sources of data were used to formulate the practice guideline recommendations. The focus of this practice guideline is the appropriate diagnosis and initial treatment of a child presenting with AOM. The guideline provides a specific, stringent definition of AOM. It addresses pain management, initial observation versus antibiotic treatment, appropriate choices of antibiotic agents, and preventive measures. It also addresses recurrent AOM, which was not included in the 2004 guideline. Decisions were made on the basis of a systematic grading of the quality of evidence and benefit-harm relationships. The practice guideline underwent comprehensive peer review before formal approval by the AAP. This clinical practice guideline is not intended as a sole source of guidance in the management of children with AOM. Rather, it is intended to assist primary care clinicians by providing a framework for clinical decision-making. It is not intended to replace clinical judgment or establish a protocol for all children with this condition. These recommendations may not provide the only appropriate approach to the management of this problem. PMID- 23439908 TI - Chronic acetaminophen exposure in pediatric acute liver failure. AB - BACKGROUND: Acetaminophen (N-acetyl-p-aminophenol [APAP]) is a widely used medication that can cause hepatotoxicity. We examined characteristics and outcomes of children with chronic exposure (CE) to APAP in the multinational Pediatric Acute Liver Failure (PALF) Study. METHODS: A total of 895 children enrolled from 2002 to 2009 were grouped by APAP exposure history as: CE (received multiple doses ?x{2265}2 days; n = 83), single dose exposure (SE; n = 85), and no exposure (NE; n = 498). CE was the reference group for pairwise comparisons. Median values are shown. RESULTS: Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008). CONCLUSIONS: Children in the PALF study with CE had lower bilirubin and higher alanine aminotransferase than those with NE. Outcomes with CE were worse than with SE but better than with NE. Potential reasons for this outcomes advantage over non-APAP-exposed subjects should be explored. PMID- 23439910 TI - Practices of unregulated tanning facilities in Missouri: implications for statewide legislation. AB - BACKGROUND: The incidence of skin cancer has increased in the United States, concomitant with increased UV radiation (UVR) exposure among young adults. We examined whether tanning facilities in Missouri, a state without indoor-tanning regulations, acted in accordance with the Food and Drug Administration's recommendations and consistently imparted information to potential clients about the known risks of UVR. METHODS: We conducted a statewide telephone survey of randomly selected tanning facilities in Missouri. Each tanning facility was surveyed twice, in the morning (7 am-3 pm) and evening (3-10 pm), on different days, to determine intrasalon consistency of information provided to potential clients at different times. RESULTS: On average, 65% of 243 tanning-facility operators would allow children as young as 10 or 12 years old to use indoor tanning devices, 80% claimed that indoor tanning would prevent future sunburns, and 43% claimed that there were no risks associated with indoor tanning. Intrasalon inconsistencies involved allowable age of use, and UVR exposure type and duration. Morning tanning-facility employees were more likely to allow consumers to start with maximum exposure times and UV-A-emitting devices (P < .001), whereas evening employees were more likely to allow 10- or 12-year-old children to use indoor-tanning devices (P = .008). CONCLUSIONS: Despite increasing evidence that UVR exposure in indoor-tanning devices is associated with skin cancer, ocular damage, and premature photoaging, tanning facilities in Missouri often misinformed consumers regarding these risks and lack of health benefits and inconsistently provided information about the Food and Drug Administration's guidelines for tanning devices. PMID- 23439911 TI - Comprehensive post-arthroscopic management of a middle-aged adult with glenohumeral osteoarthritis: a case report. AB - Comprehensive Arthroscopic Management (CAM) is a new glenohumeral debridement procedure developed as a joint preserving alternative to total shoulder arthroplasty (TSA). The procedure consists of several arthroscopic components including: A. scar tissue and chondral debridement, B. synovectomy, C. inferior humeral osteoplasty, D. capsular release, E. axillary nerve decompression, and F. tenodesis of the long head of the biceps. In this case, an active, middle age patient who failed physical therapy treatment and corticosteroid injections was evaluated and diagnosed with glenohumeral osteoarthritis. Anterior- posterior (AP) and axillary radiographs showed grade IV changes of the articular cartilage, confirming the diagnosis. The patient was not an ideal candidate for TSA because of her age, activity level, and concern for implant survival; therefore surgical intervention was performed using the CAM procedure. After the surgery, the patient demonstrated increased joint space as shown using radiographic imaging. The patient underwent intensive postoperative rehabilitation with a heavy emphasis on joint range of motion (ROM) and capsular mobility. By eight weeks she achieved 85% active ROM compared to her uninvolved shoulder, and a 55% improvement on the Pennsylvania Shoulder Score. Radiographic imaging provided an understanding of the severity of the arthritic changes present in this patient, identified the limited potential of continued conservative management, and showed structural changes that may be correlated with improved function following the surgical intervention. For patients less than 55 years of age diagnosed with severe glenohumeral osteoarthritis, the CAM procedure and intensive, motion focused therapy presents a promising treatment combination. LEVEL OF EVIDENCE: IIIb. PMID- 23439912 TI - Clinical variants, stages, and management of basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common paraneoplastic disease among human neoplasms. The tumor affects mainly photoexposed areas, most often in the head and seldom appears on genitalia and perigenital region. BCC progresses slowly and metastases are found in less than 0.5% of the cases; however, a considerable local destruction and mutilation could be observed when treatment is neglected or inadequate. Different variants as nodular, cystic, micronodular, superficial, pigment BCC are described in literature and the differential diagnosis in some cases could be difficult. The staging of BCC is made according to Tumor, Node, Metastasis (TNM) classification and is essential for performing the adequate treatment. Numerous therapeutic methods established for treatment of BCC, having their advantages or disadvantages, do not absolutely dissolve the risk of relapses. The early diagnostics based on the good knowledge and timely organized and adequate treatment is a precondition for better prognosis. Despite the slow progress and numerous therapeutic methods, the basal cell carcinoma should not be underestimated. PMID- 23439914 TI - Efflux pump-mediated resistance in chemotherapy. AB - Efflux pump mechanisms perform important physiological functions such as prevention of toxin absorption from the gastrointestinal tract, elimination of bile from the hepatocytes, effective functioning of the blood-brain barrier and placental barrier, and renal excretion of drugs. They exist in all living cells, but those in the bacterial and mammalian cells are more important to the clinician and pharmacologist, as they constitute an important cause of antimicrobial drug resistance, which contributes to treatment failure, high medical bills, and increased mortality / morbidity. This review was aimed at highlighting the role of efflux pump mechanisms in microbial resistance to chemotherapeutic agents. It was also aimed to elucidate their structure and mechanisms of action so as to integrate the efflux pump mechanisms in the design and development of novel antimicrobial agents. Findings from previous studies and research on this subject assessed through Google search, Pubmed, Hinari websites, as well as standard textbooks on chemotherapy, provided the needed information in the process of this review. Efflux pump inhibitors are promising strategies for preventing and reverting efflux-mediated resistance to chemotherapeutic agents. They are usually employed as adjuncts in antimicrobial and cancer chemotherapy. Toxicity, more common with the older-generation inhibitors such as verapamil and reserpine, constitutes the greatest impediment to their clinical applications. No efflux pump inhibitor has been approved for routine clinical use, as a result of doubtful clinical efficacy and unacceptably high incidence of adverse effects, particularly inhibition of the P-450 drug metabolizing enzyme. At present, their applications are mainly restricted to epidemiological studies. Nonetheless, the search for efficacious and tolerable efflux pump inhibitors continues because of the potential benefits. There is a need to consider efflux pump substrate selectivity in the design and development of novel chemotherapeutic agents. PMID- 23439913 TI - microRNA biogenesis and turnover in plants. AB - microRNAs (miRNAs) are short RNAs that regulate gene expression in eukaryotes. The biogenesis and turnover of miRNAs determine their spatiotemporal accumulation within tissues. miRNA biogenesis is a multistep process that entails transcription, processing, nuclear export, and formation of the miRNA-ARGONAUTE complex. Factors that perform each of these steps have been identified. Generation of mature miRNAs from primary transcripts, i.e., miRNA processing, is a key step in miRNA biogenesis. Our understanding of miRNA processing has expanded beyond the enzyme that performs the reactions, as more and more additional factors that impact the efficiency and accuracy of miRNA processing are uncovered. In contrast to miRNA biogenesis, miRNA turnover is an important but poorly understood process that contributes to the steady-state levels of miRNAs. Enzymes responsible for miRNA degradation have only recently been identified. This review describes the processes of miRNA maturation and degradation in plants. PMID- 23439915 TI - Glucose-6 phosphate dehydrogenase deficiency and psychotic illness. AB - Mr. T, a 28-year-old unmarried male, a diagnosed case of Glucose-6 Phosphate Dehydrogenase (G6PD) deficiency since childhood, presented with 13 years of psychotic illness and disturbed biological functions. He showed poor response to antipsychotics and mood stabilizers and had three prior admissions to Psychiatry. There was a family history of psychotic illness. The General Physical Examination and Systemic Examination were unremarkable. Mental Status Examination revealed increased psychomotor activity, pressure of speech, euphoric affect, prolixity, delusion of persecution, delusion of grandiosity, delusion of control, thought withdrawal and thought insertion, and second and third person auditory hallucinations, with impaired judgment and insight. A diagnosis of schizophrenia paranoid type, with a differential diagnosis of schizoaffective disorder manic subtype, was made. This case is being reported for its rarity and atypicality of clinical presentation, as well as a course of psychotic illness in the G6PD Deficiency state,with its implications on management. PMID- 23439916 TI - Interplay between heat shock proteins HSP101 and HSA32 prolongs heat acclimation memory posttranscriptionally in Arabidopsis. AB - Heat acclimation improves the tolerance of organisms to severe heat stress. Our previous work showed that in Arabidopsis (Arabidopsis thaliana), the "memory" of heat acclimation treatment decayed faster in the absence of the heat-stress associated 32-kD protein HSA32, a heat-induced protein predominantly found in plants. The HSA32 null mutant attains normal short-term acquired thermotolerance but is defective in long-term acquired thermotolerance. To further explore this phenomenon, we isolated Arabidopsis defective in long-term acquired thermotolerance (dlt) mutants using a forward genetic screen. Two recessive missense alleles, dlt1-1 and dlt1-2, encode the molecular chaperone heat shock protein101 (HSP101). Results of immunoblot analyses suggest that HSP101 enhances the translation of HSA32 during recovery after heat treatment, and in turn, HSA32 retards the decay of HSP101. The dlt1-1 mutation has little effect on HSP101 chaperone activity and thermotolerance function but compromises the regulation of HSA32. In contrast, dlt1-2 impairs the chaperone activity and thermotolerance function of HSP101 but not the regulation of HSA32. These results suggest that HSP101 has a dual function, which could be decoupled by the mutations. Pulse chase analysis showed that HSP101 degraded faster in the absence of HSA32. The autophagic proteolysis inhibitor E-64d, but not the proteasome inhibitor MG132, inhibited the degradation of HSP101. Ectopic expression of HSA32 confirmed its effect on the decay of HSP101 at the posttranscriptional level and showed that HSA32 was not sufficient to confer long-term acquired thermotolerance when the HSP101 level was low. Taken together, we propose that a positive feedback loop between HSP101 and HSA32 at the protein level is a novel mechanism for prolonging the memory of heat acclimation. PMID- 23439918 TI - Micro-patterned ZnO semiconductors for high performance thin film transistors via chemical imprinting with a PDMS stamp. AB - Chemical imprinting was conducted on ZnO semiconductor films via a chemical reaction at the contact regions between a micro-patterned PDMS stamp and ZnO films. In addition, we applied the chemical imprinting on Li doped ZnO thin films for high performance TFTs fabrication. The representative micro-patterned Li doped ZnO TFTs showed a field effect mobility of 4.2 cm(2) V(-1) s(-1) after sintering at 300 degrees C. PMID- 23439919 TI - Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of non-lymph node thoracic lesions. AB - AIMS: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) has shown excellent diagnostic capabilities for mediastinal and hilar lymphadenopathy. However, its value in thoracic non-lymph node lesions is less clear. This study was designed to assess the value of EBUS-TBNA in distinguishing malignant from benign thoracic non-lymph node lesions. METHODS: From October 2009 to August 2011, 552 patients underwent EBUS-TBNA under local anesthesia and with conscious sedation. We retrospectively reviewed 81 of these patients who had tracheobronchial wall-adjacent intrapulmonary or isolated mediastinal non-lymph node lesions. On-site cytological evaluation was not used. Immunohistochemistry (IHC) was performed to distinguish the origin or type of malignancy when necessary. RESULTS: EBUS-TBNA was performed in 68 tracheobronchial wall-adjacent intrapulmonary and 13 isolated mediastinal non-lymph node lesions. Of the 81 patients, 77 (95.1%, 60 malignancies and 17 benignancies) were diagnosed through EBUS-TBNA, including 57 primary lung cancers, 2 mediastinal tumors, 1 pulmonary metastatic adenocarcinoma, 7 inflammation, 5 tuberculosis, 3 mediastinal cysts, 1 esophageal schwannoma, and 1 focal fibrosis. There were four false-negative cases (4.9%). Of the 60 malignancies, there were 9 (15.0%) which originally had no definite histologic origin or type. Thus, IHC was performed, with 7 (77.8%) being subsequently confirmed. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in distinguishing malignant from benign lesions were 93.4% (60/64), 100% (17/17), 100% (60/60), 81.0% (17/21), and 95.1% (77/81), respectively. CONCLUSION: EBUS-TBNA is a safe procedure with a high sensitivity for distinguishing malignant from benign thoracic non-lymph node lesions within the reach of EBUS-TBNA, with IHC usually providing a more definitive diagnosis. PMID- 23439920 TI - The Effects of Predictability in Daily Husbandry Routines on Captive Rhesus Macaques (Macaca mulatta). AB - Rhesus macaques (Macaca mulatta) housed indoors experience many routine husbandry activities on a daily basis. The anticipation of these events can lead to stress, regardless of whether the events themselves are positive or aversive in nature. The specific goal of this study was to identify whether increasing the predictability of husbandry events could decrease stress and anxiety in captive rhesus macaques. This study was conducted on 39 single-housed subjects in four indoor rooms at the Oregon National Primate Research Center. Temporal and signaled predictability were added to four daily husbandry events: morning and afternoon feeding, enrichment distribution, and room cleaning. Temporally predictable husbandry events occurred reliably at the same time daily, while signaled predictable husbandry events were preceded by a distinct event-specific signal in the form of a doorbell. Informal tests prior to study onset found the doorbells not to be aversive to the subjects. Subjects received each of four treatments: unpredictable events, temporally predictable events, signaled predictable events, and temporally and signaled predictable events. Change in stress was evaluated by monitoring changes in motor stereotypies and displacement behaviors. Our results showed that subjects displayed less stress and anticipatory behaviors related to feeding and enrichment events when the events were temporally predictable (P < 0 .0001). When husbandry events were preceded by a reliable signal, subjects vocalized less prior to the event and were less responsive to activity outside of the room (P < 0 .01). However this may have come at a cost as the animals were extremely reactive to the doorbell signals and showed a heightened stress response during the actual husbandry events (P < 0 .01). Similar to temporal predictability alone, when temporal predictability was combined with signaled predictability subjects displayed less stress and anticipatory behaviors related to feeding and enrichment events (P < 0 .0001). In addition, when both forms of predictability were combined subjects showed less stress behaviors while waiting for daily room cleaning (P < 0 .01). When signaled predictability was paired with temporal predictability subjects no longer had the negative response to the doorbell signal, as they were able to predict and anticipate when the events would occur. Because these results are not necessarily applicable to animals that are given control over their environment or housed in a group setting, the management recommendation that can be made from this study is that temporal predictability of feeding reduces stress and anxiety and is thus beneficial to captive indoor single-housed rhesus macaques. PMID- 23439917 TI - Jasmonate controls leaf growth by repressing cell proliferation and the onset of endoreduplication while maintaining a potential stand-by mode. AB - Phytohormones regulate plant growth from cell division to organ development. Jasmonates (JAs) are signaling molecules that have been implicated in stress induced responses. However, they have also been shown to inhibit plant growth, but the mechanisms are not well understood. The effects of methyl jasmonate (MeJA) on leaf growth regulation were investigated in Arabidopsis (Arabidopsis thaliana) mutants altered in JA synthesis and perception, allene oxide synthase and coi1-16B (for coronatine insensitive1), respectively. We show that MeJA inhibits leaf growth through the JA receptor COI1 by reducing both cell number and size. Further investigations using flow cytometry analyses allowed us to evaluate ploidy levels and to monitor cell cycle progression in leaves and cotyledons of Arabidopsis and/or Nicotiana benthamiana at different stages of development. Additionally, a novel global transcription profiling analysis involving continuous treatment with MeJA was carried out to identify the molecular players whose expression is regulated during leaf development by this hormone and COI1. The results of these studies revealed that MeJA delays the switch from the mitotic cell cycle to the endoreduplication cycle, which accompanies cell expansion, in a COI1-dependent manner and inhibits the mitotic cycle itself, arresting cells in G1 phase prior to the S-phase transition. Significantly, we show that MeJA activates critical regulators of endoreduplication and affects the expression of key determinants of DNA replication. Our discoveries also suggest that MeJA may contribute to the maintenance of a cellular "stand-by mode" by keeping the expression of ribosomal genes at an elevated level. Finally, we propose a novel model for MeJA-regulated COI1-dependent leaf growth inhibition. PMID- 23439921 TI - Dynamic neuromuscular stabilization & sports rehabilitation. AB - Dynamic neuromuscular (core) stability is necessary for optimal athletic performance and is not achieved purely by adequate strength of abdominals, spinal extensors, gluteals or any other musculature; rather, core stabilization is accomplished through precise coordination of these muscles and intra-abdominal pressure regulation by the central nervous system. Understanding developmental kinesiology provides a framework to appreciate the regional interdependence and the inter-linking of the skeleton, joints, musculature during movement and the importance of training both the dynamic and stabilizing function of muscles in the kinetic chain. The Dynamic Neuromuscular Stabilization (DNS) approach provides functional tools to assess and activate the intrinsic spinal stabilizers in order to optimize the movement system for both pre-habilitation and rehabilitation of athletic injuries and performance. LEVEL OF EVIDENCE: 5. PMID- 23439922 TI - Triorchidism with torsion. AB - Polyorchidism is a rare anomaly; triorchidism is the commonest type and is frequently associated with cryptorchidism, inguinal hernia, and testicular torsion. It is also reported as an increased risk of testicular malignancy. We report a case of 72-year-old man with left supernumerary testes in the left hemiscrotum. He presented with pain in his left hemiscrotum of short duration. Physical examination revealed tender hemiscrotum. Both ultrasound and MRI examinations revealed polyorchidism. One of the testes in the left hemiscrotum revealed features of torsion and hemorrhagic necrosis. Polyorchidism is a rare entity. In most cases, sonography alone is diagnostic of polyorchidism. Magnetic resonance imaging may provide additional information in complicated cases of polyorchidism. PMID- 23439923 TI - Favorable outcome in atheroembolic renal disease with pulse steroid therapy. AB - Atheroembolic renal disease is characterized by renal failure secondary to occlusion of renal vasculature by cholesterol containing atheromatous plaques. Clinical presentations of this disease entity are myriad, with limited therapeutic options and unfavorable outcomes. This report describes an elderly male patient with peripheral vascular disease who developed acute renal failure during hospital admission for rectal bleed, and was diagnosed with atheroembolic renal disease on renal biopsy. The patient was managed with pulse steroid therapy and had a favorable outcome. PMID- 23439924 TI - Spinal anesthesia plus ketamine-midazolam sedation for pediatric orthopedic surgery in a developing country. AB - INTRODUCTION: Spinal anesthesia produces a profound and uniformly distributed sensory block with rapid onset and muscle relaxation, and results in complete control of cardiovascular and stress responses. Ketamine is an anesthetic agent that is widely used for pediatric sedations in settings where safety and efficacy of the agents are mandatory because of limited healthcare resources. The authors report on their experience in a refugee hospital located in Bol-la (Saharawi, Algeria). METHODS: Spinal anesthesia was performed for orthopedic surgery procedures in children. Before the spinal puncture, the patients were sedated with intramuscular ketamine followed by intravenous ketamine and midazolam. Boluses of midazolam were also administered throughout the surgery to keep the patients sedated; spinal anesthesia was performed with levobupivacaine 0.25 mg/kg. RESULTS: There were no intraoperative adverse events; vital signs were within the normal pediatric ranges during the procedures and there was no need to switch to general anesthesia. In the postoperative period, no symptoms of dural puncture headache or postoperative delirium or nightmares were reported. CONCLUSION: Based on the authors' experience, the combination of spinal anesthesia and sedation with midazolam and ketamine was found to be a safe approach for children undergoing orthopedic surgery in a low resources setting. PMID- 23439926 TI - Use of generalized additive models and cokriging of spatial residuals to improve land-use regression estimates of nitrogen oxides in Southern California. AB - Land-use regression (LUR) models have been developed to estimate spatial distributions of traffic-related pollutants. Several studies have examined spatial autocorrelation among residuals in LUR models, but few utilized spatial residual information in model prediction, or examined the impact of modeling methods, monitoring site selection, or traffic data quality on LUR performance. This study aims to improve spatial models for traffic-related pollutants using generalized additive models (GAM) combined with cokriging of spatial residuals. Specifically, we developed spatial models for nitrogen dioxide (NO(2)) and nitrogen oxides (NO(x)) concentrations in Southern California separately for two seasons (summer and winter) based on over 240 sampling locations. Pollutant concentrations were disaggregated into three components: local means, spatial residuals, and normal random residuals. Local means were modeled by GAM. Spatial residuals were cokriged with global residuals at nearby sampling locations that were spatially auto-correlated. We compared this two-stage approach with four commonly-used spatial models: universal kriging, multiple linear LUR and GAM with and without a spatial smoothing term. Leave-one-out cross validation was conducted for model validation and comparison purposes. The results show that our GAM plus cokriging models predicted summer and winter NO(2) and NO(x) concentration surfaces well, with cross validation R(2) values ranging from 0.88 to 0.92. While local covariates accounted for partial variance of the measured NO(2) and NO(x) concentrations, spatial autocorrelation accounted for about 20% of the variance. Our spatial GAM model improved R(2) considerably compared to the other four approaches. Conclusively, our two-stage model captured summer and winter differences in NO(2) and NO(x) spatial distributions in Southern California well. When sampling location selection cannot be optimized for the intended model and fewer covariates are available as predictors for the model, the two-stage model is more robust compared to multiple linear regression models. PMID- 23439927 TI - The role of recombinant activated factor VII in cardiac surgery. AB - Recombinant factor VIIa may reduce surgical blood loss and transfusion of blood products in cardiac surgery. However, the true risks of its use in this setting remains to be elucidated, especially when it is administered with other potent pro-haemostatic agents. We reviewed the recent literature on this topic and suggest that the off label use of recombinant factor VIIa is likely to continue. It is our institutional practice to use it in the operating room at a dose of 90 mcg/Kg to ensure there is no obvious correctable surgical source of blood loss, and to be certain that bleeding has stopped before the chest is closed. PMID- 23439925 TI - Essential tremor, the cerebellum, and motor timing: towards integrating them into one complex entity. AB - Essential tremor (ET) is the most common movement disorder in humans. It is characterized by a postural and kinetic tremor most commonly affecting the forearms and hands. Isolated head tremor has been found in 1-10% of patients, suggesting that ET may be a composite of several phenotypes. The exact pathophysiology of ET is still unknown. ET has been repeatedly shown as a disorder of mild cerebellar degeneration, particularly in postmortem studies. Clinical observations, electrophysiological, volumetric and functional imaging studies all reinforce the fact that the cerebellum is involved in the generation of ET. However, crucial debate exists as to whether ET is a neurodegenerative disease. Data suggesting that it is neurodegenerative include postmortem findings of pathological abnormalities in the brainstem and cerebellum, white matter changes on diffusion tensor imaging, and clinical studies demonstrating an association with cognitive and gait changes. There is also conflicting evidence against ET as a neurodegenerative disease: the improvement of gait abnormalities with ethanol administration, lack of gray matter volume loss on voxel-based morphometry, failure to confirm the prominent presence of Lewy bodies in the locus ceruleus, and other pathological findings. To clarify this issue, future research is needed to describe the mechanism of cellular changes in the ET brain and to understand the order in which they occur. The cerebellum has been shown to be involved in the timing of movement and sensation, acting as an internal timing system that provides the temporal representation of salient events spanning hundreds of milliseconds. It has been reported that cerebellar timing function is altered in patients with ET, showing an increased variability of rhythmic hand movements as well as diminished performance during predictive motor timing task. Based on current knowledge and observations, we argue that ET is essentially linked with cerebellar degeneration, or at least cerebellar dysfunction, together with disturbance of motor timing. We explain the context of our current understanding on this topic, highlighting possible clinical consequences for patients suffering from ET and future research directions. PMID- 23439928 TI - The inhibitory effect of eupatilin on the agonist-induced regulation of vascular contractility. AB - The present study was undertaken to investigate the influence of eupatilin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Eupatilin more significantly relaxed fluoride-induced vascular contraction than thromboxane A(2) or phorbol ester-induced contraction suggesting as a possible anti-hypertensive on the agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, eupatilin significantly inhibited fluoride-induced increases in pMYPT1 levels. On the other hand, it didn't significantly inhibit phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving the primarily inhibition of Rho-kinase activity and the subsequent phosphorylation of MYPT1. This study provides evidence regarding the mechanism underlying the relaxation effect of eupatilin on agonist-induced vascular contraction regardless of endothelial function. PMID- 23439929 TI - Use of the LUCAS mechanical chest compression device for percutaneous coronary intervention during cardiac arrest: is it really a game changer? AB - Cardiopulmonary support including closed chest compression is a mainstay in the management of cardiac arrest. However, traditional means (i.e. manual) chest compression may be logistically challenging, especially in patients requiring emergent invasive procedures such as percutaneous coronary intervention for cardiac arrest due to acute myocardial infarction. The LUCAS mechanical chest compression device provides external and automated closed chest compression, thus enabling even complex invasive procedures without interrupting cardiopulmonary support. Nonetheless, no randomized trial has proved to date its benefit in comparison to standard manual chest compression, and to date only observational studies and consensus opinion support its clinical use. PMID- 23439930 TI - Effect of on-call-related sleep deprivation on physicians' mood and alertness. AB - BACKGROUND AND OBJECTIVE: Physicians may experience periods of acute sleep deprivation while on-call, in addition to baseline chronic sleep deprivation which may affect physicians' performance and patients' safety. The purpose of this study was to determine the effect of acute sleep deprivation due to working long on-call shifts on mood and alertness, both of which may impair physicians' performance. METHODS: Eighty-eight junior physicians working in one university hospital completed a questionnaire, before and after completion of a shift, that collected data regarding socio-demographic factors, patterns of work and sleep, Profile of Mood States (POMS), and Stanford Sleepiness Scale. Based on duration of sleep the physicians had during on-call in comparison to their usual average sleep, the participants were categorized into group 1 (those who slept many fewer hours), group 2 (those who slept fewer hours), or group 3 (those who slept the same number of hours). RESULTS: More than 87% of the participant slept 5 or fewer hours while working an on-call shift. Among all participants, the percentage of physicians who were alert post-on-call was significantly reduced compared to the percentage pre-on-call (P = 0.001). The post-on-call total POMS scores of groups 1 and 2 were significantly worse than their pre-on-call scores (P = 0.001 and 0.038, respectively), while there was no significant difference between the pre- and post-on-call POMS scores of group 3 (P = 0.165). CONCLUSION: Acute sleep loss due to working long on-call shifts significantly decreases daytime alertness and negatively affects the mood state of junior physicians. PMID- 23439931 TI - Tremor: clinical phenomenology and assessment techniques. AB - BACKGROUND: Tremors are among the most common movement disorders. As there can be considerable variability in the manner in which clinicians assess tremor, objective quantitative tools such as electromyography, accelerometry, and computerized, spiral analysis can be very useful in establishing a clinical diagnosis and in research settings. METHODS: In this review, we discuss the various methods of quantitative tremor analysis and the classification and pathogenesis of tremor. The most common pathologic tremors and an approach to the diagnosis of tremor etiology are described. CONCLUSIONS: Pathologic tremors are common, and the diagnosis of underlying etiology is not always straightforward. Computerized quantitative tremor analysis is a valuable adjunct to careful clinical evaluation in distinguishing tremulous diseases from physiologic tremors, and can also help shed light on their pathogenesis. PMID- 23439932 TI - A universal and multiplex kinase assay using gamma-[(18)O(4)]-ATP. AB - We have synthesized gamma-[(18)O4]-ATP and used it to develop a non-radioactive and multiplex method. Significantly, this novel approach can be applied to any kinases without using a purified enzyme or a fluorescent substrate. Using this approach, the effectiveness and specificity of inhibitors on several kinases could be readily determined. PMID- 23439933 TI - A retrospective analysis of the first Yemeni experience on Artisan phakic intraocular lens for the treatment of moderate and high myopia. AB - OBJECTIVES: To evaluate the outcome and safety of the iris-fixated Artisan phakic intraocular lens (PIOL) for the correction of moderate and high myopia. MATERIALS AND METHODS: A retrospective non-controlled clinical study of the data of patients who underwent Artisan PIOLs between March 2006 and July 2008 was evaluated. Pre-operative examination included age, gender, refraction, uncorrected (UCVA) and best spectacle corrected (BSCVA) visual acuity, predictability and safety were analyzed. Post-operative time course ranged from 12 to 36 months. RESULTS: An Artisan myopia lens was implanted in 62 eyes of 39 patients. The mean pre-operative spherical equivalent (SE) was -13.17 +/- 5.62 D. The pre-operative myopia ranged from -4.5 to -24 D. Mean patient age was 25.44 +/ 5.22 years. At last follow-up visit, residual SE was within +/-1.00 D in 36 eyes (58.1%) and +/-2.00 D in 56 eyes (90.3%). In the last visit UCVA was equal to or better than pre-operative BSCVA in 57 (91.9%) of the eyes. One eye (1.6%) lost one Snellen line, three eyes (4.8%) lost two or more Snellen lines and one eye lost vision (1.6%). Post-operative complications included anterior chamber reaction in one eye, rise in intraocular pressure in two eyes and retinal detachment in one eye. CONCLUSION: When laser keratorefractive surgery is not an option, implantation of Artisan PIOL to correct moderate to high myopia results in a stable and good refractive result with few complications that must be kept in mind. PMID- 23439934 TI - Ion-pairing reverse-phase high performance liquid chromatography method for simultaneous estimation of atenolol and indapamide in bulk and combined dosage form. AB - A sensitive, accurate, precise and validated ion-pairing reverse-phase liquid chromatographic method for the quantitative determination of atenolol and indapamide in bulk and tablet dosage form was developed. The proposed ion-pairing reverse-phase high performance liquid chromatography method utilises C(18) column with 5 MUm, 150*4.6 mm i.d. column and mobile phase consisting of 0.1% w/v solution of octane sulphonic acid, sodium salt and methanol (55:45 v/v), (pH 2.8) and ultraviolet detection at 235 nm. A linearity range of 1-250 MUg/ml and 1-25 MUg/ml for atenolol and indapamide, respectively, was obtained. The mean recoveries are 100.48 and 99.82% for atenolol and indapamide, respectively. The method was validated as per International Conference on Harmonization guidelines. PMID- 23439936 TI - A two-scale Weibull approach to the failure of porous ceramic structures made by robocasting: possibilities and limits. AB - This paper introduces our approach to modeling the mechanical behavior of cellular ceramics, through the example of calcium phosphate scaffolds made by robocasting for bone-tissue engineering. The Weibull theory is used to deal with the scaffolds' constitutive rods statistical failure, and the Sanchez-Palencia theory of periodic homogenization is used to link the rod- and scaffold-scales. Uniaxial compression of scaffolds and three-point bending of rods were performed to calibrate and validate the model. If calibration based on rod-scale data leads to over-conservative predictions of scaffold's properties (as rods' successive failures are not taken into account), we show that, for a given rod diameter, calibration based on scaffold-scale data leads to very satisfactory predictions for a wide range of rod spacing, i.e. of scaffold porosity, as well as for different loading conditions. This work establishes the proposed model as a reliable tool for understanding and optimizing cellular ceramics' mechanical properties. PMID- 23439937 TI - Further Evidence for Celiac Disease-associated Chorea. AB - BACKGROUND: A number of neurological conditions have been reported to be associated with gluten sensitivity, including ataxia, peripheral neuropathy, epilepsy, and occasionally, chorea. The pathogenic role of anti-gliadin antibodies has been questioned, and pathophysiology remains controversial. CASE REPORT: I report chorea in a patient with celiac disease, which responded to a gluten-restricted diet. The response of the movement disorder to change in diet strongly suggests a functional role for anti-gliadin antibodies in the generation of chorea, probably involving basal ganglia targets. DISCUSSION: Gluten sensitivity may be a treatable cause of chorea. PMID- 23439935 TI - Coping changes the brain. AB - One of the earliest and most consistent findings in behavioral neuroscience research is that learning changes the brain. Here we consider how learning as an aspect of coping in the context of stress exposure induces neuroadaptations that enhance emotion regulation and resilience. A systematic review of the literature identified 15 brain imaging studies in which humans with specific phobias or post traumatic stress disorder (PTSD) were randomized to stress exposure therapies that diminished subsequent indications of anxiety. Most of these studies focused on functional changes in the amygdala and anterior corticolimbic brain circuits that control cognitive, motivational, and emotional aspects of physiology and behavior. Corresponding structural brain changes and the timing, frequency, and duration of stress exposure required to modify brain functions remain to be elucidated in future research. These studies will advance our understanding of coping as a learning process and provide mechanistic insights for the development of new interventions that promote stress coping skills. PMID- 23439938 TI - The edge-to-edge technique for mitral valve repair. AB - The edge-to-edge technique was introduced in the surgical armamentarium of mitral valve repair in 1991 and has progressively been used to restore mitral competence in the setting of degenerative, post-endocarditis and functional mitral regurgitation. Appropriate indications and awareness of the important technical aspects of the procedure are prerequisites for a good outcome. The free edges of the mitral leaflets have to be approximated in correspondence of the site of the regurgitant jet in such a way that mitral regurgitation is corrected without producing stenosis. A prosthetic ring is usually implanted to stabilize the repair. Middle and long-term results are now available for degenerative mitral regurgitation (bileaflet prolapse, anterior leaflet prolapse and commissural prolapse). Of particular interest is the finding that the edge-to-edge technique for correction of anterior leaflet prolapse is providing a freedom from reoperation similar to that obtained in patients with posterior leaflet prolapse treated with quadrangular resection. Degenerative or post-endocarditis commissural prolapse/flail of the mitral valve can be effectively corrected by this technique. In patients with functional mitral regurgitation, the use of the edge-to-edge repair, added to the undersized annuloplasty, has been associated with a significantly lower recurrence of mitral regurgitation in the follow-up compared to isolated undersized annuloplasty. Almost 20 years after its introduction, the edge-to-edge technique remains an effective and versatile method to treat mitral regurgitation. Its simplicity and reproducibility have led to its clinical application by percutaneous methods opening a new age in the fascinating field of reconstructive mitral valve surgery. PMID- 23439939 TI - Prevalence of depression and anxiety in irritable bowel syndrome: A clinic based study from India. AB - BACKGROUND: Irritable Bowel Syndrome (IBS) is a very common gastrointestinal dysfunction. Despite strong evidence of high prevalence of depression and anxiety in IBS there is very limited research on this in India. MATERIALS AND METHODS: Cases of IBS and controls with non-ulcerative dyspepsia were recruited from a gastroenterology clinic in Mumbai, India. Presence of anxiety disorder and depression were assessed by using the Hamilton Anxiety rating scale and Hamilton Depression rating scale respectively. Prevalence rates of anxiety and depression were established and Odds Ratio (OR) was calculated to determine the association of depression and anxiety disorders with IBS. RESULTS: In IBS cases, the prevalence of depression and anxiety disorder was 37.1% and 31.4% respectively. In patients with IBS the OR for depression was 6.3 (95% CI 1.6-24.74, P=0.009) and the OR for anxiety disorder was 7.56 (95% CI 1.53-37.29, P=0.01). CONCLUSION: The prevalence of depression and anxiety disorder in IBS is very high. Therefore, screening of IBS patients for anxiety and depression would facilitate better interventions and consequently better outcomes. PMID- 23439941 TI - Depression associated with dysembryoblastic neuroepithelial tumor. AB - Dysembryoblastic neuroepithelial tumor (DNET), a benign, rare tumor of the brain, commonly presents with generalized or partial epilepsy, post-epilepsy sequelae of psychotic, depressive or anxiety symptoms or disorders, or is usually asymptomatic. We report the first case in scientific literature of temporal lobe DNET presenting with only major depressive disorder, without epilepsy. A 24-year old single male, presented with pervasive sadness, easy fatigability, loss of interest in his daily activities, decreasing appetite associated with poor of quality sleep, poor attention and concentration, pessimism about the future, and headaches. He was diagnosed with severe depression, without psychotic symptoms. Magnetic resonance imaging of the brain showed a lobulated hyperintense temporal lobe mass of 2.7 * 2.2 mm in the hippocampus region suggestive of a DNET. Electroencephalography, thyroid function tests, blood sugar, and electrocardiogram were normal. The depression responded well to tablet Escitalopram 10 mg once daily initially, with no adverse effects reported. PMID- 23439940 TI - Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference. AB - BACKGROUND: There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first international consensus conference on this topic. METHODS: The consensus was a continuous international internet-based process with a final meeting on June 28th 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting and ranking. RESULTS: Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, the use of preoperative intra-aortic balloon counterpulsation and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. CONCLUSION: This international consensus conference has identified the non surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality. PMID- 23439942 TI - Evaluating the effectiveness of topical application of natural honey and benzydamine hydrochloride in the management of radiation mucositis. AB - BACKGROUND: Radiation mucositis is an early effect of head and neck radiotherapy. Mucositis can cause ulcers, and patients may experience pain and dysphagia which need proper management. This study was conducted in 60 patients with oral malignancy. AIM: To evaluate the effect of natural honey and 0.15% benzydamine hydrochloride on onset and severity of radiation mucositis and to compare it with control. MATERIALS AND METHODS: This study was conducted in the Department of Oral Medicine and Radiology, Tamilnadu Government Dental College and Hospital, Chennai, from April to December 2010. The sample size comprised of 60 patients, of both genders, diagnosed with oral malignancy clinically and histopathologically and planned for radiotherapy. The patients were assigned into three groups by random sampling. Each group consisted of 20 patients. Group 1 patients were instructed for topical application of natural honey, groups 2 and 3 were instructed for topical application of 0.15% benzydamine hydrochloride and 0.9% normal saline respectively. The onset of mucositis and the severity of mucositis were graded during the course of the radiotherapy and two weeks after radiotherapy, with WHO mucositis grading in all the three groups and statistically analysed with SPSS version 11 software. RESULTS: A significant reduction in mucositis in honey-received patients compared with 0.15% benzydamine hydrochloride, 0.9% normal saline applied patients occurred. The differences between the groups were statistically significant (P < 0.001). CONCLUSION: Pure natural honey can be an effective agent in managing radiation induced oral mucositis. Honey could be a simple, potent and inexpensive agent, which is easily available, and it can be a better therapeutic agent in managing radiation mucositis in developing countries like India for the management of this morbidity. PMID- 23439943 TI - Investigation of extended blinks and interblink intervals in subjects with and without dry eye. AB - BACKGROUND: The purpose of this study was to investigate the occurrence and duration of extended blinks >= 70 msec and their associated interblink intervals in normal subjects and in subjects with mild to moderate dry eye. METHODS: This single-center, prospective, double-blind study included 11 subjects with dry eye and eight subjects with normal eyes. Extended blinks were defined as lid closure in at least two successive video frames (>=70 msec). Digital video imaging of each subject's eyes was recorded while the subject viewed a 10-minute documentary. The subjects did not know that blink was the outcome being measured. Following capture, the videos were manually analyzed in a masked fashion for the occurrence of extended blinks. The length of the interblink interval (ie, time between blinks) before and after these extended blinks (the interblink interval ratio) was calculated, as well as differences in lid contact times. RESULTS: The dry eye group had a median extended blink duration which was 2.53 times longer than that of the normal group. For subjects with dry eye, interblink intervals post-extended blink were significantly longer than interblink intervals pre extended blink (P < 0.001). Interblink intervals did not lengthen significantly in normal subjects. In both groups, the duration of the extended blink was significantly (P = 0.001) and positively correlated with interblink interval ratio (post-extended to pre-extended blink interblink interval), such that for each doubling of extended blink duration, the interblink interval ratio increased by 10%. Blinks longer than one second in duration occurred almost exclusively in subjects with dry eye. CONCLUSION: THIS STUDY REPORTS THREE CENTRAL FINDINGS: blink duration tended to be longer in subjects with dry eye; a lengthening of the interblink interval after an extended blink occurred in subjects with dry eye but not in those without dry eye; and a longer blink duration was associated with a significantly increased interblink interval ratio in all subjects. PMID- 23439944 TI - Wntless in Wnt secretion: molecular, cellular and genetic aspects. AB - Throughout the animal kingdom, Wnt-triggered signal transduction pathways play fundamental roles in embryonic development and tissue homeostasis. Wnt proteins are modified as glycolipoproteins and are secreted into the extracellular environment as morphogens. Recent studies on the intracellular trafficking of Wnt proteins demonstrate multiple layers of regulation along its secretory pathway. These findings have propelled a great deal of interest among researchers to further investigate the molecular mechanisms that control the release of Wnts and hence the level of Wnt signaling. This review is dedicated to Wntless, a putative G-protein coupled receptor that transports Wnts intracellularly for secretion. Here, we highlight the conclusions drawn from the most recent cellular, molecular and genetic studies that affirm the role of Wntless in the secretion of Wnt proteins. PMID- 23439945 TI - Clinicoepidemiological study of skin manifestations in patients of chronic renal failure on hemodialysis. AB - BACKGROUND: Chronic renal failure (CRF) is associated with a variety of cutaneous manifestations as a result of underlying etiology as well as the various treatment modalities. AIM: To evaluate the prevalence of various dermatoses in patients with CRF on hemodialysis and to study the effect of hemodialysis on the intensity of pruritus. MATERIALS AND METHODS: A total of 35 patients of CRF on hemodialysis having at least one cutaneous manifestation were included in the study. RESULTS: Twenty-four (68.71%) cases in our study belonged to the age group of 50-69 years, out of which 16 cases were in the sixth decade. Xerosis and pruritus occurred in 80% and 65.71% of cases, respectively. Other common findings included pallor (68.57%), dyspigmentation (34.29%), cutaneous infections (34.39%), acquired perforating dermatosis (17.4%), and nail changes (60%). Hemodialysis failed to improve pruritus in 17 (73.9%) of our patients. Twenty-six patients (74.28%) suffered from hypertension, 13 of them also were known cases of type II diabetes mellitus. Five patients suffered exclusively from type II diabetes mellitus. CONCLUSIONS: In our small study, xerosis was the commonest finding and pruritus, the commonest symptom. The intensity of pruritus was largely unaffected by hemodialysis. PMID- 23439946 TI - Target synthesis of a novel porous aromatic framework and its highly selective separation of CO(2)/CH(4). AB - A novel porous aromatic framework based on tetra-(4-anilyl)-methane and cyanuric chloride has been designed and synthesized successfully, which possesses permanent porosity and high selectivity of CO2 towards CH4. PMID- 23439949 TI - Sideline management of acute dislocation of the glenohumeral joint- a unique approach to athlete self-reduction. AB - The acute anterior dislocation of the glenohumeral joint (GHJ) poses a challenge to sports medicine providers at all levels and in all settings. This macrotraumatic injury occurs in athletes who participate in a wide variety of sports, most typically as a result of contact or collision mechanisms. Quick and effective relocation of the GHJ is an important skill for on the sideline or on the field management of this type of dislocation when appropriate and allowable by facility protocol. This clinical suggestion describes one possible technique for athlete self-reduction that may be appropriate in some circumstances. This is in contrast to forcible reduction by the health professional, which is outside of the scope of this clinical commentary. LEVEL OF EVIDENCE: 5. PMID- 23439947 TI - Expectancy learning from probabilistic input by infants. AB - Across the first few years of life, infants readily extract many kinds of regularities from their environment, and this ability is thought to be central to development in a number of domains. Numerous studies have documented infants' ability to recognize deterministic sequential patterns. However, little is known about the processes infants use to build and update representations of structure in time, and how infants represent patterns that are not completely predictable. The present study investigated how infants' expectations fora simple structure develope over time, and how infants update their representations with new information. We measured 12-month-old infants' anticipatory eye movements to targets that appeared in one of two possible locations. During the initial phase of the experiment, infants either saw targets that appeared consistently in the same location (Deterministic condition) or probabilistically in either location, with one side more frequent than the other (Probabilistic condition). After this initial divergent experience, both groups saw the same sequence of trials for the rest of the experiment. The results show that infants readily learn from both deterministic and probabilistic input, with infants in both conditions reliably predicting the most likely target location by the end of the experiment. Local context had a large influence on behavior: infants adjusted their predictions to reflect changes in the target location on the previous trial. This flexibility was particularly evident in infants with more variable prior experience (the Probabilistic condition). The results provide some of the first data showing how infants learn in real time. PMID- 23439950 TI - A Rare Case of Inherited Factor-II Deficiency Causing Life-Threatening Menorrhagia. AB - Menorrhagia is a common gynecological symptom. In adolescents, the cause is generally dysfunctional uterine bleeding. Menorrhagia may also be due to undiagnosed coagulation defects, endocrine disorders, gynecological abnormalities of the uterus, or other systemic disorders. Menorrhagia may be the only clinical manifestation of an inherited bleeding disorder. We report a case of inherited hypoprothrombinemia (factor II deficiency), a rare bleeding disorder as the cause of life-threatening menorrhagia. In the absence of a readily identifiable cause, all adolescents with menorrhagia should be examined for bleeding disorders. PMID- 23439951 TI - Progressive development of polycystic kidney disease in the mouse model expressing Pkd1 extracellular domain. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slow progression of multiple cysts in both kidneys that lead to renal insufficiency in mid-life or later. ADPKD is associated with mutations mainly in the PKD1 gene (encoding polycystin-1 or PC1) and less frequently in the PKD2 gene (encoding polycystin-2 or PC2). To mimic naturally occurring human PKD1 mutations and gain insight into the PC1 extracellular domain function, four transgenic mouse lines were established with exclusively the extracellular domain of the Pkd1 gene (Pkd1(extra)) under endogenous transcriptional regulation. Expression of the Pkd1(extra) transgene was 2- to 80-fold above endogenous levels. Strikingly, the Pc1(extra) protein was more abundant, proportionally to the endogenous levels. All four transgenic mouse lines consistently displayed progressive renal cystic phenotype. Consequently, these transgenic mice reproducibly developed renal functional alterations similar to human ADPKD with proteinuria, renal insufficiency, anemia and died of renal failure late in life. In precystic kidneys, the Pkd1(extra) transgene modulated Pc2 expression and thereby, uncovered a potential Pc1-mutant/Pc2 pathogenic crosstalk mechanism. Moreover, the pathophysiologic mechanism also implicates c-myc, a major modulator of cystogenesis. Altogether, the novel Pkd1(extra) mouse model is the first Pc1 extracellular mutant that reproduces human ADPKD clinical progression and physiopathology. PMID- 23439952 TI - Combined high thoracic and lumbar epidural block for a patient with severe peripheral vascular disease undergoing axillo bifemoral bypass surgery. AB - A 63 years old patient with severely impaired pulmonary function presented with bilateral lower limb vascular blockade and was operated for emergency aortobifemoral bypass. The patient was considered to be at very high risk for general anesthesia but doing the case under regional anesthesia was also challenging because of the multiple dermatomal levels needed to be anesthetized and because of the potential of adverse effects with such extensive block. There are only a few reported cases of using combination of central neuraxial blocks. The procedure was successfully performed using combined high thoracic and lumbar epidural blockade with two different local anesthetics to minimizing toxicity and observing no adverse effects related to anesthesia technique. PMID- 23439954 TI - Locked twins: a rarity. AB - Locked twins is a rare, hazardous obstetric complication. Herein, we report the rare condition of an unbooked case of locked twin that attended our labor room in late stage of labor with arrested after coming head of the first twin, which was dead. Caesarean section was performed to save the second baby. Antenatal diagnosis of twin gestation with leading twin breech and second twin cephalic presentation raises index of suspicion of potential locked twin. Timely done caesarean delivery could have avoided the fetal death. PMID- 23439955 TI - Synthesis of a bicyclic diborane by selective boron carbon bond formation. AB - The bicyclic diboron species was generated with high selectivity by a combination of boron carbon bond formation and hydrogen iodide elimination events. The nature of the boracycle was evaluated using X-ray diffraction, NMR spectroscopy and density functional theory calculations. PMID- 23439956 TI - Detecting and delivering platinum anticancer drugs using fluorescent maghemite nanoparticles. AB - Rhodamine-embedded maghemite nanoparticles could act as fluorescent drug carriers to track and transport platinum anticancer drugs simultaneously. PMID- 23439953 TI - Understanding tremor in multiple sclerosis: prevalence, pathological anatomy, and pharmacological and surgical approaches to treatment. AB - BACKGROUND: Given that tremor is one of the most prevalent and disabling features of multiple sclerosis (MS), we will review the most significant milestones in tremor in this disease in recent years, focusing on prevalence, clinical features, anatomical basis, and treatment. METHODS: Data for this review were identified by searching MEDLINE with the search terms "multiple sclerosis" and "tremor". References were also identified from relevant articles published between January 1966 and May 2012. RESULTS: The predominant type of MS tremor is a large-amplitude, postural, and kinetic tremor, which most commonly affects the arms, although tremor can also involve head, neck, vocal cords, and trunk. Involvement of the tongue, jaw, or palate has not been reported. Although the anatomical basis underlying tremor in MS is poorly understood, the link between the cerebellum and the MS-related tremor is supported by clinical and experimental studies. Currently available medication is often unsuccessful in most cases. Surgical treatment can be a satisfactory alternative to treat severe and disabling tremor. DISCUSSION: Tremor in MS patients could be considered as an advanced consequence of the disease and its presence suggests a more aggressive course. MS tremor can be severe and very disabling for a small group of patients. Treatment of MS tremor remains a great challenge. Recent studies suggest that dissociating tremor from cerebellar dysfunction using selected clinical tests would be the key issue to successful surgical treatment. Understanding the pathophysiology and biochemistry of tremor production in MS may lead to new therapeutic approaches. PMID- 23439957 TI - A four-coordinate thionitrosyl complex of vanadium. AB - Addition of elemental sulfur to the vanadium nitride [(nacnac)V=N(OAr)] forms the first thionitrosyl complex of vanadium, [(nacnac)V(NS)(OAr)]. Single crystal X Ray diffraction studies and DFT calculations reveal an almost linear thionitrosyl ligand resulting from an extended pi-resonance across the VNS moiety. PMID- 23439961 TI - Watermelon stomach in end-stage renal disease patient. AB - Gastric antral vascular ectasia (GAVE), also called watermelon stomach, is a rare cause of gastrointestinal (GI) bleeding. GAVE is associated with a number of conditions, including portal hypertension, chronic kidney disease (CKD), and collagen vascular diseases, especially scleroderma. Limited reports of GAVE are present in CKD patients. Argon plasma coagulation (APC) is an effective therapy for GAVE. We describe the case of a CKD, stage V patient, who presented with recurrent blood loss in stools and transfusion-dependent anemia. Her endoscopy revealed GAVE, which was managed uneventfully with APC. PMID- 23439959 TI - Acne inversa (Hidradenitis suppurativa): A review with a focus on pathogenesis and treatment. AB - Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. This is an important link to insights into immune dysfunction, which stimulated therapeutic approaches like tumor necrosis-alpha inhibitor therapy. This new off-label drug treatment is particularly beneficial when used in combination with wide excision of inflamed skin and subcutaneous tissue. Retinoids have been reported to be helpful in secondary prevention. The standard of therapy in advanced cases is surgery with wide excisions and healing by secondary intention. This treatment results in significant reduction of complaints and achieves satisfactory body contouring. PMID- 23439960 TI - Neuroimaging of Essential Tremor: What is the Evidence for Cerebellar Involvement? AB - BACKGROUND: Clinical observations and electrophysiological studies have provided initial evidence for the involvement of the cerebellum in essential tremor (ET), the most frequent hyperkinetic disorder. Recently, this hypothesis has been reinvigorated by post-mortem studies that demonstrated a number of pathological changes in the cerebellum of ET patients compared with age-matched healthy controls. Advanced neuroimaging techniques have also made it possible to detect in vivo which cerebellar abnormalities are present in ET patients and to reveal the core mechanisms implicated in the development of motor and cognitive symptoms in ET. OBJECTIVE: We discuss the neuroimaging research investigating the brain structure and function of ET patients relative to healthy controls. In particular, we review 1) structural neuroimaging experiments assessing the density/volume of cortical/subcortical regions and the integrity of the white matter fibers connecting them; 2) functional studies exploring brain responses during motor/cognitive tasks and the function of specific neurotransmitters/metabolites within cortical-cerebellar circuits. METHODS: A search in PubMed was conducted to identify the relevant literature. DISCUSSION: Current neuroimaging research provides converging evidence for the role of the cerebellum in the pathophysiology of ET, although some inconsistencies exist, particularly in structural studies. These discrepancies may depend on the high clinical heterogeneity of ET and on differences among the experimental methods used across studies. Further investigations are needed to disentangle the relationships between specific ET phenotypes and the underlying patterns of neural abnormalities. PMID- 23439962 TI - Acute renal failure and cardiac surgery. AB - Acute renal failure (ARF) is s a major complication after cardiac surgery and its prevalence still remains high. Even minor changes in serum creatinine are related to an increase morbidity and mortality. Recently two consensus conferences have suggested new diagnostic criteria to define acute kidney injury and risk scores to better identify patients who will probably develop ARF after cardiac surgery. In fact a prompt recognition of high risk patients could allow a more aggressive therapy at a reversible stage of an incoming ARF. To date prophylactic strategies of renal function preservation during surgery include the avoidance of nephrotoxic insult and the prevention or correction of renal hypoperfusion. Although there are still no pharmacological agents able to prevent the perioperative ARF, several trials are investigating new pharmacological approaches. When prophylactic strategies fail and severe ARF occurs, renal replacement therapy becomes mandatory. The timing and the kind of renal replacement therapy remain an open issue. Further randomized case-control studies with adequate statistical power are needed to have more conclusive data. Aim of this paper is to start from the acute renal injury physiopathology to analyze the most common prophylactic and pharmacological strategies. PMID- 23439963 TI - A Comparison of Screening Tests for Soil Pb. AB - Soil has been identified as a significant source of lead (Pb) exposure for both children and adults. Therefore, identifying possibly contaminated soils by soil testing is important to protect public health. Soil Pb test results are usually reported as total Pb (mg kg(-1)), carried out using a concentrated nitric acid digestion procedure by hot plate (EPA method 3050) or microwave (EPA method 3051) followed by inductively coupled plasma atomic emission spectrometry to determine total Pb in the digest. However, this procedure is both time-consuming and expensive, sometimes costing homeowners and gardeners over $50 per sample. To make soil Pb testing more economically accessible to homeowners and gardeners, several university soil-testing laboratories offer less expensive screening tests designed to estimate total soil Pb. The first objective of this study was to compare three commonly used screening tests, modified Morgan (MM), Mehlich 3 (M3), and 1 M nitric acid (HNO(3)), to the standard total Pb testing method (EPA method 3051) to find which extractant is the most reliable predictor of total Pb. The second objective was to investigate the effect that different degrees of soil grinding have on the total Pb test and the extracted Pb concentration measured from the 1 M HNO(3) test. Results indicate that the strongest predictor of total Pb is 1 M HNO(3), followed by M3, and MM, and that thorough grinding is necessary if using less than five grams of soil in a Pb test, in order to adequately homogenize Pb-contaminated samples and achieve acceptable testing reproducibility. PMID- 23439965 TI - Revealing local, enhanced optical field characteristics of Au nanoparticle arrays with 10 nm gap using scattering-type scanning near-field optical microscopy. AB - Anomalous optical properties displayed by plasmonic structures are commonly attributed to the enhanced, local field within their corrugations. Though theoretical calculations of such field enhancements abound, experimental observations are relatively few, because only few optical microscopic techniques have enough spatial resolution. We used scattering-type scanning near-field optical microscopy to resolve local optical characteristics of a gold nanoparticle array with 10 nm gap between adjacent particles. Subnanometer resolution measurement of the optical field intensity was achieved by use of etched silicon atomic force microscopy probe tip. The result shows that, with a p polarized excitation scheme, the induced field is enhanced and the phase undergoes a large change in the gap region. The spatially-resolved signals are attributed to the electromagnetic interaction within an array of vertical dipoles. We show that scattering-type near-field optical microscopy is well suited to the investigation of field enhancements in plasmon-enhanced sensing and spectroscopy array structures. PMID- 23439964 TI - A critical appraisal of lubiprostone in the treatment of chronic constipation in the elderly. AB - Chronic constipation is a common disorder in the general population, with higher prevalence in the elderly, and is associated with worse quality of life and with greater health care utilization. Lubiprostone is an intestinal type-2 chloride channel activator that increases intestinal fluid secretion, small intestinal transit, and stool passage. Lubiprostone is currently approved by the US Food and Drug Administration for the treatment of chronic idiopathic constipation and of irritable bowel syndrome with predominant constipation. This review outlines current approaches and limitations in the treatment of chronic constipation in the elderly and discusses the results, limitations, and applicability of randomized, controlled trials of lubiprostone that have been conducted in the general and elderly population, with additional focus on the use of lubiprostone in constipation in Parkinson's disease and in opioid-induced constipation, two clinical entities that can be comorbid in elderly patients. PMID- 23439966 TI - Multichannel Electromyographic Mapping to Optimize OnabotulinumtoxinA Efficacy in Cervical Dystonia. AB - BACKGROUND: Cervical dystonia (CD) is characterized by sustained, involuntary contraction of head and neck muscles. Botulinum toxin injections are established as safe and effective, but unfortunately 15-25% of patients fail to respond. The aim of this study was to examine whether multichannel electromyogaphic mapping improved outcomes in a cohort of antibody-negative onabotulinumtoxinA non responders by more precisely identifying which muscles were involved in the dystonia. METHODS: Patients with cervical dystonia who had "failed chemodenervation therapy" administered by an outside provider were enrolled in a single-blind, randomized, crossover design study. Patients received either a multichannel electromyographic mapping study prior to the first botulinum toxin injection, which was followed by use of only a single-lead injection 16 weeks later (injected by an alternate and blinded movement disorders specialist) or vice versa. The primary outcome measure was change in total Toronto Western Spasmodic Torticollis Rating Scale score 4 weeks after each injection compared with each pre-injection baseline score. RESULTS: Nine subjects completed this study. Mean percentage improvement in Total Toronto Western Spasmodic Torticollis Rating Scale was 23.5% using multichannel electromyography compared with 9% using the single-channel technique (p = 0.11). DISCUSSION: This pilot study suggests that multichannel electromyographic mapping may result in improved efficacy in the treatment of antibody-negative onabotulinumtoxinA refractory CD. PMID- 23439967 TI - Alternating chirality in the monolayer H2TPP on Cu(110)-(2 * 1)O. AB - In this work, the structure of the tetraphenylporphyrin (H2TPP) monolayer grown on the oxygen passivated Cu(110)-(2 * 1)O surface has been investigated with LT STM and elucidated by DFT-calculations. The monolayer is commensurate with all molecules occupying the same adsorption site, but there are two molecules per unit cell. The STM images suggest alternating chirality for the molecules within one unit cell which is supported by DFT total energy calculations for monolayers on the Cu-O substrate. STM simulations for alternating and single chirality monolayers have subtle differences which indicate that the experimentally observed surface is one containing molecules with alternating chirality, that is racemicity within the unit cell. PMID- 23439968 TI - Successful reversal of recurrent spinal cord ischemia following endovascular repair of a descending thoracic aortic aneurysm. AB - Despite recent advances in technique, spinal cord ischemia remains one of the most dreaded complications of thoracic aortic surgery. Recently, it has been suggested that thoracic endovascular aortic repair may decrease the risk of paraplegia. We present a case of delayed paraplegia following thoracic endovascular aortic repair that was successfully reversed on 3 separate occasions in the same patient. This highlights the importance of vigilant clinical assessments, efficient multidisciplinary teamwork, and maintenance of the determinants of spinal cord perfusion following endovascular thoracic aortic intervention. PMID- 23439969 TI - Mechanisms behind sulfur promoted oxidation of methane. AB - The promoting effect of SO2 on the activity for methane oxidation over platinum supported on silica, alumina and ceria has been studied using a flow-reactor, in situ infrared spectroscopy and in situ high-energy X-ray diffraction experiments under transient reaction conditions. The catalytic activity is clearly dependent on the support material and its interaction with the noble metal both in the absence and presence of sulfur. On platinum, the competitive reactant adsorption favors oxygen dissociation such that oxygen self-poisoning is observed for Pt/silica and Pt/alumina. Contrarily for Pt/ceria, no oxygen self-poisoning is observed, which seems to be due to additional reaction channels via sites on the platinum-ceria boundary and/or ceria surface considerably far from the Pt crystallites. Addition of sulfur dioxide generally leads to the formation of ad SO(x) species on the supports with a concomitant removal and/or blockage/rearrangement of surface hydroxyl groups. Thereby, the methane oxidation is inhibited for Pt/silica, enhanced for Pt/alumina and temporarily enhanced followed by inhibition after long-term exposure to sulfur for Pt/ceria. The observations can be explained by competitive oxidation of SO2 and CH4 on Pt/silica, formation of new active sites at the noble metal-support interface promoting dissociative adsorption of methane on Pt/alumina, and in the case of Pt/ceria, formation of promoting interfacial surface sulfates followed by formation of deactivating bulk-like sulfate species. Furthermore, it can be excluded that reduction of detrimental high oxygen coverage and/or oxide formation on the platinum particles through SO2 oxidation is the main cause for the promotional effects observed. PMID- 23439970 TI - Clinical study of Tinea capitis in Northern Karnataka: A three-year experience at a single institute. AB - BACKGROUND: Tinea capitis is a superficial fungal infection of the hair follicle of scalp. Most of the dermatophytosis do not have such age propensity as tinea capitis which almost invariably involves the paediatric age group. The exact incidence of tinea capitis is not known. This study is done in order to isolate the species variation in an area, to know the changing patterns of occurrence of different species and their association with clinical pattern MATERIALS AND METHODS: All clinically diagnosed cases of tinea capitis which presented to our out patient department over a period of one year were included in the study. RESULTS: 70 cases of Tinea capitis were studied. DISCUSSION: Tinea capitis is a disease of prepubertal children with common in age group of 5- 15 years. The incidence varies from 0.5% to 10%. Most common presenting feature was alopecia. PMID- 23439971 TI - Off label use of lithium in the treatment of Huntington's disease: A case series. AB - Huntington's disease is characterized by choreic movements, psychiatric disorders, striatal atrophy with selective small neuronal loss, and autosomal dominant inheritance. The genetic abnormality is CAG expansion in Huntingtin gene. Newer therapeutic strategies are evolving to treat this progressive disorder. The neuroprotective agents are one such group of drugs being tried. Lithium has been used to treat Huntington's disease in the past due to its neuroprotective effects. Though the precise mechanism of action is not clear, Lithium can directly or indirectly modulate proteins involved in neuronal survival/differentiation which may account for its neuroprotective effects. We report three patients with Huntington's disease in whom Lithium prevented the progression of chorea and also helped stabilize mood. PMID- 23439972 TI - In situ determination of the surface excess upon electrochemical sulfate adsorption on Au(111) films by surface plasmon resonance. AB - For the independent and simultaneous characterization of electrochemical processes, we employ surface plasmon resonance (SPR) detection together with standard electrochemical methods. As a first test system we studied sulfate adsorption on Au(111). After careful calibration of the SPR signal we obtained submonolayer sensitivity on a millisecond time scale. The experimental data are simulated within the framework of a layer stack model of the optical interface. The sulfate adsorbate is simply described, employing the optical properties of sulfuric acid. The obtained potential dependent sulfate coverage is in reasonable agreement with independent results as presented in the literature. PMID- 23439974 TI - Adsorption of N/S heterocycles in the flexible metal-organic framework MIL 53(Fe(III)) studied by in situ energy dispersive X-ray diffraction. AB - The adsorption of N/S-containing heterocyclic organic molecules in the flexible iron(III) terephthalate MIL-53, Fe(III)(OH)(0.6)F(0.4)(O2C-C6H4-CO2).(H2O), from the liquid phase was studied with in situ energy dispersive X-ray diffraction (EDXRD), in order to follow the adsorption-induced expansion of the structure. For comparison with the diffraction data, liquid phase adsorption isotherms were recorded for uptake of benzothiophene, benzothiazole and indole in isopropanol and in heptane. The solvent not only influences pore opening but is also a competing guest. The in situ EDXRD experiments allow the kinetics of guest uptake and the competition with solvent to be monitored directly. Indole uptake is limited; this adsorbate is barely capable of opening the closed, either hydrated or dehydrated, MIL-53(Fe) structure, or of penetrating the isopropanol-containing material in the concentration range under study. When isopropanol is used as a solvent, the guest molecules benzothiophene and benzothiazole must be present at a certain threshold concentration before substantial adsorption into the metal organic framework takes place, eventually resulting in full opening of the structure. The fully expanded structures of benzothiophene or benzothiazole loaded MIL-53(Fe) materials have Imcm symmetry and a unit cell volume of ca. 1600 A(3), and upon uptake of the guest molecules by the closed form (unit cell volume ~1000 A(3)) no intermediate crystalline phases are seen. Successful uptake by MIL 53(Fe) requires that the adsorbate is primarily a good hydrogen bond acceptor; additionally, based on UV-visible spectroscopy, a charge-transfer interaction between the S atoms of benzothiophene and the aromatic rings in the MOF pore wall is proposed. PMID- 23439973 TI - Processing of self-initiated speech-sounds is different in musicians. AB - Musicians and musically untrained individuals have been shown to differ in a variety of functional brain processes such as auditory analysis and sensorimotor interaction. At the same time, internally operating forward models are assumed to enable the organism to discriminate the sensory outcomes of self-initiated actions from other sensory events by deriving predictions from efference copies of motor commands about forthcoming sensory consequences. As a consequence, sensory responses to stimuli that are triggered by a self-initiated motor act are suppressed relative to the same but externally initiated stimuli, a phenomenon referred to as motor-induced suppression (MIS) of sensory cortical feedback. Moreover, MIS in the auditory domain has been shown to be modulated by the predictability of certain properties such as frequency or stimulus onset. The present study compares auditory processing of predictable and unpredictable self initiated 0-delay speech sounds and piano tones between musicians and musical laymen by means of an event-related potential (ERP) and topographic pattern analysis (TPA) [microstate analysis or evoked potential (EP) mapping] approach. As in previous research on the topic of MIS, the amplitudes of the auditory event related potential (AEP) N1 component were significantly attenuated for predictable and unpredictable speech sounds in both experimental groups to a comparable extent. On the other hand, AEP N1 amplitudes were enhanced for unpredictable self-initiated piano tones in both experimental groups similarly and MIS did not develop for predictable self-initiated piano tones at all. The more refined EP mapping revealed that the microstate exhibiting a typical auditory N1-like topography was significantly shorter in musicians when speech sounds and piano tones were self-initiated and predictable. In contrast, non musicians only exhibited shorter auditory N1-like microstate durations in response to self-initiated and predictable piano tones. Taken together, our findings suggest that besides the known effect of MIS, internally operating forward models also facilitate early acoustic analysis of complex tones by means of faster processing time as indicated by shorter auditory N1-like microstate durations in the first ~200 ms after stimulus onset. In addition, musicians seem to profit from this facilitation also during the analysis of speech sounds as indicated by comparable auditory N1-like microstate duration patterns between speech and piano conditions. In contrast, non-musicians did not show such an effect. PMID- 23439975 TI - A rare case of keloidal granuloma faciale with extra-facial lesions. AB - Granuloma faciale (GF) is an uncommon, cutaneous disorder characterized by one to several soft, erythematous to livid papules, plaques, or nodules, usually occurring on the face. Extra-facial lesions occur rarely. We present a case report of 33-year-old male who presented with keloidal lesions on face and left shoulder. The patient didn't respond with intralesional triamcinolone and showed poor response with the addition of topical tacrolimus. Surgical excision in consultation with plastic surgeons is planned. PMID- 23439976 TI - Multiple causes for an ischemic stroke: myxoma, papillary fibroelastomas and patent foramen ovale. AB - We report a case in which multiple uncommon causes of an ischemic vascular accident coexisted in the same patient. The patient was admitted with signs of acute stroke. Investigation workup revealed a left atrial tumor (myxoma) and a patent foramen ovale. Intraoperatively, transesophageal echocardiography added new information: papillary fibroelastomas were found in the aortic valve. This finding dictated a change in the surgical plan, adding resection of aortic valve masses to the planned excision of the left atrial tumor and patent foramen ovale closure. The uniqueness of this case derives from the coexistence of rare primary cardiac tumors. There are only five cases in literature of myxoma concomitant with fibroelastoma and the occurrence of multiple fibroelastoma is also extremely rare. Moreover this case emphasizes the benefit of the intraoperative use of transesophageal echocardiography to improve the diagnosis and management of cardiac surgical patients. PMID- 23439977 TI - Retroperitoneoscopic left donor nephrectomy with duplicated IVC. AB - Vascular anomalies increase the difficulty during live donor nephrectomy. We herein report a left-sided retroperitoneoscopic living donor nephrectomy performed in a donor with a duplicated inferior vena cava (IVC). Computed tomography angiography provided accurate delineation of the venous anatomy and allowed preoperative planning. The duplicated IVC was clipped and divided just below its confluence with the left renal vein. The length of the left renal vein was sufficient for anastomosis in the recipient, and the recipient's serum creatinine was 1.21% on day 7. The donor made an uneventful recovery. Duplicated IVC is not a contraindication for left retroperitoneoscopic donor nephrectomy. PMID- 23439978 TI - Implicit inclusion of atomic polarization in modeling of partitioning between water and lipid bilayers. AB - We propose an effective and straightforward way of including atomic polarization in simulations of the partitioning of small molecules in inhomogenous media based on classical molecular dynamics with non-polarizable force fields. The approach presented here takes advantage of the relatively fast sampling of phase space obtained with additive force fields by adding the polarization effects afterwards. By using pre-polarized charges for the polar and non-polar phases together with a polarization correction term the effects of atomic polarization are effectively taken into account. The results show a clear improvement compared to using the more common setup with one set of charges obtained from gas phase ab initio calculations. It is shown that when proper measures are taken into account computer simulations with non-polarizable force fields are able to accurately determine water-membrane partitioning and preferential location of small molecules in the membrane interior. We believe that the approach presented here can be useful in rational drug design and in investigations of molecular mechanisms of anesthetic or toxic action. PMID- 23439980 TI - On the mechanism for nanoplasmonic enhancement of photon to electron conversion in nanoparticle sensitized hematite films. AB - Hematite (Fe2O3) is a promising candidate for hydrogen production via water splitting despite the difference in the characteristic lengths for photon absorption and charge carrier transport. Metallic nanoparticles supporting localized surface plasmon resonances (LSPRs), i.e. collective, non-propagating oscillations of electrons excited by an external electric field, are well-suited to improve the optoelectronic properties of hematite, in particular for ultra thin films. Several mechanisms have been proposed to explain the observed LSPR mediated performance enhancement. In this work, the improvement of incident photon-to-electron conversion efficiency (IPCE) of ultra-thin hematite photoanodes functionalized with Au nanodisks was investigated. The improvement in IPCE at wavelengths close to the bandgap in hematite was found to correlate well with the increase in optical extinction owing to the excitation of LSPR in the nanodisks. Finite-difference time-domain calculations of the near-field distribution around the nanodisks enabled us to elucidate the mechanism behind the IPCE enhancement and its variations with the position of the plasmonic resonance with respect to the bandgap of hematite. Both were attributed to an increased charge generation close to the hematite-electrolyte interface caused by the electric field enhancement in hematite. The results presented here are directly applicable to other semiconductors with similar properties to hematite and are expected to be helpful in future design of optimized photoanodes, where, for instance, functionalization with metallic nanoparticles is combined with material doping and nanostructuring. PMID- 23439979 TI - Solving the challenges of large multicenter trials in anesthesia. AB - This paper describes many of the challenges encountered when establishing a large multicentre trial in cardiac anesthesia. We address funding, authorship, multisite ethics review, patient recruitment, data quality management, communication with individual sites, and strategies to enhance cooperation and patient recruitment. PMID- 23439981 TI - Electrodeposition of germanium from the ionic liquid 1-butyl-1 methylpyrrolidinium dicyanamide. AB - The electrodeposition of germanium from the ionic liquid 1-butyl-1 methylpyrrolidinium dicyanamide ([BMP][DCA]) and a mixture of [BMP][DCA] and 1 butyl-1-methylpyrrolidinium chloride ([BMP]Cl) was studied using cyclic voltammetry and using an electrochemical quartz crystal microbalance (EQCM). [GeCl4(BuIm)2] (BuIm = N-butylimidazole) was used as germanium source as it has a solubility of 0.47 M, up to 13 times the solubility of GeCl4 in [BMP][DCA]. Cyclic voltammograms show an irreversible electrochemical behavior and two reduction waves were observed. The wave at the more positive potential was assigned to the reduction of Ge(4+) to Ge(2+). The wave at the more negative potential was attributed to the formation of Ge(0). The diffusion coefficient of Ge(4+) in [BMP][DCA] containing 0.1 M [GeCl4(BuIm)2] is 1.1 * 10(-12) m(2) s(-1), and the exchange current density is 2 * 10(-4) A m(-2) at 50 degrees C. Polymerization of dicyanamide anions took place at the anode in the solution of [BMP][DCA]. The polymerization reaction could be avoided by using an equimolar [BMP]Cl-[BMP][DCA] mixture as electrolyte. Smooth, porous germanium films were electrodeposited on both copper and silicon substrates. PMID- 23439982 TI - Investigating the role of viral integral membrane proteins in promoting the assembly of nepovirus and comovirus replication factories. AB - Formation of plant virus membrane-associated replication factories requires the association of viral replication proteins and viral RNA with intracellular membranes, the recruitment of host factors and the modification of membranes to form novel structures that house the replication complex. Many viruses encode integral membrane proteins that act as anchors for the replication complex. These hydrophobic proteins contain transmembrane domains and/or amphipathic helices that associate with the membrane and modify its structure. The comovirus Co-Pro and NTP-binding (NTB, putative helicase) proteins and the cognate nepovirus X2 and NTB proteins are among the best characterized plant virus integral membrane replication proteins and are functionally related to the picornavirus 2B, 2C, and 3A membrane proteins. The identification of membrane association domains and analysis of the membrane topology of these proteins is discussed. The evidence suggesting that these proteins have the ability to induce membrane proliferation, alter the structure and integrity of intracellular membranes, and modulate the induction of symptoms in infected plants is also reviewed. Finally, areas of research that need further investigation are highlighted. PMID- 23439984 TI - Influence of polar medium on the reorganization energy of charge transfer between dyes in a dye sensitized film. AB - We study the kinetics of the lateral hole transfer occurring between dye molecules anchored at the surface of the metal oxide in Dye Sensitized Solar Cells (DSSC). We use Marcus' charge transfer rate equation for which we need the electronic coupling between two molecules (J) and the reorganization energy (lambdatot). In DSSC the medium surrounding the dyes is highly polar. This means that the contribution of the solvent to the reorganization energy cannot be neglected. Here we elaborate a method to calculate, from first principles, the total (i.e., inner- and outer-sphere) reorganization energy of hole exchange between ruthenium dyes. The influence of the solvent and of the ions in the solvent is incorporated. The inner-sphere reorganization energy depends on the nature of the dye, 0.1 eV for ruthenium dyes with CN ligands, 0.2 eV for ruthenium dyes with NCS ligands. In acetonitrile, the solvent reorganization energy contributes for at least 80% of the total giving a total reorganization energy of around 0.86 eV for ruthenium dyes with CN ligands and 0.95 eV for ruthenium dyes with NCS ligands. We use these results to estimate the rate of hole transfer within Marcus theory. We suggest that low diffusion coefficients observed experimentally may arise from the high polarity of the medium rather than by the chemical structure of the dye. PMID- 23439983 TI - Ashy dermatosis in an 8-year-old Indian child. AB - Ashy dermatosis is a disorder of pigmentation, characterized by asymptomatic symmetric ashy gray-colored macules, in the first to third decade of life. It can, however, affect children sometime. But, there is a paucity of similar cases in Indian children. We present a case of ashy dermatosis in an 8-year-old Indian girl who presented to skin OPD with areas of ashy pigmentation, which were distributed symmetrically. Skin biopsy was consistent with lichenoid pattern histology. This case has been reported to highlight the rarity of ashy dermatosis in Indian children. PMID- 23439985 TI - Postoperative adhesive intestinal obstruction from gossypiboma. AB - Retained foreign bodies after surgery is a rare condition which can have medico legal consequences. Foreign bodies forgotten in the abdomen include towels, artery forceps, pieces of broken instruments or irrigation sets, and rubber tubes. The most common surgically retained foreign body is the laparotomy sponge. Such materials cause foreign body reaction in the surrounding tissue. The complications caused by these foreign bodies are well known, but cases are rarely published because of medico-legal implications. We report a case of 41-year-old female admitted with features of intestinal obstruction and had a previous history of hysterectomy performed 2 months back at another hospital. Pathologists must be aware of this entity and its proper reporting as the cases are liable to go to court. Surgeons must recognize the risk factors that lead to a gossypiboma and take measures to prevent it. PMID- 23439986 TI - Profile of microvascular disease in type 2 diabetes in a tertiary health care hospital in India. AB - BACKGROUND: Diabetes mellitus (DM) is a metabolic disorder complicated by microvascular and macrovascular diseases. The clinical profile of these complications has not been adequately studied in many tertiary health care centers in India. AIM: The authors studied the clinical profile of microvascular diabetes complications [peripheral sensory neuropathy (PSN), diabetic retinopathy (DR), nephropathy] in patients attending a tertiary care hospital in India. SUBJECTS AND METHODS: In this cross-sectional study, patients (n = 1529) with type 2 diabetes mellitus (T2DM) were studied for the presence of complications. PSN was diagnosed when the vibration perception threshold of big toe was >25 V. Retinopathy was diagnosed using direct ophthalmoscopy (presence of microaneurysms, exudates, and hemorrhages), and nephropathy with microalbuminuria (>=30 mg/l albumin in a spot urine sample) or low creatinine clearance (<90 ml/min) using Cockcroft-Gault formula. RESULTS: PSN was present in 37% (565/1529), nephropathy in 20% (297/1529), and retinopathy in 17% (256/1529) of the study population. Microvascular complications are seen in 48% (734/1529) patients of the study population. Increasing age (P < 0.001), long duration of diabetes (P < 0.001), and higher HbA1c (P = 0.036) were the common risk factors for all complications. Hypertriglyceridemia (P = 0.016) and low body weight (P = 0.039) predisposed to retinopathy over other microangiopathies. Overall, nephropathy was associated strongly with retinopathy (P = 0.015). CONCLUSIONS: The data showed that neuropathy was the most common microangiopathy and coexisted with other complications in many patients. Old age, long duration of disease, and poor glycemic control are the common risk factors for microvascular complications. PMID- 23439987 TI - Troponin testing after cardiac surgery. AB - Single biomarker measurements can predict outcome after cardiac surgery. and may assist in decision making about diagnostic and therapeutic steps following surgery. Although comparative data are relatively lacking some data exist to suggest that among markers of myocardial necrosis, results from cardiac troponin (cTn) measurement may be superior for risk prediction after cardiac surgery to those from the MB isoenzyme of CK (CK-MB). Loss of cardiac troponins from necrotic myocardium is not replenished through re-expression of genes that might increase protein synthesis, and release of cTn appears to represent irreversibly damaged myocardium. Not every cardiac surgical procedure is associated with the same degree of cTn elevation and forms of cardioprotection may im-portantly affect concentrations of cTn after coronary artery bypass grafting. Similarly, less cardiac injury may occur depending on the form of anesthesia used during surgery. Great caution must be exercised when utilizing cTnT or cTnI for diagnosis of post-cardiac surgery regional acute myocardial infarction: in this context clinical factors must be applied at the risk of a false diagnosis. On the other hand, concentrations of both cTnT and cTnI have repeatedly and unequivocally been shown to be prognostic for delayed recov-ery, intensive care unit utilization, as well as short- and longer-term mortality following cardiac surgery. PMID- 23439989 TI - Surface plasmon coupling in end-to-end linked gold nanorod dimers and trimers. AB - Colloidal gold nanorods were aligned end-to-end via dithiol coupling. The scattering properties of the resultant nanostructures were investigated at the single particle level by combining dark-field microscopy and high resolution scanning electron microscopy. The longitudinal surface plasmon resonance of end to-end coupled Au nanorods exhibited a red-shift as the number of rods in the chain increased. The nanostructures exhibited polarization-dependent optical properties, due to selective excitation of collective bonding and anti-bonding modes. The surface plasmon peak energy was not strongly dependent on the angle of rod-sphere-rod trimers. The experimental scattering spectra were compared with the results obtained from theoretical calculations using the Finite Element Method (FEM) and found to be in good agreement. PMID- 23439988 TI - Role of chitotriosidase (chitinase 1) under normal and disease conditions. AB - Mammalian chitinases belong to the glycosyl hydrolase 18 family based on structural homology and the family includes a large number of bacterial and eukaryotic chitinases. Among the mammalian chitinases, chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are capable of hydrolyzing the beta-(1, 4)-linkage between the adjacent N-acetyl glucosamine residues of chitin. CHIT1 is one of the most abundantly secreted proteins, being mainly produced by activated macrophages and epithelial cells. CHIT1 plays a pivotal role in the context of infectious disease including malaria and fungi infections as a host defense towards chitin in pathogen's cell structure and as a diagnostic marker of disease. In contrast, CHI1 released by activated Kupffer cells in liver could induce hepatic fibrosis and cirrhosis. Increased serum levels of CHIT1 were observed in patients with many disorders, including Gaucher's disease, bronchial asthma, and atherosclerosis. Therefore, CHIT1 seems to have dual (regulatory and pathogenic) roles depending on the disease and producing cell types during the inflammatory conditions. PMID- 23439990 TI - Older women with dementia can perform fast alternating forearm movements and performance is correlated with tests of lower extremity function. AB - BACKGROUND: The purpose of this work was to study the performance and reliability of a test of fast alternating forearm movements and its relationship with measures of lower extremity function in older women with dementia. METHODS: Fast alternating movements was studied in 26 female patients (mean age 81.7 +/- 5.9 years) with dementia and 34 controls (mean age 87.5 +/- 4.7 years). Subgroup analyses for those aged 80-89 years were performed due to significant differences in the mean ages of the study groups. Test-retest reliability for alternating forearm movements was studied in 11 patients (mean age 80.3 +/- 6.7 years) and 10 controls (mean age 87.4 +/- 1.6 years). Pulses generated were transformed to an analog signal shown on a modified electrocardiogram. Numbers of cycles at 10 and 15 seconds were calculated for the right and left hand. Walking 2 * 15 m and the Get-Up-and Go (GUG) test were performed at self-selected and maximal speed. Associations between tests of upper and lower extremity function were sought in eight patients (mean age 85 +/- 2.7 years) and 16 controls (mean age 85.1 +/- 2.8 years) and also according to types of dementia in nine patients with probable Alzheimer's disease and 10 patients with other types of dementia. RESULTS: Patients with dementia could perform the test and had significantly fewer cycles (P = 0.02-0.006) at both 10 and 15 seconds compared with controls after age adjustment. A higher number of cycles was associated with higher self-selected walking speeds in patients (r = -0.79). Test-retest reliability for alternating forearm movements was high for both patients (intraclass correlation 0.88-0.94) and controls (intraclass correlation 0.74-0.94). CONCLUSION: Alternating forearm movements at fast speed can be used as a reliable test in both patients with dementia and healthy older subjects. The test can be used as a measure of bradykinesia and might be useful as a proxy for lower extremity function in older persons with dementia when testing of the lower extremities is not applicable due to walking disability. PMID- 23439991 TI - Arterial bypass grafting of the coronary circulation. AB - Surgical coronary bypass has evolved continually, and recent developments favor performing coronary grafts with all-arterial conduits in order to obtain better long-term graft patencies. With bilateral internal mammary artery grafts and both radial arteries, four excellent arterial conduits exist for revascularization of the majority of multivessel disease patients, including those with valve disorders. Using contemporary surgical techniques, it is possible to obtain greater than 95% overall long-term graft patencies that translate into better outcomes, including improved survival, freedom from myocardial infarction, percutaneous coronary intervention , and redo coronary bypass. Two-thirds of patients receive a right internal mammary artery to the left anterior descending , a left internal mammary artery to the circumflex coronary artery system, and a radial artery to the right coronary artery Using newer management techniques, early postoperative complications, including the incidence of sternal infections, are extremely uncommon, and all-arterial grafts currently are used in over 75% of multivessel patients including those with concomitant valve disease. Because patencies and outcomes are so much better than with standard coronary bypass or percutaneous coronary intervention, referring physicians frequently favor all arterial bypass as the primary therapy for patients with prognostically serious multivessel obstruction. Thus, all-arterial bypass could play an increasingly important role in the future treatment of severe coronary atherosclerosis. PMID- 23439992 TI - The relationship between Parkinson's disease and essential tremor: review of clinical, epidemiologic, genetic, neuroimaging and neuropathological data, and data on the presence of cardinal signs of parkinsonism in essential tremor. AB - BACKGROUND: The possible relationship between essential tremor (ET) and Parkinson's disease (PD) has been controversial since the first description of PD. However, there is increasing evidence suggesting an overlap between these two disorders. The aim of this review is to examine the relationship between PD and ET, focusing on clinical, epidemiologic, genetic, neuroimaging, and neuropathological data, and the presence of cardinal parkinsonism symptoms in ET. METHODS: We conducted a PubMed search for articles published between 1966 and November 2011 regarding the relationship between ET and PD and the presence of postural tremor in PD patients; the presence of rest tremor, rigidity, and slowed movements in ET patients is reviewed. RESULTS: Clinical series, follow-up studies of ET patients, and case-control and genetic epidemiological studies indicate that ET is associated with increased risk for PD. Some neuroimaging studies and neuropathological reports suggest an association between the two diseases. ET patients show high prevalence of rest tremor, and at least seven studies described slowed movements (possibly related to cerebellar dysfunction and/or bradykinesia) in patients with ET. DISCUSSION: There is reasonable epidemiological and clinical evidence to support a link between ET and PD, although it is not clear what factors predict ET patient risk for developing PD or, more rarely, of PD patients developing ET. Future multicentric and multidisciplinary studies including epidemiological, clinical, neuroimaging, genetic, and neuropathological assessments are required to understand these associations. PMID- 23439993 TI - Familial cortical myoclonic tremor with epilepsy and cerebellar changes: description of a new pathology case and review of the literature. AB - BACKGROUND: Over 60 Asian and European families with cortical myoclonic tremor and epilepsy have been reported under various names. Cerebellar changes may be part of the syndrome. In this study, we report the neuropathology findings in a new Dutch familial cortical myoclonic tremor with epilepsy case and review the literature on this syndrome. METHODS: Neuropathological investigations were performed for a third case of the Dutch pedigree. In addition, we searched the literature for pedigrees meeting the criteria for benign familial myoclonic tremor and epilepsy. RESULTS: Our third Dutch case showed cerebellar Purkinje cell changes and a normal cerebral cortex. The pedigrees described show phenotypical differences, cerebellar symptoms and cerebellar atrophy to a variable degree. Japanese pedigrees with linkage to chromosome 8q have been reported with milder disease features than members of Italian pedigrees with linkage to chromosome 2p. French pedigrees (5p) possibly show even more severe and progressive disease, including cognitive changes and cerebellar features. DISCUSSION: Currently, familial cortical myoclonic tremor is not listed by the International League Against Epilepsy, although it can be differentiated from other epileptic syndromes. Genetic heterogeneity and phenotypical differences between pedigrees exist. Cerebellar changes seem to be part of the syndrome in at least a number of pedigrees. PMID- 23439995 TI - Clinical audit on "evaluation of special issues in adolescents with cancer treated in an adult cancer setting": an Indian experience. AB - BACKGROUND: Adolescents with cancer form a distinct group with special care needs. These patients are often cared in an adult supportive care setting where the special needs of adolescents are not met. AIM: To identify special issues in adolescents with cancer and to determine whether special needs of adolescents are met in an adult cancer setting MATERIALS AND METHODS: 10 adolescents with cancer were randomly chosen and retrospectively studied for physical, psychoscocial and emotional issues using an internally validated tool. RESULTS: Pain was the most common physical symptom seen in all 10 patients. 3 out of 10 patients were involved in decision making, 3 out of 10 patients had identity issues and 4 out of 10 patients had peer group isolation issues. Only 3 were aware of diagnosis and none were aware of treatment outcomes and mortality. 4 out of 10 had anxiety and depression and 3 out of 10 had body image issues. Sexuality, spiritual and existential issues were not explored in any of the patients studied. CONCLUSION: The outcomes of the study were in an adult oncology setting there was a poor recognition of key adolescent issues such as sexuality, body image, identity and peer group isolation. The psychosocial supports to these adolescents were minimal and spiritual and existential issues were not explored. The inferences drawn from this study suggested a need for multidisciplinary team approach oriented in handling adolescent care needs and preferably to have a dedicated space that will help the peer group to interact, bond and cope better with the illness. PMID- 23439994 TI - Biomechanical loading as an alternative treatment for tremor: a review of two approaches. AB - BACKGROUND: Tremor is the most common movement disorder and strongly increases in incidence and prevalence with aging. Although not life threatening, upper-limb tremors hamper the independence of 65% of people suffering from them affected persons, greatly impacting their quality of life. Current treatments include pharmacotherapy and surgery (thalamotomy and deep brain stimulation). However, these options are not sufficient for approximately 25% of patients. Therefore, further research and new therapeutic options are required to effectively manage pathological tremor. METHODS: This paper presents findings of two research projects in which two different wearable robots for tremor management were developed based on force loading and validated. The first consisted of a robotic exoskeleton that applied forces to tremulous limbs and consistently attenuated mild and severe tremors. The second was a neuroprosthesis based on transcutaneous neurostimulation. A total of 22 patients suffering from parkinsonian or essential tremor (ET) of different severities were recruited for experimental validation, and both systems were evaluated using standard tasks employed for neurological examination. The inclusion criterion was a postural and/or kinetic pathological upper-limb tremor resistant to medication. RESULTS: The results demonstrate that both approaches effectively suppressed tremor in most patients, although further research is required. The work presented here is based on clinical evidence from a small number of patients (n = 10 for robotic exoskeleton and n = 12 for the neuroprosthesis), but most had a positive response to the approaches. In summary, biomechanical loading is non-invasive and painless. It may be effective in patients who are insufficiently responsive (or have adverse reactions) to drugs or in whom surgery is contraindicated. DISCUSSION: This paper identifies and evaluates biomechanical loading approaches to tremor management and discusses their potential. PMID- 23439996 TI - An unusual case of foreign body aspiration in an infant. AB - Inhalation of foreign body is a serious condition in childhood and may result in acute respiratory distress, lung injury or death. A nine month old baby with history of severe respiratory distress, cyanosis and gasping breathing diagnosed as foreign body aspiration due to a balloon which was recovered post mortem during the removal of the endotracheal tube. PMID- 23439997 TI - Granular cell tumor of hand presenting as subcutaneous nodule mimicking dermal adnexal tumor: A diagnosis by cytology. AB - Granular cell tumor (GCT) is an uncommon tumor and is believed to be of schwannian origin. GCT is benign but rare malignant cases are recorded. GCT occurs in almost any part of the body. The common sites are the tongue, skin, and subcutaneous tissue. GCT of hand is an extremely rare. Till date only 17 cases are reported in the literature. Preoperative diagnosis of GCT is important, because GCT mimics dermal adnexal tumor in subcutaneous tissue, other soft tissue tumor or inflammatory lesions. GCT is composed of large polygonal cells with eosinophilic granular cytoplasm and these cells are often immunoreactive for the S-100 protein. Fine-needle aspiration cytology has been suggested to be diagnostic modality of choice and this would undoubtedly aid the correct diagnosis. Excision with wide surgical margins is curative for benign GCT. Recurrence and malignant transformation requires regular follow-up. Here, this communication documents a case of cytological diagnosis of the granular cell tumor of hand in a 21-year-old female, clinically suspected to be a dermal adnexal tumor. PMID- 23439998 TI - Carotid Endarterectomy: experience in 8743 cases. AB - INTRODUCTION: Recently published case series of patients undergoing carotid endarterectomy suggested a reduction in the rate of perioperative neurologic events when compared to those reported in the large randomized trials performed in the 1990s, without great differences between high and low risk patients. METHODS: As a major center of Vascular Surgery we prospectively collected data on 8743 carotid endarterectomy procedures (eversion technique 75%, patch closure 17.5%) performed in the period 1992-2009. RESULTS: Perioperative mortality was 0.32% (27/8743) with myocardial infarction being the most frequent cause (9 patients). Perioperative neurological morbidity was 1.04% (91/8743) with 51 major and 40 minor strokes. In 201 cases (2.3%) a cervical hematoma (suture-line bleeding in 41 cases and or diffuse oozing in 160 cases) in the early postoperative period necessitated urgent wound revision. In 262 (3.0%) cases we observed permanent or transient lesions of cranial nerves in the postoperative period. There was no significant difference in the combined ipsilateral stroke and perioperative death rate in octogenarian patients (2.1% in octogenarians and 1.2% in younger patients, p>0.05), even though an increasing trend was evident. CONCLUSIONS: Carotid endarterectomy has a reduced rate of perioperative complications when compared to those previously reported in literature. The low complication rate is related to improved preoperative patients evaluation, surgeons' increasing experience and to surgical and anesthesiological techniques. Carotid angioplasty and stenting should have their results compared to these real world results of carotid endarterectomy in order to asses their reliability when treating extracranial cerebrovascular disease. PMID- 23439999 TI - Prevalence of Human Immunodeficiency Virus Transmission among Transfused Children with Sickle Cell Anemia in Enugu Nigeria. AB - BACKGROUND: There are a number of routes for human immuno-deficiency virus (HIV) transmission in children. Blood transfusion-related HIV is still common in developing countries like Nigeria especially among high risk children such as those who require repeated blood transfusions. AIM: The aim of this study was to find the prevalence of HIV among transfused children with sickle cell anemia in Enugu. SUBJECTS AND METHODS: This is a descriptive cross-sectional study conducted at the Sickle Cell Clinic of the University of Nigeria Teaching Hospital, Enugu Sixty-nine transfused children with SCA were enrolled after obtaining consent from their caregivers and assent from older children. Non transfused children matched for age, sex, and social status with the subjects served as control. Voluntary counseling and testing were then provided. Relevant data were obtained using pretested questionnaire. Statistical Package for Social Science (SPSS) version 11 (Chicago, IL) was used for data analysis. The chi square was used to test for significant association of categorical variables and a P-value of less than 0.05 accepted as significant. RESULTS: HIV antibodies were found in 2.9% (2/69) of the subjects and in 1.6% (1/64) of the control (P = 0.604). All the infected individuals among the subjects were males, had only been transfused once and were from the lower socioeconomic class. The only infected child from the control group was a 7-year-old male and he probably acquired it through vertical transmission since the mother also tested positive to HIV antibody. CONCLUSIONS: Blood transfusion is still a risk factor for HIV transmission among children with sickle cell anemia in Nigeria. Strategies that will ensure improved blood transfusion safety at health facilities need to be strengthened. PMID- 23440000 TI - Intermediate CAG Repeats in Huntington's Disease: Analysis of COHORT. AB - BACKGROUND: There is emerging evidence that clinical and neuro-pathological manifestations of Huntington's disease (HD) may occur in individuals with intermediate length cytosine-adenine-guanine (CAG) repeats (27-35 CAG repeats) in the Huntingtin (HTT) gene. We aim to further define the clinical characteristics of individuals who possess CAG repeat lengths in this range. METHODS: Data from the Cooperative Huntington's Observational Research Trial (COHORT) were analyzed. Participants were categorized according to the number of CAG repeats into normal (<=26), intermediate (27-35) and HD (>=36) groups. The motor, cognitive and behavioral scores on the Unified Huntington's Disease Rating Scale (UHDRS) were compared between the intermediate and normal groups. RESULTS: Of 1985 individuals affected by HD or with a family history of HD who were genotyped, 50 (2.5%) had their larger CAG repeat in the intermediate range. There were statistically significant differences in scores of some motor, cognitive, and behavioral domains of UHDRS at baseline between normal and intermediate length CAG repeats. Furthermore, a significantly greater number of subjects with CAG repeats in the intermediate range reported at least one suicide attempt compared to the normal group. DISCUSSION: Our findings of motor, cognitive and behavioral abnormalities in individuals with intermediate CAG repeats suggest the presence of subtle, but relevant, disease manifestations in patients with intermediate CAG repeats. These results have important implications for the pathogenesis of the disease and genetic counseling. PMID- 23440001 TI - Post-synthesis, characterization and catalytic properties of fluorine-planted MWW type titanosilicate. AB - F-Ti-MWW was post-synthesized by implanting fluorine species into a Ti-MWW framework through an acid treatment process in the presence of ammonium fluoride. The effects of NH4F addition amount, acid treatment temperature and precursor Ti content were investigated on the incorporation of F species, the zeolite structure and the coordination sites of Ti. Fluorine-implanting improved the surface hydrophobicity of the zeolite and altered the electropositivity nearby the tetrahedral Ti sites through forming the SiO3/2F and SiO4/2F(-) units. The negative effect of SiO4/2F(-) units in F-Ti-MWW was eliminated selectively by convenient anion-exchange with various alkali chlorides. F-Ti-MWW containing the SiO3/2F units possessed better catalytic activity and reusability, and a longer catalyst lifetime than conventional Ti-MWW. PMID- 23440002 TI - Assessment of mild cognitive impairment with mini mental state examination among adults in southeast Nigeria. AB - BACKGROUND: Mild cognitive impairment is a recently described neuropsychiatric entity with the possibility of evolving into overt dementia. It has been found to respond to therapeutic intervention, thus halting or significantly retarding the progression to dementia. Resource-poor countries like Nigeria can hardly afford to provide optimal care for dementia patients. Knowledge about mild cognitive impairment in Nigeria is limited. An appreciation of the probable burden may help stimulate and galvanize appropriate public health policies in response. AIM: This cross-sectional, descriptive study sought to determine the frequency of subclinical mental state abnormalities in a cohort of apparently normal adult Nigerians. SUBJECTS AND METHODS: One hundred and thirty-five apparently normal adult Nigerians of both sexes seen at the University of Nigeria Teaching Hospital, Enugu, were interviewed. The Mini Mental State Examination (MMSE) of Folstein, Folstein, and McHugh was used to assess cognitive function in each subject at a single instance. The results obtained were analyzed using SPSS version 11.3 (Chicago, IL). Consent was obtained from each person and approval obtained from the hospital's ethics review board. RESULTS: A cut-off score of >=17 was obtained for normal cognitive function in this population using the MMSE. Minimum score obtained was 12, while the maximum score was 30. A mean (2SD) of 24.84 (7.94) was obtained on analysis of the overall MMSE scores of the 135 individuals. Cognitive impairment was identified in 5.93% (8/135) of the subjects examined. These persons thus represent otherwise normal functional individuals with unrecognized mild cognitive impairment who may be at risk of developing overt dementia in future. CONCLUSION: The concept of mild cognitive impairment needs further large-scale studies in Nigerians with possible multi-centre participation to fully elucidate the scope of the problem. Strategies for the appropriate management of dementia need to be strengthened. PMID- 23440003 TI - A review of minodronic acid hydrate for the treatment of osteoporosis. AB - Minodronic acid hydrate was the first bisphosphonate developed and approved for osteoporosis treatment in Japan. With regard to inhibition of bone resorption, minodronic acid hydrate is 1000 times more effective than etidronic acid and 10 100 times more effective than alendronic acid. Clinical trials conducted to date have focused on postmenopausal female patients suffering from primary osteoporosis. In these trials, 1 mg of oral minodronic acid hydrate was administrated once daily, and a significant increase was observed in lumbar-spine and hip-joint bone density 1-2 years after administration. All markers of bone metabolism urinary collagen type 1 cross-linked N-telopeptide, urinary free deoxypyridinoline, serum bone alkaline phosphatase, and serum osteocalcin were decreased. The incidence rate of new vertebral and nonvertebral fractures was also decreased. Therefore, effectiveness in fracture prevention was confirmed. A form of minodronic acid (50 mg) requiring once-monthly administration has been developed and is currently being used clinically. A comparative study between this new formulation and once-daily minodronic acid (1 mg) showed no significant differences between the two formulations in terms of improvement rates in lumbar spine and hip-joint bone density, changes in bone metabolism markers, or incidence of side effects. This indicates the noninferiority of the monthly formulation. Side effects such as osteonecrosis of the jaw or atypical femoral fractures were not reported with other bisphosphonates, although it is believed that these side effects may emerge as future studies continue to be conducted. On the basis of studies conducted to date, minodronic acid hydrate is considered effective for improving bone density and preventing fractures. We anticipate further investigations in the future. PMID- 23440004 TI - Cognitive features of essential tremor: a review of the clinical aspects and possible mechanistic underpinnings. AB - The classical concept of essential tremor (ET) as a monosymptomatic tremorogenic disorder has been questioned in the last decade as new evidence has been described. Clinical, neuroimaging, and pathological studies have described a probable structural basis (mainly in cerebellum) and evidence that ET is associated with subtle clinical cerebellar deficits and several non-motor clinical manifestations, such as cognitive and mood disorders. We performed literature searches in Medline, ISI Web of Knowledge, and PsycInfo databases. The aim of this review is to describe cognitive deficits associated with ET. First, we present a brief history of ET cognitive disorders presented. Second, we describe several clinical cross-sectional series demonstrating that ET is associated with mild cognitive deficits of attention, executive functions, several types of memory (working memory, immediate, short term, delayed, and possibly others) and, mood disorders (depression). Recent neuroimaging studies favor a cerebellar basis for these cognitive deficits. Population-based surveys confirm that mild cognitive dysfunction is not limited to severe ET cases, the entire ET group, including mild and undiagnosed cases, can be affected. Cohort studies indicated that ET cognitive deficits could be progressive and that ET patients had an increased risk of dementia. The mood and cognitive deficits in ET are in agreement with cognitive affective cerebellar syndrome described in patients with cerebellar disorders. New evidence, mainly from functional (neuroimaging) and prospective clinical studies would further bolster recent descriptions of ET clinical manifestations. PMID- 23440005 TI - Resting-state functional connectivity of ventral parietal regions associated with attention reorienting and episodic recollection. AB - In functional neuroimaging studies, ventral parietal cortex (VPC) is recruited by very different cognitive tasks. Explaining the contributions of VPC to these tasks has become a topic of intense study and lively debate. Perception studies frequently find VPC activations during tasks involving attention-reorienting, and memory studies frequently find them during tasks involving episodic recollection. According to the Attention to Memory (AtoM) model, both phenomena can be explained by the same VPC function: bottom-up attention. Yet, a recent functional MRI (fMRI) meta-analysis suggested that attention-reorienting activations are more frequent in anterior VPC, whereas recollection activations are more frequent in posterior VPC. Also, there is evidence that anterior and posterior VPC regions have different functional connectivity patterns. To investigate these issues, we conducted a resting-state functional connectivity analysis using as seeds the center-of-mass of attention-reorienting and recollection activations in the meta analysis, which were located in the supramarginal gyrus (SMG, around the temporo parietal junction-TPJ) and in the angular gyrus (AG), respectively. The SMG seed showed stronger connectivity with ventrolateral prefrontal cortex (VLPFC) and occipito-temporal cortex, whereas the AG seed showed stronger connectivity with the hippocampus and default network regions. To investigate whether these connectivity differences were graded or sharp, VLPFC and hippocampal connectivity was measured in VPC regions traversing through the SMG and AG seeds. The results showed a graded pattern: VLPFC connectivity gradually decreases from SMG to AG, whereas hippocampal connectivity gradually increases from SMG to AG. Importantly, both gradients showed an abrupt break when extended beyond VPC borders. This finding suggests that functional differences between SMG and AG are more subtle than previously thought. These connectivity differences can be explained by differences in the input and output to anterior and posterior VPC regions, without the need of postulating markedly different functions. These results are as consistent with integrative accounts of VPC function, such as the AtoM model, as they are with models that ascribe completely different functions to VPC regions. PMID- 23440006 TI - Metabolic hyperactivity of the medial posterior parietal lobes in psychogenic tremor. AB - BACKGROUND: The pathophysiology of psychogenic movement disorders, including psychogenic tremor (PT), is only emerging. CASE REPORT: This is a single case report of a patient who met diagnostic criteria for PT. He underwent positron emission tomography (PET) of brain with 18F-deoxyglucose at resting state. His PET study showed symmetrically increased 18F-deoxyglucose uptake in both posterior medial parietal lobes. There was no corresponding abnormality on structural imaging. DISCUSSION: Hypermetabolism of the medial aspects of posterior parietal lobes bilaterally may reflect abnormal activity of sensory integration that is important in the pathogenesis of PT. This further supports the idea that non-organic movement disorders may be associated with detectable functional brain abnormalities. PMID- 23440007 TI - Clinical Presentation of Uterine Fibroids in Nnewi, Nigeria: A 5-year Review. AB - BACKGROUND: Uterine leiomyomas are the commonest benign tumors in women, with a higher preponderance amongst Africans. Several etiological factors have been suggested, with subtle variations in clinical presentation being reported in different studies. This may constitute a determinant for the management measures undertaken. AIM: To review the clinical presentation and management measures undertaken for uterine leiomyoma. SUBJECTS AND METHODS: A retrospective study was conducted at Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi, from January 2002 to December 2006. A review of case records of patients with a diagnosis of uterine leiomyoma was done. The data were analyzed and presented in tables using comparative percentages. RESULTS: Uterine leiomyoma constituted 117 of the 1094 gynecological admissions during this study period (10.7%, 117/1094). The mean (SD) age of presentation was 35.7 (6.1) years. Most of the patients were nulliparous (76.7%, 79/103) and 51.5% (53/103) were married. The commonest mode of presentation was lower abdominal mass (66.9%, 67/103) and the least was recurrent abortion (1%, 1/103). Surgery was employed in all cases, with myomectomy being the commonest modality used in 90.3% (93/103) of cases. The common postoperative complications were prolonged pain (49.5%, 51/103) and postoperative pyrexia (34.9%, 36/103). CONCLUSION: The symptom of lower abdominal mass correlates with late presentations in our setting. This makes the application of newer therapies like laparoscopic myomectomy difficult even when they are available. Other therapies which are independent of fibroid size (like uterine artery embolization) are not readily available in our environment. This further emphasizes the importance of myomectomy as the most important treatment modality in our environment. PMID- 23440008 TI - Vascular connector devices increase the availability of minimally invasive cardiac surgery to ischemic heart patients. AB - The revival of off-pump cardiac surgery and the exploration of less invasive techniques for coronary artery bypass grafting, have lead to an increasing technical difficulty, as compared to conventional surgery using cardiopulmonary bypass. The moving target vessel in off-pump coronary artery bypass surgery, as well as the increasingly limited space in minimally invasive cardiac surgery were not convenient to many surgeons, a fact that lead many surgeons to deprive their patients the potential benefits of these techniques. Since the 1950's, surgeons have attempted to make the anastomotic procedure less cumbersome and less time consuming. Many creative ideas and devices were made, but for many different reasons, they eventually faded away. Since then, hand-sewn anastomoses have been the standard of care in coronary artery bypass grafting. Today, with the obvious need for a facilitated and fast coronary anastomosis, interest in these anastomotic devices has been re-awakened. The exact geometry, physiology and dynamics of the perfect anastomosis have thus been studied, in an attempt to provide an understanding of reasons behind anastomosis and graft failure after coronary artery bypass surgery, and eventually design the best performing device. These devices would allow for a faster, more accurate and a more reproducible coronary anastomosis using minimally invasive techniques. Also, due to a short learning curve, the standardization of percutaneous devices would allow much more surgeons to more widely adopt less invasive techniques. In summary, we see anastomotic devices as a solution to the technical challenges surgeons encounter with minimally invasive coronary artery bypass grafting. PMID- 23440009 TI - Single Fraction versus Multiple Fraction Radiotherapy for Palliation of Painful Vertebral Bone Metastases: A Prospective Study. AB - CONTEXT: Metastatic bone disease is a commonly encountered problem in oncology practice. The most useful and cost effective treatment is radiotherapy (RT). Different fractionation schedule of RT can be used to treat such condition. AIMS: Assessment of pain response in patients with vertebral bone metastasis after treating them with various radiation fractionations and to compare the toxicity profile in the treatment arms. SETTINGS AND DESIGN: A prospective randomized study was designed to include total 64 patients from July 2010 to May 2011. Patients with histopathologically proven primary malignancy having symptomatic secondary deposits to vertebra were selected for the study. Patients were randomized to two arms receiving multiple fraction of RT with 30 Gy in 10 fractions and 8 Gy in single fraction RT, respectively. MATERIALS AND METHODS: Patients with age >75 years, Karnofsky Performance Status (KPS) <40, features of cord compression were excluded from study. Initial pain response was assessed using Visual Analogue Scale (VAS) and compared using the same scale at weekly interval up to 1 month after treatment completion. RESULTS: Arm A comprised of 33 patients while 31 patients were enrolled in Arm B. Baseline patient characteristics were comparable. Eleven patients were lost to follow-up. Initial pain scores were 7.23 +/- 0.765 and 7.51 +/- 0.55 in arm A and arm B, respectively. Pain scores reduced significantly in both the arms after 1 month (4.39 +/- 1.82 in arm A; 5.25 +/- 2.39 in arm B). Time of initiation of pain response was earlier in arm A (P = 0.0281), statistically significant. Mild G-I toxicity was noted in both the arms but differences in two arms were not statistically significant (P = 0.49), no interruption of treatment was required because of side effects. CONCLUSIONS: Different fractionation of radiation has same response and toxicity in treatment of vertebral bone metastasis. Single fraction RT may be safely used to treat these cases as this is more cost effective and less time consuming. Studies may be conducted to find out particular subgroup of patients to be benefitted more by either fractionation schedule; however, our study cannot comment on that issue. PMID- 23440011 TI - Lethal midline granuloma. AB - Lethal midline granuloma is a relatively rare disease characterized by destruction and mutilation of the nose and other structures of respiratory passages. The nonspecificity of symptoms obscures the correct diagnosis and is responsible for the delay in treatment which can be detrimental as this grave disease calls for urgent intervention. We present a case report of this disease in a 35 year old male who gave a short two month history of the clinical symptoms. PMID- 23440013 TI - Survey of Current Practices: Peripheral Nerve Block Utilization by ED Physicians for Treatment of Pain in the Hip Fracture Patient Population. AB - BACKGROUND: In 2010-11 approximately 968 hip fracture patients presented to emergency departments in the Greater Toronto Local Health Integration Network (GTA-LHIN). Optimal pain management is a frequently overlooked aspect of hip fracture patient care, which may contribute to patient outcomes. Although recommendations have been published, there is currently not a standardized approach to the analgesic management of pain in the hip fracture patient. Nerve blocks, including the fascia iliaca compartment block (FICB), are more effective than traditional opioid analgesics in reducing pain after hip fracture. Research suggests that analgesia via nerve blockade is best initiated early, upon arrival to the emergency department. Emergency physicians are trained in ultrasound, and do utilize regional anaesthesia; however, the frequency of block utilization and techniques used for block insertion are unknown. We sought to undertake the first survey of Emergency Department (ED) staff and resident physicians across the GTA LHIN, looking at the current ED practice of nerve block analgesia in hip fracture patients. PURPOSE: The primary aim was to determine the prevalence and range of techniques utilized. The secondary aims were to determine the extent of training in nerve block insertion techniques, to gauge opinion on the most important objectives for future training courses, and to seek an understanding of the barriers to establishing a standardized approach for nerve block utilization in hip fracture patients. CONCLUSIONS: This data will be used to develop a multidisciplinary training program specifically for use by ED physicians. ED physicians and anesthesiologists will collaborate to standardize nerve block insertion techniques and develop an optimal analgesic management plan of hip fracture patients at Sunnybrook Hospital. PMID- 23440015 TI - Mechanism of morphology transformation during annealing of nanostructured gold films on glass. AB - Nanostructured, just-percolated gold films were prepared by evaporation on bare glass. Annealing of the films at temperatures close to or higher than the softening temperature of the glass substrate induces morphological transformation to discrete Au islands and gradual embedding of the formed islands in the glass. The mechanism and kinetics of these processes are studied here using a combination of in situ high-temperature optical spectroscopy; ex situ characterization of the island shape by high-resolution scanning electron microscopy (HRSEM), atomic force microcopy (AFM) and cross-sectional transmission electron microscopy (TEM); and numerical simulations of transmission spectra using the Multiple Multipole Program (MMP) approach. It is shown that the morphological transformation of just-percolated, 10 nm (nominal thickness) Au films evaporated on glass and annealed at 600 degrees C, i.e., in the vicinity of the substrate glass transition temperature (Tg = 557 degrees C), proceeds via three processes exhibiting different time scales: (i) fast recrystallization and dewetting, leading to formation of single-crystalline islands (minutes); the initial spectrum characteristic of a continuous Au film is transformed to that of an island film, displaying a surface plasmon (SP) absorption band. (ii) Reshaping and faceting of the single-crystalline islands accompanied by formation of circumferential glass rims around them (first few hours); the overall optical response shows a blue shift of the SP band. (iii) Gradual island embedding in the glass substrate (tens of hours), seen as a characteristic red shift of the SP band. The influence of the annealing atmosphere (air, vacuum) on the embedding process is found to be minor. Numerical modeling of the extinction cross-section corresponding to the morphological transformations during island recrystallization and embedding is in qualitative agreement with the experimental data. PMID- 23440014 TI - Onset of obsessive compulsive disorder in pregnancy with pica as the sole manifestation. AB - Pica refers to eating of non-nutritious substances, which is usually seen in childhood or pregnancy. Here we report a case of an illiterate tribal woman who developed pica as the sole manifestation of obsessive compulsive disorder, with onset during pregnancy. The patient had compulsions of eating uncooked rice or wheat, which resulted in toothache and abdominal discomfort. She had this habit in three pregnancies, consecutively. In the first two pregnancies it resolved spontaneously after puerperium, but persisted in the last one. Probably physical stress of limb edema during the third pregnancy was reason for the persistence. She responded to fluoxetine 40 mg / day after three months of treatment, without behavioral therapy. We conclude that pica may either be only a manifestation of obsessive compulsive disorder during pregnancy or it is an obsessive compulsive spectrum disorder. PMID- 23440016 TI - Impact of bispectral index monitoring on postoperative delirium in patients undergoing aortic surgery. AB - BACKGROUND: Bispectral index monitoring can facilitate anesthesia care. We evaluated the association of Bispectral index with postoperative neurological outcome and delirium in patients undergoing aortic surgery. METHODS: From 2006 to 2009, 292 consecutive patients undergoing aortic surgery were retrospectively reviewed. Patients were classified into 5 groups according to Bispectral index reduction: Group I (<=15%), Group II (15-20%), Group III (20-25%), Group IV (25 30%), and Group V (>30%). RESULTS: The number of patients in each group was : 52 (17.8%), Group I; 125 (42.8%), Group II;68 (23.3%), Group III; 33 (11.3%), Group IV; 14 (4.8%), Group V. The incidence of delirium and neurological events was higher in Group IV and Group V(90.9% and 18.2% in Group IV, and 71% and 79% in Group V; both p<0.001). Only Group V showed a longer intensive care unit stay compared to Group I (13.5+/-10.3 vs 5.4+/-6.6 days; p=0.002), Group II (7.3+/-8.6 days, p=0.005) and Group III (6.7+/-6.5 days, p=0.015). Group V also showed a longer intubation time compared to Group I (228+/-211 vs 73+/-112 hours; p=0.008) and Group II (105+/-177 hours, p=0.002). CONCLUSIONS: Our data suggest a higher incidence of neurological deficits in patients with a Bispectral index reduction of >25% from baseline. Explanations for these findings are speculative with regard to the underlying mechanisms, and larger studies are warranted to clarify these issues. PMID- 23440017 TI - Taxifolin Glycoside Blocks Human ether-a-go-go Related Gene K(+) Channels. AB - Taxifolin glycoside is a new drug candidate for the treatment of atopic dermatitis (AD). Many drugs cause side effects such as long QT syndrome by blocking the human ether-a-go-go related gene (hERG) K(+) channels. To determine whether taxifolin glycoside would block hERG K(+) channels, we recorded hERG K(+) currents using a whole-cell patch clamp technique. We found that taxifolin glycoside directly blocked hERG K(+) current in a concentration-dependent manner (EC(50)=9.6+/-0.7 uM). The activation curve of hERG K(+) channels was negatively shifted by taxifolin glycoside. In addition, taxifolin glycoside accelerated the activation time constant and reduced the onset of the inactivation time constant. These results suggest that taxifolin glycoside blocks hERG K(+) channels that function by facilitating activation and inactivation process. PMID- 23440019 TI - Current status of cardiac surgery allied health professionals in Asia. AB - More and more allied health professions are getting involved in clinical health care. One estimate reported allied health personnel makes up 60 percent of the total health workforce. In Asia, in the field of cardiothoracic surgery, allied health personnel includes perfusionists, physician assistants, physiotherapist, intensivists, rehabilitation therapists, nutritionists and social workers. They work in collaboration with surgeons to provide a range of diagnostic, technical, therapeutic, cardiac care and support services to the patients and their families.Some allied health professions are more specialized. They must adhere to national training and education standards and their professional scope of practice. For example, the training of perfusionists consists of at least five years of academic in medical schools and another three-year-long clinical training in the hospital. The cardiac intensivists usually are medical doctors with a background in cardiology. They spend 3-4 years rotating in Internal Medicine, Anesthesiology, Emergency Rooms and Intensive Care Units. There have specialized medical societies to grant certified credentials and to provide continuing education. Other allied health professions require no special training or credentials and are trained for their work by the hospitals through on-the-job training. Many young health care providers are getting involved in the allied health personnel projects. They consider this as a career ladder because of the opportunities for advancement within specific fields. PMID- 23440020 TI - beta-Substituted ferrocenyl porphyrins: synthesis, structure, and properties. AB - beta-Substituted ferrocenyl porphyrins were designed and synthesized by the Pd catalyzed Sonogashira cross-coupling reaction. The UV-vis absorption, emission, and cyclic voltammetric results indicate strong electronic communication between ferrocene and porphyrin. The porphyrin 4a is non-emissive in nature, while 4b and 4c show reduced fluorescence quantum yield. The single crystal X-ray structure of 4b is reported, which shows extensive C-H-pi interactions. PMID- 23440018 TI - Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor. AB - BACKGROUND: Harmaline and harmine are tremorigenic beta-carbolines that, on administration to experimental animals, induce an acute postural and kinetic tremor of axial and truncal musculature. This drug-induced action tremor has been proposed as a model of essential tremor. Here we review what is known about harmaline tremor. METHODS: Using the terms harmaline and harmine on PubMed, we searched for papers describing the effects of these beta-carbolines on mammalian tissue, animals, or humans. RESULTS: Investigations over four decades have shown that harmaline induces rhythmic burst-firing activity in the medial and dorsal accessory inferior olivary nuclei that is transmitted via climbing fibers to Purkinje cells and to the deep cerebellar nuclei, then to brainstem and spinal cord motoneurons. The critical structures required for tremor expression are the inferior olive, climbing fibers, and the deep cerebellar nuclei; Purkinje cells are not required. Enhanced synaptic norepinephrine or blockade of ionic glutamate receptors suppresses tremor, whereas enhanced synaptic serotonin exacerbates tremor. Benzodiazepines and muscimol suppress tremor. Alcohol suppresses harmaline tremor but exacerbates harmaline-associated neural damage. Recent investigations on the mechanism of harmaline tremor have focused on the T-type calcium channel. DISCUSSION: Like essential tremor, harmaline tremor involves the cerebellum, and classic medications for essential tremor have been found to suppress harmaline tremor, leading to utilization of the harmaline model for preclinical testing of antitremor drugs. Limitations are that the model is acute, unlike essential tremor, and only approximately half of the drugs reported to suppress harmaline tremor are subsequently found to suppress tremor in clinical trials. PMID- 23440021 TI - Triple-Flaps for lateral canthus reconstruction: A novel technique. AB - A 45 year old female presented with a pigmented lesion in the right periocular region. The mass was present on the lateral 1/3 of the lower eyelid and involving the lateral 1/8 of the upper eyelid. Full thickness excision with wide tumor-free margins was done and the residual defect was repaired. Histopathological examination confirmed the diagnosis of nodulo-ulcerative basal cell carcinoma. In this report, we describe a novel technique for reconstruction of large lateral canthus defect by using three local flaps. With triple-flaps technique extensive defects involving the lateral canthus can be repaired without difficulty with a good functional and aesthetic outcome. PMID- 23440022 TI - Speech rehabilitation of maxillectomy patients with hollow bulb obturator. AB - AIM: To evaluate the effect of hollow bulb obturator prosthesis on articulation and nasalance in maxillectomy patients. MATERIALS AND METHODS: A total of 10 patients, who were to undergo maxillectomy, falling under Aramany classes I and II, with normal speech and hearing pattern were selected for the study. They were provided with definitive maxillary obturators after complete healing of the defect. The patients were asked to wear the obturator for six weeks and speech analysis was done to measure changes in articulation and nasalance at four different stages of treatment, namely, preoperative, postoperative (after complete healing, that is, 3-4 months after surgery), after 24 hours, and after six weeks of providing the obturators. Articulation was measured objectively for distortion, addition, substitution, and omission by a speech pathologist, and nasalance was measured by Dr. Speech software. RESULTS: The statistical comparison of preoperative and six weeks post rehabilitation levels showed insignificance in articulation and nasalance. Comparison of post surgery complete healing with six weeks after rehabilitation showed significant differences in both nasalance and articulation. CONCLUSION: Providing an obturator improves the speech closer to presurgical levels of articulation and there is improvement in nasality also. PMID- 23440023 TI - Minority Student Academic Performance under the Uniform Admission Law: Evidence from the University of Texas at Austin. AB - UT-Austin administrative data between 1990 and 2003 are used to evaluate claims that students granted automatic admission based on top 10% class rank underperform academically relative to lower ranked students who graduate from highly competitive high schools. Compared with white students ranked at or below the third decile, top 10% black and Hispanic enrollees arrive with lower average standardized test scores, yet consistently performed as well or better in grades, first year persistence, and four-year graduation likelihood. A similar story obtains for top 10% graduates from Longhorn high schools verses lower-ranked students who graduated from highly competitive feeder high schools. Multivariate results reveal that high school attended rather than test scores is largely responsible for racial differences in college performance. PMID- 23440024 TI - Introduction of quantitative and qualitative cornea optical coherence tomography findings induced by collagen cross-linking for keratoconus: a novel effect measurement benchmark. AB - PURPOSE: To introduce a novel, noninvasive technique to determine the depth and extent of anterior corneal stroma changes induced by collagen cross-linking (CXL) using quantitative analysis of high-resolution anterior-segment optical coherence tomography (OCT) post-operative images. SETTING: Private clinical ophthalmology practice. PATIENTS AND METHODS: Two groups of corneal cross-sectional images obtained with the OptoVue RTVue anterior-segment OCT system were studied: group A (control) consisted of unoperated, healthy corneas, with the exception of possible refractive errors. The second group consisted of keratoconic corneas with CXL that were previously operated on. The two groups were investigated for possible quantitative evidence of changes induced by the CXL, and specifically, the depth, horizontal extent, as well as the cross-sectional area of intrastromal hyper-reflective areas (defined in our study as the area consisting of pixels with luminosity greater than the mean +2 * standard deviation of the entire stromal cross section) within the corneal stroma. RESULTS: In all images of the second group (keratoconus patients treated with CXL) there was evidence of intrastromal hyper-reflective areas. The hyper-reflective areas ranged from 0.2% to 8.8% of the cross-sectional area (mean +/- standard deviation; 3.46% +/- 1.92%). The extent of the horizontal hyper-reflective area ranged from 4.42% to 99.2% (56.2% +/- 23.35%) of the cornea image, while the axial extent (the vertical extent in the image) ranged from 40.00% to 86.67% (70.98% +/- 7.85%). There was significant statistical difference (P < 0.02) in these values compared to the control group, in which, by application of the same criteria, the same hyper-reflective area (owing to signal noise) ranged from 0.00% to 2.51% (0.74% +/- 0.63%). CONCLUSION: Herein, we introduce a novel, noninvasive, quantitative technique utilizing anterior segment OCT images to quantitatively assess the depth and cross-sectional area of CXL in the corneal stroma based on digital image analysis. Mean cross-sectional area showing evidence of CXL was 3.46% +/- 1.92% of a 6 mm long segment. PMID- 23440025 TI - Classifying the metal dependence of uncharacterized nitrogenases. AB - Nitrogenase enzymes have evolved complex iron-sulfur (Fe-S) containing cofactors that most commonly contain molybdenum (MoFe, Nif) as a heterometal but also exist as vanadium (VFe, Vnf) and heterometal-independent (Fe-only, Anf) forms. All three varieties are capable of the reduction of dinitrogen (N(2)) to ammonia (NH(3)) but exhibit differences in catalytic rates and substrate specificity unique to metal type. Recently, N(2) reduction activity was observed in archaeal methanotrophs and methanogens that encode for nitrogenase homologs which do not cluster phylogenetically with previously characterized nitrogenases. To gain insight into the metal cofactors of these uncharacterized nitrogenase homologs, predicted three-dimensional structures of the nitrogenase active site metal cofactor binding subunits NifD, VnfD, and AnfD were generated and compared. Dendrograms based on structural similarity indicate nitrogenase homologs cluster based on heterometal content and that uncharacterized nitrogenase D homologs cluster with NifD, providing evidence that the structure of the enzyme has evolved in response to metal utilization. Characterization of the structural environment of the nitrogenase active site revealed amino acid variations that are unique to each class of nitrogenase as defined by heterometal cofactor content; uncharacterized nitrogenases contain amino acids near the active site most similar to NifD. Together, these results suggest that uncharacterized nitrogenase homologs present in numerous anaerobic methanogens, archaeal methanotrophs, and firmicutes bind FeMo-co in their active site, and add to growing evidence that diversification of metal utilization likely occurred in an anoxic habitat. PMID- 23440026 TI - Applications of pulsed EPR spectroscopy to structural studies of sulfite oxidizing enzymes(). AB - Sulfite oxidizing enzymes (SOEs), including sulfite oxidase (SO) and bacterial sulfite dehydrogenase (SDH), catalyze the oxidation of sulfite (SO(3) (2-)) to sulfate (SO(4) (2-)). The active sites of SO and SDH are nearly identical, each having a 5-coordinate, pseudo-square-pyramidal Mo with an axial oxo ligand and three equatorial sulfur donor atoms. One sulfur is from a conserved Cys residue and two are from a pyranopterindithiolene (molybdopterin, MPT) cofactor. The identity of the remaining equatorial ligand, which is solvent-exposed, varies during the catalytic cycle. Numerous in vitro studies, particularly those involving electron paramagnetic resonance (EPR) spectroscopy of the Mo(V) states of SOEs, have shown that the identity and orientation of this exchangeable equatorial ligand depends on the buffer pH, the presence and concentration of certain anions in the buffer, as well as specific point mutations in the protein. Until very recently, however, EPR has not been a practical technique for directly probing specific structures in which the solvent-exposed, exchangeable ligand is an O, OH(-), H(2)O, SO(3) (2-), or SO(4) (2-) group, because the primary O and S isotopes ((16)O and (32)S) are magnetically silent (I = 0). This review focuses on the recent advances in the use of isotopic labeling, variable-frequency high resolution pulsed EPR spectroscopy, synthetic model compounds, and DFT calculations to elucidate the roles of various anions, point mutations, and steric factors in the formation, stabilization, and transformation of SOE active site structures. PMID- 23440027 TI - The physician assistant: Shifting the Paradigm of European medical practice? AB - INTRODUCTION: Physician Assistants are medical care providers working under supervision and/or in collaboration with a medical doctor. The Physician Assistant profession has its origin in the United States, but in the last decade has also reached other nations to overcome medical staffing issues. With little summarized literature available, the aim of this study is to portray the Physician Assistant movement in Europe. METHODS: A literature search was conducted in Academic Search Premier, CINAHL, ERIC and MEDLINE databases. In addition, European PA educational programs, professional associations, and local experts on the PA profession were queried. RESULTS: Currently, in Europe there are three countries in which physician assistants are trained and are working. The educational models of physician assistant training in the United Kingdom, Germany and the Netherlands differ, as do the degrees offered by the training institutions. CONCLUSIONS: There is scant literature about physician assistant training and practice in Europe available in the common scientific databases. The paucity of literature makes it difficult for an outsider to observe the developments and to value the impact of a new profession on national health systems. Further high-quality research is needed to adequately characterize physician assistant education and implementation across Europe. PMID- 23440028 TI - Review of prevalence studies of tic disorders: methodological caveats. AB - INTRODUCTION: Tic disorders are neurodevelopmental disorders of childhood associated with psychiatric comorbidity and academic problems. Estimating the prevalence and understanding the epidemiology of tic disorders is more complex than was once thought. Until fairly recently, tic disorders were thought to be rare, but today tics are believed to be the most common movement disorder, with 0.2-46.3% of schoolchildren experiencing tics during their lifetime. Tentative explanations for differing prevalence estimates include the multidimensional nature of tics with a varied and heterogeneous presentation, and the use of different epidemiological methods and study designs. METHODS: Literature review and analysis of methodological issues pertinent to epidemiological studies of tic disorders. RESULTS: Epidemiological studies of tic disorders were reviewed, and the main elements of epidemiological studies, including sample selection, case ascertainment strategy, definition of tic disorders, and the degree of coverage of the eligible population (i.e., the response rate) were examined. DISCUSSION: In order to improve the quality of epidemiological studies of tic disorders, a number of recommendations were made, including but not limited to a review of the diagnostic criteria for tic disorders, and inclusion of new tic disorder categories for those with tics of secondary etiology. PMID- 23440029 TI - Yoga experience as a predictor of psychological wellness in women over 45 years. AB - BACKGROUND: Although high levels of subjective well-being (SWB) are common in old age, a subset of older individuals is disproportionately vulnerable to negative affect. Yoga has been shown to have many short-term benefits, but researchers have not determined whether a long-term or frequent yoga practice increasingly protects older women from low levels of psychological well-being. AIMS: The purpose of this study was to examine the extent to which psychological attitudes, transcendence, mental mastery, and subjective vitality in a sample of female yoga practitioners over 45 years varied according to the length and frequency of yoga practice. MATERIALS AND METHODS: We administered online surveys to a non probability sample of 211 female yoga practitioners 45 to 80. We used weighted least squares regression analyses to evaluate the relationship of extent of yoga experience to the outcome variables after accounting for age and lifestyle factors. RESULTS: Participants had practiced yoga for as long as 50 years and for up to 28 h per week. There were significant positive relationships between yoga experience and all outcome variables. These significant relationships remained after accounting for age and lifestyle factors. When we computed yoga experience in terms of total calendar years, without accounting for hours of practice, significant relationships did not remain. Transcendence of the ordinary was the most strongly associated with current yoga practice frequency, and positive psychological attitudes were the most strongly associated with total lifetime hours of practice. CONCLUSIONS: Among a non-probability sample of female yoga practitioners between 45 and 80 years, increased yoga experience predicted increased levels of psychological well-being. Results showed a dose-response effect, with yoga experience exercising an increasingly protective effect against low levels of SWB and vitality. PMID- 23440030 TI - Knowledge and Practice of Pulp Therapy in Deciduous Teeth among General Dental Practitioners in Saudi Arabia. AB - BACKGROUND: It has been observed that the general dentists and pedodontists differ in their treatment recommendations for pulp therapy in deciduous teeth. AIM: To determine the knowledge and practice of pulp therapy in deciduous teeth by general dental practitioners (GDP) in two cities of southern Saudi Arabia. SUBJECTS AND METHODS: Fifty GDP selected at random from government and private dental clinics were questioned about pulp therapy in deciduous teeth in Abha and Najran cities using a 10-item questionnaire. The data were analyzed using IBM SPSS software version 11.0 and descriptive statistics were obtained. RESULTS: All 50 participants responded to the survey. Pulpotomy was suggested as the first line of treatment for pulp-exposed primary tooth by 32 respondents with 44 using Buckley's formocresol and 32 applying it on the pulp for 5 minutes. 43 respondents squeeze dried the cotton pellet before application on the pulp. In pulpectomy procedure 44 respondents preferred zinc oxide eugenol as obturation material with 22 using handheld reamers and 15 using slow-speed lentilospirals for obturation. 12 respondents used obturation techniques which had no scientific relevance. In order of preference Glass ionomer cement (GIC), silver amalgam, and stainless steel crowns were the materials of choice for final restoration of endodontically treated deciduous teeth. All 50 answered in the affirmative when asked if they would like to have additional information about pulp therapy in deciduous teeth. CONCLUSION: The study concluded that general dentists were regularly performing pulp therapy in decidous teeth and therefore need to be frequently updated about these procedures. PMID- 23440032 TI - Dermatopathia pigmentosa reticularis: A rare reticulate pigmentary disorder. AB - Dermatopathia pigmentosa reticularis is a rare ectodermal dysplasia with a triad of generalized reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. We report a case of a 21 year old woman who had generalized reticulate pigmentation, diffuse noncicatricial alopecia and onychodystrophy of finger and toe nails. Along with this triad she had palmoplantar keratoderma and poorly developed dermatoglyphics. There was no evidence of involvement of other ectodermally derived organ. PMID- 23440031 TI - Cell separation: Terminology and practical considerations. AB - Cell separation is a powerful tool in biological research. Increasing usage, particularly within the tissue engineering and regenerative medicine communities, means that researchers from a diverse range of backgrounds are utilising cell separation technologies. This review aims to offer potential solutions to cell sorting problems and to clarify common ambiguities in terminology and experimental design. The frequently used cell separation terms of 'purity', 'recovery' and 'viability' are discussed, and attempts are made to reach a consensus view of their sometimes ambiguous meanings. The importance of appropriate experimental design is considered, with aspects such as marker expression, tissue isolation and original cell population analysis discussed. Finally, specific technical issues such as cell clustering, dead cell removal and non-specific antibody binding are considered and potential solutions offered. The solutions offered may provide a starting point to improve the quality of cell separations achieved by both the novice and experienced researcher alike. PMID- 23440033 TI - Tardive dyskinesia with low dose amisulpride. AB - In recent years, there has been an increasing trend to use amisulpride in the treatment of dysthymia and also as an adjunct treatment in patients with major depression. At low doses (50 mg), amisulpride preferentially blocks presynaptic auto receptors, enhances dopamine release, and therefore acts as a dopaminergic compound able to resolve the dopaminergic hypo activity that characterizes depression. Based on experimental data, amisulpride is the drug of choice for dopaminergic transmission disorders, both in depression and in schizophrenia. This case highlights the development of dyskinesia in a depressed patient treated with low dose amisulpride and fluvoxamine. PMID- 23440034 TI - Graphene ultracapacitors: structural impacts. AB - The structural effects of graphene on the electrochemical properties of graphene based ultracapacitors are investigated for the first time, where the competitive impacts resulting from the edge content, specific surface area, edge/basal defects, oxygen-containing groups and metal oxides/surfactant impurities are taken into consideration, demonstrating that not one element, but all are responsible for the final behavior of graphene-based ultracapacitors. This work will be of wide importance to research producing graphene-based energy storage/generation devices. PMID- 23440035 TI - Mental Status Test Scores are Inversely Correlated with Tremor Severity: A Study of 161 Elderly Essential Tremor Cases. AB - BACKGROUND: There is an increasing awareness that patients with essential tremor (ET) may exhibit non-motor features, including cognitive dysfunction. Yet there are surprisingly few data in ET on the association, if any, between cognitive dysfunction and motor dysfunction (i.e., tremor severity). Establishing links between the cognitive and motor features of ET would imply that the two share a common underlying pathogenic process. Recent neuroimaging data support this notion. METHODS: ET cases were enrolled in a clinical-pathological study at Columbia University Medical Center, New York. The Folstein Mini-Mental State Examination (FMMSE) and Modified Mini Mental Status Examination (mMMSE) were administered. Action tremor was rated with a total tremor score (TTS). RESULTS: There were 161 ET cases (mean age 83.9+/-5.7 years, median FMMSE 28, median mMMSE 50). The FMMSE and mMMSE were inversely correlated with the TTS (r = -0.22, p = 0.005; and r = -0.17, p = 0.029). The association, while statistically significant, was modest in magnitude. In linear regression models that adjusted for age, gender, and education, the association between cognitive test scores and TTS remained robust (p<0.001). After excluding 68 (42.2%) cases taking ET medications with potential cognitive side effects, results remained unchanged. CONCLUSIONS: Each of the two cognitive test scores was associated with tremor severity such that greater cognitive dysfunction occurred in cases with more marked tremor. These data support recent imaging data, which suggest that the cerebellar neurodegeneration underlying ET may be involved in the expression of cognitive symptoms in ET. PMID- 23440037 TI - Comorbid bipolar affective disorder and obsessive compulsive disorder in childhood: a case study and brief review. AB - Obsessive compulsive disorder and bipolar affective disorder in the pediatric population show a bidirectional overlap. Few studies that have addressed this issue show that the prevalence of obsessive compulsive disorder in bipolar affective disorder patients ranges from 0 to 54%, and 1.85 to 36% of the obsessive compulsive disorder patients have a comorbid bipolar affective disorder. We report a case of a patient with an onset of obsessive compulsive disorder at two-and-a-half years of age, who developed mania after exposure to escitalopram. We suggest that in pediatric obsessive compulsive disorder cases, antidepressants be used with caution, especially in cases with a positive family history of bipolar affective disorder. PMID- 23440038 TI - The role of sitters in delirium: an update. AB - PURPOSE: The concept behind constant observation is not new. Whilst traditionally performed by nursing staff, it is now commonly performed by sitters. Details surrounding the usage, job description, training, clinical and cost effectiveness of sitters are not known; hence the reason for this review. METHODS: A literature search was performed in MEDLINE, Cochrane Database of Systematic Reviews, and PubMed from the years 1960 to October 2011. The definition for sitter used in the articles was accepted for this review. RESULTS: From this review, it is evident that sitters are being employed in a variety of settings. The question of which type of person would provide the most benefit in the sitter role is still not clear; whilst sitters have typically included family and volunteers, it may be trained volunteers who may offer the most cost-effective solution. The paucity of information available regarding the training and assessments of sitters and the lack of formal guidelines regulating sitters' use results in a lack of information available regarding these sitters, and current available evidence is conflicting regarding the benefits in terms of cost and clinical outcome. The only strong evidence relating to clinical benefit comes from the use of fully trained sitters as part of a multi-interventional program (i.e., HELP) CONCLUSIONS: Current evidence supports a role for the sitter as part of the management of patients with delirium. The most cost-effective sitter role appears to be trained volunteers. Further research is needed to determine the specific type of training required for the sitter role. The creation of a national set of regulations or guidelines would provide safeguards in the industry to ensure safe and effective patient care. PMID- 23440039 TI - Neuraxial anesthesia for cardiac surgery: thoracic epidural and high spinal anesthesia - why is it different? AB - Anesthesiologists can offer much more then stable blood pressure and heart rate in the intraoperative period. By choosing appropriate anesthetic techniques they can tremendously influence perioperative stress. This may positively impact on the overall surgical outcome. One of the most intriguing aspects of neuraxial anesthesia is its ability to attenuate the stress response to surgery. At present there is no agreement on the clinical importance of such a response but there is substantial indirect evidence that it may play an important role in a patient's outcome. Neuraxial anesthesia supplemented by general anesthesia is justified and can be safely used in cardiac surgery. The authors of this expert opinion prefer spinal anesthesia to thoracic epidural anesthesia and have been using it routinely for the last 20 years without any neurological complications. The risk of spinal hematoma from a 27G spinal needle prior to full heparinization is unknown but in our opinion is remote. Both epidural and spinal techniques can and should have a place in modern cardiac anesthesia practice and should be further investigated. PMID- 23440036 TI - Unraveling the central proopiomelanocortin neural circuits. AB - Central proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: how and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance. PMID- 23440040 TI - Circulating levels of a collagen type v propeptide fragment in a carbon tetrachloride reversible model of liver fibrosis. AB - AIM: To measure levels of the collagen V formation marker CO5-1230 during liver fibrosis progression and regression. METHODS: Monoclonal antibodies were raised against the sequence TAALGDIMGH located at the start of the C-terminal propeptide between amino acid position 1230' and 1239' (CO5-1230). An assay developed using the biotin-streptavidin system was evaluated in a rat reversible model of fibrosis. Animals were treated for duration of 4, 6 and 8 weeks. Animals that were treated for 8 weeks were left to regress for a period of 14, 20 and 26 weeks. RESULTS: Mean CO5-1230 level for control animals was found to be 8.7 ng/mL. CO5-1230 marker levels, at termination points, for CCl(4) treated animals was be 8.7 ng/mL at 4 weeks (P < 0.05, ROC: 0.83), 11.4 ng/mL at 6 weeks (P < 0.001, ROC: 0.93) and 10.8 ng/mL at 8 weeks (P < 0.05, ROC: 0.82). During regression phase, marker levels were statistically significantly decreased when compared with the marker levels at 8 weeks of treatment. Marker levels were found to be 5.9 ng/mL (P < 0.001, ROC: 0.8) after 14 weeks of regression, 3.9 ng/mL (P < 0.001, ROC: 0.95) after 20 weeks and 4.5 ng/mL (P < 0.001, ROC: 0.97) after 26 weeks of regression. CONCLUSIONS: The data indicates that CO5-1230 levels are statistically significantly increased when CCl(4) intoxication stimulus is applied in all treatment time points. CO5-1230 levels return back to control levels when the stimulus is removed. The above finding adds to our previous evaluation of the marker and suggests that CO5-1230 may be a promising potential marker for liver fibrosis staging and monitoring in both disease progression and regression. PMID- 23440041 TI - Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. AB - Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II-driven T cell help, remain unclarified. To address these questions, we have used a single B cell-based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ~25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA(+) RA patients, whereas such antibodies were not found in ACPA(-) patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA(+) antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences. PMID- 23440042 TI - Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. AB - Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children. PMID- 23440044 TI - Dioxygen adducts of rhodium N-heterocyclic carbene complexes. AB - Rhodium complexes functionalized by N-heterocyclic carbene ligands react with dioxygen to form adducts. Depending on the specifics of the ancillary ligands, oxygen binds to Rh either as a peroxide to form a fully oxidized Rh(III) complex, or as singlet dioxygen in a Rh(I) square planar complex. We have shown through analysis of a series of compounds, some previously published and some novel, that the presence of additional ligands that would support the formation of an octahedral geometry, as typically found with Rh(III) complexes, is critical for formation of the peroxide. In addition, we have demonstrated through DFT studies, that the potential energy surface with regard to the O-O bond length is relatively shallow, which provides a rationale for the distribution of bond lengths observed for apparently similar complexes analyzed by crystallography. PMID- 23440045 TI - Hole-transport functionalized copper(I) dye sensitized solar cells. AB - Ligands containing first and second generation hole-transport triphenylamino dendrons have been evaluated as ancillary ligands in copper(I) DSCs yielding an optimal efficiency of 3.77% in unmasked cells. The effects of masking the DSCs on measured parameters are discussed. PMID- 23440046 TI - Editorial. Hand surgery research. PMID- 23440043 TI - TGFbeta restores hematopoietic homeostasis after myelosuppressive chemotherapy. AB - Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGFbeta signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGFbeta signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGFbeta blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGFbeta during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGFbeta signaling after chemotherapy. This study demonstrates that context dependent activation of TGFbeta signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGFbeta signaling that dampens regeneration. PMID- 23440047 TI - Commentary on Kim et al.: characteristic radiographic features of the central ray in Apert syndrome. PMID- 23440048 TI - Commentary on Hardwicke et al. Macrodactyly - options and outcomes. PMID- 23440049 TI - Re: Le et al. Number of suture throws and its impact on the biomechanical properties of the four-strand cruciate locked flexor tendon repair with FiberWire. J Hand Surg Eur. 2012, 37: 826-31. PMID- 23440051 TI - [Ru(bpy)2dppz-idzo]2+: a colorimetric molecular "light switch" and powerful stabilizer for G-quadruplex DNA. AB - A new ruthenium complex, [Ru(bpy)2dppz-idzo](2+) (bpy = 2,2'-bipyridine, dppz idzo = dipyrido-[3,2-a:2',3'-c] phenazine-imidazolone), was synthesized and characterized. The luminescent titrations showed that the Ru-complex exhibited an outstanding "light switch" effect with an emission enhancement factor of about 300 in the presence of G-quadruplex DNA in a K(+) solution. This remarkable "light switch" behavior can even be observed by the naked eye under irradiation with UV light. To get an insight into the "light switch" mechanism, quantum chemical calculations were performed based on the DFT/TDDFT/PCM method at the B3LYP/6-31G* level. Furthermore, the CD titrations and thermal melting experiments indicated that [Ru(bpy)2dppz-idzo](2+) could not only induce the formation of an antiparallel G-quadruplex structure in the absence of monocations, but also has the ability to stabilize the G-quadruplex architecture, implying potential applications in anticancer therapeutics. Both the "light switch" effect and the structure stabilization ability of [Ru(bpy)2dppz-idzo](2+) were found to be superior to the well-known DNA molecular "light switch" [Ru(bpy)2dppz](2+). Finally, a "sandwich-like" binding model was proposed on the basis of molecular docking simulations. PMID- 23440053 TI - Kinetics and mechanism of the manganese(II) catalysed Calmagite dye oxidation using in situ generated hydrogen peroxide. AB - The kinetics and mechanism for the bleaching of Calmagite (H3CAL, 3-hydroxy-4-(2 hydroxy-5-methylphenylazo)naphthalene-1-sulfonic acid) in aqueous solution at pH 8.00 and 23 +/- 1 degrees C using in situ generated H2O2 is described. Complete mineralisation of H3CAL results with turnover frequencies (TOF = moles of H3CAL bleached per mole of manganese per hour) of 40 h(-1). The monohydroxy azo dyes Me H2CAL, Orange G and Orange II are not bleached which indicates that a requirement of dye bleaching is the coordination of the dye to the Mn centre. Spectroscopic studies show the formation of Mn(CAL)2 and Mn(CAL) species but in the presence of Tiron (1,2-dihydroxybenzene-3,5-disulfonate, disodium salt, monohydrate, Na2TH2.H2O), [Mn(CAL)(T)] is formed. It is proposed that a Mn(III)-hydroperoxide species is generated, [Mn(O2H)(CAL)(TQ)] from the in situ generated H2O2, where TQ represents the o-quinone form of Tiron, and this is the active species in the bleaching of coordinated CAL; the formation of this hydroperoxide species is supported by UV/VIS and ESI-MS data. The formation of a Mn(III) species is supported by EPR studies which also show some evidence for the presence of a labile d(5) Mn(II) species in the presence of the reducing substrate hydroxylamine (NH2OH). This would enable rapid ligand exchange for both in situ H2O2 generation and dye bleaching to occur; there is no evidence for the presence of Mn(IV)=O species. The virtue of low local concentrations of in situ generated H2O2 is shown to be important in preventing over oxidation of the catalyst and thus contributing to a robust catalytic system. PMID- 23440052 TI - Protective Effects of Oleic Acid Against Palmitic Acid-Induced Apoptosis in Pancreatic AR42J Cells and Its Mechanisms. AB - Palmitic acid (PAM), one of the most common saturated fatty acid (SFA) in animals and plants, has been shown to induce apoptosis in exocrine pancreatic AR42J cells. In this study, we investigated cellular mechanisms underlying protective effects of oleic acid (OLA) against the lipotoxic actions of PAM in AR42J cells. Exposure of cells to long-chain SFA induced apoptotic cell death determined by MTT cell viability assay and Hoechst staining. Co-treatment of OLA with PAM markedly protected cells against PAM-induced apoptosis. OLA significantly attenuated the PAM-induced increase in the levels of pro-apoptotic Bak protein, cleaved forms of apoptotic proteins (caspase-3, PARP). On the contrary, OLA restored the decreased levels of anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl xL, and Mcl-1) in PAM-treated cells. OLA also induced up-regulation of the mRNA expression of Dgat2 and Cpt1 genes which are involved in triacylglycerol (TAG) synthesis and mitochondrial beta-oxidation, respectively. Intracellular TAG accumulation was increased by OLA supplementation in accordance with enhanced expression of Dgat2 gene. These results indicate that restoration of anti apoptotic/pro-apoptotic protein balance from apoptosis toward cell survival is involved in the cytoprotective effects of OLA against PAM-induced apoptosis in pancreatic AR42J cells. In addition, OLA-induced increase in TAG accumulation and up-regulation of Dgat2 and Cpt1 gene expressions may be possibly associated in part with the ability of OLA to protect cells from deleterious actions of PAM. PMID- 23440054 TI - The development of synthetic antitumour vaccines from mucin glycopeptide antigens. AB - Based on important cell-biological and biochemical results concerning the structural difference between membrane glycoproteins of normal epithelial cells and epithelial tumour cells, tumour-associated glycopeptide antigens have been chemically synthesised and structurally confirmed. Glycopeptide structures of the tandem repeat sequence of mucin MUC1 of epithelial tumour cells constitute the most promising tumour-associated antigens. In order to generate a sufficient immunogenicity of these endogenous structures, usually tolerated by the immune system, these synthetic glycopeptide antigens were conjugated to immune stimulating components: in fully synthetic two-component vaccines either with T cell peptide epitopes or with Toll-like receptor2 lipopeptide ligands or in three component vaccines with both these stimulants. Alternatively, the synthetic glycopeptide antigens were coupled to immune stimulating carrier proteins. In particular, MUC1 glycopeptide conjugates with Tetanus toxoid proved to be efficient vaccines inducing very strong immune responses in mice. The antibodies elicited with the fully synthetic vaccines showed selective recognition of the tumour-associated glycopeptides as was shown by neutralisation and micro-array binding experiments. After booster immunisations, most of the immune responses showed the installation of an immunological memory. Immunisation with fully synthetic three-component vaccines induced immune reactions with therapeutic effects in terms of reduction of the tumour burden in mice or in killing of tumour cells in culture, while MUC1 glycopeptide-Tetanus toxoid vaccines elicited antibodies in mice which recognised tumour cells in human tumour tissues. The results achieved so far are considered to be promising for the development of an active immunisation against tumours. PMID- 23440055 TI - The MIDCAB approach in its various dimensions. AB - INTRODUCTION: Minimally invasive direct coronary artery bypass grafting (MIDCAB) offers arterial revascularization of the left anterior descending coronary artery especially in lesions unsuitable for percutaneous coronary interventions. By avoidance of sternotomy and cardiopulmonary bypass its invasivity is less than that of conventional bypass surgery. METHODS: A literature search of all published minimal invasive direct coronary artery bypass grafting studies was performed for the period from January 1995 through November 2011. Additionally, the authors reviewed their experience in more than one thousand patients treated by minimal invasive direct coronary artery bypass grafting within the last 14 years at their institution. RESULTS: Early mortally ranged from 1.2 to 1.3%. Midterm mortality ranged up to 3.2%. At 6-month follow up 3.6% grafts were occluded and 7.2% had a significant stenosis which resulted in target vessel revascularization in 3.3% of cases. The conversion rate to sternotomy or cardiopulmonary bypass ranged between 1.2 and 6.2%. CONCLUSIONS: In the past MIDCAB was predominantly used in patients with isolated lesions of the left anterior descending coronary artery. In combination with percutaneous interventions it provides an attractive option for full revascularization in multi vessel disease especially in older patients with significant comorbidities. Overall minimal invasive direct coronary artery bypass grafting is associated with few perioperative complications and with high graft patency rates in the mid term and long-term course. PMID- 23440056 TI - Intravitreal ranibizumab as salvage therapy in an extremely low-birth-weight infant with rush type retinopathy of prematurity. AB - We report the effects of intravitreal ranibizumab as salvage therapy in an extremely low-birth-weight (ELBW) infant with rush type retinopathy of prematurity (ROP). This case was a girl of 23 weeks gestational age weighing 480 g at birth. At a postconceptual age of 33 weeks, she presented with zone 1, stage 3 ROP with plus disease. Despite intravitreal bevazucimab and laser photocoagulation, extraretinal fibrovascular proliferation persisted. Intravitreal 0.25 mg (0.025 ml) ranibizumab was injected OU. After treatment, extraretinal fibrovascular proliferation disappeared. Fundus examination showed flat retinas and normal vasculature in both eyes. She has been followed up for 2 years. Intravitreal ranibizumab injection seems effective and well tolerated as salvage therapy in an ELBW infant with rush type ROP. No short-term ocular or systemic side effects were identified. More cases and longer follow-up are mandatory. PMID- 23440057 TI - Light-triggered self-healing and shape-memory polymers. AB - In this review, we highlight the recent progress made in light-controlled self healing and shape memory polymers. We analyse the materials design, underlying mechanisms and chemistries involved in the different methods developed for these two types of emerging photoresponsive materials. We show that these two seemingly different groups of functional materials are linked by a number of common approaches enabling their optical control, particularly the approaches based on the photothermal effect and photochemical reactions of photoswitching groups incorporated in polymer structures. Possible future developments and perspectives of using light as a unique trigger for polymer self-healing and shape-memory are also discussed. PMID- 23440058 TI - Stable ruthenium nitrosyl porphyrins with axial O-bonded ligands; preparation and redox behavior. AB - The six-coordinate compounds, (T(p-OMe)PP)Ru(NO)(OC6HF4) and (T(p OMe)PP)Ru(NO)(OC(=O)CF3) have been prepared and characterized by IR and NMR spectroscopy, electrochemistry and IR spectroelectrochemistry, and by X-ray crystallography. These compounds undergo macrocycle-centered oxidations, and loss of axial ligands upon reduction. PMID- 23440059 TI - Peptide-tethered monodentate and chelating histidylidene metal complexes: synthesis and application in catalytic hydrosilylation. AB - The Ndelta,Nepsilon-dimethylated histidinium salt (His*) was tethered to oligopeptides and metallated to form Ir(III) and Rh(I) NHC complexes. Peptide based histidylidene complexes containing only alanine, Ala-Ala-His*-[M] and Ala Ala-Ala-His*-[M] were synthesised ([M] = Rh(cod)Cl, Ir(Cp*)Cl2), as well as oligopeptide complexes featuring a potentially chelating methionine and tyrosine residue, Met-Ala-Ala-His*-Rh(cod)Cl and Tyr-Ala-Ala-His*-Rh(cod)Cl. Chelation of the methionine-containing histidylidene ligand was induced by halide abstraction from the rhodium centre, while tyrosine remained non-coordinating under identical conditions. High catalytic activities in hydrosilylation were achieved with all peptide-based rhodium complexes. The cationic S(Met),C(His*)-bidentate peptide rhodium catalyst outperformed the monodentate neutral peptide complexes and constitutes one of the most efficient rhodium carbene catalysts for hydrosilylation, providing new opportunities for the use of peptides as N heterocyclic carbene ligands in catalysis. PMID- 23440060 TI - Assessment of status of patients receiving palliative home care and services provided in a rural area-kerala, India. AB - CONTEXT: For the first time in India, a Pain and Palliative Care policy to guide the community-based home care initiatives was declared by the Government of Kerala state. In Kerala, majority of the panchayats (local self-governments) are now conducting home-based palliative care as part of primary health care. National focus domain areas in palliative care research are structure and process, the physical aspects, and also the social aspects of care. AIMS: The study was conducted to assess the patient's status and the services provided by palliative home care. SETTINGS AND DESIGN: The descriptive study was conducted at Mavoor panchayat-Kozhikode district of Kerala, India by collecting information from the case records, nurses diary notes of all enrolled patients. MATERIALS AND METHODS: Collecting information from the case records, nurses diary notes of all enrolled patients. STATISTICAL ANALYSIS: The data were entered using Microsoft excel for Windows XP and analyzed using SPSS 16.0 (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL, USA). RESULTS: Totally, 104 patients were enrolled. Diagnosis wise major category was degenerative diseases. There were 27% persons suffering from cerebrovascular accidents, 15.3% with malignancies, 8.7% with coronary artery disease, 5.8% with complications of diabetes, and 8.7% were with fracture of bones. The major complaints were weakness (41.3%), tiredness (31.7%), and pain (27%). Twenty-five percent persons complained of urinary incontinence, 12.5% complained of ulcer, 10.6% of edema, and 9.6% of mental/emotional agony. The activity of daily living status was as follows. Twenty-five percent subjects were completely bed ridden. 5.8% were feeding through Ryles tube, 16.3% had urinary incontinence, 9.6% were having no bowel control. CONCLUSIONS: The service could address most of the medical, psychosocial, and supportive needs of the patients and reduce their pain and symptoms. The interface between institutional-based care and home care needs more exploration and prospective studies. PMID- 23440061 TI - Contribution to PM(2.5) from domestic wood burning in a small community in Sweden. AB - Biomass burning for domestic heating has increased in many countries with cold climates in recent years. This paper presents and compares two ways of estimating the contribution of particulate matter (PM2.5) to ambient air from local domestic wood burning, using daily stationary parallel PM2.5 measurements in a wood burning area and at a reference location. In the first method (based on air mass back trajectories), daily gravimetric PM2.5 mass differences were compared between the two stations for days with low contributions from regional sources. In the second method, 28 filters from each location were chemically analysed, and source contributions were calculated using positive matrix factorisation (PMF). The trajectory method estimated the extra local contribution from domestic wood burning in the wood-burning area to be 0.7-1.1 MUg m(-3), while the PMF method gave a contribution of 0.64 MUg m(-3). With the PMF method, the total contribution to ambient air from local domestic wood burning was estimated to be 25% of the total PM2.5 mass. The estimated mass contribution using the trajectory method gave a result similar to that of the PMF method, and the method can therefore be a time- and cost-effective first step, especially when no chemical analysis is possible. PMID- 23440063 TI - Measuring cell mechanics by optical alignment compression cytometry. AB - To address the need for a high throughput, non-destructive technique for measuring individual cell mechanical properties, we have developed optical alignment compression (OAC) cytometry. OAC combines hydrodynamic drag in an extensional flow microfluidic device with optical forces created with an inexpensive diode laser to induce measurable deformations between compressed cells. In this, a low-intensity linear optical trap aligns incoming cells with the flow stagnation point allowing hydrodynamic drag to induce deformation during cell-cell interaction. With this novel approach, we measure cell mechanical properties with a throughput that improves significantly on current non destructive individual cell testing methods. PMID- 23440064 TI - Constructing memory, imagination, and empathy: a cognitive neuroscience perspective. AB - Studies on memory, imagination, and empathy have largely progressed in isolation. Consequently, humans' empathic tendencies to care about and help other people are considered independent of our ability to remember and imagine events. Despite this theoretical autonomy, work from across psychology, and neuroscience suggests that these cognitive abilities may be linked. In the present paper, I tentatively propose that humans' ability to vividly imagine specific events (as supported by constructive memory) may facilitate prosocial intentions and behavior. Evidence of a relationship between memory, imagination, and empathy comes from research that shows imagination influences the perceived and actual likelihood an event occurs, improves intergroup relations, and shares a neural basis with memory and empathy. Although many questions remain, this paper outlines a new direction for research that investigates the role of imagination in promoting empathy and prosocial behavior. PMID- 23440065 TI - Synthesis, Antiviral and Cytotoxicity Studies of Novel N-substituted Indophenazine Derivatives. AB - A series of novel N-substituted indophenazine derivatives were synthesised and screened for antiviral activity against a panel of human pathogenic viruses. New compounds were synthesised through modifying the N-hydrogen of indophenazine moiety with different substitution and formaldehyde by Mannich reaction. The structure of the synthetic compounds was characterised by means of infra red and nuclear magnetic resonance spectral data. The compound 10H-indolo-2-Amino pyridine [3,2-b] quinoxalines inhibits Herpes simplex virus-1 and vaccinia virus at a concentration of 12 MUg/ml, and the cytotoxicy was found to be 100 MUg/ml. 4 Aminobenzene sulfonamide-10H-indolo [3,2-b] quinoxalines inhibit vaccinia virus at a concentration of 12 MUg/ml and cytotoxicy was found to be 100 MUg/ml. The anti-HIV activities of the new compounds were also screened for in vitro antiviral activity against replication of HIV-1 (IIIB) and HIV-2 (ROD) in MT-4 cells using zidovudine (AZT) as standard. Pthalimide derivative inhibited the replication of HIV-2 (EC(50)=11.60 MUg/ml and CC(50)=61.63 MUg/ml) in MT-4 cells. PMID- 23440066 TI - Rapid on-site evaluation and low registration error enhance the success of electromagnetic navigation bronchoscopy. AB - BACKGROUND: Electromagnetic navigation bronchoscopy (EMN) is a novel technology which allows localizing peripheral lung lesions and mediastinal lymph nodes for sampling and thus increasing diagnostic yield of Flexible Bronchoscopy. OBJECTIVES: A prospective study was conducted to investigate the diagnostic yield of EMN with lower average fiducial target registration error (AFTRE) and rapid on site evaluation (ROSE). METHODS: Consecutive patients with peripheral lung lesion (PL) or enlarged mediastinal lymph node (MLN) which could not be diagnosed by conventional techniques and/or if the patients were not suitable for such interventions were included. The navigation procedure was continued once registration error was reached below/equal to the absolute value of 5 mm. ROSE was performed by an expert cytopathologist. RESULTS: A total of 76 patients; 22 having only PLs, 41 having only MLNs, and 13 having both PLs and MLNs together were enrolled. Thirty-two of 35 PLs (91.4%) and 85 of 102 MLNs (83.3%) were successfully sampled. Overall diagnostic yield was 89.5%. PLs and MLNs were further grouped according to their size (PLs: <20 mm vs >=20 mm, MLNs: <15 mm vs >=15 mm). The sampling yield was independent of size for both PL and MLN (P = 1.00, P = 0.38). In diagnostic EMN cases, mean AFTRE was 4.33 +/- 0.71 mm, whereas it was 5.16 +/- 0.05 mm (P = 0.008) in nondiagnostics. The total duration of procedure was 36.17 +/- 9.13 min. Pneumothorax was observed in three patients (3.9%). CONCLUSION: EMN with low AFTRE in combination with ROSE is a reliable method with high sampling and/or diagnostic rate in PLs and MLNs. PMID- 23440068 TI - Engineering of functional, perfusable 3D microvascular networks on a chip. AB - Generating perfusable 3D microvessels in vitro is an important goal for tissue engineering, as well as for reliable modelling of blood vessel function. To date, in vitro blood vessel models have not been able to accurately reproduce the dynamics and responses of endothelial cells to grow perfusable and functional 3D vascular networks. Here we describe a microfluidic-based platform whereby we model natural cellular programs found during normal development and angiogenesis to form perfusable networks of intact 3D microvessels as well as tumor vasculatures based on the spatially controlled co-culture of endothelial cells with stromal fibroblasts, pericytes or cancer cells. The microvessels possess the characteristic morphological and biochemical markers of in vivo blood vessels, and exhibit strong barrier function and long-term stability. An open, unobstructed microvasculature allows the delivery of nutrients, chemical compounds, biomolecules and cell suspensions, as well as flow-induced mechanical stimuli into the luminal space of the endothelium, and exhibits faithful responses to physiological shear stress as demonstrated by cytoskeleton rearrangement and increased nitric oxide synthesis. This simple and versatile platform provides a wide range of applications in vascular physiology studies as well as in developing vascularized organ-on-a-chip and human disease models for pharmaceutical screening. PMID- 23440069 TI - Non-monotonic size change of monodisperse Fe3O4 nanoparticles in the scale-up synthesis. AB - A non-monotonic size change of monodisperse Fe3O4 nanoparticles (NPs) with a diameter of 3-20 nm is observed in the scale-up organic-phase synthesis. The crystal structures and the valence state of the Fe ions of the as-prepared NPs were determined by X-ray diffraction (XRD) and Mossbauer spectroscopy, respectively. It is interestingly observed that particle size does not decrease monotonously with either the increase of the molar ratio of oleic acid (OA) to FeO.OH, or the decrease of precursor concentration. Furthermore, the reaction process was investigated via the time-dependent Fourier transform infrared spectra (FTIR) and the transmission electron microscopy (TEM) images, which reveal that the non-monotonic size change results from the different influence of OA on the three reaction stages including monomer formation, nucleation, and growth with increasing precursor amounts. PMID- 23440070 TI - New type of antidrying lens for vitreous surgery with a noncontact wide-angle viewing system. AB - Drying of the cornea during surgery, which causes poor visibility of the fundus, is one of the more serious problems when using a noncontact type wide-angle viewing system. We developed an antidrying corneal contact lens for use with this type of viewing system. The lens has a very thin meniscus made of polymethyl methacrylate with a large outer diameter. Following application of the viscoelastic material, the lens can be put on the cornea without using a contact lens fixation ring. The larger diameter and lightweight characteristics of our lens contributed to its overall stability. The smooth surface of this prototype lens was able to achieve an intraoperative view of good quality, not only by preventing the cornea from drying, but also by providing a smooth surface over the entire cornea. PMID- 23440071 TI - Lab-on-DVD: standard DVD drives as a novel laser scanning microscope for image based point of care diagnostics. AB - We present a novel "Lab-on-DVD" system and demonstrate its capability for rapid and low-cost HIV diagnostics by counting CD4+ cells isolated from whole blood. We show that a commercial DVD drive can, with certain modifications, be turned into an improved DVD-based laser scanning microscope (DVD-LSM). The system consists of a multi-layered disposable polymer disc and a modified commercial DVD reader with rotational control for sample handling, temperature control for optimized bioassay, a photodiode array for detection, and software for signal processing and user interface - all the necessary components required for a truly integrated lab-on-a-chip system, with the capability to deliver high-resolution images down to 1 MUm in size. Using discs modified with antibodies, we specifically captured CD4+ cells from whole blood, demonstrating single cell resolution imaging. The novel integrated DVD platform with sub-micron image resolution brings, for the first time, affordable cellular diagnostic testing to the point-of-care and should be readily applicable at resource-limited settings. PMID- 23440073 TI - Day admission for thoracic aortic surgery. AB - Elective cardiac surgical patients can be admitted on the morning of the operation. The day admission surgery is safe with optimal care for patients and provides an economical benefit. In our institution if immediate surgery is not required, patients are entered into program for serial follow up. An elective aortic intervention for open surgical or endovascular surgery is recommended when the risk of aortic rupture outweighs the risk of surgery. Patients are seen 3 to 7 days prior of day admission surgery in preoperative clinic. On the morning of surgery, the patient undergoes a reassessment to ensure no interval changes have occurred. We hereby describe our three years experience with 350 patients were referred from the Aortic Aneurysm Surveillance Program. We believe that not only patients, but all medical personal benefit from a complete preoperative evaluation of these complicated patients and this creates harmony during the entire hospitalization! PMID- 23440072 TI - Organocatalytic 1,4-conjugate addition of ascorbic acid to alpha,beta-unsaturated aldehydes: bio-inspired total syntheses of leucodrin, leudrin and proposed structure of dilaspirolactone. AB - The organocatalytic additions of ascorbic acid to various alpha,beta-unsaturated aldehydes via tandem 1,4-conjugate addition/hemiacetalization/hemiketalization were developed, which provided a rapid entry into the 5-5-5 spirodilactone cores of a family of ascorbylated natural products. Based on the described chemistry, total syntheses of leucodrin, leudrin and the proposed structure of dilaspirolactone were achieved. PMID- 23440075 TI - Total synthesis of (+/-)-sacidumlignans D and A through Ueno-Stork radical cyclization reaction. AB - Efficient synthesis of (+/-)-sacidumlignan D (4) has been successfully achieved employing Ueno-Stork radical cyclization of alpha-bromo acetal 21 as a key step. Two synthetic approaches for the symmetrical diaryl ketone 19 have been discussed in detail. Notably, sacidumlignan A (1) can be also efficiently synthesized in only 7 steps with 25% overall yield, where acid triggered tandem reaction starting from analogous Ueno-Stork cyclization product 27 played an important role. Moreover, potentially biomimetic conversion from (+/-)-sacidumlignan D (4) to sacidumlignan A (1) could be realized. PMID- 23440074 TI - Gradients of physical and biochemical cues on polyelectrolyte multilayer films generated via microfluidics. AB - The cell microenvironment is a complex and anisotropic matrix composed of a number of physical and biochemical cues that control cellular processes. A current challenge in biomaterials is the engineering of biomimetic materials which present spatially controlled physical and biochemical cues. The layer-by layer assembly of polyelectrolyte multilayers (PEM) has been demonstrated to be a promising candidate for a biomaterial mimicking the native extracellular matrix. In this work, gradients of biochemical and physical cues were generated on PEM films composed of hyaluronan (HA) and poly(l-lysine) (PLL) using a microfluidic device. As a proof of concept, four different types of surface concentration gradients adsorbed onto the films were generated. These included surface concentration gradients of fluorescent PLL, fluorescent microbeads, a cross linker, and one consisting of a polyelectrolyte grafted with a cell adhesive peptide. In all cases, reproducible centimeter-long linear gradients were obtained. Fluorescence microscopy, Fourier transform infrared spectroscopy and atomic force microscopy were used to characterize these gradients. Cell responses to the stiffness gradient and to the peptide gradient were studied. Pre osteoblastic cells were found to adhere and spread more along the stiffness gradient, which varied linearly from 200 kPa-600 kPa. Myoblast cell spreading also increased throughout the length of the increasing RGD-peptide gradient. This work demonstrates a simple method to modify PEM films with concentration gradients of non-covalently bound biomolecules and with gradients in stiffness. These results highlight the potential of this technique to efficiently and quickly determine the optimal biochemical and mechanical cues necessary for specific cellular processes. PMID- 23440076 TI - Effectiveness of cognitive training for Chinese elderly in Hong Kong. AB - In Hong Kong, the evidence for cognitive-training programs in fighting against memory complaints is lacking. This study aimed to evaluate the effectiveness of the Active Mind cognitive-training program in improving the cognitive function and quality of life (QoL) for local community-dwelling Chinese older adults. A total of 200 subjects were recruited from 20 different district elderly community centers (DECCs). Centers were randomly assigned into either the intervention group or control group. The intervention group underwent eight 1-hour sessions of cognitive training, while the control group were included in the usual group activities provided by the DECCs. Standardized neuropsychological tests (the Chinese version of Mattis Dementia Rating Scale [CDRS] and the Cantonese version of the Mini-Mental State Examination) and the QoL questionnaire SF12 were used to assess participants' cognitive function and QoL before and after the trial. A total of 176 subjects completed the study. The intervention group showed greater improvement in the cognitive function measured by total CDRS score (treatment: 12.24 +/- 11.57 vs control: 4.37 +/- 7.99; P < 0.001) and QoL measured by total SF12 score (treatment: 7.82 +/- 13.19 vs control: 3.18 +/- 11.61; P = 0.014). Subjects with lower education level were associated with better cognitive response to the cognitive-training program. The current findings indicated that the Active Mind cognitive-training program was effective in improving the cognitive function and QoL for community-dwelling Chinese older adults in Hong Kong. PMID- 23440077 TI - Soft materials based on designed self-assembling peptides: from design to application. AB - Self-assembling peptides (SAPs) are one of the useful tools to fabricate various nanostructures and resulting higher macrostructures from them based on supramolecular chemistry. Recent continuous studies on SAPs give us much important knowledge, from the design of SAPs to their application as nanomaterials and biomaterials. The process from design to application of SAPs includes steps of optimization in self-assembling properties and functionalization. This review briefly describes general designs of SAPs, control and functionalization methods of nanostructures fabricated from SAPs and recent application examples. PMID- 23440078 TI - Asymmetric synthesis of cyclo-archaeol and beta-glucosyl cyclo-archaeol. AB - An efficient asymmetric synthesis of cyclo-archaeol and beta-glucosyl cyclo archaeol is presented employing catalytic asymmetric conjugate addition and catalytic epoxide ring opening as the key steps. Their occurrence in deep sea hydrothermal vents has been confirmed by chromatographic comparison with natural samples. PMID- 23440079 TI - Mirror movements in movement disorders: a review. AB - BACKGROUND: Mirror movements (MM) are involuntary movements of homologous muscles during voluntary movements of contralateral body regions. While subtle mirroring can be present in otherwise healthy adults, overt MM may be common in many movement disorders. Examining these collective findings may further our understanding of MM and help define their usefulness as a clinical sign. METHODS: We sought to review English language research articles examining the presence, clinical significance, and/or pathophysiology of MM in Parkinson's disease (PD), corticobasal syndrome (CBS), essential tremor (ET), focal hand dystonia, Creutzfeldt-Jakob's disease (CJD), and Huntington's disease. When available, MM in these disorders were compared with those of healthy age-matched controls and congenital disorders such as Klippel-Feil syndrome and X-linked Kallman's syndrome. RESULTS: Clinical presentation of MM is common in asymmetric parkinsonian disorders (early PD, CBS) and manifests differently depending on the side affected (less affected hand in PD, more affected hand in CBS, either hand in ET, and both hands in healthy adults and congenital disorders), stage of disease (early, asymmetric PD and CJD), and presence of concomitant mirror-like overflow phenomena (focal dystonia and CBS-associated alien hand). In general, uncrossed descending corticospinal projections (congenital MM) and/or abnormal activation of the motor cortex ipsilateral to the voluntary task (most acquired MM), i.e., activation of the normal crossed corticospinal pathway, are required for the generation of MM. DISCUSSION: MM are common motor phenomena and present differently in several acquired (mostly neurodegenerative) and congenital movement disorders. Future studies on MM will enhance the clinical diagnosis of selected movement disorders and contribute to our understanding of the normal physiology of bimanual coordination. PMID- 23440080 TI - Chemotherapy in Patients with Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer: An Overview. AB - Anthracyclines and taxanes are cytotoxic agents that are commonly used for the treatment of breast cancer, including in the adjuvant, neoadjuvant, and metastatic setting. Each drug class of is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). This may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. Several classes of cytotoxic agents have been evaluated in patients with anthracycline and taxane-pretreated metastatic breast cancer (MBC), including other antitubulins (vinorelbine, ixabepilone, eribulin), antimetabolites (capecitabine, gemcitabine), topoisomerase I inhibitors (irinotecan), platinum analogues (cisplatin, carboplatin), and liposomal doxorubicin preparations. No trials have shown an overall survival advantage for combination chemotherapy in this setting, indicating that single cytotoxic agents should usually be used, expect perhaps in patients with rapidly progressive disease and/or high tumor burden. PMID- 23440081 TI - Discrimination of soluble and aggregation-prone proteins based on sequence information. AB - Understanding the factors governing protein solubility is a key to grasp the mechanisms of protein solubility and may provide insight into protein aggregation and misfolding related diseases such as Alzheimer's disease. In this work, we attempt to identify factors important to protein solubility using feature selection. Firstly, we calculate 1438 features including physicochemical properties and statistics for each protein. Random Forest algorithm is used to select the most informative and the minimal subset of features based on their predictive performance. A predictive model is built based on 17 selected features. Compared with previous models, our model achieves better performance with a sensitivity of 0.82, specificity 0.85, ACC 0.84, AUC 0.91 and MCC 0.67. Furthermore, a model using a redundancy-reduced dataset (sequence identity <= 30%) achieves the same performance as the model without redundancy reduction. Our results provide not only a reliable model for predicting protein solubility but also a list of features important to protein solubility. The predictive model is implemented as a freely available web application at . PMID- 23440082 TI - Synthesis of unsymmetrical carboxyphthalocyanines by palladium-catalyzed hydroxycarbonylation of iodo-substituted precursors. AB - Phthalocyanines (Pcs) containing a carboxylic acid functionality directly bound to the macrocycle have been synthesized, in one step and in good yields, from iodo-substituted Pc precursors. This methodology represents a convenient alternative to the commonly used method based on two consecutive oxidations of hydroxymethyl Pcs. PMID- 23440083 TI - Screening for osteoporosis in men aged 70 years and older in a primary care setting in the United States. AB - Osteoporosis in men is an underrecognized and undertreated condition. Despite the National Osteoporosis Foundation recommending osteoporosis screening in men aged 70 years and older since 2008, screening rates in the United States remain undefined. In our study, we analyzed dual-energy X-ray absorptiometry (DXA) screening rates in a primary care setting. Overall, screening rates were low (11.3%). Although there was an increase with age in both the 10-year osteoporotic and 10-year hip fracture probabilities, no association was found between increased age and bone mineral density testing using DXA. Only 23.2% of patients were prescribed bone protective treatments. The performance of DXA screening strongly predicted prescription of bone protective treatment. Increased age raised the likelihood of bone protective treatment prescriptions; however, smokers were less likely to be prescribed these medications. As the population in the United States ages, an increased awareness of this major public health problem is warranted. PMID- 23440084 TI - Complications pertaining to the detection and characterization of individual and embedded single walled carbon nanotubes by scanning electron microscopy. AB - Comparison of AFM and SEM images of single walled carbon nanotubes (SWNTs) grown within a dielectric matrix reveal subterranean nanotubes that are present within the matrix, and as such can be charge screened by the dielectric. Under adequate imaging conditions for the SWNT/silica sample the intensity of isolated nanotubes is found to be inversely proportional to the instrument dwell time (i.e., shorter dwell times were found to make SWNT intensities brighter). The threshold dwell time required to enable isolated tubes to be visible was found to be 10 MUs; moreover, the degree change in intensity was found to be nanotube specific, i.e., different SWNTs respond in a different manner at different dwell times. The results indicate that care should be taken when attempting to quantify number density and length distributions of SWNTs on or within a dielectric matrix. PMID- 23440085 TI - Synthesis of libraries of peptidomimetic compounds containing a 2-oxopiperazine unit in the main chain. AB - Peptoid libraries have been shown to be a useful source of protein-binding agents. However, simple linear peptoids lack conformational constraints, which may limit their binding affinity for proteins. Here we report facile chemistry for the assembly of 2-oxopiperazine rings into the main chain of peptoid-like oligomers, thus rigidifying the structure. This modified sub-monomer synthesis is suitable for the creation of high quality combinatorial libraries. PMID- 23440087 TI - Confinement effects and why carbon nanotube bundles can work as gas sensors. AB - Carbon nanotubes have been at the forefront of nanotechnology, leading not only to a better understanding of the basic properties of charge transport in one dimensional materials, but also to the perspective of a variety of possible applications, including highly sensitive sensors. Practical issues, however, have led to the use of bundles of nanotubes in devices, instead of isolated single nanotubes. From a theoretical perspective, the understanding of charge transport in such bundles, and how it is affected by the adsorption of molecules, has been very limited, one of the reasons being the sheer size of the calculations. A frequent option has been the extrapolation of knowledge gained from single tubes to the properties of bundles. In the present work we show that such procedure is not correct, and that there are qualitative differences in the effects caused by molecules on the charge transport in bundles versus isolated nanotubes. Using a combination of density functional theory and recursive Green's function techniques we show that the adsorption of molecules randomly distributed onto the walls of carbon nanotube bundles leads to changes in the charge density and consequently to significant alterations in the conductance even in pristine tubes. We show that this effect is driven by confinement which is not present in isolated nanotubes. Furthermore, a low concentration of dopants randomly adsorbed along a two-hundred nm long bundle drives a change in the transport regime; from ballistic to diffusive, which can account for the high sensitivity to different molecules. PMID- 23440086 TI - Major themes for 2011 in cardiovascular anesthesia and intensive care. AB - The past year has witnessed major advances in of cardiovascular anesthesia and intensive care. Perioperative interventions such as anesthetic design, inotrope choice, glycemic therapy, blood management, and noninvasive ventilation have significant potential to enhance perioperative outcomes even further.The major theme for 2011 is the international consensus conference that focused on ancillary interventions likely to reduce mortality in cardiac anesthesia and intensive care. This landmark conference prioritized volatile anesthetics, levosimendan, and insulin therapy for their promising life-saving perioperative potential. Although extensive evidence has demonstrated the cardioprotective effects of volatile anesthetics, levosimendan as well as glucose, insulin and potassium therapy, the clinical relevance of these beneficial effects remains to be fully elucidated. Furthermore, controversy still persists about how tight perioperative glucose control should be in adult cardiac surgery because of the risk of hypoglycemia.A second major theme in 2011 has been perioperative hemostasis with the release of multispecialty guidelines. Furthermore, hemostatic agents such as recombinant factor VIIa and tranexamic acid have been studied intensively, even in the setting of major non-cardiac surgery. This review then highlights the remaining two major themes for 2011, namely the expanding role of noninvasive ventilation in our specialty and the formation of the Roland Hetzer International Cardiothoracic and Vascular Surgery Society.In conclusion, it is time for large adequately powered multicenter trials to test whether prioritized perioperative interventions truly reduce mortality and morbidity in cardiac surgical patients. This essential paradigm shift represents a major clinical opportunity for the global cardiovascular anesthesia and critical care community. PMID- 23440088 TI - Guest encapsulation and coronene-C60 exchange in supramolecular zinc porphyrin tweezers, grids and prisms. AB - Using a variant of the HETPHEN concept, heteroleptic 2D and 3D metallosupramolecular structures, such as tweezer T, grid G and tetragonal prism P, were fabricated quantitatively and characterised by (1)H NMR, (13)C NMR, (1)H (1)H COSY, DOSY as well as ESI-MS. All structures encapsulate C60, with P showing the highest binding affinity (Kassoc = 3.3 * 10(6) M(-1)). The association constant increases along the series T < G < P, most likely due to the enhanced structural rigidity and better coplanarity of the two zinc porphyrin units. In contrast to T and G, the tetragonal prism P shows notable encapsulation of coronene (Kassoc = 1.1 * 10(4) M(-1)). In T and G, on the other hand, complexation of coronene is kinetically inhibited by the bulky mesityl rings at the porphyrin periphery. As illustrated in the facile displacement of coronene by C60 in coronene@P to furnish C60@P, P behaves as a flexible and guest-adaptive host. PMID- 23440089 TI - Comparison of lymphocyte apoptotic index and qualitative DNA damage in yoga practitioners and breast cancer patients: A pilot study. AB - BACKGROUND: Yoga is found to be effective in reducing stress levels and radiation induced DNA damage, and improving the quality of life, in breast cancer patients. The present study was aimed at comparing the apoptotic index (AI) and DNA damage of advanced yoga practitioners with those of breast cancer patients. MATERIALS AND METHODS: This cross-sectional pilot study compared three groups (n = 9 each) of age-matched subjects viz. (1) Carcinoma breast patients in stage II or III undergoing radiation therapy after completing three cycles of chemotherapy; (2) Senior yoga practitioners who were practicing asanas, pranayama and meditation daily for more than 10 years; and (3) Normal healthy volunteers. Peripheral blood lymphocytes were isolated, and qualitative DNA damage (QDD) and AI were evaluated by single-cell gel electrophoresis assay. Approximately 500 cells were counted in each case. Number of cells that were normal, undergoing apoptosis, and with DNA damage were categorized and percentages were calculated. RESULTS: Data being normally distributed, one-way analysis of variance (ANOVA) showed significant interaction between groups in AI (P = 0.016) and QDD (P = 0.045). On post-hoc analysis using Scheffe test, AI was significantly lower in non-yoga volunteers as compared with the breast cancer group (P = 0.019) and QDD was significantly lower in yoga practitioners when compared with non-yoga volunteers (P = 0.047). CONCLUSION: Cellular dysfunction (QDD) requires restorative mechanisms (AI) to restore the system to a balance. The results of this pilot study show trends, which indicate that in ill-health, there is inadequate restorative mechanisms (AI) although dysfunction (QDD) is high. Through regular practice of yoga, cellular dysfunction can be lowered, thus necessitating reduced restorative mechanisms. AI and QDD could also be useful indicators for predicting the three zones of health viz. disease, health, and positive health. PMID- 23440090 TI - Synthesis of phthalazinones via palladium(II)-catalysed intramolecular oxidative C-H/C-H cross-coupling of N'-methylenebenzohydrazides. AB - A palladium(II)-catalysed intramolecular oxidative C-H/C-H cross-coupling of N' methylenebenzohydrazides to phthalazin-1(2H)-ones has been developed. This cyclization is believed to mechanistically proceed via electrophilic ortho palladation and subsequent C-arylation of the carbon-nitrogen double bond. PMID- 23440091 TI - Vortex fluidic entrapment of functional microalgal cells in a magnetic polymer matrix. AB - Composite materials based on superparamagnetic magnetite nanoparticles embedded in polyvinylpyrrolidone (PVP) are generated in a continuous flow vortex fluidic device (VFD). The same device is effective in entrapping microalgal cells within this material, such that the functional cells can be retrieved from aqueous dispersions using an external magnet. PMID- 23440092 TI - Carrier sheet density constrained anomalous current saturation of graphene field effect transistors: kinks and negative differential resistances. AB - There has recently been a great deal of interest and excitement in applying graphene field effect transistors (GFETs) in digital and radio frequency (RF) circuits and systems. Peculiar output characteristics such as kinks and negative differential resistance (NDR) in a strong field are the unique transport properties of GFETs. Here we demonstrate that these unusual features are attributed to a carrier sheet density constrained transport framework. Simulation results based on a simple analytic model which includes the linear DOS structure are in very good agreement with experimental data. The kernel mechanism of NDR is ascribed to the fact that the total current increase of a channel with a high average carrier density is constrained by its minimum sheet density. Utilizing in situ Kelvin probe force microscopy (KPFM), the principle which naturally distinguishes NDR from kinks is further verified by studying the spatially resolved surface potential distribution along the channel. The influence and potential application of GFETs' unique output characteristics in the digital and RF fields are also proposed. PMID- 23440093 TI - [Relationship between subclinical atherosclerosis, blood pressure, and lipid profile in obese children and adolescents: a systematic review]. AB - The present study aimed to systematically review the literature about intima media thickness (IMT), blood pressure (BP), and lipid profile (LP) in obese and non-obese children and adolescents. The search was carried out in electronic databases (PubMed, Bireme, and Elsevier ScienceDirect) between 2000-2010. The following keywords, in English, were used: "obesity", "adolescents", "atherosclerosis" and "child", using two combinations: obesity+child+atherosclerosis and obesity+adolescents+atherosclerosis. The electronic search resulted in 3,211 manuscripts. After analysis of the inclusion criteria, 13 papers were selected. Of these, two studies showed significant correlation between IMT and the variables BP, LDL, and triglycerides. In other studies, no significant correlations were found. There is a wide methodological variability across the studies. However, obese children and adolescents had higher values of IMT, BP, and LP. PMID- 23440094 TI - [Implementation of a structured healthy lifestyle program to reduce cardiometabolic risk]. AB - The objective this study was to describe the methodology and implementation of lifestyle change program in individuals at cardiometabolic risk seen at the public health system in Sao Paulo. The Programa de Prevencao de Diabetes Mellitus (PDM) aims at improving the overall metabolic profile of individuals with prediabetes or metabolic syndrome without diabetes; its goals were > 5% weight loss, dietary fiber intake > 20 g per day, saturated fatty acids intake < 10% per day, and > 150 minutes of physical activity per week. The first edition of the PDM lasted 18 months and involved an interdisciplinary team (endocrinologist, psychologist, nutritionist, and physical educator) to plan and conduct group sessions with the participants. The structure and systematic of the sessions were planned using a psychoeducative approach in order to facilitate the process of lifestyle changes. Based on the Experience with the PDM, some reflections and recommendations are made. This study may indicate ways for health professionals to tailor local care conditions and promote a healthy lifestyle, working with a new perspective. PMID- 23440095 TI - Cigarette smoke exposure severely reduces peripheral insulin sensitivity without changing GLUT4 expression in oxidative muscle of Wistar rats. AB - OBJECTIVE: To evaluate the effect of exposure to cigarette smoke and running training on a treadmill on the expression of glucose transporter GLUT4 in oxidative soleus muscle of rats. MATERIALS AND METHODS: Wistar rats were divided into: (C) control, (E) exercise control, (SS), sedentary smoker, and (ES) exercise smoker. Insulin Tolerance Test, Western blotting, and RT-PCR were performed for the evaluation of GLUT4 levels. RESULTS: The SS group presented lower insulin sensitivity with reduced GLUT4 protein in the plasma membrane (PM), no changes in the microsomal fraction, but increased mRNA content. Training reversed this condition. No intervention altered total GLUT4 content of the oxidative muscle. CONCLUSION: These results suggest that passive smoking stimulates GLUT4 transcription without changing total protein content, but impairs the ability of GLUT4 translocation to the PM. On the other hand, training seems to reduce the deleterious effects, even under the influence of cigarette smoking. PMID- 23440096 TI - [Bioelectrical impedance and visceral fat: a comparison with computed tomography in adults and elderly]. AB - OBJECTIVE: To evaluate the association between electrical bioimpedance analysis (BIA) and visceral fat (VF) in adult and elderly patients. SUBJECTS AND METHODS: This was a cross-sectional study, with a sample of 191 subjects (52% women, 49% elderly) stratified by sex, age and body mass. Computerized tomography (VF area) and BIA (percentage of total body fat (%TBF-BIA), phase angle, reactance and resistance) data were generated. Statistical analysis was based on Pearson's Correlation Coefficient, Anova, Pearson's Chi-square, and ROC curves. RESULTS: VF areas > 130 cm2 were more prevalent among the elderly and among men. Adult females showed a stronger correlation between GV and %TBF-BIA. The other groups showed similar results and statistically significant correlations. Correlations between GV and phase angle were weak and not statistically significant. ROC Curves analyzes showed the following %TBF-BIA, which identified excess VF: for male subjects: 21.5% (adults) and 24.25% (elderly); for female subjects: 35.05% (adults) and 38.45% (elderly) with sensitivity of 78.6%, 82.1%, 83.3%, and 66.7%, and specificity of 70.6%, 62.5%, 79.1%, and 69%, respectively. CONCLUSION: BIA was found to have satisfactory sensitivity and specificity to predict VF; however, other devices and other techniques should be investigated to improve VF prediction. PMID- 23440097 TI - [Prevalence of dyslipidemia in middle-aged adults with NOS3 gene polymorphism and low cardiorespiratory fitness]. AB - OBJECTIVE: To evaluate the influence of the interaction between endothelial nitric oxide synthase gene (NOS3) polymorphisms at positions -786T>C, Glu298Asp and intron 4b/a, and cardiorespiratory fitness on plasma nitrite/nitrate levels, blood pressure, lipid profile, and prevalence of cardiometabolic disorders. SUBJECTS AND METHODS: Ninety-two volunteers were genotyped for NOS3 polymorphisms at positions (-786T>C and Glu298Asp) and (intron 4b/a) and divided according to the genotype: non-polymorphic (NP) and polymorphic (P). After that, they were subdivided according to the cardiorespiratory fitness associated with genotype: high (HNP and HP) and low (LNP and LP). RESULTS: The subjects with polymorphism for the interactions at positions Glu298Asp + intron 4b/a, and Glu298Asp+-786T>C showed the highest values in total cholesterol, as well as dyslipidemia. CONCLUSION: Our findings show that NOS3 gene polymorphisms at positions -786T>C, Glu298Asp, and intron 4b/a exert negative effects on the lipid profile compared with those who do not carry polymorphisms. PMID- 23440098 TI - Associations among physical activity, comorbidities, depressive symptoms and health-related quality of life in type 2 diabetes. AB - OBJECTIVE: To investigate associations between physical activity, comorbidity severity, depressive symptoms, and health-related quality of life in type 2 diabetes mellitus. SUBJECTS AND METHODS: All individuals, 200 patients and 50 controls, aged from 40 to 60 years, were investigated by interview, and all variables were measured concurrently. Physical activity was evaluated by the International Physical Activity Questionnaire (IPAQ), Health-Related Quality of Life (HRQL) by the Short-Form Health Survey (SF-36), comorbidity severity by the Charlson Comorbidity Index (CCI), and depressive symptoms by the Beck Depression Inventory (BDI-II > 16). Single and multiple regression analysis evaluated the effects of independent variables on physical activity. RESULTS: The patients had more depressive symptoms and greater comorbidity severity (p < 0.005). Diabetic patients showed better activity levels (IPAQ) (p < 0.005). Functional Capacity, General State of Health, and Physical Limitation were the most affected subscales in the SF-36 evaluation of the HRQL. Sedentary diabetic patients had higher waist circumference, waist-to-hip ratios, more depressive symptoms, and worse HRQL. Functional capacity (p = 0.000), followed by General State of Health (p = 0.02), were the health status measure subscales independently associated with physical activity. CONCLUSIONS: The findings suggest that increasing patient independence and treating depressive symptoms can promote physical activity for type 2 diabetes mellitus patients. It is suggested that group activities and caregivers/family support might compensate for the patient dependence, and increase adherence to exercise programs in those that are less active. PMID- 23440099 TI - [Emerging comorbidities in Graves' disease patients treated with radioiodine with more than 10 years of follow-up]. AB - OBJECTIVES: To evaluate the occurrence of cardiovascular disease and malignant tumors and the mortality rate in patients who received radioiodine treatment for hyperthyroidism due to Grave's disease with at least ten years of follow-up. MATERIALS AND METHODS: The medical records of all patients who were treated with I131 for Graves' disease at Hospital Universitario Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, were reviewed retrospectively, between January, 1981 and November, 1999. RESULTS: Data from 107 patients (14 men and 93 women), with median age of 54 years were analyzed. Comparing the group of patients who were treated with I131 therapy with a group of euthyroid patients post-treatment with antithyroid drugs, a significant increase in the occurrence of hypertension and dyslipidemia was observed, but not in mortality rate. CONCLUSION: To evaluate the real influence of the treatment with radioactive iodine in the occurrence of these comorbidities and the mortality rate, we need a longer follow-up. The age and time of exposure to the effects of hyperthyroidism seem to influence the occurrence of these comorbidities. PMID- 23440100 TI - [Evaluation of TSH cutoff value in blood-spot samples in neonatal screening for the diagnosis of congenital hypothyroidism in the Programa "Primeiros Passos" - IEDE/RJ]. AB - OBJECTIVE: To analyze the confirmed or not-confirmed cases of neonatal screening (CH) screened in the Programa "Primeiros Passos", stratifying them into TSH blood spot (TSH-BS) ranges. MATERIALS AND METHODS: To stratify, in ranges of TSH-BS as a function of TSH serum (TSH-S), the cases called for a confirmatory test from January, 2006 to July, 2009. RESULTS: Around 37% of the confirmed cases (475) showed TSH-F > 9.5 mUi/L, but most of the confirmed cases were in lower TSH-F ranges. Among the unconfirmed cases (4,613), most were found in the lower ranges. There was no TSH-F range exclusive to unconfirmed cases. CONCLUSION: TSH-BS cutoff value used is crucial in the diagnosis of CH and should be low, even if more confirmatory tests are performed. More studies are needed to determine the best cutoff value of TSH-BS for neonatal screening. PMID- 23440101 TI - [Triiodothyronine does not increase osteogenic differentiation reduced by age in bone marrow mesenchymal stem cells of female rats]. AB - OBJECTIVE: To examine if triiodothyronine (T3) increases osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs) of adult rats compared with young rats. MATERIALS AND METHODS: BMMSCs were cultured in osteogenic medium and distributed into six groups: 1) BMMSCs of young rats; 2) BMMSCs of adult rats; 3, 4, 5 and 6) BMMSCs of adult rats with T3 (0.01, 1, 100 to 1000 nM). We analyzed alkaline phosphatase activity, dimethylthiazol (MTT) conversion, and collagen synthesis at 7, 14, and 21 days, and percentage of cells per field and number of mineralized nodules at 21 days of differentiation. RESULTS: T3 reduced MTT conversion, alkaline phosphatase activity, collagen synthesis, and the synthesis of mineralizalized nodules in at least one of the doses and periods studied (p < 0.05). Values were lower when compared with young and adult rats BMMSCs (p < 0.05) without T3. CONCLUSION: T3 has a negative effect on the factors involved in osteogenic differentiation of BMMSC from adult rats. PMID- 23440102 TI - [Thyroid dysfunction and amiodarone]. AB - Although most patients remain clinically euthyroid, some develop amiodarone induced hyperthyroidism (HPEAI) or hypothyroidism (HPOAI). The authors present a retrospective analysis of ten patients with amiodarone-induced thyroid dysfunction. Six patients were female and mean amiodarone intake was 17.7 months. HPOIA was more common (six patients). From all the patients with HPEAI, two had type 2, one had type 1, and one had type 3 hyperthyroidism. Symptoms suggestive of thyroid dysfunction occurred in five patients, most of them with HPOAI. In HPEAI, the most frequent symptom was exacerbation of arrhythmia (three patients). Discontinuation of amiodarone and treatment with levothyroxine was chosen in 83.3% of the HPOAI cases, while thyonamide treatment with corticosteroids and without amiodarone was the option in 75% of the HPEAI cases. There were three deaths, all in patients with HPEAI. HPEAI is potentially fatal. The clinical picture may be vague, so the thyroid monitoring is mandatory. PMID- 23440103 TI - Parathyroid carcinoma and hungry bone syndrome. AB - We hereby report two patients with parathyroid carcinoma presenting extremely high calcium and PTH levels, severe bone disease, and palpable neck mass at diagnosis. They both underwent parathyroidectomy, and one of them evolved to lung metastasis. Important hypocalcemia was observed after surgery in both: after parathyroidectomy in one patient, and only after surgical removal of the metastasis in the other. Both required intravenous calcium replacement, thus revealing hungry bone syndrome (HBS). HBS usually reflects rapid mineralization after correction of hyperparathyroidism. The more severe the bone disease before surgery, the more prone the patient is to HBS after surgery. Despite being an unfavorable outcome, HBS state suggests that surgical removal of hypersecretory parathyroid tissue was accomplished. In this study, HBS was observed in both patients, who presented severe bone disease prior to surgery. HBS would be expected post-operatively in successful parathyroid carcinoma removal. PMID- 23440104 TI - Can Metabolic Factors be used Prognostically for Short-Term Mortality in HIV Infected Patients? AB - BACKGROUND: Metabolic abnormalities are common throughout the course of human immunodeficiency virus (HIV) infection and may occur either due to HIV infection or as a result of side effects of antiretroviral therapy. It has been established that dyslipidemia and dysglycemia associated with HIV disease reduce the long term survival of the patients, but their role for predicting prognosis of short term mortality in HIV patients is unknown. AIM: To study dyslipidemia and dysglycemia as a prognostic indicator for short-term mortality (<3 months) in HIV patients. SUBJECTS AND METHODS: An observational, prospective study was conducted at a tertiary care center over a period of 6 months. Consecutive HIV-positive patients hospitalized (both, HIV status known prior to hospitalization and the diagnosis made for the first time at admission) in medical wards from March to May 2010 were studied. All patients had their random blood sugars, fasting blood sugars (if possible), fasting lipid profile, and cluster of differentiation 4 (CD4) counts tested at the time of enrollment. The patients were followed for a period of 3 months, at the end of which they were categorized as survivors and non-survivors, and the demographic, clinical, and investigational parameters were compared between the above groups. Data was analyzed by applying Mann-Whitney U test, two sample t-test, Fisher-Exact test, and stepwise logistic regression analysis of significance, using the computer-based program, Stata, version 11.1. RESULTS: A total of 82 patients were enrolled for the study of which 64 (78.05%) were males and 18 (21.95%) were females, with a mean (SD) age of 34.00 (7.0) years. The mean CD4 count was 206.23 (129.5) cells/mm(3). The overall mortality within 3 months was 20.7% (17/82). Mycobacterium tuberculosis as opportunistic infection was found in 42 patients, out of which 13 expired (P=0.02). Patients with low high-density lipoprotein (HDL) and hypertriglyceridemia (adjusted OR = 22.92, P value = 0.03, adjusted OR = 3.4, P value = 0.02, respectively) had high likelihood of mortality within 3 months. CONCLUSIONS: Low HDL and hypertriglyceridemia also appear to be promising short-term mortality markers in HIV patients apart from established factors like low CD4 counts, co-morbid conditions, and opportunistic infections like M. tuberculosis infection. This study warrants further studies with a larger sample size to establish HDL and triglyceride as markers of disease progression and short-term mortality in HIV infection. PMID- 23440105 TI - Association of oral glucocorticoid use with an increased risk of acute pancreatitis: a population-based nested case-control study. AB - IMPORTANCE: Oral glucocorticoid use has been suggested to cause acute pancreatitis in several case reports. However, no epidemiological study has investigated this association. OBJECTIVE: To conduct a nationwide population based case-control study to investigate the potential association between oral glucocorticoid use and acute pancreatitis. DESIGN: In this population-based case control study, all individuals aged 40 to 84 years who developed a first episode of acute pancreatitis between 2006 and 2008 in Sweden were identified. SETTING: Population-based, nationwide, register-based study. PARTICIPANTS: A total of 6161 cases with a first episode of acute pancreatitis and 61,637 controls were included in the final analyses. Cases were all patients diagnosed as having a first episode of acute pancreatitis during the study period, defined by the diagnosis code K85 in the International Statistical Classification of Diseases, 10th Revision (ICD-10). Controls were randomly selected from the source population at risk of developing acute pancreatitis. For each case, 10 controls, matched for age, sex, and calendar period, were randomly selected from the general population. Oral glucocorticoid use was assessed from the Swedish Prescribed Drug Register. Current, recent, and former users were defined as patients who collected their glucocorticoid prescription within 30, 31 to 180, and after 180 days before the index date, respectively. MAIN OUTCOME MEASURES: Unconditional logistic regression was performed to calculate the odds ratios (ORs) with 95% confidence intervals for the association between oral glucocorticoid use and acute pancreatitis. Multivariable adjustment was made for potential confounders including, among others, alcohol abuse, diabetes, and concomitant drug use. RESULTS: The study included 6161 cases of acute pancreatitis and 61,637 controls. The risk of acute pancreatitis was increased among current users of oral glucocorticoids compared with nonusers (OR, 1.53; 95% CI, 1.27-1.84). This risk was highest 4 to 14 days after drug dispensation (OR, 1.73; 95% CI, 1.31-2.28) and attenuated thereafter. There was no association between oral glucocorticoid use and acute pancreatitis immediately after drug dispensation. There was no increased risk of acute pancreatitis among recent or former users of glucocorticoids compared with nonusers. CONCLUSIONS AND RELEVANCE: Current oral glucocorticoid use is associated with an increased risk of acute pancreatitis. PMID- 23440106 TI - Further emergent evidence for the vitamin D endocrine system involvement in autoimmune rheumatic disease risk and prognosis. PMID- 23440107 TI - Studies on protozoa in ancient remains--a review. AB - Paleoparasitological research has made important contributions to the understanding of parasite evolution and ecology. Although parasitic protozoa exhibit a worldwide distribution, recovering these organisms from an archaeological context is still exceptional and relies on the availability and distribution of evidence, the ecology of infectious diseases and adequate detection techniques. Here, we present a review of the findings related to protozoa in ancient remains, with an emphasis on their geographical distribution in the past and the methodologies used for their retrieval. The development of more sensitive detection methods has increased the number of identified parasitic species, promising interesting insights from research in the future. PMID- 23440108 TI - Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors. AB - The goal of treatment of chronic hepatitis C is to achieve a sustained virological response, which is defined as exhibiting undetectable hepatitis C virus (HCV) RNA levels in serum following therapy for at least six months. However, the current treatment is only effective in 50% of patients infected with HCV genotype 1, the most prevalent genotype in Brazil. Inhibitors of the serine protease non-structural protein 3 (NS3) have therefore been developed to improve the responses of HCV-infected patients. However, the emergence of drug-resistant variants has been the major obstacle to therapeutic success. The goal of this study was to evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV from 37 patients infected with HCV genotype 1 had not been treated with protease inhibitors. Plasma viral RNA was used to amplify and sequence the HCV NS3 gene. The results indicate that the catalytic triad is conserved. A large number of substitutions were observed in codons 153, 40 and 91; the resistant variants T54A, T54S, V55A, R155K and A156T were also detected. This study shows that resistance mutations and genetic polymorphisms are present in the NS3 region of HCV in patients who have not been treated with protease inhibitors, data that are important in determining the efficiency of this new class of drugs in Brazil. PMID- 23440109 TI - Inflammation in disseminated lesions: an analysis of CD4+, CD20+, CD68+, CD31+ and vW+ cells in non-ulcerated lesions of disseminated leishmaniasis. AB - Disseminated leishmaniasis (DL) differs from other clinical forms of the disease due to the presence of many non-ulcerated lesions (papules and nodules) in non contiguous areas of the body. We describe the histopathology of DL non-ulcerated lesions and the presence of CD4-, CD20-, CD68-, CD31- and von Willebrand factor (vW)-positive cells in the inflamed area. We analysed eighteen biopsies from non ulcerated lesions and quantified the inflamed areas and the expression of CD4, CD20, CD68, CD31 and vW using Image-Pro software (Media Cybernetics). Diffuse lymphoplasmacytic perivascular infiltrates were found in dermal skin. Inflammation was observed in 3-73% of the total biopsy area and showed a significant linear correlation with the number of vW+ vessels. The most common cells were CD68+ macrophages, CD20+ B-cells and CD4+ T-cells. A significant linear correlation between CD4+ and CD20+ cells and the size of the inflamed area was also found. Our findings show chronic inflammation in all DL non-ulcerated lesions predominantly formed by macrophages, plasmacytes and T and B-cells. As the inflamed area expanded, the number of granulomas and extent of the vascular framework increased. Thus, we demonstrate that vessels may have an important role in the clinical evolution of DL lesions. PMID- 23440110 TI - Clonal multidrug-resistant Corynebacterium striatum within a nosocomial environment, Rio de Janeiro, Brazil. AB - Corynebacterium striatum is a potentially pathogenic microorganism with the ability to produce outbreaks of nosocomial infections. Here, we document a nosocomial outbreak caused by multidrug-resistant (MDR) C. striatum in Rio de Janeiro, Brazil. C. striatum identification was confirmed by 16S rRNA and rpoB gene sequencing. Fifteen C. striatum strains were isolated from adults (half of whom were 50 years of age and older). C. striatum was mostly isolated in pure culture from tracheal aspirates of patients undergoing endotracheal intubation procedures. The analysis by pulsed-field gel electrophoresis (PFGE) indicated the presence of four PFGE profiles, including two related clones of MDR strains (PFGE I and II). The data demonstrated the predominance of PFGE type I, comprising 11 MDR isolates that were mostly isolated from intensive care units and surgical wards. A potential causal link between death and MDR C. striatum (PFGE types I and II) infection was observed in five cases. PMID- 23440112 TI - Detection of replication-defective hepatitis A virus based on the correlation between real-time polymerase chain reaction and ELISA in situ results. AB - ELISA in situ can be used to titrate hepatitis A virus (HAV) particles and real time polymerase chain reaction (RT-PCR) has been shown to be a fast method to quantify the HAV genome. Precise quantification of viral concentration is necessary to distinguish between infectious and non-infectious particles. The purpose of this study was to compare cell culture and RT-PCR quantification results and determine whether HAV genome quantification can be correlated with infectivity. For this purpose, three stocks of undiluted, five-fold diluted and 10-fold diluted HAV were prepared to inoculate cells in a 96-well plate. Monolayers were then incubated for seven, 10 and 14 days and the correlation between the ELISA in situ and RT-PCR results was evaluated. At 10 days post incubation, the highest viral load was observed in all stocks of HAV via RT-PCR (10(5) copies/mL) (p = 0.0002), while ELISA revealed the highest quantity of particles after 14 days (optical density = 0.24, p < 0.001). At seven days post infection, there was a significant statistical correlation between the results of the two methods, indicating equivalents titres of particles and HAV genome during this period of infection. The results reported here indicate that the duration of growth of HAV in cell culture must be taken into account to correlate genome quantification with infectivity. PMID- 23440111 TI - Shigella in Brazilian children with acute diarrhoea: prevalence, antimicrobial resistance and virulence genes. AB - Diarrhoeal disease is still considered a major cause of morbidity and mortality among children. Among diarrhoeagenic agents, Shigella should be highlighted due to its prevalence and the severity of the associated disease. Here, we assessed Shigella prevalence, drug susceptibility and virulence factors. Faeces from 157 children with diarrhoea who sought treatment at the Children's Hospital Joao Paulo II, a reference children's hospital in Belo Horizonte, state of Minas Gerais, Brazil, were cultured and drug susceptibility of the Shigella isolates was determined by the disk diffusion technique. Shigella virulence markers were identified by polymerase chain reaction. The bacterium was recovered from 10.8% of the children (88.2% Shigella sonnei). The ipaH, iuc, sen and ial genes were detected in strains isolated from all shigellosis patients; set1A was only detected in Shigella flexneri. Additionally, patients were infected by Shigella strains of different ial, sat, sen and set1A genotypes. Compared to previous studies, we observed a marked shift in the distribution of species from S. flexneri to S. sonnei and high rates of trimethoprim/sulfamethoxazole resistance. PMID- 23440113 TI - Morphological and molecular characterisation of Heliconema hainanensis sp. nov. (Spirurina: Physalopteridae) from congers in the South China Sea, with a key to the species of Heliconema. AB - Heliconema hainanensis sp. nov. collected from Uroconger lepturus (Richardson) (Anguilliformes: Congridae), Muraenesox cinereus (Forsskal) and Congresox talabonoides (Bleeker) (Anguilliformes: Muraenesocidae) in the South China Sea was described using light and scanning electron microscopy. The new species differs from its congeners by the following morphology: pseudolabia, the number and arrangement of caudal papillae (4 pairs of pedunculate precloacal papillae arranged in 2 groups of 2 and 2 pairs and 6 pairs of pedunculate postcloacal papillae arranged in 4 groups of 1, 2, 1 and 2 pairs), the length of spicules [left spicule 0.51-0.69 mm, right spicule 0.20-0.27 mm, spicule (right:left) ratio 1:2.20-2.69] and the morphology of the female tail tip. In addition, specimens of the new species collected from the three different hosts and specimens of an unidentified species of Heliconema collected from U. lepturus were characterised using molecular methods by sequencing the internal transcribed spacer (ITS) of ribosomal DNA. Analyses and comparison of the ITS sequence of H. hainanensis sp. nov. with Heliconema sp. support the validity of the new species based on morphological observations. An identification key to the species of Heliconema is also provided. PMID- 23440115 TI - New Culicoides Latreille of the subgenus Mataemyia Vargas from Para, Brazil (Diptera: Ceratopogonidae). AB - Two new species of Culicoides Latreille of the Neotropical subgenus Mataemyia Vargas are described and illustrated based on female specimens from Juruti, Para, Brazil and compared with their similar congeners. This paper also presents a diagnosis of the subgenus Mataemyia and a systematic key for the identification of the 19 species of the subgenus. PMID- 23440114 TI - Response to treatment in Brazilian patients with chronic hepatitis C is associated with a single-nucleotide polymorphism near the interleukin-28B gene. AB - A single-nucleotide polymorphism (SNP) upstream of interleukin (IL)28B was recently identified as an important predictor of the outcome of chronic hepatitis C patients treated with pegylated interferon plus ribavirin (PEG-IFN/RBV). The aim of this study was to investigate the association between the IL28B gene polymorphism (rs12979860) and virological response in chronic hepatitis C patients. Brazilian patients (n = 263) who were infected with hepatitis C virus (HCV) genotype 1 and were receiving PEG-IFN/RBV were genotyped. Early virological response (EVR) (12 weeks), end-of-treatment response (EOTR) (48 weeks), sustained virological response (SVR) (72 weeks) and relapse were evaluated using conventional and quantitative polymerase chain reaction (PCR) assays. The frequency of the C allele in the population was 39%. Overall, 43% of patients experienced SVR. The IL28B CC genotype was significantly associated with higher treatment response rates and a lower relapse rate compared to the other genotypes [84% vs. 58% EVR, 92% vs. 63% EOTR, 76% vs. 38% SVR and 17% vs. 40% relapse rate in CC vs. other genotypes (CT and TT), respectively]. Thus, the IL28B genotype appears to be a strong predictor of SVR following PEG-IFN/RBV therapy in treatment-naive Brazilian patients infected with HCV genotype 1. This study, together with similar research examining other SNPs, should help to define adequate protocols for the treatment of patients infected with HCV genotype 1, especially those with a poor prognosis. PMID- 23440116 TI - Antileishmanial activity of diterpene acids in copaiba oil. AB - Leishmaniasis is a neglected tropical disease. According to the World Health Organization, there are approximately 1.5-two million new cases of cutaneous leishmaniasis each year worldwide. Chemotherapy against leishmaniasis is based on pentavalent antimonials, which were developed more than a century ago. The goals of this study were to investigate the antileishmanial activity of diterpene acids in copaiba oil, as well as some possible targets of their action against Leishmania amazonensis. Methyl copalate and agathic, hydroxycopalic, kaurenoic, pinifolic and polyaltic acids isolated from Copaifera officinales oleoresins were utilised. Ultrastructural changes and the specific organelle targets of diterpenes were investigated with electron microscopy and flow cytometry, respectively. All compounds had some level of activity against L. amazonensis. Hydroxycopalic acid and methyl copalate demonstrated the most activity against promastigotes and had 50% inhibitory concentration (IC50) values of 2.5 and 6.0 ug/mL, respectively. However, pinifolic and kaurenoic acid demonstrated the most activity against axenic amastigote and had IC50 values of 3.5 and 4.0 ug/mL, respectively. Agathic, kaurenoic and pinifolic acid caused significant increases in plasma membrane permeability and mitochondrial membrane depolarisation of the protozoan. In conclusion, copaiba oil and its diterpene acids should be explored for the development of new antileishmanial drugs. PMID- 23440117 TI - Extended genetic analysis of Brazilian isolates of Bacillus cereus and Bacillus thuringiensis. AB - Multiple locus sequence typing (MLST) was undertaken to extend the genetic characterization of 29 isolates of Bacillus cereus and Bacillus thuringiensis previously characterized in terms of presence/absence of sequences encoding virulence factors and via variable number tandem repeat (VNTR). Additional analysis involved polymerase chain reaction for the presence of sequences (be, cytK, inA, pag, lef, cya and cap), encoding putative virulence factors, not investigated in the earlier study. MLST analysis ascribed novel and unique sequence types to each of the isolates. A phylogenetic tree was constructed from a single sequence of 2,838 bp of concatenated loci sequences. The strains were not monophyletic by analysis of any specific housekeeping gene or virulence characteristic. No clear association in relation to source of isolation or to genotypic profile based on the presence or absence of putative virulence genes could be identified. Comparison of VNTR profiling with MLST data suggested a correlation between these two methods of genetic analysis. In common with the majority of previous studies, MLST was unable to provide clarification of the basis for pathogenicity among members of the B. cereus complex. Nevertheless, our application of MLST served to reinforce the notion that B. cereus and B. thuringiensis should be considered as the same species. PMID- 23440118 TI - Time-based distribution of Staphylococcus saprophyticus pulsed field gel electrophoresis clusters in community-acquired urinary tract infections. AB - The epidemiology of urinary tract infections (UTI) by Staphylococcus saprophyticus has not been fully characterised and strain typing methods have not been validated for this agent. To evaluate whether epidemiological relationships exist between clusters of pulsed field gel-electrophoresis (PFGE) genotypes of S. saprophyticus from community-acquired UTI, a cross-sectional surveillance study was conducted in the city of Rio de Janeiro, Brazil. In total, 32 (16%) female patients attending two walk-in clinics were culture-positive for S. saprophyticus. Five PFGE clusters were defined and evaluated against epidemiological data. The PFGE clusters were grouped in time, suggesting the existence of community point sources of S. saprophyticus. From these point sources, S. saprophyticus strains may spread among individuals. PMID- 23440119 TI - The efficiency of concentration methods used to detect enteric viruses in anaerobically digested sludge. AB - The presence of enteric viruses in biosolids can be underestimated due to the inefficient methods (mainly molecular methods) used to recover the viruses from these matrices. Therefore, the goal of this study was to evaluate the different methods used to recover adenoviruses (AdV), rotavirus species A (RVA), norovirus genogroup II (NoV GII) and the hepatitis A virus (HAV) from biosolid samples at a large urban wastewater treatment plant in Brazil after they had been treated by mesophilic anaerobic digestion. Quantitative polymerase chain reaction (PCR) was used for spiking experiments to compare the detection limits of feasible methods, such as beef extract elution and ultracentrifugation. Tests were performed to detect the inhibition levels and the bacteriophage PP7 was used as an internal control. The results showed that the inhibitors affected the efficiency of the PCR reaction and that beef extract elution is a suitable method for detecting enteric viruses, mainly AdV from biosolid samples. All of the viral groups were detected in the biosolid samples: AdV (90%), RVA, NoV GII (45%) and HAV (18%), indicating the viruses' resistance to the anaerobic treatment process. This is the first study in Brazil to detect the presence of RVA, AdV, NoV GII and HAV in anaerobically digested sludge, highlighting the importance of adequate waste management. PMID- 23440120 TI - Regulatory volume decrease in Leishmania mexicana: effect of anti-microtubule drugs. AB - The trypanosomatid cytoskeleton is responsible for the parasite's shape and it is modulated throughout the different stages of the parasite's life cycle. When parasites are exposed to media with reduced osmolarity, they initially swell, but subsequently undergo compensatory shrinking referred to as regulatory volume decrease (RVD). We studied the effects of anti-microtubule (Mt) drugs on the proliferation of Leishmania mexicana promastigotes and their capacity to undergo RVD. All of the drugs tested exerted antiproliferative effects of varying magnitudes [ansamitocin P3 (AP3)> trifluoperazine > taxol > rhizoxin > chlorpromazine]. No direct relationship was found between antiproliferative drug treatment and RVD. Similarly, Mt stability was not affected by drug treatment. Ansamitocin P3, which is effective at nanomolar concentrations, blocked amastigote-promastigote differentiation and was the only drug that impeded RVD, as measured by light dispersion. AP3 induced 2 kinetoplasts (Kt) 1 nucleus cells that had numerous flagella-associated Kts throughout the cell. These results suggest that the dramatic morphological changes induced by AP3 alter the spatial organisation and directionality of the Mts that are necessary for the parasite's hypotonic stress-induced shape change, as well as its recovery. PMID- 23440121 TI - Potential sources of Triatoma infestans reinfesting peridomiciles identified by morphological characterization in Los Llanos, La Rioja, Argentina. AB - The presence of Triatoma infestans in habitats treated with insecticides constitutes a frequent problem in endemic areas. Basing our study on the hypothesis that descendants of a residual population should be more similar to the pre-treatment population than to any other, we compared the indications of two quantitative morphological approaches. This study seeks to find the origin of 247 T. infestans from three populations found in two chicken coops and a goat corral after treatment with insecticides. The results obtained by quantitative morphology suggest that the T. infestans found between three-34 months after the application of insecticides formed mixed populations with insects derived from residual foci and neighbouring habitats. Our analyses also showed the presence of a phenotype which does not resemble neither the pre-treatment phenotype nor the one from neighbouring populations, suggesting the presence of a particular post treatment phenotype. The heads size showed some variations in males from different populations and remained unchanged in females, which reinforces the hypothesis of an intraspecific competition for food with priority for females. This article presents, for the first time, the combined analysis of geometric morphometry of heads and antennal phenotypes to identify the composition of reinfesting populations. PMID- 23440122 TI - Cross-reactive anti-PfCLAG9 antibodies in the sera of asymptomatic parasite carriers of Plasmodium vivax. AB - The PfCLAG9 has been extensively studied because their immunogenicity. Thereby, the gene product is important for therapeutics interventions and a potential vaccine candidate. Antibodies against synthetic peptides corresponding to selected sequences of the Plasmodium falciparum antigen PfCLAG9 were found in sera of falciparum malaria patients from Rondonia, in the Brazilian Amazon. Much higher antibody titres were found in semi-immune and immune asymptomatic parasite carriers than in subjects suffering clinical infections, corroborating original findings in Papua Guinea. However, sera of Plasmodium vivax patients from the same Amazon area, in particular from asymptomatic vivax parasite carriers, reacted strongly with the same peptides. Bioinformatic analyses revealed regions of similarity between P. falciparum Pfclag9 and the P. vivax ortholog Pvclag7. Indirect fluorescent microscopy analysis showed that antibodies against PfCLAG9 peptides elicited in BALB/c mice react with human red blood cells (RBCs) infected with both P. falciparum and P. vivax parasites. The patterns of reactivity on the surface of the parasitised RBCs are very similar. The present observations support previous findings that PfCLAG9 may be a target of protective immune responses and raises the possibility that the cross reactive antibodies to PvCLAG7 in mixed infections play a role in regulate the fate of Plasmodium mixed infections. PMID- 23440123 TI - Plasmid-based controls to detect rpoB mutations in Mycobacterium tuberculosis by quantitative polymerase chain reaction-high-resolution melting. AB - Quantitative polymerase chain reaction-high-resolution melting (qPCR-HRM) analysis was used to screen for mutations related to drug resistance in Mycobacterium tuberculosis. We detected the C526T and C531T mutations in the rifampicin resistance-determining region (RRDR) of the rpoB gene with qPCR-HRM using plasmid-based controls. A segment of the RRDR region from M. tuberculosis H37Rv and from strains carrying C531T or C526T mutations in the rpoB were cloned into pGEM-T vector and these vectors were used as controls in the qPCR-HRM analysis of 54 M. tuberculosis strains. The results were confirmed by DNA sequencing and showed that recombinant plasmids can replace genomic DNA as controls in the qPCR-HRM assay. Plasmids can be handled outside of biosafety level 3 facilities, reducing the risk of contamination and the cost of the assay. Plasmids have a high stability, are normally maintained in Escherichia coli and can be extracted in large amounts. PMID- 23440124 TI - IL-10 release by bovine epithelial cells cultured with Trichomonas vaginalis and Tritrichomonas foetus. AB - Trichomonas vaginalis and Tritrichomonas foetus are parasitic protists of the human and bovine urogenital tracts, respectively. Several studies have described the cytotoxic effects of trichomonads on urogenital tract epithelial cells. However, little is known about the host cell response against trichomonads. The aim of this study was to determine whether T. foetus and T. vaginalis stimulated the release of the cytokine interleukin (IL)-10 from cultured bovine epithelial cells. To characterise the inflammatory response induced by these parasites, primary cultures of bovine oviduct epithelial cells were exposed to either T. vaginalis or T. foetus. Within 12 h after parasite challenge, supernatants were collected and cytokine production was analysed. Large amounts of IL-10 were detected in the supernatants of cultures that had been stimulated with T. foetus. Interestingly, T. vaginalis induced only a small increase in the release of IL-10 upon exposure to the same bovine cells. Thus, the inflammatory response of the host cell is species-specific. Only T. foetus and not T. vaginalis induced the release of IL-10 by bovine oviduct epithelial cells. PMID- 23440125 TI - Outbreak of carbapenem-resistant Klebsiella pneumoniae: two-year epidemiologic follow-up in a tertiary hospital. AB - This study describes a carbapenem-resistant Klebsiella pneumoniae (CRKP) outbreak that occurred from October 2008-December 2010. Polymerase chain reaction assays were performed to detect the blaKPC gene and molecular typing was performed using pulsed-field gel electrophoresis (PFGE). There were 33 CRKP infections; PFGE revealed five genotypes: genotype A in five (15%), B in 18 (55%), C in eight (24%) and two unique profiles. Genotype B was disseminated in all hospital units and belonged to the same clone identified in 11 different hospitals in the state of Sao Paulo. Sixteen (48%) patients died. Seven isolates (21%) were resistant to polymyxin B and 45% were resistant to tigecycline and amikacin. PMID- 23440126 TI - Molecular diagnosis of eosinophilic meningitis due to Angiostrongylus cantonensis (Nematoda: Metastrongyloidea) by polymerase chain reaction-DNA sequencing of cerebrospinal fluids of patients. AB - Cerebrospinal fluid (CSF) samples from clinically diagnosed patients with detectable Angiostrongylus cantonensis-specific antibodies (n = 10), patients with clinically suspected cases that tested negative for A. cantonensis antibodies (n = 5) and patients with cerebral gnathostomiasis (n = 2) and neurocysticercosis (n = 2) were examined by a single-step polymerase chain reaction (PCR) method using the AC primers for the 66-kDa native protein gene. The PCR method detected A. cantonensis DNA in CSF samples from four of 10 serologically confirmed angiostrongyliasis cases. The PCR results were negative for the remaining CSF samples. The nucleotide sequences of three positive CSF-PCR samples shared 98.8-99.2% similarity with the reference sequence of A. cantonensis. These results indicate the potential application of this PCR assay with clinical CSF samples for additional support in the confirmation of eosinophilic meningitis due to A. cantonensis. PMID- 23440127 TI - A survey strategy for human respiratory syncytial virus detection among haematopoietic stem cell transplant patients: epidemiological and methodological analysis. AB - Human respiratory syncytial virus (HRSV) causes severe infections among children and immunocompromised patients. We compared HRSV infections among Haematopoietic Stem Cell Transplant program (HSCT) patients and children using direct immunofluorescence (DFA), point-of-care RSV Bio Easy(r) and a polymerase chain reaction (PCR) assay. Overall, 102 samples from HSCT patients and 128 from children obtained positivity rate of 18.6% and 14.1% respectively. PCR sensitivity was highest mainly on samples collected after five days of symptoms onset. A combination of both DFA and reverse transcriptase-PCR methods for HSCT high-risk patients is the best diagnostic flow for HRSV diagnosis among these patients. PMID- 23440128 TI - Molecular identification of Rickettsia parkeri infecting Amblyomma triste ticks in an area of Argentina where cases of rickettsiosis were diagnosed. AB - Specimens of the hard tick Amblyomma triste were found infected with Rickettsia parkeri in an area of Argentina (General Lavalle, Buenos Aires Province) where cases of human illness attributed to this microorganism have been reported. Molecular detection of R. parkeri was based on polymerase chain reactions that amplify a ca. 400-bp fragment of the 23S-5S intergenic spacer and a ca. 500-bp fragment of the gene encoding a 190-kDa outer membrane protein. Three (6.97%) of 43 A. triste ticks were determined to be positive for R. parkeri. These results provide strong evidence that A. triste is the vector of R. parkeri in the study area. The findings of this work have epidemiological relevance because human parasitism by A. triste ticks has been frequently recorded in some riparian areas of Argentina and Uruguay and new cases of R. parkeri rickettsiosis might arise in the South American localities where humans are exposed to the bites of this tick species. PMID- 23440129 TI - Techniques for the detection of pathogenic Cryptococcus species in wood decay substrata and the evaluation of viability in stored samples. AB - In this study, we evaluated several techniques for the detection of the yeast form of Cryptococcus in decaying wood and measured the viability of these fungi in environmental samples stored in the laboratory. Samples were collected from a tree known to be positive for Cryptococcus and were each inoculated on 10 Niger seed agar (NSA) plates. The conventional technique (CT) yielded a greater number of positive samples and indicated a higher fungal density [in colony forming units per gram of wood (CFU x g(-1))] compared to the humid swab technique (ST). However, the difference in positive and false negative results between the CT-ST was not significant. The threshold of detection for the CT was 0.05.103 CFU x g( 1), while the threshold for the ST was greater than 0.1.103 CFU(-1). No colonies were recovered using the dry swab technique. We also determined the viability of Cryptococcus in wood samples stored for 45 days at 25oC using the CT and ST and found that samples not only continued to yield a positive response, but also exhibited an increase in CFU x g(-1), suggesting that Cryptococcus is able to grow in stored environmental samples. The ST.1, in which samples collected with swabs were immediately plated on NSA medium, was more efficient and less laborious than either the CT or ST and required approximately 10 min to perform; however, additional studies are needed to validate this technique. PMID- 23440130 TI - Retraction. PMID- 23440131 TI - Reassurance after diagnostic testing with a low pretest probability of serious disease: systematic review and meta-analysis. AB - IMPORTANCE: Diagnostic tests are often ordered by physicians in patients with a low pretest probability of disease to rule out conditions and reassure the patient. OBJECTIVE: To study the effect of diagnostic tests on worry about illness, anxiety, symptom persistence, and subsequent use of health care resources in patients with a low pretest probability of serious illness. EVIDENCE ACQUISITION: Systematic review and meta-analysis. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, PsychINFO, CINAHL, and ProQuest Dissertations electronic databases through December 31, 2011, for eligible randomized controlled trials. We independently identified studies for inclusion and extracted the data. Disagreements were resolved by discussion. We performed meta-analysis if heterogeneity was low or moderate (I2 < 50%). RESULTS: Fourteen randomized controlled trials that included 3828 patients met the inclusion criteria and were analyzed with outcomes categorized as short term (<=3 months) or long term (>3 months). Three trials showed no overall effect of diagnostic tests on illness worry (odds ratio, 0.87 [95% CI, 0.55-1.39]), and 2 showed no effect on nonspecific anxiety (standardized mean difference, 0.06 [ 0.16 to 0.28]). Ten trials showed no overall long-term effect on symptom persistence (odds ratio, 0.99 [95% CI, 0.85-1.15]). Eleven trials measured subsequent primary care visits. We observed a high level of heterogeneity among trials (I2 = 80%). Meta-analysis after exclusion of outliers suggested a small reduction in visits after investigation (odds ratio, 0.77 [95% CI, 0.62-0.96]). CONCLUSIONS AND RELEVANCE: Diagnostic tests for symptoms with a low risk of serious illness do little to reassure patients, decrease their anxiety, or resolve their symptoms, although the tests may reduce further primary care visits. Further research is needed to maximize reassurance from medically necessary tests and to develop safe strategies for managing patients without testing when an abnormal result is unlikely. PMID- 23440132 TI - Two days and two very special visits at RAMB headquarters. PMID- 23440133 TI - Alternative for pre-anesthetic sedation and for surgical procedures in children: use of intranasal midazolam. PMID- 23440134 TI - Burning sensation and rupture of a totally implantable venous catheter. PMID- 23440135 TI - Anaphylaxis: diagnosis. PMID- 23440137 TI - Trends in prostate cancer incidence and mortality in a mid-sized Northeastern Brazilian city. AB - OBJECTIVE: International data have reported prostate cancer as the most frequent among men, and the third highest in mortality. A rise in incidence has been observed in the course of recent decades, probably influenced by early detection, mainly in asymptomatic men, through regular screening with prostate-specific antigen (PSA) testing. The purpose of this study was to contribute to information on trends in prostate cancer incidence and mortality using population-based data. METHODS: This was an exploratory ecological study of time trends, aiming at describing changes in prostate cancer incidence and mortality in Aracaju, Sergipe, Brazil, from 1996 to 2006. Rates were calculated from data of the Registro de Cancer de Base Populacional de Aracaju. Trends were calculated using the Joinpoint Regression Program. RESULTS: For the study period, 1,490 incident cases and 334 deaths were included. Incident cases were more common after 50 years of age, and deaths after 55 years. Age-standardized incidence rates of 46.6 and 50.0/100,000 were observed in the early years of the series, and then progressively increased, with rates higher than 100.0/100,000 in later years. For mortality, age-standardized rates varied from 21.6 and 16.6/100,000 to 24.1 and 28.9/100,000 in later years. Joinpoint analysis identified one joinpoint for the incidence series, resulting in two trends, the first with annual percent change of 34% and the second with 5.8%; for the mortality series no joinpoint was identified, and the annual percent change was 2.1%. CONCLUSION: There was a sharp increase in incidence rates during the study period, probably due to screening. Mortality rates had a small upward trend, and did not show major changes during the study period. PMID- 23440138 TI - Cystatin C, kidney function, and cardiovascular risk factors in primary hypertension. AB - OBJECTIVE: To investigate the clinical usefulness of serum cystatin C (Scys) and cystatin C-based equations for the screening of chronic kidney disease in primary hypertensive patients, and correlate these markers with risk factors for cardiovascular disease. METHODS: A cross-sectional study was performed in 199 middle-aged adults at a basic health unit. Kidney function assessment included measurements of serum creatinine (Scr) and Scys levels, 24-hour microalbuminuria (MA), as well as glomerular filtration rate (GFR) through Larsson and Modification of Diet in Renal Disease (MDRD) study equations. Bland- Altman plot analysis was used to calculate the agreement between equations. RESULTS: High levels of Scys were found in 22% of the patients, even with normal values of GFR estimated by MDRD study equation. Systolic blood pressure and MA correlated better with Scys than Scr, but there was no correlation between Scys and diastolic blood pressure. Gender, age > 60 years, MA, and uric acid were significantly associated with high Scys levels. After multivariate analysis, only age > 60 yrs (RR = 6.4; p < 0.001) and male gender (RR = 3.0; p = 0.006) remained associated with high Scys levels. CONCLUSION: Cystatin C can be used as a screening marker both for detecting mild declines of renal function and for preventing the risk of cardiovascular events in hypertensive subjects with presumably normal renal function. PMID- 23440139 TI - Clinical and obstetrical management of pregnant women with autoimmune hepatitis complicated by moderate or severe thrombocytopenia. AB - OBJECTIVE: To describe the management of prenatal care and delivery in patients bearing autoimmune hepatitis associated with moderate or severe thrombocytopenia. METHODS: This study was performed in a tertiary level university hospital. Thirteen pregnancies in ten patients diagnosed with autoimmune hepatitis, complicated by thrombocytopenia, were retrospectively analyzed. The inclusion criteria were as follows: clinical diagnosis of autoimmune hepatitis, moderate or severe thrombocytopenia (platelet count < 100 x 103/mm3), gestational age at birth over 22 weeks, and patient followed-up by a specialized team at the institution. The variables studied were: maternal age, parity, treatment regimen, platelet count, examinations for investigation of hepatic function, type of delivery, weight at birth, and gestational age at the time of delivery. RESULTS: The average maternal age was 24.5 years (SD = 5.3) and six (50%) occurred in nulliparous women. During pregnancy, monotherapy with prednisone was adopted in 11 cases (92%). According to the autoantibody profiles, seven pregnancies (58%) had the autoimmune hepatitis type I diagnosis, two pregnancies had type II (17%), and three pregnancies (25%) had cryptogenic chronic hepatitis (undetectable titers of autoantibodies). Portal hypertension was featured in 11 pregnancies (92%). The average gestational age at delivery was 36.9 weeks (SD = 1.5 weeks), with an average weight at birth of 2,446 g (SD = 655 g). Eight infants (67%) were small for gestational age. At the time of delivery, severe thrombocytopenia was featured in four cases (33%) and cesarean surgery was performed in seven cases (58%). Complications at delivery occurred in three cases (25%), one patient presented uterine atony, and two patients presented perineal bruising. There was no perinatal or maternal death. CONCLUSION: The complications of thrombocytopenic patients with autoimmune hepatitis are elevated; nevertheless, with appropriate attention and care, they can be resolved. The association between two severe pathologies appears to increase the risk of prematurity and fetal growth restriction, demanding specialized prenatal care, as well as surveillance of newborn well-being. PMID- 23440140 TI - Congenital pancreas malformations: a clinical case report. AB - OBJECTIVE: This study aimed to review the congenital malformation known as agenesis of the dorsal pancreas (ADP) and other pancreatic birth defects, based on a rare and exemplary clinical case of pancreatic malformations. The intent was to review the latest information published in the national and international literature on pancreatic birth defects, and to investigate the diversity of clinical presentations of ADP and other congenital pancreas abnormalities. The purpose was to identify which situations have therapeutic indication, the most appropriate time to institute treatment, and the currently available medical or surgical treatment of pancreatic congenital malformations. RESULTS: ADP is a very rare malformation that occurs during organogenesis. In the last decades, a large volume of embryological and genetic information has been obtained, helping to understand the causes of pancreatic malformations, which must be studied and understood as a whole. CONCLUSION: Pancreatic malformations are infrequently studied causes of acute and chronic pancreatic in adults. The possibility of pancreatic malformations should always be considered in patients with acute or chronic pancreatitis with no evident cause. PMID- 23440141 TI - Nutritional status in the oldest elderly and associated factors. AB - OBJECTIVE: To verify factors associated with nutritional status in an oldest elderly communitydwelling population in Southern Brazil. METHODS: This cross sectional epidemiological and household-based study involved all subjects (n = 134) aged > 80 years who were living in Antonio Carlos (Santa Catarina state, Brazil). Nutritional status was assessed by body mass index (BMI < 22.0 kg/m2, underweight; BMI > 27.0 kg/m2, overweight). Explanatory variables in the study were: gender (women/ men), literacy (knows how to write and read - yes/no), living conditions (lives alone/with company), cognitive function (normal/altered), eating difficulty (yes/no), medication use (none to two/three or more), morbidity (none to two/three or more diseases), alimentary pattern (adequate/inadequate), alcohol consumption (none to one day a week, two or more days a week), cigarette smoking (never/current or former smoker), physical activity level (< 150 min/week; > 150 min/week), and sitting time (< 4 hours/day; > 4 hours but < 6 hours/ day; > 6 hours/day). RESULTS: Prevalence of underweight was 27.3% in men and 12.8% in women (p < 0.01), and was positively associated with altered cognitive function (OR: 3.52) and inversely related with greater medication use (OR: 0.34). Overweight affected 25.5% of men and 53.8% of women. It was negatively associated with illiteracy (OR: 0.12) and positively associated with female gender (OR: 2.58). CONCLUSION: There are differences between men and women regarding nutritional status. The factors associated to nutritional status of the oldest elderly from Antonio Carlos are specific to the vulnerability condition (underweight and overweight). PMID- 23440142 TI - Correlation between indicators of abdominal obesity and serum lipids in the elderly. AB - OBJECTIVE: To verify the correlation between anthropometric indicators of abdominal obesity and serum lipids in the elderly. METHODS: Cross-sectional, descriptive, and analytical study conducted with elderly individuals of both genders enrolled in the Family Health Strategy Program of Campina Grande, PB, Brazil. Abdominal obesity was assessed by waist circumference (WC), abdominal circumference (AC), and waist/hip ratio (WHR). Lipid profile was verified by levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and non-high density lipoprotein (non-HDL). RESULTS: A total of 321 elderly patients were evaluated (67.6% women). There were significant correlations between abdominal obesity indicators and lipid levels only in the group of women. WC, AC, and WHR correlated with TG and HDL. Only WHR showed correlation with non-HDL. The highest correlations were observed between WHR and TG (r = 0.292, p < 0.01) and between WC and HDL (r = -0.281, p < 0.01). WC was a predictor of 9.2% of the variation in HDL, and WHR was a predictor of 7.3% of the variation in TG. CONCLUSION: The indicators of abdominal obesity that best correlated with serum lipids in elderly women were WC and WHR. They were predictors of alterations in HDL and TG levels in women, respectively. PMID- 23440143 TI - Effects of physical exercises and nutritional guidance on the cardiovascular risk profile of obese children. AB - OBJECTIVE: To analyze the effects of a supervised physical exercise and nutritional guidance program, conducted with a playful basis, on the cardiovascular risk profile of obese children. METHODS: Forty-four children aged between 8 and 11 years, divided into two groups, were paired by gender and age: intervention group (n = 22) and control group (n = 22). The following parameters were measured before and after the intervention: body mass, height, waist circumference, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, fasting glucose, high-sensitive C-reactive protein, blood pressure, and carotid intima-media thickness. Both groups continued their traditional medical treatment. The case group exercised with recreational activities three times a week during 12 weeks, and participated in a weekly nutritional guidance session. The control group did not participate in the intervention described. Descriptive statistics, paired and unpaired Student's t test, Mann-Whitney's U test, and the Wilcoxon test were used, with a significance level of p < 0.05. RESULTS: 32 children concluded the study (16 in each group). At the end of the study, the case group showed a significant reduction in the body mass index (BMI) (p = 0.001), total cholesterol (p = 0.001), LDL cholesterol (p = 0.001), diastolic blood pressure (p = 0.010), and average (p = 0.003) and maximum (p = 0.002) carotid intima-media thickness. The control group showed a significant increase in waist circumference (p = 0.001), blood glucose (p = 0.025), C-reactive protein (p = 0.016), a reduction of HDL cholesterol (p = 0.012) and total cholesterol (p = 0.042), and an increase in the average (p = 0.012) and maximum (p = 0.024) carotid intima-media thickness. CONCLUSION: The program proved effective in the reduction of obesity indicators and of the intima media thickness, a direct and early signal of atherosclerosis. PMID- 23440144 TI - Metabolic syndrome in obese adolescents: what is enough? AB - OBJECTIVE: To study the agreement among three distinct criteria for metabolic syndrome (MS) adapted to adolescents, and to identify associated factors for MS. METHODS: Cross-sectional study with 65 obese subjects aged 10 to 18 years, attended to at the Outpatient Clinic for Obese Children and Adolescents at the Clinical Hospital of the Universidade Estadual de Campinas (Unicamp). MS was defined using the criteria of the World Health Organization (WHO), the International Diabetes Federation (IDF), and the Adult Treatment Panel III (ATP III). Clinical, anthropometrical, and laboratorial data were associated to MS. RESULTS: From the 65 subjects, none had MS according to the WHO criteria, while 18 were diagnosed with MS (27.6%) according to the IDF, and 19 (29.2%) according to the ATP III. Agreement between IDF and ATP III was excellent (kappa 81%). In this study, puberty and triglycerides levels showed significant statistical difference when comparing subjects with and without MS, the first for ATP III (p = 0.03), and the second for IDF (p = 0.005) and ATP III (p = 0.001) criteria. CONCLUSION: The WHO criteria does not seem to be adequate for adolescents. IDF and ATP III criteria had an excellent agreement. Puberty and triglycerides were associated with MS. PMID- 23440145 TI - Brazilian guidelines for biorepositories and biobanks of human biological material. AB - OBJECTIVE: To characterize the participatory and democratic creation of the Brazilian guidelines for biorepositories and biobanks of human biological material with the purpose of research based on the ethical principles of human dignity, autonomy, beneficence, justice, and precaution. METHODS: An interdisciplinary work group was constituted to prepare the document, considering the following criteria: experience in biobank operation, regional representation, type of stored biological material, and bioethics specialists. Members of the National Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA), also participated due to their regulatory competence. Members from the National Commission on Ethics in Research (Comissao Nacional de Etica em Pesquisa - Conep) participated as the social control organization. RESULTS: The document, based on ethical, legal, and technical guidelines, presents the concepts, activities, purposes, and differences between biorepositories and biobanks; forms of consent on the part of the subject; in addition to other aspects permeated by concerns regarding the appropriate use of information. The Brazilian guidelines for biorepository and biobank of human biological material with the purpose of research contains 39 articles, which are distributed in five chapters. CONCLUSION: The importance of legislation arises from the ethical concern, considering morals and taking into account the legal aspects, which translate into a document that does not end in itself. The dynamics of science always leads to changes in paradigms, which can go beyond the existing laws. PMID- 23440146 TI - Update on viral community-acquired pneumonia. AB - Viral pneumonia is a prevalent cause of respiratory infection in immunocompetent adults. It has varied presentation, from mild to severe respiratory failure, requiring mechanical ventilation. However, in Brazil, there have been few studies on the clinical presentation and diagnosis of this infection. Thus, the authors of the present article intend to review the main viral agents that cause community-acquired pneumonia and to discuss the currently available diagnostic and therapeutic methods. PMID- 23440147 TI - C-reactive protein: clinical applications and proposals for a rational use. AB - C-reactive protein (CRP) is an acute-phase protein whose requests have been growing exponentially in several countries, including Brazil. In this study, the use of CRP in several clinical situations was reviewed by a group of physicians comprised by specialists in internal medicine, medical emergencies, intensive care, screening, and laboratory medicine, aiming to analyze the applicable literature and to propose guidelines for a more rational use of this laboratory test. The result was the creation of flowcharts guiding CRP request, adjusted to four different healthcare environments, namely, intensive care units, emergency room, wards, and outpatient clinics. These flowcharts, as well as a more detailed discussion on several clinical recommendations for the test, are presented in this study. PMID- 23440148 TI - Priming of NK cell anti-viral effector mechanisms by direct recognition of human cytomegalovirus. AB - Natural killer (NK) cells play an important role in the defense against viral infections. Activation of resting NK cells is tightly controlled by the balance of surface inhibitory and activating receptors and aided by cytokines released by accessory cells along the anti-viral response. On the other hand, NK cells express functional pattern recognition receptors (PRRs) whose function has been mostly addressed by the use of synthetic agonists. The present study was undertaken to investigate whether NK cells could directly recognize a complex pathogen such as Human Cytomegalovirus (HCMV). Exposure of primary human NK cells to HCMV (TB40/E strain) induced the expression of CD69, promoted IFNgamma secretion, and increased their cytotoxic activity against HCMV-infected autologous monocyte-derived dendritic cells. The divergent response induced by infective and UV-inactivated virions indicated the involvement of different NK cell sensors in the recognition of HCMV. The fact that NK cell activation could be partially prevented by blocking mAb specific for IFNAR and TLR2, together with the induction of IFNbeta mRNA, supported the involvement of IFNbeta and TLR2 in the response to HCMV. Thus, our data indicate that simultaneous activation of several PRRs leads to the autonomous priming of NK cell effector functions and could be a previously unappreciated mechanism presumably contributing to the control of HCMV infection. PMID- 23440150 TI - Pyoderma gangrenosum with an underlying ulcerative colitis associated with bone tuberculosis. AB - Pyoderma gangrenosum is a rare noninfective neutrophilic dermatosis, characterized by progressive painful ulceration. It is frequently associated with systemic disorders like inflammatory bowel disease, rheumatoid arthritis and myeloproliferative diseases. However, its association with infectious diseases in particular with tuberculosis is extremely rare. Diagnosis is based on the history of an underlying disease, a typical clinical presentation, histopathology and exclusion of other diseases leading to ulcerations of similar appearance. Immunosuppression with corticosteroids remains the mainstay of treatment. We report a case of a 49-year-old male with long-standing ulcerative colitis, associated with tuberculosis of hip, who presented with nonhealing ulcers over the lower extremity. PMID- 23440149 TI - Types and origins of diagnostic errors in primary care settings. AB - IMPORTANCE: Diagnostic errors are an understudied aspect of ambulatory patient safety. OBJECTIVES: To determine the types of diseases missed and the diagnostic processes involved in cases of confirmed diagnostic errors in primary care settings and to determine whether record reviews could shed light on potential contributory factors to inform future interventions. DESIGN: We reviewed medical records of diagnostic errors detected at 2 sites through electronic health record based triggers. Triggers were based on patterns of patients' unexpected return visits after an initial primary care index visit. SETTING: A large urban Veterans Affairs facility and a large integrated private health care system. PARTICIPANTS: Our study focused on 190 unique instances of diagnostic errors detected in primary care visits between October 1, 2006, and September 30, 2007. MAIN OUTCOME MEASURES: Through medical record reviews, we collected data on presenting symptoms at the index visit, types of diagnoses missed, process breakdowns, potential contributory factors, and potential for harm from errors. RESULTS: In 190 cases, a total of 68 unique diagnoses were missed. Most missed diagnoses were common conditions in primary care, with pneumonia (6.7%), decompensated congestive heart failure (5.7%), acute renal failure (5.3%), cancer (primary) (5.3%), and urinary tract infection or pyelonephritis (4.8%) being most common. Process breakdowns most frequently involved the patient-practitioner clinical encounter (78.9%) but were also related to referrals (19.5%), patient-related factors (16.3%), follow-up and tracking of diagnostic information (14.7%), and performance and interpretation of diagnostic tests (13.7%). A total of 43.7% of cases involved more than one of these processes. Patient-practitioner encounter breakdowns were primarily related to problems with history-taking (56.3%), examination (47.4%), and/or ordering diagnostic tests for further workup (57.4%). Most errors were associated with potential for moderate to severe harm. CONCLUSIONS AND RELEVANCE: Diagnostic errors identified in our study involved a large variety of common diseases and had significant potential for harm. Most errors were related to process breakdowns in the patient-practitioner clinical encounter. Preventive interventions should target common contributory factors across diagnoses, especially those that involve data gathering and synthesis in the patient-practitioner encounter. PMID- 23440151 TI - [Key elements in implementing adverse event notification systems in Latin American hospitals]. AB - OBJECTIVE: To develop recommendations for the design and implementation of adverse event notification systems based on the experiences of the Latin American countries. METHODS: Employing the qualitative Metaplan methodology, proposals were obtained from 17 experts on adverse event notification systems from Argentina, Brazil, Chile, Colombia, Cuba, Mexico, and Peru and three from the Pan American Health Organization. The characteristics, scope, barriers and constraints, data entry method, type of analysis, and information feedback on adverse event notification systems were reviewed and how to involve professionals in this process was discussed. The proposals were prioritized through an analysis of the responses, debate, and collective deliberation. RESULTS: A total of 73 recommendations were obtained on the characteristics that adverse event notification systems should have and 90 on barriers and constraints. There was agreement that legal security for professionals, a culture of safety in health facilities, incentives, a nimble system for providing professionals with results, and a single taxonomy are key to the successful implementation of adverse event notification systems, which must endeavor to protect patient safety in order to improve health care. CONCLUSIONS: Adverse event notification systems must be tailored to the needs of each health center. They exist to enable the health system to learn from experience. Confidentiality, anonymity, voluntary participation, a single taxonomy, and legal security for professionals are critical elements of adverse event notification systems. PMID- 23440152 TI - [Geographic distribution of wild rabies risk and evaluation of the factors associated with its incidence in Colombia, 1982-2010]. AB - OBJECTIVE: To update the information on the geographic distribution of bat transmitted rabies foci in Colombia and evaluate the biotic and abiotic conditions associated with the incidence of this disease in the country. METHODS: Observational study of a database containing information on the wild rabies foci identified between 1982 and 2010 and the cattle population in each municipality. The municipalities were classified according to the disease's risk of transmission, and an environmental characterization of 15 variables was carried out. A maximum entropy model was developed to predict which areas had conditions appropriate for the presence of the Desmodus rotundus vector infected by the virus and to evaluate the importance of the variables employed. RESULTS: There were 2 330 foci in 359 (31.8%) of the country's 1 128 municipalities; 144 municipalities were classified as high risk. The highest incidence rates were found in Monteria, Valledupar, Riohacha, Aguachica, Unguia, Acandi, Rio de Oro, Tibu, Sahagun, and San Onofre. Rabies foci were found year-round but were more frequent (linear correlation [r] = 0.64) during the dry months (January to April). Temperature and precipitation were the variables contributing the greatest robustness to the prediction model. CONCLUSIONS: Prevention and control measures should be implemented in high-risk municipalities. The best months for conducting vaccination campaigns are June, November, and December. In future analyses, biotic interaction variables should be included to improve the predictive capacity of the model. PMID- 23440153 TI - HIV testing rates among pregnant women in Managua, Nicaragua, 2010-2011. AB - OBJECTIVE: To determine and report the rate and pattern of HIV testing among pregnant women receiving ambulatory prenatal care, and the total number of positive cases in pregnant women in Managua, Nicaragua. METHODS: A retrospective epidemiological review was conducted to assess HIV testing rates among pregnant women in Managua attending district-level health centers in 2010 and 2011, with a focus on a single district (District 6.1). RESULTS: A total of 39.4% of pregnant women receiving prenatal care at Managua health centers in 2010 received an HIV test, and this number increased to 49.8% in 2011 (P < 0.001; phi statistic, 0.10). In 2010, 27 pregnant women in Managua were found to be HIV positive, corresponding to 0.17% of those who were tested. In 2011, 31 tested positive (0.12% of those who were tested). Comparisons between 2010 and 2011 at the District 6.1 level reflect an increase in women who received HIV tests from 24.2% in 2010 to 49.3% in 2011 (P < 0.001; phi statistic, 0.26). In District 6.1, two pregnant women were identified as HIV positive in 2010 and three in 2011, corresponding to 0.32% and 0.13% of pregnant women tested, respectively. CONCLUSIONS: Despite significant improvements in HIV testing rates from 2010 to 2011, the numbers tested remain below the goal recommended by the Pan American Health Organization (PAHO) in order to achieve virtual elimination of mother-to child transmission by 2015 (> 95%). Patterns of testing demonstrated increased rates coinciding with a health fair in District 6.1, but effects were short lived. Therefore, new approaches are necessary to bolster prenatal HIV screening efforts within Managua and District 6.1 in Nicaragua. PMID- 23440154 TI - [Tuberculosis in indigenous peoples in the Brazilian Amazon: an epidemiological study in the Upper Rio Negro region]. AB - OBJECTIVE: To describe the sociodemographic, clinical, and epidemiological characteristics of reported tuberculosis cases among indigenous individuals of Sao Gabriel de Cachoeira, State of Amazonas, Brazil, and to identify the factors associated with mortality during treatment; and to estimate the prevalence of latent tuberculosis infection (LTBI) and associated factors and obtain information on the therapeutic course and the individual perceptions regarding acquistion of tuberculosis in the district of Iauarete. METHODS: Firstly, a retrospective epidemiological study (1997 to 2007) was conducted using data from the Brazilian Notifiable Diseases Surveillance System (SINAN). Next, a cross sectional study (2010) was conducted with respiratory symptomatic subjects and contacts of Iauarete. RESULTS: Seven hundred and twenty-three new cases were reported, with incidence of 273.4/100 000 and mortality of 13.2/100 000. There was a predominance of males (57%), aged > 45 years (37.6%), people with no schooling (42.7%), and cases from rural areas (76.9%). Patients aged 0 to 20 years were at lower risk of death when compared to those aged > 45 years (OR = 0.3; IC95%: 0.1 a 0.9). In Iauarete, with 15.3% of the reported cases, 184 people were interviewed. A prevalence of LTB of 76.1% was reported. Tuberculin skin test > 5 mm was associated with the > 15-year old age group, history of active tuberculosis, and radiological alterations. A previous history of tuberculosis was cited by 54 people (29.3%). The main explanation for the disease was "puffing/poisoning" (24.1%). The therapeutic course included industrialized drugs (42.6%), medicinal plants/roots, shamanism, and prayer (42.7%). CONCLUSIONS: The risk of tuberculosis infection and disease in this population was high. Despite the reduced incidence resulting from recent efforts, tuberculosis control requires closer surveillance of contacts and improvement in communication strategies between health teams and indigenous populations. PMID- 23440155 TI - [Validity and reliability of the Argentine version of the PCAT-AE for the evaluation of primary health care]. AB - OBJECTIVE: To determine the validity and reliability of the version of the Primary Care Assessment Tool for adult users, adapted for Argentina (known as AR PCAT-AE). METHODS: Two cross-sectional pilot studies were conducted among people over age 17, largely through self-administered questionnaires. Items that were equivalent to the original version of the PCAT and 13 others proposed for the instruments were analyzed. The factorial validity and reliability of the scores for each dimension were studied. The validity indicators were: factors that had three or more items with a factorial load of > 0.35, item-total correlation > 0.30, and interpretation of the solution according to the theoretical model. RESULTS: The factorial analysis yielded nine factors that explained 57.4% of the variability. Considering the pre-established criteria for validity, two items were excluded from the dimensions of continuity and comprehensiveness and six were added to comprehensiveness and cultural competency. In the dimensions, the percentage of questions with an item-total correlation of greater than 0.30 ranged from 67% to 100% and the Chronbach's (alpha) coefficient of internal consistency ranged from 0.44 to 0.90. CONCLUSIONS: The validity and reliability of the AR-PCAT-AE questionnaire are adequate, maintaining high equivalence with the original version. The process presented could be adopted in other contexts to advance the evaluation of primary health care functions with quality tools. PMID- 23440156 TI - [The cholera epidemic in Latin America: reemergence, morbidity, and mortality]. AB - OBJECTIVE: To determine morbidity and mortality from cholera during different segments of the period 1991-2011 in the countries of Latin America. METHODS: Using information sources from a nonsystematic literature search for works on cholera epidemics, a mixed ecological study was conducted aimed at a time series analysis of morbidity, mortality, and case-fatality in cholera-related health events between 1991 and 2011 in 18 Latin American countries. RESULTS: During the period 1991-2011, 1 839 037 cases of cholera were reported in Latin America, with 19 538 deaths and a case fatality rate of 1.06%. The most affected countries were Peru between 1991 and 2002-with a maximum annual cumulative incidence of 1 452.72 cases per 100 000 population but a low case fatality rate (0.72%)-and Haiti between 2010 and 2011, with a maximum annual cumulative incidence of 3 319.13 per 100 000 population and a case fatality rate of 1.32%. CONCLUSIONS: The cholera epidemic has resulted in high morbidity, mortality, and case fatality in some Latin American countries, due largely to basically socioeconomic and climatic factors. The reemergence of this disease and the many factors related to how cholera outbreaks evolve call for the development and strengthening of regional prevention and control strategies in the countries as well as a study on the determinants that influence the emergence and reemergence of infectious diseases in Latin America. PMID- 23440157 TI - [Hospital self-management policy in Chile: perceptions of decision-makers]. AB - OBJECTIVE: To learn the perceptions of decision-makers concerning the imple-men-t ation stage of a hospital self-management policy in two highly complex hospitals in southern Chile. METHODS: A descriptive, exploratory, qualitative study based on semi-structured in-depth interviews of decision-makers at the Regional Hospital of Valdivia and the Hospital San Jose de Osorno from August 2010 to December 2011. A convenience sample of 26 decision-makers was selected. The 26 interviews were recorded and transcribed verbatim. The information was analyzed using inductive content analysis. RESULTS: The interviewees consider the concept of self-management to be determined by autonomy in decision-making about resource allocation and the financing of health service delivery in the hospitals. They also stated that human resources and financing policies should be included to improve the implementation stage. They related weaknesses with the lack of organizational capabilities and managerial skills in the health teams implementing the changes. CONCLUSIONS: Conceptually, the hospital self-management policy is based on financial autonomy, and implementation is affected by persistent capacity gaps in policy design. PMID- 23440158 TI - [The Bolsa Familia cash transfer program and food and nutrition security in Brazil: a critical review of the literature]. AB - OBJECTIVE: To critically review studies evaluating the impact of Bolsa Familia (PBF), a federal cash transfer program, for food and nutrition security in Brazil. METHODS: The Cochrane Library, LILACS, Medline and SciELO databases were searched, as well as public organization websites. All studies based on primary data were selected. The following were excluded: studies using secondary data, review articles, studies that did now allow the establishment of associations between PBF and food and nutrition security, as well as studies evaluating food security strictly in sanitary terms. RESULTS: Ten studies were included. Of these, five concluded that PBF had a positive impact on the food and nutrition security of participating families. Three studies observed an increase in the consumption of foods with higher calorie content and less nutritional value. This change in dietary habits is a risk factor for the development of overweight, obesity, and noncommunicable chronic diseases. CONCLUSIONS: The guarantee of food and nutrition security requires programs that focus on both malnutrition and overweight and obesity. Cash transfer programs such as the PBF can contribute more effectively to the nutritional well-being of participants if they are combined with other types of interventions, such as actions to promote healthy eating. PMID- 23440159 TI - Legislation on violence against women: overview of key components. AB - This study aimed to determine if legislation on violence against women (VAW) worldwide contains key components recommended by the Pan American Health Organization (PAHO) and the United Nations (UN) to help strengthen VAW prevention and provide better integrated victim protection, support, and care. A systematic search for VAW legislation using international legal databases and other electronic sources plus data from previous research identified 124 countries/territories with some type of VAW legislation. Full legal texts were found for legislation from 104 countries/territories. Those available in English, Portuguese, and Spanish were downloaded and compiled and the selection criteria applied (use of any of the common terms related to VAW, including intimate partner violence (IPV), and reference to at least two of six sectors (education, health, judicial system, mass media, police, and social services) with regard to VAW interventions (protection, support, and care). A final sample from 80 countries/territories was selected and analyzed for the presence of key components recommended by PAHO and the UN (reference to the term "violence against women" in the title; definitions of different types of VAW; identification of women as beneficiaries; and promotion of (reference to) the participation of multiple sectors in VAW interventions). Few countries/territories specifically identified women as the beneficiaries of their VAW legislation, including those that labeled their legislation "domestic violence" law ( n = 51), of which only two explicitly mentioned women as complainants/survivors. Only 28 countries/territories defined the main forms of VAW (economic, physical, psychological, and sexual) in their VAW legislation. Most highlighted the role of the judicial system, followed by that of social services and the police. Only 28 mentioned the health sector. Despite considerable efforts worldwide to strengthen VAW legislation, most VAW laws do not incorporate the key recommended components. Significant limitations were found in the legislative content, its application, and the extent to which it provided women with integrated protection, support, and care. In developing new VAW legislation, policymakers should consider the vital role of health services. PMID- 23440160 TI - National prevalence survey in Brazil to evaluate the quality of microbiology laboratories: the importance of defining priorities to allocate limited resources. AB - This report describes a survey of microbiology laboratories (n = 467) serving Brazilian hospitals with >=10 intensive care beds and/or involved in the government health care adverse event reporting system. Coordinators were interviewed and laboratories classified as follows: Level 0 (no minimal functioning conditions-85.4% of laboratories); Level 1 (minimal functioning conditions but inadequate execution of basic routine-6.7%); Level 2 (minimal functioning conditions and adequate execution of basic routine but no adequate procedures for quality control-5.8%); Level 3 (minimal functioning conditions, adequate execution of basic routine, and adequate procedures for quality control, but no direct communication with the infection control department-0.9%); Level 4 (minimal functioning conditions, adequate execution of basic routine, adequate procedures for quality control, and direct communication with infection control, but no available advanced resources-none); and Level 5 (minimal functioning conditions, adequate execution of basic routine, adequate procedures for quality control, direct communication with infection control, and available advanced resources-0.9%). Twelve laboratories did not perform Ziehl-Neelsen staining; 271 did not have safety cabinets; and >30% without safety cabinets had automated systems. Low quality was associated with serving hospitals not participating in government adverse-event program; private hospitals; nonteaching hospitals; and those outside state capitals. Results may reflect what occurs in many other countries where defining priorities is important due to limited resources. PMID- 23440161 TI - Patient information about warfarin: an assessment of accuracy and readability. PMID- 23440162 TI - Diffusion of botulinum toxins. AB - BACKGROUND: It is generally agreed that diffusion of botulinum toxin occurs, but the extent of the spread and its clinical importance are disputed. Many factors have been suggested to play a role but which have the most clinical relevance is a subject of much discussion. METHODS: This review discusses the variables affecting diffusion, including protein composition and molecular size as well as injection factors (e.g., volume, dose, injection method). It also discusses data on diffusion from comparative studies in animal models and human clinical trials that illustrate differences between the available botulinum toxin products (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB). RESULTS: Neither molecular weight nor the presence of complexing proteins appears to affect diffusion; however, injection volume, concentration, and dose all play roles and are modifiable. Both animal and human studies show that botulinum toxin products are not interchangeable, and that some products are associated with greater diffusion and higher rates of diffusion related adverse events than others. DISCUSSION: Each of the botulinum toxins is a unique pharmacologic entity. A working knowledge of the different serotypes is essential to avoid unwanted diffusion-related adverse events. In addition, clinicians should be aware that the factors influencing diffusion may range from properties intrinsic to the drug to accurate muscle selection as well as dilution, volume, and dose injected. PMID- 23440163 TI - Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: New U.S. Preventive Services Task Force (USPSTF) recommendation statement on vitamin D and calcium supplementation to prevent fractures in adults. METHODS: The USPSTF commissioned 2 systematic evidence reviews and a meta analysis on vitamin D supplementation with or without calcium to assess the effects of supplementation on bone health outcomes in community-dwelling adults, the association of vitamin D and calcium levels with bone health outcomes, and the adverse effects of supplementation. POPULATION: These recommendations apply to noninstitutionalized or community-dwelling asymptomatic adults without a history of fractures. This recommendation does not apply to the treatment of persons with osteoporosis or vitamin D deficiency. RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men. (I statement)The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (I statement)The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (D recommendation). PMID- 23440164 TI - Significance of first-degree atrioventricular block in acute endocarditis. PMID- 23440165 TI - Visualisation of the left anterior descending coronary artery on CT images used for breast radiotherapy planning. AB - OBJECTIVE: To assess the visualisation of the left anterior descending (LAD) coronary artery on CT images used for breast radiation treatment planning. METHODS: Delineation of the LAD artery was achieved for 25 breast patients by 1 radiologist and 1 radiation oncologist independently on two sets of images for each patient: one pre-operative CT scan using intravenous (IV) contrast media to determine the primary gross tumour volume (GTV) and one post-operative CT scan used for treatment planning. A Student's paired t-test was used to compare the number of CT slices in which the LAD was visible for each patient in the two series. Interpolations and extrapolations of the LAD volume were performed for the left-sided cases using a published heart atlas in order to report doses to the LAD structure. RESULTS: There was a non-significant difference between the results with and without IV contrast media (p=0.34 for the radiologist; p=0.90 for the radiation oncologist). The visible LAD artery corresponded to a 30% portion (range 12-47%) of the interpolated structure. The maximum dose to the left artery varied widely, from 2.7 to 41.7 Gy, in the group of patients with left breast tumours. The largest values (>25 Gy) corresponded to those patients in whom the LAD artery distal extremity lay inside the breast fields. CONCLUSIONS: With the current planning CT protocol, only one-third of the LAD artery could be objectively visualised. Contrast-enhanced imaging used for GTV delineation before the breast surgery did not improve the visualisation of the artery. ADVANCES IN KNOWLEDGE: This study has revealed the lack of consistency that may be encountered when contouring heart vessels, thereby questioning the reliability of dose reporting. PMID- 23440166 TI - CT findings of pulmonary non-tuberculous mycobacterial infection in non-AIDS immunocompromised patients: a case-controlled comparison with immunocompetent patients. AB - OBJECTIVE: To describe CT findings of non-tuberculous mycobacteria (NTM) pulmonary infection in non-AIDS immunocompromised patients (ICPs) and to compare these findings with those in immunocompetent patients. METHODS: From July 2000 to August 2007, 369 patients (mean age 58.3 years; 169 males and 200 females) with pulmonary NTM infection were retrospectively reviewed. Of these 369 patients, 24 ICPs (mean age 64.8 years; 15 males and 9 females) were identified. 16 patients had diabetes mellitus, and 6 patients had received long-term steroid therapy. One had received solid organ transplantation and one had received high-dose chemotherapy for haematological disease. 24 age- and sex-matched immunocompetent patients (mean age 64.6 years; 15 males and 9 females) were selected as the control group from the same registry. CT images were reviewed in consensus by three chest radiologists, who were blinded to immune status. Each lung lobe was evaluated in terms of extent of the lesion, bronchiectasis, parenchymal opacity and the presence of ancillary findings. results: A total of 287 lobes were evaluated in ICPs and the control group. The ICPs showed a higher prevalence of ill-defined nodules, with cavities and large opacity >2 cm with/without cavity (p=0.03, 0.04 and 0.02, respectively). Regardless of the immune status, the most common CT findings were bronchiectasis and ill-defined nodules without cavity. CONCLUSION: The most common CT findings of pulmonary NTM infection in ICPs were bronchiectasis and ill-defined nodules, similar to those in the control group. Ill-defined nodules with cavity and large opacity >2 cm with/without cavity were more frequently found in ICPs. ADVANCES IN KNOWLEDGE: In patients affected by NTM infection, large opacities and cavitation in pulmonary nodules are more frequent in ICPs than in immunocompetent patients. PMID- 23440167 TI - HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. AB - BACKGROUND: Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown. OBJECTIVE: To investigate whether persons with HIV infection develop hepatitis C virus (HCV)-related liver disease at younger ages than similar persons without HIV. DESIGN: Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol. SETTING: Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study. PARTICIPANTS: 1176 current and former injection drug users with antibodies to HCV. MEASUREMENTS: Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels. RESULTS: Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older. LIMITATION: The process of liver fibrosis began before the study in most persons. CONCLUSION: In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse. PMID- 23440168 TI - Ethics in medical research: General principles with special reference to psychiatry research. AB - Ethics is an understanding of the nature of conflicts arising from moral imperatives and how best we may deal with them. Ethics in medical research deals with the conflicts of interest across various levels. Guidelines have been proposed for standardized ethical practice throughout the globe. The four fundamental principles of ethics which are being underscored are autonomy, non maleficence, beneficence, and justice. Some special ethical issues have particular relevance to psychiatric research arising primarily from the specific vulnerabilities of those with mental illness and the risks posed by some research methodologies. Accordingly, sensitivity is required in the design of psychiatric research. It is suggested that though the value of published guidelines and the help that may be available from research ethics committees is quite great, the primary responsibility for maintaining high standards of practice in research rests with research workers themselves. PMID- 23440170 TI - Concerted changes in N and C primary metabolism in alfalfa (Medicago sativa) under water restriction. AB - Although the mechanisms of nodule N(2) fixation in legumes are now well documented, some uncertainty remains on the metabolic consequences of water deficit. In most cases, little consideration is given to other organs and, therefore, the coordinated changes in metabolism in leaves, roots, and nodules are not well known. Here, the effect of water restriction on exclusively N(2) fixing alfalfa (Medicago sativa L.) plants was investigated, and proteomic, metabolomic, and physiological analyses were carried out. It is shown that the inhibition of nitrogenase activity caused by water restriction was accompanied by concerted alterations in metabolic pathways in nodules, leaves, and roots. The data suggest that nodule metabolism and metabolic exchange between plant organs nearly reached homeostasis in asparagine synthesis and partitioning, as well as the N demand from leaves. Typically, there was (i) a stimulation of the anaplerotic pathway to sustain the provision of C skeletons for amino acid (e.g. glutamate and proline) synthesis; (ii) re-allocation of glycolytic products to alanine and serine/glycine; and (iii) subtle changes in redox metabolites suggesting the implication of a slight oxidative stress. Furthermore, water restriction caused little change in both photosynthetic efficiency and respiratory cost of N(2) fixation by nodules. In other words, the results suggest that under water stress, nodule metabolism follows a compromise between physiological imperatives (N demand, oxidative stress) and the lower input to sustain catabolism. PMID- 23440171 TI - The Arabidopsis CDK inhibitor ICK3/KRP5 is rate limiting for primary root growth and promotes growth through cell elongation and endoreduplication. AB - The coordination of plant cell division and expansion controls plant morphogenesis, development, and growth. Cyclin-dependent kinases (CDKs) are not only key regulators of cell division but also play an important role in cell differentiation. In plants, CDK activity is modulated by the binding of INHIBITOR OF CDK/KIP-RELATED PROTEIN (ICK/KRP). Previously, ICK2/KRP2 has been shown to mediate auxin responses in lateral root initiation. Here are analysed the roles of all ICK/KRP genes in root growth. Analysis of ick/krp null-mutants revealed that only ick3/krp5 was affected in primary root growth. ICK3/KRP5 is strongly expressed in the root apical meristem (RAM), with lower expression in the expansion zone. ick3/krp5 roots grow more slowly than wildtype controls, and this results not from reduction of division in the proliferative region of the RAM but rather reduced expansion as cells exit the meristem. This leads to shorter final cell lengths in different tissues of the ick3/krp5 mutant root, particularly the epidermal non-hair cells, and this reduction in cell size correlates with reduced endoreduplication. Loss of ICK3/KRP5 also leads to delayed germination and in the mature embryo ICK3/KRP5 is specifically expressed in the transition zone between root and hypocotyl. Cells in the transition zone were smaller in the ick3/krp5 mutant, despite the absence of endoreduplication in the embryo suggesting a direct effect of ICK3/KRP5 on cell growth. It is concluded that ICK3/KRP5 is a positive regulator of both cell growth and endoreduplication. PMID- 23440172 TI - On the 'lost' crops of the neolithic Near East. AB - The claim that the 'classic' eight 'founder crop' package (einkorn wheat, emmer wheat, barley, lentil, pea, chickpea, bitter vetch, and flax) underlying the emergence of agriculture in the Near East is a relic of a larger number of domesticated species is addressed. The 'lost' crops concept relies on the idea that additional taxa were at certain points in time and in certain locations genuine crops, which were later abandoned. The issue is highly relevant to the debate concerning mono- versus polyphyletic domestication, because if there were numerous 'false starts' that were subsequently lost, this implies that plant domestication occurred over a protracted time period, and across a wide geographic range. Different criteria were used for declaring those taxa as 'lost' crops, including, but not limited to (i) identification in archaeobotanical assemblages of grains from species which are not known as crops at present; (ii) identification of such grains in what is interpreted to have been Neolithic storage facilities; and (iii) recent botanical observations on populations of crop wild relatives in disturbed habitats. The evidence for four presumed 'lost' crops (wild oat, rambling vetch, rye, and wild black lentil) and the broad bean is evaluated, and discussed in light of data on Croatian and Israeli wild pea, and Moroccan wild lentil in disturbed habitats. Based on present knowledge, the broad bean might emerge as a founder crop (without an identified wild progenitor). The same may hold true for rye, which was never lost since its adoption in the Pre-Pottery Neolithic B period in Anatolia. In the remaining three cases, there are alternative, more likely, explanations for the archaeological finds or the recent botanical observations rather than 'lost' domestication episodes. PMID- 23440174 TI - To supplement or not to supplement: the U.S. Preventive Services Task Force recommendations on calcium and vitamin D. PMID- 23440173 TI - Ask-Advise-Connect: a new approach to smoking treatment delivery in health care settings. AB - IMPORTANCE: Several national health care-based smoking cessation initiatives have been recommended to facilitate the delivery of evidence-based treatments, such as quitline (telephone-based tobacco cessation services) assistance. The most notable examples are the 5 As (Ask, Advise, Assess, Assist, Arrange) and Ask. Advise. Refer. (AAR) programs. Unfortunately, rates of primary care referrals to quitlines are low, and most referred smokers fail to call for assistance. OBJECTIVE: To evaluate a new approach--Ask-Advise-Connect (AAC)--designed to address barriers to linking smokers with treatment. DESIGN: A pair-matched, 2 treatment-arm, group-randomized design in 10 family practice clinics in a single metropolitan area. Five clinics were randomized to the AAC (intervention) and 5 to the AAR (control) conditions. In both conditions, clinic staff were trained to assess and record the smoking status of all patients at all visits in the electronic health record, and smokers were given brief advice to quit. In the AAC clinics, the names and telephone numbers of smokers who agreed to be connected were sent electronically to the quitline daily, and patients were called proactively by the quitline within 48 hours. In the AAR clinics, smokers were offered a quitline referral card and encouraged to call on their own. All data were collected from February 8 through December 27, 2011. SETTING: Ten clinics in Houston, Texas. PARTICIPANTS: Smoking status assessments were completed for 42,277 patients; 2052 unique smokers were identified at AAC clinics, and 1611 smokers were identified at AAR clinics. INTERVENTIONS: Linking smokers with quitline-delivered treatment. MAIN OUTCOME MEASURE: Impact was based on the RE AIM (Reach, Efficacy, Adoption, Implementation, and Maintenance) conceptual framework and defined as the proportion of all identified smokers who enrolled in treatment. RESULTS: In the AAC clinics, 7.8% of all identified smokers enrolled in treatment vs 0.6% in the AAR clinics (t4 = 9.19 [P < .001]; odds ratio, 11.60 [95% CI, 5.53-24.32]), a 13-fold increase in the proportion of smokers enrolling in treatment. CONCLUSIONS AND RELEVANCE: The system changes implemented in the AAC approach could be adopted broadly by other health care systems and have tremendous potential to reduce tobacco-related morbidity and mortality. PMID- 23440176 TI - Left behind: ensuring clarity and completeness of our educational materials and messages. PMID- 23440177 TI - Summaries for patients. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. PMID- 23440175 TI - Error detection and representation in the olivo-cerebellar system. AB - Complex spikes generated in a cerebellar Purkinje cell via a climbing fiber have been assumed to encode errors in the performance of neuronal circuits involving Purkinje cells. To reexamine this notion in this review, I analyzed structures of motor control systems involving the cerebellum. A dichotomy was found between the two types of error: sensory and motor errors play roles in the feedforward and feedback control conditions, respectively. To substantiate this dichotomy, here in this article I reviewed recent data on neuronal connections and signal contents of climbing fibers in the vestibuloocular reflex (VOR), optokinetic eye movement response, saccade, hand reaching, cursor tracking, as well as some other cases of motor control. In our studies, various sources of sensory and motor errors were located in the neuronal pathways leading to the inferior olive. We noted that during the course of evolution, control system structures involving the cerebellum changed rather radically from the prototype seen in the flocculonodular lobe and vermis to that applicable to the cerebellar hemisphere. Nevertheless, the dichotomy between sensory and motor errors is maintained. PMID- 23440178 TI - Tramadol dependence: a case series from India. AB - Tramadol is an atypical, centrally acting, synthetic analgesic, acting through opioid and non-opioid systems. We present a series of seven cases, all men, who sought treatment at our centre for tramadol-dependence. The majority were using other opioids at some point in their lives. Their tramadol use had begun with a prescription of tramadol for opioid detoxification, for headache and body pains, and as an alternative to injectable opioids. The doses of tramadol used varied from 50 to 1500 mg per day. All subjects reported an experience of euphoria with tramadol use. Four patients were put on naltrexone, but had poor compliance. This case series underscores the need for caution, while using tramadol in substance dependent patients. PMID- 23440179 TI - Effect of bosentan on exercise capacity and clinical worsening in patients with dual down and eisenmenger syndrome. AB - This single-center, retrospective analysis evaluated long-term bosentan treatment in adult patients (n = 7) with both Down and Eisenmenger syndromes (DS-ES). Laboratory tests, 6-minute walk distance (6MWD), functional class, and Doppler echocardiography were assessed at baseline and during 2 years' follow-up. Improvements or maintenance of 6MWD were observed (68 m improvement from baseline at month 12) after bosentan initiation. 6MWD was maintained up to year 2. Overall, 6 patients experienced a significant improvement in functional class during 2 years' therapy (P = 0.01). There were no significant changes in parameters measured by Doppler echocardiography. None of the patients required either hospitalization or additional pulmonary arterial hypertension (PAH) therapy because of PAH progression. Bosentan treatment was generally well tolerated; no liver function abnormalities or serious adverse drug reactions were noted. In this DS-ES cohort, bosentan seemed to be well tolerated and clinically effective. PMID- 23440180 TI - Content and quality of information provided on canadian dementia websites. AB - PURPOSE: Information about dementia is important for persons with dementia (PWD) and their caregivers and the Internet has become the key source of health information. We reviewed the content and quality of information provided on Canadian websites for Alzheimer's disease (AD). METHODS: We used the terms "dementia" and "Alzheimer" in Google to identify Canadian dementia websites. The contents of websites were compared to 16 guideline recommendations provided in Canadian Consensus Conference on Diagnosis and Treatment of Dementia. The quality of information provided on websites was evaluated using the DISCERN instrument. The content and quality of information provided on selected websites were then described. RESULTS: Seven websites were identified, three of which provided relatively comprehensive and high-quality information on dementia. Websites frequently provided information about diagnosis of dementia, its natural course, and types of dementia, while other topics were less commonly addressed. The quality of information provided on the websites varied, and many websites had several areas where the quality of information provided was relatively low according to the DISCERN instrument. CONCLUSIONS: There is variation in the content and quality of dementia websites, although some websites provide high quality and relatively comprehensive information which would serve as a useful resource for PWD, caregivers, and healthcare providers. Improvements in the content and quality of information provided on AD websites would provide PWD and their caregivers with access to better information. PMID- 23440181 TI - Volatile anaesthetic myocardial protection: a review of the current literature. AB - Ischaemic preconditioning is a powerful innate adaptive phenomenon whereby brief periods of sublethal ischaemia result in marked tolerance to subsequent lethal ischaemia. Halogenated anaesthetics have been shown to mimic ischaemic preconditioning, modifying and attenuating ischaemia reperfusion injury. This review aims to present the current animal and human data, discuss the possible mechanisms of action and review the clinical evidence for volatile anaesthetic induced myocardial protection. There is class Ia evidence for the myocardial protective properties of sevoflurane and desflurane in low risk patients undergoing coronary artery bypass grafting surgery. These volatile anaesthetics have been shown to improve clinical outcomes and health economics following cardiac surgery, reducing intensive care and hospital stay. The evidence for the benefit of volatile anaesthetics in non-cardiac surgery is less robust and further large randomized controlled trials are required to elucidate this question. PMID- 23440183 TI - A 28-year-old snowboarder presents with chronic ankle pain. PMID- 23440184 TI - Availability of potassium on the nutrition facts panel of US packaged foods. PMID- 23440185 TI - The brain uses adaptive internal models of scene statistics for sensorimotor estimation and planning. AB - Because of uncertainty and noise, the brain should use accurate internal models of the statistics of objects in scenes to interpret sensory signals. Moreover, the brain should adapt its internal models to the statistics within local stimulus contexts. Consider the problem of hitting a baseball. The impoverished nature of the visual information available makes it imperative that batters use knowledge of the temporal statistics and history of previous pitches to accurately estimate pitch speed. Using a laboratory analog of hitting a baseball, we tested the hypothesis that the brain uses adaptive internal models of the statistics of object speeds to plan hand movements to intercept moving objects. We fit Bayesian observer models to subjects' performance to estimate the statistical environments in which subjects' performance would be ideal and compared the estimated statistics with the true statistics of stimuli in an experiment. A first experiment showed that subjects accurately estimated and used the variance of object speeds in a stimulus set to time hitting behavior but also showed serial biases that are suboptimal for stimuli that were uncorrelated over time. A second experiment showed that the strength of the serial biases depended on the temporal correlations within a stimulus set, even when the biases were estimated from uncorrelated stimulus pairs subsampled from the larger set. Taken together, the results show that subjects adapted their internal models of the variance and covariance of object speeds within a stimulus set to plan interceptive movements but retained a bias to positive correlations. PMID- 23440186 TI - Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. AB - Bisphenol A (BPA) is a ubiquitous compound that is emerging as a possible toxicant during embryonic development. BPA has been shown to epigenetically affect the developing nervous system, but the molecular mechanisms are not clear. Here we demonstrate that BPA exposure in culture led to delay in the perinatal chloride shift caused by significant decrease in potassium chloride cotransporter 2 (Kcc2) mRNA expression in developing rat, mouse, and human cortical neurons. Neuronal chloride increased correspondingly. Treatment with epigenetic compounds decitabine and trichostatin A rescued the BPA effects as did knockdown of histone deacetylase 1 and combined knockdown histone deacetylase 1 and 2. Furthermore, BPA evoked increase in tangential interneuron migration and increased chloride in migrating neurons. Interestingly, BPA exerted its effect in a sexually dimorphic manner, with a more accentuated effect in females than males. By chromatin immunoprecipitation, we found a significant increase in binding of methyl-CpG binding protein 2 to the "cytosine-phosphate-guanine shores" of the Kcc2 promoter, and decrease in binding of acetylated histone H3K9 surrounding the transcriptional start site. Methyl-CpG binding protein 2-expressing neurons were more abundant resulting from BPA exposure. The sexually dimorphic effect of BPA on Kcc2 expression was also demonstrated in cortical neurons cultured from the offspring of BPA-fed mouse dams. In these neurons and in cortical slices, decitabine was found to rescue the effect of BPA on Kcc2 expression. Overall, our results indicate that BPA can disrupt Kcc2 gene expression through epigenetic mechanisms. Beyond increase in basic understanding, our findings have relevance for identifying unique neurodevelopmental toxicity mechanisms of BPA, which could possibly play a role in pathogenesis of human neurodevelopmental disorders. PMID- 23440187 TI - Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. AB - Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, including obesity, cardiovascular disease, and cognitive impairment, but the mechanisms involved remain largely unexplored. Twenty-six participants were exposed to 1 wk of insufficient sleep (sleep-restriction condition 5.70 h, SEM = 0.03 sleep per 24 h) and 1 wk of sufficient sleep (control condition 8.50 h sleep, SEM = 0.11). Immediately following each condition, 10 whole-blood RNA samples were collected from each participant, while controlling for the effects of light, activity, and food, during a period of total sleep deprivation. Transcriptome analysis revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms (PER1, PER2, PER3, CRY2, CLOCK, NR1D1, NR1D2, RORA, DEC1, CSNK1E), sleep homeostasis (IL6, STAT3, KCNV2, CAMK2D), oxidative stress (PRDX2, PRDX5), and metabolism (SLC2A3, SLC2A5, GHRL, ABCA1). Biological processes affected included chromatin modification, gene-expression regulation, macromolecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation. The identified biological processes may be involved with the negative effects of sleep loss on health, and highlight the interrelatedness of sleep homeostasis, circadian rhythmicity, and metabolism. PMID- 23440188 TI - Electrokinetic properties of the mammalian tectorial membrane. AB - The tectorial membrane (TM) clearly plays a mechanical role in stimulating cochlear sensory receptors, but the presence of fixed charge in TM constituents suggests that electromechanical properties also may be important. Here, we measure the fixed charge density of the TM and show that this density of fixed charge is sufficient to affect mechanical properties and to generate electrokinetic motions. In particular, alternating currents applied to the middle and marginal zones of isolated TM segments evoke motions at audio frequencies (1 1,000 Hz). Electrically evoked motions are nanometer scaled (~5-900 nm), decrease with increasing stimulus frequency, and scale linearly over a broad range of electric field amplitudes (0.05-20 kV/m). These findings show that the mammalian TM is highly charged and suggest the importance of a unique TM electrokinetic mechanism. PMID- 23440189 TI - Lifespan of neurons is uncoupled from organismal lifespan. AB - Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits. In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longer-living host. PMID- 23440191 TI - Fostering advances in interdisciplinary climate science. PMID- 23440190 TI - Free energy landscape for the binding process of Huperzine A to acetylcholinesterase. AB - Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (DeltaG(off)?). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development. PMID- 23440192 TI - A post-Kyoto partner: considering the stratospheric ozone regime as a tool to manage nitrous oxide. AB - Nitrous oxide (N2O) is the largest known remaining anthropogenic threat to the stratospheric ozone layer. However, it is currently only regulated under the 1997 Kyoto Protocol because of its simultaneous ability to warm the climate. The threat N2O poses to the stratospheric ozone layer, coupled with the uncertain future of the international climate regime, motivates our exploration of issues that could be relevant to the Parties to the ozone regime (the 1985 Vienna Convention and its 1987 Montreal Protocol) should they decide to take measures to manage N2O in the future. There are clear legal avenues to regulate N2O under the ozone regime as well as several ways to share authority with the existing and future international climate treaties. N2O mitigation strategies exist to address the most significant anthropogenic sources, including agriculture, where behavioral practices and new technologies could contribute significantly to reducing emissions. Existing policies managing N2O and other forms of reactive nitrogen could be harnessed and built on by the ozone regime to implement N2O controls. There are several challenges and potential cobenefits to N2O control which we discuss here: food security, equity, and implications of the nitrogen cascade. The possible inclusion of N2O in the ozone regime need not be viewed as a sign of failure of the United Nations Framework Convention on Climate Change to adequately deal with climate change. Rather, it could represent an additional valuable tool in sustainable development diplomacy. PMID- 23440194 TI - Evidence for maize (Zea mays) in the Late Archaic (3000-1800 B.C.) in the Norte Chico region of Peru. AB - For more than 40 y, there has been an active discussion over the presence and economic importance of maize (Zea mays) during the Late Archaic period (3000-1800 B.C.) in ancient Peru. The evidence for Late Archaic maize has been limited, leading to the interpretation that it was present but used primarily for ceremonial purposes. Archaeological testing at a number of sites in the Norte Chico region of the north central coast provides a broad range of empirical data on the production, processing, and consumption of maize. New data drawn from coprolites, pollen records, and stone tool residues, combined with 126 radiocarbon dates, demonstrate that maize was widely grown, intensively processed, and constituted a primary component of the diet throughout the period from 3000 to 1800 B.C. PMID- 23440193 TI - KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia. AB - We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K(+) channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward IK1 at potentials above -55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia. PMID- 23440195 TI - Metal ions control product specificity of isoprenyl diphosphate synthases in the insect terpenoid pathway. AB - Isoprenyl diphosphate synthases (IDSs) produce the ubiquitous branched-chain diphosphates of different lengths that are precursors of all major classes of terpenes. Typically, individual short-chain IDSs (scIDSs) make the C10, C15, and C20 isoprenyl diphosphates separately. Here, we report that the product length synthesized by a single scIDS shifts depending on the divalent metal cofactor present. This previously undescribed mechanism of carbon chain-length determination was discovered for a scIDS from juvenile horseradish leaf beetles, Phaedon cochleariae. The recombinant enzyme P. cochleariae isoprenyl diphosphate synthase 1 (PcIDS1) yields 96% C10-geranyl diphosphate (GDP) and only 4% C15 farnesyl diphosphate (FDP) in the presence of Co(2+) or Mn(2+) as a cofactor, whereas it yields only 18% C10 GDP but 82% C15 FDP in the presence of Mg(2+). In reaction with Co(2+), PcIDS1 has a Km of 11.6 MUM for dimethylallyl diphosphate as a cosubstrate and 24.3 MUM for GDP. However, with Mg(2+), PcIDS1 has a Km of 1.18 MUM for GDP, suggesting that this substrate is favored by the enzyme under such conditions. RNAi targeting PcIDS1 revealed the participation of this enzyme in the de novo synthesis of defensive monoterpenoids in the beetle larvae. As an FDP synthase, PcIDS1 could be associated with the formation of sesquiterpenes, such as juvenile hormones. Detection of Co(2+), Mn(2+), or Mg(2+) in the beetle larvae suggests flux control into C10 vs. C15 isoprenoids could be accomplished by these ions in vivo. The dependence of product chain length of scIDSs on metal cofactor identity introduces an additional regulation for these branch point enzymes of terpene metabolism. PMID- 23440196 TI - Syllabic discrimination in premature human infants prior to complete formation of cortical layers. AB - The ontogeny of linguistic functions in the human brain remains elusive. Although some auditory capacities are described before term, whether and how such immature cortical circuits might process speech are unknown. Here we used functional optical imaging to evaluate the cerebral responses to syllables at the earliest age at which cortical responses to external stimuli can be recorded in humans (28 to 32-wk gestational age). At this age, the cortical organization in layers is not completed. Many neurons are still located in the subplate and in the process of migrating to their final location. Nevertheless, we observed several points of similarity with the adult linguistic network. First, whereas syllables elicited larger right than left responses, the posterior temporal region escaped this general pattern, showing faster and more sustained responses over the left than over the right hemisphere. Second, discrimination responses to a change of phoneme (ba vs. ga) and a change of human voice (male vs. female) were already present and involved inferior frontal areas, even in the youngest infants (29-wk gestational age). Third, whereas both types of changes elicited responses in the right frontal region, the left frontal region only reacted to a change of phoneme. These results demonstrate a sophisticated organization of perisylvian areas at the very onset of cortical circuitry, 3 mo before term. They emphasize the influence of innate factors on regions involved in linguistic processing and social communication in humans. PMID- 23440198 TI - Transketolase reaction under credible prebiotic conditions. AB - A transketolase reaction was catalyzed by cyanide ion under prebiotic conditions instead of its modern catalyst, thiamine pyrophosphate (TPP). Cyanide ion converted fructose plus glyceraldehyde to erythrose plus xylulose, the same products as are formed in modern biochemistry (but without the phosphate groups on the sugars). Cyanide was actually a better catalyst than was TPP in simple solution, where there is a negligible concentration of the C-2 anion of TPP, but of course not with an enzyme in modern biology. The cyanide ion was probably not toxic on prebiotic earth, but only when the oxygen atmosphere developed and iron porphyrin species were needed, which cyanide poisons. Thus, catalyses by TPP that are so important in modern biochemistry in the Calvin cycle for photosynthesis and the gluconic acid pathway for glucose oxidation, among other processes, were probably initially performed instead by cyanide ion until its toxicity with metalloproteins became a problem and primitive enzymes were present to work with TPP, or most likely its primitive precursors. PMID- 23440199 TI - Profile of Janet Hemingway. PMID- 23440200 TI - Reemerging role of cable properties in action potential initiation. PMID- 23440201 TI - Green-up dates in the Tibetan Plateau have continuously advanced from 1982 to 2011. AB - As the Earth's third pole, the Tibetan Plateau has experienced a pronounced warming in the past decades. Recent studies reported that the start of the vegetation growing season (SOS) in the Plateau showed an advancing trend from 1982 to the late 1990s and a delay from the late 1990s to 2006. However, the findings regarding the SOS delay in the later period have been questioned, and the reasons causing the delay remain unknown. Here we explored the alpine vegetation SOS in the Plateau from 1982 to 2011 by integrating three long-term time-series datasets of Normalized Difference Vegetation Index (NDVI): Global Inventory Modeling and Mapping Studies (GIMMS, 1982-2006), SPOT VEGETATION (SPOT VGT, 1998-2011), and Moderate Resolution Imaging Spectroradiometer (MODIS, 2000 2011). We found GIMMS NDVI in 2001-2006 differed substantially from SPOT-VGT and MODIS NDVIs and may have severe data quality issues in most parts of the western Plateau. By merging GIMMS-based SOSs from 1982 to 2000 with SPOT-VGT-based SOSs from 2001 to 2011 we found the alpine vegetation SOS in the Plateau experienced a continuous advancing trend at a rate of ~1.04 d.y(-1) from 1982 to 2011, which was consistent with observed warming in springs and winters. The satellite derived SOSs were proven to be reliable with observed phenology data at 18 sites from 2003 to 2011; however, comparison of their trends was inconclusive due to the limited temporal coverage of the observed data. Longer-term observed data are still needed to validate the phenology trend in the future. PMID- 23440202 TI - Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. AB - Vx-770 (Ivacaftor), a Food and Drug Administration (FDA)-approved drug for clinical application to patients with cystic fibrosis (CF), shifts the paradigm from conventional symptomatic treatments to therapeutics directly tackling the root of the disease: functional defects of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel caused by pathogenic mutations. The underlying mechanism for the action of Vx-770 remains elusive partly because this compound not only increases the activity of wild-type (WT) channels whose gating is primarily controlled by ATP binding/hydrolysis, but also improves the function of G551D-CFTR, a disease-associated mutation that abolishes CFTR's responsiveness to ATP. Here we provide a unified theory to account for this dual effect of Vx 770. We found that Vx-770 enhances spontaneous, ATP-independent activity of WT CFTR to a similar magnitude as its effects on G551D channels, a result essentially explaining Vx-770's effect on G551D-CFTR. Furthermore, Vx-770 increases the open time of WT-CFTR in an [ATP]-dependent manner. This distinct kinetic effect is accountable with a newly proposed CFTR gating model depicting an [ATP]-dependent "reentry" mechanism that allows CFTR shuffling among different open states by undergoing multiple rounds of ATP hydrolysis. We further examined the effect of Vx-770 on R352C-CFTR, a unique mutant that allows direct observation of hydrolysis-triggered gating events. Our data corroborate that Vx 770 increases the open time of WT-CFTR by stabilizing a posthydrolytic open state and thereby fosters decoupling between the gating cycle and ATP hydrolysis cycle. The current study also suggests that this unique mechanism of drug action can be further exploited to develop strategies that enhance the function of CFTR. PMID- 23440203 TI - Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. AB - We profiled microRNAs (miRNAs) in cell-free serum and plasma samples from human volunteers using deep sequencing of barcoded small RNA cDNA libraries. By introducing calibrator synthetic oligonucleotides during library preparation, we were able to calculate the total as well as specific concentrations of circulating miRNA. Studying trios of samples from newborn babies and their parents we detected placental-specific miRNA in both maternal and newborn circulations and quantitated the relative contribution of placental miRNAs to the circulating pool of miRNAs. Furthermore, sequence variation in the placental miRNA profiles could be traced to the specific placenta of origin. These deep sequencing profiles, which may serve as a model for tumor or disease detection, allow us to define the repertoire of miRNA abundance in the circulation and potential uses as biomarkers. PMID- 23440204 TI - Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation. AB - Somatic hypermutation and clonal selection lead to B cells expressing high affinity antibodies. Here we show that somatic mutations not only play a critical role in antigen binding, they also affect the thermodynamic stability of the antibody molecule. Somatic mutations directly involved in antigen recognition by antibody 93F3, which binds a relatively small hapten, reduce the melting temperature compared with its germ-line precursor by up to 9 degrees C. The destabilizing effects of these mutations are compensated by additional somatic mutations located on surface loops distal to the antigen binding site. Similarly, somatic mutations enhance both the affinity and thermodynamic stability of antibody OKT3, which binds the large protein antigen CD3. Analysis of the crystal structures of 93F3 and OKT3 indicates that these somatic mutations modulate antibody stability primarily through the interface of the heavy and light chain variable domains. The historical view of antibody maturation has been that somatic hypermutation and subsequent clonal selection increase antigen-antibody specificity and binding energy. Our results suggest that this process also optimizes protein stability, and that many peripheral mutations that were considered to be neutral are required to offset deleterious effects of mutations that increase affinity. Thus, the immunological evolution of antibodies recapitulates on a much shorter timescale the natural evolution of enzymes in which function and thermodynamic stability are simultaneously enhanced through mutation and selection. PMID- 23440205 TI - Quinone-dependent proton transfer pathways in the photosynthetic cytochrome b6f complex. AB - As much as two-thirds of the proton gradient used for transmembrane free energy storage in oxygenic photosynthesis is generated by the cytochrome b6f complex. The proton uptake pathway from the electrochemically negative (n) aqueous phase to the n-side quinone binding site of the complex, and a probable route for proton exit to the positive phase resulting from quinol oxidation, are defined in a 2.70-A crystal structure and in structures with quinone analog inhibitors at 3.07 A (tridecyl-stigmatellin) and 3.25-A (2-nonyl-4-hydroxyquinoline N-oxide) resolution. The simplest n-side proton pathway extends from the aqueous phase via Asp20 and Arg207 (cytochrome b6 subunit) to quinone bound axially to heme c(n). On the positive side, the heme-proximal Glu78 (subunit IV), which accepts protons from plastosemiquinone, defines a route for H(+) transfer to the aqueous phase. These pathways provide a structure-based description of the quinone-mediated proton transfer responsible for generation of the transmembrane electrochemical potential gradient in oxygenic photosynthesis. PMID- 23440206 TI - PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR) targeted therapies. AB - Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it. PMID- 23440207 TI - Model-free forecasting outperforms the correct mechanistic model for simulated and experimental data. AB - Accurate predictions of species abundance remain one of the most vexing challenges in ecology. This observation is perhaps unsurprising, because population dynamics are often strongly forced and highly nonlinear. Recently, however, numerous statistical techniques have been proposed for fitting highly parameterized mechanistic models to complex time series, potentially providing the machinery necessary for generating useful predictions. Alternatively, there is a wide variety of comparatively simple model-free forecasting methods that could be used to predict abundance. Here we pose a rather conservative challenge and ask whether a correctly specified mechanistic model, fit with commonly used statistical techniques, can provide better forecasts than simple model-free methods for ecological systems with noisy nonlinear dynamics. Using four different control models and seven experimental time series of flour beetles, we found that Markov chain Monte Carlo procedures for fitting mechanistic models often converged on best-fit parameterizations far different from the known parameters. As a result, the correctly specified models provided inaccurate forecasts and incorrect inferences. In contrast, a model-free method based on state-space reconstruction gave the most accurate short-term forecasts, even while using only a single time series from the multivariate system. Considering the recent push for ecosystem-based management and the increasing call for ecological predictions, our results suggest that a flexible model-free approach may be the most promising way forward. PMID- 23440208 TI - Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. AB - Mutations in the K(V)7.2 gene encoding for voltage-dependent K(+) channel subunits cause neonatal epilepsies with wide phenotypic heterogeneity. Two mutations affecting the same positively charged residue in the S4 domain of K(V)7.2 have been found in children affected with benign familial neonatal seizures (R213W mutation) or with neonatal epileptic encephalopathy with severe pharmacoresistant seizures and neurocognitive delay, suppression-burst pattern at EEG, and distinct neuroradiological features (R213Q mutation). To examine the molecular basis for this strikingly different phenotype, we studied the functional characteristics of mutant channels by using electrophysiological techniques, computational modeling, and homology modeling. Functional studies revealed that, in homomeric or heteromeric configuration with K(V)7.2 and/or K(V)7.3 subunits, both mutations markedly destabilized the open state, causing a dramatic decrease in channel voltage sensitivity. These functional changes were (i) more pronounced for channels incorporating R213Q- than R213W-carrying K(V)7.2 subunits; (ii) proportional to the number of mutant subunits incorporated; and (iii) fully restored by the neuronal K(v)7 activator retigabine. Homology modeling confirmed a critical role for the R213 residue in stabilizing the activated voltage sensor configuration. Modeling experiments in CA1 hippocampal pyramidal cells revealed that both mutations increased cell firing frequency, with the R213Q mutation prompting more dramatic functional changes compared with the R213W mutation. These results suggest that the clinical disease severity may be related to the extent of the mutation-induced functional K(+) channel impairment, and set the preclinical basis for the potential use of K(v)7 openers as a targeted anticonvulsant therapy to improve developmental outcome in neonates with K(V)7.2 encephalopathy. PMID- 23440209 TI - Superiority illusion arises from resting-state brain networks modulated by dopamine. AB - The majority of individuals evaluate themselves as superior to average. This is a cognitive bias known as the "superiority illusion." This illusion helps us to have hope for the future and is deep-rooted in the process of human evolution. In this study, we examined the default states of neural and molecular systems that generate this illusion, using resting-state functional MRI and PET. Resting-state functional connectivity between the frontal cortex and striatum regulated by inhibitory dopaminergic neurotransmission determines individual levels of the superiority illusion. Our findings help elucidate how this key aspect of the human mind is biologically determined, and identify potential molecular and neural targets for treatment for depressive realism. PMID- 23440210 TI - Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure. AB - The nuclear receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) is an important coordinator of glucose homeostasis through its function in different organs such as the endocrine pancreas, adipose tissue, skeletal muscle, and liver. Recently we have demonstrated that COUP-TFII expression in the hypothalamus is restricted to a subpopulation of neurons expressing the steroidogenic factor 1 transcription factor, known to play a crucial role in glucose homeostasis. To understand the functional significance of COUP-TFII expression in the steroidogenic factor 1 neurons, we generated hypothalamic ventromedial nucleus-specific COUP-TFII KO mice using the cyclization recombination/locus of X-overP1 technology. The heterozygous mutant mice display insulin hypersensitivity and a leaner phenotype associated with increased energy expenditure and similar food intake. These mutant mice also present a defective counterregulation to hypoglycemia with altered glucagon secretion. Moreover, the mutant mice are more likely to develop hypoglycemia associated autonomic failure in response to recurrent hypoglycemic or glucopenic events. Therefore, COUP-TFII expression levels in the ventromedial nucleus are keys in the ability to resist the onset of hypoglycemia-associated autonomic failure. PMID- 23440212 TI - Spatial extent of an outbreak in animal epidemics. AB - Characterizing the spatial extent of epidemics at the outbreak stage is key to controlling the evolution of the disease. At the outbreak, the number of infected individuals is typically small, and therefore, fluctuations around their average are important: then, it is commonly assumed that the susceptible-infected recovered mechanism can be described by a stochastic birth-death process of Galton-Watson type. The displacements of the infected individuals can be modeled by resorting to brownian motion, which is applicable when long-range movements and complex network interactions can be safely neglected, like in the case of animal epidemics. In this context, the spatial extent of an epidemic can be assessed by computing the convex hull enclosing the infected individuals at a given time. We derive the exact evolution equations for the mean perimeter and the mean area of the convex hull, and we compare them with Monte Carlo simulations. PMID- 23440211 TI - Membrane protein thermodynamic stability may serve as the energy sink for sorting in the periplasm. AB - Thermodynamic stabilities are pivotal for understanding structure-function relationships of proteins, and yet such determinations are rare for membrane proteins. Moreover, the few measurements that are available have been conducted under very different experimental conditions, which compromises a straightforward extraction of physical principles underlying stability differences. Here, we have overcome this obstacle and provided structure-stability comparisons for multiple membrane proteins. This was enabled by measurements of the free energies of folding and the m values for the transmembrane proteins PhoP/PhoQ-activated gene product (PagP) and outer membrane protein W (OmpW) from Escherichia coli. Our data were collected in the same lipid bilayer and buffer system we previously used to determine those parameters for E. coli outer membrane phospholipase A (OmpLA). Biophysically, our results suggest that the stabilities of these proteins are strongly correlated to the water-to-bilayer transfer free energy of the lipid-facing residues in their transmembrane regions. We further discovered that the sensitivities of these membrane proteins to chemical denaturation, as judged by their m values, was consistent with that previously observed for water soluble proteins having comparable differences in solvent exposure between their folded and unfolded states. From a biological perspective, our findings suggest that the folding free energies for these membrane proteins may be the thermodynamic sink that establishes an energy gradient across the periplasm, thus driving their sorting by chaperones to the outer membranes in living bacteria. Binding free energies of these outer membrane proteins with periplasmic chaperones support this energy sink hypothesis. PMID- 23440213 TI - Species distributions in response to individual soil nutrients and seasonal drought across a community of tropical trees. AB - Tropical forest vegetation is shaped by climate and by soil, but understanding how the distributions of individual tree species respond to specific resources has been hindered by high diversity and consequent rarity. To study species over an entire community, we surveyed trees and measured soil chemistry across climatic and geological gradients in central Panama and then used a unique hierarchical model of species occurrence as a function of rainfall and soil chemistry to circumvent analytical difficulties posed by rare species. The results are a quantitative assessment of the responses of 550 tree species to eight environmental factors, providing a measure of the importance of each factor across the entire tree community. Dry-season intensity and soil phosphorus were the strongest predictors, each affecting the distribution of more than half of the species. Although we anticipated clear-cut responses to dry-season intensity, the finding that many species have pronounced associations with either high or low phosphorus reveals a previously unquantified role for this nutrient in limiting tropical tree distributions. The results provide the data necessary for understanding distributional limits of tree species and predicting future changes in forest composition. PMID- 23440214 TI - Folding and ligand recognition of the TPP riboswitch aptamer at single-molecule resolution. AB - Thiamine pyrophosphate (TPP)-sensitive mRNA domains are the most prevalent riboswitches known. Despite intensive investigation, the complex ligand recognition and concomitant folding processes in the TPP riboswitch that culminate in the regulation of gene expression remain elusive. Here, we used single-molecule fluorescence resonance energy transfer imaging to probe the folding landscape of the TPP aptamer domain in the absence and presence of magnesium and TPP. To do so, distinct labeling patterns were used to sense the dynamics of the switch helix (P1) and the two sensor arms (P2/P3 and P4/P5) of the aptamer domain. The latter structural elements make interdomain tertiary contacts (L5/P3) that span a region immediately adjacent to the ligand-binding site. In each instance, conformational dynamics of the TPP riboswitch were influenced by ligand binding. The P1 switch helix, formed by the 5' and 3' ends of the aptamer domain, adopts a predominantly folded structure in the presence of Mg(2+) alone. However, even at saturating concentrations of Mg(2+) and TPP, the P1 helix, as well as distal regions surrounding the TPP-binding site, exhibit an unexpected degree of residual dynamics and disperse kinetic behaviors. Such plasticity results in a persistent exchange of the P3/P5 forearms between open and closed configurations that is likely to facilitate entry and exit of the TPP ligand. Correspondingly, we posit that such features of the TPP aptamer domain contribute directly to the mechanism of riboswitch-mediated translational regulation. PMID- 23440215 TI - Identification of parameters through which surface chemistry determines the lifetimes of hot electrons in small Au nanoparticles. AB - This paper describes measurements of the dynamics of hot electron cooling in photoexcited gold nanoparticles (Au NPs) with diameters of ~3.5 nm, and passivated with either a hexadecylamine or hexadecanethiolate adlayer, using ultrafast transient absorption spectroscopy. Fits of these dynamics with temperature-dependent Mie theory reveal that both the electronic heat capacity and the electron-phonon coupling constant are larger for the thiolated NPs than for the aminated NPs, by 40% and 30%, respectively. Density functional theory calculations on ligand-functionalized Au slabs show that the increase in these quantities is due to an increased electronic density of states near the Fermi level upon ligand exchange from amines to thiolates. The lifetime of hot electrons, which have thermalized from the initial plasmon excitation, increases with increasing electronic heat capacity, but decreases with increasing electron phonon coupling, so the effects of changing surface chemistry on these two quantities partially cancel to yield a hot electron lifetime of thiolated NPs that is only 20% longer than that of aminated NPs. This analysis also reveals that incorporation of a temperature-dependent electron-phonon coupling constant is necessary to adequately fit the dynamics of electron cooling. PMID- 23440216 TI - Time-varying functional network information extracted from brief instances of spontaneous brain activity. AB - Recent functional magnetic resonance imaging studies have shown that the brain is remarkably active even in the absence of overt behavior, and this activity occurs in spatial patterns that are reproducible across subjects and follow the brain's established functional subdivision. Investigating the distribution of these spatial patterns is an active area of research with the goal of obtaining a better understanding of the neural networks underlying brain function. One intriguing aspect of spontaneous activity is an apparent nonstationarity, or variability of interaction between brain regions. It was recently proposed that spontaneous brain activity may be dominated by brief traces of activity, possibly originating from a neuronal avalanching phenomenon. Such traces may involve different subregions in a network at different times, potentially reflecting functionally relevant relationships that are not captured with conventional data analysis. To investigate this, we examined publicly available functional magnetic resonance imaging data with a dedicated analysis method and found indications that functional networks inferred from conventional correlation analysis may indeed be driven by activity at only a few critical time points. Subsequent analysis of the activity at these critical time points revealed multiple spatial patterns, each distinctly different from the established functional networks. The spatial distribution of these patterns suggests a potential functional relevance. PMID- 23440217 TI - Direct involvement of DprA, the transformation-dedicated RecA loader, in the shut off of pneumococcal competence. AB - Natural bacterial transformation is a genetically programmed process allowing genotype alterations that involves the internalization of DNA and its chromosomal integration catalyzed by the universal recombinase RecA, assisted by its transformation-dedicated loader, DNA processing protein A (DprA). In Streptococcus pneumoniae, the ability to internalize DNA, known as competence, is transient, developing suddenly and stopping as quickly. Competence is induced by the comC-encoded peptide, competence stimulating peptide (CSP), via a classic two component regulatory system ComDE. Upon CSP binding, ComD phosphorylates the ComE response-regulator, which then activates transcription of comCDE and the competence-specific sigma(X), leading to a sudden rise in CSP levels and rendering all cells in a culture competent. However, how competence stops has remained unknown. We report that DprA, under sigma(X) control, interacts with ComE~P to block ComE-driven transcription, chiefly impacting sigma(X) production. Mutations of dprA specifically disrupting interaction with ComE were isolated and shown to map mainly to the N-terminal domain of DprA. Wild-type DprA but not ComE interaction mutants affected in vitro binding of ComE to its promoter targets. Once introduced at the dprA chromosomal locus, mutations disrupting DprA interaction with ComE altered competence shut-off. The absence of DprA was found to negatively impact growth following competence induction, highlighting the importance of DprA for pneumococcal physiology. DprA has thus two key roles: ensuring production of transformants via interaction with RecA and competence shut-off via interaction with ComE, avoiding physiologically detrimental consequences of prolonged competence. Finally, phylogenetic analyses revealed that the acquisition of a new function by DprA impacted its evolution in streptococci relying on ComE to regulate comX expression. PMID- 23440218 TI - Both information and social cohesion determine collective decisions in animal groups. AB - During consensus decision making, individuals in groups balance personal information (based on their own past experiences) with social information (based on the behavior of other individuals), allowing the group to reach a single collective choice. Previous studies of consensus decision making processes have focused on the informational aspects of behavioral choice, assuming that individuals make choices based solely on their likelihood of being beneficial (e.g., rewarded). However, decisions by both humans and nonhuman animals systematically violate such expectations. Furthermore, the typical experimental paradigm of assessing binary decisions, those between two mutually exclusive options, confounds two aspects common to most group decisions: minimizing uncertainty (through the use of personal and social information) and maintaining group cohesion (for example, to reduce predation risk). Here we experimentally disassociate cohesion-based decisions from information-based decisions using a three-choice paradigm and demonstrate that both factors are crucial to understanding the collective decision making of schooling fish. In addition, we demonstrate how multiple informational dimensions (here color and stripe orientation) are integrated within groups to achieve consensus, even though no individual is explicitly aware of, or has a unique preference for, the consensus option. Balancing of personal information and social cues by individuals in key frontal positions in the group is shown to be essential for such group-level capabilities. Our results demonstrate the importance of integrating informational with other social considerations when explaining the collective capabilities of group-living animals. PMID- 23440219 TI - Forces shaping a Hox morphogenetic gene network. AB - The Abdominal-B selector protein induces organogenesis of the posterior spiracles by coordinating an organ-specific gene network. The complexity of this network begs the questions of how it originated and what selective pressures drove its formation. Given that the network likely formed in a piecemeal fashion, with elements recruited sequentially, we studied the consequences of expressing individual effectors of this network in naive epithelial cells. We found that, with exception of the Crossveinless-c (Cv-c) Rho GTPase-activating protein, most effectors exert little morphogenetic effect by themselves. In contrast, Cv-c expression causes cell motility and down-regulates epithelial polarity and cell adhesion proteins. These effects differ in cells endogenously expressing Cv-c, which have acquired compensatory mechanisms. In spiracle cells, the down regulation of polarity and E-cadherin expression caused by Cv-c-induced Rho1 inactivation are compensated for by the simultaneous spiracle up-regulation of guanine nucleotide exchange factor (GEF) proteins, cell polarity, and adhesion molecules. Other epithelial cells that have coopted Cv-c to their morphogenetic gene networks are also resistant to Cv-c's deleterious effects. We propose that cooption of a novel morphogenetic regulator to a selector cascade causes cellular instability, resulting in strong selective pressure that leads that same cascade to recruit molecules that compensate it. This experimental-based hypothesis proposes how the frequently observed complex organogenetic gene networks are put together. PMID- 23440220 TI - Toward high-energy-density, high-efficiency, and moderate-temperature chip-scale thermophotovoltaics. AB - The challenging problem of ultra-high-energy-density, high-efficiency, and small scale portable power generation is addressed here using a distinctive thermophotovoltaic energy conversion mechanism and chip-based system design, which we name the microthermophotovoltaic (MUTPV) generator. The approach is predicted to be capable of up to 32% efficient heat-to-electricity conversion within a millimeter-scale form factor. Although considerable technological barriers need to be overcome to reach full performance, we have performed a robust experimental demonstration that validates the theoretical framework and the key system components. Even with a much-simplified MUTPV system design with theoretical efficiency prediction of 2.7%, we experimentally demonstrate 2.5% efficiency. The MUTPV experimental system that was built and tested comprises a silicon propane microcombustor, an integrated high-temperature photonic crystal selective thermal emitter, four 0.55-eV GaInAsSb thermophotovoltaic diodes, and an ultra-high-efficiency maximum power-point tracking power electronics converter. The system was demonstrated to operate up to 800 degrees C (silicon microcombustor temperature) with an input thermal power of 13.7 W, generating 344 mW of electric power over a 1-cm(2) area. PMID- 23440221 TI - Recruitment of oriens-lacunosum-moleculare interneurons during hippocampal ripples. AB - Sharp wave-associated ~200-Hz ripple oscillations in the hippocampus have been implicated in the consolidation of memories. However, knowledge on mechanisms underlying ripples is still scarce, in particular with respect to synaptic involvement of specific cell types. Here, we used cell-attached and whole-cell recordings in vitro to study activity of pyramidal cells and oriens-lacunosum moleculare (O-LM) interneurons during ripples. O-LM cells received ripple associated synaptic input that arrived delayed (3.3 +/- 0.3 ms) with respect to the maximum amplitude of field ripples and was locked to the ascending phase of field oscillations (mean phase: 209 +/- 6 degrees ). In line, O-LM cells episodically discharged late during ripples (~6.5 ms after the ripple maximum), and firing was phase-locked to field oscillations (mean phase: 219 +/- 9 degrees ). Our data unveil recruitment of O-LM neurons during ripples, suggesting a previously uncharacterized role of this cell type during sharp wave-associated activity. PMID- 23440222 TI - Onchocerca volvulus-neurotransmitter tyramine is a biomarker for river blindness. AB - Onchocerciasis, also known as "river blindness", is a neglected tropical disease infecting millions of people mainly in Africa and the Middle East but also in South America and Central America. Disease infectivity initiates from the filarial parasitic nematode Onchocerca volvulus, which is transmitted by the blackfly vector Simulium sp. carrying infectious third-stage larvae. Ivermectin has controlled transmission of microfilariae, with an African Program elimination target date of 2025. However, there is currently no point-of-care diagnostic that can distinguish the burden of infection--including active and/or past infection- and enable the elimination program to be effectively monitored. Here, we describe how liquid chromatography-MS-based urine metabolome analysis can be exploited for the identification of a unique biomarker, N-acetyltyramine-O,beta-glucuronide (NATOG), a neurotransmitter-derived secretion metabolite from O. volvulus. The regulation of this tyramine neurotransmitter was found to be linked to patient disease infection, including the controversial antibiotic doxycycline treatment that has been shown to both sterilize and kill adult female worms. Further clues to its regulation have been elucidated through biosynthetic pathway determination within the nematode and its human host. Our results demonstrate that NATOG tracks O. volvulus metabolism in both worms and humans, and thus can be considered a host-specific biomarker for onchocerciasis progression. Liquid chromatography-MS based urine metabolome analysis discovery of NATOG not only has broad implications for a noninvasive host-specific onchocerciasis diagnostic but provides a basis for the metabolome mining of other neglected tropical diseases for the discovery of distinct biomarkers and monitoring of disease progression. PMID- 23440224 TI - The quitline is calling: comment on "Ask-Advise-Connect". PMID- 23440225 TI - Phorbol 12-Myristate 13-Acetate Enhances Long-Term Potentiation in the Hippocampus through Activation of Protein Kinase Cdelta and epsilon. AB - Many intracellular proteins and signaling cascades contribute to the sensitivity of N-methyl-D-aspartate receptors (NMDARs). One such putative contributor is the serine/threonine kinase, protein kinase C (PKC). Activation of PKC by phorbol 12 myristate 13-acetate (PMA) causes activation of extracellular signal-regulated kinase (ERK) and promotes the formation of new spines in cultured hippocampal neurons. The purpose of this study was to examine which PKC isoforms are responsible for the PMA-induced augmentation of long-term potentiation (LTP) in the CA1 stratum radiatum of the hippocampus in vitro and verify that this facilitation requires NMDAR activation. We found that PMA enhanced the induction of LTP by a single episode of theta-burst stimulation in a concentration dependent manner without affecting to magnitude of baseline field excitatory postsynaptic potentials. Facilitation of LTP by PMA (200 nM) was blocked by the nonspecific PKC inhibitor, Ro 31-8220 (10uM); the selective PKCdelta inhibitor, rottlerin (1uM); and the PKCepsilon inhibitor, TAT-epsilonV1-2 peptide (500 nM). Moreover, the NMDAR blocker DL-APV (50uM) prevented enhancement of LTP by PMA. Our results suggest that PMA contributes to synaptic plasticity in the nervous system via activation of PKCdelta and/or PKCepsilon, and confirm that NMDAR activity is required for this effect. PMID- 23440226 TI - Industry sponsorship and research outcome: a Cochrane review. PMID- 23440229 TI - Specific biases for identifying facial expression of emotion in children and adolescents with conversion disorders. AB - OBJECTIVE: This study aimed to assess how children and adolescents with conversion disorders identify universal facial expressions of emotion and to determine whether identification of emotion in faces relates to subjective emotional distress. METHODS: Fifty-seven participants (41 girls and 16 boys) aged 8.5 to 18 years with conversion disorders and 57 age- and sex-matched healthy controls completed a computerized task in which their accuracy and reaction times for identifying facial expressions were recorded. To isolate the effect of individual emotional expressions, participants' reaction times for each emotion (fear, anger, sadness, disgust, and happiness) were subtracted from their reaction times for the neutral control face. Participants also completed self report measures of subjective emotional distress. RESULTS: Children/Adolescents with conversion disorders showed faster reaction times for identifying expressions of sadness (t(112) = -2.2, p = .03; 444 [609] versus 713 [695], p = .03) and slower reactions times for happy expressions (t(99.3) = 2.28, p <= .024; -33 [35] versus 174 [51], p = .024), compared with controls (F(33.75, 419.81) = 3.76, p < .001). There were no significant correlations (at the corrected p value of .01) between reaction times and subjective reports of perceived distress (r values ranged from 092 to 0.221; p > .018). There were also no differences in identification accuracy for any emotion (p > .82). CONCLUSIONS: The observation of faster reaction times to sad faces in children and adolescents with conversion disorders suggests increased vigilance and motor readiness to emotional signals that are potential threats to self or to close others. These effects may occur before conscious processing. PMID- 23440228 TI - Examining the relationship between depression and asthma exacerbations in a prospective follow-up study. AB - BACKGROUND: Although depression has been linked with asthma, its relationship with asthma exacerbations, including emergency department (ED) visits and oral steroid (OS) use, has not been well documented. The aim is to investigate whether depression increases exacerbations among patients with asthma. METHOD: The study included 568 participants with asthma who were between 18 and 56 years old, were taking an inhaled corticosteroid, and participated in baseline and follow-up surveys. Surveys and medical records from a large, health system were collected as part of the Adherence Feedback for Improving Respiratory Medication Use trial. Number of ED visits and OS prescription fills for asthma were calculated for 12 month periods before and after the follow-up survey. Depression was measured using a standardized two-item instrument. Negative binomial regression and modified proportional hazards models were used. RESULTS: Among patients with asthma, those who had depression (n = 187; 32.9%) were at increased risk for an asthma-related ED visit (adjusted relative risk = 1.96, 95% confidence interval [CI] = 1.02-3.75), but not an OS fill (adjusted relative risk = 0.98; 95% CI = 0.72-1.32). Participants with depression and asthma who received psychiatric treatment via antidepressant medication (n = 126; 22.2%) or psychotherapy (n = 39; 6.9%) were more likely to have an ED visit (medication hazard ratio = 2.09, 95% CI = 1.35-3.25; psychotherapy hazard ratio = 2.07, 95% CI = 1.38-3.22). CONCLUSIONS: This study suggests a temporal relationship between depression and asthma-related ED visits. Research and practice must consider the importance of these comorbid conditions. Trial Registration ClinicalTrials.gov identifier: NCT00459368. PMID- 23440230 TI - Status and development of allied health personnel in cardiothoracic surgery in Latin America. AB - INTRODUCTION: The role of allied health personnel (not physician) in cardiothoracic surgery has evolved substantially since the beginnings of this discipline in the 70's, especially in developed countries. METHODS: To explore the status of allied health personnel in cardiothoracic surgery in Latin America, a research was geared to know the general context of human resources in public health and specifically in cardiothoracic surgery. Official data from the World Health Organization and the Pan American Health Organization were acquired. An on line survey was sent to Latin-American cardiothoracic surgeons through either scientific societies or personal e-mail, to get direct information on human resources management of the surgical services. RESULTS: There is lack of information on the medical literature regarding the allied health personnel activities in the region. Sixty one Latin American cardiothoracic centers answered the survey. The survey revealed that the profile of the allied health personnel is outlined by nurses, perfusion and anesthesiology technicians; whose routine activities are restricted to minor controls. CONCLUSIONS: At the moment, the lack of information and official data generates difficulties in analyzing the development status of allied health personnel in cardiothoracic surgery departments in the region of Latin America. In the light of the results and growing interest of developed countries in incorporating the allied health personnel to improve the work capacity and the quality of care in cardiothoracic surgery centers, it would be sensible to develop policies oriented to train and organize this activity in Latin America. PMID- 23440234 TI - Impact of loneliness and living alone. PMID- 23440235 TI - Impact of loneliness and living alone--reply. PMID- 23440236 TI - Health status in elderly persons living alone. PMID- 23440237 TI - Health status in elderly persons living alone--reply. PMID- 23440238 TI - Gait speed and high blood pressure. PMID- 23440239 TI - Hypertension and mortality in the elderly: further insights. PMID- 23440240 TI - Walking speed is a useful marker of frailty in older persons. PMID- 23440241 TI - Walking speed is a useful marker of frailty in older persons--reply. PMID- 23440243 TI - Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome. AB - Children with Down syndrome have an increased incidence of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia. The majority of these cases harbor somatic mutations in the GATA1 gene, which results in the loss of full-length GATA1. Only a truncated isoform of GATA1 that lacks the N-terminal 83 amino acids (GATA1-S) remains. We found through genetic studies of 106 patients with TAM that internally deleted GATA1 proteins (GATA1-IDs) lacking amino acid residues 77-119 or 74-88 (created by splicing mutations) contributed to the genesis of TAM in 6 patients. Analyses of GATA1-deficient embryonic megakaryocytic progenitors revealed that the GATA1 function in growth restriction was disrupted in GATA1-IDs. In contrast, GATA1-S promoted megakaryocyte proliferation more profoundly than that induced by GATA1 deficiency. These results indicate that the internally deleted regions play important roles in megakaryocyte proliferation and that perturbation of this mechanism is involved in the pathogenesis of TAM. PMID- 23440242 TI - Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. AB - In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients-children and adults alike-which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses. PMID- 23440244 TI - RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an EMU myc/Bcl-2 mouse model. AB - ABT-737 is a promising chemotherapeutic agent that promotes apoptosis by acting as a selective BH3 mimetic to neutralize Bcl-2-like family members. One shortcoming with its use is that Mcl-1, a member of the Bcl-2 family, is poorly inhibited by ABT-737 and thus is a major cause of resistance. We performed a short hairpin RNA (shRNA)-based drop-out screen to identify novel genes and pathways that could reverse resistance to ABT-737 treatment in Eu-myc/Bcl-2 lymphoma cells engineered to rely on endogenous Mcl-1 for survival. Several drug sensitive shRNAs were identified that were selectively depleted in the presence of ABT-737. Of these, 2 independent shRNAs targeting the RNA/DNA helicase Dhx9 were found to sensitize lymphomas to ABT-737 to an extent comparable to control Mcl-1 shRNAs. Although Dhx9 suppression sensitized both mouse and human cells to ABT-737 treatment, it did so without altering MCL-1 levels. Rather, loss of Dhx9 appeared to activate a p53-dependent apoptotic program, through aggravation of replicative stress, which was found to be both necessary and sufficient for the ABT-737-shDhx9 synthetic lethal relationship. PMID- 23440245 TI - A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance. AB - Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML-RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdac1 has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells. PMID- 23440246 TI - Self-assembly of DNA nanoprisms with only two component strands. AB - We report a symmetric design strategy to reduce the number of required DNA component strands in 3D self-assembly and have demonstrated this strategy by construction of a series of 3D DNA nanoprisms out of only two DNA strands. PMID- 23440248 TI - Cystoid macular edema as the initial manifestation of choroidal melanoma. AB - Uveal melanomas are a common clinical entity that initially present in a variety of ways. Cystoid macular edema is caused by many conditions, but it is rarely associated with uveal melanoma. We report two cases of patients that presented with visually significant cystoid macular edema that was later found to be secondary to choroidal melanoma. We describe the patients' course and treatment and provide a mechanism for the potential cause of edema in patients with uveal melanoma. PMID- 23440247 TI - Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the beta2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: a randomised trial. AB - BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting beta2 agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease. OBJECTIVE: To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma. METHODS: Patients (aged >=12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 ug or FF/VI 200/25 ug once daily in the evening, or fluticasone propionate (FP) 500 ug twice daily. Safety evaluations included adverse events (AEs), non fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate. RESULTS: On-treatment AEs were similar across groups (FF/VI 66-69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6-7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p<=0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 ug and 1.09 [0.87 to 1.38] for FF/VI 200/25 ug). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia's formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [Tmax], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 ug]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 ug]). Mean heart rate (24 h Holter monitoring) decreased from screening values in all groups (0.2-1.1 bpm FF/VI vs 5 bpm FP; Week 52). CONCLUSIONS: FF/VI (100/25 ug or 200/25 ug) administered once daily over 52 weeks was well tolerated by patients aged >=12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern. CLINICALTRIALS.GOV: NCT01018186. PMID- 23440249 TI - alpha-Pinene Rich Volatile Constituents of Cupressus torulosa D. Don from Uttarakhand Himalaya. AB - The aim of the present study was to investigate the various chemical components present in the volatile oil of the leaf of Cupressus torulosa and to find variation of essential oil components among the populations. Twenty-two, 17 and 20 compounds were identified with 95.45, 95.45 and 91.45% in Kalsi, Joshimath and Jeharikhal, respectively were identified by gas chromatography-mass spectrometry and quantify by gas chromatography and flame ionization detector (GC-FID). The major compound identified was alpha-pinene in all the populations and it varied between 30.30 and 34.26%. Results of the study stated that alpha-pinene, delta- 3 carene, limonene and sabinene components were detected in high concentration, thus competent for use in related industries and as a favourite ornamental aromatic tree. PMID- 23440250 TI - Digital analysis of flap parameter accuracy and objective assessment of opaque bubble layer in femtosecond laser-assisted LASIK: a novel technique. AB - BACKGROUND: The purpose of this study was to determine flap parameter accuracy, extent of the opaque bubble layer, and incidence of skip lines in femtosecond laser-assisted stromal in situ keratomileusis (LASIK) using the WaveLight((r)) FS200 laser and optoelectronic clinical measurements. METHODS: Images from 101 flaps were automatically recorded during consecutive routine LASIK procedures performed using the WaveLight FS200 femtosecond laser and the EX500 excimer laser. Digital processing of these images was used to evaluate objectively the diameter of FS200-created flaps, by comparing planned versus achieved procedures and to evaluate the incidence and extent (area) of the opaque bubble layer. RESULTS: The intended flap diameters were between 8.00 mm and 9.50 mm. The achieved flap diameters showed extremely high precision, and were on average 0.16 +/- 0.04 mm smaller for a 8.00 mm intended flap diameter, -0.12 +/- 0.03 mm smaller for a 8.50 mm flap, and up +0.06 +/- 0.06 mm wider for a 9.50 mm flap. With an average flap area of 72.4 mm(2), the mean area of the opaque bubble layer (4.1 +/- 4.3 [range 0-14.34] mm(2)) corresponded to a 6% opaque bubble layer-to flap area. Specifically, 80% of the femtosecond-created flaps had an essentially zero opaque bubble layer (<2.7% of the flap area). CONCLUSION: In our clinical experience, flaps created using FS200 and this novel highly objective assessment technique demonstrate both precision and reproducibility. The incidence of opaque bubble layer was minimal. PMID- 23440252 TI - The effect of community-managed palliative care program on quality of life in the elderly in rural Tamil Nadu, India. AB - BACKGROUND: HelpAge India has been facilitating community-managed palliative care program in the villages of Tamil Nadu, India. OBJECTIVE: To evaluate the effect of perceived quality of life in the elderly in the project villages in rural Tamil Nadu. MATERIALS AND METHODS: It was a community-based evaluation study. Considering the mean difference of 0.6, design effect-2, precision-5%, power 80%, and 10% non-response, a sample size of 450 elderly persons (more than 60 years) was adequate. Sample was selected by two-stage cluster sampling. Tamil version of "WHO-Quality of Life-brief questionnaire" was used. Trained interviewers made house-to-house visits and obtained information by personally interviewing the subjects. RESULTS: The mean score for perceived physical quality of life in the project area was (10.47 +/- 1.80 SD) high than the mean score (10.17 +/- 1.82 SD) in the control area (P = 0.013) and the mean score for psychological support (10.13 +/- 2.25 SD) in project area was high than the mean score (9.8 +/- 2.29 SD) in control area (P = 0.043). There was no effect on domain of social relationship and environment. CONCLUSIONS: In the project villages, the perceived physical quality of life and psychological support among elderly persons was significantly better than the control villages. PMID- 23440251 TI - The molecular basis for disease phenotype in chronic Chlamydia-induced arthritis. AB - Genital Chlamydia trachomatis infections can elicit an inflammatory arthritis in some individuals, and recent surprising studies have demonstrated that only ocular (trachoma) strains, not genital strains, of the organism are present in the synovial tissues of patients with the disease. This observation suggests an explanation for the small proportion of genitally-infected patients who develop Chlamydia-induced arthritis. Other recent studies have begun to identify the specific chlamydial gene products that elicit the synovial inflammatory response during both active and quiescent disease, although much more study will be required to complete the understanding of that complex process of host-pathogen interaction. Several newly developed experimental methods and approaches for study of the process will enable identification of new therapeutic targets, and possibly strategies for prevention of the disease altogether. PMID- 23440253 TI - Effect of volunteering on risk factors for cardiovascular disease in adolescents: a randomized controlled trial. AB - IMPORTANCE: The idea that individuals who help others incur health benefits themselves suggests a novel approach to improving health while simultaneously promoting greater civic orientation in our society. The present study is the first experimental trial, to our knowledge, of whether regular volunteering can reduce cardiovascular risk factors in adolescents. OBJECTIVE: To test a novel intervention that assigned adolescents to volunteer with elementary school-aged children as a means of improving adolescents' cardiovascular risk profiles. DESIGN: Randomized controlled trial, with measurements taken at baseline and 4 months later (postintervention). SETTING: Urban public high school in western Canada. PARTICIPANTS: One hundred six 10th-grade high school students who were fluent in English and free of chronic illnesses. INTERVENTION: Weekly volunteering with elementary school-aged children for 2 months vs wait-list control group. MAIN OUTCOME MEASURES: Cardiovascular risk markers of C-reactive protein level, interleukin 6 level, total cholesterol level, and body mass index. RESULTS: No statistically significant group differences were found at baseline. Postintervention, adolescents in the intervention group showed significantly lower interleukin 6 levels (log10 mean difference, 0.13; 95% CI, 0.004 to 0.251), cholesterol levels (log10 mean difference, 0.03; 95% CI, 0.003 to 0.059), and body mass index (mean difference, 0.39; 95% CI, 0.07 to 0.71) compared with adolescents in the control group. Effects for C-reactive protein level were marginal (log10 mean difference, 0.13; 95% CI, -0.011 to 0.275). Preliminary analyses within the intervention group suggest that those who increased the most in empathy and altruistic behaviors, and who decreased the most in negative mood, also showed the greatest decreases in cardiovascular risk over time. CONCLUSIONS AND RELEVANCE: Adolescents who volunteer to help others also benefit themselves, suggesting a novel way to improve health. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01698034. PMID- 23440255 TI - Glucose metabolism in cardiovascular surgery. AB - During the past few years, it has become evident that metabolic control is a major determinant of postoperative outcomes, not only for diabetic patients but for all patients undergoing surgery.In cardiac and vascular surgery, myocardial ischemia is a common challenge and the management of hyperglycemia should be part of the strategy aimed at optimizing cardiac protection during these types of surgery, since performed in high risk patients. Little informations are available on the relation between glucose substrate and the type of anesthesia and few studies have been performed on glucose metabolism in the perioperative risk assessment as well as on intraoperative and post surgical management of hyperglycemia in patients submitted to cardiac and vascular surgery. Evidence exists that even slight increased in glycemia are detrimental for patients (diabetic and non) elective for cardiac and vascular surgery, though the precise details of the timing of insulin therapy, the desired target serum glucose level, and the duration of therapy are so far to be completely elucidated. Anesthestiologists can therefore affect outcome by simply preserving a normal blood glucose concentration initiating in the operating room. The challenge to optimize glucose control should begin during preoperative evaluation. PMID- 23440254 TI - Probing oxidative stress: Small molecule fluorescent sensors of metal ions, reactive oxygen species, and thiols. AB - Oxidative stress is a common feature shared by many diseases, including neurodegenerative diseases. Factors that contribute to cellular oxidative stress include elevated levels of reactive oxygen species, diminished availability of detoxifying thiols, and the misregulation of metal ions (both redox-active iron and copper as well as non-redox active calcium and zinc). Deciphering how each of these components interacts to contribute to oxidative stress presents an interesting challenge. Fluorescent sensors can be powerful tools for detecting specific analytes within a complicated cellular environment. Reviewed here are several classes of small molecule fluorescent sensors designed to detect several molecular participants of oxidative stress. We focus our review on describing the design, function and application of probes to detect metal cations, reactive oxygen species, and intracellular thiol-containing compounds. In addition, we highlight the intricacies and complications that are often faced in sensor design and implementation. PMID- 23440257 TI - DSM-5--the future arrived. PMID- 23440258 TI - Deep brain stimulation for the treatment of tremor and ataxia associated with abetalipoproteinemia. AB - BACKGROUND: Abetalipoproteinemia is a rare disorder of fat absorption, characterized by vitamin deficiency, acanthocytosis, and neurologic symptoms including ataxia and tremor. CASE REPORT: A 41-year-old male with abetalipoproteinemia is presented. He underwent staged bilateral thalamic deep brain stimulation (DBS) for the treatment of his tremors. After DBS, the patient achieved significant improvements in his tremors, ataxia, and quality of life. DISCUSSION: Thalamic DBS proved to be both safe and efficacious in the management of ataxia and tremors in a patient with abetalipoproteinemia. This is the first report of DBS in abetalipoproteinemia in the literature. PMID- 23440256 TI - Assessment scales in stroke: clinimetric and clinical considerations. AB - As stroke care has developed, there has been a need to robustly assess the efficacy of interventions both at the level of the individual stroke survivor and in the context of clinical trials. To describe stroke-survivor recovery meaningfully, more sophisticated measures are required than simple dichotomous end points, such as mortality or stroke recurrence. As stroke is an exemplar disabling long-term condition, measures of function are well suited as outcome assessment. In this review, we will describe functional assessment scales in stroke, concentrating on three of the more commonly used tools: the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index. We will discuss the strengths, limitations, and application of these scales and use the scales to highlight important properties that are relevant to all assessment tools. We will frame much of this discussion in the context of "clinimetric" analysis. As they are increasingly used to inform stroke-survivor assessments, we will also discuss some of the commonly used quality-of-life measures. A recurring theme when considering functional assessment is that no tool suits all situations. Clinicians and researchers should chose their assessment tool based on the question of interest and the evidence base around clinimetric properties. PMID- 23440259 TI - Anesthetic management for percutaneous aortic valve implantation: an overview of worldwide experiences. AB - Transcatheter aortic valve implantation is an emergent technique for high risk patients with aortic stenosis. Transcatheter aortic valve implantation poses significant challenges about its management, due to the procedure itself (i.e. the passage of large stiff sheaths in diseased vessels, the valve dilatation and the prosthesis positioning during a partial cardiac standstill) and the population of elder and high-risk patients who undergo the implantation. Retrograde transfemoral approach is the most popular procedure and a great number of cases is reported. Nevertheless, there is not a consensus regarding the intraoperative anesthesiological strategies, which vary in the different Centers. Sedation plus local anesthesia or general anesthesia are both valid alternatives and can be applied according to patient's characteristics and procedural instances. Most groups started the implantation program with a general anesthesia; indeed, it offers many advantages, mainly regarding the possibility of an early diagnosis and treatment of potential complications, through the use of the transesophageal echocardiography. However, after the initial experiences, many groups began to employ routinely sedation plus local anesthesia for transcatheter aortic valve implantation and their procedural and periprocedural success demonstrates that it is feasible, with many possible advantages. Many aspects about perioperative anesthetic management for transcatheter aortic valve implantation are still to be defined. Aim of this work is to clarify the different management strategies through a review of the available literature published in pubmed till June 2011. PMID- 23440260 TI - Saudi regulations for the accreditation of sleep medicine physicians and technologists. AB - The professional content of sleep medicine has grown significantly over the past few decades, warranting the recognition of sleep medicine as an independent specialty. Because the practice of sleep medicine has expanded in Saudi Arabia over the past few years, a national regulation system to license and ascertain the competence of sleep medicine physicians and technologists has become essential. Recently, the Saudi Commission for Health Specialties formed the National Committee for the Accreditation of Sleep Medicine Practice and developed national accreditation criteria. This paper presents the newly approved Saudi accreditation criteria for sleep medicine physicians and technologists. PMID- 23440261 TI - miRNA-181b increases the sensitivity of pancreatic ductal adenocarcinoma cells to gemcitabine in vitro and in nude mice by targeting BCL-2. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease and is usually resistant to chemotherapy. MicroRNA-181b (miR-181b) has been reported to be associated with chemoresistance in various types of cancer. In this study, we investigated the effects of miR-181b on the chemosensitivity of PDAC cells to gemcitabine and the underlying molecular events. miR-181b mimics and inhibitors were synthesized for transient gene transfection in vitro. Lentivirus carrying miR-181b mimics were used to infect PDAC cells for nude mouse xenograft assays by implanting infected PDAC cells into recipient mice. Cell viability was determined by MTT assays, while gene expression was assessed using qRT-PCR, western blot analysis and enzyme-linked immunosorbent assay (ELISA). miR-181b targeting BCL-2 expression was assessed by a dual-luciferase activity assay. The data showed that miRNA-181b expression sensitized PDAC cells to gemcitabine treatment. Although gemcitabine-resistant PDAC cell sublines (SW1990/GR and CFPAC-1/GR) expressed higher levels of miRNA-181b, gemcitabine induced higher levels of apoptosis in PDAC cells transfected with miRNA-181b mimics. The nude mouse xenograft assay data showed that miR-181b transfection also sensitized the cells to gemcitabine treatment in vivo. Molecularly, bioinformatics data predicted that miR-181b was able to bind to BCL-2 mRNA 3'UTR. The dual luciferase activity assay revealed that miRNA-181b downregulated BCL-2 expression. The results from western blot analysis showed a reduced BCL-2 expression following miR-181b transfection but an enhanced caspase-3 activity in miRNA-181b mimic-transfected PDAC cells. This study demonstrates that miRNA-181b sensitizes PDAC cells to gemcitabine by targeting BCL-2. PMID- 23440262 TI - Quantitative comparison of protein dynamics in live cells and in vitro by in-cell (19)F-NMR. AB - Here we describe how a (19)F-probe incorporated into an endogenous protein by a chemical biology method revealed protein dynamics. By explicit determination of ligand-bound and unbound structures with X-ray crystallography, the quantitative comparison of the protein's dynamics in live cells and in vitro is presented. These results clearly demonstrated the greater conformational fluctuations of the intracellular protein, partially due to macromolecular crowding effects. PMID- 23440263 TI - A control model to evaluate pharmacotherapy for allergic rhinitis in children. AB - IMPORTANCE: Although the question of whether early diagnosis and treatment of pediatric allergic rhinitis (AR) improve disease control is important, a more crucial question is whether we can evaluate the effect of treatment on disease control using an impairment-risk model. OBJECTIVE: To conduct a systematic review evaluating application of a control model based on domains of impairment and risk (similar to that used for asthma) in pharmacotherapy for children with AR. EVIDENCE ACQUISITION: We searched the MEDLINE and EMBASE databases (January 1, 1996, through May 31, 2012) for controlled studies lasting 2 weeks or longer in children with confirmed diagnoses of AR, including measures assessing impairment and/or risk of comorbid conditions. RESULTS: Sixteen controlled clinical trials, including more than 3000 children (aged 2-18 years) with AR (seasonal, n = 2290; perennial, n = 800), met the study criteria. All medication classes improved impairment related to AR, but between-treatment comparisons were limited because of different assessments. Intranasal steroids improved risk outcomes associated with asthma and obstructive sleep apnea. Small single studies suggested possible effects of oral antihistamines on asthma and sleep-disordered breathing. No risk data were available for nasal antihistamines or montelukast sodium. CONCLUSIONS: Treatment of AR, particularly with intranasal steroids, improves disease control in children by reducing disease-associated impairment and risk. All AR medications with proved efficacy probably improve impairment, paralleling symptom reduction. Intranasal steroids may reduce the likelihood of comorbidities that increase health care use. These observations, although limited by different protocols and outcomes measures among studies, support current practice recommendations. Studies that use standardized measures of impairment to permit better comparison and appropriate protocols for risk evaluation are needed. PMID- 23440264 TI - Progressive leg pain and weakness. AB - A 54-year-old man presented with progressive asymmetric leg pain and weakness. He had a history of invasive squamous cell carcinoma that was fully treated 2 years earlier. His leg symptoms progressed relentlessly during several months. Imaging studies demonstrated enhancement of the cauda equina and leptomeninges of the lower spinal cord. Initial cerebrospinal fluid examination showed an elevated protein concentration and lymphocytic pleocytosis with no malignant cells on cytological analysis. There was short-term improvement in symptoms and cerebrospinal fluid abnormalities with intravenous steroids. Two additional cerebrospinal fluid studies showed normal cytological findings, elevated IgG synthesis, and elevated antibody titers to varicella-zoster virus. Over time, the patient worsened, developed cranial neuropathies, and ultimately died. The pathological diagnosis and the approach to the clinical data are discussed. PMID- 23440265 TI - Diagnostic testing and the illusory reassurance of normal results: comment on "Reassurance after diagnostic testing with a low pretest probability of serious disease". PMID- 23440266 TI - Blockade of DNA methylation enhances the therapeutic effect of gefitinib in non small cell lung cancer cells. AB - The sensitivity of lung cancer to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been found to be associated with mutations in the tyrosine kinase domain of EGFR. However, not all mutations are sensitive to gefitinib. While CpG island methylation in the promoter region of the EGFR gene and transcriptional silencing are common in solid tumors, the role of the EGFR gene promoter methylation in affecting resistance to TKIs in non-small cell lung cancer (NSCLC) remains unknown. In this study, we examined the correlation between EGFR gene promoter methylation and the therapeutic effect of gefitinib in NSCLC cells. Three NSCLC cell lines with different EGFR mutation statuses and levels of sensitivity to EGFR-TKIs were used in this study: H1650 (del E746 A750), H1299 (wild-type EGFR) and PC-9 (del E746-A750). Cells were treated with gefitinib or 5-aza-2'-deoxy cytidine (5-aza-CdR), a methylation inhibitor, alone or in combination. Subsequently, the methylation status of the EGFR gene promoter was examined by methylation-specific PCR (MSP). Cell survival and apoptosis assays were performed using the Cell Counting Kit-8 (CCK-8) and flow cytometry. In addition, western blot analysis and quantitative real-time PCR were used to examine the expression levels of EGFR protein and mRNA. Our study showed that the promoter region of the EGFR gene in PC-9 cells was unmethylated, and that the cells were sensitive to gefitinib. By contrast, the promoter region of the EGFR gene in the H1650 and H1299 cells was methylated, and the cells were resistant to gefitinib. Of note, the combination treatment with 5-aza-CdR and gefitinib further enhanced the growth inhibitory effects and led to the induction of apoptosis, while a significant reduction in the expression of EGFR protein and mRNA was observed in the H1650 and H1299 cells. These results suggest that blockade of DNA methylation may enhance the antitumor effects of EGFR-TKIs and gefitinib in NSCLC cells. Thus, EGFR gene promoter methylation may be a potential mechanism for acquired resistance to gefitinib. PMID- 23440267 TI - Voluntary heart rate reduction following yoga using different strategies. AB - BACKGROUND/AIMS: One month of yoga training has been shown to reduce the pulse rate voluntarily without using external cues. Hence, the present study was designed to understand the strategies used by yoga practitioners and autonomic changes associated with voluntary heart rate reduction. MATERIALS AND METHODS: Fifty volunteers (group mean age +/- S.D., 25.4 +/- 4.8 years; 25 males) were assessed in two trials on separate days. Each trial was for 12 minutes, with a 'pre' state and 'during' state of 6 minutes each. For both trials the 'pre' state was relaxation with eyes closed. In the 'during' state of Trial I, subjects were asked to voluntarily reduce their heart rate using a strategy of their choice. From their responses to specific questions it was determined that 22 out of 50 persons used breath regulation as a strategy. Hence, in the 'during' state of Trial II, subjects were asked to voluntarily reduce their heart rate by breath regulation. RESULTS: In the first trial, the heart rate was reduced by an average of 19.6 beats per minute and in the second trial (with breath regulation exclusively) an average decrease of 22.2 beats per minute was achieved. CONCLUSIONS: Hence, the strategy used did not markedly alter the outcome. PMID- 23440268 TI - Indian cabinet defers decision on National Urban Health Mission. PMID- 23440269 TI - An unsafe ward. PMID- 23440270 TI - Postpartum management of hypertension. PMID- 23440271 TI - Do work factors modify the association between chronic health problems and sickness absence among older employees? AB - OBJECTIVES: The aim of this study was to (i) assess how common chronic health problems and work-related factors predict sickness absence and (ii) explore whether work-related factors modify the effects of health problems on sickness absence. METHODS: A one-year longitudinal study was conducted among employed persons aged 45-64 years from the Study on Transitions in Employment, Ability and Motivation (N = 8984). The presence of common chronic health problems and work related factors was determined at baseline and self-reported sickness absence at one-year follow-up by questionnaire. Multinomial multivariate logistic regression analyses were conducted to assess associations between health, work factors, and sickness absence, and relative excess risk due to interaction (RERI) techniques were used to test effect modification. RESULTS: Common health problems were related to follow-up sickness absence, most strongly to high cumulative sickness absence (> 9 days per year). Baseline psychological health problems were strongly related to high sickness absence at follow-up [odds ratio (OR) 3.67, 95% confidence interval (95% CI) 2.80-4.82]. Higher job demands at baseline increased the likelihood of high sickness absence at follow-up among workers with severe headaches [RERI 1.35 (95% CI 0.45-2.25)] and psychological health problems [RERI 3.51 (95% CI 0.67-6.34)] at baseline. Lower autonomy at baseline increased the likelihood of high sickness absence at follow-up among those with musculoskeletal [RERI 0.57 (95% CI 0.05-1.08)], circulatory [RERI 0.82 (95% CI 0.00-1.63)], and psychological health problems [RERI 2.94 (95% CI 0.17-5.70)] at baseline. CONCLUSIONS: Lower autonomy and higher job demands increased the association of an array of common chronic health problems with sickness absence, and thus focus should be placed on altering these factors in order to reduce sickness absence and essentially promote sustainable employability. PMID- 23440272 TI - False-positive transient ischemic attack due to intraocular lesion. PMID- 23440273 TI - Measuring diagnostic errors in primary care: the first step on a path forward. Comment on "Types and origins of diagnostic errors in primary care settings". PMID- 23440274 TI - Of changing glial responses, modular interactions, and why a worm may turn. PMID- 23440275 TI - Regulation of AQP0 water permeability is enhanced by cooperativity. AB - Aquaporin 0 (AQP0), essential for lens clarity, is a tetrameric protein composed of four identical monomers, each of which has its own water pore. The water permeability of AQP0 expressed in Xenopus laevis oocytes can be approximately doubled by changes in calcium concentration or pH. Although each monomer pore functions as a water channel, under certain conditions the pores act cooperatively. In other words, the tetramer is the functional unit. In this paper, we show that changes in external pH and calcium can induce an increase in water permeability that exhibits either a positive cooperativity switch-like increase in water permeability or an increase in water permeability in which each monomer acts independently and additively. Because the concentrations of calcium and hydrogen ions increase toward the center of the lens, a concentration signal could trigger a regulatory change in AQP0 water permeability. It thus seems plausible that the cooperative modes of water permeability regulation by AQP0 tetramers mediated by decreased pH and elevated calcium are the physiologically important ones in the living lens. PMID- 23440276 TI - Knockdown of desmin in zebrafish larvae affects interfilament spacing and mechanical properties of skeletal muscle. AB - Skeletal muscle was examined in zebrafish larvae in order to address questions related to the function of the intermediate filament protein desmin and its role in the pathogenesis of human desminopathy. A novel approach including mechanical and structural studies of 4-6-d-old larvae was applied. Morpholino antisense oligonucleotides were used to knock down desmin. Expression was assessed using messenger RNA and protein analyses. Histology and synchrotron light-based small angle x-ray diffraction were applied. Functional properties were analyzed with in vivo studies of swimming behavior and with in vitro mechanical examinations of muscle. The two desmin genes normally expressed in zebrafish could be knocked down by ~50%. This resulted in a phenotype with disorganized muscles with altered attachments to the myosepta. The knockdown larvae were smaller and had diminished swimming activity. Active tension was lowered and muscles were less vulnerable to acute stretch-induced injury. X-ray diffraction revealed wider interfilament spacing. In conclusion, desmin intermediate filaments are required for normal active force generation and affect vulnerability during eccentric work. This is related to the role of desmin in anchoring sarcomeres for optimal force transmission. The results also show that a partial lack of desmin, without protein aggregates, is sufficient to cause muscle pathology resembling that in human desminopathy. PMID- 23440277 TI - Flavonoid regulation of EAG1 channels. AB - The voltage-gated, K(+)-selective ether a go-go 1 (EAG1) channel is expressed throughout the brain where it is thought to regulate neuronal excitability. Besides its normal physiological role in the brain, EAG1 is abnormally expressed in several cancer cell types and promotes tumor progression. Like all other channels in the KCNH family, EAG1 channels have a large intracellular carboxy terminal region that shares structural similarity with cyclic nucleotide-binding homology domains (CNBHDs). EAG1 channels, however, are not regulated by the direct binding of cyclic nucleotides and have no known endogenous ligands. In a screen of biological metabolites, we have now identified four flavonoids as potentiators of EAG1 channels: fisetin, quercetin, luteolin, and kaempferol. These four flavonoids shifted the voltage dependence of activation toward more hyperpolarizing potentials and slowed channel deactivation. All four flavonoids regulated channel gating with half-maximal concentrations of 2-8 uM. The potentiation of gating did not require the amino-terminal or post-CNBHD regions of EAG1 channels. However, in fluorescence resonance energy transfer and anisotropy-based binding assays, flavonoids bound to the purified CNBHD of EAG1 channels. The CNBHD of KCNH channels contains an intrinsic ligand, a conserved stretch of residues that occupy the cyclic nucleotide-binding pocket. Mutations of the intrinsic ligand in EAG1 (Y699A) potentiated gating similar to flavonoids, and flavonoids did not further potentiate EAG1-Y699A channels. Furthermore, the Y699A mutant CNBHD bound to flavonoids with higher affinity than wild-type CNBHD. These results suggest that the flavonoids identified here potentiated EAG1 channels by binding to the CNBHD, possibly by displacing their intrinsic ligand. EAG1 channels should be considered as a possible target for the physiological effects of flavonoids. PMID- 23440278 TI - Confocal imaging of transmembrane voltage by SEER of di-8-ANEPPS. AB - Imaging, optical mapping, and optical multisite recording of transmembrane potential (V(m)) are essential for studying excitable cells and systems. The naphthylstyryl voltage-sensitive dyes, including di-8-ANEPPS, shift both their fluorescence excitation and emission spectra upon changes in V(m). Accordingly, they have been used for monitoring V(m) in nonratioing and both emission and excitation ratioing modes. Their changes in fluorescence are usually much less than 10% per 100 mV. Conventional ratioing increases sensitivity to between 3 and 15% per 100 mV. Low sensitivity limits the value of these dyes, especially when imaged with low light systems like confocal scanners. Here we demonstrate the improvement afforded by shifted excitation and emission ratioing (SEER) as applied to imaging membrane potential in flexor digitorum brevis muscle fibers of adult mice. SEER--the ratioing of two images of fluorescence, obtained with different excitation wavelengths in different emission bands-was implemented in two commercial confocal systems. A conventional pinhole scanner, affording optimal setting of emission bands but less than ideal excitation wavelengths, achieved a sensitivity of up to 27% per 100 mV, nearly doubling the value found by conventional ratioing of the same data. A better pair of excitation lights should increase the sensitivity further, to 35% per 100 mV. The maximum acquisition rate with this system was 1 kHz. A fast "slit scanner" increased the effective rate to 8 kHz, but sensitivity was lower. In its high-sensitivity implementation, the technique demonstrated progressive deterioration of action potentials upon fatiguing tetani induced by stimulation patterns at >40 Hz, thereby identifying action potential decay as a contributor to fatigue onset. Using the fast implementation, we could image for the first time an action potential simultaneously at multiple locations along the t-tubule system. These images resolved the radially varying lag associated with propagation at a finite velocity. PMID- 23440279 TI - The voltage-sensing domain of a phosphatase gates the pore of a potassium channel. AB - The modular architecture of voltage-gated K(+) (Kv) channels suggests that they resulted from the fusion of a voltage-sensing domain (VSD) to a pore module. Here, we show that the VSD of Ciona intestinalis phosphatase (Ci-VSP) fused to the viral channel Kcv creates Kv(Synth1), a functional voltage-gated, outwardly rectifying K(+) channel. Kv(Synth1) displays the summed features of its individual components: pore properties of Kcv (selectivity and filter gating) and voltage dependence of Ci-VSP (V(1/2) = +56 mV; z of ~1), including the depolarization-induced mode shift. The degree of outward rectification of the channel is critically dependent on the length of the linker more than on its amino acid composition. This highlights a mechanistic role of the linker in transmitting the movement of the sensor to the pore and shows that electromechanical coupling can occur without coevolution of the two domains. PMID- 23440281 TI - Leukemia cells demonstrate a different metabolic perturbation provoked by 2 deoxyglucose. AB - The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG. In THP-1 cells, metabolites in the TCA cycle were not decreased to the same extent by 2-DG as in NB4 cells, which indicates that THP-1 utilizes energy sources other than glucose. TCA cycle metabolites in THP-1 cells may be derived from acetyl-CoA by fatty acid beta oxidation, which was supported by abundant detection of carnitine and acetylcarnitine in THP-1 cells. 2-DG treatment increased the levels of pentose phosphate pathway (PPP) metabolites and augmented the generation of NADPH by glucose-6-phosphate dehydrogenase. An increase in NADPH and upregulation of glutathione synthetase expression resulted in the increase in the reduced form of glutathione by 2-DG in NB4 cells. We demonstrated that a combination of 2-DG and inhibition of PPP by dehydroepiandrosterone (DHEA) effectively suppressed the growth of NB4 cells. The replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase in THP-1 cells, treated by 2-DG, might be regulated by AMPK, as the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 cells. Although 2-DG has been effective in preclinical and clinical studies, this treatment has not been fully explored due to concerns related to potential toxicities such as brain toxicity at high doses. We demonstrated that a combination of 2-DG and DHEA or compound C at a relatively low concentration effectively inhibits the growth of NB4 and THP-1 cells, respectively. These observations may aid in the identification of appropriate combinations of metabolic inhibitors at low concentrations which do not cause toxicities. PMID- 23440282 TI - Successful repetitive intravenous thrombolysis in a patient with recurrent brainstem infarctions due to megadolichobasilar ectasia. PMID- 23440283 TI - Anticancer effects of sodium butyrate on hepatocellular carcinoma cells in vitro. AB - In the present study, we investigated the anticancer effects of sodium butyrate (NaBu) on hepatocellular carcinoma (HCC) cells in vitro. As a histone deacetylase (HDAC) inhibitor, NaBu upregulated Ac-H3 and inhibited HDAC4 protein expression in a time- and dose-dependent manner. MTT assays showed that treatment with NaBu at high concentrations significantly inhibited the growth of various HCC cells. Exposure to NaBu for 24 h induced cell cycle arrest in the SMMC-7721 and HepG2 cells. NaBu also induced the apoptosis of SMMC-7721 cells. The expression levels of cell cycle- and apoptosis-related proteins were further investigated by western blot analysis using specific antibodies. The results provided a possible mechanism responsible for the inhibitory effects of NaBu on the growth of HCC cells. To further analyze the role of NaBu in cell migration, wound healing and Transwell assays were performed, indicating that NaBu significantly inhibits cell migration/invasion in HCC cells. Transforming growth factor-beta1 (TGF-beta1) induced epithelial to mesenchymal transition (EMT) has been associated with tumor cell migration and invasion. The EMT markers, E-cadherin, vimentin and N cadherin, were regulated by TGF-beta1, while NaBu inhibited this process in which HDAC4 and matrix metalloproteinase (MMP)7 may be involved. Based on our findings, we propose that NaBu may be useful as an anticancer drug for HCC therapy. PMID- 23440284 TI - Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. AB - IMPORTANCE: Acute pancreatitis has significant morbidity and mortality. Previous studies have raised the possibility that glucagonlike peptide 1 (GLP-1)-based therapies, including a GLP-1 mimetic (exenatide) and a dipeptidyl peptidase 4 inhibitor (sitagliptin phosphate), may increase the risk of acute pancreatitis. OBJECTIVE: To test whether GLP-1-based therapies such as exenatide and sitagliptin are associated with an increased risk of acute pancreatitis. We used conditional logistic regression to analyze the data. DESIGN: Population-based case-control study. SETTING: A large administrative database in the United States from February 1, 2005, through December 31, 2008. PARTICIPANTS: Adults with type 2 diabetes mellitus aged 18 to 64 years. We identified 1269 hospitalized cases with acute pancreatitis using a validated algorithm and 1269 control subjects matched for age category, sex, enrollment pattern, and diabetes complications. MAIN OUTCOME MEASURE: Hospitalization for acute pancreatitis. RESULTS: The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1-based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers. CONCLUSIONS AND RELEVANCE: In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1-based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis. PMID- 23440285 TI - Three dimensional-TiO(2) nanotube array photoanode architectures assembled on a thin hollow nanofibrous backbone and their performance in quantum dot-sensitized solar cells. AB - Facile synthesis of TiO2 nanotube branched (length ~0.5 MUm) thin hollow nanofibers is reported. The hierarchical three dimensional photoanodes (H-TiO2 NFs) (only ~1 MUm thick) demonstrate their excellent candidature as photoanodes in QD-sensitized solar cells, exhibiting ~3-fold higher energy conversion efficiency (eta = 2.8%, Jsc = 8.8 mA cm(-2)) than that of the directly grown nanotube arrays on a transparent conducting oxide (TCO) substrate (eta = 0.9%, Jsc = 2.5 mA cm(-2)). PMID- 23440286 TI - miRNA-22 suppresses colon cancer cell migration and invasion by inhibiting the expression of T-cell lymphoma invasion and metastasis 1 and matrix metalloproteinases 2 and 9. AB - Emerging evidence has demonstrated the altered expression of mRNAs in cancer development and progression. In this study, the precise role of miRNA-22 (miR-22) in colon cancer cells was investigated. Upon transfection with a miR-22 expression vector, the viability of HCT-116 human colon cancer cells was significantly reduced and tumor cell migration and invasion capacity were also suppressed. Computational in silico analysis predicted that T-cell lymphoma invasion and metastasis 1 (TIAM1) is a target gene of miR-22. This was confirmed by qRT-PCR and western blotting, which showed that miR-22 expression inhibited TIAM1 mRNA and protein expression, respectively. In addition, the expression of pro-invasive gene matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and pro angiogenic protein vascular endothelial growth factor (VEGF) were also reduced by miR-22 expression. Collectively, these data suggest that miR-22 may act as a tumor suppressor in colon cancer, most likely by targeting TIAM1 expression. PMID- 23440287 TI - Survey of the reasons for dental extraction in eastern Nigeria. AB - BACKGROUND: Extraction of teeth is the commonest surgical procedure carried out in the dental surgery setting. AIM: The purpose of this survey was to identify the causes of teeth extraction in Eastern Nigeria. SUBJECTS AND METHODS: Record forms for entering data and a self-addressed return envelope were distributed to 100 dental surgeons in Eastern Nigeria using a simple random selection. RESULTS: Seventy-one (71; 71/100) dentists responded to the request and the total extractions carried out were 3998. There were 1508 (37.7%) extractions in males and 2490 (62.3%) in females with male-to-female extraction ratio of 1:1.7. In both male and female gender, there were more teeth extractions between the ages of 11 and 30 years. Extractions were recorded more in the lower social class (47.6%; 1903/3998). There were more extractions in the permanent (85.0%; 3398/3998) than deciduous (15.0%; 600/3998). The commonest reasons for teeth extraction were caries (55.2%; 2208/3998). CONCLUSION: The result of this study shows that dental caries is the commonest reason for tooth extraction in Eastern Nigeria. It is hoped that the study will facilitate the development of treatment and preventive procedures relevant to the problems observed in this part of Nigeria, thus minimizing the loss of teeth and its expected adverse consequences. PMID- 23440288 TI - IgG4-related neuropathy: a case report. AB - IMPORTANCE: The newly recognized entity IgG4-related disease (IgG4-RD) is characterized by an elevated IgG4 serum concentration and tissue infiltration by IgG4-positive plasma cells. We describe, for the first time, the clinical features and nerve biopsy findings of a patient with IgG4-RD who presented with neuropathy in the extremities. OBSERVATIONS: A 55-year-old man had histopathologically defined IgG4-RD that manifested as sensory-motor neuropathy. The neuropathic features were multiple mononeuropathies with electrophysiological findings suggestive of axonal neuropathy. Marked thickening with abundant collagen fibers and infiltration of IgG4-positive plasma cells were observed in the epineurium of the biopsied sural nerve. A moderate degree of myelinated fiber loss without evidence of segmental demyelination was present, whereas necrotizing vasculitis was not found. Oral prednisolone therapy ameliorated the neuropathic symptoms. CONCLUSIONS AND RELEVANCE: This case of IgG4-RD presented as sensory motor neuropathy with pain and sclerosis of the skin in the extremities. The differential diagnosis of neuropathy should include IgG4-RD. PMID- 23440289 TI - High mobility group box 1 and kidney diseases (Review). AB - High mobility group box 1 (HMGB1), a non-histone DNA-binding protein, regulates nucleosome function and transcription in the nuclei of all metazoans and plants. However, extracellular HMGB1, which is actively or passively released under different conditions, can act as a key inflammatory mediator through MyD88/mitogen-activated protein kinase signaling by binding to its receptors including the receptor for advanced glycation end products or Toll-like receptors. A growing body of evidence indicates that HMGB1 plays an important role in kidney diseases, such as glomerulonephritis, lupus nephritis, antineutrophilic cytoplasmatic antibody-associated vaculitis, diabetic nephropathy, renal allograft rejection and acute kidney injury. In this review, we focus on the biology of HMGB1 and the association of HMGB1 with kidney diseases. PMID- 23440290 TI - [Motility disorders of the esophagus]. AB - Motility disorders of the esophagus comprise a heterogeneous spectrum of diseases. Primary malformations of the esophagus are now amenable to improved surgical and gastroenterological therapies; however, they often lead to persistent long-term esophageal dysmotility. Achalasia originates from impaired relaxation of the gastroesophageal sphincter apparatus. Systemic diseases may give rise to secondary disorders of esophageal motility. A number of visceral neuromuscular disorders show an esophageal manifestation but aganglionosis rarely extends into the esophagus. The growing group of myopathies includes metabolic and mitochondrial disorders with increasing levels of genetic characterization and incipient emergence of therapeutic strategies. Esophagitis with an infectious etiology causes severe dysmotility particularly in immunocompromised patients. Immunologically mediated inflammatory processes involving the esophagus are increasingly better understood. Finally, rare tumors and tumor-like lesions may impair esophageal motor function. PMID- 23440291 TI - [Serrated polyps of the duodenum. Three cases with immunohistological and molecular pathological findings]. AB - We report on three cases of serrated polyps of the duodenum which were incidental endoscopic findings in three male patients with a median age of 70 years (range 63-84 years). Architecturally the histological findings in cases 1 and 2 were similar to hyperplastic polyps of the colon. In case 3 there was a low grade intraepithelial neoplasia which covered the whole polyp. This polyp relapsed after 2 years with similar histological findings. Immunohistochemically an increased proliferative activity was found in case 3 as well as associated overexpression of p16 (INK4a) and p53. No abnormal expression of MLH1 and beta catenin was found in any of the polyps. Molecular pathological analysis showed a BRAF mutation (V600E) in case 3. A wild type sequence in the KRAS gene was found in all polyps. In conclusion, serrated polyps should be included in the diagnostic spectrum of benign duodenal polyps. PMID- 23440292 TI - Calix[4]arenes with intramolecularly bridged meta positions prepared via Pd catalysed double C-H activation. AB - The introduction of a 2-pyridylsulfoxide moiety into the upper rim of calix[4]arenes enabled the synthesis of unprecedented derivatives with intramolecularly bridged meta positions of two neighbouring aromatic subunits. Palladium-catalysed double C-H activation thus represents a straightforward way to a completely novel type of calixarenes. PMID- 23440293 TI - Promising anti-leukemic activity of atorvastatin. AB - There is a current need for novel therapeutic strategies for the treatment of chronic lymphocytic leukemia (CLL), a still incurable hematological cancer involving mainly deregulated apoptosis. The purpose of the present study was to determine ex vivo the effect of the synthetic statin, atorvastatin, a known cholesterol-lowering drug, on peripheral blood mononuclear cells obtained from CLL patients. Using flow cytometry, we investigated the viability and induction of apoptosis in leukemic cells exposed to statin by the Vybrant apoptosis assay kit #4, compared with untreated control cells. We also examined the expression levels of apoptosis-regulatory proteins (Mcl-1, Bcl-2 and Bax), as well as products of the expression/proteolysis of lamin B, poly(ADP-ribose) polymerase-1 (PARP-1) and p27Kip1 by western blot analysis. Moreover, the number of sub-G1 cells and DNA fragmentation in atorvastatin-treated leukemic cells were examined by flow cytometry and agarose gel electrophoresis, respectively. The obtained results indicated that CLL cells ex vivo were extremely sensitive to atorvastatin. The cytotoxic effect of this statin was caused by the induction of apoptosis in the leukemic cells. The induction of apoptosis in the drug-treated model cells was confirmed by the reduction or proteolysis of apoptotic markers, such as PARP-1, lamin B and p27Kip1, the increase in the number of sub-G1 cells and DNA ladder formation. During atorvastatin-triggered apoptosis, changes in the expression levels of mitochondrial outer membrane permeability regulatory proteins of the Bcl-2 family were also observed. Ex vivo promising data indicate the strong cytotoxic and pro-apoptotic potential of atorvastatin against leukemic cells, but not normal cells. The obtained data suggest that atorvastatin be considered as a therapeutic option for the treatment of CLL. PMID- 23440294 TI - Incidence of amyotrophic lateral sclerosis among American Indians and Alaska natives. AB - IMPORTANCE: More thorough evaluation of amyotrophic lateral sclerosis (ALS) and motor neuron disease in unique populations could provide clues to etiologies for these idiopathic conditions, and educational programs for American Indian and Alaska Native (AI/AN) people and health care professionals on reservations could improve awareness, understanding, diagnosis, and treatment. In the ongoing search for susceptibility genes, studying particular racial groups, such as AI/ANs,might facilitate the identification of new mutations. OBJECTIVE: To provide better understanding of ALS and secondarily of motor neuron disease among AI/AN people by estimating the incidence and prevalence among AI/ANs served by the Indian Health Service health care system. DESIGN AND SETTING: Analysis of electronic records for AI/ANs with ALS and with motor neuron disease separately for the calendar years 2002-2009 using inpatient and outpatient visit data from the Indian Health Service, which provides health care to eligible AI/ANs nationwide. PARTICIPANTS: Cases were defined by at least 2 inpatient or outpatient visits with the diagnosis. MAIN OUTCOME MEASURES: Crude and age-adjusted incidence and prevalence rates were calculated. RESULTS: Seventy-one AI/ANs were diagnosed with ALS, yielding an average annual crude incidence rate of 0.63 cases per 100 000 and an age-adjusted incidence of 0.92. The median age at onset was 56.0 years and was higher among women than men (62.0 vs 55.0 years; P=.06). Age-specific incidence increased to 70 to 74 years. The crude and age-adjusted point prevalence rates were 2.00 and 4.12, respectively. The crude and age-adjusted incidence rates for motor neuron disease were 1.08 and 1.50, respectively. The annual rates were unchanged across the study period. CONCLUSIONS AND RELEVANCE: The incidence of ALS among AI/ANs appears to be lower than that reported for white populations, a finding congruent with reports of other minority populations. Community-based studies are important to confirm these findings and to examine reasons for the low rate of ALS among AI/ANs. PMID- 23440296 TI - Mesoporous TiO(2)-Sn@C core-shell microspheres for Li-ion batteries. AB - Using amorphous TiO2 microspheres as precursors, we obtain mesoporous TiO2-Sn@C core-shell microspheres. Sn is encapsulated into a TiO2 matrix, and carbon is coated outside. This intriguing architecture can effectively buffer volume change and structural stress, thus contributing to excellent long-term cycling stability and superior high-rate cyclability. PMID- 23440297 TI - How do incentives lead to deception in advisor-client interactions? Explicit and implicit strategies of self-interested deception. AB - When confronted with important questions we like to rely on the advice of experts. However, uncertainty can occur regarding advisors' motivation to pursue self-interest and deceive the client. This can especially occur when the advisor has the possibility to receive an incentive by recommending a certain alternative. We investigated how the possibility to pursue self-interest led to explicit strategic behavior (bias in recommendation and transfer of information) and to implicit strategic behavior (bias in information processing: evaluation and memory). In Study 1 explicit strategic behavior could be identified: self interested advisors recommended more often the self-serving alternative and transferred more self-interested biased information to their client compared to the advisor without specific interest. Also deception through implicit strategic behavior was identified: self-interested advisors biased the evaluation of information less in favor of the client compared to the control group. Self interested advisors also remembered conflicting information regarding their self interest worse compared to advisors without self-interest. In Study 2 beside self interest we assessed accountability which interacted with self-interest and increased the bias: when accountability was high advisor's self-interest led to higher explicit strategic behavior (less transfer of conflicting information), and to higher implicit strategic behavior (devaluated and remembered less conflicting information). Both studies identified implicit strategic behavior as mediator which can explain the relation between self-interest and explicit strategic behavior. Results of both studies suggest that self-interested advisors use explicit and implicit strategic behavior to receive an incentive. Thus, advisors do not only consciously inform their clients "self-interested," but they are influenced unconsciously by biased information processing - a tendency which even increased with high accountability. PMID- 23440295 TI - DFMO/eflornithine inhibits migration and invasion downstream of MYCN and involves p27Kip1 activity in neuroblastoma. AB - Neuroblastoma (NB) is the most common extracranial pediatric tumor. NB patients over 18 months of age at the time of diagnosis are often in the later stages of the disease, present with widespread dissemination, and often possess MYCN tumor gene amplification. MYCN is a transcription factor that regulates the expression of a number of genes including ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines. Inhibiting ODC in NB cells produces many deleterious effects including G(1) cell cycle arrest, inhibition of cell proliferation, and decreased tumor growth, making ODC a promising target for drug interference. DFMO treatment leads to the accumulation of the cyclin-dependent kinase inhibitor p27(Kip1) protein and causes p27(Kip1)/Rb-coupled G(1) cell cycle arrest in MYCN-amplified NB tumor cells through a process that involves p27(Kip1) phosphorylation at residues Ser10 and Thr198. While p27(Kip1) is well known for its role as a cyclin-dependent kinase inhibitor, recent studies have revealed a novel function of p27(Kip1) as a regulator of cell migration and invasion. In the present study we found that p27(Kip1) regulates the migration and invasion in NB and that these events are dependent on the state of phosphorylation of p27(Kip1). DFMO treatments induced MYCN protein downregulation and phosphorylation of Akt/PKB (Ser473) and GSK3-beta (Ser9), and polyamine supplementation alleviated the DFMO-induced effects. Importantly, we provide strong evidence that p27(Kip1) mRNA correlates with clinical features and the survival probability of NB patients. PMID- 23440298 TI - Clinical impact of tumor-infiltrating CD45RO+ memory T cells on human gastric cancer. AB - Memory T cells survive for months and even years and are critical for host defense in humans. They have been recently suggested to play a significant role in tumor immunity. In this study, we aimed to investigate the clinical impact of tumor-infiltrating memory T cells on human gastric cancer. We evaluated CD45RO(+)T cells infiltrating into primary gastric cancer tissues by immunohistochemistry in 101 patients with gastric cancer. Patients were classified into 2 groups (CD45RO(+Hi) and CD45RO(+Lo)) based on the number of positively stained T cells. There was no significant correlation observed between CD45RO status and post-operative prognosis in early gastric cancer. By contrast, in advanced cancer, the post-operative overall and disease-free survival of patients with CD45RO(+Hi) were significantly improved compared to those of patients with CD45RO(+Lo). In addition, CD45RO status in the primary tumors significantly correlated with the development of post-operative recurrence, particularly peritoneal recurrence. Furthermore, the local expression of interferon-gamma (IFN-gamma) in the CD45RO(+Hi) tumors was significantly higher than that in the CD45RO(+Lo) tumors, suggesting that CD45RO(+) T cells induced local immune activation. Multivariate analysis indicated that the CD45RO(+) status was an independent prognostic factor in advanced gastric cancer. In conclusion, tumor-infiltrating CD45RO(+) memory T cells are functional and have significant prognostic value in human gastric cancer. Our data suggest that adaptive immune response is clinically critical in gastric cancer. PMID- 23440300 TI - Anticancer activity and biophysical reactivity of copper complexes of 2 (benzo[d][1,3]dioxol-5-ylmethylene)-N-alkylhydrazinecarbothioamides. AB - A series of copper complexes were synthesized from benzo[d][1,3]dioxole-5 carbaldehyde (piperonal) thio-semicarbazones (RHpTSC where R=H, CH3, C2H5 or C6H5 (Ph)). The complexes show interesting variations in geometry depending on the thiosemicarbazone; a dinuclear complex [Cu(HpTSC)Cl]2, a mononuclear complex [Cu(RHpTSC)2Cl2] (R=CH3 or C2H5) and another mononuclear complex [Cu(PhHpTSC)(PhpTSC)Cl] was generated. The complexes bind in a moderately strong fashion to DNA with binding constants on the order of 10(4)M(-1). They are also strong binders of human serum albumin with binding constants near 10(4) M(-1). The complexes show good in vitro cytotoxic profiles against two human colon cancer cell lines (HCT-116 and HT29) and two human breast cancer cell lines (MCF 7 and MDA-MB-231) with IC50 values in the low millimolar concentration range. PMID- 23440299 TI - Bacillus "next generation" diagnostics: moving from detection toward subtyping and risk-related strain profiling. AB - The highly heterogeneous genus Bacillus comprises the largest species group of endospore forming bacteria. Because of their ubiquitous nature, Bacillus spores can enter food production at several stages resulting in significant economic losses and posing a potential risk to consumers due the capacity of certain Bacillus strains for toxin production. In the past, food microbiological diagnostics was focused on the determination of species using conventional culture-based methods, which are still widely used. However, due to the extreme intra-species diversity found in the genus Bacillus, DNA-based identification and typing methods are gaining increasing importance in routine diagnostics. Several studies showed that certain characteristics are rather strain-dependent than species-specific. Therefore, the challenge for current and future Bacillus diagnostics is not only the efficient and accurate identification on species level but also the development of rapid methods to identify strains with specific characteristics (such as stress resistance or spoilage potential), trace contamination sources, and last but not least discriminate potential hazardous strains from non-toxic strains. PMID- 23440301 TI - State of the art in cardiovascular perfusion: now and in the next decade. AB - The development and improvement of cardiopulmonary bypass technology is an ongoing process. During the past decade, a number of publications on improvements and best practices have appeared, especially in the areas of biocompatibility, materials sciences, instrumentation, monitoring of physiological parameters and knowledge base (education and evidence-based medicine). Biocompatibility may be defined not only as an inherent property of a particular composition of matter, but also as a set of properties concerning shape, finish, fabrication techniques and choice of application. Materials in use for cardiopulmonary bypass have changed and coated components have been used frequently. Improvements in the area of instrumentation were achieved by adaptation of conventional cardiopulmonary bypass circuits. Miniaturization and re-design of cardiopulmonary bypass circuits (so-called minimized perfusion circuits or minimal extracorporeal circulation circuits) have made cardiopulmonary bypass technology less traumatic. A team approach, including the cardiac surgeon, the anesthesiologist and the cardiovascular perfusionist, was deemed beneficial in order to achieve further improvements. Next to choice of technology and material for a given operation, adjunct measures such as pharmaceutical treatment and blood conservation strategies need to be taken into consideration. Monitoring of variables during cardiopulmonary bypass has made some progress, while the knowledge base has expanded due to studies on best practices. For the immediate future, sound scientific knowledge and intelligent monitoring tools will allow cardiopulmonary bypass to be tailored to individual patients' needs. PMID- 23440302 TI - Ichthyosis hystrix. AB - The present report describes the condition in a three day old male child with bilateral ,linear, hyperpigmented and hyperkeratotic verrucous plaques and patchy alopecia over scalpe without any nail and skeletal abnormalities. It was suggestive of ichthyosis hystrix type of epidermal nevus,and is being reported in view of the rarity of this condition. PMID- 23440303 TI - Microvascular decompression for familial hemifacial spasm : single institute experience. AB - OBJECTIVE: The purpose of this study was to evaluate the characteristics and surgical outcomes of familial hemifacial spasm (HFS) and to discuss the role of genetic susceptibility. METHODS: Between 2001 and 2011, 20 familial HFS patients with ten different pedigrees visited our hospital. The data from comprehensive evaluation of these patients, including clinical, radiological and electrophysiological data and surgical outcomes were reviewed to characterize familial HFS and to compare the characteristics between familial HFS and sporadic HFS. RESULTS: According to the family tree, the inheritance pattern was difficult to define clearly using these data. Radiologic findings suggested that the vertebral artery (VA) was a more frequent offender in familial HFS than in sporadic cases (35.0% vs. 10.0%, p<0.001). Chi-square test showed that there were no correlation between VA tortuosity and underlying morbidity such as diabetes or hypertension (p=0.391). Eighteen out of 19 patients who underwent microvascular decompression showed no residual spasm. Other features of familial HFS overlap with sporadic cases. These findings suggest that certain genetic susceptibilities rather than hypertension or diabetes may influence vascular tortuosity and HFS development. CONCLUSION: In this study, familial HFS seems not so different from sporadic cases. Authors thought familial HFS could have heterogeneous etiology. Further study of familial HFS including clinical, anatomic, genetic, and molecular information may help identify a gene or trait that can provide insight into the mechanisms of sporadic and familial HFS. PMID- 23440304 TI - Decomposing phenotype descriptions for the human skeletal phenome. AB - Over the course of the last few years there has been a significant amount of research performed on ontology-based formalization of phenotype descriptions. The intrinsic value and knowledge captured within such descriptions can only be expressed by taking advantage of their inner structure that implicitly combines qualities and anatomical entities. We present a meta-model (the Phenotype Fragment Ontology) and a processing pipeline that enable together the automatic decomposition and conceptualization of phenotype descriptions for the human skeletal phenome. We use this approach to showcase the usefulness of the generic concept of phenotype decomposition by performing an experimental study on all skeletal phenotype concepts defined in the Human Phenotype Ontology. PMID- 23440305 TI - Histopathological Investigation of Different MCAO Modalities and Impact of Autologous Bone Marrow Mononuclear Cell Administration in an Ovine Stroke Model. AB - Translational researchers and clinicians recommend the use of large animal models in preclinical stroke research. This represents an important part of a strategy aiming to prevent past translational failures in future therapeutic developments. Thirty-five Merino rams were subjected to sham surgery (n = 3), one-branch middle cerebral artery occlusion (MCAO, n = 8) or total MCAO (n = 24). Twelve animals from the latter group received intravenous administration of 4 * 10(6) autologous mononuclear bone marrow cells (BM MNC) per kilogram 24 h after total MCAO. Animals were sacrificed at day 49 post MCAO. Histological investigations were performed to reveal (1) the impact of different MCAO modalities on a cellular level and (2) the influence of BM MNC therapy following stroke. Clear differences between one-branch and total MCAO were observed histologically with results being comparable to those seen in human patients. BM MNC treatment reduced final lesion extension, lymphocytic infiltration and axonal degeneration after MCAO. The sheep model may represent a feasible tool for translational stroke research as pathohistological findings mimic the situation in humans. Histological evidence was found for beneficial impact of autologous BM MNC therapy. Further studies are needed to assess the neurofunctional impact of the approach in the gyrencephalic brain. PMID- 23440306 TI - End of Life and Life After Death - Issues to be Addressed. AB - Being an Oncologist, I have seen many patients suffering from cancer. It pains a lot looking at them fighting the battle of life, though knowing that they would lose miserably and surrender meekly as majority of the patients report to the hospital at an advanced stage of disease and only palliative care may be the option. There is an urgent need to create - Cancer Awareness in the villages and also about the end of life care in all terminally ill patients. 20 patients in the terminal phase were questioned regarding end of life care. The common questions they asked are, why has God punished me like this? Why me on earth? Should I die so early? Why should I leave my near and dear ones and go far away, from the point of no return? Do I ever see them again? With deep sorrow and sigh, they suffer till the last breath, having the feeling of insecurity as what would happen to their dear ones. In the terminal phase, the patients wishes must be respected and their needs must be fulfilled. The health care professionals should plan an appropriate care for each patient. Most of them feel that the best place to be in end of life is the home. Research has shown that Hospice care may improve the quality of life of a patient who is dying and of the patient's family. Communication about end of life care and decision making during the final moments of a person's life are very important. The patients suffering are mainly due to the physical, psychological, social and spiritual issues. Death of a terminally ill patient should never be a sudden loss. All healthcare professionals, Social workers and Non-Governmental Organisations must install the life after death of the person, who has struggled for every breath and assure that he/she shall rest in peace and shall smile seeing their near and dear ones living with dignity and pride in the society. Ultimately, the patient must have dignity in dying. PMID- 23440307 TI - Movements Mimicking Myoclonus Associated with Spinal Cord Pathology: Is this a "Pure Motor Restless Legs Syndrome". AB - BACKGROUND: The neuroanatomic substrate of restless legs syndrome (RLS) is poorly understood, and the diagnosis is clinically made based upon subjective sensory symptoms, although a motor component is usually present. CASE REPORT: We report two cases of elderly patients with spinal pathology who were referred by neurologists for myoclonus. Both had semi-rhythmic leg movements that partially improved while standing, but denied any urge to move. These movements improved dramatically with pramipexole, a dopamine agonist used for RLS. DISCUSSION: We propose that this "myoclonus" is actually the isolated stereotypic motor component of RLS. PMID- 23440308 TI - School-community partnerships: a cluster-randomized trial of an after-school soccer program. AB - IMPORTANCE: Identifying community-based programs that increase physical activity among diverse youth could yield sustainable tools to reduce obesity and obesity disparities. OBJECTIVE: To evaluate the impact of a community-based after-school soccer and youth development program, America SCORES, on students' physical activity, weight status, and fitness. DESIGN: Cluster-randomized trial. Study measures were collected in the fall (baseline), winter (midpoint), and spring (end point) of the 2009-2010 school year. SETTING: After-school programs in 6 schools within a large urban school district. PARTICIPANTS: All 4th and 5th grade students in after-school programs at the study schools were eligible. INTERVENTION: Three schools were randomized to receive the SCORES after-school program, delivered via the train-the-trainer model. MAIN OUTCOME MEASURES: Change in minutes of after-school moderate-to-vigorous physical activity (MVPA), fitness (maximal oxygen consumption), and body mass index over 1 school year. RESULTS: Participants (n = 156) were diverse (42% Latino, 32% Asian, and 12% African American) and 76 (49%) had a body mass index at or above the 85th percentile. There were no significant group differences in the change in physical activity, fitness, or weight status among all students. However, among students with a body mass index at or above the 85th percentile, SCORES significantly increased MVPA after school (3.4 min/d; 95% CI, 0.3-6.5) and on Saturdays (18.5 minutes; 95% CI, 3.4-33.6). CONCLUSIONS AND RELEVANCE: Existing community-based programs such as SCORES can increase physical activity among low-income youth, particularly those most at risk for weight-related comorbidities. While evaluating existing programs presents special challenges, partnerships between communities, schools, and researchers are an important component of translational research to address obesity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01156103. PMID- 23440309 TI - Role of repetitive transcranial magnetic stimulation in maintenance treatment of resistant depression. AB - Troublesome side-effects and lack of efficacy of the pharmacotherapy are the two major limitations in the depression treatment. Inspite of the established modalities like switching, combination and augmentation, using pharmacological and non-pharmacological agents, nearly one-third patients do not achieve complete remission. Repetitive Transcranial Magnetic Stimulation (rTMS) is one such somatic treatment which has been extensively studied for treatment for acute depression. Drop-out rates due to adverse effects have been found to be extremely low. However, literature regarding the role of rTMS in maintenance treatment in recurrent depression is scarce, and there is no existing literature from India. In this case-report we highlight the role of rTMS in the maintenance treatment of TRD in a patient who has been followed up for about three years (four episodes). Emphasis is placed on improvement in symptoms and functioning without use of any pharmacological treatment. Further, the need for systematic study and standardization of various aspects of rTMS therapy for maintenance treatment is emphasised. PMID- 23440310 TI - Rapid Identification and Drug Susceptibility Testing of Mycobacterium tuberculosis: Standard Operating Procedure for Non-Commercial Assays: Part 1: Microscopic Observation Drug Susceptibility Assay v2.4.12. AB - Multidrug-resistant tuberculosis is an increasing public health concern in many parts of the world, especially in low-income countries, where most cases occur. Traditional mycobacteria culture and drug susceptibility testing (DST) is either time-consuming or expensive and for that reason uptake of these technologies has remained limited in many resource-constrained settings. However, several non commercial culture and DST methods that do not require sophisticated infrastructure and techniques have been developed. One such method is the microscopic observation drug susceptibility assay (MODS). In this method microcolonies that form in the liquid culture medium after specimen inoculation to drug-free and drug-containing micro-wells are detected by visual observation with a simple inverted microscope. The identification and drug susceptibility results can be obtained in 7-15 days. This standard operating procedure document has been developed through the culture and DST subgroup of the STOP TB Partnership, New Diagnostic Working Group. It is intended for laboratories that would want to use or already using this rapid non-commercial method for culture identification and DST of Mycobacterium tuberculosis, notably in resource constraint settings in Asia and Africa. PMID- 23440311 TI - Effect of yoga exercise therapy on oxidative stress indicators with end-stage renal disease on hemodialysis. AB - BACKGROUND: Oxidative stress promotes endothelial dysfunction and atherosclerosis in chronic renal disease. OBJECTIVES: This study investigated the impact of Hatha yoga on oxidative stress indicators and oxidant status, in patients with end stage renal disease (ESRD) on hemodialysis. DESIGN: This prospective randomized study consisted of 33 ESRD patients in the Hatha yoga exercise group who were matched with 35 ESRD patients in the control group. OUTCOME MEASURES: The oxidative stress indicators (malondialdehyde - MDA, protein oxidation - POX, phospholipase A2 - PLA2 activity) and the oxidative status (superoxide dismutase (SOD) and catalase activities) were determined in the blood samples taken at the pre-hemodialysis treatment, at baseline (0 months) and after four months. RESULTS: In patients in the Hatha yoga exercise group, lipid peroxidation, as indicated by MDA decreased by 4.0% after four months (P = 0.096). There was also a significant reduction in the activity of PLA from 2.68 +/- 0.02 IU / L to 2.34 IU / L (- 12.7%; P = 0.010) and POX from 2.28 +/- 0.02 nmol / mg to 2.22 +/- 0.01 nmol / mg (- 22.6%; P = 0.0001). The activity of SOD significantly increased from 12.91 +/- 0.17 U / L to 13.54 +/- 0.15 U / L (4.65%; P = 0.0001) and catalase from 79.83 +/- 0.63 U / L to 80.54 +/- 0.80 U / L (0.90%; P = 0.0001). There was a significant correlation between the pre-hemodialysis oxidative stress parameters at the zero month and after four months for the activities of PLA (r = 0.440), catalase (r = 0.872), and SOD (r = 0.775). CONCLUSIONS: These findings suggest that the Hatha yoga exercise has therapeutic, preventative, and protective effects in ESRD subjects, by decreasing oxidative stress. PMID- 23440312 TI - Child categorization. AB - Categorization is a process that spans all of development, beginning in earliest infancy yet changing as children's knowledge and cognitive skills develop. In this review article, we address three core issues regarding childhood categorization. First, we discuss the extent to which early categories are rooted in perceptual similarity versus knowledge-enriched theories. We argue for a composite perspective in which categories are steeped in commonsense theories from a young age but also are informed by low-level similarity and associative learning cues. Second, we examine the role of language in early categorization. We review evidence to suggest that language is a powerful means of expressing, communicating, shaping, and supporting category knowledge. Finally, we consider categories in context. We discuss sources of variability and flexibility in children's categories, as well as the ways in which children's categories are used within larger knowledge systems (e.g., to form analogies, make inferences, or construct theories). Categorization is a process that is intrinsically tied to nearly all aspects of cognition, and its study provides insight into cognitive development, broadly construed. WIREs Cogn Sci 2011 2 95-105 DOI: 10.1002/wcs.96 For further resources related to this article, please visit the WIREs website. PMID- 23440313 TI - In vivo MRI assessment of placental and foetal oxygenation changes in a rat model of growth restriction using blood oxygen level-dependent (BOLD) magnetic resonance imaging. AB - OBJECTIVES: To evaluate whether changes in BOLD signal intensities following hyperoxygenation are related to intrauterine growth restriction (IUGR) in a rat model. METHODS: IUGR was induced in pregnant rats by ligating the left vascular uterine pedicle at day 16 of gestation. BOLD MR imaging using a balanced steady state free-precession (balanced-SSFP) sequence on a 1.5-T system was performed on day 19. Signal intensities (SI) before and after maternal hyperoxygenation were compared in the maternal liver and in control and growth-restricted foetoplacental units (FPUs). RESULTS: Maternal hyperoxygenation resulted in a significant increase in SI in all regions of interest (P < 0.05) in the 18 rats. In the control group, the SI (mean +/- SD) increased by 21 % +/- 15 in placentas (n = 74) and 13 % +/- 8.5 in foetuses (n = 53). In the IUGR group, the increase was significantly lower: 6.5 % +/- 4 in placentas (n = 36) and 7 %+/- 5.5 in foetuses (n = 34) (P < 0.05). CONCLUSION: BOLD MRI allows non-invasive assessment of the foetoplacental response to maternal hyperoxygenation in the rat and demonstrates its alteration in an IUGR model. This imaging method may provide a useful adjunct for the early diagnosis, evaluation, and management of human IUGR. KEY POINTS: * Intra-uterine growth restriction is an important cause of perinatal morbidity and mortality. * Blood oxygen level-dependent MRI non-invasively assesses foetoplacental response to maternal hyperoxygenation. * In the rat, foetoplacental response to maternal hyperoxygenation is altered in IUGR. * Functional MRI may help to assess human IUGR. PMID- 23440315 TI - Delayed, spontaneous conversion of type 2 closure to type 1 closure following surgery for traumatic macular hole associated with submacular hemorrhage. AB - A 45-year-old man presented with diminution of vision in the left eye following a firecracker injury. Best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/125 in the left eye. Fundus examination revealed vitreous hemorrhage, a macular hole, and submacular hemorrhage in the left eye. The patient underwent vitrectomy, tissue plasminogen activator (tPA)-assisted evacuation of the submacular hemorrhage, internal limiting membrane (ILM) peeling, and 14% C3F8 gas insufflation. After two months, the BCVA remained 20/125 and optical coherence tomography (OCT) showed type 2 macular hole closure. On a follow-up, seven months after surgery, BCVA improved to 20/80, N6, with type 1 closure of the macular hole. The clinical findings were confirmed on OCT. Delayed and spontaneous conversion of the traumatic macular hole could occur several months after the primary surgery and may be associated with improved visual outcome. Larger studies are required to better understand the factors implicated in such a phenomenon. PMID- 23440316 TI - Inter-hospital extracorporeal life support. AB - A 60-year-old man with history of hypertension and unspecified left ventricular dysfunction had chest pain at home at 9 am. At 1 pm he was transported to a peripheal hospital and treated for acute myocardial infarction. At 4.30 pm, despite pharmacological and intra aortic balloon pump support , the extreme hemodynamic instability and the echocardiographic signs forced the doctors in charge to contact the "extracorporeal membrane oxygenation team" of our Intensive Care Unit. The team, that in our hospital is composed of an intensivist, a cardiac surgeon, a perfusionist and a nurse, reached the hospital at 5.15 pm and performed a percutaneous cannulation of right femoral artery and left femoral vein connecting the patient to the extracorporeal membrane oxygenation circuit. At 6.30 pm the patient on extracorporeal membrane oxygenation was transferred by ambulance to the Cardiac Surgery Intensive Care Unit of San Gerardo Hospital in Monza. On day 20 he was transferred back to the original hospital without neurological deficits, with normal renal function and normal blood gas analysis. PMID- 23440314 TI - Peripherally inserted central catheter placement in cancer patients with profound thrombocytopaenia: a prospective analysis. AB - OBJECTIVE: No studies have specifically evaluated the safety of peripherally inserted central catheter (PICC) placement in patients with profound thrombocytopaenia. We prospectively determined the frequency of haemorrhagic complications of PICC placement in cancer patients with uncorrected profound thrombocytopaenia. METHODS: Profound thrombocytopaenia was defined as a platelet count <50 * 10(9)/l. No patients received transfusions before or after the procedure. Three types of adverse effects were analysed: minor oozing, mild haematoma and major haemorrhage. RESULTS: One hundred and forty-three PICC implantations in 101 cancer patients were prospectively included in the study: seven patients (7 %) had a solid tumour and 94 (93 %) a haematological malignancy. Among these 143 procedures in thrombocytopaenic patients, 93 (65 %) were performed with a platelet count 20-50 * 10(9)/l and 50 (35 %) had lower than 20 * 10(9)/l. No major haemorrhage was observed. Minor oozing was observed in six implantations (4 %) and mild haematoma in two (1.5 %), for a total of eight minor haemorrhagic adverse events (5.5 %). In patients with a platelet count <20 * 10(9)/l, 1/50 (2 %) had minor oozing and none had minor haematoma. CONCLUSIONS: In cancer patients with uncorrected profound thrombocytopaenia, the incidence of adverse events after PICC implantation was low, and was limited to minor haemorrhagic adverse events. KEY POINTS: * PICC placement has high technical success in profound thrombocytopaenic cancer patients. * Few adverse events are encountered after PICC placement, limited to minor haemorrhage. * PICC placement does not routinely require platelet transfusion in patients with thrombocytopaenia. * Such PICC placement still seems safe when the platelet count is <20 * 10 (9) /l. PMID- 23440317 TI - Acute Hypoxia Activates an ENaC-like Channel in Rat Pheochromocytoma (PC12) Cells. AB - Cells can resist and even recover from stress induced by acute hypoxia, whereas chronic hypoxia often leads to irreversible damage and eventually death. Although little is known about the response(s) to acute hypoxia in neuronal cells, alterations in ion channel activity could be preferential. This study aimed to elucidate which channel type is involved in the response to acute hypoxia in rat pheochromocytomal (PC12) cells as a neuronal cell model. Using perfusing solution saturated with 95% N(2) and 5% CO(2), induction of cell hypoxia was confirmed based on increased intracellular Ca(2+) with diminished oxygen content in the perfusate. During acute hypoxia, one channel type with a conductance of about 30 pS (2.5 pA at -80 mV) was activated within the first 2~3 min following onset of hypoxia and was long-lived for more than 300 ms with high open probability (P(o), up to 0.8). This channel was permeable to Na(+) ions, but not to K(+), Ca(+), and Cl(-) ions, and was sensitively blocked by amiloride (200 nM). These characteristics and behaviors were quite similar to those of epithelial sodium channel (ENaC). RT-PCR and Western blot analyses confirmed that ENaC channel was endogenously expressed in PC12 cells. Taken together, a 30-pS ENaC-like channel was activated in response to acute hypoxia in PC12 cells. This is the first evidence of an acute hypoxia-activated Na(+) channel that can contribute to depolarization of the cell. PMID- 23440318 TI - Sex difference in normal thymic appearance in adults 20-30 years of age. AB - PURPOSE: To determine whether there is a sex difference in the appearance of the normal thymus in 20-30-year-old men and women. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and was compliant with HIPAA. The requirement for informed consent was waived. Images and medical records of 238 consecutive subjects without known thymic disease (175 men, 63 women) who underwent chest computed tomography with intravenous contrast material in 2008 were reviewed. Average thymic region of interest (ROI), subjective assessment of thymic attenuation by using a scale of grades 0-3, thymic anteroposterior measurement, and mean maximal thymic lobe thickness were recorded by two independent thoracic radiologists, blinded to subject age and sex. Thymic morphologic characteristics were assessed in consensus. The two-sided Wilcoxon rank-sum test, Student t test, test for linear regression, analysis of covariance, two-way factorial analysis of variance, and continuity-adjusted chi(2) test were used for statistical analysis. RESULTS: There was a significant sex difference in thymic attenuation as measured objectively by using mean thymic ROI measurement (P < .0001) and subjectively by using a scale of grades 0-3 (P < .0001), which held true when corrected for age (P < .0001). A sex difference was also found in regard to the rate of decrease in mean thymic attenuation with age, with men's thymuses exhibiting a significant decrease in attenuation during the decade, unlike women (P = .0479). There was no significant sex difference in mean maximal thymic lobe thickness (P = .8697). A quadrilateral, as opposed to triangular, configuration of the thymus was more common in women than men (P = .0034). CONCLUSION: There is a significant sex difference in normal thymic appearance in 20-30-year-old men and women. The thymus of 20-30-year-old women typically exhibits higher attenuation and more commonly exhibits a quadrilateral configuration. PMID- 23440319 TI - MR imaging-guided focal laser ablation for prostate cancer: phase I trial. AB - PURPOSE: To evaluate the feasibility and safety of magnetic resonance (MR) imaging-guided laser-based thermotherapy in men with clinically low-risk prostate cancer and a concordant lesion at biopsy and MR imaging. MATERIALS AND METHODS: This HIPAA-compliant phase I prospective study was approved by the institutional review board. Informed consent was obtained from all patients. Transperineal MR imaging-guided focal laser ablation for clinically low-risk prostate cancer was performed in patients with a Gleason score of 7 or less in three or fewer cores limited to one sextant obtained with transrectal ultrasonography (US)-guided biopsy and a concordant lesion at MR imaging. Lesions were targeted with a laser ablation system. Periprocedural complications were recorded. The International Prostate Symptom Score (IPSS) and the Sexual Health Inventory for Men (SHIM) score were collected before and after the procedure. MR imaging-guided biopsy of the ablation zone was performed 6 months after treatment. The prostate-specific antigen level, IPSS, and SHIM score before and after ablation were compared by using the Wilcoxon signed rank test. RESULTS: Treatment was successfully completed in nine patients (procedure duration, 2.5-4 hours; mean laser ablation duration, 4.3 minutes). Immediate contrast-enhanced posttreatment MR imaging showed a hypovascular defect in eight patients. Self-resolving perineal abrasion and focal paresthesia of the glans penis each occurred in one patient. The mean (+/- standard deviation) IPSS and SHIM score at baseline were 5.8 +/- 5.3 and 19.0 +/- 8.0, respectively. Average score changes were not significantly different from zero during follow-up (P = .18-.99). MR imaging-guided biopsy of the ablation zone showed no cancer in seven patients (78%) and Gleason grade 6 cancer in two (22%). CONCLUSION: Transperineal MR imaging-guided focal laser ablation appears to be a feasible and safe focal therapy option for clinically low-risk prostate cancer. PMID- 23440320 TI - CT use in hospitalized pediatric trauma patients: 15-year trends in a level I pediatric and adult trauma center. AB - PURPOSE: To evaluate the 15-year trend in the use of computed tomography (CT) in hospitalized pediatric trauma patients admitted to Harborview Medical Center (HMC) from 1996 to 2010. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant retrospective study was approved by the institutional review board. The requirement for informed consent was waived. The HMC trauma registry was linked to the billing department data, and patient and injury-related characteristics were extracted, in addition to type and frequency of CT procedures. Patients discharged from the emergency department and patients hospitalized for less than 24 hours were not included in this study. Patients were classified into three categories according to age: 0-14 years, 15-18 years, and 19-54 years (reference group). Multivariate negative binomial regression was used to compare CT usage among different age groups by adjusting for patient sex, race and/or ethnicity, insurance status, mechanism of injury, injury severity, final disposition (dead vs alive), and year of admission. The trend for CT use in children and teenagers was also evaluated. RESULTS: A total of 64 425 trauma patients 0-54 years of age were admitted during the study period. Compared with CT usage in adults 19-54 years old, usage in children up to 15 years of age was significantly lower for spine (incidence rate ratio [IRR], 0.89; 95% confidence interval [CI]: 0.85, 0.92), maxillofacial (IRR, 0.89; 95% CI: 0.81, 0.97), and thoracic (IRR, 0.91; 95% CI: 0.84, 0.99) CT. Increased use of head CT was observed in children up to 15 years old (IRR, 1.09; 95% CI: 1.05, 1.13) and 15-18 years old (IRR, 1.08; 95% CI: 1.04, 1.13). From 2008 to 2010, usage rates in children up to 15 years old and 15-18 years old was relatively unchanged or slightly decreased for almost all CT types. CONCLUSION: A decreasing or unchanged trend was observed in CT usage in hospitalized pediatric trauma patients in recent years. (c) RSNA, 2013. PMID- 23440321 TI - Use of carotid plaque neovascularization at contrast-enhanced US to predict coronary events in patients with coronary artery disease. AB - PURPOSE: To determine whether carotid plaque neovascularization as assessed with contrast-enhanced ultrasonography (US) can help predict future coronary events in patients with stable coronary artery disease (CAD). MATERIALS AND METHODS: The study was approved by the hospital ethics committee, and informed consent was obtained from all patients. Three hundred twelve consecutive patients (228 men; mean age, 63 years +/- 9; age range, 42-88 years) with both CAD and at least one carotid plaque thicker than 2.0 mm underwent both standard and contrast-enhanced carotid US. Patients with stable CAD were followed up for 8-47 months (mean, 33 months +/- 9) or until a coronary event occurred. Statistical analysis was performed with the Student t test, chi(2) analysis, Kaplan-Meier method, and Cox proportional hazards regression models. RESULTS: Contrast material enhancement of plaque was seen in 42 of 51 patients (82%) with acute coronary syndrome (ACS) and 114 of 261 patients (43.7%) with stable CAD (P < .001). Coronary events occurred during the follow-up period in 24 of 111 patients (21.6%) with contrast material enhancement of plaque and only seven of 137 patients (5.1%) without enhancement (P< .001). In 248 patients with stable CAD and follow-up, Kaplan-Meier analysis demonstrated a significantly higher probability of developing coronary events in patients with contrast material enhancement of plaque than in those without contrast material enhancement (P < .001). The presence of contrast material enhancement of plaque was a significant and independent predictor of future coronary events in patients with stable CAD (odds ratio: 3.90; 95% confidence interval: 1.60, 9.46; P = .003). CONCLUSION: Contrast material enhancement of plaque is more common in patients with ACS than in those with stable CAD and is a significant and independent predictor of future coronary events in patients with stable CAD, suggesting that noninvasive contrast-enhanced carotid US may be used as a method for risk stratification of patients with stable CAD. PMID- 23440322 TI - Radiofrequency ablation and immunostimulant OK-432: combination therapy enhances systemic antitumor immunity for treatment of VX2 lung tumors in rabbits. AB - PURPOSE: To evaluate whether antitumor immunity is enhanced systemically by combining radiofrequency ablation (RFA) and local injection of an immunostimulant, OK-432. MATERIALS AND METHODS: Experiments were approved by the institutional animal care committee. Experimental Japanese rabbits inoculated with VX2 tumors in the lung and the auricle were randomized into four groups of eight: control (supportive care), RFA (RFA of lung tumor), OK-432 (direct injection of OK-432 into lung tumor), and combination therapy (lung RFA and direct OK-432 injection into lung tumor). All procedures were performed 1 week after implantation of VX2 tumors (week 1). In addition, a VX2 tumor rechallenge test was performed in the RFA and combination therapy groups. Survival time was evaluated by means of the Kaplan-Meier method and by using the log-rank test for intergroup comparison. Mean auricle tumor volumes were calculated every week. Specific growth rates (SGRs) were calculated and compared by using the Mann Whitney test. RESULTS: The median survival times of the control, RFA, OK-432, and combination therapy groups were 23, 36.5, 46.5, and 105 days, respectively. Survival was significantly prolonged in the combination therapy group when compared with the other three groups (P <.05). The mean auricle tumor volume decreased only in the combination therapy group. The mean auricle tumor volumes of the combination therapy group from week 1 to week 7 were 205, 339, 264, 227, 143, 127, and 115 mm(3). SGR in the combination therapy group became significantly smaller than those in the other three groups (P < .05). In the rechallenge test, the volume of all reimplanted tumors decreased. CONCLUSION: Combining RFA with local injection of immunostimulant OK-432 may lead to indirectly activation of systemic antitumor immunity. PMID- 23440323 TI - Measurement of phantomless thoracic bone mineral density on coronary artery calcium CT scans acquired with various CT scanner models. AB - PURPOSE: To determine the accuracy and precision of thoracic phantomless bone mineral density (BMD) measurements obtained on coronary artery calcium (CAC) computed tomography (CT) scans by using a variety of commercially available CT scanners. MATERIALS AND METHODS: The institutional review board approved this Health Insurance Portability and Accountability Act-compliant study. A total of 4126 asymptomatic subjects (2022 [49%] men, 2104 [51%] women; mean age, 63.7 years +/- 11.8 [standard deviation]) underwent CAC CT with the use of a quantitative CT calibration phantom for evaluation of subclinical atherosclerosis. Two hundred eighty subjects also underwent CT of the chest, abdomen, and pelvis (C7 through L5). Mean BMD of three consecutive thoracic vertebrae (in the T7-T10 range) was measured in all 4126 subjects. Individual calibration factors for each phantom insert and a general calibration factor for the spine were determined for each CT scanner model. The study population was then divided into three subgroups: All calibration factors were generated from group 1 (n = 1536) and were applied and tested in group 2 (n = 1587), and effects of various image acquisition parameters were assessed in group 3 (n = 1003). Accuracy (bias) and precision of thoracic phantomless BMD measurements across 14 CT scanner models from five manufacturers were determined. RESULTS: Phantomless BMD values correlated highly with standard phantom-based quantitative CT BMD values (r = 0.987, P < .001). Bias was 3.9% +/- 1.4 for phantomless BMD measurements, and the mean coefficient of variation for the general calibration factor was 4.9% +/- 2.4. CONCLUSION: Phantomless BMD can be measured accurately on CAC CT scans acquired with a variety of CT scanners without additional radiation exposure. PMID- 23440324 TI - Development and validation of a semiquantitative brain maturation score on fetal MR images: initial results. AB - PURPOSE: To develop a valid, reliable, and simple-to-use semiquantitative visual scale of fetal brain maturation for use in clinical fetal MR imaging assessment and interpretation. MATERIALS AND METHODS: This is a retrospective assessment of data from a previous study that was prospective, institutional review board approved, and HIPAA compliant. Forty-eight normal pregnancies with a gestational age (GA) of 25 to 35 weeks were studied. A fetal total maturation score (fTMS) was developed by utilizing six subscores that evaluated cortical sulcation, myelination, and the germinal matrix and provided a single combined numerical value to be evaluated as a marker of brain maturity. The fTMS was correlated with GA and segmented brain volume. A regression model that associated GA based on the visual fTMS scoring was determined. The model was validated with a leave-one-out cross validation procedure. RESULTS: Mean GA was 29.3 weeks +/- 2.9 (standard deviation) (range, 25.2-35.3 weeks) and mean fTMS was 8.6 +/- 3.7 (range, 4-16). The intraclass correlation coefficient between the three readers (independent and blinded) was 0.948 (P < .001). The correlations were as follows: GA and brain volume, r = 0.964 (P < .001); fTMS and brain volume, r = 0.970 (P < .001); and GA and fTMS, r = 0.975 (P < .001). A regression model to calculate GA based on fTMS yielded the following equation: calculated GA (weeks) = 22.86 + 0.748 fTMS (P < .001; adjusted R(2) = 0.946). The standard error of the model for calculation of fetal GA from the visual fTMS scale was +/- 4.8 days. CONCLUSION: If validated further, the fTMS scale might be used to assess morphologic brain maturity of fetuses between 25 and 35 weeks GA on a single-case basis in a clinical setting. PMID- 23440325 TI - Seminal vesicle invasion in prostate cancer: evaluation by using multiparametric endorectal MR imaging. AB - PURPOSE: To retrospectively evaluate the diagnostic performance of multiparametric endorectal magnetic resonance (MR) imaging, including T2 weighted, diffusion-weighted (DW), and dynamic contrast material-enhanced (DCE) MR techniques, for the diagnosis of seminal vesicle invasion (SVI) and to determine the incremental value of DW MR and DCE MR images. MATERIALS AND METHODS: This retrospective HIPAA-compliant study was approved by the institutional review board, with a waiver of informed consent. The study included 131 patients (mean age, 68 years; range, 43-75 years) who underwent endorectal MR imaging before radical prostatectomy between January 2007 and April 2010. Two radiologists (A: experienced, B: less experienced) estimated the likelihood of SVI by using a five-point ordinal scale in three image-viewing settings: T2 weighted images alone; T2-weighted and DW MR images; and T2-weighted, DW MR, and DCE MR images. Sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) were calculated. Confidence intervals estimated with bootstrapping and the McNemar test or Fisher exact test were used to compare sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: Of the 131 patients, 23 (17.6%) had SVI identified after surgery. Review of T2-weighted MR images alone resulted in high specificity (93.1% and 93.6%, for radiologists A and B, respectively) and high negative predictive value (94.8% and 94.0%) but moderate sensitivity (59% and 52%) and positive predictive value (52% and 50%). Review of T2-weighted and DW MR images significantly improved specificity (96.6% [P = .02] and 98.3% [P = .003]) and positive predictive value (70% [P < .05] and 79% [P < .05]) without significantly improving AUC. Additional review of DCE MR images did not yield further incremental improvement. CONCLUSION: Additional review of DW MR images improves specificity and positive predictive value in SVI detection compared with reviewing T2-weighted images alone. Addition of DCE MR images to this combination, however, does not provide incremental value for diagnosis of SVI. PMID- 23440326 TI - Hepatocellular carcinoma: high hepatitis B viral load and mortality in patients treated with transarterial chemoembolization. AB - PURPOSE: To determine the relationship between hepatitis B virus (HBV) DNA level and the survival of patients with hepatocellular carcinoma treated by means of transarterial chemoembolization (TACE). MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. From January 2005 to March 2007, 183 patients with HBV-related hepatocellular carcinoma who underwent TACE but never received antiviral therapy were consecutively enrolled in our cohort. All patients were tested for pre-TACE serum level of HBV DNA, and overall survival was measured from date of enrollment until death from any cause. Radiologic progression was evaluated by using the modified response evaluation criteria in solid tumors by means of independent radiologic assessment. RESULTS: The median overall survival was 19 months (95% confidence interval: 13.7, 24.3) and median time to progression was 4 months (95% confidence interval: 3.03, 4.97). Multivariate analysis revealed that a high pre-TACE serum level of HBV DNA (> 2000 IU/L) was an independent risk factor for reduced overall survival (P = .021; hazard ratio [HR], 1.725), high cancer progression-related mortality (P = .014; HR, 1.936), and hepatic failure-related mortality associated with cancer progression (P = .005, HR, 3.908). Pre-TACE level of HBV DNA did not significantly affect hepatic failure-related mortality that was not caused by cancer progression. CONCLUSION: A high pre-TACE serum level of HBV DNA was associated with poor overall survival and rapid progression of hepatocellular carcinoma after TACE, and the cause of mortality was not hepatitis exacerbation but cancer progression. PMID- 23440327 TI - Comparison of four microwave ablation devices: an experimental study in ex vivo bovine liver. AB - PURPOSE: To compare volume, sphericity, and short-axis diameter of the coagulation zone of four commercially available microwave ablation systems with three technical concepts in an ex vivo setting and to formulate mathematical models to predict these quantities. MATERIALS AND METHODS: Two high-power systems (systems A and B), a system that enables simultaneous use of three antennas (system C), and a non-perfusion-cooled system that automatically adapts power and frequency (system D) were tested in ex vivo bovine livers (108 ablations). Coagulation volume, sphericity, and mean short-axis diameter were assessed, and mathematical functions were fitted for each system and assessed with the coefficient of determination (R(2)). Analysis of variance and Tukey post hoc tests were used for interdevice comparison after 5 and 10 minutes and after maximum recommended ablation time. RESULTS: Volume and short-axis diameter were determined by using a mathematical model for every system, with coefficients of determination of 0.75-0.98 and 0.70-0.97, respectively. Correlation for determination of sphericity was lower (R(2) = 0.01-0.68). Mean results with ablation performed according to manufacturer recommendations were as follows: Volume, sphericity, and short-axis diameter were 57.5 cm(3), 0.75, and 43.4 mm, respectively, for system A; 72.3 cm(3), 0.68, and 45.5 mm, respectively, for system B; 17.1 cm(3), 0.58, and 26.8 mm, respectively, for system C (one antenna); 76.5 cm(3), 0.89, and 50.6 mm, respectively, for system C (three antennas); and 56.0 cm(3), 0.64, and 40.9 mm, respectively, for system D. Systems A (mean volume, 52.4 cm(3) +/- 4.5 [standard deviation]) and B (39.4 cm(3) +/- 1.7) reach large ablation zones with 5-minute ablation. CONCLUSION: The largest ablation zone is obtained with systems B and C (three antennas) under maximum recommended ablation duration and with system A under short ablation time. The most spherical zone is obtained with system C (three antennas). PMID- 23440328 TI - Selective decontamination of the digestive tract: an update of the evidence. AB - Selective decontamination of the digestive tract has been proven to prevent severe infections and to reduce mortality in critically ill patients. Historical arguments against its use, like the development of bacterial resistance and the absence of influence on mortality, have not been confirmed. Recent clinical trials designed to evaluate these variables and meta-analyses showed remarkable reductions in the incidence of resistant bacteria and a significant beneficial effect on survival. This review will update the evidence on the efficacy of selective decontamination of the digestive tract, and the issue of emergence of resistance, using data from randomized controlled trials and meta-analyses. PMID- 23440329 TI - PRAF2 stimulates cell proliferation and migration and predicts poor prognosis in neuroblastoma. AB - Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein with four transmembrane-spanning domains that belongs to the PRAF protein family. Neuroblastoma (NB) is the most common malignant extracranial solid tumor of childhood that originates in primitive cells of the developing sympathetic nervous system. We investigated the correlation of PRAF2 mRNA expression to NB clinical and genetic parameters using Affymetrix expression analysis of a series of 88 NB tumors and examined the functional role of PRAF2 in an NB cell line using RNA interference. We found that high PRAF2 expression is significantly correlated to several unfavorable NB characteristics: MYCN amplification, high age at diagnosis, poor outcome and high INSS stage. The shRNA-mediated PRAF2 downregulation in the SK-N-SH NB cell line resulted in decreased cellular proliferation, migration and matrix-attachment. These findings were confirmed in NB patient tumor samples, where high PRAF2 expression is significantly correlated to bone and bone marrow metastasis, the main cause of death in NB patients. The present study shows that PRAF2 plays an essential role in NB tumorigenesis and metastasis. PMID- 23440330 TI - Huntingtin-associated protein 1: a potential biomarker of breast cancer. AB - It is reported that patients with Huntington's disease (HD) have a low incidence of cancer. In this study, we investigated the expression of huntingtin-associated protein 1 (HAP1), the ligand of HD's production, in breast tumor and normal tissues. We found that HAP1 expression was significantly lower in tumor compared to normal tissues. We then transfected the HAP1 gene into the breast cancer lines MCF-7 and MDA-MB-231, and results showed that the overexpression of HAP1 reduced the growth of the two cell lines. In addition, we observed that HAP1 also reduced invasion and migration, and upregulated apoptosis in MCF-7 cells; however, these changes were not observed in MDA-MB-231 cells. We also demonstrated that the expression of EGFR and apoptosis-related genes might be involved in cell proliferation and apoptosis. In conclusion, overexpression of HAP1 reduced in vitro cell growth in breast cancer cell lines, suppressed the migration and invasion, and promoted the apoptosis of certain cell lines. Therefore, HAP1 is a potential molecular target for the diagnosis and treatment of breast cancer. PMID- 23440331 TI - Evaluation of Antiulcer Properties of Ethanolic and Hot Aqueous Stem Extracts of Synclisia scabrida on Experimentally Induced Ulcer Models in Albino Mice. AB - BACKGROUND: The treatment of peptic ulcer disease poses therapeutic challenges to both patients and physicians alike because of the tendency of ulcers to relapse. Drugs used in the treatment of this disease are either costly or are associated with high incidence of adverse effects. Synclisia scabrida is a plant used in ethnomedicine for the treatment of various forms of stomach disorders and menstrual pains. The medicinal properties of the plants are claimed to reside in the roots, stems, and the leaves. AIM: This study, therefore, is to verify this claim and elucidate the probable mechanism of action by using crude stem extracts of this plant on drug- and stress-induced ulcer models in albino mice. MATERIALS AND METHODS: Crude ethanol and hot water extracts, EE and HWE respectively, of the stem were prepared. These extracts were fractionated and separated by chromatographic methods and the fractions pooled together as fractions (PF-1, PF 2, PF-3 respectively) based on their chromatographic mobility and color reactions. Phytochemical analysis was done on the extracts. Ulcer models were induced in albino mice by means of indomethacin, histamine, and stress after prior cytoprotection with orally administered crude extracts and control (cimetidine). RESULTS: Phytochemical analysis of the crude extracts and their fractions revealed the presence of cardiac glycosides (+++), tannins (+++), saponins (+), flavonoids (++), carbohydrates (++) and alkaloids (+++). Acute toxicity study on the crude extracts and their fractions revealed relative safety at the dose of 5000 mg/kg. The crude extracts (EE and HWE) and their fractions (PF-1, PF-2, PF-3) significantly (P = 0.001) protected against indomethacin-, histamine- and stress-induced ulcers. The decrease in GIT motility produced by these extracts was comparable to that produced by atropine sulfate. CONCLUSION: The findings suggest that these extracts of Synclisia scabrida possess antiulcer and antispasmodic properties, which justify the claims for its use in the treatment of various forms of stomach disorders. PMID- 23440332 TI - Electrically bistable memory devices based on poly(triphenylamine)-PCBM hybrids. AB - Due to the strong interaction between PCBM and triphenylamine, PCBM could be well distributed into poly-4-methoxytriphenylamine (P-TPA). The resulting hybrid films exhibited DRAM behavior at low PCBM concentrations, while they revealed WORM property at higher, 5 wt% and even up to 10 wt%, PCBM concentrations. PMID- 23440333 TI - Donor killer immunoglobulin-like receptor genes and reactivation of cytomegalovirus after HLA-matched hematopoietic stem-cell transplantation: HLA-C allotype is an essential cofactor. AB - Natural killer (NK) cells whose killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen (HLA) ligand are "licensed" for activity. In contrast, non-licensed NK cells display KIRs for which ligand is absent from the self genotype and are usually hyporesponsive. Surprisingly, non-licensed cells are active in tumor control after hematopoietic stem-cell transplantation (HSCT) and dominate NK response to murine cytomegalovirus (CMV) infection. From those reports, we hypothesized that control of human CMV early after HSCT is influenced by donor KIR genes whose HLA ligand is absent-from-genotype of HLA-matched donor and recipient. To investigate, we studied CMV reactivation through Day 100 after grafts involving CMV-seropositive donor and/or recipient. A multivariate proportional rates model controlled for variability in surveillance and established covariates including acute graft-versus-host disease; statistical significance was adjusted for testing of multiple KIRs with identified HLA class I ligand (2DL1, 2DL2/3, 2DS1, 2DS2, full-length 2DS4, 3DL1/3DS1, 3DL2). Among HSCT recipients (n = 286), CMV reactivation-free survival time varied with individual donor KIR genes evolutionarily specific for HLA-C: when ligand was absent from the donor/recipient genotype, inhibitory KIRs 2DL2 (P < 0.0001) and 2DL1 (P = 0.015) each predicted inferior outcome, and activating KIRs 2DS2 (P < 0.0001), 2DS1 (P = 0.016), and 2DS4 (P = 0.016) each predicted superior outcome. Otherwise, with ligand present-in-genotype, donor KIR genes had no effect. In conclusion, early after HLA-matched HSCT, individual inhibitory and activating KIR genes have qualitatively different effects on risk of CMV reactivation; unexpectedly, absence of HLA-C ligand from the donor/recipient genotype constitutes an essential cofactor in these associations. Being KIR- and HLA-C specific, these findings are independent of licensing via alternate NK cell receptors (NKG2A, NKG2C) that recognize HLA-E. PMID- 23440334 TI - Interstitial lung diseases in Saudi Arabia: A single-center study. AB - BACKGROUND: There are relatively few epidemiological studies on interstitial lung disease (ILD) worldwide. OBJECTIVE: To report the incident cases of ILD and compare our data with reports from other populations. METHODS: Newly diagnosed ILDs were prospectively collected at a single tertiary care hospital from January 2008 to December 2011. Detailed demographic and clinical data were collected at the time of diagnosis, along with the results from diagnostic procedures, including high-resolution computed tomography (HRCT), serological tests, bronchoalveolar lavage (BAL), transbronchial lung biopsy, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and surgical lung biopsy. RESULTS: A total of 330 cases were included. The mean age was 55.4 +/- 14.9 years. There was a slight predominance of females (202; 61.2%), and the male to-female ratio was 1:1.37. The most frequent disease was connective tissue disease (CTD)-associated ILD (34.8%), followed by idiopathic pulmonary fibrosis (IPF) (23.3%), sarcoidosis (20%), and hypersensitivity pneumonitis (6.3%). Non classifiable ILD was present in 1.8% of the total ILD cases. HRCT was performed in 97.3% of the cases, BAL in 17.5%, transbronchial lung biopsy in 21.8%, EBUS TBNA in 4.5%, and surgical lung biopsy in 22.7% (38.6% of which were performed among the idiopathic interstitial pneumonia cases). CONCLUSIONS: CTD-ILD and IPF were the most frequently observed ILDs in this Saudi Arabian population. Similarities and differences were found with respect to the previous reports from other countries. PMID- 23440335 TI - Profile of alisporivir and its potential in the treatment of hepatitis C. AB - Two classes of hepatitis C antiviral agents currently exist, i.e., direct-acting antivirals and host-targeting antivirals. Direct-acting antivirals target viral proteins including NS3/NS4A protease, NS5B polymerase and NS5A protein, while host-targeting antivirals target various host proteins critical for replication of the hepatitis C virus (HCV). Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A. Due to its unique mechanism of antiviral action, alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals. Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that alisporivir causes a dramatic reduction in viral loads in HCV-infected patients. Alisporivir was shown to be highly potent in treatment-naive and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon-alpha and ribavirin were similar to those associated with pegylated interferon-alpha and ribavirin used alone. A laboratory abnormality observed in some patients receiving alisporivir is hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that alisporivir plus other direct-acting antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior interferon-alpha therapy and patients with cirrhosis. In conclusion, alisporivir represents an attractive candidate component of future interferon free regimens. PMID- 23440337 TI - Prime time: sexual health outcomes at 24 months for a clinic-linked intervention to prevent pregnancy risk behaviors. AB - IMPORTANCE: Preventing early pregnancy among vulnerable adolescents requires innovative and sustained approaches. Prime Time, a youth development intervention, aims to reduce pregnancy risk among adolescent girls seeking clinic services who are at high risk for pregnancy. OBJECTIVE: To evaluate sexual risk behaviors and related outcomes with a 24-month postbaseline survey, 6 months after the conclusion of the Prime Time intervention. DESIGN: Randomized controlled trial. SETTING: Community and school-based primary care clinics. PARTICIPANTS: Of 253 sexually active 13- to 17-year-old girls meeting specified risk criteria, 236 (93.3%) completed the 24-month follow-up survey. INTERVENTION: Offered during an 18-month period, Prime Time includes case management and youth leadership programs. MAIN OUTCOME MEASURES: Self-reported consistency of condom, hormonal, and dual-method contraceptive use with most recent male sex partner and number of male sex partners in the past 6 months. RESULTS: At 24-month follow-up, the intervention group reported significantly more consistent use of condoms, hormonal contraception, and dual-method contraception than the control group. Intervention participants also reported improvements in family connectedness and self-efficacy to refuse unwanted sex, and reductions in the perceived importance of having sex. No between-group differences were found in the number of recent male sex partners. CONCLUSIONS AND RELEVANCE: This study contributes to what has been a dearth of evidence regarding youth development interventions offered through clinic settings, where access to high-risk adolescents is plentiful but few efforts have emphasized a dual approach of strengthening sexual and nonsexual protective factors while addressing risk. Findings suggest that health services grounded in a youth development framework can lead to long-term reductions in sexual risk among vulnerable youth. PMID- 23440336 TI - Long-distance communication and signal amplification in systemic acquired resistance. AB - Systemic acquired resistance (SAR) is an inducible defense mechanism in plants that confers enhanced resistance against a variety of pathogens. SAR is activated in the uninfected systemic (distal) organs in response to a prior (primary) infection elsewhere in the plant. SAR is associated with the activation of salicylic acid (SA) signaling and the priming of defense responses for robust activation in response to subsequent infections. The activation of SAR requires communication by the primary infected tissues with the distal organs. The vasculature functions as a conduit for the translocation of factors that facilitate long-distance intra-plant communication. In recent years, several metabolites putatively involved in long-distance signaling have been identified. These include the methyl ester of SA (MeSA), the abietane diterpenoid dehydroabietinal (DA), the dicarboxylic acid azelaic acid (AzA), and a glycerol-3 phosphate (G3P)-dependent factor. Long-distance signaling by some of these metabolites also requires the lipid-transfer protein DIR1 (DEFECTIVE IN INDUCED RESISTANCE 1). The relative contribution of these factors in long-distance signaling is likely influenced by environmental conditions, for example light. In the systemic leaves, the AGD2-LIKE DEFENSE RESPONSE PROTEIN1 (ALD1)-dependent production of the lysine catabolite pipecolic acid (Pip), FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1) signaling, as well as SA synthesis and downstream signaling are required for the activation of SAR. This review summarizes the involvement and interaction between long-distance SAR signals and details the recently discovered role of Pip in defense amplification and priming that allows plants to acquire immunity at the systemic level. Recent advances in SA signaling and perception are also highlighted. PMID- 23440338 TI - Do targeted agents offer clinical benefit as presurgical therapy? AB - INTRODUCTION: In the era of targeted therapy, management of patients with primary metastatic renal cell carcinoma and the tumour in place is again under investigation in randomized controlled trials. Proper patient selection for cytoreductive nephrectomy (CN) remains challenging. Presurgical targeted therapy may have potential advantages in this setting. MATERIALS AND METHODS: Data on CN and presurgical targeted therapy were reviewed in the literature. RESULTS: Despite validated prognostic scores, outcome after CN is additionally influenced by factors impacting on surgical morbidity and mortality. Patient age, comorbidity, tumour size and extent, metastatic load, surgical approach and skills are not well represented by current prognostic models.The strongest predictor of poor survival following CN is progression within 90 days of surgery. A period of presurgical targeted therapy may identify those patients with rapid disease progression prior to a planned nephrectomy or metastasectomy from which they may not benefit. In nonrandomized prospective studies of presurgical therapy, up to 26 % of patients progressed at metastatic sites prior to planned surgery. Those with intermediate risk and absence of progression had a more than 70% probability to survive 2 years or longer after CN. CONCLUSION: In the absence of biomarkers, presurgical therapy may contribute to individualizing treatment decisions. The advantages and disadvantages of this concept are investigated in a randomized EORTC trial of upfront CN versus CN after presurgical sunitinib in the absence of progression. PMID- 23440340 TI - Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy. AB - Cancer stem cells (CSCs) are known to influence chemoresistance, survival, relapse and metastasis. Aldehyde dehydrogenase (ALDH) functions as an epithelial CSC marker. In the present study, we investigated the involvement of ALDH in gastric CSC maintenance, chemoresistance and survival. Following screening for eight candidate markers (CD13, CD26, CD44, CD90, CD117, CD133, EpCAM and ALDH), five gastric cancer cell lines were found to contain small subpopulations of high ALDH activity (ALDH(high) cells). We also examined the involvement of ALDH(high) cell populations in human primary tumor samples. Immunodeficient NOD/SCID mice were inoculated with tumor tissues obtained from surgical specimens. ALDH(high) cells were found to persist in the xenotransplanted primary tumor samples. in the immunodeficient mice, ALDH(high) cells exhibited a greater sphere-forming ability in vitro and tumorigenic potential in vivo, compared with subpopulations of low ALDH activity (ALDH(low) cells). Cell cultures treated with 5-fluoro-uracil and cisplatin exhibited higher numbers of ALDH(high) cells. Notch1 and Sonic hedgehog (Shh) expression was also found to increase in ALDH(high) cells compared with ALDH(low) cells. Therefore, it can be concluded that ALDH generates chemoresistance in gastric cancer cells through Notch1 and Shh signaling, suggesting novel treatment targets. PMID- 23440339 TI - A systematic review of comparative studies on bone graft alternatives for common spine fusion procedures. AB - BACKGROUND: The increased prevalence of spinal fusion surgery has created an industry focus on bone graft alternatives. While autologous bone graft remains the gold standard, the complications and morbidity from harvesting autologous bone drives the search for reliable and safe bone graft substitutes. With the recent information about the adverse events related to bone morhogenetic protein use, it is appropriate to review the literature about the numerous products that are not solely bone morphogenetic protein. PURPOSE: The purpose of this literature review is to determine the recommendations for use of non-bone morphogenetic protein bone graft alternatives in the most common spine procedures based on a quantifiable grading system. STUDY DESIGN: Systematic literature review. METHODS: A literature search of MEDLINE (1946-2012), CINAHL (1937-2012), and the Cochrane Central Register of Controlled Trials (1940-April 2012) was performed, and this was supplemented by a hand search. The studies were then evaluated based on the Guyatt criteria for quality of the research to determine the strength of the recommendation. RESULTS: In this review, more than one hundred various studies on the ability of bone graft substitutes to create solid fusions and good patient outcomes are detailed. CONCLUSION: The recommendations for use of bone graft substitutes and bone graft extenders are based on the strength of the studies and given a grade. PMID- 23440341 TI - Conformationally preorganised hosts for anions using norbornane and fused [n]polynorbornane frameworks. AB - Norbornane and fused [n]polynorbornane frameworks are readily synthesised, can be tailored to a variety of predictable geometries and can be functionalised regiospecifically. As such, these highly preorganised scaffolds offer the supramolecular chemist an excellent starting point when designing hosts for specific guests. This feature article will highlight the evolution of our research from relatively simple norbornane based anion receptors to more sophisticated tetrathioureido functionalised fused [n]polynorbornane hosts. PMID- 23440342 TI - Damage to health from hormone disrupting chemicals warrants investigation, say WHO and UN. PMID- 23440343 TI - Campaigners demand mandatory nutritional standards for hospital food. PMID- 23440344 TI - Drug experts call for stronger regulation of tramadol to reduce misuse. PMID- 23440345 TI - NICE joins campaign for full disclosure of clinical trial data. PMID- 23440346 TI - India tightens regulation of clinical trials to safeguard participants. PMID- 23440347 TI - Type-specific prevalence of human papillomavirus in women screened for cervical cancer in Labrador, Canada. AB - BACKGROUND: A higher incidence of cervical cancer and human papillomavirus (HPV) infection has been reported in northern Canada and in First Nation, Metis and Inuit women, with some evidence to suggest that the HPV type distribution in these populations may be different from the rest of Canada. OBJECTIVE: The objective of this study was to measure the HPV type prevalence in Labrador women to determine if significant differences in HPV types could reduce the effectiveness of HPV vaccination. DESIGN: The prevalence of HPV types was determined in 1,370 women presenting for routine pap screening in Labrador between February and November 2010. Cervical cytology and HPV genotyping were performed on the same liquid-based cytology specimens. RESULTS: The overall prevalence of HPV was 21.4%; cytological abnormalities were found in 8.8% of the participants. HPV 16 and 18 were the most common high-risk HPV types. These two types were found in 52.4% of high-grade lesions. The prevalence in HPV infections was comparable across the Labrador regions. CONCLUSIONS: The present results support the potential effectiveness of the HPV immunization program in Labrador. PMID- 23440348 TI - Coronary computed tomography angiography using ultra-low-dose contrast media: radiation dose and image quality. AB - To analyze the invasiveness and image quality of coronary CT angiography (CCTA) with 80 kV. We enrolled 181 patients with low body weight and low calcium level. Of these, 154 patients were randomly assigned to 1 of 3 groups: 280 HU/80 kV (n = 51); 350 HU/80 kV (n = 51); or 350 HU/120 kV (n = 52). The amount of contrast media (CM) was decided with a CT number-controlling system. Twenty-seven patients were excluded because of an invalid time density curve by timing bolus. The predicted amount of CM, volume CT dose index, dose-length product, effective dose, image noise, and 5-point image quality were measured. The amounts of CM for the 80 kV/280 HU, 80 kV/350 HU, and 120 kV/350 HU groups were 10 +/- 4 mL, 15 +/- 7 mL, and 30 +/- 6 mL, respectively. Although image noise was greater at 80 than 120 kV, there was no significant difference in image quality between 80 kV/350 HU and 120 kV/350 HU (p = 0.390). There was no significant difference in image quality between 80 kV/280 HU and 80 kV/350 HU (4.4 +/- 0.7 vs. 4.7 +/- 0.4, p = 0.056). The amount of CM and effective dose was lower for 80 kV CCTA than for 120 kV CCTA. CCTA at 80 kV/280 HU may decrease the amount of CM and radiation dose necessary while maintaining image quality. PMID- 23440349 TI - Function and central projections of gustatory receptor neurons on the antenna of the noctuid moth Spodoptera littoralis. AB - Chemosensory information is crucial for most insects to feed and reproduce. Olfactory signals are mainly used at a distance, whereas gustatory stimuli play an important role when insects directly contact chemical substrates. In noctuid moths, although the antennae are the main olfactory organ, they also bear taste sensilla. These taste sensilla detect sugars and hence are involved in appetitive learning but could also play an important role in food evaluation by detecting salts and bitter substances. To investigate this, we measured the responses of individual taste sensilla on the antennae of Spodoptera littoralis to sugars and salts using tip recordings. We also traced the projections of their neuronal axons into the brain. In each sensillum, we found one or two neurons responding to sugars: one NaCl-responsive and one water-sensitive neuron. Responses of these neurons were dose-dependent and similar across different locations on the antenna. Responses were dependent on the sex for sucrose and on both sex and location for glucose and fructose. We did not observe a spatial map for the projections from specific regions of the antennae to the deutocerebrum or the tritocerebrum/suboesophageal ganglion complex. In accordance with physiological recordings, back-fills from individual sensilla revealed up to four axons, in most cases targeting different projection zones. PMID- 23440350 TI - tRNA residues evolved to promote translational accuracy. AB - The decoding properties of 22 structurally conservative base-pair and base-triple mutations in the anticodon hairpin and tertiary core of Escherichia coli tRNA(Ala)GGC were determined under single turnover conditions using E. coli ribosomes. While all of the mutations were able to efficiently decode the cognate GCC codon, many showed substantial misreading of near-cognate GUC or ACC codons. Although all the misreading mutations were present in the sequences of other E. coli tRNAs, they were never found among bacterial tRNA(Ala)GGC sequences. This suggests that the sequences of bacterial tRNA(Ala)GGC have evolved to avoid reading incorrect codons. PMID- 23440352 TI - Adiponectin increases glucose-induced insulin secretion through the activation of lipid oxidation. AB - The expression of adiponectin receptors has been demonstrated in human and rat pancreatic beta cells, where globular (g) adiponectin rescues rat beta cells from cytokine and fatty acid-induced apoptosis. The aim of our study was to evaluate whether adiponectin has a direct effect on insulin secretion and the metabolic pathways involved. Purified human pancreatic islets and rat beta cells (INS-1E) were exposed (1 h) to g-adiponectin, and glucose-induced insulin secretion was measured. A significant increase in glucose-induced insulin secretion was observed in the presence of g-adiponectin (1 nmol/l) with respect to control cells in both human pancreatic islets (n = 5, p < 0.05) and INS-1E cells (n = 5, p < 0.001). The effect of globular adiponectin on insulin secretion was independent of AMP-dependent protein kinase (AMPK) activation or glucose oxidation. In contrast, g-adiponectin significantly increased oleate oxidation (n = 5, p < 0.05), and the effect of g-adiponectin (p < 0.001) on insulin secretion by INS-1E was significantly reduced in the presence of etomoxir (1 MUmol/l), an inhibitor of fatty acid beta oxidation. g-Adiponectin potentiates glucose-induced insulin secretion in both human pancreatic islets and rat beta cells via an AMPK independent pathway. Increased fatty acid oxidation rather than augmented glucose oxidation is the mechanism responsible. Overall, our data indicate that, in addition to its anti-apoptotic action, g-adiponectin has another direct effect on beta cells by potentiating insulin secretion. Adiponectin, therefore, in addition to its well-known effect on insulin sensitivity, has important effects at the pancreatic level. PMID- 23440353 TI - Laser wavelength- and power-dependent plasmon-driven chemical reactions monitored using single particle surface enhanced Raman spectroscopy. AB - Plasmon-driven chemical reaction of p-nitrothiophenol (pNTP) dimerizing into p,p' dimercaptoazobenzene (DMAB) has been monitored using single particle surface enhanced Raman spectroscopy, which provides laser wavelength- and power-dependent conversion rates of the reaction. PMID- 23440351 TI - Reflections on the history of pre-mRNA processing and highlights of current knowledge: a unified picture. AB - Several strong conclusions emerge concerning pre-mRNA processing from both old and newer experiments. The RNAPII complex is involved with pre-mRNA processing through binding of processing proteins to the CTD (carboxyl terminal domain) of the largest RNAPII subunit. These interactions are necessary for efficient processing, but whether factor binding to the CTD and delivery to splicing sites is obligatory or facilitatory is unsettled. Capping, addition of an m(7)Gppp residue (cap) to the initial transcribed residue of a pre-mRNA, occurs within seconds. Splicing of pre-mRNA by spliceosomes at particular sites is most likely committed during transcription by the binding of initiating processing factors and ~50% of the time is completed in mammalian cells before completion of the primary transcript. This fact has led to an outpouring in the literature about "cotranscriptional splicing." However splicing requires several minutes for completion and can take longer. The RNAPII complex moves through very long introns and also through regions dense with alternating exons and introns at an average rate of ~3 kb per min and is, therefore, not likely detained at each splice site for more than a few seconds, if at all. Cleavage of the primary transcript at the 3' end and polyadenylation occurs within 30 sec or less at recognized polyA sites, and the majority of newly polyadenylated pre-mRNA molecules are much larger than the average mRNA. Finally, it seems quite likely that the nascent RNA most often remains associated with the chromosomal locus being transcribed until processing is complete, possibly acquiring factors related to the transport of the new mRNA to the cytoplasm. PMID- 23440354 TI - Kindlin-1 expression is involved in migration and invasion of pancreatic cancer. AB - Kindlin-1 is a novel focal adhesion protein that belongs to the kindlin family. Expression of kindlin-1 has recently been reported in lung and colon cancers, but there have been no studies on its expression in pancreatic cancer. This study aimed to investigate the expression and function of kindlin-1 in pancreatic cancer. Quantitative RT-PCR of Kindlin-1 mRNA was performed in various pancreatic cancer cell lines as well as normal pancreatic epithelial cells and fibroblasts. Immunohistochemical analysis of kindlin-1 was performed for pancreatic cancer tissues. The effects of kindlin-1 on the proliferation, migration and invasion of pancreatic cancer cells were investigated using an RNA interference technique. Kindlin-1 mRNA was highly expressed in the pancreatic cancer cell lines, but only slightly expressed in normal pancreatic epithelial cells and fibroblasts. The Kindlin-1 protein was heterogeneously expressed in the cytoplasm and membrane of pancreatic cancer cells, while normal ductal epithelial cells and stromal cells showed no expression. In vitro experiments involving knockdown of kindlin-1 in AsPC-1 and KP-2 cells revealed that the migratory and invasive abilities of the cells were significantly decreased (P<0.001), while the proliferation abilities were not affected. The present findings suggest that kindlin-1 expression is involved in the progression of pancreatic cancer via enhancement of cell migration and invasion. PMID- 23440355 TI - Nitroglycerin does not interfere with protection by remote ischemic preconditioning in patients with surgical coronary revascularization under isoflurane anesthesia. PMID- 23440356 TI - Nitric oxide-donating statins upgrade the benefits of lipid-lowering in vascular inflammation by desensitizing neutrophil activation: editorial to: "Nitric oxide donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol" by R. Baetta et al. PMID- 23440358 TI - Sclerosing angiomatoid nodular transformation of the spleen related to IgG4 associated disease: report of a case. AB - Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare benign vascular mass, with fewer than 100 cases documented. It is generally recognized as a vascular lesion that develops in the red pulp of the spleen; however, its pathogenesis is not clearly defined. We report a case of SANT of the spleen, which presents evidence to support the hypothesis that this disease entity is associated with IgG4-associated disease. Microscopically, the tumor was composed of multiple vascular structures separated by fibrous connective tissue and immunohistochemical examination revealed positive staining for CD31, CD34, factor VIII, and IgG4. Further research based on large number of cases is warranted to clarify the pathogenesis of this tumor. PMID- 23440359 TI - Sexual activity after ileal pouch-anal anastomosis in Japanese patients with ulcerative colitis. AB - PURPOSE: The aim of this study was to evaluate the sexual activity after restorative proctocolectomy with ileal J-pouch-anal anastomosis (ileoanal anastomosis) in Japanese patients with ulcerative colitis. METHODS: Sixty-one patients who had undergone ileoanal anastomosis and were followed for at least 6 months after surgery were randomly selected. Their quality of life was assessed using the Japanese version of the Inflammatory Bowel Disease Questionnaire. Scores of three or less for the item "Sex life" were predetermined to represent poor sexual activity. The medical staff then asked them the reasons for this using a non-structured interview and open-ended questions. RESULTS: Overall, 19 patients reported poor sexual activity. There was a significant difference in the scores for "Social functions" other than Sex life between individuals with poor and good sexual activities (21.6 +/- 4.6 vs. 24.1 +/- 4.2, P = 0.016). Ileoanal anastomosis after the age of 40 (OR 22, P = 0.02) and a total preoperative corticosteroid dose >=15 g (OR 7.4, P = 0.04) were significant risk factors for poor sexual activity after ileoanal anastomosis. CONCLUSION: Our results suggest that ileoanal anastomosis results in relatively poor sexual activity, which was associated with other social functions, older age and a higher dose of corticosteroids administered to Japanese patients with ulcerative colitis. PMID- 23440360 TI - Clinicopathological characteristics and long-term outcomes of colorectal cancer in elderly Chinese patients undergoing potentially curative surgery. AB - PURPOSE: The aim of this study was to determine the clinicopathological characteristics and outcomes of Chinese colorectal cancer (CRC) patients aged 75 years and older undergoing potentially curative surgery. METHODS: A total of 2,482 CRC patients at TNM stage I-III undergoing surgical treatment between 1995 and 2005 were evaluated, and patients were divided into a younger (<75 years old) and an elderly (>=75 years) group. RESULTS: There were 2,482 CRC patients in this study, of which 2,194 (88.4 %) patients were in the younger group (mean age 57 years) and 288 (11.6 %) were in the elderly group (mean age 79 years). Significant differences were observed between the two groups with regard to the American Society of Anesthesiologists' score, tumor location, co-morbidities, emergency procedures, use of chemotherapy, proportion admitted to the ICU, length of ICU stay, causes of death, T/N stage and postoperative recurrence. The postoperative mortality increased from 4.8 % in the younger group to 8.3 % in the older group (p = 0.011). Although significant differences were found in the overall 5-year survival (73 vs. 56 %, p < 0.0001) and disease-free 5-year survival (68 vs. 54 %, p < 0.0001) between the two groups, the cancer-specific 5 year survival was similar (88 vs. 85 %, p = 0.089) in both groups. CONCLUSIONS: Although elderly CRC patients have unique clinicopathological features, a higher postoperative mortality and a worse overall and disease-free survival compared with younger patients, the cancer-specific survival at five years is similar between elderly and younger patients. Elderly patients benefit from radical surgery and have a good postoperative oncological outcome, irrespective of their age. PMID- 23440361 TI - Timing of drainage tube removal after thyroid surgery: a retrospective study. AB - PURPOSE: The aim of this study was to evaluate the chronological changes in the amount of drainage fluid after thyroidectomy, and to establish standard indications for the drain to be removed. METHODS: We examined a cohort of 249 patients undergoing thyroid surgery. The patients were divided into four groups: a Graves' group, a non-dissection group, a central-dissection group and a lateral dissection group. The amount of drainage was measured every 6 h, and the drain was removed postoperatively when the drainage decreased in amount and contained serous fluid after a meal. RESULTS: In all four groups, the most drainage occurred in the first 6 h after surgery. The total amount of drainage from the operation to the time of drain removal was significantly higher in Graves' group and in the lateral-dissection group than in the other two groups. The median wound drainage significantly decreased from 12 to 18 h after surgery in all four groups. In the lateral-dissection group, the wound drainage significantly decreased again in the first 24-30 h. CONCLUSION: The findings of this study suggest that drains can be removed postoperatively if the drainage was less than 15 mL during a 6-h period and contain serous fluid. PMID- 23440362 TI - Perineal reconstruction after extra-levator abdominoperineal excision (eLAPE): a systematic review. AB - PURPOSE: Extra-levator abdominal perineal excision of rectum (eLAPE) for low rectal tumours is associated with a lower incidence of circumferential resection involvement. However, there is no consensus on the ideal technique for perineal reconstruction following eLAPE. We thereby conducted a 5-year review of perineal closure outcomes following eLAPE. METHODS: A systematic review of the literature was conducted between 2006 and July 2012. Perineal wound healing and complications in the post-operative period were examined. RESULTS: Original data following eLAPE were found in 27 studies involving 963 individuals to inform a qualitative synthesis. Pooled analysis revealed that investigators most commonly employed either biomesh closure (12 studies, n = 149), myocutaneous flap closure (9 studies, n = 201) and primary closure (4, n = 578). The incidence of minor and major wound complications and perineal hernias across the latter groups was (27.5, 13.4 and 2.7 %), (29.4, 19.4 and 0 %) and (17.1, 6.4 and 1.2 %), respectively. Two studies utilised synthetic mesh closure (n = 4) and omentoplasty (n = 31). Objective assessment of wound healing was strikingly deficient across most studies, largely due to low level retrospective evidence lacking randomised controls. Modest cohort sizes with short follow-up data were evident due to the relative novelty of eLAPE. CONCLUSION: The paucity of high quality data, suggests that a prospective, randomised trial is needed to determine the ideal technique for perineal reconstruction following eLAPE. PMID- 23440363 TI - Risk factors for delayed postpolypectomy bleeding: how to minimize your patients' risk. AB - PURPOSE: Secondary bleeding after colonoscopic polypectomy is a serious complication. Most studies show polyp size, location, and shape to be important risk factors but other factors may allow refinement of risk. The aim of this study is to look for other factors associated with delayed postpolypectomy bleeding. METHODS: This case-matched study compares patients who developed postpolypectomy bleeding with those who underwent uncomplicated polypectomy. Matching was performed for known risk factors: polyp size, location and shape, with a ratio of three controls to one subject. RESULTS: Postpolypectomy bleeding occurred in 19/494 patients with polyps >2.0 cm diameter (3.8%) and 11/4161 patients with polyps <2.0 cm (0.3%). There was a median interval of 3 days (range 0-9 days) from polypectomy to hemorrhage. Twenty-five patients were readmitted to this institution. Ten (40.0%) were transfused and 19 (76.0%) were re colonoscoped, with 13 needing either cautery (n = 7) or adrenaline injection (n = 6). Ninety patients were selected as controls, matched for polyp size, location, and shape. Mean age at polypectomy was 69.9 +/- 9.2 years for patients and 64.9 +/- 12.2 for controls (p = 0.042); 63.3% subjects were male, compared to 47.8% of controls (p = 0.140). Univariate analysis showed that older age, piecemeal polypectomy, need for additional sedation, concurrent diverticulosis and intraprocedural bleeding were significantly associated with increased risk of delayed bleeding. The associations between delayed bleeding and additional sedation, concurrent diverticulosis and intraprocedural bleeding were confirmed by multivariate logistic regression analysis. CONCLUSION: Difficult colonoscopy and intraprocedural bleeding identify patients with a particularly high risk of secondary postpolypectomy bleeding. Preventive measures should be considered in such cases. PMID- 23440364 TI - Evaluation of two-dimensional intraoperative neuromonitoring for predicting urinary and anorectal function after rectal cancer surgery. AB - PURPOSE: The aim of this study was to compare the results of two-dimensional intraoperative neuromonitoring (IONM) with the postoperative urinary and anorectal function of rectal cancer patients. METHODS: A consecutive series of 35 patients undergoing low anterior resection were investigated prospectively. IONM was performed with electric stimulations of the pelvic splanchnic nerves under simultaneous manometry of the bladder and electromyography (EMG) of the internal anal sphincter (IAS). Urinary and anorectal function were evaluated preoperatively and at follow-up by standardized questionnaires, digital rectal examination scoring system, and long-term catheterization rate. RESULTS: The rate of postoperative newly developed bladder dysfunction was 17 %. IONM with bladder manometry had a sensitivity of 100 %, specificity of 96 %, positive predictive value of 83 %, negative predictive value of 100 %, and overall accuracy of 97 %, respectively. The proportion of patients with severely impaired anorectal function at follow-up was 8 %. The sensitivity, specificity, and positive and negative predictive values for IONM with EMG of the IAS were, respectively, 100, 96, 67, and 100 % with an accuracy of 96 %. The degree of agreement for IONM with EMG of the IAS was good for anorectal function (k = 0.780) and poor for urinary function (k = 0.119). IONM with bladder manometry yielded a very good degree of agreement for urinary function (k = 0.891) and a fair agreement for anorectal function (k = 0.336). CONCLUSIONS: The two-dimensional IONM method is suitable for verification of bladder and IAS innervation. Accurate prediction of urinary and anorectal function necessitates both bladder manometry and EMG of the IAS. PMID- 23440365 TI - Seven-year follow-up after anterior sphincter reconstruction for faecal incontinence. AB - PURPOSE: The aim was to evaluate the effects of anterior sphincter repair on faecal incontinence and quality of life. PATIENTS AND METHODS: Fifty-six patients who underwent anterior anal sphincteroplasty between January 2003 and December 2005 were asked to complete questionnaires containing the Wexner Incontinence Score (a score of 0 corresponds to full continence and 20 to total incontinence) and Faecal Incontinence Quality of Life Scale preoperatively, in May 2006 (mean follow-up time, 22.8 months) and in August 2011 (mean follow-up time, 89.3 months). Thirty-nine (69.6 %) patients completed the questionnaires before the operation and in 2006, and 36 (64.3 %) in 2011. RESULTS: The overall severity of faecal incontinence improved in 26 patients (67 %), and quality of life improved in 2006 as a whole, but after a longer follow-up (in 2011), the severity of faecal incontinence was about the same as preoperatively (median, 12.0 months) in all the patients. Among younger patients (<=50 years), the situation was better, but older patients (>50 years) had an even worse situation than before the operation. In the group of younger patients, the preoperative median of the overall incontinence score was 10.5, and in 2011, it was 9.0, while in the group of older patients, the corresponding numbers were 13.0 and 15.0. In 2011, quality of life was still better than preoperatively as a whole, but the results had deteriorated from those in 2006. CONCLUSIONS: Initially, both overall faecal incontinence and quality of life improved, but younger patients achieved a greater benefit. However, the results deteriorated with a longer follow-up. Operative management should be considered preferably in relatively young subjects as their results are better. PMID- 23440366 TI - Emodin sensitizes the gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine via downregulation of NF-kappaB and its regulated targets. AB - The aim of this study was to evaluate whether emodin can overcome the chemoresistance of the gemcitabine-resistant cancer cell line (Bxpc-3/Gem) in vitro. The cell line Bxpc-3/Gem was derived from the human pancreatic cancer cell line Bxpc-3. We found that Bxpc-3/Gem cells were characterized by a series of morphological changes with a resistance index of 43.51 comparing with the parental cell line. Emodin reduced Bxpc-3/Gem cell proliferation in a dose dependent manner. Emodin and gemcitabine combination treatments resulted in decreased cell proliferation and increased apoptosis in Bxpc-3/Gem cells. In addition, combination treatments resulted in downregulation of gene and protein expression of MDR-1 (P-gp), NF-kappaB, XIAP, survivin, as well as inhibition of NF-kappaB activity and P-gp function. These observations suggest that emodin may sensitize the pancreatic cancer gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine therapy via inhibition of survival signaling. PMID- 23440367 TI - Falls and major orthopaedic surgery with peripheral nerve blockade: a systematic review and meta-analysis. AB - The objective of this systematic review with meta-analysis was to determine the risk for falls after major orthopaedic surgery with peripheral nerve blockade. Electronic databases from inception through January 2012 were searched. Eligible studies evaluated falls after peripheral nerve blockade in adult patients undergoing major lower extremity orthopaedic surgery. Independent reviewers working in duplicate extracted study characteristics, validity, and outcomes data. The Peto odds ratio (OR) with 95% confidence intervals (CIs) were estimated from each study that compared continuous lumbar plexus blockade with non continuous blockade or no blockade using a fixed effects model. Ten studies (4014 patients) evaluated the number of falls as an outcome. Five studies did not contain comparison groups. The meta-analysis of five studies [four randomized controlled trials (RCTs) and one cohort] compared continuous lumbar plexus blockade (631 patients) with non-continuous blockade or no blockade (964 patients). Fourteen falls occurred in the continuous lumbar plexus block group when compared with five falls within the non-continuous block or no block group (attributable risk 1.7%; number needed to harm 59). Continuous lumbar plexus blockade was associated with a statistically significant increase in the risk for falls [Peto OR 3.85; 95% CI (1.52, 9.72); P=0.005; I(2)=0%]. Evidence was low (cohort) to high (RCTs) quality. Continuous lumbar plexus blockade in adult patients undergoing major lower extremity orthopaedic surgery increases the risk for postoperative falls compared with non-continuous blockade or no blockade. However, attributable risk was not outside the expected probability of postoperative falls after orthopaedic surgery. PMID- 23440368 TI - Central centrifugal cicatricial alopecia. AB - Central centrifugal cicatricial alopecia is a common cause of progressive permanent apical alopecia. This unique form of alopecia includes entities previously know as "hot comb alopecia," "follicular degeneration syndrome," "pseudopelade" in African Americans and "central elliptical pseudopelade" in Caucasians. The etiology appears to be multifactorial and the condition occurs in all races. PMID- 23440369 TI - [Conversion disorders]. AB - Classification, diagnostic and therapeutic problems are central to the disease concept of conversion disorders, which are based on the presentation of psychosocial suffering by means of pseudoneurological symptoms without an organic cause. The nosological status in the current diagnostic and statistical manual of mental disorders (DSM-IV) and international classification of diseases (ICD-10) is disputed. Prevalence rates ranging from 0.3 % in the general population to 50 % in high risk clinical samples underline the relevance. Traumatic experiences play a major role in the pathogenesis. High rates of comorbid mental disorders, the danger to end in a chronic course, a high secondary illness gain and a somatic illness concept complicate psychotherapeutic approaches which are clearly indicated. Clinical experiences and open studies indicate that both psychodynamic as well as cognitive-behaviour therapies are effective. PMID- 23440370 TI - [Obituary. Christian Scharfetter (1936-2012)]. PMID- 23440371 TI - Infection rates of external ventricular drains are reduced by the use of silver impregnated catheters. AB - BACKGROUND: External ventricular drainage (EVD) placement for temporary cerebrospinal fluid (CSF) diversion is a frequent therapeutic procedure. Several types of EVD catheters are currently available, some of which have an antibacterial effect. This study compares the rates of CSF infections in patients with different types of EVD catheters. METHODS: This is a retrospective study of 403 patients with a total of 529 implanted EVDs. We analyze the occurrence of EVD associated infections, microbiological diagnosis, type of EVD catheter (plain polyurethane vs. silver-impregnated), duration of CSF diversion, primary disease, and outcome. RESULTS: There were a total of 29 patients with EVD infections in the whole study group (7.1 %). A pathogen was detected in all cases. Coagulase negative staphylococci were detected most frequently (20 out of 29 cases, 70 %). The rate of infections by catheter type was 7.6 % (11 of 145) and 13.8 % (4 out of 29) for two different types of non-coated polyurethane catheters. Silver impregnated polyurethane catheters became infected in 6.1 % (14 out of 228). The differences between non-coated and silver-coated catheters were statistically significant. CONCLUSIONS: This study provides comparative data on EVD infections with regard to the type of catheter. Silver-impregnated catheters showed significantly lower infection rates when compared to non-impregnated catheters. The results are critically discussed and compared with the published literature. PMID- 23440372 TI - Spontaneous speech of patients with gliomas in eloquent areas before and early after surgery. AB - BACKGROUND: Glioma patients often complain about problems in daily conversation. A detailed spontaneous speech analysis could provide more insight in these communicative problems; no previous studies are reported. OBJECTIVE: To select sensitive parameters in spontaneous speech pre- and post-operatively in patients with gliomas in eloquent areas. METHODS: We included 27 patients and 21 healthy controls. In addition to a naming and category fluency test, spontaneous speech was collected 1 month pre-operatively and 3 months post-operatively, and analysed with the variables: Self-corrections, Repetitions, Lexical Diversity, Incomplete Sentences and Mean Length of Utterance (MLUw). A correlation analysis was performed between the linguistic variables and tumour characteristics (grade, localisation and volume), treatment related factors, and between the linguistic variables and the language tasks. RESULTS: Pre-operatively, patients produced more Incomplete Sentences than the controls (p < 0.001). Post-operatively, patients' utterance length (MLUw) (p < 0.05) was also deviant. The quality of the spontaneous speech was influenced by tumour grade and localisation. There was no influence of tumour volume or treatment-related factors. Pre- and post operatively, patients' performance on the naming and the fluency task deviated from normal (p < 0.001). The majority of the linguistic variables did not correlate with the language tasks, pointing to a measurement of distinct linguistic aspects. CONCLUSION: Pre- and post-operatively there was a disorder in naming, category fluency and spontaneous speech, partly influenced by tumour characteristics. A spontaneous speech analysis appeared to be a valuable addition to standardised language tasks. Both measurements are important tools to obtain a complete linguistic profile. PMID- 23440373 TI - Evidence-based clinical management and utilization of new technology in European neurosurgery. AB - BACKGROUND: Evidence-based medicine (EBM) has become one of the pillars of modern patient care. However, neurosurgery has always been an experience-based and technology-driven discipline, and it remains unknown to which extent European neurosurgeons follow high-level evidence-based recommendations. METHODS: We conducted a Web-based survey with a 15-item questionnaire about evidence-based clinical management and utilization of new technology among European neurosurgeons. Two different sum scores were calculated from the questions concerning clinical practice; evidence-based treatment score and new technology score. A high evidence-based treatment score means that more clinical conditions (i.e., study questions) were managed in compliance with the available highest levels of evidence from published clinical trials. A high new technology score reflects the use of a high number of modern tools in neurosurgical practice. RESULTS: A total of 239 neurosurgeons from 30 different European countries answered the questionnaire. There were large variations among European neurosurgeons in providing evidence-based care and in utilization of various modern tools. There were significant regional differences in evidence-based treatment scores and modern technology scores with higher scores in northern and western Europe. High-volume institutions were not associated with better evidence based treatment scores, but had significantly higher new technology scores. There were significantly higher new technology scores at university hospitals and a trend towards higher evidence-based treatment scores compared to other hospitals. CONCLUSIONS: Clinical management in neurosurgery does not always comply with the best available evidence and there are large regional differences in clinical management and in utilization of various modern tools. The position of evidence based medicine in European neurosurgery seems weak and this may be a threat to the quality of care. PMID- 23440375 TI - Optimized flow cytometry protocol for analysis of surface expression of interleukin-1 receptor types I and II. AB - The biological effects of interleukin (IL)-1 are realized through binding to specific membrane-bound receptors. The efficiency of IL-1 action depends on the number of receptors on the cell. We determined the percentage of cells that express IL-1 receptor type I (IL-1RI) and IL-1 receptor type II (IL-1RII) by flow cytometry using phycoerythrin (PE)-labelled antibodies to the IL-1Rs, and the mean absolute number of membrane-bound IL-1Rs per cell using QuantiBRITE PE calibration beads. We showed that different subpopulations of immunocompetent cells expressed different numbers of molecules of membrane-bound IL-1RI and IL 1RII. We also established that when cells were stimulated with bacterial lipopolysaccharide, there was a significant increase in the number of IL-1RI expressed, and a significant decrease in the mean number of IL-1RII molecules per cell. Determination of the mean number of membrane-bound IL-1R molecules using this protocol enables us to obtain precise and reproducible data that are necessary for full evaluation of expression levels. PMID- 23440376 TI - [Capillaroscopy. An update]. AB - This article reports relevant innovations 2 years after the publication of the German consensus on nomenclature and procedure of capillaroscopy in this journal. Standardization: certified training courses in capillaroscopy under the patronage of the Rheumatism Academy have reached over 300 rheumatologists nationwide. Trained investigators clearly show greater agreement on findings than untrained experts even with years of experience. Normal findings were detected using the published terminology in a large cohort. Scientific application: the number of publications on capillaroscopy has risen significantly, prospective studies of smaller cohorts and the comparison to other methods regarding systemic sclerosis, Raynaud's disease and also miscellaneous diseases. A large prospective multicenter European study on the capillaroscopic skin ulcer risk index (CSURI) was conducted with German participation. The role as a screening tool has been confirmed by the majority of the studies. For systemic lupus erythematosus it is also increasingly being used in the diagnostic work-up as an additional investigation. Practical application: capillaroscopy has a solid and indispensable role in the diagnostic algorithm of Raynaud's disease and early diagnosis of systemic sclerosis. Videocapillaroscopy and simple USB microscopes are increasingly being used besides traditional light microscopy. PMID- 23440377 TI - [Methotrexate as combination partner of TNF inhibitors and tocilizumab: what is reasonable from an immunological viewpoint?]. AB - BACKGROUND: The prognosis of rheumatoid arthritis has been substantially improved by the treatment with biologics; however, it is still unclear which combination of biological and conventional disease-modifying antirheumatic drugs (DMARDs) is optimal to achieve remission as in clinical trials biologics were mainly studied in combination with methotrexate or as monotherapy. There are, however data that the efficacy of tumor necrosis factor (TNF) inhibitors is better in combination with methotrexate, whereas the efficacy of tocilizumab is optimal even as a monotherapy. In this article the differing dependence of TNF inhibitors and of tocilizumab on the combination with methotrexate is explained from the viewpoint of an immunologist. METHODS: A selective search and evaluation of the literature were carried out in relation to the mechanism of action of TNF inhibitors, tocilizumab and methotrexate in rheumatoid arthritis. RESULTS AND CONCLUSIONS: Methotrexate mainly targets the activation of T and B lymphocytes and TNF inhibitors suppress monocytes and myeloid dendritic cells. Tocilizumab corrects the errant activation and differentiation of T and B lymphocytes and in addition inhibits monocytes, dendritic cells and neutrophils. Therefore, TNF inhibitors and methotrexate act optimally only in combination to exert an effect on all components of the cellular immune system in rheumatoid arthritis. In contrast, tocilizumab has a broad mode of action even in monotherapy. PMID- 23440378 TI - [Pain measurement in animal models]. PMID- 23440379 TI - Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma. AB - Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long-term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor surrounding tissue (TST). OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human CCA by real-time PCR (n=27). Protein expression was determined by western blot analysis and immunohistochemistry. Data were correlated with the clinicopathological parameters of CCA. Real-time PCR demonstrated a downregulation of the expression of SLC22A1 and SLC22A3 in CCA, compared to that in TST (p<0.001). A low SLC22A1 expression was associated with a worse patient survival (p<0.05). The downregulation of SLC22A1 was significantly associated with advanced CCA stages, since tumors with a low SLC22A1 mRNA expression presented with larger tumor diameters (p=0.02). There were no significant differences in tumor characteristics or patient survival in relation to the level of SLC22A3 expression. Western blot analysis and immunohistochemistry confirmed the downregulation of OCT1 and OCT3 protein levels in cancerous tissue compared to those in TST. In conclusion, the downregulation of OCT1 is associated with tumor progression and worse overall patient survival rates. PMID- 23440380 TI - QTL mapping of slow-rusting, adult plant resistance to race Ug99 of stem rust fungus in PBW343/Muu RIL population. AB - Races of stem rust fungus pose a major threat to wheat production worldwide. We mapped adult plant resistance (APR) to Ug99 in 141 lines of a PBW343/Muu recombinant inbred lines (RILs) population by phenotyping them for three seasons at Njoro, Kenya in field trials and genotyping them with Diversity Arrays Technology (DArT) markers. Moderately susceptible parent PBW343 and APR parent Muu displayed mean stem rust severities of 66.6 and 5 %, respectively. The mean disease severity of RILs ranged from 1 to 100 %, with an average of 23.3 %. Variance components for stem rust severity were highly significant (p < 0.001) for RILs and seasons and the heritability (h (2)) for the disease ranged between 0.78 and 0.89. Quantitative trait loci (QTL) analysis identified four consistent genomic regions on chromosomes 2BS, 3BS, 5BL, and 7AS; three contributed by Muu (QSr.cim-2BS, QSr.cim-3BS and QSr.cim-7AS) and one (QSr.cim-5BL) derived from PBW343. RILs with flanking markers for these QTLs had significantly lower severities than those lacking the markers, and combinations of QTLs had an additive effect, significantly enhancing APR. The QTL identified on chromosome 3BS mapped to the matching region as the known APR gene Sr2. Four additional QTLs on chromosomes 1D, 3A, 4B, and 6A reduced disease severity significantly at least once in three seasons. Our results show a complex nature of APR to stem rust where Sr2 and other minor slow rusting resistance genes can confer a higher level of resistance when present together. PMID- 23440381 TI - Identification and QTL mapping of whitefly resistance components in Solanum galapagense. AB - Solanum galapagense is closely related to the cultivated tomato and can show a very good resistance towards whitefly. A segregating population resulting from a cross between the cultivated tomato and a whitefly resistant S. galapagense was created and used for mapping whitefly resistance and related traits, which made it possible to study the genetic basis of the resistance. Quantitative trait loci (QTL) for adult survival co-localized with type IV trichome characteristics (presence, density, gland longevity and gland size). A major QTL (Wf-1) was found for adult survival and trichome characters on Chromosome 2. This QTL explained 54.1 % of the variation in adult survival and 81.5 % of the occurrence of type IV trichomes. A minor QTL (Wf-2) for adult survival and trichome characters was identified on Chromosome 9. The major QTL was confirmed in F3 populations. Comprehensive metabolomics, based on GCMS profiling, revealed that 16 metabolites segregating in the F2 mapping population were associated with Wf-1 and/or Wf-2. Analysis of the 10 most resistant and susceptible F2 genotypes by LCMS showed that several acyl sugars were present in significantly higher concentration in the whitefly resistant genotypes, suggesting a role for these components in the resistance as well. Our results show that whitefly resistance in S. galapagense seems to inherit relatively simple compared to whitefly resistance from other sources and this offers great prospects for resistance breeding as well as elucidating the underlying molecular mechanism(s) of the resistance. PMID- 23440382 TI - The psychopathological influence of adolescent idiopathic scoliosis in korean male : an analysis of multiphasic personal inventory test results. AB - OBJECTIVE: There are few published studies which have documented psychopathological abnormalities in patients with of adolescent idiopathic scoliosis (AIS) The aim of this study was to evaluate the psychopathological influence of AIS in Korean 19-year-old males. METHODS: The authors compared the Korean military multiphasic personal inventory (KMPI) military profiles of 105 AIS cases (more than 10 degrees of Cobb's angle without surgical treatment) with the KMPI profiles of 108 normal controls. The AIS group was split depending on Cobb's angle to further evaluate this relation by the severity of AIS. RESULTS: A significantly decreased result on the faking-good response scale and an significantly increased result on the faking-bad response were observed in the AIS group compared to the control (p<0.012). The neurosis scale results, including anxiety, depression and somatization symptoms, were significantly increased in the AIS group compared to the control (p<0.010). The severity level of personality disorder and schizophrenia were also significantly increased in the AIS group (p<0.010). Differences in KMPI scale scores were not related to the severity of AIS. CONCLUSION: Young males with AIS tend to have abnormal results on the multiphasic personal inventory test compared to normal volunteers, suggesting that AIS may be related to psychopathology in the young male group in Korea. Although these psychopathology in AIS were differently observed compared to normal controls, but not interfered with military life. Clinicians are recommended to pay attention the psychopathological traits of patients with AIS. PMID- 23440385 TI - Novel effects of adenosine receptors on pericellular hyaluronan matrix: implications for human smooth muscle cell phenotype and interactions with monocytes during atherosclerosis. AB - Hyaluronan (HA) is responsive to pro-atherosclerotic growth factors and cytokines and is thought to contribute to neointimal hyperplasia and atherosclerosis. However, the specific function of the pericellular HA matrix is likely depend on the respective stimuli. Adenosine plays an important role in the phenotypic regulation of vascular smooth muscle cells (VSMC) and is thought to inhibit inflammatory responses during atherosclerosis. The aim of this study was to examine the regulation and function of HA matrix in response to adenosine in human coronary artery SMC (HCASMC). The adenosine receptor agonist NECA (10 MUM) caused a strong induction of HA synthase (HAS)1 at 6 h and a weaker induction again after 24 h. Use of selective adenosine receptor antagonists revealed that adenosine A2(B) receptors (A2(B)R) mediate the early HAS1 induction, whereas late HAS1 induction was mediated via A2(A)R and A3R. The strong response after 6 h was mediated in part via phosphoinositide-3 kinase- and mitogen-activated protein kinase pathways and was inhibited by Epac. Functionally, NECA increased cell migration, which was abolished by shRNA-mediated knock down of HAS1. In addition to HA secretion, NECA also stimulated the formation of pronounced pericellular HA matrix in HCASMC and increased the adhesion of monocytes. The adenosine-induced monocyte adhesion was sensitive to hyaluronidase. In conclusion, the current data suggest that adenosine via adenosine A2(B)R and A2(A)R/A3R induces HAS1. In turn a HA-rich matrix is formed by HCASMC which likely supports the migratory HCASMC phenotype and traps monocytes/macrophages in the interstitial matrix. PMID- 23440384 TI - Melatonin affects conjugation of 4-hydroxynonenal with glutathione in liver of pacu, a hypoxia-tolerant fish. AB - In cytosol from liver of pacu, Piaractus mesopotamicus, a hypoxia-tolerant fish that dwells in Pantanal, we found an enzyme activity capable of modulating the alkenal 4-hydroxy-2-nonenal (HNE) by conjugating it with glutathione (GST-HNE activity). HNE is a downstream metabolite from the oxidation of polyunsaturated fatty acids by reactive oxygen species arisen from mitochondria of animal cells. HNE production may increase more intensively under oxidative stress. Harmful effects to cell survival may occur when HNE increases over 10(-4) M. Pacus submitted to hypoxia in July (cold season in Pantanal) showed 40% less of this GST-HNE conjugating activity in their liver cytosol. Injecting pacus subjected to hypoxia during the cold season with a summer physiological dose of melatonin caused their liver cytosolic GST-HNE activity to increase up to the levels found in the warm season. From October to March (warm season in Pantanal), pacus are prone to oxidative stress particularly during potamodromous active oxygen demanding swimming, when they migrate up rivers to spawn. Thus, our findings point out that the higher levels of melatonin in circulation during the summer are important to avoid the increase of 4-HNE inside liver cells of this fish species. PMID- 23440386 TI - Altered expression of PTCH and HHIP in gastric cancer through their gene promoter methylation: novel targets for gastric cancer. AB - Human hedgehog-interacting protein (HHIP) and protein patched homolog (PTCH) are two negative regulators of the hedgehog signal, however, the mechanism of action in gastric cancer is unknown. Methylation of TSG promoters has been considered as a causative mechanism of tumorigenesis. In the present study, we first determined the expression of PTCH and HHIP mRNA and protein in gastric cancer tissues and adjacent normal tissues, and then detected methylation of the two genes to associate their expression and gene promoter methylation in gastric cancer. Expression in gastric cancer tissues and the cancer cells (AGS) were evaluated by reverse transcription-PCR (RT-PCR), qRT-PCR and IHC, while the methylation expression was valued by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). Cell viability and apoptosis were analyzed by MTT assay and flow cytometry following treatment with 5-aza-dc. Results showed that PTCH and HHIP expression was reduced in gastric cancer tissues that were not associated with clinical features. Moreover, methylation of the promoters was reversely correlated with the expression. Following treatment with 5-aza-dc, AGS reduced cell viability and induced apoptosis, which is associated with upregulation of HHIP expression. The data demonstrated that loss of expression of HHIP and PTCH is associated with the methylation of gene promoters. In addition, 5-aza-dc induced apoptosis correlated with the upregulation of HHIP expression in AGS. The findings demonstrated that the PTCH and HHIP genes may be novel targets for the control of gastric cancer. PMID- 23440389 TI - Combined vitrectomy and intravitreal injection versus combined laser and injection for treatment of intractable diffuse diabetic macular edema. AB - BACKGROUND: The purpose of this study was to compare the safety and efficacy of combined vitrectomy, intravitreal triamcinolone acetonide (IVTA), and bevacizumab injection with that of IVTA and bevacizumab injection and subsequent macular grid laser photocoagulation for the treatment of intractable diffuse diabetic macular edema. METHODS: This randomized controlled clinical trial was performed at Benha University Hospital, Benha, Egypt, and included 34 eyes from 34 diabetic patients diagnosed with intractable diffuse diabetic macular edema without vitreomacular traction. The patients were divided into two groups. In group 1, pars plana vitrectomy with removal of the posterior hyaloid was performed, and at the end of the procedure, IVTA 0.1 mL (40 mg/mL) and bevacizumab 1.25 mg were injected. In group 2, macular grid laser photocoagulation was performed 2 weeks after the same intravitreal injection combination as used in group 1. The main outcome measures were best-corrected visual acuity (BCVA) and central foveal thickness, which were measured using optical coherence tomography at 3, 6, and 12 months. RESULTS: Changes in BCVA and central foveal thickness at 3, 6, and 12 months from baseline were highly statistically significant (P < 0.01). Mean BCVA was better in group 1 at 3 months, nearly equal at 6 months, and less at 12 months. Mean central foveal thickness was more improved in group 1 than in group 2 at 3 months, and was better in group 2 at subsequent measurement points. The major adverse events were development of cataract (more common in group 1) and elevation of intraocular pressure (more common in group 2). CONCLUSION: The combined therapy described here could represent a solution for the treatment of intractable diabetic macular edema, and could have a favorable long-term outcome. Combined treatment of IVTA and bevacizumab plus grid laser resulted in a more favorable reduction in central foveal thickness and improvement in BCVA at 12 months than vitrectomy combined with the same injections. This small study favors the safer, cheaper, and more available line of treatment. PMID- 23440390 TI - What is the value of 'me-too' drugs? AB - The objective of this article is to estimate the value of 'follow-on' or 'me-too' drugs from the payer, industry and societal perspectives. Since me-too drugs do not bring additional clinical benefits, they are only valuable to payers if they save costs. An empirical model was constructed to identify the factors affecting whether a me-too drug results in cost savings to the pharmaceutical budgets of payers. These factors included the intensity of promotional spending, price discount and time to entry. Twenty-seven second-entrant products with limited differentiation were identified; their launch dates ranged from 1988 to 2009. On average, me-too drugs launch 2.5 years after the first entrant, with 20 % more promotional investment, and capture 38 % of market share within 4 years. Peak market share is significantly affected by share of voice (p < 0.001) but not price discount (p = 0.77). Launch delay was significant in terms of reducing both market share (p < 0.001) and price (p < 0.05). With a launch price 15 % below the incumbent, cumulative savings from use of a me-too drug peak at over $1000 million, but decrease rapidly after the first entrant becomes generic and only amount to $450 million over the me-too drug's lifecycle. With a price discount less than 10 %, cumulative savings are negative over the life of the me-too drug. Therefore, me-too drugs may be cost saving in the short term, but can represent a cost in the longer term. From a societal perspective, me-too drugs always decrease the economic surplus if they do not grow the market. If me-too drugs grow the market by 20 %, they augment, on average, the economic surplus only if the variable costs (including promotional investment) do not increase by more than $300 million per year. PMID- 23440391 TI - Female labour supply and nursing home prices. AB - Long term care in Germany is provided in nursing homes, by professional ambulatory services and by the patient's relatives at home, with the latter being predominantly provided by women. Given an increasing labour market participation of women, long term care at home by female relatives might become less frequent in the future which in turn may result in rising demand for and hence rising prices for long term care services. This paper builds upon the existing literature on the determinants of nursing home prices and investigates whether the labour market participation and the education level of women are correlated with the prices of nursing homes. To the best of our knowledge, this is the first study using panel data approaches in this field of research. Based on a full sample of nursing homes in Germany for the years 2001, 2003, 2005 and 2007, our empirical results suggest that a high share of full-time employed women aged 50 65 at the district level is not associated with higher prices of nursing homes. Furthermore, we find only weak evidence for a positive correlation of prices with the local average of women's educational level and a negative correlation with part-time employment indicating that price levels are lower in regions with higher shares of part-time employed women. PMID- 23440392 TI - Effect of a BK viruria reaction detected by qualitative polymerase chain reaction on the renal function of kidney transplant recipients. AB - The number of end stage renal failure patients receiving hemodialysis or peritoneal dialysis in Taiwan is on the increase. Of the various treatment options, kidney transplantation is considered to be the ultimate choice, however, it may lead to certain complications, including the infection or reactivation of the BK virus (BKV). Such viral complications may cause nephritis of the donated kidney and eventually dysfunction and transplantation failure. Therefore the early detection of BKV may be beneficial for kidney transplant recipients. The aim of the present study was to demonstrate the impact of BKV infection on renal function and to show the feasilibility of urine qualitative polymerase chain reaction (PCR) as a screening test in renal transplantation patients. A total of 250 patients were screened for the presence of BKV or John Cunningham virus (JCV) DNA in the urine via qualitative PCR. Subjects positive for urine screening were then further tested using blood sampling. The results showed that 16 patients (6.4%) were co-infected by BKV and JCV with a prevalence of 20.4 and 38.4%, respectively. The correlations between viral infection and renal function were further analyzed to show that an infection of BKV has significant effects on the serum creatinine concentration. The mean serum creatinine concentration of the BKV-positive patients was 1.39+/-0.09 mg/dl, which was significantly higher than that of the BKV-negative patients (1.21+/-0.03 mg/dl; P<0.05). However, JCV infection has no such effect on renal function. Taken together, these results suggested that PCR monitoring of BKV with urine samples is a rapid, non-invasive and beneficial method for the prevention of renal complications during the long term care of kidney transplant recipients. PMID- 23440393 TI - The impact of antibody/epitope affinity strength on the sensitivity of electrochemical immunosensors for detecting small molecules. AB - A displacement immunoassay involves having a labelled analogue of the analyte (the epitope) already bound to the antibody. The presence of the analyte causes a competition for antibodies, and some of the antibodies dissociates from the epitope so that it can bind with the analyte. Herein, the influence of the affinity of the surface-bound epitope for the antibody on the sensitivity and selectivity of a displacement immunosensor is explored both theoretically and experimentally. An electrochemical immunosensor described previously, where the dissociation of antibodies from an electrode surface causes an increase in current from surface-bound ferrocene species, is used for this purpose. As expected, the ease and effectiveness of the bound antibody being displaced is inversely related to the affinity of the antibody to the surface-bound epitope relative to the analyte in solution as expected. However, if the affinity constant is too low, selectivity and/or sensitivity are compromised. Experimental results are qualitatively compared with a simple mass-action model. PMID- 23440394 TI - Nafion(r) as advanced immobilisation substrate for the voltammetric analysis of electroactive microparticles: the case of some artistic colouring agents. AB - Voltammetry of microparticles is applied to characterise and to identify solid analytes of interest in the field of cultural heritage. Nafion(r) is used for the immobilisation of solid microparticles onto the surface of a glassy carbon electrode by exploiting the deposition onto the electrode surface of a micro volume of a suspension of the microsample in polymeric solution. Cyclic voltammetry and square wave voltammetry are applied to characterise and to identify the microparticles immobilised in the Nafion(r) coating. The analyte studied in this work is Prussian Blue as a typical inorganic pigment, with a relatively simple electrochemical behaviour. The proposed method is applied to a sample of Venetian marmorino plaster. The performance of Nafion(r) for this analysis is compared with that of the polymer Paraloid B72. PMID- 23440395 TI - Theta-alpha cross-frequency synchronization facilitates working memory control - a modeling study. AB - Despite decades of research, the neural mechanism of central executive and working memory is still unclear. In this paper, we propose a new neural network model for the real-time control of working memory. The key idea is to consider separately the role of neural activation from that of oscillatory phase. Neural populations encoding different information would not confuse each other when the populations have different oscillatory phases. Depending on the current situation, relevant memories bind together through phase-locking between theta frequency oscillation of a Central Unit and alpha-frequency oscillations of the relevant group of Memory Units. The Central Unit dynamically controls which Memory Units should be synchronized (and the encoded memory would be processed), and which units should be out of phase (the encoded memory is standby and would not be processed yet). Simulations of two working memory tasks are provided as examples. The model is in agreement with many recent experimental results of human scalp EEG analysis, which reported observations of neural synchronization and cross-frequency coupling during working memory tasks. This model offers a possible explanation of the underlying mechanism for these experiments. PMID- 23440396 TI - Chronic mild stress modulates 5-HT1A and 5-HT2A receptor expression in the cerebellar cortex of NC/Nga atopic-like mice. AB - Atopic eczema symptoms may worsen due to stress. In the present study, the cerebellar cortex of the atopic-like mouse NC/Nga was studied regarding the effect of chronic mild stress on expression of two well-characterized serotonergic receptors (R), 5-HT1A and 5-HT2A. In total 24 mice were used. Sixteen of these mice were subjected to unpredictable stressors for 12 weeks, and 8 mice were used as controls. In order to evoke an eczema, a mite antigen was applied to 16 mice from week 9 of the experiment. Thus, three groups of mice, stressed eczematous (SE), non-stressed eczematous (NSE) and stressed control (SC), respectively, were obtained. The expression of the 5-HT1AR was analyzed using quantitative immunohistochemistry. For evaluation of 5-HT2AR a semi quantitative technique was used, the cell density and signal intensity being measured. The highest average value for 5-HT1AR expression, in the Purkinje cells, was recorded in the NSE group, while the lowest average was in the SC group. 5-HT1AR expression differed significantly between the groups. The highest average value for density of 5-HT2AR positive Purkinje cells was evident in the SE group, while the lowest was in the SC group, this difference between groups also being statistically significant. In addition, the signal intensity was highest in the SE group, with a difference compared to the other groups. In conclusion, chronic mild stress modulates serotonergic receptor expressions in the cerebellar cortex of atopic-like mice. PMID- 23440397 TI - Are plasma resistin and omentin levels different in patients with psoriasis with or without atherosclerosis? PMID- 23440398 TI - Increased HMGB1 serum levels and altered HMGB1 expression in patients with psoriasis vulgaris. AB - High mobility group box-1 (HMGB1) has been implicated as a pro-inflammatory cytokine in the pathogenesis of various inflammatory and autoimmune diseases. However, information about HMGB1 in inflammatory skin diseases is unknown. Herein, we investigated the serum HMGB1 levels and tissue HMGB1 expression in patients with psoriasis vulgaris (PV) and atopic dermatitis (AD). Serum levels of HMGB1 in patients with PV and AD were detected by enzyme-linked immunosorbent assay (ELISA). The expression of HMGB1 in lesional skin was evaluated by immunohistochemistry and immunofluorescence. Protein levels of HMGB1 in the nuclear fraction and cytoplasmic fraction were determined by western blot. Serum levels of HMGB1 in patients with PV but not AD were significantly higher than those in nornal controls. Moreover, serum HMGB1 levels were correlated with the severity of PV according to PASI socres. Furthermore, by immunohistochemistry and immunofluorescence, we showed that the expression of HMGB1 in normal skin was almost completely restricted to the nucleus. However, abundant cytoplasmic expression of HMGB1 was observed in the epidermis in lesional skin of PV patients. In addition, western blot data indicated that HMGB1 expression was in the nucleus protein and was absent in the cytoplasm protein in control group. In contrast, HMGB1 expression in the cytoplasmic fraction was detectable in AD patients and more distinct in PV patients. Taken together, this study provides first observations on the association of HMGB1 with PV, and showed the elevated HMGB1 serum levels and altered HMGB1 distribution in lesional skin in patients with PV. We suggest that HMGB1 might be involved in the pathogenesis of PV. PMID- 23440399 TI - Adjuvant chemotherapy for breast cancer in a patient with primary autoimmune neutropenia. AB - We report an extremely rare and complex case of a 44-year-old woman diagnosed with an early stage triple negative breast cancer in the setting of primary autoimmune neutropenia with a pre-existing severe neutropenia. This case-report demonstrates that adjuvant chemotherapy for breast cancer can be administered in a patient with severe neutropenia. The management is however complicated and requires careful monitoring of side-effects related to both chemotherapy and treatment of autoimmune neutropenia. The role of chemotherapy in the treatment of triple negative breast cancer, the approach to autoimmune neutropenia and potential interactions are reviewed. To our knowledge, this is the first case reporting on the use of chemotherapy in a patient with severe pre-existing primary autoimmune neutropenia. PMID- 23440400 TI - Human leukocyte antigen antibody incompatible renal transplantation. AB - Anti-human leukocyte antigen (HLA) antibodies are recognized as an important problem in organ transplant recipients. This is because antibodies formed against a graft months or years after implantations are the major cause of late allograft failure, and also because protocols allow the transplantation of some grafts across pre-formed HLA antibodies. Advances in our understanding of anti-HLA antibody- mediated rejection (AMR) have occurred because of a better understanding of the histological findings during AMR; more sensitive and specific methods to measure anti-HLA antibodies; and through clinical investigation of patients transplanted across an HLA barrier. Despite advances in therapy and investigation, AMR remains a major problem and treatment protocols often fail to treat it successfully. This review aims to describe the issues in each of these areas and to suggest how clinicians may be able to improve the management of patients with anti-HLA antibodies. PMID- 23440401 TI - Methodological issues in clinical drug development for essential tremor. AB - Essential tremor (ET) is one of the most common tremor disorders in the world. Despite this, only two medications have received Level A recommendations from the American Academy of Neurology to treat it (primidone and propranolol). Even though these medications provide relief to a large group of ET patients, up to 50% of patients are non-responders. Additional medications to treat ET are needed. This review discusses some of the methodological issues that should be addressed for quality clinical drug development in ET. PMID- 23440402 TI - Molecular-level characterization of the structure and the surface chemistry of periodic mesoporous organosilicates using DNP-surface enhanced NMR spectroscopy. AB - We present the molecular level characterization of a phenylpyridine-based periodic mesoporous organosilicate and its post-functionalized organometallic derivatives through the fast acquisition of high quality natural isotopic abundance 1D (13)C, (15)N, and (29)Si and 2D (1)H-(13)C and (1)H-(29)Si solid state NMR spectra enhanced with dynamic nuclear polarization. PMID- 23440403 TI - Transoesophageal echocardiography during coronary artery bypass procedures: impact on surgical planning. AB - INTRODUCTION: Intraoperative transesophageal echocardiography (iTEE) is widely accepted and routinely used during heart valve surgery. However, the impact of iTEE among patients undergoing coronary artery bypass grafting (CABG) is less well documented. In this study, we aim to define the impact of iTEE in patients undergoing myocardial revascularization for severe coronary artery disease. METHODS: We analyzed clinical data and preoperative and intraoperative echocardiograms of all adults who underwent on pump coronary bypass and iTEE between January 2008 and December 2008. RESULTS: 521 patients (mean age 69+/-14 years) were studied. New prebypass findings were obtained in 82 (15.7%) patients: in 62 (11.9%) of these patients, this information changed the surgical plan. New postbypass findings were obtained in 8 patients (1.5%) and the surgical plan was altered in 4 patients (0.7%). CONCLUSIONS: Overall new findings were obtained in 90 patients (17.2%) and the surgical plan was altered in 66 patients (12.6%). These data support the routine use of iTEE among patients undergoing surgical myocardial revascularization. PMID- 23440404 TI - Conformation-dependent conductance through a molecular break junction. AB - Ab initio molecular dynamics simulations have been performed of a gold-1,4 benzenedithiol (BDT)-gold nanojunction under mechanical stress. For three different pulling rates between 10 and 40 m s(-1), it is found that the nanowire always ruptures between the second and third Au atom from the thiol sulfur. Larger rupture forces and longer extensions are required at higher pulling rates and vice versa. The electrical conductance was calculated along a pulling trajectory using the DFT-NEGF method to study the effect of thermal and stress induced structural changes on the electrical transport properties. While the mechanically induced stretching of the junction is seen to lower the time averaged conductance, thermal conformational changes are capable of altering the conductance by one order of magnitude. No single geometric quantity could be identified as the main contributor to the conductance fluctuations. Small modulations, however, can be explained in terms of C=C double bond vibrations in the BDT molecule. The dependence of the conductance on different geometric variables has further been investigated systematically by performing constrained geometry optimizations along a number of angle and dihedral coordinates. The largest changes in the conductance are observed when the Au-S-C angle and the Au S-C-C dihedral are simultaneously constrained. PMID- 23440405 TI - Prevalence and predictors of refractive error and spectacle coverage in Nakuru, Kenya: a cross-sectional, population-based study. AB - A cross-sectional study was undertaken in Nakuru, Kenya to assess the prevalence of refractive error and the spectacle coverage in a population aged >=50 years. Of the 5,010 subjects who were eligible, 4,414 underwent examination (response rate 88.1 %). LogMAR visual acuity was assessed in all participants and refractive error was measured in both eyes using a Topcon auto refractor RM8800. Detailed interviews were undertaken and ownership of spectacles was assessed. Refractive error was responsible for 51.7 % of overall visual impairment (VI), 85.3 % (n = 191) of subjects with mild VI, 42.7 % (n = 152) of subjects with moderate VI, 16.7 % (n = 3) of subjects with severe VI and no cases of blindness. Myopia was more common than hyperopia affecting 59.5 % of those with refractive error compared to 27.4 % for hyperopia. High myopia (<-5.0 DS) was also more common than extreme hyperopia (>+5.0 DS). Of those who needed distance spectacles (spectacle coverage), 25.5 % owned spectacles. In conclusion, the oldest, most poor and least educated are most likely to have no spectacles and they should be specifically targeted when refractive services are put in place. PMID- 23440406 TI - The role of the serum RANKL/OPG ratio in the healing of intertrochanteric fractures in elderly patients. AB - Intertrochanteric fractures occur most commonly in elderly patients. Osteoblasts and osteoclasts have been reported to be regulated by the receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), during bone modeling and remodeling, respectively. Based on these observations, we hypothesized that the serum levels of RANKL, OPG and the RANKL/OPG ratio are important in the healing of intertrochanteric fractures in elderly patients. Enzyme-linked immunosorbent assays were used to measure the serum concentrations of RANKL and OPG in 36 elderly patients with intertrochanteric fractures and 30 age-matched healthy control subjects, at baseline and 4, 8 and 12 weeks following injury. The RANKL/OPG ratio in the two groups was also evaluated. Similar trends in RANKL and OPG levels were detected during the fracture healing process. The serum levels of RANKL and OPG were higher in the fracture group than in the controls, and were significantly higher at baseline and 4 weeks following injury (P<0.05). Notably, although the RANKL/OPG ratio gradually increased during healing, it was lower in the fracture group than in the control group. The RANKL/OPG ratio was significantly lower immediately after and 4 weeks after injury in the fracture group (P<0.05). Our data suggest a close correlation between higher serum levels of RANKL and OPG and the fracture healing process, indicating that RANKL and OPG are involved in fracture healing. The serum RANKL/OPG ratio also appears to be significant in the healing of intertrochanteric fractures in elderly patients. PMID- 23440407 TI - Pregnancy outcome in women with pulmonary arterial hypertension: single-center experience from India. AB - BACKGROUND: A retrospective analysis of the records of all the patients of pulmonary arterial hypertension with pregnancy at AIIMS, New Delhi, India, to study maternal and perinatal outcome and to compare outcome between severe and mild pulmonary arterial hypertension. MATERIALS AND METHODS: A retrospective analysis was carried out of 30 pregnancies in women with pulmonary arterial hypertension (PAH) who delivered at >= 28 weeks of gestation from July 2006 through July 2012 at a tertiary care center in India. Pulmonary artery blood pressure (PABP) during the first trimester of pregnancy or before pregnancy was considered to define PABP as severe or mild, with severe cases having systolic PABP >50 mmHg on echocardiography. RESULTS: Out of 30 patients, 14 patients had severe PAH and 16 patients had mild PAH. Women with severe PAH had a significantly higher incidence of preterm delivery (11 vs. 3, P < 0.05), small for gestational age infants (10 vs. 2, P < 0.05) and cardiac complications (6 vs. 1, P < 0.05) compared to women with mild PAH. There was maternal mortality in a patient with Eisenmenger syndrome. In women with severe PAH and mild PAH, PABP increased in later pregnancy from 63.14 +/- 7.6 to 71.57 +/- 7.9 mmHg (P < 0.05) and from 40.37 +/- 3.6 to 41.69 +/- 4.1 mmHg (P < 0.05), respectively. CONCLUSIONS: Pregnancy in women with severe PAH is associated with higher maternal morbidity and adverse fetal outcome compared to pregnancy in women with mild PAH. PMID- 23440408 TI - Sustained Medication Reduction Following Unilateral VIM Thalamic Stimulation for Essential Tremor. AB - BACKGROUND: Deep brain stimulation (DBS) is an increasingly utilized therapeutic modality for the management of medication refractory essential tremor (ET). The aim of this study was to determine whether DBS allowed for anti-tremor medication reduction within the year after the procedure was performed. METHODS: We conducted a retrospective chart review and telephone interviews on 34 consecutive patients who had been diagnosed with ET, and who had undergone unilateral DBS surgery. RESULTS: Of the 34 patients in our cohort, 31 patients (91%) completely stopped all anti-tremor medications either before surgery (21 patients, 62%) or in the year following DBS surgery (10 patients, 29%). Patients who discontinued tremor medications before DBS surgery did so because their tremors either became refractory to anti-tremor medication, or they developed adverse events to tremor medications. Patients who stopped tremor medications after DBS surgery did so due to sufficient tremor control. Only three patients (9%) who were taking tremor medications at the time of surgery continued the use of a beta-blocker post operatively for the purpose of hypertension management in all cases. DISCUSSION: The data from this study indicate that medication cessation is common following unilateral DBS for ET. PMID- 23440409 TI - STM imaging, spectroscopy and manipulation of a self-assembled PTCDI monolayer on epitaxial graphene. AB - Scanning Tunneling Microscopy (STM), Scanning Tunneling Spectroscopy (STS), and manipulation studies were performed on an ordered self-assembled monolayer (SAM) of N,N'-bis(1-hexylheptyl)perylene-3,4:9,10-bis(dicarboximide) molecules on epitaxial graphene on hexagonal silicon carbide - SiC(0001). Four novel aspects of the molecular SAM on graphene are presented. Molecules adsorb in both armchair and zig-zag configurations, giving rise to six orientations of the molecular layer with respect to the underlying substrate. The interaction between the molecules and the graphene surface shifts the LUMO towards the Fermi level, inducing a charge transfer and the opening of a band gap in the graphene, with the LUMO inside. This decouples the LUMO from the surface rendering it invisible in the dI/dV spectroscopy. The HOMO only becomes visible at short tip-surface distances, as its energy lies within the band gap of the SiC substrate. Finally, the observed molecular defects are very particular, being composed exclusively of molecular dimers. These molecular dimers have a stronger interaction with the graphene than other molecules. PMID- 23440410 TI - Loss of T cell progenitor checkpoint control underlies leukemia initiation in Rag1-deficient nonobese diabetic mice. AB - NOD mice exhibit major defects in the earliest stages of T cell development in the thymus. Genome-wide genetic and transcriptome analyses were used to investigate the origins and consequences of an early T cell developmental checkpoint breakthrough in Rag1-deficient NOD mice. Quantitative trait locus analysis mapped the presence of checkpoint breakthrough cells to several known NOD diabetes susceptibility regions, particularly insulin-dependent diabetes susceptibility genes (Idd)9/11 on chromosome 4, suggesting common genetic origins for T cell defects affecting this trait and autoimmunity. Genome-wide RNA deep sequencing of NOD and B6 Rag1-deficient thymocytes revealed the effects of genetic background prior to breakthrough, as well as the cellular consequences of the breakthrough. Transcriptome comparison between the two strains showed enrichment in differentially expressed signal transduction genes, prominently tyrosine kinase and actin-binding genes, in accord with their divergent sensitivities to activating signals. Emerging NOD breakthrough cells aberrantly expressed both stem cell-associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit, which are normally repressed at the commitment checkpoint, and post-beta selection checkpoint genes, including Cd2 and Cd5. Coexpression of genes characteristic of multipotent progenitors and more mature T cells persists in the expanding population of thymocytes and in the thymic leukemias that emerge with age in these mice. These results show that Rag1-deficient NOD thymocytes have T cell defects that can collapse regulatory boundaries at two early T cell checkpoints, which may predispose them to both leukemia and autoimmunity. PMID- 23440411 TI - Disparate roles for STAT5 in primary and secondary CTL responses. AB - IL-2 signals during the primary response to infection are essential in shaping CD8(+) T cell fate decisions. How CD8(+) T cells integrate IL-2 signals in the development of functional memory is not well understood. Because IL-2 induces potent activation of the STAT5 transcription factor, we tested the role of STAT5 in CD8(+) memory T cell differentiation and function using a model system in which STAT5 activity is inducibly abrogated upon CD8(+) T cell activation. We report that STAT5 activity is broadly important for the expansion and effector function of all effector CTL subsets. After pathogen clearance, STAT5 was required for the survival of effector phenotype memory CTLs during the contraction phase. However, despite its role in supporting full primary CD8(+) T cell expansion, and unlike IL-2, STAT5 activity is not required for the development of memory CD8(+) T cells capable of robust secondary expansion upon rechallenge. Our findings highlight differential requirements for survival signals between primary and secondary effector CTL, and demonstrate that IL-2 dependent programming of memory CD8(+) T cells capable of secondary expansion and secondary effector differentiation is largely STAT5 independent. PMID- 23440412 TI - Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. AB - Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33(+) progenitors isolated from healthy donors' umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs' immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-L-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer. PMID- 23440413 TI - Direct alloreactivity is more susceptible to regulation by natural regulatory T cells than indirect alloreactivity. AB - The contribution of natural CD4(+)CD25(+) regulatory T cells (nTregs) in controlling graft rejection and the mechanism used remain controversial. Using the duality of the 2.102 TCR Ag recognition, we were able to study, for the first time to our knowledge, the involvement of nTregs in the two pathways of allorecognition in a murine adoptive transfer model in which TCR-transgenic nTregs were or were not depleted before transplantation. We show that nTregs used at a physiological ratio were able to delay graft rejection after direct alloreactivity by controlling proliferation and differentiation of alloreactive CD4(+) conventional T cells in draining lymph nodes. In contrast, similar results were found in the indirect alloreactivity pathway only when nTregs were used in high numbers. In the latter pathway, nTregs used at a physiological ratio failed to delay graft rejection and to control proliferation of conventional T cells. These results support recent therapeutic approaches aimed at producing and using in vitro Ag-specific Foxp3(+) nTregs to control graft rejection in transplantation. Finally, late inhibition of Th1 differentiation was shown in indirect alloreactivity, but this suppression could also be mediated by Foxp3(+) induced Tregs. PMID- 23440414 TI - IL-1 receptor regulates microRNA-135b expression in a negative feedback mechanism during cigarette smoke-induced inflammation. AB - Although microRNA-135b (miR-135b) is known to be associated with cancer, with recent work showing that it is massively induced in the pulmonary tissues of mice challenged with nanoparticles suggests a critical role for this microRNA in mediating inflammatory response. In this study, we investigated the expression and function of miR-135b in mice exposed to cigarette smoke or nontypeable Haemophilus influenzae (NTHi). Exposure to both cigarette smoke and NTHi elicited robust lung inflammation, but increased miR-135b expression was observed only in the lungs of cigarette smoke-exposed mice. Using IL-1R 1 knockout mice, we show that miR-135b expression is IL-1R1 dependent. A series of in vitro experiments confirmed the role of IL-1R1 in regulating miR-135b expression. In vitro activation of the IL-1R1 pathway in mouse embryonic fibroblast (NIH3T3) and lung epithelial (FE1) cells resulted in increased miR-135b, which was blocked by IL 1R1 antagonists or small interfering RNA-mediated silencing of IL-1R1 expression. Overexpression of mature miR-135b in NIH3T3 cells (pEGP-mmu-mir-135b) resulted in the suppression of endogenous levels of IL-1R1 expression. pEGP-mmu-miR-135b cells transiently transfected with luciferase reporter vector containing the 3'UTR of mouse IL-1R1 showed reduced luciferase activity. Finally, we demonstrate that miR-135b targets IL-1-stimulated activation of Caspase-1, the IL-1R1 downstream activator of IL-1beta leading to suppressed synthesis of the active form of IL-1beta protein. These results suggest that miR-135b expression during cigarette smoke-induced inflammation is regulated by IL-1R1 in a regulatory feedback mechanism to resolve inflammation. PMID- 23440415 TI - A nonallergenic birch pollen allergy vaccine consisting of hepatitis PreS-fused Bet v 1 peptides focuses blocking IgG toward IgE epitopes and shifts immune responses to a tolerogenic and Th1 phenotype. AB - Allergen-specific immunotherapy is the only allergen-specific and disease modifying treatment for allergy. The construction and characterization of a vaccine for birch pollen allergy is reported. Two nonallergenic peptides, PA and PB, derived from the IgE-reactive areas of the major birch pollen allergen Bet v 1 were fused to the hepatitis B surface protein, PreS, in four recombinant fusion proteins containing different numbers and combinations of the peptides. Fusion proteins expressed in Escherichia coli and purified to homogeneity showed a lack of IgE reactivity and allergenic activity when tested with sera and basophils from patients allergic to birch pollen. Compared to Bet v 1 allergen, peptides PA and PB showed reduced T cell activation in PBMCs from allergic patients, whereas PreS fusion proteins induced less IL-5 and more IL-10 and IFN-gamma. Immunization of rabbits with the fusion proteins, in particular with a PreS fusion protein 2PAPB-PreS, containing two copies of each peptide, induced high levels of IgG Abs against the major IgE-reactive site on Bet v 1 and related allergens. These IgG Abs inhibited allergic patients' IgE binding to Bet v 1 better than did IgG induced by immunization with complete Bet v 1. Furthermore, 2PAPB-PreS-induced IgG inhibited Bet v 1-induced basophil activation in allergic patients and CD23 facilitated allergen presentation. Our study exemplifies novel beneficial features for a PreS carrier-based peptide vaccine for birch pollen, which, in addition to the established reduction in allergenic activity, include the enhanced focusing of blocking Ab responses toward IgE epitopes, immunomodulatory activity, and reduction of CD23-facilitated allergen presentation. PMID- 23440416 TI - Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice. AB - Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what APCs is important for priming graft-versus-host reaction remains unknown. We demonstrate that delta-like ligand-4 (Dll4) and Dll4-positive (Dll4(high)) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4(high) i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4(high) i-DCs were CD11c(+)B220(+)PDCA-1(+), resembling plasmacytoid dentritic cells (pDCs) of naive mice. However, as compared with unstimulated pDCs, Dll4(high) i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2, and CD11b, and produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4(low)) i-DCs were CD11c(+)B220(-)PDCA-1(-), and had low levels of Jagged1. In vitro assays showed that Dll4(high) i-DCs induced significantly more IFN-gamma and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4(low) i-DCs. This effect could be blocked by anti-Dll4 Ab. In vivo administration of Dll4 Ab reduced donor-alloreactive effector T cells producing IFN-gamma and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4(high) i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4(low) i-DCs. Furthermore, Dll4 and Dll4(high) i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4(high) i-DCs. PMID- 23440417 TI - IRF7-dependent IFN-beta production in response to RANKL promotes medullary thymic epithelial cell development. AB - The contributions of IFN regulatory factor (IRF) 3/7 and the type I IFNs IFN alpha/beta to the innate host defense have been extensively investigated; however, their role in thymic development is less clear. In this study, we show that mice lacking the type I IFN receptor IFN-alpha/beta receptor (IFNAR) or the downstream transcription factor STAT1 harbor a significant reduction in self-Ag presenting, autoimmune regulator (AIRE)(+) medullary thymic epithelial cells (mTECs). Constitutive IFNAR signaling occurs in the thymic medulla in the absence of infection or inflammation. Receptor activator for NF-kappaB (RANK) ligand stimulation results in IFN-beta upregulation, which in turn inhibits RANK signaling and facilitates AIRE expression in mTECs. Finally, we find that IRF7 is required for thymic IFN-beta induction, maintenance of thymic architecture, and mTEC differentiation. We conclude that spatially and temporally coordinated cross talks between the RANK ligand/RANK and IRF7/IFN-beta/IFNAR/STAT1 pathways are essential for differentiation of AIRE(+) mTECs. PMID- 23440418 TI - Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization. AB - Complement receptor 1 (CR1) expressed on the surface of phagocytic cells binds complement-bound immune complexes (IC), playing an important role in the clearance of circulating IC. This receptor is critical to prevent accumulation of IC, which can contribute to inflammatory pathology. Accumulation of circulating IC is frequently observed during malaria, although the factors contributing to this accumulation are not clearly understood. We have observed that the surface expression of CR1 on monocytes/macrophages and B cells is strongly reduced in mice infected with Plasmodium yoelii, a rodent malaria model. Monocytes/macrophages from these infected mice present a specific inhibition of complement-mediated internalization of IC caused by the decreased CR1 expression. Accordingly, mice show accumulation of circulating IC and deposition of IC in the kidneys that inversely correlate with the decrease in CR1 surface expression. Our results indicate that malaria induces a significant decrease on surface CR1 expression in the monocyte/macrophage population that results in deficient internalization of IC by monocytes/macrophages. To determine whether this phenomenon is found in human malaria patients, we have analyzed 92 patients infected with either P. falciparum (22 patients) or P. vivax (70 patients) , the most prevalent human malaria parasites. The levels of surface CR1 on peripheral monocytes/macrophages and B cells of these patients show a significant decrease compared with uninfected control individuals in the same area. We propose that this decrease in CR1 plays an essential role in impaired IC clearance during malaria. PMID- 23440419 TI - DC-SCRIPT regulates glucocorticoid receptor function and expression of its target GILZ in dendritic cells. AB - Dendritic cells (DCs) play a central role in the immune system; they can induce immunity or tolerance depending on diverse factors in the DC environment. Pathogens, but also tissue damage, hormones, and vitamins, affect DC activation and maturation. In particular, glucocorticoids (GCs) are known for their immunosuppressive effect on DCs, creating tolerogenic DCs. GCs activate the type I nuclear receptor (NR) glucocorticoid receptor (GR), followed by induced expression of the transcription factor glucocorticoid-inducible leucine zipper (GILZ). GILZ has been shown to be necessary and sufficient for GC-induced tolerogenic DC generation. Recently, we have identified the DC-specific transcript (DC-SCRIPT) as an NR coregulator, suppressing type I steroid NRs estrogen receptor and progesterone receptor. In this study, we analyzed the effect of DC-SCRIPT on GR activity. We demonstrate that DC-SCRIPT coexists with GR in protein complexes and functions as a corepressor of GR-mediated transcription. Coexpression of DC-SCRIPT and GR is shown in human monocyte derived DCs, and DC-SCRIPT knockdown enhances GR-dependent upregulation of GILZ mRNA expression in DCs. This demonstrates that DC-SCRIPT serves an important role in regulating GR function in DCs, corepressing GR-dependent upregulation of the tolerance-inducing transcription factor GILZ. These data imply that by controlling GR function and GILZ expression DC-SCRIPT is potentially involved in the balance between tolerance and immunity. PMID- 23440420 TI - KIR3DL2 binds to HLA-B27 dimers and free H chains more strongly than other HLA class I and promotes the expansion of T cells in ankylosing spondylitis. AB - The human leukocyte Ag HLA-B27 (B27) is strongly associated with the spondyloarthritides. B27 can be expressed at the cell surface of APC as both classical beta2-microglobulin-associated B27 and B27 free H chain forms (FHC), including disulfide-bonded H chain homodimers (termed B27(2)). B27 FHC forms, but not classical B27, bind to KIR3DL2. HLA-A3, which is not associated with spondyloarthritis (SpA), is also a ligand for KIR3DL2. In this study, we show that B27(2) and B27 FHC bind more strongly to KIR3DL2 than other HLA-class I, including HLA-A3. B27(2) tetramers bound KIR3DL2-transfected cells more strongly than HLA-A3. KIR3DL2Fc bound to HLA-B27-transfected cells more strongly than to cells transfected with other HLA-class I. KIR3DL2Fc pulled down multimeric, dimeric, and monomeric FHC from HLA-B27-expressing cell lines. Binding to B27(2) and B27 FHC stimulated greater KIR3DL2 phosphorylation than HLA-A3. B27(2) and B27 FHC stimulated KIR3DL2CD3epsilon-transduced T cell IL-2 production to a greater extent than control HLA-class I. KIR3DL2 binding to B27 inhibited NK IFN gamma secretion and promoted greater survival of KIR3DL2(+) CD4 T and NK cells than binding to other HLA-class I. KIR3DL2(+) T cells from B27(+) SpA patients proliferated more in response to Ag presented by syngeneic APC than the same T cell subset from healthy and disease controls. Our results suggest that expansion of KIR3DL2-expressing leukocytes observed in B27(+) SpA may be explained by the stronger interaction of KIR3DL2 with B27 FHC. PMID- 23440421 TI - Constitutively CD40-activated B cells regulate CD8 T cell inflammatory response by IL-10 induction. AB - B cells are exposed to high levels of CD40 ligand (CD40L, CD154) in chronic inflammatory diseases. In addition, B cells expressing both CD40 and CD40L have been identified in human diseases such as autoimmune diseases and lymphoma. However, how such constitutively CD40-activated B cells under inflammation may impact on T cell response remains unknown. Using a mouse model in which B cells express a CD40L transgene (CD40LTg) and receive autocrine CD40/CD40L signaling, we show that CD40LTg B cells stimulated memory-like CD4 and CD8 T cells to express IL-10. This IL-10 expression by CD8 T cells was dependent on IFN-I and programmed cell death protein 1, and was critical for CD8 T cells to counterregulate their overactivation. Furthermore, adoptive transfer of naive CD8 T cells in RAG-1(-/-) mice normally induces colitis in association with IL-17 and IFN-gamma cytokine production. Using this model, we show that adoptive cotransfer of CD40LTg B cells, but not wild-type B cells, significantly reduced IL-17 response and regulated colitis in association with IL-10 induction in CD8 T cells. Thus, B cells expressing CD40L can be a therapeutic goal to regulate inflammatory CD8 T cell response by IL-10 induction. PMID- 23440422 TI - An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. AB - The sterol regulatory element-binding proteins (SREBP) are key transcriptional regulators of lipid metabolism and cellular growth. It has been proposed that SREBP signaling regulates cellular growth through its ability to drive lipid biosynthesis. Unexpectedly, we find that loss of SREBP activity inhibits cancer cell growth and viability by uncoupling fatty acid synthesis from desaturation. Integrated lipid profiling and metabolic flux analysis revealed that cancer cells with attenuated SREBP activity maintain long-chain saturated fatty acid synthesis, while losing fatty acid desaturation capacity. We traced this defect to the uncoupling of fatty acid synthase activity from stearoyl-CoA desaturase 1 (SCD1)-mediated desaturation. This deficiency in desaturation drives an imbalance between the saturated and monounsaturated fatty acid pools resulting in severe lipotoxicity. Importantly, replenishing the monounsaturated fatty acid pool restored growth to SREBP-inhibited cells. These studies highlight the importance of fatty acid desaturation in cancer growth and provide a novel mechanistic explanation for the role of SREBPs in cancer metabolism. PMID- 23440423 TI - Regulation of lung cancer metastasis by Klf4-Numb-like signaling. AB - Metastatic traits seem to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer. PMID- 23440424 TI - Ex vivo activation of CD56(+) immune cells that eradicate neuroblastoma. AB - Despite the use of intensive contemporary multimodal therapy, the overall survival of patients with high-risk neuroblastoma is still less than 50%. Therefore, immunotherapy without cross-resistance and overlapping toxicity has been proposed. In this study, we report the development of a novel strategy to specifically activate and expand human CD56(+) (NCAM1) natural killer (NK) immune cells from normal donors and patients with neuroblastoma. Enriched CD56(+) cells from peripheral blood were mixed with CD56(-) fraction at 1:1 ratio and cultured in the presence of OKT3, interleukin (IL)-2, and -15 for five days and then without OKT3 for 16 more days. The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule 1 (DNAM-1; CD226), perforin, and granzyme B. Successful clinical scale-up in a good manufacturing practices (GMP)-compliant bioreactor yielded effector cells that in a neuroblastoma xenograft model slowed tumor growth and extended survival without GVHD. Investigation of CD56(+) cells from patients with neuroblastoma revealed a similar postactivation phenotype and lytic activity. Our findings establish a novel and clinically expedient strategy to generate allogeneic or autologous CD56(+) cells that are highly cytotoxic against neuroblastoma with minimal risk of GVHD. PMID- 23440425 TI - Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. AB - Prostate cancer is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that fibroblast growth factor (FGF) receptors are important in prostate cancer initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21, and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require alpha-Klotho (KL) and/or beta-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as coreceptors along with classic FGF receptors (FGFR) to mediate potent biologic activity. Here we show that FGF19 is expressed in primary and metastatic prostate cancer tissues, where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion, and colony formation of prostate cancer cells at low ligand concentrations. FGF19 silencing in prostate cancer cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in prostate cancer cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biologic effects in prostate cancer. Our findings support the concept that therapies targeting FGFR signaling may have efficacy in prostate cancer and highlight FGF19 as a relevant endocrine FGF in this setting. PMID- 23440426 TI - Vascular normalization as an emerging strategy to enhance cancer immunotherapy. AB - The recent approval of Provenge has brought new hope for anticancer vaccine therapies. However, the immunosuppressive tumor microenvironment seems to impair the efficacy of vaccine therapies. The abnormal tumor vasculature creates a hypoxic microenvironment that polarizes inflammatory cells toward immune suppression. Moreover, tumors systemically alter immune cells' proliferation, differentiation, and function via secretion of growth factors and cytokines. For example, VEGF, a major proangiogenic cytokine induced by hypoxia, plays a critical role in immunosuppression via these mechanisms. Hence, antiangiogenic treatment may be an effective modality to potentiate immunotherapy. Here, we discuss the local and systemic effects of VEGF on tumor immunity and propose a potentially translatable strategy to re-engineer the tumor-immune microenvironment and improve cancer immunotherapy by using lower "vascular normalizing" doses of antiangiogenic agents. PMID- 23440427 TI - Hepatocarcinogenesis driven by GSNOR deficiency is prevented by iNOS inhibition. AB - Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers and it remains poorly managed. Human HCC development is often associated both with elevated expression of inducible nitric oxide synthase (iNOS) and with genetic deletion of the major denitrosylase S-nitrosoglutathione reductase (GSNOR/ADH5). However, their causal involvement in human HCC is not established. In mice, GSNOR deficiency causes S-nitrosylation and depletion of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (AGT) and increases rates of both spontaneous and DEN carcinogen-induced HCC. Here, we report that administration of 1400W, a potent and highly selective inhibitor of iNOS, blocked AGT depletion and rescued the repair of mutagenic O6-ethyldeoxyguanosines following DEN challenge in livers of GSNOR-deficient (GSNOR(-/-)) mice. Notably, short-term iNOS inhibition following DEN treatment had little effect on carcinogenesis in wild-type mice, but was sufficient to reduce HCC multiplicity, maximal size, and burden in GSNOR(-/-) mice to levels comparable with wild-type controls. Furthermore, increased HCC susceptibility in GSNOR(-/-) mice was not associated with an increase in interleukin 6, tumor necrosis factor-alpha, oxidative stress, or hepatocellular proliferation. These results suggested that GSNOR deficiency linked to defective DNA damage repair likely acts at the tumor initiation stage to promote HCC carcinogenesis. Together, our findings provide the first proof of principle that HCC development in the context of uncontrolled nitrosative stress can be blocked by pharmacologic inhibition of iNOS, possibly providing an effective therapy for patients with HCC. PMID- 23440428 TI - Friction coefficients and wear rates of different orthodontic archwires in artificial saliva. AB - The aim of this paper is to analyze the influence of the nature of the orthodontic archwires on the friction coefficient and wear rate against materials used commonly as brackets (Ti-6Al-4V and 316L Stainless Steel). The materials selected as orthodontic archwires were ASI304 stainless steel, NiTi, Ti, TiMo and NiTiCu. The array archwire's materials selected presented very similar roughness but different hardness. Materials were chosen from lower and higher hardness degrees than that of the brackets. Wear tests were carried out at in artificial saliva at 37 degrees C. Results show a linear relationship between the hardness of the materials and the friction coefficients. The material that showed lower wear rate was the ASI304 stainless steel. To prevent wear, the wire and the brackets have high hardness values and in the same order of magnitude. PMID- 23440429 TI - Surface modification of fiber reinforced polymer composites and their attachment to bone simulating material. AB - The purpose of this study was to investigate the effect of fiber orientation of a fiber-reinforced composite (FRC) made of poly-methyl-methacrylate (PMMA) and E glass to the surface fabrication process by solvent dissolution. Intention of the dissolution process was to expose the fibers and create a macroporous surface onto the FRC to enhance bone bonding of the material. The effect of dissolution and fiber direction to the bone bonding capability of the FRC material was also tested. Three groups of FRC specimens (n = 18/group) were made of PMMA and E glass fiber reinforcement: (a) group with continuous fibers parallel to the surface of the specimen, (b) continuous fibers oriented perpendicularly to the surface, (c) randomly oriented short (discontinuous) fibers. Fourth specimen group (n = 18) made of plain PMMA served as controls. The specimens were subjected to a solvent treatment by tetrahydrofuran (THF) of either 5, 15 or 30 min of time (n = 6/time point), and the advancement of the dissolution (front) was measured. The solvent treatment also exposed the fibers and created a surface roughness on to the specimens. The solvent treated specimens were embedded into plaster of Paris to simulate bone bonding by mechanical locking and a pull-out test was undertaken to determine the strength of the attachment. All the FRC specimens dissolved as function of time, as the control group showed no marked dissolution during the study period. The specimens with fibers along the direction of long axis of specimen began to dissolve significantly faster than specimens in other groups, but the test specimens with randomly oriented short fibers showed the greatest depth of dissolution after 30 min. The pull-out test showed that the PMMA specimens with fibers were retained better by the plaster of Paris than specimens without fibers. However, direction of the fibers considerably influenced the force of attachment. The fiber reinforcement increases significantly the dissolution speed, and the orientation of the glass fibers has great effect on the dissolving depth of the polymer matrix of the composite, and thus on the exposure of fibers. The glass fibers exposed by the solvent treatment enhanced effectively the attachment of the specimen to the bone modeling material. PMID- 23440430 TI - Size-dependent antibacterial activities of silver nanoparticles against oral anaerobic pathogenic bacteria. AB - Dental caries and periodontal disease are widespread diseases for which microorganism infections have been identified as the main etiology. Silver nanoparticles (Ag Nps) were considered as potential control oral bacteria infection agent due to its excellent antimicrobial activity and non acute toxic effects on human cells. In this work, stable Ag Nps with different sizes (~5, 15 and 55 nm mean values) were synthesized by using a simple reduction method or hydrothermal method. The Nps were characterized by powder X-ray diffraction, transmission electron microscopy and UV-vis absorption spectroscopy. The antibacterial activities were evaluated by colony counting assay and growth inhibition curve method, and corresponding minimum inhibitory concentration (MIC) against five anaerobic oral pathogenic bacteria and aerobic bacteria E. coli were determined. The results showed that Ag Nps had apparent antibacterial effects against the anaerobic oral pathogenic bacteria and aerobic bacteria. The MIC values of 5-nm Ag against anaerobic oral pathogenic bacteria A. actinomycetemcomitans, F. nuceatum, S. mitis, S. mutans and S. sanguis were 25, 25, 25, 50 and 50 MUg/mL, respectively. The aerobic bacteria were more susceptible to Ag NPs than the anaerobic oral pathogenic bacteria. In the mean time, Ag NPs displayed an obvious size-dependent antibacterial activity against the anaerobic bacteria. The 5-nm Ag presents the highest antibacterial activity. The results of this work indicated a potential application of Ag Nps in the inhibition of oral microorganism infections. PMID- 23440431 TI - Association of the COMT Met158 allele with trait impulsivity in healthy young adults. AB - Dopamine (DA) is considered to be an important neurotransmitter in the control of impulsive behavior, however, its underlying mechanisms have not been fully elucidated. Catechol-O-methyltransferase (COMT) is a key enzyme in the catabolism of DA within the prefrontal cortex (PFC) and has been suggested to play a role in the mediation of impulsive behavior. The COMT single nucleotide polymorphism (SNP) rs4680 (Val158Met) Met allele has been shown to decrease COMT enzyme activity and is associated with improved PFC cognitive function (intelligence and executive functions). Studies have associated the rs4680 genotype with impulsivity as a symptom in attention deficit hyperactivity disorder and substance abuse. However, only a few studies have assessed the effects of rs4680 on impulsiveness in healthy subjects, the results of which remain controversial. The Barratt Impulsiveness Scale (BIS-11) was applied to 82 healthy volunteers (including 42 females) who were genotyped for COMT rs4680. Subjects carrying the Met/Met genotype scored higher for the BIS-11 second-order factor Non-planning than carriers of the Val/Val genotype. No interaction between gender genotype was detected. Age, gender and education had no effect on the results. The COMT rs4680 Met/Met genotype was associated with higher impulsivity on the BIS-11 second order factor Non-planning. These results suggest that COMT enzyme activity may be important in the regulation of impulsiveness among young adults. Further studies involving larger samples should be conducted to confirm the results of the present study. PMID- 23440432 TI - Prospective comparison of late 3T MRI with conventional angiography in evaluating the patency of cerebral arteriovenous malformations treated with stereotactic radiosurgery. AB - INTRODUCTION: Risk of further haemorrhage in patients suffering from arteriovenous malformation (AVM) would be eliminated only if complete obliteration of the AVM is obtained. Therefore, these patients frequently need long-term follow-up. Conventional catheter angiography (CCA) with a risk of 0.5 %.to 1.6 % of significant neurological complications has traditionally been used for this purpose. However, magnetic resonance imaging (MRI) at 3T may be a safer alternative. The aim of this study was to evaluate if MRI at 3T can accurately evaluate closure of AVM in 2 years after stereotactic radiosurgery. METHODS: Twenty-three patients with both MRI at 3T and a CCA study were examined. The residual AVMs were evaluated by MRI at 3T against CCA in a prospective study. RESULTS: The time interval between radiosurgery and neuroimaging was on average of 25 months (range, 15-30 months) for MRI study and 33 months (range, 25-46 months) for CCA study. Ten patients showed closure of the AVM on MRI, all of which were confirmed on CCA. CONCLUSION: There was a complete agreement between late MRI at 3T scan and CCA in evaluation of AVM patency. PMID- 23440433 TI - Correlation between pulmonary function and brain volume in healthy elderly subjects. AB - INTRODUCTION: Cigarette smoking decreases brain regional gray matter volume and is related to chronic obstructive lung disease (COPD). COPD leads to decreased pulmonary function, which is represented by forced expiratory volume in one second percentage (FEV1.0 %); however, it is unclear if decreased pulmonary function is directly related to brain gray matter volume decline. Because there is a link between COPD and cognitive decline, revealing a direct relationship between pulmonary function and brain structure is important to better understand how pulmonary function affects brain structure and cognitive function. Therefore, the purpose of this study was to analyze whether there were significant correlations between FEV1.0 % and brain regional gray and white matter volumes using brain magnetic resonance (MR) image data from 109 community-dwelling healthy elderly individuals. METHODS: Brain MR images were processed with voxel based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. RESULTS: We found a significant positive correlation between the regional white matter volume of the cerebellum and FEV1.0 % after adjusting for age, sex, and intracranial volume. CONCLUSION: Our results suggest that elderly individuals who have a lower FEV1.0 % have decreased regional white matter volume in the cerebellum. Therefore, preventing decreased pulmonary function is important for cerebellar white matter volume in the healthy elderly population. PMID- 23440434 TI - Expression of pattern recognition receptors in cholesteatoma. AB - Although many immunologic mechanisms have been investigated in studies of the pathogenesis of cholesteatoma, the role of pattern recognition receptors (PRRs) has not been fully determined. Therefore, we assessed innate immune responses in patients with cholesteatoma. We prospectively evaluated 21 patients with acquired cholesteatoma between August 2010 and July 2012. Cholesteatoma specimens were obtained during surgery, and skin from the external meatus of each patient was used as a control. RNA was extracted from these tissue samples, followed by real time PCR to quantitatively assess the relative expression of toll-like receptors (TLRs), NOD-like receptors (NLRs), retinoic acid-inducible gene (RIG)-I, NO synthase (NOS) and cytokines. The levels of TLR-2, -3, -4, -6, -7, and -10, NOD 2, and IL-1 and -8 mRNAs were significantly higher in the cholesteatoma than in the skin specimens (p < .05). The expression levels of TLR-2 and -3, RIG-I, IL-6, and TNF-alpha mRNAs were significantly higher in cholesteatomas from women than from men. The levels of TLR-8, NOD-2, IL-12, and TNF-alpha mRNAs were significantly higher in recurrent than in initial cholesteatoma specimens (p < .05). Hearing level did not correlate with the levels of expression of mRNAs encoding TLRs, NLRs, NOS, RIG-I and related cytokines (p > .05). In conclusion, alterations in innate immunity triggered by PRRs are important in the pathophysiology of cholesteatoma. Gender differences and frequency of surgery may affect the expression of PRRs in cholesteatomas. PMID- 23440435 TI - Evaluation of an EMG bioimpedance measurement system for recording and analysing the pharyngeal phase of swallowing. AB - A neuroprosthetic device for treating swallowing disorders requires an implantable measurement system capable to analysing the timing and quality of the swallowing process in real time. A combined EMG bioimpedance (EMBI) measurement system was developed and is evaluated here. The study was planned and performed as a case-control study. The studies were approved by the Charite Berlin ethics committee in votes EA1/160/09 and EA1/161/09. Investigations were carried out on healthy volunteers in order to examine the usefulness and reproducibility of measurements, the ability to distinguish between swallowing and head movements and the effect of different food consistencies. The correlation between bioimpedance and anatomical and functional changes occurring during the pharyngeal phase of swallowing in non-healthy patients was examined using videofluoroscopy (VFSS). 31 healthy subjects (15?, 16?) were tested over the course of 1350 swallows and 19 (17?, 2?) non-healthy patients over the course of 54 swallows. The signal curves obtained from both transcutaneous and subcutaneous measurement were similar, characteristic and reproducible (r > 0.5) and correlated with anatomical and functional changes during the pharyngeal phase of swallowing observed using VFSS. Statistically significant differences between head movements and swallowing movements, food volumes and consistencies were found. Neither the conductivity of the food, the sex of the test subject nor the position of the measurement electrodes exerted a statistically significant effect on the measured signal. EMBI is able to reproducibly map the pharyngeal phase of swallowing and changes associated with it both transcutaneously and subcutaneously. The procedure therefore appears to be suitable for use in performing automated evaluation of the swallowing process and for use as a component of an implant. PMID- 23440436 TI - Cartilage tympanoplasty: a reliable technique for smokers. AB - The aim of this study was to report our experience with cartilage tympanoplasty (CT) in smokers and compare it with that of non-smokers using a retrospective chart review at a tertiary referral center. Between September 2008 and September 2010, cartilage tympanoplasty was performed in 52 patients. Among them, 27 were active smokers and 25 former or non-smokers. The entire tympanic membrane was replaced with conchal cartilage, shaped either as a shield for cases with intact canal wall mastoidectomies, or crashed for cases with canal wall down procedures. The mean post-operative follow-up was 12 months (range 6-18 months). A complete pre- and post-operative audiologic evaluation was obtained in all patients. Graft take was successful in all patients. The overall average pre-operative and post operative pure tone average air-bone gaps (PTA-ABG) was 52.2 dB +/- 17.7 dB and 35.4 dB +/- 17.9 dB, respectively, with an overall improvement of 16.8 dB (p < 0.001). A post-operative PTA-ABG of 25 dB or less was achieved in 39 (75 %) patients (p < 0.001). In smokers, the hearing improvement was 17.6 dB (p < 0.001) with a PTA-ABG of 25 dB or less in 19 (70 %). In non-smokers, the average hearing improvement was 16.8 dB (p < 0.0005) with a post-operative PTA-ABG of 25 dB or less in 19 (76 %), (p < 0.001). The results showed that the CT technique is a very effective procedure for smokers. Excellent graft take and satisfactory hearing results can be accomplished regardless of smoking habits. PMID- 23440437 TI - Biotreatment of chromite ore processing residue by Pannonibacter phragmitetus BB. AB - Chromite ore processing residues (COPR) is the source of the Cr(VI) contamination in the environment. Pannonibacter phragmitetus BB was used to treat two different types of COPRs in this research. The water-soluble Cr(VI) of COPR A and B is 3,982.9 and 1,181.4 mg/kg, respectively. In the column biotreatment process, P. phragmitetus BB can reduce Cr(VI) in the leachate to an undetectable level at the flow rate of 1 and 2 ml/min. In the direct biotreatment process, Cr(VI) in the liquid supernatant of COPR A and B decreased from 265 and 200 mg/l to 145 and 40 mg/kg after 240 h of incubation. In one-step and two-step biotreatment processes, Cr(VI) in the liquid supernatant of both COPRs can be reduced to an undetectable level. The toxicity characteristic leaching procedure results indicate that the Cr(VI) concentration of treated COPR A (3.48 mg/l) is lower than the identification standards for hazardous wastes of China (5 mg/l) (GB 5085.6-2007). The information obtained in this study has significance for the application of P. phragmitetus BB to remediate COPR contamination. PMID- 23440438 TI - Influence of iron and copper oxides on polychlorinated diphenyl ether formation in heterogeneous reactions. AB - Polychlorinated diphenyl ether (PCDE) has attracted great attention recently as an important type of environmental pollutant. The influence of iron and copper oxides on formation of PCDEs was investigated using laboratory-scale flow reactors under air and under nitrogen at 350 degrees C, a temperature corresponding to the post-combustion zone of a municipal solid waste incinerator. The results show that the 2,2',3,4,4',5,5',6-otachlorodiphenyl ether (OCDE) formed from the condensation of pentachlorophenol (PCP) and 1,2,4,5 tetrachlorobenzene (Cl4Bz) is the predominant congener formed on the SiO2/Fe2O3 surface with and without oxygen. This indicated that HCl elimination between PCP and 1,2,4,5-Cl4Bz molecules formed 2,2',3,4,4',5,5',6-OCDE in the presence of Fe2O3. On the other hand, decachlorodiphenyl ether, nonachlorodiphenyl ether, and OCDE were the dominant products on the SiO2/CuO surface without oxygen, although the 2,2',3,4,4',5,5',6-OCDE was the dominant product on the SiO2/CuO surface with oxygen. Therefore, the presence of Fe2O3 and CuO influences the formation and homologue distribution of PCDEs, which shifted towards the lower chlorinated species. Fe2O3 can promote both the condensation and dechlorination reaction without oxygen. On the contrary, with oxygen, Fe2O3 suppresses the condensation of chlorobenzene and chlorophenol to form PCDEs and polychlorinated dibenzo-p dioxins and polychlorinated dibenzofurans (PCDD/Fs). CuO can increase the formation of lower chlorinated PCDEs and PCDDs without oxygen. In conclusion, the different fly ash components have a major influence on PCDE emissions. PMID- 23440439 TI - Chemical and biomarker responses for site-specific quality assessment of the Lake Maggiore (Northern Italy). AB - Since the 1990s, the Lake Maggiore (Northern Italy) has been recognized as an aquatic environment contaminated by DDTs and other persistent organic pollutants, but to date just few studies were carried out to investigate the effects of pollution to aquatic organisms. The aim of this study was the application of a stepwise approach based on chemical data, a suite of biomarkers and the integration of their responses into a biomarker response index (BRI) to evaluate the site-specific quality assessment in different sampling stations of Lake Maggiore, one of the largest European lakes. We used as biological model the freshwater bivalve Zebra mussel (Dreissena polymorpha). Several hundred bivalve specimens were sampled on May 2011 from eight sampling sites located along the lake shoreline. We measured levels of DDTs, PCBs, HCHs, HCB, and PAHs accumulated in D. polymorpha soft tissues by GC/MSn, while the activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase, as well as the lipid peroxidation and protein carbonyl content were evaluated in homogenates from native bivalves as oxidative stress indices. Moreover, DNA damage was investigated by the alkaline precipitation assay. Significant imbalances of enzymatic activity were found in mussels from most of the sampling sites, as well as notable increases of damage to macromolecules. Health status of mussels from Baveno was greatly affected by lake pollution, probably due to high levels of DDTs measured in this site, while a wide variability in biomarker responses was found in all the other stations. The application of a BRI allowed distinguishing impacts of pollution to bivalves, confirming mussels from Baveno as the most threatened and revealing that also the health status of bivalves from Suna, Brissago, Pallanza, and Laveno is affected. These evidences suggest the usefulness of a specific index to integrate all the biomarker endpoints in order to provide a correct environmental risk assessment. PMID- 23440440 TI - Adsorption behavior of light green anionic dye using cationic surfactant-modified wheat straw in batch and column mode. AB - An agricultural by-product, natural wheat straw (NWS), was soaked in 1 % cationic surfactant (hexadecylpyridinium bromide, CPB) solution for 24 h (at 293 K), and modified wheat straw (MWS) was obtained. Analysis of FTIR, XFR, and nitrogen element showed that CPB was adsorbed onto surface of NWS. Then, MWS was used as adsorbent for the removal of light green dye (LG, anionic dye) from aqueous solution. The experiment was performed in batch and column mode at room temperature (293 K). Sodium chloride (up to 0.1 mol/L) existed in solution was not favor of LG dye adsorption. The equilibrium data were better described by Langmuir isotherm, and adsorption capacity of q m from Langmuir model was 70.01 +/- 3.39 mg/g. In fixed-bed column adsorption mode, the effects of initial LG concentration (30, 50, 70 mg/L) and flow rate (6.5, 9.0, 14.5 mL/min) on adsorption were presented. Thomas and modified dose-response models were used to predict the breakthrough curves using nonlinear analysis method, and both models can fit the breakthrough curves. Theoretical and experimental breakthrough curves were drawn and compared. The results implied that MWS can be used as adsorbent material to remove LG from aqueous solution. PMID- 23440441 TI - Performance of a naturally growing Parmelioid lichen Remototrachyna awasthii against organic and inorganic pollutants. AB - The present study aims to assess the level and possible sources of organic and inorganic pollutants in Mahableshwar city in Western part of India and their effect on naturally growing foliose lichen Remototrachyana awasthii (Hale & Patw.) Divakar & A. Crespo. This lichen species growing abundantly in the area was collected from eight different sites on the basis of anthropogenic activities detected in the area. The concentration of inorganic heavy metals (Al, As, Cd, Cr, Fe, Pb, Mn, and Zn) and polycyclic aromatic hydrocarbons (PAHs) were analyzed and correlated with photosynthetic pigments (Chl a, Chl b, total chlorophyll, and carotenoid) together with chlorophyll degradation and protein contents. The concentration of most of the metals at different sites was significantly greater than at the control site (P<0.001). The highest metal content was found at Bus Stand and Panchgani, a tourist place that experiences heavy traffic activities. The concentration of PAHs, particularly of two-and three-ringed PAHs, was also found to be the highest in samples collected at Bus Stand area. The chlorophyll degradation and protein content were found to be the most sensitive parameters to assess the vitality of lichen thallus against wide range of air pollutants. The effectiveness of R. awasthii as a biomonitor will be investigated in the near future by comparing this species with other biomonitors. PMID- 23440442 TI - Effect of the PA-MSHA vaccine on septic serum-induced inflammatory response. AB - Sepsis is defined as a complex clinical syndrome caused by a serious infection followed by an amplified and deregulated inflammatory response. The complex syndrome is associated with a high rate of morbidity and mortality, despite substantial clinical advances. A vaccine derived from the outer membrane proteins of the Gram-negative bacteria Pseudomonas aeruginosa (PA-MSHA) has been demonstrated to exhibit immune modulatory properties. In the present study, the effect of the PA-MSHA vaccine on the inflammatory response induced by serum from septic patients in peripheral blood mononuclear cells was determined. It was observed that PA-MSHA pretreatment inhibits the production of septic serum induced tumor necrosis factor-alpha. In addition, PA-MSHA treatment increases interleukin-10 levels and promotes the generation of CD4+CD25+Foxp3+ T cells. Thus, the results of the current study provide mechanistic insight relevant to the potential application of PA-MSHA in the treatment of sepsis. PMID- 23440443 TI - Season-long volatile emissions from peach and pear trees in situ, overlapping profiles, and olfactory attraction of an oligophagous fruit moth in the laboratory. AB - Insect herbivores that have more than one generation per year and reproduce on different host plants are confronted with substantial seasonal variation in the volatile blends emitted by their hosts. One way to deal with such variation is to respond to a specific set of compounds common to all host plants. The oriental fruit moth Cydia (=Grapholita) molesta is a highly damaging invasive pest. The stone fruit peach (Prunus persica) is its primary host, whereas pome fruits such as pear (Pyrus communis) are considered secondary hosts. In some parts of their geographic range, moth populations switch from stone to pome fruit orchards during the growing season. Here, we tested whether this temporal switch is facilitated by female responses to plant volatiles. We collected volatiles from peach and pear trees in situ and characterized their seasonal dynamics by gas chromatography-mass spectrometry. We also assessed the effects of the natural volatile blends released by the two plant species on female attraction by using Y tube olfactometry. Finally, we related variations in volatile emissions to female olfactory responses. Our results indicate that the seasonal host switch from peach to pear is facilitated by the changing olfactory effect of the natural volatile blends being emitted. Peach volatiles were only attractive early and mid season, whereas pear volatiles were attractive from mid to late season. Blends from the various attractive stages shared a common set of five aldehydes, which are suggested to play an essential role in female attraction to host plants. Particular attention should be given to these aldehydes when designing candidate attractants for oriental fruit moth females. PMID- 23440445 TI - Effects of subchronic manganese chloride exposure on tambaqui (Colossoma macropomum) tissues: oxidative stress and antioxidant defenses. AB - This study aimed to evaluate oxidative stress parameters in juvenile tambaqui (Colossoma macropomum) exposed to 3.88 mg l(-1) Mn(2+) for 96 hours. Biomarkers of oxidative stress, such as thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione-S-transferase (GST) activities, as well as content of reduced glutathione (GSH), were analyzed in gill, liver, brain, and kidney. The presence of Mn(2+) in the water corresponded to increased levels of Mn(2+) accumulation according to the following sequence: gill > kidney > brain > liver. There was a significant increase in TBARS levels (40 %) and SOD activity (80 %) in addition to a significant decrease in GSH content (41 %) in gills of fish exposed to waterborne Mn(2+). In hepatic tissue of the exposed animals, TBARS levels decreased significantly (35 %), whereas SOD (82 %) and GST activities (51 %) as well as GSH content (43 %) increased significantly. In brain of exposed juvenile fish, only significant decreases in SOD (32 %) and CAT activities (65 %) were observed. Moreover, the kidney of exposed fish showed a significant increase in TBARS levels (53 %) and a significant decrease in SOD activity (41 %) compared with the control. Thus, the changes in biomarkers of oxidative stress were different in the tissues, showing a specific toxicity of this metal to each organ. PMID- 23440444 TI - Direct and indirect plant defenses are not suppressed by endosymbionts of a specialist root herbivore. AB - Insect endosymbionts influence many important metabolic and developmental processes of their host. It has been speculated that they may also help to manipulate and suppress plant defenses to the benefit of herbivores. Recently, endosymbionts of the root herbivore Diabrotica virgifera virgifera have been reported to suppress the induction of defensive transcripts in maize roots, which may explain the finding of another study that once attacked plants become more susceptible to subsequent D. v. virgifera attack. To test this hypothesis, we cured D. v. virgifera from its major endosymbiont Wolbachia and tested whether endosymbiont-free individuals elicit different defense responses in maize roots. The presence of Wolbachia did not alter the induction of defense marker genes and resistance in a susceptible maize hybrid and a resistant line. Furthermore, attacked maize plants emitted the same amount of (E)-beta-caryophyllene, a volatile signal that serves as foraging cue for both entomopathogenic nematodes and D. v. virgifera. Finally, the effectiveness of the entomopathogenic nematode Heterorhabditis bacteriophora to infest D. v. virgifera was not changed by curing the larvae from their endosymbionts. These results show that the defense mechanisms of maize are not affected by Wolbachia. Consequently, D. v. virgifera does not seem to derive any plant-defense mediated benefits from its major endosymbiont. PMID- 23440446 TI - A battery of bioassays for the evaluation of phenanthrene biotoxicity in soil. AB - A battery of bioassays was used to assess the ecotoxicological risk of soil spiked with a range of phenanthrene levels (0.95, 6.29, 38.5, 58.7, 122, and 303 MUg g(-1) dry soil) and aged for 69 days. Multiple species (viz. Brassica rapa, Eisenia feotida, Vibrio fischeri), representing different trophic levels, were used as bioindicator organisms. Among acute toxicity assays tested, the V. fischeri luminescence inhibition assay was the most sensitive indicator of phenanthrene biotoxicity. More than 15 % light inhibition was found at the lowest phenanthrene level (0.95 MUg g(-1)). Furthermore, comet assay using E. fetida was applied to assess genotoxicity of phenanthrene. The strong correlation (r (2) >= 0.94) between phenanthrene concentration and DNA damage indicated that comet assay is appropriate for testing the genotoxic effects of phenanthrene contaminated soil. In the light of these results, we conclude that the Microtox test and comet assay are robust and sensitive bioassays to be employed for the risk evaluation of polycyclic aromatic hydrocarbon-contaminated soil. PMID- 23440447 TI - Pollution pathways of pharmaceutical residues in the aquatic environment on the island of Mallorca, Spain. AB - This work determines the principal environmental pollution pathways of pharmaceuticals on the island of Mallorca (Spain). The evaluation was made on the basis of the quantification of pharmaceutical residues by liquid chromatography tandem mass spectrometry in several environmental water samples, including wastewater-treatment plant effluents, municipal solid waste landfill leachates, groundwater (GW), and marine water. An overall set of 19 pharmaceuticals has been identified in the environment of the 27 human pharmaceuticals investigated in this study. WWTP effluents are the main source of discharge of the pharmaceuticals into the aquatic environment. The data indicate that reuse of treated domestic wastewater for irrigation (which supplies some 30 % of the total water demand in Mallorca) contributes to the contamination of GW. In addition, leaching from landfills is identified as another, but minor, possible source of introduction of pharmaceuticals to GW aquifers. Finally, WWTP effluents ending in the Mediterranean Sea, primarily highly urbanized coastal areas, cause pharmaceutical residues to occur in marine water bodies. PMID- 23440448 TI - Revisiting Classification of Eating Disorders-toward Diagnostic and Statistical Manual of Mental Disorders-5 and International Statistical Classification of Diseases and Related Health Problems-11. AB - Two of the most commonly used nosological systems- International Statistical Classification of Diseases and Related Health Problems (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV are under revision. This process has generated a lot of interesting debates with regards to future of the current diagnostic categories. In fact, the status of categorical approach in the upcoming versions of ICD and DSM is also being debated. The current article focuses on the debate with regards to the eating disorders. The existing classification of eating disorders has been criticized for its limitations. A host of new diagnostic categories have been recommended for inclusion in the upcoming revisions. Also the structure of the existing categories has also been put under scrutiny. PMID- 23440449 TI - Promotoras across the border: a pilot study addressing depression in Mexican women impacted by migration. AB - The migration of working-aged men from Mexico to the United States fractures the family-centered support structures typical of Latin America and contributes to high levels of depression in women left behind in migratory sending communities in Mexico. Mujeres en Solidaridad Apoyandose (MESA) was developed to improve depression in women through social support in a resource poor setting. MESA is a promotora intervention that trains women in the community to lead social support groups over a five-week period. The MESA curriculum uses a combination of cognitive behavioral theory techniques, psychoeducation, and social support activities aimed at alleviating or preventing depression in women. Results from this pilot efficacy study (n = 39) show that depressed participants at baseline experienced declines in depression as measured by the Center for Epidemiologic Studies Depression Scale at follow-up. Other findings demonstrate the complexity behind addressing social support and depression for women impacted by migration in different ways. PMID- 23440451 TI - Musculoskeletal injury, functional disability, and health-related quality of life in aging Mexican immigrant farmworkers. AB - Migrant and seasonal farmworkers are at high risk for musculoskeletal and other occupational injuries. Although persons aged 40-80 years account for 40 % of all US farmworkers and as many as 50 % in certain regions, little is known about their occupational health issues. The current study examined work-related persistent musculoskeletal injuries (PMIs) and their association with clinical and functional indicators of disability and health-related quality of life (HRQOL) in 177 middle-aged and elderly US-Mexico border farmworkers. At interview, 68 % reported current PMI pain; 51 % had pain at multiple sites. PMI pain was associated with increased shoulder, knee, and lower extremity dysfunction and reduced HRQOL scores. However, fewer than 25 % of injured participants received any conventional medical treatment. The study results indicated that work-related PMIs, especially multiple PMIs, caused significant functional impairment, disability, and poorer HRQOL, adversely affecting the ability of the aging farmworkers to perform work, self-care, and other daily activities. PMID- 23440452 TI - Cell phone utilization among foreign-born Latinos: a promising tool for dissemination of health and HIV information. AB - Latinos in the US are disproportionately affected by HIV and are at risk for late presentation to care. Between June 2011 and January 2012, we conducted a cross sectional survey of 209 Baltimore Latinos at community-based venues to evaluate the feasibility of using information communication technology-based interventions to improve access to HIV testing and education within the Spanish-speaking community in Baltimore. Participants had a median age of 33 years interquartile range (IQR) (IQR 28-42), 51.7 % were male, and 95.7 % were foreign-born. Approximately two-thirds (63.2 %) had been in the US less than 10 years and 70.1 % had been previously tested for HIV. Cell phone (92.3 %) and text messaging (74.2 %) was used more than Internet (52.2 %) or e-mail (42.8 %) (p < 0.01). In multivariate analysis, older age and lower education were associated with less utilization of Internet, e-mail and text messaging, but not cell phones. Interest was high for receiving health education (73.1 %), HIV education (70.2 %), and test results (68.8 %) via text messaging. Innovative cell phone-based communication interventions have the potential to link Latino migrants to HIV prevention, testing and treatment services. PMID- 23440453 TI - Mexican immigrants' attitudes and interest in health insurance: a qualitative descriptive study. AB - Mexican immigrants to the U.S. are nearly three times more likely to be without health insurance than non-Hispanic native citizens. To inform strategies to increase the number of insured within this population, we elicited immigrants' understanding of health insurance and preferences for coverage. Nine focus groups with Mexican immigrants were conducted across the State of North Carolina. Qualitative, descriptive methods were used to assess people's understanding of health insurance, identify their perceived need for health insurance, describe perceived barriers to obtaining coverage, and prioritize the components of insurance that immigrants value most. Individuals have a basic understanding of health insurance and perceive it as necessary. Participants most valued insurance that would cover emergencies, make care affordable, and protect family members. Barriers to obtaining insurance included cost, concerns about immigration status discovery, and communication issues. Strategies that address immigrants' preferences for and barriers to insurance should be considered. PMID- 23440450 TI - Examining the impact of patient characteristics and symptomatology on knowledge, attitudes, and beliefs among foreign-born tuberculosis cases in the US and Canada. AB - Foreign-born individuals represent the majority of TB cases in the US/Canada. Little is known about their TB knowledge, attitudes, and beliefs (KAB). Cross sectional survey was conducted in 22 sites in the US/Canada among foreign-born adults with active TB. Multiple regression was used to examine KAB factors against covariates. Of 1,475 participants interviewed, most answered the six knowledge items correctly. Significant predictors of correct knowledge included region of origin, education, income, age, visa status, place of diagnosis, BCG vaccination, and TB symptoms. Significant predictors of higher perceived risk/stigma scores included region of origin, age, place of diagnosis, English fluency, time in the US/Canada, TB symptoms, and household rooms. This study examines associations between TB KAB and patient and disease characteristics in foreign-born individuals in the US/Canada. The findings call for improved health education, along with efforts to reduce stigma and enhance realistic risk assessments. PMID- 23440454 TI - Comfort of two shoulder actuation mechanisms for arm therapy exoskeletons: a comparative study in healthy subjects. AB - Robotic exoskeletons can be used to study and treat patients with neurological impairments. They can guide and support the human limb over a large range of motion, which requires that the movement trajectory of the exoskeleton coincide with the one of the human arm. This is straightforward to achieve for rather simple joints like the elbow, but very challenging for complex joints like the human shoulder, which is comprised by several bones and can exhibit a movement with multiple rotational and translational degrees of freedom. Thus, several research groups have developed different shoulder actuation mechanism. However, there are no experimental studies that directly compare the comfort of two different shoulder actuation mechanisms. In this study, the comfort and the naturalness of the new shoulder actuation mechanism of the ARMin III exoskeleton are compared to a ball-and-socket-type shoulder actuation. The study was conducted in 20 healthy subjects using questionnaires and 3D-motion records to assess comfort and naturalness. The results indicate that the new shoulder actuation is slightly better than a ball-and-socket-type actuation. However, the differences are small, and under the tested conditions, the comfort and the naturalness of the two tested shoulder actuations do not differ a lot. PMID- 23440455 TI - Rapid Identification and Drug Susceptibility Testing of Mycobacterium tuberculosis: Standard Operating Procedure for Non-Commercial Assays: Part 2: Nitrate Reductase Assay v1.3.12. AB - In the previous part, we presented the standard operating procedure (SOP) of the microscopic observation drug susceptibility assay drug susceptibility testing (DST) for Mycobacterium tuberculosis. The present SOP is devoted to another non commercial culture and DST method known as nitrate reductase assay (NRA). As the name implies, the NRA detects the ability of M. tuberculosis to reduce nitrate to nitrite. In the assay, the presence of nitrite is detected by the addition of p nitrobenzoate into the growth yield. The reaction is detected by the naked eye. The incorporation of drugs in the medium allows to use the test for DST, which can be interpreted with naked eyes. The identification and drug susceptibility results can be obtained in 2-3 weeks. This SOP document has been developed through the culture and DST subgroup of the STOP tuberculosis (TB) Partnership New Diagnostic Working Group. It is intended for laboratories that would want to use or already using this rapid non-commercial method for culture identification and DST of M. tuberculosis, notably in resource-constraint settings in Asia and Africa. PMID- 23440456 TI - Effect of the integrated approach of yoga therapy on platelet count and uric acid in pregnancy: A multicenter stratified randomized single-blind study. AB - BACKGROUND: Yoga improves maternal and fetal outcomes in pregnancy. Platelet Count and Uric acid (Ua) are valuable screening measures in high-risk pregnancy. AIM: To examine the effect of yoga on platelet counts and serum Ua in high-risk pregnancy. MATERIALS AND METHODS: This stratified randomized controlled trial, conducted by S-VYASA University at St. John's Medical College Hospital and Gunasheela Maternity Hospital, recruited 68 women with high-risk pregnancy (30 yoga and 38 controls) in the twelfth week of pregnancy. The inclusion criteria were: Bad obstetrics history, twin pregnancies, maternal age < 20 or > 35 years, obesity (BMI > 30), and genetic history of pregnancy complications. Those with normal pregnancy, anemia (< 10 grams%dl), h/o clotting disorders; renal, hepatic or heart disease; seizure disorder; or structural abnormalities in the pelvis, were excluded. The yoga group practiced simple meditative yoga (three days / week for three months). RESULTS: At baseline, all women had normal platelet counts (> 150*10(9)/L) with a decrease as pregnancy advanced. Ua (normal at baseline) increased in both groups. No one developed abnormal thrombocytopenia or hyperuricemia. Healthy reduction in platelet count (twelfth to twentieth week) occurred in a higher (P < 0.001, Chi(2) test) number of women in the yoga group than the control group. A similar trend was found in uric acid. Significantly lesser number of women in the yoga group (n = 3) developed pregnancy-induced hypertension (PIH) / pre-eclampsia (PE) than those in the control group (n = 12), with absolute risk reduction (ARR) by 21%. CONCLUSION: Antenatal integrated yoga from the twelfth week is safe and effective in promoting a healthy progression of platelets and uric acid in women with high-risk pregnancy, pointing to healthy hemodilution and better physiological adaptation. PMID- 23440457 TI - A hyperpolarization-activated ion current of amphibian oocytes. AB - A comparative analysis of a hyperpolarization-activated ion current present in amphibian oocytes was performed using the two-electrode voltage-clamp technique in Xenopus laevis, Xenopus tropicalis, and Ambystoma mexicanum. This current appears to be driven mainly by Cl(-) ions, is independent of Ca(2+), and is made evident by applying extremely negative voltage pulses; it shows a slow activating phase and little or no desensitization. The pharmacological profile of the current is complex. The different channel blocker used for Cl(-), K(+), Na(+) and Ca(2+) conductances, exhibited various degrees of inhibition depending of the species. The profiles illustrate the intricacy of the components that give rise to this current. During X. laevis oogenesis, the hyperpolarization-activated current is present at all stages of oocytes tested (II-VI), and the amplitude of the current increases from about 50 nA in stage I to more than 1 MUA in stage VI; nevertheless, there was no apparent modification of the kinetics. Our results suggest that the hyperpolarization-activated current is present both in order Anura and Urodela oocytes. However, the electrophysiological and pharmacological characteristics are quite perplexing and seem to suggest a mixture of ionic conductances that includes the activation of both anionic and cationic channels, most probably transiently opened due to the extreme hyperpolarizion of the plasma membrane. As a possible mechanism for the generation of the current, a kinetic model which fits the data suggests the opening of pores in the plasma membrane whose ion selectivity is dependent on the extracellular Cl(-) concentration. The extreme voltage conditions could induce the opening of otherwise latent pores in plasma membrane proteins (i.e., carriers), resembling the 'slippage' events already described for some carriers. These observations should be valuable for other groups trying to express cloned, voltage-dependent ion channels in oocytes of amphibian in which hyperpolarizing voltage pulses are applied to activate the channels. PMID- 23440458 TI - Class 3 inhibition of hERG K+ channel by caffeic acid phenethyl ester (CAPE) and curcumin. AB - Human ether-a-go-go-related gene (hERG) K(+) channel current (I hERG ) is inhibited by various compounds and genetic mutations, potentially resulting in cardiac arrhythmia. Here, we investigated effects of caffeic acid phenethyl ester (CAPE) and curcumin, two natural anti-inflammatory polyphenols, on I hERG in HEK 293 cells overexpressed with hERG. CAPE dose-dependently decreased repolarization tail current of hERG (I hERG,tail; IC50, 10.6 +/- 0.5 MUM). CAPE also shifted half-activation voltage (V 1/2) to the left (from -17.5 to -26.5 mV) and accelerated activation and inactivation kinetics. The CAPE inhibition of I hERG,tail was not attenuated in the pore-blocker site mutants of hERG (Y652A and F656A). A point mutation of Cys723 (C723S) mimicked the effects of CAPE and caused a left shift of V 1/2 and acceleration of I hERG,tail deactivation. However, I hERG,tail inhibition by CAPE was still observed in C723S. Taken together, CAPE inhibits hERG channel by class 3 mechanism, i.e., modification of gating, not by blocking the pore. Curcumin induced changes of I hERG similar to those of CAPE, while additional interaction with pore-blocking sites was suggested from attenuated I hERG,tail inhibition in Y652A and F656A. Interestingly, I hERG induced by human action potential voltage clamp was increased by CAPE while decreased by curcumin. Mathematical simulation of action potential derived from the experimental results of CAPE and curcumin supports that CAPE, but not curcumin, would induce shortening of AP duration by facilitation of I hERG . The above results revealed intriguing roles of Cys723 in hERG kinetics and suggested that conventional drug screening by using step pulse protocol for I hERG,tail would overlook the hERG kinetic modulations that could compensate the decrease of I hERG,tail. PMID- 23440459 TI - A link between fertility and K+ homeostasis: role of the renal H,K-ATPase type 2. AB - Renal K(+) retention is activated during pregnancy through a mechanism unknown to date. Here, we showed that the renal stimulation of H,K-ATPase type 2 (HKA2), whose expression was recently identified to be progesterone-dependent, is part of the mechanism favoring K(+) accumulation during gestation. Moreover, investigation of the gestational phenotype of HKA2-null mice compared to their wild-type (WT) littermate revealed a decrease in fertility (gestation was successful in 33 % of HKA2-null mice vs. 83 % of WT mice) and in litter size (6.5 +/- 0.6 and 7.8 +/- 0.4 fetuses per litter, respectively). We also observed that urinary K(+) excretion decreased by 20 % and plasma K(+) concentration rose slightly (11 %) in WT mice during gestation (relative to basal conditions). In contrast, the renal excretion of K(+) and plasma K(+) levels in HKA2-null mice remained constant during gestation, whereas fecal K(+) excretion increased. As a consequence, HKA2-null mice did not accumulate K(+) in their extracellular compartment as efficiently as WT mice did. Finally, the link between inefficient K(+) balance adaptations and gestational complications was established when we observed that these complications could be reversed with an increased K(+) uptake. Altogether, these results define a novel physiological role for the HKA2 transporter and uncover a link between K(+) metabolism and fertility. PMID- 23440460 TI - Validation study of 131I-RRL: assessment of biodistribution, SPECT imaging and radiation dosimetry in mice. AB - Tumor angiogenesis is important in the growth and metastasis of malignant tumors. In our previous study, we demonstrated that an arginine-arginine-leucine (RRL) peptide is a tumor endothelial cell-specific binding sequence that may be used as a molecular probe for the imaging of malignant tumors in vivo. The aim of the present study was to further explore the characteristics of 131I-RRL by biodistribution tests, and to estimate the radiation dosimetry of 131I-RRL for humans using mice data. The RRL peptide was radiolabeled with 131I by a chloramine-T (CH-T) method. The radiolabeling efficiency and radiochemical purity were then characterized in vitro. 131I-RRL was injected intravenously into B16 xenograft-bearing Kunming mice. Biodistribution analysis and in vivo imaging were performed periodically. The radiation dosimetry in humans was calculated according to the organ distribution and the standard medical internal radiation dose (MIRD) method in mice. All data were analyzed by statistical and MIRDOSE 3.1 software. The labeling efficiency of 131I-RRL reached 70.0+/-2.91% (n=5), and the radiochemical purity exceeded 95% following purification. In mice bearing B16 xenografts, 131I-RRL rapidly cleared from the blood and predominantly accumulated in the kidneys, the stomach and the tumor tissue. The specific uptake of 131I-RRL in the tumor increased over time and was significantly higher than that of the other organs, 24-72 h following injection (P<0.05). The ratio of tumor-to skeletal muscle (T/SM) tissue exceeded 4.75, and the ratio of the tumor-to-blood (T/B) tissue peaked at 3.36. In the single-photon emission computed tomography (SPECT) imaging of Kunming mice bearing B16 xenografts, the tumors were clearly identifiable at 6 h, and significant uptake was evident 24-72 h following administration of 131I-RRL. The effective dose for the adult male dosimetric model was estimated to be 0.0293 mSv/MBq. Higher absorbed doses were estimated for the stomach (0.102 mGy/MBq), the small intestines (0.0699 mGy/MBq), the kidneys (0.0611 mGy/MBq) and the liver (0.055 mGy/MBq). These results highlight the potential of 131I-RRL as a ligand for the SPECT imaging of tumors. Administration of 131I-RRL led to a reasonable radiation dose burden and was safe for human use. PMID- 23440461 TI - The effect of raising and lowering tryptophan levels on human mood and social behaviour. AB - Acute tryptophan depletion (ATD) studies indicate that low serotonin can lower mood and also increase aggression, although results vary somewhat between studies with similar participants. Lowering of mood after ATD is related to the susceptibility of the study participants to clinical depression, and some participants show no effect on mood. This indicates that low serotonin can contribute to lowered mood, but cannot-by itself-cause lowered mood, unless other unknown systems interact with serotonin to lower mood. Studies using tryptophan supplementation demonstrate that increased serotonin can decrease quarrelsomeness and increase agreeableness in everyday life. Social interactions that are more agreeable and less quarrelsome are associated with better mood. Thus, serotonin may have direct effects on mood, but may also be able to influence mood through changes in social behaviour. The increased agreeableness and decreased quarrelsomeness resulting from increases in serotonin will help foster congenial relations with others and should help to increase social support. As social support and social isolation have an important relationship with both physical and mental health, more research is needed on the implications of the ability of serotonin to modulate social behaviour for the regulation of mood, and for future physical and mental health. PMID- 23440462 TI - Imaging the serotonin 1A receptor using [11C]WAY100635 in healthy controls and major depression. AB - As a neurotransmitter, serotonin (5-HT) is widely used throughout the brain and known to play a role in many processes including emotion and brain development. Of the 15 subtypes of 5-HT receptors, the 1A receptor (5-HT(1A)) has been implicated in depression and suicide. Using the [carbonyl-(11)C]WAY100635 ([(11)C]WAY) ligand and positron emission tomography, we have studied the 5 HT(1A) receptor, first in a group of healthy controls, then in two separate groups of subjects with major depressive disorder (MDD) (antidepressant exposed and not recently medicated), and, lastly, in a group of subjects remitted from MDD. All MDD subjects were medication-free at the time of scan. We found higher 5 HT(1A) binding potential (BP(F)) in MDD subjects not recently exposed to an antidepressant compared with controls and recently medicated MDD subjects; and higher BP(F) in subjects with the C(-1019)G promoter polymorphism. We replicated these findings in a novel cohort and reconciled our discrepant findings with other groups using alternate quantification techniques. We also reported higher BP(F) in subjects remitted from a major depressive episode than in controls. From this work, we proposed a temporal model in which 5-HT(1A) BP(F) may be a trait abnormality of MDD. To further explore the genetic components of MDD and utility of 5-HT(1A) imaging as a potential tool for biomarker or treatment response prediction, these findings should be replicated in a larger cohort using the [(11)C]CUMI-101 agonist tracer. PMID- 23440463 TI - Using the high-risk family design to identify biomarkers for major depression. AB - The familial nature of major depressive disorder (MDD) is now well recognized. We followed children and grandchildren of probands with and without MDD to examine transmission of depression over generations, and to identify early vulnerability markers prior to the onset of disease. The study now includes three generations and five completed assessment waves spanning 25 years, with a sixth wave underway. Beginning with the fourth wave, we collected measures of brain structure (magnetic resonance imaging, MRI) and physiology (electroencephalography, EEG) and DNA in order to examine at a biological level why the offspring of depressed parents were at higher risk. In this paper, we provide an overview of the study design, the main findings, including new data, and the role of the high-risk design in translational research. We demonstrate that offspring of depressed parents ('high-risk'), when compared with those of non-depressed parents ('low-risk'), were at increased risk for depressive and anxiety disorders, with anxiety appearing earlier and being a predisposing factor for MDD. Offspring with two generations previously affected were at greatest risk. Thinning of the cortical mantle (MRI) and reduced resting-state activity (EEG) within the right parieto-temporal hemisphere differentiated high- from low risk offspring, regardless of whether the offspring had MDD, suggesting that these measures might serve as familial trait markers for depression and related syndromes. The high- and low-risk offspring also differed by serotonin transporter promoter length polymorphism genotypes, even though the same genotypes were not associated with the presence of MDD. The high-risk epidemiological design appears to be a particularly valuable asset in translational research as it allows targeting of biological processes that emerge prior to the onset of disease, and identifies individuals at high risk for the disorder who may carry the trait or marker but not yet be affected. PMID- 23440464 TI - Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans. AB - A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms mediating these effects are not fully understood. Recent studies have evaluated molecular mechanisms mediating the effects of serotonin signalling on corticolimbic circuit function using a multi-modal neuroimaging strategy incorporating positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging. This multi-modal neuroimaging strategy can be integrated with additional techniques including imaging genetics and pharmacological challenge paradigms to more clearly understand how serotonin signalling modulates neural pathways underlying sensitivity to threat. Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment strategies. PMID- 23440465 TI - Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress-diathesis model of depression. AB - The functioning of the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic (5-HT) system are known to be intertwined with mood. Alterations in these systems are often associated with depression. However, neither are sufficient to cause depression in and of themselves. It is now becoming increasingly clear that the environment plays a crucial role, particularly, the perinatal environment. In this review, we posit that early environmental stress triggers a series of epigenetic mechanisms that adapt the genome and programme the HPA axis and 5-HT system for survival in a harsh environment. We focus on DNA methylation as it is the most stable epigenetic mark. Given that DNA methylation patterns are in large part set within the perinatal period, long-term gene expression programming by DNA methylation is especially vulnerable to environmental insults during this period. We discuss specific examples of genes in the 5-HT system (serotonin transporter) and HPA axis (glucocorticoid receptor and arginine vasopressin enhancer) whose DNA methylation state is associated with early life experience and may potentially lead to depression vulnerability. We conclude with a discussion on the relevance of studying epigenetic mechanisms in peripheral tissue as a proxy for those occurring in the human brain and suggest avenues for future research. PMID- 23440466 TI - Genetics of impulsive behaviour. AB - Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon HTR2B stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery. PMID- 23440467 TI - 'It's the way that you look at it'--a cognitive neuropsychological account of SSRI action in depression. AB - The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant drugs. However, neither the way in which serotonin may alleviate depressed mood nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients. PMID- 23440469 TI - The neurobiology of depression--revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies. AB - The serotonin system originates from a small number of neurons (a few hundred thousand of the 100 billion in man) located in the midbrain raphe nuclei, that project widely throughout the central nervous system to influence a large array of inter-related biological functions, not least of which are circuits involved in mood and emotion. The serotonin hypothesis of depression has postulated that a reduction in serotonin leads to increased predisposition to depression. Indeed, it has become evident from therapeutic strategies that affect serotonin activity, that alterations in serotonin may not only predispose to depression, but also to aggressive behaviour, impulsivity, obsessive-compulsive behaviour and suicide. Many potential mechanisms known to alter the genes that regulate the serotonin system, including developmental epigenetic modifications, are presented, as additional evidence implicating the serotonin system. This second issue of two special issues of Philosophical Transactions B presents a series of reviews, perspectives and new findings that argue that the serotonin hypothesis remains an important idea that continues to guide research into the aetiology and treatment of depression. PMID- 23440470 TI - Serotonin and beyond: therapeutics for major depression. AB - The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent. PMID- 23440468 TI - Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity. AB - Individuals with obsessive-compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene * gene interactions, gene * environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders. PMID- 23440473 TI - Cotrimoxazole as a potential effect modifier of the association between vitamin D status and risk of opportunistic infection among HIV-infected Tanzanian adults. PMID- 23440474 TI - Reply to Seraphin. PMID- 23440471 TI - The serotonergic system in mood disorders and suicidal behaviour. AB - A stress-diathesis explanatory model of suicidal behaviour has proved to be of heuristic value, and both clinical and neurobiological components can be integrated into such a model. A trait deficiency in serotonin input to the anterior cingulate and ventromedial prefrontal cortex is found in association with suicide, and more recently non-fatal suicidal behaviour, and is linked to decision-making and suicide intent by imaging and related studies in vivo. The same neural circuitry and serotonin deficiency may contribute to impulsive aggressive traits that are part of the diathesis for suicidal behaviour and are associated with early onset mood disorders and greater risk for suicidal behaviour. Other brain areas manifest deficient serotonin input, that is, a trait related to recurrent major depressive disorder and bipolar disorder. Thus the serotonin system is involved in both the diathesis for suicidal behaviour in terms of decision-making, and to a major stressor, namely episodes of major depression. PMID- 23440475 TI - Perceptions of parents on how religion influences adolescents' sexual behaviours in two Ghanaian communities: implications for HIV and AIDS prevention. AB - To understand the role of religion in the sexual behaviours of adolescents, the views of parents who are key agents of socialization were examined from two south eastern communities in Ghana. Focus Group interviews were conducted with mothers (and female caregivers) of adolescents and one with fathers (and male caregivers) of adolescents. Thematic analysis was used to analyse the data. Findings indicated that parents from one community perceived religion as playing a double edged role in adolescents' sexual behaviours as on one hand it played a protective role by restraining adolescents from risky sexual behaviours; on the other hand it disparaged the existing traditional measures that regulated adolescents' sexual behaviour. However, parents from the other community found a collaborative interface between the existing social control measures-communal socialization and proscriptive morality with religious ethics. Religious socialization, social capital theory and the concept of social suffering are used to explain some of the findings of this study. Implications for HIV and AIDS education and prevention are also discussed. PMID- 23440476 TI - External dacryocystorhinostomy: Tips and tricks. AB - Dacryocystorhinostomy or DCR is one of the most common oculoplastics surgery performed. It is a bypass procedure that creates an anastomosis between the lacrimal sac and the nasal mucosa via a bony ostium. It may be performed through an external skin incision or intranasally with or without endoscopic visualization. This article will discuss the indications, goals, and simple techniques for a successful outcome of an external DCR. PMID- 23440477 TI - Investigating the European perspective of neonatal point-of-care echocardiography in the neonatal intensive care unit--a pilot study. AB - Point-of-care functional neonatal echocardiography (fnECHO) is increasingly used to assess haemodynamic status or patency of the ductus arteriosus (PDA). In Australasia, 90 % of neonatal intensive care units (NICUs) practice point-of-care fnECHO. The Australian Society of Ultrasound Medicine offers a training certificate for fnECHO. In Europe, the use and indications of fnECHO and the extent of point-of-care fnECHO training and accreditation are unknown. We aimed to assess utilisation and training of fnECHO in Europe. For this, we conducted an email survey of 45 randomly chosen tertiary NICUs in 17 European countries. The recall rate was 89 % (n = 40). Neonatologists with skills in fnECHO worked in 29 NICUs (74 %), but paediatric cardiologists would routinely perform most fnECHOs. Twenty-four-hour echocardiography service was available in 31 NICUs (78 %). Indications for fnECHO included assessment of haemodynamic volume status (53 %), presence or absence of pulmonary hypertension of the neonate (55 %), indication for and effect of volume replacement therapy (58 %), PDA assessment and monitoring of PDA treatment (80 %). Teaching of fnECHO was offered to trainees in 22 NICUs (55 %). Teaching of fnECHO was provided by paediatric cardiologists (55 %) or by neonatologists (45 %). Only six (15 %) national colleges accredited fnECHO teaching courses. CONCLUSION: fnECHO is widely practiced by neonatologists across Europe for a broad range of clinical questions. However, there is a lack of formal training and accreditation of fnECHO skills. This could be addressed by designing a dedicated European fnECHO training programme and by agreeing on a common European certificate of fnECHO. PMID- 23440479 TI - Management of ADHD in children across Europe: patient demographics, physician characteristics and treatment patterns. AB - This study was a retrospective chart review performed to examine and describe physician practice patterns in managing attention deficit/hyperactivity disorder (ADHD) across Europe. Physicians treating ADHD in the UK, France, Germany, Italy, the Netherlands and Spain were recruited. Each physician abstracted medical records of five patients (aged 6-17 years at time of review) with a documented diagnosis of ADHD made between January 2004 and June 2007. Data provided by the physician via the abstraction included (a) physician characteristics, (b) patient characteristics, (c) ADHD diagnosis and (d) ADHD outcomes (adherence, symptom control and satisfaction). A total of 779 patients met study inclusion criteria. In the overall population, patients' mean (SD) age at time of diagnosis was 8.9 (2.6) years. The predominant treatment choice was long-acting methylphenidate, which was prescribed to more than 56 % of patients. According to physicians, only 30.8 % of patients showed 'complete symptom control' on current treatment and only 31.8 % of physicians reported being 'very satisfied' with their patients' current treatment. Physicians' assessments of complete symptom control and physician satisfaction with treatment were low, indicating unmet needs with current ADHD management in Europe. PMID- 23440478 TI - Defining new guidelines for screening the 22q11.2 deletion based on a clinical and dysmorphologic evaluation of 194 individuals and review of the literature. AB - The 22q11.2 deletion is the most frequent interstitial deletion in humans and presents a wide phenotypic spectrum, with over 180 clinical manifestations described. Distinct studies have detected frequencies of the deletion ranging from 0 % to 75 %, depending on the studied population and selection criteria adopted. Due to the lack of consensus in this matter, several studies have been conducted aiming to define which patients would be eligible for screening; however, the issue is still up for debate. In order to contribute to the delineation of possible clinical and dysmorphologic guidelines to optimize decision making in the clinical setting, 194 individuals with variable features of the 22q11.2 deletion syndromes (22q11.2DS) were evaluated. Group I, clinical suspicion of 22q11.2DS with palatal anomalies; Group II, clinical suspicion without palatal anomalies; Group III, cardiac malformations associated with the 22q11.2DS; and Group IV, juvenile-onset schizophrenia. Multiplex ligation dependent probe amplification was used for screening the 22q11.2 deletion, which was detected in 45 patients (23.2 %), distributed as such: Group I, 35/101 (34.7 %); Group II, 4/18 (22.2 %); Group III, 6/52 (11.5 %); and Group IV, 0/23 (0 %). Clinical data were analyzed by frequency distribution and statistically. Based on the present results and on the review of the literature, we propose a set of guidelines for screening patients with distinct manifestations of the 22q11.2DS in order to maximize resources. In addition, we report the dysmorphic features which we found to be statistically correlated with the presence of the 22q11.2DS. PMID- 23440480 TI - The use of ethanol in paediatric formulations in New Zealand. AB - Children's right to access safe and effective medicines is recognised globally. Ethanol, used in paediatric liquid formulations as a solvent and preservative, is associated with safety concerns with respect to both acute ingestion and chronic exposure. In addition, families may have cultural or religious values making ethanol use inappropriate when alternatives are available. International guidelines aim to reduce, and if possible eliminate, the use of ethanol in paediatric medicines. Guidelines on labelling vary globally, limiting the ability of health professionals and patients to make informed decisions on appropriate medicines. This study aimed to explore the availability of ethanol-containing medicines for use in the paediatric population in New Zealand and to discuss findings alongside international guidelines. Forty-seven paediatric liquid medicines were identified containing ethanol. The ethanol concentration could be determined in 35 of these medicines and ranged from 0.6 % v/v to an alarming 76 % v/v ethanol. If recommended dosing instructions are followed, the ethanol consumed per dose is not expected to cause acute toxic effects. The medicines identified are indicated for both acute and chronic use, including digoxin (10.1 11.4 % v/v ethanol) which is used in patients of all ages, including preterm neonates. CONCLUSION: Stronger guidance should be provided to reduce the use of ethanol in paediatric medicines, in New Zealand and globally. If ethanol is used, full disclosure of its presence and concentration on the product label is essential to enable prescribers and patients to make informed decisions on the most suitable pharmaceutical formulations. PMID- 23440481 TI - Cardiorespiratory fitness predicts clustered cardiometabolic risk in 10-11.9-year olds. AB - The aim of this study was to investigate levels of clustered cardiometabolic risk and the odds of being 'at risk' according to cardiorespiratory fitness status in children. Data from 88 10-11.9-year-old children (mean age 11.05 +/- 0.51 years), who participated in either the REACH Year 6 or the Benefits of Fitness Circuits for Primary School Populations studies were combined. Waist circumference, systolic blood pressure, diastolic blood pressure, glucose, triglycerides, high density lipoprotein cholesterol, adiponectin and C-reactive protein were assessed and used to estimate clustered cardiometabolic risk. Participants were classified as 'fit' or 'unfit' using recently published definitions (46.6 and 41.9 mL/kg/min for boys and girls, respectively), and continuous clustered risk scores between fitness groups were assessed. Participants were subsequently assigned to a 'normal' or 'high' clustered cardiometabolic risk group based on risk scores, and logistic regression analysis assessed the odds of belonging to the increased cardiometabolic risk group according to fitness. The unfit group exhibited significantly higher clustered cardiometabolic risk scores (p < 0.001) than the fit group. A clear association between fitness group and being at increased cardiometabolic risk (B = 2.509, p = 0.001) was also identified, and participants classed as being unfit were found to have odds of being classified as 'at risk' of 12.30 (95 % CI = 2.64-57.33). Conclusion Assessing cardiorespiratory fitness is a valid method of identifying children most at risk of cardiometabolic pathologies. The ROC thresholds could be used to identify populations of children most at risk and may therefore be used to effectively target a cardiometabolic risk-reducing public health intervention. PMID- 23440482 TI - Treatment with linezolid in a neonate with meningitis caused by methicillin resistant Staphylococcus epidermidis. AB - Recent findings have focused on the possible role of linezolid (LZD) as a suitable candidate for the treatment of central nervous system infections. LZD treatment for meningitis has been sporadically reported in adults, but there are no reports in neonates or infants. We report a case of meningitis caused by methicillin-resistant Staphylococcus epidermidis (MRSE) in a neonatal girl. The patient had intraventricular hemorrhage on postnatal day 1 and was treated with ventricular drainage. Twenty-two days after drainage, the patient developed a fever and seizure. Although ampicillin and ceftriaxone were given empirically for meningitis, an increased cell count and protein were observed in cerebrospinal fluid (CSF). Vancomycin (VCM) was administered intravenously because MRSE was detected from CSF 2 days after the administration of ampicillin and ceftriaxone. However, intravenous administration of VCM did not show any effect. Subsequent treatment of LZD successfully reduced the cell count and protein in CSF. CONCLUSION: LZD may be a treatment option for neonates and infants for drain associated meningitis caused by MRSE. PMID- 23440484 TI - New invagination procedure for pancreaticojejunostomy using only four sutures: reply. PMID- 23440483 TI - Current treatment and outcome of esophageal perforations in adults: systematic review and meta-analysis of 75 studies. AB - BACKGROUND: The current prognosis of esophageal perforation and the efficacy of available treatment methods are not well defined. METHODS: We performed a systematic review of esophageal perforations published from January 2000 to April 2012 and subjected a proportion of the retrieved data to a meta-analysis. Meta regression was performed to determine predictors of mortality immediately after esophageal perforation. RESULTS: Analysis of 75 studies resulted in a pooled mortality of 11.9 % [95 % confidence interval (CI) 9.7-14.3: 75 studies with 2,971 patients] with a mean hospital stay of 32.9 days (95 % CI 16.9-48.9: 28 studies with 1,233 patients). Cervical perforations had a pooled mortality of 5.9 %, thoracic perforations 10.9 %, and intraabdominal perforations 13.2 %. Mortality after esophageal perforation secondary to foreign bodies was 2.1 %, iatrogenic perforation 13.2 %, and spontaneous perforation 14.8 %. Treatment started within 24 h after the event resulted in a mortality rate of 7.4 % compared with 20.3 % in patients treated later (risk ratio 2.279, 95 % CI 1.632 3.182). Primary repair was associated with a pooled mortality of 9.5 %, esophagectomy 13.8 %, T-tube or any other tube repair 20.0 %, and stent-grafting 7.3 %. CONCLUSIONS: Results of recent studies indicate that mortality after esophageal perforation is high despite any definitive surgical or conservative strategy. Stent-grafting is associated with somewhat lower mortality rates, but studies may be biased by patient selection and limited experience. PMID- 23440485 TI - Effect of preserving the hepatic vagal nerve during laparoscopic Nissen fundoplication on postoperative biliary functions. AB - BACKGROUND: Cutting the hepatic branch of the anterior vagus nerve (HB-AVn) technically facilitates the laparoscopic Nissen fundoplication. The aim of this study was to investigate the effects of preserving or sacrificing this branch on postoperative gallbladder functions. METHODS: The patients (n = 40) were prospectively randomized into two groups. The HB-AVn was preserved during the dissection of the lesser omentum in the first group. The nerve was cut in the second group. Postoperative fasting gallbladder volumes were calculated by ultrasonography. Postoperative gallbladder ejection fraction (GEF) and gallbladder emptying time (GET) were determined by calculating intestinal transit time scintigraphically. RESULTS: Fasting gallbladder volumes and GEF values were not different between the groups. On the other hand, in patients with HB-AVn preserved, GET measurements were found to be significantly shorter than those with HB-AVn sacrificed. CONCLUSIONS: Sacrificing the hepatic branch causes prolongation in the GET. This change in the motor functions of the gallbladder does not cause any symptomatic effect during the early postoperative period. However, the delay in the GET may increase the risk of gallbladder stone formation in the long term. PMID- 23440486 TI - No surgery for full-thickness rectal prolapse: what happens with continence? AB - BACKGROUND: Surgery is the only validated means of treating overt rectal prolapses, but both patients and physicians may decline or postpone the surgical approach. However, little is known on the functional outcome of nonoperated rectal prolapse. The aim of the present study was to highlight the natural history of overt rectal prolapse in patients for whom surgery was avoided or delayed. PATIENTS AND METHODS: A total of 206 patients complaining of full thickness rectal prolapse were referred to a single institution that provided anorectal physiology for functional anorectal disorders. Standardized questionnaires, anorectal manometry, endosonography, and evacuation proctography constituted a prospective database. Fecal incontinence was evaluated with the Cleveland Clinic score (CCIS), and constipation was evaluated with the Knowles Eccersley Scott Symptom score (KESS). RESULTS: Forty-two nonoperated patients (mean age: 61 +/- 16 years) were compared to those of operated patients paired according to age and gender: the mean follow-up was 44 +/- 26 months. The two groups had a similar past-history, follow-up, stool frequency, and main complaints, but lower quantified symptomatic scores and a better quality of life were reported in the nonsurgical group. At the end of follow-up, the nonsurgical group did not show any variation in CCI and KESS scores. By contrast, these two scores significantly improved in the rectopexy group. Sixteen nonoperated patients experienced a degradation of their continence status with an average increase of 5 +/- 4.3 points of the CCIS. The patients with a CCIS <7 at referral were likely to deteriorate as compared to those having a higher score. Patients with a symptom history longer than 4 years never improved and in two-thirds continence deteriorated throughout the follow-up. CONCLUSION: In the absence of the surgical option, patients with a 4-year duration of rectal prolapse and those with mild incontinence had no chance of improvement. These findings may be taken into account when surgery of rectal prolapse is not chosen. PMID- 23440487 TI - Prevalence of hypertension among urban slum dwellers in Lagos, Nigeria. AB - Urban slum dwellers are not only prone to develop communicable diseases but also to non-communicable disease (NCDs). The extent and magnitude of NCDs among slum dwellers is largely unknown in Nigeria. A total of 964 adults aged 20-81 years (male 330 and female 634) residing in the urban slum of Ajegunle in Lagos State, Nigeria were studied to determine the prevalence of hypertension and associated factors. The overall prevalence of hypertension was 38.2 %. Of the 368 respondents identified as having hypertension, only 50 (5.2 %) respondents were previously aware of their diagnosis. Of the 50 known hypertensive patients, 48(96 %) had poor control of their high blood pressure. The socio-demographic factors significantly associated with hypertension status were age, sex, education, religion, BMI, and marital status. The study concludes a high prevalence of hypertension among urban slums dwellers in Lagos. The need for government to develop policies for the control of hypertension, improve access to early diagnosis and provide an enabling socioeconomic environment while promoting healthy living. PMID- 23440488 TI - Interrupting violence: how the CeaseFire Program prevents imminent gun violence through conflict mediation. AB - Cities are increasingly adopting CeaseFire, an evidence-based public health program that uses specialized outreach workers, called violence interrupters (VIs), to mediate potentially violent conflicts before they lead to a shooting. Prior research has linked conflict mediation with program-related reductions in homicides, but the specific conflict mediation practices used by effective programs to prevent imminent gun violence have not been identified. We conducted case studies of CeaseFire programs in two inner cities using qualitative data from focus groups with 24 VIs and interviews with eight program managers. Study sites were purposively sampled to represent programs with more than 1 year of implementation and evidence of program effectiveness. Staff with more than 6 months of job experience were recruited for participation. Successful mediation efforts were built on trust and respect between VIs and the community, especially high-risk individuals. In conflict mediation, immediate priorities included separating the potential shooter from the intended victim and from peers who may encourage violence, followed by persuading the parties to resolve the conflict peacefully. Tactics for brokering peace included arranging the return of stolen property and emphasizing negative consequences of violence such as jail, death, or increased police attention. Utilizing these approaches, VIs are capable of preventing gun violence and interrupting cycles of retaliation. PMID- 23440489 TI - Symptoms associated with pregnancy complications along the Thai-Burma border: the role of conflict violence and intimate partner violence. AB - To assess the association between lifetime violence victimization and self reported symptoms associated with pregnancy complications among women living in refugee camps along the Thai-Burma border. Cross-sectional survey of partnered women aged 15-49 years living in three refugee camps who reported a pregnancy that resulted in a live birth within the past 2 years with complete data (n = 337). Variables included the lifetime prevalence of any violence victimization, conflict victimization, intimate partner violence (IPV) victimization, self reported symptoms of pregnancy complications, and demographic covariates. Logistic generalized estimating equations, accounting for camp-level clustering, were used to assess the relationships of interest. Approximately one in six women (16.0 %) reported symptoms related to pregnancy complications for their most recent birth within the last 2 years and 15 % experienced violence victimization. In multivariable analyses, any form of lifetime violence victimization was associated with 3.1 times heightened odds of reporting symptoms (95 % CI 1.8 5.2). In the final adjusted model, conflict victimization was associated with a 3.0 increase in odds of symptoms (95 % CI 2.4-3.7). However, lifetime IPV victimization was not associated with symptoms, after accounting for conflict victimization (aOR: 1.8; 95 % CI 0.4-9.0). Conflict victimization was strongly linked with heightened risk of self-reported symptoms associated with pregnancy complications among women in refugee camps along the Thai-Burma border. Future research and programs should consider the long-term impacts of conflict victimization in relation to maternal health to better meet the needs of refugee women. PMID- 23440490 TI - A Multiple Indicators Multiple Cause (MIMIC) model of respiratory health and household factors in Chinese children: the seven Northeastern cities (SNEC) study. AB - In China, with the rapid economic development and improvement of living standards over the past few decades, the household living environment has shifted dramatically. The aim of the present study is to assess the impact of home environment factors on respiratory symptoms and asthma in Chinese children. Investigators analyzed data collected in the 25 districts from the seven Northeastern cities to examine health effects on respiratory symptoms and asthma in 31,049 children aged 2-14 years. Factor analysis was used to reduce 33 children's lifestyle and household variables to six new 'factor' variables. The multiple indicators multiple causes approach was used to examine the relationship between indoor air pollution and respiratory health status, controlling for covariates. Factor analyses generated six factor variables of potential household risk factors from an original list of 33 variables. The respiratory symptoms and asthma were significantly associated with the recent home renovation factor (estimate = 0.076, p < 0.001), pet ownership factor (estimate = 0.095, p < 0.001), environmental tobacco smoke (ETS) exposure factor (estimate = 0.181, p < 0.001) and PVC-flooring factor (estimate = 0.031, p = 0.007). Home ventilation factor was not related to any respiratory condition (estimate = 0.028, p = 0.074). Independent respiratory health effects existed for multiple household environmental factors recent home renovation, pet ownership, ETS, and PVC flooring. PMID- 23440491 TI - Nutritional factors associated with antenatal depressive symptoms in the early stage of pregnancy among urban South Indian women. AB - Many women of reproductive age from developing countries have poor nutritional status, and the prevalence of depression during pregnancy is high. The objective of the present study was to assess the prevalence of antenatal depressive symptoms in early pregnancy, and to identify the demographic and nutritional factors associated with these symptoms in a sample of urban South Indian pregnant women. This cross-sectional study was the baseline assessment of a prospective randomized controlled trial of vitamin B12 supplementation in urban pregnant south Indian women between the ages of 18 and 40 years ( www.clinicaltrials.gov : NCT00641862). 365 women in their first trimester of pregnancy were screened for depressive symptoms at an urban clinic in Karnataka, South India, using the Kessler Psychological Distress Scale (K-10). Nutritional, clinical and biochemical factors were also assessed. Mean (SD) age of the cohort was 22.6 (3.7) years and mean (SD) BMI was 20.4 (3.3) kg/m(2). 121 (33 %) of the women in the 1st trimester had symptoms consistent with depression (K-10 score >6). In multivariate log binomial regression analysis, presence of antenatal depressive symptoms in the first trimester were positively associated with vomiting, prevalence ratio (PR) = 1.54 (95 % CI 1.10, 2.16) and negatively with anemia, PR = 0.67 (95 % CI 0.47, 0.96). Nutrient intakes, serum vitamin B12, methylmalonic acid, homocysteine and red cell folate levels were not associated with measures of depression. Antenatal depressive symptoms in early pregnancy are highly prevalent in urban Indian women and are more common in women with vomiting and without anemia. In this cross-sectional data, blood concentrations of vitamin B12 and folate were not associated with depressive symptoms. The relationship between nutritional status and depressive symptoms may require larger and longitudinal studies. PMID- 23440493 TI - A missing arch of the atlas vertebra in a patient struck by a tram. PMID- 23440492 TI - Anti-tumour activity of phosphoinositide-3-kinase antagonist AEZS 126 in models of triple-negative breast cancer. AB - PURPOSE: Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies. METHODS: Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots. RESULTS: AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line. CONCLUSION: We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC. PMID- 23440495 TI - Description and variability of temporal venous vascularization: clinical relevance in temporoparietal free flap technique. AB - The few studies on the venous vascularization of the temporal area indicate a high variability among individuals. The preoperative knowledge of the venous vascularization of the temporal area is critical for microsurgical reconstruction, such as temporoparietal fascia free flap, and especially in understanding the anatomy of the veins for flap survival. Therefore, we conducted an anatomic study to confirm the classification of Legre et al. and a radiologic study to examine the venous network of the temporal area. We found three frequent patterns of the temporal venous network: (1) Type I (the most common), with a predominant temporal vein; (2) Type II, with a predominant posterior auricular vein; (3) Type III, when both veins were equally important. Because of this great variability, the use of a temporal flap for reconstruction of the head and neck should be restricted, and the examination of venous vascularization appears to be necessary before surgery. Here, we report a three-dimensional description of the venous temporal vascularization by computer tomography, which is particularly useful before temporoparietal flaps. PMID- 23440497 TI - Variations of the radial recurrent artery of clinical interest. AB - PURPOSE: The anatomy of the radial recurrent artery (RRA) is important for different clinical procedures: interventional cardiology and microsurgery of the forearm; however, few studies have analysed its morphology: number, course, relations and distribution. METHODS: The RRA was analysed in 332 upper limbs divided into two groups: (1) normal pattern of the arterial axis of the upper limb (266 cases), (2) associated with major arterial variations (66 cases). RESULTS: A second or accessory RRA existed in 31.2 % in group 1, and 30.3 % in group 2. In both groups, the second RRA originated from the brachial (100 %) and always (100 %) coursed behind the bicipital tendon. The accessory RRA supplied the brachioradialis, brachialis and biceps brachii muscles. The RRA in group 1, originated mostly from the radial artery (75 %), followed by radioulnar division and ulno-interosseous trunk. In group 2, the RRA arise from the brachioradial artery (65 %), or from the radial artery (in cases of ulnar or brachial artery variation). The course of the RRA behind the biceps brachii tendon was observed in 9.4 % of group 1 and in 6.1 % of group 2. The RRA supplied the brachioradialis, extensor carpi radialis longus and brevis, and supinator muscles. The RRA and accessory RRA anastomosed forming a ring around the biceps brachii tendon in 0.75 % in group 1 and in 13.6 % in group 2, the latter group having an important clinical interest. CONCLUSIONS: The variability of the RRA may provide an advantage for microsurgical procedures of the elbow and disadvantage during transradial catheterism. PMID- 23440494 TI - RNA interference-mediated FANCF silencing sensitizes OVCAR3 ovarian cancer cells to adriamycin through increased adriamycin-induced apoptosis dependent on JNK activation. AB - In the present study, we downregulated FANCF expression by small interfering RNA (siRNA) in OVCAR ovarian cancer cells to address the effects of decreased FANCF expression on the function of the Fanconi anemia (FA)/breast cancer susceptibility gene (BRCA) pathway. Furthermore, we investigated whether this method increases the sensitivity of OVCAR3 cells to adriamycin (ADM) and the possible mechanism(s). We found that silencing of FANCF inactivated the FA/BRCA pathway by decreasing the monoubiquitination and focus formation of FANCD2 and reduced the function of the FA/BRCA pathway, resulting in the inhibition of cell proliferation, increased cell apoptosis and DNA damage in OVCAR3 cells. Moreover, we observed that silencing of FANCF enhanced the antiproliferative effect of ADM in OVCAR3 cells and increased ADM intracellular accumulation consequently sensitizing OVCAR3 cells to ADM. Furthermore, silencing of FANCF increased cell apoptosis of OVCAR3 cells which was caused by decreased mitochondrial membrane potential (MMP)-induced DNA damage, activated Jun N-terminal kinase (JNK), increased release of cytochrome c, increased expression of cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP) dependent on JNK activation following treatment of ADM. Collectively, we confirm that silencing of FANCF sensitizes OVCAR3 ovarian cancer cells to ADM, suggesting that FANCF may serve as a potential target for therapeutic strategies in the treatment of ovarian cancer. PMID- 23440496 TI - Three-dimensional templating arthroplasty of the humeral head. AB - BACKGROUND: No anatomical study has been conducted over Asian population to design humeral head prosthesis for the population concerned. This study was done to evaluate the accuracy of commercially available humeral head prosthetic designs, in replicating the humeral head anatomy. METHODS: CT scan data of 48 patients were taken and their 3D CAD models were generated. Then, humeral head prosthetic design of a BF shoulder system produced by a standardized, commercially available company (Zimmer) was used for templating shoulder arthroplasty and the humeral head size having the perfect fit was assessed. These data were compared with the available data in the literature. RESULTS: All the humeral heads were perfectly matched by one of the sizes available. The average head size was 48.5 mm and the average head thickness was 23.5 mm. The results matched reasonably well with the available data in the literature. CONCLUSIONS: The humeral head anatomy can be recreated reasonably well by the commercially available humeral head prosthetic designs and sizes. Their dimensions are similar to that of the published literature. PMID- 23440498 TI - Beta response of LiMgPO4:Tb,B based OSL discs for personnel monitoring applications. AB - Properties such as high optically stimulated luminescent (OSL) sensitivity, ease of preparation and dose linearity over nine decades (uGy-kGy) make LiMgPO4:Tb, B (LMP) a unique phosphor for dosimetry applications. This led to the investigation of the beta response of highly sensitive LMP-based Teflon-embedded OSL discs for personnel monitoring applications. A PTB beta secondary standard calibration setup (BSS2), which contains three beta sources viz. (147)Pm, (85)Kr and (90)Sr/(90)Y, was used. The relative response with respect to (137)Cs photons for 0.4-mm thick LMP discs was found to be ~7.32, ~53.5 and 100 % for (147)Pm, (85)Kr and (90)Sr/(90)Y beta energies, respectively. The response of LMP discs under various filter combinations viz. 0.18-mm thick mylar (25 mg cm(-2)), 0.625-mm thick Poly-allyl-diglycol carbonate (PADC, 81 mg cm(-2)), 1-mm thick polythene (95 mg cm(-2)), 1-mm thick Perspex (118 mg cm(-2)), 1.25-mm thick PADC (162 mg cm(-2)) and 1.6-mm thick (189 mg cm(-2)) Perspex filters was also studied and the ratio of the response of open disc to the response under filters (DOpen/DFilter) of different thicknesses (mg cm(-2)) was evaluated. Studies were also performed for the mixed field of low- ((85)Kr) and high-energy ((90)Sr/(90)Y) beta particles and the DOpen/DFilter ratio was evaluated. The angular dependence of the response of OSL discs to (85)Kr and (90)Sr/(90)Y beta sources was also studied. Studies were also carried out for (204)Tl, (32)P, natural uranium and (106)Ru/(106)Rh beta sources and the ratios of the response of open disc to that of under 1.6-mm thick Perspex (DOpen/DFilter) filter were measured. A study with various beta sources for the evaluation of the DOpen/DFilter ratio was necessary as these ratios are used to estimate the energy of beta particles and to apply the correction factor while evaluating the beta dose/design of dose estimation algorithms. PMID- 23440499 TI - Response of pMOS dosemeters on gamma-ray irradiation during its re-use. AB - Response of pMOS dosemeters during two successive irradiations with gamma-ray irradiation to a dose of 35 Gy and annealing at room and elevated temperature has been studied. The response was followed on the basis of threshold voltage shift, determined from transfer characteristics, as a function of absorbed dose or annealing time. It was shown that the threshold voltage shifts during first and second irradiation for the gate bias during irradiation of 5 and 2.5 V insignificantly differ although complete fading was not achieved after the first cycle of annealing. In order to analyse the defects formed in oxide and at the interface during irradiation and annealing, which are responsible for threshold voltage shift, midgap and charge-pumping techniques were used. It was shown that during first irradiation and annealing a dominant influence to threshold voltage shift is made by fixed oxide traps, while at the beginning of the second annealing cycle, threshold voltage shift is a consequence of both fixed oxide traps and slow switching traps. PMID- 23440500 TI - IL-12Rbeta2 is critical for survival of primary Francisella tularensis LVS infection. AB - Using a panel of vaccines that provided different degrees of protection, we previously identified the IL-12 receptor subunit beta2 as a mediator, whose relative expression correlated with strength of protection against secondary lethal challenge of vaccinated mice with an intracellular bacterium, the LVS of Francisella tularensis. The present study therefore tested the hypothesis that IL 12Rbeta2 is an important mediator in resistance to LVS by directly examining its role during infections. IL-12Rbeta2 KO mice were highly susceptible to LVS primary infection, administered i.d. or i.n. The LD50 of LVS infection of KO mice were 2 logs lower than those of WT mice, regardless of route. Five days after infection with LVS, bacterial organ burdens were significantly higher in IL 12Rbeta2 KO mice. IL-12Rbeta2 KO mice infected with lethal doses of LVS had more severe liver pathology, including significant increases in the liver enzymes ALT and AST. Despite decreased levels of IFN-gamma, LVS-vaccinated IL-12Rbeta2 KO mice survived large lethal LVS secondary challenge. Consistent with in vivo protection, in vitro intramacrophage LVS growth was well-controlled in cocultures containing WT or IL-12Rbeta2 KO LVS-immune splenocytes. Thus, survival of secondary LVS challenge was not strictly dependent on IL-12Rbeta2. However, IL 12Rbeta2 is important in parenteral and mucosal host resistance to primary LVS infection and in the ability of WT mice to clear LVS infection and serves to restrict liver damage. PMID- 23440501 TI - Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans. AB - Aged individuals have increased morbidity and mortality following influenza and other viral infections, despite previous exposure or vaccination. Mouse and human studies suggest increased senescence and/or exhaustion of influenza virus specific CD8 T cells with advanced age. However, neither the relationship between senescence and exhaustion nor the underlying transcriptional pathways leading to decreased function of influenza virus-specific cellular immunity in elderly humans are well-defined. Here, we demonstrate that increased percentages of CD8 T cells from aged individuals express CD57 and KLRG1, along with PD-1 and other inhibitory receptors, markers of senescence, or exhaustion, respectively. Expression of T-box transcription factors, T-bet and Eomes, were also increased in CD8 T cells from aged subjects and correlated closely with expression of CD57 and KLRG1. Influenza virus-specific CD8 T cells from aged individuals exhibited decreased functionality with corresponding increases in CD57, KLRG1, and T-bet, a molecular regulator of terminal differentiation. However, in contrast to total CD8 T cells, influenza virus-specific CD8 T cells had altered expression of inhibitory receptors, including lower PD-1, in aged compared with young subjects. Thus, our data suggest a prominent role for senescence and/or terminal differentiation for influenza virus-specific CD8 T cells in elderly subjects. PMID- 23440502 TI - Caregiver Substance Abuse and Children's Exposure to Violence in a Nationally Representative Child Welfare Sample. AB - Using data from the National Survey of Child and Adolescent Well-Being II (NSCAW II), this article examines the impact of caregiver substance abuse on children's exposure to violence in the home in a nationally representative sample of families involved with child protective services (CPS). Logistic regression analyses indicate an increased risk of witnessing mild and severe violence in the home for children whose primary caregiver was abusing alcohol or drugs. However, analyses did not find statistically significant relationships between child report of direct victimization in the home by mild or severe violence and caregiver alcohol or drug abuse. PMID- 23440503 TI - Pre-protective effect of lipoic acid on injury induced by H2O2 in IPEC-J2 cells. AB - Alpha-lipoic acid (LA) is considered to be a universal antioxidant. The intestine is very sensitive to a wide range of stressors for it exposed in a complex microenvironment that usually contained excess free radicals. The objective of this study was to evaluate the pre-protective effect of LA on intestinal epithelial cell injury induced by H2O2. In this research, IPEC-J2 cells were divided into three groups: the control group, the H2O2-treated group, and the LA pre-protective group. Cell viability, intracellular ROS, DNA damage integrity, and antioxidant enzyme activity of all groups were measured. Quantitative reverse transcription-PCR was used to determine the influence of oxidative stress and LA on the GH/IGF-1 axis in IPEC-J2 cells. The research selected 1 mM H2O2 and 10 MUg/ml as modeling concentration. The data indicated that H2O2 can significantly increase the intracellular free radicals, leading to serious DNA damage and significantly reduce superoxide dismutase, glutathione peroxidase, catalase, and lipase activity. LA-protected IPEC-J2 cells against H2O2-induced injury by scavenging hydroxyl radical. In the current study, LA pre-protective group share a lower intracellular ROS and lower DNA damage compare to H2O2-treated group (P < 0.01); and also, a higher lipase activity were detected in LA pre-protective group compare to H2O2-treated group (P < 0.05). But the mechanism between oxidative stress, LA effect, and GH/IGF-1 axis is still unknown. The model used in the current study is also suitable for other feed additive screening. PMID- 23440504 TI - Life form and water source interact to determine active time and environment in cryptogams: an example from the maritime Antarctic. AB - Antarctica, with its almost pristine conditions and relatively simple vegetation, offers excellent opportunities to investigate the influence of environmental factors on species performance, such information being crucial if the effects of possible climate change are to be understood. Antarctic vegetation is mainly cryptogamic. Cryptogams are poikilohydric and are only metabolically and photosynthetically active when hydrated. Activity patterns of the main life forms present, bryophytes (10 species, ecto- and endohydric), lichens (5 species) and phanerogams (2 species), were monitored for 21 days using chlorophyll a fluorescence as an indicator of metabolic activity and, therefore, of water regime at a mesic (hydration by meltwater) and a xeric (hydration by precipitation) site on Leonie Island/West Antarctic Peninsula (67 degrees 36'S). Length of activity depended mainly on site and form of hydration. Plants at the mesic site that were hydrated by meltwater were active for long periods, up to 100 % of the measurement period, whilst activity was much shorter at the xeric site where hydration was entirely by precipitation. There were also differences due to life form, with phanerogams and mesic bryophytes being most active and lichens generally much less so. The length of the active period for lichens was longer than in continental Antarctica but shorter than in the more northern Antarctic Peninsula. Light intensity when hydrated was positively related to the length of the active period. High activity species were strongly coupled to the incident light whilst low activity species were active under lower light levels and essentially uncoupled from incident light. Temperatures were little different between sites and also almost identical to temperatures, when active, for lichens in continental and peninsular Antarctica. Gradients in vegetation cover and growth rates across Antarctica are, therefore, not likely to be due to differences in temperature but more likely to the length of the hydrated (active) period. The strong effect on activity of the mode of hydration and the life form, plus the uncoupling from incident light for less active species, all make modelling of vegetation change with climate a more difficult exercise. PMID- 23440505 TI - Acquisition of species-specific perfume blends: influence of habitat-dependent compound availability on odour choices of male orchid bees (Euglossa spp.). AB - Male orchid bees (Euglossini, Apidae, Hymenoptera) expose species-specific blends of volatile chemicals (perfume bouquets) during their courtship display. The perfumes are acquired by collecting fragrant substances from environmental sources, which are then accumulated in specialised hind leg pouches. To balance the perfume composition, the males need to find and collect the required substances in specific relative amounts while facing seasonal, local or habitat dependent differences in compound availability. Experience-dependent choice of odours, i.e. 'learned avoidance' of recently collected components, has been proposed as the mechanism that mediates the accumulation of the stereotypical compound ratios. In the present study, we used the presence of certain compounds in male hind leg pouches as proxy for the respective local compound availability, and investigated whether differences in content are correlated with differences in chemical choice assays. Our results suggest that volatile availability differs between localities (n = 16) as well as habitats (n = 2; coastal vs. inland) across the Yucatan peninsula, Mexico, for both studied species. Male Euglossa dilemma showed a pronounced preference for benzyl benzoate and eugenol at locations where those compounds were rare in hind leg extracts, as predicted by the learned avoidance model. No equivalent correlations were found for Euglossa viridissima. This is the first study to combine chemical analyses of perfumes with bioassays of odour choice. It strengthens the view that negative feedback from collected odours modifies future chemical choice and helps males to acquire specific perfume blends. PMID- 23440506 TI - Urine post equivalent daily cranberry juice consumption may opsonize uropathogenicity of Escherichia coli. AB - Basic studies have proven that cranberries may prevent urinary tract infections through changing the adhesiveness of Escherichia coli (E. coli) to urothelial cells. Various cranberry preparations, including extract powder, capsules, and juice, have been shown to be effective in clinical and epidemiological research. Because cranberries are most commonly consumed as juice in a diluted concentration, the aim of this study was to investigate whether the equivalent daily dose of cranberry juice is sufficient to modify host urine to change the uropathogenicity of E. coli. Urine from rats taking an equivalent daily dose of cranberry juice has been shown to decrease the capability of E. coli in hemagglutination, urothelium adhesion, nematode killing, and biofilm formation. All these changes occurred after E. coli was incubated in cranberry metabolite containing urine, defined as urine opsonization. Urine opsonization of E. coli resulted in 40.9% (p = 0.0038) decrease in hemagglutination ability, 66.7% (p = 0.0181) decrease in urothelium adhesiveness, 16.7% (p = 0.0004) increase in the 50% lethal time in killing nematodes, and 53.9% (p = 5.9 * 10(-4)) decrease in biofilm formation. Thus, an equivalent daily dose of cranberry juice should be considered sufficiently potent to demonstrate urine opsonization in E. coli. PMID- 23440507 TI - Analysis of genomic aberrations associated with the clinicopathological parameters of rectal cancer by array-based comparative genomic hybridization. AB - The aim of the present study was to screen and identify the chromosomal aberrations that are correlated with clinicopathological characteristics of rectal cancer using array-based comparative genomic hybridization (array-CGH). Forty-eight fresh frozen tumor tissues of rectal carcinoma were analyzed by array CGH. The results showed that most frequent gains included 8q24.3, 20q11.21 q13.32, 20q13.33 and losses in 8p23.3-p12, 17p13.1-p12 and 18q11.2-q23 were noted. Fourteen amplifications and seven homozygous deletions were identified in the rectal cancer samples. Losses of 4p16.1-p15.31, 8p21.1-p12 and gains of 7p12.3-p12.1 and 13q33.1-q34 were associated with positive lymph node status and advanced clinical stage (stages III and IV). The 17q24.2-25.3 gain was more frequent in patients with distant metastasis. Integrated analysis indicated that overexpression of PDP1, TRIB1, C13orf27, FOXA2, PMEPA1 and PHACTR3 was associated with gains, and underexpression of FHOD, SMAD4 and BCL2 was associated with losses. Pathway enrichment analysis showed that pathways of nitrogen metabolism, oxidative phosphorylation, cell cycle, maturity onset diabetes of young, cytokine cytokine receptor interaction, MAPK signaling pathway and dentatorubropallidoluysian atrophy were influenced by copy number changes. PMID- 23440508 TI - Mathematical model for positioning the FtsZ contractile ring in Escherichia coli. AB - During bacterial cytokinesis, a proteinaceous contractile ring assembles in the cell middle. The Z ring tethers to the membrane and contracts, when triggered, to form two identical daughter cells. One mechanism for positioning the ring involves the MinC, MinD and MinE proteins, which oscillate between cell poles to inhibit ring assembly. Averaged over time, the concentration of the inhibitor MinC is lowest at midcell, restricting ring assembly to this region. A second positioning mechanism, called Nucleoid Occlusion, acts through protein SlmA to inhibit ring polymerization in the location of the nucleoid. Here, a mathematical model was developed to explore the interactions between Min oscillations, nucleoid occlusion, Z ring assembly and positioning. One-dimensional advection reaction-diffusion equations were built to simulate the spatio-temporal concentrations of Min proteins and their effect on various forms of FtsZ. The resulting partial differential equations were numerically solved using a finite volume method. The reduced chemical model assumed that the ring is composed of overlapping FtsZ filaments and that MinC disrupts lateral interactions between filaments. SlmA was presumed to break long FtsZ filaments into shorter units. A term was developed to account for the movement of FtsZ subunits in membrane-bound filaments as they touch and align with other filaments. This alignment was critical in forming sharp stable rings. Simulations qualitatively reproduced experimental results showing the incorrect positioning of rings when Min proteins were not expressed, and the formation of multiple rings when FtsZ was overexpressed. PMID- 23440509 TI - Who was the infector--probabilities in the presence of variability in latent and infectious times. AB - The probability that an observed infection has been transmitted from a particular member of a set of potential infectors is calculated. The calculations only use knowledge of the times of infection. It is shown that the probabilities depend on individual variability in latent and infectious times. The analysis are based on different background information and different assumptions on the progress of infectivity. The results are illustrated by numerical calculations and simulations. PMID- 23440510 TI - Direct competition results from strong competition for limited resource. AB - We study a model of competition for resource through a chemostat-type model where species consume the common resource that is constantly supplied. We assume that the species and resources are characterized by a continuous trait. As already proved, this model, although more complicated than the usual Lotka-Volterra direct competition model, describes competitive interactions leading to concentrated distributions of species in continuous trait space. Here we assume a very fast dynamics for the supply of the resource and a fast dynamics for death and uptake rates. In this regime we show that factors that are independent of the resource competition become as important as the competition efficiency and that the direct competition model is a good approximation of the chemostat. Assuming these two timescales allows us to establish a mathematically rigorous proof showing that our resource-competition model with continuous traits converges to a direct competition model. We also show that the two timescales assumption is required to mathematically justify the corresponding classic result on a model consisting of only finite number of species and resources (MacArthur in, Theor Popul Biol 1:1-11, 1970). This is performed through asymptotic analysis, introducing different scales for the resource renewal rate and the uptake rate. The mathematical difficulty relies in a possible initial layer for the resource dynamics. The chemostat model comes with a global convex Lyapunov functional. We show that the particular form of the competition kernel derived from the uptake kernel, satisfies a positivity property which is known to be necessary for the direct competition model to enjoy the related Lyapunov functional. PMID- 23440511 TI - Roux en Y gastric bypass increases ethanol intake in the rat. AB - Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors. PMID- 23440513 TI - Complete starch hydrolysis by the synergistic action of amylase and glucoamylase: impact of calcium ions. AB - Starch hydrolysis was performed by the synergistic action of amylase and glucoamylase. For that purpose glucoamylase (Dextrozyme) and two amylases (Liquozyme and Termamyl) in different combinations were investigated. Experiments were carried out in the repetitive- and fed-batch modes at 65 degrees C and pH 5.5 with and without the addition of Ca(2+) ions. 100 % conversion of starch to glucose was achieved in batch experiments. Calcium ions significantly enhanced stability of the amylase Termamyl. The intensity of synergism between amylase Termamyl and glucoamylase Dextrozyme was higher than in the experiments carried out with amylase Liquozyme and Dextrozyme. Mathematical model of the complete reaction system was developed. Using the model, a possible explanation of the synergism between the amylase and glucoamylase was provided. PMID- 23440514 TI - Quantitative real-time expression profiling of aquaporins-isoforms and growth response of Brassica juncea under arsenite stress. AB - The present study analyzed the expression level of aquaporins of plasma membrane intrinsic protein (PIP) class in response to arsenite (AsIII) exposure of 100 MUM from 0.5 h to 8 days in Brassica juncea. The expression levels of most of the PIPs were down-regulated during the course of AsIII exposure. This led to decrease in total water content of plants, which in turn hampered seedling growth. The level of reactive oxygen species (superoxide radicals and hydrogen peroxide), lipid peroxidation and root oxidizability increased significantly upon exposure to AsIII as compared to that of control leading to an increase in cell death. The study proposes that the down-regulation of PIPs happened presumably to regulate AsIII levels, which, however, occurred at the cost of reduced growth, disturbed water balance and induced oxidative stress. PMID- 23440512 TI - Vitamin A and retinoid signaling: genomic and nongenomic effects. AB - Vitamin A or retinol is arguably the most multifunctional vitamin in the human body, as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs, and PPARbeta/delta), polymorphic retinoic acid (RA) response elements, and multiple coregulators. It also involves extranuclear and nontranscriptional effects, such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. These new concepts expand the scope of the biologic functions of vitamin A and RA. PMID- 23440515 TI - SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells. AB - SGT1 (suppressor of G2 allele of Skp1) plays a role in various cellular processes including kinetochore assembly and protein ubiquitination by interacting with Skp1, a component of SCF E3 ligase complex. However, the function of SGT1 in cancer is largely unknown. Here, we showed that SGT1 was over-expressed in gastric cancer tissues and silencing of SGT1 by siRNAs significantly inhibited the growth and colony formation of gastric cancer cells. We further showed that SGT1 could regulate Akt signaling pathway by modulating Akt ser473 phosphorylation status. Moreover, we found that SGT1 was able to regulate the stability of PHLPP1, which is the direct phosphatase for Akt ser473 phosphorylation. Immunoprecipitation assay revealed that SGT1 could enhance the binding between PHLPP1 and beta-TrCP which has been documented to be able to target PHLPP1 for destruction. Decreased PHLPP1 in SGT1 over-expressed gastric cancer cells failed to dephosphorylate Akt and resulted in increased Akt ser473 phosphorylation and amplified downstream Akt signaling. Thus, our data revealed a previously uncovered role of SGT1 in gastric cancer development, and suggested that SGT1 could be a promising anti-cancer target to against gastric cancer. PMID- 23440516 TI - Behavioral evidence for possible simultaneous induction of hyperacusis and tinnitus following intense sound exposure. AB - Many human subjects suffering from chronic tinnitus also suffer from hyperacusis, a heightened perception of loudness at moderate to intense sound levels. While numerous studies suggest that animals develop chronic tinnitus following intense noise exposure, it is not yet clear whether sound exposure also induces chronic hyperacusis-like responses in animals. We addressed this question by examining the chronic effects of intense sound exposure on the acoustic startle response (ASR) and its suppression by background noise containing brief gaps. We compared startle amplitudes in intense tone-exposed (10 kHz, 115 dB SPL, 4 h) and age matched controls at 2-28 weeks post-exposure. While both groups showed similar startle thresholds, exposed animals showed a hyperacusis-like augmentation of ASR at high stimulus levels. Addition of background noise had little effect on ASR in controls but had a strong suppressive effect on startle in exposed animals, indicating a sensitization to background noise. When the background noise contained a gap preceding the startle stimulus, ASR was suppressed in control animals, but exposed animals showed a marked weakening of gap-induced suppression of ASR. This weakening of gap-induced startle suppression is consistent with the interpretation that the gap may have been masked by tinnitus. The associated hyper-responsiveness to startle stimuli presented alone and the sensitization to background noise suggest that hyperacusis may have also been induced. The results indicate that noise exposure leads to increases in the gain of auditory responsiveness and may offer a model of the association of hyperacusis with tinnitus. PMID- 23440517 TI - Localization in reverberation with cochlear implants: predicting performance from basic psychophysical measures. AB - Users of bilateral cochlear implants (CIs) experience difficulties localizing sounds in reverberant rooms, even in rooms where normal-hearing listeners would hardly notice the reverberation. We measured the localization ability of seven bilateral CI users listening with their own devices in anechoic space and in a simulated reverberant room. To determine factors affecting performance in reverberant space we measured the sensitivity to interaural time differences (ITDs), interaural level differences (ILDs), and forward masking in the same participants using direct computer control of the electric stimulation in their CIs. Localization performance, quantified by the coefficient of determination r(2) and the root mean squared error, was significantly worse in the reverberant room than in anechoic conditions. Localization performance in the anechoic room, expressed as r(2), was best predicted by subject's sensitivity to ILDs. However, the decrease in localization performance caused by reverberation was better predicted by the sensitivity to envelope ITDs measured on single electrode pairs, with a correlation coefficient of 0.92. The CI users who were highly sensitive to envelope ITDs also better maintained their localization ability in reverberant space. Results in the forward masking task added only marginally to the predictions of localization performance in both environments. The results indicate that envelope ITDs provided by CI processors support localization in reverberant space. Thus, methods that improve perceptual access to envelope ITDs could help improve localization with bilateral CIs in everyday listening situations. PMID- 23440519 TI - Interactions of linoleic and alpha-linolenic acids in the development of fatty acid alterations in cystic fibrosis. AB - Patients with cystic fibrosis (CF) exhibit characteristic polyunsaturated fatty acid abnormalities, including low linoleic acid and high arachidonic acid levels that are thought to contribute to the pathophysiology of this disease. Recent studies indicate that changes in fatty acid metabolism are responsible for these abnormalities. This study examines the role of fatty acid substrate concentrations in the development of these alterations in a cultured cell model of CF. By incubating cells with varying concentrations of exogenous fatty acids, it shows that increasing the concentration of substrates from the parallel n-3 and n-6 polyunsaturated fatty acid pathways (linoleic acid and alpha-linolenic acid, respectively) not only increases formation of the products in that pathway, but also reduces metabolism in the parallel pathway. In particular, we demonstrate that high levels of linoleic acid and low levels of alpha-linolenic acid are required to observe the typical fatty acid alterations of cystic fibrosis. These results shed light on the mechanisms of fatty acid metabolic abnormalities in cystic fibrosis. They also have implications for the nutritional therapy of CF, highlighting the importance of specific fatty acid content, and in understanding the anti-inflammatory effects of n-3 fatty acids. PMID- 23440518 TI - Post cardiac arrest therapeutic hypothermia in adult patients, state of art and practical considerations. AB - The importance of therapeutic hypothermia in selected categories of patients has been widely demonstrated. Laboratory, animal, and human studies permitted to understand the molecular mechanisms underlying cooling and its importance in preventing the ischemia/reperfusion injury of the brain. The development of new technologies offered the possibility to reach the desired temperature effectively and rapidly, reducing related side effects. Nevertheless, the application of systematic protocols of cooling has not been adequately reached in many hospitals. In this paper the most recent findings regarding hypothermia, its physiological bases and ways of application are reviewed. PMID- 23440520 TI - TRPM7 Is Essential for RANKL-Induced Osteoclastogenesis. AB - The transient receptor potential melastatin type 7 (TRPM7) channel is a widely expressed non-selective cation channel with fusion to the C-terminal alpha kinase domain and regarded as a key regulator of whole body Mg(2+) homeostasis in mammals. However, the roles of TRPM7 during osteoclastogenesis in RAW264.7 cells and bone marrow-derived monocyte/macrophage precursor cells (BMMs) are not clear. In the present study, we investigate the roles of TRPM7 in osteoclastogenesis using methods of small interfering RNA (siRNA), RT-PCR, patch-clamp, and calcium imaging. RANKL (receptor activator of NF-kappaB ligand) stimulation did not affect the TRPM7 expression and TRPM7-mediated current was activated in HEK293, RAW264.7, and BMM cells by the regulation of Mg(2+). Knock-down of TRPM7 by siTRPM7 reduced intracellular Ca(2+) concentration ([Ca(2+)](i)) increases by 0 mM [Mg(2+)](e) in HEK293 cells and inhibited the generation of RANKL-induced Ca(2+) oscillations in RAW264.7 cells. Finally, knock-down of TRPM7 suppressed RANKL-mediated osteoclastogenesis such as activation and translocation of NFATc1, formation of multinucleated cells, and the bone resorptive activity, sequentially. These results suggest that TRPM7 plays an essential role in the RANKL-induced [Ca(2+)](i) oscillations that triggers the late stages of osteoclastogenesis. PMID- 23440521 TI - Ecarin modified rotational thrombelastometry: a point-of-care applicable alternative to monitor the direct thrombin inhibitor argatroban. AB - PURPOSE: Adequate monitoring of the effect of the direct thrombin inhibitor argatroban may facilitate individualized dosing and perioperative management of anticoagulation. Ecarin Clotting Time is proposed for this purpose, but has the major disadvantage of limited availability. There is a point-of-care applicable ecarin-activated test modification for rotational thrombelastometry (ROTEM(r)) which is sensitive to direct thrombin inhibitors. The aim of the study was to evaluate the correlation between argatroban concentration and this ecarin modified thrombelastometry (EMT). METHODS: In this in vitro experiment, blood drawn from healthy volunteers was spiked with argatroban at clinically relevant concentrations and analyzed with ROTEM(r) using EMT. The main endpoint was the clotting time (CT). RESULTS: EMT-CT was prolonged with increasing argatroban concentrations (from 83.3 +/- 6.7 s without argatroban to 743.5 +/- 138.2 s at 2 MUg/ml argatroban). The correlation between argatroban concentration and EMT-CT was high (r = 0.94) and statistically significant (p < 0.01). CONCLUSION: These promising preclinical results mandate further clinical research to determine an EMT-CT target range regarding the clinical outcomes of thrombosis and bleeding. PMID- 23440522 TI - Autologous stem cell transplantation in adults with metastatic sarcoma of the Ewing family: a single centre experience. AB - BACKGROUND: Adults with metastatic Ewing family sarcomas (ES) after being treated with standard therapy for localised disease have limited treatment options with curative intent. The aim of this retrospective single centre study was to evaluate the efficacy of autologous stem cell transplantation (ASCT) in this patient population. METHODS: We report on seven consecutive patients with ES. Four patients with initial localised disease developed distant metastases after being treated with initial standard pre-operative chemotherapy followed by surgery and subsequent standard post-operative chemotherapy. Three patients with initial metastatic disease were pre-treated with standard polychemotherapy. All patients received high-dose chemotherapy (HDCT) followed by ASCT for metastatic disease. RESULTS: For patients with initial metastatic disease, partial remission (PR) was achieved in three patients prior to HDCT. Type of response subsequent to ASCT was complete response (CR) in four patients with initial localised disease and CR in two patients with initial metastatic disease. No patient died within the first 100 days after HDCT. Side effects were rare and manageable. CONCLUSION: This retrospective analysis suggests that ASCT may be considered in patients with metastatic ES, previously treated with standard therapy. PMID- 23440523 TI - Duloxetine-induced life-threatening long QT syndrome. PMID- 23440524 TI - Detection of Plasmodium sp.-infested Anopheles hyrcanus (Pallas 1771) (Diptera: Culicidae) in Austria, 2012. AB - On July 15, 2012, adult Anopheles hyrcanus (Pallas 1771) mosquitoes were caught next to a farm barn near Rust, Burgenland, close to Lake Neusiedl National Park in eastern Austria. Six weeks later, adults of this invasive species were also found in a sheep shelter outside the village of Oggau and another 2 weeks later, in a horse barn in Morbisch. The morphological typing was confirmed genetically by amplification and sequencing of a 1,404-bp-long fragment within the 5.8S ribosomal RNA gene, the internal transcribed spacer 2, and the 28S ribosomal RNA gene. Out of two A. hyrcanus pools analyzed, one was found positive for Plasmodium sp. A 460-bp-long sequence within the mitochondrial cytochrome b region revealed 100 % identity to a sequence of a Plasmodium parasite identified in a New Zealand bellbird (Anthornis melanura). The Austrian finding sites are close to the Hungarian border. In Hungary, the occurrence of A. hyrcanus was already reported in 1963. A. hyrcanus is considered the most important potential vector of malaria in southern France today. In Austria, sporadic autochthonous malaria cases could emerge, caused by immigration from malaria-endemic countries and heavy tourism. However, the broad population coverage of the Austrian health care system makes the reestablishment of endemic areas for malaria unlikely. PMID- 23440526 TI - Clinical outcomes for a novel 6 degrees of freedom image guided localization method for frameless radiosurgery for intracranial brain metastases. AB - Stereotactic radiosurgery (SRS) is an accepted method of treatment for intracranial brain metastases with sub-millimeter accuracy. Frameless radiosurgery (FRS) is becoming an alternative to framed SRS due to its less invasive requirements. The purpose of this study is to describe the clinical outcomes and local patterns of failure for a novel 6 degrees of freedom CT guided method of localization for FRS of intracranial brain metastases. 42 patients underwent linear accelerator-based FRS to 94 intracranial brain metastases between 01/2009 and 07/2011. 78 and 22 % of treated sites were intact metastases and resection cavities, respectively. 55 % of patients had undergone prior brain radiotherapy (45 % SRS, 26 % whole brain radiation therapy). The 1 year actuarial local recurrence rate was 18 %, with a median imaging follow-up period of 13.2 months. Single fraction equivalent dose was the most important predictor of local recurrence. The 1 year actuarial first distant brain recurrence and total intracranial recurrence rate was 58 and 69 %, respectively. The crude radiographic radiation necrosis rate was 3 %. Of the 10 local recurrence events, 8 (80 %) were in-field only, 1 (10 %) was marginal only, and 1 (10 %) was both. The preponderance of in-field only patterns of failure suggests that geographic miss is not a major contributor to local recurrence using this novel localization method for FRS. The 1 year local control rate is comparable to other similar published series of framed and frameless radiosurgery. PMID- 23440527 TI - Breaking new ground in the mind: an initial study of mental brittle transformation and mental rigid rotation in science experts. AB - The current study examines the spatial skills employed in different spatial reasoning tasks, by asking how science experts who are practiced in different types of visualizations perform on different spatial tasks. Specifically, the current study examines the varieties of mental transformations. We hypothesize that there may be two broad classes of mental transformations: rigid body mental transformations and non-rigid mental transformations. We focus on the disciplines of geology and organic chemistry because different types of transformations are central to the two disciplines: While geologists and organic chemists may both confront rotation in the practice of their profession, only geologists confront brittle transformations. A new instrument was developed to measure mental brittle transformation (visualizing breaking). Geologists and organic chemists performed similarly on a measure of mental rotation, while geologists outperformed organic chemists on the mental brittle transformation test. The differential pattern of skill on the two tests for the two groups of experts suggests that mental brittle transformation and mental rotation are different spatial skills. The roles of domain general cognitive resources (attentional control, spatial working memory, and perceptual filling in) and strategy in completing mental brittle transformation are discussed. The current study illustrates how ecological and interdisciplinary approaches complement traditional cognitive science to offer a comprehensive approach to understanding the nature of spatial thinking. PMID- 23440528 TI - Variable stability of preferences in spatial reasoning. PMID- 23440529 TI - Research in psychiatry: between Sisyphus and Peter. PMID- 23440530 TI - EROL scale: a new behavioural olfactory measure and its relationship with anxiety and depression symptoms. AB - INTRODUCTION: The main objective of this study was to develop and validate a new olfactory measure that assesses the influence of olfaction on several emotional, behavioural, and cognitive issues: The Relational Scale of Olfaction (EROL). A secondary objective was to explore the relationship between the olfactory function and the anxiety and depression symptoms by means of EROL and the Hospital Anxiety and Depression Scale (HADS). A positive relationship between anxiety symptoms and the olfactory function was hypothesized. Regarding depressive symptoms, a significant relationship with the olfactory scores was not expected. METHOD: Psychometric properties of EROL scale and correlations between HADS and EROL were tested in a sample from the general population. RESULTS: EROL showed an adequate level of test-retest reliability (ICC=.748) and good internal consistency (Cronbach's alpha=.761). Convergent validity with other olfactory measures was satisfactory. A one-factor solution was found for the scale. HADS showed a significant relationship with EROL (r=.280, p<.01), but the analysis through dimensions revealed that only the anxiety subscale correlated significantly and moderately with the olfactory measure (r=.325, p<.001), whereas the correlation with the depression subscale was non-significant (r=.146, p>.05). CONCLUSIONS: Given that EROL displayed good psychometrical properties, it appears as a suitable tool to assess the olfactory function in general population. The relationship between this olfactory scale and anxiety symptoms found in this study is an interesting issue that requires further research. PMID- 23440531 TI - Blood alcohol level tests in nightlife recreational settings as a preventive tool. AB - BACKGROUND: Getting drunk is a common practice in the nightlife context and is related to risk behaviors. One potentially preventive strategy would be to conduct breathalyzer (blood alcohol content level-BAC) tests in situ, encouraging the young people to take responsibility. The aim of this study is to evaluate the efficacy of such a measure. METHOD: A sample of 555 young people were interviewed in the most popular nightlife recreational areas in three Spanish cities. After they answered to a brief questionnaire, the breathalyzer test was done and they were then informed of the results and also informed about the results, telling them what the maximum authorized rate of alcohol in expired air was for driving. After, they were asked about their drinking intentions for the rest of the night, and if they we going to be driving. RESULTS: Only 21.6% stated that they would stop drinking or drink less, while a similar percentage (21.5%) said they would drink even more than they had intended after finding out their BAC. The logistic regression indicated that the decision to drink more or less was influenced by the BAC level, the amount they had planned to drink prior to the test and high scores on "sensation seeking." Those who decided to drive had lower BAC levels and had planned to drink less prior to the interview. CONCLUSIONS: Prevention strategies involving attempts to change behavior through informing drinkers of their own BAC are controversial, since although for some it leads to their drinking less, in other cases the young people end up drinking more than they had planned. PMID- 23440532 TI - Metabolic syndrome and health-related quality of life in patients with schizophrenia. AB - The association of metabolic syndrome (MetS) with health-related quality of life (HRQol) in schizophrenia is poorly documented. The relationship between MetS, HRQol and global functioning were examined. For this goal, 76 individuals with schizophrenia and schizoaffective disorder (DSM-IV criteria) were interviewed to obtain sociodemographic data, lifestyle habits, psychopathology (PANSS scale), global functioning (GAF scale), sef-reported quality of life (EQ-5D scale) and the anthropometric measures and blood test results. MetS was defined by the NCEP (2005) criteria. The prevalence of MetS was 36.8%. MetS was directly associated with personal background of dyslipidaemia and diabetes mellitus. Subjects with MetS had greater weight, BMI, waist, blood pressure, triglycerides, fasting glucose and a lower HDL-cholesterol. The MetS is also associated with age, inactive employment status and better self-care. The EQ VAS (visual analogue scale) of EQ-5D shows that subjects with MetS who practice physical activity indicates a better subjctive perception of health, which remarks the necessity of improving healthy lifestyle and an interdisciplinary treatment of the MetS. There is no association between global functioning and HRQol. This is the first study which investigates the relationship between MetS, HRQol and GAF in individuals with schizophrenia in the European context. PMID- 23440533 TI - Relationship between personality traits and panic disorder. AB - Panic disorder is a chronic course disorder that causes important distress and impaired social function. The relationship between personality disorders and panic disorder has been studied, and determines its severity, course and treatment, but it has not been studied the relationship between personality traits and outcome of panic disorder. 82 patients with a first episode of panic disorder are selected and followed during 1 year, to analyze the existence and kind of relationship between their personality traits and the outcome of their disorder. PMID- 23440534 TI - Paving the way for new research strategies in mental disorders. First part: the recurring crisis of psychiatry. AB - Psychiatry is going through a deep crisis, both as a scientific discipline as a medical speciality. In the present paper we consider in length what we consider to be the three aspects that could explain the situation: the recurring disappointment in classification; the persistence of dualistic perspectives in research; and third, the continuing of a localizacionism inadequate to explain normal and pathological behaviour. Psychiatry lacks a definition of mental disorder that covers all situations, there are difficulties in drawing a precise distinction between normality and psychopathology, and the majority of these “diagnostic” categories are not validated by biological criteria. Furthermore, there is still a debate on the nature of the symptoms of mental disorders, a confusion classification and diagnosis and a preoccupation with the growing inflation of diagnostic categories. Dualism is at the core of psychopathology, simply because Cartesian dualism led to the development of modern science, but the price paid includes the split-up of mental and physical phenomena and illnesses and of psychiatry and the rest of medicine. Localizationism, that is, the approach to brain function considering that particular pychological functions are carried out by particular brain areas or centers, helps to understand many clinical and psychological phenomena, but have largely fild in explaining the nature of most mental disorders. In a second part of this article we provide some strategies that could help to go beyond the present impasse. PMID- 23440536 TI - Schizophrenia: analysis and psychological treatment according to the clinical staging. AB - The present paper provides an overview of the recent contributions to the study of the course of schizophrenia. This is not a disorder as chronic and as acute at its start as traditionally thought. Beyond the positive and negative symptoms and different subtypes of illness, it is important to call attention to the development and course of schizophrenia. According to this approach, the aim of this paper is to review the most recent studies on schizophrenia according to clinical stages. With this aim, we review the research carried out by leading research teams and recently published clinical practice guidelines (Birmingham Group, Melbourne Group, GPCSNS, NICE) in relation to the course, the main features, and more adjusted treatment alternatives, aimed to improve the characteristic symptoms of each stage of the disease. Finally, we point out the necessity to integrate this approach with the proposed changes for the upcoming DSM-V. This review identifies effective treatment options for each of the phases of the disease defined by the clinical stage approach. PMID- 23440535 TI - Is psychological treatment efficacious for attention deficit hyperactivity disorder (ADHD)? Review of non-pharmacological treatments in children and adolescents with ADHD. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children and adolescents, and has a great impact on the psychological development of affected patients. Even though its efficacy is proven, the use of medication for ADHD has several limitations, and non-pharmacological interventions are considered a necessary component of treatment. METHODOLOGY: This work is a review of evidence-based non pharmacological treatments with demonstrated efficacy for ADHD in children and adolescents, analyzed by age groups. RESULTS: Non-pharmacological treatments that have shown scientific evidence of efficacy are psychological and psychoeducational interventions. Psychological interventions include behavioral therapy, parent training (PT) and social skills training. Psychoeducational interventions include a set of practices to improve learning and are carried out in the school setting. Scientific evidence of efficacy in preschool children is limited to PT, while different psychological and psychoeducational interventions have been shown to be beneficial in school-age children. The available evidence for non-pharmacological treatment in adolescence is so far insufficient. CONCLUSIONS: Though more randomized controlled trials are necessary for non pharmacological interventions to become established practices, there are clear indications of their efficacy. For more severe cases of ADHD, a combination of non-pharmacological and pharmacological treatment is recommended. PMID- 23440537 TI - [Olanzapine long-acting post-injection syndrome: a case report and brief review]. AB - The introduction of long-acting injectable atypical antipsychotics has ensured adherence to treatment in patients with low awareness of the disorder, with an acceptable rate of side effects. In the case of long acting olanzapine injection in particular, has particular relevance the existence of a special side-effect called post-injection syndrome. This rare side effect consisting in the presence of symptoms of olanzapine overdose after intramuscular administration of medication has led to restrictions on the use of the drug and the need for patient observation for three hours after each injection. We report a case of postinjection syndrome, to our knowledge, the first in Spain since the commercialization of Zypadhera. As in most cases described in the literature have symptoms of overdosage of olanzapine (dysarthria, sedation, fatigue, etc.) that are selflimiting without any therapeutic measure and are accompanied by supratherapeutic plasma levels of olanzapine. PMID- 23440539 TI - Causes of hyperferritinaemia. PMID- 23440538 TI - Antiretroviral drug regimens to prevent mother-to-child transmission of HIV: a review of scientific, program, and policy advances for sub-Saharan Africa. AB - Considerable advances have been made in the effort to prevent mother-to-child HIV transmission (PMTCT) in sub-Saharan Africa. Clinical trials have demonstrated the efficacy of antiretroviral regimens to interrupt HIV transmission through the antenatal, intrapartum, and postnatal periods. Scientific discoveries have been rapidly translated into health policy, bolstered by substantial investment in health infrastructure capable of delivering increasingly complex services. A new scientific agenda is also emerging, one that is focused on the challenges of effective and sustainable program implementation. Finally, global campaigns to "virtually eliminate" pediatric HIV and dramatically reduce HIV-related maternal mortality have mobilized new resources and renewed political will. Each of these developments marks a major step in regional PMTCT efforts; their convergence signals a time of rapid progress in the field, characterized by an increased interdependency between clinical research, program implementation, and policy. In this review, we take stock of recent advances across each of these areas, highlighting the challenges--and opportunities--of improving health services for HIV-infected mothers and their children across the region. PMID- 23440540 TI - A young patient of hereditary renal hypouricaemia presenting with exercise induced rhabdomyolysis and acute kidney injury. AB - Hereditary renal hypouricaemia (HRH) is a genetic disorder commonly associated with exercise-induced acute kidney injury (AKI). We report the case of a 19-year old man who was admitted to hospital with exercise-induced AKI and who was subsequently shown to have HRH. We believe this to be the first description of a case of HRH co-presenting with rhabdomyolysis. PMID- 23440541 TI - Association between C-reactive protein, pro-oxidant-antioxidant balance and traditional cardiovascular risk factors in an Iranian population. AB - BACKGROUND: Inflammatory states are known to cause an imbalance in the redox status. We aimed to study the possible associations between pro-oxidant antioxidant balance (PAB) and serum high-sensitive C-reactive protein (hs-CRP) concentrations and traditional cardiovascular disease (CVD) risk factors in an unselected Iranian population and in groups of individuals with specific disease. METHODS: The study was conducted among an unselected population of 758 male subjects. Biochemical markers, including hs-CRP and PAB values, were measured. RESULTS: Serum hs-CRP concentrations were positively associated with serum PAB values (r = 0.260, P <= 0.001). Univariate analysis showed that PAB values were statistically higher in individuals who were obese or smokers compared with non obese and non-smokers individuals (P < 0.01). While serum hs-CRP concentrations were significantly higher in older subjects, subjects with obesity, diabetes mellitus, metabolic syndrome, central obesity, hypertriglyceridaemia, higher low density lipoprotein cholesterol concentrations, positive history of CVD and lower physical activity than subjects without these risk factors (P < 0.05). Comparing hs-CRP and PAB values in different CVD risk score subgroups showed a significant incremental rise in both parameters as CVD risk score increased (P < 0.05). Using multiple linear regression analysis we found a strong association between PAB values and hs-CRP concentrations. CONCLUSIONS: This study showed that among Iranian subjects, the inflammatory marker, hs-CRP, was strongly and positively associated with a marker of oxidative stress and also with several traditional risk factors of CVD. Moreover, the impact of traditional cardiovascular risk factors on hs-CRP concentrations and PAB values differed. PMID- 23440542 TI - A hypokalaemic woman with nephrocalcinosis: rebirth of old knowledge. AB - The coexistence of hypokalaemia and nephrocalcinosis poses a challenge in rapid diagnosis and appropriate management. We describe a 38-year-old woman who presented with thirst, intermittent carpopedal spasm, paresthaesia of both hands and progressive weakness of lower extremities for two years. She had a history of chronic hypokalaemia of unknown cause with intermittent potassium supplementation for 7-8 y and bilateral nephrocalcinosis notable for one year. She denied vomiting, diarrhoea or use of laxatives, alcohol or diuretics. Her blood pressure was normal. Laboratory investigations showed hypokalaemia (2.7 mmol/L) and metabolic alkalosis (HCO3(-) 32.6 mmol/L, pH 7.46). Two random urine samples both showed a consistently high urine K(+) excretion but with excretion rates of Na(+), Cl(-) and divalent cations which were high in one sample but not the other. Ingestion of furosemide 120 mg daily for body image for 7-8 y was uncovered. With furosemide cessation and potassium supplementation, her hypokalaemia with neuromuscular symptoms was corrected but nephrocalcinosis persisted. Surreptitious use of diuretics for various purposes should be kept in mind as an important cause of hypokalaemia and/or nephrocalcinosis. Measurement of electrolyte concentrations in at least two random urine samples is warranted to distinguish it from true renal tubular disorders and extrarenal causes. PMID- 23440543 TI - Effects of SARA on oxygen-glucose deprivation in PC12 cell line. AB - Ischemic stroke is a major composition of cerebrovascular disease, seriously threatening to human health in the world. Activin A (ActA), belonging to transforming growth factor-beta (TGF-beta) super family, plays an important role in the hypoxic-ischemic brain injury through ActA/Smads pathway. While as an essential phosphorylation assistor in TGF-beta signaling, the functions and mechanisms of smad anchor for receptor activation (SARA) in ischemic brain injury remain poorly understood. To solve this problem and explore the pathological processes of ischemic stroke, we used an Oxygen-Glucose deprivation (OGD) model in nerve growth factor-induced differentiated rattus PC12 pheochromocytoma cells and down regulated the expressions of SARA by RNA interference technology. Our results showed that the repression of SARA before OGD exposure reduced the expressions of Smad2, 3, 4 mRNA and the phosphorylation rate of Smad2 protein, but it did not affect the mRNA expressions of Smad7. After OGD treatment, ActA/Smads pathway was activated and the expression of SARA in the SARA pre repression group was significantly up-regulated. The pre-repression of SARA increased the sensitivities of nerve-like cells to OGD damage. Moreover, the mRNA expression of Smad7 which was supposed to participate in the negative feedback of ActA/Smads pathway was also elevated due to OGD injury. Taken together, these results suggest a positive role of SARA in assisting the phosphorylation of Smad2 and maintaining the neuron protective effect of ActA/Smads pathway. PMID- 23440545 TI - Factors that affect sleep quality: perceptions made by patients in the intensive care unit after thoracic surgery. AB - OBJECTIVE: This study identifies factors affecting sleep patterns among thoracic surgery patients in the intensive care unit (ICU) and compares the perceptions of sleep-disturbing factors between nurses and patients. METHODS: One hundred and fifty-two patients and 40 nurses were surveyed using the Pittsburgh Sleep Quality Index (PSQI) and self-designed questionnaires (for patients and nurses). All statistical analyses were carried out by SPSS, and the following statistical methods were used to evaluate the data: chi-squared test and logistic regression. RESULTS: Of 152 patients, 46.1 % reported poor sleep quality during their hospitalization; their PSQI total score was 6.95 +/- 3.713. Of these, 69.1 % indicated that their sleep quality was poorer than before; 50.0 % of them changed their sleep patterns. Significant discrepancies exist between nurses and patients in the perceptions of sleep-disturbing factors of patients. CONCLUSION: Thoracic surgical patients' perceptions of their sleep in the ICU indicate poor sleep quality, which is decided by a variety of disturbing factors. Perceptions of these factors varied greatly between surveyed patients and nurses. PMID- 23440544 TI - Toxicogenomic studies of human neural cells following exposure to organophosphorus chemical warfare nerve agent VX. AB - Organophosphorus (OP) compounds represent an important group of chemical warfare nerve agents that remains a significant and constant military and civilian threat. OP compounds are considered acting primarily via cholinergic pathways by binding irreversibly to acetylcholinesterase, an important regulator of the neurotransmitter acetylcholine. Many studies over the past years have suggested that other mechanisms of OP toxicity exist, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. Here we performed a microarray study in which cultured human neural cells were exposed to 0.1 or 10 MUM of VX for 1 h. Global gene expression changes were analyzed 6, 24, and 72 h post exposure. Functional annotation and pathway analysis of the differentially expressed genes has revealed many genes, networks and canonical pathways that are related to nervous system development and function, or to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In particular, the neuregulin pathway impacted by VX exposure has important implications in many nervous system diseases including schizophrenia. These results provide useful information valuable in developing suitable antidotes for more effective prevention and treatment of, as well as in developing biomarkers for, VX-induced chronic neurotoxicity. PMID- 23440546 TI - International radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting. AB - PURPOSE: This study explored international radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting (RINV). METHODS: Radiation oncology trainees who were members of the national radiation oncology associations of the USA, Canada, Netherlands, Australia, New Zealand, France, Spain and Singapore completed a Web-based survey. Respondents estimated the risks of nausea and vomiting associated with six standardised radiotherapy only clinical case vignettes modelled after international anti-emetic guidelines and then committed to prophylactic, rescue or no therapy as an initial management approach for each case. RESULTS: One hundred and seventy-six trainees from 11 countries responded. Only 28 % were aware of any anti-emetic guideline. In general, risk estimates and management approaches for the high-risk and minimal risk cases varied less and were more in line with guideline standards than were estimates and approaches for the moderate- and low-risk cases. Prophylactic therapy was the most common approach for the high-risk and a moderate-risk case (83 and 71 % of respondents respectively), while rescue therapy was the most common approach for a second moderate-risk case (69 %), two low-risk cases (69 and 76 %) and a minimal risk case (68 %). A serotonin receptor antagonist was the most commonly recommended prophylactic agent. On multivariate analysis, a higher estimated risk of nausea predicted for recommending prophylactic therapy, and a lower estimated risk of nausea predicted for recommending rescue therapy. CONCLUSIONS: Radiation oncology trainee risk estimates and recommended management approaches for RINV clinical case vignettes varied and matched guideline standards more often for high-risk and minimal risk cases than for moderate- and low-risk cases. Risk estimates of nausea specifically were strong predictors of management decisions. PMID- 23440548 TI - An unusual cause of cardiogenic shock: tricuspid regurgitation and right ventricular perforation due to vena cava filter migration. AB - Dislocation and migration of the inferior vena cava filter to the right heart is an uncommon but serious complication, requiring prompt diagnosis and appropriate therapy. We report the case of a seventy-year old man, who had previously undergone vena cava filter implantation and who was admitted to the Intensive Care Unit due to acute respiratory distress with the suspect of pneumonia-related sepsis. Due to the worsening of hemodynamics and the development of cardiogenic shock, the patient underwent bedside echocardiography, which on the contrary revealed dislocation of the filter and the entrapment of the device within the tricuspid valve and chordae tendineae. This evidence was confirmed also by the chest-abdominal X-ray. The patient underwent tricuspid valve surgical replacement and successfully recovered. The transthoracic and transesophageal echocardiographies performed in the intensive care unit were able to first orient the diagnostic efforts toward the correct cause. PMID- 23440547 TI - Weight changes correlate with alterations in subjective physical function in advanced cancer patients referred to a specialized nutrition and rehabilitation team. AB - PURPOSE: The aim of this study is to assess whether short-term weight gain correlates with improvements in subjective markers of quality of life and physical function in patients referred to a clinic for management of cancer cachexia. METHODS: A retrospective review of the records of 306 patients referred to a specialized multi-disciplinary supportive care team with particular interest in treating cancer cachexia. Weight changes between each of the first three clinic visits, were correlated with the corresponding changes in patient-rated performance status, perceived strength and quality of life. In a second cohort of 56 patients, the correlation between perceived strength and quality of life was re-tested using a more detailed quality of life tool. RESULTS: Even over short time intervals positive correlations were observed for weight change vs. change in patient-rated performance status (Rs > 0.15, P < 0.05), and for changes in perceived strength vs. quality of life (Rs > 0.33, P < 0.001). The correlation between changes in patient-rated strength and quality of life was consistent across all subgroups studied and was reproducible when using a different, validated, quality of life tool (FAACT) in a second independent patient cohort. CONCLUSIONS: Weight gains are associated with subjective improvements in physical functioning, and changes in perceived physical strength are consistently correlated with quality of life. PMID- 23440549 TI - Regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine. AB - Based on its lower Log P value relative to metoprolol, a marker for the low/high permeability (P(eff)) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F(abs)) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P(eff)-F(abs) correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine's BCS classification. Pseudoephedrine's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine's permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine's complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P(eff) and F(abs) is involved in its absorption. Rather, it reflects the complexity behind P(eff) when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P(eff) that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum. PMID- 23440550 TI - Diagnostic accuracy of fine needle aspiration cytology for high-grade salivary gland tumors. AB - BACKGROUND: Preoperative differentiation between high-grade malignancy and others (benign or low-grade tumors) is more important than differentiation between malignant and benign tumors for surgical planning, treatment outcome, and prognosis in salivary gland tumors. Fine needle aspiration cytology (FNAC) has a relatively low sensitivity for differentiating malignant from benign salivary tumors. However, the diagnostic performance of FNAC has not been studied in predicting high-grade salivary malignancy, which can significantly affect patient care. METHODS: Experienced cytopathologists reevaluated the adequate FNAC on 521 salivary gland tumors. The diagnostic performances of FNAC for total malignancy and high-grade malignancy were calculated, and the results were validated in independent 105 cases. In cases of high-grade cancer on FNAC, we recorded the additional diagnostic procedures and the change of surgical extent to decide how FNAC impacts clinical practice. RESULTS: The sensitivity, specificity, and diagnostic accuracy of FNAC in differentiating malignant from benign tumors were 64.2 % (95 % confidence interval 52.3-75.0), 98.4 % (96.5-99.3), and 92.1 % (89.1 94.6). Meanwhile, FNAC predicted high-grade malignancy accurately (94.6 % [80.0 99.5], 99.2 % [97.8-99.7], 98.9 % [97.3-99.6], respectively), a finding reproduced with similar results in the validation set. FNAC indicative of high grade malignancy added additional imaging assessments in 94.9 %, frozen biopsy samples during surgery (tumor and lymph nodes) in 71.2 %, and changed the extent of surgery in 59.0 %. CONCLUSIONS: FNAC has an excellent diagnostic performance in discriminating high-grade salivary cancer, which guides clinical decision and surgical planning in salivary gland tumors. PMID- 23440551 TI - Effective low-dose escalation of indocyanine green for near-infrared fluorescent sentinel lymph node mapping in melanoma. AB - BACKGROUND: Regional lymph node metastasis is the strongest prognostic factor in patients with melanoma. Published reports that used lymphoscintigraphy with radioactive colloids and blue dye demonstrated accurate sentinel lymph node (SLN) identification in inguinal nodes and axillary nodes, but decreased accuracy in cervical, popliteal, epitrochlear, and parascapular nodes. Near-infrared imaging (NIR) may utilize indocyanine green (ICG) to improve SLN identification. The safety, feasibility and optimal dose of albumin-bound ICG (ICG:HSA) was assessed by NIR to improve SLN mapping in patients with melanoma. METHODS: Twenty-five consecutive patients with biopsy-proven melanoma underwent standard SLN mapping with preoperatively administered technetium-99 m nanocolloid (Tc-99 m). Intraoperative NIR fluorescence imaging was performed after injection of 1.0 ml of 100, 250 or 500 MUM of ICG:HSA in four quadrants around the primary lesion. RESULTS: NIR fluorescent imaging demonstrated accuracy of 98 % when compared with radioactive colloid. A total of 65 lymph nodes were identified (65 with Tc-99 m, 64 with ICG:HSA). Overall, successful mapping that used either technique was 96 % as one patient failed to map with either modality. As the dose of ICG was increased, the signal-to-background ratio increased from a median of 3.1 to 8.4 to 10.9 over the range of 100, 250, and 500 MUM, respectively. CONCLUSIONS: SLN mapping with ICG:HSA is feasible and accurate in melanoma. ICG has the added advantage of a low cost and an intraoperative technique that does not alter the surgical field, thus allowing for easy identification of SLNs. PMID- 23440552 TI - [67-year-old patient with recurrent gastroduodenal ulcer]. PMID- 23440553 TI - New agents in the arsenal to fight castrate-resistant prostate cancer. AB - Prior to 2010, the treatment options for castrate-resistant prostate cancer (CRPC) were limited. In the past 3 years, four new agents have been approved by the US Food and Drug Administration for use in CRPC. These four agents differ in their mechanisms of action and highlight the progress made in our understanding of CRPC, and more importantly, provide options with proven clinical benefit. This review examines the development, investigational evolution, adverse events, and future direction of: 1) the androgen receptor inhibitor, enzalutamide, 2) androgen biosynthesis inhibitor, abiraterone, 3) novel taxane chemotherapy, cabazitaxel, and 4) autologous immunotherapeutic agent, sipuleucel-T. PMID- 23440554 TI - Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy. AB - BACKGROUND: Individuals with celiac disease (CD) are at increased risk of lymphoproliferative malignancy (LPM). We examined if a family history of LPM or any cancer influenced the risk of LPM in individuals with CD. METHODS: We identified 28,996 individuals with biopsy-verified CD (equal to villous atrophy, Marsh histopathology stage 3), of whom 616 had family history of LPM. Cox regression then estimated hazard ratios (HRs) for LPM in these 616 compared with two control groups. We also examined the risk of LPM in CD individuals with a family history of any cancer (n = 8,439). RESULTS: During follow-up, 2/616 CD individuals with a family history of LPM, and 235/28,380 CD individuals without a family history of LPM developed LPM themselves. CD individuals with a family history of LPM were not at increased risk of LPM compared to general population controls (HR = 1.18; 95 % CI = 0.27-5.10), or compared to CD individuals without a family history of LPM (adjusted HR = 0.31; 95 % CI = 0.08-1.23). We found no increased risk of LPM in CD individuals with a family history of any cancer. CONCLUSION: This study found no evidence that a family history of LPM or any cancer increases the risk of future LPM in individuals with CD. Despite the large number of study participants, this study is nevertheless limited by few positive events due to a low absolute risk of LPM even in individuals with CD. PMID- 23440555 TI - Insulin-related biomarkers and their relationship with hepatic fibrosis risk in patients with psoriasis, metabolic syndrome and non-alcoholic fatty liver disease. PMID- 23440556 TI - Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group. AB - Radiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease. METHODS: mIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children's Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178). Individual mIBG scans were evaluated at 10 different anatomic regions, with the scoring of each site (0-3) based on the extent of disease at that anatomic region. RESULTS: There was no correlation between CS at diagnosis and subsequent treatment outcome. Patients with a CS > 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores <= 2 (3-y EFS: 15.4% +/- 5.3% vs. 44.9% +/- 3.9%, respectively; P < 0.001). A postinduction CS > 2 identified a cohort of patients at greater risk for an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis karyorrhexis index, and histologic grade. For MYCN-amplified tumors, the presence (CS > 0) versus absence (CS = 0) of residual mIBG avidity after induction was associated with a significantly worse outcome (3-y EFS: 11.8% +/- 7.8% vs. 49.6% +/- 7.7%, respectively; P = 0.003). After transplantation, patients with a CS > 0 had an EFS inferior to that of patients with a CS of 0 (3-y EFS: 28.9% +/- 6.8% vs. 49.3% +/- 4.9%, respectively [n = 133]; P = 0.009). CONCLUSION: Curie scoring carries prognostic significance in the management of patients with high-risk neuroblastoma. In particular, patients with CSs > 2 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies. PMID- 23440558 TI - In vivo visualization and quantification of (Disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice. AB - Hepatic transport of (99m)Tc-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. METHODS: Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle- or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with (99m)Tc-mebrofenin (n = 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. RESULTS: Normal hepatobiliary clearance of (99m)Tc-mebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/1b(-/-)/(-/-) mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2(-/-) mice had a higher liver AUC (P = 0.009), a delayed emergence time of (99m)Tc-mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. (99m)Tc mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). CONCLUSION: The current study visualized and quantified hepatic uptake and biliary efflux of (99m)Tc-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters. PMID- 23440560 TI - Suicide risk and sexual orientation: a critical review. AB - Many studies have reported higher rates of suicide attempts among sexual minority individuals compared with their heterosexual counterparts. For suicides, however, it has been argued that there is no sexual orientation risk difference, based on the results of psychological autopsy studies. The purpose of this article was to clarify the reasons for the seemingly discrepant findings for suicide attempts and suicides. First, we reviewed studies that investigated if the increased suicide attempt risk of sexual minorities resulted from biased self-reports or less rigorous assessments of suicide attempts. Second, we reanalyzed the only two available case-control autopsy studies and challenge their original "no difference" conclusion by pointing out problems with the interpretation of significance tests and by applying Bayesian statistics and meta-analytical procedures. Third, we reviewed register based and clinical studies on the association of suicides and sexual orientation. We conclude that studies of both suicide attempts and suicides do, in fact, point to an increased suicide risk among sexual minorities, thus solving the discrepancy. We also discuss methodological challenges inherent in research on sexual minorities and potential ethical issues. The arguments in this article are necessary to judge the weight of the evidence and how the evidence might be translated into practice. PMID- 23440559 TI - The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: revisiting the enigma. AB - The aim of this article is to provide a comprehensive and updated review of the key neuropsychiatric and neuropsychological complaints associated with chronic fatigue syndrome (CFS). Neuropsychiatric and neuropsychological difficulties are common in CFS and are linked primarily to disorders of mood, affect and behaviour. The neuropsychiatric complaint most frequently encountered amongst CFS patients is depression and in particular major depressive disorder (MDD). Despite decades of research, the precise aetiological relationship between CFS and MDD remains poorly understood. This has resulted in the development of a number of interesting and polarised hypotheses regarding the aetiological nature of CFS. Recent scientific advances have however begun to unravel a number of interesting inflammatory and immunological explanations that suggest CFS and MDD are distinct yet interrelated conditions. The possibility that the overlap between CFS and MDD might be explained in terms of shared oxidative and nitrosative (IO&NS) pathways is an area of intense research interest and is reviewed in detail in this article. The overlap between CFS and MDD is further differentiated by variations in HPA axis activity between the two disorders. Important immunological differences between MDD and CFS are also reviewed with particular emphasis on antiviral RNase L pathways in CFS. In addition to the presence of neuropsychiatric complaints, CFS is also associated with neuropsychological symptoms such as impaired attention, memory and reaction time. The key neuropsychological problems reported by CFS patients are also included in the review in an effort to understand the significance of cognitive impairment in CFS. PMID- 23440561 TI - Attraction to male facial masculinity in gay men in China: relationship to intercourse preference positions and sociosexual behavior. AB - Distinctions are commonly made regarding preferences for insertive or receptive anal intercourse within gay male communities. Three sexual self-labels are typically specified: "top," meaning a man who prefers the insertive role, "bottom," meaning a man who prefers the receptive role, and "versatile," meaning a man willing to perform either role. In this study, we examined the association between intercourse position preference and preference for male facial masculinity among 447 gay men across multiple cities in China. Each participant was shown 10 pairs of male faces sequentially, with each pair consisting of a masculinized and feminized version of the same base face. Tops preferred the feminized male face over the masculinized face, bottoms preferred the masculinized male face over the feminized face, and versatiles did not have a preference. Tops preferred more feminized male faces than did bottoms and versatiles. Preferences for male facial masculinity were also associated with sociosexual orientation and the nature of the associations differed by sex role preferences. Among tops, men who were less restricted preferred more feminine male faces compared to men who were more restricted. Among bottoms, men who were less restricted preferred more masculine male faces compared to men who were more restricted. Among versatiles, there was no association between sociosexual orientation and preferences for male facial masculinity. These findings provide new evidence that less sociosexually restricted men have stronger preferences for sexual dimorphism in the sexual partners they prefer than do more restricted men. PMID- 23440562 TI - Sexual sensation seeking and Internet sex-seeking of Middle Eastern men who have sex with men. AB - Despite recent evidence of stabilization in many developed nations, new human immunodeficiency virus (HIV) infections remain a public health concern globally. Efforts remain fragile in a number of world regions due to incomplete or inconsistent social policies concerning HIV, criminalization of same-sex encounters, social stigma, and religious doctrine. Middle Eastern men who have sex with men (MSM) remain one of the most hidden and stigmatized of all HIV risk groups. High-risk sexual bridging networks from these men to low prevalence populations (e.g., to spouse to offspring) are emerging HIV transmission pathways throughout the region. This cross-sectional, exploratory study investigated Sexual Sensation Seeking Scale (SSSS) scores to predict numbers of recent MSM sexual activities and to predict any recent unprotected receptive anal intercourse (URAI) activities in 86 Middle Eastern MSM who resided in the Middle East and who used the Internet to sex-seek. In a multivariate hierarchical regression, higher SSSS scores predicted higher numbers of recent MSM sexual activities (p = .028) and URAI (p = .022). In a logistic regression, higher SSSS scores increased the likelihood of engaging in URAI activities threefold (OR 3.0, 95 % CI 1.15-7.85, p = .025). Age and drug/alcohol use during sexual activities served as covariates in the regression models and were not significant in any analyses. Despite numerous hurdles, adopting Internet-based, non-restricted HIV education and prevention public health programs in the Middle East could instrumentally enhance efforts toward reducing the likelihood of new HIV transmissions in MSM and their sexual partners, ultimately contributing to an improved quality of life. PMID- 23440563 TI - Exploring the relationship between gender nonconformity and mental health among black South african gay and bisexual men. PMID- 23440564 TI - Validation of a Dutch version of the Neurological Fatigue Index (NFI-MS) for patients with multiple sclerosis in the Netherlands. AB - PURPOSE: Fatigue is a complex, multidimensional construct. Most questionnaires measuring fatigue do not meet the standards for good measurement properties. Therefore, the Neurological Fatigue Index for multiple sclerosis (NFI-MS) is recently developed using thorough methods. The aim of this study was to develop and validate the Dutch version of the NFI-MS. METHODS: The original English version of the NFI-MS was translated into Dutch using a forward-backward procedure. Reliability (intraclass correlation coefficient (ICC) and standard error of measurement (SEM)) were assessed for the summary score and the four subscale scores separately. Construct validity was assessed by testing hypotheses about expected correlations between the NFI-MS and other constructs (e.g. impact on functioning and depression) and expected differences on NFI scores between groups defined on the basis of disease type and work status. RESULTS: The reliability analyses (n = 118) showed that the ICC was 0.78 (NFI-MS summary) and ranged from 0.75 to 0.83 for the four subscales and the SEM was 2.5 (NFI-MS summary) and ranged from 1.1 to 2.2 for the four subscales. For construct validity (n = 136), 50 out of the 57 expected hypotheses were confirmed (88 %). CONCLUSION: The present study shows that the Dutch version of the NFI-MS is a reliable and valid self-report questionnaire for measuring fatigue in Dutch patients with MS. PMID- 23440565 TI - The Impact of A "Brief ECT Orientation Module" on The Knowledge and Attitudes of Medical Students Towards ECT in India. AB - BACKGROUND: Electroconvulsive therapy (ECT) continues to be an intervention that attracts controversy in spite of its proven efficacy. There is limited literature on attitude and knowledge of medical students towards ECT from Asian and African countries. AIM: The current study assesses the impact of a "Brief ECT Orientation Module" on the knowledge of and attitudes of Indian medical students towards modified ECT. SUBJECTS AND METHODS: The study was conducted at a tertiary care multi-specialty hospital associated with a government medical college. The students were administered the study questionnaire on Day 1 of Psychiatry clerkship. Following this, they were administered the Brief ECT Orientation Module. Assessment was made using a questionnaire with items related to knowledge and attitude towards ECT before and after "Brief ECT Orientation Module." RESULTS: Fifty-nine students completed the study. There was a significant improvement in knowledge of medical students on all the three domains of the questionnaire for assessment of knowledge about ECT-related facts. A change in attitudes towards ECT was also observed following Brief ECT Orientation Module, especially among those who witnessed ECT administration. CONCLUSION: The findings of the current study suggest that the Brief ECT Orientation Module is effective in improving the knowledge and attitude of medical students towards ECT. PMID- 23440566 TI - Axillary arteriovenous fistula after axillary plexus block. AB - This report presents the case of a 51-year-old man who had an axillary arteriovenous fistula (AVF) as a complication of an axillary plexus block that was performed for internal fixation for a right forefinger phalanx fracture 4 years previously. While performing the axillary plexus block, a 22-gauge needle was placed inside the axillary sheath by observing the pulsations of the axillary artery. A pulsatile mass was found in the right axilla 1 day after the block was performed. Apart from this soft mass, the patient had no symptoms of vascular nerve damage. As the mass gradually increased in size, it became painful. During the past 3 months, in particular, the patient experienced repeated attacks of intermittent sharp pain and requested surgery. Digital subtraction angiography, performed 4 years after the axillary block, showed a tumor-like dilation was developing in both the right axillary artery and vein, almost simultaneously. Thus, the diagnosis of AVF was confirmed. The false aneurysm sac was excised and lateral repair of the axillary artery and vein was carried out under general anesthesia. Postoperative recovery was uneventful. The possible occurrence of an AVF after axillary plexus block should be kept in mind, because early diagnosis and treatment are necessary to avoid development of AVF and false aneurysm. PMID- 23440567 TI - Stability analysis of associative memory network composed of stochastic neurons and dynamic synapses. AB - We investigate the dynamical properties of an associative memory network consisting of stochastic neurons and dynamic synapses that show short-term depression and facilitation. In the stochastic neuron model used in this study, the efficacy of the synaptic transmission changes according to the short-term depression or facilitation mechanism. We derive a macroscopic mean field model that captures the overall dynamical properties of the stochastic model. We analyze the stability and bifurcation structure of the mean field model, and show the dependence of the memory retrieval performance on the noise intensity and parameters that determine the properties of the dynamic synapses, i.e., time constants for depressing and facilitating processes. The associative memory network exhibits a variety of dynamical states, including the memory and pseudo memory states, as well as oscillatory states among memory patterns. This study provides comprehensive insight into the dynamical properties of the associative memory network with dynamic synapses. PMID- 23440568 TI - Endoscopic mucosal ablation: a novel technique for a giant nonampullary duodenal adenoma. PMID- 23440569 TI - HIV seroconversion in the third trimester of pregnancy: using raltegravir to prevent mother-to-child transmission. AB - We describe a case of acute HIV infection in the third trimester of pregnancy associated with an extremely high viral load and the use of raltegravir to prevent HIV mother-to-child transmission. PMID- 23440571 TI - Lymphoepithelioma-like gastric carcinoma: an unusual consequence of Epstein-Barr virus infection in an HIV-infected woman. AB - Lymphoepithelioma-like-gastric carcinoma (LEL-GC) is an Epstein-Barr virus (EBV) associated neoplasm of the stomach reported to have a better prognosis than conventional gastric adenocarcinoma. Unlike other EBV-associated malignancies, particularly lymphoproliferative disorders and undifferentiated nasopharyngeal carcinoma, for which risk has been shown to increase in human immunodeficiency virus (HIV) infection, LEL-GC remains rare; only one HIV-infected patient with LEL-GC has been reported previously. We describe an aggressive case of EBV associated LEL-GC in a woman co-infected with HIV 1 and hepatitis C virus. In situ hybridization of an endoscopic biopsy specimen for EBV-encoded small RNA confirmed the presence of this agent exclusively in the gastric cancer cells. Our patient had recently started antiretroviral therapy, suggesting that immune reconstitution may have been a factor in presentation of this tumour. PMID- 23440570 TI - Effects of once-daily darunavir/ritonavir versus lopinavir/ritonavir on metabolic parameters in treatment-naive HIV-1-infected patients at week 96: ARTEMIS. AB - In the ARTEMIS trial, 689 treatment-naive, HIV-1-infected adults received darunavir/ritonavir (DRV/r) 800/100 mg every day or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose plus fixed-dose tenofovir/emtricitabine. Week 96 metabolic parameters are reported. Adverse events (AEs) classed as metabolism/nutrition disorders were observed in 14% of DRV/r and 22% of LPV/r patients. Lipid-related AEs were reported in fewer DRV/r (8%) than LPV/r (16%) patients. A small increase in glucose and insulin levels was observed at week 96 in both groups. Lipoma was the only lipodystrophy-related AE reported in >1% of patients (DRV/r, n = 1; LPV/r, n = 4) and no grade 3 or 4 lipodystrophy-related AEs were reported. No clinically relevant changes from baseline were seen in anthropometric measurements in either group. Median mid-waist/hip ratio at week 96 was comparable to baseline in both arms. Over 96 weeks, DRV/r had a similar effect on glucose and insulin levels but a more favourable lipid profile than LPV/r in treatment-naive, HIV-infected patients. PMID- 23440572 TI - Decontamination of a polychlorinated biphenyls-contaminated soil by phytoremediation-assisted bioaugmentation. AB - A 70 day pot experiment was conducted for the cleaning-up of a PCBs-contaminated soil (104 mg kg(-1) soil DW) using bioaugmentation with Burkholderia xenovorans LB400 (LB400) assisted or not by the use of tall fescue (Festuca arundinacea). The total cultivable bacteria of the soil were higher with the presence of plants. Real-time PCR showed that LB400 (targeting 16S-23S rRNA ITS) survived with abundance related to total bacteria (targeting 16S rRNA) being higher with fescue (up to a factor of three). Bioaugmentation had a positive effect on fescue biomass and more specifically on roots (by a factor of three). PCB dissipation (sum of congeners 28, 52, 101, 118, 153, 180) averaged 13 % (bioaugmented planted) up to 32 % (non bioaugmented-planted), without any significant difference between treatments. Basically our results demonstrated that indigenous bacteria were able to dissipate PCBs (26.2 % dissipation). PCB dissipation was not related to the abundance of LB400 or to the total bacterial counts. Bioaugmentation or fescue altered the structure of the bacterial community of the soil, not the combination of both. Principal component analysis showed that bioaugmentation tended to improve the control of the process (lower variability in PCB dissipation). Opposite to that bioaugmentation increased the variability of the structure of the bacterial community. PMID- 23440573 TI - Proceedings of the 12th National Conference on Anticoagulant Therapy. PMID- 23440574 TI - Pathophysiology and management of thrombosis in cancer: 150 years of progress. AB - The association of thrombosis with cancer has been recognized since the middle of the nineteenth century. It remains a common and serious complication of the cancer itself, as well as chemotherapy. Thrombosis is the second leading cause of death in cancer patients, second only to the cancer itself. For many years the treatment options for managing thrombosis in cancer had been static, but the past decade has seen significant evolution in the management, with the clear superiority of low molecular weight heparin over warfarin for secondary prevention of thrombosis. This article will review the understanding and management of thrombosis in cancer. PMID- 23440575 TI - Retinal artery occlusions in children. AB - The purpose of this study is to present a case of RAO in a 13 year old girl with a preceding history of hyperextension of the neck at her hairdressers for a long duration and use of her mobile phone handset resting it against the side of her neck presumably exerting some pressure on carotids during the same time. Materials and methods of this study was reported as case report and review of literature. A 13 year-old girl presented with the left supero-nasal scotoma due to an inferior temporal branch retinal artery occlusion (BRAO). She underwent extensive investigations and no underlying cause was discovered. She gave a history of cervical extension over a long period of time while having the hair coloured twice in the preceding week. She also mentioned that she was using her mobile phone more or less continuously during both these occasions keeping it against her neck. Given the above history it is possible that the pressure on the ipsilateral carotid arteries or the prolong neck extension may have been responsible for the formation of a platelet embolus resulting in the BRAO. In conclusion, although cerebro-vascular accidents due to 'beauty parlor stroke syndrome' (JAMA 269:2085-2086, 1993) have been reported previously it has not been reported in children to our knowledge. On the other hand, 'beauty parlor stroke syndrome' occurs due to a dissection of the vertebral arteries or due to mechanical compression of the vertebral arteries during the prolonged hyperextension of the neck. The central retinal artery originates from the internal carotid circulation and it is highly unlikely for an embolus to enter the retinal circulation from the vertebral arteries. Therefore, the authors favour the possibility that the compulsive use of a mobile phone exerting pressure on the carotid arteries for a long time may have led to the formation of an embolus and subsequent RAO in this case. PMID- 23440576 TI - Mobile DNA distributions refine the phylogeny of "matsutake" mushrooms, Tricholoma sect. Caligata. AB - "Matsutake" mushrooms are formed by several species of Tricholoma sect. Caligata distributed across the northern hemisphere. A phylogenetic analysis of matsutake based on virtually neutral mutations in DNA sequences resolved robust relationships among Tricholoma anatolicum, Tricholoma bakamatsutake, Tricholoma magnivelare, Tricholoma matsutake, and Tricholoma sp. from Mexico (=Tricholoma sp. Mex). However, relationships among these matsutake and other species, such as Tricholoma caligatum and Tricholoma fulvocastaneum, were ambiguous. We, therefore, analyzed genomic copy numbers of sigma marY1 , marY1, and marY2N retrotransposons by comparing them with the single-copy mobile DNA megB1 using real-time polymerase chain reaction (PCR) to clarify matsutake phylogeny. We also examined types of megB1-associated domains, composed of a number of poly (A) and poly (T) reminiscent of RNA-derived DNA elements among these species. Both datasets resolved two distinct groups, one composed of T. bakamatsutake, T. fulvocastaneum, and T. caligatum that could have diverged earlier and the other comprising T. magnivelare, Tricholoma sp. Mex, T. anatolicum, and T. matsutake that could have evolved later. In the first group, T. caligatum was the closest to the second group, followed by T. fulvocastaneum and T. bakamatsutake. Within the second group, T. magnivelare was clearly differentiated from the other species. The data suggest that matsutake underwent substantial evolution between the first group, mostly composed of Fagaceae symbionts, and the second group, comprised only of Pinaceae symbionts, but diverged little within each groups. Mobile DNA markers could be useful in resolving difficult phylogenies due to, for example, closely spaced speciation events. PMID- 23440577 TI - Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2 b]quinoline-9,11-dione derivatives. AB - A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC16 = 0.7 MUM) and 31 (IC16 = 1.7 MUM) and 33 (IC16 = 1.7 MUM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C11 position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents. PMID- 23440578 TI - Increased long-term immunity to Bacillus anthracis protective antigen in mice immunized with a CIA06B-adjuvanted anthrax vaccine. AB - Anthrax is an acute infectious disease caused by Bacillus anthracis. We previously reported that the adjuvant CIA06B, which consists of TLR4 agonist CIA05 and aluminum hydroxide (alum), enhanced the immune response to anthrax protective antigen (PA) in mice. This study was carried out to determine whether CIA06B can enhance long-term immune responses to PA in mice. BALB/c mice were immunized intramuscularly three times at 2-week intervals with recombinant PA alone or PA combined with alum or CIA06B. At 8 and 24 weeks post-immunization, the immunological responses including serum anti-PA IgG antibody titer, toxin neutralizing antibody titer, splenic cytokine secretion and the frequency of PA specific memory B cells were assessed. Compared with mice injected with PA alone or PA plus alum, mice injected with PA plus CIA06B had higher titers of serum anti-PA IgG antibodies, and higher frequencies of PA-specific memory B cells and interferon-gamma secreting cells. Furthermore, anti-PA antibodies induced by CIA06B were more effective in neutralizing anthrax toxin. These results demonstrated that CIA06B is capable of providing long-term immunity when used as an adjuvant in a PA-based anthrax vaccine. PMID- 23440579 TI - Antimalarial activity of nepodin isolated from Rumex crispus. AB - The purpose of this study is to define the antimalarial activity of Rumex crispus. To identify an active compound that is isolated from R. crispus, bioassay-based chromatographic fractionation and purification is carried out from 70 % ethanol extract of R. crispus; then, an active compound, nepodin, is identified by spectroscopic analysis. Anitmalarial activity is measured by PfNDH2 assay, cytotoxicity, and animal test. From NADH:quinone oxidoreductase enzyme (PfNDAH2) assay, nepodin exhibited significant IC50 values that were 0.74 +/- 0.07 and 0.79 +/- 0.06 MUg/ml against P. falciparum chloroquine-sensitive (3D7) and P. falciparum chloroquine-resistant (S20), respectively. Nepodin showed a potential selective inhibition (SI index: ratio of 50 % cytotoxic concentration to 50 % effective anti-plasmodial concentration) of 161.6 and 151.4 against P. falciparum 3D7 and P. falciparum S20. In the animal test, all groups of nepodin treatment of 10, 50, and 250 mg/kg were active with a parasitemia suppression of 97.1 +/- 3.3, 99.1 +/- 3.7, and 99.1 +/- 2.6 %, respectively. The survival time with nepodin treatment was increased by 14.6 +/- 2.5, 16.2 +/- 1.5, and 19.8 +/- 1.7 days at each dose, respectively. This study newly identified the plant R. crispus containing nepodin, which is a potential antimalarial compound. It exhibited the inhibitory activity of PfNDH2 and prolonged the survival time on the group of nepodin treatment; moreover, it inhibited the parasitemia in the animal test. PMID- 23440580 TI - Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics. AB - Hypoxia-inducible factors (HIFs) are master regulators of angiogenesis and cellular adaptation in hypoxic microenvironments. Accumulating evidence indicates that HIFs also regulate cell survival, glucose metabolism, microenvironmental remodeling, cancer metastasis, and tumor progression, and thus, HIFs are viewed as therapeutic targets in many diseases. Epigenetic changes are involved in the switching 'on' and 'off' of many genes, and it has been suggested that the DNA hypermethylation of specific gene promoters, histone modifications (acetylation, phosphorylation, and methylation) and small interfering or micro RNAs be regarded epigenetic gene targets for the regulation of disease-associated cellular changes. Furthermore, the hypoxic microenvironment is one of the most important cellular stress stimuli in terms of the regulation of cellular epigenetic status via histone modification. Therefore, drug development and therapeutic approaches to ischemic diseases or cancer for targeting HIFs by modulation of epigenetic status become an attractive area. Here, the authors provide a review of the literature regarding the targeting of HIF, a key modulator of hypoxic-cell response under various disease conditions, by modulating histone or DNA using endogenous small RNAs or exogenous chemicals. PMID- 23440581 TI - Quality assessment and discrimination of the roots of Cynanchum auriculatum and Cynanchum wilfordii by HPLC-UV analysis. AB - Cynanchum auriculatum and Cynanchum wilfordii are widely used as folk medicine in Eastern Asia. However, the indeterminacy in the authentic original plant material has resulted in the same appellative name being given to the two plants, and they are commonly misused. Therefore, it is necessary to establish an analytical method for discrimination as well as quality control of the two species. This study was to develop HPLC-UV methods for quality assessment of C. auriculatum and C. wilfordii and discrimination between the two species. Two HPLC methods to analyze eight marker compounds were established and validated. The first method analyzed seven marker compounds simultaneously on a reversed-phase column, while the second method analyzed a single marker compound, conduritol F, which exists only in C. wilfordii, on a Si-column. Thirty-nine batches of C. auriculatum and nineteen batches of C. wilfordii that were collected from different geographical regions of South Korea were analyzed by these methods. The constructed data matrix was subjected to principal components analysis and hierarchical cluster analysis in order to classify the samples. The established methods offer a potential strategy for authentication and differentiation of the two species. PMID- 23440582 TI - Novel 1-(4-substituted benzylidene)-4-(1-(substituted methyl)-2,3-dioxoindolin-5 yl)semicarbazide derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) and MDR-TB strain. AB - A series of eighteen new 1-(4-substituted benzylidene)-4-(1-(substituted methyl) 2,3-dioxoindolin-5-yl)semicarbazide derivatives were designed, synthesized and characterized by spectral and elemental analyses. The derivatives were screened in vitro for antimicrobial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) and MDR-TB strains. The activity was expressed as the minimum inhibitory concentration in MUg/mL. Among the tested compounds 7j, 7m, 7o and 7q possesses equipotent activity as standard drug Isoniazid against MTB while 7m and 7q exhibited higher activity against MDR-TB strain when compared with both the reference drugs isoniazid and rifampicin. Basic structure activity relationships are presented. PMID- 23440583 TI - A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats. AB - In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of MU-opioid receptor agonists: fentanyl (4 anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (+/-)-cis-3 methyl fentanyl (CM), (+/-)-cis-3-carbomethoxy fentanyl (C), (+/-)trans-3 carbomethoxy fentanyl (T) and (+/-)-cis-3 butyl fentanyl (B) produced dose dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27)>F(1)>C(0.35)>=T(0.11)>=B(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43)>F(1)>C(0.46)>=T(0.11)>=B(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy alpha,alpha,17-trimethyl-, (5alpha,7alpha) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56)>O(5)>=T(2.6)>M(1), and similar to this, the relative order of hyperthermic potency was: E(37)>O(3)>=T(2.3)>M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings. PMID- 23440584 TI - ERCP. PMID- 23440585 TI - Small-bowel enteroscopy. PMID- 23440586 TI - Gastrointestinal bleeding. PMID- 23440587 TI - Endoscopic ultrasound. PMID- 23440588 TI - Nonpolypoid colorectal neoplasms: a challenge in endoscopic surveillance of patients with Lynch syndrome. AB - BACKGROUND AND STUDY AIMS: Patients with Lynch syndrome may develop colorectal cancer (CRC), despite intensive colonoscopic surveillance. Nonpolypoid colorectal neoplasms might be a major contributor to the occurrence of these cancers. The aim of this case - control study was to compare the endoscopic appearance of colorectal neoplasms between patients with Lynch syndrome and control individuals at average risk for CRC. PATIENTS AND METHODS: The endoscopists at the Maastricht University Medical Center were first given training to ensure familiarity with the appearance and classification of nonpolypoid lesions. Patients with Lynch syndrome and patients at average risk for CRC who underwent elective colonoscopy at the Center were prospectively included. Nonpolypoid lesions were defined as lesions with a height of less than half the diameter, and advanced histology was defined as the presence of high grade dysplasia or early cancer. RESULTS: A total of 59 patients with Lynch syndrome (mean age 48.7 years, 47.5 % men) and 590 matched controls (mean age 50.2 years, 47.5 % men) were included. In patients with Lynch syndrome, adenomas were significantly more likely to be nonpolypoid than they were in controls: 43.3 % vs. 16.9 % (OR 3.60, 95 %CI 1.90 - 6.83; P < 0.001). This was particularly true for proximal adenomas: 58.1 % vs. 16.3 % (OR 6.93, 95 %CI 2.92 - 16.40; P < 0.001). Adenomas containing advanced histology were more often nonpolypoid in patients with Lynch syndrome than in controls (4/5, 80.0 % vs. 5/17, 29.4 %; P = 0.19). Serrated polyps were also more often nonpolypoid in patients with Lynch syndrome than in controls: 49.2 % vs. 20.4 % (OR 3.57, 95 %CI 1.91 - 6.68; P < 0.001). CONCLUSIONS: In patients with Lynch syndrome, colorectal neoplasms are more likely to have a nonpolypoid shape than those from average risk patients, especially in the proximal colon. These findings suggest that proficiency in recognition and endoscopic resection of nonpolypoid colorectal lesions are needed to ensure colonoscopic prevention against CRC in this high risk population. PMID- 23440589 TI - Genetic genealogy comes of age: perspectives on the use of deep-rooted pedigrees in human population genetics. AB - In this article, we promote the implementation of extensive genealogical data in population genetic studies. Genealogical records can provide valuable information on the origin of DNA donors in a population genetic study, going beyond the commonly collected data such as residence, birthplace, language, and self reported ethnicity. Recent studies demonstrated that extended genealogical data added to surname analysis can be crucial to detect signals of (past) population stratification and to interpret the population structure in a more objective manner. Moreover, when in-depth pedigree data are combined with haploid markers, it is even possible to disentangle signals of temporal differentiation within a population genetic structure during the last centuries. Obtaining genealogical data for all DNA donors in a population genetic study is a labor-intensive task but the vastly growing (genetic) genealogical databases, due to the broad interest of the public, are making this job more time-efficient if there is a guarantee for sufficient data quality. At the end, we discuss the advantages and pitfalls of using genealogy within sampling campaigns and we provide guidelines for future population genetic studies. PMID- 23440590 TI - Effect of oxygen free radicals and nitric oxide on apoptosis of immune organ induced by selenium deficiency in chickens. AB - Selenium is an essential element with antioxidant roles in immune regulation, but there is little understanding of how Se acts in apoptosis in the immune organs of birds. The aim of study was to evaluate the influence of Se deficiency on oxygen free radicals, NO and apoptosis in immune organ of chickens. 160 1-day-old chickens were randomly assigned to two groups of 80 each and were fed on a low-Se diet (0.032 mg/kg Se) or a control diet (0.282 mg/kg Se), respectively. OFR production in blood was determined on days 30, 45, 60 and 75, respectively. The iNOS-NO system activity in immune organ (thymus, spleen, bursa of fabricius) was identified by NO content and NOS activity assay on days 30, 45, 60 and 75, respectively. Apoptosis was measured by DNA ladder analysis, ultrastructural observations, TdT-mediated dUTP nick end labeling TUNEL assay and flow cytometric analysis of apoptotic DNA. The transcription of factor-associated suicide, caspase-3 mRNA was tested by fluorescence quantitative PCR. The results showed that OFR production, NO and inducible NO synthases (iNOS) activity in the low-Se group were significantly increased (p < 0.05) than in the control group. In addition, apoptosis was observed in chicken immune organ in the low-Se group. The degree and the number of apoptotic cells rose in a time-dependent manner. The expression of Fas and caspase-3 mRNA increased (p < 0.05) than in the control group. It indicated that the oxidative stress and NO played a causative role in the apoptosis of immune tissues induced by selenium deficiency. PMID- 23440591 TI - Direct effects of Moringa oleifera Lam (Moringaceae) acetone leaf extract on broiler chickens naturally infected with Eimeria species. AB - Avian coccidiosis is one of the most important diseases of poultry and it is responsible for a large number of all broiler mortalities worldwide. The control of this disease relies mainly on the use of anticoccidial drugs. However, herbal preparations could be an alternative for the treatment against coccidiosis in chickens. The direct effects of Moringa oleifera acetone extracts on broiler chickens naturally infected with mixed Eimeria species was investigated to determine the relative efficacy of the extracts against coccidiosis in birds. The investigations were carried out in seven groups (ten chickens per group). The birds were given various doses (1.0, 2.0, 3.0, 4.0 and 5.0 g/kg body weight) of acetone extract of leaves of M. toltrazuril (positive control) and untreated (negative control). The extract was evaluated for anticoccidial activity by means of inhibition of oocyst output in faeces, faecal score, weight gain and mortality. Haematological indices were evaluated by standard methods. The group treated with 1.0 g/ kg body weight Moringa oleifera extract produced the least inhibitory effect on oocyst shed in the faeces (96.4%), while the groups treated with 2.0 g/kg, 3.0 g/kg, 4.0 g/kg and 5.0 g/kg body weight of the extract produced 97.4, 98.7, 99.1 and 99.8%, respectively. Body weight gains of infected chickens treated with the extract significantly improved (p < 0.05), and faecal scores were milder. Packed cell volume, haemoglobin concentration and red blood count of the treated birds were significantly (p < 0.05) higher than those of the infected untreated group. Moringa oleifera leaves could find application in the treatment of avian coccidiosis in veterinary practice. PMID- 23440592 TI - Gliomas in children. AB - OPINION STATEMENT: Gliomas are the most common brain tumor in children and represent nearly 50 % of all pediatric central nervous system (CNS) tumors. They are a heterogeneous group of diseases, ranging from highly malignant and frequently fatal to histologically benign and curable by surgery alone. A uniform treatment approach to these tumors is not practical, due to their histological and biological heterogeneity. Low-grade gliomas (LGGs) are best treated with maximally safe surgical resection, generally achievable for hemispheric or cerebellar locations. Patients with deep midline, optic pathway/hypothalamic, and brain stem locations should undergo subtotal resection or biopsy only. If a complete resection is not feasible, subtotal resection followed by adjuvant chemotherapy or radiotherapy is the standard approach; however, observation alone with serial neuroimaging is used in some asymptomatic, surgically inaccessible lesions. Chemotherapy is used first-line in cases of residual or progressive disease, to avoid or delay radiation therapy and its associated side effects. Regimens demonstrating objective responses and increased progression free survival (PFS) include carboplatin and vincristine (CV), thioguanine/procarbazine/CCNU/vincristine (TPCV), or weekly vinblastine. High grade gliomas (HGGs) are less common in children than in adults, though are similar in their aggressive clinical behavior, resistance to therapy, and dismal outcomes. There is not a single "standard of care" therapy for non-metastatic HGGs, but generally accepted is an aggressive attempt at a complete surgical resection, followed by multimodality therapy with focal radiation and chemotherapy. The use of temozolomide (TMZ) during and following radiotherapy is common, though it appeared not to improve the outcome in a cooperative group clinical trial when compared to an historical control cohort. The angiogenesis inhibitor bevacizumab, used alone or in combination with irinotecan, is also commonly used as maintenance therapy after radiation. Current trials are prospectively comparing TMZ to newer agents (vorinostat, bevacizumab) in a randomized phase II trial. Brainstem gliomas are a unique category of childhood gliomas. Approximately 80 % of childhood brainstem gliomas arise within the pons as diffuse intrinsic pontine gliomas (DIPG). When biopsied, these are usually HGGs and carry a dismal prognosis. Standard therapy is focal radiation (54-58 Gy), preferably on a clinical trial testing concurrent chemotherapy or biologic agent. No standard chemotherapy agent has impacted survival. The remaining 20 % of brainstem gliomas are low-grade, arise in the midbrain, dorsal medulla, or cervicomedullary junction, and are indolent in nature with a much better prognosis. Improvement in the outcome of all childhood gliomas will require increased knowledge of the underlying biology of these tumors, in order to treat with more biologically based and precise therapies. PMID- 23440593 TI - Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. AB - CONTEXT: Idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (HP) are diffuse parenchymal lung diseases characterized by a mixture of inflammation and fibrosis, leading to lung destruction and finally death. AIMS: The aim of this study was to compare different pathophysiological mechanisms, such as angiogenesis, coagulation, fibrosis, tissue repair, inflammation, epithelial damage, oxidative stress, and matrix remodeling, in both disorders using bronchoalveolar lavage (BAL). METHODS: at diagnosis, patients underwent bronchoscopy with BAL and were divided into three groups: Control (n = 10), HP (n = 11), and IPF (n = 11), based on multidisciplinary approach (clinical examination, radiology, and histology): Multiplex searchlight technology was used to analyze 25 proteins representative for different pathophysiological processes: Eotaxin, basic fibroblast growth factor (FGFb), fibronectin, hepatocyte growth factor (HGF), interleukine (IL)-8, IL-12p40, IL-17, IL-23, monocyte chemotactic protein (MCP-1), macrophage-derived chemokine (MDC), myeloperoxidase (MPO), matrix metalloproteinase (MMP)-8, MMP-9, active plasminogen activating inhibitor 1 (PAI-1), pulmonary activation regulated chemokine (PARC), placental growth factor (PlGF), protein-C, receptor for advanced glycation end products (RAGE), regulated on activation normal T cells expressed and secreted (RANTES), surfactant protein-C (SP-C), transforming growth factor-beta1 (TGF-beta1), tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue factor, thymic stromal lymphopoietin (TSLP), and vascular endothelial growth factor (VEGF). RESULTS: All patients suffered from decreased pulmonary function and abnormal BAL cell differential compared with control. Protein levels were increased in both IPF and HP for MMP-8 (P = 0.022), MMP-9 (P = 0.0020), MCP-1 (P = 0.0006), MDC (P = 0.0048), IL-8 (P = 0.013), MPO (P = 0.019), and protein-C (P = 0.0087), whereas VEGF was decreased (P = 0.0003) compared with control. HGF was upregulated in HP (P = 0.0089) and active PAI-1 was upregulated (P = 0.019) in IPF compared with control. Differences in expression between IPF and HP were observed for IL-12p40 (P = 0.0093) and TGF-beta1 (P = 0.0045). CONCLUSIONS: Using BAL, we demonstrated not only expected similarities but also important differences in both disorders, many related to the innate immunity. These findings provide new clues for further research in both disorders. PMID- 23440595 TI - Normative beliefs about aggression and cyber aggression among young adults: a longitudinal investigation. AB - This longitudinal study examined normative beliefs about aggression (e.g., face to-face, cyber) in relation to the engagement in cyber aggression 6 months later among 126 (69 women) young adults. Participants completed electronically administered measures assessing their normative beliefs, face-to-face and cyber aggression at Time 1, and cyber aggression 6 months later (Time 2). We found that men reported more cyber relational and verbal aggression when compared to women. After controlling for each other, Time 1 face-to-face relational aggression was positively related to Time 2 cyber relational aggression, whereas Time 1 face-to face verbal aggression was positively related to Time 2 cyber verbal aggression. Normative beliefs regarding cyber aggression was positively related to both forms of cyber aggression 6 months later, after controlling for normative beliefs about face-to-face aggression. Furthermore, a significant two-way interaction between Time 1 cyber relational aggression and normative beliefs about cyber relational aggression was found. Follow-up analysis showed that Time 1 cyber relational aggression was more strongly related to Time 2 cyber relational aggression when young adults held higher normative beliefs about cyber relational aggression. A similar two-way interaction was found for cyber verbal aggression such that the association between Time 1 and Time 2 cyber verbal aggression was stronger at higher levels of normative beliefs about cyber verbal aggression. Results are discussed in terms of the social cognitive and behavioral mechanisms associated with the engagement of cyber aggression. PMID- 23440594 TI - The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules in glioma cells is mediated by cell cycle regulation, differentiation, and the inhibition of survival pathways. AB - Despite recent advances in radiotherapy, chemotherapy, and surgical techniques, glioblastoma multiforme (GBM) prognosis remains dismal. There is an urgent need for new therapeutic strategies. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intense interest in recent years because they can provide sustained, controlled, and targeted delivery. Here, we investigate the mechanisms involved in the antiproliferative effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNC) in glioma cells. IndOH LNC were able to reduce cell viability by inducing apoptotic cell death in C6 and U138-MG glioma cell lines. Interestingly, IndOH-LNC did not affect the viability of primary astrocytes, suggesting that this formulation selectively targeted transformed cells. Mechanistically, IndOH-LNC induced inhibition of cell growth and cell-cycle arrest to be correlated with the inactivation of AKT and beta catenin and the activation of GSK-3beta. IndOH-LNC also induced G0/G1 and/or G2/M phase arrest, which was accompanied by a decrease in the levels of cyclin D1, cyclin B1, pRb, and pcdc2 and an increase in the levels of Wee1 CDK inhibitor p21(WAF1). Additionally, IndOH-LNC promoted GBM cell differentiation, observed as upregulation of glial fibrillary acidic protein (GFAP) protein and downregulation of nestin and CD133. Taken together, the crosstalk among antiproliferative effects, cell-cycle arrest, apoptosis, and cell differentiation should be considered when tailoring pharmacological interventions aimed at reducing glioma growth by using formulations with multiples targets, such as IndOH-LNC. PMID- 23440596 TI - Gene Expression Profiling Reveals Regulation of ERK Phosphorylation by Androgen Induced Tumor Suppressor U19/EAF2 in the Mouse Prostate. AB - U19/EAF2 is regulated by androgens in the prostate and capable of regulating transcriptional elongation of RNA Pol II via interaction with the ELL family proteins. Inactivation of U19/EAF2 induces tumorigenesis in multiple organs; however the mechanism of U19/EAF2 tumor suppression remains unclear. To elucidate potential mechanisms of U19/EAF2 action, we performed cDNA microarray analysis and identified 164 mRNA transcripts regulated by U19/EAF2 in the mouse ventral prostate. Bioinformatics analysis indicated that U19/EAF2 knockout activates the RAS-BRAF-ERK signaling pathway, which is known to play important roles in carcinogenesis. qPCR verified increased expression of BRAF mRNA, and immunostaining and Western blot analysis demonstrated increased expression of p ERK at the protein level suggested U19/EAF2 knockout activates this important pathway. These findings indicate that loss of EAF2 up-regulates transcription of RAS cascade genes including Grb2, PI3K, and BRAF, leading to elevated p-ERK levels, which may represent a major functional role of U19/EAF2 in the prostate. Furthermore, these observations suggest that U19/EAF2 is a key player in crosstalk between androgen receptor and the RAS-BRAF-ERK signaling pathway. PMID- 23440597 TI - Dual treatment of hemichorea-hemiballismus syndrome with tetrabenazine and chemodenervation. AB - BACKGROUND: Hemichorea-hemiballismus involves unilateral involuntary flailing movements and random jerking movements involving proximal or distal muscles. We describe a case of hemichorea-hemiballismus with dystonia after stroke. Treatment with tetrabenazine and chemodenervation produced beneficial responses. Effective treatment of both hemichorea-hemiballismus and dystonia due to stroke has not been reported. CASE REPORT: A 65-year-old male developed left hemichorea hemiballismus and dystonia after a right hemisphere stroke. He underwent initial treatment with neuroleptics and anticonvulsants without improvement. Subsequent treatment with tetrabenazine improved the hemichorea-hemiballismus and chemodenervation reduced the dystonia. DISCUSSION: Hemichorea-hemiballismus associated with dystonia can be improved with both tetrabenazine and chemodenervation. PMID- 23440599 TI - [Surgical management of persisting fistulas after salvage-laryngectomy]. AB - BACKGROUND: The salvage-laryngectomy (SLE) has compared to the laryngectomy a high risk for complications. The salivary fistula is the most frequent complication with an incidence range from 3% to 65% according to the literature. MATERIAL AND METHODS: From 2004-2011 we included in this study 16 patients with a recurrent or secondary T4a-squamous cell carcinoma (HNSCC) of the larynx or pyriform sinus undergoing a SLE. 6 HNSCC were located at the pyriform sinus (44%) and 9 at the larynx (56%). The aim of this retrospective study was to analyze the risk of developing a postoperative fistula after SLE as well as to present our surgical concept of persisting fistula treatment. RESULTS: 6 out of these 16 patients (38%) had a persisting fistula which needed a secondary surgical closure. In all of these cases we used a "sandwich"-concept which included a reconstruction of the pharynx by the pectoralis myofascial flap and another regional rotation flap as the deltopectoral flap or the latissimus dorsi flap for skin reconstruction of the neck. With this concept we were able to successfully close the fistula after the SLE in all 6 cases. CONCLUSION: By using our "sandwich"-concept we provide a multi-layered fistula closure with insertion of vital muscle tissue and a double epithelium. This guarantees a secure barrier to the saliva and prevents effectively a further fistula. PMID- 23440601 TI - Exploring Adsorption of Water and Ions on Carbon Surfaces using a Polarizable Force Field. AB - Graphene, carbon nanotubes, and fullerenes are of great interest due to their unique properties and diverse applications in biology, molecular electronics, and materials science. Therefore, there is demand for methods that can accurately model the interface between carbon surfaces and their environment. In this letter we compare results for complexes of water, potassium ion, and chloride ion with graphene, carbon nanotube, and fullerene surfaces using a standard non polarizable force field (OPLS-AA), a polarizable force field (OPLS-AAP), DFT, and ab initio theory. For interactions with water, OPLS-AA with the TIP3P or TIP4P water models describes the interactions with benzene (C(6)H(6)) and coronene (C(24)H(12)) well; however, for acenes larger than circumcoronene (C(54)H(18)) and especially for C(60), the interaction energies are somewhat too weak and polarization is needed. For ions interacting with carbon surfaces, inclusion of polarization is essential, and OPLS-AAP is found to perform well in comparison to the highest-level quantum mechanical methods. Overall, OPLS-AAP provides an accurate and computationally efficient force field for modeling condensed-phase systems featuring carbon surfaces. PMID- 23440598 TI - Update on the Non-Huntington's Disease Choreas with Comments on the Current Nomenclature. AB - CHOREA CAN BE CAUSED BY A MULTITUDE OF ETIOLOGIES: neurodegenerative, pharmacological, structural, metabolic, and others. In absence of other apparent causes, exclusion of Huntington's disease is often a first step in the diagnostic process. There are a number of neurodegenerative disorders whose genetic etiology has been identified in the past decade. Molecular diagnosis has enabled genetic identification of disorder subtypes which were previously grouped together, such as the neurodegeneration with brain iron accumulation disorders and the neuroacanthocytosis syndromes, as well as identification of phenotypic outliers for recognized disorders. Correct molecular diagnosis is essential for genetic counseling and, hopefully, ultimately genetic therapies. In addition, there has recently been recognition of other disorders which can mimic neurodegenerative disorders, including paraneoplastic and prion disorders. This article focuses upon recent developments in the field but is not intended to provide an exhaustive review of all causes of chorea, which is available elsewhere. I also discuss the nomenclature of these disorders which has become somewhat unwieldy, but may ultimately be refined by association with the causative gene. PMID- 23440602 TI - Visualization of mitotic arrest of cell cycle with bioluminescence imaging in living animals. AB - PURPOSE: Visualization of the cell cycle in living subjects has long been a big challenge. The present study aimed to noninvasively visualize mitotic arrest of the cell cycle with an optical reporter in living subjects. PROCEDURES: An N terminal cyclin B1-luciferase fusion construct (cyclin B-Luc) controlled by the cyclin B promoter, as a mitosis reporter, was generated. HeLa or HCT116 cells stably expressing cyclin B-Luc reporter were used to evaluate its cell cycle dependent regulation and ubiquitination-mediated degradation. We also evaluated its feasibility to monitor the mitotic arrest caused by Taxotere both in vitro and in vivo. RESULTS: We showed that the cyclin B-Luc fusion protein was regulated in a cell cycle-dependent manner and accumulated in the mitotic phase (M phase) in cellular assays. The regulation of cyclin B-Luc reporter was mediated by proteasome ubiquitination. In the present study, in vitro imaging showed that antimitotic reagents like Taxotere upregulated the reporter through cell cycle arrest in the M phase. Noninvasive longitudinal bioluminescence imaging further demonstrated an upregulation of the reporter consistent with mitotic arrest induced in tumor xenograft models. Induction of this reporter was also observed with a kinesin spindle protein inhibitor, which causes cell cycle blockage in the M phase. CONCLUSIONS: Our results demonstrate that the cyclin B Luc reporter can be used to image whether compounds are capable, in vivo, of causing an M phase arrest and/or altering cyclin B turnover. This reporter can also be potentially used in high-throughput screening efforts aimed at discovering novel molecules that will cause cell cycle arrest at the M phase in cultivated cell lines and animal models. PMID- 23440603 TI - Implications of systemic dysfunction for the etiology of malignancy. AB - The current approach to treatment in oncology is to replace the generally cytotoxic chemotherapies with pharmaceutical treatment which inactivates specific molecular targets associated with cancer development and progression. The goal is to limit cellular damage to pathways perceived to be directly responsible for the malignancy. Its underlying assumptions are twofold: (1) that individual pathways are the cause of malignancy; and (2) that the treatment objective should be destruction-either of the tumor or the dysfunctional pathway. However, the extent to which data actually support these assumptions has not been directly addressed. Accumulating evidence suggests that systemic dysfunction precedes the disruption of specific genetic/molecular pathways in most adult cancers and that targeted treatments such as kinase inhibitors may successfully treat one pathway while generating unintended changes to other, non-targeted pathways. This article discusses (1) the systemic basis of malignancy; (2) better profiling of pre cancerous biomarkers associated with elevated risk so that preventive lifestyle modifications can be instituted early to revert high-risk epigenetic changes before tumors develop; (3) a treatment emphasis in early stage tumors that would target the restoration of systemic balance by strengthening the body's innate defense mechanisms; and (4) establishing better quantitative models of systems to capture adequate complexity for predictability at all stages of tumor progression. PMID- 23440605 TI - A client-server framework for 3D remote visualization of radiotherapy treatment space. AB - Radiotherapy is safely employed for treating wide variety of cancers. The radiotherapy workflow includes a precise positioning of the patient in the intended treatment position. While trained radiation therapists conduct patient positioning, consultation is occasionally required from other experts, including the radiation oncologist, dosimetrist, or medical physicist. In many circumstances, including rural clinics and developing countries, this expertise is not immediately available, so the patient positioning concerns of the treating therapists may not get addressed. In this paper, we present a framework to enable remotely located experts to virtually collaborate and be present inside the 3D treatment room when necessary. A multi-3D camera framework was used for acquiring the 3D treatment space. A client-server framework enabled the acquired 3D treatment room to be visualized in real-time. The computational tasks that would normally occur on the client side were offloaded to the server side to enable hardware flexibility on the client side. On the server side, a client specific real-time stereo rendering of the 3D treatment room was employed using a scalable multi graphics processing units (GPU) system. The rendered 3D images were then encoded using a GPU-based H.264 encoding for streaming. Results showed that for a stereo image size of 1280 * 960 pixels, experts with high-speed gigabit Ethernet connectivity were able to visualize the treatment space at approximately 81 frames per second. For experts remotely located and using a 100 Mbps network, the treatment space visualization occurred at 8-40 frames per second depending upon the network bandwidth. This work demonstrated the feasibility of remote real-time stereoscopic patient setup visualization, enabling expansion of high quality radiation therapy into challenging environments. PMID- 23440606 TI - Functional plasticity of the human humerus: shape, rigidity, and muscular entheses. AB - The relationship between the mechanical loading undergone by a bone and its form has been widely assumed as a premise in studies aiming to reconstruct behavioral patterns from skeletal remains. Nevertheless, this relationship is complex due to the existence of many factors affecting bone structure and form, and further research combining structural and shape characteristics is needed. Using two block PLS, which is a test to analyze the covariance between two sets of variables, we aim to investigate the relationship between upper-limb entheseal changes, cross-sectional properties, and contour shape of the humeral diaphysis. Our results show that individuals with strongly marked entheseal changes have increased diaphyseal rigidities. Bending rigidities are mainly related to entheseal changes of muscles that cross the shoulder. Moreover, the entheseal changes of muscles that participate in the rotation of the arm are related to mediolaterally flatter and ventrodorsally broader humeral shapes in the mid proximal diaphysis. In turn, this diaphyseal shape is related to diaphyseal rigidity, especially to bending loadings. The shape of the diaphysis of the rest of the humerus does not covary either with rigidity or with entheseal changes. The results indicate that large muscular scars, such as those found in the mid proximal diaphyses, seem to be related to diaphyseal shape, whereas this relationship is not seen for areas with less direct influences of powerful muscles. PMID- 23440607 TI - Electromagnetic energy radiated from mobile phone alters electrocardiographic records of patients with ischemic heart disease. AB - BACKGROUND: Electromagnetic energy radiated from mobile phones did not show significant effect on the blood pressure, heart rate, and electrocardiographic (ECG) parameters in animals and humans. AIM: This study aimed to investigate the effect of radiofrequency of mobile phone on the electrocardiographic parameters in patients with history of ischemic heart disease, taking into consideration the gender factor. SUBJECTS AND METHODS: A total number of 356 participants (129 males and 227 females) were admitted in this study. They were grouped into: subjects without cardiac diseases (Group I), patients with ischemic heart disease (Group II), and patients with history of cardiac diseases not related to myocardial ischemia (Group III). Electrocardiogram was obtained from each patient when the mobile phone was placed at the belt level and over precordium in turn off mode (baseline) and turn-on mode for 40 sec ringing. The records of ECG were electronically analyzed. RESULTS: Prolongation of QTc interval was significantly observed in male gender of Groups I and III (P < 0.001). Male patients of Group II showed significant QTc interval prolongation (P = 0.01) and changes in the voltage criteria (P = 0.001). These changes were not observed in female patients with ischemic heart disease. The position of mobile at the belt level or over the precordium showed effects on the heart. CONCLUSIONS: The radiofrequency of cell phone prolongs the QT interval in human beings and it interferes with voltage criteria of ECG records in male patients with myocardial ischemia. PMID- 23440608 TI - Silicon detectors for combined MR-PET and MR-SPECT imaging. AB - Silicon based devices can extend PET-MR and SPECT-MR imaging to applications, where their advantages in performance outweigh benefits of high statistical counts.Silicon is in many ways an excellent detector material with numerous advantages, among others: excellent energy and spatial resolution, mature processing technology, large signal to noise ratio, relatively low price, availability, versatility and malleability. The signal in silicon is also immune to effects of magnetic field at the level normally used in MR devices. Tests in fields up to 7 T were performed in a study to determine effects of magnetic field on positron range in a silicon PET device. The curvature of positron tracks in direction perpendicular to the field's orientation shortens the distance between emission and annihilation point of the positron. The effect can be fully appreciated for a rotation of the sample for a fixed field direction, compressing range in all dimensions. A popular Ga-68 source was used showing a factor of 2 improvement in image noise compared to zero field operation. There was also a little increase in noise as the reconstructed resolution varied between 2.5 and 1.5 mm.A speculative applications can be recognized in both emission modalities, SPECT and PET.Compton camera is a subspecies of SPECT, where a silicon based scatter as a MR compatible part could inserted into the MR bore and the secondary detector could operate in less constrained environment away from the magnet. Introducing a Compton camera also relaxes requirements of the radiotracers used, extending the range of conceivable photon energies beyond 140.5 keV of the Tc 99m.In PET, one could exploit the compressed sub-millimeter range of positrons in the magnetic field. To exploit the advantage, detectors with spatial resolution commensurate to the effect must be used with silicon being an excellent candidate. Measurements performed outside of the MR achieving spatial resolution below 1 mm are reported. PMID- 23440609 TI - Polyneuropathy and myopathy in the elderly. AB - Critical illness polyneuropathy and myopathy is associated with intensive care unit therapies; it is an independent predictor of mortality and will be increasingly affecting the practice of critical care. Most patients with this illness are over 50 years of age, and as our population demographics shift in favor of an aging population, physicians must be aware that this malady will have a rising incidence in the perioperative period. Intensivists, anesthesiologists, surgeons, and geriatricians/internists must remain vigilant. Here we present a concise overview of critical illness polyneuropathy and myopathy, its diagnosis, associations, and possible interventions. PMID- 23440610 TI - Incorporating data from various trial designs into a mixed treatment comparison model. AB - Estimates of relative efficacy between alternative treatments are crucial for decision making in health care. Bayesian mixed treatment comparison models provide a powerful methodology to obtain such estimates when head-to-head evidence is not available or insufficient. In recent years, this methodology has become widely accepted and applied in economic modelling of healthcare interventions. Most evaluations only consider evidence from randomized controlled trials, while information from other trial designs is ignored. In this paper, we propose three alternative methods of combining data from different trial designs in a mixed treatment comparison model. Naive pooling is the simplest approach and does not differentiate between-trial designs. Utilizing observational data as prior information allows adjusting for bias due to trial design. The most flexible technique is a three-level hierarchical model. Such a model allows for bias adjustment while also accounting for heterogeneity between-trial designs. These techniques are illustrated using an application in rheumatoid arthritis. PMID- 23440611 TI - The relationship between anemia, liver disease, and hepcidin levels in hemodialysis patients with hepatitis. AB - We investigated the role of hepcidin in ameliorating anemia in hemodialysis patients with hepatitis. A total of 72 hemodialysis patients with hepatitis were classified according to their requirement of erythropoietin (EPO). Anemia parameters, C-reactive protein (CRP), and biochemical measurements were recorded along with the hepcidin. The number of patients receiving no EPO was higher among patients with liver disease when compared with those without liver disease (P = 0.002). The mean hepcidin levels of the patients who did not receive EPO did not differ statistically from those of the patients who received the maximum dose (P = 0.5). The hepcidin levels of patients with liver disease who received no EPO were lower compared to those patients without liver disease who received the maximum dose (P = 0.04). There was a positive correlation between hepcidin and mean platelet levels (r = 0.26, P = 0.027) and annual intravenous iron dose (r = 0.31, P = 0.007). In hemodialysis patients with hepatitis, liver disease may be one of the factors affecting erythropiesis, related with decreased hepcidin levels and iron hemostasis. Further studies are needed to verify these associations. PMID- 23440613 TI - A new day dawning: Hemerocallis (daylily) as a future model organism. AB - Genetic model organisms have revolutionized science, and today, with the rapid advances in technology, there is significant potential to launch many more plant species towards model status. However, these new model organisms will have to be carefully selected. Here, we argue that Hemerocallis (daylily) satisfies multiple criteria for selection and deserves serious consideration as a subject of intensive biological investigation. Several attributes of the genus are of great biological interest. These include the strict control of flower opening and, within a short period, the precisely regulated floral death by a programmed cell death system. The self-incompatibility system in Hemerocallis is also noteworthy and deserves more attention. Importantly, the genus is widely cultivated for food, medicinal value and ornamental interest. Hemerocallis has considerable potential as a 'nutraceutical' food plant and the source of new compounds with biomedical activity. The genus has also been embraced by ornamental plant breeders and the extraordinary morphological diversity of hybrid cultivars, produced within a relatively short time by amateur enthusiasts, is an exceptional resource for botanical and genetic studies. We explore these points in detail, explaining the reasons why this genus has considerable value-both academic and socio-economic-and deserves new resources devoted to its exploration as a model. Its impact as a future model will be enhanced by its amenability to cultivation in laboratory and field conditions. In addition, established methods for various tissue and cell culture systems as well as transformation will permit maximum exploitation of this genus by science. PMID- 23440612 TI - Regulatory genomics: Insights from the zebrafish. AB - The sequencing of many vertebrate species over the last decade has opened up the possibility of using comparative genomics as a powerful tool to elucidate regulatory elements in the vertebrate genome. The zebrafish has played a pivotal role in this process. Its genome has been used in large-scale genome comparisons to locate vertebrate specific regulatory elements and also it has been an excellent model system to test out the predicted DNA sequences for their ability to drive reporter gene expression in vivo. In spite of all the successes there have still been some issues in using the zebrafish as a model system for these kinds of assays. This review will shed some light on the successes and failures of the zebrafish in pushing forward regulatory genomics. PMID- 23440614 TI - Sudarshan kriya yoga: Breathing for health. AB - Breathing techniques are regularly recommended for relaxation, stress management, control of psychophysiological states, and to improve organ function. Yogic breathing, defined as a manipulation of breath movement, has been shown to positively affect immune function, autonomic nervous system imbalances, and psychological or stress-related disorders. The aim of this study was to assess and provide a comprehensive review of the physiological mechanisms, the mind-body connection, and the benefits of Sudarshan Kriya Yoga (SKY) in a wide range of clinical conditions. Various online databases searched were Medline, Psychinfo, EMBASE, and Google Scholar. All the results were carefully screened and articles on SKY were selected. The references from these articles were checked to find any other potentially relevant articles. SKY, a unique yogic breathing practice, involves several types of cyclical breathing patterns, ranging from slow and calming to rapid and stimulating. There is mounting evidence to suggest that SKY can be a beneficial, low-risk, low-cost adjunct to the treatment of stress, anxiety, post-traumatic stress disorder, depression, stress-related medical illnesses, substance abuse, and rehabilitation of criminal offenders. PMID- 23440615 TI - Rapid Identification and Drug Susceptibility Testing of Mycobacterium tuberculosis: Standard Operating Procedure for Non-Commercial Assays: Part 3: Colorimetric Redox Indicator Assay v1.3.12. AB - The previous two standard operating procedures (SOPs) related to the culture and drug susceptibility testing (DST) of Mycobacterium tuberculosis with the microscopic observation drug susceptibility assay (Part 1) and nitrate reductase assay (Part 2). The present SOP is devoted to a third non-commercial culture and DST method known as colorimetric redox indicator assay (CRI). As its name indicates, the CRI detects the ability of the M. tuberculosis to reduce the colored oxidation-reduction indicator when added to a liquid culture of M. tuberculosis, after exposing the growth to different anti-mycobacterial drugs. The change in the color of the indicator denotes the proportionate number of viable Mycobacteria in the medium. The identification and DST results can be obtained in 7-8 days. This SOP document has been developed through the culture and DST subgroup of the STOP tuberculosis (TB) Partnership New Diagnostic Working Group. It is intended for laboratories that would want to use or already use this rapid non-commercial method for culture identification and DST of M. tuberculosis, notably in resource-constraint settings in Asia and Africa. PMID- 23440617 TI - Heterotopic ossification rates after acetabular fracture surgery are unchanged without indomethacin prophylaxis. AB - BACKGROUND: We previously found no reduction in heterotopic ossification (HO) rates after acetabular surgery with indomethacin compared with a placebo. We subsequently abandoned routine indomethacin therapy after acetabular surgery but questioned whether the incidence had changed using a posterior approach. QUESTIONS/PURPOSES: We therefore determined (1) the incidence of HO after acetabular fracture surgery through a posterior approach; (2) the incidence of symptoms attributable to HO; and (3) the rate of reoperation for HO. METHODS: We retrospectively reviewed the records of all 423 patients with acetabular fractures following our clinical protocol change; of these, 120 were treated with a Kocher-Langenbeck approach and included. The presence of radiographic HO was documented a minimum of 10 weeks postoperatively using the classification of Brooker et al. Symptoms and reoperations were recorded. RESULTS: The overall incidence of radiographic HO was 47% (56 of 120 patients): 26% Class I-II 13% Class III, and 8% Class IV. Overall, 15% of patients developed symptoms; 3.3% underwent reoperations for excision of HO. There were no major differences between the incidence of moderate and severe HO in this study when compared with the indomethacin and placebo groups from the prior study. CONCLUSIONS: Our incidence of moderate and severe HO has not changed since discontinuing indomethacin. These findings support our institutional decision to abandon routine indomethacin prophylaxis after acetabular surgery. We recommend improved surgical techniques to limit damage to the abductors and improved risk stratification of patients when considering treatment options for HO prophylaxis. PMID- 23440616 TI - Success after treatment of periprosthetic joint infection: a Delphi-based international multidisciplinary consensus. AB - BACKGROUND: The lack of agreement regarding what constitutes successful treatment for periprosthetic joint infections (PJI) makes it difficult to compare the different strategies of management that are used in clinical practice and in research studies. QUESTIONS/PURPOSES: The aims of this study were to create a consensus definition for success after PJI treatment, and to provide a universal, multidimensional framework for reporting of studies regarding PJI treatment. METHODS: A two-round basic Delphi method was used to reach a consensus definition. We invited 159 international experts (orthopaedic surgeons, infectious disease specialists, and clinical researchers) from 17 countries to participate; 59 participated in the first round, and 42 participated in the second round. The final definition consisted of all statements that achieved strong agreement (80% or greater of participants considering a criterion relevant for defining success). RESULTS: The consensus definition of a successfully treated PJI is: (1) infection eradication, characterized by a healed wound without fistula, drainage, or pain, and no infection recurrence caused by the same organism strain; (2) no subsequent surgical intervention for infection after reimplantation surgery; and (3) no occurrence of PJI-related mortality (by causes such as sepsis, necrotizing fasciitis). The Delphi panel agreed to defining midterm results as those reported 5 or more years after the definitive PJI surgery, and long-term results as those reported 10 or more years after surgery. Although no consensus was reached on the definition of short-term results, 71% of the participants agreed that 2 years after the definitive PJI surgery is acceptable to define it. CONCLUSIONS: This multidimensional definition of success after PJI treatment may be used to report and compare results of treatment of this catastrophic complication. LEVEL OF EVIDENCE: Level V, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23440618 TI - Method of fixation does not influence the overall risk of rerevision in first time cup revisions. AB - BACKGROUND: During the last two decades, uncemented fixation has been increasingly preferred worldwide during cup revision surgery. In Sweden, the number of uncemented cup revisions has been increasing during the last decade. However, it is unclear whether the risk of rerevision differs between cemented and uncemented cups. QUESTION/PURPOSES: We determined (1) the risk of rerevision after cemented and uncemented fixation; (2) the influence of concomitant stem revision on the risk of rerevision of the cup; (3) the difference in risk of rerevision of an uncemented cup revision compared with liner revision only; and (4) whether the surgical incision influenced the risk of rerevision. METHODS: Between 1979 and 2010, 19,342 first-time cup revisions were reported to the Swedish Hip Arthroplasty Register. From these, 749 were excluded (hip resurfacing, cases with tumor diagnoses, and missing data) leaving 18,593 (73% cemented) for further analysis. We used a Cox regression model adjusted for age, sex, primary diagnosis, method of fixation, concomitant stem revision, and cemented/uncemented fixation to assess risk of rerevision. RESULTS: The relative risk for rerevision for any reason did not differ between cemented and uncemented fixation (relative risk [RR], 0.94). If the stem was not revised at index revision, the risk of further cup revision increased twofold (RR, 1.91). Liner revisions were associated with a 70% increased risk for rerevision of the cup as a result of any reason and especially because of dislocation (RR, 2.94). The surgical incision did not influence the overall risk for rerevision (direct lateral/posterolateral: RR, 1.02) or the risk of rerevision resulting from dislocation (RR, 0.91). CONCLUSIONS: We found no difference in the overall risk of rerevision between cemented and uncemented fixation. Liner exchange had a higher risk for rerevision when compared with cases being rerevised with a new uncemented cup. PMID- 23440619 TI - Femoral remodeling around Charnley total hip arthroplasty is unpredictable. AB - BACKGROUND: There are two unusual remodeling patterns of the proximal femur around well-fixed Charnley total hip arthroplasties: cortical thinning leading to endosteal widening around the femoral component and hypertrophy of the distal femoral cortex. Previous studies have shown remodeling patterns are affected by stem design and occur early postoperatively. It is unclear if these changes are related to patient demographics or if they progress throughout the lifetime of the implant. QUESTIONS/PURPOSES: We determined if patient demographic variables influence remodeling patterns after cemented Charnley total hip arthroplasty and if the observed remodeling changes persist long-term. METHODS: We retrospectively reviewed the radiographs of 106 well-fixed Charnley femoral components. Using a novel digital edge detection program, we determined the femoral remodeling pattern and time-related changes in femoral dimensions. The minimum followup was 20 years (mean, 25.3 years; range, 19.5-37 years). RESULTS: We found no association between remodeling type and age at surgery, sex, preoperative diagnosis, body mass index, or postoperative activity level. There was also no association between initial implant alignment and remodeling type. Cortical thickening in the distal hypertrophy group was an early phenomenon occurring primarily within the first 2 years, whereas cortical thinning begins later and is a more progressive process. CONCLUSIONS: These data show remodeling after cemented Charnley total hip arthroplasty is not related to patient demographic variables; however, distal cortical hypertrophy can be predicted in the early postoperative period. PMID- 23440620 TI - Magnetic tracking in the operation room using the da Vinci((r)) telemanipulator is feasible. AB - In recent years, robotic assistance for surgical procedures has grown on a worldwide scale, particularly for use in more complex operations. Such operations usually require meticulous handling of tissue, involve a narrow working space and limit the surgeon's sense of orientation in the human body. Improvement in both tissue handling and working within a narrow working space might be achieved through the use of robotic assistance. Soft tissue navigation might improve orientation by visualizing important target and risk structures intraoperatively, thereby possibly improving patient outcome. Prerequisites for navigation are its integration into the surgical workflow and accurate localization of both the instruments and patient. Magnetic tracking allows for good integration but is susceptible to distortion through metal or electro-magnetic interference, which may be caused by the operation table or a robotic system. We have investigated whether magnetic tracking can be used in combination with the da Vinci((r)) (DV) telemanipulator in terms of stability and precision. We used a common magnetic tracking system (Aurora((r)), NDI Inc.) with the DV in a typical operation setup. Magnetic field distortion was evaluated using a measuring facility, with the following reference system: without any metal (R), operation table alone (T), DV in standby (D) and DV in motion (Dm). The maximum error of the entire tracking volume for R, T, D and Dm was 9.9, 32.8, 37.9 and 37.2 mm, respectively. Limiting the tracking volume to 190 mm (from cranial to caudal) resulted in a maximum error of 4.0, 8.3, 8.5 and 8.9 mm, respectively. When used in the operation room, magnetic tracking shows high errors, mainly due to the operation table. The target area should be limited to increase accuracy, which is possible for most surgical applications. The use of the da Vinci((r)) telemanipulator only slightly aggravates the distortion and can thus be used in combination with magnetic tracking systems. PMID- 23440621 TI - A comparison of the clinical outcomes of decompression alone and fusion in elderly patients with two-level or more lumbar spinal stenosis. AB - OBJECTIVE: We compared the results of two surgical techniques by retrospective study of 60 elderly patients (65 years or older) who underwent either decompression alone or fusion for the treatment of two-level or more lumbar spinal stenosis. METHODS: During the period of 2003 and 2008, two-level or more decompression alone or fusion was performed for lumbar spinal stenosis by three surgeons at our institution. Patients were allocated to two groups by surgical modality, namely, to a decompression group (31 patients) or a fusion group (29 patients). Overall mean age was 71.1 years (range, 65-84) and mean follow-up was 5.5 years (range, 3-9). A retrospective review of clinical, radiological, and surgical data was conducted. RESULTS: No significant difference between the two groups was found with respect to age, follow-up period, surgical levels, or preoperative condition. At the last follow-up, correction of lumbar lordotic angle (determined radiologically) was better in the fusion group. However, clinical outcomes including visual analogue scale, Oswestry Disability Index, and the Odom's criteria were not significantly different in the two groups. On the other hand, surgical outcomes, such as, operation time, estimated blood loss, and surgical complications were significantly better in the decompression alone group. CONCLUSION: Our findings suggest that decompressive laminectomy alone achieves good outcomes in patients with two-level or more lumbar spinal stenosis, associated with an advanced age, poor general condition, or osteoporosis. PMID- 23440622 TI - Major themes for 2009 in cardiothoracic and vascular anesthesia. AB - The hybrid operating room is the venue for transcatheter therapy with the convergence of three specialties: cardiac surgery, cardiovascular anesthesiology, and interventional cardiology. Transcatheter aortic valve replacement is proof that cardiac specialists have embraced the endovascular revolution. Since pharmacologic and ischemic myocardial conditioning are safe and effective, they are currently the focus of multiple trials. Angiotensin blockade, anemia and endoscopic saphenous vein harvesting worsen outcome after coronary artery bypass grafting (CABG). Although off-pump CABG is equivalent to on-pump CABG, it may improve outcomes in high-risk groups. Although percutaneous coronary intervention (PCI) significantly decreases mortality after myocardial infarction, the evidence is less convincing for intra-aortic balloon counterpulsation. Even though prasugrel was recently approved for platlet blockade in PCI, it may be superceded by ticagrelor. Although PCI and CABG appear equivalent for multivessel coronary disease, CABG lowers revascularization rates and also has superior outcomes in diabetics and the elderly. Hetastarch and N-acetylcysteine both increase bleeding and transfusion in cardiac surgery. Factor VII can treat life-threatening bleeding, but its safety requires further evaluation. Since eltrombopag and romiplostim stimulate platelet production, they may have a future role in hemostasis after cardiac surgery. Even though fenoldopam, atrial natriuretic peptide and sodium bicarbonate are nephroprotective, further trials must confirm these findings. Intensive insulin therapy offers no further outcome advantage and significantly increases hypoglycemic risk. The past year has witnessed the advent of a new clinical venue, new devices, and new drugs. The coming year will most likely advance these achievements. PMID- 23440623 TI - The use of methylene blue in abdominal aortic surgery: a case report. AB - The open abdominal aortic surgery includes a well-known phase in which arterial blood flow is stopped by occluding clamps, resulting in peculiar physiologic changes usually superimposed on advanced pathologic conditions. An anesthetic plan should aim at providing hemodynamic stability and preserving organ function. Clamp removal leads to an acute fall in blood pressure following a decrease in systemic vascular resistance, caused by reactive hyperemia due to opening of the previously minimally perfused vascular beds. Several different mediators, including the nitrous oxide (NO) pathway, have been thought to be responsible for this hemodynamic effect. The massive production of NO by the inducible isoform of NO synthase could be partially responsible for the profound vasodilatation and myocardial dysfunction. The dye methylene blue (MB) has been used as to prevent vasodilatation in other clinical situations like sepsis, cardiopulmonary bypass and liver transplantation. We describe its use in a patient with poor hemodynamic status, who was submitted to aortic aneurism repair with infrarenal cross clamp. The intervention was also associated with a severe bleeding. In this case MB allowed us to control hypotension with relatively low doses of vasopressors. PMID- 23440624 TI - Divorce in Korea: Trends and Educational Differentials. AB - The authors extend comparative research on educational differences in divorce by analyzing data from Korea. A primary motivation was to assess whether the theoretically unexpected negative educational gradient in divorce in Japan is also observed in Korea. Using vital statistics records, for marriages and divorces registered between 1991 and 2006, the authors calculated cumulative probabilities of divorce, by marriage cohort (N = 5,734,577) and educational attainment. The results indicated that the relationship between education and divorce was negative even in the earliest cohort and that this negative gradient has become more pronounced in more recent cohorts. Contrary to expectations, however, little evidence was found that the concentration of divorce at lower levels of education was exacerbated by the Asian economic crisis in the late 1990s. The authors discuss these findings in light of conventional emphases on the costs of divorce and highlight the importance of better understanding this distinctive east Asia pattern of divorce. PMID- 23440625 TI - Anti-inflammatory and anti-superbacterial activity of polyphenols isolated from black raspberry. AB - The fruit of the black raspberry (Rubus coreanus Miquel) has been employed in traditional medicine, and recent studies have demonstrated its measureable biological activities. However, the root of the black raspberry has not been studied. Therefore, in this study, we evaluated the anti-inflammatory and antibacterial properties of the root and unripe fruit polyphenols of the black raspberry. Both polyphenols proved to have anti-inflammatory activity as evidenced by the decreased nitric oxide (NO), cytokines (IL-1beta , IL-6, and IL 10) and prostaglandin E2 (PGE(2)) levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. However, root polyphenols showed stronger anti inflammatory activity than fruit polyphenols. LPS-induced mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 levels were also decreased, confirming the anti-inflammatory activity. Root polyphenols showed lethal activity against methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Acinetobacter baumannii (CRAB), and Bacillus anthracis. In contrast, the black raspberry fruit did not demonstrate these properties. These data provide the first demonstration that black raspberry root has potential anti-inflammatory and anti-superbacterial properties that can be exploited as alternatives for use in the food and cosmetic industries and/or as pharmaceuticals. PMID- 23440626 TI - Simple and rapid determination of myristicin in human serum. AB - Myristicin (5-allyl-1-methoxy-2,3-methylenodioxybenzene) is the main component of nutmeg (Myristica fragrans Houtt.) essential oil. The increasing use of myristicin as a cheap hallucinogenic intoxicant, frequently causing fatal cases of myristicin poisoning, requires new methods for determination of this compound in blood. This report describes the rapid, simple, and useful procedure for myristicin analysis in human serum, involving myristicin-protein complex degradation before chromatographic analysis. The developed method is characterized by a high recovery (above 99 %), a low detection limit (6.0 ng/g) and good repeatability (average RDS of 2.01 %). PMID- 23440627 TI - The effectiveness of heliox in acute respiratory distress syndrome. AB - INTRODUCTION: The management of acute respiratory distress syndrome (ARDS) was investigated with the use of heliox in an experimental model. OBJECTIVES: To investigate whether heliox can be considered a new therapeutic approach in ARDS. METHODS: ARDS was designed in Wistar albino male rats, 250-300 g in weight, by intratracheal instillation of physiological saline solution. Anesthezied and tracheotomized rats with ARDS were pressure-controlled ventilated. At the end of 210 min, helium gas was tried. All rats were assigned to two groups: Group 1 (n = 10) was the control group, and was given no treatment; group 2 (n = 7) was given heliox (He: O(2) = 50:50). The heliox group received heliox for 1 h continously. Rats were continued to be kept on a ventilator through the experiment. Two hours after the last inhalation, both lungs of the rats were excised for both histopathological examination and immunohistochemical evaluation. STATISTICAL ANALYSIS USED: Histopathological grading were expressed as median interquartile range. Mann-Whitney U-test was used to assess the relationships between the variables. RESULTS: The infiltation of neutrophils were decreased in rats treated with heliox. Edema in the interstitial and intraalveolar areas was less than that of the control rats. Also, the diminishing of perivascular and/or intraalveolar hemorrhage was apperant. Hyaline membrane (HM) formation decreased in the heliox group compared with the control group. Decreased inducible nitric oxide synthase expression was shown via immunohistochemical examination in the heliox group. CONCLUSION: The present study histopathologically indicated the effectiveness of heliox in the decreasing of neutrophil infiltation, interstitial/intraalveolar edema, perivascular and/or intraalveolar hemorrhage and HM formation in ARDS. Besides the known effect of heliox in obstructive lung disease, inhaled heliox therapy could be associated with the improvement of inflamation in ARDS. PMID- 23440628 TI - [Clinical relevance and indications for cardiac magnetic resonance imaging 2013: an interdisciplinary expert statement]. AB - During the last years the indications of Cardiac Magnetic Resonance Imaging (CMRI) have been continuously expanded. However, the acceptance of the method by cardiologists and radiologists does not correlate with respect to the diagnostic potential. Several factors, such as expensive equipment, relatively long examination times, high technical know how and lack of remuneration, limit the application of CMRI in everyday clinical practice. Furthermore, doctors tend to apply more conventional, well established diagnostic procedures, the access to the method is still limited and there exist difficulties in the interdisciplinary collaboration. The interdisciplinary Austrian approach to Cardiac Imaging is aimed to improve the aforementioned problems and to support the implementation of CMRI in the diagnostic tree of cardiac diseases thus enabling a cost efficient management of patients in cardiology. PMID- 23440630 TI - Evaluation of release retarding property of gum damar and gum copal in combination with hydroxypropyl methylcellulose. AB - The formulations consisting of a hydrophilic and hydrophobic material were investigated for effect on drug-release pattern from the matrices. Gum damar and gum copal being water-insoluble were used to study the efficiency of combined matrices to sustain the release of drug. Hydroxypropyl methylcellulose K100M and diclofenac sodium were used as the hydrophilic material and model drug, respectively. The influence of concentration of hydroxypropyl methylcellulose on drug release pattern of hydrophobic material was determined. The optimum ratio of drug: polymer was found to be 1:1. The hydrophobic:hydrophilic polymer ratio of 75:25 was found to have a similar release pattern as that of marketed formulation. At this ratio, the initial burst-release that occurred in individual hydrophobic matrices was lowered to a great extent. The release of drug was found to follow Higuchi's equation as the concentration of hydrophobic material was increased. The formulations were compared with marketed formulation Voveran SR, and a correlation was drawn accordingly. PMID- 23440631 TI - The effect of intraoperative hypotension on the outcomes of initial hybrid palliation for single ventricle congenital heart disease: an historical cohort study. AB - BACKGROUND: The "hybrid procedure" is an alternative surgical palliation strategy for single ventricle congenital heart disease. The purported benefit is improved cognitive ability secondary to avoidance of cardiopulmonary bypass in the neonatal period when neuronal apoptosis is greater. It is unknown whether survival is improved after this procedure. Intraoperative hypotension is common in these patients, and we hypothesized that this hypotension was associated with mortality or morbidity. METHODS: We reviewed the records of 58/58 patients undergoing a first-stage hybrid procedure from 2004 to 2010 in a tertiary pediatric academic centre. Risk factors for poor outcome and the association between intraoperative hypotension and morbidity or mortality were investigated. RESULTS: Average preoperative arterial blood pressure (ABP) [systolic/diastolic presented as mean (standard deviation)] were 68 (12.7) / 38 (9.4) mmHg. Post induction ABP was 65 (15.2) / 37 (8.6) mmHg. The average intraoperative nadir of ABP was 45 (7.0) / 26 (4.8) mmHg. On return to the intensive care unit (ICU), the average ABP was 69 (13.7) / 38 (11.6) mmHg. The nadir lasted longer than ten minutes in 32/58 patients. The mortality at 48 hr, 60 days, and 12 months was 3/58 (5%), 10/58 (17%), and 15/58 (26%), respectively. Six patients returned to the ICU on extracorporeal membrane oxygenation (ECMO). There was a weak statistical correlation between the average mean and diastolic BP pre-induction and changes of > 20% in systolic and diastolic BP during the case. CONCLUSION: In this patient cohort, we can show an association between short periods of intraoperative hypotension and mortality or return to the ICU on ECMO, but the importance of this is not certain. PMID- 23440632 TI - 3D myocardial T1 mapping at 3T using variable flip angle method: pilot study. AB - PURPOSE: Myocardial T1 mapping is an emerging technique that could improve cardiovascular magnetic resonance diagnostic accuracy. In this study, a variable flip angle approach with B1 correction is proposed at 3T on the myocardium, employing standard 3D spoiled fast gradient echo and echo planar imaging sequences. METHODS: The method was tested on phantoms to determine the set of standard 3D spoiled fast gradient echo angles adapted to myocardial T1 measurements and was compared to the inversion-recovery spin-echo reference T1 method. Seven volunteers underwent magnetic imaging resonance to acquire myocardial T1 maps and T1 values of the human heart. RESULTS: This original method demonstrated good reproducibility in phantoms and a significant correlation between variable flip angle T1 values and reference inversion recovery spin-echo T1 values. It yielded myocardial T1 values consistent with expected T1 and an increasing homogenization of myocardial segments owing to B1 correction. The mean myocardial T1 value was 1341 +/- 42 ms. CONCLUSION: Myocardial 3D T1 mapping using the variable flip angle approach can potentially be useful for evaluating fibrosis on the entire myocardium using a standard clinical sequence. PMID- 23440633 TI - Signal scaling improves the signal-to-noise ratio of measurements with segmented 2D-selective radiofrequency excitations. AB - PURPOSE: Segmented 2D-selective radiofrequency excitations can be used to acquire irregularly shaped target regions, e.g., in single-voxel MR spectroscopy, without involving excessive radiofrequency pulse durations. However, segments covering only outer k-space regions nominally use reduced B1 amplitudes (i.e., smaller flip angles) and yield lower signal contributions, which decreases the efficiency of the measurement. The purpose of this study was to show that applying the full flip angle for all segments and scaling down the acquired signal appropriately (signal scaling) retains the desired signal amplitude but reduces the noise level accordingly and, thus, increases the signal-to-noise ratio. METHODS: The principles and improvements of signal scaling were demonstrated with MR imaging and spectroscopy experiments at 3 T for a single-line segmentation of a blipped planar trajectory. RESULTS: The observed signal-to-noise ration gain depended on the 2D-selective radiofrequency excitation's resolution, field-of-excitation, and its excitation profile and was between 40 and 500% for typical acquisition parameters. CONCLUSION: Signal scaling can further improve the performance of measurements with segmented 2D-selective radiofrequency excitations, e.g., for MR spectroscopy of anatomically defined voxels. PMID- 23440634 TI - Strontium isotope (87Sr/86Sr) variability in the Nile Valley: identifying residential mobility during ancient Egyptian and Nubian sociopolitical changes in the New Kingdom and Napatan periods. AB - As a successful technique for identifying residential mobility in other areas, this study investigates the feasibility of using 87Sr/86Sr analysis to track the movements of the ancient peoples of Egypt and Nubia in the Nile Valley, who interacted via trade, warfare, and political occupations over millennia. Dental enamel from faunal remains is used to examine variability in strontium sources in seven regional sites; human enamel samples are analyzed from eight Nile Valley sites in order to trace human movements. The faunal samples show a wide range of 87Sr/86Sr values demonstrating that some animals were raised in a variety of locales. The results of the human samples reveal overlap in 87Sr/86Sr values between Egyptian and Nubian sites; however, Egyptian 87Sr/86Sr values (mean/median [0.70777], sd [0.00027]) are statistically higher than the Nubian 87Sr/86Sr values (mean [0.70762], median [0.70757], sd [0.00036], suggesting that it is possible to identify if immigrant Egyptians were present at Nubian sites. Samples examined from the site of Tombos provide important information regarding the sociopolitical activities during the New Kingdom and Napatan periods. Based on a newly established local 87Sr/86Sr range, human values, and bioarchaeological evidence, this study confirms the preliminary idea that immigrants, likely from Egypt, were present during the Egyptian New Kingdom occupation of Nubia. In the subsequent Napatan period when Nubia ruled Egypt as the 25th Dynasty, 87Sr/86Sr values are statistically different from the New Kingdom component and indicate that only locals were present at Tombos during this developmental time. PMID- 23440635 TI - Interpreting meta-regression: application to recent controversies in antidepressants' efficacy. AB - A recent meta-regression of antidepressant efficacy on baseline depression severity has caused considerable controversy in the popular media. A central source of the controversy is a lack of clarity about the relation of meta regression parameters to corresponding parameters in models for subject-level data. This paper focuses on a linear regression with continuous outcome and predictor, a case that is often considered less problematic. We frame meta regression in a general mixture setting that encompasses both finite and infinite mixture models. In many applications of meta-analysis, the goal is to evaluate the efficacy of a treatment from several studies, and authors use meta-regression on grouped data to explain variations in the treatment efficacy by study features. When the study feature is a characteristic that has been averaged over subjects, it is difficult not to interpret the meta-regression results on a subject level, a practice that is still widespread in medical research. Although much of the attention in the literature is on methods of estimating meta regression model parameters, our results illustrate that estimation methods cannot protect against erroneous interpretations of meta-regression on grouped data. We derive relations between meta-regression parameters and within-study model parameters and show that the conditions under which slopes from these models are equal cannot be verified on the basis of group-level information only. The effects of these model violations cannot be known without subject-level data. We conclude that interpretations of meta-regression results are highly problematic when the predictor is a subject-level characteristic that has been averaged over study subjects. PMID- 23440636 TI - Acquisition parameters optimization of a transmission electron forward scatter diffraction system in a cold-field emission scanning electron microscope for nanomaterials characterization. AB - Transmission electron forward scatter diffraction (t-EFSD) is a new technique providing crystallographic information with high resolution on thin specimens by using a conventional electron backscatter diffraction (EBSD) system in a scanning electron microscope. In this study, the impact of tilt angle, working distance, and detector distance on the Kikuchi pattern quality were investigated in a cold field emission scanning electron microscope (CFE-SEM). We demonstrated that t EFSD is applicable for tilt angles ranging from -20 degrees to -40 degrees . Working distance (WD) should be optimized for each material by choosing the WD for which the EBSD camera screen illumination is the highest, as the number of detected electrons on the screen is directly dependent on the scattering angle. To take advantage of the best performances of the CFE-SEM, the EBSD camera should be close to the sample and oriented towards the bottom to increase forward scattered electron collection efficiency. However, specimen chamber cluttering and beam/mechanical drift are important limitations in the CFE-SEM used in this work. Finally, the importance of t-EFSD in materials science characterization was illustrated through three examples of phase identification and orientation mapping. PMID- 23440637 TI - Preparation and characterizations of polyclonal antibodies against STAR protein QKI7b. AB - Quaking (QKI) proteins are important regulators of RNA metabolism and cellular signal transduction. Recent studies have shown that isoforms of QKI proteins, which include QKI5/6/7/7b in human cells, play important roles in the development of neurological diseases and human cancers. In comparison with QKI5/6/7, however, there are little data on QKI7b due to lack of specific antibodies. Here, we reported the preparation and initial characterizations of polyclonal antibodies against human QKI7b. Utilizing a chemically synthesized C-terminal peptide fragment of human QKI7b, we raised two preparations of rabbit antiserum. We found that these antibodies were able to recognize human QKI7b, but not QKI5/6/7. Our immunofluorescence staining showed that in LO2 hepatocytes, QKI7b localizes predominantly in the perinuclear cytoplasm and less abundantly in the nucleus. In clinical samples, we showed that like QKI5/6/7 proteins, QKI7b protein was also significantly downregulated in most human colorectal cancer tissues. These antibodies, therefore, might be useful in future functional studies of QKI7b. PMID- 23440638 TI - The interaction of polysaccharide from Auricularia polytricha with quantum dots and the protection of plasmid DNA from damage. AB - As a kind of folk medicine, edible mushrooms are known to be of medicinal characteristics, for example antitumor activity. However, the mechanism is not clear. In this study, the fluorescence (FL) spectroscopy was used to study the binding reactions of polysaccharide extracted from Auricularia polytricha with quantum dots (QDs). The modified Stern-Volmer quenching constant at different temperatures and corresponding thermodynamic parameters were calculated (?G < 0, ?H < 0, and ?S < 0). The results show that the quenching constant is inversely correlated with temperature. It indicates that the quenching mechanism is the static quenching in nature rather than dynamic quenching. The negative values of free energy (?G < 0) suggest that the binding process is spontaneous; ?H < 0 and ?S < 0 suggest that the binding of polysaccharide to QDs is enthalpy-driven. QDs were found to damage the plasmid DNA according to atomic force microscopy images. DNA damage is the important factor to induce tumor. Many chemical substances can induce tumor, which has been proved by modern medical science. In the presence of polysaccharide from A. polytricha, however, DNA was protected from damage due to polysaccharide winding around QDs, which is the basis for the bioeffect of polysaccharides. This study helps to understand that antitumor activity of edible mushrooms is attributed to protection of DNA from damage in the presence of harmful substances. PMID- 23440639 TI - [Preoperative CT imaging in infectious endocarditis before urgent indication for heart valve replacement: whole body computerized tomography including coronary evaluation]. PMID- 23440640 TI - Manifestation of acute Leriche syndrome as cauda equina syndrome. PMID- 23440641 TI - [Meningeose with recurrent medulloblastoma : diffusion restriction, but no contrast enhancement]. PMID- 23440642 TI - [Synchronous, ipsilateral occurrence of a glomus jugular and carotid glomus tumor, a rare differential diagnosis of a cholesteatoma in a 14 year old boy]. PMID- 23440643 TI - [Pseudomyxoma peritonei -- early stage revealed in MRI]. PMID- 23440644 TI - Primary acinar cell carcinoma of the liver. PMID- 23440645 TI - Shiga toxin-producing E. coli O104:H4 outbreak 2011 in Germany: radiological features of enterohemorrhagic colitis. AB - PURPOSE: In 2011 a nationwide outbreak of Shiga toxin-producing E. coli (STEC) O104:H4 infection occurred in Germany with severe hemorrhagic colitis and hemolytic-uremic syndrome (HUS). We defined abdominal radiologic findings in these patients and correlated them with clinical parameters. MATERIALS AND METHODS: 23 patients (7 men; age: 48 +/- 19 years) with O104:H4 colitis and/or HUS received abdominal CT (n = 12) or radiographs (n = 11). Colonic distension, air-fluid levels, and free intraabdominal air were assessed. Colonic wall thickening, contrast enhancement, pericolic stranding, and ascites were evaluated on CT. Laboratory parameters and clinical presentation were reviewed. Chi-square test, Student's t-test, McNemar's test and Spearman correlation were performed. RESULTS: Colonic lumen distension was seen in 16/23 patients (69.6 %). The ascending colon (11/23 patients; 47.8 %) and transverse colon (12/23 patients; 52.2 %) were dilated significantly more often (p = 0.006 and p = 0.003, respectively) than the descending colon (1/23; 4.3 %). All 12 patients undergoing CT scanning had abnormally thickened colonic wall segments, 3 (25 %) had pancolic involvement and 9 (75 %) had segmental involvement. The descending colon was predominantly affected (11/12 patients; 91.7 %) and thickened significantly more often than other colonic segments (p < 0.001). CONCLUSION: The segmental type of STEC O104:H4 colitis mainly affects the descending colon with upstream distension of the transverse/ascending colon and differs from other types of colitis. PMID- 23440646 TI - [MR enterography sequence evaluation for patients with Crohn's disease]. AB - PURPOSE: To evaluate a routine MR enterography (MRE) protocol for patients with Crohn's disease (CD) in order to assess and rank the subjectively most important sequences regarding diagnostic decisions. MATERIALS AND METHODS: We prospectively examined 84 patients (42 male) with known CD using a coronal T2 / T1-weighted balanced SSFP (TrueFISP), axial T2-weighted single shot TSE (HASTE) as well as an axial T1-weighted gradient-echo sequence (2D-FLASH) before intravenous contrast application and a 2D-FLASH sequence with axial and coronal orientation after intravenous contrast application. 4 experienced radiologists subjectively evaluated the sequences independently using a scale between 1 and 5 (1 = excellent; 5 = non-diagnostic) regarding their diagnostic significance for a final radiologic decision. The ranking of the different sequences was statistically tested by the Friedman analysis. RESULTS: The following ranking was found: HASTE sequences were ranked prior to contrast-enhanced axial gradient-echo (2D-FLASH). The third to fifth ranking was TrueFISP, the axial contrast-enhanced 2D-FLASH and the 2D-FLASH without contrast, respectively. Differences between the first and second rank were significant (p < 0.05), and all other differences were highly significant (p < 0.01). CONCLUSION: The stable and fast T2-weighted MR sequences without intravenous contrast represented by axial HASTE and coronal TrueFISP were ranked as number 1 and 3. The examination protocol should be completed by a coronal T1-weighted gradient-echo-sequence after contrast injection, which can be supplemented by an axial acquisition. The T1-weighted gradient-echo sequence without contrast could be omitted. PMID- 23440647 TI - [Exposition of the operator's eye lens and efficacy of radiation shielding in fluoroscopically guided interventions]. AB - PURPOSE: Efficacy of radiation protection tools for the eye lens dose of the radiologist in fluoroscopic interventions. MATERIALS AND METHODS: A patient phantom was exposed using a fluoroscopic system. Dose measurements were made at the eye location of the radiologist using an ionization chamber. The setting followed typical fluoroscopic interventions. The reduction of scattered radiation by the equipment-mounted shielding (undercouch drapes and overcouch top) was evaluated. The ceiling-suspended lead acrylic glass screen was tested in scattered radiation generated by a slab phantom. The protective properties of different lead glass goggles and lead acrylic visors were evaluated by thermoluminescence measurements on a head phantom in the primary beam. RESULTS: The exposition of the lens of about 110 to 550 MUSv during radiologic interventions is only slightly reduced by the undercouch drapes. Applying the top in addition to the drapes reduces the lens dose by a factor of 2 for PA projections. In 25 degrees LAO the dose is reduced by a factor between 1.2 and 5. The highest doses were measured for AP angulations furthermore the efficacy of the equipment-mounted shielding is minimal. The ceiling-suspended lead screen reduced scatter by a factor of about 30. The lead glass goggles and visors reduced the lens dose up to a factor of 8 to 10. Depending on the specific design, the tested models are less effective especially for radiation from lateral with cranial angulation of the beam. Occasionally the visors even caused an increase of dose. CONCLUSION: The exposition of the eye lens can be kept below the new occupational limit recommended by the ICRP if the radiation shielding equipment is used consistently. PMID- 23440648 TI - [Percutaneous thrombus aspiration and thrombolysis for the treatment of acute portal vein thrombosis in a 5-year-old child]. AB - Early portal vein thrombosis is a frequent and severe complication following pediatric liver transplantation. The clinical presentation is characterized by signs and symptoms of portal hypertension such as ascites and digestive hemorrhage. Primary treatment consists of heparin therapy. In the case of persistent or progressive thrombosis or symptoms, surgical thrombectomy or retransplantation should be considered. However, surgical intervention is associated with significant morbidity and mortality. We report on successful minimally invasive percutaneous thrombus aspiration and thrombolysis for the treatment of acute portal vein thrombosis in a 5-year-old child post liver transplantation. PMID- 23440649 TI - Time-resolved noncontrast enhanced 4-D dynamic magnetic resonance angiography using multibolus TrueFISP-based spin tagging with alternating radiofrequency (TrueSTAR). AB - PURPOSE: The goal of this study was to introduce a new noncontrast enhanced 4D dynamic MR angiography (dMRA) technique termed multibolus TrueFISP-based spin tagging with alternating radiofrequency (TrueSTAR). METHODS: Multibolus TrueFISP based spin tagging with alternating radiofrequency was developed by taking advantage of the phenomenon that the steady-state signal of TrueFISP is minimally disturbed by periodically inserted magnetization preparations (e.g., spin tagging) that are sandwiched by two alpha/2 RF pulses. Both theoretical analysis and experimental studies were carried out to optimize the proposed method which was compared with both pulsed and pseudo-continuous arterial spin labeling-based dMRA in healthy volunteers. Optimized multibolus dMRA was also applied in a patient with arteriovenous malformation to demonstrate its potential clinical utility. RESULTS: Multibolus dMRA offered a prolonged tagging bolus compared to the standard single-bolus dMRA, and allowed improved visualization of the draining veins in the arteriovenous malformation patient. Compared to pseudo continuous arterial spin labeling-based dMRA, multibolus dMRA provided visualization of the full passage of the labeled blood with the flexibility for both static and dynamic magnetic resonance angiography. CONCLUSION: By combining the benefits of pulsed and pseudo-continuous arterial spin labeling-based dMRA, multibolus TrueFISP-based spin tagging with alternating radiofrequency can prolong and enhance the tagging bolus without sacrificing imaging speed or temporal resolution. PMID- 23440650 TI - [Traditional bonesetter's gangrene of limb in children in Regional Hospital of Kaolack (Senegal)]. AB - Little published data exist on the morbidity and mortality associated with poor trauma care in developing countries. This report highlights our experience with iatrogenic limb gangrene related to fracture management by traditional bonesetters. Children with bonesetter's gangrene were identified from a prospectively recorded paediatric surgery database at the Regional Hospital of Kaolack in Central Senegal. 21 children were treated for bonesetter's gangrene during a 18-month period (January 2007 up to June 2008). The average age was 10 years (range, 5 to 15 years). Bonesetter's gangrene was more common in boys (90.5%) and occurred almost exclusively in children from rural areas where access to health care was limited. 16 children underwent proximal extremity amputation. Complications included one case of tetanus. Bonesetter's gangrene is a preventable complication that results from a failure of child health planners to recognize the importance of basic trauma care. Management of fractures should be considered an essential component of child health programs in developing countries. PMID- 23440651 TI - Diffusion-weighted imaging for evaluation of uterine arterial embolization of fibroids. AB - PURPOSE: To determine whether diffusion-weighted imaging (DWI) characteristics could predict the effectiveness of uterine arterial embolization in treatment of fibroids. METHODS: This retrospective study included 17 women (27 fibroids) who underwent uterine arterial embolization for fibroids. MR imaging (1.5 T) was performed before, 1 week and 6 months after uterine arterial embolization. The volume, T2 signal, T1 signal, enhancement after contrast media injection, DWI signal (b = 500 s/mm(2) ) and apparent diffusion coefficient (ADC) were assessed for fibroids. RESULTS: DWI signal or ADC, whether before or 1 week after the procedure, did not show a statistical relationship to success of uterine arterial embolization. On the 1-week follow-up, 22% of fibroids enhanced vs. 85% on baseline, P < 0.0001 and DW signal intensity increased. ADC values in fibroids decreased between baseline and 1-week (1.61 vs. 1.53 * 10(-3) mm(2) /s, P = 0.13). On 6-months, ADC continued to decrease compared with baseline (1.27 * 10( 3) mm(2) /s, P = 0.002), but with a lower signal on DWI. No changes were observed in myometrium ADC at any time point. CONCLUSION: Our study demonstrated that DWI and ADC reflected early and delayed changes in fibroids after embolization; however, we were not able to demonstrate a statistically significant relationship with outcome. PMID- 23440652 TI - Exploring prehistory in the North American southwest with mitochondrial DNA diversity exhibited by Yumans and Athapaskans. AB - A recent study of mitochondrial DNA variation in Native American populations from the American Southwest detected signatures of a population expansion of subhaplogroup B2a, dated to 2,105 years before present (99.5% confidence interval, 1,273-3,773 YBP), following the introduction and intensification of maize agriculture in the region. Only one Yuman group and no Athapaskan speakers were analyzed in previous studies. Here we report mtDNA haplogroup and hypervariable region (HVR I, and II) sequence data from 263 extant Yuman speakers, representing the major branches of the Yuman language family, in addition to the Western Apache (Athapaskan) to further investigate the demographic context and geographic extent of this expansion. Data presented indicate that the expansion of B2a is only slightly older [2,410 YBP (99.5% CI: 1,458-4,320 YBP)] than previously estimated and not significantly. Despite large confidence intervals there are implications for the origin and expansion of the Yuman language family. Cultural transformations due to the inundation and draining of Lake Cahuilla may explain in part the frequencies of this lineage among the Kumeyaay and other Yuman and Takic groups in Southern California. This may have been the result of group fissions and fusions followed by migration and interaction that included expanded trade networks and intermarriage among Yuman speakers. In addition, a series of in-situ genetic bottlenecks is proposed to have occurred among the Western Apache leading to increasing homogeneity within haplogroup A, culminating in an admixture event with the Yavapai. PMID- 23440654 TI - Paroxysmal Kinesigenic Dyskinesia-like Symptoms in a Patient with Tourette Syndrome. AB - BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by episodic dystonia or choreiform movements provoked by sudden voluntary movement. PKD is not commonly reported in Tourette syndrome (TS). We describe a unique case of TS with PKD-like episodic dyskinesia that responded to carbamazepine. CASE REPORT: A 36-year-old male with long-standing TS developed paroxysmal "cramping". Attacks were provoked by quick, sudden arm movements, which induced dystonic cramping, or by reaching overhead, which caused painful contraction of truncal muscles. The spells typically lasted 5-20 seconds and occurred multiple times daily. The patient's mother suffered from intermittent dystonic toe curling. In view of the similarity of symptoms to PKD, carbamazepine was prescribed at 400 mg daily. The symptoms resolved completely. Inadvertent discontinuation led to relapse, and resumption led to recapture of benefit. DISCUSSION: This case demonstrates the possibility that PKD-like symptoms may co-occur with TS and may be responsive to carbamazepine. PMID- 23440655 TI - [Out-of-hospital obstetrics]. PMID- 23440653 TI - Fish allergy: in review. AB - Globally, the rising consumption of fish and its derivatives, due to its nutritional value and divergence of international cuisines, has led to an increase in reports of adverse reactions to fish. Reactions to fish are not only mediated by the immune system causing allergies, but are often caused by various toxins and parasites including ciguatera and Anisakis. Allergic reactions to fish can be serious and life threatening and children usually do not outgrow this type of food allergy. The route of exposure is not only restricted to ingestion but include manual handling and inhalation of cooking vapors in the domestic and occupational environment. Prevalence rates of self-reported fish allergy range from 0.2 to 2.29 % in the general population, but can reach up to 8 % among fish processing workers. Fish allergy seems to vary with geographical eating habits, type of fish processing, and fish species exposure. The major fish allergen characterized is parvalbumin in addition to several less well-known allergens. This contemporary review discusses interesting and new findings in the area of fish allergy including demographics, novel allergens identified, immunological mechanisms of sensitization, and innovative approaches in diagnosing and managing this life-long disease. PMID- 23440656 TI - [Planned non-hospital births in industrialized countries: bureaucratic dream vs. professional responsibility]. AB - This article addresses in how far planned non-hospital births should be an alternative to planned hospital births. Advocates of planned non-hospital deliveries have emphasised patient safety, patient satisfaction, cost effectiveness, and respect for women's rights. We provide a critical evaluation of each of these claims and have doubts that the information available for the pregnant women and the public is in accord with professional responsibility. We understand that the increasing rates of interventions and operative deliveries in hospital births demand an answer, but we doubt that planned home birth is the appropriate professional solution. Complications during non-hospital births inevitably demand a transport of mother and child to a perinatal centre. The time delay by itself is an unnecessary risk for both and this cannot be abolished by bureaucratic quality criteria as introduced for non-hospital births in Germany. Evidence-based studies have shown that modern knowledge of the course of delivery including ultrasound as well as intensive care during the delivery all reduce the rate of operative deliveries. Unfortunately, this is not well-known and only rarely considered during any delivery. All these facts, however, are the best arguments to find a cooperative model within perinatal centres to combine the art of midwifery with modern science, reduction of pain and perinatal care of the pregnant women before, during and after birth. We therefore call on obstetricians, midwifes and health-care providers as well as health politicians to carefully analyse the studies from Western countries showing increasing risks if the model of intention-to-treat is considered and accoordingly not to support planned non-hospital births nor to include these models into prospective trials. Alternatively, we recommend the introduction of a home-like climate within hospitals and perinatal centres, to avoid unnecessary invasive measures and to really care for the pregnant mother before, during and after delivery within a cooperative model without the lack of patient safety for both mother and child in case of impending or acute emergencies. PMID- 23440657 TI - [Midwife-led birth centres: an alternative to hospital childbirth?]. AB - After midwife-led birth centres had been included into the Social Security Statute Book (S134a SGB V) and thus become covered by German Public Health Insurance since April 1st, 2007 contract negotiations on flat rate costs have followed. Meanwhile the 2nd edition of this -agreement has come into effect. The present contribution describes how this non-hospital obstetric care has developed in the last 3 years. The medical care situation is explained based on legal conditions. Special attention is paid to regulations concerning quality management as well as the certification or auditing required to remain listed in the national register of midwife-led units at the Social Health Insurance. Results are shown from data collected by the Associa-tion for Quality Assurance on Out-of-hospital births (QUAG) and from a pilot project which also contains comparisons with clinical findings. The discussion refers to data taken from German as well as international publications. The conclusion points out some aspects in need of further development. PMID- 23440658 TI - Effects of smoking specified as cigarettes per day and maternal body mass index on hypertensive disorders of pregnancy. AB - BACKGROUND: We have previously described the prevalence in pregnancy of hypertension, proteinuria, oedema and preeclampsia/eclampsia according to maternal body mass index (BMI) and smoking status. We found that these disorders were less frequent among smoking women. To investigate whether this relationship is causal or a chance finding, we here present an analysis according to BMI and smoking specified according to the number of cigarettes consumed per day. MATERIALS AND METHODS: Data were from the German Perinatal Survey of 1998-2000. We classified women by BMI as underweight (BMI<18.5 kg/m2), normal weight (BMI 18.5-24.99 kg/m2), overweight (25.0-29.99 kg/m2), or obese (BMI>=30 kg/m2). Smoking was categorised as being a non-smoker or smoking 1-7, 8-14 or >= 15 cigarettes per day. Datasets from 433 669 singleton pregnancies with information on maternal BMI and smoking were included in the analysis. RESULTS: In all BMI categories hypertension, moderate to severe oedema, and preeclampsia/eclampsia became less prevalent with increasing maternal cigarette consumption. CONCLUSIONS: Dose-dependence was not convincing for proteinuria.Dose-dependence in the relationship between smoking and hypertensive disorders of pregnancy argues against a chance finding and for a causal relationship. PMID- 23440659 TI - [Megacystis-microcolon intestinal hypoperistalsis syndrome (MMIHS) as a rare differential diagnosis of foetal megacystis on ultrasonography]. AB - INTRODUCTION: Foetal megacystis (incidence 1:1 500) occurring in the first trimester may already be a sign of congenital malformation. Often, urethral valves are causally responsible in male foetuses far more frequently than urethral atresia. As a further differential diagnosis, the "prune-belly syndrome" needs to be distinguished. Far more difficult to classify prenatally is the rare MMIHS which, in contrast to the diagnosis of urethral valves, is associated with an unfavourable prognosis. CASE REPORT: This is a report on a 28-year-old IG/0P, whose foetus of 26+4 gestational weeks was found on ultrasonography for the first time to have a megacystis of 48 mm diameter and bilateral hydronephrosis. The female foetus was surrounded by a normal amount of amniotic fluid which, during the further course of the pregnancy, developed into polyhydramnios. The serial puncture of the urinary bladder showed a normal karyotype and no impairment of the renal concentrating capacity or of protein loss. By reason of an immense enlargement of the abdomen due to the 100 mm large urinary bladder, a Caesarean section was conducted at 36+0 gestational weeks. A catheter could be inserted into the urinary bladder postpartum easily. However, nourishment was not possible and after radiological examination, MMIHS was diagnosed. CONCLUSION: In the case of a foetal megacystis detected by ultrasonography, especially associated with polyhydramnios and female gender, the rare MMIHS, which is infaust, should be taken into consideration. PMID- 23440660 TI - Metabolic management in overweight subjects with naive impaired fasting glycaemia by means of a highly standardized extract from Cynara scolymus: a double-blind, placebo-controlled, randomized clinical trial. AB - The aim of this study is to evaluate the efficacy of a dietary supplementation with an extract from Cynara scolymus (Cs) on the glucose pattern in a group of patients with naive impaired fasting glycaemia (IFG). A randomized, double-blind, placebo-controlled trial has been performed in 55 overweight subjects with IFG (fasting blood glucose [FBG]: 6.11 +/- 0.56 mmol/l). These subjects were randomly assigned to supplement their diet with either an extract from Cs (600 mg/d) (26 subjects) or placebo (29 matched subjects) for 8 weeks. The decrease of FBG was the primary endpoint. The assessment of Homeostatic Metabolic Assessment (HOMA), glycosylated haemoglobin, A1c-Derived Average Glucose (ADAG), lipidic pattern and anthropometric parameters were the secondary endpoints. The within groups and percent changes from baseline were analyzed by the signed rank test. The comparison between groups was performed by Wilcoxon's two sample test. The supplemented group had significant decreases of: FBG (-9.6%), HOMA (-11.7%), glycosylated haemoglobin (-2.3%), ADAG (-3.1%) and lipidic pattern. The placebo group did not show any significant difference. Compared with the placebo, the supplemented group showed a significant difference in FBG, HOMA and lipidic pattern. These data demonstrate the efficacy of Cs extract on the reduction of glycometabolic parameters in overweight subjects with IFG. PMID- 23440661 TI - Penetration resistance: a new approach to the energetics of indentations. AB - This article deals with quantitative applications of the penetration resistance (k = FN/h3/2) of experimental indentation loading curves without fittings or simulations in terms of the various energetic contributions for an improved understanding. The total applied work upon indentation with pyramids, cones and also spheres is partitioned between the indentation and the long-range effects including friction in a constant 80/20 ratio for mathematical reasons and thus for all of the diverse materials and methods. Long-range effects such as molecular migrations, rosettes, shear-bands, pile-up, sink-in, and elastic stress are recalled. An easy integration of (higher) parabolas with known exponent is presented. The constant ratios of applied work, indentation work, and long-range work allow for separation of surface effect work, reliable calculations of adhesion energies, and phase transformation energies. Corrections of Sneddon/Love and of Johnson, Kendall, Roberts (JKR) derived equations are now required. PMID- 23440663 TI - Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS: The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end-organ damage. RISK STRATIFICATION: In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. RISK ADAPTED INITIAL THERAPY: Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard-risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12-18 months. MAINTENANCE THERAPY: After initial therapy, lenalidomide maintenance is considered for standard-risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in pateints with intermediate or high-risk myeloma. MANAGEMENT OF REFRACTORY DISEASE: Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. PMID- 23440662 TI - Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. AB - Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B-cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not-reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence-in-situ hybridization performed in four SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM-CMML and one patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (P < 0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD. PMID- 23440664 TI - A practical and scalable manufacturing process for an anti-fungal agent, Nikkomycin Z. AB - A scalable and reliable manufacturing process for Nikkomycin Z HCl on a 170 g scale has been developed and optimized. The process is characterized by a 2.3 g/L fermentation yield, 79% purification yield, and >98% relative purity of the final product. This method is suitable for further scale up and cGMP production. The Streptomyces tendae DeltaNikQ strain developed during the course of this study is superior to any previously reported strain in terms of higher yield and purity of Nikkomycin Z. PMID- 23440665 TI - Development of a question prompt list as a communication intervention to reduce racial disparities in cancer treatment. AB - Racial disparities have been found in the use of chemotherapy as cancer treatment. These disparities may be, in part, due to well-documented differences in the quality of communication during clinical interactions with oncologists and Black versus White patients. In this study using a community-based participatory research approach, academic researchers, community members, and oncologists formed a partnership to develop a communication intervention to address racial disparities in cancer care. Partners developed a question prompt list (QPL), a simple tool that can be used to improve communication, and thus treatment, during clinical interactions in which oncologists and Black patients discuss chemotherapy. Partners endorsed the use of a QPL, provided specific suggestions for content and format, conducted and analyzed qualitative interviews with Black patients receiving chemotherapy, and approved the final version. The feasibility and effectiveness of the QPL that resulted from this research process are currently under evaluation in a separate study. PMID- 23440666 TI - Successful medical management of a left ventricular thrombus and aneurysm following failed thrombolysis in myocardial infarction. AB - We report the case of a patient with an extensive anterior myocardial infarction complicated by left ventricular systolic dysfunction, left ventricular apical thrombus and an apical left ventricular aneurysm following failed thrombolysis. We obtained serial two-dimensional echocardiograms at short intervals in the acute phase and also during the months of recovery and follow up. The patient was successfully and exclusively medically managed. PMID- 23440667 TI - Whole-body and local RF absorption in human models as a function of anatomy and position within 1.5T MR body coil. AB - PURPOSE: Radiofrequency energy deposition in magnetic resonance imaging must be limited to prevent excessive heating of the patient. Correlations of radiofrequency absorption with large-scale anatomical features (e.g., height) are investigated in this article. THEORY AND METHODS: The specific absorption rate (SAR), as the pivotal parameter for quantifying absorbed radiofrequency, increases with the radial dimension of the patient and therefore with the large scale anatomical properties. The absorbed energy in six human models has been modeled in different Z-positions (head to knees) within a 1.5T bodycoil. RESULTS: For a fixed B1+ incident field, the whole-body SAR can be up to 2.5 times higher (local SAR up to seven times) in obese adult models compared to children. If the exposure is normalized to 4 W/kg whole-body SAR, the local SAR can well-exceed the limits for local transmit coils and shows intersubject variations of up to a factor of three. CONCLUSIONS: The correlations between anatomy and induced local SAR are weak for normalized exposure, but strong for a fixed B1+ field, suggesting that anatomical properties could be used for fast SAR predictions. This study demonstrates that a representative virtual human population is indispensable for the investigation of local SAR levels. PMID- 23440668 TI - Serum C-reactive protein and leptin for assessment of nutritional status in patients on maintenance hemodialysis. AB - Nutrition is one of the key parameters in predicting morbidity and mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Body weight, body mass index, and visceral protein levels (serum protein, albumin, prealbumin, and transferrin) have traditionally been used as markers for nutritional status. Serum leptin and C-reactive protein (CRP), have been recently added to the list of markers for nutritional status. This study was a comparative assessment of serum leptin and CRP for nutritional status in patients with ESRD on maintenance hemodialysis. A total of 40 patients with ESRD on maintenance hemodialysis and a similar number of age-, gender-, and BMI-matched healthy individuals were studies. Complete medical history was obtained and relevant clinical examination including anthropometry was carried out. All the individuals were subjected to routine investigations and special investigations (serum leptin and CRP). Data were analyzed using Student's t-test and correlation was found using Pearson's correlation coefficient. Mean value of serum leptin for the study group (1.44 +/- 0.72 ng/ml) was found to be significantly higher than that of the control group (0.68 +/- 0.55 ng/ml). In addition, we also observed a positive correlation between serum leptin and BMI (r = 0.350, P<0.05). For CRP, we observed that the study group (3.93 +/- 1.20 mg/ml) had a significantly higher value vis-a-vis the control group (0.28 +/- 0.24 mg/ml). However, CRP and BMI did not show a significant correlation. Based on the above observations, we conclude that serum leptin is a better biomarker than CRP for assessing nutritional status in patients with ESRD on maintenance hemodialysis. PMID- 23440669 TI - Interactions of rosiglitazone and anti-arrhythmic drugs in animal model. AB - BACKGROUND: Diabetes increases the risk of vascular problems by two times compared with a healthy individual, with deposition of fats in blood vessel and this includes cardiovascular disease. The treatment regimens for patients suffering from both diseases generally include prolonged use of anti-diabetic drugs for diabetes and anti-arrhythmic drugs for cardiac arrhythmias. AIM: The aim of the study is to compare the influence of Mexiletine and Disopyramide on the pharmacodynamics (PDs) of Rosiglitazone in normal and diabetic rats. MATERIALS AND METHODS: The study was conducted in normal rats and diabetic induced rats (with Alloxan monohydrate 100 mg/kg body weight). Albino rats weighing between 160 and 280 g were administered oral doses of Rosiglitazone 0.72 mg/kg, Mexiletine 36 mg/kg, or Disopyramide 18 mg/kg of bodyweight and their combination, with 1 week of washout between treatments. Eighteen rats were divided into three sub-sets with six rats in each sub-set. After 4 days, the blood glucose was estimated to confirm the diabetes. The Analysis of Covariance (ANCOVA) using MedCalc((r)) software Version 11.6.1.0 was performed to analyze mean change in blood glucose between treatments with body weight as co-variable and treatment as factor for normal and diabetic rats. RESULTS: No statistically significant difference in mean change in blood glucose between Rosiglitazone in comparison with Rosiglitazone + Mexiletine or Rosiglitazone + Disopyramide was observed in normal and diabetic rats (P = 0.606). The maximum mean change in blood glucose for Rosiglitazone and Rosiglitazone + Mexiletine or Rosiglitazone + Disopyramide was observed at 1 h and 8 h in normal and diabetic rats. The post hoc analysis showed baseline correction method has increased the reliability of the results (P < 0.001). CONCLUSION: The study concludes that PD activity of Rosiglitazone was not affected by the anti-arrhythmic drugs. This study introduced a new statistical methodology for analyzing the blood glucose endpoint. PMID- 23440670 TI - Epidural analgesia in high risk cardiac surgical patients. AB - Cardiac surgery is associated with high morbidity and mortality in patients with renal, hepatic or pulmonary dysfunction, advanced age and morbid obesity. Thoracic epidural analgesia is associated with decreased morbidity in these patients. Thoracic epidural analgesia in cardiac surgery is associated with haemodynamic stability, decreased catecholamine response, good pulmonary function, early extubation and discharge from intensive care unit. It is an important component of fast tracking in cardiac surgery as well. Its use has significantly increased over the years and has been used as an adjuvant to general anaesthesia as well as the sole anaesthetic technique in selected groups of patients. Proper selection of patients for thoracic epidural analgesia is mandatory. Timing of epidural catheter insertion and removal should be judiciously selected. The risk of epidural hematoma secondary to anticoagulation or residual effects of antiplatelet drug that can be reduced by taking standard precautions. In conclusion thoracic epidural analgesia in high risk cardiac surgery might decrease pulmonary, cardiovascular or renal complications, provide excellent analgesia and allow early extubation. PMID- 23440671 TI - Environmental exposure as an independent risk factor of chronic bronchitis in northwest Russia. AB - BACKGROUND: In some parts of the northwest Russia, Murmansk region, high exposures to heavy mining and refining industrial air pollution, especially sulphur dioxide, have been documented. OBJECTIVE: Our aim was to evaluate whether living in the mining area would be an independent risk factor of the respiratory symptoms. DESIGN: A cross-sectional survey of 200 Murmansk region adult citizens was performed. The main outcome variable was prolonged cough with sputum production that fulfilled the criteria of chronic bronchitis. RESULTS: Of the 200 participants, 53 (26.5%) stated that they had experienced chronic cough with phlegm during the last 2 years. The prevalence was higher among those subjects living in the mining area with its high pollution compared to those living outside this region (35% vs. 18%). Multivariable regression model confirmed that the risk for the chronic cough with sputum production was elevated in a statistical significant manner in the mining and refining area (adjusted OR 2.16, 95% CI 1.07-4.35) after adjustment for smoking status, age and sex. CONCLUSIONS: The increased level of sulphur dioxide emitted during nickel mining and refining may explain these adverse health effects. This information is important for medical authorities when they make recommendations and issue guidelines regarding the relationship between environmental pollution and health outcomes. PMID- 23440672 TI - A primary care-based interdisciplinary team approach to the treatment of chronic pain utilizing a pragmatic clinical trials framework. AB - Chronic pain affects at least 116 million adults in the USA and exacts a tremendous cost in suffering and lost productivity. While health systems offer specialized pain services, the primary care setting is where most patients seek and receive care for pain. Primary care-based treatment of chronic pain by interdisciplinary teams (including behavioral specialists, nurse case managers, physical therapists, and pharmacists) is one of the most effective approaches for improving outcomes and managing costs. To ensure robust integration of such services into sustainable health-care programs, evaluations must be conducted by researchers well versed in the methodologies of clinical trials, mixed methods and implementation research, bioinformatics, health services, and cost effectiveness. Recent national health policy changes, in addition to the increasing recognition of the high prevalence and cost of chronic pain conditions, present a unique opportunity to shift the care paradigm for patients with chronic pain. PMID- 23440673 TI - Elucidation of relaxin-3 binding interactions in the extracellular loops of RXFP3. AB - Relaxin-3 is a highly conserved neuropeptide in vertebrate species and binds to the Class A G protein-coupled receptor (GPCR) RXFP3. Relaxin-3 is involved in a wide range of behaviors, including feeding, stress responses, arousal, and cognitive processes and therefore targeting of RXFP3 may be relevant for a range of neurological diseases. Structural knowledge of RXFP3 and its interaction with relaxin-3 would both increase our understanding of ligand recognition in GPCRs that respond to protein ligands and enable acceleration of the design of drug leads. In this study we have used comparative sequence analysis, molecular modeling and receptor mutagenesis to investigate the binding site of the native ligand human relaxin-3 (H3 relaxin) on the human RXFP3 receptor. Previous structure function studies have demonstrated that arginine residues in the H3 relaxin B-chain are critical for binding interactions with the receptor extracellular loops and/or N-terminal domain. Hence we have concentrated on determining the ligand interacting sites in these domains and have focused on glutamic (E) and aspartic acid (D) residues in these regions that may form electrostatic interactions with these critical arginine residues. Conserved D/E residues identified from vertebrate species multiple sequence alignments were mutated to Ala in human RXFP3 to test the effect of loss of amino acid side chain on receptor binding using a Eu-labeled relaxin-3 agonist. Finally data from mutagenesis experiments have been used in ligand docking simulations to a homology model of human RXFP3 based on the peptide-bound chemokine receptor 4 (CXCR4) structure. These studies have resulted in a model of the relaxin-3 interaction with RXFP3 which will inform further interrogation of the agonist binding site. PMID- 23440674 TI - DRINKING TO GET DRUNK AMONG INCOMING FRESHMEN COLLEGE STUDENTS. AB - This study examined college freshmen who intentionally drink alcohol to get drunk (DTGD). Survey data from 307 incoming freshmen college students living in freshmen residence halls who reported drinking alcohol in the last 30 days were analyzed. The majority (76.9%) of these self-reported drinkers reported DTGD. Relative to other freshmen drinkers, those who reported DTGD were significantly more likely to have consumed alcohol before going out to a party or bar, participated in a drinking game, drank heavily on a non-school night but not on a school night, used liquor, used beer, combined alcohol and drugs, experienced a hangover, vomited, passed out, and/or blacked out. The associations support DTGD as a measure of pre-meditated, controlled, and intentional consumption of alcohol to reach a state of inebriation. Common intentional drunkenness as observed in this study population may have implications for college alcohol risk reduction programs. PMID- 23440675 TI - Yogic practice and diabetes mellitus in geriatric patients. AB - BACKGROUND: Stress has negative effect on health and type 2 diabetes patients may be at an increased risk. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can increase lipid peroxidation and insulin resistance. The objective of the present study was to demonstrate the efficacy of yogic practice in geriatric patients with type 2 diabetes mellitus and also to compare the efficacy with the state of glycaemic control. MATERIALS AND METHODS: Seventy three (73) healthy elderly patients of type 2 diabetes mellitus in the age group of 60 to 70 years with a history of diabetes for 5 to 10 years and with poor glycaemic control (HbA(1c) >8 %) residing in Kozhikode district were recruited for the study. The subjects were divided into three groups according to their glycaemic control. Group I with HbA(1c) 8.6-9.7 %, group II with HbA(1c) 9.8-10.7 % and group III with HbA(1c) 10.8-12.7 %. Participants did yogic practice under the supervision of experienced trainer, daily 90 minutes and for three months. Biochemical estimation of HbA(1c), glucose, lipid profile, cortisol, ferritin, malondialdehyde (MDA) and catalase activity were carried out on 0 day and 90(th) day. Seventy patients participated in a comparable control session. RESULTS: The participants in the test group showed statistically significant (P < 0.001) decrease in glucose, HbA(1c), lipids, cortisol, ferritin, MDA and significant increase in catalase activity after yogic practice. CONCLUSIONS: Yoga may improve risk profiles induced by stress in geriatric patients with type 2 diabetes and may have promise for the prevention or delay in diabetes complications. And at all stages of the disease a significant improvement can be achieved by yogic practice in geriatric diabetes. PMID- 23440676 TI - Animal Models of Alzheimer's Disease: Utilization of Transgenic Alzheimer's Disease Models in Studies of Amyloid Beta Clearance. AB - Glial cells in Alzheimer's disease (AD) have been shown to be capable of clearing or at least restricting the accumulation of toxic amyloid beta (Abeta) deposits. Recently, bone marrow (BM)-derived monocytic cells have been recognized in experimental studies to be superior in their phagocytic properties when compared to their brain endogenous counterparts. In human AD, BM-derived monocytic cells may have deficiencies in their capacity to restrict plaque growth. Therefore, enhancement of phagocytic properties of cells of monocyte origin, both brain endogenous microglia and BM-derived monocytic cells, offers an attractive therapeutic approach to fight off AD. Transgenic mouse models with aberrant Abeta deposition offer a valuable tool for discovery of novel pathways to facilitate cell-mediated Abeta uptake. This article reviews the most recent findings on the phagocytic capacity of cells with monocytic origin in various transgenic AD models and describes the methods to study phagocytic activity of these cells. PMID- 23440678 TI - Evaluation of endometrium for chronic endometritis by using syndecan-1 in abnormal uterine bleeding. AB - CONTEXT: Chronic endometritis is a condition observed in 3-10% of women with abnormal uterine bleeding (AUB). Diagnosis depends upon the histological detection of plasma cells within the inflammatory infiltrate in the endometrium. Plasma cells on H and E may be obscured by a mononuclear infiltrate, plasmacytoid stromal cells, abundant stromal mitosis, a pronounced predecidual reaction, menstrual features or secondary changes due to exogenous progesterone treatment prior to biopsy. AIMS: The objective of this study was to determine utility of syndecan-1 in diagnosis of chronic endometritis in patients with AUB, and to see if any of the secondary histologic features in endometrial biopsy, correlated with the presence of plasma cells on immunohistochemistry (IHC). MATERIALS AND METHODS: Fifty endometrial biopsies with a clinical diagnosis of AUB were taken. Endometrium in proliferative phase, secretory phase, endometrial polyps, and disordered proliferative endometrium were studied for the presence of plasma cells. IHC was done using syndecan-1. The secondary histologic features of chronic endometritis like gland architectural irregularity, spindled stroma, stromal edema and hemorrhage with the presence of plasma cells was statistically analysed. Values of P < 0.05 were considered as significant. RESULTS: Plasma cells were seen in 11 (69%) of DPE, 8 (66%) of PEB, and 1 (7%) of normal proliferative endometrium and in 2 (40%) of secretory endometrium. Presence of stromal breakdown showed a significant association with plasma cells (P = 0.02) whereas gland architecture irregularity (P = 0.28), stromal edema (P = 0.71) and spindled stromal (P = 0.72) did not show a significant association. CONCLUSIONS: Plasma cells were significantly present in AUB patients. Syndecan-1 maybe helpful in unusual cases, where chronic endometritis is suspected as the cause of clinically significant ongoing abnormal bleeding. PMID- 23440677 TI - Stages: sub-Fourier dynamic shim updating using nonlinear magnetic field phase preparation. AB - Heterogeneity of the static magnetic field in magnetic resonance imaging may cause image artifacts and degradation in image quality. The field heterogeneity can be reduced by dynamically adjusting shim fields or dynamic shim updating, in which magnetic field homogeneity is optimized for each tomographic slice to improve image quality. A limitation of this approach is that a new magnetic field can be applied only once for each slice, otherwise image quality would improve somewhere to its detriment elsewhere in the slice. The motivation of this work is to overcome this limitation and develop a technique using nonlinear magnetic fields to dynamically shim the static magnetic field within a single Fourier encoded volume or slice, called sub-Fourier dynamic shim updating. However, the nonlinear magnetic fields are not used as shim fields; instead, they impart a strong spatial dependence to the acquired MR signal by nonlinear phase preparation, which may be exploited to locally improve magnetic field homogeneity during acquisition. A theoretical description of the method is detailed, simulations and a proof-of-principle experiment are performed using a magnet coil with a known field geometry. The method is shown to remove artifacts associated with magnetic field homogeneity in balanced steady-state free-precession pulse sequences. We anticipate that this method will be useful to improve the quality of magnetic resonance images by removing deleterious artifacts associated with a heterogeneous static magnetic field. PMID- 23440679 TI - Short segment fixation for thoracolumbar burst fracture accompanying osteopenia : a comparative study. AB - OBJECTIVE: The purpose of this study was to compare the results of three types of short segment screw fixation for thoracolumbar burst fracture accompanying osteopenia. METHODS: The records of 70 patients who underwent short segment screw fixation for a thoracolumbar burst fracture accompanying osteopenia (-2.5< mean T score by bone mineral densitometry <-1.0) from January 2005 to January 2008 were reviewed. Patients were divided into three groups based on whether or not bone fusion and bone cement augmentation procedure 1) Group I (n=26) : short segment fixation with posterolateral bone fusion; 2) Group II (n=23) : bone cement augmented short segment fixation with posterolateral bone fusion; 3) Group III (n=21) : bone cement augmented, short segment percutaneous screw fixation without bone fusion. Clinical outcomes were assessed using a visual analogue scale and modified MacNab's criteria. Radiological findings, including kyphotic angle and vertebral height, and procedure-related complications, such as screw loosening or pull-out, were analyzed. RESULTS: No significant difference in radiographic or clinical outcomes was noted between patients managed using the three different techniques at last follow up. However, Group I showed more correction loss of kyphotic deformities and vertebral height loss at final follow-up, and Group I had higher screw loosening and implant failure rates than Group II or III. CONCLUSION: Bone cement augmented procedure can be an efficient and safe surgical techniques in terms of achieving better outcomes with minimal complications for thoracolumbar burst fracture accompanying osteopenia. PMID- 23440680 TI - Fenoldopam to prevent renal replacement therapy after cardiac surgery. Design of the FENO-HSR study. AB - INTRODUCTION: Acute kidney injury requiring renal replacement therapy is a serious complication following cardiac surgery associated with poor clinical outcomes. Until now no drug showed nephroprotective effects. Fenoldopam is a dopamine-1 receptor agonist which seems to be effective in improving postoperative renal function. The aim of this paper is to describe the design of the FENO-HSR study, planned to assess the effect of a continuous infusion of fenoldopam in reducing the need for renal replacement therapy in patients with acute kidney injury after cardiac surgery. METHODS: We're performing a double blind, placebo-controlled multicentre randomized trial in over 20 Italian hospitals. Patients who develop acute renal failure defined as R of RIFLE score following cardiac surgery are randomized to receive a 96-hours continuous infusion of either fenoldopam (0.025-0.3 ug/kg/min) or placebo. RESULTS: The primary endpoint will be the rate of renal replacement therapy. Secondary endpoints will be: mortality, time on mechanical ventilation, length of intensive care unit and hospital stay, peak serum creatinine and the rate of acute renal failure (following the RIFLE score). CONCLUSIONS: This trial is planned to assess if fenoldopam could improve relevant outcomes in patients undergoing cardiac surgery who develop acute renal dysfunction. Results of this double-blind randomized trial could provide important insights to improve the management strategy of patients at high risk for postoperative acute kidney injury. PMID- 23440681 TI - The variable roads to sacrifice: Isotopic investigations of human remains from Chotuna-Huaca de los Sacrificios, Lambayeque, Peru. AB - This study investigates two key variables-residential context and subsistence among sacrificial victims dating to the Late Horizon (A.D. 1450-1532) in the Huaca de los Sacrificios at the Chotuna-Chornancap Archaeological Complex in north coastal Peru. We investigate whether aspects of sacrifice in this distant coastal province mirrored that found in Inca heartland contexts such as the capacocha, or remained more typical of coastal sacrificial traditions. Stable carbon, nitrogen, and oxygen isotope values were characterized in bone carbonate, bone collagen, and hair keratin to estimate geographic residence during the decade before death and diet in the decade, versus months, before death. Bone delta18 Ocarbonate values have a mean (+/-SD) of 26.8 +/- 1.1%, bone delta13 Ccarbonate values -6.7 +/- 1.7%, and bone delta(13) Ccollagen values 11.8 +/- 1.3%; bone delta15 Ncollagen values have a mean of 11.5 +/- 1.3%. Combined hair delta13 Ckeratin values have a mean of -12.8 +/- 1.6%, and hair delta15 Nkeratin values 10.8 +/- 1.3%. In contrast to contemporaneous coastal and highland contexts, we are unable to identify immigrants among the sacrificed individuals or changes in diet that indicate provisioning with a standardized diet leading up to death. Instead, results suggest that victims were local to the area, but consumed moderately variable diets consistent with local subsistence patterns. These findings suggest a distinct pattern of human sacrifice in the Late Horizon and underscore the regional and temporal variation in sacrificial practices in the central Andes. PMID- 23440682 TI - Comparative effect of clopidogrel plus aspirin and aspirin monotherapy on hematological parameters using propensity score matching. AB - BACKGROUND: Clopidogrel and aspirin are antiplatelet agents that are recommended to reduce the risk of recurrent stroke and other cardiovascular events. Dual antiplatelet therapy with clopidogrel and aspirin has been shown to increase the risk of hemorrhage, but the effects of the drugs on laboratory parameters have not been well studied in real-world clinical settings. Therefore, we evaluated and compared the effects of combination therapy with clopidogrel plus aspirin and aspirin monotherapy on laboratory parameters. METHODS: We used data from the Nihon University School of Medicine Clinical Data Warehouse obtained between November 2004 and May 2011 to identify cohorts of new users (n = 130) of clopidogrel (75 mg/day) plus aspirin (100 mg/day) and a propensity score matched sample of new users (n = 130) of aspirin alone (100 mg/day). We used a multivariate regression model to compare serum levels of creatinine, aspartate aminotransferase, and alanine aminotransferase, as well as hematological parameters including hemoglobin level, hematocrit, and white blood cell, red blood cell, and platelet counts up to 2 months after the start of administration of the study drugs. RESULTS: There were no significant differences for any characteristics and baseline laboratory parameters between users of clopidogrel plus aspirin and users of aspirin alone. Reductions in white blood cell and red blood cell counts, hemoglobin levels, and hematocrit in users of clopidogrel plus aspirin were significantly greater than those in users of aspirin alone. CONCLUSION: Our findings suggest that adverse hematological effects may be greater with combination clopidogrel plus aspirin therapy than with aspirin monotherapy. PMID- 23440683 TI - Gaussian mixture model-based classification of dynamic contrast enhanced MRI data for identifying diverse tumor microenvironments: preliminary results. AB - Tumor hypoxia develops heterogeneously, affects radiation sensitivity and the development of metastases. Prognostic information derived from the in vivo characterization of the spatial distribution of hypoxic areas in solid tumors can be of value for radiation therapy planning and for monitoring the early treatment response. Tumor hypoxia is caused by an imbalance between the supply and consumption of oxygen. The tumor oxygen supply is inherently linked to its vasculature and perfusion which can be evaluated by dynamic contrast enhanced (DCE-) MRI using the contrast agent Gd-DTPA. Thus, we hypothesize that DCE-MRI data may provide surrogate information regarding tumor hypoxia. In this study, DCE-MRI data from a rat prostate tumor model were analysed with a Gaussian mixture model (GMM)-based classification to identify perfused, hypoxic and necrotic areas for a total of ten tumor slices from six rats, of which one slice was used as training data for GMM classifications. The results of pattern recognition analyzes were validated by comparison to corresponding Akep maps defining the perfused area (0.84 +/- 0.09 overlap), hematoxylin and eosin (H&E) stained tissue sections defining necrosis (0.64 +/- 0.15 overlap) and pimonidazole-stained sections defining hypoxia (0.72 +/- 0.17 overlap), respectively. Our preliminary data indicate the feasibility of a GMM-based classification to identify tumor hypoxia, necrosis and perfusion/permeability from non-invasively acquired, in vivo DCE-MRI data alone, possibly obviating the need for invasive procedures, such as biopsies, or exposure to radioactivity, such as positron emission tomography (PET) exams. PMID- 23440684 TI - Anti-Oxidative and Anti-Inflammatory Effects of QGC in Cultured Feline Esophageal Epithelial Cells. AB - Quercetin-3-O-beta-D-glucuronopyranoside (QGC) is a flavonoid glucoside extracted from Rumex Aquaticus Herba. In the present study, anti-oxidative and anti inflammatory effects of QGC were tested in vitro. Epithelial cells obtained from cat esophagus were cultured. When the cells were exposed to acid for 2 h, cell viability was decreased to 36%. Pretreatment with 50 uM QGC for 2 h prevented the reduction in cell viability. QGC also inhibited the productions of intracellular ROS by inflammatory inducers such as acid, lipopolysaccharide, indomethacin and ethanol. QGC significantly increased the activities of superoxide dismutase (SOD) and catalase, and also induced the expression of SOD2, while it restored the decrease of catalase expression in cells exposed to acid. QGC inhibited NF-kappaB translocation, cyclooxygenase-2 expression and PGE(2) secretion in cells exposed to acid, which plays an important role in the pathogenesis of esophagitis. The data suggest that QGC may well be one of the promising substances to attenuate oxidative epithelial cell injury and inflammatory signaling in esophagus inflammation. PMID- 23440685 TI - Open repair of descending thoracic aneurysms. AB - INTRODUCTION: Current strategies for operative treatment of a thoracic aortic aneurysm consist of open repair with surgical graft replacement or endovascular exclusion. To reduce mortality and morbidity of open repair, a multimodal approach has gradually evolved by maximizing organ protection. METHODS: On a total of 1108 patients treated in our Center from 1993 for pathology involving the thoracic aorta, we reviewed the prospectively collected data of 194 consecutive patients who underwent open thoracic aortic aneurysm repair, 104 (54%) for degenerative aneurysms, 65 (34%) for dissections, 25 (12%) for other pattern of disease. Left Heart Bypass was used in 82% of cases, clamp and sew technique in 16%, hypotermic circulatory arrest in 2%. RESULTS: Overall perioperative mortality was 4.1%. The rate of pulmonary complications was 8.8%. The rate of cardiac complications, i.e. new onset myocardial necrosis demonstrated by positive blood tests, was 6.2%. The rate of renal complications was 7.2%. Cerebrovascular accident, defined as a new neurologic deficit lasting more than 24 hours confirmed by imaging, occurred in 2.0% of patients. The rate of spinal cord ischemia, manifesting either as paraplegia or paraparesis, was 4.6%. CONCLUSIONS: Mortality and morbidity rates of open thoracic aortic aneurysm repair are currently satisfactory especially in fit patients. In order to define surgical indications and the role of endovascular repair, consideration of age of the patient, comorbidity, symptoms, life expectancy, likely quality of life (if asymptomatic), aortic diameter, aneurysm morphology, aneurysm extent, suitability of landing zones, and operator experience are all distinctly relevant. PMID- 23440686 TI - Dynamic evolution of interface roughness during friction and wear processes. AB - Dynamic evolution of surface roughness and influence of initial roughness (S(a) = 0.282-6.73 um) during friction and wear processes has been analyzed experimentally. The mirror polished and rough surfaces (28 samples in total) have been prepared by surface polishing on Ti-6Al-4V and AISI 1045 samples. Friction and wear have been tested in classical sphere/plane configuration using linear reciprocating tribometer with very small displacement from 130 to 200 um. After an initial period of rapid degradation, dynamic evolution of surface roughness converges to certain level specific to a given tribosystem. However, roughness at such dynamic interface is still increasing and analysis of initial roughness influence revealed that to certain extent, a rheology effect of interface can be observed and dynamic evolution of roughness will depend on initial condition and history of interface roughness evolution. Multiscale analysis shows that morphology created in wear process is composed from nano, micro, and macro scale roughness. Therefore, mechanical parts working under very severe contact conditions, like rotor/blade contact, screws, clutch, etc. with poor initial surface finishing are susceptible to have much shorter lifetime than a quality finished parts. PMID- 23440687 TI - Cross-sex hormonal replacement: is this really effective? an experimental clue. AB - Castrated rats of either sex were used in this work, and sex hormones of their own gender or cross-sex hormones were administered for 4 months. Animals were then put through 5 min of myocardial ischemia followed by a 5-min reperfusion injury. Electrocardiographic recordings were made and serum was obtained. Sex hormone levels were measured. Cardiac frequency was calculated, arterial pressure was determined, and the levels of lactate dehydrogenase (LDH), creatinine kinase (CK), and thiobarbituric acid reactive species (TBARs) were analyzed. Proinflammatory cytokine levels were measured in homogenized hearts; besides this, five hearts of each experimental group were obtained and fixed for histopathologic analysis. In male rats with estradiol replacement, the incidence of tachyarrhythmias and CK levels were higher when compared to the rest of the animals. Their cytokine levels were also elevated when compared to the group that received testosterone. Estradiol replacement protected female rats from variations in all of the parameters evaluated, whereas testosterone did not show a protective effect. In the presence of testosterone, the incidence of tachyarrhythmia was higher and TBARs, cytokines, CK, and LDH levels were also elevated. The results shown reinforce the idea that cross-sex hormone administration can damage the cardiovascular system. PMID- 23440688 TI - Reirradiation of recurrent salivary gland malignancies with fractionated stereotactic body radiation therapy. AB - PURPOSE: The purpose of this study was to review a single-institution experience with the reirradiation of recurrent salivary gland tumors using fractionated stereotactic radiosurgery (SBRT). METHODS: Between 2003 and 2011, 18 patients diagnosed with recurrent, previously irradiated, salivary gland carcinomas were treated with SBRT reirradiation. Median age was 68 for all patients with most tumors being of major salivary gland origin. Most patients did not undergo surgical resection, and among those that did, all had positive margins. Only seven patients received chemotherapy, and the median SBRT dose was 30 Gy given in five fractions with a median cumulative dose of 91.1 Gy. RESULTS: The median overall survival (OS), progression-free survival (PFS), and local control (LRC) were 11.5, 3.5, and 5.5 months, respectively. The 2-year OS, PFS, and LRC rates were 39%, 24%, and 53%, respectively. Statistical analysis identified presence of gross disease and interval to reirradiation as negative predictors of survival outcomes on both univariate and multivariate analyses (p < 0.05). On multivariate analysis, tumor volume was a negative predictor of survival outcomes (p < 0.05). Long-term toxicity analysis revealed four patients in the reirradiated group with soft tissue necrosis, which correlated with the cumulative dose (p = 0.01). CONCLUSION: Our data suggest that SBRT is a reasonable treatment option for reirradiation of salivary gland tumors, but further studies are warranted. PMID- 23440689 TI - Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib. AB - Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR-ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19-74 years) were enrolled. Twenty patients received IM for post-transplant relapse. After a median follow-up of 15.8 months (1.4-28.2 months) after IM discontinuation, nine of the non-transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4% and 66.3% in the non-transplant group, respectively. Of nine patients re-treated with IM, eight patients re-achieved MMR at a median of 1.7 months (0.9-2.8 months). Seven of these patients re-achieved UMRD at a median of 5.6 months (2.8 12.1 months). Previous transplantation, IM duration, and UMRD duration were significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post-transplant relapse. PMID- 23440690 TI - The influence of nitrate on the physiology of the yeast Dekkera bruxellensis grown under oxygen limitation. AB - A previous study showed that the use of nitrate by Dekkera bruxellensis might be an advantageous trait when ammonium is limited in sugarcane substrate for ethanol fermentation. The aim of the present work was to evaluate the influence of nitrate on the yeast physiology during cell growth in different carbon sources under oxygen limitation. If nitrate was the sole source of nitrogen, D. bruxellensis cells presented slower growth, diminished sugar consumption and growth-associated ethanol production, when compared to ammonium. These results were corroborated by the increased expression of genes involved in the pentose phosphate (PP) pathway, the tricarboxylic acid (TCA) cycle and ATP synthesis. The presence of ammonium in the mixed medium restored most parameters to the standard conditions. This work may open up a line of investigation to establish the connection between nitrate assimilation and energetic metabolism in D. bruxellensis and their influence on its fermentative capacity in oxygen-limited or oxygen-depleted conditions. PMID- 23440691 TI - Initial clinical evaluation of a non-contrast-enhanced MR angiography method in the distal lower extremities. AB - PURPOSE: To report the initial experience and diagnostic performance applying a novel flow-dependent non-contrast-enhanced MR angiography (NCE-MRA) method, in patients with suspected peripheral vascular disease, in comparison with established contrast-enhanced MRA (CE-MRA). METHODS: The lower legs of 34 patients were imaged at 1.5 T with both NCE-MRA and CE-MRA. The NCE-MRA method consisted of a cardiac-gated balanced-SSFP sequence with controllable flow suppression preparation. Flow-suppressed and unsuppressed datasets were subtracted to obtain angiograms. Two experienced radiologists assessed both NCE MRA and CE-MRA images, first independently and then in consensus to resolve significant disagreements. Signal loss, vessel conspicuity, vascular disease, venous contamination, artifacts, and diagnostic confidence were assessed. RESULTS: Using the CE-MRA as the "gold standard," the per-segment sensitivity and specificity for detection of significant disease were 81.7% and 90.9%, respectively. Mean diagnostic confidence (scale 0-4) was 3.4 for NCE-MRA and 3.9 for CE-MRA. Most vessel segments were well visualized but the popliteal arteries often suffered some technique-related signal loss. CONCLUSIONS: The NCE-MRA method was able to visualize most vessel segments with good or excellent confidence, few artifacts, and excellent background suppression, giving moderate agreement with CE-MRA. However, some segments were poorly visualized, probably due to flow profile distortion in these patients. PMID- 23440692 TI - A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis. AB - OBJECTIVE: Genetic factors account for an estimated 45-58% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. METHODS: A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. RESULTS: SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 * 10(-4)). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 * 10(-5)). CONCLUSION: SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood. PMID- 23440693 TI - Tropisetron suppresses collagen synthesis in skin fibroblasts via alpha7 nicotinic acetylcholine receptor and attenuates fibrosis in a scleroderma mouse model. AB - OBJECTIVE: There is increasing evidence that serotonin (5-hydroxytryptamine [5 HT]) and distinct 5-HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that tropisetron, a routinely used antiemetic agent previously characterized as a 5-HT(3/4) receptor modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo. METHODS: Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca(2+) measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of tropisetron were detected by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence. The murine model of bleomycin-induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real-time RT-PCR analysis, Western immunoblotting, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunohistochemical analysis. RESULTS: Tropisetron suppressed collagen synthesis induced by transforming growth factor beta1 (TGFbeta1). This effect was independent of 5-HT(3/4) receptor but was mediated via alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Suppression of TGFbeta1-induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c-Jun, or MAPK pathway. In vivo, tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin. CONCLUSION: Tropisetron directly reduces collagen synthesis in HDFs via an alpha7nAChR-dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin- induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma. PMID- 23440694 TI - Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. AB - OBJECTIVE: To investigate the roles of serum Th1 and Th2 cytokines in Kawasaki disease (KD) and determine whether the Th1/Th2 cytokine profiles in children with KD may be involved in intravenous immunoglobulin (IVIG) resistance and development of coronary artery lesions (CALs). METHODS: Serum Th1 and Th2 cytokines, including interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha), interleukin-10 (IL-10), IL-6, IL-4, and IL-2, were measured using a cytometric bead array in the serum of 143 patients with KD before and after treatment with IVIG (pre-IVIG, at 3 days after temperature normalization following IVIG treatment [post-IVIG], and 1 month posttreatment). RESULTS: Levels of IL-6, IL-10, TNFalpha, and IFNgamma were significantly increased in KD patients pre-IVIG. Post-IVIG, the levels of IL-6, IL-10, and IFNgamma quickly decreased. The levels of TNFalpha decreased significantly after IVIG treatment in KD patients without CALs post-IVIG and in KD patients who were IVIG responders, but increased slightly in KD patients with CALs post-IVIG and in KD patients who were IVIG nonresponders. Before IVIG treatment, the levels of IL-4, IL-6, IL-10, and IFNgamma were significantly higher in KD patients with CALs than in those without CALs. The post-IVIG levels of IL-6 and IL-10 were significantly higher in IVIG nonresponders than in IVIG responders. Pre-IVIG, an IL-10 level >8 pg/ml had a sensitivity of 75.0% and a specificity of 64.4% for predicting CALs, while a TNFalpha level <2 pg/ml had a sensitivity of 66.7% and a specificity of 74.2% for predicting IVIG resistance. Post-IVIG, an IL-6 level >10 pg/ml had a sensitivity of 67.9% and a specificity of 81.7% for predicting CALs, while an IL-10 level >6 pg/ml had a sensitivity of 53.6% and a specificity of 86% for predicting CALs. CONCLUSION: Determination of the serum Th1/Th2 cytokine profile may be helpful for predicting the disease prognosis and targeting treatment strategies in patients with KD. PMID- 23440695 TI - Hearing loss in Muckle-Wells syndrome. AB - OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin-1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes. METHODS: A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype-specific risk of progression of hearing loss was determined. RESULTS: A total of 33 patients ages 3-75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss. CONCLUSION: Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions. PMID- 23440698 TI - J-refocused 1H PRESS DEPT for localized 13C MR spectroscopy. AB - Proton point-resolved spectroscopy (PRESS) localization has been combined with distortionless enhanced polarization transfer (DEPT) in multinuclear MRS to overcome the signal contamination problem in image-selected in vivo spectroscopy (ISIS)-combined DEPT, especially for lipid detection. However, homonuclear proton scalar couplings reduce the DEPT enhancement by modifying the spin coherence distribution under J modulation during proton PRESS localization. Herein, a J refocused proton PRESS-localized DEPT sequence is presented to obtain simultaneously enhanced and localized signals from a large number of metabolites by in vivo (13) C MRS. The suppression of J modulation during PRESS and the substantial recovery of signal enhancement by J-refocused PRESS-localized DEPT were demonstrated theoretically by product operator formalism, numerically by the spin density matrix simulations for different scalar coupling conditions, and experimentally with a glutamate phantom at various TEs, as well as a colza oil phantom. The application of the sequence for localized detection of saturated and unsaturated fatty acids in the calf bone marrow and skeletal muscle of healthy subjects yielded high signal enhancements simultaneously obtained for all components. PMID- 23440699 TI - Immunisation with foamy virus Bet fusion proteins as novel strategy for HIV-1 epitope delivery. AB - The induction of 2F5- and 4E10-like antibodies broadly neutralising HIV-1 and targeting the membrane external proximal region (MPER) of the transmembrane envelope protein gp41 would be a major advancement for the development of a preventive HIV-1 vaccine, but successful attempts remain rare. Recent studies demonstrated that broadly reactive antibodies develop relatively late during infection and after intensive affinity maturation. Therefore, a prolonged antigen delivery might be beneficial to induce them. Replicating foamy viruses which are characterised by apathogenic but persistent infection could represent suitable carrier viruses for this purpose. In order to develop such a system, we modified the accessory foamy virus Bet protein to contain the MPER of gp41, or the MPER linked to the stabilising fusion peptide proximal region of gp41 and analysed here the antigenic and immunogenic properties of such hybrid proteins. The antigens, expressed and purified to homogeneity, were recognised by the monoclonal antibodies 2F5 and 4E10 with nanomolar affinities and induced high levels of antibodies specific to gp41 after immunisation of rats. The antisera also bound to virus particles attached to infected cells, and peptide-based epitope mapping showed that they recognised the 2F5 epitope. Although no HIV-1 neutralising activity was observed, the presented data demonstrate that using the foamy virus Bet for HIV-1 epitope delivery is successfully applicable. Together with the attractive potential for sustained antigen expression after transfer to replicating virus, these results should therefore provide a first basis for the development of chimeric foamy viruses as novel HIV-1 vaccine vectors. PMID- 23440700 TI - Neuroprotection and axonal regeneration after lumbar ventral root avulsion by re implantation and mesenchymal stem cells transplant combined therapy. AB - Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progressive death of segmental motoneurons (MN) leading to permanent paralysis. The chances for functional recovery after ventral root avulsion are very poor owing to the loss of avulsed neurons and the long distance that surviving neurons have to re-grow axons from the spinal cord to the corresponding targets. Following unilateral avulsion of L4, L5 and L6 spinal roots in adult rats, we performed an intraspinal transplant of mesenchymal stem cells (MSC) and surgical re-implantation of the avulsed roots. Four weeks after avulsion the survival of MN in the MSC-treated animals was significantly higher than in vehicle-injected rats (45% vs. 28%). Re-implantation of the avulsed roots in the injured spinal cord allowed the regeneration of motor axons. By combining root re implantation and MSC transplant the number of surviving MN at 28 days post-injury was higher (60%) than in re-implantation alone animals (46%). Electromyographic tests showed evidence of functional re-innervation of anterior tibialis and gastrocnemius muscles by the regenerated motor axons only in rats with the combined treatment. These results indicate that MSC are helpful in enhancing neuronal survival and increased the regenerative growth of injured axons. Surgical re-implantation and MSC grafting combined had a synergic neuroprotective effect on MN and on axonal regeneration and muscle re-innervation after spinal root avulsion. PMID- 23440701 TI - Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down regulates Bcr-Abl protein. AB - Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl/LC3 co-localization in both K562 and CML patient cells. Bcr Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib. PMID- 23440702 TI - Costs of diagnosing dementia: results from SveDem, the Swedish Dementia Registry. AB - OBJECTIVE: Diagnostic of different dementia disorders is an important part of dementia care. So far, there is limited knowledge about how dementia is diagnosed in clinical routine, and there are few reports on the costs of the dementia work up leading to a diagnosis. Here, we examine the costs of diagnostic dementia work up in Sweden. METHODS: The analyses were made on the data from the Swedish Dementia Registry (SveDem) and included 11,561 dementia patients diagnosed during 2007-2010, mainly not only in specialist care (SC) (n = 53) but also some primary care centres (PC). We have studied differences in the use of investigations for dementia diagnostics such as cognitive tests, blood and cerebrospinal fluid analyses, radiological examinations and assessments of functions. Unit costs for each diagnostic investigation were combined with the use of these investigations for all cases in the database. Results are presented versus gender and stratified for age. RESULTS: The number of diagnostic tests performed was 2.8 in PC and 4.6 in SC. The average costs (?1 = SEK9 and US$1 = SEK7 in 2010) were SEK6777 in PC and SEK11,682 in SC. Age was the strongest cost predictor while there were no gender differences. There were also regional differences, ranging from SEK8231 to SEK14,734 in SC. CONCLUSIONS: The SveDem database offers valuable information on the diagnostic procedures for dementia in daily clinical practice. The differences between PC and SC in diagnostic costs reflect national guidelines. The age effect needs to be studied more. PMID- 23440703 TI - Sleep estimation using BodyMedia's SenseWearTM armband in patients with obstructive sleep apnea. AB - OBJECTIVES: We aimed to evaluate the validity of the BodyMedia's SenseWearTM Armband (BSA) device in estimating total sleep time (TST) in patients with obstructive sleep apnea (OSA). METHODS: Simultaneous overnight recordings of in laboratory polysomnography (PSG) and BSA were performed on (1) 107 OSA patients (mean age of 45.2 +/- 14.3 years, mean apnea hypopnea index of 43 +/- 35.7/hr and (2) 30 controls matched with OSA patients for age and body mass index. An agreement analysis between the PSG and BSA scoring results was performed using the Bland and Altman method. RESULTS: There was no significant difference in OSA patients between BSA and PSG with regard to TST, total wake time, and sleep efficiency. There was also no significant difference in the controls between BSA and PSG with regard to TST, total wake time, and sleep efficiency. Bland Altman plots showed strong agreement between TST, wake time, and sleep efficiency for both OSA and the controls. The intraclass correlation coefficients revealed perfect agreement between BSA and PSG in different levels of OSA severity and both genders. CONCLUSION: The current data suggest that BSA is a reliable method for determining sleep in patients with OSA when compared against the gold standard test (PSG). BSA can be a useful tool in determining sleep in patients with OSA and can be combined with portable sleep studies to determine TST. PMID- 23440704 TI - The effect of route of administration in thymoquinone toxicity in male and female rats. AB - The maximum tolerated dose for intraperitoneal injection and oral ingestion of thymoquinone was determined in male and female Wistar rats. A range of dose levels of thymoquinone: 20, 30 and 40 mg/kg body weight for intraperitoneal injection and 200, 300 and 500 mg/kg body weight for oral ingestion were tested for acute toxicity in rats. The results showed that the maximum tolerated dose for intraperitoneal injection was 22.5 mg/kg in male rats and 15 mg/kg in females, whereas for oral ingestion it was 250 mg/kg in both male and female rats. There were different signs of toxicity shown in rats which received intraperitoneal injection from those that received oral ingestion of thymoquinone. Rats which received intraperitoneal injection of thymoquinone showed toxicity signs which were related to acute pancreatitis. Meanwhile, rats which received oral ingestion of thymoquinone showed transient toxicity signs. Two deaths were reported at dose of 500 mg/kg as a result of bowel obstruction complications. The data presented in this study indicate that the route of administration of thymoquinone could have an influence on thymoquinone toxicity outcome in both genders. PMID- 23440705 TI - Steady-state first-pass perfusion (SSFPP): a new approach to 3D first-pass myocardial perfusion imaging. AB - PURPOSE: To describe and characterize a new approach to first-pass myocardial perfusion utilizing balanced steady-state free precession acquisition without the use of saturation recovery or other magnetization preparation. THEORY: The balanced steady-state free precession sequence is inherently sensitive to contrast agent enhancement of the myocardium. This sensitivity can be used to advantage in first-pass myocardial perfusion imaging by eliminating the need for magnetization preparation. METHODS: Bloch equation simulations, phantom experiments, and in vivo 2D imaging studies were run comparing the proposed technique with three other methods: saturation recovery spoiled gradient echo, saturation recovery steady-state free precession, and steady-state spoiled gradient echo without magnetization preparation. Additionally, an acquisition reconstruction strategy for 3D perfusion imaging is proposed and initial experience with this approach is demonstrated in healthy subjects and one patient. RESULTS: Phantom experiments verified simulation results showing the sensitivity of the balanced steady-state free precession sequence to contrast agent enhancement in solid tissue is similar to that of magnetization-prepared acquisitions. Images acquired in normal volunteers showed the proposed technique provided superior signal and signal-to-noise ratio compared with all other sequences at baseline as well as postcontrast. CONCLUSIONS: A new approach to first-pass myocardial perfusion is presented that obviates the need for magnetization preparation and provides high signal-to-noise ratio. PMID- 23440706 TI - Emergency hospital admissions for the elderly: insights from the Devon Predictive Model. AB - BACKGROUND: In the UK, people aged 85 and over are the fastest growing population group and are predicted to double in number by 2030. Emergency hospital admissions are also rising. METHODS: All emergency admissions for the registered population in Devon to all English hospitals were analysed by age, and admission rates per thousand registered were calculated. The Devon Predictive Model (DPM) was built, using local data, to predict emergency admissions in the following 12 months. This model was compared with the Combined Predictive Model over five risk categories. RESULTS: The registered Devon population on 31 March 2011 was 761 652 with 65 892 emergency admissions in 2010/2011. The DPM had 89 variables including several local factors which strengthened the model. Three of the four most powerful predictors were age 85-89, 90-94 and 95 and over. The positive predictive value for the DPM was better than the CPM's in all five risk categories. Half (49.6%) of all emergency admissions were from those aged 65 or over. Admissions rose progressively and significantly in each successive elderly age band. At age 85 and over there were 420 emergency admissions per thousand registered. CONCLUSIONS: Age, especially 85 and over, has been undervalued as a risk factor for emergency hospital admissions. PMID- 23440707 TI - Socioeconomic and ethnic inequalities in screen-detected breast cancer in London. AB - BACKGROUND: We investigated socioeconomic and ethnic inequalities in screen detected breast cancer in London-a city with relatively low breast cancer screening uptake and a diverse population. METHODS: Data on 11 957 breast cancers in London women aged 50-64 between 1998 and 2005 were extracted from the Thames Cancer Registry. We investigated the relationship between socioeconomic deprivation and the incidence and 5-year relative survival of screen-detected and non screen-detected cancers. Using logistic regression analysis we explored whether differences in screen-detected cancers between White, Asian and Black women were influenced by age and socioeconomic deprivation. RESULTS: The incidence of screen-detected breast cancer was lower in deprived women and their 5-year relative survival was worse than affluent women. However, survival differences were smaller for screen-detected disease. Among women with breast cancer the odds ratios (OR) for screen-detected disease differed between ethnic groups and these differences were not influenced by adjustment for age and deprivation. Compared with White women, Indian women had higher odds (OR 1.50, 95% confidence interval (1.23-1.84)], and Black Caribbean [0.68 (0.54-0.87)] and Black African women [0.53 (0.38-0.76)] significantly lower odds. CONCLUSION: A sustained focus on increasing screening uptake among deprived women and in Black communities could decrease inequalities in early diagnosis. PMID- 23440708 TI - Feasibility study of transanal total mesorectal excision. AB - BACKGROUND: Laparoscopic resection of colorectal cancers is a safe alternative to open surgery. The conversion rate to open surgery remains fairly constant but is associated with increased morbidity. A new approach to the surgical excision of rectal cancer is transanal total mesorectal excision (TME), in which the rectum is mobilized peranally using endoscopic instruments. This feasibility study describes initial results with transanal TME. METHODS: Between June and August 2012, five consecutive unselected patients with rectal carcinoma underwent surgical excision of rectal tumours by means of transanal TME. RESULTS: Transanal endoscopic dissection of the complete rectum was possible in all patients. Histopathological examination confirmed clear surgical margins and an intact mesorectal fascia in all patients. One patient developed a presacral abscess. Median duration of operation was 175 (range 160-194) min. CONCLUSION: Transanal TME using the down-to-up principle is feasible. Whether the oncological and clinical results are comparable with those of standard laparoscopic or open TME has yet to be proven. PMID- 23440709 TI - Methods in Protein Science. PMID- 23440710 TI - SCIRR39 promotes differentiation of oligodendrocyte precursor cells and regulates expression of myelin-associated inhibitory factors. AB - SCIRR39 is an identified upregulated gene in rat primary neuron injury and/or regeneration process. However, roles of SCIRR39 in the regeneration of central nervous system (CNS) injury are still largely unexplored. Using real-time quantitative PCR and Western blotting, SCIRR39 expression was detected in oligodendrocyte precursor cells (OPCs) and oligodendrocytes. Moreover, the results from cell proliferation and cell cycle indicated that SCIRR39 inhibited OPCs proliferation and induced cell cycle arrest in G0/G1 and G2/M phases. Importantly, SCIRR39 positively regulated OPC differentiation and the expression of myelin basic protein. We also examined the effect of SCIRR39 on expression of myelin-associated inhibitory factors, including myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo A. Nogo A level was markedly regulated by SCIRR39 overexpression or knockdown in oligodendrocytes and cortical neurons co-cultures, while the expression of MAG and OMgp was not obviously changed by SCIRR39 overexpression or knockdown. Taken together, our results indicate the important role of SCIRR39 either in OPC differentiation or in axon myelination, and may provide a new therapeutic target for the treatment of CNS injury. PMID- 23440711 TI - Special Dermatology/Plastic Surgery Issue 2013. PMID- 23440712 TI - Improved sensation in a palmar hand burn scar with fractional CO(2) laser treatments. PMID- 23440714 TI - Endoluminal laser delivery mode and wavelength effects on varicose veins in an ex vivo model. AB - BACKGROUND AND OBJECTIVES: Endovenous laser ablation (EVLA) has been shown to be effective for the elimination of saphenous veins and associated reflux. Mechanism is known to be heat related, but precise way in which heat causes vein ablation is not completely known. This study aimed to determine the effects of various endovenous laser wavelengths and delivery modes on ex vivo human vein both macroscopically and microscopically. We also evaluated whether protected-tip fibers, consisting of prototype silica fibers with a metal tube over the distal end, reduced vein wall perforations compared with non-protected-tip fibers. MATERIALS AND METHODS: An ex vivo EVLA model with human veins harvested during ambulatory phlebectomy procedures was used. Six laser fiber combinations were tested: 810 nm continuous wave (CW) diode laser with a flat tip fiber, 810 CW diode laser with a protected tip fiber, 1,320 nm pulsed Nd:YAG laser, 1,310 nm CW diode laser, 1,470 nm CW diode laser, and 2,100 nm pulsed Ho:YAG laser. RESULTS: Perforation or full thickness necrosis of a portion of the vein wall was observed in 5/11 (45%), 0/11 (0%), 3/22 (14%), 7/11 (64%), 4/6 (67%), and 5/10 (50%) of cross-sections of veins treated with the 810 nm CW diode laser with a flat tip fiber, the 810 CW diode laser with a protected tip fiber, the 1,320 nm pulsed Nd:YAG laser, the 1,310 nm CW diode laser, the 1,470 nm CW diode laser, and the 2,100 nm pulsed Ho:YAG laser, respectively. CONCLUSION: Our results have shown that the delivery mode, pulsed Nd:YAG versus CW, may be just as important as the wavelength. Therefore, the 1,310 nm CW laser may not be equivalent to the 1,320 nm pulsed laser. In addition, protected 810 nm fibers may be less likely to yield wall perforations than their non-protected counterparts. PMID- 23440713 TI - Microarray analysis of port wine stains before and after pulsed dye laser treatment. AB - BACKGROUND AND OBJECTIVES: Neither the pathogenesis of port wine stain (PWS) birthmarks nor tissue effects of pulsed dye laser (PDL) treatment of these lesions is fully understood. There are few published reports utilizing gene expression analysis in human PWS skin. We aim to compare gene expression in PWS before and after PDL, using DNA microarrays that represent most, if not all, human genes to obtain comprehensive molecular profiles of PWS lesions and PDL associated tissue effects. MATERIALS AND METHODS: Five human subjects had PDL treatment of their PWS. One week later, three biopsies were taken from each subject: normal skin (N); untreated PWS (PWS); PWS post-PDL (PWS + PDL). Samples included two lower extremity lesions, two facial lesions, and one facial nodule. High-quality total RNA isolated from skin biopsies was processed and applied to Affymetrix Human gene 1.0ST microarrays for gene expression analysis. We performed a 16 pair-wise comparison identifying either up- or down-regulated genes between N versus PWS and PWS versus PWS + PDL for four of the donor samples. The PWS nodule (nPWS) was analyzed separately. RESULTS: There was significant variation in gene expression profiles between individuals. By doing pair-wise comparisons between samples taken from the same donor, we were able to identify genes that may participate in the formation of PWS lesions and PDL tissue effects. Genes associated with immune, epidermal, and lipid metabolism were up-regulated in PWS skin. The nPWS exhibited more profound differences in gene expression than the rest of the samples, with significant differential expression of genes associated with angiogenesis, tumorigenesis, and inflammation. CONCLUSION: In summary, gene expression profiles from N, PWS, and PWS + PDL demonstrated significant variation within samples from the same donor and between donors. By doing pair-wise comparisons between samples taken from the same donor and comparing these results between donors, we were able to identify genes that may participate in formation of PWS and PDL effects. Our preliminary results indicate changes in gene expression of angiogenesis-related genes, suggesting that dysregulation of angiogenic signals and/or components may contribute to PWS pathology. PMID- 23440716 TI - Homolytic reactive mass spectrometry of fullerenes: peculiarities of the reactions of C60 with aromatic compounds in the ionization chambers of mass spectrometers and in solution. AB - C60 reacted with PhH, PhCl, BnH, BnNH2, and o-C2H2B10H10 in the electron impact (EI) ion source of a mass spectrometer at 300 degrees C forming phenyl, benzyl, and o-carboranyl adducts, respectively, stabilized by hydrogen addition and loss. Besides, the additions to C60 of methyl and phenyl radicals for toluene, and a phenyl radical for benzylamine were observed. A homolytic reaction mechanism was suggested involving the reaction of the radicals formed from the aromatics under EI with C60 at the ionization chamber walls. While the ion/molecule reaction of C60 with benzene performed by Sun et al. under chemical ionization conditions at 200 degrees C afforded the complex C60*PhH(+*), quite a different isomer, HC60Ph(+*), was detected in the present study as a sequence of the different reaction mechanisms. C60 also reacted with benzyl bromide in the laser desorption/ionization (LDI) source of a mass spectrometer to give C60CPh(+). Phenyl and benzyl derivatives of C60 were found, respectively, when the reactions of the fullerene with PhCl, BnH, and BnBr were performed in solution under ultra violet irradiation. For the reaction with toluene, the strong chemically induced dynamic electron polarization of the intermediate benzylfullerenyl radical with the reverse phase effect was found. The coincidence of the results of the mass spectrometry and solution reactions of C60 with aromatics, even though incomplete, additionally supports the hypothesis, formulated earlier, that the former results can predict the latter ones to a significant extent and shows that this conclusion is valid for both EI and LDI initiated reactions in mass spectrometers. PMID- 23440718 TI - Fragmentation chemistry of [Met-Gly]*+, [Gly-Met]*+, and [Met-Met]*+ radical cations. AB - Radical cations [Met-Gly](*+), [Gly-Met](*+), and [Met-Met](*+) have been generated through collision-induced dissociation (CID) of [Cu(II)(CH3CN)2(peptide)](*2+) complexes. Their fragmentation patterns and dissociation mechanisms have been studied both experimentally and theoretically using density functional theory at the UB3LYP/6-311++G(d,p) level. The captodative structure, in which the radical is located at the alpha-carbon of the N-terminal residue and the proton is on the amide oxygen, is the lowest energy structure on each potential energy surface. The canonical structure, with the charge and spin both located on the sulfur, and the distonic ion with the proton on the terminal amino group, and the radical on the alpha-carbon of the C terminal residue have similar energies. Interconversion between the canonical structures and the captodative isomers is facile and occurs prior to fragmentation. However, isomerization to produce the distonic structure is energetically less favorable and cannot compete with dissociation except in the case of [Gly-Met](*+). Charge-driven dissociations result in formation of [b(n) - H](*+) and a(1) ions. Radical-driven dissociation leads to the loss of the side chain of methionine as CH3-S-CH=CH2 producing alpha-glycyl radicals from both [Gly-Met](*+) and [Met-Met](*+). For [Met-Met](*+), loss of the side chain occurs at the C-terminal as shown by both labeling experiments and computations. The product, the distonic ion of [Met-Gly](*+), NH3 (+)CH(CH2CH2SCH3)CONHCH(*)COOH dissociates by loss of CH3S(*). The isomeric distonic ion NH3 (+)CH2CONHC(*)(CH2CH2SCH3)COOH is accessible directly from the canonical [Gly Met](*+) ion. A fragmentation pathway that characterizes this ion (and the distonic ion of [Met-Met](*+)) is homolytic fission of the Cbeta-Cgamma bond to lose CH3SCH2(*). PMID- 23440717 TI - omniSpect: an open MATLAB-based tool for visualization and analysis of matrix assisted laser desorption/ionization and desorption electrospray ionization mass spectrometry images. AB - We present omniSpect, an open source web- and MATLAB-based software tool for both desorption electrospray ionization (DESI) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) that performs computationally intensive functions on a remote server. These functions include converting data from a variety of file formats into a common format easily manipulated in MATLAB, transforming time-series mass spectra into mass spectrometry images based on a probe spatial raster path, and multivariate analysis. OmniSpect provides an extensible suite of tools to meet the computational requirements needed for visualizing open and proprietary format MSI data. PMID- 23440719 TI - LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-beta binding protein 4, was previously discovered in a genome-wide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. METHODS: We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form the VTTT and IAAM LTBP4 haplotypes. RESULTS: Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 +/- 3.3 years compared to 10.7 +/- 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to transforming growth factor (TGF) beta displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4' role as a regulator of TGFbeta. INTERPRETATION: LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients. PMID- 23440721 TI - Is 20% of a loaf enough? PMID- 23440720 TI - Executive functioning in older adults with hoarding disorder. AB - BACKGROUND: Hoarding disorder (HD) is a chronic and debilitating psychiatric condition. Midlife HD patients have been found to have neurocognitive impairment, particularly in areas of executive functioning, but the extent to which this is due to comorbid psychiatric disorders has not been clear. AIMS/METHOD: The purpose of the present investigation was to examine executive functioning in geriatric HD patients without any comorbid Axis I disorders (n = 42) compared with a healthy older adult comparison group (n = 25). We hypothesized that older adults with HD would perform significantly worse on measures of executive functioning (Wisconsin Card Sort Task [Psychological Assessment Resources, Lutz, Florida, USA] ( Psychological Assessment Resources, 2003) and the Wechsler Adult Intelligence Scale-IV digit span and letter-number sequencing tests [Pearson, San Antonio, TX, USA]). RESULTS: Older adults with HD showed significant differences from healthy older controls in multiple aspects of executive functioning. Compared with healthy controls, older adults with HD committed significantly more total, non-perseverative errors and conceptual level responses on the Wisconsin Card Sort Task and had significantly worse performance on the Wechsler Adult Intelligence Scale-IV digit span and letter-number sequencing tests. Hoarding symptom severity was strongly correlated with executive dysfunction in the HD group. CONCLUSIONS: Compared with demographically-matched controls, older adults with HD have dysfunction in several domains of executive functioning including mental control, working memory, inhibition, and set shifting. Executive dysfunction is strongly correlated with hoarding severity and is not because of comorbid psychiatric disorders in HD patients. These results have broad clinical implications suggesting that executive functioning should be assessed and taken into consideration when developing intervention strategies for older adults with HD. PMID- 23440722 TI - Correction of gradient-induced phase errors in radial MRI. AB - PURPOSE: To correct gradient-induced phase errors in radial MRI. METHODS: Gradient-induced eddy currents affect the MRI data acquisition by gradient delays and phase errors that may lead to severe image artifacts for non-Cartesian imaging scenarios such as radial trajectories. While gradient delays are dealt with by respective shifts of the acquisition window during radial image acquisition, this work introduces a simple method for quantifying and correcting phase errors from the actual data prior to image reconstruction. For a given gradient system, the approach yields a specific phase error per gradient that can be used for correcting the raw data. RESULTS: Phantom studies at 9.4 T demonstrated marked improvements in radial image quality. It could be shown that the phase correction is not compromised by data undersampling. Moreover, the selective correction of gradient-induced phase errors retained the phase information caused by different concentrations of a paramagnetic contrast agent. CONCLUSION: The proposed method does not require additional reference measurements and separately corrects for phase errors induced by eddy currents, while retaining the residual phase of the object which may carry physiologic information. PMID- 23440723 TI - Deregulation of protein phosphatase expression in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a highly malignant disease of myeloid cell line. AML is the most frequent adult leukemia with inadequate treatment possibility. The protein phosphatases are critical regulators of cell signaling, and deregulation of protein phosphatases always contribute to cell transformation. Although many studies established a relationship between protein phosphatases and leukemia, little is known about the role of this group of proteins in AML. To address this issue, we initially identified the complete catalog of human protein phosphatase genes and used this catalog to study deregulation of protein phosphatases in AML. Using mRNA expression data of AML patients, we show that 11 protein phosphatases are deregulated in AML within 174 protein phosphatases. The GO enrichment study suggests that these genes are involved in multiple biological processes other than protein de-phosphorylation. Expression of DUSP10, PTPRC, and PTPRE was significantly higher than average expression in AML, and a linear combination of DUSP10, MTMR11, PTPN4, and PTPRE expressions provides important information about disease subtypes. Our results provide an overview of protein phosphatase deregulation in AML. PMID- 23440724 TI - Association of isolated short fetal femur with intrauterine growth restriction. AB - OBJECTIVES: To analyze the outcomes of fetuses referred because of short femur length. METHODS: This was a retrospective study of all singleton pregnancies referred to a tertiary care referral hospital with a femur length below the 5(th) percentile. All ultrasound scan reports, including Doppler, fetal karyotyping, pregnancy outcome and neonatal data were analyzed. RESULTS: In 112 patients, 87 (78%) had an isolated short femur and 25 (22%) had a non-isolated short femur. The non-isolated cases consisted of chromosomal disorders (n = 6), skeletal abnormalities (n = 6), multiple abnormalities (n = 12) and 1 genetic disorder. In the isolated group 37 cases (43%) were intrauterine growth restricted (positive likelihood ratio 1.20, negative likelihood ratio 0.45). In 33 cases the short femur was unexplained and 17 referrals were considered false-positive. The growth restricted group had significant more abnormal Doppler measurements (p = 0.01), caesarean deliveries (p = 0.043) and admissions to the neonatal intensive care unit (p = 0.001). CONCLUSION: An isolated short femur is associated with intrauterine growth restriction and adverse pregnancy outcome. PMID- 23440725 TI - Synthesis and protective effects of novel salidroside analogues on glucose and serum depletion induced apoptosis in PC12 cells. AB - Salidroside is a natural product isolated from Rhodiola rosea L. which possesses a wide range of biological activities, especially neuroprotective effects in the treatment of ischemic stroke. In an attempt to improve its neuroprotective effects, a series of novel salidroside analogues were synthesized and their neuroprotective activities were evaluated against the glucose and serum depletion induced cell death in differentiated PC12 cells. Most target compounds displayed protective effects on the cell viability, especially for compound 6, which had a great potency superior to salidroside. MTT assay and Hoechst 33342 staining collectively showed that pretreatment with 6 attenuated cell viability loss and reduced apoptotic death in cultured PC12 cells with glucose and serum depletion. And its neuroprotective effects might be associated with the increase of the apoptosis-related protein Bcl-2/Bax expression ratio, and also with the inhibition of caspase-3 activation. Therefore, our new findings may provide potentially important information for further development of salidroside analogues and lay the basis for further studies on the cerebral ischemic stroke and neurodegenerative diseases for human clinical treatment. PMID- 23440726 TI - Blind(fold)ed by science: a constant target-heading angle is used in visual and nonvisual pursuit. AB - Previous work investigating the strategies that observers use to intercept moving targets has shown that observers maintain a constant target-heading angle (CTHA) to achieve interception. Most of this work has concluded or indirectly assumed that vision is necessary to do this. We investigated whether blindfolded pursuers chasing a ball carrier holding a beeping football would utilize the same strategy that sighted observers use to chase a ball carrier. Results confirm that both blindfolded and sighted pursuers use a CTHA strategy in order to intercept targets, whether jogging or walking and irrespective of football experience and path and speed deviations of the ball carrier during the course of the pursuit. This work shows that the mechanisms involved in intercepting moving targets may be designed to use different sensory mechanisms in order to drive behavior that leads to the same end result. This has potential implications for the supramodal representation of motion perception in the human brain. PMID- 23440727 TI - Increasing self-other integration through divergent thinking. AB - Increasing evidence suggests that people may cognitively represent themselves and others just like any other, nonsocial event. Here, we provide evidence that the degree of self-other integration (as reflected by the joint Simon effect; JSE) is systematically affected by the control characteristics of temporally overlapping but unrelated and nonsocial creativity tasks. In particular, the JSE was found to be larger in the context of a divergent-thinking task (alternate uses task) than in the context of a convergent-thinking task (remote association task). This suggests that self-other integration and action corepresentation are controlled by domain-general cognitive-control parameters that regulate the integrativeness (strong vs. weak top-down control and a resulting narrow vs. broad attentional focus) of information processing irrespective of its social implications. PMID- 23440728 TI - Time does not flow without language: spatial distance affects temporal duration regardless of movement or direction. AB - Much evidence has suggested that people conceive of time as flowing directionally in transverse space (e.g., from left to right for English speakers). However, this phenomenon has never been tested in a fully nonlinguistic paradigm where neither stimuli nor task use linguistic labels, which raises the possibility that time is directional only when reading/writing direction has been evoked. In the present study, English-speaking participants viewed a video where an actor sang a note while gesturing and reproduced the duration of the sung note by pressing a button. Results showed that the perceived duration of the note was increased by a long-distance gesture, relative to a short-distance gesture. This effect was equally strong for gestures moving from left to right and from right to left and was not dependent on gestures depicting movement through space; a weaker version of the effect emerged with static gestures depicting spatial distance. Since both our gesture stimuli and temporal reproduction task were nonlinguistic, we conclude that the spatial representation of time is nondirectional: Movement contributes, but is not necessary, to the representation of temporal information in a transverse timeline. PMID- 23440729 TI - Current Gaps in Understanding the Molecular Basis of FXTAS. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with defining clinical features that include kinetic tremor, gait ataxia, and parkinsonism, with associated features spanning medical, cognitive, and psychiatric clinical domains. The emerging model for the pathogenesis of FXTAS is that of RNA toxicity as a consequence of the sequestration of RNA binding proteins by the expanded CGG-repeat element within the FMR1 message, thus compromising the normal functions of those proteins. A principal challenge at this point is to determine precisely which proteins are involved in FXTAS pathogenesis and how to prevent or reverse this process. A second challenge is to determine why there is incomplete penetrance of FXTAS among premutation carriers with identical CGG-repeat lengths, and what the protective factors are in some carriers. Finally, the discovery in premutation mice of early neurodevelopmental abnormalities, some occurring even during late embryogenesis, raises the question of whether FXTAS is the end-stage of a life-long process of neuronal dysregulation. If an extended pre-clinical phase precedes the development of FXTAS, there is great potential for therapeutic intervention, years or even decades before its clinical features are manifest. PMID- 23440730 TI - Annual number of lung cancer deaths potentially avertable by screening in the United States. AB - BACKGROUND: The National Lung Screening Trial (NLST), which was conducted between 2002 and 2009, demonstrated that screening with low-dose computed tomography (LDCT) reduced lung cancer mortality by 20% among screening-eligible populations compared with chest x-ray. In this article, the authors provide an estimate of the annual number of lung cancer deaths that can be averted by screening, assuming the screening regimens adopted in the NLST are fully implemented in the United States. METHODS: The annual number of lung cancer deaths that can be averted by screening was estimated as a product of the screening effect, the US population size (obtained from the 2010 US Census data), the prevalence of screening eligibility (estimated using the 2010 National Health Interview Survey [NHIS] data), and the lung cancer mortality rates among screening-eligible populations (estimated using the NHIS data from 2000-2004 and the third National Health and Nutrition Examination Survey linked mortality files). Analyses were performed separately by sex, age, and smoking status, with Poisson regression analysis used for mortality rate estimation. Uncertainty of the estimates of the number of avertable lung cancer deaths was quantified by simulation. RESULTS: Approximately 8.6 million Americans (95% confidence interval [95% CI], 8.0 million-9.2 million), including 5.2 million men (95% CI, 4.8 million-5.7 million) and 3.4 million women (95% CI, 3.0 million -3.8 million), were eligible for lung cancer screening in 2010. If the screening regimen adopted in the NLST was fully implemented among these screening-eligible US populations, a total of 12,250 (95% CI, 10,170-15,671) lung cancer deaths (8990 deaths in men and 3260 deaths in women) would be averted each year. CONCLUSIONS: The data from the current study indicate that LDCT screening could potentially avert approximately 12,000 lung cancer deaths per year in the United States. Further studies are needed to estimate the number of avertable lung cancer deaths and the cost-effectiveness of LDCT screening under different scenarios of risk, various screening frequencies, and various screening uptake rates. PMID- 23440731 TI - Analysis of image heterogeneity using 2D Minkowski functionals detects tumor responses to treatment. AB - PURPOSE: The acquisition of ever increasing volumes of high resolution magnetic resonance imaging (MRI) data has created an urgent need to develop automated and objective image analysis algorithms that can assist in determining tumor margins, diagnosing tumor stage, and detecting treatment response. METHODS: We have shown previously that Minkowski functionals, which are precise morphological and structural descriptors of image heterogeneity, can be used to enhance the detection, in T1 -weighted images, of a targeted Gd(3+) -chelate-based contrast agent for detecting tumor cell death. We have used Minkowski functionals here to characterize heterogeneity in T2 -weighted images acquired before and after drug treatment, and obtained without contrast agent administration. RESULTS: We show that Minkowski functionals can be used to characterize the changes in image heterogeneity that accompany treatment of tumors with a vascular disrupting agent, combretastatin A4-phosphate, and with a cytotoxic drug, etoposide. CONCLUSIONS: Parameterizing changes in the heterogeneity of T2 -weighted images can be used to detect early responses of tumors to drug treatment, even when there is no change in tumor size. The approach provides a quantitative and therefore objective assessment of treatment response that could be used with other types of MR image and also with other imaging modalities. PMID- 23440732 TI - GSK-3beta polymorphism discriminates bipolar disorder and schizophrenia: a systematic meta-analysis. AB - Glycogen synthase kinase 3 (GSK-3) is a well-known conserved and ubiquitous protein kinase and playing a pivotal role in neurodevelopment, neurogenesis, learning/memory, and neuronal cell death. Dysfunction of GSK-3 had been seen in multiple neurodegenerative and psychiatric diseases. Bipolar disorder and schizophrenia are two common psychiatric diseases first occur in adolescence or young adulthood. They share similar risk genes as well as clinical symptoms, which make it is difficult to be discriminated from each other. Here, by using meta-analysis we reported that glycogen synthase kinase 3beta promoter inactive mutant rs334558 may contribute to the development of schizophrenia not bipolar disorder. This might be used to distinguish these two diseases. PMID- 23440735 TI - Signal intensity changes of the fetal liver on MRI in-phase and out-of-phase sequence. AB - OBJECTIVE: To study signal intensity (SI) of the fetal liver by MRI in-phase and out-of-phase over gestational age (GA). METHODS: A total of 91 pregnant women from 19 to 38 gestational weeks were imaged using MRI. Liver-to-spleen SI ratios of the right and left fetal liver lobes on in-phase and out-of-phase were measured, calculated, and compared with each other. Curves of liver-to-spleen SI ratio of the right and left liver lobe were plotted by GA. RESULTS: Liver-to spleen SI ratio of the right lobe on in-phase was different from that of the left liver lobe (t = 3.95; p < 0.001). A statistically significant difference was also found for out-of-phase SI ratios (t = 3.69; p < 0.001). Curves of liver-to-spleen SI ratio of the fetal liver on in-phase and out-of-phase showed changes against GA. CONCLUSION: Liver-to-spleen SI ratio is different between the right and left liver lobe, which probably results from the different blood supply. Curves of liver-to-spleen SI ratios between 19 to 38 gestational weeks reflect the changes of decreasing function of blood production by fetal liver. In-phase and out-of phase may have clinical use in the early detection of disordered fetal growth and metabolism. PMID- 23440733 TI - Integration or fragmentation? Racial diversity and the American future. AB - Over the next generation or two, America's older, largely white population will increasingly be replaced by today's disproportionately poor minority children. All future growth will come from populations other than non-Hispanic whites as America moves toward a majority-minority society by 2043. This so-called Third Demographic Transition raises important implications about changing racial boundaries in the United States, that is, about the physical, economic, and sociocultural barriers that separate different racial and ethnic groups. America's racial transformation may place upward demographic pressure on future poverty and inequality as today's disproportionately poor and minority children grow into adult roles. Racial boundaries will be reshaped by the changing meaning of race and ethnicity, shifting patterns of racial segregation in neighborhoods and the workplace, newly integrating (or not) friendship networks, and changing rates of interracial marriage and childbearing. The empirical literature provides complicated lessons and offers few guarantees that growing racial diversity will lead to a corresponding breakdown in racial boundaries-that whites and minorities will increasingly share the same physical and social spaces or interact as coequals. How America's older population of elected officials and taxpayers responds today to America's increasingly diverse population will provide a window to the future, when today's children successfully transition (or not) into productive adult roles. Racial and ethnic inclusion will be reshaped by changing ethnoracial inequality, which highlights the need to invest in children-now. PMID- 23440736 TI - Importance of collection methods and stability of oral fluid samples for hepatitis B surface antigen detection. AB - BACKGROUND: Oral fluid (OF) sample collection and stability for HBsAg detection are not fully established. This study aims to investigate the applicability of OF collectors and sample stability for Hepatitis B virus surface antigen detection. METHODS: Paired serum and OF samples were obtained from 191 individuals, and Chembio (Chembio Diagnostic System, USA) and Salivette (Sarstedt, Germany) devices were used for OF collection. Two HBsAg enzyme immunoassays (EIAs) were used (HBsAg One kit, Radim, Rome, Italy and ETI-MAK-4, DiaSorin, Vercelli, Italy) to determine the most efficient method according OF collector. Sample volume, incubation time, and cutoff (CO) value were evaluated. The stability of OF samples was determined under different environmental conditions. RESULTS: Chembio samples analyzed using DiaSorin EIA without modification of the manufacturer's instructions, demonstrated a sensitivity of 95.24% and a specificity of 100%. Salivette samples analyzed with Radim EIA with receiver operating characteristic (ROC) curve for calculating the CO showed a sensitivity of 78.26% and a specificity of 89.88%. HBsAg was detected in Chembio and Salivette samples under different environmental conditions, but the Chembio samples were the most stable. CONCLUSIONS: Both collectors can be used for HBsAg detection in OF samples, but some modifications of commercial EIAs should be incorporated for Salivette device. OF samples were reliably stable and could be stored for up to 90 days at 2-8 degrees C. PMID- 23440737 TI - Reproduction of motion artifacts for performance analysis of prospective motion correction in MRI. AB - PURPOSE: Despite numerous publications describing the ability of prospective motion correction to improve image quality in magnetic resonance imaging of the brain, a reliable approach to assess this improvement is still missing. A method that accurately reproduces motion artifacts correctable with prospective motion correction is developed, and enables the quantification of the improvements achieved. METHODS: A software interface was developed to simulate rigid body motion by changing the scanning coordinate system relative to the object. Thus, tracking data recorded during a patient scan can be used to reproduce the prevented motion artifacts on a volunteer or a phantom. The influence of physiological motion on image quality was investigated by filtering these data. Finally, the method was used to reproduce and quantify the motion artifacts prevented in a patient scan. RESULTS: The accuracy of the method was tested in phantom experiments and in vivo. The calculated quality factor, as well as a visual inspection of the reproduced artifacts shows a good correspondence to the original. CONCLUSION: Precise reproduction of motion artifacts assists qualification of prospective motion correction strategies. The presented method provides an important tool to investigate the effects of rigid body motion on a wide range of sequences, and to quantify the improvement in image quality through prospective motion correction. PMID- 23440738 TI - Sleep and Anesthesia Interactions: A Pharmacological Appraisal. AB - Anesthetics have been used in clinical practice for over a hundred years, yet their mechanisms of action remain poorly understood. One tempting hypothesis to explain their hypnotic properties posits that anesthetics exert a component of their effects by "hijacking" the endogenous arousal circuitry of the brain. Modulation of activity within sleep- and wake-related neuroanatomic systems could thus explain some of the varied effects produced by anesthetics. There has been a recent explosion of research into the neuroanatomic substrates affected by various anesthetics. In this review, we will highlight the relevant sleep architecture and systems and focus on studies over the past few years that implicate these sleep-related structures as targets of anesthetics. These studies highlight a promising area of investigation regarding the mechanisms of action of anesthetics and provide an important model for future study. PMID- 23440740 TI - Type IV pili of Acidithiobacillus ferrooxidans can transfer electrons from extracellular electron donors. AB - Studies on Acidithiobacillus ferrooxidans accepting electrons from Fe(II) have previously focused on cytochrome c. However, we have discovered that, besides cytochrome c, type IV pili (Tfp) can transfer electrons. Here, we report conduction by Tfp of A. ferrooxidans analyzed with a conducting-probe atomic force microscope (AFM). The results indicate that the Tfp of A. ferrooxidans are highly conductive. The genome sequence of A. ferrooxidans ATCC 23270 contains two genes, pilV and pilW, which code for pilin domain proteins with the conserved amino acids characteristic of Tfp. Multiple alignment analysis of the PilV and PilW (pilin) proteins indicated that pilV is the adhesin gene while pilW codes for the major protein element of Tfp. The likely function of Tfp is to complete the circuit between the cell surface and Fe(II) oxides. These results indicate that Tfp of A. ferrooxidans might serve as biological nanowires transferring electrons from the surface of Fe(II) oxides to the cell surface. PMID- 23440739 TI - Comparison of brown and white adipose tissues in infants and children with chemical-shift-encoded water-fat MRI. AB - PURPOSE: To compare fat-signal fractions (FFs) and T2* values between brown (BAT) and white (WAT) adipose tissue located within the supraclavicular fossa and subcutaneous depots, respectively. MATERIALS AND METHODS: Twelve infants and 39 children were studied. Children were divided into lean and overweight/obese subgroups. Chemical-shift-encoded water-fat magnetic resonance imaging (MRI) was used to quantify FFs and T2* metrics in the supraclavicular and adjacent subcutaneous adipose tissue depots. Linear regression and t-tests were performed. RESULTS: Infants had lower supraclavicular FFs than children (P < 0.01) but T2* values were similar (P = 0.5). Lean children exhibited lower supraclavicular FFs and T2* values than overweight children (P < 0.01). In each individual infant and child, supraclavicular FFs were consistently lower than adjacent subcutaneous FFs. Supraclavicular T2* values were consistently lower than subcutaneous T2* values in children, but not in infants. FFs in both depots were positively correlated with age and weight in infants (P < 0.01). In children, they were correlated with weight and body mass index (BMI) (P < 0.01), but not age. Correlations between T2* and anthropometric variables existed in children (P < 0.01), but were absent in infants. CONCLUSION: Cross-sectional comparisons suggest variations in FF and T2* values in the supraclavicular and subcutaneous depots of infants and children, which are potentially indicative of physiological differences in adipose tissue fat content, amount, and metabolic activity. PMID- 23440741 TI - Effect of the root canal final rinse protocols on the debris and smear layer removal and on the push-out strength of an epoxy-based sealer. AB - The aim of the present study was to evaluate the efficacy of QMiX, SmearClear, and 17% EDTA for the debris and smear layer removal from the root canal and its effects on the push-out bond strength of an epoxy-based sealer by scanning electron microscopy (SEM). Forty extracted human canines (n = 10) were assigned to the following final rinse protocols: G1-distilled water (control), G2-17% EDTA, G3-SmearClear, and G4-QMiX. The specimens were submitted to a SEM analysis to evaluate the presence of debris and smear layer, respectively, in the apical or cervical segments. In sequence, forty extracted human maxillary canines with the root canals instrumented were divided into four groups (n = 10) similar to the SEM analysis study. After the filling with AH Plus, the roots were transversally sectioned to obtain dentinal slices. The specimens were submitted to a push-out bond strength test using an electromechanical testing machine. The statistical analysis for the SEM and push-out bond strength studies were performed using the Kruskal-Wallis and Dunn tests (alpha = 5%). There was no difference among the G2, G3, and G4 efficacy in removing the debris and smear layer (P > 0.05). The efficacy of these groups was superior to the control group. The push-out bond strength values of G2, G3, and G4 were superior to the control group. The ability to remove the debris and smear layer by SmearClear and QMiX was as effective as the 17% EDTA. The final rinse with these solutions promoted similar push-out bond strength values. PMID- 23440742 TI - An examination of concordance and cultural competency in the diabetes care pathway: South Asians living in the United Kingdom. AB - The Care Pathway project used a multilevel and multimethod approach to explore access to the care pathway for diabetic renal disease. Taking what was known about the outcomes of ethnic minority patients with diabetic renal disease; the study sought to explore and further understand how and why South Asian patients' experiences may be different from the majority of population in relation to access. Through improved understanding of any observed inequalities, the study aimed to inform the development of culturally competent diabetes services. The design incorporated audits of patient indicators for diabetes and renal health at key points in the pathway: Diagnosis of diabetes and referral to specialist renal services in two years- 2004 and 2007, and qualitative individual interviews with patients and providers identified through the 2007 samples. This article describes the care provider perspective of access to diabetes care from a thematic analysis of 14 semistructured interviews conducted with professionals, at three study sites, with different roles in the diabetes pathway. National policy level initiatives to improve quality have been mirrored by quality improvements at the local practice level. These achievements, however, have been unable to address all aspects of care that service providers identified as important in facilitating access to all patient groups. Concordance emerged as a key process in improving access to care within the pathway system, and barriers to this exist at different levels and are greater for South Asian patients compared to White patients. A conceptual model of concordance as a process through which access to quality diabetes care is achieved and its relation to cultural competency is put forward. The effort required to achieve access and concordance among South Asian patients is inversely related to cultural competency at policy and practice levels. These processes are underpinned by communication. PMID- 23440744 TI - Mechanism of experimental autoimmune neuritis in Lewis rats: the dual role of macrophages. AB - Human peripheral demyelinating diseases, such as Guillain-Barre syndrome (GBS), are characterized by inflammation and demyelination in the peripheral nervous system. Similarities in the pathology between GBS and the animal model of experimental autoimmune neuritis (EAN) indicate that autoimmune responses are involved in both diseases. This article summarizes the general aspects of the EAN model in Lewis rats and discusses the potential role of macrophages in the progression of EAN. A better understanding of macrophages may help to design alternative therapeutic strategies for organ-specific autoimmune diseases, including GBS. PMID- 23440743 TI - Unraveling a municipal effluent's toxicity to Tripneustes gratilla sperm fertilization. AB - A tiered investigative approach was employed to characterize and identify substances responsible for the persistent toxicity of a primary-treated municipal effluent to gametes of the Hawaiian sea urchin, Tripneustes gratilla. Toxicity identification evaluation (TIE) procedures from the US Environmental Protection Agency were modified to account for the tolerance of T. gratilla gametes to various sample manipulations. Microtox rapid toxicity screening was applied in some aspects of the study after verifying a correlation between the pattern of toxic responses of T. gratilla gametes and that of the bioluminescent bacteria Vibrio fischeri. Toxicity identification evaluation phase I manipulations revealed a toxicity profile implicating surfactants as possible toxicants, and TIE phase II toxicity assessment of isolated fractions coupled with colorimetric surfactant analyses confirmed the possible role of surfactants in effluent toxicity. The toxic effects of standard reference surfactants on T. gratilla fertilization indicated a concordance with the effects of the more nonpolar effluent fractions. Treatability studies showed that biodegradation by activated sludge eliminated effluent toxicity to urchin gametes. PMID- 23440745 TI - Performance evaluation of LUMIPULSE G1200 autoimmunoanalyzer for the detection of serum hepatitis B virus markers. AB - BACKGROUND: We evaluated recently introduced automated immunoassay analyzer LUMIPULSE G1200 (Fujirebio, Inc., Tokyo, Japan) for detecting serologic hepatitis B virus (HBV) markers by comparison with the results by ARCHITECT i4000SR (Abbott, Abbott Park, IL). METHODS: Precision performance was evaluated over 20 days. HBV surface antigen (HBsAg), HBV e antigen (HBeAg), antibodies to HBV core antigen (anti-HBc), antibodies to HBeAg (anti-HBe), and antibodies to HBsAg (anti HBs) in a total of 1,000 serum samples were assessed by the two analyzers. Discrepant results were retested by COBAS e411 (Roche Diagnostics, Mannheim, Germany). RESULTS: LUMIPULSE showed excellent precision performance of total imprecision less than 3.5% coefficient of variation. The qualitative results between the two analyzers were agreed with each other in 92.0-99.8% of the specimens according to the different HBV markers. The degrees of reactions for HBeAg were moderately correlated between the two analyzers (r = 0.60), and those of other HBV markers were well correlated (r = 0.80 or greater). However, there were 183 discrepancies among 1,000 cases, and most of them showed degree of reaction around the cutoff values. CONCLUSIONS: LUMIPULSE G1200 showed well concordant results with ARCITHECT for hepatitis B serologic tests. However, results near the cutoff values would need to be retested with other immunoassay or molecular methods, when the serological profiles of HBV markers are unusual or are not correlated to the clinical conditions of the patient, due to discrepancies between the immunoassay analyzers. PMID- 23440746 TI - A new approach to studying ion uptake by actinomycetes. AB - A streptomycete that had the ability to avidly sequester iron via siderophores was previously isolated from environmental soil samples. The chelating agent expressed by this organism is confirmed by HPLC as desferrioxamine E. Although the traditional chromo azuerol sulphate (CAS) assay for detection of siderophores is based upon the chelation of iron we were interested to examine the relationship of these iron-capturing molecules with other ions. Consequently, a new approach was employed that enabled the assessment of the affinity of the siderophore moieties for other ions by adapting the CAS assay. The present study reveals that the isolate produced a siderophore that was capable of sequestering a range of ions including Mn, Co, Cd, Ni, Al, Li, Cu, Zn and Mg. On the basis of the assay described it would appear that the organism sequesters copper more readily than iron. This raises an age-old debate surrounding the replacement of copper as a fundamentally essential element with iron as a consequence of the evolution of the di-oxygen environment. PMID- 23440747 TI - Diversity in size and signal intensity in multilocular cystic ovarian masses: new parameters for distinguishing metastatic from primary mucinous ovarian neoplasms. AB - PURPOSE: To differentiate primary mucinous ovarian neoplasms from metastatic ones with MR using diversity in size and signal intensity of multilocular cystic masses. MATERIALS AND METHODS: Twenty-eight cases of primary malignant or borderline mucinous malignant neoplasms and 14 metastatic ovarian tumors were retrospectively reviewed. We analyzed whether the tumor was unilateral or bilateral, the diversity in the size and signal intensity of each loculus in multilocular tumors, namely the size ratio of the smallest/largest loculus (size diversity ratio), and the standard deviation of the signal intensity at the level with the most varying signal on T2-weighted images within tumors (signal diversity ratio). We performed statistical analysis using the Mann-Whitney U test. RESULTS: Bilateral tumors were more commonly observed among metastatic tumors than primary mucinous tumors (2/28 in primary versus 11/14 in metastatic, P < 0.01). The size diversity ratio was higher in primary mucinous tumors than in metastatic tumors (mean, 50.2 versus 23.2; P < 0.01). The signal diversity ratio was also higher in primary mucinous tumors than in metastatic tumors (334.3 versus 231.2; P < 0.01). CONCLUSION: Bilateral tumors were more common among metastatic tumors, which tended to be composed of cysts of uniform sizes and signal intensities compared with those of primary mucinous tumors. PMID- 23440748 TI - Saltwater flotation for more efficient matrix separation of wetland macroinvertebrates does not affect total mercury or methylmercury concentrations. AB - The authors compared benthic wetland invertebrate matrix separation techniques (handpicking vs saltwater flotation) to test for effects on invertebrate mercury concentrations. Neither total mercury nor methylmercury concentrations differed significantly between techniques across 8 taxa. Matrix separation by the flotation technique took significantly less time and resulted in significantly greater abundance recovery in some taxa. The authors conclude that the saltwater based flotation technique does not lead to mercury contamination or analytical interference issues. PMID- 23440749 TI - Cerebral Scedosporium apiospermum infection presenting with intestinal manifestations. AB - We present a case of cerebral Scedosporium apiospermum infection presenting with intestinal manifestations in a 64-year-old male patient on immunosuppression for orthotopic liver transplantation. At admission, the patient's chief complaint was chronic watery diarrhea and he was found to have colonic ulcers on endoscopy. His hospital course was complicated by a tonic-clonic seizure caused by a left frontal brain abscess, with the causative agent being identified by culture. He was treated with lobectomy, high-dose intravenous voriconazole, and liposomal amphotericin with clinical, endoscopic, and histologic improvement. To our knowledge, S. apiospermum has not been previously described as a cause of colitis. The septate branching appearance of the Scedosporium species is similar to the more common Aspergillus species. This case of gastrointestinal Scedosporium brings into question previously reported cases of isolated gastrointestinal aspergillosis diagnosed by histopathology. Clinical suspicion for S. apiospermum must be maintained in immunosuppressed patients presenting with neurologic and gastrointestinal symptoms. PMID- 23440750 TI - Determination of total oxidative stress and total antioxidant capacity before and after the treatment of iron-deficiency anemia. AB - BACKGROUND: Oxidative stress is an imbalance between the reactive oxygen species and antioxidant system. In this study, total oxidative stress (TOS) and total antioxidant capacity (TAC) were investigated with a new and practical method in childhood iron-deficiency anemia. METHOD: During the study period 80 children between 6 and 60 months were enrolled; 40 children (study group) had iron deficiency anemia, and 40 children (control group) were healthy. Complete blood count, serum iron, iron-binding capacity, ferritin levels, TOS, and TAC were evaluated. Children diagnosed iron-deficiency anemia were treated with oral ferric iron. After 2 months of the treatment, blood tests of the study groups were repeated to check the challenge. RESULTS: TAC was similar between both groups (1.55 +/- 0.26 in control group 1.53 +/- 0.19 mmol Trolox Eq./l). Additionally, TOS was significantly higher in iron-deficiency anemia group before treatment with iron (24.3 +/- 18.5, in controls groups 14.4 +/- 7.1 mmol Trolox Eq./l). We have shown that TAC did not change (before treatment 1.55 +/- 0.26, after treatment 1.54 +/- 0.26 mmol Trolox Eq./l) although TOS decreased significantly after the treatment of iron-deficiency anemia (before treatment 24.3 +/- 18.5, after treatment 12.4 +/- 6.9 mmol Trolox Eq./l). We did not find any correlation between hemoglobin, serum iron, iron-binding capacity, ferritin levels, and TOS or TAC among iron-deficiency anemia patients. CONCLUSION: As a result of this study, oxidative stress increases in children with iron-deficiency anemia and this increase can be returned to normal levels by treatment. PMID- 23440752 TI - Dilatation of the ascending aorta in patients with congenitally bicuspid aortic valves. AB - INTRODUCTION: The cause of ascending aortic dilatation occurring in patients with congenitally bicuspid aortic valves was investigated. METHODS: Flow patterns through human aortic roots with congenitally bicuspid aortic valves as well as through porcine constricted aortas were studied in a left heart simulator. Vibration was recorded as a measure of turbulence in the post-stenotic segment. Histological changes in fetal aortas with isolated congenitally bicuspid aortic valves were compared to fetal aortas with congenitally bicuspid aortic valves and hypoplastic left hearts, as well as to normal fetal aortas with tricuspid aortic valves. RESULTS: Congenitally bicuspid aortic valves were anatomically stenotic even in the absence of pressure gradients and without history of relevant symptoms. Histology of the aortic wall in isolated fetal congenitally bicuspid aortic valves was similar to that of fetal aortas with normal tri-leaflet aortic valves, but was abnormal if congenitally bicuspid aortic valves was associated with other cardiovascular anomalies. Flow studies revealed that turbulence and vibration in the post-stenotic aortic segments generated by the stenosis were proportional to the degree of the narrowing. CONCLUSIONS: Congenitally bicuspid aortic valves are inherently stenotic, asymmetrical, generate turbulence and vibration. This not only leads to early failure but also to injury of the ascending aortic wall and ascending aortic dilatation. The more progressive form of ascending aortic dilatation occurs in patients where congenitally bicuspid aortic valves is combined with other inborn anomalies and may require a radical procedure (replacement). PMID- 23440751 TI - Ex vivo MR volumetry of human brain hemispheres. AB - PURPOSE: The aims of this work were to (a) develop an approach for ex vivo MR volumetry of human brain hemispheres that does not contaminate the results of histopathological examination, (b) longitudinally assess regional brain volumes postmortem, and (c) investigate the relationship between MR volumetric measurements performed in vivo and ex vivo. METHODS: An approach for ex vivo MR volumetry of human brain hemispheres was developed. Five hemispheres from elderly subjects were imaged ex vivo longitudinally. All datasets were segmented. The longitudinal behavior of volumes measured ex vivo was assessed. The relationship between in vivo and ex vivo volumetric measurements was investigated in seven elderly subjects imaged both antemortem and postmortem. RESULTS: This approach for ex vivo MR volumetry did not contaminate the results of histopathological examination. For a period of 6 months postmortem, within-subject volume variation across time points was substantially smaller than intersubject volume variation. A close linear correspondence was detected between in vivo and ex vivo volumetric measurements. CONCLUSION: Regional brain volumes measured with this approach for ex vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem. Furthermore, the linear relationship between in vivo and ex vivo MR volumetric measurements suggests that this approach captures information linked to antemortem macrostructural brain characteristics. PMID- 23440753 TI - [Nocturnal frontal lobe epilepsy is often misdiagnosed as sleep disorders in children: a case series]. AB - INTRODUCTION. We present a series of children who underwent a video polysomnographic recording at our Sleep and Epilepsy Unit, who received a diagnosis of nocturnal frontal lobe epilepsy (NFLE). AIMS. To describe electroclinical and video polygraphic features of paediatric NFLE that differentiate this condition from other sleep disorders that overlap and mimic the sleep motor and autonomic events of NFLE. PATIENTS AND METHODS. The inclusion criterion was that the patients have their first video-EEG-PSG recording in our laboratory. RESULTS. Twenty-four out of 190 children were diagnosed with NFLE (group 1); while 166 had other sleep disorders (group 2). Among children diagnosed with NFLE, seven were referred for sleep-disordered breathing, seven for parasomnias, two for insomnia, two for hypersomnia, and one for periodic limb movements, while five were referred for epilepsy. In group 1, perinatal history was normal in most cases (21 out of 24) and a familiar history of epilepsy was found in four cases. Sleep-disordered breathing was diagnosed as a comorbid condition in four children. Standard EEG was normal in 21 cases. Interictal EEG showed epileptic discharges in four cases, while ictal EEG was expressed by a rhythmic theta activity preceded by an arousal and/or a short background desynchronization, movement artifacts, and autonomic changes. All seizures, repeated highly stereotyped motor events, were followed by stage shifts and/or a postural change and, by short awakenings. CONCLUSIONS. We found a high percentage of children with NFLE, often misdiagnosed or associated with other sleep disorders, which may be a trigger for nocturnal seizures. PMID- 23440754 TI - [Evaluation of the substantia nigra by means of transcranial ultrasound imaging]. AB - AIM. To describe the prevalence of hyperechogenicity of the substantia nigra in two samples of patients: one group who had been diagnosed with Parkinson's disease (PD) in accordance with United Kingdom Parkinson's Disease Society criteria and a control population, so as to be able to establish the reference values for our neurosonology laboratory. SUBJECTS AND METHODS. Two samples of patients consisting of healthy controls with no neurodegenerative disease and patients with PD were selected. Planimetric measurements of the area of echogenicity in the substantia nigra were performed in both groups. The greatest area of echogenicity measured on each side of each patient was considered. Descriptive statistics of the sample were carried out. The ROC curve was constructed in order to show the overall precision, sensitivity and specificity of transcranial Doppler ultrasonography in comparison to the clinical diagnosis of PD. RESULTS. Altogether 45 patients with PD and 91 controls were analysed. Using our own cut-off point (percentile 90 of the controls = 0.22 cm2), hyperechogenicity of the substantia nigra was observed in 73.33% of patients with PD and 8.79% of the controls (p = 0). An area below the curve of 93% was seen, which represents good overall precision for transcranial Doppler ultrasonography in the diagnosis of PD. CONCLUSIONS. The evaluation of the substantia nigra conducted in our laboratory using ultrasound imaging reveals significant differences between subjects with PD and normal subjects. The values obtained in our laboratory are slightly below those established as an international reference and offer excellent values for specificity and an acceptable level of sensitivity in our locale. PMID- 23440755 TI - [Electrodiagnostic criteria for childhood Guillain-Barre syndrome. Eight years' experience]. AB - INTRODUCTION. The Guillan-Barre syndrome is the most frequent case of acute flacid paralysis in children. The diagnostic criteria differ according to the demyelinating or axonal variant and the prevalence by geographical area. The electro-myographic study permits identifying variants, evaluating the prognosis and predicting the evolution, is in addition an objective tool for the monitoring. AIM. To describe the electromyographic characteristics of the Guillain-Barre syndrome evaluated in hospital and its classification by physiopathological pattern. PATIENTS AND METHODS. All the cases diagnosed between 2005 and 2012 are included. Studies of motor and sensitive nervous conduction and F waves in 14 girls and 11 boys between 1 and 13 years of age. RESULTS. 19 cases of acute inflammatory demyelinating polyneuropathy (AIDP) and five of acute motor axonal neuropathy (AMAN) were diagnosed. The electromyogram was performed between 1 and 30 days after the beginning of symptoms. In AIDP cases, multifocal demyelination, four of them with the preserved sural and 13 with alteration and absence of F wave were objectified. In the cases of AMAN, four had low amplitude potential and in one of them they were not evoked. CONCLUSIONS. The demyelinating form of the illness is the most frequent although the high number of AMAN cases stands out, probably related to the population object of study. The evolution was favorable in three cases of motor axonal neuropathy and in 15 accute demyelinating polyneuropathy. In four cases the symptoms became chronic; three of them with persistent demyelination a similar occurrence in other studies with children. PMID- 23440756 TI - [Spontaneous intracranial hypotension syndrome: two case reports]. AB - INTRODUCTION. Spontaneous intracranial hypotension is caused by spontaneous spinal cerebrospinal fluid leaks and is known for causing orthostatic headaches, and a wide variety of associated symptoms have been reported. CASE REPORTS. We described two cases with spontaneous intracranial hypotension, treated in a short period of time, who presented with orthostatic headache and the neuroimaging studies showed subdural collections. Both patients were diagnosed of spinal cerebrospinal fluid leaks and treated with blood patches. CONCLUSIONS. Although intracranial hypotension is not an uncommon pathology, it usually presents diagnostic problems due to the diversity of symptoms that can occur. MRI is essential for the diagnosis by showing enhancement of the pachymeninges following administration of gadolinium and to prove the cerebrospinal fluid leak are useful spinal MRI, the computerized tomography myelography and the radionuclide cisternography. If conservative treatment falls, the epidural blood patch is the initial treatment of choice, reserving surgery for patients with persistent symptoms. PMID- 23440757 TI - [Neuroarchitecture of musical emotions]. AB - The emotional response to music, or musical emotion, is a universal response that draws on diverse psychological processes implemented in a large array of neural structures and mechanisms. Studies using electroencephalography, functional magnetic resonance, lesions and individuals with extent musical training have begun to elucidate some of these mechanisms. The objective of this article is reviewing the most relevant studies that have tried to identify the neural correlates of musical emotion from the more automatic to the more complex processes, and to understand how these correlates interact in the brain. The article describes how the presentation of music perceived as emotional is associated with a rapid autonomic response in thalamic and subthalamic structures, accompanied by changes in the electrodermal and endocrine responses. It also explains how musical emotion processing activates auditory cortex, as well as a series of limbic and paralimbic structures, such as the amygdala, the anterior cingulate cortex or the hippocampus, demonstrating the relevant contribution of the limbic system to musical emotion. Further, it is detailed how musical emotion depends to a great extent on semantic and syntactic process carried out in temporal and parietofrontal areas, respectively. Some of the recent works demonstrating that musical emotion highly relies on emotional simulation are also mentioned. Finally, a summary of these studies, their limitations, and suggestions for further research on the neuroarchitecture of musical emotion are given. PMID- 23440759 TI - [Rupture of a temporal arachnoid cyst with the formation of a subdural hygroma and brain herniation]. PMID- 23440760 TI - [A new case of oculopharyngeal dystrophy caused by pathological expansion in the PABNP1 gene]. PMID- 23440761 TI - [New proposals for the diagnosis and classification of language disorders: have we incorporated the most suitable criteria?]. PMID- 23440762 TI - Synthesis of highly substituted tetrahydrofurans by catalytic polar-radical crossover cycloadditions of alkenes and alkenols. PMID- 23440763 TI - Viral infection transiently reverses activation receptor-mediated NK cell hyporesponsiveness in an MHC class I-independent mechanism. AB - Continuous engagement of the Ly49H activating receptor with its ligand (m157) in a transgenic mouse expressing m157 (m157-Tg) results in hyporesponsiveness of Ly49H(+) NK cells. The same interaction, during murine cytomegalovirus (MCMV) infection, leads to activation of Ly49H(+) NK cells. MCMV infection results in decreased MHC class I (MHC-I) expression on the infected cell as well as inflammatory responses, both of which do not take place in the uninfected m157-Tg mouse, potentially allowing for activation of NK cells in the context of MCMV infection. In this study, we demonstrated that viral infection transiently reverses activation receptor-mediated NK cell hyporesponsiveness in an MHC-I independent mechanism. Furthermore, Ly49H(+) NK cells in an MHC-I-deficient environment remained hyporesponsive in the context of m157 expression, even when mature WT splenocytes were transferred into m157-Tg mice in an MHC-I-deficient environment. However, the administration of cytokines TNF-alpha, IL-12, and IFN beta resulted in a partial recovery from activation receptor-induced hyporesponsiveness. Thus, the release of the aforementioned cytokines during MCMV infection and not the downregulation of MHC-I expression appears to be responsible for partial resolution of Ly49H receptor-induced NK cell hyporesponsiveness. PMID- 23440765 TI - Diagnostic issues of binge eating in eating disorders. AB - BACKGROUND: Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for eating disorders (EDs) are problematic and due to be revised. One area of debate concerns binge eating. AIMS: We investigated the impact of four aspects of binge eating (binge size, loss of control, frequency of objective and subjective binge eating) assessed by questionnaire and interview in adult ED patients on concurrent and follow-up symptoms. METHOD: Data came from two independent naturalistic Swedish ED databases (N = 2354, with 12-month follow-up; and N = 597, with 36-month follow-up). RESULTS: We found fair concurrent validity of criteria assessed using questionnaire, but poor concurrent validity for interview assessment, and no prognostic validity regardless of assessment method. CONCLUSIONS: The findings give support to some planned DSM-5 revisions, but challenge the assumption of binge eating as a useful diagnostic criterion, as well as having implications for measurement. PMID- 23440764 TI - Stimulated echo diffusion tensor imaging and SPAIR T2 -weighted imaging in chronic exertional compartment syndrome of the lower leg muscles. AB - PURPOSE: To evaluate the performance of diffusion tensor imaging (DTI) in the evaluation of chronic exertional compartment syndrome (CECS) as compared to T2 weighted (T2w) imaging. MATERIALS AND METHODS: Using an Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA) compliant protocol, spectral adiabatic inversion recovery (SPAIR) T2w imaging and stimulated echo DTI were applied to eight healthy volunteers and 14 suspected CECS patients before and after exertion. Longitudinal and transverse diffusion eigenvalues, mean diffusivity (MD), and fractional anisotropy (FA) were measured in seven calf muscle compartments, which in patients were classified by their response on T2w: normal (<20% change), and CECS (>20% change). Mixed model analysis of variance compared subject groups and compartments in terms of response factors (post/pre-exercise ratios) of DTI parameters. RESULTS: All diffusivities significantly increased (P < 0.0001) and FA decreased (P = 0.0014) with exercise. Longitudinal diffusion responses were significantly smaller than transversal diffusion responses (P < 0.0001). Nineteen of 98 patient compartments were classified as CECS on T2w. MD increased by 3.8 +/- 3.4% (volunteer), 7.4 +/- 4.2% (normal), and 9.1 +/- 7.0% (CECS) with exercise. CONCLUSION: DTI shows promise as an ancillary imaging method in the diagnosis and understanding of the pathophysiology in CECS. Future studies may explore its utility in predicting response to treatment. PMID- 23440766 TI - Terminal repeat retrotransposons as DNA markers in fungi. AB - In this study, we demonstrate that ClIRAP primers designed using the transposable element RetroCl1 sequence from Colletotrichum lindemuthianum can be used to generate an efficient IRAP (inter-retrotransposon amplified polymorphism) molecular marker to study intra- and inter-species diversity in fungi. It has been previously demonstrated that primers generated from this TRIM-like element can be used in the Colletotrichum species. We now prove that the RetroCl1 sequence can also be used to analyze diversity in different fungi. IRAP profiles were successfully generated for 27 fungi species from 11 different orders, and intra-species genetic variability was detected in six species. The ClIRAP primers facilitate the use of the IRAP technique for a variety of fungi without prior knowledge of the genome. PMID- 23440767 TI - [Mechanical restraint: the clinical practice in a psychiatric university hospital]. AB - BACKGROUND: Public opinion on psychiatric medicine is still dominated by images of repression; in particular, the aspects of involuntary admissions, restraint, isolation, or involuntary administration of medication contribute significantly to public prejudice. Furthermore, violations of individual privacy rights and the use of coercion in psychiatry is an ethical challenge. The aim of this study was to describe the "practice of mechanical restraint" at a university hospital in Austria. METHODS: In this study, all admissions to the closed ward at the Department of Psychiatry of the University Clinic of Innsbruck between July and December 2009 were assessed through retrospective data analysis. RESULTS: 529 admissions were identified during the study period. In 148 admitted patients mechanical restraint was arranged at least once. Mechanical restraint was used most frequently and over the longest period of time in patients of the ICD diagnosis group F0. In most cases, "self- harm" had been the reason for restraint. Fourteen percent of the restraints were due to a "danger to others". In patients with "danger to others", a 5 point fixation was used significantly more often than in patients without danger to others, where a restriction by bedrail and/or abdominal belt was most common. CONCLUSIONS: A comparison of these data with those of other centers is limited due to diverse documentation systems. A unified approach in terms of an effective quality management would be desirable in this regard. PMID- 23440768 TI - Thermoresponsive diblock copolymer with tunable soluble-insoluble and soluble insoluble-soluble transitions. AB - The thermoresponsive transition behavior of a diblock copolymer consisting of poly(ethylene glycol) methyl ether (mPEG) and poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) in aqueous solutions has been investigated. With a specific composition, the copolymer showed a unique tunable phase transition from no response in acidic media to a soluble-insoluble (S-I) transition in neutral media and an S-I-S transition in basic media either in the presence of salt or for salt-free solutions. The S-I-S transition can be tuned over a wide temperature range even to an S-I type transition just by adding salts. In addition, phase transitions can occur in both pure water and saline solution under practical conditions (30-80 degrees C), which makes them suitable for a broad range of applications. PMID- 23440770 TI - Spiral trajectory design: a flexible numerical algorithm and base analytical equations. AB - PURPOSE: Spiral-based trajectories for magnetic resonance imaging can be advantageous, but are often cumbersome to design or create. This work presents a flexible numerical algorithm for designing trajectories based on explicit definition of radial undersampling, and also gives several analytical expressions for charactering the base (critically sampled) class of these trajectories. THEORY AND METHODS: Expressions for the gradient waveform, based on slew and amplitude limits, are developed such that a desired pitch in the spiral k-space trajectory is followed. The source code for this algorithm, written in C, is publicly available. Analytical expressions approximating the spiral trajectory (ignoring the radial component) are given to characterize measurement time, gradient heating, maximum gradient amplitude, and off-resonance phase for slew limited and gradient amplitude-limited cases. Several numerically calculated trajectories are illustrated, and base Archimedean spirals are compared with analytically obtained results. RESULTS: Several different waveforms illustrate that the desired slew and amplitude limits are reached, as are the desired undersampling patterns, using the numerical method. For base Archimedean spirals, the results of the numerical and analytical approaches are in good agreement. CONCLUSION: A versatile numerical algorithm was developed, and was written in publicly available code. Approximate analytical formulas are given that help characterize spiral trajectories. PMID- 23440769 TI - Semiquantitative analysis of apolipoprotein A-I modified by advanced glycation end products in diabetes mellitus. AB - BACKGROUND: Apolipoprotein A-I (Apo A-I), the major component of high-density lipoprotein (HDL), is modified by reactive alpha-oxoaldehydes, such as methylglyoxal (MG) and glycolaldehyde (GA), and these modifications affect the function of Apo A-I. GA- and MG-modified Apo A-I serum levels were semiquantitatively evaluated in diabetic patients to elucidate the association of each protein with diabetes and to determine its appropriateness as a serum marker of diabetes. METHODS: We enrolled 44 subjects in this study (diabetic subjects, n = 24; nondiabetic subjects, n = 20). GA- and MG-modified Apo A-I levels in serum were determined by sandwich enzyme-linked immunosorbent assay (ELISA) by using anti-GA or anti-MG antibody and anti-Apo A-I antibody. RESULTS: The GA-modified Apo A-I levels did not significantly differ between the diabetic and nondiabetic subjects (1.00 +/- 0.38 vs. 0.96 +/- 0.22). However, the MG-modified Apo A-I levels in the diabetic subjects were significantly higher than those in the nondiabetic subjects (1.33 +/- 0.52 vs. 0.90 +/- 0.20). In addition, MG-modified Apo A-I levels correlated with the glycated hemoglobin (HbA1c) levels, HDL cholesterol levels, and the homeostasis model assessments of insulin resistance, which are indicators of insulin resistance. CONCLUSION: The MG-modified Apo A-I level may be an indicator of diabetic dyslipidemia and insulin resistance. PMID- 23440771 TI - Risk assessment using the species sensitivity distribution method: data quality versus data quantity. AB - Species sensitivity distributions (SSDs) are cumulative distributions of measures of species sensitivity to a stressor or toxicant, and are used to estimate concentrations that will protect p% of a community (PCp ). There is conflict between the desire to use high-quality sensitivity data in SSDs, and to construct them with a large number of species forming a representative sample. Trade-offs between data quality and quantity were investigated using the effects of increasing salinity on the macroinvertebrate community from the Hunter River catchment, in eastern Australia. Five SSDs were constructed, representing five points along a continuum of data quality versus data quantity and representativeness. This continuum was achieved by the various inclusion/exclusion of censored data, nonmodeled data, and extrapolation from related species. Protective concentrations were estimated using the Burr type III distribution, Kaplan-Meier survival function, and two Bayesian statistical models. The dominant taxonomic group was the prime determinant of protective concentrations, with an increase in PC95 values resulting from a decrease in the proportion of Ephemeropteran species included in the SSD. In addition, decreases in data quantity in a SSD decreased community representativeness. The authors suggest, at least for salinity, that the inclusion of right censored data provides a more representative sample of species that reflects the natural biotic assemblage of an area to be protected, and will therefore improve risk assessment. PMID- 23440772 TI - Alkene trifluoromethylation coupled with C-C bond formation: construction of trifluoromethylated carbocycles and heterocycles. PMID- 23440773 TI - The evolutionary arms race between NK cells and viruses: who gets the short end of the stick? AB - NK cells are innate lymphocytes that play a key role in the control of various viral infections. Recent studies indicate that NK cells may acquire some features of adaptive immune cells, including the formation of long-lived memory cells. A large and growing body of data indicates that NK cells regulate the adaptive immune response as well. The function and the activation status of NK cells are tightly regulated by signals induced by a broad range of inhibitory and activating cell surface receptors and cytokines released by other immune cells. Here, we review the function of mouse NK-cell receptors involved in virus control and in the regulation of the adaptive immune response. In addition, we discuss viral strategies used to evade NK-cell-mediated control during infection. Finally, the role of several activating Ly49 receptors specific for mouse cytomegalovirus (MCMV), as well as some controversial issues in the field, will be discussed. PMID- 23440775 TI - Instruments for chorionic villus sampling for prenatal diagnosis. AB - BACKGROUND: Chorionic villus sampling (CVS) is the method of choice for obtaining fetal tissue for prenatal diagnosis before 15 weeks of pregnancy. CVS can be performed using either a transabdominal or transcervical approach. The type of instrument and technique used could have a significant impact on the outcome of the procedure. An ability to manoeuvre the instrument within the uterine cavity without puncturing the gestational sac, to see the tip of the instrument on ultrasound scanning and to minimise the number of instrument passes into the uterus are particularly important. OBJECTIVES: To compare the efficacy and safety of different instruments and techniques used to obtain chorionic tissue in early pregnancy by the transabdominal or transcervical route. Primary outcomes included failure to obtain an adequate sample (greater than 5 mg of chorionic villi), need for reinsertion of the instrument, pain, and miscarriage following the procedure. Secondary outcomes included mean weight of tissue obtained, successful culture, difficult instrument insertion, poor visualisation of instrument, vaginal bleeding following the procedure and cost per procedure. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2012). SELECTION CRITERIA: Randomised trials comparing different instruments (forceps, cannula, needle) or techniques for CVS using either transabdominal or transcervical approach. DATA COLLECTION AND ANALYSIS: Two review authors assessed eligibility and trial quality. MAIN RESULTS: For transcervical CVS, forceps and cannulae were evaluated in five trials involving 472 women. When a cannula was used, operators failed to obtain an adequate sample (greater than 5 mg of chorionic villi) more often (average risk ratio (RR) 3.81; 95% confidence interval (CI) 1.52 to 9.56). There was no difference in the need for reinsertion of instruments (average RR 2.44; 95% CI 0.83 to 7.20). However, inserting a cannula was more painful (RR 1.93; 95% CI 1.11 to 3.37). There was no difference in spontaneous miscarriage when the use of a cannula was compared with biopsy forceps (RR 1.00; 95% CI 0.14 to 6.96). One study reported the cost of the procedures and found CVS with a cannula to be more expensive (mean difference (MD) $183.7; 95% CI 152.62 to 214.78).When different types of cannulae for transcervical CVS were compared, a Portex cannula was more likely to result in an inadequate sample (RR 2.23; 95% CI 1.25 to 3.98) compared with the silver cannula and to result in a difficult (RR 3.26; 95% CI 1.38 to 7.67) or painful (RR 5.81; 95% CI 1.41 to 23.88) procedure when compared with the aluminium cannula.For transabdominal CVS, two trials comparing different needle techniques were included involving 285 women. One study using an ex vivo system of term placentae was excluded. The included trials compared different continuous negative pressure aspiration techniques with a discontinuous negative pressure system created by a syringe attached to a 20 gauge needle. The studies produced discrepant results. One study found there was no significant difference between groups in the mean weight of chorionic villi obtained (MD 0.40; 95% CI -2.25 to 3.05) or in failure to obtain an adequate sample (more than 5 mg of chorionic villi) on the first attempt (RR 1.02; 95% CI 0.54 to 1.93), whereas the other study found both of these outcomes to be significantly less favourable with the standard discontinuous technique using a syringe (mean weight of chorionic villi obtained: MD -14.80; 95% CI -21.71 to -7.89; failure to obtain an adequate sample on the first attempt: RR 2.73; 95% CI 1.08 to 6.92). There was no difference in rate of miscarriage following the procedure in either study (RR 7.15; 95% CI 0.37 to 136.50; RR 2.93; 95% CI 0.12 to 70.00). Perceived pain by the patient was similar between groups (MD 0.00; 95% CI -0.04 to 0.04) as was success of culture (no failed cases). AUTHORS' CONCLUSIONS: For transcervical CVS, although there is some evidence to support the use of small forceps instead of cannulae, the evidence is not strong enough to support change in practice for clinicians who have become familiar with a particular technique. For transabdominal CVS, based on current evidence, there is no difference in clinically important outcomes with the use of a continuous compared with a discontinuous negative pressure needle aspiration system. PMID- 23440776 TI - Antibiotics for acute otitis media in children. AB - BACKGROUND: Acute otitis media (AOM) is one of the most common diseases in early infancy and childhood. Antibiotic use for AOM varies from 56% in the Netherlands to 95% in the USA, Canada and Australia. OBJECTIVES: To assess the effects of antibiotics for children with AOM. SEARCH METHODS: We searched CENTRAL (2012, Issue 10), MEDLINE (1966 to October week 4, 2012), OLDMEDLINE (1958 to 1965), EMBASE (January 1990 to November 2012), Current Contents (1966 to November 2012), CINAHL (2008 to November 2012) and LILACS (2008 to November 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing 1) antimicrobial drugs with placebo and 2) immediate antibiotic treatment with expectant observation (including delayed antibiotic prescribing) in children with AOM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: For the review of antibiotics against placebo, 12 RCTs (3317 children and 3854 AOM episodes) from high-income countries were eligible. However, one trial did not report patient-relevant outcomes, leaving 11 trials with generally low risk of bias. Pain was not reduced by antibiotics at 24 hours (risk ratio (RR) 0.89; 95% confidence interval (CI) 0.78 to 1.01) but almost a third fewer had residual pain at two to three days (RR 0.70; 95% CI 0.57 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) 20) and fewer had pain at four to seven days (RR 0.79; 95% CI 0.66 to 0.95; NNTB 20). When compared with placebo, antibiotics did not alter the number of abnormal tympanometry findings at either four to six weeks (RR 0.92; 95% CI 0.83 to 1.01) or at three months (RR 0.97; 95% CI 0.76 to 1.24), or the number of AOM recurrences (RR 0.93; 95% CI 0.78 to 1.10). However, antibiotic treatment did lead to a statistically significant reduction of tympanic membrane perforations (RR 0.37; 95% CI 0.18 to 0.76; NNTB 33) and halved contralateral AOM episodes (RR 0.49; 95% CI 0.25 to 0.95; NNTB 11) as compared with placebo. Severe complications were rare and did not differ between children treated with antibiotics and those treated with placebo. Adverse events (such as vomiting, diarrhoea or rash) occurred more often in children taking antibiotics (RR 1.34; 95% CI 1.16 to 1.55; number needed to treat for an additional harmful outcome (NNTH) 14). Funnel plots do not suggest publication bias. Individual patient data meta-analysis of a subset of included trials found antibiotics to be most beneficial in children aged less than two with bilateral AOM, or with both AOM and otorrhoea.For the review of immediate antibiotics against expectant observation, five trials (1149 children) were eligible. Four trials (1007 children) reported outcome data that could be used for this review. From these trials, data from 959 children could be extracted for the meta-analysis on pain at days three to seven. No difference in pain was detectable at three to seven days (RR 0.75; 95% CI 0.50 to 1.12). No serious complications occurred in either the antibiotic group or the expectant observation group. Additionally, no difference in tympanic membrane perforations and AOM recurrence was observed. Immediate antibiotic prescribing was associated with a substantial increased risk of vomiting, diarrhoea or rash as compared with expectant observation (RR 1.71; 95% CI 1.24 to 2.36). AUTHORS' CONCLUSIONS: Antibiotic treatment led to a statistically significant reduction of children with AOM experiencing pain at two to seven days compared with placebo but since most children (82%) settle spontaneously, about 20 children must be treated to prevent one suffering from ear pain at two to seven days. Additionally, antibiotic treatment led to a statistically significant reduction of tympanic membrane perforations (NNTB 33) and contralateral AOM episodes (NNTB 11). These benefits must be weighed against the possible harms: for every 14 children treated with antibiotics, one child experienced an adverse event (such as vomiting, diarrhoea or rash) that would not have occurred if antibiotics had been withheld. Antibiotics appear to be most useful in children under two years of age with bilateral AOM, or with both AOM and otorrhoea. For most other children with mild disease, an expectant observational approach seems justified. We have no trials in populations with higher risks of complications. PMID- 23440777 TI - Antibiotics for treating bacterial vaginosis in pregnancy. AB - BACKGROUND: Bacterial vaginosis is an imbalance of the normal vaginal flora with an overgrowth of anaerobic bacteria and a lack of the normal lactobacillary flora. Women may have symptoms of a characteristic vaginal discharge but are often asymptomatic. Bacterial vaginosis during pregnancy has been associated with poor perinatal outcomes and, in particular, preterm birth (PTB). Identification and treatment may reduce the risk of PTB and its consequences. OBJECTIVES: To assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2012), searched cited references from retrieved articles and reviewed abstracts, letters to the editor and editorials. SELECTION CRITERIA: Randomised trials comparing antibiotic treatment with placebo or no treatment, or comparing two or more antibiotic regimens in pregnant women with bacterial vaginosis or intermediate vaginal flora whether symptomatic or asymptomatic and detected through screening. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included 21 trials of good quality, involving 7847 women diagnosed with bacterial vaginosis or intermediate vaginal flora.Antibiotic therapy was shown to be effective at eradicating bacterial vaginosis during pregnancy (average risk ratio (RR) 0.42; 95% confidence interval (CI) 0.31 to 0.56; 10 trials, 4403 women; random-effects, T2 = 0.19, I2 = 91%). Antibiotic treatment also reduced the risk of late miscarriage (RR 0.20; 95% CI 0.05 to 0.76; two trials, 1270 women, fixed-effect, I2 = 0%).Treatment did not reduce the risk of PTB before 37 weeks (average RR 0.88; 95% CI 0.71 to 1.09; 13 trials, 6491 women; random-effects, T2 = 0.06, I2 = 48%), or the risk of preterm prelabour rupture of membranes (RR 0.74; 95% CI 0.30 to 1.84; two trials, 493 women). It did increase the risk of side-effects sufficient to stop or change treatment (RR 1.66; 95% CI 1.02 to 2.68; four trials, 2323 women, fixed-effect, I2 = 0%).In this updated review, treatment before 20 weeks' gestation did not reduce the risk of PTB less than 37 weeks (average RR 0.85; 95% CI 0.62 to 1.17; five trials, 4088 women; random-effects, T2 = 0.06, I2 = 49%).In women with a previous PTB, treatment did not affect the risk of subsequent PTB (average RR 0.78; 95% CI 0.42 to 1.48; three trials, 421 women; random-effects, T2 = 0.19, I2 = 72%).In women with abnormal vaginal flora (intermediate flora or bacterial vaginosis), treatment may reduce the risk of PTB before 37 weeks (RR 0.53; 95% CI 0.34 to 0.84; two trials, 894 women).One small trial of 156 women compared metronidazole and clindamycin, both oral and vaginal, with no significant differences seen for any of the pre-specified primary outcomes. Statistically significant differences were seen for the outcomes of prolongation of gestational age (days) (mean difference (MD) 1.00; 95% CI 0.26 to 1.74) and birthweight (grams) (MD 75.18; 95% CI 25.37 to 124.99) however these represent relatively small differences in the clinical setting.Oral antibiotics versus vaginal antibiotics did not reduce the risk of PTB (RR 1.09; 95% CI 0.78 to 1.52; two trials, 264 women). Oral antibiotics had some advantage over vaginal antibiotics (whether metronidazole or clindamycin) with respect to admission to neonatal unit (RR 0.63; 95% CI 0.42 to 0.92, one trial, 156 women), prolongation of gestational age (days) (MD 9.00; 95% CI 8.20 to 9.80; one trial, 156 women) and birthweight (grams) (MD 342.13; 95% CI 293.04 to 391.22; one trial, 156 women).Different frequency of dosing of antibiotics was assessed in one small trial and showed no significant difference for any outcome assessed. AUTHORS' CONCLUSIONS: Antibiotic treatment can eradicate bacterial vaginosis in pregnancy. The overall risk of PTB was not significantly reduced. This review provides little evidence that screening and treating all pregnant women with bacterial vaginosis will prevent PTB and its consequences. When screening criteria were broadened to include women with abnormal flora there was a 47% reduction in preterm birth, however this is limited to two included studies. PMID- 23440778 TI - Discharge planning from hospital to home. AB - BACKGROUND: Discharge planning is a routine feature of health systems in many countries. The aim of discharge planning is to reduce hospital length of stay and unplanned readmission to hospital, and improve the co-ordination of services following discharge from hospital. OBJECTIVES: To determine the effectiveness of planning the discharge of individual patients moving from hospital. SEARCH METHODS: We updated the review using the Cochrane EPOC Group Trials Register, MEDLINE, EMBASE and the Social Science Citation Index (last searched in March 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared an individualised discharge plan with routine discharge care that was not tailored to the individual patient. Participants were hospital inpatients. DATA COLLECTION AND ANALYSIS: Two authors independently undertook data analysis and quality assessment using a pre designed data extraction sheet. Studies are grouped according to patient group (elderly medical patients, patients recovering from surgery and those with a mix of conditions) and by outcome. Our statistical analysis was done on an intention to treat basis, we calculated risk ratios for dichotomous outcomes and mean differences for continuous data using fixed-effect meta-analysis. When combining outcome data was not possible, because of differences in the reporting of outcomes, we have presented the data in narrative summary tables. MAIN RESULTS: We included twenty-four RCTs (8098 patients); three RCTS were identified in this update. Sixteen studies recruited older patients with a medical condition, four recruited patients with a mix of medical and surgical conditions, one recruited patients from a psychiatric hospital, one from both a psychiatric hospital and from a general hospital, and two trials patients admitted to hospital following a fall (110 patients). Hospital length of stay and readmissions to hospital were statistically significantly reduced for patients admitted to hospital with a medical diagnosis and who were allocated to discharge planning (mean difference length of stay -0.91, 95% CI -1.55 to -0.27, 10 trials; readmission rates RR 0.82, 95% CI 0.73 to 0.92, 12 trials). For elderly patients with a medical condition there was no statistically significant difference between groups for mortality (RR 0.99, 95% CI 0.78 to 1.25, five trials) or being discharged from hospital to home (RR 1.03, 95% CI 0.93 to 1.14, two trials). This was also the case for trials recruiting patients recovering from surgery and a mix of medical and surgical conditions. In three trials, patients allocated to discharge planning reported increased satisfaction. There was little evidence on overall healthcare costs. AUTHORS' CONCLUSIONS: The evidence suggests that a discharge plan tailored to the individual patient probably brings about reductions in hospital length of stay and readmission rates for older people admitted to hospital with a medical condition. The impact of discharge planning on mortality, health outcomes and cost remains uncertain. PMID- 23440779 TI - Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. OBJECTIVES: The primary objective of this review was to investigate the effectiveness of NSAIDs in achieving a reduction in menstrual blood loss in women of reproductive years with HMB. SEARCH METHODS: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2012 and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with either each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their heavy menstrual blood loss. DATA COLLECTION AND ANALYSIS: Eighteen RCTs were identified that fulfilled the inclusion criteria for this review and data were extracted independently. Odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes were estimated from the data of nine trials. The results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data and one trial with missing variances were described in data tables. MAIN RESULTS: As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than either tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs but this did not appear to affect the acceptability of treatment. There were no statistically significant differences between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system (Progestasert), oral contraceptive pill (OCC)) but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. AUTHORS' CONCLUSIONS: NSAIDs reduce HMB when compared with placebo but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCC or another type of intrauterine system, Progestasert. PMID- 23440780 TI - Vaccines for preventing pneumococcal infection in adults. AB - BACKGROUND: Diseases caused by Streptococcus pneumoniae (S. pneumoniae) continue to cause substantial morbidity and mortality globally. Whilst pneumococcal polysaccharide vaccines (PPVs) have the potential to prevent disease and death, the degree of protection afforded against various clinical endpoints and within different populations is uncertain. OBJECTIVES: To assess the efficacy and effectiveness of PPVs in preventing pneumococcal disease or death in adults. We did not assess adverse events. SEARCH METHODS: We searched CENTRAL 2012, Issue 6, MEDLINE (January 1966 to June Week 2, 2012) and EMBASE (1974 to June 2012). SELECTION CRITERIA: We considered randomised controlled trials (RCTs) in adults, provided the study outcome met the definition of the outcome considered in the review. We also considered non-RCTs in adults, where the study assessed PPV effectiveness against culture-confirmed invasive pneumococcal disease (IPD), provided the study controlled for important confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality of RCTs and three review authors extracted the data. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. Two review authors assessed study quality and extracted data for non-RCTs. We calculated ORs and 95% CIs using a random-effects model following the conversion of each study outcome to a log OR and standard error (SE). MAIN RESULTS: Twenty-five studies met our inclusion criteria (18 RCTs involving 64,852 participants and seven non-RCTs involving 62,294 participants). Meta-analysis of the RCTs found strong evidence of PPV efficacy against IPD with no statistical heterogeneity (OR 0.26, 95% CI 0.14 to 0.45; random-effects model, I(2) statistic = 0%). There was efficacy against all cause pneumonia in low-income (OR 0.54, 95% CI 0.43 to 0.67, I(2) statistic = 19%) but not high-income countries in either the general population (OR 0.71, 95% CI 0.45 to 1.12, I(2) statistic = 93%) or in adults with chronic illness (OR 0.93, 95% CI 0.73 to 1.19, I(2) statistic = 10%). PPV was not associated with substantial reductions in all-cause mortality (OR 0.90, 95% CI 0.74 to 1.09; random-effects model, I(2) statistic = 69%). Vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness. Non-RCTs provided evidence for protection against IPD in populations for whom the vaccine is currently utilised (OR 0.48, 95% CI 0.37 to 0.61; random-effects model, I(2) statistic = 31%). This review did not consider adverse events as it was outside the scope of the review. AUTHORS' CONCLUSIONS: This meta-analysis provides evidence supporting the recommendation for PPV to prevent IPD in adults. The evidence from RCTs is less clear with respect to adults with chronic illness. This might be because of lack of effect or lack of power in the studies. The meta analysis does not provide evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality. PMID- 23440781 TI - WITHDRAWN: Spinal manipulative therapy for low-back pain. AB - BACKGROUND: Low-back pain is a costly illness for which spinal manipulative therapy is commonly recommended. Previous systematic reviews and practice guidelines have reached discordant results on the effectiveness of this therapy for low-back pain. OBJECTIVES: To resolve the discrepancies related to the use of spinal manipulative therapy and to update previous estimates of effectiveness, by comparing spinal manipulative therapy with other therapies and then incorporating data from recent high-quality randomized, controlled trials (RCTs) into the analysis. SEARCH METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and CINAHL were electronically searched from their respective beginning to January 2000, using the Back Group search strategy; references from previous systematic reviews were also screened. SELECTION CRITERIA: Randomized, controlled trials (RCT) that evaluated spinal manipulative therapy for patients with low-back pain, with at least one day of follow-up, and at least one clinically-relevant outcome measure. DATA COLLECTION AND ANALYSIS: Two authors, who served as the authors for all stages of the meta-analysis, independently extracted data from unmasked articles. Comparison treatments were classified into the following seven categories: sham, conventional general practitioner care, analgesics, physical therapy, exercises, back school, or a collection of therapies judged to be ineffective or even harmful (traction, corset, bed rest, home care, topical gel, no treatment, diathermy, and minimal massage). MAIN RESULTS: Thirty-nine RCTs were identified. Meta-regression models were developed for acute or chronic pain and short-term and long-term pain and function. For patients with acute low-back pain, spinal manipulative therapy was superior only to sham therapy (10-mm difference [95% CI, 2 to 17 mm] on a 100-mm visual analogue scale) or therapies judged to be ineffective or even harmful. Spinal manipulative therapy had no statistically or clinically significant advantage over general practitioner care, analgesics, physical therapy, exercises, or back school. Results for patients with chronic low-back pain were similar. Radiation of pain, study quality, profession of manipulator, and use of manipulation alone or in combination with other therapies did not affect these results. AUTHORS' CONCLUSIONS: There is no evidence that spinal manipulative therapy is superior to other standard treatments for patients with acute or chronic low-back pain. PMID- 23440782 TI - Vitamin C for preventing and treating the common cold. AB - BACKGROUND: Vitamin C (ascorbic acid) for preventing and treating the common cold has been a subject of controversy for 70 years. OBJECTIVES: To find out whether vitamin C reduces the incidence, the duration or severity of the common cold when used either as a continuous regular supplementation every day or as a therapy at the onset of cold symptoms. SEARCH METHODS: We searched CENTRAL 2012, Issue 11, MEDLINE (1966 to November week 3, 2012), EMBASE (1990 to November 2012), CINAHL (January 2010 to November 2012), LILACS (January 2010 to November 2012) and Web of Science (January 2010 to November 2012). We also searched the U.S. National Institutes of Health trials register and WHO ICTRP on 29 November 2012. SELECTION CRITERIA: We excluded trials which used less than 0.2 g per day of vitamin C and trials without a placebo comparison. We restricted our review to placebo controlled trials. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We assessed 'incidence' of colds during regular supplementation as the proportion of participants experiencing one or more colds during the study period. 'Duration' was the mean number of days of illness of cold episodes. MAIN RESULTS: Twenty-nine trial comparisons involving 11,306 participants contributed to the meta-analysis on the risk ratio (RR) of developing a cold whilst taking vitamin C regularly over the study period. In the general community trials involving 10,708 participants, the pooled RR was 0.97 (95% confidence interval (CI) 0.94 to 1.00). Five trials involving a total of 598 marathon runners, skiers and soldiers on subarctic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64).Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9745 episodes). In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration.Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the duration or severity of colds in the therapeutic trials.The majority of included trials were randomised, double-blind trials. The exclusion of trials that were either not randomised or not double-blind had no effect on the conclusions. AUTHORS' CONCLUSIONS: The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted. PMID- 23440783 TI - Sucrose for analgesia in newborn infants undergoing painful procedures. AB - BACKGROUND: Administration of oral sucrose with and without non-nutritive sucking is the most frequently studied non-pharmacological intervention for procedural pain relief in neonates. OBJECTIVES: To determine the efficacy, effect of dose and safety of oral sucrose for relieving procedural pain in neonates. SEARCH METHODS: We used the standard methods of the Cochrane Neonatal Review Group. Electronic and manual searches were performed in November 2011 for published randomised controlled trials (RCTs) in MEDLINE (1950 to November 2011), EMBASE (1980 to 2011), CINAHL (1982 to November 2011) and the Cochrane Central Register of Controlled Trials (The Cochrane Library). We did not impose language restrictions. SELECTION CRITERIA: RCTs in which term, preterm, or both term and preterm neonates (postnatal age maximum of 28 days after reaching 40 weeks' postmenstrual age) received sucrose for procedural pain. Control conditions included no treatment, water, pacifier, positioning/containing or breastfeeding. DATA COLLECTION AND ANALYSIS: Main outcome measures were physiological, behavioural, or both pain indicators with or without composite pain scores. A mean difference (MD) with 95% confidence intervals (CI) using the fixed-effect model was reported for continuous outcome measures. Trial quality was assessed as per The Cochrane Collaboration MAIN RESULTS: Fifty-seven studies enrolling 4730 infants were included. Results from only a few studies could be combined in meta analyses. When Premature Infant Pain Profile (PIPP) scores were pooled, sucrose groups had significantly lower scores at 30 seconds (weighted mean difference (WMD) -1.76; 95% CI -2.54 to - 0.97; 4 trials; 264 neonates] and 60 seconds (WMD 2.05; 95% CI -3.08 to -1.02; 3 trials' 195 neonates) post-heel lance. For retinopathy of prematurity (ROP) examinations, sucrose did not significantly reduce PIPP scores (WMD -0.65; 95% CI -1.88 to 0.59; 3 trials; 82 neonates). There were no differences in adverse effects between sucrose and control groups. Sucrose significantly reduced duration of total crying time (WMD -39 seconds; 95% CI -44 to -34; 2 trials; 88 neonates), but did not reduce duration of first cry during heel lance (WMD -9 seconds; 95% CI -20 to 2; 3 trials; 192 neonates). Oxygen saturation (%) was significantly lower in infants given sucrose during ROP examination compared to controls (WMD -2.6; 95% CI -4.9 to - 0.2; 2 trials; 62 neonates). Results of individual trials that could not be incorporated in meta analyses supported these findings. The effects of sucrose on long-term neurodevelopmental outcomes are unknown. AUTHORS' CONCLUSIONS: Sucrose is safe and effective for reducing procedural pain from single events. An optimal dose could not be identified due to inconsistency in effective sucrose dosage among studies. Further investigation on repeated administration of sucrose in neonates and the use of sucrose in combination with other non-pharmacological and pharmacological interventions is needed. Sucrose use in extremely preterm, unstable, ventilated (or a combination of these) neonates needs to be addressed. Additional research is needed to determine the minimally effective dose of sucrose during a single painful procedure and the effect of repeated sucrose administration on immediate (pain intensity) and long-term (neurodevelopmental) outcomes. PMID- 23440784 TI - Skin grafting for venous leg ulcers. AB - BACKGROUND: Venous leg ulceration is a recurrent, chronic, disabling condition. It affects up to one in 100 people at some time in their lives. Standard treatments are simple dressings and compression bandages or stockings. Sometimes, despite treatment, ulcers remain open for months or years. Sometimes skin grafts are used to stimulate healing. These may be taken, or grown into a dressing, from the patient's own uninjured skin (autografts), or applied as a sheet of bioengineered skin grown from donor cells (allograft). Preserved skin from other animals, such as pigs, has also been used (xenografts). OBJECTIVES: To assess the effect of skin grafts for treating venous leg ulcers. SEARCH METHODS: For this update we modified the search strategies and conducted searches of The Cochrane Wounds Group Specialised Register (searched 27 July 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7); Ovid MEDLINE (2008 to July Week 3 2012); Ovid MEDLINE (In-Process & Other Non Indexed Citations, July 26, 2012); Ovid EMBASE (2008 to 2012 Week 29); and EBSCO CINAHL (2008 to 26 July 2012). We did not apply date or language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) of skin grafts in the treatment of venous leg ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook data extraction and assessment of study quality. MAIN RESULTS: For this update of the review, we identified one new trial, bringing the total to 17 trials (1034 participants) - all of which were generally at moderate or high risk of bias. In 12 trials participants also received compression bandaging.Eleven trials compared a graft with standard care in which no graft was used. Two of these trials (102 participants) compared a dressing with an autograft; three trials (80 participants) compared frozen allografts with dressings, and two trials (45 participants) compared fresh allografts with dressings. Two trials (345 participants) compared tissue-engineered skin (bilayer artificial skin) with a dressing. In two trials (97 participants) a single-layer dermal replacement was compared with standard care.Six trials compared alternative skin grafting techniques. The first trial (92 participants) compared autografts with frozen allograft, a second (51 participants) compared a pinch graft (autograft) with porcine dermis (xenograft), the third (110 participants) compared growth-arrested human keratinocytes and fibroblasts with placebo, the fourth (10 participants) compared an autograft delivered on porcine pads with an autograft delivered on porcine gelatin microbeads, the fifth trial (92 participants) compared a meshed graft with a cultured keratinocyte autograft, and the sixth trial (50 participants) compared a frozen keratinocyte allograft with a lyophilised (freeze-dried) keratinocyte allografts.Significantly more ulcers healed when treated with bilayer artificial skin than with dressings. There was insufficient evidence from the other trials to determine whether other types of skin grafting increased the healing of venous ulcers. AUTHORS' CONCLUSIONS: Bilayer artificial skin, used in conjunction with compression bandaging, increases venous ulcer healing compared with a simple dressing plus compression. Further research is needed to assess whether other forms of skin grafts increase ulcer healing. PMID- 23440785 TI - Ginkgo biloba extract for age-related macular degeneration. AB - BACKGROUND: Ginkgo is used in the treatment of peripheral vascular disease and 'cerebral insufficiency'. It is thought to have several potential mechanisms of action including increased blood flow, platelet activating factor antagonism, and prevention of membrane damage caused by free radicals. Vascular factors and oxidative damage are thought to be two potential mechanisms in the pathology of age-related macular degeneration (AMD). OBJECTIVES: The objective of this review was to determine the effect of Ginkgo biloba extract on the progression of AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2012), EMBASE (January 1980 to October 2012), Allied and Complementary Medicine Database (AMED) (January 1985 to October 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 5 October 2012. We searched the reference lists of identified reports and the Science Citation Index. We also contacted investigators of included studies for additional information. SELECTION CRITERIA: All randomised trials in people with AMD where Ginkgo biloba extract had been compared to control were included. DATA COLLECTION AND ANALYSIS: The review author extracted data using a standardised form. The data were verified with the trial investigators. Trial quality was assessed. MAIN RESULTS: Two published trials were identified that randomised a total of 119 people. In one study conducted in France, 20 people were randomly allocated to Gingko biloba extract EGb 761 80 mg twice daily or placebo. In the other study conducted in Germany, 99 people were randomly allocated to two different doses of Ginkgo biloba extract EGb 761 (240 mg per day and 60 mg per day). Treatment duration in both studies was six months. Both trials reported some positive effects of Ginkgo biloba on vision however their results could not be pooled. Adverse effects and quality of life for people with AMD were not reported. AUTHORS' CONCLUSIONS: The question as to whether people with AMD should take Ginkgo biloba extract to prevent progression of the disease has not been answered by research to date. Two small trials have suggested possible benefit of Gingko biloba on vision and further trials are warranted. Ginkgo biloba is widely used in China, Germany, and France. Future trials should be larger, and last longer, in order to provide a more robust measure of the effect of Gingko biloba extract on AMD. PMID- 23440786 TI - Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset tonic-clonic seizures. AB - BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone. OBJECTIVES: To review the best evidence comparing phenobarbitone and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group trials register (31 May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 5 of 12, The Cochrane Library 2012) and MEDLINE (1946 to May week 4, 2012). We hand-searched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of phenobarbitone monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled estimate of HRs and 95% CIs. MAIN RESULTS: Data have been obtained for four of eight studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 63% of the potential data.The main overall results (pooled HR, 95% CI) were (a) time to treatment withdrawal 1.62 (1.23 to 2.14); (b) time to 12-month remission 0.90 (0.69 to 1.18) (c) time to six-month remission 0.92 (0.73 to 1.16) and (d) time to first seizure 0.85 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal. However, this result may have been confounded by several factors including substantial statistical heterogeneity between studies and lack of blinding in two studies. AUTHORS' CONCLUSIONS: The results of this review show that phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to adverse effects. Several factors may have confounded the results of this review. PMID- 23440787 TI - Pressure-relieving interventions for treating diabetic foot ulcers. AB - BACKGROUND: Diabetes-related foot ulceration is a major contributor to morbidity in diabetes. Diabetic foot ulcers are partly a consequence of abnormal foot pressures and pressure relief is a widely used treatment for healing diabetes related plantar foot ulcers, but the most effective method for healing is unclear. OBJECTIVES: To determine the effects of pressure-relieving interventions on the healing of foot ulcers in people with diabetes. SEARCH METHODS: For this update we searched the Cochrane Wounds Group Specialised Register (searched 2 November 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10); Ovid MEDLINE (1950 to October Week 4 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, October 31, 2012); Ovid EMBASE (1980 to 2012 Week 43); and EBSCO CINAHL (1982 to 1 November 2012). There were no restrictions based on language or publication status. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of pressure-relieving interventions on the healing of foot ulcers in people with diabetes. DATA COLLECTION AND ANALYSIS: Data from eligible trials were extracted, and summarised using a data extraction sheet, by two review authors independently. MAIN RESULTS: Fourteen trials (709 participants) met the inclusion criteria for the review. One study compared two different types of non-removable casts with no discernable difference between the groups. Seven studies (366 participants) compared non removable casts with removable pressure-relieving devices. In five of those studies non-removable casts were associated with a statistically significant increase in the number of ulcers healed compared with the removable device (RR 1.17 95% CI 1.01 to 1.36: P value = 0.04).Two studies (98 participants) found that significantly more ulcers healed with non-removable casts than with dressings alone. Achilles tendon lengthening combined with a non-removable cast in one study resulted in significantly more healed ulcers at 7 months than non removable cast alone (RR 2.23; 95% CI 1.32 to 3.76). More ulcers remained healed at two years in this group (RR 3.41; 95% CI 1.42 to 8.18).Other comparisons included surgical debridement of ulcers; felt fitted to the foot; felted foam dressings and none of these showed a statistically significant treatment effect in favour of the intervention. AUTHORS' CONCLUSIONS: Non-removable, pressure relieving casts are more effective in healing diabetes related plantar foot ulcers than removable casts, or dressings alone. Non-removable devices, when combined with Achilles tendon lengthening were more successful in one forefoot ulcer study than the use of a non-removable cast alone. PMID- 23440788 TI - Depot versus daily administration of gonadotrophin-releasing hormone agonist protocols for pituitary down regulation in assisted reproduction cycles. AB - BACKGROUND: Gonadotrophin-releasing hormone agonist (GnRHa) is commonly used to switch off (down regulate) the pituitary gland and thus suppress ovarian activity in women undergoing in vitro fertilisation (IVF). Other fertility drugs (gonadotrophins) are then used to stimulate ovulation in a controlled manner. Among the various types of pituitary down regulation protocols in use, the long protocol achieves the best clinical pregnancy rate. The long protocol requires GnRHa administration until suppression of ovarian activity occurs, within approximately 14 days. GnRHa can be used either as daily low-dose injections or through a single injection containing higher doses of the drug (depot). It is unclear which of these two forms of administration is best, and whether single depot administration may require higher doses of gonadotrophins. OBJECTIVES: To compare the effectiveness and safety of a single depot dose of GHRHa versus daily GnRHa doses in women undergoing IVF. SEARCH METHODS: We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012) and LILACS (1982 to July 2012). We also screened the reference lists of articles. SELECTION CRITERIA: We included RCTs comparing depot and daily administration of GnRHa for long protocols in IVF treatment cycles in couples with any cause of infertility, using various methods of ovarian stimulation. The primary review outcomes were live birth or ongoing pregnancy, clinical pregnancy and ovarian hyperstimulation syndrome (OHSS). Other outcomes included number of oocytes retrieved, miscarriage, multiple pregnancy, number of gonadotrophin (FSH) units used for ovarian stimulation, duration of gonadotrophin treatment, cost and patient convenience. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed study quality. For dichotomous outcomes, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) per woman randomised. Where appropriate, we pooled studies. MAIN RESULTS: Sixteen studies were eligible for inclusion (n = 1811 participants), 12 (n = 1366 participants) of which were suitable for meta-analysis. No significant heterogeneity was detected.There were no significant differences between depot GnRHa and daily GnRHa in live birth/ongoing pregnancy rates (OR 0.95, 95% CI 0.70 to 1.31, seven studies, 873 women), but substantial differences could not be ruled out. Thus for a woman with a 24% chance of achieving a live birth or ongoing pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 18% and 29%.There was no significant difference between the groups in clinical pregnancy rate (OR 0.96, 95% CI 0.75 to 1.23, 11 studies, 1259 women). For a woman with a 30% chance of achieving clinical pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 25% and 35%.There was no significant difference between the groups in the rate of severe OHSS (OR 0.84, 95% CI 0.29 to 2.42, five studies, 570 women), but substantial differences could not be ruled out. For a woman with a 3% chance of severe OHSS using daily GnRHa injections, the corresponding risk using GnRHa depot would be between 1% and 6%.Compared to women using daily GnRHa, those on depot administration required significantly more gonadotrophin units for ovarian stimulation (standardised mean difference (SMD) 0.26, 95% CI 0.08 to 0.43, 11 studies, 1143 women) and a significantly longer duration of gonadotrophin use (mean difference (MD) 0.65, 95% CI 0.46 to 0.84, 10 studies, 1033 women).Study quality was unclear due to poor reporting. Only four studies reported live births as an outcome and only five described adequate methods for concealment of allocation. AUTHORS' CONCLUSIONS: We found no evidence of a significant difference between depot and daily GnRHa use for pituitary down regulation in IVF cycles using the long protocol, but substantial differences could not be ruled out. Since depot GnRHa requires more gonadotrophins and a longer duration of use, it may increase the overall costs of IVF treatment. PMID- 23440789 TI - Cooling for newborns with hypoxic ischaemic encephalopathy. AB - BACKGROUND: Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. OBJECTIVES: To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. SELECTION CRITERIA: We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. DATA COLLECTION AND ANALYSIS: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). MAIN RESULTS: We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. AUTHORS' CONCLUSIONS: There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention. PMID- 23440790 TI - Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery. AB - BACKGROUND: Atrial fibrillation is a common post-operative complication of cardiac surgery and is associated with an increased risk of post-operative stroke, increased length of intensive care unit and hospital stays, healthcare costs and mortality. Numerous trials have evaluated various pharmacological and non-pharmacological prophylactic interventions for their efficacy in preventing post-operative atrial fibrillation. We conducted an update to a 2004 Cochrane systematic review and meta-analysis of the literature to gain a better understanding of the effectiveness of these interventions. OBJECTIVES: The primary objective was to assess the effects of pharmacological and non pharmacological interventions for preventing post-operative atrial fibrillation or supraventricular tachycardia after cardiac surgery. Secondary objectives were to determine the effects on post-operative stroke or cerebrovascular accident, mortality, cardiovascular mortality, length of hospital stay and cost of treatment during the hospital stay. SEARCH METHODS: We searched the Cochrane Central Register of ControlLed Trials (CENTRAL) (Issue 8, 2011), MEDLINE (from 1946 to July 2011), EMBASE (from 1974 to July 2011) and CINAHL (from 1981 to July 2011). SELECTION CRITERIA: We selected randomized controlled trials (RCTs) that included adult patients undergoing cardiac surgery who were allocated to pharmacological or non-pharmacological interventions for the prevention of post operative atrial fibrillation or supraventricular tachycardia, except digoxin, potassium (K(+)), or steroids. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted study data and assessed trial quality. MAIN RESULTS: One hundred and eighteen studies with 138 treatment groups and 17,364 participants were included in this review. Fifty-seven of these studies were included in the original version of this review while 61 were added, including 27 on interventions that were not considered in the original version. Interventions included amiodarone, beta-blockers, sotalol, magnesium, atrial pacing and posterior pericardiotomy. Each of the studied interventions significantly reduced the rate of post-operative atrial fibrillation after cardiac surgery compared with a control. Beta-blockers (odds ratio (OR) 0.33; 95% confidence interval) CI 0.26 to 0.43; I(2) = 55%) and sotalol (OR 0.34; 95% CI 0.26 to 0.43; I(2) = 3%) appear to have similar efficacy while magnesium's efficacy (OR 0.55; 95% CI 0.41 to 0.73; I(2) = 51%) may be slightly less. Amiodarone (OR 0.43; 95% CI 0.34 to 0.54; I(2) = 63%), atrial pacing (OR 0.47; 95% CI 0.36 to 0.61; I(2) = 50%) and posterior pericardiotomy (OR 0.35; 95% CI 0.18 to 0.67; I(2) = 66%) were all found to be effective. Prophylactic intervention decreased the hospital length of stay by approximately two-thirds of a day and decreased the cost of hospital treatment by roughly $1250 US. Intervention was also found to reduce the odds of post-operative stroke, though this reduction did not reach statistical significance (OR 0.69; 95% CI 0.47 to 1.01; I(2) = 0%). No significant effect on all-cause or cardiovascular mortality was demonstrated. AUTHORS' CONCLUSIONS: Prophylaxis to prevent atrial fibrillation after cardiac surgery with any of the studied pharmacological or non-pharmacological interventions may be favored because of its reduction in the rate of atrial fibrillation, decrease in the length of stay and cost of hospital treatment and a possible decrease in the rate of stroke. However, this review is limited by the quality of the available data and heterogeneity between the included studies. Selection of appropriate interventions may depend on the individual patient situation and should take into consideration adverse effects and the cost associated with each approach. PMID- 23440791 TI - Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C. AB - BACKGROUND: The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated. This situation exists because there are very few randomized clinical trials that have used clinical events (mortality or manifestations of decompensated cirrhosis) as outcomes, because those clinical events only occur after many years of infection. Patients in whom initial therapy fails to produce sustained viral responses do become potential candidates for retreatment; some of these individuals are not candidates for ribavirin or protease inhibitors and consideration could be given to retreatment with interferon alone. OBJECTIVES: To assess the benefits and harms of interferon monotherapy retreatment in chronic hepatitis C patients and to validate the currently employed surrogate outcomes in this group of patients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until 16 August 2012. SELECTION CRITERIA: Randomized trials comparing interferon versus placebo or no treatment in chronic hepatitis C nonresponders and relapsers to previous interferon. DATA COLLECTION AND ANALYSIS: The primary outcomes were mortality (all-cause and hepatic), quality of life, and adverse events. Secondary outcomes were liver-related morbidity, sustained viral responses, biochemical responses, histologic improvements, and costs. We used both fixed-effect and random-effects model meta-analyses, reporting only the former if no difference existed. MAIN RESULTS: Seven trials were identified. Two of them were at low risk of bias (the HALT-C and EPIC3 trials) and included 1676 patients. Both of these trials addressed the role of long-term low-dose pegylated interferon therapy in patients with severe fibrosis (demonstrated on liver biopsy) and were designed to assess the clinical outcomes. The remaining five trials included 300 patients and were at high risk of bias. Based on all trials reporting the outcomes, no significant difference was observed in either all-cause mortality (78/843 (9.3%) versus 62/867 (7.2%); risk ratio (RR) 1.30, 95% confidence interval (CI) 0.95 to 1.79; 3 trials) or hepatic mortality (41/532 (7.7%) versus 40/552 (7.2%); RR 1.07, 95% CI 0.70 to 1.63; 2 trials); however, when only the two trials at low risk of bias were combined, all-cause mortality was significantly higher in the recipients of the pegylated interferon (78/828 (9.4%) versus 57/848 (6.7%); RR 1.41, 95% CI 1.02 to 1.96) although trial sequential analysis could not exclude the possibility of random error. There was less variceal bleeding in the recipients of the interferon (4/843 (0.5%) versus 18/867 (2.1%); RR 0.24, 95% CI 0.09 to 0.67; 3 trials), although again trial sequential analysis could not exclude the presence of a type I error and the effect could not be confirmed in a random-effects model meta-analysis. No significant differences were seen with regard to the development of ascites, encephalopathy, hepatocellular carcinoma, or the need for liver transplantation. One trial reported quality of life data; the pain score was significantly worse in the recipients of the pegylated interferon. Adverse effects tended to be more common in the interferon recipients; the ones that were significantly more common included hematologic complications, infections, flu-like symptoms, and rash. The recipients of interferon had significantly more sustained viral responses (20/557 (3.6%) versus 1/579 (0.2%); RR 15.38, 95% CI 2.93 to 80.71; 4 trials) and a type I error was excluded by trial sequential analysis. The METAVIR activity score also improved (36/55 (65%) versus 20/46 (43.5%); RR 1.49, 95% CI 1.02 to 2.18; 2 trials). No significant differences were seen with regard to histologic fibrosis assessments. AUTHORS' CONCLUSIONS: The clinical data were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon. In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events. On the other hand, the treatment did result in improvement in some surrogate outcomes, namely sustained viral responses and histologic evidence of inflammation. Interferon monotherapy retreatment cannot be recommended for these patients. No clinical data are available for patients with less severe fibrosis. The sustained viral response cannot be used as a surrogate marker for hepatitis C treatment in this clinical setting with low sustained viral response rates and needs to be validated in others in which higher sustained viral response rates are reported. PMID- 23440792 TI - Phytomedicines (medicines derived from plants) for sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD), a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. There has been little systematic appraisal of their benefits. OBJECTIVES: To assess the benefits and risks of phytomedicines in people with SCD of all types, of any age, in any setting. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN) and the Allied and Complimentary Medicine Database (AMED).Dates of most recent searches:Haemoglobinopathies Trials Register: 05 July 2012;ISRCTN: 28 December 2009;AMED: August 2003. SELECTION CRITERIA: Randomised or quasi-randomised trials with participants of all ages with SCD, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. MAIN RESULTS: Two trials (182 participants) and two phytomedicines Niprisan((r)) (also known as Nicosan((r))) and Ciklavit((r)) were included. The Phase IIB (pivotal) trial suggests that Niprisan((r)) was effective in reducing episodes of severe painful SCD crisis over a six-month period. It did not affect the risk of severe complications or the level of anaemia. No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit((r))) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non significant) on the level of anaemia. AUTHORS' CONCLUSIONS: While Niprisan((r)) appeared to be safe and effective in reducing severe painful crises over a six month follow-up period, further trials are required to assess its role in the management of people with SCD and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit((r)). Based on the published results for Niprisan((r)) and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines used in managing SCD. PMID- 23440793 TI - Vibroacoustic stimulation for fetal assessment in labour in the presence of a nonreassuring fetal heart rate trace. AB - BACKGROUND: Fetal vibroacoustic stimulation (VAS) is a simple, non-invasive technique where a device is placed on the maternal abdomen over the region of the fetal head and sound is emitted at a predetermined level for several seconds. It is hypothesised that the resultant startle reflex in the fetus and subsequent fetal heart rate (FHR) acceleration or transient tachycardia following VAS provide reassurance of fetal well-being. This technique has been proposed as a tool to assess fetal well-being in the presence of a nonreassuring cardiotocographic (CTG) trace during the first and second stages of labour. OBJECTIVES: To evaluate the clinical effectiveness and safety of VAS in the assessment of fetal well-being during labour, compared with mock or no stimulation for women with a singleton pregnancy exhibiting a nonreassuring FHR pattern. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 September 2012) and reference lists of all retrieved articles. We sought unpublished trials and abstracts submitted to major international congresses and contacted expert informants. SELECTION CRITERIA: All published and unpublished randomised trials that compared maternal and fetal/neonatal/infant outcomes when VAS was used to evaluate fetal status in the presence of a nonreassuring CTG trace during labour, compared with mock or no stimulation. DATA COLLECTION AND ANALYSIS: Two review authors independently sought to assess for inclusion all the potential studies we identified as a result of the search strategy. We planned to resolve any disagreement through discussion or, if required, to consult a third person. Where there was uncertainty about a particular study, we attempted to contact study authors for additional information. However, these attempts were unsuccessful. MAIN RESULTS: The search strategies yielded six studies for consideration of inclusion. However, none of these studies fulfilled the requirements for inclusion in this review. AUTHORS' CONCLUSIONS: There are currently no randomised controlled trials that address the safety and efficacy of VAS used to assess fetal well-being in labour in the presence of a nonreassuring CTG trace. Although VAS has been proposed as a simple, non-invasive tool for assessment of fetal well-being, there is insufficient evidence from randomised trials on which to base recommendations for use of VAS in the evaluation of fetal well-being in labour in the presence of a nonreassuring CTG trace. PMID- 23440794 TI - Screening for prostate cancer. AB - BACKGROUND: Any form of screening aims to reduce disease-specific and overall mortality, and to improve a person's future quality of life. Screening for prostate cancer has generated considerable debate within the medical and broader community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. To better inform individual patient decision-making and health policy decisions, we need to consider the entire body of data from randomised controlled trials (RCTs) on prostate cancer screening summarised in a systematic review. In 2006, our Cochrane review identified insufficient evidence to either support or refute the use of routine mass, selective, or opportunistic screening for prostate cancer. An update of the review in 2010 included three additional trials. Meta-analysis of the five studies included in the 2010 review concluded that screening did not significantly reduce prostate cancer-specific mortality. In the past two years, several updates to studies included in the 2010 review have been published thereby providing the rationale for this update of the 2010 systematic review. OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer-specific mortality or all-cause mortality and to assess its impact on quality of life and adverse events. SEARCH METHODS: An updated search of electronic databases (PROSTATE register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CANCERLIT, and the NHS EED) was performed, in addition to handsearching of specific journals and bibliographies, in an effort to identify both published and unpublished trials. SELECTION CRITERIA: All RCTs of screening versus no screening for prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The original search (2006) identified 99 potentially relevant articles that were selected for full-text review. From these citations, two RCTs were identified as meeting the inclusion criteria. The search for the 2010 version of the review identified a further 106 potentially relevant articles, from which three new RCTs were included in the review. A total of 31 articles were retrieved for full-text examination based on the updated search in 2012. Updated data on three studies were included in this review. Data from the trials were independently extracted by two authors. MAIN RESULTS: Five RCTs with a total of 341,342 participants were included in this review. All involved prostate-specific antigen (PSA) testing, with or without digital rectal examination (DRE), though the interval and threshold for further evaluation varied across trials. The age of participants ranged from 45 to 80 years and duration of follow-up from 7 to 20 years. Our meta analysis of the five included studies indicated no statistically significant difference in prostate cancer-specific mortality between men randomised to the screening and control groups (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). The methodological quality of three of the studies was assessed as posing a high risk of bias. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial were assessed as posing a low risk of bias, but provided contradicting results. The ERSPC study reported a significant reduction in prostate cancer-specific mortality (RR 0.84, 95% CI 0.73 to 0.95), whilst the PLCO study concluded no significant benefit (RR 1.15, 95% CI 0.86 to 1.54). The ERSPC was the only study of the five included in this review that reported a significant reduction in prostate cancer-specific mortality, in a pre-specified subgroup of men aged 55 to 69 years of age. Sensitivity analysis for overall risk of bias indicated no significant difference in prostate cancer-specific mortality when referring to the meta analysis of only the ERSPC and PLCO trial data (RR 0.96, 95% CI 0.70 to 1.30). Subgroup analyses indicated that prostate cancer specific mortality was not affected by the age at which participants were screened. Meta-analysis of four studies investigating all-cause mortality did not determine any significant differences between men randomised to screening or control (RR 1.00, 95% CI 0.96 to 1.03). A diagnosis of prostate cancer was significantly greater in men randomised to screening compared to those randomised to control (RR 1.30, 95% CI 1.02 to 1.65). Localised prostate cancer was more commonly diagnosed in men randomised to screening (RR 1.79, 95% CI 1.19 to 2.70), whilst the proportion of men diagnosed with advanced prostate cancer was significantly lower in the screening group compared to the men serving as controls (RR 0.80, 95% CI 0.73 to 0.87). Screening resulted in a range of harms that can be considered minor to major in severity and duration. Common minor harms from screening include bleeding, bruising and short-term anxiety. Common major harms include overdiagnosis and overtreatment, including infection, blood loss requiring transfusion, pneumonia, erectile dysfunction, and incontinence. Harms of screening included false-positive results for the PSA test and overdiagnosis (up to 50% in the ERSPC study). Adverse events associated with transrectal ultrasound (TRUS)-guided biopsies included infection, bleeding and pain. No deaths were attributed to any biopsy procedure. None of the studies provided detailed assessment of the effect of screening on quality of life or provided a comprehensive assessment of resource utilization associated with screening (although preliminary analyses were reported). AUTHORS' CONCLUSIONS: Prostate cancer screening did not significantly decrease prostate cancer-specific mortality in a combined meta-analysis of five RCTs. Only one study (ERSPC) reported a 21% significant reduction of prostate cancer-specific mortality in a pre-specified subgroup of men aged 55 to 69 years. Pooled data currently demonstrates no significant reduction in prostate cancer-specific and overall mortality. Harms associated with PSA-based screening and subsequent diagnostic evaluations are frequent, and moderate in severity. Overdiagnosis and overtreatment are common and are associated with treatment-related harms. Men should be informed of this and the demonstrated adverse effects when they are deciding whether or not to undertake screening for prostate cancer. Any reduction in prostate cancer-specific mortality may take up to 10 years to accrue; therefore, men who have a life expectancy less than 10 to 15 years should be informed that screening for prostate cancer is unlikely to be beneficial. No studies examined the independent role of screening by DRE. PMID- 23440795 TI - Statins for the primary prevention of cardiovascular disease. AB - BACKGROUND: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of CVD is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with CVD. The case for primary prevention was uncertain when the last version of this review was published (2011) and in light of new data an update of this review is required. OBJECTIVES: To assess the effects, both harms and benefits, of statins in people with no history of CVD. SEARCH METHODS: To avoid duplication of effort, we checked reference lists of previous systematic reviews. The searches conducted in 2007 were updated in January 2012. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2022, Issue 4), MEDLINE OVID (1950 to December Week 4 2011) and EMBASE OVID (1980 to 2012 Week 1).There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of statins versus placebo or usual care control with minimum treatment duration of one year and follow-up of six months, in adults with no restrictions on total, low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted data. Outcomes included all-cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), revascularisation, change in total and LDL cholesterol concentrations, adverse events, quality of life and costs. Odds ratios (OR) and risk ratios (RR) were calculated for dichotomous data, and for continuous data, pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated. We contacted trial authors to obtain missing data. MAIN RESULTS: The latest search found four new trials and updated follow-up data on three trials included in the original review. Eighteen randomised control trials (19 trial arms; 56,934 participants) were included. Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (OR 0.86, 95% CI 0.79 to 0.94); as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81), combined fatal and non-fatal CHD events RR 0.73 (95% CI 0.67 to 0.80) and combined fatal and non-fatal stroke (RR 0.78, 95% CI 0.68 to 0.89). Reduction of revascularisation rates (RR 0.62, 95% CI 0.54 to 0.72) was also seen. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event. AUTHORS' CONCLUSIONS: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins. PMID- 23440796 TI - Pain relief for women undergoing oocyte retrieval for assisted reproduction. AB - BACKGROUND: Various methods of conscious sedation and analgesia have been used for pain relief during oocyte recovery in in vitro fertilisation (IVF) and intra cytoplasmic sperm injection (ICSI) procedures. The choice of agent has also been influenced by the quality of sedation and analgesia as well as by concerns about possible detrimental effects on reproductive outcomes. OBJECTIVES: To assess the effectiveness and safety of different methods of conscious sedation and analgesia on pain relief and pregnancy outcomes in women undergoing transvaginal oocyte retrieval. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL (from their inception to present); the National Research Register and Current Controlled Trials. We searched reference lists of included studies for relevant studies and contacted authors for information on unpublished and ongoing trials. There was no language restriction. The search was updated in July 2012. SELECTION CRITERIA: Only randomised controlled trials comparing different methods of conscious sedation and analgesia for pain relief during oocyte recovery were included. DATA COLLECTION AND ANALYSIS: Quality assessment and data extraction were performed independently by two review authors. Interventions were classified and analysed under broad categories or strategies of sedation and pain relief to compare different methods and administrative protocols of conscious sedation and analgesia. Outcomes were extracted and the data were pooled when appropriate. MAIN RESULTS: With this update, nine new studies were identified resulting in a total of 21 trials including 2974 women undergoing oocyte retrieval. These trials compared five different categories of conscious sedation and analgesia: 1) conscious sedation and analgesia versus placebo; 2) conscious sedation and analgesia versus other active interventions such as general and acupuncture anaesthesia; 3) conscious sedation and analgesia plus paracervical block versus other active interventions such as general, spinal and acupuncture anaesthesia; 4) patient-controlled conscious sedation and analgesia versus physician administered conscious sedation and analgesia; and 5) conscious sedation and analgesia with different agents or dosage. Evidence was generally of low quality, mainly due to poor reporting of methods, small sample sizes and inconsistency between the trials.Conflicting results were shown for women's experience of pain. Compared to conscious sedation alone, more effective pain relief was reported when conscious sedation was combined with electro-acupuncture: intra-operative pain mean difference (MD) on 1 to 10 visual analogue scale (VAS) of 3.00 (95% CI 2.23 to 3.77); post-operative pain MD in VAS units of 2.10 (95% CI 1.40 to 2.80; N = 61, one trial, low quality evidence); or paracervical block (MD not calculable).The pooled data of four trials showed a significantly lower intra operative pain score with conscious sedation plus paracervical block than with electro-acupuncture plus paracervical block (MD on 10-point VAS of -0.66; 95% CI 0.93 to -0.39; N = 781, 4 trials, low quality evidence) with significant statistical heterogeneity (I(2) = 76%). Patient-controlled sedation and analgesia was associated with more intra-operative pain than physician-administered sedation and analgesia (MD on 10-point VAS of 0.60; 95% CI 0.16 to 1.03; N = 379, 4 trials, low quality evidence) with high statistical heterogeneity (I(2) = 83%). Post-operative pain was reported in only nine studies. As different types and dosages of sedative and analgesic agents, as well as administrative protocols and assessment tools, were used in these trials the data should be interpreted with caution.There was no evidence of a significant difference in pregnancy rate in the 12 studies which assessed this outcome, and pooled data of four trials comparing electro-acupuncture combined with paracervical block with conscious sedation and analgesia plus paracervical block showed an odds ratio (OR) of 0.96 (95% CI 0.72 to 1.29; N = 783, 4 trials) for pregnancy. High levels of women's satisfaction were reported for all modalities of conscious sedation and analgesia as assessed in 12 studies. Meta-analysis of all the studies was not attempted due to considerable heterogeneity.For the rest of the trials a descriptive summary of the outcomes was presented. AUTHORS' CONCLUSIONS: The evidence from this review of 21 randomised controlled trials did not support one particular method or technique over another in providing effective conscious sedation and analgesia for pain relief during and after oocyte recovery. The simultaneous use of more than one method of sedation and pain relief resulted in better pain relief than one modality alone. The various approaches and techniques reviewed appeared to be acceptable and were associated with a high degree of satisfaction in women. As women vary in their experience of pain and in coping strategies, the optimal method may be individualised depending on the preferences of both the women and the clinicians and resource availability. PMID- 23440797 TI - Surgical implantation of steroids with antiangiogenic characteristics for treating neovascular age-related macular degeneration. AB - BACKGROUND: Neovascular age-related macular degeneration (AMD) is associated with rapid vision loss due to choroidal neovascularization (CNV), leakage, and scarring. Steroids have gained attention in their role for the treatment of neovascular AMD for their antiangiogenic and anti-inflammatory properties. OBJECTIVES: This review aims to examine effects of steroids with antiangiogenic properties in the treatment of neovascular AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2012), EMBASE (January 1980 to November 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 November 2012. SELECTION CRITERIA: We included randomized controlled clinical trials of intra- and peri-ocular antiangiogenic steroids in people diagnosed with neovascular AMD. DATA COLLECTION AND ANALYSIS: Two authors independently screened abstracts and full-text articles, assessed risk of bias in the included trials, and extracted data. We did not conduct a meta-analysis. MAIN RESULTS: We included three trials after screening a total of 1503 abstracts and 21 full-text articles. The three trials included a total of 809 participants. One trial compared different doses of acetonide anecortave acetate with placebo, a second trial compared triamcinolone acetonide versus placebo, and the third trial compared anecortave acetate against photodynamic therapy (PDT). We did not conduct a meta-analysis owing to heterogeneity of interventions and comparisons. The risk ratio for loss of 3 or more lines of vision at 12 months follow-up was 0.8 (95% confidence interval (CI) 0.45 to 1.45) with 3 mg anecortave acetate, 0.45 (95% CI = 0.21 to 0.97) with 15 mg anecortave acetate, 0.91 (0.52 to 1.58) with 30 mg anecortave acetate, 0.97 (95% CI 0.74 to 1.26) with triamcinolone acetonide, all compared to placebo and 1.08 (95% CI 0.91 to 1.29) with anecortave acetate compared with PDT. AUTHORS' CONCLUSIONS: Based on the included trials, we found no evidence that antiangiogenic steroids prevent visual loss in patients with neovascular AMD. With the emergence of anti-vascular endothelial growth factor modalities, based on evidence summarized in this review, it is unclear what role steroids have in treating patients with neovascular AMD. PMID- 23440798 TI - Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. AB - BACKGROUND: Various options exist for treating endometriosis, including surgical, medical, such as ovarian suppression, or a combination of these strategies. Surgical treatment of endometriosis aims to remove visible areas of endometriosis. The aim of medical therapy is to inhibit growth of endometriotic implants by induction of a hypo-estrogenic state. Treatment with a hormone releasing intrauterine device, using levonorgestrel (LNG-IUD), has also been suggested. OBJECTIVES: To determine whether postoperative LNG-IUD insertion in women with endometriosis improves pain and reduces recurrence of symptoms compared with no postoperative treatment, postoperative insertion of a placebo, or postoperative therapy. SEARCH METHODS: The following databases were searched from inception to June 2012: Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, CINAHL, and the World Health Organization (WHO) International Clinical Trials Registry Platform. EMBASE was searched from 2010 to June 2012. The citation lists of relevant publications, review articles, abstracts of scientific meetings, and included studies were also searched. SELECTION CRITERIA: Trials were included if they compared women undergoing surgical treatment for endometriosis with uterine preservation and then randomised within three months to LNG-IUD insertion versus no postoperative treatment, placebo (inert IUD), or other treatment. Diagnostic laparoscopy alone was not considered suitable treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted data to allow for an intention-to-treat analysis. For dichotomous data, the risk ratio (RR) and 95% confidence interval (CI) were calculated using the Mantel-Haenszel random effects method. For continuous data, the mean difference (MD) and 95% CI were calculated using the inverse variance random-effects method. MAIN RESULTS: Three randomised controlled trials were included. In two trials, there was a statistically significant reduction in the recurrence of painful periods in the LNG-IUD group compared with expectant management (RR 0.22, 95% CI 0.08 to 0.60, 95 women, I(2) = 0%, moderate strength of evidence). The proportion of women who were satisfied with their treatment was also higher in the LNG-IUD group but did not reach statistical significance (RR 1.21, 95% CI 0.80 to 1.82, 95 women, I(2) = 0%). The number of women reporting a change in menstruation was significantly higher in the LNG-IUD group (RR 37.80, 95% CI 5.40 to 264.60, 95 women, I(2) = 0%) but the number of women not completing the allocated treatment did not differ between groups (RR 0.66, 95% CI 0.08 to 5.25, I(2) = 43%).In one trial, women receiving LNG-IUD noted lower pain scores compared with women receiving gonadotrophin-releasing hormone agonists (MD -0.16, 95% CI -2.02 to 1.70, 40 women) but this did not reach statistical significance. AUTHORS' CONCLUSIONS: There is limited but consistent evidence showing that postoperative LNG-IUD use reduces the recurrence of painful periods in women with endometriosis. Further well-designed RCTs are needed to confirm these findings. PMID- 23440799 TI - Laser-assisted in-situ keratomileusis (LASIK) versus photorefractive keratectomy (PRK) for myopia. AB - BACKGROUND: Myopia (also known as short-sightedness or near-sightedness) is an ocular condition in which the refractive power of the eye is greater than is required, resulting in light from distant objects being focused in front of the retina instead of directly on it. The two most commonly used surgical techniques to permanently correct myopia are photorefractive keratectomy (PRK) and laser assisted in-situ keratomileusis (LASIK). OBJECTIVES: To compare the effectiveness and safety of LASIK and PRK for correction of myopia by examining post-treatment uncorrected visual acuity, refractive outcome, loss of best spectacle-corrected visual acuity, pain scores, flap complications in LASIK, subepithelial haze, adverse events, quality of life indices and higher order aberrations. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2012), EMBASE (January 1980 to November 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 November 2012. We also searched the reference lists of the studies and the Science Citation Index. SELECTION CRITERIA: We included randomised controlled trials comparing LASIK and PRK for the correction of any degree of myopia. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We summarised data using the odds ratio and mean difference. We combined odds ratios using a random-effects model after testing for heterogeneity. MAIN RESULTS: We included 13 trials (1135 participants, 1923 eyes) in this review. Nine of these trials randomised eyes to treatment, two trials randomised people to treatment and treated both eyes, and two trials randomised people to treatment and treated one eye. None of the paired trials reported an appropriate paired analysis. We considered the overall quality of evidence to be low for most outcomes because of the risk of bias in the included trials. There was evidence that LASIK gives a faster visual recovery than PRK and is a less painful technique. Results at one year after surgery were comparable: most analyses favoured LASIK but they were not statistically significant. AUTHORS' CONCLUSIONS: LASIK gives a faster visual recovery and is a less painful technique than PRK. The two techniques appear to give similar outcomes one year after surgery. Further trials using contemporary techniques are required to determine whether LASIK and PRK as currently practised are equally safe. Randomising eyes to treatment is an efficient design, but only if analysed properly. In future trials, more efforts could be made to mask the assessment of outcome. PMID- 23440800 TI - Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour. AB - BACKGROUND: This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are malignant disorders of the placenta that include invasive hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Choriocarcinoma and invasive hydatidiform mole respond well to chemotherapy: low-risk tumours are treated with single-agent chemotherapy (e.g. methotrexate or actinomycin D), whereas high-risk tumours are treated with combination chemotherapy (e.g. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine)). Various drug combinations may be used for high-risk tumours; however, the comparative efficacy and safety of these regimens is not clear. OBJECTIVES: To determine the efficacy and safety of combination chemotherapy in treating high-risk GTN. SEARCH METHODS: For the original review, we searched the Cochrane Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2008), MEDLINE, EMBASE and CBM in May 2008. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to September 2012. In addition, we searched online clinical trial registries for ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing first-line combination chemotherapy interventions in women with high-risk GTN. DATA COLLECTION AND ANALYSIS: Two review authors independently collected data using a data extraction form. Meta-analysis could not be performed as we included only one study. MAIN RESULTS: We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens. AUTHORS' CONCLUSIONS: CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary. PMID- 23440801 TI - Oral zinc for treating diarrhoea in children. AB - BACKGROUND: In developing countries, diarrhoea causes around two million child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization and UNICEF. OBJECTIVES: To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea. SEARCH METHODS: In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2011, Issue 11), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contacted researchers. SELECTION CRITERIA: Randomized controlled trials comparing oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery. DATA COLLECTION AND ANALYSIS: Both authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. Diarrhoea duration and severity were the primary outcomes. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using the fixed- or random-effects model) and assessed heterogeneity.The quality of evidence has been assessed using the GRADE methods MAIN RESULTS: Twenty-four trials, enrolling 9128 children, met our inclusion criteria. The majority of the data is from Asia, from countries at high risk of zinc deficiency, and may not be applicable elsewhere. Acute diarrhoea. There is currently not enough evidence from well conducted randomized controlled trials to be able to say whether zinc supplementation during acute diarrhoea reduces death or hospitalization (very low quality evidence).In children aged greater than six months with acute diarrhoea, zinc supplementation may shorten the duration of diarrhoea by around 10 hours (MD 10.44 hours, 95% CI -21.13 to 0.25; 2175 children, six trials, low quality evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, six trials, moderate quality evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around 27 hours (MD -26.98 hours, 95% CI -14.62 to -39.34; 336 children, three trials, high quality evidence).Conversely, In children aged less than six months, the available evidence suggests zinc supplementation may have no effect on mean diarrhoea duration (MD 5.23 hours, 95% CI -4.00 to 14.45; 1334 children, two trials, low quality evidence), and may even increase the proportion of children whose diarrhoea persists until day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, one trial, moderate quality evidence).No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (RR 1.59, 95% 1.27 to 1.99; 5189 children, 10 trials, high quality evidence). Persistent diarrhoea. In children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (MD -15.84 hours, 95% CI -25.43 to -6.24; 529 children, five trials, moderate quality evidence). AUTHORS' CONCLUSIONS: In areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged six months or more.The current evidence does not support the use of zinc supplementation in children below six months of age. PMID- 23440802 TI - Laparoscopic surgery for presumed benign ovarian tumor during pregnancy. AB - BACKGROUND: The surgical management of ovarian tumors in pregnancy is similar to that of non-pregnant women. The procedures include resection of the tumor (enucleation), removal of an ovary or ovaries (oophorectomy), or surgical excision of the fallopian tube and ovary (salpingo-oophorectomy). The procedure can be done by open surgery (laparotomy) or keyhole surgery (laparoscopy) technique. The benefits of laparoscopic surgery include shorter hospital stay, earlier return to normal activity, and reduced postoperative pain. However, conventional laparoscopic surgery techniques required the infusion of gas carbon dioxide in the peritoneum to distend the abdomen and displace the bowel upward to create the room for surgical manipulation. Serious complications such as abnormally high levels of carbon dioxide in the circulating blood (hypercarbia) and perforation of internal organs have also been reported. These serious complication may be harmful to the fetus. OBJECTIVES: To compare the effects of using laparoscopic surgery for benign ovarian tumor during pregnancy on maternal and fetal health and the use of healthcare resources. SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 11 November 2012. SELECTION CRITERIA: Randomized controlled trials with reported data that compared outcomes of laparoscopic surgery for benign ovarian tumor in pregnancy to conventional laparotomy technique. DATA COLLECTION AND ANALYSIS: Two review authors planned to independently assess trial quality and extract data. MAIN RESULTS: The updated search did not identify any randomized controlled trials. AUTHORS' CONCLUSIONS: The practice of laparoscopic surgery for benign ovarian tumour during pregnancy is associated with benefits and harms. However, the evidence for the magnitude of these benefits and harms is drawn from case series studies, associated with potential bias. The results and conclusions of these studies must therefore be interpreted with caution.The available case series studies of laparoscopic surgery for benign ovarian tumour during pregnancy provide limited insight into the potential benefits and harms associated with this new surgical technique in pregnancy. Randomized controlled trials are required to provide the most reliable evidence regarding the benefits and harms of laparoscopic surgery for benign ovarian tumour during pregnancy. PMID- 23440803 TI - Antibiotics for treating acute chest syndrome in people with sickle cell disease. AB - BACKGROUND: The clinical presentation of acute chest syndrome is similar whether due to infectious or non-infectious causes, thus antibiotics are usually prescribed to treat all episodes. Many different pathogens, including bacteria, have been implicated as causative agents of acute chest syndrome. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from acute chest syndrome. OBJECTIVES: To determine whether an empirical antibiotic treatment approach (used alone or in combination): 1. is effective for acute chest syndrome compared to placebo or standard treatment; 2. is safe for acute chest syndrome compared to placebo or standard treatment;Further objectives are to determine whether there are important variations in efficacy and safety: 3. for different treatment regimens, 4. by participant age, or geographical location of the clinical trials. SEARCH METHODS: We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 19 October 2012), African Index Medicus (1982 to 3 November 2012). and the World Health Organization International Clinical Trials Registry Platform Search Portal (19 October 2012).Date of most recent search of the Haemoglobinopathies Trials Register: 29 October 2012. SELECTION CRITERIA: We searched for published or unpublished randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess trial quality by standard Cochrane Collaboration methodologies, but no eligible randomised controlled trials were identified. MAIN RESULTS: For this update, we were unable to find any randomised controlled trials on antibiotic treatment approaches for acute chest syndrome in people with sickle cell disease. AUTHORS' CONCLUSIONS: This update was unable to identify randomised controlled trials on efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from acute chest syndrome. Randomised controlled trials are needed to establish the optimum antibiotic treatment for this condition. PMID- 23440804 TI - Amniotomy for shortening spontaneous labour. AB - BACKGROUND: Intentional artificial rupture of the amniotic membranes during labour, sometimes called amniotomy or 'breaking of the waters', is one of the most commonly performed procedures in modern obstetric and midwifery practice. The primary aim of amniotomy is to speed up contractions and, therefore, shorten the length of labour. However, there are concerns regarding unintended adverse effects on the woman and baby. OBJECTIVES: To determine the effectiveness and safety of amniotomy alone for routinely shortening all labours that start spontaneously. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2010). SELECTION CRITERIA: Randomised controlled trials comparing amniotomy alone versus intention to preserve the membranes. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two authors assessed identified studies for inclusion, assessed risk of bias and extracted data. Primary analysis was by intention to treat. MAIN RESULTS: We have included 15 studies in this updated review, involving 5583 women. In the current review, data for women with spontaneous normal labour were pooled with data from one trial (involving 61 women) where women had spontaneous, but prolonged labour.There was no clear statistically significant difference between the amniotomy and control groups in length of the first stage of labour (mean difference (MD) -20.43 minutes, 95% confidence interval (CI) -95.93 to 55.06), caesarean section (risk ratio (RR) 1.27, 95% CI 0.99 to 1.62), maternal satisfaction with childbirth experience (standardised mean difference (SMD) 0.27, 95% CI -0.49 to 1.04) or low Apgar score less than seven at five minutes (RR 0.57, 95% CI 0.31 to 1.06). There was no consistency between papers regarding the timing of amniotomy during labour in terms of cervical dilatation. AUTHORS' CONCLUSIONS: On the basis of the findings of this review, we cannot recommend that amniotomy should be introduced routinely as part of standard labour management and care. We recommend that the evidence presented in this review should be made available to women offered an amniotomy and may be useful as a foundation for discussion and any resulting decisions made between women and their caregivers. PMID- 23440805 TI - Primary surgery versus primary radiotherapy with or without chemotherapy for early adenocarcinoma of the uterine cervix. AB - BACKGROUND: For early squamous cell carcinoma of the uterine cervix, the outcome is similar after either primary surgery or primary radiotherapy. There are reports that this is not the case for early adenocarcinoma (AC) of the uterine cervix: some studies have reported that the outcome is better after primary surgery. There are no systematic reviews about surgery versus chemoradiation in the treatment of cervical cancer. This is an updated version of the original Cochrane review published in Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006248. DOI: 10.1002/14651858.CD006248. OBJECTIVES: The objectives of this review were to compare the effectiveness and safety of primary surgery for early stage AC of the uterine cervix with primary radiotherapy or chemoradiation. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, MEDLINE (1950 to July week 5, 2009), EMBASE (1980 to week 32, 2009) and we also searched the related articles feature of PubMed and the Web of Science. We also checked the reference lists of articles. For this update, the searches were re-run in June 2012: MEDLINE 2009 to June week 2, 2012, EMBASE 2009 to 2012 week 24, CENTRAL Issue 6, 2012, Cochrane Gynaecological Specialised Register June 2012. SELECTION CRITERIA: Studies of treatment of patients with early AC of the uterine cervix were included. Treatment included surgery, surgery followed by radiotherapy, radiotherapy and chemoradiation. DATA COLLECTION AND ANALYSIS: Forty-three studies were selected by the search strategy and 30 studies were excluded. Twelve studies were considered for inclusion. Except for one randomised controlled trial (RCT), all other studies were retrospective cohort studies with variable methodological quality and had limitations of a retrospective study. Comparing the results from these retrospective studies was not possible due to diverging treatment strategies. MAIN RESULTS: Analysis of a subgroup of one RCT showed that surgery for early cervical AC was better than radiotherapy. However, the majority of operated patients required adjuvant radiotherapy, which is associated with greater morbidity. Furthermore, the radiotherapy in this study was not optimal, and surgery was not compared to chemoradiation, which is currently recommended in most centres. Finally, modern imaging techniques (i.e. magnetic resonance imaging (MRI) and positive emission tomography - computed tomography (PET-CT) scanning) allow better selection of patients and node-negative patients can now be more easily identified for surgery, thereby reducing the risk of 'double trouble' caused by surgery and adjuvant radiotherapy. AUTHORS' CONCLUSIONS: We recommend surgery for early-stage AC of the uterine cervix in carefully staged patients. Primary chemoradiation remains a second best alternative for patients unfit for surgery; chemoradiation is probably first choice in patients with (MRI or PET-CT suspected) positive lymph nodes. Since the last version of this review no new studies were found. PMID- 23440806 TI - Use of plastic adhesive drapes during surgery for preventing surgical site infection. AB - BACKGROUND: Surgical site infection has been estimated to occur in about 15% of clean surgery and 30% of contaminated surgery cases. Using plastic adhesive drapes to protect the wound from organisms that may be present on the surrounding skin during surgery is one strategy used to prevent surgical site infection. Results from non-randomised studies have produced conflicting results about the efficacy of this approach, but no systematic review has been conducted to date to guide clinical practice. OBJECTIVES: To assess the effect of adhesive drapes used during surgery on surgical site infection, cost, mortality and morbidity. SEARCH METHODS: For this third update we searched the Cochrane Wounds Group Specialised Register (searched 19 July 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7); Ovid MEDLINE (1946 to July Week 2, 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, July 18, 2012); Ovid EMBASE (1974 to Week 28, 2012); and EBSCO CINAHL (1982 to July 6, 2012). SELECTION CRITERIA: Randomised controlled trials comparing any plastic adhesive drape with no plastic adhesive drape, used alone or in combination with woven (material) drapes or disposable (paper) drapes, in patients undergoing any type of surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and assessed studies for trial quality and both independently extracted data. We contacted study authors for additional information. MAIN RESULTS: We identified no new studies for this third update. The review includes five studies involving 3082 participants comparing plastic adhesive drapes with no drapes and two studies involving 1113 participants comparing iodine-impregnated adhesive drapes with no drapes. A significantly higher proportion of patients in the adhesive drape group developed a surgical site infection when compared with no drapes (risk ratio (RR) 1.23, 95% confidence interval (CI) 1.02 to 1.48, P = 0.03). Iodine-impregnated adhesive drapes had no effect on the surgical site infection rate (RR 1.03, 95% CI 0.06 to 1.66, P = 0.89). Length of hospital stay was similar in the adhesive drape and non-adhesive drape groups. AUTHORS' CONCLUSIONS: There was no evidence from the seven trials that plastic adhesive drapes reduce surgical site infection rates, and some evidence that they increase infection rates. Further trials may be justified, using blinded outcome assessment to examine the effect of adhesive drapes on surgical site infection, based on different wound classifications. PMID- 23440807 TI - Educational games for health professionals. AB - BACKGROUND: The use of games as an educational strategy has the potential to improve health professionals' performance (e.g. adherence to standards of care) through improving their knowledge, skills and attitudes. OBJECTIVES: The objective was to assess the effect of educational games on health professionals' performance, knowledge, skills, attitude and satisfaction, and on patient outcomes. SEARCH METHODS: We searched the following databases in January 2012: MEDLINE, AMED, CINAHL, Cochrane Central Database of Controlled Trials, EMBASE, EPOC Register, ERIC, Proquest Dissertations & Theses Database, and PsycINFO. Related reviews were sought in DARE and the above named databases. Database searches identified 1546 citations. We also screened the reference lists of included studies in relevant reviews, contacted authors of relevant papers and reviews, and searched ISI Web of Science for papers citing studies included in the review. These search methods identified an additional 62 unique citations for a total of 1608 for this update. SELECTION CRITERIA: We included randomized controlled trials (RCT), controlled clinical trials (CCT), controlled before and after (CBA) and interrupted time-series analysis (ITS). Study participants were qualified health professionals or in postgraduate training. The intervention was an educational game with "a form of competitive activity or sport played according to rules". DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest that included patient outcomes, professional behavior (process of care outcomes), and professional's knowledge, skills, attitude and satisfaction. MAIN RESULTS: The search strategy identified a total of 2079 unique citations. Out of 84 potentially eligible citations, we included two RCTs. The game evaluated in the first study used as a reinforcement technique, was based on the television game show "Family Feud" and focused on infection control. The study did not assess any patient or process of care outcomes. The group that was randomized to the game had statistically higher scores on the knowledge test (P = 0.02). The second study compared game-based learning ("Snakes and Ladders" board game) with traditional case-based learning of stroke prevention and management. The effect on knowledge was not statistically different between the two groups immediately and 3 months after the intervention. The level of reported enjoyment was higher in the game-based group. AUTHORS' CONCLUSIONS: The findings of this systematic review neither confirm nor refute the utility of games as a teaching strategy for health professionals. There is a need for additional high-quality research to explore the impact of educational games on patient and performance outcomes. PMID- 23440808 TI - Intravitreal low molecular weight heparin and 5-Fluorouracil for the prevention of proliferative vitreoretinopathy following retinal reattachment surgery. AB - BACKGROUND: Proliferative vitreoretinopathy (PVR) is a significant cause of failure in retinal reattachment surgery. Various pharmacological agents have shown potential benefit in reducing postoperative PVR risk. OBJECTIVES: This review aimed to compare the use of intravitreal low molecular weight heparin (LMWH) alone or with 5-Fluorouracil (5-FU) versus placebo, as an adjunct in the prevention of PVR following retinal reattachment surgery. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), MEDLINE (January 1950 to October 2012), EMBASE (January 1980 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 October 2012. SELECTION CRITERIA: We only included randomised controlled trials (RCTs) that compared intravitreal LMWH alone or with 5-FU, versus placebo for the prevention of postoperative PVR in patients undergoing primary vitrectomy for rhegmatogenous retinal detachment repair. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information. MAIN RESULTS: We included two RCTs (with a total of 789 participants) comparing LMWH with 5-FU infusion and placebo. However, we did not perform a meta-analysis because of significant heterogeneity between these studies. One study found a significant beneficial effect of LMWH with 5-FU in reducing postoperative PVR compared to placebo (RR: 0.48, 95% confidence interval: 0.25 to 0.92), in 174 patients who were viewed at high-risk of developing postoperative PVR. The other study included 615 unselected cases of rhegmatogenous retinal detachment and could not show a difference between LMWH with 5-FU infusion and placebo in reducing PVR rates (RR:1.45, 95% confidence interval: 0.76 to 2.76). AUTHORS' CONCLUSIONS: Results from this review indicate that there is inconsistent evidence from two studies on patients at different risk of PVR on the effect of LMWH and 5-FU used during vitrectomy to prevent PVR. Future research should be conducted on high risk patients only, until a benefit is confirmed at least in this patient subgroup. PMID- 23440809 TI - Homocysteine-lowering interventions for preventing cardiovascular events. AB - BACKGROUND: Cardiovascular disease (including coronary artery disease, stroke and congestive heart failure), is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor is elevated circulating total homocysteine levels, which are associated with cardiovascular events. This is an update of a review previously published in 2009. OBJECTIVES: To assess the clinical effectiveness of homocysteine-lowering interventions in people with or without pre-existing cardiovascular disease. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2012, Issue 2), MEDLINE (1950 to Feb week 2 2012), EMBASE (1980 to 2012 week 07), and LILACS (1986 to February 2012). We also searched ISI Web of Science (1970 to February 2012). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using I(2). We used a random-effects model. MAIN RESULTS: In this updated systematic review, we identified four new randomised trials, resulting in a total of 12 randomised controlled trials involving 47,429 participants. In general terms, the trials had a low risk of bias. Homocysteine-lowering interventions compared with placebo did not significantly affect non-fatal or fatal myocardial infarction (pooled RR 1.02, 95% CI 0.95 to 1.10, I(2) = 0%), stroke (pooled RR 0.91, 95% CI 0.82 to 1.0, I(2) = 11%) or death by any cause (pooled RR 1.01 (95% CI 0.96 to 1.07, I(2): 6%)). Homocysteine-lowering interventions compared with placebo did not significantly affect serious adverse events (cancer) (1 RR 1.06, 95% CI 0.98 to 1.13; I(2) = 0%). AUTHORS' CONCLUSIONS: This updated Cochrane review found no evidence to suggest that homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination should be used for preventing cardiovascular events. Furthermore, there is no evidence suggesting that homocysteine-lowering interventions are associated with an increased risk of cancer. PMID- 23440810 TI - Thyroid hormones for acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI), which is common in hospitalised patients, is associated with significant morbidity and mortality. Despite recent advances in treatment, AKI outcomes have not changed substantially during the past four decades, and incidence is increasing. There is an urgent need to explore novel therapeutic agents and revisit some older drugs to review their roles in the management of AKI. Although thyroid hormone therapy has shown promise in experimental animal studies, clinical efficacy and safety have not been systematically assessed for the management of people with AKI. OBJECTIVES: To evaluate the benefits and harms of thyroid hormones for the treatment of hospitalised adults with AKI of any aetiology. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, and EMBASE. We also checked the reference lists of retrieved studies and articles.Date of search: November 2012 SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs (in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that compared any dose or form of thyroid hormone therapy alone or in combination with other agents compared with placebo or supplemental treatment (such as furosemide, dopamine, or atrial natriuretic peptide) in adult AKI patients. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. The quality of included studies was assessed using the Cochrane Collaboration's risk of bias assessment tool. For dichotomous outcomes (death, need for renal replacement therapy (RRT), progression to end-stage kidney disease (ESKD)), we planned to express results as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (length of hospital stay, durations of AKI and RRT), we planned to use the mean difference (MD). MAIN RESULTS: Two studies, enrolling 97 participants, met our inclusion criteria. The studies differed significantly in terms of study populations, natural history of AKI (multifactorial AKI in patients with native kidneys versus delayed graft function associated with acute tubular necrosis in transplant recipients), and study interventions; hence, data were not meta-analysed. One study reported a significant increase in the risk of all-cause mortality associated with thyroid hormone interventions compared with placebo (59 participants, RR 3.32, 95% CI 1.21 to 9.12); no deaths were reported in the other study. Both studies reported no significant difference in the need for RRT associated with thyroid hormone therapy when compared to placebo. Neither study reported incidence of progression to ESKD. There was a significantly longer duration of AKI (MD 2.00 days, 95% CI 0.18 to 3.82) and RRT (5.00 days, 95% CI 2.05 to 7.95) associated with thyroid hormone therapy compared with placebo in one study; no differences in durations of AKI (MD 2.00 days, 95% CI -3.53 to 7.53) and RRT (MD 2.00 days, 95% CI -2.36 to 6.36) were noted in the other study. One study reported similar lengths of stay in the intensive care unit and hospital in both intervention and control arms (MD -0.20 days, 95% CI -8.17 to 7.77); the other did not report this outcome. No adverse events were noted to be associated with thyroid hormone therapy in either study. Adequate data were not available to assess changes in kidney function or numbers of RRT sessions. Both included studies were small and methodological quality was suboptimal. AUTHORS' CONCLUSIONS: We found a paucity of large, high quality studies to inform analysis of thyroid hormone interventions for the treatment of people with AKI. Current evidence suggested that thyroid hormone therapy may be associated with worse outcomes for patients with established AKI; therefore, its use for these patients should be avoided. The role of thyroid hormone therapy in preventing AKI has not been adequately investigated and may be considered in future clinical studies. PMID- 23440811 TI - Intravenous immunoglobulin as adjuvant therapy for Wegener's granulomatosis. AB - BACKGROUND: Wegener's granulomatosis (WG) is a necrotizing small-vessel vasculitis that can affect any organ in the body but mainly affects the upper and lower respiratory tract, the kidneys, joints, skin and eyes. The current mainstay of remission induction therapy is systemic corticosteroids in combination with oral daily cyclophosphamide (CYC) which induces remission in 75% to 100% of cases. Although standard therapy is effective in inducing partial or complete remission, 50% of complete remissions are followed by at least one relapse. This is an update of a review first published in 2009. OBJECTIVES: To determine if intravenous immunoglobulin (IVIg) adjuvant therapy provides a therapeutic advantage over and above treatment with systemic corticosteroids in combination with immunosuppressants for the treatment of WG. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched November 2012) and CENTRAL (2012, Issue 11). Trial databases were searched by the TSC for details of ongoing and unpublished studies. No date or language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials (RCTs), or quasi RCTs, or randomized cross over trials. Participants had to be adults with a confirmed diagnosis of WG. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Relative risk was used to analyze dichotomous variables, and mean difference (MD) was used to analyze continuous variables. MAIN RESULTS: We included one RCT with 34 participants who were randomly assigned to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. There were no significant differences between adjuvant IVIg and adjuvant placebo in mortality, serious adverse events, time to relapse, open label rescue therapy, and infection rates. The fall in disease activity score, derived from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95% Confidence interval (CI) 1.12 to 3.48, P < 0.01) and three months (MD 1.80; 95% CI 0.35 to 3.25, P = 0.01). There was a significant increase in total adverse events in the IVIg group (relative risk (RR) 3.50; 95% CI 1.44 to 8.48, P < 0.01). AUTHORS' CONCLUSIONS: There is insufficient evidence from one RCT that IVIg adjuvant therapy provides a therapeutic advantage compared with the combination of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2 g/kg for a 70 kg patient = $8,400), it should be limited to treat WG in the context of a well conducted RCT powered to detect patient-relevant outcomes. PMID- 23440812 TI - Interventions for HIV-associated nephropathy. AB - BACKGROUND: Human immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of end stage kidney disease (ESKD) in human immunodeficiency virus-1 (HIV-1) serotype patients and it mostly affects patients of African descent. It rapidly progresses to ESKD if untreated. The goal of treatment is directed toward reducing HIV-1 replication and/or slowing the progression of chronic kidney disease. The following pharmacological agents have been used for the treatment of HIVAN: antiretroviral therapy, angiotensin-converting enzyme inhibitors (ACEi), steroids and recently cyclosporin. Despite this, the effect of each intervention is yet to be evaluated. OBJECTIVES: To evaluate the benefits and harms of adjunctive therapies in the management of HIVAN and its effects on symptom severity and all-cause mortality. SEARCH METHODS: In January 2012 we searched the Cochrane Renal Group's Specialised Register, AIDS Education Global Information System (AEGIS database), ClinicalTrial.gov, the WHO International Clinical Trials Registry Portal, and reference lists of retrieved articles without language restrictions. In our original review we searched CENTRAL, MEDLINE, EMBASE, and AIDSearch, in addition to contacting individual researchers, research organisations and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of any therapy used in the treatment of HIVAN. DATA COLLECTION AND ANALYSIS: We independently screened the search outputs for relevant studies and to retrieve full articles when necessary. For dichotomous outcomes results were to be expressed as risk ratios with 95% confidence intervals, and for continuous scales of measurement the mean difference was to be used. MAIN RESULTS: We identified four relevant ongoing studies: one is still ongoing; two have completed recruitment but are yet to be published; and the fourth study was suspended for unspecified reasons. No completed RCTs or quasi-RCTs were identified. We summarised and tabulated the data from the observational studies, however no formal analyses were performed. AUTHORS' CONCLUSIONS: There is currently no RCT-based evidence upon which to base guidelines for the treatment of HIVAN, however three ongoing studies have been identified. Data from observational studies suggest steroids and angiotensin converting enzyme inhibitors appear to improve kidney function in patients with HIVAN, however no formal analyses were performed in this review. This review highlights the need for good quality RCTs to address the effects of interventions for treating this group. PMID- 23440813 TI - Cervical assessment by ultrasound for preventing preterm delivery. AB - BACKGROUND: Measurement of cervical length (CL) by transvaginal ultrasound (TVU) is predictive of preterm birth (PTB). It is unclear if this screening test is effective for prevention of PTB. OBJECTIVES: To assess the effectiveness of antenatal management based on transvaginal ultrasound of cervical length (TVU CL) screening for preventing PTB. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2012), reviewed the reference lists of all articles and contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: Published and unpublished randomized controlled trials including pregnant women between the gestational ages of 14 to 32 weeks screened with TVU CL for risk of PTB. This review focuses exclusively on studies based on knowledge versus no knowledge of TVU CL results. DATA COLLECTION AND ANALYSIS: All potential studies identified from the search were independently assessed for inclusion by three review authors. We also analyzed studies for quality measures and extracted data. MAIN RESULTS: Of the 13 trials identified, five were eligible for inclusion (n = 507). Three included singleton gestations with preterm labor (PTL); one included singleton gestations with preterm premature rupture of membranes (PPROM); and one included twin gestations with or without PTL.In the three trials of singleton gestations with PTL, 290 women were randomized; 147 to knowledge and 143 to no knowledge of TVU CL. Knowledge of TVU CL results was associated with a non-significant decrease in PTB at less than 37 weeks (22.3% versus 34.7%, respectively; average risk ratio 0.59, 95% confidence interval (CI) 0.26 to 1.32; two trials, 242 women) and at less than 34 weeks (6.9% verus 12.6%; RR 0.55, 95% CI 0.25 to 1.20; three trials, 256 women). Delivery occurred at a later gestational age in the knowledge versus no knowledge groups (mean difference (MD) 0.64 weeks, 95% CI 0.03 to 1.25; three trials, 290 women). For all other outcomes for which there were available data (PTB at less than 34 or 28 weeks; birthweight less than 2500 grams; perinatal death; maternal hospitalization; tocolysis; and steroids for fetal lung maturity), there was no evidence of a difference between groups.The trial of singleton gestations with PPROM (n = 92) evaluated as its primary outcome safety of TVU CL in this population, and not its effect on management. There was no evidence of a difference in incidence of maternal and neonatal infections between the TVU CL and no TVU CL groups.In the trial of twin gestations with or without PTL (n = 125), there was no evidence of a difference in PTB at less than 36, 34, or 30 weeks, gestational age at delivery, and other perinatal and maternal outcomes between the TVU CL and the no TVU CL groups. Life-table analysis revealed significantly less PTB at less than 35 weeks in the TVU CL group compared with the no TVU CL group (P = 0.02). AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with TVU CL. Since there is a non-significant association between knowledge of TVU CL results and a lower incidence of PTB at less than 37 weeks in symptomatic women, we encourage further research. Future studies should look at specific populations separately (e.g., singleton versus twins; symptoms of PTL or no such symptoms), report on all pertinent maternal and perinatal outcomes, and include cost-effectiveness analyses. Most importantly, future studies should include a clear protocol for management of women based on TVU CL results, so that it can be easily evaluated and replicated. PMID- 23440814 TI - Vigabatrin for refractory partial epilepsy. AB - BACKGROUND: Epilepsy is a common neurological condition which affects between 0.5% and 1% of the population. Approximately 30% of people with epilepsy do not respond to treatment with currently available drugs. The majority of these people have partial epilepsy. Vigabatrin is an antiepileptic drug licensed for use in the treatment of refractory epilepsy. No major side effects associated with the use of vigabatrin were detected by initial randomised controlled trials of the drug. However, longer-term observational studies have subsequently identified that its use is associated with asymptomatic visual field constriction. OBJECTIVES: The objective of this review was to synthesise evidence from short term, randomised, placebo-controlled trials of vigabatrin. We summarised the effects of vigabatrin on seizures and short-term side effects when used as an add on treatment for people with drug-resistant partial epilepsy. A review of longer term observational studies and estimates of proportions of patients developing visual field constrictions is currently being undertaken and results will be cited in this review in due course. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (12 October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 9), MEDLINE (1946 to October week 1, 2012) and reference lists of articles. We also contacted the manufacturers of vigabatrin (Hoechst Marion Roussel). SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors assessed trials for inclusion and extracted data. Primary analysis was by intention-to-treat (ITT). Outcomes evaluated included 50% or greater reduction in seizure frequency, treatment withdrawal and side effects observable in the short term. Results are presented on the risk ratio (RR) scale with 95% or 99% confidence intervals (CI). MAIN RESULTS: Eleven suitable trials that tested vigabatrin doses between 1000 mg and 6000 mg were identified and included in the analysis. There were 982 observations on 747 patients in the primary ITT analysis of treatment efficacy. Patients treated with vigabatrin were significantly more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.58, 95% CI 1.87 to 3.57). Those treated with vigabatrin were also significantly more likely to have treatment withdrawn (RR 2.49, 95% CI 1.05 to 5.88), and were more likely to experience a number of side effects, significantly so for fatigue or drowsiness. There was some evidence of small study effect bias, with smaller studies tending to report greater estimates of RR than larger studies. It is possible, therefore, that the actual RR of obtaining 50% reduction in seizure frequency is less than that obtained by a meta-analysis of fully published studies. AUTHORS' CONCLUSIONS: This review of randomised controlled trials showed that vigabatrin can reduce seizure frequency in people with drug-resistant partial epilepsy. Short-term follow-up of patients showed that some side effects were associated with its use. Further analysis of longer-term observational studies is required to evaluate how likely patients are to develop visual field defects and whether such side effects are associated with dose and duration of drug use. PMID- 23440815 TI - Intrapartum antibiotics for known maternal Group B streptococcal colonization. AB - BACKGROUND: Maternal colonization with group B streptococcus (GBS) during pregnancy increases the risk of neonatal infection by vertical transmission. Administration of intrapartum antibiotic prophylaxis (IAP) during labor has been associated with a reduction in early onset GBS disease (EOGBSD). However, treating all colonized women during labor exposes a large number of women and infants to possible adverse effects without benefit. OBJECTIVES: To assess the effect of IAP for maternal GBS colonization on neonatal: 1) all cause mortality and 2) morbidity from proven and probable EOGBSD, late onset GBS disease (LOD), maternal infectious outcomes and allergic reactions to antibiotics. SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 10 November 2012. SELECTION CRITERIA: Randomized trials assessing the impact of maternal IAP on neonatal GBS infections were included. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility and quality of the studies. MAIN RESULTS: We did not identify any new trials from the updated search so the results remain unchanged as follows.Three trials (involving 852 women) evaluating the effects of IAP versus no treatment were included. The risk of bias was high. The use of IAP did not significantly reduce the incidence of all cause mortality, mortality from GBS infection or from infections caused by bacteria other than GBS. The incidence of early GBS infection was reduced with IAP compared to no treatment (risk ratio 0.17, 95% confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI 14 to 100, I(2) 0%). The incidence of LOD or sepsis from organisms other than GBS and puerperal infection was not significantly different between groups.One trial (involving 352 women) compared intrapartum ampicillin versus penicillin and reported no significant difference in neonatal or maternal outcomes. AUTHORS' CONCLUSIONS: Intrapartum antibiotic prophylaxis appeared to reduce EOGBSD, but this result may well be a result of bias as we found a high risk of bias for one or more key domains in the study methodology and execution. There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD.Ideally the effectiveness of IAP to reduce neonatal GBS infections should be studied in adequately sized double-blind controlled trials. The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions. PMID- 23440816 TI - Interventions for nail psoriasis. AB - BACKGROUND: Psoriasis is a common skin disease that can also involve the nails. All parts of the nail and surrounding structures can become affected. The incidence of nail involvement increases with duration of psoriasis. Although it is difficult to treat psoriatic nails, the condition may respond to therapy. OBJECTIVES: To assess evidence for the efficacy and safety of the treatments for nail psoriasis. SEARCH METHODS: We searched the following databases up to March 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched trials databases and checked the reference lists of retrieved studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: All RCTs of any design concerning interventions for nail psoriasis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial risk of bias and extracted the data. We collected adverse effects from the included studies. MAIN RESULTS: We included 18 studies involving 1266 participants. We were not able to pool due to the heterogeneity of many of the studies.Our primary outcomes were 'Global improvement of nail psoriasis as rated by a clinician', 'Improvement of nail psoriasis scores (NAS, NAPSI)', 'Improvement of nail psoriasis in the participant's opinion'. Our secondary outcomes were 'Adverse effects (and serious adverse effects)'; 'Effects on quality of life'; and 'Improvement in nail features, pain score, nail thickness, thickness of subungual hyperkeratosis, number of affected nails, and nail growth'. We assessed short term (3 to 6 months), medium-term (6 to 12 months), and long-term (> 12 months) treatments separately if possible.Two systemic biologic studies and three radiotherapy studies reported significant results for our first two primary outcomes. Infliximab 5 mg/kg showed 57.2% nail score improvement versus -4.1% for placebo (P < 0.001); golimumab 50 mg and 100 mg showed 33% and 54% improvement, respectively, versus 0% for placebo (P < 0.001), both after medium-term treatment. Infliximab and golimumab also showed significant results after short term treatment. From the 3 radiotherapy studies, only the superficial radiotherapy (SRT) study showed 20% versus 0% nail score improvement (P = 0.03) after short-term treatment.Studies with ciclosporin, methotrexate, and ustekinumab were not significantly better than their respective comparators: etretinate, ciclosporin, and placebo. Nor were studies with topical interventions (5-fluorouracil 1% in Belanyx(r) lotion, tazarotene 0.1% cream, calcipotriol 50 ug/g, calcipotriol 0.005%) better than their respective comparators: Belanyx(r) lotion, clobetasol propionate, betamethasone dipropionate with salicylic acid, or betamethasone dipropionate.Of our secondary outcomes, not all included studies reported adverse events; those that did only reported mild adverse effects, and there were more in studies with systemic interventions. Only one study reported the effect on quality of life, and two studies reported nail improvement only per feature. AUTHORS' CONCLUSIONS: Infliximab, golimumab, SRT, grenz rays, and electron beam caused significant nail improvement compared to the comparative treatment. Although the quality of trials was generally poor, this review may have some implications for clinical practice.Although powerful systemic treatments have been shown to be beneficial, they may have serious adverse effects. So they are not a realistic option for people troubled with nail psoriasis, unless the patient is prescribed these systemic treatments because of cutaneous psoriasis or psoriatic arthritis or the nail psoriasis is severe, refractory to other treatments, or has a major impact on the person's quality of life. Because of their design and timescale, RCTs generally do not pick up serious side-effects. This review reported only mild adverse effects, recorded mainly for systemic treatments. Radiotherapy for psoriasis is not used in common practice. The evidence for the use of topical treatments is inconclusive and of poor quality; however, this does not imply that they do not work.Future trials need to be rigorous in design, with adequate reporting. Trials should correctly describe the participants' characteristics and diagnostic features, use standard validated nail scores and participant-reported outcomes, be long enough to report efficacy and safety, and include details of effects on nail features. PMID- 23440817 TI - Pharmacological therapies for maintenance treatments of opium dependence. AB - BACKGROUND: Pharmacologic therapies for maintenance treatment of heroin dependence have been used and studied widely. Systematic reviews have demonstrated the effectiveness of such therapies. Opium dependence is associated with less problems and impairments and is less likely to be used by injecting, with consequent reductions in risk of overdose and blood-borne diseases. Although it is a common substance use disorder in many countries, a systematic review of the literature is lacking on the maintenance treatment for opium dependence. OBJECTIVES: To evaluate the effectiveness and safety of various pharmacological therapies on maintenance of opium dependence (alone or in combination with psychosocial interventions) compared to no intervention, detoxification, different doses of the same intervention, other pharmacologic interventions and any psychosocial interventions. SEARCH METHODS: We searched the following sources up to February 2012: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, regional databases (IMEMR and ASCI), national databases (Iranmedex and Iranpsych), main electronic sources of ongoing trials and reference lists of all relevant papers. Also, we contacted known investigators from some Asian countries to obtain details about unpublished trials. SELECTION CRITERIA: Randomised controlled clinical trials (RCTs) comparing any maintenance pharmacologic intervention versus no intervention, other pharmacologic or non-pharmacologic intervention for opium dependence. DATA COLLECTION AND ANALYSIS: Two reviewers assessed the risks of biases and extracted data, independently. MAIN RESULTS: Three RCTs recruiting 870 opium dependents were included. The studies made different comparisons so it was not possible to pool data. Only retention rate was assessed by the studies. Two studies compared different doses of buprenorphine: in one study, 4 mg/day of buprenorphine was compared with doses of 2 mg/day and 1 mg/day and in another study, 8 mg/day of buprenorphine was compared with doses of 3 mg/day and 1 mg/day. Comparisons showed a statistically significant difference between groups; higher doses of buprenorphine increased the probability of retention in treatment. The studies had high risks of biases. In the third study, after a process of detoxification, baclofen (60 mg/day) was compared with placebo for maintenance treatment. The difference in retention rate between groups was high, but it was not statistically significant. AUTHORS' CONCLUSIONS: It is not possible to conclude about the use of any kind of pharmacologic therapies for maintenance treatment of opium dependence. PMID- 23440818 TI - Intramuscular versus intravenous anti-D for preventing Rhesus alloimmunization during pregnancy. AB - BACKGROUND: Antibodies to the red cell Rhesus D (RhD) antigen can be produced during pregnancy in a RhD-negative mother carrying a RhD-positive fetus, in particular following feto-maternal haemorrhage at birth or following any procedure that may cause feto-maternal haemorrhage. While the first baby is usually not harmed, these antibodies may cause haemolytic disease of the fetus/newborn (HDFN) in subsequent RhD-positive babies. RhD incompatibility is a major cause of HDFN.To reduce the risk of HDFN, anti-D is given to RhD-negative mothers at 28 or 30 weeks of pregnancy and within 72 hours of potential maternal exposure to fetal red cells. Anit-D is currently available in both intramuscular (IM) and intravenous (IV) preparations. OBJECTIVES: To compare the efficacy and effectiveness of IM versus IV anti-D IgG in preventing RhD alloimmunization in RhD-negative pregnant women. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2012). SELECTION CRITERIA: Randomized controlled trials, quasi-randomized trials and cluster-randomized trials comparing IM and IV anti-D for preventing RhD alloimmunization in RhD negative pregnant women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. Two review authors extracted data. Data were checked for consistency by both authors. MAIN RESULTS: Two studies involving 447 (with sample sizes 14 and 432) RhD negative women were included. The studies compared IM and IV administration of anti-D prophylaxis. In both studies the women received a 1500 IU (300 microgram) dose of Rhophylac during week 28 of gestation. There was no incidence of RhD alloimmunization in either of the studies, as the sample size was insufficient for meaningful comparison of this uncommon outcome. One of the studies found that the mean anti-D IgG concentrations after IV and IM administration differed up to seven days (36.1 (2.6) ng/mL IV; 19.8 (8.7) ng/mL IM on day seven). However, from two to three weeks post-administration, the concentrations were similar for both routes of administration. None of the women involved in the studies developed antibodies against the RhD antigen. AUTHORS' CONCLUSIONS: It appears that IM and IV administration of anti-D are equally effective. The number of included studies and the number of participants are not enough to assess whether there are any differences. Anti-D can be administered by IM or IV injection. The choice of IM or IV route of administration will depend on the available preparations, the dose to be administered and also on the patients' preferences. This review found insufficient information upon which to guide practice due to the limited number of included studies, small sample sizes and methodological limitations. PMID- 23440819 TI - Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. AB - BACKGROUND: Cesarean delivery is one of the most common surgical procedures performed by obstetricians. Infectious morbidity after cesarean delivery can have a tremendous impact on the postpartum woman's return to normal function and her ability to care for her baby. Despite the widespread use of prophylactic antibiotics, postoperative infectious morbidity still complicates cesarean deliveries. OBJECTIVES: To determine if cleansing the vagina with an antiseptic solution before a cesarean delivery decreases the risk of maternal infectious morbidities, including endometritis and wound complications. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (8 August 2012). SELECTION CRITERIA: We included randomized and quasi-randomized trials assessing the impact of vaginal cleansing immediately before cesarean delivery with any type of antiseptic solution versus a placebo solution/standard of care on post-cesarean infectious morbidity. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility and quality of the studies. MAIN RESULTS: Five trials randomizing 1946 women (1766 analyzed) evaluated the effects of vaginal cleansing (all with povidone-iodine) on post-cesarean infectious morbidity. The risk of bias was generally low, with the quality of most of the studies being high. Vaginal preparation immediately before cesarean delivery significantly reduced the incidence of post-cesarean endometritis from 7.2% in control groups to 3.6% in vaginal cleansing groups (average risk ratio (RR) 0.39, 95% confidence interval (CI) 0.16 to 0.97, five trials, 1766 women). The risk reduction was particularly strong for women with ruptured membranes (1.4% in the vaginal cleansing group versus 15.4% in the control group; RR 0.13, 95% CI 0.02 to 0.66, two trials, 148 women). No other outcomes realized statistically significant differences between the vaginal cleansing and control groups. No adverse effects were reported with the povidone-iodine vaginal cleansing. AUTHORS' CONCLUSIONS: Vaginal preparation with povidone-iodine solution immediately before cesarean delivery reduces the risk of postoperative endometritis. This benefit is particularly realized for women undergoing cesarean delivery with ruptured membranes. As a simple, generally inexpensive intervention, providers should consider implementing preoperative vaginal cleansing with povidone-iodine before performing cesarean deliveries. PMID- 23440820 TI - Enteral feeding methods for nutritional management in patients with head and neck cancers being treated with radiotherapy and/or chemotherapy. AB - BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 3, 2010.For many patients with head and neck cancer, oral nutrition will not provide adequate nourishment during treatment with radiotherapy or chemoradiotherapy due to the acute toxicity of treatment, obstruction caused by the tumour, or both. The optimal method of enteral feeding for this patient group has yet to be established. OBJECTIVES: To compare the effectiveness of different enteral feeding methods used in the nutritional management of patients with head and neck cancer receiving radiotherapy or chemoradiotherapy using the clinical outcomes, nutritional status, quality of life and rates of complications. SEARCH METHODS: Our extensive search included the Cochrane ENT Group Trials Register, CENTRAL, PubMed, EMBASE, CINAHL, AMED and ISI Web of Science. The date of the most recent search was 13 February 2012. SELECTION CRITERIA: Randomised controlled trials comparing one method of enteral feeding with another, e.g. nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) feeding, for adult patients with a diagnosis of head and neck cancer receiving radiotherapy and/or chemoradiotherapy. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data using standardised forms. We contacted study authors for additional information. MAIN RESULTS: One randomised controlled trial met the criteria for inclusion in this review. No further studies were identified when we updated the searches in 2012.Patients diagnosed with head and neck cancer, being treated with chemoradiotherapy, were randomised to PEG or NG feeding. In total only 33 patients were eligible for analysis as the trial was terminated early due to poor accrual. A high degree of bias was identified in the study.Weight loss was greater for the NG group at six weeks post-treatment than for the PEG group (P = 0.001). At six months post-treatment, however, there was no significant difference in weight loss between the two groups. Anthropometric measurements recorded six weeks post-treatment demonstrated lower triceps skin fold thickness for the NG group compared to the PEG group (P = 0.03). No statistically significant difference was found between the two different enteral feeding techniques in relation to complication rates or patient satisfaction. The duration of PEG feeding was significantly longer than for the NG group (P = 0.0006). In addition, the study calculated the cost of PEG feeding to be 10 times greater than that of NG, though this was not found to be significant. There was no difference in the treatment received by the two groups. However, four PEG fed patients and two NG fed patients required unscheduled treatment breaks of a median of two and six days respectively.We identified no studies of enteral feeding involving any form of radiologically inserted gastrostomy (RIG) feeding or comparing prophylactic PEG versus PEG for inclusion in the review. AUTHORS' CONCLUSIONS: There is not sufficient evidence to determine the optimal method of enteral feeding for patients with head and neck cancer receiving radiotherapy and/or chemoradiotherapy. Further trials of the two methods of enteral feeding, incorporating larger sample sizes, are required. PMID- 23440821 TI - Skin preparation with alcohol versus alcohol followed by any antiseptic for preventing bacteraemia or contamination of blood for transfusion. AB - BACKGROUND: Blood for transfusion may become contaminated at any point between collection and transfusion and may result in bacteraemia (the presence of bacteria in the blood), severe illness or even death for the blood recipient. Donor arm skin is one potential source of blood contamination, so it is usual to cleanse the skin with an antiseptic before blood donation. One-step and two-step alcohol based antiseptic regimens are both commonly advocated but there is uncertainty as to which is most effective. OBJECTIVES: To assess the effects of cleansing the skin of blood donors with alcohol in a one-step compared with alcohol in a two-step procedure to prevent contamination of collected blood or bacteraemia in the recipient. SEARCH METHODS: For this second update we searched the Cochrane Wounds Group Specialised Register (searched 20 November 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) The Cochrane Library 2012, Issue 11; Ovid MEDLINE (20011 to November Week 2 2012); Ovid MEDLINE (In Process & Other Non-Indexed Citations November 20, 2012); Ovid EMBASE ( 20011 to 2012 Week 46); and EBSCO CINAHL ( 2008 to 15 November 2012). SELECTION CRITERIA: All randomised trials (RCTs) comparing alcohol based donor skin cleansing in a one-step versus a two-step process that includes alcohol and any other antiseptic for pre-venepuncture skin cleansing were considered. Quasi randomised trials were to have been considered in the absence of RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. MAIN RESULTS: No studies (RCTs or quasi RCTs) met the inclusion criteria. AUTHORS' CONCLUSIONS: We did not identify any eligible studies for inclusion in this review. It is therefore unclear whether a two-step, alcohol followed by antiseptic skin cleansing process prior to blood donation confers any reduction in the risk of blood contamination or bacteraemia in blood recipients, or conversely whether a one-step process increases risk above that associated with a two-step process. PMID- 23440822 TI - Acupuncture for hypoxic ischemic encephalopathy in neonates. AB - BACKGROUND: Hypoxic ischemic encephalopathy (HIE) in the neonate is associated with high mortality and morbidity. Effective treatment options are limited and therefore alternative therapies such as acupuncture are increasingly used. OBJECTIVES: We sought to determine the efficacy and safety of acupuncture on mortality and morbidity in neonates with HIE. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Cochrane Neonatal Specialized Register, MEDLINE, AMED, EMBASE, PubMed, CINAHL, PsycINFO, WHO International Clinical Trials Registry Platform, and various Chinese medical databases in November 2012. SELECTION CRITERIA: We planned to include randomized or quasi-randomized controlled trials comparing needle acupuncture to a control group that used no treatment, placebo or sham treatment in neonates (less than 28 days old) with HIE. Co-interventions were allowed as long as both the intervention and the control group received the same co interventions. We excluded trials that evaluated therapy that did not involve penetration of the skin with a needle or trials that compared different forms of acupuncture only. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed trials for inclusion. If trials were identified, the review authors planned to assess trial quality and extract data independently. We planned to use the risk ratio (RR), risk difference (RD), and number needed to benefit (NNTB) or harm (NNTH) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) with 95% CI for continuous outcomes. MAIN RESULTS: No trial satisfied our predefined inclusion criteria. Existing trials only evaluated acupuncture in older infants who survived HIE. There are currently no randomized controlled trials evaluating the efficacy of acupuncture for treatment of HIE in neonates. The safety of acupuncture for HIE in neonates is unknown. AUTHORS' CONCLUSIONS: The rationale for acupuncture in neonates with HIE is unclear and the evidence from randomized controlled trial is lacking. Therefore, we do not recommend acupuncture for the treatment of HIE in neonates. High quality randomized controlled trials on acupuncture for HIE in neonates are needed. PMID- 23440823 TI - Topical treatment for facial burns. AB - BACKGROUND: Burn injuries are an important health problem. They occur frequently in the head and neck region - the area central to a person's identity, that provides our most expressive means of communication. Topical interventions are currently the cornerstone of treatment of partial-thickness burns to the face. OBJECTIVES: To assess the effects of topical interventions on wound healing in people with facial burns of any depth. SEARCH METHODS: We searched the Cochrane Wounds Group Specialised Register (searched 12 November 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10); Ovid MEDLINE (1950 to November Week 1 2012); Ovid MEDLINE - In-process & Other Non-Indexed Citations (searched November 12, 2012); Ovid EMBASE (1980 to 2012 Week 45); and EBSCO CINAHL (1982 to 9 November 2012) for relevant trials. We did not apply date or language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated the effects of topical treatment for facial burns were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed and included the references identified by the search strategy. Included trials were assessed using a risk of bias form, and data were extracted using a standardised data extraction sheet. For dichotomous and continuous outcomes, we calculated risk ratios and mean differences, respectively, both with 95% confidence intervals (CI). MAIN RESULTS: We included five RCTs, comprising a total of 119 participants. Two studies compared two different antimicrobial agents and three compared a biological or bioengineered skin substitute with an antimicrobial agent. All studies had small sample sizes and were at high risk of bias. Heterogeneity of interventions and outcomes prevented pooling of data. In three studies time to complete wound healing was significantly shorter for those using a skin substitute than for those using an antibacterial agent, but the quality of the evidence was low. Pain was significantly reduced with the use of skin substitutes in both studies that reported this outcome in all groups, range mean differences -2.00 (95% CI -3.82 to -0.18) to -4.00 (95% CI -5.05 to -2.95) on a 10-point scale. AUTHORS' CONCLUSIONS: There is insufficient high quality research and evidence to enable conclusions to be drawn about the effects of topical interventions on wound healing in people with facial burns. PMID- 23440824 TI - Position in the second stage of labour for women with epidural anaesthesia. AB - BACKGROUND: Epidural analgesia for pain relief in labour prolongs the second stage of labour and results in more instrumental deliveries. It has been suggested that a more upright position of the mother during all or part of the second stage may counteract these adverse effects. OBJECTIVES: To assess the effects of different birthing positions (upright versus recumbent) during the second stage of labour, on important maternal and fetal outcomes for women with epidural analgesia. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2012) and reference lists of retrieved studies SELECTION CRITERIA: All randomised or quasi-randomised trials including pregnant women (either primigravidae or multigravidae) in the second stage of induced or spontaneous labour receiving epidural analgesia of any kind.We assumed the experimental type of intervention to be the maternal use of any upright position during the second stage of labour, compared with the control intervention of the use of any recumbent position. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed risk of bias, and extracted data. Data were checked for accuracy. We contacted authors to try to obtain missing data. MAIN RESULTS: Five randomised controlled trials, involving 879 women, were included in the review.Overall, we identified no statistically significant difference between upright and recumbent positions on our primary outcomes of operative birth (caesarean or instrumental vaginal) (average risk ratio (RR) 0.97; 95% confidence interval (CI) 0.76 to 1.29; five trials, 874 women), or duration of the second stage of labour measured as the randomisation to birth interval (average mean difference -22.98 minutes; 95% CI 99.09 to 53.13; two trials, 322 women). Nor did we identify any clear differences in the incidence of instrumental birth or caesarean section separately, nor in any other important maternal or fetal outcome, including trauma to the birth canal requiring suturing, operative birth for fetal distress, low cord pH or admission to neonatal intensive care unit. However, the CIs around each estimate were wide, and clinically important effects have not been ruled out.There were no data reported on excess blood loss, prolonged second stage or maternal experience and satisfaction with labour. Similarly, there were no analysable data on Apgar scores, and no data reported on the need for ventilation or for perinatal death. AUTHORS' CONCLUSIONS: There are insufficient data to say anything conclusive about the effect of position for the second stage of labour for women with epidural analgesia. Women with an epidural should be encouraged to use whatever position they find comfortable in the second stage of labour. Future research should involve large trials of positions that women can maintain and predefined endpoints. One large trial is ongoing. PMID- 23440825 TI - High-volume haemofiltration for sepsis. AB - BACKGROUND: Severe sepsis and septic shock are leading causes of death in the intensive care unit (ICU). This is despite advances in the management of patients with severe sepsis and septic shock including early recognition, source control, timely and appropriate administration of antimicrobial agents, and goal directed haemodynamic, ventilatory and metabolic therapies. High-volume haemofiltration (HVHF) is a blood purification technique which may improve outcomes in critically ill patients with severe sepsis or septic shock. The technique of HVHF has evolved from renal replacement therapies used to treat acute kidney injury (AKI) in critically ill patients in the ICU. OBJECTIVES: This review assessed whether HVHF improves clinical outcome in adult critically ill patients with sepsis in an ICU setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 7); MEDLINE (1990 to August 2011), EMBASE (1990 to August 2011); LILACS (1982 to August 2011), Web of Science (1990 to August 2011), CINAHL (1982 to August 2011) and specific websites. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to standard or usual dialysis therapy; and RCTs and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to no similar dialysis therapy. The studies involved adults in critical care units. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data and assessed trial quality. We sought additional information as required from trialists. MAIN RESULTS: We included three randomized trials involving 64 participants. Due to the small number of studies and participants, it was not possible to combine data or perform sub-group analyses. One trial reported ICU and 28-day mortality, one trial reported hospital mortality and in the third, the number of deaths stated did not match the quoted mortality rates. No trials reported length of stay in ICU or hospital and one reported organ dysfunction. No adverse events were reported. Overall, the included studies had a low risk of bias. AUTHORS' CONCLUSIONS: There were no adverse effects of HVHF reported.There is insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and or septic shock except as interventions being investigated in the setting of a randomized clinical trial. These trials should be large, multi centred and have clinically relevant outcome measures. Financial implications should also be assessed. PMID- 23440826 TI - Treating BCG-induced disease in children. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine to prevent tuberculosis, routinely administered at birth as part of the World Health Organization global expanded immunisation programme. Given intradermally, it can cause adverse reactions, including local, regional, distant and disseminated manifestations that may cause parental distress. Rarely, it can cause serious illness and even death. Among those patients with immunocompromised conditions, such as the human immunodeficiency virus (HIV) infection, the complication rate is even higher. OBJECTIVES: To assess the effects of different interventions for treating BCG-induced disease in children. SEARCH METHODS: The following databases were searched: the Cochrane Infectious Diseases Group Specialized Register and Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (The Cochrane Library 2012, Issue 4); MEDLINE (1966 to November 2012); EMBASE (1947 to November 2012); and LILACS (1980 to November 2012). The metaRegister of Controlled Trials (mRCT) and the WHO trials search portal. Conference proceedings for relevant abstracts and experts were also contacted to identify studies. No language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any medical or surgical treatment modality for BCG-induced disease in children. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated titles, applied inclusion criteria, and assessed the risk of bias of studies. The primary outcomes were the failure rate of therapies for all types of BCG vaccine-induced complications and the time to resolution of illness measured in months. The secondary outcomes were death from BCG vaccine-induced disease and the all-cause mortality. Risk ratios (RRs) were used as measure of effect for dichotomous outcomes and mean differences for continuous outcomes. MAIN RESULTS: Five RCTs analysing 341 children addressed the primary outcomes and were included. Four arms compared oral antibiotics to no intervention or placebo, one arm evaluated needle aspiration compared to no intervention, and another evaluated the use of locally instilled isoniazid versus oral erythromycin.Two small studies evaluated oral isoniazid; we are uncertain of whether this intervention has an effect on clinical failure (RR 1.48; 95% Confidence Interval (CI) 0.79 to 2.78; 54 participants, two studies, very low quality evidence). Similarly, for oral erythromycin, we are uncertain if there is an effect (clinical failure RR 1.03; 95% CI 0.70 to 1.53; 148 participants, three studies, very low quality evidence), and for oral isoniazid plus rifampicin (clinical failure, RR 1.20; 95% CI 0.51 to 2.83; 35 participants, one study, very low quality evidence).In patients with lymphadenitis abscess, needle aspiration may reduce clinically persistent BCG-induced disease at 6 to 9 months of follow up (RR 0.13; 95% CI 0.03 to 0.55; 77 participants, one study, low quality evidence). In another study of patients with the same condition, aspiration plus local instillation of isoniazid reduces time to clinical cure compared to aspiration plus oral erythromycin (mean difference 1.49 months less; 95% CI 0.82 to 2.15 less; 27 participants, one study).No RCTs of HIV-infected infants with a BCG-induced disease evaluated the use of antibiotics or other therapies for reducing the rate of clinical failure or the time to clinical resolution. No data on mortality secondary to the interventions for treating BCG-induced disease were reported. AUTHORS' CONCLUSIONS: It is unclear if oral antibiotics (isoniazid, erythromycin, or a combination of isoniazid plus rifampicin) are effective for the resolution of BCG-induced disease. Most non-suppurated lymphadenitis will resolve without treatment in 4 to 6 months. Patients with lymphadenitis abscess might benefit from needle aspiration and possibly local instillation of isoniazid could shorten recovery time. Included studies were generally small and could be better conducted. Further research should evaluate the use of needle aspiration and local instillation of isoniazid in fluctuant nodes. Therapeutic and preventive measures in HIV-infected infants could be important given the higher risk of negative outcomes in this group. PMID- 23440827 TI - Paracetamol/acetaminophen (single administration) for perineal pain in the early postpartum period. AB - BACKGROUND: Perineal pain is a common but poorly studied adverse outcome following childbirth. Pain may result from perineal trauma due to bruising, spontaneous tears, surgical incisions (episiotomies), or in association with operative births (ventouse or forceps assisted births). OBJECTIVES: To determine the efficacy of a single administration of paracetamol (acetaminophen) systemic drugs used in the relief of acute postpartum perineal pain SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 6 November 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing paracetamol (acetaminophen) in a single dose compared with placebo for women with early postpartum perineal pain. We excluded quasi-RCTs and cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors assessed each paper for inclusion and extracted data. One review author reviewed the decisions and confirmed calculations for pain relief scores. MAIN RESULTS: We did not identify any new trials from the updated search so the results remain unchanged as follows.We have included 10 studies describing two dosages of paracetamol. Of these, five studies (526 women) assessed 500 mg to 650 mg and six studies (841 women) assessed 1000 mg of paracetamol. We chose to use random effects meta-analyses because of the heterogeneity in dosage used. Studies were from the 1970s to the early 1990s, and there was insufficient information to assess the risk of bias adequately, hence the findings need to be interpreted within this context.More women experienced pain relief with paracetamol compared with placebo (average risk ratio (RR) 2.14, 95% confidence interval (CI) 1.59 to 2.89, 10 studies, 1279 women). In addition, there were significantly fewer women having additional pain relief with paracetamol compared with placebo (RR 0.34, 95% CI 0.21 to 0.55, eight studies, 1132 women). Both the 500 mg to 650 mg and 1000 mg doses were effective in providing more pain relief than placebo.Maternal and neonatal potential adverse drug effects were not assessed in any of the included studies. Indeed few secondary outcomes were assessed. AUTHORS' CONCLUSIONS: More women experienced pain relief, and fewer had additional pain relief, with paracetamol compared with placebo, although potential adverse effects were not assessed and generally the quality of studies was unclear. PMID- 23440828 TI - Human chorionic gonadotrophin (hCG) for preventing miscarriage. AB - BACKGROUND: Recurrent miscarriage (RM) is defined as the loss of three or more consecutive pregnancies. Further research is required to understand the causes of RM, which remain unknown for many couples. Human chorionic gonadotrophin (hCG) is vital for maintaining the corpus luteum, but may have additional roles during implantation which support its use as a therapeutic agent for RM. OBJECTIVES: To determine the efficacy of hCG in preventing further miscarriage in women with a history of unexplained RM. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2012) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials investigating the efficacy of hCG versus placebo or no treatment in preventing RM. Quasi randomised trials are included. Cluster-randomised trials and trials with a cross over design are excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed the methodological quality of each study. Date were extracted by two review authors and checked for accuracy. MAIN RESULTS: We included five studies (involving 596 women). Meta analysis suggested a statistically significant reduction in miscarriage rate using hCG.The number of women needed to treat to prevent subsequent pregnancy loss was seven. However, when two studies of weaker methodological quality were removed, there was no longer a statistically significant benefit (risk ratio 0.74; 95% confidence interval 0.44 to 1.23). There were no documented adverse effects of using hCG. AUTHORS' CONCLUSIONS: The evidence supporting hCG supplementation to prevent RM remains equivocal. A well-designed randomised controlled trial of adequate power and methodological quality is required to determine whether hCG is beneficial in RM. PMID- 23440829 TI - Exercise for improving outcomes after osteoporotic vertebral fracture. AB - BACKGROUND: Vertebral fractures are associated with increased morbidity (e.g., pain, reduced quality of life), and mortality. Therapeutic exercise is a non pharmacologic conservative treatment that is often recommended for patients with vertebral fractures to reduce pain and restore functional movement. OBJECTIVES: Our objectives were to evaluate the benefits and harms of exercise interventions of four weeks or greater (alone or as part of a physical therapyintervention) versus non-exercise/non-active physical therapy intervention, no intervention or placebo on the incidence of future fractures and adverse events among adults with a history of osteoporotic vertebral fracture(s). We were also examined the effects of exercise on the following secondary outcomes: falls, pain, posture,physical function, balance,mobility, muscle function,quality of life and bone mineral density of the lumbar spine or hip measured using dual-energy X-ray absorptiometry (DXA).We also reported exercise adherence. SEARCH METHODS: We searched the following databases: The Cochrane Library ( Issue 11 of 12, November 2011), MEDLINE (2005 to 2011), EMBASE (1988 to November 23, 2011), CINAHL (Cumulative Index to Nursing and Allied Health Literature, 1982 to November 23, 2011), AMED (1985 to November 2011), and PEDro (Physiotherapy Evidence Database, www.pedro.fhs.usyd.edu.au/index.html, 1929 to November 23, 2011. Ongoing and recently completed trials were identified by searching the World Health Organization International Clinical Trials Registry Platform (to December 2009). Conference proceedings were searched via ISI and SCOPUS, and targeted searches of proceedings of the American Congress of Rehabilitation Medicine and American Society for Bone and Mineral Research. Search terms or MeSH headings included terms such as vertebral fracture AND exercise OR physical therapy. SELECTION CRITERIA: We considered all randomized controlled trials and quasi-randomized trials comparing exercise or active physical therapy interventions with placebo/non-exercise/non-active physical therapy interventions or no intervention implemented in individuals with a history of vertebral fracture and evaluating the outcomes of interest. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data using a pre-tested data abstraction form. Disagreements were resolved by consensus, or third party adjudication. The Cochrane Collaboration's tool for assessing risk of bias was used to evaluate each study. Studies were grouped according to duration of follow up (i.e., a) four to 12 weeks; b) 16 to 24 weeks; and c) 52 weeks); a study could be represented in more than one group depending on the number of follow-up assessments. For continuous data, we report mean differences (MDs) of the change or percentage change from baseline. Data from two studies were pooled for one outcome using a fixed-effect model. MAIN RESULTS: Seven trials (488 participants, four male participants) were included. Substantial variability across the seven trials prevented any meaningful pooling of data for most outcomes. No trials assessed the effect of exercise on incident fractures, adverse events or incident falls. Individual trials reported that exercise could improve pain, performance on the Timed Up and Go test, walking speed, back extensor strength, trunk muscle endurance, and quality of life. However, the findings should be interpreted with caution given that there were also reports of no significant difference between exercise and control groups for pain, Timed Up and Go test performance, trunk extensor muscle strength and quality of life. Pooled analyses from two studies revealed a significant between-group difference in favour of exercise for Timed Up and Go performance (MD -1.13 seconds, 95% confidence interval (CI) -1.85 to 0.42, P = 0.002). Individual studies also reported no significant between-group differences for posture or bone mineral density. Adherence to exercise varied across studies. The risk of bias across all studies was variable; low risk across most domains in four studies, and unclear or high risk in most domains for three studies. AUTHORS' CONCLUSIONS: No definitive conclusions can be made regarding the benefits of exercise for individuals with vertebral fracture. Although individual trials did report benefits for some pain, physical function and quality of life outcomes, the findings should be interpreted with caution given that findings were inconsistent and the quality of evidence was very low. The small number of trials and variability across trials limited our ability to pool outcomes or make conclusions. Evidence regarding the effects of exercise after vertebral fracture, particularly for men, is scarce. A high-quality randomized trial is needed to inform exercise prescription for individuals with vertebral fractures. PMID- 23440830 TI - Surgical versus conservative interventions for displaced intra-articular calcaneal fractures. AB - BACKGROUND: Fractures of the calcaneus (heel bone) comprise up to 2% of all fractures. These fractures are mostly caused by a fall from a height, and are common in younger adults. Treatment can be surgical or non-surgical; however, there is clinical uncertainty over optimal management. OBJECTIVES: To assess the effects of surgical compared with conservative treatment of displaced intra articular calcaneal fractures in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to July 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011 Issue 3), MEDLINE (1948 to July 2011), EMBASE (1980 to 2011 Week 27), the WHO International Clinical Trials Registry Platform, Current Controlled Trials, and Orthopaedic Trauma Association annual meeting archives (1996 to 2011). Reference lists of retrieved articles were checked. No language restrictions were applied. SELECTION CRITERIA: Randomised and quasi-randomised controlled clinical studies comparing surgical versus conservative management for displaced intra-articular calcaneal fractures. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, selected studies, extracted data and assessed risk of bias. Primary outcomes were function (e.g. walking ability) and chronic pain. Risk ratios were calculated for dichotomous outcomes and mean differences for continuous outcomes. Missing standard deviations were calculated from P values. MAIN RESULTS: Four trials were included (602 participants). Three trials were small single-centre trials, and the fourth a large multi-centre trial including 424 participants. All trials had methodological flaws, usually failure to conceal allocation and incomplete follow-up data, which put them at high risk of bias. Follow-up ranged from 1 to 15 years after treatment.Data for functional outcomes, including walking ability, from three trials could not be pooled. The strongest evidence was from the multi-centre trial. This showed no statistically or clinically significant differences between the surgical and conservatively treated groups at three years follow-up in the ''validated disease-specific" score (0 to 100: perfect result; 424 participants; mean difference (MD) 4.30, 95% confidence interval (CI) -1.11 to 9.71; P = 0.12). There was no significant difference between the two groups in the risk of chronic pain at follow-up (19/40 versus 24/42; risk ratio (RR) 0.79, 95% CI 0.53 to 1.18; 2 trials). The multi centre trial found no statistically or clinically significant difference between the two groups in health-related quality of life at three years follow-up (SF-36 (0 to 100: best outcome): MD 4.00, 95% CI -1.16 to 9.16; P = 0.13).Two small trials provided some limited evidence of a tendency for a higher return to previous employment after surgery (27/34 versus 15/27; RR 1.45, 95% CI 0.75 to 2.81; I2 = 55%; 2 trials). One small trial found no difference between the two groups in the ability to wear normal shoes, whereas another small trial found that surgery resulted in more people who were able to wear all shoes comfortably. There was a higher rate of major complications, such as surgical site infection, after surgery compared with conservative treatment (57/206 versus 42/218; RR 1.44, 95% CI 1.01 to 2.04; 1 trial). Conversely, significantly fewer surgical participants had subtalar arthrodeses due to the development of subtalar arthritis (7/206 versus 37/218; RR 0.20, 95% CI 0.09 to 0.44; 1 trial). There were no significant differences between the two groups in range of movement outcomes or radiological measurements (e.g. Bohler's angle). AUTHORS' CONCLUSIONS: The bulk of the evidence in this review derives from one large multi centre but inadequately reported trial conducted over 15 years ago. This found no significant differences between surgical or conservative treatment in functional ability and health related quality of life at three years after displaced intra articular calcaneal fracture. Though it reported a greater risk of major complications after surgery, subtalar arthrodeses for the development of subtalar arthritis was significantly greater after conservative treatment.Overall, there is insufficient high quality evidence relating to current practice to establish whether surgical or conservative treatment is better for adults with displaced intra-articular calcaneal fracture. Evidence from adequately powered randomised, multi-centre controlled trials, assessing patient-centred and clinically relevant outcomes is required. However, it would be prudent to reassess this need after an update of the review that incorporates new evidence from a currently ongoing multi-centre trial. PMID- 23440831 TI - Red flags to screen for vertebral fracture in patients presenting with low-back pain. AB - BACKGROUND: Low-back pain (LBP) is a common condition seen in primary care. A principal aim during a clinical examination is to identify patients with a higher likelihood of underlying serious pathology, such as vertebral fracture, who may require additional investigation and specific treatment. All 'evidence-based' clinical practice guidelines recommend the use of red flags to screen for serious causes of back pain. However, it remains unclear if the diagnostic accuracy of red flags is sufficient to support this recommendation. OBJECTIVES: To assess the diagnostic accuracy of red flags obtained in a clinical history or physical examination to screen for vertebral fracture in patients presenting with LBP. SEARCH METHODS: Electronic databases were searched for primary studies between the earliest date and 7 March 2012. Forward and backward citation searching of eligible studies was also conducted. SELECTION CRITERIA: Studies were considered if they compared the results of any aspect of the history or test conducted in the physical examination of patients presenting for LBP or examination of the lumbar spine, with a reference standard (diagnostic imaging). The selection criteria were independently applied by two review authors. DATA COLLECTION AND ANALYSIS: Three review authors independently conducted 'Risk of bias' assessment and data extraction. Risk of bias was assessed using the 11-item QUADAS tool. Characteristics of studies, patients, index tests and reference standards were extracted. Where available, raw data were used to calculate sensitivity and specificity with 95% confidence intervals (CI). Due to the heterogeneity of studies and tests, statistical pooling was not appropriate and the analysis for the review was descriptive only. Likelihood ratios for each test were calculated and used as an indication of clinical usefulness. MAIN RESULTS: Eight studies set in primary (four), secondary (one) and tertiary care (accident and emergency = three) were included in the review. Overall, the risk of bias of studies was moderate with high risk of selection and verification bias the predominant flaws. Reporting of index and reference tests was poor. The prevalence of vertebral fracture in accident and emergency settings ranged from 6.5% to 11% and in primary care from 0.7% to 4.5%. There were 29 groups of index tests investigated however, only two featured in more than two studies. Descriptive analyses revealed that three red flags in primary care were potentially useful with meaningful positive likelihood ratios (LR+) but mostly imprecise estimates (significant trauma, older age, corticosteroid use; LR+ point estimate ranging 3.42 to 12.85, 3.69 to 9.39, 3.97 to 48.50 respectively). One red flag in tertiary care appeared informative (contusion/abrasion; LR+ 31.09, 95% CI 18.25 to 52.96). The results of combined tests appeared more informative than individual red flags with LR+ estimates generally greater in magnitude and precision. AUTHORS' CONCLUSIONS: The available evidence does not support the use of many red flags to specifically screen for vertebral fracture in patients presenting for LBP. Based on evidence from single studies, few individual red flags appear informative as most have poor diagnostic accuracy as indicated by imprecise estimates of likelihood ratios. When combinations of red flags were used the performance appeared to improve. From the limited evidence, the findings give rise to a weak recommendation that a combination of a small subset of red flags may be useful to screen for vertebral fracture. It should also be noted that many red flags have high false positive rates; and if acted upon uncritically there would be consequences for the cost of management and outcomes of patients with LBP. Further research should focus on appropriate sets of red flags and adequate reporting of both index and reference tests. PMID- 23440833 TI - Interventions for treating persistent and intractable hiccups in adults. AB - BACKGROUND: Persistent and intractable hiccups (typically defined as lasting for more than 48 hours and one month respectively) can be of serious detriment to a patient's quality of life, although they are relatively uncommon. A wide range of pharmacological and non-pharmacological interventions have been used for the treatment of persistent and intractable hiccups. However, there is little evidence as to which interventions are effective or harmful. OBJECTIVES: The objective of this review was to evaluate the effectiveness of pharmacological and non-pharmacological interventions used in the treatment of persistent and intractable hiccups of any aetiology in adults. SEARCH METHODS: Studies were identified from the following databases: CENTRAL, CDSR, DARE, MEDLINE, EMBASE, CINAHL, PsychINFO and SIGLE (last search March 2012). The search strategy for all the databases searched was based on the MEDLINE search strategy presented in Appendix 1. No additional handsearching of journals was undertaken. Investigators who are known to be carrying out research in this area were contacted for unpublished data or knowledge of the grey literature. SELECTION CRITERIA: Studies eligible for inclusion in this review were randomised controlled trials (RCTs) or controlled clinical trials (CCTs). INCLUSION CRITERIA: adults (over 18 years old) diagnosed with persistent or intractable hiccups (hiccups lasting more than 48 hours), treated with any pharmacological or non-pharmacological intervention. EXCLUSION CRITERIA: less than ten participants; no assessment of change in hiccup frequency or intensity in outcome measures. DATA COLLECTION AND ANALYSIS: Two independent review authors assessed each abstract and title for relevance. Disagreement on eligibility was resolved by discussion. Where no abstract was available the full paper was obtained and assessed. We obtained full copies of the studies which met the inclusion criteria for further assessment. Two review authors independently collected data from each appropriate study and entered them into the software Review Manager 5. Two independent review authors assessed the risk of bias using the RevMan 5 'Risk of bias' table following guidance from the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009). MAIN RESULTS: A total of four studies (305 participants) met the inclusion criteria. All of these studies sought to determine the effectiveness of different acupuncture techniques in the treatment of persistent and intractable hiccups. All four studies had a high risk of bias, did not compare the intervention with placebo, and failed to report side effects or adverse events for either the treatment or control groups. Due to methodological differences we were unable to perform a meta-analysis of the results. No studies investigating pharmacological interventions for persistent and intractable hiccups met the inclusion criteria. AUTHORS' CONCLUSIONS: There is insufficient evidence to guide the treatment of persistent or intractable hiccups with either pharmacological or non pharmacological interventions.The paucity of high quality studies indicate a need for randomised placebo-controlled trials of both pharmacological and non pharmacological treatments. As the symptom is relatively rare, trials would need to be multi-centred and possibly multi-national. PMID- 23440832 TI - Pharmacotherapy for hyperuricemia in hypertensive patients. AB - BACKGROUND: High blood pressure represents a major public health problem. Worldwide, approximately one fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a linkage between hyperuricemia and hypertension. Hyperuricemia affects 25-40 % of patients with untreated hypertension. A much lower prevalence has been reported in normotensives or in the general population. However, whether lowering serum uric acid (SUA) might lower blood pressure (BP) is an unanswered question. OBJECTIVES: To determine whether uric acid lowering agents reduce BP in patients with primary hypertension. SEARCH METHODS: Electronic searches of the following sources were performed without language restriction: Cochrane Hypertension Group Specialised Register (1946 to May 2012), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2012 Issue 4), MEDLINE (1946 to May 2012), EMBASE (1974 to May 2012), LILACS (1982 to July 2012), Scirus and ClinicalTrials.gov. Authors of relevant papers were also contacted regarding further published and unpublished work. SELECTION CRITERIA: To be included in this review, the studies had to meet the following criteria: 1) Randomised or quasi-randomised with a group assigned to receive a uric acid lowering agent and another group assigned to receive placebo; 2) Double-blind, single-blind or open label; 3) Parallel or crossover trial; 4) For crossover trial, a washout period of at least two weeks; 5) Minimum treatment duration of four weeks; 6) Participants with diagnosis of essential hypertension and hyperuricemia, serum uric acid greater than 6 in women, 7 in men and 5.5 in children/adolescents; 7) Outcome measures includes change in casual or ambulatory, systolic or diastolic blood pressure. DATA COLLECTION AND ANALYSIS: Two independent reviewers collected the data using a data extraction form. Disagreements were resolved by discussion. Risk of bias was accessed by the Cochrane Collaboration Risk of Bias Tool. MAIN RESULTS: Three hundred and thirty-six abstracts were examined. One study (enrolling hypertensive and hyperuricemic patients) met the inclusion criteria for the review and was independently rated by both authors. No other studies were identified by the supplementary searches. The study identified as eligible for this review was a randomised controlled trial conducted in the USA (FEIG 2008 ) . This well designed double-blind, placebo-controlled, crossover trial randomised 30 adolescents (11-17 years), newly diagnosed stage 1 primary hypertension and with SUA >= 6mg/dl, to receive allopurinol 200 mg twice daily for 4 weeks, and placebo for 4 weeks, with a 2 week washout period between treatments. Casual BP during the allopurinol phase decreased - 6.9 mmHg (95 % CI, - 4.5 to - 9.3), systolic, and - 5.1 mmHg (95 % CI, - 2.5 to - 7.8), diastolic, versus during the placebo phase, - 2.0 mmHg (95 % CI, 0.3 to - 4.3) systolic and - 2.4 mmHg (95 % CI, 0.2 to - 4.1) diastolic. For the secondary outcome (change in 24 ambulatory BP), change in systolic BP with allopurinol was - 6.3 mmHg (95 % CI, - 3.8 to - 8.9), systolic, and - 4.6 mmHg (95% CI, - 2.4 to - 6.8), diastolic, and with placebo, 0.8 mmHg (95 % CI, 3.4 to - 2.9) systolic and - 0.3 mmHg (95 % CI, 2.3 to - 2.1) diastolic. P-value results ranged from 0.004 to 0.05. No participant dropout occurred and no adverse effects were seen in patients treated with allopurinol. AUTHORS' CONCLUSIONS: Meta-analysis was not possible in this systematic review. In the one study that matched the inclusion criteria allopurinol decreased "in office" and ambulatory systolic and diastolic BP. Because there was only one included RCT, the number of patients providing data on pharmacotherapy for hyperuricemia in hypertension is small and restricted to adolescents with recently diagnosed mild essential hypertension. Hence, there is insufficient evidence to recommend the use of allopurinol or other hypouricemic drugs as an initial or adjuvant treatment of hypertension and more RCTs are needed. PMID- 23440834 TI - Cerebrolysin for vascular dementia. AB - BACKGROUND: Vascular dementia is a common disorder without definitive treatments. Cerebrolysin seems to be a promising intervention based on its potential neurotrophic and pro-cognitive effects, but studies of its efficacy have yielded inconsistent results. OBJECTIVES: To assess the efficacy and safety of Cerebrolysin for vascular dementia. SEARCH METHODS: We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 4 November 2012 using the terms: Cerebrolysin, Cere, FPF1070, FPF-1070. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. SELECTION CRITERIA: All randomized controlled trials of Cerebrolysin for treating vascular dementia without language restriction. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials and evaluated the methodological quality, then extracted and analysed data from the included trials. MAIN RESULTS: Six randomized controlled trials with a total of 597 participants were eligible. The meta-analyses revealed a beneficial effect of Cerebrolysin on general cognitive function measured by mini-mental state examination (MMSE) (weighted mean difference (WMD) 1.10; 95% confidence interval (CI) 0.37 to 1.82) or Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog+) (WMD -4.01; 95% CI -5.36 to -2.66). It also improved patients' global clinical function evaluated by the response rates (relative risk (RR) 2.71, 95% CI 1.83 to 4.00). Only non-serious adverse events were observed in the included trials, and there was no significant difference in occurrence of non serious side effects between groups (RR 0.97, 95% CI 0.49 to 1.94). AUTHORS' CONCLUSIONS: Cerebrolysin may have positive effects on cognitive function and global function in elderly patients with vascular dementia of mild to moderate severity, but there is still insufficient evidence to recommend Cerebrolysin as a routine treatment for vascular dementia due to the limited number of included trials, wide variety of treatment durations and short-term follow-up in most of the trials. PMID- 23440835 TI - Telephone communication of HIV testing results for improving knowledge of HIV infection status. AB - BACKGROUND: This is one of three Cochrane reviews that examine the role of the telephone in HIV/AIDS services. Both in developed and developing countries there is a large proportion of people who do not know they are infected with HIV. Knowledge of one's own HIV serostatus is necessary to access HIV support, care and treatment and to prevent acquisition or further transmission of HIV. Using telephones instead of face-to-face or other means of HIV test results delivery could lead to more people receiving their HIV test results. OBJECTIVES: To assess the effectiveness of telephone use for delivery of HIV test results and post-test counselling.To evaluate the effectiveness of delivering HIV test results by telephone, we were interested in whether they can increase the proportion of people who receive their HIV test results and the number of people knowing their HIV status. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed Central, PsycINFO, ISI Web of Science, Cumulative Index to Nursing & Allied Health (CINAHL), WHOs The Global Health Library and Current Controlled Trials from 1980 to June 2011. We also searched grey literature sources such as Dissertation Abstracts International,CAB Direct Global Health, OpenSIGLE, The Healthcare Management Information Consortium, Google Scholar, Conference on Retroviruses and Opportunistic Infections, International AIDS Society and AEGIS Education Global Information System, and reference lists of relevant studies for this review. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-randomised controlled trials (qRCTs), controlled before and after studies (CBAs), and interrupted time series (ITS) studies comparing the effectiveness of telephone HIV test results notification and post-test counselling to face-to-face or other ways of HIV test result delivery in people regardless of their demographic characteristics and in all settings. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched, screened, assessed study quality and extracted data. A third reviewer resolved any disagreement. MAIN RESULTS: Out of 14 717 citations, only one study met the inclusion criteria; an RCT conducted on homeless and high-risk youth between September 1998 and October 1999 in Portland, United States. Participants (n=351) were offered counselling and oral HIV testing and were randomised into face-to face (n=187 participants) and telephone (n=167) notification groups. The telephone notification group had the option of receiving HIV test results either by telephone or face-to-face. Overall, only 48% (n=168) of participants received their HIV test results and post-test counselling. Significantly more participants received their HIV test results in the telephone notification group compared to the face-to-face notification group; 58% (n=106) vs. 37% (n=62) (p < 0.001). In the telephone notification group, the majority of participants who received their HIV test results did so by telephone (88%, n=93). The study could not offer information about the effectiveness of telephone HIV test notification with HIV positive participants because only two youth tested positive and both were assigned to the face-to-face notification group. The study had a high risk of bias. AUTHORS' CONCLUSIONS: We found only one eligible study. Although this study showed the use of the telephone for HIV test results notification was more effective than face-to-face delivery, it had a high-risk of bias. The study was conducted about 13 years ago in a high-income country, on a high-risk population, with low HIV prevalence, and the applicability of its results to other settings and contexts is unclear. The study did not provide information about telephone HIV test results notification of HIV positive people since none of the intervention group participants were HIV positive. We found no information about the acceptability of the intervention to patients' and providers', its economic outcomes or potential adverse effects. There is a need for robust evidence from various settings on the effectiveness of telephone use for HIV test results notification. PMID- 23440836 TI - Antenatal interventions for reducing weight in obese women for improving pregnancy outcome. AB - BACKGROUND: Being obese and pregnant is associated with substantial risks for the mother and her child. Current weight management guidance for obese pregnant women is limited. The latest recommendations suggest that obese pregnant women should gain between 5.0 and 9.1 kg during the pregnancy period, and weight loss is discouraged. However, observational studies indicate that some obese pregnant women, especially those who are heavier, lose weight during pregnancy. Furthermore, some obese pregnant women may intentionally lose weight. The safety of weight loss when pregnant and obese is not substantiated; some observational studies suggest that risks associated with weight loss such as pre-eclampsia are improved, but others indicate that the incidence of small- for-gestational infants are increased. It is important to evaluate interventions that are designed to reduce weight in obese pregnant women so that the safety of weight loss during this period can be established. OBJECTIVES: To evaluate the effectiveness of interventions that reduce weight in obese pregnant women. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2012) and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials, 'quasi-random' studies and cluster-randomised trials comparing a weight-loss intervention with routine care or more than one weight loss intervention. Cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: We identified no studies that met the inclusion criteria for this review. MAIN RESULTS: There were no included trials. AUTHORS' CONCLUSIONS: There are no trials designed to reduce weight in obese pregnant women. Until the safety of weight loss in obese pregnant women can be established, there can be no practice recommendations for these women to intentionally lose weight during the pregnancy period. Further study is required to explore the potential benefits, or harm, of weight loss in pregnancy when obese before weight loss interventions in pregnancy can be designed. Qualitative research is also required to explore dietary habits of obese pregnant women, especially those who are morbidly obese. PMID- 23440837 TI - Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. AB - BACKGROUND: Patients with progressive diseases often experience muscle weakness, which impacts adversely on levels of independence and quality of life. In those who are unable or unwilling to undertake traditional forms of exercise, neuromuscular electrical stimulation (NMES) may provide an alternative method of enhancing leg muscle strength. Programmes appear to be well tolerated and have led to improvements in muscle function, exercise capacity and quality of life. However, estimates regarding the effectiveness of NMES from individual studies lack power and precision. OBJECTIVES: PRIMARY OBJECTIVE: to evaluate the effectiveness of NMES for improving muscle strength in adults with advanced disease. SECONDARY OBJECTIVE: to examine the acceptability and safety of NMES, and changes in muscle function (strength or endurance), muscle mass, exercise capacity, breathlessness and health-related quality of life. SEARCH METHODS: Studies were identified from searches of The Cochrane Library, MEDLINE, EMBASE, CINAHL and PsycINFO databases to July 2012, citation searches, conference proceedings and previous systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in adults with advanced chronic obstructive pulmonary disease (COPD), chronic heart failure, cancer or human immunodeficiency virus/acquired immunodeficency syndrome (HIV/AIDS) comparing a programme of NMES as a sole or adjunct intervention to no treatment, placebo NMES or an active control. We imposed no language restriction. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on study design, participants, interventions and outcomes. We assessed risk of bias using the Cochrane Collaboration's tool. We calculated mean differences (MD) or standardised mean differences (SMD) between intervention and control groups for outcomes with sufficient data; for other outcomes we described findings from individual studies. MAIN RESULTS: Eleven studies involving a total of 218 participants met the inclusion criteria across COPD, chronic heart failure and thoracic cancer. NMES significantly improved quadriceps strength by a SMD of 0.9 (95% confidence interval (CI) 0.33 to 1.46), equating to approximately 25 Newton metres (Nm) (95% CI 9 to 41). Mean differences across various walking tests, favouring NMES, were 40 m (95% CI -4 to 84) for the six-minute walk test, 69 m (95% CI 19 to 119) for the incremental shuttle walk test and 160 m (95% CI 34 to 287) for the endurance shuttle walk test. Limited evidence was available for the assessment of other secondary outcomes. AUTHORS' CONCLUSIONS: NMES appears an effective means of improving muscle weakness in adults with progressive diseases such as COPD, chronic heart failure and cancer. Further research is required to clarify its place in clinical practice, by determining the optimal parameters for a NMES programme, the patients most likely to benefit, and its impact on morbidity and service use. PMID- 23440838 TI - Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. AB - BACKGROUND: Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are detectable in 10% to 15% of women seeking treatment for subfertility. OBJECTIVES: To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods in women with otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Specialised Register (6 August 2012), the Cochrane Central Register of Controlled Trials (T he Cochrane Library 2012, Issue 7), MEDLINE (1950 to October 2012), EMBASE (1974 to October 2012), CINAHL (from inception to October 2012) and other electronic sources of trials including trial registers, sources of unpublished literature and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from January 2008 to October 2012) and we contacted experts in the field. SELECTION CRITERIA: Randomised comparisons between operative hysteroscopy versus control in women with otherwise unexplained subfertility or undergoing IUI, IVF or ICSI and suspected major uterine cavity abnormalities diagnosed by ultrasonography, saline infusion/gel instillation sonography, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods. Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. MAIN RESULTS: Two studies met the inclusion criteria and neither reported the primary outcomes of live birth and complications from the procedure. In women with otherwise unexplained subfertility and submucous fibroids, there is no evidence of benefit with hysteroscopic myomectomy compared to regular fertility-oriented intercourse during 12 months for clinical pregnancy (odds ratio (OR) 2.4, 95% confidence interval (CI) 0.97 to 6.2, P = 0.06, 94 women) and miscarriage (OR 1.5, 95% CI 0.47 to 5.0, P = 0.47, 94 women) (very low-quality evidence). The hysteroscopic removal of polyps prior to IUI increases the odds of clinical pregnancy (experimental event rate (EER) 63%) compared to diagnostic hysteroscopy and polyp biopsy only (control event rate (CER) 28%) (OR 4.4, 95% CI 2.5 to 8.0, P < 0.00001, 204 women, high-quality evidence). AUTHORS' CONCLUSIONS: Hysteroscopic myomectomy might increase the odds of clinical pregnancy in women with unexplained subfertility and submucous fibroids, but the evidence is at present not conclusive. The hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI might increase the clinical pregnancy rate. More randomised studies are needed to substantiate the effectiveness of the hysteroscopic removal of suspected endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions in women with unexplained subfertility or prior to IUI, IVF or ICSI. PMID- 23440839 TI - Multidisciplinary rehabilitation after primary brain tumour treatment. AB - BACKGROUND: Brain tumours can cause significant disability, which may be amenable to multidisciplinary rehabilitation. However, the evidence base for this is unclear. OBJECTIVES: To assess the effectiveness of multidisciplinary rehabilitation in adults after primary brain tumour treatment, especially the types of approaches that are effective (settings, intensity) and the outcomes that are affected. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (March week 2, 2012), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 3, 2012), MEDLINE (1966 to March week 2, 2012), EMBASE (1980 to March week 2, 2012), PEDro (1982 to March 2012) and LILACS (1982 to March week 2, 2012). We checked the bibliographies of papers identified and contacted the authors and known experts in the field to seek published and unpublished trials. SELECTION CRITERIA: Controlled clinical trials (randomised and non-randomised clinical trials) that compared multidisciplinary rehabilitation in primary brain tumour with either routinely available local services or lower levels of intervention, or studies that compared multidisciplinary rehabilitation in different settings or at different levels of intensity. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed study quality, extracted data and performed a 'best evidence' synthesis based on methodological quality. MAIN RESULTS: No randomised controlled trials (RCTs) or controlled clinical trials (CCTs) were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs were available for synthesis of 'best evidence' for multidisciplinary rehabilitation after treatment for brain tumour patients. However, this does not suggest the ineffectiveness of multidisciplinary rehabilitation but rather highlights the challenges in trial design and rigour, outcome measurement and complexities of care in this population. For completeness of literature, 12 observational studies (with high risk of bias) involving patients with brain tumours were included. These studies provided 'very low level' evidence suggesting that multidisciplinary rehabilitation (inpatient, home based) may improve functional outcomes, and ambulatory programmes (outpatient and home-based) may improve vocation and quality of life. These conclusions are tentative at best, given gaps in current research in this area. Further research is needed into appropriate and robust study designs, outcome measurement, caregiver needs, evaluation of optimal settings, type, intensity, duration of therapy, and cost-effectiveness of multidisciplinary rehabilitation in the brain tumour population. PMID- 23440840 TI - Anti-vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion. AB - BACKGROUND: Branch retinal vein occlusion (BRVO) is one of the most common occurring retinal vascular abnormalities. The pathogenesis of BRVO is thought to involve both retinal vein compression and damage to the vessel wall, possibly leading to thrombus formation at sites where retinal arterioles cross retinal veins. The most common cause of visual loss in patients with BRVO is macular oedema (MO). Grid or focal laser photocoagulation has been shown to reduce the risk of visual loss and improve visual acuity (VA) in up to two thirds of individuals with MO secondary to BRVO, however, limitations to this treatment exist and newer modalities have suggested equal or improved efficacy. Recently, antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) has been used successfully to treat MO resulting from a variety of causes. As elevated intraocular levels of VEGF have been demonstrated in patients with retinal vein occlusions there is a strong basis for the hypothesis that anti-VEGF agents may be beneficial in the treatment of vascular leakage and MO. OBJECTIVES: To investigate the efficacy and safety of intravitreal anti-VEGF agents for preserving or improving vision in the treatment of MO secondary to BRVO. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2012), EMBASE (January 1980 to August 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2012, the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 7 August 2012 and the clinical trials registers on 10 September 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi RCTS of at least six months duration where anti-VEGF treatment was compared with another treatment, no treatment, or placebo. We excluded trials where combination treatments (anti-VEGF plus other treatments) were used and trials that investigated the dose and duration of treatment without a comparison group (other treatment/no treatment/sham). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data. The primary outcome was the proportion of participants with an improvement from baseline in best-corrected visual acuity (BCVA) of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart at six months and at 12 months of follow up. The secondary outcomes we report are the proportion of participants who lost greater than or equal to 15 ETDRS letters (3 lines) and the mean VA change at six months and any additional follow-up intervals as well as the change in central retinal thickness on optical coherence tomography (OCT) from baseline and final reported follow-up, the number and type of complications, the number of additional interventions administered and any adverse outcomes. Where available, the cost benefit and quality of life data reported in the primary studies is presented. MAIN RESULTS: We found one RCT and one quasi-RCT that met the inclusion criteria after independent and duplicate review of the search results. The studies used different anti-VEGF agents and different study groups which were not directly comparable.One multi-centre RCT (BRAVO) conducted in the USA randomised 397 individuals and compared monthly intravitreal ranibizumab (0.3 mg and 0.5 mg) injections with sham injection. The study only included individuals with non-ischaemic BRVO. Although repeated injections of ranibizumab appeared to have a favourable effect on the primary outcome, approximately 50% of the ranibizumab 0.3 mg group and 45% of the ranibizumab 0.5 mg group received rescue laser treatment which may have an important effect on the primary outcome. In addition, during the six-month observation period 93.5% of individuals in the sham group received intravitreal ranibizumab (0.5 mg). This cross-over design limits the ability to compare the long-term impact of ranibizumab versus a pure control group.The second trial was a small study (n = 30) from Italy with limitations in study design that reported a benefit of as-required intravitreal bevacizumab (1.25 mg) over laser photocoagulation in MO secondary to BRVO. We present the evidence from these trials and other interventional case series. AUTHORS' CONCLUSIONS: The available RCT evidence suggests that repeated treatment of non-ischaemic MO secondary to BRVO with the anti-VEGF agent ranibizumab may improve clinical and visual outcomes at six and 12 months. However, the frequency of re-treatment has not yet been determined and the impact of prior or combined treatment with laser photocoagulation on the primary outcome is unclear. Results from ongoing studies should assess not only treatment efficacy but also, the number of injections needed for maintenance and long-term safety and the effect of any prior treatment. PMID- 23440841 TI - Gases for establishing pneumoperitoneum during laparoscopic abdominal surgery. AB - BACKGROUND: Laparoscopic surgery is now widely performed to treat various abdominal diseases. Currently, carbon dioxide is the most frequently used gas for insufflation of the abdominal cavity (pneumoperitoneum). Many other gases have been introduced as alternatives to carbon dioxide for establishing pneumoperitoneum. OBJECTIVES: To assess the safety, benefits, and harms of different gases for establishing pneumoperitoneum in patients undergoing laparoscopic abdominal surgery. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and Chinese Biomedical Literature Database (CBM) until September 2012. SELECTION CRITERIA: We only included randomized controlled trials comparing different gases for establishing pneumoperitoneum in patients undergoing laparoscopic abdominal surgery under general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors identified the trials for inclusion, collected the data, and assessed the risk of bias independently. We performed the meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) or standardized mean difference (SMD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: Carbon dioxide pneumoperitoneum versus nitrous oxide pneumoperitoneum Three trials randomized 196 participants (the majority with low anaesthetic risk) to carbon dioxide pneumoperitoneum (n =96) or nitrous oxide pneumoperitoneum (n =100). All of the trials were of high risk of bias. Two trials (n=143) showed lower pain scores in nitrous oxide pneumoperitoneum at various time points on the first post-operative day. One trial (n=53) showed no difference in the pain scores between the groups. There were no significant differences in cardiopulmonary complications, surgical morbidity, or cardiopulmonary changes between the groups. There were no serious adverse events related to either carbon dioxide or nitrous oxide pneumoperitoneum. Carbon dioxide pneumoperitoneum versus helium pneumoperitoneum Four trials randomized 144 participants (the majority with low anaesthetic risk) to carbon dioxide pneumoperitoneum (n =75) or helium pneumoperitoneum (n =69). All of the trials were of high risk of bias. Fewer cardiopulmonary changes were observed with helium pneumoperitoneum than carbon dioxide pneumoperitoneum. There were no significant differences in cardiopulmonary complications, surgical morbidity, or pain scores. There were three serious adverse events (subcutaneous emphysema) related to helium pneumoperitoneum. Carbon dioxide pneumoperitoneum versus any other gas pneumoperitoneum There were no randomized controlled trials comparing carbon dioxide pneumoperitoneum to any other gas pneumoperitoneum. AUTHORS' CONCLUSIONS: 1. Nitrous oxide pneumoperitoneum during laparoscopic abdominal surgery appears to decrease post-operative pain in patients with low anaesthetic risk.2. Helium pneumoperitoneum decreases the cardiopulmonary changes associated with laparoscopic abdominal surgery. However, this did not translate into any clinical benefit over carbon dioxide pneumoperitoneum in patients with low anaesthetic risk.3. The safety of nitrous oxide and helium pneumoperitoneum has yet to be established. More randomized controlled trials on this topic are needed. Future trials should include more patients with high anaesthetic risk. Furthermore, such trials need to use adequate methods to reduce the risk of bias. PMID- 23440843 TI - Selenium supplementation for the primary prevention of cardiovascular disease. AB - BACKGROUND: Selenium is a key component of a number of selenoproteins which protect against oxidative stress and have the potential to prevent chronic diseases including cardiovascular disease (CVD). However, observational studies have shown inconsistent associations between selenium intake and CVD risk; in addition, there is concern around a possible increased risk of type 2 diabetes with high selenium exposure. OBJECTIVES: To determine the effectiveness of selenium only supplementation for the primary prevention of CVD and examine the potential adverse effect of type 2 diabetes. SEARCH METHODS: The following electronic databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 of 12, October 2012) on The Cochrane Library; MEDLINE (Ovid) (1946 to week 2 October 2012); EMBASE Classic + EMBASE (Ovid) (1947 to 2012 Week 42); CINAHL (EBSCO) (to 24 October 2012); ISI Web of Science (1970 to 24 October 2012); PsycINFO (Ovid) (1806 to week 3 October 2012); Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database and Health Economics Evaluations Database (Issue 4 of 4, October 2012) on The Cochrane Library. Trial registers and reference lists of reviews and articles were searched and experts in the field were approached. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials on the effects of selenium only supplementation on major CVD end-points, mortality, changes in CVD risk factors, and type 2 diabetes were included both in adults of all ages from the general population and in those at high risk of CVD. Trials were only considered where the comparison group was placebo or no intervention. Only studies with at least three months follow-up were included in the meta-analyses, shorter term studies were dealt with descriptively. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Twelve trials (seven with duration of at least three months) met the inclusion criteria, with 19,715 participants randomised. The two largest trials that were conducted in the USA (SELECT and NPC) reported clinical events. There were no statistically significant effects of selenium supplementation on all cause mortality (RR 0.97, 95% CI 0.88 to 1.08), CVD mortality (RR 0.97, 95% CI 0.79 to 1.2), non-fatal CVD events (RR 0.96, 95% CI 0.89 to 1.04) or all CVD events (fatal and non-fatal) (RR 1.03, 95% CI 0.95 to 1.11). There was a small increased risk of type 2 diabetes with selenium supplementation but this did not reach statistical significance (RR 1.06, 95% CI 0.97 to 1.15). Other adverse effects that increased with selenium supplementation, as reported in the SELECT trial, included alopecia (RR 1.28, 95% CI 1.01 to 1.62) and dermatitis grade 1 to 2 (RR 1.17, 95% CI 1.0 to 1.35). Selenium supplementation reduced total cholesterol but this did not reach statistical significance (WMD - 0.11 mmol/L, 95% CI - 0.3 to 0.07). Mean high density lipoprotein (HDL) levels were unchanged. There was a statistically significant reduction in non-HDL cholesterol (WMD - 0.2 mmol/L, 95% CI - 0.41 to 0.00) in one trial of varying selenium dosage. None of the longer term trials examined effects on blood pressure. Overall, the included studies were regarded as at low risk of bias. AUTHORS' CONCLUSIONS: The limited trial evidence that is available to date does not support the use of selenium supplements in the primary prevention of CVD. PMID- 23440842 TI - Xpert(r) MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. AB - BACKGROUND: Accurate and rapid detection of tuberculosis (TB) and drug resistance are critical for improving patient care and decreasing the spread of TB. Xpert(r) MTB/RIF assay (Xpert) is a rapid, automated test that can detect both TB and rifampicin resistance, within two hours after starting the test, with minimal hands-on technical time, but is more expensive than conventional sputum microscopy. OBJECTIVES: To assess the diagnostic accuracy of Xpert for pulmonary TB (TB detection), both where Xpert was used as an initial test replacing microscopy, and where Xpert was used as an add-on test following a negative smear microscopy result.To assess the diagnostic accuracy of Xpert for rifampicin resistance detection where Xpert was used as the initial test, replacing conventional culture-based drug susceptibility testing.The population of interest was adults suspected of having pulmonary TB or multidrug-resistant TB (MDR-TB), with or without HIV infection. SEARCH METHODS: We performed a comprehensive search of the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials. We performed searches on 25 September 2011 and we repeated them on 15 December 2011, without language restriction. SELECTION CRITERIA: We included randomized controlled trials, cross-sectional, and cohort studies that used respiratory specimens to compare Xpert with culture for detecting TB and Xpert with conventional phenotypic drug susceptibility testing for detecting rifampicin resistance. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted a set of data using a standardized data extraction form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using the QUADAS-2 tool. We carried out meta-analyses to estimate the pooled sensitivity and specificity of Xpert separately for TB detection and rifampicin resistance detection using a bivariate random-effects model. We estimated the median pooled sensitivity and specificity and their 95% credible intervals (CrI). MAIN RESULTS: We identified 18 unique studies as eligible for this review, including two multicentre international studies, one with five and the other with six distinct study centres. The majority of studies (55.6%) were performed in low-income and middle-income countries. In 17 of the 18 studies, Xpert was performed by trained technicians in reference laboratories.When used as an initial test replacing smear microscopy (15 studies, 7517 participants), Xpert achieved a pooled sensitivity of 88% (95% CrI 83% to 92%) and pooled specificity of 98% (95% CrI 97% to 99%). As an add-on test following a negative smear microscopy result (14 studies, 5719 participants), Xpert yielded a pooled sensitivity of 67% (95% CrI 58% to 74%) and pooled specificity of 98% (95% CrI 97% to 99%). In clinical subgroups, we found the following accuracy estimates: the pooled sensitivity was 98% (95% CrI 97% to 99%) for smear-positive, culture-positive TB and 68% (95% CrI 59% to 75%) for smear-negative, culture-positive TB (15 studies); the pooled sensitivity was 80% (95% CrI 67% to 88%) in people living with HIV and 89% (95% CrI 81% to 94%) in people without HIV infection (four studies). For rifampicin resistance detection (11 studies, 2340 participants), Xpert achieved a pooled sensitivity of 94% (95% CrI 87% to 97%) and pooled specificity of 98% (95% CrI 97% to 99%). In a separate analysis, Xpert could distinguish between TB and nontuberculous mycobacteria (NTM) in clinical samples with high accuracy: among 139 specimens with NTM, Xpert was positive in only one specimen that grew NTM.In a hypothetical cohort of 1000 individuals suspected of having rifampicin resistance (a proxy for MDR-TB), where the prevalence of rifampicin resistance is 30%, we estimated that on average Xpert would wrongly identify 14 patients as being rifampicin resistant. In comparison, where the prevalence of rifampicin resistance is only 2%, we estimated that the number of individuals wrongly identified as rifampicin resistant would increase to 20, an increase of 43%. AUTHORS' CONCLUSIONS: This review shows that Xpert used as an initial diagnostic test for TB detection and rifampicin resistance detection in patients suspected of having TB, MDR-TB, or HIV-associated TB is sensitive and specific. Xpert may also be valuable as an add-on test following microscopy for patients who have previously been found to be smear-negative. An Xpert result that is positive for rifampicin resistance should be carefully interpreted and take into consideration the risk of MDR-TB in a given patient and the expected prevalence of MDR-TB in a given setting.Studies in this review mainly assessed sensitivity and specificity of the test when used in reference laboratories in research investigations. Most studies were performed in high TB burden countries. Ongoing use of Xpert in high TB burden countries will contribute to the evidence base on the diagnostic accuracy and clinical impact of Xpert in routine programmatic and peripheral health care settings, including settings where the test is performed at the point of care. PMID- 23440844 TI - Surgical interventions for treating distal humeral fractures in adults. AB - BACKGROUND: Distal humeral fractures in adults are relatively uncommon injuries that require surgical intervention in most cases. There is a lack of consensus regarding the best management of distal humeral fractures in adults, including the role of conservative treatment, appropriate surgical approach, fixation strategies, the role of total elbow arthroplasty and handling of nerves such as the ulnar nerve. OBJECTIVES: To assess the effects (benefits and harms) of surgical interventions for distal humeral fractures in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (May 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012 Issue 4), MEDLINE (1946 to April Week 4 2012), EMBASE (1980 to 2012 Week 17), Current Controlled Trials (1st May 2012), the WHO International Clinical Trials Registry Platform (1st May 2012) and the bibliographies of trial reports and relevant articles. SELECTION CRITERIA: All randomised and quasi randomised controlled trials pertinent to the management of distal humeral fractures in adults were included. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, assessed of risk of bias and extracted data. Pooling of data was impossible due to study heterogeneity. MAIN RESULTS: Three small randomised controlled trials, with a total of 109 participants with Orthopaedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen (OTA/AO) type C distal humeral fractures, were included. Overall, the quality of the available evidence is limited. As well as the small sample sizes and detection bias from the lack of blinding of subjective outcomes, the methods and results of all three trials were incompletely reported.One trial, involving 42 participants, compared open reduction-internal fixation (ORIF) with total elbow arthroplasty (TEA) in patients aged over 65 years. Of the 40 participants followed up for two years, five allocated ORIF underwent intraoperative conversion to TEA. These participants were crossed-over to the TEA group in the analyses. The reported Mayo Elbow Performance Score (MEPS) results were consistently better in the TEA group at follow-up after 6, 12, and 24 months, whereas the Disability of the Arm, Shoulder, Hand (DASH) scores showed short term (after 6 months), but not longer term (after 12 and 24 months), superiority in the TEA group. The reoperation rate, complication rate and elbow range of motion results showed no statistically significant differences between the two groups. While an intention-to-treat analysis of treatment failure, where the five cross-over participants are placed in their original allocated group, is in favour of TEA, the result did not reach statistical significance (9/21 versus 3/21; RR 3.00, 95% CI 0.94 to 9.55).The second trial, involving 38 patients but reporting results for 35, compared perpendicular versus parallel double plate fixation strategies. There was a consistent finding of a lack of significant differences between the two treatment groups in terms of MEPS, re-operation for complications (3/17 versus 3/18; RR 1.06, 95% CI 0.25 to 4.54), complications and elbow joint range of motion.The third trial, which included 29 patients with preoperative ulnar nerve compression symptoms, compared anterior subfascial transposition with in situ decompression of the ulnar nerve. Although results for complete recovery of ulnar nerve function (12/15 versus 8/14; RR 1.4, 95% CI 0.83 to 2.35) and grades based on the Bishop rating system tended to favour the transposition group, none of the differences were statistically significant. AUTHORS' CONCLUSIONS: Overall, this review found there is either no or insufficient evidence from randomised or quasi-randomised controlled trials to determine whether surgery is, and which surgical interventions are, the most appropriate for the management of different types of distal humerus fractures. Well designed and reported large and multi-centre randomised controlled trials testing current interventions, such as pre-contoured and locking plating systems, are needed. PMID- 23440845 TI - Slum upgrading strategies involving physical environment and infrastructure interventions and their effects on health and socio-economic outcomes. AB - BACKGROUND: Slums are densely populated, neglected parts of cities where housing and living conditions are exceptionally poor. In situ slum upgrading, at its basic level, involves improving the physical environment of the existing area, such as improving and installing basic infrastructure like water, sanitation, solid waste collection, electricity, storm water drainage, access roads and footpaths, and street lighting, as well as home improvements and securing land tenure. OBJECTIVES: To explore the effects of slum upgrading strategies involving physical environment and infrastructure interventions on the health, quality of life and socio-economic wellbeing of urban slum dwellers in low and middle income countries (LMIC). Where reported, data were collected on the perspectives of slum dwellers regarding their needs, preferences for and satisfaction with interventions received. SEARCH METHODS: We searched for published and unpublished studies in 28 bibliographic databases including multidisciplinary (for example Scopus) and specialist databases covering health, social science, urban planning, environment and LMIC topics. Snowballing techniques included searching websites, journal handsearching, contacting authors and reference list checking. Searches were not restricted by language or publication date. SELECTION CRITERIA: We included studies examining the impact of slum upgrading strategies involving physical environment or infrastructure improvements (with or without additional co-interventions) on the health, quality of life and socio-economic wellbeing of LMIC urban slum dwellers. Randomised controlled trials (RCTs), controlled before and after studies (CBAs) and interrupted time series (ITS) were eligible for the main analysis. Controlled studies with only post-intervention data (CPI) and uncontrolled before and after (UBA) studies were included in a separate narrative to examine consistency of results and to supplement evidence gaps in the main analysis. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias for each study. Differences between the included study interventions and outcomes precluded meta-analysis so the results were presented in a narrative summary with illustrative harvest plots. The body of evidence for outcomes within the main analysis was assessed according to GRADE as very low, low, moderate or high quality. MAIN RESULTS: We identified 10,488 unique records, with 323 screened as full text. Five studies were included for the main analysis: one RCT with a low risk, two CBAs with a moderate risk and two CBAs with a high risk of bias. Three CBAs evaluated multicomponent slum upgrading strategies. Road paving only was evaluated in one RCT and water supply in one CBA. A total of 3453 households or observations were included within the four studies reporting sample sizes.Most health outcomes in the main studies related to communicable diseases, for which the body of evidence was judged to be low quality. One CBA with a moderate risk of bias found that diarrhoeal incidence was reduced in households which received water connections from a private water company (risk ratio (RR) 0.53; 95% confidence interval (CI) 0.27 to 1.04) and the severity of diarrhoeal episodes (RR 0.48; 95% CI 0.19 to 1.22). There was no effect for duration of diarrhoea. Road paving did not result in changes in parasitic infections or sickness in one RCT. After multicomponent slum upgrading, claims for a waterborne disease as opposed to a non-waterborne disease reduced (RR 0.64; 95% CI 0.27 to 0.98) in one CBA with a high risk of bias but there was no change in sanitation related mortality in a CBA with a moderate risk of bias.The majority of socio economic outcomes reported within the main studies related to financial poverty, for which the body of evidence was of very low quality. Results were mixed amongst the main studies; one RCT and two CBAs reported no effect on the income of slum dwellers following slum upgrading. One further CBA found significant reduction in monthly water expenditure (mean difference (MD) -17.11 pesos; 95% CI -32.6 to -1.62). One RCT also showed mixed results for employment variables, finding no effect on unemployment levels but increased weekly worked hours (MD 4.68; 95% CI -0.46 to 9.82) and lower risk of residents intending to migrate for work (RR 0.78; 95% CI 0.60 to 1.01).There was no evidence available to assess the impact of slum upgrading on non-communicable diseases or social capital. Maternal and perinatal conditions, infant mortality, nutritional deficiencies, injuries, self-reported quality of life, education and crime were evaluated in one study each.Nine supporting studies were included that measured varying outcomes (6794 households or observations within eight studies reporting sample sizes). One CPI evaluated cement flooring only while three UBAs and five CPIs evaluated multicomponent slum upgrading strategies. All studies but one had a high risk of bias.The studies reinforced main study findings for diarrhoea incidence and water related expenditure. Findings for parasitic infections and financial poverty were inconsistent with the main studies. In addition, supporting studies reported a number of disparate outcomes that were not evaluated in the main studies.Five supporting studies included some limited information on slum dweller perspectives. They indicated the importance of appropriate siting of facilities, preference for private facilities, delivering synergistic interventions together, and ensuring that infrastructure was fit for purpose and systems were provided for cleaning, maintenance and repair. AUTHORS' CONCLUSIONS: A high risk of bias within the included studies, heterogeneity and evidence gaps prevent firm conclusions on the effect of slum upgrading strategies on health and socio economic wellbeing. The most common health and socio-economic outcomes reported were communicable diseases and indicators of financial poverty. There was a limited but consistent body of evidence to suggest that slum upgrading may reduce the incidence of diarrhoeal diseases and water-related expenditure. The information available on slum dwellers' perspectives provided some insight to barriers and facilitators for successful implementation and maintenance of interventions.The availability and use of reliable, comparable outcome measures to determine the effect of slum upgrading on health, quality of life and socio economic wellbeing would make a useful contribution to new research in this important area. Given the complexity in delivering slum upgrading, evaluations should look to incorporate process and qualitative information alongside quantitative effectiveness data to determine which particular interventions work (or don't work) and for whom. PMID- 23440846 TI - Behavioral interventions for improving contraceptive use among women living with HIV. AB - BACKGROUND: Contraception services can help meet the family planning goals of women living with HIV as well as prevent mother-to-child transmission. Due to the increased availability of antiretroviral therapy, survival has improved for people living with HIV, and more HIV-positive women may desire to have a child or another child. This review examines behavioral interventions to improve contraceptive use, for family planning, among women who are HIV-positive. OBJECTIVES: We systematically reviewed studies that examined behavioral interventions for HIV-positive women that were intended to inform contraceptive choice, encourage contraceptive use, or promote adherence to a contraceptive regimen. SEARCH METHODS: Through October 2012, we searched MEDLINE, CENTRAL, POPLINE, EMBASE, CINAHL, PsycINFO, ClinicalTrials.gov and ICTRP. For other relevant papers, we examined reference lists and unpublished project reports, and contacted investigators in the field. SELECTION CRITERIA: Studies evaluated a behavioral intervention for improving contraceptive use for contraception. The comparison could be another behavioral intervention, usual care, or no intervention. We also considered studies that compared HIV-positive women versus HIV-negative women. We included nonrandomized (observational) studies as well as randomized trials.Primary outcomes were pregnancy and contraception use, e.g., uptake of a new method, improved use or continuation of current method. Secondary outcomes were knowledge of contraceptive effectiveness and attitude about contraception in general or about a specific contraceptive method. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. One author entered the data into RevMan and a second verified accuracy. We examined the quality of evidence using the Newcastle-Ottawa Quality Assessment Scale.Given the need to control for confounding factors in observational studies, we used adjusted estimates from the models when available. Where we did not have adjusted analyses, we calculated the odds ratio (OR) with 95% confidence interval (CI). Due to varied study designs, we did not conduct meta-analysis. MAIN RESULTS: The seven studies meeting our inclusion criteria had a total of 8882 women. All were conducted in Africa. Three studies compared a special intervention versus standard services. In one, the special intervention site showed greater use of non-condom contraceptives per visit (OR 6.40; 95% CI 5.37 to 7.62) and reported a lower pregnancy incidence. In another study, use of modern contraceptives was more likely for women at sites with enhanced versus basic integrated services (OR 2.48; 95% CI 1.31 to 4.72), but the groups did not differ significantly in change from baseline. In the third study, new use of modern contraceptives, excluding condoms, was less likely for women with integrated services versus those with routine care (OR 0.56; 95% CI 0.42 to 0.75), but new use of condoms was more likely (OR 1.73; 95% CI 1.52 to 1.98).Four older studies compared HIV-positive women versus HIV-negative women. None showed any significant difference between the HIV-status groups in use of modern contraceptives. Two did not provide an intervention for the HIV-negative women. In the larger of the two studies, HIV positive women were less likely to become pregnant (OR 0.55; 95% CI 0.43 to 0.69). HIV-positive women were more likely to discontinue their hormonal contraceptive (OR 2.52; 95% CI 1.53 to 4.14) but more likely to use condoms (OR 2.82; 95% CI 2.18 to 3.65) and spermicide (OR 2.36; 95% CI 1.69 to 3.30). Two studies provided the intervention to both HIV-status groups. One included many of the women from the study just mentioned, and also showed fewer pregnancies for HIV-positive women (OR 0.39; 95% CI 0.23 to 0.68). In the other study, the HIV status groups were not significantly different for pregnancy or consistent condom use. AUTHORS' CONCLUSIONS: Comparative research on contraceptive counseling for HIV-positive women has been limited. We found little innovation in the behavioral interventions. Our ability to make statements about overall results is hampered by varied study designs, interventions, and outcome assessments. The quality of evidence was moderate. Since some of these studies were conducted, improvements in HIV treatment have influenced the fertility intentions of HIV-positive people.The family planning field needs better ways to help women choose an appropriate contraceptive and continue using that chosen method. Women with HIV may have special concerns regarding family planning. Research could focus on assessing the woman's needs and training providers to address those issues rather than delivering standardized information. PMID- 23440847 TI - Tranexamic acid for reducing mortality in emergency and urgent surgery. AB - BACKGROUND: Emergency or urgent surgery, which can be defined as surgery which must be done promptly to save life, limb, or functional capacity, is associated with a high risk of bleeding and death. Antifibrinolytic agents, such as tranexamic acid, inhibit blood clot breakdown (fibrinolysis) and can reduce perioperative bleeding. Tranexamic acid has been shown to reduce the need for a blood transfusion in adult patients undergoing elective surgery but its effects in patients undergoing emergency or urgent surgery is unclear. OBJECTIVES: To assess the effects of tranexamic acid on mortality, blood transfusion and thromboembolic events in adults undergoing emergency or urgent surgery. SEARCH METHODS: We searched the following electronic databases: the Cochrane Injuries Group's Specialised Register (22 August 2012); Cochrane Central Register of Controlled Trials (2012, issue 8 of 12); MEDLINE (Ovid SP) 1950 to August Week 2, 2012; PubMed 1 June 2012 to 22 August 2012; EMBASE (Ovid SP) 1980 to 2012 Week 33; ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) 1990 to 22 August 2012; ISI Web of Science: Science Citation Index Expanded (SCI EXPANDED) 1970 to 22 August 2012. We also searched online trial registers on 22 August 2012 to identify unpublished studies. SELECTION CRITERIA: Randomised controlled trials comparing tranexamic acid with no tranexamic acid or placebo in adults undergoing emergency or urgent surgery. DATA COLLECTION AND ANALYSIS: Two authors examined titles, abstracts and keywords of citations from the electronic databases for eligibility and extracted data for analysis and risk of bias assessment. Outcome measures of interest were mortality, receipt of a blood transfusion, units of blood transfused, reoperation, seizures and thromboembolic events (myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism). MAIN RESULTS: We identified five trials involving 372 people that met the inclusion criteria. Three trials (260 patients) contributed data to the analyses. The effect of tranexamic acid on mortality (RR 1.01; 95% CI 0.14 to 7.3) is uncertain. However, tranexamic acid reduces the probability of receiving a blood transfusion by 30% although the estimate is imprecise (RR 0.70; 95% CI 0.52 to 0.94). The effect on deep venous thrombosis (RR 2.29; 95% CI 0.68 to 7.66), and stroke (RR 2.79; 95% CI 0.12 to 67.10) is uncertain. There were no events of pulmonary embolism or myocardial infarction. None of the trials reported units of blood transfused, reoperation, or seizure outcomes. AUTHORS' CONCLUSIONS: There is evidence that tranexamic acid reduces blood transfusion in patients undergoing emergency or urgent surgery. There is a need for a large pragmatic clinical trial to assess the effects of routine use of tranexamic acid on mortality in a heterogeneous group of urgent and emergency surgical patients. PMID- 23440848 TI - Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. AB - BACKGROUND: Fibromyalgia syndrome (FMS) is a clinically well-defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life (QOL). Drug therapy focuses on reducing key symptoms and improving quality of life. OBJECTIVES: To assess the benefits and harms of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo for treating FMS symptoms in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2012, Issue 9), MEDLINE (1966 to September 2012), EMBASE (1980 to September 2012), www.clinicalstudyresults.org (U.S. marketed pharmaceuticals) (to September 2012) and www.clinicaltrials.gov (to September 2012) for published and ongoing trials and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomized, controlled trials of any formulation of SNRIs against placebo for the treatment of FMS in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data from the included studies, and assessed the risks of bias of the studies. Discrepancies were resolved by discussion. MAIN RESULTS: Ten studies were included with a total of 6038 participants. Five studies investigated duloxetine against placebo, and five investigated milnacipran against placebo. A total of 3611 participants were included into duloxetine or milnacipran groups and 2427 participants into placebo groups. The studies had a low risk of bias in general. Duloxetine and milnacipran had a small incremental effect over placebo in reducing pain (standardized mean difference (SMD) -0.23; 95% confidence interval (CI) -0.29 to -0.18; 6.1% relative improvement). One-hundred and ninety two participants per 1000 on placebo reported an at least 50% pain reduction compared to 280 per 1000 on SNRIs (Risk ratio (RR) 1.49, 95% CI 1.35 to 1.64; number needed to treat to benefit (NNTB) 11, 95% CI 9 to 15). Duloxetine and milnacipran did not reduce fatigue substantially (SMD -0.14; 95% CI -0.19 to 0.08; 2.5% relative improvement; NNTB 17, 95% CI 12 to 29), and did not improve QOL substantially (SMD -0.20; 95% CI -0.25 to -0.14; 4.6% relative improvement; NNTB 12, 95% CI 9 to 17) compared to placebo. There were no statistically significant differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95% CI -0.16 to 0.03; 2.5% relative improvement). One-hundred and seven participants per 1000 on placebo dropped out due to adverse events compared to 196 per 1000 on SNRIs. The dropout rate due to adverse events in the duloxetine and milnacipran groups was statistically significantly higher than in placebo groups (RR 1.83, 95% CI 1.53 to 2.18; number needed to treat to harm (NNTH) 11, 95% CI 9 to 13). There was no statistically significant difference in serious adverse events between either duloxetine or milnacipran and placebo (RR 0.78, 95% CI 0.55 to 1.12). AUTHORS' CONCLUSIONS: The SNRIs duloxetine and milnacipran provided a small incremental benefit over placebo in reducing pain. The superiority of duloxetine and milnacipran over placebo in reducing fatigue and limitations of QOL was not substantial. Duloxetine and milnacipran were not superior to placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. The most frequently reported symptoms leading to stopping medication were nausea, dry mouth, constipation, headache, somnolence/dizziness and insomnia. Rare complications of both drugs may include suicidality, liver damage, abnormal bleeding, elevated blood pressure and urinary hesitation. PMID- 23440849 TI - Fish and amphibians as potential reservoirs of Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. AB - BACKGROUND: Buruli ulcer is a skin disease often associated with proximity to certain water bodies in Africa. Much remains unknown about the reservoir and transmission of this disease. Previous studies have suggested that fish may concentrate Mycobacterium ulcerans, the etiological agent of the disease, in their gills and intestines and serve as passive reservoirs of the bacterium. The objective of this study was to test the hypothesis that fish and amphibians serve as natural reservoirs of M. ulcerans or other closely related mycolactone producing mycobacteria. METHODS: Polymerase chain reaction targeting the enoyl reductase (ER) domain present in mlsA, which is required for mycolactone production, was used to screen water, fish, and amphibians from water bodies in Ghana for the presence of mycolactone-producing mycobacteria, and positive specimens were subjected to variable number tandem repeat (VNTR) typing. RESULTS: The use of VNTR typing revealed the presence of Mycobacterium liflandii in a tadpole and a fish, and M. ulcerans in an adult frog. Similarity percentage analysis (SIMPER) showed that the predatory cichlid Hemichromis bimaculatus was associated with ER-positive water bodies. No amphibian species or fish-feeding guild served as a reliable indicator of the presence of mycolactone-producing mycobacteria in a water body, and there was no significant difference between fish and amphibian positivity rates (P-value=0.106). There was a significant difference between water bodies in the total number of ER-positive specimens (P value=0.0164). CONCLUSIONS: Although IS2404-positive tadpoles and fish have been reported, this is the first VNTR confirmation of M. ulcerans or M. liflandii in wild amphibian and fish populations in West Africa. Results from this study suggest that amphibians should be carefully examined as potential reservoirs for M. ulcerans in West Africa, and that H. bimaculatus may be useful as an indicator of habitats likely to support mycolactone-producing mycobacteria. PMID- 23440850 TI - MR thermometry in the human prostate gland at 3.0T for transurethral ultrasound therapy. AB - PURPOSE: To investigate the spatial, temporal, and temperature resolution of a segmented gradient echo echo-planar imaging (EPI) technique as applied to proton resonance frequency (PRF) shift thermometry at 3 T in the human prostate gland, and to determine appropriate sequence parameters for magnetic resonance imaging (MRI)-controlled transurethral ultrasound thermal therapy. MATERIALS AND METHODS: Eleven healthy volunteers (age range 23-58) were scanned at 3 T with a 16-channel torso coil to study the behavior of a gradient echo EPI thermometry sequence. The temperature stability and geometric distortion were assessed for 11 different parameter sets. In a further five volunteers, the prostate T2* was measured. RESULTS: For all scan parameters investigated, the temperature standard deviation within the prostate was less than 1 degrees C, while the distortion was less than 1 mm. Temperature stability was best with higher TE values (up to 25 msec), larger voxel sizes and lower EPI factors, but this had to be balanced against requirements for good spatial and temporal resolution. Prostate T2* values ranged from 30-50 msec. CONCLUSION: A good balance between temperature stability and temporal/spatial resolution is obtained with TE = 15 msec, voxel size = 1.14 mm, and EPI factor = 9, resulting in a dynamic scan time of 7.2 seconds for the nine slices. PMID- 23440851 TI - Initiation of clathrin-mediated endocytosis: all you need is two? AB - Clathrin-mediated endocytosis is a major route for the retrieval of plasma membrane cargoes, and defects of this process can cause catastrophic human dysfunctions. However, the processes governing how a clathrin-coated profile (ccp) is initiated are still murky. Despite an ever-growing cast of molecules proposed as triggers of ccp nucleation and increasingly sophisticated bioimaging techniques examining clathrin-mediated endocytosis, it is yet unknown if ccp formation is governed by a universal mechanism. A recent paper by Cocucci et al. has tracked single-molecule events to identify that stable accumulation of ccps requires the near-simultaneous arrival of two AP2 adaptors bridged by one clathrin triskelion. This commentary examines the role of AP2 in cargo-mediated endocytosis in the light of recent advances in biophotonics, chemical inhibitors and genetics, examines the claims of other molecules to be the initiators of ccp formation and proposes future directions in research into this topic. Editor's suggested further reading in BioEssays: The evolution of dynamin to regulate clathrin-mediated endocytosis Abstract Clathrin-mediated endocytosis: What works for small, also works for big Abstract. PMID- 23440859 TI - Native and novel language prosodic sensitivity in English-speaking children with and without dyslexia. AB - Children with reading disability and normal reading development were compared in their ability to discriminate native (English) and novel language (Mandarin) from nonlinguistic sounds. Children's preference for native versus novel language sounds and for disyllables containing dominant trochaic versus non-dominant iambic stress patterns was also assessed. Participants included second and third grade monolingual native English speakers with reading disability (N = 18) and normal reading development (N = 18). Children selected from pairs of novel, native, and nonlinguistic sounds that was more like language. Both groups discriminated disyllabic linguistic sounds (native and novel) from nonlinguistic sounds. Both groups showed preference for the dominant English trochaic stress pattern over the non-dominant iambic stress pattern. Implications for development of prosodic sensitivity in relation to reading skills and future research are discussed. PMID- 23440860 TI - A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination. AB - Differentiation of oligodendrocyte precursor cells (OPCs) is the most important event for the myelination of central nervous system (CNS) axons during development and remyelination in demyelinating diseases, while the underlying molecular mechanisms remain largely unknown. Here we show that NMDA receptor (NMDAR) is a functional regulator of OPCs differentiation and remyelination. First, GluN1, GluN2A, and GluN2B subunits are expressed in oligodendrocyte lineage cells (OLs) in vitro and in vivo by immunostaining and Western blot analysis. Second, in a purified rat OPC culture system, NMDARs specially mediate OPCs differentiation by enhancing myelin proteins expression and the processes branching at the immature to mature oligodendrocyte transition analyzed by a serial of developmental stage-specific antigens. Moreover, pharmacological NMDAR antagonists or specific knockdown of GluN1 by RNA interference in OPCs prevents the differentiation induced by NMDA. NMDA can activate the mammalian target of rapamycin (mTOR) signal in OPCs and the pro-differentiation effect of NMDA is obstructed by the mTOR inhibitor rapamycin, suggesting NMDAR exerts its effect through mTOR-dependent mechanism. Furthermore, NMDA increases numbers of myelin segments in DRG-OPC cocultures. Finally, NMDAR specific antagonist MK801 delays remyelination in the cuprizone model examined by LFB-PAS, immunofluorescence and electron microscopy. This effect appears to result from inhibiting OPCs differentiation as more NG2(+) OPCs but less GST-pi(+) mature oligodendrocytes are observed. Together, these results indicate that NMDAR plays a critical role in the regulation of OPCs differentiation in vitro and remyelination in cuprizone model which may provide potential target for the treatment of demyelination disease. PMID- 23440861 TI - Red fluorescent probe for monitoring the dynamics of cytoplasmic calcium ions. PMID- 23440862 TI - Accumulation and effects of 90-day oral exposure to Dechlorane Plus in quail (Coturnix coturnix). AB - While a number of studies have addressed bioaccumulation of the flame retardant Dechlorane Plus (DP), little information is available regarding the adverse effects of DP on animals, especially on bird species. In the present study, male common quails (Coturnix coturnix) were consecutively exposed to commercial DP-25 by gavage for 90 d at 1-mg/kg/d, 10-mg/kg/d, and 100-mg/kg/d dosages. Concentrations of DP isomers in liver, muscle, and serum were determined after exposure. Liver enzyme activity involved in xenobiotic biotransformation processes and oxidative stress was measured, as well as glutathione and maleic dialdehyde content. The results showed that DP was more prone to accumulate in the liver than in muscle and serum in all exposed groups. In tested tissues, syn DP dominated in the high-exposure groups (10 and 100 mg/kg/d), whereas anti-DP tended to accumulate in the low-exposure group (1 mg/kg/d). The concentration ratios of anti-DP to total DP (fanti values) in the tissues examined were close to commercial DP in the low-exposure group; however, the fanti values were significantly decreased in the high-exposure groups. Enzyme activity of 7 pentoxyresorufin-O-demethylase (PROD) decreased significantly in all exposed groups compared with the control group, whereas activity of erythromycin N demethylase (ERND) and the antioxidant enzyme catalase significantly increased in high-exposure groups. The results implied that DP exposure levels influenced isomeric compositions in organs and that DP exposure altered hepatic alkoxyresorufin O-dealkylase (AROD) activity and contributed to the biological effects of DP. PMID- 23440863 TI - Orthogonalizing crusher and diffusion-encoding gradients to suppress undesired echo pathways in the twice-refocused spin echo diffusion sequence. AB - PURPOSE: The twice-refocused spin echo sequence is widely used in diffusion imaging due to its excellent performance in reducing eddy currents. The three radio frequency pulses give rise to eight separate signal pathways. Because there is no general solution for the size and arrangement for crusher gradients, with constant size and orientation, that is effective for all arbitrary diffusion sensitizing b-values and directions, this article introduces and validates a solution whereby the crusher and diffusion-encoding gradients are always kept orthogonal, thus ensuring their independence. METHODS: The cancellation of the crusher and diffusion gradients was demonstrated. Subsequently, crusher gradients were implemented in such a way that they were always orthogonal to the diffusion gradient. Phantom and in-vivo experiments were performed to ascertain that orthogonally implemented crusher gradients alleviate the problem without lowering image quality. RESULTS: In all experiments, when the crusher gradients' action was cancelled by the diffusion-encoding gradients artifactual signal modulation was observed. When orthogonal gradients were implemented the artifacts were eliminated without detrimental effects on image quality. CONCLUSIONS: Orthogonal crushers are easy to implement and can be used for any variant of diffusion imaging sequences (e.g., diffusion tensor imaging, fiber diameter mapping) where the twice-refocused scheme is used. PMID- 23440864 TI - Ascertaining the role of Taiwan as a source for the Austronesian expansion. AB - Taiwanese aborigines have been deemed the ancestors of Austronesian speakers which are currently distributed throughout two-thirds of the globe. As such, understanding their genetic distribution and diversity as well as their relationship to mainland Asian groups is important to consolidating the numerous models that have been proposed to explain the dispersal of Austronesian speaking peoples into Oceania. To better understand the role played by the aboriginal Taiwanese in this diaspora, we have analyzed a total of 451 individuals belonging to nine of the tribes currently residing in Taiwan, namely the Ami, Atayal, Bunun, Paiwan, Puyuma, Rukai, Saisiyat, Tsou, and the Yami from Orchid Island off the coast of Taiwan across 15 autosomal short tandem repeat loci. In addition, we have compared the genetic profiles of these tribes to populations from mainland China as well as to collections at key points throughout the Austronesian domain. While our results suggest that Daic populations from Southern China are the likely forefathers of the Taiwanese aborigines, populations within Taiwan show a greater genetic impact on groups at the extremes of the current domain than populations from Indonesia, Mainland, or Southeast Asia lending support to the "Out of Taiwan" hypothesis. We have also observed that specific Taiwanese aboriginal groups (Paiwan, Puyuma, and Saisiyat), and not all tribal populations, have highly influenced genetic distributions of Austronesian populations in the pacific and Madagascar suggesting either an asymmetric migration out of Taiwan or the loss of certain genetic signatures in some of the Taiwanese tribes due to endogamy, isolation, and/or drift. PMID- 23440865 TI - Chasing shadows: what determines DTI metrics in gray matter regions? An in vitro and in vivo study. AB - PURPOSE: To characterize the relationship between superparamagnetic ferritin bound iron and diffusion tensor scalars in vitro, and validate the results in vivo. MATERIALS AND METHODS: The in vitro model consisted of a series of 40-mL 1.1% agarose gels doped with ferritin covering and exceeding those concentrations normally found within healthy human gray matter. Additionally, regions of interest were placed in the caudate, putamen, and globus pallidus of 29 healthy volunteer subjects 19-80 years of age. Carr-Purcell-Meiboom-Gill sequence (CPMG) and diffusion tensor imaging (DTI) data were collected at 1.5 Tesla (T) and 3T in vitro, and at 1.5T in vivo. RESULTS: In vitro, linear relationships were observed between ferritin-bound iron concentration, R2 (1/T2 ) and 1/SNR. Eigenvalue repulsion with increasing R2 (decreasing SNR) was reflected in an artifactual increase of fractional anisotropy. In vivo, similar relationships were observed, with mean diffusivity also decreasing linearly with increasing R2 . Lambda 3 showed the strongest correlation with R2 both in vitro and in vivo. CONCLUSION: The observation that DTI metrics correlate with ferritin-bound iron is an important consideration in the design and interpretation of studies exploring the diffusion characteristics of gray matter regions, especially in studies focused on adolescence as well as diseases associated with altered brain-iron load such as pantothenate kinase-associated neurodegeneration, Huntington disease and multiple system atrophy. PMID- 23440866 TI - Personality as a predictor of general health in captive golden snub-nosed monkeys (Rhinopithecus roxellana). AB - Increasing studies in human and animals have shown that personality is related to biological profile and affects health outcomes. Understanding the link between personality and health will contribute to preventing illness and promoting well being in non-human primates. The present study examined whether personality predicted health outcomes in captive golden snub-nosed monkeys (Rhinopithecus roxellana). Personality was measured by rating on a list of traits and four factors (Aggressiveness, Sociability, Mellowness, and Excitability) were extracted. Morbidity was measured by occurrence, duration, and number of illnesses, as well as (mean and maximum) digestive dysfunction symptoms scores. Morbidity measurements were coded from illness history which was recorded during the 27 months since the personality assessment. The results showed that lower Aggressiveness predicted greater number of illness, longer illness duration, and more serious digestive dysfunction. In addition, Mellowness, Excitability, and age by Sociability interaction influenced digestive function significantly. Low mellow individuals, high excitable individuals, high sociable younger individuals and low sociable older individuals had poorer digestive function. The present study demonstrated that personality was associated with morbidity in captive R. roxellanae and stress might contribute to this association. Personality assessment provided useful information on individual vulnerability. Carefully looking for early signs of illness among vulnerable individuals is expected to reduce health risks, which would promote welfare in captive non-human primates. PMID- 23440867 TI - Promising new molecular targeted therapies in head and neck cancer. AB - Despite advances in multimodality therapies for the treatment of squamous cell carcinoma of the head and neck (SCCHN), survival rates, functional outcomes and toxicities of therapy remain poor. The recognition of the prognostic value of human papillomavirus (HPV) status, and the advent of biologically targeted therapies with potential for decreased toxicities and increased selectivity, represent significant developments in our understanding of SCCHN. Targeted agents currently approved or under investigation for SCCHN include epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab, nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatanib, dacomitinib), vascular endothelial growth factor receptor (VEGFR) inhibitors (bevacizumab, sorafenib, sunitinib, vandetanib) and various inhibitors of other pathways and targets, including phosphatidylinositol 3' kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), MET and insulin-like growth factor receptor (IGF-1R). On-going clinical trials are evaluating these emerging agents and their combinations in the treatment of SCCHN. PMID- 23440868 TI - C-4 modified sialosides enhance binding to Siglec-2 (CD22): towards potent Siglec inhibitors for immunoglycotherapy. PMID- 23440870 TI - Analysis and correction of biases in cross-relaxation MRI due to biexponential longitudinal relaxation. AB - PURPOSE: Cross-relaxation imaging (CRI) is a family of quantitative magnetization transfer techniques that utilize images obtained with off-resonance saturation and longitudinal relaxation rate (R1) maps reconstructed by the variable flip angle (VFA) method. It was demonstrated recently that a significant bias in an apparent VFA R1 estimation occurs in macromolecule-rich tissues due to magnetization transfer (MT)-induced biexponential behavior of longitudinal relaxation of water protons. The purpose of this article is to characterize theoretically and experimentally the resulting bias in the CRI maps and propose methods to correct it. THEORY: The modified CRI algorithm is proposed, which corrects for such biases and yields accurate parametric bound pool fraction f, cross-relaxation rate k, and R1 maps. Additionally, an analytical correction procedure is introduced to recalculate previously obtained parameter values. RESULTS: The systematic errors due to unaccounted MT-induced biexponential relaxation can be characterized as an overestimation of R1, f, and k, with a relative bias comparable with the magnitude of f. The phantom and human in vivo experiments demonstrate that both proposed modified CRI and analytical correction approaches significantly improve the accuracy of the CRI method. CONCLUSION: The accuracy of the CRI method can be considerably improved by taking into account the contribution of MT-induced biexponential longitudinal relaxation into variable flip angle R1 measurements. PMID- 23440871 TI - Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death. AB - Dyshomeostasis of cytosolic Zn(2+) is a critical mediator of neuronal damage during excitotoxicity. However, the role of this cation in oligodendrocyte pathophysiology is not well understood. The current study examined the contribution of Zn(2+) deregulation to oligodendrocyte injury mediated by AMPA receptors. Oligodendrocytes loaded with the Zn(2+)-selective indicator FluoZin-3 responded to mild stimulation of AMPA receptors with fast cytosolic Zn(2+) rises that resulted from intracellular release, as they were not blocked by the extracellular Zn(2+) chelator Ca-EDTA. Pharmacological experiments suggested that AMPA-induced Zn(2+) mobilization depends on cytosolic Ca(2+) accumulation, arises from mitochondria and protein-bound pools, and is triggered by mechanisms that do not involve the generation of reactive oxygen species. Moreover, intracellular Zn(2+) rises resulting from AMPA receptor activation seem to be promoted by Ca(2+)-dependent cytosolic acidification. Addition of the cell-permeable Zn(2+) chelator TPEN significantly reduced mitochondrial membrane depolarization, reactive oxygen species production, and cell death by sub-maximal activation of AMPA receptors both in vitro and in situ, suggesting that Zn(2+) deregulation is an important mediator of oligodendrocyte excitotoxicity. These data provide evidence that strategies aimed at maintaining Zn(2+) homeostasis may be useful for the treatment of disorders in which excitotoxicity is an important trigger of oligodendroglial death. PMID- 23440869 TI - Redox-neutral copper(II) carboxylate catalyzed alpha-alkynylation of amines. PMID- 23440872 TI - Toxicological implications of microcystins for zebrafish embryos in the presence of other environmental pollutants. AB - Microcystins (MCs) interact with environmental contaminants as well as various other congeners of the MC family in the natural environment and with antioxidants in the exposed organisms. These interactions are likely to modify the toxicological behavior of MCs at the cellular level. The present study was conducted to determine the toxicological response of extracellular MCs in aquatic systems under environmentally relevant conditions. Microcystin-leucine-arginine (MCLR) and microcystin-arginine-arginine (MCRR) were introduced at different concentrations in a single-component (MCLR or MCRR) or dual-component (MCLR and MCRR) system to zebrafish embryos in the presence of inorganic elements (Hg, As, Pb, and Cd) and nutrient species (NO3 (-) , PO4 (3-) , and Cl(-1) ). Hatchability, heart rate, and mortality of zerbrafish embryos were monitored together with changes in the activity of glutathione-S-transferase (GST) to evaluate their response on exposure to MCLR and MCRR. There was a significant reduction in all these parameters at higher doses of MCLR and MCRR (>100 ng/mL), implying bioaccumulation of these MCs in embryos and adverse effects on early development stages of the fish. It was further observed that PO4 (3-) and Cl(-) enhanced the toxic effects of MCLR and MCRR while NO3 (-) attenuated their toxic effects. In contrast, all 4 toxic elements together increased the toxicity of MCLR and MCRR to embryos compared with their single-component counterparts. Thus, the toxic effects of MCs depend not only on their relative environmental concentrations, but also on those of other environmental pollutants and the levels of antioxidants in exposed organisms. PMID- 23440876 TI - Volume Modulated Arc Therapy (VMAT) for pulmonary Stereotactic Body Radiotherapy (SBRT) in patients with lesions in close approximation to the chest wall. AB - PURPOSE: Chest wall pain and discomfort has been recognized as a significant late effect of radiation therapy in historical and modern treatment models. Stereotactic Body Radiotherapy (SBRT) is becoming an important treatment tool in oncology care for patients with intrathoracic lesions. For lesions in close approximation to the chest wall with motion management, SBRT techniques can deliver high dose to the chest wall. As an unintended target of consequence, there is possibility of imposing significant chest wall pain and discomfort as a late effect of therapy. The purpose of this paper is to evaluate the potential role of Volume Modulated Arc Therapy (VMAT) technologies in decreasing chest wall dose in SBRT treatment of pulmonary lesions in close approximation to the chest wall. MATERIALS AND METHODS: Ten patients with pulmonary lesions of various sizes and tomography in close approximation to the chest wall were selected for retrospective review. All volumes including tumor target, chest wall, ribs, and lung were contoured with maximal intensity projection maps and four-dimensional computer tomography planning. Radiation therapy planning consisted of static techniques including Intensity Modulated Radiation Therapy compared to VMAT therapy to a dose of 60 Gy in 12 Gy fraction dose. Dose volume histogram to rib, chest wall, and lung were compared between plans with statistical analysis. RESULTS: In all patients, dose and volume were improved to ribs and chest wall using VMAT technologies compared to static field techniques. On average, volume receiving 30 Gy to the chest wall was improved by 74%; the ribs by 60%. In only one patient did the VMAT treatment technique increase pulmonary volume receiving 20 Gy (V20). CONCLUSIONS: VMAT technology has potential of limiting radiation dose to sensitive chest wall regions in patients with lesions in close approximation to this structure. This would also have potential value to lesions treated with SBRT in other body regions where targets abut critical structures. PMID- 23440873 TI - Distribution and association of mTOR with its cofactors, raptor and rictor, in cumulus cells and oocytes during meiotic maturation in mice. AB - Mammalian target of rapamycin (mTOR), a Ser/Thr protein kinase, is the catalytic component of two distinct signaling complexes, mTOR-raptor complex (mTORC1) and mTOR-rictor complex (mTORC2). Recently, studies have demonstrated mitosis specific roles for mTORC1, but the functions and expression dynamics of mTOR complexes during meiotic maturation remain unclear. In the present study, to evaluate the roles of respective mTOR complexes in maternal meiosis and compare them with those in mitosis, we sought to elucidate the spatiotemporal immunolocalization of mTOR, the kinase-active Ser2448- and Ser2481-phosphorylated mTOR, and raptor and rictor during cumulus-cell mitosis and oocyte meiotic maturation in mice. mTOR principally accumulated around the chromosomes and on the spindle. Phosphorylated mTOR (Ser2448 and Ser2481) exhibited elevated fluorescence intensities in the cytoplasm and punctate localization adjacent to the chromosomes, on the spindle poles, and on the midbody during mitotic and meiotic maturation, suggesting functional homology of mTOR between the two cell division systems, despite their mechanistically distinctive spindles. Raptor colocalized with mTOR during both types of cell division, indicating that mTORC1 is predominantly associated with these events. Mitotic rictor uniformly distributed through the cytoplasm, and meiotic rictor localized around the spindle poles of metaphase-I oocytes, suggesting functional divergence of mTORC2 between mitosis and female meiosis. Based on the general function of mTORC2 in the organization of the actin cytoskeleton, we propose that mTORC1 controls spindle function during mitosis and meiosis, while mTORC2 contributes to actin dependent asymmetric division during meiotic maturation in mice. PMID- 23440877 TI - Effects of social status and stress on patterns of gastrointestinal parasitism in wild white-handed gibbons (Hylobates lar). AB - Although gibbons (family Hylobatidae) are typically monogamous, polyandrous groups occur regularly. Stress associated with elevated intragroup competition among males in polyandrous groups may increase susceptibility to infectious disease. To better understand this interplay, as well as to provide the first comprehensive assessment of parasitism in free-ranging gibbons, we characterized the richness of gastrointestinal parasites and examined their prevalence in males from 14 groups (10 pair-living, 4 multi-male) of white-handed gibbons (Hylobates lar) at Khao Yai National Park, Thailand. From September 2008 to May 2009, 324 fecal samples were collected from 23 individually recognizable male gibbons and screened for gastrointestinal helminths and protozoa after isolation via fecal floatation, sedimentation, and immunofluorescent antibody detection. A total of 10 parasite species recovered, including seven nematodes, two protozoans, and one trematode. Parasite richness and species-specific prevalence were examined relative to social organization (pair-living vs. multi-male), male status (primary vs. secondary), age (subadult, adult, senior), fecal glucocorticoid levels, and time of the year. No relationship was found between parasite richness and sociodemographic or physiological factors. Similarly, prevalence of infection with parasite species was not associated with the majority of sociodemographic factors; however, Ternidens sp. and Balantidium coli varied seasonally and Trichuris sp. decreased with increasing age. Moreover, observational data suggest that competition is low in this gibbon population, and our findings are consistent with those observations in that cooperative defense may offset stress and reduce susceptibility to infection. PMID- 23440879 TI - Carboxylate-assisted ruthenium(II)-catalyzed hydroarylations of unactivated alkenes through C-H cleavage. PMID- 23440880 TI - Analyzing visual signals as visual scenes. AB - The study of visual signal design is gaining momentum as techniques for studying signals become more sophisticated and more freely available. In this paper we discuss methods for analyzing the color and form of visual signals, for integrating signal components into visual scenes, and for producing visual signal stimuli for use in psychophysical experiments. Our recommended methods aim to be rigorous, detailed, quantitative, objective, and where possible based on the perceptual representation of the intended signal receiver(s). As methods for analyzing signal color and luminance have been outlined in previous publications we focus on analyzing form information by discussing how statistical shape analysis (SSA) methods can be used to analyze signal shape, and spatial filtering to analyze repetitive patterns. We also suggest the use of vector-based approaches for integrating multiple signal components. In our opinion elliptical Fourier analysis (EFA) is the most promising technique for shape quantification but we await the results of empirical comparison of techniques and the development of new shape analysis methods based on the cognitive and perceptual representations of receivers. Our manuscript should serve as an introductory guide to those interested in measuring visual signals, and while our examples focus on primate signals, the methods are applicable to quantifying visual signals in most taxa. PMID- 23440878 TI - Three-dimensional amide proton transfer MR imaging of gliomas: Initial experience and comparison with gadolinium enhancement. AB - PURPOSE: To investigate the feasibility of a three-dimensional amide-proton transfer (APT) imaging sequence with gradient- and spin-echo readouts at 3 Tesla in patients with high- or low-grade gliomas. MATERIALS AND METHODS: Fourteen patients with newly diagnosed gliomas were recruited. After B0 inhomogeneity correction on a voxel-by-voxel basis, APT-weighted images were reconstructed using a magnetization-transfer-ratio asymmetry at offsets of +/-3.5 ppm with respect to the water resonance. Analysis of variance post hoc tests were used for statistical evaluations, and results were validated with pathology. RESULTS: In six patients with gadolinium-enhancing high-grade gliomas, enhancing tumors on the postcontrast T1 -weighted images were consistently hyperintense on the APT weighted images. Increased APT-weighted signal intensity was also clearly visible in two pathologically proven, high-grade gliomas without gadolinium enhancement. The average APT-weighted signal was significantly higher in the lesions than in the contralateral normal-appearing brain tissue (P < 0.001). In six low-grade gliomas, including two with gadolinium enhancement, APT-weighted imaging showed iso-intensity or mild punctate hyperintensity within all the lesions, which was significantly lower than that seen in the high-grade gliomas (P < 0.001). CONCLUSION: The proposed three-dimensional APT imaging sequence can be incorporated into standard brain MRI protocols for patients with malignant gliomas. PMID- 23440881 TI - The diversity-oriented synthesis of pteridines - achievements and potential for development. AB - The importance of pteridines in the key cofactors, tetrahydrofolate and tetrahydrobiopterin, has encouraged the development of the chemistry and chemical biology of pteridines. In order to investigate the latter, versatile synthetic methods are required to prepare designed relatives of the natural cofactors for use as potential drugs or biological probes. Recently, diversity-oriented synthesis has become a particularly powerful and versatile approach to the synthesis of pteridines and related heterocyclic compounds. This article describes and discusses available methods using radical, electrophilic, nucleophilic, and organometal mediated substitution reactions. PMID- 23440883 TI - Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems. AB - PURPOSE: Magnetic resonance imaging (MRI) is widely used in human brain research to evaluate the effects of healthy aging and development, as well as neurological disorders. Although standardized methods for quality assurance of human MRI instruments have been established, such approaches have typically not been translated to small animal imaging. We present a method for the generation and analysis of customized phantoms for small animal MRI systems that allows rapid and accurate system stability monitoring. METHODS: Computer-aided design software was used to produce a customized phantom using a rapid prototyping printer. Automated registration algorithms were used on three-dimensional images of the phantom to allow system stability to be easily monitored over time. RESULTS: The design of the custom phantom allowed reliable placement relative to the imaging coil. Automated registration showed superior ability to detect gradient changes reflected in the images than with manual measurements. Registering images acquired over time allowed monitoring of gradient drifts of less than one percent. CONCLUSION: A low cost, MRI compatible phantom was successfully designed using computer-aided design software and a three-dimensional printer. Registering phantom images acquired over time allows monitoring of gradient stability of the MRI system. PMID- 23440884 TI - Metal and selenium concentrations in blood and feathers of petrels of the genus Procellaria. AB - Concentrations of copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb), mercury (Hg), and selenium (Se) were determined in blood and feathers of spectacled (Procellaria conspicillata) and white-chinned (Procellaria aequinoctialis) petrels, species that are phylogenetically related, but with distinct ecological niches. In winter, they feed on similar foods, indicated by an overlapping range of whole-blood stable isotopes values (delta(15) N; delta(13) C). No relation was found between blood metal concentration and stable isotope values. In spectacled petrels, metal concentrations appeared lower in blood (Cu = 0.79-20.77 ug/g; Zn = 10.95-28.02 ug/g; Cd = 1.73-10.11 ug/g; Pb = 5.02-26.03 ug/g; Hg = 0.84-9.86 ug/g) than in feathers (Cu = 1.05-21.57 ug/g; Zn = 45.30-81.49 ug/g; Cd = 3.76 10.44 ug/g; Pb = 16.53-59.00 ug/g; Hg = 4.24-24.03 ug/g). In white-chinned petrels, metal concentrations also appeared lower in blood (Cu = 0.62-10.4 ug/g; Zn = 10.73-24.69 ug/g; Cd = 2.00-6.31 ug/g; Pb = 5.72-24.03 ug/g) than in feathers (Cu = 2.68-23.92 ug/g; Zn = 48.96-93.54 ug/g; Cd = 5.72-24.03 ug/g; Pb = 18.62-55.51 ug/g), except for Hg (blood = 0.20-15.82 ug/g; feathers = 0.19-8.91 ug/g). Selenium (0.24-14.18 ug/g) and Hg (0.22-1.44 ug/g) concentrations showed a positive correlation in growing feathers of spectacled petrels. Blood and feather Hg levels were higher in spectacled petrels while feathers Cu and Zn concentrations were greater in white-chinned petrels. Juvenile white-chinned petrels exhibited greater blood Hg concentrations than adults. In the south Atlantic Ocean, discards from commercial fishing operations consumed by spectacled petrels year-round and by white-chinned petrels during the wintering period have elevated Hg concentrations. Because Hg toxicity is associated with behavioral and reproductive changes in birds, it could potentially have impacts on breeding of these seabirds, as both species are listed as threatened by extinction. PMID- 23440885 TI - Radixin expression in microglia after cortical stroke lesion. AB - Stroke induces extensive tissue remodeling, resulting in the activation of several cell types in the brain as well as recruitment of blood-borne leucocytes. Radixin is part of a cytoskeleton linker protein family with the ability to connect transmembrane proteins to the actin cytoskeleton, promoting cell functions involving a dynamic cytoskeleton such as morphological changes, cell division and migration which are common events of different cell types after stroke. In the healthy adult brain radixin is expressed in Olig2(+) cells throughout the brain and in neural progenitor cells in the subventricular zone. In the current study, we detected a 2.5 fold increase in the number of radixin positive cells in the peri-infarct cortex two weeks after the induction of cortical stroke by photothrombosis. Similarly, the number of Olig2(+) cells increased in the peri-infarct area after stroke; however, the number of radixin(+)/Olig2(+) cells was unchanged. Neural progenitor cells maintained radixin expression on their route to the infarct. More surprising however, was the expression of radixin in activated microglia in the peri-infarct cortex. Seventy percent of Iba1(+) cells expressed radixin after stroke, a population which was not present in the control brain. Furthermore, activation of radixin was predominantly detected in the peri-infarct region of oligodendrocyte progenitors and microglia. The specific location of radixin(+) cells in the peri infarct region and in microglia suggests a role for radixin in microglial activation after stroke. PMID- 23440887 TI - Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake. AB - Previously, we reported a long-lasting inhibition of transport mediated by organic anion-transporting polypeptides (OATPs) in humans and rats by cyclosporin A (CsA). In the present study, we examined the effects of several other compounds on OATP1B1-mediated transport, with a focus on long-lasting inhibition. Effects of coincubation, preincubation, or preincubation plus coincubation of 12 compounds on uptake of estrone 3-sulfate (E1 S) in OATP1B1-expressing HEK293T cells were examined. The OATP1B1 inhibitors used in the present study inhibited OATP1B1-mediated uptake of E1 S in a concentration-dependent manner. Among them, saquinavir and ritonavir in addition to CsA exhibited long-lasting inhibitory effects on OATP1B1-mediated transport of E1 S at >= 5 and 25 MUM, respectively, even after they were washed out from the incubation buffer. After preincubation with saquinavir, its inhibitory effect on OATP1B1 remained for at least 6 h, whereas the effect of ritonavir did not remain. Protein expression of OATP1B1 was not altered by preincubation with 25 MUM saquinavir or ritonavir. The present study firstly showed that saquinavir and ritonavir as well as CsA have long lasting inhibitory effects on OATP1B1. But, at plasma unbound concentrations of saquinavir and ritonavir in clinical situations, they may not cause long-lasting inhibition of OATP1B1. PMID- 23440886 TI - Polyunsaturated fatty acid derived signaling in reproduction and development: insights from Caenorhabditis elegans and Drosophila melanogaster. AB - Polyunsaturated fatty acids (PUFAs) exhibit a diverse range of critical functions in biological systems. PUFAs modulate the biophysical properties of membranes and, along with their derivatives, the eicosanoids and endocannabinoids, form a wide array potent lipid signaling molecules. Much of our early understanding of PUFAs and PUFA-derived signaling stems from work in mammals; however, technological advances have made comprehensive lipid analysis possible in small genetic models such as Caenorhabditis elegans and Drosophila melanogaster. These models have a number of advantages, such as simple anatomy and genome-wide genetic screening techniques, which can broaden our understanding of fatty-acid derived signaling in biological systems. Here we review what is known about PUFAs, eicosanoids, and endocannabinoids in the development and reproduction of C. elegans and D. melanogaster. Fatty acid signaling appears to be fundamental for multicellular organisms, and simple invertebrates often employ functionally similar pathways. In particular, studies in C. elegans and Drosophila are providing insight into the roles of PUFAs and PUFA-derived signaling in early developmental processes, such as meiosis, fertilization, and early embryonic cleavage. PMID- 23440888 TI - Mathematical relationships between metrics of chemical bioaccumulation in fish. AB - Five widely used metrics of bioaccumulation in fish are defined and discussed, namely the octanol-water partition coefficient (KOW ), bioconcentration factor (BCF), bioaccumulation factor (BAF), biomagnification factor (BMF), and trophic magnification factor (TMF). Algebraic relationships between these metrics are developed and discussed using conventional expressions for chemical uptake from water and food and first-order losses by respiration, egestion, biotransformation, and growth dilution. Two BCFs may be defined, namely as an equilibrium partition coefficient KFW or as a nonequilibrium BCFK in which egestion losses are included. Bioaccumulation factors are shown to be the product of the BCFK and a novel equilibrium multiplier M containing 2 ratios, namely, the diet-to-water concentration ratio and the ratio of uptake rate constants for respiration and dietary uptake. Biomagnification factors are shown to be proportional to the lipid-normalized ratio of the predator/prey values of BCFK and the ratio of the equilibrium multipliers. Relationships with TMFs are also discussed. The effects of chemical hydrophobicity, biotransformation, and growth are evaluated by applying the relationships to a range of illustrative chemicals of varying KOW in a linear 4-trophic-level food web with typical values for uptake and loss rate constants. The roles of respiratory and dietary intakes are demonstrated, and even slow rates of biotransformation and growth can significantly affect bioaccumulation. The BCFK s and the values of M can be regarded as the fundamental determinants of bioaccumulation and biomagnification in aquatic food webs. Analyzing data from food webs can be enhanced by plotting logarithmic lipid-normalized concentrations or fugacities as a linear function of trophic level to deduce TMFs. Implications for determining bioaccumulation by laboratory tests for regulatory purposes are discussed. PMID- 23440890 TI - Regio- and enantioselective copper(I)-catalyzed hydroboration of borylalkenes: asymmetric synthesis of 1,1-diborylalkanes. PMID- 23440889 TI - Neuron-Enriched Gene Expression Patterns are Regionally Anti-Correlated with Oligodendrocyte-Enriched Patterns in the Adult Mouse and Human Brain. AB - An important goal in neuroscience is to understand gene expression patterns in the brain. The recent availability of comprehensive and detailed expression atlases for mouse and human creates opportunities to discover global patterns and perform cross-species comparisons. Recently we reported that the major source of variation in gene transcript expression in the adult normal mouse brain can be parsimoniously explained as reflecting regional variation in glia to neuron ratios, and is correlated with degree of connectivity and location in the brain along the anterior-posterior axis. Here we extend this investigation to two gene expression assays of adult normal human brains that consisted of over 300 brain region samples, and perform comparative analyses of brain-wide expression patterns to the mouse. We performed principal components analysis (PCA) on the regional gene expression of the adult human brain to identify the expression pattern that has the largest variance. As in the mouse, we observed that the first principal component is composed of two anti-correlated patterns enriched in oligodendrocyte and neuron markers respectively. However, we also observed interesting discordant patterns between the two species. For example, a few mouse neuron markers show expression patterns that are more correlated with the human oligodendrocyte-enriched pattern and vice-versa. In conclusion, our work provides insights into human brain function and evolution by probing global relationships between regional cell type marker expression patterns in the human and mouse brain. PMID- 23440891 TI - Grammatical sensitivity and working memory in children with language impairment. AB - Children with primary language impairment (LI) show a deficit in processing different grammatical structures, verb inflections, and syntactically complex sentences among other things (Clahsen-Hansen 1997; Leonard et al. 1997). Cross linguistic research has shown that the pattern of performance is language specific. We examined grammatical sensitivity to word order and agreement violations in 50 Hungarian-speaking children with and without LI. The findings suggest a strong association between sensitivity to grammatical violations and working memory capacity. Variations in working memory performance predicted grammatical sensitivity. Hungarian participants with LI exhibited a weakness in detecting both agreement and word order violations. PMID- 23440893 TI - Preference reversal between impulsive and self-control choice. AB - In a concurrent-chains procedure, pigeons chose between reinforcers varying in delay and amount. Reinforcer amount was determined by duration of access to grain, and delay was determined by fixed-interval schedules in the terminal links. Preference was measured by the ratio of responses in initial links. Dependent scheduling of variable-interval schedules in initial links ensured that delay and amount were not confounded with frequency of outcomes, which remained equal for the two choices. In Experiment 1, in components signaled by red keys in the initial links, small and large reinforcers were delivered after delays of 1 s and 10 s respectively. In components signaled by green, additional time was added to both delays. Smaller-sooner reinforcers were preferred in red components. In green components, smaller-sooner reinforcers were preferred at short delays, and choices for the larger-later reinforcer generally increased with increasing duration of the added delay. At longer delays, up to 15 s, the larger-later reinforcer was preferred. That is, the pigeons showed within-session preference reversal, with impulsive choice at short delays in red components and self control choice at long delays in green components. In Experiment 2, added delay to both reinforcement and reinforcer amount were varied. Sensitivity of initial link response ratios to ratios of amount increased with increasing duration of the added delay. This interaction between delay and amount was predicted if the temporal discounting functions assumed the magnitude effect in which discounting rate was inversely proportional to amount. It was also predicted by the contextual choice model of performance in concurrent-chains procedures. PMID- 23440892 TI - Very small embryonic-like cells: biology and function of these potential endogenous pluripotent stem cells in adult tissues. AB - Very small embryonic-like cells (VSELs), found in murine bone marrow and other adult tissues, are small, non-hematopoietic cells expressing markers of pluripotent embryonic and primordial germ cells. A similar cell type in humans has begun to be characterized, though with a slightly different phenotype and surface markers. Consistent with expression of pluripotency genes, murine VSELs differentiate into cell types from three germ-layer lineages in vitro, though pluripotency has yet to be shown at the single-cell level or in vivo. VSELs appear to be quiescent under steady state conditions, apparently due to partially erased imprinting and overexpression of cell cycle inhibitory genes. In vivo, VSELs can enter the cell cycle under stress conditions, but which factors regulate quiescence versus proliferation and self-renewal versus differentiation are as yet unknown, and in vitro conditions that induce proliferation and self renewal have yet to be defined. Future experiments are needed to address whether a VSEL niche actively regulates quiescence in vivo or quiescence is cell autonomous under steady state conditions. Insights into these mechanisms may help to address whether or not VSELs could play a role in regenerative medicine in the future. PMID- 23440894 TI - Knee cartilage MRI with in situ mechanical loading using prospective motion correction. AB - PURPOSE: To assess the feasibility of high resolution knee cartilage MRI with in situ mechanical loading using optical tracking to compensate for motion. METHODS: In vivo cartilage MRI with in situ mechanical loading is demonstrated on a clinical 3T system for the patellofemoral as well as for the tibiofemoral knee joint using a T1-weighted spoiled three-dimensional gradient-echo sequence. Prospective motion correction is performed with a moire phase tracking system consisting of an in-bore camera and a single tracking marker attached to the skin. RESULTS: Rigid-body approximation required for prospective correction with optical motion tracking is fulfilled well enough for the patellofemoral as well as for the tibiofemoral joint when the tracking marker is attached to the knee cap and the shin, respectively. Presaturation proves to be efficient in suppressing pulsation artifacts from the popliteal artery and residual motion artifacts primarily arising from nonrigid motion of the posterior knee compartment. CONCLUSION: The proposed technique enables knee cartilage imaging under in situ mechanical loading with submillimeter spatial resolution devoid of significant motion artifacts and thus appropriate for cartilage volumetry. It has the potential to provide new insight into the biomechanics of the knee and might complement the panoply of diagnostic MR methods for osteoarthritis. PMID- 23440895 TI - Fluorescent probes for G-quadruplex structures. AB - Mounting evidence supports the presence of biologically relevant G-quadruplexes in single-cell organisms, but the existence of endogenous G-quadruplex structures in mammalian cells remains highly controversial. This is due, in part, to the common misconception that DNA and RNA molecules are passive information carriers with relatively little structural or functional complexity. For those working in the field, however, the lack of available tools for characterizing DNA structures in vivo remains a major limitation to addressing fundamental questions about structure-function relationships of nucleic acids. In this review, we present progress towards the direct detection of G-quadruplex structures by using small molecules and modified oligonucleotides as fluorescent probes. While most development has focused on cell-permeable probes that selectively bind to G quadruplex structures with high affinity, these same probes can induce G quadruplex folding, thereby making the native conformation of the DNA or RNA molecule (i.e., in the absence of probe) uncertain. For this reason, modified oligonucleotides and fluorescent base analogues that serve as "internal" fluorescent probes are presented as an orthogonal means for detecting conformational changes, without necessarily perturbing the equilibria between G quadruplex, single-stranded, and duplex DNA. The major challenges and motivation for the development of fluorescent probes for G-quadruplex structures are presented, along with a summary of the key photophysical, biophysical, and biological properties of reported examples. PMID- 23440896 TI - Detergent-resistant plasma membrane proteome to elucidate microdomain functions in plant cells. AB - Although proteins and lipids have been assumed to be distributed homogeneously in the plasma membrane (PM), recent studies suggest that the PM is in fact non uniform structure that includes a number of lateral domains enriched in specific components (i.e., sterols, sphingolipids, and some kind of proteins). These domains are called as microdomains and considered to be the platform of biochemical reaction center for various physiological processes. Microdomain is able to be extracted as detergent-resistant membrane (DRM) fractions, and DRM fractions isolated from some plant species have been used for proteome and other biochemical characterizations to understand microdomain functions. Profiling of sterol-dependent proteins using a putative microdomain-disrupting agent suggests specific lipid-protein interactions in the microdomain. Furthermore, DRM proteomes dynamically respond to biotic and abiotic stresses in some plant species. Taken together, these results suggest that DRM proteomic studies provide us important information to understand physiological functions of microdomains that are critical to prosecute plant's life cycle successfully in the aspect of development and stress responses. PMID- 23440897 TI - CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. AB - The studies on fractalkine and its unique receptor CX3CR1 in neurological disorders yielded contrasting results. We have explored the consequences of CX3CR1 deletion in ischemic (30' MCAo) mice on: (1) brain infarct size; (2) microglia dynamism and morphology; (3) expression of markers of microglia/macrophages (M/M) activation and polarization. We observed smaller infarcts in cx3cr1(-/-) (26.42 +/- 7.41 mm(3) , mean +/- sd) compared to wild type (36.29 +/- 11.57) and cx3cr1(-/+) (34.49 +/- 8.91) mice. We longitudinally analyzed microglia by in vivo two-photon microscopy before, 1 and 24 h after transient ischemia. Microglia were stationary in both cx3cr1(-/-) and cx3cr1(-/+) mice throughout the study. In cx3cr1(-/-) mice, they displayed a significantly higher number of ramifications >10 MUm at baseline and at 24 h after ischemia compared to cx3cr1(-/+) mice, indicating that CX3CR1 deficiency impaired the development of microglia hypertrophic/amoeboid morphology. At 24 h after ischemia, we performed post mortem quantitative immunohistochemistry for different M/M markers. In cx3cr1(-/-) immunoreactivity for CD11b (M/M activation) and for CD68 (associated with phagocytosis) were decreased, while that for CD45(high) (macrophage and leukocyte recruitment) was increased. In addition, immunoreactivity for Ym1 (M2 polarization) was enhanced, while that for iNOS (M1) was decreased. Our data show that in cx3cr1(-/-) mice protection from ischemia at early time points after injury is associated with a protective inflammatory milieu, characterized by the promotion of M2 polarization markers. PMID- 23440898 TI - Functional morphology of the female genital organs in the peruvian red uakari monkey (Cacajao calvus ucayalii). AB - Functional morphology may provide important information that could improve methodologies for the diagnosis of the reproductive phase of females, and develop assisted breeding techniques for wildlife. This study examined features of genital organs in 19 Peruvian red uakari monkey (Cacajao calvus ucayalii) females in different reproductive stages, collected from wild animals hunted for food by rural communities in the North-eastern Peruvian Amazon, in order to provide knowledge on the reproductive physiology of this species. The observed mean ovulation rate was 1.4 follicles, and the observed maximal follicle diameter was 0.8 cm. After ovulation, the matured follicle luteinizes resulting in functional CL. In case of oocyte fertilization, the pregnancy CL grows to a maximum of 1.2 cm in diameter, and luteal volume per female decreases related to the advance of pregnancy. Pregnant females also present follicular activity until late pregnancy, but non-ovulated follicles do not undergo atretic processes and apparently transform to accessory CL, resulting in a contribution of 30% of the total luteal volume. All pregnant females delivered a single fetus at term, resulting in a rate of reproductive wastage of 20% of oocytes or embryos. The endometrium and the endometrial glands in non-pregnant females in the follicular phase show a significant increase related to the follicular growth, reaching a high proliferation in non-pregnant females in the luteal phase. The red uakari monkey showed different vaginal epithelium features in accordance with the reproductive state of the female, suggesting that vaginal cytology could be a successful methodology with which to characterize the estrous cycle of this species. The present reproductive evaluation of the Peruvian red uakari monkey provides important information that could improve the development of assisted reproductive techniques in non-human primates. PMID- 23440899 TI - Prevalence of disc degeneration in asymptomatic korean subjects. Part 1 : lumbar spine. AB - OBJECTIVE: Asymptomatic patients show high degeneration prevalence at lumbar disc in previous literatures. Unfortunately, there are few Korean data, so the authors attempted to analyze the prevalence of disc degeneration in highly selective asymptomatic Korean subjects using MRI. METHODS: We performed 3 T MRI sagittal scans from T12 to S1 on 102 asymptomatic subjects (50 men and 52 women) who visited our hospital between the ages of 14 and 82 years (mean age 46.3 years). All images were read independently by three observers (two neurosurgeons and one neuroradiologist) who were not given any information about the subjects. We classified grading for lumbar disc herniation (HN), annular fissure (AF), and nucleus degeneration (ND), using disc degeneration classification. RESULTS: The prevalence of HN, AF, and ND were 81.4%, 76.1%, and 75.8% respectively. Almost all levels showed an age-related proportional tendency with some exceptions. CONCLUSION: In asymptomatic Korean subjects, the abnormal findings showed high prevalence of AF, ND, and extrusion. Especially in young ages, the authors found that bulging, protrusion, and AF showed high prevalence at L4/5 and L5/S1. And ND showed high prevalence at L5/S1. So, all lumbar disc degenerations are not pathologic, especially in children and adolescents. PMID- 23440900 TI - Stability-indicating Reversed-phase Liquid Chromatographic Method for Simultaneous Determination of Losartan Potassium and Ramipril in Tablets. AB - A stability-indicating reversed-phase liquid chromatographic method has been developed and validated for simultaneous determination of losartan potassium and ramipril. Separations were achieved using a C(18) column with mobile phase consisting of acetonitrile and (0.2% v/v, pH 2.5) aqueous trifluoroacetic acid (45:55, v/v) in isocratic mode at 1 ml/min flow rate. Column effluent was monitored at 210 nm using a UV detector. The method was validated for selectivity, linearity, accuracy, precision, sensitivity and robustness. Novel microwave-assisted forced degradation technique was employed for evaluation of selectivity. The method demonstrated excellent linearity for losartan potassium and ramipril with regression coefficients of 0.9999 and 0.9998, respectively. The linearity range was found to be 62.5-5000 ng/ml and 125-10,000 ng/ml with the mean percentage recoveries of 100.36% (+/-2.27) and 100.16% (+/-3.33) for losartan potassium and ramipril, respectively. In a robustness study, a full factorial design revealed that the analytical response remains unaffected by small variations in the critical chromatographic factors. The method was found to be sensitive with quantification limits of 44.30 and 79.93 ng/ml for losartan potassium and ramipril. The method was successfully employed for the determination of losartan potassium and ramipril in commercially available and in house prepared tablets. PMID- 23440901 TI - Temporal plasticity in annelid development--ontogeny of Phyllodoce groenlandica (Phyllodocidae, Annelida) reveals heterochronous patterns. AB - The variety of annelid larval types and developmental modes reflects the high diversity and variability within these lophotrochozoans. However, our knowledge of pattern formation and tissue development in annelids and allies is scarce. In order to gain more data concerning neurogenesis and myogenesis in annelid trochophores, we analyzed different larval stages of Phyllodoce groenlandica using immunohistochemical staining techniques and subsequent confocal laser scanning microscopy (clsm). Focusing on pre-metamorphic stages, we reconstruct the process of tissue and body formation within planktonic polychaetous trochophore larvae. Our investigations revealed detailed knowledge of general developmental modes in Annelida and exhibit ontogenetic heterochrony of tissue development between two closely related annelid species. As such, P. groenlandica shows a delayed onset of nervous system development when compared with P. maculata. In contrast to the latter species, we were not able to detect the posterior sensory organ in larval P. groenlandica. We draw conclusions concerning general development of annelid trochophores and provide data showing new insights into the plasticity of body plans in Annelida. PMID- 23440902 TI - Tissue engineered aortic valve. AB - Several prostheses are available to replace degenerative diseased aortic valves with unique advantages and disadvantages. Bioprotheses show excellent hemodynamic behavior and low risk of thromboembolic complications, but are limited by tissue deterioration. Mechanical heart valves have extended durability, but permanent anticoagulation is mandatory. Tissue engineering created a new generation heart valve, which overcome limitations of biological and mechanical heart valves due to remodelling, regeneration and growth potential. Several publications are available in using tissue engineered heart valves in right ventricular outflow tract reconstruction. Limited experiences are available on these heart valves implanted into the systemic circulation. This overview shows the current state on the development of tissue engineered aortic heart valves. PMID- 23440903 TI - The Relationship between Smoking, Socioeconomic Status and Grip Strength among Community-dwelling Elderly Men in Korea: Hallym Aging Study. AB - OBJECTIVES: Low grip strength is associated with decline in bone mineral density (BMD) and increased risk of spine fracture among the elderly. Smoking, a major factor determining BMD, is also known to have an indirect effect on bone loss. This study investigated whether smoking is associated with grip strength in the community-dwelling elderly in Korea. METHODS: This study was an outcome of the second of three waves of the Hallym Aging Study from January to May 2007, a population-based study of Koreans aged 45 years and upwards dwelling in Chuncheon. Its 218 subjects comprised men aged 65 years or over. They were evaluated at a general hospital for socioeconomic status, smoking history, and various clinical measures including grip strength. RESULTS: Grip strength was higher in non-, ex-, and current smokers (33.7 kg, 30.6 kg, and 29.3 kg, respectively). Current smoking was found to increase the risk of decreased grip strength (adjusted odds ratio [aOR], 4.58; 95% confidence interval [CI],1.31 to 16.04) compared with non-smoking, after adjustment for potential covariates including socioeconomic status. After adjustment for smoking effect, education of fewer than six years and monthly income of fewer than 500,000 Korean won increased the risk of decreased grip strength compared with education of more than six years (aOR, 2.88; 95% CI, 1.08 to 7.66) and monthly income of more than 1,500,000 Korean won (aOR, 2.86; 95% CI, 1.08 to 7.54). CONCLUSIONS: These results showed that current smoking, low education and low income were independent risk factors for decreased grip strength among elderly men in Korea. PMID- 23440904 TI - Preference for a fixed combination of brinzolamide/timolol versus dorzolamide/timolol among patients with open-angle glaucoma or ocular hypertension. AB - OBJECTIVE: To assess ocular discomfort upon instillation and patient preference for brinzolamide/timolol relative to dorzolamide/timolol, in patients with open angle glaucoma or ocular hypertension. METHODS: This was a multicenter, prospective, patient-masked, randomized, crossover study. On day 0, patients received one drop of brinzolamide/timolol in one eye and one drop of dorzolamide/timolol in the contralateral eye. On day 1, patients were randomly assigned to receive one drop of either brinzolamide/timolol or dorzolamide/timolol in both eyes; on day 2, patients received one drop of the alternate treatment in both eyes. Measures included a patient preference question on day 2 (primary) and mean ocular discomfort scale scores on days 1 and 2 (secondary). Safety assessments included adverse events, visual acuity, and slit lamp examinations. RESULTS: Of 120 patients who enrolled, 115 completed the study. Of these, 112 patients instilled both medications and expressed a study medication preference on day 2. A significantly greater percentage preferred brinzolamide/timolol to dorzolamide/timolol (67.0% versus 30.4%; P < 0.001). The ocular discomfort (expressed as mean [standard deviation]) with brinzolamide/timolol was significantly lower than with dorzolamide/timolol (day 2:1.9 [2.3] versus 3.7 [2.8], respectively [P = 0.0003]; both days combined: 2.1 [2.5] versus 3.5 [2.9], respectively [P = 0.00014]). On day 1, five patients receiving brinzolamide/timolol reported five nonserious adverse events (AEs): flu (n = 1), bitter taste (n = 2), and headache (n = 2). Four events, bitter taste (two events) and headache (two events), were considered related to brinzolamide/timolol. Events were mild in intensity, except bitter taste of moderate intensity reported by one patient. No AEs were reported at day 2. All AEs resolved without additional treatment. No clinically relevant changes from baseline were observed in best-corrected visual acuity or slit-lamp examinations of ocular signs. CONCLUSION: Patients had less discomfort with brinzolamide/timolol than with dorzolamide/timolol, and more expressed a preference for brinzolamide/timolol. Both treatments were generally safe and well tolerated. PMID- 23440905 TI - Perioperative evaluation of primary hemostasis in patients undergoing mitral valve repair. AB - INTRODUCTION: No data exist on the prevalence of primary hemostatic defects and acquired von Willebrand disease in mitral valve prolapse with severe regurgitation. METHODS: Primary hemostasis was evaluated by PFA-100, von Willebrand Factor Antigen (vWF:Ag) and Ristocetin cofactor (vWF:RiCof) assays in a prospective observational trial. Sixty-five consecutive patients with mitral regurgitation (study group) or aortic stenosis (control group) who were operated for mitral valve repair or aortic valve replacement were enrolled in the study. RESULTS: There were no differences in Closure Time in the two groups at all time points. The concentration of plasma vWF: Ag was within normal limits in all patients preoperatively; after surgery, a significant increase was observed in both groups from baseline (199 +/- 144 mcg/dL vs. 295 +/-141 mcg/dL in the study group, p=0.002; 243 +/- 141 mcg/dLl vs 338 +/- 154 mcg/dL in the control group, p=0.009). The ratio of vWF:RiCof to vWF:Ag was slightly decreased preoperatively in both groups (ratio= 0.91) and showed a marked increase in the postoperative period (ratio=0.22) as, probably, new hemostatically effective large multimeric forms of vWF were released. CONCLUSIONS: Patients who present for surgery with a valvular pathology with high shear stress have some degree of primary hemostasis defect; nevertheless, the potent stimulus of surgery and the correction of the underlying disease allow quick restoration of vWF activity and normalization of PFA-100. PMID- 23440906 TI - Antibiogram of salmonella isolates from blood with an emphasis on nalidixic Acid and chloramphenicol susceptibility in a tertiary care hospital in coastal karnataka: a prospective study. AB - BACKGROUND: Enteric fever is caused by the serotypes Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B and Salmonella Paratyphi C. After emergence of multidrug resistant Salmonellae Ciprofloxacin, a fluorquinolone antibiotic was the first-line therapy. Treatment failure was observed with Ciprofloxacin soon and such strains showed in-vitro resistance to Nalidixic acid. Recent reports suggest re-emergence of Chloramphenicol sensitive strains and increasing Nalidixic acid resistance. This study is aimed at detecting the current trend in the antibiogram of Salmonella isolates from blood culture in coastal Karnataka, with an emphasis on antibiotic susceptibility of Nalidixic acid and Chloramphenicol and evaluate, if there is a need to modify the strategies in the antibiotic therapy for enteric fever. MATERIALS AND METHODS: Blood samples received for culture in the laboratory between June 2009 and August 2011 was cultured in Brain Heart infusion broth, bile broth or in a commercial BACTEC culture media. The growth from blood cultures were processed for identification and antibiotic susceptibility as per standard methods. Antibiotic susceptibility for Ampicillin, Trimethoprim-sulphamethoxazole, Chloramphenicol, Ciprofloxacin, Ceftriaxone and Nalidixic acid were noted. RESULTS: Out of 9053 blood culture specimens received, Salmonella was isolated from 103 specimens. There were 85 Salmonella Typhi isolates, 16 Salmonella Paratyphi A and two Salmonella Paratyphi B. Salmonella Typhi and Salmonella Paratyphi A showed the highest resistance to Nalidixic acid. Salmonella Typhi showed highest susceptibility to Ceftriaxone and Salmonella Paratyphi A to trimethoprim-sulphamethoxazole and Chloramphenicol. Two isolates were multidrug resistant. One Salmonella Paratyphi A was resistant to Ceftriaxone. CONCLUSION: Routine screening of Nalidixic acid susceptibility is practical to predict fluorquinolone resistance in Salmonella and preventing therapeutic failure while treating with it. It is worthwhile to consider replacing fluorquinolones with Chloramphenicol or Ceftriaxone as the first line of therapy for enteric fever. Periodic analysis of Salmonella antibiogram should be done to formulate the best possible treatment strategies. PMID- 23440907 TI - Metabolic and hormonal responses to a single session of kumite (free non-contact fight) and kata (highly ritualized fight) in karate athletes. AB - BACKGROUND: Several studies report martial arts as a good model for investigating neuroendocrine responses to competitive fighting. However, little is known on the metabolic responses elicited by elite athletes during fighting. In particular, the metabolic picture in elite athletes of martial arts is little known. AIM: In the present study, our aim was to investigate the acute effects of a session of karate practice on the glucose-insulin system. SUBJECTS AND METHODS: Ten healthy individuals (6M/4F; BMI: 22.1 +/- 0.7 kg/m(2); 21.9 +/- 1.1 years, mean +/- SE) who practice karate in national or international competitions were enrolled. All participants completed two experimental trials in a randomised-crossover fashion. A basal blood sample was collected from each athlete to assess plasma glucose, insulin, cortisol, testosterone and catecholamines, before karate training session. In two separate days, another blood sample was collected from each participants after 3 min of real fighting (kumite) and 3 min of ritualized simulation of combat (kata). RESULTS: In both trials, plasma glucose resulted to be higher at the end the of performance compared to the basal (p < 0.001 after kumite and p < 0.02 after kata). In contrast, insulin was similar in the basal and after physical activity in the two trials. Catecholamines were higher after kata and kumite sessions with respect to the basal values (p < 0.04) and, in particular, epinephrine post-kumite values were much greater than those measured after kata. CONCLUSIONS: Our results indicate that unlike performances of karate (kumite and kata) elicit different plasma glucose increases. In particular, we found that glucose and epinephrine concentrations increased more after kumite than after kata. PMID- 23440908 TI - Differential Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on Motor Behavior and Dopamine Levels at Brain Regions in Three Different Mouse Strains. AB - Developing an animal model for a specific disease is very important in the understanding of the underlying mechanism of the disease and allows testing of newly developed new drugs before human application. However, which of the plethora of experimental animal species to use in model development can be perplexing. Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a very well known method to induce the symptoms of Parkinson's disease in mice. But, there is very limited information about the different sensitivities to MPTP among mouse strains. Here, we tested three different mouse strains (C57BL/6, Balb-C, and ICR) as a Parkinsonian model by repeated MPTP injections. In addition to behavioral analysis, endogenous levels of dopamine and tetrahydrobiopterin in mice brain regions, such as striatum, substantia nigra, and hippocampus were directly quantified by liquid chromatography-tandem mass spectrometry. Repeated administrations of MPTP significantly affected the moving distances and rearing frequencies in all three mouse strains. The endogenous dopamine concentrations and expression levels of tyrosine hydroxylase were significantly decreased after the repeated injections, but tetrahydrobiopterin did not change in analyzed brain regions. However, susceptibilities of the mice to MPTP were differed based on the degree of behavioral change, dopamine concentration in brain regions, and expression levels of tyrosine hydroxylase, with C57BL/6 and Balb-C mice being more sensitive to the dopaminergic neuronal toxicity of MPTP than ICR mice. PMID- 23440910 TI - Erroneously low continuous ScvO2 reading due to red blood cells transfusion. AB - Hemoglobin oxygen saturation in superior vena cava (ScvO(2)) is used as a parameter to guide hemodynamic management in shock patients and it can be continuously read through a central venous catheter equipped with a fiberoptic spectrophotometric probe (Edwards PreSep catheter) connected to a specific monitor (Edwards Vigileo). We report of an episode of erroneous ScvO(2) reading by this technology in a patient with septic shock who was receiving an erythrocytes transfusion through the PreSep catheter main lumen. We think this artifact should be known by intensivists since it can lead to ScvO(2) misinterpretation and subsequent erroneous therapeutic decisions. PMID- 23440909 TI - Relationships between hypercarbic reactivity, cerebral blood flow, and arterial circulation times in patients with moyamoya disease. AB - PURPOSE: To evaluate the correlation between angiographic measures of Moyamoya disease and tissue-level impairment from measurements of tissue perfusion and cerebrovascular reactivity (CVR). MATERIALS AND METHODS: The relationship between perfusion-weighted arterial spin labeling (ASL) and hypercarbic blood oxygenation level dependent (BOLD) CVR and time-to-peak (TTP) were compared with angiographically measured risk factors, including arterial circulation time (ACT) and modified Suzuki Score (mSS) in patients (n = 15) with Moyamoya disease. RESULTS: Hemodynamic contrasts provided information not apparent from structural or angiographic imaging. Mean z-statistics demonstrate that BOLD is significantly (P = 0.017) higher in low mSS hemispheres (z-statistic = 5.0 +/- 2.5) compared with high mSS hemispheres (z-statistic = 3.7 +/- 1.7), suggesting that regions with less advanced stages of Moyamoya disease have higher reactivity. After correcting for multiple comparisons, a strong trend for a direct relationship (R = 0.38; P = 0.03) between BOLD TTP and ACT was observed, and a significant inverse relationship between CBF and ACT (R = -0.47; P = 0.01) was found, demonstrating that BOLD and ASL contrasts reflect DSA measures of vascular compromise in Moyamoya disease, albeit with different sensitivity. CONCLUSION: Correlative measures between angiography and hemodynamic methods suggest that BOLD and ASL could be used for expanding the diagnostic imaging infrastructure in Moyamoya patients and potentially tracking tissue response to revascularization. PMID- 23440911 TI - Accelerated perturbation-resilient block-iterative projection methods with application to image reconstruction. AB - We study the convergence of a class of accelerated perturbation-resilient block iterative projection methods for solving systems of linear equations. We prove convergence to a fixed point of an operator even in the presence of summable perturbations of the iterates, irrespective of the consistency of the linear system. For a consistent system, the limit point is a solution of the system. In the inconsistent case, the symmetric version of our method converges to a weighted least squares solution. Perturbation resilience is utilized to approximate the minimum of a convex functional subject to the equations. A main contribution, as compared to previously published approaches to achieving similar aims, is a more than an order of magnitude speed-up, as demonstrated by applying the methods to problems of image reconstruction from projections. In addition, the accelerated algorithms are illustrated to be better, in a strict sense provided by the method of statistical hypothesis testing, than their unaccelerated versions for the task of detecting small tumors in the brain from X ray CT projection data. PMID- 23440912 TI - Essential Tremor Prevalence is Low in the Druze Population in Northern Israel. AB - BACKGROUND: Essential tremor (ET) and Parkinson's disease (PD) are probably the most common movement disorders. As ethnic differences have been reported in ET, we designed the present study to evaluate the prevalence of ET and that of Parkinson's disease (PD) in the Druze villages of northern Israel. METHODS: A two phase, door-to-door survey was undertaken. Residents aged >=51 years who agreed to participate and answered "yes" to tremor or PD-related screening questions and 3% of subjects who screened negative were evaluated. Diagnostic criteria for ET were similar to those used in Sicilian and Spanish studies. PD was diagnosed according to Gelb's criteria. RESULTS: The target population consisted of 9,086, the study cohort of 3,980 residents. Tremor was observed in 36 subjects. In 27, the tremor fully met the criteria for ET. The prevalence of ET (age >=65) was 1.49% (95% CI 0.91-2.07%). PD was diagnosed in 23 subjects. The prevalence of PD (age >=65) was 1.13 (95% CI 0.62-1.64%). Leucine-rich repeat protein kinase 2 (G2019S mutation) was evaluated in subjects diagnosed with tremor PD and those screened for assessment of the validity of the questionnaire. None carried the mutation. DISCUSSION: The prevalence of ET in the Druze population is low and similar to the prevalence of PD. PMID- 23440913 TI - Is abdominal aortic calcification score a cost-effective screening tool to predict atherosclerotic carotid plaque and cardiac valvular calcification in patients with end-stage renal disease? AB - Abdominal aortic calcification (AAC), cardiac valvular calcification (CVC), and atherosclerotic carotid plaque (CP) are known cardiovascular risk factors. The accuracy of the AAC score in predicting CP and CVC in patients with end-stage renal disease (ESRD) is assessed in this study. Twenty-two consecutive prevalent dialysis patients (group 1) and 26 consecutive nondialysis stage V chronic kidney disease patients (group 2) were assessed for their demographic and laboratory variables. Lateral radiograph of the lumbosacral spine was used to assess the AAC score. CP and CVC were assessed using carotid sonography and echocardiogram, respectively. Prevalence of AAC, CP, and CVC in groups 1 and 2 was, respectively, 72.7%, 81.8%, and 72.7% and 76.9%, 80.8%, and 57.7%. AAC was strongly associated with CP and CVC in both groups (P < 0.001). Tests of accuracy for the AAC score as a predictor of CP and CVC showed sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio of a positive test, and likelihood ratio of a negative test, respectively, in group 1: 83%, 75%, 93%, 50%, 3.32, and 0.23 and 85%, 77%, 87%, 70%, 4.5, and 0.29, and in group 2: 90%, 95%, 83%, 69%, 3.9, 0.41, and 82%, 91%, 77%, 71%, 4.1, and 0.21. Reproducibility of the AAC score among observers was acceptable. The AAC score can predict CP and CVC with moderate accuracy in ESRD patients. However, as our study was underpowered, the findings need validation in larger, adequately powered studies. PMID- 23440914 TI - Cryoextraction: A novel approach to remove aspirated chewing gum. AB - The extraction of aspirated foreign bodies can prove challenging at times, requiring even rigid bronchoscopy. Cryotherapy probes have been reported to help with extraction of foreign bodies. We present a case where successful "cryoextraction" was performed on an aspirated chewing gum. The case highlights the fact that this technique is useful to extract all materials that have water content. This technique can be performed through flexible bronchoscopy and can save patients from more aggressive approaches. PMID- 23440915 TI - Polychlorinated biphenyls in adult black bass and yellow perch were not associated with their reproductive success in the upper Hudson River, New York, USA. AB - Although production and use of polychlorinated biphenyls (PCBs) ceased nearly 35 yr ago, questions still remain concerning the potential chronic effects these compounds may have on wild fish, including their reproductive success. In the upper Hudson River, New York, USA, fish were exposed to PCBs primarily from 2 manufacturing plants located approximately 320 km upstream of New York City, New York, from the 1940s to 1977. The authors collected yellow perch (Perca flavescens), smallmouth bass (Micropterus dolomieu), and largemouth bass (M. salmoides) using electrofishing, measured PCBs in these adults, and estimated abundance and size of their offspring at age 1 yr (age-1 fish). Fish were collected annually from 2004 to 2009 from 1 control site upstream of the PCB discharge sites and from 2 sites downstream from where PCBs were released. These sites (pools) are separated by a series of dams, locks, and canals. Muscle tissue wet weight PCB and lipid-based PCB concentrations in adults in the 2 PCB exposure pools averaged approximately 1 to 3 ug/g and 100 to 500 ug/g, respectively. Age-1 abundances were not related to adult PCB concentrations but were inversely related to river flow. Size of age-1 fish was slightly greater at the PCB exposure sites. Levels of PCBs in yellow perch, largemouth bass, and smallmouth bass in the upper Hudson River did not impair or reduce recruitment or reproductive success. PMID- 23440916 TI - Self-liganded Suzuki-Miyaura coupling for site-selective protein PEGylation. PMID- 23440917 TI - Fast accurate MR thermometry using phase referenced asymmetric spin-echo EPI at high field. AB - PURPOSE: A novel highly accurate method for MR thermometry, effective at high field, is introduced and validated, which corrects for slow and fast field fluctuations by means of reference images. METHODS: An asymmetric spin-echo echo planar imaging sequence was made frequency-selective to water or a reference substance by controlling the slice-select gradient polarity and the duration of the excitation and refocusing radiofrequency pulses. Images were acquired pairwise, and the temperature-sensitive water images were corrected for field fluctuations using the reference images. In a phantom radiofrequency heating experiment, dissolved dimethyl sulfoxide was used as a reference substance. Temperature stability was tested in vivo on the human brain, referenced using subcutaneous scalp fat. Water and fat phase images were acquired only 50 ms apart. Bloch simulations validated the frequency selection accuracy. RESULTS: Asymmetric spin-echo imaging using a simple frequency selection method provides highly accurate referenced MR thermometry in phantoms and in vivo at 7 T. Effects of field fluctuations caused by field drift, breathing, and heart beat were corrected. The technique is highly robust against B1 inhomogeneities. CONCLUSION: Frequency selection using gradient-reversal can enable fast accurate referenced in vivo MR thermometry, assisting thermal characterization of radiofrequency coils and possibly in vivo SAR monitoring. PMID- 23440918 TI - The C-terminal extended serine residue is absolutely required in nosiheptide maturation. AB - Serine qua non: Substitution of the extended Ser13 in the core peptide of nosiheptide by analogous amino acids prevented enamide dealkylation of the terminal residue for nosiheptide maturation. PMID- 23440921 TI - Characterization and evaluation of olive germplasm in southern Italy. AB - BACKGROUND: The southern Italian region of Campania has suitable pedo-climatic conditions and a large varietal heritage able to produce oils with high typicality. The aim of this study was to characterize 20 cultivars belonging to Campania's olive germplasm, evaluating their vegetative and production aspects and their oil quality characteristics. The study was conducted from 2003 to 2009, observing the following aspects in six plants per variety: entry into production, vigour, ripening and drupe oil content. The following analyses were carried out on monovarietal oils, obtained by microextractor: acid composition, polyphenol content and aromatic profile. RESULTS: The agronomic results showed early entry into production for the cultivars Racioppella, Ortolana, Biancolilla and Carpellese. However, entry into production was delayed for Ritonnella, Ortice, Cornia and Rotondella. As regards vegetative behaviour, Asprinia, from the province of Caserta and Pisciottana and Carpellese, from the province of Salerno, proved the most vigorous cultivars. CONCLUSION: Groups of similar cultivars emerged from chemical and sensory analysis of their oils, while other accessions were well characterized and separated from each other, showing a high level of diversity and specificity. PMID- 23440919 TI - PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR. AB - PINK1 (PTEN induced putative kinase 1), a familial Parkinson's disease (PD) related gene, is expressed in astrocytes, but little is known about its role in this cell type. Here, we found that astrocytes cultured from PINK1-knockout (KO) mice exhibit defective proliferative responses to epidermal growth factor (EGF) and fetal bovine serum. In PINK1-KO astrocytes, basal and EGF-induced p38 activation (phosphorylation) were increased whereas EGF receptor (EGFR) expression and AKT activation were decreased. p38 inhibition (SB203580) or knockdown with small interfering RNA (siRNA) rescued EGFR expression and AKT activation in PINK1-KO astrocytes. Proliferation defects in PINK1-KO astrocytes appeared to be linked to mitochondrial defects, manifesting as decreased mitochondrial mass and membrane potential, increased intracellular reactive oxygen species level, decreased glucose-uptake capacity, and decreased ATP production. Mitochondrial toxin (oligomycin) and a glucose-uptake inhibitor (phloretin) mimicked the PINK1-deficiency phenotype, decreasing astrocyte proliferation, EGFR expression and AKT activation, and increasing p38 activation. In addition, the proliferation defect in PINK1-KO astrocytes resulted in a delay in the wound healing process. Taken together, these results suggest that PINK1 deficiency causes astrocytes dysfunction, which may contribute to the development of PD due to delayed astrocytes-mediated repair of microenvironment in the brain. PMID- 23440922 TI - Evaluation of reproduction and raising offspring in a nursery-reared SPF baboon (Papio hamadryas anubis) colony. AB - Baboons (Papio hamadryas anubis) of a conventional breeding colony were nursery reared to create a specific pathogen-free (SPF) baboon-breeding program. Because the founding generations were nursery-reared until 2 years of age, it was suspected that the SPF baboons would exhibit increased reproductive challenges as adults. Mothering behavior was of interest, because SPF females were not exposed to parental role models during the nursery-rearing process. We compared reproductive data from the SPF baboon breeding program during its first 10 years with data from age-matched baboons during the same period from an established, genetically-similar conventional breeding colony. We also evaluated records documenting mother-infant behaviors within the SPF colony. The average age of menarche in SPF females was 3.3 years. The overall live birth rate of both SPF and conventional females was approximately 90%, with no difference in pregnancy outcome between the two colonies. The average age at first conception for SPF females was earlier (4.2 years) than that of the conventional females (4.7 years). In both colonies, primiparous females were more likely to abort than multiparous females. Similarly, primiparous females were more likely to lose their infants to death or human intervention. A mothering score system was developed in the SPF colony to facilitate intervention of poor mother-infant relationships. Records revealed 70% of SPF mothers were able to raise one or more of their infants successfully to at least 180 days of age, which did not differ from conventional mothers. SPF females returned to post-partum amenorrhea 27 days sooner on average than the conventional females, independent of dam age. The nursery-rearing process used for recruitment into the SPF colony therefore did not have an adverse effect on reproduction or rearing offspring. PMID- 23440923 TI - A trial of a real-time alert for clinical deterioration in patients hospitalized on general medical wards. AB - BACKGROUND: With limited numbers of intensive care unit (ICU) beds available, increasing patient acuity is expected to contribute to episodes of inpatient deterioration on general wards. OBJECTIVE: To prospectively validate a predictive algorithm for clinical deterioration in general-medical ward patients, and to conduct a trial of real-time alerts based on this algorithm. DESIGN: Randomized, controlled crossover study. SETTING/PATIENTS: Academic center with patients hospitalized on 8 general wards between July 2007 and December 2011. INTERVENTIONS: Real-time alerts were generated by an algorithm designed to predict the need for ICU transfer using electronically available data. The alerts were sent by text page to the nurse manager on intervention wards. MEASUREMENTS: Intensive care unit transfer, hospital mortality, and hospital length of stay. RESULTS: Patients meeting the alert threshold were at nearly 5.3-fold greater risk of ICU transfer (95% confidence interval [CI]: 4.6-6.0) than those not satisfying the alert threshold (358 of 2353 [15.2%] vs 512 of 17678 [2.9%]). Patients with alerts were at 8.9-fold greater risk of death (95% CI: 7.4-10.7) than those without alerts (244 of 2353 [10.4%] vs 206 of 17678 [1.2%]). Among patients identified by the early warning system, there were no differences in the proportion of patients who were transferred to the ICU or who died in the intervention group as compared with the control group. CONCLUSIONS: Real-time alerts were highly specific for clinical deterioration resulting in ICU transfer and death, and were associated with longer hospital length of stay. However, an intervention notifying a nurse of the risk did not result in improvement in these outcomes. PMID- 23440924 TI - Communicating quantitative risks and benefits in promotional prescription drug labeling or print advertising. AB - PURPOSE: Under the Food, Drug, and Cosmetic Act, all promotional materials for prescription drugs must strike a fair balance in presentation of risks and benefits. How to best present this information is not clear. We sought to determine if the presentation of quantitative risk and benefit information in drug advertising and labeling influences consumers', patients', and clinicians' information processing, knowledge, and behavior by assessing available empirical evidence. METHODS: We used PubMed for a literature search, limiting to articles published in English from 1990 forward. Two reviewers independently reviewed the titles and abstracts for inclusion, after which we reviewed the full texts to determine if they communicated risk/benefit information either: (i) numerically (e.g., percent) versus non-numerically (e.g., using text such as "increased risk") or (ii) numerically using different formats (e.g., "25% of patients", "one in four patients", or use of pictographs). We abstracted information from included articles into standardized evidence tables. The research team identified a total of 674 relevant publications, of which 52 met our inclusion criteria. Of these, 37 focused on drugs. RESULTS AND CONCLUSIONS: Presenting numeric information appears to improve understanding of risks and benefits relative to non-numeric presentation; presenting both numeric and non-numeric information when possible may be best practice. No single specific format or graphical approach emerged as consistently superior. Numeracy and health literacy also deserve more empirical attention as moderators. PMID- 23440920 TI - Glycoprotein targeted therapeutics: a new era of anti-herpes simplex virus-1 therapeutics. AB - Herpes simplex virus type-1 (HSV-1) is among the most common human pathogens worldwide. Its entry into host cells is an intricate process that relies heavily on the ability of the viral glycoproteins to bind host cellular proteins and to efficiently mediate fusion of the virus envelope with the cell membrane. Acquisition of HSV-1 results in a lifelong latent infection. Because of the cycles of reactivation from a latent state, much emphasis has been placed on the management of infection through the use of DNA synthesis inhibitors. However, new methods are needed to provide more effective treatment at earlier phases of the viral infection and to prevent the development of drug resistance by the virus. This review outlines the infection process and the common therapeutics currently used against the fundamental stages of HSV-1 replication and fusion. The remainder of this article will focus on a new approach for HSV-1 infection control and management, the concept of glycoprotein-receptor targeting. PMID- 23440925 TI - An artificial oxygenase built from scratch: substrate binding site identified using a docking approach. PMID- 23440926 TI - Identification of chondrocyte-binding peptides by phage display. AB - As an initial step toward targeting cartilage tissue for potential therapeutic applications, we sought cartilage-binding peptides using phage display, a powerful technology for selection of peptides that bind to molecules of interest. A library of phage displaying random 12-amino acid peptides was iteratively incubated with cultured chondrocytes to select phage that bind cartilage. The resulting phage clones demonstrated increased affinity to chondrocytes by ELISA, when compared to a wild-type, insertless phage. Furthermore, the selected phage showed little preferential binding to other cell types, including primary skin fibroblast, myocyte and hepatocyte cultures, suggesting a tissue-specific interaction. Immunohistochemical staining revealed that the selected phage bound chondrocytes themselves and the surrounding extracellular matrix. FITC-tagged peptides were synthesized based on the sequence of cartilage-binding phage clones. These peptides, but not a random peptide, bound cultured chondrocytes, and extracelluar matrix. In conclusion, using phage display, we identified peptide sequences that specifically target chondrocytes. We anticipate that such peptides may be coupled to therapeutic molecules to provide targeted treatment for cartilage disorders. PMID- 23440927 TI - Dynamic contrast-enhanced MRI in mice at high field: estimation of the arterial input function can be achieved by phase imaging. AB - PURPOSE: Quantitative dynamic contrast-enhanced MRI requires an accurate arterial input function (AIF). At high field, increased susceptibility effects and decreased longitudinal relaxivity of contrast agents lead to predominant T2* effects in blood vessels, producing a dip in signal during passage of the contrast agent bolus. This study determined phase-derived AIFs in mice at 11.7 T. METHODS: AIFs were measured in aorta/vena cava for five FBV/N mice and in iliac arteries/veins for five NMRI mice with a fast low angle shot sequence, simultaneously with tumor imaging (temporal resolution: 1.19 s). Gadoterate was injected into the tail vein as a bolus (0.286 mmol Gd/kg). An in vitro study was also performed to calculate the relationship between DeltaPhi and gadolinium concentration. RESULTS: The phantom system confirmed the linear relationship between measured DeltaPhi and gadolinium concentration. In vivo, a dip in arterial magnitude signal made it impossible to quantify the AIF. With phase imaging, a clear quantifiable bolus peak was obtained; peak measured concentration in plasma was 4.9 +/- 0.9 mM for FBV/N mice and 8.0 +/- 0.6 mM for NMRI mice, close to the expected concentration of 6.8 mM. CONCLUSION: Phase imaging seems to be an appropriate means to measure the AIF of mice at high field. PMID- 23440928 TI - Carnosine inhibits Abeta(42) aggregation by perturbing the H-bond network in and around the central hydrophobic cluster. AB - Aggregation of the amyloid-beta peptide (Abeta) into fibrillar structures is a hallmark of Alzheimer's disease. Thus, preventing self-assembly of the Abeta peptide is an attractive therapeutic strategy. Here, we used experimental techniques and atomistic simulations to investigate the influence of carnosine, a dipeptide naturally occurring in the brain, on Abeta aggregation. Scanning force microscopy, circular dichroism and thioflavin T fluorescence experiments showed that carnosine does not modify the conformational features of Abeta42 but nonetheless inhibits amyloid growth. Molecular dynamics (MD) simulations indicated that carnosine interacts transiently with monomeric Abeta42 by salt bridges with charged side chains, and van der Waals contacts with residues in and around the central hydrophobic cluster ((17)LVFFA(21)). NMR experiments on the nonaggregative fragment Abeta12-28 did not evidence specific intermolecular interactions between the peptide and carnosine, in agreement with MD simulations. However, a close inspection of the spectra revealed that carnosine interferes with the local propensity of the peptide to form backbone hydrogen bonds close to the central hydrophobic cluster (residues E22, S26 and N27). Finally, MD simulations of aggregation-prone Abeta heptapeptide segments show that carnosine reduces the propensity to form intermolecular backbone hydrogen bonds in the region 18-24. Taken together, the experimental and simulation results (cumulative MD sampling of 0.2 ms) suggest that, despite the inability of carnosine to form stable contacts with Abeta, it might block the pathway toward toxic aggregates by perturbing the hydrogen bond network near residues with key roles in fibrillogenesis. PMID- 23440929 TI - New functions of Muller cells. AB - Muller cells, the major type of glial cells in the retina, are responsible for the homeostatic and metabolic support of retinal neurons. By mediating transcellular ion, water, and bicarbonate transport, Muller cells control the composition of the extracellular space fluid. Muller cells provide trophic and anti-oxidative support of photoreceptors and neurons and regulate the tightness of the blood-retinal barrier. By the uptake of glutamate, Muller cells are more directly involved in the regulation of the synaptic activity in the inner retina. This review gives a survey of recently discoved new functions of Muller cells. Muller cells are living optical fibers that guide light through the inner retinal tissue. Thereby they enhance the signal/noise ratio by minimizing intraretinal light scattering and conserve the spatial distribution of light patterns in the propagating image. Muller cells act as soft, compliant embedding for neurons, protecting them in case of mechanical trauma, and also as soft substrate required for neurite growth and neuronal plasticity. Muller cells release neuroactive signaling molecules which modulate neuronal activity, are implicated in the mediation of neurovascular coupling, and mediate the homeostasis of the extracellular space volume under hypoosmotic conditions which are a characteristic of intense neuronal activity. Under pathological conditions, a subset of Muller cells may differentiate to neural progenitor/stem cells which regenerate lost photoreceptors and neurons. Increasing knowledge of Muller cell function and responses in the normal and diseased retina will have great impact for the development of new therapeutic approaches for retinal diseases. PMID- 23440930 TI - Usefulness of (1) H-MRS in differentiating bilirubin encephalopathy from severe hyperbilirubinemia in neonates. AB - PURPOSE: To evaluate the usefulness of (1) H-MRS in differentiating bilirubin encephalopathy from severe hyperbilirubinemia in neonates. MATERIALS AND METHODS: There were 11 patients enrolled in the neonatal bilirubin encephalopathy (NBE) group, 8 patients in the neonatal hyperbilirubinemia (NH) group, and 9 healthy, age-matched neonates were included as controls. All patients and controls underwent (1) H-MRS and conventional magnetic resonance (MR) sequences. The spectroscopic regions of interest were the bilateral basal ganglia and the thalamus, and a spatial resolution of 1.0 cm(3) was obtained. RESULTS: Peak-area ratios of NAA/Cr and NAA/ Cho in the basal ganglia were found to be significantly lower for the NBE group compared with the NH and control groups (P < 0.05). In contrast, there was no significant difference in the NAA/Cr ratios calculated for basal ganglia of the NH and control groups. Peak-area ratios of NAA/Cr and NAA/Cho in the thalamus were decreased for the NBE group compared with the NH and control groups, but the differences were not significant (P > 0.05). There was a significant correlation between NAA/Cr ratios for basal ganglia and the total serum bilirubin (TSB) peak level in the NBE group (P < 0.05). CONCLUSION: (1) H MRS is useful in the differential diagnosis of NBE from severe hyperbilirubinemia in neonates, especially when the symptoms of NBE are atypical (subtle) and MRI does not reveal clear abnormalities. PMID- 23440931 TI - Improving adverse drug event detection in critically ill patients through screening intensive care unit transfer summaries. AB - PURPOSE: This study aimed to determine the frequency and type of adverse drug events (ADEs) identified in intensive care unit (ICU) transfer summaries and in the hospital discharge summaries to demonstrate the effectiveness of ICU transfer summary surveillance in the identification of ADEs. METHODS: A retrospective electronic medical record review was conducted for medical ICU patients admitted between January 2009 and April 2009 to a large, academic medical center. The Harvard Practice Scale and the modified Leonard Assessment Scale were used to evaluate the presence of an ADE from the ICU transfer and hospital discharge summaries. RESULTS: Two hundred and fifty-four patients were identified for inclusion with a median medical ICU length of stay of 4.5 days and hospital length of stay of 13 days. The ICU transfer summary review revealed 173 ADEs among 124 unique patients with a rate of 33.9 ADEs per 1000 hospital patient days. Sixty-nine ADEs among 63 unique patients were identified through the hospital discharge summary with a rate of 13.5 ADEs per 1000 hospital patient days. Only 23.1% of ADEs discussed in the ICU transfer summary were also discussed in the hospital discharge summary. CONCLUSIONS: The use of ICU transfer summaries is an effective tool to increase ADE detection. The use of an ICU transfer summary should be considered as an adjunct method to an existing ADE surveillance system for heightened pharmacovigilance. PMID- 23440932 TI - Improving antioxidant status in aged mice by 50% ethanol extract from red bean fermented by Bacillus subtilis. AB - BACKGROUND: The purpose of this study was to investigate the effects of 50% ethanol extracts from red bean non-fermented (RBE) and fermented by Bacillus subtilis (RBNE) on the antioxidant status of aged ICR mouse. RESULTS: Compared to 2-month-old ICR mouse, the plasma total antioxidant status (TAS) in 12-month-old ICR mouse decreased about 57%, while malondialdehyde (MDA) levels in the liver and brain of 12-month-old ICR mouse increased 56% and 30%, respectively. Orally administration of RBE or RBNE could completely recover the changes of MDA and plasma TAS levels due to the aging process. Vitamin E contents declined 88% in the liver and 74% in the brain of aged ICR mouse. At a level of 0.3 or 0.6 g kg( 1) body weight, RBNE raised vitamin E content in the liver and brain; however, RBE showed no significant influence. All antioxidant enzymes activities in the liver and brain of aged ICR mouse decreased compared to those activities in 2 month-old ICR mouse. RBNE could significantly enhance the superoxide dismutase activity in the brain of aged ICR mouse. CONCLUSION: Oral administration of RBE or RBNE could improve antioxidant status in aged ICR mouse. Fermentation by Bacillus subtilis could enhance the antioxidant properties of red bean. PMID- 23440933 TI - Effective chiral discrimination of tetravalent polyamines on the compaction of single DNA molecules. PMID- 23440934 TI - Where do you want to spend your last days of life? Low concordance between preferred and actual site of death among hospitalized adults. AB - BACKGROUND: Death in the U.S. frequently occurs in institutions despite the overwhelming majority of persons who state that they prefer to die at home. Little research to date has examined how well individual preferences compare to actual site of death. OBJECTIVES: Determine the concordance between preferred and actual place of death and examine independent predictors for concordance. DESIGN: Observational cohort study. SETTING: Three area hospitals including a safety net hospital, veterans' hospital, and academic tertiary referral center. PATIENTS: 458 adult patients admitted to the general medical service from 2003-2005. MEASUREMENTS: Patients were asked where they preferred to spend their last days of life. Data on date and actual site of death from 2005-2009 was collected from hospital records and death certificates. RESULTS: The majority of patients preferred to die at home (75% n = 343). Low income and being married were significantly associated with a preference to die at home compared to nursing home or inpatient hospice (OR 2.71 95% CI 1.30-5.67 and OR 2.44 95% CI 1.14-5.21 respectively). Of the 123 patients who died during the follow up period, most (66% n = 80) died in an institutional setting. Overall concordance between preferred and actual site of death was only 37% (n = 41). Female gender was significantly associated with concordance between preferred and actual site of death (OR 3.30 95% CI 1.25-8.72). CONCLUSIONS: Concordance between preferred and actual site of death is low and female gender was the sole patient level variable associated with concordance. PMID- 23440935 TI - Aquatic toxicity assessment of phosphate compounds. AB - OBJECTIVES: Tricalcium phosphate and calcium hydrogenorthophosphate are high production volume chemicals, mainly used as foodstuff additives, pharmaceuticals, lubricants, synthetic resin, and disinfectants. Phosphate has the potential to cause increased algal growth leading to eutrophication in the aquatic environment. However, there is no adequate information available on risk assessment or acute and chronic toxicity. The aim of this research is to evaluate the toxic potential of phosphate compounds in the aquatic environment. METHODS: An aquatic toxicity test of phosphate was conducted, and its physico-chemical properties were obtained from a database recommended in the Organization for Economic Cooperation and Development (OECD) guidance manual. An ecotoxicity test using fish, Daphnia, and algae was conducted by the good laboratory practice facility according to the OECD TG guidelines for testing of chemicals, to secure reliable data. RESULTS: THE RESULTS OF THE ECOTOXICITY TESTS OF TRICALCIUM PHOSPHATE AND CALCIUM HYDROGENORTHOPHOSPHATE ARE AS FOLLOWS: In an acute toxicity test with Oryzias latipes, 96 hr 50% lethal concentration (LC(50)) was >100 (measured:>2.14) mg/L and >100 (measured: >13.5) mg/L, respectively. In the Daphnia test, 48 hr 50% effective concentration (EC(50)) was >100 (measured: >5.35) mg/L and >100 (measured: >2.9) mg/L, respectively. In a growth inhibition test with Pseudokirchneriella subcapitata, 72 hr EC(50) was >100 (measured: >1.56) mg/L and >100 (measured: >4.4) mg/L, respectively. CONCLUSIONS: Based on the results of the ecotoxicity test of phosphate using fish, Daphnia, and algae, L(E)C(50) was above 100 mg/L (nominal), indicating no toxicity. In general, the total phosphorus concentration including phosphate in rivers and lakes reaches levels of several ppm, suggesting that phosphate has no toxic effects. However, excessive inflow of phosphate into aquatic ecosystems has the potential to cause eutrophication due to algal growth. PMID- 23440937 TI - Five ethical and clinical challenges psychiatrists may face when treating patients with borderline personality disorder who are or may become suicidal. AB - This article discusses five core ethical and clinical questions psychiatrists should consider when they treat patients with borderline personality disorder who are or may be suicidal. These questions include whether psychiatrists should tell patients their diagnosis, what they should tell them about their suicide risk, whether they should be "always" available by phone, when they should hospitalize these patients involuntarily, and how they should respond after these patients have attempted suicide and return for further care. This discussion highlights the ethical components of these questions. Optimal ethical and clinical interventions, in most cases, overlap. Psychiatrists may accomplish the most clinically by sharing with these patients some of the above conflicts that they face and/or the rationales for doing what they will do. These interventions may maximize the autonomy patients with borderline personality disorder and at the same time be clinically optimal, increasing a sense of self-efficacy and patient psychiatrist trust in the patients. PMID- 23440936 TI - Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer's disease. AB - Accurate ante mortem diagnosis in frontotemporal lobar degeneration (FTLD) is crucial to the development and implementation of etiology-based therapies. Several neurodegenerative disease-associated proteins, including the major protein constituents of inclusions in Alzheimer's disease (AD) associated with amyloid-beta (Abeta(1-42)) plaque and tau neurofibrillary tangle pathology, can be measured in cerebrospinal fluid (CSF) for diagnostic applications. Comparative studies using autopsy-confirmed samples suggest that CSF total-tau (t-tau) and Abeta(1-42) levels can accurately distinguish FTLD from AD, with a high t-tau to Abeta(1-42) ratio diagnostic of AD; however, there is also an urgent need for FTLD-specific biomarkers. These analytes will require validation in large autopsy confirmed cohorts and face challenges of standardization of within- and between laboratory sources of error. In addition, CSF biomarkers with prognostic utility and longitudinal study of CSF biomarker levels over the course of disease are also needed. Current goals in the field include identification of analytes that are easily and reliably measured and can be used alone or in a multi-modal approach to provide an accurate prediction of underlying neuropathology for use in clinical trials of disease modifying treatments in FTLD. To achieve these goals it will be of the utmost importance to view neurodegenerative disease, including FTLD, as a clinicopathological entity, rather than exclusively a clinical syndrome. PMID- 23440938 TI - Immature Rubus coreanus Shows a Free Radical-Scavenging Effect and Inhibits Cholesterol Synthesis and Secretion in Liver Cells. AB - Rubus coreanus fruits have been employed as a traditional medicine for centuries in the Asia-Pacific region. Its pharmacological action differs according to the different extraction methods utilized and the degree of fruit ripening. In this study, we determined the cellular effect of different ethanol extracts of mature and immature Rubus coreanus fruits in human hepatic cell line, HepG2 cells. The antioxidant activity, effect on superoxide dismutase activity and cholesterol biosynthesis efficiency was also evaluated. Immature Rubus coreanus extract showed higher antioxidant capability, compared with that of its mature fractions. Cellular antioxidant proteins including HO-1, Cu/Zn-superoxide dismutase and catalase were highly expressed in the presence of Rubus coreanus. Cholesterol levels in HepG2 cells treated with the water fraction of immature Rubus coreanus were significantly reduced. This antihyperlipidaemic action of Rubus coreanus is a consequence of cholesterol biosynthesis and extracellular secretion in HepG2 cells. These results indicate that among different ethanol fraction of mature and immature Rubus coreanus fruit extracts, water extract of immature fruit extract shows higher antioxidant as well as higher antihyperlipidaemic action. PMID- 23440939 TI - Mobile computed tomography : three year clinical experience in Korea. AB - OBJECTIVE: Obtaining real-time image is essential for neurosurgeons to minimize invasion of normal brain tissue and to prompt diagnosis of intracranial event. The aim of this study was to report our three-year experience with a mobile computed tomography (mCT) for intraoperative and bedside scanning. METHODS: A total of 357 mCT (297 patients) scans from January 2009 to December 2011 in single institution were reviewed. After excluding post-operative routine follow up, 202 mCT were included for analysis. Their medical records such as diagnosis, clinical application, impact on decision making, times, image quality and radiologic findings were assessed. RESULTS: Two-hundred-two mCT scans were performed in the operation room (n=192, 95%) or intensive care unit (ICU) (n=10, 5%). Regarding intraoperative images, extent of resection of tumor (n=55, 27.2%), degree of hematoma removal (n=42, 20.8%), confirmation of catheter placement (n=91, 45.0%) and monitoring unexpected complications (n=4, 2.0%) were evaluated. A total of 14 additional procedures were introduced after confirmation of residual tumor (n=7, 50%), hematoma (n=2, 14.3%), malpositioned catheter (n=3, 21.4%) and newly developed intracranial events (n=2, 14.3%). Every image was obtained within 15 minutes and image quality was sufficient for interpretation. CONCLUSION: mCT is feasible for prompt intraoperative and ICU monitoring with enhanced diagnostic certainty, safety and efficiency. PMID- 23440940 TI - Coarctation of the aorta. AB - The surgical treatment of an aortic coarctation requires a resection of the stenotic area and direct suture of the aorta. An extended mobilization allows an enlargement of a hypoplastic distal aortic arch. In ductal dependent circulation, the distal aortic arch can be enlarged with a patch before tackling the coarctation itself. Postsurgical aortic arch stenoses often require a surgical intervention. Our preferred method is an anatomic correction with an enlargement plasty either on the concavity or on the convexity of the arch, depending on the local anatomy. An extra-anatomic bypass is also an option. PMID- 23440942 TI - Antiphospholipid antibodies in iraqi women with recurrent mid-trimester abortions. AB - PURPOSE: Antiphospholipid antibodies are often associated with recurrent pregnancy loss, and although many studies have addressed this association in Western countries, such studies are not so frequent from developing countries. The current study aims to determine the frequency of Antiphospholipid antibodies (Anticardiolipin antibodies and Lupus anticoagulant) among Iraqi women with recurrent mid-trimester abortions and to evaluate various tests used for their detection. MATERIALS AND METHODS: Two hundred women with recurrent mid-trimester abortions were randomly enrolled from a main referral center in Baghdad-Iraq. The enrollees had their IgG and IgM anticardiolipin antibodies assayed by ELISA, and Lupus anticoagulant by a combination of the following screening tests : Activated Partial Thromboplastine Time (APTT), and Partial Thromboplastine Time-LA (PTT LA), Kaolin Clotting Time (KCT) and confirmation was made by Hexagonal phospholipid neutralization test. RESULTS: The women were aged between 19 and 45 years (median 30 years). Fifty three (26.5%) had one or both anticardiolipin antibodies present, while 27 (13.5%) were positive for lupus anticoagulant. The KCT and KCT index appeared to be the most sensitive tests, while the KCT index and APTT were the most specific for Lupus anticoagulant. Patients with antiphospholipid antibodies had higher rates of history of thrombosis, thrombocytopenia and family history of recurrent abortion (P = 0.0009, 0.0056 and 0.0003 respectively). CONCLUSIONS: Antiphospholipid antibodies constitute an important cause of recurrent mid-trimester abortion in Iraqi women, with frequencies intermediate between Western and Indian reports. While thrombocytopenia and thrombosis are well documented associations of antiphospholipid antibodies, the significant association with family history of recurrent fetal loss is intriguing and requires further scrutiny. PMID- 23440941 TI - Fertility in Advanced Societies: A Review of Research: La fecondite dans les societes avancees: un examen des recherches. AB - This paper provides a review of fertility research in advanced societies, societies in which birth control is the default option. The central aim is to provide a comprehensive review that summarizes how contemporary research has explained ongoing and expected fertility changes across time and space (i.e., cross- and within-country heterogeneity). A secondary aim is to provide an analytical synthesis of the core determinants of fertility, grouping them within the analytical level in which they operate. Determinants are positioned at the individual and/or couple level (micro-level), social relationships and social networks (meso-level); and, by cultural and institutional settings (macro-level). The focus is both on the quantum and on the tempo of fertility, with a particular focus on the postponement of childbearing. The review incorporates both theoretical and empirical contributions, with attention placed on empirically tested research and whether results support or falsify existing theoretical expectations. Attention is also devoted to causality and endogeneity issues. The paper concludes with an outline of the current challenges and opportunities for future research. PMID- 23440943 TI - Wear patterns of taper connections in retrieved large diameter metal-on-metal bearings. AB - Wear of the modular taper between head and shaft has been related to clinical failure resulting from adverse reactions to metallic debris. The problem has become pronounced in large metal-on-metal bearings, but the mechanism has not yet been fully understood. We analyzed retrieved components from five patients revised with various diagnoses. Two distinct wear patterns were observed for the head tapers. Three samples demonstrated "asymmetric" wear towards the inner end of the head taper. The other two showed "axisymmetric" radial wear (up to 65 um) presenting the largest wear volumes (up to 20 mm(3)). Stem tapers demonstrated relatively little wear, and the fine thread on the stem taper surface was observed to be imprinted on the taper inside of the head. Our findings demonstrate that the cobalt-chrome head wears preferentially to the titanium stem taper. "asymmetric" wear suggests toggling due to the offset of the joint force vector from the taper. In contrast, samples with "axisymmetric" radial wear and a threaded imprint suggested that corrosion led to head subsidence onto the stem taper with gradual rotation. PMID- 23440944 TI - Impact of Micellar Vehicles on in situ Intestinal Absorption Properties of Beta Lapachone in Rats. AB - The aim of the present study was to examine the effect of micellar systems on the absorption of beta-lapachone (b-lap) through different intestinal segments using a single-pass rat intestinal perfusion technique. B-lap was solubilized in mixed micelles composed of phosphatidylcholine and sodium deoxycholate, and in sodium lauryl sulfate (SLS)-based conventional micelles. Both mixed micelles and SLS micelles improved the in situ permeability of b-lap in all intestinal segments tested although the mixed micellar formulation was more effective in increasing the intestinal absorption of b-lap. The permeability of b-lap was greatest in the large intestinal segments. Compared with SLS micelles, the effective permeability coefficient values measured with mixed micelles were 5- to 23-fold higher depending on the intestinal segment. Our data suggest that b-lap should be delivered to the large intestine using a mixed micellar system for improved absorption. PMID- 23440945 TI - Putting congeniality effects into context: Investigating the role of context in attitude memory using multiple paradigms. AB - In three experiments, we evaluated remembering and intentional forgetting of attitude statements that were either congruent or incongruent with participants' own political attitudes. In Experiment 1, significant directed forgetting was obtained for incongruent statements, but not for congruent statements. In addition, in the remember group, recall was better for incongruent statements than congruent statements. To explain these findings, we propose a contextual competition at retrieval hypothesis, according to which incongruent statements become more strongly associated with their episodic context during encoding than do congruent statements. At the time of retrieval, incongruent statements compete with congruent statements due to the greater amount of contextual information stored in their memory trace. We tested this hypothesis in Experiment 2 by studying free recall of congruent and incongruent statements in a mixed-pure list design. In Experiment 3, memory for incongruent and congruent statements was tested under recognition test conditions that varied in terms of how much direct retrieval of contextual details they required. Overall, the results supported the contextual competition hypothesis, and they indicate the importance of context strength in both the remembering and intentional forgetting of attitude information. PMID- 23440946 TI - Accelerated isotropic sub-millimeter whole-heart coronary MRI: compressed sensing versus parallel imaging. AB - PURPOSE: To enable accelerated isotropic sub-millimeter whole-heart coronary MRI within a 6-min acquisition and to compare this with a current state-of-the-art accelerated imaging technique at acceleration rates beyond what is used clinically. METHODS: Coronary MRI still faces major challenges, including lengthy acquisition time, low signal-to-noise-ratio (SNR), and suboptimal spatial resolution. Higher spatial resolution in the sub-millimeter range is desirable, but this results in increased acquisition time and lower SNR, hindering its clinical implementation. In this study, we sought to use an advanced B1-weighted compressed sensing technique for highly accelerated sub-millimeter whole-heart coronary MRI, and to compare the results to parallel imaging, the current-state of-the-art, where both techniques were used at acceleration rates beyond what is used clinically. Two whole-heart coronary MRI datasets were acquired in seven healthy adult subjects (30.3 +/- 12.1 years; 3 men), using prospective 6-fold acceleration, with random undersampling for the proposed compressed sensing technique and with uniform undersampling for sensitivity encoding reconstruction. Reconstructed images were qualitatively compared in terms of image scores and perceived SNR on a four-point scale (1 = poor, 4 = excellent) by an experienced blinded reader. RESULTS: The proposed technique resulted in images with clear visualization of all coronary branches. Overall image quality and perceived SNR of the compressed sensing images were significantly higher than those of parallel imaging (P = 0.03 for both), which suffered from noise amplification artifacts due to the reduced SNR. CONCLUSION: The proposed compressed sensing-based reconstruction and acquisition technique for sub-millimeter whole-heart coronary MRI provides 6-fold acceleration, where it outperforms parallel imaging with uniform undersampling. PMID- 23440947 TI - Cytologic features of the endometrial adenocarcinoma: comparison of ThinPrep and BD SurePath preparations. AB - We compared the cytoarchitectural features used for the cytologic diagnosis of endometrial adenocarcinoma (EC) using ThinPrep(r) (TPS = ThinPrep Sample) and BD SurePathTM (SPS = SurePath Sample) preparations. In 20 patients, a direct endometrial sample using the Uterobrush was obtained. Nineteen cases of EA and one case of carcinosarcoma were studied. TPS and SPS were performed according to the manufacturer's recommendations. Moreover, after the TPS preparation, the residual material was also used to prepare an SPS sample (TP-SPS = ThinPrep Surepath sample). The following points were investigated in both preparations: (1) number of cell clumps; SPS had a significantly higher (20.9) than TPS (1.7) and TP-SPS (10.3); (2) long axis of clumps; SPS had a significantly higher (215.4) than TPS (146.0); (3) rate of cell clumps with longer axes than 200 MUm; SPS had a significantly higher (36.7) than TPS (15.2) and TP-SPS (24.2). TP-SPS showed higher values than TPS; (4) nuclear area; TPS had a significant higher (61.2) than SPS (40.8) and TP-SPS (38.6); (5) degree of overlapping nuclei; SPS (3.4) had a significantly higher number of overlapping nuclei than TPS (0.7) and TP-SPS (2.1); (6) nuclear chromatin pattern; no significant differences for the nuclear chromatin pattern were found in the three different methods. The poor performance of TPS versus SPS and TP-SPS was explained with the heavy blood contamination of the samples, and the absence of adhesive coating in the slides is used for TPS. Further investigation of technical differences in liquid-based cytology methodologies is needed. PMID- 23440948 TI - Movement disorders after stroke in adults: a review. AB - BACKGROUND: Movement disorders occur in association with stroke and may have important clinical implications. METHODS: We reviewed the medical literature regarding the clinical phenomenology, prevalence, localization and etiologic implications, and treatments for movement disorders occurring after stroke in adult patients. RESULTS: Movement disorders occur uncommonly after stroke and include both hyperkinetic and parkinsonian conditions. They can occur at the time of stroke or appear as a later manifestation. Stroke lesions are typically due to small vessel cerebrovascular disease in the middle or posterior cerebral artery territory, vessels supplying the basal ganglia. Hemorrhagic lesions are more likely to induce hyperkinetic movements. Movement disorders in the setting of stroke tend to resolve spontaneously over time. Medical and surgical therapies are available to treat the movement problems. DISCUSSION: Movement disorders after stroke can be helpful in localizing lesions after stroke, determining the etiology of stroke, may need to be a target for therapy and may importantly influence long term outcome. PMID- 23440949 TI - A novel technique for the reconstruction of resected sternoclavicular joints: A case report with a review of the literature. AB - Sternal metastasis in thyroid cancer is an uncommon occurrence with only a handful of cases of chest wall resections being done. Sternal reconstruction for both primary and secondary tumors has been performed using various techniques and materials such as the mesh, methyl acrylate resin, and steel plates; however, this is a case of papillary thyroid cancer involving the sternum in a 50-year-old woman who had resection of the sternum with reconstruction using titanium bars and clips (STRATOS system) fixed to the clavicles with an underlying Proceed mesh. STRATOS system showed good recovery postoperatively. The functional results were excellent with the patient being able to perform all daily activities unassisted after 1 month and almost complete range of motion with acceptable limitations in power of the shoulder muscles after 2 months. We have reviewed all the English language publications of the subject by doing Medline search for the last 25 years and we present here the surgical management of this pathology with our novel approach by using the titanium steel bars to stabilize both medial aspects of the resected clavicles as a promising therapy for manubrial reconstruction and clavicular fixation. PMID- 23440950 TI - Coarse grained molecular dynamics simulation of nanoconfined water. AB - A coarse-grained (CG) model for the simulation of nanoconfined water between graphene surfaces is developed. For this purpose, mixed-grained simulations are done, in which the two-site water model of Riniker and van Gunsteren [S. Riniker, W. F. van Gunsteren, J. Chem. Phys. 2011, 134, 084110] is simulated between atomistically resolved graphene surfaces. In the developed pure CG model, the two interaction sites of water and a combination of eight carbon atoms in the graphene surface are grouped together to construct water and surface CG beads. The pure CG potentials are constructed by iteratively matching the radial distribution functions and the density profiles of water beads in the pore with the corresponding mixed-grained distributions. The constructed potentials are shown to be pore-size transferable, capable of predicting structural properties of confined water over the whole range of pore sizes, ranging from extremely narrow pores to bulk water. The model is used to simulate a number of nanoconfined systems of a variety of pore sizes at constant temperature, constant parallel component of pressure, and constant surface area of the confining surfaces. The model is shown to predict the layering of water in contact with the surfaces, and the solvation force is in complete agreement with the mixed-grained model. It is shown that water molecules in the pore have smaller parallel diffusion coefficients compared to bulk water. Well-organized layers beside the surfaces are shown to have lower diffusion coefficients than diffuse layers. More information on the dynamics of water in the pore is obtained by calculating the rate of water exchange between slabs parallel to the surfaces. The time scale to achieve equilibrium for this process, depending on the pore width and on the degree of layering of water beside the surfaces, is a few nanoseconds in nanometric pores. PMID- 23440951 TI - Coronary angiography and angioplasty in a patient with an iliac artery volvolus. AB - A 70-year-old Caucasian male underwent to percutaneous revascularization through arterial iliac "volvolus" by extralong direct stenting using a long 8 french introducer with an optimal angiographic result and clinical outcome. PMID- 23440952 TI - Prevalence of chronic kidney diseases and its determinants among perimenopausal women in a rural area of North India: A community-based study. AB - The burden of noncommunicable diseases is rising in India. A high prevalence of lifestyle-related diseases in perimenopausal women in the community makes them vulnerable to chronic kidney diseases (CKD). A cross-sectional community-based study was carried out among women >35 years of age in the village of Ballabgarh, Haryana (north India). Eligible women were selected by the probability proportionate to size sampling method. Estimation of glomerular filtration rate (GFR) was carried out by using the age- and body surface area (BSA)-adjusted Cockcroft-Gault (CG) and modification of diet in renal disease (MDRD) equations. Association of risk factors such as obesity, hyperlipidemia, hypertension, and diabetes mellitus with CKD was also assessed using multivariate logistic regression analysis. A total of 455 women were studied. The prevalence of low GFR (<60 mL/min/1.73 m(2)) by the CG/BSA equations and MDRD equation was found to be 18.2% (95% confidence interval 14.6, 21.8) and 5.9% (95% confidence interval 3.7, 8.1), respectively. Obesity (odds ratio 15.5) (P = 0.002), hyperlipidemia (odds ratio: 2.5) (P = 0.017), and age (P < 0.001) were significantly associated with reduced GFR on multivariate logistic regression analysis. This study observed a high prevalence of CKD and its risk factors among perimenopausal women in a rural community in north India. The study highlights the need of a multipronged, community-based intervention strategy that includes a high-risk screening approach and awareness generation about CKD and its risk factors in the community. PMID- 23440953 TI - Rare oesophageal tumours: experience of one centre. AB - AIM OF STUDY: The aim of this study is to compare demographic and clinical data as well as applied treatment methods in patients with rare benign and malignant tumours of the oesophagus. METHODS: Eight hundred and thirty patients with oesophageal cancer were treated in the Department of Surgical Oncology in 1960 2005. In 15 cases (1.8 %), rare benign (n = 11) or malignant (n = 4) types of tumours were diagnosed. Patients with rare oesophageal tumours were included in the study, excluding those with squamous cell carcinoma or adenocarcinoma of the oesophagus. Demographic and clinical data were analysed from each patient qualified for the study. Oesophageal X-rays with contrast medium, gastroscopies and, as of 1991, computed tomographies (CTs) were performed as preoperative diagnostic procedures. RESULTS: In the postoperative histopathological examinations, all benign tumours proved to be oesophageal leiomyomas. Four different malignant tumours-a sarcoma, a neuroendocrine carcinoma, a lymphoma, and a squamous cell carcinoma in a patient with Crohn's disease, were diagnosed in the other four patients. In a group of 15 patients with rare oesophageal tumours there were ten (66.7 %) males and five (33.3 %) females. In patients with benign and malignant tumours, the mean age for the benign group reached 44 years (range: 26-75 years old) and 54.7 years (range: 47-59 years old) for the malignant group. In the preoperative period, symptoms such as swallowing disturbances, retrosternal pains, and epigastric pains were observed. Dysphagia was the leading symptom in patients with benign and malignant oesophageal tumours. Out of 15 patients, surgical procedure was carried out in 13 cases with rare oesophageal tumours. In the group of 11 patients, with benign tumours, ten (90.2 %) warranted surgical treatment. Three patients (75 %) with malignant oesophageal tumours underwent an extensive Akiyama procedure of oesophageal resection. Chemo- and radiotherapy alone were performed on one (25 %) patient with oesophageal lymphoma. Postoperative complications were observed in only four (26.6 %) patients; pneumonia in the postoperative period was diagnosed in two patients who underwent surgery; infections of the postoperative wounds were diagnosed in the other two patients. CONCLUSIONS: Benign oesophageal tumours are characterised by similar clinical symptoms to malignant tumours of this organ. It is more complicated to obtain biopsy specimens for a histopathological examination in cases of benign tumours in comparison to malignant tumours. Treatment methods should be adjusted individually for each patient with a rare oesophageal tumour. For rare benign oesophageal tumours, the results of treatment are very good; however, for malignant tumours the prognosis depends on their histopathological type. PMID- 23440954 TI - Arylamine-catalyzed enamine formation: cooperative catalysis with arylamines and acids. PMID- 23440955 TI - Axiomatic foundations for cost-effectiveness analysis. AB - We show that individual utilities can be measured in units of healthy life years. Social preferences over these life metric utilities are assumed to satisfy the Pareto principle, anonymity, and invariance to a change in origin. These axioms generate a utilitarian social welfare function implying the use of cost effectiveness analysis in ordering health projects, based on maximizing the healthy years equivalents gained from a fixed health budget. For projects outside the health sector, our cost-effectiveness axioms imply a form of cost-benefit analysis where both costs and benefits are measured in equivalent healthy life years. PMID- 23440956 TI - Graphene-bonded and -encapsulated si nanoparticles for lithium ion battery anodes. AB - Silicon (Si) has been considered a very promising anode material for lithium ion batteries due to its high theoretical capacity. However, high-capacity Si nanoparticles usually suffer from low electronic conductivity, large volume change, and severe aggregation problems during lithiation and delithiation. In this paper, a unique nanostructured anode with Si nanoparticles bonded and wrapped by graphene is synthesized by a one-step aerosol spraying of surface modified Si nanoparticles and graphene oxide suspension. The functional groups on the surface of Si nanoparticles (50-100 nm) not only react with graphene oxide and bind Si nanoparticles to the graphene oxide shell, but also prevent Si nanoparticles from aggregation, thus contributing to a uniform Si suspension. A homogeneous graphene-encapsulated Si nanoparticle morphology forms during the aerosol spraying process. The open-ended graphene shell with defects allows fast electrochemical lithiation/delithiation, and the void space inside the graphene shell accompanied by its strong mechanical strength can effectively accommodate the volume expansion of Si upon lithiation. The graphene shell provides good electronic conductivity for Si nanoparticles and prevents them from aggregating during charge/discharge cycles. The functionalized Si encapsulated by graphene sample exhibits a capacity of 2250 mAh g-1 (based on the total mass of graphene and Si) at 0.1C and 1000 mAh g-1 at 10C, and retains 85% of its initial capacity even after 120 charge/discharge cycles. The exceptional performance of graphene encapsulated Si anodes combined with the scalable and one-step aerosol synthesis technique makes this material very promising for lithium ion batteries. PMID- 23440958 TI - Apparent diffusion coefficient ratio between axillary lymph node with primary tumor to detect nodal metastasis in breast cancer patients. AB - PURPOSE: To evaluate the ratios of apparent diffusion coefficient (ADC) calculated from diffusion weighted imaging (DWI) between axillary lymph nodes with primary breast tumor lesions in the detection of axillary lymph nodes metastasis in breast cancer patients. MATERIALS AND METHODS: A total of 36 patients with breast tumors and their axillary lymph nodes were included in this study for MR image scan. The ADC values were calculated using DW-MR imaging software. The ADC values and the ADC ratios of axillary lymph nodes in patients with primary breast lesion were compared among benign and metastatic axillary lymph nodes. All the diagnosis were confirmed by histopathological examination. RESULTS: The mean ADC value of metastatic lymph nodes was significantly lower than those of benign lymph nodes (0.787 * 10(-3) mm(2)/s +/- 0.145 versus 1.043 * 10(-3) mm(2)/s +/- 0.257) (P < 0.05). In addition, ADC ratio of metastatic lymph nodes with breast lesion was significantly lower than those of benign lymph nodes with breast tumor lesions (0.986 +/- 0.17 versus 1.375 +/- 0.417) (P < 0.05). Once the ADC ratio was fixed at 0.889 * 10(-3) mm(2)/s, the sensitivity, specificity, and accuracy were 82.22%, 82.35% and 82.28%, respectively. The cutoff of ADC ratio was at 1.097 * 10(-3) mm(2)/s, the sensitivity, specificity, and accuracy can be up to 84.44%, 88.24%, and 86.08%. CONCLUSION: ADC value and ADC ratio could be used as a reliable parameter to detect the axillary lymph nodes metastasis in breast cancer patients, and ADC ratio has a higher accuracy. PMID- 23440957 TI - ZnO nanowire arrays for enhanced photocurrent in PbS quantum dot solar cells. AB - Vertical arrays of ZnO nanowires can decouple light absorption from carrier collection in PbS quantum dot solar cells and increase power conversion efficiencies by 35%. The resulting ordered bulk heterojunction devices achieve short-circuit current densities in excess of 20 mA cm(-2) and efficiencies of up to 4.9%. PMID- 23440959 TI - Associations of gender and age with the reporting of drug-induced hepatic failure: data from the VigiBaseTM. AB - Patient gender and age are considered to be the risk factors for developing drug induced liver injury (DILI). The aim of this study was to analyze gender and age differences in reporting of drug-induced hepatic failure (HF) to the VigiBaseTM. VigiBaseTM was screened for the HF reports submitted from 2000 to 2009. The information retrieved referred to the suspected drug, age, gender, and a reporting country. Variables were examined by using descriptive statistics and the binomial test. During the 10-year period there were in total 6,370 HF reports from 38 countries. After the exclusion of cases with missing gender data (379 cases), females counted for 54.03%. The largest portion of HF cases referred to age <55 (42.57%) with female predominance (56.81%), whereas age >=55 (32.57%) showed almost even gender distribution. Overall, there were 941 different drugs or their combinations reported. Females significantly predominated in HF cases associated with analgesics, antiepileptics, antiinflamatory and antirheumatic drugs, psychoanaleptics, antibacterials for systemic use, and antidiabetic drugs. Males were significantly overrepresented in HF cases associated with antivirals for systemic use. Differences between genders and/or age groups in the reporting of drug-induced HF depend on drug and/or drug class but may be influenced by multiple factors. PMID- 23440960 TI - Calcium dynamics during NMDA-induced membrane potential oscillations in lamprey spinal neurons--contribution of L-type calcium channels (CaV1.3). AB - NMDA receptor-dependent, intrinsic membrane potential oscillations are an important element in the operation of the lamprey locomotor network. They involve a cyclic influx of calcium, leading to an activation of calcium-activated potassium (KCa) channels that in turn contributes to the termination of the depolarized plateau and membrane repolarization. In this study, we have investigated the calcium dynamics in different regions of lamprey spinal neurons during membrane potential oscillations, using confocal calcium imaging in combination with intracellular recordings. Calcium fluctuations were observed in both soma and dendrites, timed to the oscillations. The calcium level increased sharply at the onset of membrane depolarization, to reach its maximum by the end of the plateau. The calcium peak in distal dendrites typically occurred earlier than in the soma during the oscillatory cycle. The L-type calcium channel blocker nimodipine increased the duration of the depolarized plateau phase in most cells tested, whereas the agonist Bay K 8644 decreased plateau duration. Bay K 8644 increased the amplitude of calcium fluctuations, particularly in distal dendrites, whereas nimodipine caused a decrease, suggesting that L-type low voltage-activated calcium channels are mainly localized in these regions. Our results thus indicate that dendritic CaV1.3-like calcium channels are activated during NMDA-mediated membrane potential oscillations. This calcium influx activates KCa channels involved in plateau termination. PMID- 23440961 TI - Dipeptidyl-peptidase-like-proteins confer high sensitivity to the scorpion toxin AmmTX3 to Kv4-mediated A-type K+ channels. AB - K+ channels containing Kv4.2 and Kv4.3 pore-forming subunits mediate most of the subthreshold-operating somatodendritic A-type K+ current in CNS neurons. These channels are believed to be important in regulating the frequency of repetitive firing, the backpropagation of action potential into dendrites, and dendritic integration and plasticity. Moreover, they have been implicated in several diseases from pain to epilepsy and autism spectrum disorders. The lack of toxins that specifically and efficiently block these channels has hampered studies aimed at confirming their functional role and their involvement in disease. AmmTX3 and other related members of the alpha-KTX15 family of scorpion toxins have been shown to block the A-type K+ current in cultured neurons, but their specificity has been questioned because the toxins do not efficiently block the currents mediated by Kv4.2 or Kv4.3 subunits expressed in heterologous cells. Here we show that the high-affinity blockade of Kv4.2 and Kv4.3 channels by AmmTX3 depends on the presence of the auxiliary subunits DPP6 and DPP10. These proteins are thought to be components of the Kv4 channel complex in neurons and to be important for channel expression in dendrites. These studies validate the use of AmmTX3 as a blocker of the Kv4-mediated A-type K+ current in neurons. PMID- 23440962 TI - Spreading vasodilatation in the murine microcirculation: attenuation by oxidative stress-induced change in electromechanical coupling. AB - Regulation of blood flow in microcirculatory networks depends on spread of local vasodilatation to encompass upstream arteries; a process mediated by endothelial conduction of hyperpolarization. Given that endothelial coupling is reduced in hypertension, we used hypertensive Cx40ko mice, in which endothelial coupling is attenuated, to investigate the contribution of the renin-angiotensin system and reduced endothelial cell coupling to conducted vasodilatation of cremaster arterioles in vivo. When the endothelium was disrupted by light dye treatment, conducted vasodilatation, following ionophoresis of acetylcholine, was abolished beyond the site of endothelial damage. In the absence of Cx40, sparse immunohistochemical staining was found for Cx37 in the endothelium, and endothelial, myoendothelial and smooth muscle gap junctions were identified by electron microscopy. Hyperpolarization decayed more rapidly in arterioles from Cx40ko than wild-type mice. This was accompanied by a shift in the threshold potential defining the linear relationship between voltage and diameter, increased T-type calcium channel expression and increased contribution of T-type (3 MUmol l(-1) NNC 55-0396), relative to L-type (1 MUmol l(-1) nifedipine), channels to vascular tone. The change in electromechanical coupling was reversed by inhibition of the renin-angiotensin system (candesartan, 1.0 mg kg(-1) day(-1) for 2 weeks) or by acute treatment with the superoxide scavenger tempol (1 mmol l(-1)). Candesartan and tempol treatments also significantly improved conducted vasodilatation. We conclude that conducted vasodilatation in Cx40ko mice requires the endothelium, and attenuation results from both a reduction in endothelial coupling and an angiotensin II-induced increase in oxidative stress. We suggest that during cardiovascular disease, the ability of microvascular networks to maintain tissue integrity may be compromised due to oxidative stress-induced changes in electromechanical coupling. PMID- 23440963 TI - Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody. AB - In myasthenia gravis, the neuromuscular junction is impaired by the antibody mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4 diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK induced AChR loss by prolonging the activity of ACh in the synaptic cleft. PMID- 23440964 TI - Glutamatergic modulation of synaptic-like vesicle recycling in mechanosensory lanceolate nerve terminals of mammalian hair follicles. AB - Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca(2+) sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor. PMID- 23440965 TI - Automated cell-specific laser detection and ablation of neural circuits in neonatal brain tissue. AB - A key feature of neurodegenerative disease is the pathological loss of neurons that participate in generating behaviour. To investigate network properties of neural circuits and provide a complementary tool to study neurodegeneration in vitro or in situ, we developed an automated cell-specific laser detection and ablation system. The instrument consists of a two-photon and visible-wavelength confocal imaging setup, controlled by executive software, that identifies neurons in preparations based on genetically encoded fluorescent proteins or Ca(2+) imaging, and then sequentially ablates cell targets while monitoring network function concurrently. Pathological changes in network function can be directly attributed to ablated cells, which are logged in real time. Here, we investigated brainstem respiratory circuits to demonstrate single-cell precision in ablation during physiological network activity, but the technique could be applied to interrogate network properties in neural systems that retain network functionality in reduced preparations in vitro or in situ. PMID- 23440966 TI - Sheep model for osteoporosis: sustainability and biomechanical relevance of low turnover osteoporosis induced by hypothalamic-pituitary disconnection. AB - Hypothalamo-pituitary disconnection (HPD) leads to low bone turnover and osteoporosis in sheep. To determine the sustainability of bone loss and its biomechanical relevance, we studied HPD-sheep 24 months after surgery (HPD + OVX 24) in comparison to untreated control (Control), ovariectomized sheep (OVX), and sheep 12 months after HPD (HPD + OVX-12). We performed histomorphometric, HR pQCT, and qBEI analyses, as well as biomechanical testing of all ewes studied. Twenty-four months after HPD, histomorphometric analyses of the iliac crest showed a significant reduction of BV/TV by 60% in comparison to Control. Cortical thickness of the femora measured by HR-pQCT did not change between 12 and 24 months after HPD but remained decreased by 30%. These structural changes were caused by a persisting depression of osteoblast and osteoclast cellular activity. Biomechanical testing of the femora showed a significant reduction of bending strength, whereas calcium content and distribution was found to be unchanged. In conclusion, HPD surgery leads to a persisting low turnover status with negative turnover balance in sheep followed by dramatic cortical and trabecular bone loss with consequent biomechanical impairment. PMID- 23440967 TI - Detection of Demodex folliculorum from nipple discharge. PMID- 23440968 TI - Quick water-selective excitation of fast relaxing tissues with 3D UTE sequences. AB - PURPOSE: The aim of this study was to implement a time effective 1-1 double pulse water-selective excitation (WE) into a three-dimensional ultrashort echo time (UTE) sequence (WE-UTE) for visualization of short-T2 tissues with positive contrast and sufficient suppression of surrounding fat. METHODS: First, an analytical description of magnetization components in the steady state applying WE-UTE was derived and results were compared with numerical simulations based on Bloch's equations. Parameters were optimized for best positive contrast between short-T2 tissues and fat under consideration of variable relaxation properties over a broad range. Maximal signal yield and signal efficiency of on-resonant protons were compared with UTE sequences with and without off-resonance fat saturation (FatSat). WE-UTE was exemplarily applied for in-vivo musculoskeletal imaging on a 3T whole-body MR unit. RESULTS: Steady state magnetization of WE-UTE could be described analytically and showed excellent accordance with numerical simulations. Even for tissues with T2 = 1 ms WE-UTE resulted in 79% of maximal signal yield of UTE without FatSat and was more efficient regarding signal yield if compared with UTE with FatSat. Using WE-UTE in-vivo tendons and ligaments could be well delineated with positive contrast to surrounding fat. CONCLUSION: WE-UTE provides a quick method for visualizing short-T2 tissues with positive contrast. PMID- 23440969 TI - EMLasso: logistic lasso with missing data. AB - In clinical settings, missing data in the covariates occur frequently. For example, some markers are expensive or hard to measure. When this sort of data is used for model selection, the missingness is often resolved through a complete case analysis or a form of single imputation. An alternative sometimes comes in the form of leaving the most damaged covariates out. All these strategies jeopardise the goal of model selection. In earlier work, we have applied the logistic Lasso in combination with multiple imputation to obtain results in such settings, but we only provided heuristic arguments to advocate the method. In this paper, we propose an improved method that builds on firm statistical arguments and that is developed along the lines of the stochastic expectation maximisation algorithm. We show that our method can be used to handle missing data in both categorical and continuous predictors, as well as in a nonpenalised regression. We demonstrate the method by applying it to data of 273 lung cancer patients. The objective is to select a model for the prediction of acute dysphagia, starting from a large set of potential predictors, including clinical and treatment covariates as well as a set of single-nucleotide polymorphisms. PMID- 23440970 TI - Direct annulations toward phosphorylated oxindoles: silver-catalyzed carbon phosphorus functionalization of alkenes. PMID- 23440971 TI - Aggregation of small molecules: from dimers to crystals. PMID- 23440972 TI - What makes workers with disabilities happy? The importance of non-pecuniary characteristics. AB - The paper examines the determinants of the levels of job satisfaction reported by non-disabled and disabled workers, with special attention to the contribution of non-pecuniary job aspects. Using longitudinal data from the German Socio-Economic Panel, we estimate job satisfaction equations for non-disabled and disabled workers. The existence of unhealthy environments, hard manual work, capacity to learn and good relationships with colleagues and supervisors all have a greater influence on job satisfaction for disabled workers than for their non-disabled counterparts. PMID- 23440973 TI - Neuropathological correlate of the "concentric target sign" in MRI of HIV associated cerebral toxoplasmosis. AB - Cerebral toxoplasmosis is a frequent cause of focal brain lesions in the setting of immunodeficiency states, particularly acquired immune deficiency syndrome (AIDS), and magnetic resonance imaging (MRI) is an important diagnostic modality to differentiate toxoplasmosis from tuberculoma, and primary central nervous system lymphoma with diverse therapeutic implications. Several imaging patterns have been described in cerebral toxoplasmosis. The "concentric target sign" is a recently described MRI sign on T2-weighted imaging of cerebral toxoplasmosis that has concentric alternating zones of hypo- and hyperintensities. It is believed to be more specific than the well-known "eccentric target sign" in the diagnosis of cerebral toxoplasmosis and hence more useful in differentiation from other focal brain lesions in the context of AIDS. The concentric target sign, seen in deep parenchymal lesions, is distinct from the surface-based cortical "eccentric" target sign. The histopathological correlate of the latter has been recently described, but that of the concentric target sign is not known. In this study we describe the neuropathological correlate of this concentric target sign from the postmortem of a 40-year-old man with AIDS-associated cerebral toxoplasmosis. The concentric alternating zones of hypo/hyper/iso/intensities corresponded to zones of hemorrhage/fibrin-rich necrosis with edema/coagulative compact necrosis/inflammation with foamy histiocytes admixed with hemorrhage forming the outermost zone, respectively. The exclusive specificity of this sign in cerebral toxoplasmosis remains to be further elucidated. PMID- 23440974 TI - Highly ordered hollow oxide nanostructures: the Kirkendall effect at the nanoscale. AB - Highly ordered ultra-long oxide nanotubes are fabricated by a simple two-step strategy involving the growth of copper nanowires on nanopatterned template substrates by magnetron sputtering, followed by thermal annealing in air. The formation of such tubular nanostructures is explained according to the nanoscale Kirkendall effect. The concept of this new fabrication route is also extendable to create periodic zero-dimensional hollow nanostructures. PMID- 23440975 TI - Multifunctional epidermal electronics printed directly onto the skin. AB - Materials and designs are presented for electronics and sensors that can be conformally and robustly integrated onto the surface of the skin. A multifunctional device of this type can record various physiological signals relevant to health and wellness. This class of technology offers capabilities in biocompatible, non-invasive measurement that lie beyond those available with conventional, point-contact electrode interfaces to the skin. PMID- 23440976 TI - Imaging early stage osteogenic differentiation of mesenchymal stem cells. AB - Stem cells, such as mesenchymal stem cells (MSCs), contribute to bone fracture repair if they are delivered to the injury site. However, it is difficult to assess the retention and differentiation of these cells after implantation. Current options for non-invasively tracking the transplanted stem cells are limited. Cell-based therapies using MSCs would benefit greatly through the use of an imaging methodology that allows cells to be tracked in vivo and in a timely fashion. In this study, we implemented an in vivo imaging methodology to specifically track early events such as differentiation of implanted human MSCs (hMSCs). This system uses the collagen type 1 (Col1alpha1) promoter to drive expression of firefly luciferase (luc) in addition to a constitutively active promoter to drive the expression of green fluorescent protein (GFP). The resulting dual-promoter reporter gene system provides the opportunity for osteogenic differentiation-specific luc expression for in vivo imaging and constitutive expression of GFP for cell sorting. The function of this dual promoter reporter gene was validated both in vitro and in vivo. In addition, the ability of this dual-promoter reporter system to image an early event of osteogenic differentiation of hMSCs was demonstrated in a murine segmental bone defect model in which reporter-labeled hMSCs were seeded into an alginate hydrogel scaffold and implanted directly into the defect. Bioluminescence imaging (BLI) was performed to visualize the turn-on of Col1alpha1 upon osteogenic differentiation and followed by X-ray imaging to assess the healing process for correlation with histological analyses. PMID- 23440978 TI - Appropriate in vitro methods for genotoxicity testing of silver nanoparticles. AB - OBJECTIVES: We investigated the genotoxic effects of 40-59 nm silver nanoparticles (Ag-NPs) by bacterial reverse mutation assay (Ames test), in vitro comet assay and micronucleus (MN) assay. In particular, we directly compared the effect of cytochalasin B (cytoB) and rat liver homogenate (S9 mix) in the formation of MN by Ag-NPs. METHODS: Before testing, we confirmed that Ag-NPs were completely dispersed in the experimental medium by sonication (three times in 1 minute) and filtration (0.2 um pore size filter), and then we measured their size in a zeta potential analyzer. After that the genotoxicity were measured and especially, S9 mix and with and without cytoB were compared one another in MN assay. RESULTS: Ames test using Salmonella typhimurium TA98, TA100, TA1535 and TA1537 strains revealed that Ag-NPs with or without S9 mix did not display a mutagenic effect. The genotoxicity of Ag-NPs was also evaluated in a mammalian cell system using Chinese hamster ovary cells. The results revealed that Ag-NPs stimulated DNA breakage and MN formation with or without S9 mix in a dose dependent manner (from 0.01 ug/mL to 10 ug/mL). In particular, MN induction was affected by cytoB. CONCLUSIONS: All of our findings, with the exception of the Ames test results, indicate that Ag-NPs show genotoxic effects in mammalian cell system. In addition, present study suggests the potential error due to use of cytoB in genotoxic test of nanoparticles. PMID- 23440979 TI - Fine-needle sampling provides appreciable diagnostic yield in lesions of post kala azar dermal leishmaniasis: analysis of four cases from North Eastern India. AB - Post-kala-azar dermal leishmaniasis (PKDL) is a sequel of visceral leishmaniasis (VL), usually occurring 6 months to 3 years after VL. Spectrum of cutaneous lesions in PKDL can be hypopigmented macules, nodules, plaques, or erythema. It is usually diagnosed clinically, supplemented by ancillary techniques like skin smear examination, histopathology, polymerase chain reaction, and monoclonal antibody test. Literature on the role of cytology in the diagnosis of PKDL is extremely limited. Here we highlight the appreciable yield of fine-needle sampling in four cases of PKDL, which may be considered as a useful diagnostic aid. PMID- 23440980 TI - Synthesis, spectroscopy, and computational analysis of photoluminescent bis(aminophenyl)-substituted thiophene derivatives. AB - Substituted oligothiophenes have a long history in the field of organic electronics, as they often combine outstanding electro-optical properties with the ease of synthesis. To assist the rational selection of the most promising structures to be synthesized, there is the demand for tools that allow prediction of the properties of the materials. In this study, we present strategies for synthesis and computational characterization, with respect to the fluorescence behavior of oligothiophene-based materials for organoelectronic applications. In a combined approach, sophisticated computational methodologies are directly compared to experimental results. The M06-2X functional in combination with the polarizable continuum model in a state-specific formulation for excited-state solvation proved to be particularly reliable. In addition, a semiclassical approach for describing the vibrational broadening of the spectra is employed. As a result, a robust procedure for the prediction of the fluorescence spectra of oligothiophene derivatives is presented. PMID- 23440981 TI - Acutely presenting kissing lesions of the ankle: an atypical Trevor's disease and literature review of other unusual presentations of the disease. AB - Trevor's disease, an intra-articular variant of osteochondroma, has been reported previously in various unusual forms. The present article describes acutely presenting, intra-articular kissing lesions in a 4-year-old girl. A high index of suspicion and elaborate awareness on the part of the treating surgeon are essential to diagnose as well as manage such cases. PMID- 23440982 TI - Orbital floor triamcinolone causing Cushing's syndrome in a patient treated with Kaletra for HIV 1. AB - We report the first known case of iatrogenic cushingoid features following orbital floor triamcinolone, a synthetic corticosteroid, in a patient taking Kaletra (200 mg lopinavir/50 mg ritonavir) twice daily and Truvada (tenofovir/emtricitabine) once daily for HIV 1. Previous reports have included similar findings following epidural triamcinolone injections and with inhaled fluticasone. PMID- 23440983 TI - Incidental renal artery pseudoaneurysm after percutaneous native renal biopsy. AB - Renal artery pseudoaneurysm (RAP) is an uncommon but potentially life-threatening condition that is often difficult to diagnose. Rarely, it can occur as a complication associated with a percutaneous renal biopsy procedure. The clinical manifestations vary from asymptomatic lesions found incidentally on imaging studies to a mass causing high blood pressure, pain, haematuria and rupture. Although the risk of rupture is considered low, RAP is associated with a high death rate if ruptured. Currently, with the aid of high-quality interventional radiology, this challenging pathology can be effectively treated. In this report, we describe a case of RAP that was incidentally discovered 4 years after percutaneous renal biopsy which was successfully treated with selective angiographic embolisation. PMID- 23440984 TI - Unilateral acute angle closure glaucoma. AB - A 52-year-old gentleman presented with 1-week history of severe right-sided headache associated with reduced vision in his right, amblyopic eye. Examination revealed raised intraocular pressure at 64 mm Hg. The anterior chamber (AC) was shallow and there was a dense cataract with no red reflex or fundal view. The contralateral eye had a deep anterior chamber with normal pressure and a clear lens. He was treated initially for acute angle closure glaucoma. The anterior chamber remained shallow and the intraocular pressure uncontrolled, despite maximum medical therapy. Owing to the absent fundal view and unilateral AC shallowing, further imaging was performed and a choroidal mass was found to be responsible for anterior displacement of the lens and shallowing of the angle. He went on to have an enucleation of the right eye, and histological examination confirmed the diagnosis of choroidal melanoma. PMID- 23440986 TI - Large Gartner cyst. AB - Gartner cyst is usually an asymptomatic vaginal cyst, measuring less than 2 cm, frequently found during a routine gynaecological examination. Very rarely, as these cysts are closed structures, they may increase in size because of mucus production. We describe here a case of a large Gartner cyst of approximately 8 cm, its differential diagnosis, investigation and vaginal surgical approach (with illustrations), that progressed uneventfully. PMID- 23440985 TI - Testicular metastasis of colorectal carcinoma: an unusual presentation. AB - Metastasis of colorectal carcinoma to testis is rare. The authors report a case of 35-year-old man with right testicular mass. Contrast-enhanced CT scan (CECT) of testes showed testicular mass with ascitis and enlargement of retroperitoneal lymphnodes. Thus, a provisional diagnosis of disseminated primary testicular tumour was made. On subsequent high orchidectomy pathological examination revealed mucinous adenocarcinoma with CDX2 positivity thereby suggesting the possibility of metastasis from adenocarcinoma. Further, the diagnostic evaluation revealed a colorectal mass, which was inoperable (stage IV) and found to be primary colorectal mucinous adenocarcinoma. The authors conclude that occult colorectal carcinoma may rarely metastasise to testis and this unusual presentation may produce diagnostic dilemma. Although rare, metastases to testes should be considered as a differential diagnosis, especially where symptoms are unusual for primary malignancy. PMID- 23440987 TI - The use of Gore Bio-A in the management of the open abdomen. AB - Non-permanent, non-woven options for the closure of an open abdomen have previously been limited to biologics such as Permacol or Strattice. Gore Bio-A is constructed from biocompatible synthetic fibres, the use of which has only been described in the repair of inguinal hernia, hiatal hernia and fistula-in-ano. A 60-year-old male underwent emergency laparotomy, partial gastrectomy and formation of a feeding jejunostomy for a strangulated and perforated intrathoracic hiatus hernia. His abdominal wall subsequently dehisced for which he underwent laparostomy and subsequent early closure with a Gore Bio-A mesh, secured in an onlay manner with 2/0 vicryl. Functional and cosmetic outcomes were satisfactory and the patient was discharged home. The use of Gore Bio-A is a safe, feasible and cost effective alternative to traditional biologics for the closure of a laparostomy, deployment of which is safe within a contaminated field. Further prospective data is needed to clarify its role. PMID- 23440988 TI - A microscopically calcified Meckel's diverticulum: a histopathological perspective of a case of both gastric and pancreatic mucosae. AB - A 2-year-old child presented with a 1-week history of abdominal pain and non bilious vomiting. Upon examination, the abdomen was distended and faecal aspirate was noted from a nasogastric tube. Ultrasound scan and a failed air enema demonstrated intestinal intussusception warranting a surgical intervention. The intraoperative findings were of an ileocolic intussusception that was reduced and a Meckel's diverticulum (MD) was noted as a lead point necessitating resection with an end-to-end anastomosis. Histopathological analysis revealed a heterotopic MD containing both gastric and pancreatic mucosae with dystrophic calcification. MD is a pathologically diverse condition. The commonest histopathological picture in MD is that of an ectopic gastric mucosa at the terminal ileum. The histopathological analysis of this case demonstrated the interesting heterotopic results with calcification, which the histopathologist needs to be aware of when interpreting a surgical specimen with a clinical picture consistent with intussusception. PMID- 23440990 TI - Adrenal haematoma as a complication of adrenal vein sampling. PMID- 23440989 TI - Zebra lines in osteogenesis imperfecta on bisphosphonate therapy. PMID- 23440991 TI - Absence of aneuploidy and gastrointestinal tumours in a man with a chromosomal 2q13 deletion and BUB1 monoallelic deficiency. AB - Chromosomal instability is a potentially critical step in the development of colorectal cancer. The budding uninhibited by benzimidazole 1 (BUB1) gene is a highly conserved protein that plays a critical role at the spindle assembly checkpoint during cell division. BUB1 mutations function in a dominant-negative fashion and have been implicated in causing dysfunctional kinetochore attachments, premature chromatid separation, accelerated mis-segregation of whole chromosomes and aneuploidy. BUB1 mutations have been observed in patients with colorectal cancers. We report a remarkable case of BUB1 haploinsufficiency owing to a 1.7 Mb deletion of chromosome 2q13 in a 54-year-old man with no prior history of carcinoma. These mutant alleles were observed in both tissue from the hand and peripheral blood. Aneuploidy was not observed on cytogenetic analysis. These findings highlight the insufficiency of BUB1 haploinsufficiency to directly stimulate tumourigenesis, and suggest that other factors may be more critical to this process. PMID- 23440992 TI - Fibrolipoma of the eustachian ostium. AB - Nasopharyngeal fibrolipoma is extremely rare, with only four case reports in the literature. However, lipoma of the eustachian tube is the rarest with a single case report in the literature. A 50-year-old woman presented with obstruction of both nostrils for the past 1 year. CT scan showed a mass in the postnasal space extending from the right side of the nasopharynx to the oropharynx. The nasal endoscopy found a polypoidal mass arising from the posterior-inferior margin of the right eustachian tube ostium and extending to the oropharynx. Histopathological examination of the excised polyp found features suggestive of fibrolipoma. Fibrolipoma is characterised by prominent bundles of mature collagenous or myxocollagenous stroma intermixed with mature adipocytes. CT is useful in the diagnosis of lipoma but MRI is preferable. This is the second case of eustachian tube fibrolipoma to be reported in the literature that emphasises the role of nasal endoscopy and rarity of this tumour. PMID- 23440993 TI - Brain abscess as an initial presentation in a patient of hereditary haemorrhagic telangiectasia caused by a novel ENG mutation. AB - Hereditary haemorrhagic telangiectasia (HHT) is a rare inherited autosomal dominant vascular dysplasia involving multiple organs. Brain abscess is an uncommon and potential fatal complication. We report a case of HHT caused by a novel ENG mutation who initially presented as brain abscess. The patient, with a family history of epistaxis, presented with fever, headache and right-sided haemiparesis. Upon examination, brain MRI showed a contrast-enhanced abscess on the left fronto-parietal region. Open brain drainage was performed and pus culture yielded Actinomyces meyeri. The chest image revealed multiple pulmonary arterio-venous fistulas. HHT was diagnosed according to Curacao criteria. Genetic analysis revealed a novel duplication on exon 6 of ENG gene, which segregates with symptomatic subjects in her family. Clinicians should be cautiously aware of HHT as a differential diagnosis if patients presented with an unknown entry source of intracerebral infections. PMID- 23440994 TI - Multiband phase-constrained parallel MRI. AB - PURPOSE: Parallel MRI methods are typically associated with a degradation of the signal-to-noise ratio (SNR). High scan time reduction factors are therefore restricted to applications with high intrinsic SNR. One possibility to increase the intrinsic SNR is to simultaneously excite several slices by means of multiband radio-frequency (RF) pulses and subsequently separate the slices by parallel MRI reconstruction algorithms. However, the separation of closely spaced slices may suffer from severe noise amplification when there is insufficient coil sensitivity variation along the slice direction. The purpose of this work is to apply a phase-constrained reconstruction for multiband experiments to minimize the noise amplification. METHODS: Pre-defined phase differences between neighboring slices are induced and slice separation is performed by a phase constrained parallel MRI reconstruction. Phase differences between neighboring slices are tailored to achieve optimal slice separation with minimized noise amplification. The potential of the method is demonstrated through multiband in vivo experiments. RESULTS: Noise amplification in multiband phase-constrained reconstructions is significantly reduced in comparison to standard multiband reconstruction when the phase difference between neighboring slices (distance = 12 mm) is 90 degrees . CONCLUSIONS: Multiband phase-constrained parallel MRI has the potential for accelerated multi-slice imaging with an improved SNR performance. PMID- 23440995 TI - Alcohol: the lubricant to suicidality. AB - Suicide is a major public health problem in the United States as well as around the world. The significant role that alcohol plays in suicidality is well known and accepted in the scientific community. The use of alcohol does not necessarily lead to suicide, but through its action and effects, alcohol is an important proximal risk factor for suicidal behavior. There is very little data showing how and why alcohol exerts such tremendous influence and "lubricates the gears" to propel the act of committing suicide. This article will elucidate the complex relationship between alcohol and suicide and how alcohol use can lead to suicide. The article also describes how alcohol affects brain neurophysiology in regards to suicidal behavior. PMID- 23440996 TI - Targeting Multidrug Resistant Mycobacterium tuberculosis HtrA2 with Identical Chemical Entities of Fluoroquinolones. AB - Tuberculosis is a highly communicable and chronic respiratory disease caused by pathogenic bacterium Mycobacterium tuberculosis. The drug - resistant species of Mycobacterium tuberculosis are tough to cure due to its resistant activity toward potential drugs. Available inhibitors of tuberculosis include few antimicrobial fluoroquinolone agents like ciprofloxacin, ofloxacin, and moxifloxacin to treat resistant Mycobacterium strains. Literature study elucidates that macromolecular target namely, HtrA2 of Mycobacterium tuberculosis play a dual role of protease and chaperone. These two activities are dependent on temperature, with low temperatures promoting the chaperone function and high temperatures promoting serine protease activity. Under normal physiological conditions HtrA2 acts as a quality control factor and promotes cell survival. In the present investigation, we screened fluoroquinolone such as ciprofloxacin, moxifloxacin and ofloxacin and their analogues based on better Docking score, absorption, distribution, metabolism and excretion screening and Lipinski's rule of 5, to find out their efficiency on resistant strain through in silico study. From the results observed, the analogues are suggested to be potent inhibitors of HtrA2 with sufficient scope for further exploration. PMID- 23440997 TI - Why are the oldest old less generous? Explanations for the unexpected age-related drop in charitable giving. AB - Previous research has demonstrated that the generally positive relationship between age and the presence of charitable giving becomes negative at the oldest ages. We investigate potential causes of this drop in charitable giving among the oldest old including changes in health, cognition, egocentric networks, religious attendance, and substitution of charitable bequest planning. A longitudinal analysis of data from the United States Health and Retirement Survey indicates that the drop in charitable giving is mediated largely by changes in the frequency of church attendance, with only modest influences from changes in health and cognition. PMID- 23440998 TI - Elevated peri-transplant distress in caregivers of allogeneic blood or marrow transplant patients. AB - PURPOSE: A full-time 24/7 caregiver is required for 100 days or longer following an allogeneic blood or marrow transplant during which time caregivers have multiple demands. Although distress in caregivers is documented, generalization is limited by small sample sizes, restricted range of assessments, and lack of information as to which caregivers may be more vulnerable to distress. The purpose of this study was to describe the peri-transplant psychological status of a sample of caregivers of allogeneic transplant patients. METHODS: We assessed caregiver mood, stress, burden, and sleep using valid self-report measures in 109 caregivers of allogeneic transplant patients prior to stem cell transplantation. Caregivers' scores were compared with norms or established cutoff scores for behavioral measures. Additionally, demographic characteristics such as age and sex were tested as predictors of distress. RESULTS: Caregivers showed significant levels of anxiety, stress, intrusion and avoidance behaviors, and poor sleep at the start of transplant compared with established norms. Younger caregivers were more distressed than older caregivers. There were no differences in levels of distress between male and female caregivers. CONCLUSION: The peri-transplant period is a time of heightened anxiety and distress for caregivers of allogeneic transplant patients. This study indicates that caregivers would benefit from support programs in the peri-transplant period. Recommendations for types of support that may be helpful to caregivers are provided, but additional research is needed to validate that these programs would help caregivers providing care to patients receiving an allogeneic transplant in the peri-transplant period. PMID- 23441000 TI - Detection of methicillin resistance in Staphylococcus aureus by polymerase chain reaction and conventional methods: a comparative study. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide, which has emerged over the past 30 years as a leading cause of both nosocomial and community-acquired infections. Accurate and rapid identification of MRSA in clinical specimens is essential for timely decision on effective antimicrobial chemotherapy. AIM: The present study was conducted to compare two conventional phenotypic methods, oxacillin disk diffusion (ODD) method and mannitol salt agar (MSA) with oxacillin, with polymerase chain reaction (PCR) for mecA gene (as standard). MATERIALS AND METHODS: A total of 165 consecutive clinical isolates of S. aureus received at the Department of Microbiology in our tertiary care teaching hospital were included in the study. All the isolates were subjected to ODD (1 MUg) method, culture in MSA with oxacillin, and PCR for mecA gene. RESULTS: The sensitivity and specificity of ODD test were found to be 93.5% (86.4-97.3%) and 83.5% (79.2 85.8%), respectively, and that of MSA with oxacillin were found to be 87.1% (79.5 92.3%) and 89.3% (84.8-92.5%), respectively. The time taken for diagnosing MRSA by conventional methods is 48-72 h, which is more as compared to PCR which takes 18-24 h. CONCLUSION: This study recommends advocating PCR for mecA gene on a regular basis for detecting methicillin resistance in S. aureus isolates isolated from sterile body fluids or from special units such as intensive care units. PMID- 23441002 TI - Non small cell carcinoma metastasis to meningioma. AB - "Tumor-to-tumor" metastasis is a rare event; meningioma has been reported as the most common primary intracranial tumor to harbor cancer metastases. Several hypotheses have been previously proposed to explain this occurrence, but the exact mechanism by which these metastases develop into meningiomas is not yet understood. Magnetic resonance imaging and spectroscopy have been valuable diagnostic tools, but preoperative diagnosis of metastasis to meningioma remains highly difficult. We present a case report of a metastasis of non-small cell lung cancer into an intracranial meningioma. PMID- 23441001 TI - Emotional and non-emotional pathways to impulsive behavior and addiction. AB - Impulsivity is tightly linked to addiction. However, there are several pathways by means of which impulsive individuals are more prone to become addicts, or to suffer an addiction more intensely and for a longer period. One of those pathways involves an inadequate appraisal or regulation of positive and negative emotions, leading to lack of control over hazardous behaviors, and inappropriate decisions. In the present work, we assessed cocaine-dependent individuals (CDI; n = 20), pathological gamblers (PG; n = 21), and healthy controls (HC; n = 23) in trait impulsivity measures (UPPS-P model's dimensions), and decision-making tasks (Go/No-go; delay-discounting task). During the Go/No-go task, electroencephalographic (EEG) activity was recorded, and Go/No-go stimuli-evoked potentials (ERP) were extracted. Theory-driven ERP analyses focused on the No-go > Go difference in the N2 ERP. Our results show that negative urgency is one of the several psychological features that distinguish addicts from HC. Nevertheless, among the dimensions of trait impulsivity, negative urgency is unique at independently covarying with gambling over-pathologization in the PG sample. Cocaine-dependent individuals performed more poorly than gamblers in the Go/No-go task, and showed abnormal Go/No-go stimuli-evoked potentials. The difference between the No-go stimulus-evoked N2, and the Go one was attenuated by severity and intensity of chronic cocaine use. Emotional dimensions of impulsivity, however, did not influence Go/No-go performance. PMID- 23440999 TI - Experimental vaccines against potentially pandemic and highly pathogenic avian influenza viruses. AB - Influenza A viruses continue to emerge and re-emerge, causing outbreaks, epidemics and occasionally pandemics. While the influenza vaccines licensed for public use are generally effective against seasonal influenza, issues arise with production, immunogenicity, and efficacy in the case of vaccines against pandemic and emerging influenza viruses, and highly pathogenic avian influenza virus in particular. Thus, there is need of improved influenza vaccines and vaccination strategies. This review discusses advances in alternative influenza vaccines, touching briefly on licensed vaccines and vaccine antigens; then reviewing recombinant subunit vaccines, virus-like particle vaccines and DNA vaccines, with the main focus on virus-vectored vaccine approaches. PMID- 23441004 TI - 2012 ISMRM Lauterbur Lecture. MRI: from science to society. AB - In this 2012 ISMRM Lauterbur Lecture, my goal is to challenge the members of the ISMRM to think critically about how we approach our research. From the perspective of a leader of an academic health sciences center, which is also a health care delivery system, I address three specific questions: Are we developing great technologies? Are we advancing scientific knowledge? Are we advancing human health? Specifically, with respect to increasing pressure in health care to improve patient outcomes and lower costs, I ask members to consider how we select the areas of research we focus on and whether we have sufficiently prioritized research that assesses the impact of our MR methods on patient outcomes. For imaging research to meet higher standards of evidence-based medicine, multicenter consortia should be developed, potentially under the auspices of the ISMRM, and priority should be given to developing investigators with expertise in health services research. PMID- 23441003 TI - Influence of Fimasartan (a Novel AT(1) Receptor Blocker) on Catecholamine Release in the Adrenal Medulla of Spontaneously Hypertensive Rats. AB - The aim of this study was to determine whether fimasartan, a newly developed AT(1) receptor blocker, can affect the CA release in the isolated perfused model of the adrenal medulla of spontaneously hypertensive rats (SHRs). Fimasartan (5~50 uM) perfused into an adrenal vein for 90 min produced dose- and time dependently inhibited the CA secretory responses evoked by ACh (5.32 mM), high K(+) (56 mM, a direct membrane depolarizer), DMPP (100 uM) and McN-A-343 (100 uM). Fimasartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with fimasartan (15 uM), the CA secretory responses evoked by Bay-K-8644 (10 uM, an activator of L-type Ca(2+) channels), cyclopiazonic acid (10 uM, an inhibitor of cytoplasmic Ca(2+)-ATPase), and veratridine (100 uM, an activator of Na(+) channels) as well as by angiotensin II (Ang II, 100 nM), were markedly inhibited. In simultaneous presence of fimasartan (15 uM) and L-NAME (30 uM, an inhibitor of NO synthase), the CA secretory responses evoked by ACh, high K(+), DMPP, Ang II, Bay-K-8644, and veratridine was not affected in comparison of data obtained from treatment with fimasartan (15 uM) alone. Also there was no difference in NO release between before and after treatment with fimasartan (15 uM). Collectively, these experimental results suggest that fimasartan inhibits the CA secretion evoked by Ang II, and cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization from the rat adrenal medulla. It seems that this inhibitory effect of fimasartan may be mediated by blocking the influx of both Na(+) and Ca(2+) through their ion channels into the rat adrenomedullary chromaffin cells as well as by inhibiting the Ca(2+) release from the cytoplasmic calcium store, which is relevant to AT(1) receptor blockade without NO release. PMID- 23441005 TI - Early and prolonged ECG alterations resembling a myocardial injury after severe amitriptyline poisoning. AB - Evidence of cardiovascular toxicity is present in the majority of tricyclic antidepressant overdoses. We report the case of a 63-year-old woman admitted to our department with a severe amitriptyline poisoning. The ECG at admission showed a pattern mimicking an acute anteroseptal subepicardial infarction. This pattern persisted for 11 days. Myocardial enzymes and echocardiographic findings never confirmed an ischemic event. At discharge, the ECG returned normal without cardiac or neurologic sequelae. Our experience suggest that after severe tricyclic antidepressant ingestion, ECG alterations resembling myocardial injury may occur early and last for a longer period than previously reported. PMID- 23441006 TI - Chronic obstructive pulmonary disease lost in translation: Why are the inhaled corticosteroids skeptics refusing to go? AB - A survey of pulmonologists attending a clinical meeting of the Saudi Thoracic Society found that only 55% of responders considered that inhaled corticosteroids (ICS) had a positive effect on quality of life in Chronic Obstructive Pulmonary Disease (COPD). Why the divergence of opinion when all the guidelines have concluded that ICS improve quality of life and produce significant bronchodilation? ICS unequivocally reduce the rate of exacerbations by a modest 20%, but this does not extend to serious exacerbations requiring hospitalization. Bronchodilatation with ICS is now documented to be restricted to some phenotypes of COPD. Withdrawal of ICS trials reported a modest decline of FEV(1) (<5%) in half the studies and no decline in the other half. In spite of the guidelines statements, there is no concurrence on whether ICS improve the quality of life and there is no conclusive evidence that the combination of long-acting beta2 agonists (LABA) with ICS is superior to LABA alone in that regard. The explanation for these inconclusive results may be related to the fact that COPD consists of three different phenotypes with divergent responses to LABA and ICS. Therapy tailored to phenotype is the future for COPD. PMID- 23441007 TI - Solvatochromic effect on the photoluminescence of MoS2 monolayers. AB - The effect of surrounding solvents on the photoluminescence (PL) of MoS2 monolayers on Si/SiO2 substrates is studied. A redshift (up to -60 meV) is observed for MoS2 monolayers with nonhalogenated solvent surroundings. A blueshift (up to 60 meV) and intensity increase (2-50 times) are observed for monolayers with halogenated solvent surroundings. PMID- 23441010 TI - Thyroid fine-needle aspiration cytology: is there a place to virtual cytology? AB - Telecytology has been used for education, training, and consultation. Cytological studies from gynecological, nongynecological and fine-needle aspiration cytology (FNAC) specimens (including studies of thyroid FNAC) analyzed the diagnostic accuracy and reproducibility of telecytology-based predominantly on static digital images. The aim of this study was to evaluate the diagnostic reproducibility of virtual cytology by measuring intraobserver and interobserver agreements among two cytopathologists, using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) nomenclature. 502 glass slides from 222 cases of thyroid FNAC were retrieved and scanned by a high-resolution scanner generating whole slides images (virtual cytology). Conventional and virtual cytology were analyzed by a skilled cytopathologist and the intraobserver agreement rate was 77.5% with the corresponding kappa value of 0.54, suggesting a moderate agreement between both methods. A second cytopathologist analyzed the same slides only by virtual cytology and the interobserver agreement rate was 80.2% with the corresponding kappa value of 0.57, suggesting a moderate agreement between both cytopathologists. The virtual cytology resulted in a higher proportion of aspirates classified as nondiagnostic (20.3 and 14.9% for the first and second cytopathologist, respectively) as compared to conventional cytology (8.1%). Regarding specific diagnostic categories as defined by the BSRTC nomenclature, the follicular lesion of undetermined significance category presented the lowest concordance rates, corresponding to 5.9% intraobserver agreement and no (0.0%) interobserver agreement. We suggest that virtual cytology can be an alternative to conventional cytology in assessment of thyroid FNAC specimens, but nondiagnostic aspirates obtained by virtual cytology should be reassessed by conventional cytology. PMID- 23441011 TI - C(sp3)-F bond formation: a free-radical approach. PMID- 23441012 TI - Understanding photophysical effects of cucurbituril encapsulation: a model study with acridine orange in the gas phase. AB - Encapsulation of dyes by cucurbituril macrocycles has proven profitable as a strategy to alter fluorescence characteristics in useful ways. Encapsulation generally results in longer fluorescence lifetimes, enhanced brightness, and solvatochromic effects not normally seen in the condensed phase. These effects have been attributed variously to both the removal of interactions with solvent molecules and to the confined environment of extremely low polarizability provided by the cucurbituril interior. It is difficult to disentangle these effects in solution. Here, we present results from gas-phase experiments designed to separate these effects, using cucurbit[7]uril (CB7), and the cationic dye acridine orange (AOH(+)) as a probe. Fluorescence properties of gaseous AOH(+) are compared with those of the gaseous AOH(+)-CB7 complex and with the properties of the dye and complex in aqueous solution. The dependence on the local environment of several spectroscopic properties is discussed, including the fluorescence excitation and emission maxima, the size of the Stokes shift, fluorescence lifetime and relative brightness. An understanding of the modulation of fluorescence properties by the local environment, such as that promoted by this work, will aid in the rational design of improved fluorophores and fluorescent sensors. PMID- 23441009 TI - Diagnostic and statistical manual-5: Position paper of the Indian Psychiatric Society. AB - The development of the Diagnostic and Statistical Manual-5 (DSM-5) has been an exhaustive and elaborate exercise involving the review of DSM-IV categories, identifying new evidence and ideas, field testing, and revising issues in order that it is based on the best available evidence. This report of the Task Force of the Indian Psychiatric Society examines the current draft of the DSM-5 and discusses the implications from an Indian perspective. It highlights the issues related to the use of universal categories applied across diverse cultures. It reiterates the evidence for mental disorders commonly seen in India. It emphasizes the need for caution when clinical categories useful to specialists are employed in the contexts of primary care and in community settings. While the DSM-5 is essentially for the membership of the American Psychiatric Association, its impact will be felt far beyond the boundaries of psychiatry and that of the United States of America. However, its atheoretical approach, despite its pretensions, pushes a purely biomedical agenda to the exclusion of other approaches to mental health and illness. Nevertheless, the DSM-5 should serve a gate-keeping function, which intends to set minimum standards. It is work in progress and will continue to evolve with the generation of new evidence. For the DSM-5 to be relevant and useful across the cultures and countries, it needs to be broad-based and consider social and cultural contexts, issues, and phenomena. The convergence and compatibility with International Classification of Diseases-11 is a worthy goal. While the phenomenal effort of the DSM-5 revision is commendable, psychiatry should continue to strive for a more holistic understanding of mental health, illness, and disease. PMID- 23441013 TI - Application of direct virtual coil to dynamic contrast-enhanced MRI and MR angiography with data-driven parallel imaging. AB - PURPOSE: To demonstrate the feasibility of direct virtual coil (DVC) in the setting of 4D dynamic imaging used in multiple clinical applications. THEORY AND METHODS: Three dynamic imaging applications were chosen: pulmonary perfusion, liver perfusion, and peripheral MR angiography (MRA), with 18, 11, and 10 subjects, respectively. After view-sharing, the k-space data were reconstructed twice: once with channel-by-channel (CBC) followed by sum-of-squares coil combination and once with DVC. Images reconstructed using CBC and DVC were compared and scored based on overall image quality by two experienced radiologists using a five-point scale. RESULTS: The CBC and DVC showed similar image quality in image domain. Time course measurements also showed good agreement in the temporal domain. CBC and DVC images were scored as equivalent for all pulmonary perfusion cases, all liver perfusion cases, and four of the 10 peripheral MRA cases. For the remaining six peripheral MRA cases, DVC were scored as slightly better (not clinically significant) than the CBC images by Radiologist A and as equivalent by Radiologist B. CONCLUSION: For dynamic contrast-enhanced MR applications, it is clinically feasible to reduce image reconstruction time while maintaining image quality and time course measurement using the DVC technique. PMID- 23441015 TI - Diffuse large B-cell extranodal lymphoma of the uterine cervix: an incidental pap smear finding with histological and immunohistochemical correlation. PMID- 23441016 TI - One-pot procedure for the introduction of three different bonds onto terminal alkynes through N-sulfonyl-1,2,3-triazole intermediates. PMID- 23441014 TI - RNA interference by feeding in vitro-synthesized double-stranded RNA to planarians: methodology and dynamics. AB - BACKGROUND: The ability to assess gene function is essential for understanding biological processes. Currently, RNA interference (RNAi) is the only technique available to assess gene function in planarians, in which it has been induced by means of injection of double-stranded RNA (dsRNA), soaking, or ingestion of bacteria expressing dsRNA. RESULTS: We describe a simple and robust RNAi protocol, involving in vitro synthesis of dsRNA that is fed to the planarians. Advantages of this protocol include the ability to produce dsRNA from any vector without subcloning, resolution of ambiguities in quantity and quality of input dsRNA, as well as time and ease of application. We have evaluated the logistics of inducing RNAi in planarians using this methodology in careful detail, from the ingestion and processing of dsRNA in the intestine, to timing and efficacy of knockdown in neoblasts, germline, and soma. We also present systematic comparisons of effects of amount, frequency, and mode of dsRNA delivery. CONCLUSIONS: This method gives robust and reproducible results and is amenable to high-throughput studies. Overall, this RNAi methodology provides a significant advance by combining the strengths of current protocols available for dsRNA delivery in planarians and has the potential to benefit RNAi methods in other systems. PMID- 23441017 TI - Phase stability and elastic properties of chromium borides with various stoichiometries. AB - Phase stability is important to the application of materials. By first-principles calculations, we establish the phase stability of chromium borides with various stoichiometries. Moreover, the phases of CrB3 and CrB4 have been predicted by using a newly developed particle swarm optimization (PSO) algorithm. Formation enthalpy-pressure diagrams reveal that the MoB-type structure is more energetically favorable than the TiI-type structure for CrB. For CrB2, the WB2 type structure is preferred at zero pressure. The predicted new phase of CrB3 belongs to the hexagonal P-6m2 space group and it transforms into an orthorhombic phase as the pressure exceeds 93 GPa. The predicted CrB4 (space group: Pnnm) phase is more energetically favorable than the previously proposed Immm structure. The mechanical and thermodynamic stabilities of predicted CrB3 and CrB4 are verified by the calculated elastic constants and formation enthalpies. The full phonon dispersion calculations confirm the dynamic stability of WB2 type CrB2 and predicted CrB3. The large shear moduli, large Young's moduli, low Poisson ratios, and low bulk and shear modulus ratios of CrB4-PSC and CrB4-PSD indicate that they are potential hard materials. Analyses of Debye temperature, electronic localization function, and electronic structure provide further understanding of the chemical and physical properties of these borides. PMID- 23441018 TI - Size-controllable synthesis and functionalization of ultrafine polymeric nanoparticles. PMID- 23441019 TI - Correlation of muscle BOLD MRI with transcutaneous oxygen pressure for assessing microcirculation in patients with systemic sclerosis. AB - PURPOSE: To prospectively compare calf muscle BOLD MRI with transcutaneous oxygen pressure (TcPO2 ) measurement in patients with systemic sclerosis (SSc) and healthy volunteers and thereby get insight into the pathogenesis of vasculopathy in this connective tissue disorder. MATERIALS AND METHODS: Twelve patients with SSc (6 women and 6 men, mean age 53.5 +/- 10.0 years) and 12 healthy volunteers (4 men and 8 women, mean age 47 +/- 12.1 years) were examined using muscle BOLD MRI and TcPO2. A cuff compression at mid-thigh level was performed to provoke ischemia and reactive hyperemia. BOLD measurements were acquired on a 3 Tesla whole body-scanner in the upper calf region using a multi-echo EPI-sequence with four echo-times (TE: 9/20/31/42 ms) and a repetition time of 2 s. Empirical cross correlation analysis depending on time lags between BOLD- and TcPO2-measurements was performed. RESULTS: Maximal cross-correlation of BOLD T2*- and TcPO2 measurements was calculated as 0.93 (healthy volunteers) and 0.90 (SSc patients) for a time lag of approximately 40 s. Both modalities showed substantial differences regarding time course parameters between the SSc patients and healthy volunteers. CONCLUSION: Skeletal muscle BOLD MRI correlated very well with TcPO2 . T2* changes seem to reflect reoxygenation deficits in deeper muscle tissue of SSc patients. PMID- 23441021 TI - Antiplasmodial Potential of the African Mistletoe: Agelanthus dodoneifolius Polh and Wiens. AB - Preparations of Agelanthus dodoneifolius have been used in the traditional Nigerian medicine to treat malaria and this practice has remained till date without scientific validation. The antiplasmodial property of the water extract of Agelanthus dodoneifolius was evaluated in vivo and in vitro against Plasmodium berghei and clinical isolates of Plasmodium falciparum, respectively. There was a dose-dependent inhibition of parasitaemia in the in vivo antiplasmodial tests likewise, the in vitro screening demonstrated a strong and concentration dependent activity (21.54 MUg/ml < IC(50) < 50 MUg/ml) of the extract against the clinical isolates of Plasmodium falciparum. The phytochemical analysis revealed the presence of tannins, saponins, sterols, glycosides, phenols, anthraquinones, terpenes, reducing sugars and resins. It also showed a strong free-radical scavenging activity on 2, 2-diphenyl-2-picrylhydrazyl. The oral median lethal dose (LD(50)) in mice was estimated to be greater than 5000 mg/kg. Our results evidence that Agelanthus dodoneifolius may contain biologically active principles those are relevant in the treatment of malaria, thus supporting further studies of its active components. PMID- 23441020 TI - Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation. AB - Cre/LoxP-mediated recombination allows for conditional gene activation or inactivation. When combined with an independent lineage-tracing reporter allele, this technique traces the lineage of presumptive genetically modified Cre expressing cells. Several studies have suggested that floxed alleles have differential sensitivities to Cre-mediated recombination, which raises concerns regarding utilization of Cre-reporters to monitor recombination of other floxed loci of interest. Here, we directly investigate the recombination correlation, at cellular resolution, between several floxed alleles induced by Cre-expressing mouse lines. The recombination correlation between different reporter alleles varied greatly in otherwise genetically identical cell types. The chromosomal location of floxed alleles, distance between LoxP sites, sequences flanking the LoxP sites, and the level of Cre activity per cell all likely contribute to observed variations in recombination correlation. These findings directly demonstrate that, due to non-parallel recombination events, commonly available Cre reporter mice cannot be reliably utilized, in all cases, to trace cells that have DNA recombination in independent-target floxed alleles, and that careful validation of recombination correlations are required for proper interpretation of studies designed to trace the lineage of genetically modified populations, especially in mosaic situations. PMID- 23441022 TI - Median-Based Incremental Cost-Effectiveness Ratio (ICER). AB - Cost-effectiveness analysis (CEA) is a type of economic evaluation that examines the costs and health outcomes of alternative strategies and has been extensively applied in health sciences. The incremental cost-effectiveness ratio (ICER), which represents the additional cost of one unit of outcome gained by one strategy compared with another, has become a popular methodology in CEA. Despite its popularity, limited attention has been paid to summary measures other than the mean for summarizing cost as well as effectiveness in the context of CEA. Although some apparent advantages of other central tendency measures such as median for cost data that are often highly skewed are well understood, thus far, the median has rarely been considered in the ICER. In this paper, we propose the median-based ICER, along with inferential procedures, and suggest that mean and median-based ICERs be considered together as complementary tools in CEA for informed decision making, acknowledging the pros and cons of each. If the mean and median-based CEAs are concordant, we may feel reasonably confident about the cost-effectiveness of an intervention, but if they provide different results, our confidence may need to be adjusted accordingly, pending further evidence. PMID- 23441023 TI - Factors Affecting the Sustainability of Self-Run Recovery Homes in the United States. AB - This study examined the sustainability rates of 214 self-run substance abuse recovery homes called Oxford Houses (OHs) over a six-year period. We list five factors needed to sustain an OH: affordable housing, residents following OH principles, resident income, institutional support, and community support. Results indicated a high sustainability rate (86.9%) in which 186 OHs remained open and 28 OHs closed. Reasons for houses closing (N = 14) included lack of affordable housing, which we classified as an external factor. Houses that closed because of internal factors (N = 13) included residents who were unable to adhere to OH rules, and insufficient income of residents. No house-level differences for income, sense of community, average lengths of stay, house age, or neighborhood characteristics were found between the houses that closed versus houses that remained open. Because the OH system relies on residents to sustain individual houses located in ordinary residential neighborhoods, these findings suggest that OH sustainability depends on locale, primarily access to affordable housing and adequate job opportunities for residents. PMID- 23441025 TI - Comparison of the lysis centrifugation method with the conventional blood culture method in cases of sepsis in a tertiary care hospital. AB - INTRODUCTION: Physicians and microbiologists have long recognized that the presence of living microorganisms in the blood of a patient carries with it considerable morbidity and mortality. Hence, blood cultures have become critically important and frequently performed test in clinical microbiology laboratories for diagnosis of sepsis. OBJECTIVES: To compare the conventional blood culture method with the lysis centrifugation method in cases of sepsis. MATERIALS AND METHODS: Two hundred nonduplicate blood cultures from cases of sepsis were analyzed using two blood culture methods concurrently for recovery of bacteria from patients diagnosed clinically with sepsis - the conventional blood culture method using trypticase soy broth and the lysis centrifugation method using saponin by centrifuging at 3000 g for 30 minutes. RESULTS: Overall bacteria recovered from 200 blood cultures were 17.5%. The conventional blood culture method had a higher yield of organisms, especially Gram positive cocci. The lysis centrifugation method was comparable with the former method with respect to Gram negative bacilli. The sensitivity of lysis centrifugation method in comparison to conventional blood culture method was 49.75% in this study, specificity was 98.21% and diagnostic accuracy was 89.5%. In almost every instance, the time required for detection of the growth was earlier by lysis centrifugation method, which was statistically significant. Contamination by lysis centrifugation was minimal, while that by conventional method was high. Time to growth by the lysis centrifugation method was highly significant (P value 0.000) as compared to time to growth by the conventional blood culture method. CONCLUSION: For the diagnosis of sepsis, combination of the lysis centrifugation method and the conventional blood culture method with trypticase soy broth or biphasic media is advocable, in order to achieve faster recovery and a better yield of microorganisms. PMID- 23441024 TI - Structural plasticity of climbing fibers and the growth-associated protein GAP 43. AB - Structural plasticity occurs physiologically or after brain damage to adapt or re establish proper synaptic connections. This capacity depends on several intrinsic and extrinsic determinants that differ between neuron types. We reviewed the significant endogenous regenerative potential of the neurons of the inferior olive (IO) in the adult rodent brain and the structural remodeling of the terminal arbor of their axons, the climbing fiber (CF), under various experimental conditions, focusing on the growth-associated protein GAP-43. CFs undergo remarkable collateral sprouting in the presence of denervated Purkinje cells (PCs) that are available for new innervation. In addition, severed olivo cerebellar axons regenerate across the white matter through a graft of embryonic Schwann cells. In contrast, CFs undergo a regressive modification when their target is deleted. In vivo knockdown of GAP-43 in olivary neurons, leads to the atrophy of their CFs and a reduction in the ability to sprout toward surrounding denervated PCs. These findings demonstrate that GAP-43 is essential for promoting denervation-induced sprouting and maintaining normal CF architecture. PMID- 23441026 TI - Complex hallucinations and panic attacks in a 13-year-old with migraines: the alice in wonderland syndrome. AB - This case report describes a 13-year-old girl whose family requested a referral from the pediatrician for Child and Adolescent Mental Health Services in order to understand her recent onset of bizarre behavior. On assessment, she was found to have episodes of complex audiovisual hallucinations and panic attacks with intervals of complete recovery associated with episodes of migraine headaches. The "Alice in Wonderland Syndrome," which is intimately associated with migraine and epilepsy, as well as a number of other neurological conditions, could explain her episodic neurobehavioral disturbance. PMID- 23441027 TI - Telepsychiatry: Promise, potential, and challenges. AB - Despite the high prevalence and potentially disabling consequences of mental disorders, specialized mental health services are extremely deficient, leading to the so-called 'Mental Health Gap'. Moreover, the services are concentrated in the urban areas, further worsening the rural-urban and tertiary primary care divide. Strengthening of and expanding the existing human resources and infrastructure, and integrating mental health into primary care appear to be the two major solutions. However, both the strategies are riddled with logistic difficulties and have a long gestation period. In such a scenario, telepsychiatry or e-mental health, defined as the use of information and communication technology to provide or support psychiatric services across distances, appears to be a promising answer. Due to its enormous potential, a review of the existing literature becomes imperative. An extensive search of literature was carried out and has been presented to delineate the modes of communication, acceptability and satisfaction, reliability, outcomes, cost-effectiveness, and legal and ethical challenges related to telepsychiatry. Telepsychiatry has been applied for direct patient care (diagnosis and management), consultation, and training, education, and research purposes. Both real-time, live interaction (synchronous) and store forward (asynchronous) types of technologies have been used for these purposes. A growing amount of literature shows that training, supervision, and consultation by specialists to primary care physicians through telepsychiatry has several advantages. In this background, we have further focused on the models of telepsychiatry best suited for India, considering that mental health care can be integrated into primary care and taken to the doorstep of patients in the community. PMID- 23441029 TI - Design and performance study of an orthopaedic surgery robotized module for automatic bone drilling. AB - BACKGROUND: Many orthopaedic operations involve drilling and tapping before the insertion of screws into a bone. This drilling is usually performed manually, thus introducing many problems. These include attaining a specific drilling accuracy, preventing blood vessels from breaking, and minimizing drill oscillations that would widen the hole. Bone overheating is the most important problem. To avoid such problems and reduce the subjective factor, automated drilling is recommended. METHODS: Because numerous parameters influence the drilling process, this study examined some experimental methods. These concerned the experimental identification of technical drilling parameters, including the bone resistance force and temperature in the drilling process. During the drilling process, the following parameters were monitored: time, linear velocity, angular velocity, resistance force, penetration depth, and temperature. RESULTS: Specific drilling effects were revealed during the experiments. The accuracy was improved at the starting point of the drilling, and the error for the entire process was less than 0.2 mm. The temperature deviations were kept within tolerable limits. The results of various experiments with different drilling velocities, drill bit diameters, and penetration depths are presented in tables, as well as the curves of the resistance force and temperature with respect to time. Real-time digital indications of the progress of the drilling process are shown. CONCLUSIONS: Automatic bone drilling could entirely solve the problems that usually arise during manual drilling. An experimental setup was designed to identify bone drilling parameters such as the resistance force arising from variable bone density, appropriate mechanical drilling torque, linear speed of the drill, and electromechanical characteristics of the motors, drives, and corresponding controllers. Automatic drilling guarantees greater safety for the patient. Moreover, the robot presented is user-friendly because it is simple to set robot tasks, and process data are collected in real time. PMID- 23441030 TI - Quantification of protein mixture in chromatographic separation using multi wavelength UV spectra. AB - In therapeutic protein production, the protein purification with chromatographic processes is of high importance in separating the qualified proteins from the impurities for consistent product quality. Therefore, to aid real-time monitoring of the protein purification processes, various kinds of methodologies have been proposed until now. However, the majority of them still rely on the use of a single ultraviolet (UV) absorbance or the utilization of expensive and time consuming instruments, thus requiring a simple, fast, and cost-effective methodology for protein quantification. In this study, the feasibility of using multiwavelength UV spectroscopy was investigated as an alternative tool for the real-time monitoring of the protein mixtures in protein purification. To this end, three different proteins were selected as a model system for the protein mixture, and the multivariate UV spectra were analyzed to construct the reliable quantification models for different proteins of interest. By using various chemometrics tools, such as partial least squares (PLS), the validity of estimating the protein concentration from the UV spectra of the mixture samples was rigorously analyzed with their prediction performance, and the results indicated that the multiwavelength UV spectra had sufficient sensitivity and accuracy to estimate the protein concentrations in mixture, demonstrating its usefulness for the rapid quantification of the protein mixtures in protein purification. PMID- 23441028 TI - AMPK and Exercise: Glucose Uptake and Insulin Sensitivity. AB - AMPK is an evolutionary conserved sensor of cellular energy status that is activated during exercise. Pharmacological activation of AMPK promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in obesity and contribute to the development of insulin resistance. AMPK deficient mouse models have been used to provide direct genetic evidence either supporting or refuting a role for AMPK in regulating these processes. Exercise promotes glucose uptake by an insulin dependent mechanism involving AMPK. Exercise is important for improving insulin sensitivity; however, it is not known if AMPK is required for these improvements. Understanding how these metabolic processes are regulated is important for the development of new strategies that target obesity-induced insulin resistance. This review will discuss the involvement of AMPK in regulating skeletal muscle metabolism (glucose uptake, glycogen synthesis, and insulin sensitivity). PMID- 23441032 TI - Kinetic of procalcitonin in patients with cardiogenic shock following acute myocardial infarction: preliminary data. AB - INTRODUCTION: Procalcitonin concentrations are considered as a component of the inflammatory response and as an acute-phase marker, after shock or tissue injury (i.e. burn, trauma, surgery) or infections and sepsis. No data are so far available on the dynamics of procalcitonin levels in patients with cardiogenic shock following ST-elevation myocardial infarction, with no clinical or laboratory sign of infection. METHODS: We evaluated procalcitonin values every day during intensive cardiac care staying in ten cardiogenic shock patients admitted to our intensive cardiac care unit. NT-pro Brain Natriuretic Peptide, C Reactive Protein and APACHE II score were also assessed. RESULTS: Six patients survived, whereas 4 patients died. A progressive reduction in procalcitonin values was observed in cardiogenic shock patients who survived, whereas the lack of changes in procalcitonin concentrations was documented in cardiogenic shock patients who died (survivors: slope = -3.76; dead: slope = -0.81, p=0.004). Furthermore, higher values of glycemia, NT-pro Brain Natriuretic Peptide and C Reactive Protein (as well as higher APACHE II scores) were detectable in dead patients in respect to survivors. CONCLUSIONS: In our preliminary study we observed that in patients with cardiogenic shock and no sign of infections a reduction of procalcitonin levels was detectable only in survivors. Moreover, higher values of NT- Brain Natriuretic Peptide, a marked systemic inflammation (higher values of C Reactive Protein) and higher severity score (as depicted by APACHE II) are associated with an ominous prognosis in cardiogenic shock patients. PMID- 23441031 TI - Pain catastrophizing: an updated review. AB - Pain catastrophizing has been described for more than half a century which adversely affects the pain coping behavior and overall prognosis in susceptible individuals when challenged by painful conditions. It is a distinct phenomenon which is characterized by feelings of helplessness, active rumination and excessive magnification of cognitions and feelings toward the painful situation. Susceptible subjects may have certain demographic or psychological predisposition. Various models of pain catastrophizing have been proposed which include attention-bias, schema-activation, communal-coping and appraisal models. Nevertheless, consensus is still lacking as to the true nature and mechanisms for pain catastrophizing. Recent advances in population genomics and noninvasive neuroimaging have helped elucidate the known determinants and neurophysiological correlates behind this potentially disabling behavior. PMID- 23441033 TI - The mechanism of allosteric coupling in choline kinase alpha1 revealed by the action of a rationally designed inhibitor. AB - Applying a CHOK hold: Combined experimental and computational studies of the binding mode of a rationally designed inhibitor of the dimeric choline kinase alpha1 (CHOKalpha1) explain the molecular mechanism of negative cooperativity (see scheme) and how the monomers are connected. The results give insight into how the symmetry of the dimer can be partially conserved despite a lack of conservation in the static crystal structures. PMID- 23441034 TI - Chondrosarcoma apoplexy in thoracic spine. AB - Chondrosarcoma is a very uncommon malignant primary bone tumor, especially, it occurs extremely rare in the spine. A 52-year-old man was admitted to the emergency room with sudden paraplegia. Twelve hours prior to a paraplegic event, he visited an outpatient clinic with discomfort and tenderness around the medial border of the right scapular, and his neurologic status was absolutely intact. Magnetic resonance imaging showed a lobulated soft tissue mass from T3 to T5, which extended to the epidural space. Computed tomography scans showed soft tissue mass on the spinal posterior arch and osteolytic change of the adjacent bony structures. Emergent surgery was performed and the lesion was removed. Dark reddish blood and gel-like material were encountered around the dura and posterior arch during the operation. Multiple pulmonary nodules were found on a chest CT scan and a biopsy of one of them had been proven to be a metastasis of chondrosarcoma. The histologic examination showed dedifferentiated chondrosarcoma. The patient's neurologic deficit was improved slowly from ASIA A to ASIA D. Chondrosarcoma in the spine is extremely rare, even more with acute hemorrhage and sudden expansion into the epidural space. We named it chondrosarcoma apoplexy. We should consider the possibility of a hemorrhagic event when the patient's neurologic deficit worsens suddenly with spinal bone tumor. PMID- 23441035 TI - Reversible and tissue-specific activation of MAP kinase signaling by tamoxifen in Braf(V637)ER(T2) mice. AB - Deregulated MAP kinase (MAPK) signaling plays key roles in developmental and adult disease processes, but the experimental activation of MAPK is a currently unresolved task. For the reversible induction of MAPK signaling, we generated transgenic mice harboring a tamoxifen inducible BRAF(V637E)ER(T2) fusion protein. The expression of the inducible BRAF kinase can be directed by Cre/loxP-mediated recombination to selected cell types and enables the highly specific activation of MAPK signalling in vivo. We show that MAPK signaling can be transiently activated in the brain, liver, or kidney of Braf(V637E)ER(T2) mice by a single injection of tamoxifen. Braf(V637E)ER(T2) mice provide a new versatile tool to study disease mechanisms elicited by MAPK activation, complementing gene knockout technology that is restricted to the analysis of loss-of-function phenotypes. PMID- 23441036 TI - Towards the automatic computational assessment of enlarged perivascular spaces on brain magnetic resonance images: a systematic review. AB - Enlarged perivascular spaces (EPVS), visible in brain MRI, are an important marker of small vessel disease and neuroinflammation. We systematically evaluated the literature up to June 2012 on possible methods for their computational assessment and analyzed confounds with lacunes and small white matter hyperintensities. We found six studies that assessed/identified EPVS computationally by seven different methods, and four studies that described techniques to automatically segment similar structures and are potentially suitable for EPVS segmentation. T2-weighted MRI was the only sequence that identified all EPVS, but FLAIR and T1-weighted images were useful in their differentiation. Inconsistency within the literature regarding their diameter and terminology, and overlap in shape, intensity, location, and size with lacunes, conspires against their differentiation and the accuracy and reproducibility of any computational segmentation technique. The most promising approach will need to combine various MR sequences and consider all these features for accurate EPVS determination. PMID- 23441037 TI - Expression of Foxi3 is regulated by ectodysplasin in skin appendage placodes. AB - BACKGROUND: Foxi3 is a member of the large forkhead box family of transcriptional regulators, which have a wide range of biological activities including manifold developmental processes. Heterozygous mutation in Foxi3 was identified in several hairless dog breeds characterized by sparse fur coat and missing teeth. A related phenotype called hypohidrotic ectodermal dysplasia (HED) is caused by mutations in the ectodysplasin (Eda) pathway genes. RESULTS: Expression of Foxi3 was strictly confined to the epithelium in developing ectodermal appendages in mouse embryos, but no expression was detected in the epidermis. Foxi3 was expressed in teeth and hair follicles throughout embryogenesis, but in mammary glands only during the earliest stages of development. Foxi3 expression was decreased and increased in Eda loss- and gain-of-function embryos, respectively, and was highly induced by Eda protein in embryonic skin explants. Also activin A treatment up regulated Foxi3 mRNA levels in vitro. CONCLUSIONS: Eda and activin A were identified as upstream regulators of Foxi3. Foxi3 is a likely transcriptional target of Eda in ectodermal appendage placodes suggesting that HED phenotype may in part be produced by compromised Foxi3 activity. In addition to hair and teeth, Foxi3 may have a role in nail, eye, and mammary, sweat, and salivary gland development. PMID- 23441038 TI - High-performance partially aligned semiconductive single-walled carbon nanotube transistors achieved with a parallel technique. AB - Single-walled carbon nanotubes (SWNTs) are widely thought to be a strong contender for next-generation printed electronic transistor materials. However, large-scale solution-based parallel assembly of SWNTs to obtain high-performance transistor devices is challenging. SWNTs have anisotropic properties and, although partial alignment of the nanotubes has been theoretically predicted to achieve optimum transistor device performance, thus far no parallel solution based technique can achieve this. Herein a novel solution-based technique, the immersion-cum-shake method, is reported to achieve partially aligned SWNT networks using semiconductive (99% enriched) SWNTs (s-SWNTs). By immersing an aminosilane-treated wafer into a solution of nanotubes placed on a rotary shaker, the repetitive flow of the nanotube solution over the wafer surface during the deposition process orients the nanotubes toward the fluid flow direction. By adjusting the nanotube concentration in the solution, the nanotube density of the partially aligned network can be controlled; linear densities ranging from 5 to 45 SWNTs/MUm are observed. Through control of the linear SWNT density and channel length, the optimum SWNT-based field-effect transistor devices achieve outstanding performance metrics (with an on/off ratio of ~3.2 * 10(4) and mobility 46.5 cm(2) /Vs). Atomic force microscopy shows that the partial alignment is uniform over an area of 20 * 20 mm(2) and confirms that the orientation of the nanotubes is mostly along the fluid flow direction, with a narrow orientation scatter characterized by a full width at half maximum (FWHM) of <15 degrees for all but the densest film, which is 35 degrees . This parallel process is large-scale applicable and exploits the anisotropic properties of the SWNTs, presenting a viable path forward for industrial adoption of SWNTs in printed, flexible, and large-area electronics. PMID- 23441039 TI - Mitochondrial energetic metabolism-some general principles. AB - In nonphotosynthetic organisms, mitochondria are the power plant of the cell, emphasizing their great potentiality for adenosine triphosphate (ATP) synthesis from the redox span between nutrients and oxygen. Also of great importance is their role in the maintenance of the cell redox balance. Even though crystallographic structures of respiratory complexes, ATP synthase, and ATP/adenosine diphosphate (ADP) carrier are now quite well known, the coupling between ATP synthesis and cell redox state remains a controversial issue. In this review, we will present some of the processes that allow a modular coupling between ATP synthesis and redox state. Furthermore, we will present some theoretical approaches of this highly integrated system. PMID- 23441040 TI - Rotating proton pumping ATPases: subunit/subunit interactions and thermodynamics. AB - In this article, we discuss single molecule observation of rotational catalysis by E. coli ATP synthase (F-ATPase) using small gold beads. Studies involving a low viscous drag probe showed the stochastic properties of the enzyme in alternating catalytically active and inhibited states. The importance of subunit interaction between the rotor and the stator, and thermodynamics of the catalysis are also discussed. "Single Molecule Enzymology" is a new trend for understanding enzyme mechanisms in biochemistry and physiology. PMID- 23441043 TI - Selective assembly and disassembly of a water-soluble Fe10L15 prism. PMID- 23441041 TI - Mitochondria as a pharmacological target: magnum overview. AB - Mitochondria, responsible for energy metabolism within the cell, act as signaling organelles. Mitochondrial dysfunction may lead to cell death and oxidative stress and may disturb calcium metabolism. Additionally, mitochondria play a pivotal role in cardioprotective phenomena and a variety of neurodegenerative disorders ranging from Parkinson's to Alzheimer's disease. Mitochondrial DNA mutations may lead to impaired respiration. Hence, targeting the mitochondria with drugs offers great potential for new therapeutic approaches. The purpose of this overview is to present the recent state of knowledge concerning the interactions of various substances with mitochondria. PMID- 23441044 TI - Compound designs for dose-finding in the presence of nondesignable covariates. AB - Compound optimal designs are considered where one component of the design criterion is a traditional optimality criterion such as the D-optimality criterion, and the other component accounts for higher efficacy with low toxicity. With reference to the dose-finding problem, we suggest the technique to choose weights for the two components that makes the optimization problem simpler than the traditional penalized design. We allow general bivariate responses for efficacy and toxicity. We then extend the procedure in the presence of nondesignable covariates such as age, sex, or other health conditions. A new breast cancer treatment is considered to illustrate the procedures. PMID- 23441045 TI - Zebrafish tbx5 paralogs demonstrate independent essential requirements in cardiac and pectoral fin development. AB - BACKGROUND: T-box genes constitute a large family of transcriptional regulators involved in developmental patterning. Homozygous mutation of tbx5 leads to embryonic lethal cardiac phenotypes and forelimb malformations in vertebrate models. Haploinsufficiency of tbx5 results in Holt-Oram syndrome, a human congenital disease characterized by cardiac and forelimb defects. Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. Recently, a second zebrafish tbx5 gene was described, termed tbx5b. RESULTS: Our phylogenetic analyses confirm tbx5b as a paralog that likely arose in the teleost-specific whole genome duplication ~270 MYA. Using morpholino depletion studies, we find that tbx5b is required in the heart for embryonic survival, and influences the timing and morphogenesis of pectoral fin development. Because tbx5a hypomorphic mutations are embryonic lethal, tbx5a and tbx5b functions in the heart must not be completely redundant. Consistent with this hypothesis, simultaneous depletion of both tbx5 paralogs did not lead to more severe phenotypes, and injection of wild-type mRNA from one tbx5 paralog was not sufficient to cross-rescue phenotypes of the paralogous gene. CONCLUSIONS: Collectively, these data indicate that, despite similar spatio-temporal expression patterns, tbx5a and tbx5b have independent functions in heart and fin development. PMID- 23441046 TI - Development of validated quantitative structure-retention relationship models for retention indices of plant essential oils. AB - Quantitative structure-retention relationship (QSRR) models were developed for the retention indices of 505 frequently reported components of plant essential oils. Multiple linear regression was used to build QSRR models for the dimethyl silicone, dimethyl silicone with 5% phenyl groups, and polyethylene glycol stationary phases. We tried to improve the variable selection and modeling method based on prediction method for selecting the optimum descriptors from the molecular weight, 75 topological indices, and 170 atom-type E-state indices. The three-variable QSRR models perform high correlation coefficients of 0.937 for dimethyl silicone and 0.933 for dimethyl silicone with 5% phenyl groups stationary phase. Four variables were selected to developed QSRR model for the polyethylene glycol stationary phase. The leave-one-out and leave-many-out cross validations, bootstrapping, and y-randomization test showed the three models are robust and have no chance correlation. The external validation with the test set showed the three models present high externally predictive power. The three models presented high-quality fit, internally, and externally predictive power. It is expected that the models can effectively predict retention indices of essential oils components without experimental value. PMID- 23441047 TI - Functional roles of glycogene and N-glycan in multidrug resistance of human breast cancer cells. AB - Drug resistance is a major problem in cancer chemotherapy. Aberrant glycosylation has been known to be associated with cancer chemoresistance. Aim of this work is to investigate the alterations of glycogene and N-glycan involved in multidrug resistance (MDR) in human breast cancer cell lines. Using real-time polymerase chain reaction (PCR) for quantification of glycogenes, fluorescein isothiocyanate (FITC)-lectin binding for glycan profiling, and mass spectrometry for N-glycan composition, the expression of glycogenes, glycan profiling, and N-glycan composition differed between drug-resistant MCF/ADR cells and the parental MCF-7 line. Further analysis of the N-glycan regulation by tunicamycin (TM) application or PNGase F treatment in MCF/ADR cells showed partial inhibition of the N-glycan biosynthesis and increased sensitivity to chemotherapeutic drugs dramatically both in vitro and in vivo. Using an RNA interference strategy, we showed that the downregulation of MGAT5 in MCF/ADR cells could enhance the chemosensitivity to antitumor drugs both in vitro and in vivo. Conversely, a stable high expression of MGAT5 in MCF-7 cells could increase resistance to chemotherapeutic drugs both in vitro and in vivo. In conclusion, the alterations of glycogene and N-glycan in human breast cancer cells correlate with tumor sensitivity to chemotherapeutic drug and have significant implications for the development of new treatment strategies. (c) 2013 IUBMB Life, 65(5):409-422, 2013. PMID- 23441048 TI - Bactericidal Activity of Methanol Extracts of Crabapple Mangrove Tree (Sonneratia caseolaris Linn.) Against Multi-Drug Resistant Pathogens. AB - The crabapple mangrove tree, Sonneratia caseolaris Linn. (Family: Sonneratiaceae), is one of the foreshore plants found in estuarine and tidal creek areas and mangrove forests. Bark and fruit extracts from this plant have previously been shown to have an anti-oxidative or cytotoxic effect, whereas flower extracts of this plant exhibited an antimicrobial activity against some bacteria. According to the traditional folklore, it is medicinally used as an astringent and antiseptic. Hence, this investigation was carried out on the extract of the leaves, pneumatophore and different parts of the flower or fruit (stamen, calyx, meat of fruit, persistent calyx of fruit and seeds) for antibacterial activity using the broth microdilution method. The antibacterial activity was evaluated against five antibiotic-sensitive species (three Gram positive and two Gram-negative bacteria) and six drug-resistant species (Gram positive i.e. Methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium and Gram-negative i.e. Extended-spectrum beta-lactamase Escherichia coli, multidrug-resistant-Pseudomonas aeruginosa and Acenetobacter baumannii). The methanol extracts from all tested parts of the crabapple mangrove tree exhibited antibacterial activity against both Gram-positive and Gram negative bacteria, but was mainly a bactericidal against the Gram-negative bacteria, including the multidrug-resistant strains, when compared with only bacteriostatic on the Gram-positive bacteria. Using Soxhlet apparatus, the extracts obtained by sequential extraction with hexane, dichloromethane and ethyl acetate revealed no discernable antibacterial activity and only slightly, if at all, reduced the antibacterial activity of the subsequently obtained methanol extract. Therefore, the active antibacterial compounds of the crabapple mangrove tree should have a rather polar structure. PMID- 23441049 TI - Transitioning Streaming to Trapping in DC Insulator-based Dielectrophoresis for Biomolecules. AB - Exploiting dielectrophoresis (DEP) to concentrate and separate biomolecules has recently shown large potential as a microscale bioanalytical tool. Such efforts however require tailored devices and knowledge of all interplaying transport mechanisms competing with dielectrophoresis (DEP). Specifically, a strong DEP contribution to the overall transport mechanism is necessary to exploit DEP of biomolecules for analytical applications such as separation and fractionation. Here, we present improved microfluidic devices combining optical lithography and focused ion beam milling (FIBM) for the manipulation of DNA and proteins using insulator-based dielectrophoresis (iDEP) and direct current (DC) electric fields. Experiments were performed on an elastomer platform forming the iDEP microfluidic device with integrated nanoposts and nanopost arrays. Microscale and nanoscale iDEP was studied for lambda-DNA (48.5 kbp) and the protein bovine serum albumin (BSA). Numerical simulations were adapted to the various tested geometries revealing excellent qualitative agreement with experimental observations for streaming and trapping DEP. Both the experimental and simulation results indicate that DC iDEP trapping for lambda-DNA occurs with tailored nanoposts fabricated via FIBM. Moreover, streaming iDEP concentration of BSA is improved with integrated nanopost arrays by a factor of 45 compared to microfabricated arrays. PMID- 23441050 TI - Metal and Metalloid Contaminants in Atmospheric Aerosols from Mining Operations. AB - Mining operations are potential sources of airborne metal and metalloid contaminants through both direct smelter emissions and wind erosion of mine tailings. The warmer, drier conditions predicted for the Southwestern US by climate models may make contaminated atmospheric dust and aerosols increasingly important, with potential deleterious effects on human health and ecology. Fine particulates such as those resulting from smelting operations may disperse more readily into the environment than coarser tailings dust. Fine particles also penetrate more deeply into the human respiratory system, and may become more bioavailable due to their high specific surface area. In this work, we report the size-fractionated chemical characterization of atmospheric aerosols sampled over a period of a year near an active mining and smelting site in Arizona. Aerosols were characterized with a 10-stage (0.054 to 18 MUm aerodynamic diameter) multiple orifice uniform deposit impactor (MOUDI), a scanning mobility particle sizer (SMPS), and a total suspended particulate (TSP) collector. The MOUDI results show that arsenic and lead concentrations follow a bimodal distribution, with maxima centered at approximately 0.3 and 7.0 MUm diameter. We hypothesize that the sub-micron arsenic and lead are the product of condensation and coagulation of smelting vapors. In the coarse size, contaminants are thought to originate as aeolian dust from mine tailings and other sources. Observation of ultrafine particle number concentration (SMPS) show the highest readings when the wind comes from the general direction of the smelting operations site. PMID- 23441052 TI - Blood donation in Nigeria: standard of the donated blood. AB - OBJECTIVE: The objective was to determine the basic hematological parameters of remunerated blood donors in Benin City and to compare them with those of voluntary donors. MATERIALS AND METHODS: This is a prospective study conducted in a tertiary health facility in Benin City. Pretransfusion samples were obtained from blood bags after gentle mixing and analyzed for hematological parameters. Samples were analyzed using the hematology autoanalyzer MODEL SYSMEX KN21. RESULT: A total of 215 samples were obtained comprising 160 remunerated (paid) and 55 voluntary donor samples. In the paid donors, the mean hemoglobin concentration (Hb) and hematocrit (HCT) 7.7+/-2.9 and 28.8+/-8.5 respectively. This was significantly lower than those of voluntary donors who had 13.9+/-1.2 and 42.2+/-3.3 with P < 0.001. The mean values of the red cell counts (RBC), white cell counts (WBC), mean cell volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were significantly lower in paid donors as P-values were < 0.001. MCV was significantly low but not compared to the other parameters as P=0.04. There was no significant difference in the platelet count. CONCLUSION: Paid donors in Benin City have significantly lower hematological parameters than controls. PMID- 23441051 TI - IPS multicentric study: Functional somatic symptoms in depression. AB - BACKGROUND: As a pilot project, Indian Psychiatric Society conducted the first multicentric study involving diverse settings from teaching institutions in public and private sectors and even privately run psychiatric clinics. AIM OF THE STUDY: To study the typology of functional somatic complaints (FSC) in patients with first episode depression. MATERIALS AND METHODS: A total of 741 patients from 16 centers across the country participated in the study. They were assessed on Bradford Somatic Symptom inventory for FSC, Beck Depression Inventory for severity of depression, and Comprehensive Psychopathological Rating Scale- anxiety index (CPRS-AI) for anxiety symptoms. RESULTS: The mean age of the study sample was 38.23 years (SD-11.52). There was equal gender distribution (male - 49.8% vs. females 50.2%). Majority of the patients were married (74.5%), Hindus (57%), and from nuclear family (68.2%). A little over half of the patients were from urban background (52.9%). The mean duration of illness at the time of assessment was 25.55 months. Most of the patients (77%) had more than 10 FSCs, with 39.7% having more than 20 FSCs as assessed on Bradford Somatic Inventory. The more common FSC as assessed on Bradford Somatic Inventory were lack of energy (weakness) much of the time (76.2%), severe headache (74%) and feeling tired when not working (71%), pain in legs (64%), aware of palpitations (59.5%), head feeling heavy (59.4%), aches and pains all over the body (55.5%), mouth or throat getting dry (55.2%), pain or tension in neck and shoulder (54%), head feeling hot or burning (54%), and darkness or mist in front of the eyes (49.1%). The prevalence and typology of FSCs is to a certain extent influenced by the sociodemographic variables and severity of depression. CONCLUSION: Functional somatic symptoms are highly prevalent in Indian depressed patients and hence deserve more attention while diagnosing depression in Indian setting. PMID- 23441053 TI - Brown adipose tissue as a regulator of energy expenditure and body fat in humans. AB - Brown adipose tissue (BAT) is recognized as the major site of sympathetically activated nonshivering thermogenesis during cold exposure and after spontaneous hyperphagia, thereby controling whole-body energy expenditure and body fat. In adult humans, BAT has long been believed to be absent or negligible, but recent studies using fluorodeoxyglucose-positron emission tomography, in combination with computed tomography, demonstrated the existence of metabolically active BAT in healthy adult humans. Human BAT is activated by acute cold exposure, being positively correlated to cold-induced increases in energy expenditure. The metabolic activity of BAT differs among individuals, being lower in older and obese individuals. Thus, BAT is recognized as a regulator of whole-body energy expenditure and body fat in humans as in small rodents, and a hopeful target combating obesity and related disorders. In fact, there are some food ingredients such as capsaicin and capsinoids, which have potential to activate and recruit BAT via activity on the specific receptor, transient receptor potential channels, thereby increasing energy expenditure and decreasing body fat modestly and consistently. PMID- 23441055 TI - The influence of action effects in task-switching. AB - According to ideomotor theories, intended effects caused by a certain action are anticipated before action execution. In the present study, we examined the question of whether action effects play a role in cued task-switching. In our study, the participants practiced task-response-effect mappings in an acquisition phase, in which action effects occur after a response in a certain task context. In the ensuing transfer phase, the previously practiced mappings were changed in a random, unpredictable task-response-effect mapping. When changed into unpredictable action-effects, RT as well as switch-costs increased, but this occurred mainly in trials with short preparation time and not with long preparation time. Moreover, switch costs were generally smaller with predictable action-effects than with unpredictable action-effects. This suggests that anticipated task-specific action effects help to activate the relevant task-set before task execution when the task is not yet already prepared based on the cue. PMID- 23441054 TI - Cytokines in the systemic inflammatory response syndrome: a review. AB - INTRODUCTION: Patients subject to major surgery, suffering sepsis, major trauma, or following cardiopulmonary bypass exhibit a systemic inflammatory response. This inflammatory response involves a complex array of inflammatory polypeptide molecules known as cytokines. It is well accepted that the loss of local control of the release of these cytokines leads to systemic inflammation and potentially deleterious consequences including the Systemic Inflammatory Response Syndrome, Multi-Organ Dysfunction Syndrome, shock and death. METHODS: The Medline database was searched for literature on mechanisms involved in the development of SIRS and potential targets for modifying the inflammatory response. We focus on the novel therapy of cytokine adsorption as a promising removal technology. RESULTS: Accumulating data from human studies and experimental animal models suggests that both pro- and anti- inflammatory cytokines are released following a variety of initiating stimuli including endotoxin release, complement activation, ischaemia reperfusion injury and others. DISCUSSION: Pro-and anti-inflammatory cytokines interact in a complex and unpredictable manner to influence the immune system and eventually cause multiple end organ effects. Cytokine adsorption therapy provides a potential solution to improving outcomes following Systemic Inflammatory Response Syndrome. PMID- 23441056 TI - Helical colloidal sphere structures through thermo-reversible co-assembly with molecular microtubes. PMID- 23441058 TI - The surgical management of traumatic c6-c7 spondyloptosis. AB - A case of traumatic spondyloptosis of the cervical spine at the C6-C7 level is reported. The patient was treated succesfully with a anterior-posterior combined approach and decompression. The patient had good neurological outcome after surgery. A-51-year-old female patient was transported to our hospital's emergency department after a vehicle accident. The patient was quadriparetic (Asia D, MRC power 4/5) with severe neck pain. Plain radiographs, computerize tomography and spinal magnetic resonance imaging (MRI) showed C6-7 spondyloptosis and C5, C6 posterior element fractures. Gardner-Wells skeleton traction was applied. Spinal alignment was reachived by traction and dislocation was decreased to a grade 1 spondylolisthesis. Then the patient was firstly operated by anterior approach. Anterior stabilization and fusion was firstly achieved. Seven days after first operation the patient was operated by a posterior approach. The posterior stabilization and fusion was achieved. Postoperative lateral X-rays and three dimensional computed tomography showed the physiological realignment and the correct screw placements. The patient's quadriparesis was improved significantly. Subaxial cervical spondyloptosis is a relatively rare clinical entity. In this report we present a summary of the clinical presentation, the surgical technique and outcome of this rarely seen spinal disorder. PMID- 23441057 TI - PedsQLTM sickle cell disease module: feasibility, reliability, and validity. AB - BACKGROUND: Sickle cell disease (SCD) is an inherited chronic disease that is characterized by complications such as recurrent painful vaso-occlusive events that require frequent hospitalizations and contribute to early mortality. The objective of the study was to report on the initial measurement properties of the new PedsQLTM SCD Module for pediatric patient self-report ages 5-18 years and parent proxy-report for ages 2-18 years. PROCEDURE: The 43-item PedsQLTM SCD Module was completed in a multisite study by 243 pediatric patients with SCD and 313 parents. Participants also completed the PedsQLTM 4.0 Generic Core Scales and PedsQLTM Multidimensional Fatigue Scale. RESULTS: The PedsQLTM SCD Module Scales evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report alpha = 0.95; parent proxy-report alpha = 0.97), and good reliability for the nine individual scales (patient self-report alpha = 0.69 0.90; parent proxy-report alpha = 0.83-0.97). Intercorrelations with the PedsQLTM Generic Core Scales and PedsQLTM Multidimensional Fatigue Scales were medium (0.30) to large (0.50) range, supporting construct validity. PedsQLTM SCD Module Scale Scores were generally worse for patients with severe versus mild disease. Confirmatory factor analysis demonstrated an acceptable to excellent model fit. CONCLUSIONS: The PedsQLTM SCD Module demonstrated acceptable measurement properties. The PedsQLTM SCD Module may be utilized in the evaluation of SCD specific health-related quality of life in clinical research and practice. In conjunction with the PedsQLTM Generic Core Scales and the PedsQLTM Multidimensional Fatigue Scale, the PedsQLTM SCD Module will facilitate the understanding of the health and well-being of children with SCD. PMID- 23441059 TI - Online molecularly imprinted solid-phase extraction coupled to liquid chromatography-tandem mass spectrometry for the determination of hormones in water and sediment samples. AB - The molecularly imprinted SPE directly coupled to RP LC-MS/MS method has been developed and successfully validated for the determination of six hormones in water and sediment samples. The method is based on the use the home-made column filled with a molecularly imprinted sorbent (imprinted against estrogens) that was used under nonaqueous conditions. Thus, its high selectivity could be utilized resulting in low matrix components' coextraction. The method showed excellent recovery (92-105%) and satisfactory sensitivity (LOQs water: 1.9-4.0 ng/L; LOQs sediment: 0.2-0.5 ng/g). The intra- and interprecision for water and sediment was in the range of 4.0-6.0% and 4.4-7.6%, respectively. Finally, 20 water and sediment samples collected from the Svratka river were analyzed. Only estrone was quantified in eight water samples (4.4-7.1 ng/L); no analytes were found in sediment samples. PMID- 23441060 TI - Effect of caffeine on information processing: evidence from stroop task. AB - BACKGROUND: Caffeine is a pyschostimulant present in various beverages and known to alter alertness and performance by acting on the central nervous system. Its effects on central nervous system have been studied using EEG, evoked potentials, fMRI, and neuropsychological tests. The Stroop task is a widely used tool in psychophysiology to understand the attention processes and is based on the principle that processing of two different kinds of information (like the word or colour) is parallel and at different speeds with a common response channel. AIM: To study the effect of caffeine on classical color word Stroop task. MATERIALS AND METHODS: This study was conducted on 30 male undergraduate students by performing a test before and 40 minutes after consuming 3 mg/Kg caffeine and evaluating the effect of caffeine on Stroop interference and facilitation. RESULTS: The results revealed that practice has no effect on the performance in a Stroop task. However, there was reduction in Stroop interference and increase in facilitation after consumption of caffeine as was evident by changes in the reaction times in response to neutral, incongruent, and congruent stimuli. CONCLUSION: We hypothesize that caffeine led to faster processing of relevant information. PMID- 23441061 TI - Expression of Ski can act as a negative feedback mechanism on retinoic acid signaling. AB - BACKGROUND: Retinoic acid signaling is essential for many aspects of early development in vertebrates. To control the levels of signaling, several retinoic acid target genes have been identified that act to suppress retinoic acid signaling in a negative feedback loop. The nuclear protein Ski has been extensively studied for its ability to suppress transforming growth factor-beta (TGF-beta) signaling but has also been implicated in the repression of retinoic acid signaling. RESULTS: We demonstrate that ski expression is up-regulated in response to retinoic acid in both early Xenopus embryos and in human cell lines. Blocking retinoic acid signaling using a retinoic acid antagonist results in a corresponding decrease in the levels of ski mRNA. Finally, overexpression of SKI in human cells results in reduced levels of CYP26A1 mRNA, a known target of retinoic acid signaling. CONCLUSIONS: Our results, coupled with the known ability of Ski to repress retinoic acid signaling, demonstrate that Ski expression is a novel negative feedback mechanism acting on retinoic acid signaling. PMID- 23441062 TI - Tetrahydrobiopterin in nitric oxide synthase. AB - SUMMARY: Nitric oxide synthase (NOS) is a critical enzyme for the production of the messenger molecule nitric oxide (NO) from L-arginine. NOS enzymes require tetrahydrobiopterin as a cofactor for NO synthesis. Besides being one of the few enzymes to use this cofactor, the role of tetrahydrobiopterin in NOS catalytic mechanism is different from other enzymes: during the catalytic cycle of NOS, tetrahydrobiopterin forms a radical species that is again reduced, thus effectively regenerating after each NO synthesis cycle. In this review, we summarize our current knowledge about the role of tetrahydrobiopterin in the structure, function, and catalytic mechanism of NOS enzymes. PMID- 23441063 TI - Transradial intervention for patients with ST elevation myocardial infarction with or without cardiogenic shock. AB - OBJECTIVES: To compare clinical outcomes between transradial (TRI) and transfemoral intervention (TFI) in primary percutaneous coronary intervention (PCI) in patients with ST elevation myocardial infarction (STEMI) with or without shock. BACKGROUND: TRI for STEMI has benefits in TRI high volume centers. However, TRI has not been reported for STEMI with shock even in such centers. METHODS: We retrospectively studied 425 STEMI patients who underwent primary PCI. Patients were divided into four groups according to approach site and presence of cardiogenic shock, including TRI without shock (TR group, n = 273), TRI with shock (TRS group, n = 38), TFI without shock (TF group, n = 71), and TFI with shock (TFS group, n = 43). RESULTS: PCI success rates were similar among the four groups. The TR group was superior to the TF group in terms of shorter cath lab to first device activation time, and lower access site complications, and 30-day mortality rates (1.1% vs. 11.3%, P < 0.001). In shock patients, cardiopulmonary arrest was commonly observed in both the TRS and TFS groups (42.1% and 51.2%, respectively). The TRS group showed a trend toward a shorter door to first device activation time compared to the TFS group and lower access site complications; however, 30-day mortality rate was 28.9% in TRS and 25.6% in TFS group (P = 0.7). CONCLUSIONS: In TRI high volume center, TRI for STEMI was safe and feasible as a default approach. TRI could be applied to severe shock patients with similar clinical outcome to TFI. PMID- 23441064 TI - Squeezing new life out of polymers. PMID- 23441065 TI - Patient-perceived facilitators in the transition of care for young adult survivors of childhood cancer. AB - BACKGROUND: A new challenge has emerged in optimizing the transition of pediatric survivorship care to similarly focused programs that are age-appropriate for young adults. The purpose of this study is to identify components of a clinical survivorship program that facilitate the transition of care for young adult survivors of childhood cancer from a pediatric to adult care-setting. PROCEDURE: Prior to transition, a descriptive study of childhood cancer survivors was conducted using a cross-sectional study design. A questionnaire was used to identify which clinical components of a survivorship program would most influence their decision to transition care to an adult medical center. RESULTS: Of 129 invited survivors, 103 participated (80%). Most survivors were age 16-19 years (40/103, 39%) or 20-24 years (37/103, 36%). When asked if the participant was willing to transition their survivorship care to an adult facility, 97 (95%) responded affirmatively. The clinical components most frequently rated "Very Important" in the decision to transition were the acceptance of insurance (80/103, 78%) followed by the presence of a provider knowledgeable in childhood cancer (68/103, 66%). The clinical components most frequently rated "Very Important" or "Important" were the availability of flexible scheduling (102/103, 99%) followed by the comprehensive nature of the care provided (101/103, 98%). CONCLUSIONS: The decision to transition survivorship care to age-appropriate care settings is complex and not well understood. Issues related to insurance, clinical team composition and scheduling appear to be most important for young adult survivors making this decision. Pediatr Blood Cancer 2013;601365-1368. (c) 2013 Wiley Periodicals, Inc. PMID- 23441066 TI - Heat-shock-mediated conditional regulation of hedgehog/gli signaling in zebrafish. AB - BACKGROUND: Hedgehog (Hh) signaling is required for embryogenesis and continues to play key roles postembryonically in many tissues, influencing growth, stem cell proliferation, and tumorigenesis. Systems for conditional regulation of Hh signaling facilitate the study of these postembryonic Hh functions. RESULTS: We used the hsp70l promoter to generated three heat-shock-inducible transgenic lines that activate Hh signaling and one line that represses Hh signaling. Heat-shock activation of these transgenes appropriately recapitulates early embryonic loss or gain of Hh function phenotypes. Hh signaling remains activated 24 hr after heat shock in the Tg(hsp70l:shha-EGFP) and Tg(hsp70l:dnPKA-BGFP) lines, while a single heat shock of the Tg(hsp70l:gli1-EGFP) or Tg(hsp70l:gli2aDR-EGFP) lines results in a 6- to 12-hr pulse of Hh signal activation or inactivation, respectively. Using both in situ hybridization and quantitative polymerase chain reaction, we show that these lines can be used to manipulate Hh signaling through larval and juvenile stages. A ptch2 promoter element was used to generate new reporter lines that allow clear visualization of Hh responding cells throughout the life cycle, including graded Hh responses in the embryonic central nervous system. CONCLUSIONS: These zebrafish transgenic lines provide important new experimental tools to study the embryonic and postembryonic roles of Hh signaling. PMID- 23441067 TI - Alantolactone inhibits growth of K562/adriamycin cells by downregulating Bcr/Abl and P-glycoprotein expression. AB - Alantolactone, a sesquiterpene lactone containing an alpha-methylene-gamma lactone group, is the active component of Inula helenium (Compositae), a traditional Chinese medicinal herb. It has been reported that alantolactone has the capacity to inhibit tumor cell growth through induction of apoptosis. The purpose of this study was to assess the effects of alantolactone in the adriamycin (ADR)-resistant human erythroleukemia cell line K562/ADR, and provide evidence that it might function as a potent therapeutic agent in chronic myelogenous leukemia (CML) patients with Bcr/Abl and the multidrug-resistance phenotype. Our results showed that alantolactone significantly inhibited K562/ADR cell growth by downregulating Bcr/Abl and P-glycoprotein expression. Alantolactone also induced apoptosis via modulation of protein levels of Bcl-2 family members, caspase activation, poly ADP ribose polymerase cleavage, and cytochrome C release. We also observed that alantolactone induced cell-cycle arrest in the G2/M phase, downregulated cyclin B1 and cyclin-dependent protein kinase 1, and upregulated the cyclin-dependent kinase inhibitor p21. Together, these results demonstrate that alantolactone may be a potent therapeutic agent against CML, and a potential Bcr/Abl inhibitor. PMID- 23441068 TI - One-year head to head comparison of the neointimal response between sirolimus eluting stent with reservoir technology and everolimus eluting stent: an optical coherence tomography study. AB - OBJECTIVE: to compare the vascular healing process between the sirolimus-eluting NEVO and the everolimus-eluting Xience stent by optical coherence tomography (OCT) at 1-year follow-up. BACKGROUND: Presence of durable polymer on a drug eluting metallic stent may be the basis of an inflammatory reaction with abnormal healing response. The NEVO stent, having a bioresorbable polymer eluted by reservoir technology, may overcome this problem. METHODS: All consecutive patients, who received NEVO or Xience stent implantation between September 2010 and October 2010 in our institution, were included. Vascular healing was assessed at 1-year as percentage of uncovered struts, neointimal thickness (NIT), in stent/stent area obstruction and pattern of neointima. RESULTS: A total 47 patients (2:1 randomization, n = 32 NEVO, n = 15 Xience) were included. Eighteen patients underwent angiographic follow-up (eight patients with nine lesions for NEVO vs. 10 patients with 11 lesions for Xience). The angiographic late loss was numerically higher but not statistically different in NEVO compared with Xience treated lesions (0.38 +/- 0.47 mm vs. 0.18 +/- 0.27 mm; P = 0.171). OCT analysis of 4,912 struts demonstrated similar rates of uncovered struts (0.5 vs. 0.7%, P = 0.462), higher mean NIT (177.76 +/- 87.76 um vs. 132.22 +/- 30.91 um; P = 0.170) and in stent/stent area obstruction (23.02 +/- 14.74% vs. 14.17 +/- 5.94%, P = 0.120) in the NEVO as compared with Xience. CONCLUSION: The NEVO stent with a reservoir technology seems to exhibit more neointimal proliferation as compared to Xience stent. The findings of our study, which currently represent the unique data existing on this reservoir technology, would need to be confirmed in a large population. PMID- 23441069 TI - Bio-inspired catalytic imine reduction by rhodium complexes with tethered Hantzsch pyridinium groups: evidence for direct hydride transfer from dihydropyridine to metal-activated substrate. PMID- 23441070 TI - Treatment of cardiac infantile fibrosarcoma. PMID- 23441071 TI - Allele-specific expression at the RET locus in blood and gut tissue of individuals carrying risk alleles for Hirschsprung disease. AB - RET common variants are associated with Hirschsprung disease (HSCR; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well-known HSCR-associated RET haplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level of RET expression when compared with the wild-type counterpart. As allele-specific expression (ASE) contributes to phenotypic variability in health and disease, we investigated whether RET ASE could contribute to the overall reduction of RET mRNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non-HSCR individuals) and peripheral blood mononuclear cells (PBMCs; 16 HSCR and 14 non-HSCR individuals). Analysis of the data generated by SNaPshot and Pyrosequencing revealed that the RET risk haplotype is significantly more expressed in gut than in PBMCs (P = 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of total RET expression levels between gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the RET risk haplotype. Nonrandom RET ASE occurs in ganglionic gut regardless of the disease status. RET ASE should not be excluded as a disease mechanism acting during development. PMID- 23441072 TI - Alkylglycerol monooxygenase. AB - Alkylglycerol monooxygenase (E.C. 1.14.16.5), also called glyceryl ether monooxygenase, is a tetrahydrobiopterin-dependent enzyme. It is the only enzyme known to cleave the ether bond of alkylglycerols and lyso-alkylglycerol phospholipids, including lyso-platelet activating factor. Although it has been first described already in 1964, it was not possible so far to purify the protein. It took until 2010 to assign a sequence to this labile integral membrane enzyme by bioinformatic selection of candidate genes, recombinant expression of these, and sensitive monitoring of the enzymatic activity by a fluorescence-based assay. The sequence shows no significant similarity with the other known tetrahydrobiopterin-dependent enzymes but contains the fatty acid hydroxylase protein motif signature. Proteins containing this signature are all labile and catalyze reactions similar to the alkylglycerol monooxygenase reaction. They are thought to use a di-iron centre for catalysis. Site directed mutagenesis of alkylglycerol monooxygenase defined a region of the active site and a conserved glutamate residue important for tetrahydrobiopterin interaction. Current research now focuses on defining a physiological role of this enzyme which occurs not only in mammals but also in commonly used model organisms such as zebrafish and the nematode Caenorhabditis elegans. PMID- 23441073 TI - Regulation of cell death in cancer-possible implications for immunotherapy. AB - Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future. PMID- 23441074 TI - Transdural Nerve Rootlet Entrapment in the Intervertebral Disc Space through Minimal Dural Tear : Report of 4 Cases. AB - Four patients underwent lumbar surgery. In all four patients, the dura was minimally torn during the operation. However, none exhibited signs of postoperative cerebrospinal fluid leakage. In each case, a few days after the operation, the patient suddenly experienced severe recurring pain in the leg. Repeat magnetic resonance imaging showed transdural nerve rootlets entrapped in the intervertebral disc space. On exploration, ventral dural tears and transdural nerve rootlet entrapment were confirmed. Midline durotomy, herniated rootlet repositioning, and ventral dural tear repair were performed, and patients' symptoms improved after rootlet repositioning. Even with minimal dural tearing, nerve rootlets may become entrapped, resulting in severe recurring symptoms. Therefore, the dural tear must be identified and repaired during the first operation. PMID- 23441075 TI - Membranous diaphragm formation after simultaneous kissing stenting with sirolimus eluting stents for the left main bifurcation: insight from optical coherence tomography findings. AB - Two patients who underwent simultaneous kissing stenting with sirolimus-eluting stents in the left main coronary artery were investigated with optical coherence tomography (OCT) at just more than 1 year postoperatively. In both cases, follow up angiogram indicated complete coverage of the new metal carina with a membranous diaphragm, yet OCT showed varying tissue-coverage patterns transitioning from stent inflow to stent outflow. These patterns included single strut coverage, bridge-like membrane formation between more than 1 strut, and end to-end coverage of the carina; no uncovered stent struts were detected. OCT also demonstrated mixed patterns of tissue characteristics on the metal carina, ranging from poor endothelialization to modest neointima formation. These varying tissue characteristics suggest that the process of tissue coverage in the metal carina is different from that occurring on the vessel wall; this may indicate delayed healing in the carina. PMID- 23441076 TI - Assessment methods in surgical training in the United Kingdom. AB - A career in surgery in the United Kingdom demands a commitment to a long journey of assessment. The assessment methods used must ensure that the appropriate candidates are selected into a programme of study or a job and must guarantee public safety by regulating the progression of surgical trainees and the certification of trained surgeons. This review attempts to analyse the psychometric properties of various assessment methods used in the selection of candidates to medical school, job selection, progression in training, and certification. Validity is an indicator of how well an assessment measures what it is designed to measure. Reliability informs us whether a test is consistent in its outcome by measuring the reproducibility and discriminating ability of the test. In the long journey of assessment in surgical training, the same assessment formats are frequently being used for selection into a programme of study, job selection, progression, and certification. Although similar assessment methods are being used for different purposes in surgical training, the psychometric properties of these assessment methods have not been examined separately for each purpose. Because of the significance of these assessments for trainees and patients, their reliability and validity should be examined thoroughly in every context where the assessment method is being used. PMID- 23441077 TI - Perception of illness in patients with traumatic brain injury. AB - BACKGROUND: Perception of illness plays an important role in recovery process. It affects our coping behaviors, adherence to treatment and preventive measures taken for healthy recovery. AIMS: The aim of the study is to examine perception of illness in patients with traumatic brain injury (TBI). MATERIALS AND METHODS: This was a cross sectional study design done on sample of 31 patients with mild to moderate TBI. Depression anxiety stress scales-21 (DASS-21), Brief illness perception questionnaire (IPQ) and Rivermead Post Concussion Symptoms Questionnaire (RPQ) was used. STATISTICAL ANALYSIS: Descriptive and correlational statistics was used. RESULTS: The results indicated that overall higher percentage falls within low and medium range of IPQ. However higher percentage falls within higher range, on coherence and emotional response subscales of IPQ. Consequence, timeline, personal control, treatment control, concern, emotional control, and total of the subscales of IPQ were positively correlated with RPQ3 and RPQ13 at 0.01 and 0.05 level of significance. A significant correlation was found between demographic variables and subscales of IPQ at 0.01 and 0.05 level of significance. CONCLUSION: The study shows one to one relationship between symptoms experienced by patients, how they perceive their illness and socio demographic variables. PMID- 23441078 TI - Nutritional status and cardiac autophagy. AB - Autophagy is necessary for the degradation of long-lasting proteins and nonfunctional organelles, and is activated to promote cellular survival. However, overactivation of autophagy may deplete essential molecules and organelles responsible for cellular survival. Lifelong calorie restriction by 40% has been shown to increase the cardiac expression of autophagic markers, which suggests that it may have a cardioprotective effect by decreasing oxidative damage brought on by aging and cardiovascular diseases. Although cardiac autophagy is critical to regulating protein quality and maintaining cellular function and survival, increased or excessive autophagy may have deleterious effects on the heart under some circumstances, including pressure overload-induced heart failure. The importance of autophagy has been shown in nutrient supply and preservation of energy in times of limitation, such as ischemia. Some studies have suggested that a transition from obesity to metabolic syndrome may involve progressive changes in myocardial inflammation, mitochondrial dysfunction, fibrosis, apoptosis, and myocardial autophagy. PMID- 23441079 TI - Statistical analysis on morphology development of some semialicyclic polyimides using atomic force microscopy. AB - The morphological features and surface texture parameters of some polyimide films prepared from a flexible and alicyclic dianhydride, in combination with five aromatic diamines, were evaluated by atomic force microscopy (AFM) in order to determine their applicability in electronics. By means of the surface roughness, shape of the surface height distribution, and angular and radial texture, a precise description of the actual surface topographies at the interface with other materials was made. The polyimide structures led to the development of different surface morphologies (from granular to porous and from bumpy to spiky). The relief diversity was described by the entropy of morphology, which had a similar trend with the root mean square roughness, which presents low values, i.e. 0.5-1.8 nm. Three-dimensional AFM images and the corresponding angular spectra, together with texture aspect ratio and texture direction index (close to 1), indicate that no predominant orientation exists on the investigated surfaces. The redundancy in the morphology was associated with the concept of fractals, the maximum redundancy being achieved for the polyimide with the most complex polymer chain conformation. These results provide useful insights in selecting the polyimide structure, which has the optimal morphology, roughness, orientation, bearing properties, or self-similarity for microelectronic applications such as: substrate for display backplanes, planar technology, microelectronic packaging, etc. PMID- 23441080 TI - Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: a North American perspective. AB - BACKGROUND: Anthracycline agents are used for treatment of acute myeloid leukemia (AML) but may cause late-onset cardiomyopathy. Current frontline therapy for AML in North America, as reflected in the approach of the Children's Oncology Group (COG) and other pediatric consortia, is adapted from the anthracyline-intensive Medical Research Council (MRC) regimen. The purpose of this study was to describe early post-treatment cardiac function as a potential indicator of acute and long term risk associated with this approach. PROCEDURE: A multi-center retrospective cohort analysis was conducted of AML survivors diagnosed from 2004 to 2009 and treated with MRC-based regimens. Change in left ventricular shortening fraction (LVSF) on echocardiogram was determined from baseline to latest post treatment/pre-relapse value; associations with potential predictors were examined. RESULTS: This cohort of pediatric survivors (n = 52) was assessed at a median interval of 13 months from end of treatment. Mean cumulative anthracycline dose was 339 +/- 14 mg/m(2) . Mean baseline and post-treatment LVSF were 39.3 +/- 0.8% and 35.4 +/- 0.9%, respectively; mean percent change for individuals was 8.4 +/- 2.8% (P < 0.001). Cardiac-directed medications were initiated in four patients (7.7%). Decline in LVSF was significantly associated with cumulative anthracycline dose, increasing BMI and Hispanic ethnicity. CONCLUSION: Early, significant decline in LVSF was observed following treatment with these MRC-based regimens. Elevated BMI and Hispanic ethnicity were identified as new independent risk factors. Children and adolescents so treated are at substantial risk for late-onset cardiomyopathy, require monitoring with annual echocardiogram per current COG survivorship guidelines, and are good candidates for appropriate cardioprotection strategies. PMID- 23441081 TI - Mechanisms of tryptophan and tyrosine hydroxylase. AB - The aromatic amino acid hydroxylases tryptophan hydroxylase and tyrosine hydroxylase are responsible for the initial steps in the formation of serotonin and the catecholamine neurotransmitters, respectively. Both enzymes are nonheme iron-dependent monooxygenases that catalyze the insertion of one atom of molecular oxygen onto the aromatic ring of their amino acid substrates, using a tetrahydropterin as a two electron donor to reduce the second oxygen atom to water. This review discusses the current understanding of the catalytic mechanism of these two enzymes. The reaction occurs as two sequential half reactions: a reaction between the active site iron, oxygen, and the tetrahydropterin to form a reactive Fe(IV) O intermediate and hydroxylation of the amino acid by the Fe(IV) O. The mechanism of formation of the Fe(IV) O is unclear; however, considerable evidence suggests the formation of an Fe(II) -peroxypterin intermediate. The amino acid is hydroxylated by the Fe(IV) O intermediate in an electrophilic aromatic substitution mechanism. PMID- 23441082 TI - Provisional side branch-stenting for coronary bifurcation lesions: evidence of improving procedural and clinical outcomes with contemporary techniques. AB - OBJECTIVES: To determine whether recent technical modifications have improved clinical outcomes for patients undergoing contemporary bifurcation lesion percutaneous coronary intervention (PCI). BACKGROUND: Provisional side branch (SB)-stenting has become the preferred strategy for bifurcation PCI. Newer generation drug-eluting stents (DESs), the proximal optimization technique (POT), and the use of noncompliant (NC) balloons for final kissing inflation (FKI) have the potential to optimize outcomes. METHOD: We compared baseline characteristics, procedural and clinical outcomes in 300 consecutive patient pairs treated in 2005 and 2009. The primary outcome measure was the cumulative incidence of major adverse cardiac events (MACE) at 2-years. RESULTS: Compared to 2005, patients undergoing PCI in 2009 were at higher risk: prior myocardial infarction (18% vs. 8%, P = 0.0004), left ventricular function (EF 54 +/- 13% vs. 61 +/- 12%, P < 0.0001). Cypher (53 vs. 3%, P < 0.001) and Taxus (47 vs. 11%, P < 0.0001) stents were used more frequently in 2005, and Xience V in 2009 (0 vs. 47%, P < 0.0001). In 2009, the POT was performed in 36% and NC balloons used for FKI in 81%. SB stenting was required less frequently in 2009 (9% vs. 22%, P < 0.001). Two-year MACE was significantly lower in 2009 than 2005 (5.7 vs. 11.3%, P = 0.02), a difference driven by fewer cardiac deaths (2.0 vs. 5.0%, P = 0.05). MACE was independently associated with left main bifurcation treatment [hazard ratio (HR) 1.85:95%, CI 1.04-3.29; P = 0.036], side-branch stenting (HR 2.31:95% CI 1.27 4.20; P = 0.006), and PCI in 2005 (HR 1.86:95% CI 1.03-3.37; P = 0.004). CONCLUSIONS: Together, contemporary techniques and newer generation DES appear to improve outcomes and are both recommended for widespread uptake in patients undergoing provisional SB stenting for coronary bifurcation lesions. PMID- 23441083 TI - Histochemical comparison of the nonhost tomato with resistant wheat against Blumeria graminis f. sp. tritici. AB - The nonhost interaction of tomato-Blumeria graminis f. sp. tritici (Bgt) and resistant host interaction of wheat-Bgt were compared histochemically. The percentage of appressorium formation had no significant difference on tomato and wheat leaves. Papilla formation occurred earlier and more on host wheat than on nonhost tomato leaves, while the incidence of hypersensitive cell death was much higher in the nonhost interaction. Whole-cell H2O2 accumulation and hypersensitive cell death usually appeared in haustorium-invaded wheat epidermal cells. In contrast, the vast majority of non-haustorium epidermal cells were associated with H2O2 accumulation and hypersensitive cell death on tomato. Localized H2O2 accumulation and hypersensitive response were detected in effective papillae in both interactions. The peak percentage of haustorium formation was less than 7% in the nonhost interaction while reached 43% in the incompatible host interaction. These results indicate that hypersensitive cell death and papillae are likely to play an important role in preventing Bgt penetration and development on tomato and wheat leaves, both defense responses involving H2O2 accumulation. This study further implies that the nonhost and incompatible interactions share similar cytological mechanisms. PMID- 23441084 TI - Psychological Morbidity Status Among the Rural Geriatric Population of Tamil Nadu, India: A Cross-sectional Study. AB - BACKGROUND: Mental health problems like depression, cognitive impairment, anxiety, sleep disorders, and so on, arising out of senility, neurosis, and living conditions are common in the geriatric population. AIMS: To study the psychiatric morbidity among the rural elderly. SETTINGS AND DESIGN: A community based, cross-sectional study. MATERIALS AND METHODS: A study was conducted on 800 rural elderly subjects, aged 60 years and more, living in ten randomly selected villages, served by the Rural Health Training Center (RHTC), Valadi, in Tamilnadu state, India. Cognitive functioning was assessed by the Mini Mental Status Examination (MMSE), and the depression by the Geriatric Depression Scale - Shorter version. STATISTICAL ANALYSIS: The data was analyzed with SPSS 16 version statistical software using proportions, and the chi-square. RESULTS: A majority of the subjects were widows / widowers, illiterates, living with family, and showing economic dependency. The prevalence of cognitive impairment was 43.25%, with a mean MMSE score of 23.32+/-4.4, and the depression was 47.0% and 6.16+/ 3.4. Cognitive impairment, depression, and a disturbed sleep pattern were associated with female sex, age, illiteracy, poverty, loneliness, and the low socioeconomic status of the family. CONCLUSIONS: The study showed a definite association between the sociodemographic factors and psychiatric morbidity. Encouraging the Non-governmental Organizations (NGOs) working for the elderly, running of separate geriatric clinics, and effective implementation of schemes like old age pension are some of the measures to be taken. PMID- 23441085 TI - Chemical regulation of carbon quantum dots from synthesis to photocatalytic activity. AB - Carbon quantum dots (CQDs) were synthesized by heating various carbon sources in HNO3 solution at reflux, and the effects of HNO3 concentration on the size of the CQDs were investigated. Furthermore, the oxygen-containing surface groups of as prepared CQDs were selectively reduced by NaBH4 , leading to new surface states. The experimental results show that the sizes of CQDs can be tuned by HNO3 concentration and then influence their photoluminescent behaviors; the photoluminescent properties are related to both the size and surface state of the CQDs, but the photocatalytic activities are determined by surface states alone. The different oxygen-containing groups on the surface of the CQDs can induce different degrees of the band bending upward, which determine the separation and combination of the electron-hole pairs. The high upward band bending, which is induced by C=O and COOH groups, facilitates separation of the electron-hole pairs and then enhances high photocatalytic activity. In contrast, the low upward band bending induced by C-OH groups hardly prevents the electron-hole pairs from surface recombination and then exhibits strong photoluminescence. Therefore, both the photocatalytic activities and optical properties of CQDs can be tuned by their surface states. PMID- 23441086 TI - A novel phenotype variant of severe congenital neutropenia caused by G6PC3 deficiency. AB - Severe congenital neutropenia type 4 (SCN4) is associated with mutations in the G6PC3 gene. To date, all patients bearing the p.Gly260Arg variant of the G6PC3 gene show heart defects. Here, we present a case of the p.Gly260Arg variant in a patient who did not have structural or functional heart anomalies. Treatment with granulocyte colony-stimulating factor recovered the absolute neutrophil count and neutrophil functional competence. PMID- 23441087 TI - High pacing rates for management of aortic insufficiency after balloon aortic valvuloplasty or transcatheter aortic valve replacement. AB - Aortic insufficiency (AI) after transcatheter aortic valve replacement (TAVR) is difficult to manage when associated with congestive heart failure. AI after balloon aortic valvuloplasty (BAV) may be catastrophic, especially in patients who are not candidates for TAVR. We describe the use of urgent temporary pacing, followed by permanent pacing, to increase the heart rate to diminish diastolic filling time for the short term management of AI after BAV or TAVR. The strategy is particularly useful in patients who already have permanent pacemakers, which are common in this population. PMID- 23441088 TI - The relationship between measures of obesity and incident heart failure: the multi-ethnic study of atherosclerosis. AB - OBJECTIVE: To evaluate the strength of association of body mass index (BMI) and waist circumference (WC) with incident heart failure (HF), exploring our associations by ethnicity and age. DESIGN AND METHODS: 6,809 participants, aged 45-84 years old, without clinical cardiovascular disease (2000-2002), from the Multi-Ethnic Study of Atherosclerosis were included. Cox-Proportional hazards models were used to examine associations of BMI and WC with incident HF. The predictive abilities of BMI and WC were compared using receiver operating characteristic curves. RESULTS: Over a median follow-up of 7.6 years, there were 176 cases. BMI and WC were associated with incident HF in men (1.33 [1.10-1.61] and 1.38 [1.18-1.62], respectively] and women (1.70 [1.33-2.17] and 1.64 [1.29 2.08], respectively). These associations became non-significant after adjusting for obesity-related conditions (hypertension, dysglycemia, hypercholesterolemia, left ventricular hypertrophy, kidney disease, and inflammation). The associations of BMI and WC did not vary significantly by ethnicity or age-group, but were inverse in Hispanic men. The area under the curve for BMI and WC was 0.749 and 0.750, respectively, in men and 0.782 and 0.777, respectively, in women. CONCLUSIONS: The association between obesity and incident HF is largely mediated by obesity-related conditions. BMI and WC have similar predictive abilities for incident HF. PMID- 23441089 TI - MPL W515L mutation in pediatric essential thrombocythemia. AB - Essential thrombocythemia (ET) is extremely rare in the pediatric population. In most patients no molecular abnormality can be found, with about 40% of pediatric patients harboring a JAK2 V617F mutation. Another recurrent mutation, involving a W to L or K transversion at MPL codon 515, has been reported in about 3-8% of adult ET patients. Herein we describe this mutation in a pediatric patient. PMID- 23441090 TI - The sulfonylurea receptor Sur is dispensable for chitin synthesis in Drosophila melanogaster embryos. AB - BACKGROUND: Chitin produced by membrane-inserted chitin synthases is an important constituent of the arthropod cuticle and midgut peritrophic matrix. Chitin synthesis inhibitors are common insecticides in pest control. As the target of sulfonylurea-derived insecticides such as diflubenzuron, the ABC transporter sulfonylurea receptor (Sur) has been postulated to be an essential cofactor of chitin synthesis. However, direct evidence for this assumption is missing. RESULTS: Here, a study has been made of the phenotype of Drosophila melanogaster larvae suffering completely eliminated Sur function. Taken together, it is found that cuticle architecture is normal and chitin amounts are not diminished in the cuticle of these animals, indicating that Sur is dispensable for chitin synthesis. CONCLUSION: The data obtained suggest that there must exist another sulfonylurea-sensitive ABC transporter that either instead of Sur is the true sulfonylurea-sensitive transporter involved in chitin synthesis or is able to substitute Sur function during cuticle formation. Identification and characterisation of this factor is pivotal for understanding the mode of action of sulfonylurea as insecticide. PMID- 23441092 TI - SIOP PODC: recommendations for supportive care of children with cancer in a low income setting. AB - These supportive care recommendations were prepared to guide doctors who practice in areas with significantly limited resources but who have sufficient infrastructure and training to treat children with cancer with curative intent. The success of any cancer treatment regimen depends largely on the availability and quality of supportive care and this also determines the intensity of treatment that can be delivered. We present practical recommendations on how to prevent infections, general nursing care, management of febrile neutropenia, nutritional assessment and support, treatment of co-infections and the social support to help prevent failure to complete treatment in resource poor settings. PMID- 23441091 TI - Macrophages are unsuccessful in clearing aggregated alpha-synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats. AB - With age, alpha-synuclein (alpha-SYNC) misfolds and forms insoluble deposits of protein in the myenteric plexus, leading presumably to dystrophy and degeneration in the circuitry controlling gastrointestinal (GI) function. The present experiment examined aggregates of alpha-SYNC in the aging small intestine and investigated how macrophages in the wall of the GI tract respond to these aberrant deposits. Groups of adult and aged Fisher 344 rats were studied. Whole mounts of duodenal, jejunal, and ileal smooth muscle wall, including the myenteric plexus, were prepared. Double labeling immunohistochemistry was used to stain alpha-SYNC protein and the phenotypic macrophage antigens CD163 and MHCII. Alpha-synuclein accumulated in dense aggregates in axons of both postganglionic and preganglionic neurons throughout the small intestine. Staining patterns suggested that deposits of protein occur initially in axonal terminals and then spread retrogradely toward the somata. Macrophages that were adjacent to dystrophic terminal processes were swollen and contained vacuoles filled with insoluble alpha-SYNC, and these macrophages commonly had the phenotype of alternatively activated phagocytes. The present results suggest that macrophages play an active phagocytotic role in removing alpha-SYNC aggregates that accumulate with age in the neural circuitry of the gut. Our observations further indicate that this housekeeping response does not clear the protein sufficiently to eliminate all synucleinopathies or their precursor aggregates from the healthy aging GI tract. Thus, accumulating deposits of insoluble alpha-SYNC in the wall of the GI tract may contribute, especially when compounded by disease or inflammation, to the age-associated neuropathies in the gut that compromise GI function. PMID- 23441094 TI - Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes. AB - Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69-77. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 23441095 TI - Egg wash wastewater: estrogenic risk or environmental asset? AB - Commercial production of eggs and egg products requires the washing of eggs to remove urinary-fecal material and broken egg residue. In the case of one Ohio farming facility, 1.6 million birds produce 1.4 million eggs per day, using approximately 50 mL of wash water/egg or approximately 70,000 L per day. The aqueous waste stream was evaluated for estrogenicity to determine if potential for endocrine disruption would result from agricultural application of such wastewater. Samples collected the Fall (October) of 2010 included: water from 2 egg washers operating in series, inlet pipe to the treatment lagoon, a lagoon composite, and products used within the facility in the cleaning of equipment and treatment of the waste. In February 2011, the treatment lagoon was fitted with an extensive aeration system and subsequent sample sets were collected on 3 consecutive days in May and November. Samples were extracted by solid phase extraction and assayed for estrogenic activity using the in vitro E-Screen assay. Raw untreated wastewater from the egg washers contained 17beta-estradiol equivalents (E2 Eqs) ranging from 9 to 18 ng/L, pipe grab samples entering into the treatment lagoon ranged from <0.14 to 4.4 ng/L (variability related to time of emptying of egg wash tanks), whereas treatment lagoon water contained 0.3 to 4.0 ng/L E2 Eq. Addition of an aeration system to the treatment lagoon eliminated surface "frothing," reduced noxious odor emission, and E2 Eqs were lower than the pre-aeration concentrations (4 ng/L [n = 1, no statistical comparison possible] vs 0.3 to 1.4 ng/L in 2011). Because of matrix effects, estrogens were not quantifiable by LC-MS2 in even egg washwater extracts, at concentrations in which internal deuterated estrogen standards were quantifiable. Estrone and E2 parent ions were detected in egg washwater samples only, and confirmatory ion fragments were detected in only one of these samples. Estrogenicity of the wastewater from the treatment lagoon was already at the proposed aquatic no effect concentration for 17beta-E2 and would be expected to decrease further as wastewater passes through 2 consecutive storage ponds before application on field crops for irrigation. The original project plan was to follow the wastewater as it was applied by aerial irrigation and concomitant surface runoff, but based on the consistent and extremely low concentration of estrogenic activity of the wastewater from the treatment lagoon, it was concluded that activity would be below limits of quantitation by E-Screen in water used for irrigation from the storage ponds. Use of egg wash wastewater--or gray water--to irrigate crops removes the cost and burden of wastewater treatment by the local wastewater plant, poses little to no potential threat of estrogenic endocrine disruption, and supports the conservation of water resources through the use of wastewater irrigation. PMID- 23441093 TI - Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. AB - BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 * 10(-5) and P = 3.0 * 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options. PMID- 23441096 TI - Expression of Bacteroides fragilis hemolysins in vivo and role of HlyBA in an intra-abdominal infection model. AB - Bacteroides fragilis is the most frequent opportunistic pathogen isolated from anaerobic infections. However, there is a paucity of information regarding the genetic and molecular aspects of gene expression of its virulence factors during extra-intestinal infections. A potential virulence factor that has received little attention is the ability of B. fragilis to produce hemolysins. In this study, an implanted perforated table tennis "ping-pong" ball was used as an intra abdominal artificial abscess model in the rat. This procedure provided sufficient infected exudate for gene expression studies in vivo. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify the relative expression of hlyA, hlyB, hlyC, hlyD, hlyE, hlyF, hlyG, and hlyIII mRNAs. The hlyA mRNA was induced approximately sixfold after 4 days postinfection compared with the mRNA levels in the inoculum culture prior to infection. The hlyB mRNA increased approximately sixfold after 4 days and 12-fold after 8 days postinfection. Expression of hlyC mRNA increased sixfold after 1 day, 45-fold after 4 days, and 16-fold after 8 days postinfection, respectively. The hlyD and hlyE mRNAs were induced approximately 40-fold and 30-fold, respectively, after 4 days postinfection. The hlyF expression increased approximately threefold after 4 days postinfection. hlyG was induced approximately fivefold after 4 and 8 days postinfection. The hlyIII mRNA levels had a steady increase of approximately four , eight-, and 12-fold following 1, 4, and 8 days postinfection, respectively. These findings suggest that B. fragilis hemolysins are induced and differentially regulated in vivo. Both parent and hlyBA mutant strains reached levels of approximately 3-8 * 10(9) cfu/mL after 1 day postinfection. However, the hlyBA mutant strain lost 2 logs in viable cell counts compared with the parent strain after 8 days postinfection. This is the first study showing HlyBA is a virulence factor which plays a role in B. fragilis survival in an intra-abdominal abscess model. PMID- 23441099 TI - Development of self-assembling mixed protein micelles with temperature-modulated avidities. AB - Elastin-like polypeptides (ELPs) are polypentapeptides that undergo hydrophobic collapse and aggregation above a specific transition temperature, Tt . ELP diblocks sharing a common "core" block (I60) but varying "outer" blocks (A80, P40) were designed, where Tt,I < Tt,A < Tt,P . The formation of ~55 nm diameter mixed micelles from these ELP diblocks was verified using dynamic light scattering (DLS), multiangle light scattering (MALS) and fluorescence resonance energy transfer (FRET). To confer affinity to the blood circulating protein fibrinogen, a fibrinogen-binding tetrapeptide sequence (GPRP) was fused to A80 I60, while P40-I60 was fused to a non-binding control (GPSP). The self assembling, peptide-displaying, mixed micelles exhibit temperature-modulated avidities for immobilized and soluble fibrinogen at 32 degrees C and 42 degrees C. In this initial proof-of-concept design, the engineered mixed micelles were shown to disengage fibrinogen at elevated temperatures. The modular nature of this system can be used for developing in vivo depot systems that will only be triggered to release in situ upon specific stimuli. PMID- 23441101 TI - Silicon vacancy color center photoluminescence enhancement in nanodiamond particles by isolated substitutional nitrogen on {100} surfaces. AB - Fluorescent nanodiamonds were produced by incorporation of silicon-vacancy (Si-V) defect centers in as-received diamonds of averaged size ~255 nm using microwave plasma chemical vapor deposition. The potential for further enhancement of Si-V emission in nanodiamonds (NDs) is demonstrated through controlled nitrogen doping by adding varying amounts of N(2) in a H(2) + CH(4) feedgas mixture. Nitrogen doping promoted strong narrow-band (FWHM ~ 10 nm) emission from the Si-V defects in NDs, as confirmed by room temperature photoluminescence. At low levels, isolated substitutional nitrogen in {100} growth sectors is believed to act as a donor to increase the population of optically active (Si-V)(-) at the expense of optically inactive Si-V defects, thus increasing the observed luminescence from this center. At higher levels, clustered nitrogen leads to deterioration of diamond quality with twinning and increased surface roughness primarily on {111} faces, leading to a quenching of the Si-V luminescence. Enhancement of the Si-V defect through controlled nitrogen doping offers a viable alternative to nitrogen vacancy defects in biolabeling/sensing applications involving sub-10 nm diamonds for which luminescent activity and stability are reportedly poor. PMID- 23441100 TI - Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin d and prostate cancer risk. AB - BACKGROUND: Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D. METHODS: We created a tanning, a skin color, and a freckling score as combinations of single nucleotide polymorphisms that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and prostate-specific antigen detected prostate cancer in 3,123 White British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study. RESULTS: The freckling score was inversely associated with 25(OH)D levels [change in 25(OH)D per score unit -0.27; 95% CI, -0.52% to -0.01%], and the tanning score was positively associated with prostate cancer risk (OR = 1.05; 95% CI, 1.02-1.09), after adjustment for population stratification and potential confounders. CONCLUSIONS: Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer. IMPACT: The use of pigmentation-related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk. PMID- 23441102 TI - Mussel-inspired histidine-based transient network metal coordination hydrogels. AB - Transient network hydrogels cross-linked through histidine-divalent cation coordination bonds were studied by conventional rheologic methods using histidine modified star poly(ethylene glycol) (PEG) polymers. These materials were inspired by the mussel, which is thought to use histidine-metal coordination bonds to impart self-healing properties in the mussel byssal thread. Hydrogel viscoelastic mechanical properties were studied as a function of metal, pH, concentration, and ionic strength. The equilibrium metal-binding constants were determined by dilute solution potentiometric titration of monofunctional histidine-modified methoxy PEG and were found to be consistent with binding constants of small molecule analogs previously studied. pH-dependent speciation curves were then calculated using the equilibrium constants determined by potentiometric titration, providing insight into the pH dependence of histidine-metal ion coordination and guiding the design of metal coordination hydrogels. Gel relaxation dynamics were found to be uncorrelated with the equilibrium constants measured, but were correlated to the expected coordination bond dissociation rate constants. PMID- 23441103 TI - Prosodic boundary strength: An articulatory and perceptual study. AB - This study examines the production and perception of Intonational Phrase (IP) boundaries. In particular, it investigates (1) whether the articulatory events that occur at IP boundaries can exhibit temporal distinctions that would indicate a difference in degree of disjuncture, and (2) to what extent listeners are sensitive to the effects of such differences among IP boundaries. Two experiments investigate these questions. An articulatory kinematic experiment examines the effects of structural differences between IP boundaries on the production of those boundaries. In a perception experiment listeners then evaluate the strength of the junctures occurring in the utterances produced in the production study. The results of the studies provide support for the existence of prosodic strength differences among IP boundaries and also demonstrate a close link between the production and perception of prosodic boundaries. The results are discussed in the context of possible linguistic structural explanations, with implications for cognitive accounts for the creation, implementation, and processing of prosody. PMID- 23441104 TI - Children's Engagement within the Preschool Classroom and Their Development of Self-Regulation. AB - This study used an observational measure to examine how individual children's engagement with teachers, peers, and tasks was associated with gains in self regulation. A sample of 341 preschoolers was observed and direct assessments and teacher reports of self- regulation were obtained in the fall and spring of the preschool year. RESEARCH FINDINGS: Children's positive engagement with teachers was related to gains in compliance/executive function and children's active engagement with tasks was associated with gains in emotion regulation across the year. Engaging positively with teachers or peers was especially supportive of children's gains in task orientation and reductions in dysregulation. PRACTICE & POLICY: Results are discussed in relation to Vygotsky's developmental theory, emphasizing that psychological processes are developed in the context of socially embedded interactions. Systematically observing how a child interacts with peers, teachers, and learning tasks in the preschool classroom holds potential to inform the creation of professional development aimed at supporting teachers in fostering individual children's development within the early education environment. PMID- 23441105 TI - On the Rate of Boronate Ester Formation in ortho-Aminomethyl Functionalized Phenyl Boronic Acids. AB - The role of the ortho-aminomethyl functional group in phenyl boronic acids for sugar complexation is a topic of debate. To decipher its effect on the kinetics of boronate ester formation, we first performed pseudo-first order kinetics analyses at five pH values up to 4 mM in fructose, revealing a first-order kinetic dependence upon fructose. Under these conditions, the reaction is in equilibrium and does not reach completion, but at 50 mM fructose saturation is achieved revealing zero-order dependence upon fructose. This indicates rate determining creation of an intermediate prior to reaction with fructose, which we propose involves leaving group departure of inserted solvent. Further, the region of kinetics displaying zero-order dependence has a kinetic isotope effect (KIE) of 1.42, showing involvement of a proton transfer in the leaving group departure. The ratio of forward and reverse rate constants branching from the intermediate shows that fructose is several thousand times more nucleophilic than the solvent. Overall, the data supports a mechanism where the o-aminomethyl group lowers the pK(a) of the proximal boronic acid and acts as a general-acid (as an ammonium) to facilitate leaving group departure. Consequently, by microscopic reversibility the resulting amine must perform general-base catalysis to deliver fructose. PMID- 23441106 TI - Cannabinoid receptor 1 blockade protects human retinal pigment epithelial cells from oxidative injury. AB - BACKGROUND: Because oxidative stress is assumed to be a key mechanism in the pathological process of age-related macular degeneration (AMD), increasing numbers of studies have focused on discovering new pathways and treatments for reducing oxidative damage. Our work investigates the potential role of the cannabinoid receptor 1 (CB1) in oxidative stress of primary human retinal pigment epithelial (RPE) cells, a cellular model of AMD. METHODS: Primary human RPE cells were cultured and exposed to hydrogen peroxide for 24 h to induce oxidative damage. The expression of and changes in the CB1 receptor were determined with western blot assay and confocal imaging. The CB1 receptor in the RPE cells was inhibited with small interfering RNA (siRNA) or rimonabant (SR141716). Cell viability, apoptosis, and reactive oxygen species production were measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulforhodamine B assay, annexin V and propidium iodide staining, and the dichlorofluorescein fluorescence assay, respectively. Intracellular superoxide dismutase activity was assayed with a commercially available assay kit. Phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) protein expression and activation of signaling molecules were assessed with western blot analysis. RESULTS: We showed that human RPE cells express the CB1 receptor. In addition, oxidative stress upregulates the expression of the CB1 receptor. Deleting the CB1 receptor or treating with the CB1 receptor antagonist rimonabant (SR141716) rescued RPE cells from hydrogen peroxide-induced oxidative damage. Rimonabant pretreatment effectively reduced the apoptosis of RPE cells, inhibited the generation of intracellular reactive oxygen species and elevated the activity of superoxide dismutase. In addition, rimonabant significantly strengthened the oxidative stress-induced activation of the PI3K/Akt signaling pathway. CONCLUSIONS: The results demonstrate the expression and regulation of CB1 receptors in human RPE cells. Inhibiting the CB1 receptor may be an effective therapeutic strategy for AMD by downregulating oxidative stress signaling and facilitating PI3K/Akt activation. PMID- 23441107 TI - The contribution of GPR98 and DFNB31 genes to a Spanish Usher syndrome type 2 cohort. AB - BACKGROUND: Usher syndrome type 2 (USH2) is an autosomal recessive disease characterized by moderate to severe hearing loss and retinitis pigmentosa. To date, three disease-causing genes have been identified, USH2A, GPR98, and DFNB31, of which USH2A is clearly the major contributor. The aim of this work was to determine the contribution of GPR98 and DFNB31 genes in a Spanish cohort of USH2A negative patients using exhaustive molecular analysis, including sequencing, dosage, and splicing analysis. METHODS: Linkage analysis was performed to prioritize the gene to study, followed by sequencing of exons and intron-exon boundaries of the selected gene, GPR98 (90 exons) or DFNB31 (12 exons). Functional splicing analyses and comparative genomic hybridization array to detect large rearrangements were performed when appropriate. RESULTS: We confirmed that mutations in GPR98 contribute a significant but minor role to Usher syndrome type 2. In a group of patients referred for molecular diagnosis, 43 had been found to be positive for USH2A mutations, the remaining 19 without USH2A alterations were screened, and seven different mutations were identified in the GPR98 gene in seven patients (five in the homozygous state), of which six were novel. All detected mutations result in a truncated protein; deleterious missense mutations were not found. No pathological mutations were identified in the DFNB31 gene. CONCLUSIONS: In Spain, USH2A and GPR98 are responsible for 95.8% and 5.2% of USH2 mutated cases, respectively. DFNB31 plays a minor role in the Spanish population. There was a group of patients in whom no mutation was found. These findings confirm the importance of including at least GPR98 analysis for comprehensive USH2 molecular diagnosis. PMID- 23441108 TI - Complement factor H Val62Ile variant and risk of age-related macular degeneration: a meta-analysis. AB - PURPOSE: To evaluate the precise association of complement factor H (CFH) Val62Ile polymorphism with age-related macular degeneration (AMD) susceptibility. METHODS: We performed a meta-analysis using databases including PubMed, EMBASE, and Web of Science to find relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed-effect and random-effects models. The inconsistency index (I(2)) was used to assess heterogeneity. Funnel plots and Egger's test were used to evaluate publication bias. Sensitivity analysis was also performed. RESULTS: Fourteen studies including 4,438 patients with AMD and 6,099 controls based on the search criteria were involved in the meta-analysis. In overall populations, the pooled OR(1) for genotype GA+GG versus homozygous genotype AA was 2.28 (95% confidence interval (CI): 1.48-3.52), the OR(2) of heterozygous genotype GA versus AA was 1.58 (95% CI: 1.13-2.19), the OR(3) of homozygous genotype GG versus AA was 2.90 (95% CI: 1.95-4.30), and the OR(4) of allele G versus A was 1.77 (95% CI: 1.43-2.21). In Asian populations, our results provided substantial evidence that the Val62Ile variant was significantly associated with AMD (OR(4) = 1.85, 95% CI: 1.63-2.09). However, in Caucasian populations, no significant association of Val62Ile with AMD was established in all circumstances. CONCLUSIONS: Our analysis provides substantial evidence that the Val62Ile variant is significantly associated with AMD in Asian populations. However, our results have demonstrated no link between the Val62Ile polymorphism and AMD in Caucasian populations. PMID- 23441109 TI - Pathogenic mutations in two families with congenital cataract identified with whole-exome sequencing. AB - PURPOSE: Congenital cataract is one of the most frequent causes of visual impairment and childhood blindness. Approximately one quarter to one third of congenital cataract cases may have a genetic cause. However, phenotypic variability and genetic heterogeneity hamper correct genetic diagnosis. In this study, we used whole-exome sequencing (WES) to identify pathogenic mutations in two Korean families with congenital cataract. METHODS: Two affected members from each family were pooled and processed for WES. The detected variants were confirmed with direct sequencing. RESULTS: WES readily identified a CRYAA mutation in family A and a CRYGC mutation in family B. The c.61C>T (p.R21W) mutation in CRYAA has been previously reported in a family with congenital cataract and microcornea. The novel mutation, c.124delT, in CRYGC may lead to a premature stop codon (p.C42Afs*60). CONCLUSIONS: This study clearly shows the efficacy of WES for rapid genetic diagnosis of congenital cataract with an unknown cause. WES will be the first choice for clinical services in the near future, providing useful information for genetic counseling and family planning. PMID- 23441110 TI - Quantification of individual proteins in silicone hydrogel contact lens deposits. AB - PURPOSE: The aim of this study was to quantify specific proteins deposited on daily wear silicone hydrogel lenses used in combination with multipurpose disinfecting solutions (MPDSs) by applying multiple-reaction-monitoring mass spectrometry (MRM-MS). METHODS: Balafilcon A or senofilcon A contact lenses used with different MPDSs on a daily wear schedule were collected. Each worn lens was extracted and then digested with trypsin. MRM-MS was applied to quantify the amounts of lysozyme, lactoferrin, lipocalin-1, proline-rich protein-4, and keratin-1 in the extracts. RESULTS: The amount of protein extracted from the contact lenses was affected by the individual wearers, lens material, and type of care system used. Higher amounts of proteins were extracted from lenses after wear when they were used with an MPDS containing polyhexamethylene biguanide (PHMB) and poloxamer 407 compared with MPDSs containing polyquaternium-1 (PQ 1)/alexidine dihydrochloride with Tetronic 904 or PQ-1/ PHMB with poloxamine and sulfobetaine (p < 0.05). There was a correlation between the amount of lipocalin 1 or keratin-1 extracted from lenses and symptoms of ocular dryness. CONCLUSIONS: The MRM-MS technique is a promising approach that could be used to reveal associations of individual proteins deposited on lenses with performance of contact lenses during wear. PMID- 23441111 TI - Transplantation of tissue-engineered human corneal endothelium in cat models. AB - PURPOSE: To evaluate the performance of reconstructed tissue-engineered human corneal endothelium (TE-HCE) by corneal transplantation in cat models. METHODS: TE-HCE reconstruction was performed by culturing 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate (DiI)-labeled monoclonal HCE cells on denuded amniotic membranes (dAMs) in 20% fetal bovine serum-containing Dulbecco's Modified Eagle's Medium/Ham's Nutrient Mixture F12 (1:1) medium and 5% CO(2) at 37 degrees C on a 24-well culture plate. The reconstructed TE-HCE was transplanted into cat corneas via lamellar keratoplasty with all of the endothelium and part of Descemet's membrane stripped. Postsurgical corneas were monitored daily with their histological properties examined during a period of 104 days after transplantation. RESULTS: The reconstructed TE-HCE at a density of 3,413.33 +/- 111.23 cells/mm(2) in average established intense cell-cell and cell dAM junctions. After lamellar keratoplasty surgery, no obvious edema was found in TE-HCE-transplanted cat corneas, which were transparent throughout the monitoring period. In contrast, intense corneal edema developed in dAM-transplanted cat corneas, which were turbid. The corneal thickness gradually decreased to 751.33 +/- 11.37 MUm on day 104 after TE-HCE transplantation, while that of dAM eye was over 1,000 MUm in thickness during the monitoring period. A monolayer of endothelium consisting of TE-HCE-originated cells at a density of 2,573.33 +/- 0.59 cells/mm(2) attached tightly to the surface of remnant Descemet's membrane over 104 days; this was similar to the normal eye control in cell density. CONCLUSIONS: The reconstructed TE-HCE was able to function as a corneal endothelium equivalent and restore corneal function in cat models. PMID- 23441112 TI - Changes in zebrafish (Danio rerio) lens crystallin content during development. AB - PURPOSE: The roles that crystallin proteins play during lens development are not well understood. Similarities in the adult crystallin composition of mammalian and zebrafish lenses have made the latter a valuable model for examining lens function. In this study, we describe the changing zebrafish lens proteome during development to identify ontogenetic shifts in crystallin expression that may provide insights into age-specific functions. METHODS: Two-dimensional gel electrophoresis and size exclusion chromatography were used to characterize the lens crystallin content of 4.5-day to 27-month-old zebrafish. Protein spots were identified with mass spectrometry and comparisons with previously published proteomic maps, and quantified with densitometry. Constituents of size exclusion chromatography elution peaks were identified with sodium dodecyl sulfate polyacrylamide gel electrophoresis. RESULTS: Zebrafish lens crystallins were expressed in three ontogenetic patterns, with some crystallins produced at relatively constant levels throughout development, others expressed primarily before 10 weeks of age (betaB1-, betaA1-, and gammaN2-crystallins), and a third group primarily after 10 weeks (alpha-, betaB3-, and gammaS-crystallins). Alpha crystallins comprised less than 1% of total lens protein in 4.5-day lenses and increased to less than 7% in adult lenses. The developmental period between 6 weeks and 4 months contained the most dramatic shifts in lens crystallin expression. CONCLUSIONS: These data provide the first two-dimensional gel electrophoresis maps of the developing zebrafish lens, with quantification of changing crystallin abundance and visualization of post-translational modification. Results suggest that some crystallins may play stage specific roles during lens development. The low levels of zebrafish lens alpha-crystallin relative to mammals may be due to the high concentrations of gamma-crystallins in this aquatic lens. Similarities with mammalian crystallin expression continue to support the use of the zebrafish as a model for lens crystallin function. PMID- 23441113 TI - Genetic analysis of the forkhead transcriptional factor 2 gene in three Chinese families with blepharophimosis syndrome. AB - PURPOSE: Clinically, blepharophimosis syndrome (BPES) has been divided into two subsets according to the association of ocular malformation with (type I) or without (type II) premature ovarian failure (POF). BPES is ascribed to mutations in the forkhead transcriptional factor 2 (FOXL2) gene. This study aimed at identifying clinical features and mutations within the FOXL2 gene in three Chinese families with BPES. METHODS: A clinical and molecular genetic investigation was performed in affected and unaffected members from three Chinese families with BPES. Genomic DNA was prepared from leucocytes of peripheral venous blood, the entire coding region of FOXL2 were amplified with PCR, and direct DNA sequencing of the PCR products was performed for mutations in FOXL2. RESULTS: Three mutations in FOXL2 were found in three families, including c.672_701dup30, c.663_692dup30, and c.475dupC. Of the three, the c.475dupC (p.His159fs) was novel in family C and resulted in a frameshift mutation to generate a truncated protein owing to a premature stop codon at codon 238. The new duplication mutation was associated with BPES type II. The c.672_701dup30 (p.Ala224_Ala234dup10) and the c.663_692dup30 (p.Ala221_Ala231dup10) were detected in family A and family B, respectively, leading to expansions of the polyalanine (poly-Ala) tract that is frequently the hot spot of mutations within FOXL2. CONCLUSIONS: Our results expand the spectrum of FOXL2 mutations, and further indicate the association of a novel duplication mutation leading to a truncated protein with BPES type II. The other two known mutations may support the previous hypothesis regarding expansions of the polyalanine tract associated with BPES type II as a mutational hot spot in FOXL2. PMID- 23441114 TI - In vitro effects of verteporfin on ocular cells. AB - PURPOSE: Photodynamic therapy (PDT) laser light in conjunction with the benzoporphyrin derivative verteporfin is a current clinical treatment for choroidal vascular diseases such as age-related macular degeneration. The aim of this study was to examine the effects of PDT laser-activated and inactive verteporfin on various cultured ocular cells. METHODS: Primary human scleral fibroblasts (hFibro), primary human trabecular meshwork (TM) cells (hTMC), primary porcine TM cells (pTMC), and a human retinal pigment epithelial cell line (ARPE-19 cells) were treated with verteporfin with and without activation by PDT laser. Cell viability was determined according to mitochondrial enzyme activity (3-(4,5- dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay). RESULTS: PDT laser treatment alone was insufficient to cause significant cell death in any of the cell types tested. Twenty-four-hour exposure to inactive verteporfin (without PDT laser) caused a dose-dependent decrease in cell viability in hFibro and hTMC, and to a lesser extent ARPE-19 cells. Verteporfin (0.5 ug/ml) without PDT laser activation caused a slight but statistically insignificant reduction in cell viability in hFibro (81.5% +/- 19.3%), pTMC (82.9% +/- 6.7%), hTMC (80.3% +/- 7.7%), and ARPE-19 cells (84.5% +/- 14.9%). Verteporfin (0.5 ug/ml) plus 50 uJ/cm(2) PDT laser treatment significantly decreased viability in hFibro (13.5% +/- 3.3%), pTMC (7.1% +/- 1.5%), hTMC (11.1% +/- 5.2%), and ARPE-19 (44.5% +/- 7.8%). Similar results were obtained in cells where verteporfin incubation was followed by washout before PDT laser, indicating that verteporfin is internalized by the studied cell lines. CONCLUSIONS: PDT laser-induced cell death was obtained with coincubation of verteporfin or preincubation followed by washout. These results suggest a potential future use of PDT therapy for selective in vivo removal of targeted ocular cells beyond the current use for destroying vascular endothelial cells. PMID- 23441115 TI - MicroRNAs in vitreus humor from patients with ocular diseases. AB - PURPOSE: Based on evidence that microRNAs (miRNAs) are found in many biologic fluids (e.g., urine, saliva, pleural fluid), we sought to detect the presence of miRNAs and analyze their profile in vitreous humor (VH) from patients affected by various ocular diseases. METHODS: MiRNAs were purified from VH samples taken during vitrectomy, by using the Qiagen miRNeasy Mini Kit. The expression profile on 745 miRNAs was performed by using TaqMan Low Density Array. Single TaqMan expression assays were performed on 18 VH samples (six each from patients with choroidal melanomas, retinal detachment, or macular hole) for miRNAs commonly expressed in serum or retinal cells: let-7b, miR-21, miR-26a, miR-146a, miR-199 3p, miR-210, miR-374a*, miR-532-5p. RNA extracted from serum of six healthy donors or from formalin-fixed, paraffin-embedded samples of choroidal melanocytes from four uveal melanomas (epithelioid cells) and from three unaffected eyes were used as controls. RESULTS: We identified the presence of 94 circulating small RNAs in the vitreous, some of which (miR-9, miR-9*, miR-125a-3p, miR-184, miR 211, miR-214, miR-302c, miR-452, miR-628, miR-639) are particularly abundant in the VH but downrepresented or not detectable in serum. MiR-146a and miR-26a were overexpressed more than threefold in VH from patients with uveal melanomas compared to the other pathological groups (Wilcoxon signed-rank test, p value < 0.05). CONCLUSIONS: Our experimental data suggest that a specific set of circulating miRNAs is secreted in the vitreous, which is quite different from the miRNA pattern in serum, and that the quantity of vitreal miRNAs could change, depending on the pathologies of the eye. PMID- 23441116 TI - Polymorphisms in matrix metalloproteinases MMP1 and MMP9 are associated with primary open-angle and angle closure glaucoma in a Pakistani population. AB - PURPOSE: Matrix metalloproteinases (MMPs) play an important role in remodeling of the extracellular matrix during development and growth of various tissues including the eye. Various functional polymorphisms in MMPs have been implicated in the pathogenesis of different types of glaucoma. The aim of the present study was to investigate the role of various polymorphisms in Pakistani patients with glaucoma. METHODS: The present case-control study included 112 patients with primary open-angle glaucoma (POAG), 82 patients with primary angle closure glaucoma (PACG), and 118 control subjects. Genotyping of polymorphisms was done using PCR followed by restriction fragment length polymorphism analysis. RESULTS: A significant difference in the genotype frequencies of MMP1 rs1799750 (-1607 1G/2G) was observed between the patients with POAG and the control subjects (p = 0.001). This was attributed to the female subjects (p < 0.001), while the association was not significant in male subjects (p > 0.47). In addition, a significant difference was observed in genotype frequencies of MMP9 rs17576 (c.836A>G) in patients with PACG compared to the control subjects (p < 0.001), which after gender stratification remained significant in men (p = 0.009) but not in women (p = 0.14). No significant associations were found for MMP7 (c.-181T>C) and MMP9 (c.-1562C>T) polymorphisms. CONCLUSIONS: Our data suggest that the MMP1 rs1799750 (-1607 1G/2G) and MMP9 rs17576 polymorphisms might be of value for further study as potential gender-dependent risk factors for developing POAG and PACG, respectively, in Pakistan. PMID- 23441117 TI - Evaluation of lysyl oxidase-like 1 gene polymorphisms in pseudoexfoliation syndrome in a Korean population. AB - PURPOSE: The purpose of this study was to evaluate association profiles of lysyl oxidase-like 1 (LOXL1) gene polymorphisms with pseudoexfoliation syndrome (XFS) in a Korean population. METHODS: A total of 110 Korean patients with XFS and 127 control subjects were included in this study. Genotypes of three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing, and a case-control association study was performed. Genotype frequencies of each SNP were compared according to the XFS phenotypes. RESULTS: All three SNPs were significantly associated with XFS. The T allele at rs1048661 (odds ratio [OR] = 14.29, 95% confidence interval [CI] = 6.25 33.3) and the C allele at rs2165241 (OR = 7.14, 95% CI = 1.59-33.3) were risk alleles in Korean subjects, which was consistent with findings in other Asian populations. However, our findings were opposite to results from Caucasian populations in which the risk alleles at rs1048661 and rs2165241 were G and T, respectively. At the rs3825942, the G allele (OR = 12.50, 95% CI = 2.94-50.0) was a risk allele for XFS, which was similar to results from most other ethnic groups except black South Africans in whom the A allele increased the risk. In the haplotype analysis, the T-G-C haplotype composed of all three risk alleles was significantly overrepresented in XFS and conferred an 11.36 fold (95% CI = 5.97 23.49) increased likelihood of XFS. There was no significant association between the genotype frequencies of the three SNPs and the XFS phenotypes. CONCLUSIONS: Three SNPs of LOXL1 (rs1048661, rs3825942, and 2,165,241) are highly associated with XFS in a Korean population. The risk alleles of these SNPs were similar to those of other Asian populations, such as Japanese or Chinese, but differed from non-Asian populations, suggesting that still unidentified genetic or environmental factors may contribute to disease expression. PMID- 23441118 TI - Screening for large rearrangements of the RB1 gene in Iranian patients with retinoblastoma using multiplex ligation-dependent probe amplification. AB - PURPOSE: To screen deletions/duplications of the RB1 gene in a large cohort of Iranian patients using the multiplex ligation-dependent probe amplification (MLPA) technique. METHODS: A total of 121 patients with retinoblastoma, involving 55 unilateral and 66 bilateral or familial retinoblastomas, were included in this study. Among these patients, 121 blood and 43 tissue samples were available. DNA was extracted from the blood and tissue samples and analyzed with an RB1-specific MLPA probe set. The mutation findings were validated with SYBR Green Real-Time PCR. RESULTS: Twenty-two mutations were found in 21 patients; of these, ten mutations were detected in patients with isolated unilateral retinoblastoma. CONCLUSIONS: Our results suggested that MLPA is a fast, reliable, and powerful method for detecting deletions/duplications in patients with retinoblastoma. PMID- 23441120 TI - Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity. AB - PURPOSE: Retinopathy of prematurity (ROP) is a complex disease with a genetic predisposition, but little is known about its genetic background. It has a clinical resemblance to familial exudative vitreoretinopathy (FEVR), a hereditary disease characterized by defects in the development of retinal vessels. Several studies have suggested that mutations in the causative genes for FEVR may account for a proportion of advanced ROP, but conflicting data have also been reported for some variants. To address the possibility of genetic involvement of FEVR genes in ROP, we performed comprehensive sequence analyses of 53 Japanese patients with advanced ROP for the FEVR-causing genes. METHODS: Peripheral blood DNA was obtained from 53 patients referred to our hospitals for retinal surgery. Polymerase chain reaction followed by direct sequencing of the coding regions of the known FEVR-causing genes (FZD4, LRP5, TSPAN12, and NDP) and a noncoding exon of the NDP gene was performed. Possible pathogenicity of the sequence changes were analyzed by orthologous protein sequence alignment and by computational predictions. RESULTS: We identified six different nonsynonymous DNA variants in the coding region of either the FZD4 gene (p.H69Y, p.R127H, and p.Y211H) or the LRP5 gene (p.R1219H, p.H1383P, and p.T1540M) in seven patients. The corresponding codons of these changes were highly conserved among species, and these changes were predicted to be pathogenic by at least two of four computational prediction programs. No such changes were found in the TSPAN12 and NDP genes. CONCLUSIONS: Six possibly pathogenic variants of FZD4 or LRP5 were found in seven advanced ROP patients. Although these variants do not yet provide definitive evidence that they are causal, the results imply a role of the FZD4 and LRP5 genes in the development of advanced ROP. PMID- 23441119 TI - Carbon turnover in the water-soluble protein of the adult human lens. AB - PURPOSE: Human eye lenses contain cells that persist from embryonic development. These unique, highly specialized fiber cells located at the core (nucleus) of the lens undergo pseudo-apoptosis to become devoid of cell nuclei and most organelles. Ostensibly lacking in protein transcriptional capabilities, it is currently believed that these nuclear fiber cells owe their extreme longevity to the perseverance of highly stable and densely packed crystallin proteins. Maintaining the structural and functional integrity of lenticular proteins is necessary to sustain cellular transparency and proper vision, yet the means by which the lens actually copes with a lifetime of oxidative stress, seemingly without any capacity for protein turnover and repair, is not completely understood. Although many years of research have been predicated upon the assumption that there is no protein turnover or renewal in nuclear fiber cells, we investigated whether or not different protein fractions possess protein of different ages by using the (14)C bomb pulse. METHODS: Adult human lenses were concentrically dissected by gently removing the cell layers in water or shaving to the nucleus with a curved micrometer-controlled blade. The cells were lysed, and the proteins were separated into water-soluble and water-insoluble fractions. The small molecules were removed using 3 kDa spin filters. The (14)C/C was measured in paired protein fractions by accelerator mass spectrometry, and an average age for the material within the sample was assigned using the (14)C bomb pulse. RESULTS: The water-insoluble fractions possessed (14)C/C ratios consistent with the age of the cells. In all cases, the water-soluble fractions contained carbon that was younger than the paired water-insoluble fraction. CONCLUSIONS: As the first direct evidence of carbon turnover in protein from adult human nuclear fiber cells, this discovery supports the emerging view of the lens nucleus as a dynamic system capable of maintaining homeostasis in part due to intricate protein transport mechanisms and possibly protein repair. This finding implies that the lens plays an active role in the aversion of age-related nuclear (ARN) cataract. PMID- 23441121 TI - Protective effect of paraoxonase 1 gene variant L55M in retinal vein occlusion. AB - PURPOSE: To determine if the paraoxonase 1 L55M and paraoxonase 1 Q192R gene polymorphisms have an effect on the risk of having a retinal vein occlusion (RVO). METHODS: This case-control prospective study included 120 patients with RVO and 84 control subjects. All subjects were screened for age, gender, hypertension, diabetes, body mass index, fibrinogen, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol, and very low-density lipoprotein. Subjects were also questioned about their smoking habits. Genomic DNA was extracted from peripheral leukocytes from EDTA anticoagulated blood. Genotyping of the paraoxonase 1 L55M and paraoxonase 1 Q192R polymorphisms was performed using real-time PCR. RESULTS: The frequency of the paraoxonase 1 (PON1) 55 LL genotype was significantly lower in patients with RVO than in the control subjects (28% versus 55%; p = 0.005). Logistic regression analyses were also conducted. After adjusting for gender, diabetes, hypertension, plasma fibrinogen levels, and high-density lipoprotein cholesterol, the lower LL genotype was found to be an independent predictor of RVO (beta = 1.755; odds ratio = 5.783; p < 0.001; 95% confidence interval = 2.579 12.967). CONCLUSIONS: Subjects with a lower frequency PON1 55 LL genotype had a higher risk of RVO. These results indicate that paraoxonase gene polymorphisms may be a possible risk factor for RVO. We suggest that the LL genotype may have a protective role in the pathogenesis of RVO in the Turkish population. PMID- 23441122 TI - Protective effect of caffeine against high sugar-induced transcription of microRNAs and consequent gene silencing: a study using lenses of galactosemic mice. AB - PURPOSE: Previous studies have shown that caffeine prevents the formation of cataracts induced by a high-galactose diet and consequent oxidative stress. The objective of this study was to investigate if this protective effect is reflected in the attenuation of the transcription of microRNAs (miRNAs) known to induce apoptosis and cell death by gene silencing. METHODS: Young CD-1 mice were fed either a normal laboratory diet or a diet containing 25% galactose with or without 1% caffeine. One week later, the animals were euthanized, and the lenses isolated and promptly processed for RNA isolation and subsequent preparation of cDNAs by reverse transcriptase reaction. Mature miRNA (miR)-specific cDNAs were then quantified with PCR in a 96-well microRNA-specific cassette using an ABI7900HT PCR machine. RESULTS: As expected from previous studies, the lenses were positive for all 84 miRs corresponding to the miRNA probes present in the cassette wells. However, the levels of at least 19 miRs were significantly elevated in galactosemic lenses compared to those in the normal lenses. The majority are proapoptotic. Such elevation was inhibited by caffeine. This has been demonstrated for the first time. CONCLUSIONS: Since aberrant elevation of miRNAs silences various genes and consequently deactivates protein translation, and since caffeine downregulates such aberration, the beneficial effect of caffeine could be attributed to its ability to suppress elevation of toxic miRs and consequent gene silencing. PMID- 23441123 TI - Stability of small non-coding RNA reference gene expression in the rat retina during exposure to cyclic hyperoxia. AB - PURPOSE: Oxygen-induced retinopathy (OIR) is a robust animal model of human retinopathy of prematurity that readily allows changes in retinal gene and microRNA (miRNA) expression in response to fluctuations in oxygen levels to be studied. We sought to identify small non-coding RNA (ncRNA) genes that showed stable expression upon exposure to varying levels of oxygen, with different developmental stages and in different rat strains, to act as reference genes for normalizing miRNA expression in a rat model of OIR. METHODS: Expression of five small ncRNAs (U6 snRNA, miR-16, U87, 4.5S RNA (H) "Variant 1", and 5S ribosomal RNA [rRNA]) were tested on a standard RNA pool and representative retinal samples from P5, P6, P9, and P14 from room air- and cyclic hyperoxia-exposed rats using reverse transcription (RT)-qPCR, to assess the effect of developmental stage and exposure to fluctuations in oxygen levels, respectively. Two strains of inbred albino rats, Fischer 344 (F344, resistant to OIR) and Sprague-Dawley rats (SD, susceptible to OIR), were used to assess the effect of rat strain on the stability of the small ncRNAs. RESULTS: In this rat model of OIR, 5S rRNA expression was variable with strain, fluctuations in oxygen levels, and developmental stage. U6 snRNA was stably expressed with changes in oxygen levels, and minimal variation was observed with strain and developmental stage. MiR-16 showed less stable expression with changes in oxygen levels and between strains compared to U6 snRNA. Some variation in expression in response to developmental stage was also observed. The PCR amplification efficiencies of the U6 snRNA and miR-16 TaqMan assays were 56% and 78%, respectively. U87 and 4.5S RNA (H) "Variant 1" expression varied with strain, exposure to cyclic hyperoxia, and in particular developmental stage, and was at low levels in the neonatal rat retina. CONCLUSIONS: We conclude that U6 snRNA and miR-16 are the most suitable reference RNAs for normalizing miRNA expression, as they are relatively stable with strain, exposure to cyclic hyperoxia, and developmental stage in a rat model of OIR. PMID- 23441124 TI - Tear levels of SFRP1 are significantly reduced in keratoconus patients. AB - PURPOSE: To measure secreted frizzled-related protein 1 (SFRP1) levels in human tears and to investigate tear SFRP1 as a potential biomarker for keratoconus (KC). METHODS: Tears were collected from control (n = 33) and KC patients (n = 33) using micropipette tubes. Total tear protein was measured using a FluoroProfile Protein Quantification kit. An in-house enzyme-linked immunosorbent assay (ELISA) was developed to measure SFRP1 in control and KC tears. Statistical analyses of age, gender, the association of SFRP1, and total tear protein with KC were conducted. RESULTS: Tear SFRP1 was significantly decreased in KC, compared to age-matched controls (3.41 ng/MUl +/- 3.12 versus 5.55 ng/MUl +/- 5.62, respectively; p = 0.039). Conversely, total tear protein was significantly increased in KC, compared to age-matched controls (12.38 MUg/MUl +/- 4.76 versus 9.40 MUg/MUl +/- 3.88, respectively; p = 0.038). The ratio of SFRP1/total tear protein was also found to be significantly decreased in the KC group (p = 0.007). No significant association between tear SFRP1 and total tear protein was detected. CONCLUSIONS: Tear SFRP1 was significantly decreased in age-matched KC versus control patients, and may be further reduced in moderate KC. Tear-SFRP1 levels alone do not provide an obvious biomarker for KC; however, our results provide further evidence that tear-protein profiles are altered in KC, and suggest the involvement of SFRPs in the pathogenesis of KC. PMID- 23441125 TI - Pathological changes of the anatomical structure and markers of the limbal stem cell niche due to inflammation. AB - PURPOSE: The corneoscleral limbus is the site of corneal epithelial stem cells (SC). The aim of this study is to evaluate the expression of different SC markers in the normal human limbus and to determine how this is affected by inflammation. METHODS: Corneoscleral specimens from healthy and inflamed donor eyes were examined by immunohistochemistry/immunofluorescence for p63, vimentin, laminin 5, integrin alpha6, beta1, beta4, ABCG2, desmoglein 3, connexin 43, N-cadherin, and cytokeratins 12 and 15. The distribution and anatomic structure of the limbal crypts and the percentage of SC marker antigens in healthy donors were analyzed. In inflamed tissues, we evaluated the anatomic structure of the limbal epithelial crypt (LEC) and the positivity for SC markers. RESULTS: In normal limbus, the niche structures were distributed differently. The variability of their number correlated with the percentage of p63 positivity. Integrin beta1 staining directly correlated with p63 positivity while the remaining proteins were variably and widely distributed. Double staining for p63 and vimentin did not reveal any co-localization. In inflamed eyes, the basal cells in the crypts were "stretched" and surrounded by inflammatory cells, and only a few SC markers were still present. CONCLUSIONS: Diseases involving the limbus may result in marked changes of expression of SC markers within the LEC and also alter the crypt structure. PMID- 23441126 TI - Inhibition of lymphangiogenesis and angiogenesis in breast tumor xenografts and lymph nodes by a peptide derived from transmembrane protein 45A. AB - Angiogenesis, the formation of new blood vessels from preexisting blood vessels, is a process that supports tumor growth and metastatic dissemination. Lymphangiogenesis also facilitates metastasis by increasing dissemination through the lymphatic vessels (LVs). Even after treatment with antiangiogenic agents, breast cancer patients are vulnerable to LV-mediated metastasis. We report that a 14-amino acid peptide derived from transmembrane protein 45A shows multimodal inhibition of lymphangiogenesis and angiogenesis in breast cancer. The peptide blocks lymphangiogenic and angiogenic phenotypes of lymphatic and blood endothelial cells induced by tumor-conditioned media prepared from MDA-MB-231 breast cancer cells. The peptide delays growth of MDA-MB-231 tumor xenografts and normalizes tumor-conditioned lymph nodes (LNs). These studies demonstrate the antilymphangiogenic and antiangiogenic potential of the peptide against primary tumors and premetastatic, tumor-conditioned regional LNs. Mechanistically, the peptide blocks vascular endothelial growth factor receptors 2 and 3 (VEGFR2/3) and downstream proteins by binding to neuropilin 1/2 (NRP1/2) and inhibiting VEGFR2/3 and NRP1/2 complex formation in the presence of VEGFA/C. PMID- 23441127 TI - Gene expression profiles can predict panitumumab monotherapy responsiveness in human tumor xenograft models. AB - BACKGROUND: Epidermal growth factor receptor (EGFR)-targeted agents have demonstrated clinical benefit in patients with cancer. Identifying tissue-of origin-independent predictive biomarkers is important to optimally treat patients. We sought to identify a gene array profile that could predict responsiveness to panitumumab, a fully human EGFR-binding antibody, using preclinical models of human cancer. METHODS: Mice bearing 25 different xenograft models were treated twice weekly with panitumumab or immunoglobulin G2 control to determine their responsiveness to panitumumab. Samples from these xenografts and untreated xenografts were arrayed on the Affymetrix human U133A gene chip to identify gene sets predicting responsiveness to panitumumab using univariate and multivariate analyses. The predictive models were validated using the leave-one group-out (LOO) method. RESULTS: Of the 25 xenograft models tested, 12 were responsive and 13 were resistant to panitumumab. Unsupervised analysis demonstrated that the xenograft models clustered by tissue type rather than responsiveness to panitumumab. After normalizing for tissue effects, samples clustered by responsiveness using an unsupervised multidimensional scaling. A multivariate selection algorithm was used to select 13 genes that could stratify xenograft models based on responsiveness after adjustment for tissue effects. The method was validated using the LOO method on a training set of 22 models and confirmed independently on three new models. In contrast, a univariate gene selection method resulted in higher misclassification rates. CONCLUSION: A model was constructed from microarray data that prospectively predict responsiveness to panitumumab in xenograft models. This approach may help identify patients, independent of disease origin, likely to benefit from panitumumab. PMID- 23441128 TI - The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. AB - The tumor microenvironment can polarize innate immune cells to a proangiogenic phenotype. Decidual natural killer (dNK) cells show an angiogenic phenotype, yet the role for NK innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non small cell lung cancer (NSCLC) and controls using flow cytometric and functional analyses. The CD56(+)CD16(-) NK subset in NSCLC patients, which represents the predominant NK subset in tumors and a minor subset in adjacent lung and peripheral blood, was associated with vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and interleukin-8 (IL-8)/CXCL8 production. Peripheral blood CD56(+)CD16(-) NK cells from patients with the squamous cell carcinoma (SCC) subtype showed higher VEGF and PlGF production compared to those from patients with adenocarcinoma (AdC) and controls. Higher IL-8 production was found for both SCC and AdC compared to controls. Supernatants derived from NSCLC CD56(+)CD16(-) NK cells induced endothelial cell chemotaxis and formation of capillary-like structures in vitro, particularly evident in SCC patients and absent from controls. Finally, exposure to transforming growth factor-beta(1) (TGFbeta(1)), a cytokine associated with dNK polarization, upregulated VEGF and PlGF in peripheral blood CD56(+)CD16(-) NK cells from healthy subjects. Our data suggest that NK cells in NSCLC act as proangiogenic cells, particularly evident for SCC and in part mediated by TGFbeta(1). PMID- 23441129 TI - Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib. AB - Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients. PMID- 23441130 TI - The roles of telomerase in the generation of polyploidy during neoplastic cell growth. AB - Polyploidy contributes to extensive intratumor genomic heterogeneity that characterizes advanced malignancies and is thought to limit the efficiency of current cancer therapies. It has been shown that telomere deprotection in p53 deficient mouse embryonic fibroblasts leads to high rates of polyploidization. We now show that tumor genome evolution through whole-genome duplication occurs in ~15% of the karyotyped human neoplasms and correlates with disease progression. In a panel of human cancer and transformed cell lines representing the two known types of genomic instability (chromosomal and microsatellite), as well as the two known pathways of telomere maintenance in cancer (telomerase activity and alternative lengthening of telomeres), telomere dysfunction-driven polyploidization occurred independently of the mutational status of p53. Depending on the preexisting context of telomere maintenance, telomerase activity and its major components, human telomerase reverse transcriptase (hTERT) and human telomerase RNA component (hTERC), exert both reverse transcriptase-related (canonical) and noncanonical functions to affect tumor genome evolution through suppression or induction of polyploidization. These new findings provide a more complete mechanistic understanding of cancer progression that may, in the future, lead to novel therapeutic interventions. PMID- 23441131 TI - Enhanced UV-induced skin carcinogenesis in transgenic mice overexpressing proprotein convertases. AB - The proprotein convertases (PCs) furin and PACE4 process numerous substrates involved in tumor growth, invasion, and metastasis. We have previously shown that PCs increase the susceptibility to chemical skin carcinogenesis. Because of the human relevancy of UV radiation in the etiopathogenesis of human skin cancer, we investigated whether or not transgenic mice overexpressing either furin alone or both furin and PACE4 show increased susceptibility to UV carcinogenesis. After backcrossing our previously described furin and PACE4 transgenic lines, targeted to the epidermis, into a SKH-1 background, we exposed both single and double transgenic mice to UV radiation for 34 weeks. The results showed an increase in squamous cell carcinoma (SCC) multiplicity of approximately 70% in the single furin transgenic mouse line SF47 (P < .002) and a 30% increase in the other single transgenic line SF49 when compared to wild-type (WT) SKH-1 mice. Interestingly, there was also an increase in the percentage of high histologic grade SCCs in the transgenic lines compared to the WT mice, i.e., WT = 9%, SF47 = 15%, and SF49 = 26% (P < .02). Targeting both furin and PACE4 to the epidermis in double transgenic mice did not have an additive effect on tumor incidence/multiplicity but did enhance the tumor histopathologic grade, i.e., a significant increase in higher grade SCCs was seen in the bigenic mouse line SPF47 (P < .02). Thus, we observed an increased susceptibility to UV in single furin transgenic mice that was not substantially enhanced in the double furin/PACE4 transgenic mice. PMID- 23441132 TI - Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. AB - Cancer progression is a complex series of events thought to incorporate the reversible developmental process of epithelial-to-mesenchymal transition (EMT). In vitro, the microRNA-200 family maintains the epithelial phenotype by posttranscriptionally inhibiting the E-cadherin repressors, ZEB1 and ZEB2. Here, we used in situ hybridization and immunohistochemistry to assess expression of miR-200 and EMT biomarkers in formalin-fixed paraffin-embedded human colorectal adenocarcinomas. In addition, laser capture microdissection and quantitative real time polymerase chain reaction were employed to quantify levels of miR-200 in the normal epithelium, tumor core, invasive front, and stroma. We find that miR-200 is downregulated at the invasive front of colorectal adenocarcinomas that have destroyed and invaded beyond the basement membrane. However, regional lymph node metastases and vascular carcinoma deposits show strong expression of miR-200, suggesting this family of miRNAs is involved in the recapitulation of the primary tumor phenotype at metastatic sites. In contrast, adenomas and adenocarcinomas with intact basement membranes showed uniform miR-200 expression from the tumor core to the tumor-host interface. Taken together, these data support the involvement of EMT and mesenchymal-to-epithelial transition (MET) in the metastasis cascade and show that miR-200 is downregulated in the initial stages of stromal invasion but is restored at metastatic sites. PMID- 23441133 TI - Radiation-induced hypomethylation triggers urokinase plasminogen activator transcription in meningioma cells. AB - Our previous studies have shown the role of radiation-induced urokinase plasminogen activator (uPA) expression in the progression of meningioma. In the present study, we investigated whether modulation of DNA methylation profiles could regulate uPA expression. Initially, radiation treatment was found to induce hypomethylation in meningioma cells with a decrease in DNA (cytosine-5) methyltransferase 1 (DNMT1) and methyl-CpG binding domain protein (MBD) expression. However, oxidative damage by H(2)O(2) or pretreatment of irradiated cells with N-acetyl cysteine (NAC) did not show any influence on these proteins, thereby indicating a radiation-specific change in the methylation patterns among meningioma cells. Further, we identified that hypomethylation is coupled to an increase in uPA expression in these cells. Azacytidine treatment induced a dose dependent surge of uPA expression, whereas pre-treatment with sodium butyrate inhibited radiation-induced uPA expression, which complemented our prior results. Methylation-specific polymerase chain reaction on bisulfite-treated genomic DNA revealed a diminished methylation of uPA promoter in irradiated cells. Transfection with small hairpin RNA (shRNA)-expressing plasmids targeting CpG islands of the uPA promoter showed a marked decline in uPA expression with subsequent decrease in invasion and proliferation of meningioma cells. Further, radiation treatment was found to recruit SP1 transcription factor, which was abrogated by shRNA treatment. Analysis on signaling events demonstrated the activation of MAP kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) in radiation-treated cells, while U0126 (MEK/ERK inhibitor) blocked hypomethylation, recruitment of SP1, and uPA expression. In agreement with our in vitro data, low DNMT1 levels and high uPA were found in intracranial tumors treated with radiation compared to untreated tumors. In conclusion, our data suggest that radiation-mediated hypomethylation triggers uPA expression in meningioma cells. PMID- 23441134 TI - PDGFRB promotes liver metastasis formation of mesenchymal-like colorectal tumor cells. AB - In epithelial tumors, the platelet-derived growth factor receptor B (PDGFRB) is mainly expressed by stromal cells of mesenchymal origin. Tumor cells may also acquire PDGFRB expression following epithelial-to-mesenchymal transition (EMT), which occurs during metastasis formation. Little is known about PDGFRB signaling in colorectal tumor cells. We studied the relationship between PDGFRB expression, EMT, and metastasis in human colorectal cancer (CRC) cohorts by analysis of gene expression profiles. PDGFRB expression in primary CRC was correlated with short disease-free and overall survival. PDGFRB was co-expressed with genes involved in platelet activation, transforming growth factor beta (TGFB) signaling, and EMT in three CRC cohorts. PDGFRB was expressed in mesenchymal-like tumor cell lines in vitro and stimulated invasion and liver metastasis formation in mice. Platelets, a major source of PDGF, preferentially bound to tumor cells in a non-activated state. Platelet activation caused robust PDGFRB tyrosine phosphorylation on tumor cells in vitro and in liver sinusoids in vivo. Platelets also release TGFB, which is a potent inducer of EMT. Inhibition of TGFB signaling in tumor cells caused partial reversion of the mesenchymal phenotype and strongly reduced PDGFRB expression and PDGF-stimulated tumor cell invasion. These results suggest that PDGFRB may contribute to the aggressive phenotype of colorectal tumors with mesenchymal properties, most likely downstream of platelet activation and TGFB signaling. PMID- 23441135 TI - MicroRNA-145 targets the metalloprotease ADAM17 and is suppressed in renal cell carcinoma patients. AB - A disintegrin and metalloproteinase 17 (ADAM17) is a metalloprotease that is overexpressed in many cancer types, including renal cancers. However, the regulatory mechanisms of ADAM17 in cancer development and progression are poorly understood. In the present work, we provide evidence using overexpression and inhibition of microRNA 145 (miR-145) that miR-145 negatively regulates ADAM17 expression. Furthermore, we show that ADAM17 negatively regulates miR-145 through tumor necrosis factor-alpha, resulting in a reciprocal negative feedback loop. In this study, the expression of ADAM17 and miR-145 correlated negatively in renal cancer tumor tissues and cell lines, suggesting an important regulatory mechanism. Additionally, we showed that the regulation of ADAM17 is partly involved in the effects of miR-145 on proliferation and migration, whereas no involvement in chemosensitivity was observed. Importantly, in the healthy kidney, miR-145 was detected in different cell types including tubular cells, which are considered the origin of renal cancer. In renal cancer cell lines, miR-145 expression was strongly suppressed by methylation. In summary, miR-145 is downregulated in renal cancer patients, which leads to the up-regulation of ADAM17 in renal cancer. Importantly, miR-145 and ADAM17 are regulated in a reciprocal negative feedback loop. PMID- 23441137 TI - A review of the CTRC-AACR San Antonio Breast Cancer Symposium 2012. AB - The annual San Antonio Breast Cancer Symposium (SABC) is a multidisciplinary conference that covers basic molecular and cellular biology, epidemiology, diagnosis and treatment of all types of breast cancer and premalignant breast disease. In 2012, this meeting was held at the Henry B. Gonzalez Convention Center in San Antonio, Texas, United States, from 4 to 8 December.The symposium consisted of lectures within six general sections covering a range of topics in breast cancer research. These included discussions on research of breast cancer posters, a large number of specialist sessions, and several minisymposia. The report below describes much of the research presented in those general lecture sessions.The abstracts of all papers and posters presented at this conference have been published in Cancer Research as a supplement: Cancer Research (2012) 72(24), 1s-608s. PMID- 23441138 TI - A patient with chronic lymphocytic leukemia and acquired angioedema: correlation of clinical and biochemical response to CLL therapy. AB - Acquired angioedema (AAE) is a result of an acquired deficiency or inactivity of the C1 esterase inhibitor (C1-INH). There is a well-known link between AAE and lymphoplasmacytic disorders.A 65-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL), presented with recurrent episodes of angioedema. Although no association between the CLL and angioedema was initially recognized, further workup showed her to have low C1-INH levels. Chemotherapy helped prevent subsequent episodes, but three years later she redeveloped angioedema. She was then placed on ofatumumab maintenance and has since remained free of angioedema.Knowledge of this rare disease and anticipation of the link between CLL and AAE can prevent further attacks and associated morbidity. PMID- 23441139 TI - Oncoplastic surgery in the treatment of breast cancer. AB - Advances in reconstructive breast surgery with new materials and techniques now allow us to offer our patients the best possible cosmetic results without the risks associated with oncological control of the disease. These advances, in both oncological and plastic surgery, have led to a new specialisation, namely oncoplastic breast surgery, which enables us to undertake large resections and, with advance planning, to prevent subsequent deformities. This is particularly important when more than 30% of the breast volume is removed, as it allows us to obtain precise information for conservative surgery according to the site of the lesion, and also allows us to set the boundary between conservative surgery and mastectomy.Given the existence of new alloplastic materials and new reconstructive techniques, it is essential for our patients that surgeons involved in breast cancer treatment are trained in both the oncological as well as the reconstructive and aesthetic fields, to enable them to provide the best loco-regional treatment with the best cosmetic results. PMID- 23441136 TI - Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. AB - Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20*10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08*10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16*10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis. PMID- 23441141 TI - The health of geriatrics in Canada -more than meets the eye. PMID- 23441140 TI - How predictive of dementia are peripheral inflammatory markers in the elderly? AB - Dementia is a huge public health concern today owing to the exponentially increasing number of older adults it affects each year, and there has been a large number of investigators looking at potential biomarkers of dementia. Peripheral inflammatory markers have emerged as one potential class of markers that may be useful in predicting those individuals at a greater risk of developing dementia, or in expounding the underlying mechanisms or pathways of this complex disease. Although some evidence has been promising, indicating that peripheral inflammatory markers are indeed crucial in brain changes that occur in both normal aging and in dementia, results have been mixed on their usefulness for predicting dementia or cognitive decline in older adults. Here, the authors present a review of existing studies investigating inflammatory markers as potential biomarkers of dementia, highlighting some strengths and limitations of the current research and discuss the future directions for this field. PMID- 23441142 TI - Geriatric Psychiatry or Psychogeriatrics? Partnership at the CAGP/CCSMH 2012 Scientific Meeting. PMID- 23441144 TI - Why did the meerkat cross the road? Flexible adaptation of phylogenetically-old behavioural strategies to modern-day threats. AB - Risk-sensitive adaptive spatial organisation during group movement has been shown to efficiently minimise the risks associated with external ecological threats. Whether animals can draw on such behaviours when confronted with man-made threats is generally less clear. We studied road-crossing in a wild, but habituated, population of meerkats living in the Kalahari Desert, South Africa. We found that dominant females, the core member in meerkat social systems, led groups to the road significantly more often than subordinates, yet were consistently less likely to cross first. Our results suggest that a reshuffling occurs in progression order when meerkat groups reach the road. By employing a simple model of collective movement, we have shown that risk aversion alone may be sufficient to explain this reshuffling, but that the risk aversion of dominant females toward road crossing is significantly higher than that of subordinates. It seems that by not crossing first, dominant females avoid occupying the most risky, exposed locations, such as at the front of the group--a potential selfish strategy that also promotes the long-term stability and hence reproductive output of their family groups. We argue that our findings support the idea that animals can flexibly apply phylogenetically-old behavioural strategies to deal with emerging modern-day problems. PMID- 23441143 TI - In-vivo evaluation of an in situ polymer precipitation delivery system for a novel natriuretic peptide. AB - This study reports on the release of a novel natriuretic peptide, CD-NP, from an in situ polymer precipitation delivery system. Following extensive screening of in-vitro release profiles, an in-vivo evaluation of the efficacy of the delivery system was carried out in Wistar rats. Gel injection was performed subcutaneously on the back of the rats. A secondary messenger, cyclic Guanosine 3'5' Monophosphate (cGMP), was tested for verification of CD-NP bioactivity, in addition to direct measurements of CD-NP levels in plasma and urine using a radio immuno assay. Plasma evaluation showed an elevated level of CD-NP over 3 weeks' duration. Unexpectedly, plasma cGMP level followed a decreasing trend over the same duration despite high CD-NP level. Loss of drug bioactivity was ruled out as a high level of CD-NP and cGMP excretion was observed in the treatment group as compared to baseline readings. This unexpected low-plasma cGMP levels and high urinary cGMP excretion suggest that there might be other compensatory responses to regulation of the CDNP bioactivity as a result of the high drug dosing. The results stress the importance of assessing the overall bioactivity of released drug (in-vivo) concurrently in addition to measuring its concentrations, to determine the correct release profile. PMID- 23441145 TI - The importance of Acacia trees for insectivorous bats and arthropods in the Arava desert. AB - Anthropogenic habitat modification often has a profound negative impact on the flora and fauna of an ecosystem. In parts of the Middle East, ephemeral rivers (wadis) are characterised by stands of acacia trees. Green, flourishing assemblages of these trees are in decline in several countries, most likely due to human-induced water stress and habitat changes. We examined the importance of healthy acacia stands for bats and their arthropod prey in comparison to other natural and artificial habitats available in the Arava desert of Israel. We assessed bat activity and species richness through acoustic monitoring for entire nights and concurrently collected arthropods using light and pit traps. Dense green stands of acacia trees were the most important natural desert habitat for insectivorous bats. Irrigated gardens and parks in villages and fields of date palms had high arthropod levels but only village sites rivalled acacia trees in bat activity level. We confirmed up to 13 bat species around a single patch of acacia trees; one of the richest sites in any natural desert habitat in Israel. Some bat species utilised artificial sites; others were found almost exclusively in natural habitats. Two rare species (Barbastella leucomelas and Nycteris thebaica) were identified solely around acacia trees. We provide strong evidence that acacia trees are of unique importance to the community of insectivorous desert-dwelling bats, and that the health of the trees is crucial to their value as a foraging resource. Consequently, conservation efforts for acacia habitats, and in particular for the green more densely packed stands of trees, need to increase to protect this vital habitat for an entire community of protected bats. PMID- 23441146 TI - Prognostic value of TNF-related apoptosis inducing ligand (TRAIL) in acute coronary syndrome patients. AB - BACKGROUND: Apoptosis plays an important role in the development of heart failure. The aim of the prospectively designed study was to assess whether the concentration of apoptotic markers apoptosis-stimulating fragment (Fas, CD95/APO 1) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can predict prognosis in patients with acute coronary syndromes. METHODS: The concentrations of soluble Fas and TRAIL were determined in 295 patients with acute coronary syndromes. The status of all patients was evaluated at 6 months. The primary goal was a composite end-point of death and hospitalization for heart failure. The secondary end-points were re-MI, death alone and stroke alone. RESULTS: During the median follow-up of 6 months, 26 patients experienced the composite end-point. Using multivariate logistic regression, the concentration of TRAIL was the strongest significant and independent predictor of composite end point (OR 0.11 (95% CI 0.03-0.45), p = 0.002). Low concentration was associated with poor prognosis of patients. Other significant predictors of composite end point were serum creatinine (OR 7.7 (95% CI 1.1-54.5, p = 0.041) and complete revascularization (OR 0.19 (95% CI 0.05-0.78, p = 0.02). Independent significant predictors of death in the multivariate analysis were the concentration of TRAIL (OR 0.053 (95% CI 0.004-0.744), p = 0.029), older age (OR 1.20 (95% CI 1.02-1.41, p = 0.026) and serum creatinine (OR 15.1 (95% CI 1.56-145.2), p = 0.0193). Re-MI or stroke could not be predicted by any combination of obtained parameters. CONCLUSIONS: Low concentrations of soluble TRAIL represent a strong predictor of a poor prognosis in patients with acute coronary syndrome. The predictive value of TRAIL concentration is independent of age, ejection fraction, index peak troponin level, concentration of BNP or serum creatinine. PMID- 23441147 TI - A flexible mathematical model platform for studying branching networks: experimentally validated using the model actinomycete, Streptomyces coelicolor. AB - Branching networks are ubiquitous in nature and their growth often responds to environmental cues dynamically. Using the antibiotic-producing soil bacterium Streptomyces as a model we have developed a flexible mathematical model platform for the study of branched biological networks. Streptomyces form large aggregates in liquid culture that can impair industrial antibiotic fermentations. Understanding the features of these could aid improvement of such processes. The model requires relatively few experimental values for parameterisation, yet delivers realistic simulations of Streptomyces pellet and is able to predict features, such as the density of hyphae, the number of growing tips and the location of antibiotic production within a pellet in response to pellet size and external nutrient supply. The model is scalable and will find utility in a range of branched biological networks such as angiogenesis, plant root growth and fungal hyphal networks. PMID- 23441148 TI - Bats of a gender flock together: sexual segregation in a subtropical bat. AB - Competition has long been assumed to be a major driver in regulating ecological communities. Intra-specific competition is considered to be maximal as members of the same species use the same ecological niches in a similar way. Many species of animals exhibit great physiological, behavioral, and morphological differences between sexes (sexual dimorphism). Here we report an extreme geographical segregation between the sexes in the greater mouse-tailed bat (Rhinopoma microphyllum). To gain insight into the driving mechanisms of sexual segregation outside the mating season, we collected and integrated environmental, behavioral, physiological, and spatial information. We found that both sexes choose roosts with similar characteristics and the same food type, but use different habitats for different durations. Males forage around cliffs at higher and cooler elevations while females forage in lowlands around a river delta. We suggest that it is their different physiological and social needs, and not competition, that drives sexual segregation in this species. PMID- 23441149 TI - Simultaneous mapping of multiple gene loci with pooled segregants. AB - The analysis of polygenic, phenotypic characteristics such as quantitative traits or inheritable diseases remains an important challenge. It requires reliable scoring of many genetic markers covering the entire genome. The advent of high throughput sequencing technologies provides a new way to evaluate large numbers of single nucleotide polymorphisms (SNPs) as genetic markers. Combining the technologies with pooling of segregants, as performed in bulked segregant analysis (BSA), should, in principle, allow the simultaneous mapping of multiple genetic loci present throughout the genome. The gene mapping process, applied here, consists of three steps: First, a controlled crossing of parents with and without a trait. Second, selection based on phenotypic screening of the offspring, followed by the mapping of short offspring sequences against the parental reference. The final step aims at detecting genetic markers such as SNPs, insertions and deletions with next generation sequencing (NGS). Markers in close proximity of genomic loci that are associated to the trait have a higher probability to be inherited together. Hence, these markers are very useful for discovering the loci and the genetic mechanism underlying the characteristic of interest. Within this context, NGS produces binomial counts along the genome, i.e., the number of sequenced reads that matches with the SNP of the parental reference strain, which is a proxy for the number of individuals in the offspring that share the SNP with the parent. Genomic loci associated with the trait can thus be discovered by analyzing trends in the counts along the genome. We exploit the link between smoothing splines and generalized mixed models for estimating the underlying structure present in the SNP scatterplots. PMID- 23441150 TI - Task-related suppression of the brainstem frequency following response. AB - Recent evidence has shown top-down modulation of the brainstem frequency following response (FFR), generally in the form of signal enhancement from concurrent stimuli or from switching between attention-demanding task stimuli. However, it is also possible that the opposite may be true--the addition of a task, instead of a resting, passive state may suppress the FFR. Here we examined the influence of a subsequent task, and the relevance of the task modality, on signal clarity within the FFR. Participants performed visual and auditory discrimination tasks in the presence of an irrelevant background sound, as well as a baseline consisting of the same background stimuli in the absence of a task. FFR pitch strength and amplitude of the primary frequency response were assessed within non-task stimulus periods in order to examine influences due solely to general cognitive state, independent of stimulus-driven effects. Results show decreased signal clarity with the addition of a task, especially within the auditory modality. We additionally found consistent relationships between the extent of this suppressive effect and perceptual measures such as response time and proclivity towards one sensory modality. Together these results suggest that the current focus of attention can have a global, top-down effect on the quality of encoding early in the auditory pathway. PMID- 23441152 TI - Antibiotic prescribing in DR Congo: a knowledge, attitude and practice survey among medical doctors and students. AB - OBJECTIVES: Antibiotic resistance (ABR) particularly hits resource poor countries, and is fuelled by irrational antibiotic (AB) prescribing. We surveyed knowledge, attitudes and practices of AB prescribing among medical students and doctors in Kisangani, DR Congo. METHODS: Self-administered questionnaires. RESULTS: A total of 184 questionnaires were completed (response rate 94.4%). Knowledge about AB was low (mean score 4.9/8 points), as was the estimation of local resistance rates of S. Typhi and Klebsiella spp.(correct by 42.5% and 6.9% of respondents respectively). ABR was recognized as a problem though less in their own practice (67.4%) than nation- or worldwide (92.9% and 85.5%, p<.0001). Confidence in AB prescribing was high (88.6%) and students consulted more frequently colleagues than medical doctors when prescribing (25.4% versus 11.6%, p= 0.19). Sources of AB prescribing included pharmaceutical companies (73.9%), antibiotic guidelines (66.3%), university courses (63.6%), internet-sites (45.7%) and WHO guidelines (26.6%). Only 30.4% and 16.3% respondents perceived AB procured through the central procurement and local pharmacies as of good quality. Local AB guidelines and courses about AB prescribing are welcomed (73.4% and 98.8% respectively). CONCLUSIONS: This data shows the need for interventions that support rational AB prescribing. PMID- 23441151 TI - Efficacy of a marine bacterial nuclease against biofilm forming microorganisms isolated from chronic rhinosinusitis. AB - BACKGROUND: The persistent colonization of paranasal sinus mucosa by microbial biofilms is a major factor in the pathogenesis of chronic rhinosinusitis (CRS). Control of microorganisms within biofilms is hampered by the presence of viscous extracellular polymers of host or microbial origin, including nucleic acids. The aim of this study was to investigate the role of extracellular DNA in biofilm formation by bacteria associated with CRS. METHODS/PRINCIPAL FINDINGS: Obstructive mucin was collected from patients during functional endoscopic sinus surgery. Examination of the mucous by transmission electron microscopy revealed an acellular matrix punctuated occasionally with host cells in varying states of degradation. Bacteria were observed in biofilms on mucosal biopsies, and between two and six different species were isolated from each of 20 different patient samples. In total, 16 different bacterial genera were isolated, of which the most commonly identified organisms were coagulase-negative staphylococci, Staphylococcus aureus and alpha-haemolytic streptococci. Twenty-four fresh clinical isolates were selected for investigation of biofilm formation in vitro using a microplate model system. Biofilms formed by 14 strains, including all 9 extracellular nuclease-producing bacteria, were significantly disrupted by treatment with a novel bacterial deoxyribonuclease, NucB, isolated from a marine strain of Bacillus licheniformis. Extracellular biofilm matrix was observed in untreated samples but not in those treated with NucB and extracellular DNA was purified from in vitro biofilms. CONCLUSION/SIGNIFICANCE: Our data demonstrate that bacteria associated with CRS form robust biofilms which can be reduced by treatment with matrix-degrading enzymes such as NucB. The dispersal of bacterial biofilms with NucB may offer an additional therapeutic target for CRS sufferers. PMID- 23441153 TI - Utilizing descriptive statements from the biodiversity heritage library to expand the Hymenoptera Anatomy Ontology. AB - Hymenoptera, the insect order that includes sawflies, bees, wasps, and ants, exhibits an incredible diversity of phenotypes, with over 145,000 species described in a corpus of textual knowledge since Carolus Linnaeus. In the absence of specialized training, often spanning decades, however, these articles can be challenging to decipher. Much of the vocabulary is domain-specific (e.g., Hymenoptera biology), historically without a comprehensive glossary, and contains much homonymous and synonymous terminology. The Hymenoptera Anatomy Ontology was developed to surmount this challenge and to aid future communication related to hymenopteran anatomy, as well as provide support for domain experts so they may actively benefit from the anatomy ontology development. As part of HAO development, an active learning, dictionary-based, natural language recognition tool was implemented to facilitate Hymenoptera anatomy term discovery in literature. We present this tool, referred to as the 'Proofer', as part of an iterative approach to growing phenotype-relevant ontologies, regardless of domain. The process of ontology development results in a critical mass of terms that is applied as a filter to the source collection of articles in order to reveal term occurrence and biases in natural language species descriptions. Our results indicate that taxonomists use domain-specific terminology that follows taxonomic specialization, particularly at superfamily and family level groupings and that the developed Proofer tool is effective for term discovery, facilitating ontology construction. PMID- 23441154 TI - Integrative analyses identify osteopontin, LAMB3 and ITGB1 as critical pro metastatic genes for lung cancer. AB - OBJECTIVE: To explore the key regulatory genes associated with lung cancer in order to reduce its occurrence and progress through silencing these key genes. METHODS: To identify the key regulatory genes involved in lung cancer, we performed a combination of gene array and bioinformatics analyses to compare gene transcription profiles in 3 monoclonal cell strains with high, medium or low metastatic abilities, which were separated from the SPC-A-1sci and SPC-A-1 cell lines by limiting dilution monoclone assay. We then analyzed those genes' biological activities by knocking down their expression in SPC-A-1sci cells using siRNA and lenti-viral shRNA vectors, followed by determinations of the invasion and migration capabilities of the resulting cell lines in vitro as well as their potential for inducing occurrence and metastasis of lung cancer in vivo. To examine the clinical relevance of these findings, we analyzed the expression levels of the identified genes in human lung cancer tissues (n = 135) and matched adjacent normal tissues by immunohistochemical (IHC) staining. RESULTS: Three monoclonal cell strains characterized with high, medium or low metastatic abilities were successfully selected. Gene array and bioinformatics analyses implied that osteopontin, LAMB3 and ITGB1 were key genes involved in lung cancer. Knockdown of these genes suppressed human lung cancer cell invasion and metastasis in vitro and in vivo. Clinical sample analyses indicated that osteopontin, LAMB3 and ITGB1 protein expression levels were higher in lung cancer patients, compared to non-cancerous adjacent tissues, and correlated with lymphatic metastasis. CONCLUSIONS: We confirmed that osteopontin, LAMB3 and ITGB1 played important roles in the occurrence and metastasis of lung cancer, thus provided important clues to understanding the molecular mechanism of metastasis and contributing to the therapeutic treatment of lung cancer. PMID- 23441155 TI - Genetic polymorphism of glucokinase on the risk of type 2 diabetes and impaired glucose regulation: evidence based on 298,468 subjects. AB - BACKGROUND: Glucokinase (GCK) is the key glucose phosphorylation enzyme which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) based on its enzyme function as the first rate-limiting step in the glycolysis pathway and regulates glucose-stimulated insulin secretion. In the past decade, the relationship between GCK and T2D has been reported in various ethnic groups. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis. METHODS: Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. RESULTS: A total of 24 articles involving 88,229 cases and 210,239 controls were included. An overall random-effects per-allele OR of 1.06 (95% CI: 1.03-1.09; P<10(-4)) was found for the GCK -30G>A polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians; whereas no significant associations were found among Asians. In addition, we found that the -30G>A polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. Besides, -30G>A homozygous was found to be significantly associated with increased fasting plasma glucose level with weighted mean difference (WMD) of 0.15 (95%: 0.05-0.24, P = 0.001) compared with G/G genotype. CONCLUSIONS: This meta-analysis demonstrated that the -30G>A polymorphism of GCK is a risk factor associated with increased T2D susceptibility, but these associations vary in different ethnic populations. PMID- 23441156 TI - Yahtzee: an anonymized group level matching procedure. AB - Researchers often face the problem of needing to protect the privacy of subjects while also needing to integrate data that contains personal information from diverse data sources. The advent of computational social science and the enormous amount of data about people that is being collected makes protecting the privacy of research subjects ever more important. However, strict privacy procedures can hinder the process of joining diverse sources of data that contain information about specific individual behaviors. In this paper we present a procedure to keep information about specific individuals from being "leaked" or shared in either direction between two sources of data without need of a trusted third party. To achieve this goal, we randomly assign individuals to anonymous groups before combining the anonymized information between the two sources of data. We refer to this method as the Yahtzee procedure, and show that it performs as predicted by theoretical analysis when we apply it to data from Facebook and public voter records. PMID- 23441157 TI - Operating Cooperatively (OC) sensor for highly specific recognition of nucleic acids. AB - Molecular Beacon (MB) probes have been extensively used for nucleic acid analysis because of their ability to produce fluorescent signal in solution instantly after hybridization. The indirect binding of MB probe to a target analyte offers several advantages, including: improved genotyping accuracy and the possibility to analyse folded nucleic acids. Here we report on a new design for MB-based sensor, called 'Operating Cooperatively' (OC), which takes advantage of indirect binding of MB probe to a target analyte. The sensor consists of two unmodified DNA strands, which hybridize to a universal MB probe and a nucleic acid analyte to form a fluorescent complex. OC sensors were designed to analyze two human SNPs and E. coli 16S rRNA. High specificity of the approach was demonstrated by the detection of true analyte in over 100 times excess amount of single base substituted analytes. Taking into account the flexibility in the design and the simplicity in optimization, we conclude that OC sensors may become versatile and efficient tools for instant DNA and RNA analysis in homogeneous solution. PMID- 23441158 TI - Where have all the parasites gone? Modelling early malaria parasite sequestration dynamics. AB - Traditional approaches to measuring the level of malaria infection involve counting the proportion of parasite-infected red blood cells (iRBC) in circulating blood, known as parasitaemia. However, iRBC can also accumulate within the microvasculature of tissues and organs, a process called sequestration. Thus measurements of parasitemia do not necessarily reflect the total parasite burden (TPB). Recent experimental advances have allowed TPB measurements to be made in humans and experimental models. TPB is particularly important because it is the best current predictor of malaria disease severity and death in humans. Understanding the relationship between freely circulating iRBC versus tissue-sequestered iRBC is an important question in infection dynamics. The recent ability to experimentally measure the dynamics of iRBC in blood and tissue during murine malaria provides an exciting potential window into sequestration, but new modeling approaches are clearly required to understand these interactions. We present a model of malaria dynamics during early infection that incorporates iRBC that both circulate in the blood and sequester in tissue microvasculature. We explore the effect that perturbations to the system have on the ratio of the number of iRBC between these compartments, and consider which changes are most consistent with experimental data from mice. Using this model we predict an increase in the clearance rate of sequestered iRBCs around the time when mild symptoms become apparent, but a more pronounced increase in the rate of sequestration of iRBCs associated with the onset of severe malaria symptoms. PMID- 23441159 TI - PKCdelta as a regulator for TGFbeta1-induced alpha-SMA production in a murine nonalcoholic steatohepatitis model. AB - The precise mechanism of TGFbeta1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCdelta affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCdelta in TGFbeta1 mediated alpha-SMA expression was investigated using NASH model mice. In preparation of the NASH model, male C57BL6/J mice were fed a methionine-choline deficient (MCD) diet for 3 weeks, after which time they were intraperitoneally injected with lipopolysaccharide (LPS). In addition, Tlr4(Lps-d) (CH3/HeJ) mice were used to demonstrate the TGFbeta1 signaling's dependency on TLR4 induction. Liver histology and hepatic hepatitis markers were investigated, and hepatic gene expression levels were determined by real-time PCR. Acute liver injury by LPS injection specifically elevated not only alpha-SMA expression but also phospho PKCdelta in this model. In contrast, Tlr4(Lps-d) (CH3/HeJ) and blockade of TGFbeta1 receptor by SB431542 resulted in a significant reduction of PKCdelta activation and alpha-SMA expression. Moreover, the TGFbeta1-induced alpha-SMA production was significantly reduced by a specific PKCdelta inhibitor. These findings suggested that PKCdelta plays a critical role in TGFbeta1-induced alpha SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCdelta in the regulation of alpha-SMA expression in NASH liver tissues, and the impaired induction of PKCdelta phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCdelta inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCdelta represents a promising target for treating NASH. PMID- 23441160 TI - Identification of genes to differentiate closely related Salmonella lineages. AB - BACKGROUND: Salmonella are important human and animal pathogens. Though highly related, the Salmonella lineages may be strictly adapted to different hosts or cause different diseases, from mild local illness like gastroenteritis to fatal systemic infections like typhoid. Therefore, rapid and accurate identification of Salmonella is essential for timely and correct diagnosis of Salmonella infections. The current identification methods such as 16S rRNA sequencing and multilocus sequence typing are expensive and time consuming. Additionally, these methods often do not have sufficient distinguishing resolution among the Salmonella lineages. METHODOLOGIES/PRINCIPAL FINDINGS: We compared 27 completely sequenced Salmonella genomes to identify possible genomic features that could be used for differentiation of individual lineages. We concatenated 2372 core genes in each of the 27 genomes and constructed a neighbor-joining tree. On the tree, strains of each serotype were clustered tightly together and different serotypes were unambiguously separated with clear genetic distances, demonstrating systematic genomic divergence among the Salmonella lineages. We made detailed comparisons among the 27 genomes and identified distinct sets of genomic differences, including nucleotide variations and genomic islands (GIs), among the Salmonella lineages. Two core genes STM4261 and entF together could unambiguously distinguish all Salmonella lineages compared in this study. Additionally, strains of a lineage have a common set of GIs and closely related lineages have similar sets of GIs. CONCLUSIONS: Salmonella lineages have accumulated distinct sets of mutations and laterally acquired DNA (e.g., GIs) in evolution. Two genes entF and STM4261 have diverged sufficiently among the Salmonella lineages to be used for their differentiation. Further investigation of the distinct sets of mutations and GIs will lead to novel insights into genomic evolution of Salmonella and greatly facilitate the elucidation of pathogeneses of Salmonella infections. PMID- 23441161 TI - Increased drinking following social isolation rearing: implications for polydipsia associated with schizophrenia. AB - Primary polydipsia, excessive drinking without known medical cause, is especially associated with a diagnosis of schizophrenia. We used animal models of schizophrenia-like symptoms to examine the effects on schedule-induced polydipsia: post-weaning social isolation rearing, subchronic MK-801 treatment (an NMDA-receptor antagonist) or the two combined. Male, Sprague-Dawley rats reared in groups or in isolation beginning at postnatal day 21 were further divided to receive subchronic MK-801 (0.5 mg/kg twice daily) or saline for 7 days beginning on postnatal day 62. Following a 4-day withdrawal period, all groups were trained on a schedule-induced polydipsia paradigm. Under food-restriction, animals reared in isolation and receiving food pellets at 1-min intervals developed significantly more drinking behavior than those reared with others. The addition of subchronic MK-801 treatment did not significantly augment the amount of water consumed. These findings suggest a predisposition to polydipsia is a schizophrenia-like behavioral effect of post-weaning social isolation. PMID- 23441162 TI - HLA-B35 and dsRNA induce endothelin-1 via activation of ATF4 in human microvascular endothelial cells. AB - Endothelin 1 (ET-1) is a key regulator of vascular homeostasis. We have recently reported that the presence of Human antigen class I, HLA-B35, contributes to human dermal microvascular endothelial cell (HDMEC) dysfunction by upregulating ET-1 and proinflammatory genes. Likewise, a Toll-like receptor 3 (TLR3) ligand, Poly(I:C), was shown to induce ET-1 expression in HDMECs. The goal of this study was to determine the molecular mechanism of ET-1 induction by these two agonists. Because HLA-B35 expression correlated with induction of Binding Immunoglobulin Protein (BiP/GRP78) and several heat shock proteins, we first focused on ER stress and unfolded protein response (UPR) as possible mediators of this response. ER stress inducer, Thapsigargin (TG), HLA-B35, and Poly(I:C) induced ET 1 expression with similar potency in HDMECs. TG and HLA-B35 activated the PERK/eIF2alpha/ATF4 branch of the UPR and modestly increased the spliced variant of XBP1, but did not affect the ATF6 pathway. Poly(I:C) also activated eIF2alpha/ATF4 in a protein kinase R (PKR)-dependent manner. Depletion of ATF4 decreased basal expression levels of ET-1 mRNA and protein, and completely prevented upregulation of ET-1 by all three agonists. Additional experiments have demonstrated that the JNK and NF-kappaB pathways are also required for ET-1 upregulation by these agonists. Formation of the ATF4/c-JUN complex, but not the ATF4/NF-kappaB complex was increased in the agonist treated cells. The functional role of c-JUN in responses to HLA-B35 and Poly(I:C) was further confirmed in ET-1 promoter assays. This study identified ATF4 as a novel activator of the ET-1 gene. The ER stress/UPR and TLR3 pathways converge on eIF2alpha/ATF4 during activation of endothelial cells. PMID- 23441163 TI - Lectins offer new perspectives in the development of macrophage-targeted therapies for COPD/emphysema. AB - We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells ('efferocytosis') in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using beta-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with beta-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies. PMID- 23441164 TI - Molecular signatures associated with HCV-induced hepatocellular carcinoma and liver metastasis. AB - Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV) infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis. CONCLUSIONS: A diagnostic molecular signature complementing conventional pathologic assessment was identified. PMID- 23441165 TI - High-resolution mutational profiling suggests the genetic validity of glioblastoma patient-derived pre-clinical models. AB - Recent advances in the ability to efficiently characterize tumor genomes is enabling targeted drug development, which requires rigorous biomarker-based patient selection to increase effectiveness. Consequently, representative DNA biomarkers become equally important in pre-clinical studies. However, it is still unclear how well these markers are maintained between the primary tumor and the patient-derived tumor models. Here, we report the comprehensive identification of somatic coding mutations and copy number aberrations in four glioblastoma (GBM) primary tumors and their matched pre-clinical models: serum-free neurospheres, adherent cell cultures, and mouse xenografts. We developed innovative methods to improve the data quality and allow a strict comparison of matched tumor samples. Our analysis identifies known GBM mutations altering PTEN and TP53 genes, and new actionable mutations such as the loss of PIK3R1, and reveals clear patient-to patient differences. In contrast, for each patient, we do not observe any significant remodeling of the mutational profile between primary to model tumors and the few discrepancies can be attributed to stochastic errors or differences in sample purity. Similarly, we observe ~96% primary-to-model concordance in copy number calls in the high-cellularity samples. In contrast to previous reports based on gene expression profiles, we do not observe significant differences at the DNA level between in vitro compared to in vivo models. This study suggests, at a remarkable resolution, the genome-wide conservation of a patient's tumor genetics in various pre-clinical models, and therefore supports their use for the development and testing of personalized targeted therapies. PMID- 23441166 TI - Bridging cancer biology with the clinic: relative expression of a GRHL2-mediated gene-set pair predicts breast cancer metastasis. AB - Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e-6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2 associated clinical character (p = 6.8e-6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets. PMID- 23441167 TI - EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta analysis. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) gene copy number (GCN) has been previously demonstrated to correlate with the clinical outcome of colorectal cancer (CRC) treated with anti-EGFR monoclonal antibodies (mAbs), although it remains controversial. We conducted a systematic review and meta analysis to assess EGFR GCN as a potential biomarker of survival for patients with advanced CRC receiving treatment with anti-EGFR mAbs. METHODS: We systematically identified articles investigating EGFR GCN by fluorescent or chromogenic in situ hybridization or other detection techniques in patients with metastatic CRC treated with panitumumab or cetuximab, (last search: 10 August 2012). Eligible studies had to report on overall survival (OS), progression-free survival (PFS) or time-to-progression (TTP), stratified by EGFR GCN. Summary hazard ratios (HRs) were calculated using random-effects models. RESULTS: Among 13 identified studies, 10 (776 patients, 302 with increased GCN), 8 (893 patients, 282 with increased GCN) and 3 (149 patients, 66 with increased GCN) were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR GCN was associated with increased OS (HR = 0.62; 95% CI 0.50-0.77; P<0.001), PFS (HR = 0.65; 95% CI 0.47-0.89; P = 0.008) but not TTP (HR = 0.71; 95% CI 0.44 1.14; P = 0.157). It was also shown that EGFR GCN is independent of other factors such as KRAS status. Among those populations received second-line or higher treatment, increased EGFR GCN was strongly associated with improved survival (for OS, HR = 0.60; 95% CI 0.47-0.75; P<0.001; for PFS, HR = 0.59; 95% CI 0.47-0.75; P<0.001), whereas it did not influence survival in patients that received first line therapy. CONCLUSION: Among the anti-EGFR-treated patients, increased EGFR GCN appears to be associated with improved survival outcomes. The effect on survival appears to be related to patients receiving the line of treatment. PMID- 23441168 TI - Cognitive performance as a zeitgeber: cognitive oscillators and cholinergic modulation of the SCN entrain circadian rhythms. AB - The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals that can synchronize or entrain to environmental cues. Although light exerts powerful influences on SCN output, other non-photic stimuli can modulate the SCN as well. We recently demonstrated that daily performance of a cognitive task requiring sustained periods of attentional effort that relies upon basal forebrain (BF) cholinergic activity dramatically alters circadian rhythms in rats. In particular, normally nocturnal rats adopt a robust diurnal activity pattern that persists for several days in the absence of cognitive training. Although anatomical and pharmacological data from non-performing animals support a relationship between cholinergic signaling and circadian rhythms, little is known about how endogenous cholinergic signaling influences SCN function in behaving animals. Here we report that BF cholinergic projections to the SCN provide the principal signal allowing for the expression of cognitive entrainment in light-phase trained animals. We also reveal that oscillator(s) outside of the SCN drive cognitive entrainment as daily timed cognitive training robustly entrains SCN-lesioned arrhythmic animals. Ablation of the SCN, however, resulted in significant impairments in task acquisition, indicating that SCN-mediated timekeeping benefits new learning and cognitive performance. Taken together, we conclude that cognition entrains non-photic oscillators, and cholinergic signaling to the SCN serves as a temporal timestamp attenuating SCN photic-driven rhythms, thereby permitting cognitive demands to modulate behavior. PMID- 23441169 TI - Survival benefit of adding chemotherapy to intensity modulated radiation in patients with locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate the contribution of chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) and to identify the optimal combination treatment strategy. PATIENTS AND METHODS: Between 2006 and 2010, 276 patients with stage II IVb NPC were treated by IMRT alone or IMRT plus chemotherapy. Cisplatin-based chemotherapy included neoadjuvant or concurrent, or neoadjuvant plus concurrent protocols. The IMRT alone and chemoradiotherapy groups were well-matched for prognostic factors, except N stage, with more advanced NPC in the chemoradiotherapy arm. RESULTS: With a mean follow-up of 33.8 months, the 3-year actuarial rates of overall survival (OS), metastasis-free survival (MFS), relapse free survival (RFS), and disease-free survival (DFS) were 90.3%, 84.2%, 80.3%, and 69.2% for all of the patients, respectively. Compared with the IMRT alone arm, patients treated by concurrent chemoradiotherapy had a significantly better DFS (HR = 2.64; 95% CI, 1.12-6.22; P = 0.03), patients with neoadjuvant concurrent chemoradiotherapy had a significant improvement in RFS and DFS (HR = 4.03; 95% CI, 1.35-12.05; P = 0.01 and HR = 2.43; 95% CI, 1.09-5.44; P = 0.03), neoadjuvant chemoradiotherapy provided no significant benefit in OS, MFS, RFS, and DFS. Stage group and alcohol consumption were prognostic factors for OS and N stage was a significant predictor for DFS. CONCLUSIONS: Addition of concurrent or neoadjuvant-concurrent chemotherapy to IMRT is available to prolong RFS or DFS for locoregionally advanced NPC. Such work could be helpful to guide effective individualized therapy. PMID- 23441170 TI - Cerebral neovascularization and remodeling patterns in two different models of type 2 diabetes. AB - We previously reported intense pial cerebral collateralization and arteriogenesis in a mild and lean model of type 2 diabetes (T2D), Goto-Kakizaki (GK) rats. Increased cerebral neovascularization differed regionally and was associated with poor vessel wall maturity. Building upon these findings, the goals of this study were to determine whether a) glycemic control prevents this erratic cerebral neovascularization in the GK model, and b) this pathological neovascularization pattern occurs in Lepr(db/db) model, which is the most commonly used model of T2D for studies involving cerebral complications of diabetes. Vascular volume, surface area and structural parameters including microvessel/macrovessel ratio, non-FITC (fluorescein) perfusing vessel abundance, vessel tortuosity, and branch density were measured by 3D reconstruction of FITC stained vasculature in GK rats or Lepr(db/db) mice. GK rats exhibited an increase in all of these parameters, which were prevented by glycemic control with metformin. In Lepr(db/db) mice, microvascular density was increased but there was no change in nonFITC-perfusing vessels. Increased PA branch density was associated with reduced branch diameter. These results suggest that T2D leads to cerebral neovascularization and remodeling but some structural characteristics of newly formed vessels differ between these models of T2D. The prevention of dysfunctional cerebral neovascularization by early glucose control suggests that hyperglycemia is a mediator of this response. PMID- 23441171 TI - Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection. AB - Ebola virus (EBOV) is an enveloped RNA virus that causes hemorrhagic fever in humans and non-human primates. Infection requires internalization from the cell surface and trafficking to a late endocytic compartment, where viral fusion occurs, providing a conduit for the viral genome to enter the cytoplasm and initiate replication. In a concurrent study, we identified clomiphene as a potent inhibitor of EBOV entry. Here, we screened eleven inhibitors that target the same biosynthetic pathway as clomiphene. From this screen we identified six compounds, including U18666A, that block EBOV infection (IC(50) 1.6 to 8.0 uM) at a late stage of entry. Intriguingly, all six are cationic amphiphiles that share additional chemical features. U18666A induces phenotypes, including cholesterol accumulation in endosomes, associated with defects in Niemann-Pick C1 protein (NPC1), a late endosomal and lysosomal protein required for EBOV entry. We tested and found that all six EBOV entry inhibitors from our screen induced cholesterol accumulation. We further showed that higher concentrations of cationic amphiphiles are required to inhibit EBOV entry into cells that overexpress NPC1 than parental cells, supporting the contention that they inhibit EBOV entry in an NPC1-dependent manner. A previously reported inhibitor, compound 3.47, inhibits EBOV entry by blocking binding of the EBOV glycoprotein to NPC1. None of the cationic amphiphiles tested had this effect. Hence, multiple cationic amphiphiles (including several FDA approved agents) inhibit EBOV entry in an NPC1-dependent fashion, but by a mechanism distinct from that of compound 3.47. Our findings suggest that there are minimally two ways of perturbing NPC1-dependent pathways that can block EBOV entry, increasing the attractiveness of NPC1 as an anti filoviral therapeutic target. PMID- 23441172 TI - miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1. AB - The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-beta, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/alpha-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR 21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets. PMID- 23441173 TI - Association between MMP1 -1607 1G>2G polymorphism and head and neck cancer risk: a meta-analysis. AB - BACKGROUND: MMP1 is an important member of the MMP endopeptidase family that plays a critical role in the development of head and neck cancer (HNC). Several studies have investigated the association between the MMP1 -1607 1G>2G polymorphism and risk of HNC, but their results have been inconsistent. Here, we conducted a meta-analysis to further explore the role of the MMP1 -1607 1G>2G polymorphism in HNC development. METHODS: We identified all eligible studies in the electronic databases of PubMed, ISI Web of Knowledge, MEDLINE, Embase, and Google Scholar (from January 2000 to June 2012). A meta-analysis was performed to evaluate the association between the MMP1 -1607 1G>2G polymorphism and risk of HNC by calculating odds ratios (OR) and 95% confidence interval (CIs). RESULTS: Twelve studies were included in this meta-analysis. In overall comparison, significant associations were found using the recessive and allelic contrast models (OR, 1.38; 95% CI, 1.07-1.79 and OR, 1.27; 95% CI, 1.05-1.53, respectively), but no association was detected using the dominant model. In the stratified analyses by several variables, significant associations were observed using the recessive, dominant, and allelic contrast models in the Asian population (OR, 1.64; 95% CI, 1.29-2.08; OR, 1.39; 95% CI, 1.06-1.82; and OR, 1.41; 95% CI, 1.21-1.65, respectively), European population (OR, 0.58; 95% CI, 0.40-0.84; OR, 0.64; 95% CI, 0.44-0.92; and OR, 0.68; 95% CI, 0.54-0.85, respectively), and population-based subgroup (OR, 1.24; 95% CI,1.05-1.47; OR,1.48; 95% CI,1.04-2.12; and OR, 1.22; 95% CI, 1.07-1.38, respectively). Furthermore, significant associations were detected in oral cavity cancer and nasopharyngeal cancer under the recessive model. CONCLUSION: Our results suggest that the MMP1 -1607 1G>2G polymorphism is associated with risk of HNC and that it plays different roles in Asian and European populations. Further studies with large sample size are needed to validate our findings. PMID- 23441174 TI - Risk for high depressive symptoms in diagnosed and previously undetected diabetes: 5-year follow-up results of the Heinz Nixdorf Recall study. AB - OBJECTIVE: The objective of this study was to determine the risk for the development of high depressive symptoms in study participants with diagnosed and previously undetected diabetes mellitus compared to those without diabetes in a prospective population-based cohort study in Germany. METHODS: We estimated the 5 year cumulative incidence of high depressive symptoms in participants without high depressive symptoms at baseline (n = 3,633, 51.4% men, mean age (SD) 59.1 (7.6) years, 7.0% diagnosed diabetes, 5.3% previously undetected diabetes) from the population-based Heinz Nixdorf Recall study. Diabetes was assessed by self report, medication, and blood glucose. High depressive symptoms were assessed using CES-D. We calculated odds ratios and their corresponding 95% confidence interval, using multiple logistic regression analyses. RESULT: Cumulative 5-year incidences (95% CI) of high depressive symptoms in participants with diagnosed, undetected, and without diabetes were 7.1 (4.2-10.9), 4.1 (1.8-8.0), and 6.5 (5.6 7.4), respectively. The age-sex-adjusted OR for developing high depressive symptoms was 1.22 (0.74-2.03) in participants with diagnosed compared to those without diabetes, and 1.00 (0.59-1.68) after adjustment for BMI, physical activity, education, stroke, and myocardial infarction. The age-sex adjusted OR for developing high depressive symptoms in participants with previously undetected diabetes compared to those without diabetes was 0.72; 0.35-1.48; and fully adjusted 0.62; 0.30-1.30. CONCLUSION: We found no significant associations, maybe due to low power. However, our results are in line with a recent meta analysis suggesting that risk of developing high depressive symptoms in patients with diagnosed diabetes may be moderately higher than in those without diabetes, and that comorbidity may explain in part this association. In participants with previously undetected diabetes, this first longitudinal study indicates that the risk is not increased or may even be decreased. These results support the hypothesis that high depressive symptoms develop due to diabetes-related burden and comorbidity and not due to hyperglycemia or hyperinsulinaemia. PMID- 23441175 TI - The mitogen-activated protein kinase p38alpha regulates tubular damage in murine anti-glomerular basement membrane nephritis. AB - p38 mitogen-activated protein kinase (MAPK) is thought to play a central role in acute and chronic inflammatory responses. Whether p38MAPK plays a pathogenic role in crescentic GN (GN) and which of its four isoforms is preferentially involved in kidney inflammation is not definitely known. We thus examined expression and activation of p38MAPK isoforms during anti-glomerular basement membrane (GBM) nephritis. Therefore, p38alpha conditional knockout mice (MxCre p38alpha(Delta/Delta)) were used to examine the role of p38alpha in anti-GBM induced nephritis. Both wild type and MxCre-p38alpha(Delta/Delta) mice developed acute renal failure over time. Histological examinations revealed a reduced monocyte influx and less tubular damage in MxCre-p38alpha(Delta/Delta) mice, whereas glomerular crescent formation and renal fibrosis was similar. Likewise, the levels of pro- and anti-inflammatory cytokines such as TNF, IL-1 and IL-10 were similar, but IL-8 was even up-regulated in MxCre-p38alpha(Delta/Delta) mice. In contrast, we could detect strong down-regulation of chemotactic cytokines such as CCL-2, -5 and -7, in the kidneys of MxCre-p38alpha(Delta/Delta) mice. In conclusion, p38alpha is the primary p38MAPK isoform expressed in anti-GBM nephritis and selectively affects inflammatory cell influx and tubular damage. Full protection from nephritis is however not achieved as renal failure and structural damage still occurs. PMID- 23441176 TI - Imaging of intratumoral inflammation during oncolytic virotherapy of tumors by 19F-magnetic resonance imaging (MRI). AB - BACKGROUND: Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate (19)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy. METHODOLOGY/PRINCIPAL FINDINGS: The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by (1)H/(19)F MRI of mock-infected and GLV-1h68 infected tumor-bearing mice revealed a significant accumulation of the (19)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the (19)F signal hot spots and CD68(+)-macrophages. Thereby, the CD68(+)-macrophages encapsulate the GFP positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the (19)F signal correlated with the extent of viral spreading within tumors. CONCLUSIONS/SIGNIFICANCE: These results suggest (19)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, (19)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response. PMID- 23441177 TI - Identification of a novel protein-protein interaction motif mediating interaction of GPCR-associated sorting proteins with G protein-coupled receptors. AB - GPCR desensitization and down-regulation are considered key molecular events underlying the development of tolerance in vivo. Among the many regulatory proteins that are involved in these complex processes, GASP-1 have been shown to participate to the sorting of several receptors toward the degradation pathway. This protein belongs to the recently identified GPCR-associated sorting proteins (GASPs) family that comprises ten members for which structural and functional details are poorly documented. We present here a detailed structure-function relationship analysis of the molecular interaction between GASPs and a panel of GPCRs. In a first step, GST-pull down experiments revealed that all the tested GASPs display significant interactions with a wide range of GPCRs. Importantly, the different GASP members exhibiting the strongest interaction properties were also characterized by the presence of a small, highly conserved and repeated "GASP motif" of 15 amino acids. We further showed using GST-pull down, surface plasmon resonance and co-immunoprecipitation experiments that the central domain of GASP-1, which contains 22 GASP motifs, is essential for the interaction with GPCRs. We then used site directed mutagenesis and competition experiments with synthetic peptides to demonstrate that the GASP motif, and particularly its highly conserved core sequence SWFW, is critically involved in the interaction with GPCRs. Overall, our data show that several members of the GASP family interact with GPCRs and highlight the presence within GASPs of a novel protein protein interaction motif that might represent a new target to investigate the involvement of GASPs in the modulation of the activity of GPCRs. PMID- 23441178 TI - Relative contributions of Vibrio polysaccharide and quorum sensing to the resistance of Vibrio cholerae to predation by heterotrophic protists. AB - Protozoan grazing is a major mortality factor faced by bacteria in the environment. Vibrio cholerae, the causative agent of the disease cholera, is a natural inhabitant of aquatic ecosystems, and its survival depends on its ability to respond to stresses, such as predation by heterotrophic protists. Previous results show that grazing pressure induces biofilm formation and enhances a smooth to rugose morphotypic shift, due to increased expression of Vibrio polysaccharide (VPS). In addition to negatively controlling vps genes, the global quorum sensing (QS) regulator, HapR, plays a role in grazing resistance as the DeltahapR strain is efficiently consumed while the wild type (WT) is not. Here, the relative and combined contributions of VPS and QS to grazing resistance were investigated by exposing VPS and HapR mutants and double mutants in VPS and HapR encoding genes at different phases of biofilm development to amoeboid and flagellate grazers. Data show that the WT biofilms were grazing resistant, the VPS mutants were less resistant than the WT strain, but more resistant than the QS mutant strain, and that QS contributes to grazing resistance mainly in mature biofilms. In addition, grazing effects on biofilms of mixed WT and QS mutant strains were investigated. The competitive fitness of each strain in mixed biofilms was determined by CFU and microscopy. Data show that protozoa selectively grazed the QS mutant in mixed biofilms, resulting in changes in the composition of the mixed community. A small proportion of QS mutant cells which comprised 4% of the mixed biofilm biovolume were embedded in grazing resistant WT microcolonies and shielded from predation, indicating the existence of associational protection in mixed biofilms. PMID- 23441179 TI - Complete genome analysis of the C4 subgenotype strains of enterovirus 71: predominant recombination C4 viruses persistently circulating in China for 14 years. AB - Genetic recombination is a well-known phenomenon for enteroviruses. To investigate the genetic characterization and the potential recombination of enterovirus 71 (EV71) circulating in China, we determined the 16 complete genome sequences of EV71 isolated from Hand Foot Mouth Disease (HFMD) patients during the large scale outbreak and non-outbreak years since 1998 in China. The full length genome sequences of 16 Chinese EV71 in present study were aligned with 186 genome sequences of EV71 available from GenBank, including 104 China mainland and 82 international sequences, covering the time period of 1970-2011. The oldest strains of each subgenotype of EV71 and prototype strains of HEV-A were included to do the phylogenetic and Simplot analysis. Phylogenetic analysis indicated that all Chinese strains were clustered into C4 subgenotype of EV71, except for HuB/CHN/2009 clustered into A and Xiamen/CHN/2009 clustered into B5 subgenotype. Most of C4 EV71 were clustered into 2 predominant evolutionary branches: C4b and C4a evolutionary brunches. Our comprehensive recombination analysis showed the evidence of genome recombination of subgenotype C4 (including C4a and C4b) sequences between structural genes from genotype C EV71 and non-structural genes from the prototype strains of CAV16, 14 and 4, but the evidence of intratypic recombination between C4 strains and B subgenotype was not enough strong. This intertypic recombination C4 viruses were first seen in 1998 and became the predominant endemic viruses circulating in China mainland for at least 14 years. A shift between C4a and C4b evolutionary brunches of C4 recombination viruses were observed, and C4a viruses have been associated with large scale nationwide HFMD outbreak with higher morbidity and mortality since 2007. PMID- 23441180 TI - Genetic analysis of grain filling rate using conditional QTL mapping in maize. AB - The grain filling rate (GFR) is an important dynamic trait that determines the final grain yield and is controlled by a network of genes and environment factors. To determine the genetic basis of the GFR, a conditional quantitative trait locus (QTL) analysis method was conducted using time-related phenotypic values of the GFR collected from a set of 243 immortalized F(2) (IF(2)) population, which were evaluated at two locations over 2 years. The GFR gradually rose in the 0-15 days after pollination (DAP) and 16-22 DAP, reaching a maximum at 23-29 DAP, and then gradually decreasing. The variation of kernel weight (KW) was mainly decided by the GFR, and not by the grain filling duration (GFD). Thirty-three different unconditional QTLs were identified for the GFR at the six sampling stages over 2 years. Among them, QTLs qGFR7b, qGFR9 and qGFR6d were identified at the same stages at two locations over 2 years. In addition, 14 conditional QTLs for GFR were detected at five stages. The conditional QTL qGFR7c was identified at stage V|IV (37-43 DAP) at two locations over 2 years, and qGFR7b was detected at the sixth stage (44-50 DAP) in all four environments, except at Anyang location in 2009. QTLs qQTL7b and qQTL6f were identified by unconditional and conditional QTL mapping at the same stages, and might represent major QTLs for regulating the GFR in maize in the IF(2) population. Moreover, most of the QTLs identified were co-located with QTLs from previous studies that were associated with GFR, enzyme activities of starch synthesis, soluble carbohydrates, and grain filling related genes. These results indicated that the GFR is regulated by many genes, which are specifically expressed at different grain filling stages, and the specific expression of the genes between 16-35 DAP might be very important for deciding the final kernel weight. PMID- 23441181 TI - Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema. AB - RATIONALE: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. METHODS: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. MAIN RESULTS: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. CONCLUSIONS: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. PMID- 23441182 TI - Identification of a novel nonsense mutation p.Tyr1957Ter of CACNA1A in a Chinese family with episodic ataxia 2. AB - Type 2 episodic ataxia (EA2) is the most common subtype among a group of rare hereditary syndromes characterized by recurrent attacks of ataxia. More than 60 mutations and several gene rearrangements due to large deletions in CACNA1A gene have been reported so far for the cause of EA2. Because CACNA1A gene is a large gene containing 47 exons and there is no hot spot mutation, direct sequencing will be a challenge in clinical genetic testing. In this study, we used next generation sequencing technology to identify a novel nonsense mutation of CACNA1A (p.Tyr1957Ter, NP_001120693.1) resulting in truncated protein without 305 amino acids in the c-terminus. Sanger sequencing confirmed the heterozygous mutation of CACNA1A in a Chinese family with 11 affected individuals. Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain. This is the first report of EA2 in a Chinese family that carries a novel mutation in CACNA1A gene and had abdominal pain as a novel phenotype associated with EA2. PMID- 23441183 TI - Pramanicin analog induces apoptosis in human colon cancer cells: critical roles for Bcl-2, Bim, and p38 MAPK signaling. AB - Pramanicin (PMC) is an antifungal agent that was previously demonstrated to exhibit antiangiogenic and anticancer properties in a few in vitro studies. We initially screened a number of PMC analogs for their cytotoxic effects on HCT116 human colon cancer cells. PMC-A, the analog with the most potent antiproliferative effect was chosen to further interrogate the underlying mechanism of action. PMC-A led to apoptosis through activation of caspase-9 and 3. The apoptotic nature of cell death was confirmed by abrogation of cell death with pretreatment with specific caspase inhibitors. Stress-related MAPKs JNK and p38 were both activated concomittantly with the intrinsic apoptotic pathway. Moreover, pharmacological inhibition of p38 proved to attenuate the cell death induction while pretreatment with JNK inhibitor did not exhibit a protective effect. Resistance of Bax -/- cells and the protective nature of caspase-9 inhibition indicate that mitochondria play a central role in PMC-A induced apoptosis. Early post-exposure elevation of cellular Bim and Bax was followed by a marginal Bcl-2 depletion and Bid cleavage. Further analysis revealed that Bcl-2 downregulation occurs at the mRNA level and is critical to mediate PMC-A induced apoptosis, as ectopic Bcl-2 expression substantially spared the cells from death. Conversely, forced expression of Bim proved to significantly increase cell death. In addition, analyses of p53-/- cells demonstrated that Bcl-2/Bim/Bax modulation and MAPK activations take place independently of p53 expression. Taken together, p53-independent transcriptional Bcl-2 downregulation and p38 signaling appear to be the key modulatory events in PMC-A induced apoptosis. PMID- 23441184 TI - Blood-brain barrier permeability of normal appearing white matter in relapsing remitting multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) affects the integrity of the blood-brain barrier (BBB). Contrast-enhanced T1 weighted magnetic resonance imaging (MRI) is widely used to characterize location and extent of BBB disruptions in focal MS lesions. We employed quantitative T1 measurements before and after the intravenous injection of a paramagnetic contrast agent to assess BBB permeability in the normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS). METHODOLOGY/PRINCIPAL FINDINGS: Fifty-nine patients (38 females) with RR-MS undergoing immunomodulatory treatment and nine healthy controls (4 females) underwent quantitative T1 measurements at 3 tesla before and after injection of a paramagnetic contrast agent (0.2 mmol/kg Gd-DTPA). Mean T1 values were calculated for NAWM in patients and total cerebral white matter in healthy subjects for the T1 measurements before and after injection of Gd-DTPA. The pre-injection baseline T1 of NAWM (945+/-55 [SD] ms) was prolonged in RR-MS relative to healthy controls (903+/-23 ms, p = 0.028). Gd-DTPA injection shortened T1 to a similar extent in both groups. Mean T1 of NAWM was 866+/-47 ms in the NAWM of RR-MS patients and 824+/-13 ms in the white matter of healthy controls. The regional variability of T1 values expressed as the coefficient of variation (CV) was comparable between the two groups at baseline, but not after injection of the contrast agent. After intravenous Gd-DTPA injection, T1 values in NAWM were more variable in RR-MS patients (CV = 0.198+/-0.046) compared to cerebral white matter of healthy controls (CV = 0.166+/-0.018, p = 0.046). CONCLUSIONS/SIGNIFICANCE: We found no evidence of a global BBB disruption within the NAWM of RR-MS patients undergoing immunomodulatory treatment. However, the increased variation of T1 values in NAWM after intravenous Gd-DTPA injection points to an increased regional inhomogeneity of BBB function in NAWM in relapsing-remitting MS. PMID- 23441185 TI - Optimal low temperature and chilling period for both summer and winter diapause development in Pieris melete: based on a similar mechanism. AB - The cabbage butterfly, Pieris melete hibernates and aestivates as a diapausing pupa. We present evidence that the optimum of low temperature and optimal chilling periods for both summer and winter diapause development are based on a similar mechanism. Summer or winter diapausing pupae were exposed to different low temperatures of 1, 5, 10 or 15 degrees C for different chilling periods (ranging from 30 to 120 d) or chilling treatments started at different stages of diapause, and were then transferred to 20 degrees C, LD12.5:11.5 to terminate diapause. Chilling temperature and duration had a significant effect on the development of aestivating and hibernating pupae. The durations of diapause for both aestivating and hibernating pupae were significantly shorter when they were exposed to low temperatures of 1, 5 or 10 degrees C for 50 or 60 days, suggesting that the optimum chilling temperatures for diapause development were between 1 and 10 degrees C and the required optimal chilling period was about 50-60 days. Eighty days of chilling was efficient for the completion of both summer and winter diapause. When chilling periods were >=90 days, the durations of summer and winter diapause were significantly lengthened; however, the adult emergence was more synchronous. The adaptive significance of a similar mechanism on summer and winter diapause development is discussed. PMID- 23441186 TI - Ex vivo-growth response of porcine small intestinal bacterial communities to pharmacological doses of dietary zinc oxide. AB - Piglets were fed diets containing 57 (low) or 2425 (high) mg zinc from analytical grade zinc oxide (ZnO) .kg(-1) feed. Digesta samples from the stomach and jejuna of 32, 39, 46 and 53 d old animals (n = 6 per group) were incubated in media containing 80, 40, 20 and 0 ug.mL(-1) soluble zinc from ZnO. Turbidity was recorded for 16 h and growth parameters were calculated. Additionally, DNA extracts of selected samples were analyzed via qPCR for different bacterial groups. Samples from animals fed the low dietary zinc concentration always showed highest rate of growth and lowest lag times in media without added zinc. However, media supplemented with zinc displayed highest growth rates and lowest lag time in the high dietary zinc group. Specific growth rates and lag time showed significant differences on day 32 and 39 of age, but rarely on days 46 and 53 of age. Bacterial growth in digesta samples from the high dietary zinc group was less influenced by zinc and recovered growth more rapidly than in the low dietary zinc group. Specific growth rates and bacterial cell numbers from qPCR results showed that lactobacilli were most susceptible to zinc, while bifidobacteria, enterobacteria and enterococci exhibited increased growth rates in samples of animals from the high dietary zinc treatment. No treatment related differences were observed for clostridial cluster IV and the Bacteroides-Prevotella Porphyromonas cluster. The diversity of enterobacteria after incubation was always higher in the high dietary zinc treatment or in medium supplemented with 80 ug.mL(-1) soluble ZnO. This study has shown that a pharmacological dosage of ZnO leads to a reduced ex vivo-bacterial growth rate of bacteria from the stomach and jejunum of weaned piglets. In view of the rapid bacterial adaptation to dietary zinc, the administration of ZnO in feeds for weaned piglets might only be beneficial in a short period after weaning. PMID- 23441187 TI - Uric acid spherulites in the reflector layer of firefly light organ. AB - BACKGROUND: In firefly light organs, reflector layer is a specialized tissue which is believed to play a key role for increasing the bioluminescence intensity through reflection. However, the nature of this unique tissue remains elusive. In this report, we investigated the role, fine structure and nature of the reflector layer in the light organ of adult Luciola cerata. PRINCIPAL FINDINGS: Our results indicated that the reflector layer is capable of reflecting bioluminescence, and contains abundant uric acid. Electron microscopy (EM) demonstrated that the cytosol of the reflector layer's cells is filled with densely packed spherical granules, which should be the uric acid granules. These granules are highly regular in size (~700 nm in diameter), and exhibit a radial internal structure. X ray diffraction (XRD) analyses revealed that an intense single peak pattern with a d-spacing value of 0.320 nm is specifically detected in the light organ, and is highly similar to the diffraction peak pattern and d-spacing value of needle formed crystals of monosodium urate monohydrate. However, the molar ratio evaluation of uric acid to various cations (K(+), Na(+), Ca(2+) and Mg(2+)) in the light organ deduced that only a few uric acid molecules were in the form of urate salts. Thus, non-salt uric acid should be the source of the diffraction signal detected in the light organ. CONCLUSIONS: In the light organ, the intense single peak diffraction signal might come from a unique needle-like uric acid form, which is different from other known structures of non-salt uric acid form. The finding of a radial structure in the granules of reflector layer implies that the spherical uric acid granules might be formed by the radial arrangement of needle-formed packing matter. PMID- 23441188 TI - Genomic EWS-FLI1 fusion sequences in Ewing sarcoma resemble breakpoint characteristics of immature lymphoid malignancies. AB - Chromosomal translocations between the EWS gene and members of the ETS gene family are characteristic molecular features of the Ewing sarcoma. The most common translocation t(11;22)(q24;q12) fuses the EWS gene to FLI1, and is present in 85-90% of Ewing sarcomas. In the present study, a specifically designed multiplex long-range PCR assay was applied to amplify genomic EWS-FLI1 fusion sites from as little as 100 ng template DNA. Characterization of the EWS-FLI1 fusion sites of 42 pediatric and young adult Ewing sarcoma patients and seven cell lines revealed a clustering in the 5' region of the EWS-breakpoint cluster region (BCR), in contrast to random distribution of breakpoints in the FLI1-BCR. No association of breakpoints with various recombination-inducing sequence motifs was identified. The occurrence of small deletions and duplications at the genomic junction is characteristic of involvement of the non-homologous end-joining (NHEJ) repair system, similar to findings at chromosomal breakpoints in pediatric leukemia and lymphoma. PMID- 23441189 TI - Comparison of the genome-wide DNA methylation profiles between fast-growing and slow-growing broilers. AB - INTRODUCTION: Growth traits are important in poultry production, however, little is known for its regulatory mechanism at epigenetic level. Therefore, in this study, we aim to compare DNA methylation profiles between fast- and slow-growing broilers in order to identify candidate genes for chicken growth. Methylated DNA immunoprecipitation-sequencing (MeDIP-seq) was used to investigate the genome wide DNA methylation pattern in high and low tails of Recessive White Rock (WRR(h); WRR(l)) and that of Xinhua Chickens (XH(h); XH(l)) at 7 weeks of age. The results showed that the average methylation density was the lowest in CGIs followed by promoters. Within the gene body, the methylation density of introns was higher than that of UTRs and exons. Moreover, different methylation levels were observed in different repeat types with the highest in LINE/CR1. Methylated CGIs were prominently distributed in the intergenic regions and were enriched in the size ranging 200-300 bp. In total 13,294 methylated genes were found in four samples, including 4,085 differentially methylated genes of WRR(h) Vs. WRR(l), 5,599 of XH(h) Vs. XH(l), 4,204 of WRR(h) Vs. XH(h), as well as 7,301 of WRR(l) Vs. XH(l). Moreover, 132 differentially methylated genes related to growth and metabolism were observed in both inner contrasts (WRR(h) Vs. WRR(l) and XH(h) Vs. XH(l)), whereas 129 differentially methylated genes related to growth and metabolism were found in both across-breed contrasts (WRR(h) Vs. XH(h) and WRR(l) Vs. XH(l)). Further analysis showed that overall 75 genes exhibited altered DNA methylation in all four contrasts, which included some well-known growth factors of IGF1R, FGF12, FGF14, FGF18, FGFR2, and FGFR3. In addition, we validate the MeDIP-seq results by bisulfite sequencing in some regions. CONCLUSIONS: This study revealed the global DNA methylation pattern of chicken muscle, and identified candidate genes that potentially regulate muscle development at 7 weeks of age at methylation level. PMID- 23441190 TI - A remote cis-acting variant at 3q links glomerular NCK1 to diabetic nephropathy. AB - We have previously reported genetic association of a single nucleotide polymorphism (SNP), rs1866813, at 3q locus with increased risk of diabetic nephropathy (DN). The SNP is located approximately 70 kb downstream of a cluster of four genes. This raises a question how the remote noncoding polymorphism affects the risk of DN. In this study, we tested a long-range regulatory potential of this variant by a series of experiments. In a luciferase assay, two alleles of the SNP showed differential effects on the luciferase activity in transfected cells in vitro. Using transgenic zebrafish, we further demonstrated in vivo that two alleles of the SNP differentially regulated GFP expression in zebrafish podocytes. Immunofluorescence staining and Western blotting verified that only Nck1 of the four nearby genes was predominantly expressed in mouse glomeruli as well as in podocytes. Furthermore, genotypes of the SNP rs1866813 were correlated with NCK1 expression in immortalized lymphocytes from diabetic patients. The risk allele was associated with increased NCK1 expression compared to the non-risk allele, consistent with the results of the reporter-based studies. Interestingly, differential expression of glomerular Nck1 between mouse strains carrying the nephropathy-prone 129/Sv allele and nephropathy-resistant C57BL/6 allele was also observed. Our results show that the DN-associated SNP rs1866813 is a remote cis-acting variant differentially regulating glomerular NCK1 expression. This finding implicates an important role for glomerular NCK1 in DN pathogenesis under hyperglycemia. PMID- 23441191 TI - Cyclic game dynamics driven by iterated reasoning. AB - Recent theories from complexity science argue that complex dynamics are ubiquitous in social and economic systems. These claims emerge from the analysis of individually simple agents whose collective behavior is surprisingly complicated. However, economists have argued that iterated reasoning--what you think I think you think--will suppress complex dynamics by stabilizing or accelerating convergence to Nash equilibrium. We report stable and efficient periodic behavior in human groups playing the Mod Game, a multi-player game similar to Rock-Paper-Scissors. The game rewards subjects for thinking exactly one step ahead of others in their group. Groups that play this game exhibit cycles that are inconsistent with any fixed-point solution concept. These cycles are driven by a "hopping" behavior that is consistent with other accounts of iterated reasoning: agents are constrained to about two steps of iterated reasoning and learn an additional one-half step with each session. If higher order reasoning can be complicit in complex emergent dynamics, then cyclic and chaotic patterns may be endogenous features of real-world social and economic systems. PMID- 23441192 TI - Human concentrative nucleoside transporter 3 transfection with ultrasound and microbubbles in nucleoside transport deficient HEK293 cells greatly increases gemcitabine uptake. AB - Gemcitabine is a hydrophilic clinical anticancer drug that requires nucleoside transporters to cross plasma membranes and enter cells. Pancreatic adenocarcinomas with low levels of nucleoside transporters are generally resistant to gemcitabine and are currently a clinical problem. We tested whether transfection of human concentrative nucleoside transporter 3 (hCNT3) using ultrasound and lipid stabilized microbubbles could increase gemcitabine uptake and sensitivity in HEK293 cells made nucleoside transport deficient by pharmacologic treatment with dilazep. To our knowledge, no published data exists regarding the utility of using hCNT3 as a therapeutic gene to reverse gemcitabine resistance. Our ultrasound transfection system--capable of transfection of cell cultures, mouse muscle and xenograft CEM/araC tumors--increased hCNT3 mRNA and (3)H-gemcitabine uptake by >2,000- and 3,400-fold, respectively, in dilazep treated HEK293 cells. Interestingly, HEK293 cells with both functional human equilibrative nucleoside transporters and hCNT3 displayed 5% of (3)H-gemcitabine uptake observed in cells with only functional hCNT3, suggesting that equilibrative nucleoside transporters caused significant efflux of (3)H gemcitabine. Efflux assays confirmed that dilazep could inhibit the majority of (3)H-gemcitabine efflux from HEK293 cells, suggesting that hENTs were responsible for the majority of efflux from the tested cells. Oocyte uptake transport assays were also performed and provided support for our hypothesis. Gemcitabine uptake and efflux assays were also performed on pancreatic cancer AsPC-1 and MIA PaCa-2 cells with similar results to that of HEK293 cells. Using the MTS proliferation assay, dilazep-treated HEK293 cells demonstrated 13-fold greater resistance to gemcitabine compared to dilazep-untreated HEK293 cells and this resistance could be reversed by transfection of hCNT3 cDNA. We propose that transfection of hCNT3 cDNA using ultrasound and microbubbles may be a method to reverse gemcitabine resistance in pancreatic tumors that have little nucleoside transport activity which are resistant to almost all current anticancer therapies. PMID- 23441193 TI - Accuracy of p53 codon 72 polymorphism status determined by multiple laboratory methods: a latent class model analysis. AB - INTRODUCTION: Studies on the association of a polymorphism in codon 72 of the p53 tumour suppressor gene (rs1042522) with cervical neoplasia have inconsistent results. While several methods for genotyping p53 exist, they vary in accuracy and are often discrepant. METHODS: We used latent class models (LCM) to examine the accuracy of six methods for p53 determination, all conducted by the same laboratory. We also examined the association of p53 with cytological cervical abnormalities, recognising potential test inaccuracy. RESULTS: Pairwise disagreement between laboratory methods occurred approximately 10% of the time. Given the estimated true p53 status of each woman, we found that each laboratory method is most likely to classify a woman to her correct status. Arg/Arg women had the highest risk of squamous intraepithelial lesions (SIL). Test accuracy was independent of cytology. There was no strong evidence for correlations of test errors. DISCUSSION: Empirical analyses ignore possible laboratory errors, and so are inherently biased, but test accuracy estimated by the LCM approach is unbiased when model assumptions are met. LCM analysis avoids ambiguities arising from empirical test discrepancies, obviating the need to regard any of the methods as a "gold" standard measurement. The methods we presented here to analyse the p53 data can be applied in many other situations where multiple tests exist, but where none of them is a gold standard. PMID- 23441194 TI - Enhanced effectivity of an ALK5-inhibitor after cell-specific delivery to hepatic stellate cells in mice with liver injury. AB - Transforming growth factor-beta (TGF-beta) is a major pro-fibrotic cytokine, causing the overproduction of extracellular matrix molecules in many fibrotic diseases. Inhibition of its type-I receptor (ALK5) has been shown to effectively inhibit fibrosis in animal models. However, apart from its pro-fibrotic effects, TGF-beta also has a regulatory role in the immune system and influences tumorigenesis, which limits the use of inhibitors. We therefore explored the cell specific delivery of an ALK5-inhibitor to hepatic stellate cells, a key cell in the development of liver fibrosis. We synthesized a conjugate of the ALK5 inhibitor LY-364947 coupled to mannose-6-phosphate human serum albumin (M6PHSA), which binds to the insulin-like growth factor II receptor on activated HSC. The effectivity of the conjugate was evaluated in primary HSC and in an acute liver injury model in mice. In vitro, the free drug and the conjugate significantly inhibited fibrotic markers in HSC. In hepatocytes, TGF-beta-dependent signaling was inhibited by free drug, but not by the conjugate, thus showing its cell specificity. In vivo, the conjugate localized in desmin-positive cells in the liver and not in hepatocytes or immune cells. In the acute liver injury model in mice, the conjugate reduced fibrogenic markers and collagen deposition more effectively than free drug. We conclude that we can specifically deliver an ALK5 inhibitor to HSC using the M6PHSA carrier and that this targeted drug reduces fibrogenic parameters in vivo, without affecting other cell-types. PMID- 23441195 TI - Study on invadopodia formation for lung carcinoma invasion with a microfluidic 3D culture device. AB - Invadopodia or invasive feet, which are actin-rich membrane protrusions with matrix degradation activity formed by invasive cancer cells, are a key determinant in the malignant invasive progression of tumors and represent an important target for cancer therapies. In this work, we presented a microfluidic 3D culture device with continuous supplement of fresh media via a syringe pump. The device mimicked tumor microenvironment in vivo and could be used to assay invadopodia formation and to study the mechanism of human lung cancer invasion. With this device, we investigated the effects of epidermal growth factor (EGF) and matrix metalloproteinase (MMP) inhibitor, GM6001 on invadopodia formation by human non-small cell lung cancer cell line A549 in 3D matrix model. This device was composed of three units that were capable of achieving the assays on one control group and two experimental groups' cells, which were simultaneously pretreated with EGF or GM6001 in parallel. Immunofluorescence analysis of invadopodia formation and extracellular matrix degradation was conducted using confocal imaging system. We observed that EGF promoted invadopodia formation by A549 cells in 3D matrix and that GM6001 inhibited the process. These results demonstrated that epidermal growth factor receptor (EGFR) signaling played a significant role in invadopodia formation and related ECM degradation activity. Meanwhile, it was suggested that MMP inhibitor (GM6001) might be a powerful therapeutic agent targeting invadopodia formation in tumor invasion. This work clearly demonstrated that the microfluidic-based 3D culture device provided an applicable platform for elucidating the mechanism of cancer invasion and could be used in testing other anti-invasion agents. PMID- 23441197 TI - Magnetic separation and antibiotics selection enable enrichment of cells with ZFN/TALEN-induced mutations. AB - The ability to enrich cells with targeted mutations greatly facilitates the process of using engineered nucleases, including zinc-finger nucleases and transcription activator-like effector nucleases, to construct such cells. We previously used surrogate reporters to enrich cells containing nuclease-induced mutations via flow cytometry. This method is, however, limited by the availability of flow cytometers. Furthermore, sorted cells occasionally fail to form colonies after exposure to a strong laser and hydrostatic pressure. Here we describe two different types of novel reporters that enable mutant cell enrichment without the use of flow cytometers. We designed reporters that express H-2K(k), a surface antigen, and the hygromycin resistance protein (Hygro(R)), respectively, when insertions or deletions are generated at the target sequences by the activity of engineered nucleases. After cotransfection of these reporters and the engineered nuclease-encoding plasmids, H-2K(k)- and Hygro(R)-expressing cells were isolated using magnetic separation and hygromycin treatment, respectively. We found that mutant cells were drastically enriched in the isolated cells, suggesting that these two reporters enable efficient enrichment of mutants. We propose that these two reporters will greatly facilitate the use of engineered nucleases in a wider range of biomedical research. PMID- 23441196 TI - CRISPR-Cas systems in the cyanobacterium Synechocystis sp. PCC6803 exhibit distinct processing pathways involving at least two Cas6 and a Cmr2 protein. AB - The CRISPR-Cas (Clustered Regularly Interspaced Short Palindrome Repeats--CRISPR associated proteins) system provides adaptive immunity in archaea and bacteria. A hallmark of CRISPR-Cas is the involvement of short crRNAs that guide associated proteins in the destruction of invading DNA or RNA. We present three fundamentally distinct processing pathways in the cyanobacterium Synechocystis sp. PCC6803 for a subtype I-D (CRISPR1), and two type III systems (CRISPR2 and CRISPR3), which are located together on the plasmid pSYSA. Using high-throughput transcriptome analyses and assays of transcript accumulation we found all CRISPR loci to be highly expressed, but the individual crRNAs had profoundly varying abundances despite single transcription start sites for each array. In a computational analysis, CRISPR3 spacers with stable secondary structures displayed a greater ratio of degradation products. These structures might interfere with the loading of the crRNAs into RNP complexes, explaining the varying abundancies. The maturation of CRISPR1 and CRISPR2 transcripts depends on at least two different Cas6 proteins. Mutation of gene sll7090, encoding a Cmr2 protein led to the disappearance of all CRISPR3-derived crRNAs, providing in vivo evidence for a function of Cmr2 in the maturation, regulation of expression, Cmr complex formation or stabilization of CRISPR3 transcripts. Finally, we optimized CRISPR repeat structure prediction and the results indicate that the spacer context can influence individual repeat structures. PMID- 23441198 TI - The roles of macrophages and nitric oxide in interleukin-3-enhanced HSV-Sr39tk mediated prodrug therapy. AB - The herpes simplex virus thymidine kinase/ganciclovir (HSV-sr39tk/GCV) system is a well-established prodrug system used in cancer gene therapy. However, this system is currently not effective enough to eradicate malignant tumors completely. This study aimed to evaluate whether co-expression of interleukin-3 (IL-3) could enhance the anti-tumor activity of HSV-sr39tk/GCV prodrug gene therapy using a murine TRAMP-C1 prostate tumor model. In vitro results demonstrated that HSV-sr39tk-transfected cells exhibited enhanced sensitivity to the GCV prodrug, which was not affected by co-expression of the mIL-3 gene. However, in vivo studies showed that co-expression of the mIL-3 gene significantly increased the HSV-sr39tk/GCV-induced tumor growth delay and even cured the tumor. The TRAMP-C1-specific immune response of spleen lymphocytes from mice bearing HSV-sr39tk- and IL-3-expressing TRAMP-C1 tumors was measured by ELISA. Results showed that IL-3-activated IL-4-dominant lymphocytes became IFN gamma- dominant lymphocytes after combined HSV-sr39tk/GCV therapy. The efficacy of combined therapies on tumor regression was reduced when macrophages populations were depleted by carrageenan or NO production was inhibited by administration of the iNOS inhibitor, L-NAME. These results suggest that utilizing a bicistronic vector to express HSV-sr39tk and the IL-3 gene induced an enhanced macrophage- or NO-dependent anti-tumor effect. PMID- 23441199 TI - A new low cost wide-field illumination method for photooxidation of intracellular fluorescent markers. AB - Analyzing cell morphology is crucial in the fields of cell biology and neuroscience. One of the main methods for evaluating cell morphology is by using intracellular fluorescent markers, including various commercially available dyes and genetically encoded fluorescent proteins. These markers can be used as free radical sources in photooxidation reactions, which in the presence of diaminobenzidine (DAB) forms an opaque and electron-dense precipitate that remains localized within the cellular and organelle membranes. This method confers many methodological advantages for the investigator, including absence of photo-bleaching, high visual contrast and the possibility of correlating optical imaging with electron microscopy. However, current photooxidation techniques require the continuous use of fluorescent or confocal microscopes, which wastes valuable mercury lamp lifetime and limits the conversion process to a few cells at a time. We developed a low cost optical apparatus for performing photooxidation reactions and propose a new procedure that solves these methodological restrictions. Our "photooxidizer" consists of a high power light emitting diode (LED) associated with a custom aluminum and acrylic case and a microchip-controlled current source. We demonstrate the efficacy of our method by converting intracellular DiI in samples of developing rat neocortex and post mortem human retina. DiI crystals were inserted in the tissue and allowed to diffuse for 20 days. The samples were then processed with the new photooxidation technique and analyzed under optical microscopy. The results show that our protocols can unveil the fine morphology of neurons in detail. Cellular structures such as axons, dendrites and spine-like appendages were well defined. In addition to its low cost, simplicity and reliability, our method precludes the use of microscope lamps for photooxidation and allows the processing of many labeled cells simultaneously in relatively large tissue samples with high efficacy. PMID- 23441201 TI - The root herbivore history of the soil affects the productivity of a grassland plant community and determines plant response to new root herbivore attack. AB - Insect root herbivores can alter plant community structure by affecting the competitive ability of single plants. However, their effects can be modified by the soil environment. Root herbivory itself may induce changes in the soil biota community, and it has recently been shown that these changes can affect plant growth in a subsequent season or plant generation. However, so far it is not known whether these root herbivore history effects (i) are detectable at the plant community level and/or (ii) also determine plant species and plant community responses to new root herbivore attack. The present greenhouse study determined root herbivore history effects of click beetle larvae (Elateridae, Coleoptera, genus Agriotes) in a model grassland plant community consisting of six common species (Achillea millefolium, Plantago lanceolata, Taraxacum officinale, Holcus lanatus, Poa pratensis, Trifolium repens). Root herbivore history effects were generated in a first phase of the experiment by growing the plant community in soil with or without Agriotes larvae, and investigated in a second phase by growing it again in the soils that were either Agriotes trained or not. The root herbivore history of the soil affected plant community productivity (but not composition), with communities growing in root herbivore trained soil producing more biomass than those growing in untrained soil. Additionally, it influenced the response of certain plant species to new root herbivore attack. Effects may partly be explained by herbivore-induced shifts in the community of arbuscular mycorrhizal fungi. The root herbivore history of the soil proved to be a stronger driver of plant growth on the community level than an actual root herbivore attack which did not affect plant community parameters. History effects have to be taken into account when predicting the impact of root herbivores on grasslands. PMID- 23441200 TI - Diaphanous homolog 3 (Diap3) overexpression causes progressive hearing loss and inner hair cell defects in a transgenic mouse model of human deafness. AB - We previously demonstrated that a mutation in the 5' untranslated region of Diaphanous homolog 3 (DIAPH3) results in 2 to 3-fold overexpression of the gene, leading to a form of delayed onset, progressive human deafness known as AUNA1 (auditory neuropathy, nonsyndromic, autosomal dominant, 1). To investigate the mechanism of deafness, we generated two lines of transgenic mice overexpressing Diap3, the murine ortholog of DIAPH3, on an FVB/NJ background. Line 771 exhibits a relatively mild 20 dB hearing loss at 12 kHz at 4 and 8 weeks of age, progressing to 40 dB and 60 dB losses at 16 and 24 weeks, respectively, at 12 and 24 kHz. Line 924 shows no hearing loss at 4 or 8 weeks, but manifests 35 and 50 dB threshold shifts at 16 and 24 weeks, respectively, at both 12 and 24 kHz. Notably, mice from the two transgenic lines retain distortion product otoacoustic emissions, indicative of normal cochlear outer hair cell (OHC) function despite elevation of auditory thresholds. Scanning electron microscopy of the organ of Corti demonstrates striking anomalies of the inner hair cell (IHC) stereocilia, while OHCs are essentially intact. Over time, IHCs of both lines develop elongated stereocilia that appear fused with neighboring stereocilia, in parallel to the time course of hearing loss in each line. Furthermore, we observe significant reduction in the number of IHC ribbon synapses over 24 weeks in both lines, although this reduction does not correlate temporally with onset and progression of hearing loss or stereociliary anomalies. In summary, overexpression of wild-type Diap3 in two lines of transgenic mice results in hearing loss that recapitulates human AUNA1 deafness. These findings suggest an essential role of Diap3 in regulating assembly and/or maintenance of actin filaments in IHC stereocilia, as well as a potential role at the IHC ribbon synapse. PMID- 23441202 TI - Evidence that primary visual cortex is required for image, orientation, and motion discrimination by rats. AB - The pigmented Long-Evans rat has proven to be an excellent subject for studying visually guided behavior including quantitative visual psychophysics. This observation, together with its experimental accessibility and its close homology to the mouse, has made it an attractive model system in which to dissect the thalamic and cortical circuits underlying visual perception. Given that visually guided behavior in the absence of primary visual cortex has been described in the literature, however, it is an empirical question whether specific visual behaviors will depend on primary visual cortex in the rat. Here we tested the effects of cortical lesions on performance of two-alternative forced-choice visual discriminations by Long-Evans rats. We present data from one highly informative subject that learned several visual tasks and then received a bilateral lesion ablating >90% of primary visual cortex. After the lesion, this subject had a profound and persistent deficit in complex image discrimination, orientation discrimination, and full-field optic flow motion discrimination, compared with both pre-lesion performance and sham-lesion controls. Performance was intact, however, on another visual two-alternative forced-choice task that required approaching a salient visual target. A second highly informative subject learned several visual tasks prior to receiving a lesion ablating >90% of medial extrastriate cortex. This subject showed no impairment on any of the four task categories. Taken together, our data provide evidence that these image, orientation, and motion discrimination tasks require primary visual cortex in the Long-Evans rat, whereas approaching a salient visual target does not. PMID- 23441203 TI - Neurological basis for eye movements of the blind. AB - When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate. PMID- 23441205 TI - Light pollution in ultraviolet and visible spectrum: effect on different visual perceptions. AB - In general terms, lighting research has been focused in the development of artificial light with the purpose of saving energy and having more durable lamps. However, the consequences that artificial night lighting could bring to the human being and living organisms have become an important issue recently. Light pollution represents a significant problem to both the environment and human health causing a disruption of biological rhythms related not only to the visible spectrum, but also to other parts of the electromagnetic spectrum. Since the lamps emit across a wide range of the electromagnetic spectrum, all photobiological species may be exposed to another type of light pollution. By comparing five different lamps, the present study attempts to evaluate UV radiative fluxes relative to what humans and two species of insects perceive as sky glow level. We have analyzed three atmospheric situations: clear sky, overcast sky and evolving precipitable water content. One important finding suggests that when a constant illuminance of urban spaces has to be guaranteed the sky glow from the low pressure sodium lamps has the most significant effect to the visual perception of the insects tested. But having the fixed number of luminaires the situation changes and the low pressure sodium lamp would be the best choice for all three species. The sky glow effects can be interpreted correctly only if the lamp types and the required amount of scotopic luxes at the ground are taken into account simultaneously. If these two factors are combined properly, then the ecological consequences of sky glow can be partly reduced. The results of this research may be equally useful for lighting engineers, architects, biologists and researchers who are studying the effects of sky glow on humans and biodiversity. PMID- 23441204 TI - The Deinococcus radiodurans DR1245 protein, a DdrB partner homologous to YbjN proteins and reminiscent of type III secretion system chaperones. AB - The bacterium Deinococcus radiodurans exhibits an extreme resistance to ionizing radiation. A small subset of Deinococcus genus-specific genes were shown to be up regulated upon exposure to ionizing radiation and to play a role in genome reconstitution. These genes include an SSB-like protein called DdrB. Here, we identified a novel protein encoded by the dr1245 gene as an interacting partner of DdrB. A strain devoid of the DR1245 protein is impaired in growth, exhibiting a generation time approximately threefold that of the wild type strain while radioresistance is not affected. We determined the three-dimensional structure of DR1245, revealing a relationship with type III secretion system chaperones and YbjN family proteins. Thus, DR1245 may display some chaperone activity towards DdrB and possibly other substrates. PMID- 23441206 TI - Regulation of spine density and morphology by IQGAP1 protein domains. AB - IQGAP1 is a scaffolding protein that regulates spine number. We now show a differential role for IQGAP1 domains in spine morphogenesis, in which a region of the N-terminus that promotes Arp2/3-mediated actin polymerization and branching stimulates spine head formation while a region that binds to Cdc42 and Rac is required for stalk extension. Conversely, IQGAP1 rescues spine deficiency induced by expression of dominant negative Cdc42 by stimulating formation of stubby spines. Together, our observations place IQGAP1 as a crucial regulator of spine number and shape acting through the N-Wasp Arp2/3 complex, as well as upstream and downstream of Cdc42. PMID- 23441207 TI - Osteoblast-targeted overexpression of TAZ increases bone mass in vivo. AB - Osteoblasts are derived from mesenchymal progenitors. Differentiation to osteoblasts and adipocytes is reciprocally regulated. Transcriptional coactivator with a PDZ-binding motif (TAZ) is a transcriptional coactivator that induces differentiation of mesenchymal cells into osteoblasts while blocking differentiation into adipocytes. To investigate the role of TAZ on bone metabolism in vivo, we generated transgenic mice that overexpress TAZ under the control of the procollagen type 1 promoter (Col1-TAZ). Whole body bone mineral density (BMD) of 6- to 19-week-old Col-TAZ mice was 4% to 7% higher than that of their wild-type (WT) littermates, whereas no difference was noticed in Col.1-TAZ female mice. Microcomputed tomography analyses of proximal tibiae at 16 weeks of age demonstrated a significant increase in trabecular bone volume (26.7%) and trabecular number (26.6%) with a reciprocal decrease in trabecular spacing (14.2%) in Col1-TAZ mice compared with their WT littermates. In addition, dynamic histomorphometric analysis of the lumbar spine revealed increased mineral apposition rate (42.8%) and the serum P1NP level was also significantly increased (53%) in Col.1-TAZ mice. When primary calvaria cells were cultured in osteogenic medium, alkaline phosphatase (ALP) activity was significantly increased and adipogenesis was significantly suppressed in Col1-TAZ mice compared with their WT littermates. Quantitative real-time polymerase chain reaction analyses showed that expression of collagen type 1, bone sialoprotein, osteocalcin, ALP, osterix, and Runx2 was significantly increased in calvaria cells from Col1-TAZ mice compared to their WT littermates. In vitro, TAZ enhanced Runx2-mediated transcriptional activity while suppressing the peroxisome proliferator-activated receptor gamma signaling pathway. TAZ also enhanced transcriptional activity from 3TP-Lux, which reflects transforming growth factor-beta (TGF-beta)-mediated signaling. In addition, TAZ enhanced TGF-beta-dependent nuclear translocation of Smad2/3 and Smad4. Taken together, these results suggest that TAZ positively regulates bone formation in vivo, which seems to be mediated by enhancing both Runx2 and TGF-beta signaling. PMID- 23441208 TI - Phenotypic differences in virulence and immune response in closely related clinical isolates of influenza A 2009 H1N1 pandemic viruses in mice. AB - To capture the possible genotypic and phenotypic differences of the 2009 influenza A virus H1N1 pandemic (H1N1pdm) strains circulating in adult hospitalized patients, we isolated and sequenced nine H1N1pdm viruses from patients hospitalized during 2009-2010 with severe influenza pneumonia in Kentucky. Each viral isolate was characterized in mice along with two additional H1N1 pandemic strains and one seasonal strain to assess replication and virulence. All isolates showed similar levels of replication in nasal turbinates and lung, but varied in their ability to cause morbidity. Further differences were identified in cytokine and chemokine responses. IL-6 and KC were expressed early in mice infected with strains associated with higher virulence. Strains that showed lower pathogenicity in mice had greater IFNgamma, MIG, and IL-10 responses. A principal component analysis (PCA) of the cytokine and chemokine profiles revealed 4 immune response phenotypes that correlated with the severity of disease. A/KY/180/10, which showed the greatest virulence with a rapid onset of disease progression, was compared in additional studies with A/KY/136/09, which showed low virulence in mice. Analyses comparing a low (KY/136) versus a high (KY/180) virulent isolate showed a significant difference in the kinetics of infection within the lower respiratory tract and immune responses. Notably by 4 DPI, virus titers within the lung, bronchoalveolar lavage fluid (BALf), and cells within the BAL (BALc) revealed that the KY/136 replicated in BALc, while KY/180 replication persisted in lungs and BALc. In summary, our studies suggest four phenotypic groups based on immune responses that result in different virulence outcomes in H1N1pdm isolates with a high degree of genetic similarity. In vitro studies with two of these isolates suggested that the more virulent isolate, KY/180, replicates productively in macrophages and this may be a key determinant in tipping the response toward a more severe disease progression. PMID- 23441209 TI - Affective state influences retrieval-induced forgetting for integrated knowledge. AB - BACKGROUND: Selectively testing parts of learned materials can impair later memory for nontested materials. Research has shown that such retrieval-induced forgetting occurs for low-integrated materials but may be prevented for high integrated materials. However, previous research has neglected one factor that is ubiquitous in real-life testing: affective state. METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether affect influences the resistance of integrated materials to retrieval-induced forgetting by inducing neutral, positive, or negative affect immediately before selectively testing previously learned textbook passages containing interrelated facts and concepts. As negative affect is known to promote a detail-oriented local processing style, we hypothesized that experiencing negative affect during testing may decrease the protective effects of integration and lead to reoccurrence of forgetting. By contrast, as positive affect is known to promote a relation-oriented global processing style, we hypothesized that experiencing positive affect may support effects of integration and prevent forgetting. Our findings are consistent with these predictions. No subsequent forgetting occurred when testing memories for integrated text materials in affectively neutral and positive states, whereas forgetting occurred when testing in negative states. A correlation analysis showed that forgetting decreased with higher positive affect, with participants experiencing high positive affect even showing facilitation instead of forgetting. CONCLUSIONS/SIGNIFICANCE: These findings indicate that affect can moderate the memory consequences of test taking and suggest that educators should use testing as a tool to improve memory with care. PMID- 23441210 TI - Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study. AB - BACKGROUND: Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model METHODS: Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 usec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan RESULTS: We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation CONCLUSIONS: Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS. PMID- 23441211 TI - Strain dependent variation of immune responses to A. fumigatus: definition of pathogenic species. AB - For over a century microbiologists and immunologist have categorized microorganisms as pathogenic or non-pathogenic species or genera. This definition, clearly relevant at the strain and species level for most bacteria, where differences in virulence between strains of a particular species are well known, has never been probed at the strain level in fungal species. Here, we tested the immune reactivity and the pathogenic potential of a collection of strains from Aspergillus spp, a fungus that is generally considered pathogenic in immuno-compromised hosts. Our results show a wide strain-dependent variation of the immune response elicited indicating that different isolates possess diverse virulence and infectivity. Thus, the definition of markers of inflammation or pathogenicity cannot be generalized. The profound understanding of the molecular mechanisms subtending the different immune responses will result solely from the comparative study of strains with extremely diverse properties. PMID- 23441212 TI - Autophagy inhibition promotes 5-fluorouraci-induced apoptosis by stimulating ROS formation in human non-small cell lung cancer A549 cells. AB - Chemotherapy is an important option for the treatment of various cancers including lung cancer. However, tumor resistance towards cytotoxic chemotherapy has become more common. It has been reported that autophagy is one of the processes contributing to this resistance. In the present study, we found that the anti-cancer drug 5-fluorouraci(5-FU) could induce autophagy in A549 cells. 5 FU treatment could lead to the conversion of LC3 I/II, the up-regulation of Beclin-1, the down-regulation of p62 and the formation of acidic vesicular organelles (AVOs) in A549 cells. Pre-treatment of cancer cells with 3-MA or siAtg7 could enhance 5-FU-induced apoptosis through the activation of caspases, and the caspase inhibitor z-VAD-fmk rescued the cell viability reduction. Furthermore, the inhibition of autophagy also stimulated ROS formation and scavenging of ROS by antioxidant NAC inhibited caspase-3 activity, prevented the release of cyt-c from mitochondria and eventually rescued cancer cells from 5-FU mediated apoptosis. These results suggest that 5-FU-elicited autophagic response plays a protective role against cell apoptosis and the inhibition of autophagy could sensitize them to 5-FU-induced caspase-dependent apoptosis through the stimulation of ROS formation. PMID- 23441213 TI - Cyclooxygenase-1 and prostacyclin production by endothelial cells in the presence of mild oxidative stress. AB - This study aimed at evaluating the relative contribution of endothelial cyclooxygenase-1 and -2 (COX-1 and COX-2) to prostacyclin (PGI(2)) production in the presence of mild oxidative stress resulting from autooxidation of polyphenols such as (-)-epigallocatechin 3-gallate (EGCG), using both endothelial cells in culture and isolated blood vessels. EGCG treatment resulted in an increase in hydrogen peroxide formation in human umbilical vein endothelial cells. In the presence of exogenous arachidonic acid and EGCG, PGI(2) production was preferentially inhibited by a selective COX-1 inhibitor. This effect of selective inhibition was also substantially reversed by catalase. In addition, EGCG caused vasorelaxation of rat aortic ring only partially abolished by a nitric oxide synthase inhibitor. Concomitant treatment with a selective COX-1 inhibitor completely prevented the vasorelaxation as well as the increase in PGI(2) accumulation in the perfusate observed in EGCG-treated aortic rings, while a selective COX-2 inhibitor was completely uneffective. Our data strongly support the notions that H(2)O(2) generation affects endothelial PGI(2) production, making COX-1, and not COX-2, the main source of endothelial PGI(2) under altered oxidative tone conditions. These results might be relevant to the reappraisal of the impact of COX inhibitors on vascular PGI(2) production in patients undergoing significant oxidative stress. PMID- 23441214 TI - In-silico structural and functional characterization of a V. cholerae O395 hypothetical protein containing a PDZ1 and an uncommon protease domain. AB - Vibrio cholerae, the causative agent of epidemic cholera, has been a constant source of concern for decades. It has constantly evolved itself in order to survive the changing environment. Acquisition of new genetic elements through genomic islands has played a major role in its evolutionary process. In this present study a hypothetical protein was identified which was present in one of the predicted genomic island regions of the large chromosome of V. cholerae O395 showing a strong homology with a conserved phage encoded protein. In-silico physicochemical analysis revealed that the hypothetical protein was a periplasmic protein. Homology modeling study indicated that the hypothetical protein was an unconventional and atypical serine protease belonging to HtrA protein family. The predicted 3D-model of the hypothetical protein revealed a catalytic centre serine utilizing a single catalytic residue for proteolysis. The predicted catalytic triad may help to deduce the active site for the recruitment of the substrate for proteolysis. The active site arrangements of this predicted serine protease homologue with atypical catalytic triad is expected to allow these proteases to work in different environments of the host. PMID- 23441215 TI - Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress. AB - We recently showed that differential expression of extracellular matrix (ECM) genes delineates four subgroups of breast carcinomas (ECM1, -2, -3- and -4) with different clinical outcome. To further investigate the characteristics of ECM signature and its impact on tumor progression, we conducted unsupervised clustering analyses in 6 additional independent datasets of invasive breast tumors from different platforms for a total of 643 samples. Use of four different clustering algorithms identified ECM3 tumors as an independent group in all datasets tested. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding 43 structural ECM proteins. From 26 to 41% of the cases were ECM3 enriched, and analysis of datasets relevant to gene expression in neoplastic or corresponding stromal cells showed that both stromal and breast carcinoma cells can coordinately express ECM3 genes. In in vitro experiments, beta-estradiol induced ECM3 gene production in ER-positive breast carcinoma cell lines, whereas TGFbeta induced upregulation of the genes leading to ECM3 gene classification, especially in ER-negative breast carcinoma cells and in fibroblasts. Multivariate analysis of distant metastasis-free survival in untreated breast tumor patients revealed a significant interaction between ECM3 and histological grade (p = 0.001). Cox models, estimated separately in grade I-II and grade III tumors, indicated a highly significant association between ECM3 and worse survival probability only in grade III tumors (HR = 3.0, 95% CI = 1.3-7.0, p = 0.0098). Gene Set Enrichment analysis of ECM3 compared to non-ECM3 tumors revealed significant enrichment of epithelial-mesenchymal transition (EMT) genes in both grade I-II and grade III subsets of ECM3 tumors. Thus, ECM3 is a robust cluster that identifies breast carcinomas with EMT features but with accelerated metastatic potential only in the undifferentiated (grade III) phenotype. These findings support the key relevance of neoplastic and stroma interaction in breast cancer progression. PMID- 23441217 TI - Landscape pattern determines neighborhood size and structure within a lizard population. AB - Although defining population structure according to discrete habitat patches is convenient for metapopulation theories, taking this approach may overlook structure within populations continuously distributed across landscapes. For example, landscape features within habitat patches direct the movement of organisms and define the density distribution of individuals, which can generate spatial structure and localized dynamics within populations as well as among them. Here, we use the neighborhood concept, which describes population structure relative to the scale of individual movements, to illustrate how localized dynamics within a population of lizards (Sceloporus arenicolus) arise in response to variation in landscape pattern within a continuous habitat patch. Our results emphasize links between individual movements at small scales and the emergence of spatial structure within populations which resembles metapopulation dynamics at larger scales. We conclude that population dynamics viewed in a landscape context must consider the explicit distribution and movement of individuals within continuous habitat as well as among habitat patches. PMID- 23441216 TI - Co-introduced functional CCR2 potentiates in vivo anti-lung cancer functionality mediated by T cells double gene-modified to express WT1-specific T-cell receptor. AB - BACKGROUND AND PURPOSE: Although gene-modification of T cells to express tumor related antigen-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) has clinically proved promise, there still remains room to improve the clinical efficacy of re-directed T-cell based antitumor adoptive therapy. In order to achieve more objective clinical responses using ex vivo-expanded tumor-responsive T cells, the infused T cells need to show adequate localized infiltration into the tumor. METHODOLOGY/PRINCIPAL FINDINGS: Human lung cancer cells variously express a tumor antigen, Wilms' Tumor gene product 1 (WT1), and an inflammatory chemokine, CCL2. However, CCR2, the relevant receptor for CCL2, is rarely expressed on activated T-lymphocytes. A HLA-A2402(+) human lung cancer cell line, LK79, which expresses high amounts of both CCL2 and WT1 mRNA, was employed as a target. Normal CD8(+) T cells were retrovirally gene-modified to express both CCR2 and HLA-A*2402-restricted and WT1(235-243) nonapeptide-specific TCR as an effector. Anti-tumor functionality mediated by these effector cells against LK79 cells was assessed both in vitro and in vivo. Finally the impact of CCL2 on WT1 epitope-responsive TCR signaling mediated by the effector cells was studied. Introduced CCR2 was functionally validated using gene-modified Jurkat cells and human CD3(+) T cells both in vitro and in vivo. Double gene-modified CD3(+) T cells successfully demonstrated both CCL2-tropic tumor trafficking and cytocidal reactivity against LK79 cells in vitro and in vivo. CCL2 augmented the WT1 epitope-responsive TCR signaling shown by relevant luciferase production in double gene-modified Jurkat/MA cells to express luciferase and WT1-specific TCR, and CCL2 also dose-dependently augmented WT1 epitope-responsive IFN-gamma production and CD107a expression mediated by these double gene-modified CD3(+) T cells. CONCLUSION/SIGNIFICANCE: Introduction of the CCL2/CCR2 axis successfully potentiated in vivo anti-lung cancer reactivity mediated by CD8(+) T cells double gene-modified to express WT1-specific TCR and CCR2 not only via CCL2-tropic tumor trafficking, but also CCL2-enhanced WT1-responsiveness. PMID- 23441218 TI - Infection of Brachypodium distachyon by formae speciales of Puccinia graminis: early infection events and host-pathogen incompatibility. AB - Puccinia graminis causes stem rust, a serious disease of cereals and forage grasses. Important formae speciales of P. graminis and their typical hosts are P. graminis f. sp. tritici (Pg-tr) in wheat and barley, P. graminis f. sp. lolii (Pg lo) in perennial ryegrass and tall fescue, and P. graminis f. sp. phlei-pratensis (Pg-pp) in timothy grass. Brachypodium distachyon is an emerging genetic model to study fungal disease resistance in cereals and temperate grasses. We characterized the P. graminis-Brachypodium pathosystem to evaluate its potential for investigating incompatibility and non-host resistance to P. graminis. Inoculation of eight Brachypodium inbred lines with Pg-tr, Pg-lo or Pg-pp resulted in sporulating lesions later accompanied by necrosis. Histological analysis of early infection events in one Brachypodium inbred line (Bd1-1) indicated that Pg-lo and Pg-pp were markedly more efficient than Pg-tr at establishing a biotrophic interaction. Formation of appressoria was completed (60 70% of germinated spores) by 12 h post-inoculation (hpi) under dark and wet conditions, and after 4 h of subsequent light exposure fungal penetration structures (penetration peg, substomatal vesicle and primary infection hyphae) had developed. Brachypodium Bd1-1 exhibited pre-haustorial resistance to Pg-tr, i.e. infection usually stopped at appressorial formation. By 68 hpi, only 0.3% and 0.7% of the Pg-tr urediniospores developed haustoria and colonies, respectively. In contrast, development of advanced infection structures by Pg-lo and Pg-pp was significantly more common; however, Brachypodium displayed post haustorial resistance to these isolates. By 68 hpi the percentage of urediniospores that only develop a haustorium mother cell or haustorium in Pg-lo and Pg-pp reached 8% and 5%, respectively. The formation of colonies reached 14% and 13%, respectively. We conclude that Brachypodium is an apt grass model to study the molecular and genetic components of incompatiblity and non-host resistance to P. graminis. PMID- 23441219 TI - Antibiotic inducibility of the mexXY multidrug efflux operon of Pseudomonas aeruginosa: involvement of the MexZ anti-repressor ArmZ. AB - Expression of the mexXY multidrug efflux operon in wild type Pseudomonas aeruginosa is substantially enhanced by the ribosome-targeting antimicrobial spectinomycin (18-fold) and this is wholly dependent upon the product of the PA5471 gene. In a mutant strain lacking the mexZ gene encoding a repressor of mexXY gene expression, expression of the efflux operon increases modestly (5 fold) and is still responsive (18-fold) to spectinomycin. Spectinomycin induction of mexXY expression in the mexZ mutant is, however, independent of PA5471 suggesting that PA5471 functions as an anti-repressor (dubbed ArmZ for anti repressor MexZ) that serves only to modulate MexZ's repressor activity, with additional gene(s)/gene product(s) providing for the bulk of the antimicrobial inducible mexXY expression. Consistent with PA5471/ArmZ functioning as a MexZ anti-repressor, an interaction between MexZ and ArmZ was confirmed using a bacterial 2-hybrid assay. Mutations compromising this interaction (P68S, G76S, R216C, R221W, R221Q, G231D and G252S) were identified and localized to one region of an ArmZ structural model that may represent a MexZ-interacting domain. Introduction of representative mutations into the chromosome of P. aeruginosa reduced (P68S, G76S) or obviated (R216C, R2211W) antimicrobial induction of mexXY gene expression, rendering the mutants pan-aminoglycoside-susceptible. These data confirm the importance of an ArmZ-MexZ interaction for antimicrobial-inducible mexXY expression and intrinsic aminoglycoside resistance in P. aeruginosa. PMID- 23441221 TI - Chemoresistance of human monocyte-derived dendritic cells is regulated by IL-17A. AB - Dendritic cells initiate adaptive immune responses, leading either to control cancer by effector T cells or to exacerbate cancer by regulatory T cells that inhibit IFN-gamma-mediated Th1-type response. Dendritic cells can also induce Th17-type immunity, mediated by IL-17A. However, the controversial role of this cytokine in cancer requires further investigations. We generated dendritic cells from peripheral blood monocytes to investigate lifespan, phenotype and chemoresistance of dendritic cells, treated with IL-17A with or without IFN gamma. Studying the expression of Bcl-2 family members, we demonstrated that dendritic cells constitutively express one pro-survival Bcl-2 member: MCL1. Immature dendritic cells were CD40(low)HLADR(low) CD1a(+) MCL1(+), did not express CD14, CD68 or BCL2A1, and displayed a short 2-day lifespan. IL-17A treated DC exhibited a semi-mature (CD40(high) HLADR(low)) pre-M2 (CCL22(+) CD206(+) CD163(+) IL1RN(+) IL-10(-) CXCL10(-) IL-12(-)) mixed (CD1a(+) CD14+ CD68(+)) macrophage-dendritic cell phenotype. They efficiently exerted mannose receptor-mediated endocytosis and did not produce superoxide anions, in the absence of TLR engagement. Interestingly, IL-17A promoted a long-term survival of dendritic cells, beyond 12 days, that correlated to BCL2A1 induction, a pro survival Bcl-2 family member. BCL2A1 transcription was activated by NF-kappaB, downstream of IL-17A transduction. Thus, immature dendritic cells only express MCL1, whereas IL-17A-treated dendritic cells concomitantly expressed two pro survival Bcl-2 family members: MCL1 and BCL2A1. These latter developed chemoresistance to 11 of the 17 chemotherapy agents tested. However, high doses of either vinblastine or cytarabine decreased MCL1 expression and induced dendritic cell death. When IL-17A is produced in vivo, administration of anti-IL 17A biotherapy may impair dendritic cell survival by targeting BCL2A1 expression. Consequently, depending on the effector or regulatory role of dendritic cells, blocking IL-17A, may be either dangerous or beneficial for cancer outcomes, thus contributing to the apparent controversy around the role of IL-17A in cancer. PMID- 23441220 TI - Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin) receptor. AB - Activation of the Ah receptor (AhR) by halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), can produce a wide variety of toxic and biological effects. While recent studies have shown that the AhR can bind and be activated by structurally diverse chemicals, how widespread of these AhR agonists are in environmental, biological and synthetic materials remains to be determined. Using AhR-based assays, we demonstrate the presence of potent AhR agonists in a variety of common commercial and consumer items. Solvent extracts of paper, rubber and plastic products contain chemicals that can bind to and stimulate AhR DNA binding and/or AhR-dependent gene expression in hepatic cytosol, cultured cell lines, human epidermis and zebrafish embryos. In contrast to TCDD and other persistent dioxin-like HAHs, activation of AhR-dependent gene expression by these extracts was transient, suggesting that the agonists are metabolically labile. Solvent extracts of rubber products produce AhR-dependent developmental toxicity in zebrafish in vivo, and inhibition of expression of the metabolic enzyme CYP1A, significantly increased their toxic potency. Although the identity of the responsible AhR-active chemicals and their toxicological impact remain to be determined, our data demonstrate that AhR active chemicals are widely distributed in everyday products. PMID- 23441222 TI - DNA methylation of specific CpG sites in the promoter region regulates the transcription of the mouse oxytocin receptor. AB - Oxytocin is a peptide hormone, well known for its role in labor and suckling, and most recently for its involvement in mammalian social behavior. All central and peripheral actions of oxytocin are mediated through the oxytocin receptor, which is the product of a single gene. Transcription of the oxytocin receptor is subject to regulation by gonadal steroid hormones, and is profoundly elevated in the uterus and mammary glands during parturition. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression of the oxytocin receptor in individuals with autism. Here, we hypothesized that transcription of the mouse oxytocin receptor is regulated by DNA methylation of specific sites in its promoter, in a tissue-specific manner. Hypothalamus-derived GT1-7, and mammary-derived 4T1 murine cell lines displayed negative correlations between oxytocin receptor transcription and methylation of the gene promoter, and demethylation caused a significant enhancement of oxytocin receptor transcription in 4T1 cells. Using a reporter gene assay, we showed that methylation of specific sites in the gene promoter, including an estrogen response element, significantly inhibits transcription. Furthermore, methylation of the oxytocin receptor promoter was found to be differentially correlated with oxytocin receptor expression in mammary glands and the uterus of virgin and post partum mice, suggesting that it plays a distinct role in oxytocin receptor transcription among tissues and under different physiological conditions. Together, these results support the hypothesis that the expression of the mouse oxytocin receptor gene is epigenetically regulated by DNA methylation of its promoter. PMID- 23441223 TI - Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and beta-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta amyloid peptide- (Abeta-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Abeta-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Abeta-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD. PMID- 23441224 TI - The role of TLR4 in the paclitaxel effects on neuronal growth in vitro. AB - Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode. PMID- 23441225 TI - Molecular characterisation of colour formation in the prawn Fenneropenaeus merguiensis. AB - INTRODUCTION: Body colouration in animals can have a range of functions, with predator protection an important aspect of colour in crustaceans. Colour determination is associated with the carotenoid astaxanthin, which is taken up through the diet and stabilised in the tissues by the protein crustacyanin. As a variety of genes are found to play a role in colour formation in other systems, a holistic approach was employed in this study to determine the factors involved in Fenneropenaeus merguiensis colouration. RESULTS: Full length F. merguiensis crustacyanin subunit A and C sequences were isolated. Crustacyanin subunit A and C were found in the F. merguiensis transcriptomes of the muscle/cuticle tissue, hepatopancreas, eye stalk and nervous system, using 454 next generation sequencing technology. Custom microarray analysis of albino, light and dark F. merguiensis cuticle tissue showed genes encoding actin, sarcoplasmic calcium binding protein and arginine kinase to be 4-fold or greater differentially expressed (p<0.05) and down-regulated in albinos when compared to light and dark samples. QPCR expression analysis of crustacyanin and total astaxanthin pigment extraction revealed significantly (p<0.05) lower crustacyanin subunit A and C gene transcript copy numbers and total astaxanthin levels in albinos than in the light and dark samples. Additionally, crustacyanin subunit A and C expression levels correlated positively with each other. CONCLUSIONS: This study identified gene products putatively involved in crustacean colouration, such as crustacyanin, sarcoplasmic calcium-binding protein and forms of actin, and investigated differences in gene expression and astaxanthin levels between albino, light and dark coloured prawns. These genes open a path to enhance our understanding of the biology and regulation of colour formation. PMID- 23441226 TI - Topologically heterogeneous beta cell adaptation in response to high-fat diet in mice. AB - AIMS: Beta cells adapt to an increased insulin demand by enhancing insulin secretion via increased beta cell function and/or increased beta cell number. While morphological and functional heterogeneity between individual islets exists, it is unknown whether regional differences in beta cell adaptation occur. Therefore we investigated beta cell adaptation throughout the pancreas in a model of high-fat diet (HFD)-induced insulin resistance in mice. METHODS: C57BL/6J mice were fed a HFD to induce insulin resistance, or control diet for 6 weeks. The pancreas was divided in a duodenal (DR), gastric (GR) and splenic (SR) region and taken for either histology or islet isolation. The capacity of untreated islets from the three regions to adapt in an extrapancreatic location was assessed by transplantation under the kidney capsule of streptozotocin-treated mice. RESULTS: SR islets showed 70% increased beta cell proliferation after HFD, whereas no significant increase was found in DR and GR islets. Furthermore, isolated SR islets showed twofold enhanced glucose-induced insulin secretion after HFD, as compared with DR and GR islets. In contrast, transplantation of islets isolated from the three regions to an extrapancreatic location in diabetic mice led to a similar decrease in hyperglycemia and no difference in beta cell proliferation. CONCLUSIONS: HFD-induced insulin resistance leads to topologically heterogeneous beta cell adaptation and is most prominent in the splenic region of the pancreas. This topological heterogeneity in beta cell adaptation appears to result from extrinsic factors present in the islet microenvironment. PMID- 23441227 TI - Association between plasma PFOA and PFOS levels and total cholesterol in a middle aged Danish population. AB - Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are used in a variety of consumer products and have been detected worldwide in human blood. Recent studies mainly of highly exposed populations have indicated that PFOA and PFOS may affect serum cholesterol levels, but the magnitude of the effect may be inconsistent across exposure levels. The aim of the present cross-sectional study was to investigate the association between plasma PFOA and PFOS and total cholesterol in a general, middle-aged Danish population. The study population comprised 753 individuals (663 men and 90 women), 50-65 years of age, nested within a Danish cohort of 57,053 participants. Blood samples were taken from all cohort members at enrolment (1993-1997) and stored in a biobank at -150 degrees C. Plasma levels of PFOA and PFOS and serum levels of total cholesterol were measured. The associations between plasma PFOA and PFOS levels and total cholesterol levels were analysed by generalized linear models, both crude and adjusted for potential confounders. We observed statistically significant positive associations between both perfluorinated compounds and total cholesterol, e.g. a 4.4 [95% CI = 1.1-7.8] higher concentration of total cholesterol (mg/dL) per interquartile range of PFOA plasma level. Sex and prevalent diabetes appeared to modify the association between PFOA and PFOS, respectively, and cholesterol. In conclusion, this study indicated positive associations between plasma PFOA and PFOS levels and total cholesterol in a middle-aged Danish population, although whether the observed pattern of results reflects a causal association is unclear. PMID- 23441228 TI - Downregulation of carbonic anhydrase IX promotes Col10a1 expression in chondrocytes. AB - Carbonic anhydrase (CA) IX is a transmembrane isozyme of CAs that catalyzes reversible hydration of CO(2). While it is known that CA IX is distributed in human embryonic chondrocytes, its role in chondrocyte differentiation has not been reported. In the present study, we found that Car9 mRNA and CA IX were expressed in proliferating but not hypertrophic chondrocytes. Next, we examined the role of CA IX in the expression of marker genes of chondrocyte differentiation in vitro. Introduction of Car9 siRNA to mouse primary chondrocytes obtained from costal cartilage induced the mRNA expressions of Col10a1, the gene for type X collagen alpha-1 chain, and Epas1, the gene for hypoxia-responsible factor-2alpha (HIF-2alpha), both of which are known to be characteristically expressed in hypertrophic chondrocytes. On the other hand, forced expression of CA IX had no effect of the proliferation of chondrocytes or the transcription of Col10a1 and Epas1, while the transcription of Col2a1 and Acan were up-regulated. Although HIF-2alpha has been reported to be a potent activator of Col10a1 transcription, Epas1 siRNA did not suppress Car9 siRNA induced increment in Col10a1 expression, indicating that down-regulation of CA IX induces the expression of Col10a1 in chondrocytes in a HIF-2alpha-independent manner. On the other hand, cellular cAMP content was lowered by Car9 siRNA. Furthermore, the expression of Col10a1 mRNA after Car9 silencing was augmented by an inhibitor of protein kinase A, and suppressed by an inhibitor for phosphodiesterase as well as a brominated analog of cAMP. While these results suggest a possible involvement of cAMP-dependent pathway, at least in part, in induction of Col10a1 expression by down-regulation of Car9, more detailed study is required to clarify the role of CA IX in regulation of Col10a1 expression in chondrocytes. PMID- 23441229 TI - CD8 T cell memory recall is enhanced by novel direct interactions with CD4 T cells enabled by MHC class II transferred from APCs. AB - Protection against many intracellular pathogens is provided by CD8 T cells, which are thought to need CD4 T cell help to develop into effective memory CD8 T cells. Because murine CD8 T cells do not transcribe MHC class II (MHC-II) genes, several models have proposed antigen presenting cells (APCs) as intermediaries required for CD4 T cells to deliver their help to CD8 T cells. Here, we demonstrate the presence of MHC-II molecules on activated murine CD8 T cells in vitro as well as in vivo. These MHC-II molecules are acquired via trogocytosis by CD8 T cells from their activating APCs, particularly CD11c positive dendritic cells (DCs). Transferred MHC-II molecules on activated murine CD8 T cells were functionally competent in stimulating specific indicator CD4 T cells. CD8 T cells that were "helped" in vitro and subsequently allowed to rest in vivo showed enhanced recall responses upon challenge compared to "helpless" CD8 T cells; in contrast, no differences were seen upon immediate challenge. These data indicate that direct CD8:CD4 T cell interactions may significantly contribute to help for CD8 T cells. Furthermore, this mechanism may enable CD8 T cells to communicate with different subsets of interacting CD4 T cells that could modulate immune responses. PMID- 23441230 TI - Detection of low abundance RNA molecules in individual cells by flow cytometry. AB - A variety of RNA analysis technologies are available for the detection of RNA transcripts from bulk cell populations. However, the techniques for RNA detection from individual cells have been limited. Here we adapt a novel in situ signal amplification method (the RNAScope(r) detection platform) for the analysis of intracellular RNAs in individual cells by flow cytometry. Using novel target specific probes that were designed to suppress background signals, we demonstrate the specific detection of HIV gag RNAs in HIV-infected cellular samples, in addition to bcr and abl mRNAs in the K562 cell line. This method was capable of distinguishing cells expressing low abundance RNA transcripts and correlated well with quantitative imaging analysis. Furthermore, multiple distinct RNA targets were simultaneously detected with a high specificity without interference. Overall, the sensitivity and specificity of this method will be useful for the analysis of functionally important RNA species from individual cells, even at very low copy numbers. PMID- 23441231 TI - The role of reactive oxygen species in Anopheles aquasalis response to Plasmodium vivax infection. AB - Malaria affects millions of people worldwide and hundreds of thousands of people each year in Brazil. The mosquito Anopheles aquasalis is an important vector of Plasmodium vivax, the main human malaria parasite in the Americas. Reactive oxygen species (ROS) have been shown to have a role in insect innate immune responses as a potent pathogen-killing agent. We investigated the mechanisms of free radicals modulation after A. aquasalis infection with P. vivax. ROS metabolism was evaluated in the vector by studying expression and activity of three key detoxification enzymes, one catalase and two superoxide dismutases (SOD3A and SOD3B). Also, the involvement of free radicals in the mosquito immunity was measured by silencing the catalase gene followed by infection of A. aquasalis with P. vivax. Catalase, SOD3A and SOD3B expression in whole A. aquasalis were at the same levels of controls at 24 h and upregulated 36 h after ingestion of blood containing P. vivax. However, in the insect isolated midgut, the mRNA for these enzymes was not regulated by P. vivax infection, while catalase activity was reduced 24 h after the infectious meal. RNAi-mediated silencing of catalase reduced enzyme activity in the midgut, resulted in increased P. vivax infection and prevalence, and decreased bacterial load in the mosquito midgut. Our findings suggest that the interactions between A. aquasalis and P. vivax do not follow the model of ROS-induced parasite killing. It appears that P. vivax manipulates the mosquito detoxification system in order to allow its own development. This can be an indirect effect of fewer competitive bacteria present in the mosquito midgut caused by the increase of ROS after catalase silencing. These findings provide novel information on unique aspects of the main malaria parasite in the Americas interaction with one of its natural vectors. PMID- 23441232 TI - Facial orientation and facial shape in extant great apes: a geometric morphometric analysis of covariation. AB - The organization of the bony face is complex, its morphology being influenced in part by the rest of the cranium. Characterizing the facial morphological variation and craniofacial covariation patterns in extant hominids is fundamental to the understanding of their evolutionary history. Numerous studies on hominid facial shape have proposed hypotheses concerning the relationship between the anterior facial shape, facial block orientation and basicranial flexion. In this study we test these hypotheses in a sample of adult specimens belonging to three extant hominid genera (Homo, Pan and Gorilla). Intraspecific variation and covariation patterns are analyzed using geometric morphometric methods and multivariate statistics, such as partial least squared on three-dimensional landmarks coordinates. Our results indicate significant intraspecific covariation between facial shape, facial block orientation and basicranial flexion. Hominids share similar characteristics in the relationship between anterior facial shape and facial block orientation. Modern humans exhibit a specific pattern in the covariation between anterior facial shape and basicranial flexion. This peculiar feature underscores the role of modern humans' highly-flexed basicranium in the overall integration of the cranium. Furthermore, our results are consistent with the hypothesis of a relationship between the reduction of the value of the cranial base angle and a downward rotation of the facial block in modern humans, and to a lesser extent in chimpanzees. PMID- 23441233 TI - A C. trachomatis cloning vector and the generation of C. trachomatis strains expressing fluorescent proteins under the control of a C. trachomatis promoter. AB - Here we describe a versatile cloning vector for conducting genetic experiments in C. trachomatis. We successfully expressed various fluorescent proteins (i.e. GFP, mCherry and CFP) from C. trachomatis regulatory elements (i.e. the promoter and terminator of the incDEFG operon) and showed that the transformed strains produced wild type amounts of infectious particles and recapitulated major features of the C. trachomatis developmental cycle. C. trachomatis strains expressing fluorescent proteins are valuable tools for studying the C. trachomatis developmental cycle. For instance, we show the feasibility of investigating the dynamics of inclusion fusion and interaction with host proteins and organelles by time-lapse video microscopy. PMID- 23441234 TI - Choice of activity-intensity classification thresholds impacts upon accelerometer assessed physical activity-health relationships in children. AB - BACKGROUND: It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs. METHODS: 104 children (63 girls) aged 10-14 years wore an RT3 triaxial accelerometer for seven days and measures of adiposity and cardiometabolic risk markers were taken. RESULTS: Significant associations (p< .05) in boys were found between LPA and body mass index z-score and waist circumference z-score for the Rowlands et al PT only (beta = .459 and.401, respectively) and body fat% (BF%) for the Chu et al PT only (beta = .322) and in girls with BF% for the Rowlands et al PT only (beta = .303) and systolic BP and blood glucose for the Vanhelst et al PT only (beta = -.298 and -.283, respectively). MPA was significantly (p<.05) associated with BF%, diastolic BP, and cardiorespiratory fitness (CRF) for the Chu et al PT only in girls (beta = -.436, -.529, and .446, respectively). SED was significantly (p<.05) associated with triglycerides (beta = .492) for the Rowlands et al PT only in boys and VPA with CRF (p<.05) for the Rowlands et al and Vanhelst et al PTs only in girls (beta = .416 and .352, respectively). CONCLUSIONS: The choice of PT impacted upon activity-health relationships. A consensus on appropriate accelerometer thresholds for quantifying PA intensity and sedentary behaviour is needed in order to make accurate evidence-based recommendations for health promotion. PMID- 23441236 TI - Acne Vulgaris and the Epidermal Barrier: Is Acne Vulgaris Associated with Inherent Epidermal Abnormalities that Cause Impairment of Barrier Functions? Do Any Topical Acne Therapies Alter the Structural and/or Functional Integrity of the Epidermal Barrier? AB - Acne vulgaris is a common dermatological disorder that predominantly affects teenagers, but can also affect preadolescents and post-teen individuals. Despite the fact that acne vulgaris is the most common skin disorder encountered in ambulatory dermatology practice in the United States, there has been limited research on the epidermal permeability barrier in untreated skin of people with acne vulgaris and also after use of acne therapies. This article reviews the research results and discusses the available literature on this subject area. The importance of proper skin care as a component of the management of acne vulgaris is supported by the information that is currently available. PMID- 23441235 TI - Computational analysis of siRNA recognition by the Ago2 PAZ domain and identification of the determinants of RNA-induced gene silencing. AB - RNA interference (RNAi) is a highly specialized process of protein-siRNA interaction that results in the regulation of gene expression and cleavage of target mRNA. The PAZ domain of the Argonaute proteins binds to the 3' end of siRNA, and during RNAi the attaching end of the siRNA switches between binding and release from its binding pocket. This biphasic interaction of the 3' end of siRNA with the PAZ domain is essential for RNAi activity; however, it remains unclear whether stronger or weaker binding with PAZ domain will facilitate or hinder the overall RNAi process. Here we report the correlation between the binding of modified siRNA 3' overhang analogues and their in vivo RNAi efficacy. We found that higher RNAi efficacy was associated with the parameters of lower Ki value, lower total intermolecular energy, lower free energy, higher hydrogen bonding, smaller total surface of interaction and fewer van der Waals interactions. Electrostatic interaction was a minor contributor to compounds recognition, underscoring the presence of phosphate groups in the modified analogues. Thus, compounds with lower binding affinity are associated with better gene silencing. Lower binding strength along with the smaller interaction surface, higher hydrogen bonding and fewer van der Waals interactions were among the markers for favorable RNAi activity. Within the measured parameters, the interaction surface, van der Waals interactions and inhibition constant showed a statistically significant correlation with measured RNAi efficacy. The considerations provided in this report will be helpful in the design of new compounds with better gene silencing ability. PMID- 23441237 TI - Tretinoin photostability: comparison of micronized tretinoin gel 0.05% and tretinoin gel 0.025% following exposure to fluorescent and solar light. AB - BACKGROUND: Various formulations of tretinoin have been reported to be unstable after exposure to artificial light or sunlight. The observation that tretinoin is photolabile in the presence of light led to the recommendation that tretinoin be applied in the evening in order to avoid photodegradation, which could potentially reduce efficacy. More recently, the development of innovative vehicle formulations has led, in some cases, to a marked decrease in the photodegradation of tretinoin. OBJECTIVE: To compare the photostability of a micronized aqueous based formulation of tretinoin gel 0.05% with tretinoin gel 0.025% following exposure to fluorescent and simulated solar light conditions in vitro. METHODS: Micronized tretinoin gel 0.05% and tretinoin gel 0.025% were exposed to fluorescent light over eight hours or simulated solar light up to 600mJ/cm(2) (equivalent to 30 minimal erythemal dose). Product samples were prepared and analyzed for tretinoin concentration using high-performance liquid chromatography. Additional duplicate samples were similarly prepared and analyzed after 2, 4, 6, and 8 hours. RESULTS: There was an 11-percent degradation of tretinoin 0.05% formulated as the micronized gel compared to an 86-percent degradation of tretinoin 0.025% formulated as the conventional gel following eight hours of exposure to fluorescent light in vitro. The degradation of tretinoin 0.025% in the conventional gel was greater than 83 percent within two hours. In the second light exposure study, in vitro exposure to simulated solar light provided a gradual dose-response effect with tretinoin 0.05% formulated as the micronized tretinoin gel. The photodegradation of tretinoin 0.025% in the conventional gel was more immediate and of substantial magnitude (>85%) after exposures at all minimal erythemal dose levels. CONCLUSION: Tretinoin 0.05% formulated as a micronized gel 0.05% showed minimal degradation when exposed to fluorescent light over eight hours. This same formulation exhibited a clear dose response degradation pattern when exposed to simulated solar light. In contrast, tretinoin 0.025% formulated in a conventional gel exhibited marked photodegradation within the first two hours when exposed to both light conditions in vitro. This information adds to the body of evidence that supports the observation that certain vehicle formulations may reduce the potential for photodegradation of tretinoin. PMID- 23441238 TI - Topical pimecrolimus 1% cream in the treatment of seborrheic dermatitis. AB - Seborrheic dermatitis is a multifactorial skin disease characterized by a chronic course with periods of exacerbation and remission. Although topical corticosteroids have been the mainstay of treatment, alternative therapies are often needed to avoid protracted use of topical corticosteroid therapy in order to avert side effects and to sustain control of the disorder. Topical pimecrolimus, a calcinuerin inhibitor, is a safe alternative for seborrheic dermatitis and is more ideal for long-term use. More specifically, topical pimecrolimus not only has an attractive safety profile with no risk of many of the potential side effects seen with topical corticosteroids, but also has favorable efficacy data, including more data on long-term use. This is a review of literature evaluating the efficacy and safety profile of topical pimecrolimus 1% cream for the treatment of seborrheic dermatitis. PMID- 23441239 TI - An Investigator-initiated Study to Assess the Safety and Efficacy of Imiquimod 3.75% Cream When Used After Cryotherapy in the Treatment of Hypertrophic Actinic Keratoses on Dorsal Hands and Forearms. AB - OBJECTIVE: To evaluate the efficacy of combination cryotherapy and imiquimod 3.75% cream versus cryotherapy alone in the treatment of hypertrophic actinic keratosis on the dorsal hand and forearm. METHODS: Twenty subjects with at least three hypertrophic actinic keratoses on each dorsal hand or forearm underwent cryotherapy treatment to hypertrophic actinic keratoses. Following cryotherapy, subjects were randomized to have either their right or left dorsal hand or forearm treated with imiquimod 3.75% cream to begin on the same day as cryotherapy treatment. Subjects then utilized the two weeks on, two weeks off, two weeks on regimen of imiquimod 3.75% cream application. Local skin reactions were also assessed. RESULTS: For the cryotherapy/imiquimod 3.75% arm, the median total hypertrophic actinic keratosis reduction was -5.12 and for the cryotherapy alone arm, the median total hypertrophic actinic keratosis reduction was -2.24 (P<0.0094). LIMITATIONS: Local skin reactions unbind the investigator. CONCLUSION: Cryotherapy plus imiquimod 3.75% cream resulted in a statistically significant improvement in the reduction of hypertrophic actinic keratoses than cryotherapy alone at 14 weeks. PMID- 23441241 TI - President's address: Research and development on computer-based testing and extension of clinical skill examination to a variety of fields. PMID- 23441240 TI - Optimizing treatment approaches in seborrheic dermatitis. AB - Seborrheic dermatitis is a chronic, recurring, cutaneous condition that causes erythema and flaking, sometimes appearing as macules or plaques with dry white or moist oily scales. In adults, it commonly occurs in areas with high concentrations of sebaceous glands. The face and scalp are the most frequently affected areas, and involvement of multiple sites is common. Dandruff is regarded as a mild noninflammatory form of seborrheic dermatitis. There is a high incidence of seborrheic dermatitis among persons with human immunodeficiency virus infection or Parkinson's disease. The cause of seborrheic dermatitis is not well understood, but appears to be related to the composition of the sebaceous gland secretions, the proliferation of Malessezia yeasts, and the host immune response. Treatment options for nonscalp and scalp seborrheic dermatitis include topical agents and shampoos containing antifungal agents, anti-inflammatory agents, keratolytic agents, and calcineurin inhibitors. Because multiple body sites are usually involved, the physician should examine all commonly affected areas. Patients should be made aware that seborrheic dermatitis is a chronic condition that will probably recur even after successful treatment. PMID- 23441242 TI - Editorial. PMID- 23441243 TI - Solving the initial problems involved in the writing of a biomedical paper for publication in a peer-review journal. PMID- 23441244 TI - Editorial. PMID- 23441245 TI - Communicating biomedicine at congresses: a general introduction to posters and oral presentations. PMID- 23441246 TI - ECMO, ARDS and AH1N1. PMID- 23441247 TI - The target journal: choosing the right place to submit your paper. PMID- 23441248 TI - Clinical research in intensive care. PMID- 23441249 TI - Italian thoracic anesthesia: a prospective survey. PMID- 23441250 TI - The right language: think English when writing your paper. PMID- 23441251 TI - Preventing mortality in cardiac surgery with anesthetic drugs and techniques. There is need for a consensus conference. PMID- 23441252 TI - Penetrating chest trauma: the role of emergency echo. PMID- 23441253 TI - 'Once upon a time there was a congress...'. PMID- 23441254 TI - Ethics and methodology, not bureaucracy. PMID- 23441255 TI - A 'four-leaf clover' aortic valve. PMID- 23441256 TI - Leave nothing to change: using English to navigate your presentation. PMID- 23441257 TI - Anesthesia needs large international clinical trials. PMID- 23441258 TI - 'A trouble shared is a trouble halved': how the Medical Humanities can help doctors to care while they cure. PMID- 23441260 TI - When a question becomes a nightmare: surviving the most difficult part of your presentation. PMID- 23441259 TI - A rare case of unexpected cardiac incidentaloma causing syncope. PMID- 23441261 TI - New frontiers in aortic surgery and anesthesia. PMID- 23441263 TI - Message in a body: controlling your nerves during an oral presentation. PMID- 23441262 TI - The issue of fluid balance and mortality. PMID- 23441264 TI - Non-invasive ventilation after cardiac surgery. PMID- 23441265 TI - Intracranial placement of a nasogastric tube in a non-trauma patient. PMID- 23441266 TI - Sudden hypotensive syndrome mimicking acute pulmonary embolism after major abdominal surgery. PMID- 23441267 TI - ECMO and the intensivist. PMID- 23441268 TI - A is for Abstract. PMID- 23441269 TI - A journey into clinical evidence: from case reports to mixed treatment comparisons. PMID- 23441270 TI - Severe mitral regurgitation treated by ventricular septal myectomy. PMID- 23441271 TI - A case of radiological dilemma after a central venous catheter positioning. PMID- 23441272 TI - I really think you should publish this paper: the cover letter to the editor. PMID- 23441273 TI - The making of the Roland Hetzer International Cardiothoracic and Vascular Surgery Society. PMID- 23441274 TI - I can't get (or give) no satisfaction.... PMID- 23441275 TI - First expert forum of the roland hetzer international cardiothoracic and vascular surgery society. Lisbon, portugal, october 1, 2011. PMID- 23441276 TI - A loop in the neck. PMID- 23441277 TI - Too-many-bullets spoil the broth (slightly modified English proverb). PMID- 23441278 TI - Outcomes research. PMID- 23441279 TI - Fallacious fracture of clavicle after cardiac surgery. PMID- 23441280 TI - One lump or two? PMID- 23441281 TI - When expert opinion does matter... PMID- 23441282 TI - Because good enough is never good enough. PMID- 23441283 TI - The first 24 hours after surgery: how an anesthetist, a surgeon and a nurse would like to be treated if they were patients. PMID- 23441284 TI - Surgical correction of a saccular descending aortic aneurysm. PMID- 23441285 TI - What we need to know on timing principle of nondepolarizing muscle relaxant administration. PMID- 23441286 TI - Who on earth is this person talking to? PMID- 23441287 TI - State of the art in cardiothoracic surgery: now and the next decade. PMID- 23441288 TI - Is flow really continuous in last generation continuous flow Ventricular Assist Devices? A comparison between HeartMate II and HeartWare HVAD. PMID- 23441289 TI - 2012 pandemic flu. PMID- 23441290 TI - The criteria of eligibility to the extracorporeal treatment. PMID- 23441291 TI - Wish you were here! PMID- 23441293 TI - Head-banging: relationships with borderline personality symptomatology. PMID- 23441294 TI - Treatment with aripiprazole and levetiracetam in a subject with binge drinking disorder: a case report. PMID- 23441295 TI - Buspirone: a possible cause of alopecia. PMID- 23441298 TI - The efficacy of vildagliptin in korean patients with type 2 diabetes. PMID- 23441299 TI - Letter: the risk of bladder cancer in korean diabetic subjects treated with pioglitazone (diabetes metab j 2012;36:371-8). PMID- 23441300 TI - Response: the risk of bladder cancer in korean diabetic subjects treated with pioglitazone (diabetes metab j 2012;36:371-8). PMID- 23441301 TI - At a crossroads: jump forward or fall behind. PMID- 23441303 TI - Composition of volatile in micropropagated and field grown aromatic plants from Tuscany Islands. AB - Aromatic plant species present in the natural Park of Tuscany Archipelago are used as flavoring agents and spices, as dietary supplements and in cosmetics and aromatherapy. The plants are usually collected from wild stands, inducing a depletion of the natural habitat. Therefore, micropropagation of these aromatic plants can play a role in the protection of the natural ecosystem, can guarantee a massive sustainable production and can provide standardized plant materials for diverse economical purposes. The aim of this study is to compare the volatile organic compounds produced by the wild plants with those from in vitro plantlets using headspace solid phase micro-extraction (HS-SPME) followed by capillary gas chromatography coupled to mass spectrometry (GC-MS). Typical plants of this natural area selected for this work were Calamintha nepeta L., Crithmum maritimum L., Lavandula angustifolia L., Myrtus communis L., Rosmarinus officinalis L., Salvia officinalis L. and Satureja hortensis L. Different explants were used: microcuttings with vegetative apical parts, axillary buds and internodes. Sterilization percentage, multiplication rate and shoot length, as well as root formation were measured. The volatile aromatic profiles produced from in vitro plantlets were compared with those of the wild plants, in particular for C. maritimum, R. officinalis, S. officinalis and S. hortensis. This study indicated that the micropropagation technique can represent a valid alternative to produce massive and sterile plant material characterised by the same aromatic flavour as in the wild grown plants. PMID- 23441304 TI - Sinonasal neoplasms again. PMID- 23441305 TI - Is the common cold a clinical entity or a cultural concept? AB - Common cold is the most common infectious disease of mankind and the term is widely used in the clinical literature as though it were a defined clinical syndrome. Clinical studies on this syndrome often use elaborate symptom scoring systems to diagnose a common cold. The symptom scores are based on a study conducted over 50 years ago to retrospectively diagnose experimental cold and this method cannot be applied to diagnosis of common cold in the community. Diagnosis of the common cold by virology is not feasible because of the number of viruses and the variability in the disease states caused by the viruses. Because of the familiarity of subjects with common cold and the variability in symptomatology it seems a more reasonable approach to use self-diagnosis of common cold for clinical research studies and accept that the common cold is a cultural concept and not a clinical entity. PMID- 23441306 TI - Sublingual immunotherapy in allergic rhinitis: indications, efficacy and safety. AB - Sublingual immunotherapy (SLIT) is now an established treatment for allergic rhinitis. Whilst several systematic reviews have now confirmed clinical efficacy and safety, recent analysis also confirms that therapeutic benefit persists for several years after the com- pletion of SLIT. Such findings, along with the obvious ease of administration of sublingual preparations, have clearly promoted SLIT as an attractive option for treatment of allergic rhinitis resistant to medical treatment. This article reviews the development, efficacy and safety of SLIT in allergic rhinitis and the current indications for its use. PMID- 23441307 TI - The golden ratio in facial symmetry. AB - Symmetry is believed to be a hallmark of appealing faces. However, this does not imply that the most aesthetically pleasing proportions are necessary those that arise from the simple division of the face into thirds or fifths. Based on the etymology of the word symmetry, as well as on specific examples and theories of beauty, we conclude that φ-value, a ratio also known as the golden ratio or the divine proportion, can also characterize symmetrical forms. Therefore, we propose the utilization of this ratio in facial aesthetics. PMID- 23441308 TI - Primary sinonasal malignant melanoma: a nationwide study of the Swedish population, 1960-2000. AB - OBJECTIVE: To establish population-based trends for sinonasal mucosal melanoma (SNMM) in Sweden. METHODS: We identified 186 patients from the Swedish National Cancer Registry diagnosed with primary melanomas arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2000. Incidence, gender and age, primary anatomical sites, geographic distribution, treatment and survival were investigated. RESULTS: The age-standardized incidence of SNMM increased significantly during the 41-year-period, with a higher overall incidence for females than males, but with a more rapid increase for males than for females. The incidence increased with age, peaking after the eightieth year in both genders. About 70 % of the cases were clinically amelanotic. The most common primary treatment was surgery. Five-year, disease-specific survival rates were poor for all these patients, but women had a significantly better survival time than men. For both genders the survival rate lengthened during the study period, irrespective of therapeutic strategy. CONCLUSION: SNMM is a rare disease, but the incidence in Sweden has increased significantly from 1960 through 2000, although not at the same pace as that of cutaneous malignant melanoma. Both the incidence and the survival were significantly higher in females than in males, but the reason for these gender differences is unknown. PMID- 23441309 TI - Prevalence of occupational hazards in patients with different types of epithelial sinonasal cancers. AB - BACKGROUND: Occupational exposure to carcinogens contributes greatly to the etiology of sinonasal cancer (SNC), but the role of different risk factors in determining different histological subtypes is disputed. METHODOLOGY: All consecutive surgical epithelial SNC cases (case-series study) underwent a systematic occupational medicine examination to determine previous exposure to a wide range of work-related chemical hazards. RESULTS: We investigated 65 SNC cases including intestinal-type adenocarcinoma [ITAC] squamous-cell carcinoma [SCC], and others. Occupational exposure was recognized for 39 cases. Occupational exposures were sensibly more frequent among ITAC than among SCC or other histotypes. Occupational exposure in ITAC cases was to leather or wood dust only, while among non-ITAC cases, we recognised exposure to formaldehyde, solvents and metal fumes. A high proportion of SNC with occupational exposure originated in the ethmoidal epithelium. CONCLUSION: In our case-series of SNC, a very high frequency of previous occupational exposure to carcinogens was detected, suggesting that occupational hazards may be associated to the aetiopathogenesis, primarily for ITAC, but also for other histotypes. Besides leather or wood, other chemical agents must be recognized as occupational risk factors. PMID- 23441310 TI - Endoscopic endonasal surgery for skull base tumours: technique and preliminary results in a consecutive case series report. AB - BACKGROUND: The introduction of the endoscope in transsphenoidal surgery has allowed access to lesions located in complex regions of the skull base under direct visual control. With the application of this technique, our group started treating pituitary tumours and from 2009 onwards began treating skull base lesions through extended endoscopic endonasal approaches. The AIM OF THE PRESENT STUDY is to report our experience with extended endoscopic approaches. Indications, results, limitations and complications of this new technique are also discussed. MATERIAL AND METHODS: From January 2007 to January 2012, the endonasal approach was used in 40 patients with different cancerous lesions. RESULTS: Total tumour removal, as assessed by postoperative magnetic resonance imaging, occurred in 30/ 40 patients (75%), but in 10 patients only partial removal was possible. Major complications, including cerebrospinal fluid leak, were observed in 5/40 patients (8%). One patient died 3 months after surgery due to a severe systemic sepsis. CONCLUSION: The extended endoscopic endonasal approach could be used as a minimally invasive and innovative technique for the removal of selected skull base lesions. PMID- 23441311 TI - Access to the crista galli and the foramen caecum in nasal dermal sinus cysts - lessons learned in a single tertiary care centre. AB - OBJECTIVE: Several surgical techniques have been suggested for the treatment of nasal dermal sinus cysts (NDSC). We have used several different techniques and have developed a minimally invasive approach. The aim of this study is to describe the evolution to this approach and compare the results with those achieved with our experience of more traditional techniques. METHODOLOGY/PRINCIPAL: A retrospective data collection of patients with NDSC presenting to our clinic between 1998 and 2012 was performed. We initially performed external approaches as outlined elsewhere. With an increasing number of young children requiring surgery, the technique was modified to a less invasive form. This new approach starts with mobilisation of the pit via a tiny skin incision. An open rhinoplasty approach is used to follow the fistula on the nasal bone. Once the fistula passes underneath the nasal bone, an endoscopic endonasal approach is used. Following the fistula cranially, the area of the foramen caecum can be identified. RESULTS: Twelve out of 15 patients (80%) were treated surgically. The transfacial, coronal subcranial and minimally invasive approach was used in 3 (25%), 4 (33%) and 5 patients (42%), respectively. Radical resection was achieved in all patients. Cosmetic problems were present in all patients undergoing a transfacial and in half of the patients after the coronal subcranial approach. Patients treated by the minimally invasive technique remained without sequelae. CONCLUSION: The minimally invasive approach enables a perfect exposure of the fistula up to the crista galli and provides less morbidity and better cosmetic results than the transfacial and subcranial approach. PMID- 23441312 TI - Paranasal sinus osteoma: is there any association with anatomical variations? AB - BACKGROUND: Developmental disturbances of the paranasal sinuses are proposed as the cause of osteoma. We examined whether such disturbances may result in the frequent presence of anatomical variations of the paranasal sinuses in patients with osteoma. METHODOLOGY/PRINCIPAL: The study was performed retrospectively on 2,820 patients subjected to CT examination during 2005 - 2011. Demographic and CT characteristics of osteoma, and associated pathological findings were evaluated for 104 patients with diagnosed osteoma. The presence of anatomical variations was assessed for 51 osteoma patients with a complete medical history, and for 1,233 patients from a control group. RESULTS: The prevalence of osteomas was found to be 3.69%, with male to female ratio 1.08:1. The frontal sinus was most commonly affected. The presence of anatomical variations was more frequent in patients with osteoma than in controls, with significant differences confirmed for the sphenomaxillary plate, infraorbital cell, and crista galli pneumatization. CONCLUSIONS: The paranasal sinus osteoma is associated with higher prevalence of anatomical variations. This can be explained either by the stronger influence of genetic and/or environmental factors on the development of the paranasal sinuses in patients with osteoma, or by their higher susceptibility to above mentioned factors. PMID- 23441313 TI - Eicosanoid imbalance correlates in vitro with the pattern of clinical symptoms of Samter's triad. AB - BACKGROUND: Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with chronic rhinosinusitis (CRS), nasal polyps (CRSwNP) and asthma, together known as Samter's triad. The disease is characterised by eicosanoid imbalance. In our study, we determined clinical and laboratory parameters in respect of three groups of patients: 1) CRSwNP, 2) CRSwNP and asthma (CRSwNP-A), and 3) CRSwNP with asthma and NSAID-triggered hypersensitivity (CRSwNP-AA). Our main goal was to improve the characterisation of the stages of development in Samter's triad, pointing to the homogeneous or heterogeneous course of disease. METHODOLOGY: Forty-three patients (10 CRSwNP, 14 CRSwNP-A, 19 CRSwNP-AA) and 10 control subjects were included in the study. Nasal assessment using the CRS visual analogue score, endoscopy- and computer tomography scores, allergy tests, analysis of sinus surgeries, asthma severity and in vitro functional eicosanoid tests (FET) with peripheral blood leucocytes were performed. RESULTS: The scores reflecting CRS symptoms such as nasal congestion, nasal discharge and smell impairment differed between the patients groups reflecting the severity of disease (CRSwNP-AA > CRSwNP-A > CRSwNP). Eicosanoid imbalance correlated with nasal congestion, nasal discharge and loss of smell. CONCLUSION: The data presented support the hypothesis of the continuous development of NSAID-triggered hypersensitivity, culminating in Samter's triad. PMID- 23441314 TI - Interleukin-6 -174 G/C promoter gene polymorphism in nasal polyposis and asthma. AB - BACKGROUND: Interleukin-6 (IL-6) is an inflammatory mediator linked to nasal polyposis and asthma, with a single nucleotide poly- morphism -174 G/C that seems to promote an inflammatory status. We aimed to analyze the relationship between this poly-morhism and asthmatic nasal polyposis patients. METHODOLOGY: Cross sectional study to investigate IL-6 - 174 G/C genotypes of 45 nasal polyposis with asthma patients, 63 nasal polyposis-only patients, 45 asthma-only patients and 81 subjects without both diseases. Aspirin intolerance and atopy were main exclusion criteria. IL-6 genotyping was performed using the PCR method with specific primers followed by restriction enzyme analysis, classifying patients in GG, GC or CC genotype. RESULTS: The GG genotype was the most frequent in all inflammatory groups. Less than 40% of controls presented with the GG ge- notype. There were significant differences between inflammatory groups and control group. No significant differences were seen when comparing inflammatory groups to each other, other than between nasal polyposis-only group and asthma-only group. CONCLUSION: The IL-6 74 GG genotype was found more frequently in all inflammatory groups than in controls. This genotype could influence nasal polyposis and asthma, and seems to be more important in the latter. PMID- 23441315 TI - Septorhinoplasty by disarticulation: early assessment of a new technique for morphological correction of crooked noses. AB - OBJECTIVE: This study was aimed to assess the early morphological results of a new septorhinoplasty technique based on disarticulation (SRD) between bony and cartilaginous nose structures. METHODOLOGY: A retrospective, multi-judge, blind comparison of pre- and post-operative photographs displayed on Google documents was designed. A nasal morphology analysis grid based on 10 items was fulfilled independently by 6 judges to assess pre- and post-operatively, two times with a 15 day interval, the severity of each deformity by a score between 0 and 2. The sum of all deformities in a single patient produced the individual global score of nasal deformity, which was set between 0 and 20 for each patient. Pre- and post-operative individual global scores were compared using Student's t test on paired samples. Percentages of post-operative improvement and deterioration were calculated for each item. RESULTS: Thirty-five SRD were analyzed. Before surgery, 80% of noses were humped and 86% were crooked; three months after surgery, 64% of noses had a rectilinear nasal crest on profile and 57% on facial view. The mean global score of deformities drop- ped from 11.1 before surgery to 5.8 after surgery, an improvement of 47% . Improvement rates of 82% and 74.3% were obtained, respectively, for hump profiles and orbitonasal lines. DISCUSSION: The early morphological results of SRD allow to propose this technique as a possible solution to correct crooked noses with humps. PMID- 23441316 TI - Audit: patient reported outcomes of extracorporeal septorhinoplasty. AB - BACKGROUND: Extracorporeal septorhinoplasty (ECS) presents an important option in the surgical correction of the markedly deformed and twisted nose. However, there is a paucity of literature on the qualitative outcomes of ECS. METHODOLOGY: Retrospective telephone and postal questionnaire study of operations performed over 2 years (2008-2009) under the care of a senior rhinologist at two linked hospitals in the United Kingdom. Questionnaires were designed (i) relating to the procedure and (ii) patient perceptions of surgical success, improvements in physical health, psychosocial functioning and social interactions. For succinctness a shortened version of the Glasgow Benefit Inventory was used. RESULTS: Forty-six cases were analysed eight of which were revision cases. Two cases required revision surgery and two minor complications occurred, managed conservatively. The patients had a minimum of two to three follow-ups from seven days to one year. Questionnaire scores suggested high satisfaction in response to surgical success, with notable improvements in physical health (sleep disturbance) and in general health and well-being. Regarding psychosocial functions patients reported feeling either moderately less self-conscious or not self-conscious at all post-surgery. Improvements in social interactions were less well-defined. CONCLUSION: In this audit of cases with significant deformities, ECS appears to confer high levels of satisfaction. PMID- 23441317 TI - Warfarin in idiopathic pulmonary fibrosis: friend or foe, is it a matter of genes and heparin? : a reply to Tzouvelekis. PMID- 23441318 TI - Severe vitamin D deficiency: a biomarker of exacerbation risk? : a reply to Heulens. PMID- 23441319 TI - [How long should one have to wait for professional interpreters?]. PMID- 23441320 TI - [Cancer patients should not be treated with statins]. PMID- 23441321 TI - [Screening for obsessive thoughts, depression and ADDH?]. PMID- 23441322 TI - [Research training in medical education must be strengthened]. PMID- 23441323 TI - A feverish infant with scarlatiniform erythema and pustular eruption. Acute generalized exanthematous pustulosis. PMID- 23441324 TI - Ultrafast and nonlinear optics in carbon nanomaterials. AB - Carbon-based nanomaterials-single-wall carbon nanotubes (SWCNTs) and graphene, in particular-have emerged in the last decade as novel low-dimensional systems with extraordinary properties. Because they are direct-bandgap systems, SWCNTs are one of the leading candidates to unify electronic and optical functions in nanoscale circuitry; their diameter-dependent bandgaps can be utilized for multi-wavelength devices. Graphene's ultrahigh carrier mobilities are promising for high-frequency electronic devices, while, at the same time, it is predicted to have ideal properties for terahertz generation and detection due to its unique zero-gap, zero-mass band structure. There have been a large number of basic optical studies on these materials, but most of them were performed in the weak-excitation, quasi equilibrium regime. In order to probe and assess their performance characteristics as optoelectronic materials under device-operating conditions, it is crucial to strongly drive them and examine their optical properties in highly non-equilibrium situations and with ultrashot time resolution. In this section, the reader will find the latest results in this rapidly growing field of research. We have assembled contributions from some of the leading experts in ultrafast and nonlinear optical spectroscopy of carbon-based nanomaterials. Specific topics featured include: thermalization, cooling, and recombination dynamics of photo-generated carriers; stimulated emission, gain, and amplification; ultrafast photoluminescence; coherent phonon dynamics; exciton phonon and exciton-plasmon interactions; exciton-exciton annihilation and Auger processes; spontaneous and stimulated emission of terahertz radiation; four-wave mixing and harmonic generation; ultrafast photocurrents; the AC Stark and Franz Keldysh effects; and non-perturbative light-mater coupling. We would like to express our sincere thanks to those who contributed their latest results to this special section, and the Journal of Physics: Condensed Matter staff for their help, patience and professionalism. Since this is a fast-moving field, there is absolutely no way of presenting definitive answers to all open questions, but we hope that this special section will provide an overview of the current state of knowledge regarding this topic. Furthermore, we hope that the exciting science and technology described in this section will attract and inspire other researchers and students working in related fields to enter into the study of ultrafast and nonlinear optical phenomena in carbon-based nanostructures. PMID- 23441325 TI - The impact of pump fluence on carrier relaxation dynamics in optically excited graphene. AB - The carrier dynamics in optically excited graphene is determined by an interplay between the Coulomb- and phonon-induced scattering processes. The pump fluence of the excitation pulse plays a crucial role: for high fluences the ultrafast relaxation dynamics is determined by carrier-carrier scattering, whereas for low fluences the carrier-phonon relaxation channels are predominant. On the basis of a microscopic approach, we shed light on the influence of the pump fluence on the temporal evolution of carrier and phonon occupations as well as on the many particle dephasing of the microscopic polarization. The new insights obtained contribute to a better understanding of the ultrafast carrier dynamics in graphene and can guide future pump-probe experiments. PMID- 23441326 TI - Time-resolved spectroscopy on epitaxial graphene in the infrared spectral range: relaxation dynamics and saturation behavior. AB - We present the results of pump-probe experiments on multilayer graphene samples performed in a wide spectral range, namely from the near infrared (photon energy 1.5 eV) to the terahertz (photon energy 8 meV) spectral range. In the near infrared, exciting carriers and probing at higher photon energies provides direct evidence for a hot carrier distribution. Furthermore, spectroscopic signatures of the highly doped graphene layers at the interface to SiC are observed in the near infrared range. In the mid-infrared range, the various relaxation mechanisms, in particular scattering via optical phonons and Auger-type processes, are identified by comparing the experimental results to microscopic modeling. Changes from induced transmission to induced absorption are attributed to probing above or below the Fermi edge of the graphene layers. This effect occurs for certain photon energies in the near-infrared range, where it is related to highly doped graphene layers at the interface to SiC, and in the far-infrared range for the quasi-intrinsic graphene layers. In addition to the relaxation dynamics, the saturation of pump-induced bleaching of graphene is studied. Here a quadratic dependence of the saturation fluence on the pump photon energy in the infrared spectral range is revealed. PMID- 23441327 TI - Nonlinear optics of graphene in a strong magnetic field. AB - Graphene placed in a magnetic field possesses an extremely high mid/far-infrared optical nonlinearity originating from its unusual band structure and selection rules for the optical transitions near the Dirac point. Here, we study the linear and nonlinear optical response of graphene in strong magnetic and optical fields using a quantum-mechanical density-matrix formalism. We calculate the power of the coherent terahertz radiation generated as a result of the four-wave mixing in graphene. We show that even one monolayer of graphene gives rise to an appreciable nonlinear frequency conversion efficiency and Raman gain for modest intensities of the incident infrared radiation. PMID- 23441328 TI - Alain Fischer: Winner of the Avery-Landsteiner Prize for immunology 2012. PMID- 23441329 TI - 4th EFIS-EJI South East European Summer School Immunology in Sarajevo. PMID- 23441330 TI - The EFIS-EJI Ruggero Ceppellini Advanced School of Immunology Innate Immunity 2012: from evolution to revolution. PMID- 23441331 TI - [Cancer patients should not be treated with statins. Reply]. PMID- 23441332 TI - [Screening for obsessive thoughts, depression and ADDH? Reply]. PMID- 23441333 TI - Author's response to Persson's letter. PMID- 23441334 TI - Retraction: CDP/cut is an osteoblastic coactivator of the vitamin D receptor (VDR). PMID- 23441335 TI - Violence and HIV risk among female sex workers in Southern India. AB - BACKGROUND: This study characterized the type and frequency of violence against female sex workers (FSWs) perpetrated by their clients and their main intimate or other nonpaying partner (NPP) and examined the relationship between violence and inconsistent condom use (ICU, G100%). The factors associated with client violence were also assessed. METHODS: Data were analyzed from cross-sectional surveys of FSWs in Karnataka state (2007-2008), India. Multivariable logistic regression was used to assess the following: (1) relationship between client or NPP violence (physical and/or sexual) and ICU by occasional/repeat clients or the NPP and (2) relationship between social and environmental factors and client violence. RESULTS: Of 1219 FSWs, 9.6% (111) and 3.7% (42) reported experiencing violence by clients and the NPP, respectively. In multivariable analysis, after adjusting for social and environmental factors, the odds of ICU by occasional clients were significantly higher for women who had experienced client violence (adjusted odds ratio [AOR], 2.7; 95% confidence interval (CI), 1.6-4.4). Similar results were found with repeat clients (AOR, 2.2; 95% CI, 1.4-3.4). Nonpaying partner violence was not significantly associated with ICU by the NPP. In multivariable analysis, only being recently arrested remained significantly associated with experiencing client violence (AOR, 1.8; 95% CIs, 1.0-3.3). CONCLUSIONS: The findings from this study provide evidence of a relationship between experiencing client violence and ICU by occasional and repeat clients, and a relationship between being arrested and client violence. Comprehensive structural/policy programming for FSWs, including within HIV-focused prevention programs, is urgently needed to help reduce FSWs' vulnerability to violence PMID- 23441336 TI - [Should small polyps already be removed during insertion of the colonoscope?]. PMID- 23441337 TI - [The PLAN-Score: prognosis evaluation after stroke?]. PMID- 23441339 TI - [Structured blood pressure management?]. PMID- 23441338 TI - [Plasticizers and bisphenol A: widespread endocrine active substances]. PMID- 23441340 TI - [New strategies are needed for treatment of COPD]. PMID- 23441342 TI - Protecting our public health workers. PMID- 23441341 TI - Author's reply to Lamy. PMID- 23441343 TI - Patellofemoral instability in skeletally immature athletes. PMID- 23441344 TI - Eastern opportunities. HCA founders look to nascent Chinese market. PMID- 23441346 TI - Chagas: a neglected tropical disease. PMID- 23441347 TI - Seroprevalence of Trypanosoma cruzi in blood donors at the National Blood Transfusion Services--Guyana. AB - INTRODUCTION: Blood transfusion is an important transmission route of Trypanosoma cruzi (T cruzi), a major parasitic infection in Central and South America. The limited treatment options are most effective in acute Chagas' infection. At present, there is no current data on the prevalence of T cruzi in the blood donor population of Guyana. This information is necessary to protect the supply of the blood donation programme. This study sought to determine the prevalence of T cruzi in the blood supply at the National Blood Transfusion Services of Guyana with the hope of providing knowledge to the on-going surveillance for Chagas' disease worldwide and therefore address the risk of its spread by blood transfusion. METHODS: Two commercialized ELISAs utilizing crude or recombinant T cruzi antigens were used to study 2000 blood samples voluntarily donated for the purpose of altruistic or family replacement donation retrospectively. RESULTS: The results showed that approximately 1 in 286 donations tested positive for antibodies to T cruzi. CONCLUSION: These results indicate that T cruzi continues to be a risk in Guyana and there is a need to continue screening donated blood. Trypanosoma cruzi is a life-long infection and infected persons may be asymptomatic chronic carriers of the disease. Education, housing improvement, and controlled use of insecticides should be introduced to contain Chagas' disease. PMID- 23441348 TI - Evaluation of blood bisphenol A contents: a case study. AB - OBJECTIVE: It has been recently reported that Bisphenol A (BPA) may leach out into food, beverages and water samples from the plastic ware in which it is stored. Serious health hazards have been reported from BPA. The purpose of this study is to assess the BPA contents in blood and to assess the risk of cancer. METHOD: A total of 100 individuals were selected for study according to the following five age groups: 5-10, 11-20, 21-30, 31-40 and 41-50 years. They were then further divided into normal and diseased. Age, gender, education, source of drinking water, type of food, smoking habit, any exposure to chemicals and history of cancer were elicited during interview. Blood samples were collected and processed for analysis using reversed phase-high performance liquid chromatography (rp-HPLC) in isocratic mode. The mobile phase consisted of acetonitrile and water (1:1) at a flow-rate of 1 ml min-1. RESULTS: Bisphenol A contents found in blood samples of all age groups ranged from 1.53-3.98 (mean = 2.94, SD = 0.9). P-values, for the exposed people and those having a history of cancer, were < 0.05 showing a significant relationship between BPA and cancer The United States Environmental Protection Agency (US EPA) has established a reference dose of 50 microg/L. Odd ratios and relative risk for smoking habit were < 1 while for all others they were > 1. CONCLUSION: It was concluded from the study that people using bottled water, packaged food, having a history of cancer and who had been exposed to any type of chemicals are at higher risk of disease. PMID- 23441349 TI - Paraoxonase 1 status in keratoconus: a preliminary study of activity and polymorphism. AB - OBJECTIVE: To determine the activity of paraoxonase 1 (PON1) in keratoconus in a Malaysian population in comparison with non-keratoconic subjects. METHODS: Clinical eye examinations were performed on patients with keratoconus and non keratoconic subjects after questionnaires were completed. Blood samples were collected and subjected to spectrophotometric analysis of paraoxonase and diazoxonase activities for the determination of the status of PON1 of every individual. RESULTS: Of the 11 keratoconic patients and 55 non-keratoconic control samples collected, eight patients of Indian ethnicity were keratoconic (73%), whereas 33 non-Indians were non-keratoconic (60%; p = 0.047). Paraoxonase activity was lower in Indians compared to the non-Indians ie Malays and Chinese (p = 0.008). Keratoconic subjects had a lower paraoxonase activity compared to non-keratoconics (p = 0.038). CONCLUSIONS: The reduced paraoxonase activity in keratoconic patients suggests that the keratoconic corneas were more susceptible to oxidative stress. Reduced paraoxonase activity and keratoconus status appears to be associated with ethnicity. PMID- 23441350 TI - Intensive insulin therapy in severe acute pancreatitis: a meta-analysis and systematic review. AB - OBJECTIVE: To assess the effect of intensive insulin therapy on outcomes of patients with severe acute pancreatitis. METHODS: Relevant literatures cited in these electronic databases: Medline, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNK1) database, and Excerpta Medical database (Embase) were systematically searched for randomized controlled trials (RCTs) in which intensive insulin therapy was used in severe acute pancreatitis. Length of hospitalization, acute physiology and chronic health evaluation II (APACHE II) score, incidence of complications, and adverse effects were recorded for statistical analysis. The methodological quality of the eligible studies was assessed by Jadad scale. The results were analysed by Revman 4.3 software. RESULTS: Three studies, which included a total of 118 cases, were finally reviewed. The methodological quality of the trials varied substantially In patients with severe acute pancreatitis, intensive insulin therapy was associated with shorter length of hospitalization (weighted mean difference (WMD) = -12.13, 95% confidence interval (CI) [-15.48, 8.78], p > 0.00001) and lower APACHE II score after 72 hours treatment (WMD = -3.80, 95% CI [-4.88,2. 72], p > 0.00001). One study reported insulin-related adverse event. CONCLUSION: In patients with severe acute pancreatitis, intensive insulin therapy could relieve the patient's condition earlier and shorten the length of hospitalization without serious adverse effect. PMID- 23441351 TI - Evaluating a theory-based health education intervention to improve awareness of prostate cancer among men in Western Jamaica. AB - OBJECTIVE: To evaluate the impact of a theory-based health education intervention on awareness of prostate cancer and intention to screen among men in Western Jamaica. METHODS: One hundred and eighty-eight men attending outpatient clinics in a hospital in Western Jamaica completed an interviewer-administered pretest survey. Following the pretest, participants received a health education intervention related to prostate cancer and an immediate post-test survey RESULTS: There were statistically significant increases in the percentage of correct responses between the pretest and post-test (p < 0.05). The greatest improvement was among items measuring knowledge of prostate cancer screening tests. Participants moved across the Stages of Change theoretical constructs indicating intention to screen. CONCLUSION: The sample was receptive to information about prostate cancer and the use of a theory-based educational intervention positively influenced knowledge of prostate cancer risk factors, symptoms, and types of screenings. PRACTICE IMPLICATIONS: This theory-based patient education programme can be replicated to promote awareness of prostate cancer and informed screening methods including potential risk associated with screening behaviours. PMID- 23441352 TI - An observational study of intraoperative transfusion management in a cardiac surgical unit in Trinidad and Tobago. AB - OBJECTIVE: To investigate the intraoperative transfusion requirements in off-pump coronary artery bypass grafting (OPCABG) and the cost implication of blood products and cell savers on a background of limited resources. METHODS: Prospective data collection identified 60 patients undergoing OPCABG surgery at the Eric Williams Medical Sciences Complex, Trinidad and Tobago. Data relating to these patients (including preoperative haemoglobin (Hb), graft number, presence of diabetes, ejection fraction, preoperative serum creatinine, intraoperative blood use and blood loss) and costing for cell saver disposables and prepared donor (or allogenic) blood were obtained. RESULTS: Twenty units of packed red blood cells (pRBCs) were given in theatre to 27% (16 of 60) of patients. Transfusion requirement was significantly lower in patients with fewer grafts, higher preoperative Hb level and non-diabetic patients. Cell saver disposables and one unit of pRBCs were estimated to cost TT$5000 and TT$1700, respectively. Each patient's transfusion cost TT$2125.00 per unit. CONCLUSION: The study demonstrates the financial implications of routine cell saver use in OPCABG in a setting of limited resources. The cost-effectiveness of routine cell saver use remains to be elucidated, but we recommend the selective use of cell savers in patients who are at a higher risk for transfusion. PMID- 23441353 TI - Tuberculous meningitis: a report of 60 adult cases. AB - OBJECTIVE: This was to evaluate the history, clinical and laboratory findings, outcome and prognosis of patients with tuberculous meningitis (TBM). METHOD: Between 1998 and 2009, 60 patients with TBM were evaluated, retrospectively. RESULTS: Overall, 60 patients were selected, of which 33 (55%) were male. The patients' ages ranged from 14 to 62 years. In the majority of the patients, disease was in an advanced stage on admission (66% in stage III according to the British Research Council neurological criteria). The rate of complications was highest among patients in stages II and III with an overall mortality rate of 6.6% (n = 2 of stage II patients and n = 2 of stage III patients). CONCLUSIONS: Earlier admission of the patients with TBM could provide better outcomes with regard to sequelae and mortality. Fatal cases presented with rapid deterioration and were refractory to treatment. PMID- 23441354 TI - Paediatric ocular trauma admissions to the University Hospital of the West Indies 2000-2005. AB - PURPOSE: To assess the epidemiology of paediatric ocular trauma presenting to the University Hospital of the West Indies (UHWI), Jamaica, between January 2000 and December 2005. METHODS: Retrospective review of all paediatric patients (< or = 16 years old) admitted with ocular trauma in the UHWI trauma database. RESULTS: Three hundred and ninety-seven patients were admitted with ocular trauma during the study period, 36.5% of admissions were < or = 16 years old. Males comprised 69.6% (101/145) of the paediatric admissions. The mean age was 8.3 years (95% CI 7.2, 9.4) and 8.7 years (95% CI 7.9, 9.4) for the females and males, respectively. The commonest place of injury was in the home: 47.5% and 50% in males and females, respectively Females were more likely to be involved in domestic disputes (4.8%). Stones (20.3%) were the most common causative agent of eye injury in children, only occurring in the 4-16-year old age group. The highest incidence for hospitalization of paediatric eye injury occurred in March and May, with the least admissions occurring in February. Contusions (48.3%) were the most common type of injury. Open globe injuries occurred in 35.9% of cases. Chemical burns were the least common type of injury. The admission period ranged from 1-58 days. The median hospitalization period was five days (95% CI 4.5, 6.0). CONCLUSION: Paediatric ocular injury can be age specific. Contusion was the most common ocular injury and males were more likely to be hospitalized than females. Epidemiological information is important in determining the burden of ocular disease in the population. It is also essential in planning improvement in health services and patient education for prevention of serious eye injuries. PMID- 23441356 TI - Colonoscopy in central Jamaica: results and implications. AB - The aim of this report was to determine the outcome of all patients subjected to colonoscopy at an outpatient medical facility in central Jamaica. A copy of the colonoscopy report of each consecutive patient during the period March 2007 to April 2011 was entered into a database and analysed. One thousand two hundred and fifty patients were identified with a mean age of 60 years and 56.5% were female. The most common indication for colonoscopy was bleeding (28%) but constipation (15%) and screening (11%) were also important. Caecal intubation was achieved in 96% of the group. While 30% of the group had normal findings, 32% had diverticulosis and 23% had haemorrhoids; importantly 10% had carcinomas and 11% had adenomas. Adenomas were detected in 13% of the screened patients. The most important predictor of an abnormal colonoscopy was a history of bleeding. The perforation rate was 0.24% with no perforations occurring in the latter 650 cases. PMID- 23441355 TI - Hospitalization trends in adult ocular trauma at the University Hospital of the West Indies. AB - OBJECTIVE: To assess the epidemiology of ocular trauma in adult patients admitted to the University Hospital of the West Indies (UHWI), Jamaica, between January 2000 and December 2005. METHODS: Retrospective review of all adult patients admitted with ocular trauma in the UHWI trauma database. RESULTS: Three hundred and ninety-seven patients were admitted with ocular trauma during the study period; 35.8% of admissions with ocular trauma were < or = 16 years of age. There were 252 adults (> 17 years old), 21.4% (54/252) were females and 78.6% (198/252) were males. The ratio of males to females was 3.7:1. The median age of the females and males was 32 years (95% CI 27, 35.9) and 33 years (95% CI 30, 35.0), respectively. The hospitalization period ranged from 1-283 days, mean 8.8 days in the males; and ranged from 1-39 days, mean six days in the females. March had the highest mean admissions over the six years. Severe chemical burns were the cause of the longest admissions. The most commonplace of injury was the home (30.2%) followed by in the street (28.2%); only 2% were from recreation. The most common cause of ocular injury was motor vehicle accident in 18.6%. The second most common cause was from nail hammering (14.3%); of this, 97.2% were male. Females (14.8%) were more commonly admitted from chemical injuries than males (11.1%). Of the females, 50% were due to domestic dispute and 50% were accidental bleach spills. CONCLUSION: The most common cause of ocular injury was motor vehicle accidents, nail hammering in males and chemical injuries in females. Epidemiological information is important in determining the burden of ocular disease on the population. It is essential in planning improvement in health services and patient education for prevention of serious eye injuries. PMID- 23441357 TI - A study exploring the knowledge, attitudes and practices of young people regarding dengue fever and the extent of community involvement in vector control of the disease in Trinidad and Tobago. AB - OBJECTIVE: This study intends to explore young people's knowledge, attitudes and practices regarding dengue fever in Trinidad and Tobago. METHODS: Interviews and focus groups were carried out with young people studying at the University of Trinidad and Tobago. Thematic analysis was then conducted on these scripts and recommendations for improvement were made. RESULTS: All participants had some knowledge about dengue fever; however the extent of this knowledge varied greatly. Participants knew most about the mode of spread and symptoms. All participants did something at home as a means of vector control of the disease; ensuring no stagnant water was present in containers in the yard was the most popular method of vector control. All participants were aware that the government sprayed the neighbourhoods against mosquitoes; however the majority thought they did not do this often enough. CONCLUSION: Following the results of this study, three recommendations were made: the government should spray on a more regular basis, particularly just before the rainy season; a pilot study should take place investigating whether a fining scheme would improve vector control and dengue fever health education should be improved. PMID- 23441358 TI - Health behaviour and quality of life of patients with type 2 diabetes attending selected hospitals in south western Nigeria. AB - BACKGROUND: Type 2 diabetes is a chronic disease that affects patients' general health and well-being in various ways. Modification of lifestyle is essential in preventing Type 2 diabetes including its secondary complications. OBJECTIVE: This study assessed the profile, health behaviour and quality of life of patients presenting with Type 2 diabetes and attending the diabetic clinics of Lagos State University Teaching Hospital, Lagos State and the Ring Road State Hospital, Ibadan. SUBJECTS AND METHOD: A total of 100 diabetic patients aged between 40 and 85 years participated in this study. Their physical activity levels were determined by using the International Physical Activity Questionnaire (IPAQ); quality of life (QOL) was assessed using the Diabetes Quality of Life (DQOL) Inventory questionnaire and alcohol and smoking status as well as nutrition patterns were assessed using the Alcohol, Smoking and Nutrition Questionnaire (ASNQ). Age, gender, body mass index, waist circumference, waist-hip-ratio and blood pressure were also reported. Data were presented using descriptive statistics of mean, standard deviation, percentages and are presented in figures and tables. RESULTS: Results showed that most of the participants were overweight and/or obese with 62% having a body mass index greater than 25 kg/m2. About 78% of females showed a waist circumference of > 88 cm while 48% of the male participants had a > 92 cm waist circumference. Ninety-seven per cent of the female participants had a waist-hip ratio above 0.85 while 32% of the males had above 1.0 waist-hip ratio. Using the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) classification for hypertension, 49% of the participants were found to be at stages 1 and 2 hypertension by systolic blood pressure while 43% of the participants were at stages 1 and 2 hypertension by diastolic blood pressure. Sixty-two per cent of the participants revealed a low physical activity level, 34% had a moderate physical activity level while 4% had a high physical activity level. All the participants indicated that they neither consumed alcohol nor smoked at the time of the study. Thirty-four per cent of the participants had adequate quantities of fruit, 31% of them also consumed an adequate quantity of legumes and 73% of them ate an adequate quantity of fish per week. Fifty-eight per cent of the participants took less quantities of salt with their food as compared to their peers while 95% of the participants did not add sugar to their food; 79% of them preferred their food boiled. The mean score of the participants' QOL was 31.85 +/ 7.98 out of a total score of 75. The QOL as reported by the participants thus indicated a fairly good quality of life. CONCLUSION: Patients with Type 2 diabetes were generally found to be overweight, obese, sedentary and were frequently found to be hypertensive. It is, therefore, suggested that patients need to pay attention to their weight by participating in weight reduction programmes and also improve their physical activity levels in order to reduce their risk of developing the complications associated with Type 2 diabetes. PMID- 23441359 TI - Effects of steroid treatment on bone mineral metabolism in children with glucocorticoid-sensitive nephrotic syndrome. AB - Glucocorticoids have been used in nephrotic syndrome (NS) treatment for many years. In this study, we aimed to evaluate the effect of steroids on bone mineralization in children with glucocorticoid-sensitive nephrotic syndrome (GSNS). Twenty children who were first diagnosed as GSNS received glucocorticoid therapy for four months. Before treatment, at the 4th and 12th week of initial therapy, bone mineral density (BMD) and levels of the markers for bone turnover were evaluated. At the 4th and 12th week of treatment, mean serum calcium (Ca) and osteocalcin levels were found to be significantly lower than those at the beginning of the therapy. Mean serum total alkaline phosphatase (t-ALP), bone specific alkaline phosphatase (b-ALP) and urine calcium creatinine ratio (Ca/Cr), urinary deoxypyridinoline levels were significantly increased in comparison to the beginning of therapy There was no significant relationship between serum levels of phosphate and parathyroid hormone (PTH) at the beginning of treatment and at the 4th and 12th week of treatment. Mean value of BMD was significantly lower at the 4th and 12th week of treatment than that at the beginning of the therapy In conclusion, bone mineralization was negatively affected by steroid treatment in children with NS. These children should undergo regular BMD evaluation, and an appropriate therapeutic approach should be planned. PMID- 23441360 TI - Orthodontic manpower requirements of Trinidad and Tobago. AB - OBJECTIVE: A study was done to estimate the orthodontic manpower requirements of Trinidad and Tobago. METHODS: A questionnaire was administered via e-mail to 9 of 11 orthodontists. Information from a population census, a report on the orthodontic treatment needs of children in Trinidad and Tobago and this questionnaire were used to calculate the number of orthodontists and chairside orthodontic assistants needed in Trinidad and Tobago. RESULTS: On average, 50 per cent of the 289 patients treated by each orthodontist in Trinidad and Tobago annually are children. Approximately, 13 360 patients can be expected to demand orthodontic treatment every year in this country. The number of orthodontists and chairside assistants required to treat these patients was estimated to be 44 and 154, respectively. CONCLUSIONS: Currently, Trinidad and Tobago only has a quarter of the number of orthodontists and orthodontic chairside assistants required to treat the number of patients in need. As the demand is relatively high in Trinidad and Tobago and the number of orthodontists has increased slowly and inadequately for the past decade, the orthodontists are likely to remain adequately employed and happy with their job unlike dentists who are currently in private practice for less than a year. PMID- 23441361 TI - Prevalence of root dilacerations in Central Anatolian Turkish dental patients. AB - OBJECTIVE: The aim of this study was to determine, retrospectively, the prevalence and distribution of the dilaceration of the root for each tooth-type in a sample of Central Anatolian Turkish population by using panoramic radiographs. METHOD: Panoramic radiograhs of 6912 patients (3860 women and 3052 men, mean age 29.04 years, range, 15 to 50 years) were examined for the presence of root dilacerations. Chi-square test was also used to compare the prevalence of dilacerations between male and female subjects and upper and lower jaws. RESULTS: Data showed that 1108 (16.0%) of these subjects had one or more teeth that were dilacerated and these were detected in 466 (15.2%) males and 642 (16.6%) females. Statistical analysis (chi2 test) showed a significant difference in the prevalence of dilaceration among male and female patients. Mandibular third molars were dilacerated most often (3.76%), followed by mandibular second molars (1.81%). Dilaceration was found in 1.23% of maxillary second premolars and 1.23% of mandibular second molars. CONCLUSION: Root dilacerations are not uncommon among Turkish dental patients, and their early detection could be important in treatment problems associated with it. However further larger scale studies are required to assess its prevalence in the general population in order to compare it with other ethnic groups. PMID- 23441362 TI - How an Ebstein-Barr virus may induce acute fulminant myocarditis in a young immunocompetent adult: a case report. PMID- 23441363 TI - Postpartum complicated by transverse myelitis. AB - Transverse myelitis is a very rare neurological condition associated with immunologic and infectious conditions causing interruption of the neuroanatomical pathways in a transverse plane in the spinal cord. Herein is described the fatal case of a patient that developed transverse myelitis after a Caesarean delivery, probably related to the epidural analgesia. PMID- 23441364 TI - Huge mucinous cystadenoma presenting as an acute abdomen in the puerperium. PMID- 23441365 TI - Pioglitazone associated diabetic macular oedema. PMID- 23441367 TI - Mental health. PMID- 23441366 TI - Diversity of responses to writer's dystonia--a condition resistant to treatment. PMID- 23441368 TI - Mental health policy and service system development in the English-speaking Caribbean. AB - The countries and territories comprising the English-speaking Caribbean (ESC) have made some strides in the development of mental health policy, services and systems with the expenditure in mental health as a percentage of health budgets ranging from 1% to 7%. The ESC countries have well developed primary healthcare systems. However mental health legislations in many countries are in need of reform. Some countries have developed an innovative community based, secondary care treatment model: treatment in the medical wards of general hospitals. These countries have made progress in integrating mental health into primary healthcare and have made psychotropic medication widely available at the primary care level. Notwithstanding the progress in some countries, greater effort is required in phasing out mental hospitals and integrating mental health into primary care in other ESC countries. PMID- 23441369 TI - A comparison of the psychometric strengths of the public-domain Zung Self-rating Depression Scale with the proprietary Beck Depression Inventory-II in Barbados. AB - OBJECTIVE: To compare the psychometric strengths of two venerable measures of depression, the Zung Self-rating Depression Scale (Zung SDS) and the Beck Depression Inventory-II (BDI-II) in a Caribbean university student population and to provide researchers and clinicians interested in measures of depression with psychometric evidence that differentiates the two instruments for a Caribbean sample. METHODS: Undergraduate student volunteers (n = 415; 75% females, 25% males; mean age = 25.2 years) completed the instruments as part of a larger study. Correlational analyses evaluated internal con-sistency reliabilities. Missing value analyses and corrected item-total correlations are also reported for each scale. RESULTS: The BDI-II demonstrated marginally superior internal consistency reliability (alpha = 0.88) than the Zung SDS (alpha = 0.85). Correlation between the Zung SDS and the BDI-II was strong (r = 0.67, p < 0.01). The Zung SDS was less psychometrically adequate, only 53% of respondents (compared to 81% for the BDI-II) completed the entire form, suggesting that the structure or wording of the questions may be problematic. Comparison of corrected item-total correlations and missing value analyses indicates that many Zung SDS items are problematic. A preliminary effort to evaluate the factor structure of the Zung SDS was complicated by the large number of missing values. CONCLUSION: Head-to-head comparison of the Zung SDS and the BDI-II indicates that the BDI-II demonstrates superior psychometric properties. This paper does not evaluate sensitivity and specificity; nonetheless, researchers interested in measures of depressive symptoms and clinicians looking for a tool to assess depression in Barbados can be confident in the strong psychometric properties of the BDI-II demonstrated thus far Modified versions of the Zung SDS merit further research. PMID- 23441370 TI - Evaluation of the Beck Depression Inventory in a nonclinical student sample. AB - Depression is one of the most common psychological disorders in individuals seeking psychiatric treatment, and a frequent psychological disorder among patients who seek primary healthcare. Therefore, it is vitally important to employ reliable and valid diagnostic instruments and norms, both in clinical and research work to investigate this problem. This article is part of a larger study which has been conducted for ten years now with the aim to create a clearer picture about the level of depression which may be expected in the nonclinical population in Serbia, and in that way provide a basis for comparisons when diagnosing the clinical population. The subsidiary aims were to monitor potential changes in level of depressive reactions within the set time and to examine the psychometric properties and factor structure of the Beck Depression Inventory (BDI) scale. The sample consisted of 782 students (40% male, 60% female), mean age = 23.10 years, SD = 1.782. Mean score on the BDI-IA scale was 6.69; SD = 6.412. The study showed no significant relationships between the BDI scores and sociodemographic variables such as age, economic status, and educational profile, but showed significant differences within gender (t (780) = 3.222, p = 0.001). There was also a relatively stable level of depressive reactions in this population over the previous ten years. The Cronbach's coefficient of the BDI scale was alpha = 0.860, with the majority of item-total correlations above 0.37. The three-factor structure represents cognitive aspect, affective component of depression, and somatic problems attached to depression. The cognitive factor prevails in the entire sample, which is in accordance with the Beck theory about dysfunctional attitudes, ie cognitive vulnerability is a psychological predisposition to depression. PMID- 23441371 TI - Depressive symptoms in adolescents in Jamaica. AB - BACKGROUND: Depression in adolescents is often overlooked and misdiagnosed; however it is an important mental health problem which is associated with major functional impairments across daily domains of living, and considerable morbidity. The aim of this research is to examine the prevalence of self-reported depressive symptoms among Jamaican adolescents, and the associated sociodemographic factors. SUBJECTS AND METHOD: This cross-sectional study included 3003 students between 10 and 15 years old in Jamaica. Survey methodology was used in the collection of the data. RESULTS: Of the sample of students, 47% were males. One hundred and thirty-four (4.5%) reported having depressive symptoms. The factors significantly associated with depressive symptoms were negative community attributes (B = 1.1; p = 0.001), protective factors within the home (B = 0.72; p = 0.000), gender (B = 1.92; p = 0.000), and learning problems (B = 3.1; p = 0.000). CONCLUSION: Results indicate rates of depressive symptomatology reported among adolescents in Jamaica are consistent with rates reported in the literature. PMID- 23441372 TI - Depression among cardiovascular disease patients on a consultation-liaison service at a general hospital in Jamaica. AB - OBJECTIVE: The prevalence of cardiovascular disease in Jamaica and other Caribbean countries has been steadily rising. Depression has been associated with increased morbidity and mortality in patients with cardiovascular disease. Against this background, the authors compared the co-occurrence of depressive illnesses among general hospital inpatients with cardiovascular disease and those without cardiovascular disease. METHOD: Psychiatric and non-psychiatric diagnoses on all inpatients referred to the consultation-liaison psychiatry service at a general hospital in Jamaica were recorded over a one-year period and analysed using chi-square, t-tests, binary logistic regression and odds ratio. Statistical significance was taken at the 0.05 level. RESULTS: Of the 201 patients referred, 17.9% had cardiovascular disease and 19.9% had depressive illnesses. One third of patients with cardiovascular disease were depressed. They were also significantly more likely than other patients to have a depressive illness (OR = 2.93, 95% CI: 1.25, 6.85). CONCLUSION: Special attention to the prevention, detection and treatment of depression should be applied to patients with cardiovascular disease. PMID- 23441373 TI - Bullying, mental health, and parental involvement among adolescents in the Caribbean. AB - OBJECTIVE: To examine the relationships between peer victimization, mental health, and parental involvement among middle school students in the Caribbean. METHODS: Data from the Global School-based Student Health Survey (GSHS) conducted in the Cayman Islands, St Lucia, St Vincent and the Grenadines, and Trinidad and Tobago in 2007 were analysed using age- and gender-adjusted logistic regression models. RESULTS: About one-quarter of the 6780 participants reported having been bullied in the past month. Rates of bullying were similar for boys and girls, and younger children reported higher rates of peer victimization. Nearly 25% of students reported sadness and hopelessness, more than 10% reported loneliness and anxiety and more than 15% reported having seriously considered suicide in the past year. Bullied students were much more likely than non-bullied students to report mental health issues (p < 0.01). Students who felt that their parents were understanding and monitored their free time activities reported fewer mental health issues and were somewhat less likely to report being a victim of a bully. CONCLUSION: The strong association between bullying and poor mental health in the Caribbean emphasizes the need to develop and implement strategies for reducing bullying among children and adolescents. PMID- 23441374 TI - The epidemiology of suicide in Jamaica 2002-2010: rates and patterns. AB - OBJECTIVE: Suicide is increasingly recognized as a worldwide problem. There is a paucity of quality data pertaining to suicide in developing countries. Epidemiological analysis of suicide data elucidates prevailing patterns that facilitate risk factor identification and the development of germane programmatic responses. This paper analyses temporal variations in suicide rates for the years 2002-2010 in Jamaica and describes the sociodemographic profile of cases and method of suicide for the latter four years. METHOD: Data pertaining to suicides were extracted from the police (The Jamaica Constabulary Force) records. These were summarized and analysed with respect to person, place and time. Population statistics for the computation of rates were obtained from publications of the Statistical Institute of Jamaica. Age-standardized rates were generated for comparison of trends over time. Poisson and binomial probabilities were used to determine statistically significant differences in rates. RESULTS: Suicide rates in Jamaica have remained relatively stable for the period reviewed with mean overall annual incidence of 2.1 per 100 000 population. Rates for males were significantly higher than those for females. The majority (90.4%) of suicide cases were males. A trend for higher rates of suicide was generally noted in the 25-34-year and the 75-year and over age groups. Hanging was the main method used to commit suicide (77.5%). CONCLUSIONS: Age-adjusted rates of suicide indicate no significant changes in Jamaica over the period 2002 to 2010. Continued surveillance of suicide as well as improved recording of the circumstances surrounding suicides are recommended to promote greater understanding of suicides and this will ultimately inform intervention strategies. PMID- 23441375 TI - Suicide among adolescents in Jamaica: what do we know? AB - Suicide is increasingly acknowledged as a global problem. Yet little is known worldwide about suicide rates among adolescents. Several social factors that exist in Jamaica present as stressors and may predispose to suicide. Ascertaining prevailing patterns and associated factors is important for crafting interventions. This paper establishes adolescent suicide rates for the years 2007 2010 in Jamaica and provides related epidemiological data. METHOD: Data pertaining to suicides were extracted from standardized data collected by the police. Information regarding the number of suicides among adolescents, 9-19 years of age, was reviewed for the years 2007-2010. Sociodemographic characteristics of cases: gender, location and occupation along with related variables were also examined. Variation of rates over time was ascertained. Statistically significant associations were determined by reference to p-values and confidence intervals. RESULTS: The incidence for suicide in adolescents was 1.1 per 100 000. Rates for males were significantly higher than females. Most suicide cases were students and the majority of cases was from rural areas (65%). Hanging was the main method used to commit suicide (96.2%). Items of clothing were commonly used for this purpose. CONCLUSION: Male adolescent suicide rates showed an upward trend in contrast to the downward trend for females in the four year period studied. Continued surveillance is needed for greater understanding of adolescent suicides. Collaboration among health services, parents, schools and communities is integral in prevention efforts. Recent media coverage of suicides provides a window of opportunity to galvanize support for research and the development of intervention strategies. PMID- 23441376 TI - Suicide ideation in Jamaican youth: sociodemographic prevalence, protective and risk factors. AB - OBJECTIVE: To determine the prevalence of suicidal ideation and examine the association between suicidal ideation and sociodemographic characteristics, protective and risk factors among Jamaican youth. METHOD: In this cross-sectional study, an interviewer administered school-based survey was conducted among 2997 students 10-15 years old in Jamaica. Although there were a number of questions on suicide, this paper focusses on one question "During the past year did you ever seriously consider attempting suicide?" as the measure of suicidal ideation. RESULTS: The prevalence rate of suicidal ideation was 9.7%. Logistic regression analysis revealed that significant correlates of suicidal ideation were being female (odds ratio = 1.49), being depressed (odds ratio = 5.78), living in a rural area (odds ratio = 0.62), likes oneself (odds ratio = 0.58), indulging in aggressive behaviour (odds ratio = 1.43), has considered harming others (odds ratio = 3.11), protective factors in the home (odds ratio = 0.62), involvement in risky behaviour (odds ratio = 1.56) and being teased/bullied (odds ratio = 1.69). CONCLUSION: These findings have implication for prevention and treatment of suicidal behaviour in children and adolescents. PMID- 23441377 TI - Suicide attempt by self-poisoning: characteristics of suicide attempters seen at the Emergency Room at the University Hospital of the West Indies. AB - OBJECTIVE: To document the characteristics of self-poisoning suicide attempters who were brought to the University Hospital of the West Indies (UHWI) Emergency Room and to outline the type of drug used in the attempt. METHOD: This was a retrospective study conducted over the period 2005-2009. Data were gathered from patients' case records, log books and the hospital records using a questionnaire developed for this study. The questionnaire examined demographics, parameters of the drug ingested, patient's disposition, and reasons for attempt, final outcome and the type of discharge of patients who reported to the UHWI Emergency Room due to a suicide attempt by self-poisoning. RESULTS: Over the five-year period, 127 cases of suicide attempt by self-poisoning were reported. Significantly more females than males presented to the hospital due to self-poisoning (3:1, chi2 = 33.37; p < 0.001). Of this amount, 96 cases (75.6%) were females and 31 (24.4%) were males. The age group most recorded was 16-30 years (70.8%). The most common reason for the suicide attempt was an interpersonal conflict (52%). The drug category most often used in self-poisoning was analgesics (52%) with acetaminophens being the most common (26.2%). CONCLUSION: These findings are consistent with global suicide trends and indicate an urgent need to develop and implement national preventative and treatment measures for groups known to be at risk of suicidal attempts. PMID- 23441378 TI - The relationship between suicide and five climate issues in a large-scale and long-term study in Japan. AB - OBJECTIVE: Suicide rates in Japan were high in 1998 and have remained high since then. Many researchers have discussed the current state of suicide in Japan and the world; however, there are various opinions about the relationship between suicide and climate. SUBJECTS AND METHOD: In the present study, we report on long term data of suicide and examine five climatic issues in Japan as a whole and in 10 selected prefectures: the five with the highest suicide rates in 2006 (Akita, Iwate, Shimane, Yamagata and Miyazaki Prefectures) and the five with the lowest (Nara, Tokushima, Okayama, Kanagawa and Kyoto Prefectures). RESULTS: Annual age adjusted suicide rates were found to have a significant inverse correlation with annual mean air temperature in the five prefectures with the highest suicide rates and in the three prefectures with the lowest suicide rates among women. Annual age-adjusted suicide rates were significantly correlated with annual mean relative humidity in the three prefectures with the highest suicide rates among women and with the annual total sunshine duration in the three prefectures with the highest suicide rates among women. CONCLUSION: It is important that these associations between suicide and climatic factors be discussed further from various viewpoints, including those of many researchers and relevant organizations. PMID- 23441379 TI - The association between schizophrenia and violent or homicidal behaviour: the prevention and treatment of violent behaviour in these patients. AB - BACKGROUND AND OBJECTIVE: This review article aims to discuss and evaluate the risk factors for the development of violence and homicidal behaviour and the effectiveness and outcomes of the preferred atypical antipsychotics in patients diagnosed with schizophrenia. METHOD: For this purpose, the psychiatry literature was comprehensively reviewed. A screening of the articles in the international databases covering the period between 1970 and 2010 was performed. RESULTS: Although the risk of homicidal behaviours is higher in patients with schizophrenia compared to the overall population, little is known about the relevant conditions triggering acts of violence among the patients with schizophrenia. The available results suggest that certain factors including some sociodemographic characteristics, young age, alcoholism, substance abuse, noncompliance with treatment, fulfillment of the criteria for antisocial personality disorder and paranoid subtype, history of suicidal ideation and attempts and history of frequent hospitalization increase the potential for violent episodes. Available data show clozapine to be the most rational therapeutic choice in preventing violent behaviour in patients with schizophrenia. There is evidence from randomized controlled trials in support of the specific anti-aggressive effect of clozapine. CONCLUSION: In clinical practice, patients with a risk of committing homicide should be detected and monitored closely. There are many trials showing the efficacy of clozapine on violent and aggressive behaviour. PMID- 23441380 TI - Assesment of psychiatric symptoms and co-morbidities in patients with irritable bowel syndrome. AB - AIM: To determine the psychiatric symptom assessment of patients seeking treatment for irritable bowel syndrome (IBS) and to demonstrate the presence of more complicated psychiatric disorders. SUBJECTS AND METHOD: The participants were recruited from patients who were attending internal medicine and gastroenterology clinics and who fullfilled the Rome III criteria for IBS. Fifty patients with IBS (IBS group) and 50 patients with complaints other than gastrointestinal symptoms (control group) were randomly selected. All participants were screened by the Structured Clinical Interview for DSM-IV (SCID I), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Symptom Check list - 90 (Revised) [SCL-90-R]. RESULTS: Seventeen patients (34%) and three control subjects (6%) had at least one psychiatric diagnosis (p = 0.001). Global severity index (GSI) total scores and SCL-90-R items were significantly higher in the IBS group than the control group (0.92 +/- 0.46 vs 0.358 +/- 0.19, p < 0.001). Beck anxiety inventory and BDI scores were higher in the IBS group than the control group (p < 0.001). Axis-I psychiatric disorders diagnosed with SCID-I were significantly higher in the IBS group (34% vs 6%) [p = 0.001]. Among the Axis-I disorders, somatoform and anxiety disorders were higher in the patient group than in the control subjects (p = 0.002 and p = 0.0057) whereas there was no difference for mood disorders (p = 0.204). Seven (14%) of the patients and two (4%) of the control subjects had at least one Axis-II psychiatric disorder diagnosed with SCID-II without any significance (p = 0.159). CONCLUSION: These findings suggest that except for mood and personality disorders, almost all psychiatric symptoms and disease co-morbities with IBS are higher than in the sample without IBS. We can easily use SCL-90-R, BAI and BDI in internal medicine and gastroenterology clinics to detect psychiatric symptom levels and then to refer patients to a psychiatrist for further evaluation and treatment. PMID- 23441381 TI - Oral health status among psychiatric patients in Riyadh, Saudi Arabia. AB - OBJECTIVE: The purpose of this study is to describe the oral health status among psychiatric patients as compared to psychologically normal controls. METHOD: A convenience sample of 100 patients who regularly attended a psychiatric clinic in King Saud University, King Khalid Hospital, Riyadh, Saudi Arabia, was selected as the study group. The control group consisted of 84 age- and gender-matched volunteers. All controls were screened using the General Health Questionnaire (GHQ-28) and five persons were excluded based on this. All the participants were interviewed and a comprehensive review questionnaire designed for this survey was completed, then they were examined. The examination involved an extra-oral examination as well as examination of teeth and soft tissues using the decayed, missing, filled teeth (DMFT) index, the Silness and Loe plaque index and the bleeding index. RESULTS: The study group had more tenderness in the masticatory muscles, especially the temporalis muscle. Temporomandbular joint findings showed no significant differences between groups. Decayed, missing, filled teeth index, plaque and bleeding indices were higher among the study group. The incidence of scalloped tongue was significantly higher among psychiatric patients. CONCLUSION: Oral health status is worse among psychiatric patients, who are more likely to develop some oral conditions, such as temporomandibular disorder and dental caries. It is necessary for both dental and mental healthcare providers to be aware of patients' needs and preventive measures to be instituted for them. PMID- 23441382 TI - An issue to keep in mind regarding specific suicide prevention measures: focussing on bipolar disorder. PMID- 23441383 TI - The continued importance of suicide prevention among the elderly in Japan. PMID- 23441385 TI - Atlas of health and climate launches new collaboration between public health and meteorological communities. PMID- 23441384 TI - Nineteen years study of beta-thalassaemia in Slovakia. AB - BACKGROUND: Beta-thalassaemia is a congenital disorder caused by point mutations in a haemoglobin beta-globin chain. The heterozygous form produces microcytosis and normal iron levels, however, haemoglobin electrophoresis shows elevated amounts of haemoglobin A2 and eventually foetal haemoglobin F as well. METHODS: Between 2005-2011, in three centres in Slovakia, carriers of beta-thalassaemic genes or other haemoglobinopathies were searched for. Diagnosis was performed by haematologists whereby the family history was evaluated, together with the overall clinical condition, blood count and blood smear, iron parameters, haemolysis and haemoglobin electrophoresis testing. A proportion of patients was examined by molecular genetic methods. RESULTS: A clinical suspicion of the heterozygous form of beta-thalassaemia was documented in 402 patients (21.9%) out of a total of 1,834 examinations. From these patients, 87 underwent molecular genetic testing and mutations of beta globin genes were identified in 70 of them, where the most frequent mutations were IVS 2.1 (28.5%), IVS 1.110 (25.6%) and IVS 1.1 (11.3%). Evidence of haemoglobin S (sickle cell anaemia) was also notable in one case (patient of African origin). Unusually high levels of haemoglobin F (6 21%) were found in 23 adult subjects. CONCLUSION: The study showed that there is a higher number of heterozygotes for beta-thalassaemia and rarely haemoglobinopathies. It is necessary to continue in search of pathological gene carriers in Slovakia. PMID- 23441386 TI - Alcohol consumption and marijuana use in young adult Czechs. AB - OBJECTIVES: The main objective of the study is to explore associations between alcohol consumption and marijuana use in young adults and to discuss the opportunities for brief intervention. METHODS: Face to face structured interviews were carried out with 2,221 young adult Czechs (mean age 29.9, sd. 5.8 years). 51.4% were males. Alcohol consumption was calculated using beverage specific quantity frequency method. Alcohol-related problems were assessed using the Czech version of the AUDIT. Frequency of marijuana use in the last twelve months was asked as well. RESULTS: The overall alcohol consumption was 9.2 litres of pure alcohol per person and year. The last year prevalence of marijuana use was 21.8%. The use of marijuana positively correlated with the frequency of beer drinking (r = 0.27), frequency of heavy episodic drinking [HED] (r = 0.32) and with the summary score in AUDIT (r = 0.39). Harmful or problem drinkers (AUDIT score > or = 16) reported marijuana use more frequently than moderate drinkers (60% compared to 18.8%; OR = 6.54; 95% CI = 4.7; 9.1). OR for marihuana use in heavy episodic drinkers was 4.3 (95% CI = 3.3; 5.6). DISCUSSION: The results suggest that frequent HED and harmful drinking are closely associated with marijuana use in younger adults. Since marijuana use (including heavy use) is rather common in the Czech Republic, it would be recommendable to also extend screening and brief intervention to reduce the use of cannabis. The existing guidelines for brief intervention should be modified in order to cover marijuana consumption as well. PMID- 23441387 TI - Tuberculosis knowledge among injecting drug users visiting syringe exchange programme in Tallinn, Estonia. AB - BACKGROUND: The purpose of the current study was to describe tuberculosis (TB) knowledge, beliefs, and experience with TB services among injecting drug users. METHODS: Participants for this anonymous, cross-sectional study were recruited from a community based syringe exchange programme in Tallinn, Estonia. A structured questionnaire was completed and included information on socio demographics, health history, drug use, and knowledge about TB and HIV. RESULTS: The study included 407 people (79% male, mean age 27.9 years, mean injection drug use 9.4 years). 32.9% of participants reported HIV infection and 1.7% lifetime history of TB. 26.4% participants (n=106) reported symptoms suggestive of TB. 93% of participants recognized correctly that TB is air-borne infection and 91% that HIV is a risk factor for TB. Only 40% of the participants knew that TB diagnostics and treatment in Estonia are free of charge for everybody and 58% reported they knew where to get health care services in case they suspected that they had TB. TB transmission and treatment adherence knowledge was better among those in contact with either health care or harm reduction services, e.g the community based syringe exchange programme. CONCLUSION: Similar to HIV services, TB prevention and education should be integrated into harm reduction and drug treatment programmes to facilitate early diagnosis and treatment of TB among injecting drug users. PMID- 23441389 TI - Problematic eating behaviour in Turkish children aged 12-72 months: characteristics of mothers and children. AB - OBJECTIVE: The aim of this study was to determine prevalence of problematic eating behaviour (PEB), associated risk factors, feeding practices including place of meal, variety of diet, and habits of consuming junk food, the mothers' perception of the child growth status in comparison to his/ her peers, and the effects on anthropometric measurements. METHODS: This study was carried out among children aged 12-72 months who attended the outpatient clinic in the Ihsan Dogramaci Children's Hospital between February-June 2007. Three hundred and thirty-one mothers of children were asked to complete an extensive questionnaire covering socio-demographic characteristics and their child's general eating behaviour and feeding practices at mealtimes. Children with PEB were identified based on their mothers' statements. RESULTS: Three hundred and thirty-one cases were 3.32 +/- 1.39 years old. One hundred thirty-five mothers reported having a child with PEB. The mothers described the children's problematic behaviour as: need to walk around with the child during mealtime (45.6%), watching TV during meals (41.9%), picky or fussy eating (39%), vomiting and/or retching (25.7%), retaining food in the mouth for a long time (20.6%), and not eating solid foods (11.8%). In children who had ate neither meat nor vegetables and fruits, took cod liver oil-containing supplement during the course of the study, and had taken iron supplements in the first year of life, PEB was more frequent than in others. The mean z scores of weight for age (WAZ) were significantly lower in cases with PEB than without PEB. DISCUSSION: Counselling and supporting of the mother/caregiver could alleviate the effect of inappropriate solutions taken by families. Insistence on composing of the diet variety including especially vegetables, fruits and meat may be promoted by provision of alternative cooking/presentation samples to mothers of children who refuse some foods. Pediatricians should be alerted that lower WAZ values may be a warning indicating a problem which may cause stagnated growth in children with PEB. PMID- 23441388 TI - Risk factors affecting the incidence of infection after orthopaedic surgery: the role of chemoprophylaxis. AB - The incidence of surgical site infection and urinary tract infection following orthopaedic procedures has diminished in recent years due to modern antimicrobial prophylaxis. We conducted a case-control study (100 cases, 100 controls) in order to evaluate the risk factors associated with infection after orthopaedic procedures. The following risk factors were defined: gender, age, comorbidities [rheumatoid arthritis, diabetes mellitus, obesity (> 30 kg/m2), peripheral vessel disease], pre- and post-operative glucose levels, pre-operative and post operative length of stay (days), duration (days) of urinary catheterization, type of parenteral antibiotic prophylaxis (cefotaxime or vancomycin), time of surgery (elective or scheduled), American Society of Anesthesiologists (ASA) Score (0-3), type of surgery (fracture osteosynthesis, joint replacement, spinal surgery, other), and the type of anesthesia administered (general, epidural, spinal). Urinary tract infection was the most frequent post-surgical infection (71 out of 100 cases) followed by surgical site infection (15 out of 100 cases). Using the multivariable logistic regression model, we found out that only the type of chemoprophylaxis was statistically significant risk factor (p < 0.001) associated with post-surgical infection. More specifically, the use of vancomycin instead of cephalosporin is associated with a lower risk of infection. PMID- 23441390 TI - Vitamin D status and health correlates among apparently healthy participants in an urban, sunny region. AB - AIM: To assess vitamin D status and health correlates in a sample of apparently healthy Caucasian participants residing in an urban area, Athens, with latitude 370 58' 0" N and longitude 230 43' 0" E, after taking into consideration a broad range of purported biological, behavioural and environmental factors. METHOD: Men and women 35+ years from a selected population (n = 490) were studied. Participants completed a detailed questionnaire regarding socio-demographic, lifestyle, clinical and dietary characteristics. Biomarkers were measured after 12 h fasting. Linear and multinomial regression models were used to evaluate the association between 25(OH)D and determinants of vitamin D status. RESULTS: Results revealed that one hour increase of sunlight exposure decreased the odds of having D deficiency (i.e., < 20 ng/mL) by 70% (OR = 0.30, 95% Cl: 0.20-0.45), adjusted for age, sex, family status, physical activity, smoking habits, BMI, triglycerides, parathyroid hormone, uric acid, haptoglobin, folate acid and haemoglobin, as compared to sufficient levels (i.e., >30 ng/mL). Regarding biomarkers, parathyroid hormone and haptoglobin were found to be related with the odds of having vitamin D deficiency (OR = 1.11, 95% CI: 1.05-1.16; OR = 1.02, 95% CI: 1.00-1.03, respectively) as compared to the sufficient levels. CONCLUSIONS: Sufficient serum vitamin D levels were observed among participants with characteristics associated with reduced cardiovascular risk, such as normal BMI, increased physical activity, decreased parathyroid hormone and decreased inflammatory markers. Even a slight increase in sunlight exposure could have beneficial effects on serum vitamin D concentrations and eventually on haemoglobin and inflammatory markers levels, thus providing a simple and inexpensive lifestyle intervention that promotes public health. PMID- 23441391 TI - Dementia care and general physicians--a survey on prevalence, means, attitudes and recommendations. AB - INTRODUCTION: General physicians (GP) play a key role in providing appropriate care for people with dementia. It is important to understand their workload and opinions regarding areas for improvement. MATERIAL AND METHODS: A group of 1,109 GPs working in Mecklenburg-Western Pomerania, Gemany (1.633 million inhabitants), were identified, contacted and asked to participate in a written survey. The survey addressed five main topics: (a) the GP, (b) the GP's practice, (c) the treatment of dementia, (d) personal views, attitudes and specific competences regarding dementia and (e) the GP's recommendations for improving dementia related health care. RESULTS: The survey response rate was 31%. In total, the responding GPs estimated that they provided care to 12,587 patients with dementia every quarter year. The GPs also reported their opinions about screening instruments, treatment and recommendations for better care of dementia patients. Only 10% of them do not use screening instruments, one third felt competent in their care for patients with dementia and 54% opt for transfer of patients to a specialist for further neuropsychological testing. CONCLUSIONS: Four conclusions from this study are the following: (a) dementia care is a relevant and prevalent topic for GPs, (b) systematic screening instruments are widely used, but treatment is guided, mostly by clinical experience, (c) attitudes towards caring for people with dementia are positive, and (d) GPs recommend spending a lot more time with patients and caregivers and provision of better support in social participation. A majority of GPs recommend abolishing "Budgetierung", a healthcare budgeting system in the statutory health insurance programmes. PMID- 23441392 TI - New international protocol adopted to combat illicit trade in tobacco products. Historical consensus--a milestone, for global public health. PMID- 23441393 TI - What Polish hospital healthcare workers and lay persons know about counterfeit medicine products? AB - AIM: To report on Polish hospital health care workers' and lay persons' knowledge about counterfeit medicine products. MATERIALS AND METHODS: Cross-sectional design was used. Two types of questionnaire survey about counterfeit medicine, separate for health care professionals and lay persons were completed by 201 physicians and nurses, and 450 adult Polish residents between October 2008 and January 2009. RESULTS: Physicians and nurses working in hospitals are more aware of counterfeit medicine than lay persons and more often notice the presence of drugs from unknown sources. Nearly 90% of physicians, 80% of nurses, and more than 40% of representatives of the lay persons had heard about the possibility of importing illegal medicine from Ukraine or China. The majority of medical workers does not know the procedure for reporting suspicious medicine and do not warn their patients against purchasing medicine from unknown sources. CONCLUSIONS: Increase education of nurses and physicians about counterfeit medicine particularly including the procedure of reporting suspicious medicine from unknown sources. In practice, reinforce a role of nurses and physicians in warning their patients against purchasing medicine from unknown sources and educate them about possible health hazards and life risks. PMID- 23441394 TI - World AIDS day 2012. Closing in on global HIV targets. PMID- 23441395 TI - Comparing models of the effect of air pollutants on hospital admissions and symptoms for chronic obstructive pulmonary disease. AB - There is an increasing interest in the use of hospital admission for Chronic obstructive pulmonary disease (COPD) in studies of short-term exposure effects attributed to air pollutants. However, little is known about the effect of air pollutants on COPD symptoms. This study was undertaken to determine whether there was an association between air pollutant levels and both hospital admissions and symptoms for COPD. For model comparison, we present Generalized Linear Model, Generalized Additive Model and a general approach for Bayesian inference via Markov chain Monte Carlo in generalized additive model. Furthermore, for comparing the predictive accuracy, Artificial Neural Networks (ANN) approach is given. PMID- 23441396 TI - Civil society organisations and public health research--evidence from eight European union new member states. AB - INTRODUCTION: Civil society organisations (CSO) are not-for-profit, non governmental organisations operating in the public interest. They are the "third sector" that is strongly developed in Western European countries, ensuring the link between citizens and government and working as a counterbalance to the business sector. Their role in support of public health research deserves attention. METHODS: Within a broader European study (STEPS--Strengthening Engagement in Public Health Research), public health organisations in eight European Union new member states (Cyprus, Estonia, Latvia, Lithuania, Malta, Romania, Slovakia, Slovenia) identified national CSOs with interests in health. A questionnaire was developed jointly, translated into national languages and sent by e-mail to 474 organisations, with 128 completed responses (27%). RESULTS: Most CSOs would like to be more involved in setting or advising on public-health research policy, and greater collaboration between CSOs, professional organisations and governmental institutions. Respondents did not see CSOs directly doing research, but recommended mobilizing researchers and organsations, supporting research themes, and lobbying to use public health evidence in policy and decision-making. They could receive more education for, and discussion of, public health research, and offer support in applying for research funding. CONCLUSION: Civil society organisations can contribute importantly,in setting public health research agendas. Research commissioning should give greater recognition of this role, improve links between CSOs, researchers and governmental institutions, and develop a stronger shared basis for public health policy and practice. PMID- 23441397 TI - Organizational environment of outpatient drug treatment services in Hungary: a pilot study. AB - OBJECTIVES: Organizations engaged in drug addiction treatment started their activities only recently in Hungary. This paper examines the organisational environment in drug outpatient treatment using the example of Blue Point Foundation (BPF), a non-governmental organization (NGO). The authors describe BPF's organizational structure and functioning related to its effectiveness. METHODS: BPF staff members anonymously completed a 59-item questionnaire about its organizational characteristics and functioning. The questionnaire covered demographic data, 50 items of the Quality Control questionnaire and a SWOT (Strengths, Weakness, Opportunities, Threats) analysis. RESULTS: Policy and strategy were considered BPF's best feature, while the management of funds received the lowest rating. The assessment of the staff and that of the organization as a whole was closer to the midpoint of the scale. DISCUSSION: High risk of staff burnout and unstable organizational environment are the most important threats on the NGOs working in addictology in Hungary. PMID- 23441398 TI - Avicenna's doctrine and institutional review board in international bio-medical research. AB - Avicenna, an outstanding Persian physician and philosopher (980 AD-1037 AD), established a clinical treaty, or doctrine, without which medical experimentation would not have progressed. This doctrine emphasizes the ultimate divine power of God or a higher being over healing and mandates the patients' well-being as the crucial aspect in all medical care and experiments. The Institutional Review Board, as the ethical body that oversees clinical research, is in line with this doctrine. However, the lack of a homogenous and internationally recognized code of ethics, the decentralized work of ethics oversight committees, the improper implementation of established ethical standards and a shortage of scientific auditing capacities have raised concerns over the possible exploitation of vulnerable populations. PMID- 23441399 TI - Making the first global society for health systems research truly global. PMID- 23441400 TI - COPHES: consortium to perform human biomonitoring on a European scale (COPHES). PMID- 23441401 TI - Watch your back. PMID- 23441402 TI - Joint understanding. PMID- 23441403 TI - Excellence in health technology management. PMID- 23441404 TI - Safety summary: Patient lifts. PMID- 23441405 TI - Institute of Medicine report calls for greater oversight of health IT. PMID- 23441406 TI - Distracted doctoring. PMID- 23441407 TI - Planned software update for Philips BrightView systems scanners includes measures to reduce potential for patient contact. PMID- 23441408 TI - Power switch for Draeger Medical IICS-90 Infant Warmers may fail because of heat stress. PMID- 23441409 TI - Bad week for surgical fires. PMID- 23441410 TI - Joint Commission doesn't LOL about texting physician orders. PMID- 23441411 TI - The big picture. PMID- 23441412 TI - Law has potential to affect medical telemetry systems. PMID- 23441413 TI - Study: Patient pelvic shielding reduces operator dose in cardiac catheterization. PMID- 23441414 TI - FDA publishes survey results on ferromagnetic detector use. PMID- 23441415 TI - New FDA guidance provides insight into pre-market approval process. PMID- 23441416 TI - OSHA's revised Hazard Communication Standard requieres additional staff training. PMID- 23441418 TI - PACS facts. PMID- 23441417 TI - Without missing a beat. PMID- 23441419 TI - Health Devices staff member wins Patient Safety Award. PMID- 23441420 TI - MR-conditional pacemaker means big changes for MR providers. PMID- 23441422 TI - Transition deadline for Steris System 1 extended. PMID- 23441421 TI - CMS: manufacturer recommendations are requirements. PMID- 23441423 TI - Inappropriate use of positive airway pressure devices as life-support ventilators. PMID- 23441424 TI - MR imaging fire. PMID- 23441425 TI - Sharps advice from FDA, CDC. PMID- 23441427 TI - Advanced ventilation features. PMID- 23441426 TI - Interfacing monitoring systems with ventilators. PMID- 23441428 TI - Safety summary: Defibrillators. PMID- 23441429 TI - More on the CMS preventive maintenance directive. PMID- 23441430 TI - Metal-on-metal hips: a developing story. PMID- 23441432 TI - Making connections. PMID- 23441431 TI - GE Carescape B850 bedside monitor may not convey some ventilator alarms when equipped with GE compact airway module. PMID- 23441433 TI - ECRI Institute staff member wins clinical engineering award. PMID- 23441434 TI - Connectivity and patient safety--perspectives from the HIMSS conference. PMID- 23441435 TI - More viewpoints on metal-on-metal hips. PMID- 23441436 TI - CDC releases new guidelines on safe work practices in diagnostic laboratories. PMID- 23441437 TI - Finding: Importing outside images into PACS reduces repeat imaging. PMID- 23441438 TI - Study: Imaging beyond anatomical boundaries often occurs in chest and abdominal CT scans. PMID- 23441439 TI - Recent advances in diagnosis and therapy of allergic rhinitis and asthma in childhood. AB - Some of the most recent advances in the diagnosis and treatment of childhood asthma and allergies are here reviewed. New perspectives have been opened by in vitro diagnostic tests for allergies based on a molecular approach and novel approaches to in vivo tests (SPT or FE(NO)). A better characterization of the patients is opening new classifications of allergic asthma and rhinitis phenotypes, which allow personalizing management disease programs and targeting pharmacotherapy. Educational programs and better communication are improving awareness and compliance with medical prescriptions and adherence to guidelines. Increasing information is being acquired on the mechanisms, efficacy and safety profiles of anti-asthma and anti-allergic drugs, including antihistamines, inhaled corticosteroids, long acting beta agonists, antibiotics, anti-IgE antibodies. Progress in biotechnologies is fostering new approaches to allergen specific immunotherapy (subcutaneous, sublingual) concerning the quality, mechanisms, efficacy and safety of allergen products. PMID- 23441440 TI - Prevalence of sensitisation to oilseed rape and maize pollens in France: a multi center study carried out by the Allergo-Vigilance Network. AB - BACKGROUND: Oilseed rape and maize crops represent a large part of agriculture fields in European countries. OBJECTIVE: To establish the actual prevalence of sensitization to oilseed rape and maize pollen, and to determine if this is correlated to the amount of exposure as well as to the patient's history of atopy or asymptomatic atopy. METHODS: The study was conducted by 69 allergists belonging to the Allergo-Vigilance Network, in collaboration with the French Agency for Safety of food, and compiles the results of skin prick-tests using oilseed rape and maize pollens and seeds, as well as common aeroallergens. The patients were classified into 3 groups: nonatopic, asymptomatic atopy, and actual atopic diseases. RESULTS: Among the 5372 subjects studied (2515 children, 2857 adults), 62.3% had an atopic disease, 10.2% had an asymptomatic atopy, and 27.5% were non-atopic. The level of sensitization was higher in the subjects with atopic disease, as compared to those with asymptomatic atopy: oilseed rape pollen: 11.8% vs 8%, maize pollen, 26% vs 19%, oilseed rape seeds, 7.7% vs 6.9%, corn seeds: 8.3% vs 4.8% (p < 0.001). The rate of sensitization was significantly increased in those living in high crop density regions. The association of an atopic disease with a high rate of exposure yielded a higher rate of sensitization of 13.8% and 21.3% for rapeseed pollen, and 22.9% and 30.7% for maize pollen in both children and adults, respectively. CONCLUSIONS: The incidence of sensitisation to rapeseed and maize pollen is positively correlated to the level of exposure. This prevalence is higher in patients with actual atopic disease as compared to those with asymptomatic atopy. The frequency of sensitization confirms the allergenicity of these plants destined for food supply and demonstrates the importance of monitoring for respiratory allergies to these pollens, not only in workers exposed to these types of crops, but also in atopic patients living in regions that contain a high density of rapeseed and maize fields. Cross-reactivities between pollens and seeds could potentially elicit cross-reacting food allergies. PMID- 23441441 TI - Pattern of airway inflammation and remodelling in mild persistent atopic asthma and in mild persistent asthma related to gastroesophageal reflux. AB - BACKGROUND: The increase of basement membrane thickness (BMAT) represents a structural feature described as commonly characterizing airway remodelling in asthma, even if the non-atopic condition had been investigated only episodically from this point of view. Gastrooesophageal-reflux is a pathological condition which can frequently cause and/or sustain asthma in non-atopic individuals. OBJECTIVES: The aim of the study was to measure BMT; some inflammatory mediators in BAL; cys-leucotrienes (LTE4) in urine; e-NO, and BHR to Methacholine (MCh) in mild atopic and in mild non-atopic, GER-related asthma. METHODS: After their informed consent, 25 mild atopic (40.9 years +/- 13.1 sd, FEV1 = 95.9% pred. +/- 12.9 sd) and 39 non-atopic, GER-related asthmatics (57.3 years +/- 14.2 ds, FEVY1 = 101.3% pred. +/- 12.2 sd), nonsmoker and of a comparable asthma duration, underwent measurements of basal lung function and bronchial response to MCh (PD20 FEV1); endobronchial biopsies and BAL (in the right middle lobe), and a 24-h gastroesophageal pHmetry. RESULTS: Atopic GER-related asthma showed two distinct patterns of airway inflammation. The eosinophilic contribution to airway inflammation was systematically prevailing in the former group, such as: EOS = 10.7% +/- 13.4 sd vs 2.0% +/- 2.8 sd, p = 0.001; ECP = 344.9 mcg/l +/- 635.9 sd vs 59.2 mcg/l +/- 75.1 sd, p = 0.001. CONCLUSIONS: Data from the present study are suggesting that persistent mild atopic and mild GER-related asthma seem to represent two distinct phenotypes of asthma in terms of airway remodelling, and in particular of BMT involvement. PMID- 23441442 TI - Specific IgG levels to wheat in wheat tolerant professional cyclists may depend on a homeostatic immune response to a high consumption of wheat. AB - BACKGROUND: Implication of IgG antibodies to wheat has been alleged in gastrointestinal symptoms. Precise data on the specific IgG levels in healthy subjects are lacking. Our objectives are to compare levels of IgG antibodies to wheat protein fractions in healthy non atopic or atopic subjects, and in healthy professional cyclist subjects, taking into account the quantitative consumption of wheat. METHODS: 24 control subjects and 26 professional cyclist subjects were selected. ELISA was performed to 2 wheat commercial solutions and to 3 wheat protein fractions. RESULTS: No significant difference was observed between non atopic and atopic subjects. For wheat flour extract, physiological norm determined was 3.27 mg/L sIgG concentration +/- 1.25 CI (95% confidence intervals) for the professional cyclists (vs 1.56 mg/L +/- 0.91 CI in control subjects, p-value: 0.040). For gluten solution, physiological norm was 1.42 mg/L +/- 0.60 CI (vs 0.50 +/- 0.24 CI in control subjects, p-value: 0.010). CONCLUSION: Atopic and non atopic healthy adults have a similar level of sIgG to wheat. Increased levels of sIgG are observed correlatively with an excessive consumption, and could contribute to homeostasis of tolerance. Studies searching for a pathogenic role of sIgG in certain pathologies should take into account the quantitative consumption. PMID- 23441443 TI - IgE to staphylococcal enterotoxins are undetectable in sera from patients with nasal polyposis. AB - Nasal polyposis is a frequent disease, sometime associated with asthma and non steroidal anti-inflammatory drugs intolerance. Staphylococcus aureus colonization can play a pathogenetic role in same cases by a severe eosinophilic inflammation, which can suggest new therapeutic approaches. Staphylococcus aureus colonization has been demonstrated by local specific enterotoxins IgE dosage in polyps homogenates. This study demonstrate lack of detection of serum enterotoxins specific IgE to staphylococcal in patients with nasal polyposis, compared with healthy subjects. PMID- 23441444 TI - Intraoperative anaphylaxis: a case report of allergy to ranitidine. AB - We report the case of a 18-year old male who developed intraoperative anaphylaxis. The presence of specific IgE to ranitidine was documented This case confirms the possibility of anaphylaxis at first exposure. PMID- 23441445 TI - Aspirin desensitization in a woman with inherited thrombophilia and recurrent miscarriage. AB - Women with inherited thrombophilia and recurrent miscarriage might benefit from preconceptional antiagreggation with low-dose acetylsalicylic acid (ASA), but concerns about severe adverse reactions may prevent physicians from performing this treatment in patients with ASA hypersensitivity. We report the first known case of ASA desensitization in a 41-year-old woman with inherited thrombophilia, who had homozygosity (4G/4G polymorphism) of the plasminogen activator inhibitor 1 (PAI-1) gene and first trimester recurrent miscarriage, and had previously presented with anaphylaxis to ASA. Desensitization was completed despite one self limited adverse reaction, and the patient has maintained a daily ASA intake of 100 mg with good tolerance. PMID- 23441446 TI - [Prostatitis in China: research and clinical practice]. AB - In recent years, significant progress has been achieved in the epidemiological, basic and clinical researches on prostatitis in China. From the perspective of clinical practice, Chinese Urological Association (CUA) Guidelines on Prostatitis has been applied nationwide and promoted the standardization of the diagnosis and management of prostatitis in China. PMID- 23441447 TI - [Silencing pyruvate kinase M2 sensitizes human prostate cancer PC3 cells to gambogic acid-induced apoptosis]. AB - OBJECTIVE: To study the effect of silencing pyruvate kinase M2 (PKM2) on gambogic acid (GA)-induced apoptosis of human prostate cancer PC3 cells. METHODS: Three specific PKM2 siRNAs and one negative control siRNA (si-NC) were transfected into PC3 cells. The silencing effect of PKM2 siRNAs was determined by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot, and the effects of PKM2 siRNA on the vitality and apoptosis of GA-stimulated PC3 cells detected by MTT and AO/EB double staining, respectively. The mRNA and protein levels of c-myc and cyclin D1 were analyzed by qRT-PCR and Western blot, respectively. RESULTS: All the 3 PKM2 siRNAs effectively reduced the mRNA and protein expressions of PKM2, and PKM2 siRNA-1 exhibited the strongest silencing effect. At 24 h after transfection, the expression levels of PKM2 mRNA and protein were reduced by 70% and 85%, respectively (P < 0.05). Twenty-four hours of treatment with GA (0.5 micromol/L) following transfection with PKM2 siRNA-1 inhibited the vitality of the PC3 cells by 68%, increased their apoptosis, and significantly down-regulated the mRNA and protein levels of c-myc (50% and 35%) and cyclin D1 (60% and 20%) (P < 0.05). CONCLUSION: Inhibition of PKM2 sensitized PC3 cells to GA-induced apoptosis, suggesting that PKM2 may be a potential therapeutic target for sensitizing human prostate cancer to GA. PMID- 23441448 TI - [Methylation and protein expression of RASSF2 in prostate cancer]. AB - OBJECTIVE: To investigate the role of the epigenetic inactivation of Ras association domain family 2 (RASSF2) in the occurrence and development of prostate cancer by detecting the methylation and protein expression of RASSF2 in the tissues of prostate cancer and prostatic hyperplasia. METHODS: We obtained genome DNA from 30 formalin-fixed paraffin-embedded specimens of prostate cancer (experimental group) and another 30 of prostatic hyperplasia (control group). We detected the methylation of RASSF2 by methylation-specific PCR (MSP) and its protein expression by immunohistochemistry. RESULTS: The rates of RASSF2 promoter hypermethylation and the absence of its protein expression were 66.7% (20/30) and 70.0% (21/30) respectively in the experimental group, significantly higher than 6.7% (2/30) and 3.3% (1/30) in the control group (P < 0.05). The promoter hypermethylation of RASSF2 was significantly correlated with the absence of its protein expression (P < 0.05). CONCLUSION: The epigenetic inactivation of RASSF2 is involved in the occurrence of prostate cancer, and is expected to be a target of molecular diagnosis and treatment of prostate cancer. PMID- 23441449 TI - [Effects of serum anti-sperm antibodies positive on the Fas/Fas-L apoptosis pathway in the testis tissue and testicular germ cells of pubertal male rats]. AB - OBJECTIVE: To establish a rat model of anti-sperm antibody (AsAb)-mediated immune infertility, and investigate the effects of serum AsAb positive on the Fas/Fas-L apoptosis pathway in testis tissue and testicular germ cells of pubertal male rats. METHODS: Thirty 5-week-old Wistar male rats were included in this study, 10 killed for preparation of sperm suspension, 10 as normal controls, and the other 10 made models of AsAb-positive immune infertility (experimental group). Four weeks after modeling, the testes of the rats were harvested for observation of the changes in the testis tissue under the light microscope and detection of the expressions of Fas, Fas-L and Caspase-3 proteins by immunohistochemistry. RESULTS: Compared with the control group, the experimental group showed obvious apoptotic changes in the testis tissue and remarkably increased expressions (OD value) of Fas (161.87 +/- 5.37 vs 176.97 +/- 4.58), Fas-L (150.27 +/- 8.65 vs 187.52 +/- 7.76) and Caspase-3 (120.37 +/- 6.76 vs 157.65 +/- 7.38) (P < 0.01). CONCLUSION: Serum AsAb affected the infertility of pubertal male rats, and its mechanisms might be associated with up-regulated expression of Fas, Fas-L and Caspase-3 proteins in the Fas/Fas-L apoptotic pathway. PMID- 23441450 TI - [Increased expressions of leptin and its receptor in the epididymis of varicocele model rats and their implications]. AB - OBJECTIVE: To investigate the expressions of leptin and its receptor in the epididymis of experimental varicocele (EV) rats. METHODS: Forty male Sprague Dawley rats were randomly divided into four groups: 4-week EV (n = 12), 8-week EV (n = 12), 4-week control (n = 8), and 8-week control (n = 8). EV models were established by partial ligation of the left renal vein. The expressions of leptin and its receptor in the rat epididymis were measured by immunohistochemistry, and their mRNA expressions determined by real-time quantitative PCR. RESULTS: The expressions of leptin and its receptor in the epididymis were significantly higher in the 4- and 8-week EV groups than in the 4- and 8-week control groups (P < 0.01), with no significant difference between the two EV groups (P > 0.05). So were their mRNA expressions in the former two than in the latter two groups (P < 0.01), with no significant difference between the former two (P > 0.05). CONCLUSION: The expressions of leptin and its receptor are markedly increased in the epididymis of varicocele rats. Leptin may be involved in the mechanisms of varicocele inducing male infertility. PMID- 23441451 TI - [Construction and analysis of gene expression profiles in the testes of patients with unilateral cryptorchidism using cDNA gene chips]. AB - OBJECTIVE: To analyze the differentially expressed genes in the testicular tissues of men with unilateral cryptorchidism using cDNA gene chips. METHODS: Probes were prepared with the mRNA extracted from the testes of 6 patients with unilateral cryptorchidism and 3 normal fertile men. Then the differential gene expression profiles of the two groups were detected with cDNA gene chips containing 45 034 genes. The differentially expressed genes were analyzed with Pathway and GO in the MAS system. RESULTS: Based on the ratio of > 3.0 or < 0.33, 346 differentially expressed genes were detected in the testis tissues of the patients with unilateral cryptorchidism, among which 60 were up-regulated and 286 down-regulated. The up-regulated genes were distributed mainly on chromosomes 1, 15, 5 and 19, associated with cell cycles, sperm motility, flagellar movement, DNA replication, and chromatin modification, while the down-regulated genes, mainly on chromosomes 1, 19, 16 and 11, related with spermatogenesis and anti apoptosis. CONCLUSION: Unilateral cryptorchidism involves the variation of the expressions of multifunctional genes. The establishment of gene expression profiles of unilateral cryptorchidism in human testes may provide a new theoretical basis for analyzing the genetic factors of unilateral cryptorchidism and investigating the etiology of spermatogenic failure. PMID- 23441452 TI - [Application of CUA Guidelines on Prostatitis in the management of chronic pelvic pain syndrome: a nationwide survey]. AB - OBJECTIVE: To investigate the application of the Chinese Urological Association (CUA) Guidelines on Prostatitis and its effects on the clinical practice patterns of diagnosing and treating chronic pelvic pain syndrome (CPPS) among Chinese urologists and andrologists. METHODS: We conducted a questionnaire investigation on the application of the CUA Guidelines on Prostatitis among the urologists and andrologists of 173 hospitals in 21 cities of China, and performed statistical analyses on all the eligible questionnaires collected. RESULTS: Of the 1 056 questionnaires distributed, 851 (80.6%) were eligible, of which 71.6% were from the urologists or andrologists in grade 3 hospitals, 80.7% of them with senior or intermediate professional titles and 97.5% had studied the CUA Guidelines. Most of the subjects agreed that Type III prostatitis is a clinical syndrome, whose diagnosis should exclude other conditions with similar symptoms, and whose treatment should aim at relieving pain, alleviating urination symptoms and improving the quality of life. Those who had and those who had not studied the CUA Guidelines differed in their viewpoints on CPPS as illustrated in the book. In clinical practice, the most common treatment options for CPPS were psychological therapy (80.7%), medication (80.4%) and life style adjustment (79.6%), and the most frequently used drugs were phytotherapy (80.0%), alpha blockers (68.9%) and antibiotics (61.0%). CONCLUSION: CUA Guidelines on Prostatitis has gained a nationwide application and promoted the standardization of the management of CPPS in China. PMID- 23441453 TI - [Mental health status of infertility patients with varicocele]. AB - OBJECTIVE: To study the mental health status of infertility patients with varicocele and its relationship with infertility. METHODS: Using Hospital Anxiety and Depression scale (HAD), we assessed the psychological status of 110 infertility patients with varicocele, identified the risk factors of anxiety and depression in these patients, and analyzed the correlation among psychological and other relevant factors. Meanwhile, we recruited 61 age-matched normal fertile men as controls for comparative analysis. We also conducted logistic regression analysis on the mental health status of the 106 infertility patients with varicocele. RESULTS: The prevalence rates of anxiety were 61.32% and 13.79%, while those of depression 37.73% and 6.90% in the infertile patients and normal fertile controls, respectively, significantly higher in the former than in the latter (P < 0.05). Logistic regression analysis showed that the main risk factors of anxiety and depression of the infertile patients were the number of times they sought medical care and the severity of their testis disorders. CONCLUSION: Infertility patients with varicocele have psychological disorders, which are particularly associated with the frequency of the patients' clinic visit and the severity of their testis disorders. PMID- 23441454 TI - [Relationship between ectasia of the rete testis and the volume of seminal vesicle cyst in the epididymal head: an ultrasonographic study]. AB - OBJECTIVE: To explore the correlation between ectasia of the rete testis (ERT) and the volume of seminal vesicle cyst (SVC) in the epididymal head by ultrasonography. METHODS: This study included 36 cases of ERT diagnosed by color Doppler ultrasonography and complicated with SVC in the epididymal head (case group), and another 44 SVC cases without ERT (control group), all confirmed by surgery or fine-needle aspiration. We analyzed the differences in nationality, age, volume of SVC and resistance index of the afferent artery in the diseased testis between the two groups of patients. RESULTS: No statistically significant differences were observed between Chinese Uighurs and Hans (P > 0.05), nor in the mean age between the two groups of patients (P > 0.05). There were significant differences in the mean volume of SVC between the case and control groups ([2.081 +/- 1.147] cm3 vs [1.009 +/- 0.848 ] cm3, P < 0.01), but not in the resistance index of the afferent artery in the diseased testis (0.644 +/- 0.099 vs 0.608 +/- 0.116, P > 0.05). CONCLUSION: The volume of seminal vesicle cyst in the epididymal head plays a significant role in the formation of ectasia of the rete testis. PMID- 23441456 TI - [Giant prostatic calculus with neurogenic bladder disease and prostate diverticulum: a case report and review of the literature]. AB - OBJECTIVE: To study the etiology, clinical manifestation, diagnosis and treatment of giant prostatic calculus with neurogenic bladder disease and prostate diverticulum. METHODS: We retrospectively analyzed the clinical data of a case of giant prostatic calculus with neurogenic bladder disease and prostate diverticulum and reviewed the relevant literature. The patient was a 37-year-old man, with urinary incontinence for 22 years and intermittent dysuria with frequent micturition for 9 years, aggravated in the past 3 months. He had received surgery for spina bifida and giant vesico-prostatic calculus. The results of preoperative routine urinary examination were as follows: WBC 17 20/HPF, RBC 12 - 15/HPF. KUB, IVU and pelvic CT revealed spina bifida occulta, neurogenic bladder and giant prostatic calculus. RESULTS: The patient underwent TURP and transurethral lithotripsy with holmium-YAG laser. The prostatic calculus was carbonate apatite in composition. Urinary dynamic images at 2 weeks after surgery exhibited significant improvement in the highest urine flow rate and residual urine volume. Seventeen months of postoperative follow-up showed dramatically improved urinary incontinence and thicker urine stream. CONCLUSION: Prostate diverticulum with prostatic giant calculus is very rare, and neurogenic bladder may play a role in its etiology. Cystoscopy is an accurate screening method for its diagnosis. For the young patients and those who wish to retain sexual function, TURP combined with holmium laser lithotripsy can be employed, and intraoperative rectal examination should be taken to ensure complete removal of calculi. PMID- 23441455 TI - [Pituitary prolactinoma with severe erectile dysfunction as the initial symptom: diagnosis and treatment of 4 cases]. AB - OBJECTIVE: Pituitary prolactinoma with severe erectile dysfunction (ED) as the initial symptom is often misdiagnosed. This article explores the diagnosis and treatment of severe ED caused by pituitary prolactinoma. METHODS: We retrospectively analyzed the diagnosis and treatment of 4 cases of pituitary prolactinoma with severe ED (IIEF-5 score 5 - 7) as the initial clinical symptom confirmed by MRI. RESULTS: The 4 cases of pituitary prolactinoma-induced severe ED, with serum prolactin 10 times above the maximum normal level, were misdiagnosed for 2 years. All failed to respond to the PDE5 inhibitor therapy, and then 3 of them underwent transnasal hypophysectomy. Twenty-four months of follow-up found the level of prolactin restored to normal in 1 case (IIEF-5 = 19), and reduced to 600 and 768 IU/L respectively (IIEF-5 = 15) in the other 2. Then administration of the PDE5 inhibitor was followed, which produced satisfactory efficacy. One case was treated with oral bromocriptine, which restored the prolactin level to normal at 12 months (IIEF-5 > 21). CONCLUSION: Prolactin detection and brain MRI can help to confirm pituitary prolactinoma with severe ED at the onset. As for its treatment, in case of an extremely high level of prolactin, simple administration of the PDE5 inhibitor is ineffective. When the prolactin level is reduced after surgery or medication, the symptom of ED can be improved and, in case of no obvious relief, administration of the PDE5 inhibitor can be followed, which may achieve satisfactory results. PMID- 23441457 TI - [Diagnosis and treatment of xanthogranulomatous prostatitis: a case report and review of the literature]. AB - OBJECTIVE: To explore the diagnosis and treatment of xanthogranulomatous prostatitis. METHODS: A 75-year-old man presented with a 3-month history of difficult urination and frequent micturition, which was exacerbated for 2 days. Digital rectal examination indicated an enlarged prostate size of II degrees with hard texture but no tenderness. Serum total PSA was 172.5 microg/L. TRUS revealed 200 ml of post-micturition residual urine, thickened bladder wall, prostate size of 4.3 cm x 3.8 cm x 5.0 cm and no isochrones. MRI showed an enlarged prostate gland, with marked enlargement of the central zones and low-signal intensity of the peripheral gland, part of the prostate gland protruding to the bladder with no clear dividing line. It was diagnosed as prostate cancer initially, and confirmed by needle biopsy. RESULTS: Histopathological examination revealed large numbers of "foamy macrophages" in the lesion, with a few multinucleated giant cells, leukocytes, mononuclear, plasmocytes and fibroplasia. Immunohistochemistry showed CD68 (+) and PSA (-). The patient was treated with oral Tamsulosin and glucocorticoid and by temporary catheterization, and followed up for 20 months. Urination symptoms began to alleviate and serum PSA to decrease at 4 months. The PSA level was 9.2 microg/L at 13 months and 3.6 microg/L at 17 months. CONCLUSION: Xanthogranulomatous prostatitis is a rare clinically, which can be confirmed by histopathological examination. It is treated mainly by supportive therapy and, for the cases with severe lower urinary tract obstruction, TURP can be employed. Follow-up must be performed by possible examination of PSA and necessary needle biopsy of the prostate. PMID- 23441458 TI - [Paternal exposure to occupational electromagnetic radiation and sex ratio of the offspring: a meta-analysis]. AB - OBJECTIVE: To investigate the association between paternal exposure to occupational electromagnetic radiation and the sex ratio of the offspring. METHODS: We searched various databases, including PubMed, Embase, Cochrane Library, OVID, Bioscience Information Service (BIOSIS), China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals and Wanfang Database, for the literature relevant to the association of paternal exposure to occupational electromagnetic radiation with the sex ratio of the offspring. We conducted a meta-analysis on their correlation using Stata 11.0. RESULTS: There was no statistically significant difference in the sex ratio between the offspring with paternal exposure to occupational electromagnetic radiation and those without (pooled OR = 1.00 [95% CI: 0.95 -1.05], P = 0.875). Subgroup analysis of both case-control and cohort studies revealed no significant difference (pooled OR = 1.03 [95% CI: 0.99 -1.08], P = 0.104 and pooled OR = 0.98 [95% CI: 0.99 -1.08], P = 0.186, respectively). CONCLUSION: Paternal exposure to occupational electromagnetic radiation is not correlated with the sex ratio of the offspring. PMID- 23441459 TI - [Short-course kidney-invigorating therapy improves near-term semen quality in asthenozoospermic men with kidney deficiency]. AB - OBJECTIVE: To evaluate the effect of short-course kidney-invigorating therapy on near-term semen quality in asthenozoospermic men with kidney deficiency. METHODS: Based on the differential types in traditional Chinese medicine, 121 asthenozoospermia patients received at our clinic of andrology were divided into groups A (kidney-yin deficiency), B (kidney-yang deficiency) and C (spleen and kidney deficiency), and treated with Yougui Decoction plus Wuziyanzong Pills, Jinkuishenqi Pills plus Wuziyanzong Pills, and Shizi Decoction plus Liujunzi Decoction, respectively, all given once daily for 4 weeks. Sperm parameters of the patients were analyzed with the computer-assisted sperm analysis system before and after treatment and compared among the three groups. RESULTS: The baseline sperm concentrations in groups A, B and C ([70.4 +/- 38.6], [73.5 +/- 40.2] and [56.0 +/-34.4] x 10(6)/ml) showed no significant differences from those after medication ([74.4 +/- 32.6], [67.0 +/- 30.8] and [58.6 +/- 24.6] x 10(6)/ml) (P > 0.05). The percentages of grade a sperm in the three groups were (12.9 +/- 5.3)%, (13.7 +/- 7.7)% and (12.9 +/- 6.4)% respectively after treatment, significantly higher than (9.9 +/- 6.7)%, (9.3 +/- 5.4)% and (9.0 +/- 6.8)% before treatment (P < 0.05), and so were the percentages of grade a + b sperm ([37.4 +/- 10.2 ]%, [35.7 +/- 13.7]% and [35.9 +/- 12.3]% after treatment versus [29.6 +/- 13.2]%, [27.5 +/- 10.4]% and [28.3 +/- 12.1]% before treatment, P < 0.05). All the three groups showed significantly increased sperm motility after treatment ([53.8 +/- 10.5]%, [52.6 +/- 15.2]% and [51.1 +/- 13.1]%) as compared with the baseline levels ([44.3 +/- 14.0]%, [43.5 +/- 15.0]% and [42.4 +/- 14.9]%) (P < 0.05). The cure rate and total effectiveness rate were significantly higher in group B than in A (P < 0.05), but had no significant differences between either A and C or B and C (P > 0.05). CONCLUSION: Short course kidney-invigorating therapy can significantly improve near-term semen quality in asthenozoospermic men with kidney asthenia, especially in those with kidney-yang deficiency, and it has no obvious adverse effects. PMID- 23441460 TI - [Lipopolysaccharide affects male reproductive function through Toll-like receptors]. AB - Reproductive tract infection is one of the factors of male infertility, but the mechanisms responsible are hitherto poorly defined. Recent studies show that one of the microbial pattern-recognition receptors, Toll-like receptor (TLR) signaling pathway, plays a critical role in inflammation-induced male infertility. Lipopolysaccharide (LPS), a major component in the cell wall of gram negative bacteria, could induce inflammatory response through TLRs. A large number of researches suggest that TLRs express widely in the male reproductive tract and LPS-induced inflammatory reaction through TLRs may affect male fertility. This article presents an overview on how LPS-induced inflammation through TLRs affects male fertility in terms of its influence on the testis, epididymis and sperm quality. PMID- 23441461 TI - [Activities of the fragments of semenogelin I: an update]. AB - Semenogelin I (Sg I) and the fragments of peptides hydrolyzed from Sg I by prostate-specific antigen have multiple biological activities. There exists a controversy over the inhibitory effect of the key fragment on sperm motility. This article focuses on the sperm-inhibiting and antibacterial activities of the fragments of Sg I-derived peptides and illustrates the supposition concerning the most controversial aspect. A deeper insight into the action mechanisms of Sg I derived peptides may help improve the methods of sperm screening and provide a new perspective in the management of asthenozoospermia and urinary tract infection. PMID- 23441462 TI - [Signaling pathway of meiosis induced by retinoic acid during spermatogenesis]. AB - Retinoic acid (RA) is an oxidative metabolite of vitamin A (retinol, ROH) and plays an important role in the spermatogenesis (as in meiosis) of mammals. In mammalian testes, RA, in combination with its retinoic acid receptor (RAR), regulates the expressions of related target genes in various types of cells at different times. It activates meiosis by up-regulating the expressions of the genes that promote meiosis and down-regulate those that inhibit it during spermatogenesis in a specific stage. The results of researches on mammalian spermatogenesis have a great application value in reproductive biology, developmental biology, and reproductive engineering. Therefore, it is of considerable significance to study the signaling pathway of RA-induced meiosis during mammalian spermatogenesis. This article presents an introduction of the RA signal transduction system and its action mechanisms, as well as an overview on the signaling pathway of RA-activated meiosis during spermatogenesis. PMID- 23441463 TI - [Penile cancer and human papillomavirus infection]. AB - Human papillomavirus (HPV) infection is one of the major risk factors for penile cancer. This article presents an overview on the biological characteristics of HPVs, HPV infection in penile cancer, possible carcinogenic mechanisms of HPV, prognostic value of HPV in penile cancer, and HPV vaccine. PMID- 23441464 TI - Pathogenesis and assessment of renal function in patients with liver cirrhosis. AB - In liver cirrhosis patients awaiting liver transplantation, it is prognostically equally important to assess the renal function before and after transplantation. This is evidenced by the inclusion of serum creatinine in the Model for End-Stage Liver Disease (MELD) score. Most of the causes of renal failure in liver cirrhosis are functional, the acute kidney damage including prerenal azotemia, acute tubular necrosis and hepatorenal syndrome. A major index of the renal function, the glomerular filtration rate (GFR) is determined in a specific way in patients with liver cirrhosis. Clinically, serum creatinine is considered the best indicator of kidney function, although it is rather unreliable when it comes to early assessment of renal dysfunction. Most of the patients with liver cirrhosis have several concomitant conditions, which are the reason for the false low creatinine levels, even in the presence of moderate to severe kidney damage. This also holds for the creatinine clearance and creatinine-based estimation equations for assessment of the glomerular filtration rate (the Cockroft-Gault and MDRD formulas), which overestimate the real glomerular filtration. Clearance of exogenous markers is considered a gold standard, but the methods for their determination are rather costly and hard to apply. Alternative serum markers (e.g., cystatin C) have been used, but they should be better studied in cases of liver cirrhosis assessment. PMID- 23441465 TI - Neurocognitive impairments in brain tumor patients. AB - There is an increased scientific interest in cognitive impairments caused by brain tumors during the last decade. It has lead to the introduction and routine clinical usage of neuropsychological test batteries in brain tumor patients, thus making them an important clinical measure for the assessment of the efficacy of the different treatment regimens such as surgery, radiotherapy and chemotherapy. The effect of cognitive deficit on patients' quality of life and survival has been unequivocally proven. These are among the most common neurological symptoms associated with brain tumors. The improvement in cognitive function and delay in neurocognitive decline are acceptable endpoints in clinical trials. Cognition has been demonstrated to be an independent predictor of survival in patients with cerebral neoplasms. PMID- 23441466 TI - Exercise training modes in rehabilitation of patients with chronic heart failure. AB - Modern cardiac rehabilitation (CR) in chronic heart failure (CHF) is a multidisciplinary process with the patient being the centre of the focus. Various CR models (inpatient, outpatient and home based) have been used the last two decades in the pursuit of higher effectiveness and better results. The aim of this review is to present different exercise training modes applied in rehabilitating patients with CHF and to highlight their clinical value, advantages and disadvantages and practical implication. PMID- 23441467 TI - Reference values for forced expiration parameters in Bulgarian children and adolescents aged 7 to 18 years. AB - INTRODUCTION: A diagnosis of lung function impairment in childhood is highly dependent on the respective reference values. Population differences in the pulmonary function of children have been frequently reported. The AIM of this study was to derive normal spirometric reference values for Bulgarian children and adolescents and to compare these results with other data set including our own reference equations developed 20 years ago. MATERIAL AND METHODS: Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and parameters of maximum expiratory flow-volume curves were measured in 671 healthy Bulgarian school children (339 males and 332 females) aged 7-18 years. Multiple linear regression analysis was performed for each spirometric parameter against age, height, weight, chest circumferences and fat free mass in both sexes. RESULTS: Excluding ratios, all measured spirometric parameters increased nonlinearly with age and height, and were significantly higher in boys than girls in adolescence. Height (H) explained the maximum variance for spirometric parameters and the best fit regression equation relating functional parameters and body height was a power function (Y = a.Hb). FVC and FEV1 showed close correlations with height (r2 between 0.85 and 0.92), whereas the coefficients of determination for the flows were less close (r2 from 0.85 for PEF to 0.67 for MEF25%; always higher in boys). CONCLUSIONS: The developed prediction equations can be used in clinical practice. In comparison with reference equations based on European or USA populations, regional reference values are biologically more suitable for the interpretation of spirometric data. PMID- 23441468 TI - Psychomotor development after ganciclovir selectively treated congenital and perinatal cytomegalovirus infection. AB - AIM: To study the development of children with selectively treated cytomegalovirus infection. PATIENTS AND METHODS: We studied prospectively a risk group of 12 children with cytomegalovirus infection. These children were diagnosed by serological screening in the first three months after birth and are defined as congenital and perinatal infections. Thirteen infants with no serological evidence of previous or present cytomegalovirus infection at 4-12 months of age were used as controls. Ganciclovir in a dose of 10-15 mg/kg/day for at least 2 weeks followed by 5-7.5 mg/kg/day administered intravenously for at least 2 weeks more was given to 4 children from the risk group with PCR confirmed cytomegalovirus infection: to one with suspected congenital infection that presented with encephalitis, to two children with abnormal auditory evoked potentials (AEPs) and other non-neurological symptoms of a suspected congenital infection, and to one child with proven congenital infection with systemic manifestations. There was no infant with cytomegalic inclusion disease in the study. All other children in the risk group that had clinically manifested infection received isoprinosine in a dose of 50 mg/kg for one month. RESULTS: Psychomotor development delay at age three was found in two children from the risk group and in one child in the control group. There was no difference between the two groups regarding the frequency of paroxysmal events, sensory deficiency or frequent illnesses. CONCLUSIONS: The prognosis in cases of cytomegalovirus infection diagnosed at three years of age and treated selectively can be similar to that in infection free 3-year-old children (if there are no cases of CMV inclusion disease). PMID- 23441469 TI - Prevalence of cytomegalovirus infection in hospitalized infants. AB - Data on cytomegalovirus infection (CMV) prevalence and course in hospitalized infants are rather scarce, obsolete and considerably inconsistent. AIM: to determine the prevalence, rate of clinical manifestations, risk factors and predictive capacity of clinical manifestations of CMV infection in hospitalized infants during their first year of life. PATIENTS AND METHODS: All 163 infants hospitalized in the Pediatric Ward for Nonrespiratory Pathology in a tertiary hospital were serologically screened for cytomegalovirus infection for 10 months. In infants up to 6 months old that were CMV IgG (+) and CMV IgM (-) we followed up the CMV IgG concentration or compared it with that of their mothers. RESULTS: The CMV prevalence for the entire study sample was 33.1 +/- 3.7% (54 seropositive out of 163 examined infants); in newborns it was 19.4 +/- 6.7% (7 of 36), in infants aged 1-3 months--23.8 +/- 5.4% (15 of 63), in 4-6-month olds--28.1 +/- 8.1% (9 of 32), and in 7-12-month old--71.9 +/- 8.1% (23 of 32). The rates of clinically apparent infections in the respective groups was 33.3 +/- 6.5%, 57.01 +/- 20.2%, 53.3 +/- 13.3%, 33.3 +/- 16.6%, and 13.0 +/- 7.17%. The overall rate of clinically apparent CMV infection in all 163 children was between 11.0 +/- 2.5% and 17.2 +/- 2.9%. The probability of CMV infection increased with age and duration of breastfeeding. Hepatitis, cerebral vasculopathy and pneumonia (alone or combined) turned out to be predictors of CMV infection, but none of these symptoms had a frequency greater than 22%. CONCLUSIONS: We found a high rate of cytomegalovirus infections in hospitalized infants less than one year of age. This infection is the reason why at least 10% of the newborns and 12% of the children aged 1 to 3 months were hospitalised. The course was clinically apparent in over half of the infected children of up to 3 months of age. PMID- 23441470 TI - Mediterranean spotted fever--classification by disease course and criteria for determining the disease severity. AB - INTRODUCTION: Mediterranean spotted fever (MSF) in Bulgaria is caused by Ricketsia conorii conorii with a major vector the dog tick, Rhipicephalus sanguineus. The first cases of re-emerging MSF were reported in this country in the early 1990s after some 20 years of absence and then registered an annual increase until 2001-2003 after which the disease prevalence declined. MSF still poses a serious health problem in the country as severe, complicated cases with lethal outcome occur. The aim of this paper was to classify the forms of MSF according to the course of the disease process and to devise criteria for the disease severity in order to enable comparison of clinical manifestations of the disease at different stages of spreading, in different age groups, and between endemic and non-endemic regions in this country and abroad. PATIENTS AND METHODS: The study was carried out in a comparative aspect during the first phase of increase (1993-2003) with incidence of 11.88 per 100000 population and during the second phase of decline (2004-2011) with incidence of 9.56 per 100000 population. The disease was etiologically confirmed in 883 hospitalized patients by the positive antibody response to the specific antigen--Ricketsia conorii conorii by means of the immunofluorescence assay (IFA). The criteria we used for the classification of the forms of MSF included: 1. Typicality: forms having the most characteristic features of the MSF - eschar, fever, papular/maculopapular rash on the trunk and extremities, including hands and feet. 2. Manifestation: forms represented by all or some of the typical symptoms, giving sufficient grounds for preliminary diagnosis. 3. DURATION: fulminant, acute and protracted forms. The criteria for severity differentiate between mild, moderate, severe or malignant forms, and include clinical and laboratory parameters as shown in the present study. RESULTS: Classification of the forms according to MSF course defines them in order of severity, typicality, manifestation, duration of symptoms, complications and age characteristics. According to the accepted criteria for severity and with respect to the studied I and II phase of the disease the mild forms are 41.16%-35.62% (p > 0.05), moderate forms are 32.79%-43.11% (p < 0.01), severe forms are 16.03%-11.37% (p = 0.05), malignant forms are 6.56%-8.68% (p > 0.05), and mortality is 3.46%-1.19% (p < 0.05). The mean age was significantly higher for patients with severe forms of MSF (58.59 +/- 4.32 yrs) compared with those with moderate (46.10 +/- 3.71 yrs, p < 0.05) and mild forms (42.05 +/- 3.50 yrs, p < 0.01). For children up to 14 years old mild forms are more common than in adults over 65 (p < 0.0001). Among children up to 14 years old there were no lethal outcomes, while mortality rate in the patients older than 65 was as much as 10%. All this indicates that MSF runs a milder course in children and a severe, complicated course in the elderly. CONCLUSION: The criteria for MSF severity we have selected are based on our own experience and the experience of other authors. They are based on the reaction of human organism to the pathogenic agent and can be used during the different phases of emergence and development of rikettsial diseases, regardless of their geographic distribution. Unified use of these criteria would eliminate the differences in the data reported by different researchers regarding the disease development and severity. PMID- 23441471 TI - Attitudes toward antipsychotic medication, insight and psychopathology in outpatients with schizophrenia. AB - OBJECTIVE: Attitude toward antipsychotic medication is considered as one of the main predictors for medication adherence in schizophrenia. The present non interventional cross-sectional study aims to explore the associations between attitudes toward antipsychotic medication, insight and other clinical variables in outpatients with schizophrenia. METHOD: Attitudes toward antipsychotic medication, clinical and social variables, sociodemographic and illness-related characteristics were assessed via a set of semi-structured clinical interviews and self-rating scales in a total of 226 patients with schizophrenia on a long term antipsychotic treatment in community based settings. The associations between attitudes toward medication and severity of psychopathology, insight and medication side effects were examined. RESULTS: The greater hospitalization rate in the previous year was associated with more severe psychopathology at the time of the study, more pronounced side effects of the therapy and lack of insight. The lack of insight, the presence of more severe negative and depressive symptoms and disease duration less than 5 years correlated significantly with negative attitudes toward antipsychotic medication. The severity of medication side effects was not associated with the drug attitudes. CONCLUSION: Psychoeducational and psychotherapeutical interventions, along with pharmacotherapy, can be beneficial in forming positive attitudes toward medication and improving medication adherence in schizophrenia, especially in patients with a short duration of the disease. PMID- 23441472 TI - Antinociceptive effect of clomipramine through interaction with serotonin 5-HT2 and 5-HT3 receptor subtypes. AB - INTRODUCTION: Tricyclic antidepressants are used in the treatment of various pain syndromes. The antidepressant clomipramine inhibits predominantly the reuptake of serotonin in the central nervous system. The mechanism of its analgesic effect is not fully understood. The AIM of the present study was to find experimentally any dose-effect dependence in the analgesic effect of clomipramine and the involvement of the 5-HT2 and 5-HT3 receptors in the mechanism of this effect. MATERIAL AND METHODS: Fifty male Wistar rats were used in the study allocated to five groups (10 animals each): a saline treated control group, one positive control group treated with metamizole and three experimental groups treated with intraperitoneally administered clomipramine in doses of 5, 10 and 20 mg/kg bw, respectively. To study the role of 5-HT2 and 5-HT3 receptors in this effect we used another five groups (10 animals each): control, positive control and three experimental groups treated with clomipramine only, clomipramine and granisetrone and clomipramine and cyproheptadine, respectively. Three nociceptive tests were used: the hot plate test, analgesimeter and the acetic acid-induced writhing test. To gauge the antinociceptive action we used the increased latency in the hot plate test expressed as maximum possible effect % (%MPE), the increase in paw pressure to withdraw the hind paw in analgesimeter and decrease in the number of spinal cord writhes in the acetic acid test. RESULTS: Clomipramine in a dose of 20 mg/kg bw significantly increased the %MPE in hot plate test and the pressure to withdraw the hind paw in the analgesimeter when compared with the control. In the acetic acid test clomipramine decreased non-significantly the number of writhes compared with the controls. Granisetrone reduced non-significantly the antinociceptive effect of clomipramine in all tests. Cyproheptadine potentiated the analgesic effect of clomipramine in acetic acid test and decreased it significantly in the hot plate test. In analgesimeter cyproheptadine decreased significantly the paw pressure to withdraw the tested hind paw at 1 hour and non significantly at 2 hours. CONCLUSION: Clomipramine in the dose of 20 mg/kg bw has a pronounced antinociceptive affect towards thermal and mechanical pain stimulation. The 5-HT2 and 5-HT3 receptor subtypes are very likely involved in the mechanism of this effect. PMID- 23441473 TI - Bilateral simultaneous isthmic ectopic pregnancy after clomiphene induction. AB - A rare case of a 32-year-old patient with simultaneous bilateral isthmic tubal pregnancy. A 32-year-old woman with a 3-year history of primary infertility was admitted with light vaginal bleeding and mild abdominal pain. She was 41 days after her last menstruation and 23 day after intrauterine insemination with her husband's sperm. Clomiphene citrate (CC) was used for the induction of ovulation. In cases of ectopic pregnancy with ovulation induced by CC, doctors must be aware of the possibility of bilaterality. PMID- 23441474 TI - Parathyroid carcinoma of the mediastinum. AB - Parathyroid carcinoma accounts for about 4% of all diseases of the parathyroid glands. It usually presents as a tumor mass in the neck region. Mediastinal parathyroid carcinoma has been reported very rarely. The present paper reports an ectopic parathyroid carcinoma in the anterior mediastinum in a 54-year male that failed to be recognized antemortem. The markedly elevated serum calcium levels were repeatedly put down to laboratory errors, and the clinical features of primary hyperparathyroidism were misjudged and managed only symptomatically. The terminal cardiogenic shock was associated with myocardial infarction. Coronary plastic surgery was carried out and a stent was placed. The postmortem examination found a solid elastic tumor mass (4 cm) firmly encapsulated in the upper half of the anterior mediastinum having trabecular structure, mild nuclear and cellular polymorphism, single irregular mitoses and an area of necrosis. The mass invaded the capsule and the surrounding adipose tissue, there were tumor emboli found in the lymph and blood vessels. Immunohistochemical study showed diffuse expression of low molecular weight cytokeratin, chromogranin A and synaptophysin, and more than 20% of the tumor cells were Ki-67 positive. Glycogen granules were found in their cytoplasm. There were clearly seen metastatic calcifications in the intramural coronary vessels, the cardiomyocytes, the kidneys and the lungs. The present case report contributes considerably to the differential diagnosis of hypercalcemia. PMID- 23441475 TI - Pulmonary surfactants and their role in pathophysiology of lung disorders. AB - Surfactant is an agent that decreases the surface tension between two media. The surface tension between gaseous-aqueous interphase in the lungs is decreased by the presence of a thin layer of fluid known as pulmonary surfactant. The pulmonary surfactant is produced by the alveolar type-II (AT-II) cells of the lungs. It is essential for efficient exchange of gases and for maintaining the structural integrity of alveoli. Surfactant is a secretory product, composed of lipids and proteins. Phosphatidylcholine and phosphatidylglycerol are the major lipid constituents and SP-A, SP-B, SP-C, SP-D are four types of surfactant associated proteins. The lipid and protein components are synthesized separately and are packaged into the lamellar bodies in the AT-II cells. Lamellar bodies are the main organelle for the synthesis and metabolism of surfactants. The synthesis, secretion and recycling of the surfactant lipids and proteins is regulated by complex genetic and metabolic mechanisms. The lipid-protein interaction is very important for the structural organization of surfactant monolayer and its functioning. Alterations in surfactant homeostasis or biophysical properties can result in surfactant insufficiency which may be responsible for diseases like respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases. The biochemical, physiological, developmental and clinical aspects of pulmonary surfactant are presented in this article to understand the pathophysiological mechanisms of these diseases. PMID- 23441476 TI - Plasticity and reprogramming of differentiated ocular tissue of tadpoles of the frog, Euphlyctis cyanophlyctis under the influence of vitamin A. AB - Present study has shown that differentiated cell types may loose their definitive characteristics and acquire features of another specialized cell type. Young (3 toe stage) and mature (5 toe stage) tadpoles of the frog, Euphylictis cyanophlyctis were employed as experimental animals. Experiments were completed in two phases: in the first part of experiment, lenses were extracted from right eye balls of tadpoles and treated with vitamin A; in the second part of the experiment, meshed lentectomized eye ball tissues were implanted into the pit made on mid lateral position of the tail of young and mature tadpoles and were treated with vitamin A. The results obtained gave clear evidence of plasticity and reprogramming of terminally differentiated ocular tissue into lens, retina and even complete eye. Vitamin A was found to be good model for accelerating the reprogramming of differentiated ocular tissue in anuran frog tadpoles. PMID- 23441477 TI - Radioprotective effect of Haberlea rhodopensis (Friv.) leaf extract on gamma radiation-induced DNA damage, lipid peroxidation and antioxidant levels in rabbit blood. AB - Different concentrations of H. rhodopensis total extract (HRE; 0.03, 0.06 and 0.12 g/kg body weight) were injected im, into rabbits 2 h before collecting the blood samples. The whole blood samples were exposed in vitro to 2.0 Gy 60Co gamma radiation. The radiation-induced changes were estimated by using the chromosome aberration test (CA) and cytokinesis blocked micronucleus assay (CBMN) in peripheral lymphocytes, and by determining the malondialdehyde levels (MDA) in blood plasma and the superoxide dismutase (SOD) and catalase (CAT) activity in erythrocytes. Radiation significantly increased the chromosome aberration and micronuclei frequencies as well as MDA levels and decreased the antioxidant enzyme activity. On the other hand, the HRE pretreatment significantly decreased the CA, MN frequencies and MDA levels and increased the SOD and CAT activity in a concentration dependent manner. The most effective was the highest concentration of HRE (0.12 g/kg body weight). The results suggest that HRE as a natural product with a nantioxidant capacity could play a modulatory role against the cellular damage induced by gamma-irradiation. The possible mechanism involved in the radioprotective potential of HRE is discussed. PMID- 23441478 TI - Effects of dietary magnesium on testicular histology, steroidogenesis, spermatogenesis and oxidative stress markers in adult rats. AB - The available information on the effect of excess dietary magnesium on male reproduction is inadequate, though consumption of hard water rich in magnesium salt is not uncommon in many geographical areas. The present study has thus been undertaken to evaluate the morphological as well as cytological and functional changes in testis of magnesium administered sexually mature male Wistar rats. Significant increase in the activities of androgenic enzymes viz. delta(5)3beta hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase with concomitant increase in serum testosterone level, followed by progressive development in cytoarchitechture of genital organs, without any significant alteration in quantitative spermatogenesis were observed. The results were more marked in the groups treated for longer duration. The results further suggests that the changes that occurred after excessive magnesium in testis were not for the enhanced adrenocortical activities or for the generation of oxidative stress in reproductive organs, but for the direct action of excess magnesium on male gonads. Magnesium supplementation thus has an apparent beneficial effect on male gonadal system. PMID- 23441479 TI - Angiotensin-II down-regulates cardiac natriuretic peptide receptor-A mediated anti-hypertrophic signaling in experimental rat hearts. AB - Atrial natriuretic peptide (ANP) exerts anti-hypertrophic effects in the heart via natriuretic peptide receptor-A (NPR-A). However, ANP mediated anti hypertrophic activity is decreased in the cardiomyopathic conditions. In the present investigation the in vivo effects of angiotensin II (Ang II), a hypertrophic agonist have been studied on the ventricular expression level of NPR A in Wistar rat hearts. NPR-A expression at the protein and mRNA levels were found to be markedly reduced by 5-fold respectively in Ang II infused rats heart as compared with sham rat hearts. Moreover, cGMP production in response to ANP was reduced by 77% in the isolated cardiac membrane preparation from the Ang II infused rat hearts. Losartan treatment reversed NPR-A expression and responsiveness to ANP. This study suggests that Ang II down regulates cardiac NPR A activity by suppressing Npr1 gene transcription. PMID- 23441480 TI - Benefits of early glycemic control by insulin on sensory neuropathy and cataract in diabetic rats. AB - While there is an emphasis on the early glycemic control for its long-term benefits in preventing microvascular complications of diabetes, the biochemical mechanisms responsible for the long-lasting effects are not clearly understood. Therefore the impact of early insulin (EI) versus late insulin (LI) treatment on diabetic sensory neuropathy and cataract in streptozotocin-induced diabetic Wistar male rats were evaluated. EI group received insulin (2.5 IU/animal, once daily) treatment from day 1 to 90 while LI group received insulin from day 60 to 90. Early insulin treatment significantly reduced the biochemical markers like glucose, triglyceride, glycated hemoglobin, thiobarbituric acid reactive substances, advanced glycation end products and ratio of reduced glutathione and oxidized glutathione in diabetic rats. The late insulin treatment failed to resist the biochemical changes in diabetic rats. Diabetic rats developed sensory neuropathy as evidenced by mechanical and thermal hyperalgesia and showed a higher incidence and severity of cataract as revealed by slit lamp examination. Early insulin treatment protected the rats from the development of neuropathy and cataract, but late insulin administration failed to do so. The results demonstrate the benefits of early glycemic control in preventing neuropathy and cataract development in diabetic rats. PMID- 23441481 TI - Pharmacological evaluation of hyperin for antihyperglycemic activity and effect on lipid profile in diabetic rats. AB - Antihyperglycemic potential of hyperin at 25 and 50 mg/kg doses for 30 days to streptozotocin induced diabetic rats has been reported. In oral glucose tolerance test, hyperin treated rats showed a significant reduction in blood glucose level after 120 min. It was found that hyperin exhibited dose dependent and significant antihyperglycemic activity in streptozotocin induced diabetic rats which were nearly similar with standard drug glybenclamide. Activities of glucose-6 phosphatase, fructose-1,6-bisphosphatase, glycogen phosphorylase, glycosylated haemoglobin and level of serum urea and creatinine were significantly decreased in hyperin supplemented diabetic rats, dose dependently. Activities of hexokinase and glycogen synthase were increased with augmentation in liver glycogen, insulin and haemoglobin content in hyperin treated diabetic rats. General hematological parameters did not show any significant change in hyperin treated diabetic rats hence it is safe at these doses. Histopathological studies showed significant morphological changes in pancreatic beta-cells of streptozotocin induced diabetic rats. A decreased number of secretory granules of beta-cells were observed in diabetic rats and these pathological abnormalities were normalized after treatment with hyperin and standard drug glybenclamide. Further, hyperin decreases significant in serum total cholesterol, triglyceride, low density lipoprotein, very low density lipoprotein levels coupled with elevation of high density lipoprotein in diabetic rats. These results suggest that hyperin has a pivotal role in blood glucose level in streptozotocin induced hyperglycemia by improving the function of pancreatic islets and increasing glycolysis and decreasing gluconeogenesis. PMID- 23441482 TI - Role of ERK1/2 kinase in the expression of iNOS by NDMA in human neutrophils. AB - Potential role of ERK1/2 kinase in conjunction with p38 in the regulation of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and superoxide anion generation by human neutrophils (PMNs) exposed to N-nitrosodimethylamine (NDMA) was determined. Increased synthesis of NO due to the involvement of iNOS in neutrophils exposed to NDMA was observed. In addition, intensified activation of ERK1/2 and p38 kinases was determined in these cells. Inhibition of kinase regulated by extracellular signals (ERK1/2) pathway, in contrast to p38 pathway, led to an increased production of NO and expression of iNOS in PMNs. Moreover, as a result of inhibition of ERK1/2 pathway, a decreased activation of p38 kinase was observed in neutrophils, while inhibition of p38 kinase did not affect activation of ERK1/2 pathway in these cells. An increased ability to release superoxide anion by the studied PMNs was observed, which decreased after ERK1/2 pathway inhibition. In conclusion, in human neutrophils, ERK1/2 kinase is not directly involved in the regulation of iNOS and NO production induced by NDMA; however, the kinase participates in superoxide anion production in these cells. PMID- 23441483 TI - Cell cycle inhibitory effects of leaf extract from Curcuma vamana M. Sabu & Mangaly on mitotically synchronous cultures of Physarum polycephalum Schw. AB - Leaf extracts of C. vamana, endemic to Kerala state in India, were found to inhibit cell cycle progression in synchronous cultures of P. polycephalum in a concentration and phase-specific manner. Crude alkaloid extract (CAE) elicited maximum cell cycle delays in comparison to soxhletted chloroform, acetone and aqueous extracts. Total alkaloid content of CAE was found to be 64.9 mg/g. CAE showed lowest DPPH radical scavenging activity. Other extracts with higher free radical scavenging activity exhibited lesser cell cycle inhibiting potential. Upto 21% decrease in nuclear DNA was observed in CAE treated samples. However, genotoxicity as evidenced by comet assay was not observed. The extracts were also found to be non-toxic to human RBCs at the highest concentration tested (750 microg/mL). CAE treatment completely suppressed a 63 kDa polypeptide with a concomitant, but weak induction of a 60 kDa polypeptide suggesting that these may be cell cycle related. CAE was found to possess potent antiproliferative activity against PBLs. The study clearly demonstrates the cell cycle inhibitory activity of C. vamana leaf extracts, with CAE being the most potent of them. PMID- 23441484 TI - In vitro seed germination of economically important edible bamboo Dendrocalamus membranaceus Munro. AB - An in vitro propagation protocol using mature seeds of D. membranaceus was successfully established. Scarcity of seeds in bamboos because of their long flowering periods and irregular seed set resulting in low viability and germination potential, motivated us to undertake the present study. The effects of sterilants, light conditions, exogenous application of plant growth regulators and temperature in overcoming germination barriers in ageing seeds of bamboo were studied. It was found that HgCl2 (0.1%) along with bleach (15%) was more effective in raising aseptic cultures. Dark conditions, high temperatures around 30 degrees C and soaking of seeds in GA3 solution (50 ppm) overnight stimulated high percent of seed germination with corresponding increase in shoot length (2.7 +/- 0.7 mm) and number of sprouts (2.1 +/- 0.7) per explants during culture initiation. 6-benzylaminopurine acted synergistically with kinetin to give optimum germination rate of 70 +/- 13.9% as compared to 63.13% when used individually. For prolonged maintenance of cultures, 2% sucrose was found to be suitable for promoting photomixotrophic micropropagation. Following this procedure, about 65% survival of plantlets could be achieved during hardening. Biochemically seeds consume starchy endosperm for emergence of radicle which is taken as a sign of germination as also evident from the present study. Loss of viability and vigour after a year was confirmed by Tetrazolium chloride test. Micropropagation protocol developed here will ensure regeneration of large number of plants in a relatively short time. Conclusively, in vitro propagation protocol developed in D. membranaceus using mature seeds as an explants is reported for the first time. PMID- 23441485 TI - SRY-positive 46, XY male with vanishing testis syndrome, feminization and gynecomastia. AB - The vanishing testis with maleness is a rare syndrome with frequency of 1 in 20,000 males. Here, we report about a 30 years old male subject with vanishing testis syndrome, feminization and gynecomastia. Follicle stimulating hormone (FSH) and Leutinizing hormone (LH) levels were elevated whereas testosterone was below normal and anti-mullerian-hormone level was undetectable in the patient. The chromosomal analysis and DNA analysis of SRY and ZFY, DAX-I, AZFa, AZFb, AZFc and heterochromatic region of Y chromosome with STS primer (sY160) were done to detect any genetic changes at specified sites (both at chromosomal and molecular level). Karyotyping confirmed patient as 46, XY male, with no evidence of mosaicism in blood cells. PCR amplification of SRY gene indicated that the SRY gene of the patient was normal. PCR amplification of SRY, ZFY, DAX-I, AZFa, AZFb, AZFc gene and Y chromosome heterochromatic region using STS primer sY(160) did not reveal any microdeletions. The anti-mullerian-hormone level was undetectable indicating that the patient didn't have any testicular tissue in scrotum. Increased levels of FSH, LH and reversed androgen: estrogen ratio might have given rise to gynecomastia in the patient. SRY-positive 46,XY male with vanishing testis might be due to torsion of testis during descent in fetal period. The torsion of testis might have caused vascular occlusion and thereby regression of testicular tissue occurred, but the exact genetic condition yet to understand. PMID- 23441486 TI - In vitro activity of cefoperazone-sulbactam combination against gram negative bacilli. AB - Cefoperazone is a a-lactam antimicrobial and Sulbactam is an irreversible a lactamase inhibitor. The objective of this study was to know the susceptibility pattern of gram negative bacilli (GNB) towards cefoperazone-sulbactum. All GNB isolated from different clinical samples during the period of May, 2010 to Aug, 2010 were tested for susceptibility to cefoperazone-sulbactum, meropenem, ceftazidime, cefotaxime, ceftriaxone, chloromphenicol, cotrimoxazole, ampicillin, amikacin, nalidixic acid, ciprofloxacin, carbenicillin and piperacillin using standard Kirby-Bauer disc diffusion antimicrobial susceptibility testing method. The susceptibilities were recorded according to CLSI guidelines. A total of 406 GNB were isolated (urine: 66.7%, pus: 19.2%, and blood: 7.9%). Escherichia coli (54.4%) was most frequently isolated organisms followed by Acinetobacter species (17.7%), Klebsiella pneumoniae (9.1%) and Pseudomonas species (6.1%). Overall, 11.8% of isolates showed resistance to cefoperazone-sulbactam. Frequencies of isolates showing resistance to meropenem and amikacin were 14.7% and 26.25% respectively. Only 3.9% of Escherichia coli isolates showed resistance to cefoperazone-sulbactam. For other organisms, their lowest frequency ranging from 0-20%, exhibited resistance to meropenem. In Pseudomonas spp, in-vitro activity of amikacin was also better as only 11.1% isolates showed resistance to it. This study demonstrated the in-vitro synergistic effect of cefoperazonerazone sulbactam and meropenem having good activity against GNB compared to the activity of other commonly tested antimicrobials. Cefoperazone-sulbactam can be recommended for the clinical practice against GNB exhibiting resistant to other antimicrobials as it is cheaper alternative to meropenem. Our results also focused on the continuous surveillance of the trends and features of resistance of common antimicrobials. PMID- 23441487 TI - A study of obliquity of femoral shaft in Eastern Indian population. AB - In the erect posture, femur is not absolute vertical, being separated above from its fellow by a considerable interval, which corresponds to the breadth of the pelvis, and inclines gradually medially and downward, so as to approach its fellow, for the purpose of bringing the knee joints near the line of gravity of the body. In the present study obliquity of femoral shaft measured in 127 dry femora. Mean obliquity of femoral shaft for 62 left sided femora found 8.431 degrees with standard deviation of 2.361 degrees whereas for 65 right sided femora were found to be 7.708 degrees with standard deviation of 2.425 degrees. When total 127 femora considered, mean bicondylar angle of 8.061 +/- 2.412 degrees was obtained. Though statistically insignificant, mean bicondylar angle determined on left side was higher than that on the right side. PMID- 23441488 TI - Epidemiological study of mental morbidity in an urban slum community in India for the development of a community mental health programme. AB - A crossectional field study was carried out in an urban slum in order to assess the prevalence and nature of mental morbidity and identify stressors in the community. A face to face interview was conducted with the help of a questionnaire. The interview consisted of three sections as follows: Data identifying the informant by age, sex, marital status, education, occupation, age at marriage, number of members, children and monthly income. General Health Questionnaire (GHQ) 5- item version used as a screening instrument to assess the present mental health status of the informant and data of past illnesses in self or family and questions framed to elicit perceptions regarding mental illness, alcoholism, their causation and treatment. The subjects who scored above 2 ie 3,4,and 5 in the GHQ were requested to follow up at the Mental Health OPD and subjected to a standardized psychiatric interview by a Psychiatrist. The Diagnostic and Statistical Manual Third Revised (DSM 3 R) criteria were used for diagnosis. After the interview and examination, the appropriate treatment was instituted. A total of 443 individuals were screened. The overall prevalence rate of mental illness in the community was 61 per thousand. It is estimated that the case rate ranges from 38 to 84 per thousand within 95% confidence limits. The overall severity ranged from mild to severe morbidity. The prevalence of severe mental morbidity which includes psychosis, depressive illness, mental retardation was 22.5 per thousand. Neurosis (63.31%) especially Major Depression and Adjustment disorder, Psychosis (10.00%), Somatization disorder (6.66%) and Psychiatric symptoms secondary to physical illness were the major groups of illness. Women were found to have more mental health problems than men. The morbidity pattern also differs significantly with the gender. Neurosis was seen more among the female subjects. There was a significant association of mental health problems with low educational status, unemployment and large family size. Financial problems, marital conflicts, interpersonal conflicts and housing problems were the major stressors as perceived by the respondents. There exists significant mental health problems in the community which can be due to deleterious sociocultural factors and we recommend the integration of mental health care with general health care. PMID- 23441489 TI - Histological changes of placentas associated with intra-uterine growth restriction of fetuses: a case control study. AB - Placenta is the maternal-fetal contact zone. The placentas of "idiopathic" intra uterine growth restriction (IUGR) babies may hold the key to the etiology of growth restriction. The present study primarily aimed at evaluating the structural peculiarities of IUGR placenta. The study was conducted on 35 IUGR and 25 control placentas. Placental tissues were processed for routine histological studies, to determine numbers of syncytial knots in villi and X-cells in the basal plate. Light microscopy suggested that syncytiotrophoblastic lining was more degenerated and number of syncytial knots increased in IUGR placentas than that of the control placentas. X cells were present in both the cases, though more in IUGR. Intravillous and perivillous fibrin depositions were markedly increased in IUGR; also there were more hypovascular/avascular villi and large areas of infarction. Cumulative effects of several placental injuries, e.g. poor perfusion, presence of increased number of X-cells, increased fibrin deposition; etc for a sufficient time were likely cause of IUGR. PMID- 23441490 TI - Assessment of chronic kidney disease in Nepalese people with hypertension. AB - Hypertension is one of the leading causes to develop chronic kidney disease (CKD) and could be a risk factor for progression of CKD to end stage renal disease (ESRD).Uncontrolled hypertension worsens CKD. Hypertension control may contribute to prevent CKD in early stages and retards the progression of CKD stages to ESRD. Prevalence of CKD in people with diagnosed and chronic hypertension is known to be high, but little is known about the prevalence of CKD in those with newly diagnosed Hypertension. Present work was undertaken to see the prevalence of CKD among people with newly diagnosed hypertension. In this cross-sectional study, we accessed the CKD in newly diagnosed hypertensive patients and determined the association between hypertension and CKD. CKD was defined as either kidney dysfunction or kidney damage or both as per National Kidney Foundation Guidelines. 106 of newly diagnosed patients and 106 of normotensive controls were recruited in the study. 51.9% of newly diagnosed hypertensive patients and 23.6% of normotensive controls had CKD which was statistically significant (p-value <0.001). Difference in the mean value in eGFR and spot urine ACR (mg/mmol) between hypertensive patients and normotensive controls was statistically significant (p-Value <0.001). Both systolic BP and diastolic BP negative significantly correlated with eGFR (p-Value < 0.001 and 0.024 respectively) and positive significantly correlated with ACR (p-Value 0.003 and 0.003 respectively). The prevalence of CKD is high among people with newly diagnosed hypertension. Those, people might benefit from interventions aimed at preventing development and/or progression of both CKD and hypertension. PMID- 23441491 TI - Choledochoduodenostomy in the management of dilated common bile duct due to choledocholithiasis. AB - Choledochoduodenostomy (CDD) is the operative procedure for Choledocholithiasis in the presence of a dilated common bile duct (CBD). It has been reported as a most effective treatment of CBD stones than T-tube drainage but is regarded as a obsolete therapeutic method due to fears of higher morbidity, cholangitis, "sump" syndrome etc. This study was done prospectively to assess the aforementioned issues analyzing our two years (July 2009 - June 2011) experience.CDD was performed in 31 patients (22 females and 9 males) with aged 18 - 72 years. CBD stones were the only indications in all patients with 18 (45.1%) patients had cholangitis, 8 (35.4%) had cholecystitis and 5 (19.3%) had biliary colic. Abdominal sonogram revealed dilated CBD with single or multiple calculi. The diameter of CBD varies from 14 - 29mm with stone size being ranged from 10- 26mm.Early post operative complications were seen in 4 (12.9%) patients. Only one patient had recurrent cholangitis presented lately due to intrahepatic stones.CDD is a highly effective treatment for choledocholithiasis in all age group with low morbidity and mortality provided a wide anastomosis is accomplished. PMID- 23441492 TI - Clinico-demographic profile, sexual dysfunction and readiness to change in male alcohol dependence syndrome inpatients in a tertiary hospital. AB - Persons with prolonged and heavy alcohol use generally suffer from alcohol dependence syndrome (ADS) and develop physical, sexual as well as psychiatric co morbidity. Successful recovery to normalcy depends on multiple factors including patient's motivation. To study clinico-demographic profile, reasons for initiating alcohol use, sexual and psychiatric disorders and eagerness for treatment and quitting alcohol in ADS inpatients. Fifty consecutive ADS inpatients with matching controls were enrolled. Clinico-demographic profile, factors for initiating alcohol use, psychiatric and sexual co-morbidity and want for treatment and being abstinent was studied applying relevant scales. All subjects were males with a mean age of 37.5 years, 80% were married, majority were Hindu (88%) and from nuclear families (56%). Fifty two percent had an education level of Graduation or more and 68% of patients reported peer pressure to be the initiating factor for alcohol use. Seventy six percent had psychiatric co-morbidity including personality Problems and other Psychiatric disorders 19(38%), delirium tremens 14 (28.00%) and Mood disorders 12(24%).Depression being most common mood disorder (14%). Nicotine was the most common other substance of use 32 (64%). Sixty eight percent of the patient reported one or another sexual dysfunction. 68% of ADS inpatients acknowledged of having problems related to their drinking, expressed desire for change and were eager to avail treatment and to remain abstinent. ADS patients commonly suffer from psychiatric co-morbidity and sexual dysfunctions. They also wish to have effective treatment and to quit alcohol. PMID- 23441493 TI - Retained placenta--a major cause of maternal morbidity. AB - Retained placenta is a condition when placenta is not delivered by 30 minutes after delivery of baby. It commonly occurs among those women who deliver at home and it is responsible for more of maternal morbidity and mortality. One reason behind this is it mostly occurs in home delivery where active management of third stage of labour is lacking and once it takes place it increases the chances of post partum haemorrhage (PPH) and sepsis irrespective of place of delivery. In this prospective study carried out in a Hospital which is located at a distance of 10-12 kilometers from the centre of the capital, we tried to find out the prevalence of retained placenta, its relation with the place of delivery, steps taken to manage the cases of retained placenta and morbidity in terms of blood loss and hospital stay. The frequency of retained placenta in this study is 3.96% with majority having home delivery (82.8%). Those women who had blood loss of more than 1 litre (4.0%) all were home deliveries. Among all 12.0% cases had severe anaemia and needed significant amount of blood transfusion. All cases with retained placenta were first tried with use of oxytocics and controlled cord traction followed by manual removal of placenta under general anaesthesia. All cases were successfully managed with control cord traction (CCT) except 18 cases who needed manual removal of placenta (MRP). PMID- 23441494 TI - Internet addiction in a group of medical students: a cross sectional study. AB - The use of Internet for education, recreation and communication is increasing day by day. Nevertheless, the possibility of exploitation and addiction leading to impairment in academic performance and emotional balance cannot be denied, especially among young population. The study was aimed to measure the degree of Internet addiction among a group of medical students. Internet addiction test questionnaire developed by Young was used to assess mild, moderate and severe addiction. Amongst the study population (n=130, age 19-23 years), 40% had mild addiction. Moderate and severe addiction was found in 41.53% and 3.07% of the participants respectively. The study revealed that 24% often and 19.2% always found themselves using Internet longer than they had planned or thought. Late night Internet surfing leading to sleep deprivation was found in 31.53% of the participants. Almost one fourth of them (25.38%) occasionally tried to cut down the time they spent on the Internet but failed and 31.53% sometimes experienced restlessness when deprived of Internet access. Results reflected that a significant number of participants suffered from mild to moderate addiction. The role of counseling and education should be emphasized for prevention of Internet addiction. PMID- 23441495 TI - Distribution and ethnic variation of a-thalassemia mutations in Nepal. AB - This is the first study characterizing spectrum of beta-thalassemia mutations in Nepalese population. Mutations were analyzed in 22 patients using 10 sets of allele-specific primers. Five of the mutations, namely F.S 41/42 (--TCTT), IVS1 nt5 (G-->C), IVS1 nt1 (G-->T), 619 bp deletion and F.S 8/9 (+G), were found to constitute 87.82% of total alleles studied. F.S 41/42 (--TCTT) was the commonest mutation. -88 (C-->T), Codon 16 (--C) and Codon 15 (G-->A), had a combined frequency of 12.18%. Distribution of mutations causing beta-thalassemia in different ethnic Nepalese groups was analyzed. The mutational profile in Nepal share several similarities with that from the two neighboring countries, India and China. Detection of more than one mutation in three cases of thalassemia trait raises the likelihood of existence of multiple mutations in cis in Nepalese thalassemic carriers. Such possibility has to be carefully considered while developing prenatal screening program for Nepalese population. PMID- 23441496 TI - Correlation of the hand length and stature in adult Musahar females of Nepal; an anthropometric study. AB - Stature of a person is one of the most important and useful anthropometric parameter for establishing identification of unknown living or a dead person. A descriptive cross sectional study was done on 165 Nepalese adult Musahar females of Aurahi Village of Mahottari district, Nepal to predict the stature from their hand length. Measurement of stature and the length of both right and left hands taken with a standard standing height measuring instrument and a slide caliper respectively showed significant (p<0.001) positive correlation between the stature and hand lengths. The multiplication factor which was obtained by dividing the height of the subject by the respective hand lengths was found appropriate parameter to calculate the stature of a questioned person. The importance of the hand length alone will be of a great value for anthropologists and forensic experts. As an alternative method, the coefficient of regression and intercept which were obtained from the measured height and hand length were also proved to be equally valuable to estimate the height of a questioned person. PMID- 23441497 TI - Study on blood pressure control status and predictors of uncontrolled blood pressure among hypertensive patients under medication. AB - Widespread treatment options are available for hypertension, but the target range of blood pressure achieved with treatment has been viewed unsatisfactory worldwide. The study was designed to see what proportion of hypertensive under medication had controlled blood pressure and to analyse basic characteristics of uncontrolled subjects and factors associated with blood pressure control status. Hypertensive subjects under medication for at least 6 months were enrolled. They were interviewed and examined. Baseline characteristics and variables to be tested were recorded. Data analysis was done using SPSS. Among 147 hypertensive patients enrolled in the study 49 (33.33%) had controlled blood pressure and 98 (66.66%) had uncontrolled blood pressure despite medication. Blood pressure control status had no significant correlation with sex (p=0.90). The uncontrolled subjects had mean age more than the mean age of the total enrolled group (53.12 +/- 10.3 years versus 49.09 +/- 10.65 years). Physical activity (p=0.04) and adherence to therapy (p<0.01) had significant positive correlation with blood pressure control. There was significant positive correlation between blood pressure control status and awareness of target blood pressure (p=0.028), awareness of complications of uncontrolled blood pressure (p=0.019) and frequency of blood pressure check up (p<0.01). Blood pressure control in our set up was comparable to previously reported articles. By encouraging patients to adhere to therapy, to adopt physically active life style, creating awareness about the target blood pressure and complications of uncontrolled blood pressure and frequent blood pressure check up can improve the outcome. PMID- 23441498 TI - High-level gentamicin resistance and vancomycin resistance in clinical isolates of enterococci in a tertiary care hospital in eastern Nepal. AB - High-level gentamicin resistance and vancomycin resistance in enterococci, a family of important opportunistic pathogens, have emerged as a significant clinical problem over recent years. The present study was conducted to determine the high-level gentamicin and vancomycin resistance among the clinical isolates of enterococci. A total of 110 phenotypically identified enterococcal isolates were subjected to determination of high-level gentamicin resistance (by disk diffusion and agar dilution methods) and vancomycin resistance (by agar screening and agar dilution methods). About 36% of the isolates were found to have high level gentamicin resistance, which indicates that gentamicin no longer remains an appropriate choice for inclusion in combination therapy with cell wall-active agents. Ten percent isolates exhibited resisance to vancomycin during screening. However, agar dilution confirmed that the isolates did not have resistance to vancomycin but had reduced susceptibility to it, which indicates their impending emergence of resistance to vancomycin. PMID- 23441499 TI - Indications of admission and outcome in a newly established neonatal intensive care unit in a developing country (Nepal). AB - Establishing and running a neonatal intensive care unit in a resource poor country is a big challenge. Neonatal Intensive care units (NICU) and Paediatric Intensive care units (PICU) has been started in Patan Hospital from July 2009. The in-born neonates are admitted to NICU and the out-born neonates to PICU. A retrospective hospital based study looking at the common indications for admission and the outcome of the neonates in the intensive care unit was carried out from July 2009 to December 2010. Data was collected from the admission discharge registers at the units and from patient record files. Over the 18 month period there were total 289 neonatal admissions, 214 to NICU and 75 to PICU. More than half of the neonates (53%) admitted to NICU and PICU were preterm. The most common neonatal condition leading to Intensive care unit (ICU) admissions was respiratory distress which accounted for 42%. Of the total neonates admitted to ICUs one third (33.5 %) needed mechanical ventilation. The most common conditions needing mechanical ventilation were hyaline membrane disease (33%) and severe sepsis (24%). The overall mortality rate was 26.6% .The mortality was higher among neonates weighing less than 2.5kg (32%) compared to those weighing >2.5kg (15.5%) (P value - 0.001) and it was higher in babies born before 34 weeks of gestation (P value - 0.009). Neonatal intensive care facilities though is expensive and not readily accessible, establishing a unit can not only save some of the precious lives but also helps in managing critically sick neonates aiming for an intact survival. PMID- 23441500 TI - Inferior vena cava injury repair, a successful outcome. AB - Inferior ver a cava (IVC) injuries are very very infrequent; yet it still happens to be the most frequently injured retroperitoneal vascular structure. Fifty percent of the patients can't even make it to the hospital. Even when half of them manage to attend the hospital the mortality rates for the great vessel injury are still very high perhaps due to the low index of suspicion, delayed or inadequate volume resuscitation, difficulty in diagnosis and also due to some technical problems associated in its repair. We present a young male with an abdominal stab injury who had a near transected inferior vena cava at operation. Aggressive perioperative management and the correct judgement by our team at the right time possibly made the patient survive. The rarity of this condition and a review of the literature with some discussion are presented. PMID- 23441501 TI - Atlantoaxial rotatory fixation in a case of tubercular lymphadenitis. AB - Atlantoaxial fixation is a relatively rare cause of torticollis which may be easily missed in practice. Early diagnosis is important as this indicates a compromised atlantoaxial complex with the potential to cause neural damage or even death. Here, we report a case of atlantoaxial rotatory fixation in a 13 yr old male with torticollis for two years and history of defaulting treatment for tubercular lymphadenitis. In this case, the odontoid peg view revealed asymmetric distance between the odontoid and lateral mass of atlas which was confirmed with Fluoroscopy and Computed Tomography (CT) scan. Magnetic Resonance Imaging (MRI) was also done which showed hyperintensity in alar ligaments with posterior inclination of the odontoid peg along with cervical lymphadenopathy. PMID- 23441502 TI - Looking forward. ACS ensures quality of care from competent surgeons. PMID- 23441503 TI - A win for all: faculty-student partnerships in surgical humanitarianism. PMID- 23441504 TI - Pursuing a career in humanitarian and rural surgery: when is the best time to start? PMID- 23441506 TI - 2012 elections: $6 billion status quo. PMID- 23441505 TI - Twitter usage at Clinical Congress rises markedly over two years. PMID- 23441507 TI - The principles and outline of fracture treatment. 1931. PMID- 23441508 TI - The physician compare website. PMID- 23441509 TI - Coding for hospital admission, consultations, and emergency department visits. PMID- 23441510 TI - ACS and the Joint Commission partner on project to decrease risk of colorectal SSIs. PMID- 23441511 TI - 2012 Pediatric Report: devastating at any age. PMID- 23441512 TI - Residency training program in Nigeria; challenges and way forward. PMID- 23441513 TI - An overview of menopause associated vasomotor symptoms and options available in its management. AB - BACKGROUND: Vasomotor Symptoms are the most common and distressing menopausal complaint, for which women seek advice from their physician. OBJECTIVE: To review menopausal associated vasomotor symptoms and options available in its management. METHODS: Pertinent literature on menopause associated vasomotor symptoms, selected references, textbooks, journals and internet services using the PubMed and Medline databases were included in this review. RESULTS: Hot flushes are the most common and distressing symptom, for which women seek advice from their physician. It occurs in more than 75% of postmenopausal women. Management of hot flushes is problematic because the most recognized effective option oestrogen, is often contraindicated. This has resulted in extensive research exploring different therapeutic options for treatment of hot flushes. Currently, various safe and efficacious nonhormonal options exist but further research is still needed to improve on the treatment of hot flushes. CONCLUSION: The management of the most common and distressing vasomotor symptoms associated with menopause (hot flushes) is controversial. Regardless of the management strategy adopted, treatment options should be periodically reassessed as menopause-related vasomotor symptoms will abate with time even without any intervention in majority of postmenopausal women. PMID- 23441514 TI - Iron status of some pregnant women in Orlu town--eastern Nigeria. AB - BACKGROUND: High prevalence of anaemia has been reported among pregnant women especially in developing nations. This paper considers maternal haemoglobin (Hb) level, serum total iron, iron binding capacity, and serum ferritn iin antenatal women in Orlu-Imo State Nigeria. PATIENTS AND METHODS: Haemoglobin level, serum iron, serum ferritin, and total iron binding capacity (TIBC) were measured in different trimesters among 90 pregnant women aged 20-45 years, on iron supplements attending antenatal clinic of Imo State University Teaching Hospital Orlu. First trimester comprised of 16.7% (n = 15), second trimester comprised of 50% (n = 45) while as third trimester comprised of 33.3% (n = 30). 30 non pregnant women aged 26-40 years were used as controls. RESULT: The mean Hb level was 11.28 +/- 1.4 g/dl in first trimester, 9.51 +/- 1.9 g/dl in second trimester, 10.4 +/- 1.2 g/dl in third trimester, and 10.9 +/- 1.5 g/dl in controls. Mean serum iron level was 142 +/- 23 microg/ml in first trimester, 235 +/- 118 microg/ml in second trimester, 251 +/- 118 microg/ml in third trimester, and 99.7 +/- 19.4 microg/ml in controls. Mean serum ferritin was 57.7 +/- 30 ng/ml in first trimester, 37.6 +/- 17 ng/ml in second trimester, 37.3 +/- 20 ng/ml in third trimester, and 86.7 +/- 16.9 ng/ml in controls TIBC was 337 +/- 90 microg/dl in first trimester, 441 +/- 19 microg/dl in second trimester, 482 +/- 149 microg/dl in third trimester and 271.8 +/- 89.0 microg/ml in controls. Hb level was relatively stable in pregnancy, but was significantly (p < 0.05) lowest in the second trimester compared with controls Serum iron and TIBC progressively increased from first trimester to third trimester. Conversely, serum ferritin declined progressively from first trimester to third trimester. The increments in serum iron was statistically significant (p < 0.05) between first and second trimester, but not significant between second and third trimester. TIBC was significantly higher in third trimester compared with first trimester. Serum ferritin was significantly lower in second and third trimesters compared with controls. This implies a progressive mineral transfer from mother to fetus. TIBC and serum iron were significantly (p 0.05) lowest in non-pregnant controls compared with the three trimesters of pregnancy. Conversely ferritin was significantly (p < 0.05) higher among the non-pregnant controls compared with the three trimesters of pregnancy. This implies that the nonpregnant women had more iron store and had less iron need than their pregnant counterpart. The higher iron need in pregnancy necessitated its mobilization from its stores. CONCLUSION: This study encourages more critical antenatal care especially at second trimester of pregnancy with much emphasis on dietary supplementation of iron and minerals through adequate consumption of local vegetables and other food diets rich in iron. There was poorest antenatal attendance in the first trimester. Pregnant women in this environment should be encouraged to register early for antenatal care. PMID- 23441515 TI - The pattern of distribution of encephalocele in University of Port Harcourt Teaching Hospital--a three year experience. AB - BACKGROUND: Encephalocele is a congenital anomaly that results from failure of complete neural tube closure during foetal development. It is a known cause of mortality and morbidity in infants. This study was carried out to highlight its distribution pattern in University of Port Harcourt Teaching Hospital over a three-year-period. METHODOLOGY: This is a retrospective study of children with encephalocele admitted from January 2007 to December 2009. The following information were obtained from their medical records: sex, age at diagnosis, distribution pattern, place of origin, detailed antenatal history, maternal occupation/level of education, family history, associated anomalies and outcome of surgery. RESULTS: 17 cases (10 females and 7 males) were seen over this period. 12 presented as frontal encephalocele while 5 were occipital. Their ages at diagnosis were: prenatal (determinded by abdominal ultrasound) 5, 0-6 months 11, and 7-12 months 1. 9 of 17 mothers were unbooked. Pregnancy was uneventful in all cases. None had family history of encephalocele. 5 had multiple anomalies while 12 had only encephalocele. 10 patients had surgery, of which 9 were successful. 1 died in the immediate postoperative period. 7 patients did not have surgery. Among these, 3 died before surgery while the parents of 4 children refused operation. 10 mothers had primary education, 5 secondary, while 2 had attained tertiary education. CONCLUSION: Encephalocele may be frontal or occipital. The distribution pattern of our cases was in favour of frontal location, with slight female preponderance. PMID- 23441516 TI - The frequency and pattern of cardiac autonomic neuropathy (CAN) in type 2 DM patients in a diabetic clinic in Enugu South-East Nigeria. AB - STUDY OBJECTIVES: To determine the frequency, pattern and grades of cardiac autonomic neuropathy (CAN) in type 2 diabetic patients in a diabetes mellitus (DM) clinic in Enugu South-East Nigeria. METHODS: A cross sectional study of seventy (70) type 2 diabetic patients attending a DM clinic in Enugu South-East Nigeria was carried out. Cardiac autonomic function was determined using a battery of 5 noninvasive tests which include; Heart rate response (HRR) to Valsalva manoeuvre, HRR to deep breathing, HRR to standing, Resting heart rate, and Blood pressure (BP) response to standing. RESULTS: The frequency of cardiac autonomic neuropathy (CAN) in type 2 diabetic patients was 44.3%. Resting tachycardia was the most specific, HRR to Valsalva manoeuvre was most sensitive while BP response to standing had the best positive predictive value in detecting cardiac autonomic neuropathy. CONCLUSIONS: Cardiac autonomic neuropathy is a common complication in type 2 Diabetes Mellitus patients seen at Enugu. It is therefore recommended that tonomic function tests be part of the standard care of type 2 diabetic patients and appropriate management instituted for both primary and secondary prevention. PMID- 23441517 TI - Leukocyte profile of adult Nigerian subjects with acute musculoskeletal trauma. AB - BACKGROUND: Leukocyte levels are evidently useful in trauma assessment, prognostication and management. Leukocytosis is a known physiologic response to trauma but suggested to be absent among Africans origin. The aim of present study is to investigate the existence of leukocytosis among adult Nigerians who sustain acute musculoskeletal trauma, S and also assess its prognostic value in management. METHODS: A calculated sample size of 223 subjects participated following informed consent while 50 apparently healthy adult Nigerian volunteers served as control. Data obtained included age, sex, duration of hospitalization and leukocyte counts using improved Neuabauer chamber while differential count was done on stained thin film. RESULTS: Analyzed results expressed as mean +/- SDM show significant male dominance (p < 0.05) among the acutely traumatized subjects with majority (70%) aged between 20 and 49 years. The mean total white blood cell count was 8184.96 +/- 201.087 cells/m3, significantly higher than mean for the control group (4922.00 + 1282.264 cells/mm3) at p < 0.05. The mean values for neutrophil and lymphocytes also show significant neutrophilia and lymphocytopaenia among the test population (p < 0.05). Pearson's correlation test for duration of hospitalization was positive for higher levels of total White Blood Cell count, with strong positive correlation between the levels of neutrophil and total White Blood Cell count suggesting the source of the observed leukocytosis. CONCLUSION: Thus adult Nigerians exhibit posttraumatic neutrophilic leukocytosis contrary to some widely accepted postulations. The post-traumatic neutrophilia exhibit an inverse relationship with observed lymphocytopaenia. This can be expressed as a ratio called Neutrophil Lymphocyte Stress Factor (NLSF) and used in trauma management and prognosis determination. PMID- 23441518 TI - Family biosocial variables driving adherence to the use of insecticide treated nets among under-five children managed for malaria in a rural hospital in eastern Nigeria. AB - BACKGROUND: As the distribution and awareness of free insecticide treated nets (ITNs) for malaria control continues to grow in Nigeria in order to meet the coverage target for the year 2010, a large gap exists between acquiring them, using them, and adhering to its use by families of under-five children. Therefore, the family biosocial variables driving its adherence need to be explored if the potential benefits of the nets are to be fully harnessed by families of under-five children in Nigeria. This study was aimed at describing family biosocial variables driving adherence to the use of insecticide treated nets among under-five children managed for malaria in a rural hospital in Eastern Nigeria. MATERIALS AND METHODS: This was descriptive hospital-based study carried out from June 2008 to June 2010 on a cross section of 220 mothers of under-five children who were managed for confirmed malaria within the study period and met the selection criteria were interviewed using a pretested, structured researcher administered questionnaire. The questionnaire instrument elicited information on family biosocial variables. Adherence was assessed in the previous 6 months and graded using an ordinal scoring system of 1-4 points: score of 4 points indicated adherence while scores of 1-3 points meant nonadherence. Operationally, an adherent respondent was defined as one who scored 4 points. An under-five child was defined to have malaria if the mother gave complaint of fever, vomiting and other symptoms suggestive of malaria, had body temperature exceeding 37.5 degrees C with the asexual forms Plasmodium falciparum detected on the peripheral blood film. Reasons for nonadherence were also sought. RESULTS: The adherence rate was 33.2%. The family biosocial variables significantly associated with adherence were maternal age =30 years (p-value = 0.03), maternal occupation (house wives) (p-value = 0.03), family size less than 4 (p-value = 0.026) and spouse living together (p-value = 0.01.). Others included family belief, in the benefits of ITNs (p-value = 0.002 and source of ITNs (p-value = 0.03). The most significant predictor of adherence was living together of spouse (p-value = 0.000, OR = 3.851, CI = 1.76-6.01). The commonest reason for non-adherence was forgetfulness (p-value = 0.003). CONCLUSION: Despite high family belief in the benefits of ITNs, adherence to its use was low. Some family biosocial variables played significant roles in driving its adherence. Measures targeted at these variables and widespread family-oriented health promotion programmes are recommended in order to improve on adherence leading to family friendly ITNs communities. PMID- 23441519 TI - Postoperative vomiting and fever following tonsillectomy in Enugu, Nigeria. AB - OBJECTIVE: To determine the incidence of postoperative vomiting and fever in patients that had tonsillectomy in our centre over a five year period. METHODS: The hospital records (case files) of patients that had tonsillectomy with or without adenoidectomy under general anaesthesia at the University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu, Nigeria from January 2004 to December 2008 were retrieved and analyzed. Patients that had an adenoidectomy only were excluded. The patients were of the American Society of Anesthesiologists (ASA) I to III status. RESULTS: There were fifty two (52) patients that had tonsillectomy and adenotonsillectomy under general anaesthesia during the period under review. Forty one (41) patients were between the ages of 1-13 years (78%) and eleven (11) patients between the ages of 18-62 years (12%). There were 32 males and 20 females. The average age for all the patients was 9.03 years. There were seven (7) patients with post operative vomiting (13.4%). These included four (4) patients in the paediatric population (9.75%) and three (3) in the adult population (27.2%). Twenty one (21) patients (40.3%) developed postoperative fever. There were no deaths The other significant morbidity was postoperative pain. CONCLUSION: The number of patients that had tonsillectomy in our center was small compared to other studies. The incidence of postoperative vomiting in this study is lower than that reported from Western World, showing possible racial variations, a trend that has been reported in some earlier studies in Black populations. PMID- 23441520 TI - Fetal outcome of twin gestations in a Nigerian teaching hospital. AB - BACKGROUND: Although twin gestation is associated with increased perinatal morbidity and mortality, optimal management of this high risk pregnancy is associated with improved outcome for the mother and her baby. Globally, Nigeria has the highest incidence of twinning. This makes studies on twin gestation important, especially on the outcome of the babies which is reflection of the type of care received during the antenatal and intrapartum period. STUDY OBJECTIVE: This study was designed to determine the fetal outcomes of twin deliveries in a tertiary hospital in Nigeria's Federal Capital Territory. METHOD: This was a retrospective study of babies following twin pregnancies delivered in the hospital from 1st January 1998 to 31st December 2007. RESULTS: Out of the 600 babies reviewed, 10.2% were still births giving a still birth rate of 102 per 1000 births. Majority of the stillbirths (73.8%) occurred amongst the unbooked mothers and was higher amongst the second twins. More of the booked mothers had their babies delivered at term compared to the unbooked ones, 115 (38.3%) Vs 66 (22.0%).There was a statistically significant association between gestational age at delivery and booking status of the paturients. (X2 = 16.257, P = 0.001). The mean fetal weight was 2.395 kg +/- 0.63. There was no statistically significant difference when the weights of the first and second twin were compared. (t = 0.343, P = 0.732). Out of the 539 babies born alive, 85.0% had good Apgar score of = 7 in5 minutes, 13.0% of the first twins had moderate birth asphyxia compared to 16.0% of the second twins. The female to male ratio was 1:1.1. CONCLUSION: Twin gestation is associated with low birth weights and high still birth rate in this centre. Fetal outcome is better in the first twin compared to the second twin. Outcome for babies whose mothers were booked were better compared to the unbooked. Quality antenatal care and intrapartum management will help improve fetal outcome. PMID- 23441521 TI - Pathway to care: first points of contact and sources of referral among children and adolescent patients seen at neuropsychiatric hospital in South-Eastern Nigeria. AB - OBJECTIVE: Child and adolescents mental health services are at infancy stage of development in most Sub-Saharan African region. Little is known about help seeking behaviour for childhood neuropsychiatric disorders in Sub-Saharan Africa. This study was aimed at assessing first points of contact during help seeking and eventual sources of referral for a group of patients seen in a neuropsychiatric facility in south-eastern Nigeria. METHODS: At the point of presentation, information were obtained on where help was first sought before presenting at the hospital with the major aim of identifying other competing services. Other information obtained in addition to socio-demographic variables included information on source of referral or the source that initiated help seeking from Federal Neuropsychiatric Hospital, Enugu, South-eastern Nigeria. RESULTS: Neuropsychiatric hospital, prayer houses/faith healing centres, other hospitals, traditional healers, patent medicine stores, roadside medical laboratories and specialized school were various first points of contact noted. Relatives, family and friends, other hospitals, prayer houses and specialized school constituted sources of referral. CONCLUSIONS: The need to incorporate all these sources with the aim of improving accessibility of neuropsychiatric services for children and adolescents in this environment is paramount. PMID- 23441522 TI - Has the creation of a urology residency programme translated in to more surgical exposure for final year residents? AB - BACKGROUND: Surgical residency programmes are supposed to enhance resident operative experience. The impact of urology residency was assessed at our institution before and after establishing a structured urology training programme in 2006. MATERIALS/METHODS: Log books of final year Urological residents presented for the West African College of Surgeons (WACS) and National Postgraduate Medical College (NPMC) final part II exams from January 2007 to December 2011 at Jos University Teaching Hospital (JUTH) were reviewed. All residents had completed mandatory 3 years of urology training. The records of surgeries performed by residents were extracted. These surgeries were categorized as Endoscopic procedures, open kidney/ureter surgeries, open bladder surgeries, open prostate surgeries, open urethral and open testicular/penile sugeries. The records were compared with records of operated cases in the same category before the commencement of Urology residency training from January 2001 to December 2005. Results were presented as tables and charts. The Students unpaired t-test was used to assess significance. P value of < 0.05 was taken as significant. RESULTS: There was an overall increase in absolute number of operative cases performed by final year residents in the period after the commencement of the Urology residency programme (n = 596) compared to the period before the training began (n = 381) this however, was not statisically significant (p = 0.3). There was a decline in endoscopic surgeries done by residents after the training begun compared to the era before the training. CONCLUSION: Whereas creation of the urology training programme in JUTH has resulted in more operative cases done by trainee urologists, the exposure to endosopic surgeries has declined. This will not augur well for the training programme in the long run. Periodic rieiew of the data should be performed to maintain consistent, positive experiences for residency training. PMID- 23441523 TI - Prognosis of teeth in the line of mandibular fracture: 5-year clinical and radiological follow-up. AB - OBJECTIVE: The purpose of this article is to highlight our experience with the prognosis of teeth retained in the line of mandibular fracture after treatment of the fracture. PATIENTS AND METHODS: A prospective evaluation of 62 patients with 200 teeth in the line of mandibular fracture seen and treated at the Dental and Maxillofacial Clinic, University of Calabar Teaching Hospital, Calabar south south Nigeria between 2005 and 2009 was carried out. The focus was on 96 teeth in the line of mandibular fracture retained after reduction and immobilization of the fracture by closed reduction technique. The clinical and radiological follow up period of patients ranged between six months and 3.5 years. RESULTS: Majority of the patients 33 (53.2%) were in their third decade of life. The age of patients' ranged, from seven to 48 years with a mean of 24 +/- 2.3 years, There were 48 (77.4%) males and 14 (22.5%) females giving a male-to-female ratio of 3.4:1. One hundred and four teeth (52%) out of the 200 were extracted during treatment of the fracture. Of the remaining 96 teeth, 25 (26.0%) were anterior teeth while 71 (73.9%) were posterior. Twenty-four (25.0%) of the teeth in the line of fracture developed complications. Of those teeth involved with complications 10 (41.7%) were incisors and canine while 14 (58.3%) premolars and molars. Hypersensitivity and discolouration were the predominant complications. CONCLUSION: Appropriate case selection and thorough clinical and radiological assessment is required to reduce the rate of complications of teeth left in-situ in the mandibular fracture line after treatment. The various complications in this study were managed successfully. PMID- 23441524 TI - Haemoglobin variants among voluntary blood donors in Jos, Nigeria: the implications on blood transfusion. AB - INTRODUCTION: The normal haemoglobin is an efficient transporter of oxygen to the tissues and carbondioxide from tissues to the lungs for elimination. Various abnormal haemoglobin variants including, the sickle cell diseases, have been described with varying sickling tendencies. AIMS: This study aimed to determine the haemoglobin variants among voluntary blood donors in Jos. METHOD: Records of the age, sex, Haemoglobin level, and the haemoglobin genotype of all voluntary blood donors who donated blood at the National Blood Transfusion Service Centre, Jos, Nigeria between January 2011 and April 2012; and their haemoglobin levels and protein electrophoresis determined, were reviewed. RESULTS: A total of 937 blood donors, 658 (70.23%) males and 279 (29.79%) females, mean age 32.4 years, donated blood voluntarily, their haemoglobin electrophoretic patterns determined by alkaline cellulose acetate electrophoresis. Donor blood haemoglobin levels were determined by automation. Haemoglobin protein electrophoretic patterns identified among our donors were 77.70% AA, 21.88% AS, 0.22% SC, 0.11% AC and 0.11% SS. Mean haemoglobin levels of the donors according to their haemoglobin proteins electrophoretic patterns were, 150.4 +/- 12.5 gms/l for AA, 151.9 +/- 13.8 gms/l for AS and 131.1 +/- 5.0 gms/l for haemoglobin SC. CONCLUSION: Determination of haemoglobin protein electrophoretic patterns of blood unit for transfusion could enhance selective blood issuing based on recipient's haemoglobin type. PMID- 23441525 TI - Pregnancy in a 24 year old Nigerian woman with chronic kidney disease: challenges and outcome. AB - There is increasing incidence and prevalence of chronic kidney disease worldwide. The developing countries including Nigeria are facing greater challenges because of the prevailing poverty and high burden of infectious diseases. There are various prevalent co-morbid conditions that influence and are influenced by the status of the kidney function of the patient. These conditions pose some peculiar challenges and management of the challenges will determine the outcome. The aim of this report is to highlight the chalIenges of pregnancy in women with chronic kidney disease and possible outcome. We report a 24 years Nigerian woman diagnosed with chronic kidney disease who presented with 10 weeks gestation and deteriorating kidney function. Her management was associated with various challenges including non adherance to medications and not regular to follow up visits. She later developed ecclampsia and had intra uterine fetal death. She had various interventional measures including haemodialysis. She recovered kidney function appreciably but has defaulted follow up since discharge. PMID- 23441526 TI - Tuberculosis of the breast. AB - BACKGROUND: Tuberculosis of the breast is a rare disease with non specific manifestations. It should be included in the differential diagnosis of breast lesions in immune compromised patients especially in tuberculosis endemic areas of the world. CASE REPORT: We report a case of a 31 year old HIV positive lady who presented with an ulcerated mass on the left breast of 3 months' duration. Incision biopsy of the lesion confirmed tuberculosis of the breast. Treatment with standard anti tuberculous drugs resulted In complete resolution. CONCLUSION: A high index of suspicion is required to make a diagnosis of breast tuberculosis. The disease can be treated conservatively with standard anti tuberculous drugs while surgery is reserved for rare cases. PMID- 23441527 TI - [Kidney donation and transplantation]. PMID- 23441528 TI - [The effects of trimetazidine on QT-interval prolongation in patients with chronic kidney disease stage III-IV (predialysis CRD)]. AB - Prolonged QT interval is a predictor of cardiovascular mortality. It indicates delayed repolarization of ventricular myocardium and is considered a precursor of malignant cardiac arrhythmias and sudden cardiac death. Increased cardiovascular risk (CVR) in the presence of prolonged QT interval, corrected by heart rate (QTc), is attributed to ventricular electrical instability. Patients with chronic renal disease (CRD) usually die from sudden cardiac death before reaching the final stage, final chronic kidney disease (CRD stage V). We investigated whether patients with CRD stage III-V have prolonged QT interval, what are the possible causes of this extension, and whether in this patient population trimetazidine application may affect the reduction in QT prolongation. Our study showed one quarter of predialysis patients, mostly asymptomatic, to have QT prolongation, thus being at a higher risk of CV events. Introducing trimetazidine along with standard therapy can reduce the incidence of sudden cardiac death, and calculation of the QTc index would be a useful and economical method of screening and monitoring high risk patients. PMID- 23441529 TI - [Opatija study: observation of hemodialysis patients and titration of CERA dose just switched from another erythropoiesis stimulating agent]. AB - INTRODUCTION: Anemia is a well-documented consequence of chronic kidney disease, its frequency increases with the progression of renal failure and occurs in up to 95% of patients with end stage renal disease (ESRD). Erythropoietin stimulating agents (ESAs) have become the standard of care in the treatment of renal anemia. The use of methoxy polyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, represents an important benefit in clinical practice. AIM: The aim of the OPATIJA study was to compare the efficacy and safety of maintaining hemoglobin levels in dialysis patients and to assess its variability in a parallel-group design. Patients were randomly assigned to receive methoxy polyethylene glycolepoetin beta once monthly in "normal" dose conversion according to the label of record or "low" or "alternative" dose conversion widely spread according to previous ESA doses. SUBJECTS AND METHODS: A total of 79 patients were included in the study. The patients who had undergone continuous maintenance intravenous ESA therapy were divided into two parallel groups: group 1 including 36 patients directly switched to CERA according to the manufacturer recommended dosage; and group 2 including 43 patients that were switched by using "low" or "alternative" dose conversion widely spread according to previous ESA doses. During the 18-month period, each patient's anemia parameters, i.e. hemoglobin level, serum iron concentration, TSAT and ferritin, were monitored at intervals not longer than two months. According to hemoglobin levels, the dosage of CERA was adjusted if needed along with iron supplementation. RESULTS: At the end of the study, the two groups consisted of 51 patients: 26 of those treated with the recommended dose of CERA and 25 treated with the alternative dose. In the normal conversion group, the mean hemoglobin level during the course of the study was 104.41 g/L with the mean monthly dose of 104.33 mcg CERA. In the alternative conversion group, the mean hemoglobin level during the course of the study was 105.33 g/L with the mean monthly dose'of 113.08 mcg CERA. In the alternative conversion group, 33% of patients had Hb levels in the tight recommended range of 110-120 g/L. In 30% of patients, Hb levels were 100-110 g/L, in 29% less than 100 g/L, and in 8% more than 120 g/L. The mean Hb levels at the beginning and the end of the study did not differ significantly, except for the patient group with Hb levels >120 g/L, where 7% of patients with recommended dosing and none of the patients from the alternative dosing group had such levels (P=0.017). Hemoglobin variability higher than 10 and 20 g/L was recorded in both groups, but less frequently in the alternative CERA dosing group. CONCLUSION: Both treatments with the recommended and alternative conversion dosing achieved and maintained target hemoglobin level. Study results confirmed the need of individualized approach in the treatment of anemia in ESRD patients receiving hemodialysis, resulting in less potentially harmful hemoglobin variability. PMID- 23441530 TI - [Age and arterial hypertension in hemodialysis patients]. AB - Hypertension is common in the elderly (here defined as people older than 60 years), affecting 60%-70% of this population. In this group, isolated systolic hypertension (ISH), defined as elevated systolic blood pressure (SBP) > or = 140 mm Hg and normal diastolic blood pressure (DBP) <90 mm Hg is the predominant subtype of hypertension. AIM: The aim of this cross-sectional study was to investigate blood pressure differences according to age, especially the prevalence of ISH, in patients with end-stage renal disease (ESRD) undergoing regular maintenance hemodialysis, and to determine the importance of the interdialysis weight gain as a factor contributing to ISH. METHODS: Blood pressure was measured manually using mercury sphygmomanometer prior to and after dialysis procedure. Measurements were performed by educated staff members. Data on patient sex and age, duration of dialysis in total and weekly in hours, diabetic status, number of different antihypertensives used, and interdialysis weight gain were recorded. Patients were classified into four subgroups based on their systolic and diastolic blood pressure: normotensive (<140/<90 mm Hg); systolic-diastolic hypertension (SDH; > or = 140/> or = 90 mm Hg); ISH (> or = 140/<90 mm Hg); and isolated diastolic hypertension (IDH; <140/> or = 90 mm Hg). A total of 687 patients were included in final analysis and classified into 5 age groups: group 1, < or = 50; group 2, 50-59; group 3, 60-69; group 4, 70-79; and group 5, > or = 80. Student's t-test and ANOVA were used for continuous, normally distributed data, and chi2-test and Kruskal-Wallis test if otherwise. To identify the influence of IDWG on ISH, binary logistic regression was performed. The alpha <0.05 was considered statistically significant. RESULTS: There were 376 male and 311 female patients, mean age 63.13. In the above age groups, a decrease in the prevalence of SDH by 29.8%, 28.4%, 19.8%, 19.5% and 8.3%. (chi2=12.438, df=4, p=0.014) and an increase in the prevalence of ISH by 25.4%, 25.2%, 39.0%, 35.9% and 50.0%, respectively, was recorded (chi2=15.670, df=4, p=0.003). There was no significant statistical difference in the prevalence of IDH. Using binary logistic regression, we tried to identify the predictors of ISH. ISH was treated as a dichotomous dependent variable. Independent variables were sex, age, diabetic status, percent of body weight reduction during the process of hemodialysis, antihypertensive therapy and duration of hemodialysis in months. Age, diabetic status, usage of antihypertensive medication and IDWG were identified as significant predictors of ISH. Compared to age group 1, groups 3, 4 and 5 were associated with a 1.875-fold (1.064-3.305; p=0.030), 1.981-fold (1.116 3.519; p=0.020) and 3.963-fold (1.667-9.421; p=0.002) increase in the risk of developing ISH. Diabetic status was associated with a 1.833-fold (1.106-3.039; p=0.019) and antihypertensive medication with 2.731-fold (1.477-5.051; p=0.001) risk increase. IDWG >3% was associated with a 1.543-fold (1.074-2.217 p=0.019) risk increase of ISH. DISCUSSION: This study showed HTN to be still largely uncontrolled in patients undergoing hemodialysis. SBP remained constant in all age groups, even in the youngest, while a decrease in DBP was evident across age groups. A variety of factors contribute to this issue. Volume overload with other metabolic disorders that usually accompany chronic kidney disease (CKD) make these patients incline towards higher BP. Although IDWG in kilograms and percentage was significantly lower in older age groups, in logistic regression analysis IDWG larger than 3% was indicated as a positive predictor of ISH. When the same model was applied to SDH, IDWG >3% was not recognized as a statistically significant predictor of SDH (OR=1.225; 95%CI=0.819-1.832; p=0.323). CONCLUSION: It is possible that dietary modification involving sodium restriction may provide more benefit for patients with ISH than for those with SDH. Nevertheless, dietary modifications need to be encouraged in all patients undergoing hemodialysis. PMID- 23441531 TI - [Prevention and treatment of hepatitis C infected patients on hemodialysis]. AB - INTRODUCTION: Hepatitis C virus infection (HCV) is an important cause of morbidity and mortality in patients with end-stage renal disease (ESRD). PATIENTS AND METHODS: In this prospective, observational study, 205 patients, 37 (18%) of them with chronic HCV infection, were followed up for a one-year period at Department of Hemodialysis, Sarajevo Clinical Center, University of Sarajevo. The following parameters were analyzed: dialysis duration, sex, PCR RNA, HCV genotypes and biochemical parameters. Thirteen anti-HCV PCR RNA positive patients were treated with pegylated interferon alpha (Pegasys, Hoffman-La Roche). The goal of therapy was to reach sustained virologic response. The presence of anti HCV antibodies in serum was detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Of 37 anti-HCV positive patients, there were 20 (54%) males and 17 (45.9%) females with the mean hemodialysis duration of 143.67 +/- 57.64 months and mean age of 54.45 +/- 8.93 years. Of 37 anti-HCV positive patients, 30 (81.08%) patients were HCV RNA PCR positive. Among HCV RNA PCR positive patients, two had up to twofold elevated ALT values, one had twofold elevated AST values, and one had sixfold elevated GGT values. Thirteen RNA PCR positive patients were treated with pegylated interferon alfa for 48 weeks. Only one patient had genotype 1 virus. Upon therapy completion, only three patients were negative by PCR RNA (genotype 1b, 23.07%) at six months and yearly follow ups remained PCR negative. CONCLUSION: Sustained virologic response was achieved in three study patients. Monitoring guidelines for infection control, isolation of seropositive patients, and strict hygienic preventive measures can prevent HCV seroconversion in hemodialysis patients. PMID- 23441532 TI - [Compensated creatinine method and glomerular filtration rate estimation in a heterogeneous population of patients]. AB - Creatinine is a metabolite excreted mainly by glomerular filtration, which makes it an important endogenous indicator of kidney function. Creatinine clearance is defined as the ratio of the concentration of creatinine in serum and urine. It assesses glomerular filtration. Creatinine and creatinine clearance have the leading role in the early diagnosis, monitoring and classification of chronic kidney disease. The routine method for determining the concentration of creatinine is the Jaffe photometric method. A newer version is the compensated method. Furthermore, the recommended equation for the estimation of glomerular filtration rate (GFR) is the one based on the MDRD study (eGFR) intended for people over 18 years. The aim of the study was to evaluate how the introduction of the compensated method would affect the clinical use and influence the assessment of GFR in the interpretation of findings and treatment monitoring for people over 20 years. The study group included 130 men and 142 women whose requested laboratory test was creatinine clearance. Data were collected over 20 days at Sestre milosrdnice University Hospital. Serum creatinine concentration and eGFR were determined by the compensated and uncompensated Jaffe method. In conclusion, the compensated creatinine method is not statistically comparable with the uncompensated method, but is clinically fully applicable to the general population above the age of 20, given that the reference intervals are changed. Comparison of eGFR as estimated by the compensated and uncompensated methods to determine creatinine concentration showed the same results as the comparison of clearance. Using the compensated method yielded statistically incomparable results in GFR estimation. However, in clinical practice, patient classification according to stages of chronic kidney disease (CKD) was comparable in the male group according to clearance and eGFR (pi=0.922 and pi=0.230, respectively), while the female group was classified significantly different according to clearance and eGFR (pi<0.016 and pi<0.001, respectively). Switching to the compensated creatinine method while simultaneously applying the eGFR formula was shown to be valid, as patient classification according to CKD stages was comparable (pi=0.921); thus, the methods are reliable for use instead of creatinine clearance in the general population with various diagnoses, which can be noted in all laboratories and which is, although inhomogeneous, routinely used to measure daily creatinine clearance. PMID- 23441533 TI - [Clinical relevance of anemia treatment in patients with chronic kidney disease]. AB - INTRODUCTION: In the last ten years or so, there has been a steady increase in the number of patients with chronic kidney disease and those with end-stage renal failure who require some form of renal replacement therapy. Anemia is a well known consequence of chronic kidney disease; its prevalence increases with the progression of renal failure and occurs in up to 95% of patients in the final stages of chronic kidney disease. In recent years, the greatest advance in the treatment of renal anemia has been made by the introduction of erythropoietin preparations, the application of which has significantly improved the patients' quality of life. The aim of this study was to analyze whether the treatment of renal anemia in chronic kidney disease patients not treated by dialysis affects the outcome of their treatment, reduces the incidence of cardiovascular diseases, delays the need of dialysis, reduces morbidity and mortality, and reduces the incidence of adverse cardiovascular events. SUBJECTS AND METHODS: The study included patients with chronic kidney disease presenting for regular outpatient follow up at Department of Nephrology and Dialysis, Rijeka University Hospital Center. Patients were divided into two groups. Group 1 included patients whose renal anemia was treated with erythropoietin and group 2 patients whose anemia of chronic kidney disease was treated in any other way, regardless of the reason for the exclusion of erythropoietin. Each group included 31 patients with chronic kidney disease. During two years, each patient's laboratory parameters of chronic renal disease and renal anemia treatment were monitored at intervals not longer than six months. In addition, each patient's number of hospitalizations was recorded, taking into account the cause of hospitalization and the number of days spent in hospital. RESULTS: During the two-year period, 62 patients with chronic kidney disease were analyzed (31 patients in the groups receiving and not receiving erythropoietin each). The mean age was 66 +/- 13.5 in the group receiving erythropoietin and 68 +/- 13.6 in the group not receiving erythropoietin. There were 70% of men and 30% of women in the former group, and 53% of men and 47% of women in the latter group. Examination for comorbid conditions (diabetes, hypertension, hyperlipoproteinemia and previous stroke) revealed no statistically significant differences between the two groups of patients. There were no statistically significant differences in changes of biochemical parameters (Fe, ferritin, CRP, albumin, calcium, phosphorus) between the two groups of patients during the two-year period either. There was no statistically significant between group-difference in the glomerular filtration rate after two years, but a tendency of slower progression of renal failure was observed in patients having received erythropoietin as compared to those who did not receive erythropoietin. Moreover, the number of hospitalizations due to adverse cardiovascular events was statistically significantly lower in patients that received erythropoietin, while there was no statistically significant difference in the total number of hospitalizations, hospitalizations for other indications (infection, bleeding, and worsening of renal failure), or total number of days spent in hospital, regardless of indication. CONCLUSION: The number of patients with chronic kidney disease and those with end-stage renal failure requiring renal replacement therapy is increasing. Renal anemia, which occurs as a consequence of chronic kidney disease, is associated with increased morbidity and mortality, and with a reduced quality of life in these patients. Consequently, it is necessary to recognize this condition and apply appropriate treatment early in order to prolong life and improve the quality of life of patients with chronic kidney disease. PMID- 23441534 TI - [Renal transplantation in the elderly: characteristics of donor and recipient]. AB - Aging is a natural process that occurs in all tissues and organs resulting in a decreasing functional capacity. Aging of the population results in an increased number of elderly patients who require replacement of renal function. Renal transplantation is the method of choice for this group of patients if they have no contraindications for immunosuppressive therapy. The lack of donors is the main obstacle for renal transplantation. However, the use of organs from elderly donors for transplantation in elderly recipients is an appropriate method of renal replacement therapy in this group of patients. PMID- 23441535 TI - [Expression of bone morphogenetic proteins in kidneys]. AB - Bone morphogenetic proteins (BMPs) are a large group of growth factors. More than 20 members of BMP family have been identified to date. Based on their structural and functional properties, BMPs can be divided into 4 subgroups: BMP 2/4, BMP 5/6/7/8a/8b, BMP 9/10 and BMP 12/13/14. Each BMP has a unique structural feature that differentiates it from all other family members. BMPs take part in different stages of kidney development. For example, BMP-2 inhibits branching morphogenesis in ureteric buds; BMP-4 is expressed in metanephritic mesenchyme along the Wolff canal before kidney development, its expression is also found in the mesenchyme surrounding the ureteric bud before the invasion of the mesenchymal cells in the ureteric stem and induction completion; BMP-7 is the only bone morphogenetic protein that is crucial in kidney development. BMP family members are also included in maintaining normal kidney structure and function. Experimental models have shown that BMP-7 prevents ischemia/reperfusion damage. Expression of BMP-7 is reduced in the samples of kidney tissue with diabetic nephropathy. Also, BMP-7 mRNA is reduced in clear cell kidney carcinomas, indicating its protective effects in maintaining normal kidney structure and function. Bone morphogenetic proteins are some of the key players in regulating normal kidney development, but their role also extends into maintaining normal kidney structure and function. PMID- 23441536 TI - [Do we know all effects of heparins in hemodialyzed patients?]. AB - Anticoagulation with heparins during hemodialysis (HD) is aimed at preventing the activation of coagulation in the extracorporeal circuit. As HD patients are exposed to unfractionated and low molecular weight heparins (LMWH) for years, non hemorrhagic effects (osteoporosis, reduction of elevated blood pressure, with lesser intra- and interdialytic hypotensive episodes, effects on brain microvascular circulation and decreasing vascular dementia and Alzheimer's disease, and chronic and malignant diseases) require new trials with individualized doses of heparins. PMID- 23441537 TI - [Adequacy of peritoneal dialysis and laboratory procedures]. AB - Peritoneal dialysis is an equally valuable method for some patients. It is a method with some advantages and thus should be considered the method of choice. Are the trends of treatment with this method instead of terminal kidney disease replacement stagnating? In our ten-year retrospective study, we tried to do assess how to control the efficiency of dialysis and what was its influence on patient survival. We compared clinical state of patients, laboratory indicators of dialysis dosage (Kt/v) and peritoneal membrane transport function (PET). Patients were divided according to Kt/v values <1.7, 1.7-2.2 and >2.2. According to PET findings, they were divided into four standard groups. Kt/v and PET are unavoidable evaluation factors of peritoneal membrane and for prescribing dialysis. The transport, ultrafiltration and other membrane characteristics change with time and with inflammatory processes. On any calculation of adequacy, it is essential to distinguish diuretic and anuric patients. The adequacy of peritoneal dialysis should be incorporated in the conclusion on prescriptions and quality treatment of each individual patient. PMID- 23441538 TI - [Underestimated frequency of resistant hypertension in predialysis nondiabetic patients]. AB - The real prevalence of resistant hypertension (RH) is unknown. Studies suggest that it affects 10%-15% of patients treated for hypertension by primary care physicians. RH is defined as blood pressure (BP) remaining above the goal despite the use of optimal doses of 3 or more medicines of different classes (including a diuretic). It means BP >140/90 mm Hg for the general population and >130/80 mm Hg for patients with diabetes or kidney disease. Prior to diagnosing a patient as having RH, it is important to document medication compliance and exclude white coat hypertension, inaccurate BP measurement, and secondary causes. The role of aldosterone in RH has gained increasing recognition. There is strong evidence for the use of spironolactone as a highly effective antihypertensive agent. Aldosterone plays a significant role in RH pathogenesis, primarily due to its vasoconstrictive effects and the possibility of altering vascular compliance. In RH, there is a high prevalence of cardiac and extra-cardiac target organ damage. It is known that BP control in chronic kidney disease is the key factor for reducing cardiovascular risk and renal disease progression. The objective of the study was to evaluate the prevalence of RH in predialysis nondiabetic (CKD stage I-IV) patients. PMID- 23441539 TI - [Metabolic disorders in renal transplant recipients]. AB - INTRODUCTION: Advancements in immunosuppressive treatment of renal transplant recipients have significantly increased the graft and patient survival and significantly lowered the incidence of rejection crises. Efforts to increase long term patient and graft survival are directed to the prevention and treatment of cardiovascular diseases because they are the leading cause of mortality in these patients. Traditional risk factors for the development of cardiovascular diseases (e.g., arterial hypertension, posttransplant diabetes mellitus and metabolic lipid disorder) are up to fifty times more frequent among renal transplant recipients than in the general population. The goal of this study was to analyze the prevalence of the above mentioned metabolic disorders in renal transplant recipients, to analyze the impact of immunosuppressive therapy on the manifestation of these mentioned metabolic disorders, and to analyze the antihypertensive therapy applied. SUBJECTS AND METHODS: We analyzed 53 patients that underwent renal transplantation at Rijeka University Hospital Center during a two-year follow-up. Glomerulonephritis was the primary kidney disease in 14 (29.6%), polycystic kidney disease in 10 (18.87%), interstitial nephritis in 7 (13.21%), nephroangiosclerosis in 5 (18.5%), diabetic nephropathy in 4 (7.55%) and other diseases in 13 (24.53%) patients. RESULTS: The study included 53 patients (58.5% male), mean age 49.8 +/- 11.3 (range 27-72) years and mean dialysis treatment before transplantation 56.0 +/- 41.9 months. All patients received triple immunosuppressive therapy including a calcineurin inhibitor/MMF/corticosteroids and induction with IL-2 receptor blocker (daclizumab or basiliximab). Thirty-three (62%) patients were treated with tacrolimus and 20 (38%) with cyclosporine. The mean creatinine value was 144.92 +/- 46.49. Eighteen (34%) patients had creatinine lower than 120 mmol/L and 35 (66%) patients had a level higher than 120 mmol/L. After transplantation, 49 (92.5%) patients were treated for arterial hypertension (arterial hypertension was defined as systolic blood pressure greater than 140 mm Hg and diastolic pressure greater than 90 mm Hg or the routine use of antihypertensive therapy). Patients receiving cyclosporine had a significantly higher incidence of arterial hypertension as compared with patients on tacrolimus (P=0.025). Among patients with serum creatinine level higher than 120 mmol/L, 32 (65.3%) patients had hypertension, 9 (17%) achieved target blood pressure (<130/80 mm Hg), 8 (16.32%) were treated with one drug, 24 (48.98%) with two drugs, 15 (30.61%) with three drugs and 2 (4.09%) with more than three antihypertensives. Only four patients did not take any antihypertensive medication. The most often used antihypertensive drugs were calcium channel blockers (40.4% of patients), beta blockers (26.6%), and RAS inhibitors (9.2% of patients received ACE inhibitors and 16.5% ARB). In 6 (11.3%) patients, posttransplant diabetes mellitus developed and 21 (39.62%) patients were treated for metabolic lipid disorder. CONCLUSION: In order to identify patients at a higher risk of developing cardiovascular disease with time, it is essential that kidney transplant recipients undergo regular follow up of graft function, blood pressure, and metabolic parameters. Good graft function is important to improve the quality of life and decrease mortality of renal transplant recipients. PMID- 23441540 TI - [Adhesiolysis and partial resection of terminal ileum in a patient with kidney transplantation and severe sclerosing peritonitis]. AB - A 21-year-old female patient was diagnosed with horseshoe kidney at the age of 10. She had been treated with peritoneal dialysis from 2005 to 2009, when she received kidney from a deceased donor. The posttransplant course was complicated by development of Pseudomonas aeruginosa and Candida sepsis. Reduced immunosuppression resulted in acute rejection, which demanded graphtectomy 2 months after transplantation. She restarted peritoneal dialysis for additional 2 years. In March 2011, she received her second transplant with excellent function. Nine months after the transplantation, she developed ascites, with early satiety and vomiting. MSCT revealed severe encapsulating sclerosing peritonitis. Her overall condition deteriorated, so she underwent adhesiolysis with resection of incarcerated terminal ileum. Due to acute allograft rejection, urgent graphtectomy was performed. Currently, she is receiving everolimus and dialysis successfully, with excellent overall status. PMID- 23441541 TI - [Renal replacement therapy in a polytraumatized patient with hemophilia]. AB - Renal failure is a rare complication of hereditary coagulopathies. However, when it occurs, it rapidly progresses to a stage that requires replacement of renal function. Major problems include the choice of dialysis method, prevention of complications and supplementation of deficient factor. In hemodialysis, it is challenging to prevent system clotting and avoid bleeding. We present a case of polytraumatized male patient with hemophilia A, who developed compartment syndrome with acute renal failure. Continuous venovenous hemodialysis (CWHD) improved his condition and he recovered his kidney function. However, over the next few days he developed severe sepsis with deterioration of renal function. CWHDF (hemodiafiltration) was restarted. Several large hematomas were found in the abdominal cavity and in the inguinal region, one of them inducing compartment syndrome with leg necrosis. The patient died from cardiorespiratory arrest. PMID- 23441542 TI - [Spontaneous retroperitoneal bleeding caused by rupture of the native kidney oncocytoma twelve years after renal transplantation]. AB - Renal transplantation is the method of choice for renal replacement therapy in the majority of patients. Immunosuppressive drugs may increase the risk of developing malignancies. We present a case of a patient having undergone different renal replacement methods over 25 years. He had good graft function at 12 years of transplantation. Development of spontaneous retroperitoneal hematoma caused by rupture of the native kidney oncocytoma was complicated with sepsis and deterioration of graft function. We emphasize the importance of regular ultrasonography follow-up of native kidney, which is challenging because of fibrous changes. PMID- 23441543 TI - [The source of beta cell and proliferation]. PMID- 23441544 TI - The practice of emergency medicine in Fukuoka City Hospital, a secondary emergency facility in Japan. AB - OBJECTIVE: The transition of emergency departments and the current situation of emergency medicine (EM) in Fukuoka City Hospital (FCH) were reviewed. METHODS: The data concerning emergency medicine, such as the transition of intra-hospital emergency systems, were obtained from annual reports published in our hospital. Additionally, the data regarding educational programs for emergency room staff, the number of patients taken to the emergency room by ambulances, the activities regarding the Fukuoka Medical Rally (FMR) and the disaster relief team (DRT) were also reviewed and analyzed. RESULTS: Departments of neurology, neurosurgery, emergency, and cardiology were opened sequentially, starting in 2003, with an establishment of facilities of an emergency room (ER), intensive care unit (ICU), stroke care unit (SCU), and coronary care unit (CCU). Regarding educational programs, lectures and demonstrations on basic and advanced life support techniques were given to all staff annually starting in 2004, and resident doctors completed rotations in the ER and the ICU for three months. FCH staff consistently obtained excellent results at the FMR. Ambulance crews attended lectures and received training on EM and intra-tracheal intubation. The numbers of patients taken by ambulance to FCH increased from 129 in 2002 to 2,316 in 2011. The DRT was dispatched to respond to disasters that occurred in Japan. CONCLUSIONS: As a secondary emergency hospital, FCH has developed a system to accept emergency patients. This project will contribute to the improvement of the EM system in the area. PMID- 23441545 TI - Part 1 of 2. War or detente? PMID- 23441546 TI - 9 ways to trim your supply costs. Stress the importance of saving money wherever possible and your staff will be part of the solution. PMID- 23441547 TI - How to prevent employee embezzlement. Unscrupulous staff members know there's more than one way to steal, so take steps to protect your practice. PMID- 23441548 TI - 6 things you need to know about the MU2 final rule. Important meaningful use revisions--some optional, some mandatory--will be effective as early as January 1. PMID- 23441549 TI - You, vendor share duties for connectivity, remote access. Take proactive steps now and your patients' records always will be available when you need them. PMID- 23441551 TI - Customizing EHR templates can speed up your workflow. PMID- 23441550 TI - EHR connectivity best practices. PMID- 23441552 TI - Physician participants share more tips. Start slow, rely on support, find new ways to be productive, they say. PMID- 23441553 TI - Document and code in an EHR with care. PMID- 23441554 TI - Build a strategy to boost productivity. PMID- 23441555 TI - Tort reform, improved technology keys to reducing healthcare system costs. Interview by Lois A Bowers. PMID- 23441556 TI - Think global and act local. PMID- 23441557 TI - More for less: best patient outcomes in a time of financial restraint. AB - In many countries, expenditure on health care has increased dramatically over recent years. There have been parallel improvements in many indicators of population health, but too many patients continue to be harmed by health care or receive care that is supply-sensitive, ineffective, or poorly aligned with their needs and values. In addition to human costs, this translates into substantial waste of resource. The world has recently faced economic challenges unseen since the great depression of the 1930s. The financial situation of a country can, like a business, be expressed in three sets of accounts: statements of financial position, financial performance, and cash flow. A key test of solvency is the ability to pay debts as they become due (whether from current account or further borrowing). In general, this is a function of public debt, which for many countries has become very high. However, private debt and net financial position are also relevant to a country's financial prospects. Ultimately, borrowing is not sustainable indefinitely and given limited prospects for growth in income in the coming years, most countries will likely need to reduce or at least constrain expenditure on health care. This implies obtaining better value from the resources that are available, and we suggest that the key to this lies in improving the quality of care and, in particular, reducing variation in health care. In the United States, new legislation promoting accountable care organizations may help to do this. Cardiac surgery can be particularly effective in extending patients' lives and in improving the quality of their lives. Our ability to continue to provide cardiac surgery in the face of constrained economic times will depend on engaging more actively in ensuring that what we do is the right thing: that our operations are effective and that they truly meet the needs and values of our patients. It will also depend on doing these operations right the first time. PMID- 23441558 TI - International pediatric perfusion practice: 2011 survey results. AB - New cardiopulmonary bypass devices and new innovative methods are frequently reported in the literature; however, the actual extent to which they are adopted into clinical practice is not well known. We distributed an electronic survey to 289 domestic and international pediatric congenital surgery centers in an effort to measure attributes of current clinical practice. The survey consisted of 107 questions relating to program demographics, equipment, and techniques. Responses were received from 146 (51%) of queried centers and were stratified into five distinct geographic regions (North America, Central and South America, Oceana, Europe, and Asia). Most of the responding centers reported use of hard shell venous reservoirs. Closed venous systems were used at 50% of reporting centers in Central and South America as compared with only 3% in North America and 10% in Asia. Seventy-one percent of the programs used some form of modified ultrafiltration. Use of an arterial bubble detection system varied between 50% use (Central and South America) vs. 100% (North America and Oceana). "Del Nido" cardioplegia is more common in North America (32%) than any other continent, whereas Custodial HTK solution is much more prevalent in Europe (31%). Wide variation in practice was evident across geographic regions, suggesting opportunities for further investigation and improvement. PMID- 23441559 TI - The influence of sampling technique on ACT Plus results. AB - The manufacturer of the ACT Plus Automated Coagulation Timer, Medtronic Inc., recommends that test cartridges be prewarmed and the activating reagent resuspended (tapped/ mixed) before patient testing. In a busy clinical environment, these recommendations may be overlooked or disregarded. In this study, the impact of sampling technique on ACT Plus test results was investigated. In Series 1, two test cartridges were split into four individual chambers. Two ACT Plus machines were used, allowing for three separate comparisons to be made. The sample results from test Chambers 2 (cold/tapped), 3 (warmed/ not tapped), and 4 (cold/not tapped) were compared individually against the result from test Chamber 1, the recommended technique (warm/tapped). In Series 2, the manufacturer's recommendations were tested using a single double cartridge (warm/ tapped). Results were interpreted using the Bland-Altman method of analysis. The prewarming and tapping of cartridges before use independently influenced the agreement of results when compared with cartridges that were not prewarmed and tapped. Each factor (temperature and mixing) when excluded was found to affect the standard deviation and decrease the agreement of results. By following the manufacturer's recommendations to standardize the sampling technique, ACT Plus test results are more accurate. PMID- 23441560 TI - Nanosecond pulse electric field activation of platelet-rich plasma reduces myocardial infarct size and improves left ventricular mechanical function in the rabbit heart. AB - In the current study, we used the novel, nonchemical method of nanosecond pulsed electric fields (nsPEF) to investigate the efficiency of a protocol involving the in vivo treatment of the ischemic and reperfused heart and heart cells in culture with platelet-rich plasma (PRP). Associated with the restoration of blood flow to the ischemic tissue is a phenomenon referred to as "ischemic reperfusion injury." Clinically a type of reperfusion injury occurs during coronary bypass surgery once blood perfusion to the heart is restarted. Although the restoration of oxygen to ischemic myocardial cells is critical for tissue survival, reperfusion causes myocardial oxidative stress, attributable in part to the increased production of reactive oxygen species (ROS). Enhanced ROS production is associated with mitochondrial damage. Adult female New Zealand white rabbits were anesthetized and a left thoracotomy performed to expose the heart. The distal segment of the left anterior descending coronary artery was occluded for 15 minutes and then released so reperfusion of the tissue could occur. PRP (.21 mg/heart) or saline was injected into the ischemic area of the myocardium. Mechanical function of the left ventricle was analyzed using a Millar catheter attached to a Micro-Med Analysis System. H9c2 cells in culture were treated with 1 mL of nsPEF activated PRP (1.05 mg/flask) for 24 hours before analysis for ROS production or mitochondrial depolarization damage). The left ventricle contracted and relaxed faster and infarct size was reduced in hearts treated with PRP compared with saline. ROS production and mitochondrial depolarization were reduced in H9c2 cells treated with PRP and stimulated with hydrogen peroxide. These results provide evidence that nsPEFs can successfully be used to prepare PRP and that the PRP is functional in heart protection possibly by reducing ROS generation and stabilizing the mitochondria of the ischemic/reperfused heart. PMID- 23441561 TI - The role of extracorporeal life support in acute myocarditis: a bridge to recovery? AB - Acute myocardial failure associated with myocarditis is highly lethal. Left ventricular assist device support for these patients has been advocated to decompress the left ventricle and facilitate myocardial remodeling and recovery. Concerns exist regarding the ability of venoarterial (VA) extracorporeal life support (ECLS) to decompress the left ventricle and allow effective myocardial recovery. ECLS has several advantages, including availability, rapid deployment, and flexibility, as compared with contemporary ventricular assist devices. The objective of this study was to provide a brief review of acute myocarditis and present our series of patients. After Institutional Review Board approval, we conducted a retrospective data analysis of patients on ECLS experiencing rapidly progressive myocardial failure from a normal baseline. Patients with a history of intrinsic heart disease were excluded. All patients were thought to have myocarditis and had failed medical therapy requiring emergent ECLS support. Five patients demographics are detailed in Table 1. Patients experienced life threatening intractable dysrhythmias or cardiac arrest and were refractory to medical therapy with severe acidosis and impending multisystem organ failure. All patients were stabilized with VA ECLS, and the left ventricle and atrium were decompressed in four of five patients. A left atrial vent was placed in one patient. Myocardial recovery with successful weaning from ECLS was obtained in four of five patients and to a normal ejection fraction in three of the five. One patient failed ECLS weaning and required biventricular VAD support secondary to severe myocardial necrosis from giant cell myocarditis and was transplanted, one died, all others are alive at follow-up. ECLS is safe and effective to treat acute myocardial failure and may be used to obtain myocardial recovery in certain subsets. We devised a decision algorithm for ECLS deployment in this patient cohort and routinely use ECLS. PMID- 23441562 TI - Computational fluid dynamic analysis to prevent aortic root and valve clots during left ventricular assist device support. AB - Aortic root and valve clots are rare but well described in patients on maximal left ventricular assist device (LVAD) support. We performed a theoretical analysis using computational fluid dynamic analyses in two dimensions to try and ascertain if inflow cannula design/orientation/placement affect aortic root flow dynamics. Two-dimensional computational fluid dynamics using easy CFD-G was performed. The effect of a curved inflow cannula, a straight cannula, and one with a hole in the outer curve was analyzed. In addition, the effect of inflow conduit angulation on the ascending aorta was studied. Computational fluid dynamic (CFD) analysis predicts that stagnant blood exists in the aortic root when little or no cardiac ejection is taking place. Coronary flow is too small to affect the root flow streamlines. A hole on the root side of a curved inflow aortic cannula increases the flow in the aortic root and may decrease the incidence of root and valve thrombosis. The angle of the inflow conduit attachment to the ascending aorta was also found to be crucial with regard to aortic root blood stasis. In addition, a baffle at the tip of the inflow cannula may prove to be beneficial. Theoretical analysis using the technique of CFD predicts that inflow cannula position and design may affect the incidence of aortic root thrombosis during LVAD support when minimal cardiac ejection is occurring. PMID- 23441563 TI - Improvements in survival and neurodevelopmental outcomes in surgical treatment of hypoplastic left heart syndrome: a meta-analytic review. AB - The purpose of this study was to analyze the changes over the past two decades in hospital survival and neurodevelopmental outcomes after surgical treatment for hypoplastic left heart syndrome. The hypothesis for this study is that increasing hospital survival following the Stage I Norwood (S1N) procedure is associated with improvements in neurodevelopmental outcomes. Studies included in the meta analysis were identified by searching Ovid MEDLINE from January 1980 to October 2010. A total of 72 articles were identified. Fifteen single-center study articles were appropriate for obtaining survival data and 14 were used for neurodevelopmental outcomes. Wechsler Intelligence Test IQ scores and the Bayley II Mental Development (MDI) and Psychomotor Development Indices (PDI) were the primary neurodevelopmental outcomes included in this meta-analysis. Metaregression analysis using a mixed-effects model compared the percent survival and neurodevelopmental scores with the year of surgery. Hospital survival for the S1N operation increased significantly from 1996 to 2007 (p < .05). The overall mean survival during this time period was 80.05% (95% confidence interval [CI], 76.4-84.0%). Standardized Wechsler IQ scores increased significantly from 1989 to 1999 (p < .05) and the mean IQ was 85.09 (95% CI, 82.3-89.5). The Bayley II MDI increased significantly from 1998 to 2005 (p < .05) with a mean MDI of 86.9 (95% CI, 84.9-88.9). The Bayley II PDI increased significantly from 1998 to 2005 (p < .05) with a mean PDI of 73.4 (95% CI, 71.2-75.5). Increased survival has been associated with improved but below normal neurodevelopmental outcomes. PMID- 23441565 TI - Depression and cardiac surgery: underrecognized and undertreated. PMID- 23441564 TI - Psychological depression and cardiac surgery: a comprehensive review. AB - The psychological and neurological impact of cardiac surgery has been of keen empirical interest for more than two decades although reports showing the prognostic influence of depression on adverse outcomes lag behind the evidence documented in heart failure, myocardial infarction, and unstable angina. The paucity of research to date is surprising considering that some pathophysiological mechanisms through which depression is hypothesized to affect coronary heart disease (e.g., platelet activation, the inflammatory system, dysrhythmias) are known to be substantially influenced by the use of cardiopulmonary bypass. As such, cardiac surgery may provide a suitable exemplar to better understand the psychiatric mechanisms of cardiopathogenesis. The extant literature is comprehensively reviewed with respect to the deleterious impact of depression on cardiac and neuropsychological morbidity and mortality. Research to date indicates that depression and major depressive episodes increase major cardiovascular morbidity risk after cardiac surgery. The association between depressive disorders and incident delirium is of particular relevance to cardiac surgery staff. Contemporary treatment intervention studies are also described along with suggestions for future cardiac surgery research. PMID- 23441566 TI - Novel biomarkers for cardiac surgery-associated acute kidney injury: a skeptical assessment of their role. AB - Cardiac surgery-associated acute kidney injury (AKI) is common and is associated with a high mortality rate. Traditional biomarkers of AKI (creatinine and urea) increase slowly in response to renal injury, are insensitive to mild degrees of AKI, and are influenced by nonrenal factors. There is considerable interest in novel biomarkers of AKI such as neutrophil gelatinase-associated lipocalin that increase rapidly after renal injury, detect mild degrees of AKI, and are less subject to nonrenal factors. It has been postulated that the early diagnosis of cardiac surgery-associated AKI using novel biomarkers will result in improved outcomes. However, there is little evidence that interventions started early in the course of evolving AKI enhance renal recovery. Until effective therapies are developed that significantly improve the outcome from AKI, there is little benefit from early diagnosis using novel biomarkers. PMID- 23441568 TI - Development of the orpheus perfusion simulator for use in high-fidelity extracorporeal membrane oxygenation simulation. AB - Despite its life-sustaining potential, extracorporeal membrane oxygenation (ECMO) remains a complex treatment modality for which close teamwork is imperative with a high risk of adverse events leading to significant morbidity and mortality. The provision of adequate training and continuing education is key in mitigating these risks. Traditional training for ECMO has relied predominantly on didactic education and hands-on water drills. These methods may overemphasize cognitive skills while underemphasizing technical skills and completely ignoring team and human factor skills. These water drills are often static, lacking the time pressure, typical alarms, and a sense of urgency inherent to actual critical ECMO scenarios. Simulation-based training provides an opportunity for staff to develop and maintain technical proficiency in high-risk, infrequent events without fear of harming patients. In addition, it provides opportunities for interdisciplinary training and improved communication and teamwork among team members (1). Although simulation has become widely accepted for training of practitioners from many disciplines, there are currently, to our knowledge, no commercially available dedicated high-fidelity ECMO simulators. Our article describes the modification of the Orpheus Perfusion Simulator and its incorporation into a fully immersive, high-fidelity, point-of-care ECMO simulation model. PMID- 23441567 TI - Hyperoxia: a review of the risks and benefits in adult cardiac surgery. AB - Perioperative hyperoxia has been claimed to have a number of therapeutic advantages. However, in the setting of cardiac surgery and cardiopulmonary bypass (CPB), enthusiasm for its use has been tempered by concerns regarding the effect of high partial pressures of oxygen on cardiac, vascular, and respiratory function and the potential for exacerbation of ischemia-reperfusion injury. There is encouraging evidence from animal studies that hyperoxia is effective in myocardial preconditioning, at least in nondiseased hearts. There is also evidence that hyperoxia reduces gas microemboli production and longevity during CPB, although it is unclear whether this translates into a clinical benefit in terms of a reduction in postoperative neurological morbidity. Hyperoxia leads to changes in cardiovascular function. However, the effects of these changes remain unclear. At a tissue level, there is evidence that hyperoxia does not lead to improvement in partial pressure of oxygen. Indeed, the opposite may be the case with reductions in capillary density leading to areas of reduced tissue oxygenation. The risks of hyperoxia in association with CPB include lung injury, increased systemic reactive oxygen species generation, and exacerbation of reactive oxygen species-mediated myocardial injury at the time of reperfusion. Again, it is difficult to know whether the changes demonstrated are temporary or if they translate into a worsening of clinical outcomes. In conclusion, perhaps the key to the use of hyperoxia is in the timing. In the period pre-CPB, hyperoxia may precondition the myocardium and, paradoxically, confer a degree of protection against reactive oxygen species-induced injury at the time of reperfusion. Hyperoxia during CPB is probably harmful and should be avoided unless the risk from gas microemboli is thought to be significant, in which case the risks and benefits to the individual patient must be weighed. PMID- 23441569 TI - Extracorporeal membrane oxygenation clinical dilemmas. AB - Three scenarios are presented, based on real patients, illustrating various clinical dilemmas involving critical illness and extracorporeal membrane oxygenation (ECMO). The scenarios are outlined in the form of questions and answers. In most cases there is no single correct answer to the dilemmas presented. The pros and cons of particular interventions are discussed along with the actual treatment provided. In all cases, the ECMO circuit consisted of a polymethylpentene oxygenator (Quadrox PLS; MAQUET Cardiovascular, Hirlingen, Germany) and a centrifugal pump (Rotaflow; MAQUET Cardiovascular). Case 2 has been previously published as a letter to the editor (1). PMID- 23441571 TI - Ambipolar surface conduction in ternary topological insulator Bi2(Te1-xSex)3 nanoribbons. AB - We report the composition- and gate voltage-induced tuning of transport properties in chemically synthesized Bi2(Te1-xSex)3 nanoribbons. It is found that increasing Se concentration effectively suppresses the bulk carrier transport and induces semiconducting behavior in the temperature-dependent resistance of Bi2(Te1-xSex)3 nanoribbons when x is greater than ~10%. In Bi2(Te1-xSex)3 nanoribbons with x ~ 20%, gate voltage enables ambipolar modulation of resistance (or conductance) in samples with thicknesses around or larger than 100 nm, indicating significantly enhanced contribution in transport from the gapless surface states. PMID- 23441570 TI - Verbal expressive personality testing with older adults: 25+ years later. AB - This review builds on those conducted over 25 years ago by Panek and Hayslip in examining the literature dealing with the use of verbal expressive techniques with older adults. Such findings based on the Rorschach Ink Blot Test, Holtzman Inkblot Technique, Hand Test, Sentence Completion methods, and the Thematic Apperception Test and kindred thematic apperceptive techniques are presented and evaluated regarding the evidence for age differences, differential diagnosis, extraneous individual differences in performance, and adequacy of normative data. Although available evidence appears to warrant the continued use of verbal expressive techniques with older adults, more adequately designed studies are necessary to fully support the potential of these assessment tools for decision making with this population: assisting in diagnosis, recommending the appropriateness of various living arrangements, facilitating supportive care choices, and aiding in treatment planning. PMID- 23441572 TI - Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform. AB - Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase--both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases. PMID- 23441573 TI - Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin. AB - BACKGROUND/PURPOSE: Multiphoton microscopy has emerged in the past decade as a useful noninvasive imaging technique for in vivo human skin characterization. However, it has not been used until now in evaluation clinical trials, mainly because of the lack of specific image processing tools that would allow the investigator to extract pertinent quantitative three-dimensional (3D) information from the different skin components. METHODS: We propose a 3D automatic segmentation method of multiphoton images which is a key step for epidermis and dermis quantification. This method, based on the morphological watershed and graph cuts algorithms, takes into account the real shape of the skin surface and of the dermal-epidermal junction, and allows separating in 3D the epidermis and the superficial dermis. RESULTS: The automatic segmentation method and the associated quantitative measurements have been developed and validated on a clinical database designed for aging characterization. The segmentation achieves its goals for epidermis-dermis separation and allows quantitative measurements inside the different skin compartments with sufficient relevance. CONCLUSIONS: This study shows that multiphoton microscopy associated with specific image processing tools provides access to new quantitative measurements on the various skin components. The proposed 3D automatic segmentation method will contribute to build a powerful tool for characterizing human skin condition. To our knowledge, this is the first 3D approach to the segmentation and quantification of these original images. PMID- 23441574 TI - Developmental potential of cloned goat embryos from an SSEA3(+) subpopulation of skin fibroblasts. AB - Previous studies have demonstrated that skin stem cells expressing the pluripotency marker stage-specific embryonic antigen 3 (SSEA3) are easier to reprogram into induced pluripotent stem cells (iPSCs) than skin fibroblasts. Furthermore, it is widely speculated that the undifferentiated state may make stem cells more efficient donor cells for somatic cell nuclear transfer (SCNT). In this study, we isolated SSEA3(+) cells from goat skin fibroblast cells (SFCs) using fluorescence-activated cell sorting (FACS) and examined expression of pluripotency markers and in vitro development of cloned embryos following SCNT. Results showed that cell clusters from SSEA3(+) cells were consistently positive for alkaline phosphatase staining and pluripotency markers, Nanog, Oct4, Sox2, and SSEA3. The cleavage rate of cloned embryos derived from SSEA3(+) cells did not differ compared with SFCs (70.5+/-0.8% and 68.4+/-2.1%, respectively), but was significantly higher compared with SSEA3(-) cells (64.9+/-1.6%, p<0.05). The blastocyst rate was significantly increased in the SSEA3(+) cell group compared with the SFC and SSEA3(-) cell groups (30.3+/-1.2% vs. 21.2+/-0.9 and 19.0+/ 1.0%, respectively, p<0.05). The quality of cloned blastocysts from SSEA3(+) cells was higher compared with SFCs and SSEA3(-) cells, based on total cell number and number of apoptotic cells per blastocyst. These findings suggest that using SSEA3(+) cells as donors for SCNT is beneficial for enhancing in vitro development and quality of cloned goat embryos. PMID- 23441575 TI - Functional interplay between Arabidopsis NADPH oxidases and heterotrimeric G protein. AB - The plant NADPH oxidases produce reactive oxygen species (ROS) in response to pathogens that have diverse functions in different cellular contexts. Distinct phenotypic outcomes may derive from the interaction of NADPH oxidase-dependent ROS with other signaling components that mediate defense activation. We analyze the interaction between NADPH oxidases AtRbohD and AtRbohF and the Arabidopsis heterotrimeric G protein. The Gbeta subunit (AGB1) of the heterotrimeric G protein is required for full disease resistance to different Pseudomonas syringae strains. Genetic studies reveal that, upon P. syringae infection, AGB1 and AtRbohD and AtRbohF can function in the same pathway, as the agb1 null allele is epistatic to the NADPH oxidase null alleles, combinatorial mutants display the agb1 phenotypes, and agb1 suppresses some of the atrbohD atrbohF double mutant phenotypes. In contrast, increased susceptibility to the necrotrophic fungus Plectosphaerella cucumerina displayed by agb1 and atrbohD atrbohF is enhanced in the agb1 atrbohD atrbohF triple mutant, suggesting that NADPH oxidase and heterotrimeric G proteins mediate different response pathways in response to this necrotrophic pathogen. The defense response mediated by AGB1 is independent of pathogen-dependent salicylic acid accumulation and signaling, as the agb1 sid2 (isochorismate synthase 2) double mutant showed enhanced disease susceptibility to P. syringae and Plectosphaerella cucumerina as compared with both single mutants. This study exemplifies the complex interplay between signaling events mediating defense activation, depending on the type of plant-pathogen interaction. PMID- 23441576 TI - A rhamnose-rich O-antigen mediates adhesion, virulence, and host colonization for the xylem-limited phytopathogen Xylella fastidiosa. AB - Xylella fastidiosa is a gram-negative, xylem-limited bacterium that causes a lethal disease of grapevine called Pierce's disease. Lipopolysaccharide (LPS) composes approximately 75% of the outer membrane of gram-negative bacteria and, because it is largely displayed on the cell surface, it mediates interactions between the bacterial cell and its surrounding environment. LPS is composed of a conserved lipid A-core oligosaccharide component and a variable O-antigen portion. By targeting a key O-antigen biosynthetic gene, we demonstrate the contribution of the rhamnose-rich O-antigen to surface attachment, cell-cell aggregation, and biofilm maturation: critical steps for successful infection of the host xylem tissue. Moreover, we have demonstrated that a fully formed O antigen moiety is an important virulence factor for Pierce's disease development in grape and that depletion of the O-antigen compromises its ability to colonize the host. It has long been speculated that cell-surface polysaccharides play a role in X. fastidiosa virulence and this study confirms that LPS is a major virulence factor for this important agricultural pathogen. PMID- 23441577 TI - Guarding the green: pathways to stomatal immunity. AB - Guard cells regulate plant gas exchange and transpiration by modulation of stomatal aperture upon integrating external cues like photosynthetic effective illumination, CO2 levels and water availability and internal signals like abscisic acid (ABA). Being pores, stomata constitute a natural entry site for potentially harmful microbes. To prevent microbial invasion, stomata close upon perception of microbe-associated molecular patterns (MAMPs), and this represents an important layer of active immunity at the preinvasive level. The signaling pathways leading to stomatal closure triggered by biotic and abiotic stresses employ several common components, such as reactive oxygen species, calcium, kinases, and hormones, suggesting considerable intersection between MAMP- and ABA induced stomatal closures, which we will discuss in this review. PMID- 23441579 TI - Conformations and CH/pi interactions in aliphatic alkynes and alkenes. AB - The carbon 1s photoelectron spectra of a series of aliphatic alkynes and alkenes that have the possibility of possessing two or more conformers have been recorded with high resolution. The two conformers of 2-hexyne and 4-methyl-1-pentyne, anti and gauche, have been identified and quantified from an analysis of their carbon 1s photoelectron spectra, yielding 30 +/- 5% and 70 +/- 6% anti conformers, respectively. In the case of 1-hexyne, the photoelectron spectrum is shown to provide partial information on the distribution of conformers. Central to these analyses is a pronounced ability of the C1s photoemission process to distinguish between conformers that display weak gamma-CH/pi hydrogen bonding and those that do not. For the corresponding alkene analogs, similar analyses of their C1s photoelectron spectra do not lead to conclusive information on the conformational equilibria, mainly because of significantly smaller chemical shifts and higher number of conformers compared with the alkynes. PMID- 23441578 TI - Host-induced gene silencing in barley powdery mildew reveals a class of ribonuclease-like effectors. AB - Obligate biotrophic pathogens of plants must circumvent or counteract defenses to guarantee accommodation inside the host. To do so, they secrete a variety of effectors that regulate host immunity and facilitate the establishment of pathogen feeding structures called haustoria. The barley powdery mildew fungus Blumeria graminis f. sp. hordei produces a large number of proteins predicted to be secreted from haustoria. Fifty of these Blumeria effector candidates (BEC) were screened by host-induced gene silencing (HIGS), and eight were identified that contribute to infection. One shows similarity to beta-1,3 glucosyltransferases, one to metallo-proteases, and two to microbial secreted ribonucleases; the remainder have no similarity to proteins of known function. Transcript abundance of all eight BEC increases dramatically in the early stages of infection and establishment of haustoria, consistent with a role in that process. Complementation analysis using silencing-insensitive synthetic cDNAs demonstrated that the ribonuclease-like BEC 1011 and 1054 are bona fide effectors that function within the plant cell. BEC1011 specifically interferes with pathogen-induced host cell death. Both are part of a gene superfamily unique to the powdery mildew fungi. Structural modeling was consistent, with BEC1054 adopting a ribonuclease-like fold, a scaffold not previously associated with effector function. PMID- 23441580 TI - A gliovascular idea for the white matter repair? PMID- 23441581 TI - Racial/ethnic differences in alcohol-related suicide: a call for focus on unraveling paradoxes and understanding structural forces that shape alcohol related health. PMID- 23441584 TI - Whole body computed tomographic characteristics of skeletal and cardiac muscular metastatic neoplasia in dogs and cats. AB - Muscular metastatic neoplasia has been reported to be rare in domestic animals, however previous studies were based primarily on necropsy findings. The purpose of this retrospective study was to describe whole body computed tomography (CT) characteristics of confirmed muscular metastases in a cohort of dogs and cats presented for oncology evaluation. Medical records of 1201 oncology patients were reviewed. Included animals underwent pre and postcontrast whole body CT, and CT guided tru-cut biopsy or fine needle aspiration of one or more metastatic lesions. Twenty-one dogs and six cats met inclusion criteria, representing 2.08% of all canine oncology patients and 3.1% of all feline oncology patients. Mean age was 9.6 years. Postcontrast CT characteristics included well-demarcated, oval to-round lesions with varying enhancement patterns: ring enhancing (n = 16), heterogeneously enhancing (n = 8), or homogeneously enhancing (n = 5). Five animals showed concurrent and varying nodular patterns. In seven cases (five dogs and two cats), one single muscular nodule was observed. In 20 cases, two or more lesions were observed. In two cases, cardiac hypodense nodules were observed in the postcontrast CT, while appearing isodense in the precontrast study. Necropsy confirmed neoplasia in both of them. Locations of muscular metastases included epaxial/paraspinal muscles of the cervical, thoracic, and lumbar spine (n = 18), superficial muscles of the thoracic wall (n = 13), scapular/shoulder region (n = 3), hind limb (n = 3), and abdominal wall muscles (n = 1). Findings supported the use of pre and postcontrast whole body CT for oncologic staging in dogs and cats, especially for primary tumors characterized by a high metastatic rate. PMID- 23441583 TI - Twenty-first century mast cell stabilizers. AB - Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically to prevent allergic reactions to common allergens. Despite the relative success of the most commonly prescribed mast cell stabilizer, disodium cromoglycate, in use for the preventative treatment of bronchial asthma, allergic conjunctivitis and vernal keratoconjunctivitis, there still remains an urgent need to design new substances that are less expensive and require less frequent dosing schedules. In this regard, recent developments towards the discovery of the next generation of mast cell stabilizing drugs has included studies on substances isolated from natural sources, biological, newly synthesized compounds and drugs licensed for other indications. The diversity of natural products evaluated range from simple phenols, alkaloids, terpenes to simple amino acids. While in some cases their precise mode of action remains unknown it has nevertheless sparked interest in the development of synthetic derivatives with improved pharmacological properties. Within the purely synthetic class of inhibitors, particular attention has been devoted to the inhibition of important signalling molecules including spleen TK and JAK3. The statin class of cholesterol-lowering drugs as well as nilotinib, a TK inhibitor, are just some examples of clinically used drugs that have been evaluated for their anti allergic properties. Here, we examine each approach under investigation, summarize the test data generated and offer suggestions for further preclinical evaluation before their therapeutic potential can be realized. PMID- 23441586 TI - Evaluation of chemotherapy drug exposure at a veterinary teaching hospital in Michigan. PMID- 23441585 TI - Somatic mitochondrial DNA mutations in Chinese patients with osteosarcoma. AB - Somatic mutations in mitochondrial DNA (mtDNA) have been long proposed to drive the pathogenesis and progression of human malignancies. Previous investigations have revealed a high frequency of somatic mutations in the D-loop control region of mtDNA in osteosarcoma. However, little is known with regard to whether or not somatic mutations also occur in the coding regions of mtDNA in osteosarcoma. To test this possibility, in the present study we screened somatic mutations over the full-length mitochondrial genome of 31 osteosarcoma tumour tissue samples, and corresponding peripheral blood samples from the same cohort of patients. We detected a sum of 11 somatic mutations in the mtDNA coding regions in our series. Nine of them were missense or frameshift mutations that have the potential to hamper mitochondrial respiratory function. In combination with our earlier observations on the D-loop fragment, 71.0% (22/31) of patients with osteosarcoma carried at least one somatic mtDNA mutation, and a total of 40 somatic mutations were identified. Amongst them, 29 (72.5%) were located in the D-loop region, two (5%) were in the sequences of the tRNA genes, two (5%) were in the mitochondrial ATP synthase subunit 6 gene and seven (17.5%) occurred in genes encoding components of the mitochondrial respiratory complexes. In addition, somatic mtDNA mutation was not closely associated with the clinicopathological characteristics of osteosarcoma. Together, these findings suggest that somatic mutations are highly prevalent events in both coding and non-coding regions of mtDNA in osteosarcoma. Some missense and frameshift mutations are putatively harmful to proper mitochondrial activity and might play vital roles in osteosarcoma carcinogenesis. PMID- 23441587 TI - Comparison of treatment outcomes after transoral robotic surgery and supraglottic partial laryngectomy: our experience with seventeen and seventeen patients respectively. PMID- 23441588 TI - Energy balance of the global photovoltaic (PV) industry--is the PV industry a net electricity producer? AB - A combination of declining costs and policy measures motivated by greenhouse gas (GHG) emissions reduction and energy security have driven rapid growth in the global installed capacity of solar photovoltaics (PV). This paper develops a number of unique data sets, namely the following: calculation of distribution of global capacity factor for PV deployment; meta-analysis of energy consumption in PV system manufacture and deployment; and documentation of reduction in energetic costs of PV system production. These data are used as input into a new net energy analysis of the global PV industry, as opposed to device level analysis. In addition, the paper introduces a new concept: a model tracking energetic costs of manufacturing and installing PV systems, including balance of system (BOS) components. The model is used to forecast electrical energy requirements to scale up the PV industry and determine the electricity balance of the global PV industry to 2020. Results suggest that the industry was a net consumer of electricity as recently as 2010. However, there is a >50% that in 2012 the PV industry is a net electricity provider and will "pay back" the electrical energy required for its early growth before 2020. Further reducing energetic costs of PV deployment will enable more rapid growth of the PV industry. There is also great potential to increase the capacity factor of PV deployment. These conclusions have a number of implications for R&D and deployment, including the following: monitoring of the energy embodied within PV systems; designing more efficient and durable systems; and deploying PV systems in locations that will achieve high capacity factors. PMID- 23441589 TI - Comparison of flexible and rigid cystoscopy-assisted ureteral catheter insertion before percutaneous nephrolithotomy: a prospective randomized trial. AB - BACKGROUND AND PURPOSE: To compare the advantages of flexible and rigid cystoscopy-assisted ureteral catheter placement before prone percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: From March to September 2012, a total of 80 patients with kidney stones underwent PCNL by the same surgical team. The patients were randomly assigned into one of the groups according to the technique used for ureteral catheter insertion: Flexible cystoscopy (group 1, n=40) or rigid cystoscopy (group 2, n=40). Patient demographics and operation related factors were compared. The preparation period included positioning, cystoscopy-assisted stent insertion, and patient repositioning for PCNL. In addition, discomfort scores of the operating room (OR) staff were measured. RESULTS: The demographic values of the groups in terms of patient sex, age, body mass index, and stone size were comparable. While the mean preparation period was calculated as 9.9+/-2.3 minutes in the flexible cystoscopy group, it was significantly longer (19.7+/-2.9 minutes) in the rigid cystoscopy group (P<0.0001). In addition, the discomfort score of the OR staff was found to be significantly higher in the rigid cystoscopy group (1.1+/-0.9 vs 2.05+/-0.68, P<0.0001). The rest of the operative and postoperative parameters were similar. CONCLUSIONS: The insertion of a ureteral catheter with a flexible cystoscope before prone PCNL shortens the preparation period and minimizes the discomfort of OR staff related to patient positioning and transfer. PMID- 23441590 TI - Monolayered nanodots of transition metal oxides. AB - Monolayered nanodots of titanium, tungsten, and manganese oxides were obtained by exfoliation of the nanocrystals through aqueous solution processes at room temperature. The precursor nanocrystals of the layered compounds, such as sodium titanate (Na(0.80)Ti(1.80)?(0.2)O4.xH2O, ?: vacancy (x < 1.17)), cesium tungstate (Cs4W11O35.yH2O (y < 10.5)), and sodium manganate (Na0.44MnO2.zH2O (z < 0.85)), were synthesized in an aqueous solution. These nanocrystals of the layered compounds were delaminated into the monolayered nanodots through introduction of a bulky organic cation in the interlayer space. The resultant monolayered nanodots of the titanate and tungstate 2-5 nm in lateral size showed a remarkable blueshift of the bandgap energies. The calculation studies supported the blueshifts of the bandgap energies. The results suggest that syntheses of monolayered nanodots can expand the tuning range of the properties based on size effect. The present approaches for generation of ultrathin tiny objects can be applied to a variety of nanomaterials. PMID- 23441591 TI - Multimodal endoscopic treatment for delayed severe esophageal stricture caused by incomplete stent removal. AB - The usefulness of a covered self-expandable metallic stent for benign esophageal stricture and perforation was well established. In case of benign disease, early stent removal was recommended within 6-8 weeks after placement. A case with severe esophageal stricture caused by incomplete stent removal 7 years after stent placement for spontaneous esophageal rupture was reported. Residual stent fragments could be removed by step-by-step multimodal endoscopic treatment, producing satisfactory luminal diameter of the esophagus. In particular, stent trimming with argon plasma coagulation was safe and effective strategy. The endoscopic stent removal is minimally invasive and should be attempted before surgical intervention; however, it is most important to ensure early stent removal before tissue ingrowth or overgrowth can develop. PMID- 23441593 TI - The impact of atherosclerotic vascular disease in predicting a stroke, thromboembolism and mortality in atrial fibrillation patients: a systematic review. AB - BACKGROUND: Atrial fibrillation (AF) is commonly associated with vascular disease. Although atherosclerotic vascular disease (for example, defined as a myocardial infarction (MI), complex aortic plaque and peripheral arterial disease) has been proposed as a risk factor for a stroke, the co-existence of the two diseases increases the risk of future cardiovascular events. The objective of this study was to conduct a systematic review to assess the impact of atherosclerotic vascular disease on the primary end-point of a stroke, thromboembolism or mortality, in patients with AF. METHODS: Literature searches were performed electronically, to identify studies published between January 1990and July 2012 examining stroke and thromboembolism in relation to AF and atherosclerotic vascular disease. Nineteen articles satisfied the pre-inclusion criteria. The bibliographies were subsequently screened to retrieve further relevant studies for this review. RESULTS: Peripheral arterial disease significantly increased the stroke risk in all 10 observational studies, within a reported risk range of 1.3- to 2.5-fold. Complex aortic plaque on the descending aorta, as identified by trans-oesophageal echocardiography, was also a significant risk factor. Although a prior myocardial infarction (MI) was validated as a significant predictor of the primary end-point amongst five of the six studies, there was a degree of heterogeneity, owing to the marked difference in population sizes and the use of antithrombotic regimens between studies. CONCLUSION: Atherosclerotic vascular disease (e.g. peripheral arterial disease, complex aortic plaque and prior MI) are significant predictors of a stroke, thromboembolism and mortality in subjects with AF. PMID- 23441592 TI - Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. AB - Chronic kidney diseases share common pathogenic mechanisms that, independently from the initial injury, lead to glomerular hyperfiltration, proteinuria, and progressive renal scarring and function loss. Consistent experimental evidence supports the crucial role of proteinuria in accelerating kidney disease progression to end-stage renal failure through multiple pathways, including induction of tubular chemokine expression and complement activation. These events, in turn, lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis. The extent of proteinuria is widely recognized as a marker of the severity of chronic kidney disease and as a predictor of future decline in glomerular filtration rate. More importantly, a reduction in proteinuria invariably translates into a protection from renal function decline in patients with diabetic and non-diabetic renal disease. Recent evidence also showed the existence of a relationship between proteinuria levels and cardiovascular risk, which extends to the range of urinary albumin excretion that was previously thought 'normal'. Thus, proteinuria should be considered a valuable surrogate end point for clinical trials in patients with chronic renal diseases and a target for reno- and cardioprotecive strategies. PMID- 23441594 TI - Multiplexed, UVC-induced, sequence-dependent DNA damage detection. AB - The exposure of DNA to ultraviolet (UV) radiation causes sequence-dependent damage. Thus, there is a need for an analytical technique that can detect damage in large numbers of DNA sequences simultaneously. In this study, we have designed an assay for UVC-induced DNA damage in multiple oligonucleotides simultaneously by using a 96-well plate and a novel automated sample mover. The UVC-induced DNA damage is measured using smart probes, analogs of molecular beacons in which guanosine nucleotides act as the fluorescence quencher. Our results show that the oligonucleotide damage constants obtained with this method are reproducible and similar to those obtained in cuvettes. The calibration curve for poly-dT shows good linearity (R(2) = 0.96), with limits of detection (LOD) and quantification (LOQ) equal to 55 and 183 nm, respectively. The results show that the damage kinetics upon irradiation is sensitive to the different types of photoproducts formed in the different sequences used; i.e. poly-A oligonucleotides containing guanine are damaged at a faster rate than poly-A oligonucleotides containing either thymine or cytosine. Thus, detecting DNA damage in a 96-well plate and quantifying the damage with smart probes are a simple, fast and inexpensive mix and-read technique for multiplexed, sequence-specific DNA damage detection. PMID- 23441595 TI - Progression of retinal nerve fiber layer thinning in glaucoma assessed by cirrus optical coherence tomography-guided progression analysis. AB - PURPOSE: To evaluate the performance of Cirrus spectral domain optical coherence tomography (SD-OCT)-guided progression analysis (GPA) software to detect progression of retinal nerve fiber layer (RNFL) thinning in glaucoma patients. MATERIALS AND METHODS: This retrospective cohort study included 272 eyes of 154 glaucoma patients. Median follow-up time was 2.2 years, during which time data from at least four good-quality OCT examinations were collected. Glaucomatous eyes were classified as either early or advanced group according to visual field (VF) severity. Reference standard of glaucoma progression was defined by expert assessment of optic disc/RNFL photographs or VF GPA data, or visual field index (VFI) linear regression analysis. Sensitivity and specificity of OCT GPA, and agreement between OCT GPA findings and each reference standard strategy were estimated. RESULTS: Fifty-three eyes (19.5%) showed progression by at least one of the reference standard strategies, while OCT GPA detected progression in 36 eyes (13.2%). When expert assessment of optic disc/RNFL photographs and/or VF analysis was used as the reference standard, the sensitivity and specificity of OCT GPA employed to detect glaucoma progression were 20.8% and 88.6%. Agreement between OCT GPA and either optic disc/RNFL photographic evaluation or VF analysis was poor (kappa = 0.12 and 0.03, respectively). RNFL photographic assessment in early stage glaucoma showed best agreement with OCT GPA in terms of progression detection. DISCUSSION: The Cirrus OCT GPA detected a considerable number of eyes exhibiting glaucoma progression. OCT GPA may be useful for progression detection in earlier stage of glaucoma to complement other reference standard strategies. PMID- 23441597 TI - Hypoxia-inducible factor-1alpha and vascular endothelial growth factor in the cardioprotective effects of intermittent hypoxia in rats. AB - OBJECTIVE: This study investigated the effects of short-term intermittent hypoxia (IH) preconditioning on cardiac structure and function in rats and the influence of ischemia reperfusion (I/R) injury. Special attention was then paid to the involvement of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). METHODS: Wistar rats were given IH treatment for 1, 7, 14, or 28 days. Some of them were thereafter subject to myocardial infarction surgery. Right ventricle systolic pressure (RVSP), myocardial capillary density (CD), and mRNA/protein expression of HIF-1alpha, VEGF, and Bcl 2 in rat myocardial tissue were determined. Apoptotic cell number was determined by TUNEL staining, and concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. RESULTS: IH treatment for 1, 7, 14, and 28 days reduced the myocardial infarction size, whereas IH for 28 days increased the RVSP, ratio of right to left ventricle weight (RV/LV+S), and CD. IH up-regulated the mRNA and protein levels of HIF-1alpha, VEGF, and Bcl-2 both under normal and I/R conditions. The induced expression of HIF-1alpha and VEGF by IH reached a peak after 7 days of treatment. Moreover, IH for 28 days induced cardiomyocyte apoptosis, whereas prior treatment with IH for 1, 7, 14, and 28 days all markedly attenuated the apoptosis effected by the subsequent I/R injury. IH also decreased the concentrations of MDA but increased those of SOD in myocardial tissue of both in normal rats and following I/R. CONCLUSIONS: The present study demonstrates that short-term IH protects the heart from I/R injury through inhibiting apoptosis and oxidative stress. The up-regulation of HIF-1alpha and VEGF by short term IH may participate in the cardioprotective effect of IH. PMID- 23441598 TI - Effect of ondansetron in preventing postoperative nausea and vomiting under different conditions of general anesthesia: a preliminary, randomized, controlled study. AB - METHODS: Two hundred and forty patients were randomly allocated into six groups: Group I, anesthesia was maintained with sevoflurane; Group II, anesthesia was maintained with sevoflurane and 8 mg of ondansetron; Group III, anesthesia was maintained with propofol; Group IV, anesthesia was maintained with propofol and 8 mg of ondansetron; Group V, anesthesia was maintained with sevoflurane and propofol; Group VI, anesthesia was maintained with sevoflurane combined with propofol and 8 mg of ondansetron. RESULTS: We found that the incidence of vomiting was lower in group II (17.5%), group IV (7.5%), and group VI (10%) compared with group I (55%), group III (27.5%), and group V (30%), respectively (P < 0.05). The incidence of vomiting was also lower in group III (27.5%) and group V (30%) when compared with group I (55%) (P < 0.05). The incidence of nausea was 55% in group I, 42.5% in group II, 30% in group III, 27.5% in group IV, 30% in group V, and 30% in group VI. Groups III and V had a lower incidence of nausea than group I (P < 0.05). CONCLUSIONS: We conclude that compared with sevoflurane anesthesia alone, anesthesia with either propofol alone or propofol combined with sevoflurane resulted in a reduced incidence of vomiting and nausea during the first 24 h after surgery. Administration of ondansetron effectively reduced the incidence of vomiting but not that of nausea for all three types of general anesthesia. PMID- 23441599 TI - Modifying spiking precision in conductance-based neuronal models. AB - The temporal precision of a neuron's spiking can be characterized by calculating its "jitter," defined as the standard deviation of the timing of individual spikes in response to repeated presentations of a stimulus. Sub-millisecond jitters have been measured for neurons in a variety of experimental systems and appear to be functionally important in some instances. We have investigated how modifying a neuron's maximal conductances affects jitter using the leaky integrate-and-fire (LIF) model and an eight-conductance Hodgkin-Huxley type (HH8) model. We observed that jitter can be largely understood in the LIF model in terms of the neuron's filtering properties. In the HH8 model we found the role of individual conductances in determining jitter to be complicated and dependent on the model's spiking properties. Distinct behaviors were observed for populations with slow (<11.5 Hz) and fast (>11.5 Hz) spike rates and appear to be related to differences in a particular channel's activity at times just before spiking occurs. PMID- 23441600 TI - The 2009 revised American Thyroid Association guidelines for thyroid cancer: multifocality in T1 tumors in question, for or against a more minimalist approach? PMID- 23441601 TI - Editorial comment for Chen et al. PMID- 23441602 TI - Cluster-seeded synthesis of doped CdSe:Cu4 quantum dots. AB - We report here a method for synthesizing CdSe quantum dots (QDs) containing copper such that each QD is doped with four copper ions. The synthesis is a derivative of the cluster-seed method, whereby organometallic clusters act as nucleation centers for quantum dots. The method is tolerant of the chemical identity of the seed; as such, we have doped four copper ions into CdSe QDs using [Na(H2O)3]2[Cu4(SPh)6] as a cluster seed. The controlled doping allows us to monitor the photophysical properties of guest ions with X-ray spectroscopy, specifically XANES and EXAFS at the copper K-edge. These data reveal that copper can capture both electrons and holes from photoexcited CdSe QDs. When the dopant is oxidized, photoluminescence is quenched and the copper ions translocate within the CdSe matrix, which slows the return to an emissive state. PMID- 23441603 TI - Reality check: there is no such thing as a miracle food. AB - A recent episode of the Dr. Oz Show suggested endive, red onion, and sea bass as foods that can decrease the risk of ovarian cancer by up to 75%. However, the scientific evidence supporting these recommendations is limited. This commentary discusses some of the concerns related to the promotion of "miracle foods" by the media. Nutritional scientists and epidemiologists should be cognizant of the public health messages that are taken from their individual studies and not sensationalize the findings of a single study. PMID- 23441604 TI - Partial associations of dietary iron, smoking and intestinal bacteria with colorectal cancer risk. AB - Smoking and high red meat intake have been associated with colorectal cancer (CRC) risk. Increased iron exposure may be a common factor, favoring the colonization of certain bacterial pathogens that preferentially grow in an iron rich luminal environment. We analyzed the data from a population-based case control study of CRC and measured antibody levels against flagelin of Salmonella (FliC), one of the irontrophic bacteria, in 2 independent blood collections. The risk of CRC synergistically increased by combined exposures to heme iron intake and pack-yr (PY) of cigarette smoking (P value for the interaction = 0.039 on the continuous scale). There was a marginally significant interaction between heme iron intake and PY in increasing FliC antibody in the U.S. control subjects (P = 0.055), although no iron or smoking data were available for Dutch samples. Furthermore, FliC antibody levels were significantly higher in patients with colorectal polyps and cancer than in controls in both Dutch (3.93 vs. 2.23) (P = 0.014) and U.S. samples (6.65 vs. 4.37) (P < 0.001). Potential roles of iron from cigarette smoking and dietary heme in CRC through altering irontrophic luminal bacterial population may warrant further investigation. PMID- 23441605 TI - Dietary intake of vitamin D and calcium and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. AB - Studies assessing the effects of vitamin D or calcium intake on breast cancer risk have been inconclusive. Furthermore, few studies have evaluated them jointly. This study is the largest so far examining the association of dietary vitamin D and calcium intake with breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. During a mean follow-up of 8.8 yr, 7760 incident invasive breast cancer cases were identified among 319,985 women. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pre- and postmenopausal breast cancer risk. Comparing the highest with the lowest quintile of vitamin D intake, HR and 95% CI were 1.07 (0.87-1.32) and 1.02 (0.90-1.16) for pre- and postmenopausal women, respectively. The corresponding HR and 95% CIs for calcium intake were 0.98 (0.80-1.19) and 0.90 (0.79-1.02), respectively. For calcium intake in postmenopausal women, the test for trend was borderline statistically significant (P(trend) = 0.05). There was no significant interaction between vitamin D and calcium intake and cancer risk (P(interaction) = 0.57 and 0.22 in pre- and postmenopausal women, respectively). In this large prospective cohort, we found no evidence for an association between dietary vitamin D or calcium intake and breast cancer risk. PMID- 23441607 TI - Higher plasma homocysteine is associated with increased risk of developing colorectal polyps. AB - Colorectal adenomas are considered to be precursors of colorectal cancer. B vitamins (i.e., folate, vitamin B(6) and B(12)) are involved in homocysteine metabolism and play an important role as coenzymes in 1-carbon metabolism, which is thought to have a critical role in the progression of colorectal polyps. The purpose of this study was to examine the effects of B-vitamins and homocysteine on the risk of developing colorectal polyps. Forty-eight participants with colorectal polyps [29 adenomatous polyps (AP), 19 hyperplastic polyps (HP)], and 96 age- and sex-matched healthy controls were recruited. Fasting blood was drawn from each participant to measure hematological parameters, plasma pyridoxal 5' phosphate (PLP), serum folate and vitamin B(12), and plasma homocysteine. Participants with AP and HP had significantly higher plasma homocysteine levels than did healthy controls. There was no significant difference in serum folate and vitamin B(12) and plasma PLP among the 3 groups. B-vitamins had no significant effect on the risk of colorectal polyps. However, participants with higher plasma homocysteine [odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.13, 3.08) level exhibited significantly increased risk of colorectal polyps after adjusting for potential confounders. Plasma homocysteine was a strong predictor of the risk of colorectal polyps in participants with adequate B vitamins status. PMID- 23441606 TI - Correlates of 25-hydroxyvitamin D and breast cancer stage in the Women's Healthy Eating and Living Study. AB - Inverse associations between circulating 25-hydroxyvitamin D [25(OH)D] and breast cancer stage have been reported, thus it is critical to understand the variables that contribute to 25(OH)D levels among women with breast cancer. Among 904 women in the Women's Healthy Eating and Living Study, plasma 25(OH)D concentrations were measured and data on demographic characteristics, diet, physical activity, and tumor characteristics were collected at study entry. Statistically significant associations with 25(OH)D concentrations were observed for body mass index (BMI), body surface area (BSA), height, smoking, total vitamin D intake, physical activity, and race or ethnicity. Of the correlates of 25(OH)D, BMI, BSA, height, physical activity, and study site were associated with stage of breast cancer; however, concentrations of 25(OH)D were not significantly related to stage. In fully adjusted logistic regression models, the ORs (95% CIs) for the association between vitamin D deficiency and Stage II and III cancers were 0.85 (0.59-1.22) and 1.23 (0.71-2.15), respectively (P trend = 0.59), compared to Stage I. This study confirms previous work regarding the correlates of 25(OH)D concentrations but does not provide support for an association between vitamin D status and breast cancer stage. PMID- 23441610 TI - Use of an abridged scored Patient-Generated Subjective Global Assessment (abPG SGA) as a nutritional screening tool for cancer patients in an outpatient setting. AB - The scored Patient-Generated Subjective Global Assessment tool (PG-SGA), regarded as the most appropriate means of identifying malnutrition in cancer patients, is often challenging to implement in a busy outpatient setting. We assessed the validity of an abridged version of the PG-SGA (abPG-SGA), which forgoes the physical examination, and compared its usefulness in discerning malnutrition to the full PG-SGA and Malnutrition Screening Tool (MST). The nutritional status of 90 oncology outpatients receiving chemotherapy was assessed according to SGA global rating, PG-SGA, and MST. Receiver operating characteristic (ROC) curves were generated to estimate the sensitivity and specificity of various cut-off scores for malnutrition. Thirty-six percent of patients were malnourished (SGA). The abPG-SGA yielded 94% sensitivity and 78% specificity and area under the curve (AUC) = 0.956, which was slightly lower than PG-SGA (97% sensitivity, 86% specificity, AUC = 0.967) and higher than MST (81% sensitivity, 72% specificity, AUC = 0.823). Patient reported symptoms included loss of appetite (30%), altered taste (31%), fatigue (30%), and decreased ability to perform activities of daily living (53%). In conclusion, the abPG-SGA is a practical, informative and valid tool for detecting malnutrition in the outpatient oncology setting. PMID- 23441609 TI - Heme-induced biomarkers associated with red meat promotion of colon cancer are not modulated by the intake of nitrite. AB - Red and processed meat consumption is associated with the risk of colorectal cancer. Three hypotheses are proposed to explain this association, via heme induced oxidation of fat, heterocyclic amines, or N-nitroso compounds. Rats have often been used to study these hypotheses, but the lack of enterosalivary cycle of nitrate in rats casts doubt on the relevance of this animal model to predict nitroso- and heme-associated human colon carcinogenesis. The present study was thus designed to clarify whether a nitrite intake that mimics the enterosalivary cycle can modulate heme-induced nitrosation and fat peroxidation. This study shows that, in contrast with the starting hypothesis, drinking water added with nitrite to mimic the salivary nitrite content did not change the effect of hemoglobin on biochemical markers linked to colon carcinogenesis, notably lipid peroxidation and cytotoxic activity in the colon of rat. However, ingested sodium nitrite increased fecal nitroso-compounds level, but their fecal concentration and their nature (iron-nitrosyl) would probably not be associated with an increased risk of cancer. We thus suggest that the rat model could be relevant for study the effect of red meat on colon carcinogenesis, in spite of the lack of nitrite in the saliva of rats. PMID- 23441608 TI - Meat-related compounds and colorectal cancer risk by anatomical subsite. AB - Since meat may be involved in the etiology of colorectal cancer, associations between meat-related compounds were examined to elucidate underlying mechanisms in a population-based case-control study. Participants (989 cases/1,033 healthy controls) completed a food frequency questionnaire with a meat-specific module. Multivariable logistic regression was used to examine associations between meat variables and colorectal cancer; polytomous logistic regression was used for subsite-specific analyses. The following significant positive associations were observed for meat-related compounds: 2-amino-3,4,8-trimethylimidazo[4,5 f]quinoxaline (DiMeIQx) and colorectal, distal colon, and rectal tumors; 2-amino 3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and colorectal and colon cancer tumors; nitrites/nitrates and proximal colon cancer; 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP) and rectal cancer; and benzo[a]pyrene and rectal cancer (P-trends < 0.05). For analyses by meat type, cooking method, and doneness preference, positive associations between red processed meat and proximal colon cancer and pan-fried red meat and colorectal cancer were found (P trends < 0.05). Inverse associations were observed between unprocessed poultry and colorectal, colon, proximal colon, and rectal tumors; grilled/barbequed poultry and proximal colon cancer; and well-done/charred poultry and colorectal, colon, and proximal colon tumors (P-trends < 0.05). HCAs, PAHs, nitrites, and nitrates may be involved in colorectal cancer etiology. Further examination into the unexpected inverse associations between poultry and colorectal cancer is warranted. PMID- 23441612 TI - Identification of microRNAs regulated by isothiocyanates and association of polymorphisms inside their target sites with risk of sporadic colorectal cancer. AB - Sporadic colorectal cancer (CRC) is a typical multifactorial disease. Isothiocyanates (ITC) have been recently shown to inhibit development of CRC in many experimental models. MicroRNAs (miRNAs) are short noncoding RNAs that posttranscriptionally regulate gene expression through binding to 3' untranslated regions (3'UTR) of target mRNAs. MiRNAs are regulated by natural agents, ITCs included. In our study, using global expression profiling based on TaqMan Low Density Arrays, we identified 3 common miRNAs (miR-155, miR-23b, miR-27b) regulated by ITCs (sulforaphane, iberin) in colonic epithelial cell lines NCM460 and NCM356. In silico predictions allowed us to find 9 relevant single nucleotide polymorphisms (SNPs) localized within the 3'UTRs of genes (AGTR1, TNFAIP2, PRKCB, HSPA9, RABGAP1, DICER1, ADAM19, VWA5A, and SIRT5) targeted by these ITC-related miRNAs. Finally, we observed that homozygous CC genotype of DICER1, rs1057035, was significantly associated with decreased risk of CRC (odds ratio = 0.49; 95% confidence interval: 0.25-0.95, P = 0.036) when compared to TT homozygote genotype; also, the C allele tended to have a protective effect (P = 0.072). This study showed that miRNAs could be involved in chemoprotective effects of natural agents; their function alteration through SNPs in their binding sites and flanking regions presents a new class of CRC risk factors. PMID- 23441611 TI - Deuterium depleted water effects on survival of lung cancer patients and expression of Kras, Bcl2, and Myc genes in mouse lung. AB - Although advances in cancer therapies continue to develop, the shortness of the survival of lung cancer patients is still disappointing. Therefore, finding new adjuvant strategies is within the focus of cancer cure. Based on observations that deuterium depletion inhibits the growth of cancer cell lines and suppresses certain proto-oncogenes, we have conducted a clinical study in 129 patients with small cell and nonsmall cell lung cancers who consumed deuterium-depleted drinking water (DDW) as a nontoxic agent in addition to conventional chemotherapy and radiotherapy. Median survival time (MST) was 25.9 mo in males and 74.1 mo in female patients; the difference between genders was statistically significant (p < 0.05). Median survival of subjects with brain metastasis was 27.1 mo. Cumulative 5-yr survival probabilities were 19%, 52%, and 33% in males, females, and all patients with brain metastasis, respectively. Gene expression analysis in mouse lung indicated that DDW attenuates 7,12-dimethylbenz(a)anthracene (DMBA) induced expression of Bcl2, Kras, and Myc in females. In conclusion, DDW counteracts the DMBA-induced overexpression of Bcl2, Kras and Myc genes in mouse lung, and it may extend survival of lung cancer patients as a nontoxic anticancer dietary supplement, especially for women with tumors overexpressing cancer related genes, because MST of DDW-consuming group was 2-4 times longer than it is generally observed in lung cancer patients. PMID- 23441613 TI - Comparison of tamoxifen with edible seaweed (Eucheuma cottonii L.) extract in suppressing breast tumor. AB - The tropical edible red seaweed (Eucheuma cottonii L.) is rich in nutrients and polyphenolic compounds that may suppress cancer through its antioxidant and antiproliferative properties. The study reports on rat mammary tumor suppression and tissue antioxidant status modulation by E. cottonii ethanol extract (ECE). The effect of orally administered ECE (100 mg/kg body-weight) was compared with that of tamoxifen (10 mg/kg body-weight). Rat was induced to develop mammary tumor with subcutaneous injection of LA-7 cells (6 * 10(6) cells/rat). The ECE was more effective than tamoxifen in suppressing tumor growth (27%), improving tissues (plasma, liver, and kidney) malondialdehyde concentrations, superoxide dismutase activity and erythrocyte glutathione concentrations (P < 0.05). Unlike tamoxifen, the ECE displayed little toxicity to the liver and kidneys. The ECE exhibited strong anticancer effect with enzyme modulating properties, suggesting its potential as a suppressing agent for mammary gland tumor. PMID- 23441614 TI - Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation. AB - Dietary phytochemicals offer nontoxic therapeutic management as well as chemopreventive intervention for slow-growing prostate cancers. However, the limited success of several single-agent clinical trials suggest a paradigm shift that the health benefits of fruits and vegetables are not ascribable to individual phytochemicals, rather may be ascribed to synergistic interactions among them. We recently reported growth-inhibiting and apoptosis-inducing properties of ginger extract (GE) in in vitro and in vivo prostate cancer models. Nevertheless, the nature of interactions among the constituent ginger biophenolics, viz. 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogoal, remains elusive. Here we show antiproliferative efficacy of the most-active GE biophenolics as single-agents and in binary combinations, and investigate the nature of their interactions using the Chou-Talalay combination index (CI) method. Our data demonstrate that binary combinations of ginger phytochemicals synergistically inhibit proliferation of PC-3 cells with CI values ranging from 0.03 to 0.88. To appreciate synergy among phytochemicals present in GE, the natural abundance of ginger biophenolics was quantitated using LC-UV/MS. Interestingly, combining GE with its constituents (in particular, 6-gingerol) resulted in significant augmentation of GE's antiproliferative activity. These data generate compelling grounds for further preclinical evaluation of GE alone and in combination with individual ginger biophenols for prostate cancer management. PMID- 23441615 TI - Flavanols from Japanese quince (Chaenomeles japonica) fruit inhibit human prostate and breast cancer cell line invasiveness and cause favorable changes in Bax/Bcl-2 mRNA ratio. AB - Polyphenols are natural compounds of high structural diversity which translates into a very wide spectrum of biological activities, including chemoprevention. Here we report that a Japanese quince fruit flavanol preparation (JQFFP) caused favorable changes in Bax/Bcl-2 mRNA ratio, which rendered normal and cancer cells more resistant and more sensitive, respectively, to apoptosis. DU145 human prostate cancer cells were characterized by the most advantageous Bax/Bcl-2 ratio. The growth and invasiveness of MDA-MB-231 human breast cancer cells were strongly suppressed by JQFFP, which was accompanied with a decrease in MMP-9 activity and stimulation of TIMP-1 expression. Importantly, JQFFP did not decrease normal human prostate PNT1A cell number, whereas Bax/Bcl-2 ratio decreased which implies increased resistance to apoptosis. In conclusion, JQFFP exhibited a potent antiproliferative effect against cancer cells, inhibited their invasiveness, and decreased expression level of several genes involved in apoptosis, angiogenesis, and metastasis. PMID- 23441616 TI - Nobiletin induces apoptosis and potentiates the effects of the anticancer drug 5 fluorouracil in p53-mutated SNU-16 human gastric cancer cells. AB - Nobiletin is a typical polymethoxyl flavone from citrus fruits that has anticancer properties, but the molecular mechanism of its inhibitory effects on the growth of p53-mutated SNU-16 human gastric cancer cells has not been explored. In this study, nobiletin was found to be effective at inhibiting the proliferation of SNU-16 cells than other flavonoids. Nobiletin induced the death of SNU-16 cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase, the appearance of fragmented nuclei, an increase in the Bax/Bcl-2 ratio, the proteolytic activation of caspase-9, an increase in caspase 3 activity, and the degradation of poly(ADP-ribose) polymerase (PARP) protein. We found that the combination of nobiletin plus the anticancer drug 5-fluorouracil (5-FU) reduced the viability of SNU-16 cells in a concentration-dependent manner and exhibited a synergistic anticancer effect (combination index = 0.38) when 5 FU was used at relatively low concentrations. The expression of p53 protein increased after treatment with 5-FU, but not nobiletin, whereas the expression of p21 (WAF1/CIP1) protein increased after treatment with nobiletin, but not 5-FU. The cellular responses to nobiletin and 5-FU occurred through different pathways. The results of this study suggest the potential application of nobiletin to the enhancement of 5-FU efficiency in p53 mutant tumors. PMID- 23441617 TI - Molecular mechanism of antiproliferation potential of Acacia honey on NCI-H460 cell line. AB - Lung cancer is one of the leading causes of death worldwide. We investigated the molecular mechanism of antiproliferation potential of Acacia honey on NCI-H460 cells by cell cycle, viability, cytokines, calcium ion and gene expression analysis. Acacia honey inhibited cells proliferation, arrested G0/G1 phase, stimulated cytokines, calcium ion release as well as suppressed p53 and Bcl-2 expression in a dose-dependent manner. We proposed that the molecular mechanism of the antiproliferation potential of Acacia honey on NCI-H460 cell line is due to cell cycle arrest, stimulation of cytokines and calcium ion as well as downregulation of Bcl-2 and p53 genes. PMID- 23441618 TI - Antioxidant rich Morus alba leaf extract induces apoptosis in human colon and breast cancer cells by the downregulation of nitric oxide produced by inducible nitric oxide synthase. AB - Morus species had been used widely in the traditional medicines for various diseases. In this study we report the in vitro antiproliferative activity of the methanol extract of Morus alba. The extract is capable of inducing cytotoxicity in human colon cancer (HCT-15) cells (IC(50) = 13.8 MUg/ml) and breast cancer (MCF-7) cells (IC(50) = 9.2 MUg/ml), resulted in significant morphological changes of the cells, fragmentation of DNA, and caspase-3 activation- characteristics of apoptosis. It downregulated the amount of nitric oxide (NO) produced as a result of inducible nitric oxide (iNOS) activation. The HPLC analysis of the extract showed epicatechin (20%), myricetin (10%), quercetin hydrate (12%), luteolin (12%), and kaempferol (6%) as the major active components and ascorbic acid, gallic acid, pelargonidine, and p-coumaric acid as the minor components. To the best of our knowledge, this is the first report showing the downregulation of iNOS and induction of apoptosis by M. alba extract. PMID- 23441620 TI - Editorial: antioxidant heterocyclic compounds in drug discovery and medicinal chemistry. PMID- 23441619 TI - Fatty acid synthase inhibition induces differential expression of genes involved in apoptosis and cell proliferation in ocular cancer cells. AB - Fatty acid synthase (FASN), a lipogenic multienzyme complex, is overexpressed in the ocular cancer, retinoblastoma, and is strongly correlated with tumor invasion. Dietary nutrients are reported to exert anticancer effects through inhibition of lipid metabolism. Differential gene expression in cultured retinoblastoma cells induced by cerulenin, a chemical inhibitor of FASN, was evaluated by cDNA microarray analysis. Cerulenin treatment resulted in significant upregulation of cytochrome c (CYCS) by 1.2-fold, whereas S-phase kinase-associated protein-2 (SKP2), a negative regulator of cell cycle, and the lipid metabolic genes (PPARA, RXRA, and ACACB) were significantly downregulated by -1.59-, -1.8-, -1.83-, and -1.5-fold, respectively, in comparison with untreated cancer cells. The expressions of key differentially expressed genes were confirmed by quantitative real-time PCR. The altered expression of genes involved in cell proliferation, cell signaling, apoptosis, and cell cycle, correlated with the anticancer effects of cerulenin. FASN inhibition may thus be a potential strategy in retinoblastoma management. PMID- 23441621 TI - Gender, age, and educational level attribute to blood alcohol concentration in hospitalized intoxicated adolescents; a cohort study. AB - BACKGROUND: The prevalence of adolescents hospitalized with acute alcohol intoxication, mainly because of severe reduced consciousness, is increasing. However, the characteristics of these adolescents are mainly unidentified. In this clinical research, we aimed to identify factors that attribute to higher ethanol concentration, on which targeted alcohol health interventions can be designed. METHODS: Since 2007, alcohol intoxication among adolescents has been one of the leading topics of the Dutch Pediatric Surveillance System. In the current study, we have analyzed which demographic characteristics, general alcohol use behaviors, and clinical intoxication data were related to the blood alcohol concentration (BAC) levels at hospital admittance. We included all adolescents aged <18 years, admitted with BAC >0.0 g/l, and reduced consciousness during the years 2007, 2008, 2009, and 2010. RESULTS: A total of 2,023 adolescents with alcohol intoxication were reported, and 1,618 questionnaires were returned, of which 1,350 met our inclusion criteria. In univariate analysis, age, gender, educational level, place of alcohol purchase, place of alcohol consumption, age of first drink, and regular alcohol use during the weekend correlated with higher BAC. After multivariate analysis, older adolescents, boys, and higher educational level significantly attributed to higher BAC at admittance. CONCLUSIONS: In alcohol-intoxicated adolescents with reduced consciousness, gender, age, and also educational level correlate with BAC at admittance. Explanatory factors could be found in sensitivity to alcohol, but also in socioeconomic factors, which influence availability. Intervention strategies could be targeted more specific now for the subgroups found in this study to decrease the growing burden of adolescent alcohol intoxication, both on the societal level and on the clinical level. PMID- 23441622 TI - Impacts of Siberian biomass burning on organic aerosols over the North Pacific Ocean and the Arctic: primary and secondary organic tracers. AB - During the 2003 Chinese Arctic Research Expedition (CHINARE2003) from the Bohai Sea to the high Arctic (37 degrees N-80 degrees N), filter-based particle samples were collected and analyzed for tracers of primary and secondary organic aerosols (SOA) as well as water-soluble organic carbon (WSOC). Biomass burning (BB) tracer levoglucosan had comparatively much higher summertime average levels (476 +/- 367 pg/m(3)) during our cruise due to the influence of intense forest fires then in Siberia. On the basis of 5-day back trajectories, samples with air masses passing through Siberia had organic tracers 1.3-4.4 times of those with air masses transporting only over the oceans, suggesting substantial contribution of continental emissions to organic aerosols in the marine atmosphere. SOA tracers from anthropogenic aromatics were negligible or not detected, while those from biogenic terpenenoids were ubiquitously observed with the sum of SOA tracers from isoprene (623 +/- 414 pg/m(3)) 1 order of magnitude higher than that from monoterpenes (63 +/- 49 pg/m(3)). 2-Methylglyceric acid as a product of isoprene oxidation under high-NOx conditions was dominant among SOA tracers, implying that these BSOA tracers were not formed over the oceans but mainly transported from the adjacent Siberia where a high-NOx environment could be induced by intense forest fires. The carbon fractions shared by biogenic SOA tracers and levoglucosan in WSOC in our ocean samples were 1-2 orders of magnitude lower than those previously reported in continental samples, BB emissions or chamber simulation samples, largely due to the chemical evolution of organic tracers during transport. As a result of the much faster decline in levels of organic tracers than that of WSOC during transport, the trace-based approach, which could well reconstruct WSOC using biogenic SOA and BB tracers for continental samples, only explained ~4% of measured WSOC during our expedition if the same tracer-WSOC or tracer-SOC relationships were applied. PMID- 23441624 TI - Is it safe to decrease hemodynamic parameters to achieve bloodless surgical field during transnasal endoscopic procedures? Our experience in fifteen patients. PMID- 23441628 TI - Age-related changes in skin bio-mechanical properties: the neck skin compared with the cheek and forearm skin in Korean females. AB - BACKGROUND: There are many reports on regional variations in skin bio-mechanical properties, but few studies have been performed on the neck. The neck is sun exposed and continues to move so the neck skin can be more apt to aging. METHODS: The skin properties of the neck, cheek, and ventral forearm of 58 Korean female volunteers in good health (25-64 years old, 42.3 +/- 11.7) were assessed non invasively with skin measuring devices, and the correlation with age and wrinkles was analyzed. RESULTS: Neck skin was more extensible, elastic and visco-elastic than the cheek. The dermal layer for the neck skin was thinner and more intense than the cheek, but the results were opposite when compared with the skin of the forearm. We could observe that the subcutaneous layer was divided by the fascia with regard to the neck skin, and this thickness increased BMI-dependently. The neck skin had the correlation between R0, R3, and dermal thickness. The correlation coefficient of elasticity on the neck with ages was -0.550 and the elasticity on the neck skin was highly negatively correlated with age than any other sites. Therefore, this bio-mechanical property was important for determining the aging. TEWL was correlated with ages for only neck skin(R = 0.368). We found that the wrinkles on the neck were correlated with age, the elasticity, skin color (L*), TEWL. CONCLUSION: The biomechanical properties of the neck skin were highly correlated with age than skin parameters of other sites. These results were influenced by constant movement and sun-exposure, and therefore, the neck wrinkles were apt to form. PMID- 23441627 TI - Pneumonia-induced sepsis in mice: temporal study of inflammatory and cardiovascular parameters. AB - The aim of the present work is to provide a better comprehension of the pneumonia induced sepsis model through temporal evaluation of several parameters, and thus identify the main factors that determine mortality in this model. Klebsiella pneumoniae was inoculated intratracheally in anesthetized Swiss male mice. Inflammatory and cardiovascular parameters were evaluated 6, 24 and 48 h after the insult. The results show that severity of infection and the mortality correlated with the amount of bacteria. Six, 24 and 48 h after inoculation, animals presented pathological changes in lungs, increase in cell number in the bronchoalveolar lavage, leukopenia, increase in TNF-alpha and IL-1beta levels, hypotension and hyporesponsiveness to vasoconstrictors, the two latter characteristics of severe sepsis and septic shock. Significant numbers of bacteria in spleen and heart homogenates indicated infection spreading. Interestingly, NOS-2 expression appeared late after bacteria inoculation, whereas levels of NOS-1 and NOS-3 were unchanged. The high NOS-2 expression coincided with an exacerbated NO production in the infection focus and in plasma, as judging by nitrate + nitrite levels. This study shows that K. pneumoniae inoculation induces a systemic inflammatory response and cardiovascular alterations, which endures at least until 48 h. K. pneumoniae-induced lung infection is a clinically relevant animal model of sepsis and a better understanding of this model may help to increase the knowledge about sepsis pathophysiology. PMID- 23441623 TI - Minocycline: far beyond an antibiotic. AB - Minocycline is a second-generation, semi-synthetic tetracycline that has been in therapeutic use for over 30 years because of its antibiotic properties against both gram-positive and gram-negative bacteria. It is mainly used in the treatment of acne vulgaris and some sexually transmitted diseases. Recently, it has been reported that tetracyclines can exert a variety of biological actions that are independent of their anti-microbial activity, including anti-inflammatory and anti-apoptotic activities, and inhibition of proteolysis, angiogenesis and tumour metastasis. These findings specifically concern to minocycline as it has recently been found to have multiple non-antibiotic biological effects that are beneficial in experimental models of various diseases with an inflammatory basis, including dermatitis, periodontitis, atherosclerosis and autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. Of note, minocycline has also emerged as the most effective tetracycline derivative at providing neuroprotection. This effect has been confirmed in experimental models of ischaemia, traumatic brain injury and neuropathic pain, and of several neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis and spinal cord injury. Moreover, other pre-clinical studies have shown its ability to inhibit malignant cell growth and activation and replication of human immunodeficiency virus, and to prevent bone resorption. Considering the above mentioned findings, this review will cover the most important topics in the pharmacology of minocycline to date, supporting its evaluation as a new therapeutic approach for many of the diseases described herein. PMID- 23441629 TI - Interstitial fluid shifts to plasma compartment during blood donation. AB - BACKGROUND: A vasovagal reaction (VVR) occurs in 0.8% to 0.9% of voluntary blood donors in Japan. However, they generally tolerate the acute loss of 400 mL of whole blood rather well, perhaps because several circulatory defense mechanisms compensate for the loss. This study aimed to determine the extent to which an interstitial fluid shift contributes to the development of a VVR. STUDY DESIGN AND METHODS: Blood hemoglobin (Hb) was measured upon admission, at venipuncture, and immediately after collecting 400 mL of whole blood from 736 donors. Shifted fluid volume was calculated using a formula that included Hb levels and estimated total blood volume. RESULTS: By the end of blood collection, 188 +/- 80 and 211 +/- 82 mL of fluid, which is equivalent to almost half of the total amount of withdrawn blood, had entered the intravascular space in male and female donors, respectively. The difference between the sexes was significant despite the lower body weight and circulating blood volume of the female donors. Body weight increased, whereas age decreased the volume of shifted fluid in female donors. CONCLUSION: Blood loss after donation is quickly compensated by an interstitial fluid shift into the intravascular space and may not be the only direct cause of VVR in the setting of a whole blood donation of 400 mL. PMID- 23441630 TI - Review series - mechanotransduction from physiology to disease states. PMID- 23441631 TI - Mechanobiology in cardiac physiology and diseases. AB - Mechanosensitivity is essential for heart function just as for all other cells and organs in the body, and it is involved in both normal physiology and diseases processes of the cardiovascular system. In this review, we have outlined the relationship between mechanosensitivity and heart physiology, including the Frank Starling law of the heart and mechanoelectric feedback. We then focused on molecules involved in mechanotransduction, particularly mechanosensitive ion channels. We have also discussed the involvement of mechanosensitivity in heart diseases, such as arrhythmias, hypertrophy and ischaemic heart disease. Finally, mechanobiology in cardiogenesis is described with regard to regenerative medicine. PMID- 23441632 TI - Design and synthesis of amphiphilic xanthone-based, membrane-targeting antimicrobials with improved membrane selectivity. AB - This work describes how to tune the amphiphilic conformation of alpha-mangostin, a natural compound that contains a hydrophobic xanthone scaffold, to improve its antimicrobial activity and selectivity for Gram-positive bacteria. A series of xanthone derivatives was obtained by cationic modification of the free C3 and C6 hydroxyl groups of alpha-mangostin with amine groups of different pKa values. Modified structures using moieties with high pKa values, such as AM-0016 (3b), exhibited potent antimicrobial properties against Gram-positive bacteria. Compound 3b also killed bacteria rapidly without inducing drug resistance and was nontoxic when applied topically. Biophysical studies and molecular dynamics simulations revealed that 3b targets the bacterial inner membrane, forming an amphiphilic conformation at the hydrophobic-water interface. In contrast, moieties with low pKa values reduced the antimicrobial activity of the parent compound when conjugated to the xanthone scaffold. This strategy provides a new way to improve "hits" for the development of membrane-active antibiotics that target drug-resistant pathogens. PMID- 23441634 TI - Hiatal hernia repair with biologic mesh reinforcement reduces recurrence rate in small hiatal hernias. AB - The utility of mesh reinforcement for small hiatal hernia found especially during antireflux surgery is unknown. Initial reports for the use of biological mesh for crural reinforcement during repair for defects greater than 5 cm have been shown to decrease recurrence rates. This study compares patients with small hiatal hernias who underwent onlay biologic mesh buttress repair versus those with suture cruroplasty alone. This is a single-institution retrospective review of all patients undergoing repair of hiatal hernia measuring 1-5 cm between 2002 and 2009. The patients were evaluated based on surgical repair: one group undergoing crural reinforcement with onlay biologic mesh and other group with suture cruroplasty only. Seventy patients with hiatal hernia measuring 1-5 cm were identified. Thirty-eight patients had hernia repair with biologic mesh, and 32 patients had repair with suture cruroplasty only. Recurrence rate at 1 year was 16% (5/32) in patients who had suture cruroplasty only and 0% (0/38) in the group with crural reinforcement with absorbable mesh (statistically significant, P = 0.017). Suture cruroplasty alone appears to be inadequate for hiatal hernias measuring 1-5 cm with significant recurrence rate and failure of antireflux surgery. Crural reinforcement with absorbable mesh may reduce hiatal hernia recurrence rate in small hiatal hernias. PMID- 23441633 TI - Comparison between 2-(18) F-fluoro-2-deoxy-d-glucose positron emission tomography and contrast-enhanced computed tomography for measuring gross tumor volume in cats with oral squamous cell carcinoma. AB - Feline oral squamous cell carcinoma is one of the most refractory feline malignancies. Most patients succumb due to failure in local tumor control. 2-(18) F-fluoro-2-deoxy-D-glucose positron emission tomography ((18) F-FDG PET) is increasingly being used for veterinary oncology staging as it highlights areas with higher glucose metabolism. The goal of the current prospective study was to compare gross tumor volume measurements using (18) F-FDG PET vs. those using computed tomography (CT) for stereotactic radiation therapy planning in cats with oral squamous cell carcinoma. Twelve cats with confirmed oral squamous cell carcinoma underwent pretreatment (18) F-FDG PET/CT. Gross tumor volumes based on contrast-enhanced CT and (18) F-FDG PET were measured and compared among cats. Mean PET gross tumor volume was significantly smaller than mean CT gross tumor volume in the mandibular/maxillary squamous cell carcinoma group (n = 8, P = 0.002) and for the total number of patients (n = 12, P = 0.006), but not in the lingual/laryngeal group (n = 4, P = 0.57). Mismatch fraction analysis revealed that most of the lingual/laryngeal patients had a large region of high-(18) F-FDG activity outside of the CT gross tumor volume. This mismatch fraction was significantly greater in the lingual/laryngeal group than the mandibular/maxillary group (P = 0.028). The effect of poor spatial resolution of PET imaging was greater when the absolute tumor volume was small. Findings from this study indicated that (18) F-FDG PET warrants further investigation as a supplemental imaging modality in cats with oral squamous cell carcinoma because it detected regions of possible primary tumor that were not detected on CT images. PMID- 23441635 TI - The utility of vision during action: multiple visuomotor processes? AB - Recently, D. Elliott et al. (2010) asserted that the current control phase of a movement could be segregated in multiple processes, including impulse and limb target regulation processes. The authors aimed to provide further empirical evidence and determine some of the constraints that govern these visuomotor processes. In 2 experiments, vision was presented or withdrawn when limb velocity was above or below selected velocity criteria. The authors observed that vision provided between 0.8 and 0.9 m/s significantly improved impulse regulation processes while vision provided up to 1.1 m/s significantly increased limb-target regulation processes. These results lend support to D. Elliott et al. and provide evidence that impulse regulation and limb-target regulation can take place at different velocities during a movement. PMID- 23441636 TI - Arginine vasopressin V1a receptor-deficient mice have reduced brain edema and secondary brain damage following traumatic brain injury. AB - The formation of brain edema and subsequent intracranial hypertension are major predictors of unfavorable outcome following traumatic brain injury (TBI). Previously, we reported that arginine vasopressin (AVP) receptor antagonists reduce post-traumatic and post-ischemic brain edema in mice. The aim of the current study was to investigate further the contribution of arginine vasopressin V1a receptors to TBI-induced secondary brain damage in V1a receptor knock-out mice. V1a receptor knock-out (V1a -/-) and wild-type mice were subjected to controlled cortical impact (CCI), and edema (brain water content measured before and 24 h after CCI), primary and secondary contusion volume (15 min and 24 h after CCI), neurological function (one day before and seven days after CCI), body weight (before and seven days after CCI) and mortality were measured. Twenty-four h after CCI, V1a receptor knock-out mice had significantly less brain water content than wild-type mice (mean+/-standard error of the mean: 79.8%+/-0.3 vs. 80.6%+/-0.2, respectively), and secondary contusion volume was significantly smaller (38.2+/-1.7 mm(3) vs. 45.1+/-1.5 mm(3) in wild-type mice). Furthermore, the V1a receptor knock-out mice had less neurological dysfunction (3.2+/-0.8 vs. 7.0+/-1.4 in wild-type mice) and weight loss (1.0+/-1.0% vs. 4.9+/-1.8% in wild type mice) seven days after CCI. Our data show that mice lacking V1a receptors have less secondary brain damage following experimental traumatic brain injury. We therefore conclude that V1a receptors may represent a novel drug target for preventing post-traumatic brain edema. PMID- 23441637 TI - Evidence of transmission of a Panton-Valentine leukocidin-positive community acquired methicillin-resistant Staphylococcus aureus clone: a family affair. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) may represent a serious public health problem, owing to the spread of toxin-producing lineages. The presence of genes encoding for Panton-Valentine leukocidin (PVL) is an important virulence marker, as the clinical sequelae of PVL-positive infections are often described as more severe than those of PVL-negative S. aureus infections. To date, the presence of PVL has not appeared to be common in Italy; we describe the intrafamilial transmission of an epidemic PVL-producing CA MRSA lineage, Southwest Pacific clone (SWP). Our data suggested that the strain circulated from the father, who was recurrently affected by a soft tissue infection, to the mother, who showed nasal colonization, and to their child, who was hospitalized with symptoms of necrotizing pneumonia. In this case, we found that a recurrent skin infection that is not normally taken into account may represent a serious threat if caused by a PVL-producing strain. Our findings may have considerable implications for strategies for infection control and treatment of methicillin-resistant S. aureus infections. PMID- 23441638 TI - Modulation of sodium/iodide symporter expression in the salivary gland. AB - BACKGROUND: Physiologic iodide-uptake, mediated by the sodium/iodide symporter (NIS), in the salivary gland confers its susceptibility to radioactive iodine induced damage following (131)I treatment of thyroid cancer. Subsequent quality of life for thyroid cancer survivors can be decreased due to recurrent sialoadenitis and persistent xerostomia. NIS expression at the three principal salivary duct components in various pathological conditions was examined to better our understanding of NIS modulation in the salivary gland. METHODS: NIS expression was evaluated by immunohistochemistry in human salivary gland tissue microarrays constructed of normal, inflamed, and neoplastic salivary tissue cores. Cumulative (123)I radioactivity reflecting the combination of NIS activity with clearance of saliva secretion in submandibular and parotid salivary glands was evaluated by single-photon emission computed tomography/computed tomography imaging 24 hours after (123)I administration in 50 thyroid cancer patients. RESULTS: NIS is highly expressed in the basolateral membranes of the majority of striated ducts, yet weakly expressed in few intercalated and excretory duct cells. The ratio of (123)I accumulation between parotid and submandibular glands is 2.38+/-0.19. However, the corresponding ratio of (123)I accumulation normalized by volume of interest is 1.19+/-0.06. The percentage of NIS-positive striated duct cells in submandibular salivary glands was statistically greater than in parotid salivary glands, suggesting a higher clearance rate of saliva secretion in submandibular salivary glands. NIS expression in striated ducts was heterogeneously decreased or absent in sialoadenitis. Most ductal salivary gland tumors did not express NIS. However, Warthin's tumors of striated duct origin exhibited consistent and intense NIS staining, corresponding with radioactive iodine uptake. CONCLUSIONS: NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. NIS expression in salivary glands is decreased during inflammation and tumor formation. Further investigation may identify molecular targets and/or pharmacologic agents that allow selective inhibition of NIS expression/activity in salivary glands during radioactive iodine treatment. PMID- 23441640 TI - Directed assembly of high molecular weight block copolymers: highly ordered line patterns of perpendicularly oriented lamellae with large periods. AB - The directed assembly of block copolymer nanostructures with large periods exceeding 100 nm remains challenging because the translational ordering of long chained block copolymer is hindered by its very low chain mobility. Using a solvent-vapor annealing process with a neutral solvent, which was sequentially combined with a thermal annealing process, we demonstrate the rapid evolution of a perpendicularly oriented lamellar morphology in high molecular weight block copolymer films on neutral substrate. The synergy with the topographically patterned substrate facilitated unidirectionally structural development of ultrahigh molecular weight block copolymer thin films-even for the structures with a large period of 200 nm-leading to perfectly guided, parallel, and highly ordered line-arrays of perpendicularly oriented lamellae in the trenched confinement. This breakthrough strategy, which is applicable to nanolithographic pattern transfer to target substrates, can be a simple and efficient route to satisfy the demand for block copolymer assemblies with larger feature sizes on hundreds of nanometers scale. PMID- 23441639 TI - Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus). AB - Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50 , were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals' lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema. PMID- 23441642 TI - Editorial comment for Lisky et al. PMID- 23441641 TI - Application of an ensemble-trained source apportionment approach at a site impacted by multiple point sources. AB - Four receptor models and a chemical transport model were used to quantify PM2.5 source impacts at the St. Louis Supersite (STL-SS) between June 2001 and May 2003. The receptor models used two semi-independent data sets, with the first including ions and trace elements and the second including 1-in-6 day particle bound organics. Since each source apportionment (SA) technique has limitations, this work compares results from the five different SA approaches to better understand the biases and limitations of each. The source impacts calculated by these models were then integrated into a constrained, ensemble-trained SA approach. The ensemble method offers several improvements over the five individual SA techniques at the STL-SS. Primarily, the ensemble method calculates source impacts on days when individual models either do not converge to a solution or do not have adequate input data to develop source impact estimates. When compared with a chemical mass balance approach using measurement-based source profiles, the ensemble method improves fit statistics, reducing chi squared values and improving PM2.5 mass reconstruction. Compared to other receptor models, the ensemble method also calculates zero or negative impacts from major emissions sources (e.g., secondary organic carbon (SOC) and diesel vehicles) for fewer days. One limitation of this analysis was that a composite metals profile was used in the ensemble analysis. Although STL-SS is impacted by multiple metals processing point sources, several of the initial SA methods could not resolve individual metals processing impacts. The results of this analysis also reveal some of the subjectivities associated with applying specific SA models at the STL-SS. For instance, Positive Matrix Factorization results are very sensitive to both the fitting species and number of factors selected by the user. Conversely, Chemical Mass Balance results are sensitive to the source profiles used to represent local metals processing emissions. Additionally, the different SA approaches predict different impacts for the same source on a given day, with correlation coefficients ranging from 0.034 to 0.65 for gasoline vehicles, -0.54-0.48 for diesel vehicles, -0.29-0.81 for dust, -0.34-0.89 for biomass burning, 0.38-0.49 for metals processing, and -0.25-0.51 for SOC. These issues emphasize the value of using several different SA techniques at a given receptor site, either by comparing source impacts predicted by different models or by using an ensemble-based technique. PMID- 23441643 TI - The long-term effect of calcium hydroxide application on dentin fracture strength of endodontically treated teeth. AB - OBJECTIVE: The aim of this in vitro study was to evaluate the long-term effect of calcium hydroxide (CH) on the microtensile fracture strength (MTFS) of endodontically treated human teeth. MATERIALS AND METHODS: A total of 105 caries free extracted human mandibular incisors were used. The teeth were divided into seven experimental groups of 15 teeth each. The root canals of all the teeth were rotary instrumented. The teeth in the control group were immediately obturated and tested for MTFS. The rest of the teeth were vertically compacted with CH and a sterile saline solution mixture and sealed with temporary filling. The teeth were stored in a moist environment for 30, 90, 180, 270, 360, and 540 days. On scheduled dates, the root canals were obturated and then the teeth were tested for MTFS with an Instron testing machine. The Kruscal-Wallis test and a post hoc Dunn's multiple comparison test was utilized. The statistical significance level was established at P < 0.05. RESULTS: The introduction of CH into the root canals seems to decrease the MTFS of teeth statistically significantly through the 180th, 270th, 360th, and 540th days, respectively, compared with the control group. The results clearly indicated that there are statistically significant differences between group 2 and group 7 (P < 0.001) and between group 3 and group 7 (P < 0.05). There were no statistically significant differences between the rest of the groups (P > 0.05). CONCLUSIONS: The results indicate that long-term CH treatments can significantly reduce the strength of the teeth, causing an increase in fracture risk. PMID- 23441644 TI - Renal protective effects of early continuous venovenous hemofiltration in rhabdomyolysis: improved renal mitochondrial dysfunction and inhibited apoptosis. AB - Rhabdomyolysis (RM) and subsequent myoglobin (Mb) deposition can lead to acute kidney injury. Continuous venovenous hemofiltration (CVVH) can remove Mb, but direct renal protection is unclear. We hypothesized that CVVH can improve renal mitochondrial dysfunction in its early stage. Twenty-four mongrel dogs were randomly divided into four groups: (A) control; (B) model; (C) model + CVVH (50 mL/kg/h); and (D) model + CVVH (30 mL/kg/h). RM was induced by glycerol via intramuscular injection. The dogs were closely monitored for urine flow and renal function. Mb, plasma tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. After 8 h of CVVH, the morphological changes of renal mitochondria were observed and mitochondrial function indicators (reactive oxygen species, malondialdehyde, and respiratory control index) were detected. Western blot analysis was used to detect the expression of Mb, TNF-alpha, and IL-6 in renal tubules. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay method and Western blot analysis were used to detect apoptosis and apoptosis-related proteins. In group B, the dog urine output gradually decreased with increased blood creatinine. In groups C and D, the urine output was normal and stable. CVVH effectively eliminated Mb. High-dose CVVH was significantly better for removal efficiency than low-dose CVVH. CVVH significantly reduced the deposition of circulating Mb in the kidney in a dose-dependent manner. The impact of CVVH on TNF-alpha and IL-6 were not observed. The morphological changes of mitochondria and function indicators were significantly improved in group C compared with groups D and B. Compared with group B, renal apoptosis and apoptosis-related protein expression were inhibited in groups C and D. Group C was significantly better for mitochondrial improvement and apoptosis inhibition than group D. At the cellular and molecular level, CVVH can improve renal mitochondrial function and inhibit cell apoptosis. Early CVVH can protect from RM-caused renal injuries in a dose-dependent manner. PMID- 23441645 TI - Contrast-enhanced ultrasonographic characteristics of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism. AB - A noninvasive method for quantifying adrenal gland vascular patterns could be helpful for improving detection of adrenal gland disease in dogs. The purpose of this retrospective study was to compare the contrast-enhanced ultrasound (CEUS) characteristics of adrenal glands in 18 dogs with pituitary-dependent hyperadrenocorticism (PDH) vs. four clinically healthy dogs. Each dog received a bolus of the contrast agent (SonoVue(r), 0.03 ml/kg of body weight) into the cephalic vein, immediately followed by a 5 ml saline flush. Dynamic contrast enhancement was analyzed using time-intensity curves in two regions of interest drawn manually in the caudal part of the adrenal cortex and medulla, respectively. In healthy dogs, contrast enhancement distribution was homogeneous and exhibited increased intensity from the medulla to the cortex. In the washout phase, there was a gradual and homogeneous decrease of enhancement of the adrenal gland. For all dogs with PDH, there was rapid, chaotic, and simultaneous contrast enhancement in both the medulla and cortex. Three distinct perfusion patterns were observed. Peak perfusion intensity was approximately twice as high (P < 0.05) in dogs with PDH compared with that of healthy dogs (28.90 +/- 10.36 vs. 48.47 +/- 15.28, respectively). In dogs with PDH, adrenal blood flow and blood volume values were approximately two- to fourfold (P < 0.05) greater than those of controls. Findings from the present study support the use of CEUS as a clinical tool for characterizing canine adrenal gland disease based on changes in vascular patterns. PMID- 23441646 TI - Does skin hydration influence keratinocyte biology? In vivo evaluation of microscopic skin changes induced by moisturizers by means of reflectance confocal microscopy. AB - BACKGROUND: Skin hydration is defined as the water content of the epidermis and the dermis. In vivo reflectance confocal microscopy offers the opportunity to determine in vivo the kinetics of the skin after the application of topical products. OBJECTIVE: To define confocal features associated with dry skin and assess the microscopic effects of different moisturizers. METHODS: Ten healthy volunteers were enrolled for the study. Two different formulations were tested: petrolatum and a commercially available emulsion. Measurements were performed from baseline to 3 h after removal of the occlusion at regular time points. Nine confocal features were assessed: furrows' size, overall interkeratinocyte reflectance, furrows' morphology, scales, skin surface irregularity, non-rimmed dermal papillae, exocytosis, dermal inflammation and collagen type. Furrows' size and interkeratinocyte reflectance were also quantitated using a digital analysis. Stratum corneum capacitance was recorded. RESULTS: At baseline, RCM showed the presence of micro-scales and high skin surface irregularity score. After the application of topical products, the scale score decreased significantly; Furrow's size and Digital Furrow's Size had a marked and directly correlated decrement. Furrow's morphology and Epidermal Irregularity scores decreased from baseline to 30 min, the latter reaching a plateau in product application areas. Interestingly, interkeratinocyte reflectance progressively increased with the application of the topical products, while remained stable in the control area, confirmed by Digital Interkeratinocytes reflectance quantitation. CONCLUSION: RCM revealed that the changes involve the skin surface by reducing the micro-scales and epidermal irregularity. Even more interestingly, RCM showed that higher interkeratinocytes' brightness is seen for moisturizer, but not for the control area. This RCM finding could be linked to keratinocyte membrane protein exposure and/or substance release in the interkeratinocytic space. To sum up, RCM represents a useful imaging tool to analyze the morphologic changes at different time points following the application of topical products. PMID- 23441647 TI - Seroprevalence and incidence of hepatitis E virus infection in German blood donors. AB - BACKGROUND: Hepatitis E virus (HEV) is transmissible by transfusion. More data are needed about seroprevalence, incidence, and viremia in blood donors for the assessment of risk of transfusion-transmitted (TT)-HEV infections. STUDY DESIGN AND METHODS: Samples from 1019 whole blood donors were tested for anti-HEV immunoglobulin (Ig)G by enzyme-linked immunosorbent assay and Western blot. The incidence of HEV and presence of HEV RNA in donors who seroconverted were determined by testing archive samples and recipients of viremic donations were traced. Anti-HEV IgM and alanine transaminase (ALT) testing were also performed to assess the value of such measures in the prevention of TT-HEV infections. RESULTS: A total of 69 of 1019 donors tested positive for anti-HEV IgG (6.8% seroprevalence), and seroconversion for anti-HEV IgG occurred in seven of 69 donors within 2 years (incidence, 0.35%/year). Three of seven (42.8%) seroconverting donors provided an archive sample in which HEV RNA was detectable. One recipient of these donations was traceable; anti-HEV IgG, IgM, and HEV RNA testing were negative 41 days after transfusion. Neither ALT levels nor anti-HEV IgM detection correlated with the presence of HEV RNA. CONCLUSIONS: The seroprevalence of HEV was 6.8%, and the annual incidence 0.35%. HEV RNA was detectable in several seroconverting donors, without evidence for HEV transmission in the only traceable recipient. Since neither ALT nor anti-HEV IgM testing correlate with the presence of HEV RNA, HEV nucleic acid testing currently provides the only method for the prevention of TT-HEV infection. However, before implementation, more data about clinical relevance of TT-HEV infections and infectious dose of HEV are required. PMID- 23441648 TI - Supra-physiological efficacy at GPCRs: superstition or super agonists? AB - The concept of 'super agonism' has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. PMID- 23441649 TI - Regio- and stereocontrolled synthesis of oligostilbenoids: theoretical highlights at the supramolecular level. AB - Oligostilbenoids (e.g., ampelopsin F, viniferin, pallidol) result from homogeneous or heterogeneous coupling of monomeric stilbenoid units, leading to various chemical structures. Oligostilbenoid synthesis is regio- and stereocontrolled. To tackle this regio- and stereocontrol, a supramolecular chemistry approach is required that can be achieved by quantum chemistry. The stability of noncovalent pi-stacks, formed between two stilbenoid units prior to oxidation, is accurately evaluated with density functional theory (DFT) including dispersive effects (within the DFT-D formalism). These noncovalent arrangements drive the regiocontrol. The rest of the chemical pathway is a succession of dearomatization and rearomatization stages. The thermodynamics and kinetics of the processes are calculated with classical hybrid functionals. This study allows discrimination between the two main possible chemical pathways, namely, radical neutral and radical-radical reactions. The former appears more likely, thermodynamics and kinetics being in perfect agreement with the experimental 1:2 ratio obtained for ampelopsin F:pallidol analogues, respectively. PMID- 23441650 TI - The gunslinger effect: why are movements made faster when responding to versus initiating an action? AB - The authors replicated and extended results from the gunfight paradigm (A. Welchman, J. Stanley, M. Schomers, R. Miall, & H. Bulthoff, 2010a) in which participants moved faster when reacting to the perceived initiation of an opponent compared to initiating an action themselves. In addition to replicating these movement time effects, the authors found that time to peak velocity, peak velocity, and movement-endpoint dispersions were similarly impacted. The findings are discussed in terms of a triggering mechanism involved in ballistic and internally generated movements. PMID- 23441651 TI - BAMM: a preliminary bibliometric analysis on melanoma manuscripts. PMID- 23441656 TI - Is it too late to turn back the clock on managerialism and neoliberalism? PMID- 23441652 TI - Vancomycin minimum inhibitory concentration, host comorbidities and mortality in Staphylococcus aureus bacteraemia. AB - We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30 day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality. PMID- 23441657 TI - Acute kidney injury: global health alert. PMID- 23441658 TI - Impact of age, gender and indigenous status on access to diagnostic coronary angiography for patients presenting with non-ST segment elevation acute coronary syndromes in Australia. AB - Using Australian guidelines for management of acute coronary syndromes, we investigated the proportion of high-risk patients enrolled in the Acute Coronary Syndromes Prospective Audit registry who received a coronary angiogram. A prospective nationwide multicentre registry involving 39 Australian hospitals was used. The study cohort were patients with high-risk clinical features without ST segment elevation (n = 1948) admitted from emergency departments between 1 November 2005 and 31 July 2007. Eighty nine per cent of patients with ST segment elevation myocardial infarction and only 53% of eligible patients with high-risk acute coronary syndromes with no ST elevation received a diagnostic angiogram. Increasing age was associated with lower rates of angiography; a high-risk patient at the age of >= 70 years was 19% less likely to receive an angiogram than one at the age of <70 years (risk ratio (RR) = 0.81 95% confidence interval (CI) 0.76, 0.76). Women were 26% less likely than men to receive an angiogram (RR = 0.74; 95% CI = 0.65, 0.83). The adjusted RR from the multivariate analysis suggests that a patient at the age of >= 70 years was 35% less likely to receive an angiogram than one at the age of <70 years (RR = 0.65, 95% CI = 0.60, 0.73), and that women were 13% less likely than men to receive an angiogram (RR = 0.87, 95% CI = 0.80, 0.96). Indigenous patients were as likely to access angiography as eligible non-indigenous patients (RR = 1.03, 95% CI 0.85, 1.25). There is underinvestigation of high-risk patients without ST segment elevation in Australian hospitals, particularly for women and older patients. Indigenous patients are younger and have poorer risk profiles, and represent a group that would benefit from greater investment in prevention strategies. PMID- 23441659 TI - Audit of the aetiology and prevalence of pulmonary hypertension in a tertiary hospital setting. AB - Appropriate diagnosis and initiation of disease-specific treatment is an important therapeutic goal in idiopathic pulmonary arterial hypertension. We evaluated the prevalence and aetiology of moderate-to-severe pulmonary hypertension in a cohort of patients referred for inpatient echocardiography, with significant pulmonary hypertension documented in 4.6%. Pulmonary hypertension complicating left heart disease was the most common aetiology, with idiopathic pulmonary arterial hypertension less frequent. PMID- 23441660 TI - Tacrolimus-induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients. AB - Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5-3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus-induced TMA. We identified four patients with tacrolimus-induced TMA post-OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 +/- 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post-partum thrombotic thrombocytopenic purpura) and hepatitis C virus-related cirrhosis. All patients had tacrolimus post-OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 +/- 7.5 months. There was no mortality 6 months post-TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes. PMID- 23441661 TI - Ambiguous genitalia and hypertension in a patient with congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is an uncommon condition. Its clinical presentation with hypertension is rare. Deficiency of the steroid 11-beta hydroxylase accounts for less than 10% of CAH. We report a case of a 19-year-old patient who presents with hypertension with ambiguous genitalia secondary to adrenal steroidogenesis dysfunction. We also discuss the defects in adrenal steroidogenesis and clinical phenotypes of CAH. PMID- 23441662 TI - Monoclonal B-cell lymphocyte proliferation in a patient presenting with historical Whipple disease. PMID- 23441663 TI - Novel use of modafinal to treat severe physical and cognitive impairment post stroke. PMID- 23441664 TI - Anomalous coronary circulation presenting with flash pulmonary oedema. PMID- 23441665 TI - Ileocaecal tuberculosis: re-emergence in developed countries. PMID- 23441666 TI - Pituitary gigantism treated successfully with the growth hormone receptor antagonist, pegvisomant. PMID- 23441667 TI - Changes in 24-h ambulatory blood pressure during the 2009 earthquake at L'Aquila: a new evaluation in the same patients. PMID- 23441668 TI - Optimising the mix and match of needs and available resources for patients dying in hospital. PMID- 23441670 TI - Comment on "Two-dimensional boron monolayer sheets". PMID- 23441671 TI - Reply to "Comment on 'two-dimensional boron monolayer sheets'". PMID- 23441673 TI - Tip-enhanced Raman imaging: an emergent tool for probing biology at the nanoscale. AB - Typically limited by the diffraction of light, most optical spectroscopy methods cannot provide the spatial resolution necessary to characterize specimens at the nanoscale. An emerging exception to this rule is tip-enhanced Raman spectroscopy (TERS), which overcomes the diffraction limit through electromagnetic field localization at the end of a sharp metallic tip. As demonstrated by the Zenobi group in this issue of ACS Nano, TER imaging is an analytical technique capable of providing high-resolution chemical maps of biological samples. In this Perspective, we highlight recent advances and future applications of TER imaging as a technique for interrogating biology at the nanoscale. PMID- 23441674 TI - Increased mortality associated with cerebral contusions following trauma in the elderly: bad patients or bad management? AB - Age has been identified as an independent risk factor for poor outcome following head injury in the elderly, and postulated reasons for this include nature, nurture, and variations in management. Do elderly head injuries do worse because of a self-fulfilling prophecy of poorer management? The aim of this study was to review the management of patients with cerebral contusions according to age to identify any trends. We retrospectively reviewed prospectively collected national data on cerebral contusion admissions between March 14, 1988, and May 4, 2012, to UK hospitals held in the Trauma Audit and Research Network database. Patients were included in the study if they had cerebral contusion(s) with an abbreviated injury score (AIS) of 3 or more; no other head injury with a AIS score of 4 or more, or no injury in any other body region with AIS score of 3 or more, and known outcome data. In total, 4387 patients met the inclusion criteria. Mortality was found to increase with increasing age (p<0.001). However, time from admission to CT head imaging (p=0.003) and the likelihood of not being transferred to a center with acute neurosurgical care facilities (p<0.001) increased with increasing age, too. Further, there was a significant trend for the most senior grade of doctor to review more younger patients and for only the most junior grade of doctor to review more older patients (both, p<0.001). To conclude, our data suggest differences in management practice may contribute to the observed differences in mortality between younger and older patients suffering brain contusions. PMID- 23441675 TI - Damage from periorbital ageing to the multilayered structures and resilience of the skin in Chinese population. AB - Ageing dynamically disrupts the multilayered supporting components of the skin that are held together by cell adhesion molecules (CAMs). Skin specimens from 33 female Chinese patients undergoing lower blepharoplasty were divided into three age groups and examined by haematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and Elastica-van Gieson (EVG) stains, western blotting, surface electron microscopy (SEM) and biomechanical tension analysis. The SEM density (skin surface topology) showed a negative linear relationship with age. The triangular pattern of the skin surface in the younger group gradually broke down into quadrangular and irregular patterns in the older group. Collagens and elastic fibres in the dermis showed anisotropy and decreased density in the older groups compared with the younger group, especially in the papillary dermis. Anisotropy means that physical properties differ according to the direction of measurement. E-cadherin and integrin alphav (whose functions are to bind epidermal and dermal elements respectively) increased and decreased, respectively, in the oldest group. Skin resilience decreased significantly in this group under repetitive stress. In conclusion, a loss of skin surface textures, integrin alphav expressions, epidermal-dermal connections and dermal compactness led to the multilayered structure of the skin becoming separated. This in turn decreased resilience during ageing. These findings may therefore explain why aged skins cannot tolerate repetitive facial expressions, and why this action produces further dynamic wrinkles. PMID- 23441676 TI - Development, testing, and deployment of an air sampling manifold for spiking elemental and oxidized mercury during the Reno Atmospheric Mercury Intercomparison Experiment (RAMIX). AB - The Reno Atmospheric Mercury Intercomparison Experiment (RAMIX) was in Reno, NV from August 22, 2011 to September 16, 2011. The goals of the experiment were to compare existing and new methods for measurements of ambient elemental and oxidized Hg, and to test these with quantitative spikes of Hg(0), HgBr2, O3 and water vapor. In this paper we describe the design, testing, and deployment of a high flow manifold system designed to deliver ambient air and spiked compounds to multiple instruments simultaneously. The manifold was constructed of 1" OD PFA tubing and heated to 115 degrees C for the entire active zone. Manifold flow was controlled at ~200 LPM using a blower and a velocity sensor in a feedback control system. Permeation tubes in controlled ovens were used to deliver Hg(0) and HgBr2. Ozone was generated from a small UV lamp in a flow of high purity O2. Water vapor was generated by pumping a flow of purified N2 through heated, high purity water. The spiking delivery for Hg(0), HgBr2, O3, and water vapor after dilution in the manifold ranged up to 20 ng m(-3), 0.64 ng m(-3), 100 ppbv, and 20 g kg(-1), respectively. During laboratory tests the average transmission efficiencies for Hg(0), HgBr2, and O3 were found to be 92%, 76%, and 93%, respectively. PMID- 23441677 TI - Computed tomography of nonanesthetized cats with upper airway obstruction. AB - Upper airway obstruction is a potentially life-threatening problem in cats and for which a noninvasive, sensitive method rapid diagnosis is needed. The purposes of this prospective study were to describe a computed tomography (CT) technique for nonanesthetized cats with upper airway obstruction, CT characteristics of obstructive diseases, and comparisons between CT findings and findings from other diagnostic tests. Ten cats with clinical signs of upper airway obstruction were recruited for the study. Four cats with no clinical signs of upper airway obstruction were recruited as controls. All cats underwent computed tomography imaging without sedation or anesthesia, using a 16-slice helical CT scanner and a previously described transparent positional device. Three-dimensional (3D) internal volume rendering was performed on all CT image sets and 3D external volume rendering was also performed on cats with evidence of mass lesions. Confirmation of upper airway obstruction was based on visual laryngeal examination, endoscopy, fine-needle aspirate, biopsy, or necropsy. Seven cats were diagnosed with intramural upper airway masses, two with laryngotracheitis, and one with laryngeal paralysis. The CT and 3D volume-rendered images identified lesions consistent with upper airway disease in all cats. In cats with mass lesions, CT accurately identified the mass and location. Findings from this study supported the use of CT imaging as an effective technique for diagnosing upper airway obstruction in nonanesthetized cats. PMID- 23441678 TI - Concordance between in vivo reflectance confocal microscopy and optical histology of lymphomatoid papulosis. AB - BACKGROUND: Lymphomatoid papulosis is a primary cutaneous CD30+ T-cell lymphoma clinically characterized by a benign, chronic, recurrent course with self-limited papulo-nodular skin lesion eruption. In vivo Reflectance Confocal Microscopy is a non-invasive technique for real-time imaging of the superficial layers of the skin down to the superficial dermis with cellular-level resolution close to conventional histopathology. RCM has been previously reported to be useful in the in vivo evaluation of inflammatory diseases, skin tumours and also cutaneous lymphomas. Only two articles have been published on cutaneous lymphomas and none detailing confocal features of LyP. The aim of this manuscript was to describe the confocal features of LyP and their histological correlation to evaluate the possible application of this non-invasive tool in this T-cell lymphoma subtype clinical management. METHODS: Five patients with histological diagnosis of LyP were imaged with RCM, followed by a skin biopsy on a clinically selected lesion. RESULTS: High grade of correspondence between RCM and histopathology of LyP was observed, disclosing the potential rule of RCM at least for biopsy site selection. CONCLUSION: Future studies on RCM for LyP vs. other cutaneous T-cells lymphomas and inflammatory skin diseases are needed to assess specificity and sensibility of our preliminary data. PMID- 23441680 TI - Enthalpies and entropies of adsorption on well-defined oxide surfaces: experimental measurements. PMID- 23441681 TI - Comparison and experimental validation of fluid dynamic numerical models for a clinical ventricular assist device. AB - With the recent advances in computer technology, computational fluid dynamics (CFDs) has become an important tool to design and improve blood-contacting artificial organs, and to study the device-induced blood damage. Commercial CFD software packages are readily available, and multiple CFD models are provided by CFD software developers. However, the best approach of using CFD effectively to characterize fluid flow and to predict blood damage in these medical devices remains debatable. This study aimed to compare these CFD models and provide useful information on the accuracy of each model in modeling blood flow in circulatory assist devices. The laminar and five turbulence models (Spalart Allmaras, k-epsilon (k-epsilon), k-omega (k-omega), SST [Menter's Shear Stress Transport], and Reynolds Stress) were implemented to predict blood flow in a clinically used circulatory assist device, the CentriMag centrifugal blood pump. In parallel, a transparent replica of the CentriMag pump was constructed and selected views of the flow fields were measured with digital particle image velocimetry (DPIV). CFD results were compared with the DPIV experimental results. Compared with the experiment, all the selected CFD models predicted the flow pattern fairly well except the area of the outlet. However, quantitatively, the laminar model results were the most deviated from the experimental data. On the other hand, k-epsilon renormalization group theory models and Reynolds Stress model are the most accurate. In conclusion, for the circulatory assist devices, turbulence models provide more accurate results than the laminar model. Among the selected turbulence models, k-epsilon and Reynolds Stress Method models are recommended. PMID- 23441683 TI - Internal urethrotomy for recurrence after perineal anastomotic urethroplasty for posttraumatic pediatric posterior urethral stricture: could it be sufficient? AB - PURPOSE: To evaluate the long-term outcome of visual internal urethrotomy (VIU) after perineal anastomotic urethroplasty for posttraumatic pediatric posterior urethral strictures. PATIENTS AND METHODS: Data of 22 boys who had undergone internal urethrotomy for recurrent stricture after perineal anastomotic urethroplasty for posttraumatic posterior urethral strictures between 1998 and 2008 were analyzed retrospectively regarding patient age, interval between anastomotic urethroplasty and internal urethrotomy, stricture length, surgical technique, and postoperative complications. VIU was performed in patients in whom a guidewire could be passed beyond the stricture segment. The eventual surgical success was defined as asymptomatic voiding without clinical evidence of residual stricture (good flow rate and absence of residual urine). RESULTS: The mean (range) age of patients was 12.2 (3-17) years. All patients had a road traffic accident with associated pelvic fracture. The perineal approach for anastomotic urethroplasty was adopted in all. The estimated stricture length was 0.5 cm or less in 15 patients and was 0.5 to 1 cm in 7 patients. The interval between anastomotic urethroplasty and internal urethrotomy was early-after 12 weeks or less-in 13 children or late-beyond 12 weeks-in the remaining 9. The overall mean interval was 18 (5-63) weeks. In all patients, a guidewire could be passed through the strictured area. One VIU was performed in 17 patients, 2 VIU in 3 patients, while 3 VIU were performed in 2 patients. There was no extravasation reported. The mean follow-up duration was 98 (38-210) months. VIU was successful in 20 of 22 (90%) patients. All patients voided with no symptoms and were continent. CONCLUSIONS: VIU offers high success rate and can be sufficient in recurrent strictures of less than 1 cm length after anastomotic urethroplasty in children whenever a guidewire can be passed through the stricture area. PMID- 23441682 TI - Ca2+ -activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction. AB - BACKGROUND AND PURPOSE: We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. EXPERIMENTAL APPROACH: Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. KEY RESULTS: Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 MUM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 +/- 0.22 vs. 5.21 +/- 0.63 MUM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. CONCLUSIONS AND IMPLICATIONS: Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED. PMID- 23441684 TI - Blaming the victim: the effects of extraversion and information disclosure on guilt attributions in cyberbullying. AB - Cyberbullying victims' success in coping with bullying largely depends on schoolmates and other bystanders' social support. However, factors influencing the degree of social support have as yet not been investigated. In this article, the concept of victim blaming is applied to cyberbullying incidents. It is assumed that a cyberbullying victim receives less social support when the victim's behavior is perceived as very overt. It is further assumed that this effect's underlying process is the partial attribution of responsibility for the incident to the victim and not to the bully. The hypotheses are tested with a 2*2 online experiment. In this experiment, varying online self-presentations of a fictitious female cyberbullying victim were presented to 586 Germans aged 16-22. The victim's public Facebook profile was manipulated in terms of the victim's extraversion and the amount of personal information disclosed. The results support the hypotheses. Participants attributed more responsibility for the bullying incident to the victim when the victim was presented as extraverted and very open in revealing personal information. This diminished social support for the victim. The effect was partially mediated by the victim's perceived attractiveness. The study implies that concepts from victimization research can enhance our understanding of cyberbullying incidents. Among other factors, the victim's specific personal characteristics deserve more consideration--not only with regard to the incident itself but also regarding subsequent social dynamics and coping mechanisms. PMID- 23441685 TI - Arabic validation of the Internet addiction test. AB - Concern about Internet addiction, fuelled by the rapid increase in its usage across the globe, has spread to many parts of the world, including the Arab world. Concurrently, there has been a relentless quest for a valid tool for measuring Internet addiction. Thus far, two popular tools have been translated to Arabic: the Compulsive Internet Use Scale and the Internet addiction test (IAT). While the Arabic version of the former was proven valid by one study, the validity of the latter's Arabic version remains in question. Therefore, this study investigated the psychometric properties of the Arabic version of the IAT. An online Arabic version of the IAT was completed by 817 intermediate- and secondary-school students across Lebanon. The results showed that a one-factor model of the IAT has good psychometric properties and fits the data extremely well. This study presents evidence that the Arabic version of the IAT is valid for measuring Internet addiction among adolescents in Lebanon. PMID- 23441686 TI - Comparative study of chromatographic medium-associated mass and potential antitumor activity loss with bioactive extracts. AB - Natural product drug discovery programs often rely on the use of silica (Si) gel, reversed-phase media, or size-exclusion resins (e.g., RP-C18, Sephadex LH-20) for compound purification. The synthetic polymer-based sorbent Diaion HP20SS (cross linked polystyrene matrix) is used as an alternative to prepare purified natural product libraries. To evaluate the impact of chromatographic media on the isolation of biologically active, yet chromatographically unstable natural products, Diaion HP20SS was evaluated side-by-side with normal-phase sorbents for irreversible binding of extract constituents and their effects on bioactivity. An array of chemically diverse natural product-rich extracts was selected as a test panel, and a cell-based reporter assay for hypoxia-inducible factor-1 (HIF-1) was employed to monitor potential change(s) in bioactivity. Silica gel caused significant irreversible binding of three out of 10 extracts. Curcuma longa, Saururus cernuus, and Citrus reticulata extracts showed decreased HIF-1 inhibitory activity after elution through Si gel. An additional nonpolar column wash of HP20SS with EtOAc retained considerable bioactivities of active extracts. In general, Si gel produced the greatest loss of bioactivity. However, HP20SS elution reduced significantly HIF-1 inhibitory activity of certain extracts (e.g., Asimina triloba). PMID- 23441687 TI - If the permanent deferral were lifted would men who have sex with men want to donate blood, and if so, who would be eligible? AB - BACKGROUND: The deferral of men who have sex with men (MSM) from blood donation is controversial worldwide, with national policies varying from no explicit deferral to permanent deferral. This study assesses whether MSM have donated and would be interested in donating if the US exclusion policy were removed and who would be eligible to donate if the policy were modified to a temporary or lower risk deferral criterion. STUDY DESIGN AND METHODS: Questions about previous blood donation and interest in future donation were added to the National HIV Behavioral Surveillance survey questionnaire, which periodically gathers risk behavior information from MSM in San Francisco. RESULTS: Overall, 77.3% of 475 MSM respondents expressed interest in donating. By lower-risk criteria, 10.1% had no sexual contact in the past 6 months (2.3% in the past 12 months) and 1.9% had only lower-risk sexual contact in the past 6 months (1.5% in the past 12 months). Of the 23.4% who answered yes to having donated in the past, at least 25.2% did not comply with the current deferral of no male-male sex since 1977. CONCLUSION: The majority of MSM are interested in donating blood. Depending on how the policy would be changed (i.e., either a temporary or a behavior-based deferral criterion), substantial numbers of MSM would be eligible. PMID- 23441688 TI - Broad electrical tuning of graphene-loaded plasmonic antennas. AB - Plasmonic antennas enable the conversion of light from free space into subwavelength volumes and vice versa, which facilitates the manipulation of light at the nanoscale. Dynamic control of the properties of antennas is desirable for many applications, including biochemical sensors, reconfigurable meta-surfaces and compact optoelectronic devices. The combination of metallic structures and graphene, which has gate-voltage dependent optical properties, is emerging as a possible platform for electrically controlled plasmonic devices. In this paper, we demonstrate in situ control of antennas using graphene as an electrically tunable load in the nanoscale antenna gap. In our experiments, we demonstrate electrical tuning of graphene-loaded antennas over a broad wavelength range of 650 nm (~140 cm(-1), ~10% of the resonance frequency) in the mid-infrared (MIR) region. We propose an equivalent circuit model to quantitatively analyze the tuning behavior of graphene-loaded antenna pairs and derive an analytical expression for the tuning range of resonant wavelength. In a separate experiment, we used doubly resonant antenna arrays to achieve MIR optical intensity modulation with maximum modulation depth of more than 30% and bandwidth of 600 nm (~100 cm(-1), 8% of the resonance frequency). This study shows that combining graphene with metallic nanostructures provides a route to electrically tunable optical and optoelectronic devices. PMID- 23441689 TI - Directional adaptation of reactive saccades and hand pointing movements is not independent. AB - It is a matter of debate whether reactive saccades and hand pointing movements share common adaptive mechanism. To find out, the authors used a double-step paradigm in which the direction either of eye or of hand movements was adaptively modified in a first block of 300 trials, and the direction of the other motor system was then modified with opposite polarity in a second block of 300 trials. In a third block, single-step stimuli were used to test for after effects. The authors found that subjects adapted in the second block less well than in the first, and that aftereffects were adequate for the first rather than the second block. When the second block was extended to 500 trials, adaptation was still poor but aftereffects were now adequate for the second block. From this the authors concluded that double-step adaptation of the first motor system interferes with the subsequent adaptation of the other motor system (i.e., the adaptive mechanisms for eyes and hand are not independent). PMID- 23441690 TI - Effects of combination therapy with levamlodipine and bisoprolol on stroke in rats. AB - AIM: To examine the effects of combination with levamlodipine and bisoprolol on stroke in rats. METHODS: For acute study, Systolic blood pressure (SBP) and heart period (HP) were monitored in conscious stroke prone-spontaneously hypertensive rats (SHR-SP) and sinoaortic denervation (SAD) rats before and after intragastric administration of either drug at a single dose. Rats were subjected to middle cerebral arterial occlusion (MCAO) half an hour after drug administration; sacrificed 24 h later to measure the infarct size. For long-term study, drugs (either alone or in combination) were delivered via food to SHR-SP. The survival time was recorded. RESULTS: SBP was significantly reduced by combination therapy both in SHR-SP and SAD rats. Neutralization on heart rate (HR) was observed in combination. The drug combination increased baroreflex sensitivity (BRS) and reduced SBP variability (SBPV). In chronic experiments, the lifespan of SHR-SP rats exposed to the drug combination was longer than that in rats exposed to either drug alone. The infarct area was the smallest in subjects receiving drug combination in SD rats both with and without SAD. CONCLUSION: Combined use of levamlodipine and bisoprolol produced better protection against stroke. PMID- 23441691 TI - A DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, exacerbates neurotoxicity and upregulates Parkinson's disease-related genes in dopaminergic neurons. AB - AIMS: To investigate effects of DNA methyltransferase (DNMT) inhibitors on dopaminergic neurons and its underlied mechanism. METHODS: The DNMT inhibitor 5 aza-2'-deoxycytidine (5-aza-dC) was tested in cultured dopaminergic cells. Cell viability and apoptosis were assayed with 5-aza-dC alone. Neurotoxicity of 1 methyl-4-phenylpyridinium (MPP(+) ), 6-hydroxydopamine or rotenone was also assayed with 5-aza-dC pretreatment. And mRNA levels of several key PD-related genes were examined by semiquantitative RT-PCR. Furthermore, CpG methylation of alpha-synuclein promoter was examined by bisulfite sequencing. RESULTS: 5-aza-dC resulted in decreased cell viability and increased apoptosis in dopaminergic neuronal cells. Pretreatment with 5-aza-dC exacerbated neurotoxic damage to dopaminergic neurons induced by MPP(+) , 6-hydroxydopamine or rotenone. 5-aza-dC also induced transcriptional upregulation of the key PD-related genes tyrosine hydroxylase and alpha-synuclein. And demethylation of CpG in alpha-synuclein promoter was also induced by 5-aza-dC and MPP(+) . CONCLUSIONS: This DNMT inhibitor might influence pathogenesis of PD. And demethylation induced by DNMT inhibitor might contribute to dopaminergic neuron death, by increasing vulnerability of dopaminergic neurons to neurotoxins and by misregulating transcription of key PD-related genes. Our data also suggested DNMT inhibitors may cause multiple effects on dopaminergic neurons. PMID- 23441692 TI - Increased neurogenesis contributes to the promoted behavioral recovery by constraint-induced movement therapy after stroke in adult rats. PMID- 23441693 TI - Effects of thioredoxin-1 on neurogenesis after brain ischemia/reperfusion injury. PMID- 23441694 TI - An observational outcomes study from 1966-2008, examining pregnancy and neonatal outcomes from dialysed women using data from the ANZDATA Registry. AB - AIMS: To conduct an observational outcomes study examining pregnancy and neonatal outcomes of dialysed women aged 15-49, from 1966-2008, using data from the ANZDATA Registry. METHODS: Data from the ANZDATA Registry were captured and analysed from 1966-2008. Specific pregnancy outcomes included: live birth (LB), spontaneous abortion, stillbirth (SB) or termination of pregnancy. Delivery and neonatal outcomes, since 2001, were also analysed. RESULTS: There were 23 700 person-years (PY) of observational data during the study period with 49 pregnancies, of which 30 (79%) resulted in a LB, once terminations were excluded. Pregnancy rates: Overall the pregnancy rate was 2.07 per 1000 PY for the study interval. A significant increase in the pregnancy rate was noted for the 1996 2008 time interval (3.3 per 1000 PY, compared with 0.54 and 0.67 in the eras 1976 1985 and 1986-1995, respectively; P = 0.004). Most pregnancies were observed in the 25-29 age group: 20-24, 25-29 and 30-34 (5.31, 5.61 and 3.87 per 1000 PY, respectively). Patients on peritoneal dialysis were less likely to achieve a pregnancy compared with haemodialysis patients (P < 0.02). Live birth rates: The overall LB rate was 1.26 per 1000 PY. The rate for each of the age brackets was as follows: 3.54 for 20-24, 3.61 for 25-29, and 2.39 per 1000 PY for 30-34, compared with 0 in the 15-19 group, and 1.22, 0.2 and 0.16 per 1000 PY among the groups 35-39, 40-44 and 45-49 years, respectively. LB rates were more favourable in the younger age groups. There was no significant era, disease, dialysis modality or race effect on LB rates. Excluding terminations, the LB rate was 79%. Age-effect on pregnancy outcomes: Pregnancy outcome was not affected by age (mean ages shown): spontaneous abortions, 28.7 years (n = 3); LB, 29.3 years (n = 24); SB, 32.4 years (n = 5); terminations 30.6 years (n = 11). Maternal mortality and complications: The preeclampsia rate was 19.4% (6/31). No post-partum maternal deaths were reported. Neonatal outcomes: Since 2001, 21 neonatal outcomes were reported. One baby developed polyhydramnios, one had a congenital malformation and one post-natal death was reported. In total 53.4% were born preterm; 65% had a birthweight <2.5 kg (low birthweight) and 35% <1.5 kg (very low birthweight). Low birthweight correlated with prematurity. CONCLUSION: Seventy-nine per cent of women achieving a pregnancy in our cohort achieved a LB, although 53.4% of babies were born preterm and 65% were of low birthweight (<2.5 kg). PMID- 23441696 TI - Expert opinion on ranking risk factors for subclinical mastitis using a modified Delphi technique. AB - AIM: To collate the expert opinion of Australian dairy practitioners on the relative importance of risk factors for subclinical mastitis in dairy cattle. METHODS: A modified Delphi technique was used to collect the data over two rounds. First, participants were asked to complete a survey involving ranking the level of importance of 42 risk factors on the incidence of subclinical mastitis on a scale from 1 to 10 for two categories of subclinical mastitis; contagious and environmental. After presenting and discussing the results of the first survey, the participants were asked to complete the same survey a second time. To rank the risk factors and identify the consensus amongst the participants, the median and total variation of answers were calculated and compared between the two surveys. RESULTS: The most important factors identified by the respondents after the second survey for contagious subclinical mastitis were: Teat Disinfection Post-milking, Management of High Cell Count Cows and Presence of Chronically Infected Mastitis Cows in the Herd. The most important factors for environmental subclinical mastitis were Cleanliness of the Environment and Technique of Teat Disinfection Post-milking. CONCLUSIONS: A movement toward consensus for the more important factors and a movement away from consensus for the less important factors in the second survey were observed. The most important factors for subclinical mastitis were found to be: teat disinfection post milking, management of high cell count cows, presence of chronically infected mastitis cows in the herd and cleanliness of the environment. PMID- 23441695 TI - Aquaporin-4 expression in post-traumatic syringomyelia. AB - Aquaporin-4 (AQP4) is an astroglial water channel protein that plays an important role in the transmembrane movement of water within the central nervous system. AQP4 has been implicated in numerous pathological conditions involving abnormal fluid accumulation, including spinal cord edema following traumatic injury. AQP4 has not been studied in post-traumatic syringomyelia, a condition that cannot be completely explained by current theories of cerebrospinal fluid dynamics. Alterations of AQP4 expression or function may contribute to the fluid imbalance leading to syrinx formation or enlargement. The aim of this study was to examine AQP4 expression levels and distribution in an animal model of post-traumatic syringomyelia. Immunofluorescence and western blotting were used to assess AQP4 and glial fibrillary acidic protein (GFAP) expression in an excitotoxic amino acid/arachnoiditis model of post-traumatic syringomyelia in Sprague-Dawley rats. At all time-points, GFAP-positive astrocytes were observed in tissue surrounding syrinx cavities, although western blot analysis demonstrated an overall decrease in GFAP expression, except at the latest stage investigated. AQP4 expression was significantly higher at the level of syrinx at three and six weeks following the initial syrinx induction surgery. Significant increases in AQP4 expression also were observed in the upper cervical cord, rostral to the syrinx except in the acute stage of the condition at the three-day time-point. Immunostaining showed that AQP4 was expressed around all syrinx cavities, most notably adjacent to a mature syrinx (six- and 12-week time-point). This suggests a relationship between AQP4 and fluid accumulation in post-traumatic syringomyelia. However, whether this is a causal relationship or occurs in response to an increase in fluid needs to be established. PMID- 23441699 TI - Diabetes technology and treatment in the pediatric age group. PMID- 23441700 TI - Diabetes technology and the human factor. PMID- 23441701 TI - New therapies for diabetes management. PMID- 23441702 TI - Continuous glucose monitoring in 2012. PMID- 23441704 TI - Insulin pumps. PMID- 23441705 TI - Closing the loop. PMID- 23441706 TI - Self-monitoring of blood glucose--an overview. PMID- 23441707 TI - New insulins and insulin therapy. PMID- 23441708 TI - Insulin pens and new ways of insulin delivery. PMID- 23441709 TI - Using health information technology to prevent and treat diabetes. PMID- 23441710 TI - Technology and pregnancy. PMID- 23441711 TI - Bariatric surgery and diabetes: access denied. PMID- 23441712 TI - The year in immune intervention for type 1 diabetes. PMID- 23441713 TI - Advances in exercise, physical activity, and diabetes mellitus. PMID- 23441714 TI - Decreased serum transforming growth factor-beta1 concentration with aging is associated with the severity of emphysema in chronic obstructive pulmonary disease. AB - AIM: Age-associated changes of the lung might increase pathogenetic susceptibility to chronic obstructive pulmonary disease (COPD). Decrement in serum transforming growth factor (TGF)-beta1 concentration is reported in elderly people. As impaired TGF-beta1 signaling could cause emphysema-like changes, we hypothesized that decreased TGF-beta1 with aging is correlated with emphysema. METHODS: Symptomatic patients with or without COPD and healthy normal subjects without COPD were recruited (COPD, n = 182; smoking controls, n = 73; normal, n = 26). We investigated the correlation between TGF-beta1 and extent of emphysema and airway wall thickness, which were defined as the percentage of low attenuation area (LAA%) and large airway wall area (WA%) on pulmonary high resolution computed tomography, respectively. The correlation of pulmonary function test parameters and TGF-beta1 was evaluated. TGF-beta1 was determined by enzyme-linked immunosorbent assay. RESULTS: TGF-beta1 significantly decreased with age (P = 0.0009). When the correlation between age and TGF-beta1 was analyzed in each group, a significant inverse correlation was found in COPD patients and smoking controls (P = 0.0095 and 0.0132, respectively), whereas no correlation was observed in healthy older adults. Among COPD patients with severe emphysema, LAA% was inversely correlated with TGF-beta1 (n = 89, P = 0.0104), whereas WA% and pulmonary function test parameters were not. CONCLUSIONS: Although no correlation was found between TGF-beta1 and the severity of COPD, TGF beta1 significantly decreased as emphysema became more severe. Age-related decrease of TGF-beta1 in COPD might be associated with emphysematous alterations of the lungs in elderly subjects. PMID- 23441716 TI - Alliance of epigenetic forces for the activation of oncogenic Wnt/beta-catenin signaling. PMID- 23441715 TI - Arginase inhibition alleviates hypertension in the metabolic syndrome. AB - BACKGROUND AND PURPOSE: We have previously shown that arginase inhibition alleviates hypertension associated with in a diabetic animal model. Here, we investigated the protective effect of arginase inhibition on hypertension in metabolic syndrome. EXPERIMENTAL APPROACH: Metabolic syndrome was induced in rats by administration of fructose (10% in drinking water) for 12 weeks to induce vascular dysfunction. Three arginase inhibitors (citrulline, norvaline and ornithine) were administered daily in the last 6 weeks of study before and tail BP was recorded in conscious animals. Concentration response curves for phenylephrine (PE), KCl and ACh in addition to ACh-induced NO generation were obtained in thoracic aorta rings. Serum glucose, insulin, uric acid and lipid profile were determined as well as reactive oxygen species (ROS) and arginase activity. KEY RESULTS: Arginase activity was elevated in metabolic syndrome while significantly inhibited by citrulline, norvaline or ornithine treatment. Metabolic syndrome was associated with elevations in systolic and diastolic BP, while arginase inhibition significantly reduced elevations in diastolic and systolic BP. Metabolic syndrome increased vasoconstriction responses of aorta to PE and KCl and decreased vasorelaxation to ACh, while arginase inhibition completely prevented impaired responses to ACh. In addition, arginase inhibition prevented impaired NO generation and exaggerated ROS formation in metabolic syndrome. Furthermore, arginase inhibition significantly reduced hyperinsulinaemia and hypertriglyceridaemia without affecting hyperuricaemia or hypercholesterolaemia associated with metabolic syndrome. CONCLUSIONS AND IMPLICATIONS: Arginase inhibition alleviates hypertension in metabolic syndrome directly through endothelial-dependent relaxation/NO signalling protection and indirectly through inhibition of insulin resistance and hypertriglyceridaemia. PMID- 23441717 TI - Acid burn or cytokine sizzle in the pathogenesis of heartburn? PMID- 23441718 TI - Pediatric inflammatory bowel disease: can patterns in Asia shed some light? PMID- 23441719 TI - Mining the idiopathic genetic cholestasis syndrome. PMID- 23441720 TI - Clinical application and standardization of colorectal endoscopic submucosal dissection: is it a viable approach? PMID- 23441721 TI - Posttransfusion platelet increments after different platelet products in neonates: a retrospective cohort study. AB - BACKGROUND: In the Netherlands different platelet (PLT) products are used for neonatal transfusions: volume-reduced PLTs, PLT additive solution (PAS) II PLTs, and plasma PLTs. These are standard products at three different neonatal intensive care units where local transfusion guidelines apply. Here we assess the posttransfusion count increments with these products. STUDY DESIGN AND METHODS: We performed a retrospective cohort study of neonates who received, in the first month after birth, between January 1, 2007, and December 31, 2008, at least one PLT transfusion. Seventy-four neonates who received 197 volume-reduced PLTs transfusions, 68 neonates who received 105 PASII PLT transfusions, and eight neonates who received eight plasma PLT transfusions were analyzed. Early (within 8 hr after transfusion) and follow-up count increments (16-24 hr after transfusion) were evaluated for 191 and 81 volume-reduced PLTs, 77 and 56 PASII PLTs, and six and five plasma PLT transfusions, respectively, using a random effects model. RESULTS: Volume-reduced PLTs were transfused at twice the dose in one-fifth the volume of PASII and plasma PLTs. The early posttransfusion count increment was higher for volume-reduced PLTs at 111 * 10(9)/L (95% confidence interval [CI], 86-135) compared to PASII PLTs at 62 * 10(9)/L (95% CI, 40-84; p = 0.000) and plasma PLTs at 47 * 10(9)/L (95% CI, 14-79). The follow-up count increment was also higher for volume-reduced PLTs at 60 * 10(9)/L (95% CI, 19 100) compared to PASII PLTs at 38 * 10(9)/L (95% CI, -0.2 to 77; p = 0.082) and plasma PLTs at 4 * 10(9)/L (95% CI, -38 to 46). CONCLUSION: Neonates who received twice the PLT dose by volume-reduced PLTs had twice as high early and follow-up count increment showing similar efficacy of products. PMID- 23441722 TI - Treatment patterns with etanercept and adalimumab for psoriatic diseases in a real-world setting. AB - BACKGROUND: This study examined real-world etanercept and adalimumab treatment patterns in patients with psoriasis, psoriatic arthritis, or both. METHODS: This retrospective analysis utilized data from patients with psoriasis, psoriatic arthritis, or both from a large, US claims database. Outcome measures included persistence on index therapy; pauses (7-59 days) and gaps (>=60 days) in therapy; and rates of discontinuing, switching and restarting index therapy in nonpersistent patients. RESULTS: Of 4,453 patients, 2,534 initiated etanercept and 1,919 initiated adalimumab. In psoriasis patients (n = 2,775), 46.4% and 56.8% on etanercept and adalimumab, respectively, were persistent for >=12 months, 49.0% and 56.3% discontinued, 23.8% and 22.4% restarted and 14.9% and 11.3% switched index therapy within 12 months. In psoriatic arthritis patients (n = 1,197), 60.7% and 63.3% on etanercept and adalimumab, respectively, were persistent for >=12 months, 48.3% and 51.6% discontinued, 25.8% and 20.0% restarted and 16.5% and 17.9% switched index therapy. In patients with both (n = 481), 58.1% and 59.6% on etanercept and adalimumab, respectively, were persistent for >=12 months, 42.7% and 63.2% discontinued, 24.3% and 12.6% restarted and 21.4% and 15.8% switched index therapy. CONCLUSIONS: Treatment modifications were common in patients with psoriasis, psoriatic arthritis, or both within 12 months of initiating etanercept or adalimumab. PMID- 23441723 TI - Synthesis of silver nanoparticles confined in hierarchically porous monolithic silica: a new function in aromatic hydrocarbon separations. AB - Silver nanoparticles (Ag NPs) have been homogeneously introduced into hierarchically porous monolithic silica columns with well-defined macropores and SBA-15-type hexagonally ordered mesopores by using ethanol as the mild reductant. Within the cylindrical silica mesopores treated with aminopropyl groups as the host, monocrystalline Ag NPs and nanorods are obtained after being treated in silver nitrate/ethanol solution at room temperature for different durations of reducing time. The loading of Ag NPs in the monolith can be increased to 33 wt % by the repetitive treatment, which also led to the formation of polycrystalline Ag nanorods in the mesopores. Although the bare silica column cannot separate aromatic hydrocarbons, good separation of those molecules by noncharged Ag NPs confined in the porous structure of the monolith has been for the first time demonstrated with the Ag NP-embedded silica column. The NP-embedded monolithic silica would be a powerful separation tool for hydrocarbons with different number, position, and configuration of unsaturated bonds. PMID- 23441724 TI - Computed tomographic and radiographic characteristics of aortic lesions in 42 dogs with spirocercosis. AB - Spirocerca lupi is a common cause of vomiting, regurgitation, and sudden death in dogs that live in tropical or subtropical regions. Sudden death due to aortic rupture may occur with no preceding clinical signs. The purpose of this prospective study was to compare radiographic and computed tomographic (CT) characteristics of aortic lesions in a cohort of 42 dogs with endoscopically confirmed spirocercosis. Dorsoventral and right lateral recumbent thoracic radiographic findings were compared with pre- and postcontrast thoracic CT findings. Aortic mineralization was detected using CT in 18/42 dogs (43%). Three dogs had faint diffuse aortic wall mineralization. Using CT as the reference standard, radiographs had a sensitivity and specificity of 6% and 96%, respectively, for detecting aortic mineralization. A total of 20 aortic aneurysms were detected using CT in 15/42 dogs (36%). Using CT as the reference standard, radiographs had a sensitivity and specificity of 86% and 56%, respectively, for detecting aortic aneurysms. Respiratory motion, aortic displacement by esophageal masses and Spirocerca nodules adjacent to the aorta mimicked aneurysm formation on radiographs. Aortic thrombi were seen in two dogs in postcontrast CT images. Findings from this study indicated that aortic mineralization and aneurysm formation are common in dogs with spirocercosis. Findings also supported the use of pre- and postcontrast CT as effective methods for detecting and characterizing these lesions. PMID- 23441725 TI - Over-expression and potential role of cyclophilin A in human periodontitis. AB - BACKGROUND AND OBJECTIVE: We previously demostrated that EMMPRIN participates in the periodontitis and its interaction with Cyclophilin A possibly exists in animal periodontitis models. This study is aimed to address the expression and potential role of cyclophilin A (CypA) in human periodontitis. MATERIAL AND METHODS: Gingival tissues and peripheral blood were collected from patients with moderate to severe periodontitis or from healthy donors. Western blotting and immunohistochemistry were performed to detect the expression and distribution of CypA in the gingival tissues. Peripheral blood mononuclear cells (PBMCs) and neutrophils were isolated from the peripheral blood by Ficoll-Paque density gradient centrifugation. Chemotaxis assays were applied to evaluate the effects of different concentrations of CypA (100, 300 and 500 ng/mL) on the migration of PBMCs and neutrophils. Supernatants of human THP-1 cells were collected after treatment with 200 ng/mL of CypA for different periods of time (1, 3, 6, 12 and 24 h) to detect the levels of interleukin (IL)-1beta, IL-8 and tumor necrosis factor alpha (TNF-alpha) by ELISA. RESULTS: Western blot analyses revealed an increase of CypA expression in inflamed gingival tissues compared with healthy tissues. Immunohistochemistry identified that the over-expressed CypA was localized in the infiltrating cells and/or in the extracellular matrix in the inflamed gingival connective tissues. The positive infiltrating cells contained mononuclear cells and lobulated-nuclei neutrophils. Chemotactic assays showed that 300 ng/mL of CypA apparently facilitated the chemotaxis of PBMCs/neutrophils from healthy donors, compared with the no-treatment control (p < 0.01 for PBMCs, p < 0.05 for neutrophils), whereas 100 and 500 ng/mL of CypA only weakly enhanced the chemotaxis of PBMCs/neutrophils (p > 0.05 for PBMCs/neutrophils, not significant). The PBMCs/neutrophils from patients with periodontitis exhibited a stronger ability to migrate when stimulated with 300 ng/mL of CypA than did PBMCs/neutrophils from healthy donors (p < 0.05 for PBMCs, p < 0.01 for neutrophils). ELISA revealed that the level of TNF-alpha secreted by THP-1 cells was elevated after treatment with 200 ng/mL of CypA for 12 h compared with the no treatment 0-h control (p < 0.05). The IL-8 level was sharply raised after 3 h of stimulation with 200 ng/mL of CypA (p < 0.01 compared with 0 h), but no significant change was observed at the other time points (p > 0.05). There was no statistical difference at any of the treatment time points for the secretion of IL-1beta (p > 0.05 for 1, 3, 6, 12 and 24 h compared with 0 h). CONCLUSIONS: CypA participates in the pathogenesis of human periodontitis. It may be involved in the inflammatory response of periodontal tissues through inducing the chemotaxis of PBMCs/neutrophils and the secretion of TNF-alpha/IL-8. PMID- 23441726 TI - A multivariable model for predicting the frictional behaviour and hydration of the human skin. AB - BACKGROUND: The frictional characteristics of skin-object interactions are important when handling objects, in the assessment of perception and comfort of products and materials and in the origins and prevention of skin injuries. In this study, based on statistical methods, a quantitative model is developed that describes the friction behaviour of human skin as a function of the subject characteristics, contact conditions, the properties of the counter material as well as environmental conditions. AIMS: Although the frictional behaviour of human skin is a multivariable problem, in literature the variables that are associated with skin friction have been studied using univariable methods. In this work, multivariable models for the static and dynamic coefficients of friction as well as for the hydration of the skin are presented. MATERIALS & METHODS: A total of 634 skin-friction measurements were performed using a recently developed tribometer. Using a statistical analysis, previously defined potential influential variables were linked to the static and dynamic coefficient of friction and to the hydration of the skin, resulting in three predictive quantitative models that descibe the friction behaviour and the hydration of human skin respectively. RESULTS AND DISCUSSION: Increased dynamic coefficients of friction were obtained from older subjects, on the index finger, with materials with a higher surface energy at higher room temperatures, whereas lower dynamic coefficients of friction were obtained at lower skin temperatures, on the temple with rougher contact materials. The static coefficient of friction increased with higher skin hydration, increasing age, on the index finger, with materials with a higher surface energy and at higher ambient temperatures. The hydration of the skin was associated with the skin temperature, anatomical location, presence of hair on the skin and the relative air humidity. CONCLUSION: Predictive models have been derived for the static and dynamic coefficient of friction using a multivariable approach. These two coefficients of friction show a strong correlation. Consequently the two multivariable models resemble, with the static coefficient of friction being on average 18% lower than the dynamic coefficient of friction. The multivariable models in this study can be used to describe the data set that was the basis for this study. Care should be taken when generalising these results. PMID- 23441728 TI - Regional air quality impacts of increased natural gas production and use in Texas. AB - Natural gas use in electricity generation in Texas was estimated, for gas prices ranging from $1.89 to $7.74 per MMBTU, using an optimal power flow model. Hourly estimates of electricity generation, for individual electricity generation units, from the model were used to estimate spatially resolved hourly emissions from electricity generation. Emissions from natural gas production activities in the Barnett Shale region were also estimated, with emissions scaled up or down to match demand in electricity generation as natural gas prices changed. As natural gas use increased, emissions decreased from electricity generation and increased from natural gas production. Overall, NOx and SO2 emissions decreased, while VOC emissions increased as natural gas use increased. To assess the effects of these changes in emissions on ozone and particulate matter concentrations, spatially and temporally resolved emissions were used in a month-long photochemical modeling episode. Over the month-long photochemical modeling episode, decreases in natural gas prices typical of those experienced from 2006 to 2012 led to net regional decreases in ozone (0.2-0.7 ppb) and fine particulate matter (PM) (0.1 0.7 MUg/m(3)). Changes in PM were predominantly due to changes in regional PM sulfate formation. Changes in regional PM and ozone formation are primarily due to decreases in emissions from electricity generation. Increases in emissions from increased natural gas production were offset by decreasing emissions from electricity generation for all the scenarios considered. PMID- 23441729 TI - Disciplinary processes and the management of poor performance among UK nurses: bad apple or systemic failure? A scoping study. AB - The rise of managerialism within healthcare systems has been noted globally. This paper uses the findings of a scoping study to investigate the management of poor performance among nurses and midwives in the United Kingdom within this context. The management of poor performance among clinicians in the NHS has been seen as a significant policy problem. There has been a profound shift in the distribution of power between professional and managerial groups in many health systems globally. We examined literature published between 2000 and 10 to explore aspects of poor performance and its management. We used Web of Science, CINAHL, MEDLINE, British Nursing Index, HMIC, Cochrane Library and PubMed. Empirical data are limited but indicate that nurses and midwives are the clinical groups most likely to be suspended and that poor performance is often represented as an individual deficit. A focus on the individual as a source of trouble can serve as a distraction from more complex systematic problems. PMID- 23441731 TI - Energetics of nonbonded ortho interactions in alkylbenzenes. AB - The gas-phase enthalpies of formation for a set of ortho-substituted alkylbenzenes were obtained from CCSD(T*)-F12 and W1-F12 calculations. Most values are in keeping with available experimental data. The gas-phase enthalpies of formation of 1-ethyl-2-propylbenzene, 1-ethyl-2-isopropylbenzene, 1,2 diisopropylbenzene, 1,2,4-triethylbenzene, and 1,2,4,5-tetraethylbenzene, for which no experimental data are available, were determined as -46.0, -46.8, -68.7, -76.9, and -116.8 kJ mol(-1), respectively (estimated error bar +/-4 kJ mol(-1)). The whole set of experimental and theoretical values are in good agreement with the estimates obtained using the extended Laidler bond additivity (ELBA) method. This agreement supports the approximation used in ELBA that interactions between ortho alkyl groups (other than tertiary alkyl groups) have roughly the same magnitude as a methyl-methyl interaction. PMID- 23441732 TI - Hybrid or reverse hybrid for total hip arthroplasty? PMID- 23441730 TI - The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system. AB - The compound BAY 11-7082 inhibits IkappaBalpha [inhibitor of NF-kappaB (nuclear factor kappaB)alpha] phosphorylation in cells and has been used to implicate the canonical IKKs (IkappaB kinases) and NF-kappaB in >350 publications. In the present study we report that BAY 11-7082 does not inhibit the IKKs, but suppresses their activation in LPS (lipopolysaccharide)-stimulated RAW macrophages and IL (interleukin)-1-stimulated IL-1R (IL-1 receptor) HEK (human embryonic kidney)-293 cells. BAY 11-7082 exerts these effects by inactivating the E2-conjugating enzymes Ubc (ubiquitin conjugating) 13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulfinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1alpha (hypoxia-inducible factor 1alpha) from proteasomal degradation, suggesting that it inhibits the proteasome. The results of the present study indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B-cell lymphoma and leukaemic T cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components of the ubiquitin system and not by inhibiting NF-kappaB. PMID- 23441733 TI - Is quantitative magnetic resonance imaging valuable in the assessment of trabecular bone structure in osteoporosis? AB - OBJECTIVES: This study aims to evaluate the value of quantitative magnetic resonance imaging in the assessment of bone trabeculae in osteoporosis by comparing the results with dual-energy X-ray (DXA) absorptiometry. PATIENTS AND METHODS: The study consisted of 85 postmenopausal women (mean age 57.2 years; range 43 to 83 years) underwent both DXA absorptiometry and lumbar quantitative magnetic resonance imaging. T2 and T2* values were calculated by magnetic resonance imaging and the results were compared with bone mineral density. RESULTS: According to bone mineral density t-scores; there were 32 normal, 30 osteopenic, and 23 osteoporotic patients. T2 values of L1- L4 were different in normal with osteoporotic, and the osteopenic with osteoporotic groups. There were increased T2 values with reducing t-scores. Comparing the normal and osteopenic groups, no statistical difference was found in T2 measurements of lumbar vertebrae, except L4. T2* values of L1-L4 vertebrae were not statistically different between the study groups. CONCLUSION: T2 measurements of lumbar vertebra on quantitative magnetic resonance imaging may be useful in evaluation of bone trabeculae in osteoporosis, and may also be helpful in differentiation of osteoporotic from normal, and osteopenic from osteoporotic patients. PMID- 23441734 TI - [Investigation of body weight ratios on joint structures at different knee flexion angles in patients with unilateral knee arthroplasty]. AB - OBJECTIVES: The study aims to determine body weight ratios between extremities in patients with unilateral total knee arthroplasty (TKA) at 12 months postoperatively at the static-standing position at 30, 60 and 90 degrees of knee flexion. PATIENTS AND METHODS: The study included 52 female patients (mean age 65.6+/-10.6 years; range 40 to 83 years) who underwent unilateral primary TKA. The force-platform was used to calculate the body-weight ratios of the patients. Body weight ratios on the operated and non-operated limbs of the unilateral TKA patients were examined at standing-static position at 30, 60 and 90 degrees of knee flexion on the force-platform according to their age and body mass index (BMI). The pain levels of the patients were evaluated using the visual analog scale. RESULTS: It was found that unilateral TKA patients placed their body weight on the non-operated limb more at the standing-static position, and 30, 60 and 90 degrees of knee flexion at 12 months postoperatively (p<0.05). It was also found that as the knee flexion degree increased with age, so did TKA patients place their body weight on the nonoperated limb more (p<0.05), and that BMI had no effect on the load distribution difference over the two extremities (p>0.05). CONCLUSION: During the postoperative period, load asymmetry between the two extremities in patients with unilateral TKA remains the same due to advancing age. This accelerates the osteoarthritis process on the non-operated knee. It is concluded that the age factor should be taken into account while planning physiotherapy and rehabilitation programs for unilateral TKA patients and knee exercise programs aiming to place load over the operated limb should be arranged. PMID- 23441735 TI - Carpal tunnel syndrome in manual tea harvesters. AB - OBJECTIVES: This study aims to present the physiopathological and surgical aspects of carpal tunnel syndrome (CTS) related to manual tea harvesting based on nerve conduction studies and clinical scoring systems. PATIENTS AND METHODS: Clinical and neurophysiological scores as well as clinical and occupational variables were statistically analyzed using Boston questionnaire, modified criteria of Italian CTS study group, and modified neurophysiologic grading system of Italian CTS study group in 56 agricultural laborers who underwent surgery due to severe CTS. RESULTS: A statistically significant correlation was found among the clinical stages of the patients and age, working duration and duration of symptoms. There was a statistically significant relationship among neurophysiologic grades of the CTS in patients and the duration of symptoms and functional outcomes before and after surgery. CONCLUSION: We concluded that manual tea harvesting might be an occupational risk factor for work-related CTS development. Surgical treatment of CTS among manual tea harvesters revealed satisfactory results. PMID- 23441727 TI - Mass spectrometry of structurally modified DNA. PMID- 23441736 TI - [Radiation synovectomy therapy combined with surgical synovectomy in chronic nonspecific synovitis of the knee joint]. AB - OBJECTIVES: This study aims to investigate the effectiveness of the radiation synovectomy (RS) procedure combined with the surgical synovectomy in the treatment of chronic nonspecific synovitis, which are resistant to medical treatment. PATIENTS AND METHODS: Between March 2004 and October 2009, 17 knees of the 17 patients (15 males, 2 females; mean age 42.5 years; range 27 to 70 years) who underwent synovectomy surgery, followed by RS procedure with the 90Y at six weeks were included. At the end of a mean 48.7 months (range; 15-126 months) follow-up period, the Lysholm Knee Scale scores were used for functional assessment before and after RS procedure. The nocturnal pain, resting pain, activity pain and effusion were evaluated with the visual analog scale. The patient satisfaction was recorded as excellent, very good, good and poor. RESULTS: At the end of the follow-up period, all patients had satisfaction scores of excellent and very good. There was a statistically significant difference between all assessment scores before and after treatment (p<0.05). It was found that none of the cases had radionuclide leakage from the joint in their control scintigraphy following RS procedure. No significant complication was seen except for deep vein thrombosis developed in one case. CONCLUSION: Our study results showed that RS procedure combined with the surgical synovectomy is an effective and safe treatment method for the treatment of cases of chronic nonspecific synovitis which recurs despite medical treatment. PMID- 23441737 TI - [Unlocked using of interlocked intramedullary nails in tibial shaft fractures]. AB - OBJECTIVES: This study aims to investigate unlocked using of locked intramedullary nails in tibial shaft fractures and to compare the results to those of locked nails. PATIENTS AND METHODS: Between December 2006 and July 2011, medical records of a total of 30 patients who underwent locked (n=15) or unlocked intramedullary nails (n=15) due to tibial shaft fracture in our clinic were retrospectively analyzed. Gender distribution, mean age, injury mechanism, location and morphology of the fracture, type of open fracture and time of discharged from hospital were similar in both groups. Radiological and functional evaluation was carried out according to Johner-Wruhs criteria. RESULTS: Excellent and good functional results were obtained in unlocked group of all patients, while there were 11 excellent and good, four fair and poor results in locked group. Dynamization was performed on four patients in this group. It was similar in terms of union between the groups. There was no statistically significant difference in functional results. CONCLUSION: We concluded that unlocked nailing would be taken place in practice of traumatologic surgery at appropriate cases, although primary treatment method is locked intramedullary nailing in tibial shaft fractures. PMID- 23441738 TI - Does spinal anesthesia increase the pain and anxiety after total knee arthroplasty? a randomized prospective study. AB - OBJECTIVES: In this study, postoperative pain and anxiety level of the patients who were scheduled for spinal anesthesia (SA) and remained awake during the operation and patients who were scheduled for general anesthesia (GA) and were asleep during the operation were assessed. PATIENTS AND METHODS: Thirty-six patients who underwent total knee arthroplasty in our clinic were randomly divided into two groups. The first group (SA group) was given spinal anesthesia during operation (heavy marcaine), while the second group (GA group) underwent general anesthesia (propofol + nitric oxide). Hospital anxiety-depression (HAD) scores and visual analog scale (VAS) scores of the patients were calculated postoperatively. The patients were asked to score anxiety by the physicians. RESULTS: The mean postoperative HAD score was 24.68 in GA group, and 29.62 in SA group (p>0.05). The physicians score for patients' anxiety after surgery was 1.05 in GA group, and 1.69 in SA group (p<0.05). The mean postoperative VAS of the patients was 8.42 in GA group, and 8.87 in SA group (p>0.05). No statistically significant differences were found between the SA group and GA group in terms of HAD scores. No significant differences were found between the mean postoperative VAS scores of the groups. A statistically significant difference was found between the two groups for the physician's score for patients' postoperative anxiety. CONCLUSION: Our study results showed that total knee arthroplasty under spinal anesthesia was not associated with mood changes in patients and no increase in postoperative pain was seen. PMID- 23441739 TI - Biomechanical comparison of intact lumbar lamb spine and endoscopic discectomized lamb spine. AB - OBJECTIVES: This study aims to perform a biomechanical comparison of changes on motion segments after minimally invasive percutaneous endoscopically discectomized and intact spine and to investigate the effects of endoscopic discectomy on the lumbar spine of the lamb. MATERIALS AND METHODS: Ten fresh frozen lamb spines were used in this study. Percutaneous endoscopic discectomy was performed on each spine at L4-L5 level. The biomechanical tests for both intact spine and endoscopically discectomized spine were performed by using axial compression testing machine. The axial compression was applied to all specimens with a loading speed of 5 mm/min. 8400 N/mm moment was applied to each specimen to achieve flexion and extension motions, right and left bending through a specially designed fixture. RESULTS: In axial compression and flexion tests, the specimens were more stable based on displacement values. The displacement values of discected spines were closer to the values of intact specimens. Comparing both groups, only displacement values of the left-bending anteroposterior test were significant (p<=0.05). CONCLUSION: Percutaneous transforaminal endoscopic discectomy (PTED) has no biomechanical and clinical disadvantages. Endoscopic discectomy has also no stability disadvantages. Only anteroposterior displacement values of left bending test were statistically significant. We consider that the reason for such results were due to the fact that PTED was performed on the left side of all specimens. PMID- 23441740 TI - Do periarticular dense bone islands cause cartilage destruction? PMID- 23441741 TI - Lower limb salvage surgery using Ilizarov circular external frame for a landmine injury about the knee. AB - Limb salvage for severe trauma has been replaced amputation as the primary treatment in many trauma centers. However, the long-term outcomes after limb reconstruction or amputation have not been fully evaluated. In this report, we present the treatment results of limb salvage surgery using Ilizarov external circular frame in a male case who had a-22-cm bone loss on the left distal femur and left proximal tibia and large soft tissue defect around the knee due to stepping on a landmine with his knee. The decision to amputate a severely injured limb, being irreversible, is challenging and significantly affects the body image and the patient. Extremity salvage surgery should be considered initially when evaluating patients with high-energy injured limbs at high risk for amputation. PMID- 23441742 TI - A new syndrome mimicking Jaffe-Campanacci syndrome: a case report. AB - Jaffe-Campanacci syndrome (JCS) is a well-known condition with its clinical and radiological characteristics. Extraskeletal congenital anomalies of this syndrome include cafe-au-lait spots, mental retardation, cardiovascular abnormalities, ocular deformities, hypogonadism or cryptorchidism. Multiple non-ossifying fibromas are also characteristic bone lesions. In this article, we present a new syndrome mimicking JCS, which is characterized by a simple bone cyst and extraskeletal lesions. PMID- 23441743 TI - Solitary osteochondroma of ischial ramus causing sciatic nerve compression. AB - We present a 25-year-old male case of osteochondroma originating from ischial ramus which causes sciatica. The pelvic involvement is rare. Iliac crest of the pelvis is often involved. Ischial ramus involvement is extremely rare. In this article, we presented a rare case of ischial ramus involvement that misleading the physician to L4-L5-S1 radiculopathy. PMID- 23441744 TI - [Treatment of a pregnant patient with bilateral traumatic bimalleolar ankle fracture: a case report]. AB - The incidence of ankle fractures has been increasing among all fractures due to skeletal traumas. Bimalleolar fractures account for 25% of all ankle fractures. Bilateral traumatic bimalleolar ankle fracture is a very rare condition. In such a clinical presentation, pregnancy managed with cesarean procedure complicates the situation due to increased risk of venous thromboembolism and fatal pulmonary embolism. In this article, we report a 25-year-old female case within an eight month pregnancy period who had bilateral bimalleolar ankle fracture due to an accident in a motor-vehicle and the clinical and radiological results of surgical treatment were discussed in the light of current literature data. PMID- 23441745 TI - Solitary spinous process metastasis: a case report. AB - Vertebral column is a common site for bony metastases in patients with systemic malignancy. Patients with metastatic spinal tumors usually present with pain. Some tumors are asymptomatic and can be detected during screening examinations. Magnetic resonance imaging (MRI) of the vertebral column with the panel of available imagining methods and the clinical findings should be used for the diagnosis of spinal metastasis. A 45-year-old man was admitted with low back pain. With a history of rectum surgery and radiotherapy, he was on chemotherapy for rectum adenocarcinoma. F18 sodium fluoride positron emission tomography scan which was performed three weeks ago showed no abnormalities other than the primary surgical site. Magnetic resonance imaging of the lumbar vertebrae spine revealed a lesion on the tip of L4 spinous process. Excisional biopsy of L4 spinous process was performed. Histologic examination revealed mucinous adenocarcinoma. He had no low back pain at two-months follow-up. We could not find any solitary spinous process metastasis reported in English literature. Patients with nonspecific spinal pain with a previous cancer history should be carefully evaluated for a spinal metastasis. Even a solitary spinous process lesion may turn out to be the initial manifestation of a spinal metastasis. PMID- 23441746 TI - Pharmacological treatment for infectious corneal ulcers. AB - INTRODUCTION: Cornea ulceration and infectious keratitis are leading causes of corneal morbidity and blindness. Infectious causes are among the most frequent and most severe. Management strategies for bacterial corneal ulcers have changed significantly over the last decades, however with a more limited progress in the treatment and management of nonbacterial, infectious ulcers. AREAS COVERED: This paper provides an overview of the current principles, strategies and treatment choices for infectious corneal ulcers in adults. EXPERT OPINION: Topical application with a broad-spectrum antimicrobial remains the preferred method for the pharmacological management of infectious corneal ulcers. Increasing reports of clinical failures and in vitro resistance to antibiotics to treat the most common infectious (bacterial) corneal ulcers are increasing concerns. New approaches for improvement in the pharmacological management of corneal ulcers should focus on strategies for a more rational and evidence-based use of current antimicrobials and development of products to modulate the host immune response and to neutralize microbial toxins and other immune modulators. PMID- 23441747 TI - Colossal absorption of molecules inside single terahertz nanoantennas. AB - Molecules have extremely small absorption cross sections in the terahertz range even under resonant conditions, which severely limit their detectability, often requiring tens of milligrams. We demonstrate that nanoantennas tailored for the terahertz range resolves the small molecular cross section problem. The extremely asymmetric electromagnetic environment inside the slot antenna, which finds the electric field being enhanced by thousand times with the magnetic field changed little, forces the molecular cross section to be enhanced by >10(3) accompanied by a colossal absorption coefficient of ~170,000 cm(-1). Tens of nanograms of small molecules such as 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) and lactose drop-cast over an area of 10 mm(2), with only tens of femtograms of molecules inside the single nanoslot, can readily be detected. Our work enables terahertz sensing of chemical and biological molecules in ultrasmall quantities. PMID- 23441748 TI - Enantioselective neuroprotective effects of Tacripyrine ITH122 against oxygen and glucose deprivation in rat hippocampal slices. PMID- 23441749 TI - Inhibition of interleukin-17-stimulated interleukin-6 and -8 production by cranberry components in human gingival fibroblasts and epithelial cells. AB - BACKGROUND AND OBJECTIVE: Gingival epithelial cells and fibroblasts participate in periodontal inflammation and destruction, producing interleukin (IL)-6, a regulator of osteoclastic bone resorption, and the neutrophil chemoattractant IL 8. IL-17, a product of T-helper 17 cells, may play a role in periodontitis by stimulating cytokine production by gingival cells. The cranberry (Vaccinium macrocarpon) is rich in polyphenols, particularly proanthocyanidins, which have antioxidant and other beneficial properties. Cranberry components inhibit pro inflammatory activities of lipopolysaccharide-stimulated human macrophages, gingival fibroblasts, and epithelial cells, but little is known of its effects on IL-17-stimulated cytokine production. The objectives were to determine the effects of IL-17 +/- cranberry components on IL-6 and IL-8 production by human gingival epithelial cells and fibroblasts. MATERIAL AND METHODS: Cranberry high molecular weight non-dialyzable material (NDM), which is rich in proanthocyanidins, was derived from cranberry juice. Human gingival epithelial cells and normal human gingival fibroblasts were incubated with NDM (5-50 MUg/mL), IL-17 (0.5-100 ng/mL), or NDM + IL-17 in serum-free medium for 6 d. IL-6 and IL-8 in culture supernatants were measured by ELISA. Membrane damage and viability were assessed by lactate dehydrogenase activity released into cell supernatants and activity of a mitochondrial enzyme, respectively. Data were analyzed using ANOVA and Scheffe's F procedure for post hoc comparisons. RESULTS: In both cell lines, IL-17 (>= ~5-10 ng/mL) significantly stimulated production of IL-6 (p < 0.005) and IL-8 (p < 0.03). Non-toxic levels of NDM inhibited constitutive IL-6 and IL-8 production by epithelial cells (p <= 0.01) and fibroblasts (p <= 0.03) as well as IL-17-stimulated cytokine production by epithelial cells [IL-6 (maximum ~80% inhibition; p <= 0.0001); IL-8 (maximum ~70% inhibition; p <= 0.03)] and fibroblasts [IL-6 (maximum ~90% inhibition; p <= 0.0001); IL-8 (maximum ~80% inhibition; p <= 0.008)]. CONCLUSION: Cranberry NDM inhibition of constitutive and IL-17-stimulated IL-6 and IL-8 production by gingival fibroblasts and epithelial cells suggests that cranberry components could be useful as a host modulatory therapeutic agent to prevent or treat periodontitis. PMID- 23441750 TI - Aberrant wound healing in the horse: naturally occurring conditions reminiscent of those observed in man. AB - Impaired wound healing represents an enormous clinical and financial problem for companion animals and humans alike. Unfortunately, most models used to study healing rely on rodents, which have significant differences in the healing and scarring process and rarely develop complications. In order to better simulate impaired healing, the model should strive to reproduce the natural processes of healing and delayed healing. Wounds on the limbs of horses display similarities to wounds in humans in their epithelialization/contraction ratio, genetic influence as well as dysregulated cytokine profile and the spontaneous development of fibroproliferative disorders. Veterinarians have access to advanced wound therapies that are often identical to those provided to human patients. Wound research in large animals has resulted in new wound models as well as a better understanding of the physiology, immunology, and local environmental impact on both normal and aberrant wound healing. One such model reproduces the naturally occurring fibroproliferative disorder of horses known as exuberant granulation tissue. Comparisons between the normally healing and impaired wounds provide insight into the repair process and can facilitate product development. A better understanding of the wound healing physiopathology based on clinically accurate animal models should lead to the development of novel therapies thereby improving outcomes in both human and veterinary patients. PMID- 23441751 TI - Diagnosis of the Cu and Se status of dairy cattle in New Zealand: how many samples are needed? AB - AIM: To determine the minimum number of samples required to obtain a robust estimate of the Cu and Se status of dairy herds, as assessed by determining liver Cu and serum Se concentrations. METHODS: Results were collated from analyses of samples of liver from 18 dairy herds and serum from 19 herds, for concentrations of Cu and Se, respectively. All herds were in either the Manawatu or Rangitikei regions of the North Island of New Zealand. Data were used to determine the required sample size for each herd; firstly to estimate the population mean with 90% confidence with a precision of 27.5 nmol/L for Se in serum, and 100 MUmol/kg fresh weight (FW) for Cu in liver; and secondly to ensure that the 90% CI of the sample mean did not include specified thresholds for concentrations of Se or Cu. RESULTS: For Se concentration in serum, the SD of each batch varied from 0.5-147 nmol/L, and for Cu concentration in liver, the SD varied from 173-829 MUmol/kg FW. For Se, the minimum sample size required to estimate the population mean to within 27.5 nmol/L with 90% confidence was >10 for 13/19 batches. For Cu, the minimum sample size required to estimate the population mean to within 100 MUmol/kg FW was >10 for 17/18 batches. When estimating required sample size based on 90% CI and a threshold value, the minimum sample size to confirm the population mean of Se was >140 nmol/L was four in 17/18 batches where the sample mean was>140 nmol/L. For concentrations of Cu in liver, <=8 samples would have been sufficient for a threshold of 45 MUmol/kg FW in 16/18 batches. For the 95 MUmol/kg threshold, the minimum required was 12. For the threshold of 300 MUmol/kg FW, 6/17 batches with a mean >300 MUmol/kg FW required <= 20 samples. CONCLUSIONS: From this dataset of 21 herds, the sample size recommendation for ensuring that the population mean of Se concentration was not below the marginal threshold was similar to previous recommendations. For Cu concentrations in liver, the estimated sample size recommendations for ensuring that the population mean was not below the marginal threshold was much larger than currently recommended. CLINICAL RELEVANCE: In dairy cattle, five to six blood samples per group should be taken to determine Se status, and to effectively monitor Cu status a minimum of 12 liver samples should be taken, preferably in the autumn. PMID- 23441752 TI - Age and gender differences in correlations of leisure-time, household, and work related physical activity with physical performance in older Japanese adults. AB - AIM: This study aimed to compare relationships of leisure-time, household, and work-related physical activity (PA) with physical performance by age and gender in older Japanese adults. METHODS: This cross-sectional study included 525 community-dwelling older adults (73.3 +/- 5.2 years) recruited in 2009-2011 in Kasama City, rural Japan. We used the Physical Activity Scale for the Elderly to assess PA variables. Physical performance was evaluated by 11 performance tests: grip strength, single-leg balance, functional reach, sit-and-reach, standing time from long sitting position, sit-to-stand, timed up and go, habitual walk, hand working, and simple and choice reaction times. RESULTS: After adjusting for potential confounders, leisure-time PA in young-old (<= 74 years) men correlated significantly with eight performance tests (absolute value of Spearman's partial rank correlation coefficient: r = 0.18-0.39), whereas in old-old (>= 75 years) men it correlated with three performance tests (r = 0.20-0.23). Although leisure time PA correlated with six performance tests (r = 0.19-0.22) in young-old women, there were no significant correlations between leisure-time PA and performance tests in old-old women. Household PA of young-old men (r = 0.20-0.23) and old-old women (r = 0.26-0.34) correlated with four performance tests. In old-old men and young-old women, no significant correlation was found between household PA and performance tests. Work-related PA did not relate significantly to any performance tests in any groups. CONCLUSION: This study showed that leisure-time PA is related to physical performance, especially in young-old men and women, and household PA is especially related in young-old men and old-old women. Our findings suggest that supporting strategies for maintaining physical functions would differ by gender and age. PMID- 23441753 TI - Loading and distribution of a model small molecule drug in poly(N isopropylacrylamide) brushes: a neutron reflectometry and AFM study. AB - The structure of a hydrated poly(N-isopropylacrylamide) brush loaded with 5 vol % Isoniazid is studied as a function of temperature using neutron reflectometry (NR) and atomic force microscopy (AFM). NR measurements show that Isoniazid increases the thickness of the brush before, during and after the polymer collapse, and it is retained inside the brush at all measured temperatures. The Isoniazid concentration in the expanded brush is ~14% higher than in the bulk solution, and the concentration nearly doubles in the collapsed polymer, suggesting stronger binding between Isoniazid and the polymer compared to water, even at temperatures below the lower critical solution temperature (LCST) where the polymer is hydrophilic. Typically, additives that bind strongly to the polymer backbone and increase the hydrophilicity of the polymer will delay the onset of the LCST, which is suggested by AFM and NR measurements. The extent of small-molecule loading and distribution throughout a thermo-responsive polymer brush, such as pNIPAAm, will have important consequences for applications such as drug delivery and gating. PMID- 23441754 TI - Laparoendoscopic single-site versus conventional transperitoneal laparoscopic pyeloplasty: a prospective randomized study. AB - OBJECTIVES: To evaluate the potential benefits of laparoendoscopic single-site pyeloplasty over conventional laparoscopic pyeloplasty. METHODS: Between October 2009 and January 2012, 39 patients were enrolled in a prospective study and randomized to undergo a laparoendoscopic single-site pyeloplasty (n = 19) or conventional laparoscopic pyeloplasty (n = 20). The outcomes in the two groups were compared by using Mann-Whitney U-test and chi(2) -test, and considering a P value less than 0.05 as statistically significant. RESULTS: There was no difference in blood loss (55.67 +/- 6.71 vs 45.84 +/- 5.22 mL, P = 0.60), transfusion rates (0% for both) and hospitalization time (2.12 +/- 0.23 vs 2.06 +/- 0.34 days, P = 0.72) between the laparoendoscopic single-site pyeloplasty and conventional laparoscopic pyeloplasty groups. The time to return to normal activities was shorter (8.65 +/- 1.25 vs 11.53 +/- 1.28 days, P = 0.01), and median operative time (195.21 +/- 12.15 vs 145.62 +/- 15.34 min, P = 0.001) was longer in the laparoendoscopic single-site pyeloplasty group compared with the conventional laparoscopic pyeloplasty group. No significant intraoperative or postoperative complications occurred in either group. Compared with conventional laparoscopic pyeloplasty, laparoendoscopic single-site pyeloplasty yielded better cosmetic results and patient satisfaction. The mean follow-up period was 19.7 months (4-28 months). The success rate was 95% in both the groups. Both the visual analog scale and the postoperative use of analgesics were significantly lower in patients who underwent laparoendoscopic single-site pyeloplasty. CONCLUSIONS: Our findings suggest that laparoendoscopic single-site pyeloplasty can offer faster recovery and higher patient satisfaction than conventional laparoscopic pyeloplasty. Thus, this novel technique promises to become the treatment of choice in minimally-invasive management of ureteropelvic junction obstruction. PMID- 23441755 TI - Low prostaglandin E2 and cyclooxygenase expression in nasal mucosa fibroblasts of aspirin-intolerant asthmatics. AB - BACKGROUND AND OBJECTIVE: Anomalies in the regulation of cyclooxygenase (COX)-1 and -2 have been described in nasal polyps of aspirin-induced asthma (AIA). Whether these anomalies are specific to nasal polyps or affect all the nasal mucosa (NM) of upper airways is still unclear. The objective of this study was to compare the COX pathway in NM of AIA patients with the NM of control subjects. METHODS: Fibroblasts were isolated from NM of five AIA patients (AIA-NM) and five control subjects (control-NM). Cells were treated with 10 ng/mL interleukin (IL) 1beta for up to 72 h. Prostaglandin E2 (PGE2 ) production was measured by enzyme linked immunosorbent assay (ELISA), expression of COX-1 protein by Western blot and COX-2 protein by ELISA, Western blot and immunofluorescence techniques. RESULTS: IL-1beta increased PGE2 production and COX-1 protein expression in control-NM fibroblasts, but no changes were found in AIA-NM. IL-1beta provoked a significant time-dependent increase in COX-2 protein expression in control-NM fibroblasts but had a very mild effect on COX-2 protein expression in AIA-NM. CONCLUSIONS: Our data suggest that abnormalities in the COX pathway are not a phenomenon exclusive to nasal-polyp mucosa as they are also present in all the NM of AIA patients. These anomalies may be involved in the pathogenesis of airway inflammation and non-steroidal anti-inflammatory drug intolerance in asthma patients with chronic rhinosinusitis and nasal polyposis. PMID- 23441757 TI - On the appropriate use and interpretation of animal models in transfusion medicine research. PMID- 23441758 TI - Influence of halogen bonding interaction on supramolecular assembly of coordination compounds; head-to-tail N...X synthon repetitivity. AB - In this study, N-(3-halophenyl)-2-pyrazinecarboxamide ligands, L(3-F), L(3-Cl), L(3-Br), and L(3-I), carrying a different halogen atom on the phenyl meta position and N-phenyl-2-pyrazinecarboxamide ligand, L(H), have been employed for the synthesis of 12 mercury(II) complexes, [HgCl2(L(H))]n, 1, [HgCl2(L(3-Cl))]n, 2, [Hg2Cl4(L(3-Br))2], 3, [Hg2Cl4(L(3-I))2], 4, [Hg2Br4(L(H))2], 5, [HgBr2(L(3 F))], 6, [HgBr2(L(3-Cl))], 7, [HgBr2(L(3-Br))], 8, [HgBr2(L(3-I))], 9, [Hg2I4(L(H))2], 10, [HgI2(L(3-Br))], 11, and [HgI2(L(3-I))]n, 12. Interestingly, structural analysis clearly shows that, by the replacing of coordinated anions from chloride with bromide and iodide in each series containing the same ligand, the coordination geometry and structural motif of the resulting compounds have been dramatically affected. One of the common features in the crystal structures of these complexes is that there is a strong tendency to form halogen bonding synthons between adjacent halophenyl and pyrazine rings. The influence of these halogen bonding interactions on the supramolecular assemblies has been discussed with the help of geometrical analysis and theoretical calculations. The X...N halogen bonding distances are 2.5-9.4% shorter than the sum of the van der Waals radii of nitrogen and halogen atoms. Theoretical methods also show the halogen bonding energies within a range of -27.86 to -46.15 kJ.mol(-1). In all complexes synthesized here, the pyrazine ring is coordinated to the mercury(II) ion through the N atom syn to the carbonyl. Therefore, the second common feature of the crystal structures for complexes studied here is the selectivity of the metal ion coordination site. The halogen bond synthon repetitivity across these compounds and selectivity in the mercury(II) ion coordination site further point to application in the coordination crystal engineering research field. PMID- 23441756 TI - Effect of the TRPV1 antagonist SB-705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig. AB - BACKGROUND AND PURPOSE: Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis. EXPERIMENTAL APPROACH: The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea pig model of rhinitis was developed using intranasal challenge of capsaicin and hypertonic saline to elicit nasal secretory parasympathetic reflex responses, quantified using MRI. The inhibitory effect of SB-705498, duration of action and potency comparing oral versus intranasal route of administration were examined. KEY RESULTS: SB-705498 concentration-dependently inhibited capsaicin-induced currents in isolated trigeminal ganglion cells (pIC50 7.2). In vivo, capsaicin ipsilateral nasal challenge (0.03-1 mM) elicited concentration-dependent increases in contralateral intranasal fluid secretion. Ten per cent hypertonic saline initiated a similar response. Atropine inhibited responses to either challenge. SB-705498 inhibited capsaicin-induced responses by ~50% at 10 mg.kg-1 (oral), non-micronized 10 mg.mL-1 or 1 mg.mL-1 micronized SB 705498 (intranasal) suspension. Ten milligram per millilitre intranasal SB 705498, dosed 24 h prior to capsaicin challenge produced a 52% reduction in secretory response. SB-705498 (10 mg.mL-1, intranasal) inhibited 10% hypertonic saline responses by 70%. CONCLUSIONS AND IMPLICATIONS: The paper reports the development of a guinea pig model of rhinitis. SB-705498 inhibits capsaicin induced trigeminal currents and capsaicin-induced contralateral nasal secretions via oral and intranasal routes; efficacy was optimized using particle-reduced SB 705498. We propose that TRPV1 is pivotal in initiating symptoms of rhinitis. PMID- 23441759 TI - Analysis of the fibroblast growth factor receptor (FGFR) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network. AB - The evolution of the fibroblast growth factor (FGF)-FGF receptor (FGFR) signalling system has closely followed that of multicellular organisms. The abilities of nine FGFs (FGF-1 to FGF-9; examples of FGF subfamilies 1, 4, 7, 8, and 9) and seven FGFRs or isoforms (FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4) to support signalling in the presence of heparin, a proxy for the cellular heparan sulfate coreceptor, were assembled into a network. A connection between two FGFRs was defined as their mutual ability to signal with a particular FGF. The network contained a core of four receptors (FGFR1c, FGFR2c, FGFR3c, and FGFR4) with complete connectivity and high redundancy. Analysis of the wider network indicated that neither FGF-3 nor FGF-7 was well connected to this core of four receptors, and that divergence of a precursor of FGF subgroups 1, 4 and 9 from FGF subgroup 8 may have allowed expansion from a three-member FGFR core signalling system to the four-member core network. This increases by four-fold the number of possible signalling combinations. Synchrotron radiation CD spectra of the FGFs with heparin revealed no overall common structural change, suggesting the existence of distinct heparin-binding sites throughout the FGFs. The approach provides a potential method of identifying agents capable of influencing particular FGF-FGFR combinations, or areas of the signalling network, for experimental or therapeutic purposes. PMID- 23441760 TI - Monoclonal antibodies in gastrointestinal cancers. AB - INTRODUCTION: Among gastrointestinal cancers, colorectal and gastric neoplasms are the most frequent. The development of new targeted drugs improved the efficacy of systemic therapy in advanced stages of those malignancies. AREAS COVERED: This review highlights the main biological processes implicated in gastrointestinal cancer development and progression, such as angiogenesis and epidermal growth factor receptor (EGFR) signaling pathway. On these bases, anti EGFR and anti-vascular endothelial growth factor (VEGF) monoclonal antibodies in colorectal and gastric cancer are discussed. Data about further monoclonal antibodies in development are also reported. EXPERT OPINION: The use of monoclonal antibodies in colorectal and gastric cancers showed the best outcomes when combined with chemotherapy, even though single agent anti-EGFR antibodies seem active in particular setting of metastatic colorectal cancer (CRC) patients. It is not well defined whether the addition of anti-VEGF and anti-EGFR to chemotherapy could improve outcome in those patients susceptible to CRC-related metastases resection. Little and conflicting data are available about the role of these drugs in adjuvant setting. Tests are available to select patients with higher probability to get benefit from these treatments. Further biomarkers need to be evaluated to improve this selection and achieve "tailorization" of systemic therapy. PMID- 23441762 TI - Comparison of effects of 5 and 10 mg oral desloratadine and levocetirizine on histamine-induced wheal and flare response in healthy volunteers. AB - BACKGROUND: Levocetirizine and desloratadine are mostly used as H1-antihistamines in the treatment of allergic disease in 5 and 10 mg doses. OBJECTIVE: In this study, the efficacy of single oral dosages of 5 and 10 mg desloratadine and levocetirizine were compared by using histamine-induced wheal and flare reactions. METHODS: Eighty healthy volunteers were randomized for four double blinded treatment with desloratadine 5 and 10 mg and levocetirizine 5 and 10 mg. Wheal and flare responses were produced by histamine. Measurements were performed just before the ingestion of antihistamines (baseline) and afterward at 30, 60, 240 min and 24 h. The values obtained for each antihistamine were compared with baseline values. RESULTS: It was found that except the flare reactions at 30th min, levocetirizine 5 and 10 mg suppressed histamine-induced wheal and flare reactions more than desloratadine 5 and 10 mg did. There were not any significant differences between desloratadine 5 and 10 mg in all periods. Levocetirizine 10 mg suppressed wheal and flare reactions significantly more than levocetirizine 5 mg only at 24th h. CONCLUSION: In this study, it was observed that levocetirizine 5 and 10 mg had a higher activity than desloratadine 5 and 10 mg. PMID- 23441764 TI - It bites the heart or does it not? PMID- 23441761 TI - Enzalutamide for the treatment of prostate cancer. AB - INTRODUCTION: The FDA approval of docetaxel for metastatic castration-resistant prostate cancer (mCRPC) in 2005 marked a major milestone, as it was the first approved agent for this disease that demonstrated a survival advantage in Phase III assessment of this disease. Since 2009, several other agents have been approved by FDA, including sipuleucel-T, abiraterone, cabazitaxel and enzalutamide . Enzalutamide, a potent antiandrogen that blocks nuclear translocation of the androgen receptor (AR), is the most recently approved of these agents. AREAS COVERED: The clinical development of enzalutamide is discussed, with attention given as to how this agent will most appropriately be used among a growing list of agents for mCRPC. A MEDLINE search was conducted to identify all relevant published datasets pertaining to the drug. In addition, relevant ASCO and ESMO abstracts were searched. EXPERT OPINION: The current role and sequencing of enzalutamide may change drastically based on studies such as PREVAIL (a Phase III pre-chemotherapy assessment of enzalutamide) and planned studies to assess relevant combinations (i.e., enzalutamide with abiraterone). Outside of clinical efficacy, issues such as drug cost may ultimately dictate our utilization of agents such as enzalutamide for mCPRC. Although the development of biomarkers to guide therapy for mCRPC is ideal, there are inherent challenges in establishing biomarker-driven treatment. PMID- 23441763 TI - Reply to 'missed citation?'. PMID- 23441766 TI - Belimumab: targeted therapy for lupus. AB - Systemic lupus erythematosus (SLE), a complex autoimmune disease with multisystem involvement, is characterised by recurring flares and remissions throughout the course of illness. The agents currently being used for management include corticosteroids, antimalarials and various immunosuppressants. Belimumab, a B lymphocyte stimulator (BLyS) inhibitor has been recently approved for the treatment of SLE. This review aims to discuss the role of belimumab in the treatment of SLE and the trials leading to its FDA approval. Belimumab demonstrated high degree of activity in patients with autoantibody-positive active SLE disease on a stable treatment regimen. There was a significantly greater response compared to placebo as assessed with the SLE Responder Index (SRI) in two randomized, double-blind, phase III trials (BLISS-52 and BLISS-76). The treatment was well tolerated. Additional studies are required to evaluate belimumab in special populations and assess its long-term safety. This therapy could change the focus of management from symptomatic treatment to targeting an important step in the disease pathogenesis. It could enable development of treatment which could halt long-term progression, minimize target organ damage and thus provide a better quality of life for these patients. PMID- 23441767 TI - Natural history and imaging of subtalar and midfoot joint disease in rheumatoid arthritis. AB - Foot involvement is not uncommon and occurs early in the disease course of rheumatoid arthritis (RA). Inflammation and ongoing synovitis of foot joints lead to joint destruction and instability, tendon dysfunction, and eventually collapse of the medial longitudinal arch and pes planovalgus that contributes to difficulty in walking and gait abnormalities. This article reviews foot-related problems in patients with RA, focusing on the prevalence, natural history and role of imaging in both diagnosis and management of midfoot and subtalar joint disease in RA. PMID- 23441769 TI - How safe is Celecoxib for Asian-Indian patients with rheumatic diseases? AB - BACKGROUND: Cyclo-oxygenase (COX)-2 inhibitors have been the target of severe criticism, more so following the withdrawal of Rofecoxib. Post-marketing surveillance of Celecoxib in Asian Indians, who are predisposed to premature athero-thrombotic events, has not been studied. AIMS: To study the adverse effects of Celecoxib and compare them with those of other non-steroidal anti inflammatory drugs (NSAIDs) in an Asian Indian cohort. MATERIALS AND METHODS: This is a retrospective chart review with convenience sampling of patients on NSAIDs (at least five tablets a week, for at least 3 months prior to the study), attending the Rheumatology clinic of a tertiary care institution in south India between June 2004 and November 2004. Those with pre-existing heart disease, hypertension, thrombo-embolic disease, peptic ulcer and patients on corticosteroids were excluded. All the recorded adverse events were noted and compared between the Celecoxib and non-selective NSAID users. Univariate analysis using Chi-square test was performed. RESULTS: Of the 1387 patients included, 915 were on Celecoxib. In the NSAID group, 204 had used multiple NSAIDs in sequence. Of the Celecoxib users, 164 had switched over to an NSAID during the study period. New onset of hypertension was significantly higher in the Celecoxib users as compared to non-selective NSAID users (3.06% vs. 1.27%, P = 0.04). However, those who had switched over to NSAIDs did not show this trend. NSAID users, on the other hand, had significant gastrointestinal (GI) toxicity (2.54% vs. 0.327%, P = 0.001). A significant number of Celecoxib users who switched over to NSAIDs also developed GI toxicity (6.1% vs. 1.21%, P = 0.018) over a shorter time span, as compared to the continuous NSAID users. Multiple NSAID users had higher adverse events (6.37% vs. 2.23%, P = 0.023) as compared to single NSAID users. CONCLUSION: Celecoxib significantly increased the incidence of new onset hypertension in this cohort of Indian patients with rheumatic diseases. No thromboembolic events were documented. PMID- 23441768 TI - Cardiovascular morbidity in rheumatoid arthritis patients in North Canterbury, New Zealand 1999-2008. AB - AIM: Cardiovascular disease is a substantial contributor to increased morbidity and mortality in rheumatoid arthritis (RA). The aim of this audit was to determine the rate of cardiovascular events in a cohort of newly diagnosed RA patients. METHOD: The inpatient clinical database from Christchurch Hospital, Christchurch, New Zealand, was searched using the International Classification of Diseases 9th Revision (ICD9) and 10 codes representing RA and cardiovascular disease between 1 January 1999 and 31 December 2008. Notes were reviewed with additional demographic and medication data sought. Outpatient data for RA patients was collated from the Rheumatology Department's letter database. RESULTS: Four hundred and six patients were identified with combined ICD9 or 10 codes for RA and ischemic heart disease, of whom 194 had a confirmed myocardial event. Of these, 34 were diagnosed with RA between January 1999 and December 2008 prior to their myocardial event. Kaplan-Meier analysis showed risk of a cardiovascular event at 1 and 10 years was 0.64% and 9.4%, respectively. There were 26 confirmed deaths in the study period. The risk of death at 1 and 10 years was 0.48% and 8.16%, respectively. CONCLUSION: We have shown a relatively low prevalence of cardiovascular events in this RA population diagnosed within a 10 year period. This is consistent with other reports and likely reflects the short follow-up period. Prospective longer-term studies will be required to further investigate the relative contribution of disease activity and other parameters to cardiovascular events in patients with early RA. PMID- 23441771 TI - Admission rate and characteristics of hospitalized systemic connective tissue disorders: analysis from a nationwide Thailand healthcare database. AB - BACKGROUND: Reports of hospitalized systemic connective tissue disorders (SCNTD) are mostly disease-specific reports from institutional databases. OBJECTIVE: To clarify the admission rate, disease determination, hospital mortality rate, length of stay and hospital charges among hospitalized patients diagnosed with SCNTD. MATERIALS AND METHODS: The data were extracted from the 2010 national database of hospitalized patients provided by the Thai Health Coding Center, Bureau of Policy and Strategy, Ministry of Public Health, Thailand. Patients over 18 years having International Classification of Diseases (ICD)-10 codes for a primary diagnosis related to SCNTD were included. RESULTS: There were 6861 admissions coded as disorders related to SCNTD during the fiscal year 2010. The admission rate was 141 per 100,000 admissions. Among these, systemic lupus erythematosus (SLE) was the most common, followed by systemic sclerosis (SSc) and dermatomyositis/polymyositis (DM-PM). The overall mean length of hospital stay was 6.8 days. Small vessel vasculitis and Sjogren syndrome had the longest and the shortest hospital stays respectively (14.5 vs. 5.3 days). Hospital charges were highest among systemic vasculitis and DM-PM patients. CONCLUSION: The admission rate for SCNTD in Thailand was 141 per 100,000 admissions among which SLE was the most common. Overall hospital mortality was 4.1%. Although a lower prevalence was found among systemic vasculitis, it had a higher mortality rate, longer length of stay and greater therapeutic cost. PMID- 23441770 TI - The Malaysian Clinical Guidance on the management of postmenopausal osteoporosis, 2012: a summary. AB - AIM: This Clinical Guidance is aimed to help practitioners assess, diagnose and manage their patients with osteoporosis (OP), using the best available evidence. METHODS: A literature search using PubMed (MEDLINE) and The Cochrane Library identified all relevant articles on OP and its assessment, diagnosis and treatment, from 2005, to update from the previous edition published in 2006. The studies were assessed and the level of evidence assigned; for each statement, studies with the highest level of evidence were used to frame the recommendation. RESULTS: This article summarizes the diagnostic and treatment pathways for OP, highlighting the new data that have changed the way we assess and treat OP. Instead of starting treatment based on bone mineral density alone, there has been a move to assessing 10-year fracture risk before treatment, using tools such as the Fracture Risk Assessment Tool (FRAX). There has been a re-evaluation on calcium supplementation and more emphasis on the importance of vitamin D. There has been concern about the potential adverse effects of the long-term usage of bisphosphonates, which we have discussed fully. New drugs that have been licensed since 2006 in Malaysia have been included. CONCLUSIONS: Adequate intake of calcium (1000 mg from both diet and supplements) and vitamin D (800 IU) daily remain important in the treatment of OP. However, in confirmed OP, pharmacological therapy with anti-resorptives is the mainstay of treatment. Patients need to be regularly assessed while on medication and treatment adjusted as required. PMID- 23441772 TI - Prevalence and risk factors for chloroquine maculopathy and role of plasma chloroquine and desethylchloroquine concentrations in predicting chloroquine maculopathy. AB - AIM: To determine the prevalence and to identify the risk factors of chloroquine maculopathy (CM), and to evaluate the association of plasma chloroquine (CQ) and desethylchloroquine (DCQ) levels and CM. METHODS: Rheumatoid arthritis (RA) patients who had taken CQ for at least 6 months and stable CQ dosage for at least 2 months were included. CM was diagnosed by dilated ocular examination and automated visual field. Plasma CQ and DCQ levels were determined by liquid chromatography tandem mass spectrometry method. Logistic regression was used to explore risk factors associated with CM. RESULTS: One hundred and ninety-three patients were included with median CQ duration (range) of 50.2 months (6.0-269.8) and cumulative dose of 137.4 g (16.4-1226.5). The prevalence of CM was 13.5%. Factors associated with CM identified from univariate analysis were age > 60 years, and creatinine clearance with odds ratio (OR) (95%CI) of 5.79 (2.42, 13.84), and 0.98 (0.96, 1.00). In multivariate analysis, older age, usage > 5 years, and current dose from 2.5 mg/kg ideal body weight [IBW]/day were the factors significantly associated with CM with OR of 5.89 (2.38, 14.57), 2.94 (1.10, 7.83), and 3.32 (1.04, 10.60), respectively, while plasma CQ and DCQ showed no association with CM. CONCLUSIONS: The prevalence of CM was 13.5% among RA patients taking CQ for at least 6 months. Age > 60 years, duration of CQ usage > 5 years and current CQ dose >=2.5 mg/kg IBW/day were the risk factors for CM. The plasma CQ or DCQ levels demonstrated no correlation in developing CM. PMID- 23441773 TI - Systemic lupus erythematosus in Saudi children: long-term outcomes. AB - OBJECTIVE: To report the long-term outcome of Saudi children with systemic lupus erythematosus (SLE). METHODS: Charts of all children with SLE treated between 1990 and 2010 at King Faisal Specialist Hospital and Research Center Riyadh, were reviewed. The long-term outcome measured by pediatric adaptation of the Systemic Lupus International Collaborating Clinics American College of Rheumatology Damage Index (pSDI) and death related to SLE were determined. The data included: gender, age at disease onset, clinical features and treatment at last follow-up visit. RESULTS: One hundred and fifty-two patients (129 girls and 23 boys) were included. The mean age at onset of SLE was 8.8 +/- 2.6 years, while the mean age at diagnosis was 9.5 +/- 2.6 years and the mean disease duration was 7.5 +/- 4.6 years. All patients were treated with corticosteroid and immunosuppressive drugs. Eighty (52.6%) patients had damage with a mean SDI score of 1.3 +/- 1.7. Damage accrual was mostly in the growth (26.8%), renal (17.1%) and neuropsychiatric (15.8%) domains. Due to progressive renal disease, 14 patients required dialysis; five of them underwent renal transplant. There were nine deaths related to SLE, eight of them due to infection. Based on logistic regression, patient disease damage was significantly associated with young age at disease onset and long disease duration. Similarly, death related to SLE was influenced by early-onset disease. In contrast, gender, disease duration and therapy did not affect the suggested outcome measures. CONCLUSION: Our results are comparable to reports from other tertiary centers. Early-onset disease probably influences the long term outcome of SLE in children. Infection remains an important cause of death in children with SLE. PMID- 23441774 TI - Activity and damage in granulomatosis with polyangiitis. AB - AIM: To retrospectively analyze disease activity and damage-associated factors in granulomatosis with polyangiitis (GPA) in Turkey. METHOD: A retrospective analysis was carried out in 21 GPA patients. Assessments for activity were performed with the Birmingham Vasculitis Activity Score for GPA (BVAS/GPA) and for permanent organ damage by the Vasculitis Damage Index (VDI). RESULTS: Lower BVAS/GPA (P = 0.002), absence of renal involvement (P = 0.003) and higher creatinine clearence (P = 0.000) at diagnosis increased the likelihood of achieving remission at 6 weeks. Relapses were associated with high creatinine clearence (P = 0.021), low BVAS/GPA (P = 0.014), absence of renal involvement (P = 0.036) and proteinuria (< 0.5/24 h) (P = 0.013) at diagnosis, whereas achieving remission at 6 weeks (P = 0.012) was associated with absence of co-trimoxazole usage (P = 0.038) and less severe clinical subgroup (P = 0.034). Lower cumulative first 6 months of cyclophosphamide and methylprednisolone were associated with earlier (<= 12 months) relapses (P = 0.048 and P = 0.083, respectively). Baseline damage (VDI >= 1) was associated with a delay in diagnosis (P = 0.032), presentation with milder clinical subgroups (P = 0.052) and low serum creatinine (P = 0.013). The increase in VDI in the first 12 months (early damage) constituted most (91%) of the total damage measured at the end of follow-up. CONCLUSIONS: Despite high early remission rates, relapse represents a major problem in localized GPA in our study. Baseline damage was associated with longer diagnostic delay and lower baseline serum creatinine. The initial phase of the disease seems to be the most crucial period for mortality and accumulated damage. PMID- 23441775 TI - Circulating microparticles in neuropsychiatric systemic lupus erythematosus. AB - AIM: Phosphatidylserine-rich microparticles derived from endothelial cells, platelets and leukocytes have been implicated as surrogate markers of cellular activation in systemic lupus erythematosus (SLE). Because microparticles have also been associated with many primary neurologic diseases, this study investigated whether cellular-derived microparticles are also implicated in neuropsychiatric SLE (NPSLE). METHOD: Plasma microparticles were measured in 51 SLE patients and 22 age- and gender-matched controls. Acute NPSLE was defined as major NPSLE (acute stroke, transient ischemic attack, psychosis, isolated seizures, major cognitive disorder, or acute confusional state) and NPSLE disease activity was measured with the neurologic components of the SLE Disease Activity Index (Neuro-SLEDAI). RESULTS: Neuro-SLEDAI levels varied widely in SLE patients, consistent with variable NPSLE activity. When considering all patients with SLE, there was no difference in total microparticles relative to matched controls, 2158/MUL (interquartile range [IQR] 1214-3463) versus 2782/MUL (IQR 1586-2990; P = 0.57) nor differences in microparticles derived from either platelets (P = 0.40), monocytes (P = 0.15) or endothelial cells (P = 0.32). However, levels of circulating monocyte-derived microparticles significantly and independently correlated with NPSLE (r = -0.28; P = 0.045), corticosteroid dosage (r = -0.38; P = 0.006) and levels of circulating C5a (r = 0.54; P < 0.0001). Non-neurologic SLE disease activity was not associated with microparticles. CONCLUSION: Circulating cell-derived microparticles are reduced in active NPSLE, although the relative contribution of reduced microparticle production, increased consumption or intravascular sequestration, remain uncertain. PMID- 23441776 TI - Androgen receptor genetic variants in male patients with ankylosing spondylitis in Taiwan. AB - AIM: Ankylosing spondylitis (AS) is a chronic rheumatic disorder with gender differences. The aim of study was to investigate the association between polymorphisms of the androgen receptor (AR) gene and the susceptibility to AS in Taiwanese men of Han Chinese descent. METHODS: We conducted a case-control study with 92 male AS patients and 108 healthy controls. Trinucleotide (CAG and GGC) repeats and seven single nucleotide polymorphisms (SNPs) rs962458, rs6152, rs1204038, rs5918757, rs2361634, rs6624304 and rs1337080 in the AR gene were genotyped. RESULTS: We found that only one patient had polymorphic SNPs of the AR gene. None of the genotyped SNPs in the AR gene, originally found in Caucasians, was polymorphic in the Taiwanese men. Neither CAG nor GGC repeat lengths in the AR gene had a significant relationship with human leukocyte antigen (HLA)-B27 positivity or disease severity in AS. CONCLUSION: There were no differences in CAG and GGC lengths in the AR gene between AS and the controls. None of the genotyped SNPs in AR gene are detected to be polymorphic in male Taiwanese, which indicates that the effect of AR gene on AS may be ethnic-specific and may be conserved in East Asians compared to Caucasian populations. Still, additional studies using large sets of subjects deserve further attention, since our sample size was small with limited statistical power and supporting evidence for association between the AR gene and AS risk in the Japanese population exists. PMID- 23441777 TI - The frequency of sicca symptoms and Sjogren's syndrome in patients with systemic sclerosis. AB - OBJECTIVE: The objectives are to detect the frequency of sicca symptoms and Sjogren's syndrome (SS) in patients with systemic sclerosis (SSc) based on the diagnostic criteria of the American-European Consensus Group (AECG) and to evaluate demographic, clinical and serologic characteristics. PATIENTS AND METHOD: One hundred and eighteen SSc patients referred to our hospital were included in this study. All SSc patients were questioned with respect to sicca symptoms. Levels of rheumatoid factor (RF), anti-nuclear antibodies (ANA), anti Ro and anti-La antibodies were measured; non-stimulated saliva amounts were recorded and Schirmer test and break-up time were applied to all patients. Minor salivary gland biopsy samples were obtained from those patients giving >= 3 positive answers to sicca symptom questions, patients with positive xerostomia/xerophthalmia test results, and patients with at least one antibody being positive. Patients presenting with grade 3 and/or grade 4 sialoadenitis based on Chisholm criteria were considered pathological. RESULTS: Sicca symptoms were present in 84 of 118 patients with SSc (71.2%). Minor salivary gland biopsy samples were obtained from 74 patients. Grade 3 and/or grade 4 sialoadenitis was detected in 40 (33.9%) patients and they were diagnosed with SS. Compared to patients diagnosed with SSc alone, systemic sclerosis patients diagnosed with SS had lower pulmonary hypertension and less diffuse lung involvement. Statistically significant difference was detected in terms of sclerodactylia and telangiectasia between SSc-SS and SSc patient groups (P = 0.045 and P = 0.011, respectively). Serological assessments revealed that in the SSc-SS group, 13 patients were anti Ro antibody positive, six were anti-La antibody positive and 37 were anti topoisomerase 1 antibody positive. RF, ANA and anti-centromere antibody levels were higher in the SSc-SS group. CONCLUSION: In the present study, highly frequent sicca symptoms and Sjogren's syndrome based on AECG criteria were noted in patients with systemic sclerosis. The SSc-SS patient group had less severe clinical course and lung involvement. PMID- 23441778 TI - IgG4-related disease in Singapore: a description of two cases and review of the literature. AB - We describe a 42-year-old man who presented with painless obstructive jaundice, organomegaly and lymphadenopathy. Biopsy of the ampulla of Vater revealed the presence of increased populations of plasma cells which stained positively for immunoglobulin G4. He was treated with prednisolone and demonstrated significant clinical improvement 1 month later. A further case is described and a review of the literature is also provided. PMID- 23441779 TI - Comment on: Oxidative stress in systemic lupus erythematosus and rheumatoid arthritis patients: relationship to disease manifestations and activity. PMID- 23441780 TI - Levels of soluble adhesion molecules and their associations in inflammatory myositis. PMID- 23441781 TI - Digital ulcer in systemic sclerosis successfully treated with Waon therapy. PMID- 23441782 TI - Treatment of multicentric reticulohistiocytosis with adalimumab, minocycline, methotrexate. PMID- 23441783 TI - A case of ulcerative colitis complicating anti-tumor necrosis factor treatment for rheumatoid arthritis: successful treatment with leukocytapheresis. PMID- 23441784 TI - A novel model for simultaneous study of neointestinal regeneration and intestinal adaptation. AB - The use of autologous grafts, fabricated from tissue-engineered neointestine, to enhance insufficient compensation of intestinal adaptation for severe short bowel syndrome is a compelling idea. Unfortunately, current approaches and knowledge for neointestinal regeneration, unlike intestinal adaptation, are still unsatisfactory. Thus, we have designed a novel model of intestinal adaptation with simultaneous neointestinal regeneration and evaluated its feasibility for future basic research and clinical application. Fifty male Sprague-Dawley rats weighing 250-350 g underwent this procedure and sacrificed at 4, 8, and 12 weeks postoperatively. Spatiotemporal analyses were carried out by gross, histology, and DNA/protein quantification. Three rats died of operative complications. In early experiments, the use of hard silicone stent as tissue scaffold in 11 rats was unsatisfactory for neointestinal regeneration. In later experiments, when a soft silastic tube was used, the success rate increased up to 90.9%. Further analyses revealed that no neointestine developed without donor intestine; regenerated lengths of mucosa and muscle were positively related to time postsurgery but independent of donor length with 0.5 or 1 cm. Other parameters of neointestinal regeneration or intestinal adaptation showed no relationship to both time postsurgery and donor length. In conclusion, this is a potentially important model for investigators searching for solutions to short bowel syndrome. PMID- 23441785 TI - Where is dentistry heading? PMID- 23441786 TI - Human papillomavirus and oral disease - emerging evidence: a review. AB - Human papillomavirus (HPV) infections have received considerable attention in recent years. Of the 120 or so known types of the virus, some cause a variety of benign wart-like lesions of the skin and genital and oral mucosae, whilst others are aetiologically associated with cervical and anogenital cancers. Recent epidemiologic evidence suggests that HPV may also be an independent risk factor for oropharyngeal cancer. In this context it has been suggested that HPV virus may modulate the process of carcinogenesis in some tobacco and alcohol induced oropharyngeal cancers and act as the primary oncogenic agent for inducing carcinogenesis among non-smokers. Dental practitioners have a major role in detecting all lesions of the oral mucosa caused, or possibly caused, by HPV. This paper briefly reviews the current state of knowledge of molecular and clinical aspects of HPV infections of the oral mucosa. PMID- 23441787 TI - Stimulating the discussion on saliva substitutes: a clinical perspective. AB - Xerostomia is a significant problem commonly faced by patients and oral health practitioners. There is no cure for this condition, which commonly manifests as a side effect of medications, head and neck irradiation and other systemic conditions, such as Sjogren's syndrome and type 2 diabetes. It may also arise idiopathically. Therefore, treatment is palliative and takes the form of oral lubricants and saliva substitutes which aim to reduce symptoms associated with xerostomia as well as prevent oral disease secondary to it. Recently there has been an expansion of the number and range of products available in Australia for the palliative management of xerostomia. It is imperative then that oral health professionals have a sound understanding of the advantages and disadvantages of using such products as patients tend to be well informed about new products which are commercially available. This article discusses some of the most commonly available products used for the symptomatic relief and preventive management of xerostomia. Amongst the plethora of products available to the patient suffering from xerostomia, no single product or product range adequately reproduces the properties of natural saliva and therefore consideration of patients' concerns, needs and oral health state should be taken into account when formulating a home care regime. With Australia's ageing population and its heavier reliance on medications and treatments which may induce xerostomia, oral health professionals are likely to encounter this condition more than ever before and therefore an understanding of xerostomia and its management is essential to patient care. PMID- 23441788 TI - Oral conditions and their social impact among HIV dental patients, 18 years on. AB - BACKGROUND: A study undertaken in 1992-1993 identified that HIV-infected dental patients were substantially disadvantaged with regard to the social impact of their oral disease. The oral pain experienced by HIV-positive patients prior to the introduction of combination antiretroviral therapy (cART) was attributable to specific features of HIV-related periodontal disease and other oral manifestations of HIV such as candida infections and xerostomia. A repeat of this study in 2009-2010 provided additional information in the post-cART era. METHODS: Data were collected from three sources: the 2009-2010 HIV-positive sample, the National Survey of Adult Oral Health (NSAOH) and the original 1992-1993 study. Collation of data was by clinical and radiographic oral examination. Information about the social impact of oral conditions was obtained from the Oral Health Impact Profile. RESULTS: The caries experience of the 2009-2010 HIV-positive sample was improved with statistical significance for both mean DMFT and mean DT, while the presence of HIV-related periodontal disease still occurs. Statistically significant improvements were achieved for prevalence and severity of oral health related quality of life. CONCLUSIONS: The need for timely access to oral health care with a focus on prevention is essential for HIV-positive individuals whose health is impacted by chronic disease, smoking and salivary hypofunction. PMID- 23441789 TI - The oral health status, practices and knowledge of pregnant women in south western Sydney. AB - BACKGROUND: Current evidence highlights the importance of oral health during pregnancy. However, little is known about the oral health of pregnant women in Australia. The aim of this study was to report the oral health status, knowledge and practices of pregnant women in south-western Sydney. METHODS: A cross sectional survey of 241 pregnant women attending a large hospital in south western Sydney. RESULTS: More than half (59.3%) reported dental problems during pregnancy, less than a third (30.5%) saw a dentist in the last six months, only 10% had received any information about perinatal oral health and many (>50%) were unaware of the potential impact of poor maternal oral health on pregnancy and infant outcomes. Analysis revealed a significant difference (<0.05) in the uptake of dental services among pregnant women who had higher household incomes, private health insurance, received information about perinatal oral health and knowledge about maternal oral health. CONCLUSIONS: The participants reported significant barriers to obtaining dental care including limited access to affordable dental services and lack of awareness about the importance of maternal oral health. The findings suggest the need for preventive strategies involving dentists and antenatal providers to improve maternal oral health in Australia. PMID- 23441790 TI - Local drug delivery of 0.5% azithromycin in the treatment of chronic periodontitis among smokers. AB - BACKGROUND: Along with conventional periodontal surgical therapy, local delivery of antibiotics may provide more effective treatment in smokers by targeting tissue-invasive bacteria. The aim of this randomized, placebo-controlled, double masked clinical trial was to evaluate the adjunctive effects of subgingivally delivered 0.5% azithromycin (AZM) as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis in smokers. METHODS: Fifty-four patients were randomized and categorized into two treatment groups: Group 1 - 26 subjects who received (SRP) plus placebo gel and Group 2 - 28 subjects who received (SRP) plus 0.5% azithromycin. Clinical parameters were recorded at baseline, 3, 6 and 9 months. They included Plaque Index (PI), modified Sulcus Bleeding Index (mSBI), probing depth (PD) and clinical attachment level (CAL). RESULTS: Azithromycin resulted in significant improvements. A single application of AZM resulted in attachment gain at 9 months of 2.44 +/- 0.64 mm as compared to 0.18 +/- 0.68 mm for the placebo. Similarly, pocket depth and PI were significantly reduced but no change in the mSBI was noted. CONCLUSIONS: When compared to the placebo, the adjunctive use of 0.5% AZM resulted in significant improvement in clinical outcome in the treatment of chronic periodontitis among smokers. PMID- 23441791 TI - Comparison of periodontal open flap debridement versus closed debridement with Er,Cr:YSGG laser. AB - BACKGROUND: Traditional periodontal open flap debridement (OFD) results in reduced pocket depth (PD), clinical attachment loss (CAL), gingival recession (GR) and postoperative pain and discomfort. The quest to overcome these shortcomings has led to research into Er,Cr:YSGG laser assisted pocket therapy (ELAPT). This study was designed to compare the clinical outcomes of ELAPT versus OFD. METHODS: Fifteen patients with a PD of >=5 mm and <=8 mm at two sites were selected. Test sites (Group 1) were treated by ELAPT and the control (Group 2) by OFD. Clinical parameters were recorded at baseline, 3 and 6 months and included Plaque Index (PI), Gingival Index (GI), modified Sulcular Bleeding Index (mSBI), PD, CAL and GR. RESULTS: Both treatments produced a reduction in PI, GI, mSBI and PD, an increase in GR, and a gain in CAL at 3 and 6 months. The mean gain of CAL in Group 1 at 3 and 6 months (1.60 +/- 0.78 and 1.80 +/- 0.63) was similar (p > 0.05) to the value of Group 2 (1.93 +/- 0.88 and 2.00 +/- 0.54). GR increased significantly (p < 0.05) only in Group 2 at 3 and 6 months (1.80 +/- 0.56 and 1.87 +/- 0.64) compared to Group 1 (0.50 +/- 0.68 and 0.60 +/- 0.74). CONCLUSIONS: ELAPT compared with OFD results in similar CAL gains with less GR and significant reductions in PD, GI and mSBI, and may be considered as an alternative to surgical therapy. PMID- 23441792 TI - An in vitro study of silver and fluoride ions on remineralization of demineralized enamel and dentine. AB - BACKGROUND: The purpose of this study was to compare the effect of silver fluoride, silver nitrate and potassium fluoride on remineralization of demineralized enamel and dentine in vitro. METHODS: Forty premolars were cut into cuboidal blocks. Acid-resistant varnish was painted onto each block to cover all surfaces, except two windows, one in enamel and one in dentine. The tooth blocks were placed in demineralizing solution for 96 hours. They were then randomly divided into four groups of 10 blocks each and immersed in solutions of AgF, AgNO(3), KF or water for 3 minutes. Afterwards, they were immersed in a remineralizing solution for 108 hours. Micro CT scanning was conducted before and after remineralization. RESULTS: The increase in linear attentuation coefficient (LAC) for the enamel lesions after remineralization was 1.08/cm, 0.95/cm, 0.86/cm and 0.60/cm in the AgF, AgNO(3), KF and control groups, respectively (ANOVA, p < 0.001; AgF, AgNO(3), KF > control; AgF > KF). The increase in LAC for the dentine lesions was 1.01/cm, 0.92/cm, 0.88/cm and 0.53/cm, respectively (ANOVA, p < 0.001; AgF, AgNO(3), KF > control). CONCLUSIONS: Topical application of silver or fluoride ions can increase the mineral density of demineralized enamel and dentine lesions during remineralization. The synergistic effect of silver and fluoride ions is relatively small. PMID- 23441793 TI - Healing properties of implants inserted concomitantly with anorganic bovine bone. A histomorphometric human study. AB - BACKGROUND: The present prospective, randomized, double-blind study evaluated the bone-forming process around implants inserted simultaneously with anorganic bovine bone (ABB) in sinus grafting. METHODS: A total of 18 threaded mini implants with Osseotite (O) and Nanotite (N) surfaces were placed in seven patients (nine sites). After 12 months, the implants were retrieved and processed for histological analysis. A total of 18 cutting and grinding sections were investigated with bright-field light microscopy, circularly polarized light microscopy (CPLM), confocal scanning laser microscope (CSLM), and scanning electron microscope (SEM) with energy dispersive spectrometer (EDS). RESULTS: The bone-to-implant contact rate in native crestal bone was 62.6 +/- 0.4% for N implants and 54.3 +/- 0.5% for the O implants (p = 0.001). The collagen fibre density, as assessed by CPLM, was 79.8 +/- 6.0 nm for the N group and 74.6 +/- 4.6 nm for the O group (p < 0.05). Line scan EDS starting from ABB to newly formed bone showed a decrease in calcium content and an increase of carbon while phosphorus content was constant. CONCLUSIONS: While the N surface improved the peri-implant endosseous healing properties in the native bone, when compared to the O surface, it did not improve the healing properties in the bone-graft area. PMID- 23441794 TI - Age-related changes in maxillary and mandibular cortical bone thickness in relation to temporary anchorage device placement. AB - BACKGROUND: The aim of this study was to investigate the correlation between alveolar bone cortical thickness (ABCT) and age in the maxillae and mandible in humans. This information could then be translated into clinical application with temporary anchorage devices (TADs) in orthdontics. METHODS: Samples comprised 82 post-mortem CT datasets (41 males and 41 females) aged between 11 to 50 years, and were divided into five different age groups and gender. Alveolar ABCT was measured in the labial/buccal and palatal/lingual sides of the incisor, canine, premolar, molar and tuberosity/retromolar regions of the maxillae and mandible. Correlations between ABCT and age and gender were analysed with linear regression analysis. RESULTS: Strong correlation between ABCT and age was found for the maxilla on the labial side of the maxillary incisor region (p < 0.001). On the palatal aspect, significant correlations between ABCT and age were found in the maxillary incisor and maxillary premolar regions (p = 0.01 and p = 0.047 respectively). Significant correlation between ABCT and gender was found only at the buccal aspect of the maxillary molar region (p = 0.022). In the mandible, a statistically significant correlation between ABCT and age was found in the cortical bone of the labial side of the mandibular incisor region (p = 0.017). However, statistically significant negative correlation between ABCT and age was found in the mandibular canine region (p = 0.033). The only site to demonstrate a significant difference in change in ABCT with age between males and females was the lingual side of the retromolar region, in which female ABCT increased more than in males (slope = 0.015). CONCLUSIONS: There is minimal clinically significant correlation between ABCT and age at the alveolar bone level. Although investigations show statistically significant correlations, these may not be clinically significant as those regions are not ideal for anchorage reinforcement with TADs in orthodontic practice. PMID- 23441795 TI - Associations between area-level disadvantage and DMFT among a birth cohort of Indigenous Australians. AB - BACKGROUND: Individual-level factors influence DMFT, but little is known about the influence of community environment. This study examined associations between community-level influences and DMFT among a birth cohort of Indigenous Australians aged 16-20 years. METHODS: Data were collected as part of Wave 3 of the Aboriginal Birth Cohort study. Fifteen community areas were established and the sample comprised 442 individuals. The outcome variable was mean DMFT with explanatory variables including diet and community disadvantage (access to services, infrastructure and communications). Data were analysed using multilevel regression modelling. RESULTS: In a null model, 13.8% of the total variance in mean DMFT was between community areas, which increased to 14.3% after adjusting for gender, age and diet. Addition of the community disadvantage variable decreased the variance between areas by 4.8%, indicating that community disadvantage explained one-third of the area-level variance. Residents of under resourced communities had significantly higher mean DMFT (beta = 3.86, 95% CI 0.02, 7.70) after adjusting for gender, age and diet. CONCLUSIONS: Living in under-resourced communities was associated with greater DMFT among this disadvantaged population, indicating that policies aiming to reduce oral health related inequalities among vulnerable groups may benefit from taking into account factors external to individual-level influences. PMID- 23441796 TI - Stress analysis of different post-luting systems: a three-dimensional finite element analysis. AB - BACKGROUND: The longevity of endodontically treated teeth is usually determined by the adequacy of root canal treatments, coronal seal and favourable stress distribution within the remaining tooth tissues. The aim of this study was to investigate the influence of post material and luting cement on the biomechanics of endodontically treated teeth using three-dimensional finite element analysis (3-D FEA). METHODS: A 3 mm section of endodontically treated canine tooth was scanned and reconstructed for 3-D modelling and FE analyses. A metal post (MP) and a glass fibre post (GFP) were tested individually with four luting cements [zinc phosphate (ZPH), glass ionomer (GI), resin modified glass ionomer (RMGI) and resin based cements (RC)]. A push-out test was conducted by subjecting all models to 100 N perpendicular loading at the post. RESULTS: The maximum stresses generated along the MP-cement interface were significantly higher than corresponding stresses in the GFP-cement interface regardless of the cement type. GFP generated seven times higher stresses within the root dentine than metal posts when ZPH and GI were used, and three times higher when RMGI and RC were used. The displacement of GFP was double (50 MU) the displacement of MP (20 MU) in all groups. CONCLUSIONS: The low elastic modulus of GFP generated lower stresses along its interface and higher stresses within the root dentine, therefore the probability of debonding and root fracture in the GFP group was lower. PMID- 23441797 TI - The healing of dental extraction sockets in patients with Type 2 diabetes on oral hypoglycaemics: a prospective cohort. AB - BACKGROUND: The aim of this study was to determine whether there is a difference in delayed healing following dental extractions for Type 2 diabetics on oral hypoglycaemics and non-diabetic patients. METHODS: Prospective patients referred for dental extractions were recruited into two groups: known diabetics and non diabetics with no conditions associated with poor healing. All had a random blood glucose level (BGL). Extractions were performed using local anaesthesia. Delayed healing cases were identified and statistical evaluation performed to identify risk factors. RESULTS: There were 224 Type 2 diabetics on oral hypoglycaemics (BGL 7.51, range 4.1-17.4) and 232 non-diabetics. The diabetic group were older, more males and less smokers than the control group. Twenty-eight patients, 12 (5%) diabetic and 16 (7%) control group, had socket healing delayed for more than one week but all healed in four weeks. There were no statistical differences between delayed healing and age, gender, diabetic state, BGL or smoking. The younger control group had more healing problems. CONCLUSIONS: The traditional view that diabetics have increased delayed healing was not supported. Type 2 diabetics on oral hypoglycaemics should be treated the same as non-diabetic patients for extractions. PMID- 23441798 TI - Clinical evaluation of different adhesives used in the restoration of non-carious cervical lesions: 24-month results. AB - BACKGROUND: The aim of this study was to compare after 24 months the clinical performance of cervical restorations placed with the use of an etch-and-rinse and an all-in-one adhesive. METHODS: Twenty-four patients with at least one pair of non-carious cervical lesions participated in this study. One hundred and twenty three cervical lesions were restored (62 etch-and-rinse adhesive, Solobond M; 61 all-in-one adhesive, Futurabond NR). A nanohybrid resin composite, Grandio, was used as the restorative material. Restorations were evaluated according to modified USPHS criteria by two independent examiners. The survival rates of the restorations were calculated by the Kaplan-Meier estimator and log-rank test. The restorations in each category were compared using the Pearson chi-square test, while the performance of restorations at the baseline and at each recall time was evaluated by McNemar's test (p < 0.05). RESULTS: The recall rate of patients was 100%. The retention rates were 82% and 75% at 6 months and 77% and 62% at 12 months for Solobond M and Futurabond NR, respectively. At the 24-month recall, the retention rate was 69% for Solobond M and 49% for Futurabond NR, and this difference was statistically significant (p < 0.05). No statistically significant difference was found for colour match, marginal staining, or marginal adaptation between the adhesives (p > 0.05). None of the restorations had secondary caries, loss of anatomical form, or surface texture changes. CONCLUSIONS: Cervical restorations placed with an etch-and-rinse adhesive showed higher retention than an all-in-one adhesive. PMID- 23441799 TI - Adhesion of Streptococci to various orthodontic composite resins. AB - BACKGROUND: This investigation aimed to determine quantitatively the adhesion of Streptococcus mutans and Streptococcus sobrinus to orthodontic composite resins that were tested simultaneously using radio-markers. METHODS: Seven orthodontic composite resins were classified into seven groups: BeautyOrtho Bond (GI), Blugloo (GII), Enlight (GIII), Grengloo (GIV), Kurasper F (GV), Transbond CC (GVI) and Turbo Bond II (GVII). Thirty 4 x 4 x 1 mm blocks of each orthodontic composite resin were made (a total of 210 blocks). Both Streptococcus species were cultivated independently. For the quantitative analysis, radioactive markers were used to codify the bacteria ((3) H for Streptococcus mutans and (14) C for Streptococcus sobrinus). The blocks were submerged in a solution with microorganisms previously radiolabelled for 2 hours at 37 degrees C in constant movement. The blocks were placed in a combustion system to quantify the Streptococcus adhering to the surface of the materials by capturing the residues and measuring the radiation. RESULTS: Significant differences in bacterial adhesion were found among the groups. The lowest significant scores for both microorganisms were observed in GIII. CONCLUSIONS: The orthodontic composite resin evaluated in GIII exhibited the lowest adhesion of Streptococcus mutans and Streptococcus sobrinus, which may reduce enamel demineralization and the risk of white spot lesion formation. PMID- 23441800 TI - Impact of different fluoride concentrations and pH of dentifrices on tooth erosion/abrasion in vitro. AB - BACKGROUND: This in vitro study analysed the effect of different fluoride concentrations in acidic or neutral liquid dentifrices in protecting enamel and dentine from erosive and abrasive wear. METHODS: Bovine enamel and dentine specimens (n = 132) were randomly allocated to 11 groups (each n = 12): experimental liquid dentifrices with 550 ppm F, 1100 ppm F, 5000 ppm F or 0 ppm F/placebo (each at pH 4.5 and pH 7.0); and commercial dentifrices with 550 ppm F (Colgate Baby, pH 7.0), 1100 ppm F (Crest, pH 7.0) and 5000 ppm F (Duraphat, pH 7.0). The specimens were subjected to erosion for 90 seconds, 4 times/day, over 7 days. Immediately after the first and last erosion, the specimens were brushed for 15 seconds using one of the dentifrices. Tooth wear was measured profilometrically (MUm) and analysed by ANOVA (p < 0.05). RESULTS: All fluoridated liquid dentifrices significantly reduced enamel wear compared to the placebo and commercial dentifrices. Only liquid dentifrices with 1100 and 5000 ppm F significantly reduced dentine wear compared to placebo dentifrice. The pH had no effect, but the consistency had a significant impact on the effect of dentifrices. CONCLUSIONS: Liquid dentifrices with high F concentration appear to be a good option to prevent tooth wear. PMID- 23441801 TI - The management of benign salivary disease: a case series. AB - There are many causes for benign salivary gland disease but the most common relate to inflammation and infection. This usually revolves around duct obstruction and a reduction in the normal salivary flow from the gland into the mouth. This leads to retention of saliva, proximal to the obstruction and ascending infection from the mouth, usually because of the decrease in salivary flow. The increase in tension behind the obstruction causes significant pain and swelling, along with the inevitable infection if the obstruction is not relieved. This paper discusses the various treatments available for benign salivary gland disease, the traditional methods of treatment through to the use of endoscopic techniques which are currently available, including a discussion about the use of sialoendoscopy. PMID- 23441802 TI - Acute fetal distress following tooth extraction and abscess drainage in a pregnant patient with maxillofacial infection. AB - Oral infections have been implicated in adverse pregnancy outcomes such as pre eclampsia, premature delivery and growth retardation. A 28-year-old and 9 months pregnant otherwise healthy woman with a complaint of facial swelling and dental pain was referred to the Department of Oral and Maxillofacial Surgery. Oral examination revealed perimandibular and masticator space infection related to the left mandibular third molar tooth. Eight hours after surgical intervention, fetal distress developed. The patient was immediately taken into surgery and a male baby delivered by Caesarean section. The baby was then admitted to the intensive care unit. On the twelfth day of his admission, the baby was discharged in good health. Severe maxillofacial infection in pregnancy is a medically complicated situation which should be treated by an oral and maxillofacial surgeon in consultation with an obstetric and gynaecology service. PMID- 23441803 TI - Oral health and other characteristics of pregnant Aboriginal women compared with general population estimates. PMID- 23441806 TI - Effect of disinfecting teats post-milking or pre- and post-milking on intramammary infection and somatic cell count. AB - AIMS: To determine the effects of (a) post-milking teat disinfection compared with no disinfection and (b) pre- and post-milking teat disinfection compared with post-milking disinfection alone, on the incidence of new intramammary infection (IMI), somatic cell count (SCC) and teat skin abnormalities in dairy cows. METHODS: In Experiment 1, dairy cows in five dairy herds were randomly allocated to a post-milking teat disinfection group (n=230), that was sprayed with an iodine-based disinfectant (TeatguardPlus) for a complete lactation, or to a non-disinfected group (n=239). In Experiment 2, cows were randomly allocated to post-milking teat disinfection (n=239) or both pre- and post-milking teat disinfection (n=235), using a chloramine-T-based disinfectant (Teatsweet) for both treatments, from calving to 118-127 days in milk. The incidence of new IMI was determined by aseptic sampling of all quarters at calving, during lactation, and at trial end or at drying-off, with clinical mastitis cases sampled on detection. SCC and teat skin abnormalities were measured at 2-monthly intervals during lactation. In both experiments, disinfectant was applied by spray application. RESULTS: Cows that received post-milking teat disinfection had a lower incidence of new IMI caused by Staphylococcus aureus, Streptococcus uberis, Corynebacterium spp and coagulase negative staphylococci, had lower bulk milk SCC during lactation, and had fewer teat skin abnormalities compared with the non disinfected cows (p < 0.05). Pre-milking teat disinfection, in addition to post milking teat disinfection, did not reduce the incidence of new IMI for any pathogens and did not reduce SCC (p> 0.05). CONCLUSIONS: Post-milking teat disinfection applied as a spray is a key component in mastitis control in New Zealand. There was no benefit from the addition of pre-milking disinfection. CLINICAL RELEVANCE: This study confirms previous findings of the effectiveness of post-milking teat disinfection in reducing the incidence of IMI caused by the common mastitis-causing pathogens in New Zealand, and presents the first results of a controlled study examining pre-milking teat spraying undertaken in New Zealand commercial dairy herds. PMID- 23441807 TI - Cardiac self-efficacy and its predictors in patients with coronary artery diseases. AB - AIMS AND OBJECTIVES: To investigate cardiac self-efficacy and its predictors among patients with coronary artery diseases. BACKGROUND: Patients with coronary artery diseases must perform the health behaviour to prevent recurrent cardiac events. It has been already well known that self-efficacy is a vital factor in both initiating and maintaining health behaviours. DESIGN: Descriptive correlational and cross-sectional survey design. METHODS: Subjects were interviewed using structured study questionnaires. The data collected were statistically analysed by descriptive statistics and inferential statistics including the t-test, anova, Tukey's test, Pearson's correlation and hierarchical multiple regression analysis to determine the predictors of cardiac self efficacy. RESULTS: A convenience sample of 214 patients with coronary artery diseases was included. The mean age of subjects was 60.71 +/- 10.07 years, and three-fourths were men. The overall model significantly explained 15.8% of variance in cardiac self-efficacy. Among predictors, occupation, diagnosis, body mass index, experience of receiving patient education and awareness of risk factors had statistically significant influences on cardiac self-efficacy. CONCLUSIONS: Rather than disease knowledge, factors related to subject's perception were more likely to associate with cardiac self-efficacy. These findings might provide a theoretical basis to develop nursing interventions for enhancing cardiac self-efficacy of patients with coronary artery diseases. RELEVANCE TO CLINICAL PRACTICE: Clinical nurses taking care of patients with coronary artery diseases should consider the patients' perception on their coronary artery diseases including experience of receiving patient education, and awareness of risk factors in encouraging the cardiac self-efficacy to promote the health behaviours for the secondary prevention of coronary artery diseases. PMID- 23441808 TI - Ultralow protein adsorbing coatings from clickable PEG nanogel solutions: benefits of attachment under salt-induced phase separation conditions and comparison with PEG/albumin nanogel coatings. AB - Clickable nanogel solutions were synthesized by using the copper catalyzed azide/alkyne cycloaddition (CuAAC) to partially polymerize solutions of azide and alkyne functionalized poly(ethylene glycol) (PEG) monomers. Coatings were fabricated using a second click reaction: a UV thiol-yne attachment of the nanogel solutions to mercaptosilanated glass. Because the CuAAC reaction was effectively halted by the addition of a copper-chelator, we were able to prevent bulk gelation and limit the coating thickness to a single monolayer of nanogels in the absence of the solution reaction. This enabled the inclusion of kosmotropic salts, which caused the PEG to phase-separate and nearly double the nanogel packing density, as confirmed by quartz crystal microbalance with dissipation (QCM-D). Protein adsorption was analyzed by single molecule counting with total internal reflection fluorescence (TIRF) microscopy and cell adhesion assays. Coatings formed from the phase-separated clickable nanogel solutions attached with salt adsorbed significantly less fibrinogen than other 100% PEG coatings tested, as well as poly(L-lysine)-g-PEG (PLL-g-PEG) coatings. However, PEG/albumin nanogel coatings still outperformed the best 100% PEG clickable nanogel coatings. Additional surface cross-linking of the clickable nanogel coating in the presence of copper further reduced levels of fibrinogen adsorption closer to those of PEG/albumin nanogel coatings. However, this step negatively impacted long-term resistance to cell adhesion and dramatically altered the morphology of the coating by atomic force microscopy (AFM). The main benefit of the click strategy is that the partially polymerized solutions are stable almost indefinitely, allowing attachment in the phase-separated state without danger of bulk gelation, and thus producing the best performing 100% PEG coating that we have studied to date. PMID- 23441809 TI - Long-term effects of aerobic training versus combined aerobic and resistance training in modifying cardiovascular disease risk factors in healthy elderly men. AB - AIMS: The purpose of the present study was to compare different modes of exercise in chronic modification of cardiovascular diseases risk factors. METHODS: A total of 48 healthy elderly men were randomly assigned to an aerobic training group (n = 15, aged 71.7 +/- 4.7 years), a combined (aerobic and resistance) training group (n = 16, aged 68.5 +/- 3.5 years) and a control group (n = 17, aged 67.0 +/ 5.8 years). Both training programs were of moderate-to-vigorous intensity, 3 days per week for 9 months. Primary outcome measures included body composition, blood pressure and lipid profile. Odds ratios (OR) between hypertension, obesity and dyslipidemia were calculated. The independence between risk factors, aggregation and group factor was tested (baseline vs post-test). RESULTS: There was significant aggregation between hypertension and obesity (OR 2.57, 95% CI 1.24-5.33). After 32 weeks, there was a significant change in the number of hypertensive (chi(2) = 8.1, P = 0.004) and dyslipidemic (chi(2) = 3.9, P = 0.049) participants, and also a favorable modification in the risk factors aggregation (chi(2) = 7.9, P = 0.019), but only in the combined training group. CONCLUSIONS: Combined aerobic and resistance training is more effective in the chronic modification of blood pressure and lipid profile, and in the reduction of total risk factors aggregated. PMID- 23441810 TI - A novel technique for reconstruction of the posterior wall of the external auditory canal and tympanum using pedicled temporalis myofascia. AB - CONCLUSIONS: The procedure cleared the lesion completely and preserved the physiological function of the external auditory canal. OBJECTIVE: To develop a novel surgical procedure to treat chronic suppurative otitis media (CSOM). To explore the merit of using pedicled temporalis myofascia (PTM) and reconstruction of the posterior wall of the external auditory canal with pedicled postauricular periosteal flap and intact skin of the external auditory canal. METHODS: Forty seven patients with CSOM were chosen. Open radical mastoidectomy was used to complete clean-up lesions; the fascia of PTM was used to repair the tympanic membrane. The PTM, pedicled postauricular periosteal flap, and intact skin of the external auditory canal were used in the reconstruction of the posterior wall of the external auditory canal. All subjects were followed up for over 2 years. Hearing thresholds, including air conduction (AC), bone conduction (BC), and air bone gap (ABG) before and after surgery, and after follow-up, were compared. RESULTS: The healing rate of postoperated tympanic membrane was 95.74% and the 2 year healing rate of tympanic membrane perforation was 95.65%. The 46 ears included in the 2-year follow-up showed significant improvement between preoperative and postoperative AC and ABG values. PMID- 23441811 TI - Cold stress induces lower urinary tract symptoms. AB - Cold stress as a result of whole-body cooling at low environmental temperatures exacerbates lower urinary tract symptoms, such as urinary urgency, nocturia and residual urine. We established a model system using healthy conscious rats to explore the mechanisms of cold stress-induced detrusor overactivity. In this review, we summarize the basic findings shown by this model. Rats that were quickly transferred from room temperature (27 +/- 2 degrees C) to low temperature (4 +/- 2 degrees C) showed detrusor overactivity including increased basal pressure and decreased voiding interval, micturition volume, and bladder capacity. The cold stress-induced detrusor overactivity is mediated through a resiniferatoxin-sensitve C-fiber sensory nerve pathway involving alpha1 adrenergic receptors. Transient receptor potential melastatin 8 channels, which are sensitive to thermal changes below 25-28 degrees C, also play an important role in mediating the cold stress responses. Additionally, the sympathetic nervous system is associated with transient hypertension and decreases of skin surface temperature that are closely correlated with the detrusor overactivity. With this cold stress model, we showed that alpha1-adrenergic receptor antagonists have the potential to treat cold stress-exacerbated lower urinary tract symptoms. In addition, we showed that traditional Japanese herbal mixtures composed of Hachimijiogan act, in part, by increasing skin temperature and reducing the number of cold sensitive transient receptor potential melastatin channels in the skin. The effects of herbal mixtures have the potential to treat and/or prevent the exacerbation of lower urinary tract symptoms by providing resistance to the cold stress responses. Our model provides new opportunities for utilizing animal disease models with altered lower urinary tract functions to explore the effects of novel therapeutic drugs. PMID- 23441813 TI - Anharmonic vibrational analysis of the gas-phase infrared spectrum of 1,1 difluoroethylene using the operator van Vleck canonical perturbation theory. AB - Anharmonic vibration frequencies of 1,1-difluoroethylene (11DFE) in the gas phase are predicted by means of the numerical-analytic operator version of the canonical van Vleck perturbation theory in the second and fourth orders (CVPT2 and CVPT4). The full quartic and "semi-diagonal" sextic rectilinear normal coordinate potential energy surfaces, needed for CVPT2 and CVPT4, respectively, were obtained with the MP2/cc-pVTZ quantum-mechanical model. CVPT2 is superior to the traditional second-order vibrational perturbation theory approach (VPT2) because of the uniform general treatment of the Fermi and second-order Darling Dennison resonances. The fourth-order version, CVPT4, provides a more refined solution and proves convergence of the perturbative treatment. Labeling of the basis functions by polyad numbers breaks down the infinite Hamiltonian matrix into a block-diagonal form. The polyad expression for 11DFE has been determined as P = 14(nu1 + nu7) + 8nu2 + 6(nu3 + nu8) + 4(nu4 + nu9) + 3(nu6 + nu11 + nu12) + 2(nu5 + nu10), where the nui are quantum numbers. The theoretical prediction of anharmonic infrared absorption intensities corroborated an assignment of the majority of observed gas-phase bands up to 3500 cm(-1). The solution was refined by iteratively fitting harmonic frequencies, until predicted fundamental anharmonic frequencies matched the observed values. The average error for about 90 observed frequencies after fitting only fundamental frequencies is ~1.05 cm( 1). The fitted "semi-experimental" harmonic frequencies agree very well the quantum-mechanical predictions based on the CCSD(T)/cc-pVTZ and CCSD(T)/cc-pVQZ models. PMID- 23441812 TI - Cytokine and matrix metalloproteinase expression in fibroblasts from peri implantitis lesions in response to viable Porphyromonas gingivalis. AB - BACKGROUND AND OBJECTIVE: To assess inflammatory reactions of fibroblasts in the pathophysiology of peri-implantitis, we compared the pro-inflammatory and matrix degrading responses of gingival and granulation tissue fibroblasts from periodontally healthy controls, peri-implantitis, and periodontitis lesions to an in vitro challenge with Porphyromonas gingivalis. METHODS: Fibroblasts from periodontally healthy, peri-implantitis and periodontitis donors were challenged with viable P. gingivalis. The inflammatory reactions of fibroblasts were analyzed before and after 6 h P. gingivalis challenge, and 2.5 and 18 h after removal of the challenge. Gene expression and induction of pro-inflammatory mediators, and matrix metalloproteinases (MMPs) were assessed by real-time polymerase chain reaction. Protein expression was measured by enzyme-linked immunosorbent assay. RESULTS: Non-challenged fibroblasts from peri-implantitis and periodontitis lesions expressed higher levels of interleukin (IL)-1beta, IL 8, and monocyte chemotactic protein (MCP)-1 than fibroblasts from periodontally healthy individuals. The P. gingivalis challenge induced expression of IL-1beta, IL-8, IL-6, MCP-1, and MMP-1 in periodontitis and peri-implantitis fibroblasts, but not in fibroblasts from periodontally healthy individuals. MMP-8 expression was higher in non-challenged peri-implantitis fibroblasts than in fibroblasts from periodontally healthy individuals. However, the P. gingivalis challenge downregulated MMP-8 gene expression in peri-implantitis fibroblasts. After removal of the P. gingivalis challenge, peri-implantitis fibroblasts sustained higher induction of IL-1beta, MCP-1, and MMP-1 compared to periodontitis fibroblasts. CONCLUSIONS: Fibroblasts from peri-implantitis and periodontitis lesions gave a more pronounced inflammatory response to the P. gingivalis challenge than fibroblasts from healthy donors. They may therefore be involved in the development of inflammation in peri-implantitis and periodontitis. Moreover, the sustained upregulation of inflammatory mediators and MMP-1 in peri implantitis fibroblasts may play a role in the pathogenesis of peri-implantitis. PMID- 23441815 TI - Stabilization and delivery approaches for protein and peptide pharmaceuticals: an extensive review of patents. AB - Proteins and peptides are the building blocks of human body and act as the arsenal to combat against the invading pathogenic organisms for treatment and management of diseases. Majority of such biomacromolecules are synthesized by the human body itself. However, entry of disease causing pathogens causes misleading in the synthesis of desired proteins for antibody formation. In such alarming situations, the delivery of requisite protein and peptide from external source helps in augmenting the body's immunity. The major drawbacks underlying poor biopharmaceutical performance of high molecular weight protein and peptide drugs are due to poor oral absorption, formulation stability, degradation in the gastric milieu, susceptible to presystemic metabolism. Numerous literature recounts the application of myriad drug delivery strategies for the effective delivery of protein and peptides viz. parentral, oral, transdermal, nasal, pulmonary, rectal, buccal and ocular drug delivery systems. There are many reviews on various delivery strategies for protein and peptide pharmaceuticals, but the present review article provides a bird's eye view on various novel drug delivery systems used for enhanced delivery of protein and peptide pharmaceuticals in the light of patent literature. Apart from this, the present manuscript endeavor provides idea on possible causes and major degradation pathways responsible for poor stability of protein and peptide drugs along with recent market instances on them utilizing novel drug delivery systems. PMID- 23441814 TI - Palladium-catalyzed synthesis of N-aryl carbamates. AB - An efficient synthesis of aryl carbamates was achieved by introducing alcohols into the reaction of palladium-catalyzed cross-coupling of ArX (X = Cl, OTf) with sodium cyanate. The use of aryl triflates as electrophilic components in this transformation allowed for an expanded substrate scope for direct synthesis of aryl isocyanates. This methodology provides direct access to major carbamate protecting groups, S-thiocarbamates, and diisocyanate precursors to polyurethane materials. PMID- 23441816 TI - Ca(2+) -calmodulin interacts with DdCAD-1 and promotes DdCAD-1 transport by contractile vacuoles in Dictyostelium cells. AB - The Ca(2+) -dependent cell-cell adhesion molecule DdCAD-1, encoded by the cadA gene of Dictyostelium discoideum, is synthesized at the onset of development as a soluble protein and then transported to the plasma membrane by contractile vacuoles. Calmodulin associates with contractile vacuoles in a Ca(2+) -dependent manner, and co-localizes with DdCAD-1 on the surface of contractile vacuoles. Bioinformatics analysis revealed multiple calmodulin-binding motifs in DdCAD-1. Co-immunoprecipitation and pull-down studies showed that only Ca(2+) -bound calmodulin was able to bind DdCAD-1. Structural integrity of DdCAD-1, but not the native conformation, was required for its interaction with calmodulin. To investigate the role of calmodulin in the import of DdCAD-1 into contractile vacuoles, an in vitro import assay consisting of contractile vacuoles derived from cadA(-) cells and recombinant proteins was employed. Prior stripping of the bound calmodulin from contractile vacuoles by EGTA impaired import of DdCAD-1, which was restored by addition of exogenous calmodulin. The calmodulin antagonists W-7 and compound 48/80 blocked the binding of calmodulin onto stripped contractile vacuoles, and inhibited the import of DdCAD-1. Together, the data show that calmodulin forms a complex with DdCAD-1 and promotes the docking and import of DdCAD-1 into contractile vacuoles. STRUCTURED DIGITAL ABSTRACT: CaM physically interacts with DdCAD-1 by pull down (View Interaction: 1, 2) DdCAD-1 binds to CaM by far western blotting (View interaction) DdCAD-1 physically interacts with CaM by anti bait coimmunoprecipitation (View interaction). PMID- 23441817 TI - Embryonic fibroblasts represent a connecting link between mesenchymal and embryonic stem cells. AB - It is well established that fibroblasts and mesenchymal stem cells (MSC) share several characteristics with subtle differences. However, no study highlighting the versatility of fibroblasts beyond their multipotentiality has been reported so far. Mouse embryonic fibroblasts (MEFs) are widely used as feeder layers to support the growth of embryonic stem cells (ESC). We hypothesized that MEF may retain ES-like features in concurrence to their developmental hierarchy in addition to their multipotent nature. Hence, we performed a comparative assessment of MEF and ESC to determine their ability to differentiate into cell types other than mesoderm as well as capacity to form teratoma using routine in vitro and in vivo techniques. MEF were derived by trypsin/ EDTA (ethylenediaminetetraacetic acid) digestion from E13.5 embryos after removing heads and viscera following plastic adherence. MEFs robustly proliferated in culture until passage 15 and formed aggregates by hanging drop method. Flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry revealed the presence of key MSC markers such as CD90, CD73, Sca-1, CD44, CD29, Vimentin and absence of CD45. Additionally, they expressed SSEA-1, Oct-4, Nanog, Sox-2 and ABCG2 as pluripotency markers; Nestin, beta-III tubulin, Otx-2 (ectoderm); MEF-2, Mesp2, GATA-2 (mesoderm) and GATA-4, alpha amylase, PDX-1 (endoderm) as tri-lineage markers. Furthermore, MEFs formed representative tissues from all three germ layers upon transplantation into Balb/c mice. These unique abilities of MEF to exhibit pluripotency, in addition to fibroblast characteristics and their ready availability with less ethical concerns and low maintenance requirements make them an attractive model for further exploration as a possible tool for regenerative medicine. PMID- 23441818 TI - Review of a new fully liquid, hexavalent vaccine: Hexaxim. AB - INTRODUCTION: The introduction of injectable vaccines targeting new diseases into childhood immunization programs has resulted in the need for combination vaccines to reduce the number of injections given during early childhood and maintain acceptability of targeting multiple pathogens by vaccination. Currently, there is only one licensed hexavalent combination vaccine which targets diphtheria, polio, tetanus, Haemophilus influenzae type b, hepatitis B and pertussis. A new, fully liquid formulation hexavalent vaccine ( Hexaxim ) has been developed and is currently undergoing licensure for use in childhood immunization programs. AREAS COVERED: Safety and immunogenicity studies of Hexaxim have been undertaken in a diversity of settings, been evaluated with different dosing schedules and in comparison to the other licensed hexavalent vaccine (Infanrix hexa). This review of published journal articles and conference proceeding is focused on the studies in which Hexaxim has been evaluated and which are contributing to its pending licensure. Non-inferiority was demonstrated at the level of proportion of children developing seroprotective titers or showing seroconversion following the primary series of vaccine compared to the same target-antigens included in licensed combination vaccines. Also, Hexaxim was associated with a favorable safety and tolerability profile when administered during the first 6 months of life. Adequate and robust memory responses were elicited following a booster dose in the second year of life. EXPERT OPINION: The development of new hexavalent combination vaccines targeting established pathogens is likely to assist in improving compliance and timeliness of vaccination in infants. These formulations will, however, need to be monitored for medium- and long-term effectiveness amidst growing concern of waning immunity against diseases such as pertussis when using acellular-pertussis vaccine and possibly hepatitis B when using combination vaccines. Nevertheless, the development of such combination vaccines remains necessary to help with the introduction of other new vaccines into an already crowded childhood immunization schedules. PMID- 23441819 TI - Antibiofilm activity, pH and solubility of endodontic sealers. AB - AIM: To evaluate antibiofilm activity against Enterococcus faecalis, pH and solubility of AH Plus, Sealer 26, Epiphany SE, Sealapex, Activ GP, MTA Fillapex (MTA-F) and an experimental MTA-based Sealer (MTA-S). METHODOLOGY: Sealer samples were manipulated and stored for 2 or 7 days. Prepared sealers were evaluated by a modified direct contact test (DCT) for 5 h, 10 h or 15 h with biofilm previously induced on bovine dentine for 14 days. In the control group, the biofilm was not exposed to the sealers. The number of colony-forming units (CFU mL(-1) ) in the remaining biofilm was determined. Sealer solubility was assessed by the percentage of mass loss after 15 h of immersion in distilled water. Sealer pH was measured at 5 h, 10 h and 15 h. Statistical analysis was performed using Kruskal Wallis and Dunn or anova and Tamhane's T2 tests, at 5% significance. RESULTS: At 2 days post-manipulation, the DCT showed that Sealapex and MTA-F were associated with a reduction in the number of bacteria in all 3 contact periods evaluated, compared with the control group (P < 0.05). At 7 days, Sealapex had the greatest antibiofilm action at 10 h and 15 h. Sealapex had the highest pH values 2 and 7 days post-manipulation. Regarding the solubility, at 2 days the highest values were observed for MTA-F, MTA-S, Sealapex and Activ GP (P < 0.05). At 7 days, MTA S and MTA-F had greater solubility than the other materials (P < 0.05). AH Plus had the lowest solubility for both post-manipulation periods (P < 0.05). CONCLUSION: Sealapex and MTA-F were associated with a reduction in the number of bacteria in biofilms and had greater solubility. The high solubility and pH may be related to the antibacterial activity of these materials. PMID- 23441821 TI - IL-8 -251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population. AB - OBJECTIVES: Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate NALP3 and mediate interleukin (IL)-1beta generation from its inactive pro-form, resulting in cellular activation and an IL-8-mediated neutrophil influx into the joint. IL-8 and IL-12 are important chemokines related to the initiation and amplification of acute and chronic inflammatory processes. In this study, we investigated whether the IL-8 -251T/A and IL-12 1188A/C polymorphisms are associated with susceptibility to gout in a Chinese Han male population. METHODS: Overall, 387 patients with gout and 576 controls were included in this study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). An association analysis was carried out using the chi2 test. A genotype-phenotype analysis was also conducted. RESULTS: The T allele of IL-8 251 was associated with risk of gout [p = 0.031 (odds ratio (OR) 1.229, 95% confidence interval (CI) 1.019-1.483]. There was a clear link between the IL-12 1188 AA and AC genotypic and A allelic frequencies between gout cases and controls (p < 0.001, df = 2 by genotype; p < 0.001, OR 1.404, 95% CI 1.165-1.691 by allele). CONCLUSIONS: Our results suggest that the IL-8 -251T/A and IL-12B 1188A/C polymorphisms may be relevant host susceptibility factors for the development of gout. PMID- 23441822 TI - A generalized Kruskal-Wallis test incorporating group uncertainty with application to genetic association studies. AB - Motivated by genetic association studies of SNPs with genotype uncertainty, we propose a generalization of the Kruskal-Wallis test that incorporates group uncertainty when comparing k samples. The extended test statistic is based on probability-weighted rank-sums and follows an asymptotic chi-square distribution with k - 1 degrees of freedom under the null hypothesis. Simulation studies confirm the validity and robustness of the proposed test in finite samples. Application to a genome-wide association study of type 1 diabetic complications further demonstrates the utilities of this generalized Kruskal-Wallis test for studies with group uncertainty. The method has been implemented as an open resource R program, GKW. PMID- 23441823 TI - Low oxidation state iron(0), iron(I), and ruthenium(0) dinitrogen complexes with a very bulky neutral phosphine ligand. AB - The synthesis of a series of iron and ruthenium complexes with the ligand P(2)P3(Cy), P(CH2CH2PCy2)3 is described. The iron(0) and ruthenium(0) complexes Fe(N2)(P(2)P3(Cy)) (1) and Ru(N2)(P(2)P3(Cy)) (2) were synthesized by treatment of [FeCl(P(2)P3(Cy))](+) and [RuCl(P(2)P3(Cy))](+) with an excess of potassium graphite under a nitrogen atmosphere. The Fe(I) and Ru(I) species [Fe(N2)(P(2)P3(Cy))](+) (3) and RuCl(P(2)P3(Cy)) (4) were synthesized by treatment of [FeCl(P(2)P3(Cy))](+) and [RuCl(P(2)P3(Cy))](+) with 1 equiv of potassium graphite under a nitrogen atmosphere. The cationic dinitrogen species [Fe(N2)H(P(2)P3(Cy))](+) (6) and [Ru(N2)H(P(2)P3(Cy))](+) (7) were formed by treatment of 1 and 3, respectively, with 1 equiv of a weak organic acid. The iron(II) complex Fe(H)2(P(2)P3(Cy)) (5) was also synthesized and characterized. Complexes [RuCl(P(2)P3(Cy))][BPh4], 1, 2, 3[BPh4], 4, 5, 6[BF4], and 7[BF4] were characterized by X-ray crystallography. The Fe(I) and Ru(I) complexes 3 and 4 were characterized by electron paramagnetic resonance (EPR) spectroscopy, and the Fe(I) complex has an EPR spectrum typical of a metal-centered radical. PMID- 23441824 TI - Factors associated with quality of life after attempted suicide: a cross sectional study. AB - AIMS AND OBJECTIVES: To describe factors associated with the subjective quality of life of individuals who had attempted suicide. BACKGROUND: Although quality of life has been a focus of concern in mental health care, data are lacking on what life is like and what factors are related to an individual's quality of life after a suicide attempt. DESIGN: A cross-sectional, descriptive design was used. METHODS: Participants comprised a convenience sample of 103 individuals who had attempted suicide within the previous three months and received follow-up care from one suicide-prevention centre in northern Taiwan. Participants were assessed for depression and quality of life using the Beck Depression Inventory, Taiwan version and the World Health Organisation Quality of Life Instrument-BREF, Taiwan version, respectively. RESULTS: Almost half the participants (n = 49) had severe depression and one-third of them (n = 30) reattempted suicide while receiving follow-up care. Depression and quality-of-life scores were statistically significantly inversely correlated. participants' quality-of-life scores were most associated with their depressive level, reattempting suicide during suicidal follow-up care, high educational level and older age. CONCLUSIONS: The present study indicates that factors associated with quality of life decreased more in individuals with moderate/severe depression than in those with mild depression. In addition, individuals who reattempted suicide during follow-up care were more likely to suffer from poor life quality. RELEVANCE TO CLINICAL PRACTICE: Mental health professionals should include frequent evaluation of depressive status and quality of life in follow-up care for patients who have recently attempted suicide. Particularly, mental health professionals must treat suicidal individuals with a high tendency to reattempt suicide by establishing trust with them and allowing them to narrate their painful experiences during follow-up care. PMID- 23441825 TI - HLA class II SNP interactions and the association with type 1 diabetes mellitus in Bengali speaking patients of Eastern India. AB - BACKGROUND: Several studies have demonstrated a fundamental role for the HLA in the susceptibility of, or protection to, type 1 diabetes mellitus (T1DM). However, this has not been adequately studied in Asian Indian populations. To assess the frequency of HLA class II (DPA1, DPB1, DQA1, DQB1 and DRB1) associated to susceptibility or protection toT1DM in a Bengali population of India with diabetes. RESULTS: Single nucleotide polymorphism study. The HLA genotyping was performed by a polymerase chain reaction followed by their HLA-DP, DQ, and DRB1 genotypes and haplotypes by sequencing method. The results are studied by Plink software. The chi2 tests were used for the inferential statistics. To our knowledge, this study is the first of a kind which has attempted to check the HLA association with T1DM by SNPs analysis. The study recruited 151 patients with T1DM and same number of ethno-linguistic, sex matched non-diabetic controls. The present study found a significant SNP rs7990 of HLA-DQA1 (p = 0.009) negative correlation, again indicating that risk from HLA is considerably more with T1DM. CONCLUSIONS: This study demonstrates that the HLA class-II alleles play a major role in genetic basis of T1DM. PMID- 23441826 TI - Eupalinilide E inhibits erythropoiesis and promotes the expansion of hematopoietic progenitor cells. AB - Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to all blood cells. The ability to control HSC differentiation has the potential to improve the success of bone marrow transplants and the production of functional blood cells ex vivo. Here we performed an unbiased screen using primary human CD34(+) hematopoietic stem and progenitor cells (HSPCs) to identify natural products that selectively control their differentiation. We identified a plant derived natural product, eupalinilide E, that promotes the ex vivo expansion of HSPCs and hinders the in vitro development of erythrocytes. This activity was additive with aryl hydrocarbon receptor (AhR) antagonists, which are also known to expand HSCs and currently in clinical development. These findings reveal a new activity for eupalinilide E, and suggest that it may be a useful tool to probe the mechanisms of hematopoiesis and improve the ex vivo production of progenitors for therapeutic purposes. PMID- 23441829 TI - Double C-H bond activation of hydrocarbons by a gas phase neutral oxide cluster: the importance of spin state. AB - The neutral cluster V2O5 is generated and detected in the gas phase. Its reactivity toward butane is studied both experimentally and theoretically. Experimental results show clearly that neutral V2O5 can react with n-butane (C4H10) to generate V2O5H2, indicating double hydrogen atom transfer from C4H10 to V2O5 to produce C4H8. Further experimental evidence indicates that V2O5 is only partially reacted even at very high concentrations of C4H10. Density functional theory (DFT) studies show that the lowest energy triplet state of V2O5 is reactive toward C4H10, whereas the ground state singlet V2O5 is inert. Calculated results are in agreement with experimental findings, and a detailed reaction mechanism is provided. Reactions of V2O5H2 with several oxidants are also studied theoretically to find a path to regenerate V2O5. Neutral (3)V2O5 can also react with C2H6 to form V2O5H2 and C2H4, but only as a minor reaction channel; the major product is the adsorption product V2O5(C2H6). PMID- 23441828 TI - Validation and cross-cultural adaptation of the Falls Efficacy Scale in patients with Parkinson's disease in Serbia. AB - AIM: The aim of the present study was to assess the validity and reliability of the Falls Efficacy Scale (FES) in Parkinson's disease (PD) patients in Serbia. METHODS: A cross-sectional study was carried out at the Clinic for Neurology, between June 2011 and June 2012. A total of 201 consecutive PD outpatients were recruited. The inclusion criteria were: ability to walk independently for at least 10 m, ability to stand for at least 90 s and a Mini-Mental State Examination score >24. The exclusion criteria were: the presence of other major neurological, psychiatric, visual, audio-vestibular and orthopedic disturbances. The 10-item FES was translated according to internationally-accepted methodology. The internal reliability of the Serbian version of the FES was evaluated using Cronbach's alpha coefficient. Reproducibility of the FES was evaluated using the Spearman-Brown coefficient. To evaluate construct validity, an exploratory factor analysis (principal component analysis, varimax rotation) was carried out. RESULTS: The internal consistency of the Serbian version of the FES was 0.98. Age, duration of disease, Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale motor score, history of falls, and the Hamilton depression and anxiety scores were significantly correlated with the total FES score. On factor analysis, all 10 items were compact in a one-factor cluster, with an explained variance of 85%. Spearman-Brown's correlation coefficient between the total scores was 0.99. CONCLUSIONS: The psychometric characteristics of the Serbian version of the FES have excellent reliability and validity as an instrument for measuring the fear of falling in PD patients. PMID- 23441830 TI - Palladium-catalyzed synthesis of aromatic carboxylic acids with silacarboxylic acids. AB - Aryl iodides and bromides were easily converted to their corresponding aromatic carboxylic acids via a Pd-catalyzed carbonylation reaction using silacarboxylic acids as an in situ source of carbon monoxide. The reaction conditions were compatible with a wide range of functional groups, and with the aryl iodides, the carbonylation was complete within minutes. The method was adapted to the double and selective isotope labeling of tamibarotene. PMID- 23441831 TI - Protein-fatty acid complexes: biochemistry, biophysics and function. AB - Thirteen years ago, alpha-lactalbumin (alpha-LA) was first reported to form a complex with oleic acid (OA). This complex, called HAMLET (human alpha lactalbumin made lethal to tumour cells), was found to be cytotoxic to cancer cells. In HAMLET, alpha-LA assumes a partially unfolded conformation and can bind OA in various stoichiometries. Subsequently, different groups have been able to prepare HAMLET-like cytotoxic complexes in different ways, which all involve the destabilization of alpha-LA, and a number of different proteins have been able to form similar complexes. This suggests that the ability to form stable complexes with lipids may be a generic feature of the polypeptide chain, although the precise structural and functional details may vary from protein to protein. We review the biophysical and biochemical properties of this class of complexes, focusing on different methods of preparation, complex structure and the role of the protein and the lipid within these complexes. The cellular effects of these complexes are multifaceted and depend on the cell types. There are strong indications that OA has an essential role, whereas the protein component, rather than having a toxic effect on its own, functions as a vehicle for transporting the toxic OA to the cells and keeping the OA in solution. Fatty acids alone can affect numerous cellular signalling and metabolic pathways, in addition to playing important roles in immune responses and inflammatory processes. Further studies will aim to determine how the molecular properties of the different protein-lipid complexes correlate with their biological efficacy. PMID- 23441832 TI - Editorial comment to on- and post-treatment symptom relief by repeated instillations of heparin and alkalized lidocaine in interstitial cystitis. PMID- 23441833 TI - Treatment of seborrheic dermatitis, comparison of sertaconazole 2% cream versus ketoconazole 2% cream. AB - Objective: There are controversies in the treatment of seborrheic dermatitis. The aim of this study was to compare the efficacy of sertaconazole 2% cream as against ketoconazole 2% cream in the treatment of seborrheic dermatitis. Methods: A total of 132 patients, who had been diagnosed of seborrheic dermatitis were studied. The first group received sertaconazole 2% cream (group A), and the other received ketoconazole 2% cream (group B). At the beginning of referring and also 2 and 4 weeks after first visit, the patients were examined by a dermatologist to control improvement of clinical symptoms and drug side effects. Results: The mean age of sertaconazole and ketoconazole group was 30.18 +/- 12.36 and 34.68 +/- 10.16, respectively. Patients with moderate Scoring Index (SI) had the most frequency (76.6%) at pretreatment stage with ketoconazole 2% cream. This is when patients with mild SI had the highest frequency (53.3%) at posttreatment stage. In patients who received the sertaconazole 2% cream, the highest frequency was observed in 80% of cases with moderate SI at pretreatment stage, while patients with slight SI had the highest frequency (83.3%) at posttreatment stage. Conclusion: Sertaconazole 2% cream may be an excellent alternative therapeutic modality for treating seborrheic dermatitis. PMID- 23441827 TI - Bang-bang model for regulation of local blood flow. AB - The classical model of metabolic regulation of blood flow in muscle tissue implies the maintenance of basal tone in arterioles of resting muscle and their dilation in response to exercise and/or tissue hypoxia via the evoked production of vasodilator metabolites by myocytes. A century-long effort to identify specific metabolites responsible for explaining active and reactive hyperemia has not been successful. Furthermore, the metabolic theory is not compatible with new knowledge on the role of physiological radicals (e.g., nitric oxide, NO, and superoxide anion, O2 (-) ) in the regulation of microvascular tone. We propose a model of regulation in which muscle contraction and active hyperemia are considered the physiologically normal state. We employ the "bang-bang" or "on/off" regulatory model which makes use of a threshold and hysteresis; a float valve to control the water level in a tank is a common example of this type of regulation. Active bang-bang regulation comes into effect when the supply of oxygen and glucose exceeds the demand, leading to activation of membrane NADPH oxidase, release of O2 (-) into the interstitial space and subsequent neutralization of the interstitial NO. Switching arterioles on/off when local blood flow crosses the threshold is realized by a local cell circuit with the properties of a bang-bang controller, determined by its threshold, hysteresis, and dead-band. This model provides a clear and unambiguous interpretation of the mechanism to balance tissue demand with a sufficient supply of nutrients and oxygen. PMID- 23441834 TI - Intensive dysarthria therapy for younger children with cerebral palsy. AB - AIM: The aim of this study was to investigate if intervention targeting breath support, phonation, and speech rate increases speech intelligibility and participation in the conversational interactions of younger children with dysarthria and cerebral palsy (CP). METHOD: Fifteen children with dysarthria and CP (nine males, six females; age range 5-11 y, mean age 8 y, SD 2 y; CP type: eight spastic, four dyskinetic, one ataxia, two Worster Drought syndrome; Gross Motor Function Classification System levels II-IV, median level II) participated in this study. Children received three sessions of individual therapy per week for 6 weeks. Intelligibility of single words and connected speech was compared across five points: 1 and 6 weeks before therapy and 1, 6, and 12 weeks after therapy. Three familiar listeners and three unfamiliar listeners scored each recording. Participation in communicative interactions was measured using the Focus on the Outcomes of Communication Under Six (FOCUS) tool. Analyses of variance and paired t-tests were used to investigate change. RESULTS: Mean speech intelligibility increased after therapy to familiar listeners (single words 10.8%, 95% confidence interval [CI] 7.2-14.4; connected speech 9.4%, 95% CI 4.8 14.1) and unfamiliar listeners (single words 9.3%, 95% CI 6.8-11.8; connected speech 10.5%, 95% CI 7.3-13.8). FOCUS scores increased following therapy for parents (mean increase 30.3, 95% CI 10.2-50.4) and for teachers (28.25, 95% CI 14.4-42.1), but changes did not correlate with intelligibility. A wide variation was seen in individual responses to therapy. INTERPRETATION: Brief intensive therapy is associated with gains in intelligibility and communicative interactions for some younger children with dysarthria. PMID- 23441835 TI - Hypertensive patients' experience with adherence therapy for enhancing medication compliance: a qualitative exploration. AB - AIMS AND OBJECTIVES: To investigate the experience of non-compliant hypertensive patients who had received seven sessions of adherence therapy (AT) as part of a randomised controlled trial. BACKGROUND: AT is a patient-centred approach used to explore patient attitudes, beliefs and discrepancy toward medications that aimed to enhance patients' medication-taking behaviour. DESIGN: Qualitative analysis of semi-structured interviews with patients who had completed an AT intervention. METHODS: A convenience sample of 10 hypertensive patients who received AT as part of an exploratory randomised controlled trial (ISRCTN99494659) were included. Thematic analysis of semi-structured interviews exploring patient's views and experiences of AT was used. RESULTS: Five major themes of AT emerged; modifying attitudes and beliefs, positive impact on self efficacy, therapist motivation, positive impact on well-being and a well-designed intervention. CONCLUSIONS: patients' views about the benefit of AT were entirely consistent with our proposed mechanism of action for this intervention; that is by improving patient's beliefs and attitudes regarding taking drugs, and finding solutions to barriers that prevent adherence, patients become more complaint with their medication which in turn has a positive impact on clinical outcomes [i.e. blood pressure, hypertension complication (stroke, myocardial infarction, and recurrent hospitalisation)]. RELEVANCE TO CLINICAL PRACTICE: Exploring patients' experience with AT and recognising these five elements help in tailoring a new effective strategy according to individual needs for enhancing adherence to prescribed drugs. PMID- 23441836 TI - Assessment of viable periodontal pathogens by reverse transcription quantitative polymerase chain reaction. AB - BACKGROUND AND OBJECTIVE: Molecular biological methods for the detection of periodontitis-associated bacteria based on DNA amplification have many advantages over classical culture techniques. However, when it comes to assessing immediate therapeutic success, e.g. reduction of viable bacteria, DNA-based polymerase chain reaction is unsuitable because it does not distinguish between live and dead bacteria. Our objective was to establish a simple RNA-based method that is easily set up and allows reliable assessment of the live bacterial load. MATERIAL AND METHODS: We compared conventional quantitative real-time PCR (qPCR), propidium monoazide-qPCR and reverse transcription qPCR (RT-qPCR) for the detection of periodontal pathogens after antibiotic treatment in vitro. Applicability was tested using clinical samples of subgingival plaque obtained from patients at different treatment stages. RESULTS: The bacterial load was remarkably stable over prolonged periods when assessed by conventional qPCR, while both propidium monoazide intercalation as well as cDNA quantitation showed a decline according to decreasing numbers of viable bacteria after antibiotic treatment. Clinical samples of subgingival plaque were directly subjected to DNase I treatment and RT without previous extraction or purification steps. While the results of the DNA- and RNA-based methods are comparable in untreated patients, the classical qPCR frequently detected substantial bacterial load in treated patients where RT-qPCR no longer indicates the presence of those pathogens. The disagreement rates ranged between 4 and 20% in first visit patients and 8-50% in the group of currently treated patients. CONCLUSION: We propose to use RNA-based detection methods to verify the successful eradication of periodontal pathogens. PMID- 23441838 TI - L-carnosine modulates respiratory burst and reactive oxygen species production in neutrophil biochemistry and function: may oral dosage form of non-hydrolized dipeptide L-carnosine complement anti-infective anti-influenza flu treatment, prevention and self-care as an alternative to the conventional vaccination? AB - Influenza A is a viral disease of global dimension, presenting with high morbidity and mortality in annual epidemics, and in pandemics which are of infrequent occurrence but which have very high attack rates. Influenza vaccines of the future must be directed toward use of conserved group-specific viral antigens, such as are present in transitional proteins which are exposed during the fusion of virus to the host cell. Influenza probes revealed a continuing battle for survival between host and parasite in which the host population updates the specificity of its pool of humoral immunity by contact with and response to infection with the most recent viruses which possess altered antigenic specificity in their hemagglutinin (HA) ligand. It is well known that the HA protein is found on the surface of the influenza virus particle and is responsible for binding to receptors on host cells and initiating infection. Polymorphonuclear neutrophils (PMN) have been reported to be involved in the initial host response to influenza A virus (IAV). Early after IAV infection, neutrophils infiltrate the airway probably due to release of chemokines that attract PMN. Clearly, severe IAV infection is characterized by increased neutrophil influx into the lung or upper respiratory tract. Carnosine (beta alanyl-L-histidine) and anserine (N-beta-alanyl-1-methyl-L-histidine) are found in skeletal muscle of most vertebrates, including those used for food; for example, 100 g of chicken breast contains 400 mg (17.6 mmol/L) of carnosine and 1020 mg (33.6 mmol/l) of anserine. Carnosine-stimulated respiratory burst in neutrophils is a universal biological mechanism of influenza virus destruction. Our own studies revealed previously unappreciated functional effects of carnosine and related histidine containing compounds as a natural biological prevention and barrier against Influenza virus infection, expand public understanding of the antiviral properties of imidazole-containing dipeptide based compounds, and suggest important interactions between neutrophills and carnosine related compounds in the host response to viruses and bacteria. Carnosine and anserine were also found to reduce apoptosis of human neutrophils. In this way these histidine-containing compounds can modulate the Influenza virus release from neutrophills and reduce virus dissemination through the body of the organism. This review points the ability of therapeutic control of Influenza viral infections associated with modulation by oral nonhydrolized forms of carnosine and related histidine-containg compounds of PMN apoptosis which may be involved at least in part in the pathophysiology of the disease in animals and humans. The data presented in this article, overall, may have implications for global influenza surveillance and planning for pandemic influenza therapeutic prevention with oral forms of non-hydrolized natural L-carnosine as a suitable alternative to the conventional vaccination for various flu ailments. PMID- 23441837 TI - Own-body perception in body dysmorphic disorder. AB - INTRODUCTION: This paper reviews the literature as it relates to perceptual processes in body dysmorphic disorder (BDD). METHODS: A narrative-style review of the literature was undertaken to explore the relationship between BDD and obsessive-compulsive disorder, the empirical evidence for aberrant own-body perception in BDD, and the possible role of the parietal cortex in the disorder. RESULTS: The extant literature appears to support the postulation that BDD is underpinned by a dysfunction in somatoperception-the process by which individuals formulate a sense of what they look like. CONCLUSIONS: Investigation of somatoperceptive processes in BDD and related brain structures would provide important insight about the development and maintenance of this complex and often neglected psychiatric condition, and, in turn, help improve its treatment. PMID- 23441839 TI - Analysis of horse movements from non-commercial horse properties in New Zealand. AB - AIMS: To investigate property-level factors associated with the movement of horses from non-commercial horse properties, including the size and location of the property, number and reason for keeping horses. METHODS: Using a cross sectional survey 2,912 questionnaires were posted to randomly selected non commercial horse properties listed in a rural property database. The survey collected information about the number of horses, and reasons for keeping horses on the property, and any movement of horses in the previous 12 months. Three property-level outcomes were investigated; the movement status of the property, the frequency of movement events, and the median distance travelled from a property. Associations were examined using logistic regression and Kruskal-Wallis analysis of variance. RESULTS: In total 62.0% (488/791) of respondents reported at least one movement event in the year prior to the survey, for a total of 22,050 movement events. The number of movement events from a property varied significantly by the number of horses on the property (p<0.02), while the median distance travelled per property varied significantly by both region (p<0.03) and property size (p<0.01). Region, property size, the number of horses kept, and keeping horses for competition, recreation, racing or as pets were all significantly associated with movement status in the multivariable analyses (p<0.001). CONCLUSION AND CLINICAL RELEVANCE: This study showed that there are characteristics of non-commercial horse properties that influence movement behaviour. During an exotic disease outbreak the ability to identify properties with these characteristics for targeted control will enhance the effectiveness of control measures. PMID- 23441840 TI - Dependence of bicellar system phase behavior and dynamics on anionic lipid concentration. AB - Bicellar dispersions of chain perdeuterated 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC-d54) and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) were prepared with the molar fraction of DHPC held fixed at 20% and varying amounts of DMPC replaced by the anionic lipid 1,2-dimyristoyl-sn-glycero-3 phospho-(1'-rac-glycerol) (DMPG). (2)H NMR spectra were examined to assess the effect of added DMPG on mixture phase behavior and morphology. Quadrupole echo decay and quadrupole-Carr-Purcell-Mieboom-Gill echo train measurements provided information about slow motions contributing to echo decay in the high temperature phases. The spectra and quadrupole echo decay properties of DMPC-d54/DHPC (4:1) and DMPC-d54/DMPG/DHPC (3:1:1) were qualitatively similar. With increasing DMPG concentration, the transition between the magnetically orientable phase and the higher temperature phase became increasingly distinct, and the spectral shape and echo decay characteristics of the high temperature bicellar phase became increasingly similar to those of DMPC-d54 in the liquid crystalline phase. The observation that DMPG changes spectra in the orientable phase incrementally while increasing the distinction between the orientable and high temperature bicellar phases provides new insights into how DMPG influences bicellar mixture morphology. PMID- 23441841 TI - Effects of berberine on lipid profile in subjects with low cardiovascular risk. AB - OBJECTIVE: To evaluate the efficacy as antihypercholesterolemic agent of berberine in patients with low cardiovascular risk. RESEARCH DESIGN AND METHODS: 144 Caucasian subjects were enrolled. After a 6-month run-in period following diet and practicing physical activity, patients were randomized to take placebo or berberine 500 mg twice a day, for 3 months, in a double-blind, placebo controlled design. Berberine and placebo were then interrupted for 2 months (washout period), and all patients continued with only diet and physical activity. At the end of the washout period, patients restarted berberine or placebo twice a day for further 3 months. Anthropometric and metabolic parameters were assessed during the run-in period, at randomization, before and after the washout period. RESULTS: A decrease of body weight and BMI was observed after the run-in period. Berberine reduced total cholesterol, triglycerides and LDL cholesterol and increased HDL cholesterol after 3 months from randomization and compared with placebo. After the washout period, lipid profile worsened; afterward, when berberine was reintroduced, lipid profile improved again both compared with the washout period, and with placebo. CONCLUSIONS: Berberine is effective and safe to mildly improve lipid profile in subjects with low risk for cardiovascular disease. PMID- 23441842 TI - Covalent grafting of organic-inorganic polyoxometalates hybrids onto mesoporous SBA-15: a key step for new anchored homogeneous catalysts. AB - Covalent grafting of heteropolyanions hybrids B,alpha [As(III)W9O33{P(O)(CH2CH2CO2H)}2](5-) on 3-aminopropyl functionalized SBA-15 has been achieved through the formation of peptide bonds. The covalent link has been confirmed by using IR and (13)C CP MAS NMR spectroscopies. Electrostatic interactions between carboxylate and protonated amines have been discarded on the basis of the retention of POMs after repeated washings of the resulting material by ionic liquid (bmimCl). This is the first example of anchored monovacant polyoxometalates (POM) in which nucleophilic oxygen atoms are still available after incorporation into mesoporous supports. Further characterization of the textural properties of grafted materials has shown that they still retain an important mesoporosity, which is compatible with their potential use in heterogeneous catalysis. Such systems are thus interesting candidates for the preparation of anchored homogeneous catalysts in which the POMs would play the role of polydentate inorganic ligands for the active centers. PMID- 23441843 TI - Epigenetic reactivation of Nrf2 in murine prostate cancer TRAMP C1 cells by natural phytochemicals Z-ligustilide and Radix angelica sinensis via promoter CpG demethylation. AB - Cancer development has been linked to epigenetic modifications of cancer oncogenes and tumor suppressor genes; in advanced metastatic cancers, severe epigenetic modifications are present. We previously demonstrated that the progression of prostate tumors in TRAMP mice is associated with methylation silencing of the Nrf2 promoter and a reduced level of transcription of Nrf2 and Nrf2 target genes. Radix Angelicae Sinensis (RAS; Danggui) is a medicinal herb and health food supplement that has been widely used in Asia for centuries. Z Ligustilide (Lig) is one of the bioactive components of RAS. We investigated the potential of Lig and RAS to restore Nrf2 gene expression through epigenetic modification in TRAMP C1 cells. Lig and RAS induced the mRNA and protein expression of endogenous Nrf2 and Nrf2 downstream target genes, such as HO-1, NQO1, and UGT1A1. Bisulfite genomic sequencing revealed that Lig and RAS treatment decreased the level of methylation of the first five CpGs of the Nrf2 promoter. A methylation DNA immunoprecipitation assay demonstrated that Lig and RAS significantly decreased the relative amount of methylated DNA in the Nrf2 gene promoter region. Lig and RAS also inhibited DNA methyltransferase activity in vitro. Collectively, these results suggest that Lig and RAS are able to demethylate the Nrf2 promoter CpGs, resulting in the re-expression of Nrf2 and Nrf2 target genes. Epigenetic modifications of genes, including Nrf2, may therefore contribute to the overall health benefits of RAS, including the anticancer effect of RAS and its bioactive component, Lig. PMID- 23441844 TI - Weight of apically extruded debris following use of two canal instrumentation techniques and two designs of irrigation needles. AB - AIM: To compare the weight of apically extruded debris associated with canal shaping using K-files, and the Revo-S system using two different needle tips, open-ended and side-vented. METHODOLOGY: Forty freshly extracted mandibular premolar teeth were divided into four groups as follows; Group 1a: Hand instrumentation of root canal with open-ended needle used to provide irrigation, Group 1b: Hand instrumentation with a two side-port needle, Group 2a: Revo-S preparation with open-ended needle, Group 2b: Revo-S preparation with a two side port needle. One Eppendorf tube for each tooth was weighed with a 0.0001 electronic weighing machine before instrumentation procedures. During instrumentation, irrigation was performed after every instrument with 1 mL distilled water. On completion of the preparation, teeth were removed from the Eppendorf tubes. All of the tubes were incubated at 37 degrees C for 15 days, to evaporate the irrigant. After the incubation period, tubes were weighed again. The difference between pre-and post-debris weights was calculated, and statistical evaluation was performed using analysis of variance at 0.05 level of significance. RESULTS: No statistically significant difference was observed between K-files and the RevoS system. A significant difference was observed between needles (P < 0.05). Open-ended needles were associated with significantly more debris than side-vented needles (P < 0.05). CONCLUSIONS: Both hand and rotary canal instrumentation resulted in extrusion of debris beyond the apical foramen. No significant difference was observed between K-files and Revo-S system. Open-ended needles were associated with significantly more extruded debris than two side-port needles. PMID- 23441845 TI - Extracorporeal shockwave lithotripsy for renal stones in pediatric patients: a multivariate analysis model for estimating the stone-free probability. AB - OBJECTIVES: To define factors affecting the stone-free rate of extracorporeal shockwave lithotripsy in the treatment of pediatric renal calculi, and to establish a regression model for pretreatment prediction of stone-free probability. METHODS: From January 1999 through February 2012, 207 children with mean age 6.4 +/- 3.8 years underwent shockwave lithotripsy with Dornier Lithotripter S for treatment of renal stones. The stone-free rate was evaluated 3 months after the last shockwave lithotripsy session with non-contrast computed tomography. Treatment success was defined as complete clearance of the stones with no residual fragments. Multivariate logistic regression analysis was used to identify independent risk factors and to predict the probability of being stone free. RESULTS: The mean length of the stone was 11.6 +/- 4 mm. The stone-free rate was 71%. Independent factors that adversely affect stone-free rate were increasing stone length and calyceal site of the stone. Relative risks for not being free of stones were 1.123 for stone length, 2.673 for stones in the upper or middle calyx and 4.208 for lower calyx stones. CONCLUSION: Stone length and location are prognostic factors determining stone-free rate after shockwave lithotripsy for renal calculi in pediatric patients. Based on our analysis, shockwave lithotripsy should be recommended for renal pelvis stones up to 24 mm, upper or middle calyceal stones up to 15 mm and lower calyceal stones up to 11 mm. PMID- 23441846 TI - Syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C. AB - Divergent syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C have been achieved. The synthesis of the C15-C25 fragment featured cobalt-catalyzed modified Mukaiyama aerobic alkenol cyclization and sulfur-directed regiocontrolled Wacker oxidation of an internal alkene. The C1-C14 fragment was established by alkenyllithium addition to an aldehyde followed by a challenging olefination of a highly inert C9 ketone. PMID- 23441847 TI - Effects of an internal medicine floor interdisciplinary team on hospital and clinical outcomes of seniors with acute medical illness. AB - AIM: To examine whether an internal medicine interdisciplinary floor team enhances the hospital and clinical outcomes for seniors with acute medical illness. METHODS: Seniors admitted to medical floor teaching services of a USA teaching hospital were recruited and allocated to the interdisciplinary (ITD; n = 236) and usual care teams (n = 248). Compared with the usual care team, the interdisciplinary team physicians carried out daily "geriatric" assessment and management, and led the interdisciplinary team meeting designed for improving interprofessional collaboration. RESULTS: After controlling for patient and physician characteristics, the mean hospital length of stay in the ITD team (6.1 days; 95% CI 5.2-7.7 days) was 0.7 days shorter than that in the usual care team (6.8 days; 95% CI 5.7-8.3 days; P = 0.008). There was no significant difference in delirium and 30-day hospital readmission between care groups. CONCLUSIONS: Notwithstanding partly positive associations, the results from the present study suggest that interdisciplinary team-based care is, at best, associated with enhancing the clinical and hospital outcomes for seniors with acute medical illness. PMID- 23441848 TI - Electronically excited states of protonated aromatic hydrocarbons: phenanthrene and pyrene. AB - The first and second electronic excited states (S1 and S2) of protonated phenanthrene and protonated pyrene, having the pipi* nature, are strongly red shifted compared to corresponding electronic transitions in neutral homologues. The CC2 calculations identify an out-of-plane deformation as the most important photochemical reaction coordinate in protonated phenanthrene as well as protonated benzene. It was shown that the excited S1 states of protonated phenanthrene and protonated benzene are unstable via a torsional motion, which provides a fast access to a S1-S0 conical intersection. From the conical intersection, a barrier-less reaction path directs the system back to the minimum of the S0 potential-energy surface. In contrast to the most stable isomer of protonated phenanthrene, the most stable structure of protonated pyrene shows planar structure in both the S1 and S2 excited states, without considerable geometry deformations. PMID- 23441849 TI - The genomic consequences of adaptive divergence and reproductive isolation between species of manakins. AB - The processes of adaptation and speciation are expected to shape genomic variation within and between diverging species. Here we analyze genomic heterogeneity of genetic differentiation and introgression in a hybrid zone between two bird species (Manacus candei and M. vitellinus) using 59 100 SNPs, a whole genome assembly, and Bayesian models. Measures of genetic differentiation (FST) and introgression (genomic cline center [alpha] and rate [beta]) were highly heterogeneous among loci. We identified thousands of loci with elevated parameter estimates, some of which are likely to be associated with variation in fitness in Manacus populations. To analyze the genomic organization of differentiation and introgression, we mapped SNPs onto a draft assembly of the M. vitellinus genome. Estimates of FST, alpha, and beta were autocorrelated at very short physical distances (< 100 bp), but much less so beyond this. In addition, average statistical associations (linkage disequilibrium) between SNPs were generally low and were not higher in admixed populations than in populations of the parental species. Although they did not occur with a constant probability across the genome, loci with elevated FST, alpha, and beta were not strongly co localized in the genome. Contrary to verbal models that predict clustering of loci involved in adaptation and isolation in discrete genomic regions, these results are consistent with the hypothesis that genetic regions involved in adaptive divergence and reproductive isolation are scattered throughout the genome. We also found that many loci were characterized by both exceptional genetic differentiation and introgression, consistent with the hypothesis that loci involved in isolation are also often characterized by a history of divergent selection. However, the concordance between isolation and differentiation was only partial, indicating a complex architecture and history of loci involved in isolation. PMID- 23441851 TI - Substrate-specific conformational regulation of the receptor tyrosine kinase VEGFR2 catalytic domain. AB - The contributions of the phosphoacceptor and the catalytic domain context to protein kinase biology and inhibitor potency are routinely overlooked, which can lead to mischaracterization of inhibitor and receptor functions. The receptor tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR2) is studied as a model system using a series of phosphoacceptor substrates (k(cat)/K(m) 684 116,000 M(-1) s(-1)) to assess effects on catalysis and inhibitor binding. ATP competitive inhibitor potency toward the VEGFR2 catalytic domain (VEGFR2-CD) varies with different phosphoacceptor substrates, which is unexpected because the phosphoacceptors do not affect K(m,ATP) values. Indazole-based inhibitors are up to 60-fold more potent with two substrates (gastrin, minigastrin) relative to the others. Thus there is a component of uncompetitive inhibition because a specific phosphoacceptor enhances potency but is not strictly required. This substrate specific inhibitory potency enhancement correlates with phosphoacceptor active site saturation and is not observed with other related kinases. The effect is confined to a specific catalytic domain conformation because autophosphorylation eliminates the potency enhancement as does the addition of the juxtamembrane domain (20 amino acids). Indazole inhibitor structure-activity analysis reveals that the magnitude of potency enhancement correlates with the size of the substituent that binds in a regulatory region of the active site. VEGFR drugs profiled with VEGFR2-CD using minigastrin have potency well-correlated with inhibition of full-length, cellular VEGFR2 autophosphorylation, an indication that the minigastrin-induced conformation is biologically relevant. These findings raise the possibility that inhibitors directed toward a common target can have different biological effects based on the kinase-substrate complexes present in different cellular contexts. PMID- 23441850 TI - Isorhamnetin inhibits Prevotella intermedia lipopolysaccharide-induced production of interleukin-6 in murine macrophages via anti-inflammatory heme oxygenase-1 induction and inhibition of nuclear factor-kappaB and signal transducer and activator of transcription 1 activation. AB - BACKGROUND AND OBJECTIVE: Interleukin-6 (IL-6) is a key proinflammatory cytokine that has been considered to be important in the pathogenesis of periodontal disease. Therefore, host-modulatory agents directed at inhibiting IL-6 appear to be beneficial in terms of attenuating periodontal disease progression and potentially improving disease susceptibility. In the current study, we investigated the effect of the flavonoid isorhamnetin on the production of IL-6 in murine macrophages stimulated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in inflammatory periodontal disease, and its mechanisms of action. MATERIAL AND METHODS: Lipopolysaccharide from P. intermedia ATCC 25611 was isolated using the standard hot phenol-water method. Culture supernatants were collected and assayed for IL-6. We used real-time PCR to quantify IL-6 and heme oxygenase-1 (HO-1) mRNA expression. The expression of HO-1 protein and the levels of signaling proteins were monitored using immunoblot analyses. The DNA-binding activity of nuclear factor-kappaB (NF-kappaB) was analyzed using ELISA-based assay kits. RESULTS: Isorhamnetin significantly down regulated P. intermedia LPS-induced production of IL-6 as well as its mRNA expression in RAW264.7 cells. Isorhamnetin up-regulated the expression of HO-1 at both gene transcription and translation levels in cells stimulated with P. intermedia LPS. In addition, inhibition of HO-1 activity by tin protoporphyrin IX blocked the inhibitory effect of isorhamnetin on IL-6 production. Isorhamnetin failed to prevent LPS from activating either c-Jun N-terminal kinase or p38 pathways. Isorhamnetin did not inhibit NF-kappaB transcriptional activity at the level of inhibitory kappaB-alpha degradation. Isorhamnetin suppressed NF-kappaB signaling through inhibition of nuclear translocation and DNA binding activity of NF-kappaB p50 subunit and attenuated signal transducer and activator of transcription 1 signaling. CONCLUSION: Although further research is required to clarify the detailed mechanism of action, we propose that isorhamnetin may contribute to blockade of the host-destructive processes mediated by IL-6 and could be a highly efficient modulator of the host response in the treatment of inflammatory periodontal disease. Further research in animal models of periodontitis is required to better evaluate, the potential of isorhamnetin as a novel agent for treating periodontal disease. PMID- 23441852 TI - The corepressor activity of Alien is controlled by CREB-binding protein/p300. AB - The regulation of gene repression by corepressors is a controlled process. Surface-enhanced laser desorption ionization MS proteomic analysis and a yeast two-hybrid screen showed independently that the corepressor Alien interacts with the CREB-binding protein (CBP) coactivator. This interaction was further confirmed by coimmunoprecipitation and glutathione S-transferase pull-down experiments, suggesting that Alien interacts in vivo and in vitro with the histone acetyltransferase (HAT) coactivators CBP and its paralog p300. Acetylation detection experiments indicated that Alien is acetylated in vivo. Furthermore, Alien interacts with the central region of CBP/p300 containing the HAT domain and becomes acetylated in vitro. When an inhibitor of CBP/p300 HAT activity was employed, the Alien-mediated silencing was enhanced. Thus, these findings suggest crosstalk between corepressors and coactivators, and indicate fine-tuning of corepressor function by post-translational modification through corepressor acetylation. STRUCTURED DIGITAL ABSTRACT: p300 binds to Alien α by pull down (View interaction) Alien α physically interacts with CBP by two hybrid (View interaction) Alien α physically interacts with MLK2 by two hybrid (View interaction) p300 acetylates Alien α by acetylation assay (View interaction) Alien α physically interacts with NAP1 by two hybrid (View interaction) Alien α physically interacts with TAFI68 by two hybrid (View interaction) Alien α physically interacts with CBP by anti bait coimmunoprecipitation (View Interaction: 1, 2, 3) Alien α binds to CBP by pull down (View interaction). PMID- 23441854 TI - Tissue oxygen demand in regulation of the behavior of the cells in the vasculature. AB - The control of arteriolar diameters in microvasculature has been in the focus of studies on mechanisms matching oxygen demand and supply at the tissue level. Functionally, important vascular elements include EC, VSMC, and RBC. Integration of these different cell types into functional units aimed at matching tissue oxygen supply with tissue oxygen demand is only achieved when all these cells can respond to the signals of tissue oxygen demand. Many vasoactive agents that serve as signals of tissue oxygen demand have their receptors on all these types of cells (VSMC, EC, and RBC) implying that there can be a coordinated regulation of their behavior by the tissue oxygen demand. Such functions of RBC as oxygen carrying by Hb, rheology, and release of vasoactive agents are considered. Several common extra- and intracellular signaling pathways that link tissue oxygen demand with control of VSMC contractility, EC permeability, and RBC functioning are discussed. PMID- 23441853 TI - Tractography of white-matter tracts in very preterm infants: a 2-year follow-up study. AB - AIM: The aim of this study was to determine whether tractography of white-matter tracts can independently predict neurodevelopmental outcome in very preterm infants. METHOD: Out of 84 very preterm infants admitted to a neonatal intensive care unit, 64 (41 males, 23 females; median gestational age 29.1 weeks [range 25.6-31.9]; birthweight 1163 g [range 585-1960]) underwent follow-up at 2 years. Diffusion tensor imaging (DTI) values obtained around term were associated with a neurological examination and mental and psychomotor developmental index scores at 2 years based on the Bayley Scales of Infant Development (version 3). Univariate and logistic regression analyses tested for associations between DTI values and follow-up parameters. Cut-off values predicting motor delay and cerebral palsy (CP) were determined for fractional anisotropy, apparent diffusion coefficient (ADC), and fibre lengths. RESULTS: Infants with psychomotor delay and CP had significantly lower fractional anisotropy values (p=0.002, p=0.04 respectively) and shorter fibre lengths (p=0.02, p=0.02 respectively) of the posterior limb of the internal capsule. Infants with psychomotor delay also had significantly higher ADC values (p=0.03) and shorter fibre lengths (p=0.002) of the callosal splenium. Fractional anisotropy values of the posterior limb of the internal capsule independently predicted motor delay and CP, with sensitivity between 80 and 100% and specificity between 66 and 69%. ADC values of the splenium independently predicted motor delay with sensitivity of 100% and specificity of 65%. INTERPRETATION: Diffusion tensor imaging tractography at term-equivalent age independently predicts psychomotor delay at 2 years of age in preterm infants. PMID- 23441855 TI - Erbium: YAG laser ablation versus 70% trichloroacetic acid application in the treatment of xanthelasma palpebrarum. AB - BACKGROUND: Xanthelasma palpebrarum (XP) is characterized by soft, yellow plaques on the upper or lower eyelids that create aesthetic problems for patients. There are several methods in the treatment of XP, such as surgical excision, blepharoplasty, cryotherapy, electrocauterization, chemical cauterization using trichloroacetic acid (TCA) or bichloroacetic acid and laser ablation. OBJECTIVE: To evaluate the efficiency and complications of 70% TCA application versus erbium: YAG laser ablation in different XP lesions on the same patient. METHODS: A total of 21 patients were taken into the study-1 male and 20 females, from ages 22 to 70 years. Erbium: YAG laser ablation and 70% TCA application were performed in different XP lesions of the same patient. All patients were photographed before initiating treatment and after 4 weeks using the same digital camera. Evaluation was performed 4 weeks after the first treatment session by comparing pre-treatment and post-treatment photographs by two independent dermatologists. RESULTS: No significant difference of the improvement scores between the erbium laser and TCA was found (p = 0.248). No significant difference between the complication scores using erbium laser and TCA was found (p = 0.739). CONCLUSIONS: Both 70% TCA application and erbium: YAG laser ablation methods have similar effectiveness and complication rates. PMID- 23441856 TI - Swine liver methylomes of Berkshire, Duroc and Landrace breeds by MeDIPS. AB - Using a methyl-DNA immunoprecipitation technique in combination with next generation deep sequencing, we conducted comprehensive DNA methylation profiling of liver genomes from three pig breeds: Berkshire, Duroc and Landrace. The profiles revealed that the distribution patterns of methylation signals along the genome are conserved among the three pig breeds. Specifically, many signals in coding genes were found in introns, and most signals in the repetitive elements were identified in non-long terminal repeat (LTR) retrotransposons such as long and short interspersed repetitive elements, implying a significant association with alternative splicing and expression of retrotransposable elements respectively. Differentially methylated regions among the three pig breeds were identified in the non-LTR retrotransposons, suggesting that they may lead to differential retrotransposable element activity. Altogether, this study provides advanced swine methylome data and valuable resources for understanding the function of DNA methylation in the evolutionary divergence of different pig breeds. PMID- 23441857 TI - Signs of increased cortical hyperexcitability selectively associated with spontaneous anomalous bodily experiences in a nonclinical population. AB - INTRODUCTION: The current study examined the presence of cortical hyperexcitability, in nonclinical hallucinators, reporting different forms of anomalous bodily experiences (ABEs). Groups reporting visual out-of-body experiences and nonvisual sensed-presence experiences were examined. It was hypothesised that only those hallucinators whose experiences contained visual elements would show increased signs of visual cortical hyperexcitability. METHODS: One hundred and eighty-two participants completed the "Pattern-glare task" (involving the viewing of striped gratings with spatial frequencies irritable to visual cortex)-a task known to reflect degrees of cortical hyperexcitability associated with hallucinatory/aura experiences in neurological samples. Participants also completed questionnaire measures of anomalous "temporal-lobe experience" and predisposition to anomalous visual experiences. RESULTS: Those reporting increased levels of anomalous bodily experiences provided significantly elevated scores on measures of temporal-lobe experience. Only the visual OBE group reported significantly elevated levels of cortical hyperexcitability as assessed by the pattern-glare task. CONCLUSIONS: Collectively, the results are consistent with there being an increased degree of background cortical hyperexcitability in the cortices of individuals predisposed to some ABE-type hallucinations, even in the nonclinical population. The present study also establishes the clinical utility of the pattern-glare task for examining signs of aberrant visual connectivity in relation to visual hallucinations. PMID- 23441858 TI - Equine multisystemic eosinophilic epitheliotropic disease: a case report and review of literature. AB - CASE HISTORY: A 2-year-old Standardbred gelding presented with a history of fever over 1 week, anorexia and skin lesions on all four legs. The lesions were associated with severe pruritus and oedema, and there was no response to therapy. CLINICAL FINDINGS: The horse was in poor body condition, was lethargic and severely pruritic. Skin lesions consisted of diffuse alopecia and crusting of the distal extremities. Initially it was slightly febrile, but subsequently its temperature increased up to 40 degrees C. Ten days after admission it developed profuse watery diarrhoea and the skin lesions progressed. Skin biopsies revealed superficial and deep perivascular dermatitis with lymphoplasmacytic and eosinophilic predominance. Based on the poor prognosis the horse was subject to euthanasia. PATHOLOGICAL FINDINGS: The most notable lesions included ulcerative gastritis, typhlitis and colitis with prominent oedema of the intestines, marked subcutaneous oedema and severe thickening of the large bile ducts. Histopathology showed marked eosinophilic and lymphoplasmacytic infiltration of various tissues including the skin, gastrointestinal tract, mesenteric lymph nodes, large bile ducts, pancreatic duct and kidney. Immunohistochemistry revealed a clear predominance of CD3-positive cells in the lymphocytic infiltrations. DIAGNOSIS: Based on the clinical findings and histopathology a diagnosis of multisystemic eosinophilic epitheliotropic disease (MEED) was made. CLINICAL RELEVANCE: Multisystemic eosinophilic epitheliotropic disease is rare in horses, and usually chronic. In the current case the horse showed an apparently acute onset with high fever and rapid clinical deterioration. A diagnosis of MEED should be considered in horses presenting with weight loss and skin lesions with or without fever. A final diagnosis is based on histological results of biopsy specimens from affected organs. PMID- 23441859 TI - Nano-decoration of the Hemagglutinating Virus of Japan envelope (HVJ-E) using a layer-by-layer assembly technique. AB - In this study, we created a nanoscale layer of hyaluronic acid (HA) on the inactivated Hemagglutinating Virus of Japan envelope (HVJ-E) via a layer-by-layer (LbL) assembly technique for CD-44 targeted delivery. HVJ-E was selected as the template virus because it has shown a tumor-suppressing ability by eliciting inflammatory cytokine production in dendritic cells. Although it has been required to increase the tumor-targeting ability and reduce nonspecific binding because HVJ-E fuses with virtually all cells and induces hemagglutination in the bloodstream, complete modifications of single-envelope-type viruses with HA have been difficult. Therefore, we studied the surface zeta potential of HVJ-E at different pH values and carefully examined the deposition conditions for the first layer using three cationic polymers: poly-L-lysine (PLL), chitosan (CH), and glycol chitosan (GC). GC-coated HVJ-E particles showed the highest disperse ability under physiological pH and salt conditions without aggregation. An HA layer was then prepared via alternating deposition of HA and GC. The successive decoration of multilayers on HVJ-E has been confirmed by dynamic light scattering (DLS), zeta potentials, and transmission electron microscopy (TEM). An enzymatic degradation assay revealed that only the outermost HA layer was selectively degraded by hyaluronidase. However, entire layers were destabilized at lower pH. Therefore, the HA/GC-coated HVJ-E describe here can be thought of as a potential bomb for cancer immunotherapy because of the ability of targeting CD44 as well as the explosion of nanodecorated HA/GC layers at endosomal pH while preventing nonspecific binding at physiological pH and salt conditions such as in the bloodstream or normal tissues. PMID- 23441860 TI - Does modern treatment of early rheumatoid arthritis reduce the need for intra articular glucocorticoids? PMID- 23441861 TI - Novel antibody to a carbonic anhydrase: patent evaluation of WO2011138279A1. AB - A novel antibody against human carbonic anhydrase XII (CA XII) was developed and characterized. Its specificity for the human CA XII isoform was assessed and its ability to inhibit CA XII was found about 40 times higher than acetazolamide, a well-known CA sulfonamide inhibitor. The antibody was shown to decrease cell proliferation in cultured A549 lung carcinoma cells, making it an interesting molecule for targeting and treating some forms of CA XII overexpressing tumors. The possibility of conjugating this antibody with fluorescent markers for diagnostic purposes or with toxins or anticancer drugs for treating purposes makes it an interesting molecule for developing new combined approaches for cancer treatment. PMID- 23441862 TI - Ex vivo evaluation of various instrumentation techniques and irrigants in reducing E. faecalis within root canals. AB - AIM: To evaluate ex vivo the effectiveness of single-file instrumentation techniques compared with serial Ni-Ti rotary instrumentation with several irrigation regimens in reducing E. faecalis within root canals. METHODOLOGY: A total of 81 extracted human mandibular premolar teeth with a single root canal were infected with E. faecalis before and after canal preparation. Samples were divided randomly into 9 groups, as follows: group 1-A: sterile phosphate-buffered saline + Self-adjusting file, group 1-B: 5% sodium hypochlorite + 15% EDTA + Self adjusting file, group 1-C: 5% sodium hypochlorite + 7% maleic acid + Self adjusting file, group 2-A: sterile phosphate-buffered saline + Reciproc (R25), group 2-B: 5% sodium hypochlorite + 15% EDTA + Reciproc (R25), group 2-C: 5% sodium hypochlorite + 7% maleic acid + Reciproc (R25), group 3-A: sterile phosphate-buffered saline + ProTaper, group 3-B: 5% sodium hypochlorite + 15% EDTA + ProTaper, group 3-C: 5% sodium hypochlorite + 7% maleic acid + ProTaper. anova was used to analyse statistically the differences in terms of reduction in colony counts between the groups, and Dunn's post hoc test was used for multiple comparisons. RESULTS: All techniques and irrigation regimens significantly reduced the number of bacterial cells in the root canal (P < 0.001). Comparisons amongst the groups revealed significant differences between group 1A (sterile phosphate-buffered saline + Self-adjusting file)/group 1B (5% sodium hypochlorite + 15% EDTA + Self-adjusting file) (P = 0.031), group 1A (sterile phosphate buffered saline + Self-adjusting file)/group 2C (5% sodium hypochlorite + 7% maleic acid + Reciproc) (P = 0.003), group 2A (sterile phosphate-buffered saline + Reciproc)/group 3B (5% sodium hypochlorite + 15% EDTA + ProTaper) (P = 0.036), group 3B (5% sodium hypochlorite + 15% EDTA + ProTaper)/group 1A (sterile phosphate-buffered saline + Self-adjusting file) (P < 0.001), and group 3C (5% sodium hypochlorite + 7% maleic acid + ProTaper)/group 1A (sterile phosphate buffered saline + Self-adjusting file) (P = 0.033). CONCLUSIONS: No significant differences in terms of reduction in microbial counts were observed between single-file techniques (SAF and Reciproc) and serial Ni-Ti instrumentation technique (ProTaper) in combination with irrigants. PMID- 23441864 TI - FAVR (Filtering and Annotation of Variants that are Rare): methods to facilitate the analysis of rare germline genetic variants from massively parallel sequencing datasets. AB - BACKGROUND: Characterising genetic diversity through the analysis of massively parallel sequencing (MPS) data offers enormous potential to significantly improve our understanding of the genetic basis for observed phenotypes, including predisposition to and progression of complex human disease. Great challenges remain in resolving genetic variants that are genuine from the millions of artefactual signals. RESULTS: FAVR is a suite of new methods designed to work with commonly used MPS analysis pipelines to assist in the resolution of some of the issues related to the analysis of the vast amount of resulting data, with a focus on relatively rare genetic variants. To the best of our knowledge, no equivalent method has previously been described. The most important and novel aspect of FAVR is the use of signatures in comparator sequence alignment files during variant filtering, and annotation of variants potentially shared between individuals. The FAVR methods use these signatures to facilitate filtering of (i) platform and/or mapping-specific artefacts, (ii) common genetic variants, and, where relevant, (iii) artefacts derived from imbalanced paired-end sequencing, as well as annotation of genetic variants based on evidence of co-occurrence in individuals. We applied conventional variant calling applied to whole-exome sequencing datasets, produced using both SOLiD and TruSeq chemistries, with or without downstream processing by FAVR methods. We demonstrate a 3-fold smaller rare single nucleotide variant shortlist with no detected reduction in sensitivity. This analysis included Sanger sequencing of rare variant signals not evident in dbSNP131, assessment of known variant signal preservation, and comparison of observed and expected rare variant numbers across a range of first cousin pairs. The principles described herein were applied in our recent publication identifying XRCC2 as a new breast cancer risk gene and have been made publically available as a suite of software tools. CONCLUSIONS: FAVR is a platform-agnostic suite of methods that significantly enhances the analysis of large volumes of sequencing data for the study of rare genetic variants and their influence on phenotypes. PMID- 23441863 TI - The International Criteria for Behcet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. AB - OBJECTIVE: Behcet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment. METHODS: An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD-mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, 'leave-one-country-out' cross validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set. RESULTS: For the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring >=4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4-95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9 92.8%) was lower than that of the ISG-criteria (96.0%), yet still reasonably high. For countries with at least 90%-of-cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%. CONCLUSION: The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD. PMID- 23441865 TI - 3D-QSAR and molecular docking for the discovery of ketolide derivatives. AB - INTRODUCTION: There is an urgent need to discover novel antibiotics to overcome the growing problem of antibiotic resistance, which has become a serious concern in current medicine. Ketolides, the third generation of macrolide antibiotics, have shown promising effect against macrolide-resistant pathogens in respiratory diseases. Currently, a number of ketolide derivatives with excellent antibacterial activities have been reported, while their structure-activity relationships (SARs) were rarely explored systematically. Computer-aided drug design (CADD) such as 3D-QSAR and molecular docking are useful tools to study drug SARs in medicinal chemistry. Using these technologies, ketolide derivatives were systemically analyzed revealing important useful information about their SARs, providing useful information which can guide new drug design and optimization. AREAS COVERED: The authors provide an overview of the currently reported 3D-QSAR models of ketolide derivatives. The authors present a comprehensive SAR model obtained from in-depth 3D-QSAR and molecular docking analysis for all kinds of ketolide derivatives. EXPERT OPINION: 3D-QSAR has been shown to be a reliable tool that had successfully assisted the design of several new antibiotics with improved activity and reduced toxicity. By applying 3D-QSAR and molecular docking, a comprehensive and systematic SAR model for ketolide derivative discovery was formed, which is important to guide future drug design for the discovery of better ketolides with lower toxicity. PMID- 23441866 TI - Serotonin2c receptor constitutive activity: in vivo direct and indirect evidence and functional significance. AB - Serotonin2c (5-HT2c) receptors are widely expressed in the central nervous system where they play a pivotal role in the regulation of neuronal network excitability. Along with this fundamental physiological function, 5-HT2c receptors are thought to be implicated in the pathophysiology of several neuropsychiatric disorders and have become a major pharmacological target for the development of improved treatments of these disorders. In the past decade, many studies have focused on the constitutive activity of 5-HT2c receptors and the therapeutic potential of drugs acting as inverse agonists. Although the constitutive activity of the 5-HT2c receptor has been clearly described in vitro, the transposition of this concept to living animals is often difficult to ascertain. Nevertheless, cumulating evidence has demonstrated the functional relevance of such property in regulating physiological systems in vivo both at the level of the central and peripheral nervous systems. The present review provides an update of the growing number of studies that show, by means of pharmacological tools, the participation of the constitutive activity of 5-HT2c receptors in the control of various biochemical and behavioural functions in vivo and emphasizes the functional organization of this constitutive control together with the phasic and tonic (involving the spontaneous release of 5-HT) modalities of the 5-HT2c receptor in the brain. PMID- 23441867 TI - Increased risk of alcohol and drug use among children from deployed military families. AB - AIMS: To examine the association between military deployment of a parent and use of alcohol and drugs among children of deployed military personnel. DESIGN: Observational and cross-sectional study. SETTING: Data from the USA 2010 Iowa Youth Survey, a statewide survey of 6th, 8th and 11th graders, were analyzed during 2011. PARTICIPANTS: Of all 6th-, 8th- and 11th-grade students enrolled in Iowa in 2010, 69% (n = 78 240) completed the survey. MEASUREMENTS: Ever drink more than a few sips of alcohol and past 30-day: binge drinking, marijuana consumption, other illegal drug use and prescription drug misuse. FINDINGS: The rates of alcohol use [risk difference (RD) = 7.85, 99.91% confidence interval (CI) = 4.44-11.26], binge drinking (RD = 8.02, 99.91% CI = 4.91-11.13), marijuana use (RD = 5.30, 99.91% CI = 2.83-7.77), other illegal drug use (RD = 7.10, 99.91% CI = 4.63-9.56) and prescription drug misuse (RD = 8.58, 99.91% CI = 5.64-11.51) are greater for children of currently or recently deployed parents than for children of parents who are not in the military. The magnitude of the effects is consistent across 6th, 8th and 11th grades. Disrupted living arrangements further accentuate increased substance use, with the largest effect seen in children with a deployed parent who was not living with a parent or relative. CONCLUSIONS: Children of deployed military personnel should be considered at higher risk for substance use than children of non-military citizens. PMID- 23441869 TI - Topochemical fluorination of Sr3(M(0.5)Ru(0.5))2O7 (M = Ti, Mn, Fe), n = 2, Ruddlesden-Popper phases. AB - Reaction of the appropriate Sr3(M(0.5)Ru(0.5))2O7 (M = Ti, Mn, Fe), n = 2, Ruddlesden-Popper oxide with CuF2 under flowing oxygen results in formation of the oxide-fluoride phases Sr3(Ti(0.5)Ru(0.5))2O7F2, Sr3(Mn(0.5)Ru(0.5))2O7F2, and Sr3(Fe(0.5)Ru(0.5))2O(5.5)F(3.5) via a topochemical anion insertion/substitution process. Analysis indicates the titanium and manganese phases have Ti(4+), Ru(6+) and Mn(4+), Ru(6+) oxidation state combinations, respectively, while Mossbauer spectra indicate an Fe(3+), Ru(5.5+) combination for the iron phase. Thus, it can be seen that the soft fluorination conditions employed lead to formation of highly oxidized Ru(6+) centers in all three oxide-fluoride phases, while oxidation states of the other transition metal M cations remain unchanged. Fluorination of Sr3(Ti(0.5)Ru(0.5))2O7 to Sr3(Ti(0.5)Ru(0.5))2O7F2 leads to suppression of magnetic order as the fluorinated material approaches metallic behavior. In contrast, fluorination of Sr3(Mn(0.5)Ru(0.5))2O7 and Sr3(Fe(0.5)Ru(0.5))2O7 lifts the magnetic frustration present in the oxide phases, resulting in observation of long-range antiferromagnetic order at low temperature in Sr3(Mn(0.5)Ru(0.5))2O7F2 and Sr3(Fe(0.5)Ru(0.5))2O(5.5)F(3.5). The influence of the topochemical fluorination on the magnetic behavior of the Sr3(M(0.5)Ru(0.5))2O(x)F(y) phases is discussed on the basis of changes to the ruthenium oxidation state and structural distortions. PMID- 23441868 TI - Antimicrobial effect of photodynamic therapy using high-power blue light-emitting diode and red-dye agent on Porphyromonas gingivalis. AB - BACKGROUND AND OBJECTIVE: Antimicrobial photodynamic therapy (a-PDT) using a combination of red-colored laser/light-emitting diode (LED) and blue dye has been employed for periodontal therapy and the antimicrobial effect seems promising. Blue light, which has favorable wavelength properties, would be more effective as a light source for a-PDT because blue light itself possesses an antimicrobial effect. This study aimed to investigate the effect of a-PDT using a novel combination of high-power blue LED and red-dye agent on Porphyromonas gingivalis in vitro. MATERIAL AND METHODS: Porphyromonas gingivalis ATCC 33277 suspension was irradiated with blue LED (BL) (425-470 nm) or red LED (RL) (625-635 nm) at 30 90 J/cm(2) , or was mixed with erythrosine (ER), phloxine B (PB) or rose bengal (RB) with or without BL irradiation (30 J/cm(2) ). RL (30 J/cm(2) ) in combination with toluidine blue was employed as positive control. All the suspensions of P. gingivalis were serially diluted, plated and incubated anaerobically, and the numbers of colony-forming units (CFUs) were counted on day 7. RESULTS: BL irradiation at 60 and 90 J/cm(2) demonstrated a significant reduction in the numbers of CFUs. ER, PB and RB solutions at 160 MUg/mL showed almost no or only a minimal reduction in the numbers of CFUs. BL at 30 J/cm(2) combined with ER, PB or RB at 160 MUg/mL resulted in a log reduction of 0.9, 1.0 and 7.1, respectively, in the numbers of CFUs; 30 J/cm(2) BL with RB at 1.6, 16 and 160 MUg/mL demonstrated a log reduction of 6.3, 8.0 and 5.5, respectively; and a log reduction of 5.2 was obtained after 30 J/cm(2) RL with 16 MUg/mL TB. CONCLUSION: Within the limits of this study, BL was found to have an antimicrobial/growth-inhibiting effect on P. gingivalis, and a-PDT using a combination of BL and RB shows promise as a new technical modality for bacterial elimination in periodontal therapy. PMID- 23441870 TI - Communicative participation and speech intelligibility: complexities and challenges. PMID- 23441871 TI - Use of an enzyme-linked immunosorbent assay for detecting bovine viral diarrhoea virus antibodies in individual cow milk samples. AB - AIMS: To calculate and verify an adjustment for the test result cut-off when testing milk samples using a bovine viral diarrhoea (BVD) antibody test so that it is a better approximation of the test on serum as the reference. Previous experience has demonstrated that different cut points may be required for results from milk and serum. METHODS: Paired milk and serum samples were collected from 90 cows from three herds in two regions of New Zealand and were tested using a commercially available bovine viral diarrhoea virus (BVD) antibody ELISA. A regression equation with second-order polynomial was developed to estimate a milk sample to positive-control optical density ratio (S/P ratio) value from a serum S/P ratio, and the milk values equivalent to the recommended serum cut points were calculated. The change in milk test result agreement with the result based on serum samples was assessed primarily using weighted Kappa statistics. RESULTS: The new cut points between negative and suspect, and suspect and positive milk samples were defined as S/P ratios of >= 0.08 and >= 0.13 respectively, compared to cut points for serum samples of >= 0.20 and >= 0.30, respectively. Using the new cut points increased the level of agreement (weighted Kappa) between serum and milk from 0.58 to 0.82. CLINICAL RELEVANCE: Milk BVD antibody testing can be used to estimate serum BVD antibody status. This is particularly useful for investigations where susceptibility to infection or the incidence of new infections is of interest. CONCLUSIONS: Using new adjusted cut points for milk, ELISA BVD antibody testing resulted in a higher level of agreement with serum samples. PMID- 23441872 TI - Predictors of viral pneumonia: the need for viral testing in all patients hospitalized for nursing home-acquired pneumonia. AB - AIM: Community-acquired pneumonia (CAP) is presumed to be bacterial in origin and empirical antibiotics are almost always given on admission. However, early detection of viral infection is also very important for hospital infection control and timely use of antiviral agents. The present study aimed to compare patients with viral and bacterial pneumonia, and identify independent predictors of viral pneumonia. METHODS: A prospective cohort study was carried out in a tertiary teaching hospital in a 1-year period. Older patients (aged >= 65 years) were recruited if they were admitted for CAP confirmed by chest radiographs. RESULTS: A cohort of 488 patients was analyzed. Infective causes were found in 137 (28.1%) patients. Bacterial, viral and mixed infections were detected in 86 (17.6%), 41 (8.4%) and 10 (2.0%) patients, respectively. Bacteriology was established mostly by sputum culture and virology by nasopharyngeal aspirate (NPA) viral culture. The commonest bacterial isolates were Haemophilus influenzae (31), Pseudomonas aeruginosa (15), Mycobacterium tuberculosis (14), Klebsiella spp. (9) and Streptococcus pneumoniae (6). Influenza A virus (28, 8 were pandemic 2009 A/H1N1 subtype) and respiratory syncytial virus (16) were the most frequent viral causes. Independent predictors of viral pneumonia included nursing home residence (RR 3.056, P = 0.009) and absence of leukocytosis (RR 0.425, P = 0.026). CONCLUSIONS: All nursing home residents hospitalized for CAP should undergo NPA viral testing because of infection control, early antiviral treatment and discharge planning. We suggest that empirical antiviral agents might be considered for nursing home residents hospitalized for CAP if outbreaks of influenza-like illness are reported in nursing homes. PMID- 23441873 TI - Multiple rhodium-catalyzed cleavages of single C-C bonds. AB - The Rh(I)-catalyzed intramolecular hydroacylation of cis and trans asymmetrically substituted alkylidenecyclobutanes proceeds according to three mechanistic pathways. As shown by deuterium-labeling experiments, the mechanism accounting for the rearrangement of the cis isomers includes the cleavage of three carbon carbon bonds and a remarkable transannular 3-exo-trig carbometalation. PMID- 23441874 TI - Transport of endocannabinoids across the plasma membrane and within the cell. AB - Endocannabinoids are readily accumulated from the extracellular space by cells. Although their uptake properties have the appearance of a process of facilitated diffusion, it is by no means clear as to whether there is a plasma membrane transporter dedicated to this task. Intracellular carrier proteins that shuttle the endocannabinoid anandamide from the plasma membrane to its intracellular targets such as the metabolic enzyme, fatty acid amide hydrolase, have been identified. These include proteins with other primary functions, such as fatty acid-binding proteins and heat shock protein 70, and possibly a fatty acid amide hydrolase-like anandamide transporter protein. Thus, anandamide uptake can be adequately described as a diffusion process across the plasma membrane followed by intracellular carrier-mediated transport to effector molecules, catabolic enzymes and sequestration sites, although it is recognized that different cells are likely to utilize different mechanisms of endocannabinoid transport depending upon the utility of the endocannabinoid for the cell in question. PMID- 23441875 TI - Decomposition of lignin from sugar cane bagasse during ozonation process monitored by optical and mass spectrometries. AB - Mass spectrometry was used to monitor neutral chemical species from sugar cane bagasse that could volatilize during the bagasse ozonation process. Lignin fragments and some radicals liberated by direct ozone reaction with the biomass structure were detected. Ozone density was monitored during the ozonation by optical absorption spectroscopy. The optical results indicated that the ozone interaction with the bagasse material was better for bagasse particle sizes less than or equal to 0.5 mm. Both techniques have shown that the best condition for the ozone diffusion in the bagasse was at 50% of its moisture content. In addition, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) were employed to analyze the lignin bond disruptions and morphology changes of the bagasse surface that occurred due to the ozonolysis reactions as well. Appropriate chemical characterization of the lignin content in bagasse before and after its ozonation was also carried out. PMID- 23441876 TI - Influence of van der Waals interactions on morphology and dynamics in ultrathin liquid films at silicon oxide interfaces. AB - Single molecule tracer diffusion studies of evaporating (thinning) ultrathin tetrakis-2-ethyl-hexoxysilane (TEHOS) films on silicon with 100 nm thermal oxide reveal a considerable slowdown of the molecular mobility within less than 4 nm above the substrate (corresponding to a few molecular TEHOS layers). This is related to restricted mobility and structure formation of the liquid in this region, in agreement with information obtained from a long-time ellipsometric study of thinning TEHOS films on silicon substrates with 100 nm thermal or 2 nm native oxide. Both show evidence for the formation of up to four layers. Additionally, on thermal oxide, a lateral flow of the liquid is observed, while the film on the native oxide forms an almost flat surface and shows negligible flow. Thus, on the 2 nm native oxide the liquid mobility is even more restricted in close vicinity to the substrate as compared to the 100 nm thermal oxide. In addition, we found a significantly smaller initial film thickness in case of the native oxide under similar dipcoating conditions. We ascribe these differences to van der Waals interactions with the underlying silicon in case of the native oxide, whereas the thermal oxide suffices to shield those interactions. PMID- 23441877 TI - Metabolic profiling of Chinese tobacco leaf of different geographical origins by GC-MS. AB - Tobacco leaf obtained from different geographical areas in China was profiled using gas chromatography-mass spectrometry (GC-MS) coupled with multivariate data analyses. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) showed that the tobacco metabolome was clearly dependent on geographical origins; climatic conditions, such as temperature and precipitation, imposed a greater impact on metabolite levels than the cultivars. By orthogonal partial least-squares-discrimination analysis (OPLS-DA), 20 metabolites that contributed to the discrimination were screened, including primary metabolites (sucrose, D fructose, D-mannose, D-glucose, inositol, maleic acid, citric acid, malic acid, L threonic acid, L-proline, L-phenylalanine), secondary metabolites (chlorogenic acid, alpha- and beta-4,8,13-duvatriene-1,3-diol, nicotine, quinic acid), and four unknown metabolites. The results suggest that metabolic profiling using GC MS combined with multivariate analysis can be used to discriminate tobacco leaf of different geographical origins and to provide potential indicators of tobacco origins. PMID- 23441878 TI - Probing the photoisomerization of CHBr3 and CHI3 in solution with transient vibrational and electronic spectroscopy. AB - Transient infrared absorption spectroscopy monitors condensed-phase photodissociation dynamics of 30 mM CHBr3 and 50 mM CHI3 in liquid CCl4. The experiments have picosecond time resolution and monitor the C-H stretch region of both the parent polyhalomethanes and their photolytically generated isomers. The C-H stretching transitions of these isomers, in which the emergent halogen atom returns to form a C-X-X bonding motif, appear about 9 ps after photolysis for iso CHBr2-Br and in about 46 ps for iso-CHI2-I. These time scales are consistent with, but differ from, the time evolution of the transient electronic absorption spectra of the same samples, highlighting the subtle differences between monitoring the vibrational and electronic chromophores. The specificity of using vibrational transitions to track condensed-phase reaction dynamics permits reassessment of the transient electronic spectrum of photolysis in neat CHBr3, which has an additional prompt feature near 400 nm. Calculations show that this feature, which arises from a precursor to the isomer, is a charge-transfer transition of a contact pair between the nascent Br fragment and a nearby CHBr3 molecule. Dilution and solvent studies show that transition is independent of the solvent. The iso-CHBr2-Br transition wavelength, however, shifts over the range of 400 to 510 nm depending on the solvent. Time-dependent density functional calculations faithfully reproduce these trends. PMID- 23441879 TI - The role of cell cycle in the efficiency and activity of cancer nanomedicines. AB - INTRODUCTION: With a wealth of knowledge on the effect of nanoparticle properties, including size, shape, charge and composition, on intracellular delivery, little has been reported on the effect of the cell cycle on the intracellular delivery and activity of nanomedicines including non-viral gene delivery systems. The aim of this review is to shed a light on this topic. AREAS COVERED: It is now evident that nanoparticle cell uptake varies with the cell cycle phase. This review addresses this variation by dissecting the effect of cell population heterogeneity on the intracellular delivery and activity of nanomedicines with a special focus on non-viral gene delivery and combination therapy modalities that utilize cell cycle inhibitors as co-targets for therapy. In addition, the importance of three-dimensional (3D) culture systems in the drug delivery field within the context of the cell cycle will be addressed. EXPERT OPINION: The understanding of the cell cycle machinery has improved dramatically over the last few decades. Developing combination therapy modalities that target the cell cycle to achieve better cancer patient outcome should now be the focus. Furthermore, more effort should be placed on developing a reliable, consistent, high throughput 3D cell culture system since these systems more closely resemble the cell cycle status of in vivo tumors. A switch from 2D to 3D culture systems, to more accurately predict the in vivo efficacy of nanoparticle drug delivery systems, is desirable. PMID- 23441880 TI - Local search for the generalized tree alignment problem. AB - BACKGROUND: A phylogeny postulates shared ancestry relationships among organisms in the form of a binary tree. Phylogenies attempt to answer an important question posed in biology: what are the ancestor-descendent relationships between organisms? At the core of every biological problem lies a phylogenetic component. The patterns that can be observed in nature are the product of complex interactions, constrained by the template that our ancestors provide. The problem of simultaneous tree and alignment estimation under Maximum Parsimony is known in combinatorial optimization as the Generalized Tree Alignment Problem (GTAP). The GTAP is the Steiner Tree Problem for the sequence edit distance. Like many biologically interesting problems, the GTAP is NP-Hard. Typically the Steiner Tree is presented under the Manhattan or the Hamming distances. RESULTS: Experimentally, the accuracy of the GTAP has been subjected to evaluation. Results show that phylogenies selected using the GTAP from unaligned sequences are competitive with the best methods and algorithms available. Here, we implement and explore experimentally existing and new local search heuristics for the GTAP using simulated and real data. CONCLUSIONS: The methods presented here improve by more than three orders of magnitude in execution time the best local search heuristics existing to date when applied to real data. PMID- 23441881 TI - Targeting DSG3: from pemphigus to squamous cell carcinoma. PMID- 23441883 TI - Diabetic ketoacidosis elicits systemic inflammation associated with cerebrovascular endothelial cell dysfunction. AB - OBJECTIVE: To determine if the DKA-induced inflammation in juvenile mice provokes activation and dysfunction of CVECs. METHODS: DKA in juvenile mice was induced with administration of STZ and ALX. Blood from DKA mice was assessed for cytokines and soluble cell adhesion proteins, and either DKA plasma or exogenous compounds were applied to immortalized bEND3. RESULTS: DKA increased circulating levels of IL-6, IL-8(KC), MCP-1, IL-10, sE-selectin, sICAM-1, and sVCAM-1. Stimulation of bEND3 with DKA plasma caused cellular activation (increased ROS and activation of NF-kappaBeta), upregulation of a proadhesive phenotype (E selectin, ICAM-1, and VCAM-1), and increased leukocyte-bEND3 interaction (leukocyte rolling/adhesion). TEER, a measure of bEND3 monolayer integrity, was decreased by DKA plasma. Activation and dysfunction of bEND3 with DKA plasma were suppressed by plasma heat treatment (56 degrees C, 1 hour) and replicated with the application of DKA recombinant cytomix (IL-6, IL-8[KC], MCP-1, and IL-10), implicating circulating inflammatory protein(s) as mediators. Treatment of bEND3 with beta-OH-butyrate, the main ketone elevated in DKA, failed to mimic the DKA plasma-induced activation and dysfunction of bEND3. CONCLUSIONS: DKA elicits systemic inflammation associated with CVEC activation and dysfunction, possibly contributing to DKA-associated intracranial microvascular complications. PMID- 23441884 TI - Non-segmental vitiligo and psoriasis comorbidity - a case-control study in Italian patients. AB - BACKGROUND: A recent systematic evaluation of vitiligo and psoriasis comorbidity has not yet been reported in a large series of patients with vitiligo. OBJECTIVE: To investigate the practical/clinical implications in subjects with both vitiligo and psoriasis compared to those with vitiligo alone. METHODS: This was a case control study on 463 vitiligo patients in our clinic from March 2008 to April 2011. Medical assessment was performed by dermatologists using the modified Vitiligo European Task Force form. RESULTS: In an univariate analysis, inflammation/pruritus [odds ratio (OR) 2.42, P = 0.03], use of drugs that can induce psoriasis (OR 2.74, P = 0.01), a family history (FH) of psoriasis (OR 2.87, P = 0.02), cardiovascular disease (OR 5.70, P = 0.001), hypertension (OR 4.7, P = 0.006) and type 2 diabetes mellitus (OR 3.87, P = 0.004), were significantly correlated with patients exhibiting vitiligo and psoriasis comorbidity. A trend was found in personal history of cardiovascular disease in patients with both diseases (OR 2.99, P = 0.07). FH of vitiligo was significantly associated with patients having only vitiligo (OR 0.35, P = 0.05). Multivariate analysis demonstrated that inflammation/pruritus in vitiligo macules (OR 2.56, P = 0.047) and a FH of cardiovascular disease (OR 4.07, P = 0.02) were the most significant predictors of patients having both psoriasis and vitiligo, while the presence of organ-specific autoantibodies (OR 0.24, P = 0.007) was significantly associated with patients having only vitiligo. CONCLUSION: The presence of vitiligo and even mild psoriasis is significantly correlated with a family history of cardiovascular disease, a factor that requires greater attention and follow-up with respect to that necessary for vitiligo patients. PMID- 23441885 TI - Relationships between different tooth shapes and patient's periodontal phenotype. AB - BACKGROUND AND OBJECTIVE: The purpose of the present study was to establish whether any correlation exists between tooth shapes and patient-related factors such as gingival and periodontal characteristics. MATERIAL AND METHODS: Clinical measurements, including the width and the height of maxillary central incisor crowns, the apico incisal height of the keratinized mucosa (KM), the buccal gingival thickness (GT), the depth of the sulcus (SD), the bone-sounding depth (BS) and the height of the interproximal maxillary central papilla (Ph), were investigated in 50 healthy individuals. These individuals were then divided into three groups based on the shape of their maxillary central incisor crowns: triangular; square; or square-tapered. The three groups were analyzed to determine any significant differences among the groups in the values obtained for clinical measurements. RESULTS: There were no significant differences among the three groups in terms of the SD (p = 0.11) or the BS (p = 0.54), whilst statistically significant differences were observed for the KM (p < 0.001), the GT (p = 0.012) and the Ph (p < 0.001). CONCLUSION: The results of this study indicate that different tooth shapes are associated with significantly different values for the extent of the KM, its bucco-lingual thickness and the height of the interproximal maxillary central papilla. PMID- 23441886 TI - Role of cation interactions in the reduction process in plutonium-americium mixed oxides. AB - The oxygen to metal ratio (O/M) is directly related to oxygen potential, which strongly influences the sintering and irradiation performance of nuclear fuels. A better understanding of these two parameters is therefore of major interest. To further ascertain the correlation between O/M ratio and oxygen potential in Am bearing MOX, several thermodynamic descriptions are being developed. Despite their differences, they all involve the valence of actinide cations (e.g., U, Pu, and Am) as essential parameters. However, as no experimental data on their valence are available, these models rely on assumptions. In the present work, we coupled X-ray diffraction and X-ray absorption spectroscopy to follow the behavior of Pu and Am in three hypo-stoichiometric, U-free Pu(1-y)Am(y)O(2-x) compounds. We provide for the first time a quantitative determination of Pu and Am valences, demonstrating that plutonium reduction from Pu(4+) to Pu(3+) starts only when americium reduction from Am(4+) to Am(3+) is completed. This result fills in an important gap in experimental data, thereby improving the thermodynamic description of nuclear fuels. At last, we suggest that the O/M ratio may evolve at room temperature, especially for high Am content, which is of main concern for the fabrication of Am-loaded MOX and their storage prior to irradiation. PMID- 23441887 TI - Programmes to support chronic disease self-management: should we be concerned about the impact on spouses? AB - Chronic disease self-management support (CDSMS) programmes are widely advocated as an essential element of chronic disease care and have demonstrated increased engagement with self-care activities such as improving diet but may place additional strain on spouses. This study used an embedded mixed methods approach to explore the impact of CDSMS on spouses. Spouses were recruited as part of a larger randomised controlled trial to assess the efficacy of a health professional-led CDSMS programme (the Flinders Program) in older adults with multiple chronic conditions, compared with an attention control group. Spouses were recruited from the general community through General Practitioners located in the southern areas of Adelaide, Australia. Quantitative and qualitative data were collected between September 2009 and March 2011; a total of 25 spouses from each of the CDSMS and control groups provided data. Spousal strain was measured by the Caregiver Risk Screen (CRS). Few spouses had CRS scores indicative of moderate or high strain at baseline or upon completion of the study and CRS scores did not differ by programme allocation. Spouses of participants with poorer self-management (r = 0.34, P = 0.016) and more illness intrusiveness (r = 0.35, P = 0.013) had higher CRS scores at baseline (quantitative) and spousal strain was found to increase as a partner's well-being and capacity to self manage decreased (qualitative). Spouse presence at CDSMS sessions (20%) frequently signalled a reduced level of partner well-being. Overall, our findings suggest that CDSMS programmes in many cases will have little impact (either positive or negative) on spousal strain. A significant increase in spousal strain may occur, however, if there is deterioration in the health status of a CDSMS participant. The impact of decline in participant health status on carer strain needs to be considered in CDSMS programmes. PMID- 23441888 TI - Vibrio parahaemolyticus type IV pili mediate interactions with diatom-derived chitin and point to an unexplored mechanism of environmental persistence. AB - Vibrio parahaemolyticus is a naturally occurring bacterium common in coastal waters where it concentrates in shellfish through filter feeding. The bacterium is a human pathogen and the leading cause of seafood-borne gastroenteritis. Presently there is little information regarding mechanisms of environmental persistence of V.parahaemolyticus or an accurate early warning system for outbreak prediction. Vibrios have been shown to adhere to several substrates in the environment, including chitin, one of the most abundant polymers in the ocean. Diatoms are abundant in estuarine waters and some species produce chitin as a component of the silica cell wall or as extracellular fibrils. We examined the role of specific surface structures on the bacterium, the type IV pilins PilA and MshA, in adherence to diatom-derived chitin. Biofilm formation and adherence of V.parahaemolyticus to chitin is mediated by the ability of the bacterium to express functional type IV pili. The amount of adherence to diatom-derived chitin is controlled by increased chitin production that occurs in later stages of diatom growth. The data presented here suggest late-stage diatom blooms may harbour high concentrations of V.parahaemolyticus and could serve as the foundation for a more accurate early warning system for outbreaks of this human pathogen. PMID- 23441889 TI - Sensitivity, specificity and level of agreement of meat inspector detection of abnormal lymph nodes of farmed deer (Cervus elaphus) in New Zealand. AB - AIMS: To assess the sensitivity (Se), specificity (Sp) and level of agreement in the detection of abnormal deer mesenteric lymph nodes (MLN) by official assessors (meat inspectors) for the purpose of slaughter premise surveillance for Johne's disease in New Zealand farmed deer. METHODS: To determine Se and Sp, four meat inspectors in two commercial deer slaughter premises (DSP) each examined between 153 and 925 MLN under normal visual examination, palpation and/or incision inspection procedures. Abnormal MLN were independently defined as those with a circumference measurement of >= 55 mm and/or grossly visible pathological changes such as caseation, necrosis and/or mineralisation, while those with a circumference of <55 mm and without gross lesions were defined as normal. The inspectors' diagnosis of normal or abnormal was retrieved from the national DSP based surveillance database for Johne's disease in deer. To determine between inspector level of agreement, 54 meat inspectors visually examined two photographic images each of 19 normal and 10 abnormal MLN, and recorded their diagnosis. Between-inspector agreement was calculated based on a modification of Cohen's kappa statistic for multiple raters. The influence of covariates such as inspector age and experience on the between-inspector level of agreement were assessed using the Breslow-Day statistic and test for equal kappa coefficients. RESULTS: The weighted average Se and Sp of inspector detection of abnormal MLN was 13.3 (minimum 4.8, maximum 41.2)% and 99.9 (minimum 99.5, maximum 100.0)%, respectively. The level of between-inspector agreement in the diagnosis of abnormal and normal MLN was fair (kappa = 0.32). Employment location, inspector age, experience inspecting deer or other species, and the number of shifts inspecting deer within the previous four weeks had no influence on between inspector agreement (p > 0.10). CONCLUSIONS: Inspectors diagnosed abnormal deer MLN with a high specificity, but low sensitivity. These data supported that visual assessment of MLN characteristics was suitable for national surveillance for paratuberculosis, while highlighting the need for further emphasis on training of inspectors in abnormal lymph node detection. PMID- 23441890 TI - The setting characteristics of MTA Plus in different environmental conditions. AB - AIM: Characterization and assessment of the hydration reaction of mineral trioxide aggregate (MTA) Plus exposed to different environmental conditions. METHODOLOGY: The specific surface area, surface morphology and characterization of un-hydrated MTA Plus (Avalon Biomed Inc. Bradenton, FL, USA) were investigated. The specific surface area was compared with that of ProRoot MTA (Dentsply International, Tulsa Dental Specialties, Johnson City, TN, USA). The reaction rate was determined using calorimetry, and the hydrated cement was assessed for setting time (determined using an indentation technique), and the set material was characterized using X-ray diffraction analysis, scanning electron microscopy and X-ray energy-dispersive analysis. Atomic ratio plots were drawn to establish the relationship of the hydration products. Three different environmental conditions namely dry or immersed in either water or Hank's balanced salt solution (HBSS) were used. RESULTS: Mineral trioxide aggregate Plus had a higher specific surface area than ProRoot MTA. The hydration reaction was exothermic. The setting time of MTA Plus was retarded when in contact with fluids (P < 0.001). The setting time was longer when MTA Plus was in contact with HBSS than when in contact with water (P < 0.001). Hydration of MTA Plus resulted in the formation of calcium silicate hydrate, calcium hydroxide, ettringite and monosulfate phases. Bismuth was incorporated in the calcium silicate hydrate structure. The hydration of the core material was not affected by contact with the different solutions but the periphery exhibited microcracking, leaching of calcium hydroxide, partial decalcification of calcium silicate hydrate, inhibition of hydration in contact with the physiological solution. CONCLUSIONS: The novel MTA Plus was finer than ProRoot MTA but had a similar chemical composition. MTA Plus in direct contact with fluids exhibited partial decalcification of calcium silicate hydrate in contact with the solution, microcracking and leaching of calcium hydroxide. Interaction with a physiological solution resulted in inhibition of hydration. PMID- 23441891 TI - Multiplex templating process in one-dimensional nanoscale: controllable synthesis, macroscopic assemblies, and applications. AB - Since their detection 20 years ago, carbon nanotubes (CNTs) have captured the interest of scientists, because one-dimensional (1D) nanostructures (nanowires, nanotubes, and nanoribbons) have fascinating physical properties and many potential technological applications. These are materials with structural features limited to the range of 1-100 nm in one dimension, and unlimited in the others. When their size goes down to certain characteristic lengths, such as the Bohr radius, the wavelength of incandescent light, and the phonon mean-free path, quantum mechanical effects can occur. This results in novel optical, magnetic, and electronic characteristics. These physical properties, along with unique transport features in the longitudinal direction and large surface-to-volume ratio, make 1D nanostructures attract extensive attention in both fundamental research and engineering applications. From a synthetic point of view, it is highly desirable to develop a simple route for fabricating 1D nanostructures in large scale at low cost. On the other hand, in order to transfer the intrinsic features of individual 1D nanostructures into macroscopic scale and realize practical applications, we need to explore highly efficient and scalable assembly methods to integrate 1D nanostructures into functional macroscopic architectures. In 2006, our group developed a simple hydrothermal method for synthesizing ultrathin Te nanowires (TeNWs) using conventional chemicals. As we found through systematic study over the past several years, we can use the ultrathin TeNWs as a versatile templating material to fabricate a series of high-quality 1D nanostructures by taking the unique advantages of TeNWs, such as large-scale synthesis, high processability, and high reactivity. The obtained 1D products inherit the dimensional (high aspect ratio) and mechanical (high flexibility) features of the original TeNW templates, thus allowing us to construct macroscopic architectures by using them as nanoscale building blocks. In this Account, we describe on our recent developments in the multiplex templating synthesis of 1D nanostructures, their macroscopic assemblies, and applications. We first introduce ultrathin TeNWs and their advantages as a templating material. Through the multiplex templating process, we can prepare a family of 1D nanostructures that covers a wide range of materials, including noble metals, metal oxides, semiconductors, carbon, polymers, and their binary and multiple hybrids. We emphasize the reactivity of templating materials and the versatility of templating processes in this Account. On the basis of the templated 1D products, we then describe a series of macroscopic assemblies of 1D nanostructures, including free-standing membranes, films, hydrogels, and aerogels. These exhibit enormous potential for attractive applications, such as liquid filtration and separation, continuous-flow catalysis, electrocatalysis, polymer-based nanocomposites, and superadsorbents, and elastomeric conductors. We believe that the great versatility of templating synthesis, a scalable assembling process, and large-scale synthesis can significantly enhance the application reliability of the 1D nanostructures. PMID- 23441892 TI - Phase II clinical trial of phlebotomy for non-alcoholic fatty liver disease. AB - BACKGROUND: Elevated iron indices are described in non-alcoholic fatty liver disease and iron reduction has been suggested as a potential therapy. AIM: To determine whether phlebotomy is an effective therapy for non-alcoholic fatty liver disease. METHODS: Patients with biopsy proven non-alcoholic fatty liver disease underwent baseline evaluation to determine severity of metabolic and liver disease. A Phase II trial of phlebotomy was carried out to achieve near iron depletion (serum ferritin <=50 MUg/L or haemoglobin 100 g/L). Repeat liver biopsy, anthropometric and biochemical measurements were performed 6 months following the end of treatment. Primary outcome was improvement in liver histology, assessed using the non-alcoholic fatty liver disease activity score. RESULTS: Thirty-one patients completed follow-up. Iron reduction resulted in a significant improvement in the non-alcoholic fatty liver disease activity score ( 0.74 +/- 1.83, P = 0.019). Reductions in individual histological features of lobular inflammation (-0.29 +/- 1.07, P = 0.182), steatosis (-0.26 +/- 0.82, P = 0.134), hepatocyte ballooning (-0.19 +/- 0.70, P = 0.213) did not achieve significance nor did the score for fibrosis (-0.32 +/- 0.94, P = 0.099). CONCLUSIONS: This prospective Phase II study of phlebotomy with paired liver biopsies evaluating phlebotomy therapy in non-alcoholic fatty liver disease patients suggests that iron reduction may improve liver histology. However, the effect size of phlebotomy raises questions of whether treatment could have sufficient clinical significance to justify a definitive Phase III trial. This trial has been registered with the US National Institute of Health (clinicaltrials.gov, Identifier NCT 00641524). PMID- 23441893 TI - A new interpretative paradigm for Conformational Protein Diseases. AB - Conformational Protein Diseases (CPDs) comprise over forty clinically and pathologically diverse disorders in which specific altered proteins accumulate in cells or tissues of the body. The most studied are Alzheimerbeta's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, inclusion body myopathy, and the systemic amyloidoses. They are characterised by three dimensional conformational alterations, which are often rich in beta- structure. Proteins in this non-native conformation are highly stable, resistant to degradation, and have an enhanced tendency to aggregate with like protein molecules. The misfolded proteins can impart their anomalous properties to soluble, monomeric proteins with the same amino acid sequence by a process that has been likened to seeded crystallization. However, these potentially pathogenic proteins also have important physiological actions, which have not completely characterized. This opens up the question of what process transforms physiological actions into pathological actions and most intriguing, is why potentially dangerous proteins have been maintained during evolution and are present from yeasts to humans. In the present paper, we introduce the concept of mis-exaptation and of mis-tinkering since they may help in clarifying some of the double edged sword aspects of these proteins. Against this background an original interpretative paradigm for CPDs will be given in the frame of the previously proposed Red Queen Theory of Aging. PMID- 23441894 TI - The topology and dynamics of protein complexes: insights from intra- molecular network theory. AB - Intra-molecular interactions within complex systems play a pivotal role in the biological function. They form a major challenge to computational structural proteomics. The network paradigm treats any system as a set of nodes linked by edges corresponding to the relations existing between the nodes. It offers a computationally efficient tool to meet this challenge. Here, we review the recent advances in the use of network theory to study the topology and dynamics of protein- ligand and protein-nucleic acid complexes. The study of protein complexes networks not only involves the topological classification in term of network parameters, but also reveals the consistent picture of intrinsic functional dynamics. Current dynamical analysis focuses on a plethora of functional phenomena: the process of allosteric communication, the binding induced conformational changes, prediction and identification of binding sites of protein complexes, which will give insights into intra-protein complexes interactions. Furthermore, such computational results may elucidate a variety of known biological processes and experimental data, and thereby demonstrate a huge potential for applications such as drug design and functional genomics. Finally we describe some web-based resources for protein complexes, as well as protein network servers and related bioinformatics tools. PMID- 23441895 TI - Mechanistic aspects of lanthipeptide leaders. AB - Lanthipeptides are ribosomally synthesized and posttranslationally modified peptides produced by microorganisms. The name lanthipeptide is derived from lanthionine, a thioether-bridged amino acid installed by dedicated modification enzymes. Serines and threonines are dehydrated and subsequently coupled to cysteines, thus forming intramolecular lanthionine rings. A well-known subclass of lanthipeptides are lantibiotics: lanthipeptides with antimicrobial activity. The lantibiotic nisin is applied worldwide in the food industry to prevent food spoilage. This review focuses on lanthipeptide leader peptides, which have a crucial and central role in lanthipeptide biosynthesis. Lanthipeptide leader peptides are present at the N-terminus within precursor lanthipeptides. Intriguingly, a single leader peptide can interact with highly different modifying enzyme(s) (domains) and furthermore induce export out of the cell via a dedicated export protein. Eventually the leader peptide is cleaved off by a leader peptidase, either extracellularly or intracellularly as part of the transporter. Recent exciting mechanistic and engineering studies ignited the unraveling of the fascinating interactions of lanthipeptide leader peptides with the lanthipeptide modification enzymes and transporters. The biosynthesis of at least some lanthipeptides is performed by a highly flexible enzyme system. Novel lantibiotics can be synthesized by fusing lanthipeptide leader peptides to completely different silent lantibiotics obtained by genome mining. Moreover, the fusion of leader peptides to the N-terminus of medically and economically important therapeutic peptides has resulted in lanthioninestabilized therapeutics with enhanced bioavailability and optimized receptor interaction. PMID- 23441896 TI - Heparin and heparin binding proteins: potential relevance to reproductive physiology. AB - Glycosaminoglycans (GAGs) have crucial roles in cell-cell interaction and communication. The communication between sperm and egg during fertilization is the finest example of intercellular communication involving a protein carbohydrate recognition system. GAGs, especially heparin, are implicated in various processes, such as capacitation, acrosome reaction (AR), and sperm nuclei decondensation by interacting with a wide range of proteins, leading to fertilization. Seminal plasma (SP) comprises of multiple proteins that bind to heparin and related GAGs. Heparin binding proteins (HBPs) originating from secretions of the male accessory sex glands are known to play a vital role during fertilization events. They interact with GAGs present in the female genital tract and enhance the subsequent zona pellucida-induced AR, and thus have been correlated with fertility in some species. Several carbohydrate and zona pellucida-binding proteins, many of which belong to the spermadhesin family, are identified as HBPs. Many studies have been documented about the potential physiological role of some HBPs in various steps of fertilization. However, there is insufficient knowledge about functions executed by various HBPs and their exact mechanism and pathways. An in-depth knowledge of HBPs and their role in fertilization is of fundamental importance to resolve biological pathways and protein interactions at the molecular level. This review surveys some of the relevant findings supporting the potential role of heparin and HBPs in reproduction. It also describes consensus heparin binding sites emerging from known literature on HBPs that interact with heparin. PMID- 23441897 TI - Effects of therapeutic hypothermia on the glial proteome and phenotype. AB - Therapeutic hypothermia is a useful intervention against brain injury in experimental models and patients, but its therapeutic applications are limited due to its ill-defined mode of action. Glia cells maintain homeostasis and protect the central nervous system from environmental change, but after brain injury, glia are activated and induce glial scar formation and secondary injury. On the other hand, therapeutic hypothermia has been shown to modulate glial hyperactivation under various brain injury conditions. We considered that knowledge of the effect of hypothermia on the molecular profiles of glia and on their phenotypes would improve our understanding of the neuroprotective mechanism of hypothermia. Here, we review the findings of recent studies that examined the effect of hypothermia on proteome changes in reactive glial cells in vitro and in vivo. The therapeutic effects of hypothermia are associated with the inhibition of reactive oxygen species generation, the maintenance of ion homeostasis, and the protection of neurovascular units in cultured glial cells. In an animal model, a distinct pattern of protein alterations was detected in glia following hypothermia under ischemic/reperfusion conditions. In particular, hypothermia was found to exert a neuroprotective effect against ischemic brain injury by regulating specific glial signaling pathways, such as, glutamate signaling, cell death, and stress response, and by influencing neural dysfunction, neurogenesis, neural plasticity, cell differentiation, and neurotrophic activity. Furthermore, the proteins that were differentially expressed belonged to various pathways and could mediate diverse phenotypic changes of glia in vitro or in vivo. Therefore, hypothermia-modulated glial proteins and subsequent phenotypic changes may form the basis of the therapeutic effects of hypothermia. PMID- 23441898 TI - Neurotransmitters and microglial-mediated neuroinflammation. AB - Reciprocal interactions between cells caused by release of soluble factors are essential for brain function. So far, little attention has been paid to interactions between neurons and glia. However, in the last few decades, studies regarding such interactions have given us some important clues about possible mechanisms underlying degenerative processes in neurological diseases such as Alzheimer's disease and Parkinson's disease. Activated microglia and markers of inflammatory reactions have been consistently found in the post-mortem brains of diseased patients. But it has not been clearly understood how microglia respond to neurotransmitters released from neurons during disease progression. The main purpose of this review is to summarize studies performed on neurotransmitter receptor expression in microglia, and the effects of their activation on microglial-mediated neuroinflammation. A possible mechanism underlying transmitter-mediated modulation of microglial response is also suggested. Microglia express receptors for neurotransmitters such as ATP, adenosine, glutamate, GABA, acetylcholine, dopamine and adrenaline. Activation of GABA, cholinergic and adrenergic receptors suppresses microglial responses, whereas activation of ATP or adenosine receptors activates them. This latter effect may be due primarily to activation of a Ca(2+)-signaling pathway which, in turn, results in activation of MAP kinases and NFkB proteins with the release of proinflammatory factors. However, glutamate and dopamine are both pro- and anti inflammatory depending on the receptor subtypes expressed in microglia. More detailed studies on downstream receptor-signaling cascades are needed to understand the roles of neurotransmitters in controlling neuron-microglia interactions during inflammatory processes in disease progression. Such knowledge may suggest new methods of treatment. PMID- 23441899 TI - The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. AB - The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5 difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity. PMID- 23441900 TI - Toll-like receptors: sensor molecules for detecting damage to the nervous system. AB - Toll-like receptors (TLRs) are type I transmembrane signaling molecules that are expressed in cells of the innate immune system. In these cells, TLRs function as pattern recognition receptors (PRR) that recognize specific molecular patterns derived from microorganisms. Upon activation, TLRs trigger a cascade of intracellular signaling pathways in innate immune cells, leading to the induction of inflammatory and innate immune responses, which in turn regulate adaptive immune responses. In the nervous system, different members of the TLR family are expressed on glial cells (astrocytes, microglia, oligodendrocytes, and Schwann cells) and neurons. Recently, increasing evidence has supported the idea that TLRs also recognize endogenous molecules that are released from damaged tissue, thereby regulating inflammatory responses and subsequent tissue repair. These findings imply that TLRs on glial cells may also be involved in the inflammatory response to tissue damage in the nervous system. In this review, we discuss recent studies on TLR expression in the cells of the nervous system and their roles in acute neurological disorders involving tissue damage such as strokes, traumatic spinal cord and brain injuries, and peripheral nerve injuries. PMID- 23441901 TI - Proteins in microglial activation--inputs and outputs by subsets. AB - Microglia serve in the surveillance, maintenance and protection of the central nervous system (CNS) homeostasis and functionality. The process of transformation from their house-keeping status to reactive phenotypes upon CNS challenges is known as microglial activation. It comes also with dramatic changes in protein expression and release. Activated microglia may thereby mount a rather homogenous response, with all cells of an affected local population simultaneously upregulating the same cell surface receptors or synthesizing an identical set of soluble messengers. Yet there is increasing evidence for a constitutive heterogeneity of microglia by and within CNS regions--largely being based on protein expression as well as activities and pointing to distinct functional capacities as to microglial subtypes. Inductions of proteins with key functions in antigen presentation and inflammation, like major histocompatibility complex (MHC) class I or II molecules and tumor necrosis factor (TNF) alpha, reveal that among a pool of activated microglia individual cells can differ by actual contributions. While MHC I induction can be appropriately triggered as a panpopulational response, only a subset would organize for TNFalpha production. Similarly, MHC II expression seems to be confined to a microglial subpopulation, and disposal of myelin either under normal conditions or its removal upon CNS damage appear to be duties of specialized cells, partially with complementary distribution. Discrete synthesis of immunoregulatory proteins would thus assign a master control to certain microglia, while tasks in the clearance of endogenous material and in professional antigen presentation could be sequestered to avoid collision of incompatible functions. PMID- 23441902 TI - Comparison of efficacy of narrow band UVB therapies with UVB alone, in combination with calcipotriol, and with betamethasone and calcipotriol in vitiligo. AB - OBJECTIVE: The purpose of this study is to compare the efficacy of three therapies in the treatment of non-segmental vitiligo: a combination of topical calcipotriol, narrowband-ultraviolet B (NB-UVB), and betamethasone therapies; a combination of NB-UVB and topical calcipotriol; and NB-UVB alone. MATERIAL AND METHODS: Forty-five patients with non-segmental vitiligo presenting to our Dermatology clinic were recruited to participate in the study. Patients were randomly divided into three groups. For each patient the size of the depigmented areas was assessed according to the rule of nines. The first group was treated with a combination of topical calcipotriol, NB-UVB, and betamethasone therapies. The second group was treated with a combination of NB-UVB and topical calcipotriol and third group was treated with NB-UVB alone. Since the patients' vitiligo lesions had similar phototypes, all patients were started with 0.1 j/cm(2), regardless of their skin phototype. The dose of NB-UVB was increased 10% in each session and no further increment was done after reaching 2.5 j/cm(2). Treatment effectiveness was evaluated according to the percentage improvement in repigmentation. The quality of life of the patients was measured by the Dermatology Life Quality Index (DLQI). RESULTS: The patients were aged from 13 to 55 years (mean: 25.29). The duration of disease ranged from 3 months to 20 years. Family history was positive for vitiligo in 10 patients (22.2%). The percentage of recovery after treatment was 63.33% +/- 7.55 in group 1, 60.67% +/- 5.75 in group 2, and 46.67% +/- 7.98 in group 3. There was no statistically significant difference between groups 1 and 2, and groups 2 and 3, but there was a statistically significant difference between groups 1 and 3 (p = 0.0048). CONCLUSIONS: In conclusion, NB-UVB-alone therapy and the combined therapies are effective treatment options in the treatment of vitiligo. Future studies with larger groups are warranted to confirm our results. PMID- 23441903 TI - Prognostic value of neonatal brain imaging for very low birthweight preterm infants. PMID- 23441904 TI - Molecular interactions between lecithin and bile salts/acids in oils and their effects on reverse micellization. AB - It has been known that the addition of bile salts to lecithin organosols induces the formation of reverse wormlike micelles and that the worms are similar to long polymer chains that entangle each other to form viscoelastic solutions. In this study, we further investigated the effects of different bile salts and bile acids on the growth of lecithin reverse worms in cyclohexane and n-decane. We utilized rheological and small-angle scattering techniques to analyze the properties and structures of the reverse micelles. All of the bile salts can transform the originally spherical lecithin reverse micelles into wormlike micelles and their rheological behaviors can be described by the single-relaxation-time Maxwell model. However, their efficiencies to induce the worms are different. In contrast, before phase separation, bile acids can induce only short cylindrical micelles that are not long enough to impart viscoelasticity. We used Fourier transform infrared spectroscopy to investigate the interactions between lecithin and bile salts/acids and found that different bile salts/acids employ different functional groups to form hydrogen bonds with lecithin. Such effects determine the relative positions of the bile salts/acids in the headgroups of lecithin, thus resulting in varying efficiencies to alter the effective critical packing parameter for the formation of wormlike micelles. This work highlights the importance of intermolecular interactions in molecular self-assembly. PMID- 23441905 TI - Rhodium-catalyzed intermolecular oxidative cross-coupling of (hetero)arenes with chalcogenophenes. AB - A straightforward and efficient method for the rhodium-catalyzed intermolecular oxidative cross-coupling of arenes and heteroarenes with thio- and selenophene derivatives (chalcogenophenes) via double C-H bond cleavage has been developed by using Cu(OAc)2/AgSbF6 as an oxidant. The reaction is applicable to a wide range of (hetero)arenes carrying a directing group and chalcogenophenes to yield substituted biaryl heterocyclic derivatives and oligothiophene derivatives in moderate to high yields. PMID- 23441906 TI - Ischemia from extrinsic compression of the brachial artery by a stent in the venous outflow of a brachio-basilic arterio-venous graft. AB - Distal artery embolization is a well-known complication after mechanical thrombectomy, manifesting as limb ischemia. We describe a case of ischemia that developed after mechanical thrombectomy and stent placement in the venous anastomosis of a brachio- basilic arterio-venous graft. Subsequent investigations revealed that the stent had extrinsically compressed the adjacent brachial artery. Although balloon angioplasty of the artery initially restored flow, the patient needed surgical removal of the graft and stent to prevent persistent ischemia. PMID- 23441907 TI - Anion effects on kinetics and thermodynamics of CO2 absorption in ionic liquids. AB - A thermogravimetric technique based on a magnetic suspension balance operating in dynamic mode was used to study the thermodynamics (in terms of solubility and Henry's law constants) and kinetics (i.e., diffusion coefficients) of CO2 in the ionic liquids [bmim][PF6], [bmim][NTf2], and [bmim][FAP] at temperatures of 298.15, 308.15, and 323.15 K and pressures up to 20 bar. The experimental technique employed was shown to be a fast, accurate, and low-solvent-consuming method to evaluate the suitability of the ionic liquids (ILs) to be used as CO2 absorbents. Thermodynamic results confirmed that the solubility of CO2 in the ILs followed the order [bmim][FAP] > [bmim][NTf2] > [bmim][PF6], increasing with decreasing temperatures and increasing pressures. Kinetic data showed that the diffusion coefficients of CO2 in the ILs followed a different order, [bmim][NTf2] > [bmim][FAP] > [bmim][PF6], increasing with increasing temperatures and pressures. These results evidenced the different influence of the IL structure and operating conditions on the solubility and absorption rate of CO2, illustrating the importance of considering both thermodynamic and kinetic aspects to select adequate ILs for CO2 absorption. On the other hand, the empirical Wilke Chang correlation was successfully applied to estimate the diffusion coefficients of the systems, with results indicating the suitability of this approach to foresee the kinetic performance of ILs to absorb CO2. The research methodology proposed herein might be helpful in the selection of efficient absorption solvents based on ILs for postcombustion CO2 capture. PMID- 23441908 TI - A hybrid short read mapping accelerator. AB - BACKGROUND: The rapid growth of short read datasets poses a new challenge to the short read mapping problem in terms of sensitivity and execution speed. Existing methods often use a restrictive error model for computing the alignments to improve speed, whereas more flexible error models are generally too slow for large-scale applications. A number of short read mapping software tools have been proposed. However, designs based on hardware are relatively rare. Field programmable gate arrays (FPGAs) have been successfully used in a number of specific application areas, such as the DSP and communications domains due to their outstanding parallel data processing capabilities, making them a competitive platform to solve problems that are "inherently parallel". RESULTS: We present a hybrid system for short read mapping utilizing both FPGA-based hardware and CPU-based software. The computation intensive alignment and the seed generation operations are mapped onto an FPGA. We present a computationally efficient, parallel block-wise alignment structure (Align Core) to approximate the conventional dynamic programming algorithm. The performance is compared to the multi-threaded CPU-based GASSST and BWA software implementations. For single end alignment, our hybrid system achieves faster processing speed than GASSST (with a similar sensitivity) and BWA (with a higher sensitivity); for pair-end alignment, our design achieves a slightly worse sensitivity than that of BWA but has a higher processing speed. CONCLUSIONS: This paper shows that our hybrid system can effectively accelerate the mapping of short reads to a reference genome based on the seed-and-extend approach. The performance comparison to the GASSST and BWA software implementations under different conditions shows that our hybrid design achieves a high degree of sensitivity and requires less overall execution time with only modest FPGA resource utilization. Our hybrid system design also shows that the performance bottleneck for the short read mapping problem can be changed from the alignment stage to the seed generation stage, which provides an additional requirement for the future development of short read aligners. PMID- 23441909 TI - Penetration of laser light at 808 and 980 nm in bovine tissue samples. AB - OBJECTIVE: The purpose of this study was to compare the penetration of 808 and 980 nm laser light through bovine tissue samples 18-95 mm thick. BACKGROUND DATA: Low-level laser therapy (LLLT) is frequently used to treat musculoskeletal pathologies. Some of the therapeutic targets are several centimeters deep. METHODS: Laser light at 808 and 980 nm (1 W/cm(2)) was projected through bovine tissue samples ranging in thickness from 18 to 95 mm. Power density measurements were taken for each wavelength at the various depths. RESULTS: For 808 nm, 1 mW/cm(2) was achieved at 3.4 cm, but for 980 nm, 1 mW/cm(2) was achieved at only 2.2 cm depth of tissue. CONCLUSIONS: It was determined that 808 nm of light penetrates as much as 54% deeper than 980 nm light in bovine tissue. PMID- 23441910 TI - Recovery of intact IgG in the gastrointestinal tract of the growing rat following ingestion of an ovine serum immunoglobulin. AB - The aim of this study was to determine whether orally ingested ovine serum IgG partly resists digestion in the growing rat. Fifteen Sprague-Dawley male rats were allocated to one of three diets for a 3-week study: a control diet (CON) and two test diets containing either freeze-dried ovine serum immunoglobulin (FDOI) or inactivated ovine serum immunoglobulin (IOI). Samples of stomach chyme and intestinal digesta from the ad libitum-fed rats were subjected to ELISA and Western blot analysis. Amounts of intact ovine IgG for the FDOI diet were found to be 13.9, 20.0, 34.1, 13.0 and 36.9 MUg in the total wet digesta from the stomach chyme, duodenal, jejunal, ileal and colonic digesta respectively. Qualitative detection by Western blot revealed the presence of intact ovine serum IgG with a ~150 kDa MW. This was detected in all of the gut segments (stomach chyme, duodenal, jejunal, ileal and colonic digesta) for growing rats fed the FDOI diet. No ovine IgG was detected in the chyme or digesta from rats fed the CON or the IOI diets. Ovine serum IgG partly resisted digestion in the growing rat fed the FDOI diet and was found throughout the digestive tract. These results provide a basis to explain the reported biological effects of orally administered immunoglobulin. PMID- 23441911 TI - Isolation and characterization of new p-Terphenyls with antifungal, antibacterial, and antioxidant activities from halophilic actinomycete Nocardiopsis gilva YIM 90087. AB - A new p-terphenyl 1 and a novel p-terphenyl derivative 3 bearing a benzothiazole moiety were isolated from halophilic actinomycete Nocardiopsis gilva YIM 90087, along with known p-terphenyl 2, antibiotic novobiocin 4, cyclodipeptides 5-13, and aromatic acids 14 and 15. Their structures were elucidated on the basis of the interpretation of spectral data and by comparison of the corresponding data with those reported previously. The p-terphenyl 1 showed antifungal activity against the three pathogenic fungi, including Fusarium avenaceum, Fusarium graminearum, and Fusarium culmorum, that caused Fusarium head blight with minimal inhibitory concentrations (MICs) of 8, 16, and 128 MUg/mL, respectively. Compound 1 showed antifungal activity against Candida albicans with a MIC of 32 MUg/mL and antibacterial activity against Bacillus subtilis with a MIC of 64 MUg/mL. Novobiocin 4 showed antifungal activity against Pyricularia oryzae with a MIC of 16 MUg/mL and antibacterial activity against B. subtilis with a MIC of 16 MUg/mL and Staphylococcus aureus with a MIC of 64 MUg/mL. The 1,1-diphenyl-2-picryl hydrazyl assay suggested that 1, 3, and 4 exhibited 54.9% (2 mg/mL), 14.3% (4 mg/mL), and 47.7% (2 mg/mL) free radical scavenging activity, respectively. The positively charged 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical (ABTS(+*)) scavenging assay indicated that 1, 3, 4, and 8 exhibited 68.6% (1 mg/mL), 28.4% (2 mg/mL), 78.2% (0.5 mg/mL), and 54.6% (2 mg/mL) ABTS(+*) scavenging capacity, respectively. The superoxide anion radical scavenging assay suggested that 4 exhibited 77.9% superoxide anion radical scavenging capacity at 2 mg/mL. N. gilva YIM 90087 is a new resource for novobiocin 4. PMID- 23441912 TI - Proteomic analysis shows that individual Listeria monocytogenes strains use different strategies in response to gastric stress. AB - Ingestion of contaminated dairy products, in particular soft cheese, is one of the major routes of infection by the human pathogen Listeria monocytogenes. During cheese processing, this foodborne pathogen is exposed to sublethal acid and osmotic stress conditions, which may induce tolerance responses and influence subsequent survival in the gastric tract. The aim of the current study was to evaluate the impact on a L. monocytogenes cheese isolate (serotype 4b) and two cheese dairy isolates (T8, serotype 4b, isolated from vat; and A9, serotype 1/2b or 3b, isolated from shelf stand) of exposure to sublethal conditions of pH and salt (5.5 and 3.5% [w/v] NaCl) in a cheese-simulated medium and further challenge with gastric stress. The bacterial cells exposed to pH 7.0 and no added salt were considered non-adapted. Via two-dimensional gel electrophoresis (2-DE), the proteomes of cheese-simulated medium and gastric challenged Listeria cells were compared. All L. monocytogenes isolates were able to survive the high acidity of gastric fluid (pH 2.5), and no significant differences were observed between adapted and non-adapted cells. However, the analysis of the intracellular proteome profiles revealed a significant intra-strain variation in the protein arsenal used to respond to the adaptation in the cheese-based medium and to the gastric stress. In cheese-based medium, the three strains produced different stress proteins. All three strains showed a higher abundance of carbohydrate proteins, but there was no overlap between them. Exposure to the gastric fluid induced the production of a group of proteins in T8 adapted and non-adapted cells that had not been detected previously in the cheese-based proteome. No such response was shown by A9 and C882 strains. Taken together, this study evidences the proteome tools used by adapted and non-adapted cells to cope with the hostile microenvironment of the stomach. PMID- 23441913 TI - Detection of Toxoplasma gondii in raw caprine, ovine, buffalo, bovine, and camel milk using cell cultivation, cat bioassay, capture ELISA, and PCR methods in Iran. AB - This study was conducted to determine the presence of Toxoplasma gondii in animal milk samples in Iran. From a total of 395 dairy herds in three provinces of Iran, 66 bovine, 58 ovine, 54 caprine, 33 buffalo, and 30 camel herds were studied, and from these parts of Iran, 200 bovine, 185 ovine, 180 caprine, 164 buffalo, and 160 camel milk samples were collected from various seasons. Samples were tested for Toxoplasma gondii by cell line culture, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR) technique. Only the results of cell line cultivation were confirmed by bioassay in cat. Results indicated that all herds were infected with Toxoplasma gondii. The culture method showed that 51 out of 889 milk samples (5.73%) were positive for Toxoplasma gondii, and all 51 positive culture results were positive with bioassay in cat. The Fars province had the highest prevalence of Toxoplasma gondii (6.84%). The ELISA test showed that 41 milk samples (4.61%) were positive for the presence of Toxoplasma gondii, while the PCR showed that 46 milk samples were positive for Toxoplasma gondii. The results showed higher sensitivity of PCR and higher specificity of ELISA. Caprine had the highest (10%) and camel had the lowest (3.12%) prevalence rate of parasite. The summer season had the highest (76.47%) but winter (3.92) had the lowest incidence of Toxoplasma gondii. This study is the first prevalence report of direct detection of Toxoplasma gondii in animal milk samples in Iran. PMID- 23441914 TI - Enterotoxin-encoding genes in Staphylococcus spp. from bulk goat milk. AB - Although Staphylococcus aureus has been implicated as the main Staphylococcus species causing human food poisoning, recent studies have shown that coagulase negative Staphylococcus could also harbor enterotoxin-encoding genes. Such organisms are often present in goat milk and are the most important mastitis causing agents. Therefore, this study aimed to investigate the occurrence of enterotoxin-encoding genes among coagulase-positive (CoPS) and coagulase-negative (CoNS) staphylococci isolated from raw goat milk produced in the semi-arid region of Paraiba, the most important region for goat milk production in Brazil. Enterotoxin-encoding genes were screened in 74 staphylococci isolates (30 CoPS and 44 CoNS) by polymerase chain reaction targeting the genes sea, seb, sec, sed, see, seg, seh, and sei. Enterotoxin-encoding genes were found in nine (12.2%) isolates, and four different genes (sea, sec, seg, and sei) were identified amongst the isolates. The most frequent genes were seg and sei, which were often found simultaneously in 44.5% of the isolates. The gene sec was the most frequent among the classical genes, and sea was found only in one isolate. All CoPS isolates (n=7) harboring enterotoxigenic genes were identified as S. aureus. The two coagulase-negative isolates were S. haemolyticus and S. hominis subsp. hominis and they harbored sei and sec genes, respectively. A higher frequency of enterotoxin-encoding genes was observed amongst CoPS (23.3%) than CoNS (4.5%) isolates (p<0.05), reinforcing the importance of S. aureus as a potential foodborne agent. However, the potential risk posed by CoNS in goat milk should not be ignored because it has a higher occurrence in goat milk and enterotoxin encoding genes were detected in some isolates. PMID- 23441915 TI - Effect of ethanol shock pretreatment on the tolerance of Cronobacter sakazakii BCRC 13988 exposed to subsequent lethal stresses. AB - Cronobacter spp., formerly Enterobacter sakazakii, are human pathogens. They are the etiological agent of life-threating bacterial infections in infants. In this study, the survival behavior of C. sakazakii Bioresources Collection and Research Center (BCRC) 13988 in the presence of various ethanol concentrations was first examined. Besides, the test organism was subjected to treatment with 5% ethanol for 60 min (ethanol shock). The effect of ethanol shock on the resistance of C. sakazakii to lethal stresses, including high ethanol concentration (15%), low temperature (4 degrees C and -20 degrees C), high temperature (51 degrees C) and high acidity (pH 3.3), was investigated. Results revealed that 4-5% ethanol is the maximum concentration that will allow C. sakazakii BCRC 13988 to grow in trypticase soy broth (TSB). Etthanol at 6% and 7% or more, respectively, exerted bacteriostatic and bactericidal effects, respectively, on the test organism. Although ethanol shock did not affect the resistance of C. sakazakii to a refrigerated temperature (4 degrees C), the ethanol-shocked C. sakazakii survived better under other lethal stress conditions. After 50 min of exposure to 15% ethanol, the ethanol-shocked C. sakazakii showed a survival percentage of 16.11%, which was a 6400-fold increase over the control cells (<0.01%). On the other hand, the ethanol-shocked C. sakazakii exhibited a 45-fold higher survival after 120-min exposure to 51 degrees C. At the end of the 7-day storage at -20 degrees C, the ethanol-shocked cells exhibited a survival percentage of 0.25% which was significantly (p<0.05) higher than that (less than 0.01%) of the control. Additionally, the ethanol-shocked cells showed a survival percentage of 13.80% compared to only 1.60% noted with the control cells after exposure to pH 3.3 for 60 min. PMID- 23441916 TI - Stable plumbylene dichalcogenolate monomers with large differences in their interligand angles and the synthesis and characterization of a monothiolato Pb(II) bromide and lithium trithiolato plumbate. AB - The complexes, Pb(ChAr(Pri4))2 (Ch = O (1), S (2); Ar(Pri4) = C6H3-2,6-(C6H3-2,6 Pr(i)2)2) were synthesized by alcoholysis and salt metathesis routes and represent the first fully characterized monomeric, two-coordinate, lead dichalcogenolates in the solid state. Structural studies showed that the S-Pb-S angle (77.21(4) degrees ) is about 22 degrees narrower than the corresponding O Pb-O angle. (207)Pb NMR and electronic spectroscopy show that the separation between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) decreases from the bisaryloxo plumbylene to the bisthiolato derivative. Reaction of LiSAr(Me6) with PbBr2 in a 2:1 ratio led not to Pb(SAr(Me6))2, but to a mixture of the monothiolato lead(II) complex, {Pb(Br)(MU-SAr(Me6))}2 (3) and the lithium tristhiolato plumbate, LiPb(SAr(Me6))3 (4). 3 and 4 were isolated and purified by fractional recrystallization, and both were characterized by X-ray crystallography and spectroscopic studies. PMID- 23441917 TI - O(1D) kinetic study of key ozone depleting substances and greenhouse gases. AB - A key stratospheric loss process for ozone depleting substances (ODSs) and greenhouse gases (GHGs) is reaction with the O((1)D) atom. In this study, rate coefficients, k, for the O((1)D) atom reaction were measured for the following key halocarbons: chlorofluorocarbons (CFCs) CFCl3 (CFC-11), CF2Cl2 (CFC-12), CFCl2CF2Cl (CFC-113), CF2ClCF2Cl (CFC-114), CF3CF2Cl (CFC-115); hydrochlorofluorocarbons (HCFCs) CHF2Cl (HCFC-22), CH3CClF2 (HCFC-142b); and hydrofluorocarbons (HFCs) CHF3 (HFC-23), CHF2CF3 (HFC-125), CH3CF3 (HFC-143a), and CF3CHFCF3 (HFC-227ea). Total rate coefficients, kT, corresponding to the loss of the O((1)D) atom, were measured over the temperature range 217-373 K using a competitive reactive technique. kT values for the CFC and HCFC reactions were >1 * 10(-10) cm(3) molecule(-1) s(-1), except for CFC-115, and the rate coefficients for the HFCs were in the range (0.095-0.72) * 10(-10) cm(3) molecule(-1) s(-1). Rate coefficients for the CFC-12, CFC-114, CFC-115, HFC-23, HFC-125, HFC-143a, and HFC-227ea reactions were observed to have a weak negative temperature dependence, E/R ~ -25 K. Reactive rate coefficients, kR, corresponding to the loss of the halocarbon, were measured for CFC-11, CFC-115, HCFC-22, HCFC-142b, HFC-23, HFC-125, HFC-143a, and HFC-227ea using a relative rate technique. The reactive branching ratio obtained was dependent on the composition of the halocarbon and the trend in O((1)D) reactivity with the extent of hydrogen and chlorine substitution is discussed. The present results are critically compared with previously reported kinetic data and the discrepancies are discussed. 2D atmospheric model calculations were used to evaluate the local and global annually averaged atmospheric lifetimes of the halocarbons and the contribution of O((1)D) chemistry to their atmospheric loss. The O((1)D) reaction was found to be a major global loss process for CFC-114 and CFC-115 and a secondary global loss process for the other molecules included in this study. PMID- 23441918 TI - Novel inositol catabolic pathway in Thermotoga maritima. AB - myo-inositol (MI) is a key sugar alcohol component of various metabolites, e.g. phosphatidylinositol-based phospholipids that are abundant in animal and plant cells. The seven-step pathway of MI degradation was previously characterized in various soil bacteria including Bacillus subtilis. Through a combination of bioinformatics and experimental techniques we identified a novel variant of the MI catabolic pathway in the marine hyperthermophilic bacterium Thermotoga maritima. By using in vitro biochemical assays with purified recombinant proteins we characterized four inositol catabolic enzymes encoded in the TM0412-TM0416 chromosomal gene cluster. The novel catabolic pathway in T. maritima starts as the conventional route using the myo-inositol dehydrogenase IolG followed by three novel reactions. The first 2-keto-myo-inositol intermediate is oxidized by another, previously unknown NAD-dependent dehydrogenase TM0412 (named IolM), and a yet unidentified product of this reaction is further hydrolysed by TM0413 (IolN) to form 5-keto-l-gluconate. The fourth step involves epimerization of 5 keto-l-gluconate to d-tagaturonate by TM0416 (IolO). T. maritima is unable to grow on myo-inositol as a single carbon source. The determined in vitro specificity of the InoEFGK (TM0418-TM0421) transporter to myo-inositol-phosphate suggests that the novel pathway in Thermotoga utilizes a phosphorylated derivative of inositol. PMID- 23441920 TI - Effects of periodontal non-surgical therapy plus azithromycin on glycemic control in patients with diabetes: a randomized clinical trial. AB - BACKGROUND AND OBJECTIVE: Periodontitis may alter the systemic condition in patients with diabetes and hence interfere with glycemic control. The objective of this study was to determine the quantifiable changes in glycated hemoglobin (HbA1C) after periodontal non-surgical therapy plus azithromycin in a mixed population of patients with poorly controlled diabetes. MATERIALS AND METHODS: One hundred and five patients were randomized to receive non-surgical therapy plus azythromycin (AZ-Sca =33), non-surgical therapy plus placebo (PB-Sca = 37) and supragingival prophylaxis plus azithromycin (AZ-Pro = 35). Glycated hemoglobin, glycemia and periodontal parameters were measured at baseline, 3, 6 and 9 mo after treatment. RESULTS: Periodontal parameters were improved in the AZ Sca and PB-Sca groups as compared to the AZ-Pro group. A greater reduction in probing depth was observed in the AZ-Sca as compared to the PB-Sca group. Improvement in clinical attachment level was similar between AZ-Sca and PB-Sca groups. A reduction from 8.0% to 7.2% (?0.8%; p < 0.05) in HbA1C was observed in the AZ-Sca at 9 mo as compared to the PB-Sca group in which the reduction was from 7.9% to 7.6% (?0.3%). There was no decrease in HbA1C in the AZ-Pro group over time. Mean glycemia values decreased from 195 mg/dL to 159.2 mg/dL (?35.8 mg/dL; p < 0.05) in the AZ-Sca group whereas a decrease from 194 mg/dL to 174.8 mg/dL (?19.2 mg/dL) in the PB-Sca group at 9 mo was observed. There were no differences between the AZ-Sca and PB-Sca groups for glycemic parameters. No improvement in glycemic values in the AZ-Pro group was observed. CONCLUSIONS: A modest improvement in glycemic control was detected with a trend towards the use of non-surgical therapy plus AZ as compared to the placebo. PMID- 23441921 TI - Sensitive and substrate-specific detection of metabolically active microorganisms in natural microbial consortia using community isotope arrays. AB - The goal of this study was to develop and validate a novel fosmid-clone-based metagenome isotope array approach - termed the community isotope array (CIArray) for sensitive detection and identification of microorganisms assimilating a radiolabeled substrate within complex microbial communities. More specifically, a sample-specific CIArray was used to identify anoxic phenol-degrading microorganisms in activated sludge treating synthetic coke-oven wastewater in a single-sludge predenitrification-nitrification process. Hybridization of the CIArray with DNA from the (14) C-phenol-amended sample indicated that bacteria assimilating (14) C-atoms, presumably directly from phenol, under nitrate reducing conditions were abundant in the reactor, and taxonomic assignment of the fosmid clone end sequences suggested that they belonged to the Gammaproteobacteria. The specificity of the CIArray was validated by quantification of fosmid-clone-specific DNA in density-resolved DNA fractions from samples incubated with (13) C-phenol, which verified that all CIArray positive probes stemmed from microorganisms that assimilated isotopically labeled carbon. This also demonstrated that the CIArray was more sensitive than DNA-SIP, as the former enabled positive detection at a phenol concentration that failed to yield a 'heavy' DNA fraction. Finally, two operational taxonomic units distantly related to marine Gammaproteobacteria were identified to account for more than half of 16S rRNA gene clones in the 'heavy' DNA library, corroborating the CIArray-based identification. PMID- 23441922 TI - Prevalence of Mycobacterium avium subsp. paratuberculosis in farmed red deer (Cervus elaphus) with grossly normal mesenteric lymph nodes. AB - AIM: To estimate the prevalence of Mycobacterium avium subsp. paratuberculosis (Map) in farmed deer with no gross post-mortem evidence of Map infection slaughtered in New Zealand, and to assess predictors of infection. METHODS: Mesenteric lymph node (MLN) samples (n = 251) were collected from 60 lines of deer presented at two slaughterhouses in the North and two in the South Island of New Zealand between October 2008 and January 2009 and cultured for Map. Estimates of individual animal prevalence for each island were adjusted to account for the clustering of individual observations within herds. The national herd prevalence estimate was calculated as a weighted mean, with weights being the proportion of herds from which deer were slaughtered at North and South Island slaughterhouses among all herds slaughtering deer throughout New Zealand. Age, gender, and the presence of other carcasses with enlarged and/or granulomatous MLN in the same line (line status) were assessed as predictors of infection using multivariable logistic regression. RESULTS: A national cluster-adjusted individual animal prevalence of 45 (95% CI = 30-60)% was estimated, with North and South Island prevalences of 29 (95% CI = 16-45)% and 51 (95% CI = 36-66)%, respectively. Line status was a strong predictor of infection in young deer (OR 7.1, 95% CI = 2.4 21.5), but not in older deer. Herd-level prevalence was 44 (95% CI = 24-64)% in the North Island and 67 (95% CI = 49-85)% in the South Island. Weighted adjustment resulted in a national herd-level prevalence estimate of 59 (95% CI = 41-78)%. CONCLUSIONS: This study has provided a national baseline prevalence estimate for Map infection at the individual and herd-level, showing a contrast between the North and South Islands. More research to investigate the factors contributing to the difference in infection prevalence seen between the islands may help to identify suitable control measures for Map in deer herds. PMID- 23441923 TI - Disruption of HDX gene in premature ovarian failure. AB - We present a case of a 19-year-old phenotypically normal girl with premature ovarian failure. Cytogenetic analysis using G banding and fluorescence in situ hybridization (FISH) from cultured peripheral blood lymphocytes of the patient and the family revealed a de novo X;15 translocation and the imbalance to be 46,X,t(X;15)(Xpter -> Xq21::15q11 -> 15qter;15pter -> 15q11::Xq21 -> Xqter). ish (CEPX+, wep15+, ISNRPN+, PML+, D15S10+, wcp15-, SNRRN-, PML-)[20]. The X chromosome inactivation (XCI) assay revealed a completely skewed XCI pattern in which selective pressure favors an active maternal allele. The Affymetrix 2.7 M cytogenetics whole-Genome array confirmed the chromosomal imbalance and identified disruption of the HDX gene at Xq21, the translocation breakpoint. PMID- 23441919 TI - Biological functions of iduronic acid in chondroitin/dermatan sulfate. AB - The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides because it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties, such as migration, proliferation, differentiation, angiogenesis and the regulation of cytokine/growth factor activities. Under pathological conditions such as wound healing, inflammation and cancer, iduronic acid has diverse regulatory functions. Iduronic acid is formed by two epimerases (i.e. dermatan sulfate epimerase 1 and 2) that have different tissue distribution and properties. The role of iduronic acid in chondroitin/dermatan sulfate is highlighted by the vast changes in connective tissue features in patients with a new type of Ehler-Danlos syndrome: adducted thumb-clubfoot syndrome. Future research aims to understand the roles of the two epimerases and their interplay with the sulfotransferases involved in chondroitin sulfate/dermatan sulfate biosynthesis. Furthermore, a better definition of chondroitin/dermatan sulfate functions using different knockout models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation, as well as the role of iduronic acid in health and disease. PMID- 23441924 TI - Contrast-induced acute kidney injury following PCI. AB - BACKGROUND: Coronary revascularization using percutaneous coronary intervention (PCI) is one of the major treatments for patients with stable coronary artery disease, with approximately 1.5 million patients undergoing PCI in the United States and Europe every year. An important neglected complication of PCI is contrast-induced acute kidney injury (CI-AKI). DESIGN: In this article, we review the definition, pathogenesis and management of CI-AKI and highlight potential therapeutic options for preventing CI-AKI in post-PCI patients. RESULTS: CI-AKI is an important but underdiagnosed complication of PCI that is associated with increased in-hospital morbidity and mortality. Patients with pre-existing renal impairment and diabetes are particularly susceptible to this complication post PCI. Optimization of the patients' circulating volume remains the mainstay for preventing CI-AKI, although the best strategy for achieving this is still controversial. CONCLUSION: Following PCI, CI-AKI is an overlooked complication which is associated with significant morbidity and mortality. In this article, we review the pathophysiology of CI-AKI in patients undergoing PCI and discuss the potential therapeutic options for preventing it. PMID- 23441925 TI - Fibrin sheath and its relation to subsequent events after tunneled dialysis catheter exchange. AB - The use of tunneled catheters (TDC) for chronic hemodialysis is frequent and often fails due to fibrin or thrombus and infection. We hypothesized that the presence of fibrin sheath in TDC increases the risk for subsequent catheter malfunction and infection. We did a retrospective review of TDC exchanges and de novo placements from January 2005 to September 2011. Demographic data, information about the catheter procedure, and radiological data were collected. Final outcome analysis included 168 procedure events. Three groups of catheter procedures were identified: catheter exchange without a fibrin sheath (CE), catheter exchange with a treated fibrin sheath (CEF), and de novo catheter placements (DCP). Fibrin sheath incidence was 47%. In the CEF group, there was no statistical difference in the incidence of subsequent infections or dysfunctions (7% and 60%, respectively), when compared with the CE group (9% and 43%, respectively), (p=0.3). Mean time to subsequent dysfunction or infection was similar for CEF and CE (135 vs. 136 days, p-value, 0.98). Fibrin sheaths are common and should be evaluated when performing TDC exchange. If the fibrin sheath is treated, there is no increased incidence in subsequent catheter dysfunction or infection compared with patients without a fibrin sheath. PMID- 23441926 TI - The journey toward shared governance: the lived experience of nurse managers and staff nurses. AB - AIMS: The purpose of the study was to explore the lived experience of nurse managers and staff nurses in shared governance. BACKGROUND: Shared governance refers to systems and services aligned in partnership. The information gained by studying the lived experience of nurse managers and staff nurses in shared governance is valuable for providing knowledge of empowerment. METHODS: A qualitative design was used. Data were collected through a semi-structured interview using five questions with 11 Registered Nurses. Data were analysed through thematic analysis. RESULTS: Four themes emerged from data analysis. Nurse managers identified the journey of patient satisfaction; journey of empowerment; journey of self-management and journey of wellness. Staff nurses identified the journey of development and implementation of best practice; journey to provide quality patient care, journey to a new culture of nursing; and journey of a variety of challenges. CONCLUSIONS: This study supports the idea that collaboration between nurse managers and staff nurses develops a journey toward shared governance. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing management can use findings to empower nurses to collaborate with nurse managers toward best practice. This adds to current knowledge that partnership of nurse managers and staff nurses, supports and encourages ownership in shared governance. PMID- 23441927 TI - Real-time monitoring on the adsorption process of salicylic acid onto chitosan membrane using dielectric spectroscopy: macroscale concentration polarization and dynamics. AB - The adsorption process of salicylic acid (SA) onto chitosan membrane is monitored in real time by the dielectric relaxation spectroscopy (DRS) method. A unique dielectric relaxation, which is related to the macroscale concentration polarization layers (CPLs) in the SA solution caused by the adsorption, is observed. By modeling the measured systems composed of the membrane, the CPLs, and the SA solution, the dielectric spectra are analyzed systematically on the basis of the interfacial polarization theory. The parameters about the constituent phases, i.e., the dielectric constant epsilonm and the conductivity kappam of the chitosan membrane, the conductivity distribution (kappa1 to kappa2), and the thickness dCPL of the CPL, are obtained. The time-dependent epsilonm and kappam give insight into the microstate of the chitosan membrane during the adsorption. Furthermore, the time evolution of the conductivity gradient of the CPL, Deltakappa/dCPL, is combined to interpret the adsorption mechanism. It is suggested that the noninvasive dielectric monitoring may be applied to many adsorption and release processes. PMID- 23441929 TI - Surgical approach to the superior mid-orbit. AB - Access to the superior mid-orbit is required for procedures on the levator muscle in the correction of upper eyelid ptosis and in surgery aimed at local lesions in this region. The purpose with this human cadaver study was to clarify the anatomical substrate for a surgical approach to the levator muscle and the upper mid-orbit structures, in which the orbital septum and the retroseptal fat pad is not harmed during surgery. Macro-anatomical dissections and histological examinations were performed on five human orbits from three formalin embalmed cadaver heads. It was found that the orbital septum extends posteriorly from its junction with the levator aponeurosis. This posterior continuation of the orbital septum encloses the superior orbital fat pad and separates this from the anterior surface of the levator muscle. In between the orbital septum and the levator, there is a dissection space that provides a minimal invasive access corridor to the structures in the upper mid-orbit. PMID- 23441928 TI - A modified technique for levator resection in congenital ptosis. AB - This study describes a modified technique for levator resection in congenital ptosis and presents the results from a consecutive series of patients operated on with this method. Eighteen patients were operated on for congenital ptosis. By means of a blunt dissection through the potential space between the levator aponeurosis and the orbital septum, this operation method takes advantage of this anatomical entrance route to surgery on the levator complex, and thereby avoids violation of the orbital septum and the retroseptal fat pad. In a consecutive series of 18 patients with congenital ptosis, 88% of the patients achieved a good result according to the success criteria. In surgery for moderate congenital ptosis, the amount of levator resection is of utmost importance to obtain the desired height of the eyelid. With this method this can be obtained without violating the orbital septum. PMID- 23441930 TI - One-pot syntheses of isoquinolin-3-ones and benzo-1,4-diazepin-2,5-diones utilizing Ugi-4CR post-transformation strategy. AB - One-pot and efficient syntheses of structurally diverse isoquinolin-3-ones and isoquinolin-3-one-based benzo-1,4-diazepin-2,5-diones have been developed. The notable features of the process include the Ugi condensation of monomasked phthalaldehydes with amines, carboxylic acids, and isonitriles, followed by HClO4 mediated intramolecular condensation of the carbonyl with amide. PMID- 23441931 TI - Peripheral nerve field stimulation for sacroiliac joint pain. PMID- 23441932 TI - Effect of 2% chlorhexidine digluconate on bond strength of a glass-fibre post to root dentine. AB - AIM: To assess the immediate influence of dentine bonding systems (DBS) associated with 2% chlorhexidine digluconate (CHX) on glass-fibre post-bond strength to root dentine, in terms of coronal, middle and apical thirds. METHODOLOGY: Sixty bovine roots were root filled and randomly assigned to 1 of 6 groups (n = 10): SBMP (3-step etch-and-rinse system, Scotchbond Multi-Purpose), SB (2-step etch-and-rinse system, Single Bond 2), SE (2-step self-etching system, Clearfil SE Bond) and SBMP-CHX, SB-CHX and SE-CHX, respectively, associated with CHX. For all groups, a glass-fibre post was luted with a dual-cure resin cement, RelyX ARC. After 7-day storage, specimens were subjected to the push-out test. Failure modes were analysed under optical microscopy (40x). Bond strength values were statistically analysed by two-way anova and Bonferroni tests (P < 0.05). RESULTS: The effect of DBS was significant (P < 0.05), and SE reached higher bond strength in comparison with the other DBS tested. CHX association did not show improvement with any DBS (P > 0.05); rather, it negatively affected SE, which was detected for all thirds. There was no difference between thirds (P > 0.05), except for the SE-CHX, which presented lower values for the apical third (P < 0.05). Adhesive cement/dentine adhesive failure was predominant for all groups. CHX did not influence the failure mode for any DBS (P > 0.05). CONCLUSIONS: The performance of the dentine bonding systems was material dependent. CHX did not improve immediate bond strength; however, CHX negatively affected the bond strength of the self-etching system, especially in the third apical. PMID- 23441933 TI - Absorption, distribution, and milk secretion of the perfluoroalkyl acids PFBS, PFHxS, PFOS, and PFOA by dairy cows fed naturally contaminated feed. AB - The transfer of the perfluoroalkyl acids (PFAAs) perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS), perfluorooctanesulfonate (PFOS), and perfluorooctanoate (PFOA) from feed into tissue and milk of dairy cows was investigated. Holstein cows (n = 6) were fed a PFAA-contaminated feed for 28 days. After the PFAA-feeding period, three cows were slaughtered while the others were fed PFAA-free feed for another 21 days (depuration period). For PFAA analysis plasma, liver, kidney, and muscle tissue, urine, and milk were sampled and analyzed using high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). The average daily intake of dairy cows was 3.4 +/- 0.7, 4.6 +/- 1.0, 7.6 +/- 3.7 and 2.0 +/- 1.2 MUg/kg body weight (bw) for PFBS, PFHxS, PFOS, and PFOA, respectively. Overall, PFBS, PFHxS, PFOS, and PFOA showed different kinetics in dairy cows. In plasma, concentrations of PFBS (mean = 1.2 +/- 0.8 MUg/L) and PFOA (mean = 8.5 +/- 5.7 MUg/L) were low, whereas PFHxS and PFOS continuously increased during the PFAA-feeding period up to maximal concentrations of 419 +/- 172 and 1903 +/- 525 MUg/L, respectively. PFOS in plasma remained constantly high during the depuration period. PFOS levels were highest in liver, followed by kidney, without significant differences between feeding periods. The highest PFHxS levels were detected in liver and kidney of cows slaughtered on day 29 (61 +/- 24 and 98 +/- 31 MUg/kg wet weight (ww)). The lowest PFAA levels were detected in muscle tissue. At the end of the feeding study, cumulative secretion in milk was determined for PFOS (14 +/- 3.6%) and PFHxS (2.5 +/- 0.2%). The other two chemicals were barely secreted into milk: PFBS (0.01 +/- 0.02%) and PFOA (0.1 +/- 0.06%). Overall, the kinetics of PFOA were similar to those of PFBS and substantially differed from those of PFHxS and PFOS. The very low concentration of PFBS in plasma and milk, the relatively high urinary excretion, and only traces of PFBS in liver (0.3 +/- 0.3 MUg/kg ww) and kidney (1.0 +/- 0.3 MUg/kg ww) support the conclusion that PFBS does not accumulate in the body of dairy cows. PMID- 23441934 TI - Predictability of gene ontology slim-terms from primary structure information in Embryophyta plant proteins. AB - BACKGROUND: Proteins are the key elements on the path from genetic information to the development of life. The roles played by the different proteins are difficult to uncover experimentally as this process involves complex procedures such as genetic modifications, injection of fluorescent proteins, gene knock-out methods and others. The knowledge learned from each protein is usually annotated in databases through different methods such as the proposed by The Gene Ontology (GO) consortium. Different methods have been proposed in order to predict GO terms from primary structure information, but very few are available for large scale functional annotation of plants, and reported success rates are much less than the reported by other non-plant predictors. This paper explores the predictability of GO annotations on proteins belonging to the Embryophyta group from a set of features extracted solely from their primary amino acid sequence. RESULTS: High predictability of several GO terms was found for Molecular Function and Cellular Component. As expected, a lower degree of predictability was found on Biological Process ontology annotations, although a few biological processes were easily predicted. Proteins related to transport and transcription were particularly well predicted from primary structure information. The most discriminant features for prediction were those related to electric charges of the amino-acid sequence and hydropathicity derived features. CONCLUSIONS: An analysis of GO-slim terms predictability in plants was carried out, in order to determine single categories or groups of functions that are most related with primary structure information. For each highly predictable GO term, the responsible features of such successfulness were identified and discussed. In addition to most published studies, focused on few categories or single ontologies, results in this paper comprise a complete landscape of GO predictability from primary structure encompassing 75 GO terms at molecular, cellular and phenotypical level. Thus, it provides a valuable guide for researchers interested on further advances in protein function prediction on Embryophyta plants. PMID- 23441935 TI - Severe dietary lysine restriction affects growth and body composition and hepatic gene expression for nitrogen metabolism in growing rats. AB - Dietary lysine restriction may differentially affect body growth and lipid and nitrogen metabolism, depending on the degree of lysine restriction. This study was conducted to examine the effect of dietary lysine restriction on growth and lipid and nitrogen metabolism with two different degree of lysine restriction. Isocaloric amino acid-defined diets containing 1.4% lysine (adequate), 0.70% lysine (50% moderate lysine restriction) and 0.35% lysine (75% severe lysine restriction) were fed from the age of 52 to 77 days for 25 days in male Sprague Dawley rats. The 75% severe lysine restriction increased (p < 0.05) food intake, but retarded (p < 0.05) growth, increased (p < 0.05) liver and muscle lipid contents and abdominal fat accumulation, increased (p < 0.05) blood urea nitrogen levels and mRNA levels of the serine-synthesizing 3-phosphoglycerate dehydrogenase gene, but decreased (p < 0.05) urea cycle arginase gene mRNA levels. In contrast, the 50% lysine restriction did not significantly (p > 0.05) affect body growth and lipid and nitrogen metabolism. Our results demonstrate that severe 75% lysine restriction has detrimental effects on body growth and deregulate lipid and nitrogen metabolism. PMID- 23441938 TI - Coupling pH-responsive polymer brushes to electricity: switching thickness and creating waves of swelling or collapse. AB - Electrolysis of water is proposed as a method to couple the pH-responsive behavior of polymer brushes to an electrical stimulus. It is shown that an electrode in close proximity to a pH-responsive polymer brush can change the local solution pH, inducing either swelling or collapse of the polymer brush. By alternating the bias of the voltage applied to the electrode, either acidic or alkaline conditions can be generated, and reproducible cycles of polymer brush swelling and collapse can be achieved. It was found that the length of time which the electrical stimulus is applied to the electrodes can be as short as 10 s and that, once "switched", polymer brushes remain in the switched state for many minutes after the electrical stimulus is turned off. In other experiments, two electrodes were positioned 10 cm apart with a pH-responsive brush in between. Under these conditions waves of either acidic or alkaline solution pH could be generated which caused a coincident wave of polymer brush swelling or collapse. These waves originate from one electrode and travel across the brush surface toward the opposite electrode with a velocity of ~40 MUm s(-1). PMID- 23441936 TI - The prevalence of oesophageal eosinophilia and eosinophilic oesophagitis: a prospective study in unselected patients presenting to endoscopy. AB - BACKGROUND: Oesophageal eosinophilia (EE) is encountered in clinical practice as oesophageal biopsies are being obtained in patients with GI symptoms other than classical symptoms of eosinophilic oesophagitis (EoE). The prevalence, determinants and clinical relevance of EE identified irrespective of symptoms are unclear. AIM: To determine the prevalence and risk factors of EE with or without EoE in a nonselected group of patients undergoing endoscopy and in primary care patients. METHODS: A cross-sectional study in a single VA centre in which we obtained at least one oesophageal biopsy from patients presenting to elective endoscopy, as well as a sample of patients eligible for screening colonoscopy recruited from primary care clinics. EE was defined by >15 eosinophils in a single HPF; and EoE was defined as definite, probable or none depending on the presence of EE, acid-suppressive therapy and oesophageal symptoms. RESULTS: EE was identified in 33 of 1357 patients (2.4%, 95% CI: 1.7-3.4); of whom 9 had definite EoE (0.66%, 95% CI: 0.23-1.10), 17 had probable EoE (1.25%), and the only 7 patients had EE without EoE. The prevalence of EE was 2.3% among patients undergoing elective endoscopy and 0.1% among patients eligible for screening colonoscopy. Seasonal allergies (adjusted OR: 2.78; 95% CI: 1.26-6.11) and oesophageal strictures (4.50; 0.90-22.40) were associated with EE. CONCLUSIONS: The prevalence of EE was 2.3% among unselected patients presenting to endoscopy most of whom have EoE. EE was present in 0.1% in primary care patients none of whom had EoE. PMID- 23441937 TI - A dynamic structural model of expanded RNA CAG repeats: a refined X-ray structure and computational investigations using molecular dynamics and umbrella sampling simulations. AB - One class of functionally important RNA is repeating transcripts that cause disease through various mechanisms. For example, expanded CAG repeats can cause Huntington's and other disease through translation of toxic proteins. Herein, a crystal structure of r[5'UUGGGC(CAG)3GUCC]2, a model of CAG expanded transcripts, refined to 1.65 A resolution is disclosed that shows both anti-anti and syn-anti orientations for 1 * 1 nucleotide AA internal loops. Molecular dynamics (MD) simulations using AMBER force field in explicit solvent were run for over 500 ns on the model systems r(5'GCGCAGCGC)2 (MS1) and r(5'CCGCAGCGG)2 (MS2). In these MD simulations, both anti-anti and syn-anti AA base pairs appear to be stable. While anti-anti AA base pairs were dynamic and sampled multiple anti-anti conformations, no syn-anti <-> anti-anti transformations were observed. Umbrella sampling simulations were run on MS2, and a 2D free energy surface was created to extract transformation pathways. In addition, an explicit solvent MD simulation over 800 ns was run on r[5'GGGC(CAG)3GUCC]2, which closely represents the refined crystal structure. One of the terminal AA base pairs (syn-anti conformation), transformed to anti-anti conformation. The pathway followed in this transformation was the one predicted by umbrella sampling simulations. Further analysis showed a binding pocket near AA base pairs in syn-anti conformations. Computational results combined with the refined crystal structure show that global minimum conformation of 1 * 1 nucleotide AA internal loops in r(CAG) repeats is anti-anti but can adopt syn-anti depending on the environment. These results are important to understand RNA dynamic-function relationships and to develop small molecules that target RNA dynamic ensembles. PMID- 23441939 TI - Washington State's alcohol ignition interlock law: effects on recidivism among first-time DUI offenders. AB - OBJECTIVE: To examine the effects of changes to Washington State's ignition interlock laws: moving issuance of interlock orders from courts to the driver licensing department in July 2003 and extending the interlock order requirement to first-time offenders with blood alcohol concentrations (BACs) below 0.15 percent ("first simple driving under the influence [DUI]") in June 2004. METHOD: Trends in conviction types, interlock installation rates, and 2-year cumulative recidivism rates were examined for first-time convictions (simple, high-BAC, test refusal DUI; deferred prosecution; alcohol-related negligent driving) stemming from DUI arrests between January 1999 and June 2006. Regression analyses examined recidivism effects of the law changes and interlock installation rates. To examine general deterrent effects, trends in single-vehicle late-night crashes in Washington were compared with trends in California and Oregon. RESULTS: After the 2004 law change, the proportion of simple DUIs declined somewhat, though the proportion of negligent driving convictions (no interlock order requirement) continued an upward trend. Interlock installation rates for first simple DUIs were 3 to 6 percent in the year before the law change and one third after. Recidivism declined by an estimated 12 percent (e.g., expected 10.6% without law change vs. 9.3% among offenders arrested between April and June 2006, the last study quarter) among first simple DUI offenders and an estimated 11 percent (expected 10.2% vs. 9.1%) among all first-time offenders. There was an estimated 0.06 percentage point decrease in the recidivism rate for each percentage point increase in the proportion of first simple DUI offenders with interlocks. If installation rates had been 100 vs. 34 percent for first simple DUI offenders arrested between April and June 2006, and if the linear relationship between rates of recidivism and installations continued, recidivism could have been reduced from 9.3 to 5.3 percent. With installation rates of 100 vs. 24 percent for all first offenders, their recidivism rate could have fallen from 9.1 to 3.2 percent. Although installation rates increased somewhat after the 2003 law change, recidivism rates were not significantly affected, perhaps due to the short follow-up period before the 2004 law change. The 2004 law change was associated with an 8.3 percent reduction in single-vehicle late-night crash risk. CONCLUSIONS: Mandating interlock orders for all first DUI convictions was associated with reductions in recidivism, even with low interlock use rates, and reductions in crashes. Additional gains are likely achievable with higher rates. Jurisdictions should seek to increase use rates and reconsider permitting reductions in DUI charges to other traffic offenses without interlock order requirements. PMID- 23441941 TI - Licensing age issues: deliberations from a workshop devoted to this topic. AB - OBJECTIVE: To highlight the issues and discuss the research evidence regarding safety, mobility, and other consequences of different licensing ages. METHODS: Information included is based on presentations and discussions at a 1-day workshop on licensing age issues and a review and synthesis of the international literature. RESULTS: The literature indicates that higher licensing ages are associated with safety benefits. There is an associated mobility loss, more likely to be an issue in rural states. Legislative attempts to raise the minimum age for independent driving in the United States--for example, from 16 to 17- have been resisted, although in some states the age has been raised indirectly through graduated driver licensing (GDL) policies. CONCLUSIONS: Jurisdictions can achieve reductions in teenage crashes by raising the licensing age. This can be done directly or indirectly by strengthening GDL systems, in particular extending the minimum length of the learner period. Supplementary materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention for the following supplemental resource: List of workshop participants. PMID- 23441940 TI - The result of a baseline survey on drink driving in Nanning and Liuzhou of Guangxi Province, China. AB - OBJECTIVE: Because the official data in China on drink-driving accidents as well as related fatalities and injuries are much lower than many of the developed and developing countries in the world, the Global Road Safety Partnership (GRSP) decided to conduct a baseline survey to understand the prevalence of drink driving and related accidents in Nanning and Liuzhou, both in Guangxi Province, in order to develop targeted interventions. METHODS: The baseline survey included a roadside survey and an accident survey. Motor vehicle (including motorcycles) drivers were randomly stopped for a breath test and interview in the roadside survey. In the accident survey, all drivers involved in a road accident resulting in at least 1 person killed or seriously injured were requested to provide a blood sample. RESULTS: A total of 10,685 drivers accepted the random breath test and 10,666 drivers were interviewed in the roadside survey. An examination of the raw (unweighted) breath alcohol readings reveals that of the 10,685 breath-tested drivers, 730 (6.8%) had positive blood alcohol concentrations (BACs); 245 of these drivers (2.3% of all drivers) had BACs below 20 mg/100 mL; 415 (3.9% of all drivers) were driving under the influence (DUI; 20 mg/100 mL-80 mg/100 mL); and 70 (0.7% of all drivers) were driving while intoxicated (DWI; >=0.80 mg/100 mL). Overall, 4.6 percent of the drivers had BACs over 20 mg/100 mL (the lowest legal BAC limit in China). Among the 10,666 interviewed drivers, only 4.8 percent were aware of the lowest national BAC limit (20 mg/100 mL); 24.9 percent had been discouraged by other people from driving after drinking; 78 percent had never been stopped by the traffic police for a BAC check during the last 2 years (during 2005-2006), and only 0.3 percent had been punished for drink driving. The accident survey results revealed that an average of 34.1 percent of road accidents (Nanning: 25.7%; Liuzhou: 48%) were alcohol related; the mean BAC level of the drivers in the accidents was 156.7 mg/100 mL and the highest was 310 mg/100 mL. CONCLUSIONS: Valuable information was obtained from the baseline survey to provide a better understanding of the drink driving situation in Nanning and Liuzhou. From the survey data it can be seen that drinking and driving was a major issue in both cities. A drink driving intervention was developed with both components of public education/social marketing and enforcement activities after the survey, which was conducted in 2008. However, this article will focus on the methodology and results of the baseline survey, not the activities and outcome of the intervention. PMID- 23441942 TI - New Jersey's license plate decal requirement for graduated driver licenses: attitudes of parents and teenagers, observed decal use, and citations for teenage driving violations. AB - OBJECTIVES: On May 1, 2010, New Jersey implemented a law requiring teenagers with learner's permits or probationary licenses to display reflective decals on the front and rear license plates when they drive. The current study examined attitudes of parents and teenagers toward this requirement, use of decals, and reported violations and police enforcement of the graduated driver license law. METHOD: Statewide telephone surveys of representative samples of parents and teenagers were conducted in February to April 2010 and March to June 2011. Use of decals among probationary license holders was observed at 4 high schools in fall 2010 and in spring 2011 and hand-out surveys were distributed. Data on citations issued for violations of the graduated driver license law were obtained. RESULTS: When interviewed in spring 2011, a large majority of parents of probationary license holders, parents of learner's permit holders, and teenagers with probationary licenses disapproved of decals for probationary licenses. About two thirds of both sets of parents and about half of teenagers disapproved of decals for learner's permits. Support for decals for both license types declined significantly from 2010 to 2011. For parents and teenagers alike, opposition was mainly attributed to concern about identifying and/or targeting teenage drivers by other drivers, predators, or police. In 2011, 77 percent of parents of probationary license holders said that their teenagers had decals for the vehicles driven most often; 46 percent said their teenagers always used decals. Fifty-six percent of parents of learner's permit holders said that their teenagers had decals for the vehicles driven most often; 37 percent said that their teenagers always used decals. Teenagers' reported violations of license restrictions either increased or were similar in 2011 compared to 2010. Observed rates of decal use by probationary license holders at high schools in spring 2011 ranged from 24 to 64 percent. The number of statewide citations for teenage licensing law violations doubled in the year after the decal requirement took effect compared to the prior year. Excluding decal violations, citations increased by 52 percent. CONCLUSIONS: Early examination of New Jersey's decal requirement found widespread opposition, primarily due to concerns about identifying/targeting teenage drivers, though first-hand reports of such incidents were very rare. Many teenagers do not use the decals. Increased issuance of citations for violations of the teenage licensing law suggests that decals are facilitating police enforcement. However, based on teenagers' self reports, the requirement does not appear to have achieved the ultimate goal of increased compliance. PMID- 23441943 TI - Female drivers in the United States, 1963-2010: from a minority to a majority? AB - OBJECTIVE: This study examined the changes in the relative proportions of male and female drivers between 1963 and 2010. METHOD: The analysis used data from the Federal Highway Administration. RESULTS: During the period examined, the proportion of male drivers has gradually decreased. In 1963, males represented 60.4 percent of all drivers. Males became a minority in 2005. In 2010, they constituted 49.7 percent. A consideration of both the percentage of drivers by gender and the average annual miles driven by gender revealed that in 1963 about 76 percent of drivers on the road were males, which dropped to about 59 percent by 2010. CONCLUSIONS: Currently, females with a driver's license are slightly outnumbering males. However, because females drive less than males, the overall likelihood that a given driver on the road today is a female is still less than 50 percent. PMID- 23441944 TI - Nonfatal road traffic injuries: can road safety campaigns prevent hazardous behavior? An Italian experience. AB - OBJECTIVES: Road traffic injuries are a widespread problem and are very difficult to prevent. The purpose of this study was to verify whether intensive versus basic road safety education programs are associated with different incidence and severity of nonfatal road injuries. METHOD: The study had an ecological design and involved Local Health Authority One (LHA1) in Salerno, Italy, which includes 20 municipalities. Data on nonfatal road injuries occurring in the periods June to August 2003 and June to August 2008 were obtained from trained operators through the information system of the emergency department. All 20 municipalities received a basic community road safety education program (publicity campaign using bill-posting, brochures, mass media communication with press conferences, articles in local papers, radio and television interviews, and a dedicated LHA1 web site), and 12 municipalities also received an intensive education campaign (in secondary schools, community conferences, and activities organized by police and firefighters). The incidence and severity of nonfatal road traffic injuries were compared between June to August 2003 (before the campaign) and June to August 2008. RESULTS: The total number of injuries in all 20 municipalities in 2003 and 2008 was 907 and 755, respectively. The incidence of injuries decreased in the study period both in the 8 municipalities where only the basic campaign was run (difference in incidence = -0.4; P = .053) and in the 12 municipalities where the intensive campaign was implemented (difference in incidence = -0.5; P < .001); focusing on severity, the incidence of severe injuries decreased or remained the same in the study period in the 2 studied group. DISCUSSION: The results are coherent with other European studies and show that an overall downward trend exists but is presumably not a direct consequence of road safety education. This does not mean that such campaigns are useless (they are important to raise awareness) but that they should be supplemented with complementary activities in order to be really effective. PMID- 23441945 TI - Assessing quality of existing data sources on road traffic injuries (RTIs) and their utility in informing injury prevention in the Western Cape Province, South Africa. AB - OBJECTIVES: This study assessed whether the quality of the available road traffic injury (RTI) data was sufficient for determining the burden of RTIs in the Western Cape Province and for implementing and monitoring road safety interventions. METHODOLOGY: Underreporting was assessed by comparing data reported by the South African Police Services (SAPS) in 2008 with data from 18 provincial mortuaries. Completeness of the driver death subset of all RTIs was assessed using the capture-recapture method. RESULTS: The mortuary and police data sets comprised 1696 and 860 fatalities respectively for the year 2008. The corresponding provincial road traffic mortality rates were as follows: 32.2 deaths/100,000 population per year (95% confidence interval [CI]: 30.7-33.8) and 16.3 deaths/100,000 population per year (95% CI: 15.3-17.5). The police data set contained 820,960 crashes, involving 196,889 persons, indicating substantial duplication of crash events. There were varying proportions of missing data for demographic and other identifying variables, with age missing in nearly half of the cases in the police data set. The estimated total number of driver deaths/year was 588.6 (95% CI: 544.4-632.8), yielding estimated completeness of the mortuary and police data sets of 57.6 and 46.4 percent separately and 77.3 percent combined. CONCLUSION: This study found extensive data quality problems, including missing data, duplication, and significant underreporting of traffic injury deaths in the police data. Not all assumptions underlying the use of capture-recapture method were met in this study; hence, the estimates provided by this analysis should be interpreted with caution. There is a need to address the problems highlighted by this study in order to improve data utility for informing road safety policies. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 23441946 TI - Child and youth traffic-related injuries: use of a trauma registry to identify priorities for prevention in the United Arab Emirates. AB - OBJECTIVE: Traffic-related injuries are the main cause of death during childhood and youth in the United Arab Emirates (UAE), use of safety restraints by citizens is uncommon, rollovers are frequent, and current legislation does not protect rear-seat occupants. Because little was known about the circumstances of hospitalizations for traffic injuries to guide prevention, a trauma registry was used to assess causes and determinants for traffic-related injuries during childhood and youth (<19 years) and its value for prevention. METHODS: One hundred ninety-three children and youth with traffic injuries were admitted for more than 24 h at surgical wards of the main trauma hospital in the Al-Ain region during a 36-month period (2003-2006). Injuries were analyzed by age, nationality, road user and vehicle types, severity, anatomical region, and the presence of head injury using Injury Severity Scores (ISS) and the Abbreviated Injury Scale (AIS). RESULTS: Traffic injuries represented 40 percent (n = 193) of injuries to 0- to 19-year-olds, followed by falls (39 percent). Among 15- to 19-year-olds, who accounted for 46 percent of child and youth victims, the incidence was 150/100,000 person years, compared to an incidence of 15 to 51 for younger age groups. Overall, 53 percent were vehicle occupants, 23 percent were pedestrians, 14 percent were bicyclists, 6 percent were motorcyclists, with 4 percent other. The ratio of male-to-female victims was 6.7:1; for drivers it was 33:0; and for pedestrians, bicyclists, and motorcyclists it was between 10:1 and 12:1; injured females were mainly rear-seat passengers and the male: female ratio was 1.4:1. Seventy-one percent of pedestrians were <=9 years old. Although the ratio of UAE children to foreign children was estimated at 0.7:1 in the community, 58 percent of the injured were UAE citizens. The ratio of injured UAE: non-UAE citizens was 1.4:1 overall but 5.6:1 for drivers and 4.5:1 for motorcyclists. Forty-one percent of citizens were injured in 4-wheel drive sport utility vehicles compared to 13 percent of non-citizens. Head injuries occurred in 68 percent of vehicle occupants and 51 percent of nonoccupants, with AIS >= 3 injuries in 23 percent of occupants and 26 percent of nonoccupants. Sixty-seven percent of rear occupants had head injuries. CONCLUSIONS: Male drivers and vulnerable road users were at an unusually high risk relative to females. A relatively high frequency of traffic related head injuries among UAE children and youth, including rear-seat passengers and other vehicle occupants, suggests that considerable preventable morbidity is associated with nonuse of safety restraints and/or other factors such as excess speed and rollovers of 4-wheel drive vehicles. Trauma registries can be useful for prevention; inclusion of data on safety restraints and helmet use by road user type is essential. PMID- 23441947 TI - Teen driver risk in relation to age and number of passengers, United States, 2007 2010. AB - OBJECTIVE: To provide updated estimates of the relationship between the number and ages of passengers present in a vehicle and the crash risk per mile driven of 16- and 17-year-old drivers. METHODS: Data on crashes that occurred in years 2007 2010 and data on the number of miles driven in years 2008-2009 were examined. Rates of crash involvement and driver death per mile driven were estimated for 16 and 17-year-old drivers with no passengers; with 1, 2, and 3 or more passengers younger than age 21 (and no older passengers); and with at least 1 passenger aged 35 or older. RESULTS: For 16- and 17-year-old drivers, having 1 passenger younger than age 21 (and no older passengers) was associated with 44 percent greater risk per mile driven of being killed in a crash, compared to having no passengers (relative risk [RR]: 1.44, 95% confidence interval [CI]: 1.01-2.04). Having 2 passengers younger than age 21 was associated with double the risk of being killed in a crash, compared to having no passengers (RR: 2.02, 95% CI: 1.36 2.99). Having 3 or more passengers younger than age 21 was associated with roughly quadruple the risk of being killed in a crash, compared to having no passengers (RR: 4.39, 95% CI: 1.45-13.31). The relative risk of being involved in any police-reported crash in the presence of young passengers followed a similar pattern; however, the differences in risks of being involved in any police reported crash were smaller and were not statistically significant. Having at least 1 passenger aged 35 or older in the vehicle was associated with a 62 percent lower risk per mile driven of being killed in a crash (RR: 0.38, 95% CI: 0.24-0.60) and a 46 percent lower risk of being involved in any police-reported crash (RR: 0.54, 95% CI: 0.31-0.93) for 16- and 17-year-old drivers, compared to having no passengers. CONCLUSIONS: These results show that although the overall number of teen driver fatalities has decreased substantially over the past several years, carrying young passengers is still a significant risk factor for young drivers. In contrast, carrying adult passengers is associated with significantly lower risk of crash involvement. PMID- 23441948 TI - Who can best influence the quality of teenagers' cars? AB - OBJECTIVE: Because young drivers' vehicles have been found to offer poor occupant protection in many countries, this study sought to identify the most appropriate audience for information and publicity designed to change purchasing preferences to improve these vehicles and resultant injury outcomes. METHODS: An analysis of New Zealand vehicles crashed by drivers aged 19 years or less linked to data on the owner of the vehicle was undertaken. Details on the crashed vehicles were merged with licensing information to identify the owner's age group. RESULTS: It was presumed that most vehicles driven by teens but owned by someone aged 30 to 59 would be owned by a parent of the teen. Only 14 percent of vehicles crashed by teens were owned by teens. Generally, older vehicles with poor crashworthiness were provided for the teenage driver, whatever the age group of the owner. However, cars crashed by teens but owned by their parents were on average almost 2 years younger and had relatively superior crashworthiness than the teenager owned and crashed vehicles, although their crashworthiness was still poor compared to vehicles driven by older drivers. CONCLUSIONS: Evidently, parents are key people in making vehicle purchasing decisions regarding the cars that teenagers drive and should be the main audience for measures to improve the poor secondary safety performance of teenagers' vehicles. PMID- 23441949 TI - How effective are pictograms in communicating risk about driving-impairing medicines? AB - OBJECTIVES: To evaluate and compare the effectiveness of 2 pictograms in communicating risk in terms of respondents' level of understanding, estimated level of driving risk, and intention to change driving behavior. The added value of a side-text was also investigated. METHODS: Two experiments were conducted among 270 drivers visiting a pharmacy. Experiment one used a 2 (rating model vs. triangle model pictogram, same side-text) * 3 (minor vs. moderate vs. severe driving risk) between-subjects design. Respondents (n = 30 per condition) were exposed to one of the 6 conditions. To verify the added value of the side-text, a 2 (rating model with side-text vs. rating model without side-text) * 3 (same categories as before) between-subjects design was used. RESULTS: Although the majority of the respondents understood that the pictograms were related to driving behavior, less than 10 percent and about 36 percent of the respondents looking at the triangle model and at the rating model, respectively, understood it fully. For all categories of risk, respondents who saw the rating model pictogram associated the pictogram significantly more often with risk of medication intake for driving than those who saw the triangle model pictograms. Those exposed to the triangle model overestimated the driving risk of the lowest category and underestimated the risk of the highest category; 78.8 percent of the respondents stated they were (very) likely to change their driving behavior if they were confronted with the pictogram. The added value of the side-text was not confirmed. CONCLUSIONS: Despite not being fully self-explanatory in conveying warnings and safety-related information, the pictograms evaluated in this research provided good insight into the different levels of driving risks, especially the rating model pictogram, because respondents' intentions to change their driving behaviors increased with higher categories of risk. The added value of the side-text in the rating model pictogram was not confirmed in this research. Pictograms can be seen as a valuable means to reinforce both written and spoken information given to patients by health care providers at the time of consultation. PMID- 23441950 TI - Determining vehicle operating speed and lateral position along horizontal curves using linear mixed-effects models. AB - OBJECTIVE: Despite recent improvements in highway safety in the United States, serious crashes on curves remain a significant problem. To assist in better understanding causal factors leading to this problem, this article presents and demonstrates a methodology for collection and analysis of vehicle trajectory and speed data for rural and urban curves using Z-configured road tubes. METHODS: For a large number of vehicle observations at 2 horizontal curves located in Dexter and Ames, Iowa, the article develops vehicle speed and lateral position prediction models for multiple points along these curves. Linear mixed-effects models were used to predict vehicle lateral position and speed along the curves as explained by operational, vehicle, and environmental variables. Behavior was visually represented for an identified subset of "risky" drivers. RESULTS: Linear mixed-effect regression models provided the means to predict vehicle speed and lateral position while taking into account repeated observations of the same vehicle along horizontal curves. CONCLUSIONS: Speed and lateral position at point of entry were observed to influence trajectory and speed profiles. Rural horizontal curve site models are presented that indicate that the following variables were significant and influenced both vehicle speed and lateral position: time of day, direction of travel (inside or outside lane), and type of vehicle. PMID- 23441951 TI - Economic growth, motorization, and road traffic injuries in the Sultanate of Oman, 1985-2009. AB - BACKGROUND: Recent affluence, assisted by exploitation of hydrocarbon, has sparked unprecedented economic growth and influx of all facades of modernity in Oman. Different statistical models have examined the relationship between economic growth, motorization rates, and road traffic fatalities. However, such a relationship in Oman has never been described. OBJECTIVE: To describe and analyze the trend of road traffic injuries (RTIs) in relation to motorization rates and economic growth during the period from 1985 to 2009 using Smeed's (1949) model and Koren and Borsos's (2010) model. METHODS: The study is based on national data reported between 1985 and 2009. Data on the population and gross domestic product (GDP) per capita in U.S. dollars were gathered from the Ministry of National Economy reports. Data on the number of vehicles and road traffic crashes, fatalities, and injuries were gathered from the Royal Oman Police (ROP) reports. Crash, fatality, and injury rates per 1000 vehicles and per 100,000 population were computed. Linear regression analysis was carried out to estimate the average annual changes in the rates. Smeed's (1949) and Koren and Borsos's (2010) models were used to predict the relations between motorization and road traffic fatalities in Oman. In addition, a cross-sectional analysis of year 2007 data for a number of Arab countries was carried out. RESULTS: The GDP per capita increased from US$6551 in 1985 to US$25,110 in 2009 with an annual increase of UR$547 per capita. The motorization rates increased by 36 percent from 1745 per 10,000 population in 1985 to 2382 per 10,000 population in 2009. Both Smeed's (1949) and Koren and Borsos's (2010) models had a high goodness of fit, with R(2) greater than 0.70. This indicated that road traffic fatalities in Oman may have a direct relationship with increased motorization. The cross-sectional analysis showed that the relation between crash fatalities and motorization rates in Oman and the United Arab Emirates can be better explained by Koren and Borsos's (2010) model than other countries. CONCLUSION: Recent economic growth in Oman was associated with an increase in motorization rates, which in turn has resulted in an increased burden of road traffic fatalities and injuries. PMID- 23441952 TI - Differential effects of retinoids and inhibitors of ERK and p38 signaling on adipogenic and myogenic differentiation of P19 stem cells. AB - All-trans-retinoic acid (atRA) is an essential signaling molecule in embryonic development. It regulates cell differentiation by activating nuclear retinoic acid receptors (RAR) and retinoid-X receptors (RXR), which both control gene expression. In addition, atRA could act in the cytoplasm by modulating the activity of mitogen-activated protein kinases (MAPK) ERK and p38, which also have a role in cell differentiation. AtRA can induce the differentiation of P19 embryonic carcinoma stem cells into adipocytes, cardiomyocytes, and skeletal muscle cells, concurrently, in the same culture. We postulated that combinations of atRA, atRA analogs exhibiting selectivity for RAR or RXR, and inhibitors of ERK and p38 signaling (ERKi and p38i) could be used to favor one mesodermal fate over the others in the P19 model. In a first series of experiments, we replaced atRA by an agonist of RXR (LG100268) or RAR (TTNPB) to preferentially stimulate one group of receptors over the other. LG100268 was as adipogenic and myogenic as atRA, whereas TTNPB strongly induced adipogenesis, but not myogenesis. ERKi enhanced the myogenic action of atRA, and p38i increased both adipogenesis and myogenesis. In a second series of experiments, we combined atRA with an RAR or RXR antagonist (RARatg or RXRatg) to preferentially deactivate each receptor group in turn. The combinations atRA+RXRatg and atRA+RARatg, including or not ERKi, had similar mesodermal actions as atRA. In contrast, there was no myogenesis with atRA+RXRatg+p38i treatment, and there were no myogenesis and no adipogenesis with the atRA+RARatg+p38i combination. Overall, the results indicate that p38 has a role in mesodermal differentiation that depends on the retinoid context. Indeed, p38 in conjunction with RXR is important in myogenesis, and p38 and RAR in adipogenesis. Under the conditions tested, it was possible to stimulate adipogenesis with a block on myogenesis, whereas increased myogenesis was accompanied by adipogenesis. PMID- 23441953 TI - Whole field laser Doppler imaging of the microcirculation in psoriasis and clinically unaffected skin. AB - BACKGROUND: Angiogenesis represents a key phenomenon in psoriasis. Insights in the microcirculation within psoriatic lesions in a whole field are lacking. Recently, the Twente Optical Perfusion Camera (TOPCam) was developed, which provides the possibility of evaluating the superficial cutaneous microcirculation in a whole field. OBJECTIVES: This pilot study aims to examine whether the TOPCam can be used to visualize the microcirculation within and around psoriatic lesions, and whether it is capable of revealing vascular changes during topical treatment. METHODS: Five patients with chronic plaque psoriasis were included. The superficial microcirculation and clinical local scores (SUM score) were analyzed in two comparable lesions within one patient. At baseline and after 2, 4, 6, and 8 weeks the disease's natural course was evaluated in one plaque versus topical treatment in the other. RESULTS: The TOPCam was able to visualize an increased microcirculation within psoriatic lesions and perfusion variability due to the heartbeat. Whole field images demonstrated heterogeneity in perfusion intensity (hot and cold spots) within clinically homogeneous-looking plaques. Topical therapy induced a decrease in overall perfusion and a significant decrease in SUM score. CONCLUSION: The TOPCam is the first noninvasive technique to visualize the microcirculation of psoriatic lesions in a whole field, to correct images for the heartbeat, and to reveal heterogeneity in perfusion intensity. PMID- 23441954 TI - Changes in protein architecture and subpicosecond protein dynamics impact the reaction catalyzed by lactate dehydrogenase. AB - We have previously established the importance of a promoting vibration, a subpicosecond protein motion that propagates through a specific axis of residues, in the reaction coordinate of lactate dehydrogenase (LDH). To test the effect that perturbation of this motion would have on the enzymatic reaction, we employ transition path sampling to obtain transition path ensembles for four independent LDH enzymatic systems: the wild type enzyme, a version of the enzyme expressing heavy isotopic substitution, and two enzymes with mutations in the promoting vibration axis. We show that even slight changes in the promoting vibration of LDH result in dramatic changes in enzymatic chemistry. In the "heavy" version of the enzyme, we find that the dampening of the subpicosecond dynamics from heavy isotopic substitution leads to a drastic increase in the time of barrier crossing. Furthermore, we see that mutation of the promoting vibration axis causes a decrease in the variability of transition paths available to the enzymatic reaction. The combined results reveal the importance of the protein architecture of LDH in enzymatic catalysis by establishing how the promoting vibration is finely tuned to facilitate chemistry. PMID- 23441955 TI - Drug discovery. Editorial. PMID- 23441956 TI - Quinoline driven fluorescence turn on 1,3-bis-calix[4]arene conjugate-based receptor to discriminate Fe3+ from Fe2+. AB - The synthesis and characterization of a triazole linked quinoline appended calix[4]arene conjugate, L, and its fluorescence turn on receptor property for Fe(3+) have been demonstrated. The selective and sensitive discrimination of Fe(3+) has been shown using fluorescence and absorption titration experiments. The Fe(3+) binding to L has been further shown by ITC and ESI MS. The mode of binding of Fe(3+) by calix[4]arene conjugate has been shown by absorption, (1)H NMR and visual color change and the species were modeled based on DFT computations. The {L + Fe(3+)} has been shown to label cells with fluorescence imaging. Moreover the utility of this conjugate has been demonstrated by the combination logic gate system. PMID- 23441957 TI - Detection of serum protein biomarkers by surface enhanced laser desorption/ionization in patients with adenocarcinoma of the lung. AB - AIM: Early diagnosis of lung cancer is important for successful treatment and improving the outcome of patients. We explored novel tools for screening serum biomarkers to distinguish adenocarcinoma of the lung from healthy controls by serum protein profiles. METHODS: Serum samples were taken from 31 patients with adenocarcinoma of the lung and 31 healthy controls, matched for age, sex and smoking status. Serum samples were applied to strong anion 2(SAX-2) protein chips to generate mass spectra by surface-enhanced laser desorption/ionization time-of flight mass spectrometry (SELDI-TOF-MS). Protein peak identification and clustering were performed using Biomarker Wizard, compared by MATLAB 7.5 and a classification tree was constructed using R weka software. The validity of the classification tree was then challenged with a blind test. RESULTS: The software identified 102 peaks and m/z 14022.9 and m/z 3735.99 was used to construct a classification tree. The classification tree effectively separated adenocarcinoma of lung patients from healthy controls, achieving a validity of 100%. The blind test challenged the model with a sensitivity of 100% and a specificity of 100%. CONCLUSION: The results suggested that the SELDI-TOF-MS technique can correctly distinguish adenocarcinoma of lung patients from healthy controls and showed great potential for development as a screening test for the detection of lung cancer. PMID- 23441959 TI - Genetic and crossbreeding parameters for incidence of recorded clinical lameness in New Zealand dairy cattle. AB - AIM: To estimate genetic and crossbreeding parameters for the incidence of recorded clinical lameness in New Zealand dairy cattle. METHODS: Herd records from 76,357 cows, collected during the 2005/06 to 2008/09 milking seasons from 155 herds in the Livestock Improvement Corporation young sire progeny test scheme, were used to estimate genetic parameters and breed effects for incidence of recorded clinical lameness in HolsteinFriesian, Jersey and crossbred dairy cattle. Recorded clinical lameness was coded "1" for cows that presented at least one event of clinical lameness at any day during the season and "0" for unaffected cows. Genetic parameters were estimated using an animal model across breeds considering all and then only first lactation records. Heritability and repeatability of recorded clinical lameness were calculated from the variance component estimates both with and without logit transformation. RESULTS: The mean incidence of recorded clinical lameness per herd was 6.3 (min 2, max 34)%. The incidence of recorded clinical lameness in Holstein Friesian cows (mean 6.8, SE 0.24%) was higher than the incidence of recorded clinical lameness in crossbred (mean 6.1, SE 0.19%) and Jersey cows (mean 6.0, SE 0.28%) (p=0.0002). There was no difference in incidence between crossbred and Jersey cows (p=0.96). Estimates of the heritability of recorded clinical lameness as an untransformed trait were 0.053 (SE 0.014) for first lactation records and 0.016 (SE 0.003) for all lactation records. As a transformed (logit) trait heritabilities were 0.067 (SE 0.024) and 0.044 (SE 0.016) for first and all lactation records, respectively. The repeatability estimates of recorded clinical lameness were 0.071 (SE 0.005) and 0.107 (SE 0.011) for untransformed and logit transformed lactation records, respectively. Sire estimated breeding values for recorded clinical lameness showed the lowest values in Jersey sires, and ranged between -5 and 8%. CONCLUSIONS: Despite the low heritability of recorded clinical lameness, this study provided evidence that there is significant exploitable animal genetic variation. Selection of specific sires across and within breeds could be an option for increasing genetic resistance to lameness in New Zealand dairy cattle. PMID- 23441958 TI - Establishment and characterization of a telomerase immortalized human gingival epithelial cell line. AB - BACKGROUND AND OBJECTIVE: Gingival keratinocytes are used in model systems to investigate the interaction between periodontal bacteria and the epithelium in the initial stages of the periodontal disease process. Primary gingival epithelial cells (GECs) have a finite lifespan in culture before they enter senescence and cease to replicate, while epithelial cells immortalized with viral proteins can exhibit chromosomal rearrangements. The aim of this study was to generate a telomerase immortalized human gingival epithelial cell line and compare its in vitro behaviour to that of human GECs. MATERIAL AND METHODS: Human primary GECs were immortalized with a bmi1/hTERT combination to prevent cell cycle triggers of senescence and telomere shortening. The resultant cell-line, telomerase immortalized gingival keratinocytes (TIGKs), were compared to GECs for cell morphology, karyotype, growth and cytokeratin expression, and further characterized for replicative lifespan, expression of toll-like receptors and invasion by P. gingivalis. RESULTS: TIGKs showed morphologies, karyotype, proliferation rates and expression of characteristic cytokeratin proteins comparable to GECs. TIGKs underwent 36 passages without signs of senescence and expressed transcripts for toll-like receptors 1-6, 8 and 9. A subpopulation of cells underwent stratification after extended time in culture. The cytokeratin profiles of TIGK monolayers were consistent with basal cells. When allowed to stratify, cytokeratin profiles of TIGKs were consistent with suprabasal cells of the junctional epithelium. Further, TIGKs were comparable to GECs in previously reported levels and kinetics of invasion by wild-type P. gingivalis and an invasion defective DeltaserB mutant. CONCLUSION: Results confirm bmi1/hTERT immortalization of primary GECs generated a robust cell line with similar characteristics to the parental cell type. TIGKs represent a valuable model system for the study of oral bacteria interactions with host gingival cells. PMID- 23441960 TI - Guidelines for the diagnosis and treatment of vitiligo in Japan. AB - Vitiligo is an acquired pigment disorder in which depigmented macules result from the loss of melanocytes from the involved regions of skin and hair. The color dissimilarity on the cosmetically sensitive regions frequently induces quality of life impairment and high willingness to pay for treatment in patients with vitiligo. The Vitiligo Japanese Task Force was organized to overcome this situation and to cooperate with the Vitiligo Global Issues Consensus Conference. This guideline for the diagnosis and treatment of vitiligo in Japan is proposed to improve the circumstances of Japanese individuals with vitiligo. Its contents include information regarding the diagnosis, pathogenesis, evaluation of disease severity and effectiveness of treatment, and evidence-based recommendations for the treatment of vitiligo. The therapeutic algorithm based on the proposed recommendation is designed to cure and improve the affected lesions and quality of life of individuals with vitiligo. PMID- 23441961 TI - Oncologic multidisciplinary team meetings: evaluation of quality criteria. AB - RATIONALE, AIMS AND OBJECTIVES: To develop a guideline with quality criteria for an optimal structure and functioning of a multidisciplinary team meeting (MTM), and to assess to what extent the Dutch MTMs complied with these criteria. METHOD: A literature search and expert opinions were used to develop a guideline for optimal MTMs. In order to assess adherence to the guideline, we conducted interviews with MTM chairs and observed general and tumour-specific MTMs in seven hospitals. RESULTS: The new guideline included the following domains: (i) organization of the MTMs; (ii) membership of the MTM and roles and responsibilities of the members; (iii) the meeting itself; and (iv) documentation of meeting-recommendations. We observed good adherence to the quality criteria on the organization of the MTMs. Only the required coordinator/administrative support was often absent, particularly during general MTMs. Regarding membership of MTMs and roles, the recommended average attendance of 100% of the core disciplines was never reached and particularly the role of the chair needs improvement. Regarding the meeting itself, many interruptions took place and relevant information about the diagnoses of the cases was not available in 4-5% of the cases. Concerning the documentation of meeting-recommendations, only in a quarter of the meetings a specific form was used for the documentation. CONCLUSIONS: We found a lot of diversity in the organization of MTMs. The variation in compliance with the quality criteria may decrease with better knowledge about the quality criteria around MTMs and by overcoming practical barriers for the effective organization of MTMs. PMID- 23441962 TI - A leaky aquifer below Champlain Sea clay: closed-form solutions for natural seepage. AB - Closed-form solutions are proposed for natural seepage in semiconfined (leaky) aquifers such as those existing below the massive Champlain Sea clay layers in the Saint-Lawrence River Valley. The solutions are for an ideal horizontal leaky aquifer below an ideal aquitard that may have either a constant thickness and a constant hydraulic head at its surface, or a variable thickness and a variable hydraulic head at its surface. A few simplifying assumptions were needed to obtain the closed-form solutions. These have been verified using a finite element method, which did not make any of the assumptions but gave an excellent agreement for hydraulic heads and groundwater velocities. For example, the difference between the two solutions was smaller than 1 mm for variations in the 5 to 8 m range for the hydraulic head in the semiconfined aquifer. Note that fitting the hydraulic head data of monitoring wells to the theoretical solutions gives only the ratio of the aquifer and aquitard hydraulic conductivities, a clear case of multiple solutions for an inverse problem. Consequently, field permeability tests in the aquitard and the aquifer, and pumping tests in the aquifer, are still needed to determine the hydraulic conductivity values. PMID- 23441963 TI - A randomized, double-blind, parallel-group, placebo-controlled trial of Extract Sceletium tortuosum (Zembrin) in healthy adults. AB - OBJECTIVES: The objective of the study was to evaluate the safety and tolerability of two doses (8 mg and 25 mg once daily) of a 2:1 standardized extract of the South African medicinal plant Sceletium tortuosum (L.) N.E. Br., trademarked Zembrin,((r)) in healthy adult volunteers over a three-month period. DESIGN: This was a randomized, double-blind, parallel-group, placebo-controlled single center study. SETTING: Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, Cape Town, South Africa. PARTICIPANTS: The study took place between February 2 and July 27, 2009. Thirty-seven healthy adults were recruited from the general population. INTERVENTION: Participants were randomized to receive either one of two doses of study medication, or an identical placebo, taken once daily for 3 months. Of the 37 subjects, 12, 12, and 13 subjects received 8 mg extract Sceletium tortuosum (Zembrin), 25 mg extract Sceletium tortuosum (Zembrin), and placebo treatment, respectively. OUTCOME MEASURES: No efficacy variables were assessed. The safety and tolerability variables comprised of vital signs, physical examination, 12-lead electrocardiogram (ECG), laboratory assessments (hematology, biochemistry, and urinalysis), and the recording of adverse events (AEs). RESULTS: There were no apparent differences between the three treatments with regard to vital signs, 12-lead ECG, body weight, and physical examination from screening to the end of the 3-month treatment period. No significant changes were observed in hematology or biochemistry parameters between initial screening and the end of the study. Both doses of extract Sceletium tortuosum (Zembrin) were well-tolerated. The most commonly reported AE was headache, followed by abdominal pain and upper respiratory tract infections, all with greater incidence in the placebo group than in the treatment groups. Unsolicited positive effects on well-being were noted in patient diaries by some participants taking extract Sceletium tortuosum (Zembrin), including improved coping with stress and sleep. CONCLUSION: Both doses of extract Sceletium tortuosum (Zembrin) (8 mg and 25 mg) were well tolerated when used by healthy human subjects once daily for 3 months. PMID- 23441964 TI - Interaction of Curcumin with PEO-PPO-PEO block copolymers: a molecular dynamics study. AB - Curcumin, a naturally occurring drug molecule, has been extensively investigated for its various potential usages in medicine. Its water insolubility and high metabolism rate require the use of drug delivery systems to make it effective in the human body. Among various types of nanocarriers, block copolymer based ones are the most effective. These polymers are broadly used as drug-delivery systems, but the nature of this process is poorly understood. In this paper, we propose a molecular dynamics simulation study of the interaction of Curcumin with block copolymer based on polyethylene oxide (PEO) and polypropylene oxide (PPO). The study has been conducted considering the smallest PEO and PPO oligomers and multiple chains of the block copolymer Pluronic P85. Our study shows that the more hydrophobic 1,2-dimethoxypropane (DMP) molecules and PPO block preferentially coat the Curcumin molecule. In the case of the Pluronic P85, simulation shows formation of a drug-polymer aggregate within 50 ns. This process leaves exposed the PEO part of the polymers, resulting in better solvation and stability of the drug in water. PMID- 23441966 TI - Relational coordination between community health nurses and other professionals in delivering care to community-dwelling frail people. AB - AIMS: The first aim of this study was to investigate whether relational coordination is higher between primary care professionals and community health nurses than among other professionals. The second aim of this study was to investigate the relationship between different levels of relational coordination and primary care professionals' satisfaction with the care delivery of community health nurses. BACKGROUND: Community health nursing is based on the notion that all activities should respond to frail people's needs in a coordinated way, together with other professionals. Relational coordination is therefore important for the effective health-care delivery by these nurses. METHODS: This cross sectional study was performed among 167 professionals (n = 323, response rate 52%) who regularly worked with community health nurses. RESULTS: The results showed a higher degree of relational coordination with community health nurses than with other primary care professionals. Multilevel analyses revealed that professionals' satisfaction with the care delivered by community health nurses was influenced positively by relational coordination. CONCLUSION: Enhancing relational coordination between community health nurses and other primary care professionals in the neighborhood may improve the delivery of care to community dwelling frail people. IMPLICATIONS FOR NURSING MANAGEMENT: Comprehensive care delivery to community-dwelling frail people requires strong connections between all health and social care professionals. Community health nurses may be an important factor in strengthening these connections. PMID- 23441965 TI - The influence of simulated clinical use on the flexibility of rotary ProTaper Universal, K3 and EndoSequence nickel-titanium instruments. AB - AIM: To investigate the influence of cyclic flexural and torsional loading on the flexibility of ProTaper Universal, K3 and EndoSequence nickel-titanium instruments, in view of the hypothesis that these types of loading would decrease the flexibility of the selected NiTi rotary files. METHODOLOGY: The instruments evaluated were S2 and F1 ProTaper Universal, sizes 20 and 25, .06 taper K3, and sizes 20 and 25, .06 taper EndoSequence. Flexibility was determined by 45 degrees bending tests according to ISO 3630-1 specification. Values of the bending moment (MB ) obtained with new instruments were considered as the control group (CG). Bending tests were then conducted in instruments previously fatigued to one fourth and three-fourths of their average fatigue life (fatigue groups, FG1/4 and FG3/4), as well as after cyclic torsional loading (torsional group, TG). Fatigue tests were carried out in a bench device that allowed the files to rotate freely inside an artificial canal with an angle of curvature of 45 degrees and a radius of 5 mm. Cyclic torsional loading tests were performed that entailed rotating the instrument from zero angular deflection to 180 degrees and then returning to zero applied torque in 20 cycles. Data were analysed using one-way analysis of variance at a significance level of 5%. RESULTS: Simulated clinical use by means of flexural fatigue tests did not affect the flexibility of the instruments, except for a significant increase in flexibility observed in a few instruments (P < 0.05). In addition, comparative statistical analyses between the values of MB measured in new instruments and after cyclic torsional loading showed no significant differences between them (P > 0.05). CONCLUSIONS: The flexibility of rotary ProTaper Universal, K3 and EndoSequence NiTi instruments, measured in bending tests, was not adversely affected by simulated clinical use in curved root canals. PMID- 23441969 TI - Citrus huanglongbing: a newly relevant disease presents unprecedented challenges. AB - Citrus huanglongbing (HLB) is one of the oldest citrus diseases and has been known for over a century. HLB is caused by 'Candidatus Liberibacter' spp. that are phloem-limited, fastidious alpha-proteobacteria and infect hosts in different Kingdoms (i.e., Animalia and Plantae). When compared with well-characterized, cultivatable plant-pathogenic Gram-negative bacteria, the interactions of uncultured insect-vectored plant-pathogenic bacteria, including 'Ca. Liberibacter' spp., with their hosts remain poorly understood. 'Ca. Liberibacter' spp. have been known to cause HLB, which has been rapidly spreading worldwide, resulting in dramatic economic losses. HLB presents an unprecedented challenge to citrus production. In this review, we focus on the most recent research on citrus, 'Candidatus Liberibacter asiaticus', and psyllid interactions, specifically considering the following topics: evolutionary relationships among 'Ca. Liberibacter' spp., genetic diversity, host range, genome analysis, transmission, virulence mechanisms, and the ecological importance of HLB. Currently, no efficient management strategy is available to control HLB, although some promising progress has been made. Further studies are needed to understand citrus, 'Ca. L. asiaticus', and psyllid interactions to design innovative management strategies. Although HLB has been problematic for over a century, we can only win the battle against HLB with a coordinated and deliberate effort by the citrus industry, citrus growers, researchers, legislatures, and governments. PMID- 23441968 TI - Signatures of recombination in clonal lineages of the citrus brown spot pathogen, Alternaria alternata sensu lato. AB - Most Alternaria spp. are considered asexual but recent molecular evolution analyses of Alternaria mating-type genes show that the mating locus is under strong purifying selection, indicating a possible role in sexual reproduction. The objective of this study was to determine the mode of reproduction of an Alternaria alternata sensu lato population causing citrus brown spot in central Florida. Mating type of each isolate was determined, and isolates were sequenced at six putatively unlinked loci. Three genetically distinct subpopulations (SH1, SH4A, and SH4B) were identified using network and Bayesian population structure analyses. Results demonstrate that most subpopulations of A. alternata associated with citrus are clonal but some have the ability to extensively recombine through a cryptic sexual cycle or parasexual cycle. Although isolates were sampled in close physical proximity (~2,500-m2 area), we were able to reject a random mating model using multilocus gametic disequilibrium tests for two subpopulations, SH1 and SH4B, suggesting that these subpopulations were predominantly asexual. However, three recombination events were identified in SH1 and SH4B and localized to individuals of opposite mating type, possibly indicating meiotic recombination. In contrast, in the third subpopulation (SH4A), where only one mating type was present, extensive reticulation was evident in network analyses, and multilocus gametic disequilibrium tests were consistent with recombination. Recombination among isolates of the same mating type suggests that a nonmeiotic mechanism of recombination such as the parasexual cycle may be operating in this subpopulation. The level of gene flow detected among subpopulations does not appear to be sufficient to prevent differentiation, and perhaps future speciation, of these A. alternata subpopulations. PMID- 23441967 TI - The scaffolding protein GRASP/Tamalin directly binds to Dock180 as well as to cytohesins facilitating GTPase crosstalk in epithelial cell migration. AB - BACKGROUND: The transition of epithelial cells from their normal non-motile state to a motile one requires the coordinated action of a number of small GTPases. We have previously shown that epithelial cell migration is stimulated by the coordinated activation of Arf and Rac GTPases. This crosstalk depends upon the assembly of a multi-protein complex that contains the Arf-activating protein cytohesin 2/ARNO and the Rac activating protein Dock180. Two scaffolding proteins that bind directly to cytohesin 2 organize this complex. RESULTS: We now have found that Rac activation in response to hepatocyte growth factor (HGF) requires cytohesin 2 and Dock180. GRASP/Tamalin is one of the scaffolds that builds the complex containing cytohesin 2 and Dock180. We determine here that the Ala/Pro rich region of GRASP directly interacts with the SH3 domain of Dock180. By binding to both cytohesin 2/ARNO and Dock180, GRASP bridges the guanine nucleotide exchange factors (GEFs) that activate Arf and Rac, thereby promoting Arf-to-Rac signaling. Furthermore, we find that knockdown of GRASP impairs hepatocyte growth factor (HGF)-stimulated Rac activation and HGF-stimulated epithelial migration. CONCLUSIONS: GRASP binds directly both cytohesin 2 and Dock180 to coordinate their activities, and by doing so promotes crosstalk between Arf and Rac. PMID- 23441970 TI - Multi-level approach for the integrated assessment of polar organic micropollutants in an international lake catchment: the example of Lake Constance. AB - Polar organic micropollutants (MPs) can have ecotoxicological effects on aquatic ecosystems and their occurrence in drinking water is a threat to public health. An extensive exposure assessment of MPs in large river and lake catchments is a necessary but challenging proposition for researchers and regulators. To get a complete picture of MP exposure in a large catchment, we employed a novel integrated strategy including MP measurement in the international catchment of Lake Constance and mass-flux modeling. A comprehensive screening of 252 MPs in the lake water by high-resolution mass spectrometry was used to identify the most commonly present MPs for the study site. It was found that the wastewater borne MPs diclofenac, carbamazepine, sulfamethoxazole, acesulfame, sucralose, benzotriazole, and methylbenzotriazole accounted for the most frequent and prominent findings. The concentration pattern of these compounds in the catchment was calculated based on regionalized inputs from wastewater treatment plants (WWTPs) and substance specific elimination rates. In 52, 8, and 3 of the 112 investigated river locations the concentration exceeded the predicted no-effect levels for diclofenac, sulfamethoxazole and carbamazepine, respectively. By coupling the catchment and lake model the effect of future trends in usage as well as possible mitigation options were evaluated for the tributaries and the lake. The upgrade of the major WWTPs in the catchment with a postozonation step would lead to a load reduction between 32% and 52% for all substances except for sucralose (10%). PMID- 23441971 TI - Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs. AB - Within the field of solid organ transplantation, the patents for a number of immunosuppressive drugs have expired in the last few years. Tacrolimus, cyclosporine, and mycophenolate mofetil are now available as generic drugs. In some countries, the market penetration of these generic formulations is as high as 70%, whereas in some other countries, this figure is below 10%. Several professional societies have published position papers on the risks and benefits of generic substitution of immunosuppressive drugs. It often appears that transplant professionals are not fully aware of the requirements for registration of generic drugs. This article describes the registration requirements with a focus on bioequivalence testing, the strengths and weaknesses in this process, and the differences between Europe and the US. PMID- 23441972 TI - Quantitative Raman spectroscopy for the analysis of carrot bioactives. AB - Rapid quantitative near-infrared Fourier transform Raman analyses of the key phytonutrients in carrots, polyacetylenes and carotenoids, are reported here for the first time. Solvent extracts of 31 carrot lines were analyzed for these phytonutrients by conventional methods, polyacetylenes by GC-FID and carotenoids by visible spectrophotometry. Carotenoid concentrations were 0-5586 MUg g(-1) dry weight (DW). Polyacetylene concentrations were 74-4846 MUg g(-1) DW, highest in wild carrots. The polyacetylenes were falcarinol, 6-1237 MUg g(-1) DW; falcarindiol, 42-3475 MUg g(-1) DW; and falcarindiol 3-acetate, 27-649 MUg g(-1) DW. Strong Raman bands for carotenoids gave good correlation to results by visible spectrophotometry. A chemometric model capable of quantitating carotenoids from Raman data was developed. A classification model for rapidly distinguishing carrots with high and low polyacetylene (limit of detection = 1400 MUg g(-1)) concentrations based on Raman spectral intensity in the region of 2250 cm(-1) was produced. PMID- 23441973 TI - PRODAN dual emission feature to monitor BHDC interfacial properties changes with the external organic solvent composition. AB - We have investigated the water/benzyl-n-hexadecyldimethylammonium chloride (BHDC)/n-heptane:benzene reverse micelles (RMs) interfaces properties using 6 propionyl-2-(N,N-dimethyl)aminonaphthalene, PRODAN, as molecular probe. We have used absorption and emission (steady-state and time-resolved) spectroscopy of PRODAN to monitor the changes in the RMs interface functionalities upon changing the external organic solvent blend. We demonstrate that PRODAN is a useful probe to investigate how the external solvent composition affects the micelle interface properties. Our results show that changes in the organic solvent composition in water/BHDC/n-heptane:benzene RMs have a dramatic effect on the photophysics of PRODAN. Thus, increasing the aliphatic solvent content over the aromatic one produces PRODAN partition and PRODAN intramolecular electron transfer (ICT) processes. Additionally, the water presence in these RMs makes the PRODAN ICT process favored with the consequent decreases in the LE emission intensity and a better definition of the charge transfer (CT) band. All this evidence suggests that the benzene molecules are expelled out of the interface, and the water-BHDC interactions are stronger with more presence of water molecules in the polar part of the interface. Thus, we demonstrate that a simple change in the composition of the external phase promotes remarkable changes in the RMs interface. Finally, the results obtained with PRODAN together with those reported in a previous work in our lab reveal that the external phase is important when trying to control the properties of RMs interface. It should be noted that the external phase itself, besides the surfactant and the polar solvent sequestrated, is a very important control variable that can play a key role if we consider smart application of these RMs systems. PMID- 23441974 TI - Real-world treatment pattern and outcomes among patients who took tapentadol IR or oxycodone IR. AB - OBJECTIVE: To evaluate differences in patient characteristics, healthcare resource utilization, and healthcare costs among patients receiving immediate release (IR) formulations of tapentadol (TAP IR) or oxycodone (OXY IR). METHODS: Patients (>=18 years) who took TAP IR or OXY IR (6/1/2009-7/31/2011) were selected from the OptumInsight Clinformatics Data Mart claims database. Patients were assigned to the TAP IR or OXY IR cohort based on initial drug usage (index event). Continuous health plan coverage 60 days before (baseline period) and after (follow-up period) the index event was required. TAP IR patients were matched to OXY IR patients (1:1) using exact match of key patient characteristics and propensity score matching with patient demographics and clinical characteristics as covariates. T-test and chi-squared test were utilized to evaluate differences in patient characteristics, healthcare utilization and charges among cohorts. RESULTS: Patient profiles during the baseline period significantly differed among TAP IR users (n = 17,539) and OXY IR users (n = 85,821) in the overall study population. The matched sample of TAP IR and OXY IR patients (n = 10,185 in both cohorts) had similar patient characteristics. During the 60-day follow-up period, patients who took TAP IR had a shorter mean hospital LOS (0.21 vs 0.35 days, p < 0.0001), a lower mean number of hospitalizations (0.07 vs 0.10, p < 0.0001), and lower mean inpatient ($2900 vs $4382, p < 0.001) and outpatient healthcare charges ($10,550 vs $11,084, p = 0.047). The higher index opioid prescription charge of TAP IR ($190 vs $150, p < 0.0001) was offset by other lower healthcare charges. CONCLUSIONS: The characteristics of patients who took TAP IR were different from patients who took OXY IR in many respects. In the sub-set of patients matched on demographic and clinical characteristics, those who took TAP IR used healthcare resources to a lesser extent, which was reflected in their lower healthcare charges, relative to OXY IR users. PMID- 23441975 TI - Cost of skeletal-related events in European patients with solid tumours and bone metastases: data from a prospective multinational observational study. AB - OBJECTIVES: Patients with bone metastases often experience skeletal-related events (SREs: radiation or surgery to bone, pathologic fracture, and spinal cord compression). This study examined health resource utilization and costs associated with SREs. METHODS: Data presented are from the European cohort (Germany, Italy, Spain, and the UK) of patients with solid tumours enrolled in a multi-national, prospective, observational study in patients with solid tumours or multiple myeloma. Patients with Eastern Cooperative Oncology Group score 0-2 and life expectancy >=6 months, who experienced an SRE up to 97 days before enrolment, were eligible. Health resource utilization associated with SREs (including number/length of inpatient stays, numbers of procedures and outpatient visits) were collected through chart review for up to 97 days before enrolment and prospectively during follow-up. Country-specific cost calculations were performed. RESULTS: In total, 478 eligible patients contributed 893 SREs to this analysis. Radiation to bone occurred most frequently (66% of total). Spinal cord compression (7%) and surgery to bone (10%) were the least common events, but most likely to require inpatient stays. The most costly SREs were also spinal cord compression (mean per SRE across countries, ?4884-?12,082) and surgery to bone (?3348-?9407). Inpatient stays were the main cost drivers. LIMITATIONS: Health resource utilization used to calculate the costs associated with SREs may have been under-estimated as a result of exclusion of patients with low performance status or life expectancy; unavailable information and exclusion of resource consumption associated with pain. Thus, the estimate of associated costs is likely to be conservative. CONCLUSIONS: SREs result in considerable health resource utilization, imposing a substantial financial burden driven by inpatient stays. Treatments that prevent/delay SREs may help ease this burden, thereby providing cost savings across European healthcare systems. PMID- 23441976 TI - A new pentacyclic phenol and other constituents from the root bark of Bauhinia racemosa Lamk. AB - This work reported the isolation of one unknown (1) and 10 known compounds (2-11) from the root bark of Bauhinia racemosa Lamk. (family: Caesalpiniaceae). Racemosolone (1) was characterised as a pentacyclic phenolic compound possessing an unusual skeleton with a cycloheptane ring and a rare furopyran moiety. The structure elucidation was carried out on the basis of UV, infrared (IR), HR-ESI MS, 1D and 2D NMR spectra and finally confirmed by the single crystal X-ray analysis. The known compounds were characterised as n-tetracosane, beta sitosteryl stearate, eicosanoic acid, stigmasterol, beta-sitosterol, racemosol, octacosyl ferulate, de-O-methyl racemosol, lupeol and 1,7,8,12b-tetrahydro-2,2,4 trimethyl-2H-benzo[6,7]cyclohepta [1,2,3-de] [1] benzopyran-5,10,11 triol on the basis of spectroscopic data comparison with the literature value. Compounds with skeleton similar to 1 have never been reported from any natural or other source. PMID- 23441977 TI - Spur reactions observed by picosecond pulse radiolysis in highly concentrated bromide aqueous solutions. AB - The formation of the well-known product Br3(-), observed in the steady-state radiolysis of highly concentrated Br(-) aqueous solutions, has now been directly observed at ultrashort times corresponding to the relaxation of the spur. The transient absorption induced by picosecond pulse radiolysis of 6 M Br(-) aqueous solution was probed simultaneously at 260 nm with the third harmonic laser wave and from 350 to 750 nm with a supercontinuum generated by the fundamental laser wave. This approach allows several transient radiolytic species to be followed in parallel, particularly the solvated electron, BrOH(-*), Br2(-*), and Br3(-). The kinetics measured within 4 ns at 260 and 370 nm clearly exhibit that the decay of Br2(*-) is correlated with the formation of Br3(-). In highly concentrated Br(-) solutions, the OH(*) radical is fully replaced by Br2(*-), and the spur kinetics of OH(*) radical in pure water is comparable with that of Br2(-*). Model calculations indicate that the main OH(*) radical combination product H2O2 in pure water has formation kinetics similar to that of Br3(-) in 6 M Br(-) solutions. Moreover, they point out that oxidation of Br(-) occurs within the electron pulse both by direct energy absorption and by scavenging of the water radical cation, H2O(*+). PMID- 23441978 TI - Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. AB - OBJECTIVES: Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine. METHODS: This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given. RESULTS: Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study. CONCLUSIONS: Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution. PMID- 23441979 TI - The impact of pharmacist-initiated interventions in improving acute coronary syndrome secondary prevention pharmacotherapy prescribing upon discharge. AB - WHAT IS KNOWN AND OBJECTIVES: Pharmacists have the knowledge regarding optimal use of medications and the ability to influence physician prescribing. Successful interventions by a pharmacist to implement cardioprotective medications to a coronary artery disease patient's regimen would not only improve the patient's quality of care but may also increase his or her likelihood of survival. Therefore, the aim of this study was to (i) evaluate the effectiveness of pharmacist initiated interventions in increasing the prescription rates of acute coronary syndrome (ACS) secondary prevention pharmacotherapy at discharge, and to (ii) evaluate the acceptance rate of these interventions by prescribers. METHODS: This was a comparative study with a pre-intervention and post-intervention design. In the pre-intervention phase, a retrospective cross-sectional audit was performed. Patients with a diagnosis of acute coronary syndrome admitted to the hospital in the period from 2008 to January 2010 were identified from medical records and served as a historical control. The second phase (intervention phase) was conducted from the beginning of March to the end of September 2010. Two random samples of 190 patients with ACS were included. During the intervention phase, two hospital pharmacists made rounds with the cardiology team and gave secondary prevention recommendations when needed. The major reference for the recommendations was the Malaysian guidelines. RESULTS AND DISCUSSION: A total of 72 interventions were made by pharmacists of which drug initiation was most common (59.7%) followed by recommendations to change to another medication (23.6%) and optimization of medication dosing (16.6%). Most recommendations (72.2%) were accepted by prescribers. Majority of accepted recommendations were with beta-blockers (38.46%) followed by those with angiotensin-converting-enzyme inhibitors (ACEI) (28.8%). The intervention had a significant impact on the utilization rates of beta-blockers (increased from 75.8% to 84.7%, P = 0.028), angiotensin-converting-enzyme inhibitors/angiotensin II receptor bockers (from 65.3% to 74.7%, P = 0.044) and statins (from 91.6% to 98.4%, P = 0.002). The intervention had also led to a significant increase in the utilization rates of all these four classes together (from 42.6% to 62.6%, P = 0.001). WHAT IS NEW AND CONCLUSION: The study showed that the presence of a pharmacist on cardiology units increased the use of beta-blockers, aspirin, and statins for the secondary prophylaxis of ACS. PMID- 23441980 TI - Subthalamic deep brain stimulation for a Parkinson's disease patient with duplication of SNCA. PMID- 23441981 TI - Toxic epidermal necrolysis. PMID- 23441982 TI - Toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) is a severe mucocutaneous drug-induced syndrome that causes massive keratinocyte apoptosis and therefore hydro-electrolytic disorders and systemic infection. TEN approximately affects one to two cases per million per year. Mortality rate may reach thirty percent of cases. Thus, TEN constitutes a therapeutic emergency at diagnosis. Typically, clinical examination shows a mucocutaneous detachment involving more than thirty percent of body area. Definitive diagnosis is made on cutaneous biopsy with histological exam that shows the blister of necrotic keratinocytes. Main differential diagnosis are acute staphylococcus epidermis, acute generalized exanthematous pustulosis, linear IgA bullous dermatosis, paraneoplastic pemphigus, bullous fixed pigmented erythema, acute lupus erythematosus. In the early days, SCORTEN gives a good estimation and is now widely used as prognostic score. Drugs are generally considered as the main etiology of TEN but in some cases bacterial or viral infections could be involved. Physiopathology remains unclear even if recent advances have reported the possible implication of immune pathways based on activation of T and NK cells. Treatment of TEN requires to be instituted as soon as the diagnosis is made and the patient is preferentially referred to a specialized unit. Supportive care consist of covering areas of cutaneous detachment. No other therapy has demonstrated its efficiency, but high-dose intravenous immunoglobulin might improve the prognosis. PMID- 23441983 TI - Recoil effects in valence band photoemission of organic solids. AB - Recoil effects in valence band X-ray photoelectron spectroscopy (XPS) are studied for both abb-trifluorostyrene and styrene molecular crystal systems. The gradual changes of XPS spectra excited by several photon energies are theoretically investigated within the tight-binding approximation and harmonic approximation of lattice vibrations and have been explained in terms of not only atomic mass but also atomic orbital (AO) population. The recoil effect of valence band photoemission strongly depends on the population and partial photoionization cross section (PICS) of AOs as well as the masses of composite atoms. In abb trifluorostyrene F 2p dominant bands show the recoil shift close to free F atom recoil shift, and C 2s dominant bands show that to free C atom recoil shift, whereas the mixed bands of C and F give rise to the peak asymmetries due to their different recoil shifts. For these systems, hydrogen contribution is negligibly small which is in contrast to our previous results for the crystals composed of small organic molecules. We also discuss some potential uses of the recoil shifts for these systems. PMID- 23441984 TI - Model system Caenorhabditis elegans and neurodegenerative disease research. PMID- 23441985 TI - Evidence for genetic differentiation in timing of maturation among nine-spined stickleback populations. AB - Timing of maturation is an important life-history trait that is likely to be subjected to strong natural selection. Although population differences in timing of maturation have been frequently reported in studies of wild animal populations, little is known about the genetic basis of this differentiation. Here, we investigated population and sex differences in timing of maturation within and between two nine-spined stickleback (Pungitius pungitius) populations in a laboratory breeding experiment. We found that fish from the high-predation marine population matured earlier than fish from the low-predation pond population and males matured earlier than females. Timing of maturation in both reciprocal hybrid crosses between the two populations was similar to that in the marine population, suggesting that early timing of maturation is a dominant trait, whereas delayed timing of maturation in the pond is a recessive trait. Thus, the observed population divergence is suggestive of strong natural selection against early maturation in the piscine-predator-free pond population. PMID- 23441986 TI - Antibacterial capacity of differentiated murine embryonic stem cells during defined in vitro inflammatory conditions. AB - Embryonic stem (ES) cells are a powerful model for the development of cells responsible for the cellular immune response. Therefore, we analyzed the defense and phagocytic capacity of embryoid bodies (EBs) derived from ES cells using in the vitro inflammatory conditions caused by Escherichia coli. Further, we used this phagocytic activity to purify activated immune cells. Our data show that spontaneously differentiated 18-day-old EBs of the cell line CGR8 contained immune cells, which were positive for CD45, CD68, CD11b, F4/80, and CD19. Exposure of these EBs to E. coli with defined infection doses of bacterial colony forming units (CFUs) led to a significant time-dependent reduction of CFUs, indicating the immune responses exerted by EBs. This was paralleled by an upregulation of inflammatory cytokines, that is, IL-1beta and TNF-alpha. Western blot analysis of infected EBs indicated an upregulation of CD14 and cytochrome b 245 heavy chain (NOX2). Silencing of NOX2 significantly reduced the antibacterial capacity of EBs, which was partially explained by reduction of F4/80-positive cells. To identify, isolate, and further cultivate phagocytic active cells from differentiated EBs, a cocultivation assay of differentiated ES cells with green fluorescent protein (GFP)-labeled E. coli was established. Colocalization of GFP labeled E. coli with cells positive for CD45, CD68, and F4/80 revealed time dependent phagocytotic uptake, which was underlined by colocalization with the LysoTracker-Red((r)) dye as well as preincubation with cytochalasin D. In conclusion, a primitive immune response with efficient phagocytosis was responsible for the antibacterial capacity of differentiated EBs. PMID- 23441987 TI - The in vitro response of field strains of sheep blowflies Lucilia sericata and L. cuprina (Calliphoridae) in New Zealand to dicyclanil and triflumuron. AB - AIM: To evaluate the in vitro efficacy of triflumuron and dicyclanil against field strains of Lucilia sericata and L. cuprina in New Zealand to establish whether anecdotal reports of declining protection periods afforded by dips containing these active ingredients had validity. METHODS: Strains of field derived blowflies (Lucilia cuprina and L. sericata) were obtained from adult flies from flytraps or larvae from sheep with flystrike submitted from seven regions of the North and two regions of the South Islands of New Zealand. A total of 27 strains of L. sericata and 19 of L. cuprina were established in culture and first instar larvae obtained were exposed in vitro to dilution series of technical-grade dicyclanil (a pyrimidine carbonitrile) and triflumuron (a benzoyl urea). Concentrations lethal to 50% (LC50) and 95% (LC95) of each strain were calculated and tested by probit analysis, with the ratio of LC50 of each strain divided by LC50 of the most susceptible strain (resistance factor) derived in order to facilitate between-strain comparisons of susceptibility. RESULTS: There was considerable variation between strains of L. sericata larvae in their susceptibility to triflumuron, with those least susceptible originating from the Waikato region. Strains from both Tararua and Manawatu regions were most susceptible and East Coast strains intermediate. All strains of the species tested showed a narrow band of susceptibility to dicyclanil with no regional trends apparent. CONCLUSIONS: Representative field-strains of sheep blowflies exhibited a range of susceptibilities to both triflumuron and dicyclanil, suggestive of both genetic heterogeneity among fly populations and the spectrum of dip use in their source areas. This means there should be concerns for the long-term benefits of benzoyl urea insecticides for sheep farmers in New Zealand, but not yet for dicyclanil-based formulations. CLINICAL RELEVANCE: Flystrike is a debilitating and occasionally lethal disease in sheep such that efficacious sheep dips have prophylactic value in reducing the prevalence of the condition. PMID- 23441988 TI - Spinal cord stimulation as treatment for complex regional pain syndrome should be considered earlier than last resort therapy. AB - BACKGROUND: Spinal cord stimulation (SCS), by virtue of its historically described up-front costs and level of invasiveness, has been relegated by several complex regional pain syndrome (CRPS) treatment algorithms to a therapy of last resort. Newer information regarding safety, cost, and efficacy leads us to believe that SCS for the treatment of CRPS should be implemented earlier in a treatment algorithm using a more comprehensive approach. METHODS: We reviewed the literature on pain care algorithmic thinking and applied the safety, appropriateness, fiscal or cost neutrality, and efficacy (S.A.F.E.) principles to establish an appropriate position for SCS in an algorithm of pain care. RESULTS AND CONCLUSION: Based on literature-contingent considerations of safety, efficacy, cost efficacy, and cost neutrality, we conclude that SCS should not be considered a therapy of last resort for CRPS but rather should be applied earlier (e.g., three months) as soon as more conservative therapies have failed. PMID- 23441989 TI - Antisolvent crystallization approach to construction of CuI superstructures with defined geometries. AB - A facile high-yield production of cuprous iodide (CuI) superstructures is reported by antisolvent crystallization using acetonitrile/water as a solvent/antisolvent couple under ambient conditions. In the presence of trace water, the metastable water droplets act as templates to induce the precipitation of hollow spherical CuI superstructures consisting of orderly aligned building blocks after drop coating. With water in excess in the mixed solution, an instant precipitation of CuI random aggregates takes place due to rapid crystal growth via ion-by-ion attachment induced by a strong antisolvent effect. However, this uncontrolled process can be modified by adding polymer polyvinyl pyrrolidone (PVP) in water to restrict the size of initially formed CuI crystal nuclei through the effective coordination effect of PVP. As a result, CuI superstructures with a cuboid geometry are constructed by gradual self-assembly of the small CuI crystals via oriented attachment. The precipitated CuI superstructures have been used as competent adsorbents to remove organic dyes from the water due to their mesocrystal feature. Besides, the CuI superstructures have been applied either as a self-sacrificial template or only as a structuring template for the flexible design of other porous materials such as CuO and TiO2. This system provides an ideal platform to simultaneously investigate the superstructure formation enforced by antisolvent crystallization with and without organic additives. PMID- 23441990 TI - The role of exosomes in infectious diseases. AB - An exosome is a nano vesicle that buds from the endosomal compartment; it is produced and released by all kinds of mammalian cells. This vesicle contains a variety of proteins, lipids, mRNAs and miRNAs. These components are specific to the origin of the exosomes and contribute to cell-cell communications. Recently, it has been reported that a few single cell eukaryotic pathogens such as Cryptoccoccus neoformance and Leishmania major and donovanican secrete an exosome and influence the host immune system. In addition, it has been observed that cells infected by intracellular pathogens are capable of secreting an exosome which is involved in the fate of the infection. Furthermore, retroviruses recruit the host's endosomal compartments in order to generate viral vesicles which are similar to the exosome. Most of the exosomes involved in infectious biology can either spread or limit an infection based on the type of pathogen and its target cells. Hence, an exosome may be an appropriate candidate for a vaccine therapy in prophylaxis and treatment. PMID- 23441991 TI - Update on the principles and novel local and systemic therapies for the treatment of non-infectious uveitis. AB - Ocular inflammatory disorders constitute a sight-threatening group of diseases that might be managed according to their severity. Their treatment guidelines experience constant changes with new agents that improve the results obtained with former drugs. Nowadays we can make use of a five step protocol in which topical, periocular and systemic corticosteroids remain as the main therapy for non-infectious uveitis. In addition, immunosuppresive drugs can be added in order to enhance the anti-inflammatory effects and to play the role of corticosteroid sparing agents. These can be organized in four other steps: cyclosporine and methotrexate in a second one; azathioprine, mycophenolate and tacrolimus in a third step; biological anti-TNF drugs in fourth position; and a last one with cyclophosphamide and chlorambucil. In the present review we go through the main characteristics and complications of all these treatments and make a rational of this five-step treatment protocol for non-infectious posterior uveitis. PMID- 23441992 TI - Pro-stimulatory role of methemoglobin in inflammation through hemin oxidation and polymerization. AB - Inflammation or vascular occlusion by parasitized red blood cell contributes to the pathogenesis of cerebral malaria. The current study aimed to characterize the role of major pro-oxidant factor methemoglobin present in the malaria culture supernatant contributing in inflammation during malaria. Heme and heme polymer stimulate macrophage to secrete large amount of reactive oxygen species into the external micro-environment. The addition of methemoglobin along with heme or heme polymer amplifies production of ROS from macrophages several folds. Methemoglobin mediated stimulatory effect is not due to release of iron, enhanced production of H2O2 or mutual interaction of reaction components. Spectroscopic studies show that methemoglobin accepts heme as a substrate and oxidizes it through a single electron transfer mechanism. Heme oxidation product is a heme polymer with similar chemical and structural properties to synthetic beta-hematin. Phenyl N-t butylnitrone inhibits heme polymerization (IC50=30 nM) and indicates the absolute necessity of heme oxidation and heme free radical generation for heme polymerization. Methemoglobin produced heme polymer is a potent pro-inflammatory factor to release ROS into external microenvironment. Interestingly, methemoglobin not only produces pro-inflammatory heme polymer, but it also amplifies the potential of heme or preformed heme polymer (haemozoin or beta hematin) to produce several folds high ROS production from macrophages. This study illustrates the pro-inflammatory effect of methemoglobin, the underlying novel mechanism by which this occurs and a possible clinical intervention. Based on the results, we recommend methemoglobin directed peroxidase inhibitors as an adjuvant therapy during malaria. PMID- 23441993 TI - Injectable and thermoresponsive self-assembled nanocomposite hydrogel for long term anticancer drug delivery. AB - The purpose of this study is to develop an injectable thermoresponsive hydrogel system that can undergo sol-gel phase transition by the stimulation of body temperature with improved mechanical stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. Hexamethylene diisocyanate (HDI) was introduced into Pluronic F127 as a chain extender to improve the mechanical stability. HDI-Pluronic F127 copolymer was then incorporated with hyaluronic acid to develop a thermoresponsive nanocomposite hydrogel system. The physiochemical properties were characterized. The anticancer drug release profile and effect to inhibit tumor cells growth were analyzed in vitro and in vivo. The results showed that HDI-Pluronic F127/hyaluronic acid thermoresponsive hydrogel could undergo sol-gel transition as temperature increased to 37 degrees C. The nanocomposite polymer can spontaneously self-assemble into micellar structure with size of 100-200 nm. The release of doxorubicin (DOX) from HDI-PF127/HA composite hydrogel was a zero-order profile and maintained sustained release for over 28 days. The viability of tumor cells and size of tumor significantly decreased with incubation time, indicating the potential to have a therapeutic effect for cancer therapy. The injectable thermoresponsive nanocomposite hydrogel system was biocompatible and degradable and had the slow controlled release property for anticancer drugs with potential applications in the field of drug delivery. PMID- 23441994 TI - Ontogenetic development of intestinal length and relationships to diet in an Australasian fish family (Terapontidae). AB - BACKGROUND: One of the most widely accepted ecomorphological relationships in vertebrates is the negative correlation between intestinal length and proportion of animal prey in diet. While many fish groups exhibit this general pattern, other clades demonstrate minimal, and in some cases contrasting, associations between diet and intestinal length. Moreover, this relationship and its evolutionary derivation have received little attention from a phylogenetic perspective. This study documents the phylogenetic development of intestinal length variability, and resultant correlation with dietary habits, within a molecular phylogeny of 28 species of terapontid fishes. The Terapontidae (grunters), an ancestrally euryhaline-marine group, is the most trophically diverse of Australia's freshwater fish families, with widespread shifts away from animal-prey-dominated diets occurring since their invasion of fresh waters. RESULTS: Description of ontogenetic development of intestinal complexity of terapontid fishes, in combination with ancestral character state reconstruction, demonstrated that complex intestinal looping (convolution) has evolved independently on multiple occasions within the family. This modification of ontogenetic development drives much of the associated interspecific variability in intestinal length evident in terapontids. Phylogenetically informed comparative analyses (phylogenetic independent contrasts) showed that the interspecific differences in intestinal length resulting from these ontogenetic developmental mechanisms explained ~65% of the variability in the proportion of animal material in terapontid diets. CONCLUSIONS: The ontogenetic development of intestinal complexity appears to represent an important functional innovation underlying the extensive trophic differentiation seen in Australia's freshwater terapontids, specifically facilitating the pronounced shifts away from carnivorous (including invertebrates and vertebrates) diets evident across the family. The capacity to modify intestinal morphology and physiology may also be an important facilitator of trophic diversification during other phyletic radiations. PMID- 23441995 TI - Synergistetes cluster A in saliva is associated with periodontitis. AB - BACKGROUND AND OBJECTIVES: Synergistetes is a novel bacterial phylum consisting of gram-negative anaerobes. Increasing lines of evidence demonstrate that this phylum is associated with periodontal diseases. This study aimed to compare the presence and levels of Synergistetes clusters A and B, in saliva of patients with chronic periodontitis (CP), generalized aggressive periodontitis (G-AgP) and non periodontitis subjects, and investigate their correlation with clinical parameters. MATERIAL AND METHODS: Saliva was collected from patients with CP (n = 20), G-AgP (n = 21) and non-periodontitis subjects (n = 18). Full mouth clinical periodontal measurements were recorded. The numbers of Synergistetes cluster A and cluster B or the associated species Jonquetella anthropi were quantified by fluorescent in situ hybridization and microscopy. RESULTS: Synergistetes cluster A bacteria were detected more frequently, and at higher numbers and proportions in the two periodontitis groups, than the non-periodontitis control group. The prevalence was 27.7% in the control group, 85% in CP and 86% in G-AgP. Compared to the control group, the numbers were significantly higher by 12.5-fold in CP and 26.5-fold in G-AgP, whereas the difference between the two forms of periodontitis was not statistically significant. Within the total bacterial population, the proportion of this cluster was increased in CP and G-AgP compared to the control group, with the difference between the two forms of periodontitis being also significant. There was a positive correlation between the levels of Synergistetes cluster A in saliva and all full mouth clinical periodontal parameters. Nevertheless, Synergistetes cluster B bacteria and J. anthropi species were detected infrequently and at low levels in all the three subject groups. CONCLUSION: Synergistetes cluster A, but not cluster B, bacteria are found at higher prevalence, numbers and proportions in saliva from patients with periodontitis, than non-periodontitis subjects. These findings support the association of this cluster with periodontitis. PMID- 23441996 TI - Everolimus-induced recurrent pericardial effusion after kidney transplantation. PMID- 23441997 TI - Spatial quantification of groundwater abstraction in the irrigated Indus basin. AB - Groundwater abstraction and depletion were assessed at a 1-km resolution in the irrigated areas of the Indus Basin using remotely sensed evapotranspiration (ET) and precipitation; a process-based hydrological model and spatial information on canal water supplies. A calibrated Soil and Water Assessment Tool (SWAT) model was used to derive total annual irrigation applied in the irrigated areas of the basin during the year 2007. The SWAT model was parameterized by station corrected precipitation data (R) from the Tropical Rainfall Monitoring Mission, land use, soil type, and outlet locations. The model was calibrated using a new approach based on spatially distributed ET fields derived from different satellite sensors. The calibration results were satisfactory and strong improvements were obtained in the Nash-Sutcliffe criterion (0.52 to 0.93), bias (-17.3% to -0.4%), and the Pearson correlation coefficient (0.78 to 0.93). Satellite information on R and ET was then combined with model results of surface runoff, drainage, and percolation to derive groundwater abstraction and depletion at a nominal resolution of 1 km. It was estimated that in 2007, 68 km3 (262 mm) of groundwater was abstracted in the Indus Basin while 31 km3 (121 mm) was depleted. The mean error was 41 mm/year and 62 mm/year at 50% and 70% probability of exceedance, respectively. Pakistani and Indian Punjab and Haryana were the most vulnerable areas to groundwater depletion and strong measures are required to maintain aquifer sustainability. PMID- 23441998 TI - Editorial: matrix metalloproteinases: drug targets in cardiovascular diseases. PMID- 23441999 TI - Choice and dissonance in a European cultural context: the case of Western and Eastern Europeans. AB - Prior research demonstrates that members of collectivistic cultures are less likely to reduce cognitive dissonance after making a choice, compared to members of individualistic cultures. This difference has been attributed to different conceptualizations of choice that derive from different self-construals across cultures. In individualistic cultures, choice leads to stronger commitment to the chosen option compared to collectivistic cultures, because it implicates core aspects of the independent self, such as personal preferences. However, this cultural variation in postchoice dissonance has thus far been studied exclusively by comparing East Asians and North Americans. Building on the assumption that this difference is due to different construals of the self, we conducted an experiment with movie choices using the classic free-choice paradigm to examine differences in dissonance reduction between Western and Eastern Europeans, two populations known to differ with respect to interdependence. The results show that Eastern Europeans are less likely than Western Europeans to reduce postchoice dissonance by spreading their alternatives. Our findings speak to the generalizability of the hypothesis that in cultures differing in independence or interdependence people also differ in the way they construe choice, as well as in the way the act of choosing affects their self-concept. PMID- 23442000 TI - Human cytomegalovirus infection in humanized liver chimeric mice. AB - AIM: Cytomegalovirus is a common viral pathogen that influences the outcome of organ transplantation. To date, there is no established method to evaluate the effects of human CMV (HCMV) treatments in vivo except for human clinical trials. In the current study, we describe the development of a mouse model that supports the in vivo propagation of HCMV. METHODS: One million viable human hepatocytes, purified from human livers, were injected into the spleens of severe combined immunodeficient/albumin linked-urokinase type plasminogen activator transgenic mice. A clinical strain of HCMV was inoculated in mice with confirmed human hepatocyte engraftment or in non-chimeric controls. Infection was monitored through HCMV titers in the plasma. Mice were administrated ganciclovir (50 mg/kg per day, i.p.) beginning at 2 days post-HCMV inoculation, or human liver natural killer (NK) cells (20 * 10(6) cells/mouse, i.v.) 1 day prior to HCMV inoculation. RESULTS: Chimeric mice that received HCMV showed high plasma titers of HCMV DNA on days 1 and 6 that became undetectable by day 11 post-inoculation. In contrast, non-transplanted mice had only residual plasma inoculum detection at day 1 and no detectable viremia thereafter. The levels of HCMV DNA were reduced by ganciclovir treatment or by human liver NK cell adoptive transfer, while HCMV infected chimeric mice that were not treated sustained viremia during the follow up. CONCLUSION: Human liver chimeric mice provide an in vivo model for the study of acute HCMV infection of hepatocytes. PMID- 23442002 TI - Probabilistic models for CRISPR spacer content evolution. AB - BACKGROUND: The CRISPR/Cas system is known to act as an adaptive and heritable immune system in Eubacteria and Archaea. Immunity is encoded in an array of spacer sequences. Each spacer can provide specific immunity to invasive elements that carry the same or a similar sequence. Even in closely related strains, spacer content is very dynamic and evolves quickly. Standard models of nucleotide evolution cannot be applied to quantify its rate of change since processes other than single nucleotide changes determine its evolution. METHODS: We present probabilistic models that are specific for spacer content evolution. They account for the different processes of insertion and deletion. Insertions can be constrained to occur on one end only or are allowed to occur throughout the array. One deletion event can affect one spacer or a whole fragment of adjacent spacers. Parameters of the underlying models are estimated for a pair of arrays by maximum likelihood using explicit ancestor enumeration. RESULTS: Simulations show that parameters are well estimated on average under the models presented here. There is a bias in the rate estimation when including fragment deletions. The models also estimate times between pairs of strains. But with increasing time, spacer overlap goes to zero, and thus there is an upper bound on the distance that can be estimated. Spacer content similarities are displayed in a distance based phylogeny using the estimated times.We use the presented models to analyze different Yersinia pestis data sets and find that the results among them are largely congruent. The models also capture the variation in diversity of spacers among the data sets. A comparison of spacer-based phylogenies and Cas gene phylogenies shows that they resolve very different time scales for this data set. CONCLUSIONS: The simulations and data analyses show that the presented models are useful for quantifying spacer content evolution and for displaying spacer content similarities of closely related strains in a phylogeny. This allows for comparisons of different CRISPR arrays or for comparisons between CRISPR arrays and nucleotide substitution rates. PMID- 23442001 TI - Impact of surgeon and volume on extended lymphadenectomy at the time of robot assisted radical cystectomy: results from the International Robotic Cystectomy Consortium (IRCC). AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Lymph node dissection and it's extend during robot-assisted radical cystectomy varies based on surgeon related factors. This study reports outcomes of robot-assisted extended lymphadenectomy based on surgeon experience in both academic and private practice settings. OBJECTIVE: To evaluate the incidence of, and predictors for, extended lymph node dissection (LND) in patients undergoing robot-assisted radical cystectomy (RARC) for bladder cancer, as extended LND is critical for the treatment of bladder cancer but the role of minimally invasive surgery for extended LND has not been well-defined in a multi-institutional setting. PATIENTS AND METHODS: Used the International Robotic Cystectomy Consortium (IRCC) database. In all, 765 patients who underwent RARC at 17 institutions from 2003 to 2010 were evaluated for receipt of extended LND. Patients were stratified by age, sex, clinical stage, institutional volume, sequential case number, and surgeon volume. Logistic regression analyses were used to correlate variables to the likelihood of undergoing extended LND. RESULTS: In all, 445 (58%) patients underwent extended LND. Among all patients, a median (range) of 18 (0-74) LNs were examined. High-volume institutions (>=100 cases) had a higher mean LN yield (23 vs 15, P < 0.001). On univariable analysis, surgeon volume, institutional volume, and sequential case number were associated with likelihood of undergoing extended LND. On multivariable analysis, surgeon volume [odds ratio (OR) 3.46, 95% confidence interval (CI) 2.37-5.06, P < 0.001] and institution volume [OR 2.65, 95% CI 1.47-4.78, P = 0.001) were associated with undergoing extended LND. CONCLUSIONS: Robot-assisted LND can achieve similar LN yields to those of open LND after RC. High-volume surgeons are more likely to perform extended LND, reflecting a correlation between their growing experience and increased comfort with advanced vascular dissection. PMID- 23442003 TI - Diabetes mellitus and inflammatory pulpal and periapical disease: a review. AB - Diabetes mellitus (DM) is one of the most common metabolic disorders. DM is characterized by hyperglycaemia, resulting in wound healing difficulties and systemic and oral manifestations, which have a direct effect on dental pulp integrity. Experimental and clinical studies have demonstrated a higher prevalence of periapical lesions in patients with uncontrolled diabetes. The influence of DM on periapical bone resorption and its impact on dental intervention of such patients are reviewed, and its aetiology and pathogenesis are analysed at molecular level. Pulps from patients with diabetes have the tendency to present limited dental collateral circulation, impaired immune response, increased risk of acquiring pulp infection (especially anaerobic ones) or necrosis, besides toothache and occasional tendency towards pulp necrosis caused by ischaemia. In regard to molecular pathology, hyperglycaemia is a stimulus for bone resorption, inhibiting osteoblastic differentiation and reducing bone recovery. The relationship between poorly controlled diabetes and bone metabolism is not clearly understood. Molecular knowledge about pulp alterations in patients with diabetes could offer new therapeutic directions. Knowledge about how diabetes affects systemic and oral health has an enduring importance, because it may imply not only systemic complications but also a higher risk of oral diseases with a significant effect on pulp and periapical tissue. PMID- 23442005 TI - Density functional study of organocatalytic cross-aldol reactions between two aliphatic aldehydes: insight into their functional differentiation and origins of chemo- and stereoselectivities. AB - The chemo-, diastereo-, and enantioselectivities in proline and axially chiral amino sulfonamide-catalyzed direct aldol reactions between two enolizable aldehydes with different electronic nature have been studied with the aid of density functional theory (DFT) method. The potential energy profiles for the enamine formation between each aliphatic aldehyde and the catalyst confirm that two subject catalysts can successfully differentiate between 3-methylbutanal as an enamine component and alpha-chloroaldehydes as a carbonyl component. Transition states associated with the stereochemistry-determining C-C bond forming step with the enamine intermediate addition to the aldehyde acceptor for proline and chiral amino sulfonamide-promoted aldol reactions are reported. DFT calculations not only provide a good explanation for the formation of the sole cross-aldol product between two aliphatic aldehydes both bearing alpha-methylene protons but also well reproduce the opposite syn vs anti diastereoselectivities in the chiral amino sulfonamide and proline-catalyzed aldol reactions. PMID- 23442004 TI - Orthogonal spin labeling and Gd(III)-nitroxide distance measurements on bacteriophage T4-lysozyme. AB - We present the first example of chemoselective site-specific spin labeling of a monomeric protein with two spectroscopically orthogonal spin labels: a gadolinium(III) chelate complex and a nitroxide radical. A detailed analysis of the performance of two commercially available Gd(III) ligands in the Gd(III) nitroxide pulse double electron-electron resonance (DEER or PELDOR) experiment is reported. A modification of the flip angle of the pump pulse in the Gd(III) nitroxide DEER experiment is proposed to optimize sensitivity. PMID- 23442006 TI - Composition of artificial tear solution affects in vitro Pseudomonas aeruginosa biofilm formation on silicone hydrogel lens. AB - PURPOSE: To investigate Pseudomonas aeruginosa biofilm formation on silicone hydrogel contact lens in various artificial tears. METHODS: P. aeruginosa was cocultured with contact lenses (Senofilcon A, Acuvue Oasys Hydraclear plus((r)); Johnson & Johnson, Jacksonville, FL) in artificial tears containing hyaluronic acid (HA) (0.3%, 0.1%, or 0.1%+benzalkonium chloride) or carboxymethylcellulose (0.5% or 0.3%+dextran). P. aeruginosa biofilm was stained with crystal violet (0.1%) after 48 h of incubation. The optical density of the dissolved biofilm was measured by a spectrophotometer at 570 nm and was compared. RESULTS: P. aeruginosa biofilm formation in 3 solutions (0.3% HA, 0.1% HA+benzalkonium chloride and 0.3% carboxymethylcellulose+dextran) was significantly decreased compared to the other 2 solutions (0.1% HA and 0.5% carboxymethylcellulose) (P<0.01). CONCLUSIONS: P. aeruginosa biofilm formation on silicone hydrogel contact lens was affected by the composition of artificial tears. A higher concentration of HA and addition of benzalkonium chloride or dextran in artificial tears were helpful to prevent P. aeruginosa biofilm formation. PMID- 23442007 TI - The potential role of newer gram-positive antibiotics in the setting of osteomyelitis of adults. AB - WHAT IS KNOWN AND OBJECTIVE: To summarize available literature regarding the potential role of linezolid, daptomycin, telavancin, tigecycline and ceftaroline for the treatment of osteomyelitis caused by resistant gram-positive organisms. METHODS: Literature was obtained through PubMed searches from January 1980 to October 2011 using the terms osteomyelitis, bone, linezolid, daptomycin, telavancin, tigecycline and ceftaroline. Results were limited to those published in English. All articles identified from the PubMed searches were evaluated. Any published data related to bone penetration (animal or human) or clinical outcomes in adult osteomyelitis of these agents were included in the review. RESULTS AND DISCUSSION: Animal models report bone concentrations of 2.3 mcg/dL (vertebral) for linezolid, 0.45 mcg/mL (tibiae) for daptomycin, 0.78 mcg/mL (tibiae) for tigecycline and 0.27 mcg/mL (tibiae) for telavancin; no data are available for ceftaroline. Human studies demonstrate bone concentrations of 4.6, 17.0 and 3.9 mcg/mL (sternal, metatarsal and cancellous bone respectively) for linezolid, 4.7 mcg/mL (metatarsal) for daptomycin and 0.078 mcg/mL (unspecified) for tigecycline; no data are available for telavancin and ceftaroline. Retrospective cohort data, and prospective/retrospective case series support the use of linezolid in this setting; however, side-effects may limit use. Retrospective and prospective cohort data support daptomycin use. A retrospective case series is available supporting the use of telavancin. No data are available supporting clinical effectiveness for ceftaroline or tigecycline in the setting of osteomyelitis. WHAT IS NEW AND CONCLUSION: Limited data are available evaluating the safety and efficacy of these agents in osteomyelitis in adults. Daptomycin and telavancin may be potential alternatives or second-line agents to vancomycin in selected patients. Linezolid, because of an increase in clinically important ADRs with prolonged use, should be reserved as a second- or third-line agent. Due to a lack of clinical data and poor bone penetration, along with concerns regarding outcomes in severe infections, tigecycline's potential is limited. Little data exist regarding ceftaroline use in osteomyelitis. PMID- 23442008 TI - Unilateral rosacea in a patient with Bell's palsy. PMID- 23442009 TI - Isoporous micro/nanoengineered membranes. AB - Isoporous membranes are versatile structures with numerous potential and realized applications in various fields of science such as micro/nanofiltration, cell separation and harvesting, controlled drug delivery, optics, gas separation, and chromatography. Recent advances in micro/nanofabrication techniques and material synthesis provide novel methods toward controlling the detailed microstructure of membrane materials, allowing fabrication of membranes with well-defined pore size and shape. This review summarizes the current state-of-the-art for isoporous membrane fabrication using different techniques, including microfabrication, anodization, and advanced material synthesis. Various applications of isoporous membranes, such as protein filtration, pathogen isolation, cell harvesting, biosensing, and drug delivery, are also presented. PMID- 23442010 TI - Mesenchymal stem cell and chondrocyte fates in a multishear microdevice are regulated by Yes-associated protein. AB - Mechanical cues exert considerable influence on the fates of stem cells and terminally differentiated chondrocytes. The elucidation of the interactions between cell fate and mechanical cues in nuclear mechanotransduction will provide new clues to modulate tissue homeostasis and regeneration. In this study, we used an integrated microfluidic perfusion device to simultaneously generate multiple parameter fluid shear stresses to investigate the role of fluid flow stimuli in the regulation of Yes-associated protein (YAP) expression and the fates of mesenchymal stem cells (MSCs) and primary chondrocytes. YAP expression was regulated by the level of fluid flow stimulus in both MSCs and chondrocytes. An increase in the magnitude of stimulation enhanced the expression of YAP, ultimately resulting in an increase in osteogenesis and a decrease in adipogenesis for MSCs, and initiating dedifferentiation for chondrocytes. Cytochalasin D not only repressed nuclear YAP accumulation in the flow state, but also abrogated flow-induced effects on MSC differentiation and the chondrocyte phenotype, resulting in MSC adipogenesis and the maintenance of the chondrocyte phenotype. Our findings reveal the connection between YAP and MSC/chondrocyte fates in a fluid flow-induced mechanical microenvironment and provide new insights into the mechanisms by which mechanical cues regulate the fates of MSCs and chondrocytes. PMID- 23442011 TI - Metastasis and anesthesia: A new relationship. PMID- 23442012 TI - Lenalidomide and thalidomide in the treatment of chronic pain. AB - INTRODUCTION: The immunomodulatory and anti-inflammatory drug thalidomide was first introduced in 1957 as a sleep aid and treatment for morning sickness. It was subsequently removed from the market due to severe teratogenic side effects and then returned to the market as a treatment for myelodysplastic syndrome and multiple myeloma. Lenalidomide is an analog of thalidomide with similar efficacy but improved side-effect profile. There are reports and studies of both agents for the treatment of chronic pain, especially complex regional pain syndrome (CRPS). Effective medical and interventional therapies for CRPS are limited. The use of novel immunomodulatory and anti-inflammatory drugs such as thalidomide and lenalidomide may offer a new approach to the treatment of CRPS. AREAS COVERED: The mechanism of action, adverse effect profile, and regulatory history of thalidomide and lenalidomide will be reviewed. The literature search for pain treatment includes case series and preliminary trials for CRPS, and case reports and case series for other chronic pain conditions. EXPERT OPINION: Lenalidomide has a more favorable adverse effect profile compared to its parent compound thalidomide. Both agents, however, have significant potential adverse effects. Evidence of efficacy for chronic pain syndromes such as CRPS remains limited. Further studies are needed before these agents can be recommended for use in CRPS or other chronic pain syndromes. PMID- 23442013 TI - Parallel episodes of phyletic dwarfism in callitrichid and cheirogaleid primates. AB - The Callitrichidae are the smallest anthropoids, whereas the Cheirogaleidae include the smallest of all primates. Using species-level analyses, we show that these are derived conditions; both neonatal and adult body mass decreased in a gradual, phyletic manner in parallel across callitrichids, and across cheirogaleids. We identify lineages with particularly rapid decreases and highlight the pygmy marmoset, Callithrix pygmaea, as a phenotypic outlier. The life-history traits associated with body-mass reduction in each clade suggest that the convergent evolution of small body size was achieved by changes in different ontogenetic stages. Body-size reduction in callitrichids appears to be almost exclusively due to alterations in prenatal growth rate, whereas body-size reduction in cheirogaleids may have been largely due to reduced duration of growth phases. Finally, we use these results to discuss some of the debates surrounding the evolution of Homo floresiensis and suggest potential parallels between the evolution of H. floresiensis and callitrichids. PMID- 23442014 TI - DLVO interactions of carbon nanotubes with isotropic planar surfaces. AB - Knowledge of the interaction between carbon nanotubes (CNTs) and planar surfaces is essential to optimizing CNT applications as well as reducing their environmental impact. In this work, the surface element integration (SEI) technique was coupled with the DLVO theory to determine the orientation-dependent interaction energy between a single-walled carbon nanotube (SWNT) and an infinite isotropic planar surface. For the first time, an analytical formula was developed to describe accurately the interaction between not only pristine but also surface charged CNTs and planar surfaces with arbitrary rotational angles. Compared to other methods, the new analytical formulas were either more convenient or more accurate in describing the interaction between CNTs and planar surfaces, especially with respect to arbitrary angles. The results revealed the complex dependences of both force and torque between SWNTs and planar surfaces on the separation distances and rotational angles. With minor modifications, the analytical formulas derived for SWNTs can also be applied to multiwalled carbon nanotubes (MWNTs). The new analytical expressions presented in this work can be used as a robust tool to describe the DLVO interaction between CNTs and planar surfaces under various conditions and thus to assist in the design and application of CNT-based products. PMID- 23442015 TI - Contribution of rating scales to the assessment of executive functions. AB - Executive functions play a vital role in the everyday functioning of healthy individuals across the lifespan and have been implicated in a wide variety of clinical conditions. Historically, the assessment of executive functions in clinical and research settings relied on performance-based measures. A number of authors have argued, however, that such measures have limited ecological validity. In response to this limitation of performance-based measures, several rating scales have been developed that seek to gauge a person's or their knowledgeable informant's (e.g., parent or teacher) subjective view of executive functioning in everyday life. In this article we review evidence supporting the use of rating scales of executive function including profiles in clinical populations, biological correlates, relationships to relevant outcome measures such as academic performance, and correlations with performance-based measures. We conclude that performance-based and rating scale measures provide complementary information with respect to a child's executive functions, offering a more comprehension view than either approach alone. PMID- 23442016 TI - Association between Mycobacterium avium subspecies paratuberculosis and lymph node size in New Zealand farmed deer (Cervus elaphus). AB - AIMS: To develop and validate criteria for identification of abnormal lymph nodes (LN) at commercial slaughter, for the purpose of national surveillance for Mycobacterium avium subspecies paratuberculosis (Map) in New Zealand farmed deer. This included estimation of the predictive value of abnormal LN for Map infection; a standard circumference cut-point for measurement of abnormal LN; and identification of risk factors associated with increasing LN circumference. METHODS: In Study 1, official assessors sampled 129 LN with macroscopically visible abnormalities (abnormal LN) from 76 deer herds between May and November 2007. LN samples were cultured for Map, with culture-negative LN further examined for typical histopathological changes. The predictive value of abnormal LN for Map infection was calculated and significance of herd location (North or South Island) assessed. In Study 2, the circumferences of 412 mesenteric LN (MLN) from 79 herds were measured between October 2007 and January 2009, with samples cultured for Map and examined for eight histopathological features. The minimum circumference of an abnormal MLN was defined, based on an arbitrary >95% specificity of a culture-positive Map diagnosis. Associations between the predictor variables Map culture status, carcase weight, animal age and gender, and histopathological features, and increasing MLN circumference were assessed using a linear mixed-effects model. RESULTS: Based solely on culture, the predictive value of abnormal LN for Map infection was 92.2 (95% CI: 86.2-96.2)% with no difference between the North and South Islands (p = 0.09). Inclusion of three culture-negative LN with histopathological changes typical of Map infection increased the predictive value estimate to 94.6 (95% CI: 89.2-97.3)%. The minimum circumference of an abnormal MLN was defined as 55 mm, with a sensitivity of Map detection at this cut-point of approximately 12%. Increasing MLN circumference was positively associated with the presence of moderate follicular hyperplasia (p < 0.01), focal granulomas (p < 0.01) and a synergistic interaction between focal granulomas and Map status (p = 0.03). CONCLUSIONS: Deer MLN with macroscopically visible abnormalities and/or a circumference of >55 mm have >95% likelihood of Map infection. However, sensitivity of Map diagnosis in MLN with circumference of >55 mm was 12%, indicating use of abnormal LN as a sole criterion in national surveillance for Map in slaughtered deer will underestimate animal-level prevalence. PMID- 23442018 TI - A study of the dynamics of sex differences in adulthood. AB - Studies of gender differences using primarily young individuals show that males, on average, perform better than females in physical activities but worse than females on tests of verbal abilities. There is however a controversy about the existence of these sex differences in adulthood. Our study used 1271 participants from four cultural backgrounds (Chinese, multi-generation Canadians, Indu Canadians, and European-Canadians) divided in five age groups. We measured sex differences in the time required for participants to complete a lexical task experiment, and also assessed their verbal tempo and physical endurance using a validated temperament test (Structure of Temperament Questionnaire). We found a significant female advantage in time on the lexical task and on the temperament scale of social-verbal tempo, and a male advantage on the temperament scale of physical endurance. These sex differences, however, were more pronounced in young age groups (17-24), fading in older groups. This "middle age-middle sex" phenomenon suggests that sex differences in these two types of abilities observed in younger groups might be "a matter of age," and should not be attributed to gender in general. A one-dimensional approach to sex differences (common in meta analytic studies) therefore overlooks a possible interaction of sex differences with age. PMID- 23442017 TI - Contour analysis of an implant--soft tissue interface. AB - BACKGROUND AND OBJECTIVE: Studies of peri-implant soft tissue on in vivo models are commonly based on histological sections prepared using undecalcified or 'fracture' techniques. These techniques require the cutting or removal of implant during the specimen preparation process. The aim of this study is to explore a new impression technique that does not require any cutting or removal of implant for contour analysis of soft tissue around four types of titanium (Ti) surface roughness using an in vitro three-dimensional oral mucosal model (3D OMM). METHODS: The 3D OMM was constructed by co-culturing a keratinocyte cell line TR146 and human oral fibroblasts on to an acellular dermis scaffold. On the fourth day, a Ti disk was placed into the model. Four types of Ti surface topographies, i.e. polished, machined, sandblasted and anodized were tested. After 10 d of culture, the specimens were processed based on undecalcified (ground sectioning), electropolishing and impression techniques for contour analysis of the implant-soft tissue interface. RESULTS: Under light microscopic examination of the ground and electropolishing sections, it was found that the cell line-based oral mucosa formed a peri-implant-like epithelium attachment on to all four types of Ti surfaces. In contour analysis, the most common contour observed between the cell line-based oral mucosa and Ti surface was at an angle ranging between 45 degrees and 90 degrees . CONCLUSION: The in vitro cell line based 3D OMM formed a peri-implant-like epithelium at the implant-soft tissue interface. The contour of the implant-soft tissue interface for the four types of Ti surface was not significantly different. PMID- 23442019 TI - Reuse of liver allografts from brain-dead liver transplant recipients. PMID- 23442020 TI - Stability of an epidural analgesic admixture of levobupivacaine, fentanyl and epinephrine. AB - WHAT IS KNOWN AND OBJECTIVE: Admixtures of levobupivacaine, fentanyl and epinephrine are increasingly used in epidural pain management. Neither the compatibility nor the stability of levobupivacaine with fentanyl and epinephrine is known and therefore we examined the chemical, physical and microbiological stability of levobupivacaine-fentanyl-epinephrine and levobupivacaine-fentanyl admixtures prepared in the hospital pharmacy. METHODS: Fentanyl and epinephrine were added into commercial levobupivacaine infusion bags. The components were analysed by HPLC and assays were performed up to 60 days of storage of the bags both protected and exposed to light at room temperature and stored in the refrigerator. In addition, sterility, bacterial endotoxins, organoleptic properties, pH and mass of the admixture were determined. RESULTS AND DISCUSSION: Levobupivacaine, fentanyl and epinephrine concentrations remained within the +/- 10% specification limit during 60 days storage in the refrigerator in tightly closed secondary packing material and protected from light and for at least 40 days at room temperature. The degradation of epinephrine exceeded 10% within 60 hours when exposed to light. The solutions were microbiologically and physically stable. WHAT IS NEW AND CONCLUSION: Epidural analgesic admixtures of levobupivacaine and fentanyl with or without epinephrine have to be stored in a tightly closed secondary package protected from light. The extended stability, up to 60 days, in a refrigerator enables the centralized preparation in the hospital pharmacy. PMID- 23442021 TI - Minimum resection margin should be based on tumor size in hepatectomy for hepatocellular carcinoma in hepatoviral infection patients. AB - AIM: In patients with hepatoviral infection, although a wide resection margin can eradicate the microsatellite lesions around hepatocellular carcinoma (HCC), a large-volume hepatectomy may diminish remaining liver function and become an obstacle for treating recurrent HCC. The optimal width of the resection margin for these patients is still controversial. This study was conducted to investigate the optimal resection margin in hepatectomy for hepatoviral infection patients. METHODS: We retrospectively investigated the influences of the resection margin status on recurrence patterns and long-term prognosis in a group of 311 HCC patients with hepatoviral infection who had a solitary HCC without perioperative anti-HCC treatment. RESULTS: The resection margin status did not statistically influence the postoperative recurrence-free and overall survival rates (3-year recurrence-free survival of 61.0% vs 55.1%, P = 0.33; 5-year overall survival of 74.9% vs 81.5%, P = 0.77 in without a margin vs with a margin, respectively), although resection without a margin increased the local recurrence with marginal significance (P = 0.055). Regarding the width of the resection margin, in 30-mm or smaller HCC, resection margin did not significantly improve the prognosis among hepatoviral infection patients. However, for tumors larger than 30 mm, a resection margin wider than 3 mm showed significant impacts on the prevention of recurrence in spite of the influence of multicentric carcinogenesis. CONCLUSION: The resection margin used for eradication of microsatellite lesions showed differences that were dependent on tumor size in hepatoviral infection patients. Resection margin should be based on not only background liver function but also tumor characteristics. PMID- 23442022 TI - Evolution of bone compactness in extant and extinct moles (Talpidae): exploring humeral microstructure in small fossorial mammals. AB - BACKGROUND: Talpids include forms with different degree of fossoriality, with major specializations in the humerus in the case of the fully fossorial moles. We studied the humeral microanatomy of eleven extant and eight extinct talpid taxa of different lifestyles and of two non-fossorial outgroups and examined the effects of size and phylogeny. We tested the hypothesis that bone microanatomy is different in highly derived humeri of fossorial taxa than in terrestrial and semi aquatic ones, likely due to special mechanical strains to which they are exposed to during digging. This study is the first comprehensive examination of histological parameters in an ecologically diverse and small-sized mammalian clade. RESULTS: No pattern of global bone compactness was found in the humeri of talpids that could be related to biomechanical specialization, phylogeny or size. The transition zone from the medullary cavity to the cortical compacta was larger and the ellipse ratio smaller in fossorial talpids than in non-fossorial talpids. No differences were detected between the two distantly related fossorial clades, Talpini and Scalopini. CONCLUSIONS: At this small size, the overall morphology of the humerus plays a predominant role in absorbing the load, and microanatomical features such as an increase in bone compactness are less important, perhaps due to insufficient gravitational effects. The ellipse ratio of bone compactness shows relatively high intraspecific variation, and therefore predictions from this ratio based on single specimens are invalid. PMID- 23442023 TI - Erythrokeratodermia variabilis: first Japanese case documenting GJB3 mutation. PMID- 23442024 TI - Differential effects of subcutaneous electrical stimulation (SQS) and transcutaneous electrical nerve stimulation (TENS) in rodent models of chronic neuropathic or inflammatory pain. AB - OBJECTIVES: Electrical stimulation has been used for many years for the treatment of pain. Present-day research demonstrates that stimulation targets and parameters impact the induction of specific pain-modulating mechanisms. New targets are increasingly being investigated clinically, but the scientific rationale for a particular target is often not well established. This present study compares the behavioral effects of targeting peripheral axons by electrode placement in the subcutaneous space vs. electrode placement on the surface of the skin in a rodent model. MATERIALS AND METHODS: Rodent models of inflammatory and neuropathic pain were used to investigate subcutaneous electrical stimulation (SQS) vs. transcutaneous electrical nerve stimulation (TENS). Electrical parameters and relative location of the leads were held constant under each condition. RESULTS: SQS had cumulative antihypersensitivity effects in both inflammatory and neuropathic pain rodent models, with significant inhibition of mechanical hypersensitivity observed on days 3-4 of treatment. In contrast, reduction of thermal hyperalgesia in the inflammatory model was observed during the first four days of treatment with SQS, and reduction of cold allodynia in the neuropathic pain model was seen only on the first day with SQS. TENS was effective in the inflammation model, and in agreement with previous studies, tolerance developed to the antihypersensitivity effects of TENS. With the exception of a reversal of cold hypersensitivity on day 1 of testing, TENS did not reveal significant analgesic effects in the neuropathic pain rodent model. CONCLUSIONS: The results presented show that TENS and SQS have different effects that could point to unique biologic mechanisms underlying the analgesic effect of each therapy. Furthermore, this study is the first to demonstrate in an animal model that SQS attenuates neuropathic and inflammatory-induced pain behaviors. PMID- 23442025 TI - On the generation of the hydrated electron during the sonolysis of aqueous solutions. AB - The formation of the hydrated electron through the secondary reaction, H + OH(-) > H(2)O + e(aq), has been examined in the sonolysis of argon-saturated aqueous solutions at an ultrasound frequency of 355 kHz. The detection of the hydrated electron was achieved by measuring its reaction with the one-electron acceptors Fe(CN)(6)(3-) and methyl viologen. The results obtained indicate that hydrated electrons are produced predominately at the bubble/aqueous solution interface at comparatively high local concentrations, estimated to be >>1.5 * 10(-3) M. The half life of the hydrated electron under such conditions is estimated to be <<60 ns. PMID- 23442026 TI - The Lombard effect and other noise-induced vocal modifications: insight from mammalian communication systems. AB - Humans and non-human mammals exhibit fundamentally similar vocal responses to increased noise, including increases in vocalization amplitude (the Lombard effect) and changes to spectral and temporal properties of vocalizations. Different research focuses have resulted in significant discrepancies in study methodologies and hypotheses among fields, leading to particular knowledge gaps and techniques specific to each field. This review compares and contrasts noise induced vocal modifications observed from human and non-human mammals with reference to experimental design and the history of each field. Topics include the effects of communication motivation and subject-specific characteristics on the acoustic parameters of vocalizations, examination of evidence for a proposed biomechanical linkage between the Lombard effect and other spectral and temporal modifications, and effects of noise on self-communication signals (echolocation). Standardized terminology, cross-taxa tests of hypotheses, and open areas for future research in each field are recommended. Findings indicate that more research is needed to evaluate linkages among vocal modifications, context dependencies, and the finer details of the Lombard effect during natural communication. Studies of non-human mammals could benefit from applying the tightly controlled experimental designs developed in human research, while studies of human speech in noise should be expanded to include natural communicative contexts. The effects of experimental design and behavioural context on vocalizations should not be neglected as they may impact the magnitude and type of noise-induced vocal modifications. PMID- 23442027 TI - Proline/arginine-rich end leucine-rich repeat protein converts stem cells to ligament tissue and Zn(II) influences its nuclear expression. AB - Our objective was to facilitate ligament tissue reconstruction by characterizing the mechanism of expression of ligament tissue. To accomplish this, we searched for proteins specific to the tissue and introduced them into mesenchymal stem cells. In the two-dimensional phosphorescent gel electrophoresis, the spots in common with the normal human ligament tissue were selected after removing the spots of the normal bone tissue from those of the ossified tissue in the spinal ligament. Proline/arginine-rich end leucine-rich repeat protein (PRELP) was identified in ligament-specific locations by liquid chromatography-tandem mass spectrometry. Transfection of PRELP into mouse mesenchymal stem cells yielded ligament-like connective tissue comprised of parallel fibers. Thus, expression of the PRELP protein could reconstruct the ligament tissue. Since zinc-related proteins were found with high incidence as a result of an array analysis of PRELP's ProtoArray, it was considered that there is a relationship to the zinc metabolism. Tissue induction was mediated by the tumor necrosis factor (TNF) alpha via the zinc pathway. PRELP may be a useful gene in syndesmoplasty, provided zinc is present for tissue reconstruction. Chromosome division becomes active with the addition of zinc, and rapid tissue induction takes place in the presence of zinc and TNF-alpha. Currently, the reconstruction of a ruptured ligament tissue is difficult, but we expect that the PRELP protein expression may facilitate this process. This study describes the discovery of the gene responsible for the differentiation of stem cells into ligament tissue. This important finding may lead to treatments for gonarthrosis, cruciate ligament, and periodontal ligament ruptures, and ossification of the posterior longitudinal ligament. PMID- 23442028 TI - Highly active antiretroviral therapy is associated with decreased incidence of sexually transmitted diseases in a Taiwanese HIV-positive population. AB - There are reports of increased sexual risk behaviors in the HIV-positive population since the introduction of highly active antiretroviral therapy (HAART). Little is known about the effects of the case management (CM) program and HAART on sexually transmitted diseases (STDs) in Taiwan. HIV-positive subjects, who visited the outpatient clinics of Taoyuan General Hospital between 2007 and 2010, were enrolled. A total of 574 subjects and 14,462 person-months were reviewed. Incident STDs occurred in 104 (18.1%) subjects, and the incidence rate was 8.6 (95% confidence interval [CI], 7.1-10.5) per 100 person-years (PY). For men who have sex with men (MSM), heterosexual men and women, and injection drug users (IDU), 19.4 per 100 PY(95% CI, 15.7-24.0), 3.5 per 100 PY (95% CI, 1.4 7.3), and 1.1 per 100 PY (95% CI, 0.4-2.4) of STDs were noted, respectively; (MSM versus IDU and MSM versus heterosexual subjects, p<0.000001; heterosexual subjects versus IDU, p=0.061). Syphilis (59.6%) was the most common STD. Regular CM and no HAART (hazard ratio, 2.58; 95% CI, 1.14-5.84; p=0.02) was significantly associated with STDs in MSM. Though this retrospective study might underestimate the incidence of STDs and not draw the conclusion of causality, we concluded that the CM program and HAART are associated with lower acquisition of STDs in the Taiwanese HIV-positive population. PMID- 23442029 TI - Sociodemographic characteristics explain differences in unprotected sexual behavior among young HIV-negative gay, bisexual, and other YMSM in New York City. AB - Young gay, bisexual, and other men who have sex with men (YMSM) under age 30 in New York City are at high risk for acquiring HIV. Using the theoretical framing of fundamental causes, this analysis examined the extent to which sociodemographic factors (race/ethnicity, perceived familial socioeconomic status [SES], U.S.-born status, and sexual orientation) explain the likelihood that HIV negative YMSM ages 18 and 19 engage in unprotected sexual behavior, which may place them at risk for serconversion. Data were drawn from the baseline (Wave 1) assessment of a cohort study (N=592) collected between July 2009 and May 2011. The sample consisted predominantly of racial/ethnic minority YMSM (70.8%). A high level of association was demonstrated for each of the demographic factors with unprotected sexual behaviors. Multinomial logistic regression analyses were undertaken to examine associations between demographic covariates with the likelihood of engaging in unprotected sexual behaviors with male partners (any unprotected anal intercourse, as well as unprotected receptive anal, insertive anal, and receptive oral intercourse) irrespective of partner serostatus, in the month prior to assessment. U.S-born status and perceived socioeconomic status consistently were significant in differentiating risk behaviors. Being born outside the U.S. and perceiving a lower SES was associated with greater levels of risk. These findings suggest that efforts to address the disproportionate burden of HIV disease among YMSM in the United States must not focus solely on issues of race/ethnicity, but must be tailored and targeted to low SES and foreign-born young gay and bisexual men. It is posited that these demographic factors may lead to disproportionate levels of psychosocial burdens, which engender risk. PMID- 23442031 TI - Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial. AB - Cyproheptadine prevention of the neuropsychiatric adverse effects of an antiretroviral regimen including efavirenz has been evaluated in a randomized clinical trial. Twenty-five patients (16 males and 9 females with mean+/-SD ages of 36+/-9 years) in a cyproheptadine group, and 26 patients (17 males and 9 females with mean+/-SD ages of 34+/-7 years) in a control group completed the trial. Sexual contact and injection drug use were the main routs of HIV infection in both groups. The patients' neuropsychiatric adverse effects were evaluated based on the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Positive and Negative Syndrome Scale, Beck Depression Scale, Pittsburgh Sleep Quality Inventory, Positive and Negative Suicide Ideation, and Somatization Subscale of Symptom Checklist 90 at baseline and 4 weeks after treatment. Cyproheptadine significantly decreased the scores of Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Positive and Negative Syndrome Scale, Beck Depression Scale, Pittsburgh Sleep Quality Inventory, Positive and Negative Suicide Ideation of the patients after 4 weeks in comparison with control group. All of the scores increased in control group following antiretroviral therapy. Although short duration of the patients' follow-up was a major limitation of the study, the results of the study showed that cyprohepradine is effective in prevention of depression, anxiety, hallucination, aggressive behaviors, emotional withdrawal, poor rapport, poor impulse control, active social avoidance, suicidal ideation, and improved sleep quality of HIV-positive patients after initiation of antiretroviral therapy including efavirenz. PMID- 23442032 TI - Dehydration-induced amorphous phases of calcium carbonate. AB - Amorphous calcium carbonate (ACC) is a critical transient phase in the inorganic precipitation of CaCO3 and in biomineralization. The calcium carbonate crystallization pathway is thought to involve dehydration of more hydrated ACC to less hydrated ACC followed by the formation of anhydrous ACC. We present here computational studies of the transition of a hydrated ACC with a H2O/CaCO3 ratio of 1.0 to anhydrous ACC. During dehydration, ACC undergoes reorganization to a more ordered structure with a significant increase in density. The computed density of anhydrous ACC is similar to that of calcite, the stable crystalline phase. Compared to the crystalline CaCO3 phases, calcite, vaterite, and aragonite, the computed local structure of anhydrous ACC is most-similar to those of calcite and vaterite, but the overall structure is not well described by either. The strong hydrogen bond interaction between the carbonate ions and water molecules plays a crucial role in stabilizing the less hydrated ACC compositions compared to the more hydrated ones, leading to a progressively increasing hydration energy with decreasing water content. PMID- 23442030 TI - Providers' attitudes towards treating depression and self-reported depression treatment practices in HIV outpatient care. AB - Depression is highly prevalent among HIV-infected patients, yet little is known about the quality of HIV providers' depression treatment practices. We assessed depression treatment practices of 72 HIV providers at three academic medical centers in 2010-2011 with semi-structured interviews. Responses were compared to national depression treatment guidelines. Most providers were confident that their role included treating depression. Providers were more confident prescribing a first antidepressant than switching treatments. Only 31% reported routinely assessing all patients for depression, 13% reported following up with patients within 2 weeks of starting an antidepressant, and 36% reported systematically assessing treatment response and tolerability in adjusting treatment. Over half of providers reported not being comfortable using the full FDA-approved dosing range for antidepressants. Systematic screening for depression and best-practices depression management were uncommon. Opportunities to increase HIV clinicians' comfort and confidence in treating depression, including receiving treatment support from clinic staff, are discussed. PMID- 23442033 TI - Analytical interpretation of slug test in a vertical cutoff wall. AB - An analysis method for slug tests performed in a partially penetrating well within a vertical cutoff wall is presented. A steady-state shape factor for evaluating hydraulic conductivity of the material within the wall was derived by applying the method of images to the previously developed analytical solution of Zlotnik et al. (2010) for an infinite aquifer. Two distinct boundary conditions were considered: constant-head boundary for the case of direct contact between the wall and the aquifer, and no-flux boundary representing an impermeable filter cake on the sides of the wall. The constant-head and no-flux boundary conditions yield significantly higher and lower shape factors, respectively, than those for the infinite aquifer. Consequently the conventional line-fitting method for slug test analysis would yield an inaccurate estimate of the hydraulic conductivity of a vertical cutoff wall. PMID- 23442034 TI - Forest of gold nanowires: a new type of nanocrystal growth. AB - We report a nanowire growth that is highly unconventional: (1) nanowires can grow from substrate-bound seeds but cannot from colloidal seeds under otherwise the same conditions; (2) the nanowires grow from only one side of the seeds, with their diameter independent of the size of the seeds; and (3) vertically aligned ultrathin nanowires are obtained on substrates, using aqueous solution and ambient conditions. With carefully designed experiments, we propose and test a new mechanism that can explain these unusual phenonmena. It turns out that the strong binding of ligands in this system forces selective deposition of Au at the ligand-deficient interface between Au seeds and oxide substrates. This means of promoting anisotropic growth of nanocrystals into nanowires is previously unknown in the literature. We are able to pinpoint the site of active growth and explain the control of nanowire width. The sustained growth at the active site and the inhibited growth at its parameter push the nanocrystals upward into wires; their diameter is dependent on the dynamic competition of the two processes. The site specific growth from substrate-anchored seeds provides a rare means to create substrate-nanowire hierarchical structures in aqueous solution under ambient conditions. Rendering a surface conductive, particularly one with complex surface morphology, is now made easy. PMID- 23442035 TI - Among the eucalyptus trees. PMID- 23442036 TI - Saving death. PMID- 23442037 TI - A mother's gift. PMID- 23442038 TI - Palliative care for patients with cystic fibrosis #265. PMID- 23442039 TI - Palliative medicine and end-of-life care in idiopathic pulmonary fibrosis. PMID- 23442041 TI - Lessons learned. PMID- 23442042 TI - Patient values and preferences for end-of-life treatments: are values better predictors than a living will? AB - BACKGROUND: Advance care planning is widely considered important for good treatment decision making. Patient values have been proposed as superior to standard living wills as guides to end-of-life (EOL) care decisions on behalf of decisionally incapacitated patients. Little research has examined whether values outperform living wills as predictors of treatment preferences. OBJECTIVE: The study aimed to test whether patient values are associated with treatment preferences, compare values and preferences to responses from a standard living will, and determine whether some values are better predictors than others. DESIGN: Community-dwelling elderly men and women (n=304) were interviewed in their homes by telephone. The interview consisted of an eight-item EOL values scale, a standard living will question, preferences for four life-prolonging treatments in each of six scenarios, and sociodemographic questions. RESULTS: Principal components analysis of the EOL values revealed two factors: (1) dignity, pain management, and reluctance to burden others; and (2) religiosity and desire for longevity and following family wishes. In regression analyses, stronger preferences for life-prolonging treatments were correlated with higher scores on factor 1 and lower scores on factor 2. But when living will responses were also entered into the regression model, only religiosity, longevity, and following family wishes predicted treatment preferences independently of the living will responses. CONCLUSIONS: Providing better guidance than a living will in determining a patient's EOL treatment preferences are (1) knowledge about a patient's religiosity, (2) patient's wishes for longevity, and (3) patient's wishes for following family preferences. Wishes for dignity and pain management and reluctance to burden others do not offer better guidance than a living will. PMID- 23442043 TI - Targeting the JAK-STAT pathway in lymphoma: a focus on pacritinib. AB - INTRODUCTION: The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway mediates signaling by cytokine, chemokine and growth factor receptors on cell surface to the nucleus. JAK/STAT pathway is aberrantly activated in a variety of lymphomas, with a dual role of promoting cell survival/proliferation and immune evasion. AREAS COVERED: This review describes the preclinical rationale behind the development of JAK inhibitors in lymphoma, some of which are being evaluated in Phase I/II studies, and summarizes the characteristics and clinical results of different JAK inhibitors in clinical development. Available preclinical and clinical data about JAK inhibition in lymphoid malignancies were reviewed using a PubMed access. To date, pacritinib (SB1518), a selective JAK2/FLT3 inhibitor is the first and only JAK inhibitor that has been evaluated in patients with relapsed lymphoma. EXPERT OPINION: The preclinical rationale behind the development of pacritinib in lymphoproliferative neoplasms is strong, as the deregulation of the JAK/STAT pathway is involved in the pathogenesis of multiple lymphoma subtypes, although with different mechanisms. Pacritinib demonstrated safety and early clinical efficacy in a variety of lymphoma histologic types, providing the first proof of principle of the potential clinical value of targeting JAK/STAT pathway in lymphoma. PMID- 23442044 TI - Intergenerational effects of inbreeding in Nicrophorus vespilloides: offspring suffer fitness costs when either they or their parents are inbred. AB - Inbreeding depression is the reduction in fitness caused by mating between related individuals. Inbreeding is expected to cause a reduction in offspring fitness when the offspring themselves are inbred, but outbred individuals may also suffer a reduction in fitness when they depend on care from inbred parents. At present, little is known about the significance of such intergenerational effects of inbreeding. Here, we report two experiments on the burying beetle Nicrophorus vespilloides, an insect with elaborate parental care, in which we investigated inbreeding depression in offspring when either the offspring themselves or their parents were inbred. We found substantial inbreeding depression when offspring were inbred, including reductions in hatching success of inbred eggs and survival of inbred offspring. We also found substantial inbreeding depression when parents were inbred, including reductions in hatching success of eggs produced by inbred parents and survival of outbred offspring that received care from inbred parents. Our results suggest that intergenerational effects of inbreeding can have substantial fitness costs to offspring, and that future studies need to incorporate such costs to obtain accurate estimates of inbreeding depression. PMID- 23442046 TI - The permanent deformation of the self-adjusting files when used in canals of extracted teeth. AB - AIM: To examine the permanent deformation of self-adjusting files (SAF) when used by endodontists with no previous experience with this system. METHODOLOGY: The canals of extracted human molars were initially prepared with glide path up to size 20 K-file. The operators were first instructed on the use of the SAF in simulated canals in plastic blocks then applied the SAF in natural root canals of extracted teeth. Every 4 min, each file was withdrawn from the canal and inspected for integrity. If intact, it was used in another canal for an additional 4 min and checked again. This was repeated until all 19 SAF files were deformed. The files were collected for inspection at *50 magnification. All teeth were then examined radiographically for the presence of any metal fragments in the root canals. Permanent deformation was categorized according to the type and location occured. Three types were defined as follows: (i) detachment of one component of the file at one end while the component is retained (ii) detachment of a component at both ends and the component missing and (iii) permanent twisting of the component. Recordings were made and statistically analysed using McNemar's test. RESULTS: Mechanical failures on the 5-arch-side of SAF (odd side) were significantly more frequent in comparison with the even side (P = 0.039). Similarly, mechanical failures in arches on the odd side were also significantly more frequent compared with the even ones (P = 0.012) Longitudinal beams fractured significantly less often compared with arcs or struts (P < 0.001). In no case did complete file fracture occur, nor were metal fragments retained in the root canal. CONCLUSIONS: Deformation of SAF files occurred mainly as detachment of one of the arches or struts at connection points on the odd side of the file. In no case did its mechanical failure result in metal fragment retention in the root canal. PMID- 23442047 TI - Pemetrexed in combination with cisplatin versus cisplatin monotherapy in East Asian patients with recurrent or metastatic head and neck cancer: Results of an exploratory subgroup analysis of a phase III trial. AB - AIM: An exploratory subgroup analysis of East Asian (EA) patients in a phase III trial was conducted to assess efficacy and safety trends based on ethnicity. METHODS: The 795 patients with recurrent or metastatic squamous cell carcinoma of the head and neck included 111 EA patients randomized to pemetrexed-cisplatin (n = 55) and placebo-cisplatin (n = 56) and 684 non- EA patients randomized to pemetrexed-cisplatin (n = 343) and placebo-cisplatin (n = 341). Treatment differences in median overall survival and progression-free survival were compared using a stratified log-rank test. Survival was estimated using the Kaplan-Meier method. RESULTS: The median overall survival in the pemetrexed cisplatin and placebo-cisplatin arms of the EA group (6.8 and 5.7 months, respectively [P = 0.275]) was similar to that in the global population (7.3 and 6.3 months, respectively [P = 0.082]); the median progression-free survival in the pemetrexed-cisplatin and placebo-cisplatin arms in the EA group (2.8 and 1.9 months, respectively [P = 0.748]) was similar to that in the global population (3.6 and 2.8 months, respectively [P = 0.166]). Compared to the findings in the global population, overall survival for the EA group receiving prior platinum based therapy was longer (P = 0.042 vs P = 0.065). There was no significant interaction between treatment arms and ethnicity. CONCLUSION: Consistent with findings in the global population, pemetrexed-cisplatin did not improve survival compared with placebo-cisplatin for the EA group. However, in a subgroup analysis, pemetrexed-cisplatin showed an overall survival advantage in EA patients receiving prior platinum-based therapy. PMID- 23442048 TI - Catalytic Ugi-type condensation of alpha-isocyanoacetamide and chiral cyclic imine: access to asymmetric construction of several heterocycles. AB - Several novel heterocycles have been constructed asymmetrically on the basis of a catalytic Ugi-type condensation of alpha-isocyanoacetamide and chiral cyclic imine. The combination of phenylphosphilic acid and trifluoroethanol is exploited to promote an Ugi-type reaction with alpha-isocyanoacetamide for the first time. By means of this reaction, chiral 3-oxazolyl morpholin-2-one/piperazin-2-one derivatives are synthesized with high yields and excellent stereoselectivities. As electron-rich azadienes, these condensation products are further transformed to fused tricyclic frameworks by treatment with appropriate dienophiles such as maleic anhydride and unsaturated acyl chlorides via domino processes. Moreover, a one-pot, three-component synthesis of the chiral tricyclic frameworks from isocyanoacetamide, imine, and maleic anhydride is also feasible. PMID- 23442050 TI - The impact of highly concentrated Mo and Cu dietary supplements, fed as a bolus, on the efficacy of chelated versus inorganic Cu in cattle on a low-Cu diet. AB - AIM: To compare the efficacy of chelated versus inorganic forms of dietary Cu supplements, fed as a bolus, when challenged by a daily bolus of dietary Mo in cattle on a low-Cu diet. METHODS: Forty non-lactating, Friesian dairy cows of adequate Cu status were assigned to four groups and fed a basal diet of baled silage containing 5.3 mg Cu and 0.4 mg Mo/kg DM. The experimental design was a factorial of two chemical forms of supplemental Cu and two levels of Mo intake, provided as pelleted grain supplements made from crushed barley/molasses plus Cu and Mo. The supplements contained 140 mg Cu/kg as Cu sulphate pentahydrate (CS), 140 mg Cu/kg as Cu glycinate (CG), CS plus 38 mg Mo/kg as sodium molybdate (CS+Mo), or CG plus 38 mg Mo/kg (CG+Mo). Commencing on Day 0, supplements were fed once daily (offered 1-1.2 kg/cow) and were completely consumed within 5-10 minutes, which constitutes a bolus type of administration. Liver samples were collected by biopsy at Days -24, 13, 41 or 47, and 69 for Cu determinations. RESULTS: The diets fed to the Cu+Mo groups were roughly equivalent to 25 mg Cu and 5.7 mg Mo/kg DM. Mean initial concentration of Cu in liver for all groups was 516 (SE 54) MUmol Cu/kg fresh tissue. In cows supplemented with CS and CG, the final (Day 69) concentrations increased (p<0.01) to 939 (SE 166) and 853 (SE 163) MUmol Cu/kg, respectively. These values were not different (p=0.72). For groups CS+Mo and CG+Mo, the final concentrations of 535 (SE 122) and 453 (SE 102) MUmol Cu/kg were not different from initial values or from each other (p>0.25). The rate of accumulation of Cu in liver following bolus Cu and Mo intake was highly variable but was not affected by initial concentration of Cu in liver (p>0.9) or by the form of Cu (p>0.6). Mean rates of accumulation of Cu in liver were 4.0 (SD 3.8) and 0.65 (SD 2.0) MUmol Cu/kg fresh tissue/day for the Cu-only treatments and the Cu+Mo treatments, respectively. CONCLUSIONS: When fed together as a bolus, high Mo intake negated the effect of supplemental Cu but it did not reduce liver Cu stores. There was no difference in the reaction of dietary Mo with chelated Cu (as glycinate) versus inorganic Cu (as sulphate) dietary supplements. PMID- 23442049 TI - Sustained inhibition of HIV-1 replication by conditional expression of the E. coli-derived endoribonuclease MazF in CD4+ T cells. AB - Gene therapy using a Tat-dependent expression system of MazF, an ACA nucleotide sequence-specific endoribonuclease derived from Escherichia coli, in a retroviral vector appears to be an alternative approach to the treatment of human immunodeficiency virus type 1 (HIV-1) infection. MazF can cleave HIV-1 RNA, since it has more than 240 ACA sequences. Significant inhibition of viral replication, irrespective of HIV-1 strains, was observed in CD4(+) T cells that had been transduced with the MazF-expressing retroviral vector (MazF-T cells). The growth and viability of MazF-T cells were not affected by HIV-1 infection. Interestingly, the infectivity of HIV-1 produced from MazF-T cells was found to be lower than that from control CD4(+) T cells. A long-term culture experiment with HIV-1-infected cells revealed that viral replication was always lower in MazF-T cells than in CD4(+) T cells transduced with or without a control vector for more than 200 days. MazF was expressed and mainly localized in the cytoplasm of the infected cells. Unlike in CD4(+) T cells, the expression level of Tat gradually decreased rather than increased in MazF-T cells after HIV-1 infection. As a consequence, the expression level of MazF appeared to be well regulated and sustained during HIV-1 infection in MazF-T cells. Furthermore, the levels of cellular mRNA were not affected by HIV-1 infection. Thus, the Tat-dependent MazF expression system has great potential for inhibition of HIV-1 replication in vivo without apparent toxicity and may be able to avoid the emergence of resistant strains. PMID- 23442051 TI - Canonical transient receptor potential channel subtype 3-mediated hair cell Ca(2+) entry regulates sound transduction and auditory neurotransmission. AB - The physiological significance of canonical transient receptor potential (TRPC) ion channels in sensory systems is rapidly emerging. Heterologous expression studies show that TRPC3 is a significant Ca(2+) entry pathway, with dual activation via G protein-coupled receptor (GPCR)-phospholipase C-diacylglycerol second messenger signaling, and through negative feedback, whereby a fall in cytosolic Ca(2+) releases Ca(2+) -calmodulin channel block. We hypothesised that the latter process contributes to cochlear hair cell cytosolic Ca(2+) homeostasis. Confocal microfluorimetry with the Ca(2+) indicator Fluo-4 acetoxymethylester showed that, when cytosolic Ca(2+) was depleted, Ca(2+) re entry was significantly impaired in mature TRPC3(-/-) inner and outer hair cells. The impact of this disrupted Ca(2+) homeostasis on sound transduction was assessed with the use of distortion product otoacoustic emissions (DPOAEs), which constitute a direct measure of the outer hair cell transduction that underlies hearing sensitivity and frequency selectivity. TRPC3(-/-) mice showed significantly stronger DPOAE (2f1 - f2 ) growth functions than wild-type (WT) littermates within the frequency range of best hearing acuity. This translated to hyperacusis (decreased threshold) measured by the auditory brainstem response (ABR). TRPC3(-/-) and WT mice did not differ in the levels of temporary and permanent threshold shift arising from noise exposure, indicating that potential GPCR signaling via TRPC3 is not pronounced. Overall, these data suggest that the Ca(2+) set-point in the hair cell, and hence membrane conductance, is modulated by TRPC3s through their function as a negative feedback-regulated Ca(2+) entry pathway. This TPRC3-regulated Ca(2+) homeostasis shapes the sound transduction input-output function and auditory neurotransmission. PMID- 23442052 TI - Recurrences of hepatocellular carcinoma following complete remission by transarterial chemoembolization or radiofrequency therapy: Focused on the recurrence patterns. AB - AIM: In this study, we analyzed the rates and patterns of recurrences in hepatocellular carcinoma (HCC) patients who had achieved complete remission (CR) by transarterial chemoembolization (TACE) or radiofrequency ablation (RFA), and also examined the differences of recurrence patterns between TACE-treated and RFA treated groups. METHODS: We followed 309 consecutive HCC patients who achieved CR following TACE (n = 220) or RFA (n = 89) for a median of 68 months. Recurrence patterns were classified as local recurrence and secondary tumor according to location of recurrence (<=2 cm and >2 cm from primary tumor). RESULTS: Recurred HCC had been found in 231 out of 309 patients (75%) with CR by TACE or RFA; 112 local recurrences (48%), 100 secondary tumor (43%) and 19 both (9%). The cumulative recurrence rates at 1, 3 and 5 years were 22%, 64% and 79%, respectively. The overall recurrences at 1, 3 and 5 years following CR in the TACE-treated group was not different from those in the RFA-treated group (21%, 68% and 81% vs 26%, 56% and 84%, respectively; P = NS) However, the cumulative occurrence rates of local recurrence rates at 1, 3 and 5 years were significantly higher in the TACE-treated group compared to the RFA-treated group (15%, 53% and 65% vs 15%, 27% and 34%, respectively; P = 0.001). CONCLUSION: Recurrence of HCC is very common, even following CR by TACE or RFA. Especially, local recurrences are very frequent in cases who achieved CR by TACE, which suggests that additional ablation therapy may be beneficial to prevent recurrences following CR by TACE. PMID- 23442053 TI - Does method of birth make a difference to when women resume sex after childbirth? AB - OBJECTIVE: To investigate the timing of resumption of vaginal sex and assess associations with method of birth, perineal trauma and other obstetric and social factors. DESIGN: Prospective pregnancy cohort study of nulliparous women. SETTING: Melbourne, Australia. SAMPLE: A total of 1507 nulliparous women recruited in early pregnancy (<=24 weeks). METHOD: Women were recruited from six public hospitals. Data from hospital records and self-administered questionnaires at recruitment and 3, 6 and 12 months postpartum were analysed using univariable and multivariable logistic regression. MAIN OUTCOME MEASURE: Resumption of vaginal sex. RESULTS: Sexual activity was resumed earlier than vaginal sex, with 53% resuming sexual activity by 6 weeks postpartum, and 41% attempting vaginal sex. By 8 weeks a majority of women had attempted vaginal sex (65%), increasing to 78% by 12 weeks, and 94% by 6 months. Compared with women who had a spontaneous vaginal birth with an intact perineum, women who had a spontaneous vaginal birth with an episiotomy (adjusted odds ratio 3.43, 95% confidence interval 1.9-6.2) or sutured perineal tear (adjusted odds ratio 3.18, 95% confidence interval 2.1-4.9) were more likely not to have resumed vaginal sex by 6 weeks postpartum. Similarly, women who had an assisted vaginal birth or caesarean section had raised odds of delaying resumption of sex. CONCLUSIONS: Most women having a first birth do not resume vaginal sex until later than 6 weeks postpartum. Women who have an operative vaginal birth, caesarean section or perineal tear or episiotomy appear to delay longer. PMID- 23442054 TI - Simulating memory outcome before right selective amygdalohippocampectomy. AB - In this paper we present the case of a left-sided speech dominant patient with right medial temporal sclerosis (RMTS) and pharmacoresistant epilepsy who showed improved verbal memory during intracarotid amobarbital test (IAT) at his right hemisphere as compared with his own performance before the drug injection (baseline), as well as after right selective amygdalohippocampectomy. We suggest that the defective verbal memory shown by this patient is due to abnormal activity of his right hippocampus that interfered with the function of his left hippocampus. This hypothesis was demonstrated by the fact that disconnection of the two hippocampi, either by anesthetisation or by resection of the right hippocampus, disengaged the left hippocampus and, consequently improved its function. This paper main objective is twofold: first to contribute to the field of neuropsychology of epilepsy surgery by emphasising on postoperative memory outcomes in right medial temporal lobe epilepsy (RMTLE) patients, particularly those undergoing amygdalohippocampectomy, as the pattern of memory changes after resection of the right temporal lobe is less clear; second, by focusing on memory performance asymmetries during IAT, and comparatively considering them with neuropsychological memory performance, because of their possible prognostic simulating value. PMID- 23442055 TI - Pityriasis rosea-like drug eruption related to rituximab treatment. PMID- 23442056 TI - Possible association between TGF-beta1 polymorphism and oral cancer. AB - Oral squamous cell carcinoma (OSCC) is a worldwide health problem because it is a great cause of cancer morbidity and mortality. The transforming growth factor beta1 (TGF-beta1) is involved in the regulation of numerous immunomodulatory processes. Thus, the aim of this case-control study was to investigate the possible association between the TGF-beta1T869C polymorphism and oral cancer. The genomic DNA extracted from peripheral blood of 62 male smoker patients diagnosed with OSCC and 62 smokers without cancer was analysed. The C allele was significantly more prevalent in the oral cancer group than in the controls, and individuals carrying this allele had an estimated 2.73-fold greater relative risk of developing cancer compared with C allele noncarriers (OR = 2.73, 95% CI = 1.19 6.28). Although T allele was not statistically significant among the controls, considering the genotypic analysis, the TT homozygous genotype showed a protector effect in relation to oral cavity cancer (OR = 0.37, 95% CI = 0.16-0.84). Some clinicopathological features were also analysed for genotype distribution, and no significant differences were observed: tumour size (P > 0.70), nodal status (P > 0.10) and tumour stage (P > 0.70). This is the first report of a study assessing the importance of T869C TGF-beta polymorphism in oral cancer. It is known that the TGF-beta T869C variation results in a Leu10Pro substitution in the signal peptide sequence. Our results suggested that the C allele could increase TGF-beta secretion which suppresses antitumour immune responses and may affect the OSCC risk. PMID- 23442057 TI - Rapid recovery from acute myocarditis under levosimendan treatment: report of two cases. AB - WHAT IS KNOWN AND OBJECTIVES: Acute viral myocarditis (AVM) is an inflammatory heart disease that may lead to acute heart failure caused by cardiomyocyte loss. AVM may result in fatal outcome due to hemodynamic compromise. There is no specific treatment for AVM. Treatment is generally same as the treatment of conventional heart failure. Levosimendan is a new molecule with inotropic and vasodilator effect and is widely used for acute decompensated heart failure. DETAILS OF THE CASES: Case 1: A 48-years-old, previously healthy male patient admitted to our clinic with complaints of acute onset of rest dyspnea and orthopnea, started the day before. Cardiac chambers were enlarged on echocardiography with global hypokinesia and ejection fraction (EF) was 25%. The patient was diagnosed as AVM complicated with decompensated heart failure. Continuous infusion of 0.2 MUg/kg/min levosimendan for 24 h with treatment of conventional heart failure. Echocardiographic follow-up revealed a rapid improvement in left ventricular EF (50%) after 24 h. Case 2: A 33-years-old male patient admitted to our clinic with new onset shortness of breath and palpitation complaints. Echocardiography revealed enlarged left heart cavities with global hypocinesia (EF was 25%). The patient was diagnosed as AVM complicated with decompensated heart failure. Continuous infusion of 0.2 MUg/kg/min levosimendan for 24 h with treatment of conventional heart failure. Echocardiography revealed dramatic improvement of left ventricular systolic function (EF = 55%) 24 h later. WHAT IS NEW AND CONCLUSION: To our knowledge, there is no report or study on levosimendan therapy for AVM in humans to date. Herein, we share two cases that revealed dramatic improvement in the myocardial function with levosimendan usage during the early phase of AVM. PMID- 23442058 TI - Quantum mechanical study on the mechanism of peptide release in the ribosome. AB - A quantum mechanical study of different concerted mechanisms of peptide release in the ribosome has been carried out using the M06-2X density functional. Reoptimization with MP2 has also been carried out for the stationary points of some selected mechanisms. The uncatalyzed processes in solution have been treated with the SMD solvation model. We conclude that the 2'-OH plays an important catalytic role and that it takes place via a zwitterionic transition state, this TS being stabilized by the presence of oxyanion holes or by the solvent. The comparison with our previous study on the peptide bond formation shows that both processes proceed via two different mechanisms, in such a way that the TS of the aminolysis has an ion-pair instead of a zwitterionic character. So, despite the limitations of the model we have used, we can conclude that there is catalytic promiscuity at the peptidyl transferase center (PTC) of the ribosome. PMID- 23442059 TI - Should we continue to drain the pylorus in patients undergoing an esophagectomy? AB - A systematic review of the literature was performed to assess the necessity of a pyloric drainage procedure during an esophagectomy with gastric conduit reconstruction. Earlier data recommend performing a pyloric drainage procedure for all esophagectomies; however, recent studies have questioned this. A thorough literature search (January 2001-November 2011) was performed using the terms esophagectomy, pyloroplasty, pyloromyotomy, botulinum toxin, and pyloric drainage. Only studies that compared patient outcome after undergoing an esophagectomy with a pyloric drainage procedure with those undergoing an esophagectomy without a pyloric drainage procedure were selected. Only four studies, comprising 668 patients in total, were identified that compared patient outcome after undergoing an esophagectomy with or without a pyloric drainage procedure, and two additional meta-analyses were identified and selected for discussion. All studies were retrospective, and because of the heterogeneity of studies, patient demographics, reporting, and statistical analysis of patient outcome, pooling of data and meta-analysis could not be performed. Careful analysis demonstrated that pyloric drainage procedure was associated with a non significant trend for delayed gastric emptying and biliary reflux, while not affecting the incidence of dumping. No correlation was determined between a pyloric drainage procedure and anastomotic leaks, postoperative pulmonary complications, length of hospital stay, and overall perioperative morbidity. While there are risks associated with a pyloric drainage procedure and data exist supporting its omission during an esophagectomy, no good conclusion can be drawn from the current literature. Larger multi-institutional, prospective studies are required to definitively answer this question. PMID- 23442060 TI - Are all models wrong? Absolutely not. PMID- 23442061 TI - Investigation of MoS2 and graphene nanosheets by magnetic force microscopy. AB - For the first time, magnetic force microscopy (MFM) is used to characterize the mechanically exfoliated single- and few-layer MoS2 and graphene nanosheets. By analysis of the phase and amplitude shifts, the magnetic response of MoS2 and graphene nanosheets exhibits the dependence on their layer number. However, the solution-processed single-layer MoS2 nanosheet shows the reverse magnetic signal to the mechanically exfoliated one, and the graphene oxide nanosheet has not shown any detectable magnetic signal. Importantly, graphene and MoS2 flakes become nonmagnetic when they exceed a certain thickness. PMID- 23442062 TI - Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant. AB - Conditioning regimens used during stem cell transplant provide prolonged control or cure of the disease in patients with acute lymphoblastic leukemia (ALL). In this study, we present a comparison of treatment results for 95 patients with ALL who underwent allogeneic hematopoietic stem cell transplant (AHSCT) with total body irradiation plus cyclophosphamide (TBI + Cy) or busulfan plus cyclophosphamide (Bu + Cy) as conditioning regimen. Median age was 25 (range: 9 54) years. Median follow-up was 24 (range: 3-107) months. Median overall survival (OS) was found to be 29 months. Median event-free survival (EFS) was 9 months. Median OS was 37 months in the TBI + Cy arm, while it was 12 months in the Bu + Cy arm, suggesting a significant advantage favoring the TBI + Cy arm (p = 0.003). Median EFS was 13 months in the TBI + Cy arm, while it was 4 months in the Bu + Cy arm, indicating a significant difference (p = 0.006). In univariate and multivariate analysis, it was found that high OS and EFS were significantly correlated with TBI + Cy conditioning regimen and lack of transplant-related mortality (p < 0.05). The TBI + Cy conditioning regimen was found to be superior to the Bu + Cy regimen in patients with ALL undergoing AHSCT regarding both OS and EFS. PMID- 23442063 TI - Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. AB - Hematopoietic stem cell and solid organ transplant recipients diagnosed with biopsy-confirmed posttransplant lymphoproliferative disorder (PTLD) at our institution from 1989 to 2010 were identified. Patient-, transplant- and disease related characteristics, prognostic factors and outcome were collected and analyzed. One hundred and forty biopsy-proven cases of PTLD were included. Overall incidence in the transplant population was 2.12%, with heart transplant recipients carrying the highest risk. Most PTLDs were monomorphic (82%), with diffuse large B-cell lymphoma being the most frequent subtype. The majority of cases (70.7%) occurred > 1 year posttransplant, and 66% were Epstein-Barr virus positive. Following initial therapy the overall response rate was 68.5%. Three year relapse-free and overall survivals were 59% and 49%, respectively. At last follow-up, 44% of the patients were alive. Multivariable analysis identified several classical lymphoma-specific poor prognostic factors for the different outcome measures. The value of the International Prognostic Index was confirmed in our analysis. PMID- 23442064 TI - Clues to pathogenesis of Waldenstrom macroglobulinemia and immunoglobulin M monoclonal gammopathy of undetermined significance provided by analysis of immunoglobulin heavy chain gene rearrangement and clustering of B-cell receptors. AB - We characterized immunoglobulin heavy chain (IGH) gene rearrangements and searched for clusters of stereotyped B-cell receptors in 123 patients with Waldenstrom macroglobulinemia (WM; n = 59) or immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) (n = 64). A productive monoclonal IGHV-D-J rearrangement was obtained in 99/123 patients (80%). Immunoglobulin heavy chain variable (IGHV) genes were mutated in 94/99 patients (95%) with a median somatic hypermutation rate of 6.7% (2.1-14.5). Compared with the normal B-cell repertoire, patients with WM/IgM-MGUS showed an over representation of the IGHV3 subgroup (83% vs. 55%, p < 0.0001) and an under representation of IGHV1 (7% vs. 14%, p = 0.04) and IGHV4 (7% vs. 23%, p = 0.0001) subgroups. At the gene level, in WM/IgM-MGUS there was an over-representation of IGHV3-23 (24% vs. 12%, p = 0.0003), IGHV3-64 (3% vs. < 1%, p = 0.003), IGHV3-7 (12% vs. 4%, p = 0.0001) and IGHV3-74 (9% vs. 2%, p < 0.0001), while IGHV4-39 was never used (0 vs. 5%, p = 0.03). Intra-WM/IgM-MGUS search for HCDR3 similarity showed no association fulfilling criteria for stereotyped receptors. WM/IgM-MGUS sequences were unrelated to known chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL) or mantle cell lymphoma (MCL) subsets. In conclusion, the IGHV gene usage in WM and IgM-MGUS is remarkably biased as compared to the normal B-cell repertoire. WM and IgM-MGUS-specific HCDR3 clusters do not occur with a frequency detectable with currently available databases, not supporting a B-cell receptor-driven pathogenesis in WM and IgM-MGUS. PMID- 23442065 TI - Preemptive leucovorin administration minimizes pralatrexate toxicity without sacrificing efficacy. AB - Balancing efficacy and safety of drugs is key for successful cancer therapy, as adverse reactions can prohibit the use of efficacious treatments. Pralatrexate (PDX) is a novel antifolate with a higher affinity for tumor cells than methotrexate, Food and Drug Administration (FDA) approved for use in relapsed and refractory peripheral T-cell lymphoma (PTCL) and transformed mycosis fungoides (T MF). Patients with T-MF have a higher incidence of adverse events than patients with other lymphomas, necessitating a lower recommended dose of 15 mg/m(2) (vs. 30 mg/m(2) for PTCL). Dose-limiting toxicity (DLT) mucositis occurs in about 25% of patients with T-MF, but milder mucositis is observed in almost all patients with T-MF, frequently leading to therapy discontinuation despite clinical response. Leucovorin rescue is the standard of care for high-dose methotrexate therapy, but has not been studied or recommended for use with PDX. We report our clinical experience using leucovorin with PDX (30 mg/m(2)) with good clinical response and no DLTs. Prophylactic leucovorin deserves further investigation in prospective clinical trials to allow patients with cutaneous lymphomas to receive the full benefit of PDX therapy without intolerable toxicity. PMID- 23442066 TI - Graft-versus-lymphoma effect plus vorinostat as successful approach in a case of refractory gastric peripheral T cell lymphoma, not otherwise specified, after reduced intensity conditioning allogeneic hematopoietic cell transplant. PMID- 23442067 TI - Targeting oncogenic and epigenetic survival pathways in lymphoma. AB - In recent years, several genetic and epigenetic alterations have been identified and linked with deregulated signaling pathways that promote growth and survival of lymphoma cells. These discoveries have raised hopes that a new era of targeted therapy will eventually improve treatment outcome of lymphoma. In this focused review, we summarize emerging preclinical and clinical data supporting the development of novel agents targeting B cell receptor signaling, phosphoinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) oncogenic pathways. Furthermore, we discuss new data on targeting chromatin modulating mechanisms. PMID- 23442069 TI - Is GPR119 agonism an appropriate treatment modality for the safe amelioration of metabolic diseases? AB - INTRODUCTION: GPR119 is a recently deorphanised G-protein coupled receptor which has been suggested to be important in mediating systemic metabolic homeostasis. Research to date has primarily focused on the ability of GPR119 to promote euglycaemia and thus as a therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Indeed, previous studies have shown that GPR119 promotes glucose stimulated insulin secretion, pancreatic beta-cell function and glucagon-like peptide-1 release, all of which provide valid mechanisms through which GPR119 may improve systemic glucose homeostasis. AREAS COVERED: In the current review, the authors provide a brief overview of the known functions of GPR119 and then discuss the novel potential for GPR119 to regulate metabolic function in skeletal and cardiac muscle and how this may translate to improvements or impairments in systemic health. EXPERT OPINION: GPR119 is largely purported as being anti diabetic and has been rapidly progressed to clinical trials, mainly as anti diabetic agents. However, emerging data suggest that this class of agonists may have a detrimental effect at the level of the muscle. This may potentiate the development and progression of metabolic diseases such as T2DM. Therefore, further research is required before GPR119 receptor agonists can be prescribed with confidence as an anti-diabetic agent. PMID- 23442068 TI - Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets. AB - BACKGROUND: Genome-wide association studies (GWAS) have recently identified many new genetic variants associated with the development of type 2 diabetes. Many of these variants are in introns of known genes or between known genes, suggesting they affect the expression of these genes. The regulation of gene expression is often tissue and context dependent, for example occurring in response to dietary changes, hormone levels, or many other factors. Thus, to understand how these new genetic variants associated with diabetes risk may act, it is necessary to understand the regulation of their cognate genes. RESULTS: We identified fourteen type 2 diabetes-associated genes discovered by the first waves of GWAS for which there was little prior evidence of their potential role in diabetes (Adam30, Adamts9, Camk1d, Cdc123, Cdkal1, Cdkn2a, Cdkn2b, Ext2, Hhex, Ide, Jazf1, Lgr5, Thada and Tspan8). We examined their expression in metabolically relevant tissues including liver, adipose tissue, brain, and hypothalamus obtained from mice under fasted, non-fasted and high fat diet-fed conditions. In addition, we examined their expression in pancreatic islets from these mice cultured in low and high glucose. We found that the expression of Jazf1 was reduced by high fat feeding in liver, with similar tendencies in adipose tissue and the hypothalamus. Adamts9 expression was decreased in the hypothalamus of high fat fed mice. In contrast, the expression of Camk1d, Ext2, Jazf1 and Lgr5 were increased in the brain of non fasted animals compared to fasted mice. Most notably, the expression levels of most of the genes were decreased in islets cultured in high glucose. CONCLUSIONS: These data provide insight into the metabolic regulation of these new type 2 diabetes genes that will be important for determining how the GWAS variants affect gene expression and ultimately the development of type 2 diabetes. PMID- 23442070 TI - Local adaptation of a Drosophila parasitoid: habitat-specific differences in thermal reaction norms. AB - Local climate is an important source of selection on thermal reaction norms that has been well investigated in cline studies, where populations sampled along altitudinal or latitudinal gradients are compared. Several biotic factors vary with climate, but are rarely integrated as alternative agents of selection to climatic factors. We tested the hypothesis that habitat may select for thermal reaction norms and magnitude of phenotypic plasticity in a drosophila parasitoid, independently of the climate of origin. We sampled populations of Leptopilina boulardi, a Drosophila parasitoid in two different habitats, orchards and forests. Orchards offer laying opportunities over small distances for parasitoids, with a low variability in the number of hosts per patch, while forests offer more dispersed and more variable patches. The sampling was realized in a temperate and a Mediterranean climate. We measured egg load, volume of eggs, longevity and lipid content for parasitoids reared at two temperatures. Reaction norms were opposite for populations from forests and orchards for investment in reproduction, independently of the climate of origin. The maximal investment of resources in reproduction occurred at the lower temperature in orchards and the higher temperature in forests. Host distribution differences between habitats may explain these opposite reaction norms. We also observed a flatter reaction norm for egg load in forests than in orchards. This relative canalization may have been selected in response to the higher variability in laying opportunities observed in forests. Our results demonstrate the potential role of resource distribution in evolution of thermal plasticity. PMID- 23442072 TI - LAT1-mediated prodrug uptake: a way to breach the blood-brain barrier? PMID- 23442071 TI - Targeted modifications in adeno-associated virus serotype 8 capsid improves its hepatic gene transfer efficiency in vivo. AB - Recombinant adeno-associated virus vectors based on serotype 8 (AAV8) have shown significant promise for liver-directed gene therapy. However, to overcome the vector dose dependent immunotoxicity seen with AAV8 vectors, it is important to develop better AAV8 vectors that provide enhanced gene expression at significantly low vector doses. Since it is known that AAV vectors during intracellular trafficking are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal machinery, we modified specific serine/threonine kinase or ubiquitination targets on the AAV8 capsid to augment its transduction efficiency. Point mutations at specific serine (S)/threonine (T)/lysine (K) residues were introduced in the AAV8 capsid at the positions equivalent to that of the effective AAV2 mutants, generated successfully earlier. Extensive structure analysis was carried out subsequently to evaluate the structural equivalence between the two serotypes. scAAV8 vectors with the wild type (WT) and each one of the S/T->Alanine (A) or K-Arginine (R) mutant capsids were evaluated for their liver transduction efficiency in C57BL/6 mice in vivo. Two of the AAV8-S->A mutants (S279A and S671A), and a K137R mutant vector, demonstrated significantly higher enhanced green fluorescent protein (EGFP) transcript levels (~9- to 46-fold) in the liver compared to animals that received WT-AAV8 vectors alone. The best performing AAV8 mutant (K137R) vector also had significantly reduced ubiquitination of the viral capsid, reduced activation of markers of innate immune response, and a concomitant two-fold reduction in the levels of neutralizing antibody formation in comparison to WT-AAV8 vectors. Vector biodistribution studies revealed that the K137R mutant had a significantly higher and preferential transduction of the liver (106 vs. 7.7 vector copies/mouse diploid genome) when compared to WT-AAV8 vectors. To further study the utility of the K137R-AAV8 mutant in therapeutic gene transfer, we delivered human coagulation factor IX (h.FIX) under the control of liver-specific promoters (LP1 or hAAT) into C57BL/6 mice. The circulating levels of h.FIX:Ag were higher in all the K137R-AAV8 treated groups up to 8 weeks post-hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel AAV8 vectors for potential gene therapy of hemophilia B. PMID- 23442073 TI - Five decades of sci-fi in drug delivery. PMID- 23442076 TI - Interview with Paul Ashton: sustained-release drug delivery to the eye. PMID- 23442077 TI - Opportunities for drug-delivery research in nutraceuticals and functional foods? PMID- 23442078 TI - Electrically switchable polypyrrole film for the tunable release of progesterone. AB - BACKGROUND: Intrinsically conducting polymers, such as polypyrrole (PPy), have been utilized for drug delivery purposes as drug release rates can be tuned by electrical stimulation. Electrical stimulation can be used to switch the redox state of PPy, subsequently changing the electrostatic charge and volume of the polymer. Most literature to date has focused on the delivery of charged bioactives. This study aimed to prepare a PPy film formulation where the release rate of the uncharged drug progesterone could be electrically tuned. RESULTS & DISCUSSION: In this study PPy films loaded with progesterone are described. Drug loading levels were influenced by the concentration of drug during manufacture and polymerization time. The polymer formulation was electrically conductive and electroactive, switchable between oxidized and reduced states. Drug release was influenced by the application of electrical stimulation, the greatest release was observed on application of +0.8 V (to oxidize the polymer). Triggered release was observed in response to a period of electrical stimulation (+/-0.8 V at 0.5 Hz). CONCLUSION: This study describes the preparation of a PPy film loaded with the uncharged drug progesterone. The release rate could be tuned with electrical stimulation. PMID- 23442079 TI - Noninvasive insulin delivery: the great potential of cell-penetrating peptides. AB - Insulin, a potent therapeutic peptide used in the treatment of diabetes, is administered to patients via subcutaneous injections because of the poor pharmacokinetics associated with alternative routes of administration such as oral, nasal and pulmonary delivery. Noninvasive nasal and oral formulations are appealing to patients who need consecutive daily treatments of insulin. However, to achieve mucosal absorption of insulin via oral or nasal administration, two barriers must be overcome: the impermeability of insulin through the epithelial membranes and local digestion and enzymatic degradation. Cell-penetrating peptides (CPPs), which efficiently bring exogenous proteins and nucleic acids into cells, have great potential to facilitate insulin permeation from the intestinal lumen or nasal cavity into systemic circulation via efficient uptake by epithelial cells. In fact, the coadministration of insulin with the peptide penetratin, a typical CPP, increased intestinal and nasal insulin bioavailability to 35 and 50%, respectively. In this review, the authors describe recent findings using this novel CPP-based formulation for noninvasive delivery of insulin. PMID- 23442080 TI - Alginate-based strategies for therapeutic vascularization. AB - Therapeutic stimulation of vessel growth to improve tissue perfusion has shown promise in many regenerative medicine and tissue engineering applications. Alginate-based biomaterial systems have been investigated for growth factor and/or cell delivery as tools for modulating vessel assembly. Growth factor encapsulation allows for a sustained release of protein and protection from degradation. Implantation of growth factor-loaded alginate constructs typically shows an increase in capillary density but without vascular stabilization. Delivery of multiple factors may improve these outcomes. Cell delivery approaches focus on stimulating vascularization either via cell release of soluble factors, cell proliferation and incorporation into new vessels or alginate prevascularization prior to implantation. These methods have shown some promise but routine clinical application has not been achieved. In this review, current research on the application of alginate for therapeutic neovascularization is presented, shortcomings are addressed and the future direction of these systems discussed. PMID- 23442081 TI - Bioequivalence of inhaled drugs: fundamentals, challenges and perspectives. AB - Interest in bioequivalence (BE) of inhaled drugs derives largely from the desire to offer generic substitutes to successful drug products. The complexity of aerosol dosage forms renders them difficult to mimic and raises questions regarding definitions of similarities and those properties that must be controlled to guarantee both the quality and the efficacy of the product. Despite a high level of enthusiasm to identify and control desirable properties there is no clear guidance, regulatory or scientific, for the variety of aerosol dosage forms, on practical measures of BE from which products can be developed. As more data on the pharmaceutical and clinical relevance of various techniques, as described in this review, become available, it is likely that a path to the demonstration of BE will become evident. In the meantime, debate on this topic will continue. PMID- 23442082 TI - Receptor-based targeting of therapeutics. AB - Receptor-based targeting of therapeutics may be a fascinating proposition to improve the therapeutic efficacy of encapsulated drugs. The development of safe and effective nanomedicines is a prerequisite in the current nanotechnological scenario. Currently, the surface engineering of nanocarriers has attracted great attention for targeted therapeutic delivery by selective binding of targeting ligand to the specific receptors present on the surface of cells. In this review, we have discussed the current status of various receptors such as transferrin, lectoferrin, lectin, folate, human EGF receptor, scavenger, nuclear and integrin, which are over-expressed on the surface of cancer cells; along with the relevance of targeted delivery systems such as nanoparticles, polymersomes, dendrimers, liposomes and carbon nanotubes. The review also focuses on the effective utilization of receptor-based targeted delivery systems for the management of cancer in effective ways by minimizing the drug-associated side effects and improving the therapeutic efficacy of developed nano-architectures. PMID- 23442083 TI - Application of genomics, proteomics and metabolomics in drug discovery, development and clinic. AB - Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries. PMID- 23442085 TI - Planning of dental implant size with digital panoramic radiographs, CBCT generated panoramic images, and CBCT cross-sectional images. AB - OBJECTIVES: To compare the implant size (width and length) planned with digital panoramic radiographs, cone beam computed tomography (CBCT)-generated panoramic views, or CBCT cross-sectional images, in four implant systems. MATERIAL AND METHODS: Seventy-one patients with a total of 103 implant sites in the upper premolar and/or lower molar regions were examined with digital panoramic radiography (D-PAN) and (CBCT). A metal ball 5 mm in diameter was placed in the edentulous area for the D-PAN. CBCT data sets were reformatted to a 10-mm thick CBCT panoramic view (CBCT-pan) and 1-mm cross-sections (CBCT-cross). Measurements were performed in the images using dedicated software. All images were displayed on a monitor and assessed by three observers who outlined a dental implant by placing four reference points in the site of the implant-to-be. Differences in width and length of the implant-to-be from the three modalities were analyzed. The implant size selected in the CBCT-cross images was then compared to that selected in the other two modalities (D-PAN and CBCT-pan) for each of the implant systems separately. RESULTS: The implant-to-be (average measurements among observers) was narrower when measured in CBCT-cross compared with both D-PAN and CBCT-Pan. For premolar sites, the width also differed significantly between D-PAN and CBCT-pan modalities. The implant-to-be was also significantly shorter when recorded in CBCT-cross than in D-PAN. In premolar sites, there were no significant differences in implant length among the three image modalities. It mattered very little for the change in implant step sizes whether CBCT-cross was compared to D-PAN or CBCT-pan images. CONCLUSION: Our results show that the selected implant size differs when planned on panoramic or cross-section CBCT images. In most cases, implant size measured in cross-section images was narrower and shorter than implant size measured in a panoramic image or CBCT-based panoramic view. PMID- 23442086 TI - Manikin-based performance evaluation of elastomeric respirators against combustion particles. AB - This study investigated the effects of faceseal leakage, breathing flow, and combustion material on the overall (non-size-selective) penetration of combustion particles into P-100 half and full facepiece elastomeric respirators used by firefighters. Respirators were tested on a breathing manikin exposed to aerosols produced by combustion of three materials (wood, paper, and plastic) in a room size exposure chamber. Testing was performed using a single constant flow (inspiratory flow rate = 30 L/min) and three cyclic flows (mean inspiratory flow rates = 30, 85, and 135 L/min). Four sealing conditions (unsealed, nose-only sealed, nose and chin sealed, and fully sealed) were examined to evaluate the respirator faceseal leakage. Total aerosol concentration was measured inside (C(in)) and outside (C(out)) the respirator using a condensation particle counter. The total penetration through the respirator was determined as a ratio of the two (P = C(in) / C(out)). Faceseal leakage, breathing flow type and rate, and combustion material were all significant factors affecting the performance of the half mask and full facepiece respirators. The efficiency of P-100 respirator filters met the NIOSH certification criteria (penetration <=0.03%); it was not significantly influenced by the challenge aerosol and flow type, which supports the current NIOSH testing procedure using a single challenge aerosol and a constant airflow. However, contrary to the NIOSH total inward leakage (TIL) test protocol assuming that the result is independent on the type of the tested aerosol, this study revealed that the challenge aerosol significantly affects the particle penetration through unsealed and partially sealed half mask respirators. Increasing leak size increased total particle penetration. The findings point to some limitations of the existing TIL test in predicting protection levels offered by half mask elastomeric respirators. PMID- 23442087 TI - CBCT for the assessment of second mesiobuccal (MB2) canals in maxillary molar teeth: effect of voxel size and presence of root filling. AB - AIM: To compare detection of the second mesiobuccal (MB2) canal in maxillary molar teeth using cone-beam computed tomography (CBCT) with different voxel sizes against conventional radiographic examination when the MB1 was unprepared, prepared and filled. METHODOLOGY: Radiographic examination and 0.2-, 0.25- and 0.3-mm CBCT (n = 89) were performed in 3 stages: S1, no first mesiobuccal (MB1) canal preparation or filling; S2, after MB1 preparation and filling; and S3, after MB1 root canal filling removal and canal repreparation. Images were analysed using the i-Cat software. After RE and CBCT acquisition in S3, all the samples were clarified to directly visualize the presence of the MB2 canal. All images were analysed by a blinded, previously calibrated examiner. Accuracy, specificity and sensitivity were compared using analysis of variance (P < 0.05 level of significance). RESULTS: MB2 root canals were detected in 67% of the samples. Overall, radiographic examination was associated with lower mean accuracy values for detecting MB2 than CBCT regardless of the MB1 condition. The MB1 root canal condition did not influence MB2 detection in 0.2-mm voxel images. The presence of root fillings in the MB1 canals reduced the detection of MB2 canals, especially in the 0.3- and 0.25-mm voxel-size images (P < 0.05). CONCLUSION: CBCT was associated with higher mean values of specificity and sensibility than radiographic examination for the detection of MB2 canals. When endodontic retreatment is necessary removal of the root filling prior to the CBCT examination eliminates artefacts, thereby permitting the use of the 0.3-mm voxel protocol that has good diagnostic performance and lower radiation dose. PMID- 23442088 TI - The xylan utilization system of the plant pathogen Xanthomonas campestris pv campestris controls epiphytic life and reveals common features with oligotrophic bacteria and animal gut symbionts. AB - Xylan is a major structural component of plant cell wall and the second most abundant plant polysaccharide in nature. Here, by combining genomic and functional analyses, we provide a comprehensive picture of xylan utilization by Xanthomonas campestris pv campestris (Xcc) and highlight its role in the adaptation of this epiphytic phytopathogen to the phyllosphere. The xylanolytic activity of Xcc depends on xylan-deconstruction enzymes but also on transporters, including two TonB-dependent outer membrane transporters (TBDTs) which belong to operons necessary for efficient growth in the presence of xylo-oligosaccharides and for optimal survival on plant leaves. Genes of this xylan utilization system are specifically induced by xylo-oligosaccharides and repressed by a LacI-family regulator named XylR. Part of the xylanolytic machinery of Xcc, including TBDT genes, displays a high degree of conservation with the xylose-regulon of the oligotrophic aquatic bacterium Caulobacter crescentus. Moreover, it shares common features, including the presence of TBDTs, with the xylan utilization systems of Bacteroides ovatus and Prevotella bryantii, two gut symbionts. These similarities and our results support an important role for TBDTs and xylan utilization systems for bacterial adaptation in the phyllosphere, oligotrophic environments and animal guts. PMID- 23442089 TI - Molecular hairpin: a possible model for inhibition of tau aggregation by tannic acid. AB - Inhibition of anomalous aggregation of tau protein would be an attractive therapeutic target for Alzheimer's disease (AD). In this study, tannic acid (TA), a polymeric plant polyphenol, and its monomer, gallic acid (GA), were introduced as the references to afford a molecular framework that integrates tau binding properties and inhibitory effects. Using a thioflavin S fluorescence assay and electron microscopy, we demonstrated that TA could competently inhibit the in vitro aggregation of tau peptide R3, corresponding to the third repeat unit of the microtubule-binding domain, with an IC50 of 3.5 MUM, while GA's inhibition was comparatively piddling (with an IC50 of 92 MUM). In the isothermal titration calorimetry experiment, we found that TA could strongly bind to R3 with a large amount of heat released. Circular dichroism spectra showed TA dose-dependently suppressed the conformational transition of R3 from a random coil structure to a beta-sheet structure during the aggregation process. Finally, a structural model was built using molecular docking simulation to elucidate the possible binding sites for TA on the tau peptide surface. Our results suggest that TA recognizably interacts with tau peptide by forming a hairpin binding motif, a key framework required for inhibiting tau polymerization, in addition to hydrogen bonding, hydrophilic-hydrophobic interactions, and static electrical interactions, as reported previously. The inhibitory effect of TA on human full-length tau protein (tau441) was also verified by electron microscopy. This finding hints at the possibility of TA as a leading compound of anti-AD drugs and offers a new stratagem for the rational molecular design of a tau aggregation inhibitor. PMID- 23442090 TI - NHC-promoted asymmetric beta-lactone formation from arylalkylketenes and electron deficient benzaldehydes or pyridinecarboxaldehydes. AB - A chiral NHC catalyzes the asymmetric formal [2 + 2] cycloaddition of alkylarylketenes with both electron-deficient benzaldehydes and 2- and 4 pyridinecarboxaldehydes to generate stereodefined beta-lactones. In the benzaldehyde series, optimal product diastereo- and enantiocontrol is observed using 2-nitrobenzaldehyde (up to 93:7 dr (syn:anti) and 93% ee). Substituted 2- and 4-pyridinecarboxaldehydes are also tolerated in this process, generating the corresponding beta-lactones in good yield and enantioselectivity, although the diastereocontrol in these processes is highly dependent upon the aldehyde substitution. These processes are readily scalable, allowing multigram quantities of the beta-lactone products to be prepared. Derivatization of these products, either through ring opening into the corresponding stereodefined beta-hydroxy and beta-amino acid derivatives without loss of stereochemical integrity or via cross coupling, is demonstrated. PMID- 23442091 TI - Episodic future thinking: linking neuropsychological performance with episodic detail in young and old adults. AB - Episodic future thinking (EFT) has been linked with our ability to remember past events. However, its specific neurocognitive subprocesses have remained elusive. In Experiment 1, a study of healthy older adults was conducted to investigate the candidate subprocesses of EFT. Participants completed a standard EFT cue word task, two memory measures (Verbal Paired Associates I, Source Memory), and two measures of executive function (Trail Making Test, Tower Test). In Experiment 2, healthy young adults also completed an EFT task and neuropsychological measures. The link between neurocognitive measures and five characteristics of EFT was investigated. Specifically, it was found that Source Memory and Trail Making Test performance predicted the episodic specificity of future events in older but not younger adults. Replicating previous findings, older adults produced future events with greater semantic but fewer episodic details than did young adults. These results extend the data and emphasize the importance of the multiple subprocesses underlying EFT. PMID- 23442092 TI - Kynurenic acid, by targeting alpha7 nicotinic acetylcholine receptors, modulates extracellular GABA levels in the rat striatum in vivo. AB - Kynurenic acid (KYNA) is an astrocyte-derived non-competitive antagonist of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) and inhibits the NMDA receptor (NMDAR) competitively. The main aim of the present study was to examine the possible effects of KYNA (30 - 1000 nm), applied locally by reverse dialysis for 2 h, on extracellular GABA levels in the rat striatum. KYNA concentration dependently reduced GABA levels, with 300 nm KYNA causing a maximal reduction to ~60% of baseline concentrations. The effect of KYNA (100 nm) was prevented by co application of galantamine (5 MUm), an agonist at a site of the alpha7nAChR that is very similar to that targeted by KYNA. Infusion of 7-chlorokynurenic acid (100 nm), an NMDAR antagonist acting selectively at the glycineB site of the receptor, affected neither basal GABA levels nor the KYNA-induced reduction in GABA. Inhibition of endogenous KYNA formation by reverse dialysis of (S)-4 (ethylsulfonyl)benzoylalanine (ESBA; 1 mm) increased extracellular GABA levels, reaching a peak of 156% of baseline levels after 1 h. Co-infusion of 100 nm KYNA abolished the effect of ESBA. Qualitatively and quantitatively similar, bi directional effects of KYNA on extracellular glutamate were observed in the same microdialysis samples. Taken together, the present findings suggest that fluctuations in endogenous KYNA levels, by modulating alpha7nAChR function, control extracellular GABA levels in the rat striatum. This effect may be relevant for a number of physiological and pathological processes involving the basal ganglia. PMID- 23442093 TI - Cytomegalovirus infection is associated with increased mortality in the older population. AB - Cytomegalovirus (CMV) is a common herpesvirus infection and stimulates the expansion of very large numbers of CMV-specific T cells that reduce the CD4/CD8 ratio and suppress the number of naive T cells. CMV infection has been associated with frailty and impaired survival. We investigated the correlates of CMV and the impact of the CMV infection on mortality within a cohort of 511 individuals aged at least 65 years who were followed up for 18 years. The mean age of the participants was 74 years of which 70% were CMV-seropositive. CMV was strongly linked to socio-economic status, and CMV infection increased the annual mortality rate by 42% (Hazard ratio = 1.42, 95% CI: 1.11-1.76 after adjusting for age, sex and baseline socio-economic and health variables) corresponding to 3.7 years lower life expectancy from age 65. Infection was associated with a near doubling of cardiovascular deaths, whereas there was no increase in mortality from other causes. These results show that CMV infection markedly increases the mortality rate in healthy older individuals due to an excess of vascular deaths. These findings may have significant implications for the study of immune senescence and if confirmed more generally could have important implications for measures to optimize the health of the elderly. PMID- 23442094 TI - Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. AB - Adeno-associated virus (AAV)-based vectors are promising tools for gene therapeutic applications, in part because AAVs are nonpathogenic viruses, and vectors derived from them can drive long-term transgene expression without integration of the vector DNA into the host genome. AAVs are not strongly immunogenic, but they can, nonetheless, give rise to both a cellular and humoral immune response. As a result, a significant fraction of potential patients for AAV-based gene therapy harbors pre-existing antibodies against AAV. Because even very low levels of antibodies can prevent successful transduction, antecedent anti-AAV antibodies pose a serious obstacle to the universal application of AAV gene therapy. In this review, we discuss the current knowledge of the role of anti-AAV antibodies in AAV-based gene therapy with a particular emphasis on approaches to overcome the hurdle that they pose. PMID- 23442095 TI - Association of Interleukin 1 beta (IL-1B) gene polymorphism with early pregnancy loss risk in the North Indian population. AB - C+3953T IL-1 B single-nucleotide polymorphism (SNP) genotyping was carried out in 140 unrelated early pregnancy loss (EPL) patients and in 198 fertile healthy control women and in chorionic villous samples by PCR-RFLP. In Indian population, this is the first report on association of IL-1 B SNP C+3953T polymorphism and EPL. PMID- 23442097 TI - A new editor: same goals. PMID- 23442096 TI - Economic impact of childhood psychiatric disorder on public sector services in Britain: estimates from national survey data. AB - BACKGROUND: Approximately one in ten children aged 5-15 in Britain has a conduct, hyperactivity or emotional disorder. METHODS: The British Child and Adolescent Mental Health Surveys (BCAMHS) identified children aged 5-15 with a psychiatric disorder, and their use of health, education and social care services. Service costs were estimated for each child and weighted to estimate the overall economic impact at national level. RESULTS: Additional health, social care and education costs associated with child psychiatric disorders totalled L1.47bn in 2008. The lion's share of the costs falls to frontline education and special education services. CONCLUSIONS: There are huge costs to the public sector associated with child psychiatric disorder, particularly the education system. There is a pressing need to explore ways to reduce these costs while improving health and well-being. PMID- 23442098 TI - Ten yr of pediatric heart transplantation: a report from the Pediatric Heart Transplant Study. AB - The PHTS was founded in 1991 as a not-for-profit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2000-December 31, 2009) and summarize the changes, trends, outcomes, and lessons learned. PMID- 23442099 TI - Outcomes and predictive factors of pediatric kidney transplants: an analysis of the Thai Transplant Registry. AB - As universal coverage for pediatric kidney transplantation (KT) was introduced in Thailand in 2008, the number of recipients has been increasing. We evaluated predictive factors for graft failure to understand how to improve clinical outcomes in these children. Using data obtained from the National Transplant registry, we assessed the risk of graft failure using the Kaplan-Meier method and Cox proportional hazards regression. Altogether, 201 recipients aged <21 yr at the time of KT were studied. Living donors (LD) were significantly older than deceased donor (DD). Mean cold ischemia time of DD was 17 h. The mean donor glomerular filtration rate (GFR) was 84.0 mL/min/1.73 m(2) . Induction immunosuppressive therapy was administered more frequently in DD than in LDKT. Delayed graft function (DGF) occurred in 36 transplants. Over 719 person years of follow-up, 42 graft failures occurred. Graft survival at one, three, and five yr post-transplant were 95%, 88% and 76%, respectively. Two factors independently predicted graft failure in multivariate analysis. The hazard ratios for graft failure in patients with DGF and in patients with donor GFR of <=30 mL/min/1.73 m(2) were 2.5 and 9.7, respectively. Pediatric recipients should receive the first priority for allografts from young DD with a good GFR, and DGF should be meticulously prevented. PMID- 23442100 TI - Adolescent classroom education on knowledge and attitudes about deceased organ donation: a systematic review. AB - In many countries, adolescents can choose to register a deceased organ donation wish when they apply for a driver's license. They often receive education about deceased organ donation in order to make an informed choice. The objective of this review was to describe the effectiveness of school-based educational programs on deceased organ donation among adolescents. We reviewed any study of adolescent students receiving a school-based educational program on deceased organ donation. The outcomes were knowledge, attitudes, intent to register a preference toward deceased organ donation, and whether such education fostered family discussions about organ donation. Fifteen studies were summarized from nine countries, of which six were randomized controlled trials. Most educational programs consisted of one or two classroom sessions. The methods employed in five studies received a high-quality rating. Educational programs increased knowledge in 10 studies, and attitudes in five studies, with variable effects on intent to affirmative registration. Seven studies reported success in promoting family discussions. Adolescent classroom education is a promising strategy to improve knowledge about deceased organ donation and appears to increase public support for donation. Subjecting these programs to additional evaluation will clarify their impact on affirmative donor registration and realized donations. PMID- 23442101 TI - Alemtuzumab induction in pediatric kidney transplantation. AB - Recipient parenchymal lymphatic cells are crucial for direct and indirect pathways of allorecognition. We proposed that alemtuzumab, being infused several weeks pretransplant could eradicate peripheral lymphatic cells and promote donor specific tolerance. We present here a single center, retrospective review of 101 consecutive living-donor kidney transplantations to pediatric patients aged from seven month to 18 yr, performed between September 2006 and April 2010. Immunosupression protocol included two 30 mg doses of alemtuzumab: first given 12 29 d prior to transplantation and second at the time of transplantation. Maintenance immunosupression was based on combination of low dose and wide range CNI and mycophenolate. Patients were followed for 3.8 +/- 1.4 yr and protocol biopsies were taken one month, one, and three yr post transplant. The Kaplan Meier graft and patient survival was 96% and 97% for one yr, 89% and 93% for three yr. Biopsy proven acute rejection developed in 26% patients at one yr and in 35% at two yr, no rejections occurred beyond two yr. We conclude that alemtuzumab pretreatment prior to living related donor kidney transplantation allows to reach satisfactory middle-term results in pediatric patients with wide range and low CNI concentrations. PMID- 23442102 TI - Kidney grafts from donors <= 5 yr of age: single kidney transplantation for pediatric recipients or en bloc transplantation for adults? AB - Kidneys from donors <=5 yr of age represent a controversial issue. The purpose of this study was to compare the transplant outcomes as single and single/en bloc grafts into pediatric and adult KT recipients, respectively. All recipients of kidneys from donors <=5 yr old transplanted at our institution from 3/2003 to 12/2010 were evaluated, and corresponding data were analyzed. There were 11 pediatric and 14 adult recipients. Median donor age and body weight were 38 months and 14 kg, respectively. PNF, n = 2 and DGF, n = 1 were observed only among adult recipients. Five-yr graft survival was 100% for children and 86% for adults. There were no significant differences in graft and patient survival, PNF, DGF, acute rejection, or postoperative complications among children/single (n = 10), adults/en bloc (n = 10), and adults/single (n = 4) KT. Major complications were documented in six adult recipients and one pediatric recipient after en bloc KT. Pediatric recipients showed significantly higher GFR during the first post transplant year. Kidneys from donors <=5 yr of age have at least as good outcomes as when transplanted as single allografts into children. Although the study volume is small, it seems that children benefit from a pediatric-oriented allocation policy. PMID- 23442103 TI - IPTA Symposium: Common Challenge Topics in Pediatric Transplantation/I Brazilian Symposium of Pediatric Transplantation - Centenary Celebration of University of Sao Paulo Medical School. PMID- 23442104 TI - Recanalization of post-transplant late-onset long segmental portal vein thrombosis with bidirectional transhepatic and transmesenteric approach. AB - PV complications are the most frequent vascular complications in pediatric LT. We have experienced a case with chronic postoperative PVT that necessitates combined transhepatic and transmesenteric approach and have confirmed mid-term patency. An eight-yr-old boy had successful LDLT with a left lateral segment graft at the age of two months for HBV-related acute liver failure. Seven years after transplantation, the patient suddenly showed a melena with hypovolemic shock. Doppler ultrasound and CT revealed intrahepatic bile duct dilatation and main PVT with collateral formation at hepatic hilus and mesenterium of the Roux-en-Y jejunal loop. Urgent splenic artery embolization was performed to control the bleeding and was temporarily effective. Therefore, recanalization of PVO was attempted. Because of long segmental PVO and steep angle between the intrahepatic PV and the portal trunk, bidirectional transhepatic and transmesenteric approach was selected and resulted in deploying three metallic stents necessitating additional infusion thrombolytic therapy. The patient is now followed as an outpatient with patent stents for two yr since the procedure. For the rescue of these patients, recanalization of obstructed PV trunk with bidirectional approach would be feasible with better graft survival and less invasiveness than conventional surgical interventions. PMID- 23442106 TI - A patient-centred approach to treatment with incretin-based agents in patients with type 2 diabetes. AB - WHAT IS KNOWN AND OBJECTIVE: The 2012 position statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends a haemoglobin A1c level of <7% for most patients with type 2 diabetes (T2D). Initial therapy consists of lifestyle changes plus metformin, with an emphasis on a patient-centred approach to management. Addition of incretin-based therapy is recommended as an add-on after metformin failure, and later on in combination with basal insulin. Basal insulin is recommended from the onset in patients with A1c >=10%. The possibility of incorporating incretin-based therapy in the patient-centred approach will be investigated both in the literature and clinical experience. COMMENT: Incretin-based therapy targets multiple dysfunctional organ systems in T2D and provides sustained glycaemic control, with extraglycaemic benefits and low risk of hypoglycaemia. To initiate an incretin-based therapy that best fits an individual patient's needs, the patient's A1c level, preference and comorbid conditions should be considered along with any drug safety and adherence-related issues. WHAT IS NEW AND CONCLUSION: There is good evidence to support the patient-centred approach to T2D management. This approach allows patient treatment goals and personal preferences to be matched with the clinical profile(s) of one or more agents to formulate a treatment plan that can best achieve the goals. Incretin-based therapies are an important class of agents to consider after metformin monotherapy failure and later in combination with basal insulin. By matching patient needs with the clinical profiles of the various treatment options, pharmacists can actively engage in the practice of patient-centred care and management. PMID- 23442105 TI - Preferential interactions between lithium chloride and glucan chains in N,N dimethylacetamide drive cellulose dissolution. AB - Naturally occurring cellulose is crystalline as a consequence of the strong interactions between the glucan chains that comprise it and therefore is insoluble in most solvents. One of the few solvent systems able to dissolve cellulose is lithium chloride (LiCl) dissolved in N,N-dimethylacetamide (DMA). By an integrated application of all-atom molecular dynamics (MD) simulations, reaction path optimization, free-energy calculations, and a force-matching analysis of coarse-grained atomistic simulations, we establish that DMA-mediated preferential interactions of Li(+) cations and Cl(-) anions with glucan chains enable cellulose dissolution in LiCl/DMA. The relatively weak solvation of Li(+), Cl(-), and glucan chains by DMA results in strong effective interactions of Li(+) and Cl(-) ions with the glucans, leading to cellulose dissolution. The small size of the Li(+) cations allows them to strongly couple to multiple interaction sites on the glucan chains of cellulose, including the spatially restricted regions around the ether linkages connecting neighboring glucose residues. Li(+) cations were thus identified as the main component responsible for driving cellulose dissolution. The mechanism for explaining the solubility of cellulose in the LiCl/DMA system deduced from the analysis of atomistic-scale simulations conducted in this work is also consistent with most of the empirical observations related to cellulose dissolution in salt/amide solvent systems. PMID- 23442107 TI - Eruptive pigmentation around naevi and seborrhoeic keratoses in a patient with stage III melanoma: hyperpigmented halo or 'Nottus' phenomenon. PMID- 23442109 TI - Soil ingestion. Foreword. PMID- 23442108 TI - Nitric oxide and beta(2)-adrenoceptor activation attenuate pulmonary vasoconstriction during anaphylactic hypotension in anesthetized BALB/c mice. AB - Systemic anaphylaxis accompanies pulmonary vasoconstriction and bronchoconstriction, which may contribute to increased right heart afterload, and finally anaphylactic hypotension. However, the pulmonary response to anaphylaxis is not known in mice. We determined the pulmonary vascular and bronchial response to systemic anaphylaxis in anesthetized BALB/c mice. We also clarified the roles of beta-adrenoceptors, nitric oxide, and cyclooxygenase metabolites in these responses. Anaphylaxis was induced by an intravenous injection of the ovalbumin antigen into open-chest artificially ventilated sensitized mice. Mean arterial pressure, systolic pulmonary arterial pressure, central venous pressure, airway pressure, and aortic blood flow were continuously measured. In sensitized control mice, mean arterial pressure, and aortic blood flow substantially decreased soon after the antigen injection, while systolic pulmonary arterial pressure and airway pressure did not increase. In contrast, in mice pretreated with either the beta(2)-adrenoceptor antagonist ICI 118,551 (0.2 mg/kg; n = 6), or L-NAME (50 mg/kg; n = 6), but not with the beta(1)-adrenoceptor antagonist atenolol (2 mg/kg; n = 6) or indomethacin (5 mg/kg; n = 6), systolic pulmonary arterial pressure increased by 7 mmHg at 1.5 min after antigen. In L-NAME pretreated mice, pulmonary hypertension was sustained over 30 min of the experimental period. Airway pressure did not significantly change after antigen in any mice studied. In conclusion, pulmonary response to systemic anaphylaxis does not increase the right heart afterload and, therefore, may not contribute to the initial decrease in venous return and anaphylactic hypotension in anesthetized mice. beta(2) adrenoceptor activation and nitric oxide, but not beta(1)-adrenoceptor activation or cyclooxygenase metabolites, attenuate the antigen-induced pulmonary vasoconstriction. PMID- 23442110 TI - Derivation of a site-specific assessment criterion for benzo[a]pyrene in red shale at a former coking works. AB - A former coking works in England is being remediated to enable its redevelopment. We have developed site specific human health risk assessment criteria (SSAC) for benzo[a]pyrene (BaP) based on detailed characterisation of red shale proposed for reuse in an area allocated for residential development. Samples of red shale were analysed using the Colon-enhanced Physiologically Based Extraction Test (CEPBET) to estimate the bioaccessibility of BaP. The results indicate that between 5% and 28% of the red shale BaP is bioaccessible. A cautious value of 50% was used in calculating an SSAC. The CLEA human health assessment model was used to calculate the SSAC and any changes to the default input parameters have been discussed and justified. Based on the fact that BaP appears to be a point-of-contact, rather than a systemic, carcinogen in animal studies, individual assessment criteria were estimated for the oral, inhalation and dermal routes of entry in-line with current UK guidance. An overall SSAC of 2.5 mg/kg for BaP in red shale for the residential with home-grown produce land use was then derived as the lowest of the three route-specific assessment criteria. This value is specific to both the site and the material being assessed. The approach adopted however can be applied on other sites and for other materials to inform detailed quantitative risk assessments. PMID- 23442111 TI - Predicting lead relative bioavailability in peri-urban contaminated soils using in vitro bioaccessibility assays. AB - In this study, lead (Pb) bioaccessibility was assessed in peri-urban contaminated soils using a variety of established in vitro assays. Bioaccessibility data was then used to predict Pb relative bioavailability (RBA) using published in vivo-in vitro regression models in order to compare calculated estimates and measured values. Lead bioaccessibility varied depending on the in vitro methodology employed with the relative bioavailability leaching procedure (RBALP) and in vitro gastrointestinal (IVG) assays providing more conservative Pb bioaccessibility values compared to those determined using PBET, UBM and Rel-SBRC I assays. When Pb RBA was calculated, predicted values using PBET-G and UBM-G data were similar to measured Pb RBA values. However, Pb RBA was over-estimated by 1.6-5.5- and 2.6-6.6-fold when data and regression models from RBALP and IVG-G assays were employed. PMID- 23442112 TI - An investigation of the effect of gastrointestinal microbial activity on oral arsenic bioavailability. AB - In vitro gastrointestinal (GI) microbial activity in the colon compartment facilitates the arsenic release from soils into simulated GI fluids. Consequentially, it is possible that in vitro models that neglect to include microbial activity underestimate arsenic bioaccessibility when calculating oral exposure. However, the toxicological relevance of increased arsenic release due to microbial activity is contingent upon the subsequent absorption of arsenic solubilized in the GI lumen. The objectives of this research are to: (1) assess whether microbes in the in vitro small intestine affect arsenic solubilization from soils, (2) determine whether differences in the GI microbial community result in differences in the oral bioavailability of soil-borne arsenic. In vitro GI microbial activity in the distal small intestine increased arsenic release from soils; however, these effects were unlikely to be relevant since they were transient and demonstrated small effect sizes. In vivo arsenic absorption for juvenile swine was unaffected by antibiotic treatment. Therefore, it appears that microbial effects on arsenic release do not result in increased arsenic bioavailability. However, it remains to be seen whether the results for the limited set of soils described herein can be extrapolated to arsenic contaminated sites in general. PMID- 23442113 TI - Bioaccessible and non-bioaccessible fractions of soil arsenic. AB - In order for in vitro methods to become widely accepted as tools that accurately assess soil arsenic (As) exposure through the oral ingestion pathway, a better understanding is needed regarding which fractions of soil As are being measured in the in vitro extraction. The objective of the current study is to (1) identify in vitro bioaccessible (IVBA) and non-IVBA fractions of soil As using sequential extraction; and (2) determine the sorptive phases of soil in non-IVBA As soil fractions. Nineteen soils with a range of soil properties were spiked with 250 mg/kg of sodium arsenate and aged. In vitro bioaccessible As (IVBA As) was then determined using The Ohio State University in vitro gastrointestinal method (OSU IVG), and soil As was fractionated using sequential extraction into: (F1) non specifically sorbed; (F2) specifically sorbed; (F3) amorphous and poorly crystalline oxides of Fe and Al; (F4) well-crystallized oxides of Fe and Al and residual As phases. The IVBA As across the 19 soil ranged from 0.36 to 2.75 mmol/kg (12 to 86%) with a mean of 1.26 mmol/kg (42%) in the gastric phase and from 0.39 to 2.80 mmol/kg (13 to 87%) in the intestinal phase with a mean of 1.32 mmol/kg (43%). The results of the sequential extraction showed that IVBA As extracted by the OSU-IVG is the As present in the first two fraction (F1 and F2) of the sequential extraction. In the non-IVBA fractions, highly significant relationships (P < 0.01) exist between F3 As and log transformed F3 Fe (r (2) = 0.74), but not F3 Al. In addition, the gastric extraction dissolves a significant fraction of soil Al, but not soil Fe, therefore As sorbed to Al oxides likely contributed to IVBA As and is accounted for in the F2 fraction of the sequential extraction. In vitro methods that demonstrate the ability to extract the similar soil fractions that occur in vivo across a wide range of soil types and As contaminant sources is an important criteria for in vitro method validation. Further research that includes soils with multiple As-contaminant sources (mining, pesticide, etc.), soil As fractionation, and in vivo bioavailability is needed in order to determine if F1+F2 are the bioavailable As fractions in soils that vary in total As content and sorbed As species. PMID- 23442114 TI - Measurement modelling and mapping of arsenic bioaccessibility in Northampton, United Kingdom. AB - The human ingestion bioaccessibility of As was measured on 50 representative samples of soils selected from a 281-soil-sample geochemical survey of Northampton. The major and trace element content, pH and near infrared (NIR) spectra of the 281 soils were determined. A multiple linear regression (MLR) model using total As, major element composition and pH identified total As, pH and P to be the significant predictor variables for bioaccessible As (R2 = 0.72, median standard error of prediction = 1.5 mg kg(-1) bioaccessible As). When spectral components (SC) derived from chemometric analysis of the NIR spectra were also included in the MLR, total As, pH, Mg and two NIR spectral components were found to be significant predictor variables (R2 = 0.84, median standard error of prediction = 1.2 mg kg(-1) bioaccessible As). Correlation analysis of the SC with major element data suggested that the two NIR SC in the second model were related to different forms of Fe oxides in the soil. When plotted over a geological map of Northampton interpolated predictions of bioaccessible As showed clear geological control. The median total As concentration of the soils in Northampton was 30.2 mg kg(-1) and the median bioaccessible As was 3.0 mg kg(-1). PMID- 23442115 TI - Variability of bioaccessibility results using seventeen different methods on a standard reference material, NIST 2710. AB - Bioaccessibility is a measurement of a substance's solubility in the human gastro intestinal system, and is often used in the risk assessment of soils. The present study was designed to determine the variability among laboratories using different methods to measure the bioaccessibility of 24 inorganic contaminants in one standardized soil sample, the standard reference material NIST 2710. Fourteen laboratories used a total of 17 bioaccessibility extraction methods. The variability between methods was assessed by calculating the reproducibility relative standard deviations (RSDs), where reproducibility is the sum of within laboratory and between-laboratory variability. Whereas within-laboratory repeatability was usually better than (<) 15% for most elements, reproducibility RSDs were much higher, indicating more variability, although for many elements they were comparable to typical uncertainties (e.g., 30% in commercial laboratories). For five trace elements of interest, reproducibility RSDs were: arsenic (As), 22-44%; cadmium (Cd), 11-41%; Cu, 15-30%; lead (Pb), 45-83%; and Zn, 18-56%. Only one method variable, pH, was found to correlate significantly with bioaccessibility for aluminum (Al), Cd, copper (Cu), manganese (Mn), Pb and zinc (Zn) but other method variables could not be examined systematically because of the study design. When bioaccessibility results were directly compared with bioavailability results for As (swine and mouse) and Pb (swine), four methods returned results within uncertainty ranges for both elements: two that were defined as simpler (gastric phase only, limited chemicals) and two were more complex (gastric + intestinal phases, with a mixture of chemicals). PMID- 23442116 TI - Arsenic bioaccessibility upon gastrointestinal digestion is highly determined by its speciation and lipid-bile salt interactions. AB - The release of arsenic (As) from a contaminated food matrix during gastrointestinal digestion, i.e., its bioaccessibility, is an important estimator of its bioavailability, and therefore also its health risk. In addition, As toxicity is primarily determined by its speciation and it is not clear how different As species behave during digestion in the upper digestive tract. Here, we evaluated to what extent digestive parameters like gastric pH and bile concentration, but also food matrix constituents affect the bioaccessibility of 8 As species (As(III), As(V), MMA(V), DMA(V), MMA(III), DMA(III), MMMTA(V), DMMTA(V)). Bioaccessibility of all As standards ranged between 85% and 90% under pH 1.8. Bioaccessibility of methylated and thiolated arsenicals was decreased from 85% to 50% with increasing gastric pH to 4, yet an increasing bile salts concentration up to 30 g/L lowered the bioaccessibility of inorganic species from 83% to 70% due to interaction with Fe present in bile salts. With respect to food matrices, we noted that the fiber content did not affect As bioaccessibility, yet the presence of fat resulted in an increased bioaccessibility of both inorganic and organic arsenicals in the presence of bile salts. With respect to inorganic arsenic, the intestinal presence of trivalent Fe appeared to be the predominant factor for bioaccessibility of iAs. These data demonstrate that species dependent bioaccessibility must be considered upon ingestion and gastrointestinal digestion. PMID- 23442117 TI - Functional analysis of the novel mycorrhiza-specific phosphate transporter AsPT1 and PHT1 family from Astragalus sinicus during the arbuscular mycorrhizal symbiosis. AB - Arbuscular mycorrhizas contribute significantly to inorganic phosphate (Pi) uptake in plants. Gene networks involved in the regulation and function of the Pht1 family transporters in legume species during AM symbiosis are not fully understood. In order to characterize the six distinct members of Pht1 transporters in mycorrhizal Astragalus sinicus, we combined cellular localization, heterologous functional expression in yeast with expression/subcellular localization studies and reverse genetics approaches in planta. Pht1;1 and Pht1;4 silenced lines were generated to uncover the role of the newly discovered dependence of the AM symbiosis on another phosphate transporter AsPT1 besides AsPT4. These Pht1 transporters are triggered in Pi starved mycorrhizal roots. AsPT1 and AsPT4 were localized in arbuscule-containing cells of the cortex. The analysis of promoter sequences revealed conserved motifs in both AsPT1 and AsPT4. AsPT1 overexpression showed higher mycorrhization levels than controls for parameters analysed, including abundance of arbuscules. By contrast, knockdown of AsPT1 by RNA interference led to degenerating or dead arbuscule phenotypes identical to that of AsPT4 silencing lines. AsPT4 but not AsPT1 is required for symbiotic Pi uptake. These results suggest that both, AsPT1 and AsPT4, are required for the AM symbiosis, most importantly, AsPT1 may serve as a novel symbiotic transporter for AM development. PMID- 23442118 TI - Childhood epidermolysis bullosa acquisita associated with severe dental alterations: a case presentation. PMID- 23442120 TI - Redox signaling in plants. AB - Our aim is to deliver an authoritative and challenging perspective of current concepts in plant redox signaling, focusing particularly on the complex interface between the redox and hormone-signaling pathways that allow precise control of plant growth and defense in response to metabolic triggers and environmental constraints and cues. Plants produce significant amounts of singlet oxygen and other reactive oxygen species (ROS) as a result of photosynthetic electron transport and metabolism. Such pathways contribute to the compartment-specific redox-regulated signaling systems in plant cells that convey information to the nucleus to regulate gene expression. Like the chloroplasts and mitochondria, the apoplast-cell wall compartment makes a significant contribution to the redox signaling network, but unlike these organelles, the apoplast has a low antioxidant-buffering capacity. The respective roles of ROS, low-molecular antioxidants, redox-active proteins, and antioxidant enzymes are considered in relation to the functions of plant hormones such as salicylic acid, jasmonic acid, and auxin, in the composite control of plant growth and defense. Regulation of redox gradients between key compartments in plant cells such as those across the plasma membrane facilitates flexible and multiple faceted opportunities for redox signaling that spans the intracellular and extracellular environments. In conclusion, plants are recognized as masters of the art of redox regulation that use oxidants and antioxidants as flexible integrators of signals from metabolism and the environment. PMID- 23442119 TI - Normal exon copy number of the GLI2 and GLI3 genes in patients with esophageal atresia. AB - Esophageal atresia (EA) is a congenital developmental defect of the alimentary tract concerning the interruption of the esophagus with or without connection to the trachea. The incidence of EA is 1 in 3000-3500 of live-born infants, and occurs in both isolated and syndromic (in combination with abnormalities in other organ systems) forms. The molecular mechanisms underlying the development of EA are poorly understood. Knockout studies in mice indicate that genes like Sonic hedgehog, Gli2, and Gli3 play a role in the etiology of EA. These facts led us to hypothesize that Sonic hedgehog-GLI gene rearrangements are associated with EA in humans. To test this hypothesis, we screened patients with isolated and syndromic EA for GLI2 and/or GLI3 microrearrangements using methods to estimate the copy number (Multiplex Ligation-dependent Probe Amplification, real-time polymerase chain reaction). To our best knowledge this is the first study assessing copy number of GLI2 and GLI3 genes in patients with EA. PMID- 23442121 TI - A comparison of two sampling methods for the detection of airborne methylene bisphenyl diisocyanate. AB - The purpose of this study was to determine if there was a significant difference between two readily available sampling methodologies for airborne methylene bisphenyl diisocyanate (MDI), which is an essential precursor in the spray-on truck bed lining industry. Seventy-two personal airborne samples of MDI were collected and analyzed from nine spray-on truck bed liner businesses in northern Colorado. Wide ranges of exposure concentrations were encountered during the spray-on application, including concentrations that exceeded the OSHA permissible exposure limit. The highest airborne MDI concentration measured was 690 ppb. A statistically significant difference between field-desorbed and laboratory desorbed methods was determined. The field-desorbed sampling methodology yielded consistently higher MDI concentrations than the laboratory-desorbed sampling methodology, which suggests that immediate desorption minimizes isocyanate loss and potential underestimations. Results from the analysis of variance also indicated that different facility factors and environmental conditions within each company, such as the use of ventilation or humidity level, affected the MDI concentrations, indicating the potential for better mitigation of exposures using the hierarchy of controls. PMID- 23442122 TI - Agreement between periapical radiographs and cone-beam computed tomography for assessment of periapical status of root filled molar teeth. AB - AIM: To assess the agreement between periapical radiograph (PA) and cone-beam computed tomography (CBCT) for periapical assessment of root filled maxillary and mandibular molars. METHODOLOGY: Periapical radiograph and CBCT (iCat) images of 60 previously root filled molars (30 maxillary and 30 mandibular) were obtained at a review clinic. Agreement between PA and CBCT assessments of (i) number of canals per tooth, (ii) number of lesions per tooth, (iii) mesial-distal dimension of lesions, (iv) coronal-apical dimension of lesions and (v) presence of 'J' shaped lesions were determined in comparison analyses and correlation analysis. RESULTS: There were significant differences between PA and CBCT assessment for the mean number of canals (P < 0.001) and periapical lesions (P < 0.001), mean mesial-distal (P < 0.001) and coronal-apical dimension of the lesion (if present; P < 0.001) and the mean number of 'J'-shaped lesions (P < 0.05). The magnitude of the statistical differences (or bias) was greater for maxillary than mandibular molars regarding the number and size of the lesions identified. Correlation values were weaker between PA and CBCT assessments of maxillary molars than for mandibular molars in all parameters assessed. CONCLUSION: There were substantial disagreements between PA and CBCT for assessing the periapical status of molar teeth, especially for the maxillary arch. The findings have implications in periapical diagnosis and for evaluating the outcome of endodontic care. PMID- 23442123 TI - Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice. AB - Changes to innate cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), during aging in healthy or tumor-bearing hosts are not well understood. We compared macrophage subpopulations and MDSCs from healthy young (6-8 weeks) C57BL/6J mice to those from healthy geriatric (24-28 months) mice. Spleens, lymph nodes, and bone marrow of geriatric hosts contained significantly more M2 macrophages and MDSCs than their younger counterparts. Peritoneal macrophages from geriatric, but not young, mice co-expressed CD40 and CX3CR1 that are usually mutually exclusively expressed by M1 or M2 macrophages. Nonetheless, macrophages from geriatric mice responded to M1 or M2 stimuli similarly to macrophages from young mice, although they secreted higher levels of TGF-beta in response to IL-4. We mimicked conditions that may occur within tumors by exposing macrophages from young vs. geriatric mice to mesothelioma or lung carcinoma tumor cell-derived supernatants. While both supernatants skewed macrophages toward the M2-phenotype regardless of age, only geriatric-derived macrophages produced IL-4, suggesting a more immunosuppressive tumor microenvironment will be established in the elderly. Both geriatric- and young-derived macrophages induced allogeneic T-cell proliferation, regardless of the stimuli used, including tumor supernatant. However, only macrophages from young mice induced T-cell IFN-gamma production. We examined the potential of an IL-2/agonist anti-CD40 antibody immunotherapy that eradicates large tumors in young hosts to activate macrophages from geriatric mice. IL-2-/CD40-activated macrophages rescued T-cell production of IFN-gamma in geriatric mice. Therefore, targeting macrophages with IL-2/anti-CD40 antibody may improve innate and T-cell immunity in aging hosts. PMID- 23442124 TI - Concise approach to the carbocyclic core of the naturally occurring sphingomyelinase inhibitor scyphostatin. AB - A flexible strategy toward the carbocyclic core of the naturally occurring sphingomyelinase inhibitor scyphostatin, from the readily available Diels-Alder adducts of cyclopentadiene and 2-allyl-p-benzoquinone, has been devised. This approach leverages the stereochemical predisposition of the norbornyl-fused scaffolds to generate the desired stereochemical pattern and leads to a concise synthesis of the epoxycyclohexenoid core of scyphostatin with a manipulable allyl side arm. PMID- 23442125 TI - Reconstructing past changes in locus-specific recombination rates. AB - BACKGROUND: Recombination rates vary at the level of the species, population and individual. Now recognized as a transient feature of the genome, recombination rates at a given locus can change markedly over time. Existing inferential methods, predominantly based on linkage disequilibrium patterns, return a long term average estimate of past recombination rates. Such estimates can be misleading, but no analytical framework to infer recombination rates that have changed over time is currently available. RESULTS: We apply coalescent modeling in conjunction with a suite of summary statistics to show that the recombination history of a locus can be reconstructed from a time series of genetic samples. More usefully, we describe a new method, based on n-tuple dataset subsampling, to infer past changes in recombination rate from DNA sequences taken at a single time point. This subsampling strategy can correctly assign simulated loci to constant, increasing and decreasing recombination models with an accuracy of 84%. CONCLUSIONS: While providing an important stepping-stone to determining past recombination rates, n-tuple subsampling still exhibits a moderate error rate. Theoretical limitations indicated by coalescent theory suggest that highly accurate inference of past recombination rates will remain challenging. Nevertheless, we show for the first time that reconstructing historic recombination rates is possible in principle. PMID- 23442126 TI - Comparison between microcomputed tomography and cone-beam computed tomography radiologic bone to assess atrophic posterior maxilla density and microarchitecture. AB - PURPOSE: The aim of this study was to analyze the relationship between bone density obtained by cone-beam computed tomography (CBCT) and morphometric parameters of bone analyzed by microcomputed tomography (MU-CT). MATERIAL AND METHODS: An overall of 32 subjects <=8 mm of bone height were included in the study. One site per patient was randomly selected to obtain bone core. Totally, 27 biopsies were available for MU-CT analysis. In addition, CBCT was taken after positioning a previously fabricated acrylic resin template with a 2-mm-diameter metal rod at the randomly selected implant site to study radiographic bone density (RBD). The relationship between MU-CT and CBCT quantitative variable and RBD was analyzed using Spearman correlation. RESULTS: Positive correlations between BV/TV (r = 0.769, P < 0.001), BS/TV (r = 0.563, P = 0.002), Tb.Th (r = 0.491, P = 0.009), Tb.N (r = 0.518, P = 0.005) and vBMD (r = 0.699, P < 0.001) with RBD were identified. On the contrary, BS/BV (r = -0.509, P = 0.006), Tb.Sp (r = -0.539, P = 0.003) and Tb.Pf (r = -0.636, P < 0.001) were negatively correlated with RBD. Moreover, SMI (r = -0.380, P = 0.050) and DA (-0.245, P = 0.217) were negatively correlated but not statistically significant. CONCLUSION: This study demonstrated the correlation between radiographic bone density (RBD) and bone density assessed by MU-CT. Therefore, our data supported the use of CBCT as pre-operative tool for implant treatment planning because it is shown to be reliable to assess atrophic posterior maxilla density and microarchitecture. PMID- 23442127 TI - Two-photon-induced blue shift of core and shell optical transitions in colloidal CdSe/CdS quasi-type II quantum rods. AB - The spectral dependence of the two-photon absorption in CdSe/CdS core/shell nanocrystal heterorods has been studied via two-photon-induced luminescence excitation spectroscopy. We verified that the two-photon absorption in these samples is a purely nonlinear phenomenon, excluding the contribution from multistep linear absorption mediated by defect states. A large absorption cross section was observed for CdSe/CdS core/shell quantum rods, in the range of 10(5) GM (1 GM = 10(-50) cm(4) s phot(-1)), scaling with the total nanocrystal volume and thus independent of the core emission wavelength. In the two-photon luminescence excitation spectra, peaks are strongly blue-shifted with respect to the one-photon absorption peaks, for both core and shell transitions. The experimental results are confirmed by k.p calculations, which attribute the shift to both different parity selection rules that apply to one-photon and two-photon transitions and a low oscillator strength for two-photon transitions close to the ground-state one-photon absorption. In contrast with lead chalcogenide quantum dots, we found no evidence of a breakdown of the optical selection rules, despite the presence of band anisotropy, via the anisotropic hole masses, and the explicitly induced reduction of the electron wave function symmetry via the rod shape of the shell. The anisotropy does lead to an unexpected splitting of the electron P-states in the case of a large CdSe core encapsulated in a thin CdS shell. Hence, tuning of the core and shell dimensions and the concurrent transition from type I to quasi-type II carrier localization enables unprecedented control over the band-edge two-photon absorption. PMID- 23442128 TI - Rivers, refuges and population divergence of fire-eye antbirds (Pyriglena) in the Amazon Basin. AB - The identification of ecological and evolutionary mechanisms that might account for the elevated biotic diversity in tropical forests is a central theme in evolutionary biology. This issue is especially relevant in the Neotropical region, where biological diversity is the highest in the world, but where few studies have been conducted to test factors causing population differentiation and speciation. We used mtDNA sequence data to examine the genetic structure within white-backed fire-eye (Pyriglena leuconota) populations along the Tocantins River valley in the south-eastern Amazon Basin, and we confront the predictions of the river and the Pleistocene refuge hypotheses with patterns of genetic variation observed in these populations. We also investigated whether these patterns reflect the recently detected shift in the course of the Tocantins River. We sampled a total of 32 individuals east of, and 52 individuals west of, the Tocantins River. Coalescent simulations and phylogeographical and population genetics analytical approaches revealed that mtDNA variation observed for fire eye populations provides little support for the hypothesis that populations were isolated in glacial forest refuges. Instead, our data strongly support a key prediction of the river hypothesis. Our study shows that the Tocantins River has probably been the historical barrier promoting population divergence in fire-eye antbirds. Our results have important implications for a better understanding of the importance of large Amazonian rivers in vertebrate diversification in the Neotropics. PMID- 23442131 TI - L-cysteine efflux in erythrocytes as a function of human age: correlation with reduced glutathione and total anti-oxidant potential. AB - Thiol compounds such as cysteine (Cys) and reduced glutathione (GSH) play an important role in human aging and age-related diseases. In erythrocytes, GSH is synthesized by glutamic acid, cysteine, and glycine, but the rate of GSH synthesis is determined only by the availability of L-cysteine. Cysteine supplementation has been shown to ameliorate several parameters that are known to degenerate during human aging. We have studied L-cysteine efflux in vitro in human erythrocytes as a function of age by suspending cells in solution containing 10 mM L-cysteine for uptake; later cells were re-suspended in phosphate-buffered saline (PBS)-glucose to allow efflux. Change in the free sulfhydryl (-SH) concentration was then measured to calculate the rate of efflux. The GSH/oxidized glutathione (GSSG) ratio was taken as a control to study the oxidation/reduction state of the erythrocyte. The total anti-oxidant potential of plasma was measured in terms of ferric reducing ability of plasma (FRAP) values. We have shown a significant (p<0.0001) decline in the efflux of L-cysteine in erythrocytes during human aging, and the GSH/GSSG ratio decreases as a function of human age. The decline in L-cysteine efflux during aging correlates with the decrease in GSH and the FRAP value. This finding may help to explain the shift in the redox status and low GSH concentration that might determine the rate of L cysteine efflux observed in erythrocytes and an important factor in the development of oxidative stress in erythrocytes during aging. PMID- 23442130 TI - Sum of the parts: mass spectrometry-based metabolomics. AB - Metabolomics is a rapidly growing field of research used in the identification and quantification of the small molecule metabolites within an organism, thereby providing insights into cell metabolism and bioenergetics as well as processes important in clinical medicine, such as disposition of pharmaceutical compounds. It offers comprehensive information about thousands of low-molecular mass compounds (<1500 Da) that represent a wide range of pathways and intermediary metabolism. Because of its vast expansion in the past two decades, mass spectrometry has become an indispensable tool in "omic" analyses. The use of different ionization techniques such as the more traditional electrospray and matrix-assisted laser desorption, as well as recently popular desorption electrospray ionization, has allowed the analysis of a wide range of biomolecules (e.g., peptides, proteins, lipids, and sugars), and their imaging and analysis in the original sample environment in a workup free fashion. An overview of the current state of the methodology is given, as well as examples of application. PMID- 23442132 TI - Right diaphragmatic hernia after liver transplant in pediatrics: a case report and review of the literature. AB - Diaphragmatic hernias (DH) are an unusual complication after pediatric liver transplantation; however, they have been reported with increased frequency in the past few years. DHs are responsible for nearly half of the small bowel obstructions requiring surgical intervention in this patient population. It has been suggested that the use of a left lobe liver graft, surgical trauma, malnourishment, elevated intra-abdominal pressures, and mTor inhibitors may predispose to development of DH. The use of a segmental graft may increase the recognition of diaphragmatic hernia because the surgically damaged right hemi diaphragm often remains exposed to underlying viscera, instead of being covered by the right hepatic lobe. Treatment is surgical reduction, with up to 20% of the patients requiring resection of the herniated intestine. Herein we describe a case of DH after left segmental liver transplant in a two- yr-old boy that presented one month post left lobe split liver transplant with abdominal pain, anorexia, and respiratory distress. Just like in the majority of the reported cases, an urgent laparotomy with primary repair was performed. No resection of the herniated segment of intestine was required. For pediatric patients with otherwise unexplained respiratory or gastrointestinal symptoms after a left lateral segment liver transplant, right-sided diaphragmatic hernias should always be high in the differential diagnosis. PMID- 23442133 TI - Factors influencing pharmacy services in opioid substitution treatment. AB - INTRODUCTION AND AIM: Heroin dependence is a serious health burden in Australia. Opioid substitution treatment (OST) has been delivered in Australian community pharmacies since 1985. The effectiveness of pharmacy-based OST is evident and the demand is increasing; however, the participation rate of community pharmacies is low, with over 60% non-providers. While previous Australian studies have focused on perspectives of community pharmacists providing the service, the views of non providers have not yet been explored. This study aimed to further investigate factors influencing pharmacists' participation in provision of OST in the community pharmacy setting in New South Wales, Australia. DESIGN AND METHODS: Semi-structured interviews were conducted with 35 NSW community pharmacists (20 providers, 15 non-providers). Transcripts of interviews were thematically analysed. RESULTS: Factors influencing non-providers were mainly stigma and fear, the nature of an opt-in scheme, professionals' moral responsibilities, lack of awareness and knowledge, disproportionate distribution of clients and lack of financial support for OST clients. Providers were motivated by positive attitudes, functional relationships with OST clients/stakeholders, professional satisfaction and financial rewards. Recommendations to improve participation in OST services were offered by both groups. DISCUSSION AND CONCLUSION: This study explored views from both OST providers and non-providers, revealing a number of previously undocumented barriers that affect the uptake of OST provision in New South Wales community pharmacies. There were also profound ethical issues raised for consideration. These findings may help inform future policies aimed at encouraging pharmacists' provision of OST, to address the unmet needs of the ever increasing number of heroin-dependent clients in the community. PMID- 23442134 TI - Biological treatments for moderate-to-severe psoriasis: indirect comparison. AB - WHAT IS KNOWN AND OBJECTIVE: Psoriasis is a chronic skin disease for which there is an increasing range of treatment options. Biological agents (ustekinumab, adalimumab, infliximab and etanercept) are indicated for moderate-to-severe plaque-type psoriasis in adults who fail to respond to, have a contraindication to, or are intolerant to other systemic therapies including cyclosporine, methotrexate and PUVA Unfortunately, with new drugs, the pivotal trials leading to their licensing are often placebo-controlled trials rather than comparative trials vs. established therapies. Therefore, inference on comparative effectiveness of the newer agents must be derived indirectly, through estimation of effects of the new agents vs. a common comparator. The objective of this study is to compare the relative efficacy of the biological agents through a systematic review of the indirect clinical trial evidence. METHODS: A systematic literature search was performed for clinical trials of biological agents in psoriasis. Pivotal, randomized, double-blind, controlled (placebo) trials using intention-to treat analysis were selected for detailed analysis. Trials must include PASI 75 as a primary end point. The indirect comparison was performed using the method of Bucher adjusted with the ITC calculator (Indirect Treatment Comparisons of the Canadian Agency for Drugs and Technologies in Health), etanercept being the reference drug. We defined delta value for therapeutic equivalence as a difference in the efficacy of 25% among the different treatment options. RESULTS AND DISCUSSION: Fourteen studies (four for ustekinumab, three for adalimumab, three for infliximab and four for etanercept) were included. The indirect comparison results reveal that ustekinumab, adalimumab and infliximab were statistically superior to etanercept with an absolute risk difference for PASI 75 of 12% (95% CI = 5.9-18%), 11% (95% CI = 5.3-16.7%) and 24% (29.7-18.3%) respectively. However, in all situations, the 95% confidence interval does not achieve clinical relevance as no delta exceeds the previously set value (25%). WHAT IS NEW AND CONCLUSION: Ustekinumab, adalimumab, infliximab and etanercept can be regarded as clinical equivalents for the treatment of psoriasis. Choice between these agents therefore depends on their relative safety profiles, individual contra-indications and cost effectiveness. PMID- 23442135 TI - Changes to DNA methylation and homologous recombination frequency in the progeny of stressed plants. AB - Plants undergo changes in response to biotic and abiotic stresses that help them adjust and survive. Some of these changes may even be passed on to progeny and eventually lead to adaptive evolution. Transgenerational changes in response to stress include alterations in DNA methylation and changes in homologous recombination frequency (HRF). The progeny of plants that were stressed often show elevated HRF as well as genomic hypermethylation, although specific loci that are beneficial in times of stress may be hypomethylated. One of the possible mechanisms responsible for passing the memory to the progeny involves small interfering RNAs; Dicer-like proteins, DCL2 and DCL3, are in part required for this process. However, while epigenetic modifications are often present in the untreated progeny of stressed plants, they are not usually sustained for multiple unexposed generations. Still, transgenerational inheritance of such changes has already begun to provide evidence for an important role of epigenetics in enhancing stress resistance. PMID- 23442136 TI - Dynamics and stability: epigenetic conversions in position effect variegation. AB - Position effect variegation (PEV) refers to quasi-stable patterns of gene expression that are observed at specific loci throughout the genomes of eukaryotes. The genes subjected to PEV can be completely silenced or fully active. Stochastic conversions between these 2 states are responsible for the variegated phenotypes. Positional variegation is used by human pathogens (Trypanosoma, Plasmodium, and Candida) to evade the immune system or adapt to the host environment. In the yeasts Saccharomyces cerevisiae and Saccharomyces pombe, telomeric PEV aids the adaptation to a changing environment. In metazoans, similar epigenetic conversions are likely to accompany cell differentiation and the setting of tissue-specific gene expression programs. Surprisingly, we know very little about the mechanisms of epigenetic conversions. In this article, earlier models on the nature of PEV are revisited and recent advances on the dynamic nature of chromatin are reviewed. The normal dynamic histone turnover during transcription and DNA replication and its perturbation at transcription and replication pause sites are discussed. It is proposed that such perturbations play key roles in epigenetic conversions and in PEV. PMID- 23442137 TI - Biological embedding in mental health: an epigenomic perspective. AB - Human epidemiological studies and studies of animal models provide many examples by which early life experiences influence health in a long-term manner, a concept known as biological embedding. Such experiences can have profound impacts during periods of high plasticity in prenatal and early postnatal life. Epigenetic mechanisms influence gene function in the absence of changes in gene sequence. In contrast to the relative stability of gene sequences, epigenetic mechanisms appear, at least to some extent, responsive to environmental signals. To date, a few examples appear to clearly link early social experiences to epigenetic changes in pathways relevant for mental health in adulthood. Our recent work using high-throughput epigenomic techniques points to large-scale changes in gene pathways in addition to candidate genes involved in the response to psychosocial stress and neuroplasticity. Elucidation of which pathways are epigenetically labile under what conditions will enable a more complete understanding of how the epigenome can mediate environmental interactions with the genome that are relevant for mental health. In this mini-review, we provide examples of nascent research into the influence of early life experience on mental health outcomes, discuss evidence of epigenetic mechanisms that may underlie these effects, and describe challenges for research in this area. PMID- 23442138 TI - Nuclear organization of RNA polymerase II transcription. AB - Transcription occurs at distinct nuclear compartments termed transcription factories that are specialized for transcription by 1 of the 3 polymerase complexes (I, II, or III). Protein-coding genes appear to move in and out of RNA polymerase II (RNAPII) compartments as they are expressed and silenced. In addition, transcription factories are sites where several transcription units, either from the same chromosome or different chromosomes, are transcribed. Chromosomes occupy distinct territories in the interphase nucleus with active genes preferentially positioned on the periphery or even looped out of the territory. These chromosome territories have been observed to intermingle in the nucleus, and multiple interactions among different chromosomes have been identified in genome-wide studies. Deep sequencing of the transcriptome and RNAPII associated on DNA obtained by chromatin immunoprecipitation have revealed a plethora of noncoding transcription and intergenic accumulations of RNAPII that must also be considered in models of genome function. The organization of transcription into distinct regions of the nucleus has changed the way we view transcription with the evolving model for silencing or activation of gene expression involving physical relocation of the transcription unit to a silencing or activation compartment, thus, highlighting the need to consider the process of transcription in the 3-dimensional nuclear space. PMID- 23442140 TI - The heat shock response: A case study of chromatin dynamics in gene regulation. AB - Recent studies in transcriptional regulation using the Drosophila heat shock response system have elucidated many of the dynamic regulatory processes that govern transcriptional activation and repression. The classic view that the control of gene expression occurs at the point of RNA polymerase II (Pol II) recruitment is now giving way to a more complex outlook of gene regulation. Promoter chromatin dynamics coordinate with transcription factor binding to maintain the promoters of active genes accessible. For a large number of genes, the rate-limiting step in Pol II progression occurs during its initial elongation, where Pol II transcribes 30-50 bp and pauses for further signals. These paused genes have unique genic chromatin architecture and dynamics compared with genes where Pol II recruitment is rate limiting for expression. Further elongation of Pol II along the gene causes nucleosome turnover, a continuous process of eviction and replacement, which suggests a potential mechanism for Pol II transit along a nucleosomal template. In this review, we highlight recent insights into transcription regulation of the heat shock response and discuss how the dynamic regulatory processes involved at each transcriptional stage help to generate faithful yet highly responsive gene expression. PMID- 23442142 TI - "Extreme" renal preservation: neoadjuvant chemotherapy and percutaneous resection for upper-tract urothelial carcinoma in a patient with solitary kidney--a case report. AB - BACKGROUND AND PURPOSE: Renal preservation in selected patients with upper-tract urothelial cancer (UTUC) has been well described, offering an alternative to radical nephroureterectomy. We present our experiences in performing percutaneous treatments after neoadjuvant chemotherapy in one such patient with a large, complex, high-grade UTUC in a solitary kidney. CASE REPORT: A 55-year-old woman with a solitary kidney presented with a 5.2 cm enhancing mass with calcifications involving the left renal pelvis and lower pole. Cystoscopy and retrograde pyelography demonstrated normal bladder mucosa. Ureteroscopy revealed a large, papillary tumor occupying the renal pelvis. Ureteroscopic treatment was deemed impossible because of the lesion's volume. We proceeded with percutaneous resection after downsizing the tumor after a course of neoadjuvant chemotherapy. Using a 25F resectoscope via a percutaneous tract, resection was performed to fully excise the tumor, and the patient received two postoperative chemotherapy courses. A recurrence developed within an isolated calix 8 months postoperatively, which was also managed percutaneously. CONCLUSION: A multimodal approach in a highly motivated patient could represent a reasonable strategy for patients in whom such a therapy is desired. PMID- 23442143 TI - Sympathetic skin responses from the scalp evoked by electrical stimulation in seborrheic dermatitis. AB - Although the role of autonomic nervous system in seborrheic dermatitis (SD) is still unclear, seborrhea is sometimes accepted as a sign of autonomic dysfunction in several nervous system diseases. Therefore, we aimed to investigate the sympathetic nervous system (SNS) activity in SD by recording sympathetic skin responses (SSR) from the scalp (S-SSR). Thirty-one control subjects and 22 SD patients were studied by evoking right and left S-SSR with electrical stimulation of the right median nerve at the wrist. Mean latencies and maximum amplitudes were calculated for both sides in each group. In seven out of 31 control subjects and in 13 out of 22 patients, the S-SSR could not be elicited on either side. There were four subjects with unilateral response in the patient group. There were significantly more non-responders among the patients with SD (P < 0.000). This study suggests that in SD, the autonomic nervous system may be involved. The S-SSR is a new site for recording SSR. The responses are relatively symmetrical and can be evoked easily by electrical stimulation, and may be used to evaluate the SNS function in SD patients and also in healthy subjects. PMID- 23442139 TI - XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair. AB - DNA double strand breaks (DSBs), induced by ionizing radiation (IR) and endogenous stress including replication failure, are the most cytotoxic form of DNA damage. In human cells, most IR-induced DSBs are repaired by the nonhomologous end joining (NHEJ) pathway. One of the most critical steps in NHEJ is ligation of DNA ends by DNA ligase IV (LIG4), which interacts with, and is stabilized by, the scaffolding protein X-ray cross-complementing gene 4 (XRCC4). XRCC4 also interacts with XRCC4-like factor (XLF, also called Cernunnos); yet, XLF has been one of the least mechanistically understood proteins and precisely how XLF functions in NHEJ has been enigmatic. Here, we examine current combined structural and mutational findings that uncover integrated functions of XRCC4 and XLF and reveal their interactions to form long, helical protein filaments suitable to protect and align DSB ends. XLF-XRCC4 provides a global structural scaffold for ligating DSBs without requiring long DNA ends, thus ensuring accurate and efficient ligation and repair. The assembly of these XRCC4-XLF filaments, providing both DNA end protection and alignment, may commit cells to NHEJ with general biological implications for NHEJ and DSB repair processes and their links to cancer predispositions and interventions. PMID- 23442144 TI - Microbial degradation of an organophosphate pesticide, malathion. AB - Organophosphorus pesticide, malathion, is used in public health, residential, and agricultural settings worldwide to control the pest population. It is proven that exposure to malathion produce toxic effects in humans and other mammals. Due to high toxicity, studies are going on to design effective methods for removal of malathion and its associated compounds from the environment. Among various techniques available, degradation of malathion by microbes proves to be an effective and environment friendly method. Recently, research activities in this area have shown that a diverse range of microorganisms are capable of degrading malathion. Therefore, we aimed at providing an overview of research accomplishments on this subject and discussed the toxicity of malathion and its metabolites, various microorganisms involved in its biodegradation and effect of various environmental parameters on its degradation. PMID- 23442146 TI - Effect of low intensity pulsed ultrasound stimulation on sinus augmentation in rabbits. AB - OBJECTIVES: The objective of the present study was to evaluate the efficacy of low intensity pulsed ultrasound stimulation (LIPUS) and to determine the optimal frequency for enhancing bone regeneration in sinus augmentation using a rabbit model. MATERIAL AND METHODS: Thirty male rabbits underwent sinus augmentation. Two rectangular nasal bone windows were outlined bilaterally. LIPUS was applied at two different frequencies (1 MHz and 3 MHz) on experimental sites daily for 2, 4 and 8 weeks. Each histological area of the experimental and control sites was divided into upper and lower parts from the parietal region to a depth of 5 mm. Each area of new bone was measured. RESULTS: At 2, 4 and 8 weeks, the experimental sites in the 1 MHz group exhibited significantly more new bone growth than the control sites in both the upper and lower parts. When the upper and lower parts of each area were measured in combination there was a statistical difference between the test and control sites in the 1 MHz group at 2, 4 and 8 weeks; however, there were no statistical differences between the test and control sites in the 3 MHz group. CONCLUSIONS: The results suggest that clinical application of LIPUS for sinus augmentation may promote new bone formation, and that the effect of LIPUS for sinus augmentation at a frequency of 1 MHz was greater than at 3 MHz until 8 weeks after sinus augmentation. PMID- 23442147 TI - Nanomechanical properties of proteins and membranes depend on loading rate and electrostatic interactions. AB - Knowing the dynamic mechanical response of tissue, cells, membranes, proteins, nucleic acids, and carbohydrates to external perturbations is important to understand various biological and biotechnological problems. Atomic force microscopy (AFM)-based approaches are the most frequently used nanotechnologies to determine the mechanical properties of biological samples that range in size from microscopic to (sub)nanoscopic. However, the dynamic nature of biomechanical properties has barely been addressed by AFM imaging. In this work, we characterizethe viscoelastic properties of the native light-driven proton pump bacteriorhodopsin of the purple membrane of Halobacterium salinarum. Using force distance curve (F-D)-based AFM we imaged purple membranes while force probing their mechanical response over a wide range of loading rates (from ~0.5 to 100 MUN/s). Our results show that the mechanical stiffness of protein and membrane increases with the loading rate up to a factor of 10 (from ~0.3 to 3.2 N/m). In addition, the electrostatic repulsion between AFM tip and sample can alter the mechanical stiffness measured by AFM up to ~60% (from ~0.8 to 1.3 N/m).These findings indicate that the mechanical response of membranes and proteins and probably of other biomolecular systems should be determined at different loading rates to fully understand their properties. PMID- 23442145 TI - Acid-induced mechanism change and overpotential decrease in dioxygen reduction catalysis with a dinuclear copper complex. AB - Catalytic four-electron reduction of O2 by ferrocene (Fc) and 1,1' dimethylferrocene (Me2Fc) occurs efficiently with a dinuclear copper(II) complex [Cu(II)2(XYLO)(OH)](2+) (1), where XYLO is a m-xylene-linked bis[(2-(2 pyridyl)ethyl)amine] dinucleating ligand with copper-bridging phenolate moiety], in the presence of perchloric acid (HClO4) in acetone at 298 K. The hydroxide and phenoxo group in [Cu(II)2(XYLO)(OH)](2+) (1) undergo protonation with HClO4 to produce [Cu(II)2(XYLOH)](4+) (2) where the two copper centers become independent and the reduction potential shifts from -0.68 V vs SCE in the absence of HClO4 to 0.47 V; this makes possible the use of relatively weak one-electron reductants such as Fc and Me2Fc, significantly reducing the effective overpotential in the catalytic O2-reduction reaction. The mechanism of the reaction has been clarified on the basis of kinetic studies on the overall catalytic reaction as well as each step in the catalytic cycle and also by low-temperature detection of intermediates. The O2-binding to the fully reduced complex [Cu(I)2(XYLOH)](2+) (3) results in the reversible formation of the hydroperoxo complex ([Cu(II)2(XYLO)(OOH)](2+)) (4), followed by proton-coupled electron-transfer (PCET) reduction to complete the overall O2-to-2H2O catalytic conversion. PMID- 23442148 TI - Implantable three-dimensional salivary spheroid assemblies demonstrate fluid and protein secretory responses to neurotransmitters. AB - Radiation treatment in patients with head and neck tumors commonly results in hyposalivation and xerostomia due to the loss of fluid-secreting salivary acinar cells. Patients develop susceptibility to oral infections, dental caries, impaired speech and swallowing, reducing the quality of life. Clinical management is largely unsatisfactory. The development of a tissue-engineered, implantable salivary gland will greatly benefit patients suffering from xerostomia. This report compares the ability of a 2.5-dimensional (2.5D) and a three-dimensional (3D) hyaluronic acid (HA)-based culture system to support functional salivary units capable of producing fluid and phenotypic proteins. Parotid cells seeded on 2.5D, as well as those encapsulated in 3D HA hydrogels, self-assembled into acini like structures and expressed functional neurotransmitter receptors. Structures in 3D hydrogels merged to form organized 50 MUm spheroids that could be maintained in culture for over 100 days and merged to form structures over 500 MUm in size. Treatment of acini-like structures with the beta-adrenergic agonists norepinephrine or isoproterenol increased granule production and alpha-amylase staining in treated structures, demonstrating regain of protein secretion. Upon treatment with the M3 muscarinic agonist acetylcholine, acini-like structures activated the fluid production pathway by increasing intracellular calcium levels. The increase in intracellular calcium seen in structures in the 3D hydrogel culture system was more robust and prolonged than that in 2.5D. To compare the long-term survival and retention of acini-like structures in vivo, cell-seeded 2.5D and 3D hydrogels were implanted into an athymic rat model. Cells in 2.5D failed to maintain organized acini-like structures and dispersed in the surrounding tissue. Encapsulated cells in 3D retained their spheroid structure and structural integrity, along with the salivary biomarkers and maintained viability for over 3 weeks in vivo. This report identifies a novel hydrogel culture system capable of creating and maintaining functional 3D salivary spheroid structures for long periods in vitro that regain both fluid and protein secreting functions and are suitable for tissue restoration. PMID- 23442149 TI - WormFarm: a quantitative control and measurement device toward automated Caenorhabditis elegans aging analysis. AB - Caenorhabditis elegans is a leading model organism for studying the basic mechanisms of aging. Progress has been limited, however, by the lack of an automated system for quantitative analysis of longevity and mean lifespan. To address this barrier, we developed 'WormFarm', an integrated microfluidic device for culturing nematodes. Cohorts of 30-50 animals are maintained throughout their lifespan in each of eight separate chambers on a single WormFarm polydimethylsiloxane chip. Design features allow for automated removal of progeny and efficient control of environmental conditions. In addition, we have developed computational algorithms for automated analysis of video footage to quantitate survival and other phenotypes, such as body size and motility. As proof-of principle, we show here that WormFarm successfully recapitulates survival data obtained from a standard plate-based assay for both RNAi-mediated and dietary induced changes in lifespan. Further, using a fluorescent reporter in conjunction with WormFarm, we report an age-associated decrease in fluorescent intensity of GFP in transgenic worms expressing GFP tagged with a mitochondrial import signal under the control of the myo-3 promoter. This marker may therefore serve as a useful biomarker of biological age and aging rate. PMID- 23442150 TI - qDTY12.1: a locus with a consistent effect on grain yield under drought in rice. AB - BACKGROUND: Selection for grain yield under drought is an efficient criterion for improving the drought tolerance of rice. Recently, some drought-tolerant rice varieties have been developed using this selection criterion and successfully released for cultivation in drought-prone target environments. The process can be made more efficient and rapid through marker-assisted breeding, a well-known fast track approach in crop improvement. QTLs have been identified for grain yield under drought with large effects against drought-susceptible varieties. Most of the identified QTLs show large QTL * environment or QTL * genetic background interactions. The development of mapping populations in the background of popular high-yielding varieties, screening across environments, including the target environments, and the identification of QTLs with a consistent effect across environments can be a suitable alternative marker-assisted breeding strategy. An IR74371-46-1-1 * Sabitri backcross inbred line population was screened for reproductive-stage drought stress at the International Rice Research Institute, Philippines, and Regional Agricultural Research Station, Nepalgunj, Nepal, in the dry and wet seasons of 2011, respectively. A bulk segregant analysis approach was used to identify markers associated with high grain yield under drought. RESULTS: A QTL, qDTY12.1, significantly associated with grain yield under reproductive stage drought stress was identified on chromosome 12 with a consistent effect in two environments: IRRI, Philippines, and RARS, Nepalgunj, Nepal. This QTL explained phenotypic variance of 23.8% and contributed an additive effect of 45.3% for grain yield under drought. The positive QTL allele for qDTY12.1 was contributed by tolerant parent IR74371-46-1-1. CONCLUSIONS: In this study, qDTY12.1 showed a consistent effect across environments for high grain yield under lowland reproductive-stage drought stress in the background of popular high yielding but drought-susceptible recipient variety Sabitri. qDTY12.1 was also reported previously [Crop Sci 47:507-516, 2007] to increase grain yield under upland reproductive-stage drought stress situations. qDTY12.1 is the only QTL reported so far in rice to have shown a large effect against multiple recipient genetic backgrounds as well as under highly diverse upland and lowland rice ecosystems. qDTY12.1 can be successfully introgressed to improve grain yield under drought of popular high-yielding but drought-susceptible lowland as well as upland adapted varieties following marker-assisted breeding. PMID- 23442151 TI - Phenol formation in gamma radiolysis of aqueous benzene solution with sodium hypochlorite. AB - Phenol formation by gamma radiolysis of an aqueous benzene solution containing sodium hypochlorite is reported. The phenol formation in a benzene solution containing sodium hypochlorite irradiated with (60)Co gamma-rays is about six times higher than that without sodium hypochlorite. Ten micromolar sodium hypochlorite enhanced the formation of phenol up to a total dose of 6 Gy. Above 6 Gy in solutions containing sodium hypochlorite, the rate of phenol yield sharply decreased and was essentially the same as that without sodium hypochlorite. The yield of phenol with sodium hypochlorite is 0.89 MUmol J(-1) and is larger than the sum of yield for the radicals and reactive oxygen species by water radiolysis such as *OH, e(-), H, H2, and H2O2. The formation of phenol with sodium hypochlorite was reduced by NaCl. Results suggest that the radiolytic formation of phenol in a benzene solution with sodium hypochlorite relates to the reaction process involving chlorine atoms. Sodium hypochlorite can be applied as a sensitizer for a benzene chemical dosimetry system. The lower limit of dose detection calculated from the detection limit of phenol and the G value of phenol was estimated to be 1 * 10(-3) Gy. PMID- 23442153 TI - Peroxiredoxin 5 links mitochondrial redox signalling with calcium dynamics: impact on Parkinson's disease. PMID- 23442152 TI - Functional and molecular expression of the proton-coupled oligopeptide transporters in spleen and macrophages from mouse and human. AB - The aim of this study was to determine the expression and function of proton coupled oligopeptide transporters (POTs) in spleen and macrophages and their contribution to innate immune response induced by bacterial peptidomimetics gamma iE-DAP and MDP. Quantitative real-time PCR (qRT-PCR) and Western blot results revealed the mRNA and protein expression of PepT2, PhT1, and PhT2, but not PepT1, in the spleen of mice and humans. In comparison to lymphocytes of the spleen, macrophages had higher transcript levels of PepT2 and PhT2. The cellular uptake of Ala-Lys-AMCA in mouse splenic macrophages was pH-dependent with maximum uptake at pH 6.0, and the kinetic parameters were K(m) = 75.5 +/- 14.3 MUM and V(max) = 25.4 +/- 2.1 pmol/min per mg protein. The uptake of Ala-Lys-AMCA by mouse splenic macrophages was not inhibited by histidine but was significantly inhibited by glycyl-sarcosine (GlySar) and carnosine (P < 0.01), and by bacterial peptidomimetics gamma-iE-DAP and MDP, ligands of nucleotide-binding oligomerization domain (NOD)-containing proteins. Carnosine and GlySar, but not histidine, attenuated the inflammatory response induced by gamma-iE-DAP and MDP in mouse splenic macrophages. Functional expression of POTs was also demonstrated in THP-1 cells, and dipeptides reduced the immune response induced by gamma-iE DAP. In conclusion, our findings are novel by providing important information on the molecular and functional expression of POTs in the spleen. Moreover, it appears that the PepT2-mediated uptake of gamma-iE-DAP and MDP in macrophages further contributes to the innate immune response. PMID- 23442154 TI - Characterization of the sterol 14alpha-demethylases of Fusarium graminearum identifies a novel genus-specific CYP51 function. AB - CYP51 encodes the cytochrome P450 sterol 14alpha-demethylase, an enzyme essential for sterol biosynthesis and the target of azole fungicides. In Fusarium species, including pathogens of humans and plants, three CYP51 paralogues have been identified with one unique to the genus. Currently, the functions of these three genes and the rationale for their conservation within the genus Fusarium are unknown. Three Fusarium graminearum CYP51s (FgCYP51s) were heterologously expressed in Saccharomyces cerevisiae. Single and double FgCYP51 deletion mutants were generated and the functions of the FgCYP51s were characterized in vitro and in planta. FgCYP51A and FgCYP51B can complement yeast CYP51 function, whereas FgCYP51C cannot. FgCYP51A deletion increases the sensitivity of F. graminearum to the tested azoles. In DeltaFgCYP51B and DeltaFgCYP51BC mutants, ascospore formation is blocked, and eburicol and two additional 14-methylated sterols accumulate. FgCYP51C deletion reduces virulence on host wheat ears. FgCYP51B encodes the enzyme primarily responsible for sterol 14alpha-demethylation, and plays an essential role in ascospore formation. FgCYP51A encodes an additional sterol 14alpha-demethylase, induced on ergosterol depletion and responsible for the intrinsic variation in azole sensitivity. FgCYP51C does not encode a sterol 14alpha-demethylase, but is required for full virulence on host wheat ears. This is the first example of the functional diversification of a fungal CYP51. PMID- 23442155 TI - Effect of narrowband ultraviolet B phototherapy on melanocytic naevi. AB - BACKGROUND: Melanocytic naevi have been observed to undergo morphological changes following exposure to narrowband ultraviolet (NB-UV)B radiation. OBJECTIVES: To analyse changes in naevi exposed to NB-UVB in a large cohort of patients. METHODS: Subjects referred for phototherapy had macroscopic and dermoscopic images taken of prominent melanocytic naevi at the following time points: immediately prior to NB-UVB treatment, after 10 exposures, after 30 exposures or at the end of treatment if earlier, and 3 months after discontinuing treatment. Four dermatologists, by consensus, examined each naevus for specific clinical and dermoscopic features at each time point. The size (area) of each naevus was determined by plenimetry. RESULTS: Complete sets of images were taken for 36 out of 51 patients. The most common global dermoscopic patterns in the 440 naevi examined were reticular (50%) and globular (32%). Following NB-UVB exposure, blurring or merging of lines was observed in 45% of reticular naevi. An increase in colour intensity and in the number of dots or globules was observed in 63% of globular naevi, and 167 naevi (40%) underwent a change in size. Of these, 91/167 (54%) decreased in size, with a median area reduction of 8% (0.9-42%); while 76/167 (46%) increased in size, with a median area increase of 9% (1-76%). CONCLUSIONS: Around half of naevi exposed to a course of NB-UVB treatment undergo size or morphological changes. Naevi that enlarged tended to revert to pretreatment size 3 months after discontinuation of phototherapy. PMID- 23442157 TI - Exploring a novel ultrafine particle counter for utilization in respiratory protection studies. PMID- 23442156 TI - The influence of fetal ethanol exposure on subsequent development of the cerebral cortex as revealed by magnetic resonance imaging. AB - BACKGROUND: Fetal alcohol syndrome and related disorders (commonly referred to as fetal alcohol spectrum disorder, or FASD) cause significant hardships to the individuals affected. Previously, histological studies in animals have characterized developmental cerebral cortical abnormalities that result from prenatal ethanol (EtOH) exposure. Additionally, magnetic resonance imaging (MRI) studies have identified abnormalities associated with fetal EtOH exposure in the cerebral cortices of human children and adolescents. However, there is still a need to bridge the gap between human MRI studies and animal histological studies. The goal of the research presented here was to perform postmortem MRI experiments on rodents, during time periods relative to late human gestation through adulthood, to characterize anomalies associated with FASD throughout development. Additionally, by determining how histologically identified abnormalities are manifest in MRI measurements specifically during the critical early time points, neuroimaging-based biomarkers of FASD can potentially be identified at much earlier ages in humans, thus reducing the impact of these disorders. METHODS: Cerebral cortical volume, thickness, and surface area were characterized by ex vivo MRI in Long-Evans rat pups born from dams that were EtOH-treated, maltose/dextrin-treated, or untreated throughout gestation at 6 developmental time points (postnatal day [P] 0, P3, P6, P11, P19, and P60). RESULTS: Brain volume, isocortical volume, isocortical thickness, and isocortical surface area were all demonstrated to be reduced following prenatal exposure to EtOH. Significant differences among the treatment groups were observed throughout the range of time points studied, allowing for a comprehensive view of FASD influenced MRI outcomes throughout development. Isocortical surface area and isocortical thickness results contributed independent information important to interpreting effects of prenatal EtOH exposure on cerebral cortical development. Additionally, regional patterns in cortical thickness differences suggested primary sensory areas were particularly vulnerable to gestational EtOH exposure. CONCLUSIONS: Structural MRI measurements were in accordance with previous histological studies performed in animal models of FASD. In addition to establishing a summary of MRI outcomes throughout development in FASD, this research suggests that MRI techniques are sufficiently sensitive to detect neuroanatomical effects of fetal EtOH exposure on development of the cerebral cortex during the period of time corresponding to late gestation in humans. Importantly, this research provides a link between animal histological data and human MRI data. PMID- 23442158 TI - The RNA aptamer inhibiting human vesicular endothelial growth factor receptor 1 without affecting cytokine binding. AB - Angiogenesis, a process of new blood vessel formation, is crucial not only for many physiological events but also for a number of diseases. The signaling pathways through members of the vesicular endothelial growth factor (VEGF) family play fundamental roles in angiogenesis. In this study, we identified inhibitory RNA aptamers against human Flt-1, a receptor of VEGF. One of the isolates, aptamer #38, showed a 50% inhibitory concentration (IC50) of 23 nM in the cell based autophosphorylation assay, and the IC50 value was decreased to 6.3 nM upon removal of 32 dispensable nucleotides from parental #38 with a length of 72 nucleotides. Interestingly, the surface plasmon resonance-based or affinity resin based binding study revealed that #38 and its shortened derivative, #38Jr, do not interfere with binding of VEGF or heparin, a functional cofactor, to Flt-1. Importantly, aptamer #38 does not affect the decoy activity of soluble Flt-1. These findings suggest that #38 prevents the conformational activation of Flt-1 associated with VEGF. Therefore, aptamer #38 might provide us with a unique tool for blocking the VEGF signaling specific to Flt-1, unlike most other known VEGF signaling blockers such as VEGF inhibitors, anti-Flt-1 antibodies, and decoy soluble receptors. PMID- 23442159 TI - Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression. AB - Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG) [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non-specific form that lack the specific glioneuronal element. Our aims were to search for BRAF(V600E) mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAF(V600E) mutation with BRAF(V600E) expression and to evaluate their diagnostic and prognostic values. Ninety-six children were included. BRAF(V600E) mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAF(V600E) mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non-specific forms) and PA (12.5%). BRAF(V600E) expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAF(V600E) status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAF(V600E) mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAF(V600E) mutation in all DNT, especially the non-specific forms. PMID- 23442160 TI - Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage IB, II, and III esophageal squamous cell cancer. AB - Local failure after definitive chemoradiotherapy (CRT) for stage IB, II, and III esophageal cancer is one of the causes of poor outcome. Endoscopic mucosal resection (EMR) is an effective treatment for superficial esophageal cancer. However, its feasibility as a salvage treatment for local recurrent or residual tumors after definitive CRT for stage IB, II, and III esophageal cancer remains unclear. Between January 2000 and February 2008, 274 patients with stage IB, II, and III esophageal squamous cell cancer excluding T4 received definitive CRT at the National Cancer Center Hospital, Japan. Of these patients, nine patients with local recurrence after achieving complete response and two patients with residual tumor underwent salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively reviewed the 11 patients (13 lesions). Characteristics of all 11 patients were as follows: median age of 69 (range: 45-78); male/female: 10/1; baseline clinical stage (Union for International Cancer Control 7th) IB/IIA/IIB/III: 1/3/7/0. The depth of resected tumor was limited to the mucosal layer in seven lesions and submucosal in six lesions. En bloc resection was performed on six lesions (46%). The vertical margin was free of cancer cells in 11 lesions (84.6%). No major complications, such as hemorrhage requiring blood transfusion and perforation, were experienced. At a median follow-up period of 38.9 months (range: 5.3-94 months) after salvage EMR, no recurrence was detected in six patients (54%). Local recurrence was detected in five patients (27%). Of these patients, two had lung metastasis simultaneously, and one was also detected lung metastasis 2 months after the detection of local recurrence. The 5-year survival rate after salvage EMR was 41.6%. Salvage EMR is a feasible treatment option for local recurrent or residual lesions after definitive chemotherapy and/or radiotherapy for stage IB, II, and III esophageal squamous cell cancer. PMID- 23442161 TI - Through the looking glass: adventures in kinase inhibitor design and optimization. AB - Developing a viable new drug candidate is difficult. Developing one that is a small molecule kinase inhibitor that binds competitively with respect to ATP with superb selectivity is even more difficult, which makes the design and optimization work described by Jimenez et al. (J. Med. Chem., DOI: 10.1021/jm301465a) particularly remarkable. They took a lead from a high throughput screen against protein kinase C theta (PKCtheta) through a series of optimization steps, culminating in the demonstration of in vivo activity in mice. Having identified and improved the hinge-binding "warhead" at one end of their lead molecule, they proceeded to use structure-based design tools to guide modification of the other end to enhance selectivity over a closely related isoform of the kinase. With that accomplished, they used a series of protection and deprotection maneuvers to modify the central portion of the series scaffold to further enhance potency against the target while also improving pharmacokinetic properties. The project was a success at the preclinical level: oral administration of the ultimate analogue obtained was effective at suppressing interleukin-2 induction in mice. PMID- 23442162 TI - Psychometric properties of the Swedish version of the Scleroderma Health Assessment Questionnaire and the Cochin Hand Function Scale in patients with systemic sclerosis. AB - OBJECTIVES: To translate the visual analogue scales (VAS) in the Scleroderma Health Assessment Questionnaire (SSc HAQ) and the Cochin Hand Function Scale (CHFS) and to examine the reliability and validity of the Swedish versions of the instruments. METHOD: The reproducibility, internal consistency, acceptability, and validity of the instruments were evaluated. Eighty-three consecutive patients participated in the evaluation of the SSc HAQ and 56 in the CHFS. Sixty-six per cent fulfilled the criteria for limited systemic sclerosis (lcSSc) and 29% for diffuse systemic sclerosis (dcSSc). The patients were assessed regarding disease parameters, hand involvement, and quality of life, the latter using the 36-item short form health survey (SF-36). RESULTS: The reproducibility in the HAQ Disability Index (HAQ-DI), the VAS of pulmonary, digital ulcer, and overall disease severity, and in the CHFS was good (intra-class correlation coefficients, ICCs >= 0.75). The internal consistency was high in the HAQ-DI and the CHFS but lower in the VAS. The HAQ-DI showed higher correlations coefficients with physical-related scores in the SF-36 (rs = -0.600) than with mental-related dimensions (rs = -0.235). All VAS showed significant correlation with the item for general health (p < 0.05). The CHFS showed high correlation to hand-related items in the HAQ (rs = 0.858) and moderate correlation to the physical summary score in SF-36 (rs = -0.521). The instruments could not discriminate between lcSSc and dcSSc, although significant correlations between the CHFS and hand involvement (p < 0.05) indicate the ability of the CHFS to discriminate between mild and severe hand involvement. CONCLUSIONS: The Swedish version of the SSc HAQ and the CHFS meet the requirements of reproducibility and concurrent validity. More studies are needed to examine the capacity of these instruments to discriminate between disease severities. PMID- 23442164 TI - Trends in fentanyl prescriptions and fentanyl-related mortality in Australia. AB - INTRODUCTION AND AIMS: The study aims to quantify trends in fentanyl prescribing and fentanyl mortality in Australia within the context of concern among health professionals concerning increasing accessibility of fentanyl, and the harms that may arise as a result. DESIGN AND METHODS: This paper presents data on prescribing patterns of fentanyl by 10 year age group adjusted by population rate, detailed analyses of fentanyl-related deaths from the National Coronial Information System and deaths adjusted for prescribing levels within Australia. RESULTS: Fentany prescriptions have increased and are most prevalent among Australians aged over 80 years. One hundred and thirty-six fentanyl-related deaths were recorded during 2000-2011; 54% of decedents had a history of injecting drug use and, among this group, 95% had injected fentanyl at the time of death; 62% of deaths recorded misuse (most notably injection) of fentanyl; 50% recorded a history of drug dependence and 40% a mental health problem; 37% recorded a history of chronic pain; and 36% recorded fentanyl as being prescribed at the time of death. Deaths were primarily among Australians under 47 years of age. DISCUSSION AND CONCLUSIONS: There have been significant increases in fentanyl prescribing in Australia. It is unclear what proportion of this increase represents legitimate treatment of pain. Fentanyl deaths have also increased, although mortality is currently low in Australia. A large proportion of the deaths involved the injection of diverted fentanyl, highlighting the need for messages regarding safer injecting practices targeting people who inject drugs, and strategies to minimise the risks of diversion. PMID- 23442165 TI - Determinants of HIV/AIDS-related information needs and media use: beyond individual-level factors. AB - Despite the centrality of information and communication in the fight against HIV/AIDS, little research has investigated the factors associated with HIV/AIDS related information needs and media use in hard-hit Sub-Saharan Africa. This study explored individual-level and socioecological determinants among urban and rural residents in northwest Ethiopia. Urbanity versus rurality, education, direct experience with HIV/AIDS, perceived salience of HIV/AIDS-related information, and personal health concern were tested as predictors. Regression analyses showed that urbanity versus rurality and education are the major determinants of HIV/AIDS-related information needs and media use. Being urbanite and educated were associated with high concern about and information needs on HIV/AIDS and HIV/AIDS-related mass media use. Moreover, urbanity versus rurality and education significantly predicted preferences for specific types of HIV/AIDS related information. While rurality and low education were associated with a preference for basic HIV transmission and prevention information, urbanity was associated with a preference for information on HIV/AIDS-related care and support. In most cases, urbanity versus rurality emerged as a substantial predictor and also significantly moderated the effects of other variables. Given the evolving nature of the pandemic and its expansion to rural areas, ruralites' low information needs and media use deserve due attention. Equally, communication interventions targeting urban contexts need to move beyond providing only the ABCs of HIV transmission and prevention and should attend to urbanites' progressive information needs, which seem to have now become more on care and support so as to live and deal with the pandemic. PMID- 23442166 TI - Risk factors for impaired quality of life and psychosocial adjustment after pediatric heart, kidney, and liver transplantation. AB - Few studies compare HRQOL and PSA in children who have undergone different types of solid organ Tx. In this cross-sectional study, HRQOL and PSA were assessed in 74 Tx patients (16 heart, 44 kidney, 14 liver) at a mean age of 11.5 (range 6.3 16.7), 7.2 yr post-Tx (range 1.0-15.0). HRQOL was self-assessed using standardized health utility questionnaires (15D-17D). The patients' PSA was evaluated using the Child Behavior Checklist for parents, Youth Self-Report for patients aged 11-16 yr, and Teacher Report Form. Outcomes did not differ significantly between Tx groups. Preadolescents (8-11 yr) reported poorer HRQOL compared with same-age peers (p = 0.020). In contrast, adolescents reported similar HRQOL and PSA compared to the general population. Proxy-reports revealed more PSA problems compared with age expectations (p < 0.01), mainly in internalizing behavior (p < 0.01). Lower HRQOL was associated with shorter follow up time since Tx, congenital disease, and a psychiatric or neurological diagnosis. PSA problems were associated with family-related variables, neurological diagnosis, shorter follow-up time, and in teacher-reports longer disease duration before Tx. Different pediatric Tx groups have similar outcome. Neurological comorbidity and shorter follow-up time are important risk factors, but the impact of family-related variables on PSA indicate the need of family interventions. PMID- 23442167 TI - The effect of thiazide and loop diuretics on urinary levels of free deoxypyridinoline: an osteoclastic bone-resorption marker. AB - WHAT IS KNOWN AND OBJECTIVE: Diuretics can cause changes in calcium levels due to renal effects. Moreover, calcium levels can also vary as a result of changes in intestinal absorption and in the activity of osteoclastic cells. A marker of osteoclastic bone-resorption activity is the level of urinary free deoxypyridinoline (FDP). Deoxypyridinoline (DP) acts as a cross-link between adjacent collagen chains to provide structural rigidity. Our aim was to investigate the association between use of thiazides and loop diuretics and urinary levels FDP. METHODS: In this follow-up study, data were obtained from the Rotterdam Study, a large population-based prospective cohort study. For a subset of 658 participants, urinary levels of FDP were measured at baseline. Linear regression analysis was performed to assess the association between the use of thiazides and loop diuretics and the urinary levels of FDP. RESULTS: In women, current use of loop diuretics for less than 42 days was associated with an increased level of urinary FDP (+3.43 nmol deoxypyridinoline per mmol urinary creatinine; 95% CI 1.85; 5.02) compared with no use. However, use for a period of more than 42 days was not associated with an increased level of FDP, nor was past use of loop diuretics. For thiazide diuretics, no statistically significant associations were found. WHAT IS NEW AND CONCLUSION: In women, short-term use of loop diuretics is associated with an increased level of FDP, reflecting increased bone resorption by osteoclasts. As the difference disappears with longer term use, the clinical significance is unclear and the value of FDP as a biomarker in this setting is not established. The molecular mechanism for the observed differences in bone fracture rates with use of diuretics remains unclear. PMID- 23442168 TI - Mitochondrial genome of Protobothrops mucrosquamatus (Squamata: Viperidae: Crotalinae). AB - Protobothrops mucrosquamatus is the endangered snake that is distributed in southwestern China and other adjacent countries of Asia. We determined the complete mitochondrial genome of P. mucrosquamatus. The circle genome with the total length of 17,233 bp contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 2 control regions. Overall base composition of the complete mtDNA was 32.98% A, 25.17% T, 29.19% C and 12.67% G. All the genes in P. mucrosquamatus were distributed on the H-strand, except for the ND6 subunit gene and eight tRNA genes that were encoded on the L-strand. PMID- 23442169 TI - Copynumber: Efficient algorithms for single- and multi-track copy number segmentation. AB - BACKGROUND: Cancer progression is associated with genomic instability and an accumulation of gains and losses of DNA. The growing variety of tools for measuring genomic copy numbers, including various types of array-CGH, SNP arrays and high-throughput sequencing, calls for a coherent framework offering unified and consistent handling of single- and multi-track segmentation problems. In addition, there is a demand for highly computationally efficient segmentation algorithms, due to the emergence of very high density scans of copy number. RESULTS: A comprehensive Bioconductor package for copy number analysis is presented. The package offers a unified framework for single sample, multi-sample and multi-track segmentation and is based on statistically sound penalized least squares principles. Conditional on the number of breakpoints, the estimates are optimal in the least squares sense. A novel and computationally highly efficient algorithm is proposed that utilizes vector-based operations in R. Three case studies are presented. CONCLUSIONS: The R package copynumber is a software suite for segmentation of single- and multi-track copy number data using algorithms based on coherent least squares principles. PMID- 23442170 TI - Photocatalytically induced hydrophilicity influences bone remodelling at longer healing periods: a rabbit study. AB - OBJECTIVES: Previously, we have reported that photocatalytically active hydrophilicity of the anatase titanium dioxide (TiO2) nanoparticles coated onto commercially pure titanium discs presented significantly improved hydrophilicity after ultraviolet irradiation. As hydrophilicity has shown enhancement of osseointegration, the in vivo responses were of great interest. The aim of this study was to evaluate whether or not the photo-activated hydrophilicity generated at the time of implant placement has an effect on the longer healing periods for osseointegration. MATERIALS AND METHODS: Photocatatytically active nanostructured TiO2 powder (Degussa P-25), which consists of approximately 80% anatase and 20% rutile, was spin-coated onto commercially pure titanium discs and was heat treated thereafter. These P25-coated discs were irradiated with ultraviolet (UV) light for the test (+UV) group, and non-irradiated discs were prepared for the control (-UV) group. Both groups of discs were placed in the rabbits' tibiae. After 12 weeks of healing period, histological analysis and gene expression analysis using real-time RT-PCR were performed. RESULTS: From the histological analyses, there were no specific differences between -UV and +UV groups. However, from the gene expression analysis, ALP, RUNX-2 and IL-10 were significantly upregulated for the +UV group compared with the -UV group. CONCLUSIONS: The biologically enhancing effect to photocatalytically activated surfaces remained even after 12 weeks of healing time in terms of genetic responses. PMID- 23442171 TI - Elevated atmospheric CO2 concentration leads to increased whole-plant isoprene emission in hybrid aspen (Populus tremula * Populus tremuloides). AB - Effects of elevated atmospheric [CO2] on plant isoprene emissions are controversial. Relying on leaf-scale measurements, most models simulating isoprene emissions in future higher [CO2] atmospheres suggest reduced emission fluxes. However, combined effects of elevated [CO2] on leaf area growth, net assimilation and isoprene emission rates have rarely been studied on the canopy scale, but stimulation of leaf area growth may largely compensate for possible [CO2] inhibition reported at the leaf scale. This study tests the hypothesis that stimulated leaf area growth leads to increased canopy isoprene emission rates. We studied the dynamics of canopy growth, and net assimilation and isoprene emission rates in hybrid aspen (Populus tremula * Populus tremuloides) grown under 380 and 780 MUmol mol(-1) [CO2]. A theoretical framework based on the Chapman-Richards function to model canopy growth and numerically compare the growth dynamics among ambient and elevated atmospheric [CO2]-grown plants was developed. Plants grown under elevated [CO2] had higher C : N ratio, and greater total leaf area, and canopy net assimilation and isoprene emission rates. During ontogeny, these key canopy characteristics developed faster and stabilized earlier under elevated [CO2]. However, on a leaf area basis, foliage physiological traits remained in a transient state over the whole experiment. These results demonstrate that canopy scale dynamics importantly complements the leaf-scale processes, and that isoprene emissions may actually increase under higher [CO2] as a result of enhanced leaf area production. PMID- 23442172 TI - The virtual brain integrates computational modeling and multimodal neuroimaging. AB - Brain function is thought to emerge from the interactions among neuronal populations. Apart from traditional efforts to reproduce brain dynamics from the micro- to macroscopic scales, complementary approaches develop phenomenological models of lower complexity. Such macroscopic models typically generate only a few selected-ideally functionally relevant-aspects of the brain dynamics. Importantly, they often allow an understanding of the underlying mechanisms beyond computational reproduction. Adding detail to these models will widen their ability to reproduce a broader range of dynamic features of the brain. For instance, such models allow for the exploration of consequences of focal and distributed pathological changes in the system, enabling us to identify and develop approaches to counteract those unfavorable processes. Toward this end, The Virtual Brain (TVB) ( www.thevirtualbrain.org ), a neuroinformatics platform with a brain simulator that incorporates a range of neuronal models and dynamics at its core, has been developed. This integrated framework allows the model-based simulation, analysis, and inference of neurophysiological mechanisms over several brain scales that underlie the generation of macroscopic neuroimaging signals. In this article, we describe how TVB works, and we present the first proof of concept. PMID- 23442173 TI - Calcineurin inhibitors in liver transplantation - still champions or threatened by serious competitors? AB - Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings. PMID- 23442174 TI - Monitoring laparoscopic radiofrequency renal lesions in real time using contrast enhanced ultrasonography: an open-label, randomized, comparative pilot trial. AB - BACKGROUND AND PURPOSE: Radiofrequency ablation (RFA) has been considered as an important therapy for small renal lesions. The main limitation of RFA, however, is the lack of pathologic confirmation of complete tumor eradication. A single center, open label, randomized pilot study was designed to evaluate whether contrast-enhanced ultrasonography (CEUS) with Sonovue, performed in real time could allow us to determine the end point during laparoscopic radiofrequency ablation (LRFA) and the clinical outcome of this method. PATIENTS AND METHODS: Ninety-six patients undergoing LRFA were randomly assigned to CEUS or a control group; finally, 38 and 40 patients with a pathologic diagnosis of renal-cell carcinoma completed a 3-month follow-up. CEUS was conducted in real time during the procedure to determine the end point in the CEUS group. The primary outcome was the incomplete ablation rate according to a radiographic image at 3 months after the procedure. The secondary outcome included the local tumor control rate and disease-free survival rate. RESULTS: There were no differences in the incomplete ablation rate and disease-free survival rate between the two groups. Within a median 16-month follow-up period, three incomplete ablations and two local recurrences according to a radiographic image were found in the control group. Meanwhile, there was no incomplete ablation or recurrence but one lung metastasis in the CEUS group. The local tumor control rate was 87.5% (35/40) in the control group vs 100% (38/38) (P=0.073) in the CEUS group. CONCLUSION: In patients undergoing LRFA, there were no differences in the incomplete ablation rate and local tumor control rate between the CEUS group and the control group in our study despite a nonsignificant trend in favor of CEUS. CEUS may have the potential to provide more effective renal tumor ablation. These novel data support the need for a larger study of CEUS during LRFA surgery. PMID- 23442175 TI - Differentiation of complex vapor mixtures using versatile DNA-carbon nanotube chemical sensor arrays. AB - Vapor sensors based on functionalized carbon nanotubes (NTs) have shown great promise, with high sensitivity conferred by the reduced dimensionality and exceptional electronic properties of the NT. Critical challenges in the development of NT-based sensor arrays for chemical detection include the demonstration of reproducible fabrication methods and functionalization schemes that provide high chemical diversity to the resulting sensors. Here, we outline a scalable approach to fabricating arrays of vapor sensors consisting of NT field effect transistors functionalized with single-stranded DNA (DNA-NT). DNA-NT sensors were highly reproducible, with responses that could be described through equilibrium thermodynamics. Target analytes were detected even in large backgrounds of volatile interferents. DNA-NT sensors were able to discriminate between highly similar molecules, including structural isomers and enantiomers. The sensors were also able to detect subtle variations in complex vapors, including mixtures of structural isomers and mixtures of many volatile organic compounds characteristic of humans. PMID- 23442176 TI - Quantitative proteomic analysis identified paraoxonase 1 as a novel serum biomarker for microvascular invasion in hepatocellular carcinoma. AB - This study aimed to identify serum biomarkers for microvascular invasion (MVI) in hepatocellular carcinoma (HCC). MVI is a histological sign of micrometastasis in the liver and is considered as one of the most powerful prognostic factors in HCC. The serum of HCC patients with different vascular invasion statuses was examined by iTRAQ-based proteomic profiling. The expression levels of 24 proteins were associated with the extent of vascular invasion in the pooled samples of 45 HCC cases. Western blot analyses in 90 HCC cases confirmed the correlation of the expression level of paraoxonase 1 (PON1) with the extent of vascular invasion. ELISA assays demonstrated the diagnostic utility of the PON1 level, with the area under curve values of 0.847 and 0.889 for the MVI and gross vascular invasion, respectively, relative to the patients without vascular invasion, in a cohort of 387 additional HCC cases. Immunohistochemistry revealed that PON1 expression in tumor cells was inversely correlated with the extent of vascular invasion in 200 additional HCC cases. In conclusion, using a proteomic approach, we found that serum PON1 was a novel diagnostic biomarker for MVI. The prognostic values of serum PON1 and its possible therapeutic applications are worth further investigation. PMID- 23442177 TI - Urticaria due to patent blue V which appeared along the lymph flow. PMID- 23442178 TI - The acoustic cough monitoring and manometric profile of cough and throat clearing. AB - Cough and throat clearing might be difficult to differentiate when trying to detect them acoustically or manometrically. The aim of this study was to assess the accuracy of acoustic monitoring for detecting cough and throat clearing, and to also determine whether these two symptoms present with different manometric profiles on esophageal pressure topography. Ten asymptomatic volunteers (seven females, mean age 31.1) were trained to simulate cough and throat clearing in a randomized order every 6 minutes during simultaneous acoustic monitoring and high resolution manometry. The accuracy of automated acoustic analysis and two blinded reviewers were compared. The pattern of the events and the duration of the pressure changes were assessed using the 30 mmHg isobaric contour. There were 50 cough and 50 throat-clearing events according to the protocol. The sensitivity and specificity of automated acoustic analysis was 84% and 50% for cough, while the blinded analysis using sound revealed a sensitivity and specificity of 94% and 92%. The manometric profile of both cough and throat clearing was similar in terms of qualitative findings; however, cough was associated with a greater number of repetitive pressurizations and a more vigorous upper esophageal sphincter contraction compared with throat clearing. The acoustic analysis software has a moderate sensitivity and poor specificity to detect cough. The profile of cough and throat clearing in pressure topography revealed a similar qualitative pattern of pressurization with more vigorous pressure changes and a greater rate of repetitive pressurizations in cough. PMID- 23442179 TI - Parental stress in a paediatric intensive care unit in Punjab, India. AB - AIM: Paediatric intensive care is a fast-growing specialty in India. There are studies on parental stress in paediatric intensive care unit (PICU) in developed countries, but limited data from developing countries, where many factors may be different, are available. This paper describes various stressors in Indian parents. METHOD: One hundred parents were interviewed using the Parental Stress Scale (PSS: PICU), which rates 22 factors on a scale from 1 (not stressful) to 5 (extremely stressful). RESULTS: The average parental stress score was 3.0. The main causes of extremely stressful situations were: the parents' child having breathing difficulty; their child suffering pain; their child being unresponsive; crises in other children in the PICU. Factors least associated with stress included: not being alone with baby; and the presence of monitors and equipment. Nearly all parents (99) felt that prayer was of help. The majority (67) felt stressed during procedures, and 59 parents felt stressed by the sights and sounds of the PICU. Factors significantly related to increased stress included: the severity of illness as measured by higher paediatric risk of mortality scoring (P = 0.0136); for mothers rather than fathers (P = 0.0054): for parents <30 years (P = 0.0114); and parents of a male child (P = 0.0482). CONCLUSIONS: It is concluded that there is significant stress among parents of children admitted to an Indian PICU, and stress factors are different from studies done in developed countries. Mothers and young parents were more stressed. Type of family, income, education, number and age of children did not affect level of stress. PMID- 23442180 TI - Prediction of the physiological response of humans wearing protective clothing using a thermophysiological human simulator. AB - Most standards and devices for determining clothing properties ignore the physiological state of the wearer and are inadequate to evaluate the transient thermal properties of clothing ensembles. This study evaluated the physiological burden of different types of protective clothing and environmental conditions using the recently developed single-sector thermo-physiological human simulator and compared its performance with a thermal cylinder (without the physiological control model) and with an advanced physiological model (with a simple clothing model). A single-sector physiological simulator developed to simulate the dynamic thermal and perceptual behavior of humans over a wide range of environmental and personal conditions was successfully validated in this study through tests with clothed individuals exposed to hot and cold conditions. In comparative tests on water vapor permeable and impermeable clothing samples, the simulator provided a much more complete picture of actual clothing performance, for example, in terms of moisture retention within the clothing and the additional cooling due to the "heat pipe" effect in impermeable clothing. PMID- 23442182 TI - Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review. AB - WHAT IS KNOWN AND OBJECTIVE: Drug-induced thrombocytopenia (DITP) may be a fatal adverse reaction to many drugs. It is often misdiagnosed as primary immune thrombocytopenia (ITP), and thus diagnosis can be delayed and patients can be treated inappropriately. Amlodipine a calcium-channel blocker, and simvastatin, a statin, have very rarely been implicated in DITP. We report on an investigation of the causal relationship of amlodipine and simvastatin with thrombocytopenia occurring in the same patient, and review the literature. CASE SUMMARY: We present the case of a 78-year-old female hypertensive diabetic patient with three successive DITPs. The first attack of acute severe thrombocytopenia occurred after a 2-week course of amlodipine, and was initially misdiagnosed as ITP. Her platelet count normalized after the amlodipine was discontinued. The second attack followed her restarting simvastatin 3 weeks later. She had stopped it 2 months earlier having previously taken it for over 5 years. Again, she recovered once the simvastatin was discontinued. The third DITP attack occurred when she accidently took a single dose of amlodipine 9 months later. WHAT IS NEW AND CONCLUSION: We provide clear evidence of a causal association of amlodipine with thrombocytopenia, and probable evidence of a causal association of simvastatin with thrombocytopenia. This is the first reported case of DITPs occurring with two of the most widely prescribed drugs in the same patient. Many hypertensive patients need to take multiple drugs in order to achieve their treatment goals and this increases their risk of drug-induced adverse reactions and makes identification of the causal drug (or drugs) extremely difficult. PMID- 23442183 TI - The association between prenatal alcohol exposure and behavior at 22 years of age. AB - BACKGROUND: Prenatal alcohol exposure (PAE) affects central nervous system development, growth, and morphology at higher exposure levels. Little is known about the effects of PAE at lower exposure levels or in young adults. Research on children with higher levels of PAE has shown that PAE predicts behavior problems. The question remains whether these effects are permanent or ameliorated by maturation into adulthood. METHODS: These data are from a longitudinal study of PAE. Mothers were recruited from a prenatal clinic and interviewed during their fourth prenatal month, seventh month, and delivery. In the postpartum, mothers and offspring were seen at 8 and 18 months, and 3, 6, 10, 14, 16, and 22 years. RESULTS: At 22 years, PAE significantly predicted behavior as measured with the adult self-report. These findings were significant controlling for covariates. Exposure at each trimester predicted increased behavior problems on the Total Score, Internalizing, Externalizing, Attention, and Critical Items scales. Use across pregnancy predicted a higher rate of behavior problems compared to no use and use in the first trimester only. CONCLUSIONS: The effects were dose-response and significant at each trimester of pregnancy. However, duration across pregnancy was a better predictor than drinking during the first trimester only. Binge drinking was not a better predictor of outcome compared to average daily volume (ADV), and within categories of ADV, binge drinking did not predict more problems than nonbinge drinking. Thus, there is no safe level or safe time during pregnancy for women to drink. These data demonstrate that the effects of PAE, even at low to moderate levels, extend into young adulthood and are most likely permanent. PMID- 23442184 TI - De novo assembly and characterization of transcriptome using Illumina paired-end sequencing and identification of CesA gene in ramie (Boehmeria nivea L. Gaud). AB - BACKGROUND: Ramie fiber, extracted from vegetative organ stem bast, is one of the most important natural fibers. Understanding the molecular mechanisms of the vegetative growth of the ramie and the formation and development of bast fiber is essential for improving the yield and quality of the ramie fiber. However, only 418 expressed tag sequences (ESTs) of ramie deposited in public databases are far from sufficient to understand the molecular mechanisms. Thus, high-throughput transcriptome sequencing is essential to generate enormous ramie transcript sequences for the purpose of gene discovery, especially genes such as the cellulose synthase (CesA) gene. RESULTS: Using Illumina paired-end sequencing, about 53 million sequencing reads were generated. De novo assembly yielded 43,990 unigenes with an average length of 824 bp. By sequence similarity searching for known proteins, a total of 34,192 (77.7%) genes were annotated for their function. Out of these annotated unigenes, 16,050 and 13,042 unigenes were assigned to gene ontology and clusters of orthologous group, respectively. Searching against the Kyoto Encyclopedia of Genes and Genomes Pathway database (KEGG) indicated that 19,846 unigenes were mapped to 126 KEGG pathways, and 565 genes were assigned to http://starch and sucrose metabolic pathway which was related with cellulose biosynthesis. Additionally, 51 CesA genes involved in cellulose biosynthesis were identified. Analysis of tissue-specific expression pattern of the 51 CesA genes revealed that there were 36 genes with a relatively high expression levels in the stem bark, which suggests that they are most likely responsible for the biosynthesis of bast fiber. CONCLUSION: To the best of our knowledge, this study is the first to characterize the ramie transcriptome and the substantial amount of transcripts obtained will accelerate the understanding of the ramie vegetative growth and development mechanism. Moreover, discovery of the 36 CesA genes with relatively high expression levels in the stem bark will present an opportunity to understand the ramie bast fiber formation and development mechanisms. PMID- 23442185 TI - Massive screening of copy number population-scale variation in Bos taurus genome. AB - BACKGROUND: Copy number variations (CNVs) represent a significant source of genomic structural variation. Their length ranges from approximately one hundred to millions of base pair. Genome-wide screenings have clarified that CNVs are a ubiquitous phenomenon affecting essentially the whole genome. Although Bos taurus is one of the most important domestic animal species worldwide and one of the most studied ruminant models for metabolism, reproduction, and disease, relatively few studies have investigated CNVs in cattle and little is known about how CNVs contribute to normal phenotypic variation and to disease susceptibility in this species, compared to humans and other model organisms. RESULTS: Here we characterize and compare CNV profiles in 2654 animals from five dairy and beef Bos taurus breeds, using the Illumina BovineSNP50 genotyping array (54001 SNP probes). In this study we applied the two most commonly used algorithms for CNV discovery (QuantiSNP and PennCNV) and identified 4830 unique candidate CNVs belonging to 326 regions. These regions overlap with 5789 known genes, 76.7% of which are significantly co-localized with segmental duplications (SD). CONCLUSIONS: This large scale screening significantly contributes to the enrichment of the Bos taurus CNV map, demonstrates the ubiquity, great diversity and complexity of this type of genomic variation and sets the basis for testing the influence of CNVs on Bos taurus complex functional and production traits. PMID- 23442186 TI - Anti-CD2 producing pig xenografts effect localized depletion of human T cells in a huSCID model. AB - BACKGROUND: We investigated whether graft produced anti-human CD2, mediated by adenovirus (Adv) transduction of pig neonatal islet cell clusters (pNICC), would protect xenografts in a humanized mouse model from immune attack and whether such immunosuppression would remain local. METHODS: A mouse anti-human CD2 Ab (CD2hb11) previously generated by us was genetically engineered to produce chimeric and humanized versions. The three forms of CD2hb11 were named dilimomab (mouse), diliximab (chimeric) and dilizumab (humanized). All 3 forms of CD2hb11 Ab were tested for their ability to bind CD3(+) human T cells and to inhibit a human anti-pig xenogeneic mixed lymphocyte reaction (MLR). They were administered systemically in a humanized mouse model in order to test their ability to deplete human CD3(+) T cells and whether they induced a cytokine storm. An adenoviral vector expressing diliximab was generated for transduction of pNICC. Humanized mice were transplanted with either control-transduced pNICC or diliximab transduced pNICC and human T cells within grafts and spleens were enumerated by flow cytometry. RESULTS: Dilimomab and diliximab inhibited a human anti-pig xenogeneic response but dilizumab did not. All 3 forms of CD2hb11 Ab bound human T cells in vitro though dilimomab and diliximab exhibited 300-fold higher avidity than dilizumab. All 3 anti-CD2 Abs could deplete human CD3(+) T cells in vivo in a humanized mouse model without inducing upregulation of activation markers or significant release of cytokines. Humanized mice transplanted with diliximab transduced pNICC afforded depletion of CD3(+) T cells at the graft site leaving the peripheral immune system intact. CONCLUSIONS: Local production of a single Ab against T cells can reduce graft infiltration at the xenograft site and may reduce the need for conventional, systemic immunosuppression. PMID- 23442187 TI - The complete mitochondrial genome of the Chinese peacock, Papilio bianor (Insecta: Lepidoptera: Papilionidae). AB - The sequence of the mitochondrial genome (mitogenome) of the Chinese peacock Papilio bianor has been completed. It is 15,332 bp with an A + T content of 80.6% and contains the typical complement of 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA), and 2 ribosomal RNA (rRNA) genes. Comparison of this sequence with the sequences of the other completely sequenced insect mitogenomes showed that the gene order and orientation are basically identical to that of Drosophila yakuba with the exception of the rearrangement of one tRNA gene. Nucleotide composition is very similar with other insects, showing a high bias toward A + T. PMID- 23442188 TI - A new target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling. AB - The rational design of selective kinase inhibitors remains a great challenge. Here we describe a physics-based approach to computationally modeling the kinase inhibitor selectivity profile. We retrospectively assessed this protocol by computing the binding profiles of 17 well-known kinase inhibitors against 143 kinases. Next, we predicted the binding profile of the chemotherapy drug mitoxantrone, and chose the predicted top five kinase targets for in vitro kinase assays. Remarkably, mitoxantrone was shown to possess low nanomolar inhibitory activity against PIM1 kinase and to inhibit the PIM1-mediated phosphorylation in cancer cells. We further determined the crystal complex structure of PIM1 bound with mitoxantrone, which reveals the structural and mechanistic basis for a novel mode of PIM1 inhibition. Although mitoxantrone's mechanism of action had been originally thought to act through DNA intercalation and type II topoisomerase inhibition, we hypothesize that PIM1 kinase inhibition might also contribute to mitoxantrone's therapeutic efficacy and specificity. PMID- 23442189 TI - Fertilizer-derived uranium and its threat to human health. PMID- 23442190 TI - Conceptualizing how couples talk about cancer. AB - Scholarship on couple communication about cancer employs variable conceptualizations of communication, and common measurement strategies make questionable assumptions about communication. This study provides a descriptive foundation for a multiple-topic, multidimensional approach to studying couple talk about cancer. Based on interviews with persons treated for cancer in the last 5 years and partners, we identified 16 topics and 5 dimensions of talk. "Talk about cancer" covers a broad range of issues. The frequency, openness, difficulty, and focus of talk vary considerably for different topics and can change over time or differ between partners. Disagreements were rare but highly salient, and satisfaction with talk tended to be high. These findings suggest we move away from abstract, general measures of couple communication and that we develop descriptive advice for couples, rather than simply prescribing "be open." PMID- 23442191 TI - Toward a 3D cellular model for studying in vitro the outcome of photodynamic treatments: accounting for the effects of tissue complexity. AB - Clinical therapies have traditionally been developed using two-dimensional (2D) cell culture systems, which fail to accurately capture tissue complexity. Therefore, three-dimensional (3D) cell cultures are more attractive platforms to integrate multiple cues that arise from the extracellular matrix and cells, closer to an in vivo scenario. Here we report the development of a 3D cellular model for the in vitro assessment of the outcome of oxygen- and drug-dependent therapies, exemplified by photodynamic therapy (PDT). Using a synthetic self assembling peptide as a cellular scaffold (RAD16-I), we were able to recreate the in vivo limitation of oxygen and drug diffusion and its biological effect, which is the development of cellular resistance to therapy. For the first time, the production and decay of the cytotoxic species singlet oxygen could be observed in a 3D cell culture. Results revealed that the intrinsic mechanism of action is maintained in both systems and, hence, the dynamic mass transfer effects accounted for the major differences in efficacy between the 2D and 3D models. We propose that this methodological approach will help to improve the efficacy of future oxygen- and drug-dependent therapies such as PDT. PMID- 23442193 TI - Premature impairment of methylation pathway and cardiac metabolic dysfunction in fa/fa obese Zucker rats. AB - Increasing evidence suggests that obesity is a chronic inflammatory disease, in which adipose tissue is involved in a network of endocrine signals to modulate energy homeostasis. These oxidative-inflammatory pathways, which are associated with cardiovascular complications, are also observed during the aging process. In this study, we investigated the interaction between aging and the development of obesity in a hyperphagic rat model. Metabolic profiles of the liver, white adipose tissue (WAT) and heart from young and adult Zucker lean (fa/+) and obese (fa/fa) rats were characterized using a (1)H NMR-based metabonomics approach. We observed premature metabolic modifications in all studied organs in obese animals, some of which were comparable to those observed in adult lean animals. In the cardiac tissue, young obese rats displayed lower lactate and scyllo inositol levels associated with higher creatine, choline and phosphocholine levels, indicating an early modulation of energy and membrane metabolism. An early alteration of the hepatic methylation and transsulfuration pathways in both groups of obese rats indicated that these pathways were affected before diabetic onset. These findings therefore support the hypothesis that obesity parallels some metabolic perturbations observed in the aging process and provides new insights into the metabolic modifications occurring in prediabetic state. PMID- 23442194 TI - pH-dependent evolution of five-star gold nanostructures: an experimental and computational study. AB - Dendritic structures, such as snowflakes, have been observed in nature in far from-equilibrium growth conditions. Mimicking these structures at the nanometer scale can result in nanomaterials with interesting properties for applications, such as plasmonics and biosensors. However, reliable production and systematic fine-tuning morphologies of these nanostructures, with novel hierarchical or complex structures, along with theoretical understanding of these processes, are still major challenges in the field. Here, we report a new method of using pH to control HAuCl4 reduction by hydroxylamine for facile production of gold nanostructures with morphologies in various symmetries and hierarchies, both in solution and on solid surface. Of particular interest is the observation of five star-like dendritic and hierarchical gold nanostructures under certain reaction conditions. Phase-field modeling was used to understand the growth and formation dynamics of the five-star and other gold complex nanostructures, and the results not only explained the experimental observations, but also predicted control of the nanostructural morphologies using both pH and hydroxylamine concentrations. In addition to revealing interesting growth dynamics in forming fascinating complex gold nanostructures, the present work provides a pH-directed morphology control method as a facile way to synthesize and fine-tune the morphology of hierarchical gold nanostructures. PMID- 23442195 TI - An unusual mucocutaneous syndrome with sensorineural deafness due to connexin 26 mutations. AB - Mutations of the GJB2 gene, which encodes connexin 26, are related to a range of conditions associated with sensorineural deafness and keratinization disorders. We present the case of a newborn girl with sensorineural deafness, erythematous hyperkeratotic plaques on intertriginous areas, and parakeratosis on the oral and esophageal mucosa. She had an F142L mutation in exon 1 of the GJB2 gene, which was described previously in a patient with a similar phenotype. PMID- 23442192 TI - PDT dose parameters impact tumoricidal durability and cell death pathways in a 3D ovarian cancer model. AB - The successful implementation of photodynamic therapy (PDT)-based regimens depends on an improved understanding of the dosimetric and biological factors that govern therapeutic variability. Here, the kinetics of tumor destruction and regrowth are characterized by systematically varying benzoporphyrin derivative (BPD)-light combinations to achieve fixed PDT doses (M * J cm(-2)). Three endpoints were used to evaluate treatment response: (1) Viability evaluated every 24 h for 5 days post-PDT; (2) Photobleaching assessed immediately post-PDT; and (3) Caspase-3 activation determined 24 h post-PDT. The specific BPD-light parameters used to construct a given PDT dose significantly impact not only acute cytotoxic efficacy, but also treatment durability. For each dose, PDT with 0.25 MUM BPD produces the most significant and sustained reduction in normalized viability compared to 1 and 10 MUM BPD. Percent photobleaching correlates with normalized viability for a range of PDT doses achieved within BPD concentrations. To produce a cytotoxic response with 10 MUM BPD that is comparable to 0.25 and 1 MUM BPD a reduction in irradiance from 150 to 0.5 mW cm(-2) is required. Activated caspase-3 does not correlate with normalized viability. The parameter dependent durability of outcomes within fixed PDT doses provides opportunities for treatment customization and improved therapeutic planning. PMID- 23442196 TI - Spider phobia is associated with decreased left amygdala volume: a cross sectional study. AB - BACKGROUND: Evidence from animal and human studies imply the amygdala as the most critical structure involved in processing of fear-relevant stimuli. In phobias, the amygdala seems to play a crucial role in the pathogenesis and maintenance of the disorder. However, the neuropathology of specific phobias remains poorly understood. In the present study, we investigated whether patients with spider phobia show altered amygdala volumes as compared to healthy control subjects. METHODS: Twenty female patients with spider phobia and twenty age-matched healthy female controls underwent magnetic resonance imaging to investigate amygdala volumes. The amygdalae were segmented using an automatic, model-based segmentation tool (FSL FIRST). Differences in amygdala volume were investigated by multivariate analysis of covariance with group as between-subject factor and left and right amygdala as dependent factors. The relation between amygdala volume and clinical features such as symptom severity, disgust sensitivity, trait anxiety and duration of illness was investigated by Spearman correlation analysis. RESULTS: Spider phobic patients showed significantly smaller left amygdala volume than healthy controls. No significant difference in right amygdala volume was detected. Furthermore, the diminished amygdala size in patients was related to higher symptom severity, but not to higher disgust sensitivity or trait anxiety and was independent of age. CONCLUSIONS: In summary, the results reveal a relation between higher symptom severity and smaller left amygdala volume in patients with spider phobia. This relation was independent of other potential confounders such as the disgust sensitivity or trait anxiety. The findings suggest that greater spider phobic fear is associated with smaller left amygdala. However, the smaller left amygdala volume may either stand for a higher vulnerability to develop a phobic disorder or emerge as a consequence of the disorder. PMID- 23442197 TI - Analysis and refactoring of the A-74528 biosynthetic pathway. AB - A-74528 is a C30 polyketide natural product that functions as an inhibitor of 2',5'-oligoadenylate phosphodiesterase (2'-PDE), a key regulatory enzyme of the interferon pathway. Modulation of 2'-PDE represents a unique therapeutic approach for regulating viral infections. The gene cluster responsible for biosynthesis of A-74528 yields minute amounts of this natural product together with considerably larger quantities of a structurally dissimilar C30 cytotoxic agent, fredericamycin. Through construction and analysis of a series of knockout mutants, we identified the genes necessary for A-74528 biosynthesis. Remarkably, the formation of six stereocenters and the regiospecific formation of six rings in A-74528 appear to be catalyzed by only two tailoring enzymes, a cyclase and an oxygenase, in addition to the core polyketide synthase. The inferred pathway was genetically refactored in a heterologous host, Streptomyces coelicolor CH999, to produce 3 mg/L A-74528 in the absence of fredericamycin. PMID- 23442198 TI - The development and validation of dried blood spots for external quality assurance of syphilis serology. AB - BACKGROUND: Syphilis causes up to 1,500,000 congenital syphilis cases annually. These could be prevented if all pregnant women were screened, and those with syphilis treated with a single dose of penicillin before 28 weeks gestation. In recent years, rapid point-of-care tests have allowed greater access to syphilis screening, especially in rural or remote areas, but the lack of quality assurance of rapid testing has been a concern. We determined the feasibility of using dried blood spots (DBS) as specimens for quality assurance of syphilis serological assays. METHODS: We developed DBS extraction protocols for use with Treponema pallidum particle agglutination assay (TPPA), Treponema pallidum haemagglutination assay (TPHA) and an enzyme immunoassay (EIA) and compared the results with those using matching plasma samples from the same patient. RESULTS: Since DBS samples showed poor performance with TPHA and EIA (TPHA sensitivity was 50.5% (95% confidence interval: 39.9-61.2%) and EIA specificity was 50.4% (95% CI: 43.7-57.1%), only the DBS TPPA was used in the final evaluation. DBS TPPA showed an sensitivity of 95.5% (95% CI: 91.3-98.0%) and a specificity of 99.0% (95% CI: 98.1-99.5%) compared to TPPA using plasma samples as a reference. CONCLUSION: DBS samples can be recommended for use with TPPA, and may be of value for external quality assurance of point-of-care syphilis testing. PMID- 23442199 TI - Indocyanine green cannot predict malignancy in partial nephrectomy: histopathologic correlation with fluorescence pattern in 100 patients. AB - INTRODUCTION: Indocyanine green (ICG) is emerging as a potential adjunct to robot assisted partial nephrectomy by its ability to aid in the real-time identification of renal vasculature, renal masses, and the renal mass-parenchymal margin. The fluorescence patterns of renal masses have not been adequately described according to histology, and it remains unknown if fluorescence pattern can reliably predict histology or malignancy. We therefore describe the ICG fluorescence pattern of our first 100 robot-assisted partial nephrectomies (RAPN) and correlate with histology. MATERIALS AND METHODS: We reviewed our prospective RAPN database and categorized fluorescence pattern as isofluorescent (same as surrounding parenchyma), hypofluorescent (less than surrounding parenchyma, but with uptake), or afluorescent (no visible uptake of dye). Descriptive statistics were applied. RESULTS: All 14 cystic lesions were afluorescent and comprised 9 malignant and 5 benign masses. Eighty-six lesions were solid, of which 3 were isofluorescent including two clear-cell and one translocation tumor. The remaining 83 solid lesions were hypofluorescent and included 65 malignant and 18 benign lesions. Clear-cell was the most common histology of which 96% were hypofluorescent and 4% isofluorescent. In determining malignant vs benign lesions, hypofluorescence had a positive predictive value of 87%, negative predictive value of 52%, sensitivity of 84%, and specificity of 57%. CONCLUSIONS: A three-grade classification of renal mass ICG fluorescence pattern is correlated with some histologic findings but unable to reliably predict malignant vs benign lesions. PMID- 23442200 TI - Measuring global health-related quality of life in children undergoing hematopoietic stem cell transplant: a longitudinal study. AB - BACKGROUND: Pediatric health-related quality of life (HRQL) measures explore multiple domains of HRQL. To ease administration, burden, and implementation, we created a 7-item unidimensional global HRQL scale for children. This paper evaluates the psychometric properties of the global HRQL scale in children undergoing hematopoietic stem cell transplant (HSCT) and describes the trajectory of global HRQL scores over the 12-month course following HSCT. METHODS: As part of two longitudinal HSCT studies, HRQL was collected on 312 parent-child dyads using the Child Health Ratings Inventories. Parents of children aged 5-18 completed the pediatric global HRQL scale about their child and 117 adolescents completed the scale themselves. Psychometric properties were compared across both raters. Two repeated measures models were built to describe trajectories of (1) global HRQL for all children based on parent proxy report and (2) global HRQL for adolescents based on adolescent self-report and parent proxy report. RESULTS: Internal consistency reliability was high for parent proxy report and adolescent self-report (Cronbach's alpha 0.9, 0.8, respectively). Unidimensionality was verified using principal components analysis. Both models indicated decreased global HRQL in the presence of early complications related to HSCT and Model 1 further indicated decreased HRQL in the presence of later complications. Model 2 showed that parent proxies reported lower global HRQL scores than adolescent self report. CONCLUSIONS: This study has demonstrated the unidimensionality and strong psychometric properties of a 7-item global HRQL scale in a sample of children undergoing HSCT. Despite its brevity, scale scores vary in clinically meaningful ways. Future applications of this scale are encouraged. PMID- 23442202 TI - The coping strategies used over a two-year period by HIV-positive women who had been diagnosed during pregnancy. AB - Structured interviews were conducted with 224 HIV-positive women diagnosed during pregnancy, at antenatal clinics in Tshwane, South Africa, in order to investigate the use of coping strategies during the first two years after diagnosis. Interviews were conducted between one and four weeks after diagnosis during pregnancy, with three follow-up interviews conducted post-partum. Coping strategies were assessed with an adapted version of the Brief COPE. It was found that active coping was used more often than avoidant coping throughout the study period. Active coping increased over time, while avoidant coping decreased at first but increased again between 6 and 21 months after diagnosis. The most frequently used coping strategies included acceptance, direct action, positive reframing, religion and distraction. At first, women coped through internalised strategies. Over time, outward-focused strategies developed. Avoidant coping patterns differed from previous research indicating that women diagnosed during pregnancy deal with the consequences of HIV after the baby is born. Recommendations for mental health services are made. PMID- 23442201 TI - Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain. AB - BACKGROUND: Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co morbidities. In this study, developing rat pups were subjected to lithium pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures. FINDINGS: We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting. CONCLUSIONS: Deployment of an empirically designed 'drug cocktail' targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy. PMID- 23442203 TI - Computer game-based and traditional learning method: a comparison regarding students' knowledge retention. AB - BACKGROUND: Educational computer games are examples of computer-assisted learning objects, representing an educational strategy of growing interest. Given the changes in the digital world over the last decades, students of the current generation expect technology to be used in advancing their learning requiring a need to change traditional passive learning methodologies to an active multisensory experimental learning methodology. The objective of this study was to compare a computer game-based learning method with a traditional learning method, regarding learning gains and knowledge retention, as means of teaching head and neck Anatomy and Physiology to Speech-Language and Hearing pathology undergraduate students. METHODS: Students were randomized to participate to one of the learning methods and the data analyst was blinded to which method of learning the students had received. Students' prior knowledge (i.e. before undergoing the learning method), short-term knowledge retention and long-term knowledge retention (i.e. six months after undergoing the learning method) were assessed with a multiple choice questionnaire. Students' performance was compared considering the three moments of assessment for both for the mean total score and for separated mean scores for Anatomy questions and for Physiology questions. RESULTS: Students that received the game-based method performed better in the pos test assessment only when considering the Anatomy questions section. Students that received the traditional lecture performed better in both post-test and long term post-test when considering the Anatomy and Physiology questions. CONCLUSIONS: The game-based learning method is comparable to the traditional learning method in general and in short-term gains, while the traditional lecture still seems to be more effective to improve students' short and long-term knowledge retention. PMID- 23442204 TI - Clinical and ultrasonographic characteristics of salivary mucoceles in 13 dogs. AB - Salivary mucocele is one of the causes of submandibular swelling in dogs and is due to a collection of mucoid saliva that has leaked from a damaged salivary gland. The purpose of this case series report was to describe the clinical and ultrasonographic characteristics of confirmed salivary mucoceles in 13 dogs admitted to the Faculty of Veterinary Medicine at Cairo University. The final diagnosis of salivary mucocele was based on aspirate cytology for all dogs and additional surgical excision for seven dogs. For dogs admitted from 2 weeks to 1 month from the onset of clinical signs, the cervical mucocele appeared as a round echogenic structure with a large volume of central anechoic content. The wall was a clearly identified hyperechoic structure surrounding the gland. For dogs admitted between 1 to 2 months from the onset of clinical signs, the volume of anechoic material appeared less than that seen in the acute cases. The overall appearance of the salivary mucocele was heterogenous. For dogs admitted after 2 months from the onset of clinical signs, the salivary mucocele appeared grainy or mottled, with a heterogenous appearance and a further decrease in anechoic content. For one dog that presented after 3 months from the onset of clinical signs, the salivary mucocele was hard on palpation and appeared hyperechoic with distal acoustic shadowing. Findings from this study indicated that ultrasonographic characteristics of salivary mucoceles in dogs vary depending on the chronological stage of the disease. PMID- 23442205 TI - Global analysis of transcriptional regulators in Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus is a widely distributed human pathogen capable of infecting almost every ecological niche of the host. As a result, it is responsible for causing many different diseases. S. aureus has a vast array of virulence determinants whose expression is modulated by an intricate regulatory network, where transcriptional factors (TFs) are the primary elements. In this work, using diverse sequence analysis, we evaluated the repertoire of TFs and sigma factors in the community-associated methicillin resistant S. aureus (CA MRSA) strain USA300-FPR3757. RESULTS: A total of 135 TFs and sigma factors were identified and classified into 36 regulatory families. From these around 43% have been experimentally characterized to date, which demonstrates the significant work still at hand to unravel the regulatory network in place for this important pathogen. A comparison of the TF repertoire of S. aureus against 1209 sequenced bacterial genomes was carried out allowing us to identify a core set of orthologous TFs for the Staphylococacceae, and also allowing us to assign potential functions to previously uncharacterized TFs. Finally, the USA300 TFs were compared to those in eleven other S. aureus strains including: Newman, COL, JH1, JH9, MW2, Mu3, Mu50, N315, RF122, MRSA252 and MSSA476. We identify conserved TFs among these strains and suggest possible regulatory interactions. CONCLUSIONS: The analysis presented herein highlights the complexity of regulatory networks in S. aureus strains, identifies key conserved TFs among the Staphylococacceae, and offers unique insights into several as yet uncharacterized TFs. PMID- 23442206 TI - Administrative reinstatement interlock programs: Florida, a 10-year study. AB - BACKGROUND: Interlocks reduce driving-under-the-influence (DUI) recidivism by 64%, but offenders resist installing them, preferring to risk driving while their driver's licenses are revoked. One method of motivating offenders to install an interlock is require it for reinstatement of their driver's license. This report updates an earlier evaluation of the administrative reinstatement interlock program (ARIP) procedure implemented in Florida in 2002. METHODS: Driver records and interlock program records covering 120,000 DUI offenders were followed over 10 years. The flow through the sanction system--conviction, reinstatement, interlock program, and postinterlock period--is described. Logistical regression was used to identify the characteristics of offenders who installed interlocks, and survival analysis was used to evaluate the recidivism of offenders in the various stages in the ARIP. RESULTS: At any given time, approximately one-third of the convicted offenders were serving their license-revocation periods. Half of the offenders who completed their revocation periods remain unqualified for reinstatement because they do not fulfill other requirements. ARIP offenders who do qualify for reinstatement and install interlocks have lower recidivism rates while the devices are on their vehicles. CONCLUSIONS: After 10 years, Florida's ARIP is a mature system that succeeds in forcing all offenders in the program who qualify for reinstatement to install an interlock for at least 6 months. However, half of all offenders who complete their mandatory revocation period are either unable to or choose not to qualify for reinstatement. PMID- 23442207 TI - Effects on boar semen quality after infection with porcine reproductive and respiratory syndrome virus: a case report. AB - The effect of porcine reproductive and respiratory syndrome virus (PRRSV) on semen quality was examined in a group of 11 spontaneously infected boars in a commercial boar stud. Semen samples were collected 4 weeks prior to 4 weeks post infection (wpi). Infection with PRRSV of the European genotype subtype 1 (EU-1) was verified by specific quantitative real-time polymerase chain reaction (RT PCR) in 36% of the serum samples. All boars seroconverted before 4 wpi and remained in normal condition throughout the study. Comparison of the percentage of morphologically intact spermatozoa revealed an increase of acrosome-defective spermatozoa (P = 0.012) between -4 and 4 wpi. Significant deleterious effects on semen quality were detected for membrane integrity when semen had been stored for 2 days after sampling. Analysis of sperm subpopulations in a thermoresistance test on day 7 after sampling revealed alterations in the percentage of circular, progressively motile spermatozoa (P = 0.013), in the percentage of non-linear, progressively motile spermatozoa (P = 0.01), and on the amplitude of lateral sperm head displacement (P = 0.047). There was no difference in the incidence of mitochondrially active spermatozoa (P = 0.075). Investigation of routine production data between pre- and post-infection status showed no differences on ejaculate volume (P = 0.417), sperm concentration (P = 0.788), and percentage of motile spermatozoa (P = 0.321). This case report provides insights into a potential control strategy for PRRSV outbreaks in boar studs. PMID- 23442208 TI - Characterization of Enterococcus faecium with macrolide resistance and reduced susceptibility to quinupristin/dalfopristin in a Japanese hospital: detection of extensive diversity in erm(B)-regulator regions. AB - Cross-resistance to macrolide, lincosamide, and streptogramin B (MLSB) antibiotics is mainly mediated by the erm (erythromycin ribosome methylation) genes that encode 23S rRNA methylases in enterococi, and various mechanisms are involved in the streptogramin B resistance. Prevalence of MLSB resistance and its genetic mechanisms were analyzed for a total of 159 strains of Enterococcus faecium isolated from clinical specimens in a university hospital in Japan from 1997 to 2006. Resistance to erythromycin (EM) and clindamycin was detected in 88.1% and 89.9% of all the strains examined, respectively, and expression of resistance was totally constitutive. Although none of the strain was resistant to quinupristin/dalfopristin (Q/D), 28 strains (17.6%) showed intermediate resistance to Q/D (MIC: 2 MUg/ml). The erm(B) gene was detected in 139 strains (87.4%), and msrC was found in all the strains examined, whereas no other known MLSB resistance genes were identified. The erm(B) regulator region (RR) containing a coding region of the leader peptide was classified into 13 genetic variations (L1-L3, M, S1-S7, D, and R genotypes) in 56 strains. However, no relatedness was identified between the erm(B) RR genotype and EM resistance, or reduced susceptibility to Q/D, although most of Q/D-intermediate strains were assigned to the L1, L2, and S1 genotypes. Q/D-intermediate strains were classified into five multiple-locus variable-number tandem-repeat analysis (MLVA) types, including four types of clonal complex (CC)-C1, five sequence types (STs), including four STs of CC-17, and several resistance gene/virulence factor profiles. The present study revealed the occurrence of Q/D-intermediate E. faecium, which are composed of heterogeneous strains in Japan, and more genetic diversity in the erm(B) RRs than those reported previously. PMID- 23442209 TI - The steel scrap age. AB - Steel production accounts for 25% of industrial carbon emissions. Long-term forecasts of steel demand and scrap supply are needed to develop strategies for how the steel industry could respond to industrialization and urbanization in the developing world while simultaneously reducing its environmental impact, and in particular, its carbon footprint. We developed a dynamic stock model to estimate future final demand for steel and the available scrap for 10 world regions. Based on evidence from developed countries, we assumed that per capita in-use stocks will saturate eventually. We determined the response of the entire steel cycle to stock saturation, in particular the future split between primary and secondary steel production. During the 21st century, steel demand may peak in the developed world, China, the Middle East, Latin America, and India. As China completes its industrialization, global primary steel production may peak between 2020 and 2030 and decline thereafter. We developed a capacity model to show how extensive trade of finished steel could prolong the lifetime of the Chinese steelmaking assets. Secondary steel production will more than double by 2050, and it may surpass primary production between 2050 and 2060: the late 21st century can become the steel scrap age. PMID- 23442210 TI - Clinical usefulness of growth hormone secretion elicited by acute stimulation tests. PMID- 23442211 TI - Pitfalls and limitations in translation from biomarker discovery to clinical utility in predictive and personalised medicine. AB - Since the emergence of the so-called omics technology, thousands of putative biomarkers have been identified and published, which have dramatically increased the opportunities for developing more effective therapeutics. These opportunities can have profound benefits for patients and for the economics of healthcare. However, the transfer of biomarkers from discovery to clinical practice is still a process filled with lots of pitfalls and limitations, mostly limited by structural and scientific factors. To become a clinically approved test, a potential biomarker should be confirmed and validated using hundreds of specimens and should be reproducible, specific and sensitive. Besides the lack of quality in biomarker validation, a number of other key issues can be identified and should be addressed. Therefore, the aim of this article is to discuss a series of interpretative and practical issues that need to be understood and resolved before potential biomarkers become a clinically approved test or are already on the diagnostic market. Some of these issues are shortly discussed here. PMID- 23442212 TI - Endoscopic submucosal dissection for superficial esophageal neoplasms using the stag beetle knife. AB - Endoscopic submucosal dissection (ESD) is an accepted standard treatment for early gastric cancer but is not widely used in the esophagus because of technical difficulties. To increase the safety of esophageal ESD, we used a scissors-type device called the stag beetle (SB) knife. The aim of this study was to determine the efficacy and safety of ESD using the SB knife. We performed a single-center retrospective, uncontrolled trial. A total of 38 lesions were excised by ESD from 35 consecutive patients who were retrospectively divided into the following two groups according to the type of knife used to perform ESD: the hook knife (hook group) was used in 20 patients (21 lesions), and the SB knife (SB group) was used in 15 patients (17 lesions). We evaluated and compared the operative time, lesion size, en bloc resection rate, pathological margins free rate, and complication rate in both groups. The operative time was shorter in the SB group (median 70.0 minutes [interquartile range, 47.5-87.0]) than in the hook group (92.0 minutes [interquartile range, 63.0-114.0]) (P = 0.019), and the rate of complications in the SB group was 0% compared with 45.0% in the hook group (P = 0.004). However, the lesion size, en bloc resection rate, and pathological margins free rate did not differ significantly between the two groups. In conclusion, ESD using the SB knife was safer than that using a conventional knife for superficial esophageal neoplasms. PMID- 23442213 TI - Osteogenesis of mesenchymal stem cells by nanoscale mechanotransduction. AB - It is likely that mesenchymal stem cells will find use in many autologous regenerative therapies. However, our ability to control cell stem growth and differentiation is presently limited, and this is a major hurdle to the clinical use of these multipotent cells especially when considering the desire not to use soluble factors or complex media formulations in culture. Also, the large number of cells required to be clinically useful is currently a hurdle to using materials-based (stiffness, chemistry, nanotopography, etc.) culture substrates. Here we give a first demonstration of using nanoscale sinusoidal mechanotransductive protocols (10-14 nm displacements at 1 kHz frequency), "nanokicking", to promote osteoblastogenesis in human mesenchymal stem cell cultures. On the basis of application of the reverse piezo effect, we use interferometry to develop the optimal stem cell stimulation conditions, allowing delivery of nanoscale cues across the entire surface of the Petri dishes used. A combination of immunofluorescence, PCR, and microarray has then been used to demonstrate osteoblastogenesis, and the arrays implicate RhoA as central to osteoblastic differentiation in agreement with materials-based strategies. We validate this with pharmacological inhibition of RhoA kinase. It is easy to envisage such stimulation protocols being up-scaled to form large-scale osteoblast bioreactors as standard cell culture plates and incubators are used in the protocol. PMID- 23442214 TI - Measles outbreak in Northern Central African Republic 3 years after the last national immunization campaign. AB - BACKGROUND: Despite huge efforts to promote widespread vaccination, measles remains an important cause of morbidity and mortality worldwide, especially in African children. In March 2011, an abnormally high number of cases were reported from the Ouham Prefecture, Central African Republic to the national measles case based surveillance system. In response, reactive vaccination activities were implemented. The aims of this study were to investigate this outbreak and describe the response. METHODS: Measles cases were defined according to WHO recommendations. In the first weeks of the outbreak, blood samples were collected and sent to the Institut Pasteur in Bangui for laboratory confirmation by detection of IgM antibodies against measles virus. In addition, a portion of viral RNA was amplified from 5 IgM positive patient samples and the amplicons were sequenced for phylogenetic analysis. RESULTS: Between March and September 2011, 723 clinical cases originated from the Ouham Prefecture, including 2 deaths, were reported. Amongst 59 blood samples collected, 49 were positive for the detection of IgM. A high number of self-declared vaccinated subjects (31%) were found amongst the cases. Most of the cases were under 5 years. The causative virus was found to belong to genotype B3.1. In response, 2 sub-national supplementary immunization activities were quickly conducted and limited this outbreak to mainly 2 sub-prefectures. CONCLUSIONS: This outbreak was the largest epidemic of measles in CAR since 2002. Its occurrence, 3 years after the last national immunization campaign, highlights the necessity to pursue efforts and improve and extend immunization programs in order to reach measles elimination goal in Africa. PMID- 23442215 TI - Racial differences in cigarette brand recognition and impact on youth smoking. AB - BACKGROUND: African Americans are disproportionately exposed to cigarette advertisements, particularly for menthol brands. Tobacco industry documents outline strategic efforts to promote menthol cigarettes to African Americans at the point of sale, and studies have observed more outdoor and retail menthol advertisements in neighborhoods with more African-American residents. Little research has been conducted to examine the effect of this target marketing on adolescents' recognition of cigarette brand advertising and on smoking uptake. To our knowledge, this is the first study to examine racial differences in brand recognition and to assess the prospective relationship between brand recognition and smoking uptake. METHODS: School-based surveys assessing tobacco use and environmental and social influences to smoke were administered to 6th through 9th graders (ages 11 to 15) in an urban and racially diverse California school district. The primary outcome for the cross-sectional analysis (n = 2,589) was brand recognition, measured by students' identification of masked tobacco advertisements from the point of sale. The primary outcome for the longitudinal analysis (n = 1,179) was progression from never to ever smoking within 12 months. RESULTS: At baseline, 52% of students recognized the Camel brand, 36% Marlboro, and 32% Newport. African-American students were three times more likely than others to recognize Newport (OR = 3.03, CI = 2.45, 3.74, p < 0.01) and less likely than others to recognize Marlboro (OR = 0.60, CI = 0.48, 0.73, p < 0.01). At follow-up, 17% of never smokers reported trying smoking. In this racially diverse sample, brand recognition of Camel and Marlboro did not predict smoking initiation. Regardless of race, students who recognized the Newport brand at baseline were more likely to initiate smoking at follow-up (OR = 1.49, CI = 1.04, 2.15, p < 0.05) after adjusting for shopping frequency and other risk factors. CONCLUSIONS: The study findings illustrate that African-American youth are better able to recognize Newport cigarette advertisements, even after adjustment for exposure to smoking by parents and peers. In addition, recognition of Newport cigarette advertising predicted smoking initiation, regardless of race. This longitudinal study contributes to a growing body of evidence that supports a ban on menthol flavored cigarettes in the US as well as stronger regulation of tobacco advertising at the point of sale. PMID- 23442216 TI - Development and implementation of a mini-Clinical Evaluation Exercise (mini-CEX) program to assess the clinical competencies of internal medicine residents: from faculty development to curriculum evaluation. AB - BACKGROUND: The mini-CEX is a valid and reliable method to assess the clinical competencies of trainees. Its data could be useful for educators to redesign curriculum as a process of quality improvement. The aim of this study was to evaluate a mini-CEX assessment program in our internal medicine residency training. We investigated the impact of mini-CEX workshops as a faculty development program on the acquisition of cognitive knowledge and the difference of practice behaviors among faculty members used the mini-CEX to assess residents' performance at work. METHODS: We designed an observational, two-phase study. In the faculty development program, we started a mini-CEX workshop for trainers in 2010, and the short-term outcome of the program was evaluated by comparing the pretest and posttest results to demonstrate the improvement in cognitive knowledge on mini-CEX. From September 2010 to August 2011, we implemented a monthly mini-CEX assessment program in our internal medicine residency training. The data of these mini-CEX assessment forms were collected and analyzed. RESULTS: In the group of 49 mini-CEX workshop attendees, there was a statistically significant improvement in cognitive knowledge by comparing the pretest and posttest results (67.35 +/- 15.25 versus 81.22 +/- 10.34, p < 0.001). Among the 863 clinical encounters of mini-CEX, which involved 97 residents and 139 evaluators, 229 (26.5%), 326 (37.8%), and 308 (35.7%) evaluations were completed by the first-year, second-year, and third- year residents separately. We found a statistically significant interaction between level of training and score in dimensions of mini-CEX. The scores in all dimensions measured were better for senior residents. Participation in mini-CEX workshops as a faculty development program strengthened the adherence of trainers to the principles of mini-CEX as a formative assessment in regard to provision of feedback. However, a deficiency in engaging residents' reflection was found. CONCLUSIONS: Faculty development is a prerequisite to train evaluators in order to implement a successful mini-CEX assessment program. We demonstrated the effectiveness of our mini-CEX workshops in terms of knowledge acquisition and enhancement of giving feedback when the faculty members used the tool. Further programs on providing effective feedback should be conducted to increase the impact of the mini-CEX as a formative assessment. PMID- 23442217 TI - Molecular docking between the RNA polymerase of the Moniliophthora perniciosa mitochondrial plasmid and Rifampicin produces a highly stable complex. AB - BACKGROUND: Moniliophthora perniciosa (Stahel) Aime & Phillips-Mora is the causal agent of witches' broom disease (WBD) in cacao (Theobroma cacao). When the mitochondrial genome of this fungus had been completely sequenced, an integrated linear-type plasmid that encodes viral-like RNA polymerases was found. The structure of this polymerase was previously constructed using a homology modeling approach. METHODS: Using a virtual screening process, accessing the Kegg, PubChem and ZINC databases, we selected the eight most probable macrocyclic polymerase inhibitors to test against M. perniciosa RNA polymerase (RPO). AutoDock Vina was used to perform docking calculations for each molecule. This software returned affinity energy values for several ligand conformations. Subsequently, we used PyMOL 1.4 and Ligand Scout 3.1 to check the stereochemistry of chiral carbons, substructure, superstructure, number of rotatable bonds, number of rings, number of donor groups, and hydrogen bond receptors. RESULTS: On the basis of this evidence we selected Rifampicin, a bacterial RNA polymerase inhibitor, and then AMBER 12 was used to simulate the behavior of the RPO-Rifampicin complex after a set of 5000 ps and up to 300 K in water. This calculation returned a graph of potential energy against simulation time and showed that the ligand remained inside the active site after the simulation was complete, with an average energy of -15 x 10(2) Kcal/Mol. CONCLUSIONS: The results indicate that Rifampicin could be a good inhibitor for testing in vitro and in vivo against M. perniciosa. PMID- 23442218 TI - Assessing social cognition and pragmatic language in adolescents with traumatic brain injuries. AB - Traumatic brain injuries (TBI) in children and adolescents can impair social cognition and communication skills but there are few assessment tools suitable for adolescents. The Awareness of Social Inference Test (TASIT) uses professionally enacted audiovisual vignettes of everyday conversational exchanges and is a valid measure of social perception disorders in adults. This study examined its utility for assessing impairments in social cognition in a group of 16 adolescents with TBI, compared to a group of 16 typically developing (TD) adolescents. Adolescents with TBI were, on average, no different to their TD peers on TASIT 1 (emotion recognition) and TASIT 3 (recognizing lies and sarcasm when provided with additional cues) but performed more poorly on TASIT 2 which required them to interpret sarcastic and sincere conversational exchanges with few cues other than the demeanor of the speakers. Within the TBI group, poor performance on TASIT correlated to both relative and self-reported communication difficulties at home. It also correlated with IQ, face recognition and severity of injury as indexed by duration of post-traumatic amnesia. Overall, this study suggests TASIT is a valid measure for adolescents although it raised questions as to how effective normative data is for comparing performance in social cognition during childhood and adolescence. PMID- 23442219 TI - An overview of the health care system in Georgia: expert recommendations in the context of predictive, preventive and personalised medicine. AB - The main aim of this paper is to present the current statistics and situation of health care system in Georgia; the changes in the transition period within the society and the health care system. Also presented are the efforts from the Government and the Ministry of Labour, Health and Social Affairs of Georgia in the way of numerous initiatives and action in order to improve quality care of patients and sustain the health care system. This paper described the institutional framework, process, content and implementation of health and health care policies in Georgia in the context of predictive, preventive and personalised medicine. PMID- 23442220 TI - Accuracy and interrater reliability for the diagnosis of Barrett's neoplasia among users of a novel, portable high-resolution microendoscope. AB - The high-resolution microendoscope (HRME) is a novel imaging modality that may be useful in the surveillance of Barrett's esophagus in low-resource or community based settings. In order to assess accuracy and interrater reliability of microendoscopists in identifying Barrett's-associated neoplasia using HRME images, we recruited 20 gastroenterologists with no microendoscopic experience and three expert microendoscopists in a large academic hospital in New York City to interpret HRME images. They prospectively reviewed 40 HRME images from 28 consecutive patients undergoing surveillance for metaplasia and low-grade dysplasia and/or evaluation for high-grade dysplasia or cancer. Images were reviewed in a blinded fashion, after a 4-minute training with 11 representative images. All imaged sites were biopsied and interpreted by an expert pathologist. Sensitivity of all endoscopists for identification of high-grade dysplasia or cancer was 0.90 (95% confidence interval [CI]: 0.88-0.92) and specificity was 0.82 (95% CI: 0.79-0.85). Positive and negative predictive values were 0.72 (95% CI: 0.68-0.77) and 0.94 (95% CI: 0.92-0.96), respectively. No significant differences in accuracy were observed between experts and novices (0.90 vs. 0.84). The kappa statistic for all raters was 0.56 (95% CI: 0.54-0.58), and the difference between groups was not significant (0.64 vs. 0.55). These data suggest that gastroenterologists can diagnose Barrett's-related neoplasia on HRME images with high sensitivity and specificity, without the aid of prior microendoscopy experience. PMID- 23442221 TI - Patterns and determinants of breastfeeding and complementary feeding practices of Emirati Mothers in the United Arab Emirates. AB - BACKGROUND: Breastfeeding is the preferred method of feeding for the infant. The present study aimed at investigating the different infant feeding practices and the influencing factors in the United Arab Emirates (UAE). METHODS: A convenient sample of 593 Emirati mothers who had infants up to 2 years of age was interviewed. The interviews included a detailed questionnaire and conducted in the Maternal and Child Health Centers (MCH) and Primary Health Centers (PHC) in three cities. RESULTS: Almost all the mothers in the study had initiated breastfeeding (98%). The mean duration of breastfeeding was 8.6 months. The initiation and duration of breastfeeding rates were influenced by mother's age (P<0.034)and education(P<0.01), parity(OR=2.13; P<0.001), rooming in(OR=21.70; P<0.001), nipple problem(P<0.010) and use of contraception(P<0.034). As for the feeding patterns, the results of the multiple logistic analyses revealed that rooming in (OR=4.48; P<0.001), feeding on demand (OR=2.29; P<0.005) and feeding more frequently at night (P<0.001) emerged as significant factors associated with exclusive or predominantly breastfeeding practices. Among the 593 infants in the study, 24.1% had complementary feeding, 25% of the infants were exclusively breastfed, and 49.4% were predominantly breastfed since birth. About 30% of the infants were given nonmilk fluids such as: Anis seed drink (Yansun), grippe water and tea before 3 months of age. The majority of the infants (83.5%) in the three areas received solid food before the age of 6 months. A variety of reasons were reported as perceived by mothers for terminating breastfeeding. The most common reasons were: new pregnancy (32.5%), insufficient milk supply (24.4%) and infant weaned itself (24.4%). CONCLUSIONS: In conclusion, infant and young child feeding practices in this study were suboptimal. There is a need for a national community based breastfeeding intervention programme and for the promotion of exclusive breastfeeding as part of a primary public health strategy to decrease health risks and problems in the UAE. PMID- 23442222 TI - Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation. AB - BACKGROUND: Genetic susceptibility to colonic inflammation is poorly defined at the gene level. Although Genome Wide Association studies (GWAS) have identified loci in the human genome which confer susceptibility to Inflammatory Bowel Disease (Crohn's and Ulcerative Colitis), it is not clear if precise loci exist which confer susceptibility to inflammation at specific locations within the gut e.g. small versus large intestine. Susceptibility loci for colitis in particular have been defined in the mouse, although specific candidate genes have not been identified to date. We have previously shown that infection with Trichuris muris (T. muris) induces chronic colitis in susceptible mouse strains with clinical, histological, and immunological homology to human colonic Crohn's disease. We performed an integrative analysis of colitis susceptibility, using an F2 inter cross of resistant (BALB/c) and susceptible (AKR) mice following T. muris infection. Quantitative Trait Loci (QTL), polymorphic and expression data were analysed alongside in silico workflow analyses to discover novel candidate genes central to the development and biology of chronic colitis. RESULTS: 7 autosomal QTL regions were associated with the establishment of chronic colitis following infection. 144 QTL genes had parental strain SNPs and significant gene expression changes in chronic colitis (expression fold-change >= +/-1.4). The T. muris QTL on chromosome 3 (Tm3) mapped to published QTL in 3 unrelated experimental models of colitis and contained 33 significantly transcribed polymorphic genes. Phenotypic pathway analysis, text mining and time-course qPCR replication highlighted several potential cis-QTL candidate genes in colitis susceptibility, including FcgR1, Ptpn22, RORc, and Vav3. CONCLUSION: Genetic susceptibility to induced colonic mucosal inflammation in the mouse is conserved at Tm3 and overlays Cdcs1.1. Genes central to the maintenance of intestinal homeostasis reside within this locus, implicating several candidates in susceptibility to colonic inflammation. Combined methodology incorporating genetic, transcriptional and pathway data allowed identification of biologically relevant candidate genes, with Vav3 newly implicated as a colitis susceptibility gene of functional relevance. PMID- 23442223 TI - Morphological and acrosomal changes of canine spermatozoa during epididymal transit. AB - BACKGROUND: During epididymal transit, functional and structural modifications leading to full maturation enable male gametes to reach, recognize and fertilize the oocytes. In dogs, little is known on the modifications of spermatozoa during the passage in the epididymis. The aim of this study was to describe the motility, morphology and acrosomal patterns of canine spermatozoa retrieved from the epididymis caput, corpus and cauda. RESULTS: After the dilution required for the collection of epididymal content, sperm motility was significantly higher (P<0.0001) in the cauda compared to corpus and caput. Proportions of spermatozoa with normal morphology were significantly higher in corpus (P=0.02) and cauda (P<0.0001) compared to caput. Overall morphological abnormalities of the head and neck/midpiece were similar in the three different epididymal regions. A significantly increased prevalence of tail defects, mainly represented by single bent tails, was observed in the corpus compared to caput (P<0.0001) and cauda (P=0.006). Numbers of immature sperm with cytoplasmic droplets decreased from the proximal to the distal region of the epididymis. Particularly, proximal cytoplasmic droplets were more frequently found in spermatozoa collected from the caput epididymis than in the corpus (P<0.0001) and in the cauda (P<0.0001), whereas the occurrence of distal cytoplasmic droplets was higher in the corpus than in the caput (P=0.0003) and in the cauda (P<0.05). Significantly higher proportions of spermatozoa with intact acrosomes were retrieved from the cauda epididymis than from the caput (P=0.03) and the corpus (P=0.008). This difference was mainly due to a lower proportion of spermatozoa with abnormal acrosomes (mainly swollen acrosomes) rather than with absent acrosomes. CONCLUSIONS: Canine spermatozoa undergo several modifications in the epididymis. The acquisition of progressive motility, migration of the cytoplasmic droplet and acrosomal reshaping lead to mature spermatozoa which are then stored in the cauda epididymis. From this site, spermatozoa can be retrieved and used in assisted reproductive techniques as a valuable tool for propagating genetic traits of high value individuals that dies accidentally or undergoes orchiectomy for medical purposes. Further investigations should be also focused on the potential use of spermatozoa recovered from other epididymal regions. PMID- 23442224 TI - Evidence for IFNalpha-induced, SAMHD1-independent inhibitors of early HIV-1 infection. AB - BACKGROUND: Type I interferon (IFN) treatment of some cells, including dendritic cells, macrophages and monocytic THP-1 cells, restricts HIV-1 infection and prevents viral cDNA accumulation. Sterile alpha motif and HD domain protein 1 (SAMHD1), a dGTP-regulated deoxynucleotide triphosphohydrolase, reduces HIV-1 infectivity in myeloid cells, likely by limiting dNTPs available for reverse transcription, and has been described as IFNalpha-inducible. Myeloid cell infection by HIV-1 is enhanced by HIV-2/SIVSM Vpx, which promotes SAMHD1 degradation, or by exogenous deoxyribonucleoside (dN) addition. FINDINGS: SAMHD1 expression was not substantially influenced by IFNalpha treatment of monocyte derived macrophages or THP-1 cells. The contributions of SAMHD1 to the inhibition of HIV-1 infectivity by IFNalpha were assessed through the provision of Vpx, exogenous dN addition, or via RNAi-mediated SAMHD1 knock-down. Both Vpx and dN efficiently restored infection in IFNalpha-treated macrophages, albeit not to the levels seen with these treatments in the absence of IFNalpha. Similarly using differentiated THP-1 cells, the addition of Vpx or dNs, or SAMHD1 knock-down, also stimulated infection, but failing to match the levels observed without IFNalpha. Neither Vpx addition nor SAMHD1 knock-down reversed the IFNalpha induced blocks to HIV-1 infection seen in dividing U87-MG or THP-1 cells. Therefore, altered SAMHD1 expression or function cannot account for the IFNalpha induced restriction to HIV-1 infection seen in many cells and cell lines. CONCLUSION: IFNalpha establishes an anti-HIV-1 phenotype in many cell types, and appears to accomplish this without potentiating SAMHD1 function. We conclude that additional IFNalpha-induced suppressors of the early stages of HIV-1 infection await identification. PMID- 23442225 TI - Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes. AB - BACKGROUND: The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas beta-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. METHODS/DESIGN: This is a 2*2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. DISCUSSION: This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. TRIAL REGISTRATION: ChiCTR-TRC-12002546. PMID- 23442226 TI - Attenuated neural response to gamble outcomes in drug-naive patients with Parkinson's disease. AB - Parkinson's disease results from the degeneration of dopaminergic neurons in the substantia nigra, manifesting as a spectrum of motor, cognitive and affective deficits. Parkinson's disease also affects reward processing, but disease-related deficits in reinforcement learning are thought to emerge at a slower pace than motor symptoms as the degeneration progresses from dorsal to ventral striatum. Dysfunctions in reward processing are difficult to study in Parkinson's disease as most patients have been treated with dopaminergic drugs, which sensitize reward responses in the ventral striatum, commonly resulting in impulse control disorders. To circumvent this treatment confound, we assayed the neural basis of reward processing in a group of newly diagnosed patients with Parkinson's disease that had never been treated with dopaminergic drugs. Thirteen drug-naive patients with Parkinson's disease and 12 healthy age-matched control subjects underwent whole-brain functional magnetic resonance imaging while they performed a simple two-choice gambling task resulting in stochastic and parametrically variable monetary gains and losses. In patients with Parkinson's disease, the neural response to reward outcome (as reflected by the blood oxygen level-dependent signal) was attenuated in a large group of mesolimbic and mesocortical regions, comprising the ventral putamen, ventral tegmental area, thalamus and hippocampus. Although these regions showed a linear response to reward outcome in healthy individuals, this response was either markedly reduced or undetectable in drug naive patients with Parkinson's disease. The results show that the core regions of the meso-cortico-limbic dopaminergic system, including the ventral tegmental area, ventral striatum, and medial orbitofrontal cortex, are already significantly compromised in the early stages of the disease and that these deficits cannot be attributed to the contaminating effect of dopaminergic treatment. PMID- 23442227 TI - The UK Clinical Aptitude Test and clinical course performance at Nottingham: a prospective cohort study. AB - BACKGROUND: The UK Clinical Aptitude Test (UKCAT) was introduced in 2006 as an additional tool for the selection of medical students. It tests mental ability in four distinct domains (Verbal Reasoning, Quantitative Reasoning, Abstract Reasoning, and Decision Analysis), and the results are available to students and admission panels in advance of the selection process. Our first study showed little evidence of any predictive validity for performance in the first two years of the Nottingham undergraduate course.The study objective was to determine whether the UKCAT scores had any predictive value for the later parts of the course, largely delivered via clinical placements. METHODS: Students entering the course in 2007 and who had taken the UKCAT were asked for permission to use their anonymised data in research. The UKCAT scores were incorporated into a database with routine pre-admission socio-demographics and subsequent course performance data. Correlation analysis was followed by hierarchical multivariate linear regression. RESULTS: The original study group comprised 204/254 (80%) of the full entry cohort. With attrition over the five years of the course this fell to 185 (73%) by Year 5. The Verbal Reasoning score and the UKCAT Total score both demonstrated some univariate correlations with clinical knowledge marks, and slightly less with clinical skills. No parts of the UKCAT proved to be an independent predictor of clinical course marks, whereas prior attainment was a highly significant predictor (p <0.001). CONCLUSIONS: This study of one cohort of Nottingham medical students showed that UKCAT scores at admission did not independently predict subsequent performance on the course. Whilst the test adds another dimension to the selection process, its fairness and validity in selecting promising students remains unproven, and requires wider investigation and debate by other schools. PMID- 23442229 TI - The summer of hydrogen sulfide: highlights from two international conferences. AB - A great deal of interest has been paid recently to the hydrogen sulfide, the newest member of the gasotransmitter family. With the growing interest in the biology of H2S, the need for meetings and conferences dedicated solely to the field of H2S has also grown. In 2009, scientist from around the world met in Shanghai, China for the first time to discuss the physiological relevance of H2S. In 2012, two conferences were organized to bring scientists, clinicians, and industry representatives together to discuss the latest breakthroughs concerning the emergent field of H2S. The following is a summary report of The First European Conference on the Biology of Hydrogen Sulfide and the Second International Conference on Hydrogen Sulfide Biology and Medicine. PMID- 23442228 TI - Structural basis for dual roles of Aar2p in U5 snRNP assembly. AB - Yeast U5 small nuclear ribonucleoprotein particle (snRNP) is assembled via a cytoplasmic precursor that contains the U5-specific Prp8 protein but lacks the U5 specific Brr2 helicase. Instead, pre-U5 snRNP includes the Aar2 protein not found in mature U5 snRNP or spliceosomes. Aar2p and Brr2p bind competitively to a C terminal region of Prp8p that comprises consecutive RNase H-like and Jab1/MPN like domains. To elucidate the molecular basis for this competition, we determined the crystal structure of Aar2p in complex with the Prp8p RNase H and Jab1/MPN domains. Aar2p binds on one side of the RNase H domain and extends its C terminus to the other side, where the Jab1/MPN domain is docked onto a composite Aar2p-RNase H platform. Known Brr2p interaction sites of the Jab1/MPN domain remain available, suggesting that Aar2p-mediated compaction of the Prp8p domains sterically interferes with Brr2p binding. Moreover, Aar2p occupies known RNA binding sites of the RNase H domain, and Aar2p interferes with binding of U4/U6 di-snRNA to the Prp8p C-terminal region. Structural and functional analyses of phospho-mimetic mutations reveal how phosphorylation reduces affinity of Aar2p for Prp8p and allows Brr2p and U4/U6 binding. Our results show how Aar2p regulates both protein and RNA binding to Prp8p during U5 snRNP assembly. PMID- 23442230 TI - Pyomyositis associated with chemotherapy for endometrial cancer: a case report. AB - Pyomyositis is a rare complication of chemotherapy for non-hematological malignancies. A 58-year-old woman with endometrial carcinoma, in whom pyomyositis developed during adjuvant chemotherapy, was presented in this report. After initiating empiric antibiotic therapy for febrile neutrocytopenia, screening CT showed multiple abscesses in the lower limbs. Operative drainage of the abscess was effective. PMID- 23442231 TI - Genetically obese mice do not show increased gut permeability or faecal bile acid hydrophobicity. AB - Gut barrier dysfunction may lead to metabolic endotoxaemia and low-grade inflammation. Recent publications have demonstrated gut barrier dysfunction in obesity induced by a diet high in fat, and a pathogenetic role for luminal bile acids has been proposed. We aimed to investigate whether genetically obese mice develop increased gut permeability and alterations in luminal bile acids on a diet with a regular fat content. We used seven obese male ob/ob mice of C57BL/6J background and ten male wild-type (WT) mice of the same strain. Faeces were collected for bile acid analysis. Intestinal permeability was measured in an Ussing chamber upon euthanasia, using 4 kDa fluorescein isothiocyanate dextran, as per mille (0/00, 1/1000) of translocated dextran. We analysed the liver expression of lipopolysaccharide-binding protein (LBP), as well as serum LBP (ELISA). Intestinal permeability was not affected by genetic obesity (jejunum: 0.234 (sem 0.04) 0/00 for obese v. 0.225 (sem 0.03) 0/00 for WT, P= 0.93; colon: 0.222 (sem 0.06) 0/00 for obese v. 0.184 (sem 0.03) 0/00 for WT, P= 0.86), nor was liver LBP expression (relative expression: 0.55 (sem 0.08) for obese v. 0.55 (sem 0.13) for WT, P= 0.70). Serum LBP was 2.5-fold higher in obese than in WT mice (P= 0.001). Obese mice had increased daily excretion of total bile acids, but their faecal bile acid hydrophobicity was unchanged. In conclusion, genetic obesity did not impair gut barrier function in mice on a regular chow diet, nor was faecal bile acid hydrophobicity affected. PMID- 23442233 TI - A tribute to the late Prof. Yukihiko Nose. PMID- 23442232 TI - Dietary pattern and hypertension in Korean adults. AB - OBJECTIVE: To assess the dietary pattern associated with hypertension and pre hypertension among Korean male and female adults. DESIGN: Cross-sectional study from a representative sample of the Korean population. SETTING: The Korea National Health and Nutrition Examination Survey IV, which was conducted in 2007 and 2008. SUBJECTS: Males and females (n 5308) over the age of 20 years. RESULTS: Scores for three major dietary patterns ('whole food', 'Western' and 'drinking') were generated using a factor analysis of thirty predefined food groups based on the food items consumed. We used polytomous logistic regression analyses to obtain odds ratios and 95% confidence intervals for pre-hypertension and hypertension. Participants with a high drinking pattern score (moderate to high alcohol intake, salted fermented seafood intake) had a significantly higher prevalence of pre-hypertension or hypertension than those with a lower drinking pattern score; odds for the top quintile v. the bottom quintile were OR = 1.56 (95% CI 1.23, 1.99; P trend = 0.001) for pre-hypertension and OR = 3.05 (95% CI 2.12, 4.40; P trend < 0.001) for hypertension. The whole food pattern was not associated with either pre-hypertension or hypertension, while the Western pattern was associated with the prevalence of hypertension only among men. CONCLUSIONS: Our finding warrants further prospective studies to examine whether alcohol drinking and salty food consumption increase the risk of developing hypertension in Koreans. PMID- 23442234 TI - Dr. Yukihiko Nose: living his dream. AB - Dr. Yukihiko Nose made many contributions to medical science and in particular in the area of artificial organ technologies and their clinical applications. His passing was a great loss not only to many individuals but also to the field. His enthusiasm and passion for his work was very positive on those with whom he worked while inspiring others in friendly competition. It is very difficult to recount his many accomplishments. I have outlined those developments that I was directly involved with him at the Cleveland Clinic. These developments may be grouped under the heading of Metabolic and Immunologic Support, the name given to our research team. I hope in some small way this review also gives credit to the contributions of the many scientific and clinical professionals that were part of our teams through the years as noted in the extensive reference list provided and the support of the many industrial and corporate sponsors that we were privileged to be associated with and their developments that we studied, improved on, and applied. PMID- 23442235 TI - Effect of a bearing gap on hemolytic property in a hydrodynamically levitated centrifugal blood pump with a semi-open impeller. AB - We have developed a hydrodynamically levitated centrifugal blood pump with a semi open impeller for long-term circulatory assist. The pump uses hydrodynamic bearings to enhance durability and reliability without additional displacement sensors or control circuits. However, a narrow bearing gap of the pump has a potential for hemolysis. The purpose of this study is to develop the hydrodynamically levitated centrifugal blood pump with a semi-open impeller, and to evaluate the effect of a bearing gap on hemolytic property. The impeller levitates using a spiral-groove type thrust bearing, and a herringbone-groove type radial bearing. The pump design was improved by adopting a step type thrust bearing and optimizing the pull-up magnetic force. The pump performance was evaluated by a levitation performance test, a hemolysis test and an animal experiment. In these tests, the bearing gap increased from 1 to 63 MUm. In addition, the normalized index of hemolysis (NIH) improved from 0.415 to 0.005 g/100 l, corresponding to the expansion of the bearing gap. In the animal experiment for 24 h, the plasma-free hemoglobin remained within normal ranges (<4.0 mg/dl). We confirmed that the hemolytic property of the pump was improved to the acceptable level by expanding the bearing gap greater than 60 MUm. PMID- 23442236 TI - Evaluation of floating impeller phenomena in a Gyro centrifugal pump. AB - The Gyro centrifugal pump developed as a totally implantable artificial heart was designed with a free impeller, in which the rotational shaft (male bearing) of the impeller was completely separated from the female bearing. For this type of pump, it is very important to keep the proper magnet balance (impeller-magnet and actuator-magnet) in order to prevent thrombus formation and/or bearing wear. When the magnet balance is not proper, the impeller is jerked down into the bottom bearing. On the other hand, if magnet balance is proper, the impeller lifted off the bottom of the pump housing within a certain range of pumping conditions. In this study, this floating phenomenon was investigated in detail. The floating phenomenon was proved by observation of the impeller behavior using a transparent acrylic pump. The impeller floating phenomenon was mapped on a pump performance curve. The impeller floating phenomenon is affected by the magnet-magnet coupling distance and rotational speed of the impeller. In order to keep the proper magnet balance and to maintain the impeller floating phenomenon at the driving condition of right and left pump, the magnet-magnet coupling distance was altered by a spacer which was installed between the pump and actuator. It became clear that the same pump could handle different conditions (right and left ventricular assist), by just changing the thickness of the spacer. When magnet balance is proper, the floating impeller phenomenon occurs automatically in response to the impeller rev. It is called "the dynamic RPM suspension". PMID- 23442237 TI - Current devices for pediatric extracorporeal life support and mechanical circulatory support systems in the United States. AB - Extracorporeal life support (ECLS) and mechanical circulatory support (MCS) have become indispensable treatment tools for pediatric patients with congenital heart defects undergoing peri-operative or end-stage heart and/or lung failure. ECLS and MCS can serve as bridges to recovery, transplantation (heart or lung), destination therapy, or "bridge to bridge" long-term MCS. Dependent on patient condition, venoarterial ECMO (V-A ECMO) for heart and lung support, venovenous ECMO (V-V ECMO) for respiratory support, and MCS for uni- and biventricular support can be selected properly. Considering small patient body size, the access sites and cannulation should be selected carefully to obtain adequate blood flow, minimum injury, and easy management. The applying equipment, including tubing, cannulae, oxygenator and blood pump, need to be selected optimally in order to enable rapid setup and priming, successful cannulation and early support, and to reduce the risk of device-related morbidity and mortality. The aim of this review manuscript was to discuss briefly the current devices for pediatric ECLS and MCS available in US. PMID- 23442238 TI - A magnetic fluid seal for rotary blood pumps: Behaviors of magnetic fluids in a magnetic fluid seal. AB - A magnetic fluid (MF) seal has excellent durability. The performance of an MF seal, however, has been reported to decrease in liquids (several days). We have developed an MF seal that has a shield mechanism. The seal was perfect for 275 days in water. To investigate the effect of a shield, behaviors of MFs in a seal in water were studied both experimentally and computationally. (a) Two kinds of MF seals, one with a shield and one without a shield, were installed in a centrifugal pump. Behaviors of MFs in the seals in water were observed with a video camera and high-speed microscope. In the seal without a shield, the surface of the water in the seal waved and the turbulent flow affected behaviors of the MFs. In contrast, MFs rotated stably in the seal with a shield in water even at high rotational speeds. (b) Computational fluid dynamics analysis revealed that a stationary secondary flow pattern in the seal and small velocity difference between magnetic fluid and water at the interface. These MF behaviors prolonged the life of an MF seal in water. PMID- 23442239 TI - Correlation between the characteristics of acceleration and visco elasticity of artery wall under pulsatile flow conditions (physical meaning of I* as a parameter of progressive behaviors of atherosclerosis and arteriosclerosis). AB - Previously, I* parameter has been proposed to diagnose noninvasively the progressive degree of atherosclerosis which is considered to concern the discrimination of the progressive degree of visco elasticity of blood vessel wall. However, the detailed physical meaning of this parameter has not yet been clarified. In this paper, the theoretical analysis and experiments were conducted and the detailed physical meaning of I* parameter was clarified. The following results were obtained. I* parameter was found to well correlate with the progressive degree of visco elasticity of blood vessel wall characterized by the Ith* parameter derived based on the analysis of visco elasticity in this paper. That is, I* was found to have the physical meaning of representing the progressive degree of visco elasticity of blood vessel wall. On the basis of this results, using clinical data, two dimensional representation between the progressive degree of visco elasticity of blood vessel wall by I* and the decrease in the rigidity of blood vessel wall by PWV was found to be useful to conduct much more detailed diagnosis of atherosclerosis. PMID- 23442240 TI - Failed attempts and improvement strategies in peripheral intravenous catheterization. AB - BACKGROUND: Access to peripheral veins is necessary for sample collection, transfusion and infusion of fluids or medications. The peripheral intravenous catheterization (PIVC) procedure is the introduction of a short catheter into a peripheral vein and can be problematic, leading to multiple failed attempts. PURPOSE: To analyze scientific literature regarding difficulties in establishing peripheral intravenous access and improvement strategies. METHOD: A literature search was undertaken and secondary references were retrieved from the papers obtained from the initial search. A total of 128 papers published from 1975 to 2011 were reviewed. RESULTS: The first attempt of PIVC fails in 12-26% of adults and 24-54% of children. Factors associated with the currently utilized PIVC success include: (1) patient's characteristics such as age, gender, race, weight/BMI, co-existing medical conditions and skin/vein characteristics, (2) procedure related factors such as the insertion site and catheter caliber, and (3) the operator's expertise. Strategies to improve PIVC success include: (1) bedside techniques such as venodilation, vascular visualization and vein entry indication, (2) pain management and (3) engagement of expert health care providers. CONCLUSION: Bedside techniques have shown more improvement in PIVC success rates as opposed to pain management. Expert health care providers have shown higher performance levels with regard to the difficult cases of PIVC. PMID- 23442241 TI - Perioperative glycemic control using an artificial endocrine pancreas in patients undergoing total pancreatectomy: tight glycemic control may be justified in order to avoid brittle diabetes. AB - I dedicate this paper to the late Prof. Yukihiko Nose with all my heart. In 2001, under the direction of Prof. Nose and Prof. Brunicardi at Baylor College of Medicine, we published a review article entitled "Artificial endocrine pancreas" in JACS. Subsequently, we reported that perioperative tight glycemic control (TGC) using an artificial pancreas (AP) with a closed-loop system could stably maintain near-normoglycemia in total-pancreatectomized dogs. Based on this experimental study in Houston, since 2006, we have introduced perioperative TGC using an AP into clinical use in Kochi. As of 2011, this novel TGC method has provided safe and stable blood glucose levels in more than 400 surgical patients. In this paper, we report new clinical findings regarding perioperative TGC using an AP in total-pancreatectomized patients. TGC using an AP enables us to achieve stable glycemic control not only without hypoglycemia and hyperglycemia but also with less variation in blood glucose concentration from the target blood glucose range, even in patients with the most serious form of diabetes, so-called "brittle diabetes", undergoing total pancreatectomy. To the best of our knowledge, this is the first clinical report of TGC using an AP in patients undergoing total pancreatic resection. PMID- 23442242 TI - Application of magnetic field for biological response modification. AB - The study of magnetic effects on biological system was started in response to Dr. Nose's wish for the development of extracorporeal immunomodulation therapy. In the extracorporeal immunomodulation system, monocytes or lymphocytes in blood are stimulated by the interactions with immune-active materials. The concept of magnetic field application was introduced in order to enhance the cell activation. Therefore, the applicability of magnetic field was studied. This paper was concerned with in vitro study of magnetic field effects on macrophage/monocytes and lymphocytes activations. Time-varying magnetic field could enhance macrophages/monocytes and lymphocytes activations. PMID- 23442243 TI - Biocompatibility: bioengineering aspects. AB - Bioengineers have contributed to biocompatibility research. Many materials have been designed, synthesized and characterized by use of various analytical instruments. The blood compatibility of materials has been studied by focusing on the blood-material interfacial reactions. Although much information has been accumulated regarding such local reactions, understanding of biocompatibility is still limited. A more global approach to study is needed. A new approach to understanding biocompatibility is proposed and discussed. Three points are stressed: interaction within body's defense system and its effect on blood material reactions; induction of a systemic reaction by a local reaction, which then affects the blood-material interaction; the time sequence of such interactions between local and systemic reactions. To establish a logical approach to study biocompatibility is most important at this moment for the future progress in biocompatibility research. PMID- 23442244 TI - Human mesenchymal stem cells differentiate to epithelial cells when cultured on thick collagen gel. AB - The stem cell niche is crucial to the control of stem cell fate determination in vitro as well as in vivo, and an understanding of these niches is required for the progression of stem cell and tissue engineering. The goal of our study was to commit human mesenchymal stem cells (hMSCs) to the epithelial lineage. To do this, we cultured bone marrow-derived mesenchymal stem cells (MSCs) on plates coated with type I collagen gel with or without 10 MUM all-trans retinoic acid (ATRA).We found depth-dependent differentiation of hMSCs to the epithelial lineage, with the thick collagen gel (1900 MUm) generating more than 80% cytokeratin-18 (CK-18)-positive cells, whereas the thin collagen gel (100 MUm) generated significantly fewer CK-18-positive cells. In addition, we found that supplementation of 10 MUM ATRA enhanced CK-18 expression and induced cluster formation in cells grown on the thick collagen gel. The effect of gel depth on hMSC differentiation appears to be caused by partial cytoskeletal disruption.These results suggest that ATRA and a collagen extracellular matrix may have a synergistic effect on differentiation of human mesenchymal stem cells to epithelial lineage. PMID- 23442245 TI - Transcutaneous communication system using the human body as conductive medium: influence of transmission data current on the heart. AB - We developed a new transcutaneous communication system (TCS) that uses the human body as a conductive medium for monitoring and controlling artificial hearts and other artificial organs in the body.In this study, the physiological effect of data current discharged into the body during data transmission was evaluated by an animal experiment using a goat. The external and internal units of the new TCS each mainly consist of a data transmitter and a data receiver. The data transmitter has an amplitude shift keying (ASK) modulator (carrier frequencies: 4 and 10 MHz) and an electrode.The internal unit of the TCS was fixed on the pericardium and the external unit was placed on the left ear, and each transmitter discharged an ASK-modulated current of 7 mA (RMS) into the conscious goat. The TCS was able to transmit data for 4 weeks under full duplex communication with a transmission rate of 115 kbps. On the 28th postoperative day, an electrocardiogram was measured during data transmission. Cardiac rhythm and waveform of the electrocardiogram were not changed before and during bidirectional data transmission. Also, no adverse effect on the heart was observed by autopsy. PMID- 23442246 TI - Type 1 regulatory T cells and regulatory B cells induced by tolerogenic dendritic cells. AB - Dendritic cells (DC) are professional antigen-presenting cells that are capable of both activating immune responses and inducing tolerance. Several studies have revealed efficiency of therapeutic vaccination with tolerogenic DC (tolDC) in inhibition of experimental autoimmunity. The purpose of this study was to compare four different protocols for generation of tolDC - the antidiabetic drug troglitazone (TGZ DC), NF-kappaB inhibitor BAY 11-7082 (BAY DC), prostaglandin D2 metabolite 15d-PGJ2 (PGJ DC) and a combination of dexamethasone and 1alpha,25 dihydroxyvitamin D3 (DexVD3 DC) regarding phenotype, cytokine production and T cell stimulatory capacity. TGZ DC and BAY DC had a phenotype comparable to immature DC, while DexVD3 DC were more macrophage like. Analysis of cytokine production using cell culture supernatants from all DC populations revealed that DexVD3 DC were efficient producers of IL-10 and produced less pro-inflammatory cytokines. T cells primed with DexVD3 DC showed reduced proliferation, and further analyses of these T cells revealed that functionally effective type 1 regulatory T cells (Tr1) but not FoxP3(+) Treg were induced. Furthermore, DexVD3 DC promoted the induction of regulatory B cells (Breg). Together, these results indicate that DexVD3 DC have the best potential to be used in a tolerogenic antigen-presenting cell-based immunotherapy setting. PMID- 23442247 TI - Effects of initial stresses and time on orthodontic external root resorption. AB - Optimum stresses for a favorable response to orthodontics are still unknown. Here, we compared the effects of initial periodontal ligament (PDL) stresses over time in orthodontic external root resorption (OERR), necrosis, and the TRAP+ cell population. Forty-two rats (Fischer CDF) were treated with 10 cN of force for 5 different time periods. Finite element (FE) models of the first maxillary molars were constructed from MUCT scans to calculate initial PDL stresses. The scans were also used for OERR measurements before histology. Time, stress, and their interaction were significant to result in an OERR increase only in the regions of medium and high stress. OERR was not significantly different between control and treated animals over time in the region of low stress. After 30 days, OERR was increased by 5- and 3-fold in the zone of high- and medium-stress regions, respectively. The TRAP+ cell population initially followed the stress gradient, but changed after bone and necrotic tissue resorption. In the 30-day modeling cycle, the correspondent 3rd principal stress range to promote direct bone resorption and insignificant OERR was between -9.92 and -7.75 KPa. These translate to approximate forces of 30 to 40 cN applied at the bracket level (tipping) of a human maxillary canine. PMID- 23442248 TI - Determinants of vitamin a deficiency in children between 6 months and 2 years of age in Guinea-Bissau. AB - BACKGROUND: The World Health Organization (WHO) classifies Guinea-Bissau as having severe vitamin A deficiency (VAD). To date, no national survey has been conducted. We assessed vitamin A status among children in rural Guinea-Bissau to assess status and identify risk factors for VAD. METHODS: In a vitamin A supplementation trial in rural Guinea-Bissau, children aged 6 months to 2 years who were missing one or more vaccines were enrolled, vaccinated and randomized to vitamin A or placebo. Provided consent, a dried blood spot (DBS) sample was obtained from a subgroup of participants prior to supplementation. Vitamin A status and current infection was assessed by an ELISA measuring retinol-binding protein (RBP) and C-reactive protein (CRP). VAD was defined as RBP concentrations equivalent to plasma retinol <0.7 MUmol/L; infection was defined as CRP >5 ml/L. In Poisson regression models providing prevalence ratios (PR), we investigated putative risk factors for VAD including sex, age, child factors, maternal factors, season (rainy: June-November; dry: December-May), geography, and use of health services. RESULTS: Based on DBS from 1102 children, the VAD prevalence was 65.7% (95% confidence interval 62.9-68.5), 11% higher than the WHO estimate of 54.7% (9.9-93.0). If children with infection were excluded, the prevalence was 60.2% (56.7-63.7). In the age group 9-11 months, there was no difference in prevalence of VAD among children who had received previous vaccines in a timely fashion and those who had not. Controlled for infection and other determinants of VAD, the prevalence of VAD was 1.64 (1.49-1.81) times higher in the rainy season compared to the dry, and varied up to 2-fold between ethnic groups and regions. Compared with having an inactivated vaccine as the most recent vaccine, having a live vaccine as the most recent vaccination was associated with lower prevalence of VAD (PR=0.84 (0.74-0.96)). CONCLUSIONS: The prevalence of VAD was high in rural Guinea-Bissau. VAD varied significantly with season, ethnicity, region, and vaccination status. TRIAL REGISTRATION: Clinicaltrials.gov NCT00514891. PMID- 23442249 TI - The heme oxygenase system selectively enhances the anti-inflammatory macrophage M2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in Zucker diabetic fatty rats. AB - Cardiac function is adversely affected by pericardial adiposity. We investigated the effects of the heme oxygenase (HO) inducer, hemin on pericardial adiposity, macrophage polarization, and diabetic cardiopathy in Zucker diabetic fatty rats (ZDFs) with use of echocardiographic, quantitative real-time polymerase chain reaction, Western immunoblotting, enzyme immunoassay, and spectrophotometric analysis. In ZDFs, hemin administration increased HO activity; normalized glycemia; potentiated insulin signaling by enhancing insulin receptor substrate 1(IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB)/Akt; suppressed pericardial adiposity, cardiac hypertrophy, and left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte hypertrophy; and correspondingly reduced systolic blood pressure, total peripheral resistance, and pro-inflammatory/oxidative mediators, including nuclear factor kappaB (NF-kappaB), cJNK, c-Jun-N-terminal kinase (cJNK), endothelin (ET-1), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-1beta, activating protein 1 (AP-1), and 8-isoprostane, whereas the HO inhibitor, stannous mesoporphyrin, nullified the effects. Furthermore, hemin reduced the pro-inflammatory macrophage M1 phenotype, but enhanced the M2 phenotype that dampens inflammation. Because NF-kappaB activates TNFalpha, IL-6, and IL-1beta and TNF-alpha, cJNK, and AP-1 impair insulin signaling, the high levels of these cytokines in obesity/diabetes would create a vicious cycle that, together with 8-isoprostane and ET-1, exacerbates cardiac injury, compromising cardiac function. Therefore, the concomitant reduction of pro-inflammatory cytokines and macrophage infiltration coupled to increased expressions of IRS-1, PI3K, and PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. The hemin-induced preferential polarization of macrophages toward anti-inflammatory macrophage M2 phenotype in cardiac tissue with concomitant suppression of pericardial adiposity in ZDFs are novel findings. These data unveil the benefits of hemin against pericardial adiposity, impaired insulin signaling, and diabetic cardiomyopathy and suggest that its multifaceted protective mechanisms include the suppression of inflammatory/oxidative mediators. PMID- 23442250 TI - Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin induced pulmonary fibrosis progression. AB - Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory cells and reactive oxygen species (ROS), such as superoxide anion radical (O2(.-)). There is currently no effective treatment of IPF. We previously developed a human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx) designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-Trx on an IPF animal model of bleomycin (BLM)-induced pulmonary fibrosis. A pharmacokinetic study of HSA-Trx or Trx in BLM mice showed that the plasma retention and lung distribution of Trxc was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-Trx, but not Trx, ameliorated BLM-induced fibrosis, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-Trx suppressed active-transforming growth factor (TGF)-beta levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O2(.-) scavenging ability of HSA-Trx. Furthermore, post-treatment of HSA-Trx had a suppressive effect against BLM-induced fibrosis. These results suggest that HSA-Trx has potential as a novel therapeutic agent for IPF, because of its long-acting antioxidative and anti-inflammatory modulation effects. PMID- 23442251 TI - Risk factors associated with pterygium and its subtypes in Korea: the Korean National Health and Nutrition Examination Survey 2008-2010. AB - PURPOSE: To assess the sociodemographic and health-related risk factors associated with pterygium and its subtypes in Korea. METHODS: From 2008 to 2010, a total of 14,920 randomly selected national representative participants of the Korean National Health and Nutrition Examination Survey underwent additional ophthalmologic examinations by the Korean Ophthalmologic Society. The risk factors for pterygium in general or according to subtype (atrophic, intermediate, and fleshy) were identified using multivariate logistic regression analysis. RESULTS: The prevalence of pterygium was 6.7% (95% confidence interval, 5.9-7.5) in subjects aged 30 years or older. Older age, male sex, lower educational level, rural habitation, nonsmoking, and sun exposure were independent risk factors for pterygium. Among subjects with pterygium, older age, male sex, lower educational level, and nonsmoking were independent risk factors for all types of pterygium. Sun exposure for >5 h/d was the independent risk factor for the severe pterygium subtype. CONCLUSIONS: Socioeconomic disparities in pterygium development exist. Proper ocular examination and education to avoid excessive sun exposure would be helpful in reducing disease risk. PMID- 23442252 TI - Relationship of Bell phenomenon with Salzmann nodular degeneration. AB - PURPOSE: To determine the relationship of Bell phenomenon with the presence and the location of Salzmann nodular degeneration. METHODS: This is a noninterventional observational case series study. We reviewed the medical records of 10 patients with Salzmann nodules between 2001 and 2012. The mean age of participants was 60 years with 8 women and 2 men. A complete history and eye examination was performed with regular follow-up visits to document the progression of the disease. The data collected were as follows: age, gender, Snellen visual acuity, manifest refraction, Salzmann nodule location, presence of Bell or inverse Bell phenomenon, treatment, and associated conditions. Slit-lamp pictures to document the location of the Salzmann nodules and the direction of the Bell phenomenon were obtained. RESULTS: Five patients had inferior Salzmann nodules with a normal Bell phenomenon and 5 patients had superior nodules with inverse Bell phenomenon. Nine of 10 patients had moderate to severe meibomian gland disease and dry eye syndrome as associated conditions. Two of the patients underwent removal of the nodules with lamellar keratectomy and 1 with phototherapeutic keratectomy, all with mitomycin-C application and without recurrence of the nodules at 1 year of follow-up. CONCLUSIONS: In all 10 patients the direction of the globe rotation during a normal or inverse Bell phenomenon was directly correlated to the location of the Salzmann nodules. Specifically, patients with inverse Bell phenomenon presented with superior nodule formation, whereas patients with a normal Bell phenomenon presented with inferior nodules. PMID- 23442253 TI - A Poisson hierarchical modelling approach to detecting copy number variation in sequence coverage data. AB - BACKGROUND: The advent of next generation sequencing technology has accelerated efforts to map and catalogue copy number variation (CNV) in genomes of important micro-organisms for public health. A typical analysis of the sequence data involves mapping reads onto a reference genome, calculating the respective coverage, and detecting regions with too-low or too-high coverage (deletions and amplifications, respectively). Current CNV detection methods rely on statistical assumptions (e.g., a Poisson model) that may not hold in general, or require fine tuning the underlying algorithms to detect known hits. We propose a new CNV detection methodology based on two Poisson hierarchical models, the Poisson-Gamma and Poisson-Lognormal, with the advantage of being sufficiently flexible to describe different data patterns, whilst robust against deviations from the often assumed Poisson model. RESULTS: Using sequence coverage data of 7 Plasmodium falciparum malaria genomes (3D7 reference strain, HB3, DD2, 7G8, GB4, OX005, and OX006), we showed that empirical coverage distributions are intrinsically asymmetric and overdispersed in relation to the Poisson model. We also demonstrated a low baseline false positive rate for the proposed methodology using 3D7 resequencing data and simulation. When applied to the non-reference isolate data, our approach detected known CNV hits, including an amplification of the PfMDR1 locus in DD2 and a large deletion in the CLAG3.2 gene in GB4, and putative novel CNV regions. When compared to the recently available FREEC and cn.MOPS approaches, our findings were more concordant with putative hits from the highest quality array data for the 7G8 and GB4 isolates. CONCLUSIONS: In summary, the proposed methodology brings an increase in flexibility, robustness, accuracy and statistical rigour to CNV detection using sequence coverage data. PMID- 23442254 TI - The renoprotective effect of cGMP phosphodiesterase inhibitor and nitroprusside in a rat model of cyclosporin A-induced nephrotoxicity. AB - BACKGROUND: The cyclosporin A (CsA) nephrotoxicity limits its usefulness as an immunosuppression. We studied the administration of both nitroprusside and phosphodiesterase-5 inhibitor (udenafil) in order to determine whether these agents could ameliorate the renal injury in CsA nephrotoxicity. METHODS: 30 8 week-old SD rats were divided into 5 groups: the control (1), SQ with 15 mg/kg CsA (Group 2), CsA along with 5 mg/kg IP nitroprusside (Group 3), CsA with 10 mg/kg PO udenafil (Group 4), and CsA with udenafil and nitroprusside (Group 5). RESULTS: Group showed an increase in creatinine compared o the control group. Group 5 showed a decrease in creatinine compared to Group 2. In TUNEL, Group 2 increased apoptosis in proximal tubules compared to control. Group 5 showed a decrease in apoptosis compared to Groups 2, 3, and 4. In IHC, the eNOS in Group 2 was stronger than in the controls. Groups 3, 4, and 5 showed decreased staining intensity compared to Group 2. In IHC, the VEGF in Groups 2, 3, and 4 increased compared to the controls. The eNOS protein expression was increased in both Groups 3 and 5 compared to the controls. The VEGF protein expression was increased in Groups 3 and 5 compared to Group 2. The eNOS mRNA was decreased in Group 2 compared to the control group and tended to increase in Groups 3, 4, and 5 compared to Group 2. The VEGF mRNA was increased in Group 2 and tended to increase more in Groups 3 and 5. CONCLUSION: The udenafil and nitroprusside ameliorated renal injury in rat model of CsA nephrotoxicity. The mechanism appears to be associated with decreasing tubular apoptosis by decreasing eNOS and increasing VEGF. PMID- 23442255 TI - Effect of rosuvastatin and sevelamer on the progression of coronary artery calcification in chronic kidney disease: a pilot study. AB - INTRODUCTION: Coronary artery calcification (CAC) is highly prevalent among chronic kidney disease (CKD) patients and its strong association with mortality has been recognized early in the course of CKD. The aim of the present study was to test the effect of rosuvastatin and sevelamer hydrochloride on the progression of CAC in nondialyzed CKD patients. METHODS: An open-label, randomized and controlled pilot study was conducted including 117 CKD patients (62% men, 56.9 +/ 11.2 years, eGFR 36 +/- 16.5 ml/min). Patients were randomly assigned to rosuvastatin (n = 38; 10 mg/day), to sevelamer hydrochloride (n = 38; 2,400 mg/day) and to control (n = 41) groups. CAC (by multislice computed tomography) and biochemical analyses were performed at baseline and after 24 months. RESULTS: At baseline, CAC was observed in 55%, 58% and 61% of patients in the rosuvastatin, sevelamer hydrochloride and control groups, respectively (p = 0.87). Calcium score at baseline as well as its absolute and relative changes during 24 months were similar among the groups. Low density lipoprotein cholesterol (LDL-c) was higher and decreased significantly in the rosuvastatin group (p < 0.01). The analysis adjusting for LDL-c showed that the drug regimens were not associated with the progression of CAC (drug effect p = 0.85; time effect p < 0.001; interaction p = 0.76). CONCLUSIONS: Treatment with rosuvastatin and sevelamer hydrochloride may not delay the progression of CAC in non-dialysis dependent CKD patients. PMID- 23442256 TI - Smoking as the potential link between Kimmelstiel-Wilson lesion and non-diabetic nodular glomerulosclerosis in male patients - a single center retrospective study. AB - BACKGROUND: The histological pattern of nodular glomerulosclerosis (NGS) can be found both in diabetic nephropathy (Kimmelstiel-Wilson (KW) lesion) and non diabetic nodular glomerulosclerosis (non-diab NGS). Chronic smoking is considered to be a potential cause of non-diab NGS, but the prevalence of smokers in KW is unknown. METHODS: In a retrospective analysis, native renal biopsy specimens (n = 644, 2001 - 2011) were evaluated and male patients' characteristics, including smoking habits, were assessed within three groups: diabetic patients with KW (n = 15), diabetic patients with other classes of diabetic nephropathy (non-KW; n = 46), and patients with non-diab NGS (n = 7). RESULTS: The majority of patients in the KW and non-diab NGS groups (13/15 = 87%, 7/7 = 100%, respectively; p = 1.0 vs. KW) were smokers, unlike the non-KW group (16/46 = 35%; p = 0.001 vs. KW). Cigarette pack-years showed a similar pattern (KW: 15 (6 - 30), non-KW: 0 (0 - 21), non-diab NGS: 30 (16 - 33); p = 0.010 non-KW vs. KW, p = 0.008 non-KW vs. non-diab NGS). Other known factors responsible for the worsening of non-KW or the development of non-diab NGS did not differ in the groups (age, body mass index, duration of diabetes mellitus, HbA1c, prevalence of hypertension, duration of hypertension, serum cholesterol, triglyceride, estimated glomerular filtration rate, and renin-angiotensin-aldosteron system-blocker treatment). CONCLUSIONS: We propose that chronic cigarette smoking could play a pivotal role in the development of KW lesions. PMID- 23442257 TI - Transition from endocapillary proliferative glomerulonephritis to membranoproliferative glomerulonephritis in a patient with a prolonged human parvovirus B19 infection. AB - We report a case in which renal biopsies were performed 4 years apart in a woman with a prolonged human parvovirus B19 (HPB19) infection. When she was 29 years old the first biopsy, performed because of microscopic hematuria and mild proteinuria, showed endocapillary and mesangial proliferative glomerulonephritis in light microscopy as well as deposits of immunoglobulins (Igs) and complement C3 on capillary walls. Mesangial, intramembranous, and subepithelial hump-like electron dense deposits were seen in electron microscopy. The principal differential diagnoses, acute poststreptococcal glomerulonephritis and lupus nephritis, were unlikely, and her serological positivity for IgM antibody for HPB19 made us diagnose acute glomerulonephritis associated with HPB19 infection. The second biopsy, performed 4 years later because of persistent proteinuria and prolonged positivity for IgM antibody for HPB19, showed membranoproliferative glomerulonephritis (MPGN) with mesangial interposition and with thickening and double contours of glomerular basement membrane. In tissues obtained in both biopsies, HPB19 DNA was detected by polymerase chain reaction. HPB19 infection has been widely known to cause various glomerular diseases. This case reveals that acute endocapillary proliferative glomerulonephritis can change into MPGN during prolonged HPB19 infection. PMID- 23442258 TI - An evaluation of data quality in Canada's Continuing Care Reporting System (CCRS): secondary analyses of Ontario data submitted between 1996 and 2011. AB - BACKGROUND: Evidence informed decision making in health policy development and clinical practice depends on the availability of valid and reliable data. The introduction of interRAI assessment systems in many countries has provided valuable new information that can be used to support case mix based payment systems, quality monitoring, outcome measurement and care planning. The Continuing Care Reporting System (CCRS) managed by the Canadian Institute for Health Information has served as a data repository supporting national implementation of the Resident Assessment Instrument (RAI 2.0) in Canada for more than 15 years. The present paper aims to evaluate data quality for the CCRS using an approach that may be generalizable to comparable data holdings internationally. METHODS: Data from the RAI 2.0 implementation in Complex Continuing Care (CCC) hospitals/units and Long Term Care (LTC) homes in Ontario were analyzed using various statistical techniques that provide evidence for trends in validity, reliability, and population attributes. Time series comparisons included evaluations of scale reliability, patterns of associations between items and scales that provide evidence about convergent validity, and measures of changes in population characteristics over time. RESULTS: Data quality with respect to reliability, validity, completeness and freedom from logical coding errors was consistently high for the CCRS in both CCC and LTC settings. The addition of logic checks further improved data quality in both settings. The only notable change of concern was a substantial inflation in the percentage of long term care home residents qualifying for the Special Rehabilitation level of the Resource Utilization Groups (RUG-III) case mix system after the adoption of that system as part of the payment system for LTC. CONCLUSIONS: The CCRS provides a robust, high quality data source that may be used to inform policy, clinical practice and service delivery in Ontario. Only one area of concern was noted, and the statistical techniques employed here may be readily used to target organizations with data quality problems in that (or any other) area. There was also evidence that data quality was good in both CCC and LTC settings from the outset of implementation, meaning data may be used from the entire time series. The methods employed here may continue to be used to monitor data quality in this province over time and they provide a benchmark for comparisons with other jurisdictions implementing the RAI 2.0 in similar populations. PMID- 23442259 TI - Percutaneous vertebroplasty combined with interstitial implantation of 125I seeds in banna mini-pigs. AB - BACKGROUND: Although brachytherapy is one of the most effective ways to treat metastatic spinal tumor with little damage to surrounding healthy tissue, it may cause radiation myelopathy if an overdose occurs. Establishing a valuable animal model can help to find a method to overcome its complications. In the current study, we set up a banna mini-pig model to mimic percutaneous vertebroplasty with 125I seed implantation. METHODS: Percutaneous vertebroplasty (PVP) combined with interstitial implantation of 125I seeds, 125I seeds were transplanted into the vertebral body at the T13 level of the spine in banna mini-pigs. After raising them for up to eight months, the spinal cord and vertebral body were collected for pathological analysis. RESULTS: A potential animal model had been successfully established, no case of radiation myelopathy was found in any of the treated banna pigs, and no significant cellular impairment was noted by pathological analysis. CONCLUSIONS: It proves that PVP with 125I brachytherapy is an effective method to treat metastasis spinal tumor, and that the banna mini-pig can be a suitable model to investigate the mechanism of brachytherapy complications. PMID- 23442260 TI - Acute exercise decreases PTP-1B protein level and improves insulin signaling in the liver of old rats. AB - It is now commonly accepted that chronic inflammation associated with obesity during aging induces insulin resistance in the liver. In the present study, we investigated whether the improvement in insulin sensitivity and insulin signaling, mediated by acute exercise, could be associated with modulation of protein-tyrosine phosphatase 1B (PTP-1B) in the liver of old rats. Aging rats were subjected to swimming for two 1.5-h long bouts, separated by a 45 min rest period. Sixteen hours after the exercise, the rats were sacrificed and proteins from the insulin signaling pathway were analyzed by immunoblotting. Our results show that the fat mass was increased in old rats. The reduction in glucose disappearance rate (Kitt) observed in aged rats was restored 16 h after exercise. Aging increased the content of PTP-1B and attenuated insulin signaling in the liver of rats, a phenomenon that was reversed by exercise. Aging rats also increased the IRbeta/PTP-1B and IRS-1/PTP-1B association in the liver when compared with young rats. Conversely, in the liver of exercised old rats, IRbeta/PTP-1B and IRS-1/PTP-1B association was markedly decreased. Moreover, in the hepatic tissue of old rats, the insulin signalling was decreased and PEPCK and G6Pase levels were increased when compared with young rats. Interestingly, 16 h after acute exercise, the PEPCK and G6Pase protein level were decreased in the old exercised group. These results provide new insights into the mechanisms by which exercise restores insulin signalling in liver during aging. PMID- 23442262 TI - RECOT: a tool for the coordinate transformation of next-generation sequencing reads for comparative genomics and transcriptomics. AB - BACKGROUND: The whole-genome sequences of many non-model organisms have recently been determined. Using these genome sequences, next-generation sequencing based experiments such as RNA-seq and ChIP-seq have been performed and comparisons of the experiments between related species have provided new knowledge about evolution and biological processes. Although these comparisons require transformation of the genome coordinates of the reads between the species, current software tools are not suitable to convert the massive numbers of reads to the corresponding coordinates of other species' genomes. RESULTS: Here, we introduce a set of programs, called REad COordinate Transformer (RECOT), created to transform the coordinates of short reads obtained from the genome of a query species being studied to that of a comparison target species after aligning the query and target gene/genome sequences. RECOT generates output in SAM format that can be viewed using recent genome browsers capable of displaying next-generation sequencing data. CONCLUSIONS: We demonstrate the usefulness of RECOT in comparing ChIP-seq results between two closely-related fruit flies. The results indicate position changes of a transcription factor binding site caused sequence polymorphisms at the binding site. PMID- 23442261 TI - Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events. AB - BACKGROUND: Voriconazole is approved for treatment of invasive aspergillosis and other invasive fungal infections, but the role for therapeutic drug monitoring (TDM) is not clear. METHODS: We performed a retrospective cohort study of patients at the University of Washington Medical Center and Fred Hutchinson Cancer Research Center from 2007-2009. We compared the effect of therapeutic levels on clinical outcomes and evaluated the relationship between drug levels and adverse events. RESULTS: A total of 108 patients had voriconazole TDM performed, of whom 84 (77.8%) had a hematologic malignancy and 47 (43.5%) had undergone hematopoietic stem cell transplantation. The primary reasons for treatment were presumed pulmonary aspergillosis (n = 83, 76.8%), other invasive mould infections (n = 13, 12.0%) and candidiasis (n = 9, 8.3%). There was a high degree of variability in voriconazole drug levels among patients (r2 = 0.01; range, <0.10 - 20 mg/L). Of the 46 patients with proven or probable invasive fungal disease, 25 (54.3%) achieved partial or complete response to therapy. There was no significant relationship between therapeutic drug levels and achievement of complete or partial response at 12 weeks (OR 0.29, 95% CI: 0.05 1.34) or radiologic response (OR 1.46, 95% CI: 0.32-7.83). Overall, 45 (41.7%) patients experienced adverse events. Voriconazole levels > 5.5 mg/L were not associated with increased incidence of encephalopathy (OR 3.08, 95% CI 0.79-11.0) or hepatotoxicity (OR 2.45, 95% CI 0.49-10.1). CONCLUSIONS: Voriconazole therapeutic drug levels were not associated with improvement in clinical outcomes among patients with proven or probable invasive fungal disease. We also did not find an association between supratherapeutic drug levels and hepatoxicity or encephalopathy. It is possible that the utility of voriconazole therapeutic drug monitoring to improve clinical efficacy or decrease adverse events may be limited to a subset of high-risk patients. PMID- 23442263 TI - Neurocarta: aggregating and sharing disease-gene relations for the neurosciences. AB - BACKGROUND: Understanding the genetic basis of diseases is key to the development of better diagnoses and treatments. Unfortunately, only a small fraction of the existing data linking genes to phenotypes is available through online public resources and, when available, it is scattered across multiple access tools. DESCRIPTION: Neurocarta is a knowledgebase that consolidates information on genes and phenotypes across multiple resources and allows tracking and exploring of the associations. The system enables automatic and manual curation of evidence supporting each association, as well as user-enabled entry of their own annotations. Phenotypes are recorded using controlled vocabularies such as the Disease Ontology to facilitate computational inference and linking to external data sources. The gene-to-phenotype associations are filtered by stringent criteria to focus on the annotations most likely to be relevant. Neurocarta is constantly growing and currently holds more than 30,000 lines of evidence linking over 7,000 genes to 2,000 different phenotypes. CONCLUSIONS: Neurocarta is a one stop shop for researchers looking for candidate genes for any disorder of interest. In Neurocarta, they can review the evidence linking genes to phenotypes and filter out the evidence they're not interested in. In addition, researchers can enter their own annotations from their experiments and analyze them in the context of existing public annotations. Neurocarta's in-depth annotation of neurodevelopmental disorders makes it a unique resource for neuroscientists working on brain development. PMID- 23442264 TI - The effect of regularization in motion compensated PET image reconstruction: a realistic numerical 4D simulation study. AB - Following continuous improvement in PET spatial resolution, respiratory motion correction has become an important task. Two of the most common approaches that utilize all detected PET events to motion-correct PET data are the reconstruct transform-average method (RTA) and motion-compensated image reconstruction (MCIR). In RTA, separate images are reconstructed for each respiratory frame, subsequently transformed to one reference frame and finally averaged to produce a motion-corrected image. In MCIR, the projection data from all frames are reconstructed by including motion information in the system matrix so that a motion-corrected image is reconstructed directly. Previous theoretical analyses have explained why MCIR is expected to outperform RTA. It has been suggested that MCIR creates less noise than RTA because the images for each separate respiratory frame will be severely affected by noise. However, recent investigations have shown that in the unregularized case RTA images can have fewer noise artefacts, while MCIR images are more quantitatively accurate but have the common salt-and pepper noise. In this paper, we perform a realistic numerical 4D simulation study to compare the advantages gained by including regularization within reconstruction for RTA and MCIR, in particular using the median-root-prior incorporated in the ordered subsets maximum a posteriori one-step-late algorithm. In this investigation we have demonstrated that MCIR with proper regularization parameters reconstructs lesions with less bias and root mean square error and similar CNR and standard deviation to regularized RTA. This finding is reproducible for a variety of noise levels (25, 50, 100 million counts), lesion sizes (8 mm, 14 mm diameter) and iterations. Nevertheless, regularized RTA can also be a practical solution for motion compensation as a proper level of regularization reduces both bias and mean square error. PMID- 23442266 TI - Preseason variations in aerobic fitness and performance in elite-standard soccer players: a team study. AB - The aim of this study was to examine the effects of individual training loads considered as permanent in selected heart-rate (HR) zones on aerobic fitness and performance in elite professional soccer players. Eighteen professional soccer players were observed during the prechampionship training period (8 weeks). Speeds and HR at 2 and 4 mmol . L blood-lactate concentrations (S2, S4, respectively), VO2max, and Yo-Yo intermittent recovery test level 1 performance (Yo-Yo IR1) were assessed pretraining and posttraining. Training intensities were categorized using 3 HR zones: low intensity (
HR 4 mmol . L). Training session HRs (n = 900) showed a polarized distribution with 73.6 +/- 3.7 (2,945 +/ 148 minutes), 19.1 +/- 3.5 (763 +/- 141 minutes), and 7.3 +/- 2.9% (292 +/- 116 minutes) of the total training time spent at low, moderate, and high intensities, respectively (p < 0.001). The S2 and S4 significantly improved posttraining (+10 and 7%, respectively, p < 0.001). The VO2max and Yo-Yo IR1 values were 6 and 19.5% higher posttraining, respectively (p < 0.01). Training performed at high intensity was significantly related to relative improvement in S2 (r = 0.78, p = 0.002), S4 (r = 0.60, p = 0.03), VO2max (r = 0.65, p = 0.02), and Yo-Yo IR1 (r = 0.66, p = 0.01). The results of this study provided further evidence for HR longitudinal validity and effectiveness of the high-intensity training (i.e., >90% HRmax) in men's professional soccer. In this regard, the time spent at high intensity should be in the range of 7-8% of the total training time during preseason. PMID- 23442265 TI - Human milk oligosaccharides inhibit rotavirus infectivity in vitro and in acutely infected piglets. AB - Human milk (HM) is rich in oligosaccharides (HMO) that exert prebiotic and anti infective activities. HM feeding reduces the incidence of rotavirus (RV) infection in infants. Herein, the anti-RV activity of oligosaccharides was tested in an established in vitro system for assessing cellular binding and viral infectivity/replication, and also tested in a newly developed, acute RV infection, in situ piglet model. For the in vitro work, crude HMO isolated from pooled HM, neutral HMO (lacto-N-neotetraose, LNnT; 2'-fucosyllactose) and acidic HMO (aHMO, '-sialyllactose, 3'-SL; -sialyllactose, -SL) were tested against the porcine OSU strain and human RV Wa strain. The RV Wa strain was not inhibited by any oligosaccharides. However, the RV OSU strain infectivity was dose-dependently inhibited by sialic acid (SA)-containing HMO. 3'-SL and 6'-SL concordantly inhibited (125)I-radiolabelled RV cellular binding and infectivity/replication. For the in situ study, a midline laparotomy was performed on 21-d-old formula-fed piglets and six 10 cm loops of ileum were isolated in situ. Briefly, 2 mg/ml of LNnT, aHMO mixture (40% 6'-SL/10 % 3'-SL/50 % SA) or media with or without the RV OSU strain (1 x 10(7) focus-forming units)were injected into the loops and maintained for 6 h. The loops treated with HMO treatments p RV had lower RV replication, as assessed by non-structural protein-4 (NSP4) mRNA expression, than RV-treated loops alone. In conclusion, SA-containing HMO inhibited RV infectivity in vitro; however, both neutral HMO and SA with aHMO decreased NSP4 replication during acute RV infection in situ. PMID- 23442267 TI - Training reduces catabolic and inflammatory response to a single practice in female volleyball players. AB - We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Thirteen female, national team level, Israeli volleyball players (age 16.0 +/- 1.4 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60 minutes of volleyball practice, before and after 7 weeks of training during the initial phase of the season. Training involved tactic and technical drills (20% of time), power and speed drills (25% of time), interval sessions (25% of time), endurance-type training (15% of time), and resistance training (15% of time). To achieve greater training responses, the study was performed during the early phase (first 7 weeks) of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin like growth factor-I (IGF-I) and IGF-binding protein-3, the catabolic hormone cortisol, the proinflammatory marker interleukin-6 (IL-6), and the anti inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of vertical jump, anaerobic properties (peak and mean power by the Wingate Anaerobic Test), and predicted VO2max (by the 20-m shuttle run). Volleyball practice, both before and after the training intervention, was associated with a significant increase of serum lactate, GH, and IL-6. Training resulted in a significantly reduced cortisol response ([INCREMENT]cortisol: 4.2 +/- 13.7 vs. -4.4 +/- 12.3 ng . ml, before and after training, respectively; p < 0.02), and IL-6 response ([INCREMENT]IL-6: 1.3 +/- 1.0 vs. 0.3 +/- 0.4 pg . ml, before and after training, respectively; p < 0.01) to the same relative intensity volleyball practice. The results suggest that along with the improvement of power and anaerobic and aerobic characteristics, training reduces the catabolic and inflammatory response to exercise. PMID- 23442268 TI - Relationship between tests of physical qualities, team selection, and physical match performance in semiprofessional rugby league players. AB - This study investigated the physical qualities that discriminated state-based rugby league players competing for selection in a semiprofessional rugby league team, and determined the relationship between tests of physical qualities and physical match performance in these players. Thirty-two rugby league players (mean +/- SD age, 24 +/- 3 years) from a Queensland Cup rugby league squad participated in this study. The players performed tests of upper-body strength (3 repetition maximum [RM] bench press; 3RM weighted chin-up), upper-body strength endurance (body-mass maximum repetition bench press), lower-body strength (3RM squat), lower-body power (vertical jump), and prolonged high-intensity intermittent running ability (Yo-Yo intermittent recovery test, level 1). Global positioning system data, sampling at 10 Hz, were collected during 5 Queensland Cup rugby league matches. Selected players had greater (p < 0.05) 3RM squat, 3RM chin-up, body-mass bench press, vertical jump, and Yo-Yo intermittent recovery test performances than nonselected players. After controlling for playing position, players with better 3RM squat performances covered greater total distances (r = 0.98, p < 0.05) including greater distances at low (r = 0.98, p < 0.05) and high (r = 0.97, p < 0.05) speeds. Significant associations (r = 0.96, p < 0.05) were also found between 3RM squat performances and the number of repeated high-intensity effort bouts performed in competition. These findings highlight the importance of lower-body strength, upper-body strength and endurance, and prolonged high-intensity intermittent running ability to team selection in semiprofessional rugby league. Furthermore, our findings suggest that well developed lower-body strength contributes to effective physical match performance in semiprofessional rugby league players. PMID- 23442269 TI - Postexercise hypertrophic adaptations: a reexamination of the hormone hypothesis and its applicability to resistance training program design. AB - It has been well documented in the literature that resistance training can promote marked increases in skeletal muscle mass. Postexercise hypertrophic adaptations are mediated by a complex enzymatic cascade whereby mechanical tension is molecularly transduced into anabolic and catabolic signals that ultimately lead to a compensatory response, shifting muscle protein balance to favor synthesis over degradation. Myocellular signaling is influenced, in part, by the endocrine system. Various hormones have been shown to alter the dynamic balance between anabolic and catabolic stimuli in muscle, helping to mediate an increase or decrease in muscle protein accretion. Resistance training can have an acute impact on the postexercise secretion of several of these hormones including insulin-like growth factor, testosterone, and growth hormone (GH). Studies show that hormonal spikes are magnified after hypertrophy-type exercise that involves training at moderate intensities with shortened rest intervals as compared with high-intensity strength-oriented training. The observed positive relationship between anabolic hormones and hypertrophy-type training has led to the hormone hypothesis, which postulates that acute postexercise hormonal secretions mediate increases in muscle size. Several researchers have suggested that these transient hormonal elevations may be more critical to hypertrophic adaptations than chronic changes in resting hormonal concentrations. Theoretically, high levels of circulating hormones increase the likelihood of interaction with receptors, which may have particular hypertrophic importance in the postworkout period when muscles are primed for anabolism. Moreover, hormonal spikes may enhance intracellular signaling so that postexercise protein breakdown is rapidly attenuated and anabolic processes are heightened, thereby leading to a greater supercompensatory response. Although the hormone hypothesis has received considerable support in the literature, several researchers have questioned its veracity, with some speculating that the purpose of postexercise hormonal elevations is to mobilize fuel stores rather than promote tissue anabolism. Therefore, the purpose of this article will be to critically and objectively review the current literature, and then draw relevant conclusions as to the potential role of acute systemic factors on muscle protein accretion. PMID- 23442271 TI - The influence of agility training on physiological and cognitive performance. AB - Agility training (AT) has recently been instituted in several military communities in hopes of improving combat performance and general fitness. The purpose of this study was to determine how substituting AT for traditional military physical training (PT) influences physical and cognitive performance. Forty-one subjects undergoing military technical training were divided randomly into 2 groups for 6 weeks of training. One group participated in standard military PT consisting of calisthenics and running. A second group duplicated the amount of exercise of the first group but used AT as their primary mode of training. Before and after training, subjects completed a physical and cognitive battery of tests including V[Combining Dot Above]O2max, reaction time, Illinois Agility Test, body composition, visual vigilance, dichotic listening, and working memory tests. There were significant improvements within the AT group in V[Combining Dot Above]O2max, Illinois Agility Test, visual vigilance, and continuous memory. There was a significant increase in time-to-exhaustion for the traditional group. We conclude that AT is as effective or more effective as PT in enhancing physical fitness. Further, it is potentially more effective than PT in enhancing specific measures of physical and cognitive performance, such as physical agility, memory, and vigilance. Consequently, we suggest that AT be incorporated into existing military PT programs as a way to improve war-fighter performance. Further, it seems likely that the benefits of AT observed here occur in various other populations. PMID- 23442272 TI - Characteristics of lower extremity work during the impact phase of jumping and weightlifting. AB - Jumping and weightlifting tasks involve impact phases, where work is performed by the lower extremity to absorb energies present at contact. This study compared the lower extremity kinematic and kinetic strategies to absorb energy during the impact phase of jumping and weightlifting activities. Ten women experienced in jumping and weightlifting performed 4 tasks (landing from a jump, drop landing, clean, and power clean) in a motion analysis laboratory. Work performed at the hip, knee, and ankle were calculated during the landing and receiving phases of jumping and weightlifting tasks, respectively. Additionally, segment and joint kinematics and net joint moments were determined. The most lower extremity work was performed in the clean and drop landing, followed by landing from a jump, and the least work was performed in the power clean (p < 0.05). For all tasks, work performed by the knee extensors was the greatest contributor to lower extremity work. Knee extensor net joint moment was greater in the power clean than jump and drop landings, and greater in the clean than all other tasks (p < 0.05). Knee flexion angle was not different between the power clean and jump landing (p > 0.05) but greater in the drop landing and clean (p < 0.05). A common characteristic of the impact phase of jumping and weightlifting tasks is a large contribution of knee extensor work. Further, the correspondence in kinematics between impact phases of jumping and weightlifting tasks suggests that similar muscular strategies are used to perform both types of activities. Weightlifting tasks, particularly the clean, may be important exercises to develop the muscular strength required for impact actions due to their large knee extensor net joint moments. PMID- 23442273 TI - Effects on strength, power, and flexibility in adolescents of nonperiodized vs. daily nonlinear periodized weight training. AB - The aim of this study was to compare 2 models of resistance training (RT) programs, nonperiodized (NP) training and daily nonlinear periodized (DNLP) training, on strength, power, and flexibility in untrained adolescents. Thirty eight untrained male adolescents were randomly assigned to 1 of 3 groups: a control group, NP RT program, and DNLP program. The subjects were tested pretraining and after 4, 8, and 12 weeks for 1 repetition maximum (1RM) resistances in the bench press and 45 degrees leg press, sit and reach test, countermovement vertical jump (CMVJ), and standing long jump (SLJ). Both training groups performed the same sequence of exercises 3 times a week for a total of 36 sessions. The NP RT consisted of 3 sets of 10-12RM throughout the training period. The DNLP training consisted of 3 sets using different training intensities for each of the 3 training sessions per week. The total volume of the training programs was not significantly different. Both the NP and DNLP groups exhibited a significant increase in the 1RM for the bench press and 45 degrees leg press posttraining compared with that pretraining, but there were no significant differences between groups (p <= 0.05). The DNLP group's 1RM changes showed greater percentage improvements and effect sizes. Training intensity for the bench press and 45 degrees leg press did not significantly change during the training. In the CMVJ and SLJ tests, NP and DNLP training showed no significant change. The DNLP group showed a significant increase in the sit and reach test after 8 and 12 weeks of training compared with pretraining; this did not occur with NP training. In summary, in untrained adolescents during a 12-week training period, a DNLP program can be used to elicit similar and possible superior maximal strength and flexibility gains compared with an NP multiset training model. PMID- 23442274 TI - Daily marathon running for a week--the biochemical and body compositional effects of participation. AB - Although long-distance running, such as ultramarathons and multistage races, is increasingly popular, it maybe potentially harmful to health, despite sparse evidence. We studied 8 experienced recreational runners participating in a multiple-marathon running event in which 7 marathons were completed on consecutive days. Fasting blood chemistry and body composition were assessed before and 20-24 hours after the race. The total finish time for the 7 marathons ranged between 23:25:42 and 34:25:21 (hours:minutes:seconds). Only minor increases in circulating skeletal muscle cell damage markers, liver cell damage markers, and inflammatory markers occurred after the race. No other significant adverse biochemical effects were observed. The homeostasis model assessment of insulin resistance decreased markedly, and an improved lipid profile was found. A decrease in fat mass and increase in lean body mass was observed, resulting in no overall weight changes. In summary, the race did not cause any major adverse effects, whereas some traditional markers of cardiovascular disease improved acutely after the race. PMID- 23442275 TI - The effects of a harness safety system during maximal treadmill run testing in collegiate middle- and long-distance runners. AB - This study compared the results of graded maximal treadmill testing with and without a safety harness (SH) spotting system among collegiate middle- and long distance runners. Thirteen (n = 8 men, n = 5 women) collegiate runners completed 2 randomly selected maximal treadmill tests. One trial used an SH, and one trial used no harness. All tests were separated by at least 48 hours. The subjects began the test at a velocity of 14.5 or 12 km . h with 1% grade for men and women, respectively, and increased 0.80 kilometers/hr per stage. During each trial, metabolic data and running speed values were recorded along with the completion of a safety questionnaire. No significant difference was found for maximal oxygen consumption (60.84 +/- 8.89 vs. 60.733 +/- 9.38 ml . kg . min) and velocity at maximal oxygen consumption (5.33 +/- 0.62 vs. 5.24 +/- 0.57 m . s) between the no harness and harness trials, respectively. Test time was found to be significantly longer in the no harness trial (611.06 +/- 119.34 vs. 537.38 +/- 91.83 seconds, p < 0.05). The results of the safety questionnaire demonstrated that the runners felt significantly more comfortable during the SH trial (p < 0.05). PMID- 23442276 TI - Effects of stabilization training on trunk muscularity and physical performances in youth soccer players. AB - The purpose of the present study was to examine the effects of stabilization training on trunk muscularity and physical performances in youth male soccer players aged 12-13 yrs (n = 28). The subjects allocated to training (TG, n = 16) performed a stabilization exercise program consisting of 5 exercises (elbow-toe, elbow-heel, side bridge, modified 1-legged squat, and bent-knee push-up) 4 times per week and a training program specific to soccer 6 times per week, whereas the others (control, n = 12) conducted the soccer training only for 6 months. Before and after the intervention, the cross-sectional areas (CSAs) of 5 muscles (rectus abdominus, oblique, psoas major, quadratus lumborum, and erector spinae) were determined using magnetic resonance imaging. Furthermore, peak torques during hip extension and flexion at 1.05 rad/second, heights of squat and countermovement jumps, and time taken to sprint 15 m were also measured. After 6 months, both groups significantly increased the CSAs of the 5 muscle groups (TG: 4.4-13.4%, control: 5.5-10.9%) and improved sprint time (TG: -1.4%, control: -1.6%), without significant effect of group, but only TG significantly increased the heights of squat (5.0%) and countermovement (6.8%) jumps. In addition, a greater increase in hip extension torque was found in TG (40.8%) than in control (17.4%). The current results indicate that, at least in early adolescent soccer players, adding stabilization exercise to soccer training cannot increase the trunk muscularity, but it will improve hip extensor strength and vertical jump performance. PMID- 23442277 TI - Reliability of the ALPHA health-related fitness test battery in adolescents with Down syndrome. AB - The Assessing Levels of Physical Activity (ALPHA) health-related fitness test battery is a set of reliable, valid, and feasible tests to assess health-related physical fitness in children and in adolescents. The aim of this study was to examine the reliability of this battery in adolescents with Down syndrome (DS). The extended ALPHA health-related fitness test battery was performed twice within 1 month in 17 apparently healthy adolescents, aged 12-18 years, with DS who had an intelligence quotient >= 35. Intraclass correlation coefficient (ICC) was used to determinate test-retest reliability, and nonparametric Wilcoxon signed rank test was used to compare mean differences between measurements. With the exception of subscapular skinfold test, which obtained a moderate agreement (ICC = 0.64), all tests had a very high reliability: the 20-m shuttle-run test (ICC = 0.86), the right handgrip strength test (ICC = 0.86), the left handgrip strength test (ICC = 0.86), the standing broad jump test (ICC = 0.85), body mass index (ICC = 0.95), waist circumference (ICC = 0.98), triceps skinfold (ICC = 0.85), and the 4 * 10-m shuttle-run test (ICC = 0.92). There were no significant differences (all p > 0.05) in any of the tests. The ALPHA health-related fitness battery is reliable for measuring health-related components of fitness in adolescents with DS. PMID- 23442278 TI - Heart rate and physical activity patterns in persons with profound intellectual and multiple disabilities. AB - Because physical fitness and health are related to physical activity, it is important to gain an insight into the physical activity levels of persons with profound intellectual and multiple disabilities (PIMD). The purpose of this study was to examine heart rate patterns to measure the activity levels of persons with PIMD and to analyze these heart rate patterns according to participant characteristics, observed level of activity, days, and time of day. The heart rate patterns of 24 participants with PIMD were measured continuously using a heart rate monitor for 8 h . d for a period of 6 days. Physical activity levels were measured with questionnaires. Data were analyzed using multilevel analysis. The results indicate that the participants use only 32% of their heart rate reserve over 6 days. The intensity of heart rate reserve ranged from 1 to 62%. On a given day, wide ranges in heart rates between participants and within persons were observed. Between days, only small ranges in the heart rate were found. The participants could be grouped into 4 classes according to their heart rate. In addition, factors such as time of day, physical activity, and age are significantly related to heart rate patterns. In conclusion, this study is an important first step in exploring activity patterns based on heart rate patterns in persons with PIMD. The participants used relatively small fractions of their heart rate reserves. Time of day and age appear to have a considerable influence on heart rate patterns. The observed classes in heart rate patterns suggest that other probably more personal and psychosocial factors have significant influences on heart rate patterns, as well. PMID- 23442279 TI - Competitive athletic participation, thigh muscle strength, and bone density in elite senior athletes and controls. AB - The relationship between participation in highly competitive exercise, thigh muscle strength, and regional and total body bone mineral density (BMD) in elite senior athletes and healthy elderly controls was investigated. One hundred and four elite senior athletes (age: 72.6 +/- 6.4 years, height: 168.7 +/- 8.6 cm, mass: 72.6 +/- 13.5 kg, 57 male:47 female) and 79 healthy controls (age: 75.4 +/- 5.6 years, height: 170.8 +/- 25.5 cm, mass: 79.5 +/- 11.7 kg, 46 male:33 female) participated in this cross-sectional study. Vitamin D and calcium intake were assessed via a recall survey. Isometric knee extension and flexion peak torque were measured via a custom strength measurement device. Total body and regional BMD of the hip, radius, and spine were assessed with a dual-energy x-ray absorptiometer. For each BMD site assessed, multivariate linear regression analysis was performed in 4 steps (alpha = 0.10) to examine the contribution of (a) age, sex, bodyweight, and calcium and vitamin D intake; (b) group (elite senior athlete, control); (c) knee extension peak torque; and (d) knee flexion peak torque on BMD. Sex, age, bodyweight, and calcium and vitamin D intake explained a significant amount of variance in BMD in each site. Group was not significant. Knee extension peak torque explained an additional 3.8% of the variance in hip BMD (p = 0.06). Knee flexion peak torque was not correlated to BMD at any of the sites assessed. In conclusion, participation in highly competitive athletics was not related to total body or regional BMD. Age, sex, bodyweight, and vitamin D and calcium intake were significantly related to BMD at all the sites assessed. Quadriceps strength contributed slightly to hip BMD. Our results imply that participation in highly competitive senior athletics does not have a protective effect on BMD, perhaps because of a lower bodyweight or other confounding factors. PMID- 23442280 TI - Using a practical approach for determining the most effective stretching strategy in female college division I volleyball players. AB - The purpose of this investigation was to quantify the effects that a practical bout of static stretching (SS) and dynamic stretching (DS) has on maximal countermovement jump (CMJ) height across a time spectrum of 25 minutes in National Collegiate Athletic Association Division I varsity volleyball players. Eleven female varsity volleyball players (mean +/- SD; age 20.00 +/- 1.55 years; height 1.78 +/- 0.08 m; mass 74.55 +/- 12.18 kg) volunteered for this investigation. Three days of randomized experimental testing (SS, DS, control) were completed. The SS protocol consisted of stretching 7 muscle groups. The DS protocol consisted of the volleyball team's actual DS routine of equal duration (30 seconds) to SS. Poststretch performance measures of CMJ were determined at 1, 5, 15, and 25 minutes poststretch. Countermovement jump had an acute significant trial-by-time interaction, indicating that DS was found to produce significantly higher scores than the SS and control session at 1 and 5 minutes poststretch, but not at 15 and 25 minutes poststretch. Additionally, there was a timing interaction within trials where SS scores were significantly lower at 1 minute poststretch compared with 5 and 25 minutes poststretch, and DS scores were significantly higher at 1 and 5 minutes poststretch compared with 15 and 25 minutes poststretch. Athletes engaging in competitive power sports should continue to utilize their DS routine but may need to do so within 5 minutes before activity. PMID- 23442281 TI - Pressure pain mapping of the wrist extensors after repeated eccentric exercise at high intensity. AB - The purpose of this study was to investigate adaptation mechanisms after 2 test rounds consisting of eccentric exercise using pressure pain imaging of the wrist extensors. Pressure pain thresholds (PPTs) were assessed over 12 points forming a 3 * 4 matrix over the dominant elbow in 12 participants. From the PPT assessments, pressure pain maps were computed. Delayed onset muscle soreness was induced in an initial test round of high-intensity eccentric exercise. The second test round performed 7 days later aimed at resulting in adaptation. The PPTs were assessed before, immediately after, and 24 hours after the 2 test rounds of eccentric exercise. For the first test round, the mean PPT was significantly lower 24 hours after exercise compared with before exercise (389.5 +/- 64.1 vs. 500.5 +/- 66.4 kPa, respectively; p = 0.02). For the second test round, the PPT was similar before and 24 hours after (447.7 +/- 51.3 vs. 458.0 +/- 73.1 kPa, respectively; p = 1.0). This study demonstrated adaptive effects of the wrist extensors monitored by pain imaging technique in healthy untrained humans. A lack of hyperalgesia, i.e., no decrease in PPT underlined adaptation after the second test round of eccentric exercise performed 7 days after the initial test round. The present findings showed for the first time that repeated eccentric exercise performed twice over 2 weeks protects the wrist extensor muscles from developing exacerbated pressure pain sensitivity. Thus, the addition of eccentric components to training regimens should be considered to induce protective adaptation. PMID- 23442282 TI - Differences in horizontal vs. uphill running performance in male and female Swiss world-class orienteers. AB - In orienteering, athletes must choose the quickest route from point to point, considering if they want to run a longer flat distance rather than a shorter distance with an incline to reach the next point. Our aim was therefore, to determine an athlete's equivalence factor (EF, ratio between horizontal and uphill running performance) enabling coaches to provide individual route choice recommendations during orienteering competition. Ten male and 8 female orienteers performed 1 horizontal (MST(horizontal); 0% incline) and 1 uphill (MST(uphill); 22% incline) maximal running stage test to exhaustion on a treadmill in randomized order. The EFs were calculated based on maximal speeds achieved in both tests (MRV(horizontal/uphill)). In addition, VO2peak was measured. MRV(horizontal) was 20.4 +/- 0.6 and 17.3 +/- 0.8 km . h, and MRV(uphill) was 8.8 +/- 0.7 and 7.2 +/- 0.5 km . h (men and women). The EF was 6.3 +/- 0.7 and ranged between 5.2 and 7.4. Relative VO2peak(uphill) was 69.2 +/- 5.7 and 59.1 +/- 3.7 m l . kg . min, whereas VO2peak(horizontal) was lower 66.4 +/- 3.5 (p < 0.05) and 55.7 +/- 3.1 ml . kg . min (p < 0.01) than in VO2peak(uphill). Relative VO2peak(uphill) correlated strongly with MRV(uphill) (men: r = 0.85, p < 0.01; women: r = 0.84, p < 0.01), whereas relative VO2peak(horizontal) showed no strong correlation with MRV(horizontal) (men: r = 0.51, p = 0.12; women: r = 0.41, p = 0.32). These data show that there are relevant differences in the relation between uphill and horizontal running capacity in these athletes. Tailoring the route selection to the athletes' advantage based on the relation between their uphill and horizontal running performance and individual EF may positively impact on overall performance in orienteering competition. PMID- 23442283 TI - Differences between the elite and subelite sprinters in kinematic and dynamic determinations of countermovement jump and drop jump. AB - The aim of this study was to examine the relationship between selected variables of lower extremities explosive power measured via countermovement jump (CMJ) and drop jump (DJ) and sprinting ability over 60- and 100-m dash. Twelve national level Slovenian sprinters were assigned to 2 groups: elite (n = 6) and subelite (n = 6). The grouping criterion was performance in 60 and 100 m in official competition. Biomechanical parameters of both jumps were measured with the use of bipedal force platform and a system of 9 infraspectral charge-coupled device (CCD) cameras with a 200 Hz frequency. Differences between the groups of sprinters were examined with the use of repeated-measures analysis of variance. In CMJ, the differences (p < 0.05) between the groups were revealed in take off velocity (elites = 3.23 m . s, subelites = 2.94 m.s), height of the jump, vertical velocity of body center of gravity, and the impulse of force in the concentric phase of the jump (concentric impulse: elites = 123.91 N . s; subelites = 108.06 N . s). In the DJ, elite and subelite sprinters differentiated in the realization of movement velocity in the eccentric and concentric phases (take off velocity: elites = 3.18 m . s, subelites = 2.87 m . s; eccentric velocity: elites = 3.05 m . s, subelites = 2.81 m . s). This investigation provides evidence that vertical jumps and DJs are very important tools to meet the demands of sprint training according eccentric-concentric muscular work. The DJ showed better quality than CMJ in the neuromuscular specificity. PMID- 23442284 TI - Effects of supplemental carbohydrate ingestion during superimposed electromyostimulation exercise in elite weightlifters. AB - The purpose of this investigation was to test the effects of carbohydrate supplementation on blood parameters and force output during superimposed electromyostimulation (SEMS) single-leg isometric contractions. We hypothesized that carbohydrate ingestion before and during muscle contractions would lead to greater glucose availability and greater total force output for the session. Six elite resistance trained male subjects participated in a randomized, counterbalanced, double-blind study. The subjects were randomly assigned to placebo (PL) or carbohydrate (CHO). The subjects in CHO consumed 1 g of carbohydrate per kilogram of body mass loading dose and 0.17 g of carbohydrate . per kilogram of body mass every 6 minutes during the exercise protocol. The PL received an equal volume of a solution made of saccharin and aspartame. The exercise protocol consisted of repeated 20-second isometric contractions of quadriceps muscle at 50% maximal voluntary contraction followed by 40 seconds of rest until failure occurred. Importantly, quadriceps maximal voluntary contraction with SEMS was performed in the beginning and then every 5 minutes during the last 3 seconds of isometric contractions throughout the exercise protocol. Venous blood samples were taken preexercise, immediately postexercise, and at 5 minutes postexercise and analyzed for glucose, nonesterified fatty acids, and glycerol. Our results indicate that CHO ingestion increased (p < 0.05) plasma glucose, but no significant differences (p > 0.05) were detected for nonesterified fatty acids or glycerol. Importantly, total force output during exercise protocol was higher (p < 0.05) in CHO compared with that in PL. Therefore, our data suggest that CHO supplementation before and during exercise may be beneficial for individuals performing high-volume resistance training. PMID- 23442285 TI - Application of a body-weight-supporting kite for sprint running. AB - Improvements in sprint performance at the top level require adaptations concerning force application because ground contact time diminishes with increasing velocity. Applied training methods and devices must provoke appropriate stimuli. A knowledge about positive and negative effects of these stimuli is vital for coaches. The purpose of this study was to determine the angle of attack and lifting and retarding forces of a novel sprint training device that supports the athlete's body weight (BW), thereby decreasing ground contact time during sprints. Three different kite sizes (1.10, 1.75, 2.25 m) were investigated. A bicycle was used to accelerate the National Aeronautics and Space Administration (NASA) parawings (NPW-120, NPW-150, and NPW-170) on an indoor track to acquire data at velocities between 6.5 and 10.5 m . s. During a 5-m interval of constant speed, the resultant force of the kite was recorded on a portable computer by a load cell. The angle of attack was determined by a high speed camera, and the mean velocity in the 5-m sector was measured by a laser gauge. Lifting and retarding forces were derived from the resultant force and angle of attack. Quadratic regression equations for lifting and retarding forces, depending on the velocity, were calculated for all 3 NPWs. A clear difference (p < 0.001) depending on the kite size was revealed for lifting and retarding forces. These forces also indicated high correlation coefficients related to velocity (r > 0.98; p < 0.001), whereas the angle of attack remained almost constant across the entire velocity range in all NPWs, yielding a lift-to-drag ratio of 2.35. Because of the kite's small retarding forces, we recommend the application of the NPW during the high-speed phase of sprinting with lifting force probably counteracting adverse effects. By adding a towing system, the retarding force can be fine tuned, erased, or turned into overspeed assistance, thereby emphasizing BW support. PMID- 23442286 TI - The effect of combined resisted agility and repeated sprint training vs. strength training on female elite soccer players. AB - The aim of this study was to compare the effects of in-season combined resisted agility and repeated sprint training with strength training on soccer players' agility, linear single sprint speed, vertical jump, repeated sprint ability (RSA), and aerobic capacity. Twenty well-trained elite female soccer players of age +/- SD 19.4 +/- 4.4 years volunteered to participate in this study. The participants were randomly assigned to either the agility and repeated sprint training group or to the strength training group. All the participants were tested before and after a 10-week specific conditioning program. The pretest and posttest were conducted on 3 separate days with 1 day of low-intensity training in between. Test day 1 consisted of squat jump (SJ), countermovement jump (CMJ), and RSA. Test day 2 consisted of a 40-m maximal linear sprint and an agility test, whereas a Beep test was conducted on test day 3 to assess aerobic capacity. The agility and repeated sprint training implemented in this study did not have a significant effect on agility, although there was a tendency for moderate improvements from 8.23 +/- 0.32 to 8.06 +/- 0.21 seconds (d = 0.8). There was a significant (p < 0.01) and moderate-positive effect on Beep-test performance from level 9.6 +/- 1.4 to level 10.8 +/- 1.0, and only a trivial small effect on all other physical variables measured in this study. The strength training group had a positive, moderate, and significant (p < 0.01) effect on Beep-test performance from level 9.7 +/- 1.3 to level 10.9 +/- 1.2 (d = 1.0) and a significant (p < 0.05) but small effect (d = 0.5) on SJ performance (25.9 +/- 2.7 to 27.5 +/- 4.1 cm). Furthermore, the strength training implemented in this study had a trivial and negative effect on agility performance (d = -0.1). No between-group differences were observed. The outcome of this study indicates the importance of a well-planned program of conditioning that does not result in a decreased performance of the players, the great importance of strength and conditioning specialist in implementing the training program, and the importance of choosing the time of the year to implement such conditioning training programs. However, the fact that the present training program did not cause any decline in performance indicates that it is useful in maintaining the soccer players' physical performance during the competition period. PMID- 23442287 TI - Muscle performance, size, and safety responses after eight weeks of resistance training and protein supplementation: a randomized, double-blinded, placebo controlled clinical trial. AB - The purpose of this study was to examine the effects of 2 different types of protein supplementation on thigh muscle cross-sectional area (CSA), blood markers, muscular strength, endurance, and body composition after 8 weeks of low- or moderate-volume resistance training in healthy, recreationally trained, college-aged men. One hundred and six men were randomized into 5 groups: low volume resistance training with bioenhanced whey protein (BWPLV; n = 22), moderate-volume resistance training with BWP (BWPMV; n = 20), moderate-volume resistance training with standard whey protein (SWPMV; n = 22), moderate-volume resistance training with a placebo (PLA; n = 21), or moderate-volume resistance training with no supplementation (CON; n = 21). Except for CON, all groups consumed 1 shake before and after each exercise session and one each on the nontraining day. The BWPLV, BWPMV, and SWPMV groups received approximately 20 g of whey protein per shake, whereas the BWP groups received 5 g of additional polyethylene glycosylated (PEG) leucine. Resistance training sessions were performed 3 times per week for 8 weeks. There were no interactions (p > 0.05) for muscle strength and endurance variables, body composition, muscle CSA, and safety blood markers, but the main effects for training were observed (p <= 0.05). However, the Albumin:Globulin ratio for SWPMV was lower (p = 0.037) than BWPLV and BWPMV. Relative protein intake (PROREL) indicated a significant interaction (p < 0.001) with no differences across groups at pre; however, BWPLV, BWPMV, and SWPMV had a greater intake than did PLA or CON at post (p < 0.001). This study indicated that 8 weeks of resistance training improved muscle performance and size similarly among groups regardless of supplementation. PMID- 23442288 TI - Neuromuscular characteristics of drop and hurdle jumps with different types of landings. AB - The objective of this study was to compare drop (DJ) and hurdle jumps using a preferred, flat foot (FLAT) and forefoot (FORE) landing technique. Countermovement jump height was used to establish the hurdle and the DJ heights. The subjects performed forward hurdles and vertical DJs on a force plate. Measures included vertical ground reaction force (VGRF), contact time, leg stiffness, and rate of force development (RFD). Electromyographic (EMG) activity was measured in the rectus femoris, biceps femoris, tibialis anterior, and gastrocnemius during 3 phases: preactivity, eccentric phase, and concentric phase. All the kinetic variables favored hurdles over DJs. Specifically, hurdle preferred technique and FORE exhibited the shortest contact time and DJ FLAT the longest. The VGRF was higher in hurdle preferred and FORE than in DJ preferred, FLAT, and FORE. For stiffness and RFD, hurdle preferred and FORE were higher than DJ preferred and FLAT. Hurdle jumps showed higher rectus femoris EMG activity than DJ did during preactivity and eccentric phases but lower activity during the concentric phase. Considering the type of landing, FLAT generally demonstrated the greatest EMG activity. During the concentric phase, DJ exhibited higher rectus femoris EMG activity. Biceps femoris activity was higher with hurdles in all the phases. Gastrocnemius showed the highest EMG activity during the concentric phase, and during the eccentric phase, hurdle preferred and FORE showed the highest results. In conclusion, the hurdle FORE technique was the most powerful type of jump. PMID- 23442289 TI - Neuromuscular, hormonal, and metabolic responses to different plyometric training volumes in rugby players. AB - The purpose of this study was to investigate the effect of different volumes of plyometric exercise (i.e., 100, 200, or 300 hurdle jumps) on acute strength and jump performance and on the acute hormonal and lactate responses in rugby players. Eleven young male elite rugby players (age, 23.5 +/- 0.9 years; height, 173 +/- 4.8 cm) volunteered for the study. Maximal isometric peak torque (PT), maximal rate of force development (RFD), squat jump (SJ), and drop jump (DJ) performance were assessed before and 5 minutes, 8 hours, and 24 hours after 100, 200, or 300 jumps. In addition, total testosterone (TT), cortisol (COR), and lactate were measured before and after the 3 different plyometric exercise volumes. There were significant decreases in the PT (p < 0.02) and maximal RFD (p < 0.001) 5 minutes, 8 hours, and 24 hours after 100, 200, and 300 jumps, with no differences between the exercise volumes. Additionally, there were significant decreases in the SJ (p < 0.001) and DJ (p < 0.01) performances 24 hours after 100, 200, and 300 jumps, with no differences between the exercise volumes. However, there were significant increases in the TT (p < 0.001), COR (p < 0.05), and lactate (p < 0.001) after 100, 200, and 300 jumps, with no differences between the exercise volumes. All plyometric exercise volumes (100, 200, and 300 jumps) resulted in similar neuromuscular, metabolic, and hormonal responses. PMID- 23442290 TI - Effect of Training Status on Reliability of 1RM Testing in Women, Methodological Mistake. PMID- 23442291 TI - Effect of back squat depth on lower-body postactivation potentiation. AB - Postactivation potentiation (PAP) refers to increased muscular force generation after previous muscular activity. Various studies have used different squat variations as a PAP stimulus; however, different squat depths can have different mechanical and physiological demands that could yield different PAP levels and subsequent performance. The study aimed to compare the effects of the parallel (PS) and quarter (QS) squat on PAP. Twenty-seven, semiprofessional, male rugby union players (mean +/- SD, 18 +/- 2 years, 87.2 +/- 5.4 kg, 180.7 +/- 5.1 cm) performed a countermovement jump (BL-CMJ) followed by a 10-minute rest. Subsequently, they performed 3 PS or QS, at each squat's respective 3-repetition maximum load, in a randomized counterbalanced order. After a 5-minute rest, another countermovement jump (CMJ) was performed (POST-CMJ). Countermovement jump height (JH), peak power (PP), impulse (I), and flight time (FT) were recorded using a contact mat. BL-CMJ and POST-CMJ pairwise comparisons for all variables were conducted for each squat type to examine performance changes. Delta values were compared to examine whether one squat produced better CMJ results. Both squats induced PAP for all the variables (p < 0.05), although PS produced better results than QS (p < 0.05; JH, 4.6 +/- 2 vs. 3.5 +/- 2 cm; I, 15 +/- 6 vs. 12 +/- 5 N·s; PP, 285 +/- 109 vs. 215 +/- 96 W; FT, 34 +/- 23 vs. 26 +/- 11 milliseconds for PS vs. QS). This is the first study to demonstrate that different squat types can induce PAP and that PS is more beneficial for subsequent CMJ performance compared with QS. It is suggested that the deeper depth of PS, which increases gluteus maximum activation and work produced, is responsible for the increased CMJ performance. PMID- 23442292 TI - Nutritional knowledge in an Italian population of children, pre-adolescents and adolescents. AB - OBJECTIVE: To evaluate general knowledge about nutrition in an Italian population of children, pre-adolescents and adolescents. DESIGN: Knowledge about nutrition related items such as healthy eating, breakfast, snacks, fast food, beverages, fruits and vegetables, cereals and tubers, meat/fish/legumes/eggs, milk and dairy products, fats and dressings, and sweets was analysed by means of a self administered questionnaire (QuesCA IT) containing thirty-one questions, that was translated and adapted from a Swiss version (QuesCA) previously used in Geneva and Vaud. SETTING: North of Italy (Bergamo, Milan). SUBJECTS: Students (n 614) belonging to two different age groups: 9-11 years (GR1) and 12-16 years (GR2). RESULTS: Data analysis showed that nutritional knowledge varied in relation to the age of the participants, increasing in particular in the older group, although this difference was not statistically significant for all the considered items. Nutritional knowledge also varied in relation to the gender of the participants, with females in particular seeming to possess better cognition. For each age group there was poor knowledge about the items healthy diet, snacks, milk and dairy products, meat/fish/legumes/eggs, and fats and dressings. Moreover, the percentage of participants who declared own knowledge as insufficient was higher in GR2 compared with GR1. CONCLUSIONS: The present research demonstrates a lack of knowledge about the main concepts of healthy nutrition both in the youngest and oldest participants of the survey. This evidence, together with the presence of higher self-consciousness in GR2, should be taken into account in specific educational interventions during the school period. PMID- 23442293 TI - Knowledge about adverse drug reactions reporting among healthcare professionals in Nepal. AB - OBJECTIVE: To investigate the knowledge about ADRs and ADR reporting among healthcare professionals working at four regional pharmacovigilance centers (RPCs) of Nepal. METHODS: It was a cross sectional study, done by a survey using a validated self-administered structured questionnaire. The questionnaire was distributed to 450 healthcare professionals working at four RPCs. RESULTS: The overall response rate was 74%. Only 53% and 38% of respondents knew about the existence of National Pharmacovigilance Centre (NPC) and RPC, respectively. Among the respondents, 29% and 33% did not know what a Type A and Type B ADR was. Similarly, 30% and 45% were not aware of the common types of ADRs or the thalidomide tragedy. Only, 9% knew about Uppsala Monitoring Centre (UMC) and only 10% answered correctly about the Naranjo algorithm as a causality assessment tool for ADRs. Of the respondents, only 19% knew about spontaneous reporting system and only 18% were aware about its drawbacks. The overall mean score on knowledge about ADR among healthcare professionals was 7.64 +/- 2.38 out of the maximum possible score of 12. Whereas, the overall mean score of knowledge about ADR reporting was 3.95 +/- 1.78 out of maximum possible score of 11. CONCLUSION: Healthcare professionals working at four RPCs of Nepal have some knowledge about ADRs themselves but limited knowledge about ADR reporting. There is an urgent need of action to be taken by RPCs at the regional level and NPC at the national level to improve knowledge and ADR reporting by healthcare professionals. PMID- 23442294 TI - Medication errors through a national pharmacovigilance database approach: a study for Malta. AB - AIM: To identify medication errors in the Maltese pharmacovigilance database and describe the frequency and characteristics of these events. METHOD: A retrospective analysis of the Adverse Drug Events (ADEs) reported over 5 years in Malta was conducted. Medication errors were identified by comparing use against the product's Summary of Product Characteristics (SmPC) and then classified by type of medication error, seriousness and the stage of the medication use chain at which they occurred. RESULTS: 319 consolidated ADE reports met the inclusion criteria and were analysed. 56/319 consolidated ADEs were associated with serious patient harm. The 80-89 and the 50-59 age groups were associated with most medications used in error. 65% of errors originated in the community. Errors were identified in prescribing (52%), therapeutic monitoring (26%), patients' own (12%), dispensing (7%) and administration (3%) stages. The non-steroidal anti inflammatory drugs (NSAIDs) and antibiotics were most commonly used in errors involving wrong doses, lack of therapeutic monitoring, interactions; contra indications, prescribing for an unlicensed indication as well as an inappropriate duration of therapy. CONCLUSION: Pharmacovigilance databases are a useful source of information on medication errors and can be used to detect risks associated with the use of medicinal products. PMID- 23442295 TI - Pharmacovigilance on the turn? Adverse reactions methods in 2012. PMID- 23442296 TI - Survey on critical incident reporting in a child and adolescent mental health service. AB - AIM: To examine the prevalence and nature of critical incident reports at a generic child and adolescent mental health service. METHOD: This is a retrospective survey of all critical incident reports completed at a community based child and adolescent mental health service between 2008 and 2011. Information was obtained about the nature of incidents and actions taken. RESULTS: In a three year period, only eighteen incident report forms were completed. Staff were most frequently the victims of the incidents (50%, n = 9), followed by clients (38.8%, n = 7) and parents of clients (11.1%, n = 2). Falls were the most common incident reports (44.4%, n = 8). Two incidences were related to physical aggression and threatening behaviour by clients. CONCLUSION: Critical incident reporting was found to be uncommon overall. Most of the recorded incidents involved staff members and were of minor significance. Specific training for staff regarding incident reporting should be provided to ensure an acceptable standard of investigation is consistently carried out for all significant incidents. PMID- 23442297 TI - Drug utilization, safety and clinical use of Actos and Avandia. AB - BACKGROUND AND OBJECTIVE: The impetus for this review was recent increased warnings of cardiovascular toxicity, fractures and bladder cancer associated with glitazone use. METHODS: A drug utilization review was performed regarding the use of Actos (pioglitazone) and Avandia (rosiglitazone) at Cooper Green Mercy Hospital (CGMH), an inner city safety net hospital in Birmingham, Alabama. Pharmacy records were reviewed hospital-wide to determine usage patterns of all anti-diabetic medications. Medline and the FDA websites were searched for articles on safety and efficacy of pioglitazone and rosiglitazone. Considerations were relative utilization profile, comparative efficacy, indications, relative cost, and safety profile of the two available medications in this drug class. RESULTS: On the basis of all of these factors, a hospital-wide switch of all rosiglitazone prescriptions to all pioglitazone was implemented, which was estimated to result in savings of $83,000 for the first year. No episodes of worsening of control of diabetes were anticipated, nor were episodes of decreased efficacy or adverse effects as a result of automatically switching patients from rosiglitazone to pioglitazone at the time of prescription filling. CONCLUSIONS: The conclusions can be summarized in a number of key points. * Clinicians should follow the American Diabetes Association guidelines [1] for treatment. * The basis for diabetic control is weight loss, diet and exercise. * Initial medication management for type II Diabetes Mellitus includes metformin and insulin. * There are no circumstances in which use of glitazone medications is preferable to other medication groups, and there are no clinical circumstances in which use of glitazone medications is absolutely necessary, as opposed to other classes of diabetic medication. * There are significant contraindications, warnings and precautions to use of glitazones, which must be taken into consideration before use in every individual patient. * Glitazones in particular should not be used in the following circumstances: congestive heart failure (CHF), concurrent bladder cancer or severe osteoporosis. PMID- 23442298 TI - A prospective study of highly active antiretroviral therapy in Indian human immunodeficiency virus positive patients. AB - BACKGROUND: There are no studies performed in India on the safety of highly active antiretroviral therapy (HAART) combinations which focus on the base-line CD4+ T-cell count. Further, no data on risk factors for Adverse drug reactions (ADRs) to HAART and there is a lack of data on CD4+ T-cell count recovery after HAART. OBJECTIVES: The aim of this study was to assess risk factors for ADRs to HAART. We also compared the efficacy of HAART combinations with respect to base line CD4+ T-cell count and CD4+ T-cell counts recovery in Indian HIV positive patients. METHODS: A prospective active surveillance study was adopted at the Antiretroviral Therapy (ART) Centre, District Government Hospital, Udupi, India. HIV-infected patients were intensively monitored to identify risk factors associated with ADRs to HAART from August 2009 to May 2012. The study protocol was approved by the University ethics committee. Baseline CD4+ T-cell count before initiation of HAART and thereafter at every six months of regular follow up up to 24 months duration was included for comparison. Multivariate logistic regression analysis was used to identify predictors of high risk factors of ADRs. CD4+ T-cell count recovery after HAART from base-line CD4+ T-cell count in different HAART groups was analyzed by test of between-subject effects. P-value <0.05 was considered as statistically significant. RESULTS: A total of 1982 HIV positive patients were enrolled with 1181 (59.6%) males, and 801 (40.4%) females. On multivariate logistic regression analysis, four factors were found to be predictors of high-risk factors for ADRs to HAART: 1) CD4+ T-cell counts, 2) female gender, 3) polypharmacy and 4) opportunistic infections. Between HAART groups, a mean increase of 98 cells/MUl of CD4+ T-cell counts recovery was seen in the 3TC + NVP + D4T group (p < 0.001) at 24 months of regular follow-up. CONCLUSION: In India, Clinician should take into consideration all possible risk factors associated with the use of HAART in order to avoid and minimize ADRs. As initial CD4+ T-cell count and age of patient decides the rise of CD4+ T-cell counts with HAART. HAART should be initiated at the earliest age in order to attain maximum CD4+ T-cell counts recovery. PMID- 23442299 TI - THERACOM: a systematic review of the evidence base for interventions to improve Therapeutic Communications between black and minority ethnic populations and staff in specialist mental health services. AB - BACKGROUND: Black and Minority Ethnic (BME) groups in receipt of specialist mental health care have reported higher rates of detention under the mental health act, less use of psychological therapies, and more dissatisfaction. Although many explanations have been put forward to explain this, a failure of therapeutic communications may explain poorer satisfaction, disengagement from services and ethnic variations in access to less coercive care. Interventions that improve therapeutic communications may offer new approaches to tackle ethnic inequalities in experiences and outcomes. METHODS: The THERACOM project is an HTA funded evidence synthesis review of interventions to improve therapeutic communications between black and minority ethnic patients in contact with specialist mental health services and staff providing those services. This article sets out the protocol methods for a necessarily broad review topic, including appropriate search strategies, dilemmas for classifying different types of therapeutic communications and expectations of the types of interventions to improve them. The review methods will accommodate unexpected types of study and interventions. The findings will be reported in 2013, including a synthesis of the quantitative and grey literature. DISCUSSION: A particular methodological challenge is to identify and rate the quality of many different study types, for example, randomised controlled trials, observational quantitative studies, qualitative studies and case studies, which comprise the full range of hierarchies of evidence. We discuss the preliminary methodological challenges and some solutions. (PROSPERO registration number: CRD42011001661). PMID- 23442301 TI - Acupuncture points and skin impedance. PMID- 23442300 TI - The social ecology of water in a Mumbai slum: failures in water quality, quantity, and reliability. AB - BACKGROUND: Urban slums in developing countries that are not recognized by the government often lack legal access to municipal water supplies. This results in the creation of insecure "informal" water distribution systems (i.e., community run or private systems outside of the government's purview) that may increase water-borne disease risk. We evaluate an informal water distribution system in a slum in Mumbai, India using commonly accepted health and social equity indicators. We also identify predictors of bacterial contamination of drinking water using logistic regression analysis. METHODS: Data were collected through two studies: the 2008 Baseline Needs Assessment survey of 959 households and the 2011 Seasonal Water Assessment, in which 229 samples were collected for water quality testing over three seasons. Water samples were collected in each season from the following points along the distribution system: motors that directly tap the municipal supply (i.e., "point-of-source" water), hoses going to slum lanes, and storage and drinking water containers from 21 households. RESULTS: Depending on season, households spend an average of 52 to 206 times more than the standard municipal charge of Indian rupees 2.25 (US dollars 0.04) per 1000 liters for water, and, in some seasons, 95% use less than the WHO-recommended minimum of 50 liters per capita per day. During the monsoon season, 50% of point-of-source water samples were contaminated. Despite a lack of point-of-source water contamination in other seasons, stored drinking water was contaminated in all seasons, with rates as high as 43% for E. coli and 76% for coliform bacteria. In the multivariate logistic regression analysis, monsoon and summer seasons were associated with significantly increased odds of drinking water contamination. CONCLUSIONS: Our findings reveal severe deficiencies in water-related health and social equity indicators. All bacterial contamination of drinking water occurred due to post-source contamination during storage in the household, except during the monsoon season, when there was some point-of-source water contamination. This suggests that safe storage and household water treatment interventions may improve water quality in slums. Problems of exorbitant expense, inadequate quantity, and poor point-of-source quality can only be remedied by providing unrecognized slums with equitable access to municipal water supplies. PMID- 23442302 TI - Fully automatic measurements of axial vertebral rotation for assessment of spinal deformity in idiopathic scoliosis. AB - Reliable measurements of spinal deformities in idiopathic scoliosis are vital, since they are used for assessing the degree of scoliosis, deciding upon treatment and monitoring the progression of the disease. However, commonly used two dimensional methods (e.g. the Cobb angle) do not fully capture the three dimensional deformity at hand in scoliosis, of which axial vertebral rotation (AVR) is considered to be of great importance. There are manual methods for measuring the AVR, but they are often time-consuming and related with a high intra- and inter-observer variability. In this paper, we present a fully automatic method for estimating the AVR in images from computed tomography. The proposed method is evaluated on four scoliotic patients with 17 vertebrae each and compared with manual measurements performed by three observers using the standard method by Aaro-Dahlborn. The comparison shows that the difference in measured AVR between automatic and manual measurements are on the same level as the inter-observer difference. This is further supported by a high intraclass correlation coefficient (0.971-0.979), obtained when comparing the automatic measurements with the manual measurements of each observer. Hence, the provided results and the computational performance, only requiring approximately 10 to 15 s for processing an entire volume, demonstrate the potential clinical value of the proposed method. PMID- 23442303 TI - Genetic changes with prognostic value in histologically benign meningiomas. AB - Meningiomas add up to 25% of intracranial tumors. Although the majority is considered histologically benign, the prediction of their potential aggressiveness is still unclear. We studied the histopathology and aberrations of chromosomes 1p, 14, and 22 by FISH (fluorescence in situ hybridization) in histologically benign meningiomas of 70 patients for the purpose of defining the prognostic value of these alterations in tumoral progression and the risk of recurrence. According to the WHO histopathological criteria, the study set comprised 53 benign, 11 atypical, and 6 anaplastic meningiomas. In benign meningiomas, 25% of the cases displayed a normal karyotype, isolated monosomy 22 (36%), monosomy 22 + 1p deletion (14%), 1p deletion (10%), monosomy 22 + 14q deletion (5%), monosomy 22 + 1p deletion + 14q deletion (5%), or other alterations (5%). Grade II meningiomas presented losses in chromosome 14 in most of the cases (67%), and Grade III meningiomas showed alterations in chromosome 14 in all patients. We observed an overall relapse rate of 31%: recurrence was observed in 19% of Grade I meningiomas, 64% of Grade II, and 83% of Grade III. 9 out of 10 recurrent cases revealed abnormalities in chromosomes 1 and 14, which was a notably higher incidence compared to the series of tumors without relapse. Thus, benign meningiomas with cytogenetic alterations in chromosomes 1p and 14 may be more closely related to atypical meningiomas than benign meningiomas without these alterations, especially in terms of recurrence risk. PMID- 23442304 TI - Synchronous occurrence of paraganglioma of the glomus jugulare and olfactory groove meningioma. PMID- 23442305 TI - A review of breast cancer care and outcomes in Latin America. AB - This review presents an overview of breast cancer care, burden, and outcomes in Latin America, as well as the challenges and opportunities for improvement. Information was gleaned through a review of the literature, public databases, and conference presentations, in addition to a survey of clinical experts and patient organizations from the region. Breast cancer annual incidence (114,900 cases) and mortality (37,000 deaths) are the highest of all women's cancers in Latin America, and they are increasing. Twice as many breast cancer deaths are expected by 2030. In Peru, Mexico, Colombia, and Brazil, diagnosis and death at younger ages deprives society of numerous productive years, as does high disease occurrence in Argentina and Uruguay. Approximately 30%-40% of diagnoses are metastatic disease. High mortality-to-incidence ratios (MIRs) in Latin America indicate poor survival, partly because of the late stage at diagnosis and poorer access to treatment. Between 2002 and 2008, MIRs decreased in all countries, albeit unevenly. Costa Rica's change in MIR outpaced incidence growth, indicating impressive progress in breast cancer survival. The situation is similar, although to a lesser extent, in Colombia and Ecuador. The marginal drops of MIRs in Brazil and Mexico mainly reflect incidence growth rather than progress in outcomes. Panama's MIR is still high. Epidemiological data are scattered and of varying quality in Latin America. However, one could ascertain that the burden of breast cancer in the region is considerable and growing due to demographic changes, particularly the aging population, and socioeconomic development. Early diagnosis and population-wide access to evidence-based treatment remain unresolved problems, despite progress achieved by some countries. PMID- 23442306 TI - Induction chemotherapy for locoregionally advanced head and neck cancer: past, present, future? AB - The treatment of patients with locoregionally advanced squamous cell cancer of the head and neck is still evolving. Induction chemotherapy (IC) is widely used in this patient population and it is unclear how to best incorporate IC into multimodality treatment. Recently, the results of two randomized clinical trials were presented (the PARADIGM and Docetaxel Based Chemotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer trials), which showed no demonstrable benefit of IC followed by concurrent chemoradiation over concurrent chemoradiotherapy alone. However, a lower rate of distant metastatic disease was noted, suggesting that patients who are at high risk for metastatic disease may benefit from IC. This review summarizes how IC has evolved over the years, provides an update of recent developments, and discusses how IC may develop in the future. PMID- 23442307 TI - The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expenses and the insured cancer patient's experience. AB - PURPOSE: Cancer patients carry rising burdens of health care-related out-of pocket expenses, and a growing number of patients are considered "underinsured." Our objective was to describe experiences of insured cancer patients requesting copayment assistance and to describe the impact of health care expenses on well being and treatment. METHODS: We conducted baseline and follow-up surveys regarding the impact of health care costs on well-being and treatment among cancer patients who contacted a national copayment assistance foundation along with a comparison sample of patients treated at an academic medical center. RESULTS: Among 254 participants, 75% applied for drug copayment assistance. Forty two percent of participants reported a significant or catastrophic subjective financial burden; 68% cut back on leisure activities, 46% reduced spending on food and clothing, and 46% used savings to defray out-of-pocket expenses. To save money, 20% took less than the prescribed amount of medication, 19% partially filled prescriptions, and 24% avoided filling prescriptions altogether. Copayment assistance applicants were more likely than nonapplicants to employ at least one of these strategies to defray costs (98% vs. 78%). In an adjusted analysis, younger age, larger household size, applying for copayment assistance, and communicating with physicians about costs were associated with greater subjective financial burden. CONCLUSION: Insured patients undergoing cancer treatment and seeking copayment assistance experience considerable subjective financial burden, and they may alter their care to defray out-of-pocket expenses. Health insurance does not eliminate financial distress or health disparities among cancer patients. Future research should investigate coverage thresholds that minimize adverse financial outcomes and identify cancer patients at greatest risk for financial toxicity. PMID- 23442308 TI - A phase II study of amrubicin as a third-line or fourth-line chemotherapy for patients with non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0901. AB - Amrubicin, a third-generation synthetic anthracycline agent, has favorable clinical activity and acceptable toxicity for the treatment of patients with non small cell lung cancer (NSCLC) and small cell lung cancer. We conducted this study to evaluate the efficacy and safety of amrubicin for advanced NSCLC patients as a third- or fourth-line therapy. Eligible patients had recurrent or refractory advanced NSCLC after second- or third-line therapy. Patients received amrubicin, 35 mg/m(2) i.v. on days 1-3 every 3 weeks. The primary endpoint was the disease control rate (DCR). Secondary endpoints were the overall survival (OS) time, progression-free survival (PFS) time, response rate, and toxicity profile. Of the 41 patients enrolled, 26 received amrubicin as a third-line and 15 received it as a fourth-line therapy. The median number of treatment cycles was two (range, 1-9). Objective responses were complete response (n = 0), partial response (n = 4), stable disease (n = 21), progressive disease (n = 15), and not evaluable (n = 1), resulting in a DCR of 61.0% (95% confidence interval, 46.0% 75.9%). The overall response rate was 9.8% (95% confidence interval, 0.6%-18.8%). The median PFS interval was 3.0 months, median OS time was 12.6 months, and 1 year survival rate was 53.7%. Grade 3 or 4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Nonhematological toxicities were mild and reversible. No treatment-related deaths were observed. Amrubicin showed significant clinical activity with manageable toxicities as a third- or fourth-line therapy for patients with advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating third- or fourth-line treatment strategies for patients with advanced NSCLC. PMID- 23442310 TI - Adequacy of vitamin D intakes in children and teenagers from the base diet, fortified foods and supplements. AB - OBJECTIVE: To describe vitamin D intakes in children and teenagers and the contribution from supplements and fortified foods in addition to the base diet. DESIGN: Analysis of 7 d weighed food records collected during the Children's and Teens' National Nutrition Surveys in Ireland. Food composition data for vitamin D were updated from international analytical sources. SETTING: Nationally representative cross-sectional dietary surveys. SUBJECTS: Children (n 594; 5-12 years) and teenagers (n 441; 13-17 years). RESULTS: Median vitamin D intakes were 1.9, 2.1 and 2.4 MUg/d in 5-8-, 9-12- and 13-17-year-olds, respectively. The prevalence of vitamin D-containing supplement use was 21, 16 and 15% in 5-8-, 9 12- and 13-17-year-olds and median intakes in users ranged from 6.0 to 6.7 MUg/d. The prevalence of inadequate intakes, defined as the percentage with mean daily intakes below the Estimated Average Requirement of 10 MUg/d, ranged from 88 to 96% in supplement users. Foods fortified with vitamin D, mainly breakfast cereals, fat spreads and milk, were consumed by 71, 70 and 63 % of 5-8-, 9-12- and 13-17-year-olds. Non-supplement users who consumed vitamin D-fortified foods had median intakes of 1.9-2.5 MUg/d, compared with 1.2-1.4 MUg/d in those who did not consume fortified foods. CONCLUSIONS: It is currently not possible for children consuming the habitual diet to meet the US Institute of Medicine dietary reference intake for vitamin D. In the absence of nationally representative 25 hydroxyvitamin D data in children, the implications of this observation for prevalence of vitamin D deficiency and health consequences are speculative. PMID- 23442309 TI - Feasibility of image-guided transthoracic core-needle biopsy in the BATTLE lung trial. AB - BACKGROUND: As therapy for non-small-cell lung cancer (NSCLC) patients becomes more personalized, additional tissue in the form of core-needle biopsies (CNBs) for biomarker analysis is increasingly required for determining appropriate treatment and for enrollment into clinical trials. We report our experience with small-caliber percutaneous transthoracic (PT) CNBs for the evaluation of multiple molecular biomarkers in BATTLE (biomarker-integrated approaches of targeted therapy for lung cancer elimination), a personalized, targeted therapy NSCLC clinical trial. METHODS: The medical records of patients who underwent PTCNB for consideration of enrollment in BATTLE were reviewed for diagnostic yield of 11 predetermined molecular markers and procedural complications. Univariate and multivariate analyses of factors related to patient and lesion characteristics were performed to determine possible influences on diagnostic yield. RESULTS: One hundred and seventy PTCNBs were performed using 20-gauge biopsy needles in 151 NSCLC patients screened for the trial. The biopsy specimens of 82.9% of the patients were found to have adequate tumor tissue for analysis of the required biomarkers. On multivariate analysis, metastatic lesions were 5.4 times more likely to yield diagnostic tissue as compared with primary tumors (p = 0.0079). Pneumothorax and chest tube insertion rates were 15.3% and 9.4%, respectively. CONCLUSIONS: Image-guided 20-gauge PTCNB is safe and provides adequate tissue for analysis of multiple biomarkers in the majority of patients being considered for enrollment into a personalized, targeted therapy NSCLC clinical trial. Metastatic lesions are more likely to yield diagnostic tissue as compared with primary tumors. PMID- 23442311 TI - Invasive lobular carcinoma arising in accessory breast tissue. AB - BACKGROUND: Lobular carcinoma in accessory breast tissue is a rare occurrence. We present such a case in a 61-year-old woman. CASE PRESENTATION: A skin nodule in the axillary skin on excision biopsy revealed invasive lobular carcinoma. CONCLUSIONS: Carcinoma in accessory breast tissue is uncommon especially invasive lobular type. A high index of suspicion may avoid late diagnosis. PMID- 23442313 TI - Surface-enhanced Raman spectroscopy investigation on human breast cancer cells. AB - BACKGROUND: Nanoparticles are potentially used for early cancer detection, accurate diagnosis, and cancer treatment. RESULTS: In this paper, the breast cancer cells treated with gold colloidal suspension were carefully studied by surface-enhanced Raman scattering (SERS) spectra. Raman spectroscopy combining with high-resolution electron microscope is employed to investigate the interaction of gold nanoparticles (GNPs) with the intracellular components. The TEM images show that the GNPs are taken into the living cells and enveloped into some vesicles named 'lick up vesicles' in the cytosol. CONCLUSIONS: The SERS spectra and SERS mapping of cells indicate that the major Raman bands are mostly assigned to the vibration characteristics of proteins, and the C-H in-plane bending mode of the substituted benzene in Phenylalanine is remarkably enhanced. Finally, the interaction mechanisms of the GNPs with the intracellular components are further discussed in detail. PMID- 23442312 TI - Identification and functional analysis of cytochrome P450 complement in Streptomyces virginiae IBL14. AB - BACKGROUND: As well known, both natural and synthetic steroidal compounds are powerful endocrine disrupting compounds (EDCs) which can cause reproductive toxicity and affect cellular development in mammals and thus are generally regarded as serious contributors to water pollution. Streptomyces virginiae IBL14 is an effective degradative strain for many steroidal compounds and can also catalyze the C25 hydroxylation of diosgenin, the first-ever biotransformation found on the F-ring of diosgenin. RESULTS: To completely elucidate the hydroxylation function of cytochrome P450 genes (CYPs) found during biotransformation of steroids by S. virginiae IBL14, the whole genome sequencing of this strain was carried out via 454 Sequencing Systems. The analytical results of BLASTP showed that the strain IBL14 contains 33 CYPs, 7 ferredoxins and 3 ferredoxin reductases in its 8.0 Mb linear chromosome. CYPs from S. virginiae IBL14 are phylogenetically closed to those of Streptomyces sp. Mg1 and Streptomyces sp. C. One new subfamily was found as per the fact that the CYP Svu001 in S. virginiae IBL14 shares 66% identity only to that (ZP_05001937, protein identifer) from Streptomyces sp. Mg1. Further analysis showed that among all of the 33 CYPs in S. virginiae IBL14, three CYPs are clustered with ferredoxins, one with ferredoxin and ferredoxin reductase and three CYPs with ATP/GTP binding proteins, four CYPs arranged with transcriptional regulatory genes and one CYP located on the upstream of an ATP-binding protein and transcriptional regulators as well as four CYPs associated with other functional genes involved in secondary metabolism and degradation. CONCLUSIONS: These characteristics found in CYPs from S. virginiae IBL14 show that the EXXR motif in the K-helix is not absolutely conserved in CYP157 family and I-helix not absolutely essential for the CYP structure, too. Experimental results showed that both CYP Svh01 and CYP Svu022 are two hydroxylases, capable of bioconverting diosgenone into isonuatigenone and beta-estradiol into estriol, respectively. PMID- 23442314 TI - Spread of Influenza A(H1N1) oseltamivir-resistant viruses in Africa in 2008 confirmed by multiple introductions in Senegal. AB - BACKGROUND: Among Influenza neuraminidase inhibitors (NAIs), oseltamivir corresponds to the most widely used agent to treat influenza disease. However since 2001, several cases of resistance to NAIs have been reported for circulating seasonal A(H1N1) Influenza viruses. A direct resistance mechanism may be invoked, involving critical mutations in the viral NA gene that prevent the drug binding to its target. Same phenomenon is reported for adamantanes drugs and mutations in the M2 channel protein gene of Influenza viruses. METHODS: Reverse Transcription/Restriction Fragment Length Polymorphism (RT-PCR/RFLP) method, phenotypic testing for oseltamivir resistance, and sequencing of NA, HA and M2 genes were used in this study. Phylogenetic analyses were performed using BioEdit and Mega 5 softwares for alignment of sequences and phylogenetic trees building respectively. RESULTS: Using a simple RT-PCR/RFLP method, we found that the 86 seasonal A(H1N1) isolates from 2008 bear the oseltamivir resistance-associated mutation (H274Y) in the NA gene. In contrast all isolates isolated in Senegal in 2007 were sensitive to oseltamivir. These results were first confirmed by finding high IC50 values using a phenotypic testing for oseltamivir resistance, and secondly by sequencing the whole NA gene. Regarding M2 gene, no mutation associated to adamantanes resistance was characterized of the isolates. CONCLUSIONS: The present work provides evidence of circulation of drug-resistant seasonal A(H1N1) viruses during the 2008 influenza season (July to September) in Senegal. The results are in favor of multiple introductions of oseltamivir resistant viruses (ORV) A(H1N1) in Senegal.Phylogenetic analyses of isolates with complete sequences of N1 and HA1 genes showed that they belong to clade 2B and suggest sequential introductions in Africa. PMID- 23442315 TI - Comparison of the Airtraq and the Macintosh laryngoscope for double-lumen tube intubation: a randomised clinical trial. AB - CONTEXT: The Airtraq is a disposable optical laryngoscope that is available in a double-lumen tube version. Inserting a double-lumen tube is generally more difficult compared to conventional endotracheal intubation, mainly due to its configuration. OBJECTIVE: The aim of this study was to compare the Airtraq with the Macintosh laryngoscope for intubation with a double-lumen tube in patients undergoing elective thoracic surgery. The main outcome was time needed for successful intubation. DESIGN: Prospective, randomised clinical trial. SETTING: A single centre, University Hospital of Wurzburg, Germany, between July 2009 and June 2011. PATIENTS: After a scout laryngoscopy with a Macintosh laryngoscope, 60 adult patients were intubated by an anaesthesiologist with either an Airtraq (n = 30) or a Macintosh laryngoscope (n = 30). MAIN OUTCOME MEASURES: The time needed for correct intubation, checked by flexible bronchoscopy, was recorded. The intubation difficulty scale (IDS) and Cormack and Lehane grade were noted. Haemodynamic variables and any evidence of oropharyngeal trauma were documented as well as postoperative sore throat, hoarseness and dysphagia. RESULTS: The mean time needed for correct intubation was 20.1 +/- 16.5 s in the Airtraq group and 17.5 +/- 10 s in the Macintosh group (P = 0.86). All intubations in both groups had an IDS less than 4. The Cormack and Lehane grade was I in all 30 patients in the Airtraq group; in the Macintosh group, it was I and II in 17 and 13 patients, respectively. The incidence of hoarseness was significantly higher in the Airtraq group 24 h postoperatively (P = 0.01). CONCLUSION: There was no significant difference between the Airtraq and the Macintosh laryngoscopes regarding the time needed to insert a double-lumen tube during elective thoracic surgery. Only subtle enhancement of visualisation and a higher incidence of hoarseness were observed in the Airtraq group. The Airtraq device did not result in superior patient safety in this setting. PMID- 23442316 TI - Predicting out of intensive care unit cardiopulmonary arrest or death using electronic medical record data. AB - BACKGROUND: Accurate, timely and automated identification of patients at high risk for severe clinical deterioration using readily available clinical information in the electronic medical record (EMR) could inform health systems to target scarce resources and save lives. METHODS: We identified 7,466 patients admitted to a large, public, urban academic hospital between May 2009 and March 2010. An automated clinical prediction model for out of intensive care unit (ICU) cardiopulmonary arrest and unexpected death was created in the derivation sample (50% randomly selected from total cohort) using multivariable logistic regression. The automated model was then validated in the remaining 50% from the total cohort (validation sample). The primary outcome was a composite of resuscitation events, and death (RED). RED included cardiopulmonary arrest, acute respiratory compromise and unexpected death. Predictors were measured using data from the previous 24 hours. Candidate variables included vital signs, laboratory data, physician orders, medications, floor assignment, and the Modified Early Warning Score (MEWS), among other treatment variables. RESULTS: RED rates were 1.2% of patient-days for the total cohort. Fourteen variables were independent predictors of RED and included age, oxygenation, diastolic blood pressure, arterial blood gas and laboratory values, emergent orders, and assignment to a high risk floor. The automated model had excellent discrimination (c statistic=0.85) and calibration and was more sensitive (51.6% and 42.2%) and specific (94.3% and 91.3%) than the MEWS alone. The automated model predicted RED 15.9 hours before they occurred and earlier than Rapid Response Team (RRT) activation (5.7 hours prior to an event, p=0.003) CONCLUSION: An automated model harnessing EMR data offers great potential for identifying RED and was superior to both a prior risk model and the human judgment-driven RRT. PMID- 23442317 TI - Protocol for a systematic review of the diagnostic and prognostic utility of tests currently available for the detection of aspirin resistance in patients with established cardiovascular or cerebrovascular disease. AB - BACKGROUND: The benefits of aspirin as an anti-platelet agent are well established; however, there has been much debate about the lack of uniformity in the efficacy of aspirin to inhibit platelet function. In some patients, aspirin fails to inhibit platelets even where compliance has been verified, a phenomenon which has been termed "aspirin resistance". These patients may in turn be at a higher risk of future vascular events. The proportion of "resistant" patients identified depends on the type of platelet function test. Therefore, the aim of this systematic review is to determine which, if any, platelet function test has utility in terms of identifying patients with a high risk of vascular events. The review has been registered with PROSPERO (CRD42012002151). METHODS: Relevant studies will be sought from bibliographic databases. Trials registers will be searched for ongoing studies. Reference lists will be checked and subject experts contacted. There will be no date or language restrictions. Standard reviewing methodology to minimise bias will be employed. Any prospective studies in patients on aspirin therapy and assessing platelet function in relation to relevant clinical outcomes will be included, as will studies reporting prognostic models. Risk of bias assessment will be based on the Quality Assessment of Diagnostic Accuracy Studies guidelines, and suitable criteria for assessing quality of prognostic studies. Data on test accuracy measures, relative risks, odds or hazard ratios will be extracted and meta-analysed, where possible, using a random-effects model to account for between-study heterogeneity. Where appropriate, the causes of heterogeneity will be explored through meta-regression and sub-group or sensitivity analyses. If platelet function testing is demonstrated to have diagnostic/predictive utility in a specific population, the potential for a cost-effectiveness analysis will be considered and, if possible, an economic model constructed. This will be supported by a systematic review of existing economic evaluation studies. DISCUSSION: The results of the review could indicate if platelet function test(s) could lead to a reliable prediction of the risk of clinically important events in a defined population, and thus support investigations into adjustments to therapy in order to compensate for a predicted poor response to standard aspirin. PMID- 23442318 TI - Ethnic differences in alcohol and drug use and related sexual risks for HIV among vulnerable women in Cape Town, South Africa: implications for interventions. AB - BACKGROUND: Alcohol and other drug (AOD) use among poor Black African and Coloured women in South Africa compounds their sexual risk for HIV. Given South Africa's history of ethnic disparities, ethnic differences in sex risk profiles may exist that should be taken into account when planning HIV risk reduction interventions. This paper aims to describe ethnic differences in AOD use and AOD related sexual risks for HIV among vulnerable women from Cape Town, South Africa. METHOD: Cross-sectional data on 720 AOD-using women (324 Black African; 396 Coloured) recruited from poor communities in Cape Town were examined for ethnic differences in AOD use and AOD-related sexual risk behavior. RESULTS: Ethnic differences in patterns of AOD use were found; with self-reported drug problems, heavy episodic drinking and methamphetamine use being most prevalent among Coloured women and cannabis use being most likely among Black African women. However, more than half of Black African women reported drug-related problems and more than a third tested positive for recent methamphetamine use. More than a third of women reported being AOD-impaired and having unprotected sex during their last sexual encounter. Coloured women had four-fold greater odds of reporting that their last sexual episode was AOD-impaired and unprotected than Black African women. In addition, close to one in two women reported that their sexual partner was AOD-impaired at last sex, with Coloured women having three fold greater odds of reporting that their partner was AOD-impaired at last sex than Black African women. CONCLUSIONS: Findings support the need to develop and test AOD risk reduction interventions for women from both ethnic groups. In addition, findings point to the need for tailored interventions that target the distinct profiles of AOD use and AOD-related sex risks for HIV among Black African and Coloured women. PMID- 23442321 TI - Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with beta-catenin (CTNNB1) status. AB - Dysregulation of the WNT/beta-catenin (CTNNB1) signaling pathway is implicated in colorectal carcinoma and metabolic diseases. Considering these roles and cancer prevention, we hypothesized that tumor CTNNB1 status might influence cellular sensitivity to obesity and physical activity. In clinical follow-up of 109,046 women in the Nurses' Health Study and 47,684 men in the Health Professionals Follow-up Study, there were 861 incident rectal and colon cancers with tissue immunohistochemistry data on nuclear CTNNB1 expression. Using this molecular pathological epidemiology database, we conducted Cox proportional hazards regression analysis using data duplication method to assess differential associations of body mass index (BMI) or exercise activity with colorectal cancer risk according to tumor CTNNB1 status. Greater BMI was associated with a significantly higher risk of CTNNB1-negative cancer [multivariate HR = 1.34; 95% confidence interval (CI), 1.18-1.53 for 5.0 kg/m(2) increment; Ptrend = 0.0001] but not with CTNNB1-positive cancer risk (multivariate HR = 1.07; 95% CI, 0.92 1.25 for 5.0 kg/m(2) increment; Ptrend = 0.36; Pheterogeneity = 0.027, between CTNNB1-negative and CTNNB1-positive cancer risks). Physical activity level was associated with a lower risk of CTNNB1-negative cancer (multivariate HR = 0.93; 95% CI, 0.87-1.00 for 10 MET-h/wk increment; Ptrend = 0.044) but not with CTNNB1 positive cancer risk (multivariate HR = 0.98; 95% CI, 0.91-1.05 for 10 MET-h/wk increment; Ptrend = 0.60). Our findings argue that obesity and physical inactivity are associated with a higher risk of CTNNB1-negative colorectal cancer but not with CTNNB1-positive cancer risk. Furthermore, they suggest that energy balance and metabolism status exerts its effect in a specific carcinogenesis pathway that is less likely dependent on WNT/CTNNB1 activation. Cancer Res; 73(5); 1600-10. (c)2012 AACR. PMID- 23442323 TI - Thyroid hormone regulation of miR-21 enhances migration and invasion of hepatoma. AB - Thyroid hormone (T(3)) signaling through the thyroid hormone receptor (TRalpha1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (miR-21) is activated by T(3) through a native T(3) response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T(3) stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T(3). The Rac controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T(3). Attenuation and overexpression of miR-21 induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of beta-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRalpha1, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P = 0.005) between the tumor/nontumor ratios of TRalpha1 and miR-21 expression, whereas a negative correlation (P = 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T(3) and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion. PMID- 23442324 TI - A bootstrap approach to evaluating person and item fit to the Rasch model. AB - Historically, rule-of-thumb critical values have been employed for interpreting fit statistics that depict anomalous person and item response patterns in applications of the Rasch model. Unfortunately, prior research has shown that these values are not appropriate in many contexts. This article introduces a bootstrap procedure for identifying reasonable critical values for Rasch fit statistics and compares the results of that procedure to applications of rule-of thumb critical values for three example datasets. The results indicate that rule of-thumb values may over- or under-identify the number of misfitting items or persons. PMID- 23442322 TI - HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. AB - Although current breast cancer treatment guidelines limit the use of HER2 blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER(+)), HER2(-) luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-kappaB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1635-46. (c)2012 AACR. PMID- 23442325 TI - Using the Rasch measurement model to design a report writing assessment instrument. AB - This paper describes how the Rasch measurement model was used to develop an assessment instrument designed to measure student ability to write law enforcement incident and investigative reports. The ability to write reports is a requirement of all law enforcement recruits in the state of Michigan and is a part of the state's mandatory basic training curriculum, which is promulgated by the Michigan Commission on Law Enforcement Standards (MCOLES). Recently, MCOLES conducted research to modernize its training and testing in the area of report writing. A structured validation process was used, which included: a) an examination of the job tasks of a patrol officer, b) input from content experts, c) a review of the professional research, and d) the creation of an instrument to measure student competency. The Rasch model addressed several measurement principles that were central to construct validity, which were particularly useful for assessing student performances. Based on the results of the report writing validation project, the state established a legitimate connectivity between the report writing standard and the essential job functions of a patrol officer in Michigan. The project also produced an authentic instrument for measuring minimum levels of report writing competency, which generated results that are valid for inferences of student ability. Ultimately, the state of Michigan must ensure the safety of its citizens by licensing only those patrol officers who possess a minimum level of core competency. Maintaining the validity and reliability of both the training and testing processes can ensure that the system for producing such candidates functions as intended. PMID- 23442326 TI - Using multidimensional Rasch to enhance measurement precision: initial results from simulation and empirical studies. AB - This study aimed to explore the effect on measurement precision of multidimensional, as compared with unidimensional, Rasch measurement for constructing measures from multidimensional Likert-type scales. Many educational and psychological tests are multidimensional but common practice is to ignore correlations among the latent traits in these multidimensional scales in the measurement process. These practices may have serious validity and reliability implications. This study made use of both empirical data from 208,083 students, and simulated data simulated by 24 systematic combinations, each replicated 1000 times, of three conditions, namely, sample size, degree of dimensionality, and scale length to compare unidimensional and multidimensional approaches and to identify effects of sample size, dimensionality and scale length on measurement precision. Results showed that the multidimensional Rasch approach yielded more precise estimates than did unidimensional approach if the two dimensions were strongly correlated. The effect was more pronounced for long scales. PMID- 23442327 TI - Using the dichotomous Rasch model to analyze polytomous items. AB - One of the most important applications of the Rasch measurement models in educational assessment is the equating of tests. An important feature of attainment tests is the use of both dichotomous and polytomous items. The partial credit model (PCM) developed by Masters (1982) represents an extension of the dichotomous Rasch model for analysing polytomous item data. The dichotomous Rasch model has been used primarily to analyse dichotomous item data. Whilst the partial credit model can provide detailed information on the performance of individual score categories of polytomous items, it is mathematically more complex to use than the dichotomous Rasch model and can, under certain circumstances, present difficulties in interpreting item measures and in practical applications. This study explores the potential of using the dichotomous Rasch model to analyse polytomous items and equate tests. Results obtained from a simulation study and from analysing the data of a science achievement test indicate that the partial credit model and the dichotomous Rasch model produce similar item and person measures and equivalent cut scores on different test forms. PMID- 23442328 TI - With hiccups and bumps: the development of a Rasch-based instrument to measure elementary students' understanding of the nature of science. AB - This research describes the development process, psychometric analyses and part validation study of a theoretically-grounded Rasch-based instrument, the Nature of Science Instrument-Elementary (NOSI-E). The NOSI-E was designed to measure elementary students' understanding of the Nature of Science (NOS). Evidence is provided for three of the six validity aspects (content, substantive and generalizability) needed to support the construct validity of the NOSI-E. A future article will examine the structural and external validity aspects. Rasch modeling proved especially productive in scale improvement efforts. The instrument, designed for large-scale assessment use, is conceptualized using five construct domains. Data from 741 elementary students were used to pilot the Rasch scale, with continuous improvements made over three successive administrations. The psychometric properties of the NOSI-E instrument are consistent with the basic assumptions of Rasch measurement, namely that the items are well-fitting and invariant. Items from each of the five domains (Empirical, Theory-Laden, Certainty, Inventive, and Socially and Culturally Embedded) are spread along the scale's continuum and appear to overlap well. Most importantly, the scale seems appropriately calibrated and responsive for elementary school-aged children, the target age group. As a result, the NOSI-E should prove beneficial for science education research. As the United States' science education reform efforts move toward students' learning science through engaging in authentic scientific practices (NRC, 2011), it will be important to assess whether this new approach to teaching science is effective. The NOSI-E can be used as one measure of whether this reform effort has an impact. PMID- 23442329 TI - Application of single-level and multi-level Rasch models using the lme4 package. AB - The aim of the article is to illustrate how researchers may use the lme4 package to run multilevel Rasch models. The lme4 package is a popular open-source software and is frequently used by researchers around the world to fit generalized mixed-effects models with crossed or partially crossed random effects. The article starts with a short discussion of the reasons why a researcher might, sometimes, be motivated to use a multi-level Rasch model and presents a practical example using empirical data. The main features of the lme4 package are presented, and finally, the paper presents information about other open-source software that could alternatively be used to fit multi-level Rasch models. PMID- 23442330 TI - Rasch modeling to assess Albanian and South African learners' preferences for real-life situations to be used in mathematics: a pilot study. AB - This paper reports on an investigation on the real-life situations students in grades 8 and 9 in South Africa and Albania prefer to use in Mathematics. The functioning of the instrument used to assess the order of preference learners from both countries have for contextual situations is assessed using Rasch modeling techniques. For both the cohorts, the data fit the Rasch model. The differential item functioning (DIF) analysis rendered 3 items operating differentially for the two cohorts. Explanations for these differences are provided in terms of differences in experiences learners in the two countries have related to some of the contextual situations. Implications for interpretation of international comparative tests are offered, as are the possibilities for the cross-country development of curriculum materials related to contexts that learners prefer to use in Mathematics. PMID- 23442331 TI - Genetic risk prediction in a small cohort of healthy adults in Atlanta. AB - Compared with single markers, polygenic scores that evaluate the joint effects of multiple trait-associated variants are more effective in explaining the variance of traits and risk of diseases. In total, 182 CHDWB (Emory-Georgia Tech Center for Health Discovery and Well Being study) adults were genotyped to investigate the common variant contributions to three traits (height, BMI, serum triglycerides) and three diseases (coronary artery disease (CAD), type 2 diabetes (T2D) and asthma). Association was contrasted between weighted and simple allelic sum polygenic scores with quantitative traits, and with the Framingham risk scores for CAD and T2D. Although the cohort size is two or three orders of magnitude smaller than typical discovery cohorts, we were able to detect significant associations and to explain up to 5% of the traits by the genetic risk scores, despite a strong influence of outliers. An unexpected finding was that CAD-associated single nucleotide polymorphisms (SNPs) explain a significant amount of the variation for total serum cholesterol. Forward step-wise sequential addition of SNPs into the regression model showed that the top-ranked SNPs explain a large proportion of variance, whereas inclusion of gender and ethnicity also affect the performance of polygenic scores. PMID- 23442332 TI - Prevalence of intestinal parasites and associated risk factors among HIV/AIDS patients with pre-ART and on-ART attending dessie hospital ART clinic, Northeast Ethiopia. AB - BACKGROUND: Intestinal parasites are a major concern in most developing countries where HIV/AIDS case are concentrate and almost 80% of AIDS patients die of AIDS related infections. In the absence of ART, HIV/AIDS patients in developing countries unfortunately continue to suffer from the consequences of opportunistic parasites. But this prevalence has dramatically decreased in countries where antiretroviral agents are widely available. Therefore, the aim of this study was to assess the prevalence of intestinal parasite and risk factor among pre- ART and on ART adult HIV/ AIDS patients attending ART clinic in Dessie hospital. METHODS: A comparative cross-sectional study was conducted among pre-ART and on ART adult HIV/AIDS patients of Dessie Hospital. A total of 272 (136 from each group) study subjects were selected by using systematic random sampling. Stool sample was collected and processed using direct wet mount, formol-ether concentration technique and modified Ziehl-Neelson staining techniques. A structured questionnaire was used to collect data on Sociodemographic & associated risk factors. Data was entered and analyzed by using SPSS 16 software and logistic regressions were applied to assess any association between explanatory factors and outcome variables. RESULTS: The overall prevalence of IP in pre-ART and on-ART was 39% and 17.6%, respectively with significant decrease of intestinal parasite in the ART era (p < 0.001). All Cryptosporidium spps infections were found in the pre-ART patients and significantly associated for lower CD4 <200cells/mm3. Absence of toilet (AOR = 7.57; 95% CI = 1.3,44.22), source of water (AOR = 6.03; 95% CI = 1.14,31.98), living condition (AOR = 13.29, 95% CI = 5.14, 34.35); WHO stage (AOR = 6.06; 95% CI = 2.49,14.74) and ART status (AOR = 7.55; 95% CI = 3.24,17.59) have significant association with prevalence of intestinal parasite. CONCLUSION: The overall prevalence of IP was differ by ART status and opportunistic parasite like cryptosporidium spps were found in low CD4 counts in ART naive patients. This study identified some environmental and some clinical finding as determinant factor for IP infections. Therefore, public health measures and adherence to ART should be strengthened to improve the quality of life of these patients. PMID- 23442333 TI - Change of behaviour when selecting food products in a supermarket environment after reminding consumers about weight management. AB - OBJECTIVE: The aim was to explore how the behaviour of consumers changed while they selected food in a supermarket environment after they were reminded about weight management. This investigation was carried out from the perspective of selection criteria, reading of package labels, nutritional quality of the products selected and time taken to select a product. DESIGN: The subjects, who were actively watching their weight, participated in two consecutive tasks in a supermarket. They were given a shopping list of eleven food categories and asked to think aloud while selecting from each category a product they usually buy and a product they would use for weight management. The data (n 792 selections) were collected through interviews and a verbal analysis protocol combined with wireless audio-visual observation. SUBJECTS: Thirty-six consumers were recruited from a sample of 367 supermarket customers. SETTING: Kuopio, Finland. RESULTS: The subjects' behaviour changed radically after they were reminded about weight management. In the first selection, taste and familiarity were the main food selection criteria while in the latter selection the energy/fat content predominated. Consequently, the nutritional quality of products improved greatly because subjects read package labels twice as much in the latter selection. The time taken to select a product increased significantly, on average, from 23 (sd 10) to 60 (sd 51) s/product (P = 0.000). CONCLUSIONS: Only by reminding consumers about weight management was there a significant impact on their food selection behaviour. Marketing communication should be developed which quickly and easily promotes consumers' awareness of healthy food in supermarkets. PMID- 23442334 TI - Carnosine: can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential? AB - The dipeptide carnosine (beta-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells. PMID- 23442335 TI - Predicting the prevalence of chronic kidney disease in the English population: a cross-sectional study. AB - BACKGROUND: There is concern that not all cases of chronic kidney disease (CKD) are known to general practitioners, leading to an underestimate of its true prevalence. We carried out this study to develop a model to predict the prevalence of CKD using a large English primary care dataset which includes previously undiagnosed cases of CKD. METHODS: Cross-sectional analysis of data from the Quality Improvement in CKD trial, a representative sample of 743 935 adults in England aged 18 and over. We created multivariable logistic regression models to identify important predictive factors. RESULTS: A prevalence of 6.76% was recorded in our sample, compared to a national prevalence of 4.3%. Increasing age, female gender and cardiovascular disease were associated with a significantly increased prevalence of CKD (p < 0.001 for all). Age had a complex association with CKD. Cardiovascular disease was a stronger predictive factor in younger than in older patients. For example, hypertension has an odds ratio of 2.02 amongst patients above average and an odds ratio of 3.91 amongst patients below average age. CONCLUSION: In England many cases of CKD remain undiagnosed. It is possible to use the results of this study to identify areas with high levels of undiagnosed CKD and groups at particular risk of having CKD. TRIAL REGISTRATION: Current Controlled Trials ISRCTN: ISRCTN56023731. Note that this study reports the results of a cross-sectional analysis of data from this trial. PMID- 23442336 TI - Robust fluoroscopic tracking of fiducial markers: exploiting the spatial constraints. AB - Two new fluoroscopic fiducial tracking methods that exploit the spatial relationship among the multiple implanted fiducial to achieve fast, accurate and robust tracking are proposed in this paper. The spatial relationship between multiple implanted markers are modeled as Gaussian distributions of their pairwise distances over time. The means and standard deviations of these distances are learned from training sequences, and pairwise distances that deviate from these learned distributions are assigned a low spatial matching score. The spatial constraints are incorporated in two different algorithms: a stochastic tracking method and a detection based method. In the stochastic method, hypotheses of the 'true' fiducial position are sampled from a pre-trained respiration motion model. Each hypothesis is assigned an importance value based on image matching score and spatial matching score. Learning the parameters of the motion model is needed in addition to learning the distribution parameters of the pairwise distances in the proposed stochastic tracking approach. In the detection based method, a set of possible marker locations are identified by using a template matching based fiducial detector. The best location is obtained by optimizing the image matching score and spatial matching score through non serial dynamic programming. In this detection based approach, there is no need to learn the respiration motion model. The two proposed algorithms are compared with a recent work using a multiple hypothesis tracking (MHT) algorithm which is denoted by MHT, Tang et al (2007 Phys. Med. Biol. 52 4081-98). Phantom experiments were performed using fluoroscopic videos captured with known motion relative to an anthropomorphic phantom. The patient experiments were performed using a retrospective study of 16 fluoroscopic videos of liver cancer patients with implanted fiducials. For the motion phantom data sets, the detection based approach has the smallest tracking error (MUerr: 0.78-1.74 mm, sigmaerr: 0.39 1.16 mm) for the images taken at low exposure (50 mAs). At higher exposure (500 mAs), the stochastic method gave the best performance (MUerr: ~0.39 mm, sigmaerr: ~0.27 mm). In contrast, the tracker (MHT) that does not model the spatial constraints only performs well when there is no occluded fiducial. With the RANDO phantom data, both of our proposed methods performed well and have the mean tracking errors around ~1.8 mm with the standard deviations ~0.93 mm at 100 mAs and ~0.91 mm with 0.88 mm standard deviation at 500 mAs. The MHT tracker has the largest tracking errors with mean ~4.8 mm) and standard deviation ~2.4 mm in both sessions with the Rondo phantom data. On the patient data sets, the detection based method gave the smallest error (MUerr: 0.39 mm, sigmaerr: ~0.19 mm). The stochastic method performed well (MUerr: ~0.58 mm, sigmaerr: ~0.39 mm) when the patient breathed consistently, the accuracy dropped to (MUerr: ~1.55 mm) when the patient breathed differently across sessions. PMID- 23442337 TI - Metastasis of osteosarcoma to stomach made clinically evident by hematemesis: a case report. AB - BACKGROUND: Gastric metastasis from osteosarcoma is very rare and its clinical features are not well recognized. CASE PRESENTATION: A 73-year-old man was diagnosed with osteosarcoma and treated with four cycles of preoperative chemotherapy with ifosfamide and doxorubicin followed by wide resection. Two cycles of postoperative chemotherapy with ifosfamide and doxorubicin and ten cycles of chemotherapy with carboplatin and etoposide were administered. Eleven months after the surgery, he vomited fresh blood. Unusual progression of anemia was observed with the hematemesis. A biopsy was performed by gastrointestinal endoscopy, and the stomach tumor was diagnosed as metastasis of osteosarcoma. CONCLUSIONS: Even though gastric metastasis from osteosarcoma is very rare, all three previous reports and our case showed the presence of ulcer on the surface of the gastric lesion. We should consider the possibility of gastric metastasis in patients with osteosarcoma in whom progression of anemia or gastric hemorrhage is observed. PMID- 23442339 TI - Treatment of extra-articular and simple articular distal radial fractures with intramedullary nail versus volar locking plate. AB - The purpose of this prospective, randomized and blinded study was to compare the clinical outcomes of distal radial fractures treated with either an intramedullary nail or a volar locking plate. Sixty two patients were enrolled in the study and randomized to treatment with a MICRONAILTM (Group 1, 31 patients) or an adaptive plate (Group 2, 31 patients). Fracture types included were unstable extra-articular metaphyseal distal radial fractures and simple or multifragmentary sagittal articular distal radial fractures (AO classification types A2, A3, B1.1 and B1.2). All patients were evaluated at 6 weeks, 3 months and 12 months after surgery. Outcome measures included standard radiographic parameters, active wrist range of motion, the disabilities of the arm, shoulder and hand (DASH) and Mayo wrist scores. We concluded that treatment of this subset of distal radius fractures with minimally invasive intramedullary nailing gives better clinical outcomes at 6 weeks after surgery than treatment with a volar locking plate. By 3 and 12 months following surgery, there are no significant differences in outcome between the two treatment methods. Disadvantages of the MICRONAILTM fixation system include risk of injury to the superficial branch of the radial nerve and a narrower spectrum of indications than volar locking plates. PMID- 23442338 TI - Effectiveness of Australia's Get Healthy Information and Coaching Service: maintenance of self-reported anthropometric and behavioural changes after program completion. AB - BACKGROUND: The Get Healthy Information and Coaching Service (GHS) is a population-wide telephone-based program aimed at assisting adults to implement lifestyle improvements. It is a relatively uncommon example of the translation of efficacious trials to up-scaled real-world application. GHS participants who completed the 6-month coaching program made significant initial improvements to their weight, waist circumference, Body Mass Index (BMI), physical activity and nutrition behaviours. This study examines the maintenance of anthropometric and behaviour change improvements 6-months after program completion. METHODS: GHS coaching participants (n=1088) were recruited between February 2009 and June 2011. Participants were eligible if they completed the 6-month coaching program and had available data at 12-month follow-up (n=277). Weight, waist circumference, BMI, fruit and vegetable consumption and physical activity were collected at baseline and 6-months by GHS coaches and 12-months (6-months post program) by independent evaluators. Matched pair t-tests, mixed linear regression and logistic regression analyses were performed to assess maintenance of program effects. RESULTS: Improvements in weight (-2.9 kg, 95% CI: -3.6, -2.1), waist circumference (-5.4 cm, 95% CI: -6.7, -4.1), BMI (-1.1 units, 95% CI: -1.5, 0.8), and fruit (+0.3 serves per day, 95% CI: 0.2, 0.3) and vegetable (+0.5 serves per day 95% CI: 0.3, 0.6) consumption were observed from baseline to 12 months. Apart from vegetable consumption, there were no significant differences between 6-month and 12-month changes from baseline, indicating these risk factor improvements were maintained from the end of the coaching program. There were also improvements in the proportion of participants undertaking recommended levels of physical activity from baseline to 12-months (increase of 5.2%), however the improvements made at end of the coaching program were not maintained at the 6-month follow up. CONCLUSIONS: This study provides preliminary evidence that the GHS has potential to contribute to substantial improvements in the chronic disease risk factor profile of program completers and facilitates sustained maintenance six months after completing the coaching program. PMID- 23442340 TI - Distal scaphoid fracture and scapholunate ligament injury in a child. PMID- 23442341 TI - The relationship of trigger finger and flexor tendon volar migration after carpal tunnel release. AB - It has been suggested that the increased frequency of trigger finger (TF) after carpal tunnel release (CTR) may be caused by the volar migration of the flexor tendons at the wrist altering the tendon biomechanics at the A1 pulley. This hypothesis has not been validated. We performed pre- and post-operative ultrasonography (USG) on the affected wrists of 92 patients who underwent CTR. Pre-operative USG was performed in neutral with no tendon loading; post-operative USG was performed in neutral unloaded and in various positions of wrist flexion whilst loading the flexor tendons with gripping. The mean volar migration of the flexor tendons after CTR was 2.2 (SD 0.4) mm in the unloaded neutral position. It was 1.8 (SD 0.4) mm in patients who did not develop TF and 2.5 (SD 0.5) mm in those who did (p = 0.0067). In loaded wrist flexion, the mean volar migration of flexor tendons after CTR in patients who did not develop TF and those who did was 2.1 and 3.0 mm in 0 degrees flexion; 3.2 and 3.9 mm in 15 degrees flexion; 4.3 and 5.1 mm in 30 degrees flexion; and 4.9 and 5.8 mm in 45 degrees flexion, respectively. There were significant differences between patients with and without TF at each flexion angle. Our data indicate that patients with greater volar migration of the flexor tendons after CTR are more likely to develop TF. This conclusion supports the hypothesis that the occurrence of TF after CTR may be caused by the bowstringing effects of the flexor tendons. PMID- 23442342 TI - Incidence and diagnosis of 'the double lesion' of the triangular fibrocartilage complex. PMID- 23442343 TI - Menstrual and reproductive factors and exogenous hormone use and risk of transitional cell bladder cancer in postmenopausal women. AB - The incidence of cancer of the urinary bladder is three- to five-fold lower in women than in men. This difference may be partially explained by lower exposure to cigarette smoking and occupational chemicals. In addition, female endogenous hormones may also play a protective role in the etiology of this disease. However, limited information is available from cohort studies that have examined reproductive factors and hormone use in relation to the risk of bladder cancer. We assessed the association of menstrual and reproductive factors and exogenous hormone use with the risk of incident transitional cell cancer of the urinary bladder in a cohort of 145,548 postmenopausal women (ages 50-79 years at baseline) enrolled in the Women's Health Initiative. Over 12.7 years of follow up, 480 cases of transitional cell bladder cancer were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the exposures of interest. Relative to nulliparous women, parous women had a reduced risk of transitional cell cancer: multivariable adjusted HR 0.77, 95% CI 0.59-1.01; however, there was no clear trend with increasing number of births. Risk was significantly increased in women with a history of at least two miscarriages (HR 1.52, 95% CI 1.15-2.00). Neither other reproductive variables we studied nor the use of exogenous hormones, including type of hormone therapy, were associated with altered risk of bladder cancer. In conclusion, in this large prospective study of postmenopausal women, we found limited evidence for associations of reproductive factors or exogenous hormone use with the risk of bladder cancer. PMID- 23442344 TI - Socioeconomic status as a predictor of melanoma survival in a series of 1083 cases from Brazil: just a marker of health services accessibility? AB - Melanoma survival is determined by disease-related and patient-related factors; there is a growing body of evidence that other issues may play a role in this disease. In this study, the role of socioeconomic factors in the evolution of melanoma was evaluated. This was a retrospective study with incident cases of melanoma treated in an oncology center in Rio de Janeiro, Brazil, during the period of 1997-2004. The socioeconomic variable of choice was education (9 years or more vs. 8 years or less of school attendance). In this period, there were 1083 patients with primary melanoma of the skin, 58.1% with low school attendance. No difference was found in relation to the year of diagnosis with respect to overall survival. Five-year survival for the entire group was 67.0%. Men had worse survival [hazard ratio (HR) 1.91, 95% confidence interval (CI) 1.54 2.35]; a protective effect was found for whites (HR 0.64, 95% CI 0.49-0.84), higher educational level (HR 0.55, 95% CI 0.44-0.69), and upper limb lesions (HR 0.61, 95% CI 0.38-0.98). A higher risk of death was observed for patients with nodular melanoma (HR 1.96, 95% CI 1.49-2.58), acrolentiginous melanoma (HR 2.68, 95% CI 2.09-3.44), lesions in the soles and palms (HR 1.78, 95% CI 1.22-2.6), and increasing age (HR 1.02 for each year, 95% CI 1.01-1.02). In the multivariate analysis, after controlling for stage, age, sex, ethnicity, and clinical type, education remained a protective factor both for overall survival (HR 0.76, 95% CI 0.61-0.94) and for relapse-free survival (HR 0.76, 95% CI 0.61-0.94). In conclusion, socioeconomic status as measured by educational level represented an important factor related to melanoma clinical evolution in the cohort studied. PMID- 23442345 TI - Comments and controversies: sentinel node and lymphadenectomy in melanoma: staging or therapeutical?: what to expect from the multicenter selective lymphadenectomy trial-1 results in melanoma? PMID- 23442346 TI - Genome-wide detection of copy number variations using high-density SNP genotyping platforms in Holsteins. AB - BACKGROUND: Copy number variations (CNVs) are widespread in the human or animal genome and are a significant source of genetic variation, which has been demonstrated to play an important role in phenotypic diversity. Advances in technology have allowed for identification of a large number of CNVs in cattle. Comprehensive explore novel CNVs in the bovine genome would provide valuable information for functional analyses of genome structural variation and facilitating follow-up association studies between complex traits and genetic variants. RESULTS: In this study, we performed a genome-wide CNV detection based on high-density SNP genotyping data of 96 Chinese Holstein cattle. A total of 367 CNV regions (CNVRs) across the genome were identified, which cover 42.74 Mb of the cattle genome and correspond to 1.61% of the genome sequence. The length of the CNVRs on autosomes range from 10.76 to 2,806.42 Kb with an average of 96.23 Kb. 218 out of these CNVRs contain 610 annotated genes, which possess a wide spectrum of molecular functions. To confirm these findings, quantitative PCR (qPCR) was performed for 17 CNVRs and 13(76.5%) of them were successfully validated. CONCLUSIONS: Our study demonstrates the high density SNP array can significantly improve the accuracy and sensitivity of CNV calling. Integration of different platforms can enhance the detection of genomic structure variants. Our results provide a significant replenishment for the high resolution map of copy number variation in the bovine genome and valuable information for investigation of genomic structural variation underlying traits of interest in cattle. PMID- 23442347 TI - Coffee intake and risk of type 2 diabetes: the Multiethnic Cohort. AB - OBJECTIVE: We evaluated the influence of coffee consumption on diabetes incidence among the Hawaii component of the Multiethnic Cohort (MEC). DESIGN: Prospective cohort. SETTING: Population-based sample residing in Hawaii. SUBJECTS: After exclusions, 75 140 men and women of Caucasian, Japanese American and Native Hawaiian ancestry aged 45-75 years were part of the current analysis. All participants provided information on diet and lifestyle through an FFQ. After 14 years of follow-up 8582 incident diabetes cases were identified using self reports, medication questionnaires and health plan linkages. Hazard ratios (HR) and 95 % confidence intervals were calculated using Cox regression while adjusting for known covariates. RESULTS: The risk for diabetes associated with total coffee consumption differed by sex (P interaction < 0.0001). Women consuming >=3 cups of any type of coffee daily had a significantly lower risk (HR = 0.66; 95 % CI 0.58, 0.77; P trend < 0.0001) than those reporting <1 cup/d, whereas the relationship in men was borderline (HR = 0.89; 95 % CI 0.80, 0.99; P trend = 0.09). The same difference by sex was seen for regular coffee consumption, with HR of 0.65 (95 % CI 0.54, 0.78; P trend < 0.0001) and 0.86 (95 % CI 0.75, 0.98; P trend = 0.09) in men and women, respectively. No significant association with diabetes was apparent for decaffeinated coffee in women (HR = 0.85; 95 % CI 0.72, 1.01; P trend = 0.73) or men (HR = 1.07; 95 % CI 0.93, 1.23; P trend = 0.71). Despite small differences by ethnicity, the interaction terms between coffee intake and ethnicity were not significant. CONCLUSIONS: In this multiethnic population, regular, but not decaffeinated, coffee intake was much more protective against diabetes in women of all ethnic groups than in men. PMID- 23442348 TI - Quantifying the internal structure of categories using a neural typicality measure. AB - How categories are represented continues to be hotly debated across neuroscience and psychology. One topic that is central to cognitive research on category representation but underexplored in neurobiological research concerns the internal structure of categories. Internal structure refers to how the natural variability between-category members is coded so that we are able to determine which members are more typical or better examples of their category. Psychological categorization models offer tools for predicting internal structure and suggest that perceptions of typicality arise from similarities between the representations of category members in a psychological space. Inspired by these models, we develop a neural typicality measure that allows us to measure which category members elicit patterns of activation that are similar to other members of their category and are thus more central in a neural space. Using an artificial categorization task, we test how psychological and physical typicality contribute to neural typicality, and find that neural typicality in occipital and temporal regions is significantly correlated with subjects' perceptions of typicality. The results reveal a convergence between psychological and neural category representations and suggest that our neural typicality measure is a useful tool for connecting psychological and neural measures of internal category structure. PMID- 23442349 TI - Modulation of event-related desynchronization in robot-assisted hand performance: brain oscillatory changes in active, passive and imagined movements. AB - BACKGROUND: Robot-assisted therapy in patients with neurological disease is an attempt to improve function in a moderate to severe hemiparetic arm. A better understanding of cortical modifications after robot-assisted training could aid in refining rehabilitation therapy protocols for stroke patients. Modifications of cortical activity in healthy subjects were evaluated during voluntary active movement, passive robot-assisted motor movement, and motor imagery tasks performed under unimanual and bimanual protocols. METHODS: Twenty-one channel electroencephalography (EEG) was recorded with a video EEG system in 8 subjects. The subjects performed robot-assisted tasks using the Bi-Manu Track robot assisted arm trainer. The motor paradigm was executed during one-day experimental sessions under eleven unimanual and bimanual protocols of active, passive and imaged movements. The event-related-synchronization/desynchronization (ERS/ERD) approach to the EEG data was applied to investigate where movement-related decreases in alpha and beta power were localized. RESULTS: Voluntary active unilateral hand movement was observed to significantly activate the contralateral side; however, bilateral activation was noted in all subjects on both the unilateral and bilateral active tasks, as well as desynchronization of alpha and beta brain oscillations during the passive robot-assisted motor tasks. During active-passive movement when the right hand drove the left one, there was predominant activation in the contralateral side. Conversely, when the left hand drove the right one, activation was bilateral, especially in the alpha range. Finally, significant contralateral EEG desynchronization was observed during the unilateral task and bilateral ERD during the bimanual task. CONCLUSIONS: This study suggests new perspectives for the assessment of patients with neurological disease. The findings may be relevant for defining a baseline for future studies investigating the neural correlates of behavioral changes after robot-assisted training in stroke patients. PMID- 23442350 TI - Fabrication of biocompatible and mechanically reinforced graphene oxide-chitosan nanocomposite films. AB - BACKGROUND: Graphene oxide (GO)can be dispersed through functionalization, or chemically converted to make different graphene-based nanocomposites with excellent mechanical and thermal properties. Chitosan, a partially deacetylated derivative of chitin, is extensively used for food packaging, biosensors, water treatment, and drug delivery. GO can be evenly dispersed in chitosan matrix through the formation of amide linkages between them, which is different from previous reports focusing on preparing GO/chitosan nanocomposites through physical mixing. RESULTS: In this study, free-standing graphene oxide-chitosan (GO-chitosan) nanocomposite films have been prepared. The GO-chitosan films are biologically compatible and mechanically reinforced. Through the formation of amide linkages between GO's carboxylic acid groups and chitosan's amine groups, GO could be evenly dispersed within the chitosan matrix. We also characterized the GO-chitosan composite films using element analysis, Fourier transform infrared spectroscopy, X-ray photo electron spectroscopy, differential scanning calorimetry, and thermo gravimetric analysis. Compared to pristine chitosan film, the tensile strength of GO-chitosan film is improved by 2.5 folds and Young's modulus increases by nearly 4.6 folds. The glass transition temperature of GO chitosan composite film shifts from 118 degrees C to 158 degrees C compared to the pristine chitosan, indicating its enhanced thermal stability. GO-chitosan composite film was also evaluated for its biocompatibility with C3H10T1/2 cells by in vitro fluorescent staining. The graphene oxide-reinforced chitosan composite films could have applications in functional biomaterials. CONCLUSION: The present study describes a useful and simple method to chemically attach biocompatible chitosan onto graphene oxide. We envision that the GO-chitosan film will open avenues for next-generation graphene applications in the realm of functional biomaterial. PMID- 23442351 TI - Impact of effectiveness information format on patient choice of therapy and satisfaction with decisions about chronic disease medication: the "Influence of intervention Methodologies on Patient Choice of Therapy (IMPACT)" cluster randomised trial in general practice. AB - BACKGROUND: Risk communication is an integral part of shared decision-making in health care. In the context of interventions for chronic diseases it represents a particular challenge for all health practitioners. By using two different quantitative formats to communicate risk level and effectiveness of a cholesterol lowering drug, we posed the research question: how does the format of risk information influence patients' decisions concerning therapy, patients' satisfaction with the communication as well as confidence in the decision. We hypothesise that patients are less prone to accept therapy when the benefits of long-term intervention are presented in terms of prolongation of life (POL) in months compared to the absolute risk reduction (ARR). We hypothesise that patients presented with POL will be more satisfied with the communication and confident in their decision, suggesting understanding of the time-related term. METHODS/DESIGN: In 2009 a sample of 328 general practitioners (GPs) in the Region of Southern Denmark was invited to participate in a primary care-based clinical trial among patients making real-life clinical decisions together with their GP. Interested GPs were cluster-randomised to inform patients about cardiovascular disease (CVD) risk and the effectiveness of statin therapy using either POL or ARR. The GPs attended a training session before informing their patients. Before training and after the trial period they received a questionnaire about their attitudes to risk communication and the use of numerical information. Patients' redemptions of statin prescriptions will be registered in a regional prescription database to evaluate a possible association between redemption rates and effectiveness format. The Combined Outcome Measure for Risk Communication And Treatment Decision Making Effectiveness (COMRADE) questionnaire will be used to measure patients' confidence and satisfaction with the risk communication immediately after the conversation with their GPs. DISCUSSION: This randomised clinical trial compares the impact of two effectiveness formats on real-life risk communication between patients and GPs, including affective patient outcomes and actual choices about acceptance of therapy. Though we found difficulties in recruiting GPs, according to the study protocol we have succeeded in engaging sufficient GPs for the trial, enabling us to perform the planned analyses. PMID- 23442355 TI - Clinical neuropathology practice news 2-2013: immunohistochemistry pins IDH in glioma - molecular testing procedures under scrutiny. AB - Isocitrate dehydrogenase 1 (IDH1) gene mutations occur in ~ 60 - 90% of diffuse and anaplastic gliomas and secondary glioblastomas. IDH status is strongly associated with patient survival times and IDH testing is relevant for clinical patient management and for stratification in clinical trials. A recent interlaboratory ring trial shows that immunohistochemistry is a highly reliable method to detect the most common IDH mutation (R132H), while IDH gene sequencing is less robust. These results support initial immunohistochemistry and subsequent gene sequencing in cases with negative or inconclusive immunostaining result as valid algorithm for IDH testing. Furthermore, they highlight the need for strict quality control of DNA-based biomarker analyses on formalinfixed and paraffin embedded tumor samples. PMID- 23442353 TI - The quantitative proteomic response of Synechocystis sp. PCC6803 to phosphate acclimation. AB - BACKGROUND: Inorganic phosphate (Pi) is a critical nutrient for all life and is periodically limiting in marine and freshwater provinces, yet little is understood how organisms acclimate to fluctuations in Pi within their environment. To investigate whole cell adaptation, we grew Synechocystis sp. PCC6803, a model freshwater cyanobacterium, in 3%, and 0.3% inorganic phosphate (Pi) media. The cells were allowed to acclimate over 60 days, and cells were harvested for quantitative high throughput mass spectrometry-based proteomics using the iTRAQTM labelling technology. RESULTS: In total, 120 proteins were identified, and 52 proteins were considered differentially abundant compared to the control. Alkaline phosphatase (APase) activities correlated significantly (p < 0.05) with observed relative PhoA abundances. PstS1 and PstS2 were both observed, yet PstS1 was not differentially more abundant than the control. Phycobilisome protein abundances appeared to be coordinated, and are significantly less abundant in 0.3% Pi than 3% Pi cultures. Also, the central metabolic cell function appears to have shifted towards the production of (NADPH) reducing energy and nucleotide sugars. CONCLUSIONS: This acclimation response bears strong similarity to the previously reported response to nitrogen deprivation within Synechocystis sp. PCC 6803. However, it also demonstrates some characteristics of desiccation stress, such as the regulation of fatty acids and increased abundance of rehydrin in the 3% Pi culture. PMID- 23442357 TI - Lessons learnt after the introduction of the seven valent-pneumococcal conjugate vaccine toward broader spectrum conjugate vaccines. AB - The 7-valent pneumococcal conjugate vaccine (PCV7) is currently being introduced in the vaccine schedule of over 90 countries around the world. After the introduction of the PCV7 vaccine in the United States, a reduction of more than 90% of invasive pneumococcal disease (IPD) was reported in vaccinated children under the age of 5 years. Similar findings were reported from other countries. A reduction in community-acquired pneumonia (CAP) of > 40% has also been reported. In children under the age of 5 years, the number of primary medical visits and antibiotic usage for acute otitis media (AOM) decreased by more than 40%. In adults over 65 years of age a significant reduction of 90% in IPD caused by PCV7 serotypes was reported as well. However, after the introduction of PCV7 there were reports of increase of serotypes not included in the vaccine, such as serotype 19A in various Streptococcus pneumoniae-related diseases such as invasive disease, AOM and pneumonia. In addition, serotypes 1, 5, 7F and 19A were more prevalent in complicated cases of CAP. Recently, new vaccines covering additional serotypes such as the 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13) were introduced, and are expected to reduce S. pneumoniae-related diseases furthermore. PMID- 23442358 TI - Roles of p63 in epidermal development and tumorigenesis. AB - Epidermis is composed mainly of keratinocytes and is the ma-jor barrier of human body. The development and maintenance of normal epithelial structures and functions require the transcription factor p63. The p63 gene encodes proteins with structures similar to that of p53, including an N-terminal transactivation (TA) domain, a DNA-binding domain and a carboxy-oligomerization domain. TAp63 and DeltaNp63 (p63 isoforms without TA domain) regulate a wide range of target genes that are important for embryonal development and epithelial integrity. Mutations of p63 gene cause epidermal abnormalities characterized by ectodermal dysplasia. Recent reports have indicated that p63 plays important role in tumorigenesis as well. However, the relative importance of TAp63 and DeltaNp63 in epidermal development and tumorigenesis re-mains mostly unclear and awaits further investigation. In this review, we summarize the current knowledge on the structure and function of p63 and its isoforms. PMID- 23442359 TI - Cancer cells acquire resistance to anticancer drugs: an update. AB - The efficacy of cancer chemotherapy is often affected by the emergence of resistant can-cer cells. While biochemical and pharmaco-logical mechanisms have been proposed to ex-plain chemo-resistance, the genes involved in this process have not been fully identified. We previously used genomic DNA microarrays and quantitative RT-PCR to identify the genes associated with resistance to chemotherapeutic drugs, particularly to the genotoxic agent cisplatin. Notably, knockdown of the cisplatin resistance (CPR) genes that we identified was shown to reduce chemoresistance and to suppress the growth of tumor xenographs in cisplatin-treated mice, indicating that the newly identified CPR genes may represent potential therapy candidates to limit chemo-resistance and to improve the efficacy of anticancer drugs. In addition to genetic mutations, re-searchers have found that epigenetic changes and alternative splicing of specific genes may also allow cancer cells to become resistant to chemotherapeutic drugs. In this article, the authors present an overview of the latest findings in this field, including genetic changes, epigenetic changes and alternative splicing. PMID- 23442356 TI - Alarmins, inflammasomes and immunity. AB - The elaboration of an effective immune response against pathogenic microbes such as viruses, intracellular bacteria or protozoan parasites relies on the recognition of microbial products called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Ligation of the PRRs leads to synthesis and secretion of pro-inflammatory cytokines and chemokines. Infected cells and other stressed cells also release host-cell derived molecules, called damage-associated molecular patterns (DAMPs, danger signals, or alarmins), which are generic markers for damage. DAMPs are recognized by specific receptors on both immune and nonimmune cells, which, depending on the target cell and the cellular context, can lead to cell differentiation or cell death, and either inflammation or inhibition of inflammation. Recent research has revealed that DAMPs and PAMPs synergize to permit secretion of pro-inflammatory cytokines such as interleukin-1beta (IL 1beta): PAMPs stimulate synthesis of pro-IL-1beta, but not its secretion; while DAMPs can stimulate assembly of an inflammasome containing, usually, a Nod-like receptor (NLR) member, and activation of the protease caspase-1, which cleaves pro-IL-1beta into IL-1beta, allowing its secretion. Other NLR members do not participate in formation of inflammasomes but play other essential roles in regulation of the innate immune response. PMID- 23442360 TI - Bioengineered periosteal progenitor cell sheets to enhance tendon-bone healing in a bone tunnel. AB - BACKGROUND: Tendon-bone tunnel healing is crucial for long term success in anterior cruciate ligament (ACL) reconstruction. The periosteum contains osteochondral progenitor cells that can differentiate into osteoblasts and chondroblasts during tendon-bone healing. We developed a scaffold-free method using polymerized fibrin-coated dishes to make functional periosteal progenitor cell (PPC) sheets. Bioengineered PPC sheets for enhancing tendon-bone healing were evaluated in an extra-articular bone tunnel model in rabbit. METHODS: PPC derived from rabbit tibia periosteum, cultivated on polymerized fibrin-coated dishes and harvested as PPC sheet. A confocal microscopy assay was used to evaluate the morphology of PPC sheets. PPC sheets as a periosteum to wrap around hamstring tendon grafts were pulled into a 3-mm diameter bone tunnel of tibia, and compared with a tendon graft without PPC sheets treatment. Rabbits were sacrificed at 4 and 8 weeks postoperatively for biochemical as-say and histological assay to demonstrate the enhancement of PPC sheets in tendon-bone healing. RESULTS: PPC spread deposit on fibrin on the dish surface with continuous monolayer PPC was ob-served. Histological staining revealed that PPC sheets enhance collagen and glycosaminoglycans deposition with fibrocartilage formation in the tendon-bone junction at 4 weeks. Collagen fiber with fibrocartilage formation at tendon-bone junction was also found at 8 weeks. Matured fibrocartilage and dense collagen fiber were formed at the tendon-bone interface at 8 weeks by Masson trichrome and Safranin-O staining. CONCLUSIONS: Periosteal progenitor cell monolayer maintains the differentiated capacity and osteochondral potential in order to promote fibrocartilage formation in tendon bone junction. Bioengineered PPC sheets can offer a new feasible therapeutic strategy of a novel approach to enhance tendon-bone junction healing. PMID- 23442361 TI - Long-term results of extracorporeal shockwave therapy and core decompression in osteonecrosis of the femoral head with eight- to nine-year follow-up. AB - BACKGROUND: This study analyzed the long-term outcomes of extracorporeal shockwave therapy (ESWT) and core decompression for early osteonecrosis of the femoral head (ONFH) with 8- to 9-year follow-up. METHODS: The study cohort consisted of 48 patients with 57 hips including 23 patients with 29 hips in the ESWT group and 25 patients with 28 hips in the surgical group. Patients in ESWT group received shockwave therapy to the affected hip. Patients in surgical group underwent core decompression and autogenous cancellous bone and allogenous fibular graft. The average length of follow-up was 103.5 +/- 3.4 (ranged 93-106) months and 104.5 +/- 4.3 (ranged 95-108) months for the ESWT and the surgical group, respectively. The evaluations included clinical assessment for pain and function, X-ray and MRI of the affected hips. RESULTS: The overall clinical results were 76% good or fair and 24% poor for the ESWT group; and 21% good or fair and 79% poor for the surgical group. THA was performed in 3% and 21% at one year, 10% and 32% at 2 years and 24% and 64% at 8-9 years for ESWT and the surgical group respectively. Significant differences in pain and Harris hip scores were observed at different time intervals favoring the ESWT group. There was a trend of decrease in the size of the lesion in the ESWT group when compared with the surgical group. CONCLUSION: ESWT appears to be more effective than core decompression and bone grafting for early ONFH with 8- to 9-year long-term follow up. PMID- 23442362 TI - ER, p53 and MIB-1 are significantly associated with malignant phyllodes tumor. AB - BACKGROUND: Fibroadenomas (FA) are common while phyllodes tumors (PT) are rare and both tumors are composed of epithelial and stromal components. We evaluated the expression status of ER, Bc12, p53, and MIB-1 protein in these tumors. METHODS: One hundred and ninety-three tumors comprising of 117 FAs and 76 PTs were examined using immunohistochemistry on tissue microarray. RESULTS: The mean age of patients with FA was 28.5 years while the mean ages of patients with benign, borderline and malignant PTs were 41.7, 48.6 and 42.1 years, respectively. Also all types of PTs were large (>Scm). ER showed a strong nuclear staining in the epithelial component of all tumors while ER/3 immunoreactivity was detected in both the epithelial and stromal components ofF A and PT. ER/beta (p<0.001), and p53 (p=0.006) in the stromal component were associated with tumor size. p53 expression was significantly associated with both the epithelial and stromal components of malignant PTs (p<0.05). In the PT, the decreased expressions of p53 and MIB-1 were significantly different with positive Bc12 protein expression in the epithelial component (p=0.000). In addition, MIB-1 was also found to be associated with ER and ER/3 in the stromal component (p=0.000). CONCLUSIONS: The expression of p53 with tumor size and histological grade in PT may increase the risk for malignancy. PMID- 23442363 TI - Study of conjunctival flora in patients after peripheral blood stem cell transplantation and its correlation with tear secretion. AB - BACKGROUND: Dry eye is a major ocular complication of peripheral blood stem cell transplantation (PBSCT) and may predispose bacterial colonization to the conjunctiva. To investigate the conjunctival bacterial flora in patients receiving PBSCT, we encompassed patients who received PBSCT at least 1 year from 2002 to 2008 in this cross-sectional study. METHODS: Patients were divided into three groups in accordance to the result of the Schirmer Ia test. In the control group, we enrolled dry-eye patients with underlying disease other than hematopoietic stem cell transplantation of which the age range was similar to the study group. RESULTS: Thirty-six patients with 72 eyes were included in our study. The culture rates were 22% (8 in 36) in the first group (Schirmer Ia= 0-5 mm), 20% (4 in 20) in the second group (Schirmer Ia= 6-9 mm), and 0% (n=16) in the third group (Schirmer Ia >= 10 mm). The flora in patients receiving PBSCT were coagulase-negative Staphylococci, Staphylococcus aureus and Corynebacterium sp. The bacterial colonization rate in the post-PBSCT group was not higher than the control group (22.2% vs. 30.8% ), and coagulase-negative Staphylococci was the most common flora in the control group. CONCLUSIONS: In conclusion, despite not having statistical significance, there seems to be a positive correlation between the colonization rate and the severity of dry eye. However, bacterial profile isolated in post-PBSCT patients is not significantly different from other dry eye patients. PMID- 23442364 TI - Contribution of host, bacterial factors and antibiotic treatment to mortality in adult patients with bacteraemic pneumococcal pneumonia. AB - RATIONALE: Host and bacterial factors as well as different treatment regimens are likely to influence the outcome in patients with bacteraemic pneumococcal pneumonia. OBJECTIVES: To estimate the relative contribution of host factors as well as bacterial factors and antibiotic treatment to mortality in bacteraemic pneumococcal pneumonia. METHODS: A cohort study of 1580 adult patients with community-acquired bacteraemic pneumococcal pneumonia was conducted between 2007 and 2009 in Sweden. Data on host factors and initial antibiotic treatment were collected from patient records. Antibiotic resistance and serotype were determined for bacterial isolates. Logistic regression analyses were performed to assess risk factors for 30-day mortality. RESULTS: Smoking, alcohol abuse, solid tumour, liver disease and renal disease attributed to 14.9%, 13.1%, 13.1%, 8.0% and 7.4% of the mortality, respectively. Age was the strongest predictor, and mortality increased exponentially from 1.3% in patients <45 years of age to 26.1% in patients aged >=85 years. There was considerable confounding by host factors on the association between serotype and mortality. Increasing age, liver disease and serotype were associated with mortality in patients admitted to the ICU. Combined treatment with beta-lactam antibiotics and macrolide/quinolone was associated with reduced mortality in patients in the ICU, although confounding could not be ruled out. CONCLUSIONS: Host factors appear to be more important than the specific serotype as determinants of mortality in patients with bacteraemic pneumococcal pneumonia. Several host factors were identified that contribute to mortality, which is important for prognosis and to guide targeted prevention strategies. PMID- 23442365 TI - Intermedin in rat uterus: changes in gene expression and peptide levels across the estrous cycle and its effects on uterine contraction. AB - BACKGROUND: The present study demonstrates the expression of intermedin (IMD) and its receptor components in the uterus of the female rat during the estrous cycle and its effect on uterine contraction. METHODS: The gene expression level of intermedin and its receptor components and the peptide level of intermedin were studied by real-time RT-PCR and enzyme immunoassay (EIA) respectively. The separation of precursor and mature IMD was studied by gel filtration chromatography and EIA. The localization of IMD in the uterus was investigated by immunohistochemistry. The effect of IMD on in vitro uterine contraction was studied by organ bath technique. RESULTS: Uterine mRNAs of Imd and its receptor components and IMD levels displayed cyclic changes across the estrous cycle. Imd mRNA level was the highest at proestrus while the IMD level was the highest at diestrus. IMD was found in the luminal and glandular epithelia and IMD treatment significantly reduced the amplitude and frequency of uterine contraction but not the basal tone. Both calcitonin gene-related peptide (CGRP) receptor antagonist hCGRP8-37 and adrenomedullin (ADM) receptor antagonist hADM22-52 partially abolished the inhibitory effect of IMD on uterine contraction while the specific IMD receptor antagonist hIMD17-47 completely blocked the actions. The enzyme inhibitors of NO (L-NAME) and PI3K (Wortmannin) pathways diminished the IMD effects on uterine contraction while the cAMP/PKA blocker, KT5720, had no effect, indicating an involvement of NO and PI3K/Akt but not PKA. CONCLUSIONS: IMD and the gene expression of its receptor components are differentially regulated in the uterus during the estrous cycle and IMD inhibits uterine contraction by decreasing the amplitude and frequency. PMID- 23442366 TI - Petrous apex cholesterol granuloma: pictorial review of radiological considerations in diagnosis and surgical histopathology. AB - BACKGROUND: Petrous apex cholesterol granulomas are expansile, cystic lesions containing cholesterol crystals surrounded by foreign body giant cells, fibrous tissue reaction and chronic inflammation. Appropriate treatment relies on an accurate radiological diagnosis and an understanding of the distinguishing radiological features of relevant entities in the differential diagnosis of this condition. METHODS: Firstly, this paper presents a pictorial review of the relevant radiological features of petrous apex cholesterol granuloma, and highlights unique features relevant to the differential diagnosis. Secondly, it reviews the histopathological and radiological findings associated with surgical drainage of these lesions. RESULTS: Radiological features relevant to the differential diagnosis of petrous apex cholesterol granuloma are reviewed, together with radiological and histopathological features relevant to surgical management. Following surgical management, histopathological and radiological evidence demonstrates that the patency of the surgical drainage pathway is maintained. CONCLUSION: Accurate diagnosis of petrous apex cholesterol granuloma is essential in order to instigate appropriate treatment. Placement of a stent in the drainage pathway may help to maintain patency and decrease the likelihood of symptomatic recurrence. PMID- 23442367 TI - Building motion models of lung tumours from cone-beam CT for radiotherapy applications. AB - A method is presented to build a surrogate-driven motion model of a lung tumour from a cone-beam CT scan, which does not require markers. By monitoring an external surrogate in real time, it is envisaged that the motion model be used to drive gated or tracked treatments. The motion model would be built immediately before each fraction of treatment and can account for inter-fraction variation. The method could also provide a better assessment of tumour shape and motion prior to delivery of each fraction of stereotactic ablative radiotherapy. The two step method involves enhancing the tumour region in the projections, and then fitting the surrogate-driven motion model. On simulated data, the mean absolute error was reduced to 1 mm. For patient data, errors were determined by comparing estimated and clinically identified tumour positions in the projections, scaled to mm at the isocentre. Averaged over all used scans, the mean absolute error was under 2.5 mm in superior-inferior and transverse directions. PMID- 23442368 TI - Warm homes for older people: aims and methods of a randomised community-based trial for people with COPD. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is of increasing importance with about one in four people estimated to be diagnosed with COPD during their lifetime. None of the existing medications for COPD has been shown to have much effect on the long-term decline in lung function and there have been few recent pharmacotherapeutic advances. Identifying preventive interventions that can reduce the frequency and severity of exacerbations could have important public health benefits. The Warm Homes for Elder New Zealanders study is a community-based trial, designed to test whether a NZ$500 electricity voucher paid into the electricity account of older people with COPD, with the expressed aim of enabling them to keep their homes warm, results in reduced exacerbations and hospitalisation rates. It will also examine whether these subsidies are cost beneficial. METHODS: Participants had a clinician diagnosis of COPD and had either been hospitalised or taken steroids or antibiotics for COPD in the previous three years; their median age was 71 years. Participants were recruited from three communities between 2009 to early 2011. Where possible, participants' houses were retrofitted with insulation. After baseline data were received, participants were randomised to either 'early' or 'late' intervention groups. The intervention was a voucher of $500 directly credited to the participants' electricity company account. Early group participants received the voucher the first winter they were enrolled in the study, late participants during the second winter. Objective measures included spirometry and indoor temperatures and subjective measures included questions about participant health and wellbeing, heating, medication and visits to health professionals. Objective health care usage data included hospitalisation and primary care visits. Assessments of electricity use were obtained through electricity companies using unique customer numbers. DISCUSSION: This community trial has successfully enrolled 522 older people with COPD. Baseline data showed that, despite having a chronic respiratory illness, participants are frequently cold in their houses and economise on heating. TRIAL REGISTRATION: The clinical trial registration is http://NCT01627418. PMID- 23442369 TI - Characteristics of patients with acute ischemic stroke intubated before imaging. AB - There are no prospective data on which ischemic stroke patients require endotracheal intubation. This retrospective observational study describes the characteristics and outcomes of adult ischemic stroke patients admitted to two emergency department (ED)-ICU from January 2005 to October 2011 and who were intubated before imaging, either during the prehospital or the ED phase of care. Data were extracted from hospital charts and analyzed using descriptive statistics. During the study period, 57 of 6492 ED patients (<1%) with ischemic stroke were intubated. Of these, 31 were intubated before imaging. The median age of the study group patients was 78 years (IQR, 71-81) and 20 (64%) were men. Twenty-eight (90%) patients had a Glasgow Coma Score of 8 or less at the time of intubation. Twenty-six patients (84%) died during their hospital stay. The proportion of ED ischemic stroke patients intubated before imaging was very low. Almost all were severely ill and the majority died. PMID- 23442370 TI - Capability of Scottish emergency departments to provide physician-based prehospital critical care teams: a national survey. AB - OBJECTIVE: The aim of this study was to establish the current capabilities of emergency departments in Scotland to provide a prehospital medical team at the request of the ambulance service. METHODS: A prospective telephone survey of all major emergency departments in Scotland was conducted, requesting information on their ability to provide a prehospital team, the configuration of the team and the equipment, transport, training and governance arrangements for this service. RESULTS: All 25 major emergency departments in Scotland responded to the survey (100% response). Eighteen departments (72%) were able to provide a prehospital team, with 15 (60%) able to provide a team 24 h/day. Team composition was variable and only one-third of teams were able to deploy within 15 min. In total, 50% of departments able to respond had received no requests in the preceding 12 months and only two departments had each received more than 50 requests. Less than half of the departments checked prehospital equipment on a weekly or a more frequent basis and only three departments provided ongoing training in prehospital care. CONCLUSION: The majority of emergency departments in Scotland are able to provide a prehospital team on the request of the ambulance service. There is high variability in the composition and seniority of the team, with less ability to provide a team out of hours. With two notable exceptions, the overall activation of these prehospital teams is infrequent, and there are significant improvements required with regard to the clinical governance surrounding the provision of these teams. PMID- 23442371 TI - Serum C1q- binding adiponectin in maintenance hemodialysis patients. AB - BACKGROUND: Patients on maintenance hemodialysis (HD) have much higher levels of adiponectin (Total-APN). Adiponectin and C1q form a protein complex in human blood, and serum C1q-binding adiponectin (C1q-APN) can be measured. We recently reported that C1q-APN/Total-APN ratio rather than Total-APN correlated with atherosclerosis in diabetics. However, the characteristics of C1q-APN in HD patients remain unclear. The preset study investigated the characteristics of the adiponectin parameters including C1q-APN and also to clarify the relationship between various serum adiponectin parameters and atherosclerotic cardiovascular diseases (ACVD) in HD patients. METHODS: The single cross-sectional study subjects were 117 Japanese patients (males/females = 61/56) on regular HD. Blood Total-APN, high molecular weight-adiponectin (HMW-APN), C1q-APN and C1q concentrations were measured by enzyme-linked immunosorbent assays. ACVD were defined as stroke, coronary and peripheral artery diseases, thoracic and abdominal aneurysms. RESULTS: Stepwise regression analysis identified high density lipoprotein-cholesterol (HDL-C) as the only significant and independent determinant of C1q-APN in males, and duration of HD as the only significant and independent determinant of C1q-APN in females. Stepwise regression analysis identified uric acid, low-density lipoprotein-cholesterol and triglyceride as significant and independent determinants of C1q-APN/Total-APN ratio in males, and leukocyte count and HDL-C as significant and independent determinants of C1q APN/Total-APN ratio in females. Multiple logistic regression analysis identified inorganic phosphorus and C1q-APN or C1q-APN/C1q ratio as significant determinants of ACVD. CONCLUSIONS: Low serum C1q-APN and C1q-APN/C1q ratio, but not C1q APN/Total-APN ratio, correlated with ACVD in HD patients. TRIAL REGISTRATION: ClinicalTrials.gov: UMIN http://000004318. PMID- 23442372 TI - Optimization of selective stimulation parameters for multi-contact electrodes. AB - BACKGROUND: Multi-contact stimulating electrodes are gaining acceptance as a means for interfacing with the peripheral nervous system. These electrodes can potentially activate many independent populations of motor units within a single peripheral nerve, but quantifying their recruitment properties and the overlap in stimulation between contacts is difficult and time consuming. Further, current methods for quantifying overlap between contacts are ambiguous and can lead to suboptimal selective stimulation parameters. This study describes a novel method for optimizing stimulation parameters for multi-contact peripheral stimulating electrodes to produce strong, selective muscle contractions. The method is tested with four-contact spiral nerve-cuff electrodes implanted on bilateral femoral nerves of two individuals with spinal cord injury, but it is designed to be extendable to other electrode technologies with higher densities of contacts. METHODS: To optimize selective stimulation parameters for multi-contact electrodes, first, recruitment and overlap are characterized for all contacts within an electrode. Recruitment is measured with the twitch response to single stimulus pulses, and overlap between pairs of contacts is quantified by the deviation in their combined response from linear addition of individual responses. Simple mathematical models are fit to recruitment and overlap data, and a cost function is defined to maximize recruitment and minimize overlap between all contacts. RESULTS: Results are presented for four-contact nerve-cuff electrodes stimulating bilateral femoral nerves of two human subjects with spinal cord injury. Knee extension moments between 11.6 and 43.2 Nm were achieved with selective stimulation through multiple contacts of each nerve-cuff with less than 10% overlap between pairs of contacts. The overlap in stimulation measured in response to selective stimulation parameters was stable at multiple repeated time points after implantation. CONCLUSIONS: These results suggest that the method described here can provide an automated means of determining stimulus parameters to achieve strong muscle contractions via selective stimulation through multi contact peripheral nerve electrodes. PMID- 23442376 TI - Morphology observation of latex particles with scanning transmission electron microscopy by a hydroxyethyl cellulose embedding combined with RuO4 staining method. AB - Imaging of latex particles, especially those with low glass transition temperature (Tg) has been a challenging issue. Different sample preparation methods for characterization of the morphology of a poly(n-butyl acrylate)/polystyrene two-phase latex are discussed and compared in this study. A method via hydroxyethyl cellulose embedding combined with ruthenium tetraoxide (RuO4) staining for scanning transmission electron microscope (STEM) observation is developed. By using this method, the spherical shape of latex particles can be maintained without deformation. The degree of incorporation of RuO4 into latex particles and cellulose matrix is different, which makes latex particles readily identifiable from cellulose matrix under STEM. A series of latexes with different structures such as copolymer latex and organic-inorganic hybrid latex were also successfully investigated by this method. The results indicate this specimen preparation method can be applied to study the morphology of a wide range of latex systems. PMID- 23442375 TI - Accurate indel prediction using paired-end short reads. AB - BACKGROUND: One of the major open challenges in next generation sequencing (NGS) is the accurate identification of structural variants such as insertions and deletions (indels). Current methods for indel calling assign scores to different types of evidence or counter-evidence for the presence of an indel, such as the number of split read alignments spanning the boundaries of a deletion candidate or reads that map within a putative deletion. Candidates with a score above a manually defined threshold are then predicted to be true indels. As a consequence, structural variants detected in this manner contain many false positives. RESULTS: Here, we present a machine learning based method which is able to discover and distinguish true from false indel candidates in order to reduce the false positive rate. Our method identifies indel candidates using a discriminative classifier based on features of split read alignment profiles and trained on true and false indel candidates that were validated by Sanger sequencing. We demonstrate the usefulness of our method with paired-end Illumina reads from 80 genomes of the first phase of the 1001 Genomes Project ( http://www.1001genomes.org) in Arabidopsis thaliana. CONCLUSION: In this work we show that indel classification is a necessary step to reduce the number of false positive candidates. We demonstrate that missing classification may lead to spurious biological interpretations. The software is available at: http://agkb.is.tuebingen.mpg.de/Forschung/SV-M/. PMID- 23442377 TI - Seasonal changes of buffalo colostrum: physicochemical parameters, fatty acids and cholesterol variation. AB - BACKGROUND: Colostrum has many beneficial effects on newborns due to its main compounds (proteins, fats, lactose, essential fatty acids, amino acids) as well as protective antibodies that confer to the body. The buffaloes are the second important species for milk production in the world after cows. The importance of the species is also conferred by a longer longevity, high dry content of milk and a strong organic resistance when compared with cows. The purpose of this study was to investigate the changes of buffalo colostrum compounds such as fatty acids, cholesterol and physicochemical parameters during the first seven days postpartum and under the impact of the season, summer on pasture and winter on dry diet (hay based). RESULTS: Fat from colostrum differs depending on the postpartum day showing mean values of 11.31-7.56% (summer season) and 11.22-7.51% (winter season). These values gradually decreased starting with first day postpartum until day seven. Dry substance and protein presented a similar evolution to fat reaching the lowest values at the end of the colostral period. Lactose, ash and pH showed a gradually increase reaching the maximum on day seven postpartum. The highest titres of fatty acids from colostrum are: butyric acid (C4:0), myristic acid (C14:0), palmitic acid (C16:0), oleic acid (C18:1) and the lowest values showed up in myristoleic acid (C14:1), cis-10-pentadecanoic acid (C15:1), pentadecylic acid (C15:0) and margaric acid (C17:0) for both seasons. Higher concentrations have been recorded for the summer season in general. Cholesterol concentration decreased from 12.93 and 12.68 mg/100 mL (summer and winter season) to 9.02 and 7.88 mg/100 mL in the end of the colostral period. CONCLUSIONS: Physicochemical compounds of buffalo colostrum were influenced by season and postpartum day of milking. Excepting lactose all other parameters gradually decreased during colostral period. Fatty acids and cholesterol showed the same evolution, presenting higher values for the summer season. Specific feeding in the summer season (on pasture) did lead in more concentrated colostrum in dry substance, fatty acids and cholesterol. PMID- 23442378 TI - A uniquely adaptable pore is consistent with NALCN being an ion sensor. AB - NALCN is an intriguing, orphan ion channel among the 4x6TM family of related voltage-gated cation channels, sharing a common architecture of four homologous domains consisting of six transmembrane helices, separated by three cytoplasmic linkers and delimited by N and C-terminal ends. NALCN is one of the shortest 4x6TM family members, lacking much of the variation that provides the diverse palate of gating features, and tissue specific adaptations of sodium and calcium channels. NALCN's most distinctive feature is that that it possesses a highly adaptable pore with a calcium-like EEEE selectivity filter in radially symmetrical animals and a more sodium-like EEKE or EKEE selectivity filter in bilaterally symmetrical animals including vertebrates. Two lineages of animals evolved alternative calcium-like EEEE and sodium-like EEKE / EKEE pores, spliced to regulate NALCN functions in differing cellular environments, such as muscle (heart and skeletal) and secretory tissue (brain and glands), respectively. A highly adaptable pore in an otherwise conserved ion channel in the 4x6TM channel family is not consistent with a role for NALCN in directly gating a significant ion conductance that can be either sodium ions or calcium ions. NALCN was proposed to be an expressible Gd ( 3+) -sensitive, NMDG (+) -impermeant, non selective and ohmic leak conductance in HEK-293T cells, but we were unable to distinguish these reported currents from leaky patch currents (ILP) in control HEK-293T cells. We suggest that NALCN functions as a sensor for the much larger UNC80/UNC79 complex, in a manner consistent with the coupling mechanism known for other weakly or non-conducting 4x6TM channel sensor proteins such as Nax or Cav 1.1. We propose that NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels. PMID- 23442381 TI - Impact of different types of retirement transitions on perceived satisfaction with life. AB - PURPOSE: This study examines how life satisfaction changes as a function of the transition into retirement, distinguishing between different types of voluntary and involuntary exits. DESIGN AND METHODS: Perceived satisfaction with life (SWL) was measured among 1,388 older Dutch workers on two occasions, separated by 6 years. During that time, more than half of participants (54%) left full-time employment and entered retirement. RESULTS: Those who made a voluntarily departure from the workforce reported higher levels of perceived SWL compared with those who remained employed, whereas the life satisfaction scores of those whose departure was involuntary (due to health reasons, organizational reasons) were found to be the lowest. Other factors that had an effect on satisfaction included positive and negative health changes experienced during the 6-year interim, as well as changes in marital status due to divorce or loss of a spouse. IMPLICATIONS: These findings have important theoretical implications for the understanding of factors that shape individuals' perceptions of how they view the quality of their lives. From an applied perspective, the findings have implications for the development of organizational initiatives aimed at helping workers transition into retirement in such a way as to maintain high levels of subjective well-being. PMID- 23442379 TI - Deletions in the pyruvate pathway of Salmonella Typhimurium alter SPI1-mediated gene expression and infectivity. AB - BACKGROUND: Salmonella enterica serovar Typhimurium is a major foodborne pathogen worldwide. S. Typhimurium encodes type III secretion systems via Salmonella pathogenicity islands (SPI), producing the major effector proteins of virulence. Previously, we identified two genes of Salmonella pyruvate metabolism that were up-regulated during chicken cell infection: pyruvate formate lyase I (pflB) and bifunctional acetaldehyde-CoA/alcohol dehydrogenase (adhE). We were therefore interested in examining the role these genes may play in the transmission of Salmonella to humans. METHODS: Mutant strains of Salmonella with single gene deletions for pflB and adhE were created. Invasion and growth in human HCT-8 intestinal epithelial cells and THP-1 macrophages was examined. Quantitative PCR was performed on 19 SPI-1 genes. RESULTS: In HCT-8 cells, both mutant strains had significantly higher intracellular counts than the wild-type from 4 to 48 h post infection. Various SPI-1 genes in the mutants were up-regulated over the wild type as early as 1 h and lasting until 24 h post-infection. In THP-1 cells, no significant difference in internal Salmonella counts was observed; however, SPI-1 genes were largely down-regulated in the mutants during the time-course of infection. We also found five SPI-1 genes - hilA, hilC hilD, sicP and rtsA - which were up-regulated in at least one of the mutant strains in log-phase broth cultures alone. We have therefore identified a set of SPI-1 virulence genes whose regulation is effected by the central metabolism of Salmonella. PMID- 23442380 TI - Care of the older adult in the emergency department: nurses views of the pressing issues. AB - PURPOSE: The purpose of the study was to describe nurses' views of the issues to be addressed to improve care of the older adult in the emergency department (ED). DESIGN AND METHODS: An exploratory content analysis examined the qualitative responses of 527 registered nurses from 49 U.S. hospitals who completed the Geriatric Institutional Profile. RESULTS: 5 central themes emerged from the analysis, representing a lack of older person hospital environment fit in the ED: (a) respect for the older adult and carers, (b) correct and best procedures and treatment, (c) time and staff to do things right, (d) transitions, and (e) a safe and enabling environment. The nurses offered solutions to address lack of fit, including modifications to the social climate, policies and procedures, care systems and processes, and physical design. IMPLICATIONS: The nurses' descriptions of the pressing issues surrounding care of older adults in the ED provide useful information to consider when developing a senior-friendly ED. Results also illuminate solutions that can be taken to address issues. These solutions give direction for future intervention research. PMID- 23442382 TI - Why gerontologists should care about empirical research on religion and health: transdisciplinary perspectives. AB - A large volume of empirical research has accumulated on the relationship between religion/spirituality (R/S) and health since the year 2000, much of it involving older adults. The purpose of this article is to discuss how this body of existing research findings has important messages or important new insights for gerontologists; clinicians in medicine, psychiatry, and psychology; sociologists; and theologians. In other words, what contributions do the research findings on R/S and health make to these disciplines? In this article, experts from each of the aforementioned disciplines discuss what contributions this research can make to their own area of study and expertise. Besides emphasizing the broad relevance of research on R/S and health to many clinical and academic audiences in gerontology (i.e., addressing the "so what" question), this discussion provides clues about where R/S research might focus on in the future. PMID- 23442384 TI - Hypopharyngeal presentation of cicatricial pemphigoid: videofluorographic and direct laryngoscopic findings. AB - OBJECTIVE: Cicatricial pemphigoid can affect all mucosa of the upper aerodigestive tract; however, hypopharyngeal involvement is less frequent. CASE REPORT: This paper presents a 69-year-old male diagnosed as having cicatricial pemphigoid who was experiencing difficulty swallowing. Videofluorography with barium swallow demonstrated narrow flow through the medial hypopharynx, but not through the lateral hypopharynx. Direct laryngoscopy revealed that the postcricoid hypopharyngeal lumen had become narrow due to circumferential scar formation. Interestingly, detached thin membranous webs were observed beyond the circumferential scar. CONCLUSION: This report describes important videofluorographic and direct laryngoscopic findings showing rare hypopharyngeal involvement in a case of cicatricial pemphigoid. PMID- 23442383 TI - Efficient induction of spawning of northern leopard frogs (Lithobates pipiens) during and outside the natural breeding season. AB - BACKGROUND: Amphibian declines are now recognized globally. It is also well known that many anurans do not reproduce easily in captivity, especially when held over long periods, or if they require hibernation before breeding. A simple method to induce spawning and subsequent development of large numbers of healthy tadpoles is therefore required to meet research and conservation goals. METHODS: The method is based on simultaneous injection of both female and male leopard frogs, Lithobates pipiens (formerly called Rana pipiens) with a cocktail of a gonadotropin-releasing hormone agonist (GnRH-A) and a dopamine antagonist. We call this the AMPHIPLEX method, which is derived from the combination of the words amphibian and amplexus. Following injection, the animals are thereby induced, and perform amplexus and natural fertilization under captive conditions. RESULTS: We tested combinations of a GnRH agonist with 2 different dopamine antagonists in L. pipiens in the breeding season. The combination of des-Gly(10), D-Ala(6), Pro-NHEt(9)-GnRH (0.4 micrograms/g body weight; GnRH-A) with metoclopramide hydrochloride (10 micrograms/g body weight; MET) or domperidone (DOM) were equally effective, producing 89% and 88% successful spawning, respectively. This yielded more than 44,000 eggs for the 16/18 females that ovulated in the GnRH-A+MET group, and more than 39,000 eggs for the 15/17 females that ovulated in the GnRH-A+DOM group. We further tested the GnRH-A+MET in frogs collected in the wild in late autumn and hibernated for a short period under laboratory conditions, and report a low spawning success (43%). However, GnRH-A priming 24 hours prior to injections of the GnRH-A+MET cocktail in animals hibernated for 5-6 weeks produced out-of-season spawning (89%) and fertilization (85%) comparable to those we observed for in-season spawning. Assessment of age and weight at metamorphosis indicated that L. pipiens tadpoles resulting from out of-season spawning grew normally and metamorphosed successfully. CONCLUSION: We provide evidence for successful captive breeding of the leopard frog, L. pipiens. This simple protocol can be used to obtain large numbers of eggs in a predictable, timed manner. PMID- 23442385 TI - Controlling sensitivity and stability of ferrous-xylenol orange-gelatin 3D gel dosimeters by doping with phenanthroline-type ligands and glyoxal. AB - The ferrous-xylenol orange-gelatin (FXG) dosimeter is widely used for three dimensional ionizing radiation field mapping through optical scanning. Upon irradiation, the ferrous iron (Fe(2+)) is oxidized to ferric iron (Fe(3+)), which forms an intensely coloured complex with xylenol orange (XO). XO also acts as a diffusion-limiting additive; however, its presence may cause rapid auto-oxidation of Fe(2+) during storage and low stability of the dose response. In this work, phenanthroline-type ligands were added to FXG system in a bid to bind the ferrous iron in a stable complex and minimize the rate of the auto-oxidation, whereas glyoxal was used as a chemical cross-linker, aiming to minimize the ferric iron diffusion. It was found that addition of either 1,10-phenanthroline or 5-nitro 1,10-phenanthroline can improve the auto-oxidation behaviour of the gels. However, the initial background absorbance was slightly increased, and the sensitivity of the dosimeters was decreased. Doping with glyoxal led to a moderate decrease of the diffusion only in those gels that also contained a phenanthroline-type ligand, and did not affect the initial dose response. Glyoxal also afforded an extended period of stable background absorbance level after an initial period of bleaching of the gel. Following re-irradiation, most glyoxal containing dosimeters showed an excellent linearity of the dose response, albeit at a decreased sensitivity. We recommend further testing of FXG dosimeters, doped with phenanthroline-type ligands and glyoxal as a means for controlling the dose response and improving the long-term storage properties of the gels and the potential for dose fractionation. PMID- 23442386 TI - The role of the healthcare sector in the prevention of sexual violence against sub-Saharan transmigrants in Morocco: a study of knowledge, attitudes and practices of healthcare workers. AB - BACKGROUND: Sub-Saharan transmigrants in Morocco are extremely vulnerable to sexual violence. From a public health perspective, the healthcare system is globally considered an important partner in the prevention of sexual violence. The aim of this study is twofold. In a first phase, we aimed to identify the current role and position of the Moroccan healthcare sector in the prevention of sexual violence against sub-Saharan transmigrants. In a second phase, we wanted these results and available guidelines to be the topic of a participatory process with local stakeholders in order to formulate recommendations for a more desirable prevention of sexual violence against sub-Saharan transmigrants by the Moroccan healthcare sector. METHODS: Knowledge, attitudes and practices of healthcare workers in Morocco concerning sexual violence against sub-Saharan transmigrants and its prevention were firstly explored in semi-structured interviews after which they were discussed in a participatory process resulting in the formulation of recommendations. RESULTS: All participants (n=24) acknowledged the need for desirable prevention of sexual violence against transmigrants. Furthermore, important barriers in tertiary prevention practices, i.e. psychosocial and judicial referral and long-term follow-up, and in secondary prevention attitudes, i.e. active identification of victims were identified. Moreover, existing services for Moroccan victims of sexual violence currently do not address the sub-Saharan population. Thus, transmigrants are bound to rely on the aid of civil society. CONCLUSIONS: This research demonstrates the low accessibility of existing Moroccan services for sub-Saharan migrants. In particular, there is an absence of prevention initiatives addressing sexual violence against the sub-Saharan transmigrant population. Although healthcare workers do wish to develop prevention initiatives, they are dealing with structural difficulties and a lack of expertise. Recommendations adapted to the context of sub-Saharan transmigrants in Morocco are suggested. PMID- 23442387 TI - Autonomous regulation of the insect gut by circadian genes acting downstream of juvenile hormone signaling. AB - In temperate regions, the shortening day length informs many insect species to prepare for winter by inducing diapause. The adult diapause of the linden bug, Pyrrhocoris apterus, involves a reproductive arrest accompanied by energy storage, reduction of metabolic needs, and preparation to withstand low temperatures. By contrast, nondiapause animals direct nutrient energy to muscle activity and reproduction. The photoperiod-dependent switch from diapause to reproduction is systemically transmitted throughout the organism by juvenile hormone (JH). Here, we show that, at the organ-autonomous level of the insect gut, the decision between reproduction and diapause relies on an interaction between JH signaling and circadian clock genes acting independently of the daily cycle. The JH receptor Methoprene-tolerant and the circadian proteins Clock and Cycle are all required in the gut to activate the Par domain protein 1 gene during reproduction and to simultaneously suppress a mammalian-type cryptochrome 2 gene that promotes the diapause program. A nonperiodic, organ-autonomous feedback between Par domain protein 1 and Cryptochrome 2 then orchestrates expression of downstream genes that mark the diapause vs. reproductive states of the gut. These results show that hormonal signaling through Methoprene-tolerant and circadian proteins controls gut-specific gene activity that is independent of circadian oscillations but differs between reproductive and diapausing animals. PMID- 23442389 TI - A motivational interviewing intervention to PREvent PAssive Smoke Exposure (PREPASE) in children with a high risk of asthma: design of a randomised controlled trial. AB - BACKGROUND: Especially children at risk for asthma are sensitive to the detrimental health effects of passive smoke (PS) exposure, like respiratory complaints and allergic sensitisation. Therefore, effective prevention of PS exposure in this group of vulnerable children is important. Based on previous studies, we hypothesized that an effective intervention program to prevent PS exposure in children is possible by means of a motivational interviewing tailored program with repeated contacts focussing on awareness, knowledge, beliefs (pros/cons), perceived barriers and needs of parents, in combination with feedback about urine cotinine levels of the children. The aim of the PREPASE study is to test the effectiveness of such an intervention program towards eliminating or reducing of PS exposure in children at risk for asthma. This article describes the protocol of the PREPASE study. METHODS: The study is a one year follow-up randomized controlled trial. Families with children (0-13 years of age) having an asthma predisposition who experience PS exposure at home are randomized into an intervention group receiving an intervention or a control group receiving care as usual. The intervention is given by trained research assistants. The intervention starts one month after a baseline measurement and takes place once per month for an hour during six home based counselling sessions. The primary outcome measure is the percentage of families curtailing PS exposure in children (parental report verified with the urine cotinine concentrations of the children) after 6 months. The secondary outcome measures include: household nicotine level, the child's lung function, airway inflammation and oxidative stress, presence of wheezing and questionnaires on respiratory symptoms, and quality of life. A process evaluation is included. Most of the measurements take place every 3 months (baseline and after 3, 6, 9 and 12 months of study). CONCLUSION: The PREPASE study incorporates successful elements of previous interventions and may therefore be very promising. If proven effective, the intervention will benefit the health of children at risk for asthma and may also create opportunity to be tested in other population. TRIAL REGISTRATION NUMBER: NTR2632. PMID- 23442390 TI - Posttranslational modifications and secretion efficiency of immunogenic hepatitis B virus L protein deletion variants. AB - BACKGROUND: Subviral particles of hepatitis B virus (HBV) composed of L protein deletion variants with the 48 N-terminal amino acids of preS joined to the N terminus of S protein (1-48preS/S) induced broadly neutralizing antibodies after immunization of mice with a Semliki Forest virus vector. A practical limitation for use as vaccine is the suboptimal secretion of such particles. The role of the N-terminal preS myristoylation in the cellular retention of full-length L protein is described controversially in the literature and the relation of these data to the truncated L protein was unknown. Thus, we studied the effect of preS myristoylation signal suppression on 1-48preS/S secretion efficiency, glycosylation and subcellular distribution. FINDINGS: The findings are that 1 48preS/S is secreted, and that removal of the N-terminal myristoylation signal in its G2A variant reduced secretion slightly, but significantly. The glycosylation pattern of 1-48preS/S was not affected by the removal of the myristoylation signal (G2A mutant) but was different than natural L protein, whereby N4 of the preS and N3 of the S domain were ectopically glycosylated. This suggested cotranslational translocation of 1-48preS in contrast to natural L protein. The 1 48preS/S bearing a myristoylation signal was localized in a compact, perinuclear pattern with strong colocalization of preS and S epitopes, while the non myristoylated mutants demonstrated a dispersed, granular cytoplasmic distribution with weaker colocalization. CONCLUSIONS: The large deletion in 1-48preS/S in presence of the myristoylation site facilitated formation and secretion of protein particles with neutralizing preS1 epitopes at their surface and could be a useful feature for future hepatitis B vaccines. PMID- 23442391 TI - SPRING: an RCT study of probiotics in the prevention of gestational diabetes mellitus in overweight and obese women. AB - BACKGROUND: Obesity is increasing in the child-bearing population as are the rates of gestational diabetes. Gestational diabetes is associated with higher rates of Cesarean Section for the mother and increased risks of macrosomia, higher body fat mass, respiratory distress and hypoglycemia for the infant. Prevention of gestational diabetes through life style intervention has proven to be difficult. A Finnish study showed that ingestion of specific probiotics altered the composition of the gut microbiome and thereby metabolism from early gestation and decreased rates of gestational diabetes in normal weight women. In SPRING (the Study of Probiotics IN the prevention of Gestational diabetes), the effectiveness of probiotics ingestion for the prevention of gestational diabetes will be assessed in overweight and obese women. METHODS/DESIGN: SPRING is a multi center, prospective, double-blind randomized controlled trial run at two tertiary maternity hospitals in Brisbane, Australia. Five hundred and forty (540) women with a BMI > 25.0 kg/m(2) will be recruited over 2 years and receive either probiotics or placebo capsules from 16 weeks gestation until delivery. The probiotics capsules contain > 1x10(9) cfu each of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB-12 per capsule. The primary outcome is diagnosis of gestational diabetes at 28 weeks gestation. Secondary outcomes include rates of other pregnancy complications, gestational weight gain, mode of delivery, change in gut microbiome, preterm birth, macrosomia, and infant body composition. The trial has 80% power at a 5% 2-sided significance level to detect a >50% change in the rates of gestational diabetes in this high-risk group of pregnant women. DISCUSSION: SPRING will show if probiotics can be used as an easily implementable method of preventing gestational diabetes in the high-risk group of overweight and obese pregnant women. PMID- 23442392 TI - Tobacco control in the WHO South-East Asia Region. PMID- 23442393 TI - Best practices in tobacco control in the South-East Asia Region. AB - The tobacco epidemic is an increasing threat to public health with the tobacco burden particularly high in WHO's South-East Asia Region (SEAR). The Region has many obstacles to tobacco control, but despite these challenges, significant progress has been made in many countries. Although much work still needs to be done, SEAR countries have nevertheless implemented strong and often innovative tobacco control measures that can be classified as "best practices," with some setting global precedents. The best practice measures implemented in SEAR include bans on gutka, reducing tobacco imagery in movies, and warning about the dangers of tobacco. In a time of scarce resources, countries in SEAR and elsewhere must ensure that the most effective and cost-efficient measures are implemented. It is hoped that countries can learn from these examples and as appropriate, adapt these measures to their own specific cultural, social and political realities. PMID- 23442394 TI - Involvement of health professionals in tobacco control in the South-East Asia Region. AB - Tobacco use is widely entrenched in the South-East Asia (SEA) Region leading to high morbidity and mortality in this region. Several studies revealed that tobacco use is widespread among youth and school children. Exposure to second hand smoke was reported as around 50% or more in three countries - Myanmar (59.5%), Bangladesh (51.3%), and Indonesia (49.6%). Health profession students encompassing medical, dental, nursing and pharmacy disciplines, and even qualified health professionals are no exception from tobacco use. While they are regarded as role models in tobacco cessation programs, their tobacco addiction will carry a negative impact in this endeavour. A mere inquiry about the smoking status of patients and a brief advice by doctors or dentists increases quit rates and prompts those who have not thought about quitting to consider doing so. Evidence from some randomized trials suggests that advice from motivated physicians to their smoking patients could be effective in facilitating cessation of smoking. However, the low detection rate of smokers by many physicians and the small proportion of smokers who routinely receive advice from their physicians to quit have been identified as a matter of concern. This paper describes the role and issues of involvement of health professionals in tobacco control. Data from a variety of sources is used to assess the status. Although there are some differences, tobacco use is widespread among the students and health professional students. Exposure to second hand smoke is also a matter of concern. Tobacco related problems and tobacco control cut across a vast range of health disciplines. Building alliances among the health professional associations in a vertical way will help synergize efforts, and obtain better outcomes from use of existing resources. Health professional associations in some countries in the SEA region have already taken the initiative to form coalitions at the national level to advance the tobacco control agenda. In Thailand, a Thai Health Professional Alliance against Tobacco, with 17 allies from medical, nursing, traditional medicine, and other health professional organizations, is working in a concerted manner toward promoting tobacco control. Indian Dental Association intervention is another good example. PMID- 23442395 TI - Banning smokeless tobacco in India: policy analysis. AB - India is the second largest producer and third largest consumer of tobacco. According to GATS India Report (2009-10), the users of only smokeless tobacco (SLT) are more than double than that of smokers. SLT use is an imminent public health problem, which is contributing to high disease burden in India. It is a "unique" tobacco product due to its availability in myriad varieties, easy access, and affordability especially for adolescents. It has been studied to be a gateway product and facilitates initiation. Currently, the Food Safety and Standards Authority of India (FSSAI) have prohibited the use of tobacco and nicotine in any food products; yet, the implementation of a permanent ban on SLT across India is still pending. This paper examines how multiple legislations have failed to effectively control or regulate SLT in India and regionally; thus, there is need to strengthen SLT control efforts as "no ordinary product." PMID- 23442396 TI - Prevalence of smokeless tobacco use among adults in WHO South-East Asia. AB - Smokeless tobacco (SLT) use is an understudied problem in South-East Asia. Information on SLT use among the adult population was collected from various available sources. SLT use prevalence varies among countries in the region. The prevalence of SLT use is known for all countries at national level in the region with the exception of Bhutan and DPR Korea. For Bhutan, data pertains to Thimphu only. There is no available data on SLT use for DPR Korea. Using all available data from Bhutan, India, Myanmar, Nepal, and Sri Lanka, SLT use was found to be higher among males as compared to females; however, in Bangladesh, Indonesia, and Thailand, SLT use was higher among females as compared to males. Among males, prevalence of SLT use varied from 51.4% in Myanmar to 1.1% in Thailand. Among females, the prevalence of SLT use varied from 27.9% in Bangladesh to 1.9% in Timor-Leste. The prevalence also varies in different parts of countries. For instance, the prevalence of current use of SLT in India ranges from 48.7% in Bihar to 4.5% in Himachal Pradesh. In Thailand, prevalence of current use of tobacco use varies from 0.8% in Bangkok to over 4% in the northern (4.1%) and northeastern (4.7%) region. Among all SLT products, betel quid was the most commonly used product in most countries including Bangladesh (24.3%) and Thailand (1.8%). However, Khaini (11.6%) chewing was practiced most commonly in India. Nearly 5% of the adult population used tobacco as dentifrice in Bangladesh and India. SLT is more commonly used in rural areas and among disadvantaged groups. Questions from standard "Tobacco Questions for Surveys (TQS)" need to be integrated in routine health system surveys in respective countries to obtain standardized tobacco use data at regular intervals that will help in providing trends of SLT use in countries. PMID- 23442397 TI - Smokeless tobacco use in Myanmar. AB - Smokeless tobacco (SLT) use in various forms is highly prevalent in Myanmar. The aim of this paper is to study the socio-cultural background of SLT use and products of SLT in Myanmar and the prevalence of SLT based on surveys and from other published data bases. Information was obtained from the literature review and through search on PubMed and Google. The use of SLT is deep rooted in Myanmar culture, and there is also wide-spread belief that it is not as dangerous as smoking. SLT use is growing in Myanmar. About 9.8% of the 13-15-year-old school children and 20.8% adults use SLT; it is many-fold higher among men. The use of SLT is prevalent using many different types of tobacco and forms of its use in Myanmar. The socio-cultural acceptance and the myths were compounded by the lack of specific SLT control component in the National Tobacco Control Legislation adopted needs to be addressed as a priority through intensified community awareness programs, public education programs, and advocacy campaigns. Effective enforcement of the law and amendment to include specific components of SLT in the provisions of the law is highly recommended. The prevalence of SLT is high among school children and adults (especially in men) in Myanmar. Betel quid and tobacco is a common form of SLT use. Although control of smoking and consumption of tobacco product law exists, its implementation is weak. PMID- 23442398 TI - Smokeless tobacco use in Nepal. AB - Tobacco use is widely prevalent in different forms in Nepal. These habits are deeply rooted among different age groups and gender. There is no information available on all aspects of smokeless tobacco (SLT) use and its implications in Nepal. To review the types of SLT products available in Nepal, prevalence of SLT use, correlates of SLT use, SLT-related harm, and existing gaps in information and policy implications. This review is mainly based on information from literature, and some WHO and other documents. The prevalence of smokeless tobacco use is high, particularly among males and disadvantaged groups. SLT users have multiple habits of tobacco chewing, smoking and drinking. Despite SLT products being manufactured in the unorganized sector, they are also largely imported from India. People have easy access to various SLT products. There is a general lack of information on the health hazards of SLT use to the population. This calls for research on the issue. In order to succeed in reducing SLT use in Nepal, addressing the challenges of enforcing the Tobacco Control Act through a multisectoral approach and developing capacity of sectors other than health is of vital importance. PMID- 23442399 TI - Smokeless tobacco use in Sri Lanka. AB - To comprehensively review the issues of smokeless tobacco use in Sri Lanka . This review paper is based on a variety of sources including Medline, WHO documents, Ministry of Health and Nutrition, Colombo and from other sources. RESULTS: The prevalence of smokeless tobacco (SLT) use in Sri Lanka has been reported high, especially among rural and disadvantaged groups. Different smokeless tobacco products were not only widely available but also very affordable. An increasing popularity of SLT use among the youth and adolescents is a cause for concern in Sri Lanka. There were evidences of diverse benign, premalignant, and malignant oral diseases due to smokeless tobacco use in the country. The level of awareness about health risks related to the consumption of smokeless tobacco products was low, particularly among the people with low socio-economic status. In Sri Lanka various forms of smokeless tobacco products, some of them imported, are used. At the national level, 15.8% used smokeless tobacco products and its use is three fold higher among men compared to women. Betel quid is by far the traditional form in which tobacco is a general component. Other manufactured tobacco products include pan parag/pan masala, Mawa, Red tooth powder, Khaini, tobacco powder, and Zarda. Some 8.6% of the youth are current users of smokeless tobacco. There are studies demonstrating the harmful effects of smokeless tobacco use, especially on the oral mucosa, however, the level of awareness of this aspect is low. The highest mean expenditure on betel quid alone in rural areas for those earning Rs. 5,000/month was Rs. 952. The core issue is the easy availability of these products. To combat the smokeless tobacco problem, public health programs need to be intensified and targeted to vulnerable younger age groups. Another vital approach should be to levy higher taxation. PMID- 23442400 TI - Chemistry and toxicology of smokeless tobacco. AB - In most parts of the world, tobacco is used for smoking, whereas, in India, tobacco is used for smoking as well as in diverse smokeless forms. Absorption of toxic and carcinogenic chemicals in tobacco and other ingredients added to various products are causally associated with several non-communicable diseases including cancer, especially oral cancer, which is the leading cancer among men and the third most common cancer among women in India. This article highlights the toxicity, mutagenecity and carcinogenic effects of hazardous chemicals present in smokeless tobacco products. This endeavor was based on the extensive review of literature from various sources. The SLT products have influence on cellular metabolism, ability to cause DNA damage, and cancer in experimental animals. It is, therefore, essential to consider the collective role of chemical constituents of SLT products in the causation of adverse effect on human health. PMID- 23442401 TI - MPOWER and the Framework Convention on Tobacco Control implementation in the South-East Asia region. AB - The 11 member states of WHO's South-East Asia Region share common factors of high prevalence of tobacco use, practice of several forms of tobacco use, increasing prevalence of tobacco use among the youth and women, link of tobacco use with poverty, and influence of tobacco advertisements in propagating the use of tobacco, especially among young girls and women. The effects of tobacco use are many-fold, leading to high morbidity and mortality rates as well as loss of gross domestic product (GDP) to respective countries. The WHO Regional Office for South East Asia has been actively involved in curbing this menace essentially by way of assisting member states in implementing the WHO Framework Convention on Tobacco Control (FCTC). This paper gives an overview of these activities and discusses the opportunities and challenges in implementing the FCTC and possible practical solutions. PMID- 23442402 TI - Tobacco use, exposure to second-hand smoke, and cessation training among the third-year medical and dental students in selected Member States of South-East Asia region: a trend analysis on data from the Global Health Professions Student Survey, 2005-2011. AB - BACKGROUND: The Medical and Dental Global Health Professions Student Surveys (GHPSS) are surveys based in schools that collect self-administered data from students on the prevalence of tobacco use, exposure to second-hand smoke, and tobacco cessation training, among the third-year medical and dental students. MATERIALS AND METHODS: Two rounds of medical and dental GHPSS have been conducted in Bangladesh, India, Myanmar, Nepal, Sri Lanka, and Thailand, among the third year medical and dental students, between 2005 and 2006 and 2009 and 2011. RESULTS: The prevalence of any tobacco use among third-year male and female medical students did not change in Bangladesh, India, and Nepal between 2005 and 2006 and 2009 and 2011; however, it reduced significantly among females in Myanmar (3.3% in 2006 to 1.8% in 2009) and in Sri Lanka (2.5% in 2006 to 0.6% in 2011). The prevalence of any tobacco use among third-year male dental students did not change in Bangladesh, India, Nepal, and Thailand between 2005 and 2006 and 2009 and 2011; however, in Myanmar, the prevalence increased significantly (35.6% in 2006 to 49.5% in 2009). Among the third-year female students, a significant increase in prevalence was noticed in Bangladesh (4.0% in 2005 to 22.2% in 2009) and Thailand (0.7% in 2006 to 2.1% in 2011). It remained unchanged in the other three countries. Prevalence of exposure to second-hand smoke (SHS) both at home and in public places, among medical students, decreased significantly in Myanmar and Sri Lanka between 2006 and 2009 and in 2011. Among dental students, the prevalence of SHS exposure at home reduced significantly in Bangladesh, India, and Myanmar, and in public places in India. However, there was an increase of SHS exposure among dental students in Nepal, both at home and in public places, between 2005 and 2011. Medical students in Myanmar, Nepal, and Sri Lanka reported a declining trend in schools, with a smoking ban policy in place, between 2005 and 2006 and 2009 and 2011, while proportions of dental students reported that schools with a smoking ban policy have increased significantly in Bangladesh and Myanmar. Ever receiving cessation training increased significantly among medical students in Sri Lanka only, whereas, among dental students, it increased in India, Nepal, and Thailand. CONCLUSION: Trends of tobacco use and exposure to SHS among medical and dental students in most countries of the South East Asia Region had changed only relatively between the two rounds of GHPSS (2005-2006 and 2009-2011). No significant improvement was observed in the trend in schools with a policy banning smoking in school buildings and clinics. Almost all countries in the SEA Region that participated in GHPSS showed no significant change in ever having received formal training on tobacco cessation among medical and dental students. PMID- 23442403 TI - Predictors of tobacco smoking and smokeless tobacco use among adults in Bangladesh. AB - INTRODUCTION: To examine predictors of current tobacco smoking and smokeless tobacco use among the adult population in Bangladesh. MATERIALS AND METHODS: We used data from the 2009 Global Adult Tobacco Survey (GATS) in Bangladesh consisting of 9,629 adults aged >=15 years. Differences in and predictors of prevalence for both smoking and smokeless tobacco use were analyzed using selected socioeconomic and demographic characteristics that included gender, age, place of residence, education, occupation, and an index of wealth. RESULTS: The prevalence of smoking is high among males (44.7%, 95% confidence interval [CI]: 42.5-47.0) as compared to females (1.5%, 95% CI: 1.1-2.1), whereas the prevalence of smokeless tobacco is almost similar among both males (26.4%, 95% CI: 24.2 28.6) and females (27.9%, 95% CI: 25.9-30.0). Correlates of current smoking are male gender (odds ratio [OR] = 41.46, CI = 23.8-73.4), and adults in older age (ORs range from 1.99 in 24-35 years age to 5.49 in 55-64 years age), less education (ORs range from 1.47 in less than secondary to 3.25 in no formal education), and lower socioeconomic status (ORs range from 1.56 in high wealth index to 2.48 in lowest wealth index. Predictors of smokeless tobacco use are older age (ORs range from 2.54in 24-35 years age to 12.31 in 55-64 years age), less education (ORs range from 1.44 in less than secondary to 2.70 in no formal education), and the low (OR = 1.34, CI = 1.0-1.7) or lowest (OR = 1.43, CI = 1.1 1.9) socioeconomic status. CONCLUSION: Implementation of tobacco control strategies needs to bring special attention on disadvantaged group and cover all types of tobacco product as outlined in the WHO Framework Convention on Tobacco Control (FCTC) and WHO MPOWER to protect people's health and prevent premature death. PMID- 23442404 TI - Profile of dual tobacco users in India: an analysis from Global Adult Tobacco Survey, 2009-10. AB - INTRODUCTION: Individuals who use both smoked and smokeless tobacco products (dual tobacco users) form a special group about which little is known. This group is especially relevant to India, where smokeless tobacco use is very common. The aim of this study was to characterise the profile of dual users, study their pattern of initiation to the second product, their attitudes toward quittingas well as their cessation profile. METHODS AND MATERIALS: The GATS dataset for India was analyzed using SPSS; . RESULTS: In India, dual tobacco users (42.3 million; 5.3% of all adults; 15.4% of all tobacco users) have a profile similar to that of smokers. Some 52.6% of dual users started both practices within 2 years. The most prevalent product combination was bidi-khaini (1.79%) followed by bidi-gutka (1.50%), cigarette-khaini (1.28%), and cigarette-gutka (1.22%). Among daily users, the correlation between the daily frequencies of the use of each product was very high for most product combinations. While 36.7% of dual users were interested in quitting, only 5.0% of dual users could do so. The prevalence of ex-dual users was 0.4%. CONCLUSION: Dual users constitute a large, high-risk group that requires special attention. PMID- 23442405 TI - Social disparities in tobacco use in India: the roles of occupation, education and gender. AB - BACKGROUND: Identifying social disparities in patterns of tobacco use with regard to education, occupation, and gender characteristics can provide valuable insights into the tobacco use patterns of the population. AIM: We assessed social disparities in tobacco use, smoking, and smokeless tobacco use by examining occupation-, education-, and gender-specific patterns. SETTING: About 69,030 Indian residents >=15 years in 29 States and 2 Union Territories (UT). DESIGN: Three-stage sampling in urban areas and two-stage sampling in rural areas for selection of households. MATERIALS AND METHODS: Data has been derived from GATS 2009-2010, wherein the sample was collected through household interviews. STATISTICAL ANALYSIS: Percentages, proportions, adjusted odds ratios (ORs), and 95% confidence interval (CI) were reported. RESULTS: As a person entered adulthood, the prevalence of ever tobacco use increased by 51.5% among men and 28.8% among women. Prevalence was 2.5 times higher in men (mainly smoking) as compared to women (predominantly smokeless form). ORs for tobacco use were higher among illiterate respondents as compared to the college educated (male OR = 4.23, female OR = 8.15). Unemployed, able to work (male OR = 1.50, female OR = 1.23) showed highest risk, while students (male OR = 0.35, female OR = 0.52) showed the least. The combined effect of occupation and education showed synergistic interaction among females and antagonistic interaction among males. CONCLUSION: The study clearly underscores the individual and joint effects of education and occupation on tobacco use besides discussing variations based on gender. This can have far-reaching policy implications in addressing disparities in tobacco use. PMID- 23442406 TI - Exposure to second-hand tobacco smoke among adults in Myanmar. AB - BACKGROUND: Second-hand smoke (SHS) is a threat to people's health particularly in South-East Region including Myanmar. AIM: To describe the exposure to SHS among the adult population of Myanmar. MATERIALS AND METHODS: The analysis was done based on the data relating to SHS exposure from 2009 Noncommunicable Risk Factor Survey conducted in Myanmar. A total of 7,429 respondents aged 15-64 from a nationally representative household-based cross-sectional multi-stage probability sample were used. Gender-specific estimates of the proportion of adults exposed to SHS were examined across various socio-demographic characteristics. RESULTS: The exposure to SHS was 55.6% (52% among males and 57.8% among females) at home, 63.6% (71.9% among males and 54.7% among females) in indoor places and 23.3% (38.8% among males and 13.6% among females) in public places. SHS exposure at home was more common among females. However, males were more likely to be exposed at work and public places than females. SHS exposure at home and public places decreased with age in both sexes. In these settings, SHS exposure was related to education, residence, employment status, marital status, and income level. At workplaces, it was mainly related to educational attainment and occupational status. CONCLUSION: Exposure was significantly high in settings having partial ban as compared with settings having a complete ban. The solution is simple and straightforward, smoke-free environments. The findings emphasize the need for continuing efforts to decrease the exposure and to increase the knowledge of its harmful effects. PMID- 23442407 TI - Determinants of exposure to second-hand smoke at home and outside the home among students aged 11-17 years: results from the Mumbai Student Tobacco Survey 2010. AB - BACKGROUND: While no level of exposure to Second-hand smoke (SHS) is free of risk, 37% of students from South-East Asia region were exposed to SHS. AIMS: To estimate the prevalence of exposure to SHS and identify predictors of exposure to SHS at home and outside the home among 1,511 school students aged 11-17 years. SETTING: The City of Mumbai. STUDY DESIGN: This study used a two-stage cluster sampling design. MATERIALS AND METHODS: Mumbai Student Tobacco Survey (MSTS) was a cross-sectional study, using anonymous self-administered structured questionnaire among students. The probability of schools being selected was proportional to the enrolment into grades 8 to 10. The study aimed to sample around 60 students from selected classes in each chosen school. STATISTICAL ANALYSIS: Proportions, 95% confidence interval and adjusted odds ratios (AOR) were used. RESULTS: About 79.9% students were aware about the current smoking ban at public places and 88.1% were knowledgeable about the deleterious influence of SHS on them. Overall, 16.5% of students were exposed to SHS at home, and 39.9% outside of the home. Students from families where at least one parent used tobacco were at the greatest risk of SHS exposure at home in addition to outside the home exposure. Those students who were not aware about the smoking ban in public places were at a significantly higher risk of SHS exposure outside the home. CONCLUSION: Self-reported tobacco use status, age, parents' tobacco use, close friends' smoking, and the route they take to school were significant determinants of exposure to SHS at home and outside the home. PMID- 23442408 TI - Tobacco use and cessation counseling in India-data from the Global Health Professions Students Survey, 2005-09. AB - CONTEXT: Tobacco use by health professionals reflects the failure of healthcare systems in protecting not only beneficiaries of the system but also those involved in health care delivery. AIM: The aim of this study was to report findings from the Global Health Professions Students Survey (GHPSS) conducted in medical, dental, nursing and pharmacy schools in India. SETTINGS AND DESIGN: A cross-sectional survey was conducted in Indian dental and medical schools (in 2009), nursing (in 2007), and pharmacy (in 2008) schools. MATERIALS AND METHODS: Anonymous, self-administered GHPSS questionnaire covering demographics, tobacco use prevalence, secondhand smoke (SHS) exposure, desire to quit smoking and training received to provide cessation counseling to patients was used. STATISTICAL ANALYSIS: Proportions and prevalence were computed using SUDAAN and SPSS 15.0. RESULTS: Current cigarette smoking and other tobacco use ranged from 3.4-13.4% and 4.5-11.6% respectively, in the four health professional schools, with the highest numbers for medical schools and males. Enforcement of smoking ban in medical schools was low (53%) compared to nursing (86.4%), pharmacy (85.5%), and dental (90.8%) schools. Ninety percent students thought health professionals have a role in giving smoking cessation advice to their patients. Three out of five current smokers wanted to quit. However, one out of two reported receiving help/advice to quit. Although all expressed the need, 29.1 54.8% students received cessation training in their schools. CONCLUSION: Tobacco control policy, cessation training and initiatives to help students quit smoking should be undertaken. PMID- 23442409 TI - Intention to quit among Indian tobacco users: findings from International Tobacco Control Policy evaluation India pilot survey. AB - INTRODUCTION: Tobacco users face barriers not just in quitting, but also in thinking about quitting. The aim of this study was to understand factors encouraging intention to quit from the 2006 International Tobacco Control Policy (TCP) Evaluation India Pilot Study Survey. MATERIALS AND METHODS: A total of 764 adult respondents from urban and rural areas of Maharashtra and Bihar were surveyed through face-to-face individual interviews, with a house-to-house approach. Dependent variable was "intention to quit tobacco." Independent variables were demographic variables, peer influence, damage perception, receiving advice to quit, and referral to cessation services by healthcare professionals and exposure to anti-tobacco messages. Logistic regression model was used with odds ratio adjusted for location, age, gender, and marital status for statistical analysis. RESULTS: Of 493 tobacco users, 32.5% intended to quit. More numbers of users who were unaware about their friends' tobacco use intended to quit compared to those who were aware (adjusted OR = 8.06, 95% CI = 4.58 14.19). Higher numbers of users who felt tobacco has damaged their health intended to quit compared to those who did not feel that way (adjusted OR = 5.62, 95% CI = 3.53-8.96). More numbers of users exposed to anti-tobacco messages in newspapers/magazines (adjusted OR = 1.76, 95% CI = 1.02-3.03), restaurants (adjusted OR = 2.47, 95% CI = 1.37-4.46), radio (adjusted OR=4.84, 95% CI = 3.01 7.78), cinema halls (adjusted OR = 9.22, 95% CI = 5.31-15.75), and public transportation (adjusted OR = 10.58, 95% = 5.90-18.98) intended to quit compared to unexposed users. CONCLUSION: Anti-tobacco messages have positive influence on user's intentions to quit. PMID- 23442410 TI - An assessment of the effectiveness of tobacco control measures on behavior changes related to tobacco use among adolescents and young adults in a district in Sri Lanka. AB - INTRODUCTION: Sri Lanka became a signatory to the WHO Frame Work Convention on Tobacco Control in September 2003, and this was ratified in November 2003. With a view to reduce the use of tobacco in Sri Lanka, the National Authority on Tobacco and Alcohol Act (NATA) No. 27 of 2006 was implemented. AIM: To assess the behavior changes related to tobacco use among adolescents and young adults following exposure to tobacco control measures were implemented by NATA. MATERIALS AND METHODS: A case-control study was conducted on 42 adolescent (aged 13-19 years) and 156 young adult (aged 20-39 years) men living in Anuradhapura Divisional Secretary area in Sri Lanka. Cases (current quitters) and controls (current smokers) were compared to ascertain the outcome following the exposure to tobacco control measures. A self-administered questionnaire and focus group discussions were used to ascertain the exposure status in cases and controls. Confounding was controlled by stratification and randomization. Univariate analysis was performed by Backward Stepwise (Likelihood Ratio) method. RESULTS: Among 198 respondents, 66 (27.3% adolescents and 72.7% young adults) were quitters, while 132 smokers (18.2% adolescents and 81.8% young adults) were current smokers. Exposure to the anti-smoking media messages revealed that TV was the strongest media that motivated smokers to quit smoking. Majority (66%) of cases and control were not exposed to tobacco promotion advertisements, while 47% of the cases and 50% of the control had never seen tobacco advertisements during community events. All cases (66) as well as 89% (118) of the control had not noticed competitions or prizes sponsored by tobacco industry during last year ( P = 0.13). CONCLUSION: Tobacco control measures implemented by NATA had a favorable influence on behavior change related to smoking among quitters and current smokers. PMID- 23442412 TI - Health consequences of smokeless tobacco use. PMID- 23442411 TI - Local responses to the Maharashtra gutka and pan masala ban: a report from Mumbai. AB - BACKGROUND: The Maharashtra government has banned the production, sale, distribution and storage of gutka, and pan masala in the Maharashtra State due to the increasing burden of cancer and reproductive health problems attributable to the use of these products. In view of this, it is important to understand the way producers', sellers' and users' are adapting to the ban. OBJECTIVE: During the two months following the ban (July 19 th through Sept 30, 2012), a research team studying smokeless tobacco use and promotion in a low income community of Mumbai conducted rapid surveillance to assess the impact of the ban in the study community. MATERIALS AND METHODS: Assessment involved documenting new points of sale, informal observations of tobacco use, and interviews with thirteen shop owners and eight gutka users'. Overall changes in accessibility, availability, patterns of use of tobacco products, perception of ban, social norms and surveillance activities were assessed. RESULTS: Tobacco companies were marketing new products that resembled gutka, under similar brand logos. Surveillance, financial and social cost of selling gutka or using it in public have had an immediate effect on reducing local supply, demand and use and increasing stigma associated with its use. There was an increased recognition of ill-effects of gutka on cancer among sellers' but not overall. CONCLUSIONS: To reduce the overall consumption of tobacco in the community, it is critical to include programs that create awareness about effects of smokeless tobacco on health and sustain surveillance levels. This would maintain requirements of the ban, and sustain limits on accessibility, availability and use of these products in the community and other similar communities. PMID- 23442414 TI - Mortality in Clostridium difficile infection: a prospective analysis of risk predictors. AB - OBJECTIVES: To date, the vast majority of studies investigating risk factors for mortality in Clostridium difficile infection (CDI) have been based on retrospective, routinely collected data, and have not specifically tested the capacity of risk factors to predict outcome. We aimed to prospectively evaluate predictors of mortality in patients with CDI, utilizing established metrics of risk prediction to assess their ability to prognosticate. PATIENTS AND METHODS: We collected a cohort of all patients diagnosed with CDI at Addenbrooke's Hospital in 2010. Univariate associations between several parameters and all cause 30-day in-hospital mortality were assessed, with statistically significant parameters entered into a Cox regression model. A backwards selection procedure was used to derive a final multivariate model. RESULTS: The cohort consisted of 131 patients. From the univariate analyses white blood cell count (WBC)>15*10/l, serum albumin <25 g/l, serum creatinine >200 MUmol/l and C-reactive protein >100 nmol/l met criteria for entry into the multivariate model. WBC>15*10/l (hazard ratio 5.3, 95% confidence interval 1.7-16.8) and serum albumin level <25 g/l (hazard ratio 9.5, 95% confidence interval 1.2-74.5), were significantly associated with mortality in the final multivariate model. The model containing these variables had a C-index of 0.79, D-statistic of 2.1 and RD measure of 0.52. CONCLUSION: We have demonstrated in a prospective cohort of patients diagnosed with CDI that WBC and serum albumin, when used together, offer good risk predictive ability for mortality. Our results support the inclusion of these parameters in a clinically useful risk prediction model. PMID- 23442413 TI - Antimicrobial activity of pure platelet-rich plasma against microorganisms isolated from oral cavity. AB - BACKGROUND: Autologous platelet concentrates (PCs) have been extensively used in a variety of medical fields to promote soft and hard tissue regeneration. The significance behind their use lies in the abundance of growth factors in platelets alpha-granules that promotes wound healing. In addition, antibacterial properties of PCs against various bacteria have been recently pointed out. In this study, the antimicrobial effect of pure platelet-rich plasma (P-PRP) was evaluated against oral cavity microorganisms such as Enterococcus faecalis, Candida albicans, Streptococcus agalactiae, Streptococcus oralis and Pseudomonas aeruginosa. Blood samples were obtained from 17 patients who underwent oral surgery procedures involving the use of P-PRP. The antibacterial activity of P PRP, evaluated as the minimum inhibitory concentration (MIC), was determined through the microdilution twofold serial method. RESULTS: P-PRP inhibited the growth of Enterococcus faecalis, Candida albicans, Streptococcus agalactiae and Streptococcus oralis, but not of Pseudomonas aeruginosa strains. CONCLUSIONS: P PRP is a potentially useful substance in the fight against postoperative infections. This might represent a valuable property in adjunct to the enhancement of tissue regeneration. PMID- 23442415 TI - Adipokines and insulin resistance, predictors of response to therapy in Egyptian patients with chronic hepatitis C virus genotype 4. AB - BACKGROUND: Hepatitis C virus (HCV) infection has major health impact worldwide and is a significant cause of chronic liver disease. In Egypt, HCV is highly endemic (up to 15% of the population); 91% of the patients are infected with genotype 4. Searching for new predictors of response to therapy is mandatory to decrease the cost and the adverse effects of current therapy. AIM: The aim of this study was to clarify the usefulness of serum leptin, adiponectin, and insulin resistance (IR) as predictors of response to treatment in hepatitis C virus genotype 4 (HCVG4). METHODS: One hundred patients with chronic HCVG4 who were candidates for treatment with pegylated interferon alpha and ribavirin were included in the study. Age, sex, and BMI were determined, and quantitative HCV PCR, assessment of serum leptin, adiponectin, IR, and pretreatment liver profile, and liver biopsy were performed. RESULTS: The male to female ratio was 68/32; the mean age of the patients was 40.9 +/- 7.8 years and BMI was 28.3 +/- 10 kg/m. Sustained virological response (SVR) was achieved by 56% of the patients. On performing logistic regression, BMI [odds ratio (OR) 6.5; P=0.004], serum leptin (OR 27.8; P <= 0.001), aspartate aminotransferase (OR 1.06; P <= 0.001), IR (OR 1.15; P <= 0.001), histological activity index (OR 1.77; P=0.006), and fibrosis (OR 2.93; P=0.001) were found to be independent negative predictors of SVR, whereas serum adiponectin (OR 0.74; P <= 0.001) was found to be an independent positive predictor of SVR. Pretreatment adiponectin (cutoff 13.75; sensitivity 92.86%; specificity 86.86%) shows area under the curve of 0.879 (95% confidence interval 0.802-0.956; P<0.001) and insignificant area under the curve for leptin or IR. CONCLUSION: BMI, pretreatment high leptin levels, and IR are negative predictors for SVR and pretreatment low adiponectin levels are an independent positive predictor for SVR in HCVG4. PMID- 23442416 TI - Expression of the full-length HCV core subgenome from HCV gentoype-1a and genotype-3a and evaluation of the antigenicity of translational products. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a major public health problem in India. Detection of HCV and its genotypes by simple and economic assays is a prime requirement in the planning of antiviral treatments for patients infected with this virus. Although commercial assays are available for the detection of both HCV RNA and genotypes, efforts aimed at the development of simple and economical systems for these measurements are still going on. AIM: The present study was designed to clone and express the HCV CORE gene from HCV genotype-1a and genotype-3a and use the peptides to develop immunoassays for the detection of genotype-specific antibodies in sera samples. METHODS: One hundred and thirty five serum samples from patients with liver and renal diseases were screened for HCV RNA by real-time PCR, followed by HCV genotyping in RNA-positive sera by restriction fragment length polymorphism, sequencing, and phylogenetic analysis. The HCV CORE gene was amplified from sera carrying HCV genotype-1a and genotype 3a and cloned and expressed in the pET19b vector. The translational products were used to develop a western blot assay for the detection of genotype-specific anti HCV antibodies. RESULTS: The HCV CORE gene, from both genotypes, was cloned and expressed successfully, with production of a 26 kDa recombinant protein in either case. Using peptides in a western blot assay, 101 sera samples were tested for the anti-HCV CORE antibody. Each peptide showed a reaction with anti-HCV total antibody without showing any genotype-specific binding. This indicates that individual peptides obtained from different genotypes do not have a genotype specific epitope to bind with antibodies. CONCLUSION: Cloning and expression of the HCV CORE gene from genotype-1a and genotype-3a was successful. However, the peptides formed did not show genotype-specific binding with anti-HCV. PMID- 23442418 TI - Local residual neoplasia after endoscopic treatment of laterally spreading tumors during 15 months of follow-up. AB - BACKGROUND: Among superficial neoplastic lesions of the colon and rectum, a laterally spreading tumor (LST) is a flat elevated type at least 10 mm in size. It can be treated by conventional endoscopic resection (CER). Nevertheless, local residual neoplasia (LRN) may occur during follow-up. The aim of this prospective study was to evaluate the occurrence of LRN and the risk factors for its presence. METHODS: Consecutive patients referred for CER of an LST were included. Follow-up colonoscopies were performed after 3 and 15 months. LRN was defined histologically as the presence of neoplastic tissue in the post-CER site. RESULTS: Of a total of 127 patients with 127 lesions, follow-up could not be completed in 48 (37.8%). Of the remaining 79 (62.2%) patients (64.6% men, mean age 66.1+/-9.7 years), 63 (79.7%) were negative and 16 (20.3%) were positive for the presence of LRN after 15 months. Of 62 (78.5%) patients without LRN after 3 months, 55 (88.7%) remained negative after 15 months. Of 17 (21.5%) patients with LRN after 3 months, eight (47.1%) were negative after 15 months. In a multivariate analysis, LST size of at least 20 mm was found to be a significant risk factor after 3 months (odds ratio, 5.837; 95% confidence interval 1.199 28.425; P=0.029). After 15 months, the only significant risk factor was the presence of LRN observed after 3 months (odds ratio, 6.0; 95% confidence interval, 1.793-20.073; P=0.004). CONCLUSION: This prospective study shows that the occurrence of LRN is frequent and its treatment is less effective than reported previously. These are important limitations of CER and should be taken into consideration for the management of patients with LSTs. PMID- 23442417 TI - Radiofrequency ablation: technical and clinical long-term outcomes for single hepatocellular carcinoma up to 30 mm. AB - BACKGROUND AND AIMS: Western guidelines consider radiofrequency ablation (RF) as the standard treatment for 'very early' and 'early' hepatocellular carcinoma (HCC) in nonsurgical cirrhotic patients. RF has also been proposed as the first line therapy for 'surgical' candidates with a single nodule of 20 mm or less. The aim of this monocentric cohort study was to evaluate the technical and clinical outcomes of RF in the treatment of cirrhotic patients with a single HCC of 30 mm or less. PATIENTS AND METHODS: We included all 209 consecutive patients treated between January 2001 and June 2011. The primary endpoints were the overall survival (OS) rate and safety; the secondary endpoints were primary technique effectiveness, local tumor progression, and the disease-free survival rate. RESULTS: The 5-year OS rate of the entire sample was 44.3% (95% confidence interval: 36.7-55.8); Child-Pugh class B was the worst negative prognostic factor (hazard ratio: 2.06; P=0.008). A subgroup of 70 Child-Pugh class A patients suitable for surgical resection according to current Western operability criteria showed a 5-year OS rate of 60.6%. Treatment-related mortality and morbidity rates were 0 and 3.4%, respectively. Primary technique effectiveness rate was 95.2% after one to three RF sessions. The 5-year cumulative incidence of local tumor progression was 21.5 and 32.5% for nodules <=20 and 21-30 mm, respectively. The 5 year disease-free survival rate (comprehensive of any kind of tumor progression or death) was 17.8% (95% confidence interval: 11.1-25.8). CONCLUSION: RF is an effective and very safe therapy for HCC up to 30 mm; in 'surgical' cirrhotic patients, the OS rate was similar to those reported in surgical series, although the local recurrence rate was higher. PMID- 23442419 TI - Financial incentives, health care delivery, and the crucial role of academic medicine. PMID- 23442420 TI - A standardized approach to grading clerkships: hard to achieve and not worth it anyway. PMID- 23442421 TI - A standardized approach to grading clerkships: hard to achieve and not worth it anyway. PMID- 23442423 TI - A call for medical schools to meet a national imperative. PMID- 23442422 TI - A standardized approach to grading clerkships: hard to achieve and not worth it anyway. PMID- 23442424 TI - Looking ahead: a likely reduction of U.S. seniors' residency choices. PMID- 23442425 TI - In the real world, faster diagnoses are not necessarily more accurate. PMID- 23442426 TI - In the real world, faster diagnoses are not necessarily more accurate. PMID- 23442427 TI - A call to teach medical students clinical human rights. PMID- 23442428 TI - Haiti: how visiting educators can help the most. PMID- 23442429 TI - Haiti: how visiting educators can help the most. PMID- 23442430 TI - Physician resilience: what it means, why it matters, and how to promote it. AB - Resilience is the capacity to respond to stress in a healthy way such that goals are achieved at minimal psychological and physical cost; resilient individuals "bounce back" after challenges while also growing stronger. Resilience is a key to enhancing quality of care, quality of caring, and sustainability of the health care workforce. Yet, ways of identifying and promoting resilience have been elusive. Resilience depends on individual, community, and institutional factors. The study by Zwack and Schweitzer in this issue of Academic Medicine illustrates that individual factors of resilience include the capacity for mindfulness, self monitoring, limit setting, and attitudes that promote constructive and healthy engagement with (rather than withdrawal from) the often-difficult challenges at work. Cultivating these specific skills, habits, and attitudes that promote resilience is possible for medical students and practicing clinicians alike. Resilience-promoting programs should also strive to build community among clinicians and other members of the health care workforce. Just as patient safety is the responsibility of communities of practice, so is clinician well-being and support. Finally, it is in the self-interest of health care institutions to support the efforts of all members of the health care workforce to enhance their capacity for resilience; it will increase quality of care while reducing errors, burnout, and attrition. Successful organizations outside of medicine offer insight about institutional structures and values that promote individual and collective resilience. This commentary proposes methods for enhancing individuals' resilience while building community, as well as directions for future interventions, research, and institutional involvement. PMID- 23442431 TI - Artist's statement: Empathirises. PMID- 23442432 TI - Cancer: the perspective of a son and doctor. PMID- 23442433 TI - Medicine and the arts. Welcome to my rash, scene 1: [excerpt] by Wendy Wasserstein. Commentary. PMID- 23442436 TI - AM last page. Social accountability of medical schools. PMID- 23442437 TI - Piercing associated perichondritis of the pinna: are we treating it correctly? AB - OBJECTIVE: This paper reports a series of patients with sporadic pinna perichondritis who presented to a district general hospital over a period of 10 years. The data examined included the causative organism, risk factors and pattern of antibiotic use. METHOD: A retrospective analysis of diagnosed cases of pinna perichondritis from 2001 to 2012 was performed. A literature review of pinna perichondritis was carried out using Pubmed with the key words 'pinna perichondritis', 'pinna abscess', 'pinna infection' and 'piercing'. RESULTS: Pinna perichondritis was more likely to result from chondral than lobe piercings. The majority of cases were caused by Pseudomonas aeruginosa. CONCLUSION: Most patients were not prescribed anti-pseudomonal antibiotics on presentation. This may result in persistent infection and long-term cosmetic defects. PMID- 23442438 TI - Investigation of cortical and subcortical plasticity following short-term unilateral auditory deprivation in normal hearing adults. AB - There is growing evidence that auditory stimulation or deprivation can induce physiological and perceptual changes in the auditory system of normal hearing adults. The present study investigated cortical (hemispheric asymmetry) and subcortical (acoustic reflex threshold) changes in 11 normal hearing adults after 7 days of continuous unilateral earplug use (around 30 dB of attenuation at the high frequencies). The results revealed: (a) a decrease in high frequency acoustic reflex thresholds of around 7 dB in the ear that had been plugged and (b) no change in hemispheric asymmetry. The change in acoustic reflex is consistent with subcortical plasticity. It is unclear if homoeostatic plasticity preserved the normal hemispheric asymmetry or if this is the result of the experimental paradigm. PMID- 23442439 TI - A functional MRI study of a picture-sentence verification task: evidence of attention shift to the grammatical subject. AB - Mapping the meaning of a sentence onto visual entities is a fundamental process of daily language use, but it is unclear how attention in the visual context influences sentence comprehension. Aiming to examine this problem, we conducted a picture-sentence matching experiment with scanning using functional MRI. In the experiment, a moving picture describing an event with two colored objects was presented on a screen. A visual cue was flashed at the position of an object's appearance just before the event presentation, and participants were instructed to pay attention to the visually cued object in the picture. They were then required to read a simple Japanese sentence and to verify whether it correctly described the previous event. To examine the effects of visual cueing, we defined two conditions on the basis of the relationship between the visually cued object in an event and the grammatical subject of the subsequent sentence. When comparing the conditions in which the visually cued object was incongruent with the grammatical subject to the congruent conditions, participants showed a lower hit rate, and the right frontal eye field, which is known to be the region related to attention shift, was more activated. These findings suggest that the attention was initially allocated to an object encoded as the grammatical subject in the process of linking the content of a sentence with a visual event. Therefore, the attention was shifted from the cued object to the other object under the conditions discussed above. PMID- 23442440 TI - Hepatic macrophage activation predicts clinical decompensation in chronic liver disease. PMID- 23442441 TI - Mammary gland growth and vascularity at parturition and during lactation in primiparous ewes fed differing levels of selenium and nutritional plane during gestation. AB - BACKGROUND: Objectives were to examine the effects of selenium (Se) supply and maternal nutritional plane during gestation on mammary gland growth, cellular proliferation, and vascularity at parturition and d 20 of lactation. Rambouillet primiparous ewes (n = 84) were allocated to treatments in a 2 x 3 factorial. Factors were dietary Se (adequate Se [ASe, 11.5 MUg/kg BW] or high Se [HSe, 77.0 MUg/kg BW]) and nutritional plane (60% [RES], 100% [CON], or 140% [EXC]). At parturition, lambs were removed and 42 ewes (7/treatment) were necropsied. Remaining ewes were fed a common diet meeting requirements for lactation and mechanically milked twice daily until necropsy on d 20. At both necropsy periods, mammary glands were dissected and tissues harvested. Samples were analyzed for RNA, DNA, and protein content, cell proliferation, and vascularity. Where interactions were present (P <= 0.05), least squares means from the highest-order interaction are presented. RESULTS: Final body weight of ewes was least (P <= 0.002) in RES, intermediate for CON, and greatest for EXC, regardless of stage of the ewe at necropsy (parturition or d 20 of lactation). In ewes necropsied at parturition, mammary glands were heavier (P = 0.02) in EXC compared to RES, with CON intermediate. Concentration of RNA (mg/g) was decreased (P = 0.01) in EXC compared to CON at parturition. There was a tendency (P = 0.07) for a Se by nutrition interaction in percentage of cells proliferating where ASe-EXC ewes had greater (P <= 0.02) number of proliferating cells then all other treatments. Mammary vascular area tended (P = 0.08) to be affected by a Se by nutrition interaction where ASe-CON had less (P = 0.007) vascular area than HSe-CON ewes. In ewes necropsied at d 20 of lactation, the number of alveoli per area was decreased (P <= 0.05) in RES compared to CON and EXC-fed ewes. CONCLUSIONS: Results of this study indicate that proper maternal nutritional plane during gestation is important for mammary gland development, even out to d 20 of lactation. PMID- 23442443 TI - Effect of statistical fluctuation in Monte Carlo based photon beam dose calculation on gamma index evaluation. AB - The gamma-index test has been commonly adopted to quantify the degree of agreement between a reference dose distribution and an evaluation dose distribution. Monte Carlo (MC) simulation has been widely used for the radiotherapy dose calculation for both clinical and research purposes. The goal of this work is to investigate both theoretically and experimentally the impact of the MC statistical fluctuation on the gamma-index test when the fluctuation exists in the reference, the evaluation, or both dose distributions. To the first order approximation, we theoretically demonstrated in a simplified model that the statistical fluctuation tends to overestimate gamma-index values when existing in the reference dose distribution and underestimate gamma-index values when existing in the evaluation dose distribution given the original gamma-index is relatively large for the statistical fluctuation. Our numerical experiments using realistic clinical photon radiation therapy cases have shown that (1) when performing a gamma-index test between an MC reference dose and a non-MC evaluation dose, the average gamma-index is overestimated and the gamma passing rate decreases with the increase of the statistical noise level in the reference dose; (2) when performing a gamma-index test between a non-MC reference dose and an MC evaluation dose, the average gamma-index is underestimated when they are within the clinically relevant range and the gamma passing rate increases with the increase of the statistical noise level in the evaluation dose; (3) when performing a gamma-index test between an MC reference dose and an MC evaluation dose, the gamma passing rate is overestimated due to the statistical noise in the evaluation dose and underestimated due to the statistical noise in the reference dose. We conclude that the gamma-index test should be used with caution when comparing dose distributions computed with MC simulation. PMID- 23442442 TI - L-Arginine enhances cell proliferation and reduces apoptosis in human endometrial RL95-2 cells. AB - BACKGROUND: L-arginine is considered to be one of the most versatile amino acids due to the fact that it serves as a precursor for many important molecules in cellular physiology. When supplemented in the diet, L-arginine can increase the number of implantation sites in mice and rats, suggesting an effect at the level of the endometrium. To this end, this study determined the effect that L-arginine has on apoptosis and cell proliferation in human endometrial RL95-2 cells. RESULTS: L-arginine at physiological (200 micromol/L) and supra-physiological (800 micromol/L) concentrations increased cell proliferation at days 2 and 4 post treatment with a dose-dependent effect being observed on day 2. Additionally, inhibition of nitric oxide (NO) synthase and arginase, which are responsible for the conversion of L-arginine to NO and polyamines, respectively, reduced the proliferative effect of L-arginine. L-arginine also decreased the proportion of cells with TUNEL positive nuclei and increased the ratio of cells with healthy mitochondria compared to cells with a disrupted mitochondrial membrane potential, indicating that L-arginine prevents mitochondrial mediated apoptosis in endometrial RL95-2 cells. Furthermore, exposure to L-arginine did not affect total BAD protein expression; however, L-arginine increased the abundance of phosphorylated BAD protein. CONCLUSIONS: In summary, L-arginine added to the culture media at physiological (200 micromol/L) and supraphysiological concentrations (800 micromol/L) enhanced endometrial RL95-2 cell proliferation through mechanisms mediated by NO and polyamine biosynthesis. In addition, L arginine reduced endometrial RL95-2 mitochondrial mediated apoptosis through increased phosphorylation of BAD protein. PMID- 23442444 TI - Drug-induced immune-mediated thrombocytopenia secondary to sunitinib in a patient with metastatic renal cell carcinoma: a case report. AB - INTRODUCTION: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for first line treatment for metastatic renal cell carcinoma and imatinib-resistant metastatic gastrointestinal stromal tumors. Sunitinib administration can cause myelosuppression resulting in neutropenia and thrombocytopenia. Here we present the case of a patient with metastatic renal cell carcinoma who developed sunitinib-induced immune-mediated thrombocytopenia and who was treated with withdrawal of sunitinib and administration of intravenous immunoglobulin and steroids. CASE PRESENTATION: This case report describes a 70-year-old Aboriginal Australian with a diagnosis of metastatic renal cell carcinoma. Three weeks after the initiation of sunitinib he developed epistaxis and was admitted with thrombocytopenia (platelets 7 * 109/L) which was found to be refractory to platelet transfusion. Sunitinib was stopped and he was treated with intravenous immunoglobulin and steroids. His platelet count rapidly improved and returned to baseline in three weeks. Only two cases of sunitinib induced immune-mediated thrombocytopenia have been described in the literature. CONCLUSION: Clinicians should have a high index of suspicion for the potential of immune-mediated thrombocytopenia after the initiation of multi-targeted tyrosine kinase inhibitors such as sunitinib. This is a diagnosis of exclusion and can be safely treated by drug withdrawal. PMID- 23442445 TI - Protein engineering of nirobenzene dioxygenase for enantioselective synthesis of chiral sulfoxides. AB - Nitrobenzene dioxygenase (NBDO) from Comamonas sp. is shown here to perform enantioselective oxidation of aromatic sulfides. Several para-substituted alkyl aryl sulfides were examined and it was found that the activity of the enzyme is dependent on the size of the substrate. Saturation mutagenesis was performed on different residues in the active site in order to improve activity and selectivity. Mutagenesis at position 258 in the alpha-hydroxylase subunit of NBDO improved both activity and enantioselectivity. Substitutions in position 293 improved the activity on all substrates and had diverse influence on enantioselectivity. Mutagenesis in position 207 provided two interesting variants, V207I and V207A, with opposite enantioselectivities. Furthermore, combining two favorable mutations, N258A and F293H, provided an improved variant with both higher activity (5.20 +/- 0.01, 2.12 +/- 0.21, 2.64 +/- 0.14 and 4.01 +/- 0.34 nmol min(-1) mg protein(-1) on thioanisole, ptolyl, Cl-thioanisole and Br-thioanisole, respectively, which is 1.7, 4.6, 7.1 and 26.7-fold compared with wild type) and improved enantioselectivity (e.g. 67% enantiomeric excess for Cl thioanisole vs. 5% for wild type). Molecular docking and active site volume calculations were used to correlate between the structure of the substrates and the function of the enzymes. The results from this work suggest that the location of pro-chiral sulfides in the active site is coordinated by hydrophobic interactions and by steric considerations, which in turn influences the activity and enantioselectivity of NBDO. PMID- 23442446 TI - Redeeming qualities: exploring factors that affect women's use of reproductive health vouchers in Cambodia. AB - BACKGROUND: One approach to delivering healthcare in developing countries is through voucher programs, where vouchers are distributed to a specific population for free or subsidized health care. Recent evaluations suggest that vouchers have the potential to extend coverage of priority health services to the poor in developing countries. In Cambodia, a reproductive health voucher program was implemented in January 2011. This study aims to explore women's early experiences accessing health services with their vouchers at accredited clinics. METHODS: This qualitative exploratory study used focus group methodology to gather information from five groups of older (>25 years) and four groups of younger (18 25 years) women who were eligible for the voucher program in three rural provinces. Focus groups were digitally recorded, transcribed and translated from Khmer into English. Data analysis was an iterative process, which comprised of open coding to find commonalities that reflected categories or themes and axial coding to relate initial themes to each other. Next, a basic framework for analysis was formed by integrating the themes into the framework. RESULTS: Two overarching themes were identified in the data: 1) factors that facilitate voucher use and 2) factors that inhibit voucher use. Within each of these themes, three subthemes were identified: 1) pre-existing factors, 2) distribution factors, and 3) redemption factors. Overall, women expressed positive feelings towards the voucher program, while several areas for program improvement were identified including the importance of addressing pre-existing demand-side barriers to using reproductive health services, the need for more comprehensive counselling during voucher distribution, and the persistent cost of unofficial payments expected by midwives after delivery irrespective of voucher use. CONCLUSIONS: Early information from program beneficiaries can lead to timely and responsive changes that can help to maximize program success. This study highlights the importance of tailoring voucher programs to specific community needs, a strategy that can lead to better program uptake. PMID- 23442447 TI - Environmental scanning electron microscopy technique to identify asbestos phases inside ferruginous bodies. AB - Ferruginous bodies observed in lungs of patients affected by mesothelioma, asbestosis, and pulmonary carcinoma are important to relate the illness to exposure, environmental or occupational, to asbestos. Identification of the inorganic phase constituting the core of the ferruginous bodies, formed around asbestos but also around phases different from asbestos, is essential for legal purposes. Environmental scanning electron microscopy/energy dispersive spectroscopy was used to identify the fibrous mineral phase in the core of ferruginous bodies observed directly in thin sections of tissue, without digestion of the biological matrix. Spectra were taken with sequential analyses along a line crossing the core of the ferruginous bodies. By comparing the spectra taken near to and far from the core, the chemical elements that make up the core could be identified. PMID- 23442448 TI - "I have to do what I believe": Sudanese women's beliefs and resistance to hegemonic practices at home and during experiences of maternity care in Canada. AB - BACKGROUND: Evidence suggests that immigrant women having different ethnocultural backgrounds than those dominant in the host country have difficulty during their access to and reception of maternity care services, but little knowledge exists on how factors such as ethnic group and cultural beliefs intersect and influence health care access and outcomes. Amongst immigrant populations in Canada, refugee women are one of the most vulnerable groups and pregnant women with immediate needs for health care services may be at higher risk of health problems. This paper describes findings from the qualitative dimension of a mixed-methodological study. METHODS: A focused ethnographic approach was conducted in 2010 with Sudanese women living in an urban Canadian city. Focus group interviews were conducted to map out the experiences of these women in maternity care, particularly with respect to the challenges faced when attempting to use health care services. RESULTS: Twelve women (mean age 36.6 yrs) having experience using maternity services in Canada within the past two years participated. The findings revealed that there are many beliefs that impact upon behaviours and perceptions during the perinatal period. Traditionally, the women mostly avoid anything that they believe could harm themselves or their babies. Pregnancy and delivery were strongly believed to be natural events without need for special attention or intervention. Furthermore, the sub-Saharan culture supports the dominance of the family by males and the ideology of patriarchy. Pregnancy and birth are events reflecting a certain empowerment for women, and the women tend to exert control in ways that may or may not be respected by their husbands. Individual choices are often made to foster self and outward-perceptions of managing one's affairs with strength. CONCLUSION: In today's multicultural society there is a strong need to avert misunderstandings, and perhaps harm, through facilitating cultural awareness and competency of care rather than misinterpretations of resistance to care. PMID- 23442449 TI - Development and characterization of the replicon system of Japanese encephalitis live vaccine virus SA14-14-2. AB - BACKGROUND: Viral self-replicating sub-genomic replicons represent a powerful tool for studying viral genome replication, antiviral screening and chimeric vaccine development. Many kinds of flavivirus replicons have been developed with broad applications. FINDINGS: The replicon system of JEV live vaccine strain SA14 14-2 was successfully developed in this study. Two kinds of replicons that express enhanced green fluorescent protein (EGFP) and Renilla luciferase (R.luc) were constructed under the control of SP6 promoter, respectively. Robust EGFP and R.luc signals could be detected in the replicon-transfected BHK-21 cells. Furthermore, the potential effects of selected amino acids in the C-terminal of envelope protein on replication were characterized using the replicon system. CONCLUSIONS: Our results provide a useful platform not only for the study of JEV replication, but also for antiviral screening and chimeric vaccine development. PMID- 23442451 TI - Is there something called adult onset atopic dermatitis in India? PMID- 23442450 TI - The role of interactions between bacterial chaperone, aspartate aminotransferase, and viral protein during virus infection in high temperature environment: the interactions between bacterium and virus proteins. AB - BACKGROUND: The life cycle of a bacteriophage has tightly programmed steps to help virus infect its host through the interactions between the bacteriophage and its host proteins. However, bacteriophage-host protein interactions in high temperature environment remain poorly understood. To address this issue, the protein interaction between the thermophilic bacteriophage GVE2 and its host thermophilic Geobacillus sp. E263 from a deep-sea hydrothermal vent was characterized. RESULTS: This investigation showed that the host's aspartate aminotransferase (AST), chaperone GroEL, and viral capsid protein VP371 formed a linearly interacted complex. The results indicated that the VP371-GroEL-AST complex were up-regulated and co-localized in the GVE2 infection of Geobacillus sp. E263. CONCLUSIONS: As reported, the VP371 is a capsid protein of GVE2 and the host AST is essential for the GVE2 infection. Therefore, our study revealed that the phage could use the anti-stress system of its host to protect the virus reproduction in a high-temperature environment for the first time. PMID- 23442452 TI - Through the looking-glass. PMID- 23442453 TI - Insect bite reactions. AB - Insects are a class of living creatures within the arthropods. Insect bite reactions are commonly seen in clinical practice. The present review touches upon the medically important insects and their places in the classification, the sparse literature on the epidemiology of insect bites in India, and different variables influencing the susceptibility of an individual to insect bites. Clinical features of mosquito bites, hypersensitivity to mosquito bites Epstein Barr virus NK (HMB-EBV-NK) disease, eruptive pseudoangiomatosis, Skeeter syndrome, papular pruritic eruption of HIV/AIDS, and clinical features produced by bed bugs, Mexican chicken bugs, assassin bugs, kissing bugs, fleas, black flies, Blandford flies, louse flies, tsetse flies, midges, and thrips are discussed. Brief account is presented of the immunogenic components of mosquito and bed bug saliva. Papular urticaria is discussed including its epidemiology, the 5 stages of skin reaction, the SCRATCH principle as an aid in diagnosis, and the recent evidence supporting participation of types I, III, and IV hypersensitivity reactions in its causation is summarized. Recent developments in the treatment of pediculosis capitis including spinosad 0.9% suspension, benzyl alcohol 5% lotion, dimethicone 4% lotion, isopropyl myristate 50% rinse, and other suffocants are discussed within the context of evidence derived from randomized controlled trials and key findings of a recent systematic review. We also touch upon a non-chemical treatment of head lice and the ineffectiveness of egg-loosening products. Knockdown resistance (kdr) as the genetic mechanism making the lice nerves insensitive to permethrin is discussed along with the surprising contrary clinical evidence from Europe about efficacy of permethrin in children with head lice carrying kdr-like gene. The review also presents a brief account of insects as vectors of diseases and ends with discussion of prevention of insect bites and some serious adverse effects of mosquito coil smoke. PMID- 23442455 TI - Hand, foot, and mouth disease: current scenario and Indian perspective. AB - Hand, foot, and mouth disease (HFMD), first reported in New Zealand in 1957 is caused by Coxsackievirus A16 (CVA16) and human enterovirus 71 (HEV71) and occasionally by Coxsackievirus A4-A7, A9, A10, B1-B3, and B5. This is characterized by erythematous papulo vesicular eruptions over hand, feet, perioral area, knees, buttocks and also intraorally mostly in the children. HFMD has been known for its self limiting course. Only small scale outbreaks have been reported from United States, Europe, Australia, Japan and Brazil for the first few decades. However, since 1997 the disease has conspicuously changed its behavior as noted in different Southeast Asian countries. There was sharp rise in incidence, severity, complications and even fatal outcomes that were almost unseen before that period. Following the near complete eradication of poliovirus, HEV71, the non-polio enterovirus, may become the greatest threat to cause significant neurological complications. This adds to the fact that effective therapy or vaccine is still a far reaching goal. There are reports of disease activity in different corners of India since 2004. Although of milder degree, continuous progress to affect larger parts of the country may indicate vulnerability of India from possible future fatal outbreaks. Low level of awareness among the health care providers may prove critical. PMID- 23442456 TI - Psychodermatology: a comprehensive review. AB - Psychodermatology is an interesting domain of dermatology that overlaps with psychiatry. This arena in dermatology has received limited diligence, partly due to lack of training in this realm. We present here a comprehensive review of salient features and treatment updates in primary psychiatric dermatoses and have also discussed the role of psyche in psychophysiological cutaneous disorders. Secondary psychiatric morbidity is relatively common among patients visiting the dermatologists but often overlooked and uncared for. Dermatologist should be able to initiate basic pharmacotherapy, should be knowledgeable about various non pharmacological treatments and know the right time to refer the patient to the psychiatrist. Awareness and pertinent treatment of psychodermatological disorders among dermatologists will lead to a more holistic treatment approach and better prognosis in this unique group of patients. PMID- 23442457 TI - Efficacy and safety of erbium-doped yttrium aluminium garnet fractional resurfacing laser for treatment of facial acne scars. AB - BACKGROUND: Treatment of acne scars with ablative fractional laser resurfacing has given good improvement. But, data on Indian skin are limited. A study comparing qualitative, quantitative, and subjective assessments is also lacking. AIM: Our aim was to assess the improvement of facial acne scars with Erbium-doped Yttrium Aluminium Garnet (Er:YAG) 2940 nm fractional laser resurfacing and its adverse effects in 25 patients at a tertiary care teaching hospital. METHODS: All 25 patients received four treatment sessions with Er:YAG fractional laser at 1 month interval. The laser parameters were kept constant for each of the four sittings in all patients. Qualitative and quantitative assessments were done using Goodman and Barron grading. Subjective assessment in percentage of improvement was also documented 1 month after each session. Photographs were taken before each treatment session and 1 month after the final session. Two unbiased dermatologists performed independent clinical assessments by comparing the photographs. The kappa statistics was used to monitor the agreement between the dermatologists and patients. RESULTS: Most patients (96%) showed atleast fair improvement. Rolling and superficial box scars showed higher significant improvement when compared with ice pick and deep box scars. Patient's satisfaction of improvement was higher when compared to physician's observations. No serious adverse effects were noted with exacerbation of acne lesions forming the majority. CONCLUSION: Ablative fractional photothermolysis is both effective and safe treatment for atrophic acne scars in Indian skin.Precise evaluation of acne scar treatment can be done by taking consistent digital photographs. PMID- 23442458 TI - Behcet's disease in India: a dermatological perspective. AB - BACKGROUND: Behcet's disease (BD) is a chronic, recurrent, multi-system inflammatory disorder involving mucocutaneous (MC), ocular, intestinal, articular, vascular, urogenital and neurologic systems. BD occurs with a high prevalence in the Mediterranean population. There is scarcity of clinical data on BD from India with only three case series in the last two decades. AIMS: To study demographic profile, clinical manifestations and treatment outcome of patients with BD presenting to the dermatologic clinic in a tertiary hospital in north India. METHODS: Prospective analysis of all patients diagnosed to have BD between 1997 to 2011. RESULT: Twenty nine patients were diagnosed to have BD. The disease had a female preponderance (M:F = 1:3.8) with a mean age of disease onset of 27.4 (range 16-61) years. The prevalence of various MC and systemic manifestations are as follows: oral aphthae (100%), genital aphthae (93.1%), erythema nodosum (62%), papulopustular and acneiform lesions (31%), articular involvement (68.9%), ocular involvement (31%) and gastrointestinal (GI) involvement (3.4%) . Pathergy test positivity was observed in 31%. The treatment comprised of colchicine (16/29 patients), dapsone (7/29), dapsone with pentoxiphylline (3/29), systemic steroid (2/29), systemic steroid with methotrexate (1/29). Colchicine was effective and well tolerated in all patients. CONCLUSION: The disease occurs in a much milder form in India and is primarily mucocutaneous and arthritic. A high index of suspicion in patients with MC lesions may result in early diagnosis, management and prevention of complications of BD. We suggest colchicine as an effective and safe therapeutic option for MC and joint involvement. PMID- 23442459 TI - Vitiligo impact scale: an instrument to assess the psychosocial burden of vitiligo. AB - BACKGROUND: Vitiligo is a disease that significantly impairs quality of life. Previous studies have shown that vitiligo has an impact that may not correlate with the size and extent of depigmentation, indicating a need for an independent measure of the psychosocial burden. AIMS: To develop a rating scale to assess the psychosocial impact of vitiligo. METHODS: The study was undertaken in three broad phases: item generation, pre- and pilot testing, and test administration. Items were generated largely from a qualitative study using semi-structured interviews of patients. Face and content validity were assessed through pre- and pilot testing in 80 patients and the final version was administered to 100 patients who also received the Dermatology Life Quality Index (DLQI) and the Skindex-16. Each patient also underwent a physician global assessment (PGA) of the impact of vitiligo. Test-retest reliability was assessed in 20 patients. RESULTS: Of 72 items initially generated for the scale, 27 were retained in the final version. Subjects were able to comprehend the items and took about 5-7 min to complete the instrument. The scale was internally consistent (Cronbach's alpha = 0.85). Scores on the scale correlated moderately well with the DLQI and the Skindex (Spearman rank correlation: 0.51 and 0.65, respectively). The scale was able to discriminate between patients having mild and those having moderate and severe impact as assessed by PGA. The test-retest reliability coefficient (Spearman rank correlation) was 0.80. CONCLUSION: The Vitiligo Impact Scale appears to be a valid measure of the psychosocial impact of vitiligo and this instrument may be useful both in the clinic and in clinical trials. PMID- 23442461 TI - Morphometric study of microvessels, epidermal characteristics and inflammation in psoriasis vulgaris with their correlations. AB - BACKGROUND: Vascular proliferation, inflammation and epidermal changes are important features in the pathogenesis of psoriasis. AIMS: In this study we attempted an objective evaluation of these parameters using morphometry. METHODS: Inflammation, microvessels and epidermal parameters were assessed in 50 newly diagnosed cases of psoriasis vulgaris (between 01 Nov 2008 and 31 Oct 2011) by morphometry. Parameters studied were microvessel density, microvessel caliber, inflammatory cell density in dermis, ratio between inner and outer epidermal length, maximum epidermal thickness, minimum epidermal thickness and difference between maximum epidermal thickness and minimum epidermal thickness. RESULTS: Microvessel caliber showed moderate correlation (r = 0.645) and microvessel density, weak correlation (r = 0.226) with inflammatory cell density in dermis. Both these parameters also showed mild positive correlation with "ratio between inner and outer epidermal length". All parameters except minimum epidermal thickness showed mild positive correlation with inflammatory cell density in dermis. CONCLUSION: All microvessels and epidermal parameters showed positive correlation with dermal inflammation; and epidermal parameters exhibited positive correlation with micro-vascular dilation. It is likely that inflammation is a key factor in the pathogenesis of psoriasis. PMID- 23442460 TI - The frequency of osteoporosis in patients with pemphigus vulgaris on treatment. AB - BACKGROUND: Pemphigus vulgaris was almost fatal before the advent of glucocorticoids. Unfortunately, the high doses and prolonged administration of glucocorticoids, which often needed to control the disease, result in numerous adverse effects many of which are serious. AIMS: To evaluate the patients with pemphigus vulgaris on treatment in respect of osteoporosis and to compare the frequency of osteoporosis in these patients with the healthy ones. METHODS: The study consisted of 40 patients with pemphigus vulgaris and 34 healthy controls. Bone mineral density measurements were obtained by dual- energy X-ray absorptiometry. Blood serum, bone parameters, and biochemical hormonal measurements were examined in both groups. RESULTS: When the bone mineral density values of patients with pemphigus vulgaris were compared with those of the control group, there was no significant difference between hip bone mineral density values, while lumbar region T and Z scores were found significantly low in the patient group (p = 0.034 and p = 0.006, respectively). Osteoporosis, osteopenia, and normal dual-energy X-ray absorptiometry rates in the patient group were found to be 32.5%, 32.5%, and 35%, respectively. These rates were found to be 18%, 23%, and 59% in control group, respectively. There were more fractures in the patient group and the difference was statistically significant (p = 0.004). CONCLUSION: An increase in osteoporosis frequency and secondary fracture to osteoporosis in the patients with pemphigus vulgaris was detected. PMID- 23442462 TI - Auto-amputation of penis due to carcinoma: still a threat in the era of modern medicine: report of two cases. AB - Incidence of penile carcinoma is decreasing worldwide. Nevertheless, the incidence of penile cancer is still significant in various tropical countries, and it often presents in advanced stage. We report two unique cases of penile auto-amputation due to advanced cancer and review relevant literature. Both the patients presented with ulcerative lesion replacing penile base following automatic sloughing of the whole penis and voiding dysfunction. In addition, the first patient had metastatic inguinal lymph nodes. Supra-pubic urinary diversion was the initial management in both the patients. The first patient was treated with combined chemo-radiation, but he succumbed to death following two cycles of chemotherapy. The second patient was successfully treated with total penectomy and perineal urethrostomy. He recovered well but was lost to follow-up. PMID- 23442463 TI - Bowen's disease on finger: a diagnostic and therapeutic challenge. AB - Bowen's disease commonly presents as a solitary asymptomatic plaque involving head and neck region or lower limbs. We present a case of a sixty seven-year-old man with an itchy, oozy, crusted solitary plaque on the right ring finger of eighteen months duration with histopathology consistent with Bowen's disease. The lesion was initially treated with topical 5% imiquimod but due to relapse and inadequate response to a second course, complete surgical excision followed by full thickness skin grafting was done. Recurrence after about 6 months in the form of a small papule adjacent to the initial site was also treated with excision. This report highlights the potential of Bowen's disease to mimic more common dermatoses and a high index of suspicion, supported by histopathology, is required to diagnose and treat it without delay, which in turn may require a multimodality approach. We also reviewed the current literature on the same. PMID- 23442464 TI - Tattoo reactions--an epidemic on the surge: a report of 3 cases. AB - Tattooing has been practiced in India since ancient era. It has tremendous religious and spiritual significance. In addition, tattooing for cosmetic purposes has become quite popular in recent times. With this increasing trend, there is also an increased risk of adverse effects. Here, we have described two cases of lichenoid reaction developing to red ink in double- colored tattoos and a case of sarcoidal reaction to green tattoo. PMID- 23442465 TI - Epidermolysis bullosa pruriginosa: a rare presentation with asymptomatic lesions. AB - Epidermolysis bullosa pruriginosa (EBP) is a subtype of dominant dystrophic epidermolysis bullosa (DDEB) and is clinically characterized by pruritic lichenified plaques or prurigo-like lesions with violaceous linear scarring. Pruritus has always been described as one of the most striking features in EBP. Mutations in COL7A gene, especially in the glycine residue, have been shown to cause this form of DDEB. In this report, we describe a north Indian familial clustering of three cases of EBP, spread across two generations, presenting with hypertrophic lichenoid cutaneous lesions, which were completely asymptomatic. Clinical and histopathological analysis favored the diagnosis of EBP in all three cases. They are being reported for their unusual asymptomatic presentation. PMID- 23442466 TI - Erythema elevatum diutinum. PMID- 23442467 TI - The comparative efficacy and safety of azathioprine vs methotrexate as steroid sparing agent in the treatment of airborne-contact dermatitis due to Parthenium. PMID- 23442468 TI - Comparison of direct microscopic methods using potassium hydroxide, periodic acid Schiff, and calcofluor white with culture in the diagnosis of onychomycosis. PMID- 23442469 TI - Treatment of nevus spilus with Q switched Nd:YAG laser. PMID- 23442471 TI - Using blue gel pen to mark freckles during Q-switched laser therapy. PMID- 23442470 TI - Six novel mutations of ATP2C1 identified in eight Chinese patients with Hailey Hailey disease. PMID- 23442472 TI - Papulonecrotic tuberculid at the site of tuberculin test in a patient with concomitant erythema induratum and papulonecrotic tuberculid. PMID- 23442473 TI - Multiple cutaneous reticulohistiocytomas along the lines of Blaschko associated with lichen striatus. PMID- 23442474 TI - Xanthoma disseminatum: a red herring xanthomatosis. PMID- 23442475 TI - The "henna stone" myth. PMID- 23442477 TI - Intraneural granular cell tumor of the dorsal ramus of a thoracic nerve. PMID- 23442476 TI - Eruptive collagenoma. PMID- 23442478 TI - On the etiology and transmission of leprosy in nineteenth century Madras, India. PMID- 23442479 TI - Pregnancy and varicella infection: a resident's quest. PMID- 23442480 TI - Screening for skin diseases among primary school children in a rural area of Puducherry. PMID- 23442481 TI - Minimal erythema dose to targeted phototherapy in vitiligo patients in Indian skin. PMID- 23442482 TI - Acrodermatitis enteropathica in three siblings. PMID- 23442483 TI - Detection of the STS gene in a family with X-linked recessive ichthyosis. PMID- 23442485 TI - Superficial white onychomycosis due to Trichophyton rubrum in a two-year-old child. PMID- 23442484 TI - Late-onset acquired dermal melanocytosis on the hand of a Chinese woman. PMID- 23442486 TI - Bullous auto erythrocyte sensitization syndrome in alcohol dependence. PMID- 23442487 TI - Plica neuropathica (polonica): clinical and dermoscopic features. PMID- 23442488 TI - An unusual case of blue rubber bleb nevus syndrome with unilateral linear distribution. PMID- 23442489 TI - Achromatic atrophic macules and patches of upper extremities. PMID- 23442490 TI - Asymptomatic nodule on the scalp. PMID- 23442491 TI - Non-AIDS-defining cancers in New Orleans. AB - BACKGROUND: Non-AIDS-defining cancers in HIV-infected patients in the highly active antiretroviral therapy era have increased. To our knowledge a comprehensive review of non-AIDS-related malignancies in New Orleans has not yet been conducted. METHODS: Databases from main institutions in New Orleans were queried retrospectively for the years 2001 to 2011. The International Classification of Diseases, Ninth Revision codes were used to search for HIV infection and cancer comorbidity. RESULTS: A total of 16 patients were diagnosed with lung cancer (mean age 50 years) with 81% of the patients presenting with advanced stages. In all, 20 (mean age 47 years) were diagnosed with anal cancer, and 35% presented in late stages. In all, 14 patients (mean age 42 years) were diagnosed with Hodgkin Lymphoma, and 64% were diagnosed at late stage. A total of 5 women (mean age 44 years) were diagnosed with breast cancer with 40% of them presenting at late stage. CONCLUSION: Malignancies were diagnosed at late stages in the majority of the cases, presented with worse outcomes, and had higher recurrence rates. The role of HIV and other viruses (Epstein Barr virus, human papillomavirus) and the potential mechanisms or pathways of oncogene activation also need to be clarified. PMID- 23442492 TI - Religion and HIV/AIDS stigma in Puerto Rico: a cultural challenge for training future physicians. AB - HIV/AIDS stigma continues to be a challenge for HIV prevention and treatment. When health professionals manifest stigma it can limit access to quality treatment. With an ever-growing epidemic among Latinos, including Puerto Ricans living on the Caribbean Island, the social and structural factors that foster HIV/AIDS stigma need to be understood. In this study, we documented the association of religion with HIV/AIDS stigma in a sample of medical students in Puerto Rico. Findings suggest that importance placed on religion, and participation in religious activities, is associated with HIV/AIDS stigma for this population. PMID- 23442493 TI - HIV status among patients with tuberculosis and HIV testing practices by Connecticut health care providers. AB - Knowing the human immunodeficiency virus (HIV) status of persons infected with Mycobacterium tuberculosis is important for individual treatment and preventing transmission. This evaluation analyzed surveillance data and surveyed health care providers who care for patients with HIV and tuberculosis (TB) to understand the factors contributing to suboptimal levels of Connecticut patients with TB having a known HIV status. During 2008 to 2010, 208 (76.2%) of 273 patients had a known HIV status; 12 (5.8%) were HIV-positive. Patients who were more likely to have a known HIV status were younger (40.5 vs 54.6 years, P < .001) or received care in a TB clinic (risk ratio, 1.26; 95% confidence interval, 1.12-1.42). Among 77 providers, 48 (62.3%) completed the survey, 42 (87.5%) reported routinely offering HIV testing to patients with TB, and 26 (54.2%) reported routinely offering HIV testing to patients with latent TB infection (LTBI). We conclude that interventions for improving HIV testing should focus on non-TB clinic providers and patients with LTBI. PMID- 23442494 TI - Drug-induced lupus associated with rifabutin: a literature review. AB - Drug-induced lupus (DIL) is a rare adverse reaction to medications with features resembling idiopathic systemic lupus erythromatosis. Rifabutin/rifamycins have only rarely been reported as a cause of DIL, and no cases have been reported in blacks. A 55-year-old African American woman with HIV presented with severe generalized arthralgias and recurrent oral ulcers while receiving treatment for tuberculous meningitis. Arthralgias, which began in her knees after 5 weeks of antituberculous therapy, progressed to involve the joints in the ankles, wrists, and hands. She had no associated fever or rash. When she had these symptoms her antinuclear antibody (ANA) was 1:1280 homogenous pattern, antidouble stranded DNA was negative, antihistone antibody was strongly positive, anti-smith and antiribonucleoprotein (anti-RNP) were negative. Her symptoms resolved within 2 months of stopping rifabutin while continuing other antituberculous medications and her ANA titer started to decrease. We review the existing literature on this subject. PMID- 23442496 TI - Law and pediatric HIV testing: realizing the right to health in Kenya. AB - Realization of the right to health occurs along a continuum including national ratification of international treaties such as the Convention on the Rights of the Child, passage of domestic laws and policies that may specify modes of implementation and enforcement such as Kenya's Constitution and HIV and AIDS Prevention and Control Act, and actual implementation of domestic laws and policies such as through the regulation and delivery of health services. The stages heuristic theoretical framework describes the public policy continuum as consisting of marked stages: agenda setting, policy formulation, policy implementation, and evaluation. This case study illustrates the continuum in Kenya with regard to pediatric HIV testing. Kenya has made progress applying law, policy, and science to reduce vertical transmission of HIV and increase HIV testing of infants, although several challenges remain. Progress in policy implementation may reduce mother-to-child transmission and increase pediatric HIV testing. PMID- 23442495 TI - A qualitative analysis of the effects of depression and antidepressants on physical and work functioning among antiretroviral therapy clients in Uganda. AB - Depression is common among people living with HIV/AIDS in sub-Saharan Africa. Yet, little is known about how depression influences physical health and socioeconomic well-being in the context of antiretroviral therapy (ART). Semistructured interviews with 40 adult HIV clients receiving ART in Uganda were conducted to assess experiences prior to and after HIV diagnosis and initiation of ART. Content analysis revealed themes that were suggestive of the following patterns: (1) functioning decreased after patients were diagnosed with HIV, but improved following ART, (2) depression is associated with lower physical health functioning and work status levels after both HIV diagnosis and ART, and (3) antidepressant medication is associated with better functioning compared with patients with depression not receiving depression treatment. These findings suggest that depression plays a role in the deleterious effects of HIV on functioning, and that antidepressant treatment provided alongside ART may serve to help individuals regain functioning, particularly employment. These findings highlight the potential value of integrating depression treatment into HIV care. PMID- 23442497 TI - Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. AB - BACKGROUND: Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics. METHODS: This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics. RESULTS: Eosinophilic (>=3%) and neutrophilic (>=76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia >=3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen's kappa coefficient of 0.59 (p < 0.0001). ROC curves showed a cut-off value of 220/mm3 (AUC = 0.79, p < 0.0001) or 3% (AUC = 0.81, p < 0.0001) for blood eosinophils to identify sputum eosinophilia >=3%. Independent predictors of sputum neutrophilia were advanced age and high FRC but not blood neutrophil count. CONCLUSION: Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils. PMID- 23442498 TI - Heparanase induced by advanced glycation end products (AGEs) promotes macrophage migration involving RAGE and PI3K/AKT pathway. AB - BACKGROUND: Advanced glycation end products (AGEs), inflammatory-associated macrophage migration and accumulation are crucial for initiation and progression of diabetic vascular complication. Enzymatic activity of heparanase (HPA) is implicated strongly in dissemination of metastatic tumor cells and cells of the immune system. In addition, HPA enhances the phosphorylation of selected signaling molecules including AKT pathway independent of enzymatic activity. However, virtually nothing is presently known the role of HPA during macrophage migration exposed to AGEs involving signal pathway. METHODS: These studies were carried out in Ana-1 macrophages. Macrophage viability was measured by MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. HPA and AKT protein expression in macrophages are analysed by Western blotting and HPA mRNA expression by real time quantitative RT-PCR. Release of HPA was determined by ELISA. Macrophage migration was assessed by Transwell assays. RESULTS: HPA protein and mRNA were found to be increased significantly in AGEs-treated macrophages. Pretreatment with anti-HPA antibody which recognizes the nonenzymatic terminal of HPA prevented AGEs-induced AKT phosphorylation and macrophage migration. LY294002 (PI3k/AKT inhibitor) inhibited AGEs-induced macrophage migration. Furthermore, pretreatment with anti-receptor for advanced glycation end products (RAGE) antibody attenuated AGEs-induced HPA expression, AKT phosphorylation and macrophage migration. CONCLUSIONS: These data indicate that AGEs-induced macrophage migration is dependent on HPA involving RAGE-HPA PI3K/AKT pathway. The nonenzymatic activity of HPA may play a key role in AGEs induced macrophage migration associated with inflammation in diabetic vascular complication. PMID- 23442499 TI - Successful management of warfarin-exacerbated diffuse alveolar hemorrhage using an extracorporeal membrane oxygenation. AB - Although diffuse alveolar hemorrhage complicating warfarin therapy is rare, it generally has a worsening clinical course and can be a life threatening condition. A 56-year-old male who had undergone a pulmonary lobectomy for lung cancer 2 years before had received warfarin for about 5 months due to pulmonary vein thrombosis. The patient presented with severe dyspnea and had prolonged anticoagulation values. Chest X-ray and computed tomography revealed diffuse pulmonary consolidations, and bronchoalveolar lavage demonstrated diffuse alveolar hemorrhage. The reversal of anticoagulation was initiated, and extracorporeal membrane oxygenation was performed for refractory respiratory failure that did not improve despite maximal mechanical ventilatory support. The diffuse alveolar infiltrations resolved after 5 days, and we successfully weaned off both extracorporeal membrane oxygenation and mechanical ventilation. Herein we report the detailed course of a case that was successfully treated with extracorporeal membrane oxygenation as a bridge-to-recovery for warfarin- exacerbated diffuse alveolar hemorrhage. PMID- 23442500 TI - Clinical practice guidelines. PMID- 23442501 TI - Guidelines for privileging and credentialing physicians for sacrocolpopexy for pelvic organ prolapse. AB - Surgically complex procedures require a balance of knowledge, surgical skill, and experience with appropriate ongoing surgical volume and monitoring of outcomes and adverse events. Sacrocolpopexy has the potential to improve patient outcomes. These guidelines are meant to provide guidance for privileging and credentialing of physicians planning to implement or continue to use this procedure in their clinical practice. PMID- 23442502 TI - Factors associated with care seeking among women with accidental bowel leakage. AB - OBJECTIVE: The aim of this study was to characterize factors associated with care seeking among women with accidental bowel leakage (ABL). METHODS: A secondary analysis of 938 women with ABL identified in a community-based Internet survey of 5817 US women 45 years or older was performed. Demographics, medical history, incontinence severity, quality of life, coping, and care seeking were assessed using questions derived from validated questionnaires. Accidental bowel leakage was defined as at least 1 episode of stool leakage in the past year in the absence of acute diarrheal illness. Women with ABL were asked, "Have you ever talked to a physician about accidental leakage of stool and/or gas?" and were designated "care seekers" if they responded affirmatively. Factors associated with care seeking on univariate analysis with P < 0.1 were included in a multivariate model. RESULTS: The response rate overall was 85% (5817/6873) with 1096 women (19%) reporting ABL. Care-seeking data were available for 938 (86%). Of these, 85% were white, 6% were black/African American, 5% were of Hispanic/Latina/Spanish origin, and 4% other; median age was 55 to 59 years (range, 45 to 49, >75 years), and 87% were insured. Only 29% (268/938) of those with ABL sought care. Multivariate analysis demonstrated that care seekers were more likely to have a primary care physician (PCP), to have heard of ABL, and to have suffered longer with more severe leakage. CONCLUSIONS: More than two thirds of women with ABL do not seek care. Because those with a PCP and those who have heard of the condition are more likely to seek care, educating the public about ABL and encouraging establishment of care and communication with a PCP may decrease silent suffering. PMID- 23442503 TI - Two-year outcomes after vaginal prolapse reconstruction with mesh pelvic floor repair system. AB - OBJECTIVE: The aim of this study was to assess anatomical and functional outcomes 2 years after prolapse repair using vaginal mesh repair system. METHODS: Women enrolled in a 12-month observational study of outcomes after transvaginal mesh augmented prolapse repair were invited to participate in an extended follow-up. Subjects completed questionnaires assessing pelvic symptoms, quality of life, global satisfaction, and a pelvic examination for anatomical support and mesh complications. RESULTS: Of 118 eligible women, 85 enrolled, 82 provided subjective data at 24 months, and pelvic examination/Pelvic Organ Prolapse Quantification data are available from 79 women. Total, anterior, and posterior Prolift kits were used in 47 (55%), 25 (29%), and 13 (15%), respectively. At baseline, most of the women had stage III prolapse (75%), with the anterior compartment constituting the leading edge in 71% of subjects. At 24 months, Pelvic Organ Prolapse Quantification measures were significantly improved from baseline in all compartments, with 51 (65%) stage 0/I, 25 (31%) stage II, 3 (4%) and stage III (P < 0.001), as were quality of life scores (P < 0.001), with the exception of sexual function. Symptomatic prolapse was reported by 7 (8.5%) women, of which 4 demonstrated prolapse in the nonoperated compartment. Three subjects (4%) reported persistent pelvic pain. The 2-year mesh exposure incidence was at least 13% (11/85). The proportion reporting dyspareunia was 28.9% (13/45) and was unchanged from baseline. The median global satisfaction was 9.3 (range 2.0-10.0). CONCLUSIONS: Anatomical support, symptom relief, and satisfaction are high 24 months after mesh-augmented vaginal prolapse repair, although mesh exposure and new onset prolapse of the nonoperated compartment are not uncommon. PMID- 23442504 TI - Elevate anterior/apical: 12-month data showing safety and efficacy in surgical treatment of pelvic organ prolapse. AB - OBJECTIVE: This study aimed to assess the safety and efficacy of the Elevate Anterior/Apical transvaginal mesh procedure in pelvic organ prolapse (POP) repair at 12-months follow-up. METHODS: This prospective, multicenter, multinational study enrolled 142 patients experiencing anterior vaginal prolapse with or without apical descent (POP-Q >= stage II). Each patient received a single incision transvaginal polypropylene mesh implantation anchored to the sacrospinous ligaments bilaterally. Primary outcome was treatment success defined as POP-Q less than or equal to stage I at 1 year using the Last Failure Carried Forward method. Secondary outcomes included validated quality-of-life measures. Fourteen subjects who received a concomitant posterior apical support procedure were excluded from the analysis. RESULTS: Of the 128 subjects, 112 (87.5%) completed the 12-months follow-up. The mean age was 64.7 years. The anatomic success rate was 87.7% (95% confidence interval, 80.3%-93.1%) for the anterior compartment and 95.9% (95% confidence interval, 88.5%-99.1%) for the apical compartment. POP-Q measurements (Aa, Ba, and C) improved significantly (P < 0.001) with no significant changes to TVL (P = 0.331). Related adverse events reported at greater than 2% were mesh exposure (8; 6.3%), urinary tract infection (7; 5.5%), transient buttock pain (5; 3.9%), de novo stress incontinence (5; 3.9%), retention (5; 3.9%), dyspareunia (3; 3.2%), and hematoma (3; 2.3%). All quality-of-life scores significantly improved from baseline (P < 0.001). CONCLUSIONS: Twelve-month data show that Elevate Anterior/Apical support procedure completed through a single vaginal incision yields favorable objective and subjective outcomes. PMID- 23442505 TI - Transvaginal mesh surgery for pelvic organ prolapse: one-year outcome analysis. AB - OBJECTIVE: The aim of the study was to assess the role of Prolift + M (PP-PG) vaginal mesh surgery to correct uterovaginal prolapse not only from an anatomic but also a subjective (patient's) standpoint. METHODS: A prospective cohort of subjects treated with transvaginal mesh for prolapse between April 2009 and November 2010 was analyzed. A composite score that included subjective criteria of absence of a bothersome bulge and objective criteria based on Pelvic Organ Prolapse Quantification lower than stage II was used to assess treatment success. RESULTS: Transvaginal mesh was performed in 157 subjects (age, 64.7 +/- 11.6 years; body mass index, 28.5 +/- 4.8 kg/m) for pelvic organ prolapse. Five anterior mesh surgeries (3.2%), 48 posterior mesh surgeries (30.6%), and 104 total mesh surgeries (66.2%) were performed in subjects with stage II or greater degrees of prolapse. Stage II prolapse was noted in 44 subjects (28.0%), 91 subjects (58.0%) had stage III prolapse, and 22 subjects (14.0%) had stage IV prolapse. The mean follow-up was 13 months. Our composite success score was 88.1%. Pure anatomic success based on Pelvic Organ Prolapse Quantification lower than stage II was 94%. The mean operative time was 117.8 +/- 42.4 minutes. The mean intraoperative blood loss was 106.1 +/- 116.4 mL. There were 3 cases (2.2%) of mesh exposure in the vagina. There were no visceral injuries. The incidence of de novo dyspareunia was 6%. CONCLUSION: Transvaginal PP-PG mesh surgery is safe and effective with few postoperative morbidities. PMID- 23442506 TI - Communication between physicians and Spanish-speaking Latin American women with pelvic floor disorders: a cycle of misunderstanding? AB - OBJECTIVE: This study aimed to assess the effect of the initial visit with a specialist on disease understanding among Spanish-speaking women with pelvic floor disorders. METHODS: Spanish-speaking women with referrals suggestive of urinary incontinence (UI) and/or pelvic organ prolapse (POP) were recruited from public urogynecology clinics. Patients participated in a health literacy assessment and interview before and after their physician encounter. All interviews were analyzed using Grounded Theory qualitative methods. RESULTS: Twenty-seven women with POP (n = 6), UI (n = 11), and POP/UI (n = 10) were enrolled in this study. The mean age was 55.5 years, and most women had marginal levels of health literacy. From our qualitative analysis, 3 concepts emerged. First, was that patients had poor understanding of their diagnosis before and after the encounter regardless of how extensive the physician's explanation or level of Spanish-proficiency. Second, patients were overwhelmed with the amount of information given to them. Lastly, patients ultimately put their trust in the physician, relying on them for treatment recommendations. CONCLUSIONS: Our findings emphasize the difficulty Spanish-speaking women with low health literacy have in understanding information regarding pelvic floor disorders. In this specific population, the physician has a major role in influencing patients' treatment decisions and helping them overcome fears they may have about their condition. PMID- 23442507 TI - Variables impacting care-seeking for pelvic floor disorders among African American women. AB - OBJECTIVES: This study aimed to identify variables impacting care-seeking for pelvic floor disorders (PFDs) among (1) a general population of professional African American (AA) women and (2) professional AA women with prevalent PFD symptoms. METHODS: A cross-sectional survey of women registered for the 37th National Assembly of the Links, Inc, a volunteer service organization of professional AA women, was conducted. Our de-identified questionnaire addressed several domains including PFD symptoms, history of PFD diagnoses, attitudes regarding PFDs, and help-seeking. We asked what respondents would do if they experienced PFD symptoms and defined our outcome as the response "I would not seek care." Barriers were covariates associated with not seeking care. RESULTS: Of 568 questionnaires distributed, 362 (64%) with complete data were returned; 6.4% (23/362) of respondents reported they "would not seek care" if experiencing a PFD symptom. On logistic regression, attitude that PFDs are a normal part of aging [adjusted odds ratio (AOR), 5.56; 95% confidence interval (CI), 1.46-21.23] and concerns about insurance (AOR, 3.80; 95% CI, 1.39-10.33) were barriers to care-seeking, adjusting for health status and embarrassment about discussing PFDs.Thirty percent (110/362) of women reported having current PFD symptoms. In this subset, only 26% had accessed care. On logistic regression, prolapse symptoms in the previous 3 months and age 65 years or older were negatively associated with not seeking care (ie, were predictors of care-seeking) (AOR, 0.11; 95% CI, 0.02-0.67) and (AOR, 0.17; 95% CI, 0.03-0.85), respectively, adjusting for pelvic floor distress inventory scores. CONCLUSIONS: Among educated and insured AA women, attitudes about aging and insurance complexity are barriers to care-seeking for PFDs. In women with current PFD symptoms, recent prolapse symptoms and age 65 years or older were predictors of care-seeking. PMID- 23442508 TI - Attitudes toward hysterectomy in women undergoing evaluation for uterovaginal prolapse. AB - OBJECTIVES: To investigate attitudes toward hysterectomy in women seeking care for pelvic organ prolapse. METHODS: Two hundred twenty women referred for evaluation of prolapse without evidence of previous hysterectomy were surveyed with the Pelvic Organ Prolapse Distress Inventory; the Control Preferences Scale; and questions regarding patients' perception of the impact of hysterectomy on health, social life, and emotional well-being. Additional items presented hypothetical scenarios. Surveys were distributed in small batches until 100 responses were obtained from patients who met inclusion criteria. RESULTS: One hundred women with an intact uterus responded. Sixty percent indicated they would decline hysterectomy if presented with an equally efficacious alternative to a hysterectomy-based prolapse repair. The doctor's opinion, risk of surgical complications, and risk of malignancy were the most important factors in surgical decision making. CONCLUSIONS: Many women with prolapse prefer to retain their uterus at the time of surgery in the absence of a substantial benefit to hysterectomy. These findings should provide further impetus to investigate the efficacy of uterine-sparing procedures to help women make informed decisions regarding prolapse surgery. PMID- 23442509 TI - Prediction models for postpartum urinary and fecal incontinence in primiparous women. AB - OBJECTIVES: This study aimed to develop and internally validate a nomogram that facilitates decision making between patient and physician by predicting a woman's individual probability of developing urinary (UI) or fecal incontinence (FI) after her first delivery. METHODS: This study used Childbirth and Pelvic Symptoms Study data, which estimated the prevalence of postpartum UI and FI in primiparous women after vaginal or cesarean delivery. Two models were developed using antepartum variables, and 2 models were developed using antepartum plus labor and delivery variables. Urinary incontinence was defined by a response of leaking urine "sometimes" or "often" using the Medical, Epidemiological, and Social Aspects of Aging Questionnaire. Fecal incontinence was defined as any involuntary leakage of mucus, liquid, or solid stool using the Fecal Incontinence Severity Index. Logistic regression models allowing nonlinear effects were used and displayed as nomograms. Overall performance was assessed using the Brier score (zero equals perfect model) and concordance index (c-statistic). RESULTS: A total of 921 women enrolled in the Childbirth and Pelvic Symptoms Study, and 759 (82%) were interviewed by telephone 6 months postpartum. Two antepartum models were generated, which discriminated between women who will and will not develop UI (Brier score = 0.19, c-statistic = 0.69) and FI (Brier score = 0.10, c-statistic = 0.67) at 6 months and 2 models were generated (Brier score = 0.18, c-statistic= 0.68 and Brier score = 0.09, c-statistic = 0.68) for predicting UI and FI, respectively, for use after labor and delivery. CONCLUSIONS: These models yielded 4 nomograms that are accurate for generating individualized prognostic estimates of postpartum UI and FI and may facilitate decision making in the prevention of incontinence. PMID- 23442510 TI - Groin granuloma formation after midurethral sling. AB - BACKGROUND: Complications of midurethral transoburator slings include injuries directly associated with trocar placement or subsequent erosion of the mesh that is placed. While tissue reaction to implanted mesh material occurs, rarely does it produce clinical symptoms. We report a case of granuloma formation after a transobturator tape midurethral sling presenting as a groin mass. CASE: A 59-year old para 2 postmenopausal woman underwent uncomplicated placement of a transobturator tape midurethral sling concomitantly with prolapse repair. Two years later, she presented to her primary care physician complaining of a 1-cm groin mass. After failure of empiric treatment with antibiotics for a presumed infectious etiology, surgical resection of the mass was performed, which revealed granuloma formation surrounding the polypropylene mesh. CONCLUSION: Granuloma formation can occur years after placement of a midurethral transobturator sling. Whereas a rare complication, it is important for surgeons to consider this diagnosis during the workup of a groin mass. PMID- 23442511 TI - Labioplasty for hypertrophic labia minora contributing to recurrent urinary tract infections. AB - INTRODUCTION: Reduction labioplasty for hypertrophic labia minora is often performed for aesthetic reasons by cosmetic vaginal surgeons. However, hypertrophy of the labia minora can also result in significant morbidity because it causes physical discomfort during activity and interferes with the ability to maintain local hygiene and perform intermittent self-catheterization in certain patients. OBJECTIVES: We describe a case in which a commonly used technique for reduction labioplasty was performed on a patient who had difficulty performing intermittent catheterization and report on the aesthetic and functional outcomes. METHODS: A linear resection labioplasty was performed in a 13-year-old girl who was having increasing difficulty performing intermittent self-catheterization because of redundant labial tissue. She was also developing frequent recurrent urinary tract infections thought to be secondary to difficulty maintaining local hygiene and reduced compliance with her intermittent catheterization regimen. RESULTS: An excellent cosmetic and functional result was achieved with the procedure. Comparison of preoperative and postoperative photographs demonstrates the extent of the reduction labioplasty. The patient has not had any more difficulty with catheterization or recurrent urinary tract infections in 30 months of follow-up. CONCLUSIONS: Reduction labioplasty is indicated for hypertrophic labia minora for more than aesthetic reasons. We describe a case in which the procedure allowed the patient to more easily perform intermittent catheterization and helped eliminate her recurrent urinary tract infections. PMID- 23442513 TI - Biomechanical evaluation of the craniovertebral junction after anterior unilateral condylectomy: implications for endoscopic endonasal approaches to the cranial base. AB - BACKGROUND: : Endoscopic endonasal approaches to the craniovertebral junction and clivus, which are increasingly performed for ventral skull base pathology, may require disruption of the occipitocondylar joint. OBJECTIVE: : To study the biomechanical implications at the craniovertebral junction of progressive unilateral condylectomy as would be performed through an endonasal exposure. METHODS: : Seven upper cervical human cadaveric specimens (C0-C2) underwent nondestructive biomechanical flexibility testing during flexion-extension, axial rotation, and lateral bending at C0-C1 and C1-C2. Each specimen was tested intact, after an inferior one-third clivectomy, and after stepwise unilateral condylectomy with an anterior approach. Angular range of motion (ROM), lax zone, and stiff zone were determined and compared with the intact state. RESULTS: : At C0-C1, mobility during flexion-extension and axial rotation increased significantly with progressive condylectomy. ROM increased from 14.3 +/- 2.7 degrees to 20.4 +/- 5.2 degrees during flexion and from 6.7 +/- 3.5 degrees to 10.8 +/- 3.0 degrees during right axial rotation after 75% condyle resection (P < .01). At C1-C2, condylectomy had less effect, with ROM increasing from 10.7 +/- 2.0 degrees to 11.7 +/- 2.0 degrees during flexion, 36.9 +/- 4.8 degrees to 37.1 +/- 5.1 degrees during right axial rotation, and 4.3 +/- 1.9 degrees to 4.8 +/- 3.3 degrees during right lateral bending (P = NS). Because of marked instability, the 100% condylectomy condition was untestable. Changes in ROM were a result of changes more in the lax zone than in the stiff zone. CONCLUSION: : Lower-third clivectomy and unilateral anterior condylectomy as would be performed in an endonasal approach cause progressive hypermobility at the craniovertebral junction. On the basis of biomechanical criteria, craniocervical fusion is indicated for patients who undergo > 75% anterior condylectomy. PMID- 23442516 TI - Analysis of cervical sagittal alignment after screw-rod fixation. AB - BACKGROUND: The use of posterior instrumentation constructs is well established for subaxial cervical stabilizations/fusions. The importance of global and regional sagittal alignment has become increasingly recognized. OBJECTIVE: To perform an analysis using computed tomography scans to determine the effect of posterior instrumentation on postoperative cervical sagittal alignment at long term follow-up. METHODS: Over a period of 6 years, 56 consecutive patients (38 male and 18 female patients; mean age, 47 years) underwent cervical screw-rod fixation. Plain radiographs, computed tomography scans, and magnetic resonance images were analyzed preoperatively to assess sagittal alignment (C2-C7). Postoperatively, computed tomography scans and serial radiographs were obtained in all patients. With the use of independent observers, changes in sagittal alignment were determined by comparing the preoperative and postoperative imaging studies. RESULTS: In total, 390 screws were placed in the cervical spines of 56 patients. Definitive radiographic fusion was detected in all 56 patients (100%). There were no incidences of instrumentation failures or lucencies surrounding any screws. Patients with preoperative kyphosis (n = 19; mean, +9.9 degrees ) improved their sagittal alignment by 6.5 degrees (final mean, +3.4 degrees ), whereas patients with preoperative lordosis (n = 37; mean -15.44 degrees ) maintained their lordosis (final mean, -15.3 degrees ). Mean duration of follow up was 32.5 months. CONCLUSION: Radiographic analysis showed lateral mass fixation to be safe and effective. Certain operative techniques allowed substantial deformity correction and maintenance of long-term correction of deformity. Screw-rod fixation may be an effective method for maintaining lordotic cervical alignment in previously lordotic patients and for significantly correcting kyphotic deformity in patients with a preoperative kyphosis. PMID- 23442518 TI - Kochujang, fermented soybean-based red pepper paste, decreases visceral fat and improves blood lipid profiles in overweight adults. AB - Health benefits of Kochujang (KCJ) and its bioactive compounds have been reported in several in vitro and animal studies. OBJECTIVE: The aim of this study was to investigate the efficacy of KCJ supplementation on body composition and blood lipid profiles in overweight adults. METHODS: Sixty overweight men and women with BMI >=23 kg/m2 and waist-hip-ratio (WHR) >=0.90 for men and >=0.85 for women were randomly assigned to a KCJ supplement (n=30, 32 g/day) or placebo (n=30, 32 g/day) group for a 12-week, double-blind, placebo controlled study. We measured anthropometric parameters, serum lipid profiles, abdominal fat distribution by computerized tomography and calculated the atherosclerosis indices in 53 subjects (n=26 in KCJ group, n=27 in placebo group) who completed the study. RESULTS: After 12 weeks, the KCJ group showed a significant reduction in visceral fat (cm2) (p<0.05), although body weight (kg) and WHR did not change. Serum concentration of triglycerides and ApoB were decreased when compared to those of the placebo group. CONCLUSION: KCJ supplementation (32 g/day) for 12 weeks in overweight adults showed anti-atherosclerotic and anti-obesogenic effects. TRIAL REGISTRATION: Clinical trials.gov Identifier: NCT01532375. PMID- 23442519 TI - The critical spot eraser-a method to interactively control the correction of local hot and cold spots in IMRT planning. AB - Common problems in inverse radiotherapy planning are localized dose insufficiencies like hot spots in organs at risk or cold spots inside targets. These are hard to correct since the optimization is based on global evaluations like maximum/minimum doses, equivalent uniform doses or dose-volume constraints for whole structures. In this work, we present a new approach to locally correct the dose of any given treatment plan. Once a treatment plan has been found that is acceptable in general but requires local corrections, these areas are marked by the planner. Then the system generates new plans that fulfil the local dose goals. Consequently, it is possible to interactively explore all plans between the locally corrected plans and the original treatment plan, allowing one to exactly adjust the degree of local correction and how the plan changes overall. Both the amount (in Gy) and the size of the local dose change can be navigated. The method is introduced formally as a new mathematical optimization setting, and is evaluated using a clinical example of a meningioma at the base of the skull. It was possible to eliminate a hot spot outside the target volume while controlling the dose changes to all other parts of the treatment plan. The proposed method has the potential to become the final standard step of inverse treatment planning. PMID- 23442524 TI - Service delivery in Kenyan district hospitals - what can we learn from literature on mid-level managers? AB - BACKGROUND: There is a growing emphasis on the need to tackle inadequate human resources for health (HRH) as an essential part of strengthening health systems; but the focus is mostly on macro-level issues, such as training, recruitment, skill mix and distribution. Few attempts have been made to understand the capability of health workers, their motivation and other structural and organizational aspects of systems that influence workforce performance. We have examined literature on the roles of mid-level managers to help us understand how they might influence service delivery quality in Kenyan hospitals. In the Kenyan hospital settings, these are roles that head of departments who are also clinical or nursing service providers might play. METHODS: A computerized search strategy was run in Pub Med, Cochrane Library, Directory of Open Access Journals Social Science Research Network, Eldis, Google Scholar and Human Resources for Health web site databases using both free-text and MeSH terms from 1980 to 2011. In addition, citation searching from excluded and included articles was used and relevant unpublished literature systematically identified. RESULTS AND DISCUSSION: A total of 23 articles were finally included in the review from over 7000 titles and abstracts initially identified. The most widely documented roles of mid-level managers were decision-making or problem-solving, strategist or negotiator and communicator. Others included being a therapist or motivator, goal setting or articulation and mentoring or coaching. In addition to these roles, we identified important personal attributes of a good manager, which included interpersonal skills, delegation and accountability, and honesty. The majority of studies included in the review concerned the roles that mid-level managers are expected to play in times of organizational change. CONCLUSION: This review highlights the possible significance of mid-level managers in achieving delivery of high-quality services in Kenyan public hospitals and strongly suggests that approaches to strengthen this level of management will be valuable. The findings from this review should also help inform empirical studies of the roles of mid level managers in these settings. PMID- 23442525 TI - Reproduction and caste ratios under stress in trematode colonies with a division of labour. AB - Trematodes form clonal colonies in their first intermediate host. Individuals are, depending on species, rediae or sporocysts (which asexually reproduce) and cercariae (which develop within rediae or sporocysts and infect the next host). Some species use a division of labour within colonies, with 2 distinct redial morphs: small rediae (non-reproducing) and large rediae (individuals which produce cercariae). The theory of optimal caste ratio predicts that the ratio of caste members (small to large rediae) responds to environmental variability. This was tested in Philophthalmus sp. colonies exposed to host starvation and competition with the trematode, Maritrema novaezealandensis. Philophthalmus sp. infected snails, with and without M. novaezealandensis, were subjected to food treatments. Reproductive output, number of rediae, and the ratio of small to large rediae were compared among treatments. Philophthalmus sp. colonies responded to host starvation and competition; reproductive output was higher in well-fed snails of both infection types compared with snails in lower food treatments and well-fed, single infected snails compared with well-fed double infected snails. Furthermore, the caste ratio in Philophthalmus sp. colonies was altered in response to competition. This is the first study showing caste ratio responses to environmental pressures in trematodes with a division of labour. PMID- 23442526 TI - Detection limits of Legionella pneumophila in environmental samples after co culture with Acanthamoeba polyphaga. AB - BACKGROUND: The efficiency of recovery and the detection limit of Legionella after co-culture with Acanthamoeba polyphaga are not known and so far no investigations have been carried out to determine the efficiency of the recovery of Legionella spp. by co-culture and compare it with that of conventional culturing methods. This study aimed to assess the detection limits of co-culture compared to culture for Legionella pneumophila in compost and air samples. Compost and air samples were spiked with known concentrations of L. pneumophila. Direct culturing and co-culture with amoebae were used in parallel to isolate L. pneumophila and recovery standard curves for both methods were produced for each sample. RESULTS: The co-culture proved to be more sensitive than the reference method, detecting 102-103 L. pneumophila cells in 1 g of spiked compost or 1 m3 of spiked air, as compared to 105-106 cells in 1 g of spiked compost and 1 m3 of spiked air. CONCLUSIONS: Co-culture with amoebae is a useful, sensitive and reliable technique to enrich L. pneumophila in environmental samples that contain only low amounts of bacterial cells. PMID- 23442527 TI - New Delhi metallo-beta-lactamase: a weapon for the newly emerging drug-resistant bacteria. AB - The world has seen the emergence of many micro-organisms in the recent past, which can curb human population with their newly built genetic make-up. The latest addition to this list of panic creating organisms is, bacteria encoding the gene for New Delhi metallo-beta-lactamase (NDM-1). NDM-1 is an enzyme that can hydrolyze and inactivate carbapenems, which are used as a last resort for the treatment of multi-resistant bacterial infections. Names of these bacteria were not found in the medical literature before December 2009, because of which it can take the credit of becoming a powerful emerging bacteria, which are difficult to treat. Besides Escherichia coli and Klebsiella pneumoniae, other bacterial strains have also expressed the gene for NDM-1, which are detected in many countries. PMID- 23442528 TI - An experience of health services provided by a peripheral government teaching hospital in India: patients' perspective. AB - BACKGROUND: Patients' satisfaction has now become the most important and measurable aspect for assessing the quality of patient care services. For improvement of performance of any health system there is a need to assess patients' satisfaction as often as possible. OBJECTIVES: 1) To assess the level of patients' satisfaction as well as dissatisfaction regarding the services provided in the outdoor and indoor of different departments of a tertiary care hospital. 2) To find out the relation of some socio-demographic variables and different departments with the level of satisfaction if any. MATERIALS AND METHODS: Two predesigned pretested interview schedule (separate for outdoor and indoor) was developed covering certain domains of patients care. Overall satisfaction level was determined by using summated Likert's score. RESULTS: For outdoor, a little excess of half of the patients were satisfied in doctor-patient communication (51.0%), consultation room (53.5%), and overall (59.9%). The unsatisfied area was waiting place and time (38.6%). In the Indoor, 58.6% patients were satisfied with admission procedure, 53.2% for clinical care, 57.1% for nursing care and 45.3% with food services and the areas where more patients were not satisfied were cleanliness (40.4%), comfort (20.2%) and food services. G&O patients were less satisfied both in indoor and outdoor. Satisfaction level significantly increased with increase in age (P < 0.01),male patients (P < 0.01), lower education (P < .05) and surgical patients (P < 0.01). CONCLUSION: The level of patients' satisfaction showed deficiencies in different issues of hospital services, which should be given utmost importance by the hospital management authority for betterment. PMID- 23442529 TI - Impact of propylthiouracil on quality of life in psoriasis patients. AB - BACKGROUND: Psoriasis greatly impacts the quality of life (QOL) of patients including several dermatological conditions that are listed in the Dermatology Life Quality Index (DLQI). Decrease in psoriatic lesion as measured by Psoriasis Area Severity Index (PASI) score is associated with improvement in QOL. Propylthiouracil (PTU) was found to be clinically efficient in clearing psoriatic lesions. Our objective is to find the extent of improvement in QOL in psoriatic patients treated with PTU. MATERIALS AND METHODS: Twenty-three psoriatic patients who were taking 300 mg PTU/day were involved in the study. Clinical improvement was assessed by PASI score and QOL was assessed by DLQI questionnaire at baseline, 6 th and 12 th week of PTU treatment. RESULTS: Psoriatic patients before treatment showed significantly increased DLQI score when compared with 6 and 12 weeks of PTU treatment which was found to be decreased significantly (P < 0.001) after PTU treatment. There was a positive correlation between DLQI and PASI score at all three intervals of treatment period at P < 0.001 (r = 0.793, r = 0.834, r = 0.801), respectively. CONCLUSION: Since PTU was found to improve the QOL of psoriasis patients, this study adds an advantage of using it as treatment option in psoriasis. PMID- 23442530 TI - Emergence and control of multidrug resistant organisms in small cities in India: a wake up call. AB - CONTEXT: Urinary tract infections (UTIs) is one of the most common bacterial infections in general practice. Antimicrobial resistance in urinary pathogens, particularly the most common being Escherichia coli, is directly associated with prescribing in primary care. Diagnosis of UTI requires laboratory examination of urine sample in addition to clinical evaluation, which may lead to higher cost of treatment, but the proper treatment of the case that will lead to complete recovery with no recurrence episodes far outweigh the cost issue of microbiological investigation. Even though UTIs are a very common diagnosis, management of this condition is not consistent in general practice. This study was conducted in an effort to see the extent of presence of multi drug resistant organisms in local set up . AIMS: To describe the common urine isolates observed in the small cities of India and also to test for drug resistance among them with simple manageable tests in small-scale laboratories. MATERIALS AND METHODS: A retrospective review was conducted of Gram negative bacilli and Gram positive cocci isolated from the clinical urine samples collected from various hospitals and private practitioners in Shimoga City, Karnataka and Jamshedpur City, Jharkhand. The study period was between November 2011 to January 2012. RESULTS: A total of 788 urine samples were included in the study. It was seen that 55.8% of the total isolated organisms were multidrug resistant (MDR) in Shimoga city, Karnataka and 38.8% of the total isolated organisms were MDR in Jamshedpur city, Jharkhand. CONCLUSIONS: Only with the combined efforts of the local laboratories and clinicians, the looming threat of the pandrug resistant organisms in small cities can be avoided. However, more such studies are required from both clinicians and laboratory health care professionals in order to arrive at a common consensus, and uniformity can be brought about in the community regarding prescription practices. PMID- 23442531 TI - Acinetobacter baumannii: no more a choosy intruder? AB - CONTEXT: Acinetobacter baumannii, a non-fermenter, is fast coming up the list of pathogens causing nosocomial infections. Earlier considered to be a harmless colonizer, or at the most, a pathogen causing mostly respiratory tract infections, it has slowly but successfully emerged as a ubiquitous pathogen causing both community as well as health care associated infections. It has acquired multidrug resistance, and seems to be no more selective in mainly attacking any one or two body systems. According to recent reports, a shy selective bacterium has turned into a dangerous pathogen, capable of causing infections anywhere in the body, thereby adding extra furrows on the forehead of medical community worldwide. AIMS: To determine the range of infections caused by A. baumannii, and the frequencies thereof, in our tertiary care hospital; and to study their resistance patterns. MATERIALS AND METHODS: A total of 88 isolates of A. baumannii were found from a variety of clinical samples, from hospitalized patients as well as patients attending the outpatient departments. The isolates were subjected to disc-diffusion method for antibiotic sensitivity testing. RESULTS: Acinetobacter was mostly recovered from samples of pus, followed by endotracheal tube, urine, sputum samples, etc., Imipenem showed highest sensitivity, while other drugs with good sensitivity patterns were aminoglycosides and piperacillin-tazobactum. CONCLUSIONS: In this tertiary care institution of ours, A. baumannii isolates have shown a high frequency of drug resistance, with imipenem being the best sensitive drug. This non-fermenter is the cause of a variety of infections, irrespective of whether the individuals are hospitalized or are outdoor patients. PMID- 23442532 TI - A study on the psychosocial behavior of the disabled children in Loni, Maharashtra. AB - OBJECTIVES: To find out the changes in psychosocial behavior of the disabled children. MATERIALS AND METHODS: The study area comprises of villages under rural field practice area of Rural Medical College, Loni. 7300 children of the age group of 0-14 years from the total population of 20,533 were studied by community based cross- sectional study. House to house survey was conducted to identify disabled children using a pre-tested questionnaire by interview technique. Child behavior check list (CBCL) which was developed by T.M. Atenbach was the tool used to assess the comprehensive, multi informant evaluation of child's behavior. RESULTS: The overall prevalence rate of disabilities in children was 2.25%. Psychosocial behavioral changes were observed more in children with multiple and miscellaneous disability which includes cerebral palsy and was followed by mental retardation, locomotor disability, visual impairment and least among the children with hearing and speech impairment. Psychosocial behavioral changes among the children with disabilities were statistically significant. CONCLUSION: The result of the study necessitates organizing counseling to disabled children and parents, community based rehabilitation program and integration of disabled into the main stream education to reduce the psychosocial behavioral changes. PMID- 23442533 TI - Symptomatic gastroesophageal reflux amongst hospital personnel in South India. AB - INTRODUCTION: Prevalence of gastro-esophageal reflux (GER) disease is on the rise in South Asian countries. Though there are reports of GER prevalence amongst various ethnic populations there are fewer reports on its prevalence in different occupational groups. MATERIALS AND METHODS: To study the prevalence of GER amongst hospital personnel at the tertiary referral hospital in south India. RESULTS: Of the 1468 hospital personnel, the overall prevalence of GER was 28.5%. It was highest amongst the clerical staff (31.3%) and least among nursing students (3%). Eighty five percent of the symptomatic GER personnel were young; those below the age of 35 years had symptoms for less than 6 months while those above 55 years had symptoms for more than 6 months. Combination of reflux symptoms with ulcer or dysmotility type dyspepsia was the dominant type amongst all cadres. The nursing staff (62.5%) preferred antacids whereas the doctors (63%) preferred PPI. CONCLUSION: GER prevalence is not uncommon amongst the hospital personnel. It is significantly more common amongst doctors, clerical staff and housekeepers. PMID- 23442534 TI - Chondrosarcoma of the bone with nodal metastasis: the first case report with review of literature. AB - Primary bone sarcomas are rarely known to metastasize to lymph nodes. This is attributed to paucity of lymphatic channels in the bone. Even though some bone sarcomas like osteosarcoma are known to have nodal metastasis, such affections have not been reported with primary osseous chondrosarcoma. We describe a case of primary chondrosarcoma of proximal humerus with axillary nodal metastasis. The patient underwent a forequarter amputation with axillary nodal clearance. The histopathological examination revealed metastasis of chondrosarcoma in lymph nodes. We also have reviewed the related literature and discussed the possible mechanism of this nodal metastasis. PMID- 23442535 TI - A simple algorithm for averaging spike trains. AB - Although spike trains are the principal channel of communication between neurons, a single stimulus will elicit different spike trains from trial to trial. This variability, in both spike timings and spike number can obscure the temporal structure of spike trains and often means that computations need to be run on numerous spike trains in order to extract features common across all the responses to a particular stimulus. This can increase the computational burden and obscure analytical results. As a consequence, it is useful to consider how to calculate a central spike train that summarizes a set of trials. Indeed, averaging responses over trials is routine for other signal types. Here, a simple method for finding a central spike train is described. The spike trains are first mapped to functions, these functions are averaged, and a greedy algorithm is then used to map the average function back to a spike train. The central spike trains are tested for a large data set. Their performance on a classification-based test is considerably better than the performance of the medoid spike trains. PMID- 23442537 TI - Patterns of coronary vasomotor responses to intracoronary acetylcholine provocation. PMID- 23442536 TI - Antenatal care visit attendance, intermittent preventive treatment and bed net use during pregnancy in Gabon. AB - BACKGROUND: The World Health Organization (WHO) recommends that intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and insecticide treated bed nets (ITNs) must be provided during antenatal care (ANC) visits for malaria prevention during pregnancy. The aim of this study was to determine the level of ANC attendance and its relationship with IPTp-SP and bed net coverage in Gabonese pregnant women. METHODS: This was a cross-sectional survey performed in 2011 in sentinel sites for malaria: two ANC units (Melen and Owendo) and one delivery unit (CHL). A validated structured questionnaire was used to collect the following data: age, parity, history of the current pregnancy including gestational age at the interview, number of ANC visits already performed, date of first visit, use of malaria preventive measure and details on IPTp-SP administration. RESULTS: During the study, 1030 women were interviewed, 735 at their ANC visit and 295 at the delivery. Their median age was 24[20-29] years and 21.0% were primigravidae. More than 70.0% attended their first ANC visit during the second trimester. Among the 442 women who were at the end of their pregnancy, 71.5% had a correct attendance, at least four ANC visits, most frequently women with no education and older women; IPTp-SP was offered to 84.1% of them and 57.4% received at least two doses. The number of SP doses was correlated to the number of ANC visits. Bed net coverage was 59.0%, not associated with ANC attendance. Among the women with correct ANC attendance, only 49.5% had a complete IPTp-SP course associated with bed net use during pregnancy. In the site where SP administration was supervised, 80% had four ANC visits and 97.4% received a full 2-dose course of IPTp-SP. CONCLUSIONS: Despite a high level of correct ANC attendance in Gabon, the goal of 80% of women with 2-dose IPTp-SP during pregnancy is not achieved. Evaluations, training of health workers, as well as surveys from other areas of the country are needed to further measure the implementation and the impact of these strategies. PMID- 23442538 TI - Ankle pressures in UK South Asians with diabetes mellitus: a case control study. AB - OBJECTIVES: To study ethnic differences in ankle pressures in South Asians versus Europeans and in those with and without diabetes mellitus (DM). DESIGN: Case control. SETTING: Primary care. PARTICIPANTS: 391(DM=154) South Asian and 252(DM=72) European adults. INTERVENTION: None. MAIN OUTCOME MEASURES: Systolic blood pressure of the left (L) and right (R) brachial, posterior tibial (PT) and dorsalis pedis (DP) arteries were measured using a Doppler probe. RESULTS: In comparison with Europeans, in young South Asians, DM was diagnosed 12 years earlier but pressures were lower, p <= 0.0001 for all (RPT (146 vs 157 mm Hg), LPT (143 vs 154 mm Hg), RDP (138 vs 150 mm Hg) and LDP (137 vs 149 mm Hg)). Pack year was greater in Europeans. Odds ratios of cardiovascular disease in relation to ankle pressure were increased in South Asians with ankle brachial index between 0.9 and 1.3 or >1.3. Linear regression in South Asians identified age was an independent predictor of increased pedal pressures, DM of increased RPT and LDP, and sex of LPT and LDP. In Europeans, age was an independent predictor of increased pedal pressures, and sex and pack years were independent predictors of decreased pedal pressures. In South Asians, all ankle pressure and in Europeans, RPT, LPT and LDP were increased in subjects with DM versus without. Ankle pressures and cardiovascular disease in South Asians with DM were similar to those of 10 years older Europeans with DM. CONCLUSIONS: South Asians with DM had higher ankle pressures versus without and were similar to 10 years older Europeans with DM. Prospective studies on ankle pressures for development of diabetes or cardiovascular disease are warranted in South Asians. PMID- 23442539 TI - Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication. AB - Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity(r) pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication. PMID- 23442540 TI - Radiographic union score for hip substantially improves agreement between surgeons and radiologists. AB - BACKGROUND: Despite the prominence of hip fractures in orthopedic trauma, the assessment of fracture healing using radiographs remains subjective. The variability in the assessment of fracture healing has important implications for both clinical research and patient care. With little existing literature regarding reliable consensus on hip fracture healing, this study was conducted to determine inter-rater reliability between orthopedic surgeons and radiologists on healing assessments using sequential radiographs in patients with hip fractures. Secondary objectives included evaluating a checklist designed to assess hip fracture healing and determining whether agreement improved when reviewers were aware of the timing of the x-rays in relation to the patients' surgery. METHODS: A panel of six reviewers (three orthopedic surgeons and three radiologists) independently assessed fracture healing using sequential radiographs from 100 patients with femoral neck fractures and 100 patients with intertrochanteric fractures. During their independent review they also completed a previously developed radiographic checklist (Radiographic Union Score for Hip (RUSH)). Inter and intra-rater reliability scores were calculated. Data from the current study was compared to the findings from a previously conducted study where the same reviewers, unaware of the timing of the x-rays, completed the RUSH score. RESULTS: The agreement between surgeons and radiologists for fracture healing was moderate for "general impression of fracture healing" in both femoral neck (ICC = 0.60, 95% CI: 0.42-0.71) and intertrochanteric fractures (0.50, 95% CI: 0.33 0.62). Using a standardized checklist (RUSH), agreement was almost perfect in both femoral neck (ICC = 0.85, 95% CI: 0.82-0.87) and intertrochanteric fractures (0.88, 95% CI: 0.86-0.90). We also found a high degree of correlation between healing and the total RUSH score using a Receiver Operating Characteristic (ROC) analysis, there was an area under the curve of 0.993 for femoral neck cases and 0.989 for intertrochanteric cases. Agreement within the radiologist group and within the surgeon group did not significantly differ in our analyses. In all cases, radiographs in which the time from surgery was known resulted in higher agreement scores compared to those from the previous study in which reviewers were unaware of the time the radiograph was obtained. CONCLUSIONS: Agreement in hip fracture radiographic healing may be improved with the use of a standardized checklist and appears highly influenced by the timing of the radiograph. These findings should be considered when evaluating patient outcomes and in clinical studies involving patients with hip fractures. Future research initiatives are required to further evaluate the RUSH checklist. PMID- 23442541 TI - Pentraxin 3 production in the adipose tissue and the skeletal muscle in diabetic obese mice. AB - : Inflammation has been shown to promote obesity-induced insulin resistance. Although pentraxin (PTX) 3 is known as an anti-inflammatory factor, the effect of PTX3 on insulin sensitivity has not yet been elucidated. The aim of this study is to investigate a part of the role of PTX3 on insulin sensitivity. The authors studied the PTX3 and glucose transport protein expression levels in epididymal adipose tissue and soleus muscles of male diabetic-obese [Tsumura Suzuki obese diabetic (TSOD)] and lean control mice. The levels of PTX3 in both skeletal muscle and adipose tissue were significantly lower in TSOD mice than in controls, and there was a significant positive correlation between them. They observed a significant positive correlation between PTX3 and glucose transport protein 4 levels in skeletal muscle. This study suggests that PTX3 may play a part of role as promoting insulin sensitivity of skeletal muscle in TSOD mice. PMID- 23442542 TI - The relationship between neutrophil lymphocyte ratio with urinary protein and albumin excretion in newly diagnosed patients with type 2 diabetes. AB - BACKGROUND: Recent evidence suggests that neutrophil/lymphocyte (N/L) ratio play a role in the development and progression of cardiovascular complications. Increased urinary albumin and protein excretion has been shown to be a risk factor for cardiovascular disease. Thus, this study aimed to investigate the relationship between circulating total and differential leukocyte counts including N/L ratio with urinary protein and albumin excretion in patients with newly diagnosed type 2 diabetes. METHODS: All patients underwent history taking, physical examination, blood pressure measurement, 12-lead electrocardiographic evaluation, routine urine analysis, biochemical analysis, 24-hour urine collection to measure protein and albumin excretion and creatinine clearance. Peripheral total and differential leukocyte analyses were performed using an automated cell counter. RESULTS: In total, 80 patients were included. Spearman correlation analysis revealed that 24-hour urinary protein excretion was correlated with neutrophil count (rho = 0.280, P = 0.012), lymphocyte count (rho = -0.365, P = 0.001) and N/L ratio (rho = 0.474, P < 0.0001). Spearman correlation analysis revealed that 24-hour urinary albumin excretion was correlated with neutrophil count (rho = 0.261, P = 0.019), lymphocyte count (rho = -0.278, P = 0.013) and N/L ratio (rho = 0.415, P < 0.0001). In stepwise linear regression analysis, 24-hour urinary protein excretion was independently associated with high-density lipoprotein cholesterol (P = 0.01), blood urea (P = 0.014) and N/L ratio (P = 0.041). On the other hand, 24-hour urinary albumin excretion was independently associated with creatinine clearance (P = 0.004), albumin (P < 0.0001) and N/L ratio (P = 0.011). CONCLUSIONS: This study demonstrated that increased N/L ratio was independently related with both 24-hour urinary protein and urinary albumin excretion in newly diagnosed patients with type 2 diabetes. PMID- 23442543 TI - Carbohydrate-binding modules (CBMs) revisited: reduced amount of water counterbalances the need for CBMs. AB - BACKGROUND: A vast number of organisms are known to produce structurally diversified cellulases capable of degrading cellulose, the most abundant biopolymer on earth. The generally accepted paradigm is that the carbohydrate binding modules (CBMs) of cellulases are required for efficient saccharification of insoluble substrates. Based on sequence data, surprisingly more than 60% of the cellulases identified lack carbohydrate-binding modules or alternative protein structures linked to cellulases (dockerins). This finding poses the question about the role of the CBMs: why would most cellulases lack CBMs, if they are necessary for the efficient hydrolysis of cellulose? RESULTS: The advantage of CBMs, which increase the affinity of cellulases to substrates, was found to be diminished by reducing the amount of water in the hydrolytic system, which increases the probability of enzyme-substrate interaction. At low substrate concentration (1% w/w), CBMs were found to be more important in the catalytic performance of the cellobiohydrolases TrCel7A and TrCel6A of Trichoderma reesei as compared to that of the endoglucanases TrCel5A and TrCel7B. Increasing the substrate concentration while maintaining the enzyme-to-substrate ratio enhanced adsorption of TrCel7A, independent of the presence of the CBM. At 20% (w/w) substrate concentration, the hydrolytic performance of cellulases without CBMs caught up with that of cellulases with CBMs. This phenomenon was more noticeable on the lignin-containing pretreated wheat straw as compared to the cellulosic Avicel, presumably due to unproductive adsorption of enzymes to lignin. CONCLUSIONS: Here we propose that the water content in the natural environments of carbohydrate-degrading organisms might have led to the evolution of various substrate-binding structures. In addition, some well recognized problems of economical saccharification such as unproductive binding of cellulases, which reduces the hydrolysis rate and prevents recycling of enzymes, could be partially overcome by omitting CBMs. This finding could help solve bottlenecks of enzymatic hydrolysis of lignocelluloses and speed up commercialization of second generation bioethanol. PMID- 23442544 TI - Added value of SPECT/spiral CT versus SPECT in diagnosing solitary spinal lesions in patients with extraskeletal malignancies. AB - PURPOSE: The aim of this study was to investigate the added value of single photon emission computed tomography (SPECT)/spiral computed tomography (CT) versus SPECT alone in the differential diagnosis of solitary spinal lesions in patients with extraskeletal malignancies. MATERIALS AND METHODS: A total of 90 patients who had a solitary spine 'hot spot' that could not be definitively diagnosed using planar scintigraphy were enrolled in the study. SPECT/spiral CT was performed on the indeterminate lesions in the spine. Images were independently interpreted by two experienced nuclear medicine physicians. Each spinal lesion was graded on a four-point diagnostic scale (1, benign; 2, likely benign; 3, likely bone metastasis; 4, bone metastasis). The final diagnosis of each lesion was based on pathological confirmation or follow-up. kappa scores were used to evaluate inter-reviewer agreement and agreement of the SPECT and SPECT/spiral CT diagnoses with the final diagnosis. RESULTS: Final diagnoses revealed 25 bone metastases and 65 benign lesions. Forty percent (36/90) of the solitary spinal lesions were diagnosed as equivocal (likely benign or likely bone metastasis) according to SPECT, whereas only 5.6% (5/90) were diagnosed as equivocal according to SPECT/spiral CT. For SPECT/spiral CT-based and SPECT-based diagnoses, the kappa scores for inter-reviewer agreement were 0.889 (P<0.001, 95% confidence interval 0.824-0.954) and 0.504 (P<0.001, 95% confidence interval 0.401-0.607). The diagnostic accuracies of SPECT/spiral CT and SPECT images were 91.1% (82/90) and 58.9% (53/90), respectively (chi2=24.919, P<0.001). CONCLUSION: Compared with SPECT imaging alone, SPECT/spiral CT imaging was more accurate and valuable in the differential diagnosis of solitary spinal lesions in patients with extraskeletal malignancies. PMID- 23442545 TI - Planar images reprojected from SPECT V/Q data perform similarly to traditional planar V/Q scans in the diagnosis of pulmonary embolism. AB - OBJECTIVE: To compare the diagnostic interpretation of traditional ventilation/perfusion (V/Q) planar images with that of planar-like images reprojected from single-photon emission computed tomography (SPECT) data sets. METHODS: Retrospective data from patients who had undergone both planar and SPECT imaging were used to generate anonymized reprojected planar images, which were compared with traditional planar V/Q images. Two consultants interpreted both sets of images for 81 patients following a proforma. We assessed the agreement in the final diagnosis between the two imaging methods and between the two clinicians. We also compared the number, nature, and localization of defects, as well as image quality. Finally, we compared the diagnosis made using planar methods with the original diagnosis made using SPECT. RESULTS: There was excellent agreement in diagnosis both between the two planar methods (kappa=0.93) and between the two consultants (kappa=0.91). Similar numbers of defects were detected, with fewer matched defects being reported in the reprojected group by one of the clinicians. Localization of defects and image quality were similar for the two imaging methods. Six additional pulmonary embolisms were diagnosed using SPECT data. CONCLUSION: We have shown that the performance of reprojected planars from SPECT V/Q was similar to that of traditional planars. These results have potential important implications for patient workflow in busy nuclear medicine departments, as well as for patient comfort. PMID- 23442546 TI - Establishment and characterization of clear cell renal cell carcinoma cell lines with different metastatic potential from Chinese patients. AB - BACKGROUND: Clear cell renal cell carcinoma (ccRCC) cell lines with distinct metastatic potential are essential to study the mechanism of ccRCC metastasis. However, none of them originated from Chinese. METHODS: Primary cell cultures were performed using a primary tumor of a 49-year-old male ccRCC patient and a metastatic tumor of a 62-year-old male patient who had received nephrectomy to excise primary ccRCC 10 years ago. Cell growth, microstructure, cytogenetics, cytometry, expression of metastasis-associated molecules, tumorigenesis and metastasis were subsequently characterized. RESULTS: Two successive cell lines named NRCC from the primary ccRCC and MRCC from the metastatic ccRCC were established, respectively. Compared to NRCC, MRCC exhibited stronger anchorage independent growth and invasion potentials and contained more glycogen granules in the cytoplasm. Gains of chromosomes and some translocations were the major chromosomal aberrations in both cell strains. CD24 expression was more frequent in MRCC than in NRCC and the same was true for CD56. The transcriptional levels of TNFalpha, IL-6, VEGF, HIF2alpha, MMP2, and RhoC were significantly higher in MRCC than in NRCC. Cytosolic IkappaBalpha protein was more degraded in MRCC than in NRCC following TNFalpha treatment. Both cell lines had strong tumorigenicity in athymic nude mice. However, MRCC had strong potential in generating metastasis to lung and hemorrhagic ascites than NRCC following orthotopic transplantations. CONCLUSIONS: Cancer cells isolated from metastatic ccRCC have more malignant and metastatic potential than those from the primary tumor from the patients who shared the similar race background. Establishment of MRCC and NRCC may provide suitable models with which to investigate molecular mechanisms of ccRCC metastasis. PMID- 23442547 TI - Should I eXtract Every Six dental trial (SIXES): study protocol for a randomized controlled trial. AB - BACKGROUND: Extraction of lower first permanent molars in children is common. There is uncertainty among clinicians as to whether a 'compensating extraction' (removal of the upper first permanent molar to prevent it over erupting) is necessary despite current guidelines recommending this. As a result, unnecessary dental extractions may be carried out or children may be failing to receive extractions required to achieve optimal long-term oral health. In addition, the decision to extract fewer or more teeth affects management options (local anesthetic injections alone, inhalation sedation or general anesthesia) needed to support the child with the surgical procedure(s).The SIXES (Should I eXtract Every Six) dental trial investigates clinical effectiveness and quality of life for conventional treatment (following the guideline of compensation extraction of the upper first permanent molar) compared with the alternative intervention (removal of lower first permanent molars but no extraction of the upper). METHODS/DESIGN: This is a multicenter, two-arm parallel group randomized clinical trial. Allocation will be web-based randomization. Practitioners in primary and secondary care settings, reflecting the points of presentation and treatment of eligible patients, will recruit 400 children, aged 7 to 11 years requiring extraction of lower first permanent molars but who have upper first permanent molars of good prognosis. Baseline measures (prior to treatment) and outcome data (at one and five years, or when the patient reaches 14 years of age) will be assessed through study models and child/parent questionnaires.The primary outcome measure is degree of tipping of the lower second permanent molar, (favorable outcome is tipping less than 15 degrees ).The secondary outcomes are type of anesthetic/sedation used, residual spacing (between lower second premolar and second permanent molar), orthodontic treatment requirement, quality of life, and over-eruption in the intervention group. Assessors will be blinded where possible. DISCUSSION: SIXES dental trial investigates whether compensating extraction of upper first permanent molars should be carried out following loss of lower first permanent molars. Currently dentists and orthodontists face a dilemma in clinical decision-making, relying on the lowest level of evidence - expert opinion. SIXES will provide evidence to support decision-making and inform practices and may result in reduced tooth extractions. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01591265. PMID- 23442549 TI - Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment. AB - BACKGROUND: Wnt signaling in the colon cancer tumor microenvironment (TME) may affect cancer biologic properties including invasion and metastatic dissemination. Prior reports have suggested that the expression of select frizzled (Fz) receptors may be altered in cancers and in the TME. METHODS: Colon cancer, colonic adenoma and normal colonic mucosal specimens were obtained under institutional review board approval and analyzed for the expression of Fz1 and Fz2 by confocal fluorescent immunohistochemistry and Wnt-specific membrane array. In vitro, the effect of Wnt3a on Fz1 expression was examined in normal-derived NCM460 cells by qRT-PCR and immunohistochemistry. RESULTS: Fz1 was expressed in colon cancer and villous adenomas but not in more benign tubular adenomas. Fz1 expression was seen in normal colonic mucosa in close proximity to colon cancer, but not villous or tubular adenomas. Normal colonic mucosa distant from colon cancer did not express Fz1. Fz2 was expressed ubiquitously in cancer, adenomas and normal colonic mucosa. Fz1 expression was induced by Wnt3a in a normal colon mucosa-derived cell line in vitro. CONCLUSIONS: Fz1 is a Wnt responsive gene in colon-derived tissues. Fz1 expression exhibited increased expression in normal mucosa only in close proximity to colon cancer. This field effect was not seen with pre-malignant adenomas and may be due to Wnt/beta-catenin signaling within the TME. Fz1 may represent a new TME-directed therapeutic target for patients with colon cancer. PMID- 23442551 TI - Mucosal trapping and degradation of Nippostrongylus brasiliensis occurs in the absence of STAT6. AB - Hookworms represent a major infectious burden globally, especially in developing countries. The murine hookworm Nippostrongylus brasiliensis is normally cleared in a manner dependent on IL-13, IL4-R and STAT6 signalling. Here we have used STAT6-deficient animals to model a non-resistant population and describe 2 novel STAT6-independent processes for the clearance of N. brasiliensis. During primary infection STAT6-/- animals are able to clear gut-dwelling N. brasiliensis by a mechanism involving the trapping and degradation of worms in the gut mucosa. Here, a previously undescribed STAT6-independent up-regulation of Relm-beta was observed which correlated with the mucosal trapping and degradation of worms. Previous studies have indicated that during secondary infection STAT6 deficient animals fail to expel adult worms and remain susceptible to re-infection and long term colonization of the gut. We report here that an initial partially protective response occurs early upon re-infection in the absence of STAT6, and that a late phase protective secondary response arises in the gut of STAT6-deficient mice leading to the clearance of the majority of N. brasiliensis, through their trapping and death in the mucosal layer of the lower region of the small intestine. These findings show that there are a number of redundant effector pathways which act to reduce worm burden in the gut which can be activated by mechanisms that do not work through the dominant STAT6 signalling pathway and may be useful as targets for future vaccination strategies against resistant hookworm strains. PMID- 23442550 TI - Multimodality imaging using SPECT/CT and MRI and ligand functionalized 99mTc labeled magnetic microbubbles. AB - BACKGROUND: In the present study, we used multimodal imaging to investigate biodistribution in rats after intravenous administration of a new 99mTc-labeled delivery system consisting of polymer-shelled microbubbles (MBs) functionalized with diethylenetriaminepentaacetic acid (DTPA), thiolated poly(methacrylic acid) (PMAA), chitosan, 1,4,7-triacyclononane-1,4,7-triacetic acid (NOTA), NOTA-super paramagnetic iron oxide nanoparticles (SPION), or DTPA-SPION. METHODS: Examinations utilizing planar dynamic scintigraphy and hybrid imaging were performed using a commercially available single-photon emission computed tomography (SPECT)/computed tomography (CT) system. For SPION containing MBs, the biodistribution pattern of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs was investigated and co-registered using fusion SPECT/CT and magnetic resonance imaging (MRI). Moreover, to evaluate the biodistribution, organs were removed and radioactivity was measured and calculated as percentage of injected dose. RESULTS: SPECT/CT and MRI showed that the distribution of 99mTc-labeled ligand functionalized MBs varied with the type of ligand as well as with the presence of SPION. The highest uptake was observed in the lungs 1 h post injection of 99mTc labeled DTPA and chitosan MBs, while a similar distribution to the lungs and the liver was seen after the administration of PMAA MBs. The highest counts of 99mTc labeled NOTA-SPION and DTPA-SPION MBs were observed in the lungs, liver, and kidneys 1 h post injection. The highest counts were observed in the liver, spleen, and kidneys as confirmed by MRI 24 h post injection. Furthermore, the results obtained from organ measurements were in good agreement with those obtained from SPECT/CT. CONCLUSIONS: In conclusion, microbubbles functionalized by different ligands can be labeled with radiotracers and utilized for SPECT/CT imaging, while the incorporation of SPION in MB shells enables imaging using MR. Our investigation revealed that biodistribution may be modified using different ligands. Furthermore, using a single contrast agent with fusion SPECT/CT/MR multimodal imaging enables visualization of functional and anatomical information in one image, thus improving the diagnostic benefit for patients. PMID- 23442552 TI - Translation between the Neer- and the AO/OTA-classification for proximal humeral fractures: do we need to be bilingual to interpret the scientific literature? AB - BACKGROUND: The reporting and interpretation of data from clinical trials of proximal humeral fractures are hampered by the use of two partly incommensurable fracture classification systems: the Neer classification and the AO/OTA classification. It remains difficult to interpret and generalize results, to conduct prognostic studies, and to obtain consensus on treatment recommendations when concise definitions and a common 'fracture language' are lacking. Thus, we compared both classifications systems using primary data from large clinical studies to assess how thoroughly both systems conveyed clinically important classification information. METHODS: Classification data from each study were organized in a cross-table covering the 432 theoretically possible combinations between the 16 Neer categories and the 27 AO/OTA subgroups, and the plausibility of all observed combinations were assessed and discussed by the authors until consensus. RESULTS: We analyzed primary data from 2530 observations from seven studies providing primary data from both classification systems. Thirty-five percent (151 out of 432) of the combinations were considered 'not plausible' and thirty-four percent (149 out of 432) were considered 'problematic'. CONCLUSIONS: Clinically important information was lost within both classification systems. Most important, the varus/valgus distinction was not found within the Neer classification and a clear definition of displacement was lacking in the AO/OTA classification. We encourage surgeons and researches to report data from both classification systems for a more thorough description of the fracture patterns and to enable cross-checking of the coding. A suitable table for cross-checking of the coding is provided herein. PMID- 23442553 TI - A moment-based approach for DVH-guided radiotherapy treatment plan optimization. AB - The dose-volume histogram (DVH) is a clinically relevant criterion to evaluate the quality of a treatment plan. It is hence desirable to incorporate DVH constraints into treatment plan optimization for intensity modulated radiation therapy. Yet, the direct inclusion of the DVH constraints into a treatment plan optimization model typically leads to great computational difficulties due to the non-convex nature of these constraints. To overcome this critical limitation, we propose a new convex-moment-based optimization approach. Our main idea is to replace the non-convex DVH constraints by a set of convex moment constraints. In turn, the proposed approach is able to generate a Pareto-optimal plan whose DVHs are close to, or if possible even outperform, the desired DVHs. In particular, our experiment on a prostate cancer patient case demonstrates the effectiveness of this approach by employing two and three moment formulations to approximate the desired DVHs. PMID- 23442554 TI - Arthroscopic partial meniscectomy in middle-aged patients with mild or no knee osteoarthritis: a protocol for a double-blind, randomized sham-controlled multi centre trial. AB - BACKGROUND: Arthroscopic partial meniscectomy has been shown to be of no benefit to patients with concomitant knee osteoarthritis, but the optimal treatment of a degenerative meniscus tear in patients with mild or no knee osteoarthritis is unknown. This article describes the rationale and methodology of a randomized sham-controlled trial to assess the benefit of arthroscopic partial meniscectomy of a medial meniscus tear in patients with mild or no knee osteoarthritis. The objective of the study is to test whether the benefit from arthroscopic partial meniscectomy in patients with knee pain, medial meniscus lesion and mild/no knee osteoarthritis, is greater after arthroscopic partial meniscectomy than following sham surgery. METHODS: We will conduct a randomized controlled trial of treatment for degenerative meniscus tears in middle-aged patients (aged 35-55 years) with an MRI-verified medial meniscus lesion and mild or no knee radiographic osteoarthritis (grade 0-2 on the Kellgren & Lawrence scale). Patients will be randomized to receive either conventional arthroscopic partial meniscectomy or a sham surgery procedure. The primary outcome will be the KOOS5 derived from the 'Knee Injury and Osteoarthritis Outcome Score' at 2 years follow-up. Secondary outcomes at 2 years will include all five individual subscales of the KOOS, a global perceived effect score, the Short-Form-36 health status score, EQ-5D for economic appraisal and objective tests of muscle strength and physical function. Radiographic knee osteoarthritis will be evaluated at 5 years. DISCUSSION: Demonstration of no additional benefit from arthroscopic partial meniscectomy on pain and function should lead to a change in clinical care of patients with a degenerative meniscus tear. The results of this study will provide empirical evidence for the potential benefit/harm of arthroscopic partial meniscectomy compared to a masked sham-therapeutics intervention. PMID- 23442556 TI - A randomised controlled trial of a mindfulness intervention for men with advanced prostate cancer. AB - BACKGROUND: Prostate cancer is the most common male cancer in developed countries, and in Australia approximately one-fifth of men with prostate cancer have advanced disease. By comparison to men with localised prostate cancer, men with advanced disease report higher levels of psychological distress; poorer quality of life; and have an increased risk of suicide. To date no psychological intervention research specifically targeting men with advanced prostate cancer has been reported. In this paper we present the protocol of a current randomised controlled trial to assess the effectiveness of a professionally-led mindfulness based cognitive therapy (MBCT) group intervention to improve psychological well being in men with advanced prostate cancer. METHODS/DESIGN: Ninety-five men per condition (190 men in total) will be recruited through clinicians in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group and in major treatment centres in Queensland, New South Wales, Victoria and Western Australia. Patients are randomised to: (1) tele-based MBCT intervention or (2) patient education. A series of previously validated and reliable self-report measures will be administered to men at four time points: baseline/recruitment, and at 3, 6, and 9 months after recruitment and intervention commencement. Engagement with the principles of mindfulness and adherence to practice will be included as potential mediators of intervention effect. Primary outcomes are anxiety, depression and cancer-specific distress. Secondary outcomes are health related quality of life (QoL) and benefit finding. Disease variables (e.g. cancer grade, stage) will be assessed through medical records. DISCUSSION: This study will address a critical but as yet unanswered research question: to identify an effective way to reduce psychological distress; and improve the quality of life for men with advanced prostate cancer. TRIAL REGISTRATION: http://ACTRN12612000306819. PMID- 23442557 TI - Selective modulation of chemical and electrical synapses of Helix neuronal networks during in vitro development. AB - BACKGROUND: A large number of invertebrate models, including the snail Helix, emerged as particularly suitable tools for investigating the formation of synapses and the specificity of neuronal connectivity. Helix neurons can be individually identified and isolated in cell culture, showing well-conserved size, position, biophysical properties, synaptic connections, and physiological functions. Although we previously showed the potential usefulness of Helix polysynaptic circuits, a full characterization of synaptic connectivity and its dynamics during network development has not been performed. RESULTS: In this paper, we systematically investigated the in vitro formation of polysynaptic circuits, among Helix B2 and the serotonergic C1 neurons, from a morphological and functional point of view. Since these cells are generally silent in culture, networks were chemically stimulated with either high extracellular potassium concentrations or, alternatively, serotonin. Potassium induced a transient depolarization of all neurons. On the other hand, we found prolonged firing activity, selectively maintained following the first serotonin application. Statistical analysis revealed no significant changes in neuronal dynamics during network development. Moreover, we demonstrated that the cell-selective effect of serotonin was also responsible for short-lasting alterations in C1 excitability, without long-term rebounds.Estimation of the functional connections by means of cross-correlation analysis revealed that networks under elevated KCl concentrations exhibited strongly correlated signals with short latencies (about 5 ms), typical of electrically coupled cells. Conversely, neurons treated with serotonin were weakly connected with longer latencies (exceeding 20 ms) between the interacting neurons. Finally, we clearly demonstrated that these two types of correlations (in terms of strength/latency) were effectively related to the presence of electrical or chemical connections, by comparing Micro-Electrode Array (MEA) signal traces with intracellularly recorded cell pairs. CONCLUSIONS: Networks treated with either potassium or serotonin were predominantly interconnected through electrical or chemical connections, respectively. Furthermore, B2 response and short-term increase in C1 excitability induced by serotonin is sufficient to trigger spontaneous activity with chemical connections, an important requisite for long-term maintenance of firing activity. PMID- 23442559 TI - Heavy metal pollution of lakes along the mid-lower reaches of the Yangtze River in China: intensity, sources and spatial patterns. AB - Lakes in the middle and lower reaches of the Yangtze River form a shallow lake group unique in the World that is becoming increasingly polluted by heavy metals. Previous studies have largely focused on individual lakes, with limited exploration of the regional pattern of heavy metal pollution of the lake group in this area. This paper explores the sources, intensity and spatial patterns of heavy metal pollution of lake sediments. A total of 45 sample lakes were selected and the concentrations of key metal elements in the sediments of each lake were measured. The cluster analysis (CA), principal component analysis (PCA) and Geo-accumulation index (I(g)) analysis permitted analysis of the source and pollution intensity of the target lakes. Results suggested a notable spatial variation amongst the sample lakes. Lakes in the upper part of the lower reach of the Yangtze River surrounded by typical urban landscapes were strongly or extremely polluted, with high concentrations of Pb, Zn, Cu and Cd in their sediments. This was attributed to large amount of untreated industrial discharges and municipal sewage produced within the lake catchments. In contrast, the heavy metal pollution of lakes in the Taihu Delta area was notably lower due to industrial restructuring and implementation of effective environmental protection measures. Lakes along the middle reach of Yangtze River surrounded by agricultural areas were unpolluted to moderately polluted by heavy metals overall. Our results suggested that lakes in the central part of China require immediate attention and efforts should be made to implement management plans to prevent further degradation of water quality in these lakes. PMID- 23442558 TI - Does farming have an effect on health status? A comparison study in west Greece. AB - Investigating the health status of agricultural workers is a challenging goal. Contradictory outcomes concerning farmers' health are reported in the literature. In this cross-sectional study, certain clinical and neurobehavioral health outcomes were compared between farmers and non-farmers living in the same rural area. Farmers (328) and non-farmers (347), matched per age and sex, were selected randomly in an agricultural area in West Greece. Both groups underwent haematological and biochemical examinations and were administered two neurobehavioral tests, namely the Mini-Mental State Examination (MMSE) and the Montgomery-Asberg Depression Rating Scale (MADRS). Sociodemographic, personal medical, nutritional and lifestyle data were recorded. According to personal statements, farmers suffered from hypertension, cardiovascular, orthopaedic and ENT problems in higher frequency. Haematocrit, haemoglobin and serum cholinesterase's activity were found to be lower among farmers. Lower prevalence of hypertension and better performances on MMSE and MADRS tests were recorded in young farmers in relation to young non-farmers, while these findings were reversed in older ages. Odds Ratios were calculated through multivariate logistic regression models. Factors affecting these impairments remain to be clarified. PMID- 23442560 TI - Outbreak of ampicillin/piperacillin-resistant Klebsiella pneumoniae in a neonatal intensive care unit (NICU): investigation and control measures. AB - Klebsiella pneumoniae is a frequent cause of infectious outbreaks in Neonatal Intensive Care Units (NICUs). The aim of this paper is to describe an outbreak occurred in a 13-bed NICU and the control measures adopted in order to interrupt the chain of transmission. We described the microbiological investigations, the NICU staff compliance to the infection control measures by means of a specifically designed check-list and the control measures adopted. Six cases of primary bloodstream infections sustained by ampicillin/piperacillin-resistant Klebsiella pneumoniae were observed over a two-month period. One culture obtained from a 12% saccarose multiple-dose solution allowed the growth of Klebsiella pneumoniae. During the inspections performed by the Hospital Infection Control Team, using the check-list for the evaluation of the NICU staff compliance to the infection control measures, several breaches in the infection control policy were identified and control measures were adopted. In our case the definition of a specific check-list led to the adoption of the correct control measures. Further studies would be helpful in order to develop a standard check-list able to identify critical flows in the adhesion to the guidelines. It could be used in different NICUs and allow to obtain reproducible levels of infection control. PMID- 23442561 TI - Nonengagement in HIV care: a descriptive and qualitative study in hospitalized patients and community-based analysis. AB - Nonengagement in HIV care is a major clinical and public health challenge. To identify the risk factors and reasons, we performed (1) a retrospective study of patients admitted to the hospital with advanced HIV disease, (2) a prospective qualitative study, and (3) a population-based area-wide telephone interview. In the retrospective study, clinic care engagement was associated with age (43.9 +/- 9.1 years vs 37.9 +/- 7.2 years, P = .005) and improved from 23% to 44% (P = .03) after hospitalization. Survival was higher (93% vs 73%, P = .03) among those who engaged in care. Twelve inpatients were interviewed in the qualitative study. Themes identified for nonengagement were social stigma, indifference, or lack of understanding of care needs/denial and life care issues. In the population-based study, 145 patients were interviewed. In all, 49 denied the need for HIV care and 28 denied their HIV status. Stigma, denial, and indifference or lack of understanding of need are significant barriers to care engagement. PMID- 23442562 TI - CD4 counts in laboratory monitoring of HIV disease--experience from western India. AB - BACKGROUND: CD4 counts vary in different populations. The present study was conducted to determine CD4 counts in different World Health Organization (WHO) clinical stages in antiretroviral therapy naive individuals and to find out optimum CD4 cutoffs. METHOD: Data of adult HIV seropositive patients who underwent CD4 count and total lymphocyte count (TLC) testing were included for analysis. The severity of immunosuppression was graded based on WHO criteria. To establish optimum CD4 cutoff values, receiver-operator characteristics (ROC) curves were generated. RESULTS: Of 754 patients, 52.2% had CD4 counts <200 cells/mm3, but only 2.3% belonged to WHO stage IV. Newer CD4 cutoffs generated were 280, 120-280, <120 cells/mm3. Spearman rank correlation between CD4 counts and TLC was found to be weak (r = .32). CONCLUSION: The cutoff values of CD4 counts for HIV disease may need to be revised for India. Regular CD4 count estimation is a must for monitoring disease progression in people living with HIV/AIDS. PMID- 23442563 TI - Characteristics and follow-up of newly managed HIV-infected patients in the national referral center in Ouagadougou, Burkina Faso. AB - BACKGROUND: In sub-Saharan countries, HIV testing and treatment facilities are available, especially at subsidized rates for the past few years. METHODS: A prospective and descriptive review was conducted at Yalgado Ouedraogo Teaching Hospital Internal Medicine department in Ouagadougou, using personal case report forms, between June 2009 and August 2010 in all newly diagnosed adults with positive HIV antibody. RESULTS: The study participants consisted of 191 patients at a median age of 37 years (range, 18-65 years) and sex ratio (men/women): 0.66. In all, 110 (57.6%) patients were symptomatic. Fourteen patients were lost to follow-up. Of the 177 patients, 144 had CD4 count <350 cells/mm(3) and all have been treated. At the ninth month, weight gain and immune restoration were significant (P < .01); only 79 of the 144 patients had viral load measurement, and 76 of the 79 were undetectable. Mortality rate of treated patients was 6.25%. CONCLUSION: Laboratory tests and highly active antiretroviral therapy make the management of patients easier, but a majority of them still presented late and were still lost to follow-up. Nevertheless, we have excellent treatment success. PMID- 23442564 TI - Salmonella spinal infection: a rare case in a patient with advanced AIDS. AB - We present an unusual case of nontyphoidal Salmonella causing an epidural abscess and vertebral osteomyelitis in a severely immunocompromised patient with AIDS as well as a review of the literature. Salmonella vertebral osteomyelitis is exceptionally rare, and this is the first case report in a patient with AIDS. PMID- 23442565 TI - Nonword repetition as a predictor of long-term speech and language skills in children with cochlear implants. AB - HYPOTHESIS: The rapid phonological processing skills of children with cochlear implants early in life (ages 8-10), as measured by nonword repetition performance, will predict their language development 8 years later (ages 16-18). This core processing ability will also correlate with concurrent measures of language at both ages of testing. BACKGROUND: Understanding the causes of the wide range of performance in pediatric cochlear implant users currently constitutes a major barrier to clinical and research progress in the field. Research into children's neurocognitive abilities such as working memory capacity and verbal rehearsal speed, in addition to conventional demographic variables, has shown that these foundational skills play a key role in determining outcomes. Here, we investigate the impact of rapid phonological processing, an ability which is critical in spoken language use, for children with cochlear implants. METHODS: Fifty-two deaf children with cochlear implants completed a battery of 14 clinical and research measures of language, neurocognitive, and nonword repetition skills in 2 testing sessions 8 years apart. RESULTS: Performance on the nonword repetition task at both testing sessions correlated significantly with concurrent language abilities. Importantly, nonword repetition accuracy at age 8 to 10 also significantly predicted performance on measures of language ability at age 16 to 18 in a wide range of domains, from speech intelligibility to sentence recognition in noise. These relations were significant even when other neurocognitive measures were controlled. CONCLUSION: Early nonword repetition performance in children with cochlear implants predicts later language development and, therefore, may identify those children at high risk for poor outcomes. PMID- 23442566 TI - Relationship between tone perception and production in prelingually deafened children with cochlear implants. AB - HYPOTHESIS: Performance in tone perception and production are correlated in prelingually deafened pediatric cochlear implant (CI) users across individuals. Demographic variables, such as age at implantation, contribute to the performance variability. BACKGROUND: Poor representation of pitch information in CI devices hinders pitch perception and affects perception of lexical tones in cochlear implant users who speak tonal languages. METHODS: One hundred ten Mandarin speaking, prelingually deafened CI subjects and 125 typically developing, normal hearing subjects were recruited from Beijing, China. Lexical tone perception was measured using a computerized tone contrast test. Tone production was judged by native Mandarin-speaking adult listeners as well as analyzed acoustically and with an artificial neural network. A general linear model analysis was performed to determine factors that accounted for performance variability. RESULTS: CI subjects scored ~ 67% correct on the lexical tone perception task. The degree of differentiation of tones produced by the CI group was significantly lower than the control group as revealed by acoustic analysis. Tone production performance assessed by the neural network was highly correlated with that evaluated by human listeners. There was a moderate correlation between the overall tone perception and production performance across CI subjects. Duration of implant use and age at implantation jointly explained ~ 29% of the variance in the tone perception performance. Age at implantation was the only significant predictor for tone production performance in the CI subjects. CONCLUSION: Tone production performance in pediatric CI users is dependent on accurate perception. Early implantation predicts a better outcome in lexical tone perception and production. PMID- 23442567 TI - Usher syndrome: characteristics and outcomes of pediatric cochlear implant recipients. AB - OBJECTIVE: To evaluate the characteristics and outcomes of pediatric cochlear implant recipients diagnosed with Usher syndrome (US). STUDY DESIGN: Retrospective study of consecutive pediatric cochlear implant recipients (1991 2010). SETTING: Tertiary care children's hospital. PATIENTS: Children who received a cochlear implant who were diagnosed with US either before or after implantation. MAIN OUTCOME MEASURES: Electroretinography and ophthalmologic findings, cochlear anatomy based on preoperative imaging, age of independent ambulation, age at implantation, speech perception level, and communication method. RESULTS: Approximately 26 (3.7%) of 712 cochlear implant recipients were diagnosed with US based on the results of electroretinography and/or genetic testing. Preoperative imaging revealed no evidence of cochlear malformations. Average age of independent ambulation was 21.9 months (range, 12-30). Average age at implantation was 3.3 years (range, 6 mo to 11.6 yr). Mean follow-up after implantation was 7.8 years (range, 10 mo to 15.6 yr). Open-set speech perception was present in 92% of children, with use of a primarily oral communication mode in 69.2%. CONCLUSION: In this large series of patients with the diagnosis of US who have undergone cochlear implantation, CT and MRI imaging were normal. Significant delay in independent ambulation was present in this population secondary to abnormal vestibular function associated with US Type I. A majority of children developed significant open-set speech perception and oral communication skills. Implantation of US children provides them with the opportunity to develop useful hearing and oral communication. PMID- 23442569 TI - Communication outcomes for groups of children using cochlear implants enrolled in auditory-verbal, aural-oral, and bilingual-bicultural early intervention programs. AB - OBJECTIVE: The relative impact of early intervention approach on speech perception and language skills was examined in these 3 well-matched groups of children using cochlear implants. STUDY DESIGN: Eight children from an auditory verbal intervention program were identified. From a pediatric database, researchers blind to the outcome data, identified 23 children from auditory oral programs and 8 children from bilingual-bicultural programs with the same inclusion criteria and equivalent demographic factors. PATIENTS: All child participants were male, had congenital profound hearing loss (pure tone average >80 dBHL), no additional disabilities, were within the normal IQ range, were monolingual English speakers, had no unusual findings on computed tomography/magnetic resonance imaging, and received hearing aids and cochlear implants at a similar age and before 4 years of age. MAIN OUTCOME MEASURES: Open set speech perception (consonant-nucleus-consonant [CNC] words and Bamford-Kowal Bench [BKB] sentences) and the Peabody Picture Vocabulary Test (PPVT) were administered. RESULTS: The mean age at cochlear implant was 1.7 years (range, 0.8 3.9; SD, 0.7), mean test age was 5.4 years (range, 2.5-10.1; SD, 1.7), and mean device experience was 3.7 years (range, 0.7-7.9; SD, 1.8). Results indicate mean CNC scores of 60%, 43%, and 24% and BKB scores of 77%, 77%, and 56% for the auditory-verbal (AV), aural-oral (AO), and bilingual-bicultural (BB) groups, respectively. The mean PPVT delay was 13, 19, and 26 months for AV, AO, and BB groups, respectively. CONCLUSION: Despite equivalent child demographic characteristics at the outset of this study, by 3 years postimplant, there were significant differences in AV, AO, and BB groups. Results support consistent emphasis on oral/aural input to achieve optimum spoken communication outcomes for children using cochlear implants. PMID- 23442568 TI - Speech intonation and melodic contour recognition in children with cochlear implants and with normal hearing. AB - BACKGROUND: Cochlear implant (CI) users have difficulty perceiving some intonation cues in speech and melodic contours because of poor frequency selectivity in the cochlear implant signal. OBJECTIVES: To assess perceptual accuracy of normal hearing (NH) children and pediatric CI users on speech intonation (prosody), melodic contour, and pitch ranking, and to determine potential predictors of outcomes. HYPOTHESIS: Does perceptual accuracy for speech intonation or melodic contour differ as a function of auditory status (NH, CI), perceptual category (falling versus rising intonation/contour), pitch perception, or individual differences (e.g., age, hearing history)? METHOD: NH and CI groups were tested on recognition of falling intonation/contour versus rising intonation/contour presented in both spoken and melodic (sung) conditions. Pitch ranking was also tested. Outcomes were correlated with variables of age, hearing history, HINT, and CNC scores. RESULTS: The CI group was significantly less accurate than the NH group in spoken (CI, M = 63.1%; NH, M = 82.1%) and melodic (CI, M = 61.6%; NH, M = 84.2%) conditions. The CI group was more accurate in recognizing rising contour in the melodic condition compared with rising intonation in the spoken condition. Pitch ranking was a significant predictor of outcome for both groups in falling intonation and rising melodic contour; age at testing and hearing history variables were not predictive of outcomes. CONCLUSION: Children with CIs were less accurate than NH children in perception of speech intonation, melodic contour, and pitch ranking. However, the larger pitch excursions of the melodic condition may assist in recognition of the rising inflection associated with the interrogative form. PMID- 23442570 TI - Communication development in children who receive a cochlear implant by 12 months of age. AB - OBJECTIVE: Describe the long-term benefits of early cochlear implantation. Provide a comprehensive description of outcomes, including: language, speech production, and speech perception. Compare the communication outcomes for the early implanted children to those of normally hearing children and children who received a cochlear implant at a comparatively older age. METHOD: Retrospective review of the communication development of 35 children implanted between 6 and 12 months of age and 85 children implanted between 13 and 24 months of age. Audiologic assessments included unaided and aided audiograms, auditory brainstem response (ABR), auditory steady state response (ASSR), and otoacoustic emissons (OAEs). Formal language, speech production, and speech perception measures were administered, preimplant and at 1, 2, 3, and 5 years postimplant. RESULTS: The children who received their cochlear implant by 12 months of age demonstrated language growth rates equivalent to their normally hearing peers and achieved age appropriate receptive language scores 3 years postimplant. The children who received their cochlear implant between 13 and 24 months demonstrated a significant language delay at 3 years postimplant. Speech production development followed a similar pattern to that of normal-hearing children, although was delayed, for both groups of children. Mean open-set speech perception scores were comparable with previous reports for children and adults who use cochlear implants. CONCLUSION: Children implanted by 12 months of age demonstrate better language development compared with children who receive their cochlear implant between 13 and 24 months. This supports the provision of a cochlear implant within the first year of life to enhance the likelihood that a child with severe to-profound hearing impairment will commence elementary school with age appropriate language skills. PMID- 23442571 TI - Emergence of anxiety-like behaviours in depressive-like Cpe(fat/fat) mice. AB - Cpe(fat/fat) mice have a point mutation in carboxypeptidase E (Cpe), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of Cpe activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpe(fat/fat) mice develop obesity, diabetes and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpe(fat/fat) mice (~60 d), but appear in older animals (>90 d). These behaviours are reversed by acute treatment with diazepam or fluoxetine. In contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviours are reversed by acute administration of reboxetine. In comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wk treatment. These data demonstrate that Cpe(fat/fat) mice display depressive-like responses aged ~60 d, whereas anxiety-like behaviours emerge ~1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpe(fat/fat) mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviours are different. Since depressive like responses in the Cpe(fat/fat) mice are rescued by 2 wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression. PMID- 23442572 TI - Surveillance of lymphatic filariasis after stopping ten years of mass drug administration in rural communities in south India. AB - BACKGROUND: While various studies provided insight into the impact of mass drug administration (MDA), information on the dynamics of the post-MDA threshold level lymphatic filariasis (LF) infection facilitates understanding its disappearance pattern and determining the duration of post-MDA monitoring and evaluation. METHODS: The changes in microfilaraemia (Mf) prevalence and vector infection rates were monitored for four (2005-2008) and six years (2005-2010) respectively after stopping ten rounds of annual mass diethylcarbamazine (DEC) administration in a group of five villages located in South India. Four years after stopping MDA, circulating filarial antigenaemia (Ag) status among children and adults was also assessed in two villages. RESULTS: Overall Mf prevalence (n = 700) and vector infection rates (n=803-3520) showed a declining trend. Two villages maintained zero Mf status in each of the four years, vector infection rate was zero from the third year onwards and Ag prevalence in adults was 0.4% (n = 226). In two other villages despite persistence of Mf and vector infection there was zero vector infectivity rate during the third to sixth year and Ag prevalence among children (n = 50) was nil. In the fifth village Mf prevailed at <1.0% and Ag prevalence among 1-7 year old children was 4.6% (n = 44) and vector infectivity rate during the sixth year was 0.1% (n = 852). CONCLUSION: The incidence of sporadic new infections is evident in highly endemic communities such as the fifth village. However, there is uncertainty on the potential of the Ag positive children to reestablish infection. Six years of post-MDA monitoring and evaluation appears to be adequate to discern the status of transmission interruption and appropriate decision making. PMID- 23442573 TI - Demographic profile of sylvatic yellow fever in Brazil from 1973 to 2008. AB - BACKGROUND: Yellow fever is an acute, frequently fatal, febrile arbovirosis that in Brazil occurs only in the sylvatic form. Sylvatic yellow fever (SYF) appears in sporadic outbreaks over a large area of Brazil. In this paper, we analyze the demographic profile of 831 SYF cases that occurred between 1973 and 2008, to determine which segments of the exposed population are at greater risk. METHODS: Data were statistically analyzed and were also geo-referenced in order to observe their spatial pattern. The basic reproductive number of infections, R0, was estimated by the ratio between average life expectancy and the average age of the cases. RESULTS: SYF cases showed a modal profile of young male adults, approximately 30 years of age, living in rural areas of the states of Para, Goias, Maranhao and Minas Gerais, who were unvaccinated or whose vaccination was out of date. The disease showed a high mortality rate (51%, 421/831) among the notified cases, with death occurring on around the seventh day of illness for most patients. The R0 for SYF was estimated at approximately 2.4. CONCLUSION: The results of this study suggest that lack of vaccination coverage is a major risk factor for SYF, and that the groups most at risk are migrant laborers, farm workers and tourists. PMID- 23442574 TI - A 12-week multidomain intervention versus active control to reduce risk of Alzheimer's disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Disappointing results from clinical trials of disease-modifying interventions for Alzheimer's dementia (AD), along with reliable identification of modifiable risk factors in mid life from epidemiological studies, have contributed to calls to invest in risk-reduction interventions. It is also well known that AD-related pathological processes begin more than a decade before the development of clinical signs. These observations suggest that lifestyle interventions might be most effective when targeting non-symptomatic adults at risk of AD. To date, however, the few dementia risk-reduction programs available have targeted individual risk factors and/or were restricted to clinical settings. The current study describes the development of an evidence-based, theoretically-driven multidomain intervention to reduce AD risk in adults at risk. METHOD: The design of Body Brain Life (BBL) is a randomized controlled trial (RCT) to evaluate a 12-week online AD risk-reduction intervention. Eligible participants with several modifiable risk factors on the Australian National University (ANU) AD Risk Index (ANU-ADRI) are randomly allocated to an online only group, an online and face-to-face group, or an active control group. We aim to recruit 180 participants, to undergo a comprehensive cognitive and physical assessment at baseline, post-intervention, and 6-month follow-up assessment. The intervention comprises seven online modules (dementia literacy, risk factor education, engagement in physical, social, and cognitive lifestyles, nutrition, and health monitoring) designed using contemporary models of health behavior change. DISCUSSION: The BBL program is a novel online intervention to reduce the risk of AD in middle-aged adults at risk. The trial is currently under way. It is hypothesized that participants in the intervention arms will make lifestyle changes in several domains, and that this will lead to a reduction in their AD risk profile. We also expect to show that health behavior change is underpinned by changes in psychological determinants of behavior. If successful, the findings will contribute to the development of further dementia risk reduction interventions, and thus contribute to the urgent need to lower dementia risk factors in the population to alter future projections of disease prevalence. Longer follow-up of BBL participants and replications using large samples are required to examine whether reduction in AD risk factors will be associated with reduced prevalence. TRIAL REGISTRATION: Reg. no. ACTRN12612000147886. PMID- 23442575 TI - Effects of pyrethroid resistance on the cost effectiveness of a mass distribution of long-lasting insecticidal nets: a modelling study. AB - BACKGROUND: The effectiveness of insecticide-treated nets in preventing malaria is threatened by developing resistance against pyrethroids. Little is known about how strongly this affects the effectiveness of vector control programmes. METHODS: Data from experimental hut studies on the effects of long-lasting, insecticidal nets (LLINs) on nine anopheline mosquito populations, with varying levels of mortality in World Health Organization susceptibility tests, were used to parameterize malaria models. Both simple static models predicting population level insecticidal effectiveness and protection against blood feeding, and complex dynamic epidemiological models, where LLINs decayed over time, were used. The epidemiological models, implemented in OpenMalaria, were employed to study the impact of a single mass distribution of LLINs on malaria, both in terms of episodes prevented during the effective lifetime of the batch of LLINs, and in terms of net health benefits (NHB) expressed in disability-adjusted life years (DALYs) averted during that period, depending on net type (standard pyrethroid only LLIN or pyrethroid-piperonyl butoxide combination LLIN), resistance status, coverage and pre-intervention transmission level. RESULTS: There were strong positive correlations between insecticide susceptibility status and predicted population level insecticidal effectiveness of and protection against blood feeding by LLIN intervention programmes. With the most resistant mosquito population, the LLIN mass distribution averted up to about 40% fewer episodes and DALYs during the effective lifetime of the batch than with fully susceptible populations. However, cost effectiveness of LLINs was more sensitive to the pre intervention transmission level and coverage than to susceptibility status. For four out of the six Anopheles gambiae sensu lato populations where direct comparisons between standard LLINs and combination LLINs were possible, combination nets were more cost effective, despite being more expensive. With one resistant population, both net types were equally effective, and with one of the two susceptible populations, standard LLINs were more cost effective. CONCLUSION: Despite being less effective when compared to areas with susceptible mosquito populations, standard and combination LLINs are likely to (still) be cost effective against malaria even in areas with strong pyrethroid resistance. Combination nets are likely to be more cost effective than standard nets in areas with resistant mosquito populations. PMID- 23442577 TI - Enhanced band-edge photoluminescence from ZnO-passivated ZnO nanoflowers by atomic layer deposition. AB - The ZnO nanoflowers were synthesized by reactive vapor deposition. A secondary nucleation in the stalk/leaves interface was suggested. The photoluminescence revealed that there were many oxygen vacancies in the nanoflowers. To tune the optical properties of ZnO nanoflowers, ZnO thin films with varying thicknesses were coated on the nanoflowers by atomic layer deposition, which can distinctly improve the band-edge photoluminescence properties. PMID- 23442576 TI - Viroporin-mediated calcium-activated autophagy. AB - Autophagy is a cellular response activated by many pathogens, but the mechanism of activation is largely unknown. Recently we showed for the first time that rotavirus initiates the autophagy pathway through a calcium-mediated mechanism. Expression of the rotavirus-encoded NSP4, a pore-forming protein (viroporin), elicits the release of endoplasmic reticulum (ER) lumenal calcium into the cytoplasm of the infected cell. The increased cytoplasmic calcium activates a calcium signaling pathway involving calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) and 5' adenosine monophosphate-activated protein kinase (AMPK) to trigger autophagy. Rotavirus further manipulates autophagy membrane trafficking to transport viral ER-associated proteins to viroplasms, sites of viral genome replication and immature particle assembly. Transport of viral proteins to viroplasms is required for assembly of infectious virus. Thus, NSP4, a multifunctional viral protein known to regulate infectious particle assembly, also modulates membrane trafficking by orchestrating the activation of autophagy to benefit viral replication. PMID- 23442578 TI - Recombinant snake venom metalloproteinase inhibitor BJ46A inhibits invasion and metastasis of B16F10 and MHCC97H cells through reductions of matrix metalloproteinases 2 and 9 activities. AB - Studies have shown that the recombinant BJ46a (rBJ46a) protein can reduce matrix metalloproteinase (MMP) activities and inhibit invasion and metastasis of melanoma cells. Here, we optimized the Pichia pastoris system to evaluate rBJ46a protein as an anticancer agent. The Enzchek gelatinase/collagenase assay showed that rBJ46a inhibited MMP activities (IC50=0.119 mg/ml). Kinetic analyses using a series of double reciprocal Lineweaver-Burk plots (1/V vs. 1/S) showed a competitive mode of inhibition with rBJ46a with inhibitory efficiency against MMPs (Ki=13.6 nmol/l). Matrigel invasion assays showed significant activity of rBJ46a on tumor cells. For lung colonization assays, C57BL/6 mice were inoculated in the lateral tail vein with B16F10 cells and were treated with three i.v. injections of rBJ46a (1, 2, and 4 mg/kg) 24 h before cell inoculation, and 2 and 24 h after cell inoculation. Administration of rBJ46a suppressed lung tumor colony formation significantly. For spontaneous metastasis assays, MHCC97H cells were inoculated subcutaneously into nude mice. After 24 h, rBJ46a was administered by i.p. injections: 1, 2, and 4 mg/kg once daily for 6 days. rBJ46a decreased lung tumor colony formation significantly. Gelatin zymography showed that MMP2/MMP9 enzymatic activities in tumor cells were suppressed by rBJ46a in a dose-dependent manner, and the Km values of rBJ46a against MMP2 and MMP9 activities that were expressed in both B16F10 and MHCC97H cells were 3.6 and 1.4 MUmol/l, respectively. Thus, rBJ46a can inhibit the invasion and metastasis of tumor cells by reducing MMP2/MMP9 activities, indicating that rBJ46a may be a novel therapeutic agent for antimetastasis of tumor cells. PMID- 23442579 TI - BnSP-7 toxin, a basic phospholipase A2 from Bothrops pauloensis snake venom, interferes with proliferation, ultrastructure and infectivity of Leishmania (Leishmania) amazonensis. AB - This paper reports the effects of BnSP-7 toxin, a catalytically inactive phospholipase A2 from Bothrops pauloensis snake venom, on Leishmania (Leishmania) amazonensis. BnSP-7 presented activity against promastigote parasite forms both in the MTT assay, with IC50 of 58.7 MUg mL(-1) of toxin, and a growth curve, inhibiting parasite proliferation 60-70% at concentrations of 50-200 MUg mL(-1) of toxin 96 h after treatment. Also, the toxin presented effects on amastigotes, reducing parasite viability by 50% at 28.1 MUg mL(-1) and delaying the amastigote promastigote differentiation process. Ultrastructural studies showed that BnSP-7 caused severe morphological changes in promastigotes such as mitochondrial swelling, nuclear alteration, vacuolization, acidocalcisomes, multiflagellar aspects and a blebbing effect in the plasma membrane. Finally, BnSP-7 interfered with the infective capacity of promastigotes in murine peritoneal macrophages, causing statistically significant infectivity-index reductions (P < 0.05) of 20 35%. These data suggest that the BnSP-7 toxin is an important tool for the discovery of new parasite targets that can be exploited to develop new drugs for treating leishmaniasis. PMID- 23442580 TI - Letter from the editor: field of vaccines and immunotherapeutics. PMID- 23442582 TI - Positive Phase 1 interim results for killed whole-virus HIV vaccine. PMID- 23442584 TI - National Immunization Program in Iran: whys and why nots. AB - The national immunization program of Iran has played an important role in achievements toward the control, elimination and eradication of some important infectious diseases. However, there are challenges regarding both diseases covered by the program and the type of vaccine or route of delivery, which are discussed in this Commentary. The current immunization program does not provide vaccines for rotavirus, Haemophilus influenzae type b (Hib), varicella, pneumococcal and influenza. There are also issues regarding use of oral poliovirus vaccine (OPV) instead of inactivated vaccine (IPV) and whole cell pertussis (wP) instead of acellular pertussis vaccine (aP). We have reviewed the evidence regarding these immunization issues; it seems that at least for rotavirus and Hib, there is sufficient evidence regarding the efficiency of vaccination in Iran. OPV is currently preferred because of the endemic situation of polio in Afghanistan and Pakistan (eastern neighbors) and considerations of efficiency. More data are needed for the analysis of policies on pneumococcal and influenza vaccines and aP vaccine. PMID- 23442585 TI - Intanza ((r)) 9 ug intradermal seasonal influenza vaccine for adults 18 to 59 years of age. AB - Seasonal influenza in healthy working-age adults accounts for a substantial part of the socioeconomic burden of this disease. Intanza(r) 9 ug (sanofi pasteur) is a microneedle-delivered intradermal trivalent inactivated influenza vaccine approved in 2009 for the prevention of seasonal influenza in adults 18 to 59 years of age. The microneedle system reliably and reproducibly delivers the vaccine to the dermis. Clinical studies show that Intanza 9 ug is as immunogenic and as well tolerated in working-age adults as a reference intramuscular trivalent inactivated vaccine. Local reactions to Intanza 9 ug, mainly erythema, are transient, mostly mild or moderate, and do not affect acceptability. Intanza 9 ug is considered satisfactory by at least 95% of both vaccinees and prescribers, especially because of the short needle and rapid administration. Because Intanza(r) 9 ug offers an alternative to intramuscular vaccines, it might help increase influenza vaccine coverage rates. PMID- 23442586 TI - A post-marketing surveillance study of a human live-virus pandemic influenza A (H1N1) vaccine (Nasovac ((r)) ) in India. AB - A live attenuated pandemic H1N1 influenza vaccine was developed in India. A post marketing surveillance was conducted retrospectively in healthy individuals (3 3 years) who were vaccinated intranasally around one year before. After consent, the subjects recorded adverse events developing within 42 days. Among 7565 individuals (3 - 85 years), a total of 81 solicited adverse reactions (1%) were reported in 49 subjects (0.65%). The reactions included mild to moderate respiratory symptoms. No H1N1 case was encountered during one year postvaccination. The data show the safety of the live attenuated influenza vaccine platform developed in India. PMID- 23442587 TI - Additive preventive effect of influenza and pneumococcal vaccines in the elderly: results of a large cohort study. AB - Elderly people are at increased risk of influenza and pneumococcal diseases. Influenza increases clinical pneumococcal disease incidence. Pneumococcal vaccination could therefore be a supplement to influenza vaccination. This study evaluated all-cause mortality and antibiotic consumption according to elderly people's influenza and pneumococcal vaccination status. Its goal was to demonstrate that vaccination with both Influenza and pneumococcal vaccines decrease all-cause mortality and antibiotic consumption. From 2004-10-01 to 2004 12-31 (3 mo), elderly people (>= 65 y) who lived in the Gard department (South of France) were offered both vaccinations. Among the 68,897 subjects followed-up one year after this vaccination campaign, 21,303 (30.9%) were vaccinated with both vaccines, 18,651 (27.1%) with influenza vaccine alone, 3,769 (5.5%) with pneumococcal vaccine alone; 25,174 (36.5%) subjects were unvaccinated. Mortality rate (per 1,000 inhabitants-year) adjusted on gender, age and prior underlying chronic disease was 17.9 (95% CI: 16.3-19.6), 20.8 (19.0-22.8), 22.5 (19.0-26.6) and 24.7 (22.7-26.8), respectively. It was 42.1 (38.8-45.8) in elderly people with underlying chronic disease who received both vaccines vs. 58.1 (53.7-62.9) in unvaccinated elderly people. The decrease in mortality rate was 27.0% (20.0 34.0) in subjects who received both vaccines and 16.0% (6.0-24.0) in those who received influenza vaccine. No significant reduction in mortality rate was seen with the pneumococcal vaccine alone. Influenza and/or pneumococcal vaccinations did not decrease antibiotic consumption that drastically increases during the winter period. An additive effect was observed in the prevention of all-cause mortality with influenza and pneumococcal vaccines given together in elderly people, including in those with underlying chronic disease. PMID- 23442588 TI - Immunogenicity and safety of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine (PRV) in Indian infants. AB - OBJECTIVE: To evaluate the immunogenicity and safety of a pentavalent rotavirus vaccine (PRV) in Indian infants. STUDY DESIGN: Open-label, single-arm multicentric study. SETTING: Hospital facilities (out patients): SUBJECTS: One hundred and ten (110) healthy Indian infants were enrolled between the ages of 6 weeks and 12 weeks. INTERVENTION: Three doses of oral pentavalent rotavirus vaccine (PRV) were administered with an interval of 4 to 10 weeks (28 to 70 days). MAIN OUTCOME MEASURES: Immunogenicity of PRV was based on the proportion of infants exhibiting a > 3-fold rise in serum anti rotavirus IgA antibodies (from pre dose 1 to 14 days post dose 3). Safety was evaluated for 14 days after each dose. RESULTS: Of the 110 infants enrolled, 83% exhibited at least a 3-fold rise (seroconversion) in serum anti rotavirus IgA antibodies. There were no clinically significant adverse events reported. CONCLUSIONS: A 3-dose regimen of PRV was found to be immunogenic and well tolerated in healthy Indian infants. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; NCT00496054: PMID- 23442589 TI - Safety of post-exposure rabies prophylaxis during pregnancy: a follow-up study from Guangzhou, China. AB - This study aimed to assess the safety profile of post-exposure prophylaxis (PEP) for rabies in pregnant women. All of the subjects received the Essen vaccination regimen. Systemic and local reactions were monitored within 72 hours following the immunization, and the subjects were followed until six months after delivery. No moderate or severe adverse effects occurred in any subject following the vaccination. Among the 72 subjects in this follow-up study, four had voluntary abortions, one subject had an accidental miscarriage, and the remaining 67 subjects delivered babies vaginally or by caesarean section. All of the infants exhibited normal development.The purified Vero cell rabies vaccine and the purified chick embryo cell vaccine were both safe for the PEP of pregnant women and did not interfere with the development of the fetuses or infants. Education is needed in China to stop pregnancy terminations due to concerns about rabies vaccination risk. : PMID- 23442590 TI - Environmental factors potentially associated with mumps transmission in yeshivas during a mumps outbreak among highly vaccinated students: Brooklyn, New York, 2009-2010. AB - During 2009-2010, a large US mumps outbreak occurred affecting two-dose vaccinated 9th-12th grade Orthodox Jewish boys attending all-male yeshivas (private, traditional Jewish schools). Our objective was to understand mumps transmission dynamics in this well-vaccinated population. We surveyed 9th-12th grade male yeshivas in Brooklyn, NY with reported mumps case-students between 9/1/2009 and 3/30/2010. We assessed vaccination coverage, yeshiva environmental factors (duration of school day, density, mixing, duration of contact), and whether environmental factors were associated with increased mumps attack rates. Ten yeshivas comprising 1769 9th-12th grade students and 264 self-reported mumps cases were included. The average yeshiva attack rate was 14.5% (median: 13.5%, range: 1-31%), despite two-dose measles-mumps-rubella vaccine coverage between 90 100%. School duration was 9-15.5 h/day; students averaged 7 h face-to-face/day with 1-4 study partners. Average daily mean density was 6.6 students per 100 square feet. The number of hours spent face-to-face with a study partner and the number of partners per day showed significant positive associations (p < 0.05) with classroom mumps attack rates in univariate analysis, but these associations did not persist in multivariate analysis. This outbreak was characterized by environmental factors unique to the yeshiva setting (e.g., densely populated environment, prolonged face-to-face contact, mixing among infected students). However, these features were present in all included yeshivas, limiting our ability to discriminate differences. Nonetheless, mumps transmission requires close contact, and these environmental factors may have overwhelmed vaccine mediated protection increasing the likelihood of vaccine failure among yeshiva students. PMID- 23442591 TI - Horizontal transmission of live vaccines. PMID- 23442592 TI - Tumor-induced endothelial cell surface heterogeneity directly affects endothelial cell escape from a cell-mediated immune response in vitro. AB - Immune-mediated damage to tumor vessels is a potential means of preventing solid tumor progression. Antiangiogenic cancer vaccines capable of inducing this kind of damage include formulations comprised of endothelial cell-specific antigens. Identification of antigens capable of eliciting efficient vaccination is difficult because the endothelial cell phenotype is affected by surrounding tissues, including angiogenic stimuli received from surrounding tumor cells. Therefore, phenotype endothelial cell variations (heterogeneity) were examined in the context of the development of an efficient vaccine using mass spectrometry based cell surface profiling. This approach was applied to primary human microvascular endothelial cell (HMEC) cultures proliferated under growth stimuli provided by either normal tissues (growth supplement from human hypothalamus) or cancer cells (MCF-7, LNCap and HepG2). It was found that tumors induced pronounced, tumor type-dependent changes to HMEC surface targets that in an in vitro model of human antiangiogenic vaccination directly facilitated HMEC escape from cytotoxic T cell-mediated cell death. Furthermore, it was found that tumors influenced the HMEC phenotype unidirectionally and that HMEC imunogenicity was reciprocal to the intensity of tumor-induced changes to the HMEC surface. These findings provide data for the design of tumor-specific endothelial cell based vaccines with sufficient immunogenicity without posing a risk to the elicitation of autoimmunity if administered in vivo. PMID- 23442593 TI - Peptide vaccines for hepatocellular carcinoma. AB - Immunotherapy is a potentially attractive treatment option for patients with hepatocellular carcinoma (HCC). We have reported that glypican-3 (GPC3) is an ideal target for anticancer immunotherapy against HCC because its expression is specifically detected in > 80% of HCCs, even during the early stages. Further, increased GPC3 expression is correlated with a poor prognosis. Based on results obtained from a preclinical study using mice, we conducted a phase I clinical trial using a GPC3-derived peptide vaccine. Phase I results showed that the GPC3 derived peptide vaccine was well tolerated. Furthermore, this was the first study to show that the frequency of peptide-specific cytotoxic T lymphocytes was correlated with overall survival in patients with HCC receiving a peptide vaccine. Next, we conducted a phase II clinical trial using the GPC3-derived peptide vaccine in patients with HCC after surgery or radiofrequency ablation (adjuvant setting). We are currently evaluating a third trial involving liver biopsies removed from patients with advanced HCC before and after GPC3-derived peptide vaccination. We expect that the results of these trials will result in future drug development. PMID- 23442594 TI - Cancer targeting vaccines: surrogate measures of activity. AB - Recent FDA approval of sipuleucel-T and Ipilimumab as indicated immunologic therapy in patients with advanced prostate cancer and melanoma, respectively, has established a foothold for broader utilization of vaccine based technology in managing cancer. Despite difficulty of cell harvest and processing with sipuleucel-T and modest toxicity to Ipilimumab, when matched up with the appropriate cancer patient these immunologic approaches have provided significant benefit and have stimulated exciting forward progress in the development of new potent and less toxic (more targeted) vaccines. However, surrogate measures of activity to optimally define more sensitive subset populations and to determine length of treatment time in order to optimize management with other treatment options remain elusive. Key clinically tested vaccines under development which demonstrate correlation of patient benefit to induced immune responsiveness will be discussed. Results suggest with some vaccines correlation of patient benefit and surrogate measures of activity actually do exist. Examples will be discussed. PMID- 23442595 TI - Characterization of hepatic tumors using [11C]metomidate through positron emission tomography: comparison with [11C]acetate. AB - BACKGROUND: Using positron emission tomography (PET), we compared two tracers, [11C]metomidate ([11C]MTO) and [11C]acetate ([11C]ACE), for the characterization of hepatic tumors. METHODS: Thirty-three patients underwent PET with [11C]MTO and [11C]ACE and magnetic resonance imaging (MRI). Based on the histology of the tumor biopsy, 14 patients had hepatocellular carcinoma (HCC), 9 patients had focal nodular hyperplasia (FNH), and 10 patients had other types of hepatic tumors. Tumor uptake was evaluated by calculating the maximum and mean standardized uptake value and tumor-to-liver ratio. RESULTS: Altogether, 120 hepatic lesions (59 HCC, 18 FNH, 30 metastases of different primaries, 9 adenomas, and 4 regenerating nodules of liver cirrhosis) were detected by MRI. The overall tumor detection rate was slightly higher for [11C]MTO (39%) than for [11C]ACE (33%). [11C]ACE was more sensitive for HCC detection (50% versus 43%, respectively), whereas [11C]MTO was more sensitive for FNH detection (78% versus 44%, respectively). In HCC patients, the tumor grade correlated with [11C]ACE, but not with [11C]MTO. All of the patients with liver metastases, from various primary tumors (n = 10), were negative for both tracers. CONCLUSIONS: Due to low sensitivity, [11C]MTO and [11C]ACE PET have only limited value in diagnosing hepatic tumors. PMID- 23442596 TI - A contour-guided deformable image registration algorithm for adaptive radiotherapy. AB - In adaptive radiotherapy, deformable image registration is often conducted between the planning CT and treatment CT (or cone beam CT) to generate a deformation vector field (DVF) for dose accumulation and contour propagation. The auto-propagated contours on the treatment CT may contain relatively large errors, especially in low-contrast regions. A clinician's inspection and editing of the propagated contours are frequently needed. The edited contours are able to meet the clinical requirement for adaptive therapy; however, the DVF is still inaccurate and inconsistent with the edited contours. The purpose of this work is to develop a contour-guided deformable image registration (CG-DIR) algorithm to improve the accuracy and consistency of the DVF for adaptive radiotherapy. Incorporation of the edited contours into the registration algorithm is realized by regularizing the objective function of the original demons algorithm with a term of intensity matching between the delineated structures set pairs. The CG DIR algorithm is implemented on computer graphics processing units (GPUs) by following the original GPU-based demons algorithm computation framework (Gu et al 2010 Phys Med Biol. 55 207-219). The performance of CG-DIR is evaluated on five clinical head-and-neck and one pelvic cancer patient data. It is found that compared with the original demons, CG-DIR improves the accuracy and consistency of the DVF, while retaining similar high computational efficiency. PMID- 23442597 TI - Thiamine modulates metabolism of the phenylpropanoid pathway leading to enhanced resistance to Plasmopara viticola in grapevine. AB - BACKGROUND: Previously, we have reported the ability of thiamine (vitamin B1) to induce resistance against Plasmopara viticola in a susceptible grapevine cv. Chardonnay. However, mechanisms underlying vitamins, especially, thiamine-induced disease resistance in grapevine are still largely unknown. Here, we assessed whether thiamine could modulate phenylpropanoid pathway-derived phytoalexins in grapevine plants, as well as, the role of such secondary metabolites in thiamine induced resistance process to P. viticola. RESULTS: Our data show that thiamine treatment elicited the expression of phenylpropanoid pathway genes in grapevine plants. The expression of these genes correlated with an accumulation of stilbenes, phenolic compounds, flavonoids and lignin. Furthermore, the total anti oxidant potential of thiamine-treaded plants was increased by 3.5-fold higher level as compared with untreated-control plants. Four phenolic compounds are responsible of 97% of the total anti-oxidant potential of thiamine-treated plants. Among these compounds, is the caftaric acid, belonging to the hydroxy cinnamic acids family. This element contributed, by its own, by 20% of this total anti-oxidant potential. Epifluorescence microscopy analysis revealed a concomitant presence of unbranched-altered P. viticola mycelia and stilbenes production in the leaf mesophyll of thiamine-treated inoculated plants, suggesting that stilbenes are an important component of thiamine-induced resistance in grapevine. CONCLUSION: This work is the first to show the role of thiamine, as a vitamin, in the modulation of grapevine plant secondary metabolism contributing to an enhanced resistance to P. viticola, the most destructive fungal disease in vineyards. PMID- 23442598 TI - NGcGM3/VSSP vaccine as treatment for melanoma patients. AB - Gangliosides are glycosphingolipids that are present in the plasma membranes of vertebrates and are involved in multiple cellular processes. In the Center of Molecular Immunology an NGcGM3 ganglioside based vaccine has been developed and is conceptualized as a targeted therapy in cancer. NGcGM3/VSSP vaccine had been used as treatment of metastatic melanoma patients and had showed to be safe and immunogenic. The treatment improved antitumoral response or maintain the response obtained with previous onco-specific treatment as chemotherapy. The results indicate that the vaccine improved overall survival of metastatic melanoma patients after first line-chemotherapy. The clinical trial ongoing currently will allow corroborating these results. PMID- 23442600 TI - Comparison between unsintered hydroxyapatite/poly-L-lactic acid mesh and titanium mesh in bone regeneration of rabbit mandible. AB - PURPOSE: The purpose of this study was to compare the bone regenerative capability of using unsintered hydroxyapatite/poly-L-lactic acid (uHA/PLLA) mesh and titanium mesh. MATERIALS AND METHODS: Adult male white rabbits (n = 24) were divided into 2 groups. After incising along the mandible, 3 * 5 mm bone defects were made in both sides and covered by an uHA/PLLA mesh (n = 12) or a titanium mesh (n = 12) on the right side but no mesh on the left side (n = 12). The rabbits were sacrificed at 1, 2, and 4 weeks postoperatively, and formalin-fixed specimens were embedded in acrylic resin. The specimens were stained with hematoxylin and eosin. For immunohistochemical analysis, the specimens were treated with BMP-2. RESULTS: The titanium group and uHA/PLLA group were significantly larger than the control group regarding the bone area ratio postoperatively at 2 and 4 weeks. However, there were no significant differences between the uHA/PLLA group and titanium group regarding the BMP-2. CONCLUSIONS: This study suggested that the uHA/PLLA mesh could increase new bone formation more than the absence of a mesh in bone defects. However, there was no significant difference between uHA/PLLA mesh and the titanium mesh in bone augmentation. PMID- 23442599 TI - Effect of framework soldering on the deformation of implant abutments after framework seating: a study with strain gauges. AB - INTRODUCTION: Passive fit has been considered an important requirement for the longevity of implant-supported prostheses. Among the different steps of prostheses construction, casting is a feature that can influence the precision of fit and consequently the uniformity of possible deformation among abutments upon the framework connection. PURPOSE: This study aimed at evaluating the deformation of abutments after the connection of frameworks either cast in one piece or after soldering. MATERIALS AND METHODS: A master model was used to simulate a human mandible with 5 implants. Ten frameworks were fabricated on cast models and divided into 2 groups. Strain gauges were attached to the mesial and distal sides of the abutments to capture their deformation after the framework's screw retentions were tightened to the abutments. RESULTS: The mean values of deformation were submitted to a 3-way analysis of variance that revealed significant differences between procedures and the abutment side. The results showed that none of the frameworks presented a complete passive fit. CONCLUSION: The soldering procedure led to a better although uneven distribution of compression strains on the abutments. PMID- 23442601 TI - Spontaneous transmaxillary-transnasal implant loss: a case report. AB - Although implant placement is regarded as a safe procedure, some reports about displacement or migration to the maxillary cavity have been published. Further migration to other paranasal cavities and spontaneous loss are rare events. A case is reported of a migration to the inferior nasal meatus, which is documented by cone-beam CT, with subsequent spontaneous loss. Mucociliary clearance in combination with a local osteolytic inflammatory process likely caused this unusual migration. PMID- 23442602 TI - An in vitro evaluation of heat production during osteotomy preparation for dental implants with compressive osteotomes. AB - BACKGROUND: To assess heat production using osteotomes under conditions simulating implant placement in D3, D4 bone. MATERIAL AND METHODS: Implant osteotomes were tested (Winsix, Biosafin, Italy). Site preparations were performed on porcine ribs through a compressive fashion. The ribs were partially immersed in a custom-made water bath/water pump system that maintained the baseline temperature at 36 degrees C. Temperatures generated at different depths (2, 5, and 9 mm) during a series of 25 osteotomies were measured using 3 thermocouples connected to a digital thermometer. RESULTS: The mean temperatures never exceeded 37 degrees C and were all significantly lower than those reported during preparation with standard implant drills. Statistical evaluation of the temperature during implant site preparation showed slight significant variations between the baseline values and those of the different depth preparations. CONCLUSIONS: Within the limits of this study, the production of heat during implant preparation using osteotomes shows significant variations at different depths. However, these variations are not clinically relevant because they never increased over the values that negatively affect bone that may jeopardize osseointegration. PMID- 23442603 TI - Use of N-butyl cyanoacrylate with metacryloxisulfolane (glubran 2) surgical glue for flapless closure of oroantral communication. AB - AIM: To present first experience of the use N-butyl cyanoacrylate with metacryloxisulfolane (Glubran 2) synthetic surgical glue, in the nonsurgical closure of oroantral communication (OAC). MATERIAL AND METHODS: Two OACs, created after the exodontia of tooth 27 in 2 female patients, were sealed and closed with Glubran 2 surgical glue and monitored OACs, until the epithelization of the sockets was ended successfully. Two months postclosure of OACs, the sealed OACs were evaluated on the panoramic image and Water's view radiography. RESULTS: The extraction wounds with OACs were monitored until 23rd and 25th postinterventional days, when epithelization of socket ended successfully. On the panoramic image and Water's view radiography, there were no radiological signs of maxillary sinus pathoses. CONCLUSION: Glubran 2 can be successfully applied in the closure of OAC from 3 to 5 mm in diameter. PMID- 23442604 TI - Objective assessment, repeatability, and agreement of shoulder ROM with a 3D gyroscope. AB - BACKGROUND: Assessment of shoulder mobility is essential for diagnosis and clinical follow-up of shoulder diseases. Only a few highly sophisticated instruments for objective measurements of shoulder mobility are available. The recently introduced DynaPort MiniMod TriGyro ShoulderTest-System (DP) was validated earlier in laboratory trials. We aimed to assess the precision (repeatability) and agreement of this instrument in human subjects, as compared to the conventional goniometer. METHODS: The DP is a small, light-weight, three dimensional gyroscope that can be fixed on the distal upper arm, recording shoulder abduction, flexion, and rotation. Twenty-one subjects (42 shoulders) were included for analysis. Two subsequent assessments of the same subject with a 30-minute delay in testing of each shoulder were performed with the DP in two directions (flexion and abduction), and simultaneously correlated with the measurements of a conventional goniometer. All assessments were performed by one observer. Repeatability for each method was determined and compared as the statistical variance between two repeated measurements. Agreement was illustrated by Bland-Altman-Plots with 95% limits of agreement. Statistical analysis was performed with a linear mixed regression model. Variance for repeated measurements by the same method was also estimated and compared with the likelihood-ratio test. RESULTS: Evaluation of abduction showed significantly better repeatability for the DP compared to the conventional goniometer (error variance: DP = 0.89, goniometer = 8.58, p = 0.025). No significant differences were found for flexion (DP = 1.52, goniometer = 5.94, p = 0.09). Agreement assessment was performed for flexion for mean differences of 0.27 degrees with 95% limit of agreement ranging from -7.97 degrees to 8.51 degrees . For abduction, the mean differences were 1.19 degrees with a 95% limit of agreement ranging from -9.07 degrees to 11.46 degrees . CONCLUSION: In summary, DP demonstrated a high precision even higher than the conventional goniometer. Agreement between both methods is acceptable, with possible deviations of up to greater than 10 degrees . Therefore, static measurements with DP are more precise than conventional goniometer measurements. These results are promising for routine clinical use of the DP. PMID- 23442605 TI - Promoter hypomethylation, especially around the E26 transformation-specific motif, and increased expression of poly (ADP-ribose) polymerase 1 in BRCA-mutated serous ovarian cancer. AB - BACKGROUND: Poly (ADP-ribose) polymerase 1 (PARP1) overexpression plays a critical role in ovarian cancer progression and the clinical development of PARP1 inhibitors to treat BRCA-mutated ovarian cancer has advanced rapidly. However, the mechanism regulating PARP1 expression remains unknown. Alterations in gene expression mediated by promoter methylation are being increasingly recognized and have frequently been reported in ovarian cancer. We therefore investigated the methylation status of the PARP1 promoter region and its correlation with PARP1 expression in BRCA-mutated ovarian cancer. METHODS: DNA from BRCA-mutated serous ovarian cancer samples and adjacent normal ovarian tissues were analyzed by bisulfite sequence using primers focusing on the CpG island in the promoter region of PARP1. Expression levels of PARP1 were assessed by immunohistochemistry and real-time PCR. RESULTS: Serous ovarian cancer tissues displayed decreased DNA methylation in the promoter region of PARP1 compared to normal tissue, and methylation intensity correlated inversely with PARP1 mRNA levels. More importantly, E26 transformation-specific (ETS) defined CpG sites were significantly less methylated in ovarian cancer samples. CONCLUSIONS: These results indicate that hypomethylation of the promoter region, especially around the ETS motif might play a role in the upregulation of PARP1 expression in the progression of ovarian cancer. PMID- 23442606 TI - Perception of stress-related working conditions in hospitals (iCept-study): a comparison between physicians and medical students. AB - BACKGROUND: The students' perception of working conditions in hospitals hasn't been subject of research in Germany so far. However the perception plays an important role talking about the sustainability of working conditions. The iCept Study wants to examine the perception of medical students compared to the perception of practicing physicians. METHODS/DESIGN: The perception will be investigated with a redesigned questionnaire based upon two established and validated questionnaires. The two samples built for this study (students and physician) will be chosen from members of the labor union Marburger Bund. The iCept-Study is designed as an anonymized online-survey. DISCUSSION: The iCept Study is thought to be the basis of ongoing further investigations regarding the perception of working conditions in hospitals. The results shall serve the facilitation of improving working conditions. PMID- 23442607 TI - A preparation of murine liver fragments for in vitro studies: liver preparation for toxicological studies. AB - BACKGROUND: The aim of this study was to develop liver tissue preparation suitable for investigating toxins. Hepatocyte respiration, ATP content, urea synthesis, caspase activity and morphology were measured as a function of in vitro incubation time. Mice were anesthetized by sevoflurane inhalation. Small liver fragments were then rapidly excised and incubated at 37 degrees C in Krebs Henseleit buffer (continuously gassed with 95% O2: 5% CO2) for up to 6 h. Phosphorescence O2 analyzer was used to determine the rate of cellular mitochondrial O2 consumption (kc, MUM O2 min-1 mg-1). Cellular ATP was measured using the luciferin/luciferase system. The caspase-3 substrate N-acetyl-asp-glu val-asp-7-amino-4-methylcoumarin (Ac-DEVD-AMC) was used to monitor intracellular caspase activity; cleaved AMC moieties (reflecting caspase activity) were separated on HPLC and detected by fluorescence. FINDINGS: Respiration was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. The values of kc (mean +/- SD) for 0<= t <=6 h were 0.15 +/- 0.02 MUM O2 min-1 mg 1 (n = 18, coefficient of variation, CV = 13%), ATP content 131 +/- 69 pmol mg-1 (1<= t <=6 h, n = 16, CV = 53%), synthesized urea 0.134 +/- 0.017 mg/dL mg-1 in 50 min (0<= t <=6 h, n = 14, CV = 13%), and AMC peak area 62,540 +/- 26,227 arbitrary units mg-1 (1<= t <=6 h, n = 3, CV = 42%). Hepatocyte morphology and organelles were reasonably persevered. CONCLUSIONS: The described liver tissue preparation demonstrates stable hepatocyte structure, ultrastructure and biomarkers for up to 6 h, permitting in vitro studies. PMID- 23442608 TI - Immunogenicity and reactogenicity of two diphtheria-tetanus-whole cell pertussis vaccines in Iranian pre-school children, a randomized controlled trial. AB - The present study was undertaken to compare the immunogenicity and reactogenicity of two diphtheria-tetanus-whole cell pertussis (DTwP) vaccines administered to Iranian preschool children. In this randomized, double-blind and multicenter prospective study, 672 children aged 4-6 y were administered with either a local DTwP vaccine (DTwP-Local) (n = 337) or a commercial vaccine (DTwP-Pasteur) (n = 335). All subjects received DTwP vaccine at 4-6 y of age, following the national immunization schedule of Iran. Blood samples were collected before and 2-4 weeks after the vaccination. Immunogenicity of each vaccine was assessed by ELISA using commercial kits. Reactogenicity was assessed by the parents for seven days post booster using diary cards. The geometric mean titers (GMTs) of the antibodies induced against diphtheria and tetanus by DTwP-Local were 7.7 and 9.4 IU/ml and those of DTwP-Pasteur were 8.2 and 8.6 IU/ml, respectively. There was no significant difference between the immunogenicity of the two vaccines against diphtheria and tetanus. The GMTs of antibodies produced against pertussis were 30.2 EU/ml for DTwP-Local and 47.9 EU/ml for DTwP-Pasteur vaccines (p<0.001). Pain and fever (axillary temperature>37.5 degrees C) were the most frequent local and systemic reactions observed after the vaccination. All local and systemic reactions observed after vaccination were significantly higher in subjects immunized with DTwP-Local vaccine. Immunogenicity against diphtheria and tetanus was similar for the two vaccines, but immunogenicity of the local vaccine against pertussis was significantly less efficient than that of DTwP-Pasteur. This difference and the higher side effects of the DTwP-Local vaccine could be due to the bacterial strain or the preparation or formulation protocol of the local pertussis vaccine. PMID- 23442609 TI - In situ synthesis of P3HT-capped CdSe superstructures and their application in solar cells. AB - Organic/inorganic hybrid solar cells have great potentials to revolutionize solar cells, but their use has been limited by inefficient electron/hole transfer due to the presence of long aliphatic ligands and unsatisfying continuous interpenetrating networks. To solve this problem, herein, we have developed a one pot route for in situ synthesis of poly(3-hexylthiophene) (P3HT)-capped CdSe superstructures, in which P3HT acts directly as the ligands. These CdSe superstructures are in fact constructed from numerous CdSe nanoparticles. The presence of P3HT ligands has no obvious adverse effects on the morphologies and phases of CdSe superstructures. Importantly, higher content of P3HT ligands results in stronger photoabsorption and fluorescent intensity of CdSe superstructure samples. Subsequently, P3HT-capped CdSe superstructures prepared with 50 mg P3HT were used as a model material to fabricate the solar cell with a structure of PEDOT:PSS/P3HT-capped CdSe superstructures: P3HT/Al. This cell gives a power conversion efficiency of 1.32%. PMID- 23442610 TI - The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age. AB - INTRODUCTION: Interleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype. METHODS: 13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation. RESULTS: seven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab. CONCLUSIONS: The use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage. PMID- 23442611 TI - The effects of host defence elicitors on betacyanin accumulation in Amaranthus mangostanus seedlings. AB - The effect of elicitors associated with host defence on betacyanin accumulation in Amaranthus mangostanus seedlings was investigated. Under the conditions of the experiments, betacyanin accumulation was generally enhanced by light. Methyl jasmonate (MeJA) treatment increased betacyanin synthesis in a concentration dependent response. Seedlings treated with ethylene as 5mM Ethephon also had elevated levels of betacyanin. In contrast, salicylic acid (SA) and H(2)O(2) treatments had no influence on betacyanin contents in light or dark. Combined MeJA with Ethephon or H(2)O(2) had an additive effect on betacyanin accumulation in dark-grown seedlings. However, a decline was recorded in light-grown seedlings. Moreover, an antagonistic effect on betacyanin synthesis was found when MeJA and SA were added simultaneously. Our results indicate that betacyanin content in A. mangostanus seedlings can be upregulated by MeJA and ethylene. Both additive and antagonistic effects in regulating betacyanin synthesis in A. mangostanus seedlings were observed between MeJA and other elicitors. PMID- 23442612 TI - Effect of soy and milk protein-related compounds on Listeria monocytogenes infection in human enterocyte Caco-2 cells and A/J mice. AB - Listeria monocytogenes causes listeriosis in humans, mainly through the consumption of ready-to-eat foods such as cheese. Immunocompromised persons, the elderly, and pregnant women and their fetuses or newborns are at the highest risk for the infection. We examined the effects of dietary milk-casein (MC) and soy protein (SP), and their digested compounds tryptone (TP) and phytone peptone (PP), respectively, on L. monocytogenes invasion and infection in human enterocyte-like Caco-2 cells and A/J mice. Invasion into Caco-2 cells tended to be high with TP. In A/J mice orally infected with L. monocytogenes, viable numbers in the liver and spleen showed a tendency of decreasing with the 20% SP diet compared to the 20% MC diet. SP suppressed the inflammation marker tumour necrosis factor-alpha in spleen tissue. Furthermore, bacteria lipopolysaccharide (LPS)-stimulated nitric oxide (NO) secretion from murine macrophage RAW 264.7 cells was suppressed by PP more than TP. These results suggest that major dietary proteins might affect infection and inflammation by L. monocytogenes. PMID- 23442613 TI - Pressurised hot water extraction with on-line particle formation by supercritical fluid technology. AB - In this work, an on-line process for pressurised hot water extraction (PHWE) of antioxidants from plants as well as drying of the extract in one step by particle formation based on the use of supercritical carbon dioxide (SC-CO(2)) has been developed. This process has been called WEPO(r), water extraction and particle formation on-line. With this process, dried extracts from onion with the same composition of quercetin derivatives as non-dried extracts have been obtained as a fine powder with spherical particles from 250 nm to 4 MUm in diameter. The major compounds present in the extract were quercetin-3,4'-diglucoside, quercetin 4'-glucoside and quercetin. An auxiliary inert gas (hot N(2)) was used to enhance the drying process. Parameters such as temperature (120 degrees C), SC-CO(2) and N(2) pressures (80 and 12.5 bar, respectively) and flow rate of SC-CO(2) (10 ml/min), have been settled by trial-and-error in order to achieve a fine and constant spray formation. Water content, size and morphology, antioxidant capacity and quercetin content of the particles were studied to evaluate the efficiency of the WEPO process. Results were compared with the ones from extracts obtained by continuous flow PHWE followed by freeze-drying. Results showed that both processes gave similar results in terms of antioxidant capacity, concentration of quercetin derivatives and water content, while only WEPO was able to produce defined spherical particles smaller than 4 MUm. PMID- 23442614 TI - Profiling of volatile compounds of Phyllostachys pubescens shoots in Taiwan. AB - This study examined the influence of heating temperature and duration on volatile aromatic components of spring and winter Phyllostachys pubescens shoots using SPME. Results from GC-MS analyses revealed that the main constituents in both bamboo shoots at ambient temperature include methoxy-phenyl oxime, followed by n hexanol and 3Z-hexenal, which gives a fresh green aroma. Comparing the different compounds, between spring and winter shoots, revealed that spring bamboo shoots at ambient temperature comprise 12.30% methyl salicylate, which provides protection against insect attack, and 9.71% epi-cedrol; while winter bamboo shoots comprise 17.00% 1-octen-3-ol, which produces a distinct mushroom aroma. After heating at 100 degrees C for 60 min, a marked increase in relative content of benzyl salicylate (43.30%) and a significant decrease in methyl salicylate content in spring bamboo shoots were observed; while the major compound in winter bamboo shoots was n-heneicosane (78.09%) and the content of specific 1-octen-3-ol significantly decreased. PMID- 23442615 TI - Tenderization effect of cold-adapted collagenolytic protease MCP-01 on beef meat at low temperature and its mechanism. AB - The enzymes currently used to increase meat tenderness are all mesophilic or thermophilic proteases. This study provides insight into the tenderization effect and the mechanism of a cold-adapted collagenolytic enzyme MCP-01 on beef meat at low temperatures. MCP-01 (10 U of caseinolytic activity) reduced the meat shear force by 23% and increased the relative myofibrillar fragmentation index of the meat by 91.7% at 4 degrees C, and it also kept the fresh colour and moisture of the meat. Compared to the commercially used tenderizers papain and bromelain, MCP 01 showed a unique tenderization mechanism. MCP-01 had a strong selectivity for degrading collagen at 4 degrees C, showed a distinct digestion pattern on the myofibrillar proteins, and had a different disruption pattern on the muscle fibres under scanning electron micrograph. These results suggest that the cold adapted collagenolytic protease MCP-01 may be promising for use as a meat tenderizer at low and moderate temperatures. PMID- 23442616 TI - Integrated biocatalytic process for trehalose production and separation from rice hydrolysate using a bioreactor system. AB - Rice starch can be hydrolyzed into maltose for trehalose bioconversion by enzymatic methods. In this study, we have successfully established an efficient production system for our recombinant PTTS in large scale. Three bio-treatments were developed to simplify the separation and purification of trehalose from complex rice saccharified liquid. The trehalose conversion rate of 64.63+/-4.05% at 30 degrees C can be reached using rice hydrolysate as the substrate in a 5l fermentor system. By 1% of raw material koji fermentation, the highest concentration of bioethanol (3.61+/-0.07%) was obtained at 30 degrees C for 36 h. After 12h of reaction time, the gluconic acid (24.47+/-0.33 mM) was successfully produced by glucose oxidase (40 U/g rice) using residual glucose as a substrate. After the batch/continuous ionic exchange process, the trehalose can be successfully separated, crystallized and identified as 92.6+/-0.02% purity and 94.2% of the recovery yield, respectively. PMID- 23442617 TI - PM6 and DFT study of free radical scavenging activity of morin. AB - Flavonoids have long been recognised for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work, we have studied the properties of flavonoid morin using semiempirical and density functional theory (DFT) methods in order to validate the application of the recently developed parametric method 6 (PM6). Reaction enthalpies related to mechanisms of free radical scavenging by flavonoid morin were calculated by DFT and PM6 methods in gas-phase, water, DMSO and benzene. It has been shown that fast semiempirical PM6 method can mimic results obtained by means of more accurate time consuming DFT calculations. Thermodynamically favoured mechanism depends on reaction medium: SPLET (sequential proton loss electron transfer) is preferred in water and DMSO, and HAT (hydrogen atom transfer) is predominant in gas-phase. In benzene these two mechanisms are competitive. PMID- 23442618 TI - Effect of electrolyzed reduced water on chiral theanine and polyphenols in tea. AB - Pure D/L-theanine enantiomers were synthesized separately, and SEM was used for their crystal-structure observation. The novel enantiomeric separating method by HPLC was established using the chiral selector of beta-CD in the mobile phase. Green tea, white tea, oolong tea, black tea and Pu-erh tea were tested for theanine enantiomers by different degrees of fermentation. The significantly higher d-enantiomeric proportion of theanine was found in white tea than the others, which was probably due to its specific processing step of withering. The effect of electrolyzed reduced water (ERW) on enantiomeric theanine and polyphenols in tea was explored. There was no change of theanine, but rather a loss of ECG (epicatechin gallate) and an increasing amount of GA (gallic acid). ERW also reduced tea cream, which contains significant amount of polyphenols, indicating its potential application in the tea-beverage industry. PMID- 23442619 TI - Antioxidant mechanism of grape procyanidins in muscle tissues: redox interactions with endogenous ascorbic acid and alpha-tocopherol. AB - The present study investigates the antioxidant mechanism of grape procyanidins and, in particular, their aptitude to establish redox interactions with two important components of the endogenous antioxidant system of muscle tissues, alpha-tocopherol (alpha-TOH) and ascorbic acid (AA). To this end, the progress of lipid oxidation was monitored in fish muscle supplemented with grape procyanidins at the concentrations usually employed in antioxidant food applications, and then related to the redox stability of the endogenous alpha-TOH and AA. In addition to the lipid oxidation protective effect, the incorporation of procyanidins also provided an improvement of the redox stability of the endogenous components in a straight procyanidinic concentration-dependent manner. Results showed the capacity of procyanidins to repair oxidised alpha-TOH at medium-long term, and to delay the AA depletion. Therefore, such cooperative redox interaction of exogenous procyanidins adequately complements the natural alpha-TOH regenerative system supplied by AA that is efficient at the early post mortem stages. PMID- 23442620 TI - Chitosan-tripolyphosphate submicron particles as the carrier of entrapped rutin. AB - Chitosan (CH)-tripolyphosphate (TPP) submicron particles were formed as carriers of entrapped rutin, and the release properties characterized using simulated gastric juices and fluids of the small intestine. Particle size, charge and entrapment efficiencies were investigated as a function of the CH:TPP molar ratio (2.0:1.0-5.0:1.0). Size was found to decrease from ~814 nm for the 2.0:1:0 mass ratio to ~528 nm for the ratios between 2.5:1.0 and 4.0:1.0, and then again to ~322 nm for the 5:0:1.0 mass ratio, whereas all particles carried a positive surface charge, increasing from +21 to +59 mV as the ratio increased from 2.0:1.0 to 5.0:1.0. The percent entrapment was found to rise from 3.68% to 57.6% as the ratios increased from 2.0:1:0 to 4.0:1:0, before reaching a plateau. Submicron particles (4.0:1.0 mass ratio only) were found to retain rutin in simulated gastric fluids, whereas in conditions which simulated fluids from the small intestine, only 20% of the entrapped rutin was released and 80% remained absorbed to the CH:TPP carriers. Such particles have applications for the delivery of phenolics in food and natural health products. PMID- 23442621 TI - Protective effect of white tea extract against acute oxidative injury caused by adriamycin in different tissues. AB - Adriamycin (ADR) is an anticancer agent that increases oxidative stress in cells. We evaluated the protective effect of the long term consumption of white tea at two different doses against this drug. For this purpose rats were given distilled water (controls), 0.15 mg (Dose 1) or 0.45 mg (Dose 2) of solid tea extract/kg body weight for 12 months. All the animals received an injection of ADR, except half of the control group, which were given an injection of saline solution. This gave four experimental groups: Control (C), C+ADR, Dose 1+ADR, and Dose 2+ADR. The antioxidant activity (in liver, heart and brain microsomes) was analysed. White tea consumption for 12 months, at a non-pharmacological dose, reversed the oxidative damage caused by ADR, on both protein and lipid levels in all three organs. The heart recovered its antioxidant activity only at the highest dose of tea. PMID- 23442622 TI - The impact of industrial processing on health-beneficial tomato microconstituents. AB - The effect of industrial processing was investigated on the stability of tomato carotenoids, phenolic compounds and ascorbic acid. A deep insight in the processed products allowed the quantification of caffeic acid hexosides, which are far more important contributors than the well-known chlorogenic acid, dicaffeoylquinic acids and quercetin oligosaccharides (new feruloyl, sinapoyl and syringoyl derivatives of quercetin apiosylrhamnosylglucoside). (E)-beta-Carotene and (E)-lycopene were also quantified along with different mono- and di-(Z) isomers of lycopene which were tentatively assigned. Processing of fresh tomato into paste had an overall positive effect on the contents in phenolic compounds, no effect on lycopene and a slight and high detrimental effect on beta-carotene and ascorbic acid, respectively. The balance between the increase in tomato matrix extractability and microconstituent catabolism was further observed in two contrasted transformations of paste into sauce. Overall, the nutritional quality of tomato-processed products, except for ascorbic acid, is mainly preserved through manufacture. PMID- 23442623 TI - Effect of acetylation, oxidation and annealing on physicochemical properties of bean starch. AB - Black and Pinto bean starches were physically and chemically modified to investigate the effect of modification on digestibility and physicochemical properties of bean starch. The impact of acetylation, oxidation (ozonation) and annealing on the chemical composition, syneresis, swelling volume, pasting, thermal properties and digestibility of starches was evaluated. The physicochemical and estimated glycemic index (eGI) of the Black and Pinto bean starches treated with ozone were not significantly (P>0.05) different than that of their respective control starches. Annealed starches had improved thermal and pasting properties compared to native starches. Acetylated starches presented reduced syneresis, good pasting properties and lower eGI. Also, all modified starches had increased levels of resistant starch (RS). Therefore, the digestibility and physicochemical properties of bean starch were affected by the type of modification but there were no significant (P>0.05) differences between the Black and Pinto bean starches. PMID- 23442624 TI - Guarana powder polysaccharides: characterisation and evaluation of the antioxidant activity of a pectic fraction. AB - Guarana is a fruit from the Amazon whose seeds are used to produce guarana powder. Guarana powder is consumed by the population mainly for its stimulant activity. It has been shown that guarana seeds contain low-molar-mass compounds; however, no data have been reported concerning the polysaccharides. In this work, the polysaccharides present in guarana powder were investigated. A pectic fraction and a xylan were isolated and characterised. Antioxidant activity tests were performed with a methanolic extract and the pectic fraction at concentrations of 0.1-10 mg/ml. The methanolic extract exhibited a strong capacity for scavenging DPPH radicals (90.9% at 10 mg/ml). At the same concentration, the polysaccharide showed a DPPH(.)-scavenging activity of 68.4%. At a higher concentration, the methanolic extract and the polysaccharide exhibited similar hydroxyl radical-scavenging effects (~70%). The results suggest that the polysaccharides present in guarana can contribute to the possible biological effects of guarana powder. PMID- 23442625 TI - Structure of pectic polysaccharides isolated from onion Allium cepa L. using a simulated gastric medium and their effect on intestinal absorption. AB - The polysaccharide fraction extracted with simulated gastric juice from onion bulbs contained a mixture of galactan with short-length sugar chains, pectic polysaccharides and evident content of proteinaceous material. Galacturonan and rhamnogalacturonan were the main constituents of the linear regions of the sugar chains of the pectic polysaccharides. The ramified regions included rhamnogalacturonan-I. NMR data revealed that the side chains of the ramified region contained mainly 1,4-linked beta-D-galactopyranose residues and lesser content of 1,3-linked beta-D-galactopyranose and 1,5-linked alpha-L arabinofuranose residues. Furthermore, the proteinaceous material was determined to be partly linked to the sugar chains. The polysaccharide fraction was found to decrease absorption of ovalbumin (OVA) to the blood from the gut lumen. The serum OVA level was threefold lower in mice fed with OVA mixed with the onion pectins compared with the control group, which was administered OVA alone. Protein removal failed to abolish the inhibitory effect of the onion polysaccharides, confirming that the polysaccharide chains are the active component of onion gastric juice extract. PMID- 23442626 TI - A novel gelatin crosslinking method retards release of mulberry 1 deoxynojirimycin providing a prolonged hypoglycaemic effect. AB - Mulberry 1-deoxynojirimycin (DNJ), a potent alpha-glycosidase inhibitor, has therapeutic potency in the suppression of postprandial blood glucose levels thereby possibly preventing diabetes mellitus. However, DNJ has a relatively short half-life in vivo (about 2 h). Therefore, several doses of mulberry DNJ are required to achieve optimal therapeutic results. This study aimed to delay the release of mulberry DNJ with biodegradable matrices to maintain the intestinal DNJ concentration and prolong the hypoglycaemic effect in vivo. A novel, simple, and commercially viable method was adopted to develop DNJ-entrapped microspheres (DNJ-MSs). A higher extent of crosslinking and the larger sized DNJ-MS decreased the rate of mulberry DNJ release in vitro. Consequently, an in vivo study was performed in Wistar rats over a 6 h period. The area under curve (AUC) of rats with DNJ-MS was significantly increased, compared to animals dosed with mulberry powder (control). DNJ-MS suppressed postprandial glucose from sucrose administration at the initial and 3 h time points indicating a prolonged hypoglycaemic effect. PMID- 23442627 TI - Isolation of Bowman-Birk-Inhibitor from soybean extracts using novel peptide probes and high gradient magnetic separation. AB - Soybean proteins offer exceptional promise in the area of cancer prevention and treatment. Specifically, Bowman-Birk Inhibitor (BBI) has the ability to suppress carcinogenesis in vivo, which has been attributed to BBI's inhibition of serine protease (trypsin and chymotrypsin) activity. The lack of molecular probes for the isolation of this protein has made it difficult to work with, limiting its progress as a significant candidate in the treatment of cancer. This study has successfully identified a set of novel synthetic peptides targeting the BBI, and has demonstrated the ability to bind BBI in vitro. One of those probes has been covalently immobilised on superparamagnetic microbeads to allow the isolation of BBI from soy whey mixtures in a single step. Our ultimate goal is the use of the described synthetic probe to facilitate the isolation of this potentially therapeutic protein for low cost, scalable analysis and production of BBI. PMID- 23442628 TI - Chemical characteristics, fatty acid composition and conjugated linoleic acid (CLA) content of traditional Greek yogurts. AB - Many studies with conjugated linoleic acid (CLA) indicate that it has a protective effect against mammary cancer. Because dairy products are the most important dietary sources of CLA, we have investigated the CLA concentrations and additionally the fatty acid profiles and chemical composition of several commercial, traditional, Greek yogurts from different geographical origin. The fat content of yogurts was in the order of goattert-butylcatechol>dihydrocaffeic acid>pyrocatechol. Cysteine hydrochloride, potassium metabilsulphite, ascorbic acid, erythorbic acid, resorcylic acid and kojic acid showed competitive inhibition, whereas, citric acid and sodium azide showed mixed inhibition of PPO activity. Cysteine hydrochloride was found to be an excellent inhibitor with the low inhibitor constant of 1.8 MUM. PMID- 23442631 TI - Effect of UV-B light and different cutting styles on antioxidant enhancement of commercial fresh-cut carrot products. AB - Wounding stresses resulting from fresh-cut processing are known to enhance the antioxidant capacity (AC) of carrots by increasing the synthesis of phenolic compounds. Ultraviolet-B (UV-B) light exposure further promotes the formation of phenolic compounds. Changes in total soluble phenolics (TSP), 5-O-caffeoylquinic acid (5-CQA), total carotenoids, AC, and phenylalanine ammonia-lyase (PAL) activity of five commercial fresh-cut carrot products (baby carrots, carrot stixx, shredded carrots, crinkle cut coins, and oblong chips) were evaluated after exposure to UV-B dosage at 141.4 mJ/cm(2). Significant increases in TSP, AC and 5-CQA levels were observed for each sample following UV-B exposure. Increases in PAL activity were also observed in all carrot products, except crinkle cut coins. Total carotenoids of the carrot products were unchanged by UV-B exposure. Increases in AC levels corresponded directly with increases in the area/weight ratio (exposure area) of the fresh-cut carrot products. PMID- 23442632 TI - Bioactive composition and antioxidant potential of different commonly consumed coffee brews affected by their preparation technique and milk addition. AB - Coffee is one of the most popular beverages in the world, prepared and consumed in many different ways. Taste, aroma and composition of the coffee brew vary depending on the preparation method. Therefore, this study investigates the effect of different brewing methods on the polyphenol and methylxanthine composition and antioxidant capacity of thirteen different coffee brews. The content of total phenols and flavonoids was determined spectrophotometrically and the content of chlorogenic acid derivates (3-CQA, 4-CQA and 5-CQA) and caffeine using the high performance liquid chromatography (HPLC-PDA). Antioxidant capacity of coffee brews was evaluated by using the ABTS (2,2-azino-bis(3 ethylbenzthiazoline-6-sulfonic acid)) and FRAP (ferric-reducing antioxidant power) assays. Instant coffee brews showed the highest values in content of total phenols, chlorogenic acid derivates, caffeine and antioxidant capacity, which significantly decreased by milk addition. The antioxidant capacity of coffee brews was in compliance with the total phenol content and content of chlorogenic acid derivates. PMID- 23442633 TI - Bilberry and blueberry anthocyanins act as powerful intracellular antioxidants in mammalian cells. AB - Berry anthocyanins have pronounced health effects, even though they have a low bioavailability. The common mechanism underlying health protection is believed to relate to antioxidant activity. Berry extracts, chemically characterised for their phenolic content, were prepared from bilberries (Vaccinium myrtillusL.) and blueberries (Vaccinium corymbosumL.); the bilberry extract was further purified to obtain the anthocyanin fraction. The antioxidant activity of each extract was examined at the cellular level. For this purpose a specific assay, known as cellular antioxidant activity assay (CAA), was implemented in different cell lines: human colon cancer (Caco-2), human hepatocarcinoma (HepG2), human endothelial (EA.hy926) and rat vascular smooth muscle (A7r5). Here we show for the first time that anthocyanins had intracellular antioxidant activity if applied at very low concentrations (<1 MUg/l; nM range), thereby providing a long sought rationale for their health protecting effects in spite of their unfavorable pharmacokinetic properties. PMID- 23442634 TI - Antioxidant activity and phenolic compounds of Holotrichia parallela Motschulsky extracts. AB - Insects have been relatively unexplored as potential sources of natural antioxidants. We report the antioxidant activity of extracts of the adult large black chafer beetle Holotrichia parallela Motschulsky, a common crop pest in China. The antioxidant activity of the ethanolic extract (EE) and the water extract (WE) of adult H. parallela were evaluated by four different in vitro assays. EE showed potent metal-chelating activity and inhibition of lipid peroxidation. WE proved to be an excellent antioxidant in the scavenging of 2,2 diphenyl-1-picrylhydrazyl (DPPH) radicals and metal-chelating activity. Catechin was identified in the ethanolic extract and proteins were the main components in the water extracts. Both compounds could contribute to the antioxidant activity of the species. These results suggest that adult H. parallela might be used as a nutraceutical to alleviate oxidate-induced diseases and as a natural antioxidant additive in the food industry. PMID- 23442635 TI - Antioxidant capacity and mineral content of pulp and peel from commercial cultivars of citrus from Brazil. AB - Four Citrus species (C. sinensis, cvs. Pera and Lima; C. latifolia Tanaka cv. Tahiti; C. limettioides Tanaka cv. Sweet lime and C. reticulate, cv. Ponkan) grown in Brazil were characterised in relation to contents of minerals, ascorbic acid, total polyphenols and antioxidant capacity of pulps and peels. In general, the peels demonstrated significantly higher contents of all compounds than the pulps (p<0.05), with the exception of the Pera orange pulp that presented the highest acid ascorbic content (68 mg/100 ml), while the Tahiti lime peel presented the lowest (8 mg/100 g). Citrus showed high levels of potassium, calcium and magnesium, and the peels were considered sources of these minerals. The Ponkan mandarin peel presented the highest antioxidant capacity. The antioxidant capacity of citrus was correlated both to vitamin C and phenolics. Aside from citrus pulps, the peels are also good sources of bioactive compounds and minerals, and can be explored for their health promoting values in food products. PMID- 23442636 TI - Chemical properties and antioxidant activity of exopolysaccharides fractions from mycelial culture of Inonotus obliquus in a ground corn stover medium. AB - The medicinal mushroom Inonotus obliquus has been a folk remedy for a long time in East-European and Asian countries. We first reported the enhancement in production and antioxidant activity of exopolysaccharides by I. obliquus culture under lignocellulose decomposition. In this study, the two different sources of exopolysaccharides from the control medium and the lignocellulose (corn stover) containing medium by I. obliquus in submerged fermentation were fractionated and purified by chromatography. The exopolysaccharides from the corn stover containing medium presented significantly stronger hydroxyl and 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical-scavenging activity than the control. Three fractions from the control medium and the corn stover-containing medium were isolated respectively. The fraction of DEPL3 from the corn stover-containing medium with the highest protein content (38.3%), mannose content (49.6%), and the lowest molecular weight (29 kDa) had the highest antioxidant activity with the lowest IC50 values. In conclusion, lignocellulose decomposition changed the chemical characterisation and significantly enhanced the antioxidant activity of exopolysaccharide fractions. PMID- 23442637 TI - Composition analysis and immuno-modulatory effect of okra (Abelmoschus esculentus L.) extract. AB - The aim of this study was to analyse the composition of okra (Abelmoschus esculentus L.) extract and investigate the effect of A. esculentus L. polysaccharides (AE-PS) on the maturation and function of dendritic cells (DCs) derived from rat bone marrow hematopoietic cells (BMHCs) in vitro. BMHC-derived immature DCs (BMHC-imDCs) were extracted from rats and treated with AE-PS. The hydrolysed okra extract contained 0.6% beta-1, 3-D-glucan. AE-PS induced the presence of polymorphic nuclei and elongated protrusion in the BHMC-imDCs, indicating DC activation. Treatment with 100 MUg/mL of AE-PS increased the MHC class II and CD80/86 expression levels by 41% and 42%, respectively. Treated cells had reduced endocytosis activity. The secretion of IL-12 and IFN-gamma increased significantly by 120% and 75%, respectively, when treated with 100 MUg/mL of AE-PS. Moreover, IL-10 production was reduced by 66%. In conclusion, AE PS exhibits stimulatory effects on rat dendritic cells and promotes the secretion of T(H)1 cytokines. PMID- 23442638 TI - Variation of antioxidant activity and the levels of bioactive compounds in lipophilic and hydrophilic extracts from hot pepper (Capsicum spp.) cultivars. AB - Peppers (Capsicum spp.) are a rich source of diverse bioactive compounds with potential health-promoting properties. This study investigated the extraction efficiency of five solvents on antioxidant activities from cayenne (CA408 and Mesilla), jalapeno (Ixtapa) and serrano (Tuxtlas) pepper cultivars. Freeze-dried peppers were extracted using a Soxhlet extractor with five solvents: hexane, ethyl acetate, acetone, methanol, and methanol:water (80:20). The levels of specific bioactive compounds (phenolics, capsaicinoids, carotenoids and flavonoids) were determined by HPLC and antioxidant activities were assayed by three methods. For all pepper cultivars tested, hexane extracts had the highest levels of capsaicinoids and carotenoids, but methanol extracts had the maximum levels of flavonoids. Hexane extracts showed higher 2,2-diphenyl-1 pricrylhydrozyl (DPPH) radical-scavenging activity and higher reducing power, and acetone extracts (from Mesilla pepper) had a high reducing power. All pepper extracts, except hexane, were effective in preventing deoxyribose degradation, and the inhibition was increased by high concentrations of extracts. The results of the present study indicated that, among the different measures of antioxidant activity, DPPH radical-scavenging activity was strongly correlated with total bioactive compounds (capsaicinoids, carotenoids, flavonoids and total phenolics) in pepper cultivars. PMID- 23442639 TI - Extraction, isolation and characterisation of oil bodies from pumpkin seeds for therapeutic use. AB - Pumpkin, a member of the Cucurbitaceae family has been used frequently as functional medicines for therapeutic use. Several phytochemicals such as polysaccharides, phenolic glycosides, 13-hydroxy-9Z, 11E-octadecatrienoic acid from the leaves of pumpkin, proteins from germinated seeds, have been isolated. Here the influence of pH, ionic strength, and temperature on the properties and stability of oil bodies from pumpkin (Cucurbita) were determined with a view to patterning oil body size and structure for future therapeutic intervention. Oil bodies from pumpkin seeds were extracted, isolated, characterised using optical microscopy, zeta potential and particle size distribution obtained. During microscopic analysis, the oil bodies were more intact and in an integrated form at the time of extraction but were ruptured with time. Water extracted oil bodies were spherical for all four layers where cream had larger oil bodies then upper curd. Lower curd and supernatant had considerably smaller size with lower curd densely packed and seemed to be rich in oil bodies than any of the four layers. At pH 3, in the absence of salt, the zeta potential is approximately +30 mV, but as the salt concentration increases, the zeta potential rises at 10 mM but then decreases over the salt range. This trend continues for the upper curd, lower curd and the supernatant and the degree of the reduction (mV) in zeta potential is of the order cream0.05). The carotenoid contents of lipids from cephalothorax and hepatopancreas slightly increased within the first 2 and 4 days of iced storage (p<0.05), respectively, but decreased thereafter (p<0.05). With increasing storage time, a progressive formation of hydroperoxide was found as evidenced by the increase in the absorbance band at 3600-3200 cm(-1) in Fourier transform infrared (FTIR) spectra, and increased peroxide values (PVs) (p<0.05). The increases in thiobarbituric acid reactive substances (TBARS), p anisidine value (AnV) and free fatty acid (FFA) content of lipids were noticeable when iced storage time increased (p<0.05). Those changes indicated that lipid oxidation and hydrolysis occurred in both samples. Phospholipids (PL) were the major components in lipids from cephalothorax (82.51% of total lipids). Nevertheless, lipids from hepatopancreas contained triglyceride (TG) and PL as the dominant components (45.35% and 38.03% of total lipids, respectively). A decrease in the TG content with a concomitant increase in free fatty acid was observed at the end of storage (day 6) (p<0.05). Decreases in unsaturated fatty acids, especially eicosapentaenoic acid (EPA; C20:5(n-3)) and docosahexaenoic acid (DHA; C22:6(n-3)) were noticeable at day 6 of storage (p<0.05). Thus, the extended storage time resulted in the enhanced deterioration of extracted lipids. PMID- 23442658 TI - Effect of endogenous ascorbic acid oxidase activity and stability on vitamin C in carrots (Daucus carota subsp. sativus) during thermal treatment. AB - The purpose of this research was to study the effect of endogenous ascorbic acid oxidase (AAO) on vitamin C in carrots (Daucus carota subsp. sativus), namely Nantes, Egmont Gold and baby carrots during thermal treatment. Enzyme-substrate reaction kinetics of AAO were described using Michaelis-Menten equation. The estimated K(m) and V(max) values of AAO ranged from 50.34 to 63.54 MUM and 23.70 to 26.82 MUmol/min, respectively. Nantes carrots had the lowest AAO activity. On the other hand, Egmont Gold had the highest V(max). AAO activity in all carrot cultivars was stable up to 50 degrees C and inactivated above 50 degrees C. Irreversible thermal inactivation of AAO followed first order kinetics (55-70 degrees C) and the estimated activation energy of the three carrot cultivars situated between 114.33 and 191.45 kJ/mol. Regarding vitamin C stability, thermal treatment at 60-70 degrees C has resulted in total conversion of l-AA to DHAA due to residual AAO activity; a complete AAO inactivation was found in 80 degrees C-treated carrots with high vitamin C retention predominantly in l-AA form, up to 90%. On average, the carrots had a total vitamin C content amounting from 368.24 to 379.87 MUg/g dry matter and the Nantes carrots had the highest vitamin C content. The effectiveness of rapid inactivation of endogenous AAO via heating (>80 degrees C, 10 min) prior to matrix disruption gave protection to l AA towards enzymatic oxidation, thus resulted in a higher vitamin C content and stability in carrots. PMID- 23442659 TI - A phenolic antioxidant from the Pacific oyster (Crassostrea gigas) inhibits oxidation of cultured human hepatocytes mediated by diphenyl-1-pyrenylphosphine. AB - 3,5-Dihydroxy-4-methoxybenzyl alcohol (DHMBA), an antioxidant isolated from the Pacific oyster (Crassostrea gigas), was studied in a cell-based fluorometric antioxidant assay using human hepatocyte-derived cells (C3A) and diphenyl-1 pyrenylphosphine (DPPP) as a fluorescent probe. In comparison with two hydrophilic antioxidants, DHMBA showed the stronger inhibition of DPPP-mediated fluorescence than chlorogenic acid and l-ascorbic acid: at a concentration of 320 MUM of DPPP, the inhibition was 26.4+/-2.6%, 11.1+/-1.2%, and 0+/-2.0% for DHMBA, chlorogenic acid, and l-ascorbic acid, respectively (mean+/-SD, n=4). Their relative oxygen radical absorbance capacities (ORAC) were dissociated with their cell-based antioxidant activities: 1.47+/-0.40, 4.57+/-0.30, and 0.53+/-0.13 MUmol TE/MUmol for DHMBA, chlorogenic acid, and l-ascorbic acid, respectively (mean+/-SD, n=4). The amphiphilicity of DHMBA was better than chlorogenic acid and l-ascorbic acid might underlie this dissociation. Since the C3A cells are human hepatoma-derived cells, DHMBA might be useful in the prevention and treatment of liver diseases by involving an oxidation process. PMID- 23442660 TI - Phytochemical profile of a blend of black chokeberry and lemon juice with cholinesterase inhibitory effect and antioxidant potential. AB - In this study, black chokeberry concentrate was added (5% w/v) to lemon juice, since previous reports suggested potential health benefits of this blend. The phytochemical composition, antioxidant capacity (scavenging of DPPH, superoxide and hydroxyl radicals, and hypochlorous acid), and inhibitory activity against cholinesterase of the new blend were determined and compared with those of lemon juice and chokeberry in citric acid (5%). The chokeberry concentrate, rich in cyanidin-glycosides, quercetin derivatives, and 3-O-caffeoylquinic acid, and lemon juice, possessing flavones, flavanones, quercetin derivates, and hydroxycinnamic acids, were characterised. The new drink showed a higher antioxidant effect than the chokeberry or lemon controls for all the tested methods, except for hypochlorous acid, in which lemon juice displayed higher activity. Both the lemon juice and chokeberry controls inhibited acetylcholinesterase and butyrylcholinesterase, and this effect was increased in the new mixtures. The results of the different radical scavenging assays indicate that the lemon-black chokeberry (5% w/v) mixture was more antioxidative than the respective controls separately. Moreover, their inhibition of cholinesterase is of interest regarding neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, or senile dementia. PMID- 23442661 TI - Enzymatic synthesis of phytosteryl docosahexaneates and evaluation of their anti atherogenic effects in apo-E deficient mice. AB - Phytosterols have attracted much attention in recent years due to their health benefits, such as cholesterol lowering, anti-inflammatory, anti-atherogenicity, and anti-cancer potential. Docosahexaenoic acid (DHA) has been demonstrated to possess cardioprotective and immune-enhancing effects. Esterification of phytosterols with DHA may render improved physiochemical properties such as solubility, miscibility, oxidative stability and hence bioactivity and bioavailability. Thus, phytosteryl docosahexaneates (PS-DHA) may offer both the benefits of phytosterols and DHA, possibly in a synergistic manner. Here, we describe a method for enzymatic synthesis of phytosteryl docosahexaneates and evaluation of metabolic and cardiovascular benefits in apo-E deficient (apo E-KO) mice. The structures of phytosteryl docosahexaneates were confirmed by infrared (IR) and high performance liquid chromatography-mass spectrometry (HPLC-MS) using both normal and reverse phase chromatography. Apo E-KO mice were fed with an atherogenic diet containing 2% (w/w) PS-DHA for 7 weeks. Plasma lipid levels and the extent and complexity of atherosclerotic lesions were examined and compared with those in the control group. The PS-DHA-treated mice had significantly lower plasma cholesterol levels and three times smaller atherosclerotic lesions in the aortic roots. This pilot study suggests cardiovascular benefits for PS-DHA. Further experimental and clinical studies are needed to confirm such benefits of PS-DHA. PMID- 23442662 TI - Wine extracts from Sardinian grape varieties attenuate membrane oxidative damage in Caco-2 cell monolayers. AB - One of the most important sites of polyphenol action seems to be in the gastrointestinal system before absorption. We investigated the ability of three wine phenolic extracts, obtained from grape varieties grown in Sardinia, Cannonau (red), Vermentino and Malvasia (white), to exert an antioxidant action against tert-butyl hydroperoxide (TBH)-induced oxidative damage to Caco-2 cell monolayers as a model system of the human intestine. TBH treatment caused the disruption of epithelial integrity, measured as transepithelial electrical resistance, and markers of the peroxidation process of membrane lipids, MDA, fatty acid hydroperoxides and 7-ketocholesterol. All wine extracts were able to counteract the oxidising action of TBH and, in spite of the differences in phenolic composition, exerted a comparable activity. Our findings point out a direct antioxidant action of the wine extracts on enterocytes exposed to oxidising species and further support the opinion that total phenolic content is not essential for antioxidant activity. PMID- 23442663 TI - Kinetics of the formation of radicals in meat during high pressure processing. AB - The kinetics of the formation of radicals in meat by high pressure processing (HPP) has been described for the first time. A threshold for the radicals to form at 400 MPa at 25 degrees C and at 500 MPa at 5 degrees C has been found. Above this threshold, an increased formation of radicals was observed with increasing pressure (400-800 MPa), temperature (5-40 degrees C) and time (0-60 min). The volume of activation (DeltaV(#)) was found to have the value -17 ml mol(-1). The energy of activation (E(a)) was calculated to be 25-29 kJ mol(-1) within the pressure range (500-800 MPa) indicating high independence on the temperature at high pressures whereas the reaction was strongly dependent at atmospheric pressure (E(a)=181 kJ mol(-1)). According to the effect of the processing conditions on the reaction rate, three groups of increasing order of radical formation were established: (1) 55 degrees C at 0.1 MPa, (2) 500 and 600 MPa at 25 degrees C and 65 degrees C at 0.1 MPa, and (3) 700 MPa at 25 degrees C and 75 degrees C at 0.1 MPa. The implication of the formation of radicals as initiators of lipid oxidation under HPP is discussed. PMID- 23442664 TI - Formation of styrene dependent on fermentation management during wheat beer production. AB - Styrene is formed by the thermal decarboxylation of cinnamic acid during wort boiling or by enzymatic decarboxylation during fermentation. The enzymatic reactions proceed in parallel to the decarboxylation of ferulic- and p-cumaric acid to 4-vinylguaiacol and 4-vinylphenol by the same decarboxylase enzyme. However, the formation of styrene occurs much faster and all available cinnamic acid in wort was converted completely within a few hours. Moreover, the comparison of various manufacturing parameters shows that a higher fermentation temperature of 25 degrees C compared to 16 degrees C and an open fermentation management lead to a rapid decrease of styrene. This allows minimising the content of styrene in beer while maintaining the typical wheat beer flavours. PMID- 23442665 TI - Isolation, identification and antioxidative capacity of water-soluble phenylpropanoid compounds from Rhodiola crenulata. AB - Six water-soluble phenylpropanoid compounds obtained from Rhodiola crenulata (R. crenulata) were fractionated by high-speed counter-current chromatography (HSCCC), and purified by semi-preparative high-performance liquid chromatography (Semi-prep HPLC). The purities of the six compounds were all above 98.0% and their structures were identified by spectroscopic methods. Among them, a new compound, 2-(4-hydroxyphenyl)-ethyl-O-beta-D-glucopyranosyl-6-O-beta-D glucopyranoside (1), together with two known phenylpropanoids, p-hydroxyphenacyl beta-D-glucopyranoside (3) and picein (4) were isolated from R. crenulata for the first time. Meanwhile, the contents of six isolated ingredients from the crude extract of R. crenulata had been simultaneously detected, with satisfactory results. Furthermore, the antioxidant activities of the six compounds were accessed by measuring the radical scavenging activity against 2,2-diphenyl-1 picrylhydrazy (DPPH), and four compounds exhibited potent antioxidative activity. PMID- 23442666 TI - Angiotensin converting enzyme (ACE) inhibitory, antihypertensive and antihyperlipidaemic activities of protein hydrolysates from Rhopilema esculentum. AB - Angiotensin-converting enzyme (ACE) inhibitory, antihypertensive and antihyperlipidaemic activities of protein hydrolysates (RPH) from the jellyfish Rhopilema esculentum were investigated. R. esculentum was hydrolysed sequentially with pepsin and papain, and then the hydrolysate was ultrafiltered with a 2000 Da cut-off membrane. It was found that RPH contained high levels of Gly, Glu, Pro, Asp and Ala, having potential ACE inhibitory activity in vitro with an IC(50) of 1.28 mg/ml. It was also found that systolic blood pressure was reduced markedly in spontaneously hypertensive rats after single and chronic oral administration of RPH, indicating that RPH had an antihypertensive effect. In addition, oral administration of RPH decreased total serum cholesterol and triglyceride, and increased high-density lipoprotein cholesterol in rats fed with high-fat diet. These results indicate that RPH may prove to be a promising functional food for the prevention and treatment of hypertension and hyperlipidaemia. PMID- 23442667 TI - Food protein aggregates as vitamin-matrix carriers: impact of processing conditions. AB - We studied the ability of protein aggregates for loading and protection of alpha tocopherol, a model of heat- and light-sensitive bioactive compounds. Aqueous dispersions of whey proteins (4.5 wt.%, pH 6.7) in the absence and presence of alpha-tocopherol (4 wt.%) were prepared using an ultradisperser (10,000 rpm for 10 min and 65 degrees C), and then submitted to further high-pressure homogenisation (HPH) at 300 or 1200 bar for 12 cycles. Relative to free-vitamin dispersions, increasing HPH conditions in the presence of vitamin led to higher protein denaturation, more tryptophan quenching and wavelength blue-shift (by 10nm), in parallel with increased zeta potential values (by -10 mV), particle sizes (by 50%), and newly formed protein dimers, trimers and high molecular weight aggregates. As a result, the degree of vitamin degradation under increasing HPH and long-term storage was shown to decrease from 66% (ultradisper) to 50%, or to 30% (subject to further treatments at 300 or 1200 bar, respectively). PMID- 23442668 TI - Selective extraction, structural characterisation and antifungal activity assessment of napins from an industrial rapeseed meal. AB - This article reports an extraction-purification of napins from an industrial rapeseed meal and the assessment of their antimicrobial activity against Fusarium langsethiae. The best extraction conditions are observed at pH 2, 12% (w/w) of rapeseed meal after 15 min of extraction in water at room temperature. Under these conditions the extraction is highly selective, allowing a simple purification process (ammonium sulfate precipitation followed by desalting size exclusion chromatography) to get purified napins. These napins possessed significant anti-Fusarium activity (IC(50)=70 MUM) and a compact secondary structure rich in alpha-helix, which may explain this bioactivity. PMID- 23442669 TI - The effect of gel structure on the kinetics of simulated gastrointestinal digestion of bovine beta-lactoglobulin. AB - The structure and properties of protein gels depend on the conditions under which they are formed. Here, we assessed the susceptibility of protein to simulated gastro-duodenal digestion of weak gels with contrasting structures, produced from either purified bovine beta-lactoglobulin (beta-Lg) or whey protein isolate (WPI) at pH ranging from 2.5 to 6.5 and using different heating regimes. Gels formed close to the isoelectric point proved to be very resistant to simulated gastric digestion, with more than 85% of beta-Lg remaining and in the simulated duodenal phase of digestion. The sample heated to 85 degrees C was most resistant with over 40% remaining. In the WPI sample heated to 85 degrees C, more than 20% of the original beta-Lg content remained undigested after simulated gastro-duodenal proteolysis. These results suggest that firm particulate gels can persist longer in the GI tract and may be useful in inducing satiety and thus provide another weapon in the fight against obesity. PMID- 23442670 TI - Anti-influenza A virus effects of fructan from Welsh onion (Allium fistulosum L.). AB - A fructan that acts as an anti-influenza A virus substance was isolated from hot water extract of the green leafy part of a Welsh onion (Allium fistulosum L.). The structure of the fructan was characterised and elucidated by chemical and spectroscopic analyses. The fructan was composed of terminal (21.0%) and 2,1 linked beta-D-Fruf residues (65.3%) with 1,6-linked beta-D-Glcp residues (13.7%). The molecular weight of the polysaccharide and polydispersity was estimated to be 1.5*10(3) and 1.18, respectively. Although the fructan did not show anti influenza A virus activity in vitro, it demonstrated an inhibitory effect on virus replication in vivo when it was orally administered to mice. In addition, the polysaccharide enhanced the production of neutralising antibodies against influenza A virus. Therefore, the antiviral mechanism of the polysaccharide seemed to be dependent on the host immune system, i.e., enhancement of the host immune function was achieved by the administration of the polysaccharide. From our observations, the fructan from Welsh onions is suggested to be one of the active principles which exert an anti-influenza virus effect. PMID- 23442671 TI - Regulation of virus-induced inflammatory response by beta-carotene in RAW264.7 cells. AB - Carotenoids are effective antioxidants, which can quench singlet oxygen, suppress lipid peroxidation, and prevent oxidative damage. Both Pseudorabies virus (PRV) and human Herpes simplex virus (HSV) are DNA viruses, and their pathogenesis and immunobiology are similar. However, PRV does not infect humans. Therefore, PRV was used to infect murine macrophages (RAW264.7 cells), to mimic HSV-induced inflammation. Meanwhile, the influence of beta-carotene on PRV-induced inflammation was also investigated. Results indicated that beta-carotene inhibited (p<0.05) NO, IL-1beta, IL-6, and MCP-1 production in PRV-infected RAW264.7 cells. beta-Carotene also suppressed (p<0.05) NF-kappaB (p50 and p65), phosphorylation of extracellular-signal-related kinase (ERK), p38, and c-Jun N terminal kinase (JNK) expression. It could be concluded that the anti inflammatory effect of beta-carotene is mainly through a suppression of cytokine expression in PRV-induced inflammation, which results from NF-kappaB inactivation. beta-Carotene can be considered a potential anti-inflammatory agent for DNA-virus infection. PMID- 23442672 TI - Neuroprotective effect of alkyl hydroxytyrosyl ethers in rat brain slices subjected to a hypoxia-reoxygenation model. AB - The aim of the present study was to investigate the antioxidant and possible neuroprotective and antioxidant effects of five alkyl hydroxytyrosyl (HT) ethers (ethyl, butyl, hexyl, octyl and dodecyl) in rat brain slices. None of the compounds modified lipid peroxidation or glutathione concentrations (GSH) in oxygenated samples. The effects of oxidative stress were investigated with ferrous salts to induce lipid peroxidation and diethylmaleate (DEM) to reduce GSH. All compounds inhibited lipid peroxidation with an inhibitory concentration 50% (IC(50)) one tenth that of HT. These compounds, especially the butyl derivative, prevented GSH depletion after incubation with DEM. We also explored the neuroprotective effect of these compounds in an experimental model of hypoxia reoxygenation in rat brain slices. All compounds showed neuroprotective and antioxidant effects. Our results established a relationship between these effects and the length of the carbon chain (maximum effect in the range of C4-C8). PMID- 23442674 TI - Comparison of dynamic viscoelastic and physicochemical properties of pressurised and pasteurised longan juices with xanthan addition. AB - Physical and biochemical properties of pressurised and pasteurised longan juices with various xanthan additions, such as viscoelastic behaviour, colour L (lightness), -a(*) (greenness), b(*) (yellowness), DeltaE (total different colours) and BI (Browning Index) parameters, polyphenol oxidase (PPO) activity, ascorbic acid, gallic acid, ellagic acid, total phenols and antioxidant capacity (DPPH assay) were studied. Viscoelastic determination indicated that longan juice with 0.15% xanthan addition was optimal for a fruit drink. Colour parameters showed pressurised longan juice at 500 MPa was brighter and more transparent than fresh and other processed juices. PPO was completely inactivated in pasteurised juices, whereas in pressurised juices at 300 and 500 MPa, the activities were more than 100% and 95-99%, respectively. Bioactive components including ascorbic acid were significantly reduced according to treatment severities, whereas gallic and ellagic acids were relatively stable in all processed juices. Total phenols and DPPH radical-scavenging activity decreased significantly on pasteurisation, but were stable on pressurisation. PMID- 23442673 TI - Protection of curcumin against fructose-induced hyperuricaemia and renal endothelial dysfunction involves NO-mediated JAK-STAT signalling in rats. AB - Increasing evidence has demonstrated that excess fructose consumption as a risk factor for metabolic syndrome causes hyperuricaemia and renal injury. Curcumin, a natural plant phenolic food additive, lowered serum urate, creatinine and blood urea nitrogen levels, and increased urinary urate and nitrate/nitrites levels, as well as renal nitric oxide (NO) production in fructose-fed rats. Moreover, curcumin regulated urate transport-related proteins and inhibited activation of the JAK2-STAT3 cascade and overexpression of SOCS3 and TGF-beta1 in the kidneys of fructose-fed rats. These results suggested that the anti-hyperuricaemic and renal protective actions of curcumin might be the result of renal NO-mediated JAK2-STAT3 signalling and TGF-beta1 normality, which ameliorated renal endothelial dysfunction to improve renal urate transporter system in this model. The present study may provide the evidence for the potential use of a functional food ingredient curcumin because of its action against hyperuricaemia and renal injury induced by high fructose intake. PMID- 23442675 TI - Synthesis and evaluation of antioxidant and antifungal activities of novel ricinoleate-based lipoconjugates of phenolic acids. AB - Syntheses of four castor oil fatty acid-based novel lipoconjugates of phenolic acids were carried out following Mitsunobu methodology. The lipid part consists of methyl ricinoleate and its saturated analogue, methyl-12-hydroxystearate and the phenolic moieties are ferulic and vanillic acid. Synthesised compounds are evaluated for antioxidant activity using three in vitro assays (DPPH radical scavenging assay, DSC studies for oxidative induction temperature of linoleic acid and autoxidation of linoleic acid in Tween 20 micellar medium) and compared with three widely used antioxidants in the food industry, BHT, alpha-tocopherol, and dodecyl gallate. Synthesised compounds are found to exhibit good antiradical activity. These compounds also exhibited very good antifungal activity against studied fungal strains. All these results suggested the applicability of the synthesised compounds as potent lipophilic antioxidants for combating oxidative stress. PMID- 23442676 TI - Evaluation of Leuconostoc citreum HO12 and Weissella koreensis HO20 isolated from kimchi as a starter culture for whole wheat sourdough. AB - Leuconostoc citreum HO12 and Weissella koreensis HO20 isolated from kimchi were evaluated as starter cultures in the making of whole wheat sourdough bread. After 24h of fermentation at 25 degrees C, both lactobacilli grew to the final cell numbers of ca. 10(9)cfu/g dough, and both doughs had similar pHs and total titratable acidities. In addition, the fermentation quotient of the dough with Lc. citreum HO12 was slightly lower than that of the dough with W. koreensis HO20 (1.6 versus 2.8). Sourdoughs and bread with 50% sourdough produced with the starter cultures exhibited consistent ability to retard the growth of bread spoilage fungi (Penicillium roqueforti and Aspergillus niger) and rope-forming bacterium (Bacillus subtilis). Sourdough breads underwent a significant reduction in bread firming during storage. It seems that both lactobacilli have the potential to improve the shelf-life of wheat bread. The results indicate that the selected lactobacilli have unique fermentation characteristics and produce sourdough breads with overall satisfactory quality. PMID- 23442677 TI - Antioxidant and antiinflammatory properties of germinated and hydrolysed Brazilian soybean flours. AB - The effect of germination in combination with Alcalase hydrolysis of Brazilian soybean cultivar BRS 133 on the production of soybean flours with bioactive peptides as modulators of oxidative stress and markers of inflammation was monitored. The electrophoretic profile showed a weak protein breakdown during germination. However, a strong breakdown of the proteins can be observed after the first hour of hydrolysis with Alcalase. MALDI-TOF-MS analysis of the protein extracts showed differences in the intensity and profile of peptide mass fingerprint due to germination and hydrolysis. Germinated flour showed higher soluble protein concentration and antioxidant capacity. All soybean protein extracts and protein hydrolysates produced (G0, G18 and G72) showed a significant (p<0.05) inhibition on inflammatory markers such as nitric oxide (20.5-69.3%), iNOS (22.8-93.6%), PGE(2) (64.0-88.3%), COX-2 (36.2-76.7%), and TNF-alpha (93.9 99.5%) in LPS-induced RAW 264.7 macrophages. However, protein extracts of flours with 18 h of germination were more potent in inhibiting pro-inflammatory responses when compared to 72 h. It can be concluded that a combination of 72 h of soybean BRS 133 germination and 1h Alcalase hydrolysis resulted in the formation of bioactive compounds with more potent antioxidant activity, and improvement in the reduction of some of the markers of inflammation. PMID- 23442678 TI - Antioxidant activity of phenolic fractions in olive mill wastewater. AB - Olive mill wastewater (OMW) contains a substantial amount of valuable antioxidant phenols that can be recovered for industrial application as food additives and pharmaceuticals. The present study was aimed at extracting different phenolic OMW fractions, and determining their antioxidant potential. Five different OMW fractions were obtained using fractionation techniques, their antioxidant potential determined by DPPH, ORAC and a beta-carotene bleaching test. The total phenol level ranged between 115 and 170 mg/l. The phenolic compounds present in individual fractions were identified using the HPLC-PAD method, where the main compounds were hydroxytyrosol, tyrosol, caffeic acid, vanillic acid, verbascoside, oleuropein, ferulic acid, and p-coumaric acid. The five OMW fractions showed different antioxidant levels depending on the test used. DPPH test showed that the fraction of alkyl aromatic alcohols (AAAs) was the best with EC(50) of 20 mg/l and the pure hydroxytyrosol with 2 mg/l. ORAC test showed that AAA and semi hydrolysed total phenol (s-TP) fractions were significantly better than Trolox when compared to 20 mg/l of Trolox. PMID- 23442679 TI - The effects of Caulerpa microphysa enzyme-digested extracts on ACE-inhibitory activity and in vitro anti-tumour properties. AB - The aim of this study was to determine the ACE inhibitory activity and its anti cancer properties of Caulerpa microphysa extracts. C. microphysa samples were digested with Flavourzyme, Alcalase, and pepsin. The ACE inhibitory activity of enzyme-digested C. microphysa decreased in the order of digestion with pepsin>Flavourzyme>Alcalase; that is, pepsin-extracted samples had significantly higher activity than the other enzyme extractions. To test its anti-tumour effects in vitro C. microphysa pepsin-digested extracts were applied to BALB/c mice with transplanted myelomonocytic leukaemia (WEHI-3) and Human promyelocytic leukaemia (HL-60) cell lines. The growth of both cell lines was inhibited, and extracts induced DNA damage, evaluated with a comet assay. The data demonstrate that C. microphysa pepsin-digested extract had the ability to anti-tumour effects. Further application as a health food is worthy of investigation. PMID- 23442680 TI - Ordered structure and thermal property of acid-modified high-amylose rice starch. AB - High-amylose cereal starch has a great benefit on human health. Acid modification is very helpful for application of high-amylose starch in food and non-food industries. In this study, the ordered structure of acid-modified high-amylose rice starch was investigated by GPC, HPAEC, (13)C CP/MAS NMR and XRD. Acid preferentially degraded the amylose, then A chain and short B chain of amylopectin. Relative double helix content and crystallinity both initially increased sharply and then progressively with acid hydrolysis. The relative crystallinity of starches obtained from (13)C CP/MAS NMR was higher than that from XRD. The onset gelatinisation temperature decreased, while the peak and conclusion temperatures increased with increasing hydrolysis time. The endothermic value initially increased and then decreased with acid hydrolysis. The swelling power decreased while solubility increased after acid hydrolysis. These results add to our understanding of the effect of acid hydrolysis on the high-amylose rice starch. PMID- 23442681 TI - The effect of delactosed whey permeate on phytochemical content of canned tomatoes. AB - The effect of delactosed whey permeate (DWP) treatment on antioxidant and phyto chemical components of canned Irish plum tomatoes were investigated. Tomatoes were sterilised for 5 min (F(0)) at 120 degrees C and stored for 6 months. The DWP treatment retained significantly (p<0.05) higher levels of ascorbic acid and lycopene of tomatoes. The antioxidant activity of DWP treated tomatoes was higher (7%) than the control at the end of storage. The firmness in DWP-treated fruits was around 40% higher than that in control. All the parameters decreased significantly (p<0.05) during storage except lycopene and total phenols. Lycopene content showed no significant change and total phenols increased during storage. The changes in ascorbic acid, antioxidant activity and texture were fitted well to Weibull kinetic models with high coefficients of determination (R(2)) and low RMSE (root mean sum of squared error). The results clearly indicate that DWP enhanced the retention of antioxidant compounds in tomatoes during storage. PMID- 23442682 TI - Polysaccharides from peach pulp: structure and effects on mouse peritoneal macrophages. AB - Pulp from peaches contained polygalacturonic acid and arabinogalactan as main polysaccharides, which were isolated and characterised. The polygalacturonic acid (AE-CWI) contained 95% GalA and its (13)C NMR spectrum showed signals at delta 98.9, 78.0, 71.4, 69.1, 68.4, and 175.1 from C-1, C-4, C-5, C-3, C-2, and C-6 respectively, from (1->4)-linked alpha-GalpA units. Methylation-MS analysis of carboxy-reduced material (AE-CWI-CR) gave 90% of 2,3,6-Me(3)-galactitol acetate. The arabinogalactan (AE-AG) was composed mainly of Ara (41%) and Gal (50%) and was characterised (methylation analysis and (13)C NMR) as a type II arabinogalactan. It induced peritoneal macrophage activation in mice, ~70% of cells treated with this fraction (1-50 MUg/mL) having morphology of activated cells. However, NO production in macrophages treated with AE-AG was not affected. This suggests a new biological activity for peach polysaccharides. PMID- 23442684 TI - Isoflavone determination in spontaneous legumes identified by DNA barcodes. AB - Isoflavones have been associated with several health protective effects. In this work spontaneous legume plants were screened as putative sources of dietary isoflavones. A molecular identification of the collected species was performed throughout DNA barcoding using ITS, rbcL, rpoC1 and matK sequences. The use of a multi-locus barcoding system complemented with basic morphological information allowed the unequivocal identification at the species level of 90% of the samples. The determination of isoflavone content was performed by high performance liquid chromatography with diode-array detection. Total average contents in the studied species were significantly different, Ononis natrix and Cytisus scoparius possessing the highest total isoflavones content (396 and 273 mg kg(-1), respectively) and Lotus creticus, the lowest (20 mg kg(-1)). The correlation of total isoflavone content with the phylogeny of this set of plants as determined by the rpoC1 sequences was evaluated for the first time. PMID- 23442685 TI - Analysis of some selected catechins and caffeine in green tea by high performance liquid chromatography. AB - Green tea seems to have a positive impact on health due to the catechins-found as flavanols. Thus, the present study was aimed to develop a low cost reversed phase high performance liquid chromatographic (HPLC) method for simultaneous determination of flavanol contents, namely catechin (C), epicatechin (EC), epigallocatechin (EGC), epicatechin 3-gallate (ECG) and epigallocatechin 3 gallate (EGCG) and caffeine in 29 commercial green tea samples available in a Saudi Arabian local market. A C-18 reversed-phase column, acetonitrile trifluoroacetic acid as a mobile phase, coupled with UV detector at 205 nm, was successfully used for precise analysis of the tested analytes in boiled water of digested tea leaves. The average values of N (No. of theoretical plates), HETP (height equivalent of theoretical plates) and R(s) (separation factor) (at 10 MUg ml(-1) of the catechins EC, EGC, EGCG and ECG) were 2.6*10(3)+/-1.2*10(3), 1.7*10(-3)+/-4.7*10(-4) cm and 1.7+/-5.53*10(-2), respectively. The developed HPLC method demonstrated excellent performance, with low limits of detection (LOD) and quantification (LOQ) of the tested catechins of 0.004-0.05 MUg ml(-1) and 0.01-0.17 MUg ml(-1), respectively, and recovery percentages of 96-101%. The influence of infusion time (5-30 min) and temperature on the content of the flavanols was investigated by HPLC. After a 5 min infusion of the tea leaves, the average concentrations of caffeine, catechin, EC, EGC, ECG and EGCG were found to be in the ranges 0.086-2.23, 0.113-2.94, 0.58-10.22, 0.19-24.9, 0.22-13.9 and 1.01-43.3 mg g(-1), respectively. The contents of caffeine and catechins followed the sequence: EGCG>EGC>ECG>EC>C>caffeine. The method was applied satisfactorily for the analysis of (+)-catechin, even at trace and ultra trace concentrations of catechins. The method was rapid, accurate, reproducible and ideal for routine analysis. PMID- 23442686 TI - A strategy for high-speed countercurrent chromatography purification of specific antioxidants from natural products based on on-line HPLC method with radical scavenging assay. AB - We have proposed a novel and first strategy of high-speed countercurrent chromatography (HSCCC) purification for the efficient and effective discovery of antioxidant from natural product based on on-line HPLC method with radical scavenging assay. To achieve a strategy for HSCCC purification, the antioxidants in materials are identified by on-line HPLC with DPPH radical scavenging assay. Then, the optimal condition of target peaks would be investigated for the two phase solvent system, and purified by HSCCC. In this study, the specific antioxidants in red cabbage, perilla and elderberry pigments were evaluated by on line HPLC with DPPH radical scavenging assay, and purified by HSCCC technique. Specific antioxidants could be rapidly pinpointed in complex mixtures by on-line HPLC with DPPH radical scavenging assay. Then, the optimal two-phase solvent systems were investigated using these HPLC peaks. Finally, the purification of these nine antioxidants form three mixtures were performed by HSCCC. Using mass spectrometric analysis, these antioxidants were confirmed to cyanidin-based anthocyanin from red cabbage and elderberry pigments, and luteolin-based flavones from perrilla pigment. Due to the advantages derived from on-line HPLC with DPPH radical scavenging assay and HSCCC technique, a rapid, efficient and effective strategy has been developed for the discovery of antioxidants from natural products. PMID- 23442687 TI - Blends of olive oil and sunflower oil: characterisation and olive oil quantification using fatty acid composition and chemometric tools. AB - A method capable of recognising the percentage of olive oil in a blend is required to verify whether its labelling complies with the statements set out by the Commission Regulation (EC) No. 1019/2002. In this study an analytical methodology was developed in order to define blends of olive oil and sunflower oil, which contain 50% of olive oil, compared to blends with 40% and 60% of it, respectively. Methyl esters of fatty acids were analysed by GC-FID and processed through chemometric tools (PCA, TFA, SIMCA and PLS). A strong differentiation of blends according to the amount of olive oil contained and a quantification model with a standard error of prediction of 1.51% were obtained. As this issue represents a significant analytical challenge, variability associated with the fatty acid composition of olive oil was first studied. PMID- 23442688 TI - Development and validation of a grouping method for pesticides analysed in foodstuffs. AB - The cost effective monitoring of hundreds of pesticide residues in foodstuffs of vegetable origin involves the definition of groups of analytes associated with homogeneous performance parameters of the used analytical method. The performance of the analytical method only needs to be tested on a daily base for some of these group's compounds. This work proposes a strategy for defining groups of compounds with homogeneous physical-chemical properties based on the evaluation of the similarity of the multivariate pattern of five of these properties namely: molar mass, melting point, vapour pressure at 20 degrees C, n-octanol-water partition coefficient and solubility in water at 20 or 25 degrees C. Three independent and competing multivariate analysis tools, namely Principal Component Analysis, Hierarchical Clustering and K-Mean Clustering were used. This strategy was successfully used to group 100 pesticides into nine clusters, with 1-40 pesticides, represented by a compound with within group average properties. The developed grouping method was validated using physical-chemical data from other references or compounds and produced groups consistent with the performance of the studied determination of pesticide residues in dried red bean. The mean analyte recoveries of groups with larger dimension are statistically different for a confidence level of 95%. The within group coefficients of variance of mean analyte recoveries of larger groups ranged from 6.7% to 8.5%. This grouping method can reduce the number of recovery tests performed for the validation of the analytical method or test quality control. PMID- 23442689 TI - Headspace fingerprinting as an untargeted approach to compare novel and traditional processing technologies: a case-study on orange juice pasteurisation. AB - As a rule, previous studies have generally addressed the comparison of novel and traditional processing technologies by a targeted approach, in the sense that only the impact on specific quality attributes is investigated. By contrast, this work focused on an untargeted strategy, in order to take into account unexpected and unintended effects of (novel) processing, and to possibly uncover unknown compounds resulting from alternative processing. The potential of headspace GC-MS fingerprinting was explored as a tool to compare the impact of thermal, high pressure (HP) and pulsed electric field (PEF) processing for mild pasteurisation of orange juice. This study demonstrated that when processing conditions are selected based on equivalent microbial safety, the impact of heat, HP and PEF pasteurisation on the volatile profile of orange juice can be considered comparable. During refrigerated storage, however, indirect impact differences were revealed, which were attributed to differences in degree of enzyme inactivation. PMID- 23442690 TI - Aroma profile of Garnacha Tintorera-based sweet wines by chromatographic and sensorial analyses. AB - The aroma profiles obtained of three Garnacha Tintorera-based wines were studied: a base wine, a naturally sweet wine, and a mixture of naturally sweet wine with other sweet wine obtained by fortification with spirits. The aroma fingerprint was traced by GC-MS analysis of volatile compounds and by sensorial analysis of odours and tastes. Within the volatiles compounds, sotolon (73 MUg/L) and acetoin (122 MUg/L) were the two main compounds found in naturally sweet wine. With regards to the odorant series, those most dominant for Garnacha Tintorera base wine were floral, fruity and spicy. Instead, the most marked odorant series affected by off-vine drying of the grapes were floral, caramelized and vegetal wood. Finally, odorant series affected by the switch-off of alcoholic fermentation with ethanol 96% (v/v) fit for human consumption followed by oak barrel aging were caramelized and vegetal-wood. A partial least square test (PLS 2) was used to detect correlations between sets of sensory data (those obtained with mouth and nose) with the ultimate aim of improving our current understanding of the flavour of Garnacha Tintorera red wines, both base and sweet. Based on the sensory dataset analysis, the descriptors with the highest weight for separating base and sweet wines from Garnacha Tintorera were sweetness, dried fruit and caramel (for sweet wines) vs. bitterness, astringency and geranium (for base wines). PMID- 23442691 TI - Standardization of UV-visible data in a food adulteration classification problem. AB - This study evaluates the performance of multivariate calibration transfer methods in a classification context. The spectral variation caused by some experimental conditions can worsen the performance of the initial multivariate classification model but this situation can be solved by implementing standardization methods such as Piecewise Direct Standardization (PDS). This study looks at the adulteration of culinary spices with banned dyes such as Sudan I, II, III and IV. The samples are characterised by their UV-visible spectra and Partial Least Squares-Discriminant Analysis (PLS-DA) is used to discriminate between unadulterated samples and samples adulterated with any of the four Sudan dyes. Two different datasets that need to be standardised are presented. The standardization process yields positive classification results comparable to those obtained from the initial PLS-DA model, in which high classification performance was achieved. PMID- 23442693 TI - Quantification of hesperidin in citrus-based foods using a fungal diglycosidase. AB - A simple enzymatic-spectrophotometric method for hesperidin quantification was developed by means of a specific fungal enzyme. The method utilises the diglycosidase alpha-rhamnosyl-beta-glucosidase (EC 3.2.1.168) to quantitatively hydrolyse hesperidin to hesperetin, and the last is measured by its intrinsic absorbance in the UV range at 323 nm. The application of this method to quantify hesperidin in orange (Citrus sinensis) juices was shown to be reliable in comparison with the standard method for flavonoid quantification (high performance liquid chromatography, HPLC). The enzymatic method was found to have a limit of quantification of 1.8 MUM (1.1 mg/L) hesperidin, similar to the limit usually achieved by HPLC. Moreover, it was feasible to be applied to raw juice, without sample extraction. This feature eliminated the sample pre-treatment, which is mandatory for HPLC, with the consequent reduction of the time required for the quantification. PMID- 23442692 TI - A rapid method to isolate soluble royal jelly proteins. AB - Soluble royal jelly (RJ) proteins (SRJPs) include the major RJ protein (MRJP) family, which contribute to the physiological actions of RJ. Although SRJPs are prepared using conventional methods involving dialysis and centrifugation, dialysis is a time-consuming process. We have therefore developed a simple method to isolate SRJPs from RJ. This new method produces 20-fold higher levels of SRJPs than that of the conventional procedure; hence, the levels obtained by the new and existing methods were compared. A 1-h ultracentrifugation separated SRJPs in the supernatant into upper, middle and lower layers. Each layer was analyzed by size-exclusion HPLC, SDS-PAGE and 2-DE. The upper and middle layers contained MRJP2 (52 kDa) and MRJP3 (60-70 kDa), while the lower layer contained MRJP1 (290 kDa). In nature, MRJP1 is a monomer and/or oligomer. When the lower layer was analyzed by Superose 12 HPLC, MRJP1 was predominantly an oligomer. Our MRJP isolation method reduces the procedure time by using ultracentrifugation without dialysis to obtain SRJPs and produces layers containing MRJP1 oligomers, MRJP2 and MRJP3. PMID- 23442694 TI - Simultaneously determination of methyl and inorganic mercury in fish species by cold vapour generation atomic absorption spectrometry. AB - A simple and rapid non-chromatographic method was developed to determine methylmercury (MeHg) and inorganic mercury (iHg) levels in muscles tissues of 10 freshwater fish species. The MeHg and iHg were determined by cold vapour atomic absorption spectrometry after alkaline wet digestion of samples. The digested samples were reduced sequentially with stannous chloride and sodium tetrahydroborate for iHg and MeHg, respectively. Parameters such as carrier gas flow rate (argon), volume of oxidizing and potassium persulphate solutions were investigated in detail. The accuracy of the technique was evaluated by using certified reference material (DORM-2) and spiking the both Hg species in muscles tissue of a fish. The limits of detection were 0.117 and 0.133 MUg kg(-1) for MeHg and iHg, respectively. The concentrations of MeHg and iHg in muscles tissues of ten fish species were found in the range of (28.4-56.3) and (3.01-8.11) MUg kg(-1), respectively. PMID- 23442695 TI - Pharmacokinetics and residues of tetracycline in crucian carp muscle using capillary electrophoresis on-line coupled with electrochemiluminescence detection. AB - A novel and sensitive determination for tetracycline (TC) in crucian carp muscle was developed by using capillary electrophoresis coupled with electrochemiluminescence (ECL) detection. The conditions affected separation and detection were examined in detail. The linearity range of TC concentration was from 0.005 to 10 MUg mL(-1) with a correlation coefficient of 0.9992. The detection limit of TC (S/N=3) was 1.8 ng mL(-1). The relative standard deviations of the ECL intensity and the migration time for eleven consecutive injections of 1.0 MUg mL(-1) TC were 1.6% and 0.8%, respectively. The recovery of TC was 97.8% (n=5). After administration of 75 mg kg(-1) TC, the maximum concentration and peak time of TC in crucian carp muscle were 7.33 mg kg(-1) and 8h, respectively. After administration of TC, TC concentration demonstrated trivial variation in the period from 48 to 96 h. PMID- 23442696 TI - Pitfalls in the desulphation of glucosinolates in a high-throughput assay. AB - Glucosinolates are phytochemicals with health promoting properties. Determination as desulpho-glucosinolates is widely used and a desulphation in microtiter plates has been applied to reach high throughput. The use of various sulphatase concentrations and volumes throughout literature necessitates the identification of an appropriate desulphation procedure in microtiter plates. High sulphatase concentrations (>=15 mg/ml) decreased the concentration of the internal standard glucotropaeolin, whereas the other glucosinolates were less affected. Due to the calculation based on the recovery of glucotropaeolin, this leads to an overestimation of GL concentrations after desulphation with high sulphatase concentrations. A glucosidase side-activity, present in the crude sulphatase powder, is likely causing this phenomenon. At lower sulphatase concentrations (1 mg/ml) glucoiberin and glucoraphanin were insufficiently desulphated. Combining these effects results in a small range of applicable sulphatase concentrations. A purified sulphatase preparation resulted in good recoveries for a diversity of samples and is hence recommended for high throughput desulphation in microtiter plates. PMID- 23442697 TI - Certification of the reference material of water content in water saturated 1 octanol by Karl Fischer coulometry, Karl Fischer volumetry and quantitative nuclear magnetic resonance. AB - Certified reference materials (CRMs) of water content are widely used in the calibration and validation of Karl Fischer coulometry and volumetry. In this study, the water content of the water saturated 1-octanol (WSO) CRM was certified by Karl Fischer coulometry, volumetry and quantitative nuclear magnetic resonance (Q NMR). The water content recovery by coulometry was 99.76% with a diaphragm less electrode and Coulomat AG anolyte. The relative bias between the coulometry and volumetry results was 0.06%. In Q NMR, the water content of WSO is traceable to the International System (SI) of units through the purity of internal standard. The relative bias of water content in WSO between Q NMR and volumetry was 0.50%. The consistency of results for these three independent methods improves the accuracy of the certification of the RM. The certified water content of the WSO CRM was 4.76% with an expanded uncertainty of 0.09%. PMID- 23442698 TI - Evaluation of the volatile profile of 33 Pyrus ussuriensis cultivars by HS-SPME with GC-MS. AB - Evaluation of the volatile compounds in fruit provides useful information for plant breeding for improved fruit aroma. In this study, headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC MS) was used to assess the volatile profile of 33 cultivars of the Chinese pear Pyrus ussuriensis. In all, 108 volatile compounds were identified and there were significant differences in the composition and concentration of volatiles among cultivars. On the basis of principal components analysis (PCA), the cultivars could be divided into four groups: Group 1 contained Reli, Jinxiang, Hongbalixiang, Baibalixiang and Fuwuxiang, cultivars with a high concentration of esters and a low concentration of hydrocarbons. Group 2 contained Qiuxiang, Fuanjianba, Longxiang, Guanhongxiao, Shanli24 and Wuxiangli, cultivars with high concentrations of hydrocarbons and low concentrations of esters. Group 3 contained Shatangli and Manyuanxiang, cultivars with high concentrations of aldehydes. Group 4 contained the other 25 cultivars. PMID- 23442699 TI - Determination of hyperin in seed of Cuscuta chinensis Lam. by enhanced chemiluminescence of CdTe quantum dots on calcein/K3Fe(CN)6 system. AB - In this paper, 3-mercaptocarboxylic acid (MPA) modified CdTe quantum dots (QDs) were used as sensitizers, to enhance the chemiluminescence (CL) of the calcein/K(3)Fe(CN)(6) system. A new CL system of CdTe/calcein/K(3)Fe(CN)(6) was developed. The effects of reactant concentrations and the particle sizes of CdTe QDs on the CL emission were investigated in detail. The possible enhancement mechanism of the CL was also further investigated based on the photoluminescence (PL) and CL spectra. Polyphenols such as chlorogenic acid, quercetin, hyperin, catechin and kaempferol, were observed to inhibit the CL signal of the CdTe/calcein/K(3)Fe(CN)(6) system and determined by the proposed method. The proposed method was applied to the determination of hyperin in seed of Cuscuta chinensis Lam. and the results obtained were satisfactory. PMID- 23442700 TI - Determination of trichothecenes and zearalenones in grain cereal, flour and bread by liquid chromatography tandem mass spectrometry. AB - Although analytical methods have been already reported for legislated mycotoxins as trichothecenes and zearalenone (ZON) separately, we describe the optimization of a simple and rapid multimycotoxin method for the determination of a total of 12 mycotoxins simultaneously, nine trichothecenes (NIV, DON, FUS-X, DAS, 15 AcDON, 3-AcDON, NEO, HT-2, T-2 T2), and zearalenone and its metabolites (ZON, alpha-ZOL, beta-ZOL), of different origin (wheat, oat, barley and spelt) and in three different products where these substance can be present (grain, flour and bread) reach the food chain and cause toxic effect either in humans or animals. The extraction procedure was based on a mixture of acetonitrile/water (84/16, v/v), which provided the highest recoveries and the lowest matrix effect. DON-d1 was used as internal standard (I.S.) which helped to compensate the significant matrix effect observed for some matrices, and to obtain high success in the method validation and to reach the parameters compiled in Commission Decision, 2002/657/EC. Analytes were determinate by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Relative recoveries obtained were higher than 70% for the studied mycotoxins the four cereal. Good linearity (r(2)>0.992) was obtained and quantification limits (2.5-25 ng/g) were below European regulatory levels. Repeatability, expressed as relative standard deviation, was always lower than 11%, whereas interday precision was lower than 11% for the developed method. PMID- 23442701 TI - Finding of pesticides in fashionable fruit juices by LC-MS/MS and GC-MS/MS. AB - Products labelled as containing extracts from two mushrooms (cordyceps plus reishi) and the juices from acai, goji, mangosteen, noni, pomegranate, and sea buckthorn have been analysed for 174 different pesticides, using the validated QuEChERS method for sample preparation and electrospray LC-MS/MS in the positive ion mode for analysis. Pesticides were found in 10 of the 21 samples analysed. Most pesticides found were below the tolerance levels (1-6 MUg/g, depending on the pesticide), but some were not. This included boscalid, dimethomorph, iprovalicarb, pyridaben, pyrimethanil, and imazalil, for which there is no tolerance reported or zero tolerance in any fruit. However, genuine acai that was harvested in the state of Para and lyophilised in Rio de Janeiro had no detectable pesticides, when analysed by both LC-MS/MS and GC-MS/MS, which can detect 213 more pesticides and industrial chemicals. Likewise no pesticides were found in one sample each of cordyceps plus reishi, sea buckthorn and noni. PMID- 23442702 TI - Optimisation of digestion method for determination of arsenic in shrimp paste sample using atomic absorption spectrometry. AB - The microwave digestion method was developed and verified for the determination of arsenic in shrimp paste samples. Experimental design for five factors (HNO(3) and H(2)O(2) volumes, sample weight, microwave power and digestion time) were used for the optimisation of sample digestion. For this purpose, two level half factorial design, which involves 16 experiments, was adopted. The concentration of arsenic was analysed by graphite furnace atomic absorption spectrometry. Design Expert(r) 7.0 software was used to interpret all data obtained. The combination of 2 mL HNO(3) and 1 mL H(2)O(2) volumes, 0.1g sample weight, 1400 W power and 5 min digestion time was found to be the optimum parameters required to digest the shrimp paste samples. Tests with spiked samples presented good recoveries with relative standard deviations between 0.32% and 5.35%. PMID- 23442703 TI - A SNP-based PCR-RFLP capillary electrophoresis analysis for the identification of the varietal origin of olive oils. AB - Authenticity and traceability of high quality monovarietal extra virgin olive oils is a major concern for markets and consumers. Although analytical chemistry techniques are widely used to satisfy these needs recently developed DNA-based methods can serve as complementary approaches. A SNP database comprising 10 Greek olive varieties was constructed and five SNPs, residing in restriction sites, were selected for the development of a PCR-RFLP capillary electrophoresis method to discriminate these varieties using leaf DNA as template. An identification key was constructed indicating that five SNPs were adequate to discriminate nine out of the 10 varieties. As a proof of principle the assay was applied on DNA extracted from five of their corresponding monovarietal olive oils. Three SNPs were able to identify the varietal origin of these olive oils confirming the validity of this approach. PMID- 23442704 TI - Coupled extruder-headspace, a new method for analysis of the essential oil components of Coriandrum sativum fruits. AB - A new method involving concurrent single screw extruder combined with continuous headspace dynamic for the extraction and identification of the essential oil of Coriandrum sativum L. fruit was developed. The effect of six different nozzle diameters (5, 6, 7, 8, 9 and 10 mm) on the content and chemical composition of the essential oil of coriander fruit was studied. The oils from fruit samples were obtained by OMEGA 20 extruder. The result showed that the highest yield (0.53%) was obtained by the diameter of the nozzle was 8mm. Twenty-nine components were determined in essential oils, which were mostly hydrocarbons and alcohol monoterpenes. The main components linalool, alpha-pinene, gamma terpinene, p-cymene and limonene showed significant variations with drying trials. PMID- 23442705 TI - Rapid analysis of cyclamate in foods and beverages by gas chromatography-electron capture detector (GC-ECD). AB - A rapid method for determination of sodium cyclamate in foods and beverages was developed. Sodium cyclamate was converted to N,N-dichloridecyclohexylamine by reaction with sodium hypochlorite under acid condition. N,N dichloridecyclohexylamine was subsequently extracted by n-hexane and determined by gas chromatography. Conditions such as derivatization time, the concentration of sodium hypochlorite and sulphuric acid were optimised. Amino acids, aliphatic amines, and food additives such as preservatives, dyes and sweeteners showed no interference for quantification of cyclamate. The correlation coefficient of calibration curve was 0.9993 in the range of 5.0-250mg/L. The limits of detection (LOD) and limits of quantification (LOQ) were calculated as three or ten times the signal-to-noise ratio (S/N), respectively. The LOD and LOQ for yellow wine and fruit juice were 0.05 and 0.2mg/L, respectively. The LOD and LOQ for cake and preserved fruit were 0.25 and 0.8mg/kg, respectively. The intra-day and inter-day RSD were 0.28% and 1.1% (n=5), respectively. The method was successfully applied for determination of cyclamate in yellow wine, cake, fruit juice and preserved fruit. This method was simple, fast, and sensitive. It was suitable for the determination of cyclamate in foods and beverages for safety and quality control inspections. PMID- 23442706 TI - Assessment of the ribose-induced Maillard reaction as a means of gelatine powder identification and quality control. AB - The addition of ribose to bovine or porcine gelatine solutions followed by heating at 95 degrees C yielded brown solutions with different pH, colour (CIE L(*) and b(*)) and absorbance (A(420*) values. These differences were used for gelatine powder identification, differentiation and quality control. Differentiation analysis of the Maillard reaction parameters was conducted using cluster analysis (CA) and confidence intervals (CI). The potential use of the method as a quality control procedure was evaluated by using statistical process control (SPC). CA revealed that the two types of gelatine could be classified into two different groups. CI (95% confidence) revealed that the absorbance and colour values could be used as indicators for differentiation between the two types of gelatine because the intervals between the Maillard reaction parameters of the samples were far apart. The methodology demonstrated good reproducibility because it behaved predictably based on the X--S charts generated from the SPC charts. PMID- 23442707 TI - Development of a new method for determination of exopolysaccharide quantity in fermented milk products and its application in technology of kefir production. AB - An easy-to-use method for quantitative analysis of bacterial exopolysaccharides (EPS) was developed. The acid treatment was resultant in removing proteins and lactose and allowed to avoid long-term operation as dialysis. It was shown that, as opposed to anthron and phenol-sulphuric acid methods, reducing sugars method after EPS hydrolysis with glucose as standard provided reliable results, no matter to the EPS monosaccharide composition. EPS quantity in kefir of different brands was varied greatly, approximately at 50-200 mg/l, showing potential to enhance kefiran production by alteration of technological process. The temperature optimum for EPS production by kefir grains and kefir starter was about 30 degrees C, while the rise of temperature increased soluble EPS in culturing media by means of extraction from kefir grain body. PMID- 23442709 TI - Analytical capability of a medium power capacitively coupled plasma for the multielemental determination in multimineral/multivitamin preparations by atomic emission spectrometry. AB - A method for multielemental (Ca, Cr, Cu, Fe, K, Mg, Mn, Na, P and Zn) determination in multimineral/multivitamins by atomic emission spectrometry in a medium power radiofrequency capacitively coupled plasma (275 W) and low Ar consumption (0.4 L min(-1)) is proposed. Determinations were performed on commercially available tablets and a standard reference material after acidic high-pressure microwave assisted digestion and using the standard additions procedure. The detection limits (mg g(-1)) were in the range 0.003 (Na)-1.5 (P) and were not depreciated by the non-spectral interference of mineral matrices of K, Ca, Mg and Na excepting Zn and P. Found concentrations corresponded generally to the labelled contents with recovery in the range of 90-107% and 1.0-13.0% repeatability. The proposed technique could be an advantageous alternative to the more expensive inductively coupled plasma atomic emission spectrometry in the quality control of multimineral/multivitamin preparations. PMID- 23442708 TI - Development of a highly sensitive and specific monoclonal antibody-based enzyme linked immunosorbent assay for determination of doxycycline in chicken muscle, liver and egg. AB - A modified indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) method was developed using a highly sensitive and specific monoclonal antibody (McAb) to determine doxycycline (DC) residues in chicken tissues and egg. The McAb against DC was produced by hybridoma technique and a modified ic-ELISA was characterised in terms of sensitivity, specificity, precision and accuracy. At optimal experimental conditions, the standard curve was constructed at concentrations ranged from 0.01 to 100 ng/ml. The IC(50) value was 1.32+/-0.18 ng/ml. The limit of detection was 0.14+/-0.02 ng/g. The recoveries of DC from spiked chicken liver, muscle, and egg at levels of 50-600 ng/g were 84.6-85.5%, 88.2-89.1%, and 84.4-89.3%, respectively. The coefficient variations (CVs) were 5.1-9.3%, 3.7-11.3%, and 4.7-9.8%, respectively. Linear regression analysis showed good correlation, with r(2) values 0.9909 for chicken liver and 0.9916 for chicken muscle. PMID- 23442710 TI - The compositional characterisation of Romanian grape seed oils using spectroscopic methods. AB - In the present study, we developed a method for the grape seed oil compositional characterisation using (1)H NMR spectroscopy directly applied on oils without sample derivatisation (as triglycerides). Using (1)H NMR spectroscopy data and systems of chemometric equations, we established the composition of grape seed oils on four classes of fatty acids. Spectral information from (1)H NMR and FT-IR spectroscopy was used to make the differences between grape seed oils and genuine common oils. Applying the PCA (Principal Component Analysis) method to the spectral information, it was evaluated the application potential in authenticity control of grape seed oils from common genuine oils (sunflower, soybean, linseed and rapeseed). PMID- 23442711 TI - Use of near infrared transmittance spectroscopy to predict fatty acid composition of chicken meat. AB - In the present study, near infrared transmittance (NIT) spectroscopy was tested as a potential analytical technique to predict the FA profile of ground chicken breast (Pectoralis superficialis) considering the wavelengths between 850 and 1050 nm. Calibration equations were built using reference data expressed as (i) percentage of total FA and (ii) absolute concentration, i.e., mg of FA in 100 g of fresh meat. Calibrations developed on FA expressed in absolute concentration were much more accurate than those developed on percentage of total FA. The highest performances were obtained for two groups of FA, namely saturated and monounsaturated (R(CV)(2) of 0.90 and 0.93, and SE(CV) of 53.59 and 70.13 mg of FA on 100 g of meat, respectively), and for few individual FA (palmitic acid, oleic acid), having R(CV)(2) higher than 0.9. Sample pre-processing (milling) and different spectra pre-treatments were necessary to maximise the performance. Polyunsaturated FA were the hardest components to determine (R(CV)(2) of 0.62 and SE(CV) of 61.96 mg of FA on 100g of meat) and results suggest that NIT spectroscopy cannot be referred to as reliable method to predict these constituents. PMID- 23442712 TI - Analysis of phenolic compounds in olive oil by solid-phase extraction and ultra high performance liquid chromatography-tandem mass spectrometry. AB - In this study a simultaneous determination of several classes of polyphenolic compounds (benzoic acid derivates, cinnamic acid derivates, phenyl ethyl alcohols, flavones and other phenolic acids) in feed oils has been carried out by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). Solid-phase extraction (SPE) with Diol and C(18) cartridges were compared in terms of recovery and number of extracted compounds, obtaining better results when Diol cartridges were used. The analytical procedure was validated, obtaining recoveries ranging from 70% (vanillic acid) to 111% (gallic acid) with repeatability values (expressed as relative standard deviations, RSDs) lower than 20% at two concentration levels (500 and 1000 MUg/kg). Limits of quantification (LOQs) were always equal or lower than 50 MUg/kg except for gentisic acid (100 MUg/kg). Finally the method was applied to different types of feed oils, and it can be observed that higher concentrations of polyphenols were found in olive oil, whereas pomace olive oil and sunflower oil had the lowest level of these compounds. PMID- 23442713 TI - Systematic optimisation of coupled microwave-assisted extraction-solid phase extraction for the determination of pesticides in infant milk formula via LC MS/MS. AB - An extraction method consisting of both microwave-assisted extraction (MAE) and solid phase extraction (SPE) was developed to extract pesticides of different polarities in infant milk formula. An experimental central face composite design was established to evaluate the effects of several MAE variables simultaneously such as temperature and pH of extractant. With Derringer desirability function, all pesticides were optimally extracted at 102 degrees C within 20 min with 4.56 mL of extractant consisting of 0.1% of water in methanol at pH 12. Extraction efficiency was subsequently analysed with LC-MS/MS. The extraction recoveries ranging from 72% to 111% were obtained for all pesticides at fortification level of 5-100 MUg kg(-1) with relative standard deviations (RSDs) of less than 8%. Compared with Soxhlet/SPE, the MAE/SPE method utilised less solvent and higher recoveries were achieved with a shorter extraction time. PMID- 23442714 TI - Optimisation of olive oil phenol extraction conditions using a high-power probe ultrasonication. AB - A new method of ultrasound probe assisted liquid-liquid extraction (US-LLE) combined with a freeze-based fat precipitation clean-up and HPLC-DAD-FLD-MS detection is described for extra virgin olive oil (EVOO) phenol analysis. Three extraction variables (solvent type; 100%, 80%, 50% methanol, sonication time; 5, 10, 20 min, extraction steps; 1-5) and two clean-up methods (n-hexane washing vs. low temperature fat precipitation) were studied and optimised with aim to maximise extracts' phenol recoveries. A three-step extraction of 10 min with pure methanol (5 mL) resulted in the highest phenol content of freeze-based defatted extracts (667 MUg GAE g(-1)) from 10 g of EVOO, providing much higher efficiency (up to 68%) and repeatability (up to 51%) vs. its non-sonicated counterpart (LLE agitation) and n-hexane washing. In addition, the overall method provided high linearity (r(2)>=0.97), precision (RSD: 0.4-9.3%) and sensitivity with LODs/LOQs ranging from 0.03 to 0.16 MUg g(-1) and 0.10-0.51 MUg g(-1) of EVOO, respectively. PMID- 23442715 TI - Comparative study of different clean-up techniques for the determination of lambda-cyhalothrin and cypermethrin in palm oil matrices by gas chromatography with electron capture detection. AB - Solid phase extraction (SPE) and dispersive solid-phase extraction (d-SPE) were compared and evaluated for the determination of lambda-cyhalothrin and cypermethrin in palm oil matrices by gas chromatography with an electron capture detector (GC-ECD). Several SPE sorbents such as graphitised carbon black (GCB), primary secondary amine (PSA), C(18), silica, and florisil were tested in order to minimise fat residues. The results show that mixed sorbents using GCB and PSA obtained cleaner extracts than a single GCB and PSA sorbents. The average recoveries obtained for each pesticide ranged between 81% and 114% at five fortification levels with the relative standard deviation of less than 7% in all cases. The limits of detection for these pesticides were ranged between 0.025 and 0.05 MUg/g. The proposed method was applied successfully for the residue determination of both lambda-cyhalothrin and cypermethrin in crude palm oil samples obtained from local mills throughout Malaysia. PMID- 23442716 TI - Multiresidue pesticide analysis in Korean ginseng by gas chromatography-triple quadrupole tandem mass spectrometry. AB - In this study, a new analytical method was developed based on gas chromatography triple quadrupole tandem mass spectrometry (GC-MS/MS) and used to determine 32 multiclass pesticides in ginseng products. The analytical method was validated, yielding recovery rates in the range of 55.2-108.3%, with precision values expressed as relative standard deviation (RSD) lower or equal to 12% at the spiking levels of 30, 100, and 1000 MUg/kg. Correlation coefficients and LOQs (limit of quantification) were in the range 0.9801-0.9989 and 0.15-70 g/kg, respectively. With these validation data and this method, multiresidue pesticides of ginseng samples (fresh ginseng (n=118), red ginseng (n=24), dried ginseng (n=10)) were analysed. Among them, the most frequently detected pesticide was tolclofos-methyl. Tolclofos-methyl was detected in 86.4% of fresh ginseng (18.25 404.5 MUg/kg), 91.7% of red ginseng (13.14-119.4 MUg/kg), and 87.5% of dried ginseng (23.15-3673 MUg/kg). PMID- 23442717 TI - Determination of trace elements in commonly consumed medicinal herbs by ICP-MS and multivariate analysis. AB - The concentrations of Cr, Mn, Fe, Co, Ni, Cu, Zn, Rb, Sr and Pb elements in thirty medicinal herb samples widely consumed in Kayseri, Turkey were determined by using inductively coupled plasma mass spectrometry (ICP-MS). The samples were digested with concentrated nitric acid and hydrogen peroxide in a microwave system. The decreasing sequence of the mean metal levels in medicinal herbs is as follows: Fe>Sr>Mn>Zn>Rb>Cu>Ni>Cr>Co>Pb. Correlation analysis, principal component analysis and cluster analysis were applied to the data matrix to evaluate analytical results. It was found that four principal components account for 80.6% of the total variance in the data. In order to verify the accuracy of the method, GBW07605 Tea Certified Reference Material was analysed. PMID- 23442718 TI - Dynamic headspace solid-phase microextraction combined with one-dimensional gas chromatography-mass spectrometry as a powerful tool to differentiate banana cultivars based on their volatile metabolite profile. AB - In this study the effect of the cultivar on the volatile profile of five different banana varieties was evaluated and determined by dynamic headspace solid-phase microextraction (dHS-SPME) combined with one-dimensional gas chromatography-mass spectrometry (1D-GC-qMS). This approach allowed the definition of a volatile metabolite profile to each banana variety and can be used as pertinent criteria of differentiation. The investigated banana varieties (Dwarf Cavendish, Prata, Maca, Ouro and Platano) have certified botanical origin and belong to the Musaceae family, the most common genomic group cultivated in Madeira Island (Portugal). The influence of dHS-SPME experimental factors, namely, fibre coating, extraction time and extraction temperature, on the equilibrium headspace analysis was investigated and optimised using univariate optimisation design. A total of 68 volatile organic metabolites (VOMs) were tentatively identified and used to profile the volatile composition in different banana cultivars, thus emphasising the sensitivity and applicability of SPME for establishment of the volatile metabolomic pattern of plant secondary metabolites. Ethyl esters were found to comprise the largest chemical class accounting 80.9%, 86.5%, 51.2%, 90.1% and 6.1% of total peak area for Dwarf Cavendish, Prata, Ouro, Maca and Platano volatile fraction, respectively. Gas chromatographic peak areas were submitted to multivariate statistical analysis (principal component and stepwise linear discriminant analysis) in order to visualise clusters within samples and to detect the volatile metabolites able to differentiate banana cultivars. The application of the multivariate analysis on the VOMs data set resulted in predictive abilities of 90% as evaluated by the cross-validation procedure. PMID- 23442719 TI - Fractal colour: a new approach for evaluation of acrylamide contents in biscuits. AB - A new method to evaluate the content of acrylamide (AA) in biscuits was proposed. Principal component analysis (PCA) and least-squares support vector machine (LS SVM) combined with fractal colour were developed and compared with the model based on other colour spaces, such as RGB, CMYK and L(*)a(*)b(*). The results of this study show fractal colour has the best performance for the classification of the biscuits contained different levels of AA by PCA. In addition, the prediction capacity of LS-SVM based on fractal colour [root mean square error (RMSE)=15.70 ng/g, coefficient of determination (R(2))=0.99] is much better than that based on RGB (RMSE=26.08 ng/g, R(2)=0.98) and CMYK (RMSE=17.99 ng/g, R(2)=0.99), though worse than L(*)a(*)b(*) (RMSE=7.56 ng/g, R(2)=1.00). Therefore, fractal colour could be a new colour feature to characterise the colour information for the evaluation of AA content in biscuits. PMID- 23442720 TI - Establishment of magnetic beads-based enzyme immunoassay for detection of chloramphenicol in milk. AB - In this research, magnetic beads-based enzyme immunoassays were investigated for rapid analysis of chloramphenicol (CAP) in milk. To improve sensitivity of CAP determination, two kinds of immunomagnetic separation methods were designed and compared. Magnetic polystyrene microspheres were conjugated with anti-CAP antibody (Method I) or goat-anti-mouse IgG (Method II). The whole determination could be finished in 1.25 h. Both methods showed high sensitivity to CAP in buffer, and obtained an IC(50) value of 0.05 ng mL(-1) for Method I and 0.4 ng mL(-1) for Method II. The methods showed high specificity, only showing a little cross-reaction towards CAP succinate. The two methods were applied to detect CAP in milk. The recovery rates were 80-106% and the coefficients of variation (CVs) were 4.7-15%. The immunomagnetic assay showed promising potential in rapid screening field for CAP analysis. Between the two methods, Method I is more sensitive, and Method II is more suitable for producing a general assay by changing a primary antibody for another analyte. PMID- 23442721 TI - Optimization of conditions of solvent-free microwave extraction and study on antioxidant capacity of essential oil from Schisandra chinensis (Turcz.) Baill. AB - In this article, solvent-free microwave extraction (SFME) of essential oil from Schisandra chinensis (Turcz.) Baill was studied. A multivariate study based on central composite design (CCD) was used to evaluate the influence of three major variables affecting the performance of SFME. The optimum parameters were extraction time 30 min, irradiation power 385 W and moisture content of the fruits was 68%. The extraction yield of essential oil was 11 ml/kg under the optimum conditions. The antioxidant capacity of essential oils extracted by different methods were determined, and compared with traditional antioxidants. GC MS showed the different composition of essential oil extracted by hydro distillation (HD), steam-distillation (SD) and SFME. S. chinensis materials treated by different methods were observed by scanning electronic microscopy (SEM) and thermo-gravimetric analysis (TGA). Micrographs and thermo gravimetric loss provided more evidences to prove SFME of essential oil is more completed than HD and SD. PMID- 23442722 TI - Microsphere-based flow cytometric immunoassay for the determination of citrinin in red yeast rice. AB - The determination of citrinin (CIT) by a microsphere-based flow cytometric immunoassay (MFCI) has been developed. In the method, the carboxyl-modified microspheres were conjugated with CIT-Ovalbumin (OVA) antigen. CIT competed with the CIT-OVA antigen on the surface of the microspheres for the anti-CIT McAb. Under the optimised conditions, IC(50) value was 1.0 ng/mL and the limit of detection reached 0.005 ng/mL. The cross-reactivity was less than 0.01% against each of the four mycotoxins such as aflatoxin B(1) (AFB(1)), ochratoxin A (OTA), zearalenone (ZEA), deoxynilvalenol (DON). In the work, the MFCI could accurately determine CIT in the real red yeast rice. The systematic error was low with the coefficient of variation (CV) from 5.24% to 8.16% by the MFCI. The mean recovery of CIT from artificially contaminated red yeast rice was from 89% to 94%, with CV from 7.2% to 8.7%. The experimental data showed that the precision, sensitivity and specificity of the developed MFCI method for the determination of CIT were satisfactory. PMID- 23442723 TI - Determination of nitrite in meat products and water using dapsone with combined spot test/diffuse reflectance on filter paper. AB - This paper describes a simple, portable and environmentally friendly procedure for the determination of nitrite by combined spot test/diffuse reflectance spectroscopy on filter-paper. The method is based on the diazotization reaction of dapsone (4,4'-diamino-diphenyl sulphone, DAP) and (naphthyl)ethylenediamine hydrochloride (NED) with nitrite in acidic medium, yielding a coloured compound on the surface of a filter paper. Experimental design methodologies were used to optimise the measurement conditions. The reflectometric measurements were carried out at 545 nm and the linear range obtained was 0.29-5.0 mg L(-1) of nitrite (R=0.997), with detection and quantification limits of 0.09 and 0.29 mg L(-1), respectively. The proposed method was applied successfully to the analysis of nitrite in meat products and well water samples. PMID- 23442724 TI - Determination of spinetoram and its metabolites in amaranth and parsley using QuEChERS-based extraction and liquid chromatography-tandem mass spectrometry. AB - In this study, a simultaneous method was developed for the determination of spinetoram (XDE-175-J and XDE-175-L) and its demethyl metabolites (N-demethyl-175 J and N-demethyl-175-L) and formyl metabolites (N-formyl-175-J and N-formyl-175 L) in the minor crops; amaranth and parsley. The method uses quick, easy, cheap, effective, rugged, and safe (QuEChERS)-based extraction. Afterwards, the analytes were quantified and confirmed via liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) in the positive ion mode using multiple reaction monitoring (MRM). Calibration curves were linear over the calibration ranges for all the analytes tested with r(2)>0.993. Limits of detection and quantitation were 0.01 and 0.03 mg/kg for all the tested analytes in amaranth and parsley, respectively. Recovery values, at spiking levels 0.05 and 0.25 mg/kg, ranged from 71.0% to 115.2% with relative standard deviations <15%, except for N formyl-175-J in both amaranth and parsley. This method was applied to field incurred samples and was shown to provide an adequate sensitivity and performance for the simultaneous determination of spinetoram and metabolites. To the best of our knowledge, this is the first time spinetoram and its metabolites were quantified using LC-MS/MS in minor crops. PMID- 23442725 TI - Free amino acid profiling in grain amaranth using LC-MS/MS. AB - Reliable and reproducible techniques for identification and quantification of amino acids usually require derivatization. However, techniques such as LC-MS/MS may perhaps sideline the derivatization with significant accuracy. Understanding the interaction between free amino acids and several physiological processes apparently requires that the pool be studied in the seed itself. Data on free amino acid content of grain amaranth is very inadequate. The present analysis revealed a higher concentration of essential amino acids especially Threonine and Tryptophan than non essential amino acids. The study constitutes first report of use of LC-MS/MS method for analysing the free amino acid composition of amaranth grain. PMID- 23442726 TI - Vaccination against RSV: is maternal vaccination a good alternative to other approaches? AB - The respiratory syncytial virus (RSV) is the major cause of lower respiratory tract illness (LRI) in infants worldwide. Also persons with heart/lung disease or an immunodeficiency disorder, and the elderly are at increased risk for severe LRI upon RSV infection. Although there is at present no licensed RSV vaccine available, it is a priority target for several vaccine developers. For the implementation of a future RSV vaccination within national immunization schemes, various strategies can be considered even without the availability of extended clinical data on RSV vaccines. For this purpose, the extensive knowledge on RSV with respect to disease pathology, epidemiology and immunology can be used. This article discusses different aspects that should be considered to enable a successful implementation of a new RSV vaccine in national immunization programs. In addition, gaps in knowledge that needs further attention are identified. The maternal immunization strategy is highlighted, but also vaccination in the youngest infants and specific risk group immunization strategies are evaluated in this paper. Key factors such as the seasonality of RSV disease, interference of maternal antibodies and the immaturity of the infants' immune system are addressed. PMID- 23442727 TI - A dynamic model of some malaria-transmitting anopheline mosquitoes of the Afrotropical region. II. Validation of species distribution and seasonal variations. AB - BACKGROUND: The first part of this study aimed to develop a model for Anopheles gambiae s.l. with separate parametrization schemes for Anopheles gambiae s.s. and Anopheles arabiensis. The characterizations were constructed based on literature from the past decades. This part of the study is focusing on the model's ability to separate the mean state of the two species of the An. gambiae complex in Africa. The model is also evaluated with respect to capturing the temporal variability of An. arabiensis in Ethiopia. Before conclusions and guidance based on models can be made, models need to be validated. METHODS: The model used in this paper is described in part one (Malaria Journal 2013, 12:28). For the validation of the model, a data base of 5,935 points on the presence of An. gambiae s.s. and An. arabiensis was constructed. An additional 992 points were collected on the presence An. gambiae s.l.. These data were used to assess if the model could recreate the spatial distribution of the two species. The dataset is made available in the public domain. This is followed by a case study from Madagascar where the model's ability to recreate the relative fraction of each species is investigated. In the last section the model's ability to reproduce the temporal variability of An. arabiensis in Ethiopia is tested. The model was compared with data from four papers, and one field survey covering two years. RESULTS: Overall, the model has a realistic representation of seasonal and year to year variability in mosquito densities in Ethiopia. The model is also able to describe the distribution of An. gambiae s.s. and An. arabiensis in sub-Saharan Africa. This implies this model can be used for seasonal and long term predictions of changes in the burden of malaria. Before models can be used to improving human health, or guide which interventions are to be applied where, there is a need to understand the system of interest. Validation is an important part of this process. It is also found that one of the main mechanisms separating An. gambiae s.s. and An. arabiensis is the availability of hosts; humans and cattle. Climate play a secondary, but still important, role. PMID- 23442728 TI - Identification of effective screening strategies for cardiovascular disease prevention in a developing country: using cardiovascular risk-estimation and risk reduction tools for policy recommendations. AB - BACKGROUND: Recent increases in cardiovascular risk-factor prevalences have led to new national policy recommendations of universal screening for primary prevention of cardiovascular disease in Malaysia. This study assessed whether the current national policy recommendation of universal screening was optimal, by comparing the effectiveness and impact of various cardiovascular screening strategies. METHODS: Data from a national population based survey of 24 270 participants aged 30 to 74 was used. Five screening strategies were modelled for the overall population and by gender; universal and targeted screening (four age cut-off points). Screening strategies were assessed based on the ability to detect high cardiovascular risk populations (effectiveness), incremental effectiveness, impact on cardiovascular event prevention and cost of screening. RESULTS: 26.7% (95% confidence limits 25.7, 27.7) were at high cardiovascular risk, men 34.7% (33.6, 35.8) and women 18.9% (17.8, 20). Universal screening identified all those at high-risk and resulted in one high-risk individual detected for every 3.7 people screened, with an estimated cost of USD60. However, universal screening resulted in screening an additional 7169 persons, with an incremental cost of USD115,033 for detection of one additional high-risk individual in comparison to targeted screening of those aged >=35 years. The cost, incremental cost and impact of detection of high-risk individuals were more for women than men for all screening strategies. The impact of screening women aged >=45 years was similar to universal screening in men. CONCLUSIONS: Targeted gender- and age-specific screening strategies would ensure more optimal utilisation of scarce resources compared to the current policy recommendations of universal screening. PMID- 23442729 TI - Effects of chronic social defeat stress on behaviour, endoplasmic reticulum proteins and choline acetyltransferase in adolescent mice. AB - The present study investigated the effects of social defeat stress on the behaviours and expressions of 78-kDa glucose-regulated protein (Grp78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) and choline acetyltransferase (Chat) in the brains of adolescent mice. Adolescent male C57BL/6J mice were divided into two groups (susceptible and unsusceptible) after 10 d social defeat stress. In expt 1, behavioural tests were conducted and brains were processed for Western blotting on day 21 after stress. In expt 2, social avoidance tests were conducted and brains were subsequently processed for Western blotting on day 12 after stress. Chronic social defeat stress produced more pronounced depression-like behaviours such as decreased locomotion and social interaction, increased anxiety-like behaviours and immobility, and impaired memory performance in susceptible mice. Moreover, susceptible mice showed greater expression of Grp78 and CHOP in the amygdala (Amyg) on days 12 and 21 compared with the other groups. Susceptible and unsusceptible groups showed significant increases in Grp78 and CHOP expression in the prefrontal cortex (PFC) and hippocampus (Hipp) on day 12 compared with the control group; this persisted until day 21. The levels of Chat measured on days 12 and 21 were significantly lower in the PFC, Amyg and Hipp of all defeated mice compared with controls. The findings of the behavioural tests indicate that chronic social defeat in adolescents produces anxiety-like behaviours, social withdrawal, despair-like behaviours and cognitive impairment. The Grp78, CHOP and Chat results suggest that the selective response of endoplasmic reticulum stress proteins in the Amyg plays an important role in the vulnerability-stress model of depression. PMID- 23442731 TI - PubMed searches: overview and strategies for clinicians. AB - PubMed is a biomedical and life sciences database maintained by a division of the National Library of Medicine known as the National Center for Biotechnology Information (NCBI). It is a large resource with more than 5600 journals indexed and greater than 22 million total citations. Searches conducted in PubMed provide references that are more specific for the intended topic compared with other popular search engines. Effective PubMed searches allow the clinician to remain current on the latest clinical trials, systematic reviews, and practice guidelines. PubMed continues to evolve by allowing users to create a customized experience through the My NCBI portal, new arrangements and options in search filters, and supporting scholarly projects through exportation of citations to reference managing software. Prepackaged search options available in the Clinical Queries feature also allow users to efficiently search for clinical literature. PubMed also provides information regarding the source journals themselves through the Journals in NCBI Databases link. This article provides an overview of the PubMed database's structure and features as well as strategies for conducting an effective search. PMID- 23442732 TI - Effect of emergency major abdominal surgery on CD4 cell count among HIV positive patients in a sub-Saharan Africa tertiary hospital--a prospective study. AB - BACKGROUND: Surgery plays a key role in HIV palliative care, specifically in the diagnosis and treatment of HIV related and non-related conditions. Yet major surgery depresses the immune system. Whereas the surgical consequences of HIV infection are well described, there is a paucity of published data, in resource limited settings, on the effects of major surgery on the immune system. The purpose of this study was to determine the effect of major abdominal surgery on CD4 count in HIV positive and HIV negative patients after emergency major surgery. METHODS: A prospective cohort study was done for patients who underwent emergency major abdominal surgery. Their peri-operative CD4 counts were done for both HIV- and HIV + patients. Median CD4s were used in analysis.Mann Whitney test of significance was used for continuous data and Fisher' exact test used for categorical data. IRB approval was obtained. RESULTS: A total of 101 patients were recruited, 25 HIV positive and 76 HIV negative. The median CD4 cell reduction was higher in the HIV negative group (-68 cells) than HIV positive group (-29 cells) (p = 0.480).There was a general increase in the median CD4 change by 72 cells for the HIV positives and 95 cells for the HIV negatives (p = 0.44). CD4 change rose in both the HIV positive and negative groups by 27 cells for the HIV positives and 28 cells for the HIV negatives (p = 0.94). Relative Risk was 0.96, {CI 0.60 - 1.53}. CONCLUSION: Major emergency abdominal surgery had no significant effect on CD4 cell count among HIV positive patients. PMID- 23442733 TI - Cerebral blood flow with [15O]water PET studies using an image-derived input function and MR-defined carotid centerlines. AB - Full quantitative analysis of brain PET data requires knowledge of the arterial input function into the brain. Such data are normally acquired by arterial sampling with corrections for delay and dispersion to account for the distant sampling site. Several attempts have been made to extract an image-derived input function (IDIF) directly from the internal carotid arteries that supply the brain and are often visible in brain PET images. We have devised a method of delineating the internal carotids in co-registered magnetic resonance (MR) images using the level-set method and applying the segmentations to PET images using a novel centerline approach. Centerlines of the segmented carotids were modeled as cubic splines and re-registered in PET images summed over the early portion of the scan. Using information from the anatomical center of the vessel should minimize partial volume and spillover effects. Centerline time-activity curves were taken as the mean of the values for points along the centerline interpolated from neighboring voxels. A scale factor correction was derived from calculation of cerebral blood flow (CBF) using gold standard arterial blood measurements. We have applied the method to human subject data from multiple injections of [(15)O]water on the HRRT. The method was assessed by calculating the area under the curve (AUC) of the IDIF and the CBF, and comparing these to values computed using the gold standard arterial input curve. The average ratio of IDIF to arterial AUC (apparent recovery coefficient: aRC) across 9 subjects with multiple (n = 69) injections was 0.49 +/- 0.09 at 0-30 s post tracer arrival, 0.45 +/- 0.09 at 30-60 s, and 0.46 +/- 0.09 at 60-90 s. Gray and white matter CBF values were 61.4 +/- 11.0 and 15.6 +/- 3.0 mL/min/100 g tissue using sampled blood data. Using IDIF centerlines scaled by the average aRC over each subjects' injections, gray and white matter CBF values were 61.3 +/- 13.5 and 15.5 +/- 3.4 mL/min/100 g tissue. Using global average aRC values, the means were unchanged, and intersubject variability was noticeably reduced. This MR-based centerline method with local re-registration to [(15)O]water PET yields a consistent IDIF over multiple injections in the same subject, thus permitting the absolute quantification of CBF without arterial input function measurements. PMID- 23442734 TI - A fast and efficient method for preparation of high-quality RNA from fungal mycelia. AB - BACKGROUND: Fungal RNA samples are usually isolated from fungal mycelia grown in liquid culture, which relies on prolific growth of the fungus in liquid media. The fungal biomass is then collected by vacuum filtration, which can result in low recovery for samples with reduced biomass due to poor growth in liquid media. FINDINGS: Here we report an alternative culturing method, based on growth on solid media which is independent of the ability of a fungus to grow in liquid culture. We show that growth on solid media overlayed with a nylon membrane is superior to other culturing methods, producing large amounts of biomass and allowing for easy harvesting of fungal mycelia. Furthermore, we show that mycelium harvested with this method yielded high-quality RNA, superior to RNA isolated from liquid grown mycelium. We also show that inclusion of a second chloroform extraction step in the procedure significantly increases RNA yield. CONCLUSIONS: This method is particularly useful for fungal species that show poor or no growth in liquid media, but are easily cultured on solid media. Culturing can be performed on small petri dishes, which significantly reduces handling and therefore allowing growth and isolation of RNA from multiple strains in a high throughput manner. The obtained RNA samples are of high quality in sufficient quantities for several northern blot experiments or quantitative RT-PCR experiments. PMID- 23442735 TI - Classification, morphology and molecular pathology of premalignant lesions of the pancreas. AB - Over the past few years there have been substantial advances in our knowledge of premalignant lesions of the pancreas. Given the dismal prognosis of untreated pancreatic cancer, and the small proportion of patients who are operative candidates, an understanding of these premalignant lesions is essential for the development of strategies for early diagnosis and prevention. The 2010 WHO classification has added new entities, including intraductal tubular papillary neoplasms (ITPNs), and clarified the nomenclature and grading of previously recognised precursor lesions of pancreatic adenocarcinoma, such as intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and pancreatic intraepithelial neoplasia (PanIN). In particular, there has been an upsurge of interest in the natural history of IPMN, driven partly by improvements in imaging modalities and the consequent apparent increase in their incidence, and partly by recognition that subtypes based on location or histological appearance define groups with significantly different behaviours. In mid 2012 revised international guidelines for the classification and management of IPMNs and MCNs were published, although in several respects these guidelines represent a consensus view rather than being evidence-based. In recent years major advances in molecular technologies, including whole-exome sequencing, have significantly enhanced our knowledge of pancreatic premalignancy and have identified potentially highly specific diagnostic biomarkers such as mutations in GNAS and RNF43 that could be used to pre-operatively assess pancreatic cysts. PMID- 23442736 TI - Breast cancer precursors: diagnostic issues and current understanding on their pathogenesis. AB - The development of breast malignancy has been recognised to progress through a number of morphological precursor lesions. More recently, specific molecular alterations have been recognised in these precursor lesions. These changes appear to determine a specific malignant phenotype, which in turn, may realign the current opinion on the classification of breast cancer along molecular characteristics. This review will highlight the morphological features of these precursor lesions and their relationship to the complex molecular processes involved in their development. PMID- 23442737 TI - Premalignant lesions of the lower female genital tract: cervix, vagina and vulva. AB - Premalignant lesions of the lower female genital tract encompassing the cervix, vagina and vulva are variably common and many, but by no means all, are related to infection by human papillomavirus (HPV). In this review, pathological aspects of the various premalignant lesions are discussed, mainly concentrating on new developments. The value of ancillary studies, mainly immunohistochemical, is discussed at the appropriate points. In the cervix, the terminology and morphological features of premalignant glandular lesions is covered, as is the distinction between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma, which may be very problematic. A spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation is emerging with lobular endocervical glandular hyperplasia (LEGH), including so called atypical LEGH, representing a possible precursor of non HPV-related cervical adenocarcinomas exhibiting gastric differentiation; these include the cytologically bland adenoma malignum and the morphologically malignant gastric type adenocarcinoma. Stratified mucin producing intraepithelial lesion (SMILE) is a premalignant cervical lesion with morphological overlap between cervical intraepithelial neoplasia (CIN) and AIS and which is variably regarded as a form of reserve cell dysplasia or stratified AIS. It is now firmly established that there are two distinct types of vulval intraepithelial neoplasia (VIN) with a different pathogenesis, molecular events, morphological features and risk of progression to squamous carcinoma. These comprise a more common HPV-related usual type VIN (also referred to as classic, undifferentiated, basaloid, warty, Bowenoid type) and a more uncommon differentiated (simplex) type which is non-HPV related and which is sometimes associated with lichen sclerosus. The former has a relatively low risk of progression to HPV-related vulval squamous carcinoma and the latter a high risk of progression to non-HPV related vulval squamous carcinoma. Various aspects of vulval Paget's disease are also discussed. PMID- 23442738 TI - Gastrointestinal dysplasia. AB - The term dysplasia (intraepithelial neoplasia) is used to refer to neoplastic but non-invasive epithelium. Dysplasia in the gastrointestinal tract is considered a carcinoma precursor and a marker of high cancer risk for the site at which it is found. It is diagnosed by pathologists using a set of cytological and architectural features. There are many pitfalls in the diagnosis of gastrointestinal dysplasia. One reason for difficulty in dysplasia diagnosis is the significant heterogeneity in the appearances of each grade of dysplasia. In addition, the features that characterise dysplasia are only subtly different from those of regenerating epithelium, particularly at the low end of the spectrum, making this distinction difficult. For these reasons, and because of significant implications of this diagnosis for patient care, the interpretations of biopsies taken for dysplasia surveillance are considered challenging by most pathologists. In this article, we review definition, classification, and histological features and grading of gastrointestinal dysplasia with focus on Barrett's oesophagus (BE) related dysplasia, gastric epithelial dysplasia (GED) and dysplasia arising in the background of inflammatory bowel disease (IBD). We also discuss observer variability and the role of adjunctive markers in dysplasia diagnosis, and limitation with regard to surveillance of patients with BE and IBD due to sampling error. PMID- 23442739 TI - Psychomotor depressive symptoms may differentially respond to venlafaxine. AB - Predicting differential antidepressant efficacy remains an elusive goal in major depressive disorder (MDD). The aims of this study were three-fold. Firstly, to examine if psychomotor retardation symptoms (item 8 on the 17-item Hamilton Depression Rating Scale) improve preferentially to venlafaxine (VEN) over escitalopram (ESC) treatment. Secondly, whether the 18 item CORE psychomotor signs scale predicted antidepressant remission. Finally, to investigate the role of two norepinephrine transporter gene (NET) polymorphisms (rs2242446 and rs5569) on antidepressant efficacy. Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. MDD (n=113) were treated with ESC or VEN prospectively for 8 weeks and rated serially with the Hamilton Depression Rating Scale. In a subsample (n=51) of patients from one of the three recruitment sites, the CORE psychomotor signs scale was also administered at baseline. Participants treated with VEN had significantly greater reduction in psychomotor retardation symptoms than those treated with ESC. The CORE scale did not predict antidepressant response or remission. Neither NET polymorphism moderated antidepressant efficacy. Findings suggest possible preferential utility of a selective serotonin and noradrenaline reuptake inhibitor in cases of MDD presenting with greater psychomotor retardation. The moderate to small sample size makes a type II error risk possible, and the negative findings need to be interpreted with caution. The positive finding of preferential efficacy of VEN for psychomotor retardation symptoms has potential translational utility. PMID- 23442741 TI - Optical and microstructural properties of ZnO/TiO2 nanolaminates prepared by atomic layer deposition. AB - ZnO/TiO2 nanolaminates were grown on Si (100) and quartz substrates by atomic layer deposition at 200 degrees C using diethylzinc, titanium isopropoxide, and deionized water as precursors. All prepared multilayers are nominally 50 nm thick with a varying number of alternating TiO2 and ZnO layers. Sample thickness and ellipsometric spectra were measured using a spectroscopic ellipsometer, and the parameters determined by computer simulation matched with the experimental results well. The effect of nanolaminate structure on the optical transmittance is investigated using an ultraviolet-visible-near-infrared spectrometer. The data from X-ray diffraction spectra suggest that layer growth appears to be substrate sensitive and film thickness also has an influence on the crystallization of films. High-resolution transmission electron microscopy images show clear lattice spacing of ZnO in nanolaminates, indicating that ZnO layers are polycrystalline with preferred (002) orientation while TiO2 layers are amorphous. PMID- 23442740 TI - Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study. AB - INTRODUCTION: Experimental evidence suggests a protective role for circulating 25 hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent. METHODS: We conducted a case control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH)D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: No association was observed between circulating levels of 25(OH)D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH)D > 0.70). An inverse association between 25(OH)D levels and breast cancer risk was observed among women who were <= 45 years of age (ORQ5-Q1 = 0.48, 95% CI = 0.30-0.79, ptrend = 0.01) or premenopausal at enrollment (ORQ5-Q1 = 0.67, 95% CI = 0.48 0.92, ptrend = 0.03). CONCLUSIONS: Circulating 25(OH)D levels were not associated with breast cancer risk overall, although we could not exclude the possibility of a protective effect in younger women. Recommendations regarding vitamin D supplementation should be based on considerations other than breast cancer prevention. PMID- 23442742 TI - White-matter microstructure in previously drug-naive patients with schizophrenia after 6 weeks of treatment. AB - BACKGROUND: It is not clear whether the progressive changes in brain microstructural deficits documented in previous longitudinal magnetic resonance imaging (MRI) studies might be due to the disease process or to other factors such as medication. It is important to explore the longitudinal alterations in white-matter (WM) microstructure in antipsychotic-naive patients with first episode schizophrenia during the very early phase of treatment when relatively 'free' from chronicity. METHOD: Thirty-five patients with first-episode schizophrenia and 22 healthy volunteers were recruited. High-resolution diffusion tensor imaging (DTI) was obtained from participants at baseline and after 6 weeks of treatment. A 'difference map' for each individual was calculated from the 6 week follow-up fractional anisotropy (FA) of DTI minus the baseline FA. Differences in Positive and Negative Syndrome Scale (PANSS) scores and Global Assessment of Functioning (GAF) scores between baseline and 6 weeks were also evaluated and expressed as a 6-week/baseline ratio. RESULTS: Compared to healthy controls, there was a significant decrease in absolute FA of WM around the bilateral anterior cingulate gyrus and the right anterior corona radiata of the frontal lobe in first-episode drug-naive patients with schizophrenia following 6 weeks of treatment. Clinical symptoms improved during this period but the change in FA did not correlate with the changes in clinical symptoms or the dose of antipsychotic medication. CONCLUSIONS: During the early phase of treatment, there is an acute reduction in WM FA that may be due to the effects of antipsychotic medications. However, it is not possible to entirely exclude the effects of underlying progression of illness. PMID- 23442743 TI - Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas. AB - BACKGROUND: Recent studies suggest that bacterial endotoxins may be associated with various chronic diseases, including colorectal adenomas and cancer. Given the evidence linking inflammation and colorectal cancer, we sought to determine if plasma endotoxin concentrations are associated with indicators of systemic or local inflammation and colorectal adenomas. METHODS: This cross-sectional study consisted of participants who underwent screening colonoscopies and included adenoma cases (n=138) and non-adenoma controls (n=324). Plasma concentrations of endotoxin were measured with Limulus Amebocyte Lysate (LAL) assay. We quantified concentrations of inflammatory cytokines, interleukin-4 (IL-4), IL-6, IL-8, IL 10, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN gamma) in plasma by ELISA and mRNA expression levels in rectal mucosal biopsies by quantitative RT-PCR. Interleukin-17 was evaluated only in the rectal mucosa. RESULTS: Compared to subjects with low plasma endotoxin concentrations, those with higher concentrations were more likely to have adenomas (OR 1.4, 95% CI 1.0 2.1). Among subjects with adenomas, those with villous histology were more likely to have higher endotoxin concentrations (5.4 vs. 4.1EU/mL, p=0.05) and lower plasma IFN-gamma (0 vs. 1.64 pg/mL, p=0.02) compared to those with only tubular adenomas. Cases showed a trend of having higher plasma TNF-alpha levels than controls (p=0.06), but none of the other plasma or rectal mucosal cytokine levels differed between cases and controls. Elevated mucosal IL-12 levels were associated with having multiple adenomas (p=0.04). Higher concentrations of plasma endotoxin predicted increased plasma IL-12 levels (OR 1.5, 95% CI 1.0-2.2) and rectal mucosal IL-12 (OR 1.9, 95% CI 1.0-3.7) and IL-17 gene expression (OR 2.2, 95% CI 1.0-4.6). CONCLUSIONS: These findings suggest that interactions between elevated plasma endotoxin concentrations and inflammatory cytokines may be relevant to the development of colorectal adenomas. PMID- 23442744 TI - Efficacy and toxicity of thirteen plant leaf acetone extracts used in ethnoveterinary medicine in South Africa on egg hatching and larval development of Haemonchus contortus. AB - BACKGROUND: Helminthiasis is a major limitation to the livestock industry in Africa. Haemonchus contortus is the singular most important helminth responsible for major economic losses in small ruminants. The high cost of anthelmintics to small farmers, resistance to available anthelmintics and residue problems in meat and milk consumed by humans further complicates matters. The use of plants and plant extracts as a possible source of new anthelmintics has received more interest in the last decade. Our aim was not to confirm the traditional use, but rather to determine activity of extracts.Based on our past experience acetone was used as extractant. Because it is cheaper and more reproducible to evaluate the activity of plant extracts, than doing animal studies, the activity of acetone leaf extracts of thirteen plant species used traditionally in ethnoveterinary medicine in South Africa were determined using the egg hatch assay and the larval development test. Cytotoxicity of these extracts was also evaluated using the MTT cellular assay. RESULTS: Extracts of three plant species i.e. Heteromorpha trifoliata, Maesa lanceolata and Leucosidea sericea had EC50 values of 0.62 mg/ml, 0.72 mg/ml and 1.08 mg/ml respectively for the egg hatch assay. Clausena anisata; (1.08 mg/ml) and Clerodendrum glabrum; (1.48 mg/ml) extracts were also active. In the larval development assay the H. trifoliata extract was the most effective with an EC50 of 0.64 mg/ml followed by L. sericea (1.27 mg/ml). The activities in the larval development test were generally lower in most plant species than the egg hatch assay. Based on the cytotoxicity results C. anisata was the least toxic with an LC50 of 0.17 mg/ml, while Cyathea dregei was the most toxic plant with an LC50 of 0.003 mg/ml. The C. anisata extract had the best selectivity index with a value of 0.10 and 0.08 for the two assays, followed by H. trifoliata and L. sericea with values of 0.07, 0.07 and 0.05, 0.04. The C. dregei extract had the worst selectivity index with a value of 0.00019 for both assays. CONCLUSION: The result of this study indicates which species should be further investigated in depth for isolation of compounds. PMID- 23442746 TI - Retraction: Zhong Ye; Darya O. Mishchuk; Natasha S. Stephens and Carolyn M. Slupsky. Dextran sulfate sodium inhibits alanine synthesis in Caco-2 cells. Int. J. Mol. Sci. 2011, 12, 2325-2335. AB - It has been brought to our attention by the corresponding author that the results presented this article [1] are in error due to the fact that the media supplement glutaMAX was used in place of L-glutamine for culture of the control cells, while L-glutamine was used for culture of the treated cells. All authors have confirmed that the reported result could not be reproduced using the correct culture conditions. We would like to thank the authors for pointing out this error thereby upholding the ethics of scientific publication. The Editorial Team and Publisher have agreed with the authors that this manuscript should be retracted. We apologize for any inconvenience this may have caused. PMID- 23442745 TI - Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease. AB - BACKGROUND: The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG). METHODS: The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a lower 1,5-AG group (n = 36) and a higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups. RESULTS: The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT. CONCLUSION: Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease. PMID- 23442747 TI - Trends in health and health inequalities among major states of India: assessing progress through convergence models. AB - Convergence in health and health inequalities reflects not only a sense of equity, but also provides a critical assessment tool for monitoring the health progress of differently placed individuals. This study examines convergence hypothesis for health and health inequalities across major Indian states, using both standard and cutting-edge convergence metrics. The findings lend support to the convergence in average health status among the states and the socioeconomic group of India, examined through select health indicators. However, results also suggest a setback in convergence in decline of health inequalities in recent times, particularly in life expectancy at birth, child immunization and underweight. Evidence signals that from the late 1990s, convergence in decline of health inequalities are replaced by emerging divergence. This paper contributes to health policy and planning by identifying areas where, India needs to work to achieve efficiency with equity in health status across geographical divisions and social groups. PMID- 23442749 TI - Massive postoperative pulmonary artery tumor embolism from renal cell carcinoma. PMID- 23442748 TI - A controlled, parallel, cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso. AB - BACKGROUND: In malaria-endemic countries, large proportions of infected individuals are asymptomatic, constituting a reservoir of parasites for infection of newly hatched mosquitoes. This study evaluated the impact of screening and treatment of asymptomatic carriers of Plasmodium falciparum. METHODS: Eighteen villages were randomized (1:1) to study arms and inhabitants participated in four community screening campaigns: three before the rainy season ~1 month apart, and the fourth after the rains at ~12 months. On day 1 of campaigns 1-3, asymptomatic carriers in the intervention arm were identified by rapid diagnostic test and treated with artemether-lumefantrine. Outcomes were symptomatic malaria with parasite density >5,000/MUL per person-year in children < 5 years and change in haemoglobin between days 1 and 28 of campaign 1. RESULTS: At 12 months, the number of symptomatic malaria episodes with a parasite density >5,000/MUL per person-year in children < 5 years was not significantly different between arms (1.69 vs 1.60, p = 0.3482). Mean haemoglobin change in asymptomatic carriers during campaign 1 was greater in the intervention vs control arm (+0.53 g/dL vs 0.21 g/dL, p < 0.0001). ANCOVA demonstrated that mean asymptomatic carriage at the cluster level was lower in the intervention vs control arm at day 1 of campaigns 2 (5.0% vs 34.9%, p < 0.0001) and 3 (3.5% vs 31.5%, p < 0.0001), but showed only a small difference at day 1 of campaign 4 (34.6% vs 37.6%, p = 0.2982). Mean gametocyte carriage was lower in the intervention vs control arm at day 1 of campaigns 2 and 3 (0.7% vs 5.4%, p < 0.0001; 0.5% vs 5.8%, p < 0.0001), but was similar at day 1 of campaign 4 (4.9% vs 5.1%, p = 0.7208). CONCLUSIONS: Systematic screening and treatment of asymptomatic carriers at the community level did not reduce clinical malaria incidence in the subsequent transmission season, indicating greater levels of parasite clearance are required to achieve a sustained impact in this setting. PMID- 23442750 TI - Retrograde light-guided laryngoscopy for tracheal intubation: clinical practice and comparison with conventional direct laryngoscopy. AB - BACKGROUND: Tracheal intubation with conventional laryngoscopy requires many trials until beginners are sufficiently skilled in intubating patients safely. To facilitate intubation, the authors used retrograde light-guided laryngoscopy (RLGL) and compared its feasibility with conventional direct laryngoscopy (DL). METHODS: Twenty operators participated in a prospective, randomized, open-label, parallel-arm study. These operators intubated 205 patients randomly according to a computer-generated procedure by using either DL or RLGL (five intubations with each technique). The primary outcome was the success rate of tracheal intubation. The authors evaluated the success rate of tracheal intubation, the time to glottic exposure and tracheal intubation, and the Cormack and Lehane grades. RESULTS: Compared with DL, the success rate was greater in the RLGL group for all five intubations (72% vs. 47%; rate difference, 25%; 95% CI [11.84-38.16%], P < 0.001). This was associated with a shorter time to glottic exposure (median [25th and 75th percentile]; 27 [15; 42] vs. 45 [30; 73] s, P < 0.001), shorter intubation time (66 [44; 120] vs. 120 [69; 120] s, P < 0.001), and decreased throat soreness (mean +/- SD; visual analog scale, 2.1 +/- 0.9 vs. 3.7 +/- 1.0 cm, P = 0.001) in the RLGL group compared to the DL group. CONCLUSION: RLGL is an alternative intubation technique. In our study, it enables beginners to intubate patients more successfully and quickly than conventional DL. PMID- 23442752 TI - Magnetic resonance imaging analysis of the spread of local anesthetic solution after ultrasound-guided lateral thoracic paravertebral blockade: a volunteer study. AB - BACKGROUND: This study was designed to examine the spread of local anesthetic (LA) via magnetic resonance imaging after a standardized ultrasound-guided thoracic paravertebral blockade. METHODS: Ten volunteers were enrolled in the study. We performed ultrasound-guided single-shot paravertebral blocks with 20 ml mepivacaine 1% at the thoracic six level at both sides on two consecutive days. After each paravertebral blockade, a magnetic resonance imaging investigation was performed to investigate the three-dimensional spread of the LA. In addition, sensory spread of blockade was evaluated via pinprick testing. RESULTS: The median (interquartile range) cranial and caudal distribution of the LA relative to the thoracic six puncture level was 1.0 (2.5) and 3.0 (0.75) [=4.0 vertebral levels] for the left and 0.5 (1.0) and 3.0 (0.75) [=3.5 vertebral levels] for the right side. Accordingly, the LA distributed more caudally than cranially. The median (interquartile range) number of sensory dermatomes which were affected by the thoracic paravertebral blockade was 9.8 (6.5) for the left and 10.7 (8.8) for the right side. The sensory distribution of thoracic paravertebral blockade was significantly larger compared with the spread of LA. CONCLUSIONS: Although the spread of LA was reproducible, the anesthetic effect was unpredictable, even with a standardized ultrasound-guided technique in volunteers. While it can be assumed that approximately 4 vertebral levels are covered by 20 ml LA, the somatic distribution of the thoracic paravertebral blockade remains unpredictable. In a significant percentage, the LA distributes into the epidural space, prevertebral, or to the contralateral side. PMID- 23442753 TI - Reducing wastage of inhalation anesthetics using real-time decision support to notify of excessive fresh gas flow. AB - BACKGROUND: Reduced consumption of inhalation anesthetics can be safely achieved by reducing excess fresh gas flow (FGF). In this study the authors describe the use of a real-time decision support tool to reduce excess FGF to lower, less wasteful levels. METHOD: The authors applied a decision support tool called the Smart Anesthesia ManagerTM (University of Washington, Seattle, WA) that analyzes real-time data from an Anesthesia Information Management System to notify the anesthesia team if FGF exceeds 1 l/min. If sevoflurane consumption reached 2 minimum alveolar concentration-hour under low flow anesthesia (FGF < 2 l/min), a second message was generated to increase FGF to 2 l/min, to comply with Food and Drug Administration guidelines. To evaluate the tool, mean FGF between surgical incision and the end of procedure was compared in four phases: (1) a baseline period before instituting decision rules, (2) Intervention-1 when decision support to reduce FGF was applied, (3) Intervention-2 when the decision rule to reduce flow was deliberately inactivated, and (4) Intervention-3 when decision rules were reactivated. RESULTS: The mean +/- SD FGF reduced from 2.10 +/- 1.12 l/min (n = 1,714) during baseline to 1.60 +/- 1.01 l/min (n = 2,232) when decision rules were instituted (P < 0.001). When the decision rule to reduce flow was inactivated, mean FGF increased to 1.87 +/- 1.15 l/min (n = 1,732) (P < 0.001), with an increasing trend in FGF of 0.1 l/min/month (P = 0.02). On reactivating the decision rules, the mean FGF came down to 1.59 +/- 1.02 l/min (n = 1,845). Through the Smart Anesthesia MessengerTM system, the authors saved 9.5 l of sevoflurane, 6.0 l of desflurane, and 0.8 l isoflurane per month, translating to an annual savings of $104,916. CONCLUSIONS: Real-time notification is an effective way to reduce inhalation agent usage through decreased excess FGFs. PMID- 23442754 TI - Comparison of equivolume, equiosmolar solutions of mannitol and hypertonic saline with or without furosemide on brain water content in normal rats. AB - BACKGROUND: Mannitol and hypertonic saline (HS) are used by clinicians to reduce brain water and intracranial pressure and have been evaluated in a variety of experimental and clinical protocols. Administering equivolume, equiosmolar solutions in healthy animals could help produce fundamental data on water translocation in uninjured tissue. Furthermore, the role of furosemide as an adjunct to osmotherapy remains unclear. METHODS: Two hundred twenty isoflurane anesthetized rats were assigned randomly to receive equivolume normal saline, 4.2% HS (1,368 mOsm/L 25% mannitol (1,375 mOsm/L), normal saline plus furosemide (8 mg/kg), or 4.2% HS plus furosemide (8 mg/kg) over 45 min. Rats were killed at 1, 2, 3, and 5 h after completion of the primary infusion. Outcome measurements included body weight; urinary output; serum and urinary osmolarity and electrolytes; and brain, lung, skeletal muscle, and small bowel water content. RESULTS: In the mannitol group, the mean water content of brain tissue during the experiment was 78.0% (99.3% CI, 77.9-78.2%), compared to results from the normal saline (79.3% [99.3% CI, 79.1-79.5%]) and HS (78.8% [99.3% CI, 78.6-78.9%]) groups (P < 0.001), whereas HS plus furosemide yielded 78.0% (99.3% CI, 77.8 78.2%) (P = 0.917). After reaching a nadir at 1 h, brain water content increased at similar rates for mannitol (0.27%/h [99.3% CI, 0.14-0.40%/h]) and HS (0.27%/h [99.3% CI, 0.17-0.37%/h]) groups (P = 0.968). CONCLUSIONS: When compared to equivolume, equiosmolar administration of HS, mannitol reduced brain water content to a greater extent over the entire course of the 5-h experiment. When furosemide was added to HS, the brain-dehydrating effect could not be distinguished from that of mannitol. PMID- 23442755 TI - Surgical versus low-dose progestin treatment for endometriosis-associated severe deep dyspareunia II: effect on sexual functioning, psychological status and health-related quality of life. AB - STUDY QUESTION: Does surgical and low-dose progestin treatment differentially affect endometriosis-associated severe deep dyspareunia in terms of sexual functioning, psychological status and health-related quality of life? SUMMARY ANSWER: Surgery and progestin treatment achieved essentially similar benefits at 12-month follow-up, but with different temporal trends. WHAT IS ALREADY KNOWN: Conservative surgery and hormonal therapies have been used independently for endometriosis-associated deep dyspareunia with inconsistent results. STUDY DESIGN, SIZE, DURATION: Patient preference, parallel cohort study with 12-month follow-up. The effect of conservative surgery at laparoscopy versus treatment with a low dose of norethisterone acetate per os (2.5 mg/day) in women with persistent/recurrent severe deep dyspareunia after first-line surgery was compared. PARTICIPANTS/MATERIALS AND SETTING, METHODS: A total of 51 patients chose repeat surgery and 103 progestin treatment. Variations in sexual function, psychological well-being and quality of life were measured by means of the Female Sexual Function Index (FSFI), the Hospital Anxiety and Depression Scale (HADS) and the Endometriosis Health Profile-30 (EHP-30). MAIN RESULTS AND THE ROLE OF CHANCE: Four women in the surgery group and 21 women in the progestin group withdrew from the study for various reasons. Total FSFI scores, anxiety and depression scores and EHP-30 scores improved immediately after surgery, but worsened with time, whereas the effect during progestin use increased more gradually, but progressively, without overall significant between-group differences at 12-month follow-up. A tendency was observed towards a slightly better total FSFI score after surgery at the end of the study period. LIMITATIONS, REASONS FOR CAUTION: Treatments were not randomly allocated, and distribution of participants as well as of dropouts between study arms was unbalanced. However, the possibility of choosing the treatment allowed assessment of the maximum potential effect size of the interventions. WIDER IMPLICATIONS OF THE FINDINGS: Both surgery and medical treatment with progestins are valuable options for improving the detrimental impact of endometriosis-associated dyspareunia on sexual functioning and quality of life. Women should be aware of the pros and cons of both options to decide which one best suits their needs. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a research grant from the University of Milan School of Medicine (PUR number 2009-ATE-0570). None of the authors have a conflict of interest. PMID- 23442756 TI - Addition of highly purified HMG after corifollitropin alfa in antagonist-treated poor ovarian responders: a pilot study. AB - STUDY QUESTION: Will sequential administration of highly purified (hp)-HMG after corifollitropin alfa in a GnRH antagonist protocol benefit women with poor ovarian response according to the Bologna criteria? SUMMARY ANSWER: Corifollitropin alfa followed by hp-HMG in a GnRH antagonist protocol results in very promising pregnancy rates, albeit only in young (<40 years old) poor ovarian responders fulfilling the Bologna criteria. WHAT IS KNOWN ALREADY: Poor ovarian responders fulfilling the Bologna criteria have a very poor prognosis in terms of successful IVF outcome. Although a recent study demonstrated low pregnancy rates in this group of patients after treatment with corifollitropin alfa followed by recombinant FSH in a GnRH antagonist protocol, previous studies showed that the addition of LH activity in 36- to 39-year-old women significantly increases implantation rates. STUDY DESIGN, SIZE, DURATION: In this retrospective pilot study, we included poor ovarian responders fulfilling the Bologna criteria treated with a completely novel protocol, with corifollitropin alfa followed by hp-HMG in a GnRH antagonist setting. Overall, 51 patients were treated within a period of 1 year (August 2011-August 2012). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients received 150 MUg corifollitropin alfa on second day of the menstrual cycle followed by a fixed daily dose of 0.25 mg of GnRH antagonist on Day 7 of the cycle onwards. On the ninth day of the cycle, a daily fixed dose of 300 IU hp-HMG was administered until the day of ovulation triggering. The primary outcome was ongoing pregnancy rate per patient. MAIN RESULTS AND THE ROLE OF CHANCE: Among 47 eligible women, 29 patients were <40 years old and 18 patients were >= 40 years old. No differences were observed in endocrine profile, number of cycles with oocyte retrieval (66 versus 67%) and cycles with embryo transfer (62 versus 61%) in women <40 versus >= 40 years old, respectively. However, 8 of the 29 women <40 years old had an ongoing pregnancy (28%) compared with 0 of 18 patients who were >= 40 years of age (P = 0.017). LIMITATIONS, REASONS FOR CAUTION: Owing to the specific retrospective study design, bias cannot be ruled out and these results should not be extrapolated to other treatment protocols for poor ovarian responders. Therefore, caution should be taken when interpreting the results. WIDER IMPLICATIONS OF THE FINDINGS: The promising results from this pilot study of corifollitropin alfa followed by hp-HMG stimulation indicate a potential beneficial effect in young poor ovarian responders fulfilling the Bologna criteria. The data provide the rationale for performing a randomized controlled trial to determine if there is sound evidence for a clinical introduction of this protocol. STUDY FUNDING/COMPETING INTEREST(S): No conflicts of interest to declare. No specific funding was received for this study. PMID- 23442757 TI - International Committee for Monitoring Assisted Reproductive Technologies (ICMART) world report: assisted reproductive technology 2004. AB - STUDY QUESTION: Have changes in assisted reproductive technology (ART) practice and outcomes occurred globally between 2003 and 2004? SUMMARY ANSWER: Globally, ART practice has changed with an increasing prevalence of the use of ICSI rather than conventional IVF. In 2004, a small but increasing number of countries are incorporating single embryo transfer. There remain unacceptably high rates of three or more embryo transfers in select countries resulting in multiple births and adverse perinatal outcomes. WHAT IS KNOWN ALREADY: World data on the availability, effectiveness and safety of ART have been published since 1989. The number of embryos transferred is a major determinant of the iatrogenic increase in multiple pregnancies and is highly correlated with the likelihood of multiple birth and excess perinatal morbidity and mortality. STUDY DESIGN, SIZE, DURATION: Cross-sectional survey of countries and regions undertaking surveillance of ART procedures started in 2004 and their corresponding outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of total, 2184 clinics from 52 reporting countries and regions. Number of ART clinics, types of cycles and procedures, pregnancy, delivery and multiple birth rates and perinatal outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 954 743 initiated cycles resulted in an estimated 237 809 babies born. This was a 2.3% increase in the number of reported cycles from 2003. The availability of ART varied by country and ranged from 14 to 3844 treatment cycles per million population. Over one-third (37.2%) of ART clinics performed <100 cycles per year with only 19.9% performing >= 500 cycles per year. Of all cycles, 60.6% were ICSI. Frozen embryo transfers (FETs) represented 31% of the initiated cycles. The overall delivery rate per fresh aspiration for IVF and ICSI was 20.2% compared with 16.6% per FET. The average number of embryos transferred was 2.35. Single (16.3%) and double embryo transfers accounted for 73.2% of cycles. The overall proportion of deliveries with twins and triplets from IVF and ICSI was 25.1 and 1.8%, respectively, but varied widely by country and region. The proportion of premature deliveries per fresh aspiration for IVF and ICSI was 33.7% compared with 26.3% per FET. The perinatal death rate was 25.8 per 1000 births for fresh aspiration for IVF and ICSI compared with 14.2 per 1000 births per FET. LIMITATIONS, REASONS FOR CAUTION: Data are incomplete with seven countries not providing data to the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in 2004 that had in 2003. The validity of data reflects current data collection practice. In 2004, 79.3% of the clinics in participating countries reported to their national or regional registries and to ICMART. In addition, the number of ART cycles per million population is a measure which is affected by a country's government policy, regulation, funding and the number of service providers. WIDER IMPLICATIONS OF THE FINDINGS: ART practice, effectiveness and outcomes vary markedly internationally. Notably, the increasing proportion of cycles that are FET, the change in practice to single embryo transfer and the cessation of the transfer of three or more embryos in some countries has resulted in improved perinatal outcomes with minimal impact on pregnancy rates. STUDY FUNDING/COMPETING INTEREST(S): ICMART receives financial support from ASRM, ESHRE, FSA, Japan Society for Reproductive Medicine, REDLARA, MEFS and SART. PMID- 23442758 TI - Overly honest M&M sections. PMID- 23442759 TI - The expression and functionality of stromal caveolin 1 in human adenomyosis. AB - STUDY QUESTION: What is the expression pattern and functionality of caveolin 1 (CAV1) in the endometrium of patients with adenomyosis? SUMMARY ANSWER: The stromal CAV1 expression is down-regulated that leads to the release of a variety of molecules that either enhance the metastatic capacity of endometrial cells or contribute to adenomyosis-associated dysmenorrhea. WHAT IS KNOWN ALREADY: Adenomyosis is characterized by invasion of endometrium into the uterine myometrium. CAV1 has been linked to tumor progression and clinical outcome in a variety of human malignancies; however, its role in adenomyosis development and adenomyosis-associated dysmenorrhea is still poorly recognized. STUDY DESIGN, SIZE, DURATION: We retrospectively analyzed the expression levels of CAV1 and RANTES protein using immunohistochemistry in 65 patients who were pathologically diagnosed with adenomyosis and 12 control women without related pathology, who were subjected to surgery between 2009 and 2010. Endometrial tissues from six additional normal females without related pathology were collected from 2011 to 2012; these tissues were subjected to subsequent primary cell culture experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: The expression of CAV1 and RANTES was examined by immunohistochemistry in ectopic endometrium and paired eutopic endometrium of 65 adenomyosis patients and 12 control patients. Primary endometrial stromal cells (ESCs) and endometrial epithelial cells (EECs) were isolated from 6 additional control females without related pathology. The expression of CAV1 in ESCs was either (i) inhibited by siRNA transfection and methyl-beta-cyclodextrin (MbetaCD) treatment or (ii) increased by pcDNA3.1/CAV1 transfection. The impact of each treatment on the proliferation, migration and invasion of both ESCs and EECs was evaluated by methylthiazolydiphenyl tetrazolium assay, colony formation assay, Transwell migration and invasion assay. Furthermore, ESC treatment with MbetaCD and siCAV1 was assessed for the effect on the expression of a panel of inflammatory cytokines. The levels of two pain mediators, nitric oxide (NO) and prostaglandin E2 (PGE2), were assessed in CAV-1-depleted and control ESCs, whereas immunoblotting was performed to characterize signaling pathways downstream to loss of stromal CAV1 in endometrium. The correlation between dysmenorrhea severity and stromal CAV1 and RANTES expression was further examined using 'Pearson's' correlation analysis. MAIN RESULTS: Stromal CAV1 expression in ectopic endometrium of adenomyosis patients was significantly lower than that of paired eutopic endometrium or normal controls as analyzed by immunohistochemistry (P < 0.001). Although no significant difference was observed in the proliferation of CAV1-depleted ESCs when compared with control group, EECs cultured with conditioned media from CAV1 depleted ESCs demonstrated a significantly elevated proliferation rate when compared with those treated with control ESC-conditioned media. Moreover, both CAV1-depleted ESCs and EECs cultured with conditioned media from CAV1-depleted ESCs showed enhanced migration and invasion capacity when compared with control group (P < 0.05). In contrast, incubation with conditioned media of ESCs with enforced CAV1 expression led to decreased proliferation capacity of EECs. Furthermore, the expression of RANTES in ESCs treated with MbetaCD and siCAV1 was significantly increased. Stromal RANTES expression in the ectopic endometrium of adenomyosis patients was significantly higher than that of paired eutopic endometrium or normal controls as analyzed by immunohistochemistry (P = 0.0026). Stromal CAV1 expression in eutopic endometrium was significantly lower in women with more severe dysmenorrhea (P < 0.05) and was negatively correlated with dysmenorrhea severity in adenomyosis patients (r(2) = 0.1549; P = 0.012, 'Pearson's' chi(2) test), whereas stromal RANTES expression in eutopic endometrium was significantly higher in women with more severe dysmenorrhea (P < 0.05) and was positively correlated with dysmenorrhea severity in adenomyosis patients (r(2) = 0.1646; P = 0.0094, 'Pearson's' chi(2) test). Silencing of CAV1 in ESCs led to increased release of NO and PGE2 when compared with control and was associated with enhanced activity of ERK-FAK signaling pathway. LIMITATIONS, REASONS FOR CAUTION: This study assessed the functional role of stromal CAV1 and RANTES in a small number of human adenomyosis samples by immunohistochemistry and in primary human ESCs by functional studies. In future investigations, a larger sample size should be adopted and the functional role of stromal CAV1 should be further characterized in animal models. WIDER IMPLICATIONS OF THE FINDINGS: Loss of stromal CAV1 expression may play a critical role in the pathogenesis of adenomyosis and is correlated with adenomyosis-related dysmenorrhea. STUDY FUNDING: National Basic Research Program of China and Ph.D. Programs Foundation of Ministry of Education of China. COMPETING INTEREST: None. PMID- 23442760 TI - Keratinocyte cytoskeletal roles in cell sheet engineering. AB - BACKGROUND: There is an increasing need to understand cell-cell interactions for cell and tissue engineering purposes, such as optimizing cell sheet constructs, as well as for examining adhesion defect diseases. For cell-sheet engineering, one major obstacle to sheet function is that cell sheets in suspension are fragile and, over time, will contract. While the role of the cytoskeleton in maintaining the structure and adhesion of cells cultured on a rigid substrate is well-characterized, a systematic examination of the role played by different components of the cytoskeleton in regulating cell sheet contraction and cohesion in the absence of a substrate has been lacking. RESULTS: In this study, keratinocytes were cultured until confluent and cell sheets were generated using dispase to remove the influence of the substrate. The effects of disrupting actin, microtubules or intermediate filaments on cell-cell interactions were assessed by measuring cell sheet cohesion and contraction. Keratin intermediate filament disruption caused comparable effects on cell sheet cohesion and contraction, when compared to actin or microtubule disruption. Interfering with actomyosin contraction demonstrated that interfering with cell contraction can also diminish cell cohesion. CONCLUSIONS: All components of the cytoskeleton are involved in maintaining cell sheet cohesion and contraction, although not to the same extent. These findings demonstrate that substrate-free cell sheet biomechanical properties are dependent on the integrity of the cytoskeleton network. PMID- 23442761 TI - Risk factors for Clostridium difficile acquisition in infants: importance of study design. PMID- 23442762 TI - Reply to Stoesser et al. PMID- 23442763 TI - Seropositivity and higher immunoglobulin g antibody levels against cytomegalovirus are associated with mortality in the population-based European prospective investigation of Cancer-Norfolk cohort. AB - BACKGROUND: The relationship between cytomegalovirus (CMV) infection and mortality among immunocompetent individuals is uncertain. We aimed to examine whether seropositivity for CMV and the level of CMV immunoglobulin G (IgG) antibody are associated with all-cause and cause-specific mortality. METHODS: We used data from a random sample of 13 090 participants aged 40-79 years at recruitment in 1993-1997 to the European Prospective Investigation of Cancer Norfolk population-based cohort study. We measured baseline IgG antibody levels against CMV. Death certificates were obtained for all participants who died before 31 March 2011. Codes for the underlying cause of death were used to investigate cause-specific mortality. RESULTS: A total of 2514 deaths occurred during a mean follow-up of 14.3 years (SD, 3.3 years). Compared to seronegative participants (age- and sex-adjusted mortality rate, 12.4 [95% confidence interval {CI}, 11.3-13.2] per 1000 person-years at risk), rates increased across thirds of IgG antibody levels (score test of trend P < .0001). CMV seropositivity (prevalence 59%) was associated with increased all-cause mortality (age- and sex adjusted hazard ratio [HR], 1.16 [95% CI, 1.07-1.26]), similarly in men and women (P for interaction = .52). The association persisted after additionally adjusting for measures of socioeconomic status and possible confounders. Cause-specific analyses suggested that increased mortality from cardiovascular disease (HR, 1.06 [95% CI, .91-1.24]), cancer (HR, 1.13 [95% CI, .98-1.31]), and other causes (HR, 1.23 [95% CI, 1.04-1.47) all appeared to contribute to the overall associations. CONCLUSIONS: Seropositivity and higher IgG antibody levels against CMV are associated with increased mortality and after adjustment for a range of potential confounders in the general population. PMID- 23442765 TI - The feasibility of using a conventional flexible RF coil for an online MR-guided radiotherapy treatment. AB - The purpose of this paper is to evaluate the impact of a flexible radiofrequency coil on the treatment delivery of an online MR-guided radiotherapy treatment. For this study, we used a Synergy MR body coil (Philips, Best) in combination with the current MRL prototype of the UMC Utrecht. The compatibility of the coil is evaluated in two steps. First, we evaluated the dosimetric impact of the MR coil on both a simple and a complex irradiation strategy for treating spinal bone metastases. This tumor site will likely be chosen for the first in-man treatments with the UMC Utrecht MRL system. Second, we investigated the impact of the treatment beam on the MRI performance of the body coil. In case a single posterior-anterior rectangular field was applied, dose to the target volume was underestimated up to 2.2% as a result of beam attenuation in the MR coil. This underestimation however, decreased to 1% when a stereotactic treatment strategy was employed. The presence of the MR coil in or near the distal site of the treatment beam decreased the exit dose when a magnetic field was present. The MRI performance of the coil was unaffected as the result of the radiation. It is feasible to use the Synergy MR body coil for an online MR-guided radiotherapy treatment without any modification to the coil or attenuation correction methods in the planning stage. The effect of the MRI coil on the dose delivery is minimal and there is no effect of the treatment beam on the SNR of the acquired MRI data. PMID- 23442766 TI - Structural, electrical, and optical properties of Ti-doped ZnO films fabricated by atomic layer deposition. AB - High-quality Ti-doped ZnO films were grown on Si, thermally grown SiO2, and quartz substrates by atomic layer deposition (ALD) at 200 degrees C with various Ti doping concentrations. Titanium isopropoxide, diethyl zinc, and deionized water were sources for Ti, Zn, and O, respectively. The Ti doping was then achieved by growing ZnO and TiO2 alternately. A hampered growth mode of ZnO on TiO2 layer was confirmed by comparing the thicknesses measured by spectroscopic ellipsometry with the expected. It was also found that the locations of the (100) diffraction peaks shift towards lower diffraction angles as Ti concentration increased. For all samples, optical transmittance over 80% was obtained in the visible region. The sample with ALD cycle ratio of ZnO/TiO2 being 20 had the lowest resistivity of 8.874 * 10-4 Omega cm. In addition, carrier concentration of the prepared films underwent an evident increase and then decreased with the increase of Ti doping concentration. PMID- 23442767 TI - Negative psychotic symptoms and impaired role functioning predict transition outcomes in the at-risk mental state: a latent class cluster analysis study. AB - BACKGROUND: Many research groups have attempted to predict which individuals with an at-risk mental state (ARMS) for psychosis will later develop a psychotic disorder. However, it is difficult to predict the course and outcome based on individual symptoms scores. METHOD: Data from 318 ARMS individuals from two specialized services for ARMS subjects were analysed using latent class cluster analysis (LCCA). The score on the Comprehensive Assessment of At-Risk Mental States (CAARMS) was used to explore the number, size and symptom profiles of latent classes. RESULTS: LCCA produced four high-risk classes, censored after 2 years of follow-up: class 1 (mild) had the lowest transition risk (4.9%). Subjects in this group had the lowest scores on all the CAARMS items, they were younger, more likely to be students and had the highest Global Assessment of Functioning (GAF) score. Subjects in class 2 (moderate) had a transition risk of 10.9%, scored moderately on all CAARMS items and were more likely to be in employment. Those in class 3 (moderate-severe) had a transition risk of 11.4% and scored moderately severe on the CAARMS. Subjects in class 4 (severe) had the highest transition risk (41.2%), they scored highest on the CAARMS, had the lowest GAF score and were more likely to be unemployed. Overall, class 4 was best distinguished from the other classes on the alogia, avolition/apathy, anhedonia, social isolation and impaired role functioning. CONCLUSIONS: The different classes of symptoms were associated with significant differences in the risk of transition at 2 years of follow-up. Symptomatic clustering predicts prognosis better than individual symptoms. PMID- 23442768 TI - Regional differences in prostaglandin E2 metabolism in human colorectal cancer liver metastases. AB - BACKGROUND: Prostaglandin (PG) E2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE2 content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE2 in human CRC cells in vitro. METHODS: Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE2 levels, 15 PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) beta. RESULTS: PGE2 levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15 PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE2. Combined 15-PGDH expression and loss of membranous E cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo. CONCLUSIONS: There is significant intra-tumoral heterogeneity in PGE2 content, 15 PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE2 metabolism should be targeted for novel treatment of advanced CRC. PMID- 23442769 TI - Rule out of acute aortic dissection with plasma matrix metalloproteinase 8 in the emergency department. AB - INTRODUCTION: Matrix metalloproteinases (MMPs) are involved in aortic pathophysiology. Preliminary studies have detected increased plasma levels of MMP8 and MMP9 in patients with acute aortic dissection (AAD). However, the performance of plasma MMP8 and MMP9 for the diagnosis of AAD in the emergency department is at present unknown. METHODS: The levels of MMP8 and MMP9 were measured by ELISA on plasma samples obtained from 126 consecutive patients evaluated in the emergency department for suspected AAD. All patients were subjected to urgent computed tomography (CT) scan for final diagnosis. RESULTS: In the study cohort (N = 126), AAD was diagnosed in 52 patients and ruled out in 74 patients. Median plasma MMP8 levels were 36.4 (interquartile range 24.8 to 69.3) ng/ml in patients with AAD and 13.2 (8.1 to 31.8) ng/ml in patients receiving an alternative final diagnosis (P <0.0001). Median plasma MMP9 levels were 169.2 (93.0 to 261.8) ng/ml in patients with AAD and 80.5 (41.8 to 140.6) ng/ml in patients receiving an alternative final diagnosis (P = 0.001). The area under the curve (AUC) on receiver-operating characteristic (ROC) analysis of MMP8 and MMP9 for the diagnosis of AAD was respectively 0.75 and 0.70, as compared to 0.87 of D-dimer. At the cutoff of 3.6 ng/ml, plasma MMP8 had a sensitivity of 100.0% (95% CI, 93.2% to 100.0%) and a specificity of 9.5% (95% CI, 3.9% to 18.5%) and ruled out AAD in 5.6% of patients. Combination of plasma MMP8 with D dimer increased the AUC on ROC analysis to 0.89. Presence of MMP8 <11.0 ng/ml and D-dimer <1.0 or <2.0 ug/ml provided a negative predictive value of 100% and ruled out AAD in 13.6% and 21.4% of patients respectively. CONCLUSIONS: Low levels of plasma MMP8 can rule out AAD in a minority of patients. Combination of plasma MMP8 and D-dimer at individually suboptimal cutoffs could safely rule out AAD in a substantial proportion of patients evaluated in the emergency department. PMID- 23442770 TI - Physical reparative treatment in reptiles. AB - BACKGROUND: The tissue growth necessary to achieve a complete or partial restitution ad integrum as a result of injury to soft tissue and/or hard times in reptiles is variable and often needs long time in relation to the species, to the habitat and to their intrinsic physiological characteristics. The purpose of this work was to see if the tissue optimization (TO) treatment with radio electric asymmetric conveyer (REAC) provided good results in these animals and whether its use translates into reduced time of tissue repair. This paper describes preliminary results with in promoting the tissue repair in reptiles. CASES PRESENTATION: A 5 year old male Testudo graeca (Leo) and Trachemys scripta scripta (Mir) and a 15 year old female Testudo hermanni (Juta) were evaluated because of soft tissue injuries. A female 25 year old Trachemys scripta elegans (Ice), a female 2.5 year old Trachemys scripta scripta (Penelope) as well as a 50 year old male Testudo graeca (Margherito) were evaluated because of wounds of the carapace. Following debridement and traditional therapies, Leo, Penelope and Margherito were exposed to the radio electric asymmetric conveyer (REAC) device, with a specific treatment protocol, named tissue optimization-basic (TO-B). Also Ice and Mir were subjected to REAC treatment after wounds debridement. Juta was treated only with REAC treatment. Complete wound healing was evident after 17 days for Leo, 7 days for Penelope, 27 days for Mir, 78 days for Ice and after 14 days for Margherito. Juta showed a considerable tissue activation in 2 days and complete wound healing in 5 days. CONCLUSION: Our findings suggest that REAC TO-B treatment may provide advantages over other traditional methods after complete wound healing in Leo, and also suitable healing in the other patients. Then REAC device with its specific treatment TO-B protocol, which induces tissue repair without causing severe stress to the patient, could be a potential therapy for tissue damage healing in reptiles. Further studies still need to be conducted to support our observations. PMID- 23442771 TI - Morphometric analyses of canine blood microfilariae isolated by the Knott's test enables Dirofilaria immitis and D. repens species-specific and Acanthocheilonema (syn. Dipetalonema) genus-specific diagnosis. AB - BACKGROUND: Considering the increasing importance of small animals travel medicine and the spread of filariae with zoonotic potential to non-endemic European areas, routine filarial diagnosis in dogs is becoming important. Dirofilaria immitis, D. repens, Acanthocheilonema dracunculoides and A. reconditum are the most common canine filarial nematodes presenting blood circulating microfilariae (mf) which can be differentiated to species level by the acid phosphatase activity patterns or by PCR. Available data on the size of the mf vary considerably in the literature. The aim of this study was to validate morphometric criteria for filarial identification in blood samples of dogs after concentration of mf with the modified Knott's technique. METHODS: Morphometric analysis of 10 mf from samples identified to species level by acid phosphatase activity and partially confirmed by PCR were performed with specimens from 377 dogs. RESULTS: The mean length and width of D. immitis mf from 60 dogs were 301.77 +/- 6.29 MUm and 6.30 +/- 0.26 MUm, of D. repens mf from 171 dogs 369.44 +/- 10.76 MUm 8.87 +/- 0.58 MUm, of A. dracunculoides mf from 133 dogs 259.43 +/- 6.69 MUm and 5.09 +/- 0.47 MUm and of A. reconditum mf from 13 dogs 264.83 +/- 5.47 MUm and 4.63 +/- 0.52 MUm.For a subset of 30 samples, morphometric analysis was repeated with identical results in two laboratories. Furthermore, the size of mf concentrated and fixed by the Knott's technique was shown to be stable over 105 days. CONCLUSIONS: The Knott's test enables to clearly distinguish between D. immitis, D. repens and Acanthocheilonema spp. However, due to the overlapping size ranges of A. dracunculoides and A. reconditum, biochemical or molecular methods are required to distinguish these two species. PMID- 23442772 TI - Magnetic resonance-based attenuation correction for PET/MR hybrid imaging using continuous valued attenuation maps. AB - OBJECTIVES: Attenuation correction of positron emission tomographic (PET) data is critical in providing accurate and quantitative PET volumes. Deriving an attenuation map (MU-map) from magnetic resonance (MR) volumes is a challenge in PET/MR hybrid imaging. The difficulty lies in differentiating cortical bone from air from standard MR sequences because both these classes yield little to no MR signal and thus shows no distinguishable information. The objective of this contribution is 2-fold: (1) to generate and evaluate a continuous valued computed tomography (CT)-like attenuation map (MU-map) with continuous density values from dedicated MR sequences and (2) to compare its PET quantification accuracy with respect to a CT-based attenuation map as the criterion standard and other segmentation-based attenuation maps for studies of the head. MATERIALS AND METHODS: Three-dimensional Dixon-volume interpolated breath-hold examination and ultrashort echo time sequences were acquired for each patient on a Siemens 3-T Biograph mMR PET/MR hybrid system and the corresponding patient CT on a Siemens Biograph 64. A pseudo-CT training was done using the epsilon-insensitive support vector regression ([Latin Small Letter Open E]-SVR) technique on 5 patients who had CT/MR/PET triplets, and the generated model was evaluated on 5 additional patients who were not included in the training process. Four MU-maps were compared, and 3 of them derived from CT: scaled CT (MU-map CT), 3-class segmented CT without cortical bone (MU-map no bone), 4-class segmented CT with cortical bone (MU-map bone), and 1 from MR sequences via [Latin Small Letter Open E]-SVR technique previously mentioned (ie, MR predicted [MU-map MR]). Positron emission tomographic volumes with each of the previously mentioned MU-maps were reconstructed, and relative difference images were calculated with respect to MU map CT as the criterion standard. RESULTS: For PET quantification, the proposed method yields a mean (SD) absolute error of 2.40% (3.69%) and 2.16% (1.77%) for the complete brain and the regions close to the cortical bone, respectively. In contrast, PET using MU-map no bone yielded 10.15% (3.31%) and 11.03 (2.26%) for the same, although PET using MU-map bone resulted in errors of 3.96% (3.71%) and 4.22% (3.91%). Furthermore, it is shown that the model can be extended to predict pseudo-CTs for other anatomical regions on the basis of only MR information. CONCLUSIONS: In this study, the generation of continuous valued attenuation maps from MR sequences is demonstrated and its effect on PET quantification is evaluated in comparison with segmentation-based MU-maps. A less-than-2-minute acquisition time makes the proposed approach promising for a clinical application for studies of the head. However, further experiments are required to validate and evaluate this technique for attenuation correction in other regions of the body. PMID- 23442773 TI - Initial in vivo experience with a novel type of MR-safe pushable coils for MR guided embolizations. AB - OBJECTIVE: Conventional detachable embolization coils are made from platinum or stainless steel and may thus be a magnetic resonance (MR) safety hazard because of resonant device heating. The objective of this experimental study was to assess the feasibility of MR-guided embolization procedures with a novel type of nonmetallic and, therefore, intrinsically MR-safe pushable coil. MATERIALS AND METHODS: The embolization coils are made from a polymer and coated with a hydrogel, which expands during contact with liquids. Magnetic resonance-guided embolizations were performed in 6 healthy domestic pigs by deploying up to 3 polymer pushable coils via an active tracking catheter under real-time magnetic resonance imaging monitoring. To assess the renal perfusion deficit induced by the coil embolization, intra-arterial 3-dimensional contrast-enhanced magnetic resonance angiography (3D ce-MRA) data sets were acquired before and every 5 minutes after coil placement until complete vessel occlusion. RESULTS: The MR guided embolizations were successful in 5 of the 6 animals. The 3D ce-MRA data sets indicated first perfusion deficits within 2 to 40 minutes after coil deployment. Complete vessel occlusion was achieved after 6 to 53 minutes. In 1 animal, no perfusion defect could be detected. Because our experiments were designed as a preliminary proof-of-concept study, different sizes and numbers of all-polymer hydrocoils were deployed at different anatomical positions, making the drawing of correlation between the size/number of deployed coils and the occlusion efficiency difficult. The all-polymer hydrocoils did not induce any artifacts on the MR images, either in the real-time MR images, which were recorded during the embolization, or in the subsequently acquired 3D ce-MRA images. CONCLUSIONS: Our results demonstrated that the novel all-polymer and intrinsically MR-safe pushable hydrocoils may become a promising tool for MR guided embolization procedures. PMID- 23442774 TI - Dynamic contrast-enhanced MRI of the liver in Mrp2-deficient rats using the hepatobiliary contrast agent Gd-EOB-DTPA. AB - OBJECTIVES: The objective of this study was to compare the hepatic uptake and biliary excretion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) in control and multidrug resistance-associated protein 2 (Mrp2) deficient rats by noninvasive dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and the impact of Mrp2 deficiency on organic anion-transporting polypeptide 1 (Oatp1) transporters and liver vascularization by immunohistochemistry. MATERIALS AND METHODS: Twenty rats were used in the normal control (n = 10) and Mrp2-deficient rat groups (n = 10). Dynamic contrast enhanced magnetic resonance imaging studies were performed using Gd-EOB-DTPA (0.025 mmol Gd/kg; 0.1 mL/kg body weight) as the contrast agent. The percentages of relative enhancement were calculated at each time point after Gd-EOB-DTPA injection. In addition, relative enhancement maps were generated through pixel-by pixel calculations before the injection and at 5, 10, 20, 30, and 40 minutes after the injection. After the DCE-MRI study, blood was sampled from all rats and 6 blood sample parameters, serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, and total bile acids, were measured. Rat livers were processed for histologic diagnosis to clarify contrast agent uptake/efflux by examining Oatp1, Mrp2, and platelet endothelial cell adhesion molecule immunohistochemical staining. RESULTS: The relative enhancement of the Mrp2-deficient, Eisai hyperbilirubinuria rats (EHBRs) (48.6% [3.4%]) was significantly lower than that of the control rats (64.0% [3.2%]; P < 0.001) 5 minutes after the Gd-EOB-DTPA injection. Thereafter, the relative enhancement observed in the EHBRs (10 minutes, 59.6% [5.4%]; 20 minutes, 67.8% [4.1%]; 30 minutes, 69.1% [4.2%]; 40 minutes, 71.0% [4.2%]; P < 0.0001) was significantly higher than that in the control rats at the same time points after the Gd-EOB-DTPA injection. The aspartate aminotransferase and alanine aminotransferase values were not significantly different between the 2 groups. However, total bilirubin, direct bilirubin, indirect bilirubin, and total bile acids levels in EHBRs were significantly higher than those in the control rats. The percentages of the Mrp2-positive cells in the control rats were higher compared with the EHBRs (control, 0.3% [0.1%]; EHBR, 14.1% [3.6%]; P < 0.01). However, the percentages of the Oatp1-positive cells were not different between the 2 groups. Moreover, the percentages of the platelet endothelial cell adhesion molecule-positive cells in the blood vessels of the control rat livers were higher compared with the EHBRs (control, 17.5% [3.3%]; EHBR, 9.5% [3.9%]; P < 0.01). CONCLUSIONS: The utility of noninvasive DCE-MRI with Gd-EOB-DTPA as a tool for the assessment of Mrp2-deficient hyperbilirubinuria rats was demonstrated. We also clarified that the lower vascular density in the EHBRs may cause delayed uptake of the contrast agent compared with the control rats. In addition, the lower Mrp2 transporter expression may cause the lower efflux of the contrast agent from the Mrp2-deficient rats compared with the control rats. PMID- 23442775 TI - Integrated whole-body PET/MR hybrid imaging: clinical experience. AB - OBJECTIVES: Integrated whole-body positron emission tomography (PET)/magnetic resonance (MR) scanners have recently been introduced and potentially offer new possibilities in hybrid imaging of oncologic patients. Integration of PET in a whole-body MR system requires new PET detector technology and new approaches to attenuation correction of PET data based on MR imaging. The aim of this study was to evaluate the clinical performance and image quality parameters of integrated whole-body PET/MR hybrid imaging in intraindividual comparison with PET/CT in oncologic patients. MATERIALS AND METHODS: Eighty patients underwent a single injection, dual-imaging protocol including whole-body PET/computed tomography (CT) and subsequent whole-body PET/MR hybrid imaging. Positron emission tomography/computed tomography was performed after adequate resting time (73 +/- 13 minutes post injectionem of 227 +/- 52.7 MBq Fluor-18-Fluordesoxyglucose, 3 minutes of acquisition time for each of 7 bed positions), followed by PET/MR (172 +/- 33 minutes post injectionem, 10 minutes acquisition time for each of 4 bed positions). Positron emission tomographic data for both modalities were reconstructed iteratively. Two observers evaluated the following parameters: qualitative correlation of tracer-avid lesions in PET/CT versus PET/MR and PET image quality of PET/CT versus PET/MR. Magnetic resonance image quality of standard sequences (T1-weighted, T2-weighted), performance of the Dixon sequence for MR-based attenuation correction in comparison with corresponding T1-weighted images, artifacts in PET/MR data, and spatial coregistration of PET and MR data were evaluated by another observer. RESULTS: In 70 of the 80 patients, both image data sets were complete. In these patients, 192 tracer-avid lesions were identified on PET/CT; 195, on PET/MR. A total of 187 lesions were identified concordantly by both modalities, and this corresponds to an agreement rate of 97.4%. The overall PET image quality was rated good to excellent for PET from PET/CT (12/28, excellent, 42.9%; 16/28, good, 57.1%; 0/28, poor, 0.0%) and slightly superior compared with PET from PET/MR, which was rated good (3/28, excellent, 10.7%; 20/28, good, 71.4%; 5/28, poor, 17.9%) in a subset of 28 patients. The overall image quality of the MR image data sets in all 70 of the 80 patients was rated excellent (260/280, excellent, 92.8%; 15/280, good, 5.4%; 5/280, poor, 1.8%). The Dixon sequence and conversion to MU-maps for MR-based attenuation correction provided robust tissue segmentation in all 280 bed positions of the acquired PET/MR data. No artifacts such as elevated noise and radiofrequency disturbances related to hardware cross talk between the PET and MR components in the hybrid system could be detected in the MR images. No major spatial mismatches between PET and MR data were detected. CONCLUSIONS: Integrated PET/MR hybrid imaging is feasible in a clinical setting with similar detection rates as those of PET/CT. Attenuation correction can be performed sufficiently with Dixon sequences, although bone is disregarded. The administration of specific radiotracers and dedicated imaging sequences will foster this hybrid imaging modality in various indications. PMID- 23442776 TI - Real-time MR-guided lumbosacral periradicular injection therapy using an open 1.0 T MRI system: an outcome study. AB - OBJECTIVES: The objective of this study was to evaluate the accuracy, safety, and efficacy of magnetic resonance (MR)-guided periradicular nerve root injection therapy using an open 1.0-T magnetic resonance imaging (MRI) system with fast dynamic imaging. MATERIALS AND METHODS: Between April 2008 and November 2011, a total of 249 MR-guided periradicular nerve root injections were performed in 141 patients experiencing lumbosacral radicular pain. All interventions were performed in an open 1.0-T MRI system. An interactive proton-density-weighted fast spin-echo sequence was used for real-time guidance. An in-room monitor, a wireless MR mouse for operator-controlled multiplanar imaging, a flexible surface coil, and an MR-compatible 20-G needle were used. Informed consent was obtained from all patients. Clinical outcome was evaluated through clinical follow-up and a questionnaire before injection therapy (baseline) and 6 months after using a numeric visual analog scale. RESULTS: All procedures were technically successful. No major complications occurred. At 6 months, of the 103 patients (197 injections; 57 men, 46 women; mean age, 49.5 years; range, 20-80) who enrolled in the outcome analysis, 14.6% reported complete remission of radicular pain; 53.4%, significant relief of pain; 22.3%, mild relief; and 9.7%, no relief of pain. We found a significant decrease of the visual analog scale score from the preintervention compared with the follow-up after 6 months (P < 0.001). No significant difference in the outcome was observed between the patients with degenerative foraminal stenoses and the patients with herniated disks. CONCLUSIONS: Magnetic resonance fluoroscopy-guided periradicular injection therapy for the lumbosacral spine under open 1.0-T MRI guidance is accurate, safe, and efficient in the symptomatic treatment of radicular pain. This technique may be a promising alternative to fluoroscopy- or computed tomography guided spinal injections in the lumbosacral region, especially for young patients and patients undergoing serial therapeutic regimens. PMID- 23442777 TI - Reply to letter: "End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study". PMID- 23442778 TI - Thoracolumbosacral spinal subdural abscess: magnetic resonance imaging appearance and limited surgical management. AB - STUDY DESIGN: Case report and review of relevant literature. OBJECTIVE: To report a rare case of a thoracolumbosacral spinal subdural abscess (SSA) and highlight the magnetic resonance imaging (MRI) appearance and surgical management. SUMMARY OF BACKGROUND DATA: SSA is rare, as most intraspinal abscesses are epidural in location. Extensive thoracolumbosacral SSA has only rarely been reported. The MRI features and options for limited surgical management are not well described. METHODS: A case report of SSA is presented and relevant literature is reviewed. RESULTS: An elderly female presented with worsening back pain and sepsis. MRI demonstrated an extensive intraspinal abscess, extending from the upper thoracic spine to the sacrum. Both axial and sagittal images demonstrated a subdural location of the collection, with preservation of the dorsal epidural fat and mass effect on the spinal cord. Cord compression was most marked at the T8 level. Limited midthoracic laminectomies were performed. The epidural space seemed normal intraoperatively. A limited longitudinal durotomy yielded purulent fluid. After intraoperative irrigation, primary dural repair was performed. At 2-year follow-up, the patient had no clinical, radiographical, or laboratory evidence of residual or recurrent spinal infection. CONCLUSION: Careful review of MRI can localize an intraspinal abscess to the subdural space. Even for extensive subdural collections, limited operative management can achieve excellent clinical outcome. LEVEL OF EVIDENCE: N/A. PMID- 23442779 TI - Short-term experience with a new absorbable composite cage (beta-tricalcium phosphate-polylactic acid) in patients after stand-alone anterior cervical discectomy and fusion. AB - STUDY DESIGN: Prospective clinical single center series with 50 patients to include, with planned follow-up intervals at 3 and 12 months postoperative. OBJECTIVE: Absorbable cages were developed with the purpose to enhance fusion rates and to reduce the rate of cage subsidence. The gradual increase of load transfer during cage degradation facilitates new bone formation, which possibly leads to higher arthrodesis rates. SUMMARY OF BACKGROUND DATA: Absorbable cages consisting of a mixture of polylactic and polyglycolic acid (PLLA-PGLA) or poly (L-lactide-co-D, L-lactide) experimentally showed disappointing results with formation of cartilage and fibrous tissue components, which was much less pronounced using composite cages consisting of a polymer and calciumphosphate. METHODS: Patients showing degenerative cervical mono- or bi-level pathology were prospectively included. Using anteroposterior and lateral radiographs, segmental height of the treated segments was determined quantitatively. Cage characteristics were described qualitatively. Clinical data such as the Neck Disability Index, pain severity on the visual analogue scale were collected at all time points separately for neck and arm. RESULTS: A total of 33 patients were included, with a mean age of 51.9 +/- 9 years. As cage dislocations occurred in 4 out of 33 patients (12.1%), the study was prematurely discontinued. All patients with cage dislocations were surgically revised. Clinical outcome of the remaining patients showed significant improvement of visual analogue scale neck pain from 6.0 +/- 2.5 to 2.8 +/- 2.3 (P < 0.005), visual analogue scale arm pain from 5.3 +/- 2.7 to 1.6 +/- 1.6 (P < 0.005), and Neck Disability Index from 21.2 +/- 8.6 to 12.5 +/- 9.6 (P < 0.005) after surgery. CONCLUSION: Because of the high rate of cage dislocations, the use of the present composite cage cannot be recommended as a stand-alone device unless implant fixation will not be improved significantly. Evaluation of clinical and radiological long-term effects is essential to estimate the potential benefit of composite cages. LEVEL OF EVIDENCE: 2. PMID- 23442780 TI - Transforaminal versus anterior lumbar interbody fusion in long deformity constructs: a matched cohort analysis. AB - STUDY DESIGN: Prospectively enrolled, retrospectively analyzed matched cohort analysis. OBJECTIVE: Evaluate the relative merits of transforaminal lumbar interbody fusion (TLIF) and anterior lumbar interbody fusion (ALIF) when performed in long deformity constructs. SUMMARY OF BACKGROUND DATA: Interbody fusion is frequently used at the caudal levels of long-segment spinal deformity instrumentation constructs to protect the sacral implants and enhance fusion rates. However, there is a paucity of literature regarding which technique is more efficacious. METHODS: Forty-two patients who underwent TLIF and 42 patients who underwent ALIF were matched with respect to age, sex, comorbidities, curve magnitude, fusion length, and ALIF/TLIF level. Radiographs and clinical outcomes were compared at minimum 2-year follow-up. RESULTS: Age averaged 54.0 years and instrumented vertebrae averaged 13.6. TLIFs had less operative time (481 vs. 595 min, P = 0.0007), but greater blood loss (2011 vs. 1281 mL, P = 0.0002). Overall complications (TLIF, 12/42 vs. ALIF, 15/42) and neurological complications (TLIF, 4/42 vs. ALIF, 3/42) did not differ. One pseudarthrosis occurred at an ALIF level, with none at TLIF levels. Patients who underwent ALIF began with lower SRS scores but showed more improvement (44.4 to 70.7 vs. 58.6 to 70.6, P = 0.0043). ODI scores in both groups improved similarly. Regionally, ALIFs engendered more lordosis than TLIFs at L3-S1 (gain of 6.9 degrees vs. -2.6 degrees , P < 0.0001) but not T12-S1 (gain of 11.5 degrees vs. 7.9 degrees , P = 0.29). Locally, ALIFs created more lordosis at L4-L5 (gain of 5.6 degrees vs. -1.7 degrees , P < 0.0001) and L5-S1 (gain of 2.5 degrees vs. -1.4 degrees , P = 0.022), but not at L3-L4 (gain of 5.3 degrees vs. 4.0 degrees , P = 0.65). Patients who underwent TLIF obtained greater correction of anteroposterior Cobb angles in lumbar (reduction of 22.4 degrees vs. 9.9 degrees , P < 0.0001) and lumbosacral curves (reduction of 10.3 degrees vs. 3.4 degrees , P < 0.0001). CONCLUSION: Spinal deformity surgery used TLIFs rather than ALIFs resulted in shorter operative time with no difference in complication rates. ALIFs provided more segmental lordosis, whereas TLIFs afforded better correction of scoliotic curves. PMID- 23442781 TI - A geometric morphometric assessment of hand shape and comparison to the 2D:4D digit ratio as a marker of sexual dimorphism. AB - Twin studies are extremely useful for investigating hypotheses of genetic influence on a range of behavioral and physical traits in humans. Studies of physical traits, however, are usually limited to size-related biological characteristics because it is inherently difficult to quantify the morphological counterpart - shape. In recent years, the development of geometry-preserving analytical techniques built upon multivariate statistical methodologies has produced a new discipline in biological shape analysis known as geometric morphometrics. In this study of hand shape analysis, we introduce the reader already familiar with the field of twin research to the potential utility of geometric morphometrics and demonstrate the cross-discipline applicability of methods. We also investigate and compare the efficacy of the 2D:4D ratio, a commonly used marker of sexual dimorphism, to the fully multivariate approach of shape analysis in discriminating between male and female sex. Studies of biological shape variation utilizing geometric morphometric techniques may be completed with software freely available on the Internet and time invested to master the small learning curve in concepts and theory. PMID- 23442782 TI - Broadband beamforming compensation algorithm in CI front-end acquisition. AB - BACKGROUND: To increase the signal to noise ratio (SNR) and to suppress directional noise in front-end signal acquisition, microphone array technologies are being applied in the cochlear implant (CI). Due to size constraints, the dual microphone-based system is most suitable for actual application. However, direct application of the array technology will result in the low frequency roll-off problem, which can noticeably distort the desired signal. METHODS: In this paper, we theoretically analyze the roll-off characteristic on the basis of CI parameters and present a new low-complexity compensation algorithm. We obtain the linearized frequency response of the two-microphone array from modeling and analysis for further algorithm realization. REALIZATION AND RESULTS: Linear method was used to approximate the theoretical response with adjustable delay and weight parameters. A CI dual-channel hardware platform is constructed for experimental research. Experimental results show that our algorithm performs well in compensation and realization. DISCUSSIONS: We discuss the effect from environment noise. Actual daily noise with more low-frequency energy will weaken the algorithm performance. A balance between low-frequency distortion and corresponding low-frequency noise need to be considered. CONCLUSIONS: Our novel compensation algorithm uses linear function to obtain the desired system response, which is a low computational-complexity method for CI real-time processing. Algorithm performance is tested in CI CIS modulation and the influence of experimental distance and environmental noise were further analyzed to evaluate algorithm constraint. PMID- 23442784 TI - Association between cortisol awakening response and memory function in major depression. AB - BACKGROUND: While impaired memory and altered cortisol secretion are characteristic features of major depression, much less is known regarding the impact of antidepressant medication. We examined whether the cortisol awakening response (CAR) is increased in depressed patients with and without medication compared with healthy controls (HC) and whether CAR is associated with memory function in each group. METHOD: We examined 21 patients with major depression without medication, 20 depressed patients on antidepressant treatment, and 41 age , sex- and education-matched healthy subjects. We tested verbal (Auditory Verbal Learning Task) and visuospatial (Rey figure) memory and measured CAR on two consecutive days. RESULTS: Patient groups did not differ in severity of depression. We found a significant effect of group (p = 0.03) for CAR. Unmedicated patients exhibited a greater CAR compared with medicated patients (p = 0.04) with no differences between patient groups and HC. We found a significant effect of group for verbal (p = 0.03) and non-verbal memory (p = 0.04). Unmedicated patients performed worse compared with medicated patients and HC in both memory domains. Medicated patients and HC did not differ. Regression analyses revealed a negative association between CAR and memory function in depressed patients, but not in HC. CONCLUSIONS: While in unmedicated depressed patients the magnitude of CAR is associated with impaired memory, medicated patients showed a smaller CAR and unimpaired cognitive function compared with HC. Our findings are compatible with the idea that antidepressants reduce CAR and partially restore memory function even if depressive psychopathology is still present. PMID- 23442783 TI - An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population. AB - BACKGROUND: This study updated our knowledge of UK primary care neuropathic pain incidence rates and prescribing practices. METHODS: Patients with a first diagnosis of post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) or phantom limb pain (PLP) were identified from the General Practice Research Database (2006 - 2010) and incidence rates were calculated. Prescription records were searched for pain treatments from diagnosis of these conditions and the duration and daily dose estimated for first-line and subsequent treatment regimens. Recording of neuropathic back and post-operative pain was investigated. RESULTS: The study included 5,920 patients with PHN, 5,340 with PDN, and 185 with PLP. The incidence per 10,000 person-years was 3.4 (95% CI 3.4, 3.5) for PHN; and 0.11 (95% CI 0.09, 0.12) for PLP. Validation of the PDN case definition suggested that was not sensitive. Incident PHN increased over the study period. The most common first-line treatments were amitriptyline or gabapentin in the PDN and PLP cohorts, and amitriptyline or co-codamol (codeine-paracetamol) in PHN. Paracetamol, co-dydramol (paracetamol-dihydrocodeine) and capsaicin were also often prescribed in one or more condition. Most first-line treatments comprised only one therapeutic class. Use of antiepileptics licensed for neuropathic pain treatment had increased since 2002-2005. Amitriptyline was the only antidepressant prescribed commonly as a first-line treatment. CONCLUSION: The UK incidence of diagnosed PHN has increased with the incidence of back-pain and post operative pain unclear. While use of licensed antiepileptics increased, prescribing of therapy with little evidence of efficacy in neuropathic pain is still common and consequently treatment was often not in-line with current guidance. PMID- 23442785 TI - Nurses' perspectives on the suffering of preterm infants. AB - The concept of suffering is discussed among those who are cognitively aware and verbally capable to express their suffering. Due to immaturity, preterm infants' abilities to express suffering are limited. Relieving suffering is an ethical and juridical demand of good nursing care. The purpose of this study is to describe nurses' perceptions of the suffering of preterm infants. A descriptive qualitative approach was selected. Data were collected from essays written by nurses (n = 19) working in the neonatal intensive care unit. Inductive content analysis guided by the research question was performed. The nurses described individually determined suffering of the preterm infants according to four categories: suffering ruled by maturation, existence of suffering, individual threshold of suffering and interpreting the cues of suffering. Suffering of preterm infants is manifested by population-specific features, emphasising the need to develop sensitive interventions for relieving their suffering. PMID- 23442786 TI - How to avoid and prevent coercion in nursing homes: a qualitative study. AB - In many Western countries, studies have demonstrated extensive use of coercion in nursing homes, especially towards patients suffering from dementia. This article examines what kinds of strategies or alternative interventions nursing staff in Norway used when patients resist care and treatment and what conditions the staff considered as necessary to succeed in avoiding the use of coercion. The data are based on interdisciplinary focus group interviews with nursing home staff. The study revealed that the nursing home staff usually spent a lot of time trying a wide range of approaches to avoid the use of coercion. The most common strategies were deflecting and persuasive strategies, limiting choices by conscious use of language, different kinds of flexibility and one-to-one care. According to the staff, their opportunities to use alternative strategies effectively are greatly affected by the nursing home's resources, by the organization of care and by the staff's competence. PMID- 23442789 TI - Eleganolone, a diterpene from the French marine alga Bifurcaria bifurcata inhibits growth of the human pathogens Trypanosoma brucei and Plasmodium falciparum. AB - Organic extracts of 20 species of French seaweed have been screened against Trypanosoma brucei rhodesiense trypomastigotes, the parasite responsible for sleeping sickness. These extracts have previously shown potent antiprotozoal activities in vitro against Plasmodium falciparum and Leishmania donovani. The selectivity of the extracts was also evaluated by testing cytotoxicity on a mammalian L6 cell line. The ethyl acetate extract of the brown seaweed, Bifurcaria bifurcata, showed strong trypanocidal activity with a mild selectivity index (IC(50) = 0.53 ug/mL; selectivity index (SI) = 11.6). Bio-guided fractionation led to the isolation of eleganolone, the main diterpenoid isolated from this species. Eleganolone contributes only mildly to the trypanocidal activity of the ethyl acetate extract (IC(50) = 45.0 uM, SI = 4.0). However, a selective activity against P. falciparum erythrocytic stages in vitro has been highlighted (IC(50) = 7.9 uM, SI = 21.6). PMID- 23442788 TI - Characterization of palytoxin binding to HaCaT cells using a monoclonal anti palytoxin antibody. AB - Palytoxin (PLTX) is the reference compound for a group of potent marine biotoxins, for which the molecular target is Na+/K+-ATPase. Indeed, ouabain (OUA), a potent blocker of the pump, is used to inhibit some PLTX effects in vitro. However, in an effort to explain incomplete inhibition of PLTX cytotoxicity, some studies suggest the possibility of two different binding sites on Na+/K+-ATPase. Hence, this study was performed to characterize PLTX binding to intact HaCaT keratinocytes and to investigate the ability of OUA to compete for this binding. PLTX binding to HaCaT cells was demonstrated by immunocytochemical analysis after 10 min exposure. An anti-PLTX monoclonal antibody-based ELISA showed that the binding was saturable and reversible, with a K(d) of 3 * 10-10 M. However, kinetic experiments revealed that PLTX binding dissociation was incomplete, suggesting an additional, OUA-insensitive, PLTX binding site. Competitive experiments suggested that OUA acts as a negative allosteric modulator against high PLTX concentrations (0.3-1.0 * 10-7 M) and possibly as a non-competitive antagonist against low PLTX concentrations (0.1-3.0 * 10-9 M). Antagonism was supported by PLTX cytotoxicity inhibition at OUA concentrations that displaced PLTX binding (1 * 10-5 M). However, this inhibition was incomplete, supporting the existence of both OUA-sensitive and -insensitive PLTX binding sites. PMID- 23442790 TI - Thalassospiramide G, a new gamma-amino-acid-bearing peptide from the marine bacterium Thalassospira sp. AB - In the chemical investigation of marine unicellular bacteria, a new peptide, thalassospiramide G (1), along with thalassospiramides A and D (2-3), was discovered from a large culture of Thalassospira sp. The structure of thalassospiramide G, bearing gamma-amino acids, such as 4-amino-5-hydroxy-penta 2-enoic acid (AHPEA), 4-amino-3,5-dihydroxy-pentanoic acid (ADPA), and unique 2 amino-1-(1H-indol-3-yl) ethanone (AIEN), was determined via extensive spectroscopic analysis. The absolute configuration of thalassospiramide D (3), including 4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), was rigorously determined by 1H-1H coupling constant analysis and chemical derivatization. Thalassospiramides A and D (2-3) inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells, with IC(50) values of 16.4 and 4.8 MUM, respectively. PMID- 23442792 TI - Protein Structure Idealization: How accurately is it possible to model protein structures with dihedral angles? AB - : Previous studies show that the same type of bond lengths and angles fit Gaussian distributions well with small standard deviations on high resolution protein structure data. The mean values of these Gaussian distributions have been widely used as ideal bond lengths and angles in bioinformatics. However, we are not aware of any research done to evaluate how accurately we can model protein structures with dihedral angles and ideal bond lengths and angles.Here, we introduce the protein structure idealization problem. We focus on the protein backbone structure idealization. We describe a fast O(nm/epsilon) dynamic programming algorithm to find an idealized protein backbone structure that is approximately optimal according to our scoring function. The scoring function evaluates not only the free energy, but also the similarity with the target structure. Thus, the idealized protein structures found by our algorithm are guaranteed to be protein-like and close to the target protein structure.We have implemented our protein structure idealization algorithm and idealized the high resolution protein structures with low sequence identities of the CULLPDB_PC30_RES1.6_R0.25 data set. We demonstrate that idealized backbone structures always exist with small changes and significantly better free energy. We also applied our algorithm to refine protein pseudo-structures determined in NMR experiments. PMID- 23442791 TI - Transposon activation mutagenesis as a screening tool for identifying resistance to cancer therapeutics. AB - BACKGROUND: The development of resistance to chemotherapies represents a significant barrier to successful cancer treatment. Resistance mechanisms are complex, can involve diverse and often unexpected cellular processes, and can vary with both the underlying genetic lesion and the origin or type of tumor. For these reasons developing experimental strategies that could be used to understand, identify and predict mechanisms of resistance in different malignant cells would be a major advance. METHODS: Here we describe a gain-of-function forward genetic approach for identifying mechanisms of resistance. This approach uses a modified piggyBac transposon to generate libraries of mutagenized cells, each containing transposon insertions that randomly activate nearby gene expression. Genes of interest are identified using next-gen high-throughput sequencing and barcode multiplexing is used to reduce experimental cost. RESULTS: Using this approach we successfully identify genes involved in paclitaxel resistance in a variety of cancer cell lines, including the multidrug transporter ABCB1, a previously identified major paclitaxel resistance gene. Analysis of co occurring transposons integration sites in single cell clone allows for the identification of genes that might act cooperatively to produce drug resistance a level of information not accessible using RNAi or ORF expression screening approaches. CONCLUSION: We have developed a powerful pipeline to systematically discover drug resistance in mammalian cells in vitro. This cost-effective approach can be readily applied to different cell lines, to identify canonical or context specific resistance mechanisms. Its ability to probe complex genetic context and non-coding genomic elements as well as cooperative resistance events makes it a good complement to RNAi or ORF expression based screens. PMID- 23442793 TI - Wading through the waves of human embryonic hemogenesis. PMID- 23442794 TI - MicroRNAs and the cellular response to rapamycin: potential role in diagnosis and therapy. PMID- 23442795 TI - Can liberating p53 from E6 free patients from HPV-related head and neck tumors? PMID- 23442796 TI - High level production of tyrosinase in recombinant Escherichia coli. AB - BACKGROUND: Tyrosinase is a bifunctional enzyme that catalyzes both the hydroxylation of monophenols to o-diphenols (monophenolase activity) and the subsequent oxidation of the diphenols to o-quinones (diphenolase activity). Due to the potential applications of tyrosinase in biotechnology, in particular in biocatalysis and for biosensors, it is desirable to develop a suitable low-cost process for efficient production of this enzyme. So far, the best production yield reported for tyrosinase was about 1 g L(-1), which was achieved by cultivating the filamentous fungus Trichoderma reesei for 6 days. RESULTS: In this work, tyrosinase from Verrucomicrobium spinosum was expressed in Escherichia coli and its production was studied in both batch and fed-batch cultivations. Effects of various key cultivation parameters on tyrosinase production were first examined in batch cultures to identify optimal conditions. It was found that a culture temperature of 32 degrees C and induction at the late growth stage were favorable, leading to a highest tyrosinase activity of 0.76 U mL(-1). The fed batch process was performed by using an exponential feeding strategy to achieve high cell density. With the fed-batch process, a final biomass concentration of 37 g L(-1) (based on optical density) and a tyrosinase activity of 13 U mL(-1) were obtained in 28 hours, leading to a yield of active tyrosinase of about 3 g L(-1). The highest overall volumetric productivity of 103 mg of active tyrosinase per liter and hour (corresponding to 464 mU L(-1) h(-1)) was determined, which is approximately 15 times higher than that obtained in batch cultures. CONCLUSIONS: We have successfully expressed and produced gram quantities per liter of active tyrosinase in recombinant E. coli by optimizing the expression conditions and fed batch cultivation strategy. Exponential feed of substrate helped to prolong the exponential phase of growth, to reduce the fermentation time and thus the cost. A specific tyrosinase production rate of 103 mg L(-1) h(-1) and a maximum volumetric activity of 464 mU L(-1) h(-1) were achieved in this study. These levels have not been reported previously. PMID- 23442797 TI - The BET protein FSH functionally interacts with ASH1 to orchestrate global gene activity in Drosophila. AB - BACKGROUND: The question of how cells re-establish gene expression states after cell division is still poorly understood. Genetic and molecular analyses have indicated that Trithorax group (TrxG) proteins are critical for the long-term maintenance of active gene expression states in many organisms. A generally accepted model suggests that TrxG proteins contribute to maintenance of transcription by protecting genes from inappropriate Polycomb group (PcG) mediated silencing, instead of directly promoting transcription. RESULTS AND DISCUSSION: Here we report a physical and functional interaction in Drosophila between two members of the TrxG, the histone methyltransferase ASH1 and the bromodomain and extraterminal family protein FSH. We investigated this interface at the genome level, uncovering a widespread co-localization of both proteins at promoters and PcG-bound intergenic elements. Our integrative analysis of chromatin maps and gene expression profiles revealed that the observed ASH1-FSH binding pattern at promoters is a hallmark of active genes. Inhibition of FSH binding to chromatin resulted in global down-regulation of transcription. In addition, we found that genes displaying marks of robust PcG-mediated repression also have ASH1 and FSH bound to their promoters. CONCLUSIONS: Our data strongly favor a global coactivator function of ASH1 and FSH during transcription, as opposed to the notion that TrxG proteins impede inappropriate PcG-mediated silencing, but are dispensable elsewhere. Instead, our results suggest that PcG repression needs to overcome the transcription-promoting function of ASH1 and FSH in order to silence genes. PMID- 23442798 TI - The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion. AB - Previously, we have identified the RUNX1 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared with primary cultures derived from matched primary (prior to CT) tumors. Here we show that RUNX1 displays a trend of hypomethylation, although not significant, in omental metastases compared with primary EOC tumors. Surprisingly, RUNX1 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. The RUNX1 expression levels were almost identical in primary tumors and omental metastases, suggesting that RUNX1 hypomethylation might have a limited impact on its overexpression in advanced (metastatic) stage of the disease. Knockdown of the RUNX1 expression in EOC cells led to sharp decrease of cell proliferation and induced G 1 cell cycle arrest. Moreover, RUNX1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX1 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX1 gene in EOC progression and suggest that RUNX1 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX1 and other members of the RUNX gene family in ovarian tumorigenesis. PMID- 23442799 TI - Dma/RNF8 proteins are evolutionarily conserved E3 ubiquitin ligases that target septins. AB - The budding yeast proteins Dma1 and Dma2 are members of the unique FHA-RING domain protein family and are linked to mitotic regulation and septin organization by ill-defined mechanisms. We show that Dma2 has ubiquitin ligase activity, and that septins Shs1 and Cdc11 are likely direct in vivo targets. We further propose that human RNF8, rather than Chfr, is the mammalian Dma homolog. As in yeast, RNF8 localizes to the centrosomes and cell division sites and promotes ubiquitylation of the septin SEPT7, whose depletion increases cell division anomalies. Together, these findings reveal evolutionary and functional conservation of Dma proteins, and suggest that RNF8 maintains genome stability through independent, yet analogous, nuclear and cytoplasmic ubiquitylation activities. PMID- 23442800 TI - An E2 enzyme Ubc11 is required for ubiquitination of Slp1/Cdc20 and spindle checkpoint silencing in fission yeast. AB - For ordered mitotic progression, various proteins have to be regulated by an ubiquitin ligase, the anaphase-promoting complex or cyclosome (APC/C) with appropriate timing. Recent studies have implied that the activity of APC/C also contributes to release of mitotic checkpoint complexes (MCCs) from its target Cdc20 in the process of silencing the spindle assembly checkpoint (SAC). Here we describe a temperature-sensitive mutant (ubc11-P93L) in which cell cycle progression is arrested at mitosis. The mutant grows normally at the restrictive temperature when SAC is inactivated, suggesting that the arrest is not due to abnormal spindle assembly, but rather due to prolonged activation of SAC. Supporting this notion, MCCs remain bound to APC/C even when SAC is satisfied. The ubc11 (+) gene encodes one of the two E2 enzymes required for progression through mitosis in fission yeast. Remarkably, Slp1 (a fission yeast homolog of Cdc20), which is degraded in an APC/C-dependent manner, stays stable throughout the cell cycle in the ubc11-P93L mutant lacking the functional SAC. Other APC/C substrates, in contrast, were degraded on schedule. We have also found that a loss of Ubc4, the other E2 required for progression through mitosis, does not affect the stability of Slp1. We propose that each of the two E2 enzymes is responsible for collaborating with APC/C for a specific set of substrates, and that Ubc11 is responsible for regulating Slp1 with APC/C for silencing the SAC. PMID- 23442801 TI - Glycogen synthase kinase 3 beta activity is required for hBora/Aurora A-mediated mitotic entry. AB - The synthesis and degradation of hBora is important for the regulation of mitotic entry and exist. In G 2 phase, hBora can complex with Aurora A to activate Plk1 and control mitotic entry. However, whether the post-translational modification of hBora is relevant to the mitotic entry still unclear. Here, we used the LC MS/MS phosphopeptide mapping assay to identify 13 in vivo hBora phosphorylation sites and characterized that GSK3beta can interact with hBora and phosphorylate hBora at Ser274 and Ser278. Pharmacological inhibitors of GSK3beta reduced the retarded migrating band of hBora in cells and diminished the phosphorylation of hBora by in vitro kinase assay. Moreover, as well as in GSK3beta activity inhibited cells, specific knockdown of GSK3beta by shRNA and S274A/S278 hBora mutant-expressing cells also exhibited the reduced Plk1 activation and a delay in mitotic entry. It suggests that GSK3beta activity is required for hBora-mediated mitotic entry through Ser274 and Ser278 phosphorylation. PMID- 23442803 TI - Dealing with tobacco use and dependence within primary health care: time for action. PMID- 23442802 TI - Centrobin regulates centrosome function in interphase cells by limiting pericentriolar matrix recruitment. AB - The amount of pericentriolar matrix at the centrosome is tightly linked to both microtubule nucleation and centriole duplication, although the exact mechanism by which pericentriolar matrix levels are regulated is unclear. Here we show that Centrobin, a centrosomal protein, is involved in regulating these levels. Interphase microtubule arrays in Centrobin-depleted cells are more focused around the centrosome and are less stable than the arrays in control cells. Centrobin depleted cells initiate microtubule nucleation more rapidly than control cells and exhibit an increase in the number of growing microtubule ends emanating from the centrosome, while the parameters of microtubule plus end dynamics around the centrosome are not significantly altered. Finally, we show that Centrobin depletion results in the increased recruitment of pericentriolar matrix proteins to the centrosome, including gamma-tubulin, AKAP450, Kendrin and PCM-1. We propose that Centrobin might regulate microtubule nucleation and organization by controlling the amount of pericentriolar matrix. PMID- 23442804 TI - Development and trialling of a tool to support a systems approach to improve social determinants of health in rural and remote Australian communities: the healthy community assessment tool. AB - INTRODUCTION: The residents of many Australian rural and remote communities do not have the essential infrastructure and services required to support healthy living conditions and community members choosing healthy lifestyle options. Improving these social determinants of health is seen to offer real opportunities to improve health among such disadvantaged populations. In this paper, we describe the development and trialling of a tool to measure, monitor and evaluate key social determinants of health at community level. METHODS: The tool was developed and piloted through a multi-phase and iterative process that involved a series of consultations with community members and key stakeholders and trialling the tool in remote Indigenous communities in the Northern Territory of Australia. RESULTS: The indicators were found to be robust, and by testing the tool on a number of different levels, face validity was confirmed. The scoring system was well understood and easily followed by Indigenous and non-Indigenous study participants. A facilitated small group process was found to reduce bias in scoring of indicators. CONCLUSION: The Healthy Community Assessment Tool offers a useful vehicle and process to help those involved in planning, service provision and more generally promoting improvements in community social determinants of health. The tool offers many potential uses and benefits for those seeking to address inequities in the social determinants of health in remote communities. Maximum benefits in using the tool are likely to be gained with cross-sector involvement and when assessments are part of a continuous quality improvement program. PMID- 23442805 TI - Cardiometabolic prevention consultation in the Netherlands: screening uptake and detection of cardiometabolic risk factors and diseases--a pilot study. AB - BACKGROUND: Until now, cardiometabolic risk assessment in Dutch primary health care was directed at case-finding, and structured, programmatic prevention is lacking. Therefore, the Prevention Consultation cardiometabolic risk (PC CMR), a stepwise approach to identify and manage patients with cardiometabolic risk factors, was developed. The aim of this study was 1) to evaluate uptake rates of the two steps of the PC CMR, 2) to assess the rates of newly diagnosed hypertension, hypercholesterolemia, diabetes mellitus and chronic kidney disease and 3) to explore reasons for non-participation. METHODS: Sixteen general practices throughout the Netherlands were recruited to implement the PC CMR during 6 months. In eight practices eligible patients aged between 45 and 70 years without a cardiometabolic disease were actively invited by a personal letter ('active approach') and in eight other practices eligible patients were informed about the PC CMR only by posters and leaflets in the practice ('passive approach'). Participating patients completed an online risk estimation (first step). Patients estimated as having a high risk according to the online risk estimation were advised to visit their general practice to complete the risk profile with blood pressure measurements and blood tests for cholesterol and glucose and to receive recommendations about risk lowering interventions (second step). RESULTS: The online risk estimation was completed by 521 (33%) and 96 (1%) of patients in the practices with an active and passive approach, respectively. Of these patients 392 (64%) were estimated to have a high risk and were referred to the practice; 142 of 392 (36%) consulted the GP. A total of 31 (22%) newly diagnosed patients were identified. Hypertension, hypercholesterolemia, diabetes and chronic kidney disease were diagnosed in 13%, 11%, 1% and 0%, respectively. Privacy risks were the most frequently mentioned reason not to participate. CONCLUSIONS: One third of the patients responded to an active invitation to complete an online risk estimation. A passive invitation resulted in only a small number of participating patients. Two third of the participants of the online risk estimation had a high risk, but only one third of them attended the GP office. One in five visiting patients had a diagnosed cardiometabolic risk factor or disease. PMID- 23442806 TI - Late acute liver allograft rejection; a study of its natural history and graft survival in the current era. AB - BACKGROUND: Late acute rejection (LAR) after liver transplantation is often associated with poor clinical outcomes. We reviewed our experience of managing LAR in the current era to determine its natural history. METHODS: A database of 970 consecutive adult liver transplants was reviewed retrospectively. LAR was defined as histologically proven acute cellular rejection occurring more than 90 days after transplantation. RESULTS: The incidence of LAR was 11%, with a mean time of 565 days (median, 311 days; range, 90-2922 days) after transplantation. The highest rates for LAR were in seronegative hepatitis (17%), primary biliary cirrhosis (16%), and primary sclerosing cholangitis (13%) with an odds ratio of 2.3, 2.1, and 1.8, respectively. Logistic regression showed that younger recipients, primary biliary cirrhosis, and previous graft loss were independent predictors of LAR (P<0.001). Mean trough whole blood tacrolimus levels were at their lowest levels 1 week before the diagnosis of rejection (5.5 ng/mL; SD, 2.6) compared with levels of 7.7 ng/mL 4 weeks before rejection, showing a clear temporal relation. Graft survival was worse in those with LAR (P<0.01), whereas the best graft survival was among early acute rejection cases (85% 10-year survival; P<0.01). Poor response to treatment correlated with the development of ductopenic rejection (r=0.3; P<0.01). Approximately half with early ductopenic rejection eventually died (n=15). CONCLUSION: LAR continues to provide a risk to patient and graft survival: understanding risk factors may allow an improvement in monitoring and early intervention and so prevent early graft loss. PMID- 23442807 TI - Mediastinitis and sternal prosthesis infection successfully treated by minimally invasive omental flap transposition. AB - Purulent mediastinitis is a possible serious complication after mediastinal surgery. We report the case of a localized sternal plasmocytoma treated by sternectomy and prosthetic repair, who needed a second surgery for a fistulizing mediastinitis. Five months earlier, in another Hospital, the patient underwent sternal resection and reconstruction with a "sandwich" prosthesis (Methyl methacrylate and Marlex mesh). Suppurative mediastinitis occurred and septic shock resolution was observed after the spontaneous opening of a mediastinal cutaneous fistula. After referring to our Unit the patient underwent extensive local and systemic preparation and nutritional support; the infected prosthesis was then removed and the gap filled by a laparoscopically-prepared omental flap. Adequate preoperative management, removal of any infected material and minimally invasive omental flap transposition allowed the successful treatment of this life threatening condition. PMID- 23442808 TI - Right heart morphology and function in heart transplantation recipients. AB - BACKGROUND: The right heart is a major determinant of prognosis in cardiac transplant recipient patients. AIM: To investigate right ventricular morphology and function and their relationship with exercise capacity in cardiac transplant recipient patients using standard tranthoracic echocardiography and a new three dimensional echocardiographic software adapted for right ventricular analysis. METHODS: One hundred fifteen relatively stable cardiac transplant recipient patients (71 men; 58.3 +/- 5.8 years; 7.8 +/- 4.5 years after transplantation) and 80 healthy age-comparable and sex-comparable controls underwent standard echocardiography, tissue Doppler imaging (TDI), and three-dimensional echocardiography, focused on the right ventricular analysis. Along with left heart parameters, right ventricular measurements included end-diastolic diameters at basal and mid-cavity level; base-to-apex length; tricuspid annulus plane systolic excursion (TAPSE); TDI right ventricular systolic peak velocity (Sm); and three-dimensional ejection fraction. Using the peak systolic tricuspid regurgitation velocity (TRV) and the end-diastolic pulmonary regurgitation velocity, the modified Bernoulli equation was used to calculate the pulmonary artery systolic (PASP) and diastolic pressures. Pulmonary artery vascular conductance (PAVC) was estimated by left ventricular stroke volume/4 * (TRV - pulmonary regurgitation velocity). RESULTS: Left ventricular diameters and ejection fraction did not significantly differ between the two groups, whereas mass index was increased in cardiac transplant recipient patients (P < 0.01). Right ventricular diameters were significantly increased (P < 0.001), whereas TAPSE and right ventricular Sm were significantly lower in cardiac transplant recipient patients. Conversely, in cardiac transplant recipient patients, three dimensional right ventricular ejection fraction (RVEF) was not significantly reduced (P < 0.001), whereas both PASP and PAVC were impaired. By multivariable analysis, age at transplantation (P < 0.01) and pulmonary artery mean pressure (P < 0.001) were the only independent determinants of right ventricular diameters and RVEF in cardiac transplant. Furthermore, RVEF measured by real-time three dimensional echocardiography was a powerful independent determinant of functional capacity in cardiac transplant recipient patients. CONCLUSION: Despite the reduction of right ventricular performance along the long axis suggested by TAPSE and right ventricular Sm, the increased right ventricular diameters along with absence of a decrease in three-dimensional RVEF support the hypothesis of geometrical rather than functional changes of the right ventricle in cardiac transplant recipient patients. PMID- 23442809 TI - Mitral valve rheumatic multiple fenestrations: usefulness of 3D real-time echocardiography. AB - We describe a case that demonstrates and confirms the usefulness of 3D transesophageal echocardiography in the morphological analysis of the mitral valve in a rare occurrence of postrheumatic mitral leaflet perforation. PMID- 23442810 TI - Clinical spectrum of fascicular tachycardia. AB - AIMS: Ventricular tachycardia spreading from the anterior or posterior division of the left bundle branch is generally called fascicular tachycardia (FT). We will present our experience with FT, a type of ventricular tachycardia not necessarily implying the absence of heart disease and/or sensitivity to selective antiarrhythmic drugs, but only particular routes of left ventricular depolarization. METHODS: Since 1981 we have had the opportunity to study 10 cases of FT (nine men and one woman; aged 28-77 years, mean +/- SD 55 +/- 18.6 years) by means of echocardiography, coronary angiography (seven cases), endomyocardial biopsy (five cases), signal-averaged electrocardiogram (SAECG, nine patients), electrophysiological and electropharmacological evaluation. RESULTS: Seven patients had paroxystic, extrastimulus inducible FT that was sensitive to verapamil given intravenously (group A); three patients, on the other hand, showed repetitive or incessant FT, not modifiable by stimulation techniques and sensitive to class 1 antiarrhythmic drugs (group B). Patients presented histologic substrates ranging from the absence of heart disease to previous myocardial infarction or myocarditis. FT spontaneously disappeared within 2 years in group B, while frequently persisted in the long term in group A. CONCLUSIONS: FT is not a homogeneous group of ventricular tachycardia, as patients may differ according to clinical presentation, mechanisms that are involved in the genesis of the arrhythmia and natural history; the histologic substrate is highly variable, ranging from the total absence of heart disease to severe forms of myocardial involvement. PMID- 23442811 TI - The bivalirudin paradox: high evidence, low use. AB - A series of trials have shown that bivalirudin, a direct thrombin inhibitor that does not require the cofactor antithrombin III to be effective, is a reasonable alternative to unfractionated heparin (UFH) alone or associated with glycoprotein IIb/IIIa antagonists (GPI) in patients undergoing percutaneous coronary interventions (PCI). Particularly in patients with acute coronary syndromes (ACS), the effects of bivalirudin are striking. In the HORIZONS-AMI trial, patients with persistent ST-segment elevation (STEMI) had lower 30-day rates of net adverse clinical events and major bleeding, largely due to the significantly lower 30-day rate of non-coronary artery bypass grafting major bleeding. Bivalirudin also resulted in significantly lower rates of all-cause mortality and cardiac mortality, a benefit that extended up to 3-year follow-up. The beneficial effects of bivalirudin as compared to UFH associated with abciximab were also observed in 1721 non-ST elevation myocardial infarction (NSTEMI) patients undergoing PCI in the ISAR REACT 4 study. Although no difference was found between the two treatment strategies in the 30-day primary endpoint, bivalirudin use resulted in a lower rate of major bleeding. Despite the abundant evidence of benefit provided by bivalirudin in the treatment of ACS and the high level of recommendation received by the most recent Guidelines, its use is still low. The reasons for this underuse are multifactorial, the most likely being the preference of operators for the use of a low-cost agent, like UFH, that can be associated with a GPI. Countering platelet hyperreactivity is still the main goal of interventional cardiologists treating ACS patients invasively, apparently downplaying the pathogenetic role of thrombin in this clinical condition. PMID- 23442812 TI - Constrictive epicarditis: turtle cage or waffle operation? AB - A 72-year-old man, presenting with signs of pericarditis, was found at operation to have constrictive epicarditis. Operation consisted of pericardiectomy and creation of multiple longitudinal and transverse incisions of the epicardium. PMID- 23442815 TI - Chest pain with minimal activities and flexion of trunk: a rare case of angina. AB - A 53-year-old woman presented with effort-induced chest pain during daily activities and similar symptoms with trunk flexion. A treadmill exercise test revealed a Mobitz II atrioventricular block. Coronarography and computed tomography confirmed the diagnosis of anomalous origin of the right coronary artery from the left coronary sinus, so surgical revascularization was indicated. We discuss the peculiarity of the clinical presentation and its possible pathogenic mechanism. PMID- 23442814 TI - Microvascular obstruction complicating acute right ventricular myocardial infarction. AB - This case history describes a man with inferior myocardial infarction (MI) with right-ventricular involvement, treated with a right coronary artery stent. Magnetic resonance showed akinesia of left-ventricular inferior and inferolateral walls and right-ventricular inferior free wall with an impairment of global systolic function. There was late gadolinium enhancement (LGE) of left ventricular inferior and inferolateral walls with microvascular obstruction (MVO). LGE of the right-ventricular inferior wall was seen with a hypointense core within hyperenhanced myocardium, consistent with MVO of the infarcted right ventricular myocardium. At follow-up there was persistent akinesia of left ventricular inferior and inferolateral walls and right-ventricular systolic dysfunction. LGE was still evident with resolution of MVO. PMID- 23442816 TI - An accordion not to be played. AB - We present the case of a 52-year-old man with normal coronary arteries admitted to our department after being resuscitated from ventricular fibrillation. Transthoracic echocardiography raised suspicion of left-ventricular non compaction. Cardiac magnetic resonance excluded this, but showed several systolic bulgings of the right ventricle and a characteristic focal 'crinkling' of the right-ventricular outflow tract known as the 'accordion' sign, a specific marker of desmosomal gene mutations, thus suggesting the presence of an arrhythmogenic cardiomyopathy. Extensive mid-myocardial late gadolinium enhancement and fatty infiltration, predominantly of the left ventricle, finally confirmed the diagnosis of left dominant arrhythmogenic cardiomyopathy, a rare variant of arrhythmogenic right-ventricular cardiomyopathy. PMID- 23442813 TI - Clinical presentation of acute coronary syndrome in patients previously treated with nitrates. AB - AIMS: Several reports have suggested that nitrates limit acute ischaemic damage by a mechanism similar to preconditioning. This study aims to evaluate the effect of chronic oral nitrates on the clinical presentation and short-term outcomes of patients admitted with acute coronary syndrome (ACS). METHODS: A retrospective cohort study was conducted in patients with ACS admitted to 62 acute care units from 2010 to 2011. A propensity score-matched samples analysis was performed. RESULTS: We analysed 3171 consecutive patients, of whom 298 (9.4%) were chronically treated with nitrates. Patients previously treated with nitrates had higher comorbidity and disease severity at admission, lower prevalence of ACS with ST elevation, lower troponin elevation, higher prevalence of initial Killip class 2-4 and higher hospital mortality. The propensity score-matched analysis confirmed that previous use of nitrates is independently associated with a lower prevalence of ST-elevation ACS [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.36-0.78; P = 0.0014] and a lower troponin elevation (OR 0.61, 95% CI 0.41 0.92) but not with Killip class on admission (OR 1.18, 95% CI 0.83-1.67, P = 0.3697) or mortality (OR 0.71, 95% CI 0.37-1.38, P = 0.3196). CONCLUSION: The results support the hypothesis that nitrates have a protective effect on acute ischaemic injury. PMID- 23442818 TI - Sugary food and beverage consumption and epithelial ovarian cancer risk: a population-based case-control study. AB - BACKGROUND: Ovarian cancer is the deadliest gynecologic cancer in the US. The consumption of refined sugars has increased dramatically over the past few decades, accounting for almost 15% of total energy intake. Yet, there is limited evidence on how sugar consumption affects ovarian cancer risk. METHODS: We evaluated ovarian cancer risk in relation to sugary foods and beverages, and total and added sugar intakes in a population-based case-control study. Cases were women with newly diagnosed epithelial ovarian cancer, older than 21 years, able to speak English or Spanish, and residents of six counties in New Jersey. Controls met same criteria as cases, but were ineligible if they had both ovaries removed. A total of 205 cases and 390 controls completed a phone interview, food frequency questionnaire, and self-recorded waist and hip measurements. Based on dietary data, we computed the number of servings of dessert foods, non-dessert foods, sugary drinks and total sugary foods and drinks for each participant. Total and added sugar intakes (grams/day) were also calculated. Multiple logistic regression models were used to estimate odds ratios and 95% confidence intervals for food and drink groups and total and added sugar intakes, while adjusting for major risk factors. RESULTS: We did not find evidence of an association between consumption of sugary foods and beverages and risk, although there was a suggestion of increased risk associated with sugary drink intake (servings per 1,000 kcal; OR=1.63, 95% CI: 0.94-2.83). CONCLUSIONS: Overall, we found little indication that sugar intake played a major role on ovarian cancer development. PMID- 23442819 TI - Designing and benchmarking the MULTICOM protein structure prediction system. AB - BACKGROUND: Predicting protein structure from sequence is one of the most significant and challenging problems in bioinformatics. Numerous bioinformatics techniques and tools have been developed to tackle almost every aspect of protein structure prediction ranging from structural feature prediction, template identification and query-template alignment to structure sampling, model quality assessment, and model refinement. How to synergistically select, integrate and improve the strengths of the complementary techniques at each prediction stage and build a high-performance system is becoming a critical issue for constructing a successful, competitive protein structure predictor. RESULTS: Over the past several years, we have constructed a standalone protein structure prediction system MULTICOM that combines multiple sources of information and complementary methods at all five stages of the protein structure prediction process including template identification, template combination, model generation, model assessment, and model refinement. The system was blindly tested during the ninth Critical Assessment of Techniques for Protein Structure Prediction (CASP9) in 2010 and yielded very good performance. In addition to studying the overall performance on the CASP9 benchmark, we thoroughly investigated the performance and contributions of each component at each stage of prediction. CONCLUSIONS: Our comprehensive and comparative study not only provides useful and practical insights about how to select, improve, and integrate complementary methods to build a cutting-edge protein structure prediction system but also identifies a few new sources of information that may help improve the design of a protein structure prediction system. Several components used in the MULTICOM system are available at: http://sysbio.rnet.missouri.edu/multicom_toolbox/. PMID- 23442820 TI - The second-language vocabulary trajectories of Turkish immigrant children in Norway from ages five to ten: the role of preschool talk exposure, maternal education, and co-ethnic concentration in the neighborhood. AB - Little research has explored how preschools can support children's second language (L2) vocabulary development. This study keenly followed the progress of twemty-six Turkish immigrant children growing up in Norway from preschool (age five) to fifth grade (age ten). Four different measures of preschool talk exposure (amount and diversity of teacher-led group talk and amount and diversity of peer talk), as well as the demographic variables of maternal education and co ethnic concentration in the neighborhood, were employed to predict the children's L2 vocabulary trajectories. The results of growth analyses revealed that maternal education was the only variable predicting children's vocabulary growth during the elementary years. However, teacher-led talk, peer talk, and neighborhood predicted children's L2 vocabulary skills at age five, and these differences were maintained up to age ten. This study underscores the importance of both preschool talk exposure (teacher-led talk and peer talk) and demographic factors on L2 learners' vocabulary development. PMID- 23442817 TI - Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. AB - There are multiple sources of reactive oxygen species (ROS) in the cell. As a major site of ROS production, mitochondria have drawn considerable interest because it was recently discovered that mitochondrial ROS (mtROS) directly stimulate the production of proinflammatory cytokines and pathological conditions as diverse as malignancies, autoimmune diseases, and cardiovascular diseases all share common phenotype of increased mtROS production above basal levels. Several excellent reviews on this topic have been published, but ever-changing new discoveries mandated a more up-to-date and comprehensive review on this topic. Therefore, we update recent understanding of how mitochondria generate and regulate the production of mtROS and the function of mtROS both in physiological and pathological conditions. In addition, we describe newly developed methods to probe or scavenge mtROS and compare these methods in detail. Thorough understanding of this topic and the application of mtROS-targeting drugs in the research is significant towards development of better therapies to combat inflammatory diseases and inflammatory malignancies. PMID- 23442821 TI - A new measuring and identification approach for time-varying bioimpedance using multisine electrical impedance spectroscopy. AB - The bioimpedance measurement/identification of time-varying biological systems Z(omega, t) by means of electrical impedance spectroscopy (EIS) is still a challenge today. This paper presents a novel measurement and identification approach, the so-called parametric-in-time approach, valid for time-varying (bio )impedance systems with a (quasi) periodic character. The technique is based on multisine EIS. Contrary to the widely used nonparametric-in-time strategy, the (bio-)impedance Z(omega, t) is assumed to be time-variant during the measurement interval. Therefore, time-varying spectral analysis tools are required. This new parametric-in-time measuring/identification technique has experimentally been validated through three independent sets of in situ measurements of in vivo myocardial impedance. We show that the time-varying myocardial impedance Z(omega, t) is dominantly periodically time varying (PTV), denoted as ZPTV(omega, t). From the temporal analysis of ZPTV(omega, t), we demonstrate that it is possible to decompose ZPTV(omega, t) into a(n) (in)finite sum of fundamental (bio-)impedance spectra, the so-called harmonic impedance spectra (HIS) Zk(omega)s with [Formula: see text]. This is similar to the well-known Fourier series of a periodic signal, but now understood at the level of a periodic system's frequency response. The HIS Zk(omega)s for [Formula: see text] actually summarize in the bi-frequency (omega, k) domain all the temporal in-cycle information about the periodic changes of Z(omega, t). For the particular case k = 0 (i.e. on the omega-axis), Z0(omega) reflects the mean in-cycle behavior of the time-varying bioimpedance. Finally, the HIS Zk(omega)s are directly identified from noisy current and voltage myocardium measurements at the multisine measurement frequencies (i.e. nonparametric-in-frequency). PMID- 23442822 TI - Patterns of prokaryotic lateral gene transfers affecting parasitic microbial eukaryotes. AB - BACKGROUND: The influence of lateral gene transfer on gene origins and biology in eukaryotes is poorly understood compared with those of prokaryotes. A number of independent investigations focusing on specific genes, individual genomes, or specific functional categories from various eukaryotes have indicated that lateral gene transfer does indeed affect eukaryotic genomes. However, the lack of common methodology and criteria in these studies makes it difficult to assess the general importance and influence of lateral gene transfer on eukaryotic genome evolution. RESULTS: We used a phylogenomic approach to systematically investigate lateral gene transfer affecting the proteomes of thirteen, mainly parasitic, microbial eukaryotes, representing four of the six eukaryotic super-groups. All of the genomes investigated have been significantly affected by prokaryote-to eukaryote lateral gene transfers, dramatically affecting the enzymes of core pathways, particularly amino acid and sugar metabolism, but also providing new genes of potential adaptive significance in the life of parasites. A broad range of prokaryotic donors is involved in such transfers, but there is clear and significant enrichment for bacterial groups that share the same habitats, including the human microbiota, as the parasites investigated. CONCLUSIONS: Our data show that ecology and lifestyle strongly influence gene origins and opportunities for gene transfer and reveal that, although the outlines of the core eukaryotic metabolism are conserved among lineages, the genes making up those pathways can have very different origins in different eukaryotes. Thus, from the perspective of the effects of lateral gene transfer on individual gene ancestries in different lineages, eukaryotic metabolism appears to be chimeric. PMID- 23442823 TI - Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children. AB - Japanese encephalitis chimeric virus vaccine (JE-CV) is a licensed vaccine indicated in a single dose administration for primary immunization. This controlled phase III comparative trial enrolled children aged 36-42 mo in the Philippines. 345 children who had received one dose of JE-CV in a study two years earlier, received a JE-CV booster dose. 105 JE-vaccine-naive children in general good health were randomized to receive JE-CV (JE-vaccine naive group; 46 children) or varicella vaccine (safety control group; 59 children). JE neutralizing antibody titers were assessed using PRNT50. Immunological memory was observed in children who had received the primary dose of JE-CV before. Seven days after the JE-CV booster dose administration, 96.2% and 66.8% of children were seroprotected and had seroconverted, respectively, and the geometric mean titer (GMT) was 231 1/dil. Twenty-eight days after the JE-CV booster dose seroprotection and seroconversion were achieved in 100% and 95.3% of children, respectively, and the GMT was 2,242 1/dil. In contrast, only 15.4% of JE-CV vaccine naive children who had not received any prior JE vaccine were seroprotected seven days after they received JE-CV. One year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected. We conclude that JE CV is effective and safe, both as a single dose and when administrated as a booster dose. A booster dose increases the peak GMT above the peak level reached after primary immunization and the antibody persistence is maintained at least one year after the JE-CV booster dose administration. Five year follow up is ongoing. PMID- 23442824 TI - Quantifying the contribution of chromatin dynamics to stochastic gene expression reveals long, locus-dependent periods between transcriptional bursts. AB - BACKGROUND: A number of studies have established that stochasticity in gene expression may play an important role in many biological phenomena. This therefore calls for further investigations to identify the molecular mechanisms at stake, in order to understand and manipulate cell-to-cell variability. In this work, we explored the role played by chromatin dynamics in the regulation of stochastic gene expression in higher eukaryotic cells. RESULTS: For this purpose, we generated isogenic chicken-cell populations expressing a fluorescent reporter integrated in one copy per clone. Although the clones differed only in the genetic locus at which the reporter was inserted, they showed markedly different fluorescence distributions, revealing different levels of stochastic gene expression. Use of chromatin-modifying agents showed that direct manipulation of chromatin dynamics had a marked effect on the extent of stochastic gene expression. To better understand the molecular mechanism involved in these phenomena, we fitted these data to a two-state model describing the opening/closing process of the chromatin. We found that the differences between clones seemed to be due mainly to the duration of the closed state, and that the agents we used mainly seem to act on the opening probability. CONCLUSIONS: In this study, we report biological experiments combined with computational modeling, highlighting the importance of chromatin dynamics in stochastic gene expression. This work sheds a new light on the mechanisms of gene expression in higher eukaryotic cells, and argues in favor of relatively slow dynamics with long (hours to days) periods of quiet state. PMID- 23442825 TI - Antibacterial effects of silver diamine fluoride on multi-species cariogenic biofilm on caries. AB - BACKGROUNDS: Silver diamine fluoride (SDF) has clinical success in arresting dentin caries, this study aimed to investigate its mechanism of action. METHODS: Using a computer-controlled artificial mouth, we studied the effect of 38% SDF on cariogenic biofilms and dentin carious lesions. We used five common cariogenic bacteria (Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Lactobacillus rhamnosus and Actinomyces naeslundii) to form a cariogenic biofilm that generated carious lesions with a depth of approximately 70 um on human dentin blocks. We applied 38% SDF to the lesions in the test group and water to those in the control group. The blocks were incubated in the artificial mouth for 21 days before evaluation. Microbial kinetics, architecture, viability and distribution were evaluated every 7 days using colony forming unit (CFU), scanning electron microscopy and confocal laser scanning microscopy. The physical properties of the carious lesions were evaluated with microhardness testing, energy dispersive spectroscopy (EDS) and Fourier transform infra-red spectroscopy (FTIR). RESULTS: The CFU results revealed fewer colony forming units in the test group compared with the control group (p < 0.01). Scanning electron microscopy and confocal microscopy showed less bacterial growth in the test group, and confluent cariogenic biofilm in the control group (p < 0.01). The microhardness and weight percentages of calcium and phosphorus in the test group from the outermost 50mum were higher than in the control group (p < 0.05). EDS showed that calcium and phosphous were higher in outer 50 mum in test groups than in the control FTIR revealed less exposed collagen I in the test lesions compared with the control group (p < 0.01). CONCLUSIONS: 38% SDF inhibits multi-species cariogenic biofilm formation on dentin carious lesions and reduces the demineralization process. PMID- 23442826 TI - Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. AB - BACKGROUND: Elastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3' region of the elastin gene (exons 30-34) which result in a C terminally extended protein, though exceptions have been reported. METHODS: We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient. RESULTS: Molecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%). CONCLUSION: ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients. PMID- 23442827 TI - Incontinence-associated dermatitis in community-dwelling individuals with fecal incontinence. AB - PURPOSE: To describe the occurrence and severity of incontinence-associated dermatitis among community-dwelling individuals with fecal incontinence. DESIGN: Descriptive and comparative secondary data analysis. SUBJECTS AND SETTING: One hundred eighty-nine community-dwelling individuals with fecal incontinence who participated in a study comparing the effects of dietary fiber on fecal incontinence. METHODS: A survey on the use of absorbent products that contained questions about subjects' history of skin damage was administered at the start of the study. RESULTS: Incontinence-associated dermatitis occurred in 52.5% of the community-living individuals with fecal incontinence. The severity of incontinence-associated dermatitis was mostly mild to moderate and occurred periodically. Redness without broken skin was the most common manifestation (68%). Most individuals (95%) reported the location of skin damage to be the anal/rectal area. Those with double incontinence also reported dermatitis around the vagina or penis. Individuals with a greater severity of fecal incontinence had a greater severity of incontinence-associated dermatitis (r = 0.27, P = .000). Both the frequency of incontinence (r = 0.23, P < .002) and the amount of feces leaked (r = 0.23, P < .002) had a significant correlation with incontinence associated dermatitis severity. There were no significant differences in the occurrence or severity of incontinence-associated dermatitis by sex, age, or presence of double incontinence. CONCLUSION: A high percentage of individuals in the community with fecal incontinence suffer from incontinence-associated dermatitis at times. This population may benefit from consultation with a WOC nurse about prevention and management of incontinence-associated dermatitis. PMID- 23442828 TI - Effectiveness of wound, ostomy and continence-certified nurses on individual patient outcomes in home health care. AB - PURPOSE: To assess whether there was a significant improvement and stabilization (not worse at discharge) in pressure ulcers, lower extremity venous ulcers, surgical wounds, urinary incontinence, bowel incontinence, and urinary tract infections in home health care (HHC) patients cared for by a certified WOC nurse. SUBJECTS AND SETTING: There were 449,170 episodes of care from a national convenience sample of 785 HHC agencies with 447,309 nonmaternity, adult patients between October 1, 2008, and December 31, 2009. DESIGN: Descriptive and comparative. INSTRUMENTS AND METHODS: Data from the Outcome and Assessment Information Set documented by HHC clinicians were analyzed using mixed-effects logistic regression, propensity score analysis, and appropriate parametric and nonparametric tests. An Internet survey identified whether WOC nurses provided care to patients in an HHC agency. Home health care agencies identified records of patients receiving WOC nurse visits/consults. RESULTS: An HHC patient assigned to a WOC nurse had surgical wounds, pressure ulcers, and incontinence problems that were significantly worse than HHC patients not assigned to a WOC nurse. Patients cared for by a WOC nurse showed significant improvement and stabilization of the number of pressure ulcers and surgical wounds and the frequency of urinary and bowel incontinence, despite having problems that were more severe than other patients. Home health care patients not cared for by WOC nurses, with less-severe wound and incontinence problems, also got better. CONCLUSIONS: WOC nurses are effective in achieving positive health outcomes for pressure ulcers, surgical wounds, and incontinence in HHC patients with severe health problems. PMID- 23442829 TI - A re-evaluation of the scratch test for locating the liver edge. AB - BACKGROUND: A reliable and accurate estimation of liver size by physical examination is an important aspect of the clinical assessment of a patient. The scratch test uses auscultation to detect the lower liver edge by using the difference in sound transmission through the abdominal cavity over solid and hollow organs. The test is thought to be particularly useful if the abdomen is tense, distended, obese, or very tender. Although the sign is often taught to medical students and residents, the value of the technique for detecting the liver edge has become controversial. METHODS: The study was performed in two parts. In the first part, 18 patients undergoing upper abdominal ultrasound as outpatients were randomly selected and the scratch test was performed by two raters independently, followed by ultrasound (USG) as the reference standard. In the second part of the study, the two raters independently performed the scratch test on separate randomly selected patients (15 patients by rater 1, and 16 patients by rater 2), followed by USG. RESULTS: Agreement between raters on the scratch test was very high, with an intra-class correlation coefficient of 0.97. The agreement between the raters and the USG was 0.37 using Spearman's rho. A Bland -Altman plot indicated that, on average, raters underestimated the distance from the right costal margin to the liver edge by only about 2.4 centimeters compared to USG. This translates into 37% and 54% of raters' estimates falling within 2 and 3 cm of USG estimates. Each unit increase in BMI increased the discrepancy between raters and USG by 0.26 cm (p = 0.012). CONCLUSION: The scratch test has very high reproducibility and overall agreement between the scratch test and USG was moderate, with a spearman's rho of 0.37. The accuracy may potentially be improved by using the point of initial sound transmission rather than the point of maximal transmission. We conclude that the scratch test deserves further investigation. PMID- 23442830 TI - Prediction of carcinoma after resection in subjects with ampullary adenomas on endoscopic biopsy. AB - BACKGROUND/GOALS: The endoscopic treatment of ampullary adenomas is established; however, the false-negative rate of endoscopic biopsy for carcinoma is 20% to 30%, and it remains uncertain whether identifiable features predict malignancy. Our aim in this study was to evaluate the predictable factors of malignancy in ampullary adenomas on endoscopic biopsy. STUDY: Ninety-one subjects diagnosed with ampullary adenoma on endoscopic biopsy were confirmed after endoscopic or surgical resection of ampullary lesions between 1995 and 2011 respectively. Clinical, laboratory, radiologic, and endoscopic findings were compared between patients with adenoma and carcinoma after resection. We examined the predictors of malignancy in ampullary adenoma on endoscopic biopsy. RESULTS: The malignancy rate in ampullary adenomas on endoscopic biopsy was 26.4%. Univariate analysis revealed that presence of symptoms, villous components, high-grade dysplasia (HGD), papilla enlargement on computed tomography, duct dilatation on radiologic imaging, bilirubin>2 mg/dL, aspartate aminotransferase>40 IU/L, alanine aminotransferase>40 IU/L, and alkaline phosphatase>90 U/L were associated with malignancy in patients over 65 years of age. HGD [odds ratio, 6.86 (95% confidence interval, 1.58-29.79)] and ductal dilatation [odds ratio, 11.12 (95% confidence interval, 2.27-54.37)] were independently associated with malignancy in multivariate analysis. The sensitivity and negative predictive value for >=1 risk factors were 95.83% and 96.77%, respectively. The presence of 2 risk factors resulted in a high specificity (96%) and positive predictive value (84%) for malignancy. CONCLUSIONS: HGD and ductal dilatation are significant predictors of malignancy in ampullary adenomas. When these risk factors are present, precautions should be taken in the consideration of malignancy in patients with ampullary adenoma. PMID- 23442831 TI - Determination of the optimal time for premedication with pronase, dimethylpolysiloxane, and sodium bicarbonate for upper gastrointestinal endoscopy. AB - GOALS AND BACKGROUND: Premedication with pronase, dimethylpolysiloxane, and sodium bicarbonate improves visibility during upper gastrointestinal (UGI) endoscopy. However, the optimal time for this combination to take effect is unknown. We investigated the optimal time of pre-UGI endoscopy medication. STUDY: A randomized, investigator-blind, controlled trial. The 300 patients who were to receive premedication were randomized into 3 groups according to the following medication time before UGI endoscopy: 10 minutes (group A, n=98), 10 to 30 minutes (group B, n=97), and 30 minutes premedication (group C, n=99). Visibility scores (range, 1 to 4, with lower scores indicating better gastric mucosal visibility) were assessed for the antrum, lower body, upper body, and fundus and compared, including the sum of the scores, between the 3 groups. RESULTS: Group B had significantly lower visibility scores for the lower body, upper body, and fundus than group C (P=0.001, 0.009, and 0.002, respectively). Group A obtained significantly lower scores for the antrum and lower body than group C (P=0.007 and 0.005, respectively). The total visibility scores of groups A and B were significantly lower compared with those of group C (P=0.001, 0.003, respectively). CONCLUSIONS: Administration of pronase, dimethylpolysiloxane, and sodium bicarbonate within 30 minutes before UGI endoscopy significantly improved endoscopic visualization. However, the optimal time to achieve the best visibility was between 10 to 30 minutes before UGI endoscopy. PMID- 23442832 TI - Diverticular disease of the colon does not increase risk of repeat C. difficile infection. AB - BACKGROUND: Studies have suggested that colonic diverticulosis might increase the likelihood of repeat Clostridium difficile infection (CDI). Our study was designed to compare rates of repeat infection in patients with and without colon diverticula. METHODS: Patients who had a positive C. difficile toxin assay and colonoscopic evidence of diverticulosis were classified as CDI and diverticulosis (CDI-D), whereas those with a positive toxin assay but no such colonoscopic evidence were classified as CDI and no diverticulosis (CDI-ND). Various clinical and epidemiologic factors were recorded for each patient. Primary outcomes were "relapse" (repeat CDI within 3 mo of initial infection) and "recurrent" infection (repeat CDI>=3 mo after initial infection). Secondary outcomes 30 days after diagnosis were mortality, intensive care unit transfer, and continuous hospitalization. RESULTS: A total of 128 patients were classified as CDI-D, whereas 137 had CDI-ND. There were no significant differences between CDI-D and CDI-ND when comparing frequencies of repeat infection and its subclassifications, relapse or recurrence. There were, however, statistical associations seen between diverticulosis of the ascending colon and increased recurrence rates [hazard ratio (HR): 1.4+/-0.38, P<0.05] and decreased rates of relapse in diverticular disease of the descending (HR: 0.40+/-0.46, P<0.05), and sigmoid colon (HR: 0.39+/-0.49, P<0.05). The ascending colon association is limited by a small patient population. There were no significant differences in any of the 30-day outcomes including intensive care unit requirement, hospitalization stay, or mortality. CONCLUSIONS: Patients with diverticular disease of the colon are not at increased risk of repeat CDI. PMID- 23442833 TI - Immune therapy for nonalcoholic steatohepatitis: are we there yet? AB - Metabolic syndrome, obesity, and nonalcoholic steatohepatitis are associated with a state of chronic inflammation. The immune system and the inflammatory cascade can be involved in the development of any of the above common conditions. This association raises the question of whether immune therapy can be used for the treatment of nonalcoholic steatohepatitis. Although immune therapy is not yet feasible for clinical use, here, we review some of the recent data on the potential role of the various arms of the immune system in the development of nonalcoholic steatohepatitis and several potential therapeutic targets. PMID- 23442834 TI - Predicting early and sustained virological responses in prior nonresponders to pegylated interferon alpha-2b plus ribavirin retreated with peginterferon alpha 2a plus ribavirin and the benefit-risk ratio of retreatment. AB - GOALS: To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa). BACKGROUND: In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR. STUDY: We conducted an exploratory analysis of the retreatment with Pegasys in patients not responding to PegIntron therapy study data to better define the predictive value of cEVR for SVR in this patient population. RESULTS: In total, 157 of the 942 patients achieved a cEVR (16.7%). SVR rates were higher with 72 versus 48 weeks of retreatment in patients with a cEVR (57% vs. 35%), whereas SVR rates were <5% in patients without cEVR in both groups. The relative adverse event (AE) burden was lower with 72 weeks of treatment (8.1 vs. 10.1 AEs/y of treatment) as was the estimated number of AEs per SVR achieved (55 vs. 100). Cumulative treatment duration required to achieve 1 SVR was lower with 72 weeks of treatment (6.7 vs. 10.0 y/SVR) and lower still assuming that treatment was stopped at week 12 for non-cEVR patients (3.6 vs. 7.1 y/SVR). CONCLUSIONS: cEVR is a reliable predictor of SVR in patients retreated with peginterferon alpha-2a (40 kDa) plus ribavirin. Seventy-two-week retreatment has a more favorable benefit-risk ratio than 48 weeks, especially when cEVR is used to identify patients most likely to be cured. PMID- 23442836 TI - Multicenter trial evaluating the use of covered self-expanding metal stents in benign biliary strictures: time to revisit our therapeutic options? AB - BACKGROUND: Covered self-expanding metal stents are being used more frequently in benign biliary strictures (BBS). We report the results of a multicenter study with fully covered self-expanding metal stent (FCSEMS) placement for the management of BBS. AIM: : To prospectively evaluate the efficacy and safety of FCSEMS in the management of BBS. PATIENTS AND METHODS: Patients with BBS from 6 tertiary care centers who received FCSEMS with flared ends between April 2009 and October 2010 were included in this retrospective study.Efficacy was measured after removal of FCSEMS by evaluating stricture resolution on the basis of symptom resolution, imaging, laboratory studies, and/or choledochoscopy at removal. Safety profile was evaluated by assessing postprocedural complications. RESULTS: A total of 133 patients (78, 58.6% males) with a mean age of 59.2+/-14.8 years with BBS received stents. Of the 133 stents placed, 97 (72.9%) were removed after a mean stent duration of 95.5+/-48.7 days. Stricture resolution after FCSEMS removal was as follows: postsurgical, 11/12 (91.6%); gallstone-related disease, 16/19 (84.2%); chronic pancreatitis, 26/31 (80.7%); other etiology, 4/5 (80.0%); and anastomotic strictures, 19/31(61.2%). Ninety-four patients were included in the logistic regression analyses. Patients who had indwelling stents for >90 days were 4.3 times more likely to have resolved strictures [odds ratio, 4.3 (95% confidence interval, 1.24-15.09)] and patients with nonmigrated stents were 5.4 times more likely to have resolved strictures [odds ratio, 5.4 (95% confidence interval, 1.001-29.29)]. CONCLUSIONS: FCSEMS for BBS had an acceptable rate of stricture resolution for postsurgical strictures, gallstone-related strictures, and those due to chronic pancreatitis. Predictors for stricture resolution include longer indwell time and absence of migration. Further study is warranted to assess long-term efficacy in a prospective manner with longer than 3 month time of stent indwelling time. PMID- 23442835 TI - Obesity does not affect treatment outcomes with proton pump inhibitors. AB - BACKGROUND: Obesity is associated with increased risk of gastroesophageal reflux disease (GERD). GOAL: To evaluate the effect of obesity on symptom resolution in patients with nonerosive reflux disease (NERD) and healing rates in patients with erosive esophagitis (EE). METHODS: Two post hoc analyses were performed. Analyses included pooled data from randomized, double-blind, multicenter studies of proton pump inhibitors (PPIs) in GERD patients. RESULTS: Analysis 1 included 704 patients with NERD receiving esomeprazole 20 mg, esomeprazole 40 mg, or placebo. Analysis 2 included 11,027 patients with EE receiving esomeprazole 40 mg, omeprazole 20 mg, or lansoprazole 30 mg. For NERD patients, no significant association between baseline heartburn severity and body mass index (BMI) was observed. In EE patients, overweight (BMI 25 to <35 kg/m) and obese (BMI >=35 kg/m) patients had significantly higher rates of Los Angeles (LA) grade C or D EE than patients with BMI <25 kg/m (P<0.0001). Percentages of PPI-treated patients who achieved heartburn resolution or EE healing within a given LA grade were similar across BMI categories. Heartburn resolution was significantly associated with treatment (esomeprazole vs. placebo), increasing age, and for men versus women (all P<=0.0284). EE healing was significantly associated with PPI treatment (esomeprazole and lansoprazole vs. omeprazole), increasing age, race, presence of a hiatal hernia, and lower LA grade at baseline (all P<=0.0183). CONCLUSIONS: In patients with GERD, high BMI was associated with more severe EE at baseline. However, during PPI treatment, BMI is not a significant independent predictor of heartburn resolution or EE healing. PMID- 23442838 TI - Hepatitis B virus reactivation after chemotherapy in an HIV-positive patient. PMID- 23442837 TI - Stepwise combination of simple noninvasive fibrosis scoring systems increases diagnostic accuracy in nonalcoholic fatty liver disease. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease ranging from simple fatty liver to steatohepatitis, fibrosis, and cirrhosis. We aimed to analyze the diagnostic performance and clinical utility of simple noninvasive tests alone or in combination for the detection of advanced fibrosis in patients with NAFLD. DESIGN AND SUBJECTS: Data from 323 patients with biopsy-proven NAFLD/NASH who presented to the Clinic for Gastroenterology and Hepatology, University Hospital of Cologne between July 1998 and November 2009, were analyzed retrospectively. Sensitivity, specificity, positive predictive values, and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas for NAFLD, FIB-4, and BARD fibrosis scores. RESULTS: The area under receiver operating characteristic curves were as follows: NAFLD fibrosis score 0.96 [95% confidence interval (CI), 0.92-0.99], FIB-4 0.95 (95% CI, 0.91-1.00), BARD 0.82 (95% CI, 0.71-0.92) with negative predictive values for advanced fibrosis of 96%, 98%, and 96%, respectively. When applying the NAFLD, FIB-4, or BARD scoring systems 25%, 15%, or 26% of cases with advanced fibrosis would have been missed. Combining FIB-4 and BARD in a stepwise fashion, patients would have been correctly classified without biopsy in 67% of cases without missing a single case of advanced fibrosis. CONCLUSIONS: The FIB-4 and NAFLD fibrosis scores perform better than the BARD scoring system. Liver biopsy can securely be replaced only with a stepwise combination of simple noninvasive tests, otherwise the assessment of risk due to advanced fibrosis may be misleading in a clinically meaningful proportion of patients. PMID- 23442839 TI - Increased risk of IgA nephropathy among individuals with celiac disease. AB - GOAL: To determine the risk of future biopsy-verified IgA nephropathy (IgAN) among individuals with biopsy-verified celiac disease (CD). BACKGROUND: Individuals with CD suffer increased risk of end-stage renal disease. An association between CD and IgAN has been suggested; however, results have been inconclusive and no previous study has considered the risk of IgAN in biopsy verified CD. STUDY: We performed a population-based prospective cohort study. We identified 27,160 individuals with CD (Marsh stage III) and no previous renal disease through small-intestinal biopsy reports obtained between July 1969 and February 2008 in all (n=28) Swedish pathology departments. Individuals with IgAN were identified by biopsy reports acquired at the 4 Swedish pathology departments specialized in renal pathology. Cox regression analysis was used to determine the risk of future IgAN among individuals with CD compared with 133,949 age-matched and sex-matched reference individuals. RESULTS: Seven (0.026%) individuals with CD and 11 (0.008%) reference individuals developed IgAN. We found an increased risk of biopsy-verified IgAN among individuals with CD [hazard ratio, 3.03; 95% confidence interval, 1.22-7.56]. The risk increase remained statistically significant after adjustment for prior liver disease and country of birth. CONCLUSIONS: Individuals with CD suffer a 3-fold increased risk of future IgAN. Our findings warrant awareness of renal function in individuals with CD. PMID- 23442840 TI - Surveillance for hepatocellular carcinoma in a Medicaid cirrhotic population. AB - GOALS: To estimate the hepatocellular carcinoma surveillance in the Medicaid cirrhotic population. BACKGROUND: Most studies predate 2005 American Association for the Study of Liver Diseases surveillance recommendations and do not examine the primary target population, cirrhotics. STUDY: From 2006 to 2007, we identified adults with at least 1 cirrhosis International Classification of Disease code and 15 months of continuous enrollment in North Carolina Medicaid, recording claims for abdominal ultrasound, computed tomography, magnetic resonance imaging, and alpha-fetoprotein testing. We used multivariable logistic regression to identify factors independently associated with imaging. RESULTS: A total of 5061 subjects were identified: mean age 54 years, 54% male patients, 35% African American, 56% white. Cirrhosis risk factors were alcohol (59%), hepatitis C (30%), hepatitis B (4%), others (18%), and unknown (24%). Only 26% underwent at least 1 imaging test. Just 12% of those not hospitalized or seen in an emergency department underwent any imaging test. Care in an academic facility, younger age, female sex, viral hepatitis, and Medicare coinsurance were positively associated with imaging. Twenty-one percent saw a gastroenterologist, which increased the odds of undergoing imaging (odds ratio, 2.81; 95% confidence interval, 2.32 3.41), whereas primary care visits did not (odds ratio, 0.94; 95% confidence interval, 0.76-1.16). CONCLUSIONS: Only a quarter of North Carolina Medicaid cirrhotics underwent abdominal imaging over a 15-month period, and many tests may have been conducted without surveillance intent. Gastroenterology visits nearly tripled the odds of imaging, but primary-care visits had no effect. Efforts to improve surveillance rates in cirrhotic patients should target primary care and increased access to subspecialty care. PMID- 23442841 TI - Carbohydrate intake as a risk factor for biliary sludge and stones during pregnancy. AB - BACKGROUND: High carbohydrate intake has been linked to insulin resistance, obesity, and abnormal serum lipid profiles-conditions which favor gallstone formation. GOALS: The aim of this study was to evaluate the effect of dietary carbohydrate intake on incident gallbladder disease, defined as biliary sludge and stones, during pregnancy. STUDY: We prospectively studied 3070 pregnant women who underwent serial gallbladder ultrasound during pregnancy and at 4 to 6 weeks postpartum. All women had at least 2 study ultrasounds for comparison. A semiquantitative food frequency questionnaire was completed by subjects in the early third trimester. Multivariate logistic regression was performed to assess the risk of incident gallbladder disease across quartiles total and individual carbohydrate and individual carbohydrates (starch, sucrose, galactose, fructose, and lactose) intake. RESULTS: The cumulative incidence of gallbladder disease was 10.2% by 4 to 6 weeks postpartum. The risk of incident gallbladder disease during pregnancy was significantly higher among women in the highest quartile of total carbohydrate intake versus those in the lowest quartile (odds ratio 2.09, 95% confidence interval 1.02-4.27). High intake of fructose was associated with increased risk even after additional adjustment for total carbohydrate intake (odds ratio 2.18, 95% confidence interval 1.23-3.86, comparing highest with lowest quartile). No association was found between the intake of starch, sucrose, lactose, or galactose and the risk of incident gallbladder disease. CONCLUSIONS: High consumption of total carbohydrate and fructose may increase the risk of developing gallbladder disease during pregnancy. Dietary modification during pregnancy might reduce gallstone incidence during this time period. PMID- 23442842 TI - Eradication therapy in Helicobacter pylori-negative, gastric low-grade mucosa associated lymphoid tissue lymphoma patients: a systematic review. AB - AIM: To assess the remission rate of gastric low-grade B-cell mucosa-associated lymphoid tissue lymphoma after an eradication therapy in Helicobacter pylori negative patients. METHODS: We performed a systematic review with pooled analysis of published studies. Data were analyzed according to: (1) number of H. pylori negative patients treated with only eradication therapy; (2) number of patients in whom the complete lymphoma remission was achieved; and (3) the method used to exclude H. pylori infection. RESULTS: Overall, 11 studies with 110 patients met the inclusion criteria for this pooled analysis. H. pylori infection was excluded in all studies with at least 3 different diagnostic tests. Eradication therapy achieved a complete lymphoma regression in 17 (15.5%; 95% confidence interval, 8.7-22.2) patients. CONCLUSIONS: Eradication therapy is successful in a small but distinct subgroup of H. pylori-negative patients with low-grade mucosa-associated lymphoid tissue lymphoma. On the basis of the generally indolent behavior of this neoplasia, before resorting to aggressive, costly, and potentially more toxic oncologic therapies, it would seem reasonable to attempt eradication therapy in all patients, irrespective of their H. pylori status. PMID- 23442843 TI - Role of interleukin 28B-related gene polymorphisms in chronic hepatitis C and the response to antiviral therapy in Koreans. AB - BACKGROUND: Genetic variations in interleukin 28B (IL28B) have been strongly associated with a sustained virological response (SVR) in European and African American patients. Genetic variation of IL28B was investigated in healthy controls and chronic hepatitis C (CHC) patients, and the treatment response in the CHC patients was analyzed according to IL28B polymorphism in the Korean population. METHODS: IL28B polymorphisms (rs12979860 and rs8099917) were studied in 200 healthy controls and in 167 CHC patients who were treated with peginterferon-alpha and ribavirin. RESULTS: The prevalence of rs12979860 in healthy controls is as follows: the CC-genotype was 88.5%, the CT-genotype was 11.5%, and the TT-genotype was not found. The prevalence of rs8099917 in healthy controls is as follows: the TT-genotype was 89.5%, the TG-genotype was 10.5%, and the GG-genotype was not found. The CC-genotype of rs12979860 and the TT-genotype of rs8099917 were found to be closely related (linkage disequilibrium; D'=1.0, chi =0.9082). In 106 CHC patients treated with peginterferon and ribavirin, the SVR was 67.2% (n=58) for 1b, 91.6% (n=47) for 2a. In hepatitis C virus (HCV) genotype 1b with respect to rs12979860, the SVR in CC-genotype was 72.9% and that in CT-genotype was 40.0%. On investigating predictive factors for SVR, pretreatment low-HCV RNA levels, HCV genotype non-1, early virological response, and also the IL28B CC-genotype for rs12979860 were good indicators of an SVR. CONCLUSIONS: In Korea, genetic variation of IL28B is different from that in western countries in view of high prevalence of rs12979860 CC-genotype. It seems likely that a high SVR in Korean patients with genotype 1 CHC patients is due to the genetic polymorphism in IL28B. PMID- 23442844 TI - In response to Yamamoto. PMID- 23442845 TI - Depressive-like behaviour induced by an intracerebroventricular injection of streptozotocin in mice: the protective effect of fluoxetine, antitumour necrosis factor-alpha and thalidomide therapies. AB - Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-alpha (anti-TNF-alpha) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-alpha levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-alpha antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-alpha antibody and thalidomide were effective in preventing depressive-like behaviour and the increase in TNF-alpha levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-alpha in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression. PMID- 23442846 TI - Validation of normalized pulse volume in the outer ear as a simple measure of sympathetic activity using warm and cold pressor tests: towards applications in ambulatory monitoring. AB - Normalized pulse volume (NPV) derived from the ear has the potential to be a practical index for monitoring daily life stress. However, ear NPV has not yet been validated. Therefore, we compared NPV derived from an index finger using transmission photoplethysmography as a reference, with NPV derived from a middle finger and four sites of the ear using reflection photoplethysmography during baseline and while performing cold and warm water immersion in ten young and six middle-aged subjects. The results showed that logarithmically-transformed NPV (lnNPV) during cold water immersion as compared with baseline values was significantly lower, only at the index finger, the middle finger and the bottom of the ear-canal. Furthermore, lnNPV reactivities (DeltalnNPV; the difference between baseline and test values) from an index finger were significantly related to DeltalnNPV from the middle finger and the bottom of the ear-canal (young: r = 0.90 and 0.62, middle-aged: r = 0.80 and 0.58, respectively). In conclusion, these findings show that reflection and transmission photoplethysmography are comparable methods to derive NPV in accordance with our theoretical prediction. NPV derived from the bottom of the ear-canal is a valid approach, which could be useful for evaluating daily life stress. PMID- 23442847 TI - Dimensional control of cancer cell migration. PMID- 23442849 TI - Will the rod bend or break? Analyzing the structural resilience of cellular organelles. PMID- 23442848 TI - What determines the kinetics of the slow afterhyperpolarization (sAHP) in neurons? PMID- 23442850 TI - Benjamin Franklin, Philadelphia's favorite son, was a membrane biophysicist. AB - Benjamin Franklin, mostly known for his participation in writing The Declaration of Independence and work on electricity, was also one of the first scientists to seek to understand the properties of oil monolayers on water surfaces. During one of his many voyages across the Atlantic Ocean, Franklin observed that oil had a calming effect on waves when poured into rough ocean waters. Though at first taking a backseat to many of his other scientific and political endeavors, Franklin went on to experiment with oil, spreading monomolecular films on various bodies of water, and ultimately devised a concept of particle repulsion that is indirectly related to the hydrophobic effect. His early observations inspired others to measure the dimensions of oil monolayers, which eventually led to the formulation of the contemporary lipid bilayer model of the cell membrane. PMID- 23442851 TI - Effect of extracellular pH on selectin adhesion: theory and experiment. AB - Selectins mediate circulatory leukocyte trafficking to sites of inflammation and trauma, and the extracellular microenvironments at these sites often become acidic. In this study, we investigated the influence of slightly acidic pH on the binding dynamics of selectins (P-, L-, and E-selectin) to P-selectin glycoprotein ligand-1 (PSGL-1) via computational modeling (molecular dynamics) and experimental rolling assays under shear in vitro. The P-selectin/PSGL-1 binding is strengthened at acidic pH, as evidenced by the formation of a new hydrogen bond (seen computationally) and the observed decrease in the rolling velocities of model cells. In the case of L-selectin/PSGL-1 binding dynamics, the binding strength and frequency increase at acidic pH, as indicated by the greater cell rolling flux of neutrophils and slower rolling velocities of L-selectin-coated microspheres, respectively. The cell flux is most likely due to an increased population of L-selectin in the high-affinity conformation as pH decreases, whereas the velocities are due to increased L-selectin/PSGL-1 contacts. In contrast to P- and L-selectin, the E-selectin/PSGL-1 binding does not exhibit significant changes at acidic pH levels, as shown both experimentally and computationally. PMID- 23442852 TI - Modeling the flexural rigidity of rod photoreceptors. AB - In vertebrate eyes, the rod photoreceptor has a modified cilium with an extended cylindrical structure specialized for phototransduction called the outer segment (OS). The OS has numerous stacked membrane disks and can bend or break when subjected to mechanical forces. The OS exhibits axial structural variation, with extended bands composed of a few hundred membrane disks whose thickness is diurnally modulated. Using high-resolution confocal microscopy, we have observed OS flexing and disruption in live transgenic Xenopus rods. Based on the experimental observations, we introduce a coarse-grained model of OS mechanical rigidity using elasticity theory, representing the axial OS banding explicitly via a spring-bead model. We calculate a bending stiffness of ~10(5) nN?MUm2, which is seven orders-of-magnitude larger than that of typical cilia and flagella. This bending stiffness has a quadratic relation to OS radius, so that thinner OS have lower fragility. Furthermore, we find that increasing the spatial frequency of axial OS banding decreases OS rigidity, reducing its fragility. Moreover, the model predicts a tendency for OS to break in bands with higher spring number density, analogous to the experimental observation that transgenic rods tended to break preferentially in bands of high fluorescence. We discuss how pathological alterations of disk membrane properties by mutant proteins may lead to increased OS rigidity and thus increased breakage, ultimately contributing to retinal degeneration. PMID- 23442853 TI - Guidance of cell migration by substrate dimension. AB - There is increasing evidence to suggest that physical parameters, including substrate rigidity, topography, and cell geometry, play an important role in cell migration. As there are significant differences in cell behavior when cultured in 1D, 2D, or 3D environments, we hypothesize that migrating cells are also able to sense the dimension of the environment as a guidance cue. NIH 3T3 fibroblasts were cultured on micropatterned substrates where the path of migration alternates between 1D lines and 2D rectangles. We found that 3T3 cells had a clear preference to stay on 2D rather than 1D substrates. Cells on 2D surfaces generated stronger traction stress than did those on 1D surfaces, but inhibition of myosin II caused cells to lose their sensitivity to substrate dimension, suggesting that myosin-II-dependent traction forces are the determining factor for dimension sensing. Furthermore, oncogene-transformed fibroblasts are defective in mechanosensing while generating similar traction forces on 1D and 2D surfaces. Dimension sensing may be involved in guiding cell migration for both physiological functions and tissue engineering, and for maintaining normal cells in their home tissue. PMID- 23442854 TI - T lymphocytes orient against the direction of fluid flow during LFA-1-mediated migration. AB - As they leave the blood stream and travel to lymph nodes or sites of inflammation, T lymphocytes are captured by the endothelium and migrate along the vascular wall to permissive sites of transmigration. These processes take place under the influence of hemodynamic shear stress; therefore, we investigated how migrational speed and directionality are influenced by variations in shear stress. We examined human effector T lymphocytes on intercellular adhesion molecule 1 (ICAM-1)-coated surfaces under the influence of shear stresses from 2 to 60 dyn.cm(-2). T lymphocytes were shown to respond to shear stress application by a rapid (30 s) and fully reversible orientation of their migration against the fluid flow without a change in migration speed. Primary T lymphocytes migrating on ICAM-1 in the presence of uniformly applied SDF-1alpha were also found to migrate against the direction of shear flow. In sharp contrast, neutrophils migrating in the presence of uniformly applied fMLP and leukemic HSB2 T lymphocytes migrating on ICAM-1 alone oriented their migration downstream, with the direction of fluid flow. Our findings suggest that, in addition to biochemical cues, shear stress is a contributing factor to leukocyte migration directionality. PMID- 23442855 TI - Integrating mitochondrial energetics, redox and ROS metabolic networks: a two compartment model. AB - To understand the mechanisms involved in the control and regulation of mitochondrial reactive oxygen species (ROS) levels, a two-compartment computational mitochondrial energetic-redox (ME-R) model accounting for energetic, redox, and ROS metabolisms is presented. The ME-R model incorporates four main redox couples (NADH/NAD(+), NADPH/NADP(+), GSH/GSSG, Trx(SH)(2)/TrxSS). Scavenging systems-glutathione, thioredoxin, superoxide dismutase, catalase-are distributed in mitochondrial matrix and extra-matrix compartments, and transport between compartments of ROS species (superoxide: O(2)(?-), hydrogen peroxide: H(2)O(2)), and GSH is also taken into account. Model simulations are compared with experimental data obtained from isolated heart mitochondria. The ME-R model is able to simulate: i), the shape and order of magnitude of H(2)O(2) emission and dose-response kinetics observed after treatment with inhibitors of the GSH or Trx scavenging systems and ii), steady and transient behavior of DeltaPsi(m) and NADH after single or repetitive pulses of substrate- or uncoupler-elicited energetic-redox transitions. The dynamics of the redox environment in both compartments is analyzed with the model following substrate addition. The ME-R model represents a useful computational tool for exploring ROS dynamics, the role of compartmentation in the modulation of the redox environment, and how redox regulation participates in the control of mitochondrial function. PMID- 23442856 TI - Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels. AB - Previously identified potent and/or use-dependent mexiletine (Mex) analogs were used as template for the rational design of new Na(v)-channel blockers. The effects of the novel analogs were tested on sodium currents of native myofibers. Data and molecular modeling show that increasing basicity and optimal alkyl chain length enhance use-dependent block. This was demonstrated by replacing the amino group with a more basic guanidine one while maintaining a proper distance between positive charge and aromatic ring (Me13) or with homologs having the chirality center nearby the amino group or the aromatic ring. Accordingly, a phenyl group on the asymmetric center in the homologated alkyl chain (Me12), leads to a further increase of use-dependent behavior versus the phenyl Mex derivative Me4. A fluorine atom in paraposition and one ortho-methyl group on the xylyloxy ring (Me15) increase potency and stereoselectivity versus Me4. Charge delocalization and greater flexibility of Me15 may increase its affinity for Tyr residues influencing steric drug interaction with the primary Phe residue of the binding site. Me12 and Me15 show limited selectivity against Na(v)-isoforms, possibly due to the highly conserved binding site on Na(v). To our knowledge, the new compounds are the most potent Mex-like Na(v) blockers obtained to date and deserve further investigation. PMID- 23442857 TI - Nicotinic receptor transduction zone: invariant arginine couples to multiple electron-rich residues. AB - Gating of the muscle-type acetylcholine receptor (AChR) channel depends on communication between the ACh-binding site and the remote ion channel. A key region for this communication is located within the structural transition zone between the ligand-binding and pore domains. Here, stemming from beta-strand 10 of the binding domain, the invariant alphaArg209 lodges within the hydrophobic interior of the subunit and is essential for rapid and efficient channel gating. Previous charge-reversal experiments showed that the contribution of alphaArg209 to channel gating depends strongly on alphaGlu45, also within this region. Here we determine whether the contribution of alphaArg209 to channel gating depends on additional anionic or electron-rich residues in this region. Also, to reconcile diverging findings in the literature, we compare the dependence of alphaArg209 on alphaGlu45 in AChRs from different species, and compare the full agonist ACh with the weak agonist choline. Our findings reveal that the contribution of alphaArg209 to channel gating depends on additional nearby electron-rich residues, consistent with both electrostatic and steric contributions. Furthermore, alphaArg209 and alphaGlu45 show a strong interdependence in both human and mouse AChRs, whereas the functional consequences of the mutation alphaE45R depend on the agonist. The emerging picture shows a multifaceted network of interdependent residues that are required for communication between the ligand-binding and pore domains. PMID- 23442858 TI - Collective diffusion model for ion conduction through microscopic channels. AB - Ion conduction through microscopic channels is of central importance in both biology and nanotechnology. To better understand the current-voltage (I-V) dependence of ion channels, here we describe and prove a collective diffusion model that quantitatively relates the spontaneous ion permeation at equilibrium to the stationary ionic fluxes driven by small voltages. The model makes it possible to determine the channel conductance in the linear I-V range from equilibrium simulations without the application of a voltage. To validate the theory, we perform molecular-dynamics simulations on two channels-a conical shaped nanopore and the transmembrane pore of an alpha-hemolysin-under both equilibrium and nonequilibrium conditions. The simulations reveal substantial couplings between the motions of cations and anions, which are effectively captured by the collective coordinate in the model. Although the two channels exhibit very different linear ranges in the I-V curves, in both cases the channel conductance at small voltages is in reasonable agreement with the prediction from the equilibrium simulation. The simulations also suggest that channel charges, rather than geometric asymmetry, play a more prominent role in current rectification. PMID- 23442859 TI - Large deformation of helix F during the photoreaction cycle of Pharaonis halorhodopsin in complex with azide. AB - Halorhodopsin from Natronomonas pharaonis (pHR), a retinylidene protein that functions as a light-driven chloride ion pump, is converted into a proton pump in the presence of azide ion. To clarify this conversion, we investigated light induced structural changes in pHR using a C2 crystal that was prepared in the presence of Cl(-) and subsequently soaked in a solution containing azide ion. When the pHR-azide complex was illuminated at pH 9, a profound outward movement (~4 A) of the cytoplasmic half of helix F was observed in a subunit with the EF loop facing an open space. This movement created a long water channel between the retinal Schiff base and the cytoplasmic surface, along which a proton could be transported. Meanwhile, the middle moiety of helix C moved inward, leading to shrinkage of the primary anion-binding site (site I), and the azide molecule in site I was expelled out to the extracellular medium. The results suggest that the cytoplasmic half of helix F and the middle moiety of helix C act as different types of valves for active proton transport. PMID- 23442860 TI - Temperature dependence of IP3-mediated local and global Ca2+ signals. AB - We examined the effect of temperature (12-40 degrees C) on local and global Ca2+ signals mediated by inositol trisphosphate receptor/channels (IP3R) in human neuroblastoma (SH-SY5Y) cells. The amplitudes and spatial spread of local signals arising from single IP3R (blips) and clusters of IP3R (puffs) showed little temperature dependence, whereas their kinetics (durations and latencies) were markedly accelerated by increasing temperature. In contrast, the amplitude of global Ca2+ waves increased appreciably at lower temperatures, probably as a result of the longer duration of IP(3)R channel opening. Several parameters, including puff and blip durations, puff latency and frequency, and frequency of repetitive Ca2+ waves, showed a biphasic temperature dependence on Arrhenius plots. In all cases the transition temperature occurred at ~25 degrees C, possibly reflecting a phase transition in the lipids of the endoplasmic reticulum membrane. Although the IP3-evoked Ca2+ signals were qualitatively similar at 25 degrees C and 36 degrees C, one should consider the temperature sensitivity of IP3-mediated signal amplitudes when extrapolating from room temperature to physiological temperature. Conversely, further cooling may be advantageous to improve the optical resolution of channel gating kinetics. PMID- 23442861 TI - Autoinhibition of endophilin in solution via interdomain interactions. AB - Endophilin is a key protein involved in clathrin-mediated endocytosis. Previous computational and experimental work suggested that the N-terminal helix is embedded into the membrane to induce curvature; however, the role of the SH3 domain remains controversial. To address this issue, we performed computer simulations of the endophilin dimer in solution to understand the interaction between the N-BAR and SH3 domains and its effect on biological function. We predict that the helix binds to the SH3 domain through hydrophobic and salt bridge interactions. This protects the hydrophobic residues on both domains and keeps the SH3 domain near the end of the N-BAR domain, in agreement with previous experimental results. The complex has a binding strength similar to a few hydrogen bonds (13.0 +/- 0.6 kcal/mol), and the SH3 domain stabilizes the structure of the N-terminal helix in solution. Electrostatic calculations show a large region of strongly positive electrostatic potential near the N-terminal that can orient the helix toward the membrane and likely embed the helix into the membrane surface. This predicted mechanism suggests that endophilin can select for both curvature and electrostatic potential when interacting with membranes, highlighting the importance of the SH3 domain in regulating the function of endophilin. PMID- 23442862 TI - Understanding the role of amphipathic helices in N-BAR domain driven membrane remodeling. AB - Endophilin N-BAR (N-terminal helix and Bin/amphiphysin/Rvs) domain tubulates and vesiculates lipid membranes in vitro via its crescent-shaped dimer and four amphipathic helices that penetrate into membranes as wedges. Like F-BAR domains, endophilin N-BAR also forms a scaffold on membrane tubes. Unlike F-BARs, endophilin N-BARs have N-terminal H0 amphipathic helices that are proposed to interact with other N-BARs in oligomer lattices. Recent cryo-electron microscopy reconstructions shed light on the organization of the N-BAR lattice coats on a nanometer scale. However, because of the resolution of the reconstructions, the precise positioning of the amphipathic helices is still ambiguous. In this work, we applied a coarse-grained model to study various membrane remodeling scenarios induced by endophilin N-BARs. We found that H0 helices of N-BARs prefer to align in an antiparallel manner at two ends of the protein to form a stable lattice. The deletion of H0 helices causes disruption of the lattice. In addition, we analyzed the persistence lengths of the protein-coated tubes and found that the stiffness of endophilin N-BAR-coated tubules qualitatively agrees with previous experimental work studying N-BAR-coated tubules. Large-scale simulations on membrane liposomes revealed a systematic relation between H0 helix density and local membrane curvature fluctuations. The data also suggest that the H0 helix is required for BARs to form organized structures on the liposome, further illustrating its important function. PMID- 23442863 TI - Free energy of translocating an arginine-rich cell-penetrating peptide across a lipid bilayer suggests pore formation. AB - The molecular mechanism and energetics of the translocation of arginine-rich, cell-penetrating peptides through membranes are still under debate. One possible mechanism involves the formation of a water pore in the membrane such that the hydrophilic residues of the peptide are solvated throughout the translocating process. In this work, employing two different order parameters, we calculate the free energies of translocating a cyclic Arg(9) peptide into a lipid bilayer along one path that involves a water-pore formation and another path that does not form a separate pore. The free-energy barrier of translocating the peptide along a pore path is 80 kJ/mol lower than along a pore-free path. This suggests that the peptide translocation is more likely associated with a water-pore formation. PMID- 23442864 TI - Mechanistic differences in the membrane activity of Bax and Bcl-xL correlate with their opposing roles in apoptosis. AB - Based on their membrane-permeabilizing activity in vitro, it has been proposed that Bax-like proteins induce cytochrome c release during apoptosis via pore formation. However, antiapoptotic Bcl-2 proteins, which inhibit cytochrome c release, also display pore activity in model membranes. As a consequence, a unified description that aligns the pore activity of the Bcl-2 proteins with their apoptotic function is missing. Here, we studied the mechanism of membrane binding, oligomerization, and permeabilization by pro- and antiapoptotic Bcl-2 members at the single-vesicle level. We found that proapoptotic Bax forms large, stable pores via an all-or-none mechanism that can release cytochrome c. In contrast, antiapoptotic Bcl-xL induces transient permeability alterations in pure lipid membranes that have no consequences for the mitochondrial outer membrane but inhibit Bax membrane insertion. These differences in pore activity correlate with a distinct oligomeric state of Bax and Bcl-xL in membranes and can be reproduced in isolated mitochondria. Based on our findings, we propose new models for the mechanisms of action of Bax and Bcl-xL that relate their membrane activity to their opposing roles in apoptosis and beyond. PMID- 23442865 TI - A chimeric kinesin-1 head/kinesin-5 tail motor switches between diffusive and processive motility. AB - Homotetrameric kinesin-5 motors are essential for chromosome separation and assembly of the mitotic spindle. These kinesins bind between two microtubules (MTs) and slide them apart, toward the spindle poles. This process must be tightly regulated in mitosis. In in vitro assays, Eg5 moves diffusively on single MTs and switches to a directed mode between MTs. How allosteric communication between opposing motor domains works remains unclear, but kinesin-5 tail domains may be involved. Here we present a single-molecule fluorescence study of a tetrameric kinesin-1 head/kinesin-5 tail chimera, DK4mer. This motor exhibited fast processive motility on single MTs interrupted by pauses. Like Eg5, DK4mer diffused along MTs with ADP, and slid antiparallel MTs apart with ATP. In contrast to Eg5, diffusive and processive periods were clearly distinguishable. This allowed us to measure transition rates among states and for unbinding as a function of buffer ionic strength. These data, together with results from controls using tail-less dimers, indicate that there are two modes of interaction with MTs, separated by an energy barrier. This result suggests a scheme of motor regulation that involves switching between two bound states, possibly allosterically controlled by the opposing tetramer end. Such a scheme is likely to be relevant for the regulation of native kinesin-5 motors. PMID- 23442866 TI - Phosphorylation modulates the mechanical stability of the cardiac myosin-binding protein C motif. AB - Cardiac myosin-binding protein C (cMyBP-C) is a thick-filament-associated protein that modulates cardiac contractility through interactions of its N-terminal immunoglobulin (Ig)-like C0-C2 domains with actin and/or myosin. These interactions are modified by the phosphorylation of at least four serines located within the motif linker between domains C1 and C2. We investigated whether motif phosphorylation alters its mechanical properties by characterizing force extension relations using atomic force spectroscopy of expressed mouse N-terminal cMyBP-C fragments (i.e., C0-C3). Protein kinase A phosphorylation or serine replacement with aspartic acids did not affect persistence length (0.43 +/- 0.04 nm), individual Ig-like domain unfolding forces (118 +/- 3 pN), or Ig extension due to unfolding (30 +/- 0.38 nm). However, phosphorylation did significantly decrease the C0-C3 mean contour length by 24 +/- 2 nm. These results suggest that upon phosphorylation, the motif, which is freely extensible in the nonphosphorylated state, adopts a more stable and/or different structure. Circular dichroism and dynamic light scattering data for shorter expressed C1-C2 fragments with all four serines replaced by aspartic acids confirmed that the motif did adopt a more stable structure that was not apparent in the nonphosphorylated motif. These biophysical data provide both a mechanical and structural basis for cMyBP-C regulation by motif phosphorylation. PMID- 23442867 TI - Absolute hydration free energies of blocked amino acids: implications for protein solvation and stability. AB - Most proteins perform their function in aqueous solution. The interactions with water determine the stability of proteins and the desolvation costs of ligand binding or membrane insertion. However, because of experimental restrictions, absolute solvation free energies of proteins or amino acids are not available. Instead, solvation free energies are estimated based on side chain analog data. This approach implies that the contributions to free energy differences are additive, and it has often been employed for estimating folding or binding free energies. However, it is not clear how much the additivity assumption affects the reliability of the resulting data. Here, we use molecular dynamics-based free energy simulations to calculate absolute hydration free energies for 15 N-acetyl methylamide amino acids with neutral side chains. By comparing our results with solvation free energies for side chain analogs, we demonstrate that estimates of solvation free energies of full amino acids based on group-additive methods are systematically too negative and completely overestimate the hydrophobicity of glycine. The largest deviation of additive protocols using side chain analog data was 6.7 kcal/mol; on average, the deviation was 4 kcal/mol. We briefly discuss a simple way to alleviate the errors incurred by using side chain analog data and point out the implications of our findings for the field of biophysics and implicit solvent models. To support our results and conclusions, we calculate relative protein stabilities for selected point mutations, yielding a root-mean square deviation from experimental results of 0.8 kcal/mol. PMID- 23442868 TI - Stretching and bending fluctuations of short DNA molecules. AB - Recent measurements of the distribution of end-to-end distance in short DNA molecules infer cooperative stretching fluctuations. The assumptions underlying the analysis can be questioned if transient, thermally induced defects producing a localized decrease in bending stiffness are present in thermal equilibrium, such as regions in which DNA melts locally (bubbles), sustains large-angle bends (kinks), or can locally transform into an alternative (S-DNA) state. We study a generalized discrete worm-like chain model for DNA, capable of describing these experiments, showing that the model yields accurate fits to available experimental data. Our results indicate that DNA bending arising from such localized defects, rather than solely stretching, can be an equal contributor to end-to-end distance fluctuations for 35-bp DNA and contributes nontrivially to such fluctuations at all scales below the persistence length. The analysis suggests that such fluctuations should exhibit a scale-dependent cooperativity, specifically relevant in determining the behavior of short chains, but which saturates rapidly to a length-independent value for longer DNA, to ensure a consistent physical description of DNA across multiple scales. Our approach provides a minimal, yet accurate, coarse-grained description of DNA at the subpersistence length scales of current experimental interest. PMID- 23442869 TI - Structural insight into proteorhodopsin oligomers. AB - Oligomerization has important functional implications for many membrane proteins. However, obtaining structural insight into oligomeric assemblies is challenging, as they are large and resist crystallization. We focus on proteorhodopsin (PR), a protein with seven transmembrane alpha-helices that was found to assemble to hexamers in densely packed lipid membrane, or detergent-solubilized environments. Yet, the structural organization and the subunit interface of these PR oligomers were unknown. We used site-directed spin-labeling together with electron spin resonance lineshape and Overhauser dynamic nuclear polarization analysis to construct a model for the specific orientation of PR subunits within the hexameric complex. We found intersubunit distances to average 16 A between neighboring 55 residues and that residues 177 are >20 A apart from each other. These distance constraints show that PR has a defined and radial orientation within a hexamer, with the 55-site of the A-B loop facing the hexamer core and the 177-site of the E-F loop facing the hexamer exterior. Dynamic nuclear polarization measurements of the local solvent dynamics complement the electron spin-resonance-based distance analysis, by resolving whether protein surfaces at positions 55, 58, and 177 are exposed to solvent, or covered by protein-protein or protein-detergent contacts. PMID- 23442870 TI - Free energy cost of stretching mRNA hairpin loops inhibits small RNA binding. AB - Small RNA-mRNA binding is an essential step in RNA interference, an important cellular regulatory process. Calculations of binding free energy have been used in binding site prediction, but the cost of stretching the mRNA loop when the small RNA-mRNA duplex forms requires further exploration. Here, using both polymer physics theory and simulations, we estimate the free energy of a stretched mRNA loop. We find loop stretching significantly increases the free energy of 3' supplementary/compensatory miRNA binding and siRNA binding to mRNA hairpin loops. We also make the observation that sites where 3' supplementary binding is available may bind at the seed only, and that loop stretching often favors seed-only binding over seed plus 3' supplementary binding in mRNA hairpins. PMID- 23442871 TI - Inherent relationships among different biophysical prediction methods for intrinsically disordered proteins. AB - Intrinsically disordered proteins do not have stable secondary and/or tertiary structures but still function. More than 50 prediction methods have been developed and inherent relationships may be expected to exist among them. To investigate this, we conducted molecular simulations and algorithmic analyses on a minimal coarse-grained polypeptide model and discovered a common basis for the charge-hydropathy plot and packing-density algorithms that was verified by correlation analysis. The correlation analysis approach was applied to realistic datasets, which revealed correlations among some physical-chemical properties (charge-hydropathy plot, packing density, pairwise energy). The correlations indicated that these biophysical methods find a projected direction to discriminate ordered and disordered proteins. The optimized projection was determined and the ultimate accuracy limit of the existing algorithms is discussed. PMID- 23442872 TI - Mitochondrial colocalization with Ca2+ release sites is crucial to cardiac metabolism. AB - In cardiomyocyte subcellular structures, colocalization of mitochondria with Ca2+ release sites is implicated in regulation of cardiac energetics by facilitating Ca2+ influx into mitochondria to modulate the tricarboxylic acid (TCA) cycle. However, current experimental techniques limit detailed examination of this regulatory mechanism. Earlier, we developed a three-dimensional (3D) finite element cardiomyocyte model featuring a subcellular structure that integrates excitation-contraction coupling and energy metabolism. Here, using this model, we examined the influence of distance between mitochondria and Ca2+ release sites by comparing a normal (50-nm) distance model and a large (200-nm) distance model (LD). The influence of distance was minimal under a low pacing rate (0.25 Hz), but under a higher pacing rate (2 Hz), lower levels of mitochondrial Ca2+ and NADH, elevated phosphate, and suppressed force generation became apparent in the LD model. Such differences became greater when functional impairments (reduced TCA cycle activity, uncoupling effect, and failing excitation-contraction coupling) were additionally imposed. We concluded that juxtaposition of the mitochondria and the Ca2+ release sites is crucial for rapid signal transmission to maintain cardiac-energy balance. The idealized 3D model of cardiac excitation contraction and metabolism is a powerful tool to study cardiac energetics. PMID- 23442873 TI - Physical constraints on biological integral control design for homeostasis and sensory adaptation. AB - Synthetic biology includes an effort to use design-based approaches to create novel controllers, biological systems aimed at regulating the output of other biological processes. The design of such controllers can be guided by results from control theory, including the strategy of integral feedback control, which is central to regulation, sensory adaptation, and long-term robustness. Realization of integral control in a synthetic network is an attractive prospect, but the nature of biochemical networks can make the implementation of even basic control structures challenging. Here we present a study of the general challenges and important constraints that will arise in efforts to engineer biological integral feedback controllers or to analyze existing natural systems. Constraints arise from the need to identify target output values that the combined process plus-controller system can reach, and to ensure that the controller implements a good approximation of integral feedback control. These constraints depend on mild assumptions about the shape of input-output relationships in the biological components, and thus will apply to a variety of biochemical systems. We summarize our results as a set of variable constraints intended to provide guidance for the design or analysis of a working biological integral feedback controller. PMID- 23442875 TI - Screening South Asians for type 2 diabetes and prediabetes: (1) comparing oral glucose tolerance and haemoglobin A1c test results and (2) comparing the two sets of metabolic profiles of individuals diagnosed with these two tests. AB - BACKGROUND: The glycated haemoglobin A1c (HbA1c) level may be used for screening for type 2 diabetes and prediabetes instead of a more burdensome oral glucose tolerance test (OGTT). However, among the high-risk South Asian population, little is known about the overlap of the methods or about the metabolic profiles of those disconcordantly diagnosed. METHODS: We included 944 South Asians (18-60 years old), whom we screened with the HbA1c level and the OGTT in The Hague, the Netherlands. We calculated the area under the receiver-operator characteristic curve (AUROC) with a 95% confidence interval of HbA1c using the American Diabetes Association classifications, and determined the sensitivity and specificity with 95% confidence intervals at different thresholds. Moreover, we studied differences in metabolic characteristics between those identified by HbA1c and by the OGTT alone. RESULTS: The overlap between HbA1c and OGTT classifications was partial, both for diabetes and prediabetes. The AUROC of HbA1c for OGTT defined diabetes was 0.86 (0.79-0.93). The sensitivity was 0.46 (0.29-0.63); the specificity 0.98 (0.98-0.99). For prediabetes, the AUROC was 0.73 (0.69-0.77). Each of the 31 individuals with diabetes and 353 with prediabetes identified with the HbA1c level had a high body mass index, large waist circumference, high blood pressure, and low insulin sensitivity, all of which were similar to the values shown by those among the 19 with diabetes or 62 with prediabetes who only met the OGTT criteria, but not the HbA1c criteria. CONCLUSIONS: The HbA1c level identified a partially different group than the OGTT did. However, both those identified with the HbA1c level and those identified with the OGTT alone were at increased metabolic risk. TRIAL REGISTRATION: Dutch Trial Register: NTR1499. PMID- 23442874 TI - Genome mining for methanobactins. AB - BACKGROUND: Methanobactins (Mbns) are a family of copper-binding natural products involved in copper uptake by methanotrophic bacteria. The few Mbns that have been structurally characterized feature copper coordination by two nitrogen-containing heterocycles next to thioamide groups embedded in a peptidic backbone of varying composition. Mbns are proposed to derive from post-translational modification of ribosomally synthesized peptides, but only a few genes encoding potential precursor peptides have been identified. Moreover, the relevance of neighboring genes in these genomes has been unclear. RESULTS: The potential for Mbn production in a wider range of bacterial species was assessed by mining microbial genomes. Operons encoding Mbn-like precursor peptides, MbnAs, were identified in 16 new species, including both methanotrophs and, surprisingly, non methanotrophs. Along with MbnA, the core of the operon is formed by two putative biosynthetic genes denoted MbnB and MbnC. The species can be divided into five groups on the basis of their MbnA and MbnB sequences and their operon compositions. Additional biosynthetic proteins, including aminotransferases, sulfotransferases and flavin adenine dinucleotide (FAD)-dependent oxidoreductases were also identified in some families. Beyond biosynthetic machinery, a conserved set of transporters was identified, including MATE multidrug exporters and TonB dependent transporters. Additional proteins of interest include a di-heme cytochrome c peroxidase and a partner protein, the roles of which remain a mystery. CONCLUSIONS: This study indicates that Mbn-like compounds may be more widespread than previously thought, but are not present in all methanotrophs. This distribution of species suggests a broader role in metal homeostasis. These data provide a link between precursor peptide sequence and Mbn structure, facilitating predictions of new Mbn structures and supporting a post translational modification biosynthetic pathway. In addition, testable models for Mbn transport and for methanotrophic copper regulation have emerged. Given the unusual modifications observed in Mbns characterized thus far, understanding the roles of the putative biosynthetic proteins is likely to reveal novel pathways and chemistry. PMID- 23442876 TI - Over-expression of human cystatin C in pterygium versus healthy conjunctiva. AB - BACKGROUND: A prospective, non-randomised, transversal and comparative study, carried out in INOVA Vision Institute and Autonomous University of Aguascalientes. Pterygium is an important illness that affects 22% people from tropic and equatorial zones. Is an inflammatory process caused by UV rays, and it has a behavior similar to a neoplasm. For this study was taken into consideration 191 samples from the INOVA Vision Institute, Aguascalientes, Mexico. Include 73 pterygia samples, which were obtained during resection under sterile conditions. 44 normal conjunctiva samples were obtained from the same patients when harvesting the conjunctival autograft, or from other patients undergoing extracapsular cataract extraction from the superior bulbar region. Tears from patients with pterygium (n = 50) and normal volunteers (n = 24) were obtained using a calibrated glass micro capillary tube. The surgical conjunctiva and pterygia samples were subjected to reverse-transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. Tears were analyzed by enzyme-linked immunosorbent assays. METHODS: This was a prospective, non randomised study involving 191 biological samples taken from patients with pterygium and normal volunteers, whom were operated under local anaesthesia by either complete resection of the lesion with primary closure, or resection with conjunctival autograft. Tissue samples were fixed in 10% formaldehyde. Sections were routinely stained with hematoxylin and eosin. HCC expression was evaluated by reverse-transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and by western blotting. All tears samples were analyzed by enzyme-linked immunosorbent assays (ELISA). RESULTS: Expression levels and distribution patterns of HCC in normal conjunctiva and pterygium. Higher levels of HCC mRNAs and proteins were detected in pterygium compared with a normal conjunctiva. Immunohistochemistry revealed that HCC was localized in the apical cells of the epithelium in the normal conjunctiva. In contrast, HCC was detected in all extension of epithelial tissue, from apical to basal cells in pterygia. The concentration of HCC protein in tears was higher in patients with pterygium versus controls. CONCLUSION: HCC may play an important role in protecting normal conjunctiva, and regulating inflammatory conditions of the anterior ocular surface. PMID- 23442878 TI - Palliative care research: lessons learned by our team over the last 25 years. AB - BACKGROUND: In the last 25 years, palliative care has made major progress as an interdisciplinary specialty that addresses quality-of-life issues for patients with life-limiting illnesses and their families. Research by numerous investigators has contributed to our increasing body of knowledge to support an evidence-based practice. AIM: We highlight some lessons learned by our group in the process of conducting palliative care research, focusing in particular on symptom assessment; the management of pain, fatigue, cachexia, dyspnea, delirium, and opioid-induced neurotoxicity; and outcomes of our palliative care program. DESIGN: Narrative review of selected literature, focusing on studies conducted by our group. DATA SOURCES: This article is based on the Second Vittorio Ventafridda Memorial Lecture by Dr Eduardo Bruera, delivered at the European Association for Palliative Care, Trondheim, Norway on 8 June 2012. RESULTS: For each topic, we review some of the pivotal studies in palliative care, discuss the challenges in research design, and outline possible directions for future research. CONCLUSIONS: We conclude by sharing some of what we learned about the processes, pearls, and pitfalls of palliative care research. PMID- 23442879 TI - Tools to measure quality of life and carer burden in informal carers of heart failure patients: a narrative review. AB - BACKGROUND: Heart failure is a complex cardiac syndrome prevalent in an older population. Caring for heart failure patients through the disease trajectory presents physical and emotional challenges for informal carers. Carers have to deal with clinically unstable patients, the responsibility of managing and titrating medication according to symptoms and frequent admissions to acute care. These challenges compound the demands on caregivers' physical and psychosocial well-being. Alongside the negative impact of being a carer, positive aspects have also been demonstrated; carers describe feelings of shared responsibility of caring with professional carers and the reward of supporting a loved one, which creates a new role in their relationship. AIM: This review explores the dimensions that impact caregiver burden and quality of life in carers of patients with heart failure and highlights both the negative and positive aspects of being an informal carer for heart failure patients. DESIGN: This review followed the processes recommended for a narrative review. Studies identified were selected systematically following the PRISMA guidelines. DATA SOURCES: Searches were conducted using the Medical Subject Headings (MeSH) and keywords of the following search engines: MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Applied Social Sciences Index and Abstracts (ASSIA), PsycINFO and Cochrane for literature published until January 2012. RESULTS: Quality assessment of the studies was conducted using quality indicators, and the studies included in this review were categorised as fair or good according to the criteria. Of the 1008 studies initially identified, 16 studies met the inclusion criteria. A thematic synthesis was undertaken, and the following themes were identified Perceived carer control; Mental and emotional well-being; Types and impact of caregiving tasks; Impact of patients' physical condition; Impact of age/gender/demographic factors; Positive aspects of caregiving. CONCLUSIONS: This review highlights evidence that informal carers supporting patients with heart failure face many challenges impacting their physical and mental well-being. The studies described provide an insight into the individual dimensions that make a carer particularly vulnerable, namely, younger carers, female carers and carers with existing physical and emotional health issues. Additionally, there are external influences that increase risk of burden, including New York Heart Association Score status of the patient, if the patient has had recurrent emergency admissions or has recently been discharged home and the level of social support available to the carer. A further finding from conducting this review is that there are still limited measures of the positive aspects of caregiving. PMID- 23442880 TI - Bereaved relatives' perspectives of the patient's oral intake towards the end of life: a qualitative study. AB - BACKGROUND: Patients approaching death often have a decreasing oral intake, which can be distressing for relatives. Little is known about the relatives' experiences with and perceptions of oral intake at the end of life. AIM: This study aims to contribute to a more thorough understanding of relatives' concerns regarding decreased oral intake of the patient at the end of life. DESIGN: Qualitative interview study: semi-structured interviews were transcribed verbatim and analysed using qualitative content analysis. SETTING/PARTICIPANTS: Twenty three bereaved relatives of patients who had been referred to a New Zealand palliative care service were interviewed. RESULTS: All relatives experienced significant changes in patients' oral intake at the end of life. Oral intake towards the end of life was considered important and is perceived as meaningful by relatives in different ways, such as nutritional value, enjoyment, social time, daily routine and a way of caring. Relatives responded differently to decreasing oral intake; some accepted it as inherent to the dying process, others continued efforts to support the patient's oral intake. Some relatives perceived decreasing oral intake as the patient's choice, and some viewed maintaining oral intake as part of the battle against the disease. Relatives recalled limited communication with health-care professionals concerning oral intake at the end of life. CONCLUSIONS: This study revealed the complexity of meaning relatives' experiences with dying patients' decreasing oral intake. Their perceptions and concerns were related to their awareness of the imminent death. These findings can guide staff involved in care delivery to better support relatives. PMID- 23442881 TI - The 'dis-ease' of dying: challenges in nursing care of the dying in the acute hospital setting. A qualitative observational study. AB - BACKGROUND: Changes in health care and an ageing population have meant that more people are dying in the acute hospital setting. While palliative care principles have resulted in quality care for the dying, many patients die in an acute care, still receiving aggressive/resuscitative care. AIMS: The aims were to explore nurses' 'recognition of' and 'responsiveness to' dying patients and to understand the nurses' influence on end-of-life care. DESIGN: A qualitative approach was taken utilising non-participant observation to elicit rich data, followed by focus groups and individual semi-structured interviews for clarification. SETTING/PARTICIPANTS: This study was conducted in two acute medical wards in one health service, identified as having the highest rates of death, once palliative care and critical care areas were excluded. Twenty-five nurses consented to participate, and 20 episodes of observation were conducted. RESULTS: Nurses took a passive role in recognising dying, providing active care until a medical officer's declaration of dying. Ward design, nurse allocation and nurses' attitude to death impacts patient care. End-of-life care in a single room can have negative consequences for the dying. Nurses demonstrated varying degrees of discomfort, indicating that they were underprepared for this role. CONCLUSION: When patients are terminally ill, acknowledgement of dying is essential in providing appropriate care. It should not be assumed that all nurses are adequately prepared to provide dying care. Further work is necessary to investigate how the attitudes of nurses towards caring for dying patients in the acute hospital setting may impact care of the dying patient. PMID- 23442882 TI - Paid companions: a private care option for older adults. AB - Paid companions, operating either independently or through private home care agencies, perform a variety of services for financially secure older adults who can afford to pay for private support in their homes and in care facilities. Drawing on semi-structured, open-ended, in-person interviews and autodriven photo elicitation (whereby individuals take their own photos and discuss them later in the interviews) with 30 participants (15 companions, 8 clients, and 7 key informants), this study examined the work performed by paid companions. The findings revealed that, in many ways, the companion-provided services for clients living in their own homes resemble task-based home care work, but the work's emphasis is different. The social and emotional relationship with clients is the central focus of their work. Facility-based companions provide a unique role filling the care gap left by government cutbacks to staffing ratios which keeps elderly residents, often with dementia, involved and engaged in the world. PMID- 23442883 TI - Transcriptome analyses of primitively eusocial wasps reveal novel insights into the evolution of sociality and the origin of alternative phenotypes. AB - BACKGROUND: Understanding how alternative phenotypes arise from the same genome is a major challenge in modern biology. Eusociality in insects requires the evolution of two alternative phenotypes - workers, who sacrifice personal reproduction, and queens, who realize that reproduction. Extensive work on honeybees and ants has revealed the molecular basis of derived queen and worker phenotypes in highly eusocial lineages, but we lack equivalent deep-level analyses of wasps and of primitively eusocial species, the latter of which can reveal how phenotypic decoupling first occurs in the early stages of eusocial evolution. RESULTS: We sequenced 20 Gbp of transcriptomes derived from brains of different behavioral castes of the primitively eusocial tropical paper wasp Polistes canadensis. Surprisingly, 75% of the 2,442 genes differentially expressed between phenotypes were novel, having no significant homology with described sequences. Moreover, 90% of these novel genes were significantly upregulated in workers relative to queens. Differential expression of novel genes in the early stages of sociality may be important in facilitating the evolution of worker behavioral complexity in eusocial evolution. We also found surprisingly low correlation in the identity and direction of expression of differentially expressed genes across similar phenotypes in different social lineages, supporting the idea that social evolution in different lineages requires substantial de novo rewiring of molecular pathways. CONCLUSIONS: These genomic resources for aculeate wasps and first transcriptome-wide insights into the origin of castes bring us closer to a more general understanding of eusocial evolution and how phenotypic diversity arises from the same genome. PMID- 23442884 TI - MiR-29c is downregulated in gastric carcinomas and regulates cell proliferation by targeting RCC2. AB - BACKGROUND: Previously, using miRNA microarray, we have found that miR-29c is significantly downregulated in advanced gastric carcinoma. In the present study, we investigated whether miR-29c functions as a tumor-suppressor miRNA in gastric carcinoma cells. For this purpose, we verified the downregulation of miR-29c in gastric carcinoma tissues, and assessed the biological effect of miR-29c on gastric carcinoma cells. RESULTS: In miR-29c-transfected cells, both proliferation and colony formation ability on soft agar were significantly decreased. Although apoptosis was not induced, BrdU incorporation and the proportion of cells positive for phospho-histone H3 (S10) were significantly decreased in miR-29c-transfected cells, indicating that miR-29c may be involved in the regulation of cell proliferation. To explain the mechanism of growth suppression by miR-29c, we explored differentially expressed genes (>2-fold) in miR-29c-transfected cells in comparison with negative control transfected cells using microarray. RCC2, PPIC and CDK6 were commonly downregulated in miR-29c transfected MKN45, MKN7 and MKN74 cells, and all of the genes harbored miR-29c target sequences in the 3'-UTR of their mRNA. RCC2 and PPIC were actually upregulated in gastric carcinoma tissues, and therefore both were identified as possible targets of miR-29c in gastric carcinoma. To ascertain whether downregulation of RCC2 and/or PPIC is involved in the growth suppression by miR 29c, we transfected siRNAs against RCC2 and PPIC into MKN45 and determined cell viability, the rate of BrdU incorporation, and caspase activity. We found that RCC2-knockdown decreased both cell viability and BrdU incorporation without any increase of caspase activity, while PPIC-knockdown did not, indicating that downregulation of RCC2 may be at least partly responsible for the growth suppression by miR-29c. CONCLUSIONS: Our findings indicate that miR-29c may have tumor-suppressive functions in gastric carcinoma cells, and that its decreased expression may confer a growth advantage on tumor cells via aberrant expression of RCC2. PMID- 23442885 TI - Biological activities of alpha-pinene and beta-pinene enantiomers. AB - The antimicrobial activities of the isomers and enantiomers of pinene were evaluated against bacterial and fungal cells. The agar diffusion test showed that only the positive enantiomers of the a- and beta-isomers of pinene were active. The minimal inhibitory concentration (MIC) and minimal microbicidal concentration (MMC) of these monoterpenes were also determined, confirming that the positive enantiomers exhibited microbicidal activity against all fungi and bacteria tested with MICs ranging from 117 to 4,150 ug/mL. However, no antimicrobial activity was detected with the negative enantiomers up to 20 mg/mL. Time-kill curves showed that (+)-a-pinene and (+)-beta-pinene were highly toxic to Candida albicans, killing 100% of inoculum within 60 min. By contrast, the bactericidal effect occurred after 6 h in methicillin-resistant Staphylococcus aureus (MRSA). In combination with commercial antimicrobials, ciprofloxacin plus (+)-a-pinene or (+)-beta-pinene presented synergistic activity against MRSA whereas an indifferent effect against all fungi was detected when amphotericin B was combined with the positive enantiomers of pinene. The potential of (+)-a-pinene and (+)-beta-pinene to inhibit phospholipase and esterase activities was also evaluated, and the best inhibition results were obtained with Cryptococcus neoformans. C. albicans biofilm formation was prevented with the MIC concentration of (+)-a-pinene and twice the MIC value of (+)-beta-pinene. Finally, the cytotoxicity of the positive enantiomers of pinene to murine macrophages was evaluated, and 250 ug/mL of (+)-a-pinene and (+)-beta-pinene reduced the cell viability to 66.8% and 57.7%, respectively. PMID- 23442888 TI - Epigenetics & chromatin: interactions and processes. AB - On 11 to 13 March 2013, BioMed Central will be hosting its inaugural conference, Epigenetics & Chromatin: Interactions and Processes, at Harvard Medical School, Cambridge, MA, USA. Epigenetics & Chromatin has now launched a special article series based on the general themes of the conference. PMID- 23442887 TI - Clinical pathways for inborn errors of metabolism: warranted and feasible. AB - Inborn errors of metabolism (IEMs) are known for their low prevalence and multidisciplinary care mostly founded on expert opinion. Clinical pathways are multidisciplinary tools to organise care which provide a clear route to the best care and improve communication. In 2010 the Dutch Society for Children and Adults with an Inborn Error of Metabolism (VKS) initiated development of clinical pathways for inborn errors of metabolism. In this letter to the editor we describe why it is warranted to develop clinical pathways for IEMs and shortly discuss the process of development for these pathways in the Netherlands. PMID- 23442889 TI - Empirical mode decomposition for self-mixing Doppler signals of hemodynamic optical probes. AB - A new type of optical probe based on laser Doppler self-mixing technology, for a truly non-contact measurement in a single location, and extraction of the temporal features of the distension wave in the arterial wall, was developed. The monitoring of temporal features allows the assessment of cardiovascular function when measurement is carried out at the carotid artery. An algorithm based on the short-time Fourier transform and empirical mode decomposition was applied to the test setup self-mixing signals for the determination of waveform features, with an accuracy of a few milliseconds and a root mean square error less than 3 ms. In vivo testing signals show great consistency in the measured pulse pressure waveform. PMID- 23442891 TI - The changing understanding of the genetic and environmental causes of mental illness. PMID- 23442890 TI - Impact of antigen specificity on CD4+ T cell activation in chronic HIV-1 infection. AB - BACKGROUND: HIV infection induces chronic immune activation which is associated with accelerated disease progression; the causes of this activation, however, are incompletely understood. We investigated the activation status of CD4+ T cells specific for chronic herpes viruses and the non-persistent antigen tetanus toxoid (TT) in HIV positive and HIV negative donors to assess whether persistent infections contribute to chronic CD4+ T cell activation. METHODS: Untreated HIV+ patients and healthy, aged matched controls were recruited and activation levels assessed and compared between cells specific for persistent and non-persistent antigens. Activation levels on antigen-specific CD4+ T cells were measured by intracellular cytokine staining following in vitro stimulation with various recall antigens (CMV, EBV, HSV, VZV and TT) in conjunction with cell surface phenotyping. RESULTS: Activation levels of herpes virus-specific CD4+ T cell populations, assessed by co-expression of CD38 and HLA-DR, were significantly elevated in HIV+ individuals compared to normal controls and compared to TT specific responses. In contrast, we found similar levels of activation of TT specific CD4+ T cells in HIV+ and HIV- donors. CONCLUSIONS: These results show a disparate distribution of immune activation within CD4+ T cell populations depending on their specificity and suggest that the elevated level of immune activation that characterizes chronic HIV infection may be influenced by the persistence of other antigens. PMID- 23442892 TI - Gene-environment interaction in panic disorder and posttraumatic stress disorder. AB - Gene-environment interaction is a form of causal interplay, whereby genetic effects on phenotypic variation change as a function of environmental exposure. While conceptually appealing, there is still much debate on the veracity and the relevance of this form of etiological interdependence for psychiatric disorders. By focusing on panic disorder (PD) and posttraumatic stress disorder (PTSD), this article outlines why gene-environment interaction is controversial, why it can be important for both researchers and clinicians, and how it is investigated by quantitative genetic, molecular genetic, and genomic strategies. It is suggested that gene-environment interaction effects are more reliable and meaningful when they can be harnessed to pinpoint specific biological pathways and mechanisms. In psychiatry, this can be guided by phenotypic dissection and realized by adopting intermediate phenotypes of a physiological nature, such as carbon dioxide sensitivity for PD, or gene expression profiling after stress for PTSD. A developmental framework of reference and the possibility of transferring the investigation to animal models are additional key elements in this debate. PMID- 23442893 TI - Gene-environment interactions in major depressive disorder. AB - Family, twin, and epidemiologic studies have suggested that both genes and environment are important risk factors for the development of major depressive disorder (MDD). In the absence of consistent and strong main genetic effects, numerous studies have supported gene-environment interactions in this disorder. While the impact of negative environmental factors, such as early life stress, traumatic experiences, and negative life events have been established as risk factors, they are not sufficient to predict MDD. This article will review evidence suggesting that genetic variants moderate the effects of adversities on the development of MDD, with a focus on the importance of careful characterization of the stressful life events as well as systemic and molecular mechanisms that potentially mediate these gene-environment interactions. PMID- 23442894 TI - Studying schizophrenia as a neuroplastic disorder. PMID- 23442895 TI - A review of evidence linking disrupted neural plasticity to schizophrenia. AB - The adaptations resulting from neural plasticity lead to changes in cognition and behaviour, which are strengthened through repeated exposure to the novel environment or stimulus. Learning and memory have been hypothesized to occur through modifications of the strength of neural circuits, particularly in the hippocampus and cortex. Cognitive deficits, specifically in executive functioning and negative symptoms, may be a corollary to deficits in neural plasticity. Moreover, the main excitatory and inhibitory neurotransmitters associated with neural plasticity have also been extensively investigated for their role in the cognitive deficits associated with schizophrenia. Transcranial magnetic stimulation (TMS) represents some of the most promising approaches to directly explore the physiological manifestations of neural plasticity in the human brain. Three TMS paradigms (use-dependent plasticity, paired associative stimulation, and repetitive TMS) have been used to evaluate neurophysiological measures of neural plasticity in the healthy brain and in patients with schizophrenia, and to examine the brain's responses to such stimulation. In schizophrenia, deficits in neural plasticity have been consistently shown which parallel the molecular evidence appearing to be entwined with this debilitating disorder. Such pathophysiology may underlie the learning and memory deficits that are key symptoms of this disorder and may even be a key mechanism involved in treatment with antipsychotics. PMID- 23442896 TI - Neuroplasticity-based brain stimulation interventions in the study and treatment of schizophrenia: a review. AB - We reviewed novel brain stimulation approaches that modify neuroplasticity and are used in the treatment and study of schizophrenia. We searched PubMed and Scholars Portal using search terms related to schizophrenia, brain stimulation, and neuroplasticity. Various brain stimulation approaches simulating a range of experimental protocols that induce synaptic long-term potentiation or depression have been developed. By far, repetitive transcranial magnetic stimulation (rTMS) has been the most widely used in the field of schizophrenia. Its application has been associated with mixed results in treating treatment-resistant symptoms and cognitive deficits associated with schizophrenia. Compared to the other approaches, rTMS is probably the least similar to plasticity-inducing cellular paradigms. Other approaches, such as paired associative stimulation, theta-burst stimulation, and transcranial direct current stimulation, are in their incipient stages in the study and treatment of schizophrenia, with promising early results. Numerous brain stimulation approaches have been developed to treat resistant dimensions of schizophrenia. Notwithstanding some promising reports, optimization of the methods and large randomized controlled trials are still needed. PMID- 23442897 TI - Prospective risk factors for suicide attempts in a treated sample of patients with borderline personality disorder. AB - OBJECTIVE: People with borderline personality disorder (BPD) are at high risk for attempting suicide. There are some data to suggest that risk factors for suicide attempts change over time. We conducted a prospective cohort study to examine risk factors for suicide attempts in a treated sample of patients with BPD. METHOD: One hundred eighty participants with BPD were followed over a year-long course of dialectical behaviour therapy or general psychiatric management and then for 2 more years in naturalistic follow-up. Participants were assessed for suicidal and self-injurious behaviours at baseline, every 4 months over the 1 year treatment phase, and every 6 months over a 2-year follow-up period. Participants were classified as suicide or non-suicide attempters based on their behaviour at the end of the 1-year treatment phase and after the 2-year follow-up period. Groups were then compared on baseline clinical and demographic variables. RESULTS: Nearly 26% of participants made a suicide attempt during the 1-year treatment phase, while 16.7% reported a suicide attempt over the 2-year follow-up period. Baseline number of suicide attempts during the 4 months prior to study and severity of childhood sexual abuse predicted suicide attempts during the treatment year. Similarly, baseline suicide attempts, severity of childhood sexual abuse, and number of hospitalizations in the 4 months prior to study entry predicted suicide attempts during the 2-year follow-up. CONCLUSIONS: Risk factors for suicide attempts in this treated sample of patients with BPD were fairly stable, largely non-modifiable, and unrelated to psychopathology or psychosocial functioning at baseline. PMID- 23442898 TI - Trends in newspaper coverage of mental illness in Canada: 2005-2010. AB - OBJECTIVES: Much research suggests that the general public relies on the popular media as a primary source of information about mental illness. We assessed the broad content of articles relating to mental illness in major Canadian newspapers over a 6-year period. We also sought to assess if such content has changed over time. METHODS: We conducted a retrospective analysis of Canadian newspaper coverage from 2005 to 2010. Research assistants used a standardized guide to code 11 263 newspaper articles that mention the terms mental health, mental illness, schizophrenia, or schizophrenic. Once the articles were coded, descriptive statistics were produced for overarching themes and time trend analyses from 2005 to 2010. RESULTS: Danger, violence, and criminality were direct themes in 40% of newspaper articles. Treatment for a mental illness was discussed in only 19% of newspaper articles, and in only 18% was recovery or rehabilitation a significant theme. Eighty-three per cent of articles coded lacked a quotation from someone with a mental illness. We did not observe any significant changes over time from 2005 to 2010 in any domain measured. CONCLUSION: There is scope for more balanced, accurate, and informative coverage of mental health issues in Canada. Newspaper articles infrequently reflect the common realities of mental illness phenomenology, course, and outcome. Currently, clinicians may direct patients and family members to other resources for more comprehensive and accurate information about mental illness. PMID- 23442899 TI - Clinical and sociodemographic characteristics associated with suicidal ideation in depressed outpatients. AB - OBJECTIVE: To identify clinical and sociodemographic characteristics associated with suicidal ideation (SI) among patients seeking care for depression in routine primary and psychiatric care settings. METHODS: We examined data from 4041 treatment-seeking outpatients with major depressive disorder (MDD) to compare baseline sociodemographic and clinical characteristics of those with and without SI, and the presence or absence of baseline depressive symptoms and psychiatric comorbidities in those with SI. RESULTS: SI was significantly (P < 0.01) associated with numerous sociodemographic characteristics (that is, lower level of education, Caucasian or African American, male, unemployed, and treated in psychiatric care) and clinical features (that is, previous suicide attempt, younger age of MDD onset, greater baseline depressive symptom severity, greater number of depressive symptoms, and presence of agoraphobia and [or] generalized anxiety disorder). Elevated levels of SI at baseline were associated with decreased remission rates. CONCLUSIONS: Consistent with past findings, increased rates of SI were associated with greater depressive symptom severity as well as other features suggestive of severity of illness. Our results confirm previous findings of associations between SI and panic and (or) phobic symptoms and anxiety, but did not confirm previous findings of an association between SI and alcohol or drug use and (or) dependence. While selective serotonin reuptake inhibitor monotherapy appeared significantly helpful in reducing SI during the course of treatment, the presence of SI at baseline was found to be a associated with decreased treatment response, with patients reporting SI at the start of treatment being less likely to achieve remission. CLINICAL TRIAL REGISTRATION NUMBER: Sequenced Treatment Alternatives to Relieve Depression, NCT00021528. PMID- 23442900 TI - An extended validation of the ScottCare 320 ambulatory blood pressure monitor: recommendations for clinical application. AB - OBJECTIVES: The purpose of this study was to validate the ScottCare 320 ambulatory blood pressure monitor (ABPM) using both group-level and individual level validation procedures. The group-level validation followed a modified protocol of the European Hypertension Society's validation protocol. The individual-level validation was conducted to ensure that the monitor is valid from both a research and clinical perspective. METHODS: Participants (n=41) had three simultaneous blood pressure (BP) measurements taken by a trained listener using a mercury column sphygmomanometer and the ScottCare ABPM, which was used to validate the monitor at the group-level and the first half of the individual level validation (i.e. the difference between the ABPM and auscultatory means for each participant <5 mmHg). The second half of the individual-level validation occurred by examining participants' responses on diary questionnaires taken immediately following the BP measurements (i.e. can extreme or deviant BP values be explained by situational factors). RESULTS: At the group level, the ABPM passed the criteria laid out by the European Hypertension Society. At the individual level, the difference between the auscultatory and ABPM means was less than 5 mmHg for both systolic and diastolic BP for 36 participants on the initial attempt, and the remaining five on the second attempt. Furthermore, the deviant values were largely attributed to explainable causes, mainly movement. CONCLUSION: The ScottCare ABPM is a highly accurate monitor that can be considered valid at both the group and the individual level, and thus appropriate for both clinical and research use. PMID- 23442901 TI - Relationship between burden of infection in ungulate populations and wildlife/livestock interfaces. AB - In southern African transfrontier conservation areas (TFCAs), people, livestock and wildlife share space and resources in semi-arid landscapes. One consequence of the coexistence of wild and domestic herbivores is the risk of pathogen transmission. This risk threatens local livelihoods relying on animal production, public health in the case of zoonoses, national economies in the context of transboundary animal diseases, and the success of integrated conservation and development initiatives. The level of interaction between sympatric wild and domestic hosts, defining different wildlife/livestock interfaces, characterizes opportunities of pathogen transmission between host populations. Exploring the relationship between infection burden and different types of wildlife/domestic interfaces is therefore necessary to manage the sanitary risk in animal populations through control options adapted to these multi-host systems. Here, we assessed the infection burdens of sympatric domestic cattle (Bos taurus/Bos indicus) and African buffalo (Syncerus caffer) at an unfenced interface and compared the infection burdens of cattle populations at different wildlife/livestock interfaces in the Great Limpopo TFCA. Patterns of infection in ungulate populations varied between wild and domestic hosts and between cattle populations at different wildlife/livestock interfaces. Foot-and-mouth disease, Rift Valley fever and theileriosis infections were detected in buffalo and cattle at unfenced interfaces; bovine tuberculosis was only present in buffalo; and brucellosis and lumpy skin disease only in cattle. At unfenced interfaces, cattle populations presented significantly higher Theileria parva and brucellosis prevalence. We hypothesize that cattle populations at wildlife/livestock interfaces face an increased risk of infection compared to those isolated from wildlife, and that the type of interface could influence the diversity and quantity of pathogens shared. Additional host behavioural and molecular epidemiological studies need to be conducted to support this hypothesis. If it is confirmed, the management of wildlife/livestock interfaces will need to be considered through the prism of livestock and public health. PMID- 23442902 TI - New and notable: key new insights into membrane targeting by proteins. PMID- 23442904 TI - Simple moment-closure model for the self-assembly of breakable amyloid filaments. AB - In this work, we derive a simple mathematical model from mass-action equations for amyloid fiber formation that takes into account the primary nucleation, elongation, and length-dependent fragmentation. The derivation is based on the principle of minimum free energy under certain constraints and is mathematically related to the partial equilibrium approximation. Direct numerical comparisons confirm the usefulness of our simple model. We further explore its basic kinetic and equilibrium properties, and show that the current model is a straightforward generalization of that with constant fragmentation rates. PMID- 23442905 TI - Cell shape can mediate the spatial organization of the bacterial cytoskeleton. AB - The bacterial cytoskeleton guides the synthesis of cell wall and thus regulates cell shape. Because spatial patterning of the bacterial cytoskeleton is critical to the proper control of cell shape, it is important to ask how the cytoskeleton spatially self-organizes in the first place. In this work, we develop a quantitative model to account for the various spatial patterns adopted by bacterial cytoskeletal proteins, especially the orientation and length of cytoskeletal filaments such as FtsZ and MreB in rod-shaped cells. We show that the combined mechanical energy of membrane bending, membrane pinning, and filament bending of a membrane-attached cytoskeletal filament can be sufficient to prescribe orientation, e.g., circumferential for FtsZ or helical for MreB, with the accuracy of orientation increasing with the length of the cytoskeletal filament. Moreover, the mechanical energy can compete with the chemical energy of cytoskeletal polymerization to regulate filament length. Notably, we predict a conformational transition with increasing polymer length from smoothly curved to end-bent polymers. Finally, the mechanical energy also results in a mutual attraction among polymers on the same membrane, which could facilitate tight polymer spacing or bundling. The predictions of the model can be verified through genetic, microscopic, and microfluidic approaches. PMID- 23442903 TI - There is more than one way to model an elephant. Experiment-driven modeling of the actin cytoskeleton. AB - Mathematical modeling has established its value for investigating the interplay of biochemical and mechanical mechanisms underlying actin-based motility. Because of the complex nature of actin dynamics and its regulation, many of these models are phenomenological or conceptual, providing a general understanding of the physics at play. But the wealth of carefully measured kinetic data on the interactions of many of the players in actin biochemistry cries out for the creation of more detailed and accurate models that could permit investigators to dissect interdependent roles of individual molecular components. Moreover, no human mind can assimilate all of the mechanisms underlying complex protein networks; so an additional benefit of a detailed kinetic model is that the numerous binding proteins, signaling mechanisms, and biochemical reactions can be computationally organized in a fully explicit, accessible, visualizable, and reusable structure. In this review, we will focus on how comprehensive and adaptable modeling allows investigators to explain experimental observations and develop testable hypotheses on the intracellular dynamics of the actin cytoskeleton. PMID- 23442906 TI - Correlated spatio-temporal fluctuations in chromatin compaction states characterize stem cells. AB - Stem cells integrate signals from the microenvironment to generate lineage specific gene expression programs upon differentiation. Undifferentiated cell nuclei are easily deformable, with an active transcriptome, whereas differentiated cells have stiffer nuclei and condensed chromatin. Chromatin organization in the stem cell state is known to be highly dynamic but quantitative characterizations of its plasticity are lacking. Using fluorescence imaging, we study the spatio-temporal dynamics of nuclear architecture and chromatin compaction in mouse embryonic stem (ES) cells and differentiated states. Individual ES cells exhibit a relatively narrow variation in chromatin compaction, whereas primary mouse embryonic fibroblasts (PMEF) show broad distributions. However, spatial correlations in chromatin compaction exhibit an emergent length scale in PMEFs, although they are unstructured and longer ranged in ES cells. We provide evidence for correlated fluctuations with large amplitude and long intrinsic timescales, including an oscillatory component, in both chromatin compaction and nuclear area in ES cells. Such fluctuations are largely frozen in PMEF. The role of actin and Lamin A/C in modulating these fluctuations is described. A simple theoretical formulation reproduces the observed dynamics. Our results suggest that, in addition to nuclear plasticity, correlated spatio temporal structural fluctuations of chromatin in undifferentiated cells characterize the stem cell state. PMID- 23442907 TI - Energy for wild-type acetylcholine receptor channel gating from different choline derivatives. AB - Agonists, including the neurotransmitter acetylcholine (ACh), bind at two sites in the neuromuscular ACh receptor channel (AChR) to promote a reversible, global change in protein conformation that regulates the flow of ions across the muscle cell membrane. In the synaptic cleft, ACh is hydrolyzed to acetate and choline. Replacement of the transmitter's ester acetyl group with a hydroxyl (ACh >choline) results in a + 1.8 kcal/mol reduction in the energy for gating generated by each agonist molecule from a low- to high-affinity change of the transmitter binding site (DeltaG(B)). To understand the distinct actions of structurally related agonist molecules, we measured DeltaG(B) for 10 related choline derivatives. Replacing the hydroxyl group of choline with different substituents, such as hydrogen, chloride, methyl, or amine, increased the energy for gating (i.e., it made DeltaG(B) more negative relative to choline). Extending the ethyl hydroxide tail of choline to propyl and butyl hydroxide also increased this energy. Our findings reveal the amount of energy that is available for the AChR conformational change provided by different, structurally related agonists. We speculate that a hydrogen bond between the choline hydroxyl and the backbone carbonyl of alphaW149 positions this agonist's quaternary ammonium group so as to reduce the cation-pi interaction between this moiety and the aromatic groups at the binding site. PMID- 23442908 TI - Amphipathic lipid packing sensor motifs: probing bilayer defects with hydrophobic residues. AB - Sensing membrane curvature allows fine-tuning of complex reactions that occur at the surface of membrane-bound organelles. One of the most sensitive membrane curvature sensors, the Amphipathic Lipid Packing Sensor (ALPS) motif, does not seem to recognize the curved surface geometry of membranes per se; rather, it recognizes defects in lipid packing that arise from membrane bending. In a companion paper, we show that these defects can be mimicked by introducing conical lipids in a flat lipid bilayer, in agreement with experimental observations. Here, we use molecular-dynamics (MD) simulations to characterize ALPS binding to such lipid bilayers. The ALPS motif recognizes lipid-packing defects by a conserved mechanism: peptide partitioning is driven by the insertion of hydrophobic residues into large packing defects that are preformed in the bilayer. This insertion induces only minor modifications in the statistical distribution of the free packing defects. ALPS insertion is severely hampered when monounsaturated lipids are replaced by saturated lipids, leading to a decrease in packing defects. We propose that the hypersensitivity of ALPS motifs to lipid packing defects results from the repetitive use of hydrophobic insertions along the monotonous ALPS sequence. PMID- 23442909 TI - Conical lipids in flat bilayers induce packing defects similar to that induced by positive curvature. AB - In biological membranes, changes in lipid composition or mechanical deformations produce defects in the geometrical arrangement of lipids, thus allowing the adsorption of certain peripheral proteins. Here, we perform molecular dynamics simulations on bilayers containing a cylindrical lipid (PC) and a conical lipid (DOG). Profiles of atomic density and lateral pressure across the bilayer show differences in the acyl chain region due to deeper partitioning of DOG compared to PC. However, such analyses are less informative for the interfacial region where peripheral proteins adsorb. To circumvent this limitation, we develop, to our knowledge, a new method of membrane surface analysis. This method allows the identification of chemical defects, where hydrocarbon chains are accessible to the solvent, and geometrical defects, i.e., voids deeper than the glycerol backbone. The size and number of both types of defects increase with the number of monounsaturated acyl chains in PC and with the introduction of DOG, although the defects do not colocalize with the conical lipid. Interestingly, the size and probability of the defects promoted by DOG resemble those induced by positive curvature, thus explaining why conical lipids and positive curvature can both drive the adsorption of peripheral proteins that use hydrophobic residues as membrane anchors. PMID- 23442910 TI - An anionic phospholipid enables the hydrophobic surfactant proteins to alter spontaneous curvature. AB - The hydrophobic surfactant proteins, SP-B and SP-C, greatly accelerate the adsorption of the surfactant lipids to an air/water interface. Previous studies of factors that affect curvature suggest that vesicles may adsorb via a rate limiting structure with prominent negative curvature, in which the hydrophilic face of the lipid leaflets is concave. To determine if SP-B and SP-C might promote adsorption by inducing negative curvature, we used small-angle x-ray scattering to test whether the physiological mixture of the two proteins affects the radius of cylindrical monolayers in the inverse hexagonal phase. With dioleoyl phosphatidylethanolamine alone, the proteins had no effect on the hexagonal lattice constant, suggesting that the proteins fail to insert into the cylindrical monolayers. The surfactant lipids also contain ~10% anionic phospholipids, which might allow incorporation of the cationic proteins. With 10% of the anionic dioleoyl phosphatidylglycerol added to dioleoyl phosphatidylethanolamine, the proteins induced a dose-related decrease in the hexagonal lattice constant. At 30 degrees C, the reduction reached a maximum of 8% relative to the lipids alone at ~1% (w/w) protein. Variation of NaCl concentration tested whether the effect of the protein represented a strictly electrostatic effect that screening by electrolyte would eliminate. With concentrations up to 3 M NaCl, the dose-related change in the hexagonal lattice constant decreased but persisted. Measurements at different hydrations determined the location of the pivotal plane and proved that the change in the lattice constant produced by the proteins resulted from a shift in spontaneous curvature. These results provide the most direct evidence yet that the surfactant proteins can induce negative curvature in lipid leaflets. This finding supports the model in which the proteins promote adsorption by facilitating the formation of a negatively curved, rate-limiting structure. PMID- 23442911 TI - Effects of sphingomyelin headgroup size on interactions with ceramide. AB - Sphingomyelins (SMs) and ceramides are known to interact favorably in bilayer membranes. Because ceramide lacks a headgroup that could shield its hydrophobic body from unfavorable interactions with water, accommodation of ceramide under the larger phosphocholine headgroup of SM could contribute to their favorable interactions. To elucidate the role of SM headgroup for SM/ceramide interactions, we explored the effects of reducing the size of the phosphocholine headgroup (removing one, two, or three methyls on the choline moiety, or the choline moiety itself). Using differential scanning calorimetry and fluorescence spectroscopy, we found that the size of the SM headgroup had no marked effect on the thermal stability of ordered domains formed by SM analog/palmitoyl ceramide (PCer) interactions. In more complex bilayers composed of a fluid glycerophospholipid, SM analog, and PCer, the thermal stability and molecular order of the laterally segregated gel domains were roughly identical despite variation in SM headgroup size. We suggest that that the association between PCer and SM analogs was stabilized by ceramide's aversion for disordered phospholipids, by interfacial hydrogen bonding between PCer and the SM analogs, and by attractive van der Waals' forces between saturated chains of PCer and SM analogs. PMID- 23442912 TI - Defining the membrane-associated state of the PTEN tumor suppressor protein. AB - Phosphatase and tensin-homolog deleted on chromosome 10 (PTEN) is a tumor suppressor protein that regulates phosphatidylinositol 3-kinase (PI3-K) signaling by binding to the plasma membrane and hydrolyzing the 3' phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) to form phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2). Several loss-of-function mutations in PTEN that impair lipid phosphatase activity and membrane binding are oncogenic, leading to the development of a variety of cancers, but information about the membrane-associated state of PTEN remains sparse. We have modeled a membrane-associated state of the truncated PTEN structure bound to PI(3,4,5)P3 via multiscale molecular dynamics simulations. We show that the location of the membrane-binding surface agrees with experimental observations and is robust to changes in lipid composition. The level of membrane interaction is substantially reduced in the phosphatase domain for the triple mutant R161E/K163E/K164E, in line with experimental results. We observe clustering of anionic lipids around the C2 domain in preference to the phosphatase domain, suggesting that the C2 domain is involved in nonspecific interactions with negatively charged lipid headgroups. Finally, our simulations suggest that the oncogenicity of the R335L mutation may be due to a reduction in the interaction of the mutant PTEN with anionic lipids. PMID- 23442913 TI - Taste of sugar at the membrane: thermodynamics and kinetics of the interaction of a disaccharide with lipid bilayers. AB - Sugar recognition at the membrane is critical in various physiological processes. Many aspects of sugar-membrane interaction are still unknown. We take an integrated approach by combining conventional molecular-dynamics simulations with enhanced sampling methods and analytical models to understand the thermodynamics and kinetics of a di-mannose molecule in a phospholipid bilayer system. We observe that di-mannose has a slight preference to localize at the water phospholipid interface. Using umbrella sampling, we show the free energy bias for this preferred location to be just -0.42 kcal/mol, which explains the coexistence of attraction and exclusion mechanisms of sugar-membrane interaction. Accurate estimation of absolute entropy change of water molecules with a two-phase model indicates that the small energy bias is the result of a favorable entropy change of water molecules. Then, we incorporate results from molecular-dynamics simulation in two different ways to an analytical diffusion-reaction model to obtain association and dissociation constants for di-mannose interaction with membrane. Finally, we verify our approach by predicting concentration dependence of di-mannose recognition at the membrane that is consistent with experiment. In conclusion, we provide a combined approach for the thermodynamics and kinetics of a weak ligand-binding system, which has broad implications across many different fields. PMID- 23442914 TI - Membrane interactions and pore formation by the antimicrobial peptide protegrin. AB - Protegrin is an antimicrobial peptide with a beta-hairpin structure stabilized by a pair of disulfide bonds. It has been extensively studied by solid-state NMR and computational methods. Here we use implicit membrane models to examine the binding of monomers on the surface and in the interior of the membrane, the energetics of dimerization, the binding to membrane pores, and the stability of different membrane barrel structures in pores. Our results challenge a number of conclusions based on previous experimental and theoretical work. The burial of monomers into the membrane interior is found to be unfavorable for any membrane thickness. Because of its imperfect amphipathicity, protegrin binds weakly, at most, on the surface of zwitterionic membranes. However, it binds more favorably onto toroidal pores. Anionic charge on the membrane facilitates the binding due to electrostatic interactions. Solid-state NMR results have suggested a parallel NCCN association of monomers in dimers and association of dimers to form octameric or decameric beta-barrels. We find that this structure is not energetically plausible for binding to bilayers, because in this configuration the hydrophobic sides of two monomers point in opposite directions. In contrast, the antiparallel NCCN and especially the parallel NCNC octamers are stable and exhibit a favorable binding energy to the pore. The results of 100-ns simulations in explicit bilayers corroborate the higher stability of the parallel NCNC barrel compared with the parallel NCCN barrel. The ability to form pores in zwitterionic membranes provides a rationalization for the peptide's cytotoxicity. The discrepancies between our results and experiment are discussed, and new experiments are proposed to resolve them and to test the validity of the models. PMID- 23442916 TI - Thick filament length and isoform composition determine self-organized contractile units in actomyosin bundles. AB - Diverse myosin II isoforms regulate contractility of actomyosin bundles in disparate physiological processes by variations in both motor mechanochemistry and the extent to which motors are clustered into thick filaments. Although the role of mechanochemistry is well appreciated, the extent to which thick filament length regulates actomyosin contractility is unknown. Here, we study the contractility of minimal actomyosin bundles formed in vitro by mixtures of F actin and thick filaments of nonmuscle, smooth, and skeletal muscle myosin isoforms with varied length. Diverse myosin II isoforms guide the self organization of distinct contractile units within in vitro bundles with shortening rates similar to those of in vivo myofibrils and stress fibers. The tendency to form contractile units increases with the thick filament length, resulting in a bundle shortening rate proportional to the length of constituent myosin thick filament. We develop a model that describes our data, providing a framework in which to understand how diverse myosin II isoforms regulate the contractile behaviors of disordered actomyosin bundles found in muscle and nonmuscle cells. These experiments provide insight into physiological processes that use dynamic regulation of thick filament length, such as smooth muscle contraction. PMID- 23442915 TI - Inclusion of lateral pressure/curvature stress effects in implicit membrane models. AB - Implicit membrane models usually treat the membrane as a hydrophobic slab and neglect lateral pressure/curvature stress effects. As a result, they cannot distinguish, for example, PE from PC lipids. Here, the implicit membrane model IMM1 is extended to include these effects using a combination of classical thermodynamics and membrane elasticity theory. The proposed model is tested by molecular dynamics simulation of the peptides alamethicin, melittin, cyclotide kalata B1, 18A, and KKpL15. The lateral pressure term stabilizes interfacial binding due to the negative pressure at the hydrocarbon-water interface. In agreement with experiment, increase in the peptide/lipid molar ratio shifts the equilibrium from the interfacial to the transmembrane orientation. Simulations of mixed DOPC/DOPE bilayers show that increase of the DOPE mole fraction in general stabilizes interfacial orientations and destabilizes transmembrane orientations. The extent of the stabilization or destabilization varies depending on the exact position of the peptides. The computational results are in good agreement with experiments. PMID- 23442917 TI - Bifurcation of velocity distributions in cooperative transport of filaments by fast and slow motors. AB - Several intracellular processes are governed by two different species of molecular motors, fast and slow ones, that both move in the same direction along the filaments but with different velocities. The transport of filaments arising from the cooperative action of these motors has been recently studied by three in vitro experiments, in which the filament velocity was measured for varying fraction of the fast motors adsorbed onto substrate surfaces in a gliding assay. As the fast motor fraction was increased, two experiments found a smooth change whereas the third one observed an abrupt increase of the filament velocity. Here, we show that all of these experimental results reflect the competition between fast and slow motors and can be understood in terms of an underlying saddle-node bifurcation. The comparison between theory and experiment leads to predictions for the detachment forces of the two motor species. Our theoretical study shows the existence of three different motility regimes: 1), fast transport with a single velocity; 2), slow transport with a single velocity; and 3), bistable transport, where the filament velocity stochastically switches between fast and slow transport. We determine the parameter regions for these regimes in terms of motility diagrams as a function of the surface fraction of fast motors and microscopic single-motor parameters. An abrupt increase of the filament velocity for an increasing fraction of fast motors is associated with the occurrence of bistable transport. PMID- 23442918 TI - Role of domain interactions in the collective motion of phosphoglycerate kinase. AB - Protein function is governed by the underlying conformational dynamics of the molecule. The experimental and theoretical work leading to contemporary understanding of enzyme dynamics was mostly restricted to the large-scale movements of single-domain proteins. Collective movements resulting from a regulatory interplay between protein domains is often crucial for enzymatic activity. It is not clear, however, how our knowledge could be extended to describe collective near-equilibrium motions of multidomain enzymes. We examined the effect of domain interactions on the low temperature near equilibrium dynamics of the native state, using phosphoglycerate kinase as model protein. We measured thermal activation of tryptophan phosphorescence quenching to explore millisecond-range protein motions. The two protein domains of phosphoglycerate kinase correspond to two dynamic units, but interdomain interactions link the motion of the two domains. The effect of the interdomain interactions on the activation of motions in the individual domains is asymmetric. As the temperature of the frozen protein is increased from the cryogenic, motions of the N domain are activated first. This is a partial activation, however, and the full dynamics of the domain becomes activated only after the activation of the C domain. PMID- 23442919 TI - Computational assembly of polymorphic amyloid fibrils reveals stable aggregates. AB - Amyloid proteins aggregate into polymorphic fibrils that damage tissues of the brain, nerves, and heart. Experimental and computational studies have examined the structural basis and the nucleation of short fibrils, but the ability to predict and precisely quantify the stability of larger aggregates has remained elusive. We established a complete classification of fibril shapes and developed a tool called CreateFibril to build such complex, polymorphic, modular structures automatically. We applied stability landscapes, a technique we developed to reveal reliable fibril structural parameters, to assess fibril stability. CreateFibril constructed HET-s, Abeta, and amylin fibrils up to 17 nm in length, and utilized a novel dipolar solvent model that captured the effect of dipole dipole interactions between water and very large molecular systems to assess their aqueous stability. Our results validate experimental data for HET-s and Abeta, and suggest novel (to our knowledge) findings for amylin. In particular, we predicted the correct structural parameters (rotation angles, packing distances, hydrogen bond lengths, and helical pitches) for the one and three predominant HET-s protofilaments. We reveal and structurally characterize all known Abeta polymorphic fibrils, including structures recently classified as wrapped fibrils. Finally, we elucidate the predominant amylin fibrils and assert that native amylin is more stable than its amyloid form. CreateFibril and a database of all stable polymorphic fibril models we tested, along with their structural energy landscapes, are available at http://amyloid.cs.mcgill.ca. PMID- 23442920 TI - Direct observation of protein unfolded state compaction in the presence of macromolecular crowding. AB - Proteins fold and function in cellular environments that are crowded with other macromolecules. As a consequence of excluded volume effects, compact folded states of proteins should be indirectly stabilized due to destabilization of extended unfolded conformations. Here, we assess the role of excluded volume in terms of protein stability, structural dimensions and folding dynamics using a sugar-based crowding agent, dextran 20, and the small ribosomal protein S16 as a model system. To specifically address dimensions, we labeled the protein with BODIPY at two positions and measured Trp-BODIPY distances under different conditions. As expected, we found that dextran 20 (200 mg/ml) stabilized the variants against urea-induced unfolding. At conditions where the protein is unfolded, Forster resonance energy transfer measurements reveal that in the presence of dextran, the unfolded ensemble is more compact and there is residual structure left as probed by far-ultraviolet circular dichroism. In the presence of a crowding agent, folding rates are faster in the two-state regime, and at low denaturant concentrations, a kinetic intermediate is favored. Our study provides direct evidence for protein unfolded-state compaction in the presence of macromolecular crowding along with its energetic and kinetic consequences. PMID- 23442921 TI - Modeling the assembly of the multiple domains of alpha-actinin-4 and its role in actin cross-linking. AB - The assembly of proteins into multidomain complexes is critical for their function. In eukaryotic nonmuscle cells, regulation of the homodimeric actin cross-linking protein alpha-actinin-4 (ACTN4) during cell migration involves signaling receptors with intrinsic tyrosine kinase activity, yet the underlying molecular mechanisms are poorly understood. As a first step to address the latter, we validate here an atomic model for the ACTN4 end region, which corresponds to a ternary complex between the N-terminal actin-binding domain (ABD) and an adjacent helical neck region of one monomer, and the C-terminal calmodulin-like domain of the opposite antiparallel monomer. Mutagenesis experiments designed to disrupt this ternary complex confirm that its formation reduces binding to F-actin. Molecular dynamics simulations show that the phosphomimic mutation Y265E increases actin binding by breaking several interactions that tether the two calponin homology domains into a closed ABD conformation. Simulations also show a disorder-to-order transition in the double phosphomimic mutant Y4E/Y31E of the 45-residue ACTN4 N-terminal region, which can inhibit actin binding by latching both calponin homology domains more tightly. Collectively, these studies provide a starting point for understanding the role of external cues in regulating ACTN4, with different phenotypes resulting from changes in the multidomain assembly of the protein. PMID- 23442922 TI - Biophysical model of ion transport across human respiratory epithelia allows quantification of ion permeabilities. AB - Lung health and normal mucus clearance depend on adequate hydration of airway surfaces. Because transepithelial osmotic gradients drive water flows, sufficient hydration of the airway surface liquid depends on a balance between ion secretion and absorption by respiratory epithelia. In vitro experiments using cultures of primary human nasal epithelia and human bronchial epithelia have established many of the biophysical processes involved in airway surface liquid homeostasis. Most experimental studies, however, have focused on the apical membrane, despite the fact that ion transport across respiratory epithelia involves both cellular and paracellular pathways. In fact, the ion permeabilities of the basolateral membrane and paracellular pathway remain largely unknown. Here we use a biophysical model for water and ion transport to quantify ion permeabilities of all pathways (apical, basolateral, paracellular) in human nasal epithelia cultures using experimental (Ussing Chamber and microelectrode) data reported in the literature. We derive analytical formulas for the steady-state short-circuit current and membrane potential, which are for polarized epithelia the equivalent of the Goldman-Hodgkin-Katz equation for single isolated cells. These relations allow parameter estimation to be performed efficiently. By providing a method to quantify all the ion permeabilities of respiratory epithelia, the model may aid us in understanding the physiology that regulates normal airway surface hydration. PMID- 23442923 TI - Quantitative measurement of protein relocalization in live cells. AB - Microscope cytometry provides a powerful means to study signaling in live cells. Here we present a quantitative method to measure protein relocalization over time, which reports the absolute fraction of a tagged protein in each compartment. Using this method, we studied an essential step in the early propagation of the pheromone signal in Saccharomyces cerevisiae: recruitment to the membrane of the scaffold Ste5 by activated Gbetagamma dimers. We found that the dose response of Ste5 recruitment is graded (EC50 = 0.44 +/- 0.08 nM, Hill coefficient = 0.8 +/- 0.1). Then, we determined the effective dissociation constant (K(de)) between Ste5 and membrane sites during the first few minutes when the negative feedback from the MAPK Fus3 is first activated. K(de) changed during the first minutes from a high affinity of < 0.65 nM to a steady-state value of 17 +/- 9 nM. During the same period, the total number of binding sites decreased slightly, from 1940 +/- 150 to 1400 +/- 200. This work shows how careful quantification of a protein relocalization dynamic can give insight into the regulation mechanisms of a biological system. PMID- 23442924 TI - Highly abundant proteins favor more stable 3D structures in yeast. AB - To understand the variation of protein sequences in nature, we need to reckon with evolutionary constraints that are biophysical, cellular, and ecological. Here, we show that under the global selection against protein misfolding, there exists a scaling among protein folding stability, protein cellular abundance, and effective population size. The specific scaling implies that the several-orders of-magnitude range of protein abundances in the cell should leave imprints on extant protein structures, a prediction that is supported by our structural analysis of the yeast proteome. PMID- 23442925 TI - Recent advances in vaccine development for herpes simplex virus types I and II. AB - Despite recent advances in vaccine design and strategies, latent infection with herpes simplex virus (HSV) remains a formidable challenge. Approaches involving live-attenuated viruses and inactivated viral preparations were popular throughout the twentieth century. In the past ten years, many vaccine types, both prophylactic or therapeutic, have contained a replication-defective HSV, viral DNA or glycoproteins. New research focused on the mechanism of immune evasion by the virus has involved developing vaccines with various gene deletions and manipulations combined with the use of new and more specific adjuvants. In addition, new "prime-boost" methods of strengthening the vaccine efficacy have proven effective, but there have also been flaws with some recent strategies that appear to have compromised vaccine efficacy in humans. Given the complicated lifecycle of HSV and its unique way of spreading from cell-to-cell, it can be concluded that the development of an ideal vaccine needs new focus on cell mediated immunity, better understanding of the latent viral genome and serious consideration of gender-based differences in immunity development among humans. This review summarizes recent developments made in the field and sheds light on some potentially new ways to conquer the problem including development of dual action prophylactic microbicides that prohibit viral entry and, in addition, induce a strong antigen response. PMID- 23442926 TI - Symptom burden, palliative care need and predictors of physical and psychological discomfort in two UK hospitals. AB - BACKGROUND: The requirement to meet the palliative needs of acute hospital populations has grown in recent years. With increasing numbers of frail older people needing hospital care as a result of both malignant and non-malignant conditions, emphasis is being placed upon understanding the physical, psychological and social burdens experienced by patients. This study explores the extent of burden in two large UK hospitals, focusing upon those patients who meet palliative care criteria. Furthermore, the paper explores the use of palliative services and identifies the most significant clinical diagnostic and demographic factors which determine physical and psychological burden. METHODS: Two hospital surveys were undertaken to identify burden using the Sheffield Profile for Assessment and Referral to Care (SPARC). The Gold Standards Framework (GSF) is used to identify those patients meeting palliative care criteria. Participants were identified as being in-patients during a two-week data collection phase for each site. Data was gathered using face-to-face interviews or self-completion by patients or a proxy. Descriptive analyses highlight prevalence and use of palliative care provision. Binary logistic regression assesses clinical diagnostic predictor variables of physical and psychological burden. RESULTS: The sample consisted of 514 patients and elevated physical, psychological and social burden is identified amongst those meeting palliative care criteria (n = 185). Tiredness (34.6%), pain (31.1%), weakness (28.8%) and psychological discomfort (low mood 19.9%; anxiety 16.1%) are noted as being prevalent. A small number of these participants accessed Specialist Palliative Care (8.2%). Dementia was identified as a predictor of physical (OR 3.94; p < .05) and psychological burden (OR 2.88; p < .05), being female was a predictor of psychological burden (OR 2.00; p < .05). CONCLUSION: The paper highlights elevated levels of burden experienced by patients with palliative care requirements. Moreover, the paper also indicates that a large proportion of such patients are not in receipt of palliative approaches to their care. Furthermore, the paper identifies that those with non-malignant illnesses, especially dementia, may experience high levels of physical and psychological burden. PMID- 23442928 TI - A facile synthesis of deaza-analogues of the bisindole marine alkaloid topsentin. AB - A series of substituted ethyl 1-[(tert-butoxycarbonyl)amino]-2-methyl-5- (1 methyl-1H-indol-3-yl)-4-[(1-methyl-1H-indol-3-yl)carbonyl]-1H-pyrrole-3 carboxylates were prepared in excellent yields (82-98%) by one-pot reactions between beta-dicarbonyl compounds 12a-e and 1,2-diaza-1,3-diene (DD) 13. Derivatives 10a,c-e, deazaanalogues of the bis-indole alkaloid topsentin, screened by the National Cancer Institute (Bethesda, MD, USA) in the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity, with the exception of compound 9e, which showed moderate activity against the HOP-92 cell line of the non small cell lung cancer sub-panel and the SNB-75 cell line of the CNS sub-panel. PMID- 23442929 TI - Identification of Alternaria alternata mycotoxins by LC-SPE-NMR and their cytotoxic effects to soybean (Glycine max) cell suspension culture. AB - This present work describes the application of liquid chromatography-solid phase extraction-nuclear magnetic resonance spectroscopy to analyse Alternaria alternata crude extracts. Altenusin (1), alternariol (2), 3'-hydroxyalternariol monomethyl ether (3), and alternariol monomethyl ether (4), were separated and identified. High-resolution mass spectrometry confirmed the proposed structures. The cytotoxic effects of these compounds towards plants were determined using soybean (Glycine max) cell cultures as a model. EC(50) values which range from 0.11 (+/- 0.02) to 4.69 (+/- 0.47) MUM showed the high cytotoxicity of these compounds. PMID- 23442927 TI - microRNA response elements-regulated TRAIL expression shows specific survival suppressing activity on bladder cancer. AB - BACKGROUND: Bladder transitional cell carcinoma greatly threatens human health all over the world. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows a strong apoptosis-inducing effect on a variety of cancer cells including bladder cancer. However, adenovirus-mediated TRAIL expression still showed cytotoxicity to normal cells mainly due to lack of tumor specificity. METHODS: To solve the problem, we applied miRNA response elements (MREs) of miR 1, miR-133 and miR-218 to confer TRAIL expression with specificity to bladder cancer cells. RESULTS: Expression of miR-1, miR-133 and miR-218 was greatly decreased in bladder cancer than normal bladder tissue. Luciferase assay showed that application of the 3 MREs was able to restrain exogenous gene expression to within bladder cancer cells. Subsequently, we constructed a recombinant adenovirus with TRAIL expression regulated by MREs of miR-1, miR-133 and miR-218, namely Ad-TRAIL-MRE-1-133-218. qPCR, immunoblotting and ELISA assays demonstrated that Ad-TRAIL-MRE-1-133-218 expressed in bladder cancer cells, rather than normal bladder cells. The differential TRAIL expression also led to selective apoptosis inducing and growth-inhibiting effect of Ad-TRAIL-MRE-1-133-218 on bladder cancers. Finally, bladder cancer xenograft in mouse models further confirmed that Ad-TRAIL-MRE-1-133-218 effectively suppressed the growth of bladder cancers. CONCLUSIONS: Collectively, we demonstrated that MREs-based TRAIL delivery into bladder cancer cells was feasible and efficient for cancer gene therapy. PMID- 23442930 TI - Methyl Antcinate A suppresses the population of cancer stem-like cells in MCF7 human breast cancer cell line. AB - Methyl antcinate A (MAA) is an ergostane-type triterpenoid extracted from the fruiting bodies of Antrodia camphorate that has been reported to be a cytotoxic agent towards some types of cancer cells, such as oral cancer and liver cancer. Cancer stem cells (CSCs) are a particular population within cancer cells which are responsible for tumor initiation, drug resistance and metastasis and targeting CSCs is an emerging area in cancer therapy. In this study, we examine the effect of MAA on cancer stem-like cells in the MCF7 human breast cancer cell line. Although MAA displayed very low cytotoxic effect towards MCF7 under normal culture conditions, it did show good inhibitory effects on the self-renewal capability which was examined by mammosphere culture including primary and secondary sphere. MAA also inhibited cell migration ability of MCF7 sphere cells. By western blot analysis, MAA was shown to suppress the expression of heat shock protein 27 and increase the expression of IkBalpha and p53. In conclusion, our data demonstrate that MAA has anti-CSC activity and is worthy of future development of potent anticancer agents. PMID- 23442931 TI - Evaluation of selenite effects on selenoproteins and cytokinome in human hepatoma cell lines. AB - The need to explore new alternative therapeutic strategies and chemoprevention methods for hepatocellular carcinoma is growing significantly. Selenium is a trace element that plays a critical role in physiological processes, and is used in cancer chemoprevention. The aim of this work was to test in vitro the effect of sodium selenite on the human hepatoma cell lines, HepG2 and Huh7, to assess its effect on the expression of GPX1, SELK and SELENBP1 and also to evaluate its action on inflammation determinants such as cytokines. Our results show that: (i) the increase observed for the GPX1 and SELK expression is correlated with an increase in the sodium selenite concentration, also evidencing an inverse association between the levels of these two proteins and SELENBP1; (ii) the selenium concentrations evaluated in protein extracts increase in proportional way with the selenite concentrations used in the treatment, suggesting that other selenoproteins can also be modulated and should be evaluated in further studies, and (iii) some cytokines, VEGF and three pro-inflammatory cytokines, i.e., IL-6, IL-8, and IL-17, decreased with an increasing selenite concentration. Finally, interactomic studies show that GPX1 and SELK, and the four pro-inflammatory cytokines are functionally correlated evidencing a putative anti-inflammatory role for the selenite. PMID- 23442932 TI - A new hydroxychavicol dimer from the roots of Piper betle. AB - A new hydroxychavicol dimer, 2-(g'-hydroxychavicol)-hydroxychavicol (1), was isolated from the roots of Piper betle Linn. along with five known compounds, hydroxychavicol (2), aristololactam A II (3), aristololactam B II (4), piperolactam A (5) and cepharadione A (6). The structures of these isolated compounds were elucidated by spectroscopic methods. Compounds 1 and 2 exhibited inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils. PMID- 23442933 TI - Artificial and natural sialic acid precursors influence the angiogenic capacity of human umbilical vein endothelial cells. AB - N-acetylneuraminic acid (Neu5Ac) represents the most common terminal carbohydrate residue in many mammalian glycoconjugates and is directly involved in a number of different physiological as well as pathological cellular processes. Endogenous sialic acids derive from the biosynthetic precursor molecule N-acetyl-D mannosamine (ManNAc). Interestingly, N-acyl-analogues of D-mannosamine (ManN) can also be incorporated and converted into corresponding artificial sialic acids by eukaryotic cells. Within this study, we optimized a protocol for the chemical synthesis of various peracetylated ManN derivatives resulting in yields of approximately 100%. Correct molecular structures of the obtained products ManNAc, N-propanoyl-ManN (ManNProp) and N-butyl-ManN (ManNBut) were verified by GC-, ESI MS- and NMR-analyses. By applying these substances to human umbilical vein endothelial cells (HUVECs), we could show that each derivative was metabolized to the corresponding N-acylneuraminic acid variant and subsequently incorporated into nascent glycoproteins. To investigate whether natural and/or artificial sialic acid precursors are able to modulate the angiogenic capacity of HUVECs, a spheroid assay was performed. By this means, an increase in total capillary length has been observed when cells incorporated N-butylneuraminic acid (Neu5But) into their glycoconjugates. In contrast, the natural precursor ManNAc inhibited the growth of capillaries. Thus, sialic acid precursors may represent useful agents to modulate blood vessel formation. PMID- 23442934 TI - Lee et al., Inhibitory effect and mechanism of antiproliferation of isoatriplicolide tiglate (PCAC) from Paulownia Coreana. Molecules 2012, 17, 5945 5951: a note regarding Paulownia coreana. PMID- 23442935 TI - Hirtinone, a Novel cycloartane-type triterpene and other compounds from Trichilia hirta L. (Meliaceae). AB - One novel triterpene cycloartane-type, named hirtinone (1), six protolimonoids - nilocitin (2), dihydronilocitin B (3), melianone epimers (4) and (5), piscidinol A (6) and melianone lactone (7), one tertranortriterpenoid, hirtin (8), and one sesquiterpene, spathulenol (9), were identified in the fruits of Trichilia hirta. The structures were established by 1D and 2D NMR (1H and 13C-NMR, DEPTQ, 1H-1H COSY, 1H-1H-NOESY, HSQC and HMBC), high resolution mass spectroscopy (HR-ESI-MS) and infrared (IR) spectral data. PMID- 23442936 TI - Does a minimally invasive approach result in better pulmonary function postoperatively when compared with median sternotomy for coronary artery bypass graft? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Does a minimally invasive approach result in better pulmonary function postoperatively when compared with median sternotomy for coronary artery bypass graft?'. Procedures such as limited sternotomy and minimally invasive direct coronary artery bypass (MIDCAB) though a minithoracotomy were regarded as minimally invasive. Overall, 681 papers were found, of which eight represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, evidence level, relevant outcomes and results of these papers were tabulated. Three randomized, controlled trials (RCT) were included: One study suggested that ministernotomy dividing the corpus sterni (n = 50) offers no advantage over standard sternotomy (n = 50) during the first 10 postoperative days. Two further studies reported on minithoracotomy: one trial presented data suggesting that minithoracotomy (n = 21) is as safe as standard sternotomy with (n = 18) or without (n = 19) cardiopulmonary bypass, but without the benefit ascribed to the minimally invasive incision. A two-centre report investigated pulmonary function as a secondary outcome and claimed that minithoracotomy worsens FEV1 and FVC. The study was not powered to detect these differences as pulmonary function data were available only for one of the centres. Five non-randomized reports were also included in this analysis: These investigated outcomes after minithoracotomy or limited sternotomy compared with standard sternotomy. Patient groups were small, involving <20 subjects per group. Non-randomized studies suggested a benefit to postoperative lung function in using thoracotomy. One of these reports included only patients with severe chronic obstructive pulmonary disease (COPD) (FEV1 <70% of predicted) and detected benefits in selected patients undergoing MIDCAB. A further study was in agreement with the above statement in patients without COPD. MIDCAB may be more painful initially, but results in quicker recovery of lung function. Demonstrating the benefits of ministernotomy compared with the standard sternal incision was less clear. One paper demonstrates better outcomes when compared with standard sternotomy, while another reports no difference. We conclude that non-randomized studies support the hypothesis that minimally invasive coronary artery bypass benefits postoperative lung function in patients with known respiratory problems. PMID- 23442937 TI - Two-stage unilateral versus one-stage bilateral single-port sympathectomy for palmar and axillary hyperhidrosis. AB - OBJECTIVES: Video-assisted thoracoscopic sympathectomy is currently the best treatment for palmar and axillary hyperhidrosis. It can be performed through either one or two stages of surgery. This study aimed to evaluate the operative and postoperative results of two-stage unilateral vs one-stage bilateral thoracoscopic sympathectomy. METHODS: From November 1995 to February 2011, 270 patients with severe palmar and/or axillary hyperhidrosis were recruited for this study. One hundred and thirty patients received one-stage bilateral, single-port video-assisted thoracoscopic sympathectomy (one-stage group) and 140, two-stage unilateral, single-port video-assisted thoracoscopic sympathectomy, with a mean time interval of 4 months between the procedures (two-stage group). RESULTS: The mean postoperative follow-up period was 12.5 (range: 1-24 months). After surgery, hands and axillae of all patients were dry and warm. Sixteen (12%) patients of the one-stage group and 15 (11%) of the two-stage group suffered from mild/moderate pain (P = 0.8482). The mean operative time was 38 +/- 5 min in the one-stage group and 39 +/- 8 min in the two-stage group (P = 0.199). Pneumothorax occurred in 8 (6%) patients of the one-stage group and in 11 (8%) of the two stage group. Compensatory sweating occurred in 25 (19%) patients of the one-stage group and in 6 (4%) of the two-stage group (P = 0.0001). No patients developed Horner's syndrome. CONCLUSIONS: Both two-stage unilateral and one-stage bilateral single-port video-assisted thoracoscopic sympathectomies are effective, safe and minimally invasive procedures. Two-stage unilateral sympathectomy can be performed with a lower occurrence of compensatory sweating, improving permanently the quality of life in patients with palmar and axillary hyperhidrosis. PMID- 23442938 TI - Bronchiectasis due to pulmonary artery aneurysm. AB - Pulmonary artery aneurysm (PAA) is a rare entity. We report what we believe to be the first case of bronchiectasis resulting from a PAA, which in turn developed after a previous Senning procedure for transposition of the great vessels during infancy. The patient had bronchiectasis secondary to compression of the left main bronchus because of a PAA. Bronchiectasis is a condition indicating lung resection. Despite the patient receiving medical therapy to treat recurrent pneumonia, lobectomy was necessary to prevent this and other possible complications. PMID- 23442939 TI - Repair of anomalous origin of the left coronary artery from the pulmonary artery in infants. AB - OBJECTIVES: Anatomical repair seems an ideal method for the surgical treatment of the anomalous left coronary artery arising from the pulmonary artery (ALCAPA) in infancy. The medium-term outcome has been investigated for infants with ALCAPA following the restoration of a dual-coronary arterial circulation. METHODS: Between April 1995 and July 2012, 23 infants with a median age of 4 months underwent surgical repair of ALCAPA in our department. Direct implantation of the anomalous coronary artery into the ascending aorta was feasible in 16 patients. A trap door flap method was used in 5 cases and a tubular extension technique in 2. No infant underwent mitral valve repair at the time of ALCAPA surgery. Left ventricular function and the degree of mitral valve regurgitation were assessed during a 10-year follow-up. RESULTS: Four patients died in the early postoperative period, without independent predictors associated with this mortality. During follow-up, improvement in myocardial function occurred in all patients both early and late. There was only one improvement in severe mitral valve regurgitation. Subsequently, 2 children needed mitral valve replacement. There were no early or late reoperations of the reimplanted coronary arteries. CONCLUSIONS: Aortic reimplantation is an effective surgical treatment for ALCAPA in infants burdened with a low risk of reoperation due to coronary artery stenosis. There was good potential for myocardial recovery within the first year after surgery. Restoration of the anatomical coronary circulation did not improve mitral valve function in infants with severe preoperative mitral incompetence. PMID- 23442940 TI - Successful replacement of a HeartAssist 5 ventricular assist device with a HeartWare without removal of the original sewing/attachment rings: how to do it. AB - Despite technological advances in a newer generation of ventricular assist devices (VAD), complications, such as pump thromboses, remain a significant cause of morbidity and indeed mortality in these patients. We present the case of a 34 year old patient who underwent HeartAssist 5 (HA5) implantation as a bridge to cardiac transplant. After an initial uneventful recovery, he developed a pump thrombosis that was refractory to medical treatment. We present the surgical technique used to exchange the HA5 with a HeartWare (HVAD), leaving the old inflow-sewing ring in situ. PMID- 23442941 TI - Single-centre experience with mitral valve repair in asymptomatic patients with severe mitral valve regurgitation. AB - OBJECTIVES: Guidelines recommend surgical mitral valve repair in selected patients with asymptomatic severe mitral valve regurgitation (MR), but the role of repair remains a matter of debate. Survival analyses of operated asymptomatic patients have been reported, but long-term haemodynamics and quality of life are not well defined. The aim of this study was to report the long-term follow-up focusing on these aspects. METHODS: Our database identified patients who underwent primary isolated mitral valve repair for severe MR and were asymptomatic by New York Heart Association Class I and in sinus rhythm. To obtain sufficient length of follow-up, only patients operated on before 2006 returned for an echocardiogram and quality-of-life assessment (SF-36). RESULTS: Between May 1991 and December 2005, 46 asymptomatic patients with severe MR and a normal left ventricular function (ejection fraction >60%) were operated on. Mean age was 50.2 +/- 13.2 years and 89% of patients were male. There were no operative deaths. Mean follow-up was 8.4 +/- 3.9 years with 386 patient-years, survival was 93.3% at 12 years and comparable with the general age-matched Dutch population. Follow-up echocardiography showed that 92% had no to mild MR, and 3 patients had moderate MR. Left ventricular function was good/impaired/moderate in 66/29/5% of patients. Quality-of-life SF-36 assessment showed that mean physical and mental health components were 83 +/- 17 and 79 +/- 17, which was comparable with that of the general age- and gender-matched Dutch population. CONCLUSIONS: Our experience shows that mitral valve repair for severe MR in asymptomatic patients is safe, and has satisfactory long-term survival with a low recurrence rate of MR, good left ventricular function, and excellent quality of life that is comparable with the general Dutch population. PMID- 23442942 TI - Is a minimally invasive approach for resection of benign cardiac masses superior to standard full sternotomy? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'is a minimally invasive approach for resection of benign cardiac masses superior to standard full sternotomy?' A total of 50 papers were found using the reported search, of which, 11 represented the best evidence to answer the clinical question. The authors, country, journal, date of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All 11 papers were retrospective studies, from which 4 were case-control studies comparing the minimally invasive approach with conventional full sternotomy, and 7 were case series. There were two minimally invasive techniques used, a right mini-thoracotomy and a partial hemi sternotomy, the former being the most commonly used. The resection of benign cardiac masses is a low-risk procedure, with no mortality or conversions to full sternotomy reported. From the 4 case-control studies, cross-clamp time was similar in both groups, and only one report found a prolonged perfusion time with the minimally invasive approach. The incidence of major postoperative complications, including bleeding requiring reoperation (average from case control studies: 0-4.5 vs 0-5.8%), renal failure (0 vs 0-10%) and prolonged ventilation (6-13 vs 11-19%), for the two approaches was similar. The incidence of postoperative stroke was better for the minimally invasive approach in one study (0 vs 14%, P = 0.023). The main advantages of this technique are shorter intensive care unit (26-31 vs 46-60 h) and hospital stay (3.6-5.2 vs 6.2-7.4 days), the minimally invasive approach being significantly better in one and three reports, respectively. We conclude that minimally invasive resection of a benign cardiac mass using a right mini-thoracotomy approach can be performed with an operative morbidity and mortality at least similar to the standard full sternotomy approach. The information currently available for the minimally invasive approach for the resection of benign cardiac masses is limited and based only on retrospective studies and, therefore, prospective studies are required to confirm the potential benefits of minimally invasive surgery. PMID- 23442943 TI - Differences in sex, angiographic frequency, and parameters in patients with coronary artery anomalies: single-center screening of 25 368 patients by coronary angiography. AB - BACKGROUND: Although the prevalence of coronary artery anomalies varies in different series, the precise population frequency is unknown. MATERIALS AND METHODS: The medical records of all patients who underwent coronary angiography between January 2002 and August 2012 were retrieved, and 238 cases with coronary anomalies were evaluated. Unlike other studies, we compared several angiographic parameters (fluoroscopy time, number of images, and catheters used) in addition to frequency and sex data. RESULTS: The angiographic frequency of coronary artery anomalies was 0.94%. The most common coronary anomaly was a left anterior descending-circumflex artery originating from separate ostia (0.29%). The second most common anomaly was a right coronary artery (RCA) originating from the left sinus of Valsalva (sV) (0.23%). Overall, coronary artery anomalies (1.28 vs. 0.80%; P<0.001) and a left anterior descending-circumflex artery originating from separate ostia (41.3 vs. 25.3%, P=0.010) were more frequent in women than in men. The percentage of patients requiring more than two catheters during the procedure was significantly higher for an RCA originating from the left sV (45.7 vs. 16.7%, P<0.001) and in hypertensive patients (85.7 vs. 70.8%, P=0.015). On comparing the three most common coronary anomalies, an anomalous RCA originating from the left sV had a significantly higher value for at least one angiographic parameter. CONCLUSION: An anomalous RCA originating from the left sV is the most difficult type of anomaly to perform the ostial coronary cannulation during procedure. The results of this study may lead to the development of more suitable diagnostic catheters for an anomalous RCA originating from the left sV. PMID- 23442944 TI - Quantification of the effect of clopidogrel on enzymatic infarct size related to a percutaneous coronary intervention in patients with acute coronary syndromes: insights from the CHAMPION percutaneous coronary intervention trial. AB - OBJECTIVES: Using data from the CHAMPION percutaneous coronary intervention (PCI), we determined the relationship between clopidogrel started at least 5 days before PCI (maintenance of clopidogrel) and PCI-related enzymatic infarct size. BACKGROUND: Clopidogrel is recommended in patients with acute coronary syndrome (ACS) managed with PCI, but its effect on PCI-related myonecrosis in contemporary patients has not been quantified. PATIENTS AND METHODS: Patients with ACS (with or without ST-segment elevation) who underwent PCI and had at least three creatine kinase-MB (CK-MB) samples after PCI were included. Enzymatic infarct size was defined as the peak CK-MB concentration indexed by its upper limit of normal. Associations between maintenance clopidogrel and enzymatic infarct size were explored using multivariable linear regression (with and without missing data imputation) and propensity score analysis using inverse probability weighting. RESULTS: Of 8877 patients randomized, 6327 (71.3%) were included (median age 61 years, 73% male, 13% ACS with ST-segment elevation). Of these 6327 patients, 2015 (31.8%) were on maintenance clopidogrel. After multivariable adjustment, maintenance clopidogrel was associated with a reduction in enzymatic infarct size {beta=-0.63; 47% decrease in peak CK-MB [95% confidence interval (CI) 35, 56%]}. Multivariable linear regression with multiple imputations and inverse probability weighting propensity score analysis yielded similar results, with maintenance clopidogrel associated with 44% (95% CI 33, 53%) and 29% (95% CI 24, 33%) infarct size reductions. CONCLUSION: In this subgroup analysis of modern ACS patients, clopidogrel maintenance was independently associated with smaller enzymatic infarct size after PCI. These results are consistent with previous observations suggesting a benefit of clopidogrel on the procedural outcome and quantify this benefit. PMID- 23442945 TI - Detection and quantification of myocardial perfusion defects by resting single phase 64-slice cardiac computed tomography angiography compared with SPECT myocardial perfusion imaging. AB - OBJECTIVE: Hypoenhanced regions on cardiac computed tomography angiography (CCTA) correlate with myocardial hypoperfusion. We evaluated the ability of resting single-phase 64-slice CCTA to detect the presence of myocardial infarction (MI) compared with nuclear myocardial perfusion imaging (MPI). METHODS: One hundred and forty symptomatic patients (age 66+/-12 years, 64% men) with an irreversible perfusion defect (n=69) or a normal/reversible perfusion defect (n=71) on MPI were subjected to CCTA for further evaluation. MI on CCTA was detected visually on the basis of areas of hypoattenuation (dark) in the myocardium and the corresponding Hounsfield Units (HU) were measured. RESULTS: CCTA accurately detected MI in 62 patients with an irreversible perfusion defect on MPI, yielding a sensitivity of 90%, a specificity of 94%, a negative predictive value of 91%, and a positive predictive value of 94%. The mean HU of normal and infarcted left ventricular myocardium was 107+/-23 and 16+/-40, respectively (P<0.001). An HU cut-off of 28 detected the presence of myocardial scar with 86% sensitivity and 59% specificity. The infarct volume measured by CCTA correlated well with the summed rest score (r=0.567; P<0.001) and the summed stress score (r=0.489; P<0.001) on MPI. In a substudy of 50 patients, the GE perfusion tool yielded a sensitivity of 92%, a specificity of 73%, an negative predictive value of 91%, and a positive predictive value of 76% in detecting MI. CONCLUSION: Resting single-phase CCTA is highly accurate in detecting and quantifying MI. This study highlights a novel clinical utility of CCTA in addition to assessment of plaque burden and stenosis with no risk of additional radiation or contrast exposure to the patient. PMID- 23442946 TI - Seroepidemiology of Toxoplasma gondii infection in women of child-bearing age in central Ethiopia. AB - BACKGROUND: Toxoplasma gondii infections during pregnancy can result in abortion or congenital defects. Prevalence and risk factors of toxoplasmosis in women of child-bearing age in Ethiopia are unknown. The current study was conducted with the objectives of estimating the seroprevalence and potential risk factors in acquiring T. gondii infection by women of child-bearing age in Central Ethiopia. METHODS: A cross-sectional study was conducted from March 2011 to September 2011. Sera of 425 women were analyzed by indirect enzyme linked immunosorbent assay (ELISA). A questionnaire survey was administered for all study participants to gather information on risk factors. RESULTS: The study revealed that anti- T. gondii IgG antibodies were detected in 81.4% of the samples of which 78.4% were positive for only IgG and 3.06% positive for both IgG and IgM antibodies. Seroprevalence of IgM antibodies to T. gondii (4.0%, 95% CI: 2.14, 5.86) was suggestive of recent infections. Of the 213 pregnant women 9 (4.2 %) were IgM reactive. Out of 17 potential risk factors investigated, univariate logistic regression showed significant association of T. gondii infection with study area, age, pregnancy status, raw vegetable consumption, source of water, presence of cats at home, contact with cats, HIV status and precaution during cats' feces cleaning (P <= 0.05). The final logistic regression model revealed that: the probability of acquiring T. gondii infection by women of Debre-Zeit was 4.46 times (95% CI of adjusted odds ratio [aOR]: 1.67, 11.89; P =0.003) higher compared to women of Ambo, pregnant women were twice (95% CI aOR: 1.13, 3.59; P = 0.018) more likely to be seropositive than non-pregnant women and women who consume raw vegetable were at increased risk of infection (aOR = 2.21, 95% CI: 1.03, 4.78; P = 0.043) than women who didn't consume. CONCLUSION: The seroprevalence of T. gondii infection in women of child-bearing age in Central Ethiopia is high. Study area, pregnancy and raw vegetable consumption are risk factors to acquire T. gondii infection. Educational program, antenatal screening of pregnant women and further epidemiological studies to uncover the economic and health impact of toxoplasmosis are suggested. PMID- 23442947 TI - Waveform analysis of tremor may help to differentiate Parkinson's disease from drug-induced parkinsonism. AB - In this study, we analyzed the waveform characteristics of resting tremor by accelerometer recordings in patients with drug-induced parkinsonism (DIP) and Parkinson's disease (PD). We prospectively recruited 12 patients with tremulous PD and 12 patients with DIP presenting with resting tremor. Tremor was recorded from the more affected side and was recorded twice for a 60 s period in each patient. Peak frequency, amplitude and all harmonic peaks were obtained, and the asymmetry of the decay of the autocorrelation function, third momentum and time reversal invariance were also computed using a mathematical algorithm. Among the parameters used in the waveform analysis, the harmonic ratio, time-reversal invariance and asymmetric decay of the autocorrelation function were different between PD and DIP at a statistically significant level (all p < 0.01). The total harmonic peak power and third momentum in the time series were not significantly different. The clinical characteristics of DIP patients may be similar to those of PD patients in some cases, which makes the clinical differentiation between DIP and PD challenging. Our study shows that the identification of parameters reflecting waveform asymmetry might be helpful in differentiating between DIP and PD. PMID- 23442948 TI - Birth and developmental correlates of birth weight in a sample of children with potential sensory processing disorder. AB - BACKGROUND: Most research examining birth history (i.e. related birth complications) and developmental milestone achievement follow outcomes for infants at-risk with very specific birth weight categories and gestational age classifications. The purpose of this study was to examine how birth weight relates to infants' birth histories and developmental milestone achievement when they fall into a variety of birth weight and gestational age categories. METHODS: In the current study, we examined birth histories and onset ages for developmental milestones by analyzing a convenience sample of anonymous existing data from 663 developmental histories completed by parents at the time of an initial evaluation at a pediatric outpatient occupational therapy clinic. Infants fell into 3 birth weight categories; low birth weight (LBW), normal birth weight (NBW), and high birth weight (HBW) and 3 gestational age classifications considered with birth weight; small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). RESULTS: NBW, AGA, and SGA infants with related birth complications had lower birth weights than infants without birth complications. Larger birth weights were associated with earlier ages for independent sitting for HBW infants, earlier ages for eating solids for NBW infants, and earlier walking onsets for LBW and NBW infants. Higher birth weights were also linked with rolling at a younger age for LGA infants, earlier walking and speaking words for AGA infants, and sooner independent sitting for SGA and AGA infants. CONCLUSIONS: Our findings suggest that birth weight and gestational age categories provide unique insights into infants' birth history and developmental milestone achievement. PMID- 23442949 TI - A thin line between channels and pumps. PMID- 23442950 TI - Superresolving dendritic spines. PMID- 23442951 TI - Divide and adhere. PMID- 23442952 TI - A tale of two ions and their membrane interactions: clearly the same or clearly different? PMID- 23442953 TI - Myosin-II-mediated directional migration of Dictyostelium cells in response to cyclic stretching of substratum. AB - Living cells are constantly subjected to various mechanical stimulations, such as shear flow, osmotic pressure, and hardness of substratum. They must sense the mechanical aspects of their environment and respond appropriately for proper cell function. Cells adhering to substrata must receive and respond to mechanical stimuli from the substrata to decide their shape and/or migrating direction. In response to cyclic stretching of the elastic substratum, intracellular stress fibers in fibroblasts and endothelial, osteosarcoma, and smooth muscle cells are rearranged perpendicular to the stretching direction, and the shape of those cells becomes extended in this new direction. In the case of migrating Dictyostelium cells, cyclic stretching regulates the direction of migration, and not the shape, of the cell. The cells migrate in a direction perpendicular to that of the stretching. However, the molecular mechanisms that induce the directional migration remain unknown. Here, using a microstretching device, we recorded green fluorescent protein (GFP)-myosin-II dynamics in Dictyostelium cells on an elastic substratum under cyclic stretching. Repeated stretching induced myosin II localization equally on both stretching sides in the cells. Although myosin-II-null cells migrated randomly, myosin-II-null cells expressing a variant of myosin II that cannot hydrolyze ATP migrated perpendicular to the stretching. These results indicate that Dictyostelium cells accumulate myosin II at the portion of the cell where a large strain is received and migrate in a direction other than that of the portion where myosin II accumulated. This polarity generation for migration does not require the contraction of actomyosin. PMID- 23442954 TI - Osmotic challenge drives rapid and reversible chromatin condensation in chondrocytes. AB - Changes in extracellular osmolality have been shown to alter gene expression patterns and metabolic activity of various cell types, including chondrocytes. However, mechanisms by which physiological or pathological changes in osmolality impact chondrocyte function remain unclear. Here we use quantitative image analysis, electron microscopy, and a DNase I assay to show that hyperosmotic conditions (>400 mOsm/kg) induce chromatin condensation, while hypoosmotic conditions (100 mOsm/kg) cause decondensation. Large density changes (p < 0.001) occur over a very narrow range of physiological osmolalities, which suggests that chondrocytes likely experience chromatin condensation and decondensation during a daily loading cycle. The effect of changes in osmolality on nuclear morphology (p < 0.01) and chromatin condensation (p < 0.001) also differed between chondrocytes in monolayer culture and three-dimensional agarose, suggesting a role for cell adhesion. The relationship between condensation and osmolality was accurately modeled by a polymer gel model which, along with the rapid nature of the chromatin condensation (<20 s), reveals the basic physicochemical nature of the process. Alterations in chromatin structure are expected to influence gene expression and thereby regulate chondrocyte activity in response to osmotic changes. PMID- 23442955 TI - Live-cell superresolution imaging by pulsed STED two-photon excitation microscopy. AB - Two-photon laser scanning microscopy (2PLSM) allows fluorescence imaging in thick biological samples where absorption and scattering typically degrade resolution and signal collection of one-photon imaging approaches. The spatial resolution of conventional 2PLSM is limited by diffraction, and the near-infrared wavelengths used for excitation in 2PLSM preclude the accurate imaging of many small subcellular compartments of neurons. Stimulated emission depletion (STED) microscopy is a superresolution imaging modality that overcomes the resolution limit imposed by diffraction and allows fluorescence imaging of nanoscale features. Here, we describe the design and operation of a superresolution two photon microscope using pulsed excitation and STED lasers. We examine the depth dependence of STED imaging in acute tissue slices and find enhancement of 2P resolution ranging from approximately fivefold at 20 MUm to approximately twofold at 90-MUm deep. The depth dependence of resolution is found to be consistent with the depth dependence of depletion efficiency, suggesting resolution is limited by STED laser propagation through turbid tissue. Finally, we achieve live imaging of dendritic spines with 60-nm resolution and demonstrate that our technique allows accurate quantification of neuronal morphology up to 30-MUm deep in living brain tissue. PMID- 23442956 TI - Two-photon excitation STED microscopy in two colors in acute brain slices. AB - Many cellular structures and organelles are too small to be properly resolved by conventional light microscopy. This is particularly true for dendritic spines and glial processes, which are very small, dynamic, and embedded in dense tissue, making it difficult to image them under realistic experimental conditions. Two photon microscopy is currently the method of choice for imaging in thick living tissue preparations, both in acute brain slices and in vivo. However, the spatial resolution of a two-photon microscope, which is limited to ~350 nm by the diffraction of light, is not sufficient for resolving many important details of neural morphology, such as the width of spine necks or thin glial processes. Recently developed superresolution approaches, such as stimulated emission depletion microscopy, have set new standards of optical resolution in imaging living tissue. However, the important goal of superresolution imaging with significant subdiffraction resolution has not yet been accomplished in acute brain slices. To overcome this limitation, we have developed a new microscope based on two-photon excitation and pulsed stimulated emission depletion microscopy, which provides unprecedented spatial resolution and excellent experimental access in acute brain slices using a long-working distance objective. The new microscope improves on the spatial resolution of a regular two photon microscope by a factor of four to six, and it is compatible with time lapse and simultaneous two-color superresolution imaging in living cells. We demonstrate the potential of this nanoscopy approach for brain slice physiology by imaging the morphology of dendritic spines and microglial cells well below the surface of acute brain slices. PMID- 23442958 TI - Characterization of a ligand binding site in the human transient receptor potential ankyrin 1 pore. AB - The pharmacology and regulation of Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel activity is intricate due to the physiological function as an integrator of multiple chemical, mechanical, and temperature stimuli as well as differences in species pharmacology. In this study, we describe and compare the current inhibition efficacy of human TRPA1 on three different TRPA1 antagonists. We used a homology model of TRPA1 based on Kv1.2 to select pore vestibule residues available for interaction with ligands entering the vestibule. Site directed mutation constructs were expressed in Xenopus oocytes and their functionality and pharmacology assessed to support and improve our homology model. Based on the functional pharmacology results we propose an antagonist binding site in the vestibule of the TRPA1 ion channel. We use the results to describe the proposed intravestibular ligand-binding site in TRPA1 in detail. Based on the single site substitutions, we designed a human TRPA1 receptor by substituting several residues in the vestibule and adjacent regions from the rat receptor to address and explain observed species pharmacology differences. In parallel, the lack of effect on HC-030031 inhibition by the vestibule substitutions suggests that this molecule interacts with TRPA1 via a binding site not situated in the vestibule. PMID- 23442957 TI - Cysteine scanning of CFTR's first transmembrane segment reveals its plausible roles in gating and permeation. AB - Previous cysteine scanning studies of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have identified several transmembrane segments (TMs), including TM1, 3, 6, 9, and 12, as structural components of the pore. Some of these TMs such as TM6 and 12 may also be involved in gating conformational changes. However, recent results on TM1 seem puzzling in that the observed reactive pattern was quite different from those seen with TM6 and 12. In addition, whether TM1 also plays a role in gating motions remains largely unknown. Here, we investigated CFTR's TM1 by applying methanethiosulfonate (MTS) reagents from both cytoplasmic and extracellular sides of the membrane. Our experiments identified four positive positions, E92, K95, Q98, and L102, when the negatively charged MTSES was applied from the cytoplasmic side. Intriguingly, these four residues reside in the extracellular half of TM1 in previously defined CFTR topology; we thus extended our scanning to residues located extracellularly to L102. We found that cysteines introduced into positions 106, 107, and 109 indeed react with extracellularly applied MTS probes, but not to intracellularly applied reagents. Interestingly, whole-cell A107C-CFTR currents were very sensitive to changes of bath pH as if the introduced cysteine assumes an altered pKa-like T338C in TM6. These findings lead us to propose a revised topology for CFTR's TM1 that spans at least from E92 to Y109. Additionally, side-dependent modifications of these positions indicate a narrow region (L102-I106) that prevents MTS reagents from penetrating the pore, a picture similar to what has been reported for TM6. Moreover, modifications of K95C, Q98C, and L102C exhibit strong state dependency with negligible modification when the channel is closed, suggesting a significant rearrangement of TM1 during CFTR's gating cycle. The structural implications of these findings are discussed in light of the crystal structures of ABC transporters and homology models of CFTR. PMID- 23442959 TI - Intramolecular proton transfer in channelrhodopsins. AB - Channelrhodopsins serve as photoreceptors that control the motility behavior of green flagellate algae and act as light-gated ion channels when heterologously expressed in animal cells. Here, we report direct measurements of proton transfer from the retinylidene Schiff base in several channelrhodopsin variants expressed in HEK293 cells. A fast outward-directed current precedes the passive channel current that has the opposite direction at physiological holding potentials. This rapid charge movement occurs on the timescale of the M intermediate formation in microbial rhodopsins, including that for channelrhodopsin from Chlamydomonas augustae and its mutants, reported in this study. Mutant analysis showed that the glutamate residue corresponding to Asp(85) in bacteriorhodopsin acts as the primary acceptor of the Schiff-base proton in low-efficiency channelrhodopsins. Another photoactive-site residue corresponding to Asp(212) in bacteriorhodopsin serves as an alternative proton acceptor and plays a more important role in channel opening than the primary acceptor. In more efficient channelrhodopsins from Chlamydomonas reinhardtii, Mesostigma viride, and Platymonas (Tetraselmis) subcordiformis, the fast current was apparently absent. The inverse correlation of the outward proton transfer and channel activity is consistent with channel function evolving in channelrhodopsins at the expense of their capacity for active proton transport. PMID- 23442960 TI - Specific binding of chloride ions to lipid vesicles and implications at molecular scale. AB - Biological membranes composed of lipids and proteins are in contact with electrolytes like aqueous NaCl solutions. Based on molecular dynamics studies it is widely believed that Na(+) ions specifically bind to 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC) membranes, whereas Cl(-) ions stay in solution. Here, we present a careful comparison of recent data from electrophoresis and isothermal titration calorimetry experiments as well as molecular dynamics simulations suggesting that in fact both ions show very similar affinities. The corresponding binding constants are 0.44(+/-0.05) M(-1) for Na(+) and 0.40(+/ 0.04) M(-1) for Cl(-) ions. This is highlighted by our observation that a widely used simulation setup showing asymmetric affinities of Na(+) and Cl(-) for POPC bilayers overestimates the effect of NaCl on the electrophoretic mobility of a POPC membrane by an order of magnitude. Implications for previous simulation results on the effect of NaCl on polarization of interfacial water, transmembrane potentials, and mechanisms for ion transport through bilayers are discussed. Our findings suggest that a range of published simulations results on the interaction of NaCl with phosphocholine bilayers have to be reconsidered and revised and that force field refinements are necessary for reliable simulation studies of membranes at physiological conditions on a molecular level. PMID- 23442961 TI - Adhesion stabilizes robust lipid heterogeneity in supercritical membranes at physiological temperature. AB - Regions of contact between cells are frequently enriched in or depleted of certain protein or lipid species. Here, we explore a possible physical basis that could contribute to this membrane heterogeneity using a model system of a giant vesicle tethered to a planar supported bilayer. Vesicles contain coexisting liquid-ordered (L(o)) and liquid-disordered (L(d)) phases at low temperatures and are tethered using trace quantities of adhesion molecules that preferentially partition into one liquid phase. We find that the L(d) marker DiI-C(12) is enriched or depleted in the adhered region when adhesion molecules partition into L(d) or L(o) phases, respectively. Remarkably, adhesion stabilizes an extended zone enriched or depleted of DiI-C(12) even at temperatures >15 degrees C above the miscibility phase transition when membranes have compositions that are in close proximity to a critical point. A stable adhesion zone is also observed in plasma membrane vesicles isolated from living RBL-2H3 cells, and probe partitioning at 37 degrees C is diminished in vesicles isolated from cells with altered cholesterol levels. Probe partitioning is in good quantitative agreement with predictions of the two-dimensional Ising model with a weak applied field for both types of model membranes. These studies experimentally demonstrate that large and stable domain structure can be mediated by lipids in single-phase membranes with supercritical fluctuations. PMID- 23442962 TI - Biophysical model of bacterial cell interactions with nanopatterned cicada wing surfaces. AB - The nanopattern on the surface of Clanger cicada (Psaltoda claripennis) wings represents the first example of a new class of biomaterials that can kill bacteria on contact based solely on their physical surface structure. The wings provide a model for the development of novel functional surfaces that possess an increased resistance to bacterial contamination and infection. We propose a biophysical model of the interactions between bacterial cells and cicada wing surface structures, and show that mechanical properties, in particular cell rigidity, are key factors in determining bacterial resistance/sensitivity to the bactericidal nature of the wing surface. We confirmed this experimentally by decreasing the rigidity of surface-resistant strains through microwave irradiation of the cells, which renders them susceptible to the wing effects. Our findings demonstrate the potential benefits of incorporating cicada wing nanopatterns into the design of antibacterial nanomaterials. PMID- 23442963 TI - A comparison of coarse-grained and continuum models for membrane bending in lipid bilayer fusion pores. AB - To establish the validity of continuum mechanics models quantitatively for the analysis of membrane remodeling processes, we compare the shape and energies of the membrane fusion pore predicted by coarse-grained (MARTINI) and continuum mechanics models. The results at these distinct levels of resolution give surprisingly consistent descriptions for the shape of the fusion pore, and the deviation between the continuum and coarse-grained models becomes notable only when the radius of curvature approaches the thickness of a monolayer. Although slow relaxation beyond microseconds is observed in different perturbative simulations, the key structural features (e.g., dimension and shape of the fusion pore near the pore center) are consistent among independent simulations. These observations provide solid support for the use of coarse-grained and continuum models in the analysis of membrane remodeling. The combined coarse-grained and continuum analysis confirms the recent prediction of continuum models that the fusion pore is a metastable structure and that its optimal shape is neither toroidal nor catenoidal. Moreover, our results help reveal a new, to our knowledge, bowing feature in which the bilayers close to the pore axis separate more from one another than those at greater distances from the pore axis; bowing helps reduce the curvature and therefore stabilizes the fusion pore structure. The spread of the bilayer deformations over distances of hundreds of nanometers and the substantial reduction in energy of fusion pore formation provided by this spread indicate that membrane fusion can be enhanced by allowing a larger area of membrane to participate and be deformed. PMID- 23442964 TI - Toward a better raft model: modulated phases in the four-component bilayer, DSPC/DOPC/POPC/CHOL. AB - The liquid-liquid (Ld + Lo) coexistence region within a distearoyl phosphatidylcholine/dioleoyl-phosphatidylcholine/palmitoyl-oleoyl phosphatidylcholine/cholesterol (DSPC/DOPC/POPC/CHOL) mixture displays a nanoscopic-to-macroscopic transition of phase domains as POPC is replaced by DOPC. Previously, we showed that the transition goes through a modulated phase regime during this replacement, in which patterned liquid phase morphologies are observed on giant unilamellar vesicles (GUVs). Here, we describe a more detailed investigation of the modulated phase regime along two different thermodynamic tielines within the Ld + Lo region of this four-component mixture. Using fluorescence microscopy of GUVs, we found that the modulated phase regime occurs at relatively narrow DOPC/(DOPC+POPC) ratios. This modulated phase window shifts to higher values of DOPC/(DOPC+POPC) when CHOL concentration is increased, and coexisting phases become closer in properties. Monte Carlo simulations reproduced the patterns observed on GUVs, using a competing interactions model of line tension and curvature energies. Sufficiently low line tension and high bending moduli are required to generate stable modulated phases. Altogether, our studies indicate that by tuning the lipid composition, both the domain size and morphology can be altered drastically within a narrow composition space. This lends insight into a possible mechanism whereby cells can reorganize plasma membrane compartmentalization simply by tuning the local membrane composition or line tension. PMID- 23442965 TI - Nonequilibrium distributions and hydrodynamic coupling distort the measurement of nanoscale forces near interfaces. AB - We calculate the displacement of a single spherical particle from the minimum of a harmonic well positioned near a plane wall and immersed in a uniform flow. A failure to account for the fluctuations in particle position orthogonal to the plane (leading to fluctuations in hydrodynamic drag) results in large discrepancies, with the naive displacement calculated by assuming no fluctuations in the balance of forces. The chief criterion for neglecting such fluctuations is that the stiffness of the harmonic potential exceeds the thermal stresses on the particle by at least two orders of magnitude. For micrometer-diameter particles typically employed in force spectroscopy of DNA, macromolecules, and molecular motors, this can lead to errors of up to 100% in the measured properties. The Supporting Material to the article provides an implementation of this model intended to fit experimental measurements for the stiffness of the harmonic potential constraining the particle. PMID- 23442966 TI - Wide-angle X-ray solution scattering for protein-ligand binding: multivariate curve resolution with Bayesian confidence intervals. AB - A new way to use wide-angle x-ray solution scattering to study protein-ligand binding is presented. First, scattering patterns are measured at different protein and ligand concentrations. Multivariate curve resolution based on singular value decomposition and global analysis is applied to estimate the binding affinities and reference patterns (i.e., the scattering patterns of individual components). As validated by simulation, Bayesian confidence intervals provide accurate uncertainty estimates for the binding free energies and reference patterns. Experimental results from several protein-ligand systems demonstrate the feasibility of the approach, which promises to expand the role of wide-angle x-ray scattering as a quantitative biophysical tool. PMID- 23442967 TI - Association equilibrium of the HIV-1 capsid protein in a crowded medium reveals that hexamerization during capsid assembly requires a functional C-domain dimerization interface. AB - Polymerization of the intact capsid protein (CA) of HIV-1 into mature capsidlike particles at physiological ionic strength in vitro requires macromolecularly crowded conditions that approach those inside the virion, where the mature capsid is assembled in vivo. The capsid is organized as a hexameric lattice. CA subunits in each hexamer are connected through interfaces that involve the CA N-terminal domain (NTD); pairs of CA subunits belonging to different hexamers are connected through a different interface that involves the C-terminal domain (CTD). At physiological ionic strength in noncrowded conditions, CA subunits homodimerize through this CTD-CTD interface, but do not hexamerize through the other interfaces (those involving the NTD). Here we have investigated whether macromolecular crowding conditions are able to promote hexamerization of the isolated NTD and/or full-length CA (with an inactive CTD-CTD interface to prevent polymerization). The oligomerization state of the proteins was determined using analytical ultracentrifugation in the absence or presence of high concentrations of an inert macromolecular crowding agent. Under the same conditions that promoted efficient assembly of intact CA dimers, neither NTD nor CA with an inactive CTD-CTD interface showed any tendency to form hexamers or any other oligomer. This inability to hexamerize was observed even in macromolecularly crowded conditions. The results indicate that a functional CTD-CTD interface is strictly required for hexamerization of HIV-1 CA through the other interfaces. Together with previous results, these observations suggest that establishment of NTD-CTD interactions involved in CA hexamerization during mature HIV-1 capsid assembly requires a homodimerization-dependent conformational switching of CTD. PMID- 23442968 TI - Single-molecule imaging reveals abeta42:abeta40 ratio-dependent oligomer growth on neuronal processes. AB - Soluble oligomers of the amyloid-beta peptide have been implicated as proximal neurotoxins in Alzheimer's disease. However, the identity of the neurotoxic aggregate(s) and the mechanisms by which these species induce neuronal dysfunction remain uncertain. Physiologically relevant experimentation is hindered by the low endogenous concentrations of the peptide, the metastability of Abeta oligomers, and the wide range of observed interactions between Abeta and biological membranes. Single-molecule microscopy represents one avenue for overcoming these challenges. Using this technique, we find that Abeta binds to primary rat hippocampal neurons at physiological concentrations. Although amyloid beta(1-40) as well as amyloid-beta(1-42) initially form larger oligomers on neurites than on glass slides, a 1:1 mix of the two peptides result in smaller neurite-bound oligomers than those detected on-slide or for either peptide alone. With 1 nM peptide in solution, Abeta40 oligomers do not grow over the course of 48 h, Abeta42 oligomers grow slightly, and oligomers of a 1:1 mix grow substantially. Evidently, small Abeta oligomers are capable of binding to neurons at physiological concentrations and grow at rates dependent on local Abeta42:Abeta40 ratios. These results are intriguing in light of the increased Abeta42:Abeta40 ratios shown to correlate with familial Alzheimer's disease mutations. PMID- 23442969 TI - Initial recognition of a cellodextrin chain in the cellulose-binding tunnel may affect cellobiohydrolase directional specificity. AB - Cellobiohydrolases processively hydrolyze glycosidic linkages in individual polymer chains of cellulose microfibrils, and typically exhibit specificity for either the reducing or nonreducing end of cellulose. Here, we conduct molecular dynamics simulations and free energy calculations to examine the initial binding of a cellulose chain into the catalytic tunnel of the reducing-end-specific Family 7 cellobiohydrolase (Cel7A) from Hypocrea jecorina. In unrestrained simulations, the cellulose diffuses into the tunnel from the -7 to the -5 positions, and the associated free energy profiles exhibit no barriers for initial processivity. The comparison of the free energy profiles for different cellulose chain orientations show a thermodynamic preference for the reducing end, suggesting that the preferential initial binding may affect the directional specificity of the enzyme by impeding nonproductive (nonreducing end) binding. Finally, the Trp-40 at the tunnel entrance is shown with free energy calculations to have a significant effect on initial chain complexation in Cel7A. PMID- 23442970 TI - Do clustering monoclonal antibody solutions really have a concentration dependence of viscosity? AB - Protein solution rheology data in the biophysics literature have incompletely identified factors that govern hydrodynamics. Whereas spontaneous protein adsorption at the air/water (A/W) interface increases the apparent viscosity of surfactant-free globular protein solutions, it is demonstrated here that irreversible clusters also increase system viscosity in the zero shear limit. Solution rheology measured with double gap geometry in a stress-controlled rheometer on a surfactant-free Immunoglobulin solution demonstrated that both irreversible clusters and the A/W interface increased the apparent low shear rate viscosity. Interfacial shear rheology data showed that the A/W interface yields, i.e., shows solid-like behavior. The A/W interface contribution was smaller, yet nonnegligible, in double gap compared to cone-plate geometry. Apparent nonmonotonic composition dependence of viscosity at low shear rates due to irreversible (nonequilibrium) clusters was resolved by filtration to recover a monotonically increasing viscosity-concentration curve, as expected. Although smaller equilibrium clusters also existed, their size and effective volume fraction were unaffected by filtration, rendering their contribution to viscosity invariant. Surfactant-free antibody systems containing clusters have complex hydrodynamic response, reflecting distinct bulk and interface-adsorbed protein as well as irreversible cluster contributions. Literature models for solution viscosity lack the appropriate physics to describe the bulk shear viscosity of unstable surfactant-free antibody solutions. PMID- 23442971 TI - Single-molecule imaging of the oligomer formation of the nonhexameric Escherichia coli UvrD helicase. AB - Superfamily I helicases are nonhexameric helicases responsible for the unwinding of nucleic acids. However, whether they unwind DNA in the form of monomers or oligomers remains a controversy. In this study, we addressed this question using direct single-molecule fluorescence visualization of Escherichia coli UvrD, a superfamily I DNA helicase. We performed a photobleaching-step analysis of dye labeled helicases and determined that the helicase is bound to 18-basepair (bp) double-stranded DNA (dsDNA) with a 3' single-stranded DNA (ssDNA) tail (12, 20, or 40 nt) in a dimeric or trimeric form in the absence of ATP. We also discovered through simultaneous visualization of association/dissociation of the helicase with/from DNA and the DNA unwinding dynamics of the helicase in the presence of ATP that these dimeric and trimeric forms are responsible for the unwinding of DNA. We can therefore propose a new kinetic scheme for the helicase-DNA interaction in which not only a dimeric helicase but also a trimeric helicase can unwind DNA. This is, to our knowledge, the first direct single-molecule nonhexameric helicase quantification study, and it strongly supports a model in which an oligomer is the active form of the helicase, which carries important implications for the DNA unwinding mechanism of all superfamily I helicases. PMID- 23442972 TI - Stochastic model-assisted development of efficient low-dose viral transduction in microfluidics. AB - Adenoviruses are commonly used in vitro as gene transfer vectors in multiple applications. Nevertheless, issues such as low infection efficiency and toxicity effects on host cells have not been resolved yet. This work aims at developing a new versatile tool to enhance the expression of transduced genes while working at low viral doses in a sequential manner. We developed a microfluidic platform with automatically controlled sequential perfusion stages, which includes 10 independent channels. In addition, we built a stochastic mathematical model, accounting for the discrete nature of cells and viruses, to predict not only the percentage of infected cells, but also the associated infecting-virus distribution in the cell population. Microfluidic system and mathematical model were coupled to define an efficient experimental strategy. We used human foreskin fibroblasts, infected by replication-incompetent adenoviruses carrying EGFP gene, as the testing system. Cell characterization was performed through fluorescence microscopy, followed by image analysis. We explored the effect of different aspects: perfusion, multiplicity of infection, and temporal patterns of infection. We demonstrated feasibility of performing efficient viral transduction at low doses, by repeated pulses of cell-virus contact. This procedure also enhanced the exogenous gene expression in the sequential microfluidic infection system compared to a single infection at a higher, nontoxic, viral dose. PMID- 23442973 TI - Matrix fixed charge density modulates exudate concentration during cartilage compression. AB - Electrolyte filtration arises due to the presence of fixed charges in cartilage extracellular matrix glycosaminoglycans (GAGs). Commonly assumed negligible, it can be important for design and interpretation of streaming potential measurements and modeling assumptions. To quantify the scale of this phenomenon, chloride ion concentration in exudate of compressed cartilage was measured by Mohr's titration and explant GAG content was colorimetrically assayed. Pilot studies indicated that an appropriate strain rate for experiments was 8 * 10(-3) s(-1) to eliminate concerns of exudate evaporation and explant damage (at low and high strain rates, respectively). Exudate chloride concentration of explants equilibrated in 1* PBS was significantly (p < 0.05) lower than the bath chloride concentration at strains of 37.5, 50, and 62.5%, with clear dependence on strain magnitude. Exudate chloride concentration was also significantly lower than that of the bath when 50% strain was applied after equilibration in 0.5, 1, and 2* PBS, with a trend for an increase in this relative difference with decreasing bath concentration (p = 0.065 between 0.5 and 2* PBS). Decreasing exudate chloride concentration correlated negatively with increasing postcompression GAG concentration. No difference between exudate chloride concentration and bath chloride concentration was ever observed for compression of uncharged agarose gel controls. Findings show that exudate from compressed cartilage is dilute relative to the bath due to the presence of matrix fixed charges, and this difference can generate diffusion potentials external to the explant, which may affect streaming potential measurements particularly under conditions of low strain rates and high strains. PMID- 23442974 TI - Quantitative analysis of competition in posttranscriptional regulation reveals a novel signature in target expression variation. AB - When small RNAs are loaded onto Argonaute proteins they can form the RNA-induced silencing complexes (RISCs), which mediate RNA interference (RNAi). RISC formation is dependent on a shared pool of Argonaute proteins and RISC-loading factors, and is susceptible to competition among small RNAs. We present a mathematical model that aims to understand how small RNA competition for RISC formation affects target gene repression. We discuss that small RNA activity is limited by RISC-formation, RISC-degradation, and the availability of Argonautes. We show that different competition conditions for RISC-loading result in different signatures of RNAi determined also by the amount of RISC-recycling taking place. In particular, we find that the small RNAs, although less efficient at RISC-formation, can perform in the low RISC-recycling range as well as their more effective counterparts. Additionally, we predict that under conditions of low RISC-loading efficiency and high RISC-recycling, the variation in target levels increases linearly with the target transcription rate. Furthermore, we show that RISC-recycling determines the effect that Argonaute scarcity conditions have on target expression variation. Our observations, taken together, offer a framework of predictions that can be used to infer from data the particular characteristics of underlying RNAi activity. PMID- 23442975 TI - Quality of life as measured by the short-form 36 (SF-36) questionnaire in patients with early systemic sclerosis and undifferentiated connective tissue disease. AB - OBJECTIVE: To investigate health-related quality of life (HRQOL) in patients affected by early systemic sclerosis (eSSc) and to compare it with that of patients with undifferentiated connective tissue disease (UCTD). METHODS: At baseline, 31 eSSc and 35 UCTD patients underwent clinical evaluation, laboratory investigations, nailfold videocapillaroscopy, echocardiography, and lung function tests. All patients and 40 controls, matched for sex and age completed the Short Form-36 (SF-36) questionnaire and the Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: SF-36 scores were significantly lower in eSSc and UCTD patients than in healthy controls as regards the following domains: physical component score (PCS), mental component score (MCS), physical functioning, role physical, bodily pain, general health and mental health. PCS was negatively correlated to the HAQ-DI (rho -0.59; p=0.0004) and ESR >20 mm/h (rho -0.58; p=0.0006) in eSSc patients. No statistically significant correlation was found between PCS, MCS and HAQ-DI in UCTD patients. Age, sex, disease duration, history of arthritis, low levels of either C3 or C4, a low DLCO (carbon monoxide lung diffusion) and inversion of the E/A ratio were not correlated to PCS and MCS in either eSSc or UCTD patients. CONCLUSION: Many eSSc or UCTD patients perceive they have an impaired quality of life in both physical and mental domains. This condition has to be taken into account by the clinicians involved in the care of these patients. PMID- 23442976 TI - Caspase-3 mediated release of SAC domain containing fragment from Par-4 is necessary for the sphingosine-induced apoptosis in Jurkat cells. AB - BACKGROUND: Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that selectively activates and induces apoptosis in cancer cells, but not in normal cells. The cancer specific pro-apoptotic function of Par-4 is encoded in its centrally located SAC (Selective for Apoptosis induction in Cancer cells) domain (amino acids 137-195). The SAC domain itself is capable of nuclear entry, caspase activation, inhibition of NF-kappaB activity, and induction of apoptosis in cancer cells. However, the precise mechanism(s) of how the SAC domain is released from Par-4, in response to apoptotic stimulation, is not well explored. RESULTS: In this study, we demonstrate for the first time that sphingosine (SPH), a member of the sphingolipid family, induces caspase-dependant cleavage of Par-4, leading to the release of SAC domain containing fragment from it. Par-4 is cleaved at the EEPD131G site on incubation with caspase-3 in vitro, and by treating cells with several anti-cancer agents. The caspase-3 mediated cleavage of Par-4 is blocked by addition of the pan-caspase inhibitor z-VAD-fmk, caspase-3 specific inhibitor Ac-DEVD-CHO, and by introduction of alanine substitution for D131 residue. Moreover, suppression of SPH-induced Akt dephosphorylation also abrogated the caspase dependant cleavage of Par-4. CONCLUSION: Evidence provided here shows that Par-4 is cleaved by caspase-3 during SPH-induced apoptosis. Cleavage of Par-4 leads to the generation of SAC domain containing fragment which may possibly be essential and sufficient to induce or augment apoptosis in cancer cells. PMID- 23442977 TI - Ganghwaljetongyeum, an anti-arthritic remedy, attenuates synoviocyte proliferation and reduces the production of proinflammatory mediators in macrophages: the therapeutic effect of GHJTY on rheumatoid arthritis. AB - BACKGROUND: Ganghwaljetongyeum (GHJTY), a complex herbal decoction, is used to treat rheumatoid arthritis. However, the action mechanism of GHJTY is not still unclear on rheumatoid arthritis. In this study, we examined the beneficial effects and the action mechanisms of GHJTY on synoviocyte proliferation and inflammatory mediators. METHODS: To test the effect of GHJTY on synoviocyte proliferation, HIG-82 cells, rabbit knee synovial membrane cells, were treated with GHJTY under IL-1beta. To evaluate the effects of GHJTY on proinflammatory mediators, we tested cytokine levels in RAW264.7 cells. RESULTS: Proliferation of HIG-82 cells was significantly inhibited by GHJTY treatment. We found that GHJTY caused cytoskeleton damage to HIG-82 cells. In contrast, treatment of GHJTY did not show any cytotoxicity to other different origin cell lines, HeLa and RAW264.7 cells. GHJTY inhibited IL-1beta-mediated NF-kappaB activation in HIG-82 cells and reduced the LPS-mediated production of proinflammatory cytokines, TNF-alpha, IL 12, and NO in RAW264.7 cells. In addition, the expression of cyclooxygenase in LPS-activated RAW264.7 cells was also decreased by GHJTY treatment. CONCLUSIONS: These results suggest that GHJTY might effectively attenuate rheumatoid arthritis by inhibiting the production of proinflammatory mediators and the proliferation of synoviocytes. PMID- 23442978 TI - Australian Diabetes Foot Network: practical guideline on the provision of footwear for people with diabetes. AB - Trauma, in the form of pressure and/or friction from footwear, is a common cause of foot ulceration in people with diabetes. These practical recommendations regarding the provision of footwear for people with diabetes were agreed upon following review of existing position statements and clinical guidelines. The aim of this process was not to re-invent existing guidelines but to provide practical guidance for health professionals on how they can best deliver these recommendations within the Australian health system. Where information was lacking or inconsistent, a consensus was reached following discussion by all authors. Appropriately prescribed footwear, used alone or in conjunction with custom-made foot orthoses, can reduce pedal pressures and reduce the risk of foot ulceration. It is important for all health professionals involved in the care of people with diabetes to both assess and make recommendations on the footwear needs of their clients or to refer to health professionals with such skills and knowledge. Individuals with more complex footwear needs (for example those who require custom-made medical grade footwear and orthoses) should be referred to health professionals with experience in the prescription of these modalities and who are able to provide appropriate and timely follow-up. Where financial disadvantage is a barrier to individuals acquiring appropriate footwear, health care professionals should be aware of state and territory based equipment funding schemes that can provide financial assistance. Aboriginal and Torres Strait Islanders and people living in rural and remote areas are likely to have limited access to a broad range of footwear. Provision of appropriate footwear to people with diabetes in these communities needs be addressed as part of a comprehensive national strategy to reduce the burden of diabetes and its complications on the health system. PMID- 23442979 TI - Replacement of glutamine with the dipeptide derivative alanyl-glutamine enhances in vitro maturation of porcine oocytes and development of embryos. AB - The presence of glutamine (Gln) in in vitro maturation (IVM) and in vitro culture (IVC) medium is a more potent factor for improving porcine oocyte and embryo development than other amino acids. However Gln is inherently unstable and spontaneously breaks down into ammonia, and therefore interferes with proper development. To avoid this adverse effect, Gln was replaced in the present study with its stable dipeptide derivative alanyl-glutamine (Ala-Gln) and the effects of this replacement on porcine IVM and IVC were evaluated. Replacement of Gln with Ala-Gln during IVM did not improve nuclear maturation, however numbers of early cleaved embryos were significantly increased after activation. Blastocyst formation rates were also significantly improved by using Ala-Gln during IVM. Replacement of Gln with Ala-Gln during IVC significantly increased total cell numbers in blastocysts. Blastocyst formation rate was also significantly higher when Ala-Gln was used in both IVM and IVC. In conclusion, the use of Ala-Gln rather than Gln gives better results for development in both porcine IVM and IVC. PMID- 23442980 TI - Phenolic compounds characterization and biological activities of Citrus aurantium bloom. AB - Citrus plants are known to possess beneficial biological activities for human health. In addition, ethnopharmacological application of plants is a good tool to explore their bioactivities and active compounds. This research was carried out to evaluate the phenolic and flavonoid analysis, antioxidant properties, anti inflammatory and anti cancer activity of Citrus aurantium bloom. The total phenolics and flavonoids results revealed that methanolic extract contained high total phenolics and flavonoids compared to ethanolic and boiling water extracts. The obtained total phenolics value for methanolic Citrus aurantium bloom extract was 4.55 +/- 0.05 mg gallic acid equivalent (GAE)/g dry weight (DW), and for total flavonoids it was 3.83 +/- 0.05 mg rutin equivalent/g DW. In addition, the RP-HPLC analyses of phenolics and flavonoids indicated the presence of gallic acid, pyrogallol, syringic acid, caffeic acid, rutin, quercetin and naringin as bioactive compounds. The antioxidant activity of Citrus aurantium bloom were examined by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and the ferric reducing/antioxidant potential (FRAP). The free radical scavenging and ferric reducing power activities were higher for the methanolic extract of Citrus aurantium bloom at a concentration of 300 MUg/mL, with values of 55.3% and 51.7%, respectively, as compared to the corresponding boiling water and ethanolic extracts, but the activities were lower than those of antioxidant standards such as BHT and alpha-tocopherol. Furthermore, the anti-inflammatory result of methanolic extract showed appreciable reduction in nitric oxide production of stimulated RAW 264.7 cells at the presence of plant extract. Apart from that, the anticancer activity of the methanolic extract was investigated in vitro against human cancer cell lines (MCF-7; MDA-MB-231), human colon adenocarcinoma (HT-29) and Chang cell as a normal human hepatocyte. The obtained result demonstrated the moderate to appreciable activities against all cell line tested and the compounds present in the extracts are non-toxic which make them suitable as potential therapeutics. PMID- 23442981 TI - Anthocyanins and their variation in red wines. II. Anthocyanin derived pigments and their color evolution. AB - Originating in the grapes, anthocyanins and their derivatives are the crucial pigments responsible for the red wine color. During wine maturation and aging, the concentration of monomeric anthocyanins declines constantly, while numerous more complex and stable anthocyanin derived pigments are formed, mainly including pyranoanthocyanins, polymeric anthocyanins produced from condensation between anthocyanin and/or flavan-3-ols directly or mediated by aldehydes. Correspondingly, their structural modifications result in a characteristic variation of color, from purple-red color in young red wines to brick-red hue of the aged. Because of the extreme complexity of chemical compounds involved, many investigations have been made using model solutions of know composition rather than wine. Thus, there is a large amount of research still required to obtain an overall perspective of the anthocyanin composition and its change with time in red wines. Future findings may well greatly revise our current interpretation of the color in red wines. This paper summarizes the most recent advances in the studies of the anthocyanins derived pigments in red wines, as well as their color evolution. PMID- 23442982 TI - Molecules Best Paper Award 2012. PMID- 23442983 TI - Association of fascin-1 with mortality, disease progression and metastasis in carcinomas: a systematic review and meta-analysis. AB - BACKGROUND: Fascin-1 is an actin-bundling protein expressed in many human carcinomas, although absent from most normal epithelia. Fascin-1 promotes filopodia formation, migration and invasion in carcinoma cells; in mouse xenograft tumor models it contributes to metastasis. Fascin-1 is an interesting candidate biomarker for aggressive, metastatic carcinomas but data from individual studies of human tumors have not yet been pooled systematically. METHODS: This systematic review was conducted in accordance with PRISMA guidelines, using fixed and random effects models, as appropriate, to undertake meta-analysis. RESULTS: A total of 26 immunohistochemical studies of 5 prevalent human carcinomas were identified for meta-analysis. Fascin-1 was associated with increased risk of mortality for breast (pooled hazard ratio, (HR) = 2.58; 95% confidence interval (CI) 1.48 to 4.52; P = 0.001), colorectal (HR = 1.60 (1.37 to 1.86; P <0.001) and esophageal carcinomas (HR = 1.35; CI 1.13 to 1.60; P = 0.001). There was no evidence of association of fascin-1 with mortality in gastric and lung carcinomas. Fascin-1 was associated with increased risk of disease progression in breast (HR = 2.48; CI 1.38 to 4.46; P = 0.002) and colorectal carcinomas (HR = 2.12; CI 1.00 to 4.47; P = 0.05), but not with progression of lung carcinomas (HR = 0.95; CI 0.49 to 1.85; P = 0.9). Fascin-1 was associated with increased risk of lymph node metastasis in colorectal (pooled risk ratio (RR) = 1.47; CI 1.26 to 1.71; P <0.001) and gastric carcinomas (RR = 1.43; CI 1.21 to 1.70; P <0.001). There was no evidence of association of fascin 1 with lymph node metastasis in lung or esophageal carcinomas. Fascin-1 was associated with increased risk of distant metastasis in colorectal (RR = 1.70; CI 1.18 to 2.45; P = 0.004) and gastric carcinomas (RR = 1.93; CI 1.21 to 3.33; P = 0.02). No association with distant metastasis in esophageal carcinomas was observed. Pooling across all the carcinomas provided strong evidence for association of fascin-1 with increased risk of mortality (HR = 1.44; CI 1.24 to 1.68; P <0.001; n = 3,645), lymph node metastasis (RR = 1.36; CI 1.18 to 1.55; P <0.001; n = 2,906) and distant metastasis (1.76; 1.34 to 2.32; P <0.001; n = 1,514). CONCLUSIONS: Fascin-1 is associated consistently with increased risk of mortality in breast, colorectal and esophageal carcinomas and with metastasis in colorectal and gastric carcinomas. The results were stable to various sensitivity analyses and did not vary by predefined subgroups. These data will assist rational decision making for focusing investigations of fascin-1 as a biomarker or therapeutic target onto the most relevant carcinomas. PMID- 23442984 TI - Childhood clumsiness and peer victimization: a case-control study of psychiatric patients. AB - BACKGROUND: Poor motor and social skills as well as peer victimization are commonly reported in both ADHD and autism spectrum disorder. Positive relationships between poor motor and poor social skills, and between poor social skills and peer victimization, are well documented, but the relationship between poor motor skills and peer victimization has not been studied in psychiatric populations. METHOD: 277 patients (133 males, 144 females), mean age 31 years, investigated for ADHD or autism spectrum disorder in adulthood and with normal intelligence, were interviewed about childhood peer victimization and examined for gross motor skills. The parents completed a comprehensive questionnaire on childhood problems, the Five to Fifteen. The Five to Fifteen is a validated questionnaire with 181 statements that covers various symptoms in childhood across eight different domains, one of them targeting motor skills. Regression models were used to evaluate the relationship between motor skills and the risk and duration of peer victimization, adjusted for sex and diagnosis. RESULTS: Victims were described as more clumsy in childhood than their non-victimized counterparts. A significant independent association was found between reportedly poor childhood gross motor skills and peer victimization (adjusted odds ratio: 2.97 [95% confidence interval: 1.46-6.07], n = 235, p = 0.003). In adulthood, the victimized group performed worse on vertical jumps, a gross motor task, and were lonelier. Other factors that were expected to be associated with peer victimization were not found in this highly selected group. CONCLUSION: Poor gross motor skills constitute a strong and independent risk factor for peer victimization in childhood, regardless of sex, childhood psychiatric care and diagnosis. PMID- 23442985 TI - Populene D analogues: design, concise synthesis and antiproliferative activity. AB - An efficient and concise synthesis of nine populene D analogues was performed using an iodine-catalyzed Prins cyclization as the key transformation. The antiproliferative activity of these new pyrans against several cancer cell lines was then investigated. Among them, an isochromene with moderate activity (mean logGI(50) = 0.91) was found. Additionally, compounds with selectivity toward the tumor cell lines NCI-ADR/RES, OVCAR-3, and HT29 were discovered. PMID- 23442986 TI - Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders. AB - OBJECTIVES: During circulatory failure, the ultimate goal of treatments that increase cardiac output is to reduce tissue hypoxia. This can only occur if oxygen consumption depends on oxygen delivery. We compared the ability of central venous oxygen saturation and markers of anaerobic metabolism to predict whether a fluid-induced increase in oxygen delivery results in an increase in oxygen consumption. DESIGN: Prospective study. SETTING: ICU. PATIENTS: Fifty-one patients with an acute circulatory failure (78% of septic origin). MEASUREMENTS: Before and after a volume expansion (500 mL of saline), we measured cardiac index, o2- and Co2-derived variables and lactate. MAIN RESULTS: Volume expansion increased cardiac index >= 15% in 49% of patients ("volume-responders"). Oxygen delivery significantly increased in these 25 patients (+32% +/- 16%, p < 0.0001). An increase in oxygen consumption >= 15% concomitantly occurred in 56% of these 25 volume-responders (+38% +/- 28%). Compared with the volume-responders in whom oxygen consumption did not increase, the volume-responders in whom oxygen consumption increased >= 15% were characterized by a higher lactate (2.3 +/- 1.1 mmol/L vs. 5.5 +/- 4.0 mmol/L, respectively) and a higher ratio of the veno arterial carbon dioxide tension difference (P(v - a)Co2) over the arteriovenous oxygen content difference (C(a - v)o2). A fluid-induced increase in oxygen consumption greater than or equal to 15% was not predicted by baseline central venous oxygen saturation but by high baseline lactate and (P(v - a)Co2/C(a - v)o2 ratio (areas under the receiving operating characteristics curves: 0.68 +/- 0.11, 0.94 +/- 0.05, and 0.91 +/- 0.06). In volume-nonresponders, volume expansion did not significantly change cardiac index, but the oxygen delivery decreased due to a hemodilution-induced decrease in hematocrit. CONCLUSIONS: In volume-responders, unlike markers of anaerobic metabolism, central venous oxygen saturation did not allow the prediction of whether a fluid-induced increase in oxygen delivery would result in an increase in oxygen consumption. This suggests that along with indicators of volume-responsiveness, the indicators of anaerobic metabolism should be considered instead of central venous oxygen saturation for starting hemodynamic resuscitation. PMID- 23442987 TI - Benchmarking the incidence and mortality of severe sepsis in the United States. AB - BACKGROUND: In 1992, the first consensus definition of severe sepsis was published. Subsequent epidemiologic estimates were collected using administrative data, but ongoing discrepancies in the definition of severe sepsis produced large differences in estimates. OBJECTIVES: We seek to describe the variations in incidence and mortality of severe sepsis in the United States using four methods of database abstraction. We hypothesized that different methodologies of capturing cases of severe sepsis would result in disparate estimates of incidence and mortality. DESIGN, SETTING, PARTICIPANTS: Using a nationally representative sample, four previously published methods (Angus et al, Martin et al, Dombrovskiy et al, and Wang et al) were used to gather cases of severe sepsis over a 6-year period (2004-2009). In addition, the use of new International Statistical Classification of Diseases, 9th Edition (ICD-9), sepsis codes was compared with previous methods. MEASUREMENTS: Annual national incidence and in-hospital mortality of severe sepsis. RESULTS: The average annual incidence varied by as much as 3.5-fold depending on method used and ranged from 894,013 (300/100,000 population) to 3,110,630 (1,031/100,000) using the methods of Dombrovskiy et al and Wang et al, respectively. Average annual increase in the incidence of severe sepsis was similar (13.0% to 13.3%) across all methods. In-hospital mortality ranged from 14.7% to 29.9% using abstraction methods of Wang et al and Dombrovskiy et al. Using all methods, there was a decrease in in-hospital mortality across the 6-year period (35.2% to 25.6% [Dombrovskiy et al] and 17.8% to 12.1% [Wang et al]). Use of ICD-9 sepsis codes more than doubled over the 6 year period (158,722 - 489,632 [995.92 severe sepsis], 131,719 - 303,615 [785.52 septic shock]). CONCLUSION: There is substantial variability in incidence and mortality of severe sepsis depending on the method of database abstraction used. A uniform, consistent method is needed for use in national registries to facilitate accurate assessment of clinical interventions and outcome comparisons between hospitals and regions. PMID- 23442988 TI - Determinants of mortality after hospital discharge in ICU patients: literature review and Dutch cohort study. AB - OBJECTIVES: First, to conduct a literature review on the long-term mortality of ICU patients and its determinants. Second, to assess the influence of the found determinants at 3, 6, and 12 months mortality after hospital discharge in the Dutch ICU population. DESIGN: Combination of a literature review to evaluate determinants of long-term mortality and a Dutch cohort study in which the found determinants are applied. SETTING: PubMed and EMBASE were searched on English written articles published between 1966 and 2011. The cohort study was conducted in ICU patients from 81 Dutch mixed ICUs. DATA: A total of 24 articles with a main focus on describing or predicting the case-mix adjusted long-term mortality of the general ICU population were identified. The cohort study consisted of 48,107 ICU patients who were discharged alive from the hospital between January 1, 2007, and October 1, 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The included articles are summarized on patient and study characteristics, methods, results, and determinants used for case-mix adjustment. Additionally, the quality of the included articles was assessed using a checklist for studies on long-term survival. The median mortality rate of the general ICU population 1 year after ICU admission was 24% (range 16% to 44%). The determinants used for case-mix adjustment differed widely between the studies. In the cohort study, we found that age, reason for ICU admission, and comorbidities were associated with all long-term mortality endpoints. However, the magnitude and direction of the influence by these determinants differed for the different endpoints (i.e., 3, 6, and 12 mo after hospital discharge). CONCLUSIONS: The long-term mortality found in the included articles was difficult to compare due to low quality, variation in case-mix, study design, and differences in case-mix adjustment. The most commonly used determinants in the literature were comparable to the most important determinants found in the Dutch cohort study. PMID- 23442989 TI - Long-term health benefits and costs of measurement of carotid intima-media thickness in prevention of coronary heart disease. AB - OBJECTIVE: Recently, it was demonstrated that information on carotid intima-media thickness (CIMT) and plaque may improve coronary heart disease (CHD) risk prediction through reclassification of some individuals to the correct risk category using the Framingham risk score. Our objective was to assess the currently unknown cost-effectiveness of CIMT measurements in primary prevention. METHODS: A hypothetical cohort of men and women aged 50-59 years and at intermediate or high CHD risk based on data from the Atherosclerosis Risk in Communities Study was simulated using a Markov model. Myocardial infarction (MI) events were used as a proxy for CHD. The effectiveness of pharmaceutical treatment was varied in the analysis. Sensitivity analysis was performed to obtain robust results. RESULTS: CIMT-based reclassification induced a 1% lower absolute risk of MI and 0.01-0.02 increase in quality-adjusted life years (QALYs) for men, and a 1-3% lower risk, and 0.03-0.05 increase in QALYs for women, over a period of 20-30 years. Corresponding costs were an additional $100 per man, and a cost-saving of $200-300 per woman. Over a 10-year period CIMT measurements were cost-effective with a probability of 66% (men), and 94% (women). Over a 30-year period, CIMT measurements had acceptable cost-effectiveness for men and women. CONCLUSION: Performing CIMT measurements in asymptomatic men and women aged 50-59 years results in additional, but small, health benefits. It takes time for these health benefits to outweigh the initial CIMT measurement costs. Our results support CIMT measurements for cardiovascular risk stratification, in particular for women, when focusing on long-term health. PMID- 23442990 TI - Blood pressure in professional male football players in Norway. AB - OBJECTIVES: Scarce data exist on blood pressure (BP) and secondary effects in young athletes. Hence, we aimed to study prevalence of high BP (>=140/90 mmHg) and the association to arterial compliance, left ventricle mass and left atrium volume. METHODS: A Norwegian preparticipation cardiac screening of male professional football players enrolled 493 white European, 47 matched controls, 49 black and 53 players of other ethnicity. BP was measured as a mean of two measurements. Height and weight were self-reported, and body surface area (BSA) was calculated. The echocardiographic parameters were indexed to BSA. Heart rates (HRs) by electrocardiography and pulse pressure (PP) were considered as surrogates for sympathetic activity. Arterial compliance was calculated as stroke volume(BSA)/PP. RESULTS: The players mean age was 25 years (18-38) and mean BP 122/69 +/- 11/8 mmHg. There were no significant differences in prevalence of hypertension between all players, 39 (7%), and controls, four (9%), or between white, 32 (7%), and black, five (10%), players. There was a significant positive linear relationship between BP and left ventricle mass(BSA), left atrium volume(BSA), stroke volume(BSA), HR and PP, and negative relationship to arterial compliance(BSA). CONCLUSION: Although the prevalence of high BP in professional football players was low, our data indicate a novel association between elevated BP and reduced arterial compliance, increased left ventricle mass and left atrium volume even in young athletes. This emphasizes closer focus on BP measurements and standardized follow-up after preparticipation screening of athletes. PMID- 23442991 TI - Combining distinctive and novel loci doubles BP reduction, reverses diastolic dysfunction and mitigates LV hypertrophy. AB - OBJECTIVES: Diastolic dysfunction often represents the onset of diastolic heart failure (DHF). We previously showed in principle that diastolic function in Dahl salt-sensitive rats (DSS) can be genetically determined by quantitative trait loci (QTLs) that also modulate blood pressure (BP). METHODS: We analyzed cardiac phenotypes of four 'single' congenic strains by echocardiography, in which a specific DSS chromosome segment was replaced by its normotensive Lewis homologue. RESULTS: Two of the strains permanently lowered BP, and but attenuated diastolic dysfunction only in rats at 10 weeks of age, not at 15 weeks fed on a 2% NaCl diet starting from 8 weeks of age. We then combined multiple QTLs by integrating several 'single' congenic strains. As a result, BP was greatly reduced. Cardiac dysfunction and LV hypertrophy were continuously improved from 10 to 15 weeks, although the degree and timing of the improvement varied among different congenic combinations. CONCLUSION: Distinct QTLs exist that simultaneously modulate BP and diastolic function. These QTLs, in combination, synergistically lowered BP and permanently alleviated or reversed diastolic dysfunction. The genes that are contained in the congenic strains affecting diastolic function are not known for their specific influence on BP. Novel long-term strategies of prognosis, diagnosis and therapy for hypertensive DHF appear from this work. PMID- 23442992 TI - Contributions to debated problems. PMID- 23442993 TI - Controlling measles in NSW: how are we doing in the context of other countries in the Western Pacific? PMID- 23442994 TI - NSW Annual vaccine-preventable disease report, 2011. AB - AIM: To describe the epidemiology of selected vaccine-preventable diseases in NSW for 2011. METHODS: Data from the NSW Notifiable Conditions Information Management System were analysed by: local health district of residence, age, Aboriginality, vaccination status, and organism, where available. Risk factor and vaccination status data were collected by public health units for case-patients following notification under the NSW Public Health Act 1991*. RESULTS: Outbreaks of measles and pertussis were reported in 2011, associated with unimmunised groups for measles, and a variety of factors for pertussis. Notification rates for other selected vaccine-preventable diseases remained stable. CONCLUSION: Vaccine preventable diseases are generally well controlled in NSW. However, pertussis remains an important public health issue. To prevent measles high population vaccination coverage, including vaccination in risk groups, is essential. PMID- 23442995 TI - NSW annual immunisation coverage report, 2011. AB - This annual report, the third in the series, documents trends in immunisation coverage in NSW for children, adolescents and the elderly, to the end of 2011. METHODS: Data from the Australian Childhood Immunisation Register, the NSW School Immunisation Program and the NSW Population Health Survey were used to calculate various measures of population coverage. RESULTS: During 2011, greater than 90% coverage was maintained for children at 12 and 24 months of age. For children at 5 years of age the improvement seen in 2010 was sustained, with coverage at or near 90%. For adolescents, there was improved coverage for all doses of human papillomavirus vaccine, both doses of hepatitis B vaccine, varicella vaccine and the dose of diphtheria, tetanus and acellular pertussis given to school attendees in Years 7 and 10. Pneumococcal vaccination coverage in the elderly has been steadily rising, although it has remained lower than the influenza coverage estimates. CONCLUSION: This report provides trends in immunisation coverage in NSW across the age spectrum. The inclusion of coverage estimates for the pneumococcal conjugate, varicella and meningococcal C vaccines in the official coverage assessments for 'fully immunised' in 2013 is a welcome initiative. PMID- 23442996 TI - NSW annual report describing adverse events following immunisation, 2011. AB - AIM: This report summarises Australian passive surveillance data for adverse events following immunisation in NSW for 2011. METHODS: Analysis of de-identified information on all adverse events following immunisation reported to the Therapeutic Goods Administration. RESULTS: 449 adverse events following immunisation were reported for vaccines administered in 2011; this is slightly higher than in 2010 (n=439) and the second highest number since 2003. The most commonly reported reactions were injection site reaction, fever, allergic reaction and malaise. A large number of injection site reactions were reported following administration of the 23-valent pneumococcal polysaccharide vaccine in adults aged 65 years and over (97.4/100000 doses) and in children aged less than 7 years following administration of the 13-valent pneumococcal conjugate vaccine (29.4/100000 doses) and combined diphtheria, tetanus, pertussis (acellular) and inactivated poliovirus (quadrivalent)-containing vaccines (47.1/100000 doses). Only 10% of the reported adverse events were categorised as serious. There were two reports of death however both were attributed to causes other than vaccination. CONCLUSION: The increased number of reports in 2011 is attributable to the high rates of injection site reactions in children associated with the administration of combined diphtheria, tetanus, pertussis (acellular) and inactivated poliovirus (quadrivalent)-containing vaccines and the 13-valent pneumococcal conjugate vaccine, as well as in adults following receipt of the 23 valent pneumococcal polysaccharide vaccine. PMID- 23442997 TI - EpiReview: Measles in NSW, 2002-2011. AB - Measles has been eliminated in NSW for more than a decade; however outbreaks associated with international travel do occur. This EpiReview describes the epidemiology of measles in NSW from 2002-2011. A total of 281 cases of measles were notified during the period, an average annual notification rate of 0.41 notifications per 100 000 population (range: 0.06-1.25). There were 139 hospitalisations recorded with a measles diagnosis in the 10-year reporting period, corresponding to a rate of 0.20 hospitalisations per 100 000 population. Of the 80 measles virus specimens genotyped, five genotypes were identified: D9 (38%), D8 (24%), D4 (16%), D5 (14%) with H1 identified less frequently (9%). No single genotype was associated with local transmission across successive years. To sustain good measles control, children should be vaccinated against measles on time through routine childhood immunisation, and all young adults who travel internationally should be vaccinated. Clinician awareness remains important in the early identification and control of measles to avoid further transmission during outbreaks and to enable the timely implementation of public health measures. PMID- 23442998 TI - Bug breakfast in the bulletin: the early impact of the national HPV vaccination program. PMID- 23442999 TI - Factsheet: measles. PMID- 23443000 TI - Communicable Diseases Report, NSW, July and August 2012. PMID- 23443001 TI - Age and menarcheal status do not influence metabolic response to aerobic training in overweight girls. AB - BACKGROUND: Multidisciplinary intervention is an alternative for the treatment of children and adolescent obese. However, the influence of age and menarcheal status in the pattern of metabolic response of obese girls has not been investigated. The following study examined the effects of a 12-week multidisciplinary intervention on metabolic health in overweight girls and the contribution of age and menarcheal status on the resulting changes. METHODS: Eighty-eight overweight girls (10 - 16 years) were considered initially for this study and randomly assigned (intervention group: n = 58; control group: n = 30). Forty-six girls completed the intervention program and 16 girls completed the follow-up for the control group. The 12-week intervention included aerobic exercises (three times per week) and nutritional intervention. Anthropometrical measures (body mass, body mass index and waist circumference), menarcheal status and metabolic profiles including glucose, insulin, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assessed in the beginning and after of intervention. Additionally, were calculated homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). RESULTS: After 12-week, girls decreased significantly the body mass (76.6 +/- 14.7 to 75.7 +/- 14.6 kg) body mass index (30.1 +/- 4.0 to 29.4 +/- 4.0 kg/m2) and waist circumference (98.9 +/- 10.9 to 96.5 +/- 11.4 cm). There were differences in HDL-C (43.1 +/- 8.2 to 50.3 +/- 9.4 mg/dl), TG (120.9 +/- 64.3 to 93.3 +/- 47.9 mg/dl) and insulin (16.9 +/- 7.6 to 15.6 +/- 9.8 mg/dl). Relative contribution of age was significant only for within-subject variability in waist circumference. CONCLUSIONS: The multidisciplinary based on aerobic training intervention used in this study produced substantial benefits on metabolic health indicators in overweight girls. The changes observed were not related to inter individual variability in age and maturity status. PMID- 23443003 TI - The adhesin complex protein (ACP) of Neisseria meningitidis is a new adhesin with vaccine potential. AB - The acp gene encoding the 13-kDa adhesin complex protein (ACP) from Neisseria meningitidis serogroup B strain MC58 was cloned and expressed in Escherichia coli, and the purified recombinant ACP (rACP) was used for immunization studies. Analysis of the ACP amino acid sequences from 13 meningococcal strains, isolated from patients and colonized individuals, and 178 strains in the Bacterial Isolate Genome Sequence (BIGS) database showed the presence of only three distinct sequence types (I, II, and III) with high similarity (> 98%). Immunization of mice with type I rACP in detergent micelles and liposomes and in saline solution alone induced high levels of serum bactericidal activity (SBA; titers of 1/512) against the homologous strain MC58 and killed strains of heterologous sequence types II and III with similar SBA titers (1/128 to 1/512). Levels of expression of type I, II, or III ACP by different meningococcal strains were similar. ACP functioned as an adhesin, as demonstrated by reduced adherence of acp knockout (MC58 DeltaACP) meningococci to human cells in vitro and the direct surface binding of rACP and by the ability of anti-rACP sera to inhibit adherence of wild type bacteria. ACP also mediated the invasion of noncapsular meningococci into human epithelial cells, but it was not a particularly impressive invasin, as the internalized bacterial numbers were low. In summary, the newly identified ACP protein is an adhesin that induces cross-strain bactericidal activity and is therefore an attractive target antigen for incorporation into the next generation of serogroup B meningococcal vaccines. IMPORTANCE: Infections caused by Neisseria meningitidis serogroup B are still significant causes of mortality and morbidity worldwide, and broadly protective vaccines of defined antigen composition are not yet licensed. Here, we describe the properties of the adhesin complex protein (ACP), which we demonstrate is a newly recognized molecule that is highly conserved and expressed to similar levels in meningococci and facilitates meningococcal interactions with human cells. We also report that a recombinant ACP protein vaccine induces murine antibodies that significantly kill meningococci expressing different ACP. Taken together, these properties demonstrate that ACP merits serious consideration as a component of a broadly protective vaccine against serogroup B meningococci. PMID- 23443002 TI - Early origins of child obesity: bridging disciplines and phases of development -- September 30--October 1, 2010. AB - This report summarizes a conference: "Early Origins of Child Obesity: Bridging Disciplines and Phases of Development", held in Chicago on September 30-October 1, 2010. The conference was funded in part by the National Institutes of Health and the Williams Heart Foundation, to achieve the conference objective: forging a next-step research agenda related to the early origins of childhood obesity. This research agenda was to include working with an array of factors (from genetic determinants to societal ones) along a continuum from prenatal life to age 7, with an emphasis on how the developing child deals with the challenges presented by his/her environment (prenatal, parental, nutritional, etc.). The conference offered a unique opportunity to facilitate communication and planning of future work among a variety of researchers whose work separately addresses different periods in early life. Over the span of two days, speakers addressed existing, critical research topics within each of the most-studied age ranges. On the final day, workshops fostered the discussion needed to identify the highest priority research topics related to linking varied early factor domains. These are presented for use in planning future research and research funding. PMID- 23443004 TI - Regulation of herpes simplex virus gB-induced cell-cell fusion by mutant forms of gH/gL in the absence of gD and cellular receptors. AB - Herpesvirus entry requires the viral glycoprotein triad of gB and gH/gL to carry out fusion between the virion envelope and a cellular membrane in order to release the nucleocapsid into the target cell. Herpes simplex virus (HSV) also requires glycoprotein gD to initiate the fusion cascade by binding a cell receptor such as nectin 1 or herpesvirus entry mediator (HVEM). While the structure of gB is that of a class III fusion protein, gH/gL has no features that resemble other viral fusion proteins. Instead, it is suggested that gH/gL acts as a regulator of gB. The crystal structure of HSV-2 gH/gL was obtained with a functional protein that had a deletion of 28 residues at the gH N terminus (gHDelta48/gL). Unexplainably, monoclonal antibodies (MAbs) with virus neutralizing activity map to these residues. To reconcile these two disparate observations, we studied the ability of gHDelta48/gL to regulate fusion. Here, we show that the protein induces low (constitutive) levels of fusion by gB in the absence of gD and/or receptor. However, when gD and receptor are present, this mutant functions as well as does wild-type (wt) gH/gL for fusion. We propose that gHDelta48/gL has an intermediate structure on the pathway leading to full regulatory activation. We suggest that a key step in the pathway of fusion is the conversion of gH/gL to an activated state by receptor-bound gD; this activated gH/gL resembles gHDelta48/gL. IMPORTANCE: Herpes simplex viruses (HSVs) cause many human diseases, from mild cold sores to lethal neonatal herpes. As an enveloped virus, HSV must fuse its membrane with a host membrane in order for replication to take place. The virus uses four glycoproteins for this process, gD, gB, and gH/gL, and either of two cell receptors, herpesvirus entry mediator (HVEM) and nectin 1. Although the virus can enter the cell by direct fusion at the plasma membrane or via endocytosis, the same four glycoproteins are involved. The absence of any of these proteins abolishes the entry process. Here, we show that a mutant form of gH/gL, gHDelta48/gL, can induce fusion of gB-expressing cells in the absence of gD and a gD receptor. Our study supports the concept that gB is the HSV fusogen and its activity is regulated by gH/gL. PMID- 23443005 TI - H2-independent growth of the hydrogenotrophic methanogen Methanococcus maripaludis. AB - Hydrogenotrophic methanogenic Archaea require reduced ferredoxin as an anaplerotic source of electrons for methanogenesis. H(2) oxidation by the hydrogenase Eha provides these electrons, consistent with an H(2) requirement for growth. Here we report the identification of alternative pathways of ferredoxin reduction in Methanococcus maripaludis that operate independently of Eha to stimulate methanogenesis. A suppressor mutation that increased expression of the glycolytic enzyme glyceraldehyde-3-phosphate:ferredoxin oxidoreductase resulted in a strain capable of H(2)-independent ferredoxin reduction and growth with formate as the sole electron donor. In this background, it was possible to eliminate all seven hydrogenases of M. maripaludis. Alternatively, carbon monoxide oxidation by carbon monoxide dehydrogenase could also generate reduced ferredoxin that feeds into methanogenesis. In either case, the reduced ferredoxin generated was inefficient at stimulating methanogenesis, resulting in a slow growth phenotype. As methanogenesis is limited by the availability of reduced ferredoxin under these conditions, other electron donors, such as reduced coenzyme F(420), should be abundant. Indeed, when F(420)-reducing hydrogenase was reintroduced into the hydrogenase-free mutant, the equilibrium of H(2) production via an F(420)-dependent formate:H(2) lyase activity shifted markedly toward H(2) compared to the wild type. IMPORTANCE: Hydrogenotrophic methanogens are thought to require H(2) as a substrate for growth and methanogenesis. Here we show alternative pathways in methanogenic metabolism that alleviate this H(2) requirement and demonstrate, for the first time, a hydrogenotrophic methanogen that is capable of growth in the complete absence of H(2). The demonstration of alternative pathways in methanogenic metabolism suggests that this important group of organisms is metabolically more versatile than previously thought. PMID- 23443006 TI - Unexpected diversity during community succession in the apple flower microbiome. AB - Despite its importance to the host, the flower microbiome is poorly understood. We report a culture-independent, community-level assessment of apple flower microbial diversity and dynamics. We collected flowers from six apple trees at five time points, starting before flowers opened and ending at petal fall. We applied streptomycin to half of the trees when flowers opened. Assessment of microbial diversity using tag pyrosequencing of 16S rRNA genes revealed that the apple flower communities were rich and diverse and dominated by members of TM7 and Deinococcus-Thermus, phyla about which relatively little is known. From thousands of taxa, we identified six successional groups with coherent dynamics whose abundances peaked at different times before and after bud opening. We designated the groups Pioneer, Early, Mid, Late, Climax, and Generalist communities. The successional pattern was attributed to a set of prevalent taxa that were persistent and gradually changing in abundance. These taxa had significant associations with other community members, as demonstrated with a cooccurrence network based on local similarity analysis. We also detected a set of less-abundant, transient taxa that contributed to general tree-to-tree variability but not to the successional pattern. Communities on trees sprayed with streptomycin had slightly lower phylogenetic diversity than those on unsprayed trees but did not differ in structure or succession. Our results suggest that changes in apple flower microbial community structure are predictable over the life of the flower, providing a basis for ecological understanding and disease management. IMPORTANCE: Flowering plants (angiosperms) represent a diverse group of an estimated 400,000 species, and their successful cultivation is essential to agriculture. Yet fundamental knowledge of flower associated microbiotas remains largely unknown. Even less well understood are the changes that flower microbial communities experience through time. Flowers are particularly conducive to comprehensive temporal studies because they are, by nature, ephemeral organs. Here, we present the first culture-independent time series of bacterial and archaeal communities associated with the flowers of apple, an economically important crop. We found unexpected diversity on apple flowers, including a preponderance of taxa affiliated with Deinococcus-Thermus and TM7, phyla that are understudied but thought to be tolerant to an array of environmental stresses. Our results also suggest that changes in microbial community structure on the apple flower may be predictable over the life of the flower, providing the basis for ecological understanding and disease management. PMID- 23443007 TI - Psychometric validation of the Self-Care Inventory-Revised (SCI-R) in UK adults with type 2 diabetes using data from the AT.LANTUS Follow-on study. AB - BACKGROUND: Achieving optimal outcomes in type 2 diabetes (T2DM) involves several demanding self-care behaviours, e.g. managing diet, activity, medications, monitoring glucose levels, footcare. The Self-Care Inventory-Revised (SCI-R) is valid for use in people with T2DM in the US. Our aim was to determine its suitability for use in the UK. METHODS: 353 people with T2DM participated in the AT.LANTUS Follow-on study, completing measures of diabetes self-care (SCI-R), generic and diabetes-specific well-being (W-BQ28), and diabetes treatment satisfaction (DTSQ). Statistical analyses were conducted to explore structure, reliability, and validity of the SCI-R. RESULTS: Principal components analysis indicated a 13-item scale (items loading >0.39) with satisfactory internal consistency reliability (alpha = 0.77), although neither this model nor any alternatives were confirmed in the confirmatory factor analysis. Acceptability was high (>95% completion for all but one item); ceiling effects were demonstrated for six items. As expected, convergent validity (correlations between self-care behaviours) was found for few items. Divergent validity was supported by expected low correlations between SCI-R total and well-being (rs = 0.02-0.21) and treatment satisfaction (rs = 0.29). Known-groups validity was partially supported with significant differences in SCI-R total by HbA1c (<= 7.5% (58 mmol/mol): 72 +/- 11, >7.5% (58 mmol/mol): 68 +/- 14, p < 0.05) and diabetes duration (<= 16 years: 67 +/- 13, >16 years: 71 +/- 12, p < 0.001) but not by presence/absence of complications or by insulin treatment algorithm. CONCLUSIONS: The SCI-R is a brief, valid and reliable measure of self-care in people with T2DM in the UK. However, ceiling effects raise concerns about its potential for responsiveness in clinical trials. Individual items may be more useful clinically than the total score. PMID- 23443008 TI - Pulsatile blood flow in human bone assessed by laser-Doppler flowmetry and the interpretation of photoplethysmographic signals. AB - Human bone blood flow, mean blood speed and the number of moving red blood cells were assessed (in arbitrary units), as a function of time, during one cardiac cycle. The measurements were obtained non-invasively on five volunteers by laser Doppler flowmetry at large interoptode spacing. The investigated bones included: patella, clavicle, tibial diaphysis and tibial malleolus. As hypothesized, we found that in all bones the number of moving cells remains constant during cardiac cycles. Therefore, we concluded that the pulsatile nature of blood flow must be completely determined by the mean blood speed and not by changes in blood volume (vessels dilation). Based on these results, it is finally demonstrated using a mathematical model (derived from the radiative transport theory) that photoplethysmographic (PPG) pulsations observed by others in the literature, cannot be generated by oscillations in blood oxygen saturation, which is physiologically linked to blood speed. In fact, possible oxygen saturation changes during pulsations decrease the amplitude of PPG pulsations due to specific features of the PPG light source. It is shown that a variation in blood oxygen saturation of 3% may induce a negative change of ~1% in the PPG signal. It is concluded that PPG pulsations are determined by periodic 'positive' changes of the reduced scattering coefficient of the tissue and/or the absorption coefficient at constant blood volume. No explicit experimental PPG measurements have been performed. As a by-product of this study, an estimation of the arterial pulse wave velocity obtained from the analysis of the blood flow pulsations give a value of 7.8 m s(-1) (95% confidence interval of the sample mean distribution: [6.7, 9.5] m s(-1)), which is perfectly compatible with data in the literature. We hope that this note will contribute to a better understanding of PPG signals and to further develop the domain of the vascular physiology of human bone. PMID- 23443013 TI - Proteomic studies of urinary biomarkers for prostate, bladder and kidney cancers. AB - Urine is an ideal body fluid for the detection of protein markers produced by urological cancers as it can be sampled noninvasively and contains secreted and directly shed proteins from the prostate, bladder and kidney. Major challenges of working with urine include high inter-individual and intra-individual variability, low protein concentration, the presence of salts and the dynamic range of protein expression. Despite these challenges, significant progress is being made using modern proteomic methods to identify and characterize protein based markers for urological cancers. The development of robust, easy-to-use clinical tests based on novel biomarkers has the potential to impact upon diagnosis, prognosis and monitoring and could revolutionize the treatment and management of these cancers. PMID- 23443015 TI - Incontinence: urothelial beta1-integrin knockout suggests mechanosensory mechanism for overactive bladder. PMID- 23443016 TI - Kidney cancer: sunitinib does not accelerate tumour growth in patients. PMID- 23443014 TI - Ageing of the male germ line. AB - Several studies have demonstrated a decline in the male reproductive system, sperm quality, and fertility with advancing paternal age, yet many of the biological mechanisms that underlie this process remain poorly understood. It is unclear whether the problem arises from the progenitor spermatogonial stem cells (for example, from an accumulation of DNA damage and mutations), from the somatic niche present in the testis (consisting of Sertoli and peritubular myoid cells), or from a combination of the two. Current data, albeit from a small number of studies, suggest that both factors have a role in age-associated germ cell loss. What is clear, on the other hand, is that mounting evidence links paternal age to chromosomal damage and genetic problems in the children of older fathers. The frequency of de novo mutations increases markedly with age, leading to increased risk of breast cancer, cardiac defects, developmental disorders, behavioural disorders, and neurological disease in the children of older men. The current trend towards fathering children at a later age raises concerns regarding the risk of offspring developing complex multigene diseases. PMID- 23443017 TI - Involvement of PLA2, COX and LOX in Rhinella arenarum oocyte maturation. AB - In Rhinella arenarum, progesterone is the physiological nuclear maturation inducer that interacts with the oocyte surface and starts a cascade of events that leads to germinal vesicle breakdown (GVBD). Polyunsaturated fatty acids and their metabolites produced through cyclooxygenase (COX) and lipoxygenase (LOX) pathways play an important role in reproductive processes. In amphibians, to date, the role of arachidonic acid (AA) metabolites in progesterone (P4)-induced oocyte maturation has not been clarified. In this work we studied the participation of three enzymes involved in AA metabolism - phospholipase A2 (PLA2), COX and LOX in Rhinella arenarum oocyte maturation. PLA2 activation induced maturation in Rhinella arenarum oocytes in a dose-dependent manner. Oocytes when treated with 0.08 MUM melittin showed the highest response (78 +/- 6% GVBD). In follicles, PLA2 activation did not significantly induce maturation at the assayed doses (12 +/- 3% GVBD). PLA2 inhibition with quinacrine prevented melittin-induced GVBD in a dose-dependent manner, however PLA2 inactivation did not affect P4-induced maturation. This finding suggests that PLA2 is not the only phospholipase involved in P4-induced maturation in this species. P4-induced oocyte maturation was inhibited by the COX inhibitors indomethacin and rofecoxib (65 +/- 3% and 63 +/- 3% GVBD, respectively), although COX activity was never blocked by their addition. Follicles showed a similar response following the addition of these inhibitors. Participation of LOX metabolites in maturation seems to be correlated with seasonal variation in ovarian response to P4. During the February to June period (low P4 response), LOX inhibition by nordihydroguaiaretic acid or lysine clonixinate increased maturation by up to 70%. In contrast, during the July to January period (high P4 response), LOX inhibition had no effect on hormone-induced maturation. PMID- 23443018 TI - Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. AB - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5'-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity. PMID- 23443019 TI - Association between a 15q25 gene variant, nicotine-related habits, lung cancer and COPD among 56,307 individuals from the HUNT study in Norway. AB - Genetic studies have shown an association between single-nucleotide polymorphisms on chromosome 15q25 and smoking-related traits and diseases, such as quantity of smoking, lung cancer and chronic obstructive pulmonary disease (COPD). A discussion has centred on the variants and their effects being directly disease related or indirect via nicotine addiction. To address these discrepancies, we genotyped the single-nucleotide polymorphism rs16969968 in the CHRNA5/A3/B4 gene cluster at chromosome 15q25, in 56 307 individuals from a large homogenous population-based cohort, the North Trondelag Health Study (HUNT) in Norway. The variant was examined in relation to four different outcomes: lung cancer, loss of lung function equivalent to that of COPD, smoking behaviour and the use of smokeless tobacco (snus). Novel associations were found between rs16969968 and the motivational factor for starting to use snus, and the quantity of snus used. Our results also confirm and extend previous findings for associations between rs16969968 and lung cancer, loss of lung function equivalent to that of COPD, and smoking quantity. Our data suggest a role for rs16969968 in nicotine addiction, and the novel association with snus strengthens this observation. PMID- 23443020 TI - MED12 exon 2 mutations in histopathological uterine leiomyoma variants. AB - Uterine leiomyomas, or fibroids, are the most common human tumors. Based on histopathology, they can be divided into common leiomyomas and various relatively rare subtypes that mimic malignancy in one or more aspects. Recently, we showed that exon 2 of mediator complex subunit 12 (MED12) is mutated in up to 70% of common fibroids. To investigate the frequency of MED12 exon 2 mutations in histopathological uterine leiomyoma variants, we screened altogether 206 lesions, including 69 histopathologically common leiomyomas, 59 cellular (23 cellular and 36 highly cellular), 18 atypical and 26 mitotically active leiomyomas, as well as 34 uterine fibroid samples from 14 hereditary leiomyomatosis and renal cell cancer patients with a heterozygous germ line mutation in fumarate hydratase (FH). The uterine leiomyoma variants harbored MED12 exon 2 mutations significantly less frequently than common leiomyomas (P=2.93 * 10(-8)). In all, 6 mutations were detected among cellular fibroids (6/67; 8.96%), 3 among atypical fibroids (3/18; 16.67%) and 10 among mitotically active fibroids (10/26; 38.46%). Only mitotically active fibroids displayed a mutation frequency that was not statistically different from common leiomyomas (P=0.11). Three MED12 exon 2 mutations were detected among 34 tumors with a heterozygous germ line FH mutation (P=5.28 * 10(-7)). None of these tumors displayed biallelic inactivation of FH. Our results suggest that MED12 mutation positivity is a key characteristic of common leiomyomas. Cellular and atypical fibroids, in particular, may arise through different molecular mechanisms. The results also propose that MED12 and biallelic FH mutations may be mutually exclusive. PMID- 23443021 TI - Nebulin (NEB) mutations in a childhood onset distal myopathy with rods and cores uncovered by next generation sequencing. AB - Recessive nebulin (NEB) mutations are a common cause of nemaline myopathy (NM), typically characterized by generalized weakness of early-onset and nemaline rods on muscle biopsy. Exceptional adult cases with additional cores and an isolated distal weakness have been reported. The large NEB gene with 183 exons has been an obstacle for the genetic work-up. Here we report a childhood-onset case with distal weakness and a core-rod myopathy, associated with recessive NEB mutations identified by next generation sequencing (NGS). This 6-year-old boy presented with a history of gross-motor difficulties following a normal early development. He had distal leg weakness with bilateral foot drop, as well as axial muscle weakness, scoliosis and spinal rigidity; additionally he required nocturnal respiratory support. Muscle magnetic resonance (MR) imaging showed distal involvement in the medial and anterior compartment of the lower leg. A muscle biopsy featured both rods and cores. Initial targeted testing identified a heterozygous Nebulin exon 55 deletion. Further analysis using NGS revealed a frameshifting 4 bp duplication, c.24372_24375dup (P.Val8126fs), on the opposite allele. This case illustrates that NEB mutations can cause childhood onset distal NM, with additional cores on muscle biopsy and proves the diagnostic utility of NGS for myopathies, particularly when large genes are implicated. PMID- 23443022 TI - Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients. AB - Although SPG11 is the most common complicated hereditary spastic paraplegia, our knowledge of the long-term prognosis and life expectancy is limited. We therefore studied the disease course of all patients with a proven SPG11 mutation as tested in our laboratory, the single Dutch laboratory providing SPG11 mutation analysis, between 1 January 2009 and 1 January 2011. We identified nine different SPG11 mutations, four of which are novel, in nine index patients. Eighteen SPG11 patients from these nine families were studied by means of a retrospective chart analysis and additional interview/examination. Ages at onset were between 4 months and 14 years; 39% started with learning difficulties rather than gait impairment. Brain magnetic resonance imaging showed a thin corpus callosum and typical periventricular white matter changes in the frontal horn region (known as the 'ears-of the lynx'-sign) in all. Most patients became wheelchair bound after a disease duration of 1 to 2 decades. End-stage disease consisted of loss of spontaneous speech, severe dysphagia, spastic tetraplegia with peripheral nerve involvement and contractures. Several patients died of complications between ages 30 and 48 years, 3-4 decades after onset of gait impairment. Other relevant features during the disease were urinary and fecal incontinence, obesity and psychosis. Our study of 18 Dutch SPG11-patients shows the potential serious long term consequences of SPG11 including a possibly restricted life span. PMID- 23443023 TI - The personal experience of parenting a child with juvenile Huntington's disease: perceptions across Europe. AB - The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington's disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington's disease; living with the disease; other people's knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe. PMID- 23443024 TI - Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family. AB - This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors. PMID- 23443025 TI - The influence of clan structure on the genetic variation in a single Ghanaian village. AB - Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a* M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large. PMID- 23443026 TI - HLA-DQB1*02 and DQB1*06:03P are associated with peanut allergy. AB - Peanut allergy (PA) is a common and serious food allergy and its prevalence has increased in the past decade. Although there is strong evidence of inheritance, the genetic causes of this disease are not well understood. Previously, a large scale genome-wide association study described an association between human leukocyte antigen (HLA)-DQB1 and asthma; the aim of this study was to evaluate the association between HLA-DQB1 and PA. Genotypic and allelic profiles were established for 311 Caucasian members of a well-described Canadian group of children with PA and 226 Caucasian controls. Firth's logistic regression analyses showed associations between HLA-DQB1 alleles and PA for DQB1*02 (P=1.1 * 10(-8), odds ratio (OR)=0.09 (CI=0.03-0.23)) and DQB1*06:03P alleles (P=2.1 * 10(-2), OR=2.82 (CI=1.48-5.45)). This study of HLA in PA demonstrates specific association between two allelic groups of the HLA-DQB1 gene (DQB1*02 and DQB1*06:03P) and PA, highlighting its possible role in the development of this disease. PMID- 23443027 TI - Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X linked ciliopathy gene. AB - X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival. PMID- 23443028 TI - Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC). PMID- 23443029 TI - Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation. AB - Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p.R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1beta) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency. PMID- 23443030 TI - Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL. AB - Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.806_808delCCT: p.S269del) in the voltage-gated potassium channel KCNQ4 (DFNA2), which in silico modeling predicts to disrupt multimerization of KCNQ4 subunits. Surprisingly, 10/23 deaf relatives are non carriers of p.S269del. Further molecular characterization of the DFNA2 locus in deletion carriers ruled out the possibility of a pathogenic mutation other than p.S269del at the DFNA2A/B locus and linkage analysis showed significant linkage to DFNA2 (maximum LOD=3.3). Further support of genetic heterogeneity in family 2071 was revealed by comparisons of audio profiles between p.S269del carriers and non-carriers suggesting additional and as yet unknown etiologies. We discuss the serious implications that genetic heterogeneity, in this case observed within a single family, has on molecular diagnostics and genetic counseling. PMID- 23443031 TI - Meiotic gene-conversion rate and tract length variation in the human genome. AB - Meiotic recombination occurs in the form of two different mechanisms called crossing-over and gene-conversion and both processes have an important role in shaping genetic variation in populations. Although variation in crossing-over rates has been studied extensively using sperm-typing experiments, pedigree studies and population genetic approaches, our knowledge of variation in gene conversion parameters (ie, rates and mean tract lengths) remains far from complete. To explore variability in population gene-conversion rates and its relationship to crossing-over rate variation patterns, we have developed and validated using coalescent simulations a comprehensive Bayesian full-likelihood method that can jointly infer crossing-over and gene-conversion rates as well as tract lengths from population genomic data under general variable rate models with recombination hotspots. Here, we apply this new method to SNP data from multiple human populations and attempt to characterize for the first time the fine-scale variation in gene-conversion parameters along the human genome. We find that the estimated ratio of gene-conversion to crossing-over rates varies considerably across genomic regions as well as between populations. However, there is a great degree of uncertainty associated with such estimates. We also find substantial evidence for variation in the mean conversion tract length. The estimated tract lengths did not show any negative relationship with the local heterozygosity levels in our analysis.European Journal of Human Genetics advance online publication, 27 February 2013; doi:10.1038/ejhg.2013.30. PMID- 23443033 TI - The effect of vitamin D on insulin resistance in patients with type 2 diabetes. AB - INTRODUCTION: Over the past decade, numerous non-skeletal diseases have been reported to be associated with vitamin D deficiency including type2 diabetes mellitus (T2DM). Different studies provide evidence that vitamin D may play a functional role in glucose tolerance through its effects on insulin secretion and insulin sensitivity. This study evaluates the effects of vitamin D supplementation on insulin resistance in T2DM. METHOD: Through a before-after study, 100 patients with T2DM, 30-70 years old, were recruited from an Arak diabetes clinic as consecutive attenders. Participants were assessed for clinical and biochemistry. Serum insulin and, 25(OH)D concentration, and HOMA-IR was calculated. All measurements were performed at the beginning and the end of the study. Patients received 50,000 unit of vitamin D3 orally per week for eight weeks, Statistical analysis was made using SPSS17. The results were analyzed by descriptive tests, and a comparison between variables were made using paired T tests or Wilcoxon tests, as appropriate. RESULTS: 100 participants including 70 women (70%) and 30 men (30%) took part in the study. All results were presented as Mean+/-SD, or medians of non-normally distributed.24% of the participants were Vitamin D deficient {serum 25(OH)D <= 20 ng/ml(50 nmol/l)}.Mean serum 25 (OH) D concentration was 43.03+/- 19.28 ng/ml (107.5+/-48.2 nmol/l).The results at baseline and at the end, for FPG were 138.48+/-36.74 and 131.02+/-39 mg/dl (P=0.05), for insulin, 10.76+/-9.46 and 8.6+/-8.25 MUIu/ml (P=0.028) and for HOMA IR, 3.57+/-3.18 and 2.89+/-3.28 (P=0.008) respectively. CONCLUSION: Our data showed significant improvements in serum FPG, insulin and in HOMA-IR after treatment with vitamin D, suggested that vitamin D supplementation could reduce insulin resistance in T2DM. PMID- 23443032 TI - Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations. AB - ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case-control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (P<0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.42-2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case-control analysis comparing NSOC probands with controls (OR=1.58; 95% CI=1.12-2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI=1.38-2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface. PMID- 23443034 TI - Using the mood disorder questionnaire and bipolar spectrum diagnostic scale to detect bipolar disorder and borderline personality disorder among eating disorder patients. AB - BACKGROUND: Screening scales for bipolar disorder including the Mood Disorder Questionnaire (MDQ) and Bipolar Spectrum Diagnostic Scale (BSDS) have been plagued by high false positive rates confounded by presence of borderline personality disorder. This study examined the accuracy of these scales for detecting bipolar disorder among patients referred for eating disorders and explored the possibility of simultaneous assessment of co-morbid borderline personality disorder. METHODS: Participants were 78 consecutive female patients who were referred for evaluation of an eating disorder. All participants completed the mood and eating disorder sections of the SCID-I/P and the borderline personality disorder section of the SCID-II, in addition to the MDQ and BSDS. Predictive validity of the MDQ and BSDS was evaluated by Receiver Operating Characteristic analysis of the Area Under the Curve (AUC). RESULTS: Fifteen (19%) and twelve (15%) patients fulfilled criteria for bipolar II disorder and borderline personality disorder, respectively. The AUCs for bipolar II disorder were 0.78 (MDQ) and 0.78 (BDSD), and the AUCs for borderline personality disorder were 0.75 (MDQ) and 0.79 (BSDS). CONCLUSIONS: Among patients being evaluated for eating disorders, the MDQ and BSDS show promise as screening questionnaires for both bipolar disorder and borderline personality disorder. PMID- 23443036 TI - pynk : Breast Cancer Program for Young Women. AB - CONSIDER THIS SCENARIO: A 35-year-old recently married woman is referred to a surgeon because of a growing breast lump. After a core biopsy shows cancer, she undergoes mastectomy for a 6-cm invasive lobular cancer that has spread to 8 axillary nodes. By the time she sees the medical oncologist, she is told that it is too late for a fertility consultation, and she receives a course of chemotherapy. At clinic appointments, she seems depressed and admits that her husband has been less supportive than she had hoped. After tamoxifen is started, treatment-related sexuality problems and the probability of infertility contribute to increasing strain on the couple's relationship. Their marriage ends two years after the woman's diagnosis.Six years after her diagnosis, this woman has completed all treatment, is disease-free, and is feeling extremely well physically. However, she is upset about being postmenopausal, and she is having difficulty adopting a child as a single woman with a history of breast cancer. Could this woman and her husband have been offered additional personalized interventions that might have helped them better cope with the breast cancer diagnosis and the effects of treatment?Compared with their older counterparts, young women with breast cancer often have greater and more complex supportive care needs. The present article describes the goals, achievements, and future plans of a specialized interdisciplinary program-the first of its kind in Canada for women 40 years of age and younger newly diagnosed with breast cancer. The program was created to optimize the complex clinical care and support needs of this population, to promote research specifically targeting issues unique to young women, and to educate the public and health care professionals about early detection of breast cancer in young women and about the special needs of those women after their diagnosis. PMID- 23443037 TI - Fascin-1 is a novel biomarker of aggressiveness in some carcinomas. AB - Tremendous progress has been made in recent years towards the understanding, prevention and management of malignant disease, yet cancer remains a leading cause of global mortality and morbidity. Current approaches towards combating this disease include prevention, early detection and various treatment modalities. However, even with implementation of novel therapeutic options and preventative measures, most cancers are currently diagnosed at late stages, when treatment therapies are least effective. In a recent study published in BMC Medicine, Tan et al. performed a systematic review and meta-analysis to show that fascin-1, an actin-bundling protein, is associated with increased risk of mortality and metastasis in various cancer types. Although the study examined the association of fascin-1 with mortality, time-to-disease progression, lymph node metastasis and distant metastasis in five major cancer types, the clinical implications of these findings are still unclear and many unanswered questions remain.Please see related research article here http://www.biomedcentral.com/1741 7015/11/52. PMID- 23443038 TI - Measuring the internalized stigma of parents of persons with a serious mental illness: the factor structure of the parents' internalized stigma of mental illness scale. AB - Research has revealed that approximately one third of persons with a serious mental illness (SMI) experience elevated internalized stigma, which is associated with a large number of negative outcomes. Family members of persons with SMI are also often subject to stigma, but the degree to which these experiences are internalized and lead to self-stigma has rarely been studied. The present study investigated the factor structure of a modification of the Internalized Stigma of Mental Illness (ISMI) scale by Ritsher, Otilingam, and Grajales (Psychiatry Res 121:31-49, 2003). A central assumption of this investigation was that the factor structure of the Parents' Internalized Stigma of Mental Illness (PISMI) scale would be similar to the factor structure of the ISMI scale. A total of 194 parents of persons with SMI completed the PISMI scale. The results revealed that the PISMI scale has high internal consistency and that it is made up of three distinctive factors: discrimination experience, social withdrawal and alienation, and stereotype endorsement. These factors are similar, but not identical, to the factors that underlie the ISMI scale. This study's findings also indicate that parents' prominent reaction to self-stigma is stereotype endorsement. PMID- 23443039 TI - An evaluation of irreversible psychosurgical treatment of patients with obsessive compulsive disorder in the Netherlands, 2001-2008. AB - Admissions for irreversible psychosurgical treatment of obsessive-compulsive disorder (OCD) by the Working Group for Indication Psychosurgery in the Netherlands were analyzed, and the postsurgical effects on symptom severity and quality of life were evaluated. The data were extracted from patient records in the period 2001-2008, and there was a postoperative assessment with a semistructured interview. Fourteen patients applied, having severe OCD with mostly one or more comorbid disorders. The mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was 32 points. Four of seven patients in whom psychosurgery was deemed useful were operated on. The decrease of the Y-BOCS score from registration to after surgery was 9 points (range, 3-17 points). An improvement in social function was present in three of four patients. In conclusion, psychosurgery can be a valuable treatment option for patients with severe OCD in whom other treatments fail. PMID- 23443040 TI - An overview of data routing approaches for wireless sensor networks. AB - Recent years have witnessed a growing interest in deploying large populations of microsensors that collaborate in a distributed manner to gather and process sensory data and deliver them to a sink node through wireless communications systems. Currently, there is a lot of interest in data routing for Wireless Sensor Networks (WSNs) due to their unique challenges compared to conventional routing in wired networks. In WSNs, each data routing approach follows a specific goal (goals) according to the application. Although the general goal of every data routing approach in WSNs is to extend the network lifetime and every approach should be aware of the energy level of the nodes, data routing approaches may focus on one (or some) specific goal(s) depending on the application. Thus, existing approaches can be categorized according to their routing goals. In this paper, the main goals of data routing approaches in sensor networks are described. Then, the best known and most recent data routing approaches in WSNs are classified and studied according to their specific goals. PMID- 23443041 TI - Impact of malocclusion on oral health related quality of life in young people. AB - BACKGROUND: The objectives for this study were to assess Oral Health Related Quality of Life (OHRQoL) in young people aged 15-25 who sought orthodontic treatment, and to measure the association between orthodontic treatment need (using the IOTN), sex, age and education level, and oral health related quality of life (OHRQoL). METHODS: Survey of a consecutive series of 323 young adults aged 15 to 25 years, attending orthodontic clinics at the Faculty of Dentistry, Universiti Teknologi MARA. Participants completed the Oral Health Impact Profile 14 (OHIP-14) and had a clinical examination including the Index of Orthodontic Treatment Need- Dental Health Component (IOTN-DHC). Data analyses included descriptive statistics, One-way ANOVA and bivariate and multivariate regression models. RESULTS: The mean overall score (+/- SD) for OHIP-14 in young people aged 15-25 was 22.6 +/- 12.5. The psychological discomfort domain was the domain where highest impact was recorded with a mean (+/- SD) of 4.0 +/- 1.9. The regression analyses showed a significant association of IOTN-DHC with overall OHIP-14 score (p<0.05). Although females reported a slightly higher impact than males, this was not significant in both bivariate and multivariate analyses. Age group had a significant negative association with overall OHIP-14 score (p<0.05). The 15-18 year old group showed the highest impact on their quality of life due to malocclusion. Participants with a university education report a significantly higher impact on OHRQoL as compared to participants with only secondary education. CONCLUSION: Malocclusion has a significant negative impact on OHRQoL and its domains. This is greatest for the psychological discomfort domain. Younger people and those with a university education report higher levels of impact. There was no reported difference in impact between male and females. PMID- 23443042 TI - Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals. AB - INTRODUCTION: Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART). METHODS: In 88 HIV-1-positive individuals, drug resistance genotyping was carried out in plasma virus and provirus by population sequencing. Hypermutations were determined by three different approaches using Hypermut 2.0 software, cluster analysis and APOBEC3G mediated defectives indices. Clinical and demographic characteristics of these individuals were studied in relation to these hypermutations. RESULTS: hA3G/F mediated hypermutated sequences in proviral DNA, but not in plasma virus, were identified in 11.4% (10/88) subjects. Proviral hypermutations were observed more frequently in patients with ART failure than in ART-naive individuals (p=0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p<0.001). In therapy-naive individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Only a limited concordance was found between the drug resistance mutations in plasma RNA and proviral DNA. CONCLUSIONS: hA3G lethal hypermutation was significantly associated with ART failure in Indian HIV-1 subtype C patients. It is unlikely that viral variants, which exhibit hypermutated sequences and M184I and/or M230I, will mature and expand in vivo. PMID- 23443044 TI - A catalytic and tert-butoxide ion-mediated amidation of aldehydes with para-nitro azides. AB - We report here a new catalytic reaction in which, para-nitro azides are acylated by aldehydes to produce amides and molecular nitrogen in a single step. The transformation is believed to proceed via an electron transfer process mediated by the tert-butoxide ion, and catalysed by a thiazolium salt derived species. PMID- 23443043 TI - MicroRNAs: a new piece in the paediatric cardiovascular disease puzzle. AB - Cardiovascular diseases in children comprise a large public health problem. The major goals of paediatric cardiologists and paediatric cardiovascular researchers are to identify the cause(s) of these diseases to improve treatment and preventive protocols. Recent studies show the involvement of microRNAs (miRs) in different aspects of heart development, function, and disease. Therefore, miR based research in paediatric cardiovascular disorders is crucial for a better understanding of the underlying pathogenesis of the disease, and unravelling novel, efficient, preventive, and therapeutic means. The ultimate goal of such research is to secure normal cardiac development and hence decrease disabilities, improve clinical outcomes, and decrease the morbidity and mortality among children. This review focuses on the role of miRs in different paediatric cardiovascular conditions in an effort to encourage miR-based research in paediatric cardiovascular disorders. PMID- 23443046 TI - Gaming the competition in microbial cell-cell interactions. PMID- 23443045 TI - FOXA1 mediates p16(INK4a) activation during cellular senescence. AB - Mechanisms governing the transcription of p16(INK4a), one of the master regulators of cellular senescence, have been extensively studied. However, little is known about chromatin dynamics taking place at its promoter and distal enhancer. Here, we report that Forkhead box A1 protein (FOXA1) is significantly upregulated in both replicative and oncogene-induced senescence, and in turn activates transcription of p16(INK4a) through multiple mechanisms. In addition to acting as a classic sequence-specific transcriptional activator, FOXA1 binding leads to a decrease in nucleosome density at the p16(INK4a) promoter in senescent fibroblasts. Moreover, FOXA1, itself a direct target of Polycomb-mediated repression, antagonizes Polycomb function at the p16(INK4a) locus. Finally, a systematic survey of putative FOXA1 binding sites in the p16(INK4a) genomic region revealed an ~150 kb distal element that could loop back to the promoter and potentiate p16(INK4a) expression. Overall, our findings establish several mechanisms by which FOXA1 controls p16(INK4a) expression during cellular senescence. PMID- 23443047 TI - ParA-mediated plasmid partition driven by protein pattern self-organization. AB - DNA segregation ensures the stable inheritance of genetic material prior to cell division. Many bacterial chromosomes and low-copy plasmids, such as the plasmids P1 and F, employ a three-component system to partition replicated genomes: a partition site on the DNA target, typically called parS, a partition site binding protein, typically called ParB, and a Walker-type ATPase, typically called ParA, which also binds non-specific DNA. In vivo, the ParA family of ATPases forms dynamic patterns over the nucleoid, but how ATP-driven patterning is involved in partition is unknown. We reconstituted and visualized ParA-mediated plasmid partition inside a DNA-carpeted flowcell, which acts as an artificial nucleoid. ParA and ParB transiently bridged plasmid to the DNA carpet. ParB-stimulated ATP hydrolysis by ParA resulted in ParA disassembly from the bridging complex and from the surrounding DNA carpet, which led to plasmid detachment. Our results support a diffusion-ratchet model, where ParB on the plasmid chases and redistributes the ParA gradient on the nucleoid, which in turn mobilizes the plasmid. PMID- 23443048 TI - A role for LFA-1 in delaying T-lymphocyte egress from lymph nodes. AB - Lymphocytes use the integrin leukocyte function-associated antigen-1 (LFA-1) to cross the vasculature into lymph nodes (LNs), but it has been uncertain whether their migration within LN is also LFA-1 dependent. We show that LFA-1 mediates prolonged LN residence as LFA-1(-/-) CD4 T cells have significantly decreased dwell times compared with LFA-1(+/+) T cells, a distinction lost in hosts lacking the major LFA-1 ligand ICAM-1. Intra-vital two-photon microscopy revealed that LFA-1(+/+) and LFA-1(-/-) T cells reacted differently when probing the ICAM-1 expressing lymphatic network. While LFA-1(+/+) T cells returned to the LN parenchyma with greater frequency, LFA-1(-/-) T cells egressed promptly. This difference in exit behaviour was a feature of egress through all assessed lymphatic exit sites. We show that use of LFA-1 as an adhesion receptor amplifies the number of T cells returning to the LN parenchyma that can lead to increased effectiveness of T-cell response to antigen. Thus, we identify a novel function for LFA-1 in guiding T cells at the critical point of LN egress when they either exit or return into the LN for further interactions. PMID- 23443049 TI - Role of radiation therapy in neoadjuvant era in patients with locally advanced rectal cancer. AB - Surgery remains the primary determinant of cure in patients with localized rectal cancer, and total mesorectal excision is now widely accepted as standard of care. The widespread implementation of neoadjuvant short-course radiotherapy (RT) or long-course chemoradiotherapy (CRT) has reduced local recurrence rates from 25% to 40% to less than 10%; Preoperative RT in resectable rectal cancer has a number of potential advantages, most importantly reducing local recurrence, and down staging effect. In this article making a comprehensive literature review searching the reliable medical data bases of PubMed and Cochrane we present all available information on the role of radiation therapy alone or in combination with chemotherapy in preoperative setting of rectal cancer. Data reported show that in locally advanced rectal cancer the addition of radiation therapy or CRT pre surgically has significantly improved sphincter prevention surgery. Moreover, the addition of chemotherapy to radiation therapy in preoperative setting has significantly improved pathologic complete response rate and loco-regional control rate without improvement in sphincter preserving surgery. Finally, the results of recently published randomized trials have shown a significant improvement of pre- vs postoperative CRT on local control; however, there was no effect on overall survival. PMID- 23443050 TI - Percutaneous autologous bone marrow injection in the treatment of distal meta diaphyseal tibial nonunions and delayed unions. AB - OBJECTIVE: To report the outcomes of percutaneous autologous bone marrow injection for nonunion or delayed union of the distal tibial metaphysis in patients with prior plating. DESIGN: Consecutive case series. SETTING: Tertiary center. PATIENTS: Eleven consecutive patients (aged 24-51 years) were referred to us with a nonunion or delayed union of the distal tibial metaphysis after open reduction and internal fixation (plates and screws) at the time of fracture. The average time from initial injury to nonunion or delayed union and bone marrow treatment was 8 months (range, 3-20 months). INTERVENTION: A total of 40-80 mL of bone marrow aspirated from the posterior iliac crest and injected in and around the nonunion or delayed union site under fluoroscopic guidance. MEASUREMENTS: Healing at the injury site was evaluated using clinical and radiographic criteria, including computed tomography. Measures included American Academy of Orthopaedic Surgeons Lower Limb Core Scale (LLCS), Brief Pain Inventory, and Short Form 12 Physical Component Summary. RESULTS: Nine of the 11 patients attained bony union within 6 months of bone marrow injection. Six of these 9 patients who were followed-up an average of 4.4 years (range, 1.3-8.2 years) after the injection reported significant (P < 0.05) improvements in Lower Limb Core Scale (59.9-89.7), pain intensity (2.9-1.7), pain interference (4.6-2.3), and Short Form 12 Physical Component Summary (29.5-46.6) and 5.6 years improvement in quality-adjusted life years. CONCLUSIONS: Percutaneous autologous bone marrow injection is a minimally invasive, safe, and inexpensive treatment option for distal metaphyseal tibial nonunions or delayed unions after internal fixation and should be considered when the retained hardware seems to be intact and stable. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23443051 TI - Analysis of neurovascular safety between superior and anterior plating techniques of clavicle fractures. AB - OBJECTIVES: Clavicle fractures are commonly plated as a method of fixation, with superior and anterior techniques described. Although advantages and disadvantages have been attributed to both, it is unclear if one approach provides a lower risk of neurovascular injury. The aim of this study was to compare the potential for neurovascular injury between these 2 plate locations in a cadaveric model. METHODS: Seventeen adult fresh frozen cadavers underwent bilateral dissections exposing the clavicle and underlying neurovasculature. After taking baseline anatomical measurements, a superior and anterior clavicle plate was applied, removed and measurements were taken from the nearest screw exit site to the underlying subclavian vein/artery and brachial plexus. The differences between superior and anterior measurements were compared based on proximity with the neurovasculature. RESULTS: Distance to the vessels were unobtainable in 6 specimens (35%) plated with the anterior technique due to the trajectory of the screws projecting cephalad to the vessels. In the remaining specimens, there was no significant difference in the distance to the subclavian vein/artery and brachial plexus in the superior plate position (9.2 +/- 4.6, 12.2 +/- 5.8, and 9.8 +/- 5.2 mm, respectively) compared with the anterior plate position (8.3 +/- 3.5, 12.2 +/- 6.5, and 9.7 +/- 5.3 mm, respectively). In addition, no significant difference in potential neurovascular injury with regard to body size or gender was found. CONCLUSIONS: The majority of our specimens showed no significant difference between superior and anterior plating in regard to potential risk for injury to the underlying neurovasculature. However, there appears to be a subset of the population with a more caudal position of the neurovascular structures in which anterior plating may be potentially safer. PMID- 23443053 TI - Noninvasive assessment of the carotid and cerebrovascular atherosclerotic plaques by multidetector CT in type-2 diabetes mellitus patients with transient ischemic attack or stroke. AB - BACKGROUND: The cerebrovasuclar artery disease as a common complication of type-2 diabetes mellitus (T2DM) caused huge economic burden and lives threatening to patients. We evaluated the prevalence and morphology of carotid and cerebrovascular atherosclerotic plaques in T2DM patients with transient ischemic attack (TIA) or stroke using multidetector CT (MDCT). METHODS: 64-MDCT and dual source CT (DSCT) angiographies were performed in 195 T2DM patients with TIA or stroke (mean age 65.7+/-12.8 years; 118 men) between January 2009 to August 2011. During the process, plaque type, its distribution, extensive and obstructive natures were determined for each segment derived from the patients. RESULTS: Atherosclerotic plaques were detected in 183 (93.8%) patients. A total of 1056 segments with plaque were identified, of which 450 (42.6%) were non-calcified, 192 (18.2%) were mixed and 414 (39.2%) calcified ones. Among them, 562 (53.2%) resulted in mild stenosis, 291 (27.6%) moderate stenosis, 170 (16.1%) severe stenosis and 33 (3.1%) occlusion. Non-calcified plaques contributed 91.8% to non obstructive lumen narrowing, while mixed and calcified plaques contributed 89.0% and 65.0% respectively. CONCLUSIONS: MDCT angiography detected a high prevalence of plaques in T2DM patients with TIA or stroke. A relatively high proportion of plaques were non-calcified, as well as with non-obstructive stenosis. MDCT angiography might further enhance the detection and management of carotid and cerebrovascular atherosclerosis in T2DM patients with TIA and stroke. PMID- 23443054 TI - Broadband, polarization-sensitive photodetector based on optically-thick films of macroscopically long, dense, and aligned carbon nanotubes. AB - Increasing performance demands on photodetectors and solar cells require the development of entirely new materials and technological approaches. We report on the fabrication and optoelectronic characterization of a photodetector based on optically-thick films of dense, aligned, and macroscopically long single-wall carbon nanotubes. The photodetector exhibits broadband response from the visible to the mid-infrared under global illumination, with a response time less than 32 MUs. Scanning photocurrent microscopy indicates that the signal originates at the contact edges, with an amplitude and width that can be tailored by choosing different contact metals. A theoretical model demonstrates the photothermoelectric origin of the photoresponse due to gradients in the nanotube Seebeck coefficient near the contacts. The experimental and theoretical results open a new path for the realization of optoelectronic devices based on three dimensionally organized nanotubes. PMID- 23443055 TI - Trabeculectomy with ExPRESS: weighing the benefits and cost. AB - PURPOSE OF REVIEW: As glaucoma surgeons continue to search for an improvement over trabeculectomy, the ExPRESS miniature glaucoma shunt has gained interest as a possible contender. Peer-reviewed literature on ExPRESS is beginning to accumulate allowing an evidence-based review to assess the potential benefits and limitations compared to trabeculectomy. RECENT FINDINGS: The current surgical procedure for ExPRESS implantation will be described followed by results of studies comparing ExPRESS to trabeculectomy, focusing on the following outcomes: success, intraocular pressure, and complications. Case reports of late complications specific to the ExPRESS device will be summarized. Finally, an economic analysis comparing ExPRESS to trabeculectomy will be provided as additional evidence to contribute to the decision matrix on deciding which filtration procedure to recommend. SUMMARY: Despite a large number of ExPRESS implant procedures worldwide, there is a paucity of high-quality studies comparing ExPRESS to trabeculectomy. From the available literature to date the outcomes (success and early complications) of ExPRESS are similar to trabeculectomy. Reports of late complications related to device extrusion and malposition are beginning to be published; however, the significantly increased cost for ExPRESS surgery is likely to be the main limitation to widespread adoption of this procedure. PMID- 23443056 TI - Groundnut improvement: use of genetic and genomic tools. AB - Groundnut (Arachis hypogaea L.), a self-pollinated legume is an important crop cultivated in 24 million ha world over for extraction of edible oil and food uses. The kernels are rich in oil (48-50%) and protein (25-28%), and are source of several vitamins, minerals, antioxidants, biologically active polyphenols, flavonoids, and isoflavones. Improved varieties of groundnut with high yield potential were developed and released for cultivation world over. The improved varieties belong to different maturity durations and possess resistance to diseases, tolerance to drought, enhanced oil content, and improved quality traits for food uses. Conventional breeding procedures along with the tools for phenotyping were largely used in groundnut improvement programs. Mutations were used to induce variability and wide hybridization was attempted to tap variability from wild species. Low genetic variability has been a bottleneck for groundnut improvement. The vast potential of wild species, reservoir of new alleles remains under-utilized. Development of linkage maps of groundnut during the last decade was followed by identification of markers and quantitative trait loci for the target traits. Consequently, the last decade has witnessed the deployment of molecular breeding approaches to complement the ongoing groundnut improvement programs in USA, China, India, and Japan. The other potential advantages of molecular breeding are the feasibility to target multiple traits for improvement and provide tools to tap new alleles from wild species. The first groundnut variety developed through marker-assisted back-crossing is a root-knot nematode-resistant variety, NemaTAM in USA. The uptake of molecular breeding approaches in groundnut improvement programs by NARS partners in India and many African countries is slow or needs to be initiated in part due to inadequate infrastructure, high genotyping costs, and human capacities. Availability of draft genome sequence for diploid (AA and BB) and tetraploid, AABB genome species of Arachis in coming years is expected to bring low-cost genotyping to the groundnut community that will facilitate use of modern genetics and breeding approaches such as genome-wide association studies for trait mapping and genomic selection for crop improvement. PMID- 23443057 TI - Assessing the generalisability of the pediatric cardiac quality of life inventory in the United Kingdom. AB - PURPOSE: To demonstrate the generalisability of the Pediatric Cardiac Quality of Life Inventory in the United Kingdom. METHODS: Children and adolescents with heart disease were recruited from three tertiary paediatric cardiac centres in the United Kingdom and completed the Pediatric Cardiac Quality of Life Inventory. Item response option variability, total and subscale scores, patterns of correlation, and internal consistency were compared between the three sites. RESULTS: A total of 1537 participants--768 children/adolescents and 769 parents- were evaluated from the three sites. Patterns of item response option variability were similar and acceptable for all samples--child, adolescent, parent of child, and parent of adolescent. Internal consistency was high (0.82-0.96) for all samples from each site, and item-subscale, subscale-subscale, subscale-total, and item-total correlations were moderate to excellent for each centre. Comparisons of patterns of subscale and total score correlations between the three sites revealed no significant differences. CONCLUSION: Scores on the Pediatric Cardiac Quality of Life Inventory are generalisable in the United Kingdom, supporting the use of this measure for multi-centre studies of health-related quality of life of children and adolescents with heart disease. PMID- 23443058 TI - Inferring contemporary dispersal processes in plant metapopulations: comparison of direct and indirect estimates of dispersal for the annual species Crepis sancta. AB - Analyzing population dynamics in changing habitats is a prerequisite for population dynamics forecasting. The recent development of metapopulation modeling allows the estimation of dispersal kernels based on the colonization pattern but the accuracy of these estimates compared with direct estimates of the seed dispersal kernel has rarely been assessed. In this study, we used recent genetic methods based on parentage analysis (spatially explicit mating models) to estimate seed and pollen dispersal kernels as well as seed and pollen immigration in fragmented urban populations of the plant species Crepis sancta with contrasting patch dynamics. Using two independent networks, we documented substantial seed immigration and a highly restricted dispersal kernel. Moreover, immigration heterogeneity among networks was consistent with previously reported metapopulation dynamics, showing that colonization was mainly due to external colonization in the first network (propagule rain) and local colonization in the second network. We concluded that the differences in urban patch dynamics are mainly due to seed immigration heterogeneity, highlighting the importance of external population source in the spatio-temporal dynamics of plants in a fragmented landscape. The results show that indirect and direct methods were qualitatively consistent, providing a proper interpretation of indirect estimates. This study provides attempts to link genetic and demographic methods and show that patch occupancy models may provide simple methods for analyzing population dynamics in heterogeneous landscapes in the context of global change. PMID- 23443059 TI - Diversity and abundance of the abnormal chromosome 10 meiotic drive complex in Zea mays. AB - Maize Abnormal chromosome 10 (Ab10) contains a classic meiotic drive system that exploits the asymmetry of meiosis to preferentially transmit itself and other chromosomes containing specialized heterochromatic regions called knobs. The structure and diversity of the Ab10 meiotic drive haplotype is poorly understood. We developed a bacterial artificial chromosome (BAC) library from an Ab10 line and used the data to develop sequence-based markers, focusing on the proximal portion of the haplotype that shows partial homology to normal chromosome 10. These molecular and additional cytological data demonstrate that two previously identified Ab10 variants (Ab10-I and Ab10-II) share a common origin. Dominant PCR markers were used with fluorescence in situ hybridization to assay 160 diverse teosinte and maize landrace populations from across the Americas, resulting in the identification of a previously unknown but prevalent form of Ab10 (Ab10-III). We find that Ab10 occurs in at least 75% of teosinte populations at a mean frequency of 15%. Ab10 was also found in 13% of the maize landraces, but does not appear to be fixed in any wild or cultivated population. Quantitative analyses suggest that the abundance and distribution of Ab10 is governed by a complex combination of intrinsic fitness effects as well as extrinsic environmental variability. PMID- 23443061 TI - Solid state adaptive natural density partitioning: a tool for deciphering multi center bonding in periodic systems. AB - A new tool to elucidate chemical bonding in bulk solids, surfaces and nanostructures has been developed. Solid State Adaptive Natural Density Partitioning (SSAdNDP) is a method to interpret chemical bonding in terms of classical lone pairs and two-center bonds, as well as multi-center delocalized bonds. Here we extend the domain of AdNDP to bulk materials and interfaces, yielding SSAdNDP. We demonstrate the versatility of the method by applying it to several systems featuring both localized and many-center chemical bonding, and varying in structural complexity: boron alpha-sheet, magnesium diboride and the Na8BaSn6 Zintl phase. PMID- 23443060 TI - Competition as a source of constraint on life history evolution in natural populations. AB - Competition among individuals is central to our understanding of ecology and population dynamics. However, it could also have major implications for the evolution of resource-dependent life history traits (for example, growth, fecundity) that are important determinants of fitness in natural populations. This is because when competition occurs, the phenotype of each individual will be causally influenced by the phenotypes, and so the genotypes, of competitors. Theory tells us that indirect genetic effects arising from competitive interactions will give rise to the phenomenon of 'evolutionary environmental deterioration', and act as a source of evolutionary constraint on resource dependent traits under natural selection. However, just how important this constraint is remains an unanswered question. This article seeks to stimulate empirical research in this area, first highlighting some patterns emerging from life history studies that are consistent with a competition-based model of evolutionary constraint, before describing several quantitative modelling strategies that could be usefully applied. A recurrent theme is that rigorous quantification of a competition's impact on life history evolution will require an understanding of the causal pathways and behavioural processes by which genetic (co)variance structures arise. Knowledge of the G-matrix among life history traits is not, in and of itself, sufficient to identify the constraints caused by competition. PMID- 23443062 TI - Autoantibodies in hepatitis C: red flag or bystander effect? PMID- 23443063 TI - Methodological approaches for dietary intake assessment in formula-fed infants. AB - BACKGROUND AND OBJECTIVE: The estimation of dietary intake remains a challenge in human nutritional studies. In infants, the use of food diaries (FDs) is a suitable method already validated; however, this method is not exempt from error. In formula-fed infants, dilution of powdered formulas may produce errors. Our aim was to develop and validate standard operating procedures (SOPs) for the assessment of dietary intake in formula-fed infants, attending potential sources of error. METHODS: We analysed sources of error in a random subsample of 3-day FDs from 100 infants enrolled in the European Childhood Obesity Project. Calculations to estimate intakes were standardised and included in a software tool (SOPsystem). An evaluation of a simulated FD was performed by 9 trained nutritionists and 23 nutrition students (n=225 and n=575 bottle evaluations, respectively) to compare the results obtained when using or not the SOPsystem. Correct answers (%), coefficients of variation, and the time spent (minutes) to assess the simulated FD were analysed. RESULTS: Overall, 60% of the FDs contained reports of incorrect volumes, and 37% reported incorrect formula dilutions. When the SOPsystem was used, correct answers in the simulated FD were more frequent (P<0.001) and the mean coefficient of variation and the time spent were lower (P<0.005 and P<0.01, respectively). CONCLUSIONS: The development and implementation of SOPs with a software tool that identifies specific sources of error in record-keeping achieved a harmonised and improved process for assessing dietary intakes in formula-fed infants, minimising errors in calculations and reducing the work time invested. PMID- 23443064 TI - Multidisciplinary assessment of fitness to drive in brain tumour patients in southwestern Ontario: a grey matter. AB - BACKGROUND: Neurocognitive impairments from brain tumours may interfere with the ability to drive safely. In 9 of 13 Canadian provinces and territories, physicians have a legal obligation to report patients who may be medically unfit to drive. To complicate matters, brain tumour patients are managed by a multidisciplinary team; the physician most responsible to make the report of unfitness is often not apparent. The objective of the present study was to determine the attitudes and reporting practices of physicians caring for these patients. METHODS: A 17-question survey distributed to physicians managing brain tumour patients elicited Respondent demographicsKnowledge about legislative requirementsExperience of reportingBarriers and attitudes to reporting Fisher exact tests were performed to assess differences in responses between family physicians (fps) and specialists. RESULTS: Of 467 physicians sent surveys, 194 responded (42%), among whom 81 (42%) were specialists and 113 (58%) were fps. Compared with the specialists, the fps were significantly less comfortable with reporting, less likely to consider reporting, less likely to have patients inquire about driving, and less likely to discuss driving implications. A lack of tools, concern for the patient-physician relationship, and a desire to preserve patient quality of life were the most commonly cited barriers in determining medical fitness of patients to drive. CONCLUSIONS: Legal requirements to report medically unfit drivers put physicians in the difficult position of balancing patient autonomy and public safety. More comprehensive and definitive guidelines would be helpful in assisting physicians with this public health issue. PMID- 23443066 TI - Synthesis of green and blue fluorescent ladder-type conjugated imidazolium compounds. AB - The synthetic route to ladder-type conjugated imidazolium compounds consisting of Suzuki coupling, chlorination, and intramolecular cyclization reactions was developed. The optical properties of materials and theoretical calculations were investigated to demonstrate that methylene- and ethylene-bridged imidazolium compounds show green and blue fluorescence, respectively. The coordination ability of the counter anion had an influence on the solubility and fluorescence quantum yield of the compounds. PMID- 23443065 TI - Photothermal nanodrugs: potential of TNF-gold nanospheres for cancer theranostics. AB - Nanotechnology has been extensively explored for drug delivery. Here, we introduce the concept of a nanodrug based on synergy of photothermally-activated physical and biological effects in nanoparticle-drug conjugates. To prove this concept, we utilized tumor necrosis factor-alpha coated gold nanospheres (Au-TNF) heated by laser pulses. To enhance photothermal efficiency in near-infrared window of tissue transparency we explored slightly ellipsoidal nanoparticles, its clustering, and laser-induced nonlinear dynamic phenomena leading to amplification and spectral sharpening of photothermal and photoacoustic resonances red-shifted relatively to linear plasmonic resonances. Using a murine carcinoma model, we demonstrated higher therapy efficacy of Au-TNF conjugates compared to laser and Au-TNF alone or laser with TNF-free gold nanospheres. The photothermal activation of low toxicity Au-TNF conjugates, which are in phase II trials in humans, with a laser approved for medical applications opens new avenues in the development of clinically relevant nanodrugs with synergistic antitumor theranostic action. PMID- 23443071 TI - Giant juvenile fibroadenoma: a case and review of novel modalities in treatment. AB - A giant juvenile fibroadenoma is defined as a fibroadenoma greater than 5 centimeters in size occurring in the pediatric population. It frequently affects adolescents. Rapid growth of the mass may result in breast asymmetry and deformity. Varying techniques in surgical extirpation have been described in order to optimize aesthetics and minimize distortion. The advent of new methods to remove benign breast disease is in its infancy stages. Many practitioners are unaware of the novel options that are emerging in the treatment of fibroadenoma. We describe an excision of a 12 centimeter giant juvenile fibroadenoma and adjacent juvenile fibroadenoma using a strategically atypical incision that resulted in excellent cosmesis and contour of the breast without subsequent reconstruction. Multiple modalities of removing a fibroadenoma are described with a review of the associated risks, benefits, and long term implications as well as a discussion on the indication for reconstructive surgery in patients with giant juvenile fibroadenoma. PMID- 23443072 TI - Mammary tuberculosis in the young: a case report and literature review. AB - Tuberculosis (TB) of the breast is a rare condition with few cases reported outside of Asia. Its presence in juveniles is even more uncommon. Despite this, it is often easily treatable. The diagnosis of mammary TB should always be considered in an atypical presentation, and especially in those with high risk demographics. We present the case of a 16 year old girl with TB of the breast and review the literature currently available. PMID- 23443073 TI - Intracellular activation of acetyl-CoA by an artificial reaction promoter and its fluorescent detection. AB - The application of a new rhodamine-based fluorescent probe, RH-NH2 3 and an acyl transfer promoter, PBu3, to Hela cells induced a time-dependent increase in fluorescence in the mitochondria, which was most likely due to acetylation of RH NH2 3 with activated acetyl-CoA by the artificial reaction promoter in living cells. PMID- 23443074 TI - Finding the targets of a drug by integration of gene expression data with a protein interaction network. AB - Polypharmacology, which focuses on designing drugs that bind efficiently to multiple targets, has emerged as a new strategic trend in today's drug discovery research. Many successful drugs achieve their effects via multi-target interactions. However, these targets are largely unknown for both marketed drugs and drugs in development. A better knowledge of a drug's mode of action could be of substantial value to future drug development, in particular for side effect prediction and drug repositioning. We propose a network-based computational method for drug target prediction, applicable on a genome-wide scale. Our approach relies on the analysis of gene expression following drug treatment in the context of a functional protein association network. By diffusing differential expression signals to neighboring or correlated nodes in the network, genes are prioritized as potential targets based on the transcriptional response of functionally related genes. Different diffusion strategies were evaluated on 235 publicly available gene expression datasets for treatment with bioactive molecules having a known target. AUC values of up to more than 90% demonstrate the effectiveness of our approach and indicate the predictive power of integrating experimental gene expression data with prior knowledge from protein association networks. PMID- 23443075 TI - Medical students as human subjects in educational research. AB - INTRODUCTION: Special concerns often arise when medical students are themselves the subjects of education research. A recently completed large, multi-center randomized controlled trial of computer-assisted learning modules for surgical clerks provided the opportunity to explore the perceived level of risk of studies where medical students serve as human subjects by reporting on: 1) the response of Institutional Review Boards (IRBs) at seven institutions to the same study protocol; and 2) the thoughts and feelings of students across study sites about being research subjects. METHODS: From July 2009 to August 2010, all third-year medical students at seven collaborating institutions were eligible to participate. Patterns of IRB review of the same protocol were compared. Participation burden was calculated in terms of the time spent interacting with the modules. Focus groups were conducted with medical students at each site. Transcripts were coded by three independent reviewers and analyzed using Atlas.ti. RESULTS: The IRBs at the seven participating institutions granted full (n=1), expedited (n=4), or exempt (n=2) review of the WISE Trial protocol. 995 (73% of those eligible) consented to participate, and 207 (20%) of these students completed all outcome measures. The average time to complete the computer modules and associated measures was 175 min. Common themes in focus groups with participant students included the desire to contribute to medical education research, the absence of coercion to consent, and the low-risk nature of the research. DISCUSSION: Our findings demonstrate that risk assessment and the extent of review utilized for medical education research vary among IRBs. Despite variability in the perception of risk implied by differing IRB requirements, students themselves felt education research was low risk and did not consider themselves to be vulnerable. The vast majority of eligible medical students were willing to participate as research subjects. Participants acknowledged the time demands of their participation and were readily able to withdraw when those burdens became unsustainable. PMID- 23443077 TI - Identification of kakusei, a nuclear non-coding RNA, as an immediate early gene from the honeybee, and its application for neuroethological study. AB - The honeybee is a social insect that exhibits various social behaviors. To elucidate the neural basis of honeybee behavior, we detected neural activity in freely-moving honeybee workers using an immediate early gene (IEG) that is expressed in a neural activity-dependent manner. In European honeybees (Apis mellifera), we identified a novel nuclear non-coding RNA, termed kakusei, as the first insect IEG, and revealed the neural activity pattern in foragers. In addition, we isolated a homologue of kakusei, termed Acks, from the Japanese honeybee (Apis cerana), and detected active neurons in workers fighting with the giant hornet. PMID- 23443078 TI - Microtubule formation and activities of antioxidative enzymes in PC12 cells exposed to phosphatidylcholine hydroperoxides. AB - Aging increases free radical generation and lipid oxidation and, thereby, mediates neurodegenerative diseases. As the brain is rich in lipids (polyunsaturated fatty acids), the antioxidative system plays an important role in protecting brain tissues from oxidative injury. The changes in microtubule formation and antioxidative enzyme activities have been investigated in rat pheochromocytoma PC12 cells exposed to various concentrations of phosphatidylcholine hydroperoxides (PCOOH). We measured three typical antioxidative enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). The microtubule assembly system was dependent on the antioxidative enzyme system in cells exposed to oxidative stress. The activities of the three enzymes increased in a PCOOH exposure-dependent manner. In particular, the changes in the activity as a result of PCOOH exposure were similar in the three antioxidative enzymes. This is the first report indicating the compatibility between the tubulin-microtubule and antioxidative enzyme systems in cells that deteriorate as a result of phospholipid hydroperoxide administration from an exterior source. The descending order of sensitivity of the three enzymes to PCOOH is also discussed. PMID- 23443079 TI - Ginsenoside Rh2 induces human hepatoma cell apoptosisvia bax/bak triggered cytochrome C release and caspase-9/caspase-8 activation. AB - Ginsenoside Rh2 (G-Rh2) has been shown to induce apoptotic cell death in a variety of cancer cells. However, the details of the signal transduction cascade involved in G-Rh2-induced cell death is unclear. In this manuscript we elucidate the molecular mechanism of G-Rh2-induced apoptosis in human hepatoma SK-HEP-1 cells by demonstrating that G-Rh2 causes rapid and dramatic translocation of both Bak and Bax, which subsequently triggers mitochondrial cytochrome c release and consequent caspase activation. Interestingly, siRNA-based gene inactivation of caspase-8 effectively delays caspase-9 activation and apoptosis induced by G-Rh2, indicating that caspase-8 also plays an important role in the G-Rh2-induced apoptosis program. Taken together, our results indicate that G-Rh2 employs a multi pro-apoptotic pathway to execute cancer cell death, suggesting a potential role for G-Rh2 as a powerful chemotherapeutic agent. PMID- 23443080 TI - Cancer cell response to anthracyclines effects: mysteries of the hidden proteins associated with these drugs. AB - A comprehensive proteome map of T-lymphoblastic leukemia cells and its alterations after daunorubicin, doxorubicin and mitoxantrone treatments was monitored and evaluated either by paired comparison with relevant untreated control and using multivariate classification of treated and untreated samples. With the main focus on early time intervals when the influence of apoptosis is minimized, we found significantly different levels of proteins, which corresponded to 1%-2% of the total amount of protein spots detected. According to Gene Ontology classification of biological processes, the highest representation of identified proteins for all three drugs belong to metabolic processes of proteins and nucleic acids and cellular processes, mainly cytoskeleton organisation and ubiquitin-proteasome pathway. Importantly, we observed significant proportion of changes in proteins involved in the generation of precursor metabolites and energy typical for daunorubicin, transport proteins participating in response to doxorubicin and a group of proteins of immune system characterising response to mitoxantrone. Both a paired comparison and the multivariate evaluation of quantitative data revealed daunorubicin as a distinct member of the group of anthracycline/anthracenedione drugs. A combination of identified drug specific protein changes, which may help to explain anti-cancer activity, together with the benefit of blocking activation of adaptive cancer pathways, presents important approaches to improving treatment outcomes in cancer. PMID- 23443081 TI - An inverse relationship links temperature and substrate apparent affinity in the ion-coupled cotransporters rGAT1 and KAAT1. AB - The effects of temperature on the operation of two ion-coupled cotransporters of the SLC6A family, namely rat GAT1 (SLC6A1) and KAAT1 (SLC6A19) from Manduca sexta, have been studied by electrophysiological means in Xenopus laevis oocytes expressing these proteins. The maximal transport-associated current (I(max)) and the apparent substrate affinity (K(05)) were measured. In addition to the expected increase in transport rate (Q(10) = 3-6), both transporters showed greater K(05) values (i.e., a decrease in apparent affinity) at higher temperatures. The transport efficiency, estimated as I(max)/K(05), increased at negative potentials in both transporters, but did not show statistically significant differences with temperature. The observation that the apparent substrate affinity is inversely related to the transport rate suggests a kinetic regulation of this parameter. Furthermore, the present results indicate that the affinities estimated at room temperature for mammalian cotransporters may not be simply extrapolated to their physiological operating conditions. PMID- 23443082 TI - Genomic DNA methylation changes in NYGGF4-overexpression 3T3-L1 adipocytes. AB - NYGGF4, an obesity-related gene, is proposed to be involved in the development of insulin resistance; however, the underlying molecular mechanisms remain unclear. In the present analysis, NimbleGen tiling arrays were used to determine the patterns of genomic DNA methylation at CpG islands and promoters in NYGGF4 overexpression adipocytes. A total of 2352 CpG dinucleotides in 2018 genes and 3490 CpG dinucleotides in 3064 genes were found to be hypermethylated or hypomethylated, respectively, in NYGGF4-overexpression adipocytes. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis revealed enrichment of biological processes associated with energy metabolism and signal transduction events, including the peroxisome proliferator activated receptor gamma (PPARgamma) signaling pathway, and mitogen-activated protein kinases(MAPK) and Ras homolog gene family, member A (RhoA) signaling. These data demonstrate that differentially methylated genes are significantly overrepresented in NYGGF4-overexpression adipocytes, providing valuable clues for further exploration of the role of NYGGF4 in insulin sensitivity regulation. PMID- 23443083 TI - Elevated levels of Lewis y and integrin alpha5beta1 correlate with chemotherapeutic drug resistance in epithelial ovarian carcinoma. AB - OBJECTIVE: To measure Lewis y and integrin alpha(5)beta(1) expression in epithelial ovarian carcinoma and to correlate the levels of these molecules with ovarian carcinoma chemotherapy and prognosis. METHODS: The study population included 34 ovarian carcinoma patients with chemotherapeutic drug-resistance, six partially drug-sensitive cases, and 52 drug-sensitive cases (92 total). Immunochemistry was used to determine expression of Lewis y antigen and integrin alpha(5)beta(1) in ovarian carcinoma tissues, and correlation of these molecules with chemotherapy resistance was further investigated, Multi-factor logistic regression analysis was applied to investigate: age, surgical stage, grade, subtype of patient cases, metastasis of lymph nodes, residual tumor size, expression levels of Lewis y antigen and integrin alpha(5)beta(1) correlation with ovarian carcinoma chemotherapy resistance. RESULTS: The expression rates of Lewis y antigen and integrins alpha(5) and beta(1) were significantly greater in the drug-resistant group (91.17%, 85.29%, 88.24%) than the partially sensitive (50.00%, 33.33%, 50.00%) or sensitive groups (61.54%, 57.69%, 55.77%). Binary logistic regression analysis revealed that surgical stage, residual tumor size, and expression of integrin alpha(5) and Lewis y in ovarian carcinoma tissues were independent risk factors for chemotherapeutic drug resistance. CONCLUSIONS: Overexpression of Lewis y and integrin alpha(5) are strong risk factors for chemotherapeutic drug resistance in ovarian carcinoma patients. PMID- 23443085 TI - Fabrication of an electrically-resistive, varistor-polymer composite. AB - This study focuses on the fabrication and electrical characterization of a polymer composite based on nano-sized varistor powder. The polymer composite was fabricated by the melt-blending method. The developed nano-composite was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FeSEM), and energy-dispersive X-ray spectroscopy (EDAX). The XRD pattern revealed the crystallinity of the composite. The XRD study also showed the presence of secondary phases due to the substitution of zinc by other cations, such as bismuth and manganese. The TEM picture of the sample revealed the distribution of the spherical, nano-sized, filler particles throughout the matrix, which were in the 10-50 nm range with an average of approximately 11 nm. The presence of a bismuth-rich phase and a ZnO matrix phase in the ZnO-based varistor powder was confirmed by FeSEM images and EDX spectra. From the current-voltage curves, the non-linear coefficient of the varistor polymer composite with 70 wt% of nano filler was 3.57, and its electrical resistivity after the onset point was 861 KOmega. The non-linear coefficient was 1.11 in the sample with 100 wt% polymer content. Thus, it was concluded that the composites established a better electrical non-linearity at higher filler amounts due to the nano-metric structure and closer particle linkages. PMID- 23443084 TI - Form follows function: structural and catalytic variation in the class a flavoprotein monooxygenases. AB - Flavoprotein monooxygenases (FPMOs) exhibit an array of mechanistic solutions to a common chemical objective; the monooxygenation of a target substrate. Each FPMO efficiently couples reduction of a flavin cofactor by NAD(P)H to oxygenation of the target substrate via a (hydro)peroxyflavin intermediate. This purpose of this review is to describe in detail the Class A flavoprotein hydroxylases (FPMO) in the context of the other FPMO classes (B-F). Both one and two component FPMOs are found in nature. Two-component enzymes require, in addition to the monooxygenase, the involvement of a reductase that first catalyzes the reduction of the flavin by NAD(P)H. The Class A and B FPMOs are single-component and manage to orchestrate the same net reaction within a single peptide. The Class A enzymes have, by some considerable margin, the most complete research record. These enzymes use choreographed movements of the flavin ring that facilitate access of the organic substrates to the active site, provide a means for interaction of NADPH with the flavin, offer a mechanism to sequester the dioxygen reduction chemistry from solvent and a means to release the product. The majority of the discrete catalytic events of the catalytic cycle can be observed directly in exquisite detail using spectrophotometric kinetic methods and many of the key mechanistic conclusions are further supported by structural data. This review attempts to compile each of the key observations made for both paradigm and newly discovered examples of Class A FPMOs into a complete catalytic description of one enzymatic turnover. PMID- 23443086 TI - The pharmacological NF-kappaB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells. AB - Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-kappaB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-kappaB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-kappaB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-kappaB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-kappaB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma. PMID- 23443087 TI - Discovery of novel focal adhesion kinase inhibitors using a hybrid protocol of virtual screening approach based on multicomplex-based pharmacophore and molecular docking. AB - Focal adhesion kinase (FAK) is a tyrosine kinase that functions as a key orchestrator of signals leading to invasion and metastasis. In the current study, the multicomplex-based pharmacophore (MCBP)-guided method has been suggested to generate a comprehensive pharmacophore of FAK kinase based on seven crystal structures of FAK-inhibitor complexes. In this investigation, a hybrid protocol of virtual screening methods, comprising of pharmacophore model-based virtual screening (PB-VS) and docking-based virtual screening (DB-VS), is used for retrieving new FAK inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen several chemical databases, including the Specs (202,408 compounds) database. Thirty-five compounds were selected from the final hits and should be shifted to experimental studies. These results may provide important information for further research of novel FAK inhibitors. PMID- 23443088 TI - Effects of nickel, chlorpyrifos and their mixture on the Dictyostelium discoideum proteome. AB - Mixtures of chemicals can have additive, synergistic or antagonistic interactions. We investigated the effects of the exposure to nickel, the organophosphate insecticide chlorpyrifos at effect concentrations (EC) of 25% and 50% and their binary mixture (Ec25 + EC25) on Dictyostelium discoideum amoebae based on lysosomal membrane stability (LMS). We treated D. discoideum with these compounds under controlled laboratory conditions and evaluated the changes in protein levels using a two-dimensional gel electrophoresis (2DE) proteomic approach. Nickel treatment at EC25 induced changes in 14 protein spots, 12 of which were down-regulated. Treatment with nickel at EC50 resulted in changes in 15 spots, 10 of which were down-regulated. Treatment with chlorpyrifos at EC25 induced changes in six spots, all of which were down-regulated; treatment with chlorpyrifos at EC50 induced changes in 13 spots, five of which were down regulated. The mixture corresponding to EC25 of each compound induced changes in 19 spots, 13 of which were down-regulated. The data together reveal that a different protein expression signature exists for each treatment, and that only a few proteins are modulated in multiple different treatments. For a simple binary mixture, the proteomic response does not allow for the identification of each toxicant. The protein spots that showed significant differences were identified by mass spectrometry, which revealed modulations of proteins involved in metal detoxification, stress adaptation, the oxidative stress response and other cellular processes. PMID- 23443089 TI - Heat shock protein 90 in plants: molecular mechanisms and roles in stress responses. AB - The heat shock protein 90 (Hsp90) family mediates stress signal transduction, and plays important roles in the control of normal growth of human cells and in promoting development of tumor cells. Hsp90s have become a currently important subject in cellular immunity, signal transduction, and anti-cancer research. Studies on the physiological functions of Hsp90s began much later in plants than in animals and fungi. Significant progress has been made in understanding complex mechanisms of HSP90s in plants, including ATPase-coupled conformational changes and interactions with cochaperone proteins. A wide range of signaling proteins interact with HSP90s. Recent studies revealed that plant Hsp90s are important in plant development, environmental stress response, and disease and pest resistance. In this study, the plant HSP90 family was classified into three clusters on the basis of phylogenetic relationships, gene structure, and biological functions. We discuss the molecular functions of Hsp90s, and systematically review recent progress of Hsp90 research in plants. PMID- 23443090 TI - Structure prediction, molecular dynamics simulation and docking studies of D specific dehalogenase from Rhizobium sp. RC1. AB - Currently, there is no three-dimensional structure of D-specific dehalogenase (DehD) in the protein database. We modeled DehD using ab initio technique, performed molecular dynamics (MD) simulation and docking of D-2-chloropropionate (D-2CP), D-2-bromopropionate (D-2BP), monochloroacetate (MCA), monobromoacetate (MBA), 2,2-dichloropropionate (2,2-DCP), d,l-2,3-dichloropropionate (d,l-2,3 DCP), and 3-chloropropionate (3-CP) into the DehD active site. The sequences of DehD and D-2-haloacid dehalogenase (HadD) from Pseudomonas putida AJ1 have 15% sequence similarity. The model had 80% of the amino acid residues in the most favored region when compared to the crystal structure of DehI from Pseudomonas putida PP3. Docking analysis revealed that Arg107, Arg134 and Tyr135 interacted with D-2CP, and Glu20 activated the water molecule for hydrolytic dehalogenation. Single residue substitutions at 25-30 degrees C showed that polar residues of DehD were stable when substituted with nonpolar residues and showed a decrease in activity within the same temperature range. The molecular dynamics simulation of DehD and its variants showed that in R134A variant, Arg107 interacted with D-2CP, while in Y135A, Gln221 and Arg231 interacted with D-2CP. It is our emphatic belief that the new model will be useful for the rational design of DehDs with enhanced potentials. PMID- 23443091 TI - RORalpha, a potential tumor suppressor and therapeutic target of breast cancer. AB - The function of the nuclear receptor (NR) in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORalpha, one member of the retinoid orphan nuclear receptor (ROR) subfamily of orphan receptors, regulates various cellular and pathological activities. RORalpha is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORalpha suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORalpha can be categorized into the canonical and non canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORalpha is a potent tumor suppressor and a potential therapeutic target for breast cancer. PMID- 23443092 TI - The role of Sox genes in lung morphogenesis and cancer. AB - The human lung consists of multiple cell types derived from early embryonic compartments. The morphogenesis of the lung, as well as the injury repair of the adult lung, is tightly controlled by a network of signaling pathways with key transcriptional factors. Lung cancer is the third most cancer-related death in the world, which may be developed due to the failure of regulating the signaling pathways. Sox (sex-determining region Y (Sry) box-containing) family transcriptional factors have emerged as potent modulators in embryonic development, stem cells maintenance, tissue homeostasis, and cancerogenesis in multiple processes. Recent studies demonstrated that the members of the Sox gene family played important roles in the development and maintenance of lung and development of lung cancer. In this context, we summarize our current understanding of the role of Sox family transcriptional factors in the morphogenesis of lung, their oncogenic potential in lung cancer, and their potential impact in the diagnosis, prognosis, and targeted therapy of lung cancer. PMID- 23443093 TI - Brain metastases from colorectal cancer: microenvironment and molecular mechanisms. AB - Colorectal cancer is one of the most common digestive tract malignancies in the world. Owing to the newer and more effective systemic therapies, the life of colorectal cancer patients can be remarkably prolonged, and the incidence of brain metastases is increasing. However, little is known about the underlying mechanisms of brain metastasis from colorectal cancer. Here we review the tumor microenvironment and metastasis associated molecules in brain metastases from colorectal cancer. A further understanding of these mechanisms will help us to propose better strategies for colorectal cancer patients with brain metastasis and improve their life quality. PMID- 23443094 TI - Cholesterol-dependent energy transfer between fluorescent proteins-insights into protein proximity of APP and BACE1 in different membranes in Niemann-Pick type C disease cells. AB - Forster resonance energy transfer (FRET) -based techniques have recently been applied to study the interactions between beta-site APP-cleaving enzyme-GFP (BACE1-GFP) and amyloid precursor protein-mRFP (APP-mRFP) in U373 glioblastoma cells. In this context, the role of APP-BACE1 proximity in Alzheimer's disease (AD) pathogenesis has been discussed. FRET was found to depend on intracellular cholesterol levels and associated alterations in membrane stiffness. Here, NPC1 null cells (CHO-NPC1-/-), exhibiting increased cholesterol levels and disturbed cholesterol transport similar to that observed in Niemann-Pick type C disease (NPC), were used to analyze the influence of altered cholesterol levels on APP BACE1 proximity. Fluorescence lifetime measurements of whole CHO-wild type (WT) and CHO-NPC1-/- cells (EPI-illumination microscopy), as well as their plasma membranes (total internal reflection fluorescence microscopy, TIRFM), were performed. Additionally, generalized polarization (GP) measurements of CHO-WT and CHO-NPC1-/- cells incubated with the fluorescence marker laurdan were performed to determine membrane stiffness of plasma- and intracellular-membranes. CHO-NPC1 /- cells showed higher membrane stiffness at intracellular- but not plasma membranes, equivalent to cholesterol accumulation in late endosomes/lysosomes. Along with higher membrane stiffness, the FRET efficiency between BACE1-GFP and APP-mRFP was reduced at intracellular membranes, but not within the plasma membrane of CHO-NPC1-/-. Our data show that FRET combined with TIRF is a powerful technique to determine protein proximity and membrane fluidity in cellular models of neurodegenerative diseases. PMID- 23443095 TI - DNA damage and repair in epithelium after allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in humans, following hematoablative treatment, results in biological chimeras. In this case, the transplanted hematopoietic, immune cells and their derivatives can be considered the donor genotype, while the other tissues are the recipient genotype. The first sequel, which has been recognized in the development of chimerical organisms after allo-HSCT, is the graft versus host (GvH) reaction, in which the new developed immune cells from the graft recognize the host's epithelial cells as foreign and mount an inflammatory response to kill them. There is now accumulating evidence that this chronic inflammatory tissue stress may contribute to clinical consequences in the transplant recipient. It has been recently reported that host epithelial tissue acquire genomic alterations and display a mutator phenotype that may be linked to the occurrence of a GvH reaction. The current review discusses existing data on this recently discovered phenomenon and focuses on the possible pathogenesis, clinical significance and therapeutic implications. PMID- 23443097 TI - Muscodor albus volatiles control toxigenic fungi under Controlled Atmosphere (CA) storage conditions. AB - Muscodor albus, a biofumigant fungus, has the potential to control post-harvest pathogens in storage. It has been shown to produce over 20 volatile compounds with fungicidal, bactericidal and insecticidal properties. However, M. albus is a warm climate endophyte, and its biofumigant activity is significantly inhibited at temperatures below 5 degrees C. Conidia of seven mycotoxin producing fungi, Aspergillus carbonarius, A. flavus, A. niger, A. ochraceus, Penicillium verrucosum, Fusarium culmorum and F. graminearum, were killed or prevented from germinating by exposure to volatiles from 2 g M. albus-colonized rye grain per L of headspace in sealed glass jars for 24 h at 20 degrees C. Two major volatiles of M. albus, isobutyric acid (IBA) and 2-methyl-1-butanol (2MB) at 50 uL/L and 100 uL/L, respectively, gave differential control of the seven fungi when applied individually at 20 degrees C. When the fungi were exposed to both IBA and 2MB together, an average of 94% of the conidia were killed or suppressed. In a factorial experiment with controlled atmosphere storage (CA) at 3 degrees C and 72 h exposure to four concentrations of IBA and 2MB combinations, 50 uL/L IBA plus 100 uL/L 2MB killed or suppressed germination of the conidia of all seven fungi. Controlled atmosphere had no significant effect on conidial viability or volatile efficacy. Major volatiles of M. albus may have significant potential to control plant pathogens in either ambient air or CA storage at temperatures below 5 degrees C. However, combinations of volatiles may be required to provide a broader spectrum of control than individual volatiles. PMID- 23443096 TI - MicroRNAs in metal stress: specific roles or secondary responses? AB - In plants, microRNAs (miRNAs) control various biological processes by negatively regulating the expression of complementary target genes, either (1) post transcriptionally by cleavage or translational inhibition of target mRNA, or (2) transcriptionally by methylation of target DNA. Besides their role in developmental processes, miRNAs are main players in stress responses, including metal stress responses. Exposure of plants to excess metal concentrations disturbs the cellular redox balance and enhances ROS accumulation, eventually leading to oxidative damage or signaling. Plants modify their gene expression by the activity of miRNAs in response to metal toxicity to regulate (1) complexation of excess metals, (2) defense against oxidative stress and (3) signal transduction for controlling various biological responses. This review focuses on the biogenesis, working mechanisms and functioning of miRNAs in plants. In a final part, our current knowledge on the regulatory roles of miRNAs in plant metal stress responses is highlighted, and whether stress-regulated miRNAs have specific roles or are secondary consequences is discussed. PMID- 23443098 TI - Microsatellites in the endangered species Dyckia distachya (Bromeliaceae) and cross-amplification in other bromeliads. AB - Microsatellite markers were isolated in Dyckia distachya, an endangered bromeliad from southern Brazil, which will be useful to assess the population genetic structure and reproductive success in introduced and natural populations of this species. Twenty microsatellite loci were developed from an enriched genomic library, and nine of these were amplified. The loci were characterized in 43 individuals from introduced and wild D. distachya populations. All nine loci were polymorphic, with four to ten alleles per locus. In an introduced population the observed and expected heterozygosities ranged from 0.136-0.667 and 0.543-0.877, respectively, while in a wild population it ranged from 0.000 to 0.895 and from 0.050 to 0.811, respectively. The development of these microsatellite markers will contribute to investigations of the reproductive potential and viability of introduced populations of D. distachya as well as the single known wild population. Cross-amplification in other Bromeliaceae species was successful, with high rates in four loci, demonstrating the applicability of these microsatellite markers in other taxa. PMID- 23443099 TI - Impact of cyanidin-3-glucoside on glycated LDL-induced NADPH oxidase activation, mitochondrial dysfunction and cell viability in cultured vascular endothelial cells. AB - Elevated levels of glycated low density lipoprotein (glyLDL) are frequently detected in diabetic patients. Previous studies demonstrated that glyLDL increased the production of reactive oxygen species (ROS), activated NADPH oxidase (NOX) and suppressed mitochondrial electron transport chain (mETC) enzyme activities in vascular endothelial cells (EC). The present study examined the effects of cyanidin-3-glucoside (C3G), a type of anthocyanin abundant in dark skinned berries, on glyLDL-induced ROS production, NOX activation and mETC enzyme activity in porcine aortic EC (PAEC). Co-treatment of C3G prevented glyLDL induced upregulation of NOX4 and intracellular superoxide production in EC. C3G normalized glyLDL-induced inhibition on the enzyme activities of mETC Complex I and III, as well as the abundances of NADH dehydrogenase 1 in Complex I and cytochrome b in Complex III in EC. Blocking antibody for the receptor of advanced glycation end products (RAGE) prevented glyLDL-induced changes in NOX and mETC enzymes. Combination of C3G and RAGE antibody did not significantly enhance glyLDL-induced inhibition of NOX or mETC enzymes. C3G reduced glyLDL-induced RAGE expression with the presence of RAGE antibody. C3G prevented prolonged incubation with the glyLDL-induced decrease in cell viability and the imbalance between key regulators for cell viability (cleaved caspase 3 and B cell Lyphoma-2) in EC. The findings suggest that RAGE plays an important role in glyLDL-induced oxidative stress in vascular EC. C3G may prevent glyLDL-induced NOX activation, the impairment of mETC enzymes and cell viability in cultured vascular EC. PMID- 23443100 TI - Modulation of adipogenic conditions for prospective use of hADSCs in adipose tissue engineering. AB - Modern strategies in adipose tissue engineering (ATE) take advantage of the easy harvest, abundance and differentiation potential towards mesenchymal lineages of hADSCs. The controlled conversion of hADSCs to committed adipogenic precursors and further mature adipocytes formation is important for good long-term results in soft tissue regeneration. Thus, in this study, we report: (i) the isolation of the processed lipoaspirate (PLA) cells from adipose tissue and sanguine fractions; (ii) the phenotypic characterization of the PLA descendants; (iii) the design of a novel protocol for the modulation of adipogenic conditions in the perspectives of ATE applications. To modulate the differentiation rate through our protocol, we propose to selectively modify the formulation of the adipogenic media in accordance with the evolution of the process. Therefore, we aimed to ensure the long-term proliferation of the precursor cells and to delay the late adipogenic events. The status of differentiation was characterized in terms of intracellular lipid accumulation and reorganization of the cytoskeleton simultaneously with perilipin protein expression. Moreover, we studied the sequential activation of PPARgamma2, FAS, aP2 and perilipin genes which influence the kinetics of the adipogenic process. The strategies developed in this work are the prerequisites for prospective 3D regenerative systems. PMID- 23443102 TI - Spectral inverse quantum (Spectral-IQ) method for modeling mesoporous systems: application on silica films by FTIR. AB - The present work advances the inverse quantum (IQ) structural criterion for ordering and characterizing the porosity of the mesosystems based on the recently advanced ratio of the particle-to-wave nature of quantum objects within the extended Heisenberg uncertainty relationship through employing the quantum fluctuation, both for free and observed quantum scattering information, as computed upon spectral identification of the wave-numbers specific to the maximum of absorption intensity record, and to left-, right- and full-width at the half maximum (FWHM) of the concerned bands of a given compound. It furnishes the hierarchy for classifying the mesoporous systems from more particle-related (porous, tight or ionic bindings) to more wave behavior (free or covalent bindings). This so-called spectral inverse quantum (Spectral-IQ) particle-to-wave assignment was illustrated on spectral measurement of FT-IR (bonding) bands' assignment for samples synthesized within different basic environment and different thermal treatment on mesoporous materials obtained by sol-gel technique with n-dodecyl trimethyl ammonium bromide (DTAB) and cetyltrimethylammonium bromide (CTAB) and of their combination as cosolvents. The results were analyzed in the light of the so-called residual inverse quantum information, accounting for the free binding potency of analyzed samples at drying temperature, and were checked by cross-validation with thermal decomposition techniques by endo-exo thermo correlations at a higher temperature. PMID- 23443101 TI - Optimization of the bacterial cytochrome P450 BM3 system for the production of human drug metabolites. AB - Drug metabolism in human liver is a process involving many different enzymes. Among them, a number of cytochromes P450 isoforms catalyze the oxidation of most of the drugs commercially available. Each P450 isoform acts on more than one drug, and one drug may be oxidized by more than one enzyme. As a result, multiple products may be obtained from the same drug, and as the metabolites can be biologically active and may cause adverse drug reactions (ADRs), the metabolic profile of a new drug has to be known before this can be commercialized. Therefore, the metabolites of a certain drug must be identified, synthesized and tested for toxicity. Their synthesis must be in sufficient quantities to be used for metabolic tests. This review focuses on the progresses done in the field of the optimization of a bacterial self-sufficient and efficient cytochrome P450, P450 BM3 from Bacillus megaterium, used for the production of metabolites of human enzymes. The progress made in the improvement of its catalytic performance towards drugs, the substitution of the costly NADPH cofactor and its immobilization and scale-up of the process for industrial application are reported. PMID- 23443103 TI - Novel microsatellite markers of Meretrix petechialis and cross-species amplification in related Taxa (Bivalvia: Veneroida). AB - The Asian hard clam, Meretrix petechialis, is an economically important bivalve, but its catch and population sizes are decreasing rapidly, owing to many factors, including large-scale reclamation of its natural habitat on the western coast of the Korean peninsula. Attempts to restore the resources and production of this species require genetic structure and diversity information. In this study, we developed 15 microsatellite markers from a partial genomic library enriched in GT repeats. Nine of these markers were polymorphic, with an average allele number of six, and six were monomorphic in 95 tested individuals. No linkage disequilibrium was found between any pair of loci (p > 0.05), and deviations from the Hardy Weinberg equilibrium (HWE) test showing excess of heterozygotes was observed in only one of nine loci. In addition, no null alleles or genetic differentiation between two tested populations were detected. A cross-species amplification in 12 species of four families resulted in two M. petechialis-specific loci and three possible universal markers. This information will be useful in the future development of high-quality artificial seedlings and sustainable resource management. PMID- 23443104 TI - Differential expression profile of MicroRNAs during differentiation of cardiomyocytes exposed to polychlorinated biphenyls. AB - Exposure to persistent environmental pollutants, such as polychlorinated biphenyls (PCBs), is a risk factor for the development of congenital heart defects. MicroRNAs (miRNAs) have been shown to be involved in cardiac development. The objective of this study was to investigate changes in miRNA expression profiles during the differentiation of cardiomyocytes exposed to PCBs. For that purpose, PCBs (Aroclor 1254) at a concentration of 2.5 MUmol/L were added on day 0 of differentiation of P19 mouse embryonal carcinoma cells into cardiac myocytes. The relative expression of miRNA genes was determined by miRNA microarray and real-time reverse transcriptase polymerase chain reaction (real time RT-PCR) analyses. The microarray results revealed that 45 miRNAs, of which 14 were upregulated and 31 were downregulated, were differentially expressed in P19 cells treated with PCBs compared with control cells. The miRNA expression data was validated with real-time RT-PCR. The expression of certain potential target genes (Wnt1) was found to be reduced in P19 cells treated with PCBs, whereas the expression of other potential predicted target genes (GSK3beta) was increased. Our results demonstrate a critical role of miRNAs in mediating the effect of PCBs during the differentiation of P19 cells into cardiac myocytes. PMID- 23443105 TI - Identification and characterization of the actin-binding motif of phostensin. AB - Phostensin, a protein phosphatase 1 F-actin cytoskeleton-targeting subunit encoded by KIAA1949, consists of 165 amino acids and caps the pointed ends of actin filaments. Sequence alignment analyses suggest that the C-terminal region of phostensin, spanning residues 129 to 155, contains a consensus actin-binding motif. Here, we have verified the existence of an actin-binding motif in the C terminal domain of phostensin using colocalization, F-actin co-sedimentation and single filament binding assays. Our data indicate that the N-terminal region of phostensin (1-129) cannot bind to actin filaments and cannot retard the pointed end elongation of gelsolin-actin seeds. Furthermore, the C-terminal region of phostensin (125-165) multiply bind to the sides of actin filaments and lacks the ability to block the pointed end elongation, suggesting that the actin-binding motif is located in the C-terminal region of the phostensin. Further analyses indicate that phostensin binding to the pointed end of actin filament requires N terminal residues 35 to 51. These results suggest that phostensin might fold into a rigid structure, allowing the N-terminus to sterically hinder the binding of C terminus to the sides of actin filament, thus rendering phostensin binding to the pointed ends of actin filaments. PMID- 23443107 TI - Computational molecular nanoscience study of the properties of copper complexes for dye-sensitized solar cells. AB - In this work, we studied a copper complex-based dye, which is proposed for potential photovoltaic applications and is named Cu (I) biquinoline dye. Results of electron affinities and ionization potentials have been used for the correlation between different levels of calculation used in this study, which are based on The Density Functional Theory (DFT) and time-dependent (TD) DFT. Further, the maximum absorption wavelengths of our theoretical calculations were compared with the experimental data. It was found that the M06/LANL2DZ + DZVP level of calculation provides the best approximation. This level of calculation was used to find the optimized molecular structure and to predict the main molecular vibrations, the molecular orbitals energies, dipole moment, isotropic polarizability and the chemical reactivity parameters that arise from Conceptual DFT. PMID- 23443106 TI - Asymmetric dimethyarginine as marker and mediator in ischemic stroke. AB - Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is known as mediator of endothelial cell dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. Accordingly, clinical studies found evidence that increased ADMA levels are associated with a higher risk of cerebrovascular events. After the acute event of ischemic stroke, levels of ADMA and its analog symmetric dimethylarginine (SDMA) are elevated through augmentation of protein methylation and oxidative stress. Furthermore, cleavage of ADMA through dimethylarginine dimethylaminohydrolases (DDAHs) is reduced. This increase of dimethylarginines might be predictive for adverse clinical outcome. However, the definite role of ADMA after acute ischemic stroke still needs to be clarified. On the one hand, ADMA might contribute to brain injury by reduction of cerebral blood flow. On the other hand, ADMA might be involved in NOS-induced oxidative stress and excitotoxic neuronal death. In the present review, we highlight the current knowledge from clinical and experimental studies on ADMA and its role for stroke risk and ischemic brain injury in the hyperacute stage after stroke. Finally, further studies are warranted to unravel the relevance of the close association of dimethylarginines with stroke. PMID- 23443109 TI - Isolation and characterization of polymorphic microsatellite markers from the Chinese medicinal herb Atractylodes macrocephala (Asteraceae). AB - Atractylodes macrocephala Koidz. (Asteraceae) is an economically important Chinese medicinal herb. In this study, 15 polymorphic microsatellite markers were developed from A. macrocephala using the compound microsatellite marker technique. Levels of polymorphism within the 15 markers were assessed using 83 individuals from two wild and two cultivated populations in China. The number of alleles per locus ranged from 2 to 20, with an average of 9.9 alleles. Observed and expected heterozygosities ranged from 0.083 to 1.000 and from 0.097 to 0.938, respectively. These markers will be valuable for germplasm classification and identification, as well as for assessing the genetic diversity and spatial genetic structure among wild and cultivated populations of A. macrocephala. PMID- 23443108 TI - Drug conjugates such as Antibody Drug Conjugates (ADCs), immunotoxins and immunoliposomes challenge daily clinical practice. AB - Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future. PMID- 23443110 TI - MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer. AB - MicroRNAs are noncoding RNA molecules of 18-25 nucleotides that regulate gene expression at the post-transcriptional levels. Recent data revealed that miR-218 played key roles in tumor metastasis. Here, we described the regulation and function of miR-218 in cervical cancer. Overexpression of miR-218 reduced the proliferation of the human cervical cancer cell line HeLa and induced cell apoptosis through the AKT-mTOR signaling pathway. In addition, it forced expression of miR-218 suppressed tumor growth in the orthotopic mouse model of HeLa cells. Furthermore, miR-218 increased chemosensitivity to cisplatin (CDDP) in vitro. Our results indicated that targeting miR-218 may provide a strategy for blocking the development of cervical cancer. PMID- 23443111 TI - Wheat drought-responsive grain proteome analysis by linear and nonlinear 2-DE and MALDI-TOF mass spectrometry. AB - A comparative proteomic analysis of drought-responsive proteins during grain development of two wheat varieties Kauz (strong resistance to drought stress) and Janz (sensitive to drought stress) was performed by using linear and nonlinear 2 DE and MALDI-TOF mass spectrometry technologies. Results revealed that the nonlinear 2-DE had much higher resolution than the linear 2-DE. A total of 153 differentially expressed protein spots were detected by both 2-DE maps, of which 122 protein spots were identified by MALDI-TOF and MALDI-TOF/TOF mass spectrometry. The identified differential proteins were mainly involved in carbohydrate metabolism (26%), detoxification and defense (23%), and storage proteins (17%). Some key proteins demonstrated significantly different expression patterns between the two varieties. In particular, catalase isozyme 1, WD40 repeat protein, LEA and alpha-amylase inhibitors displayed an upregulated expression pattern in Kauz, whereas they were downregulated or unchanged in Janz. Small and large subunit ADP glucose pyrophosphorylase, ascorbate peroxidase and G beta-like protein were all downregulated under drought stress in Janz, but had no expression changes in Kauz. Sucrose synthase and triticin precursor showed an upregulated expression pattern under water deficits in both varieties, but their upregulation levels were much higher in Kauz than in Janz. These differentially expressed proteins could be related to the biochemical pathways for stronger drought resistance of Kauz. PMID- 23443112 TI - Carbohydrate stress affecting fruitlet abscission and expression of genes related to auxin signal transduction pathway in litchi. AB - Auxin, a vital plant hormone, regulates a variety of physiological and developmental processes. It is involved in fruit abscission through transcriptional regulation of many auxin-related genes, including early auxin responsive genes (i.e., auxin/indole-3-acetic acid (AUX/IAA), Gretchen Hagen3 (GH3) and small auxin upregulated (SAUR)) and auxin response factors (ARF), which have been well characterized in many plants. In this study, totally five auxin related genes, including one AUX/IAA (LcAUX/IAA1), one GH3 (LcGH3.1), one SAUR (LcSAUR1) and two ARFs (LcARF1 and LcARF2), were isolated and characterized from litchi fruit. LcAUX/IAA1, LcGH3.1, LcSAUR1, LcARF1 and LcARF2 contain open reading frames (ORFs) encoding polypeptides of 203, 613, 142, 792 and 832 amino acids, respectively, with their corresponding molecular weights of 22.67, 69.20, 11.40, 88.20 and 93.16 kDa. Expression of these genes was investigated under the treatment of girdling plus defoliation which aggravated litchi fruitlet abscission due to the blockage of carbohydrates transport and the reduction of endogenous IAA content. Results showed that transcript levels of LcAUX/IAA1, LcGH3.1 and LcSAUR1 mRNAs were increased after the treatment in abscission zone (AZ) and other tissues, in contrast to the decreasing accumulation of LcARF1 mRNA, suggesting that LcAUX/IAA1, LcSAUR1 and LcARF1 may play more important roles in abscission. Our results provide new insight into the process of fruitlet abscission induced by carbohydrate stress and broaden our understanding of the auxin signal transduction pathway in this process at the molecular level. PMID- 23443113 TI - Effects of curcumin on the proliferation and mineralization of human osteoblast like cells: implications of nitric oxide. AB - Curcumin (diferuloylmethane) is found in the rhizomes of the turmeric plant (Curcuma longa L.) and has been used for centuries as a dietary spice and as a traditional Indian medicine used to treat different conditions. At the cellular level, curcumin modulates important molecular targets: transcription factors, enzymes, cell cycle proteins, cytokines, receptors and cell surface adhesion molecules. Because many of the curcumin targets mentioned above participate in the regulation of bone remodeling, curcumin may affect the skeletal system. Nitric oxide (NO) is a gaseous molecule generated from L-arginine during the catalization of nitric oxide synthase (NOS), and it plays crucial roles in catalization and in the nervous, cardiovascular and immune systems. Human osteoblasts have been shown to express NOS isoforms, and the exact mechanism(s) by which NO regulates bone formation remain unclear. Curcumin has been widely described to inhibit inducible nitric oxide synthase expression and nitric oxide production, at least in part via direct interference in NF-kappaB activation. In the present study, after exposure of human osteoblast-like cells (MG-63), we have observed that curcumin abrogated inducible NOS expression and decreased NO levels, inhibiting also cell prolifieration. This effect was prevented by the NO donor sodium nitroprusside. Under osteogenic conditions, curcumin also decreased the level of mineralization. Our results indicate that NO plays a role in the osteoblastic profile of MG-63 cells. PMID- 23443114 TI - An institutional retrospective analysis of 93 patients with brain metastases from breast cancer: treatment outcomes, diagnosis-specific prognostic factors. AB - To evaluate the prognostic factors and indexes of a series of 93 patients with breast cancer and brain metastases (BM) in a single institution. Treatment outcomes were evaluated according to the major prognostic indexes (RPA, BSBM, GPA scores) and breast cancer subtypes. Independent prognostic factors for overall survival (OS) were identified. The median OS values according to GPA 0-1, 1.5-2, 2.5-3 and 3.5-4, were 4.5, 9.5, 14.2 and 19.1 months, respectively (p < 0.0001) and according to genetic subtypes, they were 5, 14.2, 16.5 and 17.1 months for basal-like, luminal A and B and HER, respectively (p = 0.04). Using multivariate analysis, we established a new grading system using the six factors that were identified as indicators of longer survival: age under 60 (p = 0.001), high KPS (p = 0.007), primary tumor control (p = 0.05), low number of extracranial metastases and BM (p = 0.01 and 0.0002, respectively) and triple negative subtype (p = 0.002). Three groups with significantly different median survival times were identified: 4.1, 9.5 and 26.3 months, respectively (p < 0.0001). Our new grading system shows that prognostic indexes could be improved by using more levels of classification and confirms the strength of biological prognostic factors. PMID- 23443115 TI - Identification of candidate polymorphisms on stress oxidative and DNA damage repair genes related with clinical outcome in breast cancer patients. AB - Diverse polymorphisms have been associated with the predisposition to develop cancer. On fewer occasions, they have been related to the evolution of the disease and to different responses to treatment. Previous studies of our group have associated polymorphisms on genes related to oxidative stress (rs3736729 on GCLC and rs207454 on XDH) and DNA damage repair (rs1052133 on OGG1) with a predisposition to develop breast cancer. In the present work, we have evaluated the hypothesis that these polymorphisms also play a role in a patient's survival. A population-based cohort study of 470 women diagnosed with primary breast cancer and a median follow up of 52.44 months was conducted to examine the disease-free and overall survival in rs3736729, rs207454 and rs1052133 genetic variants. Adjusted Cox regression analysis was used to that end. The Kaplan-Meier analysis shows that rs3736729 on GCLC presents a significant association with disease-free survival and overall survival. The polymorphisms rs1052133 on OGG1 and rs207454 on XDH show a trend of association with overall survival. The analysis based on hormonal receptor status revealed a stronger association. The CC genotype on rs207454 (XDH) was significantly associated with lower time of disease free survival (p = 0.024) in progesterone receptor negative (PGR-) patients and rs3736729 (GCLC) was significantly associated with disease free survival (p = 0.001) and overall survival (p = 0.012) in the subgroup of estrogen receptor negative (ER-) patients. This work suggests that unfavorable genetic variants in the rs207454 (XDH) and rs3736729 (GCLC) polymorphisms may act as predictors of the outcome in negative progesterone receptor and negative estrogen receptor breast cancer patients, respectively. PMID- 23443116 TI - Biotransformations utilizing beta-oxidation cycle reactions in the synthesis of natural compounds and medicines. AB - beta-Oxidation cycle reactions, which are key stages in the metabolism of fatty acids in eucaryotic cells and in processes with a significant role in the degradation of acids used by microbes as a carbon source, have also found application in biotransformations. One of the major advantages of biotransformations based on the beta-oxidation cycle is the possibility to transform a substrate in a series of reactions catalyzed by a number of enzymes. It allows the use of sterols as a substrate base in the production of natural steroid compounds and their analogues. This route also leads to biologically active compounds of therapeutic significance. Transformations of natural substrates via beta-oxidation are the core part of the synthetic routes of natural flavors used as food additives. Stereoselectivity of the enzymes catalyzing the stages of dehydrogenation and addition of a water molecule to the double bond also finds application in the synthesis of chiral biologically active compounds, including medicines. Recent advances in genetic, metabolic engineering, methods for the enhancement of bioprocess productivity and the selectivity of target reactions are also described. PMID- 23443117 TI - Phenolics and antioxidant activity of mulberry leaves depend on cultivar and harvest month in Southern China. AB - To elucidate the effects of cultivar and harvest month on the phenolic content and antioxidant activity of mulberry leaves, four major phenolics, including chlorogenic acid (ChA), benzoic acid (BeA), rutin (Rut) and astragalin (Ast), were quantified using an HPLC-UV method. Leaves from six mulberry cultivars, collected from April to October, were analyzed. The antioxidant activity of mulberry leaves was assessed by ferric reducing antioxidant power (FRAP), hydroxyl radical scavenging activity (HSA) and superoxide radical scavenging activity (SSA) assays. The results showed that the total values of the four phenolic compounds ranged from 2.3 dry weight (DW) to 4.2 mg/g DW, with ChA being the major compound. The mean total phenol (TP) content of the six cultivars ranged from 30.4 equivalents (GAE) mg/g DW to 44.7 GAE mg/g DW. Mulberry leaves harvested in May had the highest TP content. Moreover, the antioxidant activities of mulberry leaves harvested from April to October differed noticeably. In general, Kq 10 and May were considered to be a better cultivar and harvest month concerning phenolic content and antioxidant activity, respectively. PMID- 23443120 TI - Isolation and characterization of microsatellite markers in the domestic ferret (Mustela putorius furo). AB - The domestic ferret (Mustela putorius furo) is an important model organism for the study of avian influenza and other diseases of humans and animals, as well as a popular pet animal. In order to evaluate genetic diversity and study disease relationships in ferrets, 22 nuclear microsatellite loci (17 dinucleotide and 5 tetranucleotide) were developed from ferret genomic libraries and organized into seven multiplex sets. Polymorphism was preliminarily assessed in one population in Australia and one in the USA, sampled with 25 individuals each. The loci displayed allelic diversity ranging from 1 to 5 alleles, and expected and observed heterozygosities ranging from 0.04 to 0.65 and 0.04 to 0.76, respectively. Additionally, the loci amplified products in 15 samples from the wild ancestor, European polecat (Mustela putorius) and domestic ferret-polecat hybrids. In polecat/hybrid samples, allelic diversity ranged from 3 to 8 alleles, and expected and observed heterozygosities ranged from 0.13 to 0.81 and 0.13 to 0.80 respectively. These markers will be useful for molecular assessments of genetic diversity and applications to evolution, ecology, and health in domestic ferrets and wild polecats. PMID- 23443119 TI - Chemical composition and biological activities of the essential oils from three Melaleuca species grown in Tunisia. AB - The chemical composition of the essential oils of Melaleuca armillaris Sm., Melaleuca styphelioides Sm. and Melaleuca acuminata F. Muell., collected in Tunisia, was studied by means of GC and GC-MS analysis. In all, 46 compounds were identified, 38 for M. armillaris, 20 for M. acuminata and eight for M. styphelioides, respectively. The presence of a sesquiterpenic fraction (52.2%) characterized the oil from M. armillaris; M. sthypheliodes oil was rich in methyl eugenol, a phenolic compound (91.1%), while M. acuminata oil is mainly constituted by oxygenated monoterpenoids (95.6%). The essential oils were evaluated for their in vitro potentially phytotoxic activity against germination and initial radicle growth of Raphanus sativus L., Lepidium sativum L., Sinapis arvensis L., Triticum durum L. and Phalaris canariensis L. seeds. The radicle elongation of five seeds was inhibited at the highest doses tested, while germination of all seeds was not affected. Moreover, the essential oils showed low antimicrobial activity against eight selected microorganisms. PMID- 23443118 TI - Epigenetic deregulation of microRNAs in rhabdomyosarcoma and neuroblastoma and translational perspectives. AB - Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed. PMID- 23443122 TI - Modulation of MDR1 and MRP3 gene expression in lung cancer cells after paclitaxel and carboplatin exposure. AB - Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 MUM) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 MUM) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs. PMID- 23443121 TI - Recent advances in nanoparticle-based Forster resonance energy transfer for biosensing, molecular imaging and drug release profiling. AB - Forster resonance energy transfer (FRET) may be regarded as a "smart" technology in the design of fluorescence probes for biological sensing and imaging. Recently, a variety of nanoparticles that include quantum dots, gold nanoparticles, polymer, mesoporous silica nanoparticles and upconversion nanoparticles have been employed to modulate FRET. Researchers have developed a number of "visible" and "activatable" FRET probes sensitive to specific changes in the biological environment that are especially attractive from the biomedical point of view. This article reviews recent progress in bringing these nanoparticle-modulated energy transfer schemes to fruition for applications in biosensing, molecular imaging and drug delivery. PMID- 23443124 TI - XRCC3 gene polymorphism is associated with survival in Japanese lung cancer patients. AB - We focused on OGG1 Ser326Cys, MUTYH Gln324His, APEX1 Asp148Glu, XRCC1 Arg399Gln, and XRCC3 Thr241Met and examined the relationship between the different genotypes and survival of Japanese lung cancer patients. A total of 99 Japanese lung cancer patients were recruited into our study. Clinical data were collected, and genotypes of the target genes were identified by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Survival analysis to verify the impact of these gene polymorphisms on the clinical outcome of lung cancer showed that lung squamous cell carcinoma patients with the Thr/Met genotype at XRCC3 had a significantly shorter survival time than those with the Thr/Thr genotype (13 months versus 48 months; log-rank test, p < 0.0001). Cox regression analysis showed that the carriers of XRCC3 genotypes were at a significantly higher risk [adjusted hazard ratio (HR) = 9.35, 95% confidence interval (CI) = 2.52-34.68, p = 0.001; adjusted HR = 9.05, 95% CI = 1.89-44.39, p = 0.006]. Our results suggest that XRCC3 Thr241Met may act as a favorable prognostic indicator for lung squamous cell carcinoma patients. PMID- 23443125 TI - Bacterial over-expression and purification of the 3'phosphoadenosine 5'phosphosulfate (PAPS) reductase domain of human FAD synthase: functional characterization and homology modeling. AB - FAD synthase (FADS, EC 2.7.7.2) is a key enzyme in the metabolic pathway that converts riboflavin into the redox cofactor, FAD. Human FADS is organized in two domains: -the 3'phosphoadenosine 5'phosphosulfate (PAPS) reductase domain, similar to yeast Fad1p, at the C-terminus, and -the resembling molybdopterin binding domain at the N-terminus. To understand whether the PAPS reductase domain of hFADS is sufficient to catalyze FAD synthesis, per se, and to investigate the role of the molybdopterin-binding domain, a soluble "truncated" form of hFADS lacking the N-terminal domain (Delta(1-328)-hFADS) has been over-produced and purified to homogeneity as a recombinant His-tagged protein. The recombinant Delta(1-328)-hFADS binds one mole of FAD product very tightly as the wild-type enzyme. Under turnover conditions, it catalyzes FAD assembly from ATP and FMN and, at a much lower rate, FAD pyrophosphorolytic hydrolysis. The Delta(1-328) hFADS enzyme shows a slight, but not significant, change of K(m) values (0.24 and 6.23 uM for FMN and ATP, respectively) and of k(cat) (4.2 * 10-2 s-1) compared to wild-type protein in the forward direction. These results demonstrate that the molybdopterin-binding domain is not strictly required for catalysis. Its regulatory role is discussed in light of changes in divalent cations sensitivity of the Delta(1-328)-hFADS versus wild-type protein. PMID- 23443126 TI - Electrochemical characterization of Escherichia coli adaptive response protein AidB. AB - When exposed to known DNA-damaging alkylating agents, Escherichia coli cells increase production of four DNA repair enzymes: Ada, AlkA, AlkB, and AidB. The role of three enzymes (Ada, AlkA, and AlkB) in repairing DNA lesions has been well characterized, while the function of AidB is poorly understood. AidB has a distinct cofactor that is potentially related to the elusive role of AidB in adaptive response: a redox active flavin adenine dinucleotide (FAD). In this study, we report the thermodynamic redox properties of the AidB flavin for the first time, both for free protein and in the presence of potential substrates. We find that the midpoint reduction potential of the AidB flavin is within a biologically relevant window for redox chemistry at -181 mV, that AidB significantly stabilizes the flavin semiquinone, and that small molecule binding perturbs the observed reduction potential. Our electrochemical results combined with structural analysis allow for fresh comparisons between AidB and the homologous acyl-coenzyme A dehydrogenase (ACAD) family of enzymes. AidB exhibits several discrepancies from ACADs that suggest a novel catalytic mechanism distinct from that of the ACAD family enzymes. PMID- 23443127 TI - Evaporation rate of water as a function of a magnetic field and field gradient. AB - The effect of magnetic fields on water is still a highly controversial topic despite the vast amount of research devoted to this topic in past decades. Enhanced water evaporation in a magnetic field, however, is less disputed. The underlying mechanism for this phenomenon has been investigated in previous studies. In this paper, we present an investigation of the evaporation of water in a large gradient magnetic field. The evaporation of pure water at simulated gravity positions (0 gravity level (ab. g), 1 g, 1.56 g and 1.96 g) in a superconducting magnet was compared with that in the absence of the magnetic field. The results showed that the evaporation of water was indeed faster in the magnetic field than in the absence of the magnetic field. Furthermore, the amount of water evaporation differed depending on the position of the sample within the magnetic field. In particular, the evaporation at 0 g was clearly faster than that at other positions. The results are discussed from the point of view of the evaporation surface area of the water/air interface and the convection induced by the magnetization force due to the difference in the magnetic susceptibility of water vapor and the surrounding air. PMID- 23443123 TI - The implications of cancer stem cells for cancer therapy. AB - Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment. PMID- 23443129 TI - Oxidative stress mediated-alterations of the microRNA expression profile in mouse hippocampal neurons. AB - Oxidative stress plays a critical role in the etiology and pathogenesis of neurodegenerative disorders, and the molecular mechanisms that control the neuron response to ROS have been extensively studied. However, the oxidative stress effect on miRNA expression in hippocampal neurons has not been investigated, and little is known on the effect of ROS-modulated miRNAs on cell function. In this study, H(2)O(2) was used to stimulate the mouse primary hippocampal neurons to develop an oxidative stress cell model. The alterations of miRNAs expression were detected by microarray analysis and five miRNAs were validated by real-time RT PCR. The bioinformatic analysis of deregulated miRNAs was performed to determine their potential roles in the pathogenesis of neurological disorders. We found that H(2)O(2) mediated a total of 101 deregulated miRNAs, which mainly took part in the regulation of the MAPK pathway. Among them, miR-135b and miR-708 were up regulated significantly and their targets were predicted to be involved in DNA recombination, protein ubiquitination, protein autophosphorylation and development of neurons. These results demonstrated that oxidative stress alters the miRNA expression profile of hippocampal neurons, and the deregulated miRNAs might play a potential role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). PMID- 23443128 TI - DNA damage and repair in atherosclerosis: current insights and future perspectives. AB - Atherosclerosis is the leading cause of morbidity and mortality among Western populations. Over the past two decades, considerable evidence has supported a crucial role for DNA damage in the development and progression of atherosclerosis. These findings support the concept that the prolonged exposure to risk factors (e.g., dyslipidemia, smoking and diabetes mellitus) leading to reactive oxygen species are major stimuli for DNA damage within the plaque. Genomic instability at the cellular level can directly affect vascular function, leading to cell cycle arrest, apoptosis and premature vascular senescence. The purpose of this paper is to review current knowledge on the role of DNA damage and DNA repair systems in atherosclerosis, as well as to discuss the cellular response to DNA damage in order to shed light on possible strategies for prevention and treatment. PMID- 23443130 TI - Effects of sesamin on streptozotocin (STZ)-induced NIT-1 pancreatic beta-cell damage. AB - The protective effect of sesamin (SES) from sesame meal on NIT-1 pancreatic beta cells damaged by streptozotocin (STZ) in vitro was investigated. The cell viability, insulin secretion, the activity of superoxide dismutase(SOD), glutathione peroxidase (GSHpx) and the content of reduced glutathione (GSH) increased significantly when incubated with SES (400, 200 ug mL-1). The content of malondialdehyde (MDA), nitric oxide (NO) production, and the activity of NO synthase (NOS), inducible NOS (iNOS), decreased significantly when incubated with SES. The destructive changes of NIT-1 cells were ameliorated when treated with SES under microscopic observation. These data suggested that SES had obvious protective effect on NIT-1 pancreatic beta-cells damaged by STZ, which might be related to its effects of decreasing levels of beta-cell-destroying factors such as oxidative stress and NO synthesis. PMID- 23443131 TI - Increased insulin sensitivity and distorted mitochondrial adaptations during muscle unloading. AB - We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal muscle, HU decreased expression of pyruvate dehydrogenase kinase 4 (PDK4) and its protein level in mitochondria. HU decreased mtDNA content and mitochondrial biogenesis biomarkers. Dynamin-related protein (Drp1) in mitochondria and Mfn2 mRNA level were decreased significantly by HU. Our findings provide more extensive insight into mitochondrial adaptations to muscle disuse, involving the shift of fuel utilization towards glucose, the decreased mitochondrial biogenesis and the distorted mitochondrial dynamics. PMID- 23443132 TI - High density lipoprotein protects mesenchymal stem cells from oxidative stress induced apoptosis via activation of the PI3K/Akt pathway and suppression of reactive oxygen species. AB - The therapeutic effect of transplantation of mesenchymal stem cells (MSCs) in myocardial infarction (MI) appears to be limited by poor cell viability in the injured tissue, which is a consequence of oxidative stress and pro-apoptotic factors. High density lipoprotein (HDL) reverses cholesterol transport and has anti-oxidative and anti-apoptotic properties. We, therefore, investigated whether HDL could protect MSCs from oxidative stress-induced apoptosis. MSCs derived from the bone marrow of rats were pre-incubated with or without HDL, and then were exposed to hydrogen peroxide (H(2)O(2)) in vitro, or were transplanted into experimentally infarcted hearts of rats in vivo. Pre-incubation of MSCs with HDL increased cell viability, reduced apoptotic indices and resulted in parallel decreases in reactive oxygen species (ROS) in comparison with control MSCs. Each of the beneficial effects of HDL on MSCs was attenuated by inhibiting the PI3K/Akt pathway. Preconditioning with HDL resulted in higher MSC survival rates, improved cardiac remodeling and better myocardial function than in the MSC control group. Collectively, these results suggest that HDL may protect against H(2)O(2)-induced apoptosis in MSCs through activation of a PI3K/Akt pathway, and by suppressing the production of ROS. PMID- 23443133 TI - Propofol induces rat embryonic neural stem cell apoptosis by activating both extrinsic and intrinsic pathways. AB - Propofol has previously been shown to have detrimental effects on the developing brain. Neural stem cells, identified in the embryonic brain as well as in the adult brain, are multipotent, self-renewing cells, which are capable of differentiating into different phenotypes of the nervous system. The present study was designed to investigate propofol-induced rat embryonic neural stem cell apoptosis and its potential mechanisms. Rat embryonic neural stem cells were isolated, cultured and characterized. Treatment of these cultured stem cells with different doses of propofol was carried out and cell proliferation was assessed by MTT assay and apoptosis by flow cytometric analysis. Cellular levels of active forms of caspase-3 and caspase-8, which regulate the extrinsic apoptotic pathway, and of caspase-9 and cytochrome C, which regulate the intrinsic apoptotic pathway, were detected by western blotting. Over 95% of isolated rat embryonic neural stem cells expressed the Nestin protein, as detected by immunofluorescence staining. Using an in vitro cell culture system, we showed that propofol inhibited cell growth and induced cell apoptosis in a dose-dependent manner. Furthermore, western blot analysis showed that propofol treatment significantly elevated levels of active forms of caspase-3, caspase-8, caspase-9 and cytochrome C in the embryonic neural stem cells. Propofol induced rat embryonic neural stem cell apoptosis and activated caspase-3, caspase-8, caspase-9 and cytochrome C, suggesting that propofol-induced stem cell apoptosis may be regulated through both the extrinsic and intrinsic apoptotic pathways. PMID- 23443135 TI - SweetSEQer, simple de novo filtering and annotation of glycoconjugate mass spectra. AB - The past 15 years have seen significant progress in LC-MS/MS peptide sequencing, including the advent of successful de novo and database search methods; however, analysis of glycopeptide and, more generally, glycoconjugate spectra remains a much more open problem, and much annotation is still performed manually. This is partly because glycans, unlike peptides, need not be linear chains and are instead described by trees. In this study, we introduce SweetSEQer, an extremely simple open source tool for identifying potential glycopeptide MS/MS spectra. We evaluate SweetSEQer on manually curated glycoconjugate spectra and on negative controls, and we demonstrate high quality filtering that can be easily improved for specific applications. We also demonstrate a high overlap between peaks annotated by experts and peaks annotated by SweetSEQer, as well as demonstrate inferred glycan graphs consistent with canonical glycan tree motifs. This study presents a novel tool for annotating spectra and producing glycan graphs from LC MS/MS spectra. The tool is evaluated and shown to perform similarly to an expert on manually curated data. PMID- 23443134 TI - Identification of O-linked N-acetylglucosamine (O-GlcNAc)-modified osteoblast proteins by electron transfer dissociation tandem mass spectrometry reveals proteins critical for bone formation. AB - The nutrient-responsive beta-O-linked N-acetylglucosamine (O-GlcNAc) modification of critical effector proteins modulates signaling and transcriptional pathways contributing to cellular development and survival. An elevation in global protein O-GlcNAc modification occurs during the early stages of osteoblast differentiation and correlates with enhanced transcriptional activity of RUNX2, a key regulator of osteogenesis. To identify other substrates of O-GlcNAc transferase in differentiating MC3T3E1 osteoblasts, O-GlcNAc-modified peptides were enriched by wheat germ agglutinin lectin weak affinity chromatography and identified by tandem mass spectrometry using electron transfer dissociation. This peptide fragmentation approach leaves the labile O-linkage intact permitting direct identification of O-GlcNAc-modified peptides. O-GlcNAc modification was observed on enzymes involved in post-translational regulation, including MAST4 and WNK1 kinases, a ubiquitin-associated protein (UBAP2l), and the histone acetyltransferase CREB-binding protein. CREB-binding protein, a transcriptional co-activator that associates with CREB and RUNX2, is O-GlcNAcylated at Ser-147 and Ser-2360, the latter of which is a known site of phosphorylation. Additionally, O-GlcNAcylation of components of the TGFbeta-activated kinase 1 (TAK1) signaling complex, TAB1 and TAB2, occurred in close proximity to known sites of Ser/Thr phosphorylation and a putative nuclear localization sequence within TAB2. These findings demonstrate the presence of O-GlcNAc modification on proteins critical to bone formation, remodeling, and fracture healing and will enable evaluation of this modification on protein function and regulation. PMID- 23443136 TI - Quantitative proteomics reveals that enzymes of the ketogenic pathway are associated with prostate cancer progression. AB - Prostate cancer is the most common malignancy and the second leading cause of cancer-related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumors that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line and its androgen-independent derivative, LNCaP-SF. Utilizing stable isotope labeling with amino acids in cell culture coupled to mass spectrometry, we assessed the differential global protein expression of the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins. Bioinformatic prioritization resulted in 42 up regulated and 46 down-regulated proteins in LNCaP-SF cells relative to LNCaP cells. Our top candidate, HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, and OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells, which was further verified using Western blotting. To determine whether these enzymes were up-regulated in clinical samples, we performed quantitative PCR and immunohistochemistry on human prostate cancer tissues, from which we observed significantly increased transcript and protein levels in high-grade cancer (Gleason grade >= 8). In addition, we observed significant elevation of these enzymes in the LuCaP 96AI castration-resistant xenograft. Further assessment of ACAT1 on human castration-resistant metastatic prostate cancer tissues revealed substantially elevated expression of ACAT1 in these specimens. Taken together, our results indicate that enzymes of the ketogenic pathway are up-regulated in high-grade prostate cancer and could serve as potential tissue biomarkers for the diagnosis or prognosis of high-grade disease. PMID- 23443139 TI - Interaction between QTLs induces an advance in ethylene biosynthesis during melon fruit ripening. AB - The coexistence of both climacteric and non-climacteric genotypes and the availability of a set of genetic and genomic resources make melon a suitable model for genetic studies of fruit ripening. We have previously described a QTL, ETHQB3.5, which induces climacteric fruit ripening in the near-isogenic line (NIL) SC3-5 that harbors an introgression on linkage group (LG) III from the non climacteric melon accession PI 161375 in the, also non-climacteric cultivar, "Piel de Sapo" genetic background. In the current study, a new major QTL, ETHQV6.3, on LG VI was detected on an additional introgression in the same NIL. These QTLs are capable, individually, of inducing climacteric ripening in the non climacteric background, the effects of ETHQV6.3 being greater than that of ETHQB3.5. The QTLs interact epistatically, advancing the timing of ethylene biosynthesis during ripening and, therefore, the climacteric responses. ETHQV6.3 was fine-mapped to a 4.5 Mb physical region of the melon genome, probably in the centromeric region of LG VI. The results presented will be of value in the molecular identification of the gene underlying ETHQV6.3. PMID- 23443140 TI - How to measure reaction temperature in microwave-heated transformations. AB - High-speed microwave chemistry has attracted considerable attention in the past two decades with new and innovative applications in organic and peptide synthesis, polymer chemistry, material sciences, nanotechnology and biochemical processes continuously being reported in the literature. In particular the introduction of benchtop single-mode microwave reactors just over ten years ago has revolutionized the way many scientists today perform reactions in the laboratory. Unfortunately, the accurate measurement of reaction temperature in these devices is far from being trivial and requires both a basic understanding of microwave dielectric heating effects and use of appropriate temperature monitoring devices. In this tutorial review frequently occurring problems in the determination of accurate reaction temperatures in single-mode microwave reactors are discussed. PMID- 23443137 TI - In-depth characterization of the secretome of colorectal cancer metastatic cells identifies key proteins in cell adhesion, migration, and invasion. AB - Liver metastasis in colorectal cancer is the major cause of cancer-related deaths. To identify and characterize proteins associated with colon cancer metastasis, we have compared the conditioned serum-free medium of highly metastatic KM12SM colorectal cancer cells with the parental, poorly metastatic KM12C cells using quantitative stable isotope labeling by amino acids in cell culture (SILAC) analyses on a linear ion trap-Orbitrap Velos mass spectrometer. In total, 1337 proteins were simultaneously identified in SILAC forward and reverse experiments. For quantification, 1098 proteins were selected in both experiments, with 155 proteins showing >1.5-fold change. About 52% of these proteins were secreted directly or using alternative secretion pathways. GDF15, S100A8/A9, and SERPINI1 showed capacity to discriminate cancer serum samples from healthy controls using ELISAs. In silico analyses of deregulated proteins in the secretome of metastatic cells showed a major abundance of proteins involved in cell adhesion, migration, and invasion. To characterize the tumorigenic and metastatic properties of some top up- and down-regulated proteins, we used siRNA silencing and antibody blocking. Knockdown expression of NEO1, SERPINI1, and PODXL showed a significant effect on cellular adhesion. Silencing or blocking experiments with SOSTDC1, CTSS, EFNA3, CD137L/TNFSF9, ZG16B, and Midkine caused a significant decrease in migration and invasion of highly metastatic cells. In addition, silencing of SOSTDC1, EFNA3, and CD137L/TNFSF9 reduced liver colonization capacity of KM12SM cells. Finally, the panel of six proteins involved in invasion showed association with poor prognosis and overall survival after dataset analysis of gene alterations. In summary, we have defined a collection of proteins that are relevant for understanding the mechanisms underlying adhesion, migration, invasion, and metastasis in colorectal cancer. PMID- 23443138 TI - Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice. AB - Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials. PMID- 23443142 TI - Hypertension as a complication of circular external fixators. AB - Hypertension is not a recognized complication of circular external fixation. The aim of this study was to determine the incidence of hypertension following this procedure. A retrospective review of 57 patients was carried out between January 2006 and May 2010. At least three blood pressure readings were used to define hypertension. Five of the 41 qualifying patients (12.2%) developed hypertension. Three of these were found to have a sustained hypertension throughout the frame period, two requiring treatment for visual symptoms and left ventricular hypertrophy. A limb reconstruction surgeon needs to be alert to this potential complication to initiate prompt investigations and treatment. PMID- 23443141 TI - Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology. AB - The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms. PMID- 23443143 TI - Flexible intramedullary nailing in simple bone cysts of the proximal humerus: prospective study for high-risk cases of pathologic fracture. AB - We designed and evaluated a modified cyst index using the Picture Archiving and Communication System software for treating simple bone cysts of the proximal humerus by preventive intramedullary flexible nail insertion in symptomatic children or adolescents. From January 2007 to December 2009, cases with a cyst index of at least 4 were enrolled in the study. Of 20 total cases, 19 were prospectively followed-up for at least 2 years. The mean patient age was 10.6 years (range, 7-15 years) and the mean modified cyst index was 6.56 (range, 4.95 8.25). The mean cyst healing period was 8.7 months (range, 4-30 months) and the mean follow-up period was 31.05 months (range, 24-42 months). Seventeen lesions (89%) were classified as completely healed and two (11%) were classified as healed with residual radiolucency. In all cases, no angular deformity was found on the final follow-up radiograph. Therefore, preventive flexible intramedullary nail insertion before the occurrence of a pathologic fracture because of simple bone cysts with a modified cyst index of at least 4 in the proximal humerus is an excellent treatment option. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 23443144 TI - Predictive values for the severity of avascular necrosis from the initial evaluation in closed reduction of developmental dysplasia of the hip. AB - The severity of avascular necrosis (AVN) after closed reduction of developmental dysplasia of the hip determines the final clinical outcomes. Our study aimed to correlate the possible predictors with the severity of AVN. After follow-up of the patients on skeletal maturity, 37 patients (39 hips) were included. Age at reduction is important to predict the severity of AVN. Older patients are at a greater risk of suffering from more severe AVN. Other values such as the degree of initial dislocation or the impact of the femoral head ossific nucleus show no precognition to the severity of AVN. PMID- 23443149 TI - JAK/STAT signalling--an executable model assembled from molecule-centred modules demonstrating a module-oriented database concept for systems and synthetic biology. AB - Mathematical models of molecular networks regulating biological processes in cells or organisms are most frequently designed as sets of ordinary differential equations. Various modularisation methods have been applied to reduce the complexity of models, to analyse their structural properties, to separate biological processes, or to reuse model parts. Taking the JAK/STAT signalling pathway with the extensive combinatorial cross-talk of its components as a case study, we make a natural approach to modularisation by creating one module for each biomolecule. Each module consists of a Petri net and associated metadata and is organised in a database publically accessible through a web interface (). The Petri net describes the reaction mechanism of a given biomolecule and its functional interactions with other components including relevant conformational states. The database is designed to support the curation, documentation, version control, and update of individual modules, and to assist the user in automatically composing complex models from modules. Biomolecule centred modules, associated metadata, and database support together allow the automatic creation of models by considering differential gene expression in given cell types or under certain physiological conditions or states of disease. Modularity also facilitates exploring the consequences of alternative molecular mechanisms by comparative simulation of automatically created models even for users without mathematical skills. Models may be selectively executed as an ODE system, stochastic, or qualitative models or hybrid and exported in the SBML format. The fully automated generation of models of redesigned networks by metadata-guided modification of modules representing biomolecules with mutated function or specificity is proposed. PMID- 23443150 TI - Easy abstraction of a hydride anion from an alkyl C-H bond of a coordinated bis(N heterocyclic carbene). AB - The high basicity of a trimethylene-linked bis(NHC), acting as a chelating ligand in a ruthenium(0) complex, is responsible for its involvement in a room temperature reaction in which the metal atom to which this bis(NHC) ligand is coordinated replaces a hydride anion of the ligand trimethylene linker, which can be taken by a hydride abstractor as unusual, in that role, as [Ru3(CO)12]. PMID- 23443151 TI - Acquired thrombotic thrombocytopenic purpura. Development of an autoimmune response. AB - The von Willebrand factor (VWF)-cleaving metalloprotease, ADAMTS13 (adisintegrin and metalloprotease with thrombospondin type 1 motifs-13) is the only known target of the dysregulated immune response in acquired TTP. Autoantibodies to ADAMTS13 either neutralize its activity or accelerate its clearance, thereby causing a severe deficiency of ADAMTS13 in plasma. As a consequence, size regulation of VWF is impaired and the persistence of ultra-large VWF (ULVWF) multimers facilitates microvascular platelet aggregation causing microangiopathic haemolytic anaemia and ischaemic organ damage. Autoimmune TTP although a rare disease with an annual incidence of 1.72 cases has a mortality rate of 20% even with adequate therapy. We describe the mechanisms involved in ADAMTS13 autoimmunity with a focus on the role of B- and T-cells in the pathogenesis of this disorder. We discuss the potential translation of recent experimental findings into future therapeutic concepts for the treatment of acquired TTP. PMID- 23443152 TI - Scalable and direct growth of graphene micro ribbons on dielectric substrates. AB - Here we report on a scalable and direct growth of graphene micro ribbons on SiO(2) dielectric substrates using a low temperature chemical vapor deposition. Due to the fast annealing at low temperature and dewetting of Ni, continuous few layer graphene micro ribbons grow directly on bare dielectric substrates through Ni assisted catalytic decomposition of hydrocarbon precursors. These high quality graphene micro ribbons exhibit low sheet resistance of ~700 Omega -2100 Omega, high on/off current ratio of ~3, and high carrier mobility of ~655 cm(2)V(-1)s( 1) at room temperature, all of which have shown significant improvement over other lithography patterned CVD graphene micro ribbons. This direct approach can in principle form graphene ribbons of any arbitrary sizes and geometries. It allows for a feasible methodology towards better integration with semiconductor materials for interconnect electronics and scalable production for graphene based electronic and optoelectronic applications where the electrical gating is the key enabling factor. PMID- 23443153 TI - Protein induced by vitamin K antagonist-II (PIVKA-II) is a reliable prognostic factor in small hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) <2 cm in diameter has a favorable prognosis. Therefore surgical resection of small HCC is associated with good outcomes. However, the predisposing factors of prognosis following resection of HCC remain ill-defined. The aims of the present study were to identify the clinicopathologic characteristics and outcomes of patients with small HCC and analyze the predisposing factors for tumor recurrence after surgery. METHODS: We retrospectively reviewed 180 patients with small HCC who underwent hepatectomy between 2006 and 2010. Independent predictors of tumor recurrence were identified with Cox regression analysis. RESULTS: The 1-year, 3-year, and 5-year disease free survival rates and overall survival rates were 83.7, 68.0, 65.3, and 98.9, 96.5, 92.7 %, respectively. Multivariate analysis reported that protein induced by the vitamin K antagonist-II (PIVKA-II) >= 200 mAU/mL, alkaline phosphatase (ALP) >= 80 IU/mL, and microvascular invasion were important predisposing factors for tumor recurrence. Elevated serum PIVKA-II level was associated with microvascular invasion in small HCC, which was a powerful predisposing factor. CONCLUSIONS: Although small HCC is generally associated with a good prognosis, serum PIVKA-II level >= 200 mAU/mL, ALP >= 80 IU/L, and microvascular invasion were predisposing factors for tumor recurrence. These factors can be used to stratify patients with respect to recurrence after resection. Elevated PIVKA-II was closely associated with microvascular invasion in small HCC. These data emphasize the importance of PIVKA-II in small HCC. PMID- 23443154 TI - Low perioperative prealbumin level predicts early recurrence after curative pulmonary resection for non-small cell lung cancer. PMID- 23443155 TI - Epidemiological changes in rotavirus gastroenteritis in children under 5 years of age after the introduction of rotavirus vaccines in Korea. AB - Rotavirus gastroenteritis is the leading cause of severe acute gastroenteritis in children worldwide and is associated with high hospitalization and mortality rates in children younger than 5 years of age. Vaccination is necessary to prevent rotavirus infection. Two live attenuated and orally administered rotavirus vaccines became commercially available in Korea. The aim of this study is to describe epidemiological changes in rotavirus gastroenteritis after the introduction of rotavirus vaccines in Korea. The medical records of 11,199 children younger than 5 years of age and hospitalized for acute gastroenteritis from August 2007 to July 2010 in eight Korean hospitals were reviewed. Rotavirus was detected in stool samples obtained from 2,959 children (26.42 %). The authors evaluated the percentage of rotavirus gastroenteritis among all acute gastroenteritis hospitalizations in eight hospitals located in different geographical areas and analyzed epidemiological changes in rotavirus gastroenteritis according to age, geographical area, and season. According to the findings, the percentage of rotavirus gastroenteritis showed a decrease in children eligible for vaccination during the study period. After introduction of the vaccine, reduced rates of rotavirus detection were observed in all of the geographical areas, and the greatest reduction was observed in Seoul. In Seoul, there was a marked delay of the rotavirus season. CONCLUSION: Epidemiologic changes in Korea after the introduction of rotavirus vaccine are consistent with changes observed in other countries. PMID- 23443156 TI - Interstitial lung disease in two brothers with novel compound heterozygous ABCA3 mutations. AB - Mutations in genes critical for surfactant metabolism, including surfactant protein C (SP-C) and ABCA3, are well-recognized causes of interstitial lung disease. Recessive mutations in ABCA3 were first attributed to fatal respiratory failure in full-term neonates, but they are also increasingly being recognized as a cause of respiratory disorders with less severe phenotypes in older children and also adults. Here, we report a 20-month-old boy with interstitial lung disease caused by two distinct ABCA3 mutations. Initial treatment with methylprednisolone was unsuccessful, but the additional administration of hydroxychloroquine was effective. The family history revealed that the patient's older brother had died of idiopathic interstitial lung disease at 6 months of age, suggesting a genetic etiology of the disease. Sequence analyses of SP-C and ABCA3 genes were performed using DNA samples from the patient himself, his parents, and his brother. These analyses revealed novel compound heterozygous mutations in the coding exons of ABCA3 in both the patient and his brother: c.2741A > G, of paternal origin, and c.3715_3716insGGGGGG, of maternal origin. Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease. PMID- 23443157 TI - Probucol inhibits hydrogen peroxide to induce apoptosis of vascular smooth muscle cells. AB - The aim of this study was to investigate the effect of the antioxidant probucol on hydrogen peroxide (H2O2)-induced vascular smooth muscle cell (VSMC) apoptosis. H2O2 (1 mmol/l) was used as the VSMC apoptosis-inducing agent, and 100, 10 and 1 umol/l probucol concentrations were incubated with cells for 6 h. The cell apoptosis was observed using Annexin V-FITC, TUNEL and Hoechst 33258 staining methods. H2O2 promoted VSMC apoptosis, ASK-1 protein expression increased and Trx l protein expression decreased. Probucol reduced H2O2-induced apoptosis in a dose dependent manner; while ASK-1 protein expression decreased, Trx-1 protein expression increased. Probuco1 is capable of antagonizing the H2O2-induced apoptosis in VSMCs, which may be related to the decrease in ASK-1 protein expression and the increase in Trx-1 protein expression. PMID- 23443158 TI - Small Regulatory RNAs in the Control of Motility and Biofilm Formation in E. coli and Salmonella. AB - Biofilm formation in Escherichia coli and other enteric bacteria involves the inverse regulation of the synthesis of flagella and biofilm matrix components such as amyloid curli fibres, cellulose, colanic acid and poly-N acetylglucosamine (PGA). Physiologically, these processes reflect the transition from growth to stationary phase. At the molecular level, they are tightly controlled by various sigma factors competing for RNA polymerase, a series of transcription factors acting in hierarchical regulatory cascades and several nucleotide messengers, including cyclic-di-GMP. In addition, a surprisingly large number of small regulatory RNAs (sRNAs) have been shown to directly or indirectly modulate motility and/or biofilm formation. This review aims at giving an overview of these sRNA regulators and their impact in biofilm formation in E. coli and Salmonella. Special emphasis will be put on sRNAs, that have known targets such as the mRNAs of the flagellar master regulator FlhDC, the stationary phase sigma factor sigmaS (RpoS) and the key biofilm regulator CsgD that have recently been shown to act as major hubs for regulation by multiple sRNAs. PMID- 23443159 TI - Brain activity of thioctic Acid enantiomers: in vitro and in vivo studies in an animal model of cerebrovascular injury. AB - Oxidative stress is an imbalance between the production of free radicals and antioxidant defense mechanisms, potentially leading to tissue damage. Oxidative stress has a key role in the development of cerebrovascular and/or neurodegenerative diseases. This phenomenon is mainly mediated by an enhanced superoxide production by the vascular endothelium with its consequent dysfunction. Thioctic, also known as alpha-lipoic acid (1,2-dithiolane-3 pentanoic acid), is a naturally occurring antioxidant that neutralizes free radicals in the fatty and watery regions of cells. Both the reduced and oxidized forms of the compound possess antioxidant ability. Thioctic acid has two optical isomers designated as (+)- and (-)-thioctic acid. Naturally occurring thioctic acid is the (+)-thioctic acid form, but the synthetic compound largely used in the market for stability reasons is a mixture of (+)- and (-)-thioctic acid. The present study was designed to compare the antioxidant activity of the two enantiomers versus the racemic form of thioctic acid on hydrogen peroxide-induced apoptosis in a rat pheochromocytoma PC12 cell line. Cell viability was evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and free oxygen radical species (ROS) production was assessed by flow cytometry. Antioxidant activity of the two enantiomers and the racemic form of thioctic acid was also evaluated in spontaneously hypertensive rats (SHR) used as an in vivo model of increased oxidative stress. A 3-h exposure of PC12 cells to hydrogen peroxide (H(2)O(2)) significantly decreased cell viability and increased levels of intracellular ROS production. Pre-treatment with racemic thioctic acid or (+) enantiomer significantly inhibited H(2)O(2)-induced decrease in cell viability from the concentration of 50 MUmol/L and 20 MUmol/L, respectively. Racemic thioctic acid and (+)-salt decreased levels of intracellular ROS, which were unaffected by (-)-thioctic acid. In the brain of SHR, the occurrence of astrogliosis and neuronal damage, with a decreased expression of neurofilament 200 kDa were observed. Treatment of SHR for 30 days with (+)-thioctic acid reduced the size of astrocytes and increased the neurofilament immunoreaction. The above findings could contribute to clarify the role played by thioctic acid in central nervous system injury related to oxidative stress. The more pronounced effect of (+)-thioctic acid observed in this study may have practical therapeutic implications worthy of being investigated in further preclinical and clinical studies. PMID- 23443160 TI - Atypical protein phosphatases: emerging players in cellular signaling. AB - It has generally been considered that protein phosphatases have more diverse catalytic domain structures and mechanisms than protein kinases; however, gene annotation efforts following the human genome project appeared to have completed the whole array of protein phosphatases. Ser/Thr phosphatases are divided into three subfamilies that have different structures from each other, whereas Tyr phosphatases and dual-specificity phosphatases targeting Tyr, Ser and Thr belong to a single large family based on their common structural features. Several years of research have revealed, however, the existence of unexpected proteins, designated here as "atypical protein phosphatases", that have structural and enzymatic features different from those of the known protein phosphatases and are involved in important biological processes. In this review, we focus on the identification and functional characterization of atypical protein phosphatases, represented by eyes absent (EYA), suppressor of T-cell receptor signaling (Sts) and phosphoglycerate mutase family member 5 (PGAM5) and discuss their biological significance in cellular signaling. PMID- 23443161 TI - Covalent Immobilization of Bacillus licheniformis gamma-Glutamyl Transpeptidase on Aldehyde-Functionalized Magnetic Nanoparticles. AB - This work presents the synthesis and use of surface-modified iron oxide nanoparticles for the covalent immobilization of Bacillus licheniformis gamma glutamyl transpeptidase (BlGGT). Magnetic nanoparticles were prepared by an alkaline solution of divalent and trivalent iron ions, and they were subsequently treated with 3-aminopropyltriethoxysilane (APES) to obtain the aminosilane-coated nanoparticles. The functional group on the particle surface and the amino group of BlGGT was then cross-linked using glutaraldehyde as the coupling reagent. The loading capacity of the prepared nanoparticles for BlGGT was 34.2 mg/g support, corresponding to 52.4% recovery of the initial activity. Monographs of transmission electron microscopy revealed that the synthesized nanoparticles had a mean diameter of 15.1 +/- 3.7 nm, and the covalent cross-linking of the enzyme did not significantly change their particle size. Fourier transform infrared spectroscopy confirmed the immobilization of BlGGT on the magnetic nanoparticles. The chemical and kinetic behaviors of immobilized BlGGT are mostly consistent with those of the free enzyme. The immobilized enzyme could be recycled ten times with 36.2% retention of the initial activity and had a comparable stability respective to free enzyme during the storage period of 30 days. Collectively, the straightforward synthesis of aldehyde-functionalized nanoparticles and the efficiency of enzyme immobilization offer wide perspectives for the practical use of surface-bound BlGGT. PMID- 23443162 TI - New Anti-Inflammatory Aromatic Components from Antrodia camphorata. AB - Three new benzenoids, 3-isopropenyl-2-methoxy-6-methyl-4,5-methylenedioxy- phenol (1), 2-hydroxy-4,4'-dimethoxy-3,3'-dimethyl-5,6,5',6'-bimethylenedioxybiphenyl (2), 4,4'-dihydroxy-3,3'-dimethoxy-2,2'-dimethyl-5,6,5',6' bimethylenedioxybiphenyl (3), together with two known benzenoids, 2,3,6 trimethoxy-5-methylphenol (4) and 2,3-methylenedioxy- 4-methoxy-5-methylphenol (5), were isolated from Antrodia camphorata. Our results support that compounds 1 5 potently inhibited LPS (lipopolysaccharide)-induced nitric oxide (NO) production in a dose-dependent manner. The IC(50) values of compounds 1, 3 and 5 were 1.8 +/- 0.2, 18.8 +/- 0.6 and 0.8 +/- 0.3 MUg/mL, respectively. PMID- 23443163 TI - Incidence of Bacteriocins Produced by Food-Related Lactic Acid Bacteria Active towards Oral Pathogens. AB - In the present study we investigated the incidence of bacteriocins produced by 236 lactic acid bacteria (LAB) food isolates against pathogenic or opportunistic pathogenic oral bacteria. This set of LAB contained several strains (>=17%) producing bacteriocins active against food-related bacteria. Interestingly only Streptococcus macedonicus ACA-DC 198 was able to inhibit the growth of Streptococcus oralis, Streptococcus sanguinis and Streptococcus gordonii, while Lactobacillus fermentum ACA-DC 179 and Lactobacillus plantarun ACA-DC 269 produced bacteriocins solely against Streptococcus oralis. Thus, the percentage of strains that were found to produce bacteriocins against oral bacteria was ~1.3%. The rarity of bacteriocins active against oral LAB pathogens produced by food-related LAB was unexpected given their close phylogenetic relationship. Nevertheless, when tested in inhibition assays, the potency of the bacteriocin(s) of S. macedonicus ACA-DC 198 against the three oral streptococci was high. Fourier-transform infrared spectroscopy combined with principal component analysis revealed that exposure of the target cells to the antimicrobial compounds caused major alterations of key cellular constituents. Our findings indicate that bacteriocins produced by food-related LAB against oral LAB may be rare, but deserve further investigation since, when discovered, they can be effective antimicrobials. PMID- 23443164 TI - Long non-coding RNA in cancer. AB - Long non-coding RNAs (lncRNAs) are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. LncRNAs are deregulated in a number of cancers, demonstrating both oncogenic and tumor suppressive roles, thus suggesting their aberrant expression may be a substantial contributor in cancer development. In this review, we will summarize their emerging role in human cancer and discuss their perspectives in diagnostics as potential biomarkers. PMID- 23443165 TI - Regulation of Translation Initiation under Biotic and Abiotic Stresses. AB - Plants have developed versatile strategies to deal with the great variety of challenging conditions they are exposed to. Among them, the regulation of translation is a common target to finely modulate gene expression both under biotic and abiotic stress situations. Upon environmental challenges, translation is regulated to reduce the consumption of energy and to selectively synthesize proteins involved in the proper establishment of the tolerance response. In the case of viral infections, the situation is more complex, as viruses have evolved unconventional mechanisms to regulate translation in order to ensure the production of the viral encoded proteins using the plant machinery. Although the final purpose is different, in some cases, both plants and viruses share common mechanisms to modulate translation. In others, the mechanisms leading to the control of translation are viral- or stress-specific. In this paper, we review the different mechanisms involved in the regulation of translation initiation under virus infection and under environmental stress in plants. In addition, we describe the main features within the viral RNAs and the cellular mRNAs that promote their selective translation in plants undergoing biotic and abiotic stress situations. PMID- 23443166 TI - Irradiated human dermal fibroblasts are as efficient as mouse fibroblasts as a feeder layer to improve human epidermal cell culture lifespan. AB - A fibroblast feeder layer is currently the best option for large scale expansion of autologous skin keratinocytes that are to be used for the treatment of severely burned patients. In a clinical context, using a human rather than a mouse feeder layer is desirable to reduce the risk of introducing animal antigens and unknown viruses. This study was designed to evaluate if irradiated human fibroblasts can be used in keratinocyte cultures without affecting their morphological and physiological properties. Keratinocytes were grown either with or without a feeder layer in serum-containing medium. Our results showed that keratinocytes grown either on an irradiated human feeder layer or irradiated 3T3 cells (i3T3) can be cultured for a comparable number of passages. The average epithelial cell size and morphology were also similar. On the other hand, keratinocytes grown without a feeder layer showed heavily bloated cells at early passages and stop proliferating after only a few passages. On the molecular aspect, the expression level of the transcription factor Sp1, a useful marker of keratinocytes lifespan, was maintained and stabilized for a high number of passages in keratinocytes grown with feeder layers whereas Sp1 expression dropped quickly without a feeder layer. Furthermore, gene profiling on microarrays identified potential target genes whose expression is differentially regulated in the absence or presence of an i3T3 feeder layer and which may contribute at preserving the growth characteristics of these cells. Irradiated human dermal fibroblasts therefore provide a good human feeder layer for an effective expansion of keratinocytes in vitro that are to be used for clinical purposes. PMID- 23443167 TI - Interplay between Hepatitis C Virus and Redox Cell Signaling. AB - Hepatitis C virus (HCV) infects approximately 3% of the world's population. Currently licensed treatment of HCV chronic infection with pegylated-interferon alpha and ribavirin, is not fully effective against all HCV genotypes and is associated to severe side effects. Thus, development of novel therapeutics and identification of new targets for treatment of HCV infection is necessary. Current opinion is orienting to target antiviral drug discovery to the host cell pathways on which the virus relies, instead of against viral structures. Many intracellular signaling pathways manipulated by HCV for its own replication are finely regulated by the oxido-reductive (redox) state of the host cell. At the same time, HCV induces oxidative stress that has been found to affect both virus replication as well as progression and severity of HCV infection. A dual role, positive or negative, for the host cell oxidized conditions on HCV replication has been reported so far. This review examines current information about the effect of oxidative stress on HCV life cycle and the main redox-regulated intracellular pathways activated during HCV infection and involved in its replication. PMID- 23443168 TI - What went wrong? The flawed concept of cerebrospinal venous insufficiency. AB - In 2006, Zamboni reintroduced the concept that chronic impaired venous outflow of the central nervous system is associated with multiple sclerosis (MS), coining the term of chronic cerebrospinal venous insufficiency ('CCSVI'). The diagnosis of 'CCSVI' is based on sonographic criteria, which he found exclusively fulfilled in MS. The concept proposes that chronic venous outflow failure is associated with venous reflux and congestion and leads to iron deposition, thereby inducing neuroinflammation and degeneration. The revival of this concept has generated major interest in media and patient groups, mainly driven by the hope that endovascular treatment of 'CCSVI' could alleviate MS. Many investigators tried to replicate Zamboni's results with duplex sonography, magnetic resonance imaging, and catheter angiography. The data obtained here do generally not support the 'CCSVI' concept. Moreover, there are no methodologically adequate studies to prove or disprove beneficial effects of endovascular treatment in MS. This review not only gives a comprehensive overview of the methodological flaws and pathophysiologic implausibility of the 'CCSVI' concept, but also summarizes the multimodality diagnostic validation studies and open-label trials of endovascular treatment. In our view, there is currently no basis to diagnose or treat 'CCSVI' in the care of MS patients, outside of the setting of scientific research. PMID- 23443169 TI - Involvement of arterial baroreflex in the protective effect of dietary restriction against stroke. AB - Dietary restriction (DR) protects against neuronal dysfunction and degeneration, and reduces the risk of ischemic stroke. This study examined the role of silent information regulator T1 (SIRT1) and arterial baroreflex in the beneficial effects of DR against stroke, using two distinct stroke models: stroke-prone spontaneously hypertensive rats (SP-SHRs) and Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Sirt1 knockout (KO) mice were used to examine the involvement of sirt1. Sinoaortic denervation was used to inactivate arterial baroreflex. Dietary restriction was defined as 40% reduction of dietary intake. Briefly, DR prolonged the life span of SP-SHRs and reduced the infarct size induced by MCAO. Dietary restriction also improved the function arterial baroreflex, decreased the release of proinflammatory cytokines, and reduced end organ damage. The beneficial effect of DR on stroke was markedly attenuated by blunting arterial baroreflex. Lastly, the infarct area in sirt1 KO mice was significantly larger than in the wild-type mice. However, the beneficial effect of DR against ischemic injury was still apparent in sirt1 KO mice. Accordingly, arterial baroreflex, but not sirt1, is important in the protective effect of DR against stroke. PMID- 23443170 TI - The vascular conducted response in cerebral blood flow regulation. AB - Despite recent advances in our understanding of the molecular and cellular mechanisms behind vascular conducted responses (VCRs) in systemic arterioles, we still know very little about their potential physiological and pathophysiological role in brain penetrating arterioles controlling blood flow to the deeper areas of the brain. The scope of the present review is to present an overview of the conceptual, mechanistic, and physiological role of VCRs in resistance vessels, and to discuss in detail the recent advances in our knowledge of VCRs in brain arterioles controlling cerebral blood flow. We provide a schematic view of the ion channels and intercellular communication pathways necessary for conduction of an electrical and mechanical response in the arteriolar wall, and discuss the local signaling mechanisms and cellular pathway involved in the responses to different local stimuli and in different vascular beds. Physiological modulation of VCRs, which is a rather new finding in this field, is discussed in the light of changes in plasma membrane ion channel conductance as a function of health status or disease. Finally, we discuss the possible role of VCRs in cerebrovascular function and disease as well as suggest future directions for studying VCRs in the cerebral circulation. PMID- 23443171 TI - 'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. AB - Cerebral edema is a major contributor to morbidity associated with traumatic brain injury (TBI). The methods involved in most rodent models of TBI, including head fixation, opening of the skull, and prolonged anesthesia, likely alter TBI development and reduce secondary injury. We report the development of a closed skull model of murine TBI, which minimizes time of anesthesia, allows the monitoring of intracranial pressure (ICP), and can be modulated to produce mild and moderate grade TBI. In this model, we characterized changes in aquaporin-4 (AQP4) expression and localization after mild and moderate TBI. We found that global AQP4 expression after TBI was generally increased; however, analysis of AQP4 localization revealed that the most prominent effect of TBI on AQP4 was the loss of polarized localization at endfoot processes of reactive astrocytes. This AQP4 dysregulation peaked at 7 days after injury and was largely indistinguishable between mild and moderate grade TBI for the first 2 weeks after injury. Within the same model, blood-brain barrieranalysis of variance permeability, cerebral edema, and ICP largely normalized within 7 days after moderate TBI. These findings suggest that changes in AQP4 expression and localization may not contribute to cerebral edema formation, but rather may represent a compensatory mechanism to facilitate its resolution. PMID- 23443172 TI - Cerebral blood flow changes after brain injury in human amyloid-beta knock-in mice. AB - Traumatic brain injury (TBI) is an environmental risk factor for Alzheimer's disease (AD). Increased brain concentrations of amyloid-beta (Abeta) peptides and impaired cerebral blood flow (CBF) are shared pathologic features of TBI and AD and promising therapeutic targets. We used arterial spin-labeling magnetic resonance imaging to examine if CBF changes after TBI are influenced by human Abeta and amenable to simvastatin therapy. CBF was measured 3 days and 3 weeks after controlled cortical impact (CCI) injury in transgenic human Abeta expressing APP(NLh/NLh) mice compared to murine Abeta-expressing C57Bl/6J wild types. Compared to uninjured littermates, CBF was reduced in the cortex of the injured hemisphere in both Abeta transgenics and wild types; deficits were more pronounced in the transgenic group, which exhibited injury-induced increased concentrations of human Abeta. In the hemisphere contralateral to CCI, CBF levels were stable in Abeta transgenic mice but increased in wild-type mice, both relative to uninjured littermates. Post-injury treatment of Abeta transgenic mice with simvastatin lowered brain Abeta concentrations, attenuated deficits in CBF ipsilateral to injury, restored hyperemia contralateral to injury, and reduced brain tissue loss. Future studies examining long-term effects of simvastatin therapy on CBF and chronic neurodegenerative changes after TBI are warranted. PMID- 23443174 TI - Metabolic imaging of bilateral anterior capsulotomy in refractory obsessive compulsive disorder: an FDG PET study. AB - The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [(18)F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients. PMID- 23443173 TI - The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model. AB - The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke. PMID- 23443175 TI - Post ischemia intermittent hypoxia induces hippocampal neurogenesis and synaptic alterations and alleviates long-term memory impairment. AB - Adult hippocampal neurogenesis is important for learning and memory, especially after a brain injury such as ischemia. Newborn hippocampal neurons contribute to memory performance by establishing functional synapses with target cells. This study demonstrated that the maturation of hippocampal neurons is enhanced by postischemia intermittent hypoxia (IH) intervention. The effects of IH intervention in cultured neurons were mediated by increased synaptogenesis, which was primarily regulated by brain-derived neurotrophic factor (BDNF)/PI3K/AKT. Hippocampal neo-neurons expressed BDNF and exhibited enhanced presynaptic function as indicated by increases in the pSynapsin expression, synaptophysin intensity, and postsynapse density following IH intervention after ischemia. Postischemia IH-induced hippocampal neo-neurons were affected by presynaptic activity, which reflected the dynamic plasticity of the glutamatergic receptors. These alterations were also associated with the alleviation of ischemia-induced long-term memory impairment. Our results suggest that postischemia IH intervention rescued ischemia-induced spatial learning and memory impairment by inducing hippocampal neurogenesis and functional synaptogenesis via BDNF expression. PMID- 23443177 TI - Begin with the basics: role of 3-dimensional sonography as a first-line imaging technique in the cost-effective evaluation of gynecologic pelvic disease. PMID- 23443176 TI - Certain types of iron oxide nanoparticles are not suited to passively target inflammatory cells that infiltrate the brain in response to stroke. AB - Intravenous administration of iron oxide nanoparticles during the acute stage of experimental stroke can produce signal intensity changes in the ischemic region. This has been attributed, albeit controversially, to the infiltration of iron laden blood-borne macrophages. The properties of nanoparticles that render them most suitable for phagocytosis is a matter of debate, as is the most relevant timepoint for administration. Both of these questions are examined in the present study. Imaging experiments were performed in mice with 30 minutes of middle cerebral artery occlusion (MCAO). Iron oxide nanoparticles with different charges and sizes were used, and mice received 300 MUmol Fe/kg intravenously: either superparamagnetic iron oxide nanoparticles (SPIOs), ultrasmall SPIOs, or very small SPIOs. The particles were administered 7 days before MCAO, at the time of reperfusion, or 72 hours after MCAO. Interestingly, there was no observable signal change in the ischemic brains that could be attributed to iron. Furthermore, no Prussian blue-positive cells were found in the brains or blood leukocytes, despite intense staining in the livers and spleens. This implies that the nanoparticles selected for this study are not phagocytosed by blood-borne leukocytes and do not enter the ischemic mouse brain. PMID- 23443178 TI - Intrauterine fluid with ectopic pregnancy: a reappraisal. AB - OBJECTIVES: To determine the incidence of intrauterine fluid in patients with ectopic pregnancy and to define the characteristics that distinguish this fluid from an early intrauterine gestational sac. METHODS: We identified all patients scanned transvaginally at our institution from July 2008 through August 2011 for suspected ectopic pregnancy, who proved to have ectopic pregnancy based on pathologic, surgical, or adnexal sonographic findings. We reviewed the sonograms to characterize any fluid in the uterus as to shape, contents, and location. Fluid was classified as type A if it was pointy edged, contained echoes, and/or was clearly located within the uterine cavity or type B if it was smooth walled and anechoic and location was in the decidua or uncertain. The appearance of type A fluid is inconsistent with a gestational sac, while the appearance of type B overlaps that of a gestational sac. RESULTS: Our study population included 229 women with ectopic pregnancy. In 38 (16.6%), sonography showed fluid in the uterus, which was classified as type A in 31 and type B in 7. Only 2 patients (0.9%) had type B fluid with no adnexal findings suggestive of ectopic pregnancy. Based on these results and the published incidence of ectopic pregnancy (2% of all pregnancies), we calculated that a patient with a positive pregnancy test, an intrauterine smooth-walled anechoic cystic structure, and no adnexal mass has a 0.02% probability of ectopic pregnancy, while the probability of intrauterine pregnancy in such a patient is 99.98%. CONCLUSIONS: Fluid can be seen in the uterus in 16.6% of patients with ectopic pregnancy. On transvaginal sonography, it can be distinguished from an early intrauterine gestational sac based on shape, contents, and/or location in most cases. In the remaining cases, the fluid appears indistinguishable from, and is highly likely to represent, an early intrauterine gestation. PMID- 23443179 TI - Efficacy and safety of daily repeated sonographically guided high-intensity focused ultrasound treatment of uterine fibroids: preliminary study. AB - OBJECTIVES: To evaluate the efficacy and safety of repeated low-dose sonographically guided high-intensity focused ultrasound (HIFU) treatment of uterine fibroids. METHODS: Between April and December 2010, 24 consecutive premenopausal women with symptomatic uterine fibroids were enrolled in this study. The treatment was performed with an HIFU unit without anesthesia or sedative administration and Foley catheter insertion. The treatment was performed 40 to 70 min/d according to the tumor volume. The entire treatment was finished after 4 to 6 days of treatment. We assessed the differences in the symptom severity score, tumor volume, and contrast-enhanced volume at baseline and 1 and 3 months after treatment. The clinical success rates according to tumor volume and contrast-enhanced volume reductions and echogenicity and vascular flow changes were analyzed. The clinical success rates according to the baseline characteristics of fibroids were analyzed. We assessed adverse events during and after treatment. RESULTS: The symptom severity score, tumor volume, and contrast enhanced volume decreased significantly after repeated low-dose HIFU treatment (P < .05). There were significant correlations between tumor volume and contrast enhanced volume reduction and the decrease in the symptom severity score. The clinical success rates were significantly different according to the tumor vascularity on color Doppler sonography and the degree of enhancement on magnetic resonance imaging. Skin burns and other serious adverse events did not develop. CONCLUSIONS: Although this preliminary report had several limitations, daily repeated HIFU treatment of uterine fibroids may be a useful and safe method and can be used as a different option for HIFU treatment in patients who prefer treatment without anesthesia or sedation. PMID- 23443180 TI - Postnatal outcome of fetuses with the prenatal diagnosis of gastroschisis. AB - OBJECTIVES: The purpose of this study was to assess the postnatal outcome and complications that arise in infants with the prenatal diagnosis of gastroschisis. METHODS: Prenatal sonograms with the diagnosis of gastroschisis were identified. Maternal age, indication for sonography, gestational age at diagnosis, other sonographic abnormalities, and postnatal outcome were recorded. RESULTS: Ninety eight fetuses at 14.3 to 36 weeks' gestation had the diagnosis of gastroschisis on sonography. In 14 cases (14%), other fetal anomalies were identified, including hydronephrosis, hydrocephalus, coarctation of the aorta, and a limb anomaly. Bowel dilatation developed in 72 of 84 cases (86%) followed prenatally with sonography, and bowel wall thickening developed in 40 of 73 cases (55%). On postnatal follow-up, 57 of 68 infants (84%) had postnatal complications, many with multisystem complications, including 6 deaths, 40 with bowel-related complications, 30 with infectious complications, and 32 with anomalies involving other systems (genitourinary, cardiac, and central nervous system). The postnatal outcome did not correlate with the presence of bowel dilatation or bowel wall thickening on prenatal sonography. Only 11 infants (16.2%) had a completely uncomplicated postsurgical course. Hospital stays in survivors (n = 92) ranged from 8 to 307 days (mean, 53 days). CONCLUSIONS: Although reported survival rates are good for gastroschisis, the postoperative hospital stay is often lengthy, and complications are very common, especially those related to the gastrointestinal tract. Associated anomalies were more common in our study than previously reported. PMID- 23443181 TI - Quantitative lung index, contralateral lung area, or lung-to-head ratio to predict the neonatal outcome in isolated congenital diaphragmatic hernia? AB - OBJECTIVES: To estimate the accuracy of the quantitative lung index and contralateral lung area for prediction of the neonatal outcome in isolated congenital diaphragmatic hernia in comparison to other available prediction models. METHODS: Between January 2004 and December 2010, 108 fetuses with isolated (82 left-sided and 26 right-sided) congenital diaphragmatic hernia were prospectively evaluated. The quantitative lung index and observed-to-expected contralateral lung area were measured and compared to the neonatal survival rate and severe postnatal pulmonary arterial hypertension, along with the lung-to-head ratio, observed-to-expected lung-to-head ratio, and observed-to-expected total lung volume. RESULTS: Overall neonatal mortality was 64.8% (70 of 108). Severe pulmonary arterial hypertension was diagnosed in 68 (63.0%) of the cases, which was associated with neonatal death (P < .001). Both the quantitative lung index and observed-to-expected contralateral lung area were significantly associated with neonatal survival and pulmonary arterial hypertension (P < .001), with accuracy to predict survival of 70.9% and 70.0%, respectively, and accuracy to predict hypertension of 78.7% and 72.0%; however, they were both less accurate than the observed-to-expected total lung volume (83.3% and 86.1%; P < .01). The lung-to-head ratio (73.1% and 78.7%) and observed-to-expected lung-to-head ratio (75.9% and 72.2%; P > .05) had similar accuracy as the quantitative lung index and observed-to-expected contralateral lung area. CONCLUSIONS: The observed-to expected total lung volume is the most accurate predictor of the neonatal outcome in cases of isolated congenital diaphragmatic hernia. Both the quantitative lung index and observed-to-expected contralateral lung area, albeit reasonably accurate, do not produce the same level of accuracy and render similar results as the lung-to-head ratio and observed-to-expected lung-to-head ratio. PMID- 23443182 TI - Renal volumes measured by 3-dimensional sonography in healthy fetuses from 20 to 40 weeks. AB - OBJECTIVES: The purpose of this study was to establish reference values for fetal kidney volumes as a function of gestational age, estimated by 3-dimensional sonography using the Virtual Organ Computer-Aided Analysis (VOCAL) technique (GE Healthcare, Kretztechnik, Zipf, Austria). METHODS: Volumes of right and left kidneys were assessed in 213 healthy fetuses by 3-dimensional sonography using the VOCAL technique. Inclusion criteria were healthy women with singleton pregnancies, unremarkable comprehensive fetal sonographic findings, well-known gestational age established by first-trimester sonography, and gestational ages between 20 and 40 weeks. Exclusion criteria were patients lost to follow-up and birth weight abnormalities. Each patient was scanned once during pregnancy. Regression analysis was used to calculate unified formulas. RESULTS: The mathematical models calculated in the study were as follows: expected right kidney volume = exp[-1.01 + (0.12 * gestational age)]; and expected left kidney volume = exp[-0.90 + (0.12 * gestational age)]. No significant intraobserver or inter-observer variability was observed for the determined volumes. CONCLUSIONS: Reference values for right and left fetal kidney volumes throughout gestation using the rotational technique (VOCAL) are described. The use of this technique might aid in further definition of gestational age kidney volume standards to help in defining variations from the norm. PMID- 23443183 TI - Two- and three-dimensional contrast-enhanced sonography for assessment of renal tumor vasculature: preliminary observations. AB - OBJECTIVES: The purpose of this study was to show potential applications of 2 dimensional (2D) and 3-dimensional (3D) contrast-enhanced sonography for assessment of the vascularity of benign and malignant renal tumors. METHODS: Sixty-eight patients with renal tumors were examined with both 2D and reconstructed 3D contrast-enhanced sonography. The contrast enhancement characteristics of benign and malignant renal tumors were compared on both 2D and 3D contrast-enhanced sonograms. The diagnoses of the lesions were made by surgical pathologic examination in 50 patients and by contrast-enhanced computed tomography in 18 patients. RESULTS: Both 2D and 3D contrast-enhanced sonography showed hypoenhancement with a few small peritumoral feeding blood vessels and regular intratumoral branches in 18 benign tumors, whereas hyperenhancement with multiple irregular peritumoral feeding vessels and tortuous intratumoral branches was shown in 50 malignant tumors. Compared to 2D contrast-enhanced sonography, 3D contrast-enhanced sonography displayed more intratumoral microvessels and spatial distributions, especially for the vessel network, and tortuous branches in the malignant tumors. Compared to 2D contrast-enhanced sonography, 3D contrast enhanced sonography was better for detecting and displaying renal tumor vascularity, with a statistically significant difference (P < .05). CONCLUSIONS: Reconstructed 3D contrast-enhanced sonography is a useful complementary tool in addition to 2D contrast-enhanced sonography for assessing the characteristics and distribution of blood vascularity in renal tumors. PMID- 23443184 TI - Renal oncocytoma: contrast-enhanced sonographic features. AB - OBJECTIVES: The purpose of this study was to illustrate the features of renal oncocytoma on contrast-enhanced sonography. METHODS: Five cases of surgical pathologically proven renal oncocytoma were retrospectively reviewed and analyzed in this study. The 5 patients studied included 3 men and 2 women with a mean age of 52.3 years (range, 32-66 years). All patients underwent conventional and contrast-enhanced sonographic examinations before surgery. The sonographic features, enhancement pattern, and dynamic perfusion change of the tumors and renal parenchyma in vascular phases were evaluated and compared to computed tomography. RESULTS: On grayscale sonography, renal oncocytomas appeared as solitary hypoechoic or isoechoic masses originating from the renal cortex measuring 2 to 6 cm with a well-defined margin. Color Doppler flow imaging showed rich blood flow signals in the periphery and striplike blood flow signals within the masses. On contrast-enhanced sonography, the features of these tumors included early enhancement, hyperenhancement, and fast wash-out compared to the adjacent renal cortex. There were irregular nonenhanced areas seen in the center of the masses (n = 3) and nonenhanced thin rims seen in the periphery (n = 5). Macroscopically, the well-marginated tumors were yellowish brown with a tender texture and were located in the renal cortex. Central irregularly shaped fibrous scars were seen in 3 tumors, consistent with nonenhanced areas on contrast enhanced imaging. CONCLUSIONS: Contrast-enhanced sonography can provide valuable hemodynamic information on renal oncocytoma, which may help in making a differential diagnosis of this benign renal tumor in clinical practice. PMID- 23443185 TI - Shear wave elastographic characterization of normal and torn achilles tendons: a pilot study. AB - OBJECTIVES: The purpose of this study was to investigate the feasibility of using quantitative shear wave elastography for assessing the functional integrity of the Achilles tendon and to summarize the changes in elasticity of ruptured Achilles tendons in comparison with normal controls. METHODS: Thirty-six normal and 14 ruptured Achilles tendons were examined with shear wave elastography coupled with a linear array transducer (4-15 MHz). The elasticity value of each Achilles tendon in a longitudinal view was measured. RESULTS: The mean elasticity value +/- SD for the normal Achilles tendons was 291.91 +/- 4.38 kPa (note that there are saturated measurement phenomena for the normal Achilles tendon, so the actual value will be >300 kPa), whereas the ruptured Achilles tendons had an elasticity value of 56.48 +/- 68.59 kPa. A statistically significant difference was found in relation to the findings in healthy volunteers (P = .006). CONCLUSIONS: Our results suggest that shear wave elastography is a valuable tool that can provide complementary biomechanical information for evaluating the function of the Achilles tendon. PMID- 23443186 TI - Reliability of side-to-side sonographic cross-sectional area measurements of upper extremity nerves in healthy volunteers. AB - OBJECTIVES: In sonographic evaluations of peripheral nerves, the healthy, contralateral side may be used as an internal control for the pathologic one. Therefore, the inherent side-to-side differences must be minimal. The goal of this study was to determine the reliability of side-to-side measurements of upper extremity nerves in healthy volunteers. METHODS: Forty participants with no upper extremity abnormalities were included. Upper limb nerves were evaluated bilaterally at the usual pathologic sites by 3 musculo-skeletal radiologists in separate sessions. To assess intraobserver and interobserver agreement, sonographic examinations were repeated 2 months after the first evaluations. The median nerve, ulnar nerve, musculocutaneous nerve, and radial nerve were considered. Nonparametric tests were used for statistical analysis. RESULTS: Minimum detectable differences with relative 95% confidence intervals were reported. Intraobserver and interobserver agreements were good (0.73 < kappa < 0.85). When the combined influence of the observer and the repeated measurement was evaluated, the reliability was 80% to 87%. CONCLUSIONS: In general, the healthy contralateral side can be used as an internal control considering that changes in minimum detectable differences are related to the anatomic site considered. PMID- 23443187 TI - Normal values for longitudinal tissue velocity and strain rate imaging in individual segments of the left and right ventricles of healthy adult hearts. AB - OBJECTIVES: To quantify the normal peak mean systolic velocities and strain rate parameters in the left ventricle (LV) and right ventricle (RV) and define their regional differences in normal adult hearts. METHODS: Sixty-nine healthy volunteers (42% male; mean age +/- SD, 30.03 +/- 5.35 years) underwent color tissue Doppler and strain rate imaging. The first and second peak mean systolic velocities, peak strain, and strain rate in the systolic ejection phase were determined for 16 LV segments, the apex (17th segment), and 3 RV free wall segments. RESULTS: The first peak mean systolic velocity was measurable in less than 50% of segments in the inferior and septal (-posterior) walls and RV free wall and in greater than 70% of segments of the other LV walls. The first and second peak mean systolic velocities of all LV walls and the RV free wall decreased significantly from the basal to apical region (P < .001).The strain and strain rate in the lateral and anterior walls decreased significantly from base to apex, whereas the anteroseptal and posterior walls were homogeneous. The strain rate in the inferior wall increased remarkably from base to apex, whereas it decreased significantly from the mid level to the apex. The strain in the RV was homogeneous, whereas the strain rate decreased significantly from the mid level to the apex. The apex (17th segment) showed the lowest value for each of the study parameters. CONCLUSIONS: Longitudinal velocities decreased from base to apex, whereas deformation measurements did not show uniform patterns in LV walls and the RV free wall. In most cases, there are 1 peak systolic velocity in the inferior and septal (-posterior) walls and 2 peak systolic velocities in the other 4 LV walls. PMID- 23443188 TI - Therapeutic effects of acoustic cavitation in the presence of gold nanoparticles on a colon tumor model. AB - OBJECTIVES: Acoustic cavitation can be fatal to cells and is used to destroy cancerous tumors. The particles in a liquid decrease the ultrasonic intensity threshold needed for onset of cavitation. Bubble generation from intense pulsed light-irradiated gold nanoparticles was investigated as a means of providing nucleation sites for acoustic cavitation in cancer tissues. METHODS: This study was conducted on colon carcinoma tumors in BALB/c mice. The tumor-bearing mice were randomly divided into 7 groups (each containing 15 mice): (1) control, (2) gold nanoparticles, (3) intense pulsed light irradiation, (4) intense pulsed light + gold nanoparticles, (5) ultrasound alone, (6) ultrasound + gold nanoparticles, and (7) intense pulsed light + ultrasound + gold nanoparticles. In the respective groups, gold nanoparticles were injected into tumors. Intense pulsed light and ultrasound irradiation were performed on the tumors 24 hours after injection. Antitumor effects were estimated by evaluation of the relative tumor volume, doubling time, and 5-folding time for tumors after treatment. The cumulative survival fraction of the mice and percentage of the lost tissue volume (treated) were also assessed in different groups. RESULTS: A significant difference in the average relative tumor volumes 15 days after treatment was found between the intense pulsed light + ultrasound + gold nanoparticle group and the other groups (P < .05). The longest doubling and 5-folding times were observed in the intense pulsed light + ultrasound + gold nanoparticles and ultrasound + gold nanoparticle groups. CONCLUSIONS: Acoustic cavitation in the presence of gold nanoparticles and intense pulsed light has been introduced as a new way for improving therapeutic effects on tumors by reducing the relative tumor volume and increasing the cumulative survival fraction. PMID- 23443189 TI - Evidence of changes in brain tissue stiffness after ischemic stroke derived from ultrasound-based elastography. AB - OBJECTIVES: Ischemia, edema, elevated intracranial pressure, and reduced blood flow can occur in the brain as a result of ischemic stroke, including contralateral to the stroke via a process known as diaschisis. In this study, ultrasound elastography, an imaging process sensitive to the stiffness of tissue, including its relative fluid content, was used to study changes in the stiffness of individual cerebral hemispheres after transient ischemic injury. METHODS: Elastographic images of mouse brains were collected 24 and 72 hours after middle cerebral artery occlusion. The shear moduli of both ipsilateral and contralateral brain hemispheres for these mice were measured and compared to corresponding values of control animals. RESULTS: At 24 hours (but not 72 hours) after induction of ischemic stroke, there was a significant decrease in the shear modulus in the ipsilateral hemisphere (P < .01) and a significant increase in the shear modulus in the contralateral hemisphere compared to that of control animals (P < .01). Significant differences were also evident between ipsilateral and contralateral shear modulus values at 24 and 72 hours after infarction (P < .01 for both). CONCLUSIONS: The differences between intrahemispheric averages of shear moduli of the brains of animals with stroke at 24 and 72 hours after stroke induction likely reflect the initial formation of edema and reduction of cerebral blood flow known to develop ipsilateral to ischemic infarction, the known transient increase in intracranial pressure, as well as the known initial reduction of blood flow and subsequent development of edema in the contralateral hemisphere (diaschisis). Thus, elastography offers a possible method to detect subtle changes in brain after ischemic stroke. PMID- 23443190 TI - Interobserver agreement for thyroid elastography: value of the quality factor. AB - OBJECTIVES: The purpose of our study was to investigate interobserver agreement for thyroid ultrasound elastography and to analyze the reproducibility of real time freehand elastography in thyroid nodules. METHODS: A prospective nonrandomized double-blind study was conducted between September 2008 and June 2010. Real-time elastography of 89 thyroid nodules was performed by two radiologists, with the first radiologist evaluating each thyroid nodule 5 minutes before the second. The elastograms were obtained with the patients holding their breath and considered valid when the quality factor was 50 or higher. The region of interest was positioned to include the nodule and 0.5 cm of surrounding normal thyroid parenchyma but to exclude the carotids and esophageal-tracheal structures. The elastograms were classified on a scale of 5 different patterns. RESULTS: Observers 1 and 2 coincided in 79 elastographic patterns and disagreed on 10 nodules (11.2%). The results between the radiologists had a statistically significant agreement (P < .005), with a kappa value of 0.838. CONCLUSIONS: The introduction of a quality factor in elastographic software and the selection of elastograms with a quality factor of 50 or higher confer almost perfect interobserver agreement for thyroid nodule elastography and make elastography a reproducible technique that could be used in daily clinical practice. PMID- 23443191 TI - Subacute granulomatous (de Quervain) thyroiditis: grayscale and color Doppler sonographic characteristics. AB - OBJECTIVES: To describe the sonographic characteristics of subacute granulomatous (De Quervain) thyroiditis. METHODS: We retrospectively identified all patients at our institution during the last 11 years who had thyroid sonography with findings suggestive of subacute granulomatous thyroiditis. We then reviewed clinical data and laboratory results to establish the clinical diagnosis. A final diagnosis of subacute granulomatous thyroiditis was made on the basis of clinical symptoms, suppressed thyrotropin, an elevated erythrocyte sedimentation rate, and/or reduced or absent radionuclide uptake while hyperthyroid. RESULTS: Our study population consisted of 35 patients. Twenty-seven patients (79.4%) met clinical criteria for subacute thyroiditis. Symptoms included neck pain in 26 of 27 patients with subacute thyroiditis. The erythrocyte sedimentation rate ranged from 22 to 101 mm/h. In 21 cases (77.8%), sonography revealed focal, poorly defined, nonovoid areas of decreased echogenicity. Findings were bilateral in 16 patients and unilateral in 5. In the remaining 6, the gland or an entire lobe was diffusely heterogeneous. Color Doppler interrogation was performed in 20 patients. Flow was decreased to the sonographically abnormal areas in 19 (95%) and slightly increased in 1 patient. In all 9 patients who underwent radionuclide scanning, focal defects or large areas of decreased or absent uptake were found during the time of suppressed thyrotropin. Enlarged lymph nodes were noted in 16 patients (59.3%). CONCLUSIONS: The positive predictive value of sonography for diagnosing subacute granulomatous thyroiditis is 79.4%. The most common sonographic appearance is poorly defined regions of decreased echogenicity with decreased vascularity in the affected areas. PMID- 23443192 TI - Do radiologists agree on findings in radiographer-acquired sonographic examinations? AB - OBJECTIVES: Sonographic examinations are usually regarded as observer dependent, but a recently introduced method using documentation with cine loops acquired in a standardized way attempts to address this problem. The aim of this study was to evaluate the intraobserver and interobserver agreement of sonographic liver examinations using strictly standardized examination protocols with cine loop documentation. METHODS: Ninety-eight outpatients were examined by a radiographer using the standardized method. Three radiologists, each with 10 to 20 years of experience in sonography, reviewed the cine loops retrospectively. After 4 weeks, the review was repeated; the 3 radiologists were blinded to the initial reading. The kappa coefficient was used to analyze intraobserver and interobserver agreement, and agreement in percent was also calculated. RESULTS: The intraobserver agreement was highest for concrements in the gallbladder (kappa= 0.91-0.96) and lowest when assessing the need for further examination (kappa = 0.38-0.64). For increased liver echogenicity, kappa varied between 0.73 and 0.92 and for skip areas between 0.73 and 0.90. The interobserver agreement was also highest for concrements in the gallbladder (kappa = 0.84-1.00) and lowest for the need for further examination (kappa = -0.12-0.46). For most other findings, substantial intraobserver agreement was found. CONCLUSIONS: For sonographic examinations performed according to a standardized examination protocol by a radiographer and viewed by an experienced radiologist, good interobserver agreement was found, except for judgments of the need for further examinations. PMID- 23443193 TI - Role of spatial ability as a probable ability determinant in skill acquisition for sonographic scanning. AB - OBJECTIVES: Spatial ability refers to an individual's capacity to visualize and mentally manipulate 3-dimensional objects. Because sonographers manually manipulate 2- and 3-dimensional sonographic images to generate renderings of anatomic structures, it can be assumed that spatial ability is an ability determinant for understanding and producing these medical images. Using the theory of ability determinants of skilled performance as a conceptual framework, this study explored the relationship of spatial ability and learning sonographic scanning. METHODS: Beginning sonography students from 3 different types of educational institutions were administered a spatial ability test before their initial scanning laboratory course work. The students' spatial test scores were compared with their scanning competency performance scores after the first scanning competency test and then to the overall average of the competency scores for the 2 semesters. The spatial ability test was again administered after the 2 semester learning period to see whether the students' spatial ability had increased. RESULTS: A significant relationship between the students' spatial ability test scores and their scanning performance scores was found after the first scanning competency (r = 0.46; P < .05), and also when averaging all competency scores throughout the learning period (r = 0.49; P < .05). A moderate increase in the spatial ability of the students was also found (r = 0.32; P < .05). The incoming grade point average was found to be more predictive of the students' scanning scores than spatial or ACT scores. No relationship was found between spatial ability and student retention. CONCLUSIONS: High spatial test scores as well as a high incoming grade point average appear to be the best ability determinants in skill acquisition for sonographic scanning. PMID- 23443194 TI - An in vitro study to evaluate the utility of the "air test" to infer perineural catheter tip location. AB - Injection of air under ultrasound guidance via a perineural catheter after insertion ("air test") has been described as a means to infer placement accuracy, yet this test has never been rigorously evaluated. We tested the hypothesis that the air test predicts accurate catheter location greater than chance and determined the test's sensitivity, specificity, and positive and negative predictive values using a porcine-bovine model and blinded expert in ultrasound guided regional anesthesia. The air test improved the expert clinician's assessment of catheter tip position compared to chance, but there was no difference when compared to direct visualization of the catheter without air injection. PMID- 23443195 TI - Accuracy of sonographically guided biopsy using a freehand versus needle-guided technique: computed tomographic correlation study. AB - Sonographically guided biopsy is performed by one of two techniques: the freehand and needle-guided techniques. To our knowledge, the relationship between the location of the local anesthetic tract and the biopsy needle tract as well as direct comparison of the two biopsy techniques has not been previously validated. The aim of this study was to validate the different parameters related to the two biopsy techniques using computed tomography as the reference standard for assessing final tract positions. There were statistically significant differences between the freehand and guided techniques in the following parameters: number of passes required for contrast agent injection (P = .003), number of passes required to insert the needle (P = .005), time required to inject the anesthetic/contrast agent (P = .005), time required to insert the biopsy needle (P = .02), and distance between contrast tract and final needle position (P = .03). No statistical difference was identified for the angle between the contrast tract and needle position. This difference likely reflects the confidence of the radiologist in identifying the needle location during the procedure. Using a commercially available guide that has a fixed angle can result in a faster, more efficient, and reproducible biopsy technique compared to the freehand technique, especially for those who have less experience in performing sonographically guided biopsies. PMID- 23443196 TI - Omega-shaped variant of the umbilical artery: prenatal diagnosis and outcome. AB - The purpose of this series was to report on the observation of an anomalous course of the umbilical artery. Ten cases in a 25-month period are reported. An omega-shaped variant, coined the "omega sign," of one of two umbilical arteries or of a single umbilical artery was observed. In 2 cases, there were two umbilical arteries, one of them with the anomalous vessel. In 8 cases, the vessel was a single umbilical artery. In 1 case with a single umbilical artery and pericardial effusion, aneuploidy was found on amniocentesis. A second case was associated with multiple anomalies. A third case was associated with hypoplastic left heart syndrome. Seven cases with the omega sign as an isolated finding, with or without a single umbilical artery, had favorable outcomes. An omega-shaped variant of the umbilical artery is likely to be more common in cases of a single umbilical artery than in cases with two umbilical arteries. It is probably a normal variant when unassociated with additional sonographically detectable structural anomalies. PMID- 23443197 TI - Rapid evolution of placental chorioangioma: natural progression and outcome. PMID- 23443198 TI - Spontaneous heterotopic cesarean scar pregnancy: conservative management by transvaginal sonographic guidance and successful pregnancy outcome. PMID- 23443199 TI - Detection of intraperitoneal free fluid in healthy young men: "innocent bystander versus benign imposter". PMID- 23443200 TI - Reply to Drs Chidambaram and Venkatanarasimha. PMID- 23443201 TI - Lectin microarrays: concept, principle and applications. AB - The lectin microarray is a novel platform for glycan analysis, having emerged only in recent years. Unlike other conventional methods, e.g., liquid chromatography and mass spectrometry, it enables rapid and high-sensitivity profiling of complex glycan features without the need for liberation of glycans. Target samples include an extensive range of glycoconjugates involved in cells, tissues, body fluids, as well as synthetic glycans and their mimics. Various procedures for rapid differential glycan profiling have been developed for glycan related biomarkers. Such glycoproteomics targeting allows precise diagnosis of chronic diseases potentially related to cancer. Application of this method to evaluation of various types of stem cells resulted in the discovery of a new pluripotent cell-specific glycan marker. To explore this technology a more fundamental and extensive understanding of lectins is necessary in relation to the structural uniqueness of glycans. In this chapter, the essence of the lectin microarray is described with some focus on an evanescent-field-activated fluorescence detection principle as a system to achieve in situ (i.e., washing free) aqueous-phase observation under equilibrium conditions. The developed lectin microarray system allows even researchers with poor experience in glycan profiling to perform extensive high-throughput analysis targeting various forms of glycans and even cells. PMID- 23443202 TI - 2013 AAHA dental care guidelines for dogs and cats. AB - Veterinary dentistry is constantly progressing. The purpose of this document is to provide guidelines for the practice of companion animal dentistry for the veterinary profession. Dental care is necessary to provide optimum health and optimize quality of life. Untreated diseases of the oral cavity are painful and can contribute to local and systemic diseases. This article includes guidelines for preventive oral health care, client communication, evaluation, dental cleaning, and treatment. In addition, materials and equipment necessary to perform a medically appropriate procedure are described. PMID- 23443204 TI - The clinical manifestations of lumbar disease are correlated with self-rating depression scale scores. AB - BACKGROUND: Depression can exacerbate symptoms of chronic pain and worsen disability. The symptoms of lumbar disease may be particularly sensitive to psychological state, but statistical associations between low back pain (LBP) severity and mental health status have not been established. METHODS: Of the 151 patients with LBP, 122 completed questionnaires probing depressive symptoms, LBP severity, and degree of disability. In addition to completing self-report questionnaires, patients provided demographic and clinical information. A self rating depression scale (SDS) was used to screen for depression. Pain and disability were assessed by the visual analog scale (VAS) and the Roland-Morris disability questionnaire (RDQ), respectively. Overall clinical severity was assessed using the Japanese Orthopaedic Association (JOA) score. Kendall's tau correlation coefficients were calculated to examine the relationships among these variables. RESULTS: Ninety-four patients (77 %) were in a depressive state as indicated by SDS score >=40, including mild depression group (47 patients, SDS score from 40 to 49) and depression group (47 patients, SDS score >=50). There were only 28 patients in the no depression group (SDS score <=39). There was no significant difference in both age and pain duration among the three groups. The mean VAS score in the depression group (70 +/- 19 mm) was higher than both no depression (41 +/- 24 mm) and mild depression groups (52 +/- 21 mm). The mean JOA score in the no depression group (14 +/- 5.0 points) was higher than both mild depression (12 +/- 4.0 points) and depression groups (10 +/- 6.0 points). The mean RDQ in the depression group (15.1 +/- 6.0 points) was higher than both no depression (6.4 +/- 5.0 points) and mild depression groups (10.9 +/- 5.4 points). Factors significantly correlated with SDS score included VAS, JOA score, and RDQ score. In contrast, SDS did not correlate with patient age or pain duration. CONCLUSIONS: The majority of chronic LBP patients examined were in a depressed state and the severity of depression correlated with pain severity, degree of self-rated disability, and clinical severity. PMID- 23443203 TI - Assessment of pain due to lumbar spine diseases using MR spectroscopy: a preliminary report. AB - BACKGROUND DATA: There is a considerable difference in pain perception among individuals. In patients with chronic pain, recent studies using fMRI, PET and SPECT have shown that functional changes mainly occurred in the anterior cingulate cortex (ACC), prefrontal cortex (PFC) and thalamus. Brain magnetic resonance spectroscopy (MRS) can evaluate brain chemistry by measuring metabolites such as N-acetyl aspartate (NAA). The purpose of this study was to analyze whether brain MRS could assess pain due to lumbar spine diseases. METHODS: NAA levels were determined relative to the concentration of creatine/phosphocreatine complex (Cr) and choline (Cho), which is commonly used as an internal standard. The NAA/Cr and NAA/Cho ratios in the ACC, PFC and thalamus were compared between six patients with unilateral pain (left side) and six control patients without pain. RESULTS: In the right thalamus (contralateral side to symptom), the NAA/Cr in the patients with pain was statistically significantly lower compared with the control patients (p < 0.05). Also, in the right thalamus, the NAA/Cho in pain patients was significantly lower compared with controls (p < 0.01). When considering just the right thalamus, there were statistically significant correlations between the numerical rating scale for pain (NRS) and NAA values. CONCLUSIONS: Lumbar pain can be assessed indirectly by analyzing the decrease in NAA concentration in the thalamus. PMID- 23443206 TI - Diastereoselective synthesis of pyrrolidine derivatives via a one-pot nitro Mannich/hydroamination cascade using base and gold catalysis. AB - An efficient one-pot nitro-Mannich/hydroamination cascade reaction for the synthesis of substituted pyrrolidines bearing three stereocentres is reported. Proceeding under the control of a combination of base and gold(I) catalysts, the cascade reaction affords the pyrrolidine products in high yields with good to excellent diastereoselectivities. PMID- 23443205 TI - Low-molecular-mass metal complexes in the mouse brain. AB - The presence of labile low-molecular-mass (LMM, defined as <10 kDa) metal complexes in cells and super-cellular structures such as the brain has been inferred from chelation studies, but direct evidence is lacking. To evaluate the presence of LMM metal complexes in the brain, supernatant fractions of fresh mouse brain homogenates were passed through a 10 kDa cutoff membrane and subjected to size-exclusion liquid chromatography under anaerobic refrigerated conditions. Fractions were monitored for Mn, Fe, Co, Cu, Zn, Mo, S and P using an on-line ICP-MS. At least 30 different LMM metal complexes were detected along with numerous P- and S- containing species. Reproducibility was assessed by performing the experiment 13 times, using different buffers, and by examining whether complexes changed with time. Eleven Co, 2 Cu, 5 Mn, 4 Mo, 3 Fe and 2 Zn complexes with molecular masses <4 kDa were detected. One LMM Mo complex comigrated with the molybdopterin cofactor. Most Cu and Zn complexes appeared to be protein-bound with masses ranging from 4-20 kDa. Co was the only metal for which the "free" or aqueous complex was reproducibly observed. Aqueous Co may be sufficiently stable in this environment due to its relatively slow water-exchange kinetics. Attempts were made to assign some of these complexes, but further efforts will be required to identify them unambiguously and to determine their functions. This is among the first studies to detect low-molecular-mass transition metal complexes in the mouse brain using LC-ICP-MS. PMID- 23443210 TI - Discovering misattributed paternity in genetic counselling: different ethical perspectives in two countries. AB - Misattributed paternity or 'false' paternity is when a man is wrongly thought, by himself and possibly by others, to be the biological father of a child. Nowadays, because of the progression of genetics and genomics the possibility of finding misattributed paternity during familial genetic testing has increased. In contrast to other medical information, which pertains primarily to individuals, information obtained by genetic testing and/or pedigree analysis necessarily has implications for other biologically related members in the family. Disclosing or not a misattributed paternity has a number of different biological and social consequences for the people involved. Such an issue presents important ethical and deontological challenges. The debate centres on whether or not to inform the family and, particularly, whom in the family, about the possibility that misattributed paternity might be discovered incidentally, and whether or not it is the duty of the healthcare professional (HCP) to disclose the results and to whom. In this paper, we consider the different perspectives and reported problems, and analyse their cultural, ethical and legal dimensions. We compare the position of HCPs from an Italian and British point of view, particularly their role in genetic counselling. We discuss whether the Oviedo Convention of the Council of Europe (1997) can be seen as a basis for enriching the debate. PMID- 23443211 TI - Commercial surrogacy: how provisions of monetary remuneration and powers of international law can prevent exploitation of gestational surrogates. AB - Increasing globalisation and advances in artificial reproductive techniques have opened up a whole new range of possibilities for infertile couples across the globe. Inter-country gestational surrogacy with monetary remuneration is one of the products of medical tourism meeting in vitro fertilisation embryo transfer. Filled with potential, it has also been a hot topic of discussion in legal and bioethics spheres. Fears of exploitation and breach of autonomy have sprung from the current situation, where there is no international regulation of surrogacy agreements--only a web of conflicting national laws that generates loopholes and removes safeguards for both the surrogate and commissioning couple. This article argues the need for evidence-based international laws and regulations as the only way to resolve both the ethical and legal issues around commercial surrogacy. In addition, a Hague Convention on inter-country surrogacy agreements is proposed to resolve the muddled state of affairs and enable commercial surrogacy to demonstrate its full potential. PMID- 23443212 TI - S39, a novel Aurora B kinase inhibitor, shows potent antineoplastic activity in human Hela cervical cancer cell line. AB - Aurora kinases, frequently detected to be over-expressing in human tumors, regulate many essential events during mitosis progression and have been regarded as potentially important targets for cancer therapy. S39 is a novel potent inhibitor of Aurora B kinase with the IC50 90.07 nM in the biochemical assay in an ATP competitive manner. S39 treatment on human tumor cells can inhibit the phosphorylation of Histone H3 (Ser10), a direct downstream substrate of Aurora B kinase, indicating S39 inhibits endogenous Aurora B kinase activity in cell-based level. Furthermore, S39 treatment blocks cell proliferation, inhibits colony formation and induces apoptosis in a wide range of human tumor cell lines. These results indicate that S39 is a potential lead compound to be an Aurora B inhibitor. PMID- 23443213 TI - Adenovirus-mediated expression of BmK CT suppresses growth and invasion of rat C6 glioma cells. AB - BmK CT, one of the key toxins in the venom of the scorpion, Buthus martensii Karsch, can interact specifically with glioma cells as a chloride channel blocker and inhibit the invasion and migration of those cells via MMP-2. A recombinant adenovirus, Ad-BmK CT, was constructed and characterized by in vitro and in vivo studies, using MTT cytotoxicity assay and the glioma C6/RFP (red fluorescence protein)/BALB/c allogeneic athymic nude mice model, respectively. The adenovirus mediated expression of BmK CT displayed a high activity in suppressing rat C6 glioma cells growth and invasion thereby suggesting that this recombinant adenovirus may be a powerful method for treating glioblastoma. PMID- 23443215 TI - Nonuniform changes in MRI measurements of the thigh muscles after two hamstring strengthening exercises. AB - Although many different hamstring strengthening exercises exist, the effect on site specific activation of these exercises on different muscles of the leg is unclear. This study investigated the effects of the eccentric leg curl (LC) and lunge (L) exercises on the biceps femoris long head (BFl), biceps femoris short head (BFs), semitendinosus (ST), semimembranosus (SM), and adductor magnus (AM). Each leg of 11 male professional soccer players was randomly assigned to an LC or L exercise protocol (3 sets of 6 repetitions). Functional magnetic resonance imaging (fMRI) of the subjects' thighs were performed before and 48 hours after the intervention. Fifteen axial scans of the thigh interspaced by a distance of 1/15 right femur length (Lf) were obtained. The fMRI data were analyzed for signal intensity changes. No significant changes were observed in absolute short tau inversion recovery values for the SM and BFs. Significant changes for the ST (~21-45%) from sections 4 to 10, AM (~2-13%) at section 4, and BFl (~ -3 vs. 8%) at section 7 were noted. LC exercises load all the regions of the ST muscle. The L exercises load the proximal regions of the BFl and AM. These findings may have relevance when designing protocols for prevention and rehabilitation of hamstring injuries. PMID- 23443214 TI - Assisted closed-loop optimization of SSVEP-BCI efficiency. AB - We designed a novel assisted closed-loop optimization protocol to improve the efficiency of brain-computer interfaces (BCI) based on steady state visually evoked potentials (SSVEP). In traditional paradigms, the control over the BCI performance completely depends on the subjects' ability to learn from the given feedback cues. By contrast, in the proposed protocol both the subject and the machine share information and control over the BCI goal. Generally, the innovative assistance consists in the delivery of online information together with the online adaptation of BCI stimuli properties. In our case, this adaptive optimization process is realized by (1) a closed-loop search for the best set of SSVEP flicker frequencies and (2) feedback of actual SSVEP magnitudes to both the subject and the machine. These closed-loop interactions between subject and machine are evaluated in real-time by continuous measurement of their efficiencies, which are used as online criteria to adapt the BCI control parameters. The proposed protocol aims to compensate for variability in possibly unknown subjects' state and trait dimensions. In a study with N = 18 subjects, we found significant evidence that our protocol outperformed classic SSVEP-BCI control paradigms. Evidence is presented that it takes indeed into account interindividual variabilities: e.g., under the new protocol, baseline resting state EEG measures predict subjects' BCI performances. This paper illustrates the promising potential of assisted closed-loop protocols in BCI systems. Probably their applicability might be expanded to innovative uses, e.g., as possible new diagnostic/therapeutic tools for clinical contexts and as new paradigms for basic research. PMID- 23443216 TI - Association of balance, strength, and power measures in young adults. AB - The purpose of this study was to investigate the relationship between variables of static/dynamic balance, isometric strength, and power. Twenty-seven young healthy adults (mean age: 23 +/- 4 years) performed measurements of static (unperturbed)/dynamic (perturbed) balance, isometric strength (i.e., maximal isometric torque [MIT]; rate of torque development [RTD] of the plantar flexor), and power (i.e., countermovement jump [CMJ] height and power). No significant associations were found between variables of static and dynamic balance (r = 0.090 to +0.329, p > 0.05) and between measures of static/dynamic balance and isometric strength (r = +0.041 to +0.387, p > 0.05) and static/dynamic balance and power (r = -0.076 to +0.218, p > 0.05). Significant positive correlations (r) were detected between variables of power and isometric strength ranging from +0.458 to +0.689 (p < 0.05). Furthermore, simple regression analyses revealed that a 10% increase in mean CMJ height (4.1 cm) was associated with 22.9 N.m and 128.4 N.m.s better MIT and RTD, respectively. The nonsignificant correlation between static and dynamic balance measures and between static/dynamic balance, isometric strength, and power variables implies that these capacities may be independent of each other and may have to be tested and trained complementarily. PMID- 23443217 TI - Performance analysis in saber. AB - Fencing is a sport practiced by both men and women, which uses 3 weapons: foil, epee, and saber. In general, there are few scientific studies available in international literature; they are limited to the performance analysis of fencing bouts, yet there is nothing about saber. There are 2 kinds of competitions in the World Cup for both men and women: the "FIE GP" and "A." The aim of this study was to carry out a saber performance analysis to gain useful indicators for the definition of a performance model. In addition, it is expected to verify if it could be influenced by the type of competition and if there are differences between men and women. Sixty bouts: 33 FIE GP and 27 "A" competitions (35 men's and 25 women's saber bouts) were analyzed. The results indicated that most actions are offensive (55% for men and 49% for women); the central area of the piste is mostly used (72% for men and 67% for women); the effective fighting time is 13.6% for men and 17.1% for women, and the ratio between the action and break times is 1:6.5 for men and 1:5.1 for women. A lunge is carried out every 23.9 seconds by men and every 20 seconds by women, and a direction change is carried out every 65.3 seconds by men and every 59.7 seconds by women. The data confirm the differences between the saber and the other 2 weapons. There is no significant difference between the data of the 2 different kinds of competitions. PMID- 23443218 TI - Heat stress impairs repeated jump ability after competitive elite soccer games. AB - This study examined the effect of environmental heat stress on repeated jump performance after elite competitive soccer games. Male elite soccer players (n = 19) from 2 Scandinavian teams participated (age: 26.7 +/- 1.0 years, height: 181.7 +/- 1.1 cm, body mass: 75.8 +/- 1.0 kg). The players had a Yo-Yo IR2 performance of 1,032 +/- 42 m (range: 920-1,400 m). The players took part in the Champions League Qualification, where 6 games (3 home and 3 away) were played. The home games took place at an average ambient temperature of 12.2 +/- 0.5 degrees C (control game; CON) and the away games in hot conditions (30.0 +/- 0.3 degrees C; HOT). In the resting condition (Baseline) and immediately after CON and HOT, the players performed a repeated countermovement jump (CMJ) test consisting of 5 jumps separated by 5 seconds of recovery. Game-induced body mass loss was determined based on change in body mass after correction for fluid intake. The net loss of body mass was 3.1 +/- 0.3% in HOT, which was higher (p < 0.05) than in CON (1.7 +/- 0.2%). Mean CMJ performance after HOT was 37.9 +/- 1.1 cm, which was 6.0% lower (p < 0.05) than Baseline (40.3 +/- 1.1 cm) and tended (p = 0.08) to be lower than in the CON (39.6 +/- 1.2 cm). The mean CMJ performance after CON was not different from Baseline. Peak CMJ performance after HOT was 41.1 +/- 1.1 cm, which was not different from either Baseline or CON (42.0 +/- 1.1 and 41.7 +/- 1.2 cm, respectively). The relative decline in repeated CMJ performance from Baseline to after HOT correlated (r = 0.60; p < 0.05) to relative net loss in body mass during HOT. This study demonstrates that repeated CMJ performance deteriorates after a soccer game played in warm environmental settings, which is partly associated with severe dehydration. PMID- 23443219 TI - Analysis of the relationship between the amount of training and cognitive expertise. A study of young volleyball players. AB - The main goal of this research was to analyze the relationship between the amount of practice accumulated in training and the level of cognitive expertise achieved by volleyball players who are still in training. Another goal was to determine the number of training hours per week needed to improve knowledge significantly. The study's sample was composed of 520 volleyball players between the ages of 12 and 16 years. The independent variable was the amount of training, defined as the number of weekly hours that the volleyball player devoted to training. The dependent variable was cognitive expertise, measured by declarative knowledge and procedural knowledge. A univariate analysis of variance was done to examine the relationship between the number of weekly hours and the declarative and procedural knowledge reached by volleyball players in the athletic formation training stages. Statistical significance was set at p < 0.05. There were significant differences in knowledge according to the number of weekly training hours (p < 0.001). These results confirm that there is a relationship between the quantity of practice and the development of cognitive expertise. It is recommended that young players dedicate at least 4 hours weekly to training to achieve a significant improvement in cognitive expertise. PMID- 23443220 TI - Effects of strongman training on salivary testosterone levels in a sample of trained men. AB - Strongman exercises consist of multi-joint movements that incorporate large muscle mass groups and impose a substantial amount of neuromuscular stress. The purpose of this study was to examine salivary testosterone responses from 2 novel strongman training (ST) protocols in comparison with an established hypertrophic (H) protocol reported to acutely elevate testosterone levels. Sixteen men (24 +/- 4.4 years, 181.2 +/- 6.8 cm, and 95.3 +/- 20.3 kg) volunteered to participate in this study. Subjects completed 3 protocols designed to ensure equal total volume (sets and repetitions), rest period, and intensity between the groups. Exercise sets were performed to failure. Exercise selection and intensity (3 sets * 10 repetitions at 75% 1 repetition maximum) were chosen as they reflected commonly prescribed resistance exercise protocols recognized to elicit a large acute hormonal response. In each of the protocols, subjects were required to perform 3 sets to muscle failure of 5 different exercises (tire flip, chain drag, farmers walk, keg carry, and atlas stone lift) with a 2-minute rest interval between sets and a 3-minute rest interval between exercises. Saliva samples were collected pre exercise (PRE), immediate postexercise (PST), and 30 minutes postexercise (30PST). Delta scores indicated a significant difference between PRE and PST testosterone level within each group (p <= 0.05), with no significant difference between the groups. Testosterone levels spiked 136% (225.23 +/- 148.01 pg.ml(-1)) for the H group, 74% (132.04 +/- 98.09 pg.ml(-1)) for the ST group, and 54% (122.10 +/- 140.67 pg.ml) for the mixed strongman/hypertrophy (XST) group. A significant difference for testosterone level occurred over time (PST to 30PST) for the H group p <= 0.05. In conclusion, ST elicits an acute endocrine response similar to a recognized H protocol when equated for duration and exercise intensity. PMID- 23443221 TI - The effects of an acute dose of Rhodiola rosea on endurance exercise performance. AB - The purpose of this study was to determine the effects of an acute oral dose of 3 mg.kg(-1) of Rhodiola rosea on endurance exercise performance, perceived exertion, mood, and cognitive function. Subjects (n = 18) ingested either R. rosea or a carbohydrate placebo 1 hour before testing in a double-blind, random crossover manner. Exercise testing consisted of a standardized 10-minute warm-up followed by a 6-mile time trial (TT) on a bicycle ergometer. Rating of perceived exertion (RPE) was measured every 5 minutes during the TT using a 10-point Borg scale. Blood lactate concentration, salivary cortisol, and salivary alpha amylase were measured before warm-up, 2 minutes after warm-up, and 2 minutes after TT (n = 15). A Profile of Mood States questionnaire and a Stroop Color Test were completed before warm-up and after TT. Testing was repeated 2-7 days later with the other condition. Rhodiola rosea ingestion significantly decreased heart rate during the standardized warm-up (R. rosea = 136 +/- 17 b.min(-1); placebo = 140 +/- 17 b.min(-1); mean +/- SD; p = 0.001). Subjects completed the TT significantly faster after R. rosea ingestion (R. rosea = 25.4 +/- 2.7 minutes; placebo = 25.8 +/- 3.0 minutes; p = 0.037). The mean RPE was lower in the R. rosea trial (R. rosea = 6.0 +/- 0.9; placebo = 6.6 +/- 1.0; p = 0.04). This difference was even more pronounced when a ratio of the RPE relative to the workload was calculated (R. rosea = 0.048 +/- 0.01; placebo = 0.057 +/- 0.02; p = 0.007). No other statistically significant differences were observed. Acute R. rosea ingestion decreases heart rate response to submaximal exercise and appears to improve endurance exercise performance by decreasing the perception of effort. PMID- 23443222 TI - Guideline-based COPD management in a resource-limited setting - physicians' understanding, adherence and barriers: a cross-sectional survey of internal and family medicine hospital-based physicians in Nigeria. AB - BACKGROUND: Few data exist on the understanding and adherence to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in resource limited settings, which are mostly in sub-Saharan Africa. OBJECTIVES: To assess physicians' understanding, adherence, and barriers to implementation of GOLD guidelines in Nigeria. METHODS: A questionnaire based on the recommendations of the guidelines was self-administered by 156 physicians in departments of internal and family medicine in selected hospitals to assess physician understanding of the GOLD guidelines and barriers to its implementation. The medical records of patients with chronic obstructive pulmonary disease (COPD) were also reviewed to assess adherence to the guideline recommendations. RESULTS: The performance score of all physicians was 22.37+/-0.39 (range 0-38). Pulmonologists had the highest score (37.00+/-0.00) while medical officers had the lowest score (19.93+/-4.98) (F=10.16, df=5, p<0.001). Forty one percent of physicians knew the spirometric criteria for diagnosing COPD and 26.9% could assess the severity. In clinical practice, 32% of patients had brief smoking counselling despite 70% being smokers, 24% had spirometry and 18% had assessment of severity. Almost 60% of patients were on oral aminophylline, 72% were on an inhaled long-acting beta2 agonist and corticosteroid combination, 2% had pulmonary rehabilitation and no patients were vaccinated. Self-reported adherence to the COPD guidelines was 23.7%. Lack of familiarity (39.8%) was cited as the most common barrier to adherence to the guidelines. CONCLUSIONS: The understanding of GOLD guidelines is satisfactory among Nigerian doctors managing patients with COPD but the level of adherence is poor. Educational interventions are needed to improve the implementation of guideline-based management. PMID- 23443223 TI - Practical approach to exercise-induced bronchoconstriction in athletes. AB - Exercise-induced bronchoconstriction (EIB) is highly prevalent in athletes of all abilities and can impact on their health and performance. The majority of athletes with exertional dyspnoea will be initially assessed and managed in primary care. This report provides a practical and pragmatic approach to the assessment and management of a young athlete presenting with suspected EIB in this setting. PMID- 23443224 TI - Don't pay for poor quality spirometry tests. PMID- 23443225 TI - Practical approach to managing exercise-induced asthma in children and adults. PMID- 23443226 TI - Reforming respiratory outpatient services: a before-and-after observational study assessing the impact of a quality improvement project applying British Thoracic Society criteria to the discharge of patients to primary care. AB - BACKGROUND: Secondary care physicians caring for people with long-term conditions (LTCs) are under increasing pressure to discharge long-term follow-up patients to primary care. In respiratory medicine, the 2008 British Thoracic Society (BTS) statement on criteria for specialist referral, admission, discharge, and follow up for adults with respiratory disease remains the only available basis for this dialogue. There is widespread concern about reforming outpatient clinics to meet these demands and the impact of discharging people with respiratory LTCs to primary care. AIMS: To examine the impact of implementing BTS guidance on secondary care follow-up of patients with respiratory disease. METHODS: We undertook a clinic reform project, which included one-stop medical reviews, providing more open access appointments, and implementing the BTS criteria. The impact on patients was assessed by patient survey, and the impact on GPs was assessed by an analysis of referral patterns pre- and post-reform. RESULTS: There was a significant improvement in commissioner-mandated performance through reduction in follow-up (p=0.006) and the unscheduled hospital admission rate decreased significantly (p=0.021). However, many patients were dissatisfied with the process and re-referral rates rose. CONCLUSIONS: Our findings suggest that the delivery of a responsive service capable of sustainable management of respiratory LTCs can be achieved using the BTS criteria. It seems to be efficacious within secondary care, increasing the quality and value of the clinic activity, although hidden impacts on primary care will require further prospective studies. PMID- 23443227 TI - A new approach to grading and treating COPD based on clinical phenotypes: summary of the Spanish COPD guidelines (GesEPOC). AB - After the development of the COPD Strategy of the National Health Service in Spain, all scientific societies, patient organisations, and central and regional governments formed a partnership to enhance care and research in COPD. At the same time, the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) took the initiative to convene the various scientific societies involved in the National COPD Strategy and invited them to participate in the development of the new Spanish guidelines for COPD (Guia Espanola de la EPOC; GesEPOC). Probably the more innovative approach of GesEPOC is to base treatment of stable COPD on clinical phenotypes, a term which has become increasingly used in recent years to refer to the different clinical forms of COPD with different prognostic implications. The proposed phenotypes are: (A) infrequent exacerbators with either chronic bronchitis or emphysema; (B) overlap COPD-asthma; (C) frequent exacerbators with emphysema predominant; and (D) frequent exacerbators with chronic bronchitis predominant. The assessment of severity has also been updated with the incorporation of multidimensional indices. The severity of the obstruction, as measured by forced expiratory volume in 1 second, is essential but not sufficient. Multidimensional indices such as the BODE index have shown excellent prognostic value. If the 6-minute walking test is not performed routinely, its substitution by the frequency of exacerbations (BODEx index) provides similar prognostic properties. This proposal aims to achieve a more personalised management of COPD according to the clinical characteristics and multidimensional assessment of severity. PMID- 23443228 TI - Quality of spirometry tests and pulmonary function changes among industrial company workers in Iran: a two-year before-and-after study following an intensive training intervention. AB - BACKGROUND: Quality improvement, standardisation of spirometry testing, and interpretation of results are critically important in the occupational setting. AIMS: To determine the quality of spirometry tests and pulmonary function changes in two consecutive years among the personnel of an industrial company. METHODS: This study was performed in an oil refinery in Iran in 2011. Data on 1,004 male personnel were evaluated before and after a training course conducted according to the National Institute for Occupational Safety and Health guidelines. American Thoracic Society/European Respiratory Society guidelines were used for assessment of the acceptability and repeatability criteria. RESULTS: The most common error in the first year of evaluation was forced vital capacity >6 seconds or a 1 second plateau. Acceptability and proper interpretation significantly improved after the course (p<0.05), but repeatability did not change significantly (p>0.05). CONCLUSIONS: The results of this study show that the validity and quality of spirometric tests conducted in the studied company in Iran were unacceptable, but these improved significantly after the training intervention. The study demonstrated the lack of a systematic guideline for conducting spirometry and interpreting the results in the occupational setting in Iran, and emphasises the need for a nationwide programme to improve the quality of spirometry tests in this setting. PMID- 23443230 TI - Canadian trends in liver cancer: a brief clinical and epidemiologic overview. AB - Although primary liver cancer is rare, its incidence rate has been rising quickly in Canada, more than tripling since the early 1980s. This cancer is more common in men than women, and the age-specific incidence rates in men have been increasing significantly in all age groups from 40 years of age onward. The death rate has followed a similar upward trajectory, in part because of the low 5-year survival rate of 18% in both sexes. Infection with the hepatitis B or C virus continues to be the most common risk factor, but other factors may also play a role. Risk reduction strategies, such as viral hepatitis screening, have been recommended in other countries and warrant consideration in Canada as part of a coordinated strategy of disease prevention and control. PMID- 23443229 TI - Linoleic acid metabolite drives severe asthma by causing airway epithelial injury. AB - Airway epithelial injury is the hallmark of various respiratory diseases, but its mechanisms remain poorly understood. While 13-S-hydroxyoctadecadienoic acid (13-S HODE) is produced in high concentration during mitochondrial degradation in reticulocytes little is known about its role in asthma pathogenesis. Here, we show that extracellular 13-S-HODE induces mitochondrial dysfunction and airway epithelial apoptosis. This is associated with features of severe airway obstruction, lung remodeling, increase in epithelial stress related proinflammatory cytokines and drastic airway neutrophilia in mouse. Further, 13-S HODE induced features are attenuated by inhibiting Transient Receptor Potential Cation Channel, Vanilloid-type 1 (TRPV1) both in mouse model and human bronchial epithelial cells. These findings are relevant to human asthma, as 13-S-HODE levels are increased in human asthmatic airways. Blocking of 13-S-HODE activity or disruption of TRPV1 activity attenuated airway injury and asthma mimicking features in murine allergic airway inflammation. These findings indicate that 13 S-HODE induces mitochondrial dysfunction and airway epithelial injury. PMID- 23443231 TI - Role of TRPV1 and P2X receptors in the activation of lung vagal C-fiber afferents by inhaled cigarette smoke in rats. AB - Inhaled cigarette smoke (CS) triggers airway reflexes that are thought to result from the activation of lung vagal C-fiber afferents (LVCAs) via the action of reactive oxygen species in rats. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) and P2X receptors in LVCA activation. Activities of LVCAs were recorded in anesthetized and artificially ventilated rats. Airway challenge of CS produced a concentration-dependent fiber stimulation. Pretreatment with dimethylthiourea [DMTU; a scavenger of hydroxyl radical (OH)], capsazepine (CPZ; a TRPV1 receptor antagonist) and iso-pyridoxalphosphate-6 azophenyl-2',5'-disulphonate (iso-PPADS; a P2X receptor antagonist) separately reduced the fiber responses by 64, 40 and 44%, respectively, whereas pretreatment with hexamethonium (a nicotinic acetylcholine receptor antagonist) failed to alter the response. A combination of CPZ and iso-PPADS exerted a greater inhibitory effect compared with the effect of either single pretreatment. However, a combination of DMTU, CPZ and iso-PPADS did not further reduce the fiber response compared with the combined effect of CPZ and iso-PPADS. It was concluded that both TRPV1 and P2X receptors, but not nicotinic acetylcholine receptors, participate in the stimulation of LVCAs by inhaled CS, possibly through the action of OH. PMID- 23443232 TI - Aberrant crypt focus and fragile histidine triad protein in sporadic colorectal carcinoma. AB - AIM: To characterize aberrant crypt focus (ACF) in adjoining mucosa in sporadic colorectal carcinoma and to evaluate fragile histidine triad (Fhit) protein and Ki67. METHODS: ACF was identified grossly and classified histologically in 75 resected specimens. ACF was typed into hyperplastic ACF (HACF) and dysplastic ACF (DACF). Sections of ACF, carcinoma and normal colonic mucosa as control were studied for Fhit and Ki67 expressions by immunohistochemistry and were grouped according to staining intensity and the number of positive stained cells observed in different histological groups. Comparison was done between the different groups by Pearson's chi(2) test and gamma test for the ordinal data. P value < 0.05 was considered as significant. RESULTS: Age range was 40 to 86 years in males (mean = 43.36) and 45 to 70 years in females (mean = 56). HACF was identified in all cases studied in the non-tumorous colonic mucosa; ACF was observed as non-contiguous scattered foci, which supports the hypothesis of acquisition of single focus monoclonality by colonic epithelial cells in tumor generation. Twenty-four (32%) had DACF and were observed as closure to carcinoma foci. Intensity of Fhit expression: (1) HACF - 40% exhibited strong intensity, similar to normal, moderate in 36% and weak in 24%; (2) DACF - strong in 25%, moderate in 37.5% and weak in 37.5%; and (3) carcinoma - negative in 16%, strong in 43% and moderate and weak in 28.5% each. Significant difference was observed in intensity of the Fhit protein expressions by HACF and DACF (P < 0.05). Tumor in older patients showed a stronger Fhit intensity compared to younger patients (P = 0.036). Vegetarian diet intake and non-smokers showed stronger Fhit intensities. Advanced stage tumor, non-vegetarian diet and younger age was associated with loss of Fhit protein. Ki67 positivity was an extended crypt pattern in HACF and DACF showed extension up to the neck region of the crypts and surface epithelium. Carcinomas showed a marked increase in Ki67 expression (P < 0.05). Fhit protein had an inverse association with Ki67 expression. CONCLUSION: Weaker Fhit intensity was associated with smoking, non-vegetarian diet intake and increasing Ki67 expression. Loss of Fhit protein expression is possibly influenced by environmental factors like smoking and non-vegetarian diet intake. PMID- 23443234 TI - Identifying housing and meteorological conditions influencing residential air exchange rates in the DEARS and RIOPA studies: development of distributions for human exposure modeling. AB - Appropriate prediction of residential air exchange rate (AER) is important for estimating human exposures in the residential microenvironment, as AER drives the infiltration of outdoor-generated air pollutants indoors. AER differences among homes may result from a number of factors, including housing characteristics and meteorological conditions. Residential AER data collected in the Detroit Exposure and Aerosol Research Study (DEARS) and the Relationships of Indoor, Outdoor and Personal Air (RIOPA) study were analyzed to determine whether the influence of a number of housing and meteorological conditions on AER were consistent across four cities in different regions of the United States (Detroit MI, Elizabeth NJ, Houston TX, Los Angeles, CA). Influential factors were identified and used as binning variables for deriving final AER distributions for the use in exposure modeling. In addition, both between-home and within-home variance in AER in DEARS were quantified with the goal of identifying reasonable AER resampling frequencies for use in longitudinal exposure modeling efforts. The results of this analysis indicate that residential AER is depended on ambient temperature, the presence (or not) of central air conditioning, and the age of the home. Furthermore, between-home variability in AER accounted for the majority (67%) of the total variance in AER for Detroit homes, indicating lower within-home variability. These findings are compared with other previously published AER distributions, and the implications for exposure modeling are discussed. PMID- 23443233 TI - The factors influencing urinary arsenic excretion and metabolism of workers in steel and iron smelting foundry. AB - In order to evaluate the degree of arsenic (As) exposure and the factors influencing urinary As excretion and metabolism, 192 workers from a steel and iron smelting plant, with different type of work in production such as roller, steel smelting, iron smelting and metallic charge preparation, were recruited. Information about characteristics of each subject was obtained by questionnaire and inorganic As (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) in urine were determined. The results showed that steel smelters had significantly higher concentrations of DMA and total As (TAs) than rollers and metallic charge preparation workers, and iron and steel smelters had a higher value of primary methylation index and lower proportion of the iAs (iAs%) than rollers and metallic charge preparation workers. In steel smelters, urinary As level exceeded the biological exposure index (BEI) limit for urinary As of 35 MUg/l by 65.52%, and higher than metallic charge preparation workers (35.14%). The individuals consumed seafood in recent 3 days had a higher TAs than the individuals without seafood consumption. Multivariate logistic regression analysis showed that different jobs, taken Chinese medicine of bezoar and seafood consumption in recent 3 days were significantly associated with urinary TAs exceeded BEI limit value 35 MUg/l. Our results suggest that workers in steel and iron smelting plant had a lower level of As exposure, and seafood consumption and taking Chinese medicine of bezoar also could increase the risk of urinary TAs exceeded BEI limit value. PMID- 23443235 TI - Cotinine and trans 3'-hydroxycotinine in dried blood spots as biomarkers of tobacco exposure and nicotine metabolism. AB - Tobacco use is the major preventable cause of premature death in the United States. Second-hand smoke (SHS) exposure also contributes to a number of premature deaths as well as other negative health outcomes. An accurate assessment of tobacco smoke exposure is critical to understanding these disease processes. The plasma concentration of cotinine, the primary metabolite of nicotine, is widely accepted as a quantitative measure of tobacco and SHS exposure. However, it is not always feasible to collect plasma. Dried blood spots (DBS), which are collected routinely from newborns and often from young children for lead screening, provide an alternative sampling method. We have developed a quantitative high throughput liquid chromatography tandem mass spectrometry method for the analysis of cotinine in DBS. The limit of quantitation was 0.3 ng/g (~ 0.2 ng/ml plasma). Cotinine levels in DBS from 83 smokers and 99 non smokers exposed to SHS were determined. Plasma cotinine concentrations in these subjects ranged from <0.02 to 443 ng/ml. Cotinine was detected in DBS from 157 subjects, and the correlation between cotinine in plasma and DBS was excellent, 0.992 (P<0.001). We also determined the ratio of trans 3'-hydroxycotinine to cotinine, a measure of nicotine metabolism, in DBS from smokers. This ratio in DBS was well correlated with the ratio in plasma, 0.94 (P<0.001). In a small study, we confirmed the feasibility of using extant DBS collected for lead screening to assess SHS exposure in children. PMID- 23443236 TI - Validation of estimates of past exposure to arsenic in drinking water using historical urinary arsenic concentrations. AB - Consumption of inorganic arsenic in drinking water at high levels has been associated with chronic diseases. Research groups have estimated historic exposure using databases and models of arsenic in drinking water supplies, along with participant residential histories. Urinary arsenic species are an established biomarker of recent exposure; we compare arsenic concentrations in historically collected urine samples with predicted estimates of arsenic exposure. Using a cohort of 462 subjects with at least one urine sample collected from 1984-1992 and an arsenic exposure estimate through drinking water at the time of the urine sample, individual exposure estimates were compared with speciated urine arsenic (UAs) concentrations using correlation and multiple regression analyses. Urine inorganic arsenic (UIAs) concentrations (trivalent arsenic, pentavalent arsenic, monomethylarsonic acid, dimethylarsonic acid) were best predicted by residential water arsenic concentrations (R(2)=0.3688), compared with metrics including water consumption (R(2)=0.2038) or water concentrations at employment locations (R(2)=0.2331). UIAs concentrations showed similar correlation when stratified by whether the arsenic concentration was predicted or measured. Residential water arsenic concentrations, independent of water intake or water concentrations at places of employment, best explain the variability in UIAs concentrations, suggesting historical reconstruction of arsenic exposure that accounts for space-time variability and water concentrations may serve as a proxy for exposure. PMID- 23443237 TI - Air pollution dispersion models for human exposure predictions in London. AB - The London household survey has shown that people travel and are exposed to air pollutants differently. This argues for human exposure to be based upon space time-activity data and spatio-temporal air quality predictions. For the latter, we have demonstrated the role that dispersion models can play by using two complimentary models, KCLurban, which gives source apportionment information, and Community Multi-scale Air Quality Model (CMAQ)-urban, which predicts hourly air quality. The KCLurban model is in close agreement with observations of NO(X), NO(2) and particulate matter (PM)(10/2.5), having a small normalised mean bias ( 6% to 4%) and a large Index of Agreement (0.71-0.88). The temporal trends of NO(X) from the CMAQ-urban model are also in reasonable agreement with observations. Spatially, NO(2) predictions show that within 10's of metres of major roads, concentrations can range from approximately 10-20 p.p.b. up to 70 p.p.b. and that for PM(10/2.5) central London roadside concentrations are approximately double the suburban background concentrations. Exposure to different PM sources is important and we predict that brake wear-related PM(10) concentrations are approximately eight times greater near major roads than at suburban background locations. Temporally, we have shown that average NO(X) concentrations close to roads can range by a factor of approximately six between the early morning minimum and morning rush hour maximum periods. These results present strong arguments for the hybrid exposure model under development at King's and, in future, for in-building models and a model for the London Underground. PMID- 23443238 TI - Unexpected results in a randomized dietary trial to reduce phthalate and bisphenol A exposures. AB - Diet is a primary source of exposure for high-molecular-weight phthalates and bisphenol A (BPA), but little is known about the efficacy of various interventions to reduce exposures. We conducted a randomized trial with 10 families to test the efficacy of a 5-day complete dietary replacement (Arm 1; n=21) versus written recommendations to reduce phthalate and BPA exposures (Arm 2; n=19). We measured phthalate and BPA concentrations in urine samples at baseline, intervention, and post-intervention periods. We used Wilcoxon paired signed-rank tests to assess change in concentrations across time and multi-level mixed effects regression models to assess differences between Arms 1 and 2. Urinary di(2-ethylhexyl) phthalate (DEHP) metabolite concentrations increased unexpectedly from a median of 283.7 nmol/g at baseline to 7027.5 nmol/g during the intervention (P<0.0001) among Arm 1 participants, and no significant changes were observed for Arm 2 participants. We observed a statistically significant increase in total BPA concentration between baseline and intervention periods in Arm 1 but no significant changes in Arm 2. Arm 1 food ingredient testing for DEHP revealed concentrations of 21,400 ng/g in ground coriander and 673 ng/g in milk. Food contamination with DEHP led to unexpected increases in urinary phthalate concentrations in a trial intended to minimize exposure. In the absence of regulation to reduce phthalate and BPA concentrations in food production, it may be difficult to develop effective interventions that are feasible in the general population. An estimate of DEHP daily intake for children in the dietary replacement Arm was above the US Environmental Protection Agency oral reference dose and the European Food Safety Authority's tolerable daily intake, suggesting that food contamination can be a major source of DEHP exposure. PMID- 23443239 TI - Investigation of lead concentrations in whole blood, plasma and urine as biomarkers for biological monitoring of lead exposure. AB - Lead in blood is a major concept in biomonitoring of exposure but investigations of its alternatives are scarce. The aim of the study was to describe different lead biomarkers' variances, day-to-day and between individuals, estimating their fraction of the total variance. Repeated sampling of whole blood, plasma and urine were conducted for 48 lead-exposed men and 20 individuals under normal environmental lead exposure, in total 603 measurements. For lead workers, the fraction of the total variance attributed to differences between individuals was 91% for whole-blood lead (geometric mean 227 MUg/l; geometric standard deviation (GSD): 1.55 MUg/l); plasma 78% (0.57 MUg/l; GSD: 1.84 MUg/l); density-adjusted urine 82%; and unadjusted urine 75% (23.7 MUg/l; GSD: 2.48 MUg/l). For the individuals under normal lead exposure, the corresponding fractions were 95% of the total variance for whole blood (20.7 MUg/l; GSD: 8.6 MUg/l), 15% for plasma (0.09 MUg/l; GSD: 0.04 MUg/l), 87% for creatinine-adjusted urine and 34% for unadjusted (10.8 MUg/l; GSD: 6.7 MUg/l). Lead concentration in whole blood is the biomarker with the best ability to discriminate between individuals with different mean concentration. Urinary and plasma lead also performed acceptably in lead workers, but at low exposures plasma lead was too imprecise. Urinary adjustments appear not to increase the between-individual fraction of the total variance among lead workers but among those with normal lead exposure. PMID- 23443240 TI - A time series study of gastroenteritis and tap water quality in the Nantes area, France, 2002-2007. AB - In the Nantes area, 410,000 inhabitants are supplied with water pumped from the Loire River. The treatment of this water is carried out through a process of complete clarification and disinfection. During the study period (2002-07), the quality of drinking water complied with European microbial standards and mean turbidity in finished water was 0.05 NTU (nephelometric turbidity units). We aimed to characterize the link between produced water turbidity and other operational data and the incidence of acute gastroenteritis (AGE) in the Nantes area. The daily number of medical prescriptions for AGE was drawn from the French national health insurance system's drug reimbursement data. We modeled this time series using Poisson regression within the framework of a Generalized Additive Model. We showed that an interquartile range turbidity degradation (0.042-0.056 NTU) was connected to a 4.2% (CI95=(1.5%; 6.9%)) increase in the risk of AGE in children and a 2.9% (CI95=(0.5%; 5.4%)) increase in adults. The slope of the turbidity risk function was higher during both high- and low-water conditions of the river. High values of daily flow of produced water were also associated with higher endemic levels of AGE. PMID- 23443241 TI - Endonuclease IV discriminates mismatches next to the apurinic/apyrimidinic site in DNA strands: constructing DNA sensing platforms with extremely high selectivity. AB - A unique capability of Endonuclease IV in discrimination of mismatches neighboring a natural abasic site in DNA strands has been demonstrated, which enables genotyping of SNPs with high discrimination factors and differentiation of as low as 0.1-0.01% of target DNA strands from a large background of single base different interfering strands. PMID- 23443242 TI - Leisure-time physical activity is a significant predictor of stroke and total mortality in Japanese patients with type 2 diabetes: analysis from the Japan Diabetes Complications Study (JDCS). AB - AIMS/HYPOTHESIS: Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients. METHODS: Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years; 47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis. RESULTS: A significant reduction in HR in patients in the top (>= 15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (<= 3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease. CONCLUSIONS/INTERPRETATION: In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes. PMID- 23443244 TI - N-acetyl-L-cysteine modulates the metabolism of cis-platin in human plasma in vitro. AB - Cis-Platin (CP) is a remarkably effective Pt-based anticancer drug, but it also exhibits severe toxic side-effects, including nephrotoxicity and ototoxicity. Previous studies conducted with mammalian model organisms have clearly demonstrated that the intravenous administration of N-acetyl-L-cysteine (NAC) or sodium thiosulfate (STS) along with CP can significantly reduce these toxic side effects. A molecular understanding of the biochemical events that unfold in the bloodstream when these 'ameliorating agents' and CP are co-administered, therefore, constitutes an important first step in devising novel strategies to ultimately improve the quality of life of patients undergoing treatment with CP. We have employed size exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma atomic emission spectrometer (ICP-AES) to visualize how NAC affects the metabolism of CP in human plasma (obtained from healthy male volunteers) in vitro. Clinically relevant doses of CP and NAC were added to plasma at various NAC : CP molar ratios and the Pt-distribution was determined after 10 and 50 min. The results revealed that a putative Pt-NAC complex was formed in plasma with NAC : CP molar ratios >= 50 : 1 and that plasma protein binding of CP-derived Pt-species was marginally affected by NAC. In addition, the anti-tumor active CP remained in plasma for more than 50 min. Furthermore, NAC (but not CP) adversely affected the integrity of Fe and Zn plasma metalloproteins in a dose and a time dependent manner. Based on these in vitro data, NAC appears to be a less ideal ameliorating agent to mitigate CP toxicity compared to STS. PMID- 23443245 TI - Carbon nanotubes in cancer therapy: a more precise look at the role of carbon nanotube-polymer interactions. AB - Despite the great potential of carbon nanotubes (CNTs) in various areas of biomedicine, concerns regarding their carcinogenicity, inefficient dispersion in aqueous solutions and biological activity in vivo still remain. One important and feasible route to overcome these barriers is modification of CNTs with polymers, which are widely studied and play a vital role in biological and biomedical fields, especially in drug delivery. This comprehensive review focuses on the achievements of our and other groups in currently used methods to functionalize the surface of CNTs with polymers to produce anticancer drug delivery systems. We have intensively studied covalent and noncovalent interactions between CNTs and linear, dendritic and hyperbranched biocompatible polymers as well as biomacromolecules interactions which are very crucial to diminish the toxicity of CNTs via changing their conformations. PMID- 23443246 TI - Is there a future for restricted elimination diets in ADHD clinical practice? PMID- 23443247 TI - Tales of plagues and carnivals: Samuel R. Delany, AIDS, and the grammar of dissent. AB - While even today lesbian, gay, bisexual and transgender people might have cause to distrust the healthcare establishment, how much more fragile was the relationship between sexual minorities and health professionals in the first decade of the AIDS epidemic. Dissent from consensus healthcare and health research then was a question of survival in the face of political and medical intransigence. This article focuses on one version of AIDS dissent: The narrative representations of AIDS in fiction by the gay African-American fantasy writer Samuel R. Delany, which rejected the rigid binarism of "safe" and "unsafe" sex practices, Delany's evidence-based dissent. He also engaged in a related form of cultural dissent: speaking the unspeakably obscene, at a time when Silence = Death. Delany called into question both the inferential leaps based on limited epidemiological research that were represented in safer sex guidelines and the widespread public reticence about sexual behavior. PMID- 23443248 TI - Queer patients and the health care professional-regulatory arrangements matter. AB - This paper discusses a number of critical ethical problems that arise in interactions between queer patients and health care professionals attending them. Using real-world examples, we discuss the very practical problems queer patients often face in the clinic. Health care professionals face conflicts in societies that criminalise same sex relationships. We also analyse the question of what ought to be done to confront health care professionals who propagate falsehoods about homosexuality in the public domain. These health care professionals are more often than not motivated by strong religious convictions that conflict with mainstream medical opinion on homosexuality. We argue that they ought to be held accountable for their conduct by their professional statutory bodies, given that they abuse their professional standing to propagate sectarian views not representative of their profession. Lastly, we propose that medical schools have special responsibilities in training future health care professionals that will enable them to respond professionally to queer patients seeking health care. PMID- 23443243 TI - Insulin signalling mechanisms for triacylglycerol storage. AB - Insulin signalling is uniquely required for storing energy as fat in humans. While de novo synthesis of fatty acids and triacylglycerol occurs mostly in liver, adipose tissue is the primary site for triacylglycerol storage. Insulin signalling mechanisms in adipose tissue that stimulate hydrolysis of circulating triacylglycerol, uptake of the released fatty acids and their conversion to triacylglycerol are poorly understood. New findings include (1) activation of DNA dependent protein kinase to stimulate upstream stimulatory factor (USF)1/USF2 heterodimers, enhancing the lipogenic transcription factor sterol regulatory element binding protein 1c (SREBP1c); (2) stimulation of fatty acid synthase through AMP kinase modulation; (3) mobilisation of lipid droplet proteins to promote retention of triacylglycerol; and (4) upregulation of a novel carbohydrate response element binding protein beta isoform that potently stimulates transcription of lipogenic enzymes. Additionally, insulin signalling through mammalian target of rapamycin to activate transcription and processing of SREBP1c described in liver may apply to adipose tissue. Paradoxically, insulin resistance in obesity and type 2 diabetes is associated with increased triacylglycerol synthesis in liver, while it is decreased in adipose tissue. This and other mysteries about insulin signalling and insulin resistance in adipose tissue make this topic especially fertile for future research. PMID- 23443249 TI - Evolution of myocardial support: a shifting paradigm. PMID- 23443250 TI - Association between the endothelial nitric oxide synthase gene Glu298Asp polymorphism and coronary heart disease: a meta-analysis of 39 case-control studies. AB - Numerous studies have indicated that the human endothelial nitric oxide synthase (eNOS) gene Glu298Asp polymorphism is associated with coronary heart disease (CHD) susceptibility, however, their conclusions are inconsistent. The present meta-analysis aimed to evaluate the precise result by searching the PubMed database and using 39 case-control studies comprising 7489 cases and 7051 controls.Each study tested the association between the eNOS Glu298Asp polymorphism and CHD. A meta-analysis was then conducted using the Comprehensive Meta Analysis 2.2 software to calculate the pooled odds ratios (ORs) of five genetic models with 95% confidence intervals (CIs). Publication bias was also explored. The meta-analysis showed a significant association between the eNOS Glu298Asp polymorphism and CHD susceptibility for all the genetic models [Asp vs. Glu, OR 1.26, 95% CI 1.14-1.40, P<0.001; Asp/Asp vs. Glu/Glu, OR 1.58, 95% CI 1.23-2.02, P<0.001; Glu/Asp vs. Glu/Glu, OR 1.12, 95% CI 1.03-1.22, P=0.001; (Glu/Asp+Asp/Asp) vs. Glu/Glu, OR 1.17, 95% CI 1.07-1.27, P<0.001; Asp/Asp vs. (Glu/Glu+Glu/Asp), OR 1.59, 95% CI 1.25-2.03, P<0.001]. Subgroup and sensitivity analyses indicated that the result was robust. A weak publication bias was detected. The results indicated that the eNOS Glu298Asp polymorphism is a risk factor for developing CHD, particularly in the Asian population. PMID- 23443251 TI - Safe removal of an encrusted nephrostomy tube using a vascular sheath: a technique revisited. AB - With the advent of interventional radiology and the decrease in mortality from chronic ailments, especially malignancy, percutaneous nephrostomy has become a commonly used safe technique for temporary relief of renal tract obstruction or for urinary diversion. However, these are associated with risks of infection, particularly septicaemia, colonisation, and blockage. Another significant complication is difficulty in removal due to encrustation. We describe a useful technique used in our department for the past few years and cite four cases of variable presentation and complexity for removal of an encrusted nephrostomy tube. No mention of this technique was found recent literature. An almost similar technique was described in the 1980s "Pollack and Banner (Radiology 145:203-205, 1982), Baron and McClennan (Radiology 141:824, 1981)". It is possible that experienced operators may have used this technique. We revisit it with pictographic representation, describing its use with currently available equipment, for benefit of operators who are not aware of this technique. PMID- 23443252 TI - On the quantization of time-varying phase synchrony patterns into distinct functional connectivity microstates (FCMUstates) in a multi-trial visual ERP paradigm. AB - The analysis of functional brain connectivity has been supported by various techniques encompassing spatiotemporal interactions between distinct areas and enabling the description of network organization. Different brain states are known to be associated with specific connectivity patterns. We introduce here the concept of functional connectivity microstates (FCMUstates) as short lasting connectivity patterns resulting from the discretization of temporal variations in connectivity and mediating a parsimonious representation of coordinated activity in the brain. Modifying a well-established framework for mining brain dynamics, we show that a small sized repertoire of FCMUstates can be derived so as to encapsulate both the inter-subject and inter-trial response variability and further provide novel insights into cognition. The main practical advantage of our approach lies in the fact that time-varying connectivity analysis can be simplified significantly by considering each FCMUstate as prototypical connectivity pattern, and this is achieved without sacrificing the temporal aspects of dynamics. Multi-trial datasets from a visual ERP experiment were employed so as to provide a proof of concept, while phase synchrony was emphasized in the description of connectivity structure. The power of FCMUstates in knowledge discovery is demonstrated through the application of network topology descriptors. Their time-evolution and association with event-related responses is explored. PMID- 23443253 TI - Developmental changes of BKCa channels depend on differentiation status in cultured podocytes. AB - The podocyte is a remarkable cell type, which encases the capillaries of the kidney glomerulus. Podocytes are of keen interests because of their key roles in kidney development and disease. Large-conductance Ca(2+)-activated K(+) channels (BKCa channels) are important ion channels located in podocytes and play the essential role in regulating calcium homeostasis cell signaling. In this research, we studied the undergoing developmental changes of BKCa channels and their contribution to functional maturation of podocytes. Our results showed that the distribution of BKCa channels changed with the maturity of differentiation in a conditionally immortalized mouse podocyte cell line. Additionally, the increase of BKCa channel protein expression was detected by immunofluorescence staining with confocal microscopy in podocytes, which was consistent with the increase in the current density of BKCa channels examined by whole-cell patch-clamp technique. Our results suggested that the developmental changes of BKCa channels may help podocytes adapt to changes in pressure gradients occurring in physiological conditions. Those findings may have implications for understanding the physiology and development of kidney and will also serve as a baseline for future studies designed to investigate developmental changes of ion channel expression in podocytes. PMID- 23443254 TI - Influence of compliance on bone mineral density changes in postmenopausal women with early breast cancer on Anastrozole. AB - PURPOSE: Adjuvant treatment for hormone receptor-positive breast cancer in postmenopausal women with aromatase inhibitors is associated with increased bone loss depending on the compliance to treatment. METHODS: In this bone substudy, bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry at baseline and after 12- and 24-month treatment in 63 patients receiving Anastrozole as adjuvant treatment for hormone receptor-positive early breast cancer. To minimize the effects of confounders, a matched pair analysis (compliant N = 21, non-compliant N = 21) was performed. RESULTS: Anastrozole treatment in compliant patients leads to a decrease in BMD (g/cm(2)) at lumbar spine and total hip from baseline to 12 and 24 months (-2.57 % P = 0.004; -2.02 % P = 0.05; -2.57 % P = 0.001 and -4.18 % P = 0.003, respectively) compared to non compliant patients (-1.71 % P = 0.050; -2.00 % P = 0.085; -1.65 % P = 0.055 and 3.20 % P = 0.005, respectively). CONCLUSIONS: Anastrozole treatment in compliant patients with breast cancer resulted in a larger, increase in bone loss at 12 and 24 months compared to non-compliant patients. Bone loss stabilized in both groups at the spine from 12- to 24-month treatment, whereas maintained at the total hip. PMID- 23443255 TI - Increase of N1, N12-diacetylspermine in tissues from colorectal cancer and its liver metastasis. AB - PURPOSE: N (1),N (12)-Diacetylspermine (DiAcSpm) is a tumor marker featured by increase in the urine of patients with cancers, including early colorectal cancer, but where and how DiAcSpm is made remains unclear. We aimed to clarify whether colorectal cancer tissues produce increased amounts of DiAcSpm, and if they do, to examine whether tissue DiAcSpm level may serve as a criterion of tissue malignancy. METHODS: Tissue samples were obtained from 140 patients (13 low-grade intraepithelial neoplasia, 98 high-grade intraepithelial neoplasia and 29 colorectal cancer) treated for colorectal cancer and intraepithelial neoplasia at Tokyo Metropolitan Komagome Hospital between November 2007 and April 2011. The DiAcSpm level in cancer and adjacent normal tissue extracts was compared, and its relationship with clinical stages of the diseases was analyzed. RESULTS: DiAcSpm levels were higher in colorectal cancer tissue (p < 0.01, n = 12) and its liver metastasis (p < 0.05, n = 5) than in adjacent normal tissues. The tumor/normal ratio of tissue DiAcSpm content was examined for endoscopically obtained tumor and adjacent normal tissues from patients with intraepithelial neoplasia. The ratio was greater than 1.5 in 38 % (5/13) and 78 % (84/108) of low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia, respectively. CONCLUSIONS: Tissue DiAcSpm levels increase in the tissue of colorectal cancer and also in precancerous lesion, such as high-grade intraepithelial neoplasia. The increase is considered a sign that a tissue is acquiring malignant characteristics. It is likely that the DiAcSpm produced by cancer cells is responsible for the frequent increase in urinary DiAcSpm in early cancer patients. PMID- 23443256 TI - Oncolytic adenovirus armed with shRNA targeting MYCN gene inhibits neuroblastoma cell proliferation and in vivo xenograft tumor growth. AB - PURPOSE: MYCN amplification and p53 inactivation are two typical characteristics of aggressive neuroblastomas and are strongly associated with cancer progression and treatment failure. In an effort to develop new therapeutic agents to treat the aggressive neuroblastomas, we constructed ZD55-shMYCN, an oncolytic adenovirus ZD55 carrying short hairpin RNA (shRNA) targeting MYCN gene, and investigated the effects on proliferation of the p53-null and MYCN-amplified neuroblastoma cell line LA1-55N in vitro and in vivo by ZD55-shMYCN. METHODS: In this study, we used ZD55-shMYCN to treat p53-null and MYCN-amplified neuroblastoma cells. To confirm the ability of selective replication of the ZD55 shMYCN, we examined the expression of E1A protein by western blotting. We used quantitative real-time PCR analysis and western blotting analysis to determine the inhibitory effect of ZD55-shMYCN on MYCN expression. MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cell proliferation assay and xenograft mouse model were used to test the antigrowth efficacy of ZD55 shMYCN. RESULTS: The results showed that ZD55-shMYCN selectively replicated and significantly downregulated the MYCN expression in LA1-55N cells. ZD55-shMYCN effectively inhibited the proliferation in LA1-55N cells in vitro and significantly inhibited tumor growth in vivo xenograft tumor in nude mice. CONCLUSIONS: ZD55-shMYCN provides a novel agent for treating MYCN-amplified and p53-inactive aggressive neuroblastoma, representing a promising approach for further clinical development. PMID- 23443257 TI - The association between overall survival of prostate cancer patients and hypertension, hyperglycemia, and overweight in Southern China: a prospective cohort study. AB - PURPOSE: Hypertension, hyperglycemia, and overweight are considered associated with the development and prognosis of prostate cancer (PCa). This study is aimed at investigating the association between pre-existing hypertension, hyperglycemia, and overweight and the overall survival (OS) of PCa patients receiving androgen deprivation therapy (ADT). METHODS: We studied the clinical data of 323 patients of PCa receiving ADT in our hospital from January 2003 to August 2012 aged 50-91. The association between OS and hypertension, hyperglycemia, or overweight, both separately and together, was analyzed via Kaplan-Meier method. The distributions of clinicopathological features among groups were evaluated using Fisher's exact or chi-square test. RESULTS: 23 men (7.12 %) were lost to follow-up during this study. During a median follow-up for 43 months (range 3-119 months), 122 deaths (40.67 %) were confirmed. The five year OS rate of men with both hypertension and overweight (28.57 %) was significantly lower than that of control group (48.33 %, P = 0.024). It was also moderately lower than that of men just with hypertension (50.00 %, P = 0.095) or overweight (55.56 %, P = 0.088). Men with both hyperglycemia and overweight had significantly shorter survival time than control group (P = 0.037). The distributions of clinical information were similar among all the groups except that overweight patients had a lower proportion of PSA level over 20 ng/mL (65.38 %) than control group (84.95 %, P = 0.026). CONCLUSIONS: Pre-existing hypertension, hyperglycemia, and overweight were associated with poor prognosis of PCa patients. Men with both hypertension and overweight, or with both hyperglycemia and overweight had significantly shorter survival time. PMID- 23443259 TI - Collapsin response mediator protein 3 deacetylates histone H4 to mediate nuclear condensation and neuronal death. AB - CRMP proteins play critical regulatory roles during semaphorin-mediated neurite outgrowth, neuronal differentiation and death. Albeit having a high degree of structure and sequence resemblance to that of liver dihydropyrimidinase, purified rodent brain CRMPs do not hydrolyze dihydropyrimidinase substrates. Here we found that mouse CRMP3 has robust histone H4 deacetylase activity. During excitotoxicity-induced mouse neuronal death, calpain-cleaved, N-terminally truncated CRMP3 undergoes nuclear translocation to cause nuclear condensation through deacetylation of histone H4. CRMP3-mediated deacetylation of H4 leads to de-repression of the E2F1 gene transcription and E2F1-dependent neuronal death. These studies revealed a novel mechanism of CRMP3 in neuronal death. Together with previous well established bodies of literature that inhibition of histone deacetylase activity provides neuroprotection, we envisage that inhibition of CRMP3 may represent a novel therapeutic approach towards excitotoxicity-induced neuronal death. PMID- 23443260 TI - SOCS1 prevents potentially skin-reactive cytotoxic T lymphocytes from gaining the ability to cause inflammatory lesions. AB - Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of T lymphocyte homeostasis. SOCS1-deficient mice accumulate CD8(+) T cells, which display a memory-like phenotype and proliferate strongly to IL-15. Socs1(-/-) mice develop inflammatory skin lesions, however, the underlying mechanisms are not well understood. In order to investigate the role of SOCS1 in regulating CD8(+) T cells potentially reactive to tissue antigens (Ags) of the skin, we generated Socs1(-/-) mice expressing MHC-I-restricted Pmel-1 transgenic TCR specific to the melanoma-derived gp100 Ag, which is also expressed by normal melanocytes. Socs1(-/-) Pmel-1 cells express increased levels of memory markers CD44, Ly6C, CD122, and CD62L, and show downregulation of TCR and upregulation of CD5, suggesting in vivo TCR stimulation. However, stimulation of Socs1(-/-)Pmel-1 cells with gp100-derived peptide induced only marginal proliferation in vitro despite eliciting strong effector functions, which was associated with elevated Blimp-1 induction. Following adoptive transfer to Rag1(-/-) mice, Socs1(-/-)Pmel 1 cells underwent lymphopenia-induced proliferation and caused severe skin pathology characterized by inflammatory lesions in ears, muzzle, extremities, and eyes. These findings underscore the importance of SOCS1 in regulating potentially skin-reactive cytotoxic T lymphocytes, which could get activated under conditions that promote Ag-nonspecific, cytokine-driven proliferation. PMID- 23443261 TI - Infrared thermography for detailed registration of thermoregulation in premature infants. AB - OBJECTIVE: To evaluate skin temperature by using different positions with non contact infrared thermography (IRT) in multiple body areas of preterm infants for detailed information about temperature regulation and distribution. METHODS: The temperature of ten premature infants (median: 27 weeks; age 36 days; weight 1322 g) was determined via IRT (leg, back, arm, head, upper abdomen; diameter 1 cm, scale 0.00 degrees C), and comparison was made with two conventional sensors. There were measurements of 10 min each: first incubator phase (I1), standardized skin-to-skin care (SSC) at the beginning (SSC1), after 90 min (SSC2), and then there was a second incubator phase (I2). RESULTS: From I1 to SSC1, patients cooled down (max. 0.62 degrees C; both methods). From SSC1 to SSC2 temperature on central areas (abdomen, back) was maintained but rose distinctively on the head and leg (P<0.05). In the incubator (I2), temperature niveau in all IRT-areas was significantly lower than before SSC. CONCLUSION: Via IRT, it is possible to detect fluctuations in temperature of premature infants. The cooling in I2 after SSC should be taken into account before routine daily care. PMID- 23443262 TI - Characteristics of infants admitted with hypoglycemia to a neonatal unit. AB - BACKGROUND: Neonatal hypoglycemia is a common symptom in early infant life. The currently available literature identifies the risk factors but not the degree to which each factor lends itself to the development or severity of an ensuing hypoglycemia. METHODS: A retrospective electronic chart review of near-term and term infants (>35 weeks' gestation) admitted to a tertiary-level neonatal unit over 16 months was carried out from the initiation of electronic record keeping. RESULTS: Ninety-five infants admitted with hypoglycemia to the unit were identified with complete records available. Fifty-eight percent of the infants were males, and the median gestation was 38 weeks. Twenty-two percent of the infants were premature, whereas 18% were macrosomic. Maternal diabetes was present in 27% infants. Comorbidities were common in this cohort, with approximately two-thirds of infants having multiple morbidities. The majority of which were jaundice and infection, whereas the minor ones were respiratory distress, initial lactic acidosis, feeding issues, and temperature instability. CONCLUSIONS: Neonatal hypoglycemia continues to be a significant morbidity in near-term and term infants. The presence of multiple morbidities is common in the setting of hypoglycemia and is the main determinant of the length of stay in the neonatal unit in this study population. PMID- 23443263 TI - A novel mutation in a mother and a son with Aarskog-Scott syndrome. AB - Aarskog-Scott syndrome, also termed as faciogenital dysplasia, is an X-linked disorder consisting of short stature, craniofacial dysmorphism, shawl scrotum, cryptorchidism, and interdigital webbing. Cardiac and central nervous system abnormalities and behavioral disorders can also be detected. The gene responsible for the syndrome is called FGD1, located at Xp11.21. A 7-year-old boy was admitted to our hospital due to short stature. He was born to non-consanguineous parents after an uneventful term pregnancy. Orchiopexy for bilateral cryptorchidism was performed when he was 2 years old. At physical examination, his height was under 3 percentile, and he had broad nasal bridge, hypertelorism, wide philtrum, brachydactyly, and interdigital webbing. Cranial magnetic resonance imaging and echocardiography revealed normal findings. An eye examination showed amblyopia and astigmatism. The mother had short stature and interdigital webbing as well. Mutational analyses revealed a novel mutation (c.308-2G), hemizygous in the boy and heterozygous in the mother. Aarskog syndrome (faciogenital dysplasia) should be kept in mind in children with short stature and interdigital webbing. PMID- 23443264 TI - Turner Syndrome and apparent absent uterus: a case report and review of the literature. AB - We report on a patient who initially presented with delayed puberty and an absent uterus on imaging with ultrasound and MRI. She was subsequently diagnosed with Turner Syndrome. Turner Syndrome typically presents with early loss of ovarian function and should be considered when primary ovarian insufficiency is present with apparent absent uterus on imaging. Follow-up imaging of the apparent absent uterus post-estrogen replacement therapy is important to confirm a normal uterus. A diagnosis of an absent uterus can be psychologically traumatic for patients and families, and can have significant implications for future fertility options. PMID- 23443265 TI - Measurement imprecision of common urinary biochemical analytes on the Roche Cobas 6000 system. PMID- 23443266 TI - Evaluation of a mobile clinical pathology laboratory developed for the home care of pediatric patients following transplantation of peripheral blood precursor cells. AB - BACKGROUND: A mobile clinical pathology laboratory (MoLab) was designed, outfitted and evaluated to improve the turnaround time (TAT) of laboratory tests performed in patients who receive follow-up care at home. METHODS: Full blood counts (FBCs), basic clinical biochemistry tests on blood and urine, and basic coagulation and blood gases were measured using bench-top laboratory analyzers to perform point-of-care tests in a mobile setting. The quality of the results was evaluated on the instruments both while the vehicle was at rest and following movement during the course of routine activity. RESULTS: The equivalence of the values produced by the point-of-care testing (POCT) and central laboratory (CL) measurement procedures was demonstrated and remained stable after movement in city traffic. The TATs ranged from a few minutes for FBCs to <20 min for extended clinical biochemistry tests. CONCLUSIONS: During the first 6 months of activity, the MoLab assured the provision of laboratory results for home care patients in a matter of minutes. This approach not only allowed for real-time modifications in therapy but also reduced the number of second visits by the home care medical team. Point-of-care tests performed on the MoLab were significantly more expensive than the same tests performed in the CL. However, the savings in patient hospitalization expenses and the reduced costs resulting from fewer second daily visits completely offset the costs of using the MoLab during the first 6-month pilot phase. PMID- 23443267 TI - Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. AB - Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor alpha signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17beta-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor alpha, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80% of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs. PMID- 23443271 TI - Dirhodium(II)-catalyzed formal [3+2+1]-annulation of azomethine imines with two molecules of a diazo ketone. AB - A highly diastereoselective formal [3+2+1]-cycloaddition reaction that produces multi-functionalized bicyclic pyrazolidinone derivatives is achieved in moderate to high yield by Rh2(4S-MPPIM)4-catalyzed reaction of azomethine imines with two molecules of a diazo ketone. PMID- 23443272 TI - Associations between IQ and alcohol consumption in a population of young males: a large database analysis. AB - PURPOSE: This study aimed at exploring the relationship between intelligence quotient (IQ) and alcohol consumption in a large sample of young males. This study explored whether IQ influences alcohol drinking and which pathways might be involved. We further hypothesized that IQ differences between lifetime abstainers and former drinkers exist, and that they primarily result from different group characteristics. METHOD: Within a psychiatric-epidemiological survey using a cross-sectional design IQ-tests were administered to approximately 50,000 Swiss conscripts at age of about 20 years. The sample was divided into four alcohol consumption categories (rare, occasional, moderate and daily drinking) and two non-drinker categories (former drinking and lifetime abstinence). Probabilities for different levels of consumption or former drinking against lifetime abstention in relation to IQ were estimated using multinomial logistic regression. Models were adjusted for education, disability pension, tobacco/cannabis use, migration, parental alcohol disorders, and mental health. RESULTS: After adjusting for confounders full-scale IQ displayed positive associations with being a rare (OR 1.13; CI 95 % 1.07-1.19), occasional (OR 1.41; CI 95 % 1.33-1.48), and moderate drinker (OR 1.53; CI 95 % 1.45-1.62), and negative associations with being a former drinker (OR 0.85; CI 95 % 0.79-0.93). Daily drinking was positively associated only with the performance subscale IQ (OR 1.12; CI 95 % 1.02-1.22). Confounders contributed significantly to the IQ alcohol association and, therefore, highlight the distinction of non-drinkers into lifetime abstainers and former drinkers. CONCLUSIONS: Our data confirmed the positive link between IQ and moderate drinking. Lower IQ in non-drinkers, however, seems to be related to earlier consumption and the presence of other risk factors. PMID- 23443273 TI - Electroanalysis of the interaction between (-)-epigallocatechin-3-gallate (EGCG) and amyloid-beta in the presence of copper. AB - The misfolding of amyloid-beta (Abeta) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Polyphenols are strong antioxidants and metal chelators, with characteristics that are of beneficial therapeutic values for their development as candidates targeting neurodegenerative and metal-induced diseases. We have demonstrated here the electrochemical properties of a green tea component, (-)-epigallocatechin-3-gallate (EGCG), and its potent activity on Abeta peptides. Characterization of early interactions (<=48 h) between EGCG and Abeta was conducted using square wave voltammetry (SWV). The interaction of Cu(ii) ions with the Tyr-10 residue of Abeta was shown to be affected by surrounding His residues. Morphological changes due to the binding of EGCG and Cu(II) were also elucidated using transmission electron microscopy (TEM). Electroanalytical techniques are promising for facilitating the investigation of metals and flavonoids in drug screening studies. PMID- 23443274 TI - Metal-catalyzed double migratory cascade reactions of propargylic esters and phosphates. AB - Propargylic esters and phosphates are easily accessible substrates, which exhibit rich and tunable reactivities in the presence of transition metal catalysts. pi Acidic metals, mostly gold and platinum salts, activate these substrates for an initial 1,2- or 1,3-acyloxy and phosphatyloxy migration process to form reactive intermediates. These intermediates are able to undergo further cascade reactions leading to a variety of diverse structures. This tutorial review systematically introduces the double migratory reactions of propargylic esters and phosphates as a novel synthetic method, in which further cascade reaction of the reactive intermediate is accompanied by a second migration of a different group, thus offering a rapid route to a wide range of functionalized products. The serendipitous observations, as well as designed approaches involving the double migratory cascade reactions, will be discussed with emphasis placed on the mechanistic aspects and the synthetic utilities of the obtained products. PMID- 23443275 TI - Pictorial dissection review of the lymphatic pathways from the gallbladder to the abdominal para-aortic lymph nodes and their relationships to the surrounding structures. AB - PURPOSE: This photographic review of actual dissections was compiled to demonstrate the various lymphatic pathways and their relationships to the surrounding structures to facilitate the development of QOL surgical procedures. METHODS: For the purpose of demonstration, three male adult specimens, prepared with 10% formaldehyde solution injected through the femoral artery and preserved in 60% alcohol solution, were used. Dissection was carried out in typical fashion without the use of dyes or a microscope. The dissection results were recorded in sketches, photographs and video recording. RESULTS: Two major lymphatic pathways from the gallbladder are demonstrated: (a) the left oblique pathway to the celiac nodes, and (b) the right descending pathway to the superior retropancreaticoduodenal node (Rouviere). A third and minor pathway to the superior mesenteric nodes is suggested. CONCLUSIONS: These three pathways finally reach the para-aortic (lumbar) lymph nodes. The importance of the interaorticocaval nodes at the level of the left renal vein should be emphasized, in particular the significance of the nodes of the right descending pathway, from the viewpoint of surgical treatment of cancer of the gallbladder and the pancreas head. PMID- 23443276 TI - The little finger ulnar palmar digital artery perforator flap: anatomical basis. AB - PURPOSE: The aim of this study was to explore the cutaneous vascularization of the hypothenar region and investigate the anatomical basis for perforator propeller flaps for coverage of the flexor aspect of the little finger. METHODS: The area between the pisiform and the base of the little finger was studied in 14 hands of fresh cadavers injected with red latex. An oval flap 1.5 cm large was raised along the axis between these two points. Perforators going into the flap were dissected up to their origin from the ulnar palmar digital artery of the little finger, and their distance from the proximal edge of the A1 pulley was recorded. RESULTS: The mean number of perforator arteries entering the flap was 5.8 (range 4-8). A constant sizeable perforator was identified within 0.7 cm from the proximal margin of the A1 pulley in all 14 specimens. In the majority of cases (64 %), the most distal perforator was located at this level. Dissection of the flap was carried out suprafascially on the most distal perforator and 180 degrees rotation allowed the flap to reach the flexor surface of the fifth finger. The donor site was closed primarily. CONCLUSION: Distal perforators of the ulnar palmar digital artery of the little finger are constantly found. Our anatomical findings support the possibility of raising a propeller perforator flap from the hypothenar region for coverage of the flexor aspect of the little finger. Its clinical application could provide a quick and straightforward single stage option with a negligible donor-site morbidity for reconstruction of such defects. PMID- 23443277 TI - Duplicate origin of the posterior communicating artery diagnosed by magnetic resonance angiography. AB - Extremely rarely, a posterior communicating artery (PCoA) of "duplicate origin" occurs when two branches of the PCoA arise separately from the supraclinoid segment of the internal carotid artery (ICA) and quickly fuse to form an arterial ring. Three such cases previously reported were described as "fenestration." We report the case of this rare variation diagnosed by magnetic resonance angiography and discuss the differentiation of PCoA of duplicate origin from PCoA fenestration, supraclinoid ICA fenestration, and hyperplastic anterior choroidal artery. PMID- 23443278 TI - From personal misfortune to public liability. PMID- 23443279 TI - Concomitant overexpression of EGFR and CXCR4 is associated with worse prognosis in a new molecular subtype of non-small cell lung cancer. AB - Although the relationships between CXCR4 and EGFR expression and survival in non small cell lung cancer (NSCLC) have been studied independently, dual CXCR4/EGFR tumor status and its relationship with survival has not been previously investigated. In the present study, we examined the relationship between CXCR4 expression, EGFR expression and dual CXCR4/EGFR expression and survival in patients with NSCLC (n=125) using immunohistochemical techniques. Overall survival was estimated using Kaplan-Meier and Cox proportional hazards models adjusting for patient age, tumor stage and type of treatments. Patients with CXCR4-positive tumors were significantly associated with distant metastasis and tended to have poorer prognosis compared to patients with CXCR4-negative tumors (HR=2.172, 95% CI=1.229-3.839). No significant association between EGFR expression and survival was found; however co-expression of CXCR4/EGFR was a significant prognostic factor of worse overall survival (HR=2.741, 95% CI=1.330 5.741). Furthermore, we showed that EGF enhanced the expression of CXCR4 in NSCLC cells through the PI-3K pathway, and treatment of NSCLC cells with EGFR phosphorylation inhibitor, AG1478, resulted in downregulation of the expression of CXCR4. These results suggest an important interaction between CXCR4 and EGFR intra-cellular pathways that may activate signals of tumor progression and may provide a valid explanation for the poor overall survival rate of patients whose co-expression of CXCR4 and EGFR is detected in tissue sections. Based on EGFR and CXCR4 expression, new molecular subtypes of NSCLC established in the present study can be used for customization of NSCLC treatment. Our results also showed that EGFR and CXCR4 are potential therapeutic targets for NSCLC and that simultaneous inhibition of EGFR and CXCR4 in NSCLC patients with concomitant expression of both CXCR4 and EGFR may be an effective treatment strategy. PMID- 23443281 TI - Commentary on the March 2013 issue. PMID- 23443280 TI - Introduction to the analysis of PET data in oncology. AB - Several reviews on specific topics related to positron emission tomography (PET) ranging in complexity from introductory to highly technical have already been published. This introduction to the analysis of PET data was written as a simple guide of the different phases of analysis of a given PET dataset, from acquisition to preprocessing, to the final data analysis. Although sometimes issues specific to PET in neuroimaging will be mentioned for comparison, most of the examples and applications provided will refer to oncology. Due to the limitations of space we couldn't address each issue comprehensively but, rather, we provided a general overview of each topic together with the references that the interested reader should consult. We will assume a familiarity with the basic principles of PET imaging. PMID- 23443282 TI - Evaluation of recruited lung volume at inspiratory plateau pressure with PEEP using bedside digital chest X-ray in patients with acute lung injury/ARDS. AB - BACKGROUND: We wanted to assess whether there was a significant relationship between recruited lung volume (V(rec)) and change in density on digital processed chest x-ray measured at 2 different levels of inspiratory plateau pressure corresponding to 2 PEEP levels in patients with acute lung injury or ARDS. METHODS: In 14 subjects, PEEP 5 cm H2O and 15 cm H2O were prospectively applied in a random order for 10 min. At the end of each period, chest x-ray was taken using a digital portable device, and a pressure-volume curve of the respiratory system was performed. We also assessed P(aO2), and the static and the dynamic (C(dyn,rs)) compliance of the respiratory system. Change in end-expiratory lung volume between tidal breath and relaxation volume of the respiratory system was determined. Radiological attenuation was measured on chest x-rays in 4 regions of interest in the right lung, and in 3 regions of interest in the left lung, drawn in posterior intercostal spaces from top to bottom, by using dedicated software. The ratio of lung density in each region between PEEP 15 and PEEP 5 (rP15/P5) and their arithmetic mean (MUP15/P5) were computed. V(rec) was determined from the pressure-volume curves. RESULTS: The median value of rP15/P5 in the 98 lung levels was 0.91 (0.80-1.01), which was significantly different from 1 (P < .001). The values of rP15/P5 were not significantly different between the lung levels. The median values of V(rec) and MUP15/P5 were 288 (173-402) mL and 0.90 (0.80 0.97), respectively. There was a significant negative correlation between V(rec) and MUP15/P5 (R = -0.77, P = .01). The reduction in MUP15/P5 tended to correlate with the increase in C(dyn,rs) (R = -0.49, P = .077) or in P(aO2) (R = -0.53, P = .05) between PEEP 15 cm H2O and PEEP 5 cm H2O. CONCLUSIONS: Digital chest x-ray done at the bedside in acute lung injury/ARDS subjects was able to detect a reduction in density between PEEP 5 cm H2O and PEEP 15 cm H2O, which correlated with V(rec). PMID- 23443283 TI - Evaluation of clinical and functional parameters in female subjects with biomass smoke exposure. AB - BACKGROUND: Indoor air pollution and exposure to biomass smoke is a risk factor for pulmonary diseases among women in developing countries. We aimed to assess clinical and functional findings and exposure duration and to evaluate their relationships in patients who used biomass products as fuel and who presented to the clinic due to respiratory symptoms. METHODS: Fifty-five patients who had been referred to the hospital between January 2008 and December 2010 and who met the inclusion criteria were accepted to the study. Data on the place they live, biomass exposure duration, lung function parameters, and arterial blood gases were recorded. RESULTS: Statistically significant differences in FEV(1)%, FEV1 (L) and, FEV(1)/FVC existed between the subgroups of duration of biomass exposure (P = .001). FEV(1)% and FEV(1)/FVC were highest in the < 30 hour-years exposure group. In the presence of animal dung use, the odds ratio and 95% CI for the risk of FEV(1)/FVC < 70% was 3.5 (0.88-10.29). Subjects who used animal dung and wood for cooking and heating had severe and very severe FEV(1) stages. CONCLUSIONS: Biomass exposure can have effects on lung function test parameters. Animal dung use is primarily related to risk of deterioration of FEV(1)/FVC, when compared to other biomass fuels. Protective health measures should be taken by assessing the risks in areas where biomass exposure is intense, improving poor design of the stoves and ventilation, and switching to better clean energy sources such as natural gas and solar energy. PMID- 23443284 TI - Physician-ordered aerosol therapy versus respiratory therapist-driven aerosol protocol: the effect on resource utilization. AB - BACKGROUND: The utilization of respiratory therapist (RT) driven protocols for single interventions, such as oxygen titration and bronchopulmonary hygiene, and protocols consisting of multiple interventions have been associated with improvements in resource utilization. Based on this, we started a quality improvement project to transition the delivery of respiratory care services from physician-ordered treatments to RT-driven protocols. During the first phase of our quality improvement project, we compared the frequency of bronchodilator administration and its associated costs, between a physician-ordered bronchodilator strategy and a RT-driven bronchodilator protocol strategy. METHODS: This was a retrospective analysis of prospectively collected data obtained during the initial phase of a quality improvement project. Over a period of 2 weeks, RTs administered physician-ordered bronchodilator treatments. During this time they assessed the subjects' clinical status and what they would have recommended in regard to bronchodilator treatment frequency following an RT driven protocol. RESULTS: Forty-eight subjects were ordered bronchodilator treatments, which resulted in 88 assessments. The utilization of a protocol would have resulted in 42 (47.7%) bronchodilator orders administered "every 6 hours, as needed," and 27 (30.6%) orders administered "every 8 hours," compared with 2 (2.2%) and 2 (2.2%), respectively, in the physician-ordered group (P < .001). Conversely, physician-ordered treatments were prescribed "every 4 hours" in 56 (63.6%) cases, compared with 10 (11.3%) in the RT-driven protocol group (P < .001). Total bronchodilator therapy cost in the physician-ordered group was $1,672.85, whereas it would have been $904.53 in the RT-driven one. Per patient costs were $19.0 +/- 6.9 in the physician-ordered group, and would have been $10.3 +/- 9.4 in the RT-driven bronchodilator protocol group (P < .001). CONCLUSIONS: The application of an RT-driven bronchodilator protocol can hypothetically reduce the frequency of bronchodilator treatments, compared with a physician-ordered strategy, resulting in a theoretical reduction of costs in patients who require bronchodilator therapy. PMID- 23443285 TI - Why do patients with interstitial lung diseases fail in the ICU? a 2-center cohort study. AB - BACKGROUND: Admitting patients with interstitial lung disease (ILD) to the ICU is controversial, due to their associated high mortality when they require invasive mechanical ventilation. We aimed to determine the risk factors for mortality in ILD patients requiring ICU support due to acute respiratory failure. METHODS: An observational cohort study was performed in 2 chest diseases teaching hospitals. We included all ILD patients with acute respiratory failure admitted between 2008 and 2010. Subject demographics, noninvasive ventilation (NIV) and invasive ventilation use, and mortality were obtained from medical records. Subjects receiving NIV were divided based on their continuous or non-continuous demand for NIV. NIV failure was defined as intubation for invasive ventilation, or death during NIV. Cox regression analysis was used to determine the hazard ratio for NIV failure. RESULTS: We enrolled 120 subjects: 71 male, median age 66 years. The types of ILD were idiopathic pulmonary fibrosis (n = 96), collagen vascular disease (n = 10), silicosis (n = 9), drug induced (n = 3), and eosinophilic pneumonia (n = 2). The median (IQR) Acute Physiology and Chronic Health Evaluation (APACHE II) score was 24 (19-31), and 75 (62.5%) subjects received NIV on ICU admission, 47 (62.7%) of whom needed continuous NIV. The NIV failure rate was 49.3% (n = 37). The mortality rates of continuous NIV, non-continuous NIV, invasive ventilation, and total ICU were 61.7% (29/47), 10.7% (3/28), 89.7% (61/68), 60% (72/120), respectively. APACHE II > 20 and continuous NIV demand indicated significant risk for NIV failure: hazard ratio 2.77 (95% CI 1.19-6.45), P < .02, and 5.12, (1.44-18.19), P < .01, respectively. CONCLUSIONS: Because of higher mortality, physicians should consider invasive ventilation cautiously in the ICU management of ILD patients with acute respiratory failure. NIV may be an option in less severely ill patients with APACHE II score < 20. PMID- 23443286 TI - Measurement of alveolar recruitment at the bedside: the beginning of a new era in respiratory monitoring? PMID- 23443287 TI - Of dung and dynein arms: understanding COPD in nonsmokers. PMID- 23443288 TI - Can respiratory therapist-driven protocols improve resource utilization? PMID- 23443289 TI - Effects of expiratory positive airway pressure on dynamic hyperinflation during exercise in patients with COPD. PMID- 23443290 TI - Humidification during noninvasive ventilation in the critically ill. PMID- 23443291 TI - Earwax type and osmidrosis: prognostic factor for breast cancer? PMID- 23443292 TI - Initiating therapeutic hypothermia during transport for encephalopathy: current state and future direction. PMID- 23443293 TI - U-500R and aspart insulin for the treatment of severe insulin resistance in pregnancy associated with pregestational diabetes. AB - Severe insulin resistance as a complication of diabetes in pregnancy is seen with increasing frequency. Treatment with large doses of insulin (>300 units perday) can be practically difficult. A woman with preexisting Type 2 diabetes mellitus and poor glycemic control presented in early pregnancy requiring over 1000 units of insulin daily. She was transitioned to subcutaneous U-500 (concentrated regular insulin) in combination with a rapid-acting insulin analog achieving good glycemic control and good maternal and fetal outcomes. U-500R insulin in conjunction with a rapid-acting insulin analog can be used safely in early pregnancy to improve glycemic control in severe insulin resistance due to pregestational diabetes. PMID- 23443294 TI - Neonatal asphyxia and renal failure as the presentation of non-inherited protein C deficiency. AB - Inherited or acquired protein C (PC) deficiency leads to thromboembolic events. Plasma PC activity in infancy is physiologically lower than in adults. We describe a case of neonatal asphyxia and acute renal failure associated with isolated PC deficiency. A full-term male infant was born to a healthy mother by caesarean section because of fetal distress. The small-for-gestational age infant showed 2 and 7 of Apgar scores at 1 and 5 minutes, respectively. Hypercoagulability required repeated infusions of fresh frozen plasma. Coagulation study revealed PC activity, 6%, protein S activity, 61%, and high D dimer levels, along with normal factor VII activity and absent vitamin K deficiency. Anticoagulant and activated PC therapy improved coagulopathy and nephropathy. Imaging analyses indicated no visceral infarctions. Renal function and PC activity have been slowly normalized until 6 months of age. He had no PROC mutation or PC-deficient parents. Selective PC deficiency may occur as an acquired cause of hypercoagulable crisis in the stressed newborn. PMID- 23443295 TI - A neonate with congenital amegakaryocytic thrombocytopenia associated with a chromosomal microdeletion at 21q22.11 including the gene RUNX1. AB - We observed a neonate who had severe thrombocytopenia wherein evaluations for neonatal immune-mediated thrombocytopenia and congenital infections were negative, and the marrow findings were consistent with congenital amegakaryocytic thrombocytopenia (CAMT). A genomic microarray identified a microdeletion at 21q22.11 including the gene RUNX1. Two somewhat similar cases were recently reported, but with multiple congenital anomalies that are not present in our case. We propose that a 21q22 deletion resulting in RUNX1 haploinsufficiency can produce a phenotype similar to CAMT with various associated anomalies depending on which adjacent genes are absent or disrupted. PMID- 23443296 TI - Klippel Feil syndrome with occipital encephalocele, duodenal web, left pelvic kidney, ASD, anorectal malformation fetal and postnatal imaging. PMID- 23443297 TI - Patent ductus arteriosus treatment in preterm infants-time to consider shunt volume? PMID- 23443298 TI - Reply to McNamara and Jain. PMID- 23443300 TI - High-resolution deep imaging of live cellular spheroids with light-sheet-based fluorescence microscopy. AB - Conventional two-dimensional cell monolayers do not provide the geometrical, biochemical and mechanical cues found in real tissues. Cells in real tissues interact through chemical and mechanical stimuli with adjacent cells and via the extracellular matrix. Such a highly interconnected communication network extends along all three dimensions. This architecture is lost in two-dimensional cultures. Therefore, at least in many cases, two-dimensional cell monolayers do not represent a suitable in vitro tool to characterize accurately the biology of real tissues. Many studies performed over the last few years have demonstrated that the differences between three-dimensional and two-dimensional cultured cells are striking at the morphological and molecular levels and that three-dimensional cell cultures can be employed in order to shrink the gap between real tissues and in vitro cell models. End-point and long-term imaging of cellular and sub cellular processes with fluorescence microscopy provides direct insight into the physiological behavior of three-dimensional cell cultures and their response to chemical or mechanical stimulation. Fluorescence imaging of three-dimensional cell cultures sets new challenges and imposes specific requirements concerning the choice of a suitable microscopy technique. Deep penetration into the specimen, high imaging speed and ultra-low intensity of the excitation light are key requirements. Light-sheet-based fluorescence microscopy (LSFM) offers a favorable combination of these requirements and is therefore currently established as the technique of choice for the study of three-dimensional cell cultures. This review illustrates the benefits of cellular spheroids in the life sciences and suggests that LSFM is essential for investigations of cellular and sub-cellular dynamic processes in three-dimensions over time and space. PMID- 23443301 TI - Hydrothermal fabrication of hierarchically anatase TiO2 nanowire arrays on FTO glass for dye-sensitized solar cells. AB - Hierarchical anatase TiO(2) nano-architecture arrays consisting of long TiO(2) nanowire trunk and numerous short TiO(2) nanorod branches on transparent conductive fluorine-doped tin oxide glass are successfully synthesized for the first time through a facile one-step hydrothermal route without any surfactant and template. Dye-sensitized solar cells based on the hierarchical anatase TiO(2) nano-architecture array photoelectrode of 18 MUm in length shows a power conversion efficiency of 7.34% because of its higher specific surface area for adsorbing more dye molecules and superior light scattering capacity for boosting the light-harvesting efficiency. The present photovoltaic performance is the highest value for the reported TiO(2) nanowires array photoelectrode. PMID- 23443302 TI - Frequency and time-frequency analysis of intraoperative ECoG during awake brain stimulation. AB - Electrocortical stimulation remains the standard for functional brain mapping of eloquent areas to prevent postoperative functional deficits. The aim of this study was to investigate whether the short-train technique (monopolar stimulation) and Penfield's technique (bipolar stimulation) would induce different effects on brain oscillatory activity in awake patients, as quantified by electrocorticography (ECoG). The study population was seven patients undergoing brain tumor surgery. Intraoperative bipolar and monopolar electrical stimulation for cortical mapping was performed during awake surgery. ECoG was recorded using 1 * 8 electrode strip. Spectral estimation was calculated using a parametric approach based on an autoregressive model. Wavelet-based time frequency analysis was then applied to evaluate the temporal evolution of brain oscillatory activity. Both monopolar and bipolar stimulation produced an increment in delta and a decrease in beta powers for the motor and the sensory channels. These phenomena lasted about 4 s. Comparison between monopolar and bipolar stimulation showed no significant difference in brain activity. Given the importance of quantitative signal analysis for evaluating response accuracy, ECoG recording during electrical stimulation is necessary to characterize the dynamic processes underlying changes in cortical responses in vivo. This study is a preliminary approach to the quantitative analysis of post-stimulation ECoG signals. PMID- 23443303 TI - Colorectal cancer screening in human immunodeficiency virus population: Are they at average risk? AB - AIM: To evaluate if human immunodeficiency virus (HIV) population is getting adequate screening for colon cancer in the highly active anti-retroviral treatment (HAART) era with improved longevity, and the prevalence of polyps and adenomas in this population, when compared with the general population. METHODS: We conducted retrospective chart review of average-risk HIV population for colon cancer attending our infectious disease clinic. Individuals who underwent diagnostic colonoscopy were excluded. We extracted various demographic, HIV disease-specific and colonoscopy data including histo-pathological reports in the last 10 years. Total population was divided into a study group, who underwent screening colonoscopy and a control group who did not. We analyzed data using standard statistical methods and software. RESULTS: We found that 25% of average risk HIV-infected population was screened for colon cancer using colonoscopy. There was no difference in gender and ethnic distribution between the groups. We found wider distribution of age (50-84 years with mean 56 years) in the control group when compared to (50-73 years with mean 58 years) the study group. However, there were 89% of subjects with well-controlled HIV disease measured by HIV RNA copies of < 75 in the study group when compared with 70% in the control group (P < 0.0001). We noticed polyp detection rate of 55% and adenoma detection rate of 32% in HIV population. CONCLUSION: It is unclear whether HIV or HAART medications play a role in increased prevalence of adenomas. We suggest that when estimating the risk for colonic neoplasms, HIV population should be considered as a high risk group and screened accordingly. PMID- 23443304 TI - Biological evaluation of 9-[(6-chloropyridin-4-yl)methyl]-9H-carbazole-3-carbinol as an anticancer agent. AB - Most conventional anticancer drugs exert either anti-proliferation or anti angiogenesis activity. Recently, searching for potential multi-target agents has become an alternative strategy for cancer treatment. Several structurally different carbazole alkaloids from either natural or synthesized sources represent an important and heterogeneous class of anticancer agents. In the present study, we investigated the anticancer activity of a novel synthetic carbazole derivative, 9-[(6-chloropyridin-4-yl)methyl]-9H-carbazole-3-carbinol (HYL-6d), which is structurally different from other previously characterized carbazoles. HYL-6d-treated human breast cancer MCF-7 cells exhibited an increased population arrested at the sub-G1 and S phases, as well as an increase of p53 and decrease of cyclin D1, A and CDK2. Also, HYL-6d treatment induced MCF-7 cell apoptosis and this was accompanied by a decreased expression of Bcl-2, increased levels of p53 and Bcl-XS and the activation of caspase-9. Experimental results from human umbilical vascular endothelial cells (HUVECs) showed that HYL-6d also exerted its anti-angiogenic activity in HUVECs by inhibiting cell proliferation, migration, and tube formation induced by VEGF- or bFGF in vitro. In summary, the data indicate that HYL-6d exhibits both cytotoxic effects against human cancer cells and anti-angiogenic activities, which make it a potential therapeutic drug for cancer treatment. PMID- 23443305 TI - Is the emotion-health connection a "first-world problem"? AB - Emotions have been shown to play a critical role in health outcomes, but research on this topic has been limited to studies in industrialized countries, which prevents broad generalizations. This study assessed whether emotion-health connections persist across various regions, including less-developed countries, where the degree to which people's fundamental needs are met might be a better predictor of physical well-being. Individuals from 142 countries (N = 150,048) were surveyed about their emotions, health, hunger, shelter, and threats to safety. Both positive and negative emotions exhibited unique, moderate effects on self-reported health, and together, they accounted for 46.1% of the variance. These associations were stronger than the relative impact of hunger, homelessness, and threats to safety and were not simply attributable to countries' gross domestic products (GDPs). Furthermore, connections between positive emotion and health were stronger in low-GDP countries than in high-GDP countries. Our findings suggest that emotion matters for health around the globe and may in fact be more critical in less-developed areas. PMID- 23443307 TI - PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. AB - The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes, and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts. This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation, or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies. Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations. This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, the cross-talk between them, and the current generation of PI3K and MEK inhibitors that target them. The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials, namely malignant melanoma with BRAF or NRAS mutations, and colorectal, ovarian, pancreatic, and basal-like breast cancers. The emerging clinical profile of PI3K and MEK inhibitor combinations, as reported in Phase I trials, will also be discussed. PMID- 23443308 TI - Dodging a dogma: is treating beyond progression beneficial? PMID- 23443309 TI - Formation and decay of a compressed phase of 4,4'-biphenyldicarboxylic acid on Cu(001). AB - The molecular arrangement of 4,4'-biphenyldicarboxylic acid (BDA) on Cu(001) has been studied at high coverage and relatively high temperature (~400 K) using Low Energy Electron Microscopy, LEEM, and selected area diffraction, MULEED. Next to the previously reported c(8 * 8) structure, we also observe a compressed phase with a [structure: see text] superstructure in matrix notation. All four equivalent (rotational and mirror) domains are equally populated. Both the c(8 * 8) and the compressed phase are confined to the first layer and the latter has a 14% higher density compared to the c(8 * 8) phase. Remarkably, this compressed phase is stable only during deposition and decays after interruption of the deposition. Apparently, the density of physisorbed admolecules on top of the c(8 * 8) layer has to be above a relevant threshold to allow the formation of the compressed phase. PMID- 23443310 TI - Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique. PMID- 23443312 TI - Cardiopulmonary instability evoked by exaggerated Chilaiditi syndrome. PMID- 23443313 TI - Unravelling the labyrinth of palladium-catalysed reactions involving isocyanides. AB - Isocyanides possess a rich history in the world of synthetic chemistry. Recently the scope of this already versatile class of reagent has been expanded into its use in palladium-catalysed cascade sequences. The scope of this type of reaction is explored in depth and this tutorial review focuses on its various applications in chemical synthesis, and the wide range of systems that can be efficiently prepared using this strategy are documented. PMID- 23443311 TI - Choice of renal replacement therapy modality and dialysis dependence after acute kidney injury: a systematic review and meta-analysis. AB - PURPOSE: Choice of renal replacement therapy (RRT) modality may affect renal recovery after acute kidney injury (AKI). We sought to compare the rate of dialysis dependence among severe AKI survivors according to the choice of initial renal replacement therapy (RRT) modality applied [continuous (CRRT) or intermittent (IRRT)]. METHODS: Systematic searches of peer-reviewed publications in MEDLINE and EMBASE were performed (last update July 2012). All studies published after 2000 reporting dialysis dependence among survivors from severe AKI requiring RRT were included. Data on follow-up duration, sex, age, chronic kidney disease, illness severity score, vasopressors, and mechanical ventilation were extracted when available. Results were pooled using a random-effects model. RESULTS: We identified 23 studies: seven randomized controlled trials (RCTs) and 16 observational studies involving 472 and 3,499 survivors, respectively. Pooled analyses of RCTs showed no difference in the rate of dialysis dependence among survivors (relative risk, RR 1.15 [95 % confidence interval (CI) 0.78-1.68], I(2) = 0 %). However, pooled analyses of observational studies suggested a higher rate of dialysis dependence among survivors who initially received IRRT as compared with CRRT (RR 1.99 [95 % CI 1.53-2.59], I (2) = 42 %). These findings were consistent with adjusted analyses (performed in 7/16 studies), which found a higher rate of dialysis dependence in IRRT-treated patients [odds ratio (OR) 2.2 25 (5 studies)] or no difference (2 studies). CONCLUSIONS: Among AKI survivors, initial treatment with IRRT might be associated with higher rates of dialysis dependence than CRRT. However, this finding largely relies on data from observational trials, potentially subject to allocation bias, hence further high quality studies are necessary. PMID- 23443314 TI - Advanced microscopy of star-shaped gold nanoparticles and their adsorption-uptake by macrophages. AB - Metallic nanoparticles have diverse applications in biomedicine, as diagnostics, image contrast agents, nanosensors and drug delivery systems. Anisotropic metallic nanoparticles possess potential applications in cell imaging and therapy + diagnostics (theranostics), but controlled synthesis and growth of these anisotropic or branched nanostructures has been challenging and usually require use of high concentrations of surfactants. Star-shaped gold nanoparticles were synthesized in high yield through a seed mediated route using HEPES as a precise shape-directing capping agent. Characterization was performed using advanced electron microscopy techniques including atomic resolution TEM, obtaining a detailed characterization of nanostructure and atomic arrangement. Spectroscopy techniques showed that the particles have narrow size distribution, monodispersity and high colloidal stability, with absorbance into NIR region and high efficiency for SERS applications. Gold nanostars showed to be biocompatible and efficiently adsorbed and internalized by macrophages, as revealed by advanced FE-SEM and backscattered electron imaging techniques of complete unstained uncoated cells. Additionally, low voltage STEM and X-ray microanalysis revealed the ultra-structural location and confirmed stability of nanoparticles after endocytosis with high spatial resolution. PMID- 23443315 TI - The effect of music video clips on adolescent boys' body image, mood, and schema activation. AB - There is limited research that has examined experimentally the effects of muscular images on adolescent boys' body image, with no research specifically examining the effects of music television. The aim of the current study was to examine the effects of viewing muscular and attractive singers in music video clips on early, mid, and late adolescent boys' body image, mood, and schema activation. Participants were 180 boys in grade 7 (mean age = 12.73 years), grade 9 (mean age = 14.40 years) or grade 11 (mean age = 16.15 years) who completed pre and post-test measures of mood and body satisfaction after viewing music videos containing male singers of muscular or average appearance. They also completed measures of schema activation and social comparison after viewing the clips. The results showed that the boys who viewed the muscular clips reported poorer upper body satisfaction, lower appearance satisfaction, lower happiness, and more depressive feelings compared to boys who viewed the clips depicting singers of average appearance. There was no evidence of increased appearance schema activation but the boys who viewed the muscular clips did report higher levels of social comparison to the singers. The results suggest that music video clips are a powerful form of media in conveying information about the male ideal body shape and that negative effects are found in boys as young as 12 years. PMID- 23443316 TI - Suppression of AKT phosphorylation restores rapamycin-based synthetic lethality in SMAD4-defective pancreatic cancer cells. AB - mTOR has been implicated in survival signals for many human cancers. Rapamycin and TGF-beta synergistically induce G1 cell-cycle arrest in several cell lines with intact TGF-beta signaling pathway, which protects cells from the apoptotic effects of rapamycin during S-phase of the cell cycle. Thus, rapamycin is cytostatic in the presence of serum/TGF-beta and cytotoxic in the absence of serum. However, if TGF-beta signaling is defective, rapamycin induced apoptosis in both the presence and absence of serum/TGF-beta in colon and breast cancer cell lines. Because genetic dysregulation of TGF-beta signaling is commonly observed in pancreatic cancers-with defects in the Smad4 gene being most prevalent, we hypothesized that pancreatic cancers would display a synthetic lethality to rapamycin in the presence of serum/TGF-beta. We report here that Smad4-deficient pancreatic cancer cells are killed by rapamycin in the absence of serum; however, in the presence of serum, we did not observe the predicted synthetic lethality with rapamycin. Rapamycin also induced elevated phosphorylation of the survival kinase Akt at Ser473. Suppression of rapamycin induced Akt phosphorylation restored rapamycin sensitivity in Smad4-null, but not Smad4 wild-type pancreatic cancer cells. This study shows that the synthetic lethality to rapamycin in pancreatic cancers with defective TGF-beta signaling is masked by rapamycin-induced increases in Akt phosphorylation. The implication is that a combination of approaches that suppress both Akt phosphorylation and mTOR could be effective in targeting pancreatic cancers with defective TGF-beta signaling. PMID- 23443318 TI - Conservative management for an entero-adnexal fistula at initial presentation of advanced ovarian carcinoma. AB - Gastrointestinal fistulae can occur in ovarian cancer patients, usually in the setting of advanced relapsed disease. Treatment typically involves immediate surgery.Here, we describe a case of an abscess resulting from an intestinal fistula as the first manifestation of advanced epithelial ovarian cancer, and we review the current literature on this subject. The patient was successfully treated with a combination of chemotherapy, antibiotics, and delayed surgery. Optimal debulking was achieved without a need for bowel resection.This report is the first of conservative management of a fistula in an ovarian cancer patient in the chemotherapy-naive setting. PMID- 23443317 TI - Molecular hierarchy of heparin-binding EGF-like growth factor-regulated angiogenesis in triple-negative breast cancer. AB - Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple negative breast cancer (TNBC). However, the role of HB-EGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under two-dimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor 1alpha and NF-kappaB. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis. PMID- 23443319 TI - Physical exercise and return to work: cancer survivors' experiences. AB - PURPOSE: In this qualitative study, we aimed to explore cancer survivors' experiences with (1) return to work (RtW) and work performance, (2) a physical exercise program after treatment, and (3) the perceived link between physical exercise and work. METHODS: Semi-structured individual interviews were held with ten cancer survivors of working age who had been treated with chemotherapy and had afterwards completed a group-based supervised physical exercise program. The interviews were audio-taped and transcribed verbatim. MaxQDA was used for coding and analysis. A second assessor was involved in coding two of the interviews. RESULTS: Eight participants returned to work. Most said that they had suffered cognitive deficits that impaired their work performance. According to half of the participants, the support in RtW from their occupational physician had been insufficient. Overall, the majority of participants enjoyed the exercise program. The main perceived effects were "improved fitness" and "renewed energy." Most participants thought that physical exercise had likely contributed to their ability to return to work, primarily by increasing energy levels. Some believed that physical exercise had enhanced their work performance by improving their ability to cope with demanding work. Some respondents found that a supportive work environment stimulated their continuation of physical exercise. CONCLUSIONS: Cancer survivors experienced a positive influence of physical exercise on RtW and work performance and a positive influence of RtW on physical exercise. By stimulating and facilitating physical exercise during and after RtW, the time to lasting RtW may be shortened, work performance may be optimized, and sustained participation in physical exercise may be achieved. IMPLICATIONS FOR CANCER SURVIVORS: Stimulating and facilitating physical exercise before and during the process of RtW may enhance fitness and energy levels and may lower fatigue and cognitive symptoms during work. An integrated rehabilitation strategy combining physical exercise and adequate support in RtW may shorten the time to lasting RtW, improve work performance, and lead to sustained participation in physical exercise. Ultimately, this strategy may improve cancer survivors' quality of life. PMID- 23443320 TI - Allergy and brain tumors in the INTERPHONE study: pooled results from Australia, Canada, France, Israel, and New Zealand. AB - PURPOSE: A history of allergy has been inversely associated with several types of cancer although the evidence is not entirely consistent. We examined the association between allergy history and risk of glioma, meningioma, acoustic neuroma, and parotid gland tumors using data on a large number of cases and controls from five INTERPHONE study countries (Australia, Canada, France, Israel, New Zealand), to better understand potential sources of bias in brain tumor case control studies and to examine associations between allergy and tumor sites where few studies exist. METHODS: A total of 793 glioma, 832 meningioma, 394 acoustic neuroma, and 84 parotid gland tumor cases were analyzed with 2,520 controls recruited during 2000-2004. Conditional logistic regression models were used to obtain odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between self-reported allergy and tumor risk. RESULTS: A significant inverse association was observed between a history of any allergy and glioma (OR = 0.73, 95 % CI 0.60-0.88), meningioma (OR = 0.77, 95 % CI 0.63-0.93), and acoustic neuroma (OR = 0.64, 95 % CI 0.49-0.83). Inverse associations were also observed with specific allergic conditions. However, inverse associations with asthma and hay fever strengthened with increasing age of allergy onset and weakened with longer time since onset. No overall association was observed for parotid gland tumors (OR = 1.21, 95 % CI 0.73-2.02). CONCLUSIONS: While allergy history might influence glioma, meningioma, and acoustic neuroma risk, the observed associations could be due to information or selection bias or reverse causality. PMID- 23443321 TI - Association between allergies, asthma, and breast cancer risk among women in Ontario, Canada. AB - PURPOSE: To investigate the association between allergies, asthma, and breast cancer risk in a large, population-based case-control study. METHODS: Breast cancer cases (n = 3,101) were identified using the Ontario Cancer Registry and population controls (n = 3,471) through random digit dialing. Self-reported histories of allergies, hay fever, and asthma were collected by questionnaire. Logistic regression was used to assess associations between breast cancer risk and history of allergy/hay fever and asthma, with 16 possible confounders examined. Analyses were stratified by menopausal status. RESULTS: A history of allergies or hay fever was associated with a small reduction in breast cancer risk [age-adjusted odds ratio (AOR) = 0.86, 95 % confidence interval (CI) 0.77 0.96] and did not differ by menopausal status. Asthma was not associated with breast cancer risk overall; however, among premenopausal women, asthma was associated with a reduced risk of breast cancer (AOR = 0.72, 95 % CI 0.54-0.97). CONCLUSIONS: A history of allergies may be associated with a modest reduction in breast cancer risk. Asthma does not appear to be associated with breast cancer risk overall; however, asthma may be associated with reduced breast cancer risk among premenopausal women. PMID- 23443325 TI - Conducting polymer composite film incorporated with aligned carbon nanotubes for transparent, flexible and efficient supercapacitor. AB - Polyaniline composite films incorporated with aligned multi-walled carbon nanotubes (MWCNTs) are synthesized through an easy electrodeposition process. These robust and electrically conductive films are found to function as effective electrodes to fabricate transparent and flexible supercapacitors with a maximum specific capacitance of 233 F/g at a current density of 1 A/g. It is 36 times of bare MWCNT sheet, 23 times of pure polyaniline and 3 times of randomly dispersed MWCNT/polyaniline film under the same conditions. The novel supercapacitors also show a high cyclic stability. PMID- 23443326 TI - A heart transplant candidate with severe pulmonary hypertension and extremely high pulmonary vascular resistance. AB - Fixed pulmonary hypertension (PH) is a contraindication for heart transplantation (HTx). Several studies showed that use of a left ventricular assist device (LVAD) in patients with fixed PH who were initially deemed ineligible for HTx effectively decreased pulmonary arterial pressure (PAP), thus permitting HTx. We recently encountered a candidate for HTx who had severe PH with extremely high pulmonary vascular resistance (PVR). A 27-year-old female who had been diagnosed with dilated-phase hypertrophic cardiomyopathy and who was approved for HTx at age 25 was referred to our institute because of severe fatigability with moderate dyspnea even at rest due to severe bilateral heart failure. Despite continuous inotrope infusion, the patient's symptoms were not relieved. Right heart catheterization (RHC) disclosed a PAP of 62/40 mmHg with severely reduced cardiac output (1.8 l/min). A PVR of 15.9 Wood units suggested progressive worsening of left ventricular function with almost irreversible remodeling of the pulmonary vasculature, and the patient was thought to be contraindicated for HTx. Following 3 weeks of aggressive medical treatment, repeat RHC demonstrated PVR lowering to 8.16 Wood units. This suggested it was likely that PVR could be reversed, and the patient underwent LVAD implantation. RHC performed after LVAD implantation showed a fall in PVR from the initial, extremely high measurement of 15.9 Wood units to 3.4 Wood units at 2 months postoperatively, and to 2.2 Wood units at 1 year. The patient is currently awaiting HTx with favorable LVAD support. PMID- 23443328 TI - Which systematic review should we follow? PMID- 23443327 TI - A possible contribution of visfatin to the resolution of skin sclerosis in patients with diffuse cutaneous systemic sclerosis via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response. AB - OBJECTIVE: Visfatin is a member of the adipocytokines with pro-fibrotic, pro inflammatory and immunomodulating properties potentially implicated in the pathogenesis of certain fibrotic and inflammatory autoimmune diseases. In this study, we investigated THE CLINICAL SIGNIFICANCE OF SERUM VISFATIN LEVELS AND ITS CONTRIBUTION TO THE DEVELOPMENTAL PROCESS IN SSC. METHODS: Serum visfatin levels were determined by a specific ELISA in 57 SSc patients and 19 healthy controls. The mRNA levels of target genes were determined in normal and SSc fibroblasts by real-time RT-PCR. The levels of IL-12p70 produced by THP-1 cells were measured by a specific ELISA. RESULTS: Serum visfatin levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc and healthy controls. The only finding in a series of analyses regarding the correlation of serum visfatin levels with clinical symptoms and laboratory data was the significantly longer disease duration in dcSSc with elevated serum visfatin levels than in those with normal levels. Consistently, serum visfatin levels were significantly elevated in late-stage dcSSc (disease duration >6 years), but not in early and mid-stage dcSSc compared with healthy controls. In in vitro experiments, visfatin reversed the pro-fibrotic phenotype of SSc dermal fibroblasts and induced the expression of IL-12p70 in THP-1 cells treated with IFN-gamma plus lipopolysaccharide. CONCLUSION: Visfatin may contribute to the resolution of skin sclerosis in late stage dcSSc via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response. PMID- 23443329 TI - Crude saponins from Platycodon grandiflorum induce apoptotic cell death in RC 58T/h/SA#4 prostate cancer cells through the activation of caspase cascades and apoptosis-inducing factor. AB - Saponins are a major active component of Platycodon grandiflorum (P. grandiflorum) and are known to induce apoptosis in metastatic prostate cancer cell lines. However, thus far, no research has been conducted on the anticancer activity of saponins in RC-58T/h/SA#4 primary prostate cancer cells. In this study, we show that the treatment of prostate cancer cells with saponins extracted from P. grandiflorum (SPG) inhibits cell proliferation in a dose dependent manner. SPG significantly induced apoptotic cell death, resulting in an increase in the sub-G1 apoptotic cell population, apoptotic DNA fragmentation and morphological changes. Pre-treatment with a caspase inhibitor modestly attenuated the SPG-induced increase in the sub-G1 cell population, suggesting that caspases play a role in SPG-induced apoptosis. Moreover, SPG-induced apoptosis was associated with changes in caspase activity, the upregulation of the apoptotic protein, Bax and the downregulation of the anti-apoptotic protein, Bcl-2. Furthermore, the caspase-independent mitochondrial apoptosis factor, apoptosis inducing factor (AIF) was upregulated following SPG treatment. These findings indicate that SPG exerts its anticancer effects on RC-58T/h/SA#4 primary prostate cancer cells through mitochondrial caspase-dependent and -independent apoptotic pathways. PMID- 23443330 TI - Postarthroscopy osteonecrosis of the knee. AB - PURPOSE: Spontaneous subchondral osteonecrosis of the knee joint confined to a localized area of one condyle can occur after arthroscopic procedures. Meniscal tears, arthroscopic meniscectomy, and radiofrequency chondroplasty are aetiological factors in the development of osteonecrosis. The aim of this study was to investigate whether the incidence of osteonecrosis increased when mechanical or radiofrequency chondroplasty was used in conjunction with arthroscopic meniscectomy. METHODS: In this prospective clinical trial, arthroscopic meniscectomy was the primary treatment in 75 patients (mean age 40 +/- 13) with stage II and III degenerative changes on the articular cartilage. Patients had to meet the following criteria: 1) have preoperative MRI and plain film radiographs showing no evidence of osteonecrosis; 2) be symptomatic for at least 6 weeks before the preoperative MRI; and 3) have arthroscopically confirmed stage II or III chondral lesion. A preoperative MRI was performed for all patients. For treatment of chondral lesions, debridement with a shaver or chondroplasty with a monopolar RF energy system was used. Patients were divided into three treatment groups. Partial meniscectomy of the medial or lateral (or both) menisci was performed on all patients, but patients in group 2 additionally received mechanical debridement of the chondral lesion, and those in group 3 were additionally treated with RF chondroplasty. Patients in group 1 were treated with partial meniscectomy alone. Patients were re-examined after 6 months, at which time a repeat MRI was performed. RESULTS: Development of osteonecrosis was detected during the postoperative MRIs of five patients: two in group 1, two in group 2, and one in group 3. CONCLUSION: The addition of mechanical or RF chondroplasty to meniscectomy did not increase the number of patients with osteonecrosis. Also, RF chondroplasty, which is commonly proposed to be an aetiological factor, resulted in a decrease in the number of patients that developed osteonecrosis. LEVEL OF EVIDENCE: II. PMID- 23443331 TI - Shared epitope and radiologic progression are less prominent in elderly onset RA than young onset RA. AB - The aim of this study was to determine the influence of HLA-DRB1 and HLA-DQB1 genes on the disease susceptibility and the disease severity in elderly onset rheumatoid arthritis (EORA) compared with young onset rheumatoid arthritis (YORA) in Korean patients. Genetic analysis of HLA-DRB1 and HLA-DQB1 alleles was performed in three groups. Group 1 included 63 patients who were diagnosed with (rheumatoid arthritis) RA after the age of 60 (EORA). Group 2 consisted of 109 patients who were diagnosed with RA before the age of 60 (YORA). Group 3 involved 133 normal controls. The shared-epitope-coding alleles included the members of the HLA-DRB1*04 allele group (*0401, *0404, *0405, *0408, *0410), HLA-DRB1*01 allele group (*0101,*0102), HLA-DRB1*1001, and HLA-DRB1*1402. The disease severity was assessed by the modified total sharp score (mTSS). The shared epitope-coding alleles were more frequently observed in the RA patients than in the normal controls. The shared-epitope-coding alleles were less frequently found in EORA group than YORA group (31/63 (49.2%) in group 1, 72/109 (66.1%) in group 2, 45/133 (33.8%) group 3, p = 0.02). Although the mTSS of the group 1 was higher than group 2 at symptom onset, the overall mean mTSS of the group 1 was lower than that of group 2 (26.8 vs. 57.5, p < 0.05). HLA-DQ*04 showed the higher frequency in the patients group than in normal controls (p < 0.001). And HLA DQ*04 was less commonly found in the patients with EORA than YORA (p < 0.05). The influence of shared epitope and HLA-DQ*04 alleles may be less significant on disease susceptibility in EORA. The presence of shared-epitope-coding alleles did not appear to influence on disease severity in EORA patients as well as in YORA patients. Radiologic deterioration in EORA group was less severe than in YORA group. The presence of shared epitope and radiologic progression are less prominent in EORA patients than YORA patients. PMID- 23443332 TI - Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment. AB - The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). Little is known about the influence of exercise on the skeletal muscle matrix that supports joints affected by OA mainly when it is associated with medication taken by OA patients (non-steroid anti-inflammatory drugs (NSAID) and glucosamine). A biopsy was collected from the vastus lateralis muscle in all patients before and after 12-week period of training. The patients (age 55-69 years) were divided into three groups, treated with NSAID, glucosamine or placebo. In addition, the muscle samples were analysed by immunohistochemistry for collagen types, RAGE and capillaries ratio. An increment in immunoreactivity for type IV collagen after the training period was observed in 72 % of all biopsies when compared with their respective baseline samples. Reduced immunoreactivity of collagen type I was observed in all patients treated with glucosamine. A significant increase with training in the amount of RAGE was detected in the placebo group only (p < 0.05). Comparison of post-treatment states indicated significant differences between the placebo and glucosamine group data, demonstrating increased levels in the placebo group (p < 0.05). These findings suggest a basement membrane remodelling in favour of a strengthened extracellular matrix surrounding individual muscle fibres after 12 weeks of resistance training. Glucosamine with training appeared to attenuate RAGE accumulation more than was seen with NSAID or placebo in skeletal muscle of OA patients. PMID- 23443333 TI - A framework for understanding grocery purchasing in a low-income urban environment. AB - Research demonstrates that food desert environments limit low-income shoppers' ability to purchase healthy foods, thereby increasing their likelihood of diet related illnesses. We sought to understand how individuals in an urban American food desert make grocery-purchasing decisions, and specifically why unhealthy purchases arise. Analysis is based on ethnographic data from participant observation, 37 in-depth interviews, and three focus groups with low-income, primarily African American shoppers with children. We found participants had detailed knowledge of and preference for healthy foods, but the obligation to consistently provide food for their families required them to apply specific decision criteria which, combined with structural qualities of the supermarket environment, increased unhealthy purchases and decreased healthy purchases. Applying situated cognition theory, we constructed an emic model explaining this widely shared grocery-purchasing decision process and its implications. This context-specific understanding of behavior suggests that multifaceted, system level approaches to intervention are needed to increase healthy purchasing in food deserts. PMID- 23443334 TI - Low temperature synthesis of ordered mesoporous stable anatase nanocrystals: the phosphorus dendrimer approach. AB - The scarcity of low temperature syntheses of anatase nanocrystals prompted us to explore the use of surface-reactive fourth generation phosphorus-dendrimers as molds to control the nucleation and growth of titanium-oxo-species during the sol gel mineralization process. Unexpectedly, the dendritic medium provides at low temperature, discrete anatase nanocrystals (4.8 to 5.2 nm in size), in marked contrast to the routinely obtained amorphous titanium dioxide phase under standard conditions. Upon thermal treatment, heteroatom migration from the branches to the nanoparticle surface and the ring opening polymerization of the cyclophosphazene core provide stable, interpenetrating mesoporous polyphosphazene anatase hybrid materials (-P[double bond, length as m-dash]N-)n-TiO2. The steric hindrance of the dendritic skeleton, the passivation of the anatase surface by heteroatoms and the ring opening of the core limit the crystal growth of anatase to 7.4 nm and prevent, up to 800 degrees C, the commonly observed anatase-to rutile phase transformation. Performing this mineralization in the presence of similar surface-reactive but non-dendritic skeletons (referred to as branch mimicking dendrimers) failed to generate crystalline anatase and to efficiently limit the crystal growth, bringing thus clear evidence of the virtues of phosphorus dendrimers in the design of novel nanostructured materials. PMID- 23443335 TI - Energetic performances of the metal-organic framework ZIF-8 obtained using high pressure water intrusion-extrusion experiments. AB - The "ZIF-8-water" system displays reproducible shock-absorber behaviour over several cycles with a stored energy of 13.3 J g(-1) and an energy yield close to 85%. The combination of the main features evidenced for ZIF-8, i.e. a quite low intrusion pressure and a high stored energy, opens a field for new applications. PMID- 23443336 TI - Major vascular involvement in Behcet's disease: a retrospective study of 796 patients. AB - Behcet's disease (BD) is a multi-systemic inflammatory disorder which can affect all types and sizes of blood vessels. This study aims to evaluate the prevalence and characteristics of vascular involvement in BD. Among 796 patients diagnosed with BD, 102 patients (81 male, 21 female) with vascular involvement were included, whose detailed clinical characteristics were recorded. The diagnosis of vascular lesions was made on clinical signs, by Doppler ultrasonography, and/or angiography using computed tomographic or magnetic resonance techniques. Vascular involvement occurred in 12.8 % of BD patients. Male to female ratio was 3.86:1. Mean age at onset of vascular involvement was 29.5 +/- 11.3 years. Vascular lesion was the initial sign of BD in 28 patients, accounting for 27.5 %. Of 102 BD patients with vascular involvement, 72 had venous lesions (70.6 %) and 56 had arterial lesions (54.9 %), among which 26 (25.5 %) patients had both venous and arterial involvements. Female BD patients were more often involved with arterial lesions, whereas male BD patients developed venous lesions more often than females, P = 0.000. The most common type of vascular involvement was deep venous thrombosis in lower extremities (n = 49), other affected venous sites including inferior vena cava, superior vena cava, and cerebral venous. The prominent type of arterial lesions was dilatation (n = 25, including 24 cases of aneurysms); other types included eight cases of occlusion and 23 cases of stenosis. The main locations of arterial lesions were the aorta (n = 19), lower extremity arteries (n = 15), pulmonary arteries (n = 13), coronary arteries (n = 5), and subclavian arteries (n = 5). Compared with those without vascular lesions, ocular involvement, genital ulcers, and arthritis were significantly less frequent among patients with vasculo-BD (23.5 vs 35.2 %, P = 0.024; 54.9 vs 76.5 %, P = 0.000; 19.6 vs 30.5 %, P = 0.026), whereas a higher frequency of cardiac involvement was found in vasculo-BD patients (20.6 vs 3.6 %, P = 0.000). Vascular involvement is a complication in BD patients. This study illustrated that venous lesions are more frequently involved than arterial lesions. Vascular lesions correlated with a high frequency of cardiac involvement and a low incidence of ocular lesions, genital ulcers, and arthritis. PMID- 23443337 TI - The prevalence of fibromyalgia and its relation with headache characteristics in episodic migraine. AB - The objective of this study was to assess the prevalence of fibromyalgia (FM) in patients with episodic migraine and to evaluate the relationship between migraine characteristics and FM. One hundred and eighteen consecutive patients (mean age = 38 years, 75% women) fulfilling the International Classification of Headache Disorders-II criteria for migraine with (n = 22) and without (n = 96) aura from an outpatient headache clinic of a university hospital were evaluated. The diagnosis of FM was made based on the 1990 American College of Rheumatology classification criteria. Participants completed some self-administered questionnaires ascertaining sociodemographics, headache severity, frequency and duration, headache-related disability (Headache Impact Test [HIT-6]) and Migraine Disability Assessment Scale, widespread musculoskeletal pain (visual analog scale), depression (Beck depression inventory), anxiety (Beck anxiety inventory), sleep quality (Pittsburgh Sleep Quality Index), fatigue (Multidimensional Assessment of Fatigue), and quality of life (Short Form-36 Health Survey [SF 36]). In patients with FM, the tender point count and the Fibromyalgia Impact Questionnaire were employed. FM was diagnosed in 37 (31.4%) of the patients. FM comorbidity was equally distributed across patients with and without aura. Severity of migraine headache, HIT-6, and anxiety were especially associated with FM comorbidity. Patients suffering from migraine plus FM reported lower scores on all items of the SF-36. This study indicates that the assessment and management of coexisting FM should be taken into account in the assessment and management of migraine, particularly when headache is severe or patients suffer from widespread musculoskeletal pain. PMID- 23443338 TI - Anomalous great cardiac vein draining into the right atrium combined with a single left coronary artery. AB - In contrast to the coronary arterial system, little attention has been paid to the coronary venous system in previous literature. We report a rare case of a combined anomaly of the coronary artery and the great cardiac vein (GCV). In this patient, the right coronary artery (RCA) arose from the left coronary artery, and the GCV drained directly into the right atrium. The anomalous RCA and GCV ran parallel courses along the anterior side of the right ventricular outflow tract. We briefly review the clinical significance and the role of cardiac computed tomography in this anomaly. PMID- 23443339 TI - Changes in CT angiographic opacification of porcine coronary artery wall with patchy altered flow in vasa vasorum. AB - To evaluate the potential of whole-body CT to detect localized areas of decreased or increased vascularity in coronary arterial walls. We used both microsphere embolization of coronary artery vasa vasorum to generate small areas of hypoperfusion and surrounding hyperperfusion of the arterial wall and diet induced hypercholesterolemia. As a stimulus for localized angiogenesis, such as occurs in early plaque formation in the coronary arterial wall, microspheres were injected selectively into the LAD coronary artery lumens of anesthetized pigs. Fourteen pigs (acute) then had a segment of their LAD harvested during injection of contrast medium and snap-frozen for subsequent cryo-static micro-CT. An additional thirteen pigs (chronic) were allowed to recover, fed a high cholesterol diet and 3 months later were again anesthetized and a segment of the LAD artery harvested and scanned. The spatial distribution of the contrast agent within the arterial wall was measured in contiguous micro-CT images at right angles to the lumen axis with the area of wall in each cross-sectional image being approximately (0.1 mm)(3) in size. In the acute animals there were no localized areas of increased contrast around the hypoperfused embolized perfusion territories in the arterial wall, but in the chronic animals the hypoperfused areas were surrounded by increased contrast. These results suggest that CT might be able to detect localized regions of increased vascularity in the arterial wall as an indicator of early atherosclerotic stimulation of vasa vasorum proliferation. PMID- 23443340 TI - Additive prognostic value of the SYNTAX score over GRACE, TIMI, ZWOLLE, CADILLAC and PAMI risk scores in patients with acute ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention. AB - This study evaluated additive prognostic value of the SYNTAX score over GRACE, TIMI, ZWOLLE, CADILLAC and PAMI risk scores in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). All six scores were calculated in 209 consecutive STEMI patients undergoing pPCI. Primary end-point was the major adverse cardiovascular event (MACE--composite of cardiovascular mortality, non-fatal myocardial infarction and stroke); secondary end point was cardiovascular mortality. Patients were stratified according to the SYNTAX score tertiles (<=12; between 12 and 19.5; >19.5). The median follow-up was 20 months. Rates of MACE and cardiovascular mortality were highest in the upper tertile of the SYNTAX score (p < 0.001 and p = 0.003, respectively). SYNTAX score was independent multivariable predictor of MACE and cardiovascular mortality when added to GRACE, TIMI, ZWOLLE, and PAMI risk scores. However, the SYNTAX score did not improve the Cox regression models of MACE and cardiovascular mortality when added to the CADILLAC score. The SYNTAX score has predictive value for MACE and cardiovascular mortality in patients with STEMI undergoing primary PCI. Furthermore, SYNTAX score improves prognostic performance of well-established GRACE, TIMI, ZWOLLE and PAMI clinical scores, but not the CADILLAC risk score. Therefore, long-term survival in patients after STEMI depends less on detailed angiographical characterization of coronary lesions, but more on clinical characteristics, myocardial function and basic angiographic findings as provided by the CADILLAC score. PMID- 23443341 TI - When the tumour is not the culprit: avascular necrosis of the hip in a patient with castration-resistant prostate cancer. AB - Avascular necrosis (avn) of the hip is a well-documented side effect of corticosteroid therapy, but it has also been described as a complication of radiation and chemotherapy. Many prostate cancer patients undergo treatment with all three of those therapeutic modalities, and yet reported cases of avn of the hip in prostate cancer patients are rare. Symptoms that might potentially alert physicians to this complication are nonspecific and may be attributed to cancer progression, in particular to progressive bone metastasis.Here, we report on a 79 year-old man diagnosed with castration-resistant prostate cancer whose diagnosis of avn of the hip was confounded by his underlying malignancy. We discuss risk factors and diagnostic clues in this differential diagnosis of acute hip pain in patients with castration-resistant prostate cancer. Physicians might maintain a high index of suspicion for avn of the hip in prostate cancer patients presenting with new-onset hip pain. Surgical intervention may help to prevent the appearance of avn-associated pain and the negative impact of advanced avn on overall quality of life. PMID- 23443342 TI - Initially disadvantaged, TEL-AML1 cells expand and initiate leukemia in response to irradiation and cooperating mutations. PMID- 23443343 TI - SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias. PMID- 23443344 TI - Assessment of female prevalence of overactive bladder (OAB) in Barcelona using a self-administered screening questionnaire: the Cuestionario de Autoevaluacion del Control de la Vejiga (CACV). AB - INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) syndrome is common urological condition, usually underdiagnosed and difficult to identify. The screening of lower urinary tract symptoms (LUTS) through patient self administered questionnaires can be useful not only for timely identification of these patients but to implement early interventions for symptoms and their implication in a patients' quality of life (QOL). Our objective was to assess the prevalence of OAB symptoms in patients attending general gynecology units in Barcelona, Spain, through a self-administered screening questionnaire. MATERIALS AND METHODS: A cross-sectional, multicenter, observational, epidemiological study was carried out at general gynecology units of ten primary health centers in Barcelona, Spain. The study was conducted during a patient's single visit through self-administered forms. Patients recorded sociodemographic data, medical history and comorbidities, and scored the presence and bother related to specific urological symptoms using the Cuestionario de Autoevaluacion del Control de la Vejiga (CACV), the validated Spanish version of the Bladder Control Self Assessment Questionnaire (B-SAQ). A score >=6 on the symptoms scale of the CACV was taken as an indicator of suspected OAB. RESULTS: One thousand and four women aged between 18 and 82 participated in the study. The overall prevalence of OAB was 11.8 %. A patient being >50 years was significantly associated with suspected OAB in comparison with the younger group [odds ratio (OR) 3.1 (2.1-4.7); p < 0,001]. Overactive bladder showed significant association with factors other than age, menopause, and previous urogynecological history, such as high body mass index (BMI) and parity. CONCLUSIONS: The estimated prevalence of suspected OAB in patients attending general gynecological services in Barcelona is 11.8 %. Overweight or obese patients and those with three or more children were found to be at elevated risk for developing OAB. PMID- 23443345 TI - Transvaginal electrical stimulation with surface-EMG biofeedback in managing stress urinary incontinence in women of premenopausal age: a double-blind, placebo-controlled, randomized clinical trial. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to evaluate the results of conservative treatment of urodynamic stress urinary incontinence (SUI) using transvaginal electrical stimulation with surface-electromyography-assisted biofeedback (TVES + sEMG) in women of premenopausal age. METHODS: One hundred and two patients with SUI were divided into two groups: active (n = 68) and placebo (n = 34) TVES + sEMG. The treatment lasted for 8 weeks and consisted of two sessions per day. Women were evaluated before and after the intervention by pad test, voiding diary, urodynamic test, and the Incontinence Quality of Life Questionnaire (I-QOL). RESULTS: Mean urinary leakage on a standard pad test at the end of 8th week was significantly lower in the active than the placebo group (19.5 +/- 13.6 vs. 39.8 +/- 28.5). Mean urinary leakage on a 24-h pad test was significantly reduced in the active group at the end of 8th and 16th weeks compared with the placebo group (8.2 +/- 14.8 vs. 14.6 +/- 18.9 and 6.1 +/- 11.4 vs. 18.2 +/- 20.8, respectively). There was also a significant improvement in muscle strength as measured by the Oxford scale in the active vs the placebo group after 8 and 16 weeks (4.2 vs 2.6 and 4.1 vs 2.7, respectively). No significant difference was found between groups in urodynamic data before and after treatment. At the end of 8th week, the mean I-QOL score in the active vs the placebo group was 78.2 +/- 17.9 vs 55.9 +/- 14.2, respectively, and at the end of 16th week 80.8 +/- 24.1 vs. 50.6 +/- 14.9, respectively. CONCLUSION: Our study showed that TVES + sEMG is a trustworthy method of treatment in premenopausal women with SUI; however, its reliability needs to be established. PMID- 23443346 TI - Comparison of single-, double- and triple-combined testing, including Pap test, HPV DNA test and cervicography, as screening methods for the detection of uterine cervical cancer. AB - Cervical cancer is a serious disease that threatens the health of women worldwide. This study compared the sensitivities and false-positive rates of cervical cytology (Pap smear), human papilloma virus (HPV) DNA test, cervicography, first double-combined testing (cervical cytology and HPV DNA test), second double-combined testing (cervical cytology and cervicography) and triple-combined testing (cervical cytology, HPV DNA test and cervicography). The study included 261 patients screened for uterine cervical cancer. All women simultaneously underwent cervical cytology, HPV DNA test and cervicography for uterine cervical cancer screening and colposcopically directed biopsy for diagnostic evaluation. The triple-combined testing was consistently the most sensitive among the cervical screening tests. The second double-combined testing, with a sensitivity rate of 98.1% was more sensitive than the first double combined test (92.3%). However, cervical cytology was most specific (93.5%) and showed the highest positive predictive value (77.8%). The sensitivity of cervical cytology was markedly improved in combination with HPV DNA test and cervicography. Thus, the triple-combined testing, which improves the high false negativity of cervical cytology, may be an effective tool in uterine cervical cancer screening, pending confirmation of the effectiveness in a mass screening study. PMID- 23443348 TI - The business of care. PMID- 23443347 TI - Proteomic insights into intra- and intercellular plant-bacteria symbiotic association during root nodule formation. AB - Over the last several decades, there have been a large number of studies done on the all aspects of legumes and bacteria which participate in nitrogen-fixing symbiosis. The analysis of legume-bacteria interaction is not just a matter of numerical complexity in terms of variants of gene products that can arise from a single gene. Bacteria regulate their quorum-sensing genes to enhance their ability to induce conjugation of plasmids and symbiotic islands, and various protein secretion mechanisms; that can stimulate a collection of chain reactions including species-specific combinations of plant-secretion isoflavonoids, complicated calcium signaling pathways and autoregulation of nodulation mechanisms. Quorum-sensing systems are introduced by the intra- and intercellular organization of gene products lead to protein-protein interactions or targeting of proteins to specific cellular structures. In this study, an attempt has been made to review significant contributions related to nodule formation and development and their impacts on cell proteome for better understanding of plant bacterium interaction mechanism at protein level. This review would not only provide new insights into the plant-bacteria symbiosis response mechanisms but would also highlights the importance of studying changes in protein abundance inside and outside of cells in response to symbiosis. Furthermore, the application to agriculture program of plant-bacteria interaction will be discussed. PMID- 23443349 TI - Radiological journals in the online world: should we think Open? AB - The scientific community is becoming increasingly web-based and the role of online communication is continuously expanding. In this setting, one fact and two trends should be considered. The fact is the decision by Britain's government and by the European Union to make all papers deriving from projects that were paid for using public funds freely available online for reading and redistribution (an approach already widely used in the US). The trends are the 'open review' process and the future perspective of having online-only scientific journals; the balance of advantages and disadvantages of such an approach is debated. These factors are challenging the scientific community worldwide and radiological scientific societies should play a relevant role in driving these processes. KEY POINTS: * Research funded by the EU and Britain's government will soon be freely available * The open-review process has started in certain scientific communities, but not yet within radiology * Online communication is increasing its power within the scientific community. PMID- 23443350 TI - Radiological journals in the online world: should we think Open? A response. AB - This discussion on developments within publishing presents further thought on green, gold and hybrid models of open access. It also discusses some of the advantages and disadvantages which may be encountered by researchers, authors, institutions, scientific organisations and publishers. PMID- 23443351 TI - Ten-year experience of percutaneous image-guided radiofrequency ablation of malignant renal tumours in high-risk patients. AB - OBJECTIVES: To evaluate survival and outcomes after percutaneous radiofrequency ablation (RFA) of malignant renal tumours in high-risk patients with long-term follow-up. METHODS: Between 2002 and 2009, 62 patients (71 tumours), with a median age of 73.5 years (20-87), consecutively treated with RFA under ultrasound or computed tomography guidance for malignant renal tumours were retrospectively selected and prospectively followed until 2012, including 25 patients (40.3 %) with solitary kidney and 7 cystic cancers. Maximal tumour diameters were between 8 and 46 mm (median: 23 mm). RESULTS: Radiofrequency ablation was technically possible for all patients. Mean follow-up was 38.8 months (range: 18-78 months). Primary and secondary technique effectiveness was 95.2 % and 98.4 % per patient respectively. The rates of local tumour progression and metastatic evolution were 3.2 % and 9.7 % per patient and were associated with tumour size >4 cm (P = 0.005). The disease-free survival rates were 88.3 % and 61.9 % at 3 and 5 years. No significant difference in glomerular filtration rates before and after the procedure was observed (P = 0.107). The major complications rate was 5.9 % per session with an increased risk in the case of central locations (P = 0.006). CONCLUSIONS: Percutaneous renal RFA appears to be safe and effective with useful nephron-sparing results. KEY POINTS: * Radiofrequency ablation (RFA) is a well tolerated technique according to mid-term results. * RFA for malignant renal tumours preserved renal function in high-risk patients. * Mid-term efficacy of RFA was close to that of formal conservative surgery. * Tumour size and central location limit the efficacy and safety of RFA. PMID- 23443352 TI - Coblation vertebroplasty for complex vertebral insufficiency fractures. AB - OBJECTIVES: Coblation to create a cavity in the affected vertebral body was performed for complex fractures and/or when there was a posterior wall defect. This permitted a low-pressure injection and potentially reduces the risk of extravasation of cement into the spinal canal. METHODS: Prospective audit for outcome measures and complications allowed retrospective review of cases treated by coblation. A commercial wand inserted via a wide-bore vertebroplasty needle created a cavity before inserting cement. A visual analogue scale assessed pain and Roland Morris scoring assessed mobility. RESULTS: Thirty-two coblation procedures were performed. Primary diagnoses were myeloma, metastases, osteoporosis and trauma. Outcome measures were recorded with a 56 % success rate, 6 % no change and 32 % with mixed but mainly positive results; 6 % died before follow-up. No complications were observed; in particular no patient suffered neurological damage and none have developed subsequent fractures at the treated levels. CONCLUSIONS: This technique makes possible cementation of patients who would otherwise be unsuitable for vertebroplasty. The modest pain and disability improvement is partly due to our stringent criteria as well as fracture complexity. Further work will assess the efficacy of the method compared with conservative measures. KEY POINTS: * Treatment of vertebral compression fractures with possible posterior wall defects is controversial. * Coblation before vertebroplasty allows a low-pressure injection into fractured vertebrae. * This technique reduces risk of extravasation of cement. * No serious complication of our coblation procedures was observed. PMID- 23443353 TI - Preoperative evaluation of the cystic duct for laparoscopic cholecystectomy: comparison of navigator-gated prospective acquisition correction- and conventional respiratory-triggered techniques at free-breathing 3D MR cholangiopancreatography. AB - OBJECTIVE: To evaluate the quality of magnetic resonance cholangiopancreatography (MRCP) images obtained with a three-dimensional navigator-gated (NG) technique and compare findings with conventional respiratory-triggered (RT) images in pre laparoscopic cholecystectomy patients. METHODS: Turbo-spin-echo (TSE) RT-MRCP (average 242 s) and balanced turbo-field-echo (bTFE) NG-MRCP (average 263 s) were acquired at 1.5-T MRI for 49 pre-laparoscopic cholecystectomy patients. Two radiologists independently assessed image quality, visibility of anatomical structures, common bile duct (CBD) stones, and signal-to-noise ratios (SNRs). Interobserver agreement was also evaluated. RESULTS: The anatomical details of the cystic duct were clearly demonstrated in 33 (67.3 %, reader A) and 35 (71.4 %, reader B) patients on RT-MRCP, and in 45 (91.8 %) and 44 (89.7 %) patients on NG-MRCP. On NG-MRCP, visualisation of the cystic duct (3.22/3.12), its origin (3.57/3.55), and the gallbladder(3.61/3.59) was statistically better than on RT MRCP (2.90/2.78, 3.29/3.12, 2.98/2.88, respectively). The overall image quality was statistically better on NG-MRCP than RT-MRCP. Each technique identified the presence of CBD stones in all affected patients. The SNR was significantly higher on NG-MRCP (CHD 22.40, gallbladder 17.13) than RT-MRCP (CHD 17.05, gallbladder 9.30). Interobserver agreement was fair to perfect. CONCLUSION: Navigator-gated MRCP is more useful than respiratory-triggered MRCP for evaluating the gallbladder and cystic duct in patients scheduled for laparoscopic cholecystectomy. KEY POINTS: * Magnetic resonance cholangiopancreatography (MRCP) provides important cystic duct information before laparoscopic cholecystectomy. * Navigator-gated (NG) MRCP images were better than conventional respiratory triggered (RT) MRCP. * The signal-to-noise ratio was significantly higher for NG MRCP than for conventional RT-MRCP. * Balanced turbo-field-echo NG-MRCP is useful for evaluating the gallbladder and cystic duct. PMID- 23443354 TI - The native-invasive balance: implications for nutrient cycling in ecosystems. AB - We conducted single- and mixed-litter experiments in a hardwood forest in Long Island, New York, using leaf litter from phylogenetically paired native and invasive species. We selected long-established, abundant invasive species with wide-ranging distributions in the eastern United States that likely make substantial contributions to the litter pool of invaded areas. Overall, leaf litter from invasive species differed from native litter, though differences varied by phylogenetic grouping. Invasive litter had lower carbon:nitrogen ratios (30.9 +/- 1.96 SE vs. 32.8 +/- 1.36, P = 0.034) and invasive species lost 0.03 +/ 0.007 g of nitrogen and had 23.4 +/- 4.9 % of their starting mass remaining at the end of 1 year compared with a loss of 0.02 +/- 0.003 g nitrogen and 31.1 +/- 2.6 % mass remaining for native species. Mixing litter from two species did not alter decomposition rates when native species were mixed with other native species, or when invasive species were mixed with other invasive species. However, mixing litter of native and invasive species resulted in significantly less mass and nitrogen loss than was seen in unmixed invasive litter. Mixtures of native and invasive litter lost all but 47 +/- 2.2 % of initial mass, compared to 37 +/- 5.8 % for invasive litter and 50 +/- 5.1 % for native litter. This non additive effect of mixing native and invasive litter suggests that an additive model of metabolic characteristics may not suffice for predicting invasion impacts in a community context, particularly as invasion proceeds over time. Because the more rapid decomposition of invasive litter tends to slow to rates typical of native species when native and invasive litters are mixed together, there may be little impact of invasive species on nutrient cycling early in an invasion, when native leaf litter is abundant (providing litter deposition is the dominant control on nutrient cycling). PMID- 23443355 TI - The role of colonization in the dynamics of patchy populations of a cyclic vole species. AB - The crash phase of vole populations with cyclic dynamics regularly leads to vast areas of uninhabited habitats. Yet although the capacity for cyclic voles to re colonize such empty space is likely to be large and predicted to have become evolved as a distinct life history trait, the processes of colonization and its effect on the spatio-temporal dynamics have been little studied. Here we report from an experiment with root voles (Microtus oeconomus) specifically targeted at quantifying the process of colonization of empty patches from distant source patches and its resultant effect on local vole deme size variation in a patchy landscape. Three experimental factors: habitat quality, predation risk and inter patch distance were employed among 24 habitat patches in a 100 * 300-m experimental area. The first-born cohort in the spring efficiently colonized almost all empty patches irrespective of the degree of patch isolation and predation risk, but this was dependent on habitat quality. Just after the initial colonization wave the deme sizes in patches of the same quality were underdispersed relative to Poisson variance, indicating regulated (density dependent) settlement. Towards the end of the breeding season local demographic processes acted to smooth out the initial post-colonization differences among source and colonization patches, and among patches of initially different quality. However, at this time demographic stochasticity had also given rise to a large (overdispersed) variation in deme sizes that may have contributed to an overshadowing of the effect of other factors. The results of this experiment confirmed our expectation that the space-filling capacity of voles is large. The costs associated with transience appeared to be so low, at least at the spatial scale considered in this experiment, that such costs are not likely to substantially constrain habitat selection and colonization in the increase phase of cyclic patchy populations. PMID- 23443356 TI - A faecal index of diet quality that predicts reproductive success in a marsupial folivore. AB - Estimating the nutritional value of a herbivore's diet is difficult because it requires knowing what the animal eats, the relative quality of each component and how these components interact in relation to animal physiology. Current methods are cumbersome and rely on many assumptions that are hard to evaluate. We describe a new method for estimating relative diet quality directly from faeces that avoids the problems inherent in other methods. We combine this method with near infrared reflectance spectroscopy (NIRS) to analyse many samples and thus provide a technique with immense value in ecological studies. The method stems from the correlation between the concentrations of dietary and faecal nitrogen in herbivores eating a tannin-free diet, but a weaker relationship in browsers that ingest substantial amounts of tannins, which form complexes with proteins. These complexes reduce the availability of nitrogen and may increase faecal nitrogen concentrations. Using the tannin-binding compound, polyethylene glycol, we showed that tannin-bound nitrogen is a significant and variable part of faecal nitrogen in wild common brushtail possums (Trichosurus vulpecula). We developed a technique to measure faecal available nitrogen and found that it predicted the reproductive success of female brushtail possums in northern Australia. Faecal available nitrogen combined with NIRS provides a powerful tool for estimating the relative nutritional value of the diets of browsing herbivores in many ecological systems. It is a better indicator of diet quality than other commonly used single nutrient measures such as faecal nitrogen and foliage analysis paired with observed feeding behaviour. PMID- 23443357 TI - Colour also matters for nocturnal birds: owlet bill coloration advertises quality and influences parental feeding behaviour in little owls. AB - Chromatic signals of offspring quality have been shown to play a role in parent offspring communication in diurnal birds, but are assumed to be useless in dim light conditions because colour-based discrimination probably requires more light. A major ecological and evolutionary conundrum in this scenario is why the nestlings of some nocturnal owls display colourful beaks. Here, we test the hypothesis that yellow bill coloration of owlets of the nocturnal little owl Athene noctua may function as a chromatic signal revealing to parents aspects of quality of their offspring. In a first step, we examined physical variation in bill coloration and its covariation with owlet quality. Secondly, we studied parental provisioning in relation to an experimental manipulation of bill coloration of owlets. Bills of owlets showed higher within-nest variation in yellow-red chroma than in brightness. Plasma carotenoid concentration and nestling immunological status were not associated with chromatic or achromatic features of the bill. Interestingly, however, heavier owlets displayed more yellow bills than lighter ones. The effect of bill coloration on parental favouritism changed with brood size. Parents holding large broods preferentially fed owlets with enhanced over reduced yellow bill coloration, whereas those with small broods did not significantly bias feeding in relation to owlet bill coloration. Our results, based on integration of objective spectrophotometric assessment of colour and experimental procedures, confirm that parent little owls use bill coloration to reveal information on owlet body mass to adjust their feeding strategies, thus highlighting the importance of considering potential chromatic signals for a full comprehension of parent-offspring communication processes in nocturnal bird species. PMID- 23443358 TI - Control of 10 nm scale cylinder orientation in self-organized sugar-based block copolymer thin films. AB - The present paper describes the orientational control of 10 nm scale cylinders in sugar-based block copolymer thin films by simply varying the composition of the annealing co-solvent. The affinity of the block copolymer to the solvent vapor could be systematically adjusted in this way. PMID- 23443359 TI - Retinal vascular biomarkers for early detection and monitoring of Alzheimer's disease. AB - The earliest detectable change in Alzheimer's disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes and degeneration have previously been reported in AD using optical coherence tomography and laser Doppler techniques. This report presents results from analysis of retinal photographs from AD and healthy control participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain. We demonstrate relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD. A number of RVPs were found to be different in AD. Two of these RVPs, venular branching asymmetry factor and arteriolar length-to-diameter ratio, were also higher in healthy individuals with high plaque burden (P = 0.01 and P = 0.02 respectively, after false discovery rate adjustment). Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments. PMID- 23443361 TI - Shifts in reinforcement signalling while playing slot-machines as a function of prior experience and impulsivity. AB - Electronic gaming machines (EGMs) offer significant revenue streams for mercantile gambling. However, limited clinical and experimental evidence suggests that EGMs are associated with heightened risks of clinically problematic patterns of play. Little is known about the neural structures that might mediate the transition from exploratory EGM play to the 'addictive' play seen in problem gamblers; neither is it known how personality traits associated with gambling activity (and gambling problems) influence reinforcement processing while playing EGMs. Using functional magnetic resonance imaging in healthy participants, we show that a single episode of slot-machine play is subsequently associated with reduced amplitudes of blood-oxygenation level-dependent signals within reinforcement-related structures, such as the ventral striatum and caudate nucleus, following winning game outcomes; but increased amplitudes of anticipatory signals within the ventral striatum and amygdala while watching the game reels spin. Trait impulsivity enhanced positive signals within the ventral striatum and amygdala following the delivery of winning outcomes but diminished positive signals following the experience of almost-winning ('near-misses'). These results indicate that a single episode of slot-machine play engages the well-characterised reinforcement-learning mechanisms mediated by ascending dopamine mesolimbic and mesostriatal pathways, to shift reward value of EGMs away from game outcomes towards anticipatory states. Impulsivity, itself linked to problem gambling and heightened vulnerability to other addictive disorders, is associated with divergent coding of winning outcomes and almost-winning experiences within the ventral striatum and amygdala, potentially enhancing the reward value of successful slot-machine game outcomes but, at the same time,modulating the aversive motivational consequences of near-miss outcomes. PMID- 23443360 TI - THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction. AB - Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using Delta(9) tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction. PMID- 23443362 TI - Determining the duration of therapy for patients with community-acquired pneumonia. AB - Emerging data, including results from two systematic reviews, suggest that with appropriate antimicrobial selection, community-acquired pneumonia (CAP) can be successfully treated in less than 7 days, rather than the 7-14 days frequently utilized. Shorter course therapy has the potential not only to improve efficacy, safety, and compliance, but also to minimize the evolution of resistance. Utilization of procalcitonin as a biomarker in CAP can appropriately influence the duration of therapy without affecting mortality and cure rates. CAP treatment duration can further be reduced successfully into the clinical setting with the assistance of an antibiotic stewardship team. PMID- 23443363 TI - Analysis of continuous steering movement using a motor-based quantification system. AB - Continuous steering movement (CSM) of the upper extremity (UE) is an essential component of steering movement during vehicle driving. This study presents an integrated approach to examine the force exertion and movement pattern during CSM. We utilized a concept similar to the isokinetic dynamometer to measure the torque profiles during 180 degrees /s constant-velocity CSM. During a steering cycle, the extremity movement can be divided into stance and swing phases based upon the hand contact information measured from the hand switch devices. Data from twelve normal young adults (six males and six females) showed that there are three typical profiles of force exertion. The two hands exhibit similar time expenditures but with asymmetric force exertions and contact times in both the clockwise (CW) and counterclockwise (CCW) steering cycles. Both hands contribute more force but with less contact time in their outward CSM directions (i.e., CW for the right hand and CCW for the left hand). These findings help us to further understand CSM and have a number of important implications for future practice in clinical training. Considerably more research is required to determine the roles of the various shoulder muscles during CSM at various speeds. PMID- 23443364 TI - Determination of the shear buckling load of a large polymer composite I-section using strain and displacement sensors. AB - This paper presents a method and procedure of sensing and determining critical shear buckling load and corresponding deformations of a comparably large composite I-section using strain rosettes and displacement sensors. The tested specimen was a pultruded composite beam made of vinyl ester resin, E-glass and carbon fibers. Various coupon tests were performed before the shear buckling test to obtain fundamental material properties of the I-section. In order to sensitively detect shear buckling of the tested I-section, twenty strain rosettes and eight displacement sensors were applied and attached on the web and flange surfaces. An asymmetric four-point bending loading scheme was utilized for the test. The loading scheme resulted a high shear and almost zero moment condition at the center of the web panel. The web shear buckling load was determined after analyzing the obtained test data from strain rosettes and displacement sensors. Finite element analysis was also performed to verify the experimental results and to support the discussed experimental approach. PMID- 23443365 TI - Identification of cell-surface molecular interactions under living conditions by using the enzyme-mediated activation of radical sources (EMARS) method. AB - Important biological events associated with plasma membranes, such as signal transduction, cell adhesion, and protein trafficking, are mediated through the membrane microdomains. We have developed a novel method termed enzyme-mediated activation of radical sources (EMARS) to identify coclustering molecules on the cell surface under living conditions, which features a radical formation from an aryl azide reagent by horseradish peroxidase (HRP). For identification of molecules labeled by the EMARS reaction, antibody array system and mass spectrometry-based proteomics approaches are available. Spatio- temporally regulated interaction between b1 integrin and ErbB4 involved in fibronectin dependent cell migration and therapeutic antibody-stimulated interaction between FGFR3 and CD20 were discovered using the EMARS method. PMID- 23443366 TI - Implementation of human-machine synchronization control for active rehabilitation using an inertia sensor. AB - According to neuro-rehabilitation practice, active training is effective for mild stroke patients, which means these patients are able to recovery effective when they perform the training to overcome certain resistance by themselves. Therefore, for rehabilitation devices without backdrivability, implementation of human-machine synchronization is important and a precondition to perform active training. In this paper, a method to implement this precondition is proposed and applied in a user's performance of elbow flexions and extensions when he wore an upper limb exoskeleton rehabilitation device (ULERD), which is portable, wearable and non-backdrivable. In this method, an inertia sensor is adapted to detect the motion of the user's forearm. In order to get a smooth value of the velocity of the user's forearm, an adaptive weighted average filtering is applied. On the other hand, to obtain accurate tracking performance, a double close-loop control is proposed to realize real-time and stable tracking. Experiments have been conducted to prove that these methods are effective and feasible for active rehabilitation. PMID- 23443367 TI - Investigation of volatiles emitted from freshly cut onions (Allium cepa L.) by real time proton-transfer reaction-mass spectrometry (PTR-MS). AB - Volatile organic compounds (VOCs) in cut onions (Allium cepa L.) were continuously measured by PTR-MS during the first 120 min after cutting. The headspace composition changed rapidly due to the very reactive volatile sulfurous compounds emitted from onion tissue after cell disruption. Mass spectral signals corresponding to propanethial S-oxide (the lachrymatory factor) and breakdown products of this compound dominated 0-10 min after cutting. Subsequently, propanethiol and dipropyl disulfide predominantly appeared, together with traces of thiosulfinates. The concentrations of these compounds reached a maximum at 60 min after cutting. Propanethiol was present in highest concentrations and had an odor activity value 20 times higher than dipropyl disulfide. Thus, propanethiol is suggested to be the main source of the characteristic onion odor. Monitoring the rapid changes of VOCs in the headspace of cut onion necessitates a high time resolution, and PTR-MS is demonstrated to be a very suitable method for monitoring the headspace of freshly cut onions directly after cutting without extraction or pre-concentration. PMID- 23443368 TI - Modeling and performance analysis of movement-based group location management using RFID sensing in public transportation systems. AB - Location management, which consists of location registration and paging, is essential to provide mobile communication services to mobile stations (MSs). Since MSs riding on a public transportation system (TS) generates significant location registration signaling loads simultaneously when a TS with riding MSs moves between location areas (LAs), group location management was proposed. Under the group location management, an MS performs group registration when it gets on a TS and performs group deregistration when it gets off a TS. Then, only a TS updates its current location when it changes LA, on behalf of all riding MSs. In this paper, movement-based group location management using radio frequency identification (RFID) is proposed, where the MS's getting on and getting off behaviors are detected using RFID and only location update of a TS is carried out if the number of crossed cells from the last updated cell exceeds a predefined movement threshold, on behalf of all riding MSs. Then, we develop an analytical model for the performance analysis of the movement-based group location management and analyze the effects of various parameters on the performance. The results show that the movement-based group location management has reduced signaling cost compared with movement-based individual location management, and optimal performance can be achieved by choosing appropriate movement threshold values. PMID- 23443369 TI - Automatic method for building indoor boundary models from dense point clouds collected by laser scanners. AB - In this paper we present a method that automatically yields Boundary Representation Models (B-rep) for indoors after processing dense point clouds collected by laser scanners from key locations through an existing facility. Our objective is particularly focused on providing single models which contain the shape, location and relationship of primitive structural elements of inhabited scenarios such as walls, ceilings and floors. We propose a discretization of the space in order to accurately segment the 3D data and generate complete B-rep models of indoors in which faces, edges and vertices are coherently connected. The approach has been tested in real scenarios with data coming from laser scanners yielding promising results. We have deeply evaluated the results by analyzing how reliably these elements can be detected and how accurately they are modeled. PMID- 23443370 TI - A wireless sensor enabled by wireless power. AB - Through harvesting energy by wireless charging and delivering data by wireless communication, this study proposes the concept of a wireless sensor enabled by wireless power (WPWS) and reports the fabrication of a prototype for functional tests. One WPWS node consists of wireless power module and sensor module with different chip-type sensors. Its main feature is the dual antenna structure. Following RFID system architecture, a power harvesting antenna was designed to gather power from a standard reader working in the 915 MHz band. Referring to the Modbus protocol, the other wireless communication antenna was integrated on a node to send sensor data in parallel. The dual antenna structure integrates both the advantages of an RFID system and a wireless sensor. Using a standard UHF RFID reader, WPWS can be enabled in a distributed area with a diameter up to 4 m. Working status is similar to that of a passive tag, except that a tag can only be queried statically, while the WPWS can send dynamic data from the sensors. The function is the same as a wireless sensor node. Different WPWSs equipped with temperature and humidity, optical and airflow velocity sensors are tested in this study. All sensors can send back detection data within 8 s. The accuracy is within 8% deviation compared with laboratory equipment. A wireless sensor network enabled by wireless power should be a totally wireless sensor network using WPWS. However, distributed WPWSs only can form a star topology, the simplest topology for constructing a sensor network. Because of shielding effects, it is difficult to apply other complex topologies. Despite this limitation, WPWS still can be used to extend sensor network applications in hazardous environments. Further research is needed to improve WPWS to realize a totally wireless sensor network. PMID- 23443371 TI - Advancing profiling sensors with a wireless approach. AB - The notion of a profiling sensor was first realized by a Near-Infrared (N-IR) retro-reflective prototype consisting of a vertical column of wired sparse detectors. This paper extends that prior work and presents a wireless version of a profiling sensor as a collection of sensor nodes. The sensor incorporates wireless sensing elements, a distributed data collection and aggregation scheme, and an enhanced classification technique. In this novel approach, a base station pre-processes the data collected from the sensor nodes and performs data re alignment. A back-propagation neural network was also developed for the wireless version of the N-IR profiling sensor that classifies objects into the broad categories of human, animal or vehicle with an accuracy of approximately 94%. These enhancements improve deployment options as compared with the first generation of wired profiling sensors, possibly increasing the application scenarios for such sensors, including intelligent fence applications. PMID- 23443372 TI - A catalytic sensor for measurement of radical density in CO2 plasmas. AB - A catalytic sensor for the measurement of radical density in weakly ionized CO(2) plasmas, created in a low-pressure electrodeless discharge, is presented. The CO(2) plasma was created in a 4 cm wide borosilicate glass tube inside a copper coil connected to a radio frequency generator operating at 27.12 MHz with a nominal power of 250 W. The dissociation fraction of the CO(2) molecules was measured in the early afterglow at pressures ranging from 10 Pa to 100 Pa, and at distances of up to 35 cm along the gas stream from the glowing plasma. The radical density peaked (2 * 10(20) m-3) at 80 Pa. The density quickly decreased with increasing distance from the glowing plasma despite a rather large drift velocity. The dissociation fraction showed similar behavior, except that the maximum was obtained at somewhat lower pressure. The results were explained by rather intense surface recombination of radicals. PMID- 23443373 TI - Classification of odorants in the vapor phase using composite features for a portable e-nose system. AB - We present an effective portable e-nose system that performs well even in noisy environments. Considering the characteristics of the e-nose data, we use an image covariance matrix-based method for extracting discriminant features for vapor classification. To construct composite vectors, primitive variables of the data measured by a sensor array are rearranged. Then, composite features are extracted by utilizing the information about the statistical dependency among multiple primitive variables, and a classifier for vapor classification is designed with these composite features. Experimental results with different volatile organic compounds data show that the proposed system has better classification performance than other methods in a noisy environment. PMID- 23443374 TI - TDMA-based dual-mode communication for mobile wireless sensor networks. AB - Small highly mobile robots, and in particular micro air vehicles (MAVs), are well suited to the task of exploring unknown indoor environments such as buildings and caves. Such a task imposes a number of requirements on the underlying communication infrastructure, with differing goals during various stages of the mission. This work addresses those requirements with a hybrid communications infrastructure consisting of a stationary mesh network along with the mobile nodes. The combined network operates in two independent modes, coupling a highly efficient, low duty cycle, low throughput mode for routing and persistent sensing with a burst mode for high data rate communication. By strategically distributing available frequency channels between the mobile agents and the stationary nodes, the overall network provides reliable long-term communication paths while maximizing data throughput when needed. PMID- 23443375 TI - An efficient micro control unit with a reconfigurable filter design for wireless body sensor networks (WBSNs). AB - In this paper, a low-cost, low-power and high performance micro control unit (MCU) core is proposed for wireless body sensor networks (WBSNs). It consists of an asynchronous interface, a register bank, a reconfigurable filter, a slop feature forecast, a lossless data encoder, an error correct coding (ECC) encoder, a UART interface, a power management (PWM), and a multi-sensor controller. To improve the system performance and expansion abilities, the asynchronous interface is added for handling signal exchanges between different clock domains. To eliminate the noise of various bio-signals, the reconfigurable filter is created to provide the functions of average, binomial and sharpen filters. The slop-feature forecast and the lossless data encoder is proposed to reduce the data of various biomedical signals for transmission. Furthermore, the ECC encoder is added to improve the reliability for the wireless transmission and the UART interface is employed the proposed design to be compatible with wireless devices. For long-term healthcare monitoring application, a power management technique is developed for reducing the power consumption of the WBSN system. In addition, the proposed design can be operated with four different bio-sensors simultaneously. The proposed design was successfully tested with a FPGA verification board. The VLSI architecture of this work contains 7.67-K gate counts and consumes the power of 5.8 mW or 1.9 mW at 100 MHz or 133 MHz processing rate using a TSMC 0.18 MUm or 0.13 MUm CMOS process. Compared with previous techniques, this design achieves higher performance, more functions, more flexibility and higher compatibility than other micro controller designs. PMID- 23443376 TI - Track detection in railway sidings based on MEMS gyroscope sensors. AB - The paper presents a two-step technique for real-time track detection in single track railway sidings using low-cost MEMS gyroscopes. The objective is to reliably know the path the train has taken in a switch, diverted or main road, immediately after the train head leaves the switch. The signal delivered by the gyroscope is first processed by an adaptive low-pass filter that rejects noise and converts the temporal turn rate data in degree/second units into spatial turn rate data in degree/meter. The conversion is based on the travelled distance taken from odometer data. The filter is implemented to achieve a speed-dependent cut-off frequency to maximize the signal-to-noise ratio. Although direct comparison of the filtered turn rate signal with a predetermined threshold is possible, the paper shows that better detection performance can be achieved by processing the turn rate signal with a filter matched to the rail switch curvature parameters. Implementation aspects of the track detector have been optimized for real-time operation. The detector has been tested with both simulated data and real data acquired in railway campaigns. PMID- 23443378 TI - Pattern recognition for selective odor detection with gas sensor arrays. AB - This paper presents a new pattern recognition approach for enhancing the selectivity of gas sensor arrays for clustering intelligent odor detection. The aim of this approach was to accurately classify an odor using pattern recognition in order to enhance the selectivity of gas sensor arrays. This was achieved using an odor monitoring system with a newly developed neural-genetic classification algorithm (NGCA). The system shows the enhancement in the sensitivity of the detected gas. Experiments showed that the proposed NGCA delivered better performance than the previous genetic algorithm (GA) and artificial neural networks (ANN) methods. We also used PCA for data visualization. Our proposed system can enhance the reproducibility, reliability, and selectivity of odor sensor output, so it is expected to be applicable to diverse environmental problems including air pollution, and monitor the air quality of clean-air required buildings such as a kindergartens and hospitals. PMID- 23443379 TI - Where and when should sensors move? Sampling using the expected value of information. AB - In case of an environmental accident, initially available data are often insufficient for properly managing the situation. In this paper, new sensor observations are iteratively added to an initial sample by maximising the global expected value of information of the points for decision making. This is equivalent to minimizing the aggregated expected misclassification costs over the study area. The method considers measurement error and different costs for class omissions and false class commissions. Constraints imposed by a mobile sensor web are accounted for using cost distances to decide which sensor should move to the next sample location. The method is demonstrated using synthetic examples of static and dynamic phenomena. This allowed computation of the true misclassification costs and comparison with other sampling approaches. The probability of local contamination levels being above a given critical threshold were computed by indicator kriging. In the case of multiple sensors being relocated simultaneously, a genetic algorithm was used to find sets of suitable new measurement locations. Otherwise, all grid nodes were searched exhaustively, which is computationally demanding. In terms of true misclassification costs, the method outperformed random sampling and sampling based on minimisation of the kriging variance. PMID- 23443380 TI - Multivariate and multiscale data assimilation in terrestrial systems: a review. AB - More and more terrestrial observational networks are being established to monitor climatic, hydrological and land-use changes in different regions of the World. In these networks, time series of states and fluxes are recorded in an automated manner, often with a high temporal resolution. These data are important for the understanding of water, energy, and/or matter fluxes, as well as their biological and physical drivers and interactions with and within the terrestrial system. Similarly, the number and accuracy of variables, which can be observed by spaceborne sensors, are increasing. Data assimilation (DA) methods utilize these observations in terrestrial models in order to increase process knowledge as well as to improve forecasts for the system being studied. The widely implemented automation in observing environmental states and fluxes makes an operational computation more and more feasible, and it opens the perspective of short-time forecasts of the state of terrestrial systems. In this paper, we review the state of the art with respect to DA focusing on the joint assimilation of observational data precedents from different spatial scales and different data types. An introduction is given to different DA methods, such as the Ensemble Kalman Filter (EnKF), Particle Filter (PF) and variational methods (3/4D-VAR). In this review, we distinguish between four major DA approaches: (1) univariate single-scale DA (UVSS), which is the approach used in the majority of published DA applications, (2) univariate multiscale DA (UVMS) referring to a methodology which acknowledges that at least some of the assimilated data are measured at a different scale than the computational grid scale, (3) multivariate single-scale DA (MVSS) dealing with the assimilation of at least two different data types, and (4) combined multivariate multiscale DA (MVMS). Finally, we conclude with a discussion on the advantages and disadvantages of the assimilation of multiple data types in a simulation model. Existing approaches can be used to simultaneously update several model states and model parameters if applicable. In other words, the basic principles for multivariate data assimilation are already available. We argue that a better understanding of the measurement errors for different observation types, improved estimates of observation bias and improved multiscale assimilation methods for data which scale nonlinearly is important to properly weight them in multiscale multivariate data assimilation. In this context, improved cross-validation of different data types, and increased ground truth verification of remote sensing products are required. PMID- 23443381 TI - A DO- and pH-based early warning system of nitrification inhibition for biological nitrogen removal processes. AB - In Korea, more than 80% of municipal wastewater treatment plants (WWTPs) with capacities of 500 m3.d-1 or more are capable of removing nitrogen from wastewater through biological nitrification and denitrification processes. Normally, these biological processes show excellent performance, but if a toxic chemical is present in the influent to a WWTP, the biological processes (especially, the nitrification process) may be affected and fail to function normally; nitrifying bacteria are known very vulnerable to toxic substances. Then, the toxic compound as well as the nitrogen in wastewater may be discharged into a receiving water body without any proper treatment. Moreover, it may take significant time for the process to return back its normal state. In this study, a DO- and pH-based strategy to identify potential nitrification inhibition was developed to detect early the inflow of toxic compounds to a biological nitrogen removal process. This strategy utilizes significant changes observed in the oxygen uptake rate and the pH profiles of the mixed liquor when the activity of nitrifying bacteria is inhibited. Using the strategy, the toxicity from test wastewater with 2.5 mg.L-1 Hg2+, 0.5 mg.L-1 allythiourea, or 0.25 mg.L-1 chloroform could be successfully detected. PMID- 23443383 TI - Assessment of global carbon dioxide concentration using MODIS and GOSAT data. AB - Carbon dioxide (CO(2)) is the most important greenhouse gas (GHG) in the atmosphere and is the greatest contributor to global warming. CO(2) concentration data are usually obtained from ground observation stations or from a small number of satellites. Because of the limited number of observations and the short time series of satellite data, it is difficult to monitor CO(2) concentrations on regional or global scales for a long time. The use of the remote sensing data such as the Advanced Very High Resolution Radiometer (AVHRR) or Moderate Resolution Imaging Spectroradiometer (MODIS) data can overcome these problems, particularly in areas with low densities of CO(2) concentration watch stations. A model based on temperature (MOD11C3), vegetation cover (MOD13C2 and MOD15A2) and productivity (MOD17A2) of MODIS (which we have named the TVP model) was developed in the current study to assess CO(2) concentrations on a global scale. We assumed that CO(2) concentration from the Thermal And Near infrared Sensor for carbon Observation (TANSO) aboard the Greenhouse gases Observing SATellite (GOSAT) are the true values and we used these values to check the TVP model accuracy. The results indicate that the accuracy of the TVP model is different in different continents: the greatest Pearson's correlation coefficient (R2) was 0.75 in Eurasia (RMSE = 1.16) and South America (RMSE = 1.17); the lowest R2 was 0.57 in Australia (RMSE = 0.73). Compared with the TANSO-observed CO(2) concentration (XCO(2)), we found that the accuracy throughout the World is between -2.56~3.14 ppm. Potential sources of TVP model uncertainties were also analyzed and identified. PMID- 23443384 TI - Using an SU-8 photoresist structure and cytochrome C thin film sensing material for a microbolometer. AB - There are two critical parameters for microbolometers: the temperature coefficient of resistance (TCR) of the sensing material, and the thermal conductance of the insulation structure. Cytochrome c protein, having a high TCR, is a good candidate for infrared detection. We can use SU-8 photoresist for the thermal insulation structure, given its low thermal conductance. In this study, we designed a platform structure based on a SU-8 photoresist. We fabricated an infrared sensing pixel and recorded a high TCR for this new structure. The SU-8 photoresist insulation structure was fabricated using the exposure dose method. We experimentally demonstrated high values of TCR from 22%/K to 25.7%/K, and the measured noise was 1.2 * 10(-8) V2/Hz at 60 Hz. When the bias current was 2 MUA, the calculated voltage responsivity was 1.16 * 10(5) V/W. This study presents a new kind of microbolometer based on cytochrome c protein on top of an SU-8 photoresist platform that does not require expensive vacuum deposition equipment. PMID- 23443382 TI - Increases of quadriceps inter-muscular cross-correlation and coherence during exhausting stepping exercise. AB - The aim of this study was to examine the change of the intermuscular cross correlation and coherence of the rectus femoris (RF), vastus medialis (VM) and vastus lateralis (VL) during exhausting stepping exercise. Eleven healthy adults repeated the stepping exercise up to their individual endurance limits (RPE score reached 20), and the cross-correlation and coherence were assessed by surface electromyography (EMG) recordings. The coefficient and time lag of cross correlation and the coherence areas in the alpha (8-12 Hz), beta (15-30 Hz), gamma (30-60 Hz) and high-gamma (60-150 Hz) bands among the three muscle pairs (RF-VM, RF-VL and VM-VL) were calculated. As muscle fatigue, RF-VM and VM-VL showed increases of coefficients and the shortening of time lags. RF-VM and RF-VL showed increases of beta-band coherence in the ascent and descent phases, respectively. The increased intermuscular cross-correlation and beta-band coherence may be a compensatory strategy for maintaining the coordination of knee synergistic muscles during fatigue due to the fatigue-related disturbance of the corticospinal transmission. Therefore, the intermuscular cross-correlation and beta-band coherence may be a potential index for assessing muscle fatigue and monitoring the central control of motor function during dynamic fatiguing exercise. PMID- 23443385 TI - Detecting changes of a distant gas source with an array of MOX gas sensors. AB - We address the problem of detecting changes in the activity of a distant gas source from the response of an array of metal oxide (MOX) gas sensors deployed in an open sampling system. The main challenge is the turbulent nature of gas dispersion and the response dynamics of the sensors. We propose a change point detection approach and evaluate it on individual gas sensors in an experimental setup where a gas source changes in intensity, compound, or mixture ratio. We also introduce an efficient sensor selection algorithm and evaluate the change point detection approach with the selected sensor array subsets. PMID- 23443386 TI - Applications of surface plasmon resonance (SPR) for the characterization of nanoparticles developed for biomedical purposes. AB - Great interest is currently being devoted to the development of nanoparticles (NPs) for biomedical purposes, designed to improve the pharmacokinetic profile of their cargos (either imaging probes or drugs) and to enhance the specific targeting at the disease site. Recent works suggest that Surface Plasmon Resonance (SPR), widely used for the analysis of biomolecular interactions, represents a technique of choice for rapid and quantitative analyses of the interaction between NPs--functionalized with specific ligands--and their putative biological targets. Moreover, SPR can provide important details on the formation and the role of the protein "corona", i.e., the protein layer which coats NPs once they come into contact with biological fluids. These novel applications of SPR sensors may be very useful to characterize, screen and develop nanodevices for biomedical purposes. PMID- 23443387 TI - Study of channel characteristics for galvanic-type intra-body communication based on a transfer function from a quasi-static field model. AB - Intra-Body Communication (IBC), which modulates ionic currents over the human body as the communication medium, offers a low power and reliable signal transmission method for information exchange across the body. This paper first briefly reviews the quasi-static electromagnetic (EM) field modeling for a galvanic-type IBC human limb operating below 1 MHz and obtains the corresponding transfer function with correction factor using minimum mean square error (MMSE) technique. Then, the IBC channel characteristics are studied through the comparison between theoretical calculations via this transfer function and experimental measurements in both frequency domain and time domain. High pass characteristics are obtained in the channel gain analysis versus different transmission distances. In addition, harmonic distortions are analyzed in both baseband and passband transmissions for square input waves. The experimental results are consistent with the calculation results from the transfer function with correction factor. Furthermore, we also explore both theoretical and simulation results for the bit-error-rate (BER) performance of several common modulation schemes in the IBC system with a carrier frequency of 500 kHz. It is found that the theoretical results are in good agreement with the simulation results. PMID- 23443388 TI - Digital sun sensor multi-spot operation. AB - The operation and test of a multi-spot digital sun sensor for precise sun-line determination is described. The image forming system consists of an opaque mask with multiple pinhole apertures producing multiple, simultaneous, spot-like images of the sun on the focal plane. The sun-line precision can be improved by averaging multiple simultaneous measures. Nevertheless, the sensor operation on a wide field of view requires acquiring and processing images in which the number of sun spots and the related intensity level are largely variable. To this end, a reliable and robust image acquisition procedure based on a variable shutter time has been considered as well as a calibration function exploiting also the knowledge of the sun-spot array size. Main focus of the present paper is the experimental validation of the wide field of view operation of the sensor by using a sensor prototype and a laboratory test facility. Results demonstrate that it is possible to keep high measurement precision also for large off-boresight angles. PMID- 23443389 TI - Chirped laser dispersion spectroscopy for remote open-path trace-gas sensing. AB - In this paper we present a prototype instrument for remote open-path detection of nitrous oxide. The sensor is based on a 4.53 MUm quantum cascade laser and uses the chirped laser dispersion spectroscopy (CLaDS) technique for molecular concentration measurements. To the best of our knowledge this is the first demonstration of open-path laser-based trace-gas detection using a molecular dispersion measurement. The prototype sensor achieves a detection limit down to the single-ppbv level and exhibits excellent stability and robustness. The instrument characterization, field deployment performance, and the advantages of applying dispersion sensing to sensitive trace-gas detection in a remote open path configuration are presented. PMID- 23443390 TI - Two-dimensional radial laser scanning for circular marker detection and external mobile robot tracking. AB - This paper presents the use of an external fixed two-dimensional laser scanner to detect cylindrical targets attached to moving devices, such as a mobile robot. This proposal is based on the detection of circular markers in the raw data provided by the laser scanner by applying an algorithm for outlier avoidance and a least-squares circular fitting. Some experiments have been developed to empirically validate the proposal with different cylindrical targets in order to estimate the location and tracking errors achieved, which are generally less than 20 mm in the area covered by the laser sensor. As a result of the validation experiments, several error maps have been obtained in order to give an estimate of the uncertainty of any location computed. This proposal has been validated with a medium-sized mobile robot with an attached cylindrical target (diameter 200 mm). The trajectory of the mobile robot was estimated with an average location error of less than 15 mm, and the real location error in each individual circular fitting was similar to the error estimated with the obtained error maps. The radial area covered in this validation experiment was up to 10 m, a value that depends on the radius of the cylindrical target and the radial density of the distance range points provided by the laser scanner but this area can be increased by combining the information of additional external laser scanners. PMID- 23443391 TI - Autonomous manoeuvring systems for collision avoidance on single carriageway roads. AB - The accurate perception of the surroundings of a vehicle has been the subject of study of numerous automotive researchers for many years. Although several projects in this area have been successfully completed, very few prototypes have actually been industrialized and installed in mass produced cars. This indicates that these research efforts must continue in order to improve the present systems. Moreover, the trend to include communication systems in vehicles extends the potential of these perception systems transmitting their information via wireless to other vehicles that may be affected by the surveyed environment. In this paper we present a forward collision warning system based on a laser scanner that is able to detect several potential danger situations. Decision algorithms try to determine the most convenient manoeuvre when evaluating the obstacles' positions and speeds, road geometry, etc. Once detected, the presented system can act on the actuators of the ego-vehicle as well as transmit this information to other vehicles circulating in the same area using vehicle-to-vehicle communications. The system has been tested for overtaking manoeuvres under different scenarios and the correct actions have been performed. PMID- 23443392 TI - Recent progress in optical chemical sensors. AB - Optical chemical sensors have promoted escalating interest in the determination of various pollutants in the environment, which are creating toxicity and may cause serious health problems. This review paper focuses particularly on the recent progress and developments in this field; the working principles and basic classes of optical chemical sensors have been briefly described. PMID- 23443393 TI - Signal transmission in a human body medium-based body sensor network using a Mach Zehnder electro-optical sensor. AB - The signal transmission technology based on the human body medium offers significant advantages in Body Sensor Networks (BSNs) used for healthcare and the other related fields. In previous works we have proposed a novel signal transmission method based on the human body medium using a Mach-Zehnder electro optical (EO) sensor. In this paper, we present a signal transmission system based on the proposed method, which consists of a transmitter, a Mach-Zehnder EO sensor and a corresponding receiving circuit. Meanwhile, in order to verify the frequency response properties and determine the suitable parameters of the developed system, in-vivo measurements have been implemented under conditions of different carrier frequencies, baseband frequencies and signal transmission paths. Results indicate that the proposed system will help to achieve reliable and high speed signal transmission of BSN based on the human body medium. PMID- 23443394 TI - Wearable and implantable sensors: the patient's perspective. AB - There has been a rising interest in wearable and implantable biomedical sensors over the last decade. However, many technologies have not been integrated into clinical care, due to a limited understanding of user-centered design issues. Little information is available about these issues and there is a need to adopt more rigorous evidence standards for design features to allow important medical sensors to progress quicker into clinical care. Current trends in patient preferences need to be incorporated at an early stage into the design process of prospective clinical sensors. The first comprehensive patient data set, discussing mobile biomedical sensor technology, is presented in this paper. The study population mainly consisted of individuals suffering from arthritis. It was found that sensor systems needed to be small, discreet, unobtrusive and preferably incorporated into everyday objects. The upper extremity was seen as the favored position on the body for placement, while invasive placement yielded high levels of acceptance. Under these conditions most users were willing to wear the body-worn sensor for more than 20 h a day. This study is a first step to generate research based user-orientated design criteria's for biomedical sensors. PMID- 23443395 TI - Immunoanalysis methods for the detection of dioxins and related chemicals. AB - With the development of biotechnology, approaches based on antibodies, such as enzyme-linked immunosorbent assay (ELISA), active aryl hydrocarbon immunoassay (Ah-I) and other multi-analyte immunoassays, have been utilized as alternatives to the conventional techniques based on gas chromatography and mass spectroscopy for the analysis of dioxin and dioxin-like compounds in environmental and biological samples. These screening methods have been verified as rapid, simple and cost-effective. This paper provides an overview on the development and application of antibody-based approaches, such as ELISA, Ah-I, and multi-analyte immunoassays, covering the sample extraction and cleanup, antigen design, antibody preparation and immunoanalysis. However, in order to meet the requirements for on-site fast detection and relative quantification of dioxins in the environment, further optimization is needed to make these immuno-analytical methods more sensitive and easy to use. PMID- 23443396 TI - An amperometric immunosensor based on multi-walled carbon nanotubes-thionine chitosan nanocomposite film for chlorpyrifos detection. AB - In this work, a novel amperometric immunosensor based on multi-walled carbon nanotubes-thionine-chitosan (MWCNTs-THI-CHIT) nanocomposite film as electrode modified material was developed for the detection of chlorpyrifos residues. The nanocomposite film was dropped onto a glassy carbon electrode (GCE), and then the anti-chlorpyrifos monoclonal antibody was covalently immobilized onto the surface of MWCNTs-THI-CHIT/GCE using the crosslinking agent glutaraldehyde (GA). The modification procedure was characterized by using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Under the optimized conditions, a linear relationship between the relative change in peak current of different pulse voltammetry (DPV) and the logarithm of chlorpyrifos solution concentration was obtained in the range from 0.1 to 1.0 * 10(5) ng/mL with a detection limit of 0.046 ng/mL. The proposed chlorpyrifos immunosensor exhibited high reproducibility, stability, and good selectivity and regeneration, making it a potential alternative tool for ultrasensitive detection of chlorpyrifos residues in vegetables and fruits. PMID- 23443398 TI - Towards a hybrid energy efficient multi-tree-based optimized routing protocol for wireless networks. AB - This paper considers the problem of designing power efficient routing with guaranteed delivery for sensor networks with unknown geographic locations. We propose HECTOR, a hybrid energy efficient tree-based optimized routing protocol, based on two sets of virtual coordinates. One set is based on rooted tree coordinates, and the other is based on hop distances toward several landmarks. In HECTOR, the node currently holding the packet forwards it to its neighbor that optimizes ratio of power cost over distance progress with landmark coordinates, among nodes that reduce landmark coordinates and do not increase distance in tree coordinates. If such a node does not exist, then forwarding is made to the neighbor that reduces tree-based distance only and optimizes power cost over tree distance progress ratio. We theoretically prove the packet delivery and propose an extension based on the use of multiple trees. Our simulations show the superiority of our algorithm over existing alternatives while guaranteeing delivery, and only up to 30% additional power compared to centralized shortest weighted path algorithm. PMID- 23443397 TI - Label-free microcavity biosensors: steps towards personalized medicine. AB - Personalized medicine has the potential to improve our ability to maintain health and treat disease, while ameliorating continuously rising healthcare costs. Translation of basic research findings to clinical applications within regulatory compliance is required for personalized medicine to become the new foundation for practice of medicine. Deploying even a few of the thousands of potential diagnostic biomarkers identified each year as part of personalized treatment workflows requires clinically efficient biosensor technologies to monitor multiple biomarkers in patients in real time. This paper discusses a critical component of a regulatory system, a microcavity optical biosensor for label-free monitoring of biomolecular interactions at physiologically-relevant concentrations. While most current biosensor research focuses on improving sensitivity, this paper emphasizes other characteristics a biosensor technology requires to be practical in a clinical setting, presenting robust microcavity biosensors which are easy to manufacture and integrate with microfluidics into flexible and redesignable platforms making the microcavity biosensors deployable for continuous monitoring of biomarkers in body fluids in the clinic, in dense 2D random arrays for high-throughput applications like drug-library screening in interactomics, and of the secretory behavior of single cells in the laboratory. PMID- 23443399 TI - An ultrasensitive chemiluminescence biosensor for carcinoembryonic antigen based on autocatalytic enlargement of immunogold nanoprobes. AB - A sensitive flow injection chemiluminescence assay for carcinoembryonic antigen (CEA) detection based on signal amplification with gold nanoparticles (NPs) is reported in the present work. The sandwich system of CEA/anti-CEA/goat-anti-mouse IgG functionalized Au nanoparticles was used as the sensing platform. In order to improve detection sensitivity, a further gold enlargement step was developed based on the autocatalytic Au deposition of gold nanoprobes via the reduction of AuCl(4)- to Au0 on their surface in the presence of NH(2)OH.HCl. AuCl(4)-, which is a soluble product of gold nanoprobes, served as an analyte in the CL reaction for the indirect measurement of CEA. Under optimized conditions, the CL intensity of the system was linearly related to the logarithm of CEA concentration in the range of 100 pg?mL-1 to 1,000 ng?mL-1, with a detection limit of 20 pg?mL-1. PMID- 23443400 TI - Optical waveguide lightmode spectroscopy (OWLS) as a sensor for thin film and quantum dot corrosion. AB - Optical waveguide lightmode spectroscopy (OWLS) is usually applied as a biosensor system to the sorption-desorption of proteins to waveguide surfaces. Here, we show that OWLS can be used to monitor the quality of oxide thin film materials and of coatings of pulsed laser deposition synthesized CdSe quantum dots (QDs) intended for solar energy applications. In addition to changes in data treatment and experimental procedure, oxide- or QD-coated waveguide sensors must be synthesized. We synthesized zinc stannate (Zn(2)SnO(4)) coated (Si,Ti)O(2) waveguide sensors, and used OWLS to monitor the relative mass of the film over time. Films lost mass over time, though at different rates due to variation in fluid flow and its physical effect on removal of film material. The Pulsed Laser Deposition (PLD) technique was used to deposit CdSe QD coatings on waveguides. Sensors exposed to pH 2 solution lost mass over time in an expected, roughly exponential manner. Sensors at pH 10, in contrast, were stable over time. Results were confirmed with atomic force microscopy imaging. Limiting factors in the use of OWLS in this manner include limitations on the annealing temperature that maybe used to synthesize the oxide film, and limitations on the thickness of the film to be studied. Nevertheless, the technique overcomes a number of difficulties in monitoring the quality of thin films in-situ in liquid environments. PMID- 23443401 TI - An ultrasonic system for weed detection in cereal crops. AB - Site-specific weed management requires sensing of the actual weed infestation levels in agricultural fields to adapt the management accordingly. However, sophisticated sensor systems are not yet in wider practical use, since they are not easily available for the farmers and their handling as well as the management practice requires additional efforts. A new sensor-based weed detection method is presented in this paper and its applicability to cereal crops is evaluated. An ultrasonic distance sensor for the determination of plant heights was used for weed detection. It was hypothesised that the weed infested zones have a higher amount of biomass than non-infested areas and that this can be determined by plant height measurements. Ultrasonic distance measurements were taken in a winter wheat field infested by grass weeds and broad-leaved weeds. A total of 80 and 40 circular-shaped samples of different weed densities and compositions were assessed at two different dates. The sensor was pointed directly to the ground for height determination. In the following, weeds were counted and then removed from the sample locations. Grass weeds and broad-leaved weeds were separately removed. Differences between weed infested and weed-free measurements were determined. Dry-matter of weeds and crop was assessed and evaluated together with the sensor measurements. RGB images were taken prior and after weed removal to determine the coverage percentages of weeds and crop per sampling point. Image processing steps included EGI (excess green index) computation and thresholding to separate plants and background. The relationship between ultrasonic readings and the corresponding coverage of the crop and weeds were assessed using multiple regression analysis. Results revealed a height difference between infested and non-infested sample locations. Density and biomass of weeds present in the sample influenced the ultrasonic readings. The possibilities of weed group discrimination were assessed by discriminant analysis. The ultrasonic readings permitted the separation between weed infested zones and non-infested areas with up to 92.8% of success. This system will potentially reduce the cost of weed detection and offers an opportunity to its use in non-selective methods for weed control. PMID- 23443402 TI - A laboratory goniometer system for measuring reflectance and emittance anisotropy. AB - In this paper, a laboratory goniometer system for performing multi-angular measurements under controlled illumination conditions is described. A commercially available robotic arm enables the acquisition of a large number of measurements over the full hemisphere within a short time span making it much faster than other goniometers. In addition, the presented set-up enables assessment of anisotropic reflectance and emittance behaviour of soils, leaves and small canopies. Mounting a spectrometer enables acquisition of either hemispherical measurements or measurements in the horizontal plane. Mounting a thermal camera allows directional observations of the thermal emittance. This paper also presents three showcases of these different measurement set-ups in order to illustrate its possibilities. Finally, suggestions for applying this instrument and for future research directions are given, including linking the measured reflectance anisotropy with physically-based anisotropy models on the one hand and combining them with field goniometry measurements for joint analysis with remote sensing data on the other hand. The speed and flexibility of the system offer a large added value to the existing pool of laboratory goniometers. PMID- 23443403 TI - On-line smoothing for an integrated navigation system with low-cost MEMS inertial sensors. AB - The integration of the Inertial Navigation System (INS) and the Global Positioning System (GPS) is widely applied to seamlessly determine the time variable position and orientation parameters of a system for navigation and mobile mapping applications. For optimal data fusion, the Kalman filter (KF) is often used for real-time applications. Backward smoothing is considered an optimal post-processing procedure. However, in current INS/GPS integration schemes, the KF and smoothing techniques still have some limitations. This article reviews the principles and analyzes the limitations of these estimators. In addition, an on-line smoothing method that overcomes the limitations of previous algorithms is proposed. For verification, an INS/GPS integrated architecture is implemented using a low-cost micro-electro-mechanical systems inertial measurement unit and a single-frequency GPS receiver. GPS signal outages are included in the testing trajectories to evaluate the effectiveness of the proposed method in comparison to conventional schemes. PMID- 23443404 TI - Is lymphatic status related to regression of inflammation in Crohn's disease? AB - AIM: To investigate the status of the lymphatic vessels in the small bowel affected by Crohn's disease (CD) at the moment of surgery. METHODS: During the period January 2011-June 2011, 25 consecutive patients affected by CD were operated on in our Institution. During surgery, Patent Blue V was injected subserosally and the way it spread along the subserosa of the intestinal wall, through the mesenterial layers towards the main lymphatic collectors and eventually to the lymph nodes was observed and recorded. Since some patients had been undergone strictureplasty at previous surgery, we also examined the status of intestinal lymph vessels after previous strictureplasties. The same procedure was performed in a control group of 5 patients affected by colorectal cancer. Length of lesions, caliber, maximal thickness of the diseased intestinal wall, thickness of the wall at injection site and thickness of the mesentery were evaluated at surgery. RESULTS: We observed three features after the injection of Patent Blue V in the intestinal loops: (1) Macroscopically healthy terminal ileum of patients with CD or colon cancer showed thin lymphatic vessels linearly directed toward the mesentery; (2) In mild lesions in which the intestinal wall did not reach 8 mm of thickness, we observed short, wide and tortuous lymphatic vessels directed longitudinally along the intestinal axis toward disease-free areas and then transversally toward the mesentery; and (3) Injection in the severely affected lesions, that had a thickness of the intestinal wall over 10 mm, did not show any feature of lymphatic vessels at least on the subserosal surface. There was a correlation between the thickness of the parietal wall and the severity of the lymphatic alterations. Normal lymphatic vessels were observed at previous strictureplasties in the presence of complete regression of the inflammation. CONCLUSION: Injection of Patent Blue V in the intestinal wall could help distinguish healthy tracts of the small bowel from those macroscopically borderline. PMID- 23443405 TI - Low temperature solution-processed high performance photodiode based on Si-ZnO core-shell structure. AB - Radial heterojunction photodiodes based on a silicon nanowire arrays (SiNWs)-zinc oxide (ZnO) core-shell structure is demonstrated in this report. The heterojunction can be constructed by spin-coating ZnO nanoparticles onto SiNWs and a low temperature post-annealing process (<270 degrees C). The photodiode displays typical diode rectifying characteristics with an ideality factor of as low as 1.28, and shows an excellent photoresponse in both visible and near infrared regions in which a peak value of 0.54 A/W at zero bias was attained. The sensitivity is superior to that of previously reported devices fabricated with vacuum-deposition methods. In contrast, the planar silicon-ZnO junction only displays the peak photoresponsivity of 0.34 A/W. The superior performance of radial junction is ascribed to the highlight-harvesting capability, large interfacial area and efficient charge carrier collection arising from the core (SiNWs)-shell (ZnO) structure. Here, high temperature processes are dispensable by using facile solution-processed techniques, which avoid thermal minority lifetime degradation of silicon and simplify the fabrication process of the photodiodes. PMID- 23443406 TI - Egg arrangement in avian clutches covaries with the rejection of foreign eggs. AB - In birds, the colour, maculation, shape, and size of their eggs play critical roles in discrimination of foreign eggs in the clutch. So far, however, no study has examined the role of egg arrangement within a clutch on host rejection responses. We predicted that individual females which maintain consistent egg arrangements within their clutch would be better able to detect and reject foreign eggs than females without a consistent egg arrangement (i.e. whose eggs change positions more often across incubation). We tested this "egg arrangement hypothesis" in blackbirds (Turdus merula) and song thrush (T. philomelos). Both species are suitable candidates for research on egg rejection, because they show high inter-individual variation and individual repeatability in egg rejection responses. As predicted, using our custom-defined metrics of egg arrangement, rejecter females' clutches showed significantly more consistent patterns in egg arrangement than acceptor females' clutches. Only parameters related to blunt pole showed consistent differences between rejecters and acceptors. This finding makes biological sense because it is already known that song thrush use blunt pole cues to reject foreign eggs. We propose that a disturbance of the original egg arrangement pattern by the laying parasite may alert host females that maintain a consistent egg arrangement to the risk of having been parasitized. Once alerted, these hosts may shift their discrimination thresholds to be more restrictive so as to reject a foreign egg with higher probability. Future studies will benefit from experimentally testing whether these two and other parasitized rejecter host species may rely on the use of consistent egg arrangements as a component of their anti-parasitic defence mechanisms. PMID- 23443407 TI - Monkeys perform as well as apes and humans in a size discrimination task. AB - Whether the cognitive competences of monkeys and apes are rather similar or whether the larger-brained apes outperform monkeys in cognitive experiments is a highly debated topic. Direct comparative analyses are therefore essential to examine similarities and differences among species. We here compared six primate species, including humans, chimpanzees, bonobos, gorillas (great apes), olive baboons, and long-tailed macaques (Old World monkeys) in a task on fine-grained size discrimination. Except for gorillas, subjects of all taxa (i.e. humans, apes, and monkeys) were able to discriminate three-dimensional cubes with a volume difference of only 10 % (i.e. cubes of 50 and 48 mm side length) and performed only slightly worse when the cubes were presented successively. The minimal size discriminated declined further with increasing time delay between presentations of the cubes, highlighting the difficulty to memorize exact size differences. The results suggest that differences in brain size, as a proxy for general cognitive abilities, did not account for variation in performance, but that differential socio-ecological pressures may better explain species differences. Our study highlights the fact that differences in cognitive abilities do not always map neatly onto phylogenetic relationships and that in a number of cognitive experiments monkeys do not fare significantly worse than apes, casting doubt on the assumption that larger brains per se confer an advantage in such kinds of tests. PMID- 23443408 TI - In vivo evaluation of the interaction between titanium dioxide nanoparticle and rat liver DNA. AB - Titanium dioxide nanoparticles (TiO2 NPs) are massively produced and widely used in daily life, which may pose potential risk to human health via uncharacterized interaction between DNAs. This research aims to examine the interaction between DNA and three types of TiO2 NPs of different sizes and crystallines. The interaction between TiO2 NPs and liver DNA molecules obtained from Sprague-Dawley rats was systematically evaluated in vivo using atomic force microscopy, transmission electron microscopy, various spectroscopic techniques and gel electrophoresis. We found that TiO2 NPs (diameter <25 nm and <100 nm) in anatase crystalline can covalently interact with liver DNA by either inserting itself in between DNA base pairs or binding to DNA nucleotide via P-O-Ti-O bond. Such interaction may not be NP size-dependent but may be crystalline phase-dependent, because such interaction did not occur in rutile crystal phase, in which the DNA damage was potentially caused by reactive oxygen species. PMID- 23443409 TI - Production of a sterilised decellularised tendon allograft for clinical use. AB - Application of a high-level decontamination or sterilisation procedure and cell removal technique to tendon allograft can reduce the concerns of disease transmission, immune reaction, and may improve remodelling of the graft after implantation. The decellularised matrix can also be used as a matrix for tendon tissue engineering. One such sterilisation factor, Peracetic acid (PAA) has the advantage of not producing harmful reaction residues. The aim of this study was to evaluate the effects of PAA treatment and a cell removal procedure on the production of tendon matrix. Human patellar tendons, thawed from frozen were treated respectively as: Group 1, control with no treatment; Group 2, sterilised with PAA (0.1 % (w/v) PAA for 3 h) Group 3, decellularised (incubation successively in hypotonic buffer, 0.1 % (w/v) sodium dodecyl sulphate, and a nuclease solution); Group 4, decellularised and PAA sterilised. Histological analysis showed that no cells were visible after the decellularisation treatment. The integrity of tendon structure was maintained after decellularisation and PAA sterilisation, however, the collagen waveform was slightly loosened. No contact cytotoxicity was found in any of the groups. Determination of de-natured collagen showed no significant increase when compared with the control. This suggested that the decellularisation and sterilisation processing procedures did not compromise the major properties of the tendon. The sterilised, decellularised tendon could be suitable for clinical use. PMID- 23443410 TI - The effect of delayed percutaneous nephrolithotomy on the risk of bacteremia and sepsis in patients with neuromuscular disorders. AB - PURPOSE: To determine whether a delayed percutaneous nephrolithotomy (PCNL) reduces the rate of bacteremia/sepsis in patients with neuromuscular disorders. Patients with neuromuscular disorders are at higher risk of developing complications after PCNL. One strategy to reduce the risk of infectious complications is to place a percutaneous nephrostomy tube at least 24 h prior to performing PCNL. We analyzed the rates of bacteremia/sepsis in patients with neuromuscular disorders who had access on the day of PCNL (same-day) versus more than 24 h prior to the treatment for the stone (delayed). MATERIALS AND METHODS: We identified 246 consecutive patients who underwent PCNL at our institution between 8/2003 and 8/2008, 35 of whom (14%) had neuromuscular disorders. The primary end point was postoperative bacteremia (fever and positive blood culture) or sepsis (SIRS and documented infection), which was compared between those who had percutaneous access on the day of surgery versus those who had access at least 24 h prior to the operative event. All patients had negative urine cultures preoperatively or were treated with antibiotics for 4-7 days prior to the surgery for a positive preoperative urine culture. RESULTS: The neuromuscular disorders in the 35 patients were multiple sclerosis (16), spina bifida (10), quadriplegia (4), paraplegia/Guillain-Barre (3), and cerebral palsy (2). The rate of bacteremia/sepsis among patients with neuromuscular disorders was 14%. The rate of sepsis/bacteremia was 26% for same-day PCNL versus 0% for delayed PCNL (OR 8.4, p = 0.05). CONCLUSIONS: Delayed PCNL results in lower rates of bacteremia and/or sepsis in patients with neuromuscular disorders. PMID- 23443411 TI - MADD promotes the survival of human lung adenocarcinoma cells by inhibiting apoptosis. AB - MAPK-activating death domain protein (MADD) binds to the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor and acts as a key downstream mediator in the TRAIL-induced apoptosis pathway. The aim of this study was to evaluate the expression of MADD in normal human and adenocarcinoma tissues of the lungs and its influence on proliferation and apoptosis of A549 human lung adenocarcinoma cells. Immunohistochemistry was carried out to detect the expression of MADD in normal and tumor tissues of the lungs. Expression of the MADD gene in A549 cells was measured by reverse transcription-polymerase chain reaction. A549 cells were transfected with plasmids carrying the DNA fragment encoding MADD and lentiviral vectors used for RNA interference, respectively. MADD expression in the transfected A549 cells was determined by western blotting. Proliferation and apoptosis were detected using MTT assay and flow cytometry, respectively. It was found that non-small cell lung cancer tissues expressed MADD at higher levels compared to normal lung tissues, and the level of MADD in lung adenocarcinoma was higher compared to that in lung squamous cell carcinoma. MADD was expressed in A549 cells. Both introduction of the DNA fragment encoding MADD and RNA interference targeting MADD effectively altered levels of MADD in the A549 cells. Overexpression of MADD in the A549 cells inhibited apoptosis and increased survival whereas abrogation of MADD promoted apoptosis and reduced cell proliferation. These results suggest that MADD may be a potential therapeutic target for lung adenocarcinoma therapy involving the TRAIL-induced apoptosis pathway. PMID- 23443413 TI - The effect of different gamma doses on some properties of a CR-39 detector. AB - In the current study, the bulk etch rate, the removal thickness percentage and the track density have been examined for gamma-irradiated at doses ranging from 0 to 100 kGy. After irradiating CR-39 detectors, they got etched at 70 degrees C in different concentration of NaOH solutions for various time intervals. Results indicate that the bulk etch rate and the removal thickness percentage increase with the increase of gamma absorbed dose and the etchant solution concentration. The track density increases with increase of the etchant solution concentration for irradiated samples (0, 10, 50 kGy) up to 6.25 N NaOH, and then it decreases with the increase of the etchant solution concentration for un-irradiated samples and those irradiated with 10 kGy, and with the high doses the samples' surface got damaged. PMID- 23443412 TI - Next-generation sequencing for disorders of low and high bone mineral density. AB - To achieve an efficient molecular diagnosis of osteogenesis imperfecta (OI), Ehlers-Danlos syndrome (EDS), and osteopetrosis (OPT), we designed a next generation sequencing (NGS) platform to sequence 34 genes. We validated this platform on known cases and have successfully identified the causative mutation in most patients without a prior molecular diagnosis. INTRODUCTION: Osteogenesis imperfecta, Ehlers-Danlos syndrome, and osteopetrosis are collectively common inherited skeletal diseases. Evaluation of subjects with these conditions often includes molecular testing which has important counseling and therapeutic and sometimes legal implications. Since several different genes have been implicated in these conditions, Sanger sequencing of each gene can be a prohibitively expensive and time-consuming way to reach a molecular diagnosis. METHODS: In order to circumvent these problems, we have designed and tested a NGS platform that would allow simultaneous sequencing on a single diagnostic platform of different genes implicated in OI, OPT, EDS, and other inherited conditions, leading to low or high bone mineral density. We used a liquid-phase probe library that captures 602 exons (~100 kb) of 34 selected genes and have applied it to test clinical samples from patients with bone disorders. RESULTS: NGS of the captured exons by Illumina HiSeq 2000 resulted in an average coverage of over 900X. The platform was successfully validated by identifying mutations in six patients with known mutations. Moreover, in four patients with OI or OPT without a prior molecular diagnosis, the assay was able to detect the causative mutations. CONCLUSIONS: In conclusion, our NGS panel provides a fast and accurate method to arrive at a molecular diagnosis in most patients with inherited high or low bone mineral density disorders. PMID- 23443414 TI - On optically stimulated luminescence properties of household salt as a retrospective dosemeter. AB - Thermoluminescence (TL) and optically stimulated luminescence (OSL) in the UV (270-370 nm) spectral region have been investigated for five types of table salt (NaCl) available in Romanian supermarkets with a view to applying them in retrospective dosimetry. The salt samples gave bright TL signals with two main peaks at ~100 degrees C and at 300 or 260 degrees C, depending on the origin of the salt and bright OSL signals under continuous stimulation with blue light. The OSL signal (stimulated at 100 degrees C after a pre-heat of 10 s at 150 degrees C) was used for investigations in a standard multiple aliquot procedure. The dose response was found to be linear in the dose range investigated (up to ~100 mGy) and the lower limit of detection for the samples varied from ~0.01 to 14 mGy. These characteristics, along with the widespread abundance and low cost of household salt, confirm its potential as a retrospective dosemeter. PMID- 23443417 TI - The cover. Crosstown Sunset [corrected]. PMID- 23443419 TI - The layman, medical advertisements and the newspaper. PMID- 23443420 TI - Search for ways to reduce gun violence spurred by toll of recent shootings. PMID- 23443421 TI - More than one-third of US individuals use the Internet to self-diagnose. PMID- 23443429 TI - Antiviral therapy and hepatitis B virus-related hepatocellular carcinoma recurrence. PMID- 23443430 TI - Antiviral therapy and hepatitis B virus-related hepatocellular carcinoma recurrence. PMID- 23443431 TI - Antiviral therapy and hepatitis B virus-related hepatocellular carcinoma recurrence--reply. PMID- 23443432 TI - Personal health records and medical care use. PMID- 23443433 TI - Personal health records and medical care use--reply. PMID- 23443434 TI - Emergence of large treatment effects from small trials. PMID- 23443435 TI - Emergence of large treatment effects from small trials--reply. PMID- 23443436 TI - Prognostic assay in small, node-negative non-small cell lung cancer. PMID- 23443437 TI - Prognostic assay in small, node-negative non-small cell lung cancer--reply. PMID- 23443438 TI - Why the ethics of parsimonious medicine is not the ethics of rationing. PMID- 23443439 TI - The value of low-value lists. PMID- 23443440 TI - A piece of my mind. If only grown-ups would pay attention. PMID- 23443441 TI - Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. AB - IMPORTANCE: Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression. OBJECTIVE: To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction. DESIGN AND SETTING: The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction. INTERVENTION: Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up. MAIN OUTCOME MEASURES: The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months. RESULTS: Diastolic function (E/e') decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% CI, -2.0 to -0.9; P < .001). Peak VO2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, -0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6 minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations. CONCLUSIONS AND RELEVANCE: In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31. PMID- 23443442 TI - Bariatric surgery complications before vs after implementation of a national policy restricting coverage to centers of excellence. AB - IMPORTANCE: Starting in 2006, the Centers for Medicare & Medicaid Services (CMS) has restricted coverage of bariatric surgery to hospitals designated as centers of excellence (COE) by 2 major professional organizations. OBJECTIVE: To evaluate whether the implementation of the COE component of the national coverage decision was associated with improved bariatric surgery outcomes in Medicare patients. DESIGN, SETTING, AND PATIENTS: Retrospective, longitudinal study using 2004-2009 hospital discharge data from 12 states (n = 321,464 patients) of changes in outcomes in Medicare patients undergoing bariatric surgery (n = 6723 before and n = 15,854 after implementation of the policy). A difference-in-differences analytic approach was used to evaluate whether the national coverage decision was associated with improved outcomes in Medicare patients above and beyond existing time trends in non-Medicare patients (n = 95,558 before and n = 155,117 after implementation of the policy). MAIN OUTCOME MEASURES: Risk-adjusted rates of any complication, serious complications, and reoperation. RESULTS: Bariatric surgery outcomes improved during the study period in both Medicare and non-Medicare patients; however, this change was already under way prior to the CMS coverage decision. After accounting for patient factors, changes in procedure type, and preexisting time trends toward improved outcomes, there were no statistically significant improvements in outcomes after (vs before) implementation of the CMS national coverage decision for any complication (8.0% after vs 7.0% before; relative risk [RR], 1.14 [95% CI, 0.95-1.33]), serious complications (3.3% vs 3.6%, respectively; RR, 0.92 [95% CI, 0.62-1.22]), and reoperation (1.0% vs 1.1%; RR, 0.90 [95% CI, 0.64-1.17]). In a direct assessment comparing outcomes at hospitals designated as COEs (n = 179) vs hospitals without the COE designation (n = 519), no significant differences were found for any complication (5.5% vs 6.0%, respectively; RR, 0.98 [95% CI, 0.90-1.06]), serious complications (2.2% vs 2.5%; RR, 0.92 [95% CI, 0.84-1.00]), and reoperation (0.83% vs 0.96%; RR, 1.00 [95% CI, 0.86-1.17]). CONCLUSIONS AND RELEVANCE: Among Medicare patients undergoing bariatric surgery, there was no significant difference in the rates of complications and reoperation before vs after the CMS policy of restricting coverage to COEs. Combined with prior studies showing no association of COE designation and outcomes, these results suggest that Medicare should reconsider this policy. PMID- 23443443 TI - Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. AB - IMPORTANCE: Evidence from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database suggests that the incidence of advanced breast cancer in young women is increasing. OBJECTIVE: To quantify this trend and analyze it as a function of stage at diagnosis, race/ethnicity, residence, and hormone receptor status. DESIGN, SETTING, AND PATIENTS: Breast cancer incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis were obtained from 3 SEER registries that provide data spanning 1973-2009, 1992-2009, and 2000-2009. SEER defines localized as disease confined to the breast, regional to contiguous and adjacent organ spread (eg, lymph nodes, chest wall), and distant disease to remote metastases (bone, brain, lung, etc). MAIN OUTCOME MEASURE: Breast cancer incidence trends in the United States. RESULTS: In the United States, the incidence of breast cancer with distant involvement at diagnosis increased in 25- to 39-year-old women from 1.53 (95% CI, 1.01 to 2.21) per 100,000 in 1976 to 2.90 (95% CI, 2.31 to 3.59) per 100,000 in 2009. This is an absolute difference of 1.37 per 100,000, representing an average compounded increase of 2.07% per year (95% CI, 1.57% to 2.58%; P < .001) over the 34-year interval. No other age group or extent-of-disease subgroup of the same age range had a similar increase. For 25- to 39-year-olds, there was an increased incidence in distant disease among all races and ethnicities evaluated, especially non-Hispanic white and African American, and this occurred in both metropolitan and nonmetropolitan areas. Incidence for women with estrogen receptor-positive subtypes increased more than for women with estrogen receptor negative subtypes. CONCLUSION AND RELEVANCE: Based on SEER data, there was a small but statistically significant increase in the incidence of breast cancer with distant involvement in the United States between 1976 and 2009 for women aged 25 to 39 years, without a corresponding increase in older women. PMID- 23443444 TI - Surveillance intervals for small abdominal aortic aneurysms: a meta-analysis. AB - IMPORTANCE: Small abdominal aortic aneurysms (AAAs [3.0 cm-5.4 cm in diameter]) are monitored by ultrasound surveillance. The intervals between surveillance scans should be chosen to detect an expanding aneurysm prior to rupture. OBJECTIVE: To limit risk of aneurysm rupture or excessive growth by optimizing ultrasound surveillance intervals. DATA SOURCES AND STUDY SELECTION: Individual patient data from studies of small AAA growth and rupture were assessed. Studies were identified for inclusion through a systematic literature search through December 2010. Study authors were contacted, which yielded 18 data sets providing repeated ultrasound measurements of AAA diameter over time in 15,471 patients. DATA EXTRACTION: AAA diameters were analyzed using a random-effects model that allowed for between-patient variability in size and growth rate. Rupture rates were analyzed by proportional hazards regression using the modeled AAA diameter as a time-varying covariate. Predictions of the risks of exceeding 5.5-cm diameter and of rupture within given time intervals were estimated and pooled across studies by random effects meta-analysis. RESULTS: AAA growth and rupture rates varied considerably across studies. For each 0.5-cm increase in AAA diameter, growth rates increased on average by 0.59 mm per year (95% CI, 0.51 0.66) and rupture rates increased by a factor of 1.91 (95% CI, 1.61-2.25). For example, to control the AAA growth risk in men of exceeding 5.5 cm to below 10%, on average, a 7.4-year surveillance interval (95% CI, 6.7-8.1) is sufficient for a 3.0-cm AAA, while an 8-month interval (95% CI, 7-10) is necessary for a 5.0-cm AAA. To control the risk of rupture in men to below 1%, the corresponding estimated surveillance intervals are 8.5 years (95% CI, 7.0-10.5) and 17 months (95% CI, 14-22). CONCLUSION AND RELEVANCE: In contrast to the commonly adopted surveillance intervals in current AAA screening programs, surveillance intervals of several years may be clinically acceptable for the majority of patients with small AAA. PMID- 23443445 TI - Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. AB - The CONSORT (Consolidated Standards of Reporting Trials) Statement aims to improve the reporting of randomized controlled trials (RCTs); however, it lacks guidance on the reporting of patient-reported outcomes (PROs), which are often inadequately reported in trials, thus limiting the value of these data. In this article, we describe the development of the CONSORT PRO extension based on the methodological framework for guideline development proposed by the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network. Five CONSORT PRO checklist items are recommended for RCTs in which PROs are primary or important secondary end points. These recommendations urge that the PROs be identified as a primary or secondary outcome in the abstract, that a description of the hypothesis of the PROs and relevant domains be provided (ie, if a multidimensional PRO tool has been used), that evidence of the PRO instrument's validity and reliability be provided or cited, that the statistical approaches for dealing with missing data be explicitly stated, and that PRO-specific limitations of study findings and generalizability of results to other populations and clinical practice be discussed. Examples and an updated CONSORT flow diagram with PRO items are provided. It is recommended that the CONSORT PRO guidance supplement the standard CONSORT guidelines for reporting RCTs with PROs as primary or secondary outcomes. Improved reporting of PRO data should facilitate robust interpretation of the results from RCTs and inform patient care. PMID- 23443446 TI - Acute onset of retrosternal and epigastric pain. PMID- 23443447 TI - Defining diastolic heart failure and identifying effective therapies. PMID- 23443448 TI - Promoting quality surgical care: the next steps. PMID- 23443449 TI - JAMA patient page. Adult sinusitis. PMID- 23443450 TI - Effect of pH on the metabolic flux of Klebsiella oxytoca producing 2,3-butanediol in continuous cultures at different dilution rates. AB - The efficiency of the bioconversion process and the achievable end-product concentration decides the economic feasibility of microbial 2,3-butanediol (2,3 BDO) production. In 2,3-BDO production, optimization of culture condition is required for cell growth and metabolism. Also, the pH is an important factor that influences microbial performance. For different microorganisms and substrates, it has been shown that the distribution of the metabolites in 2,3-BDO fermentation is greatly affected by pH, and the optimum pH for 2,3-BDO production seems dependently linked to the particular strain and the substrate employed. Quantification analysis of intracellular metabolites and metabolic flux analysis (MFA) were used to investigate the effect of pH on the Klebsiella oxytoca producing 2,3-BDO and other organic acids. The main objectives of MFA are the estimation of intracellular metabolic fluxes and the identification of rate limiting step and the key enzymes. This study was conducted under continuous aerobic conditions at different dilution rates (0.1, 0.2, and 0.3 h(-1)) and different pH values (pH 5.5 and 7.0) for the steady-state experimental data. In order to obtain the flux distribution, the extracellular specific rates were calculated from the experimental data using the metabolic network model of K. oxytoca. Intracellular metabolite concentration profiles were generated using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. PMID- 23443451 TI - Mucormycosis in a patient with acute myeloid leukemia successfully treated with liposomal amphotericin B associated with deferasirox and hyperbaric oxygen. AB - We report a 38-year-old woman presenting with febrile neutropenia, acute myeloid leukemia (AML) and invasive mucormycosis. Bone marrow aspirate was characteristic of AML minimally differentiated (WHO classification 2008). Flow cytometric immunophenotyping analysis showed blasts positive for CD7, CD33, CD34, CD71, CD117, HLA-DR, MPO, and TdT, with normal karyotype (46, XX), and the absence of the FLT3-ITD and NPM1 mutations. The patient's management included chemotherapy with cytarabine and idarubicin, and treatment with liposomal amphotericin B, deferasirox, hyperbaric oxygen therapy, and antibiotics. Nowadays, she is in complete hematological remission, and CT images of control are normal. Invasive mucormycosis is an uncommon and severe condition, which involves diagnosis and treatment challenges. Clinical features and predisposing factors should be highlighted in order to enhance the suspicion index, contributing to early diagnosis and disease control. Our aim is to report classical features of this uncommon condition and to emphasize usual management challenges. PMID- 23443452 TI - Application of automated pathology reporting concepts to radiology reports. AB - OBJECTIVE: This study was designed to extend the concept of automated pathology reporting to radiology reports to find central nervous system (CNS) neoplasms that may currently go undetected. METHODS: Existing E-Path software was modified to account for the structure and language of radiology reports. Logic was added to allow registries to configure whether they want only new reports or if they also want history, metastatic, and/or previously known reports. Five hospital registries and 3 central registries participated. Three quality-control (QC) studies were conducted with fine-tuning taking place between the studies. The first QC study included random samples of 1,500 reports from 3 data sources. The second and third QC studies each included 1 random sample from 2 different data sources. RESULTS: The software was able to extract reportable CNS neoplasms with a high degree of specificity and sensitivity at 99% and 100% respectively, using the original set of coding rules. This rule set was favored by our hospital registries. Participating population-based registries preferred to receive only positive-new cases. The specificity and sensitivity for this category was 96% and 94% respectively. One hospital registry compared the cases found by the software to their registry database and found 13 additional CNS neoplasm cases in a 10 month period which represented an increase of 18%. CONCLUSION: Automated radiology reporting is a promising method of mining a previously untapped data source to find cases of CNS neoplasms that may be missed by conventional techniques. PMID- 23443453 TI - Evaluating factors associated with unknown SEER Summary Stage 2000 derived from collaborative stage at central registry level. AB - BACKGROUND: Cancer stage is critical for treatment planning and assessing disease prognosis. The percentage of unknown staged cancer cases varies considerably across state cancer registries; factors contributing to the variations in unknown stage have not been reported in the literature before. The purpose of this study was to examine whether these variations were influenced by demographic and/or clinical factors as well as the type of reporting facility. METHODS: Invasive colorectal, lung, female breast, and prostate cancers diagnosed between 2004 and 2007 were obtained from the North American Association of Central Cancer Registries (NAACCR); 47 population-based cancer registries in the United States were included. The unknown stage was based on Summary Stage 2000 codes derived from Collaborative Stage Version 1 (CSv1). Relative importance analysis was used to identify variables that were essential in predicting unknown stage. Using state central registries as analytical units, multiple linear regression was used to evaluate factors associated with the percentage of unknown stage by cancer site; potential outlier registries with a high percentage of unknown stage cases were identified using boxplots and standardized residuals. RESULTS: Overall, lung cancer had the highest percentage of unknown stage (8.3%) and prostate cancer had the largest variation of unknown stage among registries (0.6%-18.1%). The percentages of neoplasms not otherwise specified (NOS) histology, non-microscopic confirmation, and non-hospital reporting source were positively associated (p less than 0.05) with percentage of unknown stage for all studied cancer sites before adjustment. Variables that retained a positive association with unknown stage including all demographic and clinical variables, year of diagnosis, and type of reporting source were black race, metropolitan area less than 1 million population, histologies of neoplasms NOS or epithelial neoplasms NOS, diagnosis year 2005, and non-hospital reporting source for colorectal cancer; metropolitan area less than 1 million population, neoplasms NOS histology, and non-hospital reporting source for female breast; and diagnosis year 2005 and non-hospital reporting source for prostate. After adjustment, none of the predictors were significant for lung cancer. We observed 1 potential outlier registry each for colorectal, lung and female breast cancers. CONCLUSIONS: Factors associated with unknown stage differ by cancer site; however, the type of reporting source is an important predictor of unknown stage for all cancers except lung after adjustment. Central registries with high percentage of unknown stage should be made aware of their data quality issue(s). As a result, these registries can investigate those factors and provide training to registrars to improve their cancer data quality. PMID- 23443454 TI - Coding of specific subgroups of myelodysplastic syndromes in a population-based cancer registry: prospects for improvement. AB - Myelodysplastic syndromes (MDS), reportable to US cancer registries for diagnoses since 2001, are a group of myeloid neoplasms heterogeneous in prognosis and treatment, and of growing importance in an aging population. In US registries that have reported incident MDS cases by subgroup, about 50%-67% of cases have been coded as MDS "not otherwise specified" (NOS) in the International Classification of Diseases for Oncology Version 3 (ICD-O-3). For this study, MDS cases diagnosed in 2001-2009 and reported to the population-based Connecticut Tumor Registry (CTR) were analyzed. MDS was coded as NOS for 573 (56.7%) of 1,011 cases, but the proportion varied among reporting facilities hospitals (ie, from 0 to 100%), with several statistical outliers. In pathology reports obtained for 130 CTR patients diagnosed with MDS in 2008-2009, 84% of the 62 patients coded as NOS had information on a key element (ie, % of blasts in bone marrow) in ICD-O-3 coding and other classifications of MDS subgroups. These findings suggest that central cancer registries may want to work with hospital tumor registrars in improving reporting of specific MDS subgroups using ICD-O-3. The addition of % blasts from pathology reports to the site-specific factors for MDS in the Collaborative Staging System could be proposed. PMID- 23443455 TI - Leukemia as a cause of death among patients with myelodysplastic syndromes (MDS) in a population- based cancer registry: improving estimates of MDS-related mortality in the population. AB - Myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms diagnosed mostly in elderly persons, are of increasing interest in an aging population and are associated with variable risk of progression to acute myeloid leukemia (AML). The numbers of deaths related to MDS in the population are underestimated in routine US cancer mortality statistics which are based on only the underlying cause (UC) rather than multiple causes (MCs) of death recorded on death certificates. Additional MDS-related deaths, however, may be missed if some MDS patients die with mention of leukemia but not MDS on their death certificate. This requires studies of MCs of death among all MDS patients in population-based tumor registries. This study examined MCs of death among patients diagnosed with MDS in 2001- 2009 and reported to the population-based Connecticut Tumor Registry. MDS was the UC for 199 deaths (25.7% of all 773) and was coded as other than UC for 160 (20.7%). Another 121 (15.7%) death records, however, had leukemia without mention of MDS; the majority were coded to AML and most of the others as unspecified type of acute leukemia. If these 121 deaths are added to the 359 with mention of MDS, the total of MDS-related deaths would be 480 (or 62.1% of all 773 deaths). A total of 178 deaths (23.0% of all 773) were coded to leukemia as the UC, and would be included with leukemia (not MDS) in routine cancer mortality statistics. Leukemia diagnosed since 2010 in MDS patients is reportable to registries as a new primary cancer. This new rule will help central cancer registries to confirm leukemia diagnoses coded on death records, as part of the process of improving surveillance of cancer mortality rates in the population. PMID- 23443456 TI - Evaluation of primary/preferred language data collection. AB - A literature review was conducted to identify peer-reviewed articles related to primary/preferred language and interpreter-use data collection practices in hospitals, clinics, and outpatient settings to assess its completeness and quality. In January 2011, Embase (Ovid), MEDLINE (Ovid), PubMed, and Web of Science databases were searched for eligible studies. Primary and secondary inclusion criteria were applied to selected eligible articles. This extensive literature search yielded 768 articles after duplicates were removed. After primary and secondary inclusion criteria were applied, 28 eligible articles remained for data abstraction. All 28 articles in this review reported collecting primary/preferred language data, but only 18% (5/28) collected information on interpreter use. This review revealed that there remains variability in the way that primary/preferred language and interpreter use data are collected; all studies used various methodologies for evaluating and abstracting these data. Likewise, the sources from which the data were abstracted differed. PMID- 23443457 TI - Comparison of the NCRA and NAACCR Strategic Management Plans. AB - The Strategic Management Plans of the National Cancer Registrars Association (NCRA) and the North American Association of Central Cancer Registries (NAACCR) were compared, and differences noted. No uncovered subject areas were found. PMID- 23443458 TI - Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). AB - Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development. PMID- 23443459 TI - Combination of single walled carbon nanotubes/graphene oxide with paclitaxel: a reactive oxygen species mediated synergism for treatment of lung cancer. AB - Heterogeneity in tumors has led to the development of combination therapies that enable enhanced cell death. Previously explored combination therapies mostly involved the use of bioactive molecules. In this work, we explored a non conventional strategy of using carbon nanostructures (CNs) [single walled carbon nanotube (SWNT) and graphene oxide (GO)] for potentiating the efficacy of a bioactive molecule [paclitaxel (Tx)] for the treatment of lung cancer. The results demonstrated enhanced cell death following combination treatment of SWNT/GO and Tx indicating a synergistic effect. In addition, synergism was abrogated in the presence of an anti-oxidant, N-acetyl cysteine (NAC), and was therefore shown to be reactive oxygen species (ROS) dependent. It was further demonstrated using bromodeoxyuridine (BrdU) incorporation assay that treatment with CNs was associated with enhanced mitogen associated protein kinase (MAPK) activation that was ROS mediated. Hence, these results for the first time demonstrated the potential of SWNT/GO as co-therapeutic agents with Tx for the treatment of lung cancer. PMID- 23443462 TI - Influence of Si/P ordering on Na+ transport in NASICONs. AB - The influence of Si/P ordering on Na(+) transport in the high conducting NASICON composition, Na3Zr2Si2PO12, is investigated using molecular dynamics simulation. The study demonstrates that the Na(+) conductivity in the system changes by more than an order of magnitude depending on the Si/P order in the structure. This rather surprising observation is attributed to the modulations in the electrostatic potential energy landscape along the conduction channel originating out of the increased coulombic repulsion of Na(+) with P(5+) ions compared to Si(4+). The study reveals the significance of the order of framework cations in fast ion transport in solids with aliovalent substitutions. PMID- 23443460 TI - Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. AB - Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate <=0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS. PMID- 23443463 TI - Ciliary neurotrophic factor role in myelin oligodendrocyte glycoprotein expression in Cuprizone-induced multiple sclerosis mice. AB - Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. Myelin oligodendrocyte glycoprotein (MOG) is a minor component of the myelin sheath, but is an important autoantigen linked to the pathogenesis of MS. Ciliary neurotrophic factor (CNTF) has been shown to enhance the generation, maturation, and survival of oligodendrocytes in culture medium. The aim of this study was to demonstrate the role of CNTF on MOG expression in the cerebral cortex of Cuprizone-induced MS mice. The mice were treated by Cuprizone for five weeks in order to induce MS. The mice were then divided into 3 groups. The first group was injected subcutaneously (SC) by CNTF in the amount of 250 MUg/kg BW per day. The second group (SHAM) was injected SC by normal saline and the third group was left without injection as the control group. After four weeks the mice were killed and the cerebral cortex was harvested and the expression of MOG was studied by Western blotting. The data from this study show that the MOG expression was significantly increased in the CNTF-injected group as compared to the other groups. It is concluded that CNTF increases the MOG expression and may be important in the pathophysiology of MS. It is also concluded that CNTF may play a role in the process of remyelination by inducing the MOG expression. PMID- 23443464 TI - Expression of death receptor-3 in human breast cancer and its functional effects on breast cancer cells in vitro. AB - Death receptor-3 (DR3) plays controversial roles in cancer. Currently, DR3 is known to be a functional receptor of vascular endothelial growth inhibitor (VEGI). The role of DR3 in breast cancer remains unclear. The present study investigated DR3 expression in a clinical cohort of breast cancer patients and its role in breast cancer cells in vitro. The expression of DR3 was examined in a breast cancer cohort using quantitative PCR (Q-PCR) and immunohistochemistry (IHC) in comparison to the patients' data. In vitro function of DR3 was examined through the targeting of this molecule in MCF7 and MDA-MB-231 breast cancer cells using ribozyme transgene technology. Decreased DR3 expression was noted in breast cancer tissues compared to normal tissues and decreased expression of DR3 was generally associated with a poorer prognosis as well as a significantly shorter long-term survival (p=0.038). Targeting of DR3 in vitro in breast cancer cell lines resulted in impaired migratory rates compared to respective control cells. Collectively, these data suggest a complex role for DR3 in breast cancer development and progression. PMID- 23443465 TI - Salient features of mesenchymal stem cells-implications for Ewing sarcoma modeling. AB - Despite a heightened appreciation of the many defining molecular aberrations in Ewing sarcoma, the cooperative genetic environment and permissive cell of origin essential for EWS/ETS-mediated oncogenesis remain elusive. Consequently, inducible animal and in vitro models of Ewing sarcoma from a native cellular context are unable to fully recapitulate malignant transformation. Despite these shortcomings, human, and murine mesenchymal stem cells (MSCs) are the closest working in vitro systems available. MSCs are tolerant of ectopic EWS/FLI expression, which is accompanied by a molecular signature most similar to Ewing sarcoma. Whether MSCs are the elusive cell of origin or simply a tolerant platform of the EWS/FLI transcriptome, these cells have become an excellent molecular tool to investigate and manipulate oncogenesis in Ewing sarcoma. Our understanding of the biological complexity and heterogeneity of human MSCs (hMSCs) has increased substantially over time and as such, appreciation and utilization of these salient complexities may greatly enhance the efficient use of these cells as surrogate models for Ewing sarcoma tumorigenesis. PMID- 23443466 TI - Attention-deficit/hyperactivity disorder and sluggish cognitive tempo dimensions in relation to executive functioning in adolescents with ADHD. AB - Previous research has failed to find a consistent relation between Sluggish Cognitive Tempo (SCT) and executive function (EF) in youth with Attention Deficit/Hyperactivity Disorder (ADHD) when laboratory-based neuropsychological tasks of EF are used, whereas recent research with youth and adults suggests a significant relation between SCT and ratings of EF. The purpose of this study was to examine ADHD dimensions and SCT symptoms in relation to ratings of EF in adolescents with ADHD. Fifty-two adolescents (ages 12-16; 70 % male) participated in this study. Parents and teachers completed validated measures of SCT, ADHD symptoms, and EF in daily life. Adolescents' intelligence and academic achievement were also assessed. ADHD and SCT symptoms were significantly correlated with ratings of EF. Regression analyses demonstrated that, as hypothesized, ADHD hyperactive-impulsive symptoms were strongly associated with behavioral regulation EF deficits, with ADHD inattentive and SCT symptoms unrelated to behavioral regulation EF when hyperactive-impulsivity symptoms were included in the model. The parent-reported SCT Slow scale measuring motivation, initiative, and apathy predicted both parent- and teacher-reported metacognitive EF deficits above and beyond youth characteristics and ADHD symptoms. In contrast, teacher-reported ADHD inattention was most clearly associated with teacher-reported metacognitive EF deficits. This study provides preliminary evidence for the importance of SCT symptoms in relation to metacognitive EF deficits among adolescents with ADHD and the need to further investigate the overlap and distinctiveness of SCT/ADHD. Further research is needed to replicate and extend these findings. PMID- 23443467 TI - Friendship quality and social information processing in clinically anxious children. AB - The association between perceived friendship quality (FQ) and social information processing (SIP) was examined in three groups of children and their close friends aged 7-12 years: 16 anxiety disordered children with social phobia (SP); 12 anxiety disordered children without SP (No-SP); and 32 nonclinical children. Positive and negative FQ positively associated with target children's positive and negative responding on a vignette measure of SIP. SP children reported lower positive SIP than No-SP but not nonclinical children; and this was the only group difference in SIP. Target children and their friends were similar in negative but not positive SIP. Following discussion about the vignette with a close friend, all target children increased in positive SIP; negative SIP did not change. Lower FQ and a more socially anxious friend predicted higher negative target child SIP postdiscussion. Close friendships play an important role in the SIP of both clinical and nonclinical children. PMID- 23443468 TI - TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica. AB - Our gastrointestinal tract is a portal of entry for a number of bacteria and viruses. Thus, this tissue must develop ways to induce antigen-specific T cell and antibody responses quickly. Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue. Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica. Further, both neutralization of CCL20 using polyclonal antibody treatment and deletion of TLR1 resulted in a defect in CCR6+ dendritic cells (DCs), which produce innate cytokines that help to induce anti-Yersinia-specific T helper 17 (TH17) cells and IgA production. These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of TH17 immunity through the activation and recruitment of DCs. PMID- 23443469 TI - Sprengel's deformity and spinal dysraphism: connecting the shoulder and the spine. AB - BACKGROUND AND PURPOSE: Sprengel's deformity, a rare congenital malformation of the scapula, may be observed in combination with spinal dysraphism. The co occurrence of these malformations suggests an unknown shared etiology. Therefore, we reviewed the medical records of eight children presenting with both malformations and performed a review of the literature. PATIENTS AND METHODS: Databases from four university medical centers were searched for children presenting between 1992 and 2012 with spinal dysraphism and a Sprengel's deformity. CONCLUSION: The combination of spinal dysraphism and Sprengel's deformity is rare, and is associated with segmentation defects of the spine and ribs. Although the etiology of both spinal dysraphism and Sprengel's deformity remains unclear, all deformities of the spine, ribs, and shoulder might result from a common genetic defect affecting somitogenesis. PMID- 23443470 TI - Graphene-related nanomaterials: tuning properties by functionalization. AB - In this review, we discuss the most recent progress on graphene-related nanomaterials, including doped graphene and derived graphene nanoribbons, graphene oxide, graphane, fluorographene, graphyne, graphdiyne, and porous graphene, from both experimental and theoretical perspectives, and emphasize tuning their stability, electronic and magnetic properties by chemical functionalization. PMID- 23443473 TI - Evaluation of different chromogenic media for the detection of methicillin resistant Staphylococcus aureus CC398 in broilers. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) has emerged in a wide variety of animal species, including poultry. The objective of this study was to evaluate three different chromogenic media for MRSA clonal complex (CC) 398 detection in broilers. On three Belgian poultry farms, 50 broiler chickens were sampled per farm from both nose shell and cloaca. All swab specimens were enriched and inoculated the following day on three chromogenic media: chromID MRSA (bioMerieux), Brilliance MRSA 2 Agar (Oxoid) and MRSASelect (Bio-Rad). ChromID had the highest isolation rates, yet, Brilliance MRSA 2 Agar demonstrated the highest relative sensitivity, while MRSASelect and Brilliance MRSA 2 Agar showed the highest relative specificity. A subset of MRSA isolates was confirmed to be CC398 by the polymerase chain reaction (PCR) targeting sau1 hsdS1. In conclusion, Brilliance MRSA 2 Agar outperformed MRSASelect and chromID MRSA for the detection of MRSA in broilers. PMID- 23443474 TI - Emergence of Clostridium difficile infection in tuberculosis patients due to a highly rifampicin-resistant PCR ribotype 046 clone in Poland. AB - Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea. CDI is known to develop after antibiotic administration, but anti-tuberculosis agents have rarely been implicated. We documented an outbreak caused by a highly rifampicin-resistant C. difficile strain of polymerase chain reaction (PCR) ribotype 046 in patients with active tuberculosis. PMID- 23443475 TI - Prevalence and treatment of aerobic vaginitis among non-pregnant women: evaluation of the evidence for an underestimated clinical entity. AB - We sought to evaluate the evidence on the prevalence of aerobic vaginitis (AV) among symptomatic non-pregnant women, as well as the treatment administered for this clinical entity. The PubMed and Scopus databases were systematically searched. Sixteen studies met the inclusion criteria, 11 of which reported on the prevalence of possible AV, two on the prevalence of diagnosed AV, and three on the treatment and outcomes of women with diagnosed AV. The prevalence of diagnosed AV varied from 5 to 10.5 %. Streptococcus spp., Staphylococcus aureus, and coagulase-negative staphylococci were the most commonly identified Gram positive pathogens among women with possible AV, with prevalences of up to 58.7, 41.7, and 37.4 %, respectively, while Escherichia coli was the most common Gram negative pathogen identified, with a prevalence of up to 23 % among symptomatic women. Regarding antibiotic treatment for AV, the antibiotic schemes administered, which mainly consisted of suppositories of aminoglycosides, showed good effectiveness without serious adverse events provided by any of the included studies. The currently available data suggest that the prevalence of AV is not negligible, while the prevalence of possible AV is considerable. Well-designed studies comparing the prevalence of aerobic pathogens between symptomatic and asymptomatic women are warranted. PMID- 23443476 TI - Identification of a novel gene cluster in the upstream region of the S-layer gene sbpA involved in cell wall metabolism of Lysinibacillus sphaericus CCM 2177 and characterization of the recombinantly produced autolysin and pyruvyl transferase. AB - The S-layer protein SbpA of Lysinibacillus sphaericus CCM 2177 assembles into a square (p4) lattice structure and recognizes a pyruvylated secondary cell wall polymer (SCWP) as the proper anchoring structure to the rigid cell wall layer. Sequencing of 8,004 bp in the 5'-upstream region of the S-layer gene sbpA led to five ORFs-encoding proteins involved in cell wall metabolism. After cloning and heterologous expression of ORF1 and ORF5 in Escherichia coli, the recombinant autolysin rAbpA and the recombinant pyruvyl transferase rCsaB were isolated, purified, and correct folding was confirmed by circular dichroism. Although rAbpA encoded by ORF1 showed amidase activity, it could attack whole cells of Ly. sphaericus CCM 2177 only after complete extraction of the S-layer lattice. Despite the presence of three S-layer-homology motifs on the N-terminal part, rAbpA did not show detectable affinity to peptidoglycan-containing sacculi, nor to isolated SCWP. As the molecular mass of the autolysin lies above the molecular exclusion limit of the S-layer, AbpA is obviously trapped within the rigid cell wall layer by the isoporous protein lattice. Immunogold-labeling of ultrathin sectioned whole cells of Ly. sphaericus CCM 2177 with a polyclonal rabbit antiserum raised against rCsaB encoded by ORF5, and cell fractionation experiments demonstrated that the pyruvyl transferase was located in the cytoplasm, but not associated with cell envelope components including the plasma membrane. In enzymatic assays, rCsaB clearly showed pyruvyl transferase activity. By using RT-PCR, specific transcripts for each ORF could be detected. Cotranscription could be confirmed for ORF2 and ORF3. PMID- 23443477 TI - A population-based analysis of the morbidity and mortality of gallbladder surgery in the elderly. AB - BACKGROUND: Historically, emergency gallbladder surgery in elderly patients has been associated with high rates of morbidity and mortality. Recent studies have described much lower complication rates that may still overestimate morbidity. The purpose of this study was to determine the true population morbidity and mortality rates after gallbladder surgery in the elderly. METHODS: All elderly patients (defined as age 65 years or older) admitted to the hospital with a principle diagnosis related to benign gallbladder disease in the Province of Manitoba from January 1, 1995 to December 31, 2008 were identified by using administrative claims data. Outcomes after emergency gallbladder surgery, including complication rates and their predictors, were compared with outcomes after elective surgery and after nonoperative treatment for gallbladder-related hospital admissions. RESULTS: A total of 9,936 patients were included: 2,355 had emergency or urgent surgery and 4,901 had elective procedures, whereas 2,680 patients were treated without surgery. Emergency gallbladder surgery was associated with a mortality rate of 0.7 %, compared with 1.6 % for elective cases and 5.6 % for patients treated nonoperatively. Complication rates were 16.2, 17.7, and 25 % respectively. Independent predictors of 30-day mortality were age, male gender, increasing comorbidity, surgeon experience, and surgical treatment. CONCLUSIONS: Emergency gallbladder surgery in the elderly was not associated with higher mortality or complication rate compared with the elective setting. Elderly patients with gallbladder-related emergencies should be offered urgent surgery when feasible. PMID- 23443478 TI - A retrospective analysis of early and late outcome of biodegradable stent placement in the management of refractory anastomotic colorectal strictures. AB - BACKGROUND: Benign colorectal strictures are treated conventionally by endoscopic dilation. Experience using SEMS for benign colonic strictures is limited, and outcomes to date have been disappointing. Refractory colorectal strictures remain challenging to be treated with surgery. Polydioxanone-based stent are biodegradable (BD) stent CE approved for esophageal strictures. This study was designed to investigate retrospectively the safety and the efficacy of these stents for the management of strictures refractory to multiple sessions of dilation. METHODS: Patients with postsurgical benign strictures located within 20 cm from anal verge, refractory to mechanical or pneumatic dilation (at least 3 sessions) were included in this analysis. Clinical success was defined as the absence of occlusive symptoms and the ability to pass through the stricture with a regular size colonoscope. All patients were predilated before stent placement. Stents were released under fluoroscopic control. All patients were under stool softeners for 3 months. Follow-up was scheduled with endoscopic and fluoroscopic controls within 90 days from stent deployment and afterwards by telephone interview and/or ambulatory consultation. RESULTS: Eleven patients (7 males, mean age 62.3 +/- 8.5 years) were included. Technical success was achieved in all the patients. Stent migration was observed in four patients within the first 2 weeks after stent placement. Stent migration was followed by recurrence of stricture and obstructive symptoms in all the cases. Among the seven patients who completed the process of stent biodegradation, five of them had complete resolution of the stricture and relief of symptoms. Two of 11 patients required surgical treatment during the follow-up period (mean 19.8 (range 42-15) months). The overall success rate of the BD stent was 45 %. CONCLUSIONS: This retrospective analysis of a limited number of patients demonstrated that nondedicated esophageal BD stents are associated with high risk of migration and clinical success in less than 50 % of patients. Dedicated stents with large diameter and antimigration findings could potentially improve the outcome of patients with refractory benign colorectal strictures. PMID- 23443479 TI - A prospective study comparing three-port video-assisted thoracoscopy with the single-incision laparoscopic surgery (SILS) port and instruments for the video thoracoscopic approach: a pilot study. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) has proved its advantages in several procedures, mainly a shorter hospital stay, improved aesthetic results, and less postoperative pain. The authors have used this approach for several thoracic surgical procedures. METHODS: This prospective study compared 20 cases between standard three-port video-assisted thoracic surgery (VATS) and the single-incision approach using a standard abdominal SILS system. In both groups, postsurgical analgesia was provided with 15 ml of bupivacaine 0.5% at 3 h intervals via a paravertebral catheter. The hospital length of stay and chest drain duration (in hours) were recorded as well as postoperative pain using an analogic visual pain scale (AVPS). A telephone survey was conducted for all the outpatients. The Mann-Whitney U test was used for statistical analysis. RESULTS: This study of 20 procedures included 11 lung biopsies, 6 pneumothorax procedures, 2 mediastinic cystectomies, and 1 catamenial pneumothorax procedure. No statistically significant difference was reported in hospital length of stay or chest drain duration between the two groups. However, postoperative pain at 24 h was significantly less in the SILS group (AVPS, 4.40) than in the VATS group (AVPS, 6.20) (p = 0.035). The SILS group reported two minor surgical wound complications and one catamenial pneumothorax recurrence that did not require drainage. The VATS group reported one case of skin rash with no identifiable cause. CONCLUSIONS: The use of the SILS port in thoracic surgery results in less postoperative pain. This is related to the port's protective effect over the periostium and the intercostal nerve, relieving them of direct contact with surgical instruments. However, the findings showed a higher incidence of surgical wound complications with the SILS port, which can be attributed to increased pressure on the skin and soft tissues surrounding the port and to the fact that this same incision was used for chest drain placement, thus increasing the risk for complications. PMID- 23443480 TI - Comparison of short-term outcomes between laparoscopic greater curvature plication and laparoscopic sleeve gastrectomy. AB - BACKGROUND: Laparoscopic greater curvature plication (LGCP) is an emerging restrictive bariatric procedure that successfully reduces the gastric volume by plication of the gastric greater curvature. The aim of this prospective nonrandomized study was to compare short-term outcomes and associated complications between LGCP and laparoscopic sleeve gastrectomy (LSG). METHODS: From January 2011 to November 2011, a total of 39 patients were allocated to undergo either LGCP (n = 19) or LSG (n = 20). Data on the operative time, complications, hospital stay, overall cost of LSG and LGCP, body mass index loss (BMIL), percentage of excess weight loss (%EWL), loss of appetite and improvement of comorbidities were collected during the follow-up examinations. RESULTS: All procedures were completed laparoscopically. The mean operative time was 95.0 +/- 17.4 minutes for the LGCP group and 85.5 +/- 18.4 minutes for the LSG group (P = 0.107). No patient required reoperation due to an early complication. One patient in the LSG group was readmitted because of gastric stenosis. The mean hospital stay was 4.2 +/- 1.9 days in the LGCP group and 3.9 +/- 1.7 days in the LSG group (P = 0.595). The total cost of LSG was $7,826 +/- 537 compared to LGCP ($3,358 +/ 264) (P < 0.001). One year after surgery, the mean %EWL was 58.8 +/- 16.7 % (n = 11) in the LGCP group and 80.0 +/- 26.8 % (n = 11) in the LSG group (P = 0.038). Loss of feeling of hunger was reported in 27.3 % LGCP patients and 72.7 % LSG patients (P = 0.033) at 1 year after surgery. The comorbidities, including diabetes, sleep apnea and hypertension, were markedly improved in both groups 6 months after surgery. CONCLUSIONS: The short-term outcomes of our study demonstrate that compared with LSG, LGCP is inferior as a restrictive procedure for weight loss, despite its significantly smaller cost. Longer follow-up and prospective comparative trials are needed to confirm the long-term outcomes of this novel procedure and make definitive conclusions. PMID- 23443481 TI - From single protein to colorectal cancer genome landscape and network biology based biomarkers. PMID- 23443482 TI - Laparoscopic approach in perforated appendicitis: increased incidence of surgical site infection? AB - BACKGROUND: The role of laparoscopy in the setting of perforated appendicitis remains controversial. A retrospective study was conducted to evaluate the early postoperative outcomes of laparoscopic appendectomy (LA) compared to open appendectomy (OA) in patients with perforated appendicitis. METHODS: A total of 1,032 patients required an appendectomy between January 2005 and December 2009. Among these patients, 169 presented with perforated appendicitis. Operation times, length of hospital stay, overall complication rates within 30 days, and surgical site infection (SSI) rates were analyzed. RESULTS: Out of the 169 evaluated patients, 106 required LA and 63 OA. Although operation times were similar in both groups (92 +/- 31 min for LA vs. 98 +/- 45 for OA, p = 0.338), length of hospital stay was shorter in the LA group (6.9 +/- 3.8 days vs. 11.5 +/ 9.2, p < 0.001). Overall complication rates were significantly lower in the LA group (32.1 vs. 52.4 %, p < 0.001), as were incisional SSI (1.9 vs. 22.2 %, p < 0.001). Organ/space SSI rates were similar in both groups (23.6 % after LA vs. 20.6 % after OA, p = 0.657). CONCLUSIONS: For perforated appendicitis, LA results in a significantly shorter hospital stay, fewer overall postoperative complications, and fewer wound infections compared to OA. Organ/space SSI rates were similar for both procedures. LA provides a safe option for treating patients with perforated appendicitis. PMID- 23443483 TI - Clinical outcomes of argon plasma coagulation for the treatment of gastric neoplasm. AB - BACKGROUND: There are insufficient reports on the outcomes and local recurrence rates for gastric neoplasms treated using argon plasma coagulation (APC). The purpose of this study was to analyze the clinical outcomes in early gastric cancer or gastric adenoma patients following APC treatment. METHODS: Seventy-one patients were enrolled and all underwent APC at the Asan Medical Center between July 2007 and August 2011. Clinical and oncological outcomes were analyzed. RESULTS: The median follow-up period was 20 months (interquartile range 13-29 months). Among the 71 patients we evaluated, nonlifting after submucosal saline injection was found in 35 patients and 15 patients (21.2%) experienced local recurrence with a median period of 10 months (IQR 5-13 months). The rate of local recurrence was higher in the nonlifting group and the 40-W group than in the lifting group and the 60- or 80-W groups (31.4 vs. 11.1%, p = 0.045 and 31.7 vs. 6.7%, p = 0.017, respectively). Multivariate analysis showed that the power setting with the 40-W and nonlifting groups after submucosal injection was associated with local recurrence. CONCLUSIONS: APC therapy after submucosal saline injection using high power (60 or 80 W) appears to be an effective alternative in the management of gastric neoplasm. PMID- 23443484 TI - Comparison of robotic and laparoendoscopic single-site surgery systems in a suturing and knot tying task. AB - BACKGROUND: Laparoendoscopic single-site (LESS) surgery has been established for various procedures. Shortcomings of LESS surgery include loss of triangulation, instrument collisions, and poor ergonomics, making advanced laparoscopic tasks especially challenging. We compared a LESS system with a robotic single-site surgery platform in performance of a suturing and knot-tying task under clinically simulated conditions. METHODS: Each of five volunteer minimally invasive surgeons was tasked with suturing a 5 cm longitudinal enterotomy in porcine small intestine with square knots at either end, using a laparoendoscopic or da Vinci robotic single-site surgery platform, within a 20 min time limit. A saline leak test was then performed. Each surgeon performed the task twice using each system. The time to completion of the task and presence of a leak were noted. Fisher's exact test was used to compare the overall completion rate within the defined time limit, and a Wilcoxon rank test was used to compare the specific times to complete the task. A p value of <0.05 was considered significant. RESULTS: All surgeons were able to complete the task on the first try within 20 min using the robot system; 60% of surgeons were able to complete it after two attempts using the LESS surgery system. Time to completion using the robot system was significantly shorter than the time using the standard LESS system (p < 0.0001). There were no leaks after closure with the robot system; the leak rate following the standard LESS system was 90%. CONCLUSIONS: Surgeons demonstrated significantly better suturing and knot-tying capabilities using the robot single site system compared to a standard LESS system. The robotic system has the potential to expand single-site surgery to more complex tasks. PMID- 23443487 TI - A crucial role for reactive oxygen species in macrophage colony-stimulating factor-induced RANK expression in osteoclastic differentiation. AB - Macrophage colony-stimulating factor (M-CSF) is essential for differentiation from hematopoietic precursor cells into osteoclasts. M-CSF transiently increased the intracellular level of reactive oxygen species (ROS) through an NADPH oxidase (Nox) and induced the expression of receptor for activation of nuclear factor kappaB (RANK) in early-stage osteoclast precursor cells (c-fms+RANK-). Blocking of the activity of Nox with diphenylene iodonium inhibited ROS production, activation of extracellular signal-regulated kinase (ERK), and the expression of RANK, PU.1 and MITF. The suppression of Nox2, but not Nox1, expression by RNA interference inhibited ROS production and RANK expression. These results suggested that ROS produced in response to M-CSF via a process mediated by Nox2 acted as an intracellular signaling mediator for RANK expression through the activation of ERK and the expression of PU.1 and MITF in early-stage osteoclast precursor cells. PMID- 23443488 TI - Multiphase chemistry of atmospheric amines. AB - Heterogeneous reactions of amines have been recently shown to play an important role in the formation and transformation of atmospheric aerosols. This perspective summarizes the latest laboratory progress in the multiphase chemistry of amines. Particular emphasis is given to the contributions of amines to new particle formation, growth of submicron particles, and alteration in the physiochemical properties of pre-existing particles, including hygroscopicity, thermostability, density, phase, and optical properties, from exposure to gaseous amines. The atmospheric implications of the multiphase reactions of amines, including the potential impact on direct and indirect climate forcing of aerosols, and future research directions are discussed. PMID- 23443489 TI - Secondary cytoreduction versus chemotherapy alone in the treatment of patients with recurrent ovarian cancer: is a randomized trial worthwhile? PMID- 23443490 TI - Extensive multiarterial resection attending total duodenopancreatectomy and adrenalectomy for MEN-1-associated neuroendocrine carcinomas. AB - Pancreatic neuroendocrine tumors (PNTs) are relatively uncommon although these neoplasms have been noted to grow in occurrence in recent decades. Surgical removal of locally advanced PNTs involving major vessels and adjacent organs is warranted by reason of an appreciably more favorable prognosis as compared to exocrine pancreas cancer. We are reporting a case of successful multi-organ resection combined with a wide excision of the superior mesenteric, common, proper, left and right hepatic arteries (in the presence of the hepatomesenteric trunk variant of aberrant arterial anatomy) for multifocal PNTs in the setting of multiple neuroendocrine neoplasia type 1 syndrome. The procedure resulted in pain abolition, a significant improvement in the patient's life quality and allowed her to return to work. Follow-up computed tomography at 15 mo post-surgery showed no evidence of disease recurrence. PMID- 23443491 TI - The ZIC gene family encodes multi-functional proteins essential for patterning and morphogenesis. AB - The zinc finger of the cerebellum gene (ZIC) discovered in Drosophila melanogaster (odd-paired) has five homologs in Xenopus, chicken, mice, and humans, and seven in zebrafish. This pattern of gene copy expansion is accompanied by a divergence in gene and protein structure, suggesting that Zic family members share some, but not all, functions. ZIC genes are implicated in neuroectodermal development and neural crest cell induction. All share conserved regions encoding zinc finger domains, however their heterogeneity and specification remain unexplained. In this review, the evolution, structure, and expression patterns of the ZIC homologs are described; specific functions attributable to individual family members are supported. A review of data from functional studies in Xenopus and murine models suggest that ZIC genes encode multifunctional proteins operating in a context-specific manner to drive critical events during embryogenesis. The identification of ZIC mutations in congenital syndromes highlights the relevance of these genes in human development. PMID- 23443492 TI - Is the proton pump inhibitor test helpful in patients with laryngeal symptoms? AB - BACKGROUND AND OBJECTIVES: The association of gastroesophageal reflux disease (GERD) and laryngeal symptoms is not clear. We aimed to examine the symptomatic and endoscopic relations between GERD and laryngeal symptoms and also to evaluate the response to a 2-week proton pump inhibitor (PPI) trial. METHODS: Seventy-two patients experiencing persistent laryngeal symptoms >= 2/week were enrolled. The laryngeal symptoms using the 1-week laryngeal symptom score (LSS) and the typical reflux symptoms including heartburn and acid regurgitation were assessed. Transnasal-esophagogastroduodenoscopy (TN-EGD) and ambulatory 24-h esophageal pH monitoring were performed. The patients were classified into a GERD group and a non-GERD group. The GERD group was defined as the cases of the presence of typical reflux symptoms and/or reflux esophagitis and/or pathologic acid exposure. Patients were treated with 30 mg of lansoprazole bid for 14 days. RESULTS: Thirty-nine patients (54 %) were diagnosed with GERD on the basis of typical reflux symptoms, EGD, and/or pH testing. There was no significant association between the LSS and the presence of typical reflux symptoms. Also, the presence of laryngitis was not significantly related to reflux esophagitis. The 2-week PPI trial showed no significant difference in the improvement in laryngeal symptoms between the GERD and non-GERD groups. CONCLUSIONS: There was no significant symptomatic and endoscopic association between GERD and laryngeal symptoms. Therefore, GERD does not appear to be the sole cause of these symptoms. Additionally, a 2-week PPI trial is not long enough to be a diagnostic tool in patients with laryngeal symptoms. PMID- 23443493 TI - The mechanism of the down-regulation of hepatic transporters in rats with indomethacin-induced intestinal injury. AB - BACKGROUND: Previously, we reported that hepatic transporters were down-regulated consistent with intestinal injury in indomethacin (IDM)-treated rats. AIM: The purpose of this study was to characterize this mechanism of the down-regulation of hepatic transporters in IDM-treated rats. METHODS: Hepatic nuclear receptor expressions, oxidative stress condition and the expression of hepatic transporters were evaluated in rats with IDM-induced intestinal injury with or without the administration of mucosal protectant ornoprostil, a prostaglandin E1 analogue, or aminoguanidine (AG), an iNOS inhibitor. RESULTS: All the nuclear receptors examined in the present study, which regulates hepatic transporters, were decreased by the administration of IDM. Hepatic glutathione, an indicator of oxidative stress, was significantly reduced compared with control. We then determined the expression of hepatic transporters by semi-quantitative real-time RT-PCR and Western blot analysis in IDM-treated rats with or without the administration of ornoprostil or AG. Ornoprostil recovered the gene expression of Oatp1a1, Oatp1b2 and Mrp2 and protein expression of Mrp2 while it had no effect on Oatp1a1 and Oatp1b2 proteins. These results indicated that the gene expression of hepatic transporters was down-regulated in association with the intestinal injury. On the other hand, there is no effect of AG on the reduced gene expression of hepatic Oatp1a1, Oatp1b2 and Mrp2. In protein expression, AG slightly recovered Mrp2 expression accompanied by a partial decrease in portal NO levels. CONCLUSIONS: We suggest that the transcriptional process influenced by a dysfunction of hepatic nuclear receptors as well as the effect of NO on the post transcriptional process due to intestinal injury are partially involved in the down-regulation of hepatic transporters. PMID- 23443494 TI - Genome maintenance and transcription integrity in aging and disease. AB - DNA damage contributes to cancer development and aging. Congenital syndromes that affect DNA repair processes are characterized by cancer susceptibility, developmental defects, and accelerated aging (Schumacher et al., 2008). DNA damage interferes with DNA metabolism by blocking replication and transcription. DNA polymerase blockage leads to replication arrest and can gives rise to genome instability. Transcription, on the other hand, is an essential process for utilizing the information encoded in the genome. DNA damage that interferes with transcription can lead to apoptosis and cellular senescence. Both processes are powerful tumor suppressors (Bartek and Lukas, 2007). Cellular response mechanisms to stalled RNA polymerase II complexes have only recently started to be uncovered. Transcription-coupled DNA damage responses might thus play important roles for the adjustments to DNA damage accumulation in the aging organism (Garinis et al., 2009). Here we review human disorders that are caused by defects in genome stability to explore the role of DNA damage in aging and disease. We discuss how the nucleotide excision repair system functions at the interface of transcription and repair and conclude with concepts how therapeutic targeting of transcription might be utilized in the treatment of cancer. PMID- 23443496 TI - [Imaging in rheumatology]. PMID- 23443495 TI - Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats. AB - Our previous studies identified potent antioxidant effects and improvement of vascular function by telmisartan therapy in experimental diabetes and nitrate tolerance. The present study compared the beneficial effects of single telmisartan or amlodipine versus telmisartan/amlodipine combination therapy (T+A) in streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were injected once with STZ (60 mg/kg, i.v.) and 1 week later the drugs (telmisartan, amlodipine, or T+A) were administrated orally by a special diet (2.5-5 mg kg(-1) day(-1)) for another 7 weeks. We only observed a marginal beneficial on-top effect of T+A therapy over the single drug regimen that was most evident in the improvement of endothelial function (acetylcholine response) and less pronounced in the reduction of whole blood, vascular and cardiac oxidative stress (blood leukocyte oxidative burst, aortic dihydroethidine and 3-nitrotyrosine staining, as well as cardiac NADPH oxidase activity and uncoupling of endothelial nitric oxide synthase) in diabetic rats. These effects on oxidative stress parameters were paralleled by those on the expression pattern of NADPH oxidase and nitric oxide synthase isoforms. In addition, development of mild hypotension in the T+A treated rats was observed. Reasons for this moderate synergistic effect of T+A therapy may be related to the potent beneficial effects of telmisartan alone and the fact that amlodipine and telmisartan share similar pathways to improve endothelial function. Moreover, hypotension in the T+A-treated rats could partially antagonize the beneficial additive effects by counter-regulatory mechanisms (e.g., activation of the renin-angiotensin-aldosterone system). PMID- 23443497 TI - Photo quiz. A 23-year-old man presenting with fluid-filled skin lesions, patchy pigmentation, and skin breakage after trivial trauma. PMID- 23443502 TI - Efficient sleeping beauty DNA transposition from DNA minicircles. AB - DNA transposon-based vectors have emerged as new potential delivery tools in therapeutic gene transfer. Such vectors are now showing promise in hematopoietic stem cells and primary human T cells, and clinical trials with transposon engineered cells are on the way. However, the use of plasmid DNA as a carrier of the vector raises safety concerns due to the undesirable administration of bacterial sequences. To optimize vectors based on the Sleeping Beauty (SB) DNA transposon for clinical use, we examine here SB transposition from DNA minicircles (MCs) devoid of the bacterial plasmid backbone. Potent DNA transposition, directed by the hyperactive SB100X transposase, is demonstrated from MC donors, and the stable transfection rate is significantly enhanced by expressing the SB100X transposase from MCs. The stable transfection rate is inversely related to the size of circular donor, suggesting that a MC-based SB transposition system benefits primarily from an increased cellular uptake and/or enhanced expression which can be observed with DNA MCs. DNA transposon and transposase MCs are easily produced, are favorable in size, do not carry irrelevant DNA, and are robust substrates for DNA transposition. In accordance, DNA MCs should become a standard source of DNA transposons not only in therapeutic settings but also in the daily use of the SB system.Molecular Therapy - Nucleic Acids (2013) 2, e74; doi:10.1038/mtna.2013.1; published online 26 February 2013. PMID- 23443504 TI - Occipital injections for trigemino-autonomic cephalalgias: evidence and uncertainties. AB - Cluster headache is a debilitating disorder. Oral prophylactic treatments may act with a significant delay, cause side effects, or fail to control the attacks. Injections targeting the occipital nerve have raised interest for the management of CH. Their efficacy is thought to result from the anatomical convergence of trigeminal and cervical afferents in the trigeminal nucleus caudalis. Efficacy and safety of occipital injections are now documented by 2 randomized controlled trials and several case series, though the optimal technique and substance to be injected are still subject to discussion due to varied approaches in the published studies. The evidence supports the use of injected steroids, with or without the addition of an anesthetic. Side effects of local pain are common, but unlikely to be severe. Systemic effects related to steroid absorption are reported but infrequent. Occipital injections provide a rapid benefit on the frequency of attacks and can be used as an adjunct to an oral prophylactic for a quicker improvement. Whether or not this approach can be used without any oral prophylaxis is still to be determined. The technique is easy to master, has a low cost, and should be learned by physicians involved in CH management. PMID- 23443505 TI - Nicotine favors osteoclastogenesis in human periodontal ligament cells co cultured with CD4(+) T cells by upregulating IL-1beta. AB - Periodontitis, which is the main cause of tooth loss, is one of the most common chronic oral diseases in adults. Tooth loss is mainly a result of alveolar bone resorption, which reflects an increased osteoclast formation and activation. Osteoclast formation in periodontal tissue is a multistep process driven by osteoclastogenesis supporting cells such as human periodontal ligament (PDL) cells and CD4(+) T cells. Inflammatory cytokines, such as interleukin-1beta (IL 1beta), can induce osteoclastogenesis by affecting the expression of receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) in human PDL cells. Nicotine, the major component in tobacco smoking and a specific agonist of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), has been proven to regulate the expression of inflammatory cytokines in smoking-associated periodontitis. In this study, we investigated the mechanism(s) through which nicotine affects osteoclastogenesis in human PDL cells co-cultured/non-co cultured with CD4(+) T cells. Human PDL cells were stimulated with nicotine (10-5 M) and/or alpha-bungarotoxin (alpha-BTX, specific antagonist of alpha7 nAChR, 10 8 M) before being co-cultured with CD4(+) T cells. Compared with mono-culture systems, stimulation with nicotine caused an increased secretion of IL-1beta in serum of human PDL cell-CD4(+) T cell co-culture, and the expression of RANKL in human PDL cells was further upregulated co-cultured with CD4(+) T cells, while no differences were observed in the expression of OPG between the co-culture and mono-culture systems. Our data suggested that nicotine upregulated IL-1beta secretion, further upregulated RANKL expression in smoking-associated periodontitis, which may aid in the better understanding of the relationship between nicotine and alveolar bone resorption. PMID- 23443506 TI - Native kidney BK virus nephropathy associated with acute lymphocytic leukemia. AB - BACKGROUND: Polyoma BK virus nephropathy is a common complication after renal transplantation and is rarely seen in non-renal transplant recipients. There are only a couple of case reports of BK virus nephropathy in native kidneys in non transplant patients, including a recent report of a 73-year-old patient with chronic lymphatic leukemia. A variety of treatment options, including leflunomide and cidofovir, were reported in these patients. CASE DIAGNOSIS/TREATMENT: Here we report the case of a 10-year-old boy with acute lymphatic leukemia who presented with non-oliguric hypertensive acute kidney injury at the 12th maintenance cycle of his chemotherapy. The workup supported the clear diagnosis of BK virus nephropathy with tubulointerstitial changes, and the patient responded favorably to intravenous immunoglobulin therapy. CONCLUSIONS: Pediatric nephrologists need to consider BK virus nephropathy as a differential diagnosis of acute kidney injury in immunocompromised non-transplant patients. PMID- 23443503 TI - Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging. AB - Males, who are bigger and stronger than females, live shorter in most species from flies to mammals including humans. Cellular mass growth is driven in part by mTOR (Target of Rapamycin). When developmental growth is completed, then, instead of growth, mTOR drives aging, manifested by increased cellular functions, such as hyper-secretion by fibroblasts, thus altering homeostasis, leading to age-related diseases and death. We hypothesize that MTOR activity is elevated in male mice compared with females. Noteworthy, 6 months old males were 28 % heavier than females. Also levels of phosphorylated S6 (pS6) and phospho-AKT (p-AKT, Ser 473), markers of the mTOR activity, were higher in male organs tested. Levels of pS6 were highly variable among mice and correlated with body weight and p-AKT. With age, the difference between levels of pS6 between sexes tended to minimize, albeit males still had hyperactive mTOR. Unlike fasting, the intraperitoneal (i.p.) administration of rapamycin eliminated pS6 in all organs of all females measured by immunoblotting and immunohistochemistry without affecting p-AKT and blood insulin. Although i.p. rapamycin dramatically decreased levels of pS6 in males too, it was still detectable by immunoblotting upon longer exposure. Our study demonstrated that both tissue p-AKT and pS6 were higher in young male mice and were associated with increased body weight and insulin. These data can explain bigger body size and faster aging in males. Our data suggest higher efficacy of rapamycin compared to fasting. Higher sensitivity of females to rapamycin may explain more pronounced life extension by rapamycin observed in females compared to males in several studies. PMID- 23443508 TI - Complex visual hallucinations in a patient with macular degeneration: a case of the Charles Bonnet syndrome. PMID- 23443507 TI - Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. AB - BACKGROUND: The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation. METHODS: The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1=40 mg/m(2); DL2=65 mg/m(2); DL3=90 mg/m(2)). RESULTS: Thirteen patients were treated (DL1, n=6; DL2, n=4; DL3, n=3) according to a traditional "3+3" design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3-4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1-2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m(2) with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients' mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study. CONCLUSION: UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo. PMID- 23443509 TI - Effect of telecare on use of health and social care services: findings from the Whole Systems Demonstrator cluster randomised trial. AB - OBJECTIVE: to assess the impact of telecare on the use of social and health care. Part of the evaluation of the Whole Systems Demonstrator trial. PARTICIPANTS AND SETTING: a total of 2,600 people with social care needs were recruited from 217 general practices in three areas in England. DESIGN: a cluster randomised trial comparing telecare with usual care, general practice being the unit of randomisation. Participants were followed up for 12 months and analyses were conducted as intention-to-treat. DATA SOURCES: trial data were linked at the person level to administrative data sets on care funded at least in part by local authorities or the National Health Service. MAIN OUTCOME MEASURES: the proportion of people admitted to hospital within 12 months. Secondary endpoints included mortality, rates of secondary care use (seven different metrics), contacts with general practitioners and practice nurses, proportion of people admitted to permanent residential or nursing care, weeks in domiciliary social care and notional costs. RESULTS: 46.8% of intervention participants were admitted to hospital, compared with 49.2% of controls. Unadjusted differences were not statistically significant (odds ratio: 0.90, 95% CI: 0.75-1.07, P = 0.211). They reached statistical significance after adjusting for baseline covariates, but this was not replicated when adjusting for the predictive risk score. Secondary metrics including impacts on social care use were not statistically significant. CONCLUSIONS: telecare as implemented in the Whole Systems Demonstrator trial did not lead to significant reductions in service use, at least in terms of results assessed over 12 months. PMID- 23443510 TI - Living and dying with dignity in Chinese society: perspectives of older palliative care patients in Hong Kong. AB - BACKGROUND: the empirical Dignity Model has profoundly influenced the provision of palliative care for older terminally ill patients in the West, as it provides practical guidance and intervention strategies for promoting dignity and reducing distress at the end-of-life. OBJECTIVE: to examine the concept of 'living and dying with dignity' in the Chinese context, and explore the generalisability of the Dignity Model to older terminal patients in Hong Kong. METHODS: using qualitative interviews, the concept of dignity was explored among 16 older Chinese palliative care patients with terminal cancer. Framework analysis with both deductive and inductive methods was employed. RESULTS: the three major categories of themes of the Dignity Model were broadly supported. However, the subtheme of death anxiety was not supported, while two subthemes of generativity/legacy and resilience/fighting spirit manifested differently in the Chinese context. Furthermore, four new emergent themes have been identified. They include enduring pain, moral transcendence, spiritual surrender and transgenerational unity. CONCLUSION: these findings highlight both a cultural and a familial dimension in the construct of dignity, underline the paramount importance of cultural awareness and competence for working with ethnically diverse groups, and call for a culturally sensitive and family oriented approach to palliative care interventions with older Chinese terminal patients. PMID- 23443511 TI - Exploring the relationship between national economic indicators and relative fitness and frailty in middle-aged and older Europeans. AB - BACKGROUND: on an individual level, lower-income has been associated with disability, morbidity and death. On a population level, the relationship of economic indicators with health is unclear. OBJECTIVE: the purpose of this study was to evaluate relative fitness and frailty in relation to national income and healthcare spending, and their relationship with mortality. DESIGN AND SETTING: secondary analysis of data from the Survey of Health, Ageing and Retirement in Europe (SHARE); a longitudinal population-based survey which began in 2004. SUBJECTS: a total of 36,306 community-dwelling people aged 50 and older (16,467 men; 19,839 women) from the 15 countries which participated in the SHARE comprised the study sample. A frailty index was constructed as the proportion of deficits present in relation to the 70 deficits available in SHARE. The characteristics of the frailty index examined were mean, prevalence of frailty and proportion of the fittest group. RESULTS: the mean value of the frailty index was lower in higher-income countries (0.16 +/- 0.12) than in lower-income countries (0.20 +/- 0.14); the overall mean frailty index was negatively correlated with both gross domestic product (r = -0.79; P < 0.01) and health expenditure (r = -0.63; P < 0.05). Survival in non-frail participants at 24 months was not associated with national income (P = 0.19), whereas survival in frail people was greater in higher-income countries (P < 0.05). CONCLUSIONS: a country's level of frailty and fitness in adults aged 50+ years is strongly correlated with national economic indicators. In higher-income countries, not only is the prevalence of frailty lower, but frail people also live longer. PMID- 23443512 TI - Reducing cross-sensitivity of TiO2-(B) nanowires to humidity using ultraviolet illumination for trace explosive detection. AB - Environmental humidity is an important factor that can influence the sensing performance of a metal oxide. TiO2-(B) in the form of nanowires has been demonstrated to be a promising material for the detection of explosive gases such as 2,4,6-trinitrotoluene (TNT). However, the elimination of cross-sensitivity of the explosive detectors based on TiO2-(B) toward environmental humidity is still a major challenge. It was found that the cross-sensitivity could be effectively modulated when the thin film of TiO2-(B) nanowires was exposed to ultraviolet (UV) light during the detection of explosives under operating conditions. Such a modulation of sensing responses of TiO2-(B) nanowires to explosives by UV light was attributed to a photocatalytic effect, with which the water adsorbed on the TiO2-(B) nanowire surface was split and therefore the sensor response performance was less affected. It was revealed that the cross-sensitivity could be suppressed up to 51% when exposed to UV light of 365 nm wavelength with an intensity of 40 mW cm(-2). This finding proves that the reduction of cross-sensitivity to humidity through UV irradiation is an effective approach that can improve the performance of a sensor based on TiO2-(B) nanowires for the detection of explosive gas. PMID- 23443513 TI - Correlation of photobleaching, oxidation and metal induced fluorescence quenching of DNA-templated silver nanoclusters. AB - Few-atom noble metal nanoclusters have attracted a lot of interest due to their potential applications in biosensor development, imaging and catalysis. DNA templated silver nanoclusters (AgNCs) are of particular interest as different emission colors can be obtained by changing the DNA sequence. A popular analytical application is fluorescence quenching by Hg(2+), where d(10)-d(10) metallophilic interaction has often been proposed for associating Hg(2+) with nanoclusters. However, it cannot explain the lack of response to other d(10) ions such as Zn(2+) and Cd(2+). In our effort to elucidate the quenching mechanism, we studied a total of eight AgNCs prepared by different hairpin DNA sequences; they showed different sensitivity to Hg(2+), and DNA with a larger cytosine loop size produced more sensitive AgNCs. In all the cases, samples strongly quenched by Hg(2+) were also more easily photobleached. Light of shorter wavelengths bleached AgNCs more potently, and photobleached samples can be recovered by NaBH4. Strong fluorescence quenching was also observed with high redox potential metal ions such as Ag(+), Au(3+), Cu(2+) and Hg(2+), but not with low redox potential ions. Such metal induced quenching cannot be recovered by NaBH4. Electronic absorption and mass spectrometry studies offered further insights into the oxidation reaction. Our results correlate many important experimental observations and will fuel the further growth of this field. PMID- 23443514 TI - Treatment of brainstem metastases with gamma-knife radiosurgery. AB - The aim was to investigate the efficacy and safety of gamma-knife stereotactic radiosurgery (SRS) for treating brainstem metastases. The cases of 44 patients who underwent SRS as treatment for 46 brainstem metastases were retrospectively evaluated. The median age was 57 years (range 42-82 years) and the median Karnofsky performance score (KPS) was 80 (range 60-90). The primary tumor was lung carcinoma in 28 cases, breast carcinoma in 7 cases, colon carcinoma in 3 cases, renal cell carcinoma in 3 cases, malignant melanoma in 1 case, and unknown origin in 2 cases. Of the 46 metastases, 30 were in the pons, 14 were in the mesencephalon, and 2 were in the medulla oblongata. The median volume of the 46 metastases was 0.6 cc (range 0.34-7.3 cc). The median marginal dose of radiation was 16 Gy (range 10-20 Gy). Twenty-three patients (52 %) received whole brain radiotherapy prior to SRS, and 6 (14 %) received this therapy after SRS. In the remaining 15 cases (34 %), SRS was applied as the only treatment. Recursive partitioning analysis, graded prognostic assessment, and basic score for brain metastases were used to predict survival time. Local control was achieved for all but two of the 46 metastases (96 %). The overall survival time after SRS was 8 months. Female gender, KPS >70, mesencephalon tumor location, and response to treatment were associated with longer survival. Basic score for brain metastases class I and recursive partitioning analysis classification were associated with better prognosis. Peri-tumoral changes were detected radiologically at 2 (4 %) of the metastatic lesion sites but neither of these patients exhibited symptoms. Gamma-knife radiosurgery is effective for treating brainstem metastases without a higher risk for radiation necrosis. PMID- 23443515 TI - Quality of life after stereotactic radiotherapy for meningioma: a prospective non randomized study. AB - Stereotactic radiotherapy (SRT) is well-established in the treatment of meningiomas offering high local control with low toxicity. However, the impact of SRT on quality of life (QoL) of patients remains largely unknown. This work aimed to prospectively evaluate QoL (longitudinal analysis) during and after SRT of meningiomas. We performed a single center, one-armed, prospective non-randomized study to assess QoL before and at the end of SRT (median fraction dose: 1.8 Gy; median cumulative dose: 54.0 Gy) and furthermore biannually until 24 months after SRT with the "medical outcome study short form 36". This questionnaire evaluates 8 health parameters summarized in "physical component scale" (PCS) and "mental component scale" (MCS). Between 2005 and 2007, 67 patients were enrolled and treated with SRT. 42/52 patients underwent previous operations and 10/52 primary SRT. Complete follow-up data were available from 44 patients. Compared to the german normal population (GNP) a general decrease in the mean values of all parameters was observed. After SRT mean values still declined and 12 months after SRT all parameters normalized towards their initial values. The cohort (previous operations) had better values for MCS (p = 0.004). The cohort (primary SRT) had worse values for PCS that increased asymptotically 6 months after SRT to values of cohort (previous operations) (p = 0.054). Gender, age and tumor related symptoms did not affect QoL according to MCS and PCS (p > 0.05). Local control was 98 %. Treatment was well tolerated and no severe side effects were observed. Patients with meningiomas have an impaired QoL compared to GNP. The QoL assessment after SRT revealed three phases: "depressive phase", "recovery phase" and "normalization phase". Patients treated with primary SRT developed a stable increase of the mean values for PCS. Gender, age, applied dose, symptomatology did not affect QoL. PMID- 23443517 TI - [The oncology patient in intensive care]. PMID- 23443516 TI - A case of congenital syphilis. AB - We report a case of an asymptomatic 3-month-old girl presenting to the emergency department with concern for congenital syphilis. Radiographs of the lower limbs demonstrate mild diffuse periosteal reaction involving the femur, tibia, and fibula and bilaterally symmetric lucencies and erosions of the medial proximal tibial metaphysis (Wimberger's sign). PMID- 23443519 TI - Superior performance of liposomes over enzymatic amplification in a high throughput assay for myoglobin in human serum. AB - Myoglobin is one of several cardiac markers which become elevated in the blood following an acute myocardial infarction and can aid in the diagnosis of a heart attack. Here, a sandwich immunoassay for myoglobin was developed, including a thorough optimization of fluorescent dye-encapsulating liposomes versus enzymatic amplification (alkaline phosphatase and horseradish peroxidase) at each step. The optimized microtiter plate-based assay was capable of detecting as low as 11.3 pg/mL myoglobin and was successfully applied for the quantification of myoglobin in human serum. In comparison to enzymatic approaches, the liposomes demonstrated lower limits of detection, significantly reduced limits of quantification, improved signal discrimination through substantial signal enhancement, and reduced assay time. Liposomes were stable and functional at ambient temperatures for over 400 days. Finally, ease of use was greater due to lack of reliance on additional reagents, non-time-based signal enhancement, and excellent photostability. Optimal conditions identified for enzymatic approaches can also be used for liposome amplification, which makes substitution of these liposomes into existing assays straightforward. Thus, the extensive studies carried out here suggest that liposomes may be incorporated into formats currently utilizing enzymatic enhanced fluorescence with a potential for increased performance on various levels. PMID- 23443518 TI - [Chronic critically ill patients from the perspective of hematologists/oncologists]. AB - Many factors contribute to making critically ill patients with underlying hematological or oncological diseases into a special collective on intensive care units, such as an often incurable or at least doubtfully curable underlying disease, therapy associated complications and a commonly present immunosuppression. The prognosis of these patients has clearly improved in recent years so that a general reluctance in deciding to treat these patients in intensive care units can no longer be justified. Comprehensive infection diagnostics and a guideline oriented causal and supportive treatment can improve the prognosis of sepsis even in hematology/oncology patients. In the therapy of respiratory failure non-invasive ventilation is of great importance for a reduction in mortality if used early and contraindications, such as termination criteria are considered. Considerations on long-term prognosis, quality of life and palliative care are increasingly becoming topics in intensive care medicine. PMID- 23443520 TI - A high-throughput microfluidic biochip to quantify bacterial adhesion to single host cells by real-time PCR assay. AB - A high-throughput microfluidic poly-(dimethylsiloxane) biochip was developed to quantify bacterial adhesion to single host cells by real-time PCR assay. The biochip is simply structured with a two-dimensional array of 900 micro-wells, one inlet, and one outlet micro-channels. Isolation of single infected host cells into the individual micro-wells of the biochip was achieved by one-step vacuum driven microfluidics. The adhered bacterial cells were then quantified by direct on-chip real-time PCR assay with single-bacterium-detection sensitivity. The performance of this microfluidic platform was demonstrated through profiling of the association of a common bacterial pathogen, Pseudomonas aeruginosa, to single host human lung epithelial A549 cells, revealing an adherence distribution that has not been previously reported. This microfluidic platform offers a simple and effective tool for biologists to analyze pathogen-host interaction at the single cell level without the necessities of fluorescence labeling. The chip can similarly be used for other PCR-based applications requiring single-cell analysis. PMID- 23443521 TI - Sensitive detection of trace hemoglobin using fluorescence method based on functionalized quantum dots. AB - The fluorescence quenching of quantum dots by hemoglobin has been demonstrated to depend on surface functionalization, and this property has been utilized to construct a novel fluorescent method for rapid, sensitive, and selective detection of trace hemoglobin in urine at microgram level. This method shows low interference and high selectivity for hemoglobin with a limit of detection of 4.3 MUg L(-1) in water and 66.1 MUg L(-1) in urine, which are lower than those of currently used methods in labs and clinics. Spike and recovery tests in raw, acidified, and alkalized urine samples exhibit good recovery rates for the spiked concentrations close to the limit of detection. PMID- 23443522 TI - Identification of the long-acting erythropoiesis-stimulating agent darbepoetin alfa in human urine by liquid chromatography-tandem mass spectrometry. AB - The misuse of recombinant human erythropoietin (rhEPO) increases the proliferation/production of erythrocytes, which enhance oxygen transport capacities, and has grave consequences with respect to human health and fairness in sports. For sports drug testing, the current analytical methods for rhEPOs are mainly gel electrophoretic methods, such as isoelectric focusing-polyacrylamide gel electrophoresis. Mass spectrometry is fundamentally necessary for the reliable identification of rhEPOs in doping control. In this study, a high sensitivity and high-throughput mass spectrometric qualitative detection method for darbepoetin alfa in human urine was established by a bottom-up approach. The novel method involves the immunopurification of human urine (10 mL), protease digestion with endoproteinase Glu-C (V8-protease) in an ammonium bicarbonate buffer (pH 7.8) and ultra-performance liquid chromatography using a charged surface hybrid C18 column coupled with electrospray-ionisation high-sensitivity tandem mass spectrometry for improved selectivity of the target molecules. The specific fragment digested from darbepoetin alfa was (90)TLQLHVDKAVSGLRSLTTLLRALGAQKE(117) (V11). The lower limit of detection of urinary darbepoetin alfa was 1.2 pg/mL. The limit of detection for the confirmation analysis was estimated to be 5 pg/mL. The developed method allows high-throughput confirmation analysis, namely 6 h for sample preparation and an analytical run time of only 10 min per sample; this high-throughput method dramatically decreases the workload in the laboratory. Darbepoetin alfa could be identified in human urine collected after the intravenous administration of 15 MUg darbepoetin alfa (n = 3). This mass spectrometric method is an innovative and powerful tool for detecting darbepoetin alfa in human urine for doping control testing. PMID- 23443523 TI - Application of cyclic biamperometry to viability and cytotoxicity assessment in human corneal epithelial cells. AB - The application of cyclic biamperometry to viability and cytotoxicity assessments of human corneal epithelial cells has been investigated. Electrochemical measurements have been compared in PBS containing 5.0 mM glucose and minimal essential growth medium. Three different lipophilic mediators including dichlorophenol indophenol, 2-methyl-1,4-naphthoquinone (also called menadione or vitamin K3) and N,N,N',N'-tetramethyl-p-phenylenediamine have been evaluated for shuttling electrons across the cell membrane to the external medium. Transfer of these electrons to ferricyanide in the extra cellular medium results in the accumulation of ferrocyanide. The amount of ferrocyanide is then determined using cyclic biamperometry and is related to the extent of cell metabolic activity and therefore cell viability. To illustrate cytotoxicity assessment of chemicals, hydrogen peroxide, benzalkonium chloride and sodium dodecyl sulfate have been chosen as sample toxins, the cytotoxicities of which have been evaluated and compared to values reported in the literature. Similar values have been reported using colorimetric assays; however, the simplicity of this electrochemical assay can, in principle, open the way to miniaturization onto lab-on-chip devices and its incorporation into tiered-testing approaches for cytotoxicity assessment. PMID- 23443524 TI - Highly sensitive analysis of four hemeproteins by dynamically-coated capillary electrophoresis with chemiluminescence detector using an off-column coaxial flow interface. AB - Dynamic coating of the surface in capillary electrophoresis with chemiluminescence detection (CE-CL) using an off-column coaxial flow interface for the determination of four hemeproteins was developed. This method is based on the luminol-hydrogen peroxide reaction catalyzed by metalloproteins in alkaline medium. The experimental setup of the CE-CL system with the proposed off-column coaxial interface was evaluated by separation and detection of dopamine and catechol based on inhibition of the luminol-potassium ferricyanide reaction. Highly efficient separation of the two model compounds with symmetrical peak shape and satisfactory reproducibility was achieved by using this interface. In addition, in order to obtain a good resolution for hemeproteins, polyvinylpyrrolidone (PVP) combined with sodium dodecyl sulfate (SDS) were introduced as dynamic modifiers to reduce the unwanted adsorption of non-specific protein. Several parameters affecting the CE separation and CL detection were investigated in detail. Under the optimized conditions, a mixture of the four hemeproteins (horseradish peroxidase (HRP), catalase (Cat), myoglobin (Mb) and cytochrome C (Cyt C)) could be well separated within 20 min. The linear ranges of the four proteins were 5.7 * 10(-8) to 1.1 * 10(-6) mol L(-1) for HRP, 4.0 * 10( 8) to 2.0 * 10(-6) mol L(-1) for Cat, 1.1 * 10(-10) to 5.6 * 10(-8) mol L(-1) for Mb, and 3.8 * 10(-7) to 7.7 * 10(-6) mol L(-1) for Cyt C. The limits of detection (LODs) (S/N = 3) for HRP, Cat, Mb and Cyt C were 2.2 * 10(-8) mol L(-1) (104.5 amol), 1.6 * 10(-8) mol L(-1) (74 amol), 5.6 * 10(-11) mol L(-1) (0.26 amol), and 1.95 * 10(-7) mol L(-1) (0.89 fmol), respectively. The proposed method has been successfully applied to the analysis of low-level Mb in a spiked human urine sample and the recoveries were above 97%. Our primary result demonstrated that the proposed CE-CL method has great potential for Mb determination in clinical diagnosis. PMID- 23443525 TI - When jurisdictional boundaries become barriers to good patient care. AB - Canada is a pioneer in remote cancer care delivery to underserved populations; however, it is trailing behind on policies that would support clinicians in providing care using distance technologies. The current policy framework is disjointed, and discussions by professional boards about online jurisprudence associated with licensure appear to be regressive. We hope that by addressing the discrepancies in interjurisdictional practice and focusing on the key issue of "where therapy resides," we will be able to nudge dialogue and thinking closer toward the reasoning and recommendations of national telehealth organizations. We present this discussion of jurisdictional issues and e-health practice in the context of a pan-Canadian online support program developed for cancer patients and family members. Although the present paper uses online support groups as a springboard to advocate for e-health, it ultimately addresses a broader audience: that of all Canadian health care stakeholders. PMID- 23443526 TI - Return to work and sports after total hip replacement. AB - INTRODUCTION: Expectations of patients requiring total hip replacement have become higher than in the past and are often well beyond pain relief and improved mobility. Return to work and sporting activity are important factors to be considered when advising patients preoperatively. The objective of this study was to analyse the return to sports and work rates in patients still in employment and to analyse potential influencing factors. MATERIALS AND METHODS: Patients under the age of 65 who had a total hip replacement performed at a university teaching hospital were identified from the local arthroplasty database and contacted. Pre and postoperative levels of sporting activity and work were recorded. We also recorded the time point at which they returned to these activities. RESULTS: 285 total hip replacements were carried out on 239 patients. At the time of follow-up 170 of the patients were working. The mean length of time to return to work was 13.9 weeks (SD 7.7). 78 % returned to work without any restrictions, 18.6 % in heavy manual jobs. The mean time taken to return to sports or similar physical activities was 18.8 weeks (SD 8.8) weeks. Those with a lower body mass index returned to work and sporting activities faster. CONCLUSIONS: Our data show that the majority of patients undergoing total hip replacement can expect to return to work and sporting activities within 4-6 months. Activities at work are often initially limited and physical performance may not fully return to the expected level. Patients with a high body mass index take longer to return to work and sporting activities. PMID- 23443527 TI - Efficacy of treatment in peri-pelvic Morel-Lavallee lesion: a systematic review of the literature. AB - BACKGROUND: Morel-Lavallee lesion (MLL) of the peri-pelvic region is less common and various treatments have been introduced to manage the lesion. No standard treatment is recommended. We performed a systematic review of literature to (1) identify the classification of peri-pelvic MLL; (2) review the treatments of the lesion and their complications; (3) define the optimal treatment of peri-pelvic MLL. METHODS: A systematic search was performed via PubMed, ISI Web of Knowledge, and Embase for English abstract articles from 1966 to 2012. We identified 21 articles detailing 153 patients with peri-pelvic MLL, most of which were level IV studies. The treatments and clinical results were reviewed. RESULTS: For peri pelvic MLL patients, surgical intervention was better than conservative therapy. Sclerhodesis method is attended with good outcome in the symptomatic MLL patients without fractures. Patients with peri-pelvic fractures could be managed with local suction drainage or open debridement with dead space closure technique during fracture fixation. The delayed-diagnosis cases might be treated with mass resection when fibrosis capsule was obtained in magnetic resonance imaging. CONCLUSIONS: Peri-pelvic MLL can be treated with various surgical methods depending on the formation of fibrosis capsule and associated injuries. Dead space closure technique is emphasized in the treatment of MLL. Higher quality of literature is required to prove this result in future research. PMID- 23443528 TI - Treatment of thumb soft-tissue defects using a bipedicle island flap of the index finger: anatomical basis and clinical application. AB - PURPOSE: Reconstruction of the thumb with exposure of bone and tendon is challenging. We designed a bipedicle island flap from the dorsum of the index finger to repair thumb defects. One pedicle includes the radial proper palmar digital artery (PDA) of the index finger, another pedicle includes the first dorsal metacarpal artery (FDMA). The aim of the study was to investigate the anatomical basis and clinical application of this flap. METHODS: Eleven fresh cadaver hands were dissected, the FDMA and the radial proper PDA were exposed. Their origin, distribution and diameter in different locations, especially in the dorsum of the proximal phalanx of the index finger, were examined. Ten patients (11 hands) underwent thumb reconstruction using this flap. During follow-up, the flap survival and hand function were evaluated. RESULTS: The origin of the FDMA in three cadaver hands was abnormal. The FDMA was mainly distributed in the proximal area of the dorsum of the proximal phalanx. The radial proper PDA of the index finger formed one constant dorsal branch, mainly distributing in the middle and distal area of the dorsum of the proximal phalanx. All flaps survived. At follow-up, the span of the first web and the range of motion of the thumbs and index fingers reached more than 94 % of the contralateral finger. All patients were satisfied with the hand function according to the Michigan Hand Outcomes Questionnaire (MHQ). CONCLUSIONS: The bipedicle island flap has two arterial systems to provide sufficient blood supply. This technique provides another option for thumb reconstruction when a large supercharged FDMA island flap needs to be designed, or when there is an additional injury to the radial side of the dorsum of the hand or if there are anatomical variations of the FDMA, or if damage to the FDMA occurs during surgery. PMID- 23443530 TI - Orthopedic surgeon perspectives on appropriate referral of trauma patients to physical therapy (PT). AB - OBJECTIVES: To evaluate orthopedic surgeon referral of trauma patients to PT. DESIGN: Cross-sectional survey. SETTING: Alberta, Canada. PARTICIPANTS: Orthopedic surgeons and residents. METHODS: A web-based survey was utilized to poll orthopedic surgeons and residents on referral practices. Statistical analysis using Kruskal-Wallis One-Way Analysis of Variance by Ranks; Post hoc analysis using the minimum significant difference method for multiple comparisons and nonparametric correlations using Spearman's rho. RESULTS: The overall response rate was 48 %. Key indications for referral were range of motion deficits, failure to progress, strength and gait training. Of those surveyed, 72.5 and 26.1 % felt that there was either moderate or significant improvement following PT, respectively. Years in practice had a significant effect on survey responses. Residents and surgeons in practice for >20 years viewed PT as being less important in orthopedic trauma (p < 0.05) and were less likely to refer orthopedic trauma patients to PT (p < 0.05). Residents were less likely to view PT in orthopedic trauma as evidence-based (0.05) and more likely to disagree with the statement that formalized PT results in better outcomes than a prescribed home exercise program (p < 0.05). CONCLUSIONS: There are potential differences in the referral practices of orthopedists of varying levels of experience. Although outcome is viewed as positive following PT, it appears that many orthopedists view a prescribed home exercise program as an acceptable equivalent to formalized PT in the setting of orthopedic trauma. Future research should be directed at determining indicators for formalized PT. PMID- 23443529 TI - The effect of rotational deformity on patellofemoral parameters following the treatment of femoral shaft fracture. AB - OBJECTIVE: The purpose of this study was to investigate the effect of rotational deformities on patellofemoral alignment using the dynamic magnetic resonance imaging method on patients whose femur fractures were treated with intramedullary locking nails. METHODS: The dynamic patellofemoral magnetic resonance imaging results of 33 patients (5 females and 28 males) were reviewed. The mean age of the patients was 36.3 (range 19-61) years. The mean follow-up was 30.2 months (range 24-38). All the patients were given Kujala patellofemoral clinical evaluation scores at the latest follow-up. Those with less than 10 degrees of rotational deformity in either direction were classified as Group A, those with more than a 10 degrees of internal rotation deformity as Group B and more than a 10 degrees of external rotation deformity as Group C. The three groups were then compared regarding to clinical scores. Patellofemoral parameters of operated and contralateral side were also compared in each group. RESULTS: There were 14 (42.4 %) patients in Group A, 12 (36.4 %) patients in Group B and 7 (21.2 %) patients in Group C. The mean patella score in Group C (74 +/- 7.02) was significantly lower when compared with Group B (87.6 +/- 9.9) and group A (90.6 +/- 6.1) (p < 0.05). In Group C patients, medial patellar tilt was detected when compared with the intact side. There were no significant changes in patellofemoral position in either Group A or Group B. CONCLUSION: The results of this study revealed that more than 10 degrees of external rotation deformity could cause a detoriation in the patellofemoral scores. Anatomic reduction of the fracture site should be performed as soon as possible and external rotational deformities should especially be avoided in order to prevent patellofemoral malalignment. PMID- 23443531 TI - Expression of steroid and xenobiotic receptor in uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma. AB - We analyzed the expression of the steroid and xenobiotic receptor (SXR) in human uterine sarcomas and evaluated its clinical significance. Forty-seven cases with archival specimens were examined for SXR expression using immunohistochemistry. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with a HSCORE >40 were regarded as SXR-positive. Various clinicopathological variables, including the expression status of estrogen receptor (ER)-alpha, progesterone receptor (PR) and Ki67 (MIB-1) were examined. The mean SXR HSCOREs of carcinosarcoma (CS) and leiomyosarcoma (LMS) were 9.13 and 23.6, respectively, and SXR-positive rates were 3 out of 24 (12.5%) and 4 out of 17 (23.5%), respectively. SXR was not detected in endometrial stromal sarcoma (ESS). In CS cases, significant differences were detected between the expression of SXR and age and disease stages. There was no significant correlation between SXR-positive status and either disease-free survival or overall survival. Our results support an association between SXR and malignant behavior. Our results show that overexpression of SXR may represent a useful marker to identify patients with advanced-stage CS. In addition, our results showed that SXR may aid in the diagnosis of uterine sarcomas. PMID- 23443533 TI - Real-time outcome monitoring following oesophagectomy using cumulative sum techniques. AB - AIM: To examine the feasibility of prospective, real-time outcome monitoring in a United Kingdom oesophago-gastric cancer surgery unit. METHODS: The first 100 hybrid (laparoscopic abdominal phase, open thoracic phase) Ivor-Lewis oesophagectomies performed by a United Kingdom oesophago-gastric cancer surgery unit were assessed retrospectively using cumulative sum (CUSUM) techniques. The monitored outcome was 30-d post-operative mortality, with the accepted mortality risk defined as 5%. A variable life adjusted display (VLAD) was constructed by plotting a graph of cumulative mortality minus cumulative mortality risk on the y axis vs sequential case number on the x axis. This was modified to a zeroed VLAD by preventing the plot from crossing the y = 0 axis - essentially creating two plots, one examining trends where cumulative mortality was higher than mortality risk (i.e., worse than expected outcomes) where y > 0, and vice versa. Alert lines were set at y = +/- 2. At any point where a plot breaches an alert line, it is felt that the 30-d post-operative mortality rate has deviated significantly from that expected and an internal review should be performed. RESULTS: One hundred cases were assessed, with a mean age of 66.4 years, mean T stage of 2.1, and mean N stage of 0.48. Three cases were commenced using a laparoscopic technique and converted to open surgery due to technical factors. Median length of inpatient stay was 15 d. The crude 30 d mortality was 5% and the incidence of clinically significant anastomotic leak was 6%. The VLAD demonstrated a plot of cumulative mortality minus cumulative mortality risk (i.e., 5% per case) which remained in the range -1.4 to +0.5 excess mortalities. With the alert set at two greater or fewer than predicted mortalities, this method does not approach the point of triggering internal review. It is however arguable that a run of performance that is better than expected, causing the plot to be well below y = 0, would mask a subsequent run of poor performance by requiring a rise of greater than two excess mortalities to trigger the alert line. The zeroed VLAD removes this problem by preventing the plot that is examining above expected mortality from passing below y = 0, and vice versa. In this study period, no audit triggers were reached. It is therefore possible to independently assess runs of good, or poor performance and so target internal audit to the appropriate series of cases. It is important to note this technique allows targeted internal review, in response to both above and below average outcomes. This study has demonstrated the feasibility of prospective outcome monitoring using the above techniques, actual real-time implementation has the potential to pick up and reinforce good practices when performance is better than predicted, and provide an early warning system for when performance falls below that predicted. Further development is possible, including more patient specific risk adjustment using the oesophago gastric surgery physiological and operative severity score for the enumeration of mortality and morbidity score. CONCLUSION: CUSUM techniques provide a potential method of prospective, real-time outcome monitoring in oesophageal cancer surgery. PMID- 23443532 TI - The long-term impact of early adversity on late-life psychiatric disorders. AB - Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research. PMID- 23443534 TI - Dermal fibroblast infiltration of poly(epsilon-caprolactone) scaffolds fabricated by melt electrospinning in a direct writing mode. AB - Melt electrospinning in a direct writing mode is a recent additive manufacturing approach to fabricate porous scaffolds for tissue engineering applications. In this study, we describe porous and cell-invasive poly (epsilon-caprolactone) scaffolds fabricated by combining melt electrospinning and a programmable x-y stage. Fibers were 7.5 +/- 1.6 um in diameter and separated by interfiber distances ranging from 8 to 133 um, with an average of 46 +/- 22 um. Micro computed tomography revealed that the resulting scaffolds had a highly porous (87%), three-dimensional structure. Due to the high porosity and interconnectivity of the scaffolds, a top-seeding method was adequate to achieve fibroblast penetration, with cells present throughout and underneath the scaffold. This was confirmed histologically, whereby a 3D fibroblast-scaffold construct with full cellular penetration was produced after 14 days in vitro. Immunohistochemistry was used to confirm the presence and even distribution of the key dermal extracellular matrix proteins, collagen type I and fibronectin. These results show that melt electrospinning in a direct writing mode can produce cell invasive scaffolds, using simple top-seeding approaches. PMID- 23443536 TI - PI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma. AB - Inositol polyphosphate 5-phosphatases can terminate downstream signalling of phosphatidylinositol-3 kinase; however, their biological role in the pathogenesis of cancer is controversial. Here we report that the inositol polyphosphate 5 phosphatase, phosphatidylinositol 4,5-bisphosphate 5-phosphatase, has a tumour suppressive role in melanoma. Although it is commonly downregulated in melanoma, overexpression of phosphatidylinositol 4,5-bisphosphate 5-phosphatase blocks Akt activation, inhibits proliferation and undermines survival of melanoma cells in vitro, and retards melanoma growth in a xenograft model. In contrast, knockdown of phosphatidylinositol 4,5-bisphosphate 5-phosphatase results in increased proliferation and anchorage-independent growth of melanocytes. Although DNA copy number loss is responsible for downregulation of phosphatidylinositol 4,5 bisphosphate 5-phosphatase in a proportion of melanomas, histone hypoacetylation mediated by histone deacetylases HDAC2 and HDAC3 through binding to the transcription factor Sp1 at the PIB5PA gene promoter appears to be another commonly involved mechanism. Collectively, these results establish the tumour suppressive role of phosphatidylinositol 4,5-bisphosphate 5-phosphatase and reveal mechanisms involved in its downregulation in melanoma. PMID- 23443537 TI - Holographic optogenetic stimulation of patterned neuronal activity for vision restoration. AB - When natural photoreception is disrupted, as in outer-retinal degenerative diseases, artificial stimulation of surviving nerve cells offers a potential strategy for bypassing compromised neural circuits. Recently, light-sensitive proteins that photosensitize quiescent neurons have generated unprecedented opportunities for optogenetic neuronal control, inspiring early development of optical retinal prostheses. Selectively exciting large neural populations are essential for eliciting meaningful perceptions in the brain. Here we provide the first demonstration of holographic photo-stimulation strategies for bionic vision restoration. In blind retinas, we demonstrate reliable holographically patterned optogenetic stimulation of retinal ganglion cells with millisecond temporal precision and cellular resolution. Holographic excitation strategies could enable flexible control over distributed neuronal circuits, potentially paving the way towards high-acuity vision restoration devices and additional medical and scientific neuro-photonics applications. PMID- 23443538 TI - A new class of plant lipid is essential for protection against phosphorus depletion. AB - Phosphorus supply is a major factor responsible for reduced crop yields. As a result, plants utilize various adaptive mechanisms against phosphorus depletion, including lipid remodelling. Here we report the involvement of a novel plant lipid, glucuronosyldiacylglycerol, against phosphorus depletion. Lipidomic analysis of Arabidopsis plants cultured in phosphorus-depleted conditions revealed inducible accumulation of glucuronosyldiacylglycerol. Investigation using a series of sulfolipid sulfoquinovosyldiacylglycerol synthesis-deficient mutants of Arabidopsis determined that the biosynthesis of glucuronosyldiacylglycerol shares the pathway of sulfoquinovosyldiacylglycerol synthesis in chloroplasts. Under phosphorus-depleted conditions, the Arabidopsis sqd2 mutant, which does not accumulate either sulfoquinovosyldiacylglycerol or glucuronosyldiacylglycerol, was the most severely damaged of three sulfoquinovosyldiacylglycerol-deficient mutants. As glucuronosyldiacylglycerol is still present in the other two mutants, this result indicates that glucuronosyldiacylglycerol has a role in the protection of plants against phosphorus limitation stress. Glucuronosyldiacylglycerol was also found in rice, and its concentration increased significantly following phosphorus limitation, suggesting a shared physiological significance of this novel lipid against phosphorus depletion in plants. PMID- 23443539 TI - Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex. AB - Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington's disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1-protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A- and mammalian target of rapamycin-dependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-complex may serve as a therapeutic target for the treatment of CAG repeat expansion disorders. PMID- 23443541 TI - New class of nonaqueous electrolytes for long-life and safe lithium-ion batteries. AB - Long-life and safe lithium-ion batteries have been long pursued to enable electrification of the transportation system and for grid applications. However, the poor safety characteristics of lithium-ion batteries have been the major bottleneck for the widespread deployment of this promising technology. Here, we report a novel nonaqueous Li(2)B(12)F(12-x)H(x) electrolyte, using lithium difluoro(oxalato)borate as an electrolyte additive, that has superior performance to the conventional LiPF(6)-based electrolyte with regard to cycle life and safety, including tolerance to both overcharge and thermal abuse. Cells tested with the Li(2)B(12)F(9)H(3)-based electrolyte maintained about 70% initial capacity when cycled at 55 degrees C for 1,200 cycles, and the intrinsic overcharge protection mechanism was active up to 450 overcharge abuse cycles. Results from in situ high-energy X-ray diffraction showed that the thermal decomposition of the delithiated Li(1-x)[Ni(1/3)Mn(1/3)Co(1/3)](0.9)O(2) cathode was delayed by about 20 degrees C when using the Li(2)B(12)F(12)-based electrolyte. PMID- 23443540 TI - Synapsin II desynchronizes neurotransmitter release at inhibitory synapses by interacting with presynaptic calcium channels. AB - In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes gamma-aminobutyric acid asynchronous release in a Ca(2+) dependent manner by a functional interaction with presynaptic Ca(2+) channels, revealing a new role in synaptic transmission for synapsins. PMID- 23443542 TI - Substrate-mediated band-dispersion of adsorbate molecular states. AB - Charge carrier mobilities in molecular condensates are usually small, as the coherent transport, which is highly effective in conventional semiconductors, is impeded by disorder and the small intermolecular coupling. A significant band dispersion can usually only be observed in exceptional cases such as for pi stacking of aromatic molecules in organic single crystals. Here based on angular resolved photoemission, we demonstrate on the example of planar pi-conjugated molecules that the hybridization with a metal substrate can substantially increase the delocalization of the molecular states in selective directions along the surface. Supported by ab initio calculations we show how this mechanism couples the individual molecules within the organic layer resulting in an enhancement of the in-plane charge carrier mobility. PMID- 23443543 TI - Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction. AB - Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the calcium-permeable channel, transient potential melastatin-like 2 (TRPM2), via stimulation of poly ADP-ribose polymerase. Importantly, irradiation induced an irreversible loss of salivary gland fluid secretion in TRPM2+/+ mice while a transient loss was seen in TRPM2-/- mice with >60% recovery by 30 days after irradiation. Treatment of TRPM2+/+ mice with the free radical scavenger Tempol or the PARP1 inhibitor 3 aminobenzamide attenuated irradiation-induced activation of TRPM2 and induced significant recovery of salivary fluid secretion. Furthermore, TPL (4-hydroxy 2,2,6,6-tetramethylpiperidine-N-oxyl) induced complete recovery of function in irradiated TRPM2-/- mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function. PMID- 23443544 TI - Colloidal ribbons and rings from Janus magnetic rods. AB - Dipolar particles are fundamental building blocks in nature and technology, yet the effect of particle anisotropy is seldom explored. Here, we fabricate colloidal silica rods coated with a hemicylindrical magnetic layer to satisfy multiple criteria: nearly monodisperse, easily imaged and magnetic interaction that dominates over gravity. We confirm long-predicted features of dipolar assembly and stress the microstructural variety brought about by shape and constituent anisotropy, especially by extrapolating knowledge learned from literal molecules. In this colloidal system, we describe analogies to liquid crystalline deformations with bend, splay and twist; an analogy to cis/trans isomerism in organic molecules, which in our system can be controllably and reversibly switched; and a field-switching methodology to direct single ribbons into not only single but also multiple rings that can subsequently undergo hierarchical self-assembly. We highlight subtle material issues of control and design rules for reconfigurable dipolar materials with building blocks of complex shape. PMID- 23443545 TI - Tet-mediated covalent labelling of 5-methylcytosine for its genome-wide detection and sequencing. AB - 5-methylcytosine is an epigenetic mark that affects a broad range of biological functions in mammals. The chemically inert methyl group prevents direct labelling for subsequent affinity purification and detection. Therefore, most current approaches for the analysis of 5-methylcytosine still have limitations of being either density-biased, lacking in robustness and consistency, or incapable of analysing 5-methylcytosine specifically. Here we present an approach, TAmC-Seq, which selectively tags 5-methylcytosine with an azide functionality that can be further labelled with a biotin for affinity purification, detection and genome wide mapping. Using this covalent labelling approach, we demonstrate high sensitivity and specificity for known methylated loci, as well as increased CpG dinucleotide coverage at lower sequencing depth as compared with antibody-based enrichment, providing an improved efficiency in the 5-methylcytosine enrichment and genome-wide profiling. PMID- 23443546 TI - Greater efficiency of photosynthetic carbon fixation due to single amino-acid substitution. AB - The C4-photosynthetic carbon cycle is an elaborated addition to the classical C3 photosynthetic pathway, which improves solar conversion efficiency. The key enzyme in this pathway, phosphoenolpyruvate carboxylase, has evolved from an ancestral non-photosynthetic C3 phosphoenolpyruvate carboxylase. During evolution, C4 phosphoenolpyruvate carboxylase has increased its kinetic efficiency and reduced its sensitivity towards the feedback inhibitors malate and aspartate. An open question is the molecular basis of the shift in inhibitor tolerance. Here we show that a single-point mutation is sufficient to account for the drastic differences between the inhibitor tolerances of C3 and C4 phosphoenolpyruvate carboxylases. We solved high-resolution X-ray crystal structures of a C3 phosphoenolpyruvate carboxylase and a closely related C4 phosphoenolpyruvate carboxylase. The comparison of both structures revealed that Arg884 supports tight inhibitor binding in the C3-type enzyme. In the C4 phosphoenolpyruvate carboxylase isoform, this arginine is replaced by glycine. The substitution reduces inhibitor affinity and enables the enzyme to participate in the C4 photosynthesis pathway. PMID- 23443549 TI - Athermal photofluidization of glasses. AB - Azobenzene and its derivatives are among the most important organic photonic materials, with their photo-induced trans-cis isomerization leading to applications ranging from holographic data storage and photoalignment to photoactuation and nanorobotics. A key element and enduring mystery in the photophysics of azobenzenes, central to all such applications, is athermal photofluidization: illumination that produces only a sub-Kelvin increase in average temperature can reduce, by many orders of magnitude, the viscosity of an organic glassy host at temperatures more than 100 K below its thermal glass transition. Here we analyse the relaxation dynamics of a dense monolayer glass of azobenzene-based molecules to obtain a measurement of the transient local effective temperature at which a photo-isomerizing molecule attacks its orientationally confining barriers. This high temperature (T(loc)~800 K) leads directly to photofluidization, as each absorbed photon generates an event in which a local glass transition temperature is exceeded, enabling collective confining barriers to be attacked with near 100% quantum efficiency. PMID- 23443550 TI - Voltage tunability of single-spin states in a quantum dot. AB - Single spins in the solid state offer a unique opportunity to store and manipulate quantum information, and to perform quantum-enhanced sensing of local fields and charges. Optical control of these systems using techniques developed in atomic physics has yet to exploit all the advantages of the solid state. Here we demonstrate voltage tunability of the spin energy-levels in a single quantum dot by modifying how spins sense magnetic field. We find that the in-plane g factor varies discontinuously for electrons, as more holes are loaded onto the dot. In contrast, the in-plane hole g-factor varies continuously. The device can change the sign of the in-plane g-factor of a single hole, at which point an avoided crossing is observed in the two spin eigenstates. This is exactly what is required for universal control of a single spin with a single electrical gate. PMID- 23443551 TI - Topological states in a ladder-like optical lattice containing ultracold atoms in higher orbital bands. AB - Topological insulators are classified according to their symmetries. Discovery of them in electronic solids is thus restricted by orbital and crystalline symmetries available in nature. Synthetic quantum matter, such as the recent double-well optical lattices loaded with s and p orbital ultracold atoms, can exploit symmetries and interaction beyond natural conditions. Here we unveil a topological phase of interacting fermionic atoms on a two-leg ladder derived from the above experimental optical lattice by dimension reduction. The topological band structure originates from the staggered phases of sp orbital tunnelling, requiring neither spin-orbit coupling nor other known mechanisms like p-wave pairing, artificial gauge field or rotation. Upon crossing over to two dimensional coupled ladders, the edge modes from individual ladder form a parity protected flat band at zero energy. Experimental signatures are found in density correlations and phase transitions to trivial band and Mott insulators. PMID- 23443552 TI - Topological protection of bound states against the hybridization. AB - Topological invariants are conventionally known to be responsible for protection of extended states against disorder. A prominent example is the presence of topologically protected extended states in two-dimensional quantum Hall systems as well as on the surface of three-dimensional topological insulators. Here we introduce a new concept that is distinct from such cases-the topological protection of bound states against hybridization. This situation is shown to be realizable in a two-dimensional quantum Hall insulator put on a three-dimensional trivial insulator. In such a configuration, there exist topologically protected bound states, localized along the normal direction of two-dimensional plane, in spite of hybridization with the continuum of extended states. The one-dimensional edge states are also localized along the same direction as long as their energies are within the band gap. This finding demonstrates the dual role of topological invariants, as they can also protect bound states against hybridization in a continuum. PMID- 23443553 TI - Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells. AB - Haemodynamic variations are inherent to blood vessel geometries (such as bifurcations) and correlate with regional development of inflammation and atherosclerosis. However, the complex frequency spectrum characteristics from these haemodynamics have never been exploited to test whether frequency variations are critical determinants of endothelial inflammatory phenotype. Here we utilize an experimental Fourier transform analysis to systematically manipulate individual frequency harmonics from human carotid shear stress waveforms applied in vitro to human endothelial cells. The frequency spectrum, specifically the 0 th and 1st harmonics, is a significant regulator of inflammation, including NF-kappaB activity and downstream inflammatory phenotype. Further, a harmonic-based regression-model predicts eccentric NF-kappaB activity observed in the human internal carotid artery. Finally, short interfering RNA knockdown of the mechanosensor PECAM-1 reverses frequency-dependent regulation of NF-kappaB activity. Thus, PECAM-1 may have a critical role in the endothelium's exquisite sensitivity to complex shear stress frequency harmonics and provide a mechanism for the focal development of vascular inflammation. PMID- 23443554 TI - Haematopoietic cells produce BDNF and regulate appetite upon migration to the hypothalamus. AB - Brain-derived neurotrophic factor (BDNF) suppresses food intake by acting on neurons in the hypothalamus. Here we show that BDNF-producing haematopoietic cells control appetite and energy balance by migrating to the hypothalamic paraventricular nucleus. These haematopoietic-derived paraventricular nucleus cells produce microglial markers and make direct contacts with neurons in response to feeding status. Mice with congenital BDNF deficiency, specifically in haematopoietic cells, develop hyperphagia, obesity and insulin resistance. These abnormalities are ameliorated by bone marrow transplantation with wild-type bone marrow cells. Furthermore, when injected into the third ventricle, wild-type bone marrow mononuclear cells home to the paraventricular nucleus and reverse the hyperphagia of BDNF-deficient mice. Our results suggest a novel mechanism of feeding control based on the production of BDNF by haematopoietic cells and highlight a potential new therapeutic route for the treatment of obesity. PMID- 23443555 TI - Directional visible light scattering by silicon nanoparticles. AB - Directional light scattering by spherical silicon nanoparticles in the visible spectral range is experimentally demonstrated for the first time. These unique optical properties arise because of simultaneous excitation and mutual interference of magnetic and electric dipole resonances inside a single nanosphere. Such behaviour is similar to Kerker's-type scattering by hypothetic magneto-dielectric particles predicted theoretically three decades ago. Here we show that directivity of the far-field radiation pattern of single silicon spheres can be strongly dependent on the light wavelength and the nanoparticle size. For nanoparticles with sizes ranging from 100 to 200 nm, forward-to backward scattering ratio above six can be experimentally obtained, making them similar to 'Huygens' sources. Unique optical properties of silicon nanoparticles make them promising for design of novel low-loss visible- and telecom-range metamaterials and nanoantenna devices. PMID- 23443556 TI - De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. AB - Clinical interest in de novo lipogenesis has been sparked by recent studies in rodents demonstrating that de novo lipogenesis specifically in white adipose tissue produces the insulin-sensitizing fatty acid palmitoleate. By contrast, hepatic lipogenesis is thought to contribute to metabolic disease. How de novo lipogenesis in white adipose tissue versus liver is altered in human obesity and insulin resistance is poorly understood. Here we show that lipogenic enzymes and the glucose transporter-4 are markedly decreased in white adipose tissue of insulin-resistant obese individuals compared with non-obese controls. By contrast, lipogenic enzymes are substantially upregulated in the liver of obese subjects. Bariatric weight loss restored de novo lipogenesis and glucose transporter-4 gene expression in white adipose tissue. Notably, lipogenic gene expression in both white adipose tissue and liver was strongly linked to the expression of carbohydrate-responsive element-binding protein-beta and to metabolic risk markers. Thus, de novo lipogenesis predicts metabolic health in humans in a tissue-specific manner and is likely regulated by glucose-dependent carbohydrate-responsive element-binding protein activation. PMID- 23443557 TI - S-nitrosylation of phosphotransfer proteins represses cytokinin signaling. AB - Cytokinin is an essential phytohormone in plant growth and development. In Arabidopsis, cytokinin signalling is mediated by a phosphorelay that sequentially transfers phosphoryl groups from the cytokinin receptors to histidine phosphotransfer proteins (AHPs) and response regulators (ARRs). However, little is known about the regulatory mechanism of the phosphorelay. Here, we show that nitric oxide negatively regulates cytokinin signalling by inhibiting the phosphorelay activity through S-nitrosylation. S-nitrosylation of AHP1 at Cys 115 represses its phosphorylation and subsequent transfer of the phosphoryl group to ARR1. A non-nitrosylatable mutation of AHP1 renders the mutant protein insensitive to nitric oxide in repressing its phosphorylation, and partially relieves the inhibitory effect of nitric oxide on the cytokinin response. Conversely, a nitrosomimetic mutation of AHP1 causes reduced phosphorylation of AHP1 and ARR1, thereby resulting in a compromised cytokinin response. These findings illustrate a mechanism by which redox signalling and cytokinin signalling coordinate plant growth and development. PMID- 23443558 TI - Sir2a regulates rDNA transcription and multiplication rate in the human malaria parasite Plasmodium falciparum. AB - The Plasmodium falciparum histone deacetylase Sir2a localizes at telomeric regions where it contributes to epigenetic silencing of clonally variant virulence genes. Apart from telomeres, PfSir2a also accumulates in the nucleolus, which harbours the developmentally regulated ribosomal RNA genes. Here we investigate the nucleolar function of PfSir2a and demonstrate that PfSir2a fine tunes ribosomal RNA gene transcription. Using a parasite line in which PfSir2a has been disrupted, we observe that histones near the transcription start sites of all ribosomal RNA genes are hyperacetylated and that transcription of ribosomal RNA genes is upregulated. Complementation of the PfSir2a-disrupted parasites restores the ribosomal RNA levels, whereas PfSir2a overexpression in wild-type parasites decreases ribosomal RNA synthesis. Furthermore, we observe that PfSir2a modulation of ribosomal RNA synthesis is linked to an altered number of daughter merozoites and the parasite multiplication rate. These findings provide new insights into an epigenetic mechanism that controls malaria parasite proliferation and virulence. PMID- 23443559 TI - LGALS3BP regulates centriole biogenesis and centrosome hypertrophy in cancer cells. AB - Centrosome morphology and number are frequently deregulated in cancer cells. Here, to identify factors that are functionally relevant for centrosome abnormalities in cancer cells, we established a protein-interaction network around 23 centrosomal and cell-cycle regulatory proteins, selecting the interacting proteins that are deregulated in cancer for further studies. One of these components, LGALS3BP, is a centriole- and basal body-associated protein with a dual role, triggering centrosome hypertrophy when overexpressed and causing accumulation of centriolar substructures when downregulated. The cancer cell line SK-BR-3 that overexpresses LGALS3BP exhibits hypertrophic centrosomes, whereas in seminoma tissues with low expression of LGALS3BP, supernumerary centriole-like structures are present. Centrosome hypertrophy is reversed by depleting LGALS3BP in cells endogenously overexpressing this protein, supporting a direct role in centrosome aberration. We propose that LGALS3BP suppresses assembly of centriolar substructures, and when depleted, causes accumulation of centriolar complexes comprising CPAP, acetylated tubulin and centrin. PMID- 23443561 TI - Nitrogen cycle feedbacks as a control on euxinia in the mid-Proterozoic ocean. AB - Geochemical evidence invokes anoxic deep oceans until the terminal Neoproterozoic ~0.55 Ma, despite oxygenation of Earth's atmosphere nearly 2 Gyr earlier. Marine sediments from the intervening period suggest predominantly ferruginous (anoxic Fe(II)-rich) waters, interspersed with euxinia (anoxic H(2)S-rich conditions) along productive continental margins. Today, sustained biotic H(2)S production requires NO(3)(-) depletion because denitrifiers outcompete sulphate reducers. Thus, euxinia is rare, only occurring concurrently with (steady state) organic carbon availability when N(2)-fixers dominate the production in the photic zone. Here we use a simple box model of a generic Proterozoic coastal upwelling zone to show how these feedbacks caused the mid-Proterozoic ocean to exhibit a spatial/temporal separation between two states: photic zone NO(3)(-) with denitrification in lower anoxic waters, and N(2)-fixation-driven production overlying euxinia. Interchange between these states likely explains the varying H(2)S concentration implied by existing data, which persisted until the Neoproterozoic oxygenation event gave rise to modern marine biogeochemistry. PMID- 23443560 TI - GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance. AB - Efficient engulfment of apoptotic cells is critical for maintaining tissue homoeostasis. When phagocytes recognize 'eat me' signals presented on the surface of apoptotic cells, this subsequently induces cytoskeletal rearrangement of phagocytes for the engulfment through Rac1 activation. However, the intracellular signalling cascades that result in Rac1 activation remain largely unknown. Here we show that G-protein-coupled receptor kinase 6 (GRK6) is involved in apoptotic cell clearance. GRK6 cooperates with GIT1 to activate Rac1, which promotes apoptotic engulfment independently from the two known DOCK180/ELMO/Rac1 and GULP1/Rac1 engulfment pathways. As a consequence, GRK6-deficient mice develop an autoimmune disease. GRK6-deficient mice also have increased iron stores in splenic red pulp in which F4/80(+) macrophages are responsible for senescent red blood cell clearance. Our results reveal previously unrecognized roles for GRK6 in regulating apoptotic engulfment and its fundamental importance in immune and iron homoeostasis. PMID- 23443562 TI - Magnetic switching of ferroelectric domains at room temperature in multiferroic PZTFT. AB - Single-phase magnetoelectric multiferroics are ferroelectric materials that display some form of magnetism. In addition, magnetic and ferroelectric order parameters are not independent of one another. Thus, the application of either an electric or magnetic field simultaneously alters both the electrical dipole configuration and the magnetic state of the material. The technological possibilities that could arise from magnetoelectric multiferroics are considerable and a range of functional devices has already been envisioned. Realising these devices, however, requires coupling effects to be significant and to occur at room temperature. Although such characteristics can be created in piezoelectric-magnetostrictive composites, to date they have only been weakly evident in single-phase multiferroics. Here in a newly discovered room temperature multiferroic, we demonstrate significant room temperature coupling by monitoring changes in ferroelectric domain patterns induced by magnetic fields. An order of magnitude estimate of the effective coupling coefficient suggests a value of ~1 * 10(-7) sm(-1). PMID- 23443563 TI - Brownian motion and quantum dynamics of magnetic monopoles in spin ice. AB - Spin ice illustrates many unusual magnetic properties, including zero point entropy, emergent monopoles and a quasi liquid-gas transition. To reveal the quantum spin dynamics that underpin these phenomena is an experimental challenge. Here we show how crucial information is contained in the frequency dependence of the magnetic susceptibility and in its high frequency or adiabatic limit. The typical response of Dy(2)Ti(2)O(7) spin ice indicates that monopole diffusion is Brownian but is underpinned by spin tunnelling and is influenced by collective monopole interactions. The adiabatic response reveals evidence of driven monopole plasma oscillations in weak applied field, and unconventional critical behaviour in strong applied field. Our results clarify the origin of the relatively high frequency response in spin ice. They disclose unexpected physics and establish adiabatic susceptibility as a revealing characteristic of exotic spin systems. PMID- 23443564 TI - Critical fictive temperature for plasticity in metallic glasses. AB - A long-sought goal in metallic glasses is to impart ductility without conceding their strength and elastic limit. The rational design of tough metallic glasses, however, remains challenging because of the inability of existing theories to capture the correlation between plasticity, composition and processing for a wide range of glass-forming alloys. Here we propose a phenomenological criterion based on a critical fictive temperature, T(fc), which can rationalize the effect of composition, cooling rate and annealing on room-temperature plasticity of metallic glasses. Such criterion helps in understanding the widespread mechanical behaviour of metallic glasses and reveals alloy-specific preparation conditions to circumvent brittleness. PMID- 23443565 TI - Xenoturbella bocki exhibits direct development with similarities to Acoelomorpha. AB - Xenoturbella bocki, a marine animal with a simple body plan, has recently been suggested to be sister group to the Acoelomorpha, together forming the new phylum Xenacoelomorpha. The phylogenetic position of the phylum is still under debate, either as an early branching bilaterian or as a sister group to the Ambulacraria (hemichordates and echinoderms) within the deuterostomes. Although development has been described for several species of Acoelomorpha, little is known about the life cycle of Xenoturbella. Here we report the embryonic stages of Xenoturbella, and show that it is a direct developer without a feeding larval stage. This mode of development is similar to that of the acoelomorphs, supporting the newly proposed phylum Xenacoelomorpha and suggesting that the last common ancestor of the phylum might have been a direct developer. PMID- 23443566 TI - Porous materials with pre-designed single-molecule traps for CO2 selective adsorption. AB - Despite tremendous efforts, precise control in the synthesis of porous materials with pre-designed pore properties for desired applications remains challenging. Newly emerged porous metal-organic materials, such as metal-organic polyhedra and metal-organic frameworks, are amenable to design and property tuning, enabling precise control of functionality by accurate design of structures at the molecular level. Here we propose and validate, both experimentally and computationally, a precisely designed cavity, termed a 'single-molecule trap', with the desired size and properties suitable for trapping target CO(2) molecules. Such a single-molecule trap can strengthen CO(2)-host interactions without evoking chemical bonding, thus showing potential for CO(2) capture. Molecular single-molecule traps in the form of metal-organic polyhedra are designed, synthesised and tested for selective adsorption of CO(2) over N(2) and CH(4), demonstrating the trapping effect. Building these pre-designed single molecule traps into extended frameworks yields metal-organic frameworks with efficient mass transfer, whereas the CO(2) selective adsorption nature of single molecule traps is preserved. PMID- 23443567 TI - A low-temperature method to produce highly reduced graphene oxide. AB - Chemical reduction of graphene oxide can be used to produce large quantities of reduced graphene oxide for potential application in electronics, optoelectronics, composite materials and energy-storage devices. Here we report a highly efficient one-pot reduction of graphene oxide using a sodium-ammonia solution as the reducing agent. The solvated electrons in sodium-ammonia solution can effectively facilitate the de-oxygenation of graphene oxide and the restoration of pi conjugation to produce reduced graphene oxide samples with an oxygen content of 5.6 wt%. Electrical characterization of single reduced graphene oxide flakes demonstrates a high hole mobility of 123 cm(2) Vs(-1). In addition, we show that the pre-formed graphene oxide thin film can be directly reduced to form reduced graphene oxide film with a combined low sheet resistance (~350 Omega per square with ~80% transmittance). Our study demonstrates a new, low-temperature solution processing approach to high-quality graphene materials with lowest sheet resistance and highest carrier mobility. PMID- 23443568 TI - Structural domain walls in polar hexagonal manganites. AB - The domain structure in the multiferroic hexagonal manganites, h-RMnO(3) (R=Sc, Y, Dy-Lu), is currently intensely investigated, motivated by the observation of nanoscale electrical conductivity at the domain walls and intriguing sixfold topological defects at their meeting points, as well as reports of coupling between ferroelectricity, magnetism and structural antiphase domains. The detailed structure of the domain walls, as well as the origin of such couplings, however, was previously unknown. Here we use first-principles electronic structure calculations to elucidate the structure and properties of the structural domain walls in the hexagonal manganites. Our results allow us to explain why ferroelectric domain walls are always simultaneously antiphase walls, propose a mechanism for ferroelectric switching through domain-wall motion, suggest a structure for the observed sixfold topological defects and predict a topological protection of experimentally observed stripe domains in hexagonal manganites. PMID- 23443569 TI - Enhanced dihydropyridine receptor calcium channel activity restores muscle strength in JP45/CASQ1 double knockout mice. AB - Muscle strength declines with age in part due to a decline of Ca(2+) release from sarcoplasmic reticulum calcium stores. Skeletal muscle dihydropyridine receptors (Ca(v)1.1) initiate muscle contraction by activating ryanodine receptors in the sarcoplasmic reticulum. Ca(v)1.1 channel activity is enhanced by a retrograde stimulatory signal delivered by the ryanodine receptor. JP45 is a membrane protein interacting with Ca(v)1.1 and the sarcoplasmic reticulum Ca(2+) storage protein calsequestrin (CASQ1). Here we show that JP45 and CASQ1 strengthen skeletal muscle contraction by modulating Ca(v)1.1 channel activity. Using muscle fibres from JP45 and CASQ1 double knockout mice, we demonstrate that Ca(2+) transients evoked by tetanic stimulation are the result of massive Ca(2+) influx due to enhanced Ca(v)1.1 channel activity, which restores muscle strength in JP45/CASQ1 double knockout mice. We envision that JP45 and CASQ1 may be candidate targets for the development of new therapeutic strategies against decay of skeletal muscle strength caused by a decrease in sarcoplasmic reticulum Ca(2+) content. PMID- 23443570 TI - Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation. AB - A subset of transcription factors classified as neural crest 'specifiers' are also core epithelial-mesenchymal transition regulatory factors, both in the neural crest and in tumour progression. The bHLH factor Twist is among the least well studied of these factors. Here we demonstrate that Twist is required for cranial neural crest formation and fate determination in Xenopus. We further show that Twist function in the neural crest is dependent upon its carboxy-terminal WR domain. The WR domain mediates physical interactions between Twist and other core epithelial-mesenchymal transition factors, including Snail1 and Snail2, which are essential for proper function. Interaction with Snail1/2, and Twist function more generally, is regulated by GSK-3-beta-mediated phosphorylation of conserved sites in the WR domain. Together, these findings elucidate a mechanism for coordinated control of a group of structurally diverse factors that function as a regulatory unit in both developmental and pathological epithelial-mesenchymal transitions. PMID- 23443571 TI - Stretchable batteries with self-similar serpentine interconnects and integrated wireless recharging systems. AB - An important trend in electronics involves the development of materials, mechanical designs and manufacturing strategies that enable the use of unconventional substrates, such as polymer films, metal foils, paper sheets or rubber slabs. The last possibility is particularly challenging because the systems must accommodate not only bending but also stretching. Although several approaches are available for the electronics, a persistent difficulty is in power supplies that have similar mechanical properties, to allow their co-integration with the electronics. Here we introduce a set of materials and design concepts for a rechargeable lithium ion battery technology that exploits thin, low modulus silicone elastomers as substrates, with a segmented design in the active materials, and unusual 'self-similar' interconnect structures between them. The result enables reversible levels of stretchability up to 300%, while maintaining capacity densities of ~1.1 mAh cm(-2). Stretchable wireless power transmission systems provide the means to charge these types of batteries, without direct physical contact. PMID- 23443573 TI - Phenotyping bananas for drought resistance. AB - Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with "B" genome are more tolerant to abiotic stresses than those solely based on "A" genome. In particular, bananas with "ABB" genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite for any improvement program for targeted traits. In the present article, known drought tolerant traits of other crop plants are validated in bananas with different genomic backgrounds and presented. Since, banana is recalcitrant to breeding, strategies for making hybrids between different genomic backgrounds are also discussed. Stomatal conductance, cell membrane stability (CMS), leaf emergence rate, rate of leaf senescence, RWC, and bunch yield under soil moisture deficit stress are some of the traits associated with drought tolerance. Among these stress bunch yield under drought should be given top priority for phenotyping. In the light of recently released Musa genome draft sequence, the molecular breeders may have interest in developing molecular markers for drought resistance. PMID- 23443572 TI - Excitation-dependent visible fluorescence in decameric nanoparticles with monoacylglycerol cluster chromophores. AB - Organic fluorescent nanoparticles, excitation-dependent photoluminescence, hydrogen-bonded clusters and lysobisphosphatidic acid are four interesting individual topics in materials and biological sciences. They have attracted much attention not only because of their unique properties and important applications, but also because the nature of their intriguing phenomena remained unclear. Here we report a new type of organic fluorescent nanoparticles with intense blue and excitation-dependent visible fluorescence in the range of 410-620 nm. The nanoparticles are composed of ten bis(monoacylglycerol)bisphenol-A molecules and the self-assembly occurs only in elevated concentrations of 2-monoacylglycerol via radical-catalysed 3,2-acyl migration from 3-monoacylglycerol in neat conditions. The excitation-dependent fluorescence behaviour is caused by chromophores composed of hydrogen-bonded monoacylglycerol clusters, which are linked by an extensive hydrogen-bonding network between the ester carbonyl groups and the protons of the alcohols with collective proton motion and HO...C=O (n >pi) interactions. PMID- 23443574 TI - Quantum yields for the photolysis of glyoxal below 350 nm and parameterisations for its photolysis rate in the troposphere. AB - The formation of HCO and of H in the photolysis of glyoxal have been investigated over the wavelength ranges 310-335 nm for HCO and 193-340 nm for H. Dye laser photolysis was coupled with cavity ring-down spectroscopy for HCO, and with laser induced fluorescence spectroscopy for H. Absolute quantum yields were determined using actinometers based on (a) Cl2 photolysis and the Cl + HCHO reaction for HCO and (b) N2O photolysis (and O(1)D + H2) and CH2CO photolysis (and CH2 + O2) for H. The quantum yields were found to be pressure independent in this wavelength region. Quantum yields for all product channels under atmospheric conditions were calculated and compared with literature values. Differences between this work and previously published work and their atmospheric implications are discussed. PMID- 23443575 TI - Synthesis and stress relaxation of ZnO/Al-doped ZnO core-shell nanowires. AB - Doping nanostructures is an effective method to tune their electrical and photoelectric properties. Taking ZnO nanowires (NWs) as a model system, we demonstrate that atomic layer deposition (ALD) can be adopted for the realization of a doping process by the homo-epitaxial growth of a doped shell on the NW core. The Al-doped ZnO NWs have a layered superlattice structure with dopants mainly occupying the interstitial positions. After annealing, Al(3+) ions diffuse into the ZnO matrix and occupy substitutional locations, which is desirable for dopant activation. The stress accumulated during epitaxial growth is relaxed by the nucleation of dislocations, dislocation dipoles and anti-phase boundaries. We note that the proposed method can be easily adopted for doping different types of nanostructures, and fabricating superlattices and multiple quantum wells on NWs in a controllable way. PMID- 23443576 TI - The influence of thermal discomfort on the attention index of teenagers: an experimental evaluation. AB - In order to measure the effect on the attention of teenagers of thermal discomfort due to high temperature and humidity, two experiments were conducted in two different indoor conditions of temperature and humidity in non-air conditioned classrooms. The participants were a heterogeneous group of 117 teenagers, aged 12 to 18 years, and the experiments reproduced the actual conditions of teaching in a classroom in the Mediterranean climate. In order to measure the attention index, a standard Toulouse-Pieron psychological test was performed on the 117 teenagers in these two conditions, and the Predicted Mean Vote (PMV), the physiologically Equivalent Temperature (PET), the Standard effective Temperature (SET*) and the Universal Thermal Climate Index (UTCI) indices were calculated to estimate the grade of discomfort using the RayMan Pro model. Conditions of greater discomfort decreased the attention index in the whole group, especially in those aged 12-14, among whom the attention index dropped by around 45% when compared to comfortable conditions. However, teenage attention at ages 17 and 18 shows little variation in discomfort in respect to thermally comfortable conditions. In addition, the attention index for boys and girls shows the same variation in discomfort conditions. However, girls have a slightly higher attention index than boys in discomfort and thermal comfort experiments. PMID- 23443577 TI - Expression profiles of miRNAs in polarized macrophages. AB - microRNAs (miRNAs) play a crucial role in tissue development and the pathology of various diseases. However, the effects and roles of miRNAs in macrophage polarization have yet to be investigated. In this study, we analyzed and compared the miRNA expression profiles of bone marrow-derived macrophages (BMDMs) with two distinct polarizing conditions (classical macrophage activation 'M1' and alternative activation 'M2') using miRNA microarray. In total, 109 miRNAs were differentially expressed between M1 and M2. The differential expression of selected miRNAs was validated by real-time qRT-PCR: miR-181a, miR-155-5p, miR-204 5p and miR-451 were upregulated (fold change >2, P<0.05) and miR-125-5p, miR-146a 3p, miR-143-3p and miR-145-5p were downregulated (fold change <-2, P<0.05) in M1 compared with M2. In conclusion, our study may be useful for exploring the precise roles of miRNAs in macrophage differentiation and polarized activation processes in the future. PMID- 23443579 TI - Introduction to the special issue of Neuropsychology Review on cognitive enhancement and rehabilitation. PMID- 23443578 TI - A root-specific wall-associated kinase gene, HvWAK1, regulates root growth and is highly divergent in barley and other cereals. AB - Wall-associated receptor-like kinases (WAKs) are important candidates for directly linking the extracellular matrix with intracellular compartments and are involved in developmental processes and stress response. WAK gene family has been identified in plants such as Arabidopsis and rice. Here, we present a detailed analysis of the WAK1 gene from barley cv. Golden Promise, mapped to chromosome 5H. Three BAC clones corresponding to the WAK fragment were sequenced and the full-length WAK1 gene was characterized. The gene has three exons and two short introns with a coding region of 2,178 bp encoding a protein of 725 amino acids. A regulatory region was analyzed in -1,000 bp sequence upstream to start codon. Using conserved domains database and SMART, various conserved domains such as GUB WAK Bind, epidermal growth factor CA, and protein kinase C as well as other regions like signal peptides, active sites, and transmembrane domains were identified. The gene organization of HvWAK1 was compared with wheat (TaWAK1) and Arabidopsis (AtWAK1), suggesting that the WAK1 gene organization has remained highly conserved. Nonetheless, WAK1 was found to be highly divergent when compared with sequences available from barley cv. Haruna Nijo (50 %), rice (46 %), wheat (21 %), Arabidopsis (25 %), and maize (19 %). This divergence may have facilitated a better adaptation to surrounding environments due to its role in communication between the extracellular matrix, cell, and outer environment. Semiquantitative RT-PCR-based expression analysis indicates HvWAK1 expression is specific to roots. Significant differences in root growth between GP wild type and GP-Ds mutant seedlings were observed under control and salt stress conditions. PMID- 23443581 TI - Active and passive smoking and the risk of myocardial infarction in 24,968 men and women during 11 year of follow-up: the Tromso Study. AB - Active smoking is a well-established risk factor for myocardial infarction, but less is known about the impact of passive smoking, and possible sex differences in risk related to passive smoking. We investigated active and passive smoking as risk factors for myocardial infarction in an 11-year follow-up of 11,762 men and 13,206 women included in the Tromso Study. There were a total of 769 and 453 incident cases of myocardial infarction in men and women, respectively. We found linear age-adjusted relationships between both active and passive smoking and myocardial infarction incidence in both sexes. The relationships seem to be stronger for women than for men. Age-adjusted analyses indicated a stronger relationship with passive smoking in ever-smokers than in never-smokers. After adjustment for important confounders (body mass index, blood pressure, total cholesterol, HDL cholesterol and physical activity) the associations with active and passive smoking were still statistically significant. Adjusting for active smoking when assessing the effect of passive smoking and vice versa, indicated that the effect of passive smoking in men may be explained by their own active smoking. In women, living with a smoker >=30 years after the age of 20 increased the myocardial infarction risk by 40 %, even after adjusting for active smoking. Passive smoking is a risk factor for myocardial infarction on its own, but whereas the effect for men seems to be explained by their own active smoking, the effect in females remains statistically significant. PMID- 23443582 TI - Screening, case finding or primary cancer prevention in the developing world? PMID- 23443583 TI - Asymptomatic carotid artery stenosis: state of the art management. AB - In 2011, numerous guidelines were updated to advise on the optimal management of patients with asymptomatic carotid disease. Despite being based on interpretation of the same body of literature, there was actually little international consensus. Whilst we now know much more about what constitutes "state of the art" medical management, we still cannot identify the small proportion of "high risk for stroke" patients in whom to target carotid endarterectomy or carotid artery stenting. This is essential, as about 95% of patients undergoing either treatment strategy will ultimately undergo an unnecessary intervention. There is compelling evidence that the annual risk of stroke (on medical therapy) in patients with asymptomatic carotid disease has declined significantly. Guideline makers cannot continue to extrapolate rationales for justifying "mass interventions" in contemporary practice that are based on historical trial data. Accordingly, there is no consensus as to what should be considered "state of the art" management of asymptomatic carotid disease. PMID- 23443584 TI - Indications and techniques for emergency carotid interventions. AB - Mutual understanding exists among specialists of neurology, interventional radiology and vascular surgery concerning the need of interventional treatment for patients with symptomatic carotid artery stenosis. However, identification of individuals that will most likely benefit from treatment, timing of the intervention and selection of treatment mode continue to be a matter of intense debate. The aim of this manuscript was to discuss the changing attitude to this high-risk population and present evidence that points towards a resolute, fast track approach. PMID- 23443585 TI - Future imaging techniques in aortic pathologies and clinical implications. AB - Future imaging techniques in aortic pathology will be used to detect early subclinical pathological changes and to identify patients who would benefit from early surgical intervention. Current imaging for aortic pathology is mainly computed tomography (CT). This modality produces static images which are used as the basis to decide which patients require intervention. Subclinical disease can be detected experimentally by novel magnetic resonance (MR) techniques such as molecular imaging: measurement of the amount of elastin in the aortic wall has the potential to identify patients with low levels of elastin at risk of aortic dilatation. These patients could then be monitored in a more intensive aneurysm surveillance programme. Endothelial dysfunction can also be detected experimentally by MR techniques. Measurement of endothelial permeability will be used to tailor preventative medical treatment to individual patients. Aortic diameter is the main indication for treatment in both aortic aneurysms and chronic aortic dissection but may be prone to error. False lumen thrombosis detected on first-pass imaging is used as an outcome measure in randomized controlled trials. Blood pool contrast agent imaging is flow independent and is not subject to the significant error associated with current imaging methods. Four-dimensional phase contrast magnetic resonance (4D PC-MR) imaging can quantify flow in both the true and false lumens of aortic dissection. The amount and pattern of flow in the false lumen is related to the rate of aortic expansion. 4D PC-MR can demonstrate entry tears between the true and false lumens and this information can be used to guide endovascular treatment. Hybrid imaging techniques such as positron emission tomography (PET) combined with CT (PET-CT) can give information about the degree of inflammation in the aortic wall, and preliminary studies have shown that a positive scan can predict patients with dissection who are likely to have a poor outcome. These new techniques combine anatomical and functional data in a single acquisition. The richness of the data allows a greater understanding of the pathophysiology in each individual patient which will result in improved clinical outcomes. PMID- 23443586 TI - Endovascular strategies for infrarenal aneurysms with short necks. AB - The aim of this paper was to review the current options for endovascular treatment of abdominal aortic aneurysms (AAAs) with short infrarenal neck. Studies reporting endovascular treatment of AAAs with short proximal neck were reviewed. Fenestrated endovascular aneurysm repair (F-EVAR) is most frequently reported for the treatment of patients with short neck AAA, with high technical success rates (>= 99%), low operative mortality (<= 3.5%) and excellent mid- and long-term results in terms of target vessel patency (>= 97%). Chimney-EVAR (Ch EVAR) is far less reported, but also presents with high technical success rates (>97%), varying operative mortality rates (0-12.5%), and excellent short- and mid term target vessel patency (>= 96%). Ch-EVAR, however, seems to be associated with high postoperative stroke up to 6.3%, and increased proximal type I endoleak (5-31%). Standard EVAR performed outside manufacturers' instructions for use (IFU) is also documented in the treatment of short proximal neck AAA, but is associated with increased operative mortality and morbidity, type I endoleak, and migration, compared to standard EVAR in AAA with longer proximal neck length. F EVAR currently represents the most validated and reliable endovascular option for the treatment of short-neck AAA. Ch-EVAR is feasible, but lacks long-term data. Its use seems only favored in acute high surgical risk patients, in elective cases complicated with unintentional renal artery coverage or in anatomies unsuitable for F-EVAR. Standard EVAR in short neck AAA is associated with poorer outcomes and should not be recommended as first choice. PMID- 23443587 TI - Pararenal aneurysms: currently available fenestrated endografts. AB - Endovascular aneurysm repair (EVAR) is a valid treatment option for abdominal aortic aneurysm (AAA). The outcome of infrarenal EVAR is dependent on choosing patients with appropriate anatomy to allow for good proximal and distal seal. In the absence of an infrarenal neck of adequate length and quality, fenestrated stent-graft repair has emerged as an alternative treatment option. For the past decade there has only been one type of fenestrated endograft on the market. This has shown good short- and midterm outcome in many centers. This graft is custom designed for each individual patient. Over the past few years further development has led to the introduction of new, off-the-shelf stent-graft for fenestrated repair and some new companies have entered the marketplace. Most of these new devices are still in their infancy and currently undergoing clinical trials but add promise to the development of pararenal aortic repair. PMID- 23443588 TI - Open repair for juxtarenal aortic aneurysms. AB - Abdominal aortic aneurysms (AAAs) are classified as juxtarenal if their proximal extent is next to the origin of the renal arteries but does not involve them. An AAA is suprarenal if it extends above at least one renal artery and ends below the celiac axis. Juxtarenal AAAs need inter-renal or suprarenal clamping, with the aortic reconstruction usually made at the infrarenal level. Aneurysms requiring suprarenal clamping, often supraceliac, and the reconstruction (direct attachment or bypass) of at least one renal artery, are often defined as suprarenal AAAs. Endovascular aortic repair (EVAR) is feasible in most of cases of infrarenal AAAs and has been shown to be as effective as open repair (OR) in reducing aneurysm-related mortality and perioperative mortality with shorter length of stay. However, the feasibility of standard EVAR with an on-label use of commercially available devices is limited in the juxtarenal aorta. In our series, approximately, 20% to 30% of patients with an AAA are considered not eligible for standard EVAR owing to their anatomy, and in the most of the cases are patients with juxtarenal AAAs. Fenestrated and branched endografts and newer "off the shelf" techniques (such as chimney, periscope, sandwich) have been recently described, all with the purpose of widening the therapeutic range of EVAR to the treatment of aneurysms with involvement of renal and visceral arteries. However, safety, efficacy, long-term results, and cost-effectiveness of these expensive techniques have still to be carefully assessed. For these reasons, the OR is currently still considered the gold standard for treatment of juxtarenal AAAs, reserving endovascular strategies mainly for high-risk patients having comorbidities or other contraindications for conventional repair. If compared to open repair of infrarenal AAAs, juxtarenal AAA OR is technically more complex and might require specific organ-protection strategies in order to minimize ischemia reperfusion injury to kidneys and visceral organs. Because of the complexity of the surgical procedure and of the multiple clinical problems, an optimal operative strategy for the treatment of juxtarenal AAAs has not been established yet. The choice of the surgical access, clamping level, methods of organ protection and their impact on renal, respiratiry, cardiac and gastrointestinal morbidity are still debated issues. PMID- 23443589 TI - Ruptured AAA: state of the art management. AB - Since its introduction more than two decades ago, endovascular aneurysm repair (EVAR) has become the primary choice for elective treatment of abdominal aortic aneurysms (AAA) in many medical centers. The (dis)advantages, including 30-day mortality and long-term survival, of both open and endovascular elective AAA repair have been studied extensively, including four randomized trials. On the contrary, the survival benefit of EVAR for ruptured AAAs is not as well established as in elective situations. In the absence of randomized trials, the best treatment modality for ruptured AAA has not been revealed. In this manuscript, we describe the design and (preliminary) results of recently completed and ongoing randomized trials. Furthermore, the trends in management and the results of the treatment of ruptured AAA in our tertiary center over a 20 year period are presented. In the last decade, a progressive increase in the proportion of patients managed by EVAR was observed. This increase was associated with an overall increase in the number of treated patients and, simultaneously, a decrease in the overall 30-day mortality (53% versus 39%) was seen when comparing the two last decades. The 30-day mortality rates were significantly lower in the patients treated with EVAR (24%) compared to open repair (52%). The survival advantage for EVAR after ruptured AAA persisted during the first 5 years after repair, but was lost after that period. The estimated 5-year survival was 44% and 39% for EVAR and open repair, respectively. These data support that endovascular repair is an effective and safe strategy as a primary treatment modality for ruptured AAA. PMID- 23443590 TI - Surgical and endovascular treatment of occlusive aortic syndromes. AB - Aortic occlusive syndromes encompass a wide variety of aortic and aortoiliac conditions that present with devastating clinical sequale of hypertension coupled with visceral and lower limb ischemia. Clinical presentations, natural history, etio-pathology, diagnosis, management and outcomes of each of these disorders is unique. Risk factor management, endovascular intervention, and/or surgical revascularization compete and complement each other in an exciting manner to give best long-term outcomes. Common causes of aortic occlusion include: 1) atherosclerotic occlusive disease, including aortoiliac occlusive diseases (AIOD); acute aortic occlusion (embolic/thrombotic/dissection; 2) mid aortic syndrome: Takayasu arteritis; congenital aortic hypoplasia; fibromuscular dysplasia; neurofibromatosis; 3) coral reef aorta. PMID- 23443591 TI - Decision-making and techniques in hypogastric artery revascularization. AB - The aim of this article was to describe and discuss the currently available endovascular and open surgical techniques to preserve or occlude the hypogastric artery during aortoiliac aneurysm repair and thus support the process of decision making in hypogastric artery revascularization. PMID- 23443592 TI - Advanced endovascular techniques for thoracic and abdominal aortic dissections. AB - Endovascular treatment of aortic dissection is still in its infancy and consists usually of implantation of thoracic tubular stent-grafts to cover the proximal entry tear and redirect flow into the true lumen. Large registries comparing endovascular treatment by thoracic endovascular aortic repair (TEVAR) with open surgery for aortic dissection of the descending aorta have demonstrated a clear benefit for endovascular treatment with lower mortality and morbidity rates turning TEVAR into the standard treatment for complicated type B aortic dissection. With this momentum of success endovascular techniques continue to challenge open surgical techniques also in the aortic arch and the ascending aorta. TEVAR for aortic dissection has become more complex requiring an individualized treatment strategy as endovascular techniques have developed with the advent of new devices and increased experience of the operators. In many cases straight implantation of a thoracic tubular stent-graft is sufficient. But as rerouting of the blood flow can also change perfusion of vital side-branches the endovascular operator needs to have a large armamentarium of techniques and adjunctive procedures in order to sufficiently address the individual patient morphology. This chapter reviews a variety of endovascular techniques including access techniques, proximal sealing, the Petticoat-technique, false lumen deployment, fenestration techniques, branch vessel stenting and false lumen obstruction by various techniques. PMID- 23443593 TI - Intentional left subclavian artery coverage without revascularization during TEVAR. AB - At present, endovascular therapy is a well-established treatment for different types of thoracic aortic pathologies. There is growing evidence, that thoracic endovascular aortic repair (TEVAR) has advantages over open repair with regard to perioperative morbidity and mortality in the treatment of thoracic aortic aneurysms. However, in up to 50% of TEVAR procedures the proximal end of the stent-graft will (partly) cover the origin of the left subclavian artery (LSA) in order to achieve a save sealing zone. Intracranial stroke and paraplegia are feared complications and might be associated with LSA exclusion from the circulation. Unfortunately, no reliable technique is available to assess the individual risk of stroke and paraplegia in case of LSA coverage, so that the indication for LSA revascularization continues to be matter of assuming and guessing. The quality of available evidence on necessity or superfluity to revascularize the LSA is very low and studies report, to some extent, controversial outcome after intentional LSA coverage. In the light of the devastating consequences for patients in case of neurological complications due to LSA coverage the question of prophylactic LSA revascularization remains a significant problem which is elucidated and discussed in this manuscript. PMID- 23443594 TI - Chronic type B dissections: are fenestrated and branched endografts an option? AB - While there are centers reporting encouraging outcomes after endovascular repair of thoracoabdominal aortic aneurysms, chronic dissections (a specific etiological subgroup of thoracoabdominal aneurysms) present an even greater technical and clinical challenge. There are particular technical issues associated with the management of the proximal sealing zone, the need to work in a narrow aortic lumen and also to maintain perfusion of all target (visceral and supra-aortic) vessels including those perfused by the false lumen. We present here the various endovascular options available for the treatment of these complex aortic lesions. PMID- 23443595 TI - Results and clinical consequences of trials on thoracic endografting. AB - Thoracic endovascular repair (TEVR) has developed from endovascular treatment of infrarenal aortic aneurysms, and is now considered first-line treatment for a variety of thoracic aortic pathologies. In contrast to infrarenal repair, there are no large randomized controlled trials to underpin this change in practice, and most of the existing data are from smaller trials designed to evaluate the safety of a particular device. The aim of this review was to describe these studies with respect to perioperative adverse events, occurrence of device failure, mid-term aortic death, mid-term overall survival and freedom from aortic reintervention. The implications of these results are discussed in the context of their implications for clinical practice, taking into account the relative strengths and weakness of the available data. Where the individual trial design allows, direct comparison is made between TEVR and open surgical controls, and the results of TEVR applied to particular pathology groups is discussed. PMID- 23443596 TI - Spinal cord function monitoring during endovascular treatment of thoracoabdominal aneurysms: implications for staged procedures. AB - AIM: Spinal cord ischemia is a well-known complication in the treatment of thoracoabdominal aneurysms (TAAA). Despite the fact that endovascular treatment of TAAA is less invasive, spinal cord ischemia rate is not reduced if compared to open repair. METHODS: We report the results of our experience of spinal cord function monitoring by measuring motor evoked potentials (MEP) during endovascular treatment of TAAA type II and III. Depending on the level of the MEPs the decision is made whether to stage the procedure or not. We treated ten patients according to this protocol. RESULTS: In two patients, MEPs decreased 50% or more and procedures were staged. Both experienced no neurological complications after first and second procedure. No MEPs decrease was seen during the second procedures. One of the other eight patients had a temporary right lower leg pararesis. CONCLUSION: In conclusion we state that our first experience demonstrates the value of assessing spinal cord function during extensive endovascular TAAA repair with subsequent strategies to prevent paraplegia. PMID- 23443597 TI - Management of aortic aneurysms in patients with connective tissue disease. AB - Acute dissection and rupture of aortic aneurysms comprise for 1-2% of all deaths in developed countries. Dilation of the aorta is caused by several different mechanisms including inherited disorders of connective tissue. Recent reports estimate that 20% of patients presenting with thoracic aortic disease do have an underlying genetic basis of disease. PMID- 23443598 TI - Thoracoabdominal aneurysms and changes in adjacent vertebral bodies. AB - AIM: The aim of this study was to assess if chronic intermittent pressure of a thoracoabdominal aortic aneurysm (TAAA) induces structural changes in vertebral bodies and if eroded vertebral bones can still be found after the extermination of syphilis. METHODS: A retrospective analysis of computed tomography (CT) scans of patients with TAAA was performed. In the anatomical regions were the TAAA was in close contact with the vertebral bodies, the vertebral body alteration was distinguished into 4 categories. Category 0: no changes; 1: discrete changes, minimal asymmetry; 2: obvious asymmetry of the vertebral body with sustained cortical layer; 3: severe destruction of the vertebral body with loss of the cortical layer. RESULTS: Eighty-six CT scans of patients (mean age 63; range 25 82 years) with TAAA pathology were examined (24 female, 62 male). The mean aneurysm diameter was 6.5 cm (4.3-14 cm). The results for scoring were: category 0: 33 patients; category 1: 46 patients; category 2: 5 patients and category 3: 2 patients. One of the category 3 patients suffered from acute spinal cord compression with complete paraplegia. In total, 62% of patients showed some degree of changes at vertebral bodies adjacent to the TAAA. CONCLUSION: Intermittent pressure by either dissecting or non-dissecting TAAAs may induce structural changes in the vertebral bodies of the spine. Severe destruction of the bone is a rare, but existing complication. PMID- 23443600 TI - Techniques and outcome of retrograde crural artery revascularization. AB - In complex popliteal to infrapopliteal occlusions, an endovascular recanalization attempt can fail in a substantial number of cases. The additional use of a retrograde approach seems feasible and safe and can favorably modify this failure rate. However, this is a technique that requires training and is associated with a learning curve. Although this technique is widely practiced among experienced endovascular specialists, the literature contains reports of less than 100 of these cases. We present our experience with the retrograde approach for the treatment of complex tibial arterial disease. Insights into the technical aspects of the procedure and optimal case selection are discussed. PMID- 23443599 TI - Plaque debulking for femoro-popliteal occlusions: techniques and results. AB - Although currently there is a trend of using percutaneous transluminal angioplasty (PTA) and stenting for the treatment of long occlusions of superficial femoral artery, many studies reported comparable results in terms of mid- and long-term patency between PTA and stenting and plaque debulking techniques such as remote endarterectomy, directional atherectomy catheter atherectomy and laser guided atherectomy. A successful debulking procedure is strongly associated with patients comorbidities, length of lesions and clinical presentation. In the last decade many new devices have been proposed to improve debulking results. Despite encouraging data about technical feasibility and limb salvage rate, debulking is still associated with a low rate of long-term primary and secondary patency. However, randomized clinical trials are expected and can hopefully provide conclusions on the effective durability of these procedures. PMID- 23443601 TI - Alloplastic bypass material below the knee: actual rationale. AB - AIM: The greater saphenous vein is considered as material of first choice for a below-knee bypass. A high number of below knee synthetic, polytetrafluoroethylene or knitted polyester, bypass grafts in the institution of the senior author formed the basis to analyze factors for outcome of below-knee synthetic grafts. METHODS: A total of 533 patients (327 men, 206 women; age: 71.2 +/- 10.3 years), who had their first below knee bypass, were followed-up for up-to 9 (4.1 +/- 2.6) years. Survival, primary and secondary patency, and limb salvage were compared between vein bypasses and synthetic grafts by Kaplan Meier analysis. Within the group of 377 patients with synthetic grafts comorbidities, previous interventions, indications, graft diameter, and technical aspects were related to outcome including univariate (log-rank) and multivariate (Cox Proportional Hazard Ratio) statistics. RESULTS: The greater saphenous vein was superior to synthetic graft in primary and secondary patency as well as limb salvage (5 year limb salvage 73.3% vs. 56.7%, P=0.001). In patients with a synthetic bypass, relevant preoperative factors for higher patency rates were hypertension, coronary heart disease and no previous endovascular intervention. Patency and limb salvage was significantly improved for anastomoses not to a single crural vessel. Adding a St. Mary's Boot as cuff technique did not improve the results. In multivariate analysis, independent factors for higher primary patency were no previous endovascular intervention, low severity of peripheral arterial occlusive disease, coronary heart disease and age above 65. Additionally, femoropopliteal and tibioperoneal anastomoses were related to better limb salvage. CONCLUSION: The greater saphenous vein reveals the best results for below-knee bypass grafts. However, if a vein is not available, synthetic grafts appear to be an valuable alternative especially in patients with no previous radiologic intervention, coronary heart disease, and age over 65. PMID- 23443602 TI - Properties and challenges in materials used as vascular and endovascular devices. AB - In the last decades, main evolutions in the field of vascular surgery have been correlated to the development of devices allowing more reliable and safe sustainable treatment. First devices that have been proposed were vascular prostheses made of polymeric materials. The second generation of devices was stents made of metals and alloys. The third generation, endografts, associated these both materials. Materials used as vascular and endovascular devices must meet a number of requirements based on dimensional, physical and mechanical criteria. Ideally, they should demonstrate a behavior as close as possible as that of human arteries in terms of mechanical properties such as compliance, long term durability, and in terms of biological properties such as biocompatibility, luminal surface healing and thrombogenicity. We propose in the present manuscript a review of properties of materials currently used for the construction of vascular and endovascular devices, future challenges in the fields of new materials and scientific approaches and tests to understand and predict the behavior of the next generations of devices. PMID- 23443603 TI - Risk-adjusted strategies in the prevention of early arterial thrombosis following lower extremity arterial reconstruction: a comparison of unfractionated versus low molecular weight heparin. AB - AIM: In vascular surgery postoperative thrombosis prophylaxis must sufficiently prevent arterial thrombosis. This cohort study examines different therapeutic approaches of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) after vascular reconstruction. METHODS: Four hundred seventy-five patients entered the study between 2005 and 2008. Our clinical routine made a differentiation between low-risk patients (N.=375) and patients with peripheral bypass, which were grouped as high-risk (N.=148). We changed our postoperative anticoagulation management after 24 months in the low-risk and after each 16 months in the high-risk group. The anticoagulation of low-risk patients consisted of either two applications of 7.500 IU UFH subcutaneously (N.=158) or one daily application of 40 mg LMWH each up to discharge (N.=169). High-risk patients received either 25.000 IU UFH i.v. over 24 hours and 4 days (N.=48), 2-times (N.=51) or one-time weight-adjusted LMWH (N.=49) up to discharge (1 mg/kg body weight). Minor complications (bleedings) were differentiated from major early graft occlusion during the postoperative course. Further follow-up was not done for this study. RESULTS: Low risk: under LMWH, complications could be significantly reduced (P=0.001). Under LMWH significantly fewer occlusion complications occurred (P=0.01) and operation-induced hemorrhages were less frequently observed (P=0.05), this was significant in the complete low-risk group. High-risk: the one-time weight-adjusted LMWH group similarly exhibited many occlusions, like the unfractionated group (NS). The two-time LMWH treatment was significantly superior to the one-time application with respect to occlusion followed by amputations (P=0.03). Minor complications could be minimized overall by administration of LMWH and its dose reduction (NS). CONCLUSION: The differentiation between patients with high and low risk seems reasonable. An improvement could be achieved by differentiated LMWH application. Synthetic specific antifactor Xa substances (fondaparinux) or other medications could lead in future to other changes in the management of vascular surgery patients and should be further evaluated. PMID- 23443604 TI - Guidelines for treatment of patients with diabetes and infected ulcers. AB - Diabetic foot ulcers and their consequences do not only represent a major tragedy for the patient and his/her family, but also place a significant burden on the healthcare systems and society in general. Diabetic patients may develop foot ulcers due to neuropathy (autonomic, sensory, and motor deficits), angiopathy or both. As a result of the additional immunopathy associated with diabetes, the probability of these wounds to become infected is extremely high. Diabetic foot infections can be classified in mild, moderate and severe according to local and systemic signs. Their identification should lead to a prompt and systematic evaluation and treatment, ideally performed by a multidisciplinary team. Decisions concerning empirical initial antibiotic agent(s), desirable route of administration, duration and need of hospitalization should be based on the more likely involved pathogen(s), the severity of the infection, the ulcer chronicity and the presence of significant ischemia. Wound cultures, ideally from ulcer tissue, are strongly advisable and can help guiding and narrowing the antibiotic spectrum. Appropriate wound care and off-loading should not be neglected. When revascularization is required, the correct timing can be crucial for limb salvage. Since the recurrence of ulcer and infection is high, the implementation of appropriate preventive measures can be critical. Ultimately, the definitive goal in the treatment of diabetic foot infections is to prevent the amputation catastrophe. PMID- 23443605 TI - Transvaginal sono-guided aspiration of gestational sac concurrent with a local methotrexate injection for the treatment of unruptured cesarean scar pregnancy. AB - PURPOSE: Cesarean scar pregnancy (CSP) is one of the rarest forms of ectopic pregnancy. A delay in treatment can lead to massive bleeding, uterine rupture, and life-threatening maternal morbidity. We present a conservative method for the management of CSP at a single tertiary centre over a 6-year period. METHODS: Eleven patients with unruptured CSPs who were treated by transvaginal aspiration of the gestational sac followed by a local methotrexate injection were evaluated. RESULTS: Gestational age at diagnosis ranged from 5 + 2 weeks to 7 + 4 weeks. Seven of the patients had undergone two prior Caesarean sections (63.6 %). The levels of beta-hCG at the time of diagnosis ranged from 1,290 to 81,586 mIu/ml. The mean time of the procedure was 8.2 +/- 1.6 min. During follow up, 54.5 % of the patients may need an additional systemic MTX injection due to an elevation of beta-hCG. Estimated blood loss of the procedure was <50 ml and no blood transfusion is needed. This method has a shorter operative time, less blood loss and no hospitalization is needed for CSPs. All patients had their uterus successfully preserved without maternal morbidity or mortality. CONCLUSIONS: Transvaginal sono-guided sac aspiration concurrent with a local MTX injection is an effective management option for preserving the fertility of women with an unruptured CSP. However, additional systemic MTX injection may be needed if beta hCG levels >20,000 mIU/ml at diagnosis. PMID- 23443606 TI - Disruption of precise regulation of alphaPKC expression and cellular localization is associated with cervical cancer progression. AB - PURPOSE: To understand the pathogenesis of cervical cancer (CC) associated with polarity protein alphaPKC and the potential roles of alphaPKC in clinical management of CC. METHODS: Tissue samples were collected from women who received colposcopy biopsy or hysterectomy surgery, including 9 CIN1, 8 CIN2, 15 CIN3, and 12 invasive cervical squamous cancer (ICC). 16 normal controls were from the normal region of tumor samples, HE and immunofluorescence staining of alphaPKC were performed on these samples. ANOVA and Kruslal-wallis test were used to quantitate the abnormal distribution and expression level of alphaPKC among different cervical lesions. RESULTS: Disruption of polarized apical localization and increased cytoplasmic accumulation of alphaPKC were identified in cervical lesions. In normal cervical epithelium, alphaPKC was detected on the apical membrane of endocervical columnar epithelial cells and of exocervical epithelial cells located at basal layer of squamous epithelium. While in squamous metaplasia, a precancerous lesion of cervical neoplasia, the polarized apical membrane localization of alphaPKC was disrupted, and intensed cytoplasmic accumulation was identified in the immature squamous metaplastic cells. Compared with normal cervix, number of epithelial cells with abnormal alphaPKC distribution was progressively increased in CINs and ICC (P < 0.05), and cytoplasmic accumulation of alphaPKC was increased in CIN2, CIN3, and ICC compared with CIN1 (P < 0.05). CONCLUSIONS: Disruption of polarized apical localization and increased cytoplasmic accumulation of alphaPKC were associated with CC progression, indicating that precise regulation of alphaPKC may play important roles in CC progression, and alphaPKC may be a potential molecular target for clinical diagnoses and treatment of CC. PMID- 23443607 TI - Highly efficient sample preparation and quantification of constituents from traditional Chinese herbal medicines using matrix solid-phase dispersion extraction and UPLC-MS/MS. AB - In this work, a rapid and simple method based on matrix solid-phase dispersion (MSPD) and ultra performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) was developed. Guge Fengtong preparation (GGFT), a traditional Chinese herbal medicine, was investigated for validation, and eight major constituents were determined including four saponins (protodioscin, protogracillin, pseudoprotodioscin and dioscin) and four gingerols (6-gingerol, 8-gingerol, 10 gingerol and 6-shogaol). Response surface methodology and desirability function were employed to optimize the extraction conditions, such as dispersant, dispersant/sample ratio, solvent concentration, and elution volume, of MSPD. Results showed that MSPD using C18 (1.75 g) as the dispersant material and methanol (89%, v/v) as the eluting solvent (12.00 mL) resulted in a high extraction efficiency. MSPD extraction had the advantages of combining extraction and clean-up in a single step, was less time consuming and required lower solvent volumes compared with conventional methods. Quantification of chemical compounds from GGFT preparations were performed using UPLC-MS/MS in multiple-reaction monitoring mode. The proposed method afforded a low limit of detection ranging from 0.02 to 0.40 ng for saponins and gingerols. For all the analytes, recoveries ranged from 80.9% to 103% and repeatabilities were acceptable with relative standard deviations of less than 6.81%. The proposed MSPD-UPLC-MS/MS method was successfully utilized to analyze five batches of GGFTs, and the results demonstrated that this method is simple, efficient and has potential to be applied for the quality control of herbal preparations. PMID- 23443608 TI - Radiotherapy for calcaneodynia. Results of a single center prospective randomized dose optimization trial. AB - PURPOSE: The aim of this work was to compare the efficacy of two different dose fractionation schedules for radiotherapy of patients with calcaneodynia. PATIENTS AND METHODS: Between February 2006 and April 2010, 457 consecutive evaluable patients were recruited for this prospective randomized trial. All patients received radiotherapy using the orthovoltage technique. One radiotherapy series consisted of 6 single fractions/3 weeks. In case of insufficient remission of pain after 6 weeks a second radiation series was performed. Patients were randomly assigned to receive either single doses of 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before, immediately after, and 6 weeks after radiotherapy using a visual analogue scale (VAS) and a comprehensive pain score (CPS). RESULTS: The overall response rate for all patients was 87 % directly after and 88 % 6 weeks after radiotherapy. The mean VAS values before, immediately after, and 6 weeks after treatment for the 0.5 and 1.0 Gy groups were 65.5 +/- 22.1 and 64.0 +/- 20.5 (p = 0.188), 34.8 +/- 24.7 and 39.0 +/- 26.3 (p = 0.122), and 25.1 +/- 26.8 and 28.9 +/- 26.8 (p = 0.156), respectively. The mean CPS before, immediately after, and 6 weeks after treatment was 10.1 +/- 2.7 and 10.0 +/- 3.0 (p = 0.783), 5.6 +/- 3.7 and 6.0 +/- 3.9 (p = 0.336), 4.0 +/- 4.1 and 4.3 +/- 3.6 (p = 0.257), respectively. No statistically significant differences between the two single dose trial arms for early (p = 0.216) and delayed response (p = 0.080) were found. CONCLUSION: Radiotherapy is an effective treatment option for the management of calcaneodynia. For radiation protection reasons, the dose for a radiotherapy series is recommended not to exceed 3-6 Gy. PMID- 23443609 TI - Set-up uncertainty during breast radiotherapy. Image-guided radiotherapy for patients with initial extensive variation. AB - PURPOSE: The aim of this work was to establish a customized strategy for image guided radiotherapy during whole breast irradiation. Risk factors associated with extensive errors were assessed. METHODS AND MATERIALS: A series of 176 consecutive breasts in 174 patients were retrospectively assessed. Electronic portal images from 914 medial and 807 lateral directions were reviewed. On the basis of the chest wall, the deviations between the simulation and each treatment were measured. The systematic (Sigma) and random error (sigma) of population, and the planning target volume (PTV) margin (2 Sigma + 0.7sigma) were calculated for each direction. Extensive set-up errors were defined as the fraction over the PTV margins in any direction. For extensive set-up errors, chi(2) tests and logistic regression analyses were conducted. RESULTS: The medial and lateral PTV margins for the right-left, superior-inferior, and anterior-posterior axes and the rotation of collimator were 2.6 and 2.4 mm, 4.6 and 4.6 mm, and 3.1 and 3.3 mm and 2.8 and 2.9 degrees and cut-off values for extensive errors were 3, 5, and 4 mm and 3 degrees , respectively. In chi(2) tests, tumor in upper outer quadrant (p = 0.012) and chest wall thickness >= 2.0 cm (p = 0.003) for medial portals and age group (p = 0.036) for lateral portals were associated with extensive errors. In multivariate tests, the extensive error on the initial fraction had a high probability of extensive set-up errors in both medial (OR = 4.26, p < 0.001) and lateral portals (OR = 3.07, p < 0.001). CONCLUSION: In terms of the set-up uncertainty during breast irradiation, patients with extensive error in the initial treatment should be closely observed with serial image guided radiotherapy. PMID- 23443610 TI - Proton beam therapy for malignancy in Bloom syndrome. AB - BACKGROUND AND PURPOSE: Bloom syndrome is a DNA repair disorder that is hypersensitive to radiotherapy. We describe the first case in which proton beam therapy (PBT) was used in a patient with Bloom syndrome to treat oropharyngeal cancer. PATIENTS AND METHODS: The patient was a 32-year-old woman with Bloom syndrome who was diagnosed with oropharyngeal cancer staged as T2N2bM0 poorly differentiated squamous cell carcinoma. The primary tumor was located on the right tongue base and extended to the right lateral pharyngeal wall. Several right upper region lymph nodes were positive for metastases. RESULTS: We selected PBT in anticipation of dose reduction to normal tissue. The clinical target volume was defined as the area of the primary tumor and lymph node metastases plus an 8-mm margin. After treatment with 36 GyE (Gray equivalent) in 20 fractions (4-5 fractions per week), dietary intake was decreased by mucositis and intravenous hyperalimentation was started. Termination of treatment for 2.5 weeks was required to relieve mucositis. Administration of 59.4 GyE in 33 fractions markedly reduced the size of the primary tumor, but also caused moderate mucositis that required termination of PBT. One month later, lung metastases and breast cancer developed and the patient died 9 months after PBT. At this time the reduction in size of the primary tumor was maintained without severe late toxicity. CONCLUSION: We obtained almost complete response for a radiosensitive patient with a deficiency of DNA repair, indicating the excellent dose concentration of proton beam therapy. PMID- 23443611 TI - Advanced techniques in neoadjuvant radiotherapy allow dose escalation without increased dose to the organs at risk : Planning study in esophageal carcinoma. AB - PURPOSE: The goal of this work was to investigate the potential of advanced radiation techniques in dose escalation in the radiotherapy (RT) for the treatment of esophageal carcinoma. METHODS: A total of 15 locally advanced esophageal cancer (LAEC) patients were selected for the present study. For all 15 patients, we created a 3D conformal RT plan (3D-45) with 45 Gy in fractions of 1.8 Gy to the planning target volume (PTV1), which we usually use to employ in the neoadjuvant treatment of LAEC. Additionally, a 3D boost (as in the primary RT of LAEC) was calculated with 9 Gy in fractions of 1.8 Gy to the boost volume (PTV2) (Dmean) to a total dose of 54 Gy (3D-54 Gy), which we routinely use for the definitive treatment of LAEC. Three plans with a simultaneous integrated boost (SIB) were then calculated for each patient: sliding window intensity modulated radiotherapy (IMRT-SIB), volumetric modulated arc therapy (VMAT-SIB), and helical tomotherapy (HT-SIB). For the SIB plans, the requirement was that 95 % of the PTV1 receive >= 100 % of the prescription dose (45 Gy in fractions of 1.8 Gy, D95) and the PTV2 was dose escalated to 52.5 Gy in fractions of 2.1 Gy (D95). RESULTS: The median PTV2 dose for 3D-45, 3D-54, HT-SIB, VMAT-SIB, and IMRT SIB was 45, 55, 54, 56, and 55 Gy, respectively. Therefore, the dose to PTV2 in the SIB plans was comparable to the 3D-54 plan. The lung dose in the SIB plans was in the range of the standard 3D-45, which is applied for neoadjuvant radiotherapy. The mean lung dose for the same plans was 13, 15, 12, 12, and 13 Gy, respectively. The V5 lung volumes were 71, 74, 79, 75, and 73 %, respectively. The V20 lung volumes were 20, 25, 16, 18, and 19 %, respectively. CONCLUSION: New treatment planning techniques enable higher doses to be delivered for neoadjuvant radiotherapy of LAEC without a significant increase in the delivered dose to the organs at risk. Clinical investigations are warranted to study the clinical safety and feasibility of applying higher doses through advanced techniques in the neoadjuvant treatment of LAEC. PMID- 23443612 TI - Impact of inter- and intrafraction deviations and residual set-up errors on PTV margins. Different alignment techniques in 3D conformal prostate cancer radiotherapy. AB - PURPOSE: The aim of this work was to analyze interfraction and intrafraction deviations and residual set-up errors (RSE) after online repositioning to determine PTV margins for 3 different alignment techniques in prostate cancer radiotherapy. METHODS: The present prospective study included 44 prostate cancer patients with implanted fiducials treated with three-dimensional (3D) conformal radiotherapy. Daily localization was based on skin marks followed by marker detection using kilovoltage (kV) imaging and subsequent patient repositioning. Additionally, in-treatment megavoltage (MV) images were obtained for each treatment field. In an off-line analysis of 7,273 images, interfraction prostate motion, RSE after marker-based prostate localization, prostate position during each treatment session, and the effect of treatment time on intrafraction deviations were analyzed to evaluate PTV margins. RESULTS: Margins accounting for interfraction deviation, RSE and intrafraction motion were 14.1, 12.9, and 15.1 mm in anterior-posterior (AP), superior-inferior (SI), and left-right (LR) direction for skin mark alignment and 9.6, 8.7, and 2.6 mm for bony structure alignment, respectively. Alignment to implanted markers required margins of 4.6, 2.8, and 2.5 mm. As margins to account for intrafraction motion increased with treatment prolongation PTV margins could be reduced to 3.9, 2.6, and 2.4 mm if treatment time was <= 4 min. CONCLUSION: With daily online correction and repositioning based on implanted fiducials, a significant reduction of PTV margins can be achieved. The use of an optimized workflow with faster treatment techniques such as volumetric modulated arc techniques (VMAT) could allow for a further decrease. PMID- 23443613 TI - Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy. AB - PURPOSE: The goal of the present work was to assess the potential advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3D-CRT) planning in pelvic Ewing's sarcoma. PATIENTS AND METHODS: A total of 8 patients with Ewing sarcoma of the pelvis undergoing radiotherapy were analyzed. Plans for 3D-CRT and IMRT were calculated for each patient. Dose coverage of the planning target volume (PTV), conformity and homogeneity indices, as well as further parameters were evaluated. RESULTS: The average dose coverage values for PTV were comparable in 3D-CRT and IMRT plans. Both techniques had a PTV coverage of V95 > 98 % in all patients. Whereas the IMRT plans achieved a higher conformity index compared to the 3D-CRT plans (conformity index 0.79 +/- 0.12 vs. 0.54 +/- 0.19, p = 0.012), the dose distribution across the target volumes was less homogeneous with IMRT planning than with 3D-CRT planning. This difference was statistically significant (homogeneity index 0.11 +/- 0.03 vs. 0.07 +/- 0.0, p = 0.035). For the bowel, Dmean and D1%, as well as V2 to V60 were reduced in IMRT plans. For the bladder and the rectum, there was no significant difference in Dmean. However, the percentages of volumes receiving at least doses of 30, 40, 45, and 50 Gy (V30 to V50) were lower for the rectum in IMRT plans. The volume of normal tissue receiving at least 2 Gy (V2) was significantly higher in IMRT plans compared with 3D-CRT, whereas at high dose levels (V30) it was significantly lower. CONCLUSION: Compared to 3D-CRT, IMRT showed significantly better results regarding dose conformity (p = 0.012) and bowel sparing at dose levels above 30 Gy (p = 0.012). Thus, dose escalation in the radiotherapy of pelvic Ewing's sarcoma can be more easily achieved using IMRT. PMID- 23443614 TI - Anisotropy of the water-carbon interaction: molecular simulations of water in low diameter carbon nanotubes. AB - Effective Lennard-Jones models for the water-carbon interaction are derived from existing high-level ab initio calculations of water adsorbed on graphene models. The resulting potential energy well (epsilonCO + 2epsilonCH ~ 1 kJ mol(-1)) is deeper than most of the previously used values in the literature on water in carbon nanotubes (CNTs). Moreover, a substantial anisotropy of the water-carbon interaction (epsilonCO ~ 2epsilonCH) is obtained, which is neglected in most of the literature. We systematically investigate the effect of this anisotropy on structure and dynamics of TIP5P water confined in narrow, single-walled CNTs by means of molecular dynamics simulations for T = 300 K. While for isotropic models water usually forms one-dimensional, ordered chains inside (6,6) CNTs, we find frequent chain ruptures in simulations with medium to strongly anisotropic potentials. Here, the water molecules tend to form denser clusters displaying a liquid-like behaviour, allowing for self-diffusion along the CNT axis, in contrast to all previous simulations employing spherical (epsilonCH = 0) interaction models. For (7,7) CNTs we observe structures close to trigonal, helical ice nanotubes which exhibit a non-monotonous dependence on the anisotropy of the water-carbon interaction. Both for vanishing and for large values of epsilonCH we find increased fluctuations leading to a more liquid-like behaviour, with enhanced axial diffusion. In contrast, structure and dynamics of water inside (8,8) CNTs are found to be almost independent of the anisotropy of the underlying potential, which is attributed to the higher stability of the non helical fivefold water prisms. We predict this situation to also prevail for larger CNTs, as the influence of the water-water interaction dominates over that of the water-carbon interaction. PMID- 23443615 TI - Enhanced optical response of hybridized VO2/graphene films. AB - Application of graphene as transparent electrodes is an active research area due to its excellent electrical and optical properties. Vanadium dioxide (VO2) is an attractive material since it is a thermochromic material that undergoes a structural phase transition when heat is applied. The phase transition results in the change of electrical and optical characteristics. We report optical characteristics of hybrid materials of graphene and VO2. We observed a 12% improvement in infrared transmittance with VO2 films deposited on graphene sapphire substrates compared to that of bare sapphire substrates. We also found that the phase transition temperature decreases as the number of graphene layers on the substrates increases. In the case of VO2 films on the substrate that was coated with four layers of graphene, the mean phase transition temperature was lowered to ~56 degrees C. PMID- 23443616 TI - Diagnosis and management of infectious complications of childhood rheumatic diseases. AB - Progress in the diagnosis and management of pediatric rheumatic disease has improved complications from underlying disease and the survival of children. However, as a consequence, infection has now become one of the leading causes of morbidity and mortality. Differentiating between infections and disease flares in children with rheumatic conditions can often pose diagnostic quandaries. Children with rheumatic diseases are at risk of infection, not only because of the use of immune-modulating medications but also because of underlying immune dysfunction associated with their disease. Although bacterial infections are the most common, any organism can potentially be a causative agent and, at times, more invasive measures of diagnosis, for example bronchoscopy and tissue biopsies may be necessary. Maintaining a high index of suspicion of infection with prompt diagnosis and treatment are important to further improve patient outcomes. PMID- 23443617 TI - The Multinational Association for Supportive Care in Cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. AB - The Multinational Association for Supportive Care in Cancer risk index score developed, through a multinational collaboration, was published in 2000 with the aim to identify patients with chemotherapy-induced febrile neutropenia at low risk of serious medical complication development. It has been endorsed as a reliable tool since 2002 by Infectious Diseases Society of America. Ten years after, we thought worth to review its use, its characteristics in the external validations that occurred after the initial publication and also to review how the recognition of a group of patients at low risk has changed the management of febrile neutropenia. We also raise the issue of identification of high-risk patients that remains a challenge today. PMID- 23443618 TI - Association between left ventricular ejection fraction post-cardiac resynchronization treatment and subsequent implantable cardioverter defibrillator therapy for sustained ventricular tachyarrhythmias. AB - BACKGROUND: Although cardiac resynchronization therapy (CRT) can improve left ventricular ejection fraction (LVEF), it is not known whether a specific level of improvement will predict future implantable cardioverter defibrillator (ICD) therapy. METHODS AND RESULTS: CRT-defibrillator (CRT-D) was implanted in 423 patients at 1 institution between October 2, 2001 and January 19, 2007. A retrospective analysis was performed to evaluate the relationship between post CRT-D LVEF and ICD therapy for ventricular tachyarrhythmias. A landmark population of 270 patients, with post-CRT-D LVEF measured and no ICD therapy within 1 year of device implantation, was followed for subsequent outcomes. Of these, 22 patients (8.2%) had subsequent appropriate ICD therapy over a median follow-up of 1.5 years. The estimated 2-year risk of appropriate ICD therapy is 3.0% (95% confidence interval [95% CI], 0%-6.3%), 2.1% (95% CI, 0%-5.0%), and 1.5% (95% CI, 0%-3.9%) for post-CRT-D LVEF of 45%, 50%, and 55%, respectively. In patients with a primary prevention indication for CRT-D, the estimated 2-year risk is 3.3% (95% CI, 0%-7.3%), 2.5% (95% CI, 0%-6.1%), and 1.9% (95% CI, 0% 5.1%) for post-CRT-D LVEF of 45%, 50%, and 55%, respectively. CONCLUSIONS: When a CRT responder demonstrates near normalization in LVEF to >=45%, the incidence of ICD therapy for ventricular arrhythmias becomes low. Future studies are needed to determine whether an ICD is still needed in some of these patients at the time of generator replacement. PMID- 23443619 TI - Noninvasive localization of maximal frequency sites of atrial fibrillation by body surface potential mapping. AB - BACKGROUND: Ablation of high-frequency sources in patients with atrial fibrillation (AF) is an effective therapy to restore sinus rhythm. However, this strategy may be ineffective in patients without a significant dominant frequency (DF) gradient. The aim of this study was to investigate whether sites with high frequency activity in human AF can be identified noninvasively, which should help intervention planning and therapy. METHODS AND RESULTS: In 14 patients with a history of AF, 67-lead body surface recordings were simultaneously registered with 15 endocardial electrograms from both atria including the highest DF site, which was predetermined by atrial-wide real-time frequency electroanatomical mapping. Power spectra of surface leads and the body surface location of the highest DF site were compared with intracardiac information. Highest DFs found on specific sites of the torso showed a significant correlation with DFs found in the nearest atrium (rho=0.96 for right atrium and rho=0.92 for left atrium) and the DF gradient between them (rho=0.93). The spatial distribution of power on the surface showed an inverse relationship between the frequencies versus the power spread area, consistent with localized fast sources as the AF mechanism with fibrillatory conduction elsewhere. CONCLUSIONS: Spectral analysis of body surface recordings during AF allows a noninvasive characterization of the global distribution of the atrial DFs and the identification of the atrium with the highest frequency, opening the possibility for improved noninvasive personalized diagnosis and treatment. PMID- 23443620 TI - The optimal range of international normalized ratio for radiofrequency catheter ablation of atrial fibrillation during therapeutic anticoagulation with warfarin. AB - BACKGROUND: Uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFA) of atrial fibrillation is associated with a lower risk of periprocedural complications than when warfarin is temporarily discontinued. However, the optimal international normalized ratio (INR) levels during RFA have not been defined. METHODS AND RESULTS: In this retrospective analysis, RFA was performed in 1133 consecutive patients (mean age, 61+/-10 years) with paroxysmal (550) or persistent atrial fibrillation (583). Patients were grouped based on the INR on the day of RFA. There was a quadratic relationship between the INR and bleeding and vascular complications (P<0.001). Complications were less prevalent when INR was >=2.0 and <=3.0 (5% [31/572]) than when INR was <2.0 (10% [49/485]; P=0.004) and >3.0 (12% [9/76]; P=0.03). The prevalence of pericardial tamponade (1%) was similar at all INRs. From the quadratic model, the optimal range of INR was calculated as 2.1 to 2.5. INRs<2.0 and >3.0 were associated with a >2-fold increase in complications, with a further steep rise beyond an INR>3.5. Concomitant clopidogrel use was associated with a significant increase in complications at all INRs (odds ratio=3.1; +/-95% confidence interval, 1.4-7.4). Unfractionated heparin requirements to maintain a therapeutic activated clotting time during RFA was reduced by 50% in patients with an INR>2.0. CONCLUSIONS: The optimal INR range during uninterrupted periprocedural anticoagulation using warfarin is narrow. Therefore, INR levels should be carefully monitored in preparation for RFA of atrial fibrillation. PMID- 23443621 TI - Layer-by-layer micromolding of natural biopolymer scaffolds with intrinsic microfluidic networks. AB - A three-dimensional (3D) microfluidic network plays an important role in engineering thick organs. However, most of the existing methods are limited to mechanically robust synthetic biomaterials and only planar or simple microfluidic networks have been incorporated into soft natural biopolymers. Here we presented an automatic layer-by-layer micromolding strategy to reproducibly fabricate 3D microfluidic porous scaffolds directly from the aqueous solution of soft natural biopolymers. Process parameters such as the liquid volume for each layer and contact displacement were investigated to produce a structurally stable 3D microfluidic scaffold. Microscopic characterization demonstrated that the microfluidic channels were interconnected in 3D and successfully functioned as a convective pathway to transport a polymer solution. Endothelial cells grew relatively well in the porous microfluidic channels. It is envisioned that this method could provide an alternative way to reproducibly build complex 3D microfluidic networks into extracellular matrix-like scaffolds for the fabrication of soft vascularized organs. PMID- 23443622 TI - Acute myocarditis in vivax malaria: an extremely rare complication. AB - We report on the occurrence of pulmonary oedema due to acute myocarditis in an adolescent girl, from the northern Indian state of Uttarakhand, with Plasmodium vivax infection after parasite clearance. Apart from pancytopenia, there were no other features of severe malaria. With the emergence of literature about the complications encountered in P. vivax, especially from this region, a high index of suspicion for unusual cardiovascular manifestations is necessary in cases with acute malaria. PMID- 23443623 TI - Hyper-reactive malarial splenomegaly in the absence of raised IgM antibodies. AB - Hyper-reactive malarial splenomegaly (HMS) is diagnosed by the presence of massive splenomegaly, raised IgM and antimalarial antibodies and a response to antimalarial therapy. Although malaria is endemic to Pakistan, HMS is uncommon. We report on HMS in a patient with massive splenomegaly, positive Plasmodium falciparum polymerase chain reaction but normal immunoglobulin M antibody levels. The investigations were not consistent with any other diagnosis. HMS is also briefly reviewed. PMID- 23443624 TI - A case of neonatal tetanus presented within 24 hours of life. AB - Neonatal tetanus is still prevalent in developing countries such as India. Generally, neonatal tetanus is seen in babies of unimmunized mothers beyond the second day of life. A neonate presented to us on the 4th hour of birth with a periumbilical ulcer. The baby's antenatal and birth history was uneventful. The mother had been immunized against tetanus. At presentation, the baby was active, alert and sucking normally. A very small ulcer was noted below the umbilicus. Subsequently, the baby developed rigidity and a tonic spasm of its body with recurrent seizures from the 18th hour of its birth and by 21st hour. It also had a full blown clinical picture of neonatal tetanus including: masseter spasm; generalized rigidity; a high pitched cry: and intermittent opisthotonos posturing. An ulcer gradually enlarged to 5 * 4 cm and a swab from ulcer showed Clostridium tetani (both on Gram staining and culture). A review of the published literature did not reveal any case that had presented so early. Therefore, this is probably the first case of neonatal tetanus being reported within the 21st hour of birth. PMID- 23443625 TI - Strongyloides stercoralis infection presenting as an unusual cause of massive upper gastrointestinal bleeding in an immunosuppressed patient: a case report. AB - Strongyloidiasis caused by Strongyloides stercoralis is a rare but well documented cause of massive upper gastrointestinal (GI) bleeding especially in endemic areas. However, oesophagogastroduodenoscopic findings and extractions of S. stercoralis, in the adult worm form, from the duodenum is even rarer. We report a case of a 27-year-old Tanzanian woman with HIV who presented with massive upper GI bleeding. She had S. stercoralis, in the adult worm form, traversing the stomach and duodenum and extracted by oesophagogastroduodenoscopy (OGD). She was treated successfully with Ivermectine and antiretroviral therapy for HIV was initiated. Strongyloidiasis should be included in the differential diagnosis of mass upper GI bleeding in immunosuppressive patients living in, or originating from, endemic areas. We believe this to be the first case to be reported from our environment. PMID- 23443626 TI - Hepatocellular carcinoma continues to be diagnosed in the advanced stage: profile of hepatocellular carcinoma in a tertiary care hospital in South India. AB - This report is an analysis of 231 patients with hepatocellular carcinoma (HCC) from a tertiary care hospital in India. Most of the HCCs were diagnosed in cirrhotics and at an advanced stage which limited the therapeutic options. Physician awareness of this complication of cirrhosis and regular ultrasound screening of cirrhotic patients will help in detection of early stage cancers and, thus, enhance the survival rates. PMID- 23443627 TI - Rapid and complete decompression of chronic urinary retention: a safe and effective practice. AB - We carried out a prospective study of consecutive patients who presented with chronic urinary retention over a period of 2 years in order to determine the safety and effectiveness of rapid and complete decompression of chronic urinary retention. A total of 22 patients met the inclusion criteria. Although slow decompression is thought to reduce complications, it harbours the disadvantages of impracticability, time and labour demands and an increased risk of infection. Post-obstructive diuresis, haematuria and hypotension are relatively frequent in rapid and complete decompression of chronic urinary retention. However, they are mild, transient and clinically insignificant. Rapid and complete decompression of the chronically obstructed urinary bladder not only saves time, it is safe and effective and should be adopted as the standard practice. PMID- 23443628 TI - A population-based study of dosing and persistence with anti-dementia medications. AB - PURPOSE: Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer's disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the 'real world' (outside the clinical trial setting). METHODS: The Health Service Executive-Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged >70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. RESULTS: Between January 2006 and December 2010, 20,729 patients aged >70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. <75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06-1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03-1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73-0.89, p < 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0.54-0.65, p < 0.001). Persistence was significantly higher when memantine was co-prescribed with donepezil (p < 0.0001). CONCLUSION: Future studies should explore the reasons underlying non-persistence and failure to maintain dose-maximisation in patients on AD medications. There may be scope to improve the dosing and persistence with these medications in the community. PMID- 23443629 TI - Proteoform: a single term describing protein complexity. PMID- 23443630 TI - Making sure PTMs are not lost after translation. PMID- 23443631 TI - Designer TALEs team up for highly efficient gene induction. PMID- 23443632 TI - To unscramble an egg. PMID- 23443634 TI - Arginase inhibition by piceatannol-3'-O-beta-D-glucopyranoside improves endothelial dysfunction via activation of endothelial nitric oxide synthase in ApoE-null mice fed a high-cholesterol diet. AB - Elevated plasma cholesterol is a hallmark of numerous cardiovascular diseases that are closely linked to endothelial dysfunction indicating decreased nitric oxide (NO) production in the endothelium. It has been previously demonstrated that piceatannol-3'-O-beta-D-glucopyranoside (PG) inhibits arginase activity and reciprocally regulates NO production. Here, we aimed to ascertain whether PG ameliorates vascular function in wild-type (WT) and atherogenic model mice [apolipoprotein E-null mice (ApoE-/-)] and to investigate the possible underlying mechanism. Preincubation of aortic vessels from WT mice fed a normal diet (ND) with PG attenuated vasoconstriction response to U46619 and phenylephrine (PE), while the vasorelaxant response to acetylcholine (Ach) was markedly enhanced in an endothelium-dependent manner. However, the endothelium-independent NO donor, sodium nitroprusside (SNP), did not change vessel reactivity. In thoracic aorta from ApoE-/- mice, a high-cholesterol diet (HCD) induced an increase in arginase activity, a decrease in NO release and an increase in reactive oxygen species generation that was reversed by treatment with PG. The effect of PG was associated with enhanced stability of the eNOS dimer and was not dependent on the expression levels of arginase II and eNOS proteins, although eNOS expression was increased in ApoE-/- mice fed an HCD. Furthermore, PG treatment attenuated the PE dependent contractile response, and significantly improved the Ach-dependent vasorelaxation response in aortic rings from ApoE-/- mice fed an HCD. On the other hand, PG incubation neither altered the contractile response to a high K+ solution nor the relaxation response to SNP. When analyzing the L-arginine content using high-performance liquid chromatography, PG incubation increased the intracellular L-arginine concentration. PG administration in the drinking water significantly reduced fatty streak formation in ApoE-/- mice fed an HCD. These data indicate that PG improves the pathophysiology of cholesterol-mediated endothelial dysfunction. Therefore, we conclude that the development of PG as a novel effective therapy for preventing atherosclerotic diseases is warranted. PMID- 23443633 TI - Zymography methods for visualizing hydrolytic enzymes. AB - Zymography is a technique for studying hydrolytic enzymes on the basis of substrate degradation. It is a powerful, but often misinterpreted, tool yielding information on potential hydrolytic activities, enzyme forms and the locations of active enzymes. In this Review, zymography techniques are compared in terms of advantages, limitations and interpretations. With in gel zymography, enzyme forms are visualized according to their molecular weights. Proteolytic activities are localized in tissue sections with in situ zymography. In vivo zymography can pinpoint proteolytic activity to sites in an intact organism. Future development of novel substrate probes and improvement in detection and imaging methods will increase the applicability of zymography for (reverse) degradomics studies. PMID- 23443635 TI - Changes of immunological parameters with administration of Japanese Kampo medicine (Juzen-Taihoto/TJ-48) in patients with advanced pancreatic cancer. AB - BACKGROUND: The prognosis of pancreatic cancer is extremely poor regardless of various combination therapies. Immunoaugumentation against tumor cells was recently A focus. We reported that the population of Foxp3(+)CD25(+)CD4(+) regulatory T cells (Foxp3(+)Treg) was the new parameter for the estimation of host immunity and had correlation with tumor aggressiveness. Here we show the immunoaugumentation effects of Japanese Kampo medicine, Juzen-Taihoto/TJ-48, empirically considered as an immunoaugumentation drug, with investigation of Treg and other immunological parameters. PATIENTS AND METHOD: Peripheral Foxp3(+) Treg populations, CD4/CD8 ratio, and CD57(+) cells (NK cells) populations in advanced pancreatic cancer patients (n = 30, stage VI A and B according to TNM classification) were estimated after TJ-48 administration for 14 days before the anti-cancer therapy. RESULTS: Treg populations were significantly increased compared to healthy donors (Mann-Whitney U test, P < 0.001). Administration of Juzen-Taihoto/TJ-48 significantly decreased Treg populations (Mann-Whitney U test, P < 0.001) and increased the CD4/CD8 ratio (Mann-Whitney U test, P < 0.01), even though CD57(+) cell populations did not change significantly. CONCLUSIONS: Juzen-Taihoto/TJ-48 increased regulatory activities in T cells through decreasing Foxp3(+) Treg populations in advanced pancreatic cancer patients. This effect can lead to immunoaugumentation for various combination therapies. PMID- 23443636 TI - The impact of station location on water quality characterization in the Loxahatchee National Wildlife Refuge. AB - Water quality was monitored in the Loxahatchee National Wildlife Refuge based on the Consent Decree (CDN), the Enhanced Refuge (ERN), the four-part Test impacted (FPTIN), and the four-part test unimpacted (FPTUN) networks. Alkalinity, dissolved organic carbon, total organic carbon, dissolved oxygen, total dissolved solids, total suspended solids, turbidity, pH, specific conductivity, calcium, chloride, silicon, sulfate, and total phosphorus (TP) were measured from 2005 through 2009. When the ERN was used, the 10 MUg TP L(-1) Consent Decree limit would have been exceeded and would have ranged from a low of 2 months in 2009 to a high of 9 months in 2005. Based on the CDN, the limit exceeded only for 1 month in each year from 2006 through 2008. Based on the FPTIN, the 10 MUg TP L(-1) limit would have been exceeded and would have ranged from a low of 1 month in 2007 to a high of 7 months in 2005 and 2008. Based on the CDN, the limit only exceeded for 1 month in each year from 2006 through 2008. Since TP is rapidly removed from canal water intruded into the Refuge marsh, one cannot expect a water quality sampling station located 2 km from the source to reliably detect violations. This may be the primary reason why there have been very few months when TP concentration has exceeded the limit since 1992 or part four of the four part test annual 15 MUg L(-1) limit since 2006. PMID- 23443637 TI - Dissipation and residue of azoxystrobin in banana under field condition. AB - A method was developed for determining azoxystrobin in banana and cultivation soil using gas chromatography. The dissipation and residue of azoxystrobin in banana fields at GAP conditions were investigated. The average recoveries ranged from 80.3 to 96.0 % with relative standard deviations of 2.9 to 7.2 % at three different spiking levels for each matrix. The results indicated that the half life of azoxystrobin in bananas and soil ranged from 7.5 to 13.5 days in Guangdong and from 8.7 to 12.7 days in Fujian. The dissipation rates of azoxystrobin in banana and soil were almost the same. Terminal residues in banana and banana flesh (0.01 mg/kg) were all below the maximum residue limit (2 mg/kg by Codex Alimentarius Commission and China). The results demonstrated that the safety of using azoxystrobin at the recommended agriculture dosage to protect bananas from diseases. PMID- 23443640 TI - A "pillar-free", highly porous metalloporphyrinic framework exhibiting eclipsed porphyrin arrays. AB - A "pillar-free", highly porous metalloporphyrinic framework (UNLPF-1) exhibiting eclipsed porphyrin arrays has been constructed from an octacarboxylate ligand connected with paddlewheel secondary building units. UNLPF-1 possesses two types of open metal sites and exhibits an efficient selectivity toward capture of CO2 over N2. PMID- 23443639 TI - [Adverse reaction to fillers. Diagnosis and management]. AB - Injectable fillers are an established component of aesthetic medicine. In general they are safe to use. However, adverse reactions are possible for the whole spectrum of products. These reactions can occur immediately, subacute or delayed, e.g. after years. Erythema, edema, abscesses, nodule formation or even ulcerations can be observed. A correct diagnoses of these reactions is important to allow an appropriate treatment, taking into consideration the clinic, the injected material and if applicable other diseases/treatments that might contribute to these reactions. All of these reactions should be reported either to specialized registries and/or to the appropriate national agencies. Only then will we be able to learn more about these reactions and the best possible treatment. PMID- 23443638 TI - 24-Epibrassinolide regulates photosynthesis, antioxidant enzyme activities and proline content of Cucumis sativus under salt and/or copper stress. AB - Brassinosteroids have been extensively used to overcome various abiotic stresses. But its role in combined stress of salt and excess copper remains unexplored. Seeds of two cultivars (Rocket and Jumbo) of Cucumis sativus were grown in sand amended with copper (100 mg kg(-1)), and developed seedlings were exposed to salt stress in the form of NaCl (150 mM) at the 30-day stage of growth for 3 days. These seedlings were subsequently sprayed with 0 or 0.01 MUM of 24 epibrassinolide (EBL) at the 35-day stage. The plants exposed to NaCl and Cu in combination exhibited a significant decline in fresh and dry mass of plant, chlorophyll content, activities of carbonic anhydrase, net photosynthetic rate and maximum quantum yield of the PSII primary photochemistry followed by NaCl and Cu stress alone, more severely in Jumbo than in Rocket. However, the follow-up treatment with EBL to the stressed and nonstressed plant improved growth, chlorophyll content, carbonic anhydrase activity and photosynthetic efficiency, and further enhanced the activity of various antioxidant enzymes viz. catalase, peroxidase and superoxide dismutase and content of proline at the 40-day stage of growth, and the response of the hormone was more effective in Rocket than in Jumbo. The elevated level of antioxidant enzymes as well as proline could have conferred tolerance to the NaCl- and/or Cu-stressed plants resulting in improved growth, water relations and photosynthetic attributes. Furthermore, antioxidant enzyme activity and proline content were more enhanced in Rocket than in Jumbo cultivar. PMID- 23443641 TI - Regulating Force in Putting by Using the Borg CR100 scale((r)). AB - Studies investigating the regulation of force of motor actions are scarce, and particularly so in the area of sports. This is surprising, considering that in most sports precise force is of great importance. The current study demonstrates how a psychophysical scale, the Borg CR100 scale((r)) (Borg and Borg, 2001), can be used to assess subjective force as well as regulate force in putting. Psychophysical functions were calculated on the relationships between judgments of force using the CR100 scale and the length of putting shots, examined in a laboratory setting, where 44 amateur golfers played on both flat and uphill surfaces. High agreement and consistency between CR 100 ratings and distances putted was demonstrated. No significant differences in handling the scale were observed between younger (mean age ~37 years) and older (mean age ~69 years) players or between players of different skill level. This study provides a new innovative use of an existing instrument, the Borg CR 100 scale((r)), in order to understand the regulation of force needed for putts of various lengths and surfaces. These results and the potential future benefits of the psychophysical approach in golf are discussed. PMID- 23443642 TI - Do current cancer follow-up care practices meet the needs of young adult cancer survivors in Canada? A qualitative inquiry. AB - PURPOSE: The purpose of the present study was to assess whether current cancer follow-up care practices meet the needs of young adult cancer survivors in Canada. METHODS: This qualitative study used a constructivist grounded theory framework to analyze telephone interviews with cancer survivors from across Canada diagnosed between the ages of 18 and 39 years. The focus was specifically on cancer follow-up care (cfc). RESULTS: Interviews were conducted with 55 participants, and 53 interviews were used for the analysis. The overall theme that emerged from the data was the lack of age-specific cfc. Some of the subthemes that emerged were the absence or inadequacy of fertility and infertility treatment options; of psychological services such as family, couples, and sexuality counseling; of social supports such as assistance with entry or re entry into the education system or workplace; of access to supplemental health insurance; and of survivorship care plans. Based on the data resulting from the interviews, we developed a conceptual model of young-adult cfc incorporating the major themes and subthemes that emerged from our study. The proposed model aims to ensure a more age-appropriate and comprehensive approach to cfc for this group of cancer patients. CONCLUSIONS: Current Canadian cfc practices are inadequate and do not provide comprehensive care for young adult cancer survivors in Canada. The conceptual model presented here aims to ensure a more comprehensive approach to cfc that meets the needs of this unique cancer population and reduces further possible physical, psychological, or social cancer sequelae. PMID- 23443643 TI - Associated predictors of therapeutic response to uvulopharyngopalatoplasty for severe obstructive sleep apnea hypopnea syndrome. AB - The aim of this study was to determine the associated factors affecting the outcome of uvulopharyngopalatoplasty (UPPP) in patients with severe obstructive sleep apnea hypopnea syndrome (OSAHS), and to investigate whether cephalometric measurements were predictive of the therapeutic response to UPPP in patients with severe OSAHS. We retrospectively studied 51 consecutive patients who underwent revised UPPP with uvula preservation (H-UPPP), or Z-palatopharyngoplasty (ZPPP) for severe OSAHS [apnea-hypopnea index (AHI) >30]. All patients were evaluated using physical examination, Epworth Sleepiness Scale (ESS), cephalometry, and nocturnal polysomnography (PSG) before surgery and at 6-12 months after surgery. Based on the success criteria defined as an AHI of <20 and a decrease >50 %, the overall success rate was 45.1 %. The preoperative distance from the posterior border of the uvula to the middle pharyngeal wall (U-MPW) was significantly longer in the responder group than in the nonresponder group, when considering the whole group or the H-UPPP group alone. Among all study subjects, U-MPW and change in body mass index (?BMI) were the significant predictors of surgical success. U-MPW was the key predictor for H-UPPP surgical success, whereas mandibular plane angle (MPA) and Friedman stage were the key predictors for ZPPP surgical success. In conclusion, U-MPW was a significant predictor of UPPP surgical success. Patients with U-MPW >10 mm who are unwilling to receive nasal continuous positive airway pressure (CPAP) therapy might be suitable candidates for UPPP surgery. PMID- 23443644 TI - Response to the letter to the editor entitled "Maxillary sinus surgery in maxillary sinusitis with cystic fibrosis" of Alper Nabi Erkan, MD, Assoc. Prof. PMID- 23443645 TI - No thermal tool using methods in endoscopic dacryocystorhinostomy: no cautery, no drill, no illuminator, no more tears. AB - The purpose of this study was to evaluate the surgical outcome of the endoscopic dacryocystorhinostomy (DCR) without thermal tools such as cautery, drill and illuminator. The study is a retrospective analysis of patients in a tertiary care unit for oculoplastic surgery. The participants enrolled into the study are a retrospective series of 127 consecutive endonasal DCRs performed between January 2008 and March 2011. The surgical procedure in this conventional endoscopic transnasal DCR involved a manual osteotomy of the frontal process of the maxilla and removal of the lacrimal bone by punch without illuminator, cauterization and drill. We evaluated the result of the manual Endo-DCR technique without cauterization or drilling-assisted technique. Data of 127 eyes were reviewed. Full success was achieved in 90.5 % (115/127) of manual Endo-DCR technique with an average follow-up period of 6 months. Our study appears to show favorable results compared to other previously published outcomes including Endo-DCR surgery with thermal equipments. No thermal tool methods in endonasal DCR can achieve a good surgical success rate. Therefore, the newest tools, cauterization, drilling or illumination, are generally not necessary for endoscopic dacrycystorhinostomy. PMID- 23443646 TI - Effects of Pillar implants for sleep-related breathing disorders on middle ear function. AB - Pillar implants provide a reasonable outcome with minimal post-operative morbidity and complications in treating patients with sleep-disordered breathing (SDB) who had obvious palatal obstruction. The palatal structure is responsible for a normal functioning Eustachian tube; however, little is known if there is any potential otologic implication of minimally invasive palatal stiffening surgery for SDB. The aim of this study is to evaluate the effects of Pillar implantation on middle ear function. We performed a prospective study in a tertiary referral center. Thirty SDB patients (25 men, 5 women; mean age, 44.3 years) who underwent Pillar implants for treating palatal obstruction were enrolled. The subjects had normal otologic exam and no previous history of chronic ear disease. Pure-tone audiometry and tympanometry were performed pre operatively, and post-operative days 1 and 7, and months 1 and 3. Baseline and post-operative middle ear pressures (MEPs) in decipascals were compared. Statistical analysis was performed by repeated measures of ANOVA. Eight patients (8/30, 26.7%) reported otologic complaints such as ear pressure and/or otalgia within 1 week post-operatively. No permanent otologic discomfort occurred. A trend toward reduced MEP was noted in this study. The decrease in MEP became apparent on post-operative day 1 after surgery. However, mean pressure changes were no longer significantly different from pre-operative values by 1 week after surgery. Pillar implantation for SDB induces changes in middle ear function. However, the changes were temporary and not significant 1 week after surgery. PMID- 23443647 TI - Long-term results after external vocal fold medialization thyroplasty with titanium vocal fold medialization implant (TVFMI). AB - Since its introduction in 1999 by Friedrich, the titanium vocal fold medialization implant (TVFMI) is widely used for medialization thyroplasty in glottal closure insufficiency. The purpose of this study was to investigate the long-term functional outcome after medialization thyroplasty using TVFMI. Between 1999 and 2009 123 patients (mean age 55.3 years, 76 male and 47 female) underwent medialization thyroplasty with the TVFMI (96 left, 27 right). For purpose of long term follow-up, 33 patients could be examined. Prior to surgery, about 8 weeks and at least 1 year after surgery perceptual, acoustic, aerodynamic and videolaryngostroboscopic examinations have been performed. The interval between surgery and long-term follow-up was on average 57 (23-120) months. None of the 123 patients presented early major postoperative complications (e.g. implant dislocation, dyspnoea with need of tracheostomy, wound infection, postoperative bleeding). In three patients the TVFMI had to be removed 2-6 months after surgery due to granulation tissue formation. In one patient a subepithelial localization of the implant could be seen without necessity of removal. Perceptual and acoustic parameters were significantly improved after surgery with long-lasting effect even years after surgery. Airway resistance (R(aw)) showed an increase over time without a relevant negative impact on the peak expiratory flow (PEF). Medialization thyroplasty using TVFMI allows precise and save positioning of the implant with stable perceptual and acoustic improvement. The only postoperative complication was the development of endolaryngeal granulation tissue resulting in removal of the implant. PMID- 23443649 TI - Ultrafast photoinduced dynamics of halogenated cyclopentadienes: observation of geminate charge-transfer complexes in solution. AB - The photoinduced dynamics of the fully halogenated cyclopentadienes C5Cl6 and C5Br6 have been investigated in solution and gas phase by femtosecond time resolved spectroscopy. Both in solution and in gas phase, homolytic dissociation into a halogen radical and a C5X5 (X = Cl, Br) radical was observed. In liquid phase, solvent-dependent formation of charge transfer complexes between geminate radicals was observed for the first time. These complexes were found to be surprisingly stable and offered the opportunity to follow the dynamics of specific radical pairs. In the case of C5Cl6 in trichloroethanol, a reaction of the chlorine radical with molecules from the solvent cage was observed. PMID- 23443650 TI - A novel method for SLIPATM size selection, for adult patients, on the basis of chamber length. AB - PURPOSE: Nowadays the size of the streamlined liner of the pharynx airway (SLIPATM) is selected by matching the width of the thyroid cartilage of the patient to the widest dimension of the SLIPATM. The objective of this work was to improve the method of selection by matching the distance between the otobasion inferius and the most inferior margin of the cricoid cartilage (O-C) to the length of the SLIPATM chamber. METHODS: 100 patients (ASAI-II) scheduled to undergo operations under general anesthesia were randomly divided into two groups, group A (size selected by matching O-C with SLIPATM chamber length, n = 50) and group B (size selected by matching the width of the thyroid cartilage with the widest dimension of the SLIPATM, n = 50). We measured the distance between the nasopharynx and the interarytenoid fold (N-I) and investigated the correlation between O-C and N-I at the neutral head position. Number of attempts, insertion time, blood on the device, leakage, and the need to change sizes were assessed. RESULTS: A positive correlation (r = 0.68, p < 0.05) was detected between N-I and O-C. Leakage was observed in 6 % (n = 3) of group A patients and in 20 % (n = 10) of group B patients (p < 0.05). CONCLUSION: Compared with the classic size-selection method, matching the width of the thyroid cartilage with that of the SLIPATM, the size-selection method of matching SLIPATM chamber length to O-C for adult patients is more accurate. PMID- 23443651 TI - New 3d-4f heterometallic clusters built from mixed glycine and iminodiacetate acid: dioctahedron {La2Ni9} and onion-like {Gd5}?{Ni12} with interesting magnetocaloric effect. AB - The preparation, structures and properties of 3d-4f compounds, undecanuclear [La2Ni9(Gly)12(IDA)3(MU3-OH)3][La(H2O)9][Na3(H2O)7(ClO4)3](ClO4)6.5H2O (1) and isostructural heptadecanuclear [Ln5Ni12(Gly)12(IDA)6(MU3-OH)9(H2O)3](ClO4)6.11H2O (Ln = Gd (2); Nd (3); Sm (4); Tb (5); Dy (6); Y (7)) based on mixed glycine (HGly) and iminodiacetate acid (H2IDA) ligands were described. The structure of the [La2Ni9(MU3-OH)3(IDA)3(Gly)12](3+) cationic cluster in 1 can be described as a face-shared and La-centered dioctahedron. However, the [Ln5Ni12(Gly)12(IDA)6(MU3-OH)9(H2O)3](6+) cationic clusters in 2-7 bear an onion like {Ln5}?{Ni12} structure, where the trigonal bipyramid {Ln5} core is encapsulated by the outer triangular orthobicupola {Ni12} shell. Magnetic studies have been performed for these compounds, and 2 displays dominant ferromagnetic coupling and has a large magnetocaloric effect (21.8 J kg(-1) K(-1), DeltaH = 7 T). PMID- 23443652 TI - Mesenchymal stromal cell-derived extracellular matrix influences gene expression of chondrocytes. AB - Decellularized extracellular matrix (ECM) has recently gained a lot of interest as an instructive biomaterial for regenerative medicine applications. In this study, the ability of adult human mesenchymal stem cell (hMSC)-derived ECM to rescue the phenotype of osteoarthritic (OA) chondrocytes and to further stimulate the differentiation of healthy (HL) chondrocytes was evaluated. ECMs were prepared by decellularizing hMSCs cultured in basic medium (BM) and chondrogenic medium (CM). The obtained ECM was then combined with a polymeric solution of Poly (epsilon-caprolactone) (PCL) dissolved in 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol (HFIP) and electrospun meshes were fabricated. Electrospun ECM scaffolds were characterized using scanning electron microscopy (SEM) and picrosirius red staining was used to confirm the presence of collagen. OA and HL chondrocytes were cultured on scaffolds containing hMSC ECM in BM or CM and compared to PCL electrospun scaffolds without ECM. Metabolic activity and chondrogenic gene expression were assessed by Alamar blue assay and quantitative PCR (qPCR) analysis, respectively. The ECM presence resulted in a significant difference in chondrocyte metabolic activity compared to PCL scaffolds alone. HL chondrocytes cultured for 21 days in chondrogenic medium on electrospun scaffolds containing hMSC ECM from BM showed a significant increase in collagen II and aggrecan expression compared to hMSC ECM from CM and PCL scaffolds without ECM incorporation. No significant influence of hMSC ECM presence on the chondrogenic signature of OA chondrocytes was found. The influence of decellularized hMSC ECM on HL chondrocytes suggests that hMSC-derived ECM scaffolds are promising candidates for cartilage tissue engineering applications. PMID- 23443653 TI - Comparative analysis of interaction of human and yeast DNA damage recognition complexes with damaged DNA in nucleotide excision repair. AB - The human XPC-RAD23B complex and its yeast ortholog, Rad4-Rad23, are the primary initiators of global genome nucleotide excision repair. The interaction of these proteins with damaged DNA was analyzed using model DNA duplexes containing a single fluorescein-substituted dUMP analog as a lesion. An electrophoretic mobility shift assay revealed similarity between human and yeast proteins in DNA binding. Quantitative analyses of XPC/Rad4 binding to the model DNA structures were performed by fluorescent depolarization measurements. XPC-RAD23B and Rad4 Rad23 proteins demonstrate approximately equal binding affinity to the damaged DNA duplex (K(D) ~ (0.5 +/- 0.1) and (0.6 +/- 0.3) nM, respectively). Using photoreactive DNA containing 5-iodo-dUMP in defined positions, XPC/Rad4 location on damaged DNA was shown. Under conditions of equimolar binding to DNA both proteins exhibited the highest level of cross-links to 5I-dUMP located exactly opposite the damaged nucleotide. The positioning of the XPC and Rad4 proteins on damaged DNA by photocross-linking footprinting is consistent with x-ray analysis of the Rad4-DNA crystal complex. The identity of the XPC and Rad4 location illustrates the common principles of structure organization of DNA damage scanning proteins from different Eukarya organisms. PMID- 23443654 TI - Processing of DNA double-stranded breaks and intermediates of recombination and repair by Saccharomyces cerevisiae Mre11 and its stimulation by Rad50, Xrs2, and Sae2 proteins. AB - Saccharomyces cerevisiae RAD50, MRE11, and XRS2 genes are essential for telomere length maintenance, cell cycle checkpoint signaling, meiotic recombination, and DNA double-stranded break (DSB) repair via nonhomologous end joining and homologous recombination. The DSB repair pathways that draw upon Mre11-Rad50-Xrs2 subunits are complex, so their mechanistic features remain poorly understood. Moreover, the molecular basis of DSB end resection in yeast mre11-nuclease deficient mutants and Mre11 nuclease-independent activation of ATM in mammals remains unknown and adds a new dimension to many unanswered questions about the mechanism of DSB repair. Here, we demonstrate that S. cerevisiae Mre11 (ScMre11) exhibits higher binding affinity for single- over double-stranded DNA and intermediates of recombination and repair and catalyzes robust unwinding of substrates possessing a 3' single-stranded DNA overhang but not of 5' overhangs or blunt-ended DNA fragments. Additional evidence disclosed that ScMre11 nuclease activity is dispensable for its DNA binding and unwinding activity, thus uncovering the molecular basis underlying DSB end processing in mre11 nuclease deficient mutants. Significantly, Rad50, Xrs2, and Sae2 potentiate the DNA unwinding activity of Mre11, thus underscoring functional interaction among the components of DSB end repair machinery. Our results also show that ScMre11 by itself binds to DSB ends, then promotes end bridging of duplex DNA, and directly interacts with Sae2. We discuss the implications of these results in the context of an alternative mechanism for DSB end processing and the generation of single stranded DNA for DNA repair and homologous recombination. PMID- 23443655 TI - Nicotinic acid adenine dinucleotide phosphate (NAADP) activates global and heterogeneous local Ca2+ signals from NAADP- and ryanodine receptor-gated Ca2+ stores in pulmonary arterial myocytes. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+) mobilizing messenger that releases Ca(2+) from endolysosomal organelles. Recent studies showed that NAADP-induced Ca(2+) release is mediated by the two-pore channels (TPCs) TPC1 and TPC2. However, the expression of TPCs and the NAADP induced local Ca(2+) signals have not been examined in vascular smooth muscle. Here, we found that both TPC1 and TPC2 are expressed in rat pulmonary arterial smooth muscle cells (PASMCs), with TPC1 being the major subtype. Application of membrane-permeant NAADP acetoxymethyl ester to PASMCs elicited a biphasic increase in global [Ca(2+)]i, which was independent of extracellular Ca(2+) and blocked by the NAADP antagonist Ned-19 or the vacuolar H(+)-ATPase inhibitor bafilomycin A1, indicating Ca(2+) release from acidic endolysosomal Ca(2+) stores. The Ca(2+) response was unaffected by xestospongin C but was partially blocked by ryanodine or thapsigargin. NAADP triggered heterogeneous local Ca(2+) signals, including a diffuse increase in cytosolic [Ca(2+)], Ca(2+) sparks, Ca(2+) bursts, and regenerative Ca(2+) release. The diffuse Ca(2+) increase and Ca(2+) bursts were ryanodine-insensitive, presumably arising from different endolysosomal sources. Ca(2+) sparks and regenerative Ca(2+) release were inhibited by ryanodine, consistent with cross-activation of loosely coupled ryanodine receptors. Moreover, Ca(2+) release stimulated by endothelin-1 was inhibited by Ned-19, ryanodine, or xestospongin C, suggesting that NAADP-mediated Ca(2+) signals interact with both ryanodine and inositol 1,4,5-trisphosphate receptors during agonist stimulation. Our results show that NAADP mediates complex global and local Ca(2+) signals. Depending on the physiological stimuli, these diverse Ca(2+) signals may serve to regulate different cellular functions in PASMCs. PMID- 23443656 TI - Biochemical and immunological characterization of Toxoplasma gondii macrophage migration inhibitory factor. AB - Macrophage migration inhibitory factor (MIF) is a proinflammatory molecule in mammals that, unusually for a cytokine, exhibits tautomerase and oxidoreductase enzymatic activities. Homologues of this well conserved protein are found within diverse phyla including a number of parasitic organisms. Herein, we produced recombinant histidine-tagged Toxoplasma gondii MIF (TgMIF), a 12-kDa protein that lacks oxidoreductase activity but exhibits tautomerase activity with a specific activity of 19.3 MUmol/min/mg that cannot be inhibited by the human MIF inhibitor ISO-1. The crystal structure of the TgMIF homotrimer has been determined to 1.82 A, and although it has close structural homology with mammalian MIFs, it has critical differences in the tautomerase active site that account for the different inhibitor sensitivity. We also demonstrate that TgMIF can elicit IL-8 production from human peripheral blood mononuclear cells while also activating ERK MAPK pathways in murine bone marrow-derived macrophages. TgMIF may therefore play an immunomodulatory role during T. gondii infection in mammals. PMID- 23443657 TI - Inhibition of nucleotide sugar transport in Trypanosoma brucei alters surface glycosylation. AB - Nucleotide sugar transporters (NSTs) are indispensible for the biosynthesis of glycoproteins by providing the nucleotide sugars needed for glycosylation in the lumen of the Golgi apparatus. Mutations in NST genes cause human and cattle diseases and impaired cell walls of yeast and fungi. Information regarding their function in the protozoan parasite, Trypanosoma brucei, a causative agent of African trypanosomiasis, is unknown. Here, we characterized the substrate specificities of four NSTs, TbNST1-4, which are expressed in both the insect procyclic form (PCF) and mammalian bloodstream form (BSF) stages. TbNST1/2 transports UDP-Gal/UDP-GlcNAc, TbNST3 transports GDP-Man, and TbNST4 transports UDP-GlcNAc, UDP-GalNAc, and GDP-Man. TbNST4 is the first NST shown to transport both pyrimidine and purine nucleotide sugars and is demonstrated here to be localized at the Golgi apparatus. RNAi-mediated silencing of TbNST4 in the procyclic form caused underglycosylated surface glycoprotein EP-procyclin. Similarly, defective glycosylation of the variant surface glycoprotein (VSG221) as well as the lysosomal membrane protein p67 was observed in Deltatbnst4 BSF T. brucei. Relative infectivity analysis showed that defects in glycosylation of the surface coat resulting from tbnst4 deletion were insufficient to impact the ability of this parasite to infect mice. Notably, the fact that inactivation of a single NST gene results in measurable defects in surface glycoproteins in different life cycle stages of the parasite highlights the essential role of NST(s) in glycosylation of T. brucei. Thus, results presented in this study provide a framework for conducting functional analyses of other NSTs identified in T. brucei. PMID- 23443658 TI - Cross-talk between tetraspanin CD9 and transmembrane adaptor protein non-T cell activation linker (NTAL) in mast cell activation and chemotaxis. AB - Chemotaxis, a process leading to movement of cells toward increasing concentrations of chemoattractants, is essential, among others, for recruitment of mast cells within target tissues where they play an important role in innate and adaptive immunity. Chemotaxis is driven by chemoattractants, produced by various cell types, as well as by intrinsic cellular regulators, which are poorly understood. In this study we prepared a new mAb specific for the tetraspanin CD9. Binding of the antibody to bone marrow-derived mast cells triggered activation events that included cell degranulation, Ca(2+) response, dephosphorylation of ezrin/radixin/moesin (ERM) family proteins, and potent tyrosine phosphorylation of the non-T cell activation linker (NTAL) but only weak phosphorylation of the linker for activation of T cells (LAT). Phosphorylation of the NTAL was observed with whole antibody but not with its F(ab)(2) or Fab fragments. This indicated involvement of the Fcgamma receptors. As documented by electron microscopy of isolated plasma membrane sheets, CD9 colocalized with the high-affinity IgE receptor (FcepsilonRI) and NTAL but not with LAT. Further tests showed that both anti-CD9 antibody and its F(ab)(2) fragment inhibited mast cell chemotaxis toward antigen. Experiments with bone marrow-derived mast cells deficient in NTAL and/or LAT revealed different roles of these two adaptors in antigen-driven chemotaxis. The combined data indicate that chemotaxis toward antigen is controlled in mast cells by a cross-talk among FcepsilonRI, tetraspanin CD9, transmembrane adaptor proteins NTAL and LAT, and cytoskeleton-regulatory proteins of the ERM family. PMID- 23443659 TI - Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation. AB - Alzheimer disease and several other neurodegenerative disorders are characterized by the accumulation of intraneuronal fibrils comprised of the protein Tau. Tau is normally a soluble protein that stabilizes microtubules, with splice isoforms that contain either three (3-R) or four (4-R) microtubule binding repeats. The formation of Tau fibrils is thought to result in neuronal damage, and inhibitors of Tau fibrillization may hold promise as therapeutic agents. The process of Tau fibrillization can be replicated in vitro, and a number of small molecules have been identified that inhibit Tau fibril formation. However, little is known about how these molecules affect Tau fibrillization. Here, we examined the mechanism by which the previously described aminothieno pyridazine (ATPZ) series of compounds inhibit Tau fibrillization. Active ATPZs were found to promote the oxidation of the two cysteine residues within 4-R Tau by a redox cycling mechanism, resulting in the formation of a disulfide-containing compact monomer that was refractory to fibrillization. Moreover, the ATPZs facilitated intermolecular disulfide formation between 3-R Tau monomers, leading to dimers that were capable of fibrillization. The ATPZs also caused cysteine oxidation in molecules unrelated to Tau. Interestingly, methylene blue, an inhibitor of Tau fibrillization under evaluation in Alzheimer disease clinical trials, caused a similar oxidation of cysteines in Tau and other molecules. These findings reveal that the ATPZs and methylene blue act by a mechanism that may affect their viability as potential therapeutic agents. PMID- 23443660 TI - Sequential inductions of the ZEB1 transcription factor caused by mutation of Rb and then Ras proteins are required for tumor initiation and progression. AB - Rb1 restricts cell cycle progression, and it imposes cell contact inhibition to suppress tumor outgrowth. It also triggers oncogene-induced senescence to block Ras mutation. Loss of the Rb1 pathway, which is a hallmark of cancer cells, then provides a permissive environment for Ras mutation, and Ras is sufficient for invasive tumor formation in Rb1 family mutant mouse embryo fibroblasts (MEFs). These results demonstrate that sequential mutation of the Rb1 and Ras pathways comprises a tumor initiation axis. Both Rb1 and Ras regulate expression of the transcription factor ZEB1, thereby linking tumor initiation to the subsequent invasion and metastasis, which is induced by ZEB1. ZEB1 acts in a negative feedback loop to block expression of miR-200, which is thought to facilitate tumor invasion and metastasis. However, ZEB1 also represses cyclin-dependent kinase (cdk) inhibitors to control the cell cycle; its mutation in MEFs leads to induction of these inhibitors and premature senescence. Here, we provide evidence for two sequential inductions of ZEB1 during Ras transformation of MEFs. Rb1 constitutively represses cdk inhibitors, and induction of ZEB1 when the Rb1 pathway is lost is required to maintain this repression, allowing for the classic immortalization and loss of cell contact inhibition seen when the Rb1 pathway is lost. In vivo, we show that this induction of ZEB1 is required for Ras-initiated tumor formation. ZEB1 is then further induced by Ras, beyond the level seen with Rb1 mutation, and this Ras superinduction is required to reach a threshold of ZEB1 sufficient for repression of miR-200 and tumor invasion. PMID- 23443661 TI - Crystal structures of matriptase in complex with its inhibitor hepatocyte growth factor activator inhibitor-1. AB - Matriptase, a type II trans-membrane serine protease of the S1 trypsin-like family, is expressed on the surface of nearly all normal human epithelium and found in biological fluid-like human milk. Matriptase overexpression has been implicated in tumor progression in certain epithelium-derived cancer cells. Matriptase is tightly regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). It has been demonstrated that the Kunitz domain I (KD1) but not Kunitz domain II (KD2) of HAI-1 is responsible for the inhibitory activity of HAI-1 against matriptase. To investigate the molecular basis of inhibition of matriptase by HAI-1, we solved several crystal structures of matriptase serine protease domain in complex with the fragments of HAI-1. Based on these structures, we found that the binding of KD1 was different from previously predicted binding mode. The P3 arginine residue occupies the S3 specificity pocket of matriptase, but not the S4 pocket as in the cases of hepatocyte growth factor activator.HAI-1 KD1 and matriptase.sunflower trypsin inhibitor-1 complexes. The long 60-loop of matriptase makes direct contact with HAI-1 but remains flexible even in the complexes, and its apex does not bind with KD1 tightly. The interactions between this unique 60-loop and KD1 may provide an opportunity to increase the specificity and inhibitory activity of KD1 for matriptase. Furthermore, comparison between KD1 and a homology model of HAI-1 KD2 rationalizes the structural basis of why KD1 but not KD2 is responsible for the inhibitory activity of HAI-1 against matriptase. PMID- 23443662 TI - Prostasin is required for matriptase activation in intestinal epithelial cells to regulate closure of the paracellular pathway. AB - The type II transmembrane serine protease matriptase is a key regulator of epithelial barriers in skin and intestine. In skin, matriptase acts upstream of the glycosylphosphatidylinositol-anchored serine protease, prostasin, to activate the prostasin zymogen and initiate a proteolytic cascade that is required for stratum corneum barrier functionality. Here, we have investigated the relationship between prostasin and matriptase in intestinal epithelial barrier function. We find that similar to skin, matriptase and prostasin are components of a common intestinal epithelial barrier-forming pathway. Depletion of prostasin by siRNA silencing in Caco-2 intestinal epithelium inhibits barrier development similar to loss of matriptase, and the addition of recombinant prostasin to the basal side of polarized Caco-2 epithelium stimulates barrier forming changes similar to the addition of recombinant matriptase. However, in contrast to the proteolytic cascade in skin, prostasin functions upstream of matriptase to activate the endogenous matriptase zymogen. Prostasin is unable to proteolytically activate the matriptase zymogen directly but induces matriptase activation indirectly. Prostasin requires expression of endogenous matriptase to stimulate barrier formation since matriptase depletion by siRNA silencing abrogates prostasin barrier-forming activity. Active recombinant matriptase, however, does not require the expression of endogenous prostasin for barrier forming activity. Together, these data show that matriptase and not prostasin is the primary effector protease of tight junction assembly in simple columnar epithelia and further highlight a spatial and tissue-specific aspect of cell surface proteolytic cascades. PMID- 23443663 TI - SUMOylation regulates the homologous to E6-AP carboxyl terminus (HECT) ubiquitin ligase Rsp5p. AB - The post-translational modifiers ubiquitin and small ubiquitin-related modifier (SUMO) regulate numerous critical signaling pathways and are key to controlling the cellular fate of proteins in eukaryotes. The attachment of ubiquitin and SUMO involves distinct, but related, machinery. However, it is now apparent that many substrates can be modified by both ubiquitin and SUMO and that some regulatory interaction takes place between the respective attachment machinery. Here, we demonstrate that the Saccharomyces cerevisiae ubiquitin ligase Rsp5p, a member of the highly conserved Nedd4 family of ubiquitin ligases, is SUMOylated in vivo. We further show that Rsp5p SUMOylation is mediated by the SUMO ligases Siz1p and Siz2p, members of the conserved family of PIAS SUMO ligases that are, in turn, substrates for Rsp5p-mediated ubiquitylation. Our experiments show that SUMOylated Rsp5p has reduced ubiquitin ligase activity, and similarly, ubiquitylated Siz1p demonstrates reduced SUMO ligase activity leading to respective changes in both ubiquitin-mediated sorting of the manganese transporter Smf1p and polySUMO chain formation. This reciprocal regulation of these highly conserved ligases represents an exciting and previously unidentified system of cross talk between the ubiquitin and SUMO systems. PMID- 23443664 TI - Inducible cAMP early repressor regulates the Period 1 gene of the hepatic and adrenal clocks. AB - Light, restricted feeding, and hormonal inputs may operate as time givers (zeitgebers) for the circadian clock within peripheral organs through the activation of tissue-specific signaling cascades. cAMP signaling through CREM (cAMP-responsive element modulator) and its variant ICER (inducible cAMP early repressor) is linked to the circadian regulation of pineal melatonin synthesis, although little is known about its influence in other organs. We performed experiments in the absence of light and feeding-time cues to test which core clock genes are controlled by CREM/ICER in the liver and adrenal gland. In vivo, Crem loss-of-function mutation resulted in fine-tuning of all measured adrenal clock genes (Per1/2/3, Cry1/2, Bmal1, and Rev-erbalpha), whereas only Per1 and Cry1 were affected in the liver. Icer expression was circadian in the adrenal gland, with peak gene expression at zeitgeber 12 and the highest protein levels at zeitgeber ~20. The expression of both Icer and Per1 genes responded to cAMP stimuli in an immediate-early fashion. In immortal cells, forskolin induced expression of Per1 after 2 h, and de novo protein synthesis led to Per1 attenuation. We show that the de novo synthesized protein responsible for Per1 attenuation is ICER. Indeed, Per1 expression is up-regulated in cells ectopically expressing antisense Icer, and mobility shift experiments identified ICER binding to cAMP-responsive elements of the Per1 promoter. We propose that ICER acts as a noise filter for different signals that could affect transcription in the adrenal gland. Because ICER is an immediate-early repressor, the circadian nature of adrenal Icer expression could serve a role in a time-dependent gating mechanism. PMID- 23443665 TI - Nicotinamide inhibits the lysosomal cathepsin b-like protease and kills African trypanosomes. AB - Nicotinamide, a soluble compound of the vitamin B3 group, has antimicrobial activity against several microorganisms ranging from viruses to parasite protozoans. However, the mode of action of this antimicrobial activity is unknown. Here, we investigate the trypanocidal activity of nicotinamide on Trypanosoma brucei, the causative agent of African trypanosomiasis. Incubation of trypanosomes with nicotinamide causes deleterious defects in endocytic traffic, disruption of the lysosome, failure of cytokinesis, and, ultimately, cell death. At the same concentrations there was no effect on a cultured mammalian cell line. The effects on endocytosis and vesicle traffic were visible within 3 h and can be attributed to inhibition of lysosomal cathepsin b-like protease activity. The inhibitory effect of nicotinamide was confirmed by a direct activity assay of recombinant cathepsin b-like protein. Taken together, these data demonstrate that inhibition of the lysosomal protease cathepsin b-like blocks endocytosis, causing cell death. In addition, these results demonstrate for the first time the inhibitory effect of nicotinamide on a protease. PMID- 23443667 TI - 3D kinematics using dual quaternions: theory and applications in neuroscience. AB - In behavioral neuroscience, many experiments are developed in 1 or 2 spatial dimensions, but when scientists tackle problems in 3-dimensions (3D), they often face problems or new challenges. Results obtained for lower dimensions are not always extendable in 3D. In motor planning of eye, gaze or arm movements, or sensorimotor transformation problems, the 3D kinematics of external (stimuli) or internal (body parts) must often be considered: how to describe the 3D position and orientation of these objects and link them together? We describe how dual quaternions provide a convenient way to describe the 3D kinematics for position only (point transformation) or for combined position and orientation (through line transformation), easily modeling rotations, translations or screw motions or combinations of these. We also derive expressions for the velocities of points and lines as well as the transformation velocities. Then, we apply these tools to a motor planning task for manual tracking and to the modeling of forward and inverse kinematics of a seven-dof three-link arm to show the interest of dual quaternions as a tool to build models for these kinds of applications. PMID- 23443666 TI - Interferon-gamma and granulocyte/monocyte colony-stimulating factor production by natural killer cells involves different signaling pathways and the adaptor stimulator of interferon genes (STING). AB - Natural killer (NK) cells are important for innate immunity in particular through the production of IFN-gamma and GM-CSF. Both cytokines are important in restoration of immune function of tolerized leukocytes under inflammatory events. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors, rarely seeking their protein expression. We previously showed that murine spleen NK cells express TLR9 intracellularly and respond to CpG oligodeoxynucleotide (CpG-ODN) by producing IFN-gamma and GM-CSF. However, to get such production the presence of accessory cytokines (such as IL-15 and IL-18) was required, whereas CpG-ODN or accessory cytokines alone did not induce IFN-gamma or GM-CSF. We show here that TLR9 overlaps with the Golgi apparatus in NK cells. Furthermore, CpG-ODN stimulation in the presence of accessory cytokines induces the phosphorylation of c-Jun, STAT3, and IkappaBalpha. IFN-gamma and GM-CSF production requires NF-kappaB and STAT3 activation as well as Erk-dependent mechanisms for IFN-gamma and p38 signaling for GM-CSF. Using knock-out-mice, we show that UNC93b1 and IL-12 (produced by NK cells themselves) are also necessary for IFN-gamma and GM-CSF production. IFN-gamma production was found to be MyD88- and TLR9-dependent, whereas GM-CSF was TLR9-independent but dependent on STING (stimulator of interferon genes), a cytosolic adaptor recently described for DNA sensing. Our study thereby allows us to gain insight into the mechanisms of synergy between accessory cytokines and CpG-ODN in NK cells. It also identifies a new and alternative signaling pathway for CpG-ODN in murine NK cells. PMID- 23443668 TI - High performance amorphous ZnMgO/carbon nanotube composite thin-film transistors with a tunable threshold voltage. AB - Here we report the fabrication and characterization of high mobility amorphous ZnMgO/single-walled carbon nanotube composite thin film transistors (TFTs) with a tunable threshold voltage. By controlling the ratio of MgO, ZnO and carbon nanotubes, high performance composite TFTs can be obtained with a field-effect mobility of up to 135 cm(2) V(-1) s(-1), a low threshold voltage of 1 V and a subthreshold swing as small as 200 mV per decade, making it a promising new solution-processed material for high performance functional circuits. A low voltage inverter is demonstrated with a functional frequency exceeding 5 kHz, which is only limited by parasitic capacitance rather than the intrinsic material speed. The overall device performance of the composite TFTs greatly surpasses not only that of the solution-processed TFTs, but also that of the conventional amorphous or polycrystalline silicon TFTs. It therefore has the potential to open up a new avenue to high-performance, solution-processed flexible electronics which could significantly impact the existing applications, and enable a whole new generation of flexible, wearable, or disposable electronics. PMID- 23443669 TI - Pneumocystis pneumonia during primary HIV infection: a case report and review of the literature. AB - More than 90% of cases of pneumocystis pneumonia (PCP) in adults occur in patients with chronic HIV infection with CD4 counts lower than 200 cells/ml. Even though primary HIV infection can cause transient profound CD4 lymphocytopenia, PCP is rarely reported during primary HIV infection. We report a case of a 26 year-old man who was diagnosed with PCP in the setting of primary HIV infection. He was successfully treated with a 21-day course of oral co-trimoxazole. PMID- 23443670 TI - The InSiGHT database: utilizing 100 years of insights into Lynch syndrome. AB - This article provides a historical overview of the online database ( www.insight group.org/mutations ) maintained by the International Society for Gastrointestinal Hereditary Tumours. The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT. PMID- 23443671 TI - Coiled-coil irregularities of the M1 protein structure promote M1-fibrinogen interaction and influence group A Streptococcus host cell interactions and virulence. AB - Group A Streptococcus (GAS) is a human pathogen causing a wide range of mild to severe and life-threatening diseases. The GAS M1 protein is a major virulence factor promoting GAS invasiveness and resistance to host innate immune clearance. M1 displays an irregular coiled-coil structure, including the B-repeats that bind fibrinogen. Previously, we found that B-repeat stabilisation generates an idealised version of M1 (M1) characterised by decreased fibrinogen binding in vitro. To extend these findings based on a soluble truncated version of M1, we now studied the importance of the B-repeat coiled-coil irregularities in full length M1 and M1 expressed in live GAS and tested whether the modulation of M1 fibrinogen interactions would open up novel therapeutic approaches. We found that altering either the M1 structure on the GAS cell surface or removing its target host protein fibrinogen blunted GAS virulence. GAS expressing M1 showed an impaired ability to adhere to and to invade human endothelial cells, was more readily killed by whole blood or neutrophils and most importantly was less virulent in a murine necrotising fasciitis model. M1-mediated virulence of wild type GAS was strictly dependent on the presence and concentration of fibrinogen complementing our finding that M1-fibrinogen interactions are crucial for GAS virulence. Consistently blocking M1-fibrinogen interactions by fragment D reduced GAS virulence in vitro and in vivo. This supports our conclusion that M1 fibrinogen interactions are crucial for GAS virulence and that interference may open up novel complementary treatment options for GAS infections caused by the leading invasive GAS strain M1. PMID- 23443672 TI - Economic and safety implications of introducing fast tracking in congenital heart surgery. AB - BACKGROUND: The feasibility of fast-tracking children undergoing congenital heart disease surgery has not been assessed adequately. Current knowledge is based on limited single-center experiences without contemporaneous control groups. METHODS AND RESULTS: We compared administrative data for atrial septal defect (ASD) and ventricular septal defect (VSD) surgeries in children 2 months to 19 years of age at the Mount Sinai Medical Center (MSMC) with data from comparable patients at 40 centers contributing to the Pediatric Health Information System. Three-year blocks, early in and after fast tracking had been implemented at the MSMC, were examined. Seventy-seven and 89 children at MSMC undergoing ASD and VSD closure, respectively, were compared with 3103 ASD and 4180 VSD patients nationally. With fast tracking fully implemented, median length of stay at the MSMC decreased by 1 day compared with the earlier era (length of stay, 1 and 3 days for ASD and VSD, respectively). Nationally, median length of stay remained unchanged (3 days for ASD and 4 days for VSD) in the observed time periods. Hospitalization costs fell by 33% and 35% at MSMC (ASD and VSD, respectively), whereas they rose by 16% to 17% nationally. When analyzed in multiple regression models, the decrease in both length of stay and cost remained significantly greater at MSMC compared with nationally (P<0.0001 for all). Hospital mortality and 2-week readmission rates were unchanged at MSMC between the 2 time periods and were not different from the national rates. CONCLUSION: Shorter length of stay and cost savings compared with national data were observed after implementation of fast tracking. PMID- 23443673 TI - Facile synthesis of gold nanoparticle (AuNP)-carbon nanotube (CNT) hybrids through an interfacial Michael addition reaction. AB - A CNT-AuNP hybrid has been synthesized through the Michael addition reaction between thiol-functionalized single-wall CNT and small water-soluble Maleimide AuNP. The resilience and stability of this hybrid nanosystem is ensured by a covalent bond linking the nanoparticle to the CNT and by the fact that the functionalization reaction involves the organic shell of the AuNP and not its metallic core. PMID- 23443674 TI - Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins. AB - BACKGROUND: Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity. METHODS: We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case-control status. RESULTS: The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P=0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P=0.015); this difference was not significant (169 vs 183, P=0.10) when restricted to abundant OTUs. CONCLUSION: In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment. PMID- 23443675 TI - Gua Lou Gui Zhi decoction exerts neuroprotective effects on post-stroke spasticity via the modulation of glutamate levels and AMPA receptor expression. AB - Spasticity is one of the most physically debilitating disabilities following stroke and may slow down the potential success of rehabilitation. Glutamate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been shown to play a crucial role in spasticity following cerebral ischemia/reperfusion (I/R) injury. Gua Lou Gui Zhi decoction (GLGZD) is a well known traditional Chinese formula that has long been used clinically in China to treat muscular spasticity following stroke, epilepsy or spinal cord injury. However, the precise mechanisms behind its neuroprotective and anti-spasticity effects remain poorly understood. In the present study, using a rat model of focal cerebral I/R injury, we evaluated the neuroprotective and anti-spasticity effects of GLGZD and investigated the underlying mechanisms. We found that GLGZD improved neurological deficits and reduced infarct volumes in cerebral I/R injured rats. In addition, GLGZD reduced cerebral ischemic spasticity since it improved the screen test and Hoffman's reflex (H-reflex) scores. It also reduced glutamate levels in the cerebrospinal fluid and altered the expression of the AMPA receptor subunits. Our data demonstrate that GLGZD exerts neuroprotective and anti-spasticity effects in a cerebral ischemia model via the modulation of glutamate levels and AMPA receptor expression. PMID- 23443676 TI - Reactions of the tetraoxidosulfate(-) and hydroxyl radicals with poly(sodium alpha-methylstyrene sulfonate). AB - Poly(alpha-methylstyrene sulfonic acid) (PAMS) represents a class of polymers that can form the protogenic constituent in electrolyte membranes for fuel cells. Oxidative stress is thought to play an important role in the degradation of the fuel cell membranes. Having previously established that damage may be mediated via abstraction of a benzylic hydrogen, we examined model compounds similar to those used before, but with a methyl group at the alpha-position. We studied the reaction of HO and SO4(-), generated by pulse radiolysis, with model compounds in aqueous solution, and measured k = (2 +/- 0.5) * 10(10) M(-1) s(-1) and (2 - 3) * 10(10) M(-1) s(-1) for the reaction of HO with PAMS with average molecular weights of 2640 Da (PAMS-2640) and 6440 Da (PAMS-6440), respectively, at room temperature. At low pH, the decay of the hydroxycyclohexadienyl radical thus formed is accompanied by the formation of an absorption band in the visible region of the spectrum, which we tentatively assign to the radical cation of PAMS 2640 and -6440. The radical cation of PAMS-2640, formed by the reaction of SO4(-) with k = (6 +/- 1) * 10(8) M(-1) s(-1), has a local absorption maximum at 560 nm, with epsilon560 >= 1400 M(-1) cm(-1). For the reaction of HO and SO4(-) with the model compound benzenesulfonate, we measured k = (4-5) * 10(9) M(-1) s(-1) and (1.0 +/- 0.3) * 10(8) M(-1) s(-1), respectively, while the reaction of SO4(-) with PAMS-6440 proceeds with (0.8-1) * 10(9) M(-1) s(-1). The 4-sulfophenoxyl radical was generated via the reaction of N3 with 4-hydroxybenzenesulfonate; epsilon410 >= 2300 M(-1) cm(-1). Not unexpectedly, the radical cation of PAMS is longer-lived than that of polystyrene sulfonic acid. Furthermore, fragmentation may result in desulfonation. PMID- 23443677 TI - Selenoprotein-transgenic Chlamydomonas reinhardtii. AB - Selenium (Se) deficiency is associated with the occurrence of many diseases. However, excessive Se supplementation, especially with inorganic Se, can result in toxicity. Selenoproteins are the major forms of Se in vivo to exert its biological function. Expression of those selenoproteins, especially with the application of a newly developed system, is thus very important for studying the mechanism of Se in nutrition. The use of Chlamydomonas reinhardtii (C. reinhardtii) as a biological vector to express an heterogeneous protein is still at the initial stages of development. In order to investigate the possibility of using this system to express selenoproteins, human 15-KDa selenoprotein (Sep15), a small but widely distributed selenoprotein in mammals, was chosen for the expression platform test. Apart from the wild-type human Sep15 gene fragment, two Sep15 recombinants were constructed containing Sep15 open reading frame (ORF) and the selenocysteine insertion sequence (SECIS) element from either human Sep15 or C. reinhardtii selenoprotein W1, a highly expressed selenoprotein in this alga. Those Sep15-containing plasmids were transformed into C. reinhardtii CC-849 cells. Results showed that Sep15 fragments were successfully inserted into the nuclear genome and expressed Sep15 protein in the cells. The transgenic and wild-type algae demonstrated similar growth curves in low Se culture medium. To our knowledge, this is the first report on expressing human selenoprotein in green alga. PMID- 23443678 TI - Letter to editor concerning: "Intradural lumbar disc herniation: report of five cases with literature review". PMID- 23443679 TI - Measuring procedures to determine the Cobb angle in idiopathic scoliosis: a systematic review. AB - BACKGROUND: Scoliosis of the vertebral column can be assessed with the Cobb angle (Cobb 1948). This examination is performed manually by measuring the angle on radiographs and is considered the gold standard. However, studies evaluating the reproducibility of this procedure have shown high variability in intra- and inter observer agreement. Because of technical advancements, interests in new procedures to determine the Cobb angle has been renewed. This review aims to systematically investigate the reproducibility of various new techniques to determine the Cobb angle in idiopathic scoliosis and to assess whether new technical procedures are reasonable alternatives when compared to manual measurement of the Cobb angle. METHOD: Systematic review. Studies examining procedures used to determine the Cobb angle were selected. Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias. Statistical results of reliability and agreement were summarised and described. RESULTS: Eleven studies of new measuring procedures were included, all reporting the reproducibility. The new procedures can be divided into computer assisted procedures, automatic procedures and smartphone apps. CONCLUSIONS: All investigated measuring procedures showed high degrees of reliability. In general, digital procedures tend to be slightly better than manual ones. For all other measurement procedures (automatic or smartphone), results varied. Studies implementing vertebral pre-selection and observer training achieved better agreement. PMID- 23443680 TI - Influence of spinal sagittal alignment, body balance, muscle strength, and physical ability on falling of middle-aged and elderly males. AB - OBJECTIVE: Risk factors for falling in elderly people remain uncertain, and the effects of spinal factors and physical ability on body balance and falling have not been examined. The objective of this study was to investigate how factors such as spinal sagittal alignment, spinal range of motion, body balance, muscle strength, and gait speed influence falling in the prospective cohort study. METHODS: The subjects were 100 males who underwent a basic health checkup. Balance, SpinalMouse((r)) data, grip strength, back muscle strength, 10-m gait time, lumbar lateral standing radiographs, body mass index, and fall history over the previous year were examined. Platform measurements of balance included the distance of movement of the center of pressure (COP) per second (LNG/TIME), the envelopment area traced by movement of the COP (E AREA), and the LNG/E AREA ratio. The thoracic/lumbar angle ratio (T/L ratio) and sagittal vertical axis (SVA) were used as an index of sagittal balance. RESULTS: LNG/TIME and E AREA showed significant positive correlations with age, T/L ratio, SVA, and 10-m gait time; and significant negative correlations with lumbar lordosis angle, sacral inclination angle, grip strength and back muscle strength. Multiple regression analysis showed significant differences for LNG/TIME and E AREA with T/L ratio, SVA, lumbar lordosis angle and sacral inclination angle (R (2) = 0.399). Twelve subjects (12 %) had experienced a fall over the past year. Age, T/L ratio, SVA, lumbar lordosis angle, sacral inclination angle, grip strength, back muscle strength, 10-m gait time, height of the intervertebral disc, osteophyte formation in radiographs and LNG/E AREA differed significantly between fallers and non fallers. The group with SVA > 40 mm (n = 18) had a significant higher number of subjects with a single fall (6 single fallers/18: p = 0.0075) and with multiple falls (4 multiple fallers/18: p = 0.0095). CONCLUSION: Good spinal sagittal alignment, muscle strength and 10-m gait speed improve body balance and reduce the risk of fall. Muscle strength and physical ability are also important for spinal sagittal alignment. Body balance training, improvement of physical abilities including muscle training, and maintenance of spinal sagittal alignment can lead to prevention of fall. PMID- 23443681 TI - Proteome changes in wild and modern wheat leaves upon drought stress by two dimensional electrophoresis and nanoLC-ESI-MS/MS. AB - To elucidate differentially expressed proteins and to further understand post translational modifications of transcripts, full leaf proteome profiles of two wild emmer (Triticum turgidum ssp. dicoccoides TR39477 and TTD22) and one modern durum wheat (Triticum turgidum ssp. durum cv. Kiziltan) genotypes were compared upon 9-day drought stress using two-dimensional gel electrophoresis and nano scale liquid chromatographic electrospray ionization tandem mass spectrometry methods. The three genotypes compared exhibit distinctive physiological responses to drought as previously shown by our group. Results demonstrated that many of the proteins were common in both wild emmer and modern wheat proteomes; of which, 75 were detected as differentially expressed proteins. Several proteins identified in all proteomes exhibited drought regulated patterns of expression. A number of proteins were observed with higher expression levels in response to drought in wild genotypes compared to their modern relative. Eleven protein spots with low peptide matches were identified as candidate unique drought responsive proteins. Of the differentially expressed proteins, four were selected and further analyzed by quantitative real-time PCR at the transcriptome level to compare with the proteomic data. The present study provides protein level differences in response to drought in modern and wild genotypes of wheat that may account for the differences of the overall responses of these genotypes to drought. Such comparative proteomics analyses may aid in the better understanding of complex drought response and may suggest candidate genes for molecular breeding studies to improve tolerance against drought stress and, thus, to enhance yields. PMID- 23443683 TI - A systems approach for decoding mitochondrial retrograde signaling pathways. AB - Mitochondrial dysfunctions activate retrograde signaling from mitochondria to the nucleus. To identify transcription factors and their associated pathways that underlie mitochondrial retrograde signaling, we performed gene expression profiling of the cells engineered to have varying amounts of mitochondrial DNA with an A3243G mutation (mt3243) in the leucine transfer RNA (tRNA(Leu)), which reduces the abundance of proteins involved in oxidative phosphorylation that are encoded by the mitochondrial genome. The cells with the mutation exhibited reduced mitochondrial function, including compromised oxidative phosphorylation, which would activate diverse mitochondrial retrograde signaling pathways. By analyzing the gene expression profiles in cells with the mutant tRNA(Leu) and the transcription factors that recognize the differentially regulated genes, we identified 72 transcription factors that were potentially involved in mitochondrial retrograde signaling. We experimentally validated that the mt3243 mutation induced a retrograde signaling pathway involving RXRA (retinoid X receptor alpha), reactive oxygen species, kinase JNK (c-JUN N-terminal kinase), and transcriptional coactivator PGC1alpha (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha). This RXR pathway contributed to the decrease in mRNA abundances of oxidative phosphorylation enzymes encoded in the nuclear genome, thereby aggravating the dysfunction in oxidative phosphorylation caused by the reduced abundance of mitochondria-encoded enzymes of oxidative phosphorylation. Thus, matching transcription factors to differentially regulated gene expression profiles was an effective approach to understand mitochondrial retrograde signaling pathways and their roles in mitochondrial dysfunction. PMID- 23443682 TI - Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis. AB - Inactivation of the small guanosine triphosphate-binding protein Ras during receptor signal transduction is mediated by Ras guanosine triphosphatase (GTPase) activating proteins (RasGAPs). Ten different RasGAPs have been identified and have overlapping patterns of tissue distribution. However, genetic analyses are revealing critical nonredundant functions for each RasGAP in tissue homeostasis and as regulators of disease processes in mouse and man. Here, we discuss advances in understanding the role of RasGAPs in the maintenance of tissue integrity. PMID- 23443685 TI - Jean A. Sicard (1872-1929). PMID- 23443686 TI - Equivalent circuit and optimum design of a multilayer laminated piezoelectric transformer. AB - A multilayer laminated piezoelectric Pb(Zr(1-x)Ti(x))O(3) (PZT) ceramic transformer, operating in a half- wavelength longitudinal resonant mode (lambda/2 mode), has been analyzed. This piezoelectric transformer is composed of one thickness-polarized section (T-section) for exciting the longitudinal mechanical vibrations, two longitudinally polarized sections (L-section) for generating high voltage output, and two insulating layers laminated between the T-section and L section layers to provide insulation between the input and output sections. Based on the piezoelectric constitutive and motion equations, an electro-elasto electric (EEE) equivalent circuit has been developed, and correspondingly, an effective EEE coupling coefficient was proposed for optimum design of this multilayer transformer. Commercial finite element analysis software is used to determine the validity of the developed equivalent circuit. Finally, a prototype sample was manufactured and experimental data was collected to verify the model's validity. PMID- 23443684 TI - Protein complex-based analysis framework for high-throughput data sets. AB - Analysis of high-throughput data increasingly relies on pathway annotation and functional information derived from Gene Ontology. This approach has limitations, in particular for the analysis of network dynamics over time or under different experimental conditions, in which modules within a network rather than complete pathways might respond and change. We report an analysis framework based on protein complexes, which are at the core of network reorganization. We generated a protein complex resource for human, Drosophila, and yeast from the literature and databases of protein-protein interaction networks, with each species having thousands of complexes. We developed COMPLEAT (http://www.flyrnai.org/compleat), a tool for data mining and visualization for complex-based analysis of high throughput data sets, as well as analysis and integration of heterogeneous proteomics and gene expression data sets. With COMPLEAT, we identified dynamically regulated protein complexes among genome-wide RNA interference data sets that used the abundance of phosphorylated extracellular signal-regulated kinase in cells stimulated with either insulin or epidermal growth factor as the output. The analysis predicted that the Brahma complex participated in the insulin response. PMID- 23443687 TI - Tunability of aluminum nitride acoustic resonators: a phenomenological approach. AB - A phenomenological approach is developed to identify the physical parameters causing the dc-voltage-induced tunability of aluminum nitride (AlN) acoustic resonators, widely used for RF filters. The typical resonance frequency of these resonators varies from 2.038 GHz at -200 V to 2.062 GHz at +200 V. This indicates, based on these RF measurements versus dc bias and the model used, that the AlN stiffness variation versus dc bias is the prominent effect because both resonance and antiresonance experience a similar variation, respectively, 24 MHz and 19 MHz at 400 V. Picosecond ultrasonics were also used to prove independently that the acoustic velocity (and therefore AlN stiffness) is sensitive to dc bias and that the variation induced is comparable to that extracted from the resonance measurements. It turned out that the stiffness relative variation for an electric field of 1 V/MUm extracted from picosecond ultrasonics is 54 ppm-MUm/V. This is in good agreement with the value extracted from the RF measurements, namely 57.2 ppm-MUm/V. The overall tunability of these AlN resonators reaches 1.1%, which is an interesting figure, although probably not high enough for genuine applications. PMID- 23443688 TI - High-precision impedance spectroscopy: a strategy demonstrated on PZT. AB - Electrochemical impedance spectroscopy (EIS) has been recognized as a very powerful tool for studying charge and mass transport and transfer in a wide variety of electrically or electrochemically active systems. Sophisticated modeling programs make it possible to extract parameters from the impedance data, thus contributing to a better understanding of the system or material properties. For an accurate analysis, a correct modeling function is needed; this is often in the form of an equivalent circuit. It is not always possible to define the modeling function from visual inspection of the impedance dispersion. Small contributions to the overall dispersion can be masked, and hence overlooked. In this publication, a strategy is presented for high-precision impedance data analysis. A Kramers-Kronig test is used for the essential data validation. An iterative process of partial analysis and subtraction assists in deconvoluting the impedance spectrum, yielding both a vi- able model function and a set of necessary starting values for the full complex nonlinear least squares (CNLS) modeling. The advantage and possibilities of this strategy are demonstrated with an analysis of the ionic and electronic conductivity of lead zirconate titanate (PZT) as functions of temperature and oxygen partial pressure. PMID- 23443689 TI - Microwave dielectric properties of (Mg(1-x)Cox)2SnO4 ceramics for application in dual-band inverted-E-shaped monopole antenna. AB - The microwave dielectric properties of (Mg((1-x))Co(x))(2)SnO(4) ceramics were examined with a view to their exploitation for mobile communication. The (Mg((1 x))Co(x))(2)SnO(4) ceramics were prepared by the conventional solid-state method with various sintering temperatures. The X-ray diffraction patterns of the (Mg((1 x))Co(x))(2)SnO(4) ceramics revealed no significant variation of phase with sintering temperatures. Specimens were not single-phase materials; small amounts of MgO and SnO(2) as the second phases were observed in all specimens. A dielectric constant (epsilon(tau)) of 8.8, a quality factor (Q * f) of 110800 GHz (at 16.4 GHz), and a temperature coefficient of resonant frequency (tau(f)) of 66 ppm/ degrees C were obtained for(Mg(0.93)Co(0.07))(2)SnO(4) ceramics that were sintered at 1550 degrees C for 4 h. The proposed dual-band co-planar waveguide (CPW)-fed inverted-E-shaped monopole covered the industrial, scientific, medical (ISM), high-performance radio local area network (HIPERLAN), and unlicensed national information infrastructure (UNII) bands. A 13.62% bandwidth (return loss <;10 dB) of 2.43 GHz, and a 20.69% bandwidth (return loss <;10 dB) of 5.38 GHz was successfully achieved. PMID- 23443690 TI - Polyvinylidene fluoride film sensors in collocated feedback structural control: application for suppressing impact-induced disturbances. AB - Polyvinylidene fluoride (PVDF) films are light, flexible, and have high piezoelectricity. Because of these advantages, they have been widely used as sensors in applications such as underwater investigation, nondestructive damage detection, robotics, and active vibration suppression. PVDF sensors are especially preferred over conventional strain gauges in active vibration control because the PVDF sensors are easy to cut into different sizes or shapes as piezoelectric actuators and they can then be placed as collocated pairs. In this work, to focus on demonstrating the dynamic sensing performance of the PVDF film sensor, we revisit the active vibration control problem of a cantilever beam using a collocated lead zirconate titanate (PZT) actuator/PVDF film sensor pair. Before applying active vibration control, the measurement characteristics of the PVDF film sensor are studied by simultaneous comparison with a strain gauge. The loading effect of the piezoelectric actuator on the cantilever beam is also investigated in this paper. Finally, four simple, robust active vibration controllers are employed with the collocated PZT/PVDF pair to suppress vibration of the cantilever beam subjected to impact loadings. The four controllers are the velocity feedback controller, the integral resonant controller (IRC), the resonant controller, and the positive position feedback (PPF) controller. Suppression of impact disturbances is especially suitable for the purpose of demonstrating the dynamic sensing performance of the PVDF sensor. The experimental results also provide suggestions for choosing between the previously mentioned controllers, which have been proven to be effective in suppressing impact-induced vibrations. PMID- 23443691 TI - Effects of improved process for CuO-doped NKN lead-free ceramics on high-power piezoelectric transformers. AB - In this paper, the effects of the electrical proper- ties of CuO-doped (Na(0.5)K(0.5))NbO(3) (NKN) ceramics prepared separately using the B-site oxide precursor method (BO method) and conventional mixed-oxide method (MO method) on high-power piezoelectric transformers (PTs) were investigated. The performances of PTs made with these two substrates were compared. Experimental results showed that the output power and temperature stability of PTs could be enhanced because of the lower resonant impedance of the ceramics prepared using the BO method. In addition, the output power of PTs was more affected by the resonant impedance than by the mechanical quality factor (Q(m)) of the ceramics. The PTs fabricated with ceramics prepared using the BO method showed a high efficiency of more than 94% and a maximum output power of 8.98 W (power density: 18.3 W/cm(3)) with temperature increase of 3 degrees C under the optimum load resistance (5 kOmega) and an input voltage of 150 V(pp). This output power of the lead-free disk-type PTs is the best reported so far. PMID- 23443692 TI - Modeling and identification of Rosen-type transformer in nonlinear behavior. AB - This paper is about the modeling of piezoelectric transformer in nonlinear behavior conditions. In the frame of applications with high output loads, nonlinear behavior be comes non-negligible. First, the origins of nonlinearities and theoretical approaches are preliminarily discussed. Then, the model is developed for a typical Rosen-type transformer and experimental investigations are presented. The results are used to confirm the validity of the analytical model and the methodology to express the terms added to the typical constitutive piezoelectric relations. PMID- 23443693 TI - Study and comparison of different EMAT configurations for SH wave inspection. AB - Guided wave inspection has proven to be a very effective method for the rapid inspection of large structures. The fundamental shear horizontal (SH) wave mode in plates and the torsional mode in pipe-like structures are especially useful because of their non-dispersive character. Guided waves can be generated by either piezoelectric transducers or electro- magnetic acoustic transducers (EMATs), and EMATs can be based on either the Lorentz force or magnetostriction. Several EMAT configurations can be used to produce SH waves, the most common being Lorentz-force periodic permanent magnet and magnetostrictive EMATs, the latter being directly applied on the sample or with a bonded strip of highly magnetostrictive material on the plate. This paper compares the performance of these solutions on steel structures. To quantitatively assess the wave amplitude produced by different probes, a finite element model of the elementary transducers has been developed. The results of the model are experimentally validated and the simulations are further used to study the dependence of ultrasonic wave amplitude on key design parameters. The analysis shows that magnetostrictive EMATs directly applied on mild steel plates have comparatively poor performance that is dependent on the precise magneto-mechanical properties of the test object. Periodic permanent magnet EMATs generate intermediate wave amplitudes and are noncontact and insensitive to the variations in properties seen across typical steels. Large signal amplitudes can be achieved with magnetostrictive EMATs with a layer of highly magnetostrictive material attached between the transducer and the plate, but this compromises the noncontact nature of the transducer. PMID- 23443694 TI - Planar-waveguide external cavity laser stabilization for an optical link with 10( 19) frequency stability. AB - We stabilized the frequency of a compact planar-waveguide external cavity laser (ECL) on a Fabry-Perot cavity (FPC) through a Pound-Drever-Hall scheme. The residual frequency stability of the ECL is 10(-14), comparable to the stability achievable with a fiber laser (FL) locked to an FPC through the same scheme. We set up an optical link of 100 km, based on fiber spools, that reaches 10(-19) relative stability, and we show that its performances using the ECL or FL are comparable. Thus ECLs could serve as an excellent replacement for FLs in optical links where cost-effectiveness and robustness are important considerations. PMID- 23443695 TI - Frequency shifts in plate crystal resonators induced by electric, magnetic, or mechanical fields in surface films. AB - We study frequency shifts in plate crystal resonators with surface films. The films are multiphysical, including the effects of inertia, stiffness, intrinsic stress, piezoelectric coupling, and piezomagnetic coupling. Mindlin's two dimensional equations for a crystal plate with two elastic surface films are generalized to include the multiphysical effects of the films. They are used to study thickness-shear vibrations of a rotated Y-cut quartz plate with initial fields resulting from the mechanical, electric, and magnetic fields in the surface films. Frequency shifts caused by the initial fields are calculated and examined. Results show that plate crystal resonators with multiphysical surface films may be used for electric/magnetic field sensing. PMID- 23443696 TI - Optimizing circular ring arrays for forward-looking IVUS imaging. AB - Forward-looking (FL) catheter-based imaging systems are highly desirable for guiding interventions in intra- vascular ultrasound (IVUS) applications. One of the main challenges of array-based FL-IVUS systems is the large channel count, which results in increased system complexity. Synthetic phased-array processing with a reduced firing count simplifies the front-end and, hence, can enable 3-D real-time imaging. Recently, we have investigated dual-ring arrays suitable for IVUS imaging, in which the two concentric circular arrays are used separately as transmit (Tx) and receive (Rx) arrays. In this study, we present different optimized array designs based on dual and single circular rings which are suitable for synthetic phased-array processing with a reduced number of firings. To obtain an optimal firing set that produces low side lobes in the wideband response, we use a simulated annealing algorithm. In the simulations, we use 1.2 mm-diameter array configurations with 64 Tx and 58 Rx elements, a center frequency of 20 MHz and fractional bandwidths of 50% and 80%. The results show that optimized dual-ring arrays provide 8 dB improvements in peak near side-lobe level with no widening in the main lobe width when compared with full and other sparse co-arrays. PMID- 23443697 TI - Shearwave dispersion ultrasound vibrometry (SDUV) on swine kidney. AB - Shearwave dispersion ultrasound vibrometry (SDUV) is used to quantify both tissue shear elasticity and shear viscosity by evaluating dispersion of shear wave propagation speed over a certain bandwidth (50 to 500 Hz). The motivation for developing elasticity imaging techniques is the desire to diagnose disease processes. However, it is important to study the mechanical properties of healthy tissues; such data can enhance clinical knowledge and improve understanding of the mechanical properties of tissue. The purpose of this study is to evaluate the feasibility of using SDUV for in vitro measurements of renal cortex shear elasticity and shear viscosity in healthy swine kidneys. Eight excised kidneys from female pigs were used in these in vitro experiments and a battery of tests was performed to gain insight into the material proper ties of the renal cortex. In these 8 kidneys, the overall renal cortex elasticity and viscosity were 1.81 +/- 0.17 kPa and 1.48 +/- 0.49 Pa-s, respectively. In an analysis of the material properties over time after excision, there was not a statistically significant difference in shear elasticity over a 24-h period, but a statistically significant difference in shear viscosity was found. Homogeneity of the renal cortex was examined and it was found that shear elasticity and shear viscosity were statistically different within a kidney, suggesting global tissue inhomogeneity. In creases of more than 30% in shear elasticity and shear viscosity were observed after immersion in 10% formaldehyde. Finally, it was found that the renal cortex is rather anisotropic. Two values for shear elasticity and shear viscosity were measured depending on shear wave propagation direction. These various tests elucidated different aspects of the material properties and the structure of the ex vivo renal cortex. PMID- 23443698 TI - Stand-alone front-end system for high- frequency, high-frame-rate coded excitation ultrasonic imaging. AB - A stand-alone front-end system for high-frequency coded excitation imaging was implemented to achieve a wider dynamic range. The system included an arbitrary waveform amplifier, an arbitrary waveform generator, an analog receiver, a motor position interpreter, a motor controller and power supplies. The digitized arbitrary waveforms at a sampling rate of 150 MHz could be programmed and converted to an analog signal. The pulse was subsequently amplified to excite an ultrasound transducer, and the maximum output voltage level achieved was 120 V(pp). The bandwidth of the arbitrary waveform amplifier was from 1 to 70 MHz. The noise figure of the preamplifier was less than 7.7 dB and the bandwidth was 95 MHz. Phantoms and biological tissues were imaged at a frame rate as high as 68 frames per second (fps) to evaluate the performance of the system. During the measurement, 40-MHz lithium niobate (LiNbO(3)) single-element lightweight (<;0.28 g) transducers were utilized. The wire target measure- ment showed that the -6-dB axial resolution of a chirp-coded excitation was 50 MUm and lateral resolution was 120 MUm. The echo signal-to-noise ratios were found to be 54 and 65 dB for the short burst and coded excitation, respectively. The contrast resolution in a sphere phantom study was estimated to be 24 dB for the chirp-coded excitation and 15 dB for the short burst modes. In an in vivo study, zebrafish and mouse hearts were imaged. Boundaries of the zebrafish heart in the image could be differentiated because of the low-noise operation of the implemented system. In mouse heart images, valves and chambers could be readily visualized with the coded excitation. PMID- 23443699 TI - A hybrid CPU-GPGPU approach for real-time elastography. AB - Ultrasound elastography is becoming a widely available clinical imaging tool. In recent years, several real- time elastography algorithms have been proposed; however, most of these algorithms achieve real-time frame rates through compromises in elastographic image quality. Cross-correlation- based elastographic techniques are known to provide high- quality elastographic estimates, but they are computationally intense and usually not suitable for real time clinical applications. Recently, the use of massively parallel general purpose graphics processing units (GPGPUs) for accelerating computationally intense operations in biomedical applications has received great interest. In this study, we investigate the use of the GPGPU to speed up generation of cross correlation-based elastograms and achieve real-time frame rates while preserving elastographic image quality. We propose and statistically analyze performance of a new hybrid model of computation suitable for elastography applications in which sequential code is executed on the CPU and parallel code is executed on the GPGPU. Our results indicate that the proposed hybrid approach yields optimal results and adequately addresses the trade-off between speed and quality. PMID- 23443700 TI - Development of integrated preamplifier for high-frequency ultrasonic transducers and low-power handheld receiver. AB - This paper describes the design of a front-end circuit consisting of an integrated preamplifier with a Sallen-Key Butterworth filter for very-high frequency ultrasonic transducers and a low-power handheld receiver. This preamplifier was fabricated using a 0.18-MUm 7WL SiGe bi-polar complementary metal oxide semiconductor (BiCMOS) process. The Sallen-Key filter is used to increase the voltage gain of the front-end circuit for high-frequency transducers which are generally low in sensitivity. The measured peak voltage gain of the frontend circuits for the BiCMOS preamplifier with the Sallen-Key filter was 41.28 dB at 100 MHz with a-6-dB bandwidth of 91%, and the dc power consumption of the BiCMOS preamplifier was 49.53 mW. The peak voltage gain of the front-end circuits for the CMOS preamplifier with the Sallen-Key filter was 39.52 dB at 100 MHz with a-6-dB bandwidth of 108%, and the dc power consumption of the CMOS preamplifier was 43.57 mW. Pulse-echo responses and wire phantom images with a single-element ultrasonic transducer have been acquired to demonstrate the performance of the front-end circuit. PMID- 23443701 TI - Monolithic CMUT-on-CMOS integration for intravascular ultrasound applications. AB - One of the most important promises of capacitive micromachined ultrasonic transducer (CMUT) technology is integration with electronics. This approach is required to minimize the parasitic capacitances in the receive mode, especially in catheter-based volumetric imaging arrays, for which the elements must be small. Furthermore, optimization of the available silicon area and minimized number of connections occurs when the CMUTs are fabricated directly above the associated electronics. Here, we describe successful fabrication and performance evaluation of CMUT arrays for intravascular imaging on custom-designed CMOS receiver electronics from a commercial IC foundry. The CMUT-on-CMOS process starts with surface isolation and mechanical planarization of the CMOS electronics to reduce topography. The rest of the CMUT fabrication is achieved by modifying a low-temperature micromachining process through the addition of a single mask and developing a dry etching step to produce sloped sidewalls for simple and reliable CMUT-to-CMOS interconnection. This CMUT-to-CMOS interconnect method reduced the parasitic capacitance by a factor of 200 when compared with a standard wire-bonding method. Characterization experiments indicate that the CMUT on-CMOS elements are uniform in frequency response and are similar to CMUTs simultaneously fabricated on standard silicon wafers without electronics integration. Ex- periments on a 1.6-mm-diameter dual-ring CMUT array with a center frequency of 15 MHz show that both the CMUTs and the integrated CMOS electronics are fully functional. The SNR measurements indicate that the performance is adequate for imaging chronic total occlusions located 1 cm from the CMUT array. PMID- 23443702 TI - Forward problem study of an effective medium model for ultrasound blood characterization. AB - The structure factor model (SFM) is a scattering model developed to simulate the backscattering coefficient (BSC) of aggregated red blood cells (RBCs). However, the SFM can hardly be implemented to estimate the structural aggregate parameters in the framework of an inverse problem formulation. A scattering model called the effective medium theory combined with the SFM (EMTSFM) is thus proposed to approximate the SFM. The EMTSFM assumes that aggregates of RBCs can be treated as individual homogeneous scatterers, which have effective properties determined by the acoustical characteristics and concentration of RBCs within aggregates. The EMTSFM parameterizes the BSC by three indices: the aggregate radius, the concentration of RBCs with- in aggregates (the aggregate compactness), and the systemic hematocrit. The goodness of fit of the EMTSFM approximation in comparison with the SFM was then examined. Based on a 2-D study, the EMTSFM was found to approximate the SFM with relative errors less than 30% for a product of the wavenumber times the mean aggregate radius krLambdakappa <; 1.32. The main contribution of this work is the parameterization of the BSC with the RBC aggregate compactness, which is of relevance in clinical hemorheology because it reflects the binding energy between RBCs. PMID- 23443703 TI - Automatic contrast enhancement using ensemble empirical mode decomposition. AB - Ultrasound nonlinear contrast imaging using microbubble-based contrast agents has been widely investigated. However, the degree of contrast enhancement is often limited by overlap between the spectra of the tissue and microbubble nonlinear responses, which makes it difficult to separate them. The use of ensemble empirical mode decomposition (EEMD) in the Hilbert-Huang transform (HHT) was previously explored with the aim of alleviating this problem. The HHT is designed for analyzing nonlinear and nonstationary data, whereas EEMD is a method associated with the HHT that allows decomposition of data into a finite number of intrinsic mode functions (IMFs). It was found that the contrast can be effectively improved in certain IMFs, but manual selection of appropriate IMFs is still required. This prompted the present study to test the hypothesis that the contrast can be enhanced without requiring manual selection by summing appropriately weighted IMFs and demodulating the signal at appropriate frequencies. That is, a data-driven mechanism for determining weights and demodulation frequencies was derived and tested. Phantom results show that an overall contrast enhancement of up to 12.5 dB can be achieved. A fused-image representation that simultaneously displays the conventional B-mode image and the new contrast-mode image is also presented. PMID- 23443704 TI - Shear-horizontal wave-based pipe damage inspection by arrays of segmented magnetostrictive patches. AB - The lowest-branch torsional guided wave is very effective in pipe damage inspection because of its non-dispersive characteristics, but it cannot be used for the simultaneous identification of axial and circumferential locations of a defect in a pipe. Motivated by recent developments in magnetostrictive transducer technology, which is especially efficient in torsional and shear wave generation, the goal of this investigation is to extend this technology for simultaneous identification of the axial and circumferential locations of cracks by using shear horizontal (SH) waves. Unlike the conventional magnetostrictive patch method using a single complete patch wound around the pipe's circumference, the proposed method segments the patch into several pieces to generate SH waves propagating over the pipe surface. Accordingly, SH waves in a pipe are generated and sensed individually by a meander coil placed separately on each segment. By using two sets of segmented-patch arrays separated by some distance, the cylindrical surface of a pipe can be inspected both axially and circumferentially. After the underlying angular profile of the patch segment is investigated, experiments identifying the axial and circumferential locations of multiple cracks in a pipe are carried out to demonstrate the potential of the proposed methodology. PMID- 23443706 TI - Analyses of the temperature field of traveling-wave rotary ultrasonic motors. AB - In this paper, the transient and steady-state temperature field of a traveling wave rotary ultrasonic motor is analyzed by the finite element method, based on a theoretical model of power loss of this motor in rated operation. Using this model, the temperature field of this motor is calculated and the effects of the heat conductivity of friction material, motor size, ambient temperature, and pressure on the temperature field are estimated. The calculated temperature distribution and transient temperature change agree with the experimental results. The variation of heat conductivity of the friction material has little effect on the minimum temperature in the motor but this variation seriously affects the maximum temperature in the motor when the heat conductivity of the friction material is lower than 0.5 W/(m degrees C). Two indices are defined to express the non-uniformity of temperature field and how quickly the temperature field reaches its steady state for traveling-wave ultrasonic motors of different sizes. It is found that traveling-wave ultrasonic motors with different sizes have different nonuniformity of temperature field and take different amounts of time to reach thermal steady state. The maximum temperature rise is lower when the ambient temperature is higher; the maximum temperature increases as the vacuum degree increases and it is not affected by the vacuum degree when the vacuum degree is too high (<10(-3) Pa). PMID- 23443705 TI - Broadband electrical impedance matching for piezoelectric ultrasound transducers. AB - This paper presents a systematic method for designing broadband electrical impedance matching networks for piezoelectric ultrasound transducers. The design process involves three steps: 1) determine the equivalent circuit of the unmatched piezoelectric transducer based on its measured admittance; 2) design a set of impedance matching networks using a computerized Smith chart; and 3) establish the simulation model of the matched transducer to evaluate the gain and bandwidth of the impedance matching networks. The effectiveness of the presented approach is demonstrated through the design, implementation, and characterization of impedance matching networks for a broadband acoustic emission sensor. The impedance matching network improved the power of the acquired signal by 9 times. PMID- 23443707 TI - Three-dimensional variable-focus liquid lens using acoustic radiation force. AB - A liquid lens was fabricated with a focal point that can be varied in the axial and radial directions. We have been developing a variable-focus liquid lens that employs acoustic radiation force and does not contain any mechanical moving parts. Our liquid lens is more compact and has a faster response than conventional mechanical lenses. Rapid scanning of its focus at 1 kHz has been realized by excitation with an amplitude-modulation (AM) signal. The liquid lens consists of a cylindrical acrylic cell (inner diameter: 10 mm; thickness: 3 mm), two immiscible liquids with different refractive indices (water and silicone oil), and an annular piezoelectric lead zirconate titanate transducer with four electrodes. The oil-water interface functions as a lens surface and it can be deformed by the acoustic radiation force generated by the transducer; this enables the lens to act as a variable-focus lens. The variation of the oil-water interface was observed by optical coherence tomography. The laser beam path through the lens was calculated by ray-tracing simulations. The oil-water interface could be deformed and its focal point could be varied in three dimensions by controlling the input voltages of the PZT electrodes. The displacement angle in the radial direction was approximately 3 degrees when two of the electrodes were excited by an input voltage of 45 V at a frequency of 1.9 MHz. The dynamic performance of the lens was investigated using a high-speed cam- era. Excitation by AM signals with a phase difference caused the hemispherical water droplet to oscillate, enabling the focus to be scanned in the axial and radial directions. PMID- 23443708 TI - Transverse waveguide mode suppression for Pt-electrode SAW resonators on quartz and LGS. AB - SAW resonators on ST-X quartz and langasite (LGS) [0 degrees , 144 degrees , 24 degrees ] are currently being used for hydrogen fluoride (HF) vapor sensing and high-temperature sensing, respectively. For these applications, the use of Pt based electrodes allows the resonators to withstand the targeted harsh environments. This work reveals that for Pt-electrode resonators with conventional short-circuit gratings on the aforementioned quartz and LGS orientations, acoustic energy leaks from the grating region to the bus bars, thus degrading the resonator response. To resolve this problem, this paper proposes and implements open-circuit gratings for resonators fabricated with these substrate/metal combinations. The open-circuit gratings guide the acoustic energy within the grating region, resulting in greater quality factors and reduced losses in the resonator response. In addition, scalar potential theory is utilized in this work to identify transverse waveguide modes in the responses of open-circuit grating resonators on quartz and LGS. A transverse waveguide mode dispersion relation was derived to extend the scalar potential theory to account for asymmetry in the slowness curve around the propagation direction. This is the case for several commonly used LGS orientations, in particular LGS [0 degrees , 144 degrees , 24 degrees ]. Finally, this work addresses spurious transverse mode mitigation by scaling both the transducer's grating aperture and electrode overlap width. Open circuit grating resonators with appropriately scaled transducer designs were fabricated and tested, resulting in a 71% increase in quality factor and a spurious mode rejection of over 26 dBc for Pt-electrode devices on ST-X quartz. This progress directly translates into better frequency resolution and increased dynamic range for HF vapor sensors and high-temperature SAW devices. PMID- 23443709 TI - A piezoelectric single-crystal ultrasonic microactuator for driving optics. AB - At the millimeter scale, the motions or force out puts generated by conventional piezoelectric, magnetostrictive, photostrictive, or electromagnetic actuators are very limited. Here, we report a piezoelectric ultrasonic microactuator (size: 1.5 * 1.5 * 5 mm, weight: 0.1 g) made of PIN-PMN-PT single crystal. The actuator converts its high-frequency microscopic displacements (nanometer to micrometer scale) into a macro scopic, centimeter-scale linear movement of a slider via frictional force, resulting in a speed up to 50 mm/s and a very high unit volume direct driving force of 26 mN/mm(3) (which is ~100 times higher than a voice coil motor and ~4 times higher than a piezoceramic ultrasonic motor). This work shows the feasibility of using piezoelectric single-crystal-based ultrasonic microactuator for miniature drive of optics in next-generation mobiles and cameras. PMID- 23443710 TI - Characterization of an epoxy filler for piezocomposites compatible with microfabrication processes. AB - Miniature ultrasound transducer arrays that can operate at frequencies above 30 MHz are needed for high-resolution medical imaging. One way to achieve this is with a kerfless structure based on 1-3 connectivity piezocomposite with the electrodes defined by photolithography. To achieve this, not only does the composite need planar, parallel, and smooth surfaces, but it must also be made with an epoxy filler compatible with the chemicals, heat, and vacuum required for photolithography. This paper reports full characterization of an epoxy suitable for fine-scale kerfless array fabrication, including photolithographic processing. Material properties have been investigated as a function of cure temperature and for compatibility with solvents. By increasing the cure temperature, the crosslinking between the epoxy and the hardener in- creases, resulting in a higher glass transition temperature. The cured epoxy consequently has better resistance to both heat and solvents. An elevated cure temperature, near 100 degrees C, is required to optimize material properties for photolithography on 1-3 piezocomposites. The acoustic properties of the epoxy have also been studied. These are similar to other epoxies used in piezocomposite fabrication and no significant changes have been observed for the different cure temperatures. PMID- 23443711 TI - FEA modeling of CMUT with membrane stand-off structures to enable selectable frequency-mode operation. AB - A selectable, dual-frequency, capacitive micro- machined ultrasonic transducer (CMUT) designed for both high-frequency imaging and low-frequency therapeutic effect is presented. A validated finite element analysis (FEA) CMUT model was used to examine the performance of the proposed dual-frequency transducer. CMUT device simulations were used to design a hybrid device incorporating stand-off structures that divide a large, low-frequency membrane into smaller, high frequency sub-membranes when the membrane is partially collapsed so that the stand-offs contact the substrate. In low-frequency operation, simulations indicated that the peak negative pressure achieved by the hybrid device, when biased by 30.0 VDC and excited by a 2-MHz signal with 30.0 V amplitude, exceeded 190 kPa, which is sufficient for microbubble rupture. Low-frequency mode bandwidth was 93% at a center frequency of 2.1 MHz. In the high-frequency mode of operation, the device was excited by 175 Vdc and 87.5 Vac, which generated a peak negative pressure of 247 kPa. Device center frequency was 44.1 MHz with a - 6-dB fractional bandwidth of 42%. PMID- 23443712 TI - Temperature dependence of elastic properties and piezoelectric applications of BaTeMo2O9 single crystal. AB - BaTeMo(2)O(9) (BTM) single crystal, as a lead-free piezoelectric material, belongs to the monoclinic system, space group P2(1). We report the temperature dependence of the elastic constants by the transmission method over the range -50 degrees C to 150 degrees C. The first-order temperature coefficients of the elastic constant s(44) is about 180 * 10(-6)/ degrees C. Piezoelectric resonators based on BTM crystal using the thickness-stretching vibration and the shear vibration modes were designed and evaluated, which eliminated or minimized the influence of the off-principal axis coefficients. The Q(m) of one of the resonators is about 600. Our results show that the elastic constants have good temperature stability, and the resonators have already met the requirements for some piezoelectric applications. This study on the BTM crystal has revealed the application for the low-symmetry crystal. PMID- 23443713 TI - A few transient effects in AT-cut quartz thickness-shear resonators. AB - We study a few transient effects of AT-cut quartz thickness-shear resonators, including resonator turning on and turning off as well as voltage amplitude and frequency fluctuations. Mindlin's two-dimensional plate equations are used and solved analytically. Both a sudden change and a gradual change of the driving voltage are studied. It is found that for a resonator with a frequency of 1.649430868 MHz and material quality factor of Q = 105, the characteristic time scale of the transient effects is of the order of 0.1 s. PMID- 23443714 TI - Thickness-twist and face-shear waves in piezoelectric plates of monoclinic crystals. AB - We study the propagation of thickness-twist and face-shear waves in piezoelectric plates of monoclinic crystals, which include rotated Y-cut quartz and langasite as special cases. The equations of linear piezoelectricity are used. Exact solutions are obtained for both fully-electroded and unelectroded plates. Dispersion relations are plotted for both AT-cut quartz and Y-cut langasite plates. The difference in frequencies between the exact piezoelectric solutions obtained in the present paper and the approximate elastic solutions in the literature is found to be of the order of 1%, which is significant in acoustic wave resonator and sensor applications. PMID- 23443715 TI - Tunable bulk acoustic wave resonators based on Ba0.25Sr0.75TiO3 thin films and a HfO2/SiO2 bragg reflector. AB - A switchable and tunable bulk acoustic wave resonator based on a paraelectric phase Ba(0.25)Sr(0.75)TiO(3) thin film and an all-dielectric HfO(2)/SiO(2) Bragg reflector is presented. The achieved tuning range (3.8%) and effective electromechanical coupling coefficient (7.1%) are the highest reported for solidly mounted tunable bulk acoustic wave resonators. The non-conductive Bragg reflector stack provides excellent integration possibilities. PMID- 23443716 TI - Ultrasound speed varies in articular cartilage under indentation loading. AB - In ultrasound elastography, tissue strains are determined by localizing changes in ultrasound echoes during mechanical loading. The technique has been proposed for arthroscopic quantification of the mechanical properties of cartilage. The accuracy of ultrasound elastography depends on the invariability of sound speed in loaded tissue. In unconfined geometry, mechanical compression has been shown to induce variation in sound speed, leading to errors in the determined mechanical properties. This phenomenon has not been confirmed in indentation geometry, the only loading geometry applicable in situ or in vivo. In the present study, ultrasound speed during indentation of articular cartilage was characterized and the effect of variable sound speed on the strain measurements was investigated. Osteochondral samples (n = 7, diameter = 25.4 mm), prepared from visually intact bovine patellae (n = 7), were indented with a plane-ended ultrasound transducer (diameter = 5.6 mm, peak frequency: 8.1 MHz). A sequence of three compression tests (strain-rate = 10%/s, 2700-s relaxation) was applied using the mean strains of 2.2%, 4.5%, and 6.4%. Then, ultrasound speed during the ramp and stress-relaxation phases was determined using the time-of- flight technique. To investigate the role of cartilage structure and composition for sound speed in loaded articular cartilage, a sample-specific fibril-reinforced poroviscoelastic (FRPVE) finite element model was constructed and fitted to experimental mechanical data. Ultrasound speed in articular cartilage decreased significantly during dynamic indentation (p <; 0.05). The magnitude of the decrease in speed during indentation was related to the applied strain. However, the relative error in acoustically determined tissue strain was inversely related to the magnitude of true strain. The modeling results suggested that the compression-related variation in sound speed is controlled by changes in the collagen architecture during dynamic indentation. To conclude, variation in sound speed during dynamic indentation of articular cartilage may lead to significant errors in the values of measured mechanical parameters. Because the relative errors are inversely proportional to applied strain, higher strains should be used to minimize the errors in, e.g., in vivo measurements. PMID- 23443717 TI - Electrospinning-thermal treatment synthesis: a general strategy to decorate highly porous nanotubes on both internal and external side-walls with metal oxide/noble metal nanoparticles. AB - The hybrid structure of nanoparticle-decorated highly porous nanotubes combines the advantages of large specific surface areas of nanoparticles and anisotropic properties of highly porous nanotubes, which is desirable for many applications, including batteries, photoelectrochemical water splitting, and catalysis. Here, we report a novel emulsion electrospinning-thermal treatment method to synthesize the nanoparticles deposited on both side walls of nanotubes with two unique characteristics: (1) large loading amount of nanoparticles per highly porous nanotubes (with the morphology of nanoparticles); (2) intimate contact between nanoparticles and highly porous nanotubes. Both features are advantageous for the above applications that involve both surface reactions and charge transportation processes. Moreover, the emulsion electrospinning-thermal treatment method is simple and straightforward, with which we have successfully decorated various highly porous metal oxide nanotubes with metal oxide or noble metal nanoparticles. The new method will have an impact on diverse technologies such as lithium ion batteries, catalysts, and photoelectrochemical devices. PMID- 23443718 TI - Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. AB - Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Delta(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. The FDA-approved synthetic analog of THC, nabilone, has higher bioavailability and clearer dose-linearity than dronabinol. This study tested whether nabilone administration would decrease marijuana withdrawal symptoms and a laboratory measure of marijuana relapse relative to placebo. Daily, nontreatment-seeking marijuana smokers (8 men and 3 women), who reported smoking 8.3+/-3.1 marijuana cigarettes/day completed this within-subject study comprising three, 8-day inpatient phases; each phase tested a different nabilone dose (0, 6, 8 mg/day, administered in counter-balanced order on days 2-8). On the first inpatient day, participants took placebo capsules and smoked active marijuana (5.6% THC) at six timepoints. For the next 3 days, they had the opportunity to self-administer placebo marijuana (0.0% THC; withdrawal), followed by 4 days in which active marijuana was available for self administration (5.6% THC; relapse). Both nabilone dose conditions decreased marijuana relapse and reversed withdrawal-related irritability and disruptions in sleep and food intake (p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task performance. Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment. PMID- 23443719 TI - Adolescent stimulation of D2 receptors alters the maturation of dopamine dependent goal-directed behavior. AB - Adolescence is a period of high sensitivity to drugs and rewards, characterized by the immaturity of decision-making abilities. A chronic stimulation of reward systems during this period might constitute a factor of vulnerability to the development of psychiatric disorders. However, the long-term consequences of such an exposure have seldom been explored. Here, we investigate at the adult age the effects of chronic dopamine (DA) stimulation during adolescence on both the maturation of DA systems and the cognitive processes underlying goal-directed actions. We first demonstrate that chronic stimulation of D2 receptors by quinpirole during adolescence alters the development of DA systems. This treatment has particularly prominent effects on the mesocortical DA pathway where it decreases DA fibers density, DA concentration, and DA receptors expression. Furthermore, we show that quinpirole-treated rats exhibit specific impairments in instrumental goal-directed behavior, as they fail to adapt their action when action-outcome relationships change in a contingency degradation procedure. These results therefore highlight the vulnerability of DA system and prefrontal areas to prolonged stimulation during adolescence, and its potential long-term impact on cognitive functions. PMID- 23443721 TI - Oxidative stress response of Blakeslea trispora induced by iron ions during carotene production in shake flask culture. AB - The adaptive response of the fungus Blakeslea trispora to the oxidative stress induced by iron ions during carotene production in shake flask culture was investigated. The culture response to oxidative stress was studied by measuring the specific activities of catalase (CAT) and superoxide dismutase (SOD). The addition of 1.0 mM of FeCl3 to the medium was associated with a mild oxidative stress as evidenced by remarkable increase of the specific activities of SOD and CAT. On the other hand, the addition 5.0 mM of FeCl3 caused a strong oxidative stress resulting in a drastic decrease in carotene concentration. The oxidative stress in B. trispora changed the composition of the carotenes and caused a significant increase of gamma-carotene ratio. The highest concentration of carotenes (115.0 +/- 3.5 mg/g dry biomass) was obtained in the basal medium without the addition of FeCl3 after 8 days of fermentation. In this case, the carotenes consisted of beta-carotene (46.3 %), gamma-carotene (40.1 %), and lycopene (13.6 %). The addition of 1.0 mM of FeCl3 into the medium did not change the concentration of carotenes. But, the composition of carotenes was changed with a drastic increase of gamma-carotene ratio (61.6 %) and a decrease in beta carotene and lycopene ratio (31.2 and 7.2 %, respectively). PMID- 23443720 TI - Effects of dietary arachidonic acid on cortisol production and gene expression in stress response in Senegalese sole (Solea senegalensis) post-larvae. AB - Dietary fatty acids, particularly arachidonic acid (ARA), affect cortisol and may influence the expression of genes involved in stress response in fish. The involvement of ARA on stress, lipid, and eicosanoid metabolism genes, in Senegalese sole, was tested. Post-larvae were fed Artemia presenting graded ARA levels (0.1, 0.4, 0.8, 1.7, and 2.3%, dry matter basis), from 22 to 35 days after hatch. Whole-body cortisol levels were determined, before and 3 h after a 2 min air exposure, as well as the expression of phospholipase A2 (PLA 2 ), cyclooxygenase-2 (COX-2), steroidogenic acute regulatory protein (StAR), glucocorticoid receptors (GRs), phosphoenolpyruvate carboxykinase (PEPCK), and peroxisome proliferator-activated receptor alpha (PPARalpha). Relative growth rate (6.0-7.8% day(-1)) and survival at the end of the experiment (91-96%) and after stress (100%) were unaffected. Fish reflected dietary ARA content and post stress cortisol increased with ARA supply up to 1.7%, whereas 2.3% ARA seemed to enhance basal cortisol slightly and alter the response to stress. Results suggested that elevating StAR transcription might not be necessary for a short term response to acute stress. Basal cortisol and PLA 2 expression were strongly correlated, indicating a potential role for this enzyme in steroidogenesis. Under basal conditions, larval ARA was associated with GR1 expression, whereas the glucocorticoid responsive gene PEPCK was strongly related with cortisol but not GR1 mRNA levels, suggesting the latter might not reflect the amount of GR1 protein in sole. Furthermore, a possible role for PPARalpha in the expression of PEPCK following acute stress is proposed. PMID- 23443722 TI - A natural isolate producing shikimic acid: isolation, identification, and culture condition optimization. AB - Shikimic acid has wide use in pharmaceuticals due to its application in the synthesis of drug Tamiflu used in the treatment of Swine flu. The high cost and limited availability of shikimic acid isolated from plants has impeded the use of this valuable building block of the drug. In this context, fermentation route to produce shikimic acid from renewable resources has become increasingly attractive. The present study was embarked upon isolation of wild-type microorganisms able to produce shikimic acid. Out of the 42 isolates obtained from the soil, isolate GR-21 was selected as the best with initial production of 0.54 g/L shikimic acid and later identified as Citrobacter sp. The process optimization resulted in 14-fold increase in the shikimic acid production, thereby claiming this process to be a sustainable alternative for the production of this important biomolecule. The process was further scaled up to 14 L bioreactor to validate the production of shikimic acid. Further, the product formed is shikimic acid was confirmed by FTIR analysis. The current studies suggest that the selected isolate could be used as a promising agent to fulfill the worldwide demand of shikimic acid. PMID- 23443724 TI - New marker of platelet activation, SCUBE1, is elevated in hypertensive patients. AB - BACKGROUND: Hypertension is associated with an increase in platelet activation and endothelial dysfunction and leads to a tendency to cardiovascular events (CVEs). Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) is a novel platelet activation marker. There are currently no studies showing the level of SCUBE1 in hypertensive patients. The purpose of this study was to determine the level of SCUBE1 in this patient group and to investigate the parameters affecting that level. METHODS: Forty-five newly diagnosed, untreated, stage 1 hypertensive patients and 21 healthy individuals were included. Blood specimens were collected to determine SCUBE1, soluble CD40 ligand, prothrombin time, partial thromboplastin time, fibrinogen, D dimer, hemogram, lipid parameters, blood urea nitrogen, creatinine, and uric acid levels. The relation between SCUBE1 level and demographic data and biochemical parameters was then investigated. RESULTS: SCUBE1 and sCD40L levels obtained from plasma specimens from the hypertensive group were significantly higher than those of the control group (P < 0.001; P < 0.05, respectively). Hypertensive group blood pressure (BP) values and uric acid, low-density lipoprotein, total cholesterol, and triglyceride levels were also statistically higher than those of the control group. Parameters affecting SCUBE1 levels were systolic and diastolic BP, sCD40L, lipid parameters, and uric acid levels. CONCLUSIONS: We show elevated levels of SCUBE1, a novel platelet activation marker, in primary hypertensive patients. We think that, when supported by further clinical studies, this newly described marker may be useful in the monitoring of CVEs in this patient group, in which platelet activation is known to be associated with such events. PMID- 23443723 TI - Sildenafil increases sympathetically mediated vascular tone in humans. AB - BACKGROUND: Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men. METHODS: We randomized 9 healthy, middle-aged, male volunteers (mean age 45+/-2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations. RESULTS: Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% +/- 3% vs -63% +/- 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02). CONCLUSIONS: Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil. PMID- 23443725 TI - Low-dose angiotensin II infusion restores vascular function in cerebral arteries of high salt-fed rats by increasing copper/zinc superoxide dimutase expression. AB - BACKGROUND: This study examined the vasoprotective role of circulating angiotensin II (ANG II) levels in the cerebral circulation of high salt (HS)-fed (SS.BN-(D13hmgc41-13hmgc23)/Mcwi) (Ren1-BN) congenic rats, which carry a normally functioning renin allele from the Brown Norway (BN) rat on the Dahl salt sensitive genetic background. METHODS: Ren1-BN rats were placed on an HS (4.0% NaCl) diet for 3 days. The vasodilator response to acetylcholine (ACh; 10(-10) - 10(-6) mol/L) was assessed in isolated middle cerebral arteries (MCAs), and Western blots were performed to assess the expression of the antioxidant enzymes copper (Cu)/zinc (Zn) superoxide dismutase (SOD) and manganese (Mn) SOD in cerebral resistance vessels. A separate group of HS-fed animals were infused with either a subpressor dose of ANG II (100ng/kg/min) or saline vehicle via osmotic minipump for 3 days. RESULTS: HS diet eliminated acetylcholine (ACh)-induced dilation in the MCAs of the congenic rats. Western blot analysis of antioxidant enzymes showed that Cu/Zn SOD and Mn SOD expression were significantly reduced in the cerebral resistance arteries of the HS-fed rats compared with control animals fed a normal salt diet. Infusion of ANG II restored the vasodilator response to ACh in the MCAs and increased Cu/Zn SOD (but not Mn SOD) expression compared with saline-infused animals. CONCLUSIONS: These results indicate that prevention of salt-induced ANG II suppression prevents vascular dysfunction in the cerebral circulation by preventing the downregulation of Cu/Zn SOD and vascular oxidant stress that normally occurs with HS diet. PMID- 23443726 TI - Age-related changes in 11beta-hydroxysteroid dehydrogenase type 2 activity in normotensive subjects. AB - BACKGROUND: Impairment in 11beta-hydroxysteroid dehydrogenase type 2 (11beta HSD2) activity results in inefficient inactivation of cortisol to cortisone, and it can trigger hypertension through activation of the mineralocorticoid receptor. Information about age-related changes in 11beta-HSD2 activity and its physiological consequences is scarce. Our aim was to investigate whether 11beta HSD2 activity is age dependent in normotensive subjects. METHODS: We recruited 196 healthy, normotensive subjects. Of these, 93 were children (Group 1: aged 5 15 years), and 103 were adults who were divided according to their ages: Group 2: aged 30-41 years (n = 10); Group 3: aged 42-53 years (n = 72); and Group 4: aged 54-65 years (n = 21). Fasting serum cortisol, cortisone, aldosterone, and plasma renin activity (PRA) were measured. The 11beta-HSD2 activity was estimated by the cortisol/cortisone ratio. The results were expressed as median (interquartile range (IQR)) values and compared using Kruskal-Wallis and Dunn's multiple comparison tests. RESULTS: As subject age increased, cortisol concentrations increased (Group 1 median = 8.6, IQR = 6.3-10.8 ug/dl; Group 4 median = 12.4, IQR = 10.7-14.7 ug/dl; P < 0.001), and cortisone concentrations showed a gradual decrease (Group 2 median = 4.0, IQR = 3.3-4.2 ug/dl; Group 4 median =2.8, IQR = 2.6-3.3 ug/dl; P < 0.01). As a consequence, the cortisol/cortisone ratio was higher in the oldest subjects (Group 4) than in the subjects from the other 3 groups; the ratios from Group 4 to Group 1 were 4.4 (IQR = 3.7-5.1) ug/dl, 3.3 (IQR = 2.7-3.8) ug/dl, 2.5 (IQR = 2.3-3.8) ug/dl, and 2.7 (IQR = 2.1-3.4) ug/dl, respectively (P < 0.01). The PRA decreased with age. Blood pressure levels increased with age but stayed within the normal range. CONCLUSIONS: Cortisol and the cortisol/cortisone ratio increased with age, but cortisone decreased, suggesting a decrease in 11beta-HSD2 activity. These results suggest that the cortisol-mediated activation of the mineralocorticoid receptor may explain the blood pressure increase in elderly subjects. PMID- 23443727 TI - Common genetic variants in the endothelial system predict blood pressure response to sodium intake: the GenSalt study. AB - BACKGROUND We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP). METHODS After a 3-day baseline examination, during which time the usual diet was consumed, 1,906 Chinese participants received a 7-day low-sodium diet (51.3 mmol of sodium/day) followed by a 7-day high-sodium diet (307.8 mmol of sodium/day). BP measurements were obtained at baseline and at the end of each intervention using a random-zero sphygmomanometer. RESULTS The DDAH1 rs11161637 variant was associated with reduced BP salt sensitivity, conferring attenuated systolic BP (SBP) and mean arterial pressure (MAP) decreases from baseline to the low-sodium intervention (both P = 2*10(-4)). Examination of genotype-sex interactions revealed that this relation was driven by the strong associations observed in men (P for interactions = 1.10*10(-4) and 0.008, respectively). When switching from the low- to high-sodium intervention, increases in diastolic BP (DBP) and MAP were attenuated by the COL18A1 rs2838944 minor A allele (P = 1.41*10(-4) and 1.55*10( 4), respectively). Conversely, the VWF rs2239153 C variant was associated with increased salt sensitivity, conferring larger DBP and MAP reductions during low sodium intervention (P = 1.22*10(-4) and 4.44*10(-5), respectively). Ten variants from 3 independent SELE loci displayed significant genotype-sex interactions on DBP and MAP responses to low-sodium (P for interaction = 1.56*10(-3) to 1.00*10( 4)). Among men, minor alleles of 4 correlated markers attenuated BP responses to low-sodium intake, whereas minor alleles of another 4 correlated markers increased BP responses. No associations were observed in women for these variants. Further, qualitative interactions were shown for 2 correlated SELE markers. CONCLUSIONS These data support a role for the endothelial system genes in salt sensitivity. PMID- 23443728 TI - Association of a change in immunosuppressive regimen with hemodynamic and inflammatory markers of cardiovascular disease after kidney transplantation. AB - BACKGROUND: Although rejection rates and short-term graft survival have significantly improved in kidney transplantation with the introduction of calcineurin inhibitor (CNI), cardiovascular disease (CVD) and metabolic complications are being increasingly recognized as important causes of morbidity and mortality. We hypothesize that non-CNI proliferation signal inhibitor (PSI) based immunosuppressive regimen is associated with improved arterial stiffness after kidney transplantation compared with CNI-based immunosuppressive regimens. METHODS: This is a prospective, single-center study of renal transplant (RT) recipients comparing the metabolic, cardiovascular (pulse wave velocity and aortic augmentation index (AI) adjusted for heart rate (AI * 75)), inflammatory cytokines (interleukins (ILs) 6, 12, and 18) and graft-related outcomes at 3 and 15 months posttransplantation between RT recipients maintained on CNI- (CNI-CNI) or PSI-based (CNI-PSI) regimens including sirolimus and everolimus. RESULTS: Fifty and 17 RT recipients maintained on CNI-CNI and CNI-PSI, respectively, were included in this study. Median time to PSI conversion from CNI was 5 months. Compared with CNI-CNI recipients, CNI-PSI recipients had significantly lower fasting blood glucose in nondiabetics (coefficient = -16.2; 95% confidence interval (CI) = -14.4 to -18.0; P < 0.01), lower IL-18 levels (coefficient = 229.16; 95% CI = -343.94 to -114.38; P < 0.01), and lower AI * 75 (coefficient = 5.14; 95% CI = -9.99 to -0.28; P = 0.04) at 15 months posttransplant in the multivariable models. CONCLUSIONS: Our study suggests from the elimination of CNI for PSI may lower AIx75 and IL-18, both surrogate markers of CVD, but adequately powered, randomized, controlled studies are required to establish the causal relationship between immunosuppressive agents and CVD risk. PMID- 23443729 TI - Relationship between uric acid and vascular structure and function in hypertensive patients and sex-related differences. AB - BACKGROUND: We sought to analyze the relationship between uric acid (UA) and vascular structure and function based on the carotid intima-media thickness, the pulse-wave velocity (PWV), the central arterial pressure, and the augmentation index in hypertensive patients and to evaluate the sex-related differences. METHODS: A cross-sectional study was performed with 366 hypertensive individuals aged 34-75 years (men = 61.74%). The vascular structure was assessed based on the carotid intima-media thickness, the arterial stiffness was assessed by PWV, and the vascular function was assessed using hemodynamic parameters such as the central and peripheral augmentation index and the ambulatory arterial stiffness index (AASI). RESULTS: In the bivariable analysis, the PWV (r = 0.28; P < 0.01) and AASI (r = 0.25; P < 0.01) were positively correlated with UA in women. The central augmentation index (r = -0.16; P < 0.05) and peripheral augmentation index (r = -0.18; P < 0.05) were negatively correlated with UA, whereas the maximum carotid intima-media thickness (r = 0.11; P < 0.05) was positively correlated with UA in the global analysis. In the multiple linear regression analysis, a positive association between PWV and UA was observed after adjusting for classical risk factors (beta = 0.27; P = 0.01) in women only. In turn, a negative association was observed between the AASI and UA after adjusting for confounders in men (beta = -0.06; P = 0.04), with a positive association in women (beta = 0.11; P = 0.03). CONCLUSIONS: Serum UA showed a positive correlation with the mean maximum intima-media thickness and PWV, and this parameter showed a negative correlation with the central and peripheral augmentation indices, although this relationship was lost after adjusting for confounding factors. AASI showed a positive association in women and a negative association in men after adjusting for confounding factors. CLINICAL TRIALS REGISTRATION: Clinical Trials.gov Identifier: NCT01325064. PMID- 23443732 TI - Ionic conduction in the SrTiO3|YSZ|SrTiO3 heterostructure. AB - Employing previously published experimental data, we analyse the enhanced conductivity of the heterostructure comprising yttria-stabilised zirconia (YSZ) and SrTiO3. We confirm that the heterostructure's conductivity arises from SrTiO3, and we conclude that it is exclusively ionic below T ~ 540 K. The calculated excess conductance from space-charge layers is found to be negligible. PMID- 23443733 TI - Radioassay-Based Approach to Investigate Fate and Transformation of Conjugated and Free Estrogens in an Agricultural Soil. AB - Estrogens, a potent group of endocrine disruptors toward aquatic species, are primarily excreted as conjugates from humans and animals. Radioassay-based approaches with detailed speciation have been frequently conducted for environmental-fate studies for pesticides; however, such techniques have not been exploited for reproductive hormones, and especially for hormone conjugates. This article describes a simple, robust, and high-mass-recovery approach to investigate the fate and transformation of a prototype estrogen conjugate, that is, 17beta-estradiol-3-glucuronide (E2-3G), and its metabolites (free estrogens) in a laboratory soil and water matrix without the need for enzymatic cleavage and/or fluorescent derivatization. E2-3G and its metabolites were baseline resolved in a single run using high-performance liquid chromatography (HPLC) and quantified by liquid scintillation counting of the HPLC effluents. Transformation of E2-3G and the disposition of its metabolites--the free estrogens 17beta estradiol and estrone--into aqueous, sorbed, and gaseous phases, were adequately accounted for in a soil-water batch system. High mass balances ranging from 99.0% to 114.1% were obtained. Although the method gave lower sensitivity (parts per billion) than tandem mass spectrometer (parts per trillion), it offered sufficient chromatographic resolution and sensitivity to study the fate of labile estrogens in environmental matrices, using the concentration range of this study. An additional advantage of the approach was the relatively low cost of the instrumentation employed. The presented approach can be successfully applied to study the fate of conjugated hormones and their metabolites in the environment allowing simultaneous discernment of complex fate and transformation processes in soil, water, and gas. PMID- 23443734 TI - The influence of psychosocial work characteristics on the need for recovery from work: a prospective study among computer workers. AB - PURPOSE: To investigate the influence of high job demands, low job control, and high social support on need for recovery (NFR) among computer workers. METHODS: Data was obtained from a longitudinal cohort study, including 5 consecutive measurements, with an in-between period of 6 months. General estimating equations analyses were performed to assess the risk for high NFR 6 months later. Odds ratios (ORs) for high NFR were calculated for high job demands, low job control and low social support, separately. Likewise, ORs were calculated for combinations of job demands and job control, as well as for combinations of job demands, job control and social support. RESULTS: High job demands resulted in an increased risk for high NFR 6 months later, particularly in older workers. Low social support showed also an increased risk for future high NFR, but this was not the case for low job control. Furthermore, a combination of high job demands and low job control, as well as a combination of high job demands, low job control and low social support demonstrated an increased risk for future high NFR where older workers showed higher risks. CONCLUSION: This study demonstrated that adverse psychosocial work characteristics predicted future NFR among computer workers. PMID- 23443735 TI - Clinical impact of persistent left bundle-branch block after transcatheter aortic valve implantation with CoreValve Revalving System. AB - BACKGROUND: Conduction disturbances are relatively common after transcatheter aortic valve implantation. Previous data demonstrated an adverse impact of persistent left bundle-branch block (LBBB) after surgical aortic valve replacement. It is unclear whether new-onset LBBB may also impact the prognosis of patients after transcatheter aortic valve implantation. METHODS AND RESULTS: Among 1060 patients treated with a CoreValve Revalving System transcatheter aortic valve implantation between October 2007 and April 2011 in high-volume centers in Italy, we analyzed those without LBBB or pacemaker at admission (879 patients [82.9%]). We further excluded those who underwent permanent pacemaker implantation within 48 hours after the procedure (61 patients [7%]), for a final study population of 818 patients. Among them, 224 patients (group A; 27.4%) developed a persistent LBBB and the remaining 594 (group B; 72.6%) did not. Clinical characteristics were similar between groups. A low implantation was significantly more frequent in group A (15% versus 9.8%, P=0.02). No patients were censored before 1 year (median follow-up period 438 days, interquartile range 174-798 days). Survival analyses and inherent log-rank tests showed that LBBB was not associated with higher all-cause mortality, cardiac mortality, or hospitalization for heart failure at 30 days or 1 year. At 30 days, but not at 1 year, group A had a significantly higher rate of pacemaker implantation. CONCLUSIONS: In this registry of high-volume centers, persistent LBBB after CoreValve Revalving System transcatheter aortic valve implantation showed no effect on hard end points. On the other hand, LBBB was associated with a higher short-term rate of pacemaker implantation. PMID- 23443736 TI - Donor brain death exacerbates complement-dependent ischemia/reperfusion injury in transplanted hearts. AB - BACKGROUND: Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors. METHODS AND RESULTS: Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors. CONCLUSIONS: BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury. PMID- 23443737 TI - Are microglia minding us? Digging up the unconscious mind-brain relationship from a neuropsychoanalytic approach. AB - The unconscious mind-brain relationship remains unresolved. From the perspective of neuroscience, neuronal networks including synapses have been dominantly believed to play crucial roles in human mental activities, while glial contribution to mental activities has long been ignored. Recently, it has been suggested that microglia, glial cells with immunological/inflammatory functions, play important roles in psychiatric disorders. Newly revealed microglial roles, such as constant direct contact with synapses even in the normal brain, have defied the common traditional belief that microglia do not contribute to neuronal networks. Recent human neuroeconomic investigations with healthy volunteers using minocycline, an antibiotic with inhibitory effects on microglial activation, suggest that microglia may unconsciously modulate human social behaviors as "noise." We herein propose a novel unconscious mind structural system in the brain centering on microglia from a neuropsychoanalytic approach. At least to some extent, microglial activation in the brain may activate unconscious drives as "psychological immune memory/reaction" in the mind, and result in various emotions, traumatic reactions, psychiatric symptoms including suicidal behaviors, and (psychoanalytic) transference during interpersonal relationships. Microglia have the potential to bridge the huge gap between neuroscience, biological psychiatry, psychology and psychoanalysis as a key player to connect the conscious and the unconscious world. PMID- 23443740 TI - Dication magnetic ionic liquids with tuneable heteroanions. AB - Dicationic magnetic ionic liquids with heteroanionic anions allow for tunability of physicochemical properties while retaining magnetic susceptibility. PMID- 23443738 TI - Quantitative comparison of the dynamic flow waveform changes in 12 ruptured and 29 unruptured ICA-ophthalmic artery aneurysms. AB - INTRODUCTION: Studies have reported a correlation between blood flow dynamics in the cardiac cycle and vascular diseases, but research to analyze the dynamic changes of flow in cerebral aneurysms is limited. This quantitative study investigates the temporal changes in flow during a cardiac cycle (flow waveform) in different regions of aneurysms and their association with aneurysm rupture. METHODS: Twelve ruptured and 29 unruptured aneurysms from the internal carotid artery-ophthalmic artery segment were studied. Patient-specific aneurysm data were implemented to simulate blood flow. The temporal flow changes at different regions of the aneurysm were recorded to compare the flow waveforms. RESULTS: In more than 60 % of the cases, peak flow in the aneurysm sac occurred after peak flow in the artery. Flow rate varied among cases and no correlation with rupture, aneurysm flow rate, and aneurysm size was found. Higher pulsatility within aneurysm sacs was found when comparing with the parent artery (P < 0.001). Pulsatility was high throughout ruptured aneurysms, but increased from neck to dome in unruptured ones (P = 0.021). Significant changes between inflow and outflow flow profile were found in unruptured aneurysms (P = 0.023), but not in ruptured aneurysms. CONCLUSION: Quantitative analysis which considers temporal blood flow changes appears to provide additional information which is not apparent from aneurysmal flow at a single time point (i.e., peak of systole). By considering the flow waveform throughout the cardiac cycle, statistically significant differences were found between ruptured and unruptured cases - for flow profile, pulsatility and timing of peak flow. PMID- 23443741 TI - Expression of TWEAK/Fn14 in neuroblastoma: implications in tumorigenesis. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) family of cytokines, acts on responsive cells via binding to a cell surface receptor called Fn14. TWEAK binding to an Fn14 receptor or constitutive Fn14 overexpression has been shown to activate nuclear factor kappaB signaling which is important in tumorigenesis and cancer therapy resistance. In the present study, we demonstrate that TWEAK and Fn14 are expressed in neuroblastoma cell lines and primary tumors, and both are observed at increased levels in high-stage tumors. The treatment of neuroblastoma cell lines with recombinant TWEAK in vitro causes increased survival, and this effect is partially due to the activation of NF-kappaB signaling. Moreover, TWEAK induces the release of matrix metalloprotease-9 (MMP-9) in neuroblastoma cells, suggesting that TWEAK may play a role in the invasive phase of neuroblastoma tumorigenesis. TWEAK-induced cell survival was significantly reduced by silencing the TWEAK and Fn14 gene functions by siRNA. Thus, the expression of TWEAK and Fn14 in neuroblastoma suggests that TWEAK functions as an important regulator of primary neuroblastoma growth, invasion and survival and that the therapeutic intervention of the TWEAK/Fn14 pathway may be an important clinical strategy in neuroblastoma therapy. PMID- 23443742 TI - Towards the enantioselective synthesis of (-)-euonyminol--preparation of a fully functionalised lower-rim model. AB - The development of a stereoselective total synthesis of beta-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland Claisen rearrangement to establish the quaternary stereocentre at C11 (27->28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the beta-dihydroagarofuran skeleton (35->36). PMID- 23443743 TI - Enhanced care for primary hip arthroplasty: factors affecting length of hospital stay. AB - BACKGROUND: Enhanced care in joint replacement requires identification and correction of the causes of delay in discharge while ensuring practice remains safe. We conducted prospective studies of factors delaying discharge following hip replacement in 2006 and 2010. METHODS: Daily data were twice collected prospectively in 100 consecutive unselected primary cemented THR, by an independent observer. Reasons for delays in discharge and variation from the patient pathway were identified and addressed. RESULTS: The mean length of stay (LOS) in 2006 was 4.3 days and in 2010, 3.56 days (target for discharge 4 days). In 2006, 31 patients had a stay of more than 4 days, 17 due to inadequate physiotherapy provision, 10 for medical and 4 for other reasons. In 2010, 15 patients had a stay of more than 4 days, 1 patient had inadequate physiotherapy provision, in 7 cases discharge was delayed because of need for blood transfusion and 7 because of need for catheterisation. Women aged more than 70 with preoperative haemoglobin of <12 g/dL were at particularly high risk of requiring transfusion. Catheterisation was also identified as a factor causing significant increase in LOS. Patients going home in less than 4 days were more likely to have had their operation in the morning. CONCLUSION: Patient LOS is multifactorial and can be reduced by regular review of the care pathway to effect incremental changes that have a significant impact on reducing stay. PMID- 23443744 TI - Titanium elastic nails, open reduction internal fixation and non-operative management for middle third clavicle fractures: a comparative study. AB - OBJECTIVES: To compare clinical outcomes between titanium elastic nails (TENS), open reduction internal fixation (ORIF) and non-operative treatment options at mean 30 months in Allman type 1 fractures of the clavicle. DESIGN: Retrospective case matched. SETTING: Tertiary Trauma Centre, UK. PATIENTS: Treatment method was based on surgeon choice although there was no difference between groups in terms of age or gender. Those treated non-operatively tended to have a less severe fracture pattern. There were 25 patients treated with TENS, 24 with ORIF and 41 treated conservatively. Main outcome measurements are qDASH questionnaire, patient satisfaction question and clinical complication rate. RESULTS: Patients managed with TENS had significantly better clinical outcomes than both plate fixation and non-operatively managed groups. CONCLUSIONS: This study supports the use of TENS fixation of middle third clavicle fractures in significantly displaced Allman type 1 injuries. PMID- 23443745 TI - Open bicondylar Hoffa fracture with patella fracture: a case report and literature review. AB - Bicondylar Hoffa fractures are rare. We report a patient who sustained an open bicondylar Hoffa fracture with an ipsilateral transverse fracture of the patella after a high-energy motor vehicle accident. PMID- 23443746 TI - Comparison of proximal femoral nail antirotation (PFNA) with AO dynamic condylar screws (DCS) for the treatment for unstable peritrochanteric femoral fractures. AB - PURPOSE: The aim of this study was to compare the results of intramedullary fixation with those of plate-screw fixation for peritrochanteric femoral fracture patients older than 60 years old. METHODS: This article reports on a retrospective review of patients who had peritrochanteric femoral fractures and were treated with a 95 degrees fixed-angle screw plate (DCS) or an intramedullary nailing system (PFNA). Patients with 79 fractures were enrolled in the study; 47 of them were treated with the PFNA system and 37 with the DCS. Followed for at least 1 year, the treatment groups were compared by taking into consideration all demographic and trauma variables. RESULTS: No significant differences were discovered between the two groups with regard to side of injury, mechanism of trauma, associated comorbidities, AO fracture classification, average follow-up duration, mortality, and fracture reduction quality at the 1 year follow-up. The average surgical time was significantly lower in the PFNA group (57 min.) compared to the DCS group (87 min.). Longer operative time was needed in the DCS group, and thus, greater blood loss occurred compared to the PFNA group. The functional results of the PFNA group were found to be significantly better than those of the DCS group. CONCLUSIONS: Owing to some advantages, such as minimal exposure, reduced operative blood loss, and the achievement of biological fixation, PFNA is a better choice for the treatment for unstable peritrochanteric fractures. PMID- 23443747 TI - Results of treatment of chronic osteomyelitis by "gutter procedure and muscle flap transposition operation". AB - INTRODUCTION: The aim of this study was to evaluate the outcomes of creation of a gutter and muscle flap transposition method for the treatment of long-bone chronic osteomyelitis. PATIENTS AND METHODS: A total of thirty chronic osteomyelitis patients (thirty-one extremities), who had undergone the gutter creation and muscle flap transposition procedure between 2005 and 2009, were included in the study (19 male, 11 female; mean age 24.4 years; age range 2-75 years). Osteomyelitis of the long bones involved the femur in 13 patients, the tibia in 13, the humerus in 2, the fibula in 2 and the ulna in 1 patients, respectively. All the patients received post-operative antibiotic therapy of at least 6 weeks. The mean follow-up period was 28.7 months (6-53 months). At the end of this follow-up period, the patients were evaluated using clinical, laboratory and screening methods. RESULTS: Complete pain relief, disappearance of toxic symptoms, improvement in radiological findings, fistula closure and return of the blood parameters to normal ranges were accepted as successful treatment when all the afore-mentioned had been fulfilled. According to these criteria, 29 of the 30 patients had been cured. DISCUSSION: The gutter creation and muscle flap transposition method in the treatment of long-bone chronic osteomyelitis may be a successful mode of therapy when performed correctly and supported by long term antibiotherapy. PMID- 23443748 TI - Early clinical results of a new conservative hip stem. AB - Conservative stems conserve a larger amount of bone, and due to their biomechanical effect, they allow higher compression forces on the lateral column of the femur and reduce stress shielding. Since they conserve metaphyseal bone, short stems allow the use of conventional stems when revision surgery becomes necessary. The authors present the early results of a new bone conserving stem GTS (Biomet). A total of 80 patients (55 men and 25 women) were enroled in this prospective study and received 81 GTS stem (1 bilateral). Their mean age was 64.8 years (range 43-78) at the time of surgery. The mean follow-up was 16 months (range 6-24 month). The clinical assessment was performed by a single surgeon using the Merle d'Aubigne scale; radiographic complications were described. There was one calcar fracture, which required a fixation with a screw. No cases of clinical or radiological loosening were reported. GTS Conservative hip arthroplasty stem has proven to be an excellent implant for femoral hip replacement, with expectations that it may exceed the durability of other types of implants without harming the femoral diaphysis. This may facilitate eventual stem revision and give surgeons the opportunity of using a standard primary implant. PMID- 23443749 TI - Contribution of collagen fibers to the compressive stiffness of cartilaginous tissues. AB - Cartilaginous tissues such as the intervertebral disk are predominantly loaded under compression. Yet, they contain abundant collagen fibers, which are generally assumed to contribute to tensile loading only. Fiber tension is thought to originate from swelling of the proteoglycan-rich nucleus. However, in aged or degenerate disk, proteoglycans are depleted, whereas collagen content changes little. The question then rises to which extend the collagen may contribute to the compressive stiffness of the tissue. We hypothesized that this contribution is significant at high strain magnitudes and that the effect depends on fiber orientation. In addition, we aimed to determine the compression of the matrix. Bovine inner and outer annulus fibrosus specimens were subjected to incremental confined compression tests up to 60 % strain in radial and circumferential direction. The compressive aggregate modulus was determined per 10 % strain increment. The biochemical composition of the compressed specimens and uncompressed adjacent tissue was determined to compute solid matrix compression. The stiffness of all specimens increased nonlinearly with strain. The collagen rich outer annulus was significantly stiffer than the inner annulus above 20 % compressive strain. Orientation influenced the modulus in the collagen-rich outer annulus. Finally, it was shown that the solid matrix was significantly compressed above 30 % strain. Therefore, we concluded that collagen fibers significantly contribute to the compressive stiffness of the intervertebral disk at high strains. This is valuable for understanding the compressive behavior of collagen reinforced tissues in general, and may be particularly relevant for aging or degenerate disks, which become more fibrous and less hydrated. PMID- 23443751 TI - HLA Allelic Variants and Carbamazepine-Induced Hypersensitivity. PMID- 23443752 TI - When direct health-care professional communications have an impact on inappropriate and unsafe use of medicines. AB - Serious safety issues relating to drugs are communicated to health-care professionals via Direct Health-Care Professional Communications (DHPCs). We explored which characteristics determined the impact of DHPCs issued in the Netherlands for ambulatory-care drugs (2001-2008). With multiple linear regression, we examined the impact on the relative change in new drug use post DHPC of the following: time to DHPC, trend in use, degree of innovation, specialist drug, first/repeated DHPC, DHPC template, and type of safety issue. DHPCs have less impact on use of specialist drugs than nonspecialist drugs (P < 0.05). The DHPCs' impact increased after availability of a template emphasizing the main problem (P < 0.05), and for safety issues with a risk of death and/or disability (both P < 0.05) (adjusted R2 = 0.392). Risk communication can be effective, specifically in case of well-structured information, and very serious safety issues. Effectiveness may improve by tailoring DHPCs and adding other communication channels, for example for drugs that are increasingly being used. PMID- 23443750 TI - The role of transcription-independent damage signals in the initiation of epithelial wound healing. AB - Wound healing is an essential biological process that comprises sequential steps aimed at restoring the architecture and function of damaged cells and tissues. This process begins with conserved damage signals, such as Ca(2+), hydrogen peroxide (H2O2) and ATP, that diffuse through epithelial tissues and initiate immediate gene transcription-independent cellular effects, including cell shape changes, the formation of functional actomyosin structures and the recruitment of immune cells. These events integrate the ensuing transcription of specific wound response genes that further advance the wound healing response. The immediate importance of transcription-independent damage signals illustrates that healing a wound begins as soon as damage occurs. PMID- 23443753 TI - Estimation of renal cell carcinoma treatment effects from disease progression modeling. AB - To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided alpha = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC. PMID- 23443754 TI - Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG-CoA reductase inhibitors: a kinetic consideration of its mechanism. AB - Because the plasma exposure levels of rosuvastatin in Asians are generally twice those in Caucasians, the starting dose for Asians in the United States is set to half of that for non-Asians. However, the precise role of ethnicity in the clearance of rosuvastatin has not yet been clarified. This review focuses on ethnic variability in the clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) and angiotensin II receptor antagonists. The mechanisms of such variability are discussed quantitatively, with building a hypothetical model for pravastatin, and validated against other statins. Our analyses suggest that the ethnic variability in the plasma exposure of statins cannot be explained only by the difference in the allele frequencies of organic anion-transporting polypeptide (OATP)1B1 and breast cancer resistance protein (BCRP), and the intrinsic ethnic variability in the activity of OATP1B1 (the ratio of Japanese/Caucasians is 0.584) must be considered. Further work and validation with additional data will clarify the applicability of this model to other OATP1B1 substrates. PMID- 23443755 TI - Response to "HLA allelic variants and carbamazepine-induced hypersensitivity". PMID- 23443756 TI - The continuum of comparability extends to biosimilarity: how much is enough and what clinical data are necessary? AB - Experts debate the clinical evidence standards needed to approve major manufacturing changes for biologics, biosimilars, and interchangeable biosimilars. As sponsors consider their development plans, the resource investment required to develop an analytically highly similar candidate must be balanced by regulatory relief for the clinical studies required to achieve the necessary indications for the marketed product. This article discusses biosimilarity and comparability as related scientific and regulatory concepts and the usefulness of clinical data for both. PMID- 23443757 TI - Computational drug repositioning: from data to therapeutics. AB - Traditionally, most drugs have been discovered using phenotypic or target-based screens. Subsequently, their indications are often expanded on the basis of clinical observations, providing additional benefit to patients. This review highlights computational techniques for systematic analysis of transcriptomics (Connectivity Map, CMap), side effects, and genetics (genome-wide association study, GWAS) data to generate new hypotheses for additional indications. We also discuss data domains such as electronic health records (EHRs) and phenotypic screening that we consider promising for novel computational repositioning methods. PMID- 23443758 TI - Patent eligibility of induced pluripotent stem cell theranostics. PMID- 23443759 TI - Pharmacology and pharmacogenetics of pediatric ADHD with associated aggression: a review. AB - Attention deficit hyperactivity disorder (ADHD) is often associated with symptoms of aggression in children and adolescents. Clinically, this is complex because aggression can be from hyperactivity and impulsivity, or could be a distinct symptom from a comorbid diagnosis. Past research has recommended first treating the primary disorder of ADHD. Stimulants are the most common treatment for pediatric ADHD, which can be helpful in decreasing aggressive behaviors. Alpha adrenergic agonists and atomoxetine (ATX) are non-stimulant medications for ADHD and aggression, but more research is necessary to compare these drugs to stimulants. If aggressive symptoms do not improve from treating the primary disorder, aggression can be treated separately. Risperidone, lithium, valproic acid, clonidine, and guanfacine have shown positive results in reducing aggression, but studies including children with aggression and ADHD are limited. The variability in treatment tolerability in patients has stimulated research in pharmacogenetics for ADHD. Although this field is still emerging, research has found evidence supporting a link between the response rate of methylphenidate and the dopamine transporter (DAT1) and a link between the metabolism rate of atomoxetine and hepatic cytochrome 450 isozymes. Pharmacogenetics may be relevant to ADHD and associated aggression. Further research in pharmacogenetics will strive to identify patterns of genetic variations that can tailor individual treatments. PMID- 23443760 TI - The relationship between childhood abuse and psychosis for women prisoners: assessing the importance of frequency and type of victimization. AB - This study examines the relationship between childhood victimization and self reported current symptoms of psychosis in an incarcerated female population in the United States. Participants are 159 randomly selected women incarcerated in two North Carolina state prisons. Participants completed a battery of self-report measures to assess childhood victimization and current and lifetime experience of audio/visual hallucinations and delusions. In accordance with the dose-response model, we hypothesized a predictive relationship between severity, frequency, and type of victimization and psychosis for this sample of women prisoners. Results indicate that women who experienced multi-victimization were 2.4 times more likely to report current symptoms of psychosis than other women prisoners who experienced only physical or sexual victimization in childhood. Likewise, a one unit increase in frequency of childhood victimization was associated with a 3.2% increased likelihood of having reported symptoms of current psychosis. These results provide support for the dose-response model hypothesis that multi victimization is an important predictor of psychosis for the women prisoner population. Results indicate that adjusting prison-based mental health services to address the relationship of childhood victimization and symptoms of psychosis may be a key factor in improving outcomes among this population. PMID- 23443761 TI - Clinical outcomes of women with metastatic breast cancer treated with nab paclitaxel: experience from a single academic cancer centre. AB - BACKGROUND: Nab-paclitaxel is a solvent-free, taxane-based chemotherapy approved for the treatment of metastatic breast cancer (mbc). This study reports clinical benefit and toxicities experienced by women with mbc treated with nab-paclitaxel at the Ottawa Hospital Cancer Centre. METHODS: Women with mbc treated with single agent nab-paclitaxel between June 2006 and December 2010 were included in this analysis. Retrospective data obtained included demographics, disease characteristics, prior chemotherapy, nab-paclitaxel treatment, toxicity, and survival. Clinical benefit was defined as partial or complete response or stable disease (by clinical or radiologic evaluation, or both) at 6 months or more. RESULTS: Of 43 women (mean age: 57.0 years; range: 34-74 years), most had disease positive for estrogen or progesterone receptor (72.1%, 58.1%), or both. Nab paclitaxel was administered weekly (qw: 44.2%), every 3 weeks (q3w: 46.5%), q3w switched to qw (7.0%), or qw switched to q3w (2.3%). Median duration of therapy was 5.1 months (qw) and 3.0 months (q3w). Sensory neuropathy was the primary toxicity (45.4% qw, 38.1% q3w; p = 0.62). Clinical benefit was observed in most women (76.2% qw, 57.1% q3w; p = 0.20). Women receiving nab-paclitaxel had a median overall survival of 13.6 months qw (range: 8.1-28.3 months) and 10.8 months q3w (range: 5.9-17.9 months; p = 0.03). Regardless of dosing schedule, women experiencing clinical benefit lived significantly longer than those not experiencing a benefit (17.3 months vs. 7.7 months; hazard ratio: 0.14; 95% confidence interval: 0.06 to 0.33). CONCLUSIONS: Our clinical experience demonstrates that most women treated with nab-paclitaxel experienced some clinical benefit. Patients achieving clinical benefit lived significantly longer than those who did not. Nab-paclitaxel was well tolerated, with the primary toxicity being mild sensory neuropathy. Nab-paclitaxel represents another treatment option, with a favourable toxicity profile, for women with mbc. PMID- 23443762 TI - Genetic differentiation of the Euglossini (Hymenoptera, Apidae) populations on a mainland coastal plain and an island in southeastern Brazil. AB - Euglossini bees are among the main pollinators of plant species in tropical and subtropical forests in Central and South America. These bees are known as long distance pollinators due to their exceptional flight performance. Here we assessed through microsatellite loci the gene variation and genetic differentiation between populations of four abundant Euglossini species populations sampled in two areas, Picinguaba (mainland) and Anchieta Island, Ubatuba, Sao Paulo State, southeastern Brazil. There was no significant genetic differentiation between the island and mainland samples of Euglossa cordata (Fst = 0.008, P = 0.60), Eulaema cingulata (Fst = 0.029, P = 0.29) and Eulaema nigrita (Fst = 0.062, P = 0.38), but a significant gene differentiation between mainland and island samples of Euglossa stellfeldi (Fst = 0.028, P = 0.016) was detected. As expected, our results showed that the water body that separates the island from the mainland does not constitute a geographic barrier for these Euglossini bees. The absence of populational structuring of three out the four species studied corroborates previous reports on those bees, characterized by large populations, with high gene diversity and gene flow and very low levels of diploid males. But the Eg. stellfeldi results clearly point that dispersal ability is not similar to all euglossine bees, what requires the development of different conservationist strategies to the Euglossini species. PMID- 23443764 TI - Effects of colloid preload on placenta stereology and cord blood S100beta protein during cesarean section under spinal anesthesia. AB - OBJECTIVE: To determine the optimal dose of colloid preload, which is both safe and effective, for preventing hypotension in parturients undergoing cesarean section under spinal anesthesia. METHODS: Forty-five healthy, termed parturients scheduled for cesarean delivery under spinal anesthesia were randomly assigned to 3 colloid preload groups to receive gelofusine infusion at the rates of 5, 10, or 15 ml.kg(-1).h(-1) (groups I, II, and III, respectively). Colloid preload was administered 10 min before spinal anesthesia and maintained until the delivery. Blood pressure (BP) and heart rate (HR) of the parturients were monitored during the operation, and Apgar scores at 1 and 5 min after birth were recorded. S100beta protein concentration and blood gas values of the umbilical artery were also measured. The vascular adaptation in the placental villous capillary was evaluated stereologically. RESULTS: At each time point of measurement, BP and HR showed no significant differences among the 3 groups during the operation (P>0.05), but within the same group, BP and HR underwent significant variations during the operation; groups II and III maintained more stable hemodynamics compared to group I. Apgar scores and blood gas analysis, pH value, and S100beta protein in the umbilical artery showed no significant differences among the 3 groups (P>0.05). The 3 groups exhibited no significant differences in the length and volume density of the placental villous capillaries (P>0.05). CONCLUSION: Colloid preload with gelofusine administered at the rate of 10 ml.kg(-1).h(-1) can reduce the incidence and severity of hypotension in cesarean section under spinal anesthesia with the least adverse maternal and fetal effects. PMID- 23443763 TI - Characterization of a contemporaneous hybrid zone between two darter species (Etheostoma bison and E. caeruleum) in the Buffalo River System. AB - Hybrid zones have long intrigued evolutionary biologists and provide a natural laboratory to explore the evolution of reproductive isolation (speciation). Molecular characterization of hybrid zone dynamics can provide insight into the strength of reproductive isolation as well as the underlying evolutionary processes shaping gene flow. Approximately one-third of darter species naturally hybridize making this species-rich North American freshwater teleost fish clade an ideal system to investigate the extent and direction of hybridization. The objective of this study was to use diagnostic microsatellite markers to calculate genetic hybrid index scores of two syntopic, but distantly related darter species, Etheostoma bison and Etheostoma caeruleum. A combination of hybrid index scores, assignment tests, and mitochondrial haplotype profiles uncovered mixed ancestry in approximately 6 % of sampled adult individuals, supporting contemporaneous hybridization that was previously undocumented in E. bison. Moreover, hybrids were not limited to the F1 generation, but encompassed the entire suite of hybrid categories (F1, F2 and backcross hybrids). The low number of hybrids assigned to each hybrid category represents a bimodal hybrid zone, suggesting reproductive isolation is strong (but incomplete) and also advocates for the ability of hybrids to produce second-generation hybrids and backcross into both parental species, mediating introgression across species boundaries. To this end, cytonuclear profiles of the sampled parental species and hybrids were consistent with bidirectional gene flow, although there was an overall trend of asymmetric hybridization between E. caeruleum females and E. bison males. The spatiotemporal variation in hybridization rates and resulting cytonuclear patterns expanded on in this study provide a comparative genetic framework on which future studies can begin to elucidate the underlying processes that not only generate a mosaic hybrid zone, but maintain the distinctness of species in the face of gene flow. PMID- 23443765 TI - [Differences in peripheral blood gene expression profiles between liver and kidney transplantation recipients]. AB - OBJECTIVE: To investigate the differences in the gene expression profiles of the peripheral blood immune cells between liver and kidney transplantation recipients. METHODS: A dataset containing the gene expression profiles of 27 liver transplantation recipients and 25 kidney transplantation recipients (from GSE22229 and GSE28842, respectively) was downloaded from the GEO database. By combining gene set enrichment analysis (GSEA) and biological network analysis of the differentially expressed genes using Cytoscape software, we analyzed the core genes closely related to liver or kidney transplantations. RESULTS: GSEA identified 20 highly overlapping genes for liver transplantation and another 20 for kidney transplantation using leading edge analysis. Fourteen hub nodes (gene) for liver transplantation and 13 for kidney transplantation were identified by cytoscape software using interaction network analysis. Five core genes related to liver transplantation and 5 to kidney transplantation were obtained by integrating GSEA and biological network analysis. CONCLUSION: Controlling the transcription and translation of the genes of the peripheral blood immune cells is the main immune regulation mechanism in liver transplantation recipients, but in the recipients of kidney transplantation, the protein interaction network plays a more prominent role. Energy metabolism and functional regulation of the immune cells are closely related. The core genes in peripheral blood immune cells related to liver or kidney transplantation may play key roles in regulating immune functions. PMID- 23443766 TI - [Role of nuclear factor-kappaB activation in bilirubin-induced rat hippocampal neuronal apoptosis and the effect of TAT-NBD intervention]. AB - OBJECTIVE: To investigate the role of nuclear factor-kappaB (NF-kappaB) activation in bilirubin-induced apoptosis of rat hippocampal neurons and the effect of TAT-NBD intervention on bilirubin neurotoxicity. METHODS: Primary cultured rat hippocampal neurons were treated with TAT-NBD in the initial 6 or 24 h or in the latter 6 h during a 24-h bilirubin exposure of the cells (early, continuous and late intervention groups, respectively). Immunocytochemistry was performed to detect NF-kappaB p65 protein expression, and the cell survival and apoptosis were assessed with a modified MTT assay, Annexin V-FITC/PI and TUNEL assay. IL-1beta concentration in the supernatant was determined with ELISA. RESULTS: Compared with the control cells, bilirubin-treated cells showed a significantly increased NF-kappaB p65 protein expression (P<0.01), which reached the peak level at 6 and 24 h (P<0.01). The cell survival rate in early TAT-NBD intervention group was (80.784?9.767)%, significantly lower than that of the control group (P<0.01) but higher than that of bilirubin group (P<0.01); the apoptotic rate in early TAT-NBD intervention group was significantly higher than that of control group (P<0.01) but lower than that of bilirubin group (P<0.01). IL-1beta concentration was significantly lower in early TAT-NBD intervention group (15.348?0.812 pg/ml) than in bilirubin group (P<0.05). The continuous and late TAT-NBD intervention groups showed comparable cell survival rate, apoptotic rate and IL-1beta concentration with bilirubin group (P>0.05). CONCLUSION: NF kappaB bidirectionally regulates bilirubin-induced apoptosis of rat hippocampal neurons. Selective inhibition of the early peak of NF-kappaB by TAT-NBD offers neuroprotective effect. TAT-NBD can be potentially used for prophylaxis of bilirubin-induced brain injury. PMID- 23443767 TI - [Diaphragm dysfunction and expressions of calcium regulatory proteins in diabetic rats]. AB - OBJECTIVE: To study the changes in diaphragmatic function and gene expressions of calcium regulatory proteins in diabetic rats and explore the mechanism of diaphragm dysfunction in diabetes mellitus. METHODS: SD rats were randomly divided into normal control group and diabetic (induced by intraperitoneal STZ injection) group. After 4 and 8 weeks, the body weight and diaphragm to body weight ratio were measured, and the activities of succinic dehydrogenase (SDH) in the diaphragm and blood glucose were assayed. The diaphragm contractility was assessed and the alterations of diaphragm ultrastructure were observed. RT-PCR was used to detect the changes in sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and phospholamban (PLB) mRNA expressions in the diaphragm. RESULTS: The diabetic rats showed a significant weight loss with a lowered diaphragm to body weight ratio (P<0.01) and SDH activity (P<0.01). The peak twitch tension and maximum tetanic tension of the diaphragm were significantly lowered and the time to peak contraction and half relaxation time significantly prolonged (P<0.01) in the diabetic rats, which also exhibited a lowered tetanic force in response to stimulus (P<0.01). Transmission electron microscopy revealed obvious ultrastructural changes of the diaphragm in diabetic rats. RT-PCR showed significantly decreased SERCA and increased PLB mRNA expressions in diabetic rat diaphragm (P<0.01), and these changes intensified with time (P<0.01). CONCLUSION: Diabetes can cause impairment of diaphragmatic ultrastructure, mitochondrial injuries, and lowered SDH activity and ATP production. Decreased SERCA and increased PLB mRNA expressions in diabetes result in reduced Ca(2+) uptake by the diaphragm sarcoplasmic reticulum to induce diaphragm dysfunction. PMID- 23443769 TI - [Effect of mitochondrial DNA deletion on growth and invasiveness of human lymphoma Namalwa cells]. AB - OBJECTIVE: To explore the effect of mitochondrial DNA (mtDNA) deletion on the growth and invasiveness of human lymphoma Namalwa cells. METHODS: rho(0)-Namalwa cells with mtDNA deletion were generated by treating Namalwa cells with ethidium bromide and confirmed by selective rho(0) test medium analysis, PCR and Western blotting. The growth of rho(0)-Namalwa cells was evaluated by MTT assay and cell cycle analysis, and the cell migration and invasiveness were assessed with Transwell assay. Reactive oxygen species (ROS) production and cytosolic Ca(2+) were detected by flow cytometry. RESULTS: rho(0)-Namalwa cells could grow and divide normally in selective medium supplemented with uridine and pyruvate but not in nonselective medium. PCR did not yield the products of mtDNA, nor was COXII expression detected in rho(0)-Namalwa cells. rho(0)-Namalwa cells showed an obvious attenuation of cell proliferation and migration abilities with significantly lowered ROS production and cytosolic Ca(2+). CONCLUSION: The suppressed growth and migration of rho(0)-Namalwa cells may be the result of decreased ROS production and cytosolic Ca(2+). PMID- 23443768 TI - [Effects of signaling-selective parathyroid hormone peptide analog on fracture healing in orchiectomized mouse models]. AB - OBJECTIVE: To assess the effect of intermittent subcutaneous injections of signal selective parathyroid hormone (PTH) peptide analog on fracture healing in orchiectomized mouse models. METHODS: Thirty-six 7-week-old C57/BL male mice were orchiectomized and injected with hPTH(1-34), the signal-selective PTH peptide analog [Gly(1), Arg(19)]hPTH (1-34), or an identical volume of vehicle 1 week after induction of femoral fracture. At 14 and 28 days after the operation, the mice were sacrificed for measurement of bone mineral density (BMD) and bone mineral content (BMC) of the callus using by dual energy X-ray absorptiometry. The bone healing was evaluated by radiography, biomechanical testing, micro computed tomography (Micro-CT) and histological examination. RESULTS: At 14 days after the operation, BMD in PTH peptide analog group was significantly increased (P<0.05). The mouse models treated with the PTH peptide analog showed significantly lower ultimate bending force and bending rigidity than those with hPTH(1-34) treatment. X-ray and Micro-CT scanning showed that callus transformation and remodeling was better in PTH peptide analog group than in the vehicle control group but poorer than in hPTH(1-34) group. CONCLUSION: The signaling-selective PTH peptide analog G1, R19 (1-28) can accelerate fracture healing in orchiectomized mouse models, in which process cAMP/PKA pathway plays an important role. PMID- 23443770 TI - [Protective effect of hydrogen against hyperoxia-induced type II alveolar epithelial cell injury]. AB - OBJECTIVE: To investigate the protective effect of hydrogen against hyperoxia induced oxidative stress injury in premature rat type II alveolar epithelial cells (AECs). METHODS: The type II AECs isolated from premature rats were randomly divided into air (21% oxygen) control group, hyperoxia (95% oxygen) control group, air + hydrogen group, and hyperoxia+ hydrogen group. The cells with hydrogen treatment were cultured in the presence of rich hydrogen. After the corresponding exposure for 24 h, the cell morphology was observed microscopically. MTT assay was used to evaluated the cell proliferation ability, and JC-1 fluorescence probe was used to detect the mitochondrial membrane potential (deltaphi) changes of the type II AECs. The concentration of maleic dialdehyde (MDA) and superoxide dismutase (SOD) activity in the cell supernatant were detected using colorimetric method. RESULTS: No significant differences were found in cell growth or measurements between air control and air + hydrogen groups. Compared with air control group, the cells exposed to hyperoxia showed significantly suppressed proliferation, reduced mitochondrial membrane potential, increased MDA content, and decreased SOD activity. Intervention with hydrogen resulted in significantly increased cell proliferation and SOD activity and lowered MDA content, and restored the mitochondrial membrane potential in the cells with hyperoxia exposure (P<0.05). CONCLUSION: Hydrogen can significantly reduce hyperoxia-induced oxidative stress injury in premature rat type II AECs, improve the cellular antioxidant capacity, stabilize the mitochondrial membrane potential, and reduce the inhibitory effect of hyperoxia on cell proliferation. PMID- 23443771 TI - [Role of MUC2 gene in the regulation of rat intestinal barrier function by probiotics]. AB - OBJECTIVE: To investigate MUC2 expression in rat colons induced by probiotics and its effects on the inhibition of E.coli K1 (E44) penetration of the intestinal barrier by probiotics. METHODS: SD rats were subjected to intragastric administration of probiotics, E44, or probiotics +E44 on a daily basis for 7 days, and MUC2 expression in the colons was determined by RT-PCR. MUC2-targeted shRNA (shRNA MUC2) and scrambled shRNA plasmids (shRNA NC) were respectively transfected into Lovo cells, and the efficiency of MUC2 knockdown was determined using qRT-PCR. Competitive exclusion assay was used to evaluate the effects of the probiotics against E44 adhesion and invasion. RESULTS: Intestinal MUC2 mRNA expression was up-regulated in the rats after intragastric administration of probiotics, while E44 administration caused significantly lowered MUC2 expression. MUC2 expression was down-regulated (by 66.7%) by transfection with shRNA MUC2 in Lovo cells as compared with the negative control and mock control cells. The inhibition of E44 adherence and invasion by probiotics was significantly attenuated in transfected Lovo cell culture (in which the relative adhesion and invasion rates of E44 were 56.64% and 66.64%, respectively) as compared with those in the control group. CONCLUSION: The up-regulation of MUC2 in rat colons can be one of the mechanisms of the probiotics in antagonizing the translocation of the pathogenic bacteria. Silencing MUC2 expression causes attenuated inhibitory effect of the probiotics on E. coli K1 penetration across human intestinal epithelial cells. PMID- 23443772 TI - [Construction of adenoviral vectors expressing miR-30a and miR-30e]. AB - OBJECTIVE: To construct adenoviral vectors expressing mature miRNA-30a and miRNA 30e. METHODS: The target mmu-miR-30a and mmu-miR-30e genes amplified from mouse genome were digested and linked to the shuttle plasmid pSES-HUS, which was then transformed into competent AdEaseier cells for recombination. The confirmed recombinant plasmids were transfected into Hek-293 cells for production of the adenoviruses pAd-mmu-miR-30a and pAd-mmu-miR-30e. The obtained adenoviruses were used to infect Mefs cells, and the cellular expressions of mmu-miR-30a and mmu miR-30e were detected using fluorescence quantitative PCR. RESULTS: mmu-miR-30a (357 bp) and mmu-miR-30e (324 bp) containing the restriction sites were amplified and linked to the shuttle plasmid pSES-HUS, which was successfully recombined with AdEasy1. After packaging in Hek-293 cells, the adenoviral vectors were obtained, which caused an increase of mmu-miR-30a expression by 26.46?7.46 folds and mmu-miR-30e expression by 2.76?0.25 folds in transfected Mefs cells. CONCLUSION: We have successfully constructed the adenoviral vectors expressing the mature miRNAs. PMID- 23443773 TI - [Effect of quercetin on invasion, migration, proliferation and cell cycle of glioma U87 cells]. AB - OBJECTIVE: To explore the effect of quercetin on the invasion, migration, proliferation and cell cycle of glioma U87 cells. METHODS: Glioma U87 cells were treated with 50, 100, or 150 umol/L quercetin (Q(50), Q(100) and Q(150) groups, respectively) or with DMSO (Q(0) group). Transwell in vitro invasion and migration assays, Click-iT Edu test and flow cytometry were performed to evaluate the effect of quercetin on the invasion, migration, proliferation and cell cycle of U87 cells. RESULTS: After 36 h of quercetin treatment, the cells in Q(50), Q(100) and Q(150) groups showed invasive cell percentages (relative to Q(0) group) of 52.08%, 24.63%, and 13.13%, respectively (P<0.05). After quercetin treatment for 12 h, the migrating cell percentages (relative to Q(0) group) in Q(50), Q(100) and Q(150) groups were 49.46%, 26.78%, and 14.56%, respectively (P<0.05). After 24 h of quercetin treatment, the cell proliferation ratios in Q(0), Q(50), Q(100) and Q(150) groups were 25.21%, 18.38%, 16.74% and 15.24%; the cell percentages in phase G0/Gl were 71.14%, 72.71%, 69.29%, and 66.47%, phase S were 25.32%, 22.48%, 21.96%, and 23.32%, and phase G(2)/M were 3.53%, 4.80%, 8.75%, and 10.25% in the 4 groups, respectively, showing a significant difference between groups Q(100), Q(150) and group Q(0) in phase G(2)/M cell percentages (P<0.05). CONCLUSIONS: Quercetin can significantly inhibit the invasion, migration and proliferation of glioma U87 cells by blocking the cell cycle progression. PMID- 23443774 TI - [Expression of glypican-3 in lung squamous cell carcinoma and adenocarcinoma and its relation with prognosis]. AB - OBJECTIVE: To study the different expressions of glypican-3 in lung squamous cell carcinoma and adenocarcinoma and explore the association of glypican-3 with the prognosis of the patients. METHODS: Glypican-3 expression was detected immunohistochemically in the tumor tissues and adjacent tissues from 48 cases of lung squamous cell carcinoma and adenocarcinoma. Kaplan-Meier method and log-rank test were used for survival analysis of the patients. RESULTS: Glypican-3 expression was detected in the tumor tissues in 29.2% (14/48) of the cases, but not in the adjacent tissues. Of the 22 patients with lung squamous cell carcinoma, 12 (54.5%) showed positive glypican-3 expression in the tumor tissue, a rate significantly higher than that in patients with lung adenocarcinoma [7.7% (2/26), P<0.01]. In all the glypican-3-positive cases, the tumor tissues showed stronger glypican-3 expression in cases with lymph node metastasis or poor tumor differentiation. Kaplan-Meier survival analysis did not indicate a significant correlation of glypican-3 expression with the prognosis of the lung cancer patients. CONCLUSION: Patients with lung squamous cell carcinoma have higher glypican-3 expressions in the tumor tissues than those with lung adenocarcinoma, suggesting the value of glypican-3 protein as a potential marker to detect lung squamous cell carcinoma. PMID- 23443775 TI - [Estimation of ovarian response using multiple predictors of ovarian reserve in women undergoing in vitro fertilization-embryo transfer]. AB - OBJECTIVE: To analyze the value of ovarian reserve markers for predicting ovarian response in women undergoing in vitro fertilization-embryo transfer. METHODS: According to the ovarian response, 331 patients undergoing oocyte retrieval cycles were divided into of normal, poor, and high response groups. Serum anti Mvllerian hormone (AMH) was determined using AMH ELISA kit on day 3 of the menstrual cycle, antral follicle count (AFC) was measured using vaginal ultrasound, and basal serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E(2)) levels were detected using chemiluminescence method. RESULTS: Serum AMH and FSH levels, FSH/LH ratio, AFC, and the patients age, but not the basal E(2) level (P>0.05), were correlated with the number of oocytes collected (*1000/ampules of Gn) (P<0.001). AFC and serum AMH were the strongest single predictors for low ovarian response, with the areas under curve (AUC) of 0.855 (0.787-0.924) and 0.832 (0.764-0.900) (P<0.05), and cutoff values of <=9 and <=1.88 ng/ml, respectively. AFC was the strongest single predictor for high ovarian response, with an AUC of 0.787 (0.728-0.847) and the cutoff value of >=15. Logistic regression model found that the combination of AFC, serum AMH and FSH improved the predictive power for poor ovarian response, but not for high ovarian response. CONCLUSION: AFC, serum AMH, FSH, FSH/LH, and age are all predictors of ovarian response, among which AFC is the strongest single predictor. A multivariable model can improve the predictive power for low ovarian response but not for high ovarian response. PMID- 23443776 TI - [Design, synthesis and activity assessment of aryl-substituent benzyl acid targeting HIV gp41]. AB - OBJECTIVE: To synthesize novel aryl-substituent benzyl acid compounds targeting HIV gp41 and characterize their anti-HIV activities. METHODS: Twelve analogues of aryl-substituent benzyl acid were designed and synthesized by Suzuki- Miyaura cross-coupling and Knoevenagel condensation reactions using halo-benzyl acid or 3 carboxybenzeneboronic acid as the raw material. The inhibitory activities of these compounds on gp41 six-helix bundle formation were tested by ELISA, and their anti-HIV activities were determined using a luciferase assay. RESULTS: The structures of the compounds were characterized by nuclear magnetic resonance and mass spectrography. Among the 12 compounds, 5 (7b, 7c, 7d, 7e, and 7g) could inhibit the gp41 six-helix bundle formation, and 7d showed the most potent effect, and could also inhibit the replication of HIV-1 SF33 strain with an IC(50) of 20 umol/L. CONCLUSION: The synthesized aryl-substituent benzyl acid compound 7d could inhibit HIV replication by blocking the gp41 six-helix bundle formation. PMID- 23443777 TI - [Nano-Se-chondroitin sulfate inhibits T-2 toxin-induced apoptosis of cultured chondrocytes from patients with Kashin-Beck disease]. AB - OBJECTIVE: To observe the effect of nano-Se-chondroitin sulfate on the growth and apoptosis of chondrocytes from patients with Kashin-Beck disease (KBD) exposed to T-2 toxin in vitro. METHODS: Samples of the articular cartilage were obtained from 6 patients with grade II/III KBD diagnosed in line with the National Clinical Diagnostic Criteria of KBD (WS/T 207-2010) for chondrocyte separation and culture in vitro. The separated chondrocytes were treated with synthesized nano-Se-chondroitin sulfate particles and T-2 toxin, alone or in combination, and the cell growth and apoptosis were observed using MTT assay, HE staining and flow cytometry. RESULTS: The synthesized nano-Se-chondroitin sulfate, with a selenium entrapment ratio of 10.1%, spontaneously formed nanoparticles in distilled water with sizes ranging from 30 to 200 nm. Fourier-transform infrared spectroscopy suggested a possible covalent bond that bound Nano-Se and chondroitin sulfate. Within the concentration range of 50-200 ng/ml, nano-Se-chondroitin sulfate significantly inhibited T-2 toxin-induced apoptosis of the cultured chondrocytes and reduced the early apoptosis rate to (8.64?1.57)% (P<0.05). CONCLUSION: Nano Se-chondroitin sulfate can inhibit T-2 toxin-induced apoptosis of cultured chondrocytes from KBD patients in vitro, and serves as a promising candidate therapeutic agent for KBD. PMID- 23443778 TI - [Effect of ablations by pulsed versus continuous high-intensity focused ultrasound on isolated perfused porcine liver]. AB - OBJECTIVE: To compare the effect of ablations with pulsed and continuous high intensity focused ultrasound (HIFU) on the target area containing large blood vessels in isolated perfused porcine liver. METHODS: An isolated perfused liver model was established by perfusing the isolated porcine liver with autologous blood through the portal vein and hepatic artery using an cardiopulmonary bypass machine. With B-mode ultrasound guidance, a blood vessel about 4 mm in diameter was selected, and pulsed and continuous HIFU ablation at the same dose was delivered along the blood vessel at 3 mm to the vascular wall. After the ablation, the damages of the blood vessels as the acoustic channel and the target area were inspected, and the tissues at the interface of target volume and blood vessels were sampled for pathological examination. RESULTS: Neither pulsed nor continuous HIFU caused noticeable injuries of the acoustic channel vessels, but the volume of necrotic tissues in the target area differed significantly between the two groups (P<0.05). HE staining and vessel staining did not show any injuries of the blood vessels in the pathway of ultrasound ablation in neither of the groups (P>0.05). CONCLUSION: When the target area contains large blood vessels in the pathway of ultrasound ablation, pulsed HIFU can have better therapeutic efficiency to effectively induce tissue damages without affecting the blood vessels. PMID- 23443779 TI - [CD99 regulates redifferentiation of classical Hodgkin's lymphoma cell line L428 towards B cells]. AB - OBJECTIVE: To explore the effect of CD99 overexpression on the morphology and differentiation-related phenotypes of classical Hodgkin's lymphoma cell line L428 and investigate the role of CD99 gene in Hodgkin/Reed-Sternberg (HRS) cell generation and transformation. METHODS: The effect of CD99 overexpression on the cell morphology was detected by HE staining and phalloidin staining. Differentiation-related protein expressions were detected by immunocytochemistry and flow cytometry after stable transfection of CD99 gene in L428 cells. RESULTS: CD99 overexpression caused a decrease of the cell size and reorganization of the actin cytoskeleton in L428 cells. Upregulation of CD99 led to the loss of classical Hodgkin's lymphoma diagnosis marker CD30 and CD15 and the restoration of the B-cell makers of PAX5, CD19, CD79alpha, BCL-6, and CD10. CONCLUSION: CD99 overexpression leads to redifferentiation of L428 cells towards B cells, suggesting that the loss of B-cell phenotype in classical Hodgkin's lymphoma is very likely a result of down-regulated CD99 expression. PMID- 23443780 TI - [Improvement of magnetic resonance phase unwrapping method based on Goldstein Branch-cut algorithm]. AB - OBJECTIVE: The phase information of magnetic resonance (MR) phase image can be used in many MR imaging techniques, but phase wrapping of the images often results in inaccurate phase information and phase unwrapping is essential for MR imaging techniques. In this paper we analyze the causes of errors in phase unwrapping with the commonly used Goldstein Brunch-cut algorithm and propose an improved algorithm. During the unwrapping process, masking, filtering, dipole- remover preprocessor, and the Prim algorithm of the minimum spanning tree were introduced to optimize the residues essential for the Goldstein Brunch-cut algorithm. Experimental results showed that the residues, branch-cuts and continuous unwrapped phase surface were efficiently reduced and the quality of MR phase images was obviously improved with the proposed method. PMID- 23443781 TI - [Establishment of a mouse model bearing spinal metastatic human prostate cancer using fluorescence-labeled PC-3 cells]. AB - OBJECTIVE: To establish a mouse model of spinal metastasis of human prostate cancer using fluorescence-labeled PC-3 cells to allow direct observation by in vivo imaging. METHODS: PC-3 cells were infected with a lentivirus carrying green fluorescence protein (GFP) gene. The GFP-positive cell clone was expanded and prepared into cell suspension for injection into the inferior vena cava of nude mice. The tumor growth and metastasis in the mice was directly observed using an in vivo fluorescence imaging system. The tumor-bearing mice were sacrificed after 3 months for histological examination with HE staining. RESULTS: The labeled cells showed stable GFP expression both in vitro and in vivo. One week after cell injection, green fluorescence signals were detected by the in vivo fluorescence imaging system in the lower back of the mice, and at 4 weeks, the fluorescent tumor mass increased with a bone metastasis rate of 19% (3/16). Dissection of the mice at 3 months revealed lumbar tumor infiltration in 3 mice, showing a consistent result with in vivo fluorescence imaging. CONCLUSION: The nude mouse model of spinal bone metastasis of human prostate cancer established using GFP labeled PC-3 cells facilitates further study of bone metastasis of prostate cancer. PMID- 23443782 TI - [Value of magnetic resonance imaging T2* tests in detecting heart and liver iron overload in patients with beta-thalassemia major]. AB - OBJECTIVE: To assess the value of magnetic resonance imaging T2* tests in the detection of myocardial and liver iron overload in patients with beta-thalassemia major (beta-TM). METHODS: From 2010 to 2011, 28 beta-TM patients over 10 years old under blood transfusion therapy and chelation care with serum ferritin (SF)>1000 ug/L underwent myocardial and liver MRI T2* tests on a voluntary basis. The results were analyzed in relation with age, SF, and left ventricular ejection fraction (LVEF). RESULTS: Fourteen out of the 28 cases (50%) were found to have myocardial iron overload, including 7 severe cases, 2 moderate cases, and 5 mild cases. All the 28 cases had liver iron overload, including 2 mild cases, 7 moderate cases, and 19 severe cases. Two out of the 28 cases had lowered LVEF (7.14%), and one of them had severe myocardial iron overload. There was a negative correlation between myocardial MRI T2* and SF (r=-0.479, P=0.01). Myocardial MRI T2* was positively correlated with liver MRI T2* (r=0.378, P=0.047). Age was not significantly correlated with SF, LVEF, or liver MRI T2*. CONCLUSION: Magnetic resonance imaging (T2*) detection is an effective and non invasive means for detecting myocardial and liver iron overload in patients with beta-thalassemia major receiving blood transfusion. T2* combined with SF is the main diagnostic indicator to assess iron overload in the vital organs. PMID- 23443783 TI - [Prediction and identification of B-cell linear epitopes of hepatitis B e antigen]. AB - OBJECTIVE: To predict and identify B-cell linear epitopes of hepatitis B e antigen (HBeAg). METHODS: The B-cell linear epitopes of HBeAg were predicted using the software provided by NCBI Database and Immune Epitope Database (IEDB) and synthesized by a solid-phase method followed by conjugation with keyhole limpet hemocyanin (KLH). The KLH conjugates were used for immunization of New Zealand white rabbits, and the immune response of the rabbits was monitored by direct ELISA using a bovine serum albumin conjugate of the predicted epitopes. RESULTS Four new B-cell linear epitopes of HBeAg were identified, namely (1)MDIDPYKEFG(10), (37)LYREALESPEHCSP(50), (74)SNLEDPAS(81) and (127)RTPPAYRPPNAPIL(140). The rabbits immunized with the KLH conjugate showed an antibody titer over 1:512 000. The antisera of B-cell linear epitopes collected could specifically react with HBeAg as shown by ELISA. CONCLUSION: Four B-cell linear epitopes of HBeAg have been confirmed using bioinformatics methods, which provides new evidence for further functional studies of HBeAg in hepatitis B. PMID- 23443784 TI - [Effects of Sam68 gene silencing on proliferation of nasopharyngeal carcinoma cell line 5-8F and its possible molecular mechanism]. AB - OBJECTIVE: To observe the effect of Sam68 gene silencing on proliferation of nasopharyngeal carcinoma (NPC) cell line 5-8F and explore its possible molecular mechanism. METHODS: The NPC cell line 5-8F was transfected with a small interfering RNA (siRNA) targeting Sam68 and the cell proliferation changes were observed. Quantitative RT-PCR and Western blotting were used to examine the changes in the expressions of Sam68, cell cycle-related proteins, and some up stream proteins in the transfected cells. RESULTS: Transfection of 5-8F cells with Sam68-specific siRNA significantly lowered the mRNA and proteins levels of Sam68, suppressed cell proliferation, decreased the expression of Cyclin D1, and increased the expression of p27. The transfected cells showed obviously decreased expressions of p-FOXO3a, p-Akt and p-GSK-3beta, but the expressions of FOXO3a, Akt and GSK-3beta were not obviously affected. CONCLUSIONS: Sam68 modulates the proliferation of NPC cells probably by activating Akt/FOXO3a pathway and regulating the cell proliferation-related molecules. PMID- 23443785 TI - [Real-time PCR for detecting differential expressions of microRNAs in the brain of a transgenic mouse model of Alzheimer's disease]. AB - OBJECTIVE: To detect the expression of miRNA-135a-5p, miRNA-135a-2-3p, miRNA-298 5p, miRNA-466b-3p and miR-669f-3p in the brain tissue of the APPswe/PS deltaE9 double transgenic mouse model of Alzheimer's disease using real-time PCR. METHODS: Six-month-old APPswe/PS deltaE9 double transgenic mice and wild-type C57 mice of the same species were examined for the expressions of miRNA-135a-5p, miRNA-135a-2-3p, miRNA-298-5p, miRNA-466b-3p and miR-669f-3p in the brain tissue using real-time PCR. RESULTS: The relative expression levels of the 5 miRNAs in the transgenic versus the wild-type mice were 0.73?0.27 vs 1.08?0.58, 2.47?6.15 vs 1.65?0.67, 0.72?0.14 vs 1.31?0.73, 0.57?0.34 vs 1.06?0.35, and 0.63?0.26 vs 1.02?0.18, respectively, showing significance differences in the expressions of miRNA-135a-5p, miRNA-298-5p, miRNA-466b-3p, and miR-669f-3p between the two groups (P<0.05). CONCLUSIONS: miRNA-135a-5p, miRNA-298-5p, miRNA-466b-3p and miR 669f-3p are expressed differentially in APPswe/PS deltaE9 double transgenic mice, suggesting their important roles in the pathogenesis of Alzheimer disease. PMID- 23443786 TI - [Construction of digital three-dimensional models of renal stones and virtual surgery simulation]. AB - OBJECTIVE: To construct three-dimensional (3D) models of renal stones and perform percutaneous nephrolithotomy (PCNL) virtual surgery simulation. Methods CT images were obtained from 8 patients with renal stones. Images segmentation and reconstruction were performed using MIMICS 10.0 software to construct the 3D model of the renal stones, which provided the anatomical relationships between the kidney and the adjacent organs. The optimal PCNL virtual surgery simulation for each individual case was performed using FreeForm Modeling System on the basis of the 3D model. RESULTS: Eight 3D models of renal stone were constructed. The 3D model of the renal stones represented the interrelationships of the stones, intrarenal vessel, and the collecting system with the adjacent anatomical structures. Individualized PCNL virtual surgery simulations including percutaneous puncture, dilatation and pneumatic lithotripsy were performed successfully in all the 8 3D models. CONCLUSION: Digital 3D model of renal stone provides the reliable and comprehensive imaging information for surgical design, and PCNL virtual surgery simulation has important clinical significance to improve the stone clearance rate and reduce the surgical complications. PMID- 23443787 TI - [Effects of HSP90 inhibitor 17-AAG on cell cycle and apoptosis of human gastric cancer cell lines SGC-7901]. AB - OBJECTIVE: To study the effect of the HSP90 inhibitor, 17-allylamino-17 demethoxygeldanamycin (17-AAG), on cell proliferation and apoptosis of human cancer SGC-7901 cells and explore the mechanisms. METHODS: The inhibitory effect of 17-AAG on the proliferation and morphology of SGC-7901 cells was assessed with MTT assay and DNA-PI staining, respectively. Flow cytometry was employed to analyze the changes in cell cycle and apoptosis of the cells following 17-AAG exposure. The cellular expression of Fas protein was detected by immunohistochemistry. RESULTS: 17-AAG significantly suppressed the proliferation of SGC-7901 cells in a time- and dose-dependent manner. After treatment with 17 AAG for 48 h, SGC-7901 cells showed cell cycle arrested at G(2)/M stage, and the cell apoptosis rate increased with the 17-AAG concentration. The expression of Fas protein in the cytoplasm of SGC-7901 cells increased gradually with the increase of 17-AAG concentration. CONCLUSION: 17-AAG can induce apoptosis, alters the cell cycle distribution and up-regulates the expression of Fas protein in SGC 7901 cells to suppress the cell proliferation. PMID- 23443788 TI - [Low-intensity ultrasound promotes uterine involution following cesarean section]. AB - OBJECTIVE: To observe the clinical effect of low-intensity ultrasound in promoting uterine involution following cesarean section. METHODS: A total of 122 women undergoing cesarean section were randomly selected and divided into low intensity ultrasound treatment group (67 cases) and control group (55 cases). The women in the treatment group received daily low-intensity ultrasound treatment for 30 min 24 h after the delivery for 3 consecutive days, and the control group had no particular treatments. The descent of the uterine fundus and cessation of lochia was observed in the two groups. RESULTS: The treatment group showed obviously greater descent of the uterine fundus with a higher rate of cessation of vaginal bleeding than the control group at 30 days postpartum. The ratio of incomplete uterine involution was significantly lower in the treatment group than in the control group. CONCLUSION: Low-intensity ultrasound is effective in promoting uterine contraction and uterine involution following cesarean section. PMID- 23443789 TI - [Analysis of 112 cases of infectious endocarditis]. AB - OBJECTIVE: To analyze the clinical manifestations, epidemiological features, pathogens, treatment and outcomes of 112 patients with infectious endocarditis. METHODS: The clinical data were reviewed for all the patients with the diagnosis of infectious endocarditis in Nanfang Hospital over the period from 2002 to 2012. RESULTS: The average age of disease onset was 46?17.1 years among these cases. Seventy patients (62.5%) had underlying cardiac conditions, including, in the order of frequency, rheumatic heart disease, congenital cardiovascular anomalies, and senile valve degeneration. Clinically the patients presented with fever, anemia, congestive heart failure, and embolism events, etc. Echocardiography found endocardial neoplasms in 105 cases, and the mitral valve was often involved. Blood culture yielded positive results in 61 cases, and the most common causative bacteria were Streptococcus (20.5%), Staphylococcus (19.6%) and Enterococcus (5.4%). Surgical intervention was performed in 78 cases. Ninety-one patients were cured or improved after comprehensive treatment, and 10 discontinued treatment for financial reasons; 11 died of cardiac failure (8 cases), pulmonary embolism (2 cases) and central nervous system events (1 case). CONCLUSION: Infectious endocarditis shows a significant change in the clinical profiles and its mortality remains high despite improved diagnostic and therapeutic procedures. PMID- 23443790 TI - [Histone acetylation modulates influenza virus replicative intermediate dsRNA induced interleukin-6 expression in A549 cells]. AB - OBJECTIVE: To investigate the role of histone acetylation in regulating influenza virus replicative intermediate double-stranded RNA (dsRNA)-induced interleukin-6 (IL-6) expression in A549 cells. METHODS: A549 cells were treated with influenza virus replicative intermediate dsRNA, histone deacetylase (HDAC) inhibitor trichostatin A (TSA), or HADC small interfering RNA (siRNA). The changes in the cellular IL-6 promoter activities were detected by dual-luciferase assay, and IL 6 mRNA and protein expressions in the cells were determined using real-time RT PCR and ELISA, respectively. RESULTS: Influenza virus replicative intermediate dsRNA obviously up-regulated IL-6 expression in the cells. HDAC inhibitor TSA significantly enhanced the activity of IL-6 promoter and increased IL-6 mRNA expression in A549 cells, and HDAC3 may play an important role in this process. HDAC inhibitor TSA and DNMT inhibitor DAC showed no synergic effect in regulating IL-6 expression. CONCLUSIONS: Influenza virus replicative intermediate dsRNA induced IL-6 expression in A549 cells is regulated by histone acetylation. PMID- 23443791 TI - [Comparison of clinical characteristics between rifampin-dependent and rifampin- resistant patients with pulmonary tuberculosis]. AB - OBJECTIVE: To compare the clinical characteristics of rifampin-dependent (R dependent Mycobacterium tuberculosis) and rifampin-resistant (R-resistant Mycobacterium tuberculosis) patients with pulmonary tuberculosis. METHODS: The clinical data including the demographic data, age groups, course of disease, history of chemotherapy with anti-TB drugs, and results of drug susceptibility test were collected from 61 cases of R-dependent pulmonary tuberculosis and 148 cases of R-resistant pulmonary tuberculosis treated between October, 2008 and January, 2012. RESULTS: Most of the R-dependent and R-resistant patients were between 30 and 44 years of age. The R-dependent patients included 12 receiving the first treatment patients and 49 with previous treatments, and the R-resistant patients included 11 without and 137 with previous treatments. The multi-drug resistant rate was 80.3% in R-dependent group, as compared to 92.6% in R resistant group. CONCLUSION: Most of the patients infected with R-dependent Mycobacterium tuberculosis are young or middle-aged, often having serious disease conditions. Detecting rifampin dependence is important for patients with initial treatment failure. Multi-drug resistance therapy guideline should be applied to patients infected with R-dependent Mycobacterium tuberculosis to improve the cure rate. PMID- 23443792 TI - [Effect of ozonated water on physical and chemical properties of vacuum sealing drainage material]. AB - OBJECTIVE: To investigate the influence of ozonated water on physical and chemical properties of vacuum sealing drainage (VSD) materials. METHODS: VSD materials (foam and sealing membrane) were immersed in 10 ug/ml ozonated water for 1 h twice daily for 8 days. The foam appearance and microscopic structure of the materials were observed, and tensile tests and Raman spectrum scan were performed assess the effect of ozonated water. Simulated VSD devices were prepared and tested for leakproofness under negative pressure after ozonated water treatment. RESULTS: zonated water treatment for 8 days caused no obvious abnormal changes in the foam appearance or microscopic structure of the materials. The maximum tensile load of foam before and after ozonated water treatment was 4.25?0.73 kgf and 2.44?0.19 kgf (P=0.000), the momentary distance when the foam torn before and after intervention was 92.54?12.83 mm and 64.44?4.60 mm, respectively (P=0.000). The corresponding results for VSD sealing membrane were 0.70?0.58 kgf and 0.71?0.08 kgf (P=0.698), and 99.30?10.27 mm and 100.95?18.22 mm (P=0.966), respectively. Raman spectroscopy revealed changes in only several wave intensities and no new chemical groups appeared within the scan range of 400-4000 cm(-1). The VSD device was well hermetic after treatment with ozonated water. CONCLUSION: Except for a decreased stretch resistance property of the foam, VSD materials display no obvious changes in physical and chemical characteristics after treatment with ozonated water for 8 days. PMID- 23443793 TI - [Pathologically confirmed histoplasmosis: analysis of 14 cases]. AB - OBJECTIVE: To summarize the features of disease history, clinical manifestations, adjuvant examination results, diagnosis, treatments and outcome of patients with histoplasmosis. METHODS: The clinical data of 14 patients with biopsy-confirmed histoplasmosis between 2000 and 2012 in Nanfang Hospital were analyzed retrospectively. RESULTS: The clinical manifestations of histoplasmosis included fever, productive cough, chest pain, and abdominal pain, accompanied occasionally by neurological symptoms, lymph node enlargement or surface mass. Seven out of the 14 o patients had underlying immunosuppressive conditions, 9 had chest imaging changes, and 2 showed reduced white blood cells, red blood cells and platelets. The cases were initially diagnosis as tuberculosis, malignant tumor, or malignant lymphoma before the definite diagnosis was established pathologically. Ten patients received treatments with itraconazole, amphotericin B, fluconazole or voriconazole, and 9 of them responded favorably to the treatments. CONCLUSION: Histoplasmosis, with a low incidence and diverse clinical manifestations, presents with no specific imaging features to easily cause misdiagnosis and missed diagnosis, and its definite diagnosis relies on pathological examination. PMID- 23443794 TI - [Protective effect of licoflavone on gastric mucosa in rats with chronic superficial gastritis]. AB - OBJECTIVE: To evaluate the protective effect of licoflavone on gastric mucosa in rats with chronic superficial gastritis and explore the possible mechanism. METHODS: SD rat models of chronic superficial gastritis was established by intragastric administration of 0.02% ammonia and long-term irregular diet. The rat models were then randomized into model group, vitacoenzyme group and 3 licoflavone groups of high, medium, and low doses. After 30 days of treatment, the gastric histopathology, mucosal lesions, scanning electron microscopy, mucin function production by the gastric mucosa epithelial cells, serum PGE(2) level and gastric microcirculation were assessed to evaluate the protective effect of licoflavone on gastric mucosa. RESULTS: Compared with normal control rats, the rat models of chronic superficial gastritis showed significantly higher gastric mucosal injury rate, histopathological scores and gastric mucin content. Licoflavone significantly ameliorated gastric pathology and increased serum PGE(2) level, enhanced acidic mucin secretion by the epithelial cells, and improved gastric microcirculation in the rat models. CONCLUSION: Licoflavone feeding suppresses gastric mucosa injury, protects and restores the injured mucosa in rats with chronic superficial gastritis, and these effects are related with the up-regulation of serum PGE(2) level. PMID- 23443795 TI - [Effects of astaxanthin on renal fibrosis and cell apoptosis induced by partial unilateral ureteral obstruction in rats]. AB - OBJECTIVE: To study the effects of astaxanthin on renal fibrosis and apoptosis induced by partial unilateral ureteral obstruction (UUO) in rats. METHODS: Ninety six male adult SD rats were randomized into 6 equal groups, namely the blank control group, sham-operated group, UUO group, and astaxanthin group at high, medium, and low doses. Left ureteral ligation was performed in UUO and astaxanthin groups, and two days before the operation, the rats in astaxanthin groups were lavaged with 25, 50, or 100 mg/kg astaxanthin daily for 14 days, while the same volume of saline was given to rats in UUO group and sham-operated group. Renal pathological in the rats was observed with HE staining, and the expression levels of TGF-beta1, SGK1, and CTGF in the left kidney were detected immunohistochemically; the expression level of Bcl-2 and Bax were detected using Bcl-2 and Bax detection kits. RESULTS: Compared to UUO group, high- and medium dose astaxanthin groups showed obviously ameliorated renal pathologies and reduced expressions of TGF-beta1, SGK1, and CTGF in the left kidney with lessened renal cell apoptosis. CONCLUSION: Astaxanthin can reduce UUO-induced renal fibrosis and renal cell apoptosis, demonstrating the renoprotective effect of astaxanthin against renal fibrosis. PMID- 23443796 TI - [Human u-opioid receptor A118G polymorphism affects epidural patient-controlled analgesia with fentanyl]. AB - OBJECTIVE: To investigate whether A118G single nucleotide polymorphisms of the u opioid receptor (OPRM1) affects epidural patient-controlled analgesia with fentanyl after caesarean section. METHODS: A total of 100 pregnant women (ASA class I or II) scheduled for elective caesarean section were enrolled in this study. All the patients received spinal-epidural anesthesia and were screened for blood A118G polymorphism. Epidural patient-controlled analgesia with fentanyl was provided postoperatively. The pain scores, incidence of nausea and vomiting, and total self-administered epidural fentanyl dose within 48 h postoperatively were recorded. RESULTS: Ninety-six patients were finally included in this study. The percentages of the genotypes AA, AG, and GG were 36.5% (35 cases), 46.9% (45 cases), and 16.7% (16 cases), respectively. At 12 and 24 h postoperatively, the pain scores and the total fentanyl dose administered were significantly higher in group GG than in groups AA and AG. CONCLUSION: A118G single nucleotide polymorphism affects pain relief and total fentanyl dose administered in epidural patient-controlled analgesia after caesarean section. G118 homozygotes have a poorer response to fentanyl than A118 homozygotes or heterozygotes. PMID- 23443797 TI - [Primary ovarian carcinoid clinically manifested by intractable constipation: a case report]. AB - OBJECTIVE: Ovarian carcinoid tumor is a very rare, low-grade malignant tumor, and most of the patients have no typical clinical symptoms. Some patients seek medical attention for pelvic masses often found incidentally, and about one-third of the patients may present with carcinoid syndrome. We report a case of ovarian carcinoid tumor clinically manifested by intractable constipation, which is a rare condition in these patients. PMID- 23443798 TI - FOX(M1) news--it is cancer. AB - FOXM1 is an oncogenic transcription factor of the Forkhead family and it has a well-defined role in cell proliferation and cell-cycle progression. Expression of FOXM1 is excluded in quiescent or differentiated cells, but its level is highly elevated in proliferating and malignant cells. Overexpression of FOXM1 has been reported in more than 20 types of human cancer. In recent years, FOXM1 has been implicated in diverse cellular processes and also a growing body of experimental data has underlined the relevance of FOXM1 in tumorigenesis. Although FOXM1 is under the control of three major tumor suppressors (RB, p53, and p19(ARF)), it is still active in the majority of human cancers. The oncogenic potential of FOXM1 is mainly based on its ability to transcriptionally activate genes that are involved in different facets of cancer development. In this review, the contribution of FOXM1 to each of the hallmarks of cancer will be summarized and discussed. PMID- 23443799 TI - A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy. AB - Nonsteroidal anti-inflammatory drugs such as sulindac sulfide have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from COX inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of sulindac sulfide, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth-inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2 to 5 MUmol/L compared with 44 to 52 MUmol/L for sulindac sulfide. SSA also suppressed DNA synthesis and caused a G0-G1 cell-cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage was not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, whereas pan caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action, along with its increased potency and lack of COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer. PMID- 23443800 TI - ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non small cell lung cancer expressing EML4-ALK. AB - Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK. PMID- 23443801 TI - A phase II study of temozolomide in patients with advanced aerodigestive tract and colorectal cancers and methylation of the O6-methylguanine-DNA methyltransferase promoter. AB - Responses of patients with gliomas to temozolomide are determined by O(6) methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) pathways. This phase II study (NCT00423150) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers (CRC). Tumor and serum samples were screened for MGMT promoter methylation. In methylation-positive patients, 150 mg/m(2) temozolomide was administered daily on a seven-day-on, seven-day-off schedule for each 28-day cycle. The primary efficacy endpoint was response rate (RR). MMR status was determined by a microsatellite instability assay. Among 740 patients screened, 86 were positive for MGMT promoter methylation and enrolled. Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non small cell lung carcinoma. Among patients with valid methylation results in both tissue and serum samples, concordance was 81% (339 of 419). The majority of enrolled patients (69 of 86; 80%) had microsatellite stable cancer. Overall RR was 6% (5 of 86 partial responses); all responders had microsatellite stable cancer. Temozolomide resulted in low RRs in patients enriched for MGMT methylation. MGMT methylation status varied considerably in the patient population. Although serum methylation assay is an option for promoter methylation detection, tissue assay remains the standard for methylation detection. The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types, and tumor-specific factors may override validated biomarkers. PMID- 23443802 TI - Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death. AB - Oncogenic mutations in GNAQ and GNA11 genes are found in 80% of uveal melanoma. These mutations result in the activation of the RAF/MEK signaling pathway culminating in the stimulation of ERK1/2 mitogen-activated protein kinases. In this study, using a siRNA strategy, we show that mutant GNAQ signals to both MEK and AKT, and that combined inhibition of these pathways with the MEK inhibitor selumetinib (AZD6244) and the AKT inhibitor MK2206 induced a synergistic decrease in cell viability. This effect was genotype dependent as autophagic markers like beclin1 and LC3 were induced in GNAQ-mutant cells, whereas apoptosis was the mechanism of cell death of BRAF-mutant cells, and cells without either mutation underwent cell-cycle arrest. The inhibition of MEK/ATK pathways induced activation of AMP-activated protein kinase (AMPK) in the GNAQ-mutant cells. The downregulation of AMPK by siRNA or its inhibition with compound C did not rescue the cells from autophagy, rather they died by apoptosis, defining AMPK as a key regulator of mutant GNAQ signaling and a switch between autophagy and apoptosis. Furthermore, this combination treatment was effective in inhibiting tumor growth in xenograft mouse models. These findings suggest that inhibition of MEK and AKT may represent a promising approach for targeted therapy of patients with uveal melanoma. PMID- 23443803 TI - Regression of lung cancer by hypoxia-sensitizing ruthenium polypyridyl complexes. AB - The ruthenium (II) polypyridyl complexes (RPC), Delta-[(phen)2Ru(tatpp)]Cl2 (Delta-[3]Cl2) and DeltaDelta-[(phen)2Ru(tatpp)Ru(phen)2]Cl4 (DeltaDelta-[4]Cl4, are a new generation of metal-based antitumor agents. These RPCs bind DNA via intercalation of the tatpp ligand, which itself is redox-active and is easily reduced at biologically relevant potentials. We have previously shown that RPC 4(4+) cleaves DNA when reduced by glutathione to a radical species and that this DNA cleavage is potentiated under hypoxic conditions in vitro. Here, we show that 3(2+) also exhibits free radical-mediated DNA cleavage in vitro and that 3(2+) and 4(4+) both exhibit selective cytotoxicity toward cultured malignant cell lines and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 3(2+) and 4(4+) (maximum tolerable doses ~ 65 MUmol/kg) is comparable with that for cisplatin (LD50 ~ 57 MUmol/kg), but unlike cisplatin, RPCs are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 3(2+) and 4(4+) are shown to suppress growth of human non-small cell lung carcinoma (~83%), show potentiated cytotoxicity in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biologic activity suggest a promising new anticancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials. PMID- 23443804 TI - Activity of a Py-Im polyamide targeted to the estrogen response element. AB - Pyrrole-imidazole (Py-Im) polyamides are a class of programmable DNA minor groove binders capable of modulating the activity of DNA-binding proteins and affecting changes in gene expression. Estrogen receptor alpha (ERalpha) is a ligand activated hormone receptor that binds as a homodimer to estrogen response elements (ERE) and is a driving oncogene in a majority of breast cancers. We tested a selection of structurally similar Py-Im polyamides with differing DNA sequence specificity for activity against 17beta-estadiol (E2)-induced transcription and cytotoxicity in ERalpha positive, E2-stimulated T47DKBluc cells, which express luciferase under ERalpha control. The most active polyamide targeted the sequence 5'-WGGWCW-3' (W = A or T), which is the canonical ERE half site. Whole transcriptome analysis using RNA-Seq revealed that treatment of E2 stimulated breast cancer cells with this polyamide reduced the effects of E2 on the majority of those most strongly affected by E2 but had much less effect on the majority of E2-induced transcripts. In vivo, this polyamide circulated at detectable levels following subcutaneous injection and reduced levels of ER driven luciferase expression in xenografted tumors in mice after subcutaneous compound administration without significant host toxicity. PMID- 23443805 TI - Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells. AB - The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. PMID- 23443806 TI - Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. AB - An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation. PMID- 23443808 TI - Effects of miR-19b overexpression on proliferation, differentiation, apoptosis and Wnt/beta-catenin signaling pathway in P19 cell model of cardiac differentiation in vitro. AB - MicroRNA (miR)-19b is part of the miR-17-92 cluster associated with cardiac development. Here, we investigated the effects of overexpressing miR-19b on proliferation, differentiation, apoptosis, and regulation of the Wnt/beta-catenin signaling pathway in the multipotent murine P19 cell line that can be induced to undergo cardiogenesis. P19 cells were transfected with the miR-19b plasmid or empty vector, and miR-19b overexpression was verified by Quantitative Real-Time PCR (qPCR). The miR-19b or vector control stable cell lines were selected using Blasticidin S HCl, and their proliferation, cell cycle, and apoptosis levels were analyzed using the Cell Counting Kit-8 and flow cytometry. P19 cell differentiation markers, apoptosis-related genes (bax, bcl-2), and Wnt/beta catenin signaling pathway-related genes were detected by qPCR, the corresponding proteins by Western blot. Expression of the Wnt pathway and differentiation marker proteins was also verified by immunofluorescence. Morphological changes associated with apoptosis were observed by electron microscopy and Hoechst staining. On the basis of these results, we demonstrated that miR-19b overexpression promoted proliferation and differentiation but inhibited apoptosis in P19 cells; Wnt and beta-catenin expressions were decreased, while that of GSK3beta was increased with miR-19b overexpression. Overexpression of miR-19b inhibited activation of the Wnt/beta-catenin signaling pathway in P19 cells, which may regulate cardiomyocyte differentiation. Our findings may bring new insights into the mechanisms underlying cardiac diseases and suggest that miR-19b is a potential new therapeutic target for cardiovascular diseases. PMID- 23443807 TI - Spongian diterpenoids inhibit androgen receptor activity. AB - Androgen receptor is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiologic ligands for androgen receptor ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit androgen receptor transcriptional activity yielded the furanoditerpenoid spongia 13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semisynthetic analogues (T2 and T3) revealed that these diterpenoids have antiandrogen properties that include inhibition of both androgen-dependent proliferation and androgen receptor transcriptional activity by a mechanism that involved competing with androgen for androgen receptor LBD and blocking essential N/C interactions required for androgen-induced androgen receptor transcriptional activity. Structure-activity relationship analyses revealed some chemical features of T1 that are associated with activity and yielded T3 as the most potent analogue. In vivo, T3 significantly reduced the weight of seminal vesicles, which are an androgen-dependent tissue, thereby confirming the on-target activity of T3. The ability to create analogues of diterpenoids that have varying antiandrogen activity represents a novel class of chemical compounds for the analysis of androgen receptor ligand-binding properties and therapeutic development. PMID- 23443809 TI - Effect of arborvitae seed on cognitive function and alpha7nAChR protein expression of hippocampus in model rats with Alzheimer's disease. AB - The aim was to investigate the effect of the arborvitae seed on cognitive function and alpha7-nicotinic acetylcholine receptor (alpha7nAChR) protein expression of the hippocampus in model rats with Alzheimer's disease (AD). Thirty six adult Wistar rats were randomly divided into the control, test, and drug groups. A dose of Abeta1-40 was injected into the rats' hippocampus in the test and drug groups and the control rats were injected with the same amount of normal saline. After the model was successful, the rats in the control and test groups were gavaged with sodium carboxymethyl cellulose (500 mg/kg) and the rats in the drug group were gavaged with arborvitae seed powder (500 mg/kg) for 15 days. The Morris water maze test was used for cognitive function. The effect of arborvitae seed on alpha7nAChR protein immunoreactivity on the hippocampus neurons was studied by the immunohistochemistry method. Behavioral tests showed that the mean escape latencies and search time of the test group were obviously longer than the control and drug groups. The percentage of the search distance of the test group was shorter than that of the control and drug groups. The immunohistochemistry results are as follows: alpha7nAChR-positive cells and optical density in the hippocampus of the rats in the test group are less than that of the rats in the control and drug groups (all P < 0.01). Arborvitae seed can treat AD by increased expression of alpha7nAChR. PMID- 23443810 TI - Effect of miR-21 on renal fibrosis by regulating MMP-9 and TIMP1 in kk-ay diabetic nephropathy mice. AB - MicroRNAs (miRs) play important roles in initiation and progression of many pathologic processes. However, the roles of miRs in diabetic nephropathy remain unclear. This study was to determine whether miR-21 was involved in diabetic nephropathy and to explore the relationship between miR-21 and MMP9/TIMP1 expression in diabetic nephropathy. In situ hybridization studies showed that miR 21 was primarily localized and distributed in cortical glomerular and renal tubular cells in diabetic kk-ay kidney. Real-time quantitative RT-PCR demonstrated that the expression of miR-21 was significantly increased in kk-ay mice, compared with control C57BL mice. Interestingly, miR-21 expression positively correlated with urine albumin creatine ratio (ACR), TIMP1, collagen IV (ColIV), and fibronectin (FN); while negatively correlated with creatine clearance ratio (Ccr) and MMP-9 protein. Importantly, antagomir-21 not only ameliorated Ccr and ACR but also decreased TIMP1, ColIV, and FN proteins. In conclusion, our data demonstrate that miR-21 contributes to renal fibrosis by mediating MMP9/TIMP1 and that inhibition of miR-21 may be a novel target for diabetic nephropathy. PMID- 23443811 TI - Postembryonic development of the bone-eating worm Osedax japonicus. AB - Bone-eating worms of the genus Osedax exclusively inhabit sunken vertebrate bones on the seafloor. The unique lifestyle and morphology of Osedax spp. have received much scientific attention, but the whole process of their development has not been observed. We herein report the postembryonic development and settlement of Osedax japonicus Fujikura et al. (Zool Sci 23:733-740, 2006). Fertilised eggs were spawned into the mucus of a female, and the larvae swam out from the mucus at the trochophore stage. Larvae survived for 10 days under laboratory conditions. The larvae settled on bones, elongated their bodies and crawled around on the bones. Then they secreted mucus to create a tube and the palps started to develop. The palps of O. japonicus arose from the prostomium, whereas the anterior appendages of other siboglinids arose from the peristomium. The recruitment of dwarf males was induced by rearing larvae with adult females. Females started to spawn eggs 6 weeks after settlement. PMID- 23443813 TI - Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry. AB - CONTEXT: Although primary aldosteronism (PA) is the most common cause of endocrine hypertension, histopathological methods to reveal the presence and sites of aldosterone overproduction remain to be established. OBJECTIVE: The objective of the study was to investigate the significance of immunohistochemical staining to detect CYP11B2 and CYP11B1 in adrenal tissue of patients with PA. DESIGN AND PATIENTS: Thirty-two patients with PA who underwent unilateral adrenalectomy were studied. Immunohistochemical staining was performed using anti CYP11B2 and anti-CYP11B1 antibodies on paraffin-embedded sections. We analyzed the expression of each enzyme semiquantitatively by scoring staining intensity and correlating it with clinical findings. RESULTS: Twenty-two patients showed positive CYP11B2 immunostaining in their tumors (aldosterone producing adenoma, APA). Four patients with CYP11B2-negative unilateral adenomas and 4 patients without tumors on computed tomography showed aldosterone-producing cell clusters (APCCs) with CYP11B2 immunostaining in the zona glomerulosa (multiple APCCs). The remaining 2 patients had unilateral multiple adrenocortical micronodules and diffuse adrenocortical hyperplasia, respectively. In APA, CYP11B2 score adjusted for tumor volume was positively correlated with plasma aldosterone and negatively correlated with serum potassium. The APA group was divided into 3 subgroups based on relative CYP11B2 and CYP11B1 immunostaining levels. The CYP11B2/CYP11B1 equivalent and CYP11B1-dominant APA groups showed significantly higher serum cortisol after 1 mg dexamethasone and larger tumor size than the CYP11B2-dominant APA group. CONCLUSIONS: The present study clearly demonstrates that CYP11B2 immunostaining is a powerful tool for histopathological diagnosis of aldosterone overproduction in PA and for subtype classification of APA, multiple APCCs, unilateral multiple adrenocortical micronodules, and diffuse hyperplasia. PMID- 23443812 TI - Serum sex steroid levels and longitudinal changes in bone density in relation to the final menstrual period. AB - CONTEXT: The associations of serum sex steroid and FSH levels with change of bone mineral density (BMD) across the complete menopausal transition are incompletely understood. OBJECTIVE: The objective of the study was to examine the associations of annual serum levels of FSH, estradiol (E2), T, and SHBG with the rates of bone loss in 3 phases: pretransmenopausal [baseline to 1 year before the final menstrual period (FMP)], transmenopausal (1 year before to 2 years after the FMP), later postmenopausal (>= 2 years after the FMP). DESIGN: The design of the study was a repeated-measures, mixed-effects regression. SETTING: This was a community-based observational study, with a 10-year follow-up. PARTICIPANTS: A total of 720 participants of the Study of Women's Health Across the Nation Bone Study participated in the study. OUTCOME MEASURES: Annualized lumbar spine (LS) and femoral neck (FN) BMD decline was measured. RESULTS: The mean annual change in BMD was slowest in pretransmenopause (0.27%/year in FN) and fastest in transmenopause (2.16%/year in LS). In the pretransmenopausal phase, for every doubling of FSH level, LS BMD change was faster by -0.32%/year (P < .0001). In the transmenopausal phase, for every doubling of FSH level, LS BMD change was 0.35%/year faster (P < .0001); for every doubling of SHBG level, LS BMD change was -0.36%/year faster (P < .0001). In the later postmenopausal phase, for each doubling of the E2 level, the LS BMD change was slower by +0.26%/year (P = .049); for each SHBG doubling, the LS BMD change was 0.21%/year slower (P = .048). The FN associations were weaker and inconsistent. CONCLUSIONS: Higher E2 levels and lower FSH levels were associated with lower rates of LS bone loss in some but not all menopausal transition phases. PMID- 23443816 TI - Infrared photodissociation spectra of mass selected homoleptic nickel carbonyl cluster cations in the gas phase. AB - Infrared spectra of mass-selected homoleptic nickel carbonyl cluster cations including dinuclear Ni2(CO)7(+) and Ni2(CO)8(+), trinuclear Ni3(CO)9(+) and tetranuclear Ni4(CO)11(+) are measured via infrared photodissociation spectroscopy in the carbonyl stretching frequency region. The structures are established by comparison of the experimental spectra with simulated spectra derived from density functional calculations. The Ni2(CO)7(+) cation is characterized to have an unbridged asymmetric (OC)4Ni-Ni(CO)3(+) structure with a Ni-Ni single bond. The Ni2(CO)8(+) cation has a Ni-Ni half-bonded D3d structure with both nickel centers exhibiting an 18-electron configuration. The trinuclear Ni3(CO)9(+) cluster cation is determined to have an open chain like (OC)4Ni-NiCO Ni(CO)4 structure. The tetranuclear Ni4(CO)11(+) cluster cation is determined to have a tetrahedral structure with two-center and three-center bridge-bonded carbonyl units. These nickel carbonyl cluster cations all involve trigonal pyramid like Ni(CO)4 building blocks that satisfy the 18-electron configuration of the nickel centers. PMID- 23443814 TI - Congenital hypothyroidism due to defects of thyroid development and mild increase of TSH at screening: data from the Italian National Registry of infants with congenital hypothyroidism. AB - CONTEXT: Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open. OBJECTIVE: The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features. METHODS: Data recorded in the Italian National Registry of infants with CH were analyzed. RESULTS: Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of <15.0 MUU/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 MUU/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (<=15 MUU/mL), 19.6% had thyroid dysgenesis with serum TSH levels at confirmation of the diagnosis ranging from 9.9 to 708 MUU/mL. These babies would have been missed at screening if the cutoff had been higher. CONCLUSIONS: Lowering TSH cutoff in our country has enabled us to detect additional cases of permanent CH, a number of which had defects of thyroid development and severe hypothyroidism at confirmation of the diagnosis. PMID- 23443817 TI - Thermodynamic studies of U(VI) complexation with glutardiamidoxime for sequestration of uranium from seawater. AB - Glutardiamidoxime (H2B), a diamidoxime ligand that has implications in sequestering uranium from seawater, forms strong complexes with UO2(2+). Five U(VI) complexes were identified in 3% NaCl solution. The stability constants and the enthalpies of complexation were measured by potentiometry and microcalorimetry. The competition between glutardiamidoxime and carbonate for complexing U(VI) in 3% NaCl was also studied in comparison with the cyclic glutarimidedioxime ligand (H2A) previously studied. PMID- 23443815 TI - Update on treatment strategies for obesity. AB - Obesity is a disease that is defined as the accumulation of excessive amounts of body fat and is associated with increased risk of serious illness, disability, and death. In clinical practice, obesity is best assessed by calculating body mass index and measuring waist circumference. Treatment options are determined based on the body mass index, waist circumference, and adverse health consequences the patient is experiencing or is at an increased risk for facing in the future. Today, overweight and obesity impacts the majority of patients we treat in our clinical practices. Although endocrinologists are uniquely positioned to treat one of the major consequences of our current obesity epidemic, type 2 diabetes, we also need to be positioned and prepared to effectively treat one of its major causes-obesity. Type 2 diabetes and obesity are very much intertwined. Treatment of each disease affects the other. For these reasons, endocrinologists need to be experts in the treatment of obesity as well as diabetes. They should keep up with advances in obesity treatment including lifestyle, pharmaceutical, and surgical strategies. These strategies offer opportunities for improving the overall treatment for our obese patients today and will continue to improve and expand over the next decade. PMID- 23443819 TI - Associations between MMPI-2-RF validity scale scores and extra-test measures of personality and psychopathology. AB - The current study explored associations between two potentially invalidating self report styles detected by the Validity scales of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF), over-reporting and under reporting, and scores on the MMPI-2-RF substantive, as well as eight collateral self-report measures administered either at the same time or within 1 to 10 days of MMPI-2-RF administration. Analyses were conducted with data provided by college students, male prisoners, and male psychiatric outpatients from a Veterans Administration facility. Results indicated that if either an over- or under-reporting response style was suggested by the MMPI-2-RF Validity scales, scores on the majority of the MMPI-2-RF substantive scales, as well as a number of collateral measures, were significantly affected in all three groups in the expected directions. Test takers who were identified as potentially engaging in an over- or under-reporting response style by the MMPI-2-RF Validity scales appeared to approach extra-test measures similarly regardless of when these measures were administered in relation to the MMPI-2-RF. Limitations and suggestions for future study are discussed. PMID- 23443818 TI - Early analgesic treatment regimens for patients with acute abdominal pain: a nationwide survey among general surgeons. AB - INTRODUCTION: Early pain relief in patients with acute nontraumatic abdominal pain in emergency departments has been discussed for years. Some randomized trials have addressed this issue but conclusive data are lacking. In this study, we assessed the current treatment practice in German hospitals in order to evaluate the necessity of a further clinical trial. METHODS: An online survey containing 27 questions was sent to general and visceral surgeons at attending level using a mailing list provided by the Professional Board of German Surgeons (BDC) using a standard interview software. The questionnaire collected demographic data, current treatment policies about frequency of early analgesia, types of pain medication, and opinions about their use and effects. RESULTS: Four hundred ninety-five completed questionnaires were returned. Many surgeons were cautious about early analgesia in the emergency department. Forty-five percent of the surgeons would provide analgesia prior to diagnosis to the majority of patients. Within the departments, differing opinions existed regarding the analgesic treatment (41 %). Thirty-two percent of all the respondents knew about a false diagnosis after early analgesia. There was heterogeneity in the estimation of the impact of pain medication on masking of clinical symptoms. A randomized controlled trial would be supported by the majority of respondents. As influencing factors for withdrawing early analgesia, we found the examiner being over 40 years of age (p < 0.05), low experience with the clinical picture of acute abdominal pain (p < 0.05), high estimation of the masking of clinical findings (p < 0.001), and knowing about a false diagnosis after early analgesia (p < 0.001) to be significant. CONCLUSION: Discordance in the analgesic treatment regimens in patients with acute abdominal pain still exists in German hospitals. The topic remains subject of frequent discussions. More high quality data are needed before a clear guideline can be given for implementation in clinical routine management. PMID- 23443820 TI - WAIS-IV profile of cognition in schizophrenia. AB - The Wechsler Adult Intelligence Scale (WAIS) has been used extensively to study impairment across a range of cognitive domains in schizophrenia. However, cognitive performance among those with the illness has yet to be examined using the newest edition of this measure. Hence, the current study aims first, to provide WAIS-IV normative data for Canadian individuals with schizophrenia of low average intelligence; second, to examine schizophrenia performance on all WAIS-IV subtest, index and general intelligence scores relative to healthy comparison subjects; and third, to revalidate the pattern of impairment identified in this clinical group using the WAIS-III, where processing speed (PS) was most affected, followed by working memory (WM), perceptual reasoning (PR) and verbal comprehension (VC). The WAIS-IV was administered to outpatients with schizophrenia and their performance compared with age, gender, and education matched controls. WAIS-IV schizophrenia performance data are provided. Analyses revealed significant impairment on several tasks, including the new Cancellation subtest and the VC supplemental subtest, Comprehension. At the index score level, group differences in PS were significantly larger than those observed in all other cognitive domains. Impairments were also observed in WM amid relatively preserved performance in VC, thereby confirming the pattern of impairment identified using the WAIS-III. PMID- 23443821 TI - Oncoplastic breast surgery combining periareolar mammoplasty with volume displacement using a crescent-shaped cutaneous flap for early breast cancer in the upper quadrant. AB - Oncoplastic breast surgery (OBS), which combines the concepts of oncological and plastic surgery, is becoming more common, especially in Western countries; however, only a few reports have been published in Japan. We herein report the results of OBS for Japanese patients with early breast cancer in the upper quadrant. We performed oncoplastic surgery combining partial mastectomy using a periareolar incision with immediate breast reshaping using a crescent-shaped cutaneous flap in three patients with a past history of breast-feeding, ptotic breasts and lesions that were suitable for breast conserving surgery. The lesions were located in the upper quadrant and were 5, 6 and 10 cm from the nipple, respectively. The total length of the operations ranged between 86 and 192 min, with the mean being 164 min. Two patients underwent contralateral surgery to produce symmetrical breasts and one did not. The plastic period after receiving pathological results intraoperatively ranged between 47 and 120 min, with the mean period being 82 min. The observation period ranged between 6 and 12 months, and the cosmetic results were excellent in all three cases. OBS combining partial mastectomy using a periareolar incision with immediate breast reshaping using a crescent-shaped cutaneous flap was successfully performed in patients with early cancer in the upper quadrant. PMID- 23443822 TI - Initial experience with proximal ligation for profunda femoris artery aneurysms: report of three cases. AB - Profunda femoris artery aneurysms (PFAAs) are rare and difficult to diagnose in the early stage. They are often found due to the presence of complicated conditions, such as rapid expansion, rupture, or acute lower limb ischemia. Surgical procedures such as aneurysmectomy and endoaneurysmorrhaphy tend to be technically challenging because of the patient status and the extent of the aneurysm. We experienced three cases of PFAAs that were treated by proximal ligation (PL) without complete control of the distal branches. The exclusion of PFAAs was confirmed by duplex ultrasound or angiography at the end of the operation. There was no mortality in the perioperative period. During a 12-month follow-up, all cases exhibited complete exclusion of aneurysms with marked size reduction. Based on these findings, we propose that PL, with a careful follow-up for PFAA exclusion and distal limb circulation, could be an alternative treatment for complicated PFAAs. PMID- 23443823 TI - Common routes to risk. PMID- 23443824 TI - Antidepressant epigenetic action. PMID- 23443825 TI - Stryphnodendron adstringens extract associated with the hooves trimming surgical procedure for the treatment of bovine digital dermatitis. AB - Hoof care, lesion curettage, and application of 5 % Stryphnodendron adstringens bark extract (S. adstringens (Mart.) Coville) or 3 % copper sulfate on surgical wounds of cattle were carried out in this research. A total of 180 cattle with digital dermatitis were used. They were distributed into six groups of 30 animals each (GI, GII, GIII, GIV, GV, and GVI). In GI and GII, only the sick digit was trimmed; in GIII and GIV, both sick and healthy digits of the lesioned limb were trimmed; and in GV and GVI, all digits were trimmed. During the postoperative period, 5 % S. adstringens extract was applied in GI, GIII, and GV, and 3 % copper sulfate solution was applied in GII, GIV, and GVI. After 60 days of evaluation, the data were analyzed using the Chi-squared test (p <= 0.05). Both therapeutic protocols utilizing surgical curettage of the lesions were efficient for treating digital dermatitis. However, when the procedure is followed by the trimming of sick and healthy digits, the healing is optimized and a greater number of animals are rehabilitated. PMID- 23443827 TI - Obesity as malnutrition: the dimensions beyond energy balance. AB - The aetiology of obesity is seemingly simple to understand: individuals consume more energy than they expend, with the excess energy being stored in adipose tissue. Public health campaigns therefore promote dietary restraint and physical exercise, and emphasize individual responsibility for these behaviours. Increasingly, however, researchers are switching from thermodynamic to metabolic models of obesity, thereby clarifying how specific environmental factors promote lipogenesis. Obesity can best be explained not by counting 'calories in and out', but by understanding how specific dietary products and activity behaviours perturb cellular metabolism and promote net lipogenesis. This metabolic approach can furthermore be integrated with more sophisticated models of how commercial practices drive the consumer trends that promote obesogenic behaviours. Notably, obesity treatment has proven more effective if it bypasses individual responsibility, suggesting that a similar approach placing less emphasis on individual responsibility would improve the efficacy of obesity prevention. Successful obesity prevention campaigns are likely to emerge only when the public receive better 'protection' from the commercial practices that are driving the global obesity epidemic. Rather than populations failing to heed governments' public health advice, governments are currently failing the public by abandoning their responsibility for regulating commercial activities. PMID- 23443826 TI - Measuring energy expenditure in clinical populations: rewards and challenges. AB - The measurement of energy expenditure (EE) is recommended as an important component of comprehensive clinical nutrition assessments in patients with altered metabolic states, who failed to respond to nutrition support and with critical illness that require individualized nutrition support. There is evidence that EE is variable in patients with metabolic diseases, such as chronic renal disease, cirrhosis, HIV, cancer cachexia, cystic fibrosis and patients under intensive care. By using appropriate techniques and interpretations of basal or resting EE, clinicians can facilitate the adequate nutrition support with minimum negative impacts from under- or overfeeding in these patients. This review is based on our current understanding of the different components of EE and the techniques to measure them, and to re-examine advances and challenges to determine energy needs in clinical populations with more focuses on the obese, pediatric and elderly patients. In addition, technological advances have expanded the choices of market-available equipments for assessing EE, which also bring specific challenges and rewards in selecting the right equipment with specific performance criteria. Lastly, analytical considerations of interpreting the results of EE in the context of changing body composition are presented and discussed. PMID- 23443828 TI - Maternal fish consumption during pregnancy and risks of wheezing and eczema in childhood: the Generation R Study. AB - BACKGROUND/OBJECTIVES: Maternal fish consumption during pregnancy might influence the fetal immune system through anti-inflammatory effects of omega-3 fatty acids, and might affect the risks of childhood asthma and atopy. In Generation R, a prospective cohort study in the Netherlands, we examined the associations of first trimester fish consumption with childhood wheezing and eczema in the first 4 years of life. METHODS: In total, 2976 mothers completed a 293-item semiquantitative food frequency questionnaire covering dietary intake in the first trimester. The occurrence of wheezing and eczema was yearly assessed by questionnaires. RESULTS: Median weekly fish consumption was 83 (95% range 0-316) grams per week. We observed no consistent associations of maternal total-, lean- or fatty-fish consumption during pregnancy with the risks of childhood wheezing. Maternal shellfish consumption of 1-13 g per week was associated with overall increased risks of childhood wheezing and eczema (OR 1.20 (1.04, 1.40) and OR 1.18 (1.01, 1.37), respectively). Maternal fatty fish consumption of 35-69 g per week was associated with increased overall risks of childhood eczema (OR 1.17 (1.00, 1.38)), but maternal total- or lean-fish consumption was not. CONCLUSIONS: During pregnancy, shellfish consumption was associated with increased risks of wheezing and eczema, while fatty fish consumption was associated with a higher risk of eczema only. Maternal total fish or lean fish consumption were not associated with wheezing or eczema. Further studies are needed to replicate these findings and to explore underlying mechanisms. PMID- 23443829 TI - Are body mass index, waist circumference and waist-to-hip ratio associated with leptin in 90-year-old people? AB - Data on how body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) are associated with body fat in the oldest-old people are scarce. The purpose of this study was to examine if BMI, WC or WHR are associated with leptin, a biological surrogate measure of body fat in 90-year-old people. The data comes from the Vitality 90+ Study, a prospective population-based study of people living in Tampere, Finland. BMI, WC, WHR and plasma concentration of leptin were available for 160 women and 54 men aged 90 years. BMI and WC had a strong significant positive association with leptin both in women and in men, but WHR was associated with leptin only in men. In conclusion, based on the circulating level of leptin, BMI and WC, and WHR in men, reflect body fat in 90 year-old people, but WHR seems to be a poor indicator of body fat in 90-year-old women. PMID- 23443830 TI - Dietary patterns of Australian children aged 14 and 24 months, and associations with socio-demographic factors and adiposity. AB - BACKGROUND/OBJECTIVES: Previous research has shown, in predominantly European populations, that dietary patterns are evident early in life. However, little is known about early-life dietary patterns in Australian children. We aimed to describe dietary patterns of Australian toddlers and their associations with socio-demographic characteristics and adiposity. SUBJECTS/METHODS: Principal component analysis was applied to 3 days (1 * 24-h recall and 2 * 24-h record) data of 14 (n=552)- and 24 (n=493)-month-old children from two Australian studies, NOURISH and South Australian Infant Dietary Intake (SAIDI). Associations with dietary patterns were investigated using regression analyses. RESULTS: Two patterns were identified at both ages. At 14 months, the first pattern was characterised by fruit, grains, vegetables, cheese and nuts/seeds ('14-month core foods') and the second pattern was characterised by white bread, milk, spreads, juice and ice-cream ('basic combination'). Similarly, at 24 months the '24-month core foods' pattern included fruit, vegetables, dairy, nuts/seeds, meat and water, whereas the 'non-core foods' included white bread, spreads, sweetened beverages, snacks, chocolate and processed meat. Lower maternal age and earlier breastfeeding cessation were associated with higher 'basic combination' and 'non core foods' pattern scores, whereas earlier and later solid introduction were associated with higher 'basic combination' and '24-month core foods' pattern scores, respectively. Patterns were not associated with body mass index (BMI) z score. CONCLUSIONS: Dietary patterns reflecting core and non-core food intake are identifiable in Australian toddlers. These findings support the need to intervene early with parents to promote healthy eating in children and can inform future investigations on the effects of early diet on long-term health. PMID- 23443831 TI - Nutrient density in complementary feeding of infants and toddlers. AB - The paradigm of the first 1000 days of life, the period from conception to the second birthday, has been advanced as a critical window of opportunity to save a life and a child's future. Infancy and toddler life, through the first 24 months after birth, is a unique period during which human milk is recommended as either the exclusive source of nutrition (6 months) or a variable component thereof. After the maternal delivery of milk is accounted for, the remainder of the energy and nutrients needs come from complementary foods. There is an intrinsic gap left by the maternal milk supply in volume and micronutrient content in relation to expanding infant and toddler needs. The nutrient density approach provides us with a mathematical framework to manage the closing of the nutrient gap. The intrinsic nutrient content of the unprocessed foods appropriate for young children is limited. The most problematic nutrients are calcium, iron and zinc. Some manner to enhance the nutrient density of the complementary foods is an incontestable necessity. The nutrient density consideration, which identifies for us the nature of the problem, offers a tool for the titrating of the fortification to an adequate--but safe--addition. PMID- 23443832 TI - Nutritional epidemiology: New perspectives for understanding the diet-disease relationship? AB - Nutritional epidemiology is a subdiscipline of epidemiology and provides specific knowledge to nutritional science. It provides data about the diet-disease relationships that is transformed by Public Health Nutrition into the practise of prevention. The specific contributions of nutritional epidemiology include dietary assessment, description of nutritional exposure and statistical modelling of the diet-disease relationship. In all these areas, substantial progress has been made over the last years and is described in this article. Dietary assessment is moving away from the food frequency questionnaire (FFQ) as main dietary assessment instrument in large-scale epidemiological studies towards the use of short-term quantitative instruments due to the potential of gross measurement errors. Web-based instruments for self-administration are therefore evaluated of being able to replace the costly interviewer conducted 24-h-recalls. Much interest is also directed towards the technique of taking and analysing photographs of all meals ingested, which might improve the dietary assessment in terms of precision. The description of nutritional exposure could greatly benefit from standardisation of the coding of foods across studies in order to improve comparability. For the investigations of bioactive substances as reflecting nutritional intake and status, the investigation of concentration measurements in body fluids as potential biomarkers will benefit from the new high-throughput technologies of mass spectrometry. Statistical modelling of the dietary data and the diet-disease relationships can refer to complex programmes that convert quantitative short-term measurements into habitual intakes of individuals and correct for the errors in the estimates of the diet-disease relationships by taking data from validation studies with biomarkers into account. For dietary data, substitution modelling should be preferred over simple adding modelling. More attention should also be put on the investigation of non-linear relationships. The increasing complexity of the conduct and analysis of nutritional epidemiological studies is calling for a distinct and advanced training programme for the young scientists moving into this area. This will also guarantee that in the future an increasing number of high-level manuscripts will show up in this and other journals in respect of nutritional epidemiological topics. PMID- 23443833 TI - Impact of nutritional status and dietary quality on stroke: do we need specific recommendations? AB - Stroke, one of the most prevalent geriatric diseases, is a leading cause of death worldwide that often results in permanent physical disability and decreased quality of life, and can have a negative impact on families both financially and emotionally. Although many previous studies have shown relationships between the risk of stroke and nutritional factors, clear dietary recommendations for the prevention and reduction of stroke recurrence have not been established. Several factors should be considered to control and manage stroke. For example, a considerable number of patients with stroke are poorly nourished, have several comorbidities and undesirable health-related behaviors may be present. Stroke patients are less likely to consume beneficial foods, have poorer eating habits and have impoverished dietary quality. In addition, psychological factors such as depression must also be considered in stroke management. Given these factors, dietary recommendations for stroke patients should be established. In this article, we summarized the nutritional status and dietary quality of stroke patients. We also suggested some nutritional guidelines for stroke patients and for those who are at risk for stroke. PMID- 23443834 TI - Yarrowia lipolytica: the novel and promising 2-phenylethanol producer. AB - This is the first report on the ability of Yarrowia lipolytica strains to produce 2-phenylethanol (2-PE), which has not been identified for this species to date. 2 PE is a valuable aroma compound of rose-like odor. Its isolation from the other than microbial source-rose petals, is limited by the substrate availability. Thus, this chemical compound constitutes an attractive product for biotechnological conversions. To date, the ability to produce 2-PE has been described for such genera as Saccharomyces sp., Kluyveromyces sp., Geotrichum sp., and Pichia sp. This report provides evidence that Y. lipolytica is a novel 2 PE producer. Moreover, the titers of 2-PE obtained in Y. lipolytica NCYC3825 non optimized cultures, nearly 2 g/l, are competitive to titers obtained by the other species. PMID- 23443835 TI - Inference of functional divergence among proteins when the evolutionary process is non-stationary. AB - Functional shifts during protein evolution are expected to yield shifts in substitution rate, and statistical methods can test for this at both codon and amino acid levels. Although methods based on models of sequence evolution serve as powerful tools for studying evolutionary processes, violating underlying assumptions can lead to false biological conclusions. It is not unusual for functional shifts to be accompanied by changes in other aspects of the evolutionary process, such as codon or amino acid frequencies. However, models used to test for functional divergence assume these frequencies remain constant over time. We employed simulation to investigate the impact of non-stationary evolution on functional divergence inference. We investigated three likelihood ratio tests based on codon models and found varying degrees of sensitivity. Joint effects of shifts in frequencies and selection pressures can be large, leading to false signals for positive selection. Amino acid-based tests (FunDi and Bivar) were also compromised when several aspects of the substitution process were not adequately modeled. We applied the same tests to a core genome "scan" for functional divergence between light-adapted ecotypes of the cyanobacteria Prochlorococcus, and carried out gene-specific simulations for ten genes. Results of those simulations illustrated how the inference of functional divergence at the genomic level can be seriously impacted by model misspecification. Although computationally costly, simulations motivated by data in hand are warranted when several aspects of the substitution process are either misspecified or not included in the models upon which the statistical tests were built. PMID- 23443836 TI - Recent advances in the synthesis of aromatic nitro compounds. AB - Aromatic nitro compounds are important intermediates in synthetic organic chemistry as well as in the chemical industry. Numerous useful methods for their preparation have been developed in recent years. In this review, recent advances in the synthesis of aromatic nitro compounds are summarized, including the nitration of aromatic hydrocarbons, aryl boronic acids, aryl halides and pseudohalides, aryl carboxylic acids and the oxidation of aryl primary amines and azides. Their mechanisms are discussed. PMID- 23443837 TI - Controlling optoelectronic properties of carbazole-phosphine oxide hosts by short axis substitution for low-voltage-driving PHOLEDs. AB - Preserved high first triplet energy levels and improved electrical properties of two donor-acceptor type carbazole-phosphine oxide hosts were achieved through short-axis substitution to realize efficient PHOLEDs with extremely low driving voltages of 2.6 V for onset and <3.2 V at 100 cd m(-2). PMID- 23443841 TI - Comparison of contemporaneous left ventricular ejection fraction (LVEF) obtained from planar gated cardiac blood pool scans (GCBPS) and Tl-201 gated myocardial perfusion scans (MPS) using a novel solid state dedicated cardiac camera. AB - BACKGROUND: There is limited data on the concordance of left ventricular ejection fraction (LVEF) obtained via solid state dedicated cardiac cameras (SSD) and gated cardiac blood pool scans (GCBPS). This study aimed to examine the agreement of LVEF measured during GCBPS and Tl-201 myocardial perfusion scans (MPS) using SSD. METHODS: Seventy six patients were enrolled. Following stress MPS with 0.8 Mbq/kg (0.022 mCi/kg) Tl-201 and 8-frame gated rest studies after additional 15 Mbq (0.41 mCi) Tl-201, LVEFs were obtained using ECToolbox (ECT) and quantitative gated SPECT (QGS) software. Same day 16-frame planar GCBPS were performed. Interobserver variability was compared and LVEF results were compared using paired t tests, Pearson's correlation and the differences of the LVEF were plotted against GCBPS values. RESULTS: For GCBPS, ECT and QGS, the mean (+/-SD) LVEF was 52% +/- 14%, 61% +/- 18% and 48% +/- 19%, respectively. When compared to GCBPS, ECT and QGS, LVEFs had similar R values of 0.85 and 0.83, respectively, and mean differences [95% limits of agreement (LA)] of -8.6% (-27.4% to +10.2%, P < .001) and 4.2% (-17.2% to +25.6%, P = .001), respectively. CONCLUSION: While the LVEF obtained by ECT or QGS demonstrates a statistically significant correlation with GCBPS, they are significantly different and the wide 95% LA suggest that Tl-201 MPS LVEFs derived from either software package are not interchangeable with GCBPS results. PMID- 23443839 TI - Functional circuits of new neurons in the dentate gyrus. AB - The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG), a brain area considered important for differential storage of similar experiences and contexts. To better understand the functional contribution of adult neurogenesis to pattern separation processes, we recently used a novel synapse specific trans-neuronal tracing approach to identify the (sub) cortical inputs to new dentate granule cells (GCs). It was observed that newly born neurons receive sequential innervation from structures important for memory function. Initially, septal-hippocampal cells provide input to new neurons, including transient innervation from mature GCs as well as direct feedback from area CA3 pyramidal neurons. After about 1 month perirhinal (PRH) and lateral entorhinal cortex (LEC), brain areas deemed relevant to integration of novel sensory and environmental information, become substantial input to new GCs. Here, we review the developmental time-course and proposed functional relevance of new neurons, within the context of their unique neural circuitry. PMID- 23443842 TI - Low-dose paclitaxel modulates tumour fibrosis in gastric cancer. AB - Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-beta (TGF-beta) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-beta signalling pathway. The TGF-beta/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-beta/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-beta1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1+/-1.5%, P<0.01). The TGF-beta signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real time quantitative PCR and western blotting. TGF-beta signalling induced morphological changes, alpha-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-beta/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis. PMID- 23443846 TI - Changing patterns in the epidemiology of traumatic brain injury. AB - Traumatic brain injury (TBI) is a critical public health and socio-economic problem throughout the world. Reliable quantification of the burden caused by TBI is difficult owing to inadequate standardization and incomplete capture of data on the incidence and outcome of brain injury, with variability in the definition of TBI being partly to blame. Reports show changes in epidemiological patterns of TBI: the median age of individuals who experience TBI is increasing, and falls have now surpassed road traffic incidents as the leading cause of this injury. Despite claims to the contrary, no clear decrease in TBI-related mortality or improvement of overall outcome has been observed over the past two decades. In this Perspectives article, we discuss the strengths and limitations of epidemiological studies, address the variability in its definition, and highlight changing epidemiological patterns. Taken together, these analyses identify a great need for standardized epidemiological monitoring in TBI. PMID- 23443850 TI - Psychometric Properties of a Standardized Questionnaire of Knowledge, Attitude, and Practice of Iranian Medical Specialists about Viral Hepatitis. AB - BACKGROUND: Good knowledge, attitude and practice (KAP) of the physicians allow them to handle their patients in such a way that they prevent themselves from contracting, and their patients from spreading, the infection. However, the Iranian standardized KAP questionnaire of physicians about viral hepatitis is not available. So, we developed a standard questionnaire. OBJECTIVES: The purpose of this study was to provide a standard questionnaire as a basic tool for assessment of the present situation of the KAP of clinicians. It can also be used for evaluating educational programs and interventions on physicians in addition to any trends in their KAP about viral hepatitis. PATIENTS AND METHODS: In order to design and standardize a 29-item self-administered questionnaire, we developed a cross sectional pilot study on 60 Iranian physicians. Ten experts in the field of liver diseases and/or designing the questionnaire answered questions about its validity. Cronbach's Alpha (on 60 physicians that participated in a congress) and factor analysis (on 370 persons; participants of two viral hepatitis congresses in Tehran and Zanjan and physicians of two university hospitals in Ahvaz) were used in the analysis. RESULTS: Reliability was 0.7 according to Cronbach's Alpha score. Face validity was higher than 80%. Content validity of the whole parts of the questionnaire was 96.25% for clarity, 91.56% for relevancy, 96.25% for simplicity and 98.44% for consistency of each question with the questions' set. Factor analysis showed that 13 components account for 67.4% of the total variance. CONCLUSIONS: This study provided evidence that our questionnaire is a feasible, valid and reliable measure of physicians' KAP status in Iran. The factor analysis did not reveal a strong cluster structure. This questionnaire should be interpreted as a one-dimensional element by the sum of all items, rather than a multi-dimensional instrument. PMID- 23443849 TI - Metabolic dysfunction in diabetic cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) is defined as cardiac disease independent of vascular complications during diabetes. The number of new cases of DCM is rising at epidemic rates in proportion to newly diagnosed cases of diabetes mellitus (DM) throughout the world. DCM is a heart failure syndrome found in diabetic patients that is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction, occurring in the absence of hypertension and coronary artery disease. DCM and other diabetic complications are caused in part by elevations in blood glucose and lipids, characteristic of DM. Although there are pathological consequences to hyperglycemia and hyperlipidemia, the combination of the two metabolic abnormalities potentiates the severity of diabetic complications. A natural competition exists between glucose and fatty acid metabolism in the heart that is regulated by allosteric and feedback control and transcriptional modulation of key limiting enzymes. Inhibition of these glycolytic enzymes not only controls flux of substrate through the glycolytic pathway, but also leads to the diversion of glycolytic intermediate substrate through pathological pathways, which mediate the onset of diabetic complications. The present review describes the limiting steps involved in the development of these pathological pathways and the factors involved in the regulation of these limiting steps. Additionally, therapeutic options with demonstrated or postulated effects on DCM are described. PMID- 23443851 TI - p73 G4C14-to-A4T14 polymorphisms are positively correlated with triple-negative breast cancer in southwestern China. AB - p73 gene shares structural and functional similarities to p53 and plays an important role in modulating cell cycle arrest and apoptosis. A common non-coding polymorphism of p73 G4C14-to-A4T14 (rs2273953 and rs1801173) at exon 2 may affect gene expression, thus, it may lead to functional significance. The correlation of this polymorphism with clinicopathologic variables of patients with breast cancer has not been investigated. In this study, single-nucleotide polymorphisms (SNPs) of p73 G4C14-to-A4T14 were genotyped by Sequenom MassArray-iPLEX GOLD System in 170 patients with breast cancer. Data were analyzed via t test, chi-square test, and logistic regression analysis. There was no significant correlation between p73 G4C14-to-A4T14 polymorphisms and the patient characteristics, such as clinical TNM stage, menopausal status, axillary lymph node metastasis, pathological type, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2). No significant relationship was observed between the p73 G4C14-to-A4T14 polymorphism and p73 protein expression in cancer tissues. The frequency of GC/GC genotype in patients with triple negative breast cancer (TNBC) was 78.9 %, that of patients with others was 57.6 %, and the difference had statistical significance (chi ( 2 ) = 5.74, P = 0.02). p73 G4C14-to-A4T14 polymorphisms were negatively correlated with chemosensitivity for anthracycline-based chemotherapy in breast cancer (P > 0.05). p73 G4C14-to A4T14 polymorphisms are positively correlated with TNBC, and p73 gene may play a critical role in a novel therapeutic strategy to TNBC. Additional larger studies are required to test these hypotheses. PMID- 23443852 TI - Focus on cardiac pericytes. AB - The wall of myocardial terminal vessels, consisting of a continuous endothelial tube with an adventitial coat of pericytes in their extracellular matrix, constitutes a remarkably tight barrier to solute transport between the blood and the parenchyma. This constructional principle of precapillary arterioles, capillaries and postcapillary venules extends both up- and downstream into the arterial and venous limbs, where the original microvessel tube widens and becomes the innermost layer-the intima-of all the larger coronary vessels. In the myocardium's smallest functional units and in the intima of the coronaries, the pericytes play key roles by virtue of both their central histological localization and their physiological functions. Recognition and integration of these properties has led to new pathogenetic models for diverse heart diseases and suggests that current therapeutic concepts need to be revised. PMID- 23443855 TI - The effect of distance-based learning on the fifth stage medical students' perception in peripheral vascular diseases course: a questionnaire survey. PMID- 23443853 TI - Kv3.4 potassium channel-mediated electrosignaling controls cell cycle and survival of irradiated leukemia cells. AB - Aberrant ion channel expression in the plasma membrane is characteristic for many tumor entities and has been attributed to neoplastic transformation, tumor progression, metastasis, and therapy resistance. The present study aimed to define the function of these "oncogenic" channels for radioresistance of leukemia cells. Chronic myeloid leukemia cells were irradiated (0-6 Gy X ray), ion channel expression and activity, Ca(2+)- and protein signaling, cell cycle progression, and cell survival were assessed by quantitative reverse transcriptase-polymerase chain reaction, patch-clamp recording, fura-2 Ca(2+)-imaging, immunoblotting, flow cytometry, and clonogenic survival assays, respectively. Ionizing radiation induced G2/M arrest was preceded by activation of Kv3.4-like voltage-gated potassium channels. Channel activation in turn resulted in enhanced Ca(2+) entry and subsequent activation of Ca(2+)/calmodulin-dependent kinase-II, and inactivation of the phosphatase cdc25B and the cyclin-dependent kinase cdc2. Accordingly, channel inhibition by tetraethylammonium and blood-depressing substance-1 and substance-2 or downregulation by RNA interference led to release from radiation-induced G2/M arrest, increased apoptosis, and decreased clonogenic survival. Together, these findings indicate the functional significance of voltage-gated K(+) channels for the radioresistance of myeloid leukemia cells. PMID- 23443854 TI - TRPM4 channels in smooth muscle function. AB - The melastatin (M) transient receptor potential (TRP) channel TRPM4 is selective for monovalent cations and is activated by high levels of intracellular Ca(2+). TRPM4 is broadly distributed and may be involved in numerous functions, including electrical conduction in the heart, respiratory rhythm, immune response, and secretion of insulin by pancreatic beta-cells. The significance of TRPM4 in smooth muscle cell function is reviewed here. Several studies indicate that TRPM4 channels are critically important for pressure-induced cerebral arterial myocyte depolarization and myogenic vasoconstriction as well as autoregulation of cerebral blood flow. Regulation of TRPM4 activity in arterial smooth muscle cells is complex and involves release of Ca(2+) from the sarcoplasmic reticulum through inositol 1,4,5-trisphosphate receptors and translocation of TRPM4 channels to the plasma membrane in response to protein kinase Cdelta. TRPM4 is also present in colonic, urinary bladder, aortic, interlobar pulmonary and renal artery, airway, and corpus cavernosum smooth muscle cells, but its significance and regulation in these tissues is less well characterized. PMID- 23443857 TI - Variant high origin of both right and left coronary arteries from the ascending aortic wall. PMID- 23443856 TI - Acute coronary syndrome with intraventricular thrombus after using erythropoietin. PMID- 23443858 TI - [Worsening of heart failure due to right ventricular apical pacing by ICD implanted after myocardial infarction and treatment with resynchronization]. PMID- 23443859 TI - Renal coloboma syndrome associated with double- chambered right ventricle. PMID- 23443860 TI - Thoraco-omphalopagus conjoined twins [corrected]. PMID- 23443861 TI - Ischemic stroke in the course of thrombolytic treatment of prosthetic valve thrombosis: thrombolysis is suggested. PMID- 23443862 TI - Influence of gender, C- reactive protein and triglycerides in risk prediction of coronary heart disease. PMID- 23443863 TI - Can isolated ST elevation in aVR lead be a sign of acute pulmonary embolism? PMID- 23443864 TI - A deadly chain of events in a case; deep venous thrombosis, pulmonary embolism, patent foramen ovale and cerebral embolism [corrected]. PMID- 23443865 TI - [Successful endovascular stent-graft treatment in a patient with Marfan syndrome presenting with complicated acute Type B dissection]. PMID- 23443866 TI - [The effect of group education about drug usage in the patient's on warfarin therapy]. PMID- 23443867 TI - [Successful surgical closure of aortopulmonary window in a very low birth weight premature infant]. PMID- 23443868 TI - Coexistence of accessory mitral papillary muscle and ventricular septal defect. PMID- 23443869 TI - All-in-one case: constrictive pericarditis, secundum atrial septal defect, persistent left superior vena cava and anomalous drainage of hemiazygos vein to coronary sinus. PMID- 23443870 TI - Severe pulmonary vein stenosis due to invasion of metastatic lung cancer. PMID- 23443871 TI - Free-floating intra-aortic thrombus causing coronary artery occlusion: appearance in ECG-gated computed tomography with cine-images. PMID- 23443872 TI - Interventricular septal cardiac hydatid cyst mimicking hypertrophic cardiomyopathy. PMID- 23443873 TI - Tumor of the pericardium. PMID- 23443875 TI - Intracutaneous sterile water injection versus oral paracetamol for renal colic during pregnancy: a randomized controlled trial. AB - PURPOSE: The aim of this study was to assess the analgesic efficacy of intracutaneous sterile water injection compared with oral paracetamol in pregnant women with acute renal colic caused by urolithiasis. METHODS: The study included 45 patients randomized into two different groups: Group A (n = 24) received paracetamol (1,000 mg, oral), while group B (n = 21) received sterile water injections. The severity of pain was assessed by a visual analogue scale (VAS) system at baseline and at 15, 30 min, and 1 h after administering the treatments. Subjects with inadequate pain relief at 1 h received rescue analgesia. RESULTS: The VAS values prior to the start of therapy and 15, 30 min, and 1 h after therapy were 85.42 +/- 10.62, 69.17 +/- 8.3, 45.42 +/- 12.5, and 32.08 +/- 14.44 for the paracetamol group, while for the sterile water injection group, the VAS values were 90.48 +/- 11.17, 30.95 +/- 16.7, 14.76 +/- 11.23, and 10.48 +/- 8.65, respectively. There was no statistically significant difference between the starting VAS values of the two groups, but the VAS values 15, 30 min, and 1 h after paracetamol administration were statistically less in the group that received sterile water injections. Rescue analgesics at 1 h were required by eight subjects (33 %) receiving paracetamol and one subject (5 %) receiving sterile water injection. CONCLUSIONS: Intracutaneous injection of sterile water is an efficacious treatment for renal colic caused by urolithiasis in pregnant women. It was significantly superior to oral administration of paracetamol. PMID- 23443874 TI - High-density lipoprotein in uremic patients: metabolism, impairment, and therapy. AB - Several studies have shown that HDL has altered antioxidant and anti-inflammatory effects in chronic uremia, either by the reduction in its antioxidant enzymes or by the impairment of their activity. Systemic oxidative stress, which is highly prevalent in chronic kidney disease (CKD) patients, has been shown to decrease antioxidant and anti-inflammatory effects of HDL and even transform it into a pro oxidant and pro-inflammatory agent. For this reason, we believe that the propensity for accelerated cardiovascular disease in CKD is facilitated by a few key features of this disease, namely, oxidative stress, inflammation, hypertension, and disorders of lipid metabolism. In a nutshell, oxidative stress and inflammation enhance atherosclerosis leading to increased cardiovascular mortality and morbidity in this population. In this detailed review, we highlight the current knowledge on HDL dysfunction and impairment in chronic kidney disease as well as the available therapy. PMID- 23443877 TI - [Spinal prodromal phase of anti-NMDA receptor encephalitis]. PMID- 23443876 TI - [Paraneoplastic neurological syndromes]. AB - Paraneoplastic neurological syndromes (PNS) are very rare, remote effects of malignancies. Well-characterised antibodies against intracellular neuronal antigens are well-known in association with distinct tumors and with classical and non-classical syndromes. In this review article the current aspects of classification, pathophysiology, underlying tumors, antineuronal autoantibodies and diagnostic and therapeutic aspects of syndromes affecting the central nervous system are summarized. PMID- 23443878 TI - New ternary ligands consisting of an N4 bridging ligand and two terpyridines, and their Co(II) and Ni(II) dinuclear complexes. Structure, redox properties, and reaction with acid. AB - Two ternary ligands consisting of two 2,2':6',2''-terpyridines and one N4 quadridentate MU2,eta(2)-bridging ligand were synthesized. The N4 bridge is 1,4 bis(2-pyridyl)phthalazine in ligand 1, and 3,6-bis(2-pyridyl)pyridazine in ligand 2. Two Co(II) dinuclear complexes [(1)Co2(MU-OH)]3+ and [(2)Co2(MU-OH)]3+, and one Ni(II) dinuclear complex [(1)Ni2(MU-Cl)]3+ were obtained. In the crystal structures of [(1)Co2(MU-OH)]3+ and [(1)Ni2(MU-Cl)]3+, two pyridine rings are twisted around the pyridine-phthalazine bonds to avoid steric repulsion between the hydrogen atoms. The pyridine rings also showed a significant tilt from the octahedral coordination plane, which causes the large positive shift of the first reduction potentials. Upon the addition of a proton, the cobalt dinuclear complexes can release one cobalt ion selectively, and the dinuclear complexes can be easily restored by the addition of a tertiary amine. PMID- 23443879 TI - Percutaneous coronary intervention for acute coronary syndromes in eastern Nepal: a preliminary report. PMID- 23443881 TI - Mediated electron transfer in glucose oxidising enzyme electrodes for application to biofuel cells: recent progress and perspectives. AB - Glucose oxidising enzyme electrodes have long been studied for their application to biosensors and, more recently, anodes in biofuel cells. At a fundamental level, insight into enzyme electron transfer and oxidation current generation at enzyme electrodes can be gained by systematic studies on integration of surfaces, biocatalysts, and artificial substrates (mediators). In this perspective, we present an overview of methods to aid the development of glucose oxidising enzyme electrodes based on mediated electron transfer for application to continuous-use anodes in a biofuel cell. Focus is placed on the rational design of mediators, based on osmium redox complexes, and screening of the activity of such complexes as mediators for glucose oxidising enzymes. An overview of the performance of enzyme electrodes, focused predominantly on crosslinked films of redox polymers and glucose oxidase, for glucose oxidation, is presented and approaches to improve both current output and stability of such enzyme electrodes are discussed. PMID- 23443880 TI - Factors associated with referral to medical oncology and subsequent use of adjuvant chemotherapy for non-small-cell lung cancer: a population-based study. AB - BACKGROUND: Adjuvant chemotherapy (act) for non-small-cell lung cancer (nsclc) is associated with improved survival in the general population, but may be underutilized. We explored the factors associated with referral to medical oncology and subsequent use of act among all patients with resected nsclc in Ontario, Canada. METHODS: The Ontario Cancer Registry was used to identify all incident cases of nsclc diagnosed in Ontario during 2004-2006. We linked electronic records of treatment and of physician billing to identify surgery, act, and medical oncology consultation. A multivariate logistic regression model was used to evaluate factors associated with referral to medical oncology and subsequent use of act. RESULTS: Among 3354 cases of nsclc resected in Ontario during 2004-2006, 1830 (55%) were seen postoperatively by medical oncology, and 1032 (31%) were treated with act. Patients more than 70 years of age were less likely than younger patients to have a consultation [odds ratio (or): 0.4; p < 0.001]. A higher proportion of cases with stage ii or iii nsclc than with stage i disease were referred (ors: 2.7, 2.0 respectively; p < 0.005). We observed substantial geographic variation in the proportion of surgical cases referred (range: 32%-88%) that was not explained by differences in case mix. Among cases referred to medical oncology, older patients (age 60-69 years, or: 0.4; age 70+ years, or: 0.1; p < 0.001) with greater comorbidity (Charlson comorbidity index: 3+; or: 0.5; p < 0.05) and a longer postoperative stay (median length of stay: 7+ days; or: 0.7; p = 0.001) were less likely to receive act. Use of act was greater in patients with stage ii or iii than with stage i disease (ors: 3.0, 2.7 respectively; p < 0.001); use also varied with geographic location (range: 46% 63%). CONCLUSIONS: The initial decision to refer to medical oncology is associated with age and stage of disease, and those factors have an even greater effect on the decision to offer act. Comorbidity and postoperative length of stay were not associated with initial referral, but were associated with use of act in patients seen by medical oncology. PMID- 23443882 TI - Iterative separation of transmit and receive phase contributions and B1(+)-based estimation of the specific absorption rate for transmit arrays. AB - OBJECT: The specific absorption rate (SAR) can be determined from radiofrequency transmit fields measured via magnetic resonance imaging. MATERIALS AND METHODS: The proposed method estimates the SAR solely from the complex transmit field (B1(+)) by taking into account the particular properties of the electromagnetic field generated by an 8-channel transmit array. It is further based on an iterative consistency check between the measured B1(+) magnitude and an appropriate field estimate fulfilling Maxwell's equations. For testing the method, simulations and phantom experiments were performed for a multi-transmit array at 3T using a cylindrical phantom. RESULTS: The method's robustness with respect to the assumptions made about electric tissue properties as well as its stability under different initial conditions regarding the signal phase was shown. A high sensitivity to signal noise was found. Robust reconstruction results were achieved including information from more than two transmit elements. The validity of the experimental results was confirmed by a qualitative comparison to simulated electromagnetic fields. CONCLUSIONS: The method allows the determination of the SAR as well as the transmit phase of the individual channels of a multi-transmit array. With additional B0 inhomogeneity measurements, a reconstruction of the receive phase is feasible independent of the receive coil type in use. PMID- 23443884 TI - Alleviating artifacts in 1H MRI thermometry by single scan spatiotemporal encoding. AB - OBJECTIVE: Recent years have seen an increased interest in combining MRI thermometry with devices capable of destroying malignancies by heat ablation. Expected from the MR protocols are accurate and fast thermal characterizations, providing real time feedback on restricted tissue volumes and/or rapidly moving organs like liver. This article explores the potential advantages of relying on spatiotemporally encoded (SPEN) sequences for retrieving real-time thermometric images based on the water's proton resonance frequency (PRF) shifts. MATERIALS AND METHODS: Hybrid spatiotemporal/k-space encoding single-scan MRI experiments were implemented on animal and human scanners, and their abilities to deliver single- and multi-slice real-time thermometric measurements based on PRF-derived phase maps in phantoms and in vivo, were compared against echo planar imaging (EPI) and gradient-echo counterparts. RESULTS: Under comparable acquisition conditions, SPEN exhibited advantages vis-a-vis EPI in terms of dealing with inhomogeneous magnetic field distortions, with shifts arising due to changes in the central frequency offsets, with PRF distributions, and for zooming into restricted fields-of-view without special pulse sequence provisions. CONCLUSION: This work confirms the ability of SPEN sequences, particularly when implemented under fully-refocused conditions, to exploit their built-in robustness to shift- and field-derived inhomogeneities for monitoring thermal changes in real-time under in vitro and in vivo conditions. PMID- 23443883 TI - The role of tissue microstructure and water exchange in biophysical modelling of diffusion in white matter. AB - Biophysical models that describe the outcome of white matter diffusion MRI experiments have various degrees of complexity. While the simplest models assume equal-sized and parallel axons, more elaborate ones may include distributions of axon diameters and axonal orientation dispersions. These microstructural features can be inferred from diffusion-weighted signal attenuation curves by solving an inverse problem, validated in several Monte Carlo simulation studies. Model development has been paralleled by microscopy studies of the microstructure of excised and fixed nerves, confirming that axon diameter estimates from diffusion measurements agree with those from microscopy. However, results obtained in vivo are less conclusive. For example, the amount of slowly diffusing water is lower than expected, and the diffusion-encoded signal is apparently insensitive to diffusion time variations, contrary to what may be expected. Recent understandings of the resolution limit in diffusion MRI, the rate of water exchange, and the presence of microscopic axonal undulation and axonal orientation dispersions may, however, explain such apparent contradictions. Knowledge of the effects of biophysical mechanisms on water diffusion in tissue can be used to predict the outcome of diffusion tensor imaging (DTI) and of diffusion kurtosis imaging (DKI) studies. Alterations of DTI or DKI parameters found in studies of pathologies such as ischemic stroke can thus be compared with those predicted by modelling. Observations in agreement with the predictions strengthen the credibility of biophysical models; those in disagreement could provide clues of how to improve them. DKI is particularly suited for this purpose; it is performed using higher b-values than DTI, and thus carries more information about the tissue microstructure. The purpose of this review is to provide an update on the current understanding of how various properties of the tissue microstructure and the rate of water exchange between microenvironments are reflected in diffusion MRI measurements. We focus on the use of biophysical models for extracting tissue-specific parameters from data obtained with single PGSE sequences on clinical MRI scanners, but results obtained with animal MRI scanners are also considered. While modelling of white matter is the central theme, experiments on model systems that highlight important aspects of the biophysical models are also reviewed. PMID- 23443885 TI - Magnesium supplementation reduces postoperative arrhythmias after cardiopulmonary bypass in pediatrics: a metaanalysis of randomized controlled trials. AB - Postoperative arrhythmia (POA) is the most common complication encountered after cardiopulmonary bypass (CPB). The preventive effect of magnesium in POA has been confirmed by metaanalyses in adults, but less is known in pediatric patients. A metaanalysis of published trials was conducted to examine the efficacy of magnesium supplementation in POA prevention among pediatric patients undergoing CPB. Relevant trials were identified from electronic databases (Medline, Embase, Web of Science, and Cochrane library). Pooled relative risk (RR) and 95 % confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models, and heterogeneity was determined qualitatively according to I (2) and chi squared statistical analyses. Among 121 potentially relevant studies, five randomized controlled trials met the inclusion criteria, resulting in a pooled total of 348 participants. Compared with placebo, magnesium supplementation decreased the incidence of arrhythmia after CPB in pediatric patients by 66 % (RR, 0.34; 95 % CI, 0.18-0.65; P = 0.001), with no heterogeneity between trials (heterogeneity P = 0.68; I (2) = 0 %). Magnesium supplementation significantly reduces the incidence of postoperative arrhythmias in pediatric patients undergoing CPB. Although the findings encourage the use of magnesium as an alternative to postoperative arrhythmias after CPB in pediatric patients, higher quality randomized clinical trials are necessary before the findings can be generalized. PMID- 23443886 TI - Autocrine motility factor injection for motor plate regeneration and muscle function restoration--a pilot study. AB - BACKGROUND: Autocrine motility factor (AMF) is a multifunctional cytokine that promotes cellular adhesion, proliferation, motility, anti-apoptosis, and tissue repair. Direct nerve implantation (DNI) is considered to be effective in peripheral motor nerve injuries with disuse of the distal nerve; however, the repaired muscle function is not satisfactory. In our study, purified AMF was injected in reinnervated muscle after DNI with the intention of assessing if AMF, as a malignant tumor-related cytokine, could improve motor plate regeneration and neuromuscular function restoration. METHODS: Purified AMF, which was extracted from AMF-transfected myoblast-conditioned medium, was regularly injected into the rat gastrocnemius in an established rat gastrocnemius denervation and reinnervation model. The nerve conduction velocity (NCV) of the tibial nerve, peak-to-peak value (PPV), area under the curve (AUC) of the compound muscle action potential (CMAP) and the Tibial Functional Index (TFI) were measured at 8, 16 and 24 weeks after injection. The regenerated endplates in gastrocnemius were examined by histochemical staining. In another group, an AMF-free solution was injected as the control. RESULTS: After the AMF injection, the direct-nerve implanted muscle function recovery was better in terms of both the nerve velocity and the quality. The endplates in the experimental group also had a quantitative advantage in restoration. After comparing the histochemical-stained tissues, no indications of tumorigenesis were detected. CONCLUSIONS: AMF had positive effects on neuromuscular reparation and need more detailed research to determine the signalling pathways and side effects of AMF. PMID- 23443887 TI - Synthesis of L-hexoses and their related biomolecules. AB - Carbohydrates either conjugated or as free entities are major players in numerous biological processes. The desire to comprehend the nature of their functions and further develop therapeutic and diagnostic applications has fuelled the recent upsurge in the glycoscience field. Mainly accessed through chemical synthesis, homogeneous and well-defined sugar constructs are on high demand for structure activity evaluation. Although the d-sugars, particularly the d-hexoses, have dominated the carbohydrate landscape, L-hexoses also attracted attention because they are known components of important polysaccharides, antibiotics, and other natural products. Nonetheless, the L-hexose-based materials needed for making building blocks for sugar assemblies are rare and are usually expensive if commercially available. Thus, intense efforts were focused on the development of innovative and reliable methods for the acquisition of L-hexoses and their derivatives. This review outlines several efficient and cost-effective routes for the chemical syntheses of L-hexoses, particularly focusing on approaches that utilize commercially abundant sugars as starting materials. A sampling of the applications of the generated L-hexoses in preparing biologically relevant compounds is also provided. PMID- 23443888 TI - Academic career and part-time working in medicine: a cross sectional study. AB - The aim of this exploratory survey was to assess predictors for an academic career in a population of physicians working full time (FT) or part time (PT) in the north-western part of Switzerland. We also asked for individual attitudes, influences and motivations towards PT work. METHODS: In a cross-sectional study, resident and senior physicians were asked via hyperlink to complete an anonymous 91-item questionnaire. The completed questionnaires were collected anonymously online. RESULTS: Overall, 389 of 1104 (35%) questionnaires were returned for analysis. Of the respondents, 68.1% worked FT and 31.9% PT. More women than men (57.5% vs 42.5%) responded to the questionnaire and more women than men (68.2% vs 31.8%) were working as residents. Of the FT physicians, 88.9% favoured a work reduction to 60.0-90.0%; 82.9% FT and 97.0% PT physicians considered the introduction of PT work opportunities in their hospital as reasonable. A higher academic score was reached by men (mean 3.69, SD 3.39) than by women (mean 2.22, SD 2.77). Among senior physicians, PT work had a significant influence on the academic score. The possibility to do research, followed by male gender, were the two most significant factors positively influencing an academic career. CONCLUSION: The possibility to perform research remains the most important predictor for a successful academic career. Working PT diminishes the chance of academic success. PMID- 23443889 TI - The simplified SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers. AB - OBJECTIVE: Prior studies have validated the ability of the SART embryo scoring system to correlate with outcomes in cleavage stage embryo transfers. However, this scoring system has not been evaluated in blastocyst transfers. The objective of this study was to estimate the correlation between the simplified SART embryo scoring system and ART cycle outcomes in single blastocyst transfers. MATERIALS AND METHODS: All fresh, autologous single blastocyst transfers cycles from a large ART center from 2010 were analyzed. Blastocysts were given a single grade of good, fair, or poor based upon SART criteria which combines the grading of the inner cell mass and trophectoderm. Multiple logistic regression assessed the predictive value of the SART grade on embryo implantation and live birth. RESULTS: Seven hundred seventeen fresh, autologous single blastocyst transfers cycles were included in the analysis. The live birth rate was 52 % and included both elective and non-elective SBT. Chi square analysis showed higher live birth in good grade embryos as compared to fair (p=0.03) and poor (p=0.02). Univariate binary logistic regression analysis demonstrated SART embryo grading to be significantly correlated with both implantation and live birth (p<0.01). This significance persisted when patient age, BMI, and the stage of the blastocyst were controlled for with multiple logistic regression. In five patients with a poor blastocyst score, there were no live births. CONCLUSION: These data demonstrate that the SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers. Patients with a good grade embryo are excellent candidates for a single blastocyst transfer. PMID- 23443890 TI - Life stress impairs self-control in early adolescence. AB - The importance of self-control to a wide range of developmental outcomes prompted the current investigation of negative life events and self-control in early adolescence. In three prospective, longitudinal studies, negative life events reported by the mother (in Study 1) or child (in Studies 2 and 3) predicted rank order decreases in self-control over time. In all studies, self-control was measured at two different time points using questionnaires completed by three separate raters, including a classroom teacher who knew the child well and two other raters (parents, caregivers, and/or the child himself/herself). Psychological distress measured in Studies 2 and 3 mediated the deleterious effects of negative life events on self-control. These findings extend prior experimental laboratory research documenting the acute effects of stress on self control. PMID- 23443891 TI - Tuneable nanochannel formation for sample-in/answer-out devices. AB - Control of the dielectric breakdown of PDMS was achieved by limiting the current during the breakdown process. This enabled tuning of the nanochannel pore size and hence their permeability for molecules of different molecular weights. This method enabled the analysis of the drug quinine from whole blood in 3 min using a simple, disposable microfluidic device. PMID- 23443892 TI - Evaluation of CancerChatCanada: a program of online support for Canadians affected by cancer. AB - BACKGROUND: Professional-led cancer support groups can improve quality of life and address unmet needs, but most Canadians affected by cancer do not have access to or do not make use of cancer support groups. A collaborative interdisciplinary team developed, operated, and evaluated Internet-based, professional-led, live chat support groups (osgs) for cancer patients, caregivers, and survivors across Canada. OBJECTIVE: Our study aimed to report participant and participation characteristics in the pan-Canadian initiative known as CancerChatCanada, and to understand participant perspectives about the quality of communication and professional facilitation, overall satisfaction, and psychosocial benefits and outcomes. METHODS: Participants in osgs provided informed consent. Participant and participation characteristics were gathered from program data collection tools and are described using frequencies, means, and chi-squares. Patient, survivor, and caregiver perspectives were derived from 102 telephone interviews conducted after osg completion and subjected to a directed qualitative content analysis. RESULTS: The 55 professional-led osgs enrolled 351 participants from 9 provinces. More than half the participants came from rural or semirural areas, and more than 84% had no received previous cancer support. The attendance rate was 75%, the dropout rate was 26%, and 80% of participants were satisfied or very satisfied. The convenience and privacy of osgs were benefits. Meaningful communication about important and difficult topics, kinship and bonding with others, and improved mood and self-care were perceived outcomes. CONCLUSIONS: Our results demonstrate that this collaborative initiative was successful in increasing reach and access, and that pan-Canadian, professional-led osgs provide psychosocial benefit to underserved and burdened cancer patients, survivors, and family caregivers. PMID- 23443893 TI - A traceless aryl-triazene linker for DNA-directed chemistry. AB - DNA-directed synthesis of encoded combinatorial libraries of small organic compounds most often involves transfer of organic building blocks from one DNA strand to another. This requires cleavable linkers to enable cleavage of the link to the original DNA strand from which the building block is transferred. Relatively few cleavable linkers are available for DNA-directed synthesis and most often they leave an amino group at the organic molecule. Here we have extended the application of aryltriazenes as traceless linkers for DNA-directed synthesis. After reaction of one building block with a building block at another DNA strand the triazene linker is cleaved and reduced with hypophosphorous acid in high yield to leave the aryl group with a hydrogen in place of the triazene i.e. without a functional group trace. It was also demonstrated that alternatively the triazene could be converted to an azide, which was used in a cycloaddition reaction. The linker is generally stable at pH > 7 and could be stored for several months in a freezer without significant degradation. PMID- 23443894 TI - Detergent compatible alkaline lipase produced by marine Bacillus smithii BTMS 11. AB - Bacillus smithii BTMS 11, isolated from marine sediment, produced alkaline and thermostable lipase. The enzyme was purified to homogeneity by ammonium sulfate precipitation and ion exchange chromatography which resulted in 0.51 % final yield and a 4.33 fold of purification. The purified enzyme was found to have a specific activity of 360 IU/mg protein. SDS-PAGE analyses, under non-reducing and reducing conditions, yielded a single band of 45 kDa indicating the single polypeptide nature of the enzyme and zymogram analysis using methylumbelliferyl butyrate as substrate confirmed the lipolytic activity of the protein band. The enzyme was found to have 50 degrees C and pH 8.0 as optimum conditions for maximal activity. However, the enzyme was active over wide range of temperatures (30-80 degrees C) and pH (7.0-10.0). Effect of a number of metal salts, solvents, surfactants, and other typical enzyme inhibitors on lipase activity was studied to determine the novel characteristics of the enzyme. More than 90 % of the enzyme activity was observed even after 3 h of incubation in the presence of commercial detergents Surf, Sunlight, Ariel, Henko, Tide and Ujala indicating the detergent compatibility of B. smithii lipase. The enzyme was also found to be efficient in stain removal from cotton cloths. Further it was observed that the enzyme could catalyse ester synthesis between fatty acids of varying carbon chain lengths and methanol with high preference for medium to long chain fatty acids showing 70 % of esterification. Results of the study indicated scope for application of this marine bacterial lipase in various industries. PMID- 23443895 TI - Intramuscular corpora amylacea adjacent to ileal low-grade neuroendocrine tumours (typical carcinoids): a light microscopic, immunohistochemical and ultrastructural study. AB - AIMS: The purposes of this study are to (1) document the prevalence of intracytoplasmic inclusions adjacent to ileal well-differentiated neuroendocrine tumours (WNETs), (2) examine whether and how tumour and patient characteristics are associated with inclusions and (3) investigate their properties on special stains and electron microscopy in comparison with corpora amylacea (CA). METHODS: We examined the resection slides from 26 ileal, 5 gastric and 5 rectal cases of WNET. Inclusions were readily identified with H&E staining. Histochemical, immunohistochemical and ultrastructural evaluations were performed on the block with the highest number of inclusions. RESULTS: Intracytoplasmic inclusions occurred adjacent (<1 mm) to 15 of 26 (57.7%) ileal WNETs. Patients with and without inclusions were of similar mean ages (59.5 vs 57.4 years; p=0.88), but NETs with inclusions were larger than those without inclusions (3.3 vs 1.7 cm, p=0.03). Inclusions were neither associated with gastric (mean age=65 years, mean diameter=1.5 cm) or rectal WNETs (mean age=47.8 years, mean diameter=0.5 cm) (p=0.01), nor were they present >1 mm from ileal NETs. CA stained strongly for ubiquitin, DPAS and Alcian blue; faintly and peripherally for desmin and smooth muscle actin and negatively for calcium. Ultrastructurally, their appearance was consistent with filaments, some with cores of particle matter. CONCLUSIONS: Our results suggest that these inclusions are virtually identical to CA and present adjacent to the majority of ileal WNET. They may be the result of a degenerative process, possibly due to chronic myocyte stress from an infiltrating slow growing tumour mass or local hormonal effects. PMID- 23443896 TI - The more publication, the higher impact factor: citation analysis of top nine gastroenterology and hepatology journals. AB - BACKGROUND: The impact factor (IF), as the most important criterion for journal's quality measurement, is affected by the self-citation and number of publications in each journal. OBJECTIVES: To find out the relationship between the number of publications and self-citations in a journal, and their correlations with IF. MATERIALS AND METHODS: Self-citations and impact factors of nine top gastroenterology and hepatology journals were assessed during the seven recent years (2005-2011) through Journal Citation Reports (JCR, ISI Thomson Reuters). RESULTS: Although impact factors of all journals increased during the study, five out of nine journals increased the number of publications from 2005 to 2011. There was an increase in self-citation only in the journal of HEPATOLOGY (499 in 2005 vs. 707 in 2011). Impact factors of journals (6.5 +/- 3.5) were positively correlated with total number of publications (248.6 +/- 91.7) (R: 0.688, P < 0.001). Besides, the self-citation rate (238.73 +/- 195.317) was highly correlated with total number of publications in each journal (248.6 +/- 91.7) (R: 0.861, P < 0.001). On the other hand, impact factor without self-citation (6.08 +/- 3.3) had a correlation (R: 0.672, P < 0.001) with the number of published items (248.6 +/- 91.7). CONCLUSIONS: The number of articles and self-citation have definite effects on IF of a journal and because IF is the most prominent criterion for journal's quality measurement, it would be a good idea to consider factors affecting on IF such as self-citation. PMID- 23443897 TI - Alpha-synuclein promotes early neurite outgrowth in cultured primary neurons. AB - We previously showed that alpha-synuclein (alpha-Syn), a protein implicated in the pathogenesis of several neurodegenerative diseases, is a microtubule associated protein (MAP), facilitating the polymerization of tubulin into microtubules. Therefore, we hypothesized that alpha-Syn might promote neurite outgrowth, a process that requires microtubule assembly. To test this hypothesis, recombinant human wild type (WT) and mutant (A30P and A53T) alpha-Syn proteins were added to cultured primary rat cortical neurons, and their effects on early neurite outgrowth were observed. The WT and mutant alpha-Syn proteins entered the neurons after 1-4 h of incubation. However, a significant increase in neurite outgrowth was observed only in neurons treated with WT alpha-Syn. MES23.5 dopaminergic neuronal cells overexpressing WT alpha-Syn also exhibited enhanced neurite outgrowth, indicating that the ability of alpha-Syn to promote neurite outgrowth was not due to a direct action on the cell membrane or by the membrane translocation process. Co-immunoprecipitation demonstrated that the recombinant human alpha-Syn was bound to tubulin. In addition, the alpha-Syn-treated neurons displayed increased levels of polymerized tubulin. Because alpha-Syn's MAP functionality is mediated by specific domains, we generated N-terminal (a.a. 1 65), non-amyloid-beta (non-Abeta) component (NAC) (a.a. 61-95) and C-terminal (a.a. 96-140) fragments and added them to the primary neurons. After 1-4 h of incubation, the various alpha-Syn fragments had entered the neurons. However, only the NAC and C-terminal fragments, which have been previously shown to mediate MAP functionality, promoted neurite outgrowth. These results suggest that alpha-Syn promotes neurite outgrowth by facilitating the polymerization of tubulin into microtubules. PMID- 23443898 TI - Zoledronic acid and radiation: toxicity, synergy or radiosensitization? AB - INTRODUCTION: Zoledronic acid (Z) is a bisphosphonate used in hypercalcaemia related cancer, in complications for bone metastasis and in postmenopausal osteoporosis and it has been related to osteoradionecrosis, especially when associated with radiation to the head and neck structures. OBJECTIVES: To determine the radiosensitization capacity of zoledronic acid in the combined treatment with ionizing radiation (IR) by evaluating its genotoxic and cytotoxic capacities in non-tumoral cells. MATERIALS AND METHODS: The genotoxic effect of Z was studied by means of the micronucleus test in cytokinesis-blocked cells of human lymphocytes irradiated before and after a 2 Gy irradiation, while the cytotoxic effect was studied by a cell viability test in the PNT2 cell line before and after exposure to different X-ray doses (0-20 Gy) in four groups (Z alone, radiation alone, Z + IR and IR + Z). RESULTS: A dose-dependent and time dependent cytotoxic effect of Z and IR on PNT2 cells in vitro (p > 0.001) was demonstrated. With the concentrations recommended for humans, the combined treatment had a more pronounced effect than individual treatments (p < 0.001). The effect was synergic (CI < 1), increasing the Z enhancement ratio (2.6) and sensitization factor (56 %); the effect of Z was always greater after IR exposure. In the genotoxic effect, only the administration of Z after irradiation (IR + Z) increased chromosome damage (p < 0.001) and the sensibilization factor (35.7 %). CONCLUSION: High concentrations of Z are toxic, but the concentrations recommended for clinical practice in humans give it the characteristics of a radiosensitization agent, whose effect is even greater when administered after IR. PMID- 23443899 TI - Predictive value of preoperative optical coherence tomography for visual outcome following macular hole surgery: effects of imaging alignment. AB - PURPOSE: To investigate the effects of reproducibility of optical coherence tomography (OCT) measurements and imaging alignment on predictive performance for visual outcome following macular hole (MH) surgery. METHODS: We retrospectively reviewed 50 eyes that underwent MH surgery. Preoperative cross-sectional images through the center of the MH (on-center image) and through an off-center point (off-center image) were obtained from the OCT data. In each image, the following OCT parameters were either measured or calculated: minimum diameter, base diameter, hole height, temporal and nasal arm length, photoreceptor inner segment/outer segment (IS/OS) defect length, the hole form factor, the macular hole index and the tractional hole index. The IS/OS defect area was also measured. RESULTS: The reproducibility of OCT parameter values was moderate to high, and there was a significant difference in the mean measurement values between the on- and off-center images. Predictive values varied between sessions and raters, and only the preoperative photoreceptor IS/OS defect length consistently showed significant correlation with postoperative visual outcome. CONCLUSIONS: Both the reproducibility and imaging alignment might affect the predictive performance of the OCT parameter for postoperative visual outcome following MH surgery. The preoperative photoreceptor IS/OS defect length seems to be the most useful parameter in this regard. PMID- 23443900 TI - Concentric division of 10 degrees visual field tests in retinitis pigmentosa. AB - PURPOSE: The purpose of this study was to estimate the optimal size of visual field test for detecting longitudinal changes in retinitis pigmentosa (RP) by dividing the visual field. METHODS: We reviewed the results of 10 degrees static visual field tests in 19 eyes of 19 RP patients. Sixty-eight numeric value points were divided into two area types: concentric areas (A1, A1-2, A1-3, A1-4, A1-5, A1-6) and circular areas (A1, A2, A3, A4, A5, A6). Serial values of mean sensitivity in each area of each patient were analyzed by linear regression. RESULTS: Analysis of the concentric areas showed that 10 of 19 eyes had the best R (2) value in the most central area, A1. Analysis of circular areas showed that 7 of 19 eyes had the steepest slope of decline in A1. The inner-segment/outer segment (IS/OS) line was significantly shorter in eyes with low variability and evident disease progression in the inner areas than the ones in the outer areas. CONCLUSIONS: The optimal size of monitoring RP progression was different in each case and may depend on the remaining morphology of the outer retina. PMID- 23443901 TI - Randomized clinical trial of subcutaneous versus interfascial bupivacaine for pain control after midline laparotomy. AB - BACKGROUND: Although patient-controlled analgesia for pain management after abdominal surgery is common, efforts to find alternative effective methods to control postoperative pain are continuing. The aim of this study was to compare postoperative pain levels following intermittent regional administration of bupivacaine via a catheter placed in the rectus sheath or subcutaneously at abdominal surgery through midline incisions. METHODS: Consecutive patients undergoing elective midline laparotomy were assigned randomly to a group with two catheters placed over the fascia (suprafascial group) before surgical wound closure or to a group with catheters placed between the two sheaths of each rectus muscle (interfascial group). Pain levels were determined every 12 h, both at rest and with movement, by means of a standard visual analogue scale (VAS) for 72 h after surgery. The amounts of administered opioid were recorded. RESULTS: Sixty patients were enrolled in the study (30 patients in each group).The median VAS score 36 h after surgery, both at rest and with movement, was significantly lower in the interfascial group than in the suprafascial group (P<0.050). Repeated-measures ANOVA also showed a significant difference in the postoperative VAS scores (P<0.007). The amount of self-administered morphine was significantly lower in the interfascial group, overall (P = 0.001) as well as on postoperative day 1 (P = 0.001) and day 2 (P = 0.016). Bowel sounds returned more quickly in the interfascial group (P = 0.040). CONCLUSION: Locoregional catheter administration of bupivacaine following midline laparotomy is more effective when the catheter is placed in the rectus sheath compared with suprafascial delivery. REGISTRATION NUMBER: IRCT138810142982N1 (http://www.irct.ir). PMID- 23443902 TI - Experiences and perceptions of sexual harassment in the Canadian forces combat arms. AB - Recent studies examining sexual harassment in the military indicate a decrease in reports of harassment, which may be attributed to several factors, including zero tolerance policies or anti-harassment programs. However, the decrease may also be attributed to fears of losing one's job or of being derogated by colleagues if harassment is reported. This qualitative study of women employed in the Canadian combat arms examined spontaneously shared perceptions and experiences of sexual harassment. Six of the 26 women interviewed shared their experiences or perceptions of harassment, including concerns about potential repercussions of reporting. Implications for gender integration in military organizations are discussed. PMID- 23443903 TI - Comparison of whole-cell fatty acid (MIDI) or phospholipid fatty acid (PLFA) extractants as biomarkers to profile soil microbial communities. AB - The whole-cell lipid extraction to profile microbial communities on soils using fatty acid (FA) biomarkers is commonly done with the two extractants associated with the phospholipid fatty acid (PLFA) or Microbial IDentification Inc. (MIDI) methods. These extractants have very different chemistry and lipid separation procedures, but often shown a similar ability to discriminate soils from various management and vegetation systems. However, the mechanism and the chemistry of the exact suite of FAs extracted by these two methods are poorly understood. Therefore, the objective was to qualitatively and quantitatively compare the MIDI and PLFA microbial profiling methods for detecting microbial community shifts due to soil type or management. Twenty-nine soil samples were collected from a wide range of soil types across Oregon and extracted FAs by each method were analyzed by gas chromatography (GC) and GC-mass spectrometry. Unlike PLFA profiles, which were highly related to microbial FAs, the overall MIDI-FA profiles were highly related to the plant-derived FAs. Plant-associated compounds were quantitatively related to particulate organic matter (POM) and qualitatively related to the standing vegetation at sampling. These FAs were negatively correlated to respiration rate normalized to POM (RespPOM), which increased in systems under more intensive management. A strong negative correlation was found between MIDI FA to PLFA ratios and total organic carbon (TOC). When the reagents used in MIDI procedure were tested for the limited recovery of MIDI-FAs from soil with high organic matter, the recovery of MIDI-FA microbial signatures sharply decreased with increasing ratios of soil to extractant. Hence, the MIDI method should be used with great caution for interpreting changes in FA profiles due to shifts in microbial communities. PMID- 23443905 TI - [The penumbra of the heart in MRI]. PMID- 23443904 TI - Candidate of metastasis 1 regulates in vitro growth and invasion of bladder cancer cells. AB - COM1 (candidate of metastasis 1) has been recently shown to influence the metastatic ability of cancer cells and disease progression of certain solid tumours. The role of COM1 in bladder cancer remains unknown. In the present study, we examined the expression of the COM1 protein in human bladder tissues, and also its effect on growth, adhesion, migration and invasion of human bladder cancer cells, in vitro. The expression of COM1 in human bladder tissues and bladder cancer cell lines was assessed at both the mRNA and protein levels using RT-PCR and immunohistochemistry, respectively. COM1 staining was compared with tumour staging. Mammalian COM1 expression construct and anti-COM1 ribozyme transgenes were used to generate sublines of human bladder cancer cells with differential expression of COM1. The effect of COM1 on cellular functions was examined in bladder cancer cells with which COM1 was overexpressed or knocked down using a variety of in vitro assays. In normal bladder tissues, stronger staining of COM1 was seen in the cytoplasm of normal urothelial cells. In contrast, the staining was notably weak or absent in cancer cells of tumour tissues and invasive tumours had significantly low levels of staining compared with non-invasive tumours (p=0.012). Knockdown of COM1 in bladder cancer cell lines resulted in an increase in cellular growth and invasion, while overexpression of COM1 suppressed invasiveness and growth of these cells. Further investigation revealed an increased apoptosis and upregulated p21 in bladder cancer cells when COM1 was overexpressed. COM1 is expressed at low levels in human bladder cancer and in particular in invasive bladder tumours. COM1 levels are inversely correlated with the invasiveness and growth of bladder cancer cells in vitro. Induced apoptosis and upregulation of p21 are indicated in the mechanism of COM1 inhibiting bladder cancer cell growth. It suggests that COM1 is a potential tumour suppressor in human bladder cancer. PMID- 23443906 TI - Frequency and severity of pain and symptom distress among patients with chronic kidney disease receiving dialysis. AB - QUESTION UNDER STUDY: Data on pain management in haemodialysis patients with end stage renal disease are scanty. Our study aimed to collect information on the frequency and severity of pain and symptom distress among long-term dialysis patients in southern Switzerland. METHODS: Patients with chronic kidney disease stage 5, on dialysis, treated in five nephrology units in southern Switzerland, who had given informed consent and were able to complete the survey, were interviewed to assess pain and correlated symptoms using a Visual Analogue Scale (VAS), the Brief Pain Inventory and the Edmonton Symptom Assessment System. To evaluate the impact of symptoms, the Instrumental Activities of Daily Living questionnaire was used. RESULTS: One hundred and twenty-three patients, aged 36 90 years and with a mean time on dialysis of 3.5 years, were interviewed. Pain was experienced by 81 patients during the 4 weeks before the interview: 68 had chronic pain; 66 reported pain intensity higher than 5 on the VAS; 35 identified musculoskeletal pain as the most disturbing pain. Five patients used drugs to cope with pain during the night. Asthenia and fatigue were prevalent concomitant symptoms. Asthenia, fatigue, sleep disturbances, dyspnoea, loss of appetite, nausea/vomiting and anxiety were correlated with pain. The majority of the patients reported that their pain limited their daily life activities. CONCLUSIONS: Pain severity and symptom distress in dialysis patients are important, but underestimated and undertreated. They interfere with sleep quality and daily living. Routine assessment of pain burden, pain management similar to that used in palliative care, and adequate analgesic use to treat specific dialysis-associated pain syndromes should be considered in guidelines. PMID- 23443907 TI - N400 predicts recovery from disorders of consciousness. AB - OBJECTIVE: Patients with the unresponsive wakefulness syndrome (UWS; formerly vegetative state) or in a minimally conscious state (MCS) open their eyes spontaneously but show no (UWS) or only marginal (MCS) signs of awareness. Because these states can become permanent, residual information processing capacities need to be determined, and reliable outcome predictors need to be found. We assessed higher-order cortical information processing in UWS or MCS in a large group of patients using electroencephalographic event-related potentials (ERPs) and determined their long-term prognostic value for recovery. METHODS: Cognitive ERPs elicited by sound (P300) and speech (N400) were used to assess information processing in 92 behaviorally unresponsive patients diagnosed as in the state of either UWS (n=53) or MCS (n=39). ERPs were assessed with a clinical standard evaluation method and a computerized method, the t-continuous wavelet transform. The patients' clinical outcome was followed up between 2 and 14 years after discharge from the rehabilitation center. RESULTS: Within the first year of the disease, many patients showed an intact P300 and several also an N400, indicating considerable residual information processing. At clinical follow-up, about 25% of the patients recovered and regained communicative capabilities. A highly significant relationship between N400, but not P300, presence and subsequent recovery was found. INTERPRETATION: Results specify cognitive capabilities in disorders of consciousness, and determine their prognostic value. Specifically the N400 ERP is suggested as an important tool to assess information processing capacities that can predict the likelihood of recovery of patients in UWS or MCS. PMID- 23443908 TI - On the accuracy of explicitly correlated methods to generate potential energy surfaces for scattering calculations and clustering: application to the HCl-He complex. AB - We closely compare the accuracy of multidimensional potential energy surfaces (PESs) generated by the recently developed explicitly correlated coupled cluster (CCSD(T)-F12) methods in connection with the cc-pVXZ-F12 (X = D, T) and aug-cc pVTZ basis sets and those deduced using the well-established orbital-based coupled cluster techniques employing correlation consistent atomic basis sets (aug-cc-pVXZ, X = T, Q, 5) and extrapolated to the complete basis set (CBS) limit. This work is performed on the benchmark rare gas-hydrogen halide interaction (HCl-He) system. These PESs are then incorporated into quantum close coupling scattering dynamical calculations in order to check the impact of the accuracy of the PES on the scattering calculations. For this system, we deduced inelastic collisional data including (de-)excitation collisional and pressure broadening cross sections. Our work shows that the CCSD(T)-F12/aug-cc-pVTZ PES describes correctly the repulsive wall, the van der Waals minimum and long range internuclear distances whereas cc-pVXZ-F12 (X = D,T) basis sets are not diffuse enough for that purposes. Interestingly, the collision cross sections deduced from the CCSD(T)-F12/aug-cc-pVTZ PES are in excellent agreement with those obtained with CCSD(T)/CBS methodology. The position of the resonances and the general shape of these cross sections almost coincide. Since the cost of the electronic structure computations is reduced by several orders of magnitude when using CCSD(T)-F12/aug-cc-pVTZ compared to CCSD(T)/CBS methodology, this approach can be recommended as an alternative for generation of PESs of molecular clusters and for the interpretation of accurate scattering experiments as well as for a wide production of collisional data to be included in astrophysical and atmospherical models. PMID- 23443910 TI - In vitro evolution of a Friedel-Crafts deoxyribozyme. AB - We report the in vitro selection of a single-stranded 72-nucleotide DNA enzyme (deoxyribozyme) that catalyzes a Friedel-Crafts reaction between an indole and acyl imidazole in good yield and in aqueous solvent. Appreciable Friedel-Crafts product requires addition of copper nitrate and the deoxyribozyme. We observe deoxyribozyme-mediated bond formation for both in cis and in trans Friedel-Crafts reactions. PMID- 23443909 TI - The impact of lifestyle factors on the physical health of people with a mental illness: a brief review. AB - BACKGROUND: People with a mental illness are much more likely to experience poor physical health when compared to the general population, showing a higher propensity to develop the metabolic syndrome. Past focus has predominantly been upon individuals treated with antipsychotics, yet poor physical health is occurring across diagnoses. PURPOSE: The purpose of this paper is to draw attention to the major factors within the domain of lifestyle in order to support the need for more detailed and rigorous physical health assessment and ongoing monitoring for people with a mental illness. METHOD: This paper reviews existing evidence relating to lifestyle factors such as low exercise levels, poor diet and nutrition, high cholesterol levels, tobacco smoking and poor dental care, contributing to poor physical health such as a higher incidence of cardiovascular disease and type 2 diabetes. An integrative review was conducted from a multi disciplinary search of online databases and journals, focusing upon mental illness and lifestyle issues predominant in the literature. RESULTS: The findings reviewed here suggest that greater attention should be paid to the physical health assessment and ongoing monitoring of all people with mental health disorders so that preventable illness does not result in higher levels of morbidity and mortality for this disadvantaged population. CONCLUSION: Early identification aids preventive interventions and assists clinicians and mental health staff to more effectively treat emergent physical health problems. PMID- 23443912 TI - Lower BMI is a predictor of obstructive sleep apnea in elderly Thai hypertensive patients. AB - PURPOSE: The prevalence of both hypertension and obstructive sleep apnea (OSA) are increased in patients with age greater than 60 years. We studied the clinical differences of OSA in hypertensive patients with age greater or less than 60 years. In addition, rate of OSA-induced hypertension in Thai population is limited. METHODS: We retrospectively reviewed medical records of patients treated at the hypertension/sleep clinic at Srinagarind Hospital, Khon Kaen University, between 2010 and 2011. The inclusion criteria used were hypertensive patients who had at least one symptom of OSA and had been tested for the sleep study. Rate and clinical features of OSA were studied and categorized by age of 69 years. Factors associated with likelihood of having OSA in hypertensive patients age over 60 years were identified by multiple logistic regression analysis. RESULTS: During the study period, 49 patients met the criteria. Of those, 42 patients (85.71 %) had an apnea-hypopnea index (AHI) of more than 5/h. The average AHI was 22.22 +/- 13.86 times/h. The common symptoms of OSA were snoring (100 %), daytime sleepiness (28.57 %), unexplained nocturia (28.57 %), and gastroesophageal reflux disease (28.57 %). The numbers of patients with age less than 60 years and more than 60 years were 20 and 22 cases, respectively. Most patients (88.10 %) had well-controlled blood pressure level. Only BMI was significantly associated with OSA-induced hypertension in patients aged over or equal to 60 years. The adjusted odds ratio was 0.743 (0.560, 0.985). CONCLUSIONS: OSA is very common in Thai hypertensive patients aged 40-70 years who have at least one symptom of OSA. Lower BMI is a predictor of obstructive sleep apnea in elderly Thai hypertensive patients. PMID- 23443913 TI - A high-throughput nanoimmunoassay chip applied to large-scale vaccine adjuvant screening. AB - Large-scale experimentation is becoming instrumental in enabling new discoveries in systems biology and personalized medicine. We developed a multiplexed high throughput nanoimmunoassay chip capable of quantifying four biomarkers in 384 5 nL samples, for a total of 1536 assays. Our platform, compared to conventional methods, reduces volume and reagent cost by ~1000-fold. We applied our platform in the context of systems vaccinology, to assess the synergistic production of inflammatory cytokines from dendritic cells (DCs) stimulated with 10 different adjuvants that target members of the Toll-like receptor (TLR) family. We quantified these adjuvants both alone and in all pairwise combinations, for a total of 435 conditions, revealing numerous synergistic pairs. We evaluated two synergistic interactions, MPLA + Gardiquimod and MPLA + CpG-B, in a mouse model, where we measured the same inflammatory cytokines in bronchoalveolar lavage and in blood serum at 4 different time points using our chip, and observed similar synergistic effects in vivo, demonstrating the potential of our microfluidic platform to predict agonistic immunogenicity. More generally, a high-throughput, matrix-insensitive, low sample volume technology can play an important role in the discovery of novel therapeutics and research areas requiring large-scale biomarker quantitation. PMID- 23443911 TI - Dietary avocado oil supplementation attenuates the alterations induced by type I diabetes and oxidative stress in electron transfer at the complex II-complex III segment of the electron transport chain in rat kidney mitochondria. AB - Impaired complex III activity and reactive oxygen species (ROS) generation in mitochondria have been identified as key events leading to renal damage during diabetes. Due to its high content of oleic acid and antioxidants, we aimed to test whether avocado oil may attenuate the alterations in electron transfer at complex III induced by diabetes by a mechanism related with increased resistance to lipid peroxidation. 90 days of avocado oil administration prevented the impairment in succinate-cytochrome c oxidoreductase activity caused by streptozotocin-induced diabetes in kidney mitochondria. This was associated with a protection against decreased electron transfer through high potential chain in complex III related to cytochromes c + c1 loss. During Fe(2+)-induced oxidative stress, avocado oil improved the activities of complexes II and III and enhanced the protection conferred by a lipophilic antioxidant against damage by Fe(2+). Avocado oil also decreased ROS generation in Fe(2+)-damaged mitochondria. Alterations in the ratio of C20:4/C18:2 fatty acids were observed in mitochondria from diabetic animals that not were corrected by avocado oil treatment, which yielded lower peroxidizability indexes only in diabetic mitochondria although avocado oil caused an augment in the total content of monounsaturated fatty acids. Moreover, a protective effect of avocado oil against lipid peroxidation was observed consistently only in control mitochondria. Since the beneficial effects of avocado oil in diabetic mitochondria were not related to increased resistance to lipid peroxidation, these effects were discussed in terms of the antioxidant activity of both C18:1 and the carotenoids reported to be contained in avocado oil. PMID- 23443914 TI - Formal loss of an H radical by a cobalt complex via metal-ligand cooperation. AB - A (PNP)Co(I)methyl diamagnetic complex formally loses an H atom from the pincer ligand, exhibiting a long-range metal-ligand cooperation in what may be considered as an unusual example of 'C-H cleavage'. Spectroscopic data indicate that the product is a neutral Co(I) complex with a radical delocalized in the ligand backbone. PMID- 23443915 TI - Current Oncology: it all started 20 years ago ... PMID- 23443916 TI - Breast cancer and the environment: what is left to learn?: A Countercurrents Series. PMID- 23443917 TI - Indicator measures er/pr and her2 testing among women with invasive breast cancer. PMID- 23443918 TI - Effect of cancer on ovarian function in patients undergoing in vitro fertilization for fertility preservation: a reappraisal. PMID- 23443919 TI - The kiss of death: hpv rejected by religion. PMID- 23443920 TI - Advantages of exercise in breast cancer patients and survivors in addition to its mitigating effect on chest wall pain. PMID- 23443922 TI - Differential miRNA expression profiles between the first and third trimester human placentas. AB - To determine placental microRNA (miRNA) expression at different gestational age, total RNA from six first and six third trimester placentas was isolated. miRNA expression was analyzed by Affymetrix miRNA microarray, and miRNA clusters were identified by web-based programs MirClust and miRGen Cluster. qRT-PCR was carried out to validate miRNA expression, and in situ hybridization (ISH) was performed to determine compartmental localization of miRNAs within villous tissue. A total of 208 miRNA transcripts, which represent 191 mature miRNAs, were found differently expressed between first and third trimester placentas. miRNAs within the miR-17-92 cluster, C14MC, miR-371 cluster, and C19MC were significantly upregulated in the first trimester placentas. In contrast, miRNAs of the let-7 family, miR-34 family, miR-29a cluster, miR-195 cluster, and miR-181c cluster were significantly upregulated in the third trimester placentas. Increased miR 371-5p, miR-17-3p, and miR-708-5p expression and decreased miR-125b-5p and miR 139-5p expression in the first trimester placentas were confirmed by qRT-PCR. Different expression pattern for miR-371-5p and miR-125b-5p within villous tissue was demonstrated by ISH. Distinct miRNA cluster expression profiles between the first and third trimester placentas were identified. miRNAs that regulate innate/adaptive immune responses are strongly expressed in both first and third trimester placentas. miRNAs that exert oncogenic, angiogenic, and antiapoptotic properties are dominantly expressed in the first trimester placentas, whereas miRNAs that promote cell differentiation and function as tumor suppressors are strongly expressed in the third trimester placentas. These results indicate that miRNAs play critical roles in placental development. PMID- 23443923 TI - Modeling hepatic insulin sensitivity during a meal: validation against the euglycemic hyperinsulinemic clamp. AB - Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, S(I)(Lmeal) has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled ([3 (3)H]glucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r = 0.72, P < 0.001); however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60 +/- 0.64 vs. 8.73 +/- 1.07 10(-4) dl.kg(-1).min(-1) per MUU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (DeltaI(clamp) = 15.60 +/- 1.61 vs. DeltaI(meal)= 83.37 +/- 10.71 MUU/ml) as well as steady- vs. non steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test. PMID- 23443924 TI - Decreased expression of the satiety signal receptor CCKAR is responsible for increased growth and body weight during the domestication of chickens. AB - Animal domestication has resulted in changes in growth and size. It has been suggested that this may have involved selection for differences in appetite. Divergent growth between chickens selected for egg laying or meat production is one such example. The neurons expressing AGRP and POMC in the basal hypothalamus are important components of appetite regulation, as are the satiety feedback pathways that carry information from the intestine, including CCK and its receptor CCKAR (CCK1 receptor). Using 16 generations of a cross between a fast and a relatively slow growing strain of chicken has identified a region on chromosome 4 downstream of the CCKAR gene, which is responsible for up to a 19% difference in body weight at 12 wk of age. Animals possessing the high-growth haplotype at the locus have lower expression of mRNA and immunoreactive CCKAR in the brain, intestine, and exocrine organs, which is correlated with increased levels of orexigenic AGRP in the hypothalamus. Animals with the high-growth haplotype are resistant to the anorectic effect of exogenously administered CCK, suggesting that their satiety set point has been altered. Comparison with traditional breeds shows that the high-growth haplotype has been present in the founders of modern meat-type strains and may have been selected early in domestication. This is the first dissection of the physiological consequences of a genetic locus for a quantitative trait that alters appetite and gives us an insight into the domestication of animals. This will allow elucidation of how differences in appetite occur in birds and also mammals. PMID- 23443925 TI - FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. AB - Fibroblast growth factor 23 (FGF23) is a hormone released primarily by osteocytes that regulates phosphate and vitamin D metabolism. Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown whether FGF23 can directly alter cardiac function. We found that FGF23 significantly increased cardiomyocyte cell size in vitro, the expression of gene markers of cardiac hypertrophy, and total protein content of cardiac muscle. In addition, FGFR1 and FGFR3 mRNA were the most abundantly expressed FGF receptors in cardiomyocytes, and the coreceptor alpha-klotho was expressed at very low levels. We tested an animal model of chronic kidney disease (Col4a3(-/-) mice) that has elevated serum FGF23. We found elevations in common hypertrophy gene markers in Col4a3(-/-) hearts compared with wild type but did not observe changes in wall thickness or cell size by week 10. However, the Col4a3(-/-) hearts did show reduced fractional shortening (-17%) and ejection fraction (-11%). Acute exposure of primary cardiomyocytes to FGF23 resulted in elevated intracellular Ca(2+) ([Ca(2+)](i); F/F(o) + 86%) which was blocked by verapamil pretreatment. FGF23 also increased ventricular muscle strip contractility (67%), which was inhibited by FGF receptor antagonism. We hypothesize that although FGF23 can acutely increase [Ca(2+)](i), chronically this may lead to decreases in contractile function or stimulate cardiac hypertrophy, as observed with other stress hormones. In conclusion, FGF23 is a novel bone/heart endocrine factor and may be an important mediator of cardiac Ca(2+) regulation and contractile function during chronic kidney disease. PMID- 23443927 TI - Correlative analysis of immunoreactivity in confocal laser-scanning microscopy and scanning electron microscopy with focused ion beam milling. AB - Recently, three-dimensional reconstruction of ultrastructure of the brain has been realized with minimal effort by using scanning electron microscopy (SEM) combined with focused ion beam (FIB) milling (FIB-SEM). Application of immunohistochemical staining in electron microscopy (EM) provides a great advantage in that molecules of interest are specifically localized in ultrastructures. Thus, we applied immunocytochemistry for FIB-SEM and correlated this immunoreactivity with that in confocal laser-scanning microcopy (CF-LSM). Dendrites of medium-sized spiny neurons in the rat neostriatum were visualized using a recombinant viral vector, which labeled the infected neurons with membrane-targeted GFP in a Golgi stain-like fashion. Moreover, the thalamostriatal afferent terminals were immunolabeled with Cy5 fluorescence for vesicular glutamate transporter 2 (VGluT2). After detection of the sites of terminals apposed to the dendrites by using CF-LSM, GFP and VGluT2 immunoreactivities were further developed for EM by using immunogold/silver enhancement and immunoperoxidase/diaminobenzidine (DAB) methods, respectively. In contrast-inverted FIB-SEM images, silver precipitations and DAB deposits were observed as fine dark grains and diffuse dense profiles, respectively, indicating that these immunoreactivities were as easily recognizable as those in the transmission electron microscopy (TEM) images. Furthermore, in the sites of interest, some appositions displayed synaptic specializations of an asymmetric type. Thus, the present method was useful in the three-dimensional analysis of immunocytochemically differentiated synaptic connections in the central neural circuit. PMID- 23443926 TI - beta-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1alpha in skeletal muscle. AB - There are reports that the beta-adrenergic agonist clenbuterol induces a large increase in peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) in skeletal muscle. This has led to the hypothesis that the increases in PGC-1alpha and mitochondrial biogenesis induced in muscle by endurance exercise are mediated by catecholamines. In the present study, we evaluated this possibility and found that injecting rats with clenbuterol or norepinephrine induced large increases in PGC-1alpha and mitochondrial proteins in brown adipose tissue but had no effect on PGC-1alpha expression or mitochondrial biogenesis in skeletal muscle. In brown adipocytes, the increase in PGC-1alpha expression induced by beta-adrenergic stimulation is mediated by activation of p38 mitogen-activated protein kinase (p38 MAPK), which phosphorylates and activates the cAMP response element binding protein (CREB) family member activating transcription factor 2 (ATF2), which binds to a cyclic AMP response element (CRE) in the PGC-1alpha promoter and mediates the increase in PGC-1alpha transcription. Phospho-CREB does not have this effect. Our results show that the reason for the lack of effect of beta-adrenergic stimulation on PGC 1alpha expression in muscle is that catecholamines do not activate p38 or increase ATF2 phosphorylation in muscle. PMID- 23443928 TI - Endocrine therapy for postmenopausal women with hormone receptor-positive her2 negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement. AB - Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID- 23443929 TI - Sensory feedback in Parkinson's disease patients with "on"-predominant freezing of gait. PMID- 23443930 TI - Genetic variability of subgroup A and B respiratory syncytial virus strains circulating in southwestern China from 2009 to 2011. AB - Human respiratory syncytial virus (RSV) is recognized as a leading pathogen responsible for severe respiratory infections in the pediatric population, particularly in infants and young children. A previous study by the same study group revealed that the RSV BA strain was prevalent in southwestern China in epidemic seasons from 2008 to 2009. The aim of this study was to investigate the epidemiology of RSV in the following two years, the genetic variability of the G gene, and mutations at the 276th amino acid in the fusion (F) protein of RSV strains. Nine BA substrains were found in 16 subgroup B viruses by phylogenetic analysis. The G gene of genotype BA was predicted to encode proteins with five different lengths. The findings indicate that subgroup A and B RSVs alternately circulate in southwestern China and that genotype BA strains appear to be the long-term circulating ones. These epidemiological data may help in future vaccine design and further investigation of G protein function. PMID- 23443931 TI - Recombination in the evolution of human rhinovirus genomes. AB - Human rhinoviruses (HRV) are highly prevalent human respiratory pathogens that belong to the genus Enterovirus. Although recombination within the coding region is frequent in other picornavirus groups, most evidence of recombination in HRV has been restricted to the 5' untranslated region. We analysed the occurrence of recombination within published complete genome sequences of members of all three HRV species and additionally compared sequences from HRV strains spanning 14 years. HRV-B and HRV-C showed very little evidence of recombination within the coding region. In contrast, HRV-A sequences appeared to have undergone a large number of recombination events, typically involving whole type groups. This suggests that HRV-A may have been subject to extensive recombination during the period of diversification into types. This study demonstrates the rare and sporadic nature of contemporary recombination of HRV strains and contrasts with evidence of extensive recombination within HRV-A and between members of different species during earlier stages in its evolutionary diversification. PMID- 23443932 TI - The complete genomic sequence of a novel mycovirus from Rhizoctonia solani AG-1 IA strain B275. AB - The complete genome of a novel mycovirus, Rhizoctonia solani dsRNA virus 1 (RsRV1) was sequenced and analyzed. It is composed of two dsRNA genome segments, 2379 bp and 1811 bp in length, which were referred to as RsRV1-1 and RsRV1-2, respectively. RsRV1-1 contains a single open reading frame (ORF1), which has a conserved RNA-dependent RNA polymerase (RdRp) domain, whereas RsRV1-2 contains a single ORF2, which might encode a multifunctional protein. The genome organization of RsRV1 is similar to that of members of the family Partitiviridae. However, phylogenetic analysis indicated that RsRV1 formed a distinct clade together with three other unclassified viruses, suggesting that RsRV1 may belong to a new family of dsRNA mycoviruses. This is the first report of the full-length nucleotide sequence of a novel dsRNA mycovirus, RsRV1, infecting R. solani AG-1 IA strain B275, the causal agent of rice sheath blight. PMID- 23443933 TI - Baculovirus replication induces the expression of heat shock proteins in vivo and in vitro. AB - A recent handful of studies have linked baculovirus infection with the induction of heat shock proteins, a highly conserved family of cytoprotective proteins. Here, we demonstrate baculovirus-stimulated upregulation of hsp70 transcription in the natural host, Helicoverpa zea. Larvae lethally infected with Helicoverpa zea single nucleopolyhedrovirus (HzSNPV) accumulated hsp70 transcripts throughout the 72-hour course of infection in the midgut, hemocytes, and fat body. While a maximal 17- or 15-fold induction of hsp70 was noted in the midgut and hemocytes, respectively, by 72 hours postinfection, the level of hsp70 transcription in the fat body of larvae was greater than two orders of magnitude higher than in mock infected larvae. These results were largely mirrored in cultures of infected cells, and a potentiation effect was observed in cells that were both heat shocked and infected. In contrast, Spodoptera frugiperda multiple nucleopolyhedrovirus and ultraviolet-inactivated HzSNPV did not stimulate hsp70 transcription in these non-permissive larvae and in cell culture, respectively. Taken together, this report documents baculovirus-mediated upregulation of hsp70 in the host and demonstrates the requirement for productive infection for hsp70 induction in vitro and in vivo. PMID- 23443934 TI - Phylogenetic analysis of two Chinese orf virus isolates based on sequences of B2L and VIR genes. AB - Orf virus (ORFV) is an enveloped virus with a double-stranded DNA genome, causing a contagious pustular dermatitis, mainly in goats and sheep. In this study, two strains of ORFV were isolated from sheep and goat samples in Xinjiang and Shaanxi, China. The B2L and virus interferon resistance (VIR) genes of these two isolates were sequenced and analyzed after PCR amplification. Phylogenetic analysis showed that the two isolates clustered with other ORFV strains but were separated into different subgroups. The Xinjiang strain shared the highest homology with the Gansu strain, whereas the Shaanxi strain shared higher homology with the Taiwan and Hubei strains. This is the first report of the molecular characterization of ORFV in Northwest China, and it provides new information on the genotyping of the causative agents responsible for contagious ecthyma dermatitis outbreaks in China. PMID- 23443935 TI - The simultaneous occurrence of human norovirus and hepatitis E virus in a Norway rat (Rattus norvegicus). AB - Wild rats can be reservoirs and vectors for several human pathogens. An initial RT-PCR screening of the intestinal contents of Norway rats trapped in the sewer system of Copenhagen, Denmark, for caliciviruses revealed the presence of a human norovirus in one of 11 rodents. Subsequent phylogenetic analysis of the ~4.0-kb 3'-terminus of the norovirus genome resulted in the identification of a recombinant GI.b/GI.6 strain. The simultaneous detection of hepatitis E virus like particles in the feces of this rat by transmission electron microscopy was confirmed by RT-PCR and sequence determination, resulting in the identification of a novel rat hepatitis E virus. PMID- 23443936 TI - [Imaging diagnostics of the male pelvic floor]. AB - The understanding of the female pelvic floor during the last 20 years was very much influenced by the new techniques of sonographic and magnetic resonance imaging (MRI). Functional imaging of the male pelvic floor is, however, still in its infancy. In analogy to ultrasound examinations of the female pelvic floor, perineal ultrasound can be also be applied to men. The mobility of the proximal urethra, scarring of the bladder neck or implanted suburethral meshes can be easily visualized. Studies on healthy men provide information about different muscular structures during micturition. Morphology and function of the external sphincter can be visualized with transrectal or intraurethral ultrasound and also with a perineal approach. Using functional MRI the complex interactions of bladder, urethra, external sphincter and pelvic floor muscles can be evaluated. Functional MRI is so far not generally available but enables a better understanding of the function of the male pelvic floor. Imaging of the male pelvic floor makes a substantial contribution for improving surgical procedures for male incontinence in the future. PMID- 23443937 TI - Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours. AB - PURPOSE: The prognostic value of FDG PET for neuroendocrine tumours (NETs) has been reported. In this study we evaluated the role of FDG PET in predicting response and progression-free survival (PFS) after (177)Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced well differentiated grade 1/2 NETs. METHODS: We retrospectively evaluated 52 patients with progressive advanced NETs overexpressing somatostatin receptors and treated with Lu-PRRT with a cumulative activity up to 27.7 GBq divided into five courses. According to WHO 2010/ENETS classification, patients were stratified into two groups: those with grade 1 tumour (Ki-67 index <=2 %, 19 patients), and those with grade 2 tumour (Ki-67 index >3 % to <20 %, 33 patients). On the basis of the FDG PET scan, 33 patients were classified as PET-positive (PET+) and 19 as PET negative (PET-). RESULTS: FDG PET was positive in 57 % of patients with grade 1 NET and in 66 % of patients with grade 2 NET, and the rates of disease control (DC, i.e. complete response + partial response + stable disease) in grade 1 and grade 2 patients were 95 % and 79 %, respectively (P = 0.232). In PET- and PET+ patients, the DC rates were 100 % and 76 % (P = 0.020) with a PFS of 32 and 20 months, respectively (P = 0.033). Of the PET+ patients with grade 1 NET, 91 % showed disease control, whereas about one in three PET+ patients with grade 2 NET (32 %) progressed after Lu-PRRT (DC rate 68 %). CONCLUSION: These results suggest that FDG PET evaluation is useful for predicting response to Lu-PRRT in patients with grade 1/2 advanced NETs. Notably, none of PET- patients had progressed at the first follow-up examination after Lu-PRRT. Grade 2 NET and PET+ (arbitrary SUV cutoff >2.5) were frequently associated with more aggressive disease. PET+ patients with grade 2 NET, 32 % of whom did not respond to Lu-PRRT monotherapy, might benefit from more intensive therapy protocols, such as the combination of chemotherapy and PRRT. PMID- 23443939 TI - Zebrafish churchill regulates developmental gene expression and cell migration. AB - BACKGROUND: Regulation of developmental signaling pathways is essential for embryogenesis. The small putative zinc finger protein, Churchill (ChCh) has been implicated in modulation of both TGF-beta and FGF signaling. RESULTS: We used zinc finger nuclease (ZFN) mediated gene targeting to disrupt the zebrafish chch locus and generate the first chch mutations. Three induced lesions produce frameshift mutations that truncate the protein in the third of five beta-strands that comprise the protein. Surprisingly, zygotic and maternal zygotic chch mutants are viable. Mutants have elevated expression of mesodermal markers, but progress normally through early development. chch mutants are sensitive to exogenous Nodal. However, neither misregulation of FGF targets nor sensitivity to exogenous FGF was detected. Finally, chch mutant cells were found to undergo inappropriate migration in cell transplant assays. CONCLUSIONS: Together, these results suggest that chch is not essential for survival, but functions to modulate early mesendodermal gene expression and limit cell migration. PMID- 23443938 TI - Roles for BLyS family members in meeting the distinct homeostatic demands of innate and adaptive B cells. AB - B-1 and B-2 B cell populations have different progenitors, receptor diversity, anatomic location, and functions - suggesting vastly differing requisites for homeostatic regulation. There is evidence that the B lymphocyte stimulator (BLyS) family of cytokines and receptors, key factors in the homeostatic regulation of B 2 B cell subsets, is also a major player in the B-1 compartment. Here we review the development and differentiation of these two primary B cell lineages and their immune functions. We discuss evidence that BLyS or a proliferation-inducing ligand (APRIL) availability in different anatomic sites, coupled with signature BLyS receptor expression patterns on different B cell subsets, may be important for homeostatic regulation of B-1 as well as B-2 populations. Finally, we extend our working model of B cell homeostasis to integrate B-1s. PMID- 23443941 TI - Histopathological features of ductal adenocarcinoma of the prostate in 1,051 radical prostatectomy specimens. AB - Ductal adenocarcinoma (DAC) of the prostate is thought to have worse prognosis than prostatic acinar carcinoma (PAC). We aimed to evaluate the prognostic significance of histopathological patterns of DAC. A series of 1,051 radical prostatectomy specimens from Karolinska University Hospital 1998-2005 was reviewed. A ductal component was classified as classical DAC (DACC) if it had columnar, pseudostratified epithelium, elongated nuclei, and papillary, glandular, or cribriform architecture; borderline DAC (DACB) if it lacked elongated nuclei or classical architecture; and prostatic adenocarcinoma with ductal features (PCDF) if stratified high-grade nuclei were found. DACC, DACB, and PCDF were seen in 2.6, 4.0, and 1.6 % of the cases. DAC was usually mixed with PAC and constituted 10-100 % (mean 40 %) of the main tumor. Location was periurethral, peripheral, or both in 69.8, 3.5, and 26.7 %. Necrosis was seen in 31.3 %, stromal invasion of DAC in 52.3 %, and intraductal spread in 91.9 %. In DACC/DACB and PAC, extraprostatic extension was seen in 66.7 and 42.4 % (p < 0.001) and seminal vesicle invasion in 13.0 and 5.0 % (p = 0.0045). DACC, DACB, and PCDF had a hazard ratio for biochemical recurrence of 1.5 (0.7-2.8), 1.4 (0.8 2.6) and 1.2 (0.5-2.7). When PCDF was excluded from DAC, hazard ratio was 1.4 (95 % CI 0.9-2.3, p = 0.12). Location, % DAC, necrosis, stromal invasion, or Gleason score were not predictive of recurrence. This suggests that DACC and DACB are more aggressive than average PAC, while cancers with acinar architecture and pseudostratified high-grade nuclei should not be included in DAC. PMID- 23443940 TI - Primary pulmonary malignant meningioma with lymph node and liver metastasis in a centenary woman, an autopsy case. AB - Primary meningiomas arising outside the central nervous system are very rare. They have been reported in the head and neck region, in the thorax, the retroperitoneum, and the pelvis. Usually, they behave as slow-growing tumors with a good prognosis. Herein, we report an autopsy case of a 108-year-old woman, known for a right-sided slowly growing lung nodule for 39 years. Death was attributed to cachexia. At post-mortem, a 15-cm mass was present in the right inferior lobe of the lung, associated with an ipsilateral hilar lymphadenopathy, and another 10-cm mass in the liver. Histology revealed a WHO grade III meningioma. No tumor was observed in the cranial cavity. This case illustrates a rare location of meningioma and highlights its biological behavior, with a very slow progression from a most probably benign tumor to a malignant lesion with metastasis over four decades. PMID- 23443942 TI - River water quality assessment using environmentric techniques: case study of Jakara River Basin. AB - Jakara River Basin has been extensively studied to assess the overall water quality and to identify the major variables responsible for water quality variations in the basin. A total of 27 sampling points were selected in the riverine network of the Upper Jakara River Basin. Water samples were collected in triplicate and analyzed for physicochemical variables. Pearson product-moment correlation analysis was conducted to evaluate the relationship of water quality parameters and revealed a significant relationship between salinity, conductivity with dissolved solids (DS) and 5-day biochemical oxygen demand (BOD5), chemical oxygen demand (COD), and nitrogen in form of ammonia (NH4). Partial correlation analysis (r p) results showed that there is a strong relationship between salinity and turbidity (r p=0.930, p=0.001) and BOD5 and COD (r p=0.839, p=0.001) controlling for the linear effects of conductivity and NH4, respectively. Principal component analysis and or factor analysis was used to investigate the origin of each water quality parameter in the Jakara Basin and identified three major factors explaining 68.11 % of the total variance in water quality. The major variations are related to anthropogenic activities (irrigation agricultural, construction activities, clearing of land, and domestic waste disposal) and natural processes (erosion of river bank and runoff). Discriminant analysis (DA) was applied on the dataset to maximize the similarities between group relative to within-group variance of the parameters. DA provided better results with great discriminatory ability using eight variables (DO, BOD5, COD, SS, NH4, conductivity, salinity, and DS) as the most statistically significantly responsible for surface water quality variation in the area. The present study, however, makes several noteworthy contributions to the existing knowledge on the spatial variations of surface water quality and is believed to serve as a baseline data for further studies. Future research should therefore concentrate on the investigation of temporal variations of water quality in the basin. PMID- 23443943 TI - Efficacy of indigenous soil microbes in arsenic mitigation from contaminated alluvial soil of India. AB - Selected arsenic-volatilizing indigenous soil bacteria were isolated and their ability to form volatile arsenicals from toxic inorganic arsenic was assessed. Approximately 37 % of AsIII (under aerobic conditions) and 30 % AsV (under anaerobic conditions) were volatilized by new bacterial isolates in 3 days. In contrast to genetically modified organism, indigenous soil bacteria was capable of removing 16 % of arsenic from contaminated soil during 60 days incubation period while applied with a low-cost organic nutrient supplement (farm yard manure). PMID- 23443944 TI - Acetylcholinesterase in honey bees (Apis mellifera) exposed to neonicotinoids, atrazine and glyphosate: laboratory and field experiments. AB - In Quebec, as observed globally, abnormally high honey bee mortality rates have been reported recently. Several potential contributing factors have been identified, and exposure to pesticides is of increasing concern. In maize fields, foraging bees are exposed to residual concentrations of insecticides such as neonicotinoids used for seed coating. Highly toxic to bees, neonicotinoids are also reported to increase AChE activity in other invertebrates exposed to sub lethal doses. The purpose of this study was therefore to test if the honey bee's AChE activity could be altered by neonicotinoid compounds and to explore possible effects of other common products used in maize fields: atrazine and glyphosate. One week prior to pollen shedding, beehives were placed near three different field types: certified organically grown maize, conventionally grown maize or non cultivated. At the same time, caged bees were exposed to increasing sub-lethal doses of neonicotinoid insecticides (imidacloprid and clothianidin) and herbicides (atrazine and glyphosate) under controlled conditions. While increased AChE activity was found in all fields after 2 weeks of exposure, bees close to conventional maize crops showed values higher than those in both organic maize fields and non-cultivated areas. In caged bees, AChE activity increased in response to neonicotinoids, and a slight decrease was observed by glyphosate. These results are discussed with regard to AChE activity as a potential biomarker of exposure for neonicotinoids. PMID- 23443945 TI - Sources of submicron aerosol during fog-dominated wintertime at Kanpur. AB - The main objective of this atmospheric study was to determine the major sources of PM1 (particles having aerodynamic diameter <1.0 MUm) within and near the city of Kanpur, in the Indo-Gangetic Plain. Day and night, 10 h long each, filter based aerosol samples were collected for 4 months (November 2009 to February 2010) throughout the winter season. These samples were subjected to gravimetric and quantitative chemical analyses for determining water-soluble ions (NH4 (+), F(-), Cl(-), NO3 (-), and SO4 (2-)) using an ion chromatograph and trace elements using an inductively coupled plasma-optical emission spectrometer. The mean PM1 mass concentrations were recorded as 114 +/- 71 MUg/m(3) (day) and 143 +/- 86 MUg/m(3) (night), respectively. A significantly higher diurnal contribution of ions (NH4 (+), F(-), Cl(-), NO3 (-), and SO4 (2-)) in PM1 mass was observed during the fog-affected days and nights throughout the winter season, for which the average values were recorded as 38.09 +/- 13.39 % (day) and 34.98 +/- 12.59 % (night), respectively, of the total PM1 mass. This chemical dataset was then used in a source-receptor model, UNMIX, and the model results are described in detail. UNMIX provided a maximum number of five source factors, including crustal material, composite vehicle, secondary aerosol, coal combustion, and iron/steel production and metallurgical industries, as the dominant air pollution sources for this study. PMID- 23443947 TI - Technical effects of adding 1 % lidocaine to technetium sulfur colloid for sentinel lymphatic mapping in early breast cancer: analysis of data from a double blind randomized controlled trial. AB - BACKGROUND: A practice standard in sentinel lymph node (SLN) mapping in breast cancer is intradermal injection of technetium-99m sulfur colloid (Tc-99m), resulting in significant patient discomfort and pain. A previous randomized controlled trial showed that adding lidocaine to Tc-99m significantly reduced radioisotope injection-related pain. We tested whether 1 % lidocaine admixed with Tc-99m affects feasibility of SLN mapping. METHODS: Between January 2006 and April 2009, 140 patients with early breast cancer were randomly assigned (1:1:1:1) to receive standard topical 4 % lidocaine cream and intradermal Tc-99m (control) or to one of three other study groups: topical placebo cream and injection of Tc-99m containing sodium bicarbonate (NaHCO3), 1 % lidocaine, or both. All SLN data were collected prospectively. RESULTS: Study groups were comparable for clinicopathological parameters. As previously reported, the addition of 1 % lidocaine to the radioisotope solution significantly improved patient comfort. Overall SLN identification rate in the trial was 93 %. Technical aspects of SLN biopsy were similar for all groups, including time from injection to operation, first SLN (SLN 1) gamma probe counts, ex vivo counts for SLN 1 and SLN 2, and axillary bed counts. SLN identification rates were comparable statistically: control (96 %), lidocaine (90 %), sodium bicarbonate (97 %), and sodium bicarbonate-lidocaine (90 %). The control group had a significantly higher SLN 2/SLN 1 ex vivo count ratio, and the number of SLNs detected was significantly reduced in the lidocaine versus no-lidocaine groups (p < 0.05). CONCLUSIONS: Addition of 1 % lidocaine to standard radioisotope solution for SLN mapping in breast cancer is associated with fewer SLNs detected, but it does not appear to compromise SLN identification. PMID- 23443946 TI - Androgen receptor protein levels are significantly reduced in serous ovarian carcinomas compared with benign or borderline disease but are not altered by cancer stage or metastatic progression. AB - The androgen receptor (AR) is expressed in a majority of ovarian carcinomas, but its role in disease development remains unclear. In this study, AR and a novel AR molecular chaperone called small glutamine-rich tetratricopeptide repeat containing protein alpha (SGTA) were investigated to assess their potential role in ovarian carcinogenesis. First, an AR and SGTA-positive ovarian cancer cell line was identified to examine whether SGTA influenced AR subcellular localization. Next, relative protein levels of AR and SGTA were measured in two sets of clinical samples: (1) 46 serous ovarian carcinomas (stages I-IV), 9 serous borderline tumors, and 11 benign ovarian tumors; and (2) 24 patient matched stage III primary and metastatic serous ovarian tumors. Ablation of SGTA protein in OVCAR3 cells significantly increased AR nuclear localization under basal (p <= 0.001) and androgen-stimulated (p <= 0.001) conditions. In the first clinical set, AR levels were significantly lower in early- (I/II) and late-stage (III/IV) cancers compared with benign (p <= 0.001) but not borderline ovarian tumors. SGTA alone did not discriminate between groups but the AR/SGTA ratio was significantly lower in carcinomas and borderline tumors compared with benign tumors (p <= 0.001 and 0.015, respectively). In the second clinical set, matched primary and metastatic serous ovarian cancers did not significantly differ for any parameter measured. Collectively, our results suggest that SGTA can influence AR signaling in ovarian cancer cells and that AR signaling capacity may be reduced with the development but not metastatic progression of serous ovarian cancer. PMID- 23443948 TI - Emergency department admissions to a prison hospital: a retrospective cohort study from Switzerland. AB - INTRODUCTION: There are more than 10 million prison inmates throughout the world and this number is increasing continuously. Prisoners are a particularly vulnerable minority group that has special healthcare needs and demands on healthcare services and providers. The aim of this study was to give an overview of prisoners' healthcare problems leading to emergency department admission, in order to make recommendations to help to optimise treatment of this target group. METHODS: Our retrospective data analysis comprised adult (age >=16 years) prisoners admitted to our emergency department, in transit to admission to our hospital-associated medical prison ward, between 2nd February 2000 and 30th April 2012. RESULTS: A total of 1703 patients were analysed. Of these, 78.2% (n = 1333) were male and 21.8% (n = 370) female. The mean age was 36.6 years (standard deviation 14.6, range 16-92 years). The most frequent reasons for presentation were psychiatric problems (43.4%; n = 739), followed by the need for medical treatment (31.6%; n = 539) and for surgical treatment (25.0%; n = 425). Patients with medical problems were significantly older than patients with psychiatric and surgical presentations (for both p <0.001). Patients with psychiatric problems were significantly younger than those with medical or surgical problems (p <0.001). A total of 130 (7.6%) of our patients were rehospitalised within the study period. CONCLUSION: Prisoners are a vulnerable minority group within our society with limited access to medical care. Transfer of information between the emergency department and prison staff should be promoted. Further research should be carried out on prisoners' healthcare problems. PMID- 23443949 TI - Fast screening of Bifidobacterium longum sublethal stress conditions in a novel two-stage continuous culture strategy. AB - A central issue in the application of probiotics as food additives is their fastidious production and their sensitivity to many environmental stresses. The importance of inducible cell-protective mechanisms triggered by application of sublethal stresses for survival under stress conditions has been demonstrated. Continuous cultures could be a suitable and more efficient method to test stress factors on one culture instead of several repeated batch cultures. In this study, the application of a two-stage continuous culture of Bifidobacterium longum NCC2705 was investigated. The first reactor was operated under fixed conditions at 37 degrees C and pH 6.0 and used to produce cells with controlled physiology, mimicking cells in the late exponential growth phase. Stress pretreatment combinations of pH (6.0, 5.0 and 4.0), temperature (37, 45 and 47 degrees C) and NaCl (0, 5 and 10%) were tested in the second reactor. Of all tested combinations, only those of pH 4.0 significantly decreased cell viability in the second reactor compared to control conditions (37 degrees C, pH 6.0, 0% NaCl) and, therefore, could not be considered as sublethal stresses. Pretreatments with 5 or 10% NaCl had a negative effect on cell viability after gastric lethal stress. A significant improvement in cell resistance to heat lethal stress (56 degrees C, 5 min) was observed for cells pretreated at 47 degrees C. In contrast, heat pretreatment negatively affected cell viability after freeze drying and osmotic lethal stresses. The two-stage continuous culture allowed for efficient screening of several stress pretreatments during the same experiment with up to four different conditions tested per day. Optimal sublethal stress conditions can also be applied for producing cells with traditional batch cultures. PMID- 23443950 TI - In vitro evaluation of Bifidobacterium strains of human origin for potential use in probiotic functional foods. AB - The present study investigated some in vitro properties for probiotic use of four strains of bifidobacteria isolated from faeces of healthy children (Bifidobacterium longum 51A, Bifidobacterium breve 1101A, Bifidobacterium pseudolongum 1191A and Bifidobacterium bifidum 1622A). In vitro tests were carried out to compare growth rate, aerotolerance, antagonistic activity against pathogens, antimicrobial susceptibility profile and cell wall hydrophobicity. Mean doubling time of B. longum 51A was shorter compared to the other strains. All strains were aerotolerant up to 72 h of exposure to oxygen. In vitro antagonism showed that B. longum 51A and B. pseudolongum 1191A were able to produce inhibitory diffusible compounds against all pathogenic bacteria tested, but not against Candida albicans. B. longum 51A was sensitive to all the antimicrobials tested, except neomycin. The hydrophobic property of the cell wall was highest for B. bifidum 1622A. Based on these parameters, B. longum 51A showed the best potential for probiotic use among the tested strains, presenting the greatest sensitivity to antimicrobials, the best growth rate and the highest capacity to produce antagonistic substances against various pathogenic microorganisms. PMID- 23443951 TI - Immune signalling responses in intestinal epithelial cells exposed to pathogenic Escherichia coli and lactic acid-producing probiotics. AB - Enterohaemorrhagic Escherichia coli O157:H7 and adherent-invasive Escherichia coli are two groups of enteric bacterial pathogens associated with haemorrhagic colitis and Crohn's Disease, respectively. Bacterial contact with host epithelial cells stimulates an immediate innate immune response designed to combat infection. In this study, immune responses of human epithelial cells to pathogens, either alone or in combination with probiotic bacteria were studied. Industrially prepared Lactobacillus helveticus strain R0052 was first examined by microarray analysis and then compared to broth-grown strains of R0052 and Lactobacillus rhamnosus strain GG using quantitative realt-time polymerase chain reaction. Results showed host immune activation responses increased following pathogen exposure, which were differentially ameliorated using probiotics depending on both the preparation of probiotics employed and conditions of exposure. These findings provide additional support for the concept that specific probiotic strains serve as a promising option for use in preventing the risk of enteric bacterial infections. PMID- 23443952 TI - Efficacy of Bacillus clausii strain UBBC-07 in the treatment of patients suffering from acute diarrhoea. AB - This study was conducted to evaluate the anti-diarrhoeal activity of Bacillus clausii strain UBBC 07 in patients suffering from acute diarrhoea. A total of 27 patients (average age of 35.44+/-8.08 years) with acute diarrhoea were included in a prospective, Phase II clinical study after informed consent and ethical committee approval. The criteria included for all subjects were >=3 loose stool motions within 24 hours and for more than 7 days. All patients were assigned to receive one capsule of B. clausii strain UBBC-07 (containing 2*109 cfu) two times a day for a period of 10 days. Efficacy assessment of duration of diarrhoea, frequency of defecation, abdominal pain and stool consistency were tested on days 1, 3, 6 and 10. Safety was evaluated by assessing the incidence and type of adverse effects such as increase in blood pressure and pulse rate, physical examination and clinical laboratory tests, i.e. complete blood count, serum glutamic pyruvic transaminase, serum creatinine, and stool examination and microscopy, on day 1 and day 10. The results of this study clearly showed that the mean duration of diarrhoea decreased from 34.81+/-4.69 to 9.26+/-3.05 (P<0.0001) min per day, the frequency of defecation also decreased from 6.96+/ 1.05 to 1.78+/-0.50 (P<0.0001) times per day, abdominal pain decreased from 3.22+/-0.93 (severe) to 0.74+/-0.71 (absent) (P<0.0001), and stool consistency improved from 3.93+/-0.38 (watery) to 1.22+/-0.42 (soft) (P<0.0001). No significant change in safety parameters were observed during treatment. This study shows that the B. clausii strain UBBC-07 can potentially be effective in alleviating the symptoms of diarrhoea without causing any adverse effects. PMID- 23443953 TI - Identification of candidate biomarkers using the ExperionTM automated electrophoresis system in serum samples from ovarian cancer patients. AB - Ovarian cancer is the most common cause of disease-related death in women globally. Detection of ovarian cancer using new biomarkers is necessary for early diagnosis. To date, there have been no obvious biomarkers for ovarian cancer detection in the incipient stage. In this study, we discovered potential diagnostic serological biomarkers for ovarian cancer using the ExperionTM automated electrophoresis system. Sera from 14 healthy women and 84 ovarian cancer patients at stages I- IV were applied to the Experion to compare the protein expression levels. To examine the protein expression pattern of Experion data, proteins in the samples were resolved using 10 and 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and visualized by silver staining. The candidate biomarkers elevated in ovarian cancer were purified and determined using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. alpha-2-macroglobulin (173.7 kDa), ceruloplasmin (147 kDa), inter alpha-trypsin inhibitor family heavy chain-related protein (126 kDa), C-1 inhibitor (115.2 kDa) and hemoglobin alpha/beta (14.4 kDa were overexpressed in the ovarian cancer sera. This study documents a novel way to measure ovarian cancer or cancer-related proteins for biomarkers using the Experion assay system, which should be easily adaptable for high-throughput diagnosis to establish databases of ovarian cancer for clinical applications. PMID- 23443954 TI - Cardiac sympathetic denervation is not related to nigrostriatal degeneration in Parkinson's disease. AB - AIM: The aim of our study was to investigate the relationship between myocardial sympathetic degeneration and nigrostriatal impairment in patients affected by Parkinson's disease (PD) by means of (123)I-metaiodobenzylguanidine ((123)I MIBG) scintigraphy and N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4 [(123)I]iodophenyl)nortropane ((123)I FP-CIT) scintigraphy. PATIENTS AND METHODS: The study involved 37 patients with clinical diagnosis of PD (22 males and 15 females, mean age 62 years (+/-10), evaluated with (123)I FP-CIT single photon emission computed tomography (SPECT) followed by (123)I MIBG scintigraphy within 20 (+/-3) days. Early and delayed anterior chest images were acquired and the heart/mediastinum ratio (H/M ratio) was calculated. Furthermore, the population has been divided on the basis of the main clinical pattern to investigate the possible role of a tremor-dominant or an akinetic-dominant phenotype in this comparison. RESULTS: In PD population, there were no statistical relationships between early and delayed (123)I MIBG cardiac and (123)I FP-CIT striatal uptake in contralateral caudate (P > 0.05) and in contralateral putamen (P > 0.05) to the side mainly affected; no statistically significant relationships have been found at any level when considering ipsilateral striatum. We did not find statistically significant relationships when considering the single PD phenotypes. CONCLUSIONS: The results of our study suggest that cardiac sympathetic system and nigrostriatal system are differently affected in PD. In particular, the sympathetic neurodegeneration rate is not related to nigrostriatal degeneration rate and vice versa in our series as detectable scintigraphically. PMID- 23443955 TI - Changes in conjunctival cytology and tear function tests with radioiodine treatment for hyperthyroidism. AB - OBJECTIVES: Radioiodine (RAI) is used in the treatment of hyperthyroidism and differentiated thyroid cancer. Radioiodine therapy is associated with dry eyes and some side effects are seen especially due to beta rays. In this study, the functional and cytological status of lacrimal glands after RAI therapy was evaluated. METHODS: Twenty-five patients with a mean age of 55.16 years with planned low-dose RAI therapy were evaluated. Just before and 6 months after the treatment, the lacrimal glands were evaluated with tear break-up time (BUT), Schirmer's test, impression cytology and "Ocular Surface Disease Index (OSDI)" questionnaire. RESULTS: The mean value of Schirmer's test was 16.20 +/- 3.61 pre treatment and 11.28 +/- 4.39 post-treatment for the right eye, and 15.76 +/- 3.27 and 10.60 +/- 4.42 for the left eye, respectively. The mean value of Schirmer's test decreased significantly post-treatment in both eyes (p = 0.0001). The BUT score also decreased significantly post-treatment (p = 0.001). The mean value of OSDI score was 27.5 +/- 8.02 pre-treatment and 46.36 +/- 10.27 post-treatment. The mean value of OSDI score increased post-treatment (p = 0.0001). The impression scores also increased post-treatment in both eyes (p = 0.0001). CONCLUSION: Even low-dose (<=30 mci) RAI treatment affects lacrimal gland functions. Low-dose RAI causes a decrease in the value of Schirmer's test and the BUT test, and an increase in the value of OSDI score and impression scores. PMID- 23443956 TI - Assessment of atherosclerosis in oncologic patients using 18F-fluoride PET/CT. AB - OBJECTIVES: The purpose of this study was to evaluate the prevalence, distribution, and relationship of (18)F-fluoride uptake and arterial calcification in oncologic patients using (18)F-fluoride PET/CT. METHODS: Image data obtained from 29 oncologic patients undergoing whole-body (18)F-fluoride PET/CT were evaluated retrospectively. Arterial wall (18)F-fluoride uptake and calcification were analyzed both quantitatively and semiquantitatively in 8 patients with arterial (18)F-fluoride uptake. RESULTS: Arterial (18)F-fluoride uptake was observed at 35 lesions in 8 (28 %) of the 29 patients, and calcification was observed at 345 lesions in the same patients. Five of the 8 patients had prostate cancer, and the remaining patients had hepatocellular carcinoma or malignant melanoma. In these 8 patients, the prevalence of both (18)F-fluoride uptake and calcification was highest in the abdominal aorta, followed by the descending thoracic aorta and the aortic arch. Colocalization of radiotracer accumulation and calcification could be observed in the 32 lesions (91 %) with arterial (18)F-fluoride uptake, and only the 3 lesions (9 %) with arterial (18)F-fluoride uptake were not colocalized with arterial calcification. The presence of both arterial radiotracer uptake and calcification was significantly associated with advancing age (P < 0.01). CONCLUSION: Our results suggest that (18)F-fluoride PET/CT might be a useful modality for detecting active mineral deposition sites of atherosclerosis in oncologic patients. PMID- 23443957 TI - Microfluidic oxygen imaging using integrated optical sensor layers and a color camera. AB - In this work we present a high resolution oxygen imaging approach, which can be used to study 2D oxygen distribution inside microfluidic environments. The presented setup comprises a fabrication process of microfluidic chips with integrated luminescent sensing films combined with referenced oxygen imaging applying a color CCD-camera. Enhancement of the sensor performance was achieved by applying the principle of light harvesting. This principle enabled ratiometric imaging employing the red and the green channel of a color CCD-camera. The oxygen sensitive emission of platinum(ii)-5,10,15,20-tetrakis-(2,3,4,5,6 pentafluorphenyl)-porphyrin (PtTFPP) was detected by the red channel, while the emission of a reference dye was detected by the green channel. This measurement setup allowed for accurate real-time 2D oxygen imaging with superior quality compared to intensity imaging. The sensor films were subsequently used to measure the respiratory activity of human cell cultures (HeLa carcinoma cells and normal human dermal fibroblasts) in a microfluidic system. The sensor setup is well suited for different applications from spatially and temporally resolving oxygen concentration inside microfluidic channels to parallelization of oxygen measurements and paves the way to novel cell based assays, e.g. in tissue engineering, tumor biology and hypoxia reperfusion phenomena. PMID- 23443959 TI - Developing a smartphone 'app' for public health research: the example of measuring observed smoking in vehicles. AB - BACKGROUND: We have developed manual methods to gather data on the point prevalence of observed smoking in road vehicles. To enable the widespread international collection of such data, we aimed to develop a smartphone application (app) for this work. METHODS: We developed specifications for an app that described the: (1) variables that could be collected; (2) transfer of data to an online repository; (3) user interface (including visual schematics) and (4) processes to ensure the data authenticity from distant observers. The app functionality was trialled in roadside situations and the app was made publicly available. RESULTS: The smartphone app and its accompanying website were developed, tested and released over a period of 6 months. Users (n=18) who have registered themselves (and who met authentication criteria), have reported no significant problems with this application to date (observing 20 535 vehicles as of 5 July 2012). The framework, methodology and source code for this project are now freely available online and can be easily adapted for other research purposes. The prevalence of smoking in vehicles was observed in: Poland 2.7% (95% CI 2.3% to 3.1%); Australia 1.0% (95% CI 0.7% to 1.3%); New Zealand 2.9% (95% CI 2.6% to 3.2%)-similar to results using preapp methods in 2011 (3.2%, 95% CI 3.1% to 3.3%). CONCLUSIONS: This project indicates that it can be practical and feasible for health researchers to work together with information science researchers and software developers to create smartphone apps for field research in public health. Such apps may be used to collect observational data more widely, effectively and easily than through traditional (non-electronic) methods. PMID- 23443958 TI - Biology of human pentraxin 3 (PTX3) in acute and chronic kidney disease. AB - The pentraxin superfamily consists of highly conserved multimeric pattern recognition proteins, which are components of the humoral arm of innate immunity. Besides the classical pentraxins (C-reactive protein and serum amyloid P component), pentraxin 3 (PTX3) is a prototypic long pentraxin. In response to primary inflammatory signals, this multifunctional acute phase protein is produced by a variety of cell types. Recently, several clinical studies have demonstrated that PTX3 is significantly associated with kidney dysfunction and disease activity or severity in various inflammatory, cardiovascular and autoimmune diseases. In this paper, we will review the general characteristics of PTX3 focusing in particular on its fundamental biological functions in the course of acute and chronic kidney diseases. PMID- 23443960 TI - Differences on the effect of heat waves on mortality by sociodemographic and urban landscape characteristics. AB - BACKGROUND: Mortality increases during heat waves have been reported worldwide. The magnitude of these increases can vary within regions according to sociodemographic and urban landscape characteristics. The objectives of this study were to explore this variation and its determinants, and to identify the most heat-vulnerable areas by mapping heat vulnerability. METHODS: We conducted a time-stratified case-crossover analysis using daily mortality in the Barcelona metropolitan area during the warm seasons of 1999-2006. Temperature data on the date of death were assigned to each individual, which were assigned to their census tract of residence. Eight census tract-level variables on socioeconomic or built environment characteristics were obtained from the census. Residence surrounding greenness was obtained from satellite data. The relative risk (RR) of mortality after three consecutive hot days (defined as those exceeding the 95th percentile of maximum temperature) was calculated via conditional logistic regression. Effect modification was examined by including interaction terms. RESULTS: Analyses were based on 52 806 deaths. The effect of three consecutive hot days was a 30% increase in all-cause mortality (RR=1.30, 95% CI 1.24 to 1.38). Heterogeneity of this effect was observed across census tracts. The effect of heat on mortality was higher in the census tracts with a large percentage of old buildings (RR=1.21, 95% CI 1.00 to 1.46), manual workers (RR=1.25, 95% CI 0.96 to 1.64) and residents perceiving little surrounding greenness (RR=1.29, 95% CI 1.01 to 1.65). After three consecutive hot days, mortality doubled in the most heat-vulnerable census tracts. CONCLUSIONS: Sociodemographic and urban landscape characteristics are associated to mortality risk during heat waves and are useful to build heat vulnerability maps. PMID- 23443961 TI - Steric, hydrogen-bonding and structural heterogeneity effects on the nucleophilic substitution of N-(p-fluorophenyldiphenylmethyl)-4-picolinium chloride in ionic liquids. AB - The nucleophilic substitution of N-(p-fluorophenyldiphenylmethyl)-4-picolinium chloride was investigated using water and a range of alcoholic nucleophiles in ionic liquid solvents. The reactivity patterns across the nucleophiles examined could be attributed to steric factors, which mediated the relative nucleophilicities. Reducing the hydrogen-bond acidity of the ionic liquid cation was found to generally increase the rate of reaction, however, the magnitude of this rate effect could be influenced by the steric bulk of the nucleophile and the structural heterogeneity of the ionic liquid. Preferential solvation phenomena in binary mixtures of ionic liquids were examined and suggest that the mechanism behind the hydrogen-bond solvation phenomenon arises from direct cation mediated, rather than indirect anion-mediated, effects. PMID- 23443962 TI - Lung cancer: how to face the revolution? PMID- 23443963 TI - A novel melittin-MhIL-2 fusion protein inhibits the growth of human ovarian cancer SKOV3 cells in vitro and in vivo tumor growth. AB - In the current study, we produced a novel fusion protein (melittin-mutant human interleukin 2, melittin-MhIL-2) comprising a mutant human interleukin 2 (Arg88/Ala125) genetically linked to melittin. The plasmid pET15b-melittin-MhIL-2 (Arg88/Ala125) was transformed into E. coli for protein expression. The expressed melittin-MhIL-2 protein was purified using a series of purification steps. The interleukin 2 (IL-2) activity of melittin-MhIL-2 fusion protein was compared with recombinant human interleukin 2 (rhIL-2) for its ability to induce CTLL-2 proliferation. Moreover, the fusion protein directly inhibits the growth of human ovarian cancer SKOV3 cells in vitro. In an in vivo initial experiment, the fusion protein inhibited tumor growth in ovarian cancer mice. In conclusion, we generated a novel melittin-MhIL-2 fusion protein that retained functional activity of IL-2 and melittin and inhibited tumor growth in vivo. PMID- 23443964 TI - Crosslinking EEG time-frequency decomposition and fMRI in error monitoring. AB - Recent studies implicate a common response monitoring system, being active during erroneous and correct responses. Converging evidence from time-frequency decompositions of the response-related ERP revealed that evoked theta activity at fronto-central electrode positions differentiates correct from erroneous responses in simple tasks, but also in more complex tasks. However, up to now it is unclear how different electrophysiological parameters of error processing, especially at the level of neural oscillations are related, or predictive for BOLD signal changes reflecting error processing at a functional-neuroanatomical level. The present study aims to provide crosslinks between time domain information, time-frequency information, MRI BOLD signal and behavioral parameters in a task examining error monitoring due to mistakes in a mental rotation task. The results show that BOLD signal changes reflecting error processing on a functional-neuroanatomical level are best predicted by evoked oscillations in the theta frequency band. Although the fMRI results in this study account for an involvement of the anterior cingulate cortex, middle frontal gyrus, and the Insula in error processing, the correlation of evoked oscillations and BOLD signal was restricted to a coupling of evoked theta and anterior cingulate cortex BOLD activity. The current results indicate that although there is a distributed functional-neuroanatomical network mediating error processing, only distinct parts of this network seem to modulate electrophysiological properties of error monitoring. PMID- 23443966 TI - Voltage-gated membrane currents in neurons involved in odor information processing in snail procerebrum. AB - The procerebrum (PC) of the snail brain is a critical region for odor discrimination and odor learning. The morphological organization and physiological function of the PC has been intensively investigated in several gastropod species; however, the presence and distribution of ion channels in bursting and non-bursting cells has not yet been described. Therefore, the aim of our study was to identify the different ion channels present in PC neurons. Based on whole cell patch-clamp and immunohistochemical experiments, we show that Na(+) , Ca(2+)-, and K(+)-dependent voltage-gated channels are differentially localized and expressed in the cells of the PC. Different Na-channel subtypes are present in large (10-15 MUm) and small (5-8 MUm) diameter neurons, which are thought to correspond to the bursting and non-bursting cells, respectively. Here, we show that the bursting neurons possess fast sodium current (I NaT) and NaV1.9-like channels and the non-bursting neurons possess slow sodium current (I NaT) and NaV1.8-like channels in addition to the L-type Ca(-), KV4.3 (A-type K-channel) and KV2.1 channels. We suggest that the bursting and/or non-bursting character of the PC neurons is at least partly determined by the battery of ion-channels present and their cellular and subcellular compartmentalization. PMID- 23443967 TI - Protein beta-interfaces as a generic source of native peptide tectons. AB - Motifs of 7-8 amino acids were designed from the beta-continuous interfaces of non-related homo-oligomeric proteins. These peptides intrinsically self-assembled into nanoarchitectures in water, while retaining some properties of their parent interfaces, especially reversibility of assembly. These results reveal a novel source of native peptide tectons. PMID- 23443965 TI - Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase. AB - We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2' deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake. PMID- 23443968 TI - Co-occurrence of autism, childhood psychosis, and intellectual disability associated with a de novo 3q29 microdeletion. AB - Some copy number variants (CNVs) are strongly implicated in both schizophrenia and autism spectrum disorders (ASDs). Childhood-onset schizophrenia (COS) occurs rarely with 0.1-1% of all schizophrenia diagnoses manifesting before age 10. 3q29 deletions are associated with both autism and schizophrenia, and are rare-the frequency of the deletion estimated to be 1 in 1,750 in developmental disorders. Only one patient with a 3q29 deletion was identified out of the first 1,174 families with ASDs included in the Simons Simplex Collection (SSC). We report on detailed clinical findings for this patient with a de novo 3q29 deletion who, as a young child, developed a very rare overlap of symptoms of both autism and early onset psychosis. His ASD was first diagnosed at the age of 4 years and his psychotic symptoms began at 5 years old. This is only the second case reported thus far of this rare event of co-occurring autism and very early onset psychosis in a child with a 3q29 deletion. It is also the earliest case of a child with autism developing comorbid psychosis-manifesting by the age of 5 years. PMID- 23443970 TI - Polar bodies: their biological mystery and clinical meaning. PMID- 23443969 TI - Drought resistance in rice seedlings conferred by seed priming : role of the anti oxidant defense mechanisms. AB - Seed priming is a method by which seeds are subjected to different stress conditions to impart stress adaptation in seedlings germinating and growing under stressful situations. Drought stress is a major reason behind failure of crops. We studied the effects of hydropriming, dehydration priming (induced by PEG), and osmopriming (induced by NaCl and KH(2)PO(4)) on subsequent germination, growth and anti-oxidant defense mechanisms of 2-week-old rice seedlings under continuing dehydration stress. Unprimed seeds grown in PEG showed significantly lower germination and growth along with significantly higher reactive oxygen species (ROS) and lipid peroxidation levels. Among the priming methods, 5 % PEG priming was found to be the best in terms of germination and growth rate along with the lowest amount of ROS and lipid peroxidation (malondialdehyde [MDA]) values. MDA levels were reduced significantly by all of the priming methods. Hence, reduction of lipid peroxidation may be a key factor underlying the drought tolerance produced by the priming treatments. Glutathione peroxidase (GPX) activity seemed to bear an excellent correlation with oxidative stress resistance through seed priming. The PEG priming produced minimum peroxidative damage and superior germination and growth rate along with efficient GPX activity, overexpressed MnSOD and maintenance of HSP70 expression in normal as well as in drought condition. Therefore, in PEG-primed seeds the existence of robust protective mechanisms is definitely indicated. PMID- 23443972 TI - Engineered genetic information processing circuits. AB - Cells implement functions through the computation of biological information that is often mediated by genetic regulatory networks. To reprogram cells with novel capabilities, a vast set of synthetic gene circuits has recently been created. These include simple modules, such as feedback circuits, feed-forward loops, ultrasensitive networks, band-pass filters, logic gate operators and others, with each carrying a specific information processing functionality. More advanced cellular computation can also be achieved by assembling multiple simple processing modules into integrated computational cores. Further, when coupled with other modules such as sensors and actuators, integrated processing circuits enable sophisticated biological functionalities at both intra- and intercellular levels. Engineered genetic information processing circuits are transforming our ability to program cells, offering us extraordinary opportunities to explore biological mechanisms and to address real-world challenges. PMID- 23443971 TI - Metabolic phenotypes in triple-negative breast cancer. AB - The aim of study was to investigate the metabolism of tumor and stromal cells necessary to determine differential tumor-stroma metabolic interactions according to the molecular subtypes of triple-negative breast cancer (TNBC). Tissues from 132 patients of TNBC were prepared for use as tissue microarrays (TMA). Expression of CK5/6, EGFR, claudin 3, claudin 4, claudin7, E-cadherin, AR, GGT1, STAT1, and interleukin-8 was evaluated by immunohistochemical staining using TMA to classify molecular subtypes of TNBC. In addition, immunohistochemical staining for Glut1, CAIX, BNIP3, MCT4, Beclin-1, LC3A, LC3B, and p62 was performed. According to glycolytic status determined by the immunohistochemical expression of Glut-1 and CAIX in tumor and stroma, the metabolic phenotypes of the TNBCs were defined as follows: Warburg type (tumor: glycolysis, stroma: non glycolysis), reverse Warburg type (tumor: non-glycolysis, stroma: glycolysis), mixed metabolic type (tumor: glycolysis, stroma: glycolysis), and metabolic null type (tumor: non-glycolysis, stroma: non-glycolysis). TNBCs were classified as follows: 79 Warburg type (59.8 %), 7 reverse Warburg type (5.3 %), 24 mixed metabolic type (18.2 %), and 22 metabolic null type (16.7 %). There was no statistical significance between the metabolic phenotypes and molecular subtypes (P=0.706). Reverse Warburg type showed the most dysfunctional mitochondrial status for stromal cells, while Warburg type showed the most functional mitochondrial status (P=0.036). Regarding stromal autophagy status, reverse Warburg type showed the most activated status, while all of the Warburg and metabolic null types showed a non-activated status (P<0.001). In conclusion, Warburg type was the most common metabolic phenotype in TNBC, while reverse Warburg type was the most unusual. Metabolic phenotypes did not differ among the molecular subtypes of TNBCs. PMID- 23443973 TI - Valve disease in chronic venous disorders: a quantitative ultrastructural analysis by transmission electron microscopy and stereology. AB - INTRODUCTION: The ultrastructure of venous valves and walls in chronic venous disease was investigated. METHODS: Consecutive patients were categorised into one of three groups (group A: patients with C1 venous disease in accordance with CEAP (Clinical severity, Etiology, Anatomy, Pathophysiology); group B: C2 and C3; group C: C4, C5 and C6). The terminal or preterminal valve and adjacent vessel wall was harvested from the great saphenous vein. Sections were examined with a transmission electron microscope. The volumes of elastin and of collagen per unit surface area of valve were assessed, as well as the surface endothelium of valve and vessel wall. RESULTS: The study population consisted of 17 patients. The elastin ratio was analysed by means of stereology. Mean values were: in group A, 0.45 MUm3/m2; in group B, 0.67 MUm3/m2; in group C, 0.97 MUm3/m2. The ratio was similar for collagen (A, 15.7 MUm3/m2; B, 26.8 MUm3/m2; C, 30.1 MUm3/m2). Surface analysis of the valve endothelium and the adjacent vessel wall endothelium showed a trend towards increasing damage with more severe disease. CONCLUSIONS: With progression of venous disease, the valve elastin content, assessed morphologically, seems to increase, and the endothelium of the venous valve and the vein wall tend to show more damage. PMID- 23443974 TI - Splenectomy in older adults: indications and clinical outcomes. AB - The aim of this study was to improve the understanding of the indications and associated outcomes among older adults undergoing splenectomy. Data regarding patients of age >=60 years treated between 1998 and 2008 were reviewed. Fifty patients (age 71.6 +/- 8) were identified. Common indications for splenectomy included idiopathic thrombotic purpura (26.0 %) and lymphoma (28.0 %). Patient co morbidities included hypertension (54 %), coronary artery disease (24 %) and diabetes mellitus (20 %). Twenty-seven patients (54 %) underwent laparoscopic surgery; 23 (46 %) had open procedures; more than half of open splenectomies were conversions from attempted laparoscopy. Mean post-operative length of stay (LOS) was 5.9 +/- 5 days (range 1-21). Two patients died in hospital; an additional three died within 6 months. Five patients were discharged to an extended care facility (ECF). Three patients required readmission within 30 days. Increased age was associated with need for ECF (p = 0.01). Increasing LOS, but not age, was associated with 6-month mortality (p = 0.04). Although we noted a 10 % in hospital mortality rate, splenectomy appears to be safe for carefully selected older adults. PMID- 23443976 TI - Effects of the Fataki campaign: addressing cross-generational sex in Tanzania by mobilizing communities to intervene. AB - The national multimedia "Fataki" campaign aired in Tanzania from 2008 to 2011 with the goal of addressing cross-generational sex (CGS) by mobilizing communities to intervene in CGS relationships. A cross-sectional household survey was used to evaluate the campaign. Logistic regression analysis found a dose response relationship between campaign exposure and interpersonal communication about CGS, intervening in CGS relationships, and lower CGS engagement among women. No association was found between campaign exposure and current CGS involvement among men, though longer-term data collection may be needed to assess changes in relationship patterns. Findings indicated that engaging in interpersonal communication about CGS was associated with a higher likelihood of actually intervening. Strategies to generate further discussion surrounding CGS and increase impact, such as through community-based components to supplement campaigns, are discussed. PMID- 23443975 TI - Spatially monitoring oxygen level in 3D microfabricated cell culture systems using optical oxygen sensing beads. AB - Capability of measuring and monitoring local oxygen concentration at the single cell level (tens of microns scale) is often desirable but difficult to achieve in cell culture. In this study, biocompatible oxygen sensing beads were prepared and tested for their potential for real-time monitoring and mapping of local oxygen concentration in 3D micro-patterned cell culture systems. Each oxygen sensing bead is composed of a silica core loaded with both an oxygen sensitive Ru(Ph2phen3)Cl2 dye and oxygen insensitive Nile blue reference dye, and a poly dimethylsiloxane (PDMS) shell rendering biocompatibility. Human intestinal epithelial Caco-2 cells were cultivated on a series of PDMS and type I collagen based substrates patterned with micro-well arrays for 3 or 7 days, and then brought into contact with oxygen sensing beads. Using an image analysis algorithm to convert florescence intensity of beads to partial oxygen pressure in the culture system, tens of microns-size oxygen sensing beads enabled the spatial measurement of local oxygen concentration in the microfabricated system. Results generally indicated lower oxygen level inside wells than on top of wells, and local oxygen level dependence on structural features of cell culture surfaces. Interestingly, chemical composition of cell culture substrates also appeared to affect oxygen level, with type-I collagen based cell culture systems having lower oxygen concentration compared to PDMS based cell culture systems. In general, results suggest that oxygen sensing beads can be utilized to achieve real-time and local monitoring of micro-environment oxygen level in 3D microfabricated cell culture systems. PMID- 23443977 TI - Community-based accompaniment and psychosocial health outcomes in HIV-infected adults in Rwanda: a prospective study. AB - We examined whether the addition of community-based accompaniment to Rwanda's national model for antiretroviral treatment (ART) was associated with greater improvements in patients' psychosocial health outcomes during the first year of therapy. We enrolled 610 HIV-infected adults with CD4 cell counts under 350 cells/MUL initiating ART in one of two programs. Both programs provided ART and required patients to identify a treatment buddy per national protocols. Patients in one program additionally received nutritional and socioeconomic supplements, and daily home-visits by a community health worker ("accompagnateur") who provided social support and directly-observed ingestion of medication. The addition of community-based accompaniment was associated with an additional 44.3 % reduction in prevalence of depression, more than twice the gains in perceived physical and mental health quality of life, and increased perceived social support in the first year of treatment. Community-based accompaniment may represent an important intervention in HIV-infected populations with prevalent mental health morbidity. PMID- 23443978 TI - Social environmental factors and condom use among female injection drug users who are sex workers in China. AB - In order to understand the social environmental forces faced by females involved in both injection drug use and sex work, and their associations with condom use during commercial sex, 200 participants were recruited using snowball sampling methods in Liuzhou, China. Of the participants, 41.0% used condoms consistently during commercial sex in the last 6 months. Adjusting for significant background variables, factors significantly associated with consistent condom use included: monthly income, soliciting venue, pattern of sex-work organization, experience of violence, social support, others' support of condom use, and utilization of HIV/STI-related services. In the final multivariate model, history of violence (OR = 0.39, 95% CI = 0.12-0.44), service utilization (OR = 2.18, 95% CI = 1.05 5.20), clients' willingness to use condoms (OR = 2.63, 95% CI = 1.06-6.54) and social support (OR = 0.39, 95% CI = 0.12-0.44) were significant. Service gaps for FSW-IDU exist, and expansion of social services and integration of psychosocial interventions are necessary. PMID- 23443979 TI - Smoking is a risk factor of organ/space surgical site infection in orthopaedic surgery with implant materials. AB - PURPOSE: In recent guidelines, smoking is reported as a factor increasing the risk of surgical site infection (SSI). The accurate analysis of the literature shows that this recommendation relies on low level of evidence in orthopaedic surgery with material implantation (arthroplasty components or implants for internal fixation). This study aimed to assess the attributable risk of smoking on organ/space SSI in orthopaedic surgery with implants. METHODS: Risk factors of organ/space SSI were studied in a prospective cohort including 3,908 patients from June 2003 to December 2006. RESULTS: Smoking was found as a significant risk factor for organ/space SSI. We also observed a significant difference between smokers and non-smokers for surgical wound complications (hematoma, discharge or wound dehiscence) during the period between surgical procedure and discharge from hospital. CONCLUSION: This is the first large prospective report of a significant association between smoking and organ/space SSI in orthopaedic surgery with implants. PMID- 23443980 TI - The gait of patients with one resurfacing and one replacement hip: a single blinded controlled study. AB - PURPOSES: Post arthroplasty gait analysis has up till now been performed on subjects walking slowly on flat ground rather than challenging them at faster speeds or walking uphill. We therefore asked: (1) Is there a measurable difference in the performance of hip resurfacing arthroplasty (HRA) and total hip arthroplasty (THA) limbs at patients' self-determined fastest walking speeds and steepest inclines? and (2) Is there a relationship between the observed differences between the gait of HRA and THA implanted limbs and patient walking speeds and inclines. METHODS: In an ethically approved study we recruited patients with bilateral hip arthroplasties: one HRA and one THA. Nine subjects were assessed using an instrumented treadmill at a range of speeds and inclines by a blinded observer. The ground reaction forces of subjects were recorded and an age, sex and BMI matched control group was used for comparison. RESULTS: Increasing walking speed correlated strongly with between leg differences in weight acceptance (r = 0.9, p = 0.000) and push-off force (r = 0.79, p = 0.002). HRA implanted limbs accepted significantly more weight at top walking speeds (1208 N +/- 320 versus 1279 N +/- 370, p = 0.026) and pushed off with greater force when walking uphill (818 N +/- 163 versus 855 +/- 166, p = 0.012). HRA limbs more closely approximated to the gait of the normal control group. CONCLUSIONS: Arthroplasty implants do have an impact on the gait characteristics of patients. Differences in gait are more likely to be evident when assessment is made at fast speeds and walking uphill. This study suggests that HRA may enable a more normal gait. PMID- 23443981 TI - Identifying barriers preventing Latina women from accessing WIC online health information. AB - The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) is a program for low-income women and children under age five. The purpose of this study was to identify barriers to accessing online WIC resources among Latina WIC clients. Five focus groups were conducted with Spanish-speaking participants recruited from a single WIC clinic. Two key themes emerged relating to barriers in accessing WIC's online resources. The first theme, access issues, included three subthemes: lack of computer/Internet resources; family barriers to computer use; and computer literacy. The second theme, perceived value of the website, included three subthemes: limited time savings; preference for on-site education; and knowledge about the website. This is the first study to evaluate barriers to accessing online resources among Latina women in the WIC program. WIC sites attempting to increase utilization of online resources may be more successful if they serve clients with easy access to a computer with Internet access. They may also consider strategies to increase the value of the online resources, as compared to their current services offered to clients in a face-to face setting. PMID- 23443982 TI - Reality based modeling and simulation of gallbladder shape deformation using variational methods. AB - PURPOSE: Accurate soft tissue deformation modeling is important for realistic surgical simulation. The aim of this study is to develop a reality-based gallbladder model and to determine material constants that represent gallbladder wall mechanical properties. METHODS: Mechanical experiments on porcine gallbladder were performed to investigate tissue deformation, and an exponential strain energy function was used to describe the nonlinear stress-strain behavior of the gallbladder wall. A new volumetric function based upon the exponential strain energy function was proposed to model the gallbladder organ. A genetic algorithm was used to identify the material parameters of the proposed biomechanical model from the experimental data. RESULTS: The material constants of the exponential strain energy model were determined based on the experimental data. Deformation simulation and haptic rendering using the proposed gallbladder model were presented. Comparison between deformation predicted by the proposed model and that of the experimental data on gallbladder wall and gallbladder organ tissues demonstrates the applicability of this reality-based variational method for deformation simulation. CONCLUSION: An accurate soft tissue deformation model was developed using material constants identified for gallbladder. The model is suitable for interactive haptic rendering and deformation simulation. This model has potential applications for simulation of other hollow organs. PMID- 23443984 TI - Causation in psychoanalysis. AB - It has been argued that psychoanalytic and biological theories cannot be integrated because they rely on different epistemological grounds, namely on hermeneutic versus causal explanations, that are inconsistent with each other. Such inconsistency would seriously question the general possibility of neuropsychoanalytic research. Here, I review three important arguments that have been raised in favor of this inconsistency: first, that psychoanalytic attempts to overcome repression aim to go beyond causal relationships; second, that hermeneutic explanations are retrospective and context-dependent and therefore follow a different logic than causal explanations; and third, that only causal hypotheses are falsifiable, while the introspective reasons for one's own behavior are not. I present arguments against each of these statements and show that actually, causal and hermeneutic explanations are, at least in principle, consistent with each other. The challenge for neuropsychoanalytic research remains to find indeed empirical examples of theories which are causal and hermeneutic at the same time. PMID- 23443983 TI - Mesh-based method for measuring intracranial volume in patients with craniosynostosis. AB - PURPOSE: Craniosynostosis may lead to reduced intracranial volume (ICV) and disturb normal brain growth and development. Thus, ICV is an important parameter with respect to the surgical outcome. Current methods for ICV determination from computed tomography (CT) images have drawbacks. The aim of this study was to investigate the performance of the novel mesh-based method (MBM) for ICV determination with craniosynostosis patients. METHODS: Twenty-two patients operated on for scaphocephaly were included in this study. ICVs from preoperative, one-week postoperative, and one-year postoperative CT images were measured with MBM. The level of agreement with the manual segmentation method (MSM) was determined for the measurements of preoperative and one-year postoperative datasets. Repeatability was determined with re-measurements of six datasets. Measurement time was recorded for MBM. RESULTS: Mean [Formula: see text] preoperative ICV values were 895.0 [Formula: see text] 153.1 [Formula: see text] and 896.4 [Formula: see text] 147.2 [Formula: see text] as measured with MBM and MSM, respectively. Corresponding one-year postoperative values were 1,238.3 [Formula: see text] 118.7 [Formula: see text] and 1,250.1 [Formula: see text] 117.5 [Formula: see text]. The MBM allowed ICV determination from one-week postoperative datasets. Measurement time with MBM was 4 CONCLUSIONS: MBM is an efficient method for determining the ICV of craniosynostosis patients, allowing the measurement of skulls with bony defects. The repeatability and short measurement time of MBM are attributable to the user interference and assessment of the measurement process. PMID- 23443985 TI - DRD2 and ANKK1 gene polymorphisms and alcohol dependence: a case-control study among a Mendelian population of East Asian ancestry. AB - AIMS: Dopamine receptors are extensively studied in association with alcohol dependence (AD), since they are thought to be the key neural substrate for alcohol and other drug-related reinforcement and reward behaviours. The present study aims to understand the role of dopamine receptors in susceptibility to AD with respect to three sites of DRD2 gene (-141C Ins/Del, TaqIB and TaqID) and TaqIA site of ANKK1 gene among Meiteis of Manipur, a Mendelian population of India. METHODS: A total of 129 individuals who all met the DSM-IV criteria for AD and 286 controls were screened for four single-nucleotide polymorphisms (SNPs) 141C Ins/Del, TaqIB TaqID and TaqIA. Both AD cases and controls were unrelated up to first cousin. RESULTS: Early age of onset of alcohol consumption and smoking status were significantly associated with AD. Improvement in education and occupation statuses showed decreased risk of AD. The heterozygous and mutant homozygous conditions of ANKK1 TaqIA polymorphism were found to be significantly associated with AD (odds ratio = 2.13, 95% confidential interval 1.04-4.39, P < 0.05), whereas a borderline significance of the -141C Del allele was observed (P = 0.059). Such a trend was not observed between AD and the other polymorphism, i.e., TaqIB and TaqID. CONCLUSIONS: Individuals carrying the A1 allele of ANKK1 TaqIA polymorphism may be relatively more susceptible to AD. Interaction of both ANKK1 TaqIA and -141C Ins/Del polymorphism is likely to increase risk of AD phenotypes among Meiteis of Manipur, India. PMID- 23443986 TI - Ethyl glucuronide in scalp and non-head hair: an intra-individual comparison. AB - AIMS: Analysis of ethyl glucuronide (EtG), a minor metabolite of ethanol, is a valid tool for the assessment of social and chronic excessive alcohol consumption. Standardized analysis of EtG is usually done in head hair. As head hair cannot always be provided, alternative hair matrices become more and more interesting. Therefore, a study was performed that compared the intra-individual EtG concentrations in scalp hair and non-head hair (chest, arm, leg and axillary hair). METHODS: Hair samples were collected from 68 subjects undergoing an expert assessment for fitness to drive. Aqueous extracts of the hair matrix were cleaned by solid-phase extraction, using an Oasis MAX column. EtG was first derivatized with perfluoropentanoic anhydride and then quantified by GC-MS/MS in negative chemical ionization mode, using EtG-d5 as internal standard. RESULTS: For categorizing drinking behaviour, the two EtG cut-off values recommended by the Society of Hair Testing were applied for all different hair types. For chest, arm and leg hair, correct classification ratios were >83%. This corresponds to sensitivity values >78% and specificities >75%. Such values indicate together with phi coefficients (rphi) > 0.7 a high correlation of the categorization of the drinking behaviour based on these body hair EtG concentrations compared with the indexing based on scalp hair EtG-values. However, it must be taken into consideration that the time frame represented by non-head hair may extend way back. CONCLUSIONS: These results indicate that chest, arm and leg hair can be a valid alternative to assess the drinking behaviour of a subject if head hair is not available; whereas axillary hair is not suitable as alternative matrix. PMID- 23443987 TI - Prevalence and patterns of hazardous and harmful alcohol consumption assessed using the AUDIT among Bhutanese refugees in Nepal. AB - AIMS: This study sought to ascertain the prevalence of hazardous and harmful alcohol consumption among Bhutanese refugees in Nepal and to identify predictors of elevated risk in order to better understand intervention need. METHODS: Hazardous and harmful alcohol consumption was assessed using the Alcohol Use Disorder Identification Test (AUDIT) administered in a face-to-face interview in a census of two camps comprising ~8000 refugees. RESULTS: Approximately 1/5 men and 1/14 women drank alcohol and prevalence of hazardous drinking among current drinkers was high and comparable to that seen in Western countries with longstanding alcohol cultures. Harmful drinking was particularly associated with the use of other substances including tobacco. CONCLUSIONS: Assessment of the alcohol-related needs of Bhutanese refugees has permitted the design of interventions. This study adds to the small international literature on substance use in forced migration populations, about which there is growing concern. PMID- 23443988 TI - Randomized clinical trial of zoledronic acid in multiple myeloma patients undergoing high-dose chemotherapy and stem-cell transplantation. AB - BACKGROUND: A growing body of evidence is demonstrating that the nitrogen containing bisphosphonate zoledronic acid (zol) improves clinical outcomes in various cancer settings, including multiple myeloma. Those findings provided the rationale for conducting an open-label randomized controlled phase iii trial to evaluate the effect of zol on overall survival (os) and progression-free survival (pfs) in patients with previously untreated high-risk multiple myeloma. METHODS: The trial randomly assigned 308 adult patients less than 65 years of age with previously untreated symptomatic multiple myeloma (1:1) to receive zol 4 mg intravenously once every 28 days for 24 months (n = 151) or no zol (n = 157). Before autologous stem-cell transplantation (asct), all patients received a high dose noncytotoxic induction regimen of dexamethasone, all-trans-retinoic acid, and interferon alpha 2b. RESULTS: After a median follow-up of 69.8 months (range: 36.5-96 months), the 10-year pfs (66% vs. 52%, p < 0.001) and os (67% vs. 48%, p < 0.001) rates were significantly higher in treated patients than in control patients. Overall response (77% zol vs. 75% control), complete response (52% vs. 46%), and very good partial response (25% vs. 29%) rates were similar between the groups. Treatment was generally well tolerated, with no reports of renal impairment or osteonecrosis of the jaw. CONCLUSIONS: In symptomatic previously untreated multiple myeloma patients, zol combined with high-dose therapy followed by asct improved os and pfs without appreciable toxicity. These findings provide additional evidence of the meaningful anticancer activity of zol in this patient population. PMID- 23443989 TI - Mild eccentric exercise increases Hsp72 content in skeletal muscles from adult and late middle-aged rats. AB - The loss of muscle mass with age or sarcopenia contributes to increased morbidity and mortality. Thus, preventing muscle loss with age is important for maintaining health. Hsp72, the inducible member of the Hsp70 family, is known to provide protection to skeletal muscle and can be increased by exercise. However, ability to increase Hsp72 by exercise is intensity-dependent and appears to diminish with advanced age. Thus, other exercise modalities capable of increasing HSP content and potentially preventing the age related loss of muscle need to be explored. The purpose of this study was to determine if the stress from one bout of mild eccentric exercise was sufficient to elicit an increase in Hsp72 content in the vastus intermedius (VI) and white gastrocnemius (WG) muscles, and if the Hsp72 response differed between adult and late middle-aged rats. To do this, 30 adult (6 months) and late middle-aged (24 months) F344BN rats were randomly divided into three groups (n = 6/group): control (C), level exercise (16 m x min(-1)) and eccentric exercise (16 m x min(-1), 16 degree decline). Exercised animals were sacrificed immediately post-exercise or after 48 hours. Hematoxylin and Eosin staining was used to assess muscle damage, while Western Blotting was used to measure muscle Hsp72 content. A nested ANOVA with Tukey post hoc analysis was performed to determine significant difference (p < 0.05) between groups. Hsp72 content was increased in the VI for both adult and late middle-aged rats 48 hours after eccentric exercise when compared to level and control groups but no differences between age groups was observed. Hsp72 was not detected in the WG following any type of exercise. In conclusion, mild eccentric exercise can increase Hsp72 content in the rat VI muscle and this response is maintained into late middle-age. PMID- 23443992 TI - Reduction of 2,2,2-trichloro-1-arylethanones by RMgX: mechanistic investigation and the synthesis of substituted alpha,alpha-dichloroketones. AB - 2,2,2-Trichloro-1-arylethanones undergo high yielding reductions to the corresponding 2,2-dichloro-1-arylethanones in the presence of RMgX. A single electron transfer mechanism for the reaction is proposed based on trapping experiments. Reaction of the intermediate enolates with a range of electrophiles is described, providing a convenient route to substituted alpha,alpha-dichloro beta-hydroxyketones and related molecules. PMID- 23443990 TI - Cardiovascular health through young adulthood and cognitive functioning in midlife. AB - OBJECTIVE: A study was undertaken to examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels. METHODS: This analysis of the Coronary Artery Risk Development in Young Adults study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (year 0) who attended follow-up examinations at years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at year 25. RESULTS: A greater number of ideal cardiovascular metrics in young adulthood and middle age were independently associated with better cognitive function in midlife (p for trend < 0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% confidence interval [CI] = 0.93 - 1.71), a 0.77-point lower interference score on the Stroop test (95% CI= 1.03 to -0.45), and 0.12 more words on the RAVLT (95% CI = 0.04 to 0.20). Participants who had >=5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle age (p for trend < 0.01, for all). INTERPRETATION: Ideal cardiovascular health in young adulthood and its maintenance to middle age is associated with better psychomotor speed, executive function, and verbal memory in midlife. PMID- 23443991 TI - A general framework of persistence strategies for biological systems helps explain domains of life. AB - The nature and cause of the division of organisms in superkingdoms is not fully understood. Assuming that environment shapes physiology, here we construct a novel theoretical framework that helps identify general patterns of organism persistence. This framework is based on Jacob von Uexkull's organism-centric view of the environment and James G. Miller's view of organisms as matter-energy information processing molecular machines. Three concepts describe an organism's environmental niche: scope, umwelt, and gap. Scope denotes the entirety of environmental events and conditions to which the organism is exposed during its lifetime. Umwelt encompasses an organism's perception of these events. The gap is the organism's blind spot, the scope that is not covered by umwelt. These concepts bring organisms of different complexity to a common ecological denominator. Ecological and physiological data suggest organisms persist using three strategies: flexibility, robustness, and economy. All organisms use umwelt information to flexibly adapt to environmental change. They implement robustness against environmental perturbations within the gap generally through redundancy and reliability of internal constituents. Both flexibility and robustness improve survival. However, they also incur metabolic matter-energy processing costs, which otherwise could have been used for growth and reproduction. Lineages evolve unique tradeoff solutions among strategies in the space of what we call "a persistence triangle." Protein domain architecture and other evidence support the preferential use of flexibility and robustness properties. Archaea and Bacteria gravitate toward the triangle's economy vertex, with Archaea biased toward robustness. Eukarya trade economy for survivability. Protista occupy a saddle manifold separating akaryotes from multicellular organisms. Plants and the more flexible Fungi share an economic stratum, and Metazoa are locked in a positive feedback loop toward flexibility. PMID- 23443993 TI - Adsorption of divalent metal ions from aqueous solutions using graphene oxide. AB - The adsorptive properties of graphene oxide (GO) towards divalent metal ions (copper, zinc, cadmium and lead) were investigated. GO prepared through the oxidation of graphite using potassium dichromate was characterized by scanning electron microscopy (SEM), powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and infrared spectroscopy (FT-IR). The results of batch experiments and measurements by flame atomic absorption spectrometry (F-AAS) indicate that maximum adsorption can be achieved in broad pH ranges: 3-7 for Cu(II), 5-8 for Zn(II), 4-8 for Cd(II), 3-7 for Pb(II). The maximum adsorption capacities of Cu(II), Zn(II), Cd(II) and Pb(II) on GO at pH = 5 are 294, 345, 530, 1119 mg g(-1), respectively. The competitive adsorption experiments showed the affinity in the order of Pb(II) > Cu(II) ? Cd(II) > Zn(II). Adsorption isotherms and kinetic studies suggest that sorption of metal ions on GO nanosheets is monolayer coverage and adsorption is controlled by chemical adsorption involving the strong surface complexation of metal ions with the oxygen-containing groups on the surface of GO. Chemisorption was confirmed by XPS (binding energy and shape of O1s and C1s peaks) of GO with adsorbed metal ions. The adsorption experiments show that the dispersibility of GO in water changes remarkably after complexation of metal ions. After adsorption, the tendency to agglomerate and precipitate is observed. Excellent dispersibility of GO and strong tendency of GO-Me(II) to precipitate open the path to removal of heavy metals from water solution. Potential application of GO in analytical chemistry as a solid sorbent for preconcentration of trace elements and in heavy metal ion pollution cleanup results from its maximum adsorption capacities that are much higher than those of any of the currently reported sorbents. PMID- 23443994 TI - Cardiovascular and mortality risks in Parkinson's disease patients treated with entacapone. AB - The controlled trial Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) reported an unexpected increase in acute myocardial infarction (AMI) with entacapone use in patients with Parkinson's disease (PD). The authors investigated whether entacapone increased cardiovascular and mortality risk compared with the use of a non-levodopa dopamine agonist (DA) or a selective monoamine oxidase type-B inhibitor (MAOBI). Using national Medicare data, a new-user cohort of elderly patients with PD treated with entacapone was propensity score (PS) matched with new users of either DA or MAOBI. The PS model included variables for sociodemographics, cardiovascular disease, medications, prior PD treatment, and comorbidities. Cox proportional hazards regression was used to compare on-therapy time to event for AMI, stroke, and death with DA-MAOBI as a reference. Study cohorts included 8681 entacapone-treated and 17,362 DA MAOBI-treated initators who were followed for 2569 and 5385 person-years, respectively. Cohorts were closely balanced for all covariates. During follow-up, there were 106 AMIs, 89 strokes, and 201 deaths. The hazard ratio (HR) and 95% confidence interval (CI) associated with entacapone use was 0.86 (95% CI, 0.57 1.30) for AMI, 0.85 (95% CI, 0.54-1.35) for stroke, and 0.79 (95% CI, 0.58-1.07) for death. The risk was unchanged for treatment of <= 6 months' and>6 months' duration and was unaffected by adjustment for time-varying levodopa use during follow-up. The risk of each endpoint was not differentially affected by diabetes, ischemic heart disease, or kidney failure status. However, the risk of stroke was modified by the presence (HR, 2.09; 95% CI, 0.98-4.45) or absence (HR, 0.51; 95% CI, 0.27-0.95) of advanced PD-related morbidities (P value for interaction=0.004). Entacapone was not associated with an increased risk of AMI, stroke, or death in elderly patients with PD. PMID- 23443995 TI - Haematopoietic stem cell transplantation: activity in Switzerland compared with surrounding European countries. AB - Haematopoietic stem cell transplantation (HSCT) is a highly specialised procedure used to treat malignancies of the lymphohaematopoietic system as well as some acquired and inherited disorders of the blood. This analysis by the Swiss Blood Stem Cell Transplantation Group, based on data from 2008-2011, describes, treatment rates in Switzerland for specific indications and compares this with data from Germany, France, Italy and the Netherlands, corrected for the size of the population. Differences in transplant rates, in rates for particular indications, and in the use of specific transplant technologies such as use of unrelated donors, use of cord blood or mismatched family donors are described. These data are put in correlation with donor availability from international registries and with number of transplant teams and number of procedures per team all corrected for population size. PMID- 23443997 TI - Public attitudes regarding a pilot study of newborn screening for spinal muscular atrophy. AB - A population-based pilot study of newborns screening for a rare genetic condition, spinal muscular atrophy (SMA), is being conducted with funding from the National Institutes of Health. The first component of the study is to assess the ethical, legal, and social implications of population-based pilot studies with a focus on public engagement and parental decision-making for the proposed opt-out approach in this research. We conducted focus groups with members of the general public to ascertain attitudes about the pilot study and acceptability of an opt-out approach in two states, Colorado and Utah, where the pilot screening is being proposed (N = 70). We developed an informational video for the project and showed it to the groups prior to the discussion in order to inform participants about population-based research, newborn screening (NBS), permission/consent models, and SMA. Results indicated support for the conduct of pilot studies that is consistent with the current standard of practice for similar population-based programs. There was support for an opt-out approach for parental decision-making; however there was limited parental knowledge about population-based research, NBS and SMA. In general, our participants considered this pilot study to be low risk and of potential benefit to infants and families. The majority of participants were supportive of an opt-out approach with information delivered through various avenues PMID- 23443998 TI - Fate of ferrisiderophores after import across bacterial outer membranes: different iron release strategies are observed in the cytoplasm or periplasm depending on the siderophore pathways. AB - Siderophore production and utilization is one of the major strategies deployed by bacteria to get access to iron, a key nutrient for bacterial growth. The biological function of siderophores is to solubilize iron in the bacterial environment and to shuttle it back to the cytoplasm of the microorganisms. This uptake process for Gram-negative species involves TonB-dependent transporters for translocation across the outer membranes. In Escherichia coli and many other Gram negative bacteria, ABC transporters associated with periplasmic binding proteins import ferrisiderophores across cytoplasmic membranes. Recent data reveal that in some siderophore pathways, this step can also be carried out by proton-motive force-dependent permeases, for example the ferrichrome and ferripyochelin pathways in Pseudomonas aeruginosa. Iron is then released from the siderophores in the bacterial cytoplasm by different enzymatic mechanisms depending on the nature of the siderophore. Another strategy has been reported for the pyoverdine pathway in P. aeruginosa: iron is released from the siderophore in the periplasm and only siderophore-free iron is transported into the cytoplasm by an ABC transporter having two atypical periplasmic binding proteins. This review presents recent findings concerning both ferrisiderophore and siderophore-free iron transport across bacterial cytoplasmic membranes and considers current knowledge about the mechanisms involved in iron release from siderophores. PMID- 23443999 TI - Oculoplastic approach to congenital cutis laxa syndrome. AB - Cutis laxa is a rare congenital or acquired disorder of elastic tissue, characterized by loose skin with folds and multiple internal organ involvement, which may cause life-threatening complications. We present a patient with cutis laxa syndrome who had cross eyelids with esotropia. Bilateral lateral canthal tendon repositioning and bilateral medial rectus recession procedures were performed in a single session. The patient had acceptable eyelid and globe cosmesis after the procedure. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 . PMID- 23444001 TI - Anatomy and tensile strength of the abdominal head of the pectoralis major muscle in relation to transaxillary breast augmentation. AB - BACKGROUND: This study aimed to elucidate the anatomy of the abdominal head of the pectoralis major (AHPM) in relation to transaxillary breast augmentation (TBA). METHODS: In 20 hemithoraxes of fresh Korean cadavers, the width, thickness, and location of the origin of the AHPM were measured in relation to the seventh rib-costal cartilage junction. A force gauge was used to measure the force needed to detach the AHPM from its origin. In another four breasts, an implant pocket was made first, followed by observation of the AHPM. In 92 patients who underwent surgery, the AHPM was observed at its origin during performance of endoscopic TBA. RESULTS: The AHPM was observed in 23 (96%) of 24 hemithoraxes dissected. The AHPM was observed in 170 (92.4%) of 184 breasts subjected to surgery. The AHPM originated from the rectus fascia at the sixth (60%) and seventh (35%) costochondral junctions. The width of the AHPM was 23.5+/ 5.2 mm at its origin, 15.2+/-3.9 mm at midbelly, and 7.3+/-4.3 mm at insertion. The thickness of the AHPM at its origin was 1.6+/-0.5 mm. The force needed to detach AHPM from its origin was 23.5+/-12.0 N. In two cadavers of mock surgery, the AHPM could limit the boundary of the implant pocket after division of the costal origins. After division of the AHPM, the free inferior space was obtained. CONCLUSION: In submuscular or dual-plane breast augmentation, the AHPM should be cut to place the implant in the correct desired position. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23444002 TI - Time-dependent traction force microscopy for cancer cells as a measure of invasiveness. AB - The migration of tumor cells of different degrees of invasivity is studied, on the basis of the traction forces exerted in time on soft substrates (Young modulus~10 kPa). It is found that the outliers of the traction stresses can be an effective indicator to distinguish cancer cell lines of different invasiveness. Here, we test two different epithelial bladder cancer cell lines, one invasive (T24), and a less invasive one (RT112). Invasive cancer cells move in a nearly periodic motion, with peaks in velocity corresponding to higher traction forces exerted on the substrate, whereas less invasive cells develop traction stresses almost constant in time. The dynamics of focal adhesions (FAs) as well as cytoskeleton features reveals that different mechanisms are activated to migrate: T24 cells show an interconnected cytoskeleton linked to mature adhesion sites, leading to small traction stresses, whereas less invasive cells (RT112) show a less-structured cytoskeleton and unmature adhesions corresponding to higher traction stresses. Migration velocities are smaller in the case of less invasive cells. The mean squared displacement shows super-diffusive motion in both cases with higher exponent for the more invasive cancer cells. Further correlations between traction forces and the actin cytoskeleton reveal an unexpected pattern of a large actin rim at the RT112 cell edge where higher forces are colocalized, whereas a more usual cytoskeleton structure with stress fibers and FAs are found for T24 cancer cells. We conjecture that this kind of analysis can be useful to classify cancer cell invasiveness. PMID- 23444003 TI - Mitochondrial mechanisms and neurological disorders. PMID- 23444004 TI - Improving classroom quality with the RULER Approach to Social and Emotional Learning: proximal and distal outcomes. AB - The RULER Approach to Social and Emotional Learning ("RULER") is designed to improve the quality of classroom interactions through professional development and classroom curricula that infuse emotional literacy instruction into teaching learning interactions. Its theory of change specifies that RULER first shifts the emotional qualities of classrooms, which are then followed, over time, by improvements in classroom organization and instructional support. A 2-year, cluster randomized controlled trial was conducted to test hypotheses derived from this theory. Sixty-two urban schools either integrated RULER into fifth- and sixth-grade English language arts (ELA) classrooms or served as comparison schools, using their standard ELA curriculum only. Results from multilevel modeling with baseline adjustments and structural equation modeling support RULER's theory of change. Compared to classrooms in comparison schools, classrooms in RULER schools exhibited greater emotional support, better classroom organization, and more instructional support at the end of the second year of program delivery. Improvements in classroom organization and instructional support at the end of Year 2 were partially explained by RULER's impacts on classroom emotional support at the end of Year 1. These findings highlight the important contribution of emotional literacy training and development in creating engaging, empowering, and productive learning environments. PMID- 23444005 TI - "Bounded" empowerment: analyzing tensions in the practice of youth-led participatory research in urban public schools. AB - This multi-method study examines tensions in the practice of youth-led participatory research (YPAR) in urban high schools among 15 semester-cohorts. Student participants in the present study were 77 ethnically diverse youth from four high schools in a major metropolitan school district. Data were gathered using systematic classroom observations, interviews with teachers and students involved in the projects, and participant observation. The two most commonly constrained phases of the YPAR project were issue selection and action steps. A central tension in the issue selection phase for projects enacted across multiple semester cohorts was the tension between original inquiry and "traction:" Sticking with the same topic enabled sustained building of strategic alliances and expertise for making change, but limited the incoming cohort's power to define the problem to be addressed. In further analyses, we identified processes that promoted student power despite continuity-related constraints-teachers' framing and buy-in strategies, "micro-power" compensation, and alignment of students' interests with the prior cohort-as well as constraints in other phases of the projects. This study's findings regarding the promotion of youth power in the face of constraints advance the integration of theory and practice in youth led research and have implications for participatory research more broadly. PMID- 23444006 TI - A high-fat diet induces obesity and impairs bone acquisition in young male mice. AB - The postnatal development of obesity is highly associated with the excessive consumption of a high-calorie, high-fat diet (HFD). However, the correlation between HFD-induced pediatric obesity and skeletal development remains to be elucidated. In the present study, postnatal day 17 (PND17) mice were weaned on a HFD for eight weeks ad libitum to induce obesity. The HFD mice showed a significant increase in the total body weight and gonadal and abdominal fat mass compared with the control animals. Peripheral quantitative (pQ) CT scans of the tibial bone revealed that the bone mineral density (BMD), including the total, trabecular and cortical BMD, was unchanged between the HFD and control diet groups, but that it was inversely associated with body fat. By contrast, the bone mineral content (BMC) and trabecular area were significantly decreased in the HFD group compared with the control. RNA and protein were isolated from the femur. qPCR and western blot analyses showed a significant downregulation in the gene expression of the key canonical Wnt signaling molecule beta-catenin, the osteoblastic cell differentiation marker Runt-related transcription factor 2 (Runx2) and also in the beta-catenin gene encoded protein levels of the HFD mice when compared with the controls. Consistent with the increased fat mass in the HFD-induced obese animals, the expression of the adipogenic genes and aP2 was increased compared with the controls. Bone marrow cells were aspirated and the ex vivo bone marrow cell cultures showed that the number of colony-forming unit osteoblasts (CFU-OBs) per bone was significantly decreased in the samples from the HFD mice compared with those from the controls. These observations suggested that HFD-induced obesity in growing animals may affect the total available osteoblastic cell differentiation progenitors in the bone, while increasing adipogenesis. This may result in negative consequences for the bone later on in adult life. PMID- 23444007 TI - Changing interactions between physician trainees and the pharmaceutical industry: a national survey. AB - BACKGROUND: Increasingly, medical school policies limit pharmaceutical representatives' access to students and gifts from drugmakers, but little is known about how these policies affect student attitudes toward industry. OBJECTIVE: To assess interactions between trainees and the pharmaceutical industry, and to determine whether learning environment characteristics influence students' practices and attitudes. DESIGN, PARTICIPANTS: We conducted a cross sectional survey with a nationally-representative sample of first- and fourth year medical students and third-year residents, stratified by medical school, including >= 14 randomly selected trainees at each level per school. MAIN MEASURES: We measured frequency of industry interactions and attitudes regarding how such interactions affect medical training and the profession. Chi-squared tests assessed bivariate linear trend, and hierarchical logistic regression models were fitted to assess associations between trainees' attitudes and their schools' National Institutes of Health (NIH) funding levels and American Medical Student Association (AMSA) PharmFree Scorecard grades reflecting industry-related conflict of interest policies. KEY RESULTS: Among 1,610 student (49.3 % response rate) and 739 resident (43.1 %) respondents, industry-sponsored gifts were common, rising from 33.0 % (first-year students) to 56.8 % (fourth-year students) and 54 % (residents) (p < 0.001). These gifts included meals outside the hospital (reported by 5 % first-year students, 13.4 % fourth-year students, 27.5 % residents (p < 0.001)) and free drug samples (reported by 7.4 % first-year students, 14.1 % fourth-year students, 14.3 % residents (p < 0.001)). The perception that industry interactions lead to bias was prevalent, but the belief that physicians receive valuable education through these interactions increased (64.1 % to 67.5 % to 79.8 %, p < 0.001). Students in schools receiving more NIH funding reported industry gifts less often (OR = 0.51, 95 % CI: 0.38-0.68, p < 0.001), but the strength of institutional conflict of interest policies was not associated with this variable. CONCLUSIONS: Despite recent policy changes, a substantial number of trainees continue to receive gifts from pharmaceutical representatives. We found no relation between these outcomes and a school's policies concerning interactions with industry. PMID- 23444009 TI - Aerosolized ribavirin for patients with cancer and respiratory syncytial virus infection. PMID- 23444008 TI - Advanced imaging improves prediction of hemorrhage after stroke thrombolysis. AB - OBJECTIVE: Very low cerebral blood volume (VLCBV), diffusion, and hypoperfusion lesion volumes have been proposed as predictors of hemorrhagic transformation following stroke thrombolysis. We aimed to compare these parameters, validate VLCBV in an independent cohort using DEFUSE study data, and investigate the interaction of VLCBV with regional reperfusion. METHODS: The EPITHET and DEFUSE studies obtained diffusion and perfusion magnetic resonance imaging (MRI) in patients 3 to 6 hours from onset of ischemic stroke. EPITHET randomized patients to tissue plasminogen activator (tPA) or placebo, and all DEFUSE patients received tPA. VLCBV was defined as cerebral blood volume<2.5th percentile of brain contralateral to the infarct. Parenchymal hematoma (PH) was defined using European Cooperative Acute Stroke Study criteria. Reperfusion was assessed using subacute perfusion MRI coregistered to baseline imaging. RESULTS: In DEFUSE, 69 patients were analyzed, including 9 who developed PH. The >2 ml VLCBV threshold defined in EPITHET predicted PH with 100% sensitivity, 72% specificity, 35% positive predictive value, and 100% negative predictive value. Pooling EPITHET and DEFUSE (163 patients, including 23 with PH), regression models using VLCBV (p<0.001) and tPA (p=0.02) predicted PH independent of clinical factors better than models using diffusion or time to maximum>8 seconds lesion volumes. Excluding VLCBV in regions without reperfusion improved specificity from 61 to 78% in the pooled analysis. INTERPRETATION: VLCBV predicts PH after stroke thrombolysis and appears to be a more powerful predictor than baseline diffusion or hypoperfusion lesion volumes. Reperfusion of regions of VLCBV is strongly associated with post-thrombolysis PH. VLCBV may be clinically useful to identify patients at significant risk of hemorrhage following reperfusion. PMID- 23444010 TI - An ATP2B4 polymorphism protects against malaria in pregnancy. AB - Polymorphisms of ATP2B4 encoding an ubiquitous Ca(2+) pump protect against severe childhood malaria. We assessed the influence of a main polymorphism (rs10900585) on malaria among 834 delivering Ghanaian women. In homozygous primiparae, the odds of placental Plasmodium falciparum infection were reduced by 64%. No influence of the polymorphism on parasite density, low birth weight, or preterm delivery was discernible. However, malarial anemia was greatly reduced in primiparous carriers of the variant allele, paralleling the reduced impact of malaria on hemoglobin levels in this group. A common ATP2B4 polymorphism protects against malaria in pregnancy and related maternal anemia, suggesting ATP2B4 variant associated protection not to be limited to severe childhood malaria. PMID- 23444011 TI - Reply to Fatkenheuer et al. PMID- 23444012 TI - Optimum CT reconstruction parameters for vascular and hepatocellular carcinoma models in a liver phantom with multi-level dynamic computed tomography with 64 detector rows: a basic study. AB - We quantified to clarify the optimum factors for CT image reconstruction of an enhanced hepatocellular carcinoma (HCC) model in a liver phantom obtained by multi-level dynamic computed tomography (M-LDCT) with 64 detector rows. After M LDCT scanning of a water phantom and an enhanced HCC model, we compared the standard deviation (SD, 1 +/- SD), noise power spectrum (NPS) values, contrast noise ratios (CNR), and the M-LDCT image among the reconstruction parameters, including the convolution kernel (FC11, FC13, and FC15), post-processing quantum filters (2D-Q00, 2D-Q01, and 2D-Q02) and slice thicknesses/slice intervals. The SD and NPS values were lowest with FC11 and 2D-Q02. The CNR values were highest with 2D-Q02. The M-LDCT image quality was highest with FC11 and 2D-Q02, and with slice thicknesses/slice intervals of 0.5 mm/0.5 mm and 0.5 mm/0.25 mm. The optimum factors were the FC11 convolution kernel, 2D-Q02 quantum filter, and 0.5 mm slice thickness/0.5 mm slice interval or less. PMID- 23444013 TI - Role of genetic heterogeneity and epistasis in bladder cancer susceptibility and outcome: a learning classifier system approach. AB - BACKGROUND AND OBJECTIVE: Detecting complex patterns of association between genetic or environmental risk factors and disease risk has become an important target for epidemiological research. In particular, strategies that provide multifactor interactions or heterogeneous patterns of association can offer new insights into association studies for which traditional analytic tools have had limited success. MATERIALS AND METHODS: To concurrently examine these phenomena, previous work has successfully considered the application of learning classifier systems (LCSs), a flexible class of evolutionary algorithms that distributes learned associations over a population of rules. Subsequent work dealt with the inherent problems of knowledge discovery and interpretation within these algorithms, allowing for the characterization of heterogeneous patterns of association. Whereas these previous advancements were evaluated using complex simulation studies, this study applied these collective works to a 'real-world' genetic epidemiology study of bladder cancer susceptibility. RESULTS AND DISCUSSION: We replicated the identification of previously characterized factors that modify bladder cancer risk--namely, single nucleotide polymorphisms from a DNA repair gene, and smoking. Furthermore, we identified potentially heterogeneous groups of subjects characterized by distinct patterns of association. Cox proportional hazard models comparing clinical outcome variables between the cases of the two largest groups yielded a significant, meaningful difference in survival time in years (survivorship). A marginally significant difference in recurrence time was also noted. These results support the hypothesis that an LCS approach can offer greater insight into complex patterns of association. CONCLUSIONS: This methodology appears to be well suited to the dissection of disease heterogeneity, a key component in the advancement of personalized medicine. PMID- 23444014 TI - Sensory nerve terminal mitochondrial dysfunction activates airway sensory nerves via transient receptor potential (TRP) channels. AB - Mitochondrial dysfunction and subsequent oxidative stress has been reported for a variety of cell types in inflammatory diseases. Given the abundance of mitochondria at the peripheral terminals of sensory nerves and the sensitivity of transient receptor potential (TRP) ankyrin 1 (A1) and TRP vanilloid 1 (V1) to reactive oxygen species (ROS) and their downstream products of lipid peroxidation, we investigated the effect of nerve terminal mitochondrial dysfunction on airway sensory nerve excitability. Here we show that mitochondrial dysfunction evoked by acute treatment with antimycin A (mitochondrial complex III Qi site inhibitor) preferentially activated TRPA1-expressing "nociceptor-like" mouse bronchopulmonary C-fibers. Action potential discharge was reduced by the TRPA1 antagonist HC-030031. Inhibition of TRPV1 further reduced C-fiber activation. In mouse dissociated vagal neurons, antimycin A induced Ca(2+) influx that was significantly reduced by pharmacological inhibition or genetic knockout of either TRPA1 or TRPV1. Inhibition of both TRPA1 and TRPV1 was required to abolish antimycin A-induced Ca(2+) influx in vagal neurons. Using an HEK293 cell expression system, antimycin A induced concentration-dependent activation of both hTRPA1 and hTRPV1 but failed to activate nontransfected cells. Myxothiazol (complex III Qo site inhibitor) inhibited antimycin A-induced TRPA1 activation, as did the reducing agent dithiothreitol. Scavenging of both superoxide and hydrogen peroxide inhibited TRPA1 activation following mitochondrial modulation. In conclusion, we present evidence that acute mitochondrial dysfunction activates airway sensory nerves preferentially via TRPA1 through the actions of mitochondrially-derived ROS. This represents a novel mechanism by which inflammation may be transduced into nociceptive electrical signaling. PMID- 23444016 TI - Identification of radiation-sensitive expressed genes in the ICR and AKR/J mouse thymus. AB - We have investigated radiation-sensitive expressed genes (EGs), their signal pathways, and the effects of ionizing radiation in the thymus of ICR and AKR/J mice. Whole-body and relative thymus weights were taken and microarray analyses were done on the thymuses of high-dose-rate (HDR, (137) Cs, 0.8 Gy/min, a single dose of 4.5 Gy) and low-dose-rate (LDR, (137) Cs, 0.7 mGy/h, a cumulative dose of 1.7 Gy) irradiated ICR and AKR/J mice. Gene expression patterns were validated by quantitative polymerase chain reaction (qPCR). The effect of ionizing radiation on thymus cell apoptosis was measured terminal deoxynucleotidyl-transferase mediated dUTP-end labeling (TUNEL). LDR-irradiation increased the mean whole-body weight, but decreased the relative thymus weight of AKR/J mice. Radiation sensitive EGs were found by comparing HDR- and LDR-irradiated ICR and AKR/J mice. qPCR analysis showed that 12 EGs had dose and dose-rate dependent expression patterns. Gene-network analysis indicated that Ighg, Igh-VJ558, Defb6, Reg3g, and Saa2 may be involved in the immune response, leukocyte migration, and apoptosis. Our data suggest that expression of the HDR (Glut1, Glut4, and PKLR) and LDR radiation-response genes (Ighg and Igh-VJ558) can be dose or dose-rate dependent. There was an increased number of apoptotic cells in HDR-irradiated ICR mice and LDR-irradiated AKR/J mice. Thus, changes of the mean whole-body weight and relative thymus weight, EGs, signal pathways, and the effects of ionizing radiation on the thymus of ICR and AKR/J mice are described. PMID- 23444017 TI - [Tiotropium for COPD: enhanced life quality and less exacerbations]. PMID- 23444015 TI - Probing the metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology. AB - Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The molecular determinants that govern mGlu5 modulator affinity versus cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, we sought to determine the molecular interactions that contribute to PAM versus NAM pharmacology. Generation of a comparative model of the transmembrane-spanning region of mGlu5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs versus 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two nonconserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, we identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacology of certain PAMs. PMID- 23444018 TI - [Beta-blockers as first-line therapy for hypertension?]. PMID- 23444019 TI - [Chronic kidney disease: how high are the risks?--The progression of chronic kidney disease has to be influenced]. PMID- 23444020 TI - [Occupational medicine in Germany: backbone of health promotion and prevention]. PMID- 23444021 TI - [Shiftwork and health--experience from a chemical company]. AB - BACKGROUND AND OBJECTIVE: Shiftwork is an essential part of our society. At the same time scientific evaluations demonstrate possible negative effects of shiftwork on the health status of the employees. Against this background we performed different studies to evaluate these effects within the specific shift system in a large chemical site in Germany. METHODS AND STUDY GROUP: To evaluate the impact of the different working times on job-related stress perception and work-life-balance we performed a cross-sectional study with 1494 blue collar workers (825 shift- and 669 day workers). RESULTS: Employees working in the rotating shift system reported lower frequencies of perceived time pressure (p = 0.008), and lower stress levels (p = 0.01), compared to the day workers. No significant difference was found with regard to work-life-balance and other aspects of job-related stress perception within both groups. CONCLUSION: Against the general opinion and study-results in the past we did not find a negative effect of our shift-system on self-reported stress. These results are in accordance with results of other cohort-studies on the specific shift system within the company demonstrating no difference in the health status of our shift workers compared to day workers. PMID- 23444022 TI - [Raynaud's phenomenon in occupational vibration exposure]. AB - HISTORY AND ADMISSION FINDINGS: A 34-year-old female stonemason was referred for expert opinion. The question at issue was, whether she suffered from vibration induced white finger disease. She was exposed to high-frequency hand-arm vibrations for many years. She reported white finger attacks at the long fingers, which were associated with cold weather. Until this point, physical findings were normal. INVESTIGATIONS: The cold water provocation test showed a slight delay of the rewarming for the long fingers of the right hand. The nailfold capillary microscopy was normal. DIAGNOSIS AND COURSE: The slight Raynaud's phenomenon was recognized as an occupational disease with a diagnosis of vibration-induced white finger disease. About three years later, the symptoms of the Raynaud's phenomenon had deteriorated, although the patient had finished working with vibrating tools. The cold water provocation test confirmed the deterioration. At this time, the patient had inflamed swellings of some joints caused by rheumatoid arthritis. CONCLUSION: The differential diagnosis of a Raynaud's phenomenon should include occupational causes. Occupational history is diagnostically indicative. If an occupational disease is assumed, a report must be filed. With respect to German social law, the deterioration of the Raynaud's phenomenon was caused by the rheumatoid arthritis, which is regarded as independent from the job. PMID- 23444023 TI - [34-year-old patient with cardiac arrhythmia after electrical injury]. PMID- 23444024 TI - [Occupational diseases today--important knowledge for non occupational physicians]. PMID- 23444025 TI - [Biomonitoring for occupational medicine]. AB - Biomonitoring is an essential occupational-medical instrument for assessing the exposure of chemical agents of workers. It is an integral part of preventive medical examinations as far as established analytical procedures and values for evaluating biomonitoring results are available. The DFG Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has published values for evaluating biomonitoring results. Those values are health related values such as the Biological Tolerance Value (BAT) and descriptive values such as the "Biologischer Arbeitsstoff-Referenzwert" (BAR) and Exposure Equivalents for Cancerous Substances (EKA), respectively. Moreover the combination of acceptance values and tolerance values derived by the Committee on Hazardous Substances (AGS) from exposure-risk-relations with the EKA allow the deduction of risk-related values too. The European Biological Limit Value (BLV) and the Biological Guidance Value are also important in the countries of the European Union. The results of a biological monitoring represent person-related data and therefore are subject to the rules on professional confidentiality that apply to physicians. PMID- 23444026 TI - [Health surveillance for workers exposed to beryllium and diagnostic procedures in beryllium-associated diseases]. PMID- 23444027 TI - [Biological role and clinical relevance of central and peripheral circadian clocks]. AB - In most species--from cyanobacteria to humans--genetically encoded circadian clocks have evolved to adapt behavioral and physiological processes to environmental changes brought about by the Earth's rotation. Clock disruption, e. g. by shift work, can lead to circadian misalignment, promoting the development of metabolic, immune and cognitive dysfunction. In mammals, a central circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus resets subordinate, but semi-independent cellular clocks in tissues such as liver, kidney, adrenal, and many brain areas. Peripheral clocks regulate various endocrine, metabolic and immune processes, whereas central oscillators modulate basic as well as higher brain functions. For the clinical practice it is of major importance to be aware of these physiological rhythms in order to correctly interpret laboratory data and other disease symptoms. Chronomedical therapies can reduce side effects and increase efficacy by optimizing the timing of treatment or directly affect disease state by restoring internal circadian synchrony. PMID- 23444028 TI - The metalloproteinase ADAMTS1: a comprehensive review of its role in tumorigenic and metastatic pathways. AB - As it was first characterized in 1997, the ADAMTS (A Disintegrin and Metalloprotease with ThromboSpondin motifs) metalloprotease family has been associated with many physiological and pathological conditions. Of the 19 proteases belonging to this family, considerable attention has been devoted to the role of its first member ADAMTS1 in cancer. Elevated ADAMTS1 promotes pro tumorigenic changes such as increased tumor cell proliferation, inhibited apoptosis and altered vascularization. Importantly, it facilitates significant peritumoral remodeling of the extracellular matrix environment to promote tumor progression and metastasis. However, discrepancy exists, as several studies also depict ADAMTS1 as a tumor suppressor. This article reviews the current understanding of ADAMTS1 regulation and the consequence of its dysregulation in primary cancer and ADAMTS1-mediated pathways of cancer progression and metastasis. PMID- 23444029 TI - FOP in China and Japan: an overview from domestic literatures. PMID- 23444030 TI - Finding a voice through 'The Tree of Life': a strength-based approach to mental health for refugee children and families in schools. AB - The Child and Family Refugee Service at the Tavistock Centre in London has run a series of 'Tree of Life' groups for both parents and children in schools. The groups were developed in response to a concern about the majority of psychological treatments, which focus predominantly on vulnerability factors in refugee populations, and the effect that this can have on those they are attempting to help. In addition, these are modelled on western assumptions, which do not adequately take account of culture. The Tree of Life groups have provided an alternative to traditional mental health services, which many refugee families find hard to access because of perceived stigma and lack of knowledge about what is on offer. The groups employed a strength-based narrative methodology, using the tree as a creative metaphor, which enabled parents and children to develop empowering stories about their lives, which were rooted in their cultural and social histories. From this secure base, participants were able to develop shared, culturally congruent solutions to their problems. The groups have been found to benefit parents and children alike, as well as the school communities in which they have taken place. PMID- 23444031 TI - No increased sperm DNA fragmentation index in semen containing human papillomavirus or herpesvirus. AB - It remains unknown whether human papillomaviruses (HPVs) or human herpesviruses (HHVs) in semen affect sperm DNA integrity. We investigated whether the presence of these viruses in semen was associated with an elevated sperm DNA fragmentation index. Semen from 76 sperm donors was examined by a PCR-based hybridization array that identifies all HHVs and 35 of the most common HPVs. Sperm DNA integrity was determined by the sperm chromatin structure assay. HPVs or HHVs, or both, were found in 57% of semen samples; however, sperm DNA fragmentation index was not increased in semen containing these viruses. PMID- 23444032 TI - Habituation to feedback delay restores degraded visuomotor adaptation by altering both sensory prediction error and the sensitivity of adaptation to the error. AB - Sensory prediction error, which is the difference between actual and predicted sensory consequences, is a driving force of motor learning. Thus, appropriate temporal associations between the actual sensory feedback signals and motor commands for predicting sensory consequences are crucial for the brain to calculate the sensory prediction error accurately. Indeed, it has been shown that artificially introduced delays in visual feedback degrade motor learning. However, our previous study has showed that degraded adaptation is alleviated by prior habituation to the delay. Here, we investigate how the motor learning system accomplishes this alleviation. After the subjects habituated reaching movements in either 0- or 200-ms delayed cursor, visual rotation of 10 degrees was imposed to the cursor with varying delay (0, 100, 200, or 300 ms) with each delay imposed in at least 1 out of 5-6 trials. Then, the aftereffect in the next trial was quantified to evaluate the adaptation response. After habituation to the 0-ms delayed cursor, the adaptation response was maximal when the visual feedback of the perturbation was provided with 0-ms delay and gradually decreased as the delay increased. On the other hand, habituation to the 200-ms delayed cursor alleviated the degraded adaptation response to the visual perturbation imposed during the 200-ms and longer delay (300 ms). However, habituation did not affect the adaptation response to the visual perturbation imposed during delays (0- and 100-ms delay) shorter than the habituated delay (200 ms). These results may be explained by assuming that habituation to the delayed feedback not only shifts the position of the hand predicted by motor command toward the delayed cursor positions, but also increases the degree to which the brain uses a certain amount of sensory prediction error to correct a motor command. PMID- 23444033 TI - Alignment of practice guidelines with targeted-therapy drug funding policies in Ontario. AB - BACKGROUND: We evaluated clinical practice guideline (cpg) recommendations from Cancer Care Ontario's Program in Evidence-Based Care (pebc) for molecularly targeted systemic treatments (tts) and subsequent funding decisions from the Ontario Ministry of Health and Long-Term Care. METHODS: We identified pebc cpgs on tt published before June 1, 2010, and extracted information regarding the key evidence cited in support of cpg recommendations and the effect size associated with each tt. Those variables were compared with mohltc funding decisions as of June 2011. RESULTS: From 23 guidelines related to 17 tts, we identified 43 recommendations, among which 38 (88%) endorsed tt use. Among all the recommendations, 38 (88%) were based on published key evidence, with 82% (31 of 38) being supported by meta-analyses or phase iii trials. For the 38 recommendations endorsing tts, funding was approved in 28 (74%; odds ratio related to cpg recommendation: 29.9; p = 0.003). We were unable to demonstrate that recommendations associated with statistically significant improvements in overall survival [os: 14 of 16 (88%) vs. 8 of 14 (57%); p = 0.10] or disease- (dfs) or progression-free survival [pfs: 16 of 21 (76%) vs. 3 of 5 (60%); p = 0.59] were more likely to be funded than those with no significant difference. Moreover, we did not observe significant associations between funding approvals and absolute improvements of 3 months or more in os [6 of 6 (100%) vs. 3 of 6 (50%), p = 0.18] or pfs [6 of 8 (75%) vs. 10 of 12 (83%), p = 1.00]. CONCLUSIONS: For use of tts, most recommendations in pebc cpgs are based on meta-analyses or phase iii data, and funding decisions were strongly associated with those recommendations. Our data suggest a trend toward increased rates of funding for therapies with statistically significant improvements in os. PMID- 23444035 TI - Interactions between new quinolone antibacterials and diagnostic drug containing manganese. AB - A diagnostic drug containing manganese chloride tetrahydrate as a major ingredient is available since 2006. It is used in magnetic resonance imaging as a negative contrast medium for magnetic resonance cholangiopancreatography of the gastrointestinal tract. However, there is no report regarding interaction between manganese and new quinolone antibacterials. We investigated the interactions between new quinolone antibacterials and a diagnostic drug containing manganese in vitro. We evaluated the rate of formation of chelate complex by reacting new quinolone antibacterials (levofloxacin, ofloxacin, ciprofloxacin) with a diagnostic drug containing manganese. The EC50 values of the formation of chelate complex for levofloxacin, ofloxacin, and ciprofloxacin were 5.14 +/- 0.14, 5.29 +/- 0.14, and 0.96 +/- 0.04 mM, respectively. The rates of formation of chelate complex by levofloxacin, ofloxacin, and ciprofloxacin in a reaction with the diagnostic drug were 17.0, 18.9, and 55.5 % in clinical condition, respectively. Our results suggest that a complex of each antibacterial and manganese was formed, with ciprofloxacin causing the strongest interaction. In addition, our findings indicate that the degree of interaction may be an important problem in clinical settings with concomitant administration of a new quinolone antibacterial and diagnostic drug containing manganese. PMID- 23444034 TI - Insertion mutants in Drosophila melanogaster Hsc20 halt larval growth and lead to reduced iron-sulfur cluster enzyme activities and impaired iron homeostasis. AB - Despite the prominence of iron-sulfur cluster (ISC) proteins in bioenergetics, intermediary metabolism, and redox regulation of cellular, mitochondrial, and nuclear processes, these proteins have been given scarce attention in Drosophila. Moreover, biosynthesis and delivery of ISCs to target proteins requires a highly regulated molecular network that spans different cellular compartments. The only Drosophila ISC biosynthetic protein studied to date is frataxin, in attempts to model Friedreich's ataxia, a disease arising from reduced expression of the human frataxin homologue. One of several proteins involved in ISC biogenesis is heat shock protein cognate 20 (Hsc20). Here we characterize two piggyBac insertion mutants in Drosophila Hsc20 that display larval growth arrest and deficiencies in aconitase and succinate dehydrogenase activities, but not in isocitrate dehydrogenase activity; phenotypes also observed with ubiquitous frataxin RNA interference. Furthermore, a disruption of iron homeostasis in the mutant flies was evidenced by an apparent reduction in induction of intestinal ferritin with ferric iron accumulating in a subcellular pattern reminiscent of mitochondria. These phenotypes were specific to intestinal cell types that regulate ferritin expression, but were notably absent in the iron cells where ferritin is constitutively expressed and apparently translated independently of iron regulatory protein 1A. Hsc20 mutant flies represent an independent tool to disrupt ISC biogenesis in vivo without using the RNA interference machinery. PMID- 23444036 TI - Canine lymphomas: association of classification type, disease stage, tumor subtype, mitotic rate, and treatment with survival. AB - Canine lymphoma is the neoplasm most often treated by chemotherapy, yet there are few data to correlate response to therapy with its different subtypes. This study is based on biopsy specimens from 992 dogs for which lymphoma was the clinical diagnosis. All cases were phenotyped by immunohistochemistry for CD3 and CD79alpha. Cases with histiocytic proliferation were evaluated immunohistochemically for CD18. Clonality was verified in 12 cases by polymerase chain reaction (PCR). Survival (event time) data and complete survival information (cause of death or time to last follow-up) were available on 456 dogs. Additional covariate information when available included size, age, sex, phenotype, stage and grade of lymphoma, mitotic index, and treatment protocol. Because of the many subtypes of B- and T-cell lymphoma, the cases were grouped into 7 diagnostic categories: (1) benign hyperplasia; (2) low-grade B-cell; (3) high-grade B- and T-cell; (4) low-grade T-cell; (5) centroblastic large B-cell of all mitotic grades (subdivided by clinical stage); (6) immunoblastic large B-cell of all mitotic grades, and (7) high-grade peripheral T-cell. Grouping was determined by histological grade (based on mitotic rate/400* field, with low grade 0-5, intermediate 6-10, and high-grade >10) and stage for survival function estimation. No association with survival was found for size (based on breed of dog) or sex. All diagnostic categories of indolent or low-grade type had low mitotic rates, whereas those with clinically high grades had high mitotic rates. The diagnostic category with the most cases was centroblastic large B-cell lymphoma. Compared with dogs in this largest represented group of lymphomas, dogs with high-grade lymphomas had significantly higher mortality rates, and dogs with low-grade T-cell lymphomas had significantly lower mortality rates. Treatments for high-, intermediate-, and low-grade lymphomas were divided into 4 groups: absence of treatment, chemotherapy with or without hydroxydaunorubicin, and only prednisone. Dogs with low-grade T-cell (T-zone) lymphomas had the longest median survival (622 days), whereas the shortest median survival was in dogs with T-cell high-grade (peripheral T-cell) subtype (162 days). The dogs with centroblastic large B-cell lymphomas had a median survival of 127 days with low stage, 221 days with intermediate stage, and 215 days with advanced stage. Dogs with T-zone lymphoma were probably diagnosed in later stages of disease because of the lack of signs associated with progression. As with human lymphomas, a histological diagnosis with immunophenotyping is a minimal requirement for diagnosis of a specific subtype. PMID- 23444037 TI - A new nematicidal compound produced by Streptomyces albogriseolus HA10002. AB - Strain HA10002 was isolated from mangrove sediment collected from Dongzhaigang Mangrove Reserve in Hainan, China. It was selected with potent nematicidal activity and was identified as Streptomyces albogriseolus. By bioassay-guided fractionation, a new active component A22-1(S1) against root-knot nematodes was separated from its fermentation broth. On the basis of spectroscopic analyses and comparison with the data from correlative literature, the structure of S1 was established to be 6'-methyl-fungichromin, named as fungichromin B in this paper. The LD50 values of fungichromin B to the 2-stage juveniles of Meloidogyne incognita and Meloidogyne javanica were 7.64 and 7.83 MUg/ml, respectively. Further examination demonstrated fungichromin B still showed a wide antifungal spectrum, as with fungichromin. PMID- 23444038 TI - Glaciecola aquimarina sp. nov., a gammaproteobacterium isolated from coastal seawater. AB - A Gram-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, GGW-M5(T), was isolated from seawater on the southern coast in Korea, and its taxonomic position was investigated by using a polyphasic approach. Strain GGW M5(T) grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain GGW-M5(T) belonged to the genus Glaciecola, joining the cluster comprising the type strains of G. agarilytica, G. arctica, G. chathamensis, G. mesophila, G. polaris and G. psychrophila, with which it exhibited 16S rRNA gene sequence similarity values of 95.9-96.7 %. Strain GGW M5(T) exhibited sequence similarity values of 93.2-94.8 % to the type strains of the other Glaciecola species. Strain GGW-M5(T) contained Q-8 as the predominant ubiquinone and C16:1 omega7c and/or iso-C15:0 2-OH, C16:0 and C14:0 2-OH as the major fatty acids. Major polar lipids were phosphatidylglycerol, phosphatidylethanolamine and diphosphatidylglycerol. The DNA G+C content was 42.4 mol%. Differential phenotypic properties, together with the phylogenetic distinctiveness, demonstrated that strain GGW-M5(T) could be distinguished from other Glaciecola species. On the basis of the data presented, strain GGW-M5(T) is considered to represent a novel species of the genus Glaciecola, for which the name Glaciecola aquimarina sp. nov. is proposed. The type strain is GGW-M5(T) (=KCTC 32108(T) = CCUG 62918(T)). PMID- 23444039 TI - Genotypic and phenotypic diversity of Pediococcus pentosaceus strains isolated from food matrices and characterisation of the penocin operon. AB - Lactic acid bacteria (LAB) are widely used in the food industry. Pediococcus spp. belong to the LAB group and include several species that are essential for the quality of fermented food. Pediococcus pentosaceus is the species that is most frequently isolated from fermented food and beverages but its uncontrolled growth during food fermentation processes can contribute to undesired flavours. Hence, the characterisation of these bacteria at the strain level is of great importance for the quality of fermented products. Despite their importance, misidentification at the species level is common for members of the genus Pediococcus. To clarify the taxonomic relationships among strains, a multilocus sequencing approach was developed for the characterisation of a collection of 29 field strains, 1 type strain and 1 reference strain of P. pentosaceus isolated from food. These strains were also tested for several phenotypic properties of technological interest and for the production of bacteriocins. The chromosomal operon involved in the synthesis of the bacteriocin penocin was also investigated. The present study enabled a good genomic characterisation, identifying 17 sequence types, with an overview of phenotypic characteristics related to different technological abilities, and also provides a thorough characterisation of the operon involved in penocin production. PMID- 23444040 TI - Eugenol alters the integrity of cell membrane and acts against the nosocomial pathogen Proteus mirabilis. AB - Eugenol, a member of the phenylpropanoids class of chemical compounds, is a clear to pale yellow oily liquid extracted from certain essential oils especially from clove oil, nutmeg, cinnamon, and bay leaf. The antibacterial activity of eugenol and its mechanism of bactericidal action against Proteus mirabilis were evaluated. Treatment with eugenol at their minimum inhibitory concentration [0.125 % (v/v)] and minimum bactericidal concentration [0.25 % (v/v)] reduced the viability and resulted in complete inhibition of P. mirabilis. A strong bactericidal effect on P. mirabilis was also evident, as eugenol inactivated the bacterial population within 30 min exposure. Chemo-attractant property and the observance of highest antibacterial activity at alkaline pH suggest that eugenol can work more effectively when given in vivo. Eugenol inhibits the virulence factors produced by P. mirabilis as observed by swimming motility, swarming behavior and urease activity. It interacts with cellular membrane of P. mirabilis and makes it highly permeable, forming nonspecific pores on plasma membrane, which in turn directs the release of 260 nm absorbing materials and uptake of more crystal violet from the medium into the cells. SDS-polyacrylamide gel, scanning electron microscopy and Fourier transform infrared analysis further proves the disruptive action of eugenol on the plasma membrane of P. mirabilis. The findings reveal that eugenol shows an excellent bactericidal activity against P. mirabilis by altering the integrity of cell membrane. PMID- 23444041 TI - Inhibitory effects of oleanane-type triterpenes and saponins from the stem bark of Kalopanax pictus on LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells. AB - Kalopanax pictus (Araliaceae) is a deciduous tree distributed in Korea, Japan, and China. The stem bark of K. pictus has been functionally used as a traditional crude drug for the treatment of various inflammatory diseases. In the present study, we describe the inhibitory effects of oleanane-type triterpenes and saponins isolated from the stem bark of K. pictus on production of pro inflammatory cytokines in LPS-stimulated bone marrow-derived dendritic cells. Of the compounds tested, 16,23,29-trihydroxy-3-oxo-olean-12-en-28-oic acid (1), 4,23,29-trihydroxy-3,4-seco-olean-12-en-3-oate-28-oic acid (2), 3beta,6beta,23 trihydroxyolean-12-en-28-oic acid 28-O-beta-D-glucopyranoside (3), nipponogenin E (6), 3beta,6beta,23-trihydroxyolean-12-en-28-oic acid (7), and caulophyllogenin (19) significantly inhibited the production of IL-12 p40 and IL-6 with IC50 values ranging from 3.3 to 9.1 MUM. Compounds 2, 3, 7, and 19 significantly suppressed the secretion of TNF-alpha with IC50 ranging from 8.8 to 20.0 MUM. These data provide scientific support for the use of K. pictus stem bark and its triterpene and saponin components in the inhibition of pro-inflammatory cytokine secretion, including IL-12 p40, IL-6, and TNF-alpha, and for prevention and treatment of inflammatory diseases. PMID- 23444042 TI - miR-7641 modulates the expression of CXCL1 during endothelial differentiation derived from human embryonic stem cells. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that negatively regulate gene expression through binding to 3' untranslated region. We identified and characterized the novel miRNA, miR-7641, in human mesenchymal stem cells. The expression of miR-7641 was downregulated during differentiation from human embryonic stem cells to endothelial cells. The CXCL1, a member of the CXC chemokine family, is known as promoting neovascularization by binding G-protein coupled receptors and is related to endothelial cells biogenesis such as angiogenesis, and it was predicted as target gene of miR-7641 by computerized analysis and the luciferase reporter assay. The miR-7641 significantly suppressed CXCL1 of transcriptional and post-translational levels. These data suggest that miR-7641 might be related with differentiation of human endothelial cells. PMID- 23444043 TI - Phenolic constituents from Parakmeria yunnanensis and their anti-HIV-1 activity. AB - Three new phenolic compounds, yunnanensins A-C (1-3), together with fourteen known ones (4-17), were isolated from the leaves and stems of Parakmeria yunnanensis. The structures of new compounds were established on the basis of extensive spectroscopic analyses. Several compounds showed weak anti-HIV-1 activity. PMID- 23444045 TI - Association between a functional variant at PTGS2 gene 3'UTR and its mRNA expression in lymphoblastoid cell lines. AB - PTGS2 genetic 3' untranslated region (3'UTR) miRNA binding sites variants are significantly associated with cancer risk; however, the roles of genetic variants in PTGS2 gene 3'UTR and post-transcriptional regulation have not been elucidated. We report that rs689470 and rs5275 in the PTGS2 3'UTR have potential miRNA binding sites by using bioinformatics analysis. However, only the rs689470 was significantly associated with PTGS2 mRNA expression in lymphoblastoid cell lines (P = 0.026), but not for rs5275 (P = 0.626). rs689470 might be putative variants mediating the post-transcriptional regulation of target PTGS2 gene. Better understanding of how 3'UTR variants regulate PTGS2 activity will pave the way to targeting the PTGS2 pathway in cancer therapy. PMID- 23444044 TI - Probing the role of interfacial waters in protein-DNA recognition using a hybrid implicit/explicit solvation model. AB - When proteins bind to their DNA target sites, ordered water molecules are often present at the protein-DNA interface bridging protein and DNA through hydrogen bonds. What is the role of these ordered interfacial waters? Are they important determinants of the specificity of DNA sequence recognition, or do they act in binding in a primarily nonspecific manner, by improving packing of the interface, shielding unfavorable electrostatic interactions, and solvating unsatisfied polar groups that are inaccessible to bulk solvent? When modeling details of structure and binding preferences, can fully implicit solvent models be fruitfully applied to protein-DNA interfaces, or must the individualistic properties of these interfacial waters be accounted for? To address these questions, we have developed a hybrid implicit/explicit solvation model that specifically accounts for the locations and orientations of small numbers of DNA-bound water molecules, while treating the majority of the solvent implicitly. Comparing the performance of this model with that of its fully implicit counterpart, we find that explicit treatment of interfacial waters results in a modest but significant improvement in protein side-chain placement and DNA sequence recovery. Base-by-base comparison of the performance of the two models highlights DNA sequence positions whose recognition may be dependent on interfacial water. Our study offers large scale statistical evidence for the role of ordered water for protein-DNA recognition, together with detailed examination of several well-characterized systems. In addition, our approach provides a template for modeling explicit water molecules at interfaces that should be extensible to other systems. PMID- 23444046 TI - Contamination of amniotic fluid with maternal balanced t(11;22) translocation cells. PMID- 23444047 TI - Src kinases mediate VEGFR2 transactivation by the osteostatin domain of PTHrP to modulate osteoblastic function. AB - Parathyroid hormone-related protein (PTHrP) stimulates osteoblastic function through its N- and C-terminal domains. Since the osteogenic action of the latter domain appears to depend at least in part on its interaction with the vascular endothelial growth factor (VEGF) system, we aimed to explore the putative mechanism underlying this interaction in osteoblasts. Using native conditions for protein extraction and immunoblotting, we found that both PTHrP (107-139) and the shorter PTHrP (107-111) peptide (known as osteostatin), at 100 nM, promoted the appearance of a VEGF receptor (VEGFR) 2 protein band of apparent Mr. wt. 230 kDa, which likely represents its activation by dimer formation, in mouse osteoblastic MC3T3-E1 cells. Moreover, osteostatin (100 nM) maximally increased VEGFR2 phosphorylation at Tyr-1059 within 5-10 min in both MC3T3-E1 and rat osteoblastic osteosarcoma UMR-106 cells. This phosphorylation elicited by osteostatin appears to be VEGF-independent, but prevented by the VEGFR2 activation inhibitor SU1498 and also by the Src kinase inhibitors SU6656 and PP1. Furthermore, osteostatin induced phosphorylation of Src, extracellular signal-regulated kinase (ERK) and Akt with a similar time course to that observed for VEGFR2 activation in these osteoblastic cells. This osteostatin-dependent induction of ERK and Akt activation was abrogated by SU6656. Up-regulation of VEGF and osteoprotegerin gene expression as well as the pro-survival effect induced by osteostatin treatment were all prevented by both SU1498 and SU6656 in these osteoblastic cells. Collectively, these findings demonstrate that the osteostatin domain of C terminal PTHrP phosphorylates VEGFR2 through Src activation, which represents a mechanism for modulating osteoblastic function. PMID- 23444048 TI - Association of pre-diagnosis physical activity with recurrence and mortality among women with breast cancer. AB - Evidence is emerging that physical activity (PA) may improve overall survival after breast cancer diagnosis. However, the effect of PA on breast cancer recurrence and on cause-specific mortality is less investigated. We assessed the association of pre-diagnosis PA with recurrence, overall and cause-specific survival in a prospective cohort study in Germany including 3,393 non-metastatic breast cancer patients aged 50-74 years. Cox proportional hazards models were calculated adjusted for relevant prognostic factors. During a median follow-up of 5.6 years, 367 patients deceased. Overall mortality was significantly inversely associated with pre-diagnosis recreational PA. However, this effect was mainly attributed to deaths due to causes other than breast cancer. Multiple fractional polynomial analyses yielded a nonlinear association with markedly increased non breast cancer mortality for women who did not engage in any sports or cycling in the years before the breast cancer diagnosis with a hazard ratio (HR, none vs. any) of 1.71, 95% confidence interval (1.16, 2.52). There were no further risk reductions with increasing activity levels. The association with breast cancer specific mortality showed a similar dose-response but was far less pronounced with HR (none vs. any) = 1.22 (0.91, 1.64). In contrast, regarding cancer recurrence the dose-response was linear. However, this association was restricted to estrogen/progesterone receptor-negative (ER-/PR-) cases (p interaction = 0.033) with HR (highest vs. no recreational PA) = 0.53 (0.24, 1.16), p trend = 0.0045. Thus, breast cancer patients with a physically inactive lifestyle pre diagnosis may decease prematurely irrespective of their cancer prognosis. Higher levels of exercise may reduce the risk of recurrence of ER-/PR- breast tumors. PMID- 23444049 TI - Chemokines in innate and adaptive granuloma formation. AB - Granulomas are cellular inflammations that vary widely in histologic appearance depending upon the inciting agent and immunologic status of the responding host. Despite their heterogeneity, granulomas are at their core an ancient innate sequestration response characterized by the accumulation of mononuclear phagocytes. In fact, this innate cellular response was first observed by Metchnikov in simple invertebrates. Among higher vertebrates, environmental pressures have resulted in the evolution of more sophisticated adaptive immune responses which can be superimposed upon and modify the character of granulomatous inflammation. Compared to immune responses that rapidly neutralize and eliminate infectious agents, the granuloma represents a less desirable "fall back" response which still has value to the host but can be co-opted by certain infectious agents and contribute to bystander organ damage. Understanding granulomas requires an analysis of the complex interplay of innate and adaptive molecular signals that govern the focal accumulation and activity of their cellular components. Among these signals, small molecular weight chemoattractant proteins known as chemokines are potentially important contributors as they participate in both directing leukocyte migration and function. This tract will discuss the contribution of chemokines to the development of innate and adaptive granuloma formation, as well as describe their relationship to more recently evolved cytokines generated during adaptive immune responses. PMID- 23444050 TI - Single-photon ionization of organic molecules beyond 10 kDa. AB - The volatilization and soft ionization of complex neutral macromolecules at low energies has remained an outstanding challenge for several decades. Most volatilization techniques in mass spectrometry produce ions already in the source and most of them lead to particle velocities in excess of several hundred meters per second. For many macromolecules, post-ionization is inefficient since electronic or optical excitations can be followed by competing non-ionizing internal conversion, electron recapture, or fragmentation processes. Here, we explore the laser-assisted volatilization of neutral perfluoroalkyl functionalized tetraphenylporphyrins as well as their single-photon ionization using vacuum ultraviolet (VUV) light at 157 nm. A systematic investigation of the ionization curves allows us to determine the molecular velocity distribution and ionization cross sections. We demonstrate the detection of single photon ionized intact organic molecules in excess of 10 kDa from a slow molecular beam. PMID- 23444051 TI - Low mass MS/MS fragments of protonated amino acids used for distinction of their 13C-isotopomers in metabolic studies. AB - Glu, Gln, Pro, and Ala are the main amino acids involved in ammonia detoxification in mosquitoes. In order to develop a tandem mass spectrometry method (MS(2)) to monitor each carbon of the above isotopically-labeled (13)C amino acids for metabolic studies, the compositions and origins of atoms in fragments of the protonated amino acid should be first elucidated. Thus, various electrospray (ESI)-based MS(2) tools were employed to study the fragmentation of these unlabeled and isotopically-labeled amino acids and better understand their dissociation pathways. A broad range of fragments, including previously undescribed low m/z fragments was revealed. The formulae of the fragments (from m/z 130 down to m/z 27) were confirmed by their accurate masses. The structures and conformations of the larger fragments of Glu were also explored by ion mobility mass spectrometry (IM-MS) and gas-phase hydrogen/deuterium exchange (HDX) experiments. It was found that some low m/z fragments (m/z 27-30) are common to Glu, Gln, Pro, and Ala. The origins of carbons in these small fragments are discussed and additional collision induced dissociation (CID) MS(2) fragmentation pathways are proposed for them. It was also found that small fragments (<=m/z 84) of protonated, methylated Glu, and methylated Gln are the same as those of the underivatized Glu and Gln. Taken together, the new approach of utilizing low m/z fragments can be applied to distinguish, identify, and quantify (13)C-amino acids labeled at various positions, either in the backbone or side chain. PMID- 23444052 TI - Impact of pre-treatment prostate tissue androgen content on the prediction of castration-resistant prostate cancer development in patients treated with primary androgen deprivation therapy. AB - Great advances in tissue androgen analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) have made it possible to evaluate the tissue androgen content from a single needle prostate biopsy specimen. In this study, we investigated if pre-treatment androgen content in prostate biopsy specimens could predict their response to primary androgen deprivation therapy (ADT) and future castration-resistant prostate cancer (CRPC). One-hundred and sixty-five prostate cancer patients who received primary ADT were enrolled. They had received multiple core prostate needle biopsy at diagnosis, and an additional one needle biopsy specimen was obtained for tissue androgen determination using LC-MS/MS. The patients' prostate specific antigen (PSA) values were periodically followed during the treatment and patients were determined to have CRPC when their PSA value increased continuously to 25% above the nadir and a 2.0 ng/mL increase. A significant correlation was found between PSA value decline velocity (PSA half time) after ADT and pre-ADT tissue androgen content. Twenty-three patients were determined to have CRPC. These CRPC patients had a significantly high concentration of tissue T (p < 0.01) and low concentration of tissue 5alpha dihydrotestosterone (DHT) (p < 0.01), resulting in a higher tissue T/DHT ratio (p < 0.001). A multivariate Cox proportional hazard model revealed the pre-ADT tissue T/DHT ratio and Gleason score as independent predictors for CRPC development. By using the two statistically significant variables, the relative risk of CRPC development could be calculated. The results of this study suggest that the evaluation of prostate androgen content in a single needle biopsy specimen may be useful to predict future CRPC development after primary ADT. Further studies are required for the clinical application of T/DHT ratio evaluation. PMID- 23444053 TI - Neural Correlates of Switching Attentional Focus during Finger Movements: An fMRI Study. AB - Research on motor-related attentional foci suggests that switching from an internal to an external focus of attention has advantageous effects on motor performance whereas switching from an external to an internal focus has disadvantageous effects. We used functional magnetic resonance imaging to investigate the neural correlates of switching the focus of attention. Two experimental groups were trained to apply one focus direction - internal or external - on a previously learned finger tapping sequence. Participants with an internal focus training were instructed to attend to their moving fingers; those with an external focus training were instructed to attend to the response buttons. In the first half of the experiment, participants performed with their trained focus, in the second half, they were unexpectedly asked to switch to the untrained attentional focus. Our data showed that the switch from a trained internal to an unfamiliar external focus of attention elicited increased activation of the left lateral premotor cortex (PMC). We propose that this activation can be linked to the role of the PMC in action planning - probably indicating a facilitation effect on selectional motor processes. Switching from a trained external to an unfamiliar internal focus of attention revealed enhanced activation of the left primary somatosensory cortex and intraparietal lobule. We interpret these modulations as a result of the amplifying influence of afferent information on motor processing when asked to attend internally in a motor task after being trained with an external focus. PMID- 23444055 TI - Beyond the traditional definition of breakthrough pain: an observational study. AB - INTRODUCTION: Breakthrough pain (BTP) is traditionally defined as a transitory pain flare in opioid-treated patients with chronic background pain. This definition has, however, been challenged in recent years. This study aimed to analyze BTP prevalence in different pain conditions. METHODS: This was a prospective, non-interventional, observational study conducted from June to September 2011 in two Italian pain treatment reference centres. Consecutive patients aged >18 years with oncological or non-oncological pain were eligible for this study; background pain was acute/ subacute (<3 months) or chronic (>3 months). The characteristics of pain were evaluated by means of a structured interview by physicians, and patients were asked to complete a dedicated clinical study form. The following outcomes were assessed: chronic pain duration (in patients with chronic pain), BTP prevalence, and number and severity of daily BTP episodes. All outcomes were assessed in four populations of patients with: (a) chronic oncological pain; (b) chronic non-oncological pain; (c) non-chronic oncological pain; (d) non-chronic non-oncological pain. The correlation between BTP and gender was also investigated. RESULTS: Of 1,270 patients with chronic pain, 1,086 had non-oncological pain (85.5%). Most patients (68.6%) with non oncological pain were female (P = 0.001). Pain duration was significantly longer in non-oncological pain versus oncological pain groups (P = 0.002). BTP prevalence was lower in non-oncological patients (P < 0.001). No differences were reported in terms of number and severity of daily BTP episodes. BTP was more frequent in females with non-oncological pain (P = 0.04). Females had a significantly higher pain severity (P = 0.02) than males. CONCLUSION: BTP is frequently reported in patients who do not have BTP according to the traditional definition. BTP frequency and severity is similar in oncological and non oncological pain. PMID- 23444054 TI - Crystallographic and mutational studies on the tRNA thiouridine synthetase TtuA. AB - In thermophilic bacteria, specific 2-thiolation occurs on the conserved ribothymidine at position 54 (T54) in tRNAs, which is necessary for survival at high temperatures. T54 2-thiolation is achieved by the tRNA thiouridine synthetase TtuA and sulfur-carrier proteins. TtuA has five conserved CXXC/H motifs and the signature PP motif, and belongs to the TtcA family of tRNA 2 thiolation enzymes, for which there is currently no structural information. In this study, we determined the crystal structure of a TtuA homolog from the hyperthermophilic archeon Pyrococcus horikoshii at 2.1 A resolution. The P. horikoshii TtuA forms a homodimer, and each subunit contains a catalytic domain and unique N- and C-terminal zinc fingers. The catalytic domain has much higher structural similarity to that of another tRNA modification enzyme, TilS (tRNA(Ile)2 lysidine synthetase), than to the other type of tRNA 2-thiolation enzyme, MnmA. Three conserved cysteine residues are clustered in the putative catalytic site, which is not present in TilS. An in vivo mutational analysis in the bacterium Thermus thermophilus demonstrated that the three conserved cysteine residues and the putative ATP-binding residues in the catalytic domain are important for the TtuA activity. A positively charged surface that includes the catalytic site and the two zinc fingers is likely to provide the tRNA-binding site. PMID- 23444056 TI - Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: a case control study of genetic factors. AB - Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis. PMID- 23444060 TI - State of the science: the relationship between nurse staffing and patient outcomes. AB - Over a decade of research on the relationship between nurse staffing and patient outcomes has demonstrated the important role of nurses in the provision of high quality, safe care, yet currently, no evidence-based nurse staffing guidelines exist. A systematic review of reviews was conducted to explore reasons why this is the case and recommend directions for future research to improve upon this gap. Authors of the 29 included reviews reported variability in methods and measurement approaches, lack of incorporation of nurse processes and system factors that potentially affect relationships among variables, and overall inconsistencies in results across primary studies. We propose use of an Integrated Framework for a Systems Approach to Nurse Staffing Research to inform the development of applicable conceptual models. Future studies that use a systems approach and focus on establishing causal relationships among variables will potentially strengthen the evidence and advance the science in this area. PMID- 23444059 TI - Comparison of HPV DNA testing in cervical exfoliated cells and tissue biopsies among HIV-positive women in Kenya. AB - HIV-positive women are infected with human papillomavirus (HPV) (especially with multiple types), and develop cervical intraepithelial neoplasia (CIN) and cervical cancer more frequently than HIV-negative women. We compared HPV DNA prevalence obtained using a GP5+/6+ PCR assay in cervical exfoliated cells to that in biopsies among 468 HIV-positive women from Nairobi, Kenya. HPV prevalence was higher in cells than biopsies and the difference was greatest in 94 women with a combination normal cytology/normal biopsy (prevalence ratio, PR = 3.7; 95% confidence interval, CI: 2.4-5.7). PR diminished with the increase in lesion severity (PR in 58 women with high-grade squamous intraepithelial lesions (HSIL)/CIN2-3 = 1.1; 95% CI: 1.0-1.2). When HPV-positive, cells contained 2.0- to 4.6-fold more multiple infections than biopsies. Complete or partial agreement between cells and biopsies in the detection of individual HPV types was found in 91% of double HPV-positive pairs. The attribution of CIN2/3 to HPV16 and/or 18 would decrease from 37.6%, when the presence of these types in either cells or biopsies was counted, to 20.2% when it was based on the presence of HPV16 and/or 18 (and no other types) in biopsies. In conclusion, testing HPV on biopsies instead of cells results in decreased detection but not elimination of multiple infections in HIV-positive women. The proportion of CIN2/3 attributable to HPV16 and/or 18 among HIV-positive women, which already appeared to be lower than that in HIV-negative, would then further decrease. The meaning of HPV detection in cells and random biopsy from HIV-positive women with no cervical abnormalities remains unclear. PMID- 23444061 TI - The role of hair follicle nestin-expressing stem cells during whisker sensory nerve growth in long-term 3D culture. AB - We have previously reported that nestin-expressing hair follicle stem cells can differentiate into neurons, Schwann cells, and other cell types. In the present study, vibrissa hair follicles, including their sensory nerve stump, were excised from transgenic mice in which the nestin promoter drives green fluorescent protein (ND-GFP mice), and were placed in 3D histoculture supported by Gelfoam(r). beta-III tubulin-positive fibers, consisting of ND-GFP-expressing cells, extended up to 500 um from the whisker nerve stump in histoculture. The growing fibers had growth cones on their tips expressing F-actin. These findings indicate that beta-III tubulin-positive fibers elongating from the whisker follicle sensory nerve stump were growing axons. The growing whisker sensory nerve was highly enriched in ND-GFP cells which appeared to play a major role in its elongation and interaction with other nerves in 3D culture, including the sciatic nerve, the trigeminal nerve, and the trigeminal nerve ganglion. The results of the present report suggest a major function of the nestin-expressing stem cells in the hair follicle is for growth of the follicle sensory nerve. PMID- 23444062 TI - Response to the letter to the editor on congenital spigelian hernia and undescended testis. PMID- 23444063 TI - Evaluation of mangled extremity severity score (MESS) as a predictor of lower limb amputation in children with trauma. PMID- 23444064 TI - Conservative management of blunt pancreatic trauma in children: a single center experience. AB - INTRODUCTION: Blunt trauma of the pancreas represents a significant part of abdomen trauma in children with an incidence estimated at around 10%. If the conservative management is widely accepted concerning the stages I and II, it remains controversial concerning stages III and IV. The aim of our study was to perform a descriptive analysis of the nonoperative management, with a focus on the occurrence of pseudocysts. MATERIALS AND METHODS: The charts of the patients treated in our center for pancreatic trauma from 1990 to 2010 have been reviewed. It was defined by an initial lipase greater than three times the norm and an abnormal computed tomography scan. RESULTS: A total of 36 patients were included, with 26 boys (72%) and 10 girls (28%) with an average age of 8.7 years. The trauma was isolated in 13 cases (36.1%) and in 23 cases, there were other associated lesions (mainly liver [n = 9] and spleen [n = 5]). Pancreatic injuries were graded as follows: I (n = 21), II (n = 2), III (n = 7), and IV (n = 6). Pseudocysts occurred in 11 patients (30.5%) mainly in grades III (n = 3) and IV (n = 7), with an average delay of 17 days. Initial management of pseudocysts was conservative in six patients (54.6%), whereas five patients required mini invasive procedures. CONCLUSION: Nonoperative management remains a safe way to treat pancreatic injuries despite an average 30% rate of pseudocyst (PC) appearance. It allows a reduction in the number of children who required procedures to less than half of the patients where PC occurred. Furthermore, these procedures were exclusively mini-invasive. PMID- 23444065 TI - Malignant neuroendocrine tumors: incidence and outcomes in pediatric patients. AB - INTRODUCTION: Malignant neuroendocrine tumors (NETs) are rare solid tumors infrequently seen in children. This study examines current incidence trends and outcomes for children with NETs. MATERIALS AND METHODS: The Surveillance Epidemiology and End Results registry was examined for patients between birth and 19 years of age between 1973 and 2005 with NETs. RESULTS: Overall, 481 patients were identified with malignant NETs. Tumors were classified as malignant carcinoid (n = 189, 39%), central nervous system tumors (n = 127, 26%), medullary thyroid carcinoma (n = 88, 18%), neuroendocrine carcinoma (n = 50, 10%), pheochromocytoma (n = 17, 3.5%), and paraganglioma (n = 7, 1.5%). Children less than 5 years of age had worse 5-year survival ( < 50 vs. > 76% if older, p = 0.009). Blacks had lower 5-year survival compared with whites (61 vs. 81%, p = 0.001). Tumor locations with favorable prognosis included the appendix, lung, and thyroid ( > 95% 5-year survival), whereas soft tissue and ovary location were associated with poor survival (p < 0.001). In multivariate analysis, distant disease at diagnosis (odds ratio [OR] 14.9; 95% confidence interval [CI], 6.9 to 32.1) and black race (OR 3.3; 95% CI, 1.4 to 7.4) were independent predictors of death. CONCLUSION: Whites have the highest incidence of pediatric NETs. Colon/rectum, appendix, or thyroid tumor location portends favorable prognosis. Black children and those less than 5 years of age had poorer prognosis. PMID- 23444066 TI - Are routine dilatations necessary post pull-through surgery for Hirschsprung disease? AB - INTRODUCTION: We aim to compare the anastomotic stricture and enterocolitis rates between groups who either had or did not have anal dilatations (AD or NAD) prescribed routinely post pull-through surgery for Hirschsprung disease (HD); by this means, we will evaluate the benefit of routine dilatations. METHODS: A retrospective review of the records of all children operated on for HD between 1997 and 2010 was performed. Associated Down syndrome and total colonic aganglionosis were excluded. Two cohorts were identified; those who had anal dilatation prescribed routinely (AD) and those who did not (NAD). In the latter group, if an anastomotic stricture was subsequently diagnosed, anal dilatations were initiated. The anastomotic stricture and enterocolitis rates between groups were compared. Significance was set at p < 0.05. RESULTS: There were 73 children that met the inclusion criteria (30 AD and 43 NAD). The NAD group had the longer mean follow-up period of 91 versus 59 months (p = 0.026); however, follow-up duration was unrelated to the anastomotic stricture rates (p = 0.575) and enterocolitis rates (p = 0.150). The anastomotic stricture rates were 13% (n = 4) versus 14% (n = 6) (p = 1.000) for the AD and NAD groups, respectively (relative risk [95% confidence interval] RR [95% CI], 0.95 [0.29 to 3.09]; p = 0.94). The mean duration between surgery and stricture occurrence was 348 versus 74 days for the AD and NAD groups, respectively. The enterocolitis rates were 23% (n = 7) versus 28% (n = 12) (p = 0.788) for the AD and NAD groups, respectively (RR [95% CI], 0.84 [0.37 to 1.87]; p = 0.66). CONCLUSION: We have not shown a reduced risk of developing anastomotic strictures or enterocolitis if anal dilatations are prescribed routinely. However, when routine dilatations were prescribed, predominantly late onset strictures of perhaps a different etiology occurred. PMID- 23444067 TI - Current status of laparoscopic appendectomy in children: a nation wide survey in Germany. AB - INTRODUCTION: Management of appendicitis in children has changed remarkably over the last decade. The proven benefits of laparoscopic appendectomy (LA) over the open operation have made LA increasingly popular for pediatric patients. To date, no national clinical practice guideline is available for pediatric LA in Germany and the operation is not standardized. Thus, the aim of our study was to evaluate the current status of pediatric LA in Germany. MATERIALS AND METHODS: An internet based survey was conducted on pediatric LA among all 98 registered pediatric surgical units in Germany, comprising 22 questions with regard to utilization and subjective appraisal of LA, technical standards, perioperative treatment, and training aspects. RESULTS: The survey was completed by 71 of the 98 units (72%). Technical infrastructure for LA was provided in all units, but only in 79% of the units was LA, the standard approach for appendectomy. Overall quality of LA was rated better compared with open appendectomy by 52% units, equivalent by 38% and worse by 3%. The three-port technique was used by 90% of the units; 10% used a single-port approach. Dissection of the mesoappendix was done with bipolar coagulation in 55%, monopolar coagulation in 24%, harmonic knife in 6%, and endostaplers in 11% of the units. Closure of the appendiceal stump was performed using endoloops in 57%, ligations in 3%, endostaplers in 39%, and harmonic knife in 1%. Removal of the appendix was done through the port by 79%, using a retrieval bag by 18%, whereas in 3% it was removed directly through laparotomy. In case of appendiceal perforation, an intra-abdominal drain was placed in 65%. Perioperative antibiotic treatment for nonperforated appendicitis was given as a single shot in 33% of the units, for 24 hours in 17%, for 3 days in 39%, and for 5 to 7 days in 11%. LA was performed by a trainee under supervision in 87%, by a board approved pediatric surgeon in 2%, by an attending pediatric surgeon in 7%, and by the surgeon-in-chief in 4% of the units. For 93% of the sample, LA was an essential part of pediatric surgical training. CONCLUSION: LA is the favored surgical method for pediatric appendectomy in Germany. However, technical details, perioperative therapy and implementation into training programs remain inconsistent. An effort has to be made to establish national clinical practice guidelines to achieve standardization of LA. PMID- 23444068 TI - Systematic review of level 1 evidence for laparoscopic pediatric surgery: do our procedures comply with the requirements of evidence-based medicine? AB - INTRODUCTION: Laparoscopic techniques have evolved quickly in recent years and are regarded as standard procedures in pediatric surgery today. However, most studies comparing laparoscopic operations with the corresponding open procedure do not reach a high level of evidence according to the criteria of the Oxford Centre for Evidence-Based Medicine. For evidence Level 1a, a meta-analysis (MA) of different randomized controlled trials (RCTs) is required. For evidence Level 1b, at least one RCT is required. The aim of our study was to evaluate the availability of Level 1 studies comparing laparoscopic procedures with the corresponding open operation in pediatric surgery. MATERIALS AND METHODS: Systematic review of clinical Level 1 studies using PubMed. All MA and RCT were identified and individually reviewed. Only studies comparing pediatric laparoscopic procedures with the corresponding open operation were included. RCTs included in MA were only individually analyzed if they focused on additional endpoints. Endpoints of the study were advantages and disadvantages of laparoscopy compared with the open operation. RESULTS: A total of 20 manuscripts met the inclusion criteria (9 MA and 11 RCT). Studies providing evidence Level 1a were identified for five types of laparoscopic procedures (laparoscopic appendectomy, inguinal hernia repair, orchidopexy, pyloromyotomy, and varicocelectomy). Studies providing evidence Level 1b were identified for two types of laparoscopic procedures (fundoplication and pyeloplasty). The advantages of laparoscopy were less wound infections, ileus and postoperative pain (appendectomy), less retching (fundoplication), lower incidence of metachronous inguinal hernia, shorter hospital stay (appendectomy, orchiopexy, and pyeloplasty), and shorter time to full feeds (pyloromyotomy). CONCLUSION: Studies providing evidence Level 1 are only available for seven laparoscopic procedures in pediatric surgery. Effort has to be made to extend the existing Level 1 evidence and to gain high level evidence for further laparoscopic procedures. PMID- 23444069 TI - Postpubertal examination after hypospadias repair is necessary to evaluate the success of the primary reconstruction. AB - INTRODUCTION: Hypospadias is one of the most common congenital anomalies. There are many studies describing successful initial repair, but there are few studies examining long-term result. The aims of this study were to evaluate our patients that have been reconstructed for hypospadias and undergone final clinical examination after puberty and to assess how long clinical follow-up time is warranted after hypospadias repair. PATIENTS AND METHODS: A standard protocol, with visits at ages 7, 10, 13 and a final clinical examination at the age of 16, was followed. To objectify our long-term functional and aesthetic results, Hypospadias Objective Scoring Evaluation (HOSE) was used. RESULTS: A total of 114 boys reconstructed between 1989 and 2009 had undergone final clinical examination. Seventy-nine were classified as degree I, 25 as degree II, 6 degree III, 3 as degree IV, and 1 boy could not be classified retrospectively. Sixty seven boys were operated on in stages according to Byars, 25 according to Mathieu, and 14 according to Scuderi. Only eight patients needed release of chordee and realignment of skin. Ten boys needed closure of fistulas and strictures had to be operated on in four cases. At the concluding visit, 86% of the patients had an excellent result according to the total HOSE score. It was noted that six patients had developed an incurvation between the prepubertal and postpubertal checkup. CONCLUSION: It is important that the boys are followed according to a planned standardized protocol until they have passed puberty as incurvation may occur during puberty. PMID- 23444070 TI - Functional-conservative treatment of extra-articular physeal fractures of the proximal phalanges in children and adolescents. AB - BACKGROUND: Fractures of the proximal phalanges of the fingers are common injuries in children and adolescents. The majority can be treated by closed reduction and splinting, and complications are rare. The purpose of the prospective study was to document the results of functional-conservative treatment of extra-articular physeal fractures using either a functional forearm cast or the Lucerne Cast (LuCa). METHODS: Clinical and radiographic results of 13 pediatric patients having 13 extra-articular physeal fractures (e.g., juxta epiphyseal fractures, Salter-Harris type I or II physeal fractures) of the proximal phalanges were recorded through a minimum follow-up of 6 months. Intra articular physeal fractures (Salter-Harris type III or IV), fractures involving the proximal interphalangeal joint (PIPJ), pathological fractures, open fractures, and concomitant injuries of the tendons were excluded. RESULTS: Fracture consolidation was achieved in all cases within 4 weeks. No palmar apex angulations, no rotational deformities, and no PIPJ extension lags could be observed. All patients achieved full total active range of motion within 3 months. CONCLUSIONS: Well-reduced extra-articular physeal fractures of the proximal phalanges can be effectively treated using functional-conservative casts. Although children may need a functional forearm cast, a LuCa is adequate in compliant adolescents.Level of Evidence The level of evidence for the study is Level II (therapeutic studies). PMID- 23444071 TI - Surgical stress after open and transumbilical laparoscopic-assisted appendectomy in children. AB - INTRODUCTION: The transumbilical laparoscopic-assisted appendectomy (TULAA) effects on the surgical stress response in children have not been studied. Our aim is to investigate the stress response in TULAA. METHODS: A total of 35 children underwent the appendectomy by open approach (OA) or TULAA approach. Interleukins (ILs)-6, -18, and -10 were measured before (T0), at the beginning (T1a), and at the end of surgery (T1b) and 24 hours after (T2). RESULTS: An increase in IL-6 levels at T1b and T2 and in IL-18 at T2 was observed after OA. A significant increase of both IL-6 and IL-18 were observed at T2 but values were less compared with OA (11.6 +/- 4.4 vs. 31.9 +/- 8.9 pg/mL for IL-6, p = 0.0006; 145.6 vs. 174.9 pg/mL for IL-18, p = NS). CONCLUSIONS: A significant reduction in the postoperative cytokines in TULAA group suggests that this approach causes less surgical trauma in children. PMID- 23444072 TI - Pyloroduodenal duplication cysts: treatment of 11 cases. AB - INTRODUCTION: Abdominal enteric duplications are found in 1 out of 4,500 autopsies, and only 4 to 5% of them are located in the duodenum, where they may be connected with the biliary or pancreatic ducts. The aim of this study was to describe the clinical features, management, and outcome of a large series of duodenal duplication cysts. MATERIALS AND METHODS: The charts of all patients treated at our institution between 1985 and 2011 were reviewed retrospectively with particular attention to imaging, surgical technique, pathology, and outcome. RESULTS: During that period, 11 cases (81.8% females) were treated. Out of the 11 patients, 8 were symptomatic (vomiting in 3, recurrent acute pancreatitis in 2, and abdominal pain in 3) and 3 were tentatively diagnosed prenatally as choledochal cysts. Median age at surgery was 2.3 years (0 to 13.7) and preoperative diagnosis was correct in five cases. Five cysts were developed intraluminally and three communicated with the biliary duct (one), pancreatic duct (one), or both (one). Surgical treatment consisted of complete resection (four cases, including one pancreaticoduodenectomy), partial removal including all mucosa (four cases), and internal marsupialization (three cases). In all cases, the ductal communications were divided and opened into the duodenal lumen. In six cases, ectopic gastric mucosa was found. All patients recovered uneventfully. CONCLUSION: Duodenal duplication cysts are rare and may have bizarre anatomical patterns due to biliopancreatic involvement. Optimal treatment is complete surgical removal, and, if this is not possible, partial removal including the mucosa or marsupialization are also good alternatives. In cases with biliary and pancreatic tract connections, these have to be taken down carefully and drained into the duodenum. PMID- 23444073 TI - Transitioning from stiff chest tubes to soft pleural catheters: prospective assessment of a practice change. AB - BACKGROUND: Tube thoracostomies in children are required for multiple indications and can be associated with significant discomfort. In 2010, a multidisciplinary team at our institution developed a protocol to replace stiff chest tubes with 8.5-French soft pleural catheters in children requiring pleural drainage. METHODS: Before initiating the protocol, an audit sheet was developed to prospectively capture data regarding insertion, removal, complications, and success. After 8 months of new protocol utilization, these data were reviewed, along with a retrospective review of the patients' charts. RESULTS: Twenty-three patients had 33 pleural catheters inserted over an 8-month period. Mean age was 6.7 years (1 day to 17 years). Indications for insertion were pneumothorax (24%), simple effusion (24%), chylothorax (27%), parapneumonic effusion/empyema (21%), and malignant effusion (3%). Complications included premature dislodgment (33%), blockage (15%), pneumothorax (3%), and bleeding (3%). Mean duration of pleural drainage was 7.27 days (0 to 37 days). Pleural drainage was successful in 91% of patients. CONCLUSION: Soft pleural catheters are an acceptable alternative to traditional stiff chest tubes in the pediatric population. Premature dislodgment was the most common problem. Prospective audits are extremely valuable in assessing new procedural protocols and practice changes. PMID- 23444074 TI - Neurogenic appendicopathy: clinical, macroscopic, and histopathological presentation in pediatric patients. AB - BACKGROUND: The proliferation of nerve fibers in the appendix, in association with an increase of the neuropeptides such as vasoactive intestinal peptide and substance P characterizes neurogenic appendicopathy (NA), which may mimic the symptoms of acute appendicitis (AA). It may be difficult to differentiate this little known distinct pathological entity clinically from AA. The aim of this study is to describe the epidemiology, clinical signs, and histological description of NA in pediatric patients. PATIENTS AND METHODS: After institutional review board approval, all appendiceal specimens from children who underwent appendectomy between February 2006 and December 2008 were analyzed. Analysis included age, gender, clinical symptoms, blood tests, intraoperative macroscopic assessment of the appendix, and the histopathological type of NA. NA was diagnosed by hematoxylin-eosin staining and /or S-100 immunochemistry and then classified into different histopathological groups. RESULTS: Of the 385 appendix specimens examined, 29 (7.5%) met the histopathological criteria of NA. The median duration of abdominal pain was 2 days (range, 1 to 7). The surgeon characterized the appendix as follows: not inflamed in 5 (17.2%), acute in 17 (58.6%), phlegmonous in 4 (13.8%), and perforated in 3 patients (10.4%). Histopathological diagnosis of NA classified the specimen as axial neuroma in 2 (7%), mucosal in 12 (41%), and submucosal in 15 cases (52%). CONCLUSION: NA is a relatively common diagnosis in children. NA must be considered in patients with recurrent right lower quadrant pain or signs of AA, even if intraoperative findings are normal. For these patients, we recommend appendectomy and consideration of a subsequent histopathological workup. PMID- 23444075 TI - The changing pattern of pediatric both-bone forearm shaft fractures among 86,000 children from 1997 to 2009. AB - INTRODUCTION: Forearm fractures are common among children. Unlike most pediatric fractures, there is a risk of unsatisfactory results in forearm shaft fractures. The healing of a tubular bone is most unlikely in the diaphysis far away from the metaphyseal zones. The treatment of forearm shaft fractures is evolving. The purpose of the study was to analyze the pattern of forearm shaft fractures and their treatment in a population of children in recent years. MATERIALS AND METHODS: All the children (from 0 to 16 years) with a both-bone forearm shaft fracture (AO-segment 22-D) during the years 1997 to 2009 in a catchment area of about 86,000 children were included in this population-based study. There were 291 fractures in all. The age-related annual incidences, background factors, seasonal variation, injury types, treatment, reoperations, and short-term outcome were determined. RESULTS: The incidence of all forearm shaft fractures increased threefold in 1997 to 2009 (p < 0.001). Boys predominated (70%) over the girls (p < 0.001). The mean age of the patients was 8.7 years (SD, +/- 3.8) among both genders. The fractures were most common in August and most uncommon in December (p < 0.001). A fall in the playground was the most common type of injury (34%). Ninety-two percent of all patients (N = 269) were treated in the operating room and 44% (N = 119) were invasively stabilized. The incidence of invasive surgery held stable. However, elastic stable intramedullary nailing (ESIN) increased from 10% in 1998-2000 to 30% in 2007-2009 (p = 0.043). There were 77 reoperations (26%); reoperation rate was 5% (6/119) and 41% (N = 71/172) in the invasive and non-invasive treatment groups, respectively. Twenty-three percent of the patients referred did not have better than "good" short-term results. The "excellent" short-term outcome was increasing (p = 0.031). CONCLUSIONS: We found two mega trends in pediatric forearm shaft fractures in the period from 1997 to 2009: First, the number of fractures was increasing significantly. Second, the forearm shaft fractures were increasingly treated by an invasive intramedullary method. We also found a significant seasonal variation, but the reason for it is not clear. The findings are based on valuable population-based data and the results are certain. Pediatric trauma centres should prepare themselves for on-going changes in forearm shaft fractures. PMID- 23444077 TI - Orchidopexy in late childhood often associated with previously normal testicular position. AB - INTRODUCTION: The aim of this study was to determine retrospectively, the prevalence of acquired undescended testis (UDT) in boys who underwent late orchidopexies, that is, performed after the age of 2 years. METHODS: We included all patients who were 2 years or older when they underwent orchidopexy (ORP) for UDT at the Juliana Children's Hospital during 1996 to 2009. Previous testis position from birth until the date of ORP was obtained from youth health care records. RESULTS: We identified 660 boys who underwent ORP after the age of 2 years for undescended testis. For 421 of these 660 boys, the previous testicular position could be retrieved from the health records. In 143 of these 421 boys (34%), the operated testis had never been scrotal (congenital UDT), whereas in the other 278 boys (66%), a previous scrotal position had been documented twice or more (acquired UDT). CONCLUSION: Our results show that two-thirds of the boys that underwent ORP after the age of 2 had previously normal descended testes. This finding may offer an additional explanation for the discrepancy between the incidence of congenital UDT and the high rate of ORP in mid and late childhood. PMID- 23444076 TI - Increased expression of survivin in hepatoblastoma after chemotherapy. AB - BACKGROUND: Survivin, an inhibitor of apoptosis, has been reported to be associated with a worse prognosis in some malignancies. However, its expression in hepatoblastoma (HB) remains to be elucidated. We assessed the survivin expression in HB specimens collected before and after chemotherapy to elucidate the impact of survivin on the outcome of HB therapy. METHODS: HB specimens were collected before and after 2 to 4 cycles of cisplatin-based chemotherapy from 16 patients. The survivin expression level was assessed by immunohistochemical staining and real-time polymerase chain reaction. RESULTS: Out of 16, 12 HB sections collected before chemotherapy were positive for survivin as determined by immunohistochemical staining. The intensity of survivin expression was found to significantly increase after chemotherapy. Surprisingly, all of the HB specimens obtained after chemotherapy were positive for survivin. The expression of survivin messenger ribonucleic acid from a human HB cell line, Huh-6 was significantly higher when the cells were cultured with cis diamminedichloroplatinum(II) than when the cells were cultured without the drug. CONCLUSION: Our results indicate that most of the primary HB tissue specimens express survivin, and its expression increased after chemotherapy, thus suggesting that survivin may concern with the survival of tumor cells, therefore be a candidate for the target of the treatment of HB. PMID- 23444078 TI - Factors associated with a negative outcome of medication-overuse headache: a 3 year follow-up (the 'CARE' protocol). AB - AIM: To evaluate factors associated with a negative outcome in a 3-year follow-up of subjects diagnosed with medication-overuse headache (MOH) (revised-ICHD-II criteria). METHODS: All consecutive patients entering the center's inpatient detoxification program were analyzed in a prospective, non-randomized fashion. All participants were assessed by a neurologist using an ad hoc patient record form. Personality was assessed using the Minnesota Multiphasic Personality Inventory (MMPI)-2, Chi-square test, one-way analysis of variance (ANOVA), and odds ratios (OR) were calculated as appropriate. RESULTS: One-hundred and fifty patients completed the follow-up (79.3% females, age 46.40 +/- 11.31 years): 13 never stopped their drug overuse (A), 38 stopped their overuse, but relapsed at least once (B), and 99 stopped and never relapsed (C). The Group A patients differed from those in B + C as they were more frequently single (OR 0.134; P = 0.007) and unemployed (OR 3.273; P = 0.04), took a higher number of drug doses ( P < 0.001), and less frequently drank coffee (OR 3.273; P = 0.044). Personality profile: subjects in A scored higher than those in C on the following scales: Hypochondriasis ( P = 0.007), Depression ( P = 0.003), Paranoia ( P = 0.025), Fears ( P = 0.003), Obsessiveness ( P = 0.026), Bizarre Mentation ( P = 0.046), Social Discomfort ( P = 0.004), Negative Treatment Indicators ( P = 0.040), Repression ( P = 0.007), Overcontrolled Hostility ( P = 0.040), Addiction Admission ( P = 0.021), Social Responsibility ( P = 0.039), and Marital Distress ( P = 0.028). CONCLUSION: Disease outcome in MOH patients is influenced negatively by overuse severity and by specific psychological and socio-economic variables. Other possible modifier factors were voluptuary habits. PMID- 23444079 TI - Triggerless neuralgic otalgia: a case series and systematic literature review. AB - BACKGROUND: Isolated neuralgic pain in the deep ear may arise from either nervus intermedius (NIN) or glossopharyngeal (GPN) neuralgias. Current International Headache Society (IHS) International Classification of Headache Disorders, second edition (ICHD-2) criteria for these cranial neuralgias require the presence of a characteristic trigger. AIM: The aim of this article is to report cases of triggerless neuralgic otalgia to better understand a subset of patients for whom there may be diagnostic uncertainty. METHODS: Methods included an observational cohort series and systematic literature review. RESULTS: We identified five female patients with a median age at symptom onset of 58 (range: 47 to 73). Our patients generally experienced an excellent clinical response to carbamazepine. Patients were contacted by telephone at a median follow-up duration of seven years (range: four to 32) from symptom onset, at which time carbamazepine-free remissions were reported by five of five (100%) of the patients. A systematic review of the literature on neuralgic otalgia led us to conclude that NIN was most common among young women (age < 50), and GPN across a wider range of ages of either gender. Among surgically validated cases reported in the literature, triggers were frequently absent in NIN, and variably noted in GPN. CONCLUSIONS: We conclude that the presence of a trigger is not fundamental, and may be impractical, to the diagnosis of neuralgic otalgia, but remains important for specificity between NIN and GPN. PMID- 23444080 TI - The mouse transcription factor-like 5 gene encodes a protein localized in the manchette and centriole of the elongating spermatid. AB - Spermiogenesis is the final phase of spermatogenesis. During this process, haploid round spermatids differentiate into spermatozoa, with dramatic morphological changes, including elongation and condensation of the nuclei, and formation of the flagella. Meig1 is one of many genes involved in the regulation of this process. Male mice deficient in MEIG1 are sterile with a severe defect in spermiogenesis, associated with dramatic disruption of the spermatid manchette and failure of flagellogenesis. A yeast two-hybrid screen using full-length MEIG1 as bait identified transcription factor-like 5 protein (TCFL5) as a putative interacting proteins. Interestingly, this protein was also identified as a potential binding partner of SPAG16, another protein essential for spermatogenesis, and also a binding partner of MEIG1. The interaction between TCFL5 and MEIG1 was confirmed in cultured cells over-expressing the two proteins. The mouse Tcfl5 transcript is present only in the testis, and its expression is significantly increased during spermiogenesis. However, little is known about TCFL5 protein and its role in male germ cells. A rabbit polyclonal antibody was generated against the C-terminal region of TCFL5. Mouse TCFL5 protein was expressed in the testis but not in mature spermatozoa. During the first wave of spermatogenesis, TCFL5 expression was dramatically increased at day 30 after birth. In the testis and a mixture of dispersed testicular cells, the protein co localized with alpha-tubulin, a manchette marker in early elongating spermatids. The protein also localized in the centrioles of late elongating spermatids. No obvious differences in TCFL5 epitope abundance and localization were observed between wild type and the Meig1-deficient mice. These findings suggest that TCFL5 may play a role upstream of MEIG1 action, and based on putative binding partners and localization is likely to be involved in spermiogenesis and formation of the sperm flagella. PMID- 23444081 TI - Structure and function of mycobacterium glycopeptidolipids from comparative genomics perspective. AB - Glycopeptidolipids (GPLs) attached to the outer surface of the greasy cell envelope, are a class of important glycolipids synthesized by several non tuberculosis mycobacteria. The deletion or structure change of GPLs confers several phenotypical changes including colony morphology, hydrophobicity, aggregation, sliding motility, and biofilm formation. In addition, GPLs, particular serovar specific GPLs, are important immunomodulators. This review aims to summarize the advance on the structure, function and biosynthesis of mycobacterium GPLs. PMID- 23444082 TI - Can attentional control settings be maintained for two color-location conjunctions? Evidence from an RSVP task. AB - Previous investigations of the ability to maintain separate attentional control settings for different spatial locations have relied principally on a go/no-go spatial-cueing paradigm. The results have suggested that control of attention is accomplished only late in processing. However, the go/no-go task does not provide strong incentives to withhold attention from irrelevant color-location conjunctions. We used a modified version of the task in which failing to adopt multiple control settings would be detrimental to performance. Two RSVP streams of colored letters appeared to the left and right of fixation. Participants searched for targets that were a conjunction of color and location, so that the target color for one stream acted as a distractor when presented in the opposite stream. Distractors that did not match the target conjunctions nevertheless captured attention and interfered with performance. This was the case even when the target conjunctions were previewed early in the trial prior to the target (Exp. 2). However, distractor interference was reduced when the upcoming distractor was previewed early on in the trial (Exp. 3). Attentional selection of targets by color-location conjunctions may be effective if facilitative attentional sets are accompanied by the top-down inhibition of irrelevant items. PMID- 23444083 TI - The perception of object versus objectless motion. AB - Wertheimer, M. (Zeitschrift fur Psychologie und Physiologie der Sinnesorgane, 61:161-265, 1912) classical distinction between beta (object) and phi (objectless) motion is elaborated here in a series of experiments concerning competition between two qualitatively different motion percepts, induced by sequential changes in luminance for two-dimensional geometric objects composed of rectangular surfaces. One of these percepts is of spreading-luminance motion that continuously sweeps across the entire object; it exhibits shape invariance and is perceived most strongly for fast speeds. Significantly for the characterization of phi as objectless motion, the spreading luminance does not involve surface boundaries or any other feature; the percept is driven solely by spatiotemporal changes in luminance. Alternatively, and for relatively slow speeds, a discrete series of edge motions can be perceived in the direction opposite to spreading luminance motion. Akin to beta motion, the edges appear to move through intermediate positions within the object's changing surfaces. Significantly for the characterization of beta as object motion, edge motion exhibits shape dependence and is based on the detection of oppositely signed changes in contrast (i.e., counterchange) for features essential to the determination of an object's shape, the boundaries separating its surfaces. These results are consistent with area MT neurons that differ with respect to speed preference Newsome et al (Journal of Neurophysiology, 55:1340-1351, 1986) and shape dependence Zeki (Journal of Physiology, 236:549-573, 1974). PMID- 23444084 TI - Influence of a 100-km ultra-marathon on hepatitis B carrier runners. AB - This study compares the serological markers between runners who are hepatitis B virus carries (HBVc) and runners who are non-HBVc in a 100-km ultra-marathon race. Blood samples of 8 HBVc and 18 non-HBVc runners were drawn 1 week before, immediately following, and 24 h after the race. Samples were analyzed and compared between the 2 groups for liver function tests, muscle damage markers and oxidative stress cytokines. For HBVc runners, HBV-DNA (hepatitis B virus deoxyribonucleic acid) levels were also evaluated for virus reactivation. The results demonstrate a statistically significant increase in both immediate and 24 h post-race values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), high-sensitivity C reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), compared with pre-race values. No statistically significant difference was observed between the 2 groups for the values of AST, LDH, CK, hs CRP, IL-6 and TNF-alpha either before or after the race. There was also no statistically significant change in the levels of HBV-DNA in HBVc runners. These findings suggest that HBVc runners do not have higher risks of liver function impairment, muscle breakdown and inflammatory response compared to non-HBVc runners in such endurance races. PMID- 23444085 TI - Shoulder strength imbalances as injury risk in handball. AB - This study was conducted to analyze whether internal (IR) and external (ER) rotator shoulder muscles weakness and/or imbalance collected through a preseason assessment could be predictors of subsequent shoulder injury during a season in handball players. In preseason, 16 female elite handball players (HPG) and 14 healthy female nonathletes (CG) underwent isokinetic IR and ER strength test with use of a Con-Trex(r) dynamometer in a seated position with 45 degrees shoulder abduction in scapular plane, at 60, 120 and 240 degrees /s in concentric and at 60 degrees /s in eccentric, for both sides. An imbalanced muscular strength profile was determined using -statistically selected cut-offs from CG values. For HPG, all newly incurred shoulder injuries were reported during the season. There were significant differences between HPG and CG only for dominant eccentric IR strength, ER/IR ratio at 240 degrees /s and for IRecc/ERcon ratio. In HPG, IR and ER strength was higher, and ER/IR ratios lower for dominant than for nondominant side. The relative risk was 2.57 (95%CI: 1.60-3.54; P<0.05) if handball players had an imbalanced muscular strength profile. In youth female handball players IR and ER muscle strength increases on the dominant side without ER/IR imbalances; and higher injury risk was associated with imbalanced muscular strength profile. PMID- 23444086 TI - The effects of injury and illness on haemoglobin mass. AB - This study sought to quantify the effects of reduced training, surgery and changes in body mass on haemoglobin mass (Hbmass) in athletes. Hbmass of 15 athletes (6 males, 9 females) was measured 9+/-6 (mean+/-SD) times over 162+/-198 days, during reduced training following injury or illness. Additionally, body mass (n=15 athletes) and episodes of altitude training (n=2), iron supplementation (n=5), or surgery (n=3) were documented. Training was recorded and compared with pre-injury levels. Analysis used linear mixed models for ln(Hbmass), with Sex, Altitude, Surgery, Iron, Training and log(Body Mass) as fixed effects, and Athlete as a fixed and random effect. Reduced training and surgery led to 2.3% (p=0.02) and 2.7% (p=0.04) decreases in Hbmass, respectively. Altitude and iron increased Hbmass by 2.4% (p=0.03) and 4.2% (p=0.05), respectively. The effect of changes in body mass on Hbmass was not statistically significant (p=0.435).The estimates for the effects of surgery and altitude on Hbmass should be confirmed by future research using a larger sample of athletes. These estimates could be used to inform the judgements of experts examining athlete biological passports, improving their interpretation of Hbmass perturbations, which athletes claim are related to injury, thereby protecting innocent athletes from unfair sanctioning. PMID- 23444087 TI - Effects of marathon running on cardiac markers and endothelin-1 in EIH athletes. AB - The aim of the present study was to determine the changes in cardiac makers and endothelin-1 (ET-1) in marathoners with exercise induced hypertension compared to normotensive controls before and after running a marathon. Among a total of 70 volunteers, 10 marathoners with systolic blood pressure (SBP) greater than 210 mmHg during a treadmill exercise stress test were selected as an exercise-induced hypertension group (EIH) and 10 marathoners with normal SBP were selected as a control group (CON). Blood was collected from all volunteers 2 h before and immediately after a marathon: creatinine kinase (CK), CK-MB, cardiac tropoin-I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), and endothelin-1(ET 1). Cardiac markers, CK, CK-MB, and CK-MB/CK ratio significantly increased in both EIH and CON; significance was not observed between the groups. Significant increases were not observed in high sensitive-C reactive protein (hs-CRP) after the race nor between the groups. Significant increases in cTnI and NT-proBNP were observed after the race in both groups. In addition, EIH showed greater increase than CON after the race. In conclusion, increased vascular tone in EIH during a marathon increased blood pressure and myocardial burden which in turn increased myocardial cell membrane permeability to further increase myocardial tension to the point of cTnI release. PMID- 23444088 TI - The fibrotic role of phosphatidylinositol-3-kinase/Akt pathway in injured skeletal muscle after acute contusion. AB - Transforming growth factor beta (TGF-beta) is a multifunctional cytokine with fibrogenic properties. Previous studies demonstrated that Phosphatidylinositol 3 Kinase (PI3K)/Akt/ mammalian target of Ramycin (mTOR), a non-Smad TGF-beta pathway, plays an important role in the fibrotic pathogenesis of different organs such as the lung, kidney, skin and liver. However, the role of PI3k-Akt pathway in fibrosis in injured skeletal muscle is still unclear. In this study, we determined the fibrotic role of PI3K-Akt pathway in injured skeletal muscle. We established a mouse model for acute muscle contusion. Western blotting analysis showed that TGF-beta, phosphorylated Akt and phosphorylated mTOR were increased in muscles after acute contusion, which indicated that the PI3K-Akt- mTOR pathway was activated in skeletal muscle after acute contusion. The pathway was inhibited by a PI3K inhibitor, LY294002. Moreover, the expression of fibrosis markers vimentin, alpha SMA and collagen I and the area of scar decreased in injured skeletal muscle after PI3K pathway was blocked. The muscle function improved in terms of both fast-twitch and tetanic strength after PI3K/Akt pathway was inhibited in injured skeletal muscle. In conclusion, activation of PI3K-Akt-mTOR pathway might promote collagen production and scar formation in the acute contused skeletal muscle. Blocking of PI3K-Akt-mTOR pathway could improve the function of injured skeletal muscle. PMID- 23444089 TI - The potential of the skin as a readout system to test artificial turf systems: clinical and immunohistological effects of a sliding on natural grass and artificial turf. AB - The purpose of this study was to investigate the interaction of skin with natural grass and artificial turf at clinical, histological and immunohistochemical level. Therefore, 14 male volunteers performed slidings on dry natural grass, wet natural grass and artificial turf. Directly and 24 h after the slidings, a clinical picture and a 3-mm punch biopsy of the lesion were taken. Paraffin sections (6 um) were hematoxylin-eosin stained. Immunohistochemistry was performed for CD3, hBD-2, K16, K10, Ki67 and HSP70. Clinically, a sliding performed on artificial turf caused less erythema but more abrasion compared to natural grass. At histological level, artificial turf or dry natural grass damaged the stratum corneum the most. Directly after the sliding, CD3, hBD-2, K16, K10, Ki67 and HSP70 expression was normal. 24 h after a sliding on artificial turf or dry natural grass, an increase of K16, hBD-2 and HSP70 expression was observed. In this pilot study it was not possible to clearly distinguish between skin damage induced by a sliding on artificial turf and natural grass. However, small differences at clinical and histological level seem to exist. This demonstrates the potential of the skin as readout system to evaluate artificial turf systems and mechanical skin damage. PMID- 23444090 TI - Recovery (passive vs. active) during interval training and plasma catecholamine responses. AB - The effect of recovery mode (Active [AR] vs. Passive [PR]) on plasma catecholamine (Adrenaline [A] and Noradrenaline [NA]) responses to maximal exercise (Exemax) was studied during interval training (IT). 24 male subjects (21.1+/-1.1 years) were randomly assigned to a control group (CG, n=6), AR training group (ARG, n=9) or PR group (PRG, n=9). ARG and PRG participated in an IT program 3 times a week for 7 weeks. Before and after training, maximal oxygen uptake (VO2max) and maximal aerobic velocity (MAV) were measured. Plasma A and NA were determined at rest, at the end of Exemax and after 10 and 30 min of recovery. Training induced significant changes only in ARG: an increase of VO2max and MAV along with a significant increase of A and NA at the end of Exemax (2.82+/-0.15 vs. 1.03+/-0.15 nmol/l and 7.22+/-0.36 vs. 6.65+/-0.57 nmol/l, respectively p<0.05). The ratio A/NA measured at the end of Exemax also increased significantly after training (0.41+/-0.11 vs. 0.16+/-0.08, P>0.05). The present results show that IT with AR induces a significant increase of A and NA concentrations in response to maximal exercise. The study furthermore shows that IT program with AR may induce more stress than the same program with PR. PMID- 23444091 TI - Acute effects of resistance training with local vibration. AB - The aim of this study was to verify the acute effects of the application of local vibration on upper limbs during resistance training on the number of maximum repetitions, metabolic and hormonal responses. 32 volunteers performed a maximum voluntary contraction test during a lat pulldown exercise. After the test, all volunteers underwent one conventional resistance training session and one resistance training session with local vibration. In both interventions, volunteers performed 4 sets with the highest possible number of repetitions of the lat pulldown exercise at 55% of maximum voluntary contraction. During the vibratory resistance training intervention, vibration was locally applied (20-Hz and 12-mm). During the conventional resistance training, volunteers performed the same procedures without vibration. Blood samples were taken at each experimental session before and 5 min after the end of each intervention. No significant differences were observed in number of maximum repetitions between the series of vibratory and conventional training. Serum testosterone, cortisol and lactate were significantly increased after 2 interventions. Vibratory resistance training induced greater increases in testosterone and lactate concentrations. No significant changes were found in creatine kinase, creatinine or urea concentration. These data indicate that local vibration increases the metabolic and anabolic response to the resistance training, without changing the training volume. PMID- 23444092 TI - The effect of velocity on load range during isokinetic hip abduction and adduction exercise. AB - The purpose of this study was to quantify the components of acceleration, load range and deceleration through a velocity spectrum during concentric hip abduction and adduction isokinetic exercise, and to investigate the effect of load range on peak torque and work done. 16 male healthy subjects performed 3 maximal concentric reciprocal hip abduction and adduction gravity corrected repetitions in a fixed order at 60, 120, 180, 240, 300, 360 and 420 degrees . s 1, with a 30 s rest between velocities. Hip abduction and adduction results revealed that load range significantly decreased while acceleration and deceleration ROM significantly increased (p<0.05) with each increase in velocity. When the total peak torque data was corrected for load range there was a significant decrease (p<0.05) in peak torque at velocities of 300 degrees . s-1 and above, for both hip abduction and adduction. Load range correction also resulted in a significant decrease (p<0.05) in work done at velocities of 120 degrees . s-1 and above, for both hip abduction and adduction. The results demonstrate an inverse relationship between isokinetic velocity and load range during concentric hip abduction and adduction, and suggest a need for the clinician to carefully consider velocity selection when performing exercise on an isokinetic device. PMID- 23444093 TI - Evaluation of movement and physiological demands of rugby league referees using global positioning systems tracking. AB - The use of global positioning systems (GPS) technology within referees of any sport is limited. Therefore, the purpose of the current study was to evaluate the movement and physiological demands of professional rugby league referees using GPS tracking analysis. Time-motion analysis was undertaken on 8 referees using 5 Hz GPS devices and heart rate monitors throughout a series of Super League matches. 44 data sets were obtained with results identifying similar total distance covered between first and second half periods with a significant (P=0.004) reduction in the number of high velocity efforts performed between 5.51 7.0 m.s-1 (1st=21+/-8, 2nd=18+/-8). Mean distance covered from greatest to least distance, was 3 717+/-432 m, 3 009+/-402 m, 1 411+/-231 m, 395+/-133 m and 120+/ 97 m for the following 5 absolute velocity classifications, respectively; 0.51 2.0 m.s-1; 2.1-4.0 m.s-1: 4.01-5.5 m.s-1; 5.51-7.0 m.s-1; <7.01 m.s-1. Heart rate was significantly (P<0.001) greater in the first (85.5+/-3.4% maxHR) compared to the second (82.9+/-3.8% maxHR) half. This highlights the intermittent nature of rugby league refereeing, consisting of low velocity activity interspersed with high velocity efforts and frequent changes of velocity. Training should incorporate interval training interspersing high velocity efforts of varying distances with low velocity activity while trying to achieve average heart rates of ~ 84% maxHR to replicate the physiological demands. PMID- 23444094 TI - Palm cooling does not improve running performance. AB - The aim of this study was to test the efficacy of the BEX Runner palm cooling device during a combination of exercise and environmental heat stress. Twelve subjects completed two randomly ordered time-to-exhaustion runs at 75% VO2max, 30 degrees C, and 50% relative humidity with and without palm cooling. Time to exhaustion runs started once the warm-up had elicited a core temperature of 37.5 degrees C. Heart rate, Rating of Perceived Exertion, Feeling Scale, and core temperature were recorded at 2-min intervals during each run. Time to exhaustion was longer in control than treatment (46.7+/-31.1 vs. 41.3+/-26.3 min, respectively, p<0.05); however, when warm-up time was included in analysis, there was no difference between trials for total exercise time (52.5+/-24.2 vs. 54.5+/ 31.4 min, respectively). The rate-of-rise of core temperature was not different between control and treatment (0.047 vs. 0.048 degrees C . min-1, respectively). The use of the BEX Runner palm cooling device during a run in hot conditions did not eliminate or even attenuate the rise in core temperature. Exercise time in hot conditions did not increase with the use of the palm cooling device and time to exhaustion was reduced. PMID- 23444095 TI - Validity of the six-minute walk test in cancer patients. AB - The present study evaluated the validity of the six-minute walk test (6MWT) in cancer patients. 50 subjects (36 f, 14 m; 57.4+/-10.2 years; during (56%) or off (44%) cancer treatment) performed a 6MWT and a spiroergometry on a cycle ergo meter (0+25 W, 3 min) to evaluate maximum exercise capacity (VO2peak). A subsample (n=30) completed a retest of the 6MWT within 2-7 days. Patients covered a distance of 594+/-81 m during 6MWT at an average intensity of 86.3+/-9.6% of HRmax and achieved a VO2peak of 21.2+/-4.86 ml . kg - 1 . min - 1 during cycle ergometry. The distance walked correlated significantly (p<0.001) with VO2peak (r=0.67) and perceived physical function (EORTC QLQ-C30 physical function subscale) (r=0.55). Concerning reliability the intraclass correlation coefficient was r=0.93 (95%CI: +0.86;+0.97; p<0.001) and the coefficient of variation 3%. During retest participants walked 3.1% (95%CI: +1.1; +5.2) farther and achieved a higher RPE (+1.0; 95%CI: +0.3;+1.8). Limits of agreement were between - 43.1 and 76.4 m. In cancer patients the 6MWT seems to be as valid and reliable as in healthy elderly, cardiac and pulmonary patients. Thus, it can be recommended for use in cancer patients. PMID- 23444096 TI - High-intensity re-warm-ups enhance soccer performance. AB - The effects of high-intensity, short-duration, re-warm-ups on team-sport-related performance were investigated. In a randomised, cross-over study, participants performed 2*26-min periods of an intermittent activity protocol (IAP) on a non motorized treadmill, interspersed by 15-min of passive recovery (CON); 3-min small-sided game (SSG); or a 5RM leg-press. Measures included counter-movement jump, repeated-sprint, the Loughborough soccer passing test (LSPT), blood lactate concentration, heart-rate, and perceptual measures. Data were analyzed using effect size (90% confidence intervals), and percentage change; determining magnitudes of effects. A 5RM re-warm-up improved flight-time to contraction-time ratio when compared to SSG (9.8%, ES; 0.5+/-0.3) and CON (ES: 9.4%, 0.7+/-0.5) re warm-ups, remaining higher following the second IAP (8.8%, ES; 0.5+/-0.3 and 10.2%, ES; 0.6+/-0.6, respectively). Relative-maximum rate-of-force development was greater in the 5RM condition following the second IAP compared to SSG (29.3%, ES; 0.7+/-0.5) and CON (16.2%, ES; 0.6+/-0.6). Repeated-sprint ability during the second IAP improved in the 5RM re-warm-up; peak velocity, mean velocity, and acceleration were 4, 3, and 18% greater, respectively. Within groups, the SSG re warm-up improved LSPT performance post-intervention; 6.4% (ES: 0.6+/-0.8) and following the second IAP 6.2% (ES: 0.6+/-0.6), compared to pre-intervention. A 5RM leg-press re-warm-up improved physical performance, while a SSG re-warm-up enhanced skill execution following standardized intermittent exercise. PMID- 23444097 TI - New insights into the half-of-the-sites reactivity of human aldehyde dehydrogenase 1A1. AB - Aldehyde dehydrogenases (ALDHs) couple the oxidation of aldehydes to the reduction of NAD(P)(+) . These enzymes have gained importance as they have been related to the detoxification of aldehydes generated in several diseases involving oxidative stress. It has been determined that tetrameric ALDHs work only with two of their four active sites (half-of-the-sites reactivity), but the mechanistic reason for this feature remains unknown. In this study, tetrameric human aldehyde dehydrogenase class 1A1 (ALDH1A1) was dimerized to study the correlation of the oligomeric structure with the presence of half-of-the-sites reactivity. Stable dimers from ALDH1A1 were generated by combining the mutation of two residues of the dimer-dimer interface in the tetramer (previously shown to render a low-active and unstable enzyme) and the fusion of green fluorescent protein (GFP) in the C-terminus of the mutant. Some kinetic properties of the GFP fusion mutant resembled those of human aldehyde dehydrogenase class 3A1, a native dimer, in that the fusion dimer did not show burst in the generation of nicotinamide adenine dinucleotide (NADH) and was less sensitive to the action of specific modulators. The presence of primary isotope effect indicated that the rate-limiting step changed from NADH release to hydride transfer. The mutant showed higher activity with malondialdehyde and acrolein and was more resistant to inactivation by acrolein compared with the wild type. The mutant kinetic profile showed two hyperbolic components when the substrates were varied, suggesting the presence of two active sites with different affinities and catalytic capacities. In conclusion, the ALDH1A1-GFP dimeric mutant exhibits full site reactivity, suggesting that only the tetrameric structure induces the half of-the-sites reactivity. PMID- 23444099 TI - Selective inhibition of an apicoplastic aminoacyl-tRNA synthetase from Plasmodium falciparum. AB - The resistance of malaria parasites to available drugs continues to grow, and this makes the need for new antimalarial therapies pressing. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes and well-established antibacterial targets and so constitute a promising set of targets for the development of new antimalarials. Despite their potential as drug targets, apicoplastic ARSs remain unexplored. We have characterized the lysylation system of Plasmodium falciparum, and designed, synthesized, and tested a set of inhibitors based on the structure of the natural substrate intermediate: lysyl-adenylate. Here we demonstrate that selective inhibition of apicoplastic ARSs is feasible and describe new compounds that that specifically inhibit Plasmodium apicoplastic lysyl-tRNA synthetase and show antimalarial activities in the micromolar range. PMID- 23444100 TI - Intake of selected minerals and risk of premenstrual syndrome. AB - Iron, potassium, zinc, and other minerals might impact the development of premenstrual syndrome (PMS) through multiple mechanisms, but few studies have evaluated these relations. We conducted a case-control study nested within the prospective Nurses' Health Study II (1991-2001). Participants were free from PMS at baseline. After 10 years, 1,057 women were confirmed as PMS cases and 1,968 as controls. Mineral intake was assessed using food frequency questionnaires completed in 1991, 1995, and 1999. After adjustment for calcium intake and other factors, women in the highest quintile of nonheme iron intake had a relative risk of PMS of 0.64 (95% confidence interval (CI): 0.44, 0.92; P for trend = 0.04) compared with women in the lowest quintile. Women in the highest quintile of potassium intake had a relative risk of 1.46 (95% CI: 0.99, 2.15; P for trend = 0.04) compared with women in the lowest quintile. High intake of zinc from supplements was marginally associated with PMS (for intake of >=25 mg/day vs. none, relative risk = 0.69, 95% CI: 0.46, 1.02; P for trend = 0.05). Intakes of sodium, magnesium, and manganese were unrelated to PMS risk. These findings suggest that dietary minerals may be useful in preventing PMS. Additional studies are needed to confirm these relations. PMID- 23444101 TI - Evaluation of the body adiposity index in a Caucasian population: the Hordaland health study. AB - In this study, we compared the relationships of body mass index (BMI) and body adiposity index (BAI) with body fat percentage (BF%) in a Caucasian, European population. BF% was measured by dual-energy x-ray absorptiometry in a population based cross-sectional study of 5,193 middle-aged (47-49 years) and elderly (71-74 years) men and women from the Hordaland Health Study in western Norway from 1997 to 1999. In the total population, the correlation between BAI and BF% was stronger (r = 0.78) than the correlation between BMI and BF% (r = 0.56) with similar results in the middle-aged and elderly groups. However, in men and women separately, BMI was a better correlate of BF% (for men, r = 0.76; for women, r = 0.81) than was BAI (for men, r = 0.57; for women, r = 0.72). BMI was also a better correlate of BF% than was BAI assessed by partial correlations adjusted for sex (for BMI-BF%, r = 0.79; for BAI-BF%, r = 0.67). Bland-Altman plots and BF%-stratified analyses showed that BAI tended to overestimate BF% in lean subjects and to underestimate it in those with higher proportions of body fat, but that it predicted BF% well for those whose BMI was in a normal range. At the individual level and in population studies adjusted for sex, BMI outperforms BAI as a predictor of BF%. PMID- 23444103 TI - Pretibial linear vertical creases or indentations (shin dimples) associated with arthrogryposis. AB - Among 2,500 cases of arthrogryposis, 14 families and 17 individuals were identified that had a linear vertical crease (indentation/dimple) along the anterior tibia, usually bilaterally. Approximately half had developmental delay/intellectual disability and the others had normal intellectual development. There are generalized flexion contractures with the legs more severely affected than the arms. The ankles are flexed at birth suggesting a relationship of contraction of the anterior tibial compartment to the in utero development of the anterior tibial crease. Dislocated hips are seen in 60%. Hands open with physical therapy and become quite functional. Those with normal intelligence are ambulatory, often with a crouching stance. Three families had recurrence suggesting a recessive pattern of inheritance. All parents were normal. No affected individuals have had offspring. Several have had CGH arrays, which were normal. The presence of this crease in cases of arthrogryposis appears to be a helpful clinical observation and may even be pathognomonic. PMID- 23444102 TI - Association of leukocyte telomere length with breast cancer risk: nested case control findings from the Shanghai Women's Health Study. AB - Telomeres are specialized chromatin structures essential for the maintenance of chromosomal integrity and stability. Telomere shortening has been linked to multiple aging-related diseases, including cancer. Evidence associating telomere length with breast cancer risk-most of which has been from retrospective case control studies-is conflicting. We conducted a nested case-control study based on the Shanghai Women's Health Study (1997-2009) in which we evaluated the association of telomere length and breast cancer risk using peripheral blood samples collected before cancer diagnosis (601 cases and 695 controls). We used monochrome multiplex quantitative polymerase chain reaction to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios with 95% confidence intervals as the measure of association. Telomere length was inversely correlated with age (r = -0.22). Women with moderately long telomeres (those in the fourth quintile) had the lowest breast cancer risk. Risk increased in a dose-response manner with decreasing quintile of telomere length; odds ratios were 1.39 (95% confidence interval (CI): 0.95, 2.04), 1.79 (95% CI: 1.17, 2.75), and 2.39 (95% CI: 1.45, 3.92), respectively, for the third, second, and first quintiles compared with the fourth quintile. A slightly elevated risk of breast cancer (odds ratio = 1.35, 95% CI: 0.90, 2.04), although one that was not statistically significant, was found in the top quintile (longest telomeres). Our results support the hypothesis that telomere shortening is associated with increased risk of breast cancer and suggest a possible elevated risk associated with long telomeres. PMID- 23444104 TI - Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters. AB - Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5-fluorouracil (5-FU), in immunodeficient, Ad-nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5-FU therapy and of its combination with CP for syngenic HaP-T1 pancreatic cancers in immunocompetent, Ad-permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5-FU in HaP-T1 cells in vitro. I.t. AxE1CAUP/5-FU treatment inhibited the growth of subcutaneous HaP-T1 allografts. The combination with high dose CP inhibited serum Ad-neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5-FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically-approved, intermediate-dose CP also enhanced the efficacy of i.t. AxE1CAUP/5-FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad-permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV-mediated gene therapy. PMID- 23444106 TI - Conceptualization of task boundaries preserves implicit sequence learning under dual-task conditions. AB - Implicit learning in the serial reaction time (SRT) task is sometimes disrupted by the presence of a secondary distractor task (e.g., Schumacher & Schwarb Journal of Experimental Psychology: General 138:270-290, 2009) and at other times is not (e.g., Cohen, Ivry, & Keele Journal of Experimental Psychology: Learning, Memory, and Cognition 16:17-30, 1990). In the present study, we used an instructional manipulation to investigate how participants' conceptualizations of the task affect sequence learning under dual-task conditions. Two experimental groups differed only in terms of the instructions and presequence training. One group was instructed that they were completing two separate tasks, whereas the other group was instructed that they were performing a single, integrated task. The separate group showed sequence learning, while the integrated group did not. These findings suggest that the conceptualization of task boundaries affects the availability of the sequential information necessary for implicit learning. PMID- 23444107 TI - On the automaticity of contingent capture: disruption caused by the attentional blink. AB - Converging evidence has shown that onset capture can be completely eliminated by the demands of a concurrent task and during the attentional blink. In the present study, we investigated contingent capture during the attentional blink. We found that contingent capture was attenuated, or even completely eliminated, during the "blink" time of the attentional blink. These results indicate that contingent capture requires limited attentional resources. PMID- 23444108 TI - [Remission, response, and its prediction in depressive inpatients]. AB - Using mean comparisons and effect sizes to report effects of inpatient treatment, this not reveals, how many inpatients benefit from treatment and which characteristics predict the positive outcome. Several characteristics were collected from 1 533 consecutive inpatients with an episode of depression. The pre-post-effect size in the Beck Depression Inventory was 1.29 (95%-CI: 1.23; 1.36). The rate of remission was 39.5%. The rate of response was 57.8% based on the reliable change index (RCI) and 72.4% based on the percental symptom improvement. The regression model with the RCI as outcome variable was stabile in the cross-validation. A negative predictive impact was demonstrated by the depressive symptoms at treatment beginning, whereas higher assessment of physical health and higher level of education were found to be positively associated. A consistent definition of response seems essential for cross-study and cross methodological comparisons. PMID- 23444109 TI - [A questionnaire for the assessment of women's perception of their own femininity: a study on women with Mayer-Rokitansky-Kuster-Hauser-syndrome and women with polycystic ovary syndrome]. AB - Women with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) or polycystic ovary syndrome (PCOS) experience substantial changes in female body characteristics. It was investigated how this is associated with changes concerning the experience of one's own femininity. A questionnaire was developed to measure the experience of one's own femininity. The question-naire assesses how important several aspects are to women for their experience of their own femininity. Data from 49 women with MRKHS and 55 women with PCOS were compared to a non-clinical sample (932 women). The experience of their own femininity differed between the clinical groups as well as in comparison to the control sample. Diagnosis-specific characteristics emerged, which should be considered in the treatment of affected women. The developed questionnaire proved to be suitable for measuring differences in the experience of one's own femininity between groups of gynecological -patients. PMID- 23444110 TI - The fate is not always written in the genes: epigenomics in epidemiologic studies. AB - Cost-effective, high-throughput epigenomic technologies have begun to emerge, rapidly replacing the candidate gene approach to molecular epidemiology and offering a comprehensive strategy for the study of epigenetics in human subjects. Epigenome-wide association studies (EWAS) provide new opportunities for advancing our understanding of epigenetic changes associated with complex disease states. However, such analyses are complicated by the dynamic nature of DNA methylation. In contrast to genomic studies, where genotype is essentially constant across somatic cells, EWAS present a new set of challenges, largely due to differential DNA methylation across distinct cell types, particularly for studies involving heterogeneous tissue sources, and changes in the epigenetic profile that occur over time. This review describes potential applications of EWAS from the viewpoint of the molecular epidemiologist, along with special considerations and pitfalls involved in the design of such studies. PMID- 23444111 TI - Specific route mapping visualized with GFP of single-file streaming contralateral and systemic metastasis of Lewis lung carcinoma cells beginning within hours of orthotopic implantation [correction of implantion]. AB - In this study, we visualized the origin of Lewis lung carcinoma metastasis after transducing tumor cells with green fluorescent protein (GFP) and transplanting them orthotopically in the middle lobe of the right lung of nude mice. Metastasis was visualized in live tissue at single cell resolution by GFP-expression as early as 18 h post-tumor transplant. At this time, single-file streaming lung carcinoma cells already had invaded inferiorly via a tubular lymphatic structure crossing the lower lobes of the lung to the ipsilateral diaphragmatic surface. By post-implantation day 2, the ipsilateral lower lobes of the lung were involved with metastatic cells. By post-implantation day 3, the ipsilateral lower lobes of the lung and the ipsilateral diaphragmatic surface were highly involved with streaming metastatic cells trafficking in single file. By day 4 post implantation, cancer cells invaded across the diaphragm to the contralateral diaphragmatic surface. Metastatic cells then invaded superiorly through a lymphatic vessel to involve the contralateral mediastinal lymph nodes. In this model of lung cancer, the origin of metastasis was an inferior invasion from the implanted tumor via a lymphatic duct to the ipsilateral diaphragmatic surface. The cancer cells from this site invaded on the surface of the diaphragm to the contralateral diaphragmatic surface and proceeded superiorly through a lymphatic duct to contralateral lymph nodes. Other organs such as the kidneys and the adrenal glands later became involved with metastasis with the contralateral mediastinal lymph nodes as the source. The use of GFP and the highly metastatic orthotopic lung cancer model allowed the visualization of the origin of metastasis at the single-cell level and demonstrated the critical role of lymphatic ducts and the diaphragmatic surface as the path to the contralateral side. PMID- 23444112 TI - Dynamics of focal adhesions and reorganization of F-actin in VEGF-stimulated NSCs under varying differentiation states. AB - Precise migration of neural stem/progenitor cells (NSCs) is crucially important for neurogenesis and repair in the nervous system. However, the detailed mechanisms are not clear. Our previous results showed that NSCs in varying differentiation states possess different migratory ability to vascular endothelial growth factor (VEGF). In this study, we demonstrate the different dynamics of focal adhesions (FAs) and reorganization of F-actin in NSCs during spreading and migration stimulated by VEGF. We found that the migrating NSCs of 0.5 and 1 day differentiation possess more FAs at leading edge than cells of other states. Moreover, the phosphorylation of focal adhesion kinase (FAK) and paxillin in NSCs correlates closely with their differentiation states. VEGF promotes FA formation with broad lamellipodium generation at the leading edge in chemotaxing cells of 0, 0.5, and 1 day differentiation, but not in cells of 3 days differentiation. Furthermore, cells of 1 day differentiation show a maximal asymmetry of FAs between lamella and cell rear, orchestrating cell polarization and directional migration. Time-lapse video analysis shows that the disassembly of FAs and the cell tail detachment in NSCs of 1 day differentiation are more rapid, along with the concurrent enlarged size of FAs at the leading edge, leading to the most effective chemotactic response to VEGF. Collectively, these results indicate that the dynamics of FAs and reorganization of F-actin in NSCs that undergo directional migration correlate closely with their differentiation states, contributing to the different chemotactic responses of these cells to VEGF. PMID- 23444113 TI - Observation as an option for epithelial positive margin after partial glossectomy in stage I and II squamous cell carcinoma: analysis of 365 cases. AB - OBJECTIVE: This study was conducted to assess local recurrence and clinical prognosis in patients diagnosed as having a positive margin in the epithelial layer after a partial glossectomy treated by close observation. METHODS: A total of 365 cases of squamous cell carcinoma of the tongue diagnosed as clinical Stage I or II, treated by partial glossectomy in the National Cancer Center Hospital East between 1992 and 2006, were studied retrospectively. RESULTS: Pathological findings showed that 13 cases had positive margins in the epithelial layer, 4 (30.8%) of whom showed up with local recurrence in 4.4 years (3.0-5.0) on average. Lymph node recurrence was not observed and the 5-year overall survival rate was 76.2% in those 13 cases. The treatment for the recurrent cases was an additional partial glossectomy without neck dissection, which resulted in no recurrence and a survival rate of 100% after an average follow-up of 6.7 years. CONCLUSIONS: We suggest careful observation as one option for cases diagnosed with epithelial positive margin. PMID- 23444114 TI - Renal toxicity caused by brand-name versus generic cisplatin: a comparative analysis. AB - OBJECTIVE: A generic cisplatin formulation has replaced the brand-name formulation since November 2003 in our hospital. We retrospectively assessed the renal toxicity caused by the brand-name and generic cisplatin formulations. METHODS: The medical records of patients with thoracic malignancy who were treated at our hospital between November 2000 and April 2008 were reviewed. In total, 1296 eligible patients received 80 mg/m(2) of cisplatin: 499 patients were treated with the brand-name cisplatin formulation before November 2003 (Group 1) and 797 patients were treated with the generic formulation after November 2003 (Group 2). We compared the maximum serum creatinine level after chemotherapy in the two groups. RESULTS: The patient characteristics, including age, sex and performance status, and pretreatment serum creatinine levels were well balanced between the two groups. More patients received four cycles of chemotherapy in Group 2 (P < 0.0001). The median (range) of the maximum serum creatinine levels during all the chemotherapy cycles were 1.1 (0.5-4.1) mg/dl and 1.1 (0.5-4.4) mg/dl in Groups 1 and 2, respectively (P = 0.0237). The incidence of grade 0 serum creatinine elevations decreased from 47% to 39%, while that of grade 1 serum creatinine elevations increased from 32% to 41% (P = 0.0094). The incidence rates of grade 2 or 3 serum creatinine elevations were similar (21 vs. 20%). The time to serum creatinine elevation was also similar in Groups 1 and 2 (P = 0.161). CONCLUSION: Although grade 1 maximum serum creatinine level was more common in the generic cisplatin formulation group, this was attributed to the larger number of patients receiving four cycles of chemotherapy in this group. PMID- 23444115 TI - Associations of polymorphisms of rs693 and rs1042031 in apolipoprotein B gene with risk of breast cancer in Chinese. AB - BACKGROUND: Lipid synthesis is an integrated result of genetic, epigenetic and environmental factors, and also can promote growth and survival of cancer cells. Apolipoprotein B plays a central role in lipid metabolism as the major protein component of very-low-density lipoprotein and low-density lipoprotein. METHODS: We investigated the associations of polymorphisms of rs693 (-7673C>T) and rs1042031 (-12669 G>A) in the APOB gene with risk of breast cancer in 675 blood unrelated Chinese patients with breast cancer and 712 healthy controls. RESULTS: Polymorphisms of -12669 G>A and -7673C>T in the APOB gene were significantly associated with an increased risk of breast cancer (P = 0.000), especially for postmenopausal women (P = 0.000, 0.023). The positive associations still remained after further analysis of the two polymorphisms' distribution according to body mass index. However, no statistical associations were found between -12669 G>A and -7673C>T polymorphisms and other clinical characteristics, including tumor size, lymph node metastasis, histological grade, estrogen and progesterone receptor status and Her-2 status. CONCLUSIONS: rs693 and rs1042031 polymorphisms in the APOB gene increased the risk of breast cancer in Chinese, and this role of the two polymorphisms in connection with breast cancer was not dependent on body mass index. PMID- 23444116 TI - Risk factors for intravesical recurrence in patients with high-grade T1 bladder cancer in the second TUR era. AB - OBJECTIVE: We aimed to elucidate risk factors for intravesical recurrence of high grade T1 bladder cancer in the second transurethral resection era. METHODS: The analysis included 73 patients with high-grade T1 bladder cancer on initial transurethral resection. The median follow-up period was 49.2 months. Recurrence free survival, progression-free survival and risk factors related to the presence of residual tumors or recurrence-free survival were statistically analyzed. RESULTS: The pathological findings for second transurethral resection were pT0 36 (49%), pTis/a 21 (29%), pT1 13 (18%) and pT2 3 (4%), respectively. The risk factor for residual tumors at second transurethral resection was the presence of concomitant carcinoma in situ at the initial transurethral resection (P < 0.01). The bladder was preserved in all 57 patients with pT0/is/a tumors on second transurethral resection, and 43 patients (75%) received intravesical BCG therapy. Of these patients, 3-year recurrence-free survival and 3-year progression-free survival rates were 81 and 96%, respectively. In addition, the presence of pTis/a residual tumors on second transurethral resection had a significant impact on the recurrence. Five of the 13 patients with pT1 on second transurethral resection were immediately treated by radical cystectomy or radiation therapy combined with chemotherapy, and two (25%) of the eight who were treated by intravesical BCG therapy had progression including distant metastasis. CONCLUSIONS: High recurrence-free survival and progression-free survival were achieved by a second transurethral resection and intravesical BCG therapy in the patients with pT0/is/a on the second transurethral resection. In this group, the residual tumors at second transurethral resection are risk factors for intravesical recurrence. PMID- 23444117 TI - Dietary total antioxidant capacity and colorectal cancer: a large case-control study in Italy. AB - A favorable role of fruit and vegetables on colorectal cancer risk has been related to the antioxidant properties of their components. We used data from an Italian case-control study including 1,953 patients with incident, histologically confirmed colorectal cancer (1,225 colon and 728 rectal cancers). Controls were 4,154 patients admitted to hospital for acute, non-neoplastic conditions. A reproducible and valid food frequency questionnaire was used to assess subjects' usual diet. Total antioxidant capacity (TAC) was measured using Italian food composition tables in terms of ferric reducing-antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC) and total radical-trapping antioxidant parameter (TRAP). We estimated the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) through multiple logistic regression models, including terms for potential confounding factors, and energy intake. TAC was inversely related with colorectal cancer risk: the OR for the highest versus the lowest quintile was 0.68 (95% CI, 0.57-0.82) for FRAP, 0.69 (95% CI, 0.57-0.83) for TEAC and 0.69 (95% CI, 0.57-0.83) for TRAP. Corresponding values, excluding TAC deriving from coffee, were 0.75 (95% CI, 0.61-0.93) for FRAP, 0.76 (95% CI, 0.61 0.93) for TEAC and 0.71 (95% CI, 0.57-0.89) for TRAP. The inverse association was apparently-though not significantly-stronger for rectal than for colon cancer. This is the first case-control study indicating consistent inverse relations between dietary TAC and colorectal cancer risk. PMID- 23444118 TI - Vegetable matter in a cervical smear: complementary medicine complicates smear interpretation. PMID- 23444119 TI - Barriers for integrating personalized medicine into clinical practice: a qualitative analysis. AB - Personalized medicine-tailoring interventions based on individual's genetic information-will likely change routine clinical practice in the future. Yet, how practitioners plan to apply genetic information to inform medical decision making remains unclear. We aimed to investigate physician's perception about the future role of personalized medicine, and to identify the factors that influence their decision in using genetic testing in their practice. We conducted three semi structured focus groups in three health regions (Fraser, Vancouver coastal, and Interior) in British Columbia, Canada. In the focus groups, participants discussed four topics on personalized medicine: (i) physicians' general understanding, (ii) advantages and disadvantages, (iii) potential impact and role in future clinical practice, and (iv) perceived barriers to integrating personalized medicine into clinical practice. Approximately 36% (n = 9) of physicians self-reported that they were not familiar with the concept of personalized medicine. After introducing the concept, the majority of physicians (68%, n = 19 of 28) were interested in incorporating personalized medicine in their practice, provided they have access to the necessary knowledge and tools. Participants mostly believed that genetic developments will directly affect their practice in the future. The key concerns highlighted were physician's access to clinical guidelines and training opportunities for the use of genetic testing and data interpretation. Despite the challenges that personalized medicine can create, in general, physicians in the focus groups expressed strong interest in using genetic information in their practice if they have access to the necessary knowledge and tools. PMID- 23444120 TI - When voices get emotional: a corpus of nonverbal vocalizations for research on emotion processing. AB - Nonverbal vocal expressions, such as laughter, sobbing, and screams, are an important source of emotional information in social interactions. However, the investigation of how we process these vocal cues entered the research agenda only recently. Here, we introduce a new corpus of nonverbal vocalizations, which we recorded and submitted to perceptual and acoustic validation. It consists of 121 sounds expressing four positive emotions (achievement/triumph, amusement, sensual pleasure, and relief) and four negative ones (anger, disgust, fear, and sadness), produced by two female and two male speakers. For perceptual validation, a forced choice task was used (n = 20), and ratings were collected for the eight emotions, valence, arousal, and authenticity (n = 20). We provide these data, detailed for each vocalization, for use by the research community. High recognition accuracy was found for all emotions (86 %, on average), and the sounds were reliably rated as communicating the intended expressions. The vocalizations were measured for acoustic cues related to temporal aspects, intensity, fundamental frequency (f0), and voice quality. These cues alone provide sufficient information to discriminate between emotion categories, as indicated by statistical classification procedures; they are also predictors of listeners' emotion ratings, as indicated by multiple regression analyses. This set of stimuli seems a valuable addition to currently available expression corpora for research on emotion processing. It is suitable for behavioral and neuroscience research and might as well be used in clinical settings for the assessment of neurological and psychiatric patients. The corpus can be downloaded from Supplementary Materials. PMID- 23444122 TI - Radiologically Hyperdense Zones of the Patella Seem to Be Partial Osteonecroses Subsequent to Fracture Treatment. PMID- 23444121 TI - Mercury biomarkers and DNA methylation among Michigan dental professionals. AB - Modification of the epigenome may be a mechanism underlying toxicity and disease following chemical exposure. Animal and human data suggest that mercury (Hg) impacts DNA methylation. We hypothesize that methylmercury and inorganic Hg exposures from fish consumption and dental amalgams, respectively, may be associated with altered DNA methylation at global repetitive elements (long interspersed elements, LINE-1) and candidate genes related to epigenetic processes (DNMT1) and protection against Hg toxicity (SEPW1, SEPP1). Dental professionals were recruited at Michigan Dental Association (MDA) meetings in 2009 and 2010. Subjects (n=131) provided survey data (e.g. exposure sources, demographics) and biological samples for Hg measurement and epigenetic analysis. Total Hg was quantified via atomic absorption spectrophotometry in hair and urine, indicative of methylmercury and inorganic Hg exposures, respectively. Global repetitive and candidate gene methylation was quantified via pyrosequencing of bisulfite converted DNA isolated from buccal mucosa. Hair Hg (geometric mean (95% CI): 0.37 (0.31-0.44) ug/g) and urine Hg (0.70 (0.60-0.83) ug/L) were associated with sources of exposure (fish consumption and dental amalgams, respectively). Multivariable linear regression revealed a trend of SEPP1 hypomethylation with increasing hair Hg levels, and this was significant (P<0.05) among males. The trend remained when excluding non-dentists. No significant relationships between urine Hg and DNA methylation were observed. Thus, in a limited cohort, we identified an association between methylmercury exposure and hypomethylation of a potentially labile region of the genome (SEPP1 promoter), and this relationship was gender specific. PMID- 23444124 TI - Ecological context and metapopulation dynamics affect sex-ratio variation among dioecious plant populations. AB - BACKGROUND AND AIMS: Populations of dioecious flowering plants commonly exhibit heterogeneity in sex ratios and deviations from the equilibrium expectation of equal numbers of females and males. Yet the role of ecological and demographic factors in contributing towards biased sex ratios is currently not well understood. METHODS: Species-level studies from the literature were analysed to investigate ecological correlates of among-population sex-ratio variation and metapopulation models and empirical data were used to explore the influence of demography and non-equilibrium conditions on flowering sex ratios. KEY RESULTS: The survey revealed significant among-population heterogeneity in sex ratios and this was related to the degree of sampling effort. For some species, sex-ratio bias was associated with the proportion of non-reproductive individuals, with greater male bias in populations with a lower proportion of individuals that were flowering. Male-biased ratios were also found at higher altitudes and latitudes, and in more xeric sites. Simulations and empirical data indicated that clonal species exhibited greater heterogeneity in sex ratios than non-clonal species as a result of their slower approach to equilibrium. The simulations also indicated the importance of interactions between reproductive mode and founder effects, with greater departures from equilibrium in clonal populations with fewer founding individuals. CONCLUSIONS: The results indicate that sex-based differences in costs of reproduction and non-equilibrium conditions can each play important roles in affecting flowering sex ratios in populations of dioecious plants. PMID- 23444123 TI - The receptor-like kinase ERECTA contributes to the shade-avoidance syndrome in a background-dependent manner. AB - BACKGROUND AND AIMS: Plants growing at high densities perceive a decrease in the red to far-red (R/FR) ratio of incoming light. These changes in light quality trigger a suite of responses collectively known as the shade-avoidance syndrome (SAS) including hypocotyl and stem elongation, inhibition of branching and acceleration of flowering. METHODS: Quantitative trait loci (QTLs) were mapped for hypocotyl length to end-of-day far-red (EOD), a simulated shade-avoidance response, in recombinant inbred line (RIL) populations of Arabidopsis thaliana seedlings, derived from Landsberg erecta (Ler) and three accessions (Columbia, Col; Nossen, No-0; and Cape Verde Islands, Cvi-0). KEY RESULTS: Five loci were identified as being responsible for the EOD response, with a positive contribution of Ler alleles on the phenotype independently of the RIL population. Quantitative complementation analysis and transgenic lines showed that PHYB is the candidate gene for EODRATIO5 in the Ler * Cvi-0 RIL population, but not for two co-localized QTLs, EODRATIO1 and EODRATIO2 mapped in the Ler * No-0 and Ler * Col RIL populations, respectively. The ERECTA gene was also implicated in the SAS in a background-dependent manner. For hypocotyl length EOD response, a positive contribution of erecta alleles was found in Col and Van-0, but not in Ler, Cvi-0, Hir-1 or Ws. Furthermore, pleiotropic effects of ERECTA in the EOD response were also detected for petiole and lamina elongation, hyponastic growth, and flowering time. CONCLUSIONS: The results show that the analysis of multiple mapping populations leads to a better understanding of the SAS genetic architecture. Moreover, the background- and trait-dependent contribution of ERECTA in the SAS suggest that its function in shaded natural environments may be relevant for some populations in different phases of plant development. It is proposed that ERECTA is involved in canalization processes buffering the genetic variation of the SAS against environmental light fluctuations. PMID- 23444125 TI - Foreign body giant cells and osteoclasts are TRAP positive, have podosome-belts and both require OC-STAMP for cell fusion. AB - Macrophages have the ability to fuse and form multinucleated giant cells such as Osteoclast (OCs) and FBGCs. Osteoclast stimulatory transmembrane protein (OC STAMP) is an important cell surface protein involved in the formation of OCs. This study sought to determine if OC-STAMP also regulates formation of FBGCs using expression analysis and subsequent inhibition studies. qPCR and Western blot analysis showed that OC-STAMP expression is significantly higher in FBGCs compared to control monocytes (P < 0.05). Four days following cell culture, OCs were positive for TRAP and F-actin ring formation, but FBGCs were not. In contrast, FBGCs were positive for TRAP and showed podosome belts comprised of F actin on Day 8. FBGCs were subsequently plated onto dentine, but despite presenting some morphologic features of OCs (OC-STAMP expression, TRAP reactivity, and podosome belts) they failed to resorb bone. To evaluate a role for OC-STAMP in FBGCs, we inhibited this cell surface protein with anti-OC-STAMP antibody and observed that cell fusion and podosome belt formation was inhibited in both OCs and FBGCs. Our data support the hypothesis that OC-STAMP is a regulatory molecule for FBGCs; and that they are functionally distinct from OCs, despite similarities in gene expression profile, podosome belt formation, and TRAP expression. PMID- 23444127 TI - Spontaneous cutaneous endometriosis in the mons pubis region: a case report diagnosed by fine-needle aspiration biopsy. AB - Most cutaneous endometriosis develops at the site of an abdominal surgical scar. Spontaneous cutaneous endometriosis is extremely rare. We report a case of spontaneous cutaneous endometriosis in the mons pubis region. A 41-year-old woman presented with a mass in the right mons pubis, causing cyclic pain associated with menses. Fine-needle aspiration (FNA) biopsy was performed. The smears contained three cellular components: honeycombed sheets of glandular epithelial cells, fragments of ovoid-to-spindle shaped stromal cells, and background inflammatory cells, including hemosiderin-laden macrophages, histiocytes, and neutrophils. Biphasic clusters of glandular epithelial cells and stromal cells were identified. FNA cytology is a safe and useful adjunctive tool for diagnosing cutaneous endometriosis. PMID- 23444126 TI - Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts. AB - Autophagy is the main cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Beclin 1 is a key regulator of this process. In some settings autophagy and apoptosis seem to be interconnected. Recent reports indicate that fibroblasts in idiopathic pulmonary fibrosis (IPF) acquire resistance to apoptosis. Here, we examined the expression of beclin 1, and of the anti apoptotic protein Bcl-2 in human IPF fibroblasts using immunohistochemistry and molecular biology in bioptic sections, in primary cultures of fibroblasts taken from patients with IPF and in fibroblast cell lines. Expression of beclin 1 in fibroblasts from IPF was down-regulated in comparison with fibroblasts from normal lungs while the anti-apoptotic protein Bcl-2 expression was over-expressed. Treatment of fibroblast cell cultures with cisplatin induced a significant increase in beclin 1 and caspase 3 protein levels but a reduction in Bcl-2 expression. These observations were confirmed by the analysis of acid compartments and transmission electron microscopy. Our results demonstrate a modified expression of the apoptotic beclin 1 Bcl-2 proteins in human IPF fibroblasts suggesting the existence of an autophagy/apoptosis system dysfunction. PMID- 23444128 TI - Building on the past, shaping the future: the Environmental Mutagenesis and Genomics Society. AB - In late 2012, the members of the Environmental Mutagen Society voted to change its name to the Environmental Mutagenesis and Genomics Society. Here, we describe the thought process that led to adoption of the new name, which both respects the rich history of a Society founded in 1969 and reflects the many advances in our understanding of the nature and breadth of gene-environment interactions during the intervening 43 years. PMID- 23444129 TI - Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins. AB - Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a congenital malformation that leads to severe pulmonary hypertension and respiratory failure. It has been associated with deletion of, or mutation in, FOXF1 on 16q24.1, a gene encoding a forkhead transcription factor expressed in the mesenchyme of the developing lung. Here we report on the identification of a pericentric inversion on chromosome 16 (p11.2q24.1) in a case of lethal ACDMPV with atrioventricular septal defect and duodenal atresia. Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134 +/- 10 kb upstream (5'; centromeric) of FOXF1. This is suggestive of cis regulatory elements located more than 130 kb 5' of FOXF1, and analysis of genome wide data sets of chromatin modifications in two different cell types suggested that the FOXF1 regulatory domain covers more than 300 kb, and perhaps up to 433 kb, upstream of the gene, but only 3 kb downstream. The 588 kb gene-free region between FOXF1 and the next gene in the centromeric direction, IRF8, is highly conserved between species and divided into two distinct regulatory domains by an insulator element. Another putative insulator occurs just downstream of FOXF1. Our results further strengthen the association between FOXF1 and a spectrum of malformations that include ACDMPV, atrioventricular septal defects, and gastrointestinal atresia. Furthermore, the presented analysis aids in defining the critical genomic region for this syndrome. PMID- 23444130 TI - A variation of the cords of the brachial plexus on the right and a communication between the musculocutaneous and median nerves on the left upper limb: a unique case. AB - During routine anatomical dissection of the upper extremity of a 64-year-old cadaver for educational purposes, we observed variations in the brachial plexus on each side. On the right an anomaly of cord formation was present and on the left there was a communication between the musculocutaneous nerve (MCN) and median nerve (MN). On the right side the brachial plexus showed two trunks, superior (C5 and C6) and inferior (C7, C8, and T1); the middle trunk was absent. The superior trunk bifurcated into anterior and posterior divisions, the anterior division continued as the lateral cord forming the MCN. The posterior division gave off the subscapular branch. The inferior trunk trifurcated into radial, median, and ulnar nerves. The radial nerve gave off the axillary and thoracodorsal nerves. The ulnar nerve gave off the median cutaneous nerves of the arm and forearm. The median nerve received a small ascending branch from the MCN. On the right side, there was a communicating branch from the MCN to the MN in the lower third of the arm region. This communicating branch also gave rise to a muscular branch to the brachialis muscle and the lateral cutaneous nerve of forearm. No additional heads of the biceps brachii muscle were observed in either upper limb. Knowledge of the variations of the brachial plexus in humans can be valuable for operations of the shoulder joint and its repair for providing an effective block or treatment for anesthetists and also for explaining otherwise incomprehensible clinical signs for neurologists. PMID- 23444131 TI - Intramedullary thoracic spinal cord meningioma: a rare case report and review of the literature. AB - A 33-year-old male presented with a thoracic spinal intramedullary meningioma manifesting as bilateral asymmetric progressive weakness in the lower extremities. Preoperative magnetic resonance imaging (MRI) showed an intramedullary mass at the T1-T3 level. Intraoperative inspection found that the spinal cord was markedly swollen with a normal surface while dural attachment was not confirmed. Gross total removal of the tumor was achieved. The morphologic and immunohistochemical findings were compatible with the diagnosis of meningioma. Postoperatively, the patient recovered from preoperative paraplegia. Although extremely rare, meningiomas should be considered when diagnosing intramedullary tumors. PMID- 23444132 TI - Single-Incision laparoscopic surgery (SILS) for ventriculoperitoneal shunt placement. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) may facilitate safer shunt placement and lower distal obstruction rate than is seen in conventional surgery. OBJECTIVE: We reviewed our 2-year experience in SILS for ventriculoperitoneal shunt placement to evaluate its usefulness and safety.Materials and Methods In this retrospective study, we enrolled patients older than 18 years with dilated ventricle and syndromes of hydrocephalus. A total of 31 patients underwent 31 primary ventriculoperitoneal shunt placement surgery and two underwent revision surgery. All the procedures were performed by the SILS technique. RESULTS: The entire duration of ventriculoperitoneal shunt implantation ranged from 45 to 80 minutes, with mean operation time of 65 +/- 15.3 minutes. No major laparoscopy-related complications were noted. Shunt infection, peritonitis, and distal catheter malfunction occurred in one case (3.2%), proximal malfunction in one case (3.2%), and subcutaneous emphysema occurred in two cases (6.4%). The emphysema resolved within 2 days. Cosmetic results were "very good to good" in 17 patients (54.8%) and "satisfactory" in 14 patients (45.2%). The abdominal scars in most cases were nearly invisible. CONCLUSION: SILS is a safe and effective technique for ventriculoperitoneal shunt placement and can be accomplished with no higher risk of shunt infection and distal malfunction. Without an additional port, SILS allows good visualization of the peritoneal cavity to avoid major intra-abdominal complications. Only one 6-mm incision at the umbilicus area is required and is almost invisible after wound healing. PMID- 23444133 TI - Intracranial meningiomas in French West Indies and French Guiana. AB - BACKGROUND: Studies toward the end of the 20th century and in the first decade of the millennium show that meningioma represents the most common brain tumor of all types. There are no data available regarding meningiomas in the French West Indies and French Guiana. The author aimed to determine clinical and epidemiological features and provide data of meningiomas in French West Indies and French Guiana. MATERIAL AND METHODS: I reviewed the files of 358 patients who underwent surgery between January 2000 and December 2008. RESULTS: I found a sex ratio of 2.5 to 1-256 (71.5%) female to 102 (28.5%) male. Meningiomas were encountered mostly in the sixth decade of life and the most common anatomical location was cerebral convexities (29.32% of patients) followed by parasagittal and parafalcine (20.11%). The third most common was sphenoid wing meningioma. The incidence of meningiomas was 6.31 per 100,000 inhabitants. CONCLUSION: The current study attempts to estimate frequency and peculiarities of meningiomas in the French West Indies and French Guiana and is the first of its kind. PMID- 23444134 TI - A prospective, randomized, controlled trial comparing radiographic and clinical outcomes between stand-alone lateral interbody lumbar fusion with either silicate calcium phosphate or rh-BMP2. AB - OBJECT: Iliac crest autograft has traditionally been considered the gold standard for lumbar spine fusion, though it is not without drawbacks related to harvesting site pain and other complications. Bone graft alternatives, such as recombinant human bone morphogenetic protein 2 (rh-BMP2), are now widely used but also have unique risk profiles and substantially increase costs. The purpose of the current study was to compare the efficacy of rh-BMP2 and synthetic silicate calcium phosphate (SiCaP) as bone graft substitutes on fusion rates and clinical outcomes in patients undergoing single-level lumbar stand-alone extreme lateral interbody fusion (XLIF). METHODS: A prospective, randomized, controlled, clinical, and radiographic study was performed at a single institution. Thirty patients with L4 L5 degenerative disc disease (DDD) were enrolled. Patients were randomized into one of two groups, 15 underwent lumbar single-level stand-alone XLIF using SiCaP, and 15 using rh-BMP2. Clinical and radiographic results were compared between the study groups. Pain (visual analogue scale) and disability (Oswestry disability index) were assessed preoperatively and at postoperative weeks 1 and 6 and postoperative months 3, 6, 12, 24, and 36. Radiographic evaluations were performed at 6, 12, 24, and 36 months. Neurological examinations and adverse events were recorded at each visit. RESULTS: No intraoperative complications were observed in either treatment group, and clinical outcomes were similarly improved between bone graft substitutes from baseline to 36 months postoperative. Complications were transient hip flexion weakness (13%), insufficient indirect decompression (7%), subsidence (17%), excessive bone formation (4%), and adjacent segment disease (14%). Complication rates between the groups were similar, though with slightly more instances of subsidence in the SiCaP group and higher rates of excessive bone formation and adjacent segment disease in the rh-BMP2 group. Rates of fusion at different time points were different between the groups, with the SiCaP patients progressing more slowly toward solid fusion. However, at 36 months, 100% of patients undergoing XLIF achieved solid fusion. CONCLUSIONS: In stand-alone XLIF, SiCaP and rhBMP-2 bone graft substitutes both resulted in complete long-term fusion. rhBMP-2, however, seemed to result in more rapid early postoperative fusion, though with one instance of excessive bone formation in one patient that required subsequent surgical intervention. PMID- 23444135 TI - A new path for Human Cell. PMID- 23444136 TI - Selenoprotein K is required for palmitoylation of CD36 in macrophages: implications in foam cell formation and atherogenesis. AB - Selk is an ER transmembrane protein important for calcium flux and macrophage activation, but its role in foam cell formation and atherosclerosis has not been evaluated. BMDMs from Selk(-/-) mice exhibited decreased uptake of modLDL and foam cell formation compared with WT controls, and the differences were eliminated with anti-CD36 blocking antibody. CD36 expression was decreased in TNF alpha-stimulated Selk(-/-) BMDMs compared with WT controls. Fluorescence microscopy revealed TNF-alpha-induced clustering of CD36 in WT BMDMs indicative of lipid raft localization, which was absent in Selk(-/-) BMDMs. Fractionation revealed lower levels of CD36 reaching lipid rafts in TNF-alpha-stimulated Selk( /-) BMDMs. Immunoprecipitation showed that Selk(-/-) BMDMs have decreased CD36 palmitoylation, which occurs at the ER membrane and is crucial for stabilizing CD36 expression and directing its localization to lipid rafts. To assess if this phenomenon had a role in atherogenesis, a HFD was fed to irradiated Ldlr(-/-) mice reconstituted with BM from Selk(-/-) or WT mice. Selk was detected in aortic plaques of controls, particularly in macrophages. Selk(-/-) in immune cells led to reduction in atherosclerotic lesion formation without affecting leukocyte migration into the arterial wall. These findings suggest that Selk is important for stable, localized expression of CD36 in macrophages during inflammation, thereby contributing to foam cell formation and atherogenesis. PMID- 23444137 TI - PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells. AB - We have previously shown that alpha-thalassemia mental retardation X-linked (ATRX) and histone H3.3 are key regulators of telomeric chromatin in mouse embryonic stem cells. The function of ATRX and H3.3 in the maintenance of telomere chromatin integrity is further demonstrated by recent studies that show the strong association of ATRX/H3.3 mutations with alternative lengthening of telomeres in telomerase-negative human cancer cells. Here, we demonstrate that ATRX and H3.3 co-localize with the telomeric DNA and associated proteins within the promyelocytic leukemia (PML) bodies in mouse ES cells. The assembly of these telomere-associated PML bodies is most prominent at S phase. RNA interference (RNAi)-mediated knockdown of PML expression induces the disassembly of these nuclear bodies and a telomere dysfunction phenotype in mouse ES cells. Loss of function of PML bodies in mouse ES cells also disrupts binding of ATRX/H3.3 and proper establishment of histone methylation pattern at the telomere. Our study demonstrates that PML bodies act as epigenetic regulators by serving as platforms for the assembly of the telomeric chromatin to ensure a faithful inheritance of epigenetic information at the telomere. PMID- 23444138 TI - Coactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responses. AB - Nuclear receptors (NRs) are central regulators of pathophysiological processes; however, how their responses intertwine is still not fully understood. The aim of this study was to determine whether and how steroid NRs can influence each other's activity under co-agonist treatment. We used a unique system consisting of a multicopy integration of an estrogen receptor responsive unit that allows direct visualization and quantification of estrogen receptor alpha (ERalpha) DNA binding, co-regulator recruitment and transcriptional readout. We find that ERalpha DNA loading is required for other type I nuclear receptors to be co recruited after dual agonist treatment. We focused on ERalpha/glucocorticoid receptor interplay and demonstrated that it requires steroid receptor coactivators (SRC-2, SRC-3) and the mediator component MED14. We then validated this cooperative interplay on endogenous target genes in breast cancer cells. Taken together, this work highlights another layer of mechanistic complexity through which NRs cross-talk with each other on chromatin under multiple hormonal stimuli. PMID- 23444139 TI - Altered error specificity of RNase H-deficient HIV-1 reverse transcriptases during DNA-dependent DNA synthesis. AB - Asp(443) and Glu(478) are essential active site residues in the RNase H domain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). We have investigated the effects of substituting Asn for Asp(443) or Gln for Glu(478) on the fidelity of DNA-dependent DNA synthesis of phylogenetically diverse HIV-1 RTs. In M13mp2 lacZalpha-based forward mutation assays, HIV-1 group M (BH10) and group O RTs bearing substitutions D443N, E478Q, V75I/D443N or V75I/E478Q showed 2.0- to 6.6-fold increased accuracy in comparison with the corresponding wild type enzymes. This was a consequence of their lower base substitution error rates. One-nucleotide deletions and insertions represented between 30 and 68% of all errors identified in the mutational spectra of RNase H-deficient HIV-1 group O RTs. In comparison with the wild-type RT, these enzymes showed higher frameshift error rates and higher dissociation rate constants (koff) for DNA/DNA template-primers. The effects on frameshift fidelity were similar to those reported for mutation E89G and suggest that in HIV-1 group O RT, RNase H inactivation could affect template/primer slippage. Our results support a role for the RNase H domain during plus-strand DNA polymerization and suggest that mutations affecting RNase H function could also contribute to retrovirus variability during the later steps of reverse transcription. PMID- 23444140 TI - Large scale chromosomal mapping of human microRNA structural clusters. AB - MicroRNAs (miRNAs) can group together along the human genome to form stable secondary structures made of several hairpins hosting miRNAs in their stems. The few known examples of such structures are all involved in cancer development. A large scale computational analysis of human chromosomes crossing sequence analysis and deep sequencing data revealed the presence of >400 structural clusters of miRNAs in the human genome. An a posteriori analysis validates predictions as bona fide miRNAs. A functional analysis of structural clusters position along the chromosomes co-localizes them with genes involved in several key cellular processes like immune systems, sensory systems, signal transduction and development. Immune systems diseases, infectious diseases and neurodegenerative diseases are characterized by genes that are especially well organized around structural clusters of miRNAs. Target genes functional analysis strongly supports a regulatory role of most predicted miRNAs and, notably, a strong involvement of predicted miRNAs in the regulation of cancer pathways. This analysis provides new fundamental insights on the genomic organization of miRNAs in human chromosomes. PMID- 23444141 TI - Modular assembly of transposon integratable multigene vectors using RecWay assembly. AB - Studying complex biological processes such as cancer development, stem cell induction and transdifferentiation requires the modulation of multiple genes or pathways at one time in a single cell. Herein, we describe straightforward methods for rapid and efficient assembly of bacterial marker free multigene cassettes containing up to six complementary DNAs/short hairpin RNAs. We have termed this method RecWay assembly, as it makes use of both Cre recombinase and the commercially available Gateway cloning system. Further, because RecWay assembly uses truly modular components, it allows for the generation of randomly assembled multigene vector libraries. These multigene vectors are integratable, and later excisable, using the highly efficient piggyBac (PB) DNA transposon system. Moreover, we have dramatically improved the expression of stably integrated multigene vectors by incorporation of insulator elements to prevent promoter interference seen with multigene vectors. We demonstrate that insulated multigene PB transposons can stably integrate and faithfully express up to five fluorescent proteins and the puromycin-thymidine kinase resistance gene in vitro, with up to 70-fold higher gene expression compared with analogous uninsulated vectors. RecWay assembly of multigene transposon vectors allows for widely applicable modelling of highly complex biological processes and can be easily performed by other research laboratories. PMID- 23444142 TI - The MASTER (methylation-assisted tailorable ends rational) ligation method for seamless DNA assembly. AB - Techniques for assembly of designed DNA sequences are important for synthetic biology. So far, a few methods have been developed towards high-throughput seamless DNA assembly in vitro, including both the homologous sequences-based system and the type IIS-mediated system. Here, we describe a novel method designated 'MASTER Ligation', by which multiple DNA sequences can be seamlessly assembled through a simple and sequence-independent hierarchical procedure. The key restriction endonuclease used, MspJI, shares both type IIM and type IIS properties; thus, it only recognizes the methylation-specific 4-bp sites, (m)CNNR (R = A or G), and cuts DNA outside of the recognition sequences. This method was tested via successful assembly of either multiple polymerase chain reaction amplicons or restriction fragments of the actinorhodin biosynthetic cluster of Streptomyces coelicolor (~29 kb), which was further heterologously expressed in a fast-growing and moderately thermophilic strain, Streptomyces sp. 4F. PMID- 23444143 TI - Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods. AB - Gene set analysis (GSA) is used to elucidate genome-wide data, in particular transcriptome data. A multitude of methods have been proposed for this step of the analysis, and many of them have been compared and evaluated. Unfortunately, there is no consolidated opinion regarding what methods should be preferred, and the variety of available GSA software and implementations pose a difficulty for the end-user who wants to try out different methods. To address this, we have developed the R package Piano that collects a range of GSA methods into the same system, for the benefit of the end-user. Further on we refine the GSA workflow by using modifications of the gene-level statistics. This enables us to divide the resulting gene set P-values into three classes, describing different aspects of gene expression directionality at gene set level. We use our fully implemented workflow to investigate the impact of the individual components of GSA by using microarray and RNA-seq data. The results show that the evaluated methods are globally similar and the major separation correlates well with our defined directionality classes. As a consequence of this, we suggest to use a consensus scoring approach, based on multiple GSA runs. In combination with the directionality classes, this constitutes a more thorough basis for an enriched biological interpretation. PMID- 23444144 TI - Pseudo-complementary PNA actuators as reversible switches in dynamic DNA nanotechnology. AB - The structural reorganization of nanoscale DNA architectures is a fundamental aspect in dynamic DNA nanotechnology. Commonly, DNA nanoarchitectures are reorganized by means of toehold-expanded DNA sequences in a strand exchange process. Here we describe an unprecedented, toehold-free switching process that relies on pseudo-complementary peptide nucleic acid (pcPNA) by using a mechanism that involves double-strand invasion. The usefulness of this approach is demonstrated by application of these peptide nucleic acids (PNAs) as switches in a DNA rotaxane architecture. The monomers required for generating the pcPNA were obtained by an improved synthesis strategy and were incorporated into a PNA actuator sequence as well as into a short DNA strand that subsequently was integrated into the rotaxane architecture. Alternate addition of a DNA and PNA actuator sequence allowed the multiple reversible switching between a mobile rotaxane macrocycle and a stationary pseudorotaxane state. The switching occurs in an isothermal process at room temperature and is nearly quantitative in each switching step. pcPNAs can potentially be combined with light- and toehold-based switches, thus broadening the toolbox of orthogonal switching approaches for DNA architectures that open up new avenues in dynamic DNA nanotechnology. PMID- 23444145 TI - Rapamycin inhibits BMP-7-induced osteogenic and lipogenic marker expressions in fetal rat calvarial cells. AB - Bone morphogenetic proteins (BMPs) promote osteoblast differentiation and bone formation in vitro and in vivo. BMPs canonically signal through Smad transcription factors, but BMPs may activate signaling pathways traditionally stimulated by growth factor tyrosine kinase receptors. Of these, the mTOR pathway has received considerable attention because BMPs activate P70S6K, a downstream effector of mTOR, suggesting that BMP-induced osteogenesis is mediated by mTOR activation. However, contradictory effects of the mTOR inhibitor rapamycin (RAPA) on bone formation have been reported. Since bone formation is thought to be inversely related to lipid accumulation and mTOR is also important for lipid synthesis, we postulated that BMP-7 may stimulate lipogenic enzyme expression in a RAPA-sensitive mechanism. To test this hypothesis, we determined the effects of RAPA on BMP-7-stimulated expression of osteogenic and lipogenic markers in cultured fetal rat calvarial cells. Our study showed that BMP-7 promoted the expression of osteogenic and lipogenic markers. The effect of BMP-7 on osteogenic markers was greater in magnitude than on lipogenic markers and was temporally more sustained. RAPA inhibited basal and BMP-7-stimulated osteogenic and lipogenic marker expression and bone nodule mineralization. The acetyl CoA carboxylase inhibitor TOFA stimulated the expression of osteoblast differentiation markers, whereas palmitate suppressed their expression. We speculate that the BMP-7-stimulated adipogenesis is part of the normal anabolic response to BMPs, but that inappropriate activation of the lipid biosynthetic pathway by mTOR could have deleterious effects on bone formation and could explain paradoxical effects of RAPA to promote bone formation. PMID- 23444146 TI - Honing in on phenotypes: comprehensive two-dimensional gas chromatography of herbivory-induced volatile emissions and novel opportunities for system-level analyses. AB - Plant volatile organic compound (VOC) production requires a complex network of biochemical pathways, which, although well mapped from a biochemical point of view, remains only partly understood with regard to its physiological and genetic regulation. Additionally, although analytical procedures for plant VOC measurement have become increasingly faster and more sensitive in recent years, pinpointing relevant shifts in VOC production from the thousands of molecular fragments that are generated by modern mass spectrometer instruments remains challenging. Here we discuss novel opportunities for system-wide analysis provided by the implementation of non-targeted data processing and multivariate statistics in VOC analysis. We illustrate the value of implementing non-targeted data processing with examples of recent findings from our group on the interactive control exerted by salivary components of a lepidopteran herbivore, Manduca sexta, on herbivory-induced VOC emissions in the wild tobacco Nicotiana attenuata. Finally, we briefly discuss the use of multi-platform data integration for probing the nature of metabolic and regulatory systems underlying VOC emissions. PMID- 23444147 TI - Treatment preference among suicidal and self-injuring women with borderline personality disorder and PTSD. AB - OBJECTIVES: This study examined treatment preferences among suicidal and self injuring women with borderline personality disorder (BPD) and PTSD. METHOD: Women (N = 42, M(age) = 34) with BPD, PTSD and recent intentional self-injury were evaluated upon entry into a psychotherapy outcome study. RESULTS: The majority preferred a combined dialectical behavior therapy (DBT) and prolonged exposure (PE) treatment (73.8%), followed by DBT alone (26.2%), and PE alone (0%). Women who preferred the combined treatment were more likely to report a desire to obtain relief from PTSD and to receive specific DBT and PE treatment components as reasons underlying this preference. Few women (21.4%) reported concerns about PE, but those who did were more likely to prefer DBT alone. More severe PTSD re experiencing symptoms, a childhood index trauma, and less reduction in positive affect after a trauma interview predicted a preference for the combined treatment. CONCLUSIONS: These results may help to inform treatment for these complex patients. PMID- 23444148 TI - The management of cytotoxic drug wastes in Shiraz, Iran: an overview of all government and private chemotherapy settings, and comparison with national and international guidelines. AB - Excessive use of cytotoxic drugs owing to a dramatic increase in malignancy incidence leads to the production of high amounts of cytotoxic wastes. In Iran, management of hazardous wastes has been neglected in recent decades. The aim of this study was to determine the amount of intravenous cytotoxic drug wastes, their collection and disposal status in chemotherapy wards, and to compare the current status with standard guidelines in Shiraz, Iran. This cross-sectional study was performed using data collected during 2 consecutive months, from 22 June to 22 August 2011, in all 13 chemotherapy wards in Shiraz. The amount of prescribed drugs, drugs waste, collection and disposal status of cytotoxic drugs were recorded. We then compared the current status of waste collection and disposal in our samples with our national guideline. The prescription of cytotoxic drugs and the amount of total drugs waste reached approximately 6 and 0.2 kilograms respectively. Total vials volume was calculated to be approximately 1000 l in order to estimate the volume of containers required for the encapsulation method. The results demonstrated that the current status of cytotoxic waste collection and disposal is inappropriate, and none of the facilities under study followed our guidelines perfectly. The adherence to all recommendations and guidelines was poorer in private wards than in government-run ones. The management of cytotoxic wastes is inappropriate and our existing national guidelines are lacking. Suggestions for the best management of cytotoxic waste are revising the existing guidelines, allocating a sufficient budget, training healthcare workers, providing multiple administration options of cytotoxic drugs and accomplishing a surveillance system. PMID- 23444149 TI - Alternatives for solid waste management in Isfahan, Iran: a case study. AB - This articles presents the status of municipal solid waste (MSW) management practices in the city of Isfahan, Iran. It provides an overview of the generation, collection, separation, recycling and disposal of MSW. Field studies were carried out from 2009 to 2010. According to this study, the city generates about 399,000 metric tons of MSW per year, of which 72.5% is organic matter. In Isfahan more than 90% of the MSW is collected by official municipal forces and the other 10% is collected by informal collectors. About 70% of the MSW in Isfahan is composted to produce a humus material, 5% is rejected and 25% is stockpiled for future use as fuel in a waste-to-energy incineration plant. Non compostable waste and other residues are landfilled. This investigation also includes an analysis of economic benefits that could be realized by implementing incineration and a discussion of the challenges confronted in Isfahan for implementing changes to the city's existing MSW management system. This article concludes with recommendations for improving the city's MSW management system. PMID- 23444150 TI - Hybrid solid anaerobic digestion batch: biomethane production and mass recovery from the organic fraction of solid waste. AB - An experimental apparatus was constructed to perform hybrid solid anaerobic digestion batch processing of the organic fraction of municipal solid waste. The preliminary process was carried out with a high total solids concentration of about 33% w w(-1) and with an initial organic load of about 340 kg VS kg(-1). The fresh organic fraction to inoculum ratio used to enhance the anaerobic process start-up was 0.910 kg VS kg VS(-1). The process was conducted by spreading the percolate on top of the mixture. The percolate was stored in a separate section of the apparatus with a mean hydraulic retention time of about 1 day. During the process, acetate, butyrate and propionate in the percolate reached concentrations ranging from 3000 to 11 000 mg L(-1). In spite of these high concentrations, the biomethane produced from both the solid and the percolate was quite high, at about 210 NL kg VS(-1). The digestate obtained at the end of the run showed rather good features for being classified as an organic fertilizer according to Italian law. However, a residual phytotoxicity level was detected by a standardized test showing a germination index of about 50%. PMID- 23444151 TI - Development and application of the decision support system for municipal solid waste management in central Taiwan. AB - Municipal solid waste management (MSWM) is an important, practical and challenging environmental subject. The processes of a MSWM system include household collection, transportation, treatment, material recycling, compost and disposal. A regional program of MSWM is more complicated owing to the involvement of multi-municipality and multi-facility issues. Therefore, an effective decision support system capable of solving regional MSWM problems is necessary for decision-makers. This article employs linear programming techniques to establish a MSWM decision support system (MSWM-DSS) that is able to determine the least costs of regional MSWM strategies. The results of investigating a real-world case in central Taiwan indicate that a regional program is more economical and efficient. For the redeployment of MSW streams, the relatively least cost of operation for the MSWM system can still be achieved through the re-estimation of the MSWM-DSS. This tool and results are useful for MSWM policy-making in central Taiwan. PMID- 23444152 TI - Analysis of energetic and exergetic efficiency, and environmental benefits of biomass integrated gasification combined cycle technology. AB - The problem of the high carbon dioxide emissions linked to power generation makes necessary active research on the use of biofuels in gas turbine systems as a promising alternative to fossil fuels. Gasification of biomass waste is particularly of interest in obtaining a fuel to be run in gas turbines, as it is an efficient biomass-to-biofuel conversion process, and an integration into a combined cycle power plant leads to a high performance with regard to energetic efficiency. The goal of this study was to carry out an energetic, exergetic and environmental analysis of the behaviour of an integrated gasification combined cycle (IGCC) plant fuelled with different kinds of biomass waste by means of simulations. A preliminary economic study is also included. Although a technological development in gasification technology is necessary, the results of simulations indicate a high technical and environmental interest in the use of biomass integrated gasification combined cycle (BioIGCC) systems for large-scale power generation from biomass waste. PMID- 23444153 TI - Assessment of municipal solid waste management scenarios in Irkutsk (Russia) using a life cycle assessment-integrated waste management model. AB - Continuous growth in the quantity of municipal solid waste (MSW) and increasing demands for their environmentally-friendly treatment are one of the main consequences of the growing social and economic development rate in modern society. Despite ecologically sustainable trends in waste management systems around the world, open dumps are still the main waste treatment option in Russia. This study aims to help the local municipality administration in Irkutsk (Russia) identify the most appropriate direction for current waste management and its optimization. Within this study four developed MSW management scenarios were assessed and compared with respect to their ecological, economic and social aspects using a life cycle-based integrated waste management model. The evaluation results of these scenarios show that the development of environmental sustainability and the reduction of social effects lead to an increase in handling of costs of waste. The best scenario, regarding both environmental and social aspects, is scenario four, which includes the separate collection and reprocessing of recyclables in combination with an aerobic mechanical-biological pre-treatment of the residual waste before landfilling. However, this scenario is 3.6 times more expensive than the existing system. The results of all assessed scenarios were further analyzed and recommendations were made to design integrated waste management solutions that are optimal not only from the ecological and social points of view, but which are also realistic within the given economic situation. PMID- 23444154 TI - Protein tyrosine nitration in higher plants grown under natural and stress conditions. AB - Protein tyrosine nitration is a post-translational modification (PTM) mediated by reactive nitrogen species (RNS) that is linked to nitro-oxidative damages in plant cells. During the last decade, the identification of proteins undergoing this PTM under adverse environmental conditions has increased. However, there is also a basal endogenous nitration which seems to have a regulatory function. The technological advances in proteome analysis have allowed identifying these modified proteins and have shown that the number and identity of the nitrated proteins change among plant species, analysed organs and growing/culture conditions. In this work, the current knowledge of protein tyrosine nitration in higher plants under different situations is reviewed. PMID- 23444155 TI - Dentists should require DICOM as the standard for storing dental radiographs. PMID- 23444156 TI - Evaluation of bond strength and thickness of adhesive layer according to the techniques of applying adhesives in composite resin restorations. AB - Adhesive restorations have increasingly been used in dentistry, and the adhesive system application technique may determine the success of the restorative procedure. The aim of this study was to evaluate the influence of the application technique of two adhesive systems (Clearfil SE Bond and Adper Scotchbond MultiPurpose) on the bond strength and adhesive layer of composite resin restorations. Eight human third molars were selected and prepared with Class I occlusal cavities. The teeth were restored with composite using various application techniques for both adhesives, according to the following groups (n = 10): group 1 (control), systems were applied and adhesive was immediately light activated for 20 seconds without removing excesses; group 2, excess adhesive was removed with a gentle jet of air for 5 seconds; group 3, excess was removed with a dry microbrushtype device; and group 4, a gentle jet of air was applied after the microbrush and then light activation was performed. After this, the teeth were submitted to microtensile testing. For the two systems tested, no statistical differences were observed between groups 1 and 2. Groups 3 and 4 presented higher bond strength values compared with the other studied groups, allowing the conclusion that excess adhesive removal with a dry microbrush could improve bond strength in composite restorations. Predominance of adhesive fracture and thicker adhesive layer were observed via scanning electron microscopy (SEM) in groups 1 and 2. For groups 3 and 4, a mixed failure pattern and thinner adhesive layer were verified. Clinicians should be aware that excess adhesive may negatively affect bond strength, whereas a thin, uniform adhesive layer appears to be favorable. PMID- 23444157 TI - Treatment of multiple adjacent Miller Class I and II gingival recessions with collagen matrix and the modified coronally advanced tunnel technique. AB - OBJECTIVE: To clinically evaluate the treatment of Miller Class I and II multiple adjacent gingival recessions using the modified coronally advanced tunnel technique combined with a newly developed bioresorbable collagen matrix of porcine origin. METHOD AND MATERIALS: Eight healthy patients exhibiting at least three multiple Miller Class I and II multiple adjacent gingival recessions (a total of 42 recessions) were consecutively treated by means of the modified coronally advanced tunnel technique and collagen matrix. The following clinical parameters were assessed at baseline and 12 months postoperatively: full mouth plaque score (FMPS), full mouth bleeding score (FMBS), probing depth (PD), recession depth (RD), recession width (RW), keratinized tissue thickness (KTT), and keratinized tissue width (KTW). The primary outcome variable was complete root coverage. RESULTS: Neither allergic reactions nor soft tissue irritations or matrix exfoliations occurred. Postoperative pain and discomfort were reported to be low, and patient acceptance was generally high. At 12 months, complete root coverage was obtained in 2 out of the 8 patients and 30 of the 42 recessions (71%). CONCLUSION: Within their limits, the present results indicate that treatment of Miller Class I and II multiple adjacent gingival recessions by means of the modified coronally advanced tunnel technique and collagen matrix may result in statistically and clinically significant complete root coverage. Further studies are warranted to evaluate the performance of collagen matrix compared with connective tissue grafts and other soft tissue grafts. PMID- 23444158 TI - Bidirectionally positioned flap surgery: a case report with 3-year follow-up. AB - A new technique to cover recessions to take advantage of connective tissue grafts and coronally advanced flaps is proposed. A 34-year-old woman presented with a 2 mm Class I recession on the buccal aspect of her maxillary right canine. A full thickness flap was placed coronally to cover the exposed root, and a partial thickness flap was positioned apically. Complete root coverage was obtained, and the width of keratinized tissue had increased from 2 to 4 mm at the 6-month postoperative visit. These clinical outcomes were maintained for 3 years. This single surgical approach benefits from obtaining not only complete root coverage but also increasing width of keratinized tissue, without requiring a second surgical site. PMID- 23444159 TI - Prosthodontics in digital times: a case report. AB - Dentistry has not been exempt from changes in this era of technology-driven revolution. Entire workflows are already digitalized, and restorations are designed and manufactured using computer-aided solutions. This case report describes the reconstruction of 24 teeth using digital techniques. PMID- 23444160 TI - Rehabilitation of an edentulous atrophic maxilla with four unsplinted narrow diameter titanium-zirconium implants supporting an overdenture. AB - The edentulous maxilla is often affected by bone resorption, sometimes making it difficult to place standard diameter implants. Narrow diameter implants made of titanium-zirconium (Ti-Zr) alloy, which has superior mechanical properties compared with titanium, have been proposed for these difficult situations. This retrospective clinical observation reports the outcome of the use of reduced diameter implants made of Ti-Zr alloy supporting maxillary overdentures retained with locator abutments. The charts of all patients who received maxillary overdentures supported by four unsplinted implants from January 2009 to June 2010 at the Department of Periodontology and Prosthodontics, Eastman Dental Hospital, Rome, Italy, were reviewed. All patients treated with four narrow diameter Ti-Zr implants were selected for the present case series. Ten patients were found, six of whom received augmentation procedures. After 12 to 16 months of follow-up, no implants were lost, and only one implant showed bone resorption greater than 1.5 mm. Implants showed a success rate of 97.5% and a survival rate of 100%. All prostheses were successfully in function. The present case series showed promising results regarding the use of narrow diameter implants made of Ti-Zr supporting maxillary overdentures retained with locator abutments. PMID- 23444161 TI - Marginal bone loss around unsplinted mini-implants supporting maxillary overdentures: a preliminary comparative study between partial and full palatal coverage. AB - OBJECTIVE: To evaluate and compare marginal bone loss around mini-implants supporting maxillary overdentures with either partial or full palatal coverage. METHOD AND MATERIALS: Nineteen edentulous patients complaining of retention problems involving their maxillary dentures were randomly allocated in two groups. Group I (n = 10) received maxillary dentures with full palatal coverage, and group II (n = 9) received maxillary dentures with partial palatal coverage. In total, 114 mini-implants (6 per patient) were inserted using the nonsubmerged flapless surgical approach and loaded immediately with maxillary overdentures. Each implant was evaluated at the time of initial prosthetic loading and at 6, 12, and 24 months thereafter. Radiographic evaluation was performed in terms of vertical and horizontal bone loss. Implant mobility (via Periotest values) was measured using a Periotest device, and patient satisfaction was evaluated with a visual analog scale. The cumulative survival rate was calculated using Kaplan Meier analysis. RESULTS: After 2 years, the mean vertical bone loss in groups I and II was 5.38 and 6.29 mm, respectively, while the mean horizontal bone loss in groups I and II was 1.52 and 1.93 mm, respectively. Most bone resorption occurred within 6 months after overdenture insertion in both groups. Group II recorded significant higher vertical bone loss and Periotest values than group I at all observation times. The cumulative survival rates of the mini-implants were 78.4% and 53.8% for groups I and II, respectively. All patients were satisfied with their maxillary overdentures in terms of retention and chewing ability. CONCLUSION: Rehabilitation of edentulous maxillae with unsplinted mini-implants supporting overdentures and in particular with a combination of partial palatal coverage is not recommended because of excessive marginal bone resorption and the higher failure rate of mini-implants than was expected. PMID- 23444162 TI - Clinical outcome in periradicular surgery: effect of patient- and tooth-related factors--a multicenter study. AB - OBJECTIVE: To evaluate the effect of patient- and tooth-related factors on the outcome of apical surgery in a multicenter study. METHOD AND MATERIALS: A total of 281 teeth in 255 patients undergoing periradicular surgery were investigated clinically and radiographically 6 to 12 months postoperatively. RESULTS: The overall success rate was 88.0%. Sex was a significant (P = .024) predictor, with a success rate of 89.8% in females and 84.0% in males. The success rate was significantly higher in patients 31 to 40 years of age. The treatment of premolars resulted in a significantly higher success rate (91.9%) than the treatment of anterior teeth (86.1%, P = .042) and molars (86.4 %, P = .026). The loss of the buccal bone plate and the extension of apical osteolysis to the furcation area in molars resulted in a considerably lower success rate. Lesion size, preoperative pain, tenderness to percussion, fistula, and resurgery were significant factors. CONCLUSION: There are several factors influencing the success rate of apical surgery that must be taken into account when considering apical surgery as a treatment alternative. PMID- 23444163 TI - Dental treatment for high-risk patients with refractory heart failure: a retrospective observational comparison study. AB - OBJECTIVE: Heart failure affects large population groups. The understanding of the etiology, pathophysiology, and treatment of heart failure has changed considerably within the last few years. The changes have significant implications for the medical management of the disease, as well as on the ability to provide proper dental treatment for these patients. METHOD AND MATERIALS: A retrospective observational study of the outcome following dental treatment of 54 patients was performed: 32 with refractory heart failure stage D (study group) and 22 patients at risk for heart failure stages A to C (control group). Dental management of these patients concentrated on the prevention of iatrogenic, dental setting- induced, and precipitating factors of heart failure. To prevent deterioration of patients' medical condition, a comprehensive, tailored treatment including adequate anxiolysis, close monitoring, profound dental anesthesia, and close follow-up was used. A previously described three-step gradual level protocol (at home, waiting room, and dental chair) was adopted. RESULTS: All the planned dental procedures were successfully completed. Six patients experienced respiratory distress during treatment, and five patients demonstrated arrhythmias during dental treatment. Only minute differences were found between the groups regarding blood pressure and heart rate. CONCLUSION: Use of the suggested protocol facilitated the completion of planned dental treatments for all patients. Thus, providing essential dental treatment for severe heart failure patients with special attention to their medical problems and the use of medications and supporting means to prevent health-compromising situations is recommended. PMID- 23444164 TI - Radicular cyst masquerading as a multilocular radiolucency. AB - Radicular cysts are the most common cystic lesions of the jaw. Most of these lesions involve the apex of the offending tooth and appear as well-defined periapical radiolucencies. This case presents an unusually large multilocular radicular cyst crossing the midline and involving almost the entire body of the mandible. The clinical and radiographic appearance mimicked an aggressive cyst or benign tumor. The lesion was surgically excised, and the teeth were endodontically treated without any postoperative complications. PMID- 23444165 TI - Novel decision tree algorithms for the treatment planning of compromised teeth. AB - In clinical practice, dentists are faced with the dilemma of whether to treat, maintain, or extract a tooth. Of primary importance are the patient's desires and the restorability and periodontal condition of the tooth/teeth in question. Too often, clinicians extract teeth when endodontic therapy, crown-lengthening surgery, forced orthodontic eruption, or regenerative therapy can be used with predictable results. In addition, many clinicians do not consider the use of questionable teeth as provisional or transitional abutments. The aim of this article is to present a novel decision tree approach that will address the clinical deductive reasoning, based on the scientific literature and exemplified by selective case presentations, that may help clinicians make the right decision. Innovative decision tree algorithms will be proposed that consider endodontic, restorative, and periodontal assessments to improve and possibly eliminate erroneous decision making. Decision-based algorithms are dynamic and must be continually updated in accordance with new evidence-based studies. PMID- 23444166 TI - Terrestrial gastropods (Helix spp) as sentinels of primary DNA damage for biomonitoring purposes: a validation study. AB - We validated the alkaline comet assay in two species of land snail (Helix aspersa and Helix vermiculata) to test their suitability as sentinels for primary DNA damage in polluted environments. The study was conducted under the framework of a biomonitoring program for a power station in Central Italy that had recently been converted from oil to coal-fired plant. After optimizing test conditions, the comet assay was used to measure the % Tail DNA induced by in vitro exposure of hemocytes to different concentrations of a reactive oxygen species (H2 O2 ). The treatment induced significant increases in this parameter with a concentration effect, indicating the effectiveness of the assay in snail hemocytes. After evaluating possible differences between the two species, we sampled them in three field sites at different distances from the power station, and in two reference sites assumed to have low or no levels of pollution. No species differences emerged. Percent Tail DNA values in snails from the sites near the power station were higher than those from control sites. An inverse correlation emerged between % Tail DNA and distance from the power station, suggesting that the primary DNA damage decreased as distance increased away from the pollution source. Detection of a gradient of heavy metal concentration in snail tissues suggests that these pollutants are a potential cause of the observed pattern. The comet assay appears to be a suitable assay and Helix spp. populations suitable sentinels to detect the genotoxic impact of pollutants. PMID- 23444167 TI - Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles. AB - We investigated the effect of AGG interruptions on fragile X repeat instability upon transmission of fragile X intermediate and small premutation alleles with 45 69 CGG repeats. The FMR1 repeat structure was determined for 375 mothers, 48 fathers, and 538 offspring (457 maternal and 81 paternal transmissions) using a novel PCR assay to determine repeat length and AGG interruptions. The number of AGG interruptions and the length of uninterrupted CGG repeats at the 3' end were correlated with repeat instability on transmission. Maternal alleles with no AGGs conferred the greatest risk for unstable transmissions. All nine full mutation expansions were inherited from maternal alleles with no AGGs. Furthermore, the magnitude of repeat expansion was larger for alleles lacking AGG interruptions. Transmissions from paternal alleles with no AGGs also exhibited greater instability than those with one or more AGGs. Our results demonstrate that characterization of the AGG structure within the FMR1 repeat allows more accurate risk estimates of repeat instability and expansion to full mutations for intermediate and small premutation alleles. PMID- 23444168 TI - Effective application of the methanol-based PreservCyt(TM) fixative and the Cellient(TM) automated cell block processor to diagnostic cytopathology, immunocytochemistry, and molecular biology. AB - We studied the feasibility of immunocytochemistry (ICC), in situ hybridization (ISH), and polymerase chain reaction (PCR) after Cellient(TM) automated cell block processing, and tested whether methanol-based PreservCyt(TM) fixation could replace formalin fixation, in an attempt to eliminate toxic formaldehyde vapors. Immunostaining with 30 different antibodies was performed on cell blocks from 73 FNA specimens and 42 body cavity fluid specimens prepared by Cellient(TM) automated processing that uses the methanol-based fixative (PreservCyt(TM) ). For each antibody we evaluated ICC in at least three different cell block specimens and compared it with immunohistochemistry (IHC) in formalin-fixed, paraffin embedded (FFPE) histological sections from the corresponding tumors. The quality of DNA and RNA in Cellient(TM) blocks was analyzed by ISH, applying a SYT gene break-apart assay and EBER probes, respectively. Moreover, DNA quality was analyzed by PCR by using primer sets for DNA products of 100, 200, 300, 400, 500, and 600 base pairs, and evaluated by gel electrophoresis. When compared with IHC results in corresponding FFPE tumor tissue from the same patient, 24 out of 30 antibodies showed concordant ICC results. With FISH, distinctive hybridization signals were observed for SYT DNA sequences and EB virus RNA sequences. With PCR, DNA products, up to 600 base pairs in size, were readily observed after gel electrophoresis. The antibodies that showed concordant immunostaining in Cellient(TM) blocks could be applied to diagnostic algorithms that proved to be helpful in the discrimination of major tumor types (carcinoma, lymphoma, melanoma, and germ cell tumors), discrimination of carcinoma subtypes, and determination of primary tumor site in cases of metastatic carcinoma. In a separate study, we found that the application of ICC to this cell block technique provided additional diagnostic and clinically important information in 24% of 100 consecutive cases. The high quality of DNA and RNA in Cellient(TM) cell blocks allowed sensitive and specific molecular biologic analysis, in particular FISH and PCR. PMID- 23444169 TI - Comparative in vitro dissolution and in vivo bioavailability of diflunisal/naproxen fixed-dose combination tablets and concomitant administration of diflunisal and naproxen in healthy adult subjects. AB - A simple validated high-performance liquid chromatography (HPLC) assay was developed for determination of diflunisal and naproxen in human plasma samples. This is to compare the bioavailability of diflunisal-naproxen fixed-dose combination (FDC) with their separate dosage forms. The in vitro dissolution study was adopted to compare the dissolution behavior of FDC with respect to separate marketed tablets. In vivo study was conducted according to a single center, randomized, single-dose, laboratory-blinded, 2 Way, Cross-Over Study with a washout period of 10 days. Under fasting conditions, 24 healthy Egyptian male volunteers were randomly allocated to receive a single oral dose of either one FDC tablet or co-administration of two separate diflunisal and naproxen marketed tablets. Plasma samples were obtained over a 72-h interval and analyzed for diflunisal and naproxen by reversed phase liquid chromatography with UV detection. The pharmacokinetic parameters Cmax, AUC0-t, AUC0-infinity, tmax, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax, AUC0-t, and AUCt infinity of the 2 treatments were within the acceptable range (0.8-1.25) for bioequivalence. From pharmacokinetic and in vitro studies perspectives, 1 FDC tablet demonstrated similar relative bioavailability with the 2 individual reference tablets. PMID- 23444170 TI - Molecular design, synthesis and cell based HCV replicon assay of novel benzoxazole derivatives. AB - Hepatitis C virus inhibitors based on benzoxazole scaffold were designed based on molecular modeling simulation study including docking into the NS5B polymerase active site. Several compounds showed significant high simulation docking scores relative to the assigned benzimidazole lead compound. The designed compounds were synthesized, structurally elucidated and their antiviral activity was evaluated through cell-based replicon in cultured Huh 5-2 cells. A number of the synthesized compounds showed significant inhibitory activity ranging from (52.2% inhibition up to 98% at<50 ug/mL). N-Benzyl-2-phenylbenzo[1,3]oxazole-5 carboxamide (8b) and N-Phenethyl-2-phenylbenzo[1,3] oxazole-5-carboxamide (8c) demonstrated genuine HCV inhibitory activity with EC50 values of 41.6 and 24.5 ug/mL respectively. PMID- 23444171 TI - Synthesis, and docking studies of some fused-quinazolines and quinazolines carrying biological active isatin moiety as cell-cycle inhibitors of breast cancer cell lines. AB - 3 series of novel fused heterocyclic systems, viz. triazolo[4,3-a]quinazolin-7 ones (3), 1 2 4 5-tetrazino[4,3-a]-quinazolin-8-ones (5) and Schiff's bases of isatin derivatives with 2-hydrazinoquinazolin-4-ones (7) have been synthesized. Several of them showed variable and promising in vitro antiproliferative activity against the MCF-7 cells. Compounds 3a-3c, 6, 7a-7 f showed promising activity (IC50=12.45-15.79 MUM). Compound 7 f possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. In silico docking study of the compound 7 f with EGFR enzyme postulated that the designed compound might act on the same enzyme target where DJK_3021_A x-ray structure acted. PMID- 23444172 TI - Myasthenic symptoms in a patient with Kennedy's disease. PMID- 23444174 TI - Periodontal disease prevalence in the United States: a paradigm shift towards the worse? PMID- 23444173 TI - Functional studies of MP62 during male chromatin decondensation in sea urchins. AB - In amphibians, sperm histone transition post-fertilization during male pronucleus formation is commanded by histone chaperone Nucleoplasmin (NPM). Here, we report the first studies to analyze the participation of a Nucleoplasmin-like protein on male chromatin remodeling in sea urchins. In this report, we present the molecular characterization of a nucleoplasmin-like protein that is present in non fertilized eggs and early zygotes in sea urchin specie Tetrapygus niger. This protein, named MP62 can interact with sperm histones in vitro. By male chromatin decondensation assays and immunodepletion experiments in vitro, we have demonstrated that this protein is responsible for sperm nucleosome disorganization. Furthermore, as amphibian nucleoplasmin MP62 is phosphorylated in vivo immediately post-fertilization and this phosphorylation is dependent on CDK-cyclin activities found after fertilization. As we shown, olomoucine and roscovitine inhibits male nucleosome decondensation, sperm histone replacement in vitro and MP62 phosphorylation in vivo. This is the first report of a nucleoplasmin-like activity in sea urchins participating during male pronucleus formation post-fecundation. PMID- 23444175 TI - Clinical applicability of resin infiltration for proximal caries. AB - OBJECTIVE: Resin infiltration is a new microinvasive treatment to arrest the progress of proximal initial caries lesions. This study evaluated the clinical applicability of proximal caries infiltration. METHOD AND MATERIALS: In the study population of 50 children, adolescents, and young adults (mean age, 17.3 +/- 6.4 years), 10 dentists at the University of Greifswald, Greifswald, Germany, applied the infiltration material Icon on noncavitated proximal lesions in permanent and primary teeth as described by the manufacturer. The applicability was evaluated using two questionnaires filled out by clinicians and patients assessing the comfort, complexity, time, and difficulties of the application in comparison to a filling. RESULTS: The results showed good patient satisfaction with the procedure. The mean time for infiltration (24.3 +/- 7.4 minutes), which included rubber dam application (7.7 +/- 4 minutes) and the effort were perceived to be comparable to or even easier than a composite filling by clinicians. In three patients (6%), it was not possible to gain sufficient proximal space for the application of an infiltration. The location of the infiltrated tooth, separation problems, and the routine of clinicians with the infiltration technique had an effect on the duration of the infiltration. A clear learning curve with a reduction of treatment time for subsequent treatments was observed (P < .001). CONCLUSION: Resin infiltration of initial noncavitated proximal lesion showed good clinical applicability for clinicians and very high acceptance by patients. PMID- 23444176 TI - Antibacterial activity and tensile strength of provisional cements modified with fluoridecontaining varnish. AB - OBJECTIVE: To test three noneugenol provisional cements (TempBond NE, RelyX Temp NE, and Freegenol) for their antibacterial properties and to test the hypothesis that addition of fluoride varnish confers antibacterial properties on these provisional cements without compromising their tensile strength. METHOD AND MATERIALS: A total of 576 cylindrical samples were prepared (96 of each of six types) from three noneugenol provisional cements, both unmodified and modified by the addition of 5% w/w Duraphat fluoride varnish. The samples were aged in saline that was replaced twice a week for up to 90 days. Twenty-four samples of each type were removed from the saline at 1, 7, 30, or 90 days and assessed for antibacterial properties against Streptococcus mutans by using an agar diffusion test (n = 12) and tensile strength by using a diametral tensile strength test (n = 12). Data were subjected to one- and three-way ANOVA, the Tukey honestly significant difference test, and t test at a significance level of .002 (P < .002). RESULTS: TempBond NE had no antibacterial activity in its unmodified form but showed antibacterial activity when modified by the addition of 5% w/w fluoride varnish. Freegenol had the highest antibacterial activity in its unmodified form, which was not altered by the addition of the varnish. RelyX Temp NE had mild antibacterial activity that was slightly enhanced by adding the varnish. Adding the varnish reduced the tensile strength of TempBond NE and Freegenol, but did not affect the tensile strength of RelyX Temp NE. CONCLUSION: Antibacterial activity was observed for the unmodified form of Freegenol and TempBond NE after the addition of the fluoride varnish. The addition of the fluoride varnish reduced the tensile strength of both TempBond NE and Freegenol. PMID- 23444177 TI - Antimicrobial efficacy of chlorhexidine and calcium hydroxide/camphorated paramonochlorophenol on infected primary molars: a split-mouth randomized clinical trial. AB - OBJECTIVE: To compare via a split-mouth randomized clinical trial the efficacy of 1% chlorhexidine gel, calcium hydroxide/camphorated paramonochlorophenol (Callen PMCC), and a one-visit endodontic treatment against mutans streptococci and anaerobic bacteria found in primary molars with necrotic pulps and to assess clinical success rates after 12 months. METHOD AND MATERIALS: Pre- and posttreatment intracanal samples were collected from 37 teeth (from 21 children) for analysis of the number of mutans streptococci and anaerobic bacteria. Clinical and radiographic criteria were analyzed to determine treatment outcome. RESULTS: Chlorhexidine gel significantly reduced mutans streptococci levels (P = .010), whereas Callen PMCC significantly reduced the levels of anaerobic bacteria (P = .002). No differences in the reduction of mutans streptococci (P = .187) and anaerobes (P = .564) were observed between groups. The clinical success rates were 85.71% (Callen PMCC), 78.57% (chlorexidine gel), and 77.77% (one-visit treatment). CONCLUSION: Teeth treated with Callen PMCC presented the highest clinical success rate. The 1% chlorhexidine gel, as well as calcium hydroxide/camphorated paramonochlorophenol, presented limited efficacy in reducing bacteria from necrotic primary root canals. PMID- 23444178 TI - Post-endodontic treatment periodontal surgery: a case report. AB - Two patients were diagnosed with combined endodontic-periodontal lesions. Endodontic treatment was performed, followed by surgery. In addition, the regeneration process was supported by the application of an enamel matrix derivate alone or in combination with guided bone regeneration techniques. At recall visits after 24 months, the teeth were asymptomatic and marked bone regeneration had occurred in both patients. The successful post-endodontic treatment of combined endodontic-periodontal lesions, using periodontal surgery and as adjunct guided tissue regenerative techniques, is presented. Further, the possibility of saving teeth, even with severely apparent pathology, should be highlighted. PMID- 23444179 TI - Fabrication of an implant-supported overdenture using CAD/CAM technology: a clinical report. AB - This case report describes a new method for the fabrication of implant-supported overdentures that are rigidly retained by custom tapered abutments milled from commercially pure titanium using CAD/CAM technology. The dentition of a 60-year old woman was restored with six implants in the edentulous maxilla. An implant supported overdenture retained by custom tapered abutments was fabricated using CAD/CAM technology. Screw-retained abutments were designed and milled with a taper of 6 degrees. The reinforcing metallic denture base with integrated secondary crowns, exactly fitting on the tapered abutments, was fabricated from the same data set. The secondary structures could be seated tensionfree on the six abutments, creating friction in the final position. No clinical complications were observed at the 12-month follow-up examination, and the patient remained satisfied with the function and esthetics of the restoration. This case demonstrates the practicality of a fully CAD/CAM fabrication of an implant supported overdenture retained by friction only. Controlled clinical studies are needed to evaluate the long-term performance of this type of restoration. PMID- 23444180 TI - Clinical outcome of a nonsurgical and surgical treatment protocol in different types of peri-implantitis: a case series. AB - OBJECTIVE: The replacement of missing teeth with dental implants has been standard practice in dentistry for many years. The success of dental implants depends on many factors, among which the diagnosis, clinical severity, and treatment of peri-implant diseases play a key role. In this prospective case series, the influence of cumulative treatment modalities on peri-implantitis with and without pus formation on clinical outcome was assessed. METHOD AND MATERIALS: During 2010, 28 patients were referred for peri-implantitis treatment. They presented two different types of peri-implant diseases: peri-implantitis with (17 implants) or without pus formation (33 implants). After microbiologic diagnosis, all patients were treated at baseline with full-mouth scaling and root planing. Two months later, further full-mouth scaling and root planing and additional antimicrobial photodynamic therapy (aPDT) was applied. Four months after baseline, patients with pus formation additionally underwent access flap surgery. Active human matrix metalloproteinase-8 (aMMP-8) levels were measured in eluates before and after all treatment modalities and 7 months after baseline. RESULTS: Clinical parameters (probing depth, bleeding on probing) and aMMP-8-levels improved in both groups after treatment and the final examination. In periimplantitis patients without pus formation, all parameters decreased after full-mouth scaling and root planing and the additional aPDT and no surgery was necessary to improve the parameters. In patients with pus formation, the parameters decreased only after access flap surgery. CONCLUSION: The presence of pus influences the clinical outcome of the treatment of peri-implant diseases. Whereas peri-implantitis cases without pus formation can be successfully managed nonsurgically, peri-implantitis with pus formation can be effectively treated after an additional observation time of 3 months postoperatively only with additional flap surgery. PMID- 23444181 TI - Clinical outcomes in the presence and absence of keratinized mucosa in mandibular guided implant surgeries: a pilot study with a proposal for the modification of the technique. AB - OBJECTIVE: To test the hypothesis of the outcome of complete arch flapless guided implant surgery mandibular rehabilitations in the presence or absence of a residual band of keratinized mucosa (KM) < 6 mm wide in the vestibular-lingual aspect, with and without a modification of the surgical protocol. METHOD AND MATERIALS: Thirty-nine patients were included in this study (12 men and 27 women), with a mean age of 62.5 years (range, 42 to 79 years), divided into 3 groups of 13 patients according to the status of residual band of KM: group 1, KM < 6 mm rehabilitated through a modified guided surgical protocol with flap opening to preserve KM; group 2, KM >= 6 mm; and group 3, KM < 6 mm; patients from both groups 2 and 3 were rehabilitated through flapless guided implant surgery without modification of the protocol. Group 2 and 3 patients were age- and sex-matched with group 1. Outcome measures were clinical attachment loss (CAL) >= 2 mm after 1 year (backward conditional regression), incidence of dehiscences, dental plaque, bleeding, and implant infections. The level of significance chosen was 5%. RESULTS: Thirty-nine patients with 156 implants were followed for 1 year, and no dropouts occurred. Absence of a residual band of KM >= 6 mm in the vestibular-lingual aspect was significantly associated with CAL (odds ratio, 39.1; P = .036) and dehiscences (P = .003). CONCLUSION: Within the limitations of this study, the absence of a residual band of KM >= 6 mm wide in the vestibular-lingual aspect in patients rehabilitated in the complete edentulous mandible with flapless guided implant surgery may be associated with CAL and a higher incidence of dehiscences after 1 year of follow-up. This possible association needs to be confirmed in studies with stronger designs and longer follow-ups. PMID- 23444182 TI - Dental caries experience and barriers to care in young children with disabilities in Ireland. AB - OBJECTIVE: Dental caries among preschool children remains a significant dental public health problem. In Ireland, there are no national data available regarding dental caries levels in preschool children. Furthermore, the number of young children with disabilities and their dental caries levels remains unknown. The aim of the present study was to measure the dental caries levels in a sample of preschool children with disabilities. METHOD AND MATERIALS: A team of trained and calibrated dentists examined a sample of all 0- to 6-year old preschool children with disabilities in two health service administrative areas under standardized conditions. Dental caries was recorded using WHO criteria. RESULTS: Of a total of 422 participants, 337 datasets were included in the study. Of these 337 examined children, approximately 75.1% had a cognitive disability and 12.9% had a noncognitive disability. In 12% of the children, a diagnosis had not yet been established. Dental caries at dentin level was detected from the age of 4 years. The overall mean decayed/missing/ filled teeth (dmft) was 0.49 (SD, 1.39). The analysis of mean dmft levels in children with positive (dmft > 0) scores revealed a mean dmft of 1.14. CONCLUSION: The evidence from this study demonstrated that dental caries levels in preschool children with disabilities in Ireland are low when compared with the general population. Furthermore, children aged 3 years or younger exhibited no dental caries at dentin level and therefore were not affected by early childhood caries. An adjustment of current oral health prevention practice may lead to a further reduction in dental caries levels in this section of the child population. PMID- 23444183 TI - Lip and oral venous varices treated by photocoagulation with high-intensity diode laser. AB - Lip and oral venous varices are acquired benign vascular lesions characterized by a darkblue to violaceous papule or nodule, commonly found on the ventral tongue and lower lip. Although these lesions are usually asymptomatic, they can bleed if injured. This study assessed the effectiveness of photocoagulation with high intensity diode laser in the treatment of these lesions. Thirty-two patients (14 men and 18 women; mean age, 56 years) with lip and oral venous varices were examined and treated with a noncontact diode laser. With one exception, all cases were successfully treated with a single irradiation exposure session. Healing was complete in about 2 to 3 weeks; none of the patients experienced complications or recurrence. Photocoagulation with high-intensity diode laser was proven to be safe and effective for the treatment of lip and oral venous varices, with consistent results. PMID- 23444184 TI - Facts and myths regarding the maxillary midline frenum and its treatment: a systematic review of the literature. AB - OBJECTIVE: To systematically review the current literature on the maxillary midline frenum and associated conditions and complications, as well as the recommended treatment options. METHOD AND MATERIALS: A detailed MEDLINE database search was carried out to provide evidence about the epidemiology, associated pathologies, and treatment options regarding the maxillary frenum. Of the 206 initially identified articles, 48 met the inclusion criteria. RESULTS: The maxillary frenum is highly associated with a number of syndromes and developmental abnormalities. A hypertrophic frenum may be involved in the etiology of the midline diastema. There is also a tendency by orthodontists to suggest posttreatment removal of the frenum (frenectomy). Studies on the cause of gingival recession due to the maxillary frenum are inconclusive. An injured frenum in combination with other traumas and doubtful history might point to child abuse. The involvement of hyperplastic frena in the pathogenesis of peri implant diseases remains uncertain. There seems to be a clinical interest regarding lasers for surgery for treatment of maxillary frena. The superiority of laser treatment in relation to conventional surgical methods has not yet been demonstrated in the literature. CONCLUSION: A maxillary frenum is a clinical symptom in numerous syndromic conditions and plays a role in the development of the median midline diastema. Nevertheless, the contribution to gingival recession and peri-implant diseases in the region of the maxillary incisors is rather controversial. Laser techniques are reported as the method of choice for the surgical removal of frena; however, this needs to be substantiated by appropriate prospective controlled studies. PMID- 23444185 TI - The clinical and histological response of HIV-associated kidney disease to antiretroviral therapy in South Africans. AB - BACKGROUND: Little is known about the progression of kidney disease in HIV infected patients in developing countries in the era of antiretroviral therapy (ART). METHODS: HIV-infected patients were screened for kidney disease. Kidney biopsies were performed before and after initiation of ART to assess the clinical and histological response to treatment. Data were collected from all participants in accordance with the study protocol. The mean follow-up was 2.4 patient years on ART. RESULTS: There was a rapid immunological and renal response to ART. The renal response was reflected by a significant rise in the estimated glomerular filtration rate (eGFR) and rapid regression of proteinuria. The histological patterns were highly variable, ranging from non-specific lesions such as mesangial hyperplasia and interstitial nephritis to HIV-immune complex disease (HIV-ICD) with or without features of HIV-associated nephropathy (HIVAN). In the follow-up biopsies, the histological response to treatment was variable with a combination of no change, progression or regression of lesions. CONCLUSIONS: This study demonstrated a spectrum of renal histological lesions in HIV-associated kidney disease. Initiation of ART produced a rapid and sustained clinical renal response in all participants, irrespective of the histology. Follow-up biopsies showed an inconsistent histological response of lesions to treatment. In lesions that regressed, there appeared to be a discrete lag in histological response when compared with the rapid clinical response. PMID- 23444186 TI - Exposure science, the exposome, and public health. AB - This commentary discusses recent developments in exposure science and their potential contribution to improving public health. PMID- 23444187 TI - Mixed epithelial and stromal tumor--cytologic findings of an unusual renal cyst. PMID- 23444188 TI - What is the value of hyperbaric oxygen therapy in management of osteoradionecrosis of the head and neck? PMID- 23444189 TI - Outcomes in head and neck oncologic surgery at academic medical centers in the United States. AB - OBJECTIVES/HYPOTHESIS: To evaluate the impact of case volume and other variables on outcomes after head and neck oncologic surgery was performed at academic medical centers in the United States. STUDY DESIGN: Cross Sectional Ecological Study. METHODS: The University HealthSystems Consortium (UHC) database was analyzed for discharge data on all patients who underwent surgery for head and neck cancers (excluding thyroid and skin cancer) at full- member academic medical centers between quarter 4 of 2006 and quarter 4 of 2009. Multivariate and linear regression analyses and chi-square tests were applied to evaluate significant associations between hospital surgical volume and other independent variables, and to evaluate the risk of mortality, mortality index, complications, length of stay (LOS), LOS index, cost, and cost index. RESULTS: Of 22,357 surgical cases, 11,573 met our inclusion criteria. The only outcome that was statistically significant based on volume was a lower complication rate in high volume hospitals (P = 0.0486) as compared to low volume hospitals. All Payer Refined Diagnosis Related Group defined major severity of illness was the only independent variable significantly associated with higher complication rates, observed LOS, and observed cost (P <0.0001, P = 0.0139, and P = 0.0092, respectively). Management of male patients and black patients resulted in a lower cost index (P = 0.0472) and a higher complication rate (P = 0.0297), respectively. Patients with private insurance had lower complication rates, observed LOS, and observed cost (P = 0.0401, P = 0.0001, and P = 0.0187, respectively). CONCLUSIONS: After controlling for other factors, academic medical centers with a higher cumulative case volume have lower rates of complications. PMID- 23444190 TI - Characterization of human vocal fold fibroblasts derived from chronic scar. AB - OBJECTIVES/HYPOTHESIS: In vitro modeling of cell-matrix interactions that occur during human vocal fold scarring is uncommon, as primary human vocal fold scar fibroblast cell lines are difficult to acquire. The purpose of this study was to characterize morphologic features, growth kinetics, contractile properties, alpha smooth muscle actin (alpha-SMA) protein expression and gene expression profile of human vocal fold fibroblasts derived from scar (sVFF) relative to normal vocal fold fibroblasts (nVFF). STUDY DESIGN: In vitro. METHODS: We successfully cultured human vocal fold fibroblasts from tissue explants of scarred vocal folds from a 56-year-old female and compared these to normal fibroblasts from a 59-year old female. Growth and proliferation were assessed by daily cell counts, and morphology was compared at 60% confluence for 5 days. Gel contraction assays were evaluated after seeding cells within a collagen matrix. alpha-SMA was measured using western blotting and immunocytochemistry (ICC). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to assess differential extracellular matrix gene expression between the two cell types. RESULTS: sVFF were morphologically indistinguishable from nVFF. sVFF maintained significantly lower proliferation rates relative to nVFF on days 3 to 6 (day 3: P = .0138; days 4, 5, and 6: P < .0001). There were no significant differences in contractile properties between the two cell types at any time point (0 hours: P = .70, 24 hours: P = .79, 48 hours: P = .58). ICC and western blot analyses revealed increased expression of alpha-SMA in sVFF as compared with nVFF at passages 4 and 5, but not at passage 6 (passage 4: P = .006, passage 5: P = .0015, passage 6: P = .8860). Analysis of 84 extracellular matrix genes using qRT-PCR revealed differential expression of 15 genes (P < .01). CONCLUSIONS: nVFF and sVFF displayed differences in proliferation rates, alpha-SMA expression, and gene expression, whereas no differences were observed in contractile properties or morphology. Further investigation with a larger sample size is necessary to confirm these findings. PMID- 23444192 TI - On fate and flexibility in stomatal development. AB - In plants, the development of the epidermis, and the specialized stomatal lineage within it, exemplifies an old developmental problem that is newly relevant in this current era of stem cell biology: How can a tissue maintain flexibility and change its development midcourse yet still reliably generate differentiated and patterned cells? In this perspective, we endeavor to create a conceptual framework for the widespread questions in development that are raised by observations of stomatal development pathways in "default" settings and in response to environmental challenges. These general issues are related to the molecular pathways and networks recently elucidated for Arabidopsis stomatal development. Finally, the utility of developmental approaches for solving problems of signaling specificity are explored, emphasizing the specific use of the stomatal lineage as an in vivo testing ground for hormone and mitogen activated protein kinase (MAPK) signaling cascades. PMID- 23444191 TI - GenTAC registry report: gender differences among individuals with genetically triggered thoracic aortic aneurysm and dissection. AB - Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD <50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR = 0.65, P < 0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR = 0.68, P < 0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD <50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events. PMID- 23444194 TI - New targets for disease modifying osteoarthritis drugs: chondrogenesis and Runx1. PMID- 23444193 TI - New insight on the Xq28 association with systemic sclerosis. AB - OBJECTIVE: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). METHODS: We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. RESULTS: IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12*10(-3), OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26*10(-4), OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF- (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). CONCLUSIONS: Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease. PMID- 23444195 TI - Neuropeptides activate TRPV1 in rheumatoid arthritis fibroblast-like synoviocytes and foster IL-6 and IL-8 production. PMID- 23444196 TI - [In Process Citation]. PMID- 23444197 TI - Melatonin prevents dopaminergic cell loss induced by lentiviral vectors expressing A30P mutant alpha-synuclein. AB - Two hallmarks of Parkinson's disease (PD) are dopaminergic cell loss and the presence of cytoplasmic inclusions (Lewy bodies). Different point mutations in alpha-synuclein, the main constituent of Lewy bodies, have been identified in familial PD. Alpha-synuclein also constitutes one of the main components of Lewy bodies in sporadic cases of PD. Moreover, oxidant stress and generation of free radicals from both mitochondrial impairment and dopamine metabolism are considered to play critical roles in PD etiopathogenesis. Melatonin, a known potent antioxidant secreted by the pineal gland, may protect against the effect of several Parkinsonogenic compounds that are associated with progressive impairment of mitochondrial function and increased oxidative damage. However, the neuroprotective effect of melatonin has never been tested in the newly available genetic models of PD based on the viral expression of mutated alpha-synuclein. Lentiviral vectors encoding A30P mutant human alpha-synuclein (lenti-A30P) were stereotactically injected into the right substantia nigra of adult male Sprague Dawley rats and neuroprotection was examined by administration of melatonin or vehicle from two days before nigral administration of lenti-A30P until eight weeks after injection. It was found that lenti-A30P induced a significant TH+ cell-loss both in the medial and lateral substantia nigra versus the contrallateral side injected with lenti-eGFP. However, melatonin administration showed a total neuroprotective effect in both regions of the substantia nigra. In conclusion, the data here show that melatonin is neuroprotective against mutant alpha-synuclein-induced injury in the substantia nigra. PMID- 23444198 TI - Cellular control of connective tissue matrix tension. AB - The biomechanical behavior of connective tissue in response to stretching is generally attributed to the molecular composition and organization of its extracellular matrix. It also is becoming apparent that fibroblasts play an active role in regulating connective tissue tension. In response to static stretching of the tissue, fibroblasts expand within minutes by actively remodeling their cytoskeleton. This dynamic change in fibroblast shape contributes to the drop in tissue tension that occurs during viscoelastic relaxation. We propose that this response of fibroblasts plays a role in regulating extracellular fluid flow into the tissue, and protects against swelling when the matrix is stretched. This article reviews the evidence supporting possible mechanisms underlying this response including autocrine purinergic signaling. We also discuss fibroblast regulation of connective tissue tension with respect to lymphatic flow, immune function, and cancer. PMID- 23444199 TI - Attention to the neglected: prospects for research on child neglect for the next decade. AB - In 1997, the National Institutes of Health within the United States Department of Health and Human Services reviewed the state of its research on child abuse and neglect (US Department of Health and Human Services, National Institutes of Health, 1997). The findings suggested that although neglect was the most frequent type of child maltreatment, research studies were lacking. Through an unprecedented partnership across federal funding agencies for research on child neglect, research was encouraged in several areas. Over the past fifteen years, consortia of researchers have continued to increase our knowledge of child neglect and to shape the field. Nonetheless, challenges for research on child neglect remain, including the changing demographics of the nation and health disparities. Evidenced-based early interventions and treatments may be an opportunity for prevention of child neglect and improving child welfare services, particularly in an era of health care reform. Developmental researchers across the translational pipeline are encouraged to integrate child neglect research in future studies to inform prevention, treatment and policy efforts for the improved health and well-being of children, families and communities. PMID- 23444200 TI - Guest Editorial: prosthodontics: a rich past and evolving future. PMID- 23444201 TI - Sectional porcelain veneers for a maxillary midline diastema closure: a case report. AB - Diastema closure is a frequently requested, technique-sensitive cosmetic procedure. There are many techniques and materials that can be employed to close diastemas. While direct composite techniques can be economical and successful, they do present challenges in achieving satisfactory clinical and esthetic results. Traditional porcelain veneer placement may offer an excellent esthetic result, but typically requires the removal of tooth structure; as such, this is an irreversible procedure. The present article reports the case of a maxillary midline diastema closure in a healthy dentition by means of sectional porcelain veneers simply cemented onto the natural teeth and without tooth preparation. A step-bystep procedure is proposed for illustrating the proper implementation of an additive-only and noninvasive indirect technique that yields a satisfactory clinical and esthetic outcome for clinician and patient. PMID- 23444202 TI - Antibacterial temporary restorative materials incorporating polyethyleneimine nanoparticles. AB - OBJECTIVES: Temporary restorative materials (TRMs) often rapidly lose their dimensional stability and antibacterial properties after exposure to humidity and bacterial infection. Quaternary ammonium polyethyleneimine (QPEI) nanoparticles (NP) are long-lasting, stable, biocompatible, and nonvolatile antibacterial polymers. In the present study, we incorporated QPEI NP into standard TRMs and examined their influence on dimensional stability and their ability to reduce bacterial leakage. METHOD AND MATERIALS: A modified split-chamber model was used in vitro to test calcium sulfate-based and zinc oxide-eugenol- based TRMs (Coltosol and IRM, respectively). Both materials were tested with and without 2% wt/wt incorporated QPEI NP for fluid and bacterial leakage. RESULTS: The calcium sulfate-based TRM displayed the lowest microleakage and highest antibacterial resistance. Two-way A NOVA analysis of the fluid transport test results showed that incorporation of 2% wt/wt QPEI NP significantly increased the sealing ability of both TRMs (P < .01). Analysis of survival curves by the Kaplan-Meier method showed that the calcium sulfate-based TRM with 2% wt/wt QPEI NP survived the bacterial load significantly more effectively than did the zinc oxide-eugenol based TRM (P < .0001). CONCLUSION: Incorporation of 2% w/w QPEI NP may prominently improve the sealability and the antibacterial properties of TRMs. TRMs incorporating antibacterial nanoparticles may be clinically advantageous for sealing the endodontic access cavity to avoid reinfection of the root canal system during endodontic treatment. PMID- 23444203 TI - Antimicrobial efficacy of two irrigation techniques in tapered and non-tapered canal preparations. A randomized controlled clinical trial. AB - OBJECTIVE: The aim of this randomized controlled clinical trial was to investigate the antimicrobial efficacy of traditional positive pressure (PP) irrigation compared with apical negative pressure (ANP) in tapered as well as non tapered root canal preparation techniques. METHOD AND MATERIALS: Patients referred for treatment of mandibular permanent molars with necrotic pulps and apical periodontitis were considered for this study. A total of 32 eligible teeth were evaluated based on strict inclusion and exclusion criteria and randomly assigned as follows: Group 1: LightSpeed LSX 0.02 preparation and A NP irrigation (n = 8). Group 2: LightSpeed LSX 0.02 preparation and PP irrigation (n = 8). Group 3: ProTaper preparation and A NP irrigation (n = 8). Group 4: ProTaper preparation and PP irrigation (n = 8). A ll teeth were sampled immediately upon access (S1), after completion of the chemo- mechanical preparation (S2), and one week later after intracanal medication (S3). All samples were microbiologically processed immediately and plated in duplicates on aerobic plates, anaerobic plates, and chocolate plates and colonies statistically analyzed. RESULTS: No statistically significant differences were found between groups at S1. When comparing colony-forming unit (CFU) levels at S1 and S2 within groups, the reduction was statistically significant in all groups. While no significant difference was found in the proportion of teeth that culture positive at either S2 or S3 by shaping groups, a significant difference was noted when comparing PP irrigation and A NP groups. The percentage of samples in the PP irrigation group with a negative culture at both time points was 67%, compared to 100% among the A NP group. CONCLUSION: Within the limitations of the present study, taper and apical size failed to demonstrate a difference in microbiological reduction of cultivable bacteria. On the other hand, A NP revealed a significant difference when compared to PP irrigation. PMID- 23444204 TI - Treatment of infrabony periodontal defects using a resorbable biopolymer of hyaluronic acid: a randomized clinical trial. AB - OBJECTIVE: This randomized clinical study examined the use of hyaluronic acid to treat infrabony periodontal defects over a period of 24 months. METHOD AND MATERIALS: Forty subjects with a two-wall infrabony defect (probing depth [PD] >= 7 mm; clinical attachment level [CAL] >= 7 mm) were selected. The defects were randomly divided into two groups: sites treated with hyaluronic acid (test group) and those treated with open flap debridement (control group). RESULTS: The 12- and 24-month evaluations were based on clinical and radiographic parameters. The primary outcome variable was CAL. Test defects shows a mean CAL gain of 1.9 +/- 1.8 mm, while the control defects yielded a significantly lower gain of 1.1 +/- 0.7 mm. PD reduction was also significantly higher in the test group (1.6 +/- 1.2 mm) than in the control group (0.8 +/- 0.5 mm). Frequency distribution analysis of the study outcomes indicated that hyaluronic acid increased the predictability of clinically significant results (CAL gains >= 2 mm and PD reduction >= 2 mm) in the test group compared with the controls. CONCLUSIONS: The treatment of infrabony defects with hyaluronic acid offered an additional benefit in terms of CAL gain, PD reduction, and predictability compared to treatment with open flap debridement. PMID- 23444205 TI - Porcine dermal matrix for covering of recession type defects: a case series. AB - OBJECTIVE: To study the clinical applicability of porcine dermal matrix for treatment of recession type defects. METHOD AND MATERIALS: Twenty-eight gingival recessions in six patients were selected for root coverage procedures using a modified tunneling technique and porcine dermal matrix. As primary outcome, depth and width of gingival recession were assessed at baseline and at 6 and 12 months postoperatively. As a secondary outcome, the width of keratinized tissue was studied. RESULTS: At 6 and 12 months postoperatively, mean root coverage was 65.52% and 56.82%, respectively. Complete root coverage was achieved in 42.86% of the treated defects. CONCLUSION: Porcine dermal matrix may potentially be used as a replacement material for autologous tissue. However, complete root coverage was only achieved in less than half of the studied defects. PMID- 23444206 TI - Effect of periodontal therapy on the course of cyclosporin-induced gingival overgrowth: role of ABCB1 and PAI-1 gene polymorphisms. AB - OBJECTIVES: Etiological periodontal therapy is effective in reducing cyclosporin A-induced gingival overgrowth, but a high variability among subjects has been observed. This study aimed to evaluate the role of polymorphisms in PAI-1 and A BCB1 genes on the course of this side effect following periodontal therapy. METHOD AND MATERIALS: Forty-five transplant patients were subjected to nonsurgical periodontal therapy and evaluated for hypertrophy index, probing depths, bleeding, and plaque scores at baseline, and after 3 and 6 months. A BCB1 (C3435T and G2677T) and PAI-1 (4G/5G) polymorphisms were studied with polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction respectively. RESULTS: All the monitored periodontal indexes decreased significantly during the six months. Modeling of hypertrophy index by linearmixed- effect models (allowing non-normal distribution of the outcome variable hypertrophy index) resulted in the selection as the most significant model, of the one comprising the independent variables: time, C 3435T genotype, and their interaction term. This model indicated that C 3435T-mutated patients had significantly higher baseline hypertrophy index values (90% Markov chain Monte C arlo empirical confidence intervals: 5.08, 30.00). The decrease in hypertrophy index values over time showed a trend toward being faster in mutated than nonmutated patients (interaction time: C 3435T nonmutated, 90% Markov chain Monte C arlo empirical confidence interval: -11.08, -0.40). When hypertrophy index values were normalized, the significance and trend were lost. No effect of the A BCB1 G2677T and PAI-1 4G/5G polymorphisms was observed. CONCLUSION: These preliminary results suggest that C 3435T polymorphism is a genetic factor that could influence the course of cyclosporin A-induced gingival overgrowth in transplant patients subjected to periodontal therapy. PMID- 23444207 TI - Screw loading and gap formation in implant supported fixed restorations: Procera implant bridge vs. conventionally cast screw-retained restorations. AB - OBJECTIVES: It was the purpose of this finite element analysis to compare the implant-restoration connection created by Procera Implant Bridge (PIB) and conventional screw-retained prostheses with respect to screw loading and gap formation. METHOD AND MATERIALS: Finite element models representing a conventional screw-retained restoration and a PIB were set up. A horizontal load of 200N was applied on the restorations while resulting gap formation and screw loading was recorded. RESULTS: Increasing the preload of the retaining screws led to a decrease in gap formation. Smaller gaps were observed in the conventional restorations. Loading of the screws was of comparable magnitudes in both cases. CONCLUSION: The use of screw-retained implant-supported restorations representing butt-joint connections at the restorative interface may result in increased gap formation. PMID- 23444209 TI - "A capite ad calcem". PMID- 23444208 TI - Review of the complications associated with treatment of oropharyngeal cancer: a guide for the dental practitioner. AB - OBJECTIVES: Oropharyngeal cancer (OPC) is the sixth most common cancer worldwide. Focus on risk factors, improved diagnostic methods and effective management strategies have made it possible to successfully treat OPC. However, the 5-year survival rate has not improved for several years due to multiple treatment complications, tissue morbidity, loss of function, and diminished quality of life. Survivors are faced with complications like oral mucositis, hyposalivation, osteoradionecrosis, tissue fibrosis, morbidity from jaw resection, disfigurement, and loss of function that further diminish quality of life. The aim of this review is to highlight major complications associated with treatment of OPC via a literature search and review of available options for identification and management of these complications. DATA SOURCES: Relevant publications on oral complications of OPC therapy were thoroughly reviewed from the literature published between the years 1988 and 2012. We evaluated reported incidence, prevalence, and risk factors for oral complications of chemotherapy and radiotherapy for OPC. The authors conducted an electronic search using English language databases, namely PubMed Plus, Medline (Pre-Medline and Medline), Cochrane Database of Systematic Reviews (evidence-based medicine), Dentistry & Oral Sciences Source, A ccessScience, Embase, Evidence-Based Medicine Reviews Multifile, Google Scholar, ISI Journal Citation Reports, and Ovid Multi-Database. CONCLUSION: We identified the most common complications associated with the treatment of oral cancers. Based on the information gathered, there is evidence that survival of OPC extends beyond eradication of the diseased tissue. Understanding the potential treatment complications and utilizing available resources to prevent and minimize them are important. Caring for OPC survivors should be a multidisciplinary team approach involving the dentist, oncologist, internist, and social worker to improve the currently stagnant 5-year survival rate of OPC. More emphasis on improved quality of life after elimination of the cancer will ultimately improve OPC survivorship. PMID- 23444210 TI - Comparison of fluorescence in situ hybridization, NMP22 bladderchek, and urinary liquid-based cytology in the detection of bladder urothelial carcinoma. AB - The aim of this study is to evaluate the diagnostic values of the fluorescence in situ hybridization (FISH), NMP22 BladderChek, and liquid-based cytology (LBC) in the detection of bladder urothelial carcinoma (UC). Consecutive voided urine samples were collected from 138 in-house patients with a variety of urologic conditions and 37 healthy individuals as negative controls. FISH, NMP22 BladderChek, and LBC were performed on the specimens. All three tests were evaluated independently in a blinded fashion. In all, 104 out of the 175 patients enrolled in this study had histologically proven UC. LBC, FISH, and NMP22 BladderChek were successfully performed on 175, 149, and 119 cases, respectively. The three tests revealed overall sensitivities of 73.1%, 86.5%, and 67.6%, respectively. FISH was more sensitive than LBC (P=0.022) and NMP22 BladderChek (P=0.004). Combination of all the tests yielded a superior sensitivity of 96.7% compared with LBC (P<0.001), NMP22 BladderChek (P<0.001), and FISH (P=0.016), with the specificity only decreased slightly. Sensitivities of the three tests enhanced significantly with increasing UC grade (P<0.05). The positive rates of FISH and NMP22 BladderChek in equivocal cytologic diagnoses were 85.7% and 61.9% in UC, and 37.5% and 50.0% in non-UC (FISH: P=0.021; NMP22 BladderChek: P=0.683). FISH was more sensitive than LBC and NMP22 BladderChek. FISH had the ability to clarify equivocal cytologic diagnoses. Combination of all three tests showed an improvement in the sensitivity compared to any single test alone in detecting UC with the specificity slightly decreased. PMID- 23444211 TI - Methylation of the hTERT promoter: a novel cancer biomarker for leptomeningeal metastasis detection in cerebrospinal fluids. AB - PURPOSE: The diagnosis of leptomeningeal metastases is usually confirmed by the finding of malignant cells by cytologic examination in the cerebrospinal fluid (CSF). More sensitive and specific cancer biomarkers may improve the detection of tumor cells in the CSF. Promoter methylation of the human telomerase reverse transcriptase (hTERT) gene characterizes most cancer cells. The aim of this study was to develop a sensitive method to detect hTERT methylation and to explore its use as a cancer biomarker in CSF. EXPERIMENTAL DESIGN: In 77 CSF specimens from 67 patients, hTERT promoter methylation was evaluated using real-time methylation sensitive high-resolution melting (MS-HRM) and real-time TaqMan PCR and MS-HRM in a single-tube assay. RESULTS: Real-time MS-HRM assay was able to detect down to 1% hTERT-methylated DNA in a background of unmethylated DNA. PCR products were obtained from 90% (69/77) of CSF samples. No false positive hTERT was detected in the 21 non-neoplastic control cases, given to the method a specificity of 100%. The sensitivity of the real-time MS-HRM compared with the cytologic gold standard analysis was of 92% (11/12). Twenty-six CSFs from 22 patients with an hTERT methylated primary tumor showed cytologic results suspicious for malignancy; in 17 (65%) of them, a diagnosis of leptomeningeal metastases could be confirmed by the hTERT methylation test. CONCLUSION: The hTERT real-time MS-HRM approach is fast, specific, sensitive, and could therefore become a valuable tool for diagnosis of leptomeningeal metastases as an adjunct to the traditional examination of CSF. PMID- 23444212 TI - Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. AB - PURPOSE: The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation, and tumor initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells. EXPERIMENTAL DESIGN: We investigated the role of Notch activity in lung adenocarcinoma using a Notch GFP reporter construct and a gamma-secretase inhibitor (GSI), which inhibits Notch pathway activity. RESULTS: Transduction of lung cancer cells with Notch GFP reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP bright cells had the ability to form more tumor spheres in serum-free media and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 443 patients with lung adenocarcinoma. This correlation was further confirmed in an independent group of 89 patients with adenocarcinoma in which Hes-1 overexpression correlated with poor overall survival. CONCLUSIONS: Notch activity can identify lung cancer stem cell-like population and its inhibition may be an appropriate target for treating lung adenocarcinoma. PMID- 23444214 TI - Zoom Zoom: racing CARs for multiple myeloma. AB - Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma. PMID- 23444213 TI - Targeting the NF-kappaB and mTOR pathways with a quinoxaline urea analog that inhibits IKKbeta for pancreas cancer therapy. AB - PURPOSE: The presence of TNF-alpha in approximately 50% of surgically resected tumors suggests that the canonical NF-kappaB and the mTOR pathways are activated. Inhibitor of IkappaB kinase beta (IKKbeta) acts as the signaling node that regulates transcription via the p-IkappaBalpha/NF-kappaB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKbeta inhibitor. We hypothesized that targeting the NF-kappaB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways. EXPERIMENTAL DESIGN: Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-kappaB. We examined the effects of 13-197 on the downstream targets of the NF-kappaB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo. RESULTS: 13-197 inhibited the kinase activity of IKKbeta in vitro and TNF-alpha-mediated NF-kappaB transcription in cells with low MUmol/L potency. 13-197 inhibited the phosphorylation of IkappaBalpha, S6K, and eIF4EBP, induced G1 arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity. CONCLUSION: These results suggest that 13-197 targets IKKbeta and thereby inhibits mTOR and NF-kappaB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic. PMID- 23444215 TI - Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. AB - PURPOSE: Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated. EXPERIMENTAL DESIGN: We conducted a phase II trial in patients with melanoma whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg per os twice daily. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach. RESULTS: The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (~25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the five patients with melanoma accrued in the low pAKT cohort, there was one partial response (PR). Two other patients had near PRs before undergoing surgical resection of residual disease (one patient) or discontinuation of treatment due to toxicity (one patient). Among the two nonresponding, low pAKT patients with melanoma, co-mutations in MAP2K1, NF1, and/or EGFR were detected. CONCLUSIONS: Tumor regression was seen in three of five patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort. These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK inhibitors. PMID- 23444216 TI - Aflibercept. AB - Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined. PMID- 23444217 TI - MicroRNA profiling can classify acute leukemias of ambiguous lineage as either acute myeloid leukemia or acute lymphoid leukemia. AB - PURPOSE: Classification of acute leukemia is based on the commitment of leukemic cells to the myeloid or the lymphoid lineage. However, a small percentage of acute leukemia cases lack straightforward immunophenotypical lineage commitment. These leukemias of ambiguous lineage represent a heterogeneous category of acute leukemia that cannot be classified as either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL). The lack of clear classification of acute leukemias of ambiguous lineage as either AML or ALL is a hurdle in treatment choice for these patients. EXPERIMENTAL DESIGN: Here, we compared the microRNA (miRNA) expression profiles of 17 cases with acute leukemia of ambiguous lineage and 16 cases of AML, B-cell acute lymphoid leukemia (B-ALL), and T-cell acute lymphoid leukemia (T-ALL). RESULTS: We show that leukemias of ambiguous lineage do not segregate as a separate entity but exhibit miRNA expression profiles similar to AML, B-ALL, or T-ALL. We show that by using only 5 of the most lineage discriminative miRNAs, we are able to define acute leukemia of ambiguous lineage as either AML or ALL. CONCLUSION: Our results indicate the presence of a myeloid or lymphoid lineage-specific genotype, as reflected by miRNA expression, in these acute leukemias despite their ambiguous immunophenotype. miRNA-based classification of acute leukemia of ambiguous lineage might be of additional value in therapeutic decision making. PMID- 23444218 TI - beta-1,4-Galactosyltransferase III enhances invasive phenotypes via beta1 integrin and predicts poor prognosis in neuroblastoma. AB - PURPOSE: Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. beta-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly-N acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB. EXPERIMENTAL DESIGN: We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies. RESULTS: We found that B4GALT3 expression correlated with advanced clinical stages (P = 0.040), unfavorable Shimada histology (P < 0.001), and lower survival rate (P < 0.001). Multivariate analysis showed that B4GALT3 expression is an independent prognostic factor for poor survival of NB patients. B4GALT3 overexpression increased migration, invasion, and tumor growth of NB cells, whereas B4GALT3 knockdown suppressed the malignant phenotypes of NB cells. Mechanistic investigation showed that B4GALT3-enhanced migration and invasion were significantly suppressed by beta1-integrin blocking antibody. Furthermore, B4GALT3 overexpression increased lactosamine glycans on beta1 integrin, increased expression of mature beta1-integrin via delayed degradation, and enhanced phosphorylation of focal adhesion kinase. Conversely, these properties were decreased by knockdown of B4GALT3 in NB cells. CONCLUSIONS: Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of beta1-integrin in NB cells. PMID- 23444219 TI - Clinical correlates of promoter hypermethylation of four target genes in head and neck cancer: a cooperative group correlative study. AB - PURPOSE: Promoter hypermethylation is a well-documented mechanism for tumor specific alteration of suppressor gene activity in human malignancy including head and neck cancer (HNC). The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome. In this study we examined methylation of DCC, KIF1A, EDNRB, and p16(INK4a) in a large cohort of HNC patients from Eastern Cooperative Group (ECOG) 4393/Radiation Therapy Oncology Group (RTOG) 9614 to identify clinical correlates of methylation of these genes. EXPERIMENTAL DESIGN: Methylation was assessed by quantitative methylation specific PCR in DNA from tumor specimens and was considered as a continuous and a binary variable. Clinical data including demographics, stage, risk factor exposure, treatment, and outcome were collected by ECOG and RTOG. Methylation status was also correlated with mutation of TP53 (previously reported) and human papilloma virus status. RESULTS: Methylation results were available for 368 cases, 353 of which also have p53 mutation status. At least one methylation event was present in all tumors. In multivariate analysis of the entire cohort, methylation of p16 was associated with decreased survival (HR = 1.008; P = 0.045). However, in tumors with disruptive TP53 mutation (poor prognostic group), the additional presence of methylation of p16 was protective (P = 0.019 considering p16 methylation as a continuous variable). CONCLUSION: Methylation of tumor-related genes contributes to the biological behavior of HNC and influences overall survival in conjunction with other known prognostic molecular events. PMID- 23444220 TI - Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER 2-negative advanced breast cancer that progressed during or after bevacizumab. AB - PURPOSE: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. EXPERIMENTAL DESIGN: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1 14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44 0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). CONCLUSION: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. PMID- 23444222 TI - CD44 and OTP are strong prognostic markers for pulmonary carcinoids. AB - PURPOSE: Pulmonary carcinoids are well-differentiated neuroendocrine tumors showing usually a favorable prognosis. However, there is a risk for late recurrence and/or distant metastasis. Because histologic classification in typical and atypical carcinoids is difficult and its reliability to predict disease outcome varies, we evaluated three genes as potential prognostic markers, that is, orthopedia homeobox (OTP), CD44, and rearranged during transfection (RET). EXPERIMENTAL DESIGN: These genes were analyzed in 56 frozen carcinoids by quantitative real-time PCR (qRT-PCR). RET was further studied by methylation and mutation analysis. Immunohistochemistry for CD44 and OTP protein expression was conducted on 292 carcinoids. RESULTS: Low mRNA expression levels of CD44 (P = 1.8e(-5)) and OTP (P = 0.00054), and high levels of RET (P = 0.025), were strongly associated with a low 20-year survival of carcinoid patients. High RET expression was not related to promoter hypomethylation or gene mutations. A direct link between gene expression and protein levels was confirmed for CD44 and OTP but not for RET. Within all carcinoids as well as atypical carcinoids, absence of CD44 protein was significantly associated with low 20-year survival (P = 0.00014 and 0.00013, respectively). The absence of nuclear OTP followed by complete loss of expression was also significantly associated with unfavorable disease outcome in all carcinoids (P = 5.2(-6)). Multivariate analyses revealed that age at diagnosis, histopathology, stage, and cytoplasmic OTP immunoreactivity were independent predictors of prognosis. CONCLUSIONS: Our study indicates that CD44 and OTP are strong indicators of poor outcome. We therefore argue for implementation of these markers in routine diagnostics in addition to histopathology to improve subclassification of pulmonary carcinoids into prognostically relevant categories. PMID- 23444221 TI - Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors. AB - PURPOSES: To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET). EXPERIMENTAL DESIGN: Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors. RESULTS: Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors, respectively. Immunohistochemistry on a series of 132 TETs, including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1-negative tumors had a shorter time to progression and a trend for a shorter disease-related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 TETs. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro. CONCLUSION: Our data support a tumor suppressor role of FOXC1 in TETs. PMID- 23444223 TI - hTERT inhibition triggers Epstein-Barr virus lytic cycle and apoptosis in immortalized and transformed B cells: a basis for new therapies. AB - PURPOSE: Induction of viral lytic cycle, which induces death of host cells, may constitute a useful adjunct to current therapeutic regimens for Epstein-Barr virus (EBV)-driven malignancies. Human telomerase reverse transcriptase (hTERT), essential for the oncogenic process, may modulate the switch from latent to lytic infection. The possible therapeutic role of hTERT inhibition combined with antiviral drugs was investigated. EXPERIMENTAL DESIGN: EBV-negative BL41 and convertant EBV-positive BL41/B95.8 Burkitt's lymphoma cell lines and lymphoblastoid cell lines (LCL) were infected with retroviral vector encoding short hairpin RNA (shRNA) anti-hTERT and cultured with or without the prodrug ganciclovir. The effects on EBV lytic replication, cell proliferation, and apoptosis were characterized. RESULTS: hTERT silencing by shRNA induced the expression of BZLF1, EA-D, and gp350 EBV lytic proteins and triggered a complete lytic cycle. This effect was associated with downregulation of BATF, a negative regulator of BZLF1 transcription. hTERT silencing also resulted in antiproliferative and proapoptotic effects. In particular, hTERT inhibition induced an accumulation of cells in the S-phase, an effect likely due to the dephosphorylation of 4E-BP1, an AKT1-dependent substrate, which results in a decreased availability of proteins needed for cell-cycle progression. Besides inducing cell death through activation of complete EBV lytic replication, hTERT inhibition triggered AKT1/FOXO3/NOXA-dependent apoptosis in EBV-positive and negative Burkitt's lymphoma cells. Finally, ganciclovir enhanced the apoptotic effect induced by hTERT inhibition in EBV-positive Burkitt's lymphomas and LCLs. CONCLUSIONS: These results suggest that combination of antiviral drugs with strategies able to inhibit hTERT expression may result in therapeutically relevant effects in patients with EBV-related malignancies. PMID- 23444224 TI - Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer. AB - PURPOSE: Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited. EXPERIMENTAL DESIGN: We combined the data from genome-wide siRNA screens on tumor cell lethality in a lung and a head and neck cancer cell line. RESULTS: We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2 M phase transition, underlining the importance of this cell-cycle checkpoint for tumor cell survival. Five genes from this cluster (CKAP5, KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown of KIF11 (kinesin family member 11) were reproduced by inhibition of KIF11 using the small molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment. CONCLUSION: This study identified a wide array of druggable genes for both lung and head and neck cancer. In particular, multiple genes involved in the G2-M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets. PMID- 23444225 TI - Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas. AB - PURPOSE: We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy for cancers. EXPERIMENTAL DESIGN: We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the fibroblast growth factor receptor 2 (FGFR2) isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types. RESULTS: We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform ("epithelial") to IIIc isoform ("mesenchymal") in nearly 90% of ccRCCs. This switch is kidney specific as it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs (chRCC). A reexamination of tumor histology by pathologists identified FGFR2-IIIb tumors as chRCCs and clear cell papillary RCCs (ccpRCC). CONCLUSIONS: FGFR2 IIIb RCCs represent misdiagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC. PMID- 23444226 TI - PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA response in AML without t(15;17). AB - PURPOSE: In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement, the effect of all-trans-retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, preferentially expressed antigen in melanoma (PRAME) has been shown to be a dominant repressor of RAR signaling. EXPERIMENTAL DESIGN: Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA responsiveness. We profiled gene expression in diagnostic samples derived from our AML HD98B trial, in which ATRA was administered in addition to intensive chemotherapy. RESULTS: Our data revealed a PRAME expression-associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models, we could show that retinoic acid regulated cell proliferation and differentiation are impacted by PRAME expression. In patients with primary AML, repressor activity of high-PRAME levels might be overcome by the addition of ATRA as indicated by better outcome in 2 independent studies (P = 0.029). CONCLUSIONS: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR signaling, which might be reversed by ATRA. PRAME therefore represents a promising target for both ATRA treatment and possibly future immunotherapeutic approaches in AML. PMID- 23444228 TI - Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. AB - PURPOSE: Ipilimumab is a fully human monoclonal antibody against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease control rate are assessed and considered with respect to the overall study population. EXPERIMENTAL DESIGN: In the phase III study, 676 pretreated patients were randomly allocated to treatment with ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100 vaccine alone. Of these patients, 32 had a partial or complete objective response or stable disease after treatment and met the eligibility criteria for retreatment, although a total of 40 patients were retreated. RESULTS: Best overall response rates (complete responses plus partial responses) for 31 retreatment-eligible patients in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease control rates were 65.2% and 75.0%. No new types of toxicities occurred during retreatment and most events were mild-to-moderate. CONCLUSION: Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen. PMID- 23444227 TI - Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. AB - PURPOSE: Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcgamma receptor (FcgammaR)-mediated cytotoxicity. However, the role of CD8(+) CTL and FcgammaR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. EXPERIMENTAL DESIGN: FcgammaRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)-specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN gamma release assays and flow cytometry. RESULTS: FcgammaRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR(853-861)-specific CD8(+) T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR(+) tumor cells and FcgammaRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-gamma-dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (T(H)1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell-induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3. CONCLUSION: Cetuximab-activated NK cells promote DC maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through "NK-DC cross talk." FcgammaRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. EGFR specific T cells in cetuximab-treated patients with HNC may contribute to clinical response. PMID- 23444229 TI - Clinical significance of CD33 nonsynonymous single-nucleotide polymorphisms in pediatric patients with acute myeloid leukemia treated with gemtuzumab-ozogamicin containing chemotherapy. AB - PURPOSE: The purpose of this study was to evaluate clinical implications of CD33 single-nucleotide polymorphisms (SNP) in pediatric patients with acute myeloid leukemia (AML) treated with gemtuzumab-ozogamicin (GO)-based therapy. EXPERIMENTAL DESIGN: We genotyped four CD33 SNPs: rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3'UTR) in pediatric patients undergoing induction chemotherapy containing GO (COG AAML03P1 trial; n = 242) or not containing GO (St. Jude AML02 trial; n = 172). RESULTS: CD33 SNPs were correlated significantly with clinical characteristics and treatment outcome. The coding SNPs, rs35112940 and rs12459419, were significantly associated with clinical endpoints in COG-AAML03P1 but not in the St. Jude AML02 trial. Specifically, among white patients in COG-AAML03P1, the 3 year overall survival (OS) rate from remission was 84% +/- 8% for those homozygous (GG) for rs35112940 versus 68% +/- 15% for the other genotypes (P = 0.018); these patients also had a lower relapse risk and superior disease-free survival. Likewise, patients homozygous for variant allele (TT) for rs12459419 were more likely to have favorable risk disease than CC and CT genotypes (52% vs. 31%, P = 0.034) and significantly lower diagnostic blast CD33 expression than other genotypes (P < 0.001). CONCLUSION: Our data suggest that genetic variations in CD33 could impact clinical outcome of GO-based therapy in pediatric AMLs. PMID- 23444230 TI - Marfan syndrome caused by a novel FBN1 mutation with associated pigmentary glaucoma. AB - Mutations in fibrillin-1 (FBN1) cause a wide spectrum of disorders, including Marfan syndrome, which have in common defects in fibrillin-1 microfibrils. Ectopia lentis and myopia are frequently observed ocular manifestations of Marfan syndrome. Glaucoma is also associated with Marfan syndrome, though the form of glaucoma has not been well-characterized. In this report, ocular examination of a patient diagnosed with Marfan syndrome based on family history and aortic dilatation was performed, including measurement of facility of aqueous humor outflow by tonography. The patient did not have ectopia lentis at the age of 42 years. Based on optic nerve appearance, reduced outflow facility, elevated IOP with open angles and clear signs of pigment dispersion, the patient was diagnosed with pigmentary glaucoma. The patient was heterozygous for a novel truncating mutation in FBN1, p.Leu72Ter. Histology of normal human eyes revealed abundant expression of elastic fibers and fibrillin-1 in aqueous humor outflow structures. This is the first report of a patient with Marfan syndrome that is caused by a confirmed FBN1 mutation with associated pigmentary glaucoma. In addition to identifying a novel mutation of FBN1 and broadening the spectrum of associated ocular phenotypes in Marfan syndrome, our findings suggest that pigmentary glaucoma may involve defects in fibrillin-1 microfibrils. PMID- 23444231 TI - Evaluating animal models: some taxonomic worries. AB - The seminal 1993 article by LaFollette and Shanks "Animal Models in Biomedical Research: Some Epistemological Worries" introduced an influential taxonomy into the debate about the value of animal experimentation. The distinction they made between hypothetical and causal analog models served to highlight a concern regarding extrapolating results obtained in animal models to human subjects, which endures today. Although their taxonomy has made a significant contribution to the field, we maintain that it is flawed, and instead, we offer a new practice oriented taxonomy of animal models as a means to allow philosophers, modelers, and other interested parties to discuss the epistemic merits and shortcomings, purpose, and predictive capacities of specific modeling practices. PMID- 23444232 TI - How do patients contribute to signal detection? : A retrospective analysis of spontaneous reporting of adverse drug reactions in the UK's Yellow Card Scheme. AB - BACKGROUND: In 2005, spontaneous reporting of adverse drug reactions (ADRs) to the UK's Yellow Card Scheme (YCS) was extended to include patient reports. Here, we investigate the potential pharmacovigilance impact of patient reporting. OBJECTIVES: The aim of the study was to investigate the relative contribution of patient reporting to signal detection through disproportionality analysis. METHODS: Data were analysed from all reports submitted directly to the YCS between October 2005 and September 2007. Three datasets of drug-ADR pairs were created: one for patient reports, one for healthcare professional (HCP) reports and one for all reports combined. The proportional reporting ratio (PRR) method was used to identify signals of disproportionate reporting (SDRs) in each dataset. The number of SDRs identified from patient and HCP reports were compared, as well as the type of ADR and suspect drug involved. A sensitivity analysis was performed to examine how combining the patient and HCP reports may affect the SDRs identified. RESULTS: Data were received for 5,180 patient and 20,949 HCP reports, relating to 16,566 and 28,775 drug-ADR pairs, respectively, with 4,340 (10.6 %) pairs found in both datasets. A significantly higher proportion of the SDRs identified from HCP reports involved reactions classified as serious by the Medicines and Healthcare products Regulatory Agency (MHRA), compared with patient reports (n = 931, 48.0 % vs. n = 185, 28.5 %), or involved newly marketed drugs (n = 596, 30.7 % vs. n = 71, 10.9 %). The proportion of SDRs assessed as not listed on the Summary of Product Characteristics (SPC) was similar in each group (~15 %, based on a random sample). After combining the patient and HCP reports, 278 (~11 %) of the SDRs identified when each group was analysed separately no longer met the SDR criteria, including 12 potentially serious ADRs not listed on the product's SPC. On the other hand, the combined dataset identified an additional 508 SDRs that were not identified when patient or HCP reports were analysed separately. Approximately 10 % (n = 47) of these additional SDRs were assessed as serious ADRs and were not listed on the product's SPC. CONCLUSIONS: Although this study is limited to the UK experience, overall, the results suggest that patient reporting may provide a positive complementary contribution to that of HCPs. Patient reporting may make an important contribution to drug safety by identifying different SDRs not identified from HCP reports alone. The combination of reports from patients and HCPs, however, when used for the purposes of signal detection through disproportionality analysis, may result in the loss of some information. One possible strategy is to conduct such analyses using reports from patients and HCPs combined, as well as separately for each group. PMID- 23444233 TI - Sensitivity to Information Conveyed by Horizontal Contours is Correlated with Face Identification Accuracy. AB - We measured thresholds in a 1-of-10 face identification task in which stimuli were embedded in orientation-filtered Gaussian noise. For upright faces, the threshold elevation produced by the masking noise varied as a function of noise orientation: significantly greater masking was obtained with horizontal noise than with vertical noise. However, the orientation selectivity of masking was significantly less with inverted faces. The performance of an ideal observer was qualitatively similar to human observers viewing upright faces: the masking function exhibited a peak for horizontally oriented noise although the selectivity of masking was greater than what was observed in human observers. These results imply that significantly more information about facial identity was conveyed by horizontal contours than by vertical contours, and that human observers use this information more efficiently to identify upright faces than inverted faces. We also found a significant positive correlation between selectivity for horizontal information and face identification accuracy for upright, but not inverted faces. Finally, there was a significant positive correlation between horizontal tuning and the size of the face inversion effect. These results demonstrate that the use of information conveyed by horizontal contours is associated with face identification accuracy and the magnitude of the face inversion effect. PMID- 23444234 TI - Ethnicity and long-term heart rate variability in children. AB - BACKGROUND: Low heart rate variability (HRV) is associated with increased cardiovascular disease risk. South Asians are at increased risk of cardiovascular disease. METHODS: This cross-sectional, observational study compared long-term HRV between South Asian and White European (EU) children. 155 children (92 White EU, 63 South Asian) aged 8+/-1 years wore a combined heart rate and activity monitor for 7 days. From 24-h beat-to-beat heart rate recordings, long-term HRV was calculated as the SD of the average RR intervals in each 5 min period (SDANN). Physical activity, daily energy expenditure, percentage body fat and maximal oxygen consumption (VO2max) were calculated using published or commercial algorithms. RESULTS: SDANN was significantly lower during the 24-h period in South Asian compared with White EU children (113+/-27 vs 130+/-28 ms, p<0.01, mean+/-SD) and during sleep (44+/-12 vs 54+/-16 ms, p<0.01, mean+/-SD). Ethnic differences in HRV were associated with lower levels of physical activity, daily energy expenditure, VO2max, and higher percentage body fat and resting heart rate, in South Asian children. Ethnic differences in HRV persisted despite statistical adjustment for these factors. SDANN was significantly lower in girls, but sex differences were no longer apparent when VO2max, physical activity and energy expenditure were statistically controlled for. CONCLUSIONS: Our data confirm that South Asian children have lower HRV and reveal the novel information that the reduction is partially independent of physical activity and aerobic fitness. PMID- 23444235 TI - Clinical outcomes of gastrointestinal stromal tumor in southern Thailand. AB - AIM: To review a single institutional experience in clinical management of gastrointestinal stromal tumors (GIST) and analyze for factors determining treatment outcome. METHODS: Clinicopathological data of patients with a diagnosis of GIST who were treated at our institute during November 2004 to September 2009 were retrospectively reviewed. RESULTS: Ninety-nine cases were included in the analysis. Primary tumor sites were at the stomach in and small bowel in 44% and 33%, respectively. Thirty-one cases already had metastasis at presentation and the most common metastatic site was the liver. Sixty-four cases (65%) were in the high-risk category. Surgical treatment was performed in 77 cases (78%), 3 of whom received upfront targeted therapy. Complete resection was achieved in 56 cases (73% of operative cases) and of whom 27 developed local recurrence or distant metastasis at a median duration of 2 years. Imatinib was given as a primary therapy in unresectable cases (25 cases) and as an adjuvant in cases with residual tumor (21 cases). Targeted therapy gave partial response in 7 cases (15%), stable disease in 27 cases (57%) and progressive disease in 13 cases (28%). Four-year overall survival was 74% (95% CI: 61%-83%). Univariate survival analysis found that low-risk tumor, gastric site, complete resection and response to imatinib were associated with better survival. CONCLUSION: The overall outcomes of GIST can be predicted by risk-categorization. Surgery alone may not be a curative treatment for GIST. Response to targeted therapy is a crucial survival determinant in these patients. PMID- 23444236 TI - The suppressive role of p38 MAPK in cellular vacuole formation. AB - Vacuolization of the cytoplasm is one of the dramatic and frequently observed phenomena in various cell types. Cellular vacuoles occur spontaneously or via a wide range of inductive stimuli, but the molecular mechanism involved in this process remains largely unknown. In this study, we investigated the role of the p38 and JNK pathways in the formation of cytoplasmic vacuoles. We found that p38 and JNK agonist anisomycin abolishes spontaneous cytoplasmic vacuolization of HepG2 cells through p38 activation, but not through JNK activation. Importantly, blocking the activity of p38 or suppression the expression of p38 elicits cytoplasmic vacuoles formation in various cancer cells. Furthermore, cytoplasmic vacuoles induced by p38 blocking are derived from the perinuclear region. These observations provide direct evidence for a role of p38 signaling in regulating the formation of cytoplasmic vacuoles. PMID- 23444237 TI - Modulation of anabolic and catabolic responses via a porous polymer scaffold manufactured using thermally induced phase separation. AB - We describe two studies encompassing the iterative refinement of a polymer-based rhBMP-2 delivery system for bone tissue engineering. Firstly, we compared the bone-forming capacity of porous poly(D,L-lactic-co-glycolic acid) (PLGA) scaffolds produced by thermally induced phase separation (TIPS) with non-porous solvent cast poly(D,L-lactic acid) (PDLLA) used previously. Secondly, we examined the potential synergy between rhBMP-2 and local bisphosphonate in the PLGA scaffold system. In vivo ectopic bone formation studies were performed in C57BL6/J mice. Polymer scaffolds containing 0, 5, 10 or 20 ug rhBMP-2 were inserted into the dorsal musculature. At all rhBMP-2 doses, porous PLGA produced significantly higher bone volume (BV, mm3) than the solid PDLLA scaffolds. Next, porous PLGA scaffolds containing 10 ug rhBMP-2 +/- 0.2, or 2 ug zoledronic acid (ZA) were inserted into the hind-limb musculature. Co-delivery of local 10 ug rhBMP-2/2 ug ZA significantly augmented bone formation compared with rhBMP-2 alone (400 % BV increase, p < 0.01). Hydroxyapatite microparticle (HAp) addition (2 % w/w) to the 10 ug rhBMP-2/0.2 ug ZA group increased BV (200 %, p < 0.01). We propose that this was due to controlled ZA release of HAp-bound ZA. Consistent with this, elution analyses showed that HAp addition did not alter the rhBMP-2 elution, but delayed ZA release. Moreover, 2 % w/w HAp addition reduced the scaffold's compressive properties, but did not alter ease of surgical handling. In summary, our data show that refinement of the polymer selection and scaffold fabrication can enhance rhBMP-2 induced bone formation in our bone tissue engineering implant, and this can be further optimised by the local co-delivery of ZA/HAp. PMID- 23444238 TI - First-trimester uterine artery Doppler examination in pregnancies complicated by gestational diabetes mellitus with or without pre-eclampsia. AB - OBJECTIVES: To assess first-trimester placental perfusion, reflected in the uterine artery (UtA) pulsatility index (PI), in pregnancies complicated by gestational diabetes mellitus (GDM), with or without pre-eclampsia (PE), compared with those unaffected by GDM. METHODS: UtA-PI was measured at 11 + 0 to 13 + 6 weeks' gestation in 1037 singleton pregnancies that subsequently developed GDM and in 56 649 normoglycemic controls. The measured mean UtA-PI was converted to multiples of the expected normal median (MoM), corrected for maternal weight, racial origin and gestational age, and the median MoM values in the two groups were compared. RESULTS: The incidence of PE was higher in pregnancies with GDM than in controls (4.0% vs 2.3%, respectively; P = 0.001). However, there were no significant differences in the median UtA-PI MoM between the groups (1.00 (interquartile range (IQR), 0.82-1.21) vs 1.00 (IQR, 0.81-1.21); P = 0.73). The median UtA-PI in patients who developed PE was higher than in those who did not develop PE, regardless of the development of GDM. CONCLUSIONS: First-trimester placental perfusion, as assessed by UtA Doppler examination, is not impaired in women who subsequently develop GDM. The increased prevalence of PE in women with GDM cannot be attributed to impaired placentation. PMID- 23444239 TI - Bioethics and medicine. PMID- 23444240 TI - Computed microtomography visualization and quantification of mouse ischemic brain lesion by nonionic radio contrast agents. AB - AIM: To explore the possibility of brain imaging by microcomputed tomography (microCT) using x-ray contrasting methods to visualize mouse brain ischemic lesions after middle cerebral artery occlusion (MCAO). METHODS: Isolated brains were immersed in ionic or nonionic radio contrast agent (RCA) for 5 days and subsequently scanned using microCT scanner. To verify whether ex-vivo microCT brain images can be used to characterize ischemic lesions, they were compared to Nissl stained serial histological sections of the same brains. To verify if brains immersed in RCA may be used afterwards for other methods, subsequent immunofluorescent labeling with anti-NeuN was performed. RESULTS: Nonionic RCA showed better gray to white matter contrast in the brain, and therefore was selected for further studies. MicroCT measurement of ischemic lesion size and cerebral edema significantly correlated with the values determined by Nissl staining (ischemic lesion size: P=0.0005; cerebral edema: P=0.0002). Brain immersion in nonionic RCA did not affect subsequent immunofluorescent analysis and NeuN immunoreactivity. CONCLUSION: MicroCT method was proven to be suitable for delineation of the ischemic lesion from the non-infarcted tissue, and quantification of lesion volume and cerebral edema. PMID- 23444241 TI - Arsenic trioxide treatment of rabbit liver VX-2 carcinoma via hepatic arterial cannulation-induced apoptosis and decreased levels of survivin in the tumor tissue. AB - AIM: To investigate the role of tumor apoptosis-inhibitory protein survivin in arsenic trioxide-induced apoptosis in VX-2 carcinoma in the rabbit liver by means of transcatheter arterial chemoembolization. METHODS: Sixteen rabbits with 32 implanted hepatic VX-2 tumors were randomly divided into two groups. The experimental group received 2 mg of arsenic trioxide and 1 mL of ultra-fluid lipiodol co-injected via hepatic arterial cannulation and the control group received only 1 mL of lipiodol. Animals were sacrificed 3 weeks after trans catheterial arterial chemoembolization. Tumor tissue and tumor-peripheral tissue were collected for analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling staining was used to assess tumor cells apoptosis. Immunohistochemistry was used to assess the presence of survivin protein. Reverse transcription polymerase chain reaction was used to determine the expression of survivin gene. RESULTS: The number of apoptotic cells significantly increased in the tumor tissue (5.20 +/- 0.60%) compared to tumor-peripheral tissue (1.29 +/- 0.42%) of the arsenic trioxide-treated group. Survivin expression levels in the tumor tissue were significantly reduced in arsenic trioxide-treated group (7.68 +/- 0.65) compared to the control group (35.30 +/- 4.63). CONCLUSION: Transcatheter arterial chemoembolization with arsenic trioxide induced apoptosis of VX-2 carcinoma, in which tumor apoptosis-inhibitory protein survivin may have played a role. PMID- 23444242 TI - Mitochondrial and Y-chromosomal profile of the Kazakh population from East Kazakhstan. AB - AIM: To study the genetic relationship of Kazakhs from East Kazakhstan to other Eurasian populations by examining paternal and maternal DNA lineages. METHODS: Whole blood samples were collected in 2010 from 160 unrelated healthy Kazakhs residing in East Kazakhstan. Genomic DNA was extracted with Wizard genomic DNA Purification Kit. Nucleotide sequence of hypervariable segment I of mitochondrial DNA (mtDNA) was determined and analyzed. Seventeen Y-short tandem repeat (STR) loci were studied in 67 samples with the AmpFiSTR Y-filer PCR Amplification Kit. In addition, mtDNA data for 2701 individuals and Y-STR data for 677 individuals were retrieved from the literature for comparison. RESULTS: There was a high degree of genetic differentiation on the level of mitochondrial DNA. The majority of maternal lineages belonged to haplogroups common in Central Asia. In contrast, Y-STR data showed very low genetic diversity, with the relative frequency of the predominant haplotype of 0.612. CONCLUSION: The results revealed different migration patterns in the population sample, showing there had been more migration among women. mtDNA genetic diversity in this population was equivalent to that in other Central Asian populations. Genetic evidence suggests the existence of a single paternal founder lineage in the population of East Kazakhstan, which is consistent with verbal genealogical data of the local tribes. PMID- 23444243 TI - Red blood cell distribution width as a prognostic marker of mortality in patients on chronic dialysis: a single center, prospective longitudinal study. AB - AIM: To determine if red cell distribution width (RDW) is associated with all cause mortality in patients on chronic dialysis and to evaluate its prognostic value among validated prognostic biomarkers. METHODS: This is a single center, prospective longitudinal study. At the time of inclusion in January 2011, all patients were physically examined and a routine blood analysis was performed. A sera sample was preserved for determination of NT-pro-brain natriuretic peptide (NT-pro-BNP) and eosinophil cationic protein. Carotid intima media thickness (IMT) was also measured. Following one year, all-cause mortality was evaluated. RESULTS: Of 100 patients, 25 patients died during the follow-up period of one year. Patients who died had significantly higher median [range] RDW levels (16.7% [14.3-19.5] vs 15.5% [13.2-19.7], P<0.001. They had significantly higher Eastern Cooperative Oncology Group (ECOG) performance status (4 [2-4] vs 2 [1-4], Plt;0.001), increased intima-media thickness (IMT) (0.71 [0.47-1.25] vs 0.63 [0.31-1.55], P=0.011), increased NT-pro-BNP levels (8300 [1108-35000] vs 4837 [413-35000], P=0.043), and increased C-reactive protein (CRP) levels (11.6 [1.3 154.2] vs 4.9 [0.4-92.9], Plt;0.001). For each 1% point increase in RDW level as a continuous variable, one-year all cause mortality risk was increased by 54% in univariate Cox proportional hazard analysis. In the final model, when RDW was entered as a categorical variable, mortality risk was significantly increased (hazard ratio, 5.15, 95% confidence interval, 2.33 to 11.36) and patients with RDW levels above 15.75% had significantly shorter survival time (Log rank Plt;0.001) than others. CONCLUSIONS: RDW could be an additive predictor for all cause mortality in patients on chronic dialysis. Furthermore, RDW combined with sound clinical judgment improves identification of patients who are at increased risk compared to RDW alone. PMID- 23444244 TI - Abnormal circadian rhythm and cortisol excretion in autistic children: a clinical study. AB - AIM: To determine the circadian rhythm alteration of cortisol excretion and the level of corticosteroids in children with different grades of autism severity. METHODS: The study included 45 children with different grades of autism severity (low [LFA], medium [MFA], and high functioning autism [HFA]), 15 in each group, and 45 age/sex-matched children with typical development. The urinary levels of free cortisol (at three phases of 24-hour cycle), corticosteroids, vanilylmandelic acid, and 5-hydroxyindole acetic acid were determined. RESULTS: Alteration in the pattern of cortisol excretion (Phases I, II, and III) was observed in children with LFA (Phase I: 43.8 +/- 4.43 vs 74.30 +/- 8.62, P=0.000; Phase II: 21.1 +/- 2.87 vs 62 +/- 7.68, P<0.001; Phase III: 9.9 +/- 1.20 vs 40 +/ 5.73, P<0.001) and MFA (Phase I: 43.8 +/- 4.43 vs 52.6 +/- 7.90, P<0.001; Phase II: 21.1 +/- 2.87 vs 27.4 +/- 4.05, P<0.001; Phase III: 9.9 +/- 1.20 vs 19 +/- 2.50, P<0.001) compared to the control group. The corticosteroids excretion levels were higher in all the groups of children with autism than in the control group. The level of 5-hydroxyindole acetic acid was significantly higher in children with LFA (8.2 +/- 1.48 vs 6.8 +/- 0.85, P<0.001) and MFA (8.2 +/- 1.48 vs 7.4 +/- 0.89, P=0.001) and not significantly higher in children with HFA than in the control group. The changes were correlated with degrees of severity of the disorder. CONCLUSION: These data suggest that altered cortisol excretion pattern and high level of corticosteroids in urine may probably be a consequence of altered hypothalamic-pituitary-adrenal axis function, which may contribute to the pathogenesis and affect the severity of autism. PMID- 23444245 TI - Risk factors for fatal outcome in patients with opioid dependence treated with methadone in a family medicine setting in Croatia. AB - AIM: To determine the risk factors for fatal outcome in patients with opioid dependence treated with methadone at the primary care level. METHODS: A group of 287 patients with opioid dependence was monitored prospectively from 1995 to 2007. At the beginning of the study, we collected the data on patient baseline characteristics, treatment characteristics, and living environment. At the annual check-up, we collected the data on daily methadone dose, method of methadone therapy administration, and family physician's assessment of the patient's drug use status. RESULTS: Out of 287 patients, 8% died. Logistic regression analysis showed that the predictors of fatal outcome were continuation of drug use during previous therapeutic attempts (odds ratio [OR], 19.402; 95% confidence interval [CI], 1.659-226.873), maintenance therapy as the planned treatment modality (OR, 3.738; 95% CI, 1.045-13.370), living in an unstable relationship (OR, 9.275; 95% CI, 2.207-38.984), and loss of continuity of care (OR, 12.643; 95% CI, 3.001 53.253). CONCLUSION: The patients presenting these risk factors require special attention. It is important for family physicians to insist on compliance with the treatment protocol and intervene when they lose contact with the patient to prevent the fatal outcome. PMID- 23444246 TI - Ambulatory oral surgery: 1-year experience with 11680 patients from Zagreb district, Croatia. AB - AIM: To examine the types and frequencies of oral surgery diagnoses and ambulatory oral surgical treatments during one year period at the Department of Oral Surgery, University Hospital Dubrava in Zagreb, Croatia. METHODS: Sociodemographic and clinical data on 11680 ambulatory patients, treated between January 1 and of December 31, 2011 were retrieved from the hospital database using a specific protocol. The obtained data were subsequently analyzed in order to assess the frequency of diagnoses and differences in sex and age. RESULTS: The most common ambulatory procedure was tooth extraction (37.67%) and the most common procedure in ambulatory operating room was alveolectomy (57.25%). The test of proportions showed that significantly more extractions (P<0.001) and intraoral incisions (P<0.001) were performed among male patients, whereas significantly more alveolectomies and apicoectomies were performed among female patients (P<0.001). A greater prevalence of periodontal disease was found in patients residing in Zagreb than in patients residing in rural areas. CONCLUSION: The data from this study may be useful for planning of ambulatory oral surgery services, budgeting, and sustaining quality improvement, enhancing oral surgical curricula, training and education of primary health care doctors and oral surgery specialists, and promoting patients' awareness of the importance of oral health. PMID- 23444247 TI - Surviving genocide in Srebrenica during the early childhood and adolescent personality. AB - AIM: To examine how the experience of genocide in Srebrenica in the early childhood (ages 1-5) influences the psychological health in adolescence. METHODS: This study included 100 school-attending adolescents, age 15-16 (born in 1990-91) who were divided in two groups according to the place of residence from 1992 1995: the Srebrenica group - adolescents who lived in Srebrenica during the siege and the non-Srebrenica group who lived in the "free territory," were not wounded, and experienced no losses. We used the socio-demographic questionnaire created for the purposes of our study and the War Trauma Questionnaire, Posttraumatic Stress Reactions Questionnaire, Self-report Depressive Scale (Zung), Freiburg Personality Inventory, and the Lifestyle Questionnaire. RESULTS: Srebrenica adolescents experienced significantly more traumatic experiences (14.26 +/- 3.11 vs 4.86 +/- 3.16, P<0.001). Although there was no signifcant difference in the total score of posttraumatic stress reactions and intensity of depression between the two groups, significantly higher scores of posttraumatic stress reaction were noticed for several specific questions. The most prominent defense mechanisms in both groups were projection, intellectualization, and reactive formation. Srebrenica adolescents had higher sociability levels (34.7% vs 16.0%, chi(2)=7.231, P=0.020). CONCLUSION: Srebrenica adolescents reported significantly more severe PTSD symptoms and significantly greater sociability. Our findings could be used for planning treatment and improving communication and overcoming traumas in war-affected areas. PMID- 23444248 TI - Development of the Croatian model of organ donation and transplantation. AB - During the past ten years, the efforts to improve and organize the national transplantation system in Croatia have resulted in a steadily growing donor rate, which reached its highest level in 2011, with 33.6 utilized donors per million population (p.m.p.). Nowadays, Croatia is one of the leading countries in the world according to deceased donation and transplantation rates. Between 2008 and 2011, the waiting list for kidney transplantation decreased by 37.2% (from 430 to 270 persons waiting for a transplant) and the median waiting time decreased from 46 to 24 months. The Croatian model has been internationally recognized as successful and there are plans for its implementation in other countries. We analyzed the key factors that contributed to the development of this successful model for organ donation and transplantation. These are primarily the appointment of hospital and national transplant coordinators, implementation of a new financial model with donor hospital reimbursement, public awareness campaign, international cooperation, adoption of new legislation, and implementation of a donor quality assurance program. The selection of key factors is based on the authors' opinions; we are open for further discussion and propose systematic research into the issue. PMID- 23444249 TI - Transplant ethics under scrutiny - responsibilities of all medical professionals. AB - In this text, we present and elaborate ethical challenges in transplant medicine related to organ procurement and organ distribution, together with measures to solve such challenges. Based on internationally acknowledged ethical standards, we looked at cases of organ procurement and distribution practices that deviated from such ethical standards. One form of organ procurement is known as commercial organ trafficking, while in China the organ procurement is mostly based on executing prisoners, including killing of detained Falun Gong practitioners for their organs. Efforts from within the medical community as well as from governments have contributed to provide solutions to uphold ethical standards in medicine. The medical profession has the responsibility to actively promote ethical guidelines in medicine to prevent a decay of ethical standards and to ensure best medical practices. PMID- 23444250 TI - Conscience in health care and the definitions of death. AB - Brain death or neurologic death has gradually become recognized as human death over the past decades worldwide. Nevertheless, in Japan, the New York State, and the State of New Jersey, death is declared based not on brain death criteria, but on cardio-pulmonary criteria. In Japan, the 1997 Organ Transplant Law legalized brain death determination exclusively when organs were to be procured from brain dead patients. Even after 2009 law revision, the default definition of death continued to be based on cardio-pulmonary criteria, despite the criticism. The cases of Japan and the United States provide a good reference as social experiments of appreciating conscientious or religio-cultural dimensions in health care. This text theoretically examines the 1997 organ transplant law of Japan and its 2009 revision, presenting some characteristics of Japan's case compared to American cases and the implications its approach has for the rest of the world. This is an example in which a foreign idea that did not receive widespread support from Japanese citizens was transformed to fit the religio cultural landscape. PMID- 23444251 TI - The clinic as a good corporate neighbor. AB - Clinics today specialize in health repair services similar to car repair shops; procedures and prices are standardized, regulated, and inflexibly uniform. Clinics of the future have to become Health Care Centers in order to be more respected and more effective corporate neighbors in offering outreach services in health education and preventive health care. The traditional concept of care for health is much broader than repair management and includes the promotion of lay health competence and responsibility in healthy social and natural environments. The corporate profile and ethics of the clinic as a good and competitive local neighbor will have to focus on [a] better personalized care, [b] education and services in preventive care, [c] direct or web-based information and advice for general, seasonal, or age related health risks, and on developing and improving trustworthy character traits of the clinic as a corporate person and a good neighbor. PMID- 23444252 TI - Development and perspectives of theological bioethics. PMID- 23444253 TI - Deaf education in Croatia. PMID- 23444254 TI - Science, safety, and trust: the case of transgenic food. AB - Genetically modified (GM) food is discussed as an example of the controversial relation between the intrinsic uncertainty of the scientific approach and the demand of citizen-consumers to use products of science innovation that are known to be safe. On the whole, peer-reviewed studies on GM food safety do not note significant health risks, with a few exceptions, like the most renowned "Pusztai affair" and the recent "Seralini case." These latter studies have been disregarded by the scientific community, based on incorrect experimental designs and statistic analysis. Such contradictory results show the complexity of risk evaluation, and raise concerns in the citizen-consumers against the GM food. A thoughtful consideration by scientific community and decision makers of the moral values that are present in risk evaluation and risk management should be the most trustable answer to citizen-consumers to their claim for clear and definitive answers concerning safety/un-safety of GM food. PMID- 23444255 TI - Progressive disorders and associated complications. PMID- 23444256 TI - Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre exposure prophylaxis. AB - The fixed-dose combination of emtricitabine (FTC) 200 mg and tenofovir disoproxil fumarate (TDF) 300 mg (Truvada((r))), administered orally once daily, is widely used as part of first-line regimens for the treatment of HIV-1 infection. Recently, once-daily administration of FTC/TDF was approved in the USA for pre exposure prophylaxis in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in high-risk adults who are not infected. To date, results of four large, randomized, double-blind, placebo-controlled, multicentre trials with FTC/TDF as pre-exposure prophylaxis have been published. Three studies showed statistically significant reductions in the number of individuals with emergent HIV-1 infection when FTC/TDF was compared with placebo over the ~1- to 2-year study periods. Efficacy (i.e. risk reduction relative to placebo) was 44 % in the iPrEx trial in men who have sex with men, 75 % in the Partners PrEP study in heterosexual HIV-1-serodiscordant couples and 62 % in the TDF2 trial in heterosexual men and women. The fourth study (FEM-PrEP) in heterosexual women did not show a statistically significant difference between FTC/TDF and placebo, although low adherence rates reported in this trial may have been a factor. No unexpected adverse events were reported in the trials. However, since pre exposure prophylaxis involves long-term administration of drugs to healthy individuals, it is important to monitor the long-term safety of FTC/TDF (e.g. renal function, bone mineral density) in this setting. Other notable considerations include adherence, cost and the potential for development of drug resistance. Interim guidelines are available for prescribing FTC/TDF as pre exposure prophylaxis. If used appropriately in selected high-risk individuals, pre-exposure prophylaxis with FTC/TDF represents an important additional strategy to reduce the spread of HIV-1 infection, which continues to be a significant global concern. PMID- 23444257 TI - Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways. AB - BACKGROUND: Glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor of the central nervous system, is characterized by a relentless disease recurrence despite continued advancement in surgery, radiotherapy, and chemotherapy. Resistance to temozolomide (TMZ), a standard chemotherapeutic agent for GBM, remains a major challenge. Understanding the mechanisms behind TMZ resistance can direct the development of novel strategies for the prevention, monitoring, and treatment of tumor relapse. METHODS AND RESULTS: Our research platform, based on the establishment of 2 pairs of TMZ-sensitive/resistant GBM cells (D54-S and D54-R; U87-S and U87-R), has successfully identified prolyl 4 hydroxylase, beta polypeptide (P4HB) over-expression to be associated with an increased IC50 of TMZ. Elevated P4HB expression was verified using in vivo xenografts developed from U87-R cells. Clinically, we found that P4HB was relatively up-regulated in the recurrent GBM specimens that were initially responsive to TMZ but later developed acquired resistance, when compared with treatment-naive tumors. Functionally, P4HB inhibition by RNAi knockdown and bacitracin inhibition could sensitize D54-R and U87-R cells to TMZ in vitro and in vivo, whereas over-expression of P4HB in vitro conferred resistance to TMZ in both D54-S and U87-S cells. Moreover, targeting P4HB blocked its protective function and sensitized glioma cells to TMZ through the PERK arm of the endoplasmic reticulum stress response. CONCLUSIONS: Our study identified a novel target together with its functional pathway in the development of TMZ resistance. P4HB inhibition may be used alone or in combination with TMZ for the treatment of TMZ-resistant GBM. PMID- 23444258 TI - The frequency, longitudinal course, clinical associations, and causes of emotional distress during primary treatment of cerebral glioma. AB - BACKGROUND: Relatively little is known about the frequency, longitudinal course, independent associations, and reported causes of emotional distress in adults with primary cerebral glioma. We aimed to describe these features in an observational study. METHODS: This was a twin-center prospective cohort study. Eligible adults were those with a new histological diagnosis of glioma who were receiving active management. Distress was measured using the National Comprehensive Cancer Network Distress Thermometer and problem checklist. Subjects were sampled at 3 timepoints: T1 (shortly after starting chemo/radiotherapy), T2 (3 months later), and T3 (6 months later). RESULTS: T1 n = 154; T2 n = 103; T3 n = 83. Significant distress was present in 36.4 +/- 7.6% at T1, 35.9 +/- 9.3% at T2, and 33.7 +/- 10.2% at T3. Longitudinally, subjects with high distress at T1 (median Distress Thermometer score = 8; interquartile range [IQR] 7-9) remained highly distressed on follow-up (T2 median = 8, IQR 6-8; T3 median = 7, IQR 5-8) (Friedman test P = .304). Younger age, functional impairment, and concurrent major depressive disorder were independently associated with high distress (logistic regression chi(2) for model = 39.882, P < .001, R(2) = 0.312). The most frequently reported causes of distress were worry, fatigue, sleep difficulties, and sadness. Emotional difficulties were among the most common causes of distress at all 3 timepoints. CONCLUSIONS: At each timepoint, one-third of patients reported significant emotional distress, which persisted during follow-up among those initially highly distressed. Young, functionally impaired, and depressed glioma patients may particularly benefit from increased support. PMID- 23444259 TI - Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic resonance images. AB - BACKGROUND: Subtypes of glioblastoma multiforme (GBM) based on genetic and molecular alterations are thought to cause alterations in anatomic MRI owing to downstream biological changes, such as edema production, blood-brain barrier breakdown, and necrosis. The purpose of the current study was to identify a potential relationship between imaging features and the mesenchymal (MES) GBM subtype, which has the worst patient prognosis. METHODS: MRIs from 46 patients with histologically confirmed GBM were retrospectively analyzed. The volume of contrast enhancement, regions of central necrosis, and hyperintensity of T2/fluid attenuated inversion recovery (FLAIR) were measured. Additionally, the ratio of T2/FLAIR hyperintense volume to the volume of contrast enhancement and necrosis was calculated. RESULTS: The volume of contrast enhancement, volume of central necrosis, combined volume of contrast enhancement and central necrosis, and the ratio of T2/FLAIR to contrast enhancement and necrosis were significantly different in MES compared with non-MES GBM (Mann-Whitney, P < .05). Receiver operator characteristics indicated that these 4 metrics were all significant predictors of the MES phenotype. The volume ratio of T2 hyperintensity to contrast enhancement and central necrosis was significantly lower in MES vs non MES GBM (P < .0001), was a significant predictor of the MES phenotype (area under the curve = 0.93, P < .001), and could be used to stratify short- and long-term overall survival (log-rank, P = .0064 using cutoff of 3.0). These trends were also present when excluding isocitrate dehydrogenase 1 mutant tumors and incorporating covariates such as age and KPS score. CONCLUSIONS: Results suggest that volume ratio may be a simple, cost-effective, and noninvasive biomarker for quickly identifying MES GBM. PMID- 23444260 TI - Gastrokine 1 regulates NF-kappaB signaling pathway and cytokine expression in gastric cancers. AB - Gastrokine 1 (GKN1) plays an important role in the gastric mucosal defense mechanism and also acts as a functional gastric tumor suppressor. In this study, we examined the effect of GKN1 on the expression of inflammatory mediators, including NF-kappaB, COX-2, and cytokines in GKN1-transfected AGS cells and shGKN1-transfected HFE-145 cells. Lymphocyte migration and cell viability were also analyzed after treatment with GKN1 and inflammatory cytokines in AGS cells by transwell chemotaxis and an MTT assay, respectively. In GKN1-transfected AGS cells, we observed inactivation and reduced expression of NF-kappaB and COX-2, whereas shGKN1-transfected HFE-145 cells showed activation and increased expression of NF-kappaB and COX-2. GKN1 expression induced production of inflammatory cytokines including IL-8 and -17A, but decreased expression of IL-6 and -10. We also found IL-17A expression in 9 (13.6%) out of 166 gastric cancer tissues and its expression was closely associated with GKN1 expression. GKN1 also acted as a chemoattractant for the migration of Jurkat T cells and peripheral B lymphocytes in the transwell assay. In addition, GKN1 significantly reduced cell viability in both AGS and HFE-145 cells. These data suggest that the GKN1 gene may inhibit progression of gastric epithelial cells to cancer cells by regulating NF-kappaB signaling pathway and cytokine expression. PMID- 23444261 TI - The synthesis and application of Fmoc-Lys(5-Fam) building blocks. AB - Fluorescence resonance energy transfer (FRET) peptide substrates are often utilized for protease activity assays. This study has examined the preparation of FRET triple-helical peptide (THP) substrates using 5-carboxyfluorescein (5-Fam) as the fluorophore and 4,4-dimethylamino-azobenzene-4'-carboxylic acid (Dabcyl) as the quencher. The N(alpha)-(9-fluorenylmethoxycarbonyl)-N(epsilon)-(5 carboxyfluorescein)-L-lysine [Fmoc-Lys(5-Fam)] building block was synthesized utilizing two distinct synthetic routes. The first involved copper complexation of Lys while the second utilized Fmoc-Lys with microwave irradiation. Both approaches allowed convenient production of a very pure final product at a reasonable cost. Fmoc-Lys(5-Fam) and Fmoc-Lys(Dabcyl) were incorporated into the sequence of a THP substrate utilizing automated solid-phase peptide synthesis protocols. A second substrate was assembled where (7-methoxycoumarin-4-yl)-acetyl (Mca) was the fluorophore and 2,4-dinitrophenyl (Dnp) was the quencher. Circular dichroism spectroscopy was used to determine the influence of the fluorophore/quencher pair on the stability of the triple-helix. The activity of the two substrates was examined with three matrix metalloproteinases (MMPs), MMP 1, MMP-13, and MT1-MMP. The combination of 5-Fam as fluorophore and Dabcyl as quencher resulted in a triple-helical substrate that, compared with the fluorophore/quencher pair of Mca/Dnp, had a slightly destabilized triple-helix but was hydrolyzed more rapidly by MMP-1 and MMP-13 and had greater sensitivity. PMID- 23444262 TI - Recurrent agnathia-otocephaly caused by DNA replication slippage in PRRX1. AB - Agnathia-otocephaly is a rare craniofacial malformation complex that is caused by de novo heterozygous and biallelic mutations in PRRX1 in two unrelated babies, respectively. We studied the PRRX1 gene in a non-consanguineous Indonesian female infant who was diagnosed prenatally with severe retrognathia (bilateral Pruzansky type III). Her older affected brother died shortly after birth and had agnathia otocephaly. A c.266_269dupAAAA frameshift mutation in the poly A tract in PRRX1 was identified in the proband while her father only had an inframe duplication (c.267_269dupAAA) of the adenosine trinucleotide residue. Expression of both mutations in COS7 cells showed loss of function of the frame shift mutation only. Results of SNP genotyping coupled with recurrence of this novel mutation in this family are consistent with a paternally derived germline mosaicism rather than autosomal recessive inheritance as predicted by the family history. Severe retrognathia (bilateral Pruzansky III) and agnathia-otocephaly represent a spectrum of craniofacial malformations in this family. PMID- 23444263 TI - The effect of interventions to reduce potentially inappropriate antibiotic prescribing in long-term care facilities: a systematic review of randomised controlled trials. AB - BACKGROUND: The prevalence of antibiotic use in long-term care facilities (LTCF) is high and in many cases it may not be in accordance with local guidelines. It is important to review interventions that aim to improve the quality of antibiotic prescribing in this setting. OBJECTIVE: The objective of this systematic review was to collect and interpret the results of studies of interventions to improve the quality of, or appropriateness of antibiotic prescribing in LTCF in order to determine the key components for a successful intervention. DATA SOURCES: A search of The Cochrane Library, PubMed, EMBASE, ISI Web of Knowledge, International Pharmaceutical Abstracts, the Database of Abstracts of Review of Effects (DARE), the Health Technology Assessments (HTA) at the Centres for Reviews and Dissemination (CRD) and Google Scholar was conducted from their inception to August 2012. A manual search of the grey literature and relevant journals was also conducted. STUDY SELECTION: Studies were selected that were randomised controlled trials of an intervention to improve the quality of antibiotic prescribing, or increase adherence to a prescribing guideline or reduce the amount of antibiotic prescribing. All studies were conducted in the long-term care setting. The search strategy found four randomised controlled trials that met the inclusion criteria, from an initial 1,904 titles. STUDY APPRAISAL AND SYNTHESIS METHODS: The risk of bias assessment of the included studies was conducted using the Cochrane Risk of Bias Table. Due to the heterogeneity of the interventions, study designs and outcome measures, a meta analysis was not conducted. RESULTS: Four studies met the inclusion criteria for this review. Three studies directed educational material and sessions at physicians and nurses, with one of the three studies providing prescribing feedback as well. The fourth study provided educational material and prescribing feedback for physicians only. Due to the mixed and modest effects of the interventions and the variety of interventions implemented, it is difficult to attribute the success of any intervention to just one component alone. It seems that a multifaceted intervention involving small group educational sessions and the provision of educational materials is generally acceptable to nurses and physicians in LTCF. The involvement of local consensus procedures when developing guidelines and interventions may improve the success of the intervention. LIMITATIONS: A limitation of this systematic review is the small number of studies that met the inclusion criteria. CONCLUSION: Interventions in the long term care setting involving local consensus procedures, educational strategies, and locally developed guidelines may improve the quality of antibiotic prescribing, but the quality of the evidence is low. Due to the poor quality of evidence and mixed results, no definitive conclusion can be reached about the effect of the interventions. Future research in this area needs to include process evaluation research in order to define the characteristics contributing to the success or failure of any intervention. The contribution of a multidisciplinary antibiotic management team, which could include a pharmacist, a nurse and specialists in microbiology and infectious diseases and geriatrics, needs further investigation in order to improve antibiotic prescribing practices in LTCF. PMID- 23444264 TI - Sinonasal disease in polyostotic fibrous dysplasia and McCune-Albright Syndrome. AB - OBJECTIVES/HYPOTHESIS: To characterize the spectrum, symptoms, progression, and effects of endocrine dysfunction on sinonasal disease in polyostotic fibrous dysplasia (PFD) and McCune-Albright Syndrome (MAS). STUDY DESIGN: Retrospective review. METHODS: A prospectively followed cohort of subjects with PFD/MAS underwent a comprehensive evaluation that included otolaryngologic and endocrine evaluation, and imaging studies. Head and facial computed tomography scans were analyzed, and the degree of fibrous dysplasia (FD) was graded using a modified Lund-MacKay scale. Those followed for >4 years were analyzed for progression. RESULTS: A total of 106 patients meeting inclusion criteria were identified with craniofacial FD. A majority (92%) demonstrated sinonasal involvement. There were significant positive correlations between the sinonasal FD scale score and chronic congestion, hyposmia, growth hormone excess, and hyperthyroidism (P < .05 for all). Significant correlations were not found for headache/facial pain or recurrent/chronic sinusitis. Thirty-one subjects met the criteria for longitudinal analysis (follow-up mean, 6.3 years; range, 4.4-9 years). Those who demonstrated disease progression were significantly younger than those who did not (mean age, 11 vs. 25 years). Progression after age of 13 years was uncommon (n = 3) and minimal. Concomitant endocrinopathy or bisphosphonate use did not have any significant effect on progression of disease. CONCLUSIONS: Sinonasal involvement of fibrous dysplasia in PFD/MAS is common. Symptoms are usually few and mild, and disease progression occurs primarily in young subjects. Concomitant endocrinopathy is associated with disease severity, but not progression. PMID- 23444265 TI - Predictors of neonatal morbidity in fetuses with severe isolated congenital diaphragmatic hernia undergoing fetoscopic tracheal occlusion. AB - OBJECTIVES: To investigate neonatal morbidity in fetuses with severe congenital diaphragmatic hernia (CDH) treated with fetoscopic endoluminal tracheal occlusion (FETO) and compare it with historical controls with less severe forms of CDH that were managed expectantly. METHODS: This was a prospective, multicenter study on neonatal outcomes and prenatal predictors in 90 FETO survivors (78 left-sided, 12 right) and 41 controls from the antenatal CDH registry with either severe or moderate hypoplasia who were managed expectantly. We also investigated early neonatal morbidity indicators, including the need for patch repair, duration of mechanical ventilation and supplemental oxygen, age at full enteral feeding and incidence of pulmonary hypertension. RESULTS: Gestational age at delivery was predictive of duration of assisted ventilation (P = 0.046), days on supplemental oxygen (P = 0.019) and age at full enteral feeding (P = 0.020). When delivery took place after 34 weeks' gestation, neonatal morbidity of FETO cases was comparable with that of expectantly managed cases with moderate hypoplasia. CONCLUSIONS: Fetal intervention for severe CDH is associated with neonatal morbidity that is comparable with that of an expectantly managed group with less severe disease. PMID- 23444266 TI - Drive on. PMID- 23444267 TI - Adolescent and young adult understanding of the differences between chlamydia, HIV, and AIDS. AB - OBJECTIVE: To explore young people's understanding of the differences between Chlamydia, HIV, and AIDS. METHODS. Participants from a hospital-based adolescent clinic completed a self-administered written survey. Three questions assessed participants' understanding of the differences between Chlamydia, HIV, and AIDS. RESULTS: Nearly half of the 119 participants selected "No" or "Don't know" when asked if there are differences between Chlamydia and HIV and between HIV and AIDS. Increasing age was associated with correct response. CONCLUSIONS: A large proportion of youth in this sample did not know that there are differences between Chlamydia, HIV, and AIDS. Previous research suggests that some young people are afraid to be screened for Chlamydia because they fear that a Chlamydia diagnosis has the same ramifications as an AIDS diagnosis. Findings from this study indicate that more education about the differences between Chlamydia, HIV, and AIDS is needed. PMID- 23444268 TI - Pulmonary tuberculosis outbreak in a pediatric population. AB - Community-based outbreaks of Mycobacterium tuberculosis are uncommon in the United States but represent a dramatic type of epidemic that can lead to considerable investigations. Most of our knowledge regarding spread of tuberculosis (TB) has accumulated from the study of outbreaks. We describe the most recent outbreak of TB in Genesee County, Michigan. In February 2007, isoniazid-sensitive infectious pulmonary TB was identified in a 45-year-old African American grandmother who frequently provided care for her grandchildren and other children. The source case was reported to the Genesee County Health Department, which started an investigation to identify family and social contacts. We reviewed past medical records of contacts and prioritized them for evaluation based on the period of exposure to the index case. Health department staff screened contacts using clinical evaluation, tuberculin skin test, and chest radiography when indicated. Results were reviewed, and data were analyzed using descriptive inferential and epidemiological statistics. PMID- 23444269 TI - Menetrier disease in childhood: a reparative phenomenon. PMID- 23444270 TI - Neural variability, or lack thereof. AB - We do not claim that the brain is completely deterministic, and we agree that noise may be beneficial in some cases. But we suggest that neuronal variability may be often overestimated, due to uncontrolled internal variables, and/or the use of inappropriate reference times. These ideas are not new, but should be re examined in the light of recent experimental findings: trial-to-trial variability is often correlated across neurons, across trials, greater for higher-order neurons, and reduced by attention, suggesting that "intrinsic" sources of noise can only account for a minimal part of it. While it is obviously difficult to control for all internal variables, the problem of reference time can be largely avoided by recording multiple neurons at the same time, and looking at statistical structures in relative latencies. These relative latencies have another major advantage: they are insensitive to the variability that is shared across neurons, which is often a significant part of the total variability. Thus, we suggest that signal-to-noise ratios in the brain may be much higher than usually thought, leading to reactive systems, economic in terms of number of neurons, and energy efficient. PMID- 23444272 TI - A comparison of Boc and Fmoc SPPS strategies for the preparation of C-terminal peptide alpha-thiolesters: NY-ESO-1 39Cys-68Ala-COSR. AB - The synthesis of a polypeptide derived from the cancer testis antigen NY-ESO-1 bearing a C-terminal alpha-thiolester is described. Employing tert butyloxycarbonyl solid phase peptide synthesis the thiolester moiety was installed on-resin using a mercaptopropionic acid linker, thereby requiring no post synthetic manipulations and delivering the requisite alpha-thiolester polypeptide after cleavage from the resin with HF. Several 9 fluorenylmethyloxycarbonyl solid phase peptide synthesis approaches whereby the thiolester was required to be introduced in a post synthesis manner were examined concurrently. These comprised syntheses on two different "safety catch" linkers, an N-alkyl-N-acyl sulphonamide and an N-acyl benzimidazolone wherein the thiolester is generated from an activated precursor. The condensation of a mercaptan with the C-terminal carboxylate in a direct thiolesterification reaction was also examined. When using either of the three 9 fluorenylmethyloxycarbonyl-based approaches, the linear polypeptide could be assembled straightforwardly on the solid phase resin; however, a thiolesterification of the C-terminal carboxyl of the fully side chain protected peptide proved to be the most effective post-assembly method for the installation of the C-terminal thiolester. PMID- 23444271 TI - Cost effectiveness of antiarrhythmic medications in patients suffering from atrial fibrillation. AB - Atrial fibrillation (AF), a supraventricular tachycardia disorder, is the most common sustained cardiac arrhythmia affecting 1-2 % of the general population. Prevalence is highly related to age, with every fourth individual older than 40 years old developing AF during his lifetime. Due to an aging population, the prevalence of AF is estimated to at least double within the next 50 years. This article presents AF-related cost-of-illness studies and reviews 19 cost effectiveness studies and six cost studies published roughly over the past decade, which have compared different antiarrhythmic medications for AF. A systematic literature search for studies published between June 2000 and December 2011 was conducted in PubMed using the combination of keywords ((atrial fibrillation OR atrial flutter) AND cost). Current cost-effectiveness analyses of dronedarone and the pill-in-the-pocket strategy are subject to substantial uncertainties with regard to clinical benefit. Comparing rate control with rhythm control, a cost-effectiveness advantage for rate control was shown in several but not all studies. Within antiarrhythmic drug treatments, magnesium added onto ibutilide was shown to be more cost effective than ibutilide alone. Comparing chemical and electrical cardioversion, the latter was recommended as more cost effective from the healthcare system perspective in all reviewed studies but one. Catheter ablation appeared more cost effective than antiarrhythmic drugs in the medium to long run after 3.2-63.9 years. Admissions to hospital, inpatient care and interventional procedures as well as mortality benefit are key drivers for the cost effectiveness of AF medications. No clear cost-effectiveness advantage emerged for one specific antiarrhythmic drug from the studies that compared antiarrhythmic agents. Rate control as well as catheter ablation appear more cost effective than rhythm control in the treatment of AF. Rate control treatment also seems more cost effective than electrical cardioversion in AF patients. PMID- 23444274 TI - The neonicotinoid imidacloprid shows high chronic toxicity to mayfly nymphs. AB - The present study evaluated the acute and chronic toxicity of imidacloprid to a range of freshwater arthropods. Mayfly and caddisfly species were most sensitive to short-term imidacloprid exposures (10 tests), whereas the mayflies showed by far the most sensitive response to long-term exposure of all seven arthropod species tested (28-d EC10 values of approximately 0.03 ug/L). The results indicated a high aquatic risk of chronic exposure of imidacloprid to mayflies. PMID- 23444275 TI - Applications of transoral, transcervical, transnasal, and transpalatal corridors for robotic surgery of the skull base. PMID- 23444276 TI - Omission of breakfast and risk of gastric cancer in Mexico. AB - AIM: To investigate factors associated with gastric cancer (GC) in the Mexican population using a validated questionnaire. METHODS: We designed and validated in Spanish a Questionnaire to Find Factors Associated with Diseases of the Digestive Tract using GC as a model. A cross-sectional study using 49 subjects, with confirmed histopathological GC diagnosis, and 162 individuals without GC participated. Odds ratio and 95% CIs were estimated in univariate and multivariate analysis adjusted for possible confounding factors. In order to match age groups, a multivariate sub-analysis was performed in subjects >= 39 years of age and in females and males separately. RESULTS: In the univariate analysis, we found an association between GC and education to primary level or below, low socioeconomic status, the use of dental prostheses, omission of breakfast, consumption of very hot food and drink, addition of salt to prepared foods, consumption of salt-preserved foods and the pattern of alcohol consumption. We found protection against GC associated with the use of mouthwash, food refrigeration and regular consumption of fruit and vegetables. In the multivariate sub-analysis with subjects of >= 39 years, the omission of breakfast was identified as a risk factor for GC. CONCLUSION: Our study suggests an association between the omission of breakfast and the failure to refrigerate food with GC in the Mexican population. PMID- 23444278 TI - Investigating proline puckering states in diproline segments in proteins. AB - In the current study, the puckering states of the Proline ring occurring in diproline segments ((L) Pro-(L) Pro) in proteins has been investigated with a segregation made on the basis of cis and trans states for the Pro-Pro peptide bond and the conformational states for the diproline segment to investigate the effects of conformation of the diproline segment on the corresponding puckering state of the Proline ring in the segment if any. The value of the endocyclic ring torsional angles of the pyrrolidine ring has been used for calculating and visualizing various puckering states using a proposed new sign convention (+/-) nomenclature. The results have been compared to that obtained in a previous study on peptides from this group. In this study, quite interestingly, the Planar (G) conformation that was present in 14.3% of the cases in peptides, appears to be nearly a rare conformation in the case of proteins (1.9%). The present study indicates that the (C(gamma)-exo/C(gamma)-exo), (C(gamma)-exo/Twisted C(gamma) exo-C(beta)-endo) and (Twisted C(gamma)-endo-C(beta)-exo/Twisted C(gamma)-endo C(beta)-exo) categories are the most preferred combinations. For Proline rings in proteins, the states C(gamma)-exo, Twisted C(gamma)-exo-C(beta)-endo and Twisted C(gamma)-endo-C(beta)-exo are the most preferred states. Within diproline segments, the pyrrolidine ring conformations do not show a strong co-relation to the backbone conformation in which they are observed. It is likely that five membered rings have a considerable plasticity of structure and are readily deformed to accommodate a variety of energetically preferred backbone conformations. PMID- 23444277 TI - Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the "Missing Heritability" Problem. AB - CYP3A4 is the most important drug metabolizing enzyme in adult humans because of its prominent expression in liver and gut and because of its broad substrate specificity, which includes drugs from most therapeutic categories and many endogenous substances. Expression and function of CYP3A4 vary extensively both intra- and interindividually thus contributing to unpredictable drug response and toxicity. A multitude of environmental, genetic, and physiological factors are known to influence CYP3A4 expression and activity. Among the best predictable sources of variation are drug-drug interactions, which are either caused by pregnane X-receptor (PXR), constitutive androstane receptor (CAR) mediated gene induction, or by inhibition through coadministered drugs or other chemicals, including also plant and food ingredients. Among physiological and pathophysiological factors are hormonal status, age, and gender, the latter of which was shown to result in higher levels in females compared to males, as well as inflammatory processes that downregulate CYP3A4 transcription. Despite the influence of these non-genetic factors, the genetic influence on CYP3A4 activity was estimated in previous twin studies and using information on repeated drug administration to account for 66% up to 88% of the interindividual variation. Although many single nucleotide polymorphisms (SNPs) within the CYP3A locus have been identified, genetic association studies have so far failed to explain a major part of the phenotypic variability. The term "missing heritability" has been used to denominate the gap between expected and known genetic contribution, e.g., for complex diseases, and is also used here in analogy. In this review we summarize CYP3A4 pharmacogenetics/genomics from the early inheritance estimations up to the most recent genetic and clinical studies, including new findings about SNPs in CYP3A4 (*22) and other genes (P450 oxidoreductase (POR), peroxisome proliferator-activated receptor alpha (PPARA)) with possible contribution to CYP3A4 variable expression. PMID- 23444279 TI - Can mental health and readjustment be improved in UK military personnel by a brief period of structured postdeployment rest (third location decompression)? AB - OBJECTIVE: Third Location Decompression (TLD) is an activity undertaken by UK Armed Forces (UK AF) personnel at the end of an operational deployment which aims to smooth the transition between operations and returning home. We assessed whether TLD impacted upon both mental health and postdeployment readjustment. METHOD: Data collected during a large cohort study was examined to identify personnel who either engaged in TLD or returned home directly following deployment. Propensity scores were generated and used to calculate inverse probability of treatment weights in adjusted regression analyses to compare mental health outcomes and postdeployment readjustment problems. RESULTS: TLD had a positive impact upon mental health outcomes (post-traumatic stress disorder (PTSD) and multiple physical symptoms) and levels of harmful alcohol use. However, when the samples were stratified by combat exposure, although postdeployment readjustment was similar for all exposure levels, personnel experiencing low and moderate levels of combat exposure experienced the greatest positive mental health effects. CONCLUSIONS: We found no evidence to suggest that TLD promotes better postdeployment readjustment; however, we found a positive impact upon alcohol use and mental health with an interaction with degree of combat exposure. This study suggests that TLD is a useful postdeployment transitional activity that may help to improve PTSD symptoms and alcohol use in UK AF personnel. PMID- 23444280 TI - Carbon nanotubes: an insight into the mechanisms of their potential genotoxicity. AB - After the health catastrophe resulting from the widespread use of asbestos which was once hailed as a new miracle material, the increasing use of carbon nanotubes (CNTs) has spawned major concern due to their similarities in terms of size, shape and poor solubility. Assessment of genotoxicity has shown that CNTs can damage DNA in vitro and in vivo. The genotoxic potential of different CNT samples varies considerably, however, with negative findings reported in a number of studies, probably due to the enormous heterogeneity of CNTs. The observed spectrum of genotoxic effects shows similarities with those reported for asbestos fibres. Mutagenicity has been found in vivo but in bacterial assays both asbestos and CNTs have mostly tested negative. An overview of key experimental observations on CNT-induced genotoxicity is presented in the first half of this review. In the second part, the potential mechanisms of CNT-elicited genotoxicity are discussed. Whereas CNTs possess intrinsic ROS-scavenging properties they are capable of generating intracellular ROS upon interaction with cellular components, and can cause antioxidant depletion. These effects have been attributed to their Fenton-reactive metals content. In addition, CNTs can impair the functionality of the mitotic apparatus. A noteworthy feature is that frustrated phagocytosis, which is involved in asbestos-induced pathology, has been observed for specific CNTs as well. The involvement of other mechanisms generally implicated in particle toxicity, such as phagocyte activation and impairment of DNA repair, is largely unknown at present and needs further investigation. PMID- 23444281 TI - Evaluation of the impact of UGT polymorphism on the pharmacokinetics and pharmacodynamics of the novel PPAR agonist sipoglitazar. AB - Sipoglitazar is a peroxisome proliferator-activated receptor alpha, delta, and gamma agonist. During phase I, a wide distribution of clearance between individuals was observed. Hypothesized to result from a polymorphism in the uridine 5'-diphospate-glucuronosyltransferase (UGT)2B15 enzyme, pharmacogenetic samples were collected from each individual for genotyping UGT2B15 in a subsequent phase I trial in healthy subjects (n = 524) and in 2 phase II trials in type 2 diabetes subjects (n = 627), total genotype frequency was as follows: *1/*1 (22%), *1/*2 (51%), and *2/*2 (27%). The impact of genotype on exposure was assessed using a pharmacokinetic modeling approach; the influence of genotype on efficacy was evaluated using 12-week HbA1c change from baseline. Model analysis demonstrated UGT2B15 genotype accounted significantly for the variability in sipoglitazar clearance; however, a small fraction of subjects had a clearance that could not be explained entirely by genotype. HbA1c drop increased with daily drug dose. When stratified by both dose and genotype, HbA1c drop was larger in the UGT2B15*2/*2 compared with UGT2B15*1/*1 and UGT2B15*1/*2 genotypes (P < .05). In summary, UGT2B15 genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the UGT2B15*2/*2 genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype. PMID- 23444282 TI - Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. AB - Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing <=12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. PMID- 23444283 TI - Race and drug formulation influence on mycophenolic acid pharmacokinetics in stable renal transplant recipients. AB - BACKGROUND: Limited mycophenolic acid (MPA) data are available comparing racial influence on mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) pharmacokinetics. METHODS: Intrapatient MPA pharmacokinetics of MMF versus EC-MPS were compared in 13 male African American (AA) and 14 Caucasian (C) renal transplant recipients (RTRs). RTRs were switched to equivalent doses of the alternate formulation for at least 10 days prior to the second study. Mycophenolic acid clearance and dose-normalized area under the concentration-time curve(0-12) (AUC*) were determined. Mixed model statistics evaluated the main effects of race, drug formulation, and interaction of race and drug formulation (R * D) with albumin, cyclosporine trough, renal function, and diabetes and enterhepatic recirculation. RESULTS: Significant R * D was identified for MPA AUC* for EC-MPS (AA, 0.056 +/- 0.029 [mg.h/L]/mg; C, 0.080 +/- 0.044 [mg.h/L]/mg) compared with MMF (AA, 0.053 +/- 0.019 [mg.h/L]/mg; C, 0.060 +/- 0.025 [mg.h/L]/mg), P = .022. Significant R * D was identified with albumin in the model for MPA clearance for MMF (AA, 21.7 +/- 8.9 L/h; C, 20.5 +/- 10.8 L/h) compared with EC-MPS (AA, 22.2 +/- 10.1 L/h; C, 16.2 +/- 9.1 L/h), P = .032. CONCLUSIONS: Race influences MPA exposure between MMF and EC-MPS and may warrant therapeutic monitoring during formulation conversion. PMID- 23444284 TI - Population pharmacokinetic analysis of a nevirapine-based HIV-1 prevention of mother-to-child transmission program in Uganda to assess the impact of different dosing regimens for newborns. AB - Single-dose nevirapine for mothers and newborns at delivery is the simplest prevention strategy for vertical HIV-1 transmission and hence widely used in resource-constrained settings. HIV-1-positive mothers and newborns received single-dose nevirapine in a prevention of mother-to-child HIV-1 transmission (PMTCT) program in Uganda. In a pharmacokinetic investigation, breast milk and plasma samples of mothers and newborns were collected. The nonlinear mixed effects modeling approach was suitable for analysis (average: 1.8 samples/matrix/individual). For describing the nevirapine pharmacokinetics in mothers and newborns, a 1-compartment model was demonstrated to be sufficient. The plasma-placenta transfer could be quantified, revealing a transfer fraction of 11% to 25% (with a significant influence of time span between maternal nevirapine intake and birth) and a high transfer rate constant from maternal drug administration. Interindividual variability was moderate between mothers and high between newborns. Simulations revealed that newborns born early (<1 hour) after maternal nevirapine intake would benefit from a 3-fold higher nevirapine dosage (6 mg/kg) after birth for analogous protective plasma concentrations over the first 2 weeks. In contrast, postnatal nevirapine dosage seemed to be dispensable for newborns born late (>24 hours) after maternal nevirapine intake. These dosing recommendations should be evaluated in prospective studies, including additional antiretroviral drugs in accordance with current PMTCT guidelines. PMID- 23444285 TI - Pharmacokinetics of modified-release prednisone tablets in healthy subjects and patients with rheumatoid arthritis. AB - In rheumatoid arthritis (RA), nocturnal release of proinflammatory cytokines is not adequately counteracted by endogenous glucocorticoid and is associated with symptoms of morning stiffness and pain. Taking exogenous glucocorticoid during the night reduces morning stiffness significantly more than treatment at the conventional time in the morning, although waking to take tablets is unacceptable for patients. Modified-release prednisone tablets were developed to allow administration at bedtime for programmed delivery of glucocorticoid during the night. Single-center crossover studies were conducted, each in <=24 healthy subjects, to compare the pharmacokinetics of a single 5-mg oral dose of modified release prednisone and conventional prednisone, as well as the effect of food on bioavailability. There was no substantial difference in pharmacokinetic parameters of the formulations apart from the programmed delay in release of glucocorticoid from the modified-release tablets (C(max) 97%, AUC(0-infinity) 101%, 90% confidence intervals within the requisite range for bioequivalence). Administration after a full or light meal did not affect pharmacokinetic characteristics, but bioavailability was reduced under fasted conditions. Pharmacokinetic evaluation in 9 patients with RA confirmed that modified-release prednisone tablets taken at bedtime (around 22:00 h) with or after an evening meal result in programmed release of glucocorticoid 4 to 6 hours after intake. PMID- 23444286 TI - Comparing the pharmacokinetics of doxylamine/pyridoxine delayed-release combination in nonpregnant women of reproductive age and women in the first trimester of pregnancy. AB - Although Diclectin (doxylamine/pyridoxine delayed-released combination) is widely used in Canada, its pharmacokinetics (PK) during pregnancy has never been described. The objective of this study was to compare the PK of doxylamine/pyridoxine delayed-released combination in pregnant versus nonpregnant women. The apparent clearances (CL) of doxylamine and pyridoxal 5'-phosphate (PLP; the active metabolite of vitamin B(6) ) during the first-trimester pregnancy in women who participated in a Diclectin randomized trial were compared with those of healthy, adult, nonpregnant women who participated in a voluntary PK trial. Eighteen nonpregnant women were compared with 50 pregnant women who were treated with Diclectin. There was no difference in the apparent CL of doxylamine in women in their first trimester of pregnancy when compared with nonpregnant women on day 4 (median = 196.7 vs 249.5 mL/h/kg, respectively, P = .065), day 8 (median = 248.4 vs 249.5 mL/h/kg, respectively, P = .82), and day 15 (median = 200.9 vs 249.5 mL/h/kg, respectively, P = .55). No difference was found in the apparent CL of PLP on day 15 (median = 342.3 vs 314.7 mL/h/kg, respectively, P = .92). There was no pregnancy-induced effect in the apparent CL of either doxylamine or PLP in women during the first trimester of pregnancy despite the existence of morning sickness. PMID- 23444287 TI - Optimal duration of dual-antiplatelet therapy following drug-eluting stent implantation: a meta-analysis. AB - Optimal duration of dual-antiplatelet therapy (DAPT) following drug-eluting stent (DES) implantation remains uncertain. The aim of this study was to perform a meta analysis of trials evaluating the effect of DAPT duration on long-term clinical outcomes after DES implantation. The authors searched OvidMEDLINE, EMBASE, and the Cochrane Library for both randomized controlled trials and nonrandomized studies that evaluated DAPT duration on long-term clinical outcomes after DES implantation. The end point was the cumulative incidence of the composite of all cause death and nonfatal myocardial infarction (MI) at maximum follow-up. Quantitative analysis was performed to estimate the pooled hazard ratios (HRs) for the effect of DAPT duration. The pooled effect of DAPT discontinuation before 6 months significantly increased risk of death and nonfatal MI (HR, 1.46; 95% confidence interval, 1.18-1.80), but DAPT beyond 12 months did not reduce the incidence of the composite end point compared with drug discontinuation at 12 months (HR, 0.91; 95% confidence interval, 0.75-1.10). In conclusion, the current evidence suggests that 6 to 12 months of DAPT may be optimal after DES implantation. PMID- 23444288 TI - Hypersensitivity to polyethylene glycols. PMID- 23444289 TI - Are pelvic floor muscle thickness and size of levator hiatus associated with pelvic floor muscle strength, endurance and vaginal resting pressure in women with pelvic organ prolapse stages I-III? A cross sectional 3D ultrasound study. AB - AIMS: To investigate if pelvic floor muscle (PFM) thickness and area of levator hiatus (LH) are associated with manometry measured PFM function in 109 women with pelvic organ prolapse (POP) stages I-III. METHODS: In this cross-sectional study pubovisceral muscle thickness and LH area were assessed with three-dimensional transperineal ultrasound at rest and analyzed in the axial plane. PFM function was assessed with manometry and included strength, endurance, and vaginal resting pressure. Relationships were investigated using univariate linear logistic regressions models, Pearson product-moment correlation coefficient and hierarchical multiple regression. RESULTS: The mean age was 49 (SD 12). There was a significant positive moderate association between muscle thickness and PFM strength (r = 0.49, P < 0.001) and endurance (r = .45, P < 0.001). A moderate negative association was found between LH area and vaginal resting pressure (r = 0.46, P < 0.001), strength (r = -0.41, P < 0.001) and endurance (r = -0.40, P < 0.001). Multivariate analyses included PFM strength, endurance, vaginal resting pressure, age, parity, BMI and socioeconomic status. Muscle thickness was best explained by PFM strength and LH area was best explained by vaginal resting pressure. However, PFM function explained only 20.0% and 26.4% of the variance in muscle thickness and LH area after controlling for age, parity, BMI, and socioeconomic status. CONCLUSION: There are moderate associations between measurements using ultrasound and manometry in POP women. Thicker muscles and smaller LH were associated with higher strength and endurance. Smaller LH was additionally associated with higher vaginal resting pressure. Ultrasound and manometry measure different aspects of the PFM and cannot be used interchangeably. PMID- 23444290 TI - Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis. AB - HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy. PMID- 23444291 TI - Therapeutic links between Alzheimer's disease and brain cancer: drug discovery consequences. AB - It was recently reported that female survivors of breast cancer have a lower risk of Alzheimer's disease (AD). This observation led to the hypothesis that there is a link between cancer and AD. This Viewpoint provides an analysis of the consequences of this hypothesis, not only from the perspective of drug discovery for new treatments, but above all, the awareness that any AD chemotherapy will require drug administration over longer periods of time before any cognitive effects are observed. Because such drugs will probably act as neuroprotective agents, slowing the progression of AD rather than curing it, they should be prescribed as soon as the first AD symptoms are detected. After a general survey of anticancer drugs that have potential therapeutic value for AD chemotherapy, new drugs that could affect specific signal transduction pathways known to be activated by anticancer drugs are presented, with the unfolding protein response pathway being one of the most relevant biological targets for new AD chemotherapeutic agents. PMID- 23444292 TI - Does farm environment protect against type 1 diabetes mellitus? AB - AIMS/HYPOTHESIS: Hygiene hypothesis has been shown valid in respect of allergies and asthma but has not been, however, sufficiently studied in relation to type 1 diabetes mellitus. This study investigates the effect of childhood farm environment on the prevalence of type 1 diabetes mellitus in Finnish children and young adults. METHODS: Data come from a questionnaire study carried out in 2007 (N = 5805). Prevalence of type 1 diabetes mellitus was analysed according to the type of the rural exposure below the age of 18 years. Associations were estimated and tested using Bayesian methods. RESULTS: Consistent suggestive evidence of the inverse association of childhood's farm environment with the occurrence of type 1 diabetes mellitus was shown, even though conclusive results were not reached. CONCLUSION/INTERPRETATION: Exposure to a broad variety of non-pathogenic environmental microorganisms during childhood might have a protective effect on type 1 diabetes mellitus. Results clearly suggest that further research is well grounded with larger samples. PMID- 23444293 TI - A toolbox for generating single-stranded DNA in optical tweezers experiments. AB - Essential genomic transactions such as DNA-damage repair and DNA replication take place on single-stranded DNA (ssDNA) or require specific single-stranded/double stranded DNA (ssDNA/dsDNA) junctions (SDSJ). A significant challenge in single molecule studies of DNA-protein interactions using optical trapping is the design and generation of appropriate DNA templates. In contrast to dsDNA, only a limited toolbox is available for the generation of ssDNA constructs for optical tweezers experiments. Here, we present several kinds of DNA templates suitable for single molecule experiments requiring segments of ssDNA of several kilobases in length. These different biotinylated dsDNA templates can be tethered between optically trapped microspheres and can, by the subsequent use of force-induced DNA melting, be converted into partial or complete ssDNA molecules. We systematically investigated the time scale and efficiency of force-induced melting at different ionic strengths for DNA molecules of different sequences and lengths. Furthermore, we quantified the impact of microspheres of different sizes on the lifetime of ssDNA tethers in optical tweezers experiments. Together, these experiments provide deeper insights into the variables that impact the production of ssDNA for single molecules studies and represent a starting point for further optimization of DNA templates that permit the investigation of protein binding and kinetics on ssDNA. PMID- 23444294 TI - First successful pregnancy in Switzerland after prospective sex determination of the embryo through the separation of X-chromosome bearing spermatozoa. AB - QUESTION UNDER STUDY: The feasibility and the potential advantages of separating X-chromosome bearing spermatozoa for the prevention of a severe X-chromosome linked disorder with the use of intracytoplasmic sperm injection are presented. METHOD: A carrier of muscular dystrophy type Becker was treated with intracytoplasmic sperm injection, using spermatozoa previously stained with the Hoechst dye 33342 and sorted with flow cytometry. RESULTS: After transfer of one single blastocyst, an intrauterine pregnancy arose. In the ninth week of gestation, the female sex of the embryo was confirmed with proof of absence of the SRY gene of the Y-chromosome. After normal pregnancy, the patient delivered a healthy daughter. CONCLUSIONS: The staining of spermatozoa with specific markers and sorting with flow cytometry provides a means of preventing significant disease in the offspring and may help in reducing the number of surplus embryos needed for preimplantation genetic diagnosis. PMID- 23444297 TI - Resolution of defective dorsal aortae patterning in Sema3E-deficient mice occurs via angiogenic remodeling. AB - BACKGROUND: Neuronal guidance cues influence endothelial cell (EC) behavior to shape the embryonic vascular system. The repulsive neuronal guidance cue, Semaphorin 3E (Sema3E), is critical for creating avascular zones that instruct and subsequently pattern the first embryonic vessels, the paired dorsal aortae (DA). Sema3E(-) (/) (-) embryos develop highly branched plexus-like vessels during vasculogenesis, instead of smooth paired vessels. Unexpectedly, despite these severe DA patterning defects, mutant mice are viable throughout adulthood. RESULTS: Examination of Sema3E(-) (/) (-) mice reveals that the plexus-like DA resolve into single, unbranched vessels between embryonic day (E) E8.25 and E8.75. Although fusion of Sema3E(-) (/) (-) DA occurs slightly earlier than in heterozygotes, the DA are otherwise indistinguishable, suggesting a complete "rescue" in their development. Resolution of the DA null plexuses occurs by remodeling rather than by means of changes in cell proliferation or death. CONCLUSIONS: Normalization of Sema3E(-) (/) (-) DA patterning defects demonstrates resilience of embryonic vascular patterning programs. Additional repulsive guidance cues within the lateral plate mesoderm likely re-establish avascular zones lost in Sema3E(-) (/) (-) embryos and guide resolution of mutant plexus into branchless, parallel aortae. Our observations explain how Sema3E(-) (/) (-) mice survive throughout development and into adulthood, despite severe initial vascular defects. PMID- 23444298 TI - Measuring and interpreting the predictive validity of violence risk assessments: an overview of the special issue. AB - Mental health professionals are routinely called upon to assess and testify concerning the violence risk of their patients. Expert opinion on risk assessment continues to influence decisions resulting in the long-term denial of civil liberty or even death in the case of capital proceedings. Today, many clinicians use structured risk assessment tools to assist in these tasks. Although few would claim that violence can be predicted without error, all but the most skeptical would concede that our knowledge and ability to assess violence risk far exceeds that of three decades ago. This said, whether current practices are empirically, ethically, or legally valid remains a question of great importance given the consequences that may follow erroneous assessments. And while 30 years ago there was a broad (albeit often overstated) consensus that expert opinion on this topic was inherently suspect, today the field appears to operate on a broad (albeit often overstated) consensus that practices have improved to a sufficient extent to warrant the sizeable impact that violence risk assessments often have on individual liberty, levels of service, and resource allocation. PMID- 23444299 TI - Measurement of predictive validity in violence risk assessment studies: a second order systematic review. AB - The objective of the present review was to examine how predictive validity is analyzed and reported in studies of instruments used to assess violence risk. We reviewed 47 predictive validity studies published between 1990 and 2011 of 25 instruments that were included in two recent systematic reviews. Although all studies reported receiver operating characteristic curve analyses and the area under the curve (AUC) performance indicator, this methodology was defined inconsistently and findings often were misinterpreted. In addition, there was between-study variation in benchmarks used to determine whether AUCs were small, moderate, or large in magnitude. Though virtually all of the included instruments were designed to produce categorical estimates of risk - through the use of either actuarial risk bins or structured professional judgments - only a minority of studies calculated performance indicators for these categorical estimates. In addition to AUCs, other performance indicators, such as correlation coefficients, were reported in 60% of studies, but were infrequently defined or interpreted. An investigation of sources of heterogeneity did not reveal significant variation in reporting practices as a function of risk assessment approach (actuarial vs. structured professional judgment), study authorship, geographic location, type of journal (general vs. specialized audience), sample size, or year of publication. Findings suggest a need for standardization of predictive validity reporting to improve comparison across studies and instruments. PMID- 23444300 TI - Light energy collection in a porphyrin-imide-corrole ensemble. AB - An assembly consisting of three units, that is, a meso-substituted corrole (C3), 1,8 naphthaleneimide (NIE), and a Zn porphyrin (ZnP), has been synthesized. NIE is connected to C3 through a 1,3-phenylene bridge and to the ZnP unit through a direct C-C bond. The convergent synthetic strategy includes the preparation of a trans-A2B-corrole possessing the imide unit, followed by Sonogashira coupling with a meso-substituted A3B-porphyrin. The photophysical processes in the resulting triad ZnP-NIE-C3 are examined and compared with those of the corresponding C3-NIE dyad and the constituent reference models C3, NIE, and ZnP. Excitation of the NIE unit in C3-NIE leads to a fast energy transfer of 98 % efficiency to C3 with a rate k(en) =7.5*10(10) s(-1), whereas excitation of the corrole unit leads to a reactivity of the excited state identical to that of the model C3, with a deactivation rate to the ground state k=2.5*10(8) s(-1). Energy transfer to C3 and to ZnP moieties follows excitation of NIE in the triad ZnP-NIE C3. The rates are k(en) =7.5*10(10) s(-1) and k(en) =2.5*10(10) s(-1) for the sensitization of the C3 and ZnP unit, respectively. The light energy transferred from NIE to Zn porphyrin unit is ultimately funneled to the corrole component, which is the final recipient of the excitation energy absorbed by the different components of the array. The latter process occurs with a rate k(en) =3.4*10(9) s(-1) and 89 % efficiency. Energy transfer processes take place in all cases by a Forster (dipole-dipole) mechanism. The theory predicts quite satisfactorily the rate for the ZnP/C3 couple, where components are separated by about 23 A, but results in calculated rates that are one to two orders of magnitude higher for the couples NIE/ZnP (D/A) and NIE/C3, which are separated by distances of about 14 and 10 A, respectively. PMID- 23444301 TI - Systematic exploration of thioredoxin target proteins in plant mitochondria. AB - The thioredoxin (Trx) system is known to play a pivotal role in cellular redox regulation, but its target proteins in plant mitochondria remain largely uncharacterized. In this study, we systemically screened Trx target candidates in plant mitochondria. Mitochondrial protein extracts were prepared from Arabidopsis shoots, spinach leaves and potato tubers, and then subfractionated into soluble matrix and insoluble membrane fractions. Protein extracts were loaded onto an affinity column immobilizing Arabidopsis mitochondria-localized o-type Trx mutant protein, in which one of two internal cysteines at the active site was substituted by serine. Proteins forming mixed-disulfide intermediates with the mutated Trx were identified by proteomic approaches. This procedure allowed the determination of 101 Trx target candidate proteins involved in a broad spectrum of mitochondrial processes. Furthermore, biochemical assay revealed that one of the potential Trx target proteins, alternative oxidase, is actually redox regulated by Trx. This study provides insights into the regulatory mechanism of diverse functions in mitochondrial biology that are mediated through the Trx system. PMID- 23444302 TI - Environmental pH affects photoautotrophic growth of Synechocystis sp. PCC 6803 strains carrying mutations in the lumenal proteins of PSII. AB - Synechocystis sp. strain PCC 6803 grows photoautotrophically across a broad pH range, but wild-type cultures reach a higher density at elevated pH; however, photoheterotrophic growth is similar at high and neutral pH. A number of PSII mutants each lacking at least one lumenal extrinsic protein, and carrying a second PSII lumenal mutation, are able to grow photoautotrophically in BG-11 medium at pH 10.0, but not pH 7.5. We investigated the basis of this pH effect and observed no pH-specific change in variable fluorescence yield from PSII centers of the wild type or the pH-dependent DeltaPsbO:DeltaPsbU and DeltaPsbV:DeltaCyanoQ strains; however, 77 K fluorescence emission spectra indicated increased coupling of the phycobilisome (PBS) antenna at pH 10.0 in all mutants. DNA microarray data showed a cell-wide response to transfer from pH 10.0 to pH 7.5, including decreased mRNA levels of a number of oxidative stress responsive transcripts. We hypothesize that this transcriptional response led to increased tolerance against reactive oxygen species and in particular singlet oxygen. This response enabled photoautotrophic growth of the PSII mutants at pH 10.0. This hypothesis was supported by increased resistance of all strains to rose bengal at pH 10.0 compared with pH 7.5. PMID- 23444304 TI - Should statins be paused or discontinued after thrombolysis or acute intracerebral hemorrhage? No! PMID- 23444303 TI - Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts. AB - BACKGROUND AND PURPOSE: Atrial fibrillation (AF) has been associated with cognitive decline independent of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population. METHODS: This is a cross-sectional analysis of 4251 nondemented participants (mean age, 76 +/- 5 years) in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study. Medical record data were collected for the presence, subtype, and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with magnetic resonance imaging. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic factors, cardiovascular risk factors, and cerebral infarcts. RESULTS: Participants with AF had lower total brain volume compared with those without AF (P<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter hyperintensities (P<0.001 and P = 0.008, respectively), but not of white matter hyperintensities (P = 0.49). Participants with AF scored lower on tests of memory. CONCLUSIONS: AF is associated with smaller brain volume, and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts. PMID- 23444305 TI - Unassisted assessment of stroke severity using telemedicine. AB - BACKGROUND AND PURPOSE: Quantification of stroke severity through telemedicine consultation is challenging and relies on professional support at the patient's bedside. We aimed to develop a novel scale for assessing stroke severity through telemedicine without assistance from a third party (Unassisted TeleStroke Scale [UTSS]). METHODS: Stroke severity was assessed in 45 patients with suspicion of acute stroke by bedside examination using the National Institutes of Health Stroke Scale (NIHSS) and by teleconsultation using the UTSS. Scale reliability was evaluated by intrarater and interrater variability, internal consistency, and rater agreement. Concurrent and predictive validity were tested by relating the UTSS with the NIHSS and long-term outcome (modified Rankin Scale and mortality at 6 months). Clinimetric analysis of the UTSS was obtained via the Rasch model. RESULTS: The mean examination time for the UTSS was 3.1 minutes (SD, 1.1) versus 8.5 minutes for the NIHSS (SD, 2.6; P<0.001). Both UTSS and NIHSS showed excellent intrarater variability (r=0.97 and 0.98; P<0.001) and interrater variability (r=0.96 and 0.98; P<0.001), as well as excellent internal consistency and rater agreement. The UTSS correlated strongly with the NIHSS and was identified as an independent predictor of stroke outcome in logistic regression analysis. Rasch analysis indicated that the UTSS represents a unidimensional scale of stroke severity. CONCLUSIONS: The UTSS is a rapid, reliable, and valid tool for unassisted assessment of stroke severity through telemedicine. PMID- 23444306 TI - Functional role of the corticoreticular pathway in chronic stroke patients. AB - BACKGROUND AND PURPOSE: The corticoreticular pathway (CRP) is known to be an important extrapyramidal tract for walking ability. However, little is known about the functional role of the CRP in recovery of walking ability. We investigated relation between the CRP and walking ability in chronic hemiparetic stroke patients. METHODS: Among 209 consecutive patients, 54 patients, who showed complete injury of the corticospinal tract (CST) in the affected hemisphere on diffusion tensor tractography, and 20 normal subjects were recruited. Functional ambulation category was used in measurement of walking ability. The fractional anisotropy value, apparent diffusion coefficient value, and fiber volume of the CRP and CST were used for the diffusion tensor imaging parameters. RESULTS: In the affected hemisphere, no significant difference in diffusion tensor imaging parameters of the CRP was observed between patient subgroups. In the unaffected hemisphere, patients who were able to walk showed significantly increased fiber volume of the CRP, compared with patients who could not walk and normal control subjects (P<0.05), without significant difference in fractional anisotropy and apparent diffusion coefficient values. In addition, the fiber volume of the CRP in the unaffected hemisphere showed positive correlation with functional ambulation category (P<0.05). In contrast, diffusion tensor imaging parameters of the CST in the unaffected hemisphere showed no correlation with functional ambulation category (P>0.05). CONCLUSIONS: The increased fiber volume of the CRP in the unaffected hemisphere seems to be related to walking ability in patients with chronic stroke. Therefore, the compensation of the CRP in the unaffected hemisphere seems to be one of the mechanisms for recovery of walking ability after stroke. PMID- 23444307 TI - Cognitive decline after stroke: relation to inflammatory biomarkers and hippocampal volume. AB - BACKGROUND AND PURPOSE: Inflammation may contribute to cognitive impairment after stroke. Inflammatory markers are associated with hippocampal atrophy. We tested whether markers of inflammation, erythrocyte sedimentation rate (ESR), and serum levels of C-reactive protein are associated with reduced hippocampal volume and poor cognitive performance among stroke survivors. METHODS: We analyzed 368 consecutive cases from our prospective study of first-ever mild-moderate stroke patients. MRI, cognitive tests, and inflammatory markers were determined. Patients were reevaluated 6 and 12 months after the event. RESULTS: ESR remained unchanged in follow-up examinations, suggesting a chronic inflammation background in some patients. Higher levels of C-reactive protein and ESR were associated with worse performance in cognitive tests, particularly memory scores. This association was maintained for ESR (but not C-reactive protein) after adjustment for confounders (P=0.002). Patients with smaller hippocampi had inferior cognitive results. Moreover, in a multivariate regression model, higher ESR values (but not C-reactive protein) were related to reduced hippocampal volume (P=0.049). CONCLUSIONS: This report shows a strong relationship between ESR and hippocampal volume, as well as with cognitive performance among poststroke patients. This could plausibly relate to incipient cognitive decline via hippocampal pathways. PMID- 23444308 TI - Association of hypertension with stroke recurrence depends on ischemic stroke subtype. AB - BACKGROUND AND PURPOSE: The association between hypertension (HTN) and stroke recurrence is unclear, but may be influenced by different subtypes of stroke. This study aims to explore whether HTN contributes to the recurrence of certain subtypes of ischemic stroke (IS). METHODS: Data from the China National Stroke Registry was examined and 1-year follow-up data for stroke recurrence was analyzed. Trial of Org 10172 in Acute Stroke Treatment criteria was used to classify the subtypes of all IS. HTN was defined when resting blood pressure was >= 140/90 mm Hg on repeated measurements during hospitalization or a patient had been on antihypertensive medication. Recurrent stroke was defined as a new neurological deficit compatible to IS or intracerebral hemorrhage. The association between HTN and stroke recurrence in patients with different IS subtypes was analyzed by using univariable and multivariable logistic regression models. RESULTS: Of 11 560 patients with IS, 8409 (72.7%) had HTN and 2050 (17.7%) experienced a recurrent stroke within 1 year. Patients with HTN had an insignificantly higher stroke recurrence rate than those without (18.0% versus 17.0%; P=0.21). After stratification by Trial of Org 10172 in Acute Stroke Treatment subtypes, multivariable analysis revealed a significant association between HTN and stroke recurrence in small-artery occlusion subtype (odds ratio, 1.52; 95% confidence interval, 1.03-2.31), but not in the other subtypes (large artery atherosclerosis: odds ratio, 0.99; 95% confidence interval, 0.81-1.21; cardioembolic: odds ratio, 1.14; 95% confidence interval, 0.75-1.73; other: odds ratio, 0.88; 95% confidence interval, 0.71-1.09). CONCLUSIONS: Our results showed that HTN is specifically related to the recurrent strokes in patients with small vessel diseases, not other subtypes of IS. PMID- 23444309 TI - Spot sign number is the most important spot sign characteristic for predicting hematoma expansion using first-pass computed tomography angiography: analysis from the PREDICT study. AB - BACKGROUND AND PURPOSE: The spot sign score (SSS) provides risk stratification for hematoma expansion in acute intracerebral hemorrhage; however, external validation is needed. We sought to validate the SSS and assess prognostic performance of individual spot characteristics associated with hematoma expansion from a prospective multicenter intracerebral hemorrhage study. METHODS: Two hundred twenty-eight intracerebral hemorrhage patients within 6 hours after ictus were enrolled in the Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT) study, a multicenter prospective intracerebral hemorrhage cohort study. Patients were evaluated with baseline noncontrast computerized tomography, computerized tomography angiography, and 24 hour follow-up computerized tomography. Primary outcome was significant hematoma expansion (>6 mL or >33%) and secondary outcome was absolute and relative expansion. Blinded computerized tomography angiography spot sign characterization and SSS calculation were independently performed by 2 neuroradiologists and a radiology resident. Diagnostic performance of the SSS and individual spot characteristics were examined with multivariable regression, receiver operating characteristic analysis, and tests for trend. RESULTS: SSS and spot number independently predicted significant, absolute, and relative hematoma expansion (P<0.05 each) and demonstrated near perfect interobserver agreement (kappa=0.82 and kappa=0.85, respectively). Incremental risk of hematoma expansion among spot positive patients was not identified for SSS (P trend=0.720) but was demonstrated for spot number (P trend=0.050). Spot number and SSS demonstrated similar area under the curve (0.69 versus 0.68; P=0.306) for hematoma expansion. CONCLUSIONS: Multicenter external validation of the SSS demonstrates that the spot number alone provides similar prediction but improved risk stratification of hematoma expansion compared with the SSS. PMID- 23444310 TI - Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. AB - BACKGROUND AND PURPOSE: Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients. METHODS: In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes. RESULTS: One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5-2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0-5.0) compared with 7.9% (95% confidence interval, 7.2-8.7) in ischemic strokes. CONCLUSIONS: In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low. PMID- 23444311 TI - Antimicrobial activity of essential oils from Mediterranean aromatic plants against several foodborne and spoilage bacteria. AB - The antimicrobial activity of essential oils extracted from a variety of aromatic plants, often used in the Portuguese gastronomy was studied in vitro by the agar diffusion method. The essential oils of thyme, oregano, rosemary, verbena, basil, peppermint, pennyroyal and mint were tested against Gram-positive (Listeria monocytogenes, Clostridium perfringens, Bacillus cereus, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, and Staphylococcus epidermidis) and Gram-negative strains (Salmonella enterica, Escherichia coli, and Pseudomonas aeruginosa). For most essential oils examined, S. aureus, was the most susceptible bacteria, while P. aeruginosa showed, in general, least susceptibility. Among the eight essential oils evaluated, thyme, oregano and pennyroyal oils showed the greatest antimicrobial activity, followed by rosemary, peppermint and verbena, while basil and mint showed the weakest antimicrobial activity. Most of the essential oils considered in this study exhibited a significant inhibitory effect. Thyme oil showed a promising inhibitory activity even at low concentration, thus revealing its potential as a natural preservative in food products against several causal agents of foodborne diseases and food spoilage. In general, the results demonstrate that, besides flavoring the food, the use of aromatic herbs in gastronomy can also contribute to a bacteriostatic effect against pathogens. PMID- 23444312 TI - Lymph node ratio and preoperative CA 19-9 levels predict overall survival and recurrence-free survival in patients with resected pancreatic adenocarcinoma. AB - AIM: Clinicopathologic factors predicting overall survival (OS) would help identify a subset to benefit from adjuvant therapy. METHODS: One hundred and sixty-nine patients patients from 1984 to 2009 with curative resections for pancreatic adenocarcinoma were included. Tumors were staged by American Joint Committee on Cancer 7th edition criteria. Univariate and multivariable analyses were performed using Kaplan-Meier methodology or Cox proportional hazard models. Log-rank tests were performed. Statistical inferences were assessed by two-sided 5% significance level. RESULTS: Median age was 67.1 (57.2-73.0) years with equal gender distribution. Tumors were in the head (89.3%) or body/tail (10.7%). On univariate analysis, adjuvant therapy, lymph node (LN) ratio, histologic grade, negative margin status, absence of peripancreatic extension, and T stage were associated with improved OS. Adjuvant therapy, LN ratio, histologic grade, number of nodes examined, negative LN status, and absence of peripancreatic extension were associated with improved recurrence-free survival (RFS). On multivariable analysis, LN ratio and carbohydrate antigen (CA) 19-9 levels were associated with OS. LN ratio was associated with RFS. CONCLUSION: The LN ratio and CA 19-9 levels are independent prognostic factors following curative resections of pancreatic cancer. PMID- 23444314 TI - Relative risk regression models with inverse polynomials. AB - The proportional hazards model assumes that the log hazard ratio is a linear function of parameters. In the current paper, we model the log relative risk as an inverse polynomial, which is particularly suitable for modeling bounded and asymmetric functions. The parameters estimated by maximizing the partial likelihood are consistent and asymptotically normal. The advantages of the inverse polynomial model over the ordinary polynomial model and the fractional polynomial model for fitting various asymmetric log relative risk functions are shown by simulation. The utility of the method is further supported by analyzing two real data sets, addressing the specific question of the location of the minimum risk threshold. PMID- 23444315 TI - Face transplantation surgical options and open problems in cadaveric models: a review article. AB - Being first conceptualized in 2005-2006, total face transplantation is now a clinical reconstructive option in the treatment of patients with acquired facial deformity. The authors propose a review on the status of total face transplantation based on their clinical experience in dealing with traditional microsurgical head and neck reconstructions and on the basis of their published pre-clinical research investigating technical aspects of the facial allotransplantation procedure in cadaveric models. The authors first discuss the harvesting options and propose two facial flaps which address different reconstructive needs. Next, the concept of donor-recipient anatomical compatibility is introduced, and the possible outcome of the chimeric face is studied, following the insetting of a fasciocutaneous facial allograft. Finally, the authors address the major technical challenges associated with transplanting the most complex osteomyocutaneous allograft. Significant improvement has been made in the field of vascularized composite tissue allotransplantation over the last 5-6 years. The results of the 13 face transplants performed worldwide are encouraging both functionally and aesthetically, when compared with traditional reconstructive procedures. PMID- 23444313 TI - Social cognition in schizophrenia: from social stimuli processing to social engagement. AB - Social cognition consists of several skills which allow us to interact with other humans. These skills include social stimuli processing, drawing inferences about others' mental states, and engaging in social interactions. In recent years, there has been growing evidence of social cognitive impairments in patients with schizophrenia. Apparently, these impairments are separable from general neurocognitive impairments, such as attention, memory, and executive functioning. Moreover, social cognition seems to be a main determinant of functional outcome and could be used as a guide to elaborate new pharmacological and psychological treatments. However, most of these studies focus on individual mechanisms and observational perspectives; only few of them study schizophrenic patients during interactive situations. We first review evidences of social cognitive impairments both in social stimuli processing and in mental state attribution. We focus on the relationship between these functions and both general cognitive impairments and functional outcome. We next review recent game theory approaches to the study of how social engagement occurs in schizophrenic patients. The advantage of using game theory is that game-oriented tasks can assess social decision making in an interactive everyday situation model. Finally, we review proposed theoretical models used to explain social alterations and their underlying biological mechanisms. Based on interactive studies, we propose a framework which takes into account the dynamic nature of social processes. Thus, understanding social skills as a result of dynamical systems could facilitate the development of both basic research and clinical applications oriented to psychiatric populations. PMID- 23444316 TI - A stockpile of ova in the grass frog Rana temporaria is established once for the life span. Do ovaries in amphibians and in mammals follow the same evolutionary strategy? AB - Most anuran amphibians produce high numbers of eggs during several consecutive breeding seasons. The question is still open whether oocytes are formed anew as a result of oogonial proliferation after each spawning or the definitive pool of oocytes is established during the juvenile period and is sufficient for the whole reproductive life span of a female. Our quantitative studies show that primary oogonia in adult female frogs can proliferate, but they fail to differentiate further and do not enter meiosis, and thereby there is no supplementation of new generations of oocytes after each spawning. Ovaries of one-year-old grass frogs contain (median) 53,447 diplotene oocytes, in two-years-old frogs this number decreased to 33,583 and eventually reached 25,679 in virgin mature females. More than 50% decrease in the total oocyte number was accompanied by massive degeneration (atresia) of oocytes. The final number of oocytes in a female forms a stock for 11-12 breeding seasons and exceeds the number of eggs produced during the potential reproductive life span of this species. The phylogenetic context of oocyte recruitment modes in the major clades of vertebrates is discussed in respect to their ability to replenish the stock (a renewable stock in ovaries named "open" vs. a non-renewable stock in ovaries named "closed"). PMID- 23444317 TI - Drosophila CIAPIN1 homologue is required for follicle cell proliferation and survival. AB - BACKGROUND: The conserved cytokine-induced apoptosis inhibitor-1 (CIAPIN1) gene has been implicated in several processes, such as apoptosis, cell division, angiogenesis and Fe/S protein biogenesis. In this study, we identified the Drosophila CIAPIN1 homologue (D-CIAPIN1) and studied its role in ovarian development. RESULTS: We found that D-CIAPIN1 is conserved as it can complement the nonviability of the yeast CIAPIN1-deletion strain. Several D-CIAPIN1 alleles were identified, including one allele in which that codon encoding the highly conserved twin cysteine CX2 C motif is mutated, demonstrating for the first time the importance of this motif to protein function. We demonstrated D-CIAPIN1 is an essential gene required for ovarian development. We found that D-CIAPIN1 female mutants are sterile, containing rudimentary ovaries. We noted a decrease in follicle cell numbers in D-CIAPIN1 mutant egg chambers. We further demonstrated that the decrease in follicle cell numbers in D-CIAPIN1 mutants is due to a reduced mitotic index and enhanced cell death. CONCLUSIONS: Our study reveals that D-CIAPIN1 is essential for egg chamber development and is required for follicle cell proliferation and survival. PMID- 23444319 TI - Mixed modeling and sample size calculations for identifying housekeeping genes. AB - Normalization of gene expression data using internal control genes that have biologically stable expression levels is an important process for analyzing reverse transcription polymerase chain reaction data. We propose a three-way linear mixed-effects model to select optimal housekeeping genes. The mixed effects model can accommodate multiple continuous and/or categorical variables with sample random effects, gene fixed effects, systematic effects, and gene by systematic effect interactions. We propose using the intraclass correlation coefficient among gene expression levels as the stability measure to select housekeeping genes that have low within-sample variation. Global hypothesis testing is proposed to ensure that selected housekeeping genes are free of systematic effects or gene by systematic effect interactions. A gene combination with the highest lower bound of 95% confidence interval for intraclass correlation coefficient and no significant systematic effects is selected for normalization. Sample size calculation based on the estimation accuracy of the stability measure is offered to help practitioners design experiments to identify housekeeping genes. We compare our methods with geNorm and NormFinder by using three case studies. A free software package written in SAS (Cary, NC, U.S.A.) is available at http://d.web.umkc.edu/daih under software tab. PMID- 23444318 TI - Role of the cytoskeleton in muscle transcriptional responses to altered use. AB - In this work, the interaction between the loss of a primary component of the skeletal muscle cytoskeleton, desmin, and two common physiological stressors, acute mechanical injury and aging, were investigated at the transcriptional, protein, and whole muscle levels. The transcriptional response of desmin knockout (des(-/-)) plantarflexors to a bout of 50 eccentric contractions (ECCs) showed substantial overlap with the response in wild-type (wt) muscle. However, changes in the expression of genes involved in muscle response to injury were blunted in adult des(-/-) muscle compared with wt (fold change with ECC in des(-/-) and wt, respectively: Mybph, 1.4 and 2.9; Xirp1, 2.2 and 5.7; Csrp3, 1.8 and 4.3), similar to the observed blunted mechanical response (torque drop: des(-/-) 30.3% and wt 55.5%). Interestingly, in the absence of stressors, des(-/-) muscle exhibited elevated expression of many these genes compared with wt. The largest transcriptional changes were observed in the interaction between aging and the absence of desmin, including many genes related to slow fiber pathway (Myh7, Myl3, Atp2a2, and Casq2) and insulin sensitivity (Tlr4, Trib3, Pdk3, and Pdk4). Consistent with these transcriptional changes, adult des(-/-) muscle exhibited a significant fiber type shift from fast to slow isoforms of myosin heavy chain (wt, 5.3% IIa and 71.7% IIb; des(-/-), 8.4% IIa and 61.4% IIb) and a decreased insulin-stimulated glucose uptake (wt, 0.188 MUmol/g muscle/20 min; des(-/-), 0.085 MUmol/g muscle/20 min). This work points to novel areas of influence of this cytoskeletal protein and directs future work to elucidate its function. PMID- 23444320 TI - New approach of corrosion casting using direct injection of mercox into the parenchyma of different organs. PMID- 23444322 TI - Health Literacy Assessment of the STOFHLA: Paper versus electronic administration continuation study. AB - Low health literacy is associated with poor health outcomes. Research is needed to understand the mechanisms and pathways of its effects. Computer-based assessment tools may improve efficiency and cost-effectiveness of health literacy research. The objective of this preliminary study was to assess if administration of the Short Test of Functional Health Literacy in Adults (STOFHLA) through a computer-based medium was comparable to the paper-based test in terms of accuracy and time to completion. A randomized, crossover design was used to compare computer versus paper format of the STOFHLA at a Midwestern family medicine residency program. Eighty participants were initially randomized to either computer (n = 42) or paper (n = 38) format of the STOFHLA. After a 30-day washout period, participants returned to complete the other version of the STOFHLA. Data analysis revealed no significant difference between paper- and computer-based surveys (p = .9401; N = 57). The majority of participants showed "adequate" health literacy via paper- and computer-based surveys (100% and 97% of participants, respectively). Electronic administration of STOFHLA results were equivalent to the paper administration results for evaluation of adult health literacy. Future investigations should focus on expanded populations in multiple health care settings and validation of other health literacy screening tools in a clinical setting. PMID- 23444321 TI - Change in tobacco use over time in urban Indian youth: the moderating role of socioeconomic status. AB - This study investigates socioeconomic differences in patterns and trends of tobacco consumption over time among youth in India. Additionally, the distribution of tobacco use risk factors across social class was examined. The data were derived from a longitudinal study of adolescents, Project Mobilizing Youth for Tobacco Related Initiatives. Students in eight private (high socioeconomic status [SES; n = 2,881) and eight government (lower SES; n = 5,476) schools in two large cities in India (Delhi and Chennai) were surveyed annually about their tobacco use and related psychosocial risk factors from 2004 to 2006. Results suggest the relationship between SES and tobacco use over time was not consistent. At baseline (in 2004), lower SES was associated with higher prevalence of tobacco use but the relation between SES and tobacco use reversed 2 years later (2006). These findings were mirrored in the distribution of related psychosocial risk factors by SES at baseline (in 2004), and thereafter in 2006. Implications for prevention scientists and future intervention programs are considered. PMID- 23444323 TI - Expression of pro- and anti-angiogenic factors during the formation of the periocular vasculature and development of the avian cornea. AB - BACKGROUND: During embryonic development, endothelial precursor cells (angioblasts) migrate relatively long distances to form the primary vascular plexus. The migratory behavior of angioblasts and localization of the primitive blood vessels is tightly regulated by pro-angiogenic and anti-angiogenic factors encountered in the embryonic environment. Despite the importance of corneal avascularity to proper vision, it is not known when avascularity is established in the developing cornea and how pro- and anti-angiogenic factors regulate this process. RESULTS AND DISCUSSION: Using Tg(tie1:H2B:eYFP) transgenic quail embryos to visualize fluorescently labeled angioblasts, we show that the presumptive cornea remains avascular despite the invasion of cells from the periocular region where migratory angioblasts reside and form the primary vasculature. Semiquantitative reverse transcriptase polymerase chain reaction analysis and spatiotemporal examination of gene expression revealed that pro- and anti angiogenic factors were expressed in patterns indicating their potential roles in angioblast guidance. CONCLUSIONS: Our findings show for the first time that chick corneal avascularity is established and maintained during development as the periocular vasculature forms. We also identify potential candidate pro- and anti angiogenic factors that may play crucial roles during vascular patterning in the anterior eye. PMID- 23444325 TI - Evolutionary anatomy and phyletic implication of the extrinsic cardiac nervous system in the Philippine tarsier (Tarsius syrichta, Primates) in comparisons with Strepsirrhines and New World monkeys. AB - To provide information on evolutionary morphological differences and similarities between Tarsiformes (tarsiers) and other primates (Strepsirrhini and Platyrrhini), we examined the previously undescribed extrinsic cardiac nervous system (ECNS) and surrounding structures in three Philippine tarsiers (Tarsius syrichta). We found that the complicated ECNS morphology shows little variation in contrast to significant anatomical diversity of the surrounding somatic structures in tarsiers as reported in our previous primate studies. Further, our comparative morphological data on the ECNS show the following aspects of evolutionary anatomical significance; (1) the traits of the general relationship between the superior cervical ganglion and the spinal nerves are common to the Tarsii and Strepsirrhini, (2) the traits of the general composition of the cervicothoracic ganglion, its communicating branches to spinal nerves, and its cardiac nerve are common to the Tarsii and Platyrrhini, and (3) the traits of the general relationship between the middle cervical ganglion and the spinal nerves and its cardiac nerve are common among Strepsirrhini, Tarsii, and Platyrrhini. Therefore, the general anatomical characteristics of the ECNS in tarsiers retain a primitive state for some traits and exhibit a derived state for others. These characteristics of the ECNS also reflect an evolutionary history without the modification and specialization as seen in the surrounding somatic structures. It may play a key role in unifying future studies on molecular phylogeny and updating evolutionary anatomical information. PMID- 23444324 TI - Cerebral venous system and anatomical predisposition to high-altitude headache. AB - OBJECTIVE: As inspired oxygen availability falls with ascent to altitude, some individuals develop high-altitude headache (HAH). We postulated that HAH results when hypoxia-associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies. METHODS: In high-altitude studies, retinal venous distension (RVD) was ophthalmoscopically assessed in 24 subjects (6 female) and sea-level cranial magnetic resonance imaging was performed in 12 subjects ascending to 5,300m. Correlation of headache burden (summed severity scores [0-4]<=24 hours from arrival at each altitude) with RVD, and with cerebral/cerebrospinal fluid (CSF)/venous compartment volumes, was sought. In a sea-level hypoxic study, 11 subjects underwent gadolinium-enhanced magnetic resonance venography before and during hypoxic challenge (fraction of inspired oxygen=0.11, 1 hour). RESULTS: In the high-altitude studies, headache burden correlated with both RVD (Spearman rho=0.55, p=0.005) and with the degree of narrowing of 1 or both transverse venous sinuses (r=-0.56, p=0.03). It also related inversely to both the lateral+third ventricle summed volumes (Spearman rho=-0.5, p=0.05) and pericerebellar CSF volume (r=-0.56, p=0.03). In the hypoxic study, cerebral and retinal vein engorgement were correlated, and rose as the combined conduit score fell (a measure of venous outflow restriction; r=-0.66, p<0.05 and r=-0.75, p<0.05, respectively). INTERPRETATION: Arterial hypoxemia is associated with cerebral and retinal venous distension, whose magnitude correlates with HAH burden. Restriction in cerebral venous outflow is associated with retinal distension and HAH. Limitations in cerebral venous efferent flow may predispose to headache when hypoxia-related increases in cerebral arterial flow occur. PMID- 23444326 TI - Evolutionary conservation of the placodal transcriptional network during sexual and asexual development in chordates. AB - BACKGROUND: An important question behind vertebrate evolution is whether the cranial placodes originated de novo, or if their precursors were present in the ancestor of chordates. In this respect, tunicates are of particular interest as they are considered the closest relatives to vertebrates. They are also the only chordate group possessing species that reproduce both sexually and asexually, allowing both types of development to be studied to address whether embryonic pathways have been co-opted during budding to build the same structures. RESULTS: We studied the expression of members of the transcriptional network associated with vertebrate placodal formation (Six, Eya, and FoxI) in the colonial tunicate Botryllus schlosseri. During both sexual and asexual development, each transcript is expressed in branchial fissures and in two discrete regions proposed to be homologues to groups of vertebrate placodes. DISCUSSION: Results reinforce the idea that placode origin predates the origin of vertebrates and that the molecular network involving these genes was co-opted in the evolution of asexual reproduction. Considering that gill slit formation in deuterostomes is based on similar expression patterns, we discuss possible alternative evolutionary scenarios depicting gene co-option as critical step in placode and pharynx evolution. PMID- 23444327 TI - No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. AB - An association has previously been reported between susceptibility to multiple sclerosis and the rare mutant alleles of the CYP27B1 gene responsible for autosomal recessive vitamin D-dependent rickets type 1 (VDDR1). In an attempt to replicate this finding, we screened 495 multiplex families and 2,092 single affected families, together with 4,594 cases and 3,583 controls (a total of 17,073 individuals) but were unable to find any evidence supporting this putative association. Our data do not indicate that mutations responsible for VDDR1 influence the risk of developing multiple sclerosis. PMID- 23444329 TI - COP9 signalosome-regulated proteolysis: turning off ascorbic acid synthesis when the lights go out. PMID- 23444328 TI - The seirena B class floral homeotic mutant of California Poppy (Eschscholzia californica) reveals a function of the enigmatic PI motif in the formation of specific multimeric MADS domain protein complexes. AB - The products of B class floral homeotic genes specify petal and stamen identity, and loss of B function results in homeotic conversions of petals into sepals and stamens into carpels. Here, we describe the molecular characterization of seirena 1 (sei-1), a mutant from the basal eudicot California poppy (Eschscholzia californica) that shows homeotic changes characteristic of floral homeotic B class mutants. SEI has been previously described as EScaGLO, one of four B class related MADS box genes in California poppy. The C terminus of SEI, including the highly conserved PI motif, is truncated in sei-1 proteins. Nevertheless, like the wild-type SEI protein, the sei-1 mutant protein is able to bind CArG-boxes and can form homodimers, heterodimers, and several higher order complexes with other MADS domain proteins. However, unlike the wild type, the mutant protein is not able to mediate higher order complexes consisting of specific B, C, and putative E class related proteins likely involved in specifying stamen identity. Within the PI motif, five highly conserved N-terminal amino acids are specifically required for this interaction. Several families lack this short conserved sequence, including the Brassicaceae, and we propose an evolutionary scenario to explain these functional differences. PMID- 23444330 TI - Progressive transverse microtubule array organization in hormone-induced Arabidopsis hypocotyl cells. AB - The acentriolar cortical microtubule arrays in dark-grown hypocotyl cells organize into a transverse coaligned pattern that is critical for axial plant growth. In light-grown Arabidopsis thaliana seedlings, the cortical array on the outer (periclinal) cell face creates a variety of array patterns with a significant bias (>3:1) for microtubules polymerizing edge-ward and into the side (anticlinal) faces of the cell. To study the mechanisms required for creating the transverse coalignment, we developed a dual-hormone protocol that synchronously induces ~80% of the light-grown hypocotyl cells to form transverse arrays over a 2-h period. Repatterning occurred in two phases, beginning with an initial 30 to 40% decrease in polymerizing plus ends prior to visible changes in the array pattern. Transverse organization initiated at the cell's midzone by 45 min after induction and progressed bidirectionally toward the apical and basal ends of the cell. Reorganization corrected the edge-ward bias in polymerization and proceeded without transiting through an obligate intermediate pattern. Quantitative comparisons of uninduced and induced microtubule arrays showed a limited deconstruction of the initial periclinal array followed by a progressive array reorganization to transverse coordinated between the anticlinal and periclinal cell faces. PMID- 23444331 TI - Metabolic fluxes in an illuminated Arabidopsis rosette. AB - Photosynthesis is the basis for life, and its optimization is a key biotechnological aim given the problems of population explosion and environmental deterioration. We describe a method to resolve intracellular fluxes in intact Arabidopsis thaliana rosettes based on time-dependent labeling patterns in the metabolome. Plants photosynthesizing under limiting irradiance and ambient CO2 in a custom-built chamber were transferred into a (13)CO2-enriched environment. The isotope labeling patterns of 40 metabolites were obtained using liquid or gas chromatography coupled to mass spectrometry. Labeling kinetics revealed striking differences between metabolites. At a qualitative level, they matched expectations in terms of pathway topology and stoichiometry, but some unexpected features point to the complexity of subcellular and cellular compartmentation. To achieve quantitative insights, the data set was used for estimating fluxes in the framework of kinetic flux profiling. We benchmarked flux estimates to four classically determined flux signatures of photosynthesis and assessed the robustness of the estimates with respect to different features of the underlying metabolic model and the time-resolved data set. PMID- 23444334 TI - Protective effect of butylated hydroxytoluene on ferric nitrilotriacetate induced hepatotoxicity and oxidative stress in mice. AB - The present study was undertaken to evaluate the possible ameliorating effect of butylated hydroxyl toluene (BHT), associated with ferric nitrilotriacetate (Fe NTA)-induced oxidative stress and liver injury in mice. The treatment of mice with Fe-NTA alone enhances ornithine decarboxylase activity to 4.6 folds, protein carbonyl formation increased up to 2.9 folds and DNA synthesis expressed in terms of [(3)H] thymidine incorporation increased to 3.2 folds, and antioxidants and antioxidant enzymes decreased to 1.8-2.5 folds, compared with the corresponding saline-treated controls. These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of BHT. Our data show that BHT can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent. PMID- 23444333 TI - Self-incompatibility in Petunia inflata: the relationship between a self incompatibility locus F-box protein and its non-self S-RNases. AB - The highly polymorphic S (for self-incompatibility) locus regulates self incompatibility in Petunia inflata; the S-RNase regulates pistil specificity, and multiple S-locus F-box (SLF) genes regulate pollen specificity. The collaborative non-self recognition model predicts that, for any S-haplotype, an unknown number of SLFs collectively recognize all non-self S-RNases to mediate their ubiquitination and degradation. Using a gain-of-function assay, we examined the relationships between S2-SLF1 (for S2-allelic product of Type-1 SLF) and four S RNases. The results suggest that S2-SLF1 interacts with S7- and S13-RNases, and the previously identified S1- and S3-RNases, but not with S5- or S11-RNase. An artificial microRNA expressed by the S2-SLF1 promoter, but not by the vegetative cell-specific promoter, Late Anther Tomato 52, suppressed expression of S2-SLF1 in S2 pollen, suggesting that SLF1 is specific to the generative cell. The S2 pollen with S2-SLF1 suppressed was compatible with S3-, S5-, S7-, S11-, and S13 carrying pistils, confirming that other SLF proteins are responsible for detoxifying S5- and S11-RNases and suggesting that S2-SLF1 is not the only SLF in S2 pollen that interacts with S3-, S7-, and S13-RNases. Petunia may have evolved at least two types of SLF proteins to detoxify any non-self S-RNase to minimize the deleterious effects of mutation in any SLF. PMID- 23444335 TI - A study on the effects of pica and iron-deficiency anemia on oxidative stress, antioxidant capacity and trace elements. AB - Pica is defined as developmentally inappropriate consumption of nonnutritive substances for at least 1 month. There are a few studies on serum trace element levels of patients with pica. The literature contains contracting data on the levels of oxidative stress and antioxidant levels in patients with iron deficiency anemia (IDA). The effect of pica on oxidative stress and antioxidant capacity has not been investigated yet. The present study evaluated the effects of pica and IDA on oxidative stress and antioxidant capacity as well as on the levels of trace elements including serum zinc and selenium in 47 children with IDA plus pica, 22 children with IDA only and 21 nonanemic children as controls. The results demonstrated significantly lower levels of serum selenium and zinc in pica and IDA groups compared to the control group. Total oxidant levels were highest in the pica group and consistently, the lowest total antioxidant capacity was observed again in the pica group. Comparison of pica and IDA groups yielded significantly lower levels of total antioxidant levels and significantly higher oxidative stress index in the pica group. Consequently, it is thought that the detrimental effects of pica within the organism were mediated by adverse impacts on antioxidant capacity and oxidative stress. These effects should be kept in mind while managing patients with pica. PMID- 23444332 TI - The TIE1 transcriptional repressor links TCP transcription factors with TOPLESS/TOPLESS-RELATED corepressors and modulates leaf development in Arabidopsis. AB - Leaf size and shape are mainly determined by coordinated cell division and differentiation in lamina. The CINCINNATA (CIN)-like TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors are key regulators of leaf development. However, the mechanisms that control TCP activities during leaf development are largely unknown. We identified the TCP Interactor containing EAR motif protein1 (TIE1), a novel transcriptional repressor, as a major modulator of TCP activities during leaf development. Overexpression of TIE1 leads to hyponastic and serrated leaves, whereas disruption of TIE1 causes epinastic leaves. TIE1 is expressed in young leaves and encodes a transcriptional repressor containing a C-terminal EAR motif, which mediates interactions with the TOPLESS (TPL)/TOPLESS-RELATED (TPR) corepressors. In addition, TIE1 physically interacts with CIN-like TCPs. We propose that TIE1 regulates leaf size and morphology by inhibiting the activities of TCPs through recruiting the TPL/TPR corepressors to form a tertiary complex at early stages of leaf development. PMID- 23444336 TI - Cytotoxicity and uptake of archaeosomes prepared from Aeropyrum pernix lipids. AB - Archaeon Aeropyrum pernix K1 is an obligate aerobic hyperthermophilic organism with C25,25-archeol membrane lipids with head groups containing inositol. Interactions of archaeosomes, liposomes prepared from lipids of A. pernix, with mammalian cells in vitro were studied. In vitro cytotoxicity was tested on five different cell lines: rodent mouse melanoma cells (B16-F1) and Chinese hamster ovary (CHO) cells, and three human cell lines-epithelial colorectal adenocarcinoma cells (CACO-2), liver hepatocellular carcinoma cell line (Hep G2) and endothelial umbilical vein cell line (EA.hy926). Archaeosomes were nontoxic to human Hep G2, CACO-2 and mildly toxic to rodent CHO and B16-F1 cells but showed strong cytotoxic effect on EA.hy926 cells. Confocal microscopy revealed that archaeosomes are taken up by endocytosis. The uptake of archaeosomes and the release of loaded calcein are more prominent in EA.hy926 cells, which is in line with high toxicity toward these cells. The mechanisms of uptake, release and action in these cells as well as in vivo functioning have to be further studied for possible targeted drug delivery. PMID- 23444337 TI - A 90-day subchronic toxicity study of neem oil, a Azadirachta indica oil, in mice. AB - To determine the no-observed-adverse-effect level (NOAEL) of exposure and target organs of neem oil for establishing safety criteria for human exposure, the subchronic toxicity study with neem oil in mice was evaluated. The mice (10 per sex for each dose) was orally administered with neem oil with the doses of 0 (to serve as a control), 177, 533 and 1600 mg/kg/day for 90 days. After the treatment period, observation of reversibility or persistence of any toxic effects, mice were continuously fed without treatment for the following 30 days. During the two test periods, the serum biochemistry, organ weight and histopathology were examined. The results showed that the serum biochemistry and organ coefficient in experimental groups had no statistical difference compared with those of the control group. At the 90th day, the histopathological examinations showed that the 1600 mg/kg/day dose of neem oil had varying degrees of damage on each organ except heart, uterus and ovarian. After 30-day recovery, the degree of lesions to the tissues was lessened or even restored. The NOAEL of neem oil was 177 mg/kg/day for mice and the target organs of neem oil were determined to be testicle, liver and kidneys. PMID- 23444338 TI - Protective effect of vanadyl sulfate on skin injury in streptozotocin-induced diabetic rats. AB - The aim of the present study was to investigate the effect of vanadyl sulfate supplementation on the skin tissues of diabetic and control rats. In this study, 6-6.5 months old male Swiss albino rats were used. The animals were randomly divided into the following four groups: group I, control (nondiabetic intact animals); group II, vanadyl sulfate control; group III, streptozotocin (STZ) diabetic animals and group IV, STZ-diabetic animals given vanadyl sulfate. The animals were made diabetic by intraperitoneal injection of a single dose of 65 mg/kg STZ in 0.01 M citrate buffer (pH = 4.5). From day 1 to day 60, 100 mg/kg vanadyl sulfate was given daily by gavage technique to one of the control and diabetic groups. Body weights and blood glucose levels were estimated on experimental days 0, 1 and 60. On the 60th day, skin tissue samples were taken, glutathione (GSH), lipid peroxidation (LPO), nonenzymatic glycosylation (NEG) and protein levels, catalase (CAT), superoxide dismutase (SOD) and glutathione-S transferase (GST) activities were determined. Blood glucose, skin LPO and NEG levels increased, but skin GSH levels and CAT, SOD and GST activities decreased in the STZ group. Treatment with vanadyl sulfate reversed these effects. The present study showed that vanadyl sulfate exerted antioxidant properties and may prevent skin damage caused by diabetes. PMID- 23444339 TI - 503unc, a small and muscle-specific zebrafish promoter. AB - The muscle-specific UNC-45b assists in the folding of sarcomeric myosin. Analysis of the zebrafish unc-45b upstream region revealed that unc-45b promoter fragments reliably drive GFP expression after germline transmission. The muscle-specific 503-bp minimal promoter 503unc was identified to drive gene expression in the zebrafish musculature. In transgenic Tg(-503unc:GFP) zebrafish, GFP fluorescence was detected in the adaxial cells, their slow fiber descendants, and the fast muscle. At later stages, robust GFP fluorescence is eminent in the cardiac, cranial, fin, and trunk muscle, thereby recapitulating the unc-45b expression pattern. We propose that the 503unc promoter is a small and muscle-specific promoter that drives robust gene expression throughout the zebrafish musculature, making it a valuable tool for the exploration of zebrafish muscle. PMID- 23444340 TI - Hepatocellular carcinoma: a systems biology perspective. AB - Hepatocellular carcinomas (HCCs) have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel-targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment. PMID- 23444341 TI - Concurrent self-regulatory efficacy as a mediator of the goal: exercise behaviour relationship. AB - Examining exercise as a single goal-directed behaviour, without acknowledging the influence of other concurrent goals, may oversimplify the self-regulation needed in daily life. Concurrent self-regulatory efficacy, confidence in one's ability to self-regulate the management of multiple goals, was explored as a potential mediator in the relationship between value of an exercise goal and future exercise behaviour. Undergraduate students were observed during a 4-week examination period where they faced greater than usual challenges to exercising regularly. Consistent with self-efficacy theory, concurrent self-regulatory efficacy was a significant partial mediator of the value of an exercise goal exercise behaviour relationship. PMID- 23444342 TI - Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy. AB - BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy. PROCEDURE: In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin. RESULTS: Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 uU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z score. Median adiponectin level decreased from 18.0 to 14.0 ug/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively). CONCLUSIONS: Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors. PMID- 23444343 TI - Lipoxygenase6-dependent oxylipin synthesis in roots is required for abiotic and biotic stress resistance of Arabidopsis. AB - Jasmonates are oxylipin signals that play important roles in the development of fertile flowers and in defense against pathogens and herbivores in leaves. The aim of this work was to understand the synthesis and function of jasmonates in roots. Grafting experiments with a jasmonate-deficient mutant demonstrated that roots produce jasmonates independently of leaves, despite low expression of biosynthetic enzymes. Levels of 12-oxo-phytodienoic acid, jasmonic acid, and its isoleucine derivative increased in roots upon osmotic and drought stress. Wounding resulted in a decrease of preformed 12-oxo-phytodienoic acid concomitant with an increase of jasmonic acid and jasmonoyl-isoleucine. 13-Lipoxygenases catalyze the first step of lipid oxidation leading to jasmonate production. Analysis of 13-lipoxygenase-deficient mutant lines showed that only one of the four 13-lipoxygenases, LOX6, is responsible and essential for stress-induced jasmonate accumulation in roots. In addition, LOX6 was required for production of basal 12-oxo-phytodienoic acid in leaves and roots. Loss-of-function mutants of LOX6 were more attractive to a detritivorous crustacean and more sensitive to drought, indicating that LOX6-derived oxylipins are important for the responses to abiotic and biotic factors. PMID- 23444344 TI - Early induction of apple fruitlet abscission is characterized by an increase of both isoprene emission and abscisic acid content. AB - Apple (Malus domestica) fruitlet abscission represents an interesting model system to study the early phases of the shedding process, during which major transcriptomic changes and metabolic rearrangements occur within the fruit. In apple, the drop of fruits at different positions within the cluster can be selectively magnified through chemical thinners, such as benzyladenine and metamitron, acting as abscission enhancers. In this study, different abscission potentials were obtained within the apple fruitlet population by means of the above-cited thinners. A metabolomic study was conducted on the volatile organic compounds emitted by abscising fruitlets, allowing for identification of isoprene as an early marker of abscission induction. A strong correlation was also observed between isoprene production and abscisic acid (ABA) levels in the fruit cortex, which were shown to increase in abscising fruitlets with respect to nonabscising ones. Transcriptomic evidence indicated that abscission-related ABA is biologically active, and its increased biosynthesis is associated with the induction of a specific ABA-responsive 9-cis-epoxycarotenoid dioxygenase gene. According to a hypothetical model, ABA may transiently cooperate with other hormones and secondary messengers in the generation of an intrafruit signal leading to the downstream activation of the abscission zone. The shedding process therefore appears to be triggered by multiple interdependent pathways, whose fine regulation, exerted within a very short temporal window by both endogenous and exogenous factors, determines the final destiny of the fruitlets. PMID- 23444345 TI - Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961. AB - PURPOSE: Assess the intellectual and academic outcomes as well as risk factors associated with treatment for average-risk medulloblastoma in childhood using 23.4 Gy of craniospinal radiotherapy plus adjuvant chemotherapy. METHODS: From an overall sample of 379 enrolled in the parent study (COG A9961), 110 patients received a total of 192 assessments over more than 5 years with standardized IQ and academic achievement tests. Random coefficient models of the various outcomes were developed that incorporated covariates including chemotherapy regimen, age at diagnosis, sex, initial Full Scale IQ, and mutism. RESULTS: Participants in this study were found to be comparable to the overall sample in all demographic, disease, and treatment factors, except there were more gross total resections in the subsample undergoing intellectual and academic assessment. Major findings include significant decline in both intellectual and academic domains over time that were greater in children who were younger at diagnosis and had higher initial intelligence test scores. Children with mutism were at higher risk for initial effects on intelligence. No effects of sex were found. CONCLUSION: These results show progressive decline over several years post-treatment in standardized intellectual and academic scores. Despite recent improvements in therapies for these children, most notably a decrease dose of craniospinal radiation, they remain at risk. The pursuit of less toxic treatments, particularly for younger children, should continue. Neuropsychological surveillance should be routine at centers treating children with brain tumors. PMID- 23444346 TI - Genetic Drift: the Salernitan school of medicine: women, men, and children. A syndromological review of the oldest medical school in the western world. AB - Ever since the 9th century during the High Middle Ages, the "Schola Medica Salernitana," believed to be the first medical school in the western world, flourished in Salerno, a city in southern Italy. Although an important role is attributed to several men of this school, who were recognized as wise and learned doctors, modern historiography has also reevaluated and extolled the praiseworthy role of women. Contrary to the common beliefs and expectations of a woman's "place" at the time, these women were fully titled physicians. Attention was also paid to the health and welfare of children. However, there are no apparent references to physical disabilities, a mysterious omission that seems incompatible with an institution that stood as a beacon of knowledge for centuries. Mysteries, discoveries, and potential hidden messages are mingled in a fascinating medieval codex yet to be fully deciphered. The medical school reached its maximum splendor between the years of 1000 and 1300 AD. After alternating fortunes, the Salernitan institution began a slow decline due to the explosive development of other universities, such as those in Paris, Bologna, Padua, and most significantly, the nearby University of Naples. It was eventually closed by the King of Naples, Joachim Murat, November 29, 1811. PMID- 23444347 TI - Gibberellin signaling in plants. AB - The plant hormone gibberellin (GA) regulates major aspects of plant growth and development. The role of GA in determining plant stature had major impacts on agriculture in the 1960s, and the development of semi-dwarf varieties that show altered GA responses contributed to a huge increase in grain yields during the 'green revolution'. The past decade has brought great progress in understanding the molecular basis of GA action, with the cloning and characterization of GA signaling components. Here, we review the molecular basis of the GA signaling pathway, from the perception of GA to the regulation of downstream genes. PMID- 23444348 TI - Auxin 2012: a rich mea ho'oulu. AB - In December 2012, scientists from around the world gathered in Waikoloa, Hawaii for 'Auxin 2012', a meeting organized by Paula McSteen (University of Missouri, USA), Ben Scheres (Utrecht University, The Netherlands) and Yunde Zhao (University of California, San Diego, USA). At the meeting, participants discussed the latest advances in auxin biosynthesis, transport and signaling research, in addition to providing context for how these pathways intersect with other aspects of plant physiology and development. Fittingly, the meeting began with a traditional Hawaiian ceremony that recognized the centrality of the harvest of plant life ('mea ho'oulu' in Hawaiian) for continued human survival. PMID- 23444349 TI - Epigenetic mechanisms in the development and maintenance of dopaminergic neurons. AB - Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it's emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies. PMID- 23444351 TI - Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window. AB - The imprinted Airn macro long non-coding (lnc) RNA is an established example of a cis-silencing lncRNA. Airn expression is necessary to initiate paternal-specific silencing of the Igf2r gene, which is followed by gain of a somatic DNA methylation imprint on the silent Igf2r promoter. However, the developmental requirements for Airn initiation of Igf2r silencing and the role of Airn or DNA methylation in maintaining stable Igf2r repression have not been investigated. Here, we use inducible systems to control Airn expression during mouse embryonic stem cell (ESC) differentiation. By turning Airn expression off during ESC differentiation, we show that continuous Airn expression is needed to maintain Igf2r silencing, but only until the paternal Igf2r promoter is methylated. By conditionally turning Airn expression on, we show that Airn initiation of Igf2r silencing is not limited to one developmental 'window of opportunity' and can be maintained in the absence of DNA methylation. Together, this study shows that Airn expression is both necessary and sufficient to silence Igf2r throughout ESC differentiation and that the somatic methylation imprint, although not required to initiate or maintain silencing, adds a secondary layer of repressive epigenetic information. PMID- 23444350 TI - A membrane-associated beta-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. AB - The maintenance of pluripotency in mouse embryonic stem cells (mESCs) relies on the activity of a transcriptional network that is fuelled by the activity of three transcription factors (Nanog, Oct4 and Sox2) and balanced by the repressive activity of Tcf3. Extracellular signals modulate the activity of the network and regulate the differentiation capacity of the cells. Wnt/beta-catenin signaling has emerged as a significant potentiator of pluripotency: increases in the levels of beta-catenin regulate the activity of Oct4 and Nanog, and enhance pluripotency. A recent report shows that beta-catenin achieves some of these effects by modulating the activity of Tcf3, and that this effect does not require its transcriptional activation domain. Here, we show that during self-renewal there is negligible transcriptional activity of beta-catenin and that this is due to its tight association with membranes, where we find it in a complex with Oct4 and E-cadherin. Differentiation triggers a burst of Wnt/beta-catenin transcriptional activity that coincides with the disassembly of the complex. Our results establish that beta-catenin, but not its transcriptional activity, is central to pluripotency acting through a beta-catenin/Oct4 complex. PMID- 23444352 TI - Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. AB - Permanent hearing loss is caused by the irreversible damage of cochlear sensory hair cells and nonsensory supporting cells. In the postnatal cochlea, the sensory epithelium is terminally differentiated, whereas tympanic border cells (TBCs) beneath the sensory epithelium are proliferative. The functions of TBCs are poorly characterized. Using an Axin2(lacZ) Wnt reporter mouse, we found transient but robust Wnt signaling and proliferation in TBCs during the first 3 postnatal weeks, when the number of TBCs decreases. In vivo lineage tracing shows that a subset of hair cells and supporting cells is derived postnatally from Axin2 expressing TBCs. In cochlear explants, Wnt agonists stimulated the proliferation of TBCs, whereas Wnt inhibitors suppressed it. In addition, purified Axin2(lacZ) cells were clonogenic and self-renewing in culture in a Wnt-dependent manner, and were able to differentiate into hair cell-like and supporting cell-like cells. Taken together, our data indicate that Axin2-positive TBCs are Wnt responsive and can act as precursors to sensory epithelial cells in the postnatal cochlea. PMID- 23444353 TI - Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3. AB - Hematopoiesis is a classic system with which to study developmental potentials and to investigate gene regulatory networks that control choices among alternate lineages. T-cell progenitors seeding the thymus retain several lineage potentials. The transcription factor PU.1 is involved in the decision to become a T cell or a myeloid cell, and the developmental outcome of expressing PU.1 is dependent on exposure to Notch signaling. PU.1-expressing T-cell progenitors without Notch signaling often adopt a myeloid program, whereas those exposed to Notch signals remain in a T-lineage pathway. Here, we show that Notch signaling does not alter PU.1 transcriptional activity by degradation/alteration of PU.1 protein. Instead, Notch signaling protects against the downregulation of T-cell factors so that a T-cell transcriptional network is maintained. Using an early T cell line, we describe two branches of this network. The first involves inhibition of E-proteins by PU.1 and the resulting inhibition of Notch signaling target genes. Effects of E-protein inhibition can be reversed by exposure to Notch signaling. The second network is dependent on the ability of PU.1 to inhibit important T-cell transcription factor genes such as Myb, Tcf7 and Gata3 in the absence of Notch signaling. We show that maintenance of Gata3 protein levels by Myb and Notch signaling is linked to the ability to retain T-cell identity in response to PU.1. PMID- 23444354 TI - The ETS domain transcriptional repressor Anterior open inhibits MAP kinase and Wingless signaling to couple tracheal cell fate with branch identity. AB - Cells at the tips of budding branches in the Drosophila tracheal system generate two morphologically different types of seamless tubes. Terminal cells (TCs) form branched lumenized extensions that mediate gas exchange at target tissues, whereas fusion cells (FCs) form ring-like connections between adjacent tracheal metameres. Each tracheal branch contains a specific set of TCs, FCs, or both, but the mechanisms that select between the two tip cell types in a branch-specific fashion are not clear. Here, we show that the ETS domain transcriptional repressor anterior open (aop) is dispensable for directed tracheal cell migration, but plays a key role in tracheal tip cell fate specification. Whereas aop globally inhibits TC and FC specification, MAPK signaling overcomes this inhibition by triggering degradation of Aop in tip cells. Loss of aop function causes excessive FC and TC specification, indicating that without Aop-mediated inhibition, all tracheal cells are competent to adopt a specialized fate. We demonstrate that Aop plays a dual role by inhibiting both MAPK and Wingless signaling, which induce TC and FC fate, respectively. In addition, the branch specific choice between the two seamless tube types depends on the tracheal branch identity gene spalt major, which is sufficient to inhibit TC specification. Thus, a single repressor, Aop, integrates two different signals to couple tip cell fate selection with branch identity. The switch from a branching towards an anastomosing tip cell type may have evolved with the acquisition of a main tube that connects separate tracheal primordia to generate a tubular network. PMID- 23444355 TI - Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh. AB - The Sox2 transcription factor is active in stem/progenitor cells throughout the developing vertebrate central nervous system. However, its conditional deletion at E12.5 in mouse causes few brain developmental problems, with the exception of the postnatal loss of the hippocampal radial glia stem cells and the dentate gyrus. We deleted Sox2 at E9.5 in the telencephalon, using a Bf1-Cre transgene. We observed embryonic brain defects that were particularly severe in the ventral, as opposed to the dorsal, telencephalon. Important tissue loss, including the medial ganglionic eminence (MGE), was detected at E12.5, causing the subsequent impairment of MGE-derived neurons. The defect was preceded by loss of expression of the essential ventral determinants Nkx2.1 and Shh, and accompanied by ventral spread of dorsal markers. This phenotype is reminiscent of that of mice mutant for the transcription factor Nkx2.1 or for the Shh receptor Smo. Nkx2.1 is known to mediate the initial activation of ventral telencephalic Shh expression. A partial rescue of the normal phenotype at E14.5 was obtained by administration of a Shh agonist. Experiments in Medaka fish indicate that expression of Nkx2.1 is regulated by Sox2 in this species also. We propose that Sox2 contributes to Nkx2.1 expression in early mouse development, thus participating in the region specific activation of Shh, thereby mediating ventral telencephalic patterning induction. PMID- 23444356 TI - Drosophila p53-related protein kinase is required for PI3K/TOR pathway-dependent growth. AB - Cell growth and proliferation are pivotal for final organ and body size definition. p53-related protein kinase (Bud32/PRPK) has been identified as a protein involved in proliferation through its effects on transcription in yeast and p53 stabilization in human cell culture. However, the physiological function of Bud32/PRPK in metazoans is not well understood. In this work, we have analyzed the role of PRPK in Drosophila development. Drosophila PRPK is expressed in every tissue analyzed and is required to support proliferation and cell growth. The Prpk knockdown animals show phenotypes similar to those found in mutants for positive regulators of the PI3K/TOR pathway. This pathway has been shown to be fundamental for animal growth, transducing the hormonal and nutritional status into the protein translation machinery. Functional interactions have established that Prpk operates as a transducer of the PI3K/TOR pathway, being essential for TOR kinase activation and for the regulation of its targets (S6K and 4E-BP, autophagy and bulk endocytosis). This suggests that Prpk is crucial for stimulating the basal protein biosynthetic machinery in response to insulin signaling and to changes in nutrient availability. PMID- 23444357 TI - Identification of SHRUBBY, a SHORT-ROOT and SCARECROW interacting protein that controls root growth and radial patterning. AB - The timing and extent of cell division is particularly important for the growth and development of multicellular organisms. Roots of the model organism Arabidopsis thaliana have been widely studied as a paradigm for organ development in plants. In the Arabidopsis root, the plant-specific GRAS family transcription factors SHORT-ROOT (SHR) and SCARECROW (SCR) are key regulators of root growth and of the asymmetric cell divisions that separate the ground tissue into two separate layers: the endodermis and cortex. To elucidate the role of SHR in root development, we identified 17 SHR-interacting proteins. Among those isolated was At5g24740, which we named SHRUBBY (SHBY). SHBY is a vacuolar sorting protein with similarity to the gene responsible for Cohen syndrome in humans. Hypomorphic alleles of shby caused poor root growth, decreased meristematic activity and defects in radial patterning that are characterized by an increase in the number of cell divisions in the ground tissue that lead to extra cells in the cortex and endodermis, as well as additional cell layers. Analysis of genetic and molecular markers indicates that SHBY acts in a pathway that partially overlaps with SHR, SCR, PLETHORA1 and PLETHORA2 (PLT1 and PLT2). The shby-1 root phenotype was partially phenocopied by treatment of wild-type roots with the proteosome inhibitor MG132 or the gibberellic acid (GA) synthesis inhibitor paclobutrazol (PAC). Our results indicate that SHBY controls root growth downstream of GA in part through the regulation of SHR and SCR. PMID- 23444358 TI - Matrix adhesion polarizes heart progenitor induction in the invertebrate chordate Ciona intestinalis. AB - Cell-matrix adhesion strongly influences developmental signaling. Resulting impacts on cell migration and tissue morphogenesis are well characterized. However, the in vivo impact of adhesion on fate induction remains ambiguous. Here, we employ the invertebrate chordate Ciona intestinalis to delineate an essential in vivo role for matrix adhesion in heart progenitor induction. In Ciona pre-cardiac founder cells, invasion of the underlying epidermis promotes localized induction of the heart progenitor lineage. We found that these epidermal invasions are associated with matrix adhesion along the pre-cardiac cell/epidermal boundary. Through targeted manipulations of RAP GTPase activity, we were able to manipulate pre-cardiac cell-matrix adhesion. Targeted disruption of pre-cardiac cell-matrix adhesion blocked heart progenitor induction. Conversely, increased matrix adhesion generated expanded induction. We were also able to selectively restore cell-matrix adhesion and heart progenitor induction through targeted expression of Ci-Integrin beta2. These results indicate that matrix adhesion functions as a necessary and sufficient extrinsic cue for regional heart progenitor induction. Furthermore, time-lapse imaging suggests that cytokinesis acts as an intrinsic temporal regulator of heart progenitor adhesion and induction. Our findings highlight a potentially conserved role for matrix adhesion in early steps of vertebrate heart progenitor specification. PMID- 23444359 TI - PUF-8 and TCER-1 are essential for normal levels of multiple mRNAs in the C. elegans germline. AB - PUF family proteins are well-conserved regulators of cell proliferation in different developmental processes. They regulate target mRNAs by promoting degradation or by influencing translation through interaction with the translation initiation machinery. Here we show that Caenorhabditis elegans PUF-8 functions redundantly with the nuclear protein TCER-1 in the post-transcriptional maintenance of at least six germline mRNAs. The levels of spliced mRNAs in the puf-8(-) tcer-1(-) double mutant are only 10-30% of the wild type, whereas the unspliced forms increase by ~2- to 3-fold compared with the wild type. These two proteins colocalise at the inner nuclear periphery, and their absence leads to reduced germ cell proliferation and to sterility. A yeast two-hybrid screen of 31 components of the nuclear pore complex and mRNA processing machineries identified seven proteins involved in mRNA export as potential partners of PUF-8. One of these, the nuclear cap-binding protein NCBP-2, colocalises with PUF-8 in the nucleus. A 50 amino acid N-terminal domain of PUF-8 is essential for interaction with NCBP-2 and for PUF-8 to function redundantly with TCER-1. These results reveal two important unexpected aspects of PUF proteins: that, in addition to the C-terminal PUF domain, the N-terminal domain is crucial for PUF function, and that PUF proteins have a novel role in mRNA maintenance. We propose that PUF proteins, in addition to their known cytoplasmic roles, participate in nuclear processing and/or export of mRNAs. PMID- 23444360 TI - Dynamic temporal requirement of Wnt1 in midbrain dopamine neuron development. AB - Wnt1-expressing progenitors generate midbrain dopamine (MbDA) and cerebellum (Cb) neurons in distinct temporal windows and from spatially discrete progenitor domains. It has been shown that Wnt1 and Lmx1a participate in a cross-regulatory loop that is utilized during MbDA neuron development. However, Wnt1 expression dynamically changes over time and precedes that of Lmx1a. The spatial and temporal requirements of Wnt1 in development and specifically its requirement for MbDA neurons remain to be determined. To address these issues, we generated a conditional Wnt1 allele and temporally deleted Wnt1 coupled with genetic lineage analysis. Using this approach, we show that patterning of the midbrain (Mb) and Cb by Wnt1 occurs between the one-somite and the six- to eight-somite stages and is solely dependent on Wnt1 function in the Mb, but not in the Cb. Interestingly, an En1-derived domain persists after the early deletion of Wnt1 and mutant cells express OTX2. However, the En1-derived Wnt1-mutant domain does not contain LMX1a expressing progenitors, and MbDA neurons are depleted. Thus, we demonstrate an early requirement of Wnt1 for all MbDA neurons. Subsequently, we deleted Wnt1 in the ventral Mb and show a continued late requirement for Wnt1 in MbDA neuron development, but not in LMX1a-expressing progenitors. Specifically, Wnt1 deletion disrupts the birthdating of MbDA neurons and causes a depletion of MbDA neurons positioned medially and a concomitant expansion of MbDA neurons positioned laterally during embryogenesis. Collectively, our analyses resolve the spatial and temporal function of Wnt1 in Mb and Cb patterning and in MbDA neuron development in vivo. PMID- 23444362 TI - ClearT: a detergent- and solvent-free clearing method for neuronal and non neuronal tissue. AB - We describe a clearing method for enhanced visualization of cell morphology and connections in neuronal and non-neuronal tissue. Using Clear(T) or Clear(T2), which are composed of formamide or formamide/polyethylene glycol, respectively, embryos, whole mounts and thick brain sections can be rapidly cleared with minimal volume changes. Unlike other available clearing techniques, these methods do not use detergents or solvents, and thus preserve lipophilic dyes, fluorescent tracers and immunohistochemical labeling, as well as fluorescent-protein labeling. PMID- 23444361 TI - Zebrafish second heart field development relies on progenitor specification in anterior lateral plate mesoderm and nkx2.5 function. AB - Second heart field (SHF) progenitors perform essential functions during mammalian cardiogenesis. We recently identified a population of cardiac progenitor cells (CPCs) in zebrafish expressing latent TGFbeta-binding protein 3 (ltbp3) that exhibits several defining characteristics of the anterior SHF in mammals. However, ltbp3 transcripts are conspicuously absent in anterior lateral plate mesoderm (ALPM), where SHF progenitors are specified in higher vertebrates. Instead, ltbp3 expression initiates at the arterial pole of the developing heart tube. Because the mechanisms of cardiac development are conserved evolutionarily, we hypothesized that zebrafish SHF specification also occurs in the ALPM. To test this hypothesis, we Cre/loxP lineage traced gata4(+) and nkx2.5(+) ALPM populations predicted to contain SHF progenitors, based on evolutionary conservation of ALPM patterning. Traced cells were identified in SHF-derived distal ventricular myocardium and in three lineages in the outflow tract (OFT). We confirmed the extent of contributions made by ALPM nkx2.5(+) cells using Kaede photoconversion. Taken together, these data demonstrate that, as in higher vertebrates, zebrafish SHF progenitors are specified within the ALPM and express nkx2.5. Furthermore, we tested the hypothesis that Nkx2.5 plays a conserved and essential role during zebrafish SHF development. Embryos injected with an nkx2.5 morpholino exhibited SHF phenotypes caused by compromised progenitor cell proliferation. Co-injecting low doses of nkx2.5 and ltbp3 morpholinos revealed a genetic interaction between these factors. Taken together, our data highlight two conserved features of zebrafish SHF development, reveal a novel genetic relationship between nkx2.5 and ltbp3, and underscore the utility of this model organism for deciphering SHF biology. PMID- 23444363 TI - A mosaic 2q24.2 deletion narrows the critical region to a 0.4 Mb interval that includes TBR1, TANK, and PSMD14. AB - Interstitial deletions involving 2q24 have been associated with a wide range of phenotypes including intellectual disability and short stature. To date, the smallest common region among reported cases of deletions in this region is approximately 2.65 Mb and contains 15 genes. In the present case report, we describe an 18-year-old male with mild intellectual disability, short stature, and mosaicism for a 0.422 Mb deletion on 2q24.2 that was diagnosed by comparative genomic hybridization and confirmed with fluorescent in situ hybridization (FISH). This deletion, which is present in approximately 61% of cells, includes three genes: TBR1, TANK, and PSMD14. The findings suggest that the critical region for intellectual disability and short stature in 2q24.2 can be narrowed to a 0.422 Mb segment. TBR1, a transcription factor involved in early cortical development, is a strong candidate for the intellectual disability phenotype seen in our patient and in patients with larger deletions in this region of the genome. PMID- 23444364 TI - Myotubularin and PtdIns3P remodel the sarcoplasmic reticulum in muscle in vivo. AB - The sarcoplasmic reticulum (SR) is a specialized form of endoplasmic reticulum (ER) in skeletal muscle and is essential for calcium homeostasis. The mechanisms involved in SR remodeling and maintenance of SR subdomains are elusive. In this study, we identified myotubularin (MTM1), a phosphoinositide phosphatase mutated in X-linked centronuclear myopathy (XLCNM, or myotubular myopathy), as a key regulator of phosphatidylinositol 3-monophosphate (PtdIns3P) levels at the SR. MTM1 is predominantly located at the SR cisternae of the muscle triads, and Mtm1 deficient mouse muscles and myoblasts from XLCNM patients exhibit abnormal SR/ER networks. In vivo modulation of MTM1 enzymatic activity in skeletal muscle using ectopic expression of wild-type or a dead-phosphatase MTM1 protein leads to differential SR remodeling. Active MTM1 is associated with flat membrane stacks, whereas dead-phosphatase MTM1 mutant promotes highly curved cubic membranes originating from the SR and enriched in PtdIns3P. Overexpression of a tandem FYVE domain with high affinity for PtdIns3P alters the shape of the SR cisternae at the triad. Our findings, supported by the parallel analysis of the Mtm1-null mouse and an in vivo study, reveal a direct function of MTM1 enzymatic activity in SR remodeling and a key role for PtdIns3P in promoting SR membrane curvature in skeletal muscle. We propose that alteration in SR remodeling is a primary cause of X-linked centronuclear myopathy. The tight regulation of PtdIns3P on specific membrane subdomains may be a general mechanism to control membrane curvature. PMID- 23444365 TI - Promoter type influences transcriptional topography by targeting genes to distinct nucleoplasmic sites. AB - Both the sequence of a promoter and the position of a gene in 3D nuclear space play crucial roles in gene regulation, but few studies address their inter relationship. Using human and viral promoters on mini-chromosomes and RNA fluorescence in situ hybridization coupled to 'high-precision' localization, we show that promoters binding the same transcription factors and responding to the same signaling pathways tend to be co-transcribed in the same transcription factories. We go on to suggest how such spatial co-association might drive co regulation of genes under the control of similar cis-elements. PMID- 23444366 TI - 14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitylation and cytoplasmic body formation. AB - Deregulated expression of tripartite motif-containing protein 32 (TRIM32, an E3 ubiquitin-protein ligase) contributes to various diseases. Here we report, using quantitative proteomics and biochemistry, that 14-3-3 proteins bind to phosphorylated TRIM32 and prevent TRIM32 autoubiquitylation and the formation of TRIM32-containing cytoplasmic bodies, which are potential autoregulatory mechanisms that can reduce the concentration of soluble free TRIM32. The 14-3-3 TRIM32 interaction is dependent on protein-kinase-A-catalyzed phosphorylation of TRIM32 at Ser651. We found that the inhibitory effect of 14-3-3 is, in part, a consequence of disrupting the propensity of TRIM32 to undergo higher-order self association without affecting its dimerization. Consequently, dimerized TRIM32 bound to 14-3-3 was sequestered in a distinct cytoplasmic pool away from the microtubule network, whereas a TRIM32 mutant that cannot bind 14-3-3 underwent multimerization and was unavailable to facilitate cell growth. Our results reveal a novel connection between ubiquitylation and phosphorylation pathways, which could modulate a variety of cell events by stimulating the formation of the 14-3 3-TRIM32 signaling complex. PMID- 23444367 TI - Citron kinase mediates transition from constriction to abscission through its coiled-coil domain. AB - Cytokinesis is initiated by constriction of the cleavage furrow, and completed with separation of the two daughter cells by abscission. Control of transition from constriction to abscission is therefore crucial for cytokinesis. However, the underlying mechanism is largely unknown. Here, we analyze the role of Citron kinase (Citron-K) that localizes at the cleavage furrow and the midbody, and dissect its action mechanisms during this transition. Citron-K forms a stable ring-like structure at the midbody and its depletion affects the maintenance of the intercellular bridge, resulting in fusion of two daughter cells after the cleavage furrow ingression. RNA interference (RNAi) targeting Citron-K reduced accumulation of RhoA, Anillin, and septins at the intercellular bridge in mid telophase, and impaired concentration and maintenance of KIF14 and PRC1 at the midbody in late telophase. RNAi rescue experiments revealed that these functions of Citron-K are mediated by its coiled-coil (CC) domain, and not by its kinase domain. The C-terminal part of CC contains a Rho-binding domain and a cluster forming region and is important for concentrating Citron-K from the cleavage furrow to the midbody. The N-terminal part of CC directly binds to KIF14, and this interaction is required for timely transfer of Citron-K to the midbody after furrow ingression. We propose that the CC-domain-mediated translocation and actions of Citron-K ensure proper stabilization of the midbody structure during the transition from constriction to abscission. PMID- 23444369 TI - Insulin signaling via Akt2 switches plakophilin 1 function from stabilizing cell adhesion to promoting cell proliferation. AB - Downregulation of adherens junction proteins is a frequent event in carcinogenesis. How desmosomal proteins contribute to tumor formation by regulating the balance between adhesion and proliferation is not well understood. The desmosomal protein plakophilin 1 can increase intercellular adhesion by recruiting desmosomal proteins to the plasma membrane or stimulate proliferation by enhancing translation rates. Here, we show that these dual functions of plakophilin 1 are regulated by growth factor signaling. Insulin stimulation induced the phosphorylation of plakophilin 1, which correlated with reduced intercellular adhesion and an increased activity of plakophilin 1 in the stimulation of translation. Phosphorylation was mediated by Akt2 at four motifs within the plakophilin 1 N-terminal domain. A plakophilin 1 phospho-mimetic mutant revealed reduced intercellular adhesion and accumulated in the cytoplasm, where it increased translation and proliferation rates and conferred the capacity of anchorage-independent growth. The cytoplasmic accumulation was mediated by the stabilization of phosphorylated plakophilin 1, which displayed a considerably increased half-life, whereas non-phosphorylated plakophilin 1 was more rapidly degraded. Our data indicate that upon activation of growth factor signaling, plakophilin 1 switches from a desmosome-associated growth-inhibiting to a cytoplasmic proliferation-promoting function. This supports the view that the deregulation of plakophilin 1, as observed in several tumors, directly contributes to hyperproliferation and carcinogenesis in a context-dependent manner. PMID- 23444368 TI - A role for Rab14 in the endocytic trafficking of GLUT4 in 3T3-L1 adipocytes. AB - Insulin enhances the uptake of glucose into adipocytes and muscle cells by promoting the redistribution of the glucose transporter isoform 4 (GLUT4) from intracellular compartments to the cell surface. Rab GTPases regulate the trafficking itinerary of GLUT4 and several have been found on immunopurified GLUT4 vesicles. Specifically, Rab14 has previously been implicated in GLUT4 trafficking in muscle although its role, if any, in adipocytes is poorly understood. Analysis of 3T3-L1 adipocytes using confocal microscopy demonstrated that endogenous GLUT4 and endogenous Rab14 exhibited a partial colocalisation. However, when wild-type Rab14 or a constitutively-active Rab14Q70L mutant were overexpressed in these cells, the colocalisation with both GLUT4 and IRAP became extensive. Interestingly, this colocalisation was restricted to enlarged 'ring like' vesicular structures (mean diameter 1.3 um), which were observed in the presence of overexpressed wild-type Rab14 and Rab14Q70L, but not an inactive Rab14S25N mutant. These enlarged vesicles contained markers of early endosomes and were rapidly filled by GLUT4 and transferrin undergoing endocytosis from the plasma membrane. The Rab14Q70L mutant reduced basal and insulin-stimulated cell surface GLUT4 levels, probably by retaining GLUT4 in an insulin-insensitive early endosomal compartment. Furthermore, shRNA-mediated depletion of Rab14 inhibited the transit of GLUT4 through early endosomal compartments towards vesicles and tubules in the perinuclear region. Given the previously reported role of Rab14 in trafficking between endosomes and the Golgi complex, we propose that the primary role of Rab14 in GLUT4 trafficking is to control the transit of internalised GLUT4 from early endosomes into the Golgi complex, rather than direct GLUT4 translocation to the plasma membrane. PMID- 23444370 TI - Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF beta/Smad signalling. AB - Loss of tissue organization is a hallmark of the early stages of cancer, and there is considerable interest in proteins that maintain normal tissue architecture. Prostate epithelial cells cultured in Matrigel form three dimensional acini that mimic aspects of prostate gland development. The organization of these structures requires the tumor suppressor Dickkopf-3 (Dkk 3), a divergent member of the Dkk family of secreted Wnt signalling antagonists that is frequently downregulated in prostate cancer. To gain further insight into the function of Dkk-3 in the prostate, we compared the prostates of Dkk3-null mice with those of control littermates. We found increased proliferation of prostate epithelial cells in the mutant mice and changes in prostate tissue organization. Consistent with these observations, cell proliferation was elevated in acini formed by human prostate epithelial cells stably silenced for Dkk-3. Silencing of Dkk-3 increased TGF-beta/Smad signalling, and inhibitors of TGF beta/Smad signalling rescued the defective acinar phenotype caused by loss of Dkk 3. These findings suggest that Dkk-3 maintains the structural integrity of the prostate gland by limiting TGF-beta/Smad signalling. PMID- 23444371 TI - The cell polarity scaffold Lethal Giant Larvae regulates synapse morphology and function. AB - Lethal Giant Larvae (LGL) is a cytosolic cell polarity scaffold whose loss dominantly enhances neuromuscular junction (NMJ) synaptic overgrowth caused by loss of the Fragile X Mental Retardation Protein (FMRP). However, direct roles for LGL in NMJ morphological and functional development have not before been tested. Here, we use confocal imaging and two-electrode voltage-clamp electrophysiology at the Drosophila larval NMJ to define the synaptic requirements of LGL. We find that LGL is expressed both pre- and postsynaptically, where the scaffold localizes at the membrane on both sides of the synaptic interface. We show that LGL has a cell autonomous presynaptic role facilitating NMJ terminal branching and synaptic bouton formation. Moreover, loss of both pre- and postsynaptic LGL strongly decreases evoked neurotransmission strength, whereas the frequency and amplitude of spontaneous synaptic vesicle fusion events is increased. Cell-targeted RNAi and rescue reveals separable pre- and postsynaptic LGL roles mediating neurotransmission. We show that presynaptic LGL facilitates the assembly of active zone vesicle fusion sites, and that neuronally targeted rescue of LGL is sufficient to ameliorate increased synaptic vesicle cycling imaged with FM1-43 dye labeling. Postsynaptically, we show that loss of LGL results in a net increase in total glutamate receptor (GluR) expression, associated with the selective elevation of GluRIIB subunit-containing receptors. Taken together, these data indicate that the presynaptic LGL scaffold facilitates the assembly of active zone fusion sites to regulate synaptic vesicle cycling, and that the postsynaptic LGL scaffold modulates glutamate receptor composition and function. PMID- 23444373 TI - SDF2L1 interacts with the ER-associated degradation machinery and retards the degradation of mutant proinsulin in pancreatic beta-cells. AB - Stromal cell-derived factor 2-like 1 (SDF2L1) is an endoplasmic reticulum (ER) localized protein whose function is undefined. Here we show that SDF2L1 protein levels are increased in response to ER stress-inducing compounds, but not other cell stressors that we tested in insulinoma cell lines. SDF2L1 protein levels were also induced by expression of misfolded proinsulin in insulinoma cells and in islets from diabetic mice. Immunoprecipitation and binding assays demonstrated that SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin. Unexpectedly, knockdown of SDF2L1 in INS-1 (insulin 2 C96Y-GFP) cells increased the degradation kinetics of mutant proinsulin, suggesting that SDF2L1 regulates substrate availability for the ERAD system. We suggest that SDF2L1 increases the time that misfolded proteins have to achieve a correctly folded conformation and thus that SDF2L1 can act as a buffer for substrate availability for ERAD in pancreatic beta cells. PMID- 23444372 TI - Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice. AB - A link between elevated luteinizing hormone (LH) levels, GATA-4 and LH receptor (LHCGR) expression and gonadotropin-dependent adrenocortical tumorigenesis in humans and mice has been shown. To assess the mechanistic tumorigenic interrelationships between these factors, we transgenically expressed Gata4 under the 21-hydroxylase promoter (Cyp21a1, 21-OH) in C57Bl/6N mice. There was a gradual age-dependent increase of GATA-4 expression only in 21-OH-GATA-4 (TG) female adrenals, in association with slowly progressing neoplasia of non steroidogenic spindle-shaped A cells in the subcapsular cortex. Gonadectomy (GDX), apparently through direct action of elevated serum LH, markedly enhanced the adrenocortical neoplasia, which now also appeared in GDX TG males. The neoplastic areas of the post-GDX TG adrenals contained, besides A cells, larger lipid-laden, steroidogenically active and LHCGR-positive B cells. Prolonged (>10 months) exposure to elevated post-GDX LH levels resulted in formation of adrenocortical adenomas in the TG mice. Intact and GDX TG mouse adrenals displayed elevated FOG-2 and decreased GATA-6 expression. Additionally, increased expression/activation of components of the Inhbb-Acvr2a-Acvr1c-Smad2/3 signaling system was observed in 12-month-old GDX TG adrenals. Our findings show that two distinct GATA-4-dependent populations of neoplastic adrenocortical cells form: non-steroidogenic LH-independent A cells and steroidogenic LH-dependent B cells. PMID- 23444374 TI - FHOD1 is a combined actin filament capping and bundling factor that selectively associates with actin arcs and stress fibers. AB - Formins are actin polymerization factors that are known to nucleate and elongate actin filaments at the barbed end. In the present study we show that human FHOD1 lacks actin nucleation and elongation capacity, but acts as an actin bundling factor with capping activity toward the filament barbed end. Constitutively active FHOD1 associates with actin filaments in filopodia and lamellipodia at the leading edge, where it moves with the actin retrograde flow. At the base of lamellipodia, FHOD1 is enriched in nascent, bundled actin arcs as well as in more mature stress fibers. This function requires actin-binding domains located N terminally to the canonical FH1-FH2 element. The bundling phenotype is maintained in the presence of tropomyosin, confirmed by electron microscopy showing assembly of 5 to 10 actin filaments into parallel, closely spaced filament bundles. Taken together, our data suggest a model in which FHOD1 stabilizes actin filaments by protecting barbed ends from depolymerization with its dimeric FH2 domain, whereas the region N-terminal to the FH1 domain mediates F-actin bundling by simultaneously binding to the sides of adjacent F-actin filaments. PMID- 23444375 TI - Overexpression of SETbeta, a protein localizing to centromeres, causes precocious separation of chromatids during the first meiosis of mouse oocytes. AB - Chromosome segregation in mammalian oocyte meiosis is an error-prone process, and any mistake in this process may result in aneuploidy, which is the main cause of infertility, abortion and many genetic diseases. It is now well known that shugoshin and protein phosphatase 2A (PP2A) play important roles in the protection of centromeric cohesion during the first meiosis. PP2A can antagonize the phosphorylation of rec8, a member of the cohesin complex, at the centromeres and thus prevent cleavage of rec8 and so maintain the cohesion of chromatids. SETbeta is a protein that physically interacts with shugoshin and inhibits PP2A activity. We thus hypothesized that SETbeta might regulate cohesion protection and chromosome segregation during oocyte meiotic maturation. Here we report for the first time the expression, subcellular localization and functions of SETbeta during mouse oocyte meiosis. Immunoblotting analysis showed that the expression level of SETbeta was stable from the germinal vesicle stage to the MII stage of oocyte meiosis. Immunofluorescence analysis showed SETbeta accumulation in the nucleus at the germinal vesicle stage, whereas it was targeted mainly to the inner centromere area and faintly localized to the interchromatid axes from germinal vesicle breakdown to MI stages. At the MII stage, SETbeta still localized to the inner centromere area, but could relocalize to kinetochores in a process perhaps dependent on the tension on the centromeres. SETbeta partly colocalized with PP2A at the inner centromere area. Overexpression of SETbeta in mouse oocytes caused precocious separation of sister chromatids, but depletion of SETbeta by RNAi showed little effects on the meiotic maturation process. Taken together, our results suggest that SETbeta, even though it localizes to centromeres, might not be essential for chromosome separation during mouse oocyte meiotic maturation, although its forced overexpression causes premature chromatid separation. PMID- 23444376 TI - Nck enables directional cell migration through the coordination of polarized membrane protrusion with adhesion dynamics. AB - Directional migration requires the coordination of cytoskeletal changes essential for cell polarization and adhesion turnover. Extracellular signals that alter tyrosine phosphorylation drive directional migration by inducing reorganization of the actin cytoskeleton. It is recognized that Nck is an important link between tyrosine phosphorylation and actin dynamics; however, the role of Nck in cytoskeletal remodeling during directional migration and the underlying molecular mechanisms remain largely undetermined. In this study, a combination of molecular genetics and quantitative live cell microscopy was used to show that Nck is essential in the establishment of front-back polarity and directional migration of endothelial cells. Time-lapse differential interference contrast and total internal reflection fluorescence microscopy showed that Nck couples the formation of polarized membrane protrusions with their stabilization through the assembly and maturation of cell-substratum adhesions. Measurements by atomic force microscopy showed that Nck also modulates integrin alpha5beta1-fibronectin adhesion force and cell stiffness. Fluorescence resonance energy transfer imaging revealed that Nck depletion results in delocalized and increased activity of Cdc42 and Rac. By contrast, the activity of RhoA and myosin II phosphorylation were reduced by Nck knockdown. Thus, this study identifies Nck as a key coordinator of cytoskeletal changes that enable cell polarization and directional migration, which are crucial processes in development and disease. PMID- 23444377 TI - Tumor suppressor p16(INK4a) inhibits cancer cell growth by downregulating eEF1A2 through a direct interaction. AB - The tumor suppressor protein p16(INK4a) is a member of the INK4 family of cyclin dependent kinase (Cdk) inhibitors, which are involved in the regulation of the eukaryotic cell cycle. However, the mechanisms underlying the anti-proliferative effects of p16(INK4a) have not been fully elucidated. Using yeast two-hybrid screening, we identified the eukaryotic elongation factor (eEF)1A2 as a novel interacting partner of p16(INK4a). eEF1A2 is thought to function as an oncogene in cancers. The p16(INK4a) protein interacted with all but the D2 (250-327 aa) domain of eEF1A2. Ectopic expression of p16(INK4a) decreased the expression of eEF1A2 and inhibited cancer cell growth. Furthermore, suppression of protein synthesis by expression of p16(INK4a) ex vivo was verified by luciferase reporter activity. Microinjection of p16(INK4a) mRNA into the cytoplasm of Xenopus embryos suppressed the luciferase mRNA translation, whereas the combination of p16(INK4a) and morpholino-eEF1A2 resulted in a further reduction in translational activity. We conclude that the interaction of p16(INK4a) with eEF1A2, and subsequent downregulation of the expression and function of eEF1A2 is a novel mechanism explaining the anti-proliferative effects of p16(INK4a). PMID- 23444378 TI - Multi-functional norrin is a ligand for the LGR4 receptor. AB - Mammalian LGR4, 5 and 6 are seven-transmembrane receptors that are important for diverse physiological processes. These receptors are orthologous to DLGR2, a Drosophila receptor activated by the burs/pburs heterodimer important for morphogenesis. Although recent studies indicated that four R-spondin proteins are cognate ligands for LGR4, 5 and 6 receptors, several BMP antagonists in vertebrates have been postulated to be orthologous to burs and pburs. Using newly available genome sequences, we showed that norrin is a vertebrate ortholog for insect burs and pburs and stimulates Wnt signaling mediated by LGR4, but not by LGR5 and 6, in mammalian cells. Although norrin could only activate LGR4, binding studies suggested interactions between norrin and LGR4, 5 and 6. Norrin, the Norrie disease gene product, is also capable of activating Wnt signaling mediated by the Frizzled4 receptor and serves as a BMP antagonist. Mutagenesis studies indicated that different norrin mutations found in patients with Norrie disease can be categorized into subgroups according to defects for signaling through the three distinct binding proteins. Thus, norrin is a rare ligand capable of binding three receptors/binding proteins that are important for BMP and Wnt signaling pathways. PMID- 23444379 TI - The muscle dystrophy-causing DeltaK32 lamin A/C mutant does not impair the functions of the nucleoplasmic lamin-A/C-LAP2alpha complex in mice. AB - A-type lamins are components of the nuclear lamina, a filamentous network of the nuclear envelope in metazoans that supports nuclear architecture. In addition, lamin A/C can also be found in the interior of the nucleus. This nucleoplasmic lamin pool is soluble in physiological buffer, depends on the presence of the lamin-binding protein, lamina-associated polypeptide 2alpha (LAP2alpha) and regulates cell cycle progression in tissue progenitor cells. DeltaK32 mutations in A-type lamins cause severe congenital muscle disease in humans and a muscle maturation defect in Lmna(DeltaK32/DeltaK32) knock-in mice. Mutant DeltaK32 lamin A/C protein levels were reduced and all mutant lamin A/C was soluble and mislocalized to the nucleoplasm. To test the role of LAP2alpha in nucleoplasmic DeltaK32 lamin A/C regulation and functions, we deleted LAP2alpha in Lmna(DeltaK32/DeltaK32) knock-in mice. In double mutant mice the Lmna(DeltaK32/DeltaK32)-linked muscle defect was unaffected. LAP2alpha interacted with mutant lamin A/C, but unlike wild-type lamin A/C, the intranuclear localization of DeltaK32 lamin A/C was not affected by loss of LAP2alpha. In contrast, loss of LAP2alpha in Lmna(DeltaK32/DeltaK32) mice impaired the regulation of tissue progenitor cells as in lamin A/C wild-type animals. These data indicate that a LAP2alpha-independent assembly defect of DeltaK32 lamin A/C is the predominant cause of the mouse pathology, whereas the LAP2alpha-linked functions of nucleoplasmic lamin A/C in the regulation of tissue progenitor cells are not affected in Lmna(DeltaK32/DeltaK32) mice. PMID- 23444380 TI - mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by myotonic dystrophy type 1. AB - Patients with myotonic dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among these are cognitive dysfunctions, the origin of which has remained elusive, partly because of the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos identified during a pre-implantation genetic diagnosis for mutant-gene carriers, to produce early neuronal cells. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, an RNA-binding protein whose function is defective in DM1 patients, resulted in alteration of mTOR signaling, whereas gain-of-function experiments rescued the phenotype. Collectively, these results provide a mechanism by which DM1 mutation might affect a major signaling pathway and highlight the pertinence of using pluripotent stem cells to study neuronal defects. PMID- 23444381 TI - Phosphorylation of the adaptor protein SH2B1beta regulates its ability to enhance growth hormone-dependent macrophage motility. AB - Previous studies have shown that growth hormone (GH) recruits the adapter protein SH2B1beta to the GH-activated, GH receptor-associated tyrosine kinase JAK2, implicating SH2B1beta in GH-dependent actin cytoskeleton remodeling, and suggesting that phosphorylation at serines 161 and 165 in SH2B1beta releases SH2B1beta from the plasma membrane. Here, we examined the role of SH2B1beta in GH regulation of macrophage migration. We show that GH stimulates migration of cultured RAW264.7 macrophages, and primary cultures of peritoneal and bone marrow derived macrophages. SH2B1beta overexpression enhances, whereas SH2B1 knockdown inhibits, GH-dependent motility of RAW macrophages. At least two independent mechanisms regulate the SH2B1beta-mediated changes in motility. In response to GH, tyrosines 439 and 494 in SH2B1beta are phosphorylated. Mutating these tyrosines in SH2B1beta decreases both basal and GH-stimulated macrophage migration. In addition, mutating the polybasic nuclear localization sequence (NLS) in SH2B1beta or creating the phosphomimetics SH2B1beta(S161E) or SH2B1beta(S165E), all of which release SH2B1beta from the plasma membrane, enhances macrophage motility. Conversely, SH2B1beta(S161/165A) exhibits increased localization at the plasma membrane and decreased macrophage migration. Mutating the NLS or the nearby serine residues does not alter GH-dependent phosphorylation on tyrosines 439 and 494 in SH2B1beta. Mutating tyrosines 439 and 494 does not affect localization of SH2B1beta at the plasma membrane or movement of SH2B1beta into focal adhesions. Taken together, these results suggest that SH2B1beta enhances GH-stimulated macrophage motility via mechanisms involving phosphorylation of SH2B1beta on tyrosines 439 and 494 and movement of SH2B1beta out of the plasma membrane (e.g. as a result of phosphorylation of serines 161 and 165). PMID- 23444382 TI - PTP1B promotes focal complex maturation, lamellar persistence and directional migration. AB - Previous findings established that ER-bound PTP1B targets peripheral cell-matrix adhesions and positively regulates cell adhesion to fibronectin. Here we show that PTP1B enhances focal complex lifetime at the lamellipodium base, delaying their turnover and facilitating alpha-actinin incorporation. We demonstrate the presence of catalytic PTP1BD181A-alpha-actinin complexes at focal complexes. Kymograph analysis revealed that PTP1B contributes to lamellar protrusion persistence and directional cell migration. Pull-down and FRET analysis also showed that PTP1B is required for efficient integrin-dependent downregulation of RhoA and upregulation of Rac1 during spreading. A substrate trap strategy revealed that FAK/Src recruitment and Src activity are essential for the generation of PTP1B substrates in adhesions. PTP1B targets the negative regulatory site of Src (phosphotyrosine 529), paxillin and p130Cas at peripheral cell-matrix adhesions. We postulate that PTP1B modulates more than one pathway required for focal complex maturation and membrane protrusion, including alpha actinin-mediated cytoskeletal anchorage, integrin-dependent activation of the FAK/Src signaling pathway, and RhoA and Rac1 GTPase activity. By doing so, PTP1B contributes to coordinated adhesion turnover, lamellar stability and directional cell migration. PMID- 23444383 TI - Doa4 function in ILV budding is restricted through its interaction with the Vps20 subunit of ESCRT-III. AB - Assembly of the endosomal sorting complex required for transport (ESCRT)-III executes the formation of intralumenal vesicles (ILVs) at endosomes. Repeated cycles of ESCRT-III function requires disassembly of the complex by Vps4, an ATPase with a microtubule interaction and trafficking (MIT) domain that binds MIT interacting motifs (MIM1 or MIM2) in ESCRT-III subunits. We identified a putative MIT domain at the N-terminus of Doa4, which is the ubiquitin (Ub) hydrolase in Saccharomyces cerevisiae that deubiquitinates ILV cargo proteins. The Doa4 N terminus is predicted to have the alpha-helical structure common to MIT domains, and it binds directly to a MIM1-like sequence in the Vps20 subunit of ESCRT-III. Disrupting this interaction does not prevent endosomal localization of Doa4 but enhances the defect in ILV cargo protein deubiquitination observed in cells lacking Bro1, which is an ESCRT-III effector protein that stimulates Doa4 catalytic activity. Deletion of the BRO1 gene (bro1Delta) blocks ILV budding, but ILV budding was rescued upon disrupting the interaction between Vps20 and Doa4. This rescue in ILV biogenesis requires Doa4 expression but is independent of its Ub hydrolase activity. Thus, binding of Vps20 to the Doa4 N-terminus inhibits a non-catalytic function of Doa4 that promotes ILV formation. PMID- 23444384 TI - Six1 regulates proliferation of Pax7-positive muscle progenitors in zebrafish. AB - In the embryonic zebrafish, skeletal muscle fibres are formed from muscle progenitors in the paraxial mesoderm. The embryonic myotome is mostly constituted of fast-twitch-specific fibres, which are formed from a fast-specific progenitor cell pool. The most lateral fraction of the fast domain in the myotome of zebrafish embryos derives from the Pax7-positive dermomyotome-like cells. In this study, we show that two genes, belonging to the sine oculus class 1 (six1) genes (six1a and six1b), are both essential for the regulation of Pax7(+) cell proliferation and, consequently, in their differentiation during the establishment of the zebrafish dermomyotome. In both six1a and six1b morphant embryos, Pax7(+) cells are initially formed but fail to proliferate, as detected by reduced levels of the proliferation marker phosphohistone3 and reduced brdU incorporation. In congruence, overexpression of six1a or six1b leads to increased Pax7(+) cell number and reduced or alternatively delayed fibre cell differentiation. Bone morphogenetic protein signalling has previously been suggested to inhibit differentiation of Pax7(+) cells in the dermomyotome. Here we show that the remaining Pax7(+) cells in six1a and six1b morphant embryos also have significantly reduced pSmad1/5/8 levels and propose that this leads to a reduced proliferative activity, which may result in a premature differentiation of Pax7(+) cells in the zebrafish dermomyotome. In summary, we show a mechanism for Six1a and Six1b in establishing the Pax7(+) cell derived part of the fast muscle and suggest new important roles for Six1 in the regulation of the Pax7(+) muscle cell population through pSmad1/5/8 signalling. PMID- 23444385 TI - SQL-1, homologue of the Golgi protein GMAP210, modulates intraflagellar transport in C. elegans. AB - Primary cilia are microtubule-based organelles that have important sensory functions. For their function, cilia rely on the delivery of specific proteins, both by intracellular trafficking and intraflagellar transport (IFT). In the cilia of Caenorhabditis elegans, anterograde IFT is mediated by kinesin-II and OSM-3. Previously, we have shown that expression of a dominant active G protein alpha subunit (GPA-3QL) in amphid channel neurons affects the coordination of kinesin-II and OSM-3 and also affects cilia length, suggesting that environmental signals can modulate these processes. Here, we show that loss-of-function of sql 1 (suppressor of gpa-3QL 1), which encodes the homologue of the mammalian Golgi protein GMAP210, suppresses the gpa-3QL cilia length phenotype. SQL-1 localizes to the Golgi apparatus, where it contributes to maintaining Golgi organization. Loss of sql-1 by itself does not affect cilia length, whereas overexpression of sql-1 results in longer cilia. Using live imaging of fluorescently tagged IFT proteins, we show that in sql-1 mutants OSM-3 moves faster, kinesin-II moves slower and that some complex A and B proteins move at an intermediate velocity, while others move at the same velocity as OSM-3. This indicates that mutation of sql-1 destabilizes the IFT complex. Finally, we show that simultaneous inactivation of sql-1 and activation of gpa-3QL affects the velocity of OSM-3. In summary, we show that in C. elegans the Golgin protein SQL-1 plays an important role in maintaining the stability of the IFT complex. PMID- 23444387 TI - Significance of reductive metabolism in human intestine and quantitative prediction of intestinal first-pass metabolism by cytosolic reductive enzymes. AB - The number of new drug candidates that are cleared via non-cytochrome P450 (P450) enzymes has increased. However, unlike oxidation by P450, the roles of reductive enzymes are less understood. The metabolism in intestine is especially not well known. The purposes of this study were to investigate the significance of reductive metabolism in human intestine, and to establish a quantitative prediction method of intestinal first-pass metabolism by cytosolic reductive enzymes, using haloperidol, mebendazole, and ziprasidone. First, we estimated the metabolic activities for these compounds in intestine and liver using subcellular fractions. Metabolic activities were detected in human intestinal cytosol (HIC) for all three compounds, and the intrinsic clearance values were higher than those in human liver cytosol for haloperidol and mebendazole. These metabolic activities in HIC were NADPH- and/or NADH-dependent. Furthermore, the metabolic activities for all three compounds in HIC were largely inhibited by menadione, which has been used as a carbonyl reductase (CBR)-selective chemical inhibitor. Therefore, considering subcellular location, cofactor requirement, and chemical inhibition, these compounds might be metabolized by CBRs in human intestine. Subsequently, we tried to quantitatively predict intestinal availability (F(g)) for these compounds using human intestinal S9 (HIS9). Our prediction model using apparent permeability of parallel artificial membrane permeability assay and metabolic activities in HIS9 could predict F(g) in humans for the three compounds well. In conclusion, CBRs might have higher metabolic activities in human intestine than in human liver. Furthermore, our prediction method of human F(g) using HIS9 is applicable to substrates of cytosolic reductive enzymes. PMID- 23444386 TI - Modification of the catalytic function of human hydroxysteroid sulfotransferase hSULT2A1 by formation of disulfide bonds. AB - The human cytosolic sulfotransferase hSULT2A1 catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1' azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. PMID- 23444389 TI - Increased glucagon-like peptide-1 secretion may be involved in antidiabetic effects of ginsenosides. AB - Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in P. ginseng, have shown good antidiabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its antidiabetic effects via modulating GLP1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 or 300 mg/kg) daily for 4 weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase in glucose-induced GLP1 secretion and upregulation of proglucagon gene expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca2+ concentration. The metabolic inhibitor azide (3 mM), the KATP channel opener diazoxide (340 MUM), and the Ca2+ channel blocker nifedipine (20 MUM) significantly reversed Rb1-mediated GLP1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP1 secretion both in vivo and in vitro. The antidiabetic effects of ginsenosides may be a result of enhanced GLP1 secretion. PMID- 23444388 TI - Acute psychological stress results in the rapid development of insulin resistance. AB - In recent years, the roles of chronic stress and depression as independent risk factors for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding of the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES) followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared with normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue, and brain. Additionally, a rise in the murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism. PMID- 23444391 TI - Transfer of contextual cueing in full-icon display remapping. AB - Invariant spatial context can expedite visual search, an effect that is known as contextual cueing (e.g., Chun & Jiang, 1998). However, disrupting learned display configurations abolishes the effect. In current touch-based mobile devices, such as the iPad, icons are shuffled and remapped when the display mode is changed. However, such remapping also disrupts the spatial relationships between icons. This may hamper usability. In the present study, we examined the transfer of contextual cueing in four different methods of display remapping: position-order invariant, global rotation, local invariant, and central invariant. We used full icon landscape mode for training and both landscape and portrait modes for testing, to check whether the cueing transfers to portrait mode. The results showed transfer of contextual cueing but only with the local invariant and the central invariant remapping methods. We take the results to mean that the predictability of target locations is a crucial factor for the transfer of contextual cueing and thus icon remapping design for mobile devices. PMID- 23444390 TI - Where do we store the memory representations that guide attention? AB - During the last decade one of the most contentious and heavily studied topics in the attention literature has been the role that working memory representations play in controlling perceptual selection. The hypothesis has been advanced that to have attention select a certain perceptual input from the environment, we only need to represent that item in working memory. Here we summarize the work indicating that the relationship between what representations are maintained in working memory and what perceptual inputs are selected is not so simple. First, it appears that attentional selection is also determined by high-level task goals that mediate the relationship between working memory storage and attentional selection. Second, much of the recent work from our laboratory has focused on the role of long-term memory in controlling attentional selection. We review recent evidence supporting the proposal that working memory representations are critical during the initial configuration of attentional control settings, but that after those settings are established long-term memory representations play an important role in controlling which perceptual inputs are selected by mechanisms of attention. PMID- 23444392 TI - Priming of fixations during recognition of natural scenes. AB - Eye fixations allow the human viewer to perceive scene content with high acuity. If fixations drive visual memory for scenes, a viewer might repeat his/her previous fixation pattern during recognition of a familiar scene. However, visual salience alone could account for similarities between two successive fixation patterns by attracting the eyes in a stimulus-driven, task-independent manner. In the present study, we tested whether the viewer's aim to recognize a scene fosters fixations on scene content that repeats from learning to recognition as compared to the influence of visual salience alone. In Experiment 1 we compared the gaze behavior in a recognition task to that in a free-viewing task. By showing the same stimuli in both tasks, the task-independent influence of salience was held constant. We found that during a recognition task, but not during (repeated) free viewing, viewers showed a pronounced preference for previously fixated scene content. In Experiment 2 we tested whether participants remembered visual input that they fixated during learning better than salient but nonfixated visual input. To that end we presented participants with smaller cutouts from learned and new scenes. We found that cutouts featuring scene content fixated during encoding were recognized better and faster than cutouts featuring nonfixated but highly salient scene content from learned scenes. Both experiments supported the hypothesis that fixations during encoding and maybe during recognition serve visual memory over and above a stimulus-driven influence of visual salience. PMID- 23444393 TI - BJSM social media contributes to health policy rethink: a physical activity success story in Hertfordshire. AB - Strategies to modernise the National Health Service (NHS) in England have brought about the development of local organisations called Health and Wellbeing (H&WB) boards through the Health and Social Care Act 2012. These boards were intended to become a forum where key leaders and stakeholders from health and care systems work together to improve the health and well-being of their local population and reduce health inequalities. Throughout England these boards have been drafting their strategies, largely ignoring the importance of physical activity in health and well-being. In the county of Hertfordshire, the initial draft priorities were released in 2012 and physical activity promotion was not included. Using a BJSM blog, BJSM online poll, Twitter and email, an attempt was made to generate as much interest and formal feedback as possible to the draft strategy, in order to ensure the inclusion of physical activity as a priority in the revised strategy. PMID- 23444394 TI - Knowledge translation in sport injury prevention research: an example in youth ice hockey in Canada. PMID- 23444395 TI - Novel genetic markers improve measures of atrial fibrillation risk prediction. AB - AIMS: Atrial fibrillation (AF) is associated with adverse outcome. Whether recently discovered genetic risk markers improve AF risk prediction is unknown. METHODS AND RESULTS: We derived and validated a novel AF risk prediction model from 32 possible predictors in the Women's Health Study (WHS), a cohort of 20 822 women without cardiovascular disease (CVD) at baseline followed prospectively for incident AF (median: 14.5 years). We then created a genetic risk score (GRS) comprised of 12 risk alleles in nine loci and assessed model performance in the validation cohort with and without the GRS. The newly derived WHS AF risk algorithm included terms for age, weight, height, systolic blood pressure, alcohol use, and smoking (current and past). In the validation cohort, this model was well calibrated with good discrimination [C-index (95% CI) = 0.718 (0.684 0.753)] and improved all reclassification indices when compared with age alone. The addition of the genetic score to the WHS AF risk algorithm model improved the C-index [0.741 (0.709-0.774); P = 0.001], the category-less net reclassification [0.490 (0.301-0.670); P < 0.0001], and the integrated discrimination improvement [0.00526 (0.0033-0.0076); P < 0.0001]. However, there was no improvement in net reclassification into 10-year risk categories of <1, 1-5, and 5+% [0.041 (-0.044 0.12); P = 0.33]. CONCLUSION: Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF. The addition of genetic information resulted in modest improvements in predictive accuracy that did not translate into improved reclassification into discrete AF risk categories. PMID- 23444396 TI - Optical coherence tomography to reveal strut malapposition due to thrombus resolution 3 weeks after acute coronary syndrome. PMID- 23444398 TI - The difficult search for a 'partner' of statins in lipid-targeted prevention of vascular events: the re-emergence and fall of niacin. PMID- 23444397 TI - HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. AB - AIMS: Niacin has potentially favourable effects on lipids, but its effect on cardiovascular outcomes is uncertain. HPS2-THRIVE is a large randomized trial assessing the effects of extended release (ER) niacin in patients at high risk of vascular events. METHODS AND RESULTS: Prior to randomization, 42 424 patients with occlusive arterial disease were given simvastatin 40 mg plus, if required, ezetimibe 10 mg daily to standardize their low-density lipoprotein (LDL)-lowering therapy. The ability to remain compliant with ER niacin 2 g plus laropiprant 40 mg daily (ERN/LRPT) for ~1 month was then assessed in 38 369 patients and about one-third were excluded (mainly due to niacin side effects). A total of 25 673 patients were randomized between ERN/LRPT daily vs. placebo and were followed for a median of 3.9 years. By the end of the study, 25% of participants allocated ERN/LRPT vs. 17% allocated placebo had stopped their study treatment. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetes, and musculoskeletal side effects. When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy [75 (0.16%/year) vs. 17 (0.04%/year): risk ratio 4.4; 95% CI 2.6-7.5; P < 0.0001]; 7 vs. 5 were rhabdomyolysis. Any myopathy (definite or incipient) was more common among participants in China [138 (0.66%/year) vs. 27 (0.13%/year)] than among those in Europe [17 (0.07%/year) vs. 11 (0.04%/year)]. Consecutive alanine transaminase >3* upper limit of normal, in the absence of muscle damage, was seen in 48 (0.10%/year) ERN/LRPT vs. 30 (0.06%/year) placebo allocated participants. CONCLUSION: The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ~1 month, three-quarters continued to take it for ~4 years. PMID- 23444399 TI - Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. AB - Protocols to use Foxp3+ T-regulatory (Treg) cells for cellular therapy, especially postallogeneic stem cell transplantation, are currently being developed and tested by various groups. Inhibitors of DNA methyltransferase (Dnmt) enzymes have been advocated as a means to promote and stabilize Foxp3 expression in Tregs undergoing expansion in vitro before their injection in vivo. We investigated the effects of conditionally deleting two Dnmt enzymes that co immunoprecipitated with Foxp3 in Treg isolates. Deletion of Dnmt1, but not Dnmt3a, decreased the numbers and function of peripheral Tregs and impaired conversion of conventional T cells into Foxp3+ Tregs under polarizing conditions. Importantly, mice with conditional deletion of Dnmt1 in their Tregs died of autoimmunity by 3 to 4 weeks of age unless they were rescued by perinatal transfer of wild-type Tregs. Conditional Dnmt1 deletion did not affect methylation of CpG sites within Foxp3 but decreased global DNA methylation and altered Treg expression of several hundred pro-inflammatory and other genes. Hence, Dnmt1 is necessary for maintenance of the core gene program underlying Treg development and function, and its deletion within the Treg lineage leads to lethal autoimmunity. These data suggest that caution may be warranted when considering the use of DNMT inhibitors in development of Treg-based cellular therapies. PMID- 23444400 TI - EB1, p150Glued, and Clasp1 control endothelial tubulogenesis through microtubule assembly, acetylation, and apical polarization. AB - Vascular tube morphogenesis requires the establishment of endothelial cell (EC) apical-basal polarity in three-dimensional (3D) extracellular matrices. To date, there is little understanding of how EC polarity is controlled during these highly dynamic and rapid morphogenic events. We show that the microtubule tip complex proteins, end binding 1 (EB1), p150(Glued), and Clasp1, control human EC tube formation by (1) inducing microtubule assembly and asymmetric cytoskeletal polarization, whereby acetylated and detyrosinated tubulins distribute in a subapical membrane location and filamentous actin distributes basally; (2) increasing tubulin posttranslational modifications, including required acetylation events; and (3) regulating an EC lumen signaling cascade that involves membrane type 1 matrix metallopatrinase (MT1-MMP)-dependent proteolysis as well as Pak, Raf, and Erk kinases. Another regulator of this process is the microtubule stabilizing protein, tau, which binds p150(Glued) and similarly affects EC lumen formation by controlling the levels of acetylated and detyrosinated tubulins. Increased expression of the tubulin deacetylases, sirtuin 2, and histone deacetylase 6 (HDAC6), blocks EC tube formation and cytoskeletal polarization, while siRNA suppression of these deacetylases stimulates these events. Overall, this work reveals a fundamental role for microtubule tip complex proteins in coordinating microtubule assembly, posttranslational modifications including acetylation, and apical-basal cytoskeletal polarization to control the developing apical membrane surface during blood vessel tubulogenesis in 3D matrix environments. PMID- 23444402 TI - PDK1 regulates platelet activation and arterial thrombosis. AB - The effects of phosphoinositide-dependent protein kinase 1 (PDK1), a master kinase in the phosphoinositide 3-kinase/Akt pathway, on platelet activation are unknown. Accordingly, platelet-specific PDK1-deficient mice were characterized to elucidate the platelet-related function(s) of PDK1. We found that PDK1 deficiency caused mild thrombocytopenia. The aggregation of PDK1(-/-) platelets was diminished in response to low levels of thrombin, U46619, and adenosine 5' diphosphate. Further results demonstrated that PDK1 regulates thrombin-induced platelet activation by affecting alphaIIbbeta3-mediated outside-in signaling. This result provided an explanation for the diminished spreading of PDK1(-/-) platelets on immobilized fibrinogen (Fg) and the decreased rate of clot retraction in platelet-rich plasma (PRP) containing PDK1(-/-) platelets. PDK1 deficiency diminished agonist-induced Akt Ser473 phosphorylation and thoroughly abolished Akt Thr308 and Gsk3beta Ser9 phosphorylation in response to agonist treatment and platelet spreading, respectively. A Gsk3beta inhibitor fully restored the aggregation of PDK1(-/-) platelets in response to low levels of thrombin, normal spreading of PDK1(-/-) platelets on Fg, and normal clot retraction in PRP containing PDK1(-/-) platelets. Those results indicated that Gsk3beta is one of the major downstream effectors of PDK1 in thrombin-induced platelet activation and alphaIIbbeta3-mediated outside-in signaling. In addition, in vivo data demonstrated that PDK1 is an important regulator in arterial thrombosis formation. PMID- 23444401 TI - Mi2beta-mediated silencing of the fetal gamma-globin gene in adult erythroid cells. AB - An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate beta-type globin gene disorders such as sickle cell anemia and beta-thalassemia through activation of the fetal gamma-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in gamma-globin gene silencing, and Mi2beta (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2beta relieves gamma-globin gene silencing in beta-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2beta binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for gamma-globin gene silencing during beta-type globin gene switching. Remarkably, <50% knockdown of Mi2beta is sufficient to significantly induce gamma-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2beta is a potential target for therapeutic induction of fetal hemoglobin. PMID- 23444403 TI - Galectin-1 serum levels reflect tumor burden and adverse clinical features in classical Hodgkin lymphoma. AB - Galectin-1 (Gal1) is a member of a highly conserved family of carbohydrate binding proteins. It modulates innate and adaptive immune responses and fosters tumor-immune escape. Hodgkin lymphoma (HL) Reed-Sternberg cells overexpress and secrete Gal1, which selectively kills T helper (Th)1 and Th17 cells and cytotoxic T cells and promotes the immunosuppressive Th2/regulatory T-cell-predominant HL microenvironment. We developed a sandwich enzyme-linked immunosorbent assay and assessed serum Gal1 levels in 293 newly diagnosed, previously untreated patients with classical HL (cHL) enrolled in 3 risk-adapted clinical trials. Serum Gal1 levels were significantly higher in patients with cHL than in normal controls (P < .0001). Gal1 serum levels also increased with Ann Arbor stage (P = .012), areas of nodal involvement (P < .0001), and the International Prognostic Score (2-7, P = .019). We conclude that Gal1 serum levels are significantly associated with tumor burden and related clinical features in newly diagnosed cHL patients. PMID- 23444405 TI - Erk1 and Erk2 are required for maintenance of hematopoietic stem cells and adult hematopoiesis. AB - Extracellular signal-regulated kinase 1 (Erk1) and Erk2 play crucial roles in cell survival, proliferation, cell adhesion, migration, and differentiation in many tissues. Here, we report that the absence of Erk1 and Erk2 in murine hematopoietic cells leads to bone marrow aplasia, leukopenia, anemia, and early lethality. Mice doubly-deficient in Erk1 and Erk2 show rapid attrition of hematopoietic stem cells and immature progenitors in a cell-autonomous manner. Reconstitution studies show that Erk1 and Erk2 play redundant and kinase dependent functions in hematopoietic progenitor cells. Moreover, in cells transformed by the oncogenic KRas(G12D) allele, the presence of either Erk1 or Erk2 with intact kinase activity is sufficient to promote cytokine-independent proliferation. PMID- 23444404 TI - Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL 10, B7-H1, and regulatory T-cell induction. AB - Mammalian target of rapamycin (mTOR) is an important, yet poorly understood integrative kinase that regulates immune cell function. mTOR functions in 2 independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant rapamycin (RAPA) inhibits mTORC1 but not mTORC2 and causes a paradoxical reduction in anti-inflammatory interleukin (IL) 10 and B7-homolog 1 (B7-H1) expression by dendritic cells (DCs). Using catalytic mTOR inhibitors and DCs lacking mTORC2, we show that restraint of signal transducer and activator of transcription 3-mediated IL-10 and B7-H1 expression during DC maturation involves a RAPA-insensitive and mTORC2-independent mTOR mechanism. Relatedly, catalytic mTOR inhibition promotes B7-H1-dependent and IL-1beta-dependent DC induction of regulatory T cells (Tregs). Thus, we define an immunoregulatory pathway in which RAPA-sensitive mTORC1 in DCs promotes effector T-cell expansion and RAPA insensitive mTORC1 restrains T(reg) induction. These findings identify the first known RAPA-insensitive mTOR pathway that is not mediated solely by mTORC2 and have implications for the use of catalytic mTOR inhibitors in inflammatory disease settings. PMID- 23444406 TI - Circulatory support in elderly chronic heart failure patients using the CircuLite(r) Synergy(r) system. AB - OBJECTIVE: The Synergy((r)) system, a miniature partial circulatory support device, is implanted with an off-pump, minimally invasive surgical approach. In our experience, implantation of this system is associated with fewer perioperative adverse events than current full support devices. This approach therefore offers the possibility of treating elderly chronic heart-failure patients who might not ordinarily be considered for long-term circulatory support. METHODS: A total of 54 patients (12 patients >= 70 years) were implanted with the Synergy system in an off-pump minithoracotomy procedure. Mean age (54 +/ 10 vs 73 +/- 3), body surface area (1.9 +/- 0.2 vs 1.7 +/- 0.1), blood urea nitrogen (BUN) (59 +/- 33 vs 91 +/- 38), estimated glomerular filtration rate (eGFR) (71 +/- 23 vs 50 +/- 38) and haemoglobin (12.6 +/- 1.9 vs 11.3 +/- 1.3) differed significantly between young and old. RESULTS: Older patients had longer mean durations of support (337 vs 188 days). On average, both groups showed similar improvements (changes from baseline) in haemodynamics (pulmonary capillary wedge pressure -9 +/- 16 vs -10 +/- 8 mmHg; CO +1.0 +/- 0.7 vs 0.9 +/- 1.0 l/min, periferical vascular resistance (PVR) -1.2 +/- 1.5 vs = 0.8 +/- 1.7 Wood) and 6 min walk (107 +/- 120 vs 130 +/- 121 m). Older patients showed less improvement in peak VO2 (0.5 +/- 2.9 vs 1.9 +/- 3.0 ml/kg/min). Major adverse events (old vs young) between groups included major bleeding (75 vs 38%), infection (25 vs 38%), renal dysfunction (0 vs 17%) and device-related stroke (8 vs 10%). Mortality rate was 20% for the young and 40% for the elderly. CONCLUSIONS: Older patients implanted with Synergy had smaller body sizes and worse renal function than younger patients. Both groups experienced similar haemodynamic benefits and functional improvements, though peak VO2 is less improved in the elderly. Risks of bleeding and renal dysfunction appear to be increased in the elderly, though still within acceptable ranges compared with other full support devices. Minimally invasive long-term circulatory support devices, like Synergy, offer a new treatment option to the elderly chronic heart failure population. PMID- 23444407 TI - Hybrid revascularization in multivessel coronary artery disease. AB - OBJECTIVES: Minimally invasive hybrid revascularization (MIHR) by means of the left mammary artery on the left anterior descending artery [minimally invasive direct coronary artery bypass (MIDCAB)] combined with percutaneous coronary interventions (PCI) stenting may be an alternative to conventional coronary artery bypass grafting through sternotomy or multiple PCI. The purpose of this study is to retrospectively evaluate the long-term outcomes of this strategy. METHODS: Since May 1997 up to January 2011, 810 MIDCAB have been performed as isolated revascularization in 644 patients. Since 2004, MIDCAB, as a part of hybrid revascularization, was associated with PCI in 166 patients. RESULTS: In the MIDCAB group, mean age was 64.6 +/- 12.0, with 83.8% males. Two-vessel disease was 62.4%, three-vessel disease 37.6%. Overall mortality was 0.24%, perioperative acute myocardial infarction-1.6%, early reoperation-0.74%, reopening for bleeding-1.2%, case rate of haemotrasfusion-3.1%, with a mean hospital postoperative stay of 4 +/- 2.5 days. Postoperative angiographic control prior to PCI and in symptomatic patients showed patent left internal mammary artery in 100% of cases. PCI was performed in 166 patients, 64.2% before MIDCAB and 35.8% after surgery (interval 2.2 +/- 1.3 months). The mean follow-up in the MIDCAB group was 8.4 +/- 3.2 years. In the MIHR group, at the mean follow-up of 4.5 +/- 2.3 years, freedom from related cardiac death was 93% with freedom from cardiac reintervention of 83%. CONCLUSIONS: Our 13-year experience with MIDCAB demonstrates that the operation is safe and associated with a very low incidence of early and late complications. The hybrid approach provided excellent long-term outcome in terms of freedom from cardiac death and reoperation. Accurate patient selection, as well the timing of the hybrid procedure, is mandatory to optimize surgical and PCI results. PMID- 23444408 TI - Clinical registries: yes, but then appropriately! PMID- 23444409 TI - End-stage heart failure in children or patients suffering from congenital heart disease: are new treatment options emerging? PMID- 23444410 TI - Early and late outcome after surgical treatment of acquired non-malignant tracheo oesophageal fistulae. AB - OBJECTIVES: Tracheo-oesophageal fistula (TOF) is a rare, life-threatening condition. We report our results of surgical treatment and evaluation of the outcome of acquired non-malignant TOF. METHODS: Twenty-five patients (aged 49 +/- 21 years) with TOF were operated on between 2001 and 2011. Tracheo-oesophageal fistula was due to prolonged intubation/tracheostomy (84%), was secondary to other surgery (8%) or trauma (4%) or was idiopathic (4%). The tracheal defect was 2.4 +/- 1.3 cm long and was associated with tracheal stenosis in seven (28%) patients. Surgical treatment consisted of direct suturing of the oesophageal defect in two layers (or end-to-end oesophageal resection and anastomosis in one case) associated with tracheal suturing (n = 15; 60%), tracheal resection and anastomosis (n = 8; 32%) or covering of a large tracheal defect by an intercostal muscle flap or by a resorbable patch with muscle apposition (n = 2; 8%). The surgical approach was cervicotomy (n = 14; 56%), cervicotomy plus median sternotomy or split (n = 6; 24%), thoracotomy (n = 4; 16%) or cervicotomy plus sternal spit plus thoracotomy (n = 1; 4%). In 18 (72%) cases a muscular flap was used and in six (24%) a protective tracheostomy was performed. RESULTS: No perioperative deaths occurred. Morbidity occurred in eight (32%) patients; none of them required a second surgical look. At median follow-up of 41 months, the outcome was excellent or good for 22 patients (88%), two (8%) are still dependent on jejunostomy and tracheostomy for neurological diseases and one (4%) is under mechanical ventilation for end-stage respiratory failure. CONCLUSIONS: Surgical treatment of TOF is associated with good results in terms of control of acute symptoms and long-term outcome, particularly concerning oral intake and spontaneous breathing. PMID- 23444411 TI - Giant oesophageal polyp prolapse. PMID- 23444412 TI - A direct comparison of quality of life in obese and Cushing's syndrome patients. AB - OBJECTIVE: Obese (OB) individuals and patients with Cushing's syndrome (CS) often have similar clinical presentations. While each group has reduced health-related quality of life (HRQL), it is not known whether the degree of impairment is different and might distinguish between them. The objective of this study was to compare HRQL in these two populations. DESIGN: Cross-sectional study. METHODS: Three hundred and twenty-seven OB patients (48.1+/-11.7 years; 72.5% women) with weight gain and at least two features of CS were recruited from an outpatient weight management clinic. Sixty-six untreated patients with CS (41.6+/-13.2 years; 78.8% women) presented to the NIH Clinical Center for evaluation. Subjects completed the SF-36 survey and a locally created symptom questionnaire. RESULTS: After adjusting for symptom count, OB patients had a significantly higher (better HRQL) mean physical component summary (PCS) score than CS patients (44.9+/-0.6 vs 35.4+/-1.5, P<0.0001). However, the mean mental component summary (MCS) score was lower (worse HRQL) in the OB group (41.6+/-0.6 vs 50.7+/-1.6, P<0.0001). Symptom count showed significant correlations with PCS and MCS scores. BMI correlated with PCS (r=-0.29) in OB but not in CS patients. BMI was not associated with MCS in either group. CONCLUSION: HRQL is significantly different between OB and CS patients. Surprisingly, after adjusting for symptom count, OB patients showed worse mental health scores than the CS population. Significant differences in HRQL and symptom count may suggest which OB patients should be screened for CS. PMID- 23444413 TI - Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition. AB - BACKGROUND: Placental transport of iodide is required for fetal thyroid hormone production. The sodium iodide symporter (NIS) mediates active iodide transport into the thyroid and the lactating mammary gland and is also present in placenta. NIS is competitively inhibited by thiocyanate from maternal smoking, but compensatory autoregulation of iodide transport differs between organs. The extent of autoregulation of placental iodide transport remains to be clarified. OBJECTIVE: To compare the impact of maternal smoking on thyroglobulin (Tg) levels in maternal serum at delivery and in cord serum as markers of maternal and fetal iodine deficiency. METHODS: One hundred and forty healthy, pregnant women admitted for delivery and their newborns were studied before the iodine fortification of salt in Denmark. Cotinine in urine and serum classified mothers as smokers (n=50) or nonsmokers (n=90). The pregnant women reported on intake of iodine-containing supplements during pregnancy and Tg in maternal serum at delivery and in cord serum were analyzed. RESULTS: In a context of mild-to moderate iodine deficiency, smoking mothers had significantly higher serum Tg than nonsmoking mothers (mean Tg smokers 40.2 vs nonsmokers 24.4 MUg/l, P=0.004) and so had their respective newborns (cord Tg 80.2 vs 52.4 MUg/l, P=0.006), but the ratio between Tg in cord serum and maternal serum was not significantly different in smokers compared with nonsmokers (smoking 2.06 vs nonsmoking 2.22, P=0.69). CONCLUSION: Maternal smoking increased the degree of iodine deficiency in parallel in the mother and the fetus, as reflected by increased Tg levels. However, placental iodide transport seemed unaffected despite high thiocyanate levels, suggesting that thiocyanate-insensitive iodide transporters alternative to NIS are active or that NIS in the placenta is autoregulated to keep iodide transport unaltered. PMID- 23444414 TI - Overdiagnosis in screening mammography in Denmark: population based cohort study. AB - OBJECTIVE: To use data from two longstanding, population based screening programmes to study overdiagnosis in screening mammography. DESIGN: Population based cohort study. SETTING: Copenhagen municipality (from 1991) and Funen County (from 1993), Denmark. PARTICIPANTS: 57,763 women targeted by organised screening, aged 56-69 when the screening programmes started, and followed up to 2009. MAIN OUTCOME MEASURES: Overdiagnosis of breast cancer in women targeted by screening, assessed by relative risks compared with historical control groups from screening regions, national control groups from non-screening regions, and historical national control groups. RESULTS: In total, 3279 invasive breast carcinomas and ductal carcinomas in situ occurred. The start of screening led to prevalence peaks in breast cancer incidence: relative risk 2.06 (95% confidence interval 1.64 to 2.59) for Copenhagen and 1.84 (1.46 to 2.32) for Funen. During subsequent screening rounds, relative risks were slightly above unity: 1.04 (0.85 to 1.27) for Copenhagen and 1.14 (0.98 to 1.32) for Funen. A compensatory dip was seen after the end of invitation to screening: relative risk 0.80 (0.65 to 0.98) for Copenhagen and 0.67 (0.55 to 0.81) for Funen during the first four years. The relative risk of breast cancer accumulated over the entire follow-up period was 1.06 (0.90 to 1.25) for Copenhagen and 1.01 (0.93 to 1.10) for Funen. Relative risks for participants corrected for selection bias were estimated to be 1.08 for Copenhagen and 1.02 for Funen; for participants followed for at least eight years after the end of screening, they were 1.05 and 1.01. A pooled estimate gave 1.040 (0.99 to 1.09) for all targeted women and 1.023 (0.97 to 1.08) for targeted women followed for at least eight years after the end of screening. CONCLUSIONS: On the basis of combined data from the two screening programmes, this study indicated that overdiagnosis most likely amounted to 2.3% (95% confidence interval -3% to 8%) in targeted women. Among participants, it was most likely 1-5%. At least eight years after the end of screening were needed to compensate for the excess incidence during screening. PMID- 23444415 TI - Bad medicine: antenatal screening. PMID- 23444416 TI - Sudanese doctors' role in judicial amputation "breaks medical ethics". PMID- 23444417 TI - Sedative prescribing among older people doubles with move into residential care, finds study. PMID- 23444418 TI - Research council failed to clearly communicate its open access policy, say peers. PMID- 23444419 TI - GMC is to get legal power to check English skills of European doctors. PMID- 23444420 TI - Femoral nerve blocks in fractures of femur: variation in the current UK practice and a review of the literature. AB - Fractures of the femur are common orthopaedic emergencies presenting to emergency departments (ED). Femoral nerve block (FNB) is a fast, safe and effective means of providing pain relief to these patients. With the aim to analysing the variation in current practice of giving FNB in patients with fractured femur in the UK, we carried out a telephonic national survey. Out of 252 EDs contacted, 230 departments participated in the survey (91% response rate). The survey showed that 74% EDs in the UK had access to ultrasound, but only 10% EDs gave FNB regularly under ultrasound guidance. In total, 46% of EDs gave FNB by blind technique. Therefore, ultrasound-guided FNB is an underutilised method of providing pain relief for fractured femur patients. The main reasons for not using ultrasound for FNB were: lack of training, participants' confidence in giving an effective and safe FNB block blindly and time constraints. The literature review suggests that ultrasound-guided FNB has a faster onset of action, is more effective and safer than the FNB given with nerve stimulator (NS) or blindly, and probably needs lower local anaesthetic dose. The use of NS for FNB in ED might not be practical because of the likelihood of the pain resulting from the movement of the affected limb due to the contraction of the muscles caused by nerve stimulation and because of additional training needed in using NS. The studies comparing FNB given using ultrasound or NS, or given blindly, have been done in the perioperative settings. To date, there has been no randomised controlled trial in ED setting comparing FNB given blindly or under ultrasound guidance. Such a study might have provided a good evidence for modifying the current practice of blind FNB. PMID- 23444421 TI - Incidence and predictors of heart failure hospitalization and death in permanent pacemaker patients: a single-centre experience over medium-term follow-up. AB - AIM: The aim of this study was to assess the incidence and clinical predictors of the development of new-onset heart failure (HF) over medium-term follow-up, in patients treated with permanent pacing in daily clinical practice. METHODS AND RESULTS: We retrospectively enrolled all consecutive patients who underwent single- or dual-chamber pacemaker implantation at the study centre. Patients with a left ventricular ejection fraction (LVEF) <=35% or a prior diagnosis of HF were excluded. Ventricular leads were routinely implanted in the right apex. Pacemakers were implanted in 490 patients with a standard pacemaker indication and LVEF >35%. Left bundle-branch block (LBBB) was reported in 30 (8%) patients, and an LVEF <50% in 64 (13%) patients. During a follow-up of 27 +/- 21 months, 32 (7%) patients reached the combined endpoint of HF death or hospitalization. On multivariate analysis, LBBB (HR, 3.50; 95% CI, 1.1-11.1; P = 0.033) and LVEF <50% (HR, 5.1; 95% CI, 1.9-14.2; P = 0.002) were confirmed as independent predictors of HF death or hospitalization. Patients with LVEF <50% and/or LBBB displayed significantly higher rates of HF death or hospitalization (log-rank test, all P<0.001). CONCLUSION: The majority of patients with a standard indication for permanent pacing and normal LV function remained in a clinically stable condition after pacemaker implantation. However, ~7% of patients developed new-onset HF over a period of follow-up of 27 months, and the presence of LBBB and LVEF <50% at the baseline predicted HF death or hospitalization. PMID- 23444422 TI - Winding back the harms of too much medicine. PMID- 23444423 TI - Influence of initial severity of depression on effectiveness of low intensity interventions: meta-analysis of individual patient data. AB - OBJECTIVE: To assess how initial severity of depression affects the benefit derived from low intensity interventions for depression. DESIGN: Meta-analysis of individual patient data from 16 datasets comparing low intensity interventions with usual care. SETTING: Primary care and community settings. PARTICIPANTS: 2470 patients with depression. INTERVENTIONS: Low intensity interventions for depression (such as guided self help by means of written materials and limited professional support, and internet delivered interventions). MAIN OUTCOME MEASURES: Depression outcomes (measured with the Beck Depression Inventory or Center for Epidemiologic Studies Depression Scale), and the effect of initial depression severity on the effects of low intensity interventions. RESULTS: Although patients were referred for low intensity interventions, many had moderate to severe depression at baseline. We found a significant interaction between baseline severity and treatment effect (coefficient -0.1 (95% CI -0.19 to -0.002)), suggesting that patients who are more severely depressed at baseline demonstrate larger treatment effects than those who are less severely depressed. However, the magnitude of the interaction (equivalent to an additional drop of around one point on the Beck Depression Inventory for a one standard deviation increase in initial severity) was small and may not be clinically significant. CONCLUSIONS: The data suggest that patients with more severe depression at baseline show at least as much clinical benefit from low intensity interventions as less severely depressed patients and could usefully be offered these interventions as part of a stepped care model. PMID- 23444425 TI - Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. AB - OBJECTIVE: To evaluate the risk of narcolepsy in children and adolescents in England targeted for vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine (Pandemrix) from October 2009. DESIGN: Retrospective analysis. Clinical information and results of sleep tests were extracted from hospital notes between August 2011 and February 2012 and reviewed by an expert panel to confirm the diagnosis. Vaccination and clinical histories were obtained from general practitioners. SETTING: Sleep centres and paediatric neurology centres in England. PARTICIPANTS: Children and young people aged 4-18 with onset of narcolepsy from January 2008. MAIN OUTCOME MEASURES: The odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method. RESULTS: Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57,500 and 1 in 52,000 doses. CONCLUSION: The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children. PMID- 23444426 TI - The association between self-reported history of physical diseases and psychological distress in a community-dwelling Japanese population: the Ohsaki Cohort 2006 Study. AB - BACKGROUND: Patients with physical disease are known to suffer considerable psychological distress. Social support may confound the association between physical disease and psychological distress. Population-based epidemiological studies have not been conducted on the association between history of physical disease, psychological distress and social support. METHODS: Using cross sectional data from 2006, we studied 43 487 community-dwelling people aged >=40 years living in Japan. We examined the association between 13 self-reported histories of physical disease and psychological distress evaluated using the Kessler 6-item psychological distress scale (K6), defined as >=13 points out of 24. To investigate the association, we performed multiple logistic regression analyses adjusted for age, gender, social support and possible confounders. Social support, as the interaction between physical disease and psychological depression, was tested through the addition of cross-product terms to the multivariate-adjusted model. RESULTS: The following histories of physical disease were found significantly and positively associated with psychological distress: cancer, diabetes mellitus, hyperlipidemia, hypertension, myocardial infarction, stroke, gastric or duodenal ulcer, liver disease, arthritis, osteoporosis, kidney disease and fall or fracture (odds ratio, 1.2-2.3). Social support did not modify the association between most histories of physical disease and psychological distress. CONCLUSIONS: Subjects with a history of physical disease were significantly and positively associated with psychological distress, and social support did not modify this association for most physical diseases. Even after patients have left hospital following treatment for physical disease, they require continuous monitoring for psychological distress by doctors and paramedics. PMID- 23444424 TI - Effect of telehealth on quality of life and psychological outcomes over 12 months (Whole Systems Demonstrator telehealth questionnaire study): nested study of patient reported outcomes in a pragmatic, cluster randomised controlled trial. AB - OBJECTIVE: To assess the effect of second generation, home based telehealth on health related quality of life, anxiety, and depressive symptoms over 12 months in patients with long term conditions. DESIGN: A study of patient reported outcomes (the Whole Systems Demonstrator telehealth questionnaire study; baseline n=1573) was nested in a pragmatic, cluster randomised trial of telehealth (the Whole Systems Demonstrator telehealth trial, n=3230). General practice was the unit of randomisation, and telehealth was compared with usual care. Data were collected at baseline, four months (short term), and 12 months (long term). Primary intention to treat analyses tested treatment effectiveness; multilevel models controlled for clustering by general practice and a range of covariates. Analyses were conducted for 759 participants who completed questionnaire measures at all three time points (complete case cohort) and 1201 who completed the baseline assessment plus at least one other assessment (available case cohort). Secondary per protocol analyses tested treatment efficacy and included 633 and 1108 participants in the complete case and available case cohorts, respectively. SETTING: Provision of primary and secondary care via general practices, specialist nurses, and hospital clinics in three diverse regions of England (Cornwall, Kent, and Newham), with established integrated health and social care systems. PARTICIPANTS: Patients with chronic obstructive pulmonary disease (COPD), diabetes, or heart failure recruited between May 2008 and December 2009. MAIN OUTCOME MEASURES: Generic, health related quality of life (assessed by physical and mental health component scores of the SF-12, and the EQ-5D), anxiety (assessed by the six item Brief State-Trait Anxiety Inventory), and depressive symptoms (assessed by the 10 item Centre for Epidemiological Studies Depression Scale). RESULTS: In the intention to treat analyses, differences between treatment groups were small and non-significant for all outcomes in the complete case (0.480 <= P <= 0.904) or available case (0.181 <= P <= 0.905) cohorts. The magnitude of differences between trial arms did not reach the trial defined, minimal clinically important difference (0.3 standardised mean difference) for any outcome in either cohort at four or 12 months. Per protocol analyses replicated the primary analyses; the main effect of trial arm (telehealth v usual care) was non-significant for any outcome (complete case cohort 0.273 <= P <= 0.761; available case cohort 0.145 <= P <= 0.696). CONCLUSIONS: Second generation, home based telehealth as implemented in the Whole Systems Demonstrator Evaluation was not effective or efficacious compared with usual care only. Telehealth did not improve quality of life or psychological outcomes for patients with chronic obstructive pulmonary disease, diabetes, or heart failure over 12 months. The findings suggest that concerns about potentially deleterious effect of telehealth are unfounded for most patients. TRIAL REGISTRATION: ISRCTN43002091. PMID- 23444427 TI - How is alcohol consumption affected if we account for under-reporting? A hypothetical scenario. AB - BACKGROUND: This study predicts the implications of under-reporting of alcohol consumption in England for alcohol consumption above Government drinking thresholds. METHODS: Two nationally representative samples of private households in England were used: General LiFestyle survey (GLF) and Health Survey for England (HSE) 2008. Participants were 9608 adults with self-reported alcohol consumption on heaviest drinking day in the last week (HSE) and 12 490 adults with self-reported average weekly alcohol consumption (GLF). Alcohol consumption in both surveys was revised to account for under-reporting in three hypothetical scenarios. The prevalence of drinking more than UK Government guidelines of 21/14 (men/women) alcohol units a week, and 4/3 units per day, and the prevalence of binge drinking (>8/6 units) were investigated using logistic regression. RESULTS: Among drinkers, mean weekly alcohol intake increases to 20.8 units and mean alcohol intake on heaviest drinking day in the last week increases to 10.6 units. Over one-third of adults are drinking above weekly guidelines and over three quarters drank above daily limits on their heaviest drinking day in the last week. The revision changes some of the significant predictors of drinking above thresholds. In the revised scenario, women have similar odds to men of binge drinking and higher odds of drinking more than daily limits, compared with lower odds in the original survey. CONCLUSION: Revising alcohol consumption assuming equal under-reporting across the population does not have an equal effect on the proportion of adults drinking above weekly or daily thresholds. It is crucial that further research explores the population distribution of under-reporting. PMID- 23444428 TI - Prokaryotic multicellularity: a nanopore array for bacterial cell communication. AB - The transition from unicellular to multicellular life, which occurred several times during evolution, requires tight interaction and communication of neighboring cells. The multicellular cyanobacterium Nostoc punctiforme ATCC 29133 forms filaments of hundreds of interacting cells exchanging metabolites and signal molecules and is able to differentiate specialized cells in response to environmental stimuli. Mutation of cell wall amidase AmiC2 leads to a severe phenotype with formation of aberrant septa in the distorted filaments, which completely lack cell communication and potential for cell differentiation. Here we demonstrate the function of the amidase AmiC2 in formation of cell-joining structures. The AmiC2 protein localizes to the young septum between cells and shows bona fide amidase activity in vivo and in vitro. Vancomycin staining identified the overall septum morphology in living cells. By electron microscopy of isolated peptidoglycan sacculi, the submicroscopic structure of the cell junctions could be visualized, revealing a novel function for a cell wall amidase: AmiC2 drills holes into the cross-walls, forming an array of ~155 nanopores with a diameter of ~20 nm each. These nanopores seem to constitute a framework for cell-joining proteins, penetrating the cell wall. The entire array of junctional nanopores appears as a novel bacterial organelle, establishing multicellularity in a filamentous prokaryote. PMID- 23444430 TI - Don't forget pre-eclampsia in the differential diagnosis of abdominal pain in pregnancy. PMID- 23444429 TI - Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen. AB - Hepatitis B virus (HBV) is implicated in liver cancer. The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway. The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death. Responses to apoptosis induction in the HBV ORF transfected HepG2 cells were also compared with those in HBV-positive and HBV negative human hepatocellular carcinoma (HCC) cells. In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair. However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair. These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment. PMID- 23444431 TI - A more balanced approach to drug-grapefruit juice interactions. PMID- 23444432 TI - Author's reply to Backman and Bakhai. PMID- 23444433 TI - Varenicline's adverse events. Choice of summary statistics: relative and absolute measures. PMID- 23444434 TI - New European Union regulation of clinical trials is not conflicting on deferred consent in emergency situations. PMID- 23444435 TI - Antibiotic resistance and transrectal prostate biopsies. PMID- 23444436 TI - Conflicts of interest of clinicians associated with document on collaboration between doctors and drug industry still being sought. PMID- 23444437 TI - Management of ulcerative colitis shows the failings in chronic disease management in the current NHS. PMID- 23444438 TI - Don't forget bovine and porcine surgical products and haemostatic agents. PMID- 23444439 TI - Research ethics committees have the power to enforce publication of drug trial results. PMID- 23444441 TI - Low dose CT screening for lung cancer could save 12 000 US lives a year, researchers claim. PMID- 23444442 TI - Vast majority of NHS services must go out to tender, health minister says. PMID- 23444443 TI - Bring back local GPs for urgent and out of hours care. PMID- 23444444 TI - Rise in emergency department attendances not caused by changes to GP contract. PMID- 23444445 TI - Turn non-urgent cases away from the emergency department. PMID- 23444446 TI - The transition between work, sickness absence and pension in a cohort of Danish colorectal cancer survivors. AB - OBJECTIVES: The aim of this study was to evaluate the impact of socioeconomic and clinical factors on the transitions between work, sickness absence and retirement in a cohort of Danish colorectal cancer survivors. DESIGN: Register-based cohort study with up to 10 years of follow-up. SETTING: Population-based study with use of administrative health-related and socioeconomic registers. PARTICIPANTS: All persons (N=4343) diagnosed with colorectal cancer in Denmark during the years 2001-2009 while they were in their working age (18-63 years) and who were part of the labour force 1 year postdiagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: By the use of multistate models in Cox proportional hazards models, we analysed the HR for re-employment, sickness absence and retirement in models including clinical as well as health-related variables. RESULTS: 1 year after diagnosis, 62% were working and 58% continued until the end of follow-up. Socioeconomic factors were found to be associated with retirement but not with sickness absence and return to work. The risk for transition from work to sickness absence increased if the disease was diagnosed at a later stage (stage III) 1.52 (95% CI 1.21 to 1.91), not operated curatively 1.35 (95% CI 1.11 to 1.63) and with occurrence of postoperative complications 1.25 (95% CI 1.11 to 1.41). The opposite was found for the transition from sickness absence back to work. CONCLUSIONS: This nationwide study of colorectal cancer patients who have survived 1 year shows that the stage of disease, general health condition of the individual, postoperative complications and the history of sickness absence and unemployment have an impact on the transition between work, sickness absence and disability pension. This leads to an increased focus on the rehabilitation process for the more vulnerable persons who have a combination of severe disease and a history of work-related problems with episodes outside the working market. PMID- 23444447 TI - Exposure to benzene and childhood leukaemia: a pilot case-control study. AB - OBJECTIVES: Main purpose To evaluate the feasibility of a measurement-based assessment of benzene exposure in case-control studies of paediatric cancer; Additional aims To identify the sources of exposure variability; to assess the performance of two benzene biomarkers; to verify the occurrence of participation bias; to check whether exposures to benzene and to 50 Hz magnetic fields were correlated, and might exert reciprocal confounding effects. DESIGN: Pilot case control study of childhood leukaemia and exposure to benzene assessed by repeated seasonal weekly measurements in breathing zone air samples and outside the children's dwellings, with concurrent determinations of cotinine, t-t-muconic acid (MA) and sulfo-phenylmercapturic acid (S-PMA) in urine. PARTICIPANTS: 108 cases and 194 controls were eligible for inclusion. RESULTS: Full-participation was obtained from 46 cases and 60 controls, with low dropout rates before four repeats (11% and 17%); an additional 23 cases and 80 controls allowed the collection of outdoor air samples only. The average benzene concentration in personal and outdoor air samples was 3 MUg/m(3) (SD 1.45) and 2.7 MUg/m(3) (SD 1.41), respectively. Personal exposure was strongly influenced by outdoor benzene concentrations, higher in the cold seasons than in warm seasons, and not affected by gender, age, area of residence or caseness. Urinary excretion of S-PMA and personal benzene exposure were well correlated. Outdoor benzene levels were lower among participant controls compared with non-participants, but did not differ between participant and non-participant cases; the direction of the bias was found to depend on the cut-point chosen to distinguish exposed and unexposed. Exposures to benzene and extremely low-frequency magnetic fields were positively correlated. CONCLUSIONS: Repeated individual measurements are needed to account for the seasonal variability in benzene exposure, and they have the additional advantage of increasing the study power. Measurement-based assessment of benzene exposure in studies of childhood leukaemia appears feasible, although it is financially and logistically demanding. PMID- 23444448 TI - Reproducibility of tender point examination in chronic low back pain patients as measured by intrarater and inter-rater reliability and agreement: a validation study. AB - OBJECTIVES: To evaluate the reliability and agreement of digital tender point (TP) examination in chronic low back pain (LBP) patients. DESIGN: Cross-sectional study. SETTINGS: Hospital-based validation study. PARTICIPANTS: Among sick-listed LBP patients referred from general practitioners for low back examination and return-to-work intervention, 43 and 39 patients, respectively (18 women, 46%) entered and completed the study. MAIN OUTCOME MEASURES: The reliability was estimated by the intraclass correlation coefficient (ICC), and agreement was calculated for up to +/-3 TPs. Furthermore, the smallest detectable difference was calculated. RESULTS: TP examination was performed twice by two consultants in rheumatology and rehabilitation at 20 min intervals and repeated 1 week later. Intrarater reliability in the more and less experienced rater was ICC 0.84 (95% CI 0.69 to 0.98) and 0.72 (95% CI 0.49 to 0.95), respectively. The figures for inter-rater reliability were intermediate between these figures. In more than 70% of the cases, the raters agreed within +/-3 TPs in both men and women and between test days. The smallest detectable difference between raters was 5, and for the more and less experienced rater it was 4 and 6 TPs, respectively. CONCLUSIONS: The reliability of digital TP examination ranged from acceptable to excellent, and agreement was good in both men and women. The smallest detectable differences varied from 4 to 6 TPs. Thus, TP examination in our hands was a reliable but not precise instrument. Digital TP examination may be useful in daily clinical practice, but regular use and training sessions are required to secure quality of testing. PMID- 23444449 TI - Exploring the potential of expatriate social networks to reduce HIV and STI transmission: a protocol for a qualitative study. AB - INTRODUCTION: HIV diagnoses acquired among Australian men working or travelling overseas including Southeast Asia are increasing. This change within transmission dynamics means traditional approaches to prevention need to be considered in new contexts. The significance and role of social networks in mediating sexual risk behaviours may be influential. Greater understanding of expatriate and traveller behaviour is required to understand how local relationships are formed, how individuals enter and are socialised into networks, and how these networks may affect sexual intentions and behaviours. This paper describes the development of a qualitative protocol to investigate how social networks of Australian expatriates and long-term travellers might support interventions to reduce transmission of HIV and sexually transmitted infections. METHODS AND ANALYSIS: To explore the interactions of male expatriates and long term travellers within and between their environments, symbolic interactionism will be the theoretical framework used. Grounded theory methods provide the ability to explain social processes through the development of explanatory theory. The primary data source will be interviews conducted in several rounds in both Australia and Southeast Asia. Purposive and theoretical sampling will be used to access participants whose data can provide depth and individual meaning. ETHICS AND DISSEMINATION: The role of expatriate and long-term traveller networks and their potential to impact health are uncertain. This study seeks to gain a deeper understanding of the Australian expatriate culture, behavioural contexts and experiences within social networks in Southeast Asia. This research will provide tangible recommendations for policy and practice as the findings will be disseminated to health professionals and other stakeholders, academics and the community via local research and evaluation networks, conference presentations and online forums. The Curtin University Human Research Ethics Committee has granted approval for this research. PMID- 23444451 TI - A look back at 2012 and plans for 2013. PMID- 23444452 TI - Gastric varices. PMID- 23444453 TI - Dr Shanbhogue responds. PMID- 23444454 TI - Dr Trop and colleagues respond. PMID- 23444455 TI - Illuminations: intraventricular neoplasms. PMID- 23444456 TI - Illuminations: beckoning hand. PMID- 23444457 TI - [Chlamygial and mycoplasmal infections in otorhinolaryngology (a systematic review)]. AB - The objective of the present study was to analyse clinical manifestations of chlamydial and mycoplasmal infections of ENT organs as well as the methods of their diagnostics and therapeutic modalities used for their management. The authors illustrate, based on the results published in the domestic and foreign literature, the currently available diagnostic and therapeutic methods for the treatment of the above pathological conditions in otorhinolaryngology. A rationale for the further investigations of the clinical symptoms of chlamydial and mycoplasmal infections encountered in otorhinolaryngological practice has been developed. PMID- 23444458 TI - Response to poor sleep with normal sleep duration: a preventive effect on incident hypertension. PMID- 23444459 TI - Response to catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to- control hypertensive patients. PMID- 23444460 TI - Response to blood pressure and sympathetic nervous system response to renal denervation. PMID- 23444461 TI - Response to nondipping and cardiovascular risk after morning renin-angiotensin blockade. PMID- 23444462 TI - Response to catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to- control hypertensive patients: prospective case series. PMID- 23444463 TI - Response to Angiotensin-(1-7) and Bradykinin in Baroreceptor Reflex Sensitivity in Hypertension. PMID- 23444464 TI - Response to renal resistive index and cardiovascular and renal outcomes in essential hypertension. PMID- 23444465 TI - Response to creatine kinase and pressor response to orthostatic tolerance. PMID- 23444466 TI - The effectiveness of bilateral cochlear implants for severe-to-profound deafness in adults: a systematic review. AB - OBJECTIVE: Assessment of the clinical effectiveness of bilateral cochlear implantation compared with unilateral cochlear implantation or bimodal stimulation, in adults with severe-to-profound hearing loss. In 2007, the National Institute for Health and Clinical Excellence (NICE) in the U.K. conducted a systematic review on cochlear implantation. This study forms an update of the adult part of the NICE review. DATA SOURCES: The electronic databases MEDLINE and Embase were searched for English language studies published between October 2006 and March 2011. STUDY SELECTION: Studies were included that compared bilateral cochlear implantation with unilateral cochlear implantation and/or with bimodal stimulation, in adults with severe-to-profound sensorineural hearing loss. Speech perception in quiet and in noise, sound localization and lateralization, speech production, health-related quality of life, and functional outcomes were analyzed. DATA EXTRACTION: Data extraction forms were used to describe study characteristics and the level of evidence. DATA SYNTHESIS: The effect size was calculated to compare different outcome measures. CONCLUSION: Pooling of data was not possible because of the heterogeneity of the studies. As in the NICE review, the level of evidence of the included studies was low, although some of the additional studies showed less risk of bias. All studies showed a significant bilateral benefit in localization over unilateral cochlear implantation. Bilateral cochlear implants were beneficial for speech perception in noise under certain conditions and several self-reported measures. Most speech perception in quiet outcomes did not show a bilateral benefit. The current review provides additional evidence in favor of bilateral cochlear implantation, even in complex listening situations. PMID- 23444467 TI - Repetitive transcranial magnetic stimulation as a treatment for chronic tinnitus: a critical review. AB - OBJECTIVE: Because chronic tinnitus is a condition that negatively impacts the quality of life for millions of people worldwide, a safe and effective treatment for tinnitus has been sought for decades. However, a true "cure" for the most common causes of tinnitus remains elusive. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive procedure, has shown potential for reducing patients' perception or severity of tinnitus. This article provides background information about rTMS and reviews studies that investigated rTMS as a treatment for chronic tinnitus. DATA SOURCES: PubMed and Medline databases (National Center for Biotechnology Information, U.S. National Library of Medicine) were searched for the terms repetitive transcranial magnetic stimulation, tinnitus, TMS, and rTMS in articles published from 1980 to 2012. STUDY SELECTION: Articles included in this review were selected to represent a sampling of rTMS methodologies that have been used with tinnitus patients. DATA EXTRACTION: Data extraction included sample size, TMS stimulation frequency, TMS stimulation intensity, number of pulses administered per session, number of TMS sessions, and method of tinnitus assessment. DATA SYNTHESIS: Because of the heterogeneity of the studies reviewed, most of which had small populations of subjects, it was not appropriate to perform a meta-analysis. A systematic review of the literature was conducted to summarize and critique published research results. CONCLUSION: Although optimism for the clinical use of rTMS as an effective treatment for tinnitus remains high among many researchers, clinicians, and patients, several key questions and procedural issues remain unresolved. Suggestions for improving rTMS research protocols are described and discussed. PMID- 23444468 TI - Osteonecrosis of the external auditory canal associated with oral bisphosphonate therapy: case report and literature review. AB - OBJECTIVE: To present the first case of a patient with oral bisphosphonates associated ear canal osteonecrosis (BPECO), review previously published cases, and suggest a definition of BPECO. PATIENT: A 79-year-old woman with left otorrhea and earache was treated for otitis externa for 2 months. The examination revealed a deep floor of the left ear canal defect. The bisphosphonates were discontinued. By the end of the 6-week-course of intravenous antibiotics, the bone defect progression ceased. Already a month later, the defect was lined from approximately 50%. Unfortunately, the patient was lost to follow-up at this stage. She was on oral bisphosphonates for 10 years for severe osteoporosis. She had never been exposed to radiotherapy or had any surgery in the left ear. She admitted to be a habitual cotton bud user for aural toilet. RESULTS: A CT scan showed an aggressive lobulated mass consistent with carcinoma. A biopsy suggested osteomyelitis with no evidence of malignancy. The final diagnosis was agreed to be the first case of oral BPECO. INTERVENTION: Debridement, intravenous antibiotics, and cessation of bisphosphonates CONCLUSION: The BPECO is not very well-known clinical diagnosis among ENT surgeons and, therefore, often misdiagnosed for ear canal cholesteatoma, malignant otitis externa, or temporal bone malignancies. It seems reasonable to re-review patient's medical history with focus on BP medication in cases with negative biopsy. Although the BP osteonecrosis is a rare phenomenon, the large volume of BP prescription makes the number of patients at risk significant. PMID- 23444469 TI - Reply to Chakrabarti et al. PMID- 23444470 TI - Speech perception performance of double array multichannel cochlear implant users with standard and duplicated maps in each of the arrays. AB - OBJECTIVE: The present investigation evaluated the speech perception performance of patients with ossified cochlea implanted with the 24M Double Array cochlear implant, using standard and duplicated maps in each of the arrays. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Sixteen subjects received a Double Array cochlear implant. Among these, 9 fulfilled the following inclusion criteria: bilateral severe-to-profound postlingual deafness; bilateral obliterated cochlea, as shown by a computed tomographic scan; and a minimum age of 14 years to ensure reliable responses in the behavioral tests with the 3 tested maps. INTERVENTION: Rehabilitative. MAIN OUTCOME MEASURES: The speech perception performance with the 2 arrays was compared with that with a basal array duplicated map and an apical array duplicated map. Three maps were fitted: the default map with both arrays activated, a double channel map using only the electrodes of the basal array, and a double channel map programmed only with the electrodes of the apical array. The test battery was composed of a vowel test, a 4-choice word test, and sentence recognition in quiet. RESULTS: Statistical significance was reached in comparison the all tests in all programming conditions. Speech recognition in the standard map with both electrode arrays activated showed the highest scores. CONCLUSION: Performance with the 2 split electrode arrays was superior to those with the single arrays, regardless of the duplication of channels. PMID- 23444471 TI - Cochlear implantation in children 12 months of age and younger. AB - OBJECTIVE: To investigate surgical, anesthetic, and device-related complications as well as auditory and speech-language development outcomes associated with cochlear implantation (CI) in children 12 months of age and younger. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic referral center. PATIENTS: All children with severe-to-profound sensorineural hearing loss who underwent cochlear implantation at 12 months of age or younger and an audiometric control group implanted between 13 and 24 months of age. MAIN OUTCOME MEASURES: Anesthetic and surgical course; major and minor surgical, anesthetic and device related complications; postoperative disposition; postoperative auditory receptive and expressive language development. RESULTS: Twenty-six patients (41 ears) met criteria. The median duration of follow-up was 58 months. No major surgical or anesthetic complications occurred. One patient (4%) experienced device failure, which required revision surgery and implant exchange. Two other patients (8%) had individual electrode anomalies that were treated with map exclusion. At the last recorded follow-up, 73% of patients were performing at or above the level of normal-hearing age-matched peers. Patients that were implanted at 12 months of age or younger reached age-appropriate speech and language skills by 24 months of age compared with 40 months for the older pediatric control group. CONCLUSION: The current study demonstrates that CI provides substantial benefit among infant recipients. Furthermore, when performed by an experienced cochlear implant and pediatric anesthesia team, the surgical and anesthetic risks are similar to that expected with both older pediatric and adult patients. PMID- 23444472 TI - The impact of viral respiratory tract infections on long-term morbidity and mortality following lung transplantation: a retrospective cohort study using a multiplex PCR panel. AB - BACKGROUND: The major factor affecting morbidity and mortality after lung transplantation (LTX) is bronchiolitis obliterans syndrome. Earlier studies have suggested a connection between the presence of viral agents and morbidity in this patient group, but data are somewhat conflicting. The objective of this study was to investigate the development of bronchiolitis obliterans syndrome and graft loss after LTX in relation to the presence of respiratory viruses during the first year after LTX. METHOD: The study is a retrospective cohort study of 39 LTX recipients 11Y13 years after surgery. Patients were operated between January 1, 1998 and December 31, 2000 at Sahlgrenska University Hospital. The presence of virus in bronchoalveolar lavage (BAL) fluids from patients during the first year after surgery was analyzed retrospectively using a multiplex polymerase chain reaction test capable of detecting 15 respiratory agents. The time to BOS or graft loss was analyzed in relation to the positive findings in BAL during the first year after LTX. RESULTS: Patients with one or more viruses detected in BAL during the first year after transplantation demonstrated a significantly faster development of BOS (P=0.005) compared with patients with no virus detected. No significant difference in graft survival was found. CONCLUSION: Our results suggest that the long-term prognosis after LTX may be negatively affected by viral respiratory tract infections during the first year after LTX. PMID- 23444473 TI - New closed skin bone-anchored implant: preliminary results in 6 children with ear atresia. AB - OBJECTIVE: To report preliminary results of a new closed-skin, transcutaneous bone conduction device (BCD) in 6 children with high-grade ear atresia. SETTINGS: Tertiary care center; prospective study; we evaluated the gain with masking of the contralateral ear and the benefit of hearing rehabilitation with the transcutaneous BCD in noise: speech-in-noise tests, conducted in real life condition (with contralateral ear unmasked and fitted with a hearing device if done before implantation), with and without BCD, with determination of the speech reception threshold (SRT). Children and parent's satisfaction was assessed. RESULTS: Patients' ages ranged from 6 to 9 years. All had high-grade ear atresia with a preoperative mean pure-tone average (PTA) loss of 71.46 +/- 6.59 dB on air conduction and 14 +/- 4.98 dB on bone conduction. At M6, all children used the implant 5 to 12 hours daily (mean, 10) without pain or cutaneous complications. At M6, the mean air conduction PTA with transcutaneous BCD was 28.45 +/- 1.68 dB, the mean gain 43 +/- 6.96 dB, and the mean SRT gain 33.33 +/- 10.75 dB. Using speech-in-noise tests in real-life conditions, the mean SRT was statistically improved with the transcutaneous BCD (-8 +/- 2.83 dB, p = 0.0313). Both children and parents reported being satisfied or very satisfied. CONCLUSION: These preliminary results show satisfactory functional gain, cutaneous tolerance, and patients' satisfaction with the new transcutaneous BCD. PMID- 23444475 TI - Abstracts of the 21st Sylvester O'Halloran Meeting. March 1-2, 2013. Limerick Ireland. PMID- 23444474 TI - An unusual cause of delayed puberty: Berardinelli- Seip syndrome. AB - Berardinelli- Seip syndrome is an autosomal recessive disorder characterized by generalized lipoatrophy, extreme insulin resistance with dyslipidemia in childhood and development of diabetes in adolescence. Menstrual irregularities are commonly seen as a result of secondary polycystic ovarian syndrome. Delayed puberty as a manifestation of these abnormalities in girls has rarely been described earlier. We report one such case patient who had delayed puberty and portal hypertension as unique features amongst the characteristic phenotypes of this syndrome. PMID- 23444476 TI - Abstracts of the 9th Annual Meeting of the Hematology/Oncology Pharmacy Association. March 20-23, 2013. Los Angeles, California, USA. PMID- 23444477 TI - Triple test as predictive screen for unilateral weakness on caloric testing in routine practice. AB - OBJECTIVE: To investigate in vertigo patients in routine practice to what extent a rapid and straightforward triple bedside test (spontaneous nystagmus, head shaking nystagmus, and the head impulse test) can predict a normal result on caloric testing. STUDY DESIGN: Prospective, single-blind, diagnostic study. SETTING: Tertiary referral center. PATIENTS: 151 patients (78 male and 73 female subjects; mean age, 52.5 +/- 16.4 yr) presenting with acute or recent symptoms of vertigo. INTERVENTION: Diagnostic evaluation. MAIN OUTCOME MEASURE: The negative predictive value (NPV) of the triple test in relation to a normal caloric test response. RESULTS: In unilateral weakness (UW) on caloric testing (UW, >=25%), the triple test had sensitivity of 63.6%, specificity of 85.4%, a positive predictive value (PPV) of 71.4%, and an NPV of 80.4%. In other words, 80.4% of patients with a negative triple test also had a normal response on caloric testing. In pronounced canal paresis (UW, >=50%), the triple test had sensitivity of 81.8%, specificity of 81.4%, a PPV of 55.1%, and an NPV of 94.1%. Significant differences were found between 2 subgroups assessed by examiners with differing levels of experience (p < 0.05). CONCLUSION: The triple test represents a good screening tool that quickly and reliably excludes unilateral weakness and in particular pronounced canal paresis on caloric testing. PMID- 23444478 TI - Improved facial nerve outcomes using an evolving treatment method for large acoustic neuromas. AB - OBJECTIVE: To describe a successful paradigm for the treatment of large acoustic neuromas (vestibular schwannomas). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: The charts of 2,875 acoustic neuroma patients at Michigan Ear Institute were reviewed to identify 153 patients who underwent surgical resection for large acoustic neuromas (>=3 cm) between 2000 and 2009. INTERVENTION(S): Staged surgical resection or single stage surgery with or without adjuvant stereotactic radiosurgery. MAIN OUTCOME MEASURE(S): Postoperative facial nerve outcomes are reported using the House-Brackmann (HB) facial nerve grading scale and compared with historical controls from a literature review. Rates of adverse outcomes are also reported. RESULTS: Seventy five patients underwent staged surgical resection of their tumors, whereas 78 patients underwent either single stage surgery or surgery with subsequent stereotactic radiosurgery. Eighty-one percent of patients in the staged surgical resection group had a postoperative HB Grade I or II facial nerve function compared with 75% in the single stage surgical group. Overall, 78% of patients in the current study had HB Grade I or II after treatment compared with a mean of 53% in the literature for similar sized tumors. Our methods including the decision to use staged surgery when necessary, dissection of tumor with stimulating dissector-directed intraoperative monitoring, and use of adjuvant stereotactic radiosurgery are described. CONCLUSION: Using the described paradigm, large acoustic neuromas can be successfully treated with either staged or single-stage surgical resection with or without adjuvant radiosurgery to obtain more favorable facial nerve outcomes than historically reported controls while minimizing morbidity for the patient. PMID- 23444479 TI - Spontaneous resolution of pituitary apoplexy in a giant boy under 10 years old. AB - AIM: Pituitary gigantism is a very rare condition; the occurrence of pituitary apoplexy in children younger than 10 years old is even rarer. The aim of our study is to report this exceptional association. OBSERVATION: A boy aged 9 years and 6 months was hospitalized for the first time in November 2011 for symptoms suggesting pituitary apoplexy. The onset of his disease was difficult to determine as his health record has been poorly maintained. On October 10, 2011, he presented to an emergency department with a sudden drop of visual acuity with diplopia and retro-orbital headaches. An ophthalmological exam found very low visual acuity (1/20) with papillary edema. An MRI of the patient's brain revealed a hemorrhagic pituitary process reaching the chiasma, which was compressed, especially on the right side. Thereafter, the patient's vision improved spontaneously. Clinical examination was normal except for gigantism (+5 SD compared to the target stature). Hormonal assessment argued for mixed secretion [growth hormone (GH) = 39 ng/mL, n <= 5, prolactin ( PRL) = 470 ng/mL, n < 15]. Other pituitary functions were normal. Visual acuity normalized after 2 months, and an MRI showed a spontaneous reduction of the pituitary tumor. CONCLUSION: This unusual observation is a model of symptomatic pituitary apoplexy with spontaneous resolution in a boy with pituitary gigantism: phenomenon quite exceptional and worth to be reported. PMID- 23444480 TI - Contralateral botulinum toxin injection to improve facial asymmetry after acute facial paralysis. AB - HYPOTHESIS: The application of botulinum toxin to the healthy side of the face in patients with long-standing facial paralysis has been shown to be a minimally invasive technique that improves facial symmetry at rest and during facial motion, but our experience using botulinum toxin therapy for facial sequelae prompted the idea that botulinum toxin might be useful in acute cases of facial paralysis, leading to improve facial asymmetry. BACKGROUND: In cases in which medical or surgical treatment options are limited because of existing medical problems or advanced age, most patients with acute facial palsy are advised to await spontaneous recovery or are informed that no effective intervention exists. The purpose of this study was to evaluate the effect of botulinum toxin treatment for facial asymmetry in 18 patients after acute facial palsy who could not be optimally treated by medical or surgical management because of severe medical or other problems. METHODS: From 2009 to 2011, nine patients with Bell's palsy, 5 with herpes zoster oticus and 4 with traumatic facial palsy (10 men and 8 women; age range, 22-82 yr; mean, 50.8 yr) participated in this study. Botulinum toxin A (Botox; Allergan Incorporated, Irvine, CA, USA) was injected using a tuberculin syringe with a 27-gauge needle. The amount injected per site varied from 2.5 to 3 U, and the total dose used per patient was 32 to 68 U (mean, 47.5 +/- 8.4 U). RESULT: After administration of a single dose of botulinum toxin A on the nonparalyzed side of 18 patients with acute facial paralysis, marked relief of facial asymmetry was observed in 8 patients within 1 month of injection. Decreased facial asymmetry and strengthened facial function on the paralyzed side led to an increased HB and SB grade within 6 months after injection. CONCLUSION: Use of botulinum toxin after acute facial palsy cases is of great value. Such therapy decreases the relative hyperkinesis contralateral to the paralysis, leading to greater symmetric function. Especially in patients with medical problems that limit the medical or surgical treatment options, botulinum toxin therapy represents a useful alternative. PMID- 23444481 TI - "In-bone" utricle cultures--a simplified, atraumatic technique for in situ cultures of the adult mouse (Mus musculus) utricle. AB - HYPOTHESIS: The "in-bone" method of culturing utricles described here is a reliable and atraumatic technique for culturing mature mouse hair cells and studying hair cell death and protection. BACKGROUND: The current in vitro technique for studying hair cells of the mature mouse utricle involves removal from the temporal bone and free floating culture in media. This technique can be problematic because of variability in the preservation of the sensory epithelium and a steep learning curve that results in injury of the sensory epithelium in less experienced hands. We present a new atraumatic technique of culturing the utricle in situ within the temporal bone. METHODS: Leaving the temporal bone largely intact, a window is opened in the bony vestibule overlying the mouse utricle. The entire temporal bone is then placed into culture media. Utricles were cultured in situ for several days with minimal damage to the epithelium. The utricles are then fixed in situ, removed from the temporal bone, and processed. A standardized aminoglycoside-induced hair cell damage protocol was developed. RESULTS: Mature mouse utricles maintained hair cell numbers for 3 days in culture. Exposure to neomycin resulted in significant dose-dependent hair cell toxicity (p < 0.0001, 1-way analysis of variance). Exposure to the protective drug tacrine resulted in significant protection against neomycin (p < 0.05, 3-way analysis of variance). CONCLUSION: The "in-bone" technique is a reliable and atraumatic method for culturing mature mouse utricles and studying hair cell death and protection. It is easily mastered and can make in vitro study of hair cells accessible to more research groups. PMID- 23444482 TI - Vestibular evoked myogenic potentials in patients with superior semicircular canal dehiscence. AB - OBJECTIVE: To compare the audiometric and cervical vestibular evoked muscle potential (cVEMP) outcomes of ears with superior canal dehiscence (SSCD) to outcomes from normal ears and the unaffected ears of unilateral SSCD patients. STUDY DESIGN: Retrospective review of clinical testing outcomes. SETTING: Tertiary care specialty teaching hospital. PATIENTS: Three subject groups were used: 21 ears of healthy subjects, ages 21 to 52 years; 58 affected SSCD ears in patients, ages 15 to 65 years; and 26 unaffected ears of unilateral SSCD patients, ages 15 to 65 years. MAIN OUTCOME MEASURE: Results of pure-tone audiometry and cervical vestibular evoked muscle potential (cVEMP) testing. RESULTS: SSCD ears differed from normal ears or unaffected ears of unilateral SSCD patients in 2 ways: 1) they had significantly larger air-bone gaps at 250 and 500 Hz, resulting in poorer air-conduction thresholds at those frequencies, and 2) their cVEMP thresholds at 500 Hz were significantly lower. When the cVEMP threshold was adjusted for the size of the air-bone gap on the audiogram, cVEMP thresholds were significantly lower for 250-, 500-, and 1,000-Hz tone bursts compared with the other subject groups. Logistic regression indicated that the probability of predicting SSCD from the cVEMP thresholds was significant. cVEMP tuning was unaffected by SSCD. CONCLUSION: Combining 2 features associated with SSCD, the presence of an air-bone gap and the lower cVEMP threshold, into one variable, an adjusted cVEMP threshold, better separated SSCD ears from normal or unaffected SSCD ears. A probability predictive function from logistic regression of the adjusted cVEMP may be clinically applicable. PMID- 23444483 TI - Abstracts of the 10th Meeting of the German Endocrine Brain Immune Network (GEBIN). Regensburg, Germany. March 20-23, 2013. PMID- 23444484 TI - The War of Jenkins' Ear. AB - OBJECTIVE: In 1731, Spanish sailors boarded the British brig Rebecca off the coast of Cuba and sliced off the left ear of its captain, Robert Jenkins. This traumatic auriculectomy was used as a pretext by the British to declare war on Spain in 1739, a conflict that is now known as the War of Jenkins' Ear. Here, we examine the techniques available for auricular repair at the time of Jenkins' injury and relate them to the historical events surrounding the incident. METHODS: Review of relevant original published manuscripts and monographs. RESULTS: Surgeons in the mid-18th century did not have experience with repair of traumatic total auriculectomies. Some contemporary surgeons favored auricular prostheses over surgical treatment. METHODS for the reconstruction of partial defects were available, and most authors advocated a local post-auricular flap instead of a free tissue transfer. Techniques for repair of defects of the auricle lagged behind those for repair of the nose. CONCLUSION: Limitations in care of traumatic auricular defects may have intensified the significance of Jenkins' injury and helped lead to the War of Jenkins' Ear, but conflict between Britain and Spain was probably unavoidable because of their conflicting commercial interests in the Caribbean. PMID- 23444485 TI - Comments on 'Stapes surgery in profound hearing loss due to otosclerosis'. PMID- 23444486 TI - UNDP to re-engineer funding strategy. PMID- 23444487 TI - New set of Alzheimer's trials focus on prevention. PMID- 23444488 TI - Cortisol response to the Trier Social Stress test among Chinese adolescents. AB - OBJECTIVE: To compare obese and non-obese adolescents in terms of their salivary cortisol response to the Trier Socia l Stress Test ( TSST). METHODS: This is a cross - sectional study involving 41 healthy adolescents aged 12-14 years in the city of Shenyang, China. The TSST response was determined using salivary cortisol measurements, and measurements were repeated after the test period. Repeated measures ANOVA was performed to compare salivary cortisol levels between groups. RESULTS: The male group comprised of 16 individuals (10 obese and 6 non-obese), and the female group comprised 25 individuals ( 13 obese and 12 non-obese). ANOVA with repeated measures demonstrated that weight status (obese or non-obese) had a significant main effect on the measures of salivary cortisol levels during the TSST among females but not males. CONCLUSIONS: The finding suggested that weight status is associated with cortisol response to psychological stress among Chinese adolescent girls. PMID- 23444489 TI - Profile: ECCRI--cardiovascular research at the heart of Emory. PMID- 23444490 TI - William Harvey goes back to the future. PMID- 23444492 TI - Retraction notice to "Synthetic actin binding domains reveal compositional constraints for function" [Int. J. Biochem. Cell Biol. 40 (2008) 1806-1816]. PMID- 23444491 TI - Gene expression quantitation by real-time PCR. PMID- 23444493 TI - Malfeasance on an industrial scale. PMID- 23444495 TI - INN common stem:--oxacin. PMID- 23444494 TI - Argatroban: for a few selected patients. AB - Type II heparin-induced thrombocytopenia is currently managed by withdrawing heparin and replacing it with danaparoid sodium. Argatroban, a direct thrombin inhibitor anticoagulant (like lepirudin), is now authorised for this indication in France, following authorisation in several other countries since the early 2000s. Argatroban has not been compared with danaparoid in clinical trials. About 700 patients treated with argatroban in 2 trials were compared to historical controls managed by simple withdrawal of heparin and, in some cases, switching to an oral anticoagulant. Argatroban had no apparent advantages in terms of death or the need for amputation. Argatroban did not appear to increase the risk of bleeding in these trials, but evidence provided by historical comparisons is weak. The adverse effect profile includes hepatic disorders (notably fulminant hepatitis). The risk of pharmacokinetic interactions appears to below. In practice, given the absence of a proven therapeutic advantage, it is better to continue to use danaparoid for first-line treatment, reserving argatroban for the rare situations in which danaparoid is inappropriate. PMID- 23444496 TI - Linagliptin. Avoid gliptins! PMID- 23444497 TI - Do not include gliptins in your prescribing list. PMID- 23444498 TI - 13-valent pneumococcal vaccine: 50 years of age and older. AB - In adults, the 13-valent pneumococcal conjugate vaccine seems to be more immunogenic than the 23-valent polysaccharide pneumococcal vaccine for most of the 12 shared serotypes. However, in mid-2012, routine vaccination of adults has no proven efficacy. PMID- 23444499 TI - Neoadjuvant trastuzumab for breast cancer. Better to stick with proven treatments. AB - No documented increase in overall survival with neoadjuvant trastuzumab, given the lack of trials versus chemotherapy in combination with adjuvant trastuzumab. PMID- 23444500 TI - Saxagliptin + metformin. Mostly disadvantages. PMID- 23444501 TI - Dabigatran: life-threatening bleeding. AB - Dabigatran is an oral anticoagulant that inhibits thrombin but not vitamin K. In mid-2012, there was no commercial test to monitor its anticoagulant effect, nor an antidote. In mid-November 2011, the European pharmacovigilance database contained 256 reports of haemorrhagic deaths attributed to dabigatran. Nearly 800 cases of severe haemorrhage have been reported in Australia, Canada, Japan, New Zealand and the United States. A randomised trial comparing dabigatran with warfarin, and 5 studies of several hundred serious bleeding events, identified factors that increased the risk of bleeding. They included even mild renal failure, age over 75 years, body weight less than 60 kg, switching between anticoagulants, opening the dabigatran capsules before ingestion, and concomitant use of drugs that interact with dabigatran. A dabigatran dose below 220 mg per day does not protect patients from the risk of haemorrhage. In practice, dabigatran should be reserved for patients with a high risk of thrombosis in whom the target INR cannot be maintained on antivitamin K therapy alone. The risk of bleeding must be taken into account, renal function must be closely monitored, and patients and their carers must be correctly informed about this risk. PMID- 23444502 TI - SSRI antidepressants: altered psychomotor development following exposure in utero? AB - Selective serotonin reuptake inhibitor antidepressants (SSRIs) are sometimes prescribed to pregnant women. The potential consequences for the unborn child are gradually becoming clearer. In a case-control study of 298 children with autism and 1507 controls, 6.7% of mothers of autistic children had been prescribed an antidepressant during the year before delivery, compared to 3.3% of control mothers. The antidepressant was usually an SSRI. A dozen other small epidemiological studies of neurological development in children exposed to antidepressants in utero have provided mixed results. Two of these studies suggested a risk of psychomotor retardation. In practice, SSRI antidepressants should only be considered for pregnant women when non-drug measures fail and when symptoms are sufficiently serious to warrant drug therapy. PMID- 23444503 TI - Injectable paracetamol in children: yet more cases of 10-fold overdose. AB - Intravenous paracetamol injection is associated with a risk of 10-fold overdose. This is due to confusion between normal dose prescription in milligrams and administration in millilitres of injectable solution (containing 10 mg per ml). Reports of overdose show that the consequences can be severe, due to the hepatic toxicity of paracetamol, which may be fatal if the error is not detected rapidly enough for antidote (acetylcysteine) administration. In practice, injectable paracetamol should only be prescribed when oral administration is not possible. Care must be taken when calculating the dose to be administered, and the calculation must be double checked before the drug is administered. PMID- 23444504 TI - Benfluorex: in utero exposure. AB - Women were given appetite suppressants during pregnancy. PMID- 23444505 TI - Intravenous administration: frequent errors. AB - A prospective study conducted in Australia examined the errors made by 107 nurses during 568 intravenous drug administrations in hospitals. About 100 administrations had at least one serious error; most were administration rate errors. PMID- 23444506 TI - Everolimus: gastrointestinal haemorrhage. PMID- 23444507 TI - An initiative to prevent the adverse effects of metformin. AB - Collaboration between clinicians and a pharmacovigilance centre results in practical benefits for patients. PMID- 23444508 TI - Methylphenidate: abuse in Europe. AB - In Europe, methylphenidate consumption is rising at an alarming rate. Reports of abuse and addiction are also increasing. PMID- 23444509 TI - Benfluorex and cardiac valve disease: long delay in publication. PMID- 23444510 TI - First-line treatment of metastatic prostate cancer. Androgen suppression for symptomatic disease. AB - Prostate cancer sometimes metastasizes, especially to bone, which may cause pain, fractures and spinal cord compression. What are the best first-line treatment options for patients with metastatic prostate cancer? To answer this question, we conducted a review of the literature, using the standard Prescrire methodology. Suppressing androgen secretion by surgically removing the testicles (orchiectomy) or by administering a gonadorelin agonist relieves the pain associated with bone metastases in about 80% of patients. This treatment has a clear impact on symptoms, despite the lack of clinical trials versus placebo or no treatment. Its impact on overall survival is uncertain. In terms of survival, goserelin therapy appears to have similar efficacy to orchiectomy. The efficacy of other gonadorelin agonists is less well documented. Degarelix, a gonadorelin antagonist, does not appear to provide a therapeutic advantage over gonadorelin agonist. In 2012, oestrogen should not be used in the treatment of metastatic prostate cancer, because of its cardiovascular adverse effects. Antiandrogen monotherapy, preferably with flutamide, appears to be less beneficial than orchiectomy in terms of survival. Overall, adverse effects are more frequent with nonsteroidal antiandrogens than with gonadorelin agonists, but sexual dysfunction is less frequent. Cyproterone, a steroidal antiandrogen, seems to have fewer adverse effects leading to treatment discontinuation than nonsteroidal antiandrogens. There is no firm evidence that starting hormonal therapy before metastases become symptomatic is beneficial. When symptoms have disappeared and the PSA level is low, one option is to temporarily interrupt gonadorelin agonist therapy if it is poorly tolerated, even though this may shorten survival by a few months. The addition of a nonsteroidal antiandrogen to androgen suppression therapy slightly improves 5-year survival, preventing about 3 deaths per 100 patients, but at a cost of additional adverse effects. First-line hormonal treatments are initially very effective in relieving symptoms of metastatic prostate cancer. Our analysis of the available data suggests that the best treatment option is androgen suppression with goserelin. Flutamide monotherapy is an alternative for some patients. PMID- 23444511 TI - Choice of first-line treatment for metastatic prostate cancer. PMID- 23444512 TI - Drugs in wastewater: incomplete removal by treatment plants. AB - Treatment plants do not completely remove the drugs present in wastewater. The efficacy of wastewater treatment plants varies, depending on the processes used, but remains low for certain drugs. The presence of drugs in wastewater and their persistence after treatment are yet more good reasons to avoid the overconsumption of drugs and to encourage people to dispose of unused medications through organised take-back programmes. PMID- 23444513 TI - The European Union Water Framework Directive (2000). AB - European regulations define environmental quality standards for 33 "priority substances" in surface water. As of late 2012, the list of priority substances did not yet include any pharmaceuticals. PMID- 23444514 TI - The important role of public-sector research in the United States. AB - Between 1970 and 2009, US public institutions participated in the research and development of 153 drugs, including 15 vaccines. Between 1990 and 2007, nearly 10% of all the new drugs and vaccines marketed in the US and about 20% of those representing a therapeutic advance originated in public institutions. The proportion of these drugs that represented a substantial therapeutic advance was over twice that of those produced exclusively by the private sector. PMID- 23444515 TI - Ceruse: a skin lightening cosmetic at the king's court. PMID- 23444516 TI - ["Welcome to Holland": narrative emotions and social change]. PMID- 23444517 TI - James Law, America's first university veterinary professor, raised the bar for academic standards. PMID- 23444518 TI - Ruling could let drug sellers say more: Court vacates conviction for off-label promotion. PMID- 23444519 TI - Farmer hopes lawsuit will affect disease practices. PMID- 23444520 TI - Reply to Baker SJ, Baker GJ. complementary and alternative medicine. PMID- 23444521 TI - Veterinarian oversupply in small animal clinical practice. PMID- 23444522 TI - In this issue: how we think and feel influences patient care. PMID- 23444523 TI - Breath of fresh air. Our evaluation of 10 intensive care ventilators. AB - Many of the intensive care ventilators on the market today are equipped with advanced features, including features that can help wean patients more effectively and ones that can help clinicians assess a patient's status at a glance. We examine how clinically effective these advanced features have proven to be, and rate 10 units from six suppliers. PMID- 23444525 TI - FairWarning article raises concerns about AEDs. PMID- 23444524 TI - Safety summary: ventilators. PMID- 23444526 TI - Notes on the alarms summit. PMID- 23444527 TI - Defective filters may impact performance of internal vacuum in Sorin brat 2 autotransfusion systems. PMID- 23444528 TI - IOM report hits health IT. PMID- 23444529 TI - Up and running. Choosing the right equipment service option. AB - If you're trying to decide between servicing your equipment in-house or using an outside party, you know that finding the best option can be complicated. To help manage the decision process, this article includes a matrix to organize and assess all relevant factors. We also discuss equipment maintenance insurance, which allows you to cap your service costs for some or all of your equipment. PMID- 23444530 TI - Sound decisions. A guide to selecting ultrasound equipment. AB - With so many options on the market, choosing the right ultrasound equipment for your facility can be daunting. This guide will help you navigate the marketplace and choose the best model to suit your needs. PMID- 23444531 TI - Breast tomosynthesis. 3-D mammography reaches the U.S. market. AB - After many years of anticipation, FDA has approved a device for breast tomosynthesis applications: The Hologic Selenia Dimensions 3-D. But despite the advantages of the technology, certain issues--such as increased radiation dose, higher costs, and lack of insurance reimbursement--may impede widespread clinical adoption. We take a look at breast tomosynthesis and give our view on its clinical outlook. PMID- 23444532 TI - CareFusion 3100B high-frequency oscillatory ventilator diaphragms require pre-use inspection. AB - A rubber diaphragm in the driver assembly of the CareFusion 3100B high-frequency oscillatory ventilator may fail before its scheduled replacement at 4,000 hours of use, rendering the unit incapable of ventilation. CareFusion is in the process of revising the suggested replacemen schedule and adding user guidance to the device's operator's manual to address the problem. Users should thoroughly inspect the diaphragm each time they connect a breathing circuit and should remove from service any 3100B whose diaphragm shows signs of degradation. PMID- 23444533 TI - Patient data from Philips IntelliVue monitors may appear on wrong XDS remote display. AB - Under certain circumstances, when a Philips IntelliVue physiologic monitor is disconnected from an IntelliVue XDS remote display and reconnected to a different XDS remote display, monitored patient information will not be automatically transferred to the new display, but instead will reappear on the original display. As a result, the data on the original display may be associated with the wrong patient. This problem is limited to IntelliVue XDS software version H.00.xx or earlier. A software upgrade is available that permits automatic data transfer when a monitor is moved from one XDS remote display to another. PMID- 23444534 TI - Power grid frequency changes within U.S. unlikely to affect patient care; ECRI Institute requests member input. PMID- 23444535 TI - Physiologic monitoring. A guide to networking your monitoring systems. AB - There are many factors to consider when choosing a physiologic monitoring system. not only should these systems perform well clinically, but they should also be able to exchange data with other information systems. We discuss some of the ins and outs of physiologic monitoring system networking and highlight eight product lines from seven suppliers. PMID- 23444536 TI - Reducing the risk of burns during electroconvulsive therapy. AB - Poor contact between electroconvulsive therapy (ECT) electrodes and the skin can result in patient burns during ECT treatment. Proper site preparation and electrode application are essential to ensure adequate contact and to reduce the risk of burns. PMID- 23444537 TI - Certain Fisher & Paykel infant radiant warmers require inspection and possible component replacement. AB - In certain versions of Fisher & Paykel IW900 series infant radiant warmers, a wiring harness connector located near the heater head assembly may become damaged and overheat during routine use, potentially rendering the warmer inoperable. Although Fisher & Paykel states that the risk to patients is low, facilities with affected warmers should inspect the connectors and, if damage or discoloration is evident, contact the company to arrange for replacement of the wiring harness/connector assemblies. Fisher & Paykel intends to release an Advisory Notice to guide customers in the inspection. This problem affects 120 V and 100 V versions of the IW900 series warmers that were manufactured before October 1, 2010 (identified by serial numbers below 101001). PMID- 23444538 TI - Same sex relationships and HIV/AIDS in Africa: need for research and programmatic focus. PMID- 23444539 TI - Management of infertility in HIV infected couples: a review. AB - The HIV epidemic has continued to grow and remains a major challenge to mankind. In the past, ethical considerations about the resulting child and risks of sexual, vertical and nosocomial transmission of HIV prevented practitioners from offering fertility services to people living with HIV. In recent times however, the use of highly active antiretroviral therapy (HAART), has not only improved the life expectancy and quality of life of those infected but also reduced the risk of HIV transmission. The need for fertility services in the HIV-positive population has thus increased and may be employed for management of infertility and protection from transmission or acquisition of HIV infection. As such, preconception counseling, sexual health and fertility screening have become routine in the management of HIV-positive couples. The option of care include adoption, self insemination with husband sperm, embryo donation from couples who have been verified to be HIV negative, insemination with donor sperm, timed unprotected intercourse (TUI) and sperm washing combined with intrauterine insemination (IUI) and assisted reproductive technology (ART) including in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Access to these fertility services by HIV-positive clients should be facilitated as part of efforts to promote their reproductive health and rights. PMID- 23444540 TI - Prevalence of internalized homophobia and HIV associated risks among men who have sex with men in Nigeria. AB - This study assessed the level of internalized homophobia and associated factors among men who have sex with men (MSM) in Nigeria. Using respondent driven sampling, MSM were recruited in Lagos and Ibadan between July and September, 2006. Internalized homophobia was assessed as a negative composite score using an 11-item scale. A total of 1,125 MSM were interviewed. About 44.4% self-identified as homosexual or gay while 55% regarded themselves as bisexual. About a third of the respondents reported internalized homophobia. With homosexual/gay men as reference, respondents who self-identified as bisexual were two times more likely [AOR 2.1; 95 CI: 1.6 - 2.9, p < 0.001] to report internalized homophobia. Those who were HIV positive were also twice as likely to report internalized homophobia compared to those who were HIV negative [AOR 1.8; 95% CI: 1.2 - 2.7, p = 0.004]. As internalized homophobia impedes acceptance of HIV prevention programming, identifying MSM who experience internalized homophobia is integral to the success of HIV prevention programming in Nigeria. PMID- 23444541 TI - Short preceding birth intervals and child mortality in Mozambique. AB - This paper examines the risk of child mortality associated with short preceding birth intervals in Mozambique. We apply a piecewise log-rate model to a pooled dataset comprising 36,305 live births from the 1997 and 2003 Mozambique Demographic and Health Surveys (DHS). Our results show that the effects of short preceding intervals are strongest during the first month of life, particularly the first week, indicating prenatal maternal depletion as the dominant pathway. The rapid decline in mortality rates from intervals of less than six months to the category 30 to 35 months suggests an optimal waiting period of at least 30 months between one birth and the next pregnancy. 73 per cent of births had preceding intervals less than 30 months which, amidst low contraception use, indicates a potential for family planning programs to contribute to child survival and the attainment of Millennium Development Goal 4 in Mozambique. PMID- 23444542 TI - [Contribution of transvaginal ultrasound to hysterosalpingography in the etiological research on female infertility in Abidjan]. AB - We performed hysterosalpingography (HSG) and transvaginal ultrasound (TVU) in 124 Ivorian women as part of an infertility evaluation. The aim was to investigate the causes of infertility and show the advantages of combining HSG and TVU as part of a comprehensive evaluation of infertility in African woman. TVU and HSG were normal in 35.5% of cases, while in 64.5% of cases, at least one disease was demonstrated. This included uterine pathology in 50.3%, tubal disease in 25.2%, ovarian pathology in 7.5% and peritoneal pathology in 7% of cases. Of all the diseases identified by the association HSG and TVU, 71.3% were found by TVU, while 61.5% were confirmed by HSG. TVU was more efficient in identifying uterine and ovarian pathologies while HSG excelled in tubal pathology. HSG and TUV had identical performances on the peritoneal pathology. The association HSG-ETV should be systematic in the full assessment of female infertility in sub-Saharan Africa. PMID- 23444543 TI - Determinants of fertility in Namibia. AB - In-depth studies on fertility in Namibia have been lacking so far. This examines the fertility trends in Namibia over the past 2 decades and examines fertility differentials across the various sub-groups of Namibia population, and factors affecting such differentials using NDHS data. Estimates of the amount of variance in the total number of children ever born that could be explained by each of the independent variables were made using multiple regression analysis for the three data sources. Overall, results from descriptive analysis show that fertility levels in Namibia have been decreasing over the past two decades. The decrease could be associated with an increased trend in the prevalence of use of modern contraceptives which doubled since 1992. Age at first birth has remained constant but age at first marriage continues to increase. As a result, postponement of marriage increases the probability that women remain childless or that they have fewer children than desired. Replacement level is projected to be attained much faster than expected and the study recommend for further research that focuses on policy implications of family planning programmes once replacement level has been achieved to maintain it. PMID- 23444544 TI - Age differences and protected first heterosexual intercourse in Ghana. AB - Age differences between partners, where females are relatively younger than their male partners, can negatively affect power dynamics and subsequent negotiations for safe sex practices with implications on unplanned pregnancies and STIs transmission. This paper examines the effects of age differentials on condom use at first sex. Using a weighted sample of 925 women drawn from the fifth round of Ghana Demographic and Health Survey and applying complementary log-log model, the probability of first sex being protected vis-a-vis partner age differences are estimated. The results suggest that females' being ten or more years younger than their male partners at first sex was a significant indicator of non-protection while at age intervals 1-4 and 5-9 years, the probability of protected sex inflates significantly. The results demonstrate that large age disparities between partners pose a significant barrier to protection during first sex and strategies have to be developed to altering wrong perceptions associated with intergenerational sex, particularly, in settings such as Africa where gerontocratic tendencies pervade not only social relationships but sexual as well. PMID- 23444545 TI - Increased use of injectable contraception in sub-Saharan Africa. AB - National surveys show a remarkable upsurge in the use of injectable contraceptives in east and South Africa, in contrast to central and West Africa and certain other regions. Data are analyzed here from 95 surveys conducted since 1980 in 38 sub-Saharan African countries, to determine past injectable trends in the context of alternative methods and to explore related issues. In eastern and southern countries injectable use has risen to about 15%-20% of married women, equaling about 40% of all contraceptive use, with some countries above that. Increases in total use have followed increases in injectable use; that and other evidence is clear that the injectable has not merely substituted for the use of pre-existing methods but has given a net increase to total use. Rural use patterns are not much different from urban ones; however the middle and higher wealth quintiles have especially moved toward injectable use. In west and central countries traditional methods are still paramount, with modern methods increasing slightly, but total use remains quite low there. So far no plateau has appeared in total injectable use, though one may be emerging in its share of all use as other methods also increase. Most use is supplied through the public sector, which raises long-term cost issues for health ministries and donors. Many sexually active, unmarried women use the method Discontinuation rates are quite high, and alternative methods need to be kept readily available. PMID- 23444546 TI - Age of sexual debut and patterns of sexual behaviour in two local government areas in southern Nigeria. AB - The study examines the age of sexual debut and patterns of sexual behavior in Ugep, Cross River State, and Badeku and Olunloyo in Oyo State. A survey of households and individuals was conducted in the three communities; qualitative data were also collected through in-depth interviews and focus group discussion. The median age of first sex among never-married males and females were 17 years and 18 years respectively; more than one in five adolescents have had sex before age 16. Never-married males and females initiated sex earlier than ever-married, older respondents. That 14 percent of married men keep other sexual partners besides their wives is indicative of substantial extramarital relationship; also 12 percent of never-married male respondents with regular sex partners have other sexual partners. Condom use is fairly high, especially in sexual relations involving non-regular partners. The higher likelihood of alcohol use in sexual liaison with non-regular sex partners is suggestive of high prevalence of transactional sex and spontaneous or unplanned sex under the influence of alcohol, with their implications for the spread of HIV and AIDS. The study underscores the need for adolescent sexual and reproductive health education and behaviour change communication among all segments of the population and inculcation of values less favourable for the spread of sexually transmitted infections. PMID- 23444547 TI - Survival analysis of timing of first marriage among women of reproductive age in Nigeria: regional differences. AB - Early marriage is common among women in developing countries. Age at first marriage (AFM) has health implication on women and their under-five children. In Nigeria, few studies have explored AFM; the current study was designed to fill the gap. Nigeria Demographic and Health Survey, 2008 dataset on married women aged 15-49 (N = 24,986) was used. Chi-square, OLS regression and Cox proportional hazard models were used in the analysis. The mean AFM was 17.8 +/- 4.8 years and significant difference existed between the mean AFM of women in the North (16.0 +/- 3.6) and South (20.4 +/- 5.0) (p < 0.001). Region, education, religion, residence, nutritional status, age at first sexual intercourse and children ever born were significantly associated with timing of first marriage (p < 0.001). Majority of the women married between ages 15-19 years (43.1%), while very few married late (2.3%) and about 27.0% married too early (less than 15 years). Early marriage was more common in all the regions in the North than the South and the hazard was highest in the North West and North East. Women who reside in rural area (H.R = 1.15; C.I = 1.11-1.18) married early than their counterparts in the urban area. Age at first marriage was directly related to levels of education (p < 0.001). Muslim women married early (H.R = 1.34; C.I = 1.29-1.39) than Christians. Three models were generated from the data. Women married too early in Nigeria with Teenage marriage more common in the North than the South. Education has influence on AFM; therefore, women should have at least secondary education before marriage in Nigeria. PMID- 23444548 TI - Prevalence and factors associated with perpetration of non-consensual sex among students of a tertiary institution in Ibadan, Nigeria. AB - This cross-sectional survey explored the extent to which students of the Polytechnic, Ibadan had perpetrated Non-Consensual Sex (NCS). A total of 594 randomly selected students completed a questionnaire and three perpetrators were interviewed in-depth. Mean age of the survey respondents was 22.7 +/- 2.9 years. Twenty-two percent had ever perpetrated at least a form of NCS, out of which 75.9% reported involvement in this behaviour in the six months preceding the study. Forms of NCS perpetrated included unwanted touch of breast/back side (14.6%), unwanted kiss (9.4%), attempted rape (2.7%) and rape (1.7%). The predictors of perpetration of NCS were alcohol use (OR: 2.2; CI: 1.41-3.33) and cigarette smoking (OR: 2.5, CI: 1.13-5.56). In-depth interview revealed that peer group influence and alcohol consumption contributed to perpetration of NCS. Behavioural change interventions are recommended to prevent perpetration of NCS in this institution. PMID- 23444549 TI - Female genital mutilation in Sierra Leone: who are the decision makers? AB - The objectives of this study were to identify decision makers for FGM and determine whether medicalization takes place in Sierra Leone. Structured interviews were conducted with 310 randomly selected girls between 10 and 20 years in Bombali and Port Loko Districts in Northern Sierra Leone. The average age of the girls in this sample was 14 years, 61% had undergone FGM at an average age of 7.7 years (range 1-18). Generally, decisions to perform FGM were made by women, but father was mentioned as the one who decided by 28% of the respondents. The traditional excisors (Soweis) performed 80% of all operations, health professionals 13%, and traditional birth attendants 6%. Men may play a more important role in the decision making process in relation to FGM than previously known. Authorities and health professionals' associations need to consider how to prevent further medicalization of the practice. PMID- 23444550 TI - Perception and practice of female genital cutting in a rural community in southern Nigeria. AB - This study was carried out to determine the awareness and practice of FGC in a rural community in southern Nigeria. A cross sectional study was carried out among Ayadehe women in Itu, LGA Akwa Ibom State, Nigeria using a semi-structured interviewer administered questionnaire. Information obtained was analysed using SPSS version 17. A total of 218 respondents participated in the study. Majority, 215 (98.6%) were aware of the practice of FGC. Type 2 FGC was the commonest type reported by 71.2% of respondents. Prevalence of FGC was 92.7%. A total of 69.8% were circumcised at 6-12 years. Health complications experienced included excruciating pains, (36.6%), severe bleeding, (15.8%), and painful urination, (26.7%). Up to 53.5% were circumcised by traditional birth attendants. The belief that FGM should be discontinued increased with educational level. The practice of FGC was high in this community. Increased female education, community involvement and legislation are needed to reduce this practice. PMID- 23444551 TI - Provision of family planning services in Tanzania: a comparative analysis of public and private facilities. AB - Adherence to the policy guidelines and standards is necessary for family planning services. We compared public and private facilities in terms of provision of family planning services. We analyzed data from health facility questionnaire of the 2006 Tanzania Service Provision Assessment survey, based on 529 health facilities. Majority of public facilities (95.4%) offered family planning services, whereas more than half of private facilities (52.1%) did not offer those. Public facilities were more likely to offer modern contraceptives as compared to private facilities. However, private facilities were more likely to offer counseling on natural methods of family planning [AOR = 2.12 (1.15-3.92), P < or = 0.001]. Public facilities were more likely to report having guidelines or protocols for family planning services and various kinds of visual aids for family planning and STIs when compared to private facilities. This comparative analysis entails the need to enforce the standards of family planning services in Tanzania. PMID- 23444552 TI - Awareness, use and main source of information on preventive health examinations: a survey of childbearing women in Uyo, Nigeria. AB - The study determined awareness, use and the main source of information about preventive health examinations among 387 childbearing women attending three health facilities in Uyo, Nigeria. Respondents were consenting women aged 15-49 years who had a live birth in the two months preceding the survey. Respondents were interviewed using structured questionnaires during child welfare clinic visits at each facility. Awareness about pap smears and breast self examination was 14.2% and 35.3% respectively. Testing rates were highest for blood pressure checks, HIV and blood sugar and lowest for Pap smears and mammograms. Health workers were the main informants on preventive tests. Awareness and secondary education enhanced women's uptake of screening services across levels of health care. Secondary education as a minimum and intensified awareness creation about preventive health examinations through media, school based programs, durbars and public health campaigns are vital to the health and well being of women and children. PMID- 23444553 TI - Trends and differentials of adolescent motherhood in Ethiopia: evidences from 2005 Demographic and Health Survey. AB - Adolescent childbearing has undesirable consequences. Dropping out of school, high rates of abortion, maternal mortality and morbidity are noted consequences of adolescent pregnancy and childbearing. The objective of this study, which is based on the 2005 Ethiopian Demographic and Health Survey data, is to analyze the levels, trends and differentials of adolescent motherhood in Ethiopia. A multilevel logistic regression was fitted to analyze the determinants of adolescent childbearing. Adolescent motherhood in Ethiopia has shown a generally declining trend over time. The decline was more marked in the periods following the adoption of the national population policy in the country. Further, it was lower in urban areas and among women who have secondary and above level of education, but higher among women not working and those engaged in agricultural activities. Housewives and women working in the agricultural sector should be given attention to reduce the risks and consequences of adolescent motherhood. PMID- 23444554 TI - Low cost, simple, intrauterine insemination procedure with unwashed centrifuged husband's sperm for developing countries. AB - There is an increased need for low cost procedures in treating infertility particularly in developing countries. Intrauterine insemination was used long before the advent of in vitro fertilization. During the last 30 years however, intrauterine insemination has evolved with the introduction of ovulation stimulating protocols and sperm preparation methods taken from assisted reproduction techniques. Costs have risen, but the success rate has not risen to the same extent. We have therefore developed a quite simple intrauterine insemination technique which may be performed in developing countries, without the need of sophisticated equipment, costly materials, media, or disposable insemination catheters; it is quite inexpensive and may be performed by trained staff, such as nurses or midwives. 20 to 27% (depending on the aetiology of their reproduction problem) of the couples remained clinically pregnant after an average of 3.5 to 3.8 intrauterine inseminations procedures. PMID- 23444555 TI - Getting Real with Youth-Friendly Services in Africa: Report of a satellite session at the 2012 International HIV/AIDS Conference. PMID- 23444556 TI - Patient-controlled analgesic infusion pumps. Making a painless purchase. AB - Patient-controlled analgesic infusion pumps give patients the ability to self administer pain-relieving medication as needed within the limits set by a physician. The most significant risk associated with these pumps is the possibility of oversedation, potentially leading to life-threatening narcotic induced respiratory depression. We examine nine pumps, basing our ratings on safety and ease of use. PMID- 23444557 TI - RTLS end-user software. Understanding what it can do for you. AB - The end-user software of a real-time locating system is crucial. You may just be getting familiar with some of the more basic applications that are available. But real-time locating offers great possibilities for improving patient care, workflow, and the bottom line. Here's what you need to know to make the best software purchase and get the most out of your system. PMID- 23444558 TI - Energizing Richard Wolf E-Line stricture blades can result in electrosurgical burns. AB - Stricture blades sold by Richard Wolf for use with its E-Line resectoscopes can be mistaken for electrodes and used for electrosurgical applications, potentially resulting in alternate-site electrosurgical burns. Users of these products--and similar products that may be marketed by other endoscopy suppliers--must be adequately trained on the proper identification and use of these instruments. PMID- 23444559 TI - Liquid ingress into intermediate siderails of Hill-Ram TotalCare beds may cause contamination. AB - Liquids--potentially including infectious body fluids such as blood--may enter the compartments within the intermediate siderails of Hill-Rom TotalCare beds, which could cause contamination of interior surfaces. This can potentially expose staff servicing the intermediate siderails to infectious materials. When performing service on these siderails, staff should follow their facility's safety procedures for handling and disinfecting potentially contaminated equipment. Additionally, to reduce the risk of liquid ingress, service staff should replace the foam gasket used in the siderail assembly each time the siderail is opened. PMID- 23444560 TI - Hydrogen peroxide and povidone-lodine solution--a dangerous combination. AB - When mixed with povidone-iodine solution, hydrogen peroxide can release enough oxygen to cause sealed waste containers to burst open. Such risks can also result from using a sealed container to collect hydrogen peroxide that has mixed with body fluids (for instance, in a debridement procedure). Staff should be instructed to avoid both practices. PMID- 23444561 TI - Ferromagnetic detectors. Which systems are the most attractive? AB - Ferromagnetic detectors identify objects that could become dangerous within the powerful field created by a magnetic resonance system. In doing so, these devices can help minimize risks to patient and staff safety, as well as concerns about liability and equipment damage. The best detectors have high sensitivity while minimizing false alarms, are straightforward to use, and are easy to install. PMID- 23444562 TI - Incorrect installation of free-flow clamp in B. Braun Infusomat Space infusion pump may result in gravity flow. AB - Gravity flow--potentially resulting in a dangerous overinfusion--may occur with the B. Braun Infusomat Space infusion pump if the infusion set's free-flow clamp is not correctly inserted in the pump. The manufacturer is currently evaluating measures to reduce the likelihood of this error. In the interim, facilities should ensure that users are familiar with proper use of the pump and are trained to recognize signs that the infusion set was loaded incorrectly. PMID- 23444563 TI - Draeger Medical Evita and Savina ventilators may incorrectly display high-airway pressure alarm following some circuit disconnections. AB - If the patient's breathing circuit becomes disconnected during a high-airway pressure event, Draeger Medical's Evita series and Savina ventilators may continue to display an "Airway Pressure High" alarm message, rather than appropriately displaying the "Airway Pressure Low" message. This may distract staff from the true hazard, potentially inhibiting or delaying care of ventilated patients. Facilities should alert users of Evita and Savina ventilators to this behavior and direct them to verify connection of the breathing circuit when responding to "Airway Pressure High" and other high-priority alarms. PMID- 23444564 TI - Siemens Somatom Definition Flash. The latest in dual-source CT. AB - The Siemens Somatom Definition Flash is the latest dual-source CT scanner to hit the market. It provides very fast scanning, minimizing the effects of patient movement. This makes it especially valuable in trauma, pediatric, and cardiac scans. It also provides very good dose reduction. We assess the flash's benefits and limitations, as well as how it compares to other high-end scanners. PMID- 23444565 TI - Calling for help. Using outside parties for equipment servicing. AB - You may be thinking about having your equipment servicing done by the device manufacturer, or contracting with an independent servicing organization. Each choice presents its own set of issues to consider. Here's what you need to know when weighing the options. PMID- 23444566 TI - Alarms may be inaudible in some Gambro Artis dialysis systems. AB - In Gambro Artis dialysis systems with software version 6.04.16, a problem with the audible alarm mechanism may prevent users from hearing alarms. The unit will still display visual alarm indicators. Gambro is replacing the audible alarm mechanisms in affected units at no cost as part of an upgrade. Until the upgrade is performed, facilities with affected systems should inform users that alarms may be inaudible and should ensure that units are positioned so that users have clear, unobstructed views of status lights and displays. PMID- 23444567 TI - Monopolar active accessories can be connected to Covidien ForceTriad electrosurgical generators incorrectly, disabling coagulation mode. AB - The monopolar output receptacle on the Covidien ForceTriad electrosurgical generator is designed in such a way that users can unknowingly connect active accessories in the wrong orientation, disabling the system's coagulation function. The manufacturer is developing labeling for ForceTriad production units that depicts the proper orientation in which to connect the accessory during setup. Covidien is currently considering how it will address units already in the field. PMID- 23444568 TI - Can you consider using the Steris System 1 E even without a biological indicator? Yes, but decide carefully. PMID- 23444569 TI - External manual defibrillators. Focus on the Physio-Control Lifepak 15. AB - The Physio-Control Lifepak 15 is a satisfactory entry in the manual defibrillator marketplace. It doesn't offer CPR feedback, but it does have some other advantageous features. We rate the Lifepak 15 and compare it to seven other available models. PMID- 23444570 TI - Sure to shock. ECRI Institute's defibrillator checklists. AB - Defibrillators are vital lifesaving devices, and their failure to function can put patients at risk. Effective user checks can go a long way toward guaranteeing that your defibrillators will be ready for use whenever they're needed. Included in this article are two checklists for you to use--one for manual defibrillators and one for AEDs. PMID- 23444571 TI - Look who's 40! To celebrate the 40th anniversary of Health Devices, we revisit our first issue. AB - In April 1971, Health Devices premiered. Healthcare was a very different world then. Yet some of the challenges are very much the same today. Join us in looking back at our inaugural issue and at healthcare then and now. PMID- 23444572 TI - No-flow alarm disabled in respironics EverFlo oxygen concentrators equipped with optional low-flow flowmeter. AB - Respironics EverFlo oxygen concentrators can be equipped with an optional internal low-flow flowmeter, but when this flowmeter is in place, the unit will not alarm for no-flow conditions. Facilities should consider using an oxygen concentrator other than the EverFlo for pediatric patients, who may be harmed by a loss of supplemental oxygen. Facilities that choose to continue using the EverFlo with the low-flow flowmeter should ensure that pediatric patients are appropriately monitored, such as with a pulse oximeter. PMID- 23444573 TI - Confusing "No Shock Delivered" messages on Philips HeartStart XL and HeartStart MRx defibrillators may delay therapy. AB - When Philips HeartStart XL and HeartStart MRx defibrillators abort a discharge because they detect high transthoracic impedance, the message that appears may not adequately describe why the shock was not delivered. This could create confusion and delay therapy to the patient. Users should be aware of the problem so that they know what to do when such a message appears. PMID- 23444574 TI - Hospira recalls Plum A+ and Plum XL infusion pumps due to failure of audible alarm. PMID- 23444575 TI - Steris System 1 updates: transition period extended; proposed lawsuit settlement may increase compensation for users. PMID- 23444576 TI - Vital signs monitoring systems. A look at seven monitors and their connectivity solutions. AB - Because they are capable of connecting with electronic medical records, today's vital signs monitoring systems can increase the accuracy and efficiency of getting vitals data into a patient's record. But this has also made the systems more complex--not only to install and use, but also to shop for. We've evaluated seven systems to make the choice easier. PMID- 23444577 TI - Medrad Continuum MR infusion system components must remain secured in MR environment. AB - The infusion pump component of the Medrad Continuum MR infusion system contains ferromagnetic materials and may be pulled into the MR system's bore if not adequately secured. Users need to be aware that neither the pump nor any other components should be removed from the system within the scan room. Additionally, before bringing the system into the scan room, users should verify that the system is free of damage and that the pump and its mounting bracket are both firmly secured. PMID- 23444578 TI - Electromagnetic interference may cause false asystole alarms in certain Philips IntelliVue monitoring products. AB - Electromagnetic interference (EMI) may cause some Philips Healthcare IntelliVue MMS, MP2, MP5, and X2 patient monitoring products to incorrectly display a flat electrocardiogram (ECG) waveform and generate a false asystole alarm. This occurs while the devices' pace pulse rejection feature is enabled. Facilities that suspect such behavior in their inventories should contact Philips to discuss whether installation of firmware version D.02.05 will help address the problem. PMID- 23444579 TI - Upgraded software changes the oxygen sensor calibration procedure in Covidien's Puritan Bennett 840 ventilator. AB - Users need to be aware that once Covidien's Puritan Bennett 840 ventilators have received upgraded software for the neonatal configuration, a different procedure will usually be required when calibrating the units' oxygen sensor for neonatal use. Since the function of the previous "100% O2/cal 2 min" key--which some users employed for this calibration--has now changed, users should instead perform calibration through the "More Settings" menu. PMID- 23444580 TI - Top 10 technology hazards for 2012. The risks that should be at the top of your prevention list. AB - Health technology offers countless benefits. It also presents numerous risks. Most of these can be avoided--with work. But in a constantly changing environment, it's not always easy to know where best to concentrate your efforts. Our annual list will help you make smart decisions about your safety initiatives during 2012. PMID- 23444581 TI - Get hip. An introduction to total hip replacement surgery and hip implant designs. AB - As both the prevalence of hip replacement procedures and the price of implants increase dramatically--with reimbursement lagging far behind--hospitals are hard pressed to control costs. To address the problem, a growing number of facilities are becoming involved in the selection of hip implants--a task traditionally reserved for the surgeon. As nonclinical personnel take part in this process, it is crucial that they understand the technology in order to make decisions that control costs while ensuring appropriate patient benefit. PMID- 23444582 TI - Non-current diagnostic software in Hamilton Medical's Hamilton-C2 ventilators may, in rare cases, cause the ventilator to stop delivering breaths. AB - While investigating a problem report involving a Hamilton Medical Hamilton-C2 ventilator, ECRI Institute learned that the diagnostic component of software versions prior to 2.0.7 could, in rare cases, cause the ventilator to enter a fail-safe condition and terminate the delivery of breaths to the patient even though the unit may be capable of safely continuing ventilation. Hamilton has incorporated changes in the software (beginning with version 2.0.7) to reduce the possibility of this behavior occurring. Facilities using Hamilton-C2 ventilators equipped with software version 2.0.6 or earlier should contact their local Hamilton Medical representative to arrange for their units to be updated to the current software version. PMID- 23444583 TI - The story of immunization. Foreword. PMID- 23444584 TI - A time of ignorance, a time of pathos, a time of change. Preface. PMID- 23444585 TI - The case for vaccines. AB - The case for vaccines is one which has been made through scientific advancement and public health implementation, resulting in one of the most significant historical achievements for mankind. This includes the elimination of endemic smallpox, polio, measles and rubella from the U.S. This exhilarating accomplishment was sobered with the threat of smallpox through biological attack following September 11, 2001. While the unthinkable return of that vaccine preventable disease never materialized, other vaccine-preventable disease, such as pertussis, have markedly increased in many states because of never-established or waning immunity. Drivers of these current threats come both from the anti vaccine movement, through legislative efforts to expand childhood immunization exemptions and the medical establishment itself through lack of immunization prioritization in adolescent and adult populations. Therefore, the case for vaccines needs to be made both externally and internally through sound science, sound logic and sound ethics. Most powerfully, however, the case for vaccines is told through stories of real people who have suffered or died from these preventable diseases. PMID- 23444586 TI - Tyler. PMID- 23444587 TI - Telling stories of vaccine-preventable diseases: why it works. AB - In this paper, we explore the benefits of storytelling in health communication and, in particular, immunization education. During the mid-20th century polio epidemic, both personal stories and scientific information abounded in the media. However, as rates of vaccine-preventable diseases declined, narratives about the dangers of such diseases faded as did the public fear of them. Meanwhile, anti vaccine advocates flooded the media and Internet with stories of injured children and tied those injuries, such as autism, to vaccines. Medical experts often counter anti-vaccine concerns with scientific information which can fail to persuade parents. Furthermore, evidence suggests that many people misunderstand quantitative information resulting in a misinterpretation of risk. Compared to scientific information, stories relate life lessons and values. They are effective because they are memorable and relatable. Evidence also suggests that storytelling can effectively improve health knowledge and behaviors. Inspired by In Harm's Way--True Stories of Uninsured Texas Children by the Children's Defense Fund and Faces of Influenza by the American Lung Association, we published Vaccine-Preventable Disease: The Forgotten Story, a collection of photographs and personal stories of families affected by vaccine-preventable diseases. We have found that the stories included in our booklet capture all the benefits of storytelling. Given the many benefits of storytelling, providers should strive to include stories along with medical facts in their daily practice. PMID- 23444588 TI - The state of immunization 2013: we are the world. AB - Most vaccine-preventable diseases in the U.S. are at record low levels, and immunization coverage among toddlers and teenagers is high or increasing. However, importations of measles virus from other countries, resurgences of pertussis and mumps, and the 2009 pandemic of influenza A H1N1 are reminders that Americans remain vulnerable to vaccine-preventable diseases and that sustained support for public health and clinician efforts is needed. Geographic areas with high rates of exemptions from vaccinations required for school attendance place communities at risk for disease outbreaks. There has been much progress internationally in reducing the toll of vaccine-preventable diseases, through public-private partnerships like the Global Alliance for Vaccines and Immunizations (GAVI). Paralytic poliomyelitis is on the verge of eradication, with wild virus transmission continuing in only three countries - Nigeria, Afghanistan and Pakistan. Intensified efforts in those countries are critical. The Decade of Vaccines Collaboration offers an opportunity to strengthen immunization in every community and country. PMID- 23444589 TI - A brief history of vaccines: smallpox to the present. AB - Modern vaccine history began in the late 18th century with the discovery of smallpox immunization by Edward Jenner. This pivotal step led to substantial progress in prevention of infectious diseases with inactivated vaccines for multiple infectious diseases, including typhoid, plague and cholera. Each advance produced significant decreases in infection-associated morbidity and mortality, thus shaping our modem cultures. As knowledge of microbiology and immunology grew through the 20th century, techniques were developed for cell culture of viruses. This allowed for rapid advances in prevention of polio, varicella, influenza and others. Finally, recent research has led to development of alternative vaccine strategies through use of vectored antigens, pathogen subunits (purified proteins or polysaccharides) or genetically engineered antigens. As the science of vaccinology continues to rapidly evolve, knowledge of the past creates added emphasis on the importance of developing safe and effective strategies for infectious disease prevention in the 21st century. PMID- 23444590 TI - The science of vaccination: establishing safety and efficacy. AB - Vaccination remains a critically important public health tool. It has been responsible for drastically reducing the occurrence of diseases that were once responsible for invoking extreme fear and anxiety. As a consequence, vaccines themselves, and not the diseases they help prevent, have now become the focus of fear and anxiety for many. This review describes the various activities and systems that are in place to ensure that modern vaccines continue to be safe and effective. A better understanding of existing safeguards may help bolster public confidence in immunization. PMID- 23444591 TI - Current controversies in childhood vaccination. AB - As pediatric practitioners, one of the contemporary challenges in providing medical care for children is the increasing proportion of vaccination refusal. This occurs in spite of the demonstrated individual and collective benefit and cost effectiveness of vaccination. Controversies regarding vaccine components and side effects have misled parents to believe that vaccines might be harmful based on inaccurate data from the Internet, celebrities, as well as misinterpreted and frankly bad science. This belief of vaccines being harmful has led to fear and decreased immunization rates in spite of sound scientific evidence supporting the safety of vaccines and their lack of association with autism, developmental disabilities or other medical disorders. Some parents also believe in alternative ways to avoid disease, often adhering to practices that have little foundation in the best of empiric science. It is not a coincidence that recent outbreaks of vaccine-preventable diseases, including measles and pertussis (whooping cough), have occurred in areas where vaccination has declined largely due to exemptors. This article intends to review some of the common vaccine myths and controversies and to serve as a resource to provide accurate information and references for busy practitioners and the families that we serve. PMID- 23444592 TI - Roots of vaccine hesitancy. PMID- 23444593 TI - A brief history of autism, the autism/vaccine hypothesis and a review of the genetic basis of autism spectrum disorders. AB - Autism spectrum disorders (ASD) represent a common spectrum of developmental disabilities, sharing deficits in social interactions, communication and restricted interests or repetitive behaviors with difficult transitions. In this article, we review the history of the identification and classification of autism and the origin of the now widely-debunked autism/vaccine hypothesis. The differences between syndromal (complex) and non-syndromal (essential) autism are described and illustrated with case descriptions where appropriate. Finally, the evidence that autism is fundamentally a genetic disease is discussed, including family studies, the role of DNA copy number variation and known single gene mutations. PMID- 23444594 TI - Becoming a vaccine champion: evidence-based interventions to address the challenges of vaccination. AB - The incidence, prevalence, morbidity and mortality rates of vaccine-preventable diseases have decreased drastically since the advent of modern vaccination by Edward Jenner at the end of the 18th century. In recent years, however, a growing number of parents have been refusing or delaying vaccination for their children for socioeconomical, medical, religious and/or philosophical reasons. This has resulted in a loss of herd immunity that has caused a resurgence of many infectious diseases. This article describes evidence-based methods by which a pediatric clinic can become a vaccine champion by aiming at vaccination rates of 100 percent. This goal can be attained by a team effort that addresses the challenges of vaccination by using every visit as a chance to vaccinate, educate, address the fears and the concerns of the parents and provide articles and other written documentations on the benefits and side effects of vaccines. A standardized system that identifies and tracks patients who need vaccines is also essential to find those who are seldom brought to medical attention. A consistent and systematic use of these evidence-based methods by a dedicated staff is essential to attain vaccination rates close to 100 percent. PMID- 23444595 TI - Vaccinating through a lifetime: adult priorities. AB - Vaccination strategies for adults have recently been updated to include newer vaccine products and to reflect the changing epidemiology of vaccine-preventable diseases in adults. New products include vaccines against shingles and the human papillomavirus, and a combination vaccine which contains an acellular pertussis component (Tdap). In some cases, existing vaccines have been re-formulated to provide alternate routes of delivery, as is the case with the influenza vaccine, or more effective formulations, as is the case with the meningococcal vaccine. Vaccine strategies for adults are designed to respond to existing, emerging, or re-emerging infectious diseases in populations at risk. This includes the resurgence of pertussis and recent evidence showing that diabetics are at increased risk for hepatitis B. Unfortunately, large portions of the adult population do not receive recommended vaccinations. As a result, more adults die from vaccine-preventable diseases than die from motor vehicle accidents. Strategies to improve vaccine coverage include public education campaigns and making some vaccines available in nontraditional settings such as retail stores or workplaces. Within health care settings, successful strategies have included the use of standing orders, automatic reminders for physicians using the electronic health record and recall/reminder letters for patients. Appropriate use of adult vaccines plays a key role in prevention of disease and the provision of high-quality care. PMID- 23444596 TI - Pregnancy and vaccines. AB - Vaccination during pregnancy is important for both women and their offspring; however, vaccination rates can be improved, and health care providers are in a unique position to be able to do so. This article summarizes current information on vaccinations and strategies for addressing patients' concerns related to immunization during pregnancy. Particular attention is given to influenza and tetanus, diphtheria and pertussis vaccinations. PMID- 23444597 TI - Vaccine-preventable diseases and vaccination rates in South Dakota. AB - Vaccine-preventable diseases have historically caused much illness and death in South Dakota. Sixty-seven diphtheria deaths were reported in 1892 and 1,017 polio cases were reported at the peak of the polio epidemic in 1952. As vaccines have been developed, licensed and put into wide use, the rates of diphtheria, polio, measles, smallpox and other diseases have successfully decreased leading to control, statewide elimination or eradication. Other diseases, such as pertussis, have been more difficult to control by vaccination alone. Although current vaccination coverage rates for South Dakota's kindergarten children surpass the Healthy People 2020 targets of 95 percent, the coverage rates for 2-year-old children and teenagers are below the target rates. Until vaccine-preventable diseases are eradicated globally, we must vigilantly maintain high vaccination coverage rates and aggressively apply control measures to limit transmission when diseases do occur in South Dakota. PMID- 23444598 TI - The impact of vaccination among American Indians--progress and challenges. PMID- 23444599 TI - Immunization and travel. PMID- 23444600 TI - Vaccination and the health care worker. AB - Historically, health care worker vaccination has been a strategy to protect the health care worker from infectious work related risk. This article will discuss the transition to health care worker vaccination as a key patient safety initiative for hospitals and health care systems. As the case is evolving toward mandatory influenza vaccination of health care workers, we have outlined key success factors for a voluntary program in a rural frontier referral hospital. Additionally, pertussis vaccination for health care workers is discussed as to the patient safety aspects of a progressive approach further making the case for value creation on behalf of our patients we have the privilege of providing care. PMID- 23444601 TI - Influenza vaccination: a 21st century dilemma. AB - Each year, an average of 5 to 10 percent of the U.S. population has symptomatic influenza illness, 226,000 persons are hospitalized and 24,000 die due to influenza-associated illness. Hospitalization rates are highest at the extremes of age, about one per 1,000 or higher in infants, persons age 65 and older and persons with chronic medical conditions. Ninety percent of deaths are in persons age 65 and older, but deaths also occur rarely in healthy children and young adults. Current influenza vaccines are moderately effective, with current evidence suggesting that they can prevent about half of influenza-associated symptomatic illness, outpatient visits, hospitalizations and deaths, with the evidence weaker for the most serious complications. Current licensed vaccines have mild immediate adverse effects and serious adverse effects are rare. Annual estimates of influenza vaccine effectiveness against the spectrum of clinical illness and in all age groups are needed to evaluate and support current vaccine policies and to help guide more effective vaccine development. Increased use of the current imperfect vaccines could prevent substantial morbidity and mortality in the U.S. PMID- 23444602 TI - Safe handling of vaccines: the rewards of rigorous routines. AB - A recent report published by the Office of Inspector General (OIG) entitled Vaccines for Children Program: Vulnerabilities in Vaccine Management has brought to public awareness the need for increased attention to safe handling of vaccines. The maximum benefit of receiving vaccines for vaccine-preventable diseases can only be attained when we ensure that safe storage and handling occurs through strict adherence to the vaccine cold chain. This compliance can best be accomplished by identifying a vaccine coordinator that is intimately familiar with the components of the vaccine cold chain and provides the necessary oversight to ensure that all links in the chain are maintained. Utilization of helpful resources, including the Centers for Disease Control and Prevention (CDC) resources related to safe handling of vaccines, is central to a well defined process for vaccine handling. This adherence provides reassurance, both to patients receiving vaccine and providers administering it, that the safest and most effective vaccine is being delivered. PMID- 23444603 TI - The new vaccine frontier. AB - Vaccines are one of the greatest public health achievements and have had a tremendous impact on people's health and survival around the world. Nevertheless, highly prevalent infectious disease threats unresponsive to traditional immunization strategies, emerging and re-emerging threats, and non-communicable diseases amenable to immunization remain critical global health challenges. Scientific advances will reveal solutions, but it will take political, social and economic commitment from all stakeholders for these solutions to achieve their health protection benefit among the people who need them most. PMID- 23444604 TI - Vaccines in the 21st century: a cautionary tale. PMID- 23444605 TI - Seasonal flu vaccines advancing the delivery of colorectal cancer screening. PMID- 23444606 TI - Immunization schedules. PMID- 23444607 TI - [Histoplasmosis updating]. AB - Histoplasmosis, an infection caused by the fungus Histoplasma capsulatum, has been reported all over the world and is considered endemic in the American continent, including Cuba. This fungus grows on the soils contaminated with bird and bat excreta, where it produces a great number of microconidia that could cause the infection when they are inhaled. The clinical spectrum varies from asymptomatic infections to serious disseminated diseases involving one or many organ systems and affects mainly AIDS patients, patients with hematological neoplasias, transplant recipients or other immunosuppressed patients. The main risk groups include those individuals whose working activities make them be exposed to aerosols contaminated with H. capsulatum. Lab diagnosis is based on the microscopic observation, isolation and identification of the fungus in fluid or tissue samples of patients, and on specific antigen and antibodies detection. The molecular methods based on polymerase chain reaction have not been sufficiently defined, and they could be an important advance in the early diagnosis of this mycosis. Itraconazole is recommended for treatment of moderate, localized and chronic infection whereas amphotericin B is the drug of choice for disseminated and serious manifestations, particularly in its lipidic formulations. At present, histoplasmosis is considered one of the most important systemic mycoses in the Americas, and it is widely spread over all regions of Cuba. PMID- 23444608 TI - [Convalescence of pregnant women who suffered from dengue serotype 3]. AB - INTRODUCTION: dengue is an infectious disease caused by ARN genome virus and has 4 recognized serotypes (DEN-1, DEN-2, DEN-3 and DEN-4) that are transmitted by Aedes aegypti as the main vector. The clinical manifestations of dengue in pregnancy are similar to those of the general population, except that the ecosystem is made up by the mother and the fetus where the virus with its genetic characteristics is introduced and finds special conditions for development and evolution. OBJECTIVE: to study the progression of the dengue symptoms in women who got sick during their pregnancy for one year of follow-up. METHODS: an observational descriptive research was conducted to find out the existence of sequelae in women who were infected with dengue 3 during their pregnancy. A cohort of 28 pregnant women, who had been admitted to "Juan Bruno Zayas Alfonso" General Hospital at the time of the dengue outbreak from April to November 2006, was studied. The diagnosis was serologically confirmed. RESULTS: after one-year of follow-up, it was observed that amnesia (25 %) and menstrual disorders (14.3%) affected these women. Amnesia was significant when the infection occurred in the third trimester of pregnancy, p=0.0377. CONCLUSIONS: dengue 3 infection may cause amnesia in pregnant women who suffered this disease, particularly in their third trimester of pregnancy. PMID- 23444609 TI - [Dengue virus serotype 2 strains isolated from the epidemic occurred in Santiago de Cuba in 1997]. AB - INTRODUCTION: during the Cuban epidemic that occurred in Santiago de Cuba in 1997, there was observed increasing severity in the course of time, in terms of proportion of serious dengue haemorrhagic cases and deaths that could be due to the emergence of escape mutants to neutralization with greater virulent potential. OBJECTIVE: to study some biological attributes of a group of strains isolated at different points of time during the Santiago de Cuba epidemic in 1997. METHODS: nine DENV-2 strains were studied. The cytopathogenic effect, the viral growth in C6/36 HT and VERO cell lines, the virus plaque sizes, the sensitivity to temperatures, the neurovirulence in newborn mice and the influence of the pH in the union of the virus to the cell as well as in the multiplication medium were all evaluated. RESULTS: the strains isolated at the end of the epidemic differed from those of the beginning showing increased neurovirulence in newborn mice and higher viral titers and greater cytopathogenic effect in HT C6/36 cells. On the other hand, the virus and the cell union was favored by acid pH when testing strains from the beginning of the epidemic, whereas this union was favored by the basic PH in the strains isolated at the end of the epidemic CONCLUSIONS: the present study managed to show that in addition to the previously observed genotypical changes, there were phenotypical differences among the strains isolated at different points of time in the epidemic; all these aspects may be associated with differences in the viral fitness and/or in the virulent potential of these strains. PMID- 23444610 TI - [New evidence in the susceptibility to dengue infection associated to HH polymorphism of FcgammaRIIa receptor]. AB - INTRODUCTION: polymorphic variants of FcgammaRIIa receptor have been associated to susceptibility to develop several infectious diseases. The relationship between the polymorphism of this receptor and the susceptibility to dengue hemorrhagic fever was recently reported. OBJECTIVES: to explore whether the association of the homocygotic variants of the receptor to susceptibility to or protection from a disease could be also related with the IgG antibody titters and the exposure to a number of infections. METHODS: a retrospective analytical study was performed on individuals who had been infected with the dengue virus 4 during the 2006 epidemic in the City of Havana and were tracked down in 2008. A total number of 97 individuals were recruited of whom 68 had suffered dengue fever and 29 had had dengue hemorrhagic fever. A 10-mL blood sample was taken from each of them and then placed in EDTA anticoagulant for DNA isolation and 5 mL placed in dry tubes to obtain serum. The genetic polymorphism of FcgammaRIIa receptor, the total anti-dengue IgG antibody titers and the antecedent of dengue infection were determined. RESULTS: it was interesting to note that there was very significant direct relation (p< 0.0001) between high anti-dengue IgG antibodies titers and the number of infections suffered by these people. This behaviour was present in those individuals with the HH homocygotic variant. CONCLUSION: it seems that those individuals with polymorphism in FCgammaRIIa-H/H receptor would tend to non elimination of IgG antibodies through this receptor, which is associated to the number of infections suffered by the individual. PMID- 23444611 TI - [Serological study carried out in Cuban localities where confirmed western Nile virus infection is present]. AB - INTRODUCTION: first infected cases caused by West Nile virus were reported in Cuba in 2004. OBJECTIVE: to monitor and learn about the prevalence of the West Nile virus in those areas with confirmed cases. METHODS: the study was conducted in Jatibonico municipality and in the city of sancti Spiritus. A total number of 14 persons, 8 horses and 41 birds were researched to detect antibodies to flavivirus and specific antibodies to West Nile virus. RESULTS: the presence of specific antibodies to West Nile virus was confirmed in 4 samples of sera from birds and in 4 from horses. One person was confirmed as one case of asymptomatic West Nile virus infection. CONCLUSIONS: the presence of specific antibodies to West Nile virus in birds, horses and persons residing in areas where there are confirmed cases showed that a local amplification cycle had been established in Cuba before this study. PMID- 23444612 TI - [Active surveillance of adverse effects of Pandemrix vaccine to prevent influenza A(H1N1) in Cuba]. AB - INTRODUCTION: in April 2009, a new virus was identified in Mexico and North America as the cause of a respiratory disease. The virus quickly spread over other countries. On June 11, 2009 the World Health Organization (WHO) reported cases in 74 countries and territories located in 2 of its regions. The high sustained transmission of this virus worldwide led to establish the phase 6 or the pandemic phase, indicating that the situation had to do with spreading rather than increased severity. OBJECTIVES: to report on already known or new events after the administration of vaccine A(H1N1) called Pandemrix, to identify the most frequent events occurred in pregnant women and to research into the associated severe events. METHODS: a prospective descriptive study was designed to characterize the adverse effects of Pandemrix reported across the country from April 1st to June 30th, 2010. A total of 1,123,526 people were vaccinated in which 100% of pregnant women were included. RESULTS: active surveillance nationwide reported 5 763 signs and symptoms detected in 3 401 people (615 reports from pregnant women). The overall rate of reports was 302.7 x 100 000 doses administered. Adverse events such as fever, headache, pain, swelling and redness at the injection site, malaise, arthralgia, allergic reactions, nausea and vomiting were reported as common symptoms. These 10 symptoms and signs accounted for 79.1% of all the reported events. A total number of 80 317 pregnant women were vaccinated of whom 615 reported adverse effects, accounting for 0.8 % of the vaccinated pregnant women. Fever was the most notified symptom in children (193) followed by local reactions at the injection site (23), vomiting (20), arthralgia (17), headache (11), malaise (10) and high fever-related seizures (6). Eight events were analyzed as severe. CONCLUSIONS: the administration of the vaccine was related to 3 events, unrelated to other 3 events and 2 were classified as inconclusive (3 miscarriages). No deaths were reported. The capacity of the Cuban Health System for the administration of this vaccine with active surveillance in a short period of time was proved. Data from monitoring of events that were supposedly attributable to vaccination or immunization did not notify any unusual event. Therefore, no safety problem is associated to the Pandemrix vaccine. PMID- 23444613 TI - [Rapid serological diagnosis systems for human leptospirosis screening in Cuba]. AB - INTRODUCTION: human leptospirosis requires rapid and early microbiological diagnosis since it is a common lethal disease worldwide. OBJECTIVES: to increase the quality of microbiological diagnosis of this infection, to expand the knowledge on the circulation of groups of leptospiras in Cuba and to show the benefits of an agglutination assay using Cuban latex particles and of commercial immunochromatogenic systems LEPTO Dipstick, Lepto Tek Lateral Flow, Lepto Tek Dri Dot and SD Leptospira IgM-IgG. METHODS: this descriptive research used sera from positive and negative control cases to evaluate and measure the diagnostic value of rapid serological diagnosis systems with respect to the microagglutination method of reference (MAT). All the techniques used in this report are described in the Manual of Operations and Procedures of the Leptospira Lab in "Pedro Kouri" Institute of Tropical Medicine. RESULTS: all the studied diagnosis systems exhibited acceptable values of sensitivity, specificity and agreement when compared to the international microagglutination method of reference with live microorganisms. The great selectivity (antigen reactivity) and the diagnostic reliability of the diagnostic systems were confirmed; particularly the mixed Cuban-made latex, the LEPTO Dipstick and the SD Leptospira IgM-IgG. CONCLUSIONS: the procedures used in this research work exceeded the traditional methods including the microagglutination method of reference in terms of easiness, rapidity, technical simplicity and level of performance, and all were useful for the screening of antibodies to leptospiras. PMID- 23444614 TI - [Burden of disease due to bacterial meningitis, Cuba 2006]. AB - INTRODUCTION: bacterial meningitis is a real concern for physicians and general health systems of any country as well as the international bodies. OBJECTIVE: to estimate burdens of disease from morbidity and mortality caused by bacterial meningitis in Cuba during 2006. METHODS: the mortality and the incidence data of the epidemiological survey from the National Surveillance of Bacterial Meningitis of "Pedro Kouri Institute of Tropical Medicine were used. The estimation methods were based on the WHO recommendations by using the DISMOD and the required Excel spreadsheets. RESULTS: the global burden of bacterial meningitis was estimated at a total of 3527.26 Disability Adjusted Lost Years (DALYs), which accounted for 31.3 years lost per 100 000 inhabitants. Morbidity and mortality burden of bacterial meningitis without sequel weighing was 2056.25 disability adjusted lost years, being the 55.9 % caused by unidentified agent, followed by S. pneumoniae (30.9 %), N. meningitidis (9.5 %) and H influenza type b (3.6 %). The mortality burden was 2 039 years of life lost from premature death, that is, 57.8 % of the global burden. Children under five years of age contributed the biggest global burden of disability adjusted lost years, and S. penumoniae generated the biggest burden. CONCLUSION: the burden of bacterial meningitis was high. Burden of disease is an important measure to assess health problems. PMID- 23444615 TI - [First molecular detection of Rhodococcus equi in a HIV/AIDS patient in Cuba]. AB - INTRODUCTION: Rhodococcus equi is recognized as an emerging pathogen that causes important morbidity and mortality among immunocompromised patients. OBJECTIVE: to confirm the presence of R. equi in pleural fluid through the restriction fragment length polymorphism technique. METHODS: the pleural fluid sample from one AIDS patient with respiratory symptoms was used. Microbiologic culture, staining tests, phenotypic and biochemical tests and restriction fragment length polymorphism technique for the diagnosis of microorganism were performed. RESULTS: the staining technique along with the phenotypic and biochemical tests provided the presumptive diagnosis of R. equi infection, which was further confirmed by the molecular techniques. CONCLUSIONS: this paper reported the molecular detection of R. equi from one HIV/aids patient for the first time in Cuba. The results suggested that the molecular biology techniques could be used in the diagnosis and identification of R. equi. PMID- 23444616 TI - [Detection of Leishmania infantum in an experimentally-infected hamster using immunohistochemistry]. AB - INTRODUCTION: visceral leishmaniasis is considered the most severe form of this disease and can be fatal if not properly treated. In Latin America, the infection is caused by Leishmania infantum (syn. Leishmania chagasi). The unequivocal diagnosis and the selection of a suitable experimental model are required to undertake studies on this biologic agent. OBJECTIVE: to determine the advantages of immunohistochemistry in identifying Leishmania. METHODS: hamsters were inoculated with Leishmania infantum promastigotes. The body weights of every animal were monitored, and the relative weights of their spleens and livers were estimated. For identification of amastigotes, Giemsa-stained imprints and an immunohistochemistry protocol in paraffin-embedded tissues were developed. RESULTS: the infection was reproduced in the experimental model. The immunohistochemistry was positive in infected animal sections and non-reactive for the control group. When compared with the Giemsa staining, this methodology facilitated the identification, particularly in organs infected with few parasites. CONCLUSIONS: immunohistochemistry is a specific tool for detection of Leishmania since it facilitates observation and eliminates any confusion in the identification of the parasite, thus improving the quality of diagnosis. PMID- 23444617 TI - [Change of erythrocyte charge with the use of Alcian blue method in Ascaris lumbricoides extracts]. AB - INTRODUCTION: the study of the host-parasite interactions is a new challenge to understanding some aspects of the parasitic metabolism and the mechanisms of invasion, immunological evasion and damage. Ascaris lumbricoides may cause anemia and thrombosis. It was previously shown that Ascaris lumbricoides modified the superficial charge of erythrocytes, which means that the parasite can capture sialic acid from the red blood cell. OBJECTIVE: to study the effect of adult parasite extracts on the erythrocyte charge using the Alcian Blue method and to compare its sensitivity with the Polybrene method: METHODS: fifty five adult parasite extracts and Group O erythrocyte suspensions were used. The erythrocytes were treated by incubating the sediment with an equal volume of parasite extracts for one hour at 37 degrees C. The control group (erythrocytes without any contact with the parasite extracts) was incubated with pH 7.4 phosphate buffer solution. Alcian Blue method was applied and the percentage erythrocyte anionic charge was determined in the control group and in the treated red cells. The experimental coefficient of erythrocyte anionic charge was defined as the quotient between the initial and the final percentage erythrocyte anionic charge. RESULTS: it was shown that 27 out of 55 parasite extracts (49.1 %) modified the charge of the red blood cells, being their experimental coefficient of the erythrocyte anionic charge 0.75 +/- 0.1144 whereas the same coefficient amounted to 0,94 +/- 0.0445 for those which did not show any charge variation. The statistical analysis concluded that the Polybrene and Alcian Blue Methods had comparable sensitivities (p>0.20). CONCLUSIONS: A. lumbricoides is able to capture sialic acid from the erythrocyte, which would not only explain the thrombosis attributed to the parasite, but also suggest that the nematode could use this acid either in its metabolic routes or for its strategies of immunological evasion. PMID- 23444618 TI - [Clinical and therapeutic behaviour of Fasciola hepatica in a series of 87 patients]. AB - INTRODUCTION: in the last few years, the Incidence rate of fascioliosis caused by Fasciola hepatica has increased worldwide. Cuba is one of the countries that have reported sporadic cases and also some outbreaks of fasciolosis. OBJECTIVE: to describe clinical and therapeutic features of this trematodiasis of digestive transmission found in 87 patients, who had been admitted to "Pedro Kouri" Institute of Tropical Medicine from January 1996 to December 2005. METHODS: patients were divided into 2 groups according to the prescribed drug, that is, triclabendazole and dihydroemetine. The clinical variables were collected at the time of diagnosis and 90 days after treatment; the means and the standard deviation were estimated. RESULTS: males was slightly predominant (54) in our series of patients admitted to the institute service. Consumption of watercress (Nasturtium officinale) was found in almost half of the patients. Abdominal pain, fever and malaise were the most frequent symptoms. Both drugs were useful to treat F. hepatica. CONCLUSIONS: this study showed the usefulness of lab tests for diagnosis and follow-up of patients after treatment. The anti-parasitic drugs dihydroemetine and triclabendazole proved to be effective at the prescribed doses in this research with minor adverse effects. PMID- 23444619 TI - [Effective treatment of a patient infested with pediculus capitis by using 5% Indigofera suffruticosa Mill tincture]. AB - INTRODUCTION: Pediculosis capitis was very frequently reported in Cuba since the end of the 90's, particularly in some groups of school children and their relatives. The latter are involved in a chain of transmission of these insects and may play an important role at present as parasite reservoirs. OBJECTIVE: to report on the efficacy of the treatment of one female patient suffering from Pediculus capitis by using 5 % Indigofera suffruticosa Mill (anil cimarron) tincture. METHODS: a case of persistent infestation with pediculosis capitis was described in which a 55 years-old patient was firstly treated with 1% permethrin solution and later with 5 % Indigofera suffruticosa Mill tincture. RESULTS: the microscopic identification of adult parasites and pre-adult stages of the parasite confirmed the presence of pediculus capitis. The hair treatment with 1 % permethrin was not effective after two applications. As an alternative, 5 % Indigofera suffruticosa Mill tincture was used and then the population of adult ectoparasites was reduced and the infestation was eliminated after the second application, with the paramedical staff continuously taking the nits out from the patient's hair. CONCLUSION: the use of this innocuous method may become a therapeutic alternative to treat this illness. PMID- 23444620 TI - [Thirty years after the Cuban dengue hemorrhagic epidemic occurred in 1981]. AB - Cuba reported the first dengue hemorrhagic fever epidemic in the American region in 1981. More than 344 203 cases with 10 312 severe and very severe cases and 158 fatalities were reported. Thirty years after this epidemic, the established surveillance, the control actions and the performed research studies have allowed the country to keep free of dengue, although some epidemics and waves of transmission have occurred, which have finally been eliminated. This paper summarized some interesting aspects related with this epidemic as well as with the laboratory surveillance and results of some of the main research works. PMID- 23444621 TI - [Second national survey of intestinal parasitic infections in Cuba, 2009]. AB - INTRODUCTION: the intestinal parasitic infections are still endemic in Cuba, with a higher frequency in rural and mountain regions. Twenty five years after the last national survey, it deemed necessary to carry out a new national survey in order to know the prevalence of intestinal parasitic infections and to compare the obtained results between both studies. That knowledge would be valuable to work out strategies of health and to design a control program for intestinal parasitic infections in Cuba. OBJECTIVE: to determine the current prevalence of intestinal parasitic infections in Cuba and to compare these results with those obtained from the previous survey after a 25 year-period. METHODS: a cross sectional study was conducted from May to August of 2009 in a sample of Cuban population. A stool sample was collected from each individual, which was analyzed by direct examination, Willis' brine flotation method and the Kato-Katz thick smear technique. Additionally, a questionnaire was administered. RESULTS: the comparison between 1984 and 2009 surveys showed a general decrease of frequencies of intestinal parasitic infections caused by both helminths and pathogenic protozoa; however, the percentage of infections with commensal protozoa increased in 2009. In this last survey, there was observed decline of frequencies of infections with soil transmitted species, Trichuris trichiura, Ascaris lumbricoides, hookworm, and Strongyloides stercoralis and the pathogenic protozoa: Giardiau lamblia, Entamoeba histolytica/E. dispar, and the commensals: Endolimax nana and Entamoeba coli. The intestinal parasite Enterobius vermicularis was the only parasitic species that increased the frequency of infections with respect to the 1984 survey. The frequencies of parasitic and commensal infections in both studies were higher in the 5-14 y age group (school age). CONCLUSIONS: the comparison between the intestinal parasitic infections surveys of 1984 and 2009 showed a reduction in the frequencies of intestinal parasitic infections in the last survey. The finding in both studies of a higher frequency of pathogenic parasitic infections and commensal infections in the 5-14 y age group (school age) supports the recommendation of making emphasis on the control programs for intestinal parasitic infections in this age group. PMID- 23444622 TI - Epidemiological analysis of eosinophilia and elevation of immunoglobulin E as a predictable and relative risk of enteroparasitosis. AB - INTRODUCTION: among the intestinal parasites, the helminthiasis occupies a prominent position in Brazil, since it worsens malnutrition and the gives rise to neurovegetative disorders. Helminths like Ascaris lumbricoides, Enterobius vermicularis, hookworm, Trichuris trichiura and Strongyloides stercoralis stand out due to several factors that modulate the immune response of individuals. Among the protozoa are Giardia lamblia, Entamoeba histolytica. E. dispar. Parasitic helminth antigens are important to stimulate the production of cytokines such as interleukin-4 and interleukin-5, which act through the induction of IgE synthesis and activation of eosinophils. Eosinophilia is usually detectable in pre-patent period of parasitism, initially linked to B lymphocytes, under the command of Th-2 lymphokines (IL-4 and IL-5), producing IgE in response to initial exposure to an antigen or allergen. Serum IgE high levels occur in tissue migration of larvae or harboring of parasites in tissues. OBJECTIVE: to determine the presence of eosinophils and IgE elevation in children with intestinal parasites. METHODS: high levels of IgE and eosinophils were observed in groups infected and not infected (allergic) to calculate the relative risk of intestinal parasites presumptive differentiated between protozoa and helminths and check what values of these indicators are observed in the epidemiological profile of the surveyed population. RESULTS: the values obtained by calculating the relative risk for eosinophilia, compared with helminths and allergies was 11.71, but when examined by giardiasis compared with other diseases, the relative risk was 0.75. Since the comparison of helminths and giradiase, the relative risk was 27.33. Since IgE and its parameters were appropriate commit Helminth relative risk 0.39; Giardiasis had relative risk 8, 18 and Helminths compared with giardiasis had 0.03. CONCLUSION: in this study it was possible to observe that helminthiasis is connected with cases of eosinophilia with alteration of IgE, which in turn contributes to the presence of IgE eosionofilia and has an effector response against helminths that provides the expulsion of its larvae. PMID- 23444623 TI - [Evaluation of the SD Dengue Duo diagnosis system for detection of NS1 protein and IgM and IgG dengue antibodies]. AB - INTRODUCTION: SD Dengue Duo (Standard Diagnosis) commercial kit is an immunochromatographic rapid test that detects NS1 protein and IgG/IgM dengue antibodies simultaneously. OBJECTIVE: to evaluate the operational and functional characteristics of this system for the detection of virological and serological markers. METHODS: sera panel was made up by 161 samples, 113 from patients with clinically and serologically confirmed dengue caused by any of the four dengue virus serotypes and 48 negative samples. All these samples were tested by SD Dengue Duo Kit and by Platelia Dengue NSI Ag, IgM Capture ELISA and ELISA Inhibition Method used as reference assays. RESULTS: the evaluated kit showed a 57.75% sensitivity for the detection of NS1 protein, false negatives were detected in samples collected 5 days or more after fever onset in secondary infection cases. IgM detection showed 96.0% sensitivity and 98.4% specificity. Furthermore, high agreement (95.7%) in classifying dengue infection types (primary or secondary infections) was observed. The global study of the 3 markers, the sensitivity rose to 100%. CONCLUSIONS: SD Dengue Duo is a simple, easy and rapid assay; it does not require additional equipment, can be used for acute and convalescence serum samples and offers a good alternative for dengue diagnosis in those laboratories where a complete dengue virus diagnosis is difficult to perform. PMID- 23444624 TI - [Classification of dengue hemorrhagic fever using decision trees in the early phase of the disease]. AB - INTRODUCTION: dengue is a viral disease with endemic behavior. At the beginning of the illness it is not possible to know which patients will have an unfavorable evolution and develop a severe form of dengue. However, some warning symptoms and signs may be present. OBJECTIVE: to apply decision tree techniques to the exploration of signs of severity in the early phase of the illness. METHODS: the study sample was made up of 230 patients admitted with dengue to "Pedro Kouri" Institute of Tropical Medicine in 2001. The variables considered for the classification were the signs, symptoms and laboratory exams on the third day of evolution of the illness. The algorithm of classification and regression trees using the Gini's index was applied. Different loss matrices to improve the sensitivity were considered. RESULTS: the algorithm CART, corresponding to the best loss, had a sensitivity of 98,68% and global error of 0,36. Without considering loss, it obtained its sensitivity reached 74% with an error of 0,25. In both cases, the most important variables were platelets and hemoglobin. CONCLUSIONS: the study submitted rules of decision with high sensitivity and negative predictive value of utility in the clinical practice. The laboratory variables resulted more important from the informational viewpoint than the clinical ones to discriminate clinical forms of dengue. PMID- 23444625 TI - [Educational intervention on HIV aimed at adolescent students of "Camilo Cienfuegos" military school in Arroyo Arenas]. AB - INTRODUCTION: HIV infection in young people is one of the main health problems at the present time, with significant mortality and morbidity indexes and considerable costs. OBJECTIVE: to identify the level of knowledge, the sources of information and the behaviours of young students at high school in order to take educational actions that raise their knowledge on this disease and promote more healthy lifestyles. METHODS: a quasi experimental study was designed to evaluate the results of an educational intervention in 200 adolescents of "Camilo Cienfuegos" Military School located in Arroyo Arenas, Havana, which was carried out in June, 2009. Demographic variables were analyzed and the effectiveness of the educational intervention was evaluated using ratio test for independent variable analysis. RESULTS: of the 200 studied students, 26.5% were female and 73.5% male, aged 14-17 years. The main sources of knowledge for information about HIV infection were TV, parents, professors and posters. They presented appropriate knowledge levels about transmission pathways, etiology and therapy of the HIV; however, they poorly knew about the clinical aspects and prevention. After the intervention, their general knowledge (73 to 92%) and the knowledge on clinical aspects significantly improved (15 to 72%),as well as the knowledge about transmission(92 to 94%) and prevention of the disease (77 to 80%). CONCLUSIONS: the implementation of a strategy to teach young people about HIV improved the knowledge about the disease in this group of patients PMID- 23444626 TI - [Preservation of high risk fungal cultures of Histoplasma and Cryptococcus]. AB - INTRODUCTION: culture collections are responsible for providing the microbial resources for development of biological sciences. Storage in distilled water is one of the easiest and least expensive method for long-term fungal preservation. OBJECTIVE: to evaluate the usefulness of this preservation method in fungal culture of Histoplasma and Cryptococcus. METHODS: the preservation condition of the highest biological risk species from Histoplasma y Cryptococcus genera, included in the fungal culture collection of "Pedro Kouri" Institute of Tropical Medicine in Havana, was evaluated in this study. One hundred and two strains stored in distilled water, 92% of which had been preserved for more than 10 years, were analyzed. RESULTS: the percentages of recovered strains from H. capsulatum, C. neoformans and C. gattii were 64.3%; 79.1% and 100% respectively. This method of preservation proved to be satisfactory for fungal culture in labs with limited financial resources. A web-based database with interesting information about the collection was made. The importance of strict compliance with the biosafety measures in these collections, particularly with high risk pathogens. CONCLUSIONS: preservation of fungal cultures in distilled water is a very useful method for laboratories with limited resources. Culture collections should be assumed as an essential activity in order to solve increasing challenges in the development of biomedical sciences. PMID- 23444627 TI - [Tuberculosis risk assessment in the staff of the National University Pneumologic Hospital of Havana]. AB - INTRODUCTION: tuberculosis is traditionally considered as a professional disease in health care workers. OBJECTIVE: to evaluate the individual and collective tuberculosis infection risk by areas or departments in the National University Pneumologiic Hospital of Havana, Cuba. METHODS: the individual risk was assessed during 2008-2009 by means of a survey administered to the staff that includes personal data, labor location and exposition to M. tuberculosis, and a Tuberculin Skin Test (TST) was applied to 112 of them. A > or = 10 mm cut-off point was used for positivity. The collective risk was measured in each area or department by the prevalence of TB infection, the tuberculin conversion rate and the number of tuberculosis cases hospitalized per year. RESULTS: of the 183 surveyed workers, 60.7% had workers for more than 5 years in the institution. Of the 64 negative workers in the previous survey, 34.4% became positive in this survey. The latent TB infection prevalence was 50.8% (CI 95%: 43.36-58.23); higher prevalence found in nurses (64.7%-CI 95%: 38.6-84.7) and lower in health non-related technicians(30%-CI 95%: 8.1-64.6). Half of the departments or areas (17/34) were evaluated as high risk, 23.5% as intermediate risk, 11.8% as low risk and 14.7% as very low risk. CONCLUSIONS: the National Pneumologic Hospital, as it was expected, is a high risk facility for Micobacterium tuberculosis infection that may affect its workers, and most of its areas pose a potential risk potential for the staff working there. PMID- 23444628 TI - [Antileishmanial activity of six extracts from marine organisms]. AB - INTRODUCTION: infections caused by protozoa of the genus Leishmania are a global health problem with a high prevalence in underdeveloped countries. There is no vaccine against this disease at present and the treatment used is poor, so the search for more effective and safe medicines is an urgent need. OBJECTIVE: to assess the in vitro antileishmanial activity of six aqueous and hydroalcohol extracts from marine organisms. METHODS: the activity of six extracts against Leishmania amazonensis promastigots and amastigots as well as their toxicity against peritoneal macrophages in BALB/c mice. RESULTS: in the promastigot assay, the extracts from Bryothamnion Iriquetrum, Bunodosoma granulifera, Halimeda opuntia and Physalia physalis showed growth inhibition at concentrations lower than 100 microg/mL whereas in amastigots, these last two extracts were the most active and least toxic with a selectivity index of 6 and 8 respectively. CONCLUSIONS: taking these results into account, it was considered that the H. opuntia and P. physalis extracts showed a promising activity, so it is suggested that further studies on its in vivo activity be conducted. PMID- 23444630 TI - [Cuban Society of Microbiology and Parasitology]. PMID- 23444629 TI - [First report of infective endocarditis in Cuba as a result of brucellosis]. AB - INTRODUCTION: the clinical manifestations of brucellosis have been poorly researched on and the symptoms and possible complications have not been deeply studied either. OBJECTIVE: to report a case of infective endocarditis caused by brucellosis for the first time in Cuba. METHODS: a Caucasian male farmer aged 57 years was referred from Vertientes municipality to be admitted at "Manuel Ascunce Domenech" provincial hospital in Camaguey province in December, 2009. He had been presumptively diagnosed with infectious endocarditis caused by Brucella and with moderate aortic failure since he presented with fever, general malaise, fatigue, muscle and joint pains, arthritis, marked asthenia, anorexia, neurological signs, sweating and strong chest pain. In his previous hospitalization, he had been treated with antimicrobials after indication of supplementary tests such as slow serology for brucellosis; however, specific reagents were not available,so these tests were not performed until January 2010.The epidemiological history of this case included his direct contact with cows and pigs as well as wounds and minor traumas inflicted on his hands and feet resulting from his type of work. His farm is next to another farm where the cattle is also affected with brucellosis. RESULTS: the lab tests were positive with high serological titres, and although it was not possible to isolate the etiologic agent through culturing, the disease and the infective endocarditis were serologically confirmed as additional complication; this required antimicrobial treatment and drugs for the heart disease. These complications from brucellosis are barely diagnosed in the international literature, and in Cuba, this is the first report of the disease. CONCLUSIONS: the description of this case is an alert to diagnosis of infective endocarditis that may be associated with epidemiological history of brucellosis. PMID- 23444631 TI - [Leishmaniasis diagnosis: going from microscopic observation of parasite to DNA detection]. AB - INTRODUCTION: Leishmaniasis is a disease caused by several species from Leishmania genus, which has been increasingly reported in the last few years. Several genetic, immunological factors and others related to this parasite have been associated to the outcome of the infection, and the occurrence of illness in varied clinical forms. All the aforementioned has an impact on the diagnostic method that should be used. METHODS: A basic and recent literature review was made, mainly focused on general aspects of leishmaniasis as epidemiological situation of disease, life cycle and transmission, vectors, clinical presentation and diagnosis; the latter shows information about the main methods used at present. The procedure followed by the Leishmania group at "Pedro Kouri" Institute of Tropical Medicine to support the diagnostic activities was presented as well. RESULTS: Updated practical information about the chosen topics was presented, with a practical guiding approach aimed at the health personnel that must face suspected leishmaniasis cases. Tables and figures summarized relevant aspects in an organized form, as well as the working algorithm of Institute concerning diagnosis was presented. The application of molecular diagnosis by this working team was particularly underlined. CONCLUSIONS: As leishmaniasis is still out of control, opportune diagnosis remains a must. All the methods provide useful information for taking decisions on clinical management, treatment and epidemiology of this parasitosis; hence, a working algorithm was submitted in our lab based on the most useful methods under our present conditions and experience. PMID- 23444632 TI - [Antimicrobial susceptibility of Escherichia coli isolates from river water ecosystems]. AB - INTRODUCTION: Antimicrobial resistance is one of the biggest problems facing global public health. The emergence of resistant clinical and environmental strains worsens the situation. Among the microorganisms with antimicrobial resistance, Escherichia coil species stands out due to its dual role as fecal contamination indicator and pathogen. OBJECTIVES: To isolate and identify Escherichia coil isolates from water samples from polluted rivers located in La Habana, and to determine their antimicrobial in vitro susceptibility. METHODS: One hundred thirteen isolates of coliform bacteria isolated from 10 sampling stations in the capital's urban areas near Almendares, Quibu and Luyano rivers were studied in the period of February 2008 to June 2010. The identification of isolates, the determination of antimicrobial susceptibility and the search for extended-spectrum beta-lactamase were all performed using VITEK automated method. RESULTS: One hundred thirteen environmental strains of Escherichia coli were identified. It showed that 23% of the isolates were resistant to at least one of the tested antimicrobials. The highest percentages of resistance were observed to ampicilline, sulfamethoxazole-trimethoprim and ciprofloxacin. CONCLUSIONS: The presence of E. coil isolates with multiple antimicrobial resistances in these rivers clearly indicates the biological risk involving the use of their waters. PMID- 23444633 TI - [Assessment of the CromoCen ENT chromogenic medium for clinical diagnosis of Enterococcus species]. AB - INTRODUCTION: The frequent incidence of Enterococci at hospitals and their growing antimicrobial resistance worldwide make the in-hospital surveillance and control a pressing need; consequently, it is indispensable to avail of more sensitive and accurate diagnostic means. OBJECTIVE: To broaden the evaluation of functionality of CromoCen ENT chromogenic medium for the isolation and identification of Enterococcus spp. from clinical samples. METHODS: One hundred and fifty clinical samples were analyzed (urine, blood, feces, vaginal smears, skin lesion exudates and exudates from catheters) in the January-April period, 2010 by using the chromogenic medium and the corresponding conventional culture media as controls; the incidence of Enterococcus spp was evaluated. The isolations were identified with 12 biochemical tests. From the biochemical identification data, it was possible to determine the quality indicators for both CromoCen ENT and the reference media. RESULTS: The chromogenic medium encouraged the growth of Enterococcus species in 24 hours, allowing their easy recognition due to the pink coloration of the colonies. The diagnostic quality indicator values were over 95%. The highest percentage of isolates was observed in the urine samples. Enterococcus faecalis was the mostly found species. CONCLUSIONS: CromoCen ENT allowed quick and accurate identification of Enterococcus spp. from various clinical samples. PMID- 23444634 TI - [Response to therapy in multiple drug resistant tuberculosis patients]. AB - INTRODUCTION: Multiple drug resistant tuberculosis is an increasingly significant medical problem, because it means the spread of microorganisms for which "second line" drugs are required to eliminate them; therapeutic effectiveness is lower, it takes longer to treat it, leading to more adverse effects in addition to being more expensive than the conventional treatment. OBJECTIVE: To identify the response to individualized treatment in multiple drug resistant tuberculosis patients, who are non-HIV seropositive. METHOD: A descriptive study was conducted in a sample of multiple drug resistant patients, who were treated for a year under individualized courses of treatment from 2000 to 2010 in Hospital Neumologico "Benefico Juridico". Data were collected from their medical histories and from bacteriological records. RESULTS: Out of 42 patients, 85.7% were males and the average age was 48.8 years. The most common category on admission was chronically-ill patient (40.5%). The average time for negative results in direct exam was 4.6 months and in culturing was 6 months; this indicator was lower in patients regarded as failures and higher in those classified as relapses. The highest healing percentage was found in chronic patients and in those classified as failures, accounting for 23.8 and 21.4% respectively. CONCLUSIONS: The compliance with individualized treatment under direct observation in multiple drug resistant tuberculosis proved to be effective in over half of the cases. PMID- 23444635 TI - [Trends and predictions of tuberculosis, and challenges towards tuberculosis eradication in Havana City]. AB - OBJECTIVES: To describe the variation and the trend of new tuberculosis case reports in Havana from 1995 to 2010, as well as their projection and occurrence for 2011-2013. METHODS: A time series study was conducted, and the annual total and mean variation percentages of rates by clinical and bacteriological categories, age, municipal distribution and TB/HIV co-infection were analyzed. Estimation of projections by using two-parameter exponential smoothing techniques was made. RESULTS: The rate of new reported TB cases decreased from 16.8 in 1995 to 9.5 per 100 000 inhabitants in 2010 (43.5% and 2.9% of annual total variation and mean variation respectively). The rate declined by 80% in the municipalities and in 15-64 and > or = 65 years age groups. Habana Vieja and Centro Habana municipalities kept the highest rates throughout the whole period. TB/HIV coinfection notification increased from 3 out of 369 (0.8%) cases in 1995 to 37 out of 202 (18.3%) cases in 2010. A slight increase was estimated for the 2011 2013 period (9.5; 10.0; 10.5 per 100 000 population respectively) in addition to continuous rise of the number of cases with TB/HIV co-infection. CONCLUSIONS: The TB trend showed a steady decline in Havana from 1995 to 2010, with substantial reduction in the study period, except for TB/HIV co-infection in which the number of cases increases. The TB case report rates are within the expected values, although slightly above the predictions. PMID- 23444636 TI - [Residual effectiveness of temephos observed in a Mexican southeast city affected by dengue]. AB - OBJECTIVE: To study the effect of water extraction and renewal on the residual action of temephos applied at 1ppm to cement water-storage containers at home. METHODS: The study was conducted in two stages: one, determination of the granular temephos effectiveness on wild Aedes aegypti populations in order to set the monitoring baseline; and second, the measurement of the mean rate of water extraction at home and its effect on the residual activity of temephos. RESULTS: The effectiveness of granular temephos was CL95 = 0.095 ppm (IC95%: 0.079-0.118). As average, it was found that 69.2% of water stored in cement containers was daily used and renewed, which means significant dilution. For the purpose of simplifying the experiments on residual activity, water was extracted and renewed at a rate of 50% every day for 2 weeks. It was found that temephos effectiveness significantly declined from day 7 on after application. CONCLUSIONS: This rate of water extraction under study has an important effect on the residual activity of temephos. If this rate and the CL95 of granular temephos are considered in estimating the dosing, positive effects on the control of Aedes aegypti and more likely on the occurrence of resistance will be attained. PMID- 23444637 TI - [Biological properties of virus dengue-3 strains isolated during the epidemic ocurred in Havana, 2001-2002]. AB - INTRODUCTION: During dengue epidemics in Cuba, an increase in clinical severity with the epidemics progression in time, particularly in secondary infections, have been frequently observed. It is considered that this increase could be related with genetic changes in the circulating virus. OBJECTIVE: To study some biological attributes related to strains isolated at different points of time during the dengue epidemic occurred in Havana city, 2001-2002. METHODS: Nine DENV 3 strains were studied. Cytopathogenic effect, viral growth in C6/36 HT and Vero cell lines, viral plaque sizes, temperature sensitivity, neurovirulence in newborn mice and pH influence in the binding of the virus and the cell as well as in the multiplication medium were evaluated. RESULTS: DENV-3 strains were more cytopathogenic in Vero Cells. However, higher titres were obtained in C6/36 HT cells. All the strains showed reduction of viral titres and plaque size with temperature increasing and low neurovirulence. Basic pH favoured virus-cell binding whereas acid pH was only permissive for some strains isolated at the end of the epidemic. On the other hand, at pH 6.5-7, the viral multiplication medium favoured the growth of strains isolated at the beginning of the epidemic whereas the growth of those isolated at the endof the epidemic was noticeable at pH 7-8. CONCLUSIONS: This study proved the phenotypical changes among strains isolated at different points of time in the epidemic. They might be related to differences in viral fitness or in virulent potential. Nevertheless, some of the studied biological properties suggest that dengue virus-3 strains are less virulent than the Cuban dengue virus 2 strains isolated in 1997. PMID- 23444638 TI - [Segregation of Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae) niche under laboratory conditions]. AB - INTRODUCTION: Aedes and Culex are two mosquito genuses of epidemiological importance, being Aedes aegypti and Culex quinquefasciatus the predominant ones in urban areas. It is common to find both of them associated in the same breeding sites where they share a lot of things despite the literature. OBJECTIVE: To determine if there is inter-specific competence between these two species when they co-exist in a single reservoir under lab conditions. METHODS: First staging larvae, which had been kept in the insect storage deposit of the Vector Control Department, were used. The three bioassays used 2 000 mL, 1 000 mL and 500 mL of dechlorinated water. The larvae were daily fed on with 0.7 g of fish flour; temperature was 26 degrees C +/- 2 degrees C. RESULTS: The larval cycle for Aedes aegypti was 6 days in crossbreds and in controls whereas it was 8 days for Culex quinquefasciatus, regardless of variation in the number of individuals of each species and in each bioassay. The larvae of each species completely developed since food was always provided and the living space remained the same. It should be noticed that the water was not totally translucent but no pollution indicators were observed. The sexual index for each species was determined after adult vectors emerged, with 1:1 ratio for both sexes approximately. CONCLUSIONS: Under lab conditions, these species did not compete one against the other for either food or living space and there was segregation of niche that favored their co existence. PMID- 23444639 TI - Enhanced environmental disinfection systems. Can they help you reduce infection rates? AB - Enhanced environmental disinfection systems are designed to disinfect surfaces of patient rooms using vaporized agents, UV light, or other techniques. But just how effective are they at reducing healthcare-associated infection rates? The jury is still out. PMID- 23444640 TI - Surgical video displays and booms. We answer your questions about selection and installation. AB - If you're renovating your operating rooms or constructing new ones, you probably have a lot of basic questions about device requirements and the purchasing process. Do devices need to meet electrical safety standards? Is equipment described as "medical grade" better? Is it important to buy your displays from your surgical boom vendor or your integration provider? Here are answers to those and other questions we're often asked. PMID- 23444641 TI - Maquet Vasoview Hemopro VH-3000 vessel harvesting system may self-activate or fail to deactivate, potentially resulting in injury. AB - The Harvesting Tool component of the Maquet Vasoview Hemopro VH-3000 vessel harvesting system may self-activate or may fail to deactivate, increasing the chance of thermal injury to the patient or staff, or of igniting a fire. Users of this product must be aware of the potential for either of the unintended activation problems to occur and must be familiar with Maquet's recommendations for dealing with the issue, which are provided in the system's instructions for use. PMID- 23444642 TI - Incorrect key presses may cause Nutricia Flocare Infinity series enteral feeding pumps to appear to be infusing even though an occlusion exists. AB - If users of Nutricia Flocare Infinity or Flocare Infinity+ feeding pumps press the unit's Fill Set key while attempting to address an occlusion alarm, the unit's display may indicate normal device operation even though the unit is not delivering feeding solution. Failure to deliver solution may result in hypoglycemia, which can have severe outcomes for patients who have difficulty maintaining their blood sugar levels. Flocare users should become familiar with the issue and with the guidance offered in the products' instructions for use. PMID- 23444643 TI - Future shock. Proposed NFPA 99 wet location revision revives a bad idea. AB - NFPA 99 is one of the principal performance standards on electrical safety for healthcare facilities. However, a proposed change regarding what areas should be considered "wet locations" may have a big effect on the way hospitals equip their operating rooms. ECRI Institute thinks that this change is ill-advised--that it will cost hospitals money with no real benefit, and in some cases could actually increase risks. PMID- 23444644 TI - Look who's talking. A guide to interoperability groups and resources. AB - There are huge challenges in getting medical devices to communicate with other devices and to information systems. Fortunately, a number of groups have emerged to help hospitals cope. Here's a description of the most prominent ones, including useful web links for each. We also discuss the latest and most pertinent interoperability standards. PMID- 23444645 TI - Quality control lockout function on Medtronic ACT Plus coagulation timer system can be bypassed for same-patient samples. AB - If Medtronic's ACT Plus automated coagulation timer system (an activated clotting time analyzer) is used on a single patient, its quality control (QC) lockout function may not activate--that is, the device may not lock the user out from performing sample analysis when QC has not been performed within the required time frame. The unit will indicate that QC is due by beeping three times and providing an onscreen message, but it will still analyze the sample and provide the user with results. These results may be inaccurate, and if they are used to make anticoagulation therapy decisions, they may lead to incorrect and potentially dangerous heparin therapy. Users should be made aware of this behavior (which is not described in the device's user manual) and should be instructed to verify that required QC checks have been performed before analyzing each sample. PMID- 23444646 TI - Moog recalls several Curlin infusion pump models due to a software anomaly that may cause therapy to stop. PMID- 23444647 TI - Simulation mode may be mistaken for normal mode in Philips PageWriter TC series cardiographs. AB - A message intended to alert users that Philips PageWriter TC series cardiographs are in simulation mode--the text "Simulated data," which appears onscreen and in printed reports--may not be readily noticed by users. If, during patient use, clinicians believe the unit is in normal mode when it is, in fact, in simulation mode (in which a continuous loop of simulated cardiac data is displayed), they might base clinical decisions on the simulated data instead of on the patient's data. ECRI Institute believes the likelihood of patient harm is low, since simulation mode is typically used infrequently. Nonetheless, facilities should instruct staff to verify that the units are not in simulation mode during patient use and to reinforce this message during ongoing training. PMID- 23444648 TI - Cassette-size digital radiography detectors. A better way to make the switch to DR. AB - Cassette-size wireless digital radiography detectors combine the image-quality and workflow advantages of DR with the patient-positioning advantages of computed radiography--and they can be used with just about any X-ray system. Find out how three models stack up. PMID- 23444649 TI - Incorrect key presses may cause Moog Medical's Zevex Infinity enteral feeding pumps to appear to be infusing even though an occlusion exists. AB - If users of Moog Medical's Zevex Infinity series feeding pumps--the EnteraLite Infinity and the Infinity Orange--use an incorrect key-press sequence while attempting to address a downstream occlusion alarm, the pump's display may mimic normal operation even though the unit is not delivering feeding solution. Although Moog states that it has not received any reports of injury related to these devices, failure to deliver nutrition may result in hypoglycemia, which can have severe outcomes for patients who have difficulty maintaining their blood sugar levels. Users of these pumps should become familiar with this issue and with the guidance offered in the products' operator manuals. This behavior is similar to that of the Nutricia Flocare Infinity series enteral feeding pumps- also produced by Moog Medical--which we described in the May 2011 issue of Health Devices. PMID- 23444650 TI - Hip checks. PMID- 23444651 TI - Images to go. PMID- 23444652 TI - Study finds reason to revisit contrast media warming. PMID- 23444653 TI - Consumers union testifies for stronger oversight of medical implants and devices. PMID- 23444654 TI - Hospital incident reporting systems don't capture most adverse events. PMID- 23444655 TI - Casters of Hill-Rom TotalCare bariatric beds may, in rare cases, lift off the floor during manual handling of patients. PMID- 23444656 TI - Sweet 16. PMID- 23444658 TI - Safety summary: Computed tomography. PMID- 23444657 TI - Criteria and test methods for CT systems. PMID- 23444659 TI - Study: using lower volumes of contrast media can produce reasonable quality CT studies. PMID- 23444660 TI - Study: radiation protection training may reduce skin dose in interventional cardiology. PMID- 23444661 TI - Draeger-Evita 2 Dura, Evita 4, and Evita XL intensive care ventilators: must be operating or in standby mode for batteries to charge. PMID- 23444662 TI - Parks Medical to redesign vascular laboratory system pressure/cuff tubing connectors to prevent misconnections. PMID- 23444663 TI - Wireless digital radiography systems. PMID- 23444664 TI - Safe patient handling: new resources, information available. PMID- 23444665 TI - Using ECRI Institute's health technology hazard self-assessment tool--a case study. PMID- 23444666 TI - Misuse of surgical clips illustrates importance of reading product warnings and instructions. PMID- 23444667 TI - INS issues guidelines on frequency of IV site checks. PMID- 23444668 TI - Study: higher-dose modalities not essential in endovascular aneurysm repair. PMID- 23444669 TI - Draeger Infinity central stations and M300 telemetry units may display false pacer spikes. PMID- 23444670 TI - Maquet HL30 heart-lung machine arterial pumps may shut down unexpectedly. PMID- 23444671 TI - Biomet Premier femoral cutting blocks should not be used if pegs are loose. PMID- 23444672 TI - Judgment call. PMID- 23444673 TI - Health apps and safety: views from recent sources. PMID- 23444675 TI - Growth rate of U.S. CT scans is slowing. PMID- 23444674 TI - Stage 2 EHR final rule is released. PMID- 23444676 TI - IT solutions can improve clinician laboratory test follow-up. PMID- 23444677 TI - Hospitals, FDA share surgical fire safety strategies. PMID- 23444678 TI - Playing music can lower sedation requirements during interventional radiology procedures. PMID- 23444679 TI - FDA updates tubing misconnections website. PMID- 23444680 TI - Alternate-site burns from improperly seated or damaged electrosurgical pencil active electrodes. PMID- 23444682 TI - Neusoft Neuviz 16. PMID- 23444681 TI - Which smart pumps are smartest? PMID- 23444683 TI - Alerts summary: Infusion pumps. PMID- 23444684 TI - CMS releases final 2014 meaningful use clinical quality measures. PMID- 23444685 TI - With EHRs, take the bad with the good--at least for now. PMID- 23444686 TI - Modifying EHR drug interaction alerts to reduce clinician fatigue. PMID- 23444687 TI - CDRH's postmarket surveillance proposal. PMID- 23444688 TI - Computerized decision support for pediatric meds--effectiveness uncertain. PMID- 23444689 TI - AHA: data lag can make telemetry innappropriate for instantaneous ECG monitoring. PMID- 23444690 TI - EPA releases list of products effective against C. difficile. PMID- 23444691 TI - Leadership for the future. PMID- 23444692 TI - Ethical considerations for NIH funded highly transmissible H5N1. PMID- 23444693 TI - Lessons from a slave doctor of 1841. PMID- 23444695 TI - Medical scenes in Madame Bovary. PMID- 23444694 TI - "Pure and wholesome": Stephen Allen, cholera, and the nineteenth-century New York City water supply. PMID- 23444696 TI - Dancing: a fifteen-year-old's descent into madness. PMID- 23444697 TI - What difference can a student make? PMID- 23444698 TI - Optimizing CT dose. PMID- 23444699 TI - 64-channel CT systems. PMID- 23444700 TI - FDA introduces resources to address pediatric dose risks. PMID- 23444701 TI - Study analyzes CT-related cancer risks for children. PMID- 23444702 TI - Study: pediatric CT dose appropriateness criteria are lacking in many countries. PMID- 23444703 TI - Register WMTS telemetry systems to avoid possible loss of compensation. PMID- 23444704 TI - Study: low-power RF ablation can be as effective as high-power. PMID- 23444705 TI - FDA, NIOSH, and OSHA recommend blunt-tip suture needles to reduce needlesticks. PMID- 23444706 TI - Introduction: large-scale fortification, an important nutrition-specific intervention. PMID- 23444707 TI - Fortifying baladi bread in Egypt: reaching more than 50 million people through the subsidy program. AB - BACKGROUND: Micronutrient deficiencies, especially iron-deficiency anemia, are a public health problem in Egypt, where anemia rates almost doubled in the years from 2000 to 2005. In 2008, the Government of Egypt began implementation of a 5 year national program to fortify with iron and folic acid the wheat flour used in baking subsidized baladi bread, the staple food consumed by a majority of low- income groups. OBJECTIVE: To project the achievements of this national Wheat Flour Fortification Program. METHODS: This paper describes the program, estimates the production of fortified flour and consumption of fortified bread, and identifies program challenges and sustainability issues. RESULTS: Through the national Wheat Flour Fortification Program, ferrous sulfate and folic acid are now added to all wheat flour produced under the national Food Subsidy Program. Up to 50 million Egyptians nationwide are now consuming quality-assured fortified baladi bread on a daily basis. In 2011, 6.5 million MT of fortified wheat flour was produced by 143 participating public- and private-sector mills. Political changes in Egypt in 2011 did not seem to affect the program; the new leadership in the Ministry of Supply and Internal Trade remains committed to fortification of wheat flour. CONCLUSIONS: The daily intake of approximately 12 mg of iron and 600 microg of folic acid through the consumption of baladi bread suggests that the impact of the program on the prevention and reduction of iron and folate deficiencies among the Egyptian population could be significant; the results of an end-line survey are pending. PMID- 23444708 TI - Processed foods as an integral part of universal salt iodization programs: a review of global experience and analyses of Bangladesh and Pakistan. AB - BACKGROUND: Despite the reference to salt for food processing in the original definition of universal salt iodization (USI), national USI programs often do not explicitly address food industry salt. This may affect program impact and sustainability, given the increasing consumption of processed foods in developing countries. OBJECTIVE: To review experience of the use of iodized salt in the food industry globally, and analyze the market context in Bangladesh and Pakistan to test whether this experience may be applicable to inform improved national USI programming in developing countries. METHODS: A review of relevant international experience was undertaken. In Bangladesh and Pakistan, local rural market surveys were carried out. In Bangladesh, structured face-to-face interviews with bakers and indepth interviews with processed food wholesalers and retailers were conducted. In Pakistan, face-to-face structured interviews were conducted with food retailers and food labels were checked. RESULTS: Experience from industrialized countries reveals impact resulting from the use of iodized salt in the food industry. In Bangladesh and Pakistan, bread, biscuits, and snacks containing salt are increasingly available in rural areas. In Bangladesh, the majority of bakers surveyed claimed to use iodized salt. In Pakistan, 6 of 362 unique product labels listed iodized salt. CONCLUSIONS: Successful experience from developed countries needs to be adapted to the developing country context. The increasing availability of processed foods in rural Bangladesh and Pakistan provides an opportunity to increase iodine intake. However, the impact of this intervention remains to be quantified. To develop better national USI programs, further data are required on processed food consumption across population groups, iodine contents of food products, and the contribution of processed foods to iodine nutrition. PMID- 23444709 TI - Lessons learned from national food fortification projects: experiences from Morocco, Uzbekistan, and Vietnam. AB - BACKGROUND: Fortification of staple foods has been repeatedly recommended as an effective approach to reduce micronutrient deficiencies. With the increased number of fortification projects globally, there is a need to share practical lessons learned relating to their implementation and responses to project-related and external challenges. OBJECTIVE: To document the achievements, challenges, lessons learned, and management responses associated with national fortification projects in Morocco, Uzbekistan, and Vietnam. METHODS: Independent end-of-project evaluations conducted for each project served as the primary data source and contain the history of and project activities undertaken for, each fortification project. Other sources, including national policy documents, project reports from the Global Alliance for Improved Nutrition (GAIN) and other stakeholders, industry assessments, and peer-reviewed articles, were used to document the current responses to challenges and future project plans. RESULTS: All projects had key achievements related to the development of fortification standards and the procurement of equipment for participating industry partners. Mandatory fortification of wheat flour was a key success in Morocco and Uzbekistan. Ensuring the quality of fortified foods was a common challenge experienced across the projects, as were shifts in consumption patterns and market structures. Adjustments were made to the projects' design to address the challenges faced. CONCLUSIONS: National fortification projects are dynamic and must be continually modified in response to specific performance issues and broader shifts in market structure and consumption patterns. PMID- 23444710 TI - Implementing large-scale food fortification in Ghana: lessons learned. AB - BACKGROUND: Food fortification began in Ghana in 1996 when legislation was passed to enforce the iodization of salt. This paper describes the development of the Ghanaian fortification program and identifies lessons learned in implementing fortification initiatives (universal salt iodization, fortification of vegetable oil and wheat flour) from 1996 to date. OBJECTIVE: This paper identifies achievements, challenges, and lessons learned in implementing large scale food fortification in Ghana. METHODOLOGY: Primary data was collected through interviews with key members of the National Food Fortification Alliance (NFFA), implementation staff of the Food Fortification Project, and staff of GAIN. Secondary data was collected through desk review of documentation from the project offices of the National Food Fortification Project and the National Secretariat for the Implementation of the National Salt Iodization in Ghana. RESULTS: Reduction of the prevalence of goiter has been observed, and coverage of households with adequately iodized salt increased between 1996 and 2006. Two models were designed to increase production of adequately iodized salt: one to procure and distribute potassium iodate (KIO3) locally, and the second, the salt bank cooperative (SBC) model, specifically designed for small-scale artisanal salt farmers. This resulted in the establishment of a centralized potassium iodate procurement and distribution system, tailored to local needs and ensuring competitive and stable prices. The SBC model allowed for nearly 157 MT of adequately iodized salt to be produced in 2011 in a region where adequately iodized salt was initially not available. For vegetable oil fortification, implementing quantitative analysis methods for accurate control of added fortificant proved challenging but was overcome with the use of a rapid test device, confirming that 95% of vegetable oil is adequately fortified in Ghana. However, appropriate compliance with national standards on wheat flour continues to pose challenges due to adverse sensory effects, which have led producers to reduce the dosage of premix in wheat flour. CONCLUSIONS: Challenges to access to premix experienced by small producers can be overcome with a central procurement model in which the distributor leverages the overall volume by tendering for a consolidated order. The SBC model has the potential to be expanded and to considerably increase the coverage of the population consuming iodized salt in Ghana. Successful implementation of the cost-effective iCheck CHROMA rapid test device should be replicated in other countries where quality control of fortified vegetable oil is a challenge, and extended to additional food vehicles, such as wheat flour and salt. Only a reduced impact on iron deficiency in Ghana can be expected, given the low level of fortificant added to the wheat flour. An integrated approach, with complementary programs including additional iron fortified food vehicles, should be explored to maximize health impact. PMID- 23444711 TI - Fortification of Indonesian unbranded vegetable oil: public-private initiative, from pilot to large scale. AB - BACKGROUND: Despite improved economic conditions, vitamin A deficiency remains a public health problem in Indonesia. OBJECTIVE: This paper aims to describe the development of the Indonesian unbranded cooking oil fortification program and to discuss lessons learned to date and future steps necessary for implementation of mandatory, large-scale oil fortification with vitamin A. METHODS: An historic overview of the steps involved in developing the Indonesian unbranded cooking oil fortification program is given, followed by a discussion of lessons learned and next steps needed. RESULTS: Indonesia's low-income groups generally consume unbranded vegetable oil, with an average consumption of approximately 25 g/day. Unbranded oil constitutes approximately 70% of the total oil traded in the country. In 2007-10, a pilot project to fortify unbranded vegetable oil was carried out in Makassar, and an effectiveness study found that the project significantly improved the serum retinol concentrations of schoolchildren. In 2010, the pilot was expanded to two provinces (West Java and North Sumatra) involving the biggest two national refineries. In 2011, a draft national standard for fortified oil was developed, which is currently under review by the National Standard Body and is expected to be mandated nationally in 2013 as announced officially by the Government of Indonesia in national and international meetings. CONCLUSIONS: Indonesia is a leading world supplier of cooking oil. With stakeholder support, the groundwork has been laid and efforts are moving forward to implement mandatory fortification. This project could encourage Indonesian industry to fortify more edible oils for export, thus expanding their market potential and potentially reducing vitamin A deficiency in the region. PMID- 23444712 TI - Thriving public-private partnership to fortify cooking oil in the West African Economic and Monetary Union (UEMOA) to control vitamin A deficiency: Faire Tache d'Huile en Afrique de l'Ouest. AB - BACKGROUND: In sub-Saharan Africa, more than 42% of children are at risk for vitamin A deficiency, and control of vitamin A deficiency will prevent more than 600,000 child deaths annually. In the West African Economic and Monetary Union (UEMOA), an estimated 54.3% of preschool-age children are vitamin A deficient and 13% of pregnant women have night blindness. OBJECTIVE: To project the achievements of this West African coalition. METHODS: This article documents the achievements, challenges, and lessons learned associated with the development of a public-private partnership to fortify vegetable oil in West Africa through project reports and industry assessments. RESULTS: National-level food consumption surveys identified cooking oil as a key vehicle for vitamin A. Stakeholders therefore advocated for the production of fortified vegetable oil at large scale, supported industrial assessments, and reinforced the capacity of cooking oil industries to implement vitamin A fortification through effective coordination of public and private partnerships tied with standards, regulations, and social marketing. Strong alliances for food fortification were established at the regional and national levels. Stakeholders also developed policies, adopted directives, built capacity, implemented social marketing, and monitored quality enforcement systems to sustain fortification for maximum public health impact. The synergy created resulted from the unique and complementary core competencies of all the partners under effective coordination. The initiative began with the 8 UEMOA member countries and now includes all 15 countries of the Economic Community of West African States (ECOWAS), plus Cameroon, Tanzania, and Mozambique, forming a sub-Saharan Africa-wide initiative on food fortification. All members of the Professional Association of Cooking Oil Industries of the West African Economic and Monetary Union (AIFO-UEMOA) now fortify edible oil with vitamin A. Through multisector cooperation, an estimated 70% of the population has access to vitamin A-fortified edible oil in participating countries. CONCLUSIONS: Sustainable fortification of cooking oil is now a reality in all UEMOA countries. PMID- 23444713 TI - Flour fortification in South Africa: post-implementation survey of micronutrient levels at point of retail. AB - BACKGROUND: Fortification of staple foods is an effective strategy to deliver and increase the intake of micronutrients in the diet and can reduce micronutrient deficiencies. It is important to ensure that the food vehicle consistently contains adequate amounts of nutrients at the point of consumption for effective impact. OBJECTIVE: This survey aimed to gauge the level of fortification of maize and wheat flour at the retail level compared with staple food fortification regulations in South Africa to better understand the current obstacles to effective delivery of micronutrients through flour fortification and consider approaches to strengthening the program. METHODS: White bread flour and maize meal samples were collected from retail points across all provinces and analyzed for vitamin A, iron, and nicotinamide, and a database capturing the origins of the sample was populated. Nicotinamide and vitamin A results were compared against each other and evaluated against food regulations. RESULTS: The level of compliance with statutory fortification requirements was low, both for bread flour and for maize meal. There is evidence of insufficient addition of premix as opposed to losses due to vitamin A stability as seen from the strong correlation between vitamin A and nicotinamide in maize meal. CONCLUSIONS: The current levels of micronutrients added to maize meal and bread flour are unsatisfactory. This is likely to be because of insufficient addition of premix at the mills. This affects the availability and intake by consumers of fortified product and potentially prevents the desired reduction in vitamin and mineral deficiencies expected from the flour fortification program. PMID- 23444714 TI - Validation of a user-friendly and rapid method for quantifying iodine content of salt. AB - BACKGROUND: Despite considerable progress made in the past decade through salt iodization programs, over 2 billion people worldwide still have inadequate iodine intake, with devastating consequences for brain development and intellectual capacity. To optimize these programs with regard to salt iodine content, careful monitoring of salt iodine content is essential, but few methods are available to quantitatively measure iodine concentration in a simple, fast, and safe way. OBJECTIVE: We have validated a newly developed device that quantitatively measures the content of potassium iodate in salt in a simple, safe, and rapid way. METHODS: The linearity, determination and detection limit, and inter- and intra-assay variability of this colorimetric method were assessed and the method was compared with iodometric titration, using salt samples from several countries. RESULTS: Linearity of analysis ranged from 5 to 75 mg/kg iodine, with 1 mg/kg being the determination limit; the intra- and interassay imprecision was 0.9%, 0.5%, and 0.7% and 1.5%, 1.7%, and 2.5% for salt samples with iodine contents of 17, 30, and 55 mg/kg, respectively; the interoperator imprecision for the same samples was 1.2%, 4.9%, and 4.7%, respectively. Comparison with the iodometric method showed high agreement between the methods (R2 = 0.978; limits of agreement, -10.5 to 10.0 mg/kg). CONCLUSIONS: The device offers a field- and user-friendly solution to quantifying potassium iodate salt content reliably. For countries that use potassium iodide in salt iodization programs, further validation is required. PMID- 23444715 TI - Fortification of staple cereal flours with iron and other micronutrients: cost implications of following World Health Organization-endorsed recommendations. AB - BACKGROUND: Wheat and maize flours are widely used delivery vehicles for mass fortification. In lower-income countries, most, if not all, national-level cereal flour fortification programs routinely fortify with iron; however, cofortification with other micronutrients is common. Little information is available on the cost implications programs face when considering current fortification practices versus what the World Health Organization (WHO) interim consensus statement recommends. OBJECTIVE: The objectives of the present paper are to provide information on the costs of adding different chemical forms of iron and/or other micronutrients to premix formulations, and to discuss some of the issues that should be considered regarding which micronutrients to include in the premix. METHODS: Nine countries in Latin America, Africa, and Asia (three countries per region) that currently cofortify with multiple micronutrients including iron were selected based on low (< 75 g/day), medium (75 to 149 g/day), and high (> or = 150 g/day) mean population flour consumption levels. Premix costs per metric ton of flour produced were estimated for improving iron formulations and for following WHO recommendations for other micronutrients. RESULTS: For the selected programs to maintain current premix formulations and improve iron compounds, premix costs would increase by between 155% and 343% when the iron compound was switched from electrolytic iron to sodium iron ethylenediaminetetraacetate (NaFeEDTA), by 6% to 50% when it was switched from electrolytic iron to ferrous sulfate, and by 4% to 13 when iron addition rates were adjusted without switching the compound. To meet WHO recommendations for other micronutrients, premix costs would increase the most when the amounts of vitamins B12 and A were increased. CONCLUSIONS: For programs that currently cofortify with iron and additional micronutrients, the quality of the iron fortificant should not be overlooked simply to be able to afford to add more micronutrients to the premix. Micronutrients should be selected according to population needs, costs, and potential beneficial synergistic reactions the added micronutrients may have. PMID- 23444716 TI - Fortification of wheat flour and maize meal with different iron compounds: results of a series of baking trials. AB - BACKGROUND: Wheat and maize flour fortification is a preventive food-based approach to improve the micronutrient status of populations. In 2009, the World Health Organization (WHO) released recommendations for such fortification, with guidelines on the addition levels for iron, folic acid, vitamin B12, vitamin A, and zinc at various levels of average daily consumption. Iron is the micronutrient of greatest concern to the food industry, as some believe there may be some adverse interaction(s) in some or all of the finished products produced from wheat flour and maize meal. OBJECTIVE: To determine if there were any adverse interactions due to selection of iron compounds and, if differences were noted, to quantify those differences. METHODS: Wheat flour and maize meal were sourced in Kenya, South Africa, and Tanzania, and the iron compound (sodium iron ethylenediaminetetraacetate [NaFeEDTA], ferrous fumarate, or ferrous sulfate) was varied and dosed at rates according to the WHO guidelines for consumption of 75 to 149 g/day of wheat flour and > 300 g/day of maize meal and tested again for 150 to 300 g/day for both. Bread, chapatti, ugali (thick porridge), and uji (thin porridge) were prepared locally and assessed on whether the products were acceptable under industry-approved criteria and whether industry could discern any differences, knowing that differences existed, by academic sensory analysis using a combination of trained and untrained panelists and in direct side-by-side comparison. RESULTS: Industry (the wheat and maize milling sector) scored the samples as well above the minimal standard, and under academic scrutiny no differences were reported. Side-by-side comparison by the milling industry did indicate some slight differences, mainly with respect to color, although these differences did not correlate with any particular iron compound. CONCLUSIONS: The levels of iron compounds used, in accordance with the WHO guidelines, do not lead to changes in the baking and cooking properties of the wheat flour and maize meal. Respondents trained to measure against a set benchmark and/or discern differences could not consistently replicate perceived difference observations. PMID- 23444717 TI - Rice fortification: its potential for improving micronutrient intake and steps required for implementation at scale. AB - BACKGROUND: Micronutrient deficiencies affect over 2 billion people worldwide, with profound implications for health, cognitive development, education, economic development, and productivity. Fortification of staple foods is a cost-effective strategy to increase vitamin and mineral intake among the general population. Rice is consumed by billions of people (> 440 million MT/year) but is as yet rarely fortified. OBJECTIVE: To discuss the untapped opportunity of rice fortification. METHODS: Review literature and experience with rice fortification and compare to fortification of other staple foods. RESULTS: Most technologies used to fortify rice first produce the fortified kernels and then blend them with regular, polished rice. Technologies differ with regard to how nutrients are added to the rice kernels, required investment, production cost, and degree of resemblance to unfortified rice. There are, so far, limited success stories for rice fortification. Some of the main roadblocks appear to be high initial investment and associated cost; lack of government leadership; and consumer hesitation to accept variations in the characteristics of rice, or a higher price, without good understanding of the benefits. CONCLUSIONS: In countries with a large centralized rice milling industry, starting rice fortification is easier than in countries with many small mills. Countries with large safety nets that supply rice to the poorest, for free or subsidized, have a good channel to reach those most in need. Furthermore, key players from the public and private sectors should establish a coalition to support the use of fortified rice and address some of the barriers to its implementation. PMID- 23444718 TI - The Global Alliance for Improved Nutrition (GAIN): a decade of partnerships to increase access to and affordability of nutritious foods for the poor. AB - The Global Alliance for Improved Nutrition (GAIN) was established in 2002 with a mandate to galvanize efforts by the public and private sectors to end malnutrition. GAIN launched its first large-scale fortification program in 2003, and in less than a decade has scaled its operations to reach more than 600 million people with nutritionally enhanced food. GAIN has evolved considerably as an organization, expanding beyond large-scale food fortification into new program areas, focusing on maternal, infant, and young child nutrition and improvements in agricultural practices to enhance nutrition. This paper describes GAIN's evolution from a large-scale food fortification program focus to a broader nutrition program portfolio directed toward improving access and affordability of nutritious foods for the poor. As GAIN enters its second decade, it continues to respond to the challenges of a changing nutrition landscape by introducing new programs and novel partnerships and by refining its innovative program delivery models. PMID- 23444719 TI - GAIN Premix Facility: an innovative approach for improving access to quality vitamin and mineral premix in fortification initiatives. AB - BACKGROUND: Vitamin and mineral premix is one of the most significant recurring input costs for large-scale food fortification programs. A number of barriers exist to procuring adequate quality premix, including accessing suppliers, volatile prices for premix, lack of quality assurance and monitoring of delivered products, and lack of funds to purchase premix. OBJECTIVE: To develop and test a model to procure premix through a transparent and efficient process in which an adequate level of quality is guaranteed and a financial mechanism is in place to support countries or specific target groups when there are insufficient resources to cover the cost of premix. METHODS: Efforts focused on premixes used to fortify flour, such as wheat or maize (iron, zinc, B vitamins, and vitamin A), edible oils (vitamins A and D), and other food vehicles, such as fortified complementary foods, complementary food supplements, and condiments. A premix procurement model was set up with three distinct components: a certification process that establishes industry-wide standards and guidelines for premix, a procurement facility that makes premix more accessible to countries and private industry engaged in fortification, and a credit facility mechanism that helps projects finance premix purchases. RESULTS: After three years of operation, 15 premix suppliers and 29 micronutrient manufacturers have been certified, and more than US$23 million worth of premix that met quality standards has been supplied in 34 countries in Africa, Central and Southern Asia, and Eastern Europe, reaching an estimated 242 million consumers. CONCLUSIONS: The Premix Facility demonstrated its effectiveness in ensuring access to high-quality premixes, therefore enabling the success of various fortification programs. PMID- 23444720 TI - [In vitro methods of transdermal drug absorption: the skin PAMPA model]. AB - The present article summarizes the features of human skin as absorption site and describes a new model for skin penetration prediction. The parallel artificial membrane permeability assay (PAMPA), a high throughput method that serves as the basis of the model is also discussed in details demonstrating its features and published applications. The paper focuses on the steps of model development and on the comparisons to human skin datasets. The one dataset by J. Hadgraft and R. Guy, containing over 100 compounds, was divided into groups corresponding to similar experimental conditions (e.g. skin type and temperature) and drug likeness. Skin PAMPA results correlate supremely with Franz cell results measured on full thickness skin at 37 degrees C (R2=0.89). The other dataset reported by Lee et al. contains experiments with 40 compounds (27 of it is drug-like) on dermatomed skin at 32 degrees C. The Skin PAMPA permeability results show a high correlation (R2=0.84;) with it if similar experimental conditions have been applied. Intra- and inter-laboratory reproducibility has been also proved and homogeneity has been examined. The developed Skin PAMPA model is able to predict human skin permeability reasonably well, and because of its good reproducibility and 96-well based format it can be a cost effective alternative to Franz cell studies for early skin penetration prediction. PMID- 23444721 TI - [Bio-based pharmaceutical polymers, possibility of their chemical modification and the applicability of modified polymers]. AB - Different types of polymers are widely used in biomedical, pharmaceutical and cosmetic purposes. Their applications are curbed, if the polymers can not break down by the body or if the polymer itself is harmful or decompose to harmful material. Authors provide an overview of different types of pharmaceutical polymers of various sources, of the structural characterization and possibilities of their chemical modification and of the classical and instrumental analytical examination methods. The paper deals with the limitations of the use of biopolymers, as well. PMID- 23444722 TI - Top 10 health technology hazards for 2013. PMID- 23444723 TI - FCC now soliciting comments on proposal affecting WMTS telemetry users. PMID- 23444724 TI - Keeping CPOE safer. PMID- 23444725 TI - CDC to deploy EHR-compatible reporting platform. PMID- 23444726 TI - ISMP releases self-assessment tool for tubing misconnections. PMID- 23444727 TI - OSHA, NIOSH issue information on protecting workers who use chemical cleaners. PMID- 23444728 TI - Study: use of prefilled syringes is faster, safer than bedside preparation of drug infusions. PMID- 23444729 TI - Study: effectiveness of pelvic shielding depends on patient age, bladder fullness. PMID- 23444730 TI - Bunnell Life Pulse high-frequency ventilator heated wire breathing circuit may overheat and melt. PMID- 23444731 TI - B. Braun Infusomat Space infusion pumps: potential for user to unintentionally bypass drug library. PMID- 23444732 TI - CareFusion 3100A and 3100B high-frequency oscillatory ventilator breathing circuit component may be defective and not hold pressure. PMID- 23444733 TI - Luteal phase support for in vitro fertilization-embryo transfer--present and future methods to improve successful implantation. AB - PURPOSE: To present reasons for luteal phase deficiency when taking controlled ovarian hyperstimulation (COH) for purposes of inducing multiple oocytes for in vitro fertilization (IVF), and to suggest strategies to overcome the defect. METHODS: Treatment options presented include luteal phase support with human chorionic gonadotropin (hCG) injection, progesterone, estradiol, gonadotropin releasing hormone agonists, cytokines, e.g., granulocyte colony stimulating factor, and lymphocyte immunotherapy. RESULTS: hCG and progesterone produce the best results and are comparable or at best a slight edge to hCG but the latter is associated with too high a risk for ovarian hyperstimulation syndrome. Vaginal progesterone is the most efficacious with the least side-effects. CONCLUSIONS: Better methods are needed to adequately assess full correction of the luteal phase defect. In some cases the luteal phase defect associated with COH is not correctable and FSH stimulation should be reduced or all embryos frozen and defer transfer to an artificial estrogen progesterone or natural cycle. PMID- 23444734 TI - No evidence to support the concept that low serum dehydroepiandrosterone (DHEA) sulfate (s) levels are associated with less oocyte production or lower pregnancy rates. AB - PURPOSE: To determine if in a population of women with diminished oocyte reserve as evidenced by day 3 serum follicle stimulating hormone (FSH) levels > 12 mIU/ml women with lower dehydroepiandrosterone sulfate (DHEA-s) levels produce fewer oocytes or have lower pregnancy rates following in vitro fertilization-embryo transfer (IVF-ET) compared to women with higher levels. METHODS: The women were divided into poor responders (producing < or = 4 oocytes) following oocyte retrieval or good responders (> or = 5 oocytes). Mean DHEA-s levels were compared in poor vs good responders and in the subgroups of those who conceived vs those who did not conceive. RESULTS: The data clearly showed no association with low DHEA-s levels and response to controlled ovarian hyperstimulation or pregnancy rates. CONCLUSIONS: In women with elevated serum FSH low DHEA levels do not suggest that supplementation with DHEA would improve response or pregnancy rate. These data do not preclude the possibility that there is a small subset of women with normal oocyte reserve who also fail to respond to controlled ovarian hyperstimulation for some unknown reason and the problem could be remediable by DHEA supplementation. PMID- 23444735 TI - The sharing of eggs by infertile women who are trying to conceive themselves with an egg recipient for financial advantages does not jeopardize the donor's chance of conceiving. AB - PURPOSE: To determine if the sharing of oocytes by an infertile woman with an egg recipient for financial advantages has any negative impact on the success rate for the donor. METHODS: A matched controlled study was performed comparing pregnancy outcome of women undergoing in vitro fertilization-embryo transfer (IVF ET) but sharing half of their eggs with a recipient vs women undergoing IVF-ET but not sharing oocytes. RESULTS: Even though more women sharing oocytes deferred fresh transfer and cryopreserved the embryos because of a greater likelihood of ovarian hyperstimulation syndrome, there was no difference in pregnancy rates between the two groups after their first embryo transfer whether it was with fresh or frozen-thawed embryos. CONCLUSIONS: Sharing of oocytes by a woman undergoing IVF-ET does not jeopardize her chance of a successful outcome following embryo transfer. PMID- 23444736 TI - Comparison of pregnancy rates following frozen embryo transfer according to the reason for freezing: risk of ovarian hyperstimulation vs inadequate endometrial thickness. AB - PURPOSE: To determine the relative pregnancy rates following frozen embryo transfer according to the reason for deferring fresh embryo transfer and freezing all embryos. METHOD: A retrospective review over a 10-year time period of all in vitro fertilization (IVF) cycles that deferred fresh transfer and cryopreserved all embryos related to risk of ovarian hyperstimulation syndrome or if there was inadequate endometrial thickness. Pregnancy rates according to the reason for freezing were then compared. RESULTS: The clinical and live delivered pregnancy rates following frozen embryo transfer in women < or = age 39 was 42.8% and 31.9%, respectively for women deferring for risk of ovarian hyperstimulation syndrome vs 28.7% and 21.8% for those freezing for inadequate endometrial thickness (p = 0.01 and p = 0.07, respectively). CONCLUSION: Embryo cryopreservation may not be a complete panacea for problems of inadequate endometrial thickness. PMID- 23444737 TI - Induction of final follicle maturation with a gonadotropin-releasing hormone agonist in women at risk of ovarian hyperstimulation syndrome undergoing gonadotropin stimulation and intrauterine insemination: proof-of-concept study. AB - OBJECTIVE: To evaluate the reproductive performance and safety of gonadotropin stimulated intrauterine insemination (IUI) cycles in women at risk for ovarian hyperstimulation syndrome (OHSS) when final follicle maturation was induced using a gonadotropin-releasing hormone (GnRH) agonist. MATERIALS AND METHODS: Thirty three women presenting with a history of cancelled ovarian stimulation for fear of OHSS, underwent repeat gonadotropin ovarian stimulation for IUI. They were all found to be at high-risk for OHSS once more, and were counseled to receive a GnRH agonist to trigger final follicle maturation before insemination. GnRH agonist trigger of ovulation (triptorelin) was given subcutaneously every 12 hours in three repeated doses: 0.3, 0.2, 0.2 mg, respectively. RESULTS: Induction with the agonist was associated with a 30.3% take-home pregnancy rate and 20% miscarriage rate. Multiple pregnancy rates were 26.7%. There were no reported cases of clinically significant moderate/severe ovarian hyperstimulation syndrome. CONCLUSIONS: The use of a GnRH agonist to trigger final follicle maturation in stimulated cycles of hyper responders was associated with a favorable reproductive outcome and no incidence of OHSS. The rate of multiple pregnancies nevertheless was found to be uncontrollably elevated, raising serious concerns regarding the safety of this protocol in standard clinical practice in the context of IUI. PMID- 23444738 TI - Oocytes from women of advanced reproductive age do not appear to have an increased risk of zona pellucida hardening. AB - PURPOSE: To test the hypothesis that very advanced reproductive age leads to an increased risk of zona pellucida hardening by comparing fertilization rates and rates of failed fertilization with conventional oocyte insemination vs intracytoplasmic sperm injection (ICSI). METHODS: Women aged > or = 45 were given the option of ICSI vs conventional oocyte insemination in circumstances where there was no male factor present. They were advised of the theoretical benefit of ICSI overcoming zona hardening but also advised that ICSI might lower pregnancy rates and is more costly. RESULTS: There were 364 cycles evaluated and 74% chose ICSI. The failed fertilization rates were similar--28.4% (66/232) for ICSI vs 26.5% (35/132) for conventional insemination. The fertilization rates were similar 56.0% with ICSI vs 50.9% with conventional oocyte insemination. CONCLUSION: Based on similar fertilization and failed fertilization rates in women aged > or = 45 undergoing IVF-ET, zona hardening does not appear to be a consequence of reproductive aging. PMID- 23444739 TI - Ethnic disparities in perioperative management among foreigners residing in Japan. AB - The objectives of this research were to examine the current status of perioperative treatment among foreigners, to elucidate the health status/outcome disparities that contribute to ethnic differences, and to recommend counter measures to rectify these ethnic disparities. The authors identified 36 non Japanese and 111 Japanese females who underwent gynecological surgery from 2004 to 2009 at a single institution. Electronic medical records were reviewed and telephone survey was conducted in order to obtain patient background, preoperative, operative, and postoperative data. The non-Japanese group showed significantly larger number of uninsured, shorter length of stay (LOS), higher rate of emergency surgery, and higher cases of spinal anesthesia. There were significant differences in length of residency in Japan and LOS among four foreign countries. Seventy-nine percent of patients contacted by phone understood informed consent from doctors, 73.7% understood explanation in operating room (OR), and 84.2% understood explanation from anesthesiologists. This research was the first survey of the ethnic disparities in perioperative management among foreign patients treated in Osaka. The authors have demonstrated differences in operative method, emergency surgery, anesthesia, and American Society of Anesthesiologists physical status (ASA-PS) due to the difference in disease structure, language, and culture. It is recommended that the barriers between non Japanese patients and medical staff are rectified during the perioperative period when mutual understanding is needed the most. PMID- 23444740 TI - Obstetric and neonatal outcome after assisted fertilization and spontaneous conception: a comparative study. AB - PURPOSE: The widespread use of assisted reproduction technology (ART) is accompanied by concerns for potential adverse outcomes. The aim of the present study was to evaluate the impact of ART in obstetric and neonatal outcome. METHODS: Data from labor ward records from 913 consecutive births were analyzed retrospectively, and the obstetric and neonatal outcomes of pregnancies after ART were compared with those after natural conception. RESULTS: No major complications were noted after ART. A higher probability of cesarean section, lower gestational age at birth, lower birth weight and hospitalization in the Neontal Intensive Care Unit (NICU) was noted after ART, as compared with spontaneous conception. However, after exclusion of multifetal pregnancies, there was no significant difference in outcomes, except for cesarean section rates. CONCLUSIONS: The higher proportion of multiple pregnancies after ART is associated with lower gestational age at birth, lower birth weights and higher NICU hospitalization rates. PMID- 23444741 TI - Diagnostic laparoscopy findings in unexplained infertility cases. AB - OBJECTIVE: Evaluation of diagnostic laparoscopy findings in 600 unexplained infertility cases. MATERIALS AND METHODS: A total of 600 diagnostic laparoscopies performed between 1995 and 2008 were investigated. Laparoscopies were performed in the proliferative phase of the cycle, General anesthesia was performed in all cases. RESULTS: Normal genital findings were determined in 47.50% of primary infertile cases and in 47% of secondary infertile cases. Pelvic adhesion was the most frequent finding encountered and it was seen at a rate of 20% in the primary infertility group and 18% in the secondary infertility group. Endometriosis was determined to have a rate of 15% in the primary infertility group and 11.5% in the secondary infertility group. CONCLUSION: Laparoscopy has an important place in the diagnosis and planning in the treatment of infertility. Planning the convenient treatment for patients will prevent both economic loss and time loss. PMID- 23444742 TI - Pain and breastfeeding: a prospective observational study. AB - OBJECTIVE: To demonstrate that pain affects the goodness of breastfeeding. MATERIALS AND METHODS: Seventy-nine patients were interviewed regarding satisfaction in breastfeeding, tiredness, uterine pain, nipple and other pain, and analgesic use at day three and at first, second, third, and fourth week after birth. Data regarding the mode of delivery were recorded from medical charts. Milk formula supplements, bottle use, pacifier use, and nipple shields use were considered as variables suggesting unsuccessful breastfeeding. RESULTS: At third day after delivery, it appeared that analgesic use was significantly associated with milk formula supplementing, bottle use, less satisfaction in breastfeeding, and more tiredness. At first week after delivery, the presence of pain differing from nipple and uterine pain, was more likely associated with milk formula supplementing, bottle use, pacifier use, less satisfaction in breastfeeding, and more tiredness. At third week after delivery, nipple pain was directly related to tiredness, while it increased the odds of adding milk formula and using a bottle. CONCLUSION: Pain affects the goodness of breastfeeding. PMID- 23444743 TI - Clinicopathological characteristics of adnexal lesions diagnosed during pregnancy or cesarean section. AB - OBJECTIVE: The diagnosis of an incidental adnexal lesion during pregnancy has become more common after the widespread use of routine ultrasonography (US). The aim of this study was to examine the diagnostic approach, management strategy and the pathological findings in cases of adnexal lesions that were diagnosed and treated during pregnancy in our department. MATERIALS AND METHODS: This was a 15 year retrospective study. Cases of adnexal lesions detected during routine prenatal care by US or while performing cesarean section, between January 1996 and December 2010 at Aretaieion Hospital of the National University of Athens, were analyzed. RESULTS: In this study period 39 cases of adnexal lesions were diagnosed during pregnancy or cesarean section. The age of the women was between 21 and 40 years (mean age 32.4). Surgical excision of the lesions was decided in 32 cases and conservative treatment was followed in the remaining seven cases. Surgical removal of the lesions was performed during cesarean section in 13 cases of term gestations and in four cases of preterm gestations in which pregnancy termination was considered necessary. Laparotomy during the antepartum period led to excision of adnexal lesions in 15 cases. Histology revealed benign ovarian lesions in 25 cases (78.1%), borderline ovarian tumors in two cases (6.3%), malignant ovarian tumors in four cases (12.5%) and adenocarcinoma of the appendix in one case (3.1%) presenting as an ovarian mass. DISCUSSION: The management of cases diagnosed with adnexal lesions during pregnancy remains controversial. According to the literature, the estimated risk of malignancy for adnexal masses during pregnancy is low (2-3%) and complications of these lesions are extremely rare. These data suggest that adnexal masses could be managed conservatively if possible with US follow-up. On the other hand, the results of this study showed a higher incidence of malignancy among adnexal lesions that were surgically treated (15.6%). CONCLUSION: Surgical intervention and histological examination in cases suspicious for malignancy at US and clinical findings remain the treatment of choice even during pregnancy. PMID- 23444744 TI - Hysterectomy prevention using the uterine hollow obliterations (HYUNHO) method for placenta previa. AB - OBJECTIVE: We have invented a method of hysterectomy prevention called the uterine hollow obliteration (HYUNHO) method to preserve the uterus and fertility after treating placenta previa or accreta. METHODS: Eighty patients underwent cesarean section because of placenta previa between January 2003 and December 2009. All patients eligible for the study were evaluated by followup and a telephone questionnaire about fertility, menstruation recovery, and complications. RESULTS: The success rate on preserving the uterus with the HYUNHO method was 96.2%. Three cases required additional procedures, including a cesarean hysterectomy or uterine artery embolization (UAE), two cases underwent a cesarean hysterectomy after delivery, and one case underwent UAE. CONCLUSION: The HYUNHO method is a safe, easy method for placenta previa, although it should be evaluated in a randomized controlled trial. PMID- 23444745 TI - Polymorphisms in angiotensin-converting enzyme and glutathione s-transferase genes in Turkish population and risk for preeclampsia. AB - AIMS: This study was conducted to investigate whether insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) gene and polymorphisms in glutathione S-transferase (GST) M1 and T1 genes are associated with increased risk for preeclampsia. MATERIALS AND METHODS: Sixty-three patients with hypertensive disorder of pregnancy and 85 controls were evaluated in a prospective case-control study. All subjects were genotyped by polymerase chain reaction (PCR) followed by agarose gel electrophoresis. RESULTS: Allele frequencies of ACE gene I/D polymorphism were found significantly different between preeclampsia and the control groups (p = 0.001). Differences in genotype frequencies of ACE gene I/D polymorphism between the two groups were statistically significant (p = 0.004). Individuals homozygous for D allele were more likely to develop preeclampsia (OR = 2.29; 95% CI, 1.39-3.79), whereas heterozygous individuals were not at increased risk (OR = 0.92; 95% CI, 0.56 1.49), compared to individuals homozygous for I allele. The differences in frequencies of functional and null alleles of GSTM1 and GSTT1 genes between the two groups were not significant (p = 0.46 and p = 0.44, respectively). CONCLUSION: ACE gene DD genotype was found to be associated with increased risk of preeclampsia development, whereas the authors did not find any significant relationship with polymorphisms of the GSTM1 and GSTT1 genes and preeclampsia. PMID- 23444746 TI - Detection of placenta elasticity modulus by quantitative real-time shear wave imaging. AB - OBJECTIVE: To explore the clinical values in detecting the placental elastic modulus using real-time quantitative shear wave elasticity imaging. METHODS: A total of 30 women in the late pregnancy stage without complications and having normal, single pregnancies, as well as normal fetal growth, amniotic fluid index, and anterior placenta were selected. A real-time elasticity imaging shear wave ultrasonic diagnostic apparatus was used to randomly select regions of interest at the central and edge of the placenta. The elastography imaging mode was launched to measure the elasticity of the elastic modulus of these placental parts. A total of 15 measured values were obtained at the placental center and edge for each pregnancy case. Umbilical artery and uterine artery pulsatility index (PI) values for 18 cases were also randomly measured. RESULTS: The average value of 30 placental edges of the elastic modulus (n = 15) was (7.60 +/- 1.71) kPa. The average value of the 30 placental central elastic modulus (n = 15 ) was (7.84 +/- 1.68) kPa. No significant difference was observed between placenta central and edge elastic modulus. The PI mean value of umbilical artery in 18 cases was 0.94, whereas the average PI values of the uterine artery was 0.83. No linear correlation was found among the elastic modulus, the placental uterine artery PI values, and the umbilical artery PI values (p > 0.05). CONCLUSION: No difference between the placental center of normal pregnancies and the edge of the elastic modulus was detected. The elastic modulus of the placenta could be obtained in the best position. The placenta varied greatly between elastic modulus. No correlation was found between the placental elastic modulus, the uterine artery, and umbilical artery PI values. Real-time shear wave elasticity imaging technology can provide morphological evidence of placental function, which may emerge as a new clinical assessment approach. PMID- 23444747 TI - Three-dimensional ultrasound and three-dimensional power Doppler improve the preoperative evaluation of complex benign ovarian lesions. AB - PURPOSE OF INVESTIGATION: To evaluate the diagnostic accuracy of three dimensional ultrasound (3D-US) and three-dimensional power-Doppler (3DPD-US) as adjuncts to conventional B-mode-US in evaluation of complex benign ovarian lesions. METHODS: Transvaginal B-mode-US, 3D-US and 3DPD-US were performed in 29 patients with unilateral ovarian lesion. Patients were classified as low or high risk for malignancy according to a standardized scoring system composed of ten morphological and vascular parameters. Preoperative scores were matched to the histological results and the diagnostic performance of the scoring system was calculated. RESULTS: Seven out of the 16 cases of endometriomas (44%) were graded as low risk masses according to B-mode-US, while the addition of 3D-US and 3DPD US increased the accuracy to 56% and 94%, respectively. All dermoid cysts were classified as high risk cases by B-mode-US, but 3D-US and 3DPD-US correctly classified 14% and 57% of cases, respectively. The use of B-mode-US, 3D-US and 3DPD-US correctly classified all four cystadenomas. Only the use of 3DPD-US correctly classified one out of two hemorrhagic corpus luteum cases, whereas the other imaging modalities characterized these lesions as high risk. The overall diagnostic accuracy increased from 38%, 48%, ana 83% with the application of B mode-US alone, or combined with 3D-US and 3DPD-US, respectively. CONCLUSION: Conventional ultrasound supplemented with 3D-US and 3DPD-US and the evaluation of findings according to a specific scoring system can facilitate the preoperative classification of complex benign ovarian lesions. PMID- 23444748 TI - Comparison of electrolytic status (Na+, K+, Ca2+, Mg2+) in preterm and term deliveries. AB - PURPOSE OF INVESTIGATION: The objective of this study was to evaluate the electrolytic status of Na+, K+, Ca+, and Mg2+ in serum and red blood cells in idiopathic preterm and term deliveries. METHODS: The study included 105 pregnant women diagnosed with idiopathic premature delivery (study group) and 36 pregnant women with physiologically term delivery (controls). Samples of mother's blood were collected and analyzed for the level of electrolytes in the serum/plasma and red blood cells. RESULTS: Measured values of magnesium in red blood cells in the study group were far lower than physiological values, intracellular calcium levels were higher in the study group compared to levels measured in the controls. Sodium concentrations in cells were significantly lower in subjects with premature delivery. CONCLUSION: The magnesium intracellular level is the best representative value of magnesium in the body. PMID- 23444749 TI - Lymphedema of the arm after surgery for breast cancer: new physiotherapy. AB - Secondary lymphedema of the upper limb is a complication which can be found in patients who have undergone surgical breast cancer treatment with an axillary dissection. Lymphedema following breast cancer treatment remains a long-term disabling complication which cannot be treated in a decisive and radical manner. The objective of the treatment is to limit complications, to try to preserve the remaining lymphatic system and to develop new anastomosis. It consists of a specific decongestive physiotherapy, which may include a specific lymphatic drainage and skin mobilization, reducing bandages including Mobiderm (Thuasne), and sub-bandage muscular exercises. However variations in the therapy have been recorded by different teams. Our experience in treating lymphedema in Tunisia takes into consideration the epidemiological, climatic, cultural and socio economic conditions of the country. The difference in our treatment compared to what is being advocated elsewhere essentially consists of the no muscular exercise while wearing a bandage. This is compensated for by daily domestic activities, by prolonging the first two phases of treatment (the intensive phase and the stabilization phase), and by the use of the hydro gel dressing Hydrosob (Hartmann) to prevent blisters induced by the pressure imposed by Mobiderm studs of the bandage on the skin, and also by the superimposition of two types of Mobiderm bandages (small and large blocks). PMID- 23444750 TI - Oral supplementation with antioxidant agents containing alpha lipoic acid: effects on postmenopausal bone mass. AB - PURPOSE OF INVESTIGATION: Oxidative stress impacts many age-related degenerative processes, such as in postmenopausal bone loss and in antioxidant defenses that are significantly decreased in elderly osteoporotic women. The authors evaluated the effect of oral supplementation with antioxidant agents containing alpha lipoic acid (ALA) on bone mineral density (BMD) of osteopenic postmenopausal women. MATERIALS AND METHODS: Fifty postmenopausal women with osteopenia (-2.5 < T-score < -1) were prospectively enrolled and randomly assigned to orally receive ALA and other antioxidant agents (vitamin C, vitamin E, and selenium) plus calcium and vitamin D3 (n = 25), or only calcium and vitamin D3 (n = 25). The BMD was estimated at baseline and after 12 months of treatment by heel quantitative ultrasonometry (QUS). RESULTS: Forty-four patients completed the one-year study: 23 in the ALA group, 21 in the control group. The treatment of ALA group led to a better estimated BMD compared to the control group (0.401 +/- 0.026 vs 0.388 +/- 0.025 g/cm2), although this difference barely achieved a statistical significance (p = 0.048). CONCLUSION: These findings, although in a small population, could suggest that oral supplementation with antioxidant agents containing ALA may mitigate bone loss in osteopenic postmenopausal women. PMID- 23444751 TI - Perinatal outcome associated with nuchal umbilical cord. AB - INTRODUCTION: Nuchal umbilical cord (NUC) is a possible complication of pregnancy which can be associated with adverse perinatal outcome. MATERIALS AND METHODS: A retrospective study was done at the County Emergency Hospital Timisoara, Romania, between January 2009 and December 2010 and included cases with NUC at the time of delivery. Outcome variable related to the mothers and newborns were studied. RESULTS: The incidence of NUC in the studied period was 8%. Most were primiparous. There were no significant statistical differences between vaginal births and cesarean section with one minute Apgar scores higher than 8. Five percent of the studied group presented intrauterine fetal death. CONCLUSIONS: The presence of NUC implies more attention but are not associated with increased rate of operative vaginal or cesarean delivery. One minute Apgar scores in these cases are comparable. NUC can be a cause of IUFD. PMID- 23444752 TI - Intrauterine balloon tamponade as management of postpartum haemorrhage and prevention of haemorrhage related to low-lying placenta. AB - The aim of the present study was to evaluate the effectiveness of Bakri balloon in preventing and treating postpartum haemorrhage (PPH). Intrauterine Bakri balloon was used in a total of 16 patients with two different purposes: prophylactic placement of the balloon after cesarean section (CS) in six patients with low-lying placenta and therapeutic placement in ten patients with persistent bleeding from uterine atony, after spontaneous delivery, and administration of uterotonics. Intrauterine Bakri balloon was a successful approach in controlling and preventing PPH in all 16 patients. The median nadir hematocrit was 26.6% in six patients who underwent CS and 25.6% in ten patients with persistent bleeding after spontaneous delivery. The intrauterine balloon was in place for a duration of 24 hours. The median balloon infusion volume was 345 ml (range 250-455). No complications were reported. Bakri balloon tamponade was a useful measure in treating PPH unresponsive to pharmacological therapy in patients who delivered vaginally. Moreover, it was able to prevent persistent bleeding in patients who underwent CS for central placenta previa. PMID- 23444753 TI - Clinical course and complications of HELLP syndrome according to time of onset. AB - OBJECTIVE: To evaluate the impact of gestational age on clinical laboratory findings and maternal-perinatal outcomes in patients with HELLP syndrome. METHOD: A retrospective review of 74 patients with HELLP syndrome between January 2007 and October 2010 was performed. Data were stratified into two groups by gestational age at the onset of disease: group 1 (< 34 weeks) and group 2 (> or = 34 weeks). Clinical signs and symptoms, laboratory findings, and maternal and perinatal outcomes were evaluated. RESULTS: No differences were observed between the two groups in the clinical and laboratory characteristics according to onset of HELLP syndrome except for gravidity, parity, and delivery interval. Maternal complications did not differ between the groups. The perinatal mortality rate was 22.9% in total and it was 43.2% in group 1. CONCLUSIONS: The time of onset of the HELLP syndrome mainly affects neonatal outcomes. To assess the effect on maternal morbidity more studies are needed. PMID- 23444754 TI - Fertility in women survivors of hematological malignancies: what is the real role of GnRH analogue treatment? AB - PURPOSE OF INVESTIGATION: The aim of this study was to evaluate the ovarian function in women who received or not gonadotropin-releasing hormone (GnRH) analogue co-treatment compared to the control group that did not receive it. MATERIALS AND METHODS: This study analyzed 124 patients affected by hematological diseases between 1998 and 2007. The data were analyzed using R (v 2.9.1). RESULTS: In the women treated with GnRH analogue, the authors found 33% post treatment secondary amenorrhea and 6% had a pregnancy post-treatment, while in the other group the prevalence were respectively 49% and 4% (p n.s.). Moreover, in multivariate analysis the authors found bone marrow transplantation to be a risk factor for secondary amenorrhea, while the association of chemotherapy with radiotherapy was a protective factor (p < 0.05). Finally, none of the considered factors were predictive of pregnancy achievement post-treatment. CONCLUSIONS: The authors found no statistical evidence to support that Gn-RH analogue treatment preserves ovarian follicular reserve during hematologic cancer treatment, but more evidence must be obtained. PMID- 23444755 TI - Determining the optimal fentanyl dose for dilation and curettage procedures. AB - AIM: This study attempted to determine an optimal dose of fentanyl, a drug frequently used in dilation and curettage (D&C) procedures, which is commonly performed as a brief outpatient intervention. METHODS: The optimal fentanyl dose was determined using Dixon's up-and-down method. The study was accomplished with a beginning fentanyl dose of 1 microg kg(-1) with a step size of 0.1 microg kg( 1) fentanyl. RESULTS: The ED50 [95% confidence interval (CI)] for fentanyl for successful anesthesia in D&C procedures was found to be 0.45 (0.35-0.55) microg kg(-1) and the ED95 value was 0.50 (0.45-0.60) microg kg(-1). CONCLUSION: This dose is considerably lower than the standard dose that is used at present, which is 1 microg kg(-1). To the best of our knowledge, the current study is the first to show that a significantly reduced dose of fentanyl can be as effective as higher doses in D&C procedures using Dixon's up-and-down method. PMID- 23444756 TI - Prediction of fetal macrosomia with ultrasound parameters and maternal glycemic controls in gestational diabetes mellitus. AB - PURPOSE OF INVESTIGATION: Evaluation of ultrasound measurements of fetal adipose subcutaneous tissue (ASCT), abdominal circumference (AC), liver length (LL), and amniotic fluid index (AFI) in prediction of fetal macrosomia (FM) and gestational diabetes mellitus (GDM). MATERIALS AND METHODS: In a prospective clinical trial, 280 pregnant women underwent 100 g oral glucose tolerance test (oGTT) at 28th week of gestation (wg) and measurements ofAC, LL, AFI, and ASCT at 32nd, 34th, 36th, and 38th wg. RESULTS: For GDM, the best sensitivity was achieved by ACST at 32nd and 34th wg, the best specificity by LL at 32nd wg (90.6%), the best area under the curve (AUC) by LL at 34th wg (0.944). For FM the best sensitivity was achieved by AC at 32th, 34th, 36th, and 38th wg and by ASCT at 34th wg (94.2%), and the best AUC at 38th wg for AC (0.974). CONCLUSION: Ultrasound parameters of glycemic control were good predictors of FM and GDM. PMID- 23444757 TI - Comparison of pregnancy outcomes in different localizations of uterine fibroids. AB - OBJECTIVE: The basic aim of this study is to compare the pregnancy outcomes in cases with uterine fibroids located at the anterior and posterior uterine walls. MATERIALS AND METHODS: A total of 84 pregnant women with a diagnosis of uterine myoma larger than 30 millimeter (mm) in diameter were included in the study to determine the obstetric outcomes. In 64 (76.20%) patients, myomas were detected at the anterior uterine wall (group 1), while 20 (23.80%) were detected at the posterior uterine wall (group 2). All patients were followed monthly until the end of pregnancy. Demographic and obstetric characteristics were compared between the two groups. RESULTS: There were no significant differences in age, gravida, parity, and myoma size between the two groups. A significant difference existed between the groups with regard to pelvic pain. Posterior located fibroids were associated with more pelvic pain (p = 0.001). No difference was observed between the two groups with regard to the rates of preterm delivery, bleeding in early pregnancy, infants with small for gestational age, and hospitalization period during pregnancy. Women with posterior located myomas had significantly higher miscarriage rates. CONCLUSION: Our findings suggest that pregnancies with uterine fibroids are at increased risk for complications. Posterior located fibroids larger than 30 mm in diameter are associated with severe pelvic pain compared to anterior located fibroids. PMID- 23444758 TI - The optical trocar in gynecological surgery: clinical and technical outcomes. AB - Optical trocars have been introduced as an alternative technique for obtaining access to the peritoneal cavity. The advantage is that each layer of the abdominal wall can be identified avoiding inadvertent injuries due to a lack of vision. From March 2010 to March 2011, 138 women underwent laparoscopy for benign diseases. They were submitted to gynecological laparoscopy for direct optical access. There was no evidence of vascular injuries. This study confirms that the optical trocar is a safe, rapid, and effective method, that offers a real perception of the safety of the entrance into the abdomen. PMID- 23444759 TI - Does vaginal pH affect the efficacy of dinoprostone in cervical ripening/labor duration? AB - BACKGROUND: Prostaglandins are effective in the ripening of the cervix and facilitating labor induction. Vaginal pH is probably an important factor in the effectiveness of vaginal prostaglandins. The aim of this study was to evaluate the effect of vaginal pH on the function of prostaglandin vaginal tablet during labor. METHODS: This is a double-blinded clinical trial study of 147 pregnant primigravid trated in the Yahyanejad Hospital of Babol (Iran) from January 2006 to December 2007. Initial pH was measured during vaginal examination with nitrazin paper and the Bishop score was determined. All women received vaginal dinoprostone inserted in the posterior fornix of the vagina for cervical ripening and the second dose was administered if the uterine contractions were inadequate. Reassessment of the Bishop score after 12 hours, duration of latent and active phases, and also the duration of the second stage of labor were compared between the two groups with low or high vaginal pH. RESULTS: The incidence of Cesarean section was lower in women with high vaginal pH but was not statistically significant. The Bishop score after 12 hours, latent phase, and second stage durations were not different in the two groups of high or low vaginal pH, but active phase duration in patients with high pH was significantly shorter than those with low pH (p = 0.019). CONCLUSION: High vaginal pH influences the function of prostaglandin tablet as a reduction in duration of the active phase of labor. PMID- 23444760 TI - Evaluation of utero-ovarian hemodynamics in relation to fertility and stage of endometriosis. AB - OBJECTIVE: The aim of this study was to compare hemodynamic changes in the uterine and ovarian arteries between infertile women with moderate and/or severe endometriosis and healthy women. In this prospective study, 99 women in their generative age were subjected to color Doppler ultrasonography to measure hemodynamic parameters from July 2010 to January 2011. The examination was performed during the proliferative or ovulatory phase of the natural menstrual cycle in a random sample of 54 women treated for endometriosis-induced infertility and 45 healthy women were included in control examination procedure. Irrespective of considered stage, endometriosis was most often found in the ovaries, in the sacro-uterine ligaments, peritoneum, and rectovaginally. Resistance to blood flow expressed as the resistance index (RI) in the measured arteries, was significantly higher in severe endometriosis compared to moderate form. Average values of pulsation index (PI) and RI are significantly higher, in both endometriosis stages, compared to measured values in healthy women. PMID- 23444761 TI - Effects of vaginal versus oral misoprostol to terminate second-trimester pregnancy. AB - OBJECTIVES: Using surgical methods compared to medical methods, such as misoprostol for termination of pregnancy, has several side effects. This study was performed in order to compare the effect of vaginal and oral misoprostol in second-trimester pregnancy termination (14-24 weeks). MATERIALS AND METHODS: The authors performed a clinical trial study in 40 pregnant women at 14 to 24 weeks of gestation and candidates for medical interruption of pregnancy. All patients received 600 microg of vaginal misoprostol as primary dosage and then, were placed randomly in two groups consisting of 20 patients that received 400 microg of vaginal or oral misoprostol, every four hours, up to three doses. If the abortion was incomplete, oxytocin was used. Twenty-four hours after the procedure, uterine sonography was performed in all patients and if residue was found, the patients were then candidates for curettage. RESULTS: Seventeen patients (85%) in the vaginal group and 17 patients (85%) in the oral group had successful pregnancy interruption. The mean interval until the discharge of pregnancy products in the vaginal group (15/42 +/- 10/84) showed no significant difference compared to the oral group (12/65 +/- 7/8) and no significant differences in side-effects were found between the two groups. CONCLUSION: Oral misoprostol is as effective as vaginal misoprostol in performing second-trimester abortion. It appears that the vaginal misoprostol primary dose together with the continuation of oral dose is not more effective compared to the vaginal misoprostol method alone. PMID- 23444762 TI - Depression and pregnancy-associated death by suicide after spinal cord injury: a case report. AB - PURPOSE OF INVESTIGATION: To report a case of a pregnant woman with traumatic spinal cord injury complicated with a psychiatric disorder. CASE REPORT: A 24 year-old woman at 18 weeks of gestation was transferred to our hospital with a history of having jumped from a third-floor apartment patio. RESULT: A trauma survey showed no life-threatening hemorrhage, and fetal wellbeing was confirmed. Neurological examination showed complete loss of motor and sensory function in her lower extremities. Termination of pregnancy was advised and was achieved medically. Surgical intervention was performed to achieve stabilization of the spine and decompression of neural elements. After the operation, she was referred to a psychiatrist, and the administration of paroxetine, etizolam and flunitrazepam was begun. Four months after undergoing the abortion, she choked herself to death on her ward bed. CONCLUSION: Although it is rare, we should pay special attention to the substantial suicide risk of women who face severe spinal cord injury. PMID- 23444763 TI - Holoprosencephaly in clomiphene-induced pregnancy: a possible association? A case report and literature review. AB - Clomiphene is widely used for inducing ovulation. Evidence for congenital abnormalities, in particular central nervous system defects (CNS-D) and in babies born from clomiphene-induced pregnancies is conflicting. The authors report a case of holoprosencephalia (HPE) in a fetus delivered from a mother receiving clomiphene. PMID- 23444764 TI - Conservative management of massive hematoperitoneum caused by ovulation in a patient with severe form of von Willebrand disease--a case report. AB - Von Willebrand disease (VWD) is the most common inherited bleeding condition that involves extended or excessive bleeding, caused by the deficiency or defect of von Willebrand factor (VWF). Hematoperitoneum as a complication of gynecologic diseases represents acute condition which is usually caused by the hemorrhagic corpus luteum or a rupture of either ectopic pregnancy or a hemorrhagic ovarian cyst. The authors present a unique case of conservatively managed massive hematoperitoneum caused by ovulation in a patient with severe form of von Willebrand disease who had right adnexectomy due to hemorrhagic corpus luteum four months prior. This conservative management by blood product and factor concentrate support could be a method of choice in selected hemodynamically stable patients. Furthermore, recurrent bleeding episodes following ovulation could be prevented by suppression of ovulation using oral contraceptive pills. PMID- 23444765 TI - Leiomyomatosis peritonealis disseminata and pregnancy: a case report. AB - Leimyomatosis peritonealis disseminata (LPD) is a benign tumor of smooth muscle tissue. It is rare and is characterized by the development of multiple peritoneal nodules mimicking peritoneal carcinomatosis. We report a case of LPD diagnosed in a 35-year-old patient, G4/P1, without any major gynecological history. The patient underwent an elective cesarean section at 42 weeks, during which numerous peritoneal nodules ranging in size from 0.1 to 0.5 cm were found. Microscopic examination showed a proliferation of smooth-muscle cells without mitosis or atypia or necrosis. PMID- 23444766 TI - Successful pregnancy after uterovaginal anastomosis in patients with congenital atresia of cervix uteri. AB - We present a case of successful pregnancy after effective uterovaginal anastomosis in a 26-years-old patient with congenital atresia of the cervix uteri. She spontaneously achieved pregnancy after four years of uterovaginal anastomosis. Gestation was at the eighth lunar month and the delivery was done by cesarean section due to rapidly progressing fetal asphyxia. The patient gave birth to a live healthy male, weighing 1,950 g, with an Apgar score of 5 and 8 at 1 and 5 min, respectively. The postoperative course was uneventful, and leakage of lochia was normal. PMID- 23444767 TI - Severe Asherman's syndrome complicated with placenta increta conceived by intracytoplasmic sperm injection following hysteroscopic surgery. AB - Although severe Asherman's syndrome is a disease that may cause infertility, pregnancy and childbirth are possible by performing hysteroscopic surgery. However, the obstetrical outcome is not always satisfactory. We report a case where severe Asherman's syndrome occurred following a cesarean section. Hysteroscopic surgery was performed due to secondary infertility, and pregnancy was achieved through a subsequent intracytoplasmic sperm injection. At 23 weeks of gestation, the patient was hospitalized due to the threat of premature labor, and a cesarean section was performed at 29 weeks of gestation after pregnancy induced hypertension occurred. It was determined to be abnormal adherent placentation such as placenta increta through intraoperative findings, and a cesarean hysterectomy was performed. The pathological diagnosis of the uterus was placenta increta. Due to the risk of complications from placenta increta in pregnancies following hysteroscopic surgery in patients with severe Asherman's syndrome, it is important to realize the high risk involved in such cases during the pregnancy course, and careful perinatal management should be required. PMID- 23444768 TI - Ruptured subcapsular liver hematoma and pregnancy: a rare complication of severe preeclampsia: a report of a case discovered fortuitously at the Maternity Teaching Hospital of Cocody. AB - We report a case of spontaneous rupture of a subcapsular hematoma of the liver (SHL). It was discovered incidentally at the end of an emergency exploratory laparotomy performed due to unexplained hemoperitoneum with hypovolemic shock which occurred with severe preeclampsia. Diagnosis and therapeutic management are very difficult in sub-Saharan Africa due in part to the limitations and lack of medical equipment. The prognosis is usually marked by the death of the patient, as in our case. Through this clinical observation we wanted to show the interest in performing a liver ultrasound at any level of preeclampsia to detect liver abnormalities as soon as possible. PMID- 23444769 TI - Pheochromocytoma in ectopic pregnancy: a case report. AB - OBJECTIVE: To study pregnancy characteristics in women with pheochromocytoma and to improve awareness of this comorbidity among obstetricians and gynecologists. METHODS: The diagnosis and treatment of a case of ectopic pregnancy with pheochromocytoma is described. RESULTS: The patient was diagnosed with a ruptured left Fallopian tube isthmus due to pregnancy, with comorbid left adrenal pheochromocytoma. CONCLUSION: Ectopic pregnancy with heavy bleeding and elevated blood pressure is indicative of pheochromocytoma. Measurement of the levels of urinary vanillylmandelic acid and urinary and serum catecholamines, as well as ultrasonography, can help diagnose this comorbidity. PMID- 23444770 TI - Defect of methylenetetrahydrofolate reductase in a patient with ten habitual misscarriages: a case report. AB - This is a case report of a 47-year-old patient that came to our Clinic due to bleeding during the 23rd week of twin pregnancy after in vitro fertilization intracervical insemination/embryo transfer (IVF-ICI/ET) treatment. Prior to this pregnancy, this patient had had ten spontaneous miscarriages, eight of which following IVF-ICI/ET, and two following spontaneous conception, all in the eighth week of pregnancy. After several miscarriages by the age of 43, the patient was suggested to be tested for thrombophilia; it was then discovered that she had the methylenetetrahydrofolate reductase (MTHFR) gene defect, in the homozygous Tobiano (TT) form. Thus she was treated with cardiolipin and folic acid before pregnancy, and continued with folic acid after the pregnancy had been diagnosed. Fraxiparine 0.4 ml subcutaneous (s.c.) should be introduced from the second month of pregnancy until one day before delivery. It is a useful treatment for the patients with MTHFR defect, as it prevents miscarriage and promotes successful pregnancy. PMID- 23444771 TI - Endometrial osseous metaplasia and infertility: a case report. AB - Endometrial osseous metaplasia is a rare clinical entity. It causes infertility and occurs in more than 80% of cases after an abortion. Various theories have been proposed and the most accepted theory is metaplasia of the stromal cells into osteoblastic cells that produce bone. This disease may be misdiagnosed. However once diagnosed, the complete removal of bone spicules by hysteroscopy allows, in most cases, fertility to be restored. We present the case of a 36-year old patient nulliparous with a history of abortion for eight years who consulted May 5, 2008 to become pregnant. Detailed examination showed chronic endometritis with bone metaplasia as a possible cause of her infertility. Seven months after complete removal of bone fragments by hysteroscopy, the patient had a spontaneous pregnancy with normal development. She gave birth to a male infant weighing 3,000 g with an Apgar score of 9 at 1 and 5 min. Delivery and postpartum were normal. PMID- 23444772 TI - Primary umbilical endometriosis: case report and literature review. AB - We present a case of primary endometriosis of the umbilicus in a young nulliparous patient without any previous history of abdominal or pelvic surgery. Primary endometriosis of extra pelvic sites is unusual while umbilical endometriosis is quite rare. Diagnosis of endometriosis is difficult to obtain and sometimes diagnoses can be false-positive or false-negative. Some imaging procedures can be done to rule out other disorders but it is difficult to differentiate them from endometriosis. A definite diagnosis can only be established by histopathological examination. Hematoxylin and eosin (H&E) is the staining of choice. Conservative surgical excision of the lesion and drugs such as oral contraceptives and gonadotropin releasing analogues are the first-line treatment. PMID- 23444773 TI - Fanconi anemia pathway--the way of DNA interstrand cross-link repair. AB - The study of rare genetic diseases usually inspires the research of cancer biology. Fanconi anemia (FA), is a rare cancer susceptibility syndrome with an incidence of only 1 per 350,000 births. FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system. DNA crosslinking agents may led to DNA cross linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. However, FA pathway is closely linked with carcinogenesis and tumor drug resistance. This paper mainly focuses on the FA pathway and its progress in cancer research. PMID- 23444774 TI - Simultaneous high-performance liquid chromatographic determination of a rhein diclofenac prodrug and its active compounds. AB - In order to study the hydrolytic characterization of an anti-inflammatory prodrug (RD-1) in vitro, a simple, specific, precise and accurate method for the simultaneous determination of prodrug and its two hydrolytic active compounds was development using reverse phase high-performance liquid chromatography (RP-HPLC). The chromatographic separation was performed on an ODS-2 C18 column (250 mm x 4.6 mm, 5.0 microm particle size) with a simple elution programme. The mobile phase was methanol-0.1%phosphoric acid solution (adjusted pH to 2.3) (80:20, v/v); wavelength of 257nm and mobile phase flow rate of 1.0 mL/min was utilized for the quantitative analysis. Excellent linear behaviors over the investigated concentration ranges were observed with the values of R2 higher than 0.999 for all the analytes. The validated method was successfully applied to the simultaneous determination of prodrug and its active components. PMID- 23444775 TI - Rapid identification of sibutramine in dietary supplements using a stepwise approach. AB - Adulteration of botanical food supplements with undeclared synthetic drugs is a common problem. One of the most affected product groups are the slimming agents. There are no analytical protocols for the detection of synthetic adulterants from these products. The present study aimed at the development of a multistep analytical method for the quick and reliable determination of sibutramine, one of the most common adulterants among botanical food supplements. The extract of a sibutramine-containing slimming formula was analysed by colour tests, TLC, HPLC DAD, MS and NMR. The multistep method proposed by the authors allows the quick identification of sibutramine in counterfeit samples in laboratories with different instrumentation. PMID- 23444776 TI - Development and validation of a simple LC method for the determination of phenacetin, coumarin, tolbutamide, chlorzoxazone, testosterone and their metabolites as markers of cytochromes 1A2, 2A6, 2C11, 2E1 and 3A2 in rat microsomal medium. AB - Cytochrome P450 enzymes are responsible for the oxidative metabolism of most pharmaceutical compounds. A "cocktail" approach which employs simultaneous administration of a mixture of substrates of CYP enzymes was often used to assess the metabolic activity of multiple P450 forms in one experiment. Phenacetin, coumarin, tolbutamide, chlorzoxazone and testosterone are commonly used as probe substrates to evaluate cytochrome P450 function. An analytical strategy to simultaneously extract and analyze the five probe substrates and their major metabolites by HPLC-DAD was developed. The incubation was done with all the substrates in one step. The ten analytes were extracted simultaneously by solid phase extraction (SPE) from rat liver microsomes. A C18 analytical column and mobile phase composed of acetonitrile and 0.02% aqueous phosphoric acid were used for the chromatographic separation with DAD detection. Limits of quantification varied between 0.02378 and 0.2361 microg/mL which contributed to quantify all these drugs and metabolites with UV detection. The method is applicable for the modeling and description of pharmacological interactions on rat cytochromes P450 or can be used for in vitro evaluation of cytochromes 1A2, 2A6, 2C11, 2E1 and 3A2. PMID- 23444777 TI - Influence of particle shape on plasma protein adsorption and macrophage uptake. AB - The purpose of this study was to evaluate the plasma protein adsorption behavior onto different LIPOMER nanoparticles, especially looking for the first time, if the particle shape affects the protein adsorption pattern. The potential in vivo fate is discussed and compared with previous in vivo animal studies. The two dimensional polyacrylamide gel electrophoresis (2-D PAGE) was used for identification of adsorbed plasma proteins. Qualitative similar patterns were obtained from the protein adsorption analysis and four apolipoproteins with considerable quantitative differences were identified. Besides the quantitative differences in the adsorbed apolipoproteins, in vitro uptake in the human macrophage cell line U-937 of histocytic lymphoma organ revealed significantly lower uptake of the irregular glycerol monostearate LIPOMER nanoparticles. Therefore, protein adsorption does not seem to play a role in the splenotropic behavior in the sense, that adsorption of opsonins, especially spleen-specific opsonins are required for the uptake. The splenotropic uptake might be favored because all LIPOMER nanoparticles did not adsorb opsonins at all, mediating competitive uptake by liver macrophages. Differences in the in vivo uptake by the spleen were attributed to differences in particle shape with potential super position effect by the quantitative differences in the adsorbed proteins. PMID- 23444778 TI - Evaluation of sunscreen safety by in vitro skin permeation studies: effects of vehicle composition. AB - For sunscreens to be safe and effective, the lowest possible UV-filter percutaneous absorption should be achieved. In this paper, we evaluated in vitro release and permeation through human skin of two UV-filters, octyl methoxycinnammate (OMC) and butyl methoxydibenzoyl methane (BMBM) from six commercial O/W emulsions and we estimated their margin of safety (MoS). OMC and BMBM in vitro release and skin permeation were investigated in Franz-type diffusion cells and permeation data were used to calculate MoS. OMC in vitro skin permeation depended on both its concentration and vehicle composition while BMBM skin permeation depended on its release from the vehicle. MoS values were well beyond the lowest limit accepted for safe products. Although sunscreen skin permeation may depend on many factors, the commercial products investigated are safe under normal "in use" conditions. PMID- 23444779 TI - Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice. AB - Honokiol, isolated from the Chinese traditional herb magnolia, is a poorly water soluble component and has been found to have anti-tumor properties. In the current study, honokiol submicron lipid emulsions (HK-SLEs) were prepared by high pressure homogenization technology. After HK-SLEs were physically characterized, their pharmacokinetics, tissue distribution and antitumor activity after intravenous (i.v.) administration to tumor-burdened mice were examined, using honokiol solution (HK-SOL) as the control. The results showed that the mean particle size, zeta potential, pH value, osmolality, drug loading (DL)% and entrapment efficiency (EE)% of HK-SLEs were 186.6 +/- 1.7 nm, -35.65 +/- 0.67 mV, 7.22 +/- 0.26, 298 +/- 2.3 mOsm/L, 7.1 +/- 0.2% and 95.5 +/- 0.2%, respectively. HK-SLEs were stable for at least 12 months when stored at 4 +/- 2 degrees C. The pharmacokinetic results showed that the drug concentration-time curves of HK-SLEs and HK-SOL could both be described by an open two-compartment model. The half life of HK-SLEs (t1/2(alpha) = 8.014 min, t1/2(beta) = 35.784 min) was remarkably prolonged compared to that of HK-SOL (t1/2(alpha) = 4.318 min, t1/2(beta) = 15.522 min). HK-SLEs exhibited a greater AUC and reduced plasma clearance. The tissue distribution results indicated that HK-SLEs have better targeting properties to lung and tumor tissues compared with those of HK-SOL. Both HK-SLEs and HK-SOL tended to accumulate in brain tissue. In vivo study showed that HK SLEs treatment caused significant inhibition of mouse sarcoma S180 tumor growth compared to HK-SOL. These results suggest that HK-SLEs might be an effective parenteral carrier for honokiol delivery in cancer treatment. PMID- 23444780 TI - Cell uptake of paclitaxel solid lipid nanoparticles modified by cell-penetrating peptides in A549 cells. AB - The aim of this study was to investigate the cytotoxicity of paclitaxel solid lipid nanoparticles (SLN) modified with stearic acid octaarginine (SA-R8-PTX-SLN) as well as the cellular uptake of coumarin-6-loaded SLN modified with SA-R8 (SA R8-C6-SLN) in human lung cancer cells, A549. SLN were prepared using a film dispersion method; and then their particle size, zeta potential, morphology, bound efficiency of SAR8, drug loading efficiency, and in vitro release were characterized. SA-R8-PTX-SLN and SA-R8-C6-SLN were incubated with A549 cells to measure their cytotoxicity and cellular uptake, respectively. The results indicated that the cytotoxicity of SA-R8-PTX-SLN was enhanced significantly with the increasing amount of SA-R8 and the cellular uptakes of SLN increased with the incubated concentrations and the incubated time of SLN. In contrast, SA-R8-SLN could significantly enhance the cellular uptake of SLN and the cytotoxicity of PTX in A549 cells. These in vitro results suggest that SA-R8-SLN could be proposed as alternative drug delivery system. PMID- 23444781 TI - Biochemical and hematologic effects of polyvinylpyrrolidone-wrapped fullerene C60 after oral administration. AB - The fullerene C60 is used in consumer products such as cosmetics owing to its antioxidative effects and is being developed for nanomedical applications. However, knowledge regarding the safety of fullerene C60, especially after oral administration, is sparse. Here, we examined the safety of fullerene C60 in mice after 7 d of exposure to orally administered polyvinylpyrrolidone (PVP)-wrapped fullerene C60 (PVP-fullerene C60). Mice treated with PVP-fullerene C60 showed few changes in the plasma levels of various markers of kidney and liver injury and experienced no significant hematologic effects. Furthermore, the histology of the colon of PVP-fullerene C60-treated mice was indistinguishable from that of control mice. These results suggest that PVP-fullerene C60 lacks toxicity after high-dose oral administration and indicate that PVP-fullerene C60 can be considered safe for oral medication. These data provide basic information that likely will facilitate the production of safe and effective forms of fullerene C60. PMID- 23444782 TI - Effects of a new sustained-release microsphere formulation of exenatide, DA-3091, on obese and non-alcoholic fatty liver disease mice. AB - The aim of this study was to examine the effects of a new sustained-release (SR) microsphere formulation of exenatide, DA-3091, on body weight gain and hepatic injury in high fat diet (HFD)-induced obese mice and high sucrose diet (HSD) induced non-alcoholic fatty liver disease (NAFLD) mice. Then, we determined whether DA-3091 has the potency as a drug for the treatment of metabolic disease. In obese mice, after 8-week treatment, the body weight gain was significantly more suppressed by both 1 mg/kg and 2 mg/kg of DA-3091, monthly subcutaneous administered, than by 10 mg/kg/day of sibutramin, a drug against obesity. In NAFLD mice, a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, representative markers of hepatic injury, was observed after biweekly subcutaneous administration of 1 mg/kg and 2 mg/kg of DA-3091 for 8 weeks. A significant reduction in hepatic lipid accumulation was observed in DA-3091 treated groups as well. Based on these results, it is demonstrated that DA-3091 has the potency as a drug for the treatment of metabolic disease. PMID- 23444784 TI - Pharmacodynamics and toxicity of vasoactive intestinal peptide for intranasal administration. AB - The aim of this work was to study the nasal route for the delivery of vasoactive intestinal peptide (VIP) to the brain and to evaluate the toxicity of VIP nasal spray. Mice were injected intracerebroventricularly with the aggregated Abeta25 35 to mimic Alzheimer's disease. Following administration, different groups of mice were treated over one week, and their spatial learning and memory capacities were evaluated by the Morris water maze test. The toxicity of VIP nasal spray was evaluated by examining the morphology of individual rat nasal mucosa cilia and the pathology of rat nasal mucosa. Rats receiving intranasal VIP (40 microg/ml) showed good spatial memory relative to the Abeta25-35 model group, but the escape latency did not show any statistically significant difference. Intranasal administration of VIP nasal spray (200 microg/ml) improved deficits in spatial memory to the point that test animals receiving intranasal VIP showed no statistically significant differences from the normal control group in escape latency. This indicated that the nasal spray method could increase the quantity of VIP entering the brain and protect the central nervous systems of mice. Toxicity evaluation showed that the preparation could cause minor irritation, which resolved spontaneously within a week at the end of treatment. In conclusion, VIP can be delivered successfully to the brain using the intranasal route. PMID- 23444783 TI - Effects of insulin-like growth factor-1 on neurochemical phenotypes of cultured dorsal root ganglion neurons with excitotoxicity induced by glutamate. AB - Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. The neuropeptide- and neurofilament (NF)-immunoreactive (IR) neurons are two major phenotypical classes in DRG. Whether IGF-1 affects neurochemical phenotypes of DRG neurons remains unknown. In the present study, primary cultured DRG neurons were used to determine the effects of IGF-1 on neurochemical phenotypes of the neurons with excitotoxicity induced by glutamate (Glu). DRG neurons were dissociated and cultured for 48 hours and then exposed to IGF-1 (20 nmol/L), Glu (0.2 mmol/L), Glu (0.2 mmol/L) plus IGF-1 (20 nmol/L) for additional 24 hours. The DRG neurons were continuously exposed to culture media as control. After that, all above cultured DRG neurons were processed for detecting mRNA levels of calcitonin gene-related peptide (CGRP) and neurofilament-200 (NF-200) by real time-PCR analysis. CGRP and NF-200 expression in situ was determined by fluorescent labeling technique. The results showed that CGRP mRNA, but not NF-200 mRNA, increased after IGF-1 administration in the absence or presence of Glu. IGF 1 could increase the percentage of CGRP-expressing neurons, but not NF-200 expressing neurons, in the absence or presence of Glu. The ability of IGF-1 on CGRP expression may play a role in neurogenic inflammation or nociception. PMID- 23444785 TI - Incision wound healing activity of pine bark extract containing topical formulations: a study with histopathological and biochemical analyses in albino rats. AB - The present study was designed to identify and compare the in vivo wound healing capacity of a bark extract from Pinus brutia and Pycnogenol in an incision wound model in rats. O/W cream formulations were prepared incorporating 2% Pycnogenol and P. brutia bark extract. The rats were divided into three groups (n = 8). Subsequently placebo and test formulations were applied to animals once a day from day "0" until the 9th day. Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) were studied in addition to histopathological examinations. Treatment with F. brutia extract containing cream inhibited lipid peroxidation by a 35% decrease in MDA and 46.8% increase in SOD activity, whereas 19.3% decrease in MDA and 34.7% increase in SOD activity were attained with Pynogenol compared to control. The histological data revealed a better performance of P. brutia extract enriched formulation in terms of degeneration of hair roots, increased vascularization and a decrease in necrotic area. Consequently, a high wound healing activity was observed in animals treated with P. brutia extract significantly accelerating the wound healing process. PMID- 23444786 TI - We are the manifestations of our ancestor's prayers. PMID- 23444787 TI - Truth, healing, and systems change: the Maine Wabanaki-state child welfare truth and reconciliation commission process. AB - Maine state child welfare staff understand the Indian Child Welfare Act requirements, yet their knowledge of Wabanaki history is limited because it has excluded the voices of the Wabanaki people. A group of Native people and state representatives are creating a truth and reconciliation commission process in Maine, designed to reckon with this history as a way of improving the child welfare system and promoting healing for Wabanaki children and families. PMID- 23444788 TI - Moving toward reconciliation in indigenous child welfare. AB - The Touchstones of Hope reconciliation movement consists of principles (culture and language, self-determination, structural interventions, non discrimination, and holistic approach) that guide a reconciliation process of truth-telling, acknowledging, restoring and relating to reshape indigenous child welfare led by indigenous peoples and supported by their non-indigenous counterparts. This article describes a reconciliation movement in Canada grounded in Touchstones of Hope principles, involving a reconciliation process between indigenous and non indigenous individuals, which has enabled culturally relevant concepts of child welfare and plans for child safety to emerge. PMID- 23444789 TI - Findings from a national needs assessment of American Indian/Alaska native child welfare programs. AB - The National Child Welfare Resource Center for Tribes, a member of the Children's Bureau Child Welfare Training and Technical Assistance Network, conducted a national needs assessment of tribal child welfare. This assessment explored current practices in tribal child welfare to identify unique systemic strengths and challenges. A culturally based, multi-method design yielded findings in five areas: tribal child welfare practice, foster care and adoption, the Indian Child Welfare Act, legal and judicial, and program operations. PMID- 23444790 TI - Continuum of readiness for collaboration, ICWA compliance, and reducing disproportionality. AB - From 2008-2010, a California Breakthrough Series Collaborative (BSC) addressed the disproportionality of African American and American Indian/Alaska Native (AI/AN) children in public child welfare services in partnership with the Annie E. Casey Foundation, Casey Family Program, the Child and Family Policy Institute of California, and the California Department of Social Services. The result was the development of the Continuum of Readiness, to be utilized by California counties to make strategic decisions to achieve Indian Child Welfare Act (ICWA) compliance and address AI/AN dis-proportionality through collaboration with tribes and urban Indian communities. PMID- 23444791 TI - A collaborative and trauma-informed practice model for urban Indian child welfare. AB - Preventing the breakup of the American Indian family is the fundamental goal of the Indian Child Welfare Act (ICWA). However, few models exist to provide CPS workers and other practitioners with effective and practical strategies to help achieve this goal. This article presents a collaborative and trauma-informed family preservation practice model for Indian Child Welfare services with urban based American Indian families. The model encompasses both systemic and direct practice efforts that assist families facing multiple challenges in creating a nurturing and more stable family life. System-level interventions improve the cultural responsiveness of providers, encourage partnerships between CPS and community-based providers, and support ICWA compliance. Direct practice interventions, in the form of intensive case management and treatment services, help parents/caregivers become more capable of meeting their own and their children's needs by addressing challenges such as substance abuse, trauma and other mental health challenges, domestic violence, and housing instability. Evaluation of the practice model suggests that it shows promise in preventing out of-home placement of Native children, while at the same time improving parental capacity, family safety, child well-being, and family environment. PMID- 23444792 TI - Family Group Decision Making (FGDM) with Lakota families in two tribal communities: tools to facilitate FGDM implementation and evaluation. AB - This article describes an adapted Family Group Decision Making (FGDM) practice model for Native American communities, the FGDM family and community engagement process, and FGDM evaluation tools as one example for other native communities. Challenges and successes associated with the implementation and evaluation of these meetings are also described in the context of key historical and cultural factors, such as intergenerational grief and trauma, as well as past misuse of data in native communities. PMID- 23444793 TI - Best outcomes for Indian children. AB - The Wisconsin Department of Children and Families and the Midwest Child Welfare Implementation Center are collaborating with Wisconsin's tribes and county child welfare agencies to improve outcomes for Indian children by systemically implementing the Wisconsin Indian Child Welfare Act (WICWA). This groundbreaking collaboration will increase practitioners' understanding of the requirements of WICWA and the need for those requirements, enhance communication and coordination between all stakeholders responsible for the welfare of Indian children in Wisconsin; it is designed to effect the systemic integration of the philosophical underpinnings of WICWA. PMID- 23444794 TI - Native American Indian child welfare system change: implementation of a culturally appropriate practice model across three tribal child welfare systems. AB - Currently, there are 565 federally recognized tribes in the United States who are independent sovereign nations. These tribes have varying capacities to manage and administer child welfare programs. Most provide some type of child welfare service to the children and families within their tribal land. However, there are no national resources to document the number of children in foster care or the extent of abuse and neglect in the families served by tribal child welfare agencies. Information is only known about those Native American/Alaska Native families and children who are reported to state child protection agencies. Native American children represented 0.9% of all children in the United States in the late 1990s, but they comprised 3.1% of the substitute care population in state run child welfare systems (Morrison, et al., 2010). Incident rates of child welfare referrals, substantiated referrals, and foster care placement among Native American children and families are relatively high compared to other ethnic groups (Earle & Cross, 2001) but precise interpretation of Native American status is difficult due to variations in child welfare reporting systems (Magruder & Shaw, 2008). PMID- 23444795 TI - An examination of the living conditions of urban American Indian children in unmarried families: increasing cultural competence in child welfare. AB - The past 50 years have revealed dramatically shifting trends in the familial structure of American society. When examining these trends, and family research in general, the American Indian family unit has received little to no attention. This study utilized data from the Fragile Families and Child Wellbeing Study to examine the living conditions of urban American Indian children in unmarried families. Results showed that while these children appear to have a strong start, concerns are raised regarding American Indian mothers' low educational achievement and high incidence of poverty. These concerns can lead to potential issues regarding sustained development that can arise as the children grow. Therefore, child welfare workers must understand these issues and work to ameliorate them in order to provide culturally competent services to urban American Indian families and children. PMID- 23444796 TI - Current problems concerning parasitology and mycology with regard to diseases of the skin and its appendages. AB - Current issues concerning Parasitology and Mycology with regard to diseases of the skin and its appendages are presented. Aspects of diagnostics, clinical picture and therapy of skin and nail mycoses, as well as difficulties in the diagnosis and treatment of both native parasitoses (toxoplasmosis) and imported human tropical parasitoses (malaria, filariosis) have been emphasised. The clinical importance of environmental mould fungi in nosocomial infections and fungal meningitis, as well as selected properties of fungi isolated from patients with head and neck neoplasms treated by radiotherapy are discussed. Other mycological topics include the characteristics of newly-synthesized thiosemicarbazides and thiadiazoles as potential drugs against toxoplasmosis and their biological activity against Toxoplasma gondii tachyzoites, selected molecular mechanisms of resistance to azoles, Candida albicans strains and a new tool (barcoding DNA) for describing the biodiversity of potential allergenic molds. The importance of environmental factors in pathogenesis of mycoses and parasitoses is noted. The characteristics of pathogenic fungi isolated from natural ponds in Bialystok and potentially pathogenic yeast-like fungi isolated from children's recreation areas in Lodz are presented. The ongoing problem of anthropozoonoses is considered, as are the roles of stray cats and dogs in contaminating soil with the developing forms of intestinal parasites. The characteristics of the human microbiome, including population composition, activity and their importance in normal human physiology, are presented, as are the major goals of the Human Microbiome Project initiated by National Institutes of Health (NIH). PMID- 23444797 TI - Ticks of Poland. Review of contemporary issues and latest research. AB - The paper presents current knowledge of ticks occurring in Poland, their medical importance, and a review of recent studies implemented in the Polish research centres on ticks and their significance in the epidemiology of transmissible diseases. In the Polish fauna there are 19 species of ticks (Ixodida) recognized as existing permanently in our country: Argas reflexus, Argas polonicus, Carios vespertilionis, Ixodes trianguliceps, Ixodes arboricola, Ixodes crenulatus, Ixodes hexagonus, Ixodes lividus, Ixodes rugicollis, Ixodes caledonicus, Ixodes frontalis, Ixodes simplex, Ixodes vespertilionis, Ixodes apronophorus, Ixodes persulcatus, Ixodes ricinus, Haemaphysalis punctata, Haemaphysalis concinna, Dermacentor reticulatus. Occasionally, alien species of ticks transferred to the territory of Poland are recorded: Amblyomma sphenodonti, Amblyomma exornatum, Amblyomma flavomaculatum, Amblyomma latum, Amblyomma nuttalli, Amblyomma quadricavum, Amblyomma transversale, Amblyomma varanensis, Amblyomma spp., Dermacentor marginatus, Hyalomma aegyptium, Hyalomma marginatum, Ixodes eldaricus, Ixodes festai, Rhipicephalus rossicus, Rhipicephalus sanguineus. The most common species of the highest medical and veterinary importance in Poland is invariably Ixodes ricinus. The review also sets out information on the risks of tickborne diseases in recreational areas of large cities in Poland, ticks as the cause of occupational diseases and dangerous species of ticks attacking people outside the Polish borders. Selected problems of the biology of ticks, the spread of alien species transferred on hosts and prevention of tick attacks have also been presented. The Polish studies on ticks are a valuable contribution to global research on the Ixodida. PMID- 23444798 TI - Natural microbiota in viral and helminth infections. Addendum to: Personalized vaccination. II. The role of natural microbiota in a vaccine-induced immunity. AB - Numerous original and review papers have emerged over recent years concerning the natural microbiota and its interaction with the mammal host's body. This addendum supplements in short our previous review article on the role of microbiota in the host immunity paying, particular attention to such essential aspects as the composition and role of gut microbiota in viral infections as well as the interplay between the microbiota and the macrofauna inhabiting the mammalian gastrointestinal tract. The host immune system, commensal microbiota and macrofauna are elements of an integrated system in which the relationships are bidirectional. As demonstrated in the article, virus or helminth infection alters the composition of commensal gut microbiota but, in turn, commensal microbiota influences the fate of a virus or helminth infection. Natural microbiota located on external and internal surfaces of the host body is a prominent element of its health and condition, including the functioning of the immune system. The gastrointestinal tract harbors the highest number and the greatest diversity of microbial organisms, so the studies presented in the article regard gut microbiota. PMID- 23444799 TI - Demodex acutipes Bukva et Preisler, 1988 (Acari, Demodecidae)--a rare parasite of red deer (Cervus elaphus L.). AB - Two species of demodectic mites were described in the red deer Cervus elaphus, including Demodex kutzeri, which had also been found in other species of the Cervidae family in Austria, Germany, Czech Republic, Poland and North America. Whereas the other species, D. acutipes, had been previously known from only one finding in the Czech Republic. The present research included skin samples taken in winter 2012 from thirty red deer in northern Poland. Demodex acutipes (prevalence 20%, mean intensity 4.5), D. kutzeri (53.3%, 69.8) and fifteen Demodex sp. specimens (6.7%, 7.5), were found. D. acutipes is a new species for the fauna of Poland. PMID- 23444800 TI - Prevalence of coccidia infection in goats in Western Pomerania (Poland) and West Ukraine region. AB - The prevalence of coccidia infection in goats was evaluated in Western Pomerania (Poland) and West Ukraine Province. A total number of 311 goats were examined: 173 from Western Pomerania, including 139 kids (up to 6 month old), and 138 from the Lviv region including 93 juveniles. The study was based on two flotation methods, which helped to establish the number of oocysts in 1g of feces (OPG): Willis-Schlaaf for qualitative and McMaster for quantitative analysis. The species composition was established using Coudert's (Coudert 1992) and Eckert's (Eckert et al.,1995) keys. Nine Eimeria spp. were identified in feces samples in Western Pomerania and Lviv regions: E. arloingi, E. chrisienseni, E. jolchijevi, E. ninakohlyakimovae, E. alijevi, E. capina, E. caprovina, E. hirci, E. apsheronica. The prevalence of infection in Western Pomerania of adult goats was 74% with an intensity of 0-2500 OPG. The rate of infection in kids was 100% and the intensity ranged from 1800 to 28000 OPG. In West Ukraine Province, 100% of the adult goats and kids were infected. The coccidian intensity of infection ranged from 2600 to 120000 OPG in kids, from 50 to 4500 OPG in adults. Clinical conditions can influence the intensity of oocysts excretion in the feces of animals. In Western Pomerania the highest intensity of excretion of oocysts was during May-July and the lowest during November-January. In West Ukraine Province the peak of oocysts excretion was in May-July and the lowest in October-December. The results of the present investigation have implications for the control of coccidial infections in goats in Europe. PMID- 23444801 TI - An anomaly within the genital system in a female Ascaris suum Goeze. AB - The authors describe an individual of the female Ascaris suum Goeze with a unique genital system. A female with such an anomaly was found during laboratory classes of Invertebrate Zoology at the Faculty of Biology and Environmental Protection, NCU. The specimen was about 200 mm long, and the total length of the reproductive system was 1970 mm. Further comparative analysis between unchanged and changed individuals revealed differences in the length of individual sections of the studied system, as well as in the diameter of the uterus. The described case is extremely interesting because of the phenomenon of eutely occurring in nematodes. The exact cause and mechanism of abnormalities described in Ascaris suum are not known and difficult to explain experimentally because of the extremely small number of these anomalies. Moreover, the interpretation of the anomaly is difficult because of the specific behavior and complex morphogenesis of this endoparasite. PMID- 23444802 TI - [The art of communication determines professionalism]. PMID- 23444803 TI - [20 years German network for quality development in nursing: promoting the development in nursing]. PMID- 23444804 TI - [Communication in routine nursing practice professionally designed: no power in killer phrases]. PMID- 23444805 TI - [Better coping with difficult moments during morning nursing care with appropriate communication: it depends on subtle nuances in conversation]. PMID- 23444806 TI - [Biographical communication in nursing: when life histories speak with one another]. PMID- 23444807 TI - [Further translating education for multilingual nurses: a real treasure lies dormant there]. PMID- 23444808 TI - [Psychological stresses and communication in routine nursing: silence is not always golden]. PMID- 23444809 TI - [Communication in difficult and stressful situations: conquering the word winter]. PMID- 23444810 TI - [Understanding communication and interaction as health nursing care - 1: More than a fleeting smile]. PMID- 23444811 TI - [Perception of safety climate in outpatient pediatric care]. AB - In ambulant pediatric care, patients situations are becoming increasingly complex, because the lenght of hospital stay is reduced since the introduction of Diagnosis Related Groups (DRG). Consequently, the patients' safety is constantly becoming more important. The patients' safety is closely associated with the nurses' awareness of risks and the safety climate within the institution. This study is investigating how nurses of a pediatric outpatient service estimate the patients' safety and how that can be optimized, if necessary. As part of a cross sectional study, a total of 106 nurses of the pediatric outpatient service were interviewed with a modified German version of the "Patient Safety Climate Inventory (Patientensicherheitsklima-Inventar, PaSKI)". Data was analysed by a descriptive statistical method. The return rate was 80.2 percent. The results show a very high awareness of patients' safety issues as well as a high level of satisfaction concerning team collaboration. Both results have a positive influence on the safety-climate. Problems are associated mainly with the incident reporting system, e.g. with reporting critical incidents and communicating after reporting. This indicates the importance of a useable incident reporting system, which--in combination with staff training--may be an important step towards a structured risk management. Furthermore, it clarifies the importance of transparent communication after a reported incident, as also described in the literature. PMID- 23444812 TI - [Training for ICU nurses improves communication with relatives of seriously ill patients]. PMID- 23444813 TI - [Communication in routine nursing: it does not always need to be perfect]. PMID- 23444814 TI - [Needs for assistance are not a nursing problem - a definition of terms: an unresolved task]. PMID- 23444815 TI - [White lies in nursing patients with advanced dementia: "your husband has gone fishing"!]. PMID- 23444816 TI - [Nursing universities in West Germany and their significance for graduate education of administrative personnel: every matron must be a nurse"]. PMID- 23444817 TI - [Speech and communication: "what do you want from me?"]. PMID- 23444818 TI - [Comment on the article "Professional political concerns will not help us in nursing practice"]. PMID- 23444819 TI - [Financial, economic, social, public, moral crises, all chain-reactions]. PMID- 23444820 TI - [Image of the month: Hairy kidneys]. PMID- 23444821 TI - [CSF otorrhea: case report and management]. AB - Mr G, sixty-seven years old, was admitted to our hospital for a liver transplant. He suffered from a cirrhosis due to an HBV infection, complicated by an hepatocellular carcinoma. During the perioperative care, a left otorrhea was discovered. According to the clinical history, this otorrhea had been present for six weeks and followed the completion of a myringotomy. The myringotomy had been performed with a view to place a transtympanic ventilation tube for the treatment of a serous otitis media inducing a conductive hearingloss. Clinical, biological, and radiological explorations revealed a CSF leak caused by the fact that the myringotomy had been done in a temporal meningo-encephalocele. A conservative treatment allowed to stop the otorrhea. We present a short discussion about temporal meningoencephalocele and, more generally, about CSF otorrhea. PMID- 23444822 TI - [Horner's syndrome revealing a spontaneous carotid artery dissection]. AB - We report a case of spontaneous carotid artery dissection suspected by the appearance of Horner's syndrome. Under medical treatment, the intramural hematoma resolved within 3 months. The patient had an uneventful recovery, without any residual neurologic deficit. Spontaneous arterial dissection is responsible for a hematoma in the arterial wall without significant trauma. The pathogenesis remains unknown. Predisposing factors seem to exist. The clinical presentation is variable mainly due to local compression of adjacent structures which can precede a transient or permanent neurological deficit. The diagnosis is confirmed by Doppler US, CT angiography or magnetic resonance angiography, the best optional investigations. The treatment mainly consists of stroke prevention by anticoagulation versus antiplatelet therapy. The role of surgery and/or endovascular techniques has not yet been confirmed. PMID- 23444823 TI - [Limited add-on value of oral glucose-lowering agents in type 1 diabetes]. AB - Management of type 1 diabetes essentially relies upon intensive insulin therapy adjusted according to careful home blood glucose monitoring. The potential role of oral antidiabetic agents is controversial and what so ever is limited in type 1 diabetes. Nevertheless, metformin may still be useful in the presence of obesity and/or insulin resistance while acarbose could reduce the amplitude of glycaemic fluetuations, namely postprandial hyperglycaemia and late postmeal glycaemic nadir. Both drugs may also minimize weight gain that results from intensive insulin therapy. Finally, inhibitors of dipeptidyl peptidase-4 (glitpins), by inhibiting glucagon secretion, and inhibitors of renal SGLT2 cotransporters, thus promoting glucosuria independently of insulin, might also be beneficial in type 1 diabetes, although specific studies are still ongoing to verify this hypothesis. PMID- 23444824 TI - [Fibromyalgia: an unrecognized Ehlers-Danlos syndrome hypermobile type?]. AB - Some patients suffering from fibromyalgia present with clinical signs and alterations in the histopathology, immunohistochemistry and ultrastructure of the dermis similar to the Ehlers-Danlos syndrome, hypermobile type (EDSH). Some types of fibromyalgia possibly represent an undiagnosed EDSH. PMID- 23444825 TI - [Role of vitamin D in HIV infection]. AB - Besides its role in bone metabolism, vitamin D shows properties on autoimmune, oncological, cardiovascular, metabolic, or infectious diseases. In this article, we talk about interpellant relationships between vitamin D and HIV. This hormone plays an important role in HIV infection, as much at a skeletal level than in the course of the disease itself. First, we notice that a low vitamin D status is currently associated with HIV infection. Moreover, it is now known that low rate of 1,25-dihydroxyvitamin D in HIV patients is associated with advanced clinical HIV infection and increased mortality. Thus, vitamin D deficiency has to be considered as an important factor in HIV progression. Indeed, vitamin D increases macrophage activity, in some way through autophagy, and this process can inhibit HIV-1 infection. Then we consider the implications of antiretroviral therapies on vitamin D metabolism. We finally evaluate the benefits of a vitamin D supplementation in HIV + patients. PMID- 23444826 TI - [Are the concerns regarding metal-on-metal total hip arthroplasties founded in 2012?]. AB - Metal-on-metal total hip arthroplasty (MOM THA) fuels debate in the orthopedic community after statistics showed higher-than-expected short-term failures in comparison with metal-on-polyethylene THA. The problem of early failure in the young, active patient with a metal-on-polyethylene implant has prompted the research of another couple. Multiple studies showed the advantages of MOM THA. The results of MOM resurfacing and MOM THA in our hospital did not show concerning results. Nonetheless, the data in the literature shows divergent opinions. The most recent statistics indicate that the results are disappointing, particularly with specific types of implants. Several institutions, in the USA and in Europe, are developing protocols for the follow-up of patients with MOM hip implants. Today, we are headed towards imposing a moratorium on using MOM THA. PMID- 23444827 TI - [Allogeneic hematopoietic stem cell transplantation: what is the upper age limit?]. AB - In the last decades, the upper age limit for allogeneic hematopoietic cell transplantation has increased from 50-60 years to 70-75 years of age, in part due to the development of allogeneic transplantation following reduced-intensity or truly nonmyeloablative conditioning. This review describes challenges and opportunities of allogeneic hematopoietic cell transplantation in the elderly. PMID- 23444828 TI - [The spectrum of drug eruptions]. AB - Drug eruptions are frequently encountered and they represent "diseases of medical progress". They are expected in about 2% of treated patients. Their putative diagnosis is based on a set of imputability factors. Several distinct drug induced skin disorders are identified. They are initially recognized from personal experience, but the implication to a specific drug derives from the collective experience of published evidence. Their histopathological aspect is often evocative or demonstrative for the nature of the dermatosis. Some drug eruptions follow an indolent course, while others are life-threatening. PMID- 23444829 TI - Jointly tuned plasmonic-excitonic photovoltaics using nanoshells. AB - Recent advances in spectrally tuned, solution-processed plasmonic nanoparticles have provided unprecedented control over light's propagation and absorption via engineering at the nanoscale. Simultaneous parallel progress in colloidal quantum dot photovoltaics offers the potential for low-cost, large-area solar power; however, these devices suffer from poor quantum efficiency in the more weakly absorbed infrared portion of the sun's spectrum. Here, we report a plasmonic excitonic solar cell that combines two classes of solution-processed infrared materials that we tune jointly. We show through experiment and theory that a plasmonic-excitonic design using gold nanoshells with optimized single particle scattering-to-absorption cross-section ratios leads to a strong enhancement in near-field absorption and a resultant 35% enhancement in photocurrent in the performance-limiting near-infrared spectral region. PMID- 23444830 TI - Orbiting orbitals: visualization of vibronic motion at a conical intersection. AB - The Jahn-Teller (JT) active unpaired electron of single metalloporphyrin radical anions is imaged through scanning tunneling microscopy. It is demonstrated that the electron is delocalized over the porphyrin macrocycle and its topographic image is determined by vibronic motion: the orbital of the electron adiabatically follows the zero-point pseudorotation of skeletal deformations. Transformation of the polar graphs of the observed images allows visualization of the adiabatic vibrational density to which the electron is coupled. The vibronic potential at the conical intersection is visualized and the half-integer angular momentum characteristic of the Berry phase is revealed in the radial function of the electron. The measurements underscore the economy of Jahn-Teller dynamics: small atomic displacements (~10(-1) A) determined by weak interactions (~10 meV) control the motion of the electron on a 10 A scale and determine the molecular shape and function. PMID- 23444831 TI - A facile strategy toward conjugated polyelectrolyte with oligopeptide as pendants for biological applications. AB - We report a facile yet efficient strategy to synthesize biofunctionalized conjugated polyelectrolyte using click reaction between an amphiphilic oligopeptide (R10) and organic soluble polyfluorene (PF) as an example. PF-R10 shows the absorption and emission maxima at ~380 and ~430 nm in water, respectively. In addition, it exhibits enhanced fluorescence in acidic circumstance as compared to that in neutral environment because of reduced aggregation, which is confirmed by laser light scattering and atomic force microscopy studies. In view of the penetration property of the grafted R10 peptide, PF-R10 shows excellent cell uptake and labeling ability in cellular imaging. PMID- 23444832 TI - Successful treatment of rhino-orbital mucormycosis with posaconazole and hyperbaric oxygen therapy. AB - Mucormycosis is a rare, but invasive infection caused by ubiquitous molds. Amphotericin B and surgery have been known to help improve the outcome. Sporadic case reports support the use of posaconazole in adults. We report a toddler with acute lymphoblastic leukemia who acquired rhino-orbital mucormycosis caused by Rhizopus species at the end of induction chemotherapy. She was successfully treated with multiple surgical debridements, amphotericin B, posaconazole and hyperbaric oxygen therapy. In conclusion, mucormycosis is a serious infection that requires aggressive surgical and medical therapy. To the best of our knowledge the use of posaconazole combined with hyperbaric oxygen therapy has not been reported in a toddler with leukemia and invasive Rhizopus sp. infection. This approach was found to be safe and effective in our patient. PMID- 23444833 TI - Isolation, structure elucidation, and iron-binding properties of lystabactins, siderophores isolated from a marine Pseudoalteromonas sp. AB - The marine bacterium Pseudoalteromonas sp. S2B, isolated from the Gulf of Mexico after the Deepwater Horizon oil spill, was found to produce lystabactins A, B, and C (1-3), three new siderophores. The structures were elucidated through mass spectrometry, amino acid analysis, and NMR. The lystabactins are composed of serine (Ser), asparagine (Asn), two formylated/hydroxylated ornithines (FOHOrn), dihydroxy benzoic acid (Dhb), and a very unusual nonproteinogenic amino acid, 4,8 diamino-3-hydroxyoctanoic acid (LySta). The iron-binding properties of the compounds were investigated through a spectrophotometric competition. PMID- 23444834 TI - Immunohistochemical analysis of mechanoreceptors in the human posterior cruciate ligament: association with aging male. AB - INTRODUCTION: The aim of this study was to evaluate the association between frequency of the posterior cruciate ligament (PCL) mechanoreceptors and age in men. METHODS: Nineteen normal right knees harvested from human male cadavers were evaluated. Age ranged from 17 to 64 years with a mean of 35 years old. PCL was separated for sampling in femoral and tibial portions. Topographic distribution and frequency within the ligament texture were determined employing the Pro-Image digital analysis system. Mechanoreceptors were counted and classified according to the criteria proposed by Freeman & Wyke. RESULTS: A total of 1820 mechanoreceptors were found, type II being the most frequent one. Analysis of the femoral portion of the ligament showed an equivalent predominance of Types II and IV mechanoreceptors. Tibial portion had a predominance of type II mechanoreceptors, followed by type IV. At this portion, receptors Types I and III were less commonly identified. CONCLUSION: In the tibial portion of the PCL, there is predominance of Type II mechanoreceptors followed by types IV, I and III mechanoreceptors, respectively. No relationship was found between the total number of mechanoreceptors and age in the femoral and tibial portions of the PCL. PMID- 23444836 TI - Medical ghostwriting and informed consent. AB - Ghostwriting in its various forms has received critical scrutiny from medical ethicists, journal editors, and science studies scholars trying to explain where ghostwriting goes wrong and ascertain how to counter it. Recent analyses have characterized ghostwriting as plagiarism or fraud, and have urged that it be deterred through stricter compliance with journal submission requirements, conflict of interest disclosures, author-institutional censure, legal remedies, and journals' refusal to publish commercially sponsored articles. As a supplement to such efforts, this paper offers a critical assessment of medical ghostwriting as contrary to good patient care, on the grounds that it contradicts established general principles guiding clinical ethics. Specifically, I argue that ghostwriting undermines trust relationships between authors and their readers, and between these readers and their trusting patients, and in so doing contradicts the duty of respect for patient autonomy by obstructing informed consent. For this reason, complicity in ghostwriting practices should be understood as a violation of the professional ethical duties of physicians and other healthcare workers. PMID- 23444835 TI - Synthesis and immunological evaluation of a MUC1 glycopeptide incorporated into l rhamnose displaying liposomes. AB - MUC1 variable number tandem repeats (VNTRs) conjugated to tumor-associated carbohydrate antigens (TACAs) have been shown to break self-tolerance in humanized MUC1 transgenic mice. Therefore, we hypothesize that a MUC1 VNTR TACA conjugate can be successfully formulated into a liposome-based anticancer vaccine. The immunogenicity of the vaccine should be further augmented by incorporating surface-displayed l-rhamnose (Rha) epitopes onto the liposomes to take advantage of a natural antibody-dependent antigen uptake mechanism. To validate our hypothesis, we synthesized a 20-amino-acid MUC1 glycopeptide containing a GalNAc-O-Thr (Tn) TACA by SPPS and conjugated it to a functionalized Toll-like receptor ligand (TLRL). An l-Rha-cholesterol conjugate was prepared using tetra(ethylene glycol) (TEG) as a linker. The liposome-based anticancer vaccine was formulated by the extrusion method using TLRL-MUC1-Tn conjugate, Rha TEG-cholesterol, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in a total lipid concentration of 30 mM. The stability, homogeneity, and size characterization of the liposomes was evaluated by SEM and DLS measurements. The formulated liposomes demonstrated positive binding with both anti-Rha and mouse anti-human MUC1 antibodies. Groups of female BALB/c mice were immunized and boosted with a rhamnose-Ficoll (Rha-Ficoll) conjugate formulated with alum as adjuvant to generate the appropriate concentration of anti-Rha antibodies in the mice. Anti-Rha antibody titers were >25-fold higher in the groups of mice immunized with the Rha-Ficoll conjugate than the nonimmunized control groups. The mice were then immunized with the TLRL-MUC1-Tn liposomal vaccine formulated either with or without the surface displaying Rha epitopes. Sera collected from the groups of mice initially immunized with Rha-Ficoll and later vaccinated with the Rha-displaying TLRL-MUC1-Tn liposomes showed a >8-fold increase in both anti MUC1-Tn and anti-Tn antibody titers in comparison to the groups of mice that did not receive Rha-Ficoll. T-cells from BALB/c mice primed with a MUC1-Tn peptide demonstrated increased proliferation to the Rha-liposomal vaccine in the presence of antibodies isolated from Rha-Ficoll immunized mice compared to nonimmune mice, supporting the proposed effect on antigen presentation. The anti-MUC1-Tn antibodies in the vaccinated mice serum recognized MUC1 on human leukemia U266 cells. Because this vaccine uses separate rhamnose and antigenic epitope components, the vaccine can easily be targeted to different antigens or epitopes by changing the peptide without having to change the other components. PMID- 23444837 TI - Care, compassion and courage: the museum of mental health nursing - an ethnographic archaeology. AB - Like a museum with carefully positioned exhibits mental health nursing would look different if the display of fashionable dead things in its cultural lineage were viewed through a different lens. This paper has the aim of using transcribed interview data from mental health nurses to explore how their perception of nursing culture represents a particular historical identity (pseudo names given to ensure confidentiality). The paper discusses five themes about the formation of collective identity and concludes that mental health nurses are theoretically well positioned to develop and rethink social recovery models, ideas about fragmented selves and multiple histories that the postmodern age now curates. PMID- 23444838 TI - Relatives' experiences of everyday life six months after hypothermia treatment of a significant other's cardiac arrest. AB - AIMS AND OBJECTIVES: To describe relatives' experiences of needing support and information and of the impact on everyday life six months after a significant other survived cardiac arrest treated with therapeutic hypothermia at an intensive care unit. BACKGROUND: Being the relative of a cardiac arrest patient has been described as an unexpected chaotic situation. It is a unique experience because the event was unexpected, but also because of the heart disease and the uncertain neurological impact and outcome. DESIGN: The design of the study was qualitative. METHODS: Interviews with 20 relatives were conducted six months after a significant other's cardiac arrest. The interviews were recorded, transcribed verbatim and analysed using qualitative content analysis. RESULTS: Three main themes were identified: 'Difficulties managing a changed life situation', 'Feeling like I come second' and 'Feeling new hope for the future'. The most common support to relatives came from family and friends, but relatives felt abandoned by healthcare personnel when the significant other was discharged from the intensive care unit and hospital. Relatives lacked information concerning prognosis, rehabilitation and follow-up. They wished to meet others in the same situation and share experiences. Relatives also felt people around them did not understand their situation. CONCLUSIONS: Everyday life was still affected six months after the event, involving increased domestic responsibilities, restrictions in social life and constant concern for the person stricken by cardiac arrest. RELEVANCE TO CLINICAL PRACTICE: The study shows that healthcare personnel need to improve provision of support and information and provide follow up appointments for relatives to clarify prognosis and rehabilitation issues. PMID- 23444839 TI - Signalling or binding: the role of the platelet-activating factor receptor in invasive pneumococcal disease. AB - Streptococcus pneumoniae (the pneumococcus) is an opportunistic human pathogen, which causes serious invasive disease such as pneumonia, bacteraemia and meningitis. The interaction of the bacteria with host receptors precedes the development of invasive disease. One host receptor implicated in pneumococcal adhesion to, invasion of and ultimately translocation of cell layers is the platelet-activating factor receptor (PAFR). PAFR is a G-protein coupled receptor which binds PAF, a potent phospholipid activator involved in many leucocyte functions, platelet aggregation and inflammation. PAFR has been proposed to bind S. pneumoniae and as such facilitate adhesion to, uptake by and transcytosis of endothelial cells leading to invasive disease. However, there is a shortage of biochemical data supporting direct interaction between PAFR and the bacteria, in addition to conflicting data on its role in development of invasive pneumococcal disease (IPD). In this review, we will discuss current literature on PAFR and S. pneumoniae and other pathogens,including data concerning human PAFR genetic variation related to IPD clinical aspects, to shed light on the importance of PAFR in IPD. Clarification of the role of this receptor in IPD development has the potential to enable the development of novel therapeutic strategies for treating pneumococcal disease by interfering with the PAFR. PMID- 23444840 TI - Identification of free-living amoebae and amoeba-associated bacteria from reservoirs and water treatment plants by molecular techniques. AB - The occurrence of free-living amoebae (FLA) was investigated in 83 water samples from reservoirs and water treatment plants, with culture positive in 64 of them (77.1%). Polymerase chain reaction (PCR) of partial 18S rRNA gene and ITS region was performed in order to identify amoeba isolates, and the presence of Legionella pneumophila , Mycobacterium spp., Pseudomonas spp., and Microcystis aeruginosa was investigated in 43 isolates of amoebae by multiplex PCR. Of the isolated amoebae, 31 were Acanthamoeba spp., 21 were Hartmannella vermiformis, 13 were Naegleria spp., and one was Vanella spp. T2, T4, and T5 genotypes of Acanthamoeba have been identified, and T4 isolates were grouped into five subgenotypes and graphically represented with a Weblog application. Inside amoebae, L. pneumophila was detected in 13.9% (6/43) of the isolates, and Pseudomonas spp. and Mycobacterium spp. were detected in 32.6% (14/43) and 41.9% (18/43), respectively. No statistical correlation was demonstrated between FLA isolation and seasonality, but the presence of intracellular bacteria was associated with warm water temperatures, and also the intracellular presence of Mycobacterium spp. and Pseudomonas spp. were associated. These results highlight the importance of amoebae in natural waters as reservoirs of potential pathogens and its possible role in the spread of bacterial genera with interest in public and environmental health. PMID- 23444841 TI - Comparison of two different methods for urethral lengthening in female to male (metoidioplasty) surgery. AB - INTRODUCTION: Metoidioplasty presents one of the variants of phalloplasty in female transsexuals. Urethral lengthening is the most difficult part in this surgery and poses many challenges. AIM: We evaluated 207 patients who underwent metoidioplasty, aiming to compare two different surgical techniques of urethral lengthening, postoperative results, and complications. METHODS: The study encompassed a total of 207 patients, aged from 18 to 62 years, who underwent single stage metoidioplasty between September 2002 and July 2011. The procedure included lengthening and straightening of the clitoris, urethral reconstruction, and scrotoplasty with implantation of testicular prostheses. Buccal mucosa graft was used in all cases for dorsal urethral plate formation and joined with one of the two different flaps: I-longitudinal dorsal clitoral skin flap (49 patients) and II-labia minora flap (158 patients). MAIN OUTCOME MEASUREMENT: Results were analyzed using Z-test to evaluate the statistical difference between the two approaches. Also, postoperative questionnaire was used, which included questions on functioning and esthetical appearance of participating subjects as well as overall satisfaction. RESULTS: The median follow-up was 39 months (ranged 12-116 months). The total length of reconstructed urethra was measured during surgery in both groups. It ranged from 9.1 to 12.3 cm (median 9.5) in group I and from 9.4 to 14.2 cm (median 10.8) in group II. Voiding while standing was significantly better in group II (93%) than in group I (87.82%) (P < 0.05). Urethral fistula occurred in 16 patients in both groups (7.72%). There was statistically significant difference between the groups, with lower incidence in group II (5.69%) vs. group I (14.30%) (P < 0.05). Overall satisfaction was noted in 193 patients. CONCLUSION: Comparison of the two methods for urethral lengthening confirmed combined buccal mucosa graft and labia minora flap as a method of choice for urethroplasty in metoidioplasty, minimizing postoperative complications. PMID- 23444843 TI - Formation and healing of vacancies in graphene chemical vapor deposition (CVD) growth. AB - The formation and kinetics of single and double vacancies in graphene chemical vapor deposition (CVD) growth on Cu(111), Ni(111), and Co(0001) surfaces are investigated by the first-principles calculation. It is found that the vacancies in graphene on the metal surfaces are dramatically different from those in free standing graphene. The interaction between the vacancies and the metal surface and the involvement of a metal atom in the vacancy structure greatly reduce their formation energies and significantly change their diffusion barriers. Furthermore, the kinetic process of forming vacancies and the potential route of their healing during graphene CVD growth on Cu(111) and Ni(111) surfaces are explored. The results indicate that Cu is a better catalyst than Ni for the synthesis of high-quality graphene because the defects in graphene on Cu are formed in a lower concentration and can be more efficiently healed at the typical experimental temperature. This study leads to a deep insight into the atomic process of graphene growth, and the mechanism revealed in this study can be used for the experimental design of high-quality graphene synthesis. PMID- 23444842 TI - Expression, purification and biochemical characterization of Schizosaccharomyces pombe Mcm4, 6 and 7. AB - BACKGROUND: The hetero-hexamer of the eukaryotic minichromosome maintenance (MCM) proteins plays an essential role in replication of genomic DNA. The ring-shaped Mcm2-7 hexamers comprising one of each subunit show helicase activity in vitro, and form double-hexamers on DNA. The Mcm4/6/7 also forms a hexameric complex with helicase activity in vitro. RESULTS: We used an Escherichiai coli expression system to express various domains of Schizosaccharomyces pombe Mcm4, 6 and 7 in order to characterize their domain structure, oligomeric states, and possible inter-/intra-subunit interactions. We also successfully employed a co-expression system to express Mcm4/6/7 at the same time in Escherichiai coli, and have purified functional Mcm4/6/7 complex in a hexameric state in high yield and purity, providing a means for generating large quantity of proteins for future structural and biochemical studies. CONCLUSIONS: Based on our results and those of others, models were proposed for the subunit arrangement and architecture of both the Mcm4/6/7 hexamer and the Mcm2-7 double-hexamer. PMID- 23444844 TI - Characterizing the public's preferential attitudes toward end-of-life care options: a role for the threshold technique? AB - OBJECTIVES: To assess the Threshold Technique's (TT) feasibility in community wide surveys of U.S. Medicare beneficiaries' preferences for end-of-life (EOL) care options. STUDY SETTING: Study participants were community-dwelling Medicare beneficiaries in four different regions in the United States. STUDY DESIGN: During personal interviews, participants considered four EOL scenarios, each presenting a choice between a less intense and more intense care option. DATA COLLECTION: Participants selected their initially favored option. Depending on that choice, in the subsequent TT the length of life offered by the more intense option was systematically increased or decreased until the participant "switched" to his or her initially rejected option. PRINCIPAL FINDINGS: Participants were able to select an initially favored option (in 3 of the 4 scenarios; this was the less intense option). The majority of participants were able to engage with the subsequent TT. In all scenarios, regardless of the increase/decrease in the length of life offered by the more intense option, the majority of participants were unwilling to "switch" to their initially rejected option. CONCLUSIONS: In surveys of populations' preferential attitudes toward EOL care options, the TT was a feasible elicitation method, engaging most participants and measuring the strength of their attitudes. Further methodological work is merited, involving (1) populations with various participant characteristics, and (2) different attributes in the TT task itself. PMID- 23444845 TI - Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis. AB - Telocytes, a peculiar type of stromal cells, have been recently identified in a variety of tissues and organs, including human skin. Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease characterized by fibrosis of the skin and internal organs. We presently investigated telocyte distribution and features in the skin of SSc patients compared with normal skin. By an integrated immunohistochemical and transmission electron microscopy approach, we confirmed that telocytes were present in human dermis, where they were mainly recognizable by their typical ultrastructural features and were immunophenotypically characterized by CD34 expression. Our findings also showed that dermal telocytes were immunophenotypically negative for CD31/PECAM-1 (endothelial cells), alpha SMA (myofibroblasts, pericytes, vascular smooth muscle cells), CD11c (dendritic cells, macrophages), CD90/Thy-1 (fibroblasts) and c-kit/CD117 (mast cells). In normal skin, telocytes were organized to form three-dimensional networks distributed among collagen bundles and elastic fibres, and surrounded microvessels, nerves and skin adnexa (hair follicles, sebaceous and sweat glands). Telocytes displayed severe ultrastructural damages (swollen mitochondria, cytoplasmic vacuolization, lipofuscinic bodies) suggestive of ischaemia-induced cell degeneration and were progressively lost from the clinically affected skin of SSc patients. Telocyte damage and loss evolved differently according to SSc subsets and stages, being more rapid and severe in diffuse SSc. Briefly, in human skin telocytes are a distinct stromal cell population. In SSc skin, the progressive loss of telocytes might (i) contribute to the altered three-dimensional organization of the extracellular matrix, (ii) reduce the control of fibroblast, myofibroblast and mast cell activity, and (iii) impair skin regeneration and/or repair. PMID- 23444846 TI - Intra-adrenal bile ductules associated with adreno-hepatic fusion: a possible origin for adrenal epithelial cysts. AB - AIMS: To elucidate the relationship between the rare phenomenon of adrenal cysts and adreno-hepatic fusion (AHF)-related intra-adrenal bile ductules. METHODS AND RESULTS: We examined 673 right and 662 left postmortem adrenal glands. AHF was defined as an adhesion between the liver and an adrenal with closely intermingled parenchymal cells or partial absence of the capsule dividing the two organs. AHF was found in seven (1.0%) right adrenals. AHF-related intra-adrenal bile ductules were observed in four (0.6%) adrenals, and were accompanied by aberrant hepatocytes (two adrenals), microcystic changes (two adrenals) and, in one case, a 15-mm-sized cyst. The cyst-lining cells, which focally resembled the cells of the neighbouring intra-adrenal bile ductules, were positive for cytokeratin 7 (CK7), CK19 and epithelial membrane antigen, and negative for CK20, vimentin, CD34 and calretinin. Identical findings were made in bile ductules located within fused adrenals and livers. CD10 staining was weaker or absent in the microcystic or cystic bile ductules found within adrenals. CONCLUSIONS: The 15-mm cyst we describe may have been an adrenal epithelial cyst derived from AHF-related intra adrenal bile ductules, a possible pathogenesis for the rare phenomenon of right adrenal epithelial cysts. PMID- 23444847 TI - Back to basics: the value of simple diagnostic maneuvers in diagnosing supraventricular tachycardias. PMID- 23444848 TI - Three open issues on Avian Influenza--H5, H7, H9 against all odds. AB - 1. Scientific knowledge and certainties on Avian Influenza infections have been completely shaken following the emergence and spread of three "odd" subtypes, namely H5, H7 and H9. 2. These subtypes, particularly H5N1, also have public health implications in addition to causing animal disease. 3. Control of infection in animals and in-depth analysis of virus antigenic and genetic properties largely rely on the veterinary community which requires better weapons that will be efficacious only if revised tactics are developed and vigorously applied. PMID- 23444849 TI - Effects of a higher incubation temperature between embryonic day 9 and 12 on growth and meat quality characteristics of turkeys. AB - 1. The study investigated the influence of manipulating incubation temperature for a short period on the post-hatch development up to week 16 in male and female BUT Big 6 turkeys. 2. Eggs were incubated at a control temperature of 37.5 degrees C and 55% RH until d 18 when transferred to a hatcher at 37.5 degrees C and 85% RH. For a 4 d period between embryonic day 9 (ED 9) and 12, eggs were incubated at 38.5 degrees C and 55% RH (HT). 3. Birds were slaughtered at 16 weeks of age to analyse meat quality parameters of the Musculus pectoralis superficialis (MPS). 4. Across both incubation treatments, the turkey males had significantly higher live and breast weights, but lower breast yields than the females. The sex of the animals only influenced the yellowness of the MPS with lower values in the males. 5. Temperature manipulation resulted in significantly decreased live weights of HT birds compared with the control animals across all ages in both sexes. No impact of incubation treatment on meat quality characteristics was found. 6. The results indicate a negative effect of higher incubation temperature on the post-hatch growth, possibly by influencing the mechanisms that regulate the hypertrophic growth of the muscle fibres. PMID- 23444850 TI - Prevalence of nematode infection and faecal egg counts in free-range laying hens: relations to housing and husbandry. AB - 1. Faecal samples from 19 commercial, 65 week old free-range egg laying flocks were examined to assess the prevalence and number of parasitic nematode eggs. Data were collected to characterise the housing, husbandry, behaviour and welfare of the flocks to examine possible relationships with the egg counts. 2. Eggs of at least one genus of nematode were present in the faeces of all 19 flocks. Heterakis eggs were detected in 17 (89%) flocks, Ascaridia in 16 (84%), Trichostrongylus in 9 (47%), and Syngamus in 6 (32%). Faecal egg counts (FEC) were greatest for Ascaridia and Heterakis. 3. For each nematode genus, there was no significant difference in FEC between organic (N = 9) and non-organic (N = 10) flocks, or between static (N = 8) and mobile (N = 11) flocks. 4. FEC were correlated with a range of housing, husbandry and management practices which varied between the nematode genus and included depth of the litter, percentage of hens using the range, and number of dead hens. Statistical analysis indicated relationships with FEC that included light intensity above the feeder, indoor and outdoor stocking density, fearfulness in the shed and on the range, distance to the nearest shelter, and swollen toes. 5. None of the FEC for any of the genera was correlated with weekly egg production or cumulative mortality. 6. Although nematode FEC were highly prevalent among the flocks, the overall lack of relation to other welfare and production measures suggests that these infections were not severe. PMID- 23444851 TI - A commercial trial evaluating three open water sources for farmed ducks: effects on water usage and water quality. AB - 1. Providing open water to farmed ducks is beneficial for their health and behaviour but, at commercial densities, may also have negative consequences for the health of the ducks, the productivity of the farms and environmental contamination. 2. The current experiment investigated the suitability of three types of open water resources in a commercial setting, assessing their effects on water usage and water quality. The three resources were: narrow troughs (15 cm wide and 8 cm deep), intermediate troughs (20 cm wide and 12 cm deep) and wide troughs (50 cm wide and 8 cm deep). A total of 23 flocks of ducks with a mean size of 4,540 +/- 680 individuals and a final stocking density less than 17 kg/m(2) were studied. 3. Intermediate troughs used twice as much water as narrow troughs and wide troughs. Intermediate troughs had the best microbiological water quality, wide troughs had the worst physical and microbiological quality and narrow troughs tended to be intermediate. 4. Open water provision resulted in high water usage, but this might be reduced by further investigating cleaning regimes, ballcock systems and the volumetric capacity of the troughs. It was difficult to maintain good water quality, and more research is needed to investigate the long term effects on productivity and public health. PMID- 23444852 TI - Prevalence of skin lesions in turkeys at slaughter. AB - 1. The aims of this study were (i) to evaluate the prevalence of welfare-related cutaneous lesions in turkeys at the end of the rearing period and (ii) to study the correlations between lesions. 2. The percentage of lesions in each flock was determined by observation at the slaughterhouse. Sixty flocks were investigated in 13 slaughterhouses between April and July 2006. 3. All flocks showed a high proportion of turkeys with footpad lesions, with 40.7% of turkey flocks having severe footpad dermatitis. A significant number of feet had swelling of the footpad and deviated toes (60.0% and 21.4% respectively). Arthritis was observed in 25.4% of the carcases and an average of 30.1% had breast buttons on the keel. 4. Positive correlations were found between evidence of feather pecking and arthritis, toe deviations and swelling of the footpad. Deviated toes, swelling of the feet and feather pecking were negatively linked to the most severe scratches (P < 0.001). 5. A method is proposed to assess turkey welfare at the slaughterhouse based on several criteria: footpad lesions, arthritis, severe scratches, deviated toes, swelling of the footpad and breast buttons. PMID- 23444853 TI - Relationship between abdominal fat content and avian uncoupling protein gene expression in skeletal muscle of Japanese quail Coturnix japonica. AB - 1. The genetic architecture of the avian uncoupling protein (avUCP) was investigated and the relationship between avUCP gene expression and the amount of abdominal fat of Japanese quail was determined by quantitative real-time PCR. 2. The Japanese quail avUCP gene consists of six exons and five introns. Sequences of nucleotides and amino acids were 94.6% and 86.0% identical to those of the chicken avUCP gene, and phylogenetic analysis showed that the Japanese quail avUCP gene consists of the same clusters as the chicken and turkey avUCP. 3. Expression of the avUCP gene was significantly higher in the Pectoralis major (1.28 +/- 0.24) than in the Biceps femoris (0.63 +/- 0.14). 4. A positive correlation coefficient between the avUCP gene expression in the Pectoralis major and Biceps femoris was observed (r = 0.79, P = 0.02), whereas a negative correlation coefficient was observed between the abdominal fat percentage (AFP) and gene expression in both the Pectoralis major (r = -0.82, P = 0.01) and Biceps femoris (r = -0.61, P = 0.11). 5. The avUCP gene was associated with the accumulation of abdominal fat in Japanese quail and it was concluded that modulation of avUCP gene expression could be utilised to control abdominal fat accumulation in poultry. PMID- 23444854 TI - Nutrient density and slaughter age have differential effects on carcase performance, muscle and meat quality in fast and slow growing broiler genotypes. AB - 1. A 2 * 2 factorial design was used to investigate the differences in carcase, muscle and meat characteristics between fast and slow growing genotypes fed on low nutrient (LND) or high nutrient diets (HND) at their respective slaughter ages. 2. The birds were randomly assigned to treatments with 5 replicates of 145 birds for Wens Yellow-Feathered Chicken (WYFC, 5.75 birds/m(2)) or 115 birds for White Recessive Rock Chicken (WRRC, 7.25 birds/m(2)), according to the commercial recommendations for the two breeds and were fed on HND or LND. Birds were slaughtered at 63 d and 105 d of age. 3. The results showed WRRC had higher carcase yield and meat yield than that of WYFC, lower fat content, higher moisture content and lower cooking loss. The meat from WRRC was less tender and contained lower levels of polyunsaturated fatty acids (PUFA). 4. Birds fed on HND had higher breast meat yield, myofiber area and protein content in the breast muscle and lower fat content than birds fed on LND. The thigh muscle of birds fed on HND had higher levels of PUFA. Age had a positive effect on carcase parameters, but a negative effect on pH, meat tenderness and cooking loss, and the two genotypes exhibited different responses to the influence of nutrient density and age. 5. Genotype and age had the largest effect on carcase performance and meat quality. LND benefited meat quality and WRRC had larger responses in meat yield and shear force when fed on HND. PMID- 23444855 TI - Evaluation of breeding objectives for purebred and crossbred selection schemes for adoption in indigenous chicken breeding programmes. AB - 1. The aim of the study was to evaluate the genetic and economic breeding objectives for an indigenous chicken (IC) breeding programme in Kenya. 2. A closed three-tier nucleus breeding programme with three breeding objectives and two selection schemes was simulated. The breeding objectives included IC dual purpose (ICD) for both eggs and meat, IC layer (ICL) for eggs and IC broiler (ICB) for meat production. 3. Pure line selection scheme (PLS) for development of IC pure breeds and crossbreeding scheme (CBS) for the production of hybrids were considered. Two-and three-way crossbreeding strategies were evaluated under CBS and the impact of nucleus size on genetic gains and profitability of the breeding programme were investigated. 4. Males were the main contributors to genetic gains. The highest genetic gains for egg number (2.71 eggs) and growth traits (1.74 g average daily gain and 57.96 g live weight at 16 weeks) were realised under PLS in ICL and ICB, respectively. 5. The genetic response for age at first egg was desirable in all the breeding objectives, while that for fertility and hatchability were only favourable under ICL and PLS in ICD. Faecal egg count and immune antibody response had low, but positive gains except under PLS where the later was unfavourable. ICB was the most profitable breeding objective, followed by ICD and ICL under all the selection schemes. 6. Although PLS was superior in genetic gains and profitability and recommended in breeding programmes targeting ICL and ICB, a three line CBS should be considered in development of a dual purpose breed. 7. Increasing the nucleus size beyond 5% of the IC population was not attractive as it resulted in declining profitability of the breeding programme. PMID- 23444856 TI - Detection and genotyping of Toxoplasma gondii strains isolated from birds in the southwest of Iran. AB - 1. The aim of this work was to determine the frequency of occurrence of Toxoplasma gondii and genetically analyse isolates from a number of avian hosts in the southwest of Iran (Khuzestan province). The frequency of T. gondii was determined in free-range chickens (Gallus domesticus), sparrows (Passer domesticus), pigeons (Columba livia) and starlings (Sturnus vulgaris). 2. Isolates obtained from Toxoplasma-infected birds were subjected to molecular typing by PCR-restriction fragment length polymorphism (RFLP) with sequence analysis of the GRA6 gene. 3. The results showed that 41 (16.5%) of 241 samples of avian tissue were infected with T. gondii. Sparrows were most frequently infected (17 out of 64). 4. Analysis of the GRA6 gene by PCR-RFLP and DNA sequencing revealed Type II and III T. gondii were the predominant lineage, accounting for 19.5% and 80.5% of the isolates, respectively. 5. It was concluded that the use of this PCR test facilitated the diagnosis of T. gondii in avian hosts and the GRA6 PCR-RFLP method clearly differentiated between the three different T. gondii lineages. This study showed a higher prevalence of type III compared with type II T. gondii in infected avian hosts in southwestern Iran. PMID- 23444857 TI - Pharmacokinetic analysis of cefquinome in healthy chickens. AB - 1. The pharmacokinetics of cefquinome (CEQ) in chickens was determined after intravenous (IV) and intramuscular (IM) administration of 2 mg/kg body weight. Plasma concentrations were measured by high performance liquid chromatography assay with an ultraviolet detector at 265 nm wavelength. 2. Plasma concentration time data after IV administration were best fitted by a two-compartment model. The pharmacokinetic parameters following IV injection were distribution half-life 0.43 +/- 0.19 h, elimination half-life 1.29 +/- 0.10 h, total body clearance 0.35 +/- 0.04 l/kg/h, area under curve 5.33 +/- 0.55 ug/h/ml and volume of distribution at steady state 0.49 +/- 0.05 l/kg. 3. Plasma concentration-time data after IM administration were best described by a two-compartment model. The pharmacokinetic parameters after IM administration were absorption half-life 0.07 +/- 0.02 h, distribution half-life 0.58 +/- 0.27 h, elimination half-life 1.35 +/ 0.20 h, peak concentration 3.04 +/- 0.71 ug/ml and bioavailability 95.81 +/- 5.81%. 4. Cefquinome kinetics in chicken and data from other species were summarised and analysed to provide a comprehensive understanding of CEQ pharmacokinetics. PMID- 23444858 TI - Viral shedding and emission of airborne infectious bursal disease virus from a broiler room. AB - 1. The significance of airborne transmission in epidemics of infectious diseases in the livestock production industry remains unclear. The study therefore investigated the shedding route (faeces vs. exhaled air) of a vaccine strain of infectious bursal disease virus (IBDV) by broilers and the emission of airborne virus. 2. The experimental room contained 526 broilers which were orally inoculated at the age of 20 d. The airborne virus was sampled by three different bioaerosol samplers: Andersen six-stage impactor, all-glass impinger (AGI-30) and OMNI-3000. 3. Infected broilers started to shed virus in faeces on d 5 post inoculation (PI), and stopped shedding on d 12 PI. The faecal virus remained detectable for at least two d after drying under broiler room conditions. No virus was detected in the air exhaled by broilers. 4. Airborne virus was collected on d 5, 8 and 12 PI at 20 cm above the floor, and on d 8 and 12 PI in exhausted air. The emission rates of IBDV were 4.0 log10 50% tissue culture infectious dose (TCID50)/bird/d on d 8 PI, and 4.5 log10 TCID50/bird/d on d 12 PI. 5. We concluded that broilers shed IBDV mainly through their faeces. The presence of indoor airborne virus is associated with the viral presence in faeces. The successful recovery of airborne virus in exhausted air indicates there is a potential risk of virus spreading to the ambient environment via air. PMID- 23444859 TI - Characteristics of ciprofloxacin and cephalosporin resistant Escherichia coli isolated from turkeys in Great Britain. AB - 1. A field study was performed to investigate the presence and characteristics of ciprofloxacin-resistant, extended spectrum beta-lactamase (ESBL) and AmpC Escherichia coli from turkeys in Great Britain. E. coli were isolated from ~9000 boot swab samples from 27 different farms owned by four different companies. Between 1 and 14 visits were made to each farm (mean 3) at between 0 and 15 m intervals (mean ~5 m). 2. CHROMagar ECC with and without ciprofloxacin or cephalosporin antibiotics was used as selective isolation media. Representative isolates with different phenotypes were tested for mutations in gyrA and for: qnrA, B, S, qepA and aac(6')-Ib genes, for ESBL phenotype, the presence of bla genes and plasmid type, and for ampC genes Representative ciprofloxacin-resistant and CTX-M isolates were further tested for serotype and PFGE type. On ciprofloxacin selective media 55% of samples yielded ciprofloxacin resistant E. coli and of those further analysed, most had ciprofloxacin MICs >4 mg/l and mutations in gyrA. 3. For the different companies, the mean number of samples per farm with cefoxitin- or cefotaxime-resistant isolates ranged from 1.0% to 61.9% and 4.7% to 31.7% respectively. Cefotaxime-resistance was most commonly associated with an ESBL phenotype, a CTX-M-1 or CTX-M-14 sequence type and an I1 gamma or K plasmid inc type. The mechanism of cefoxitin resistance was not determined for most isolates, but where determined it was bla . 4. PFGE and serotyping showed clonally-related isolates persisting over multiple visits suggesting both more prudent use of antibiotics and improved farm hygiene are needed to address the issue of antimicrobial resistance in isolates from turkeys. PMID- 23444860 TI - Isolation of DNA from embryo and chorio-allantoic membranes and sexing by PCR in Japanese quail. AB - 1. The aim of this study was to evaluate the amount and quality of genomic DNA isolated from embryos and their chorioallantoic membranes (CAM) and to investigate the utility of different PCR methods for identifying the sex of Japanese quail embryos. 2. Fertilised eggs were incubated at 37 degrees C for 120 h and DNA was isolated from samples of embryos and CAM. Target regions of the CHD W gene or XhoI repeat sequence were amplified by PCR and examined on agarose gels or by using a capillary electrophoresis system. 3. DNA samples from embryos had significantly higher OD260 values than those from CAM, while OD260/280 values were not significantly different between embryos and CAM. 4. Gender identification was not possible by PCR amplification of the CHD gene region or XhoI repeat sequences examined on agarose gels, whereas males and females of Japanese quail were distinguishable when PCR products of the CHD gene were separated by capillary electrophoresis. 5. The results showed that high molecular weight DNA could be isolated from both embryo and CAM of Japanese quail. DNA isolated from CAM could be used for molecular genetic studies where embryos would be used for other purposes, such as in situ hybridisation. A capillary electrophoresis system could be used for identifying the gender of Japanese quail embryos. PMID- 23444861 TI - Effect of vitamins, probiotics and protein level on semen traits and seminal plasma biochemical parameters of post-moult male broiler breeders. AB - 1. A study was designed to investigate the comparative effect of supplementary vitamin E, vitamin C, probiotics and dietary crude protein concentration on semen traits and seminal plasma biochemical parameters in male broiler breeders after Zn-induced moulting. 2. A total of 180 male broiler breeders were induced to moult at 65 weeks of age by mixing ZnO in diet at the rate 3000 mg/kg of feed. After moulting, the males were divided into six groups that were given feed supplemented with: vitamin C (500 IU/kg), vitamin E (100 IU/kg), protein (140 g CP/kg), probiotics (50 mg/kg) and the combination of these components, while one group was kept as a control. Semen samples were collected weekly and semen volume, spermatozoa concentration, motility and dead spermatozoa percentage were determined. Seminal plasma was separated to determine the concentration of total antioxidant capacity (TAC), homocysteine, paraoxonase (PON1), arylesterase, ceruloplasmin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. 3. Semen volume was significantly higher in the vitamin E and C groups compared to the control. Spermatozoa motility was higher in the vitamin E group and dead spermatozoa percentage was significantly lower in the vitamin C group compared with the control group. 4. Seminal plasma TAC was higher in the vitamin E group, homocysteine was lower in the vitamin C and E groups. PON1 was higher in the combination group. Arylesterase increased significantly in the vitamin C and combination groups over time. Seminal plasma AST was significantly lower in the vitamin C and E supplemented groups whereas ALT decreased significantly only in the vitamin E group compared with the control. Higher concentrations of ceruloplasmin were observed in the combination group compared with the other treatments. 5. It was concluded that additional vitamin E and C or their combination was the most potent nutrient treatment for improving the semen traits and seminal plasma biochemical characteristics in male broiler breeders after Zn-induced moulting. PMID- 23444862 TI - The effect of a diet containing grasshoppers and access to free-range on carcase and meat physicochemical and sensory characteristics in broilers. AB - 1. Research was conducted to evaluate the impact of a diet containing grasshoppers on the carcase, physicochemical and sensory characteristics in a free-range, grassland-based broiler production system. 2. A total of 80, 28-d-old male broilers were reared on grassland containing a large population of grasshoppers (treatment PB). Control birds were reared intensively on a maize soybean diet (treatment CB). At 91 d of age, 24 birds from each treatment were slaughtered to evaluate carcase, meat and sensory characteristics. 3. Treatment PB produced birds with significantly lower live weights, breast, wing, thigh and drum weights, and higher dressing percentage and breast percentage of carcase, compared with CB. Treatment PB produced breast meat with significantly higher redness values, shear force and protein content, and lower pH values, cooking loss, moisture and fat content compared with CB. Sensory panel results for breast and thigh meats showed no treatment effect on colour and juiciness, but significantly higher scores for chewiness, flavour, aroma and overall appreciation, and lower scores for tenderness from treatment PB compared with CB. 4. Rearing chickens on rangeland may provide an alternative way to produce poultry meat which is considered superior by modern consumers. PMID- 23444863 TI - The effect of vitamin E on growth performance and meat quality in broilers given diets containing distillers' dried grain with solubles (DDGS). AB - 1. The objective of the present study was to investigate the effect of vitamin E (VE, alpha-tocopherol acetate) on growth performance and meat quality of broilers fed on diets containing maize distillers' dried grains with solubles (DDGS). 2. A total of 360 one-d-old broilers were randomly assigned to 6 groups. Each group comprised 6 replicates of 10 broilers. Broilers were allocated to 1 of 6 diets and fed for 49 d in a 3 * 2 factorial design. The dietary treatments included three concentrations of DDGS (0, 10 or 20%) and two concentrations of VE (0 or 200 mg/kg). 3. Diets containing 20% DDGS decreased the growth phase and average daily feed intake, demonstrating that small amounts of DDGS affected feed intake in broilers and that an excess of DDGS was not conducive to feed intake. 4. Different dietary concentrations of DDGS did not significantly improve colour, drip loss, cooking loss, or shear force. Supplementation with 200 mg/kg VE significantly reduced cooking loss and shear force and improved colour. 5. In conclusion, supplementation with DDGS at 10% and/or alpha-tocopherol acetate at 200 mg/kg had positive effects on growth performance and meat quality in broilers. PMID- 23444864 TI - The effect of alpha-tocopherol, sweet chestnut wood extract and their combination on oxidative stress in vivo and the oxidative stability of meat in broilers. AB - 1. This study examined the effect of alpha-tocopherol (alpha-T), sweet chestnut wood extract (SCW) and their combination on oxidative stress in vivo and oxidative stability of meat in broilers given diets rich in PUFA. 2. A total of 60 male broilers were individually caged and divided into 6 groups of 10. The C PALM group received a diet with 7.5% palm fat and the other 5 groups with 7.5% linseed oil. The linseed oil groups were either un-supplemented (C-LIN) or supplemented with alpha-T or/and SCW as follows: alphaT-85 (C-LIN diet + 68 IU vit E as all-rac-alpha-T/kg), alphaT-200 (C-LIN diet + 183 IU vit E as all-rac alpha-T/kg), SCW (C-LIN diet + 3 g SCW/kg) and alphaT-SCW (C-LIN diet + 68 IU vit E as all-rac-alpha-T/kg + 3 g SCW/kg). Different parameters of oxidative stress were measured. 3. Linseed oil induced DNA fragmentation and malondialdehyde (MDA) formation, while alpha-T reduced both parameters, and SCW reduced the DNA damage. A combination (alphaT-SCW) also reduced plasma MDA. Larger antioxidant capacity of lipid soluble compounds were recorded in groups alphaT-85, alphaT-200 and alphaT-SCW than in the controls but there were no differences between these groups in antioxidant enzymes and total antioxidant status. A combination (alphaT SCW) increased tocopherol concentrations in breast muscle and in comparison to the C-LIN group MDA concentrations were reduced in groups alphaT-85, alphaT-200 and alphaT-SCW. 4. It can be concluded that neither of the alpha-T concentrations were able to prevent all the negative effects of lipid oxidation in vivo and only high concentrations of alpha-T improved the stability of meat. With the exception of DNA damage, SCW had no impact on in vivo and in vitro measured markers of oxidative stress but may have a sparing or regenerating effect on alpha-T. PMID- 23444865 TI - Ovarian morphology and internal vis-a-vis non internal laying in relation to triacylglycerol, hormones and their receptors concentration around the age of sexual maturity in broiler breeder hens. AB - 1. Ovarian morphology, serum hormone concentrations of 17-beta-estradiol, progesterone, testosterone, tri-iodothyronine (T3), thyroxine (T4) and triacylglycerol (TAG) were investigated at 23 and 26 weeks of age in broiler breeder hens provided with ad libitum access to feed. Progesterone, oestrogen beta, thyroid-alpha and -beta receptor mRNAs were also quantified in the infundibulum at the same ages. 2. A large variation in the ovarian morphology was observed at 23 weeks of age including hens with undeveloped ovaries, non-laying hens with post ovulatory follicles (POF) and a predominance of non-laying hens without a POF. 3. Serum concentrations of triglyceride, 17-beta-estradiol and progesterone at 23 weeks of age were lower in hens with an undeveloped ovary compared with other groups of hens, whereas testosterone, triiodothyronine and thyroxin were higher. 4. At 26 weeks of age, the average number of hierarchical yellow follicles in normal layers was 7.64 +/- 0.41 whereas in internal layers, the follicular numbers were significantly greater at 8.66 +/- 0.53. The higher follicular numbers in internal layers were associated with higher serum triglyceride and progesterone concentrations. 5. Oestrogen receptor-beta and thyroid receptor-beta mRNA was up regulated in the infundibulum of internal layers compared with normal laying hens at 26 weeks of age. PMID- 23444867 TI - Morphological aspects and histological effects of the attachment organ of Parabrachiella sp. (Copepoda: Lernaeopodidae) on the grey mullet, Mugil liza Valenciennes. AB - The genus Parabrachiella Wilson, 1915 (Lernaeopodidae) is represented by copepods that are highly adapted to a parasitic way of life. In Argentina, only P. insidiosa var. lageniformis Heller, 1865, P. chevreuxii Van Beneden, 1891 and P. spinicephala Ringuelet, 1945 have been cited, but none of these have been reported on mugilids. Recently, other species of this genus were found attached to the nasal cavities of juvenile grey mullets, Mugil liza Valenciennes, from Samborombon bay, Buenos Aires province. In this study, the prevalence and mean intensity of the Parabrachiella sp. on grey mullet is investigated. In addition, the damage the parasite imposes on its hosts is examined through evaluation of histological sections and immunostaining for proliferative cell nuclear antigen (PCNA). The morphology of the parasite's bulla is described from light and scanning electron micrographs. PMID- 23444868 TI - Flurbiprofen-loaded nanoparticles prepared with polyvinylpyrrolidone using Shirasu porous glass membranes and a spray-drying technique: nano-sized formation and improved bioavailability. AB - A unique flurbiprofen-loaded nanoemulsion was listed earlier using a Shirasu porous glass (SPG) membrane emulsification technique, which gave constant emulsion droplets with a thin size distribution. In this study, a flurbiprofen loaded nanoemulsion was developed further into a solid form using polyvinylpyrrolidone (PVP) as a carrier by a spray-drying technique. The flurbiprofen-loaded nanoparticles with a weight ratio of flurbiprofen/PVP/surfactant mixture of 1/8/2 were connected with about 130,000 fold enhanced drug solubility and had a mean size of about 70 nm. In these nanoparticles, flurbiprofen was found in an altered amorphous state. Additionally, the nanoparticles gave significantly shorter T(max), and greater AUC and C(max) compared to the commercially available product. Specially, the AUC of the drug from the nanoparticles was about 10-fold greater compared to the commercially available product. Therefore, these flurbiprofen-loaded nanoparticles can be convenient for distributing a poorly water-soluble flurbiprofen with improved bioavailability using uniform nano-sized particles. PMID- 23444869 TI - Characterization and prognostic significance of mitochondrial DNA variations in acute myeloid leukemia. AB - Recent studies have suggested that mutations in the mitochondrial genome (mtDNA) may play a role in the development and response to treatment for human cancer. The aim of this study was to investigate whether mtDNA variations have any prognostic relevance, to clarify the spectra of mtDNA variation and to determine whether there was any correlation to known prognostic factors in acute myeloid leukemia (AML). To elucidate this, we sequenced the entire mtDNA in 56 AML patients and 14 control subjects. When analyzing the biologic impact of the non synonymous variations in the mtDNA coding genes, we found an inferior disease free survival for patients exhibiting variations in the two most important catalytic genes of the complex IV of the oxidative phosphorylation complexes (OXPHOS), that is, the cytochrome c oxidase subunit I and the cytochrome c oxidase subunit II (hazard ratio 2.6, P = 0.03; multivariate analysis). In addition, the most frequent variation was the T16311C in the control region, which was found in 11 (20%) of the 56 patients. This observation was confirmed in another cohort of 173 diagnostic AML samples. In this expanded group, the T16311C variation tended to be associated with chromosomal abnormalities. PMID- 23444870 TI - Genetically-modified human pluripotent stem cells: new hopes for the understanding and the treatment of neurological diseases? AB - The fundamental inaccessibility of the human neural cell types affected by neurological disorders prevents their isolation for in vitro studies of disease mechanisms or for drug screening efforts. Pluripotent stem cells represent a new interesting way to generate models of human neurological disorders, explore the physiopathological mechanisms and develop new therapeutic strategies. Disease specific human embryonic stem cells were the first source of material to be used to study certain disease states. The recent demonstration that human somatic cells, such as fibroblasts or blood cells, can be genetically converted to induced pluripotent stem cells (hiPSCs) together with the continuous improvement of methods to differentiate these cells into disease-affected neuronal subtypes opens new perspectives to model and understand a large number of human pathologies. This review focuses on the opportunities concerning the use disease specific human pluripotent stem cells as well as the different challenges that still need to be overcome. We also discuss the recent improvements in the genetic manipulation of human pluripotent stem cells and the consequences of these on disease modeling and drug screening for neurological diseases. PMID- 23444873 TI - Mini-invasive surgery for adrenocortical carcinoma in children: is it safe? AB - Laparoscopy in adrenocortical carcinoma is controversial due to high risk of local recurrence in case of per-operative spillage. We wanted to report the case of a successful laparoscopic transperitoneal adrenalectomy performed in a 3-year old girl presenting a 5.5-cm adrenocortical carcinoma. PMID- 23444874 TI - Where have all the innovations gone? PMID- 23444871 TI - Modelling human disease with pluripotent stem cells. AB - Recent progress in the field of cellular reprogramming has opened up the doors to a new era of disease modelling, as pluripotent stem cells representing a myriad of genetic diseases can now be produced from patient tissue. These cells can be expanded and differentiated to produce a potentially limitless supply of the affected cell type, which can then be used as a tool to improve understanding of disease mechanisms and test therapeutic interventions. This process requires high levels of scrutiny and validation at every stage, but international standards for the characterisation of pluripotent cells and their progeny have yet to be established. Here we discuss the current state of the art with regard to modelling diseases affecting the ectodermal, mesodermal and endodermal lineages, focussing on studies which have demonstrated a disease phenotype in the tissue of interest. We also discuss the utility of pluripotent cell technology for the modelling of cancer and infectious disease. Finally, we spell out the technical and scientific challenges which must be addressed if the field is to deliver on its potential and produce improved patient outcomes in the clinic. PMID- 23444875 TI - Making your voice heard: sharing outcomes of continuing nursing education. AB - Continuing education providers are expected to evaluate the outcomes of learning activities. Professional standards also address the expectation that those outcomes will be shared with others to validate the significance of continuing education and the role of the nursing professional development specialist. PMID- 23444872 TI - Human pluripotent stem cells for modelling human liver diseases and cell therapy. AB - The liver is affected by many types of diseases, including metabolic disorders and acute liver failure. Orthotopic liver transplantation (OLT) is currently the only effective treatment for life-threatening liver diseases but transplantation of allogeneic hepatocytes has now become an alternative as it is less invasive than OLT and can be performed repeatedly. However, this approach is hampered by the shortage of organ donors, and the problems related to the isolation of high quality adult hepatocytes, their cryopreservation and their absence of proliferation in culture. Liver is also a key organ to assess the pharmacokinetics and toxicology of xenobiotics and for drug discovery, but appropriate cell culture systems are lacking. All these problems have highlighted the need to explore other sources of cells such as stem cells that could be isolated, expanded to yield sufficiently large populations and then induced to differentiate into functional hepatocytes. The presence of a niche of "facultative" progenitor and stem cells in the normal liver has recently been confirmed but they display no telomerase activity. The recent discovery that human induced pluripotent stem cells can be generated from somatic cells has renewed hopes for regenerative medicine and in vitro disease modelling, as these cells are easily accessible. We review here the present progresses, limits and challenges for the generation of functional hepatocytes from human pluripotent stem cells in view of their potential use in regenerative medicine and drug discovery. PMID- 23444876 TI - The evolution of a cardiac catheterization laboratory fellowship. AB - This column explores the development and implementation of a cardiac catheterization laboratory nursing fellowship at a 600-bed, tertiary-care hospital that is part of a large, multi-facility health system. PMID- 23444877 TI - Multiple generations in the nursing workplace: part I. AB - This column discusses the need to understand generational differences, characteristics, and work habits to improve relational communication and teamwork. PMID- 23444879 TI - Reproductive health in indigenous Chihuahua: giving birth 'alone like the goat'. AB - INTRODUCTION: Indigenous peoples in the state of Chihuahua, Mexico, are known to outsiders as the Tarahumaras. The Tarahumaras are one of the few cultural groups known to have no traditional birth attendants, and Tarahumara women often give birth alone and outdoors. Currently, little is known about this group, their health status or their culture. OBJECTIVE: The objective of this study was to assess the state of reproductive health outcomes, risks, protective factors, beliefs and behaviors in the Tarahumara population. DESIGN: This paper reports on the qualitative results of a mixed methods study, comprised of focus groups, interviews, participatory exploratory methods, ethnographic observation and household surveys investigating the reproductive health status of the Tarahumara peoples and contextual factors influencing it. Qualitative data is presented, supported by preliminary quantitative findings. RESULTS: This study supports speculation that the Tarahumara population is burdened by severe maternal health problems. The sample size was too small to definitively assess risk factors for the outcome of maternal mortality, but qualitative findings point to some important contextual issues that contribute to participants' perceptions of susceptibility to and severity of the problem, their reproductive health beliefs and behaviors, and barriers to behavior change. Major issues included disparities in biomedical knowledge, trust between non-indigenous providers and indigenous patients, and structural issues including access to medical facilities and infrastructure. CONCLUSION: Qualitative data is drawn upon to make recommendations and identify lessons applicable to similar situations where cultural minorities suffer serious health inequities. This study underscores the importance of needs and assets assessment, as it reveals unique contextual factors that must be taken into account in intervention design. Also, collaborative partnership with community members and leaders proved to be invaluable in the research, warranting further collaboration by both governmental and non-governmental groups attempting to improve the health of this population. This becomes especially important when making and enforcing health policy. PMID- 23444880 TI - Voluntary movement controlled by the surface EMG signal for tissue-engineered skeletal muscle on a gripping tool. AB - We have developed a living prosthesis consisting of a living muscle-powered device, which is controlled by neuronal signals to recover some of the functions of a lost extremity. A tissue-engineered skeletal muscle was fabricated with two anchorage points from a primary rat myoblast cultured in a collagen Matrigel mixed gel. Differentiation to the skeletal muscle was confirmed in the tissue engineered skeletal muscle, and the contraction force increased with increasing frequency of electric stimulation. Then, the tissue-engineered skeletal muscle was assembled into a gripper-type microhand. The tissue-engineered skeletal muscle of the microhand was stimulated electrically, which was then followed by the voluntary movement of the subject's hand. The signal of the surface electromyogram from a subject was processed to mimic the firing spikes of a neuromuscular junction to control the contraction of the tissue-engineered skeletal muscle. The tele-operation of the microhand was demonstrated by optical microscope observations. PMID- 23444881 TI - Sexual quality of life in women partnered with men using intracavernous alprostadil injections after radical prostatectomy. AB - INTRODUCTION: The effects of intracavernous alprostadil injection (IAI), a primary treatment for post-radical prostatectomy (RP) erectile dysfunction (ED) (pRPED), on the sex life of women partnered with men who have undergone RP have received little attention. AIMS: The aim of this study is to investigate the sexual quality of life in female partners of men receiving IAIs for pRPED. METHODS: We retrospectively studied the sex lives of 152 women partnered with men who were being treated for pRPED with IAI and previously had normal erectile function. Women completed the Index of Sexual Life (ISL) questionnaire 1 year after their partner's RP. Male patients completed the International Index of Erectile Function (IIEF-15), the Erection Hardness Score (EHS) questionnaire, the International Consultation on Incontinence Questionnaire (ICIQ), and the UCLA Prostate Cancer Index (UCLA-PCI) urinary function questionnaire. Penile pain was assessed using the visual analog scale (VAS). Statistical analysis was performed using t-tests, Spearman correlation, and multiple linear regression. MAIN OUTCOME MEASURES: Female sexual life satisfaction (SLS), sexual drive (SD), and general life satisfaction (GLS) were assessed using the ISL questionnaire. RESULTS: Mean ages for the 104 couples included were 62.3 and 59.8 years for the men and women, respectively. Mean ISL, SD, SLS, and GLS scores at 12 months were 25.4, 3.8, 14.1, and 7.5, respectively. ISL scores were strongly correlated with IIEF-15 domains, mainly erectile function (r > 0.41, P < 0.00002) and intercourse satisfaction (r > 0.27, P < 0.005). Age and VAS, ICIQ, and UCLA-PCI scores were negatively correlated with some ISL domains. IIEF-15 erectile function and intercourse satisfaction were the most significant domains predicting female SLS. An IIEF-15 erectile function of 25 corresponded to a 75% chance of an SLS score >=18. CONCLUSION: Indexes of female sexual quality of life were low overall but were highly correlated with the partner's response level to IAI treatment. IAI related pain, increased age, and poor urinary function of the male partner appear to negatively impact female sex life. PMID- 23444882 TI - The desirable qualities of future doctors--a study of medical student perceptions. AB - BACKGROUND: There is a lack of consensus regarding the qualities possessed by the ideal doctor, and very limited research regarding the views of medical students on these qualities. AIMS: To investigate the views of commencing medical students regarding the desirable qualities of doctors. METHODS: A survey containing a set of proposed desirable qualities of doctors identified from the existing literature was completed by 158 first-year medical students. RESULTS: The survey had a 75% response rate. Students rated the individual qualities of empathy, motivation to be a doctor, good verbal communication, ethically sound, integrity and honesty as the most important. A factor analysis identified six categories of qualities: methodical processing, cognitive capacity, people skills, generic work ethic, role certainty and warmth. Significant differences in factor scores were found across subgroups of students (international and domestic students, with and without prior tertiary studies) on the following factors: methodical processing, which was scored highest by domestic students with prior tertiary studies, cognitive capacity, which was scored highest by domestic students without prior tertiary studies and generic work ethic, which was scored highest by international students. CONCLUSIONS: Medical students identified a range of desirable personal qualities of a doctor which varied according to student characteristics, including their prior educational experience. Future research aiming to define such desirable qualities should include a broader range of stakeholders, including students at different training levels and institutions. PMID- 23444883 TI - Cause or effect? The relationship between student perception of the medical school learning environment and academic performance on USMLE Step 1. AB - BACKGROUND: A school's learning environment is believed to influence academic performance yet few studies have evaluated this association controlling for prior academic ability, an important factor since students who do well in school tend to rate their school's environment more highly than students who are less academically strong. AIM: To evaluate the effect of student perception of the learning environment on their performance on a standardized licensing test while controlling for prior academic ability. METHODS: We measured perception of the learning environment after the first year of medical school in 267 students from five consecutive classes and related that measure to performance on United States Medical Licensing Examination (USMLE) Step 1, taken approximately six months later. We controlled for prior academic performance by including Medical College Admission Test score and undergraduate grade point average in linear regression models. RESULTS: Three of the five learning environment subscales were statistically associated with Step 1 performance (p < 0.05): meaningful learning environment, emotional climate, and student-student interaction. A one-point increase in the rating of the subscales (scale of 1-4) was associated with increases of 6.8, 6.6, and 4.8 points on the Step 1 exam. CONCLUSION: Our findings provide some evidence for the widely held assumption that a positively perceived learning environment contributes to better academic performance. PMID- 23444884 TI - Randomised controlled trial of the use of an educational board game in neonatology. AB - BACKGROUND: Games have been used in healthcare education to encourage active learning. AIM: To investigate whether an educational board game which had been developed in the speciality of neonatology could influence the learning experience of medical students during their neonatal attachment. METHOD: A randomised controlled trial of using the game was conducted amongst 67 student participants. RESULTS: The average final assessment score was 4.15 points higher in the group of students that played the game compared to the control group (95% CI-0.88-9.17; p = 0.09). The game was well received by the students. CONCLUSION: Although we cannot conclude firmly that the game produces an effect on learning, this study suggests that educational games should be investigated further in the delivery of undergraduate learning in specialities where exposure is brief. PMID- 23444885 TI - Feasibility of self-directed learning in clerkships. AB - BACKGROUND: Self-directed learning has been well described in preclinical settings. However, studies report conflicting results when self-directed initiatives are implemented in clinical clerkships. AIM: To explore the feasibility of self-directed learning stimulated by clinical encounter-cards (CECs) in clinical clerkships. METHODS: Two focus groups of year-four and year five students were interviewed about the usefulness of CECs to their learning in clerkships. The CECs were then introduced in two cohorts of 248 year-four and 250 year-five medical students and evaluated on a nine-point scale with regard to usefulness and feasibility. RESULTS: The pilot groups reported that the CECs had positive effects in terms of engaging in diagnostic reasoning, reflection on management plans, and professional identity formation. However, the two large cohorts of students rated the usefulness of the CECs on learning in clerkship low (year-four: mean 2.92, SD 1.54; year-five: mean 2.28, SD 1.06) along with preceptor support (year-four: mean 2.68, SD 1.62; year-five: mean 2.59, SD 1.78, p = 0.34). CONCLUSION: Self-directed CECs can have a positive effect on participation and clinical reasoning but are highly dependent on the context of use. Self-directed learning initiatives that aim to increase participation in communities of practice may not be feasible without major faculty development initiatives. PMID- 23444886 TI - AIDER: a model for social accountability in medical education and practice. AB - BACKGROUND: Social accountability in healthcare requires physicians and medical institutions to direct their research, services and education activities to adequately address health inequities. The need for greater social accountability has been addressed in numerous national and international healthcare reviews of health disparities and medical education. AIM: The aim of this work is to better understand how to identify underserved populations and address their specific needs and also to provide physicians and medical institutions with a means by which to cultivate social accountability. METHODS: The authors reviewed existing literature and prominent models focusing on social accountability, as well as medical education frameworks, and identified the need to engage underserved stakeholders and incorporate education that includes knowledge translation and reciprocity. The AIDER model was developed to satisfy the need in medical education and practice that is not explicitly addressed in previous models. RESULTS: The AIDER model (Assess, Inquire, Deliver, Educate, Respond) is a continuous monitoring process that explicitly incorporates reciprocal education and continuous collaboration with underserved stakeholders. CONCLUSION: This model is an incremental step forward in helping physicians and medical institutions foster a culture of social accountability both in individual practice and throughout the continuum of medical education. PMID- 23444887 TI - 'Discovery learning': an account of rapid curriculum change in response to accreditation. AB - BACKGROUND/AIMS: The purpose of this study was to explore the attitudes and experiences of leaders responsible for making rapid changes to a medical school curriculum in response to an adverse accreditation report. The new curriculum was based on the principles of problem-based learning ('Discovery Learning'), with changes to the way that students were assessed. METHODS: We conducted semi structured interviews with leaders responsible for education at the school two and a half years after the adoption of the new curriculum. We coded the resulting transcripts to identify major and minor themes expressed by participants. RESULTS: Thirty-five senior leaders, administrators and course directors were invited for the interview; 14 (40%) were interviewed. Five main themes were noted in the data: (1) organization and control of the curriculum; (2) changes in the practices of teaching and learning; (3) effects on faculty members; (4) sources of resistance and (5) attitudes to curriculum change in general. CONCLUSION: This study demonstrates that major curriculum change can be achieved successfully in a short period of time. This study also illustrates some of the problems associated with making rapid changes to the medical school curriculum, and highlights the importance of attitudes to change amongst the leadership of a medical school. PMID- 23444888 TI - Integration and timing of basic and clinical sciences education. AB - BACKGROUND: Medical education has traditionally been compartmentalized into basic and clinical sciences, with the latter being viewed as the skillful application of the former. Over time, the relevance of basic sciences has become defined by their role in supporting clinical problem solving rather than being, of themselves, a defining knowledge base of physicians. METHODS: As part of the national Future of Medical Education in Canada (FMEC MD) project, a comprehensive empirical environmental scan identified the timing and integration of basic sciences as a key pressing issue for medical education. Using the literature review, key informant interviews, stakeholder meetings, and subsequent consultation forums from the FMEC project, this paper details the empirical basis for focusing on the role of basic science, the evidentiary foundations for current practices, and the implications for medical education. FINDINGS: Despite a dearth of definitive relevant studies, opinions about how best to integrate the sciences remain strong. Resource allocation, political power, educational philosophy, and the shift from a knowledge-based to a problem-solving profession all influence the debate. There was little disagreement that both sciences are important, that many traditional models emphasized deep understanding of limited basic science disciplines at the expense of other relevant content such as social sciences, or that teaching the sciences contemporaneously rather than sequentially has theoretical and practical merit. Innovations in integrated curriculum design have occurred internationally. Less clear are the appropriate balance of the sciences, the best integration model, and solutions to the political and practical challenges of integrated curricula. DISCUSSION: New curricula tend to emphasize integration, development of more diverse physician competencies, and preparation of physicians to adapt to evolving technology and patients' expectations. Refocusing the basic/clinical dichotomy to a foundational/applied model may yield benefits in training widely competent future physicians. PMID- 23444889 TI - Relationship between academic performance and affective changes during the first year at medical school. AB - BACKGROUND: Entering medical school may be associated with changes in the students' life, which can affect academic motivation and impair academic performance. AIMS: This work aimed at measuring longitudinally academic motivation, anxiety, depression and social adjustment in first-year medical students and determining the relationships between these variables and academic performance, as measured mainly by grades on regular exams. METHODS: Eighty-five first-year medical students (age: 17-25 years) were included after giving informed consent. Beck's Anxiety (BAI) and Beck's Depression (BDI) Inventories, the self-reported Social Adjustment Scale (SAS-SR) and the Academic Motivation Scale (AMS) were applied two months after admission and at the end of the academic year. RESULTS: BAI scores increased throughout the year (7.3 +/- 6.6 versus 28.8 +/- 6.7; p < 0.001), whereas BDI scores did not change (6.8 +/- 5.9 versus 6.0 +/- 5.4; p > 0.10). SAS-SR subscales scores remained stable, except for a decreasing pattern for leisure/social life (1.8 +/- 0.4 versus 2.1 +/- 0.4; p < 0.001). AMS scores for motivation to know (22.2 +/- 4.5 versus 19.7 +/- 5.5; p < 0.001), to accomplish things to know (17.7 +/- 5.3 versus 15.4 +/- 5.3; p = 0.001), to experience to know (18.2 +/- 5.2 versus 15.4 +/- 5.4; p < 0.001) and by identification to know (23.5 +/- 3.5 versus 21.8 +/- 5.0; p = 0.002) decreased significantly. There were no significant correlations between academic performance and the global scores for any of the scales except for the SAS-SR subscale for academic life (r = -0.48, p < 0.001). CONCLUSIONS: Throughout the academic year, first-year medical students showed increased anxiety, decreased academic motivation and a maladjusted leisure/social life, which however does not seem to affect academic achievement. PMID- 23444890 TI - Twelve tips for making the best use of feedback. AB - BACKGROUND: Feedback is generally regarded as crucial for learning. We focus on feedback provided through instruments developed to inform self-assessment and support learners to improve performance. These instruments are being used commonly in medical education, but they are ineffective if the feedback is not well received and put into practice. METHODS: The authors formulated twelve tips to make the best use of feedback based on widely cited publications on feedback. To include recent developments and hands-on experiences in the field of medical education, the authors discussed the tips with their research team consisting of experts in the field of medical education and professional performance, to reach agreement on the most practical strategies. RESULTS: When utilizing feedback for performance improvement, medical students, interns, residents, clinical teachers and practicing physicians could make use of the twelve tips to put feedback into practice. The twelve tips provide strategies to reflect, interact and respond to feedback one receives through (validated) feedback instruments. CONCLUSIONS: Since the goal of those involved in medical education and patient care is to perform at the highest possible level, we offer twelve practical tips for making the best use of feedback in order to support learners of all levels. PMID- 23444891 TI - Evidence-based competencies for improving communication skills in graduate medical education: a review with suggestions for implementation. AB - Communicating with patients is arguably the most common and important activity in medical practice, but this activity receives relatively little emphasis in graduate medical education. We propose 12 evidence-based communication competencies that program directors can adopt as a framework for teaching and evaluating residents' communication skills. We review supporting evidence for these competencies and argue that communication should be treated like a procedural skill that must be taught and evaluated by observing real resident patient interactions. We make practical suggestions for implementing these competencies by addressing three critical components of a competency-based approach to communication skills: patient safety, faculty development, and direct observation of residents. This approach to teaching and assessing communication skills provides a rationale for incorporating routine direct observation into graduate medical education programs and also for designing communication skills training that ensures graduating residents develop the skills needed to provide safe, effective patient care. PMID- 23444892 TI - Impact of a fellowship program for faculty development on the self-efficacy beliefs of health professions teachers: a longitudinal study. AB - BACKGROUND: Teachers' belief in their ability to teach influences how much of the new knowledge and skills gained during faculty development (FD) programs are actually implemented at the workplace. AIM: To study the effect of a longitudinal FD program on the self-efficacy beliefs (SEB) of teachers of health professions using quasi-experimental methodology. METHODS: The SEB of 70 teachers of health professions enrolling for a longitudinal FD program at three sites in India and one site in South Africa and an equal number of comparable controls were measured using the "teacher efficacy belief systems-self" (TEBS-self) scale. The scale was re-administered at 6 and 12 months to both the groups. RESULTS: Teachers enrolled in the program had lower scores than controls at the beginning of the program but demonstrated a significant increase at 6 months with an effect size of 0.56. The 12-month scores demonstrated a further rise in the participating teachers. The control group maintained the scores but did not show any significant change either at 6 or at 12 months. CONCLUSION: Longitudinal FD program has positive effect on SEB of teachers. PMID- 23444893 TI - Validation and piloting of direct observation of practical skills tool to assess intubation in the Chilean context. AB - BACKGROUND: The use of Workplace-Based Assessment (WBA) has increased in recent years. AIMS: To create a modified version of Direct Observation of Procedural Skills (DOPS) adapted to the Chilean context and establish its psychometric properties. METHODS: The content validity of DOPS was established through interviews and consensus survey. To be included in the new version, the respective domain should have been considered by over 80% of interviewers and it should have a Content Validity Index (CVI and kappa statistic over 0.78 and 0.6, respectively. For four months, the new DOPS was used to assess the intubation skills of the anesthesia trainees. Generalizability theory was used to establish reliability and internal consistency. RESULTS: The interview suggested a DOPS with twelve domains. All were included in the final version as the CVI and kappa values were above 0.9 and 0.8, respectively. 585 procedures were assessed. The G coefficient was 0.90. The intubation needs to be assessed with DOPS at least six times to obtain a G coefficient of 0.80. CONCLUSIONS: The modified DOPS was a valid, reliable and practical tool for assessing the intubation procedure. Effort needs to be made to improve the staff's feedback skills. PMID- 23444894 TI - Physician, healthy system: the challenge of training doctor-citizens. AB - The need for committed "doctor-citizens" engaged in health system improvement has led to a variety of medical curricular overhauls in North America and elsewhere. In a research paper published in this edition, we evaluated one such curriculum and found it to be modestly successful. But, what are the limits of residency curriculum in producing such doctors? Much of the culture of medical practice runs against the grain of our efforts. In this piece we reflect on broader lessons learned in the process of trying to teach health policy and advocacy to family medicine residents. PMID- 23444895 TI - Does green mean healthy? Nutrition label color affects perceptions of healthfulness. AB - The food industry has recently implemented numerous front-of-package nutrition labels to readily convey key aspects a food product's nutritional profile to consumers (e.g., calories and fat content). Although seemingly well-intentioned, such labels might lead consumers to perceive relatively poor nutrition foods in a healthier light. The present research explores whether one underresearched aspect of nutrition labels-namely, their color-might influence perceptions of a product's healthfulness. In Study 1, participants perceived a candy bar as healthier when it bore a green rather than a red calorie label, despite the fact that the labels conveyed the same calorie content. Study 2 examined the perceived healthfulness of a candy bar bearing a green versus white calorie label and assessed individual differences in the importance of healthy eating. Overall, results suggest that green labels increase perceived healthfulness, especially among consumers who place high importance on healthy eating. Discussion focuses on implications for health-related judgment and nutrition labeling. PMID- 23444896 TI - Norepinephrine transport inhibition for treatment of vasovagal syncope. AB - INTRODUCTION: Norepinephrine transporter inhibitors, such as sibutramine, have been shown to prevent vasovagal syncope induced by tilt testing in healthy volunteers. As a test of concept we assessed whether sibutramine prevents fainting in highly symptomatic VVS patients. METHODS AND RESULTS: This was an open label, dose-ranging protocol of sibutramine 10, 15, and 20 mg daily for >=4 weeks per dose, with progression dictated by response and tolerance. Responders were predefined as having >50% reduction in spell frequency, compared to baseline spell frequency. The cohort included seven subjects (6 women; 32 +/- 7 years) who had a median of 593 faints over a median of 180 months. The patients had had 7 +/ 4 previous treatment attempts without a satisfactory response. The mean duration of exposure to 10 mg, 15 mg, and 20 mg doses were 45 +/- 33 days, 98 +/- 89 days, and 137 +/- 83 days. Six patients tolerated the maximum dose, and 1 patient dropped out due to adverse effects at 15 mg/day. The median frequency of spells at baseline, 10, 15, and 20 mg/day was 12, 4.4, 2.8, and 1 events/28 days (P = 0.0048). Five patients were responders and 2 were nonresponders. Among responders, the median frequency of spells at baseline, 10, 15, and 20 mg/day was 14, 4.8, 0.8, and 0.4 events per 28 days (P = 0.0089). No patients developed hypertension. CONCLUSION: In this open label series, sibutramine prevented vasovagal syncope in most highly symptomatic patients. PMID- 23444897 TI - Iodobenzene catalyzed C-H amination of N-substituted amidines using m chloroperbenzoic acid. AB - The oxidative C-H amination of N"-aryl-N'-tosyl/N'-methylsulfonylamidines and N,N'-bis(aryl)amidines has been accomplished using iodobenzene as a catalyst to furnish 1,2-disubstituted benzimidazoles in the presence of mCPBA as a terminal oxidant at room temperature. The reaction is general, and the target products can be obtained in moderate to high yields. PMID- 23444898 TI - Gene polymorphisms, tobacco exposure and oral cancer susceptibility: a study from Gujarat, West India. AB - Polymorphic variability in the enzymes involved in biotransformation of tobacco related pro-carcinogens plays an important role in modulating oral cancer susceptibility. CYP1A1*2A, CYP1A1*2C, GSTM1 and GSTT1 polymorphisms were determined in 122 oral carcinoma cases and 127 controls from Gujarat, West India using PCR-based methods. The results revealed that the polymorphic variants of CYP1A1 gene did not show association towards oral cancer risk. The GSTM1 and GSTT1 null genotypes were found to be over-represented in patients than controls, suggesting a moderate increase in risk of oral cancer. The oral cancer risk was significantly increased in the patients having either alone or concurrent deletion of GSTM1 and GSTT1. The results also suggested significant association between tobacco habits, especially chewing, variant genotypes of CYP1A1, GSTM1 and GSTT1 and oral cancer risk. Our data have provided evidence that GST polymorphism modified the susceptibility to oral cancer and individuals with variant genotypes of the three genes with tobacco habits are at significant risk of developing oral cancer. PMID- 23444899 TI - Reorganization of laryngeal motoneurons after crush injury in the recurrent laryngeal nerve of the rat. AB - Motoneurons innervating laryngeal muscles are located in the nucleus ambiguus (Amb), but there is no general agreement on the somatotopic representation and even less is known on how an injury in the recurrent laryngeal nerve (RLN) affects this pattern. This study analyzes the normal somatotopy of those motoneurons and describes its changes over time after a crush injury to the RLN. In the control group (control group 1, n = 9 rats), the posterior cricoarytenoid (PCA) and thyroarytenoid (TA) muscles were injected with cholera toxin-B. In the experimental groups the left RLN of each animal was crushed with a fine tip forceps and, after several survival periods (1, 2, 4, 8, 12 weeks; minimum six rats per time), the PCA and TA muscles were injected as described above. After each surgery, the motility of the vocal folds was evaluated. Additional control experiments were performed; the second control experiment (control group 2, n = 6 rats) was performed labeling the TA and PCA immediately prior to the section of the superior laryngeal nerve (SLN), in order to eliminate the possibility of accidental labeling of the cricothyroid (CT) muscle by spread from the injection site. The third control group (control group 3, n = 5 rats) was included to determine if there is some sprouting from the SLN into the territories of the RLN after a crush of this last nerve. One week after the crush injury of the RLN, the PCA and TA muscles were injected immediately before the section of the SLN. The results show that a single population of neurons represents each muscle with the PCA in the most rostral position followed caudalwards by the TA. One week post RLN injury, both the somatotopy and the number of labeled motoneurons changed, where the labeled neurons were distributed randomly; in addition, an area of topographical overlap of the two populations was observed and vocal fold mobility was lost. In the rest of the survival periods, the overlapping area is larger, but the movement of the vocal folds tends to recover. After 12 weeks of survival, the disorganization within the Amb is the largest, but the number of motoneurons is similar to control, and all animals recovered the movement of the left vocal fold. Our additional controls indicate that no tracer spread to the CT muscle occurred, and that many of the labeled motoneurons from the PCA after 1 week post RLN injury correspond to motoneurons whose axons travel in the SLN. Therefore, it seems that after RLN injury there is a collateral sprouting and collateral innervation. Although the somatotopic organization of the Amb is lost after a crush injury of the RLN and does not recover in the times studied here, the movement of the vocal folds as well as the number of neurons that supply the TA and the PCA muscles recovered within 8 weeks, indicating that the central nervous system of the rat has a great capacity of plasticity. PMID- 23444900 TI - Gill pathology in Scottish farmed Atlantic salmon, Salmo salar L., associated with the microsporidian Desmozoon lepeophtherii Freeman et Sommerville, 2009. AB - Gill disorders have emerged in recent years as a significant problem in the production of marine-stage Atlantic salmon Salmo salar L. The multi-aetiological condition 'proliferative gill inflammation' (PGI) has been reported to cause heavy losses in western Norway, yet reports of Scottish cases of the disease have remained anecdotal. In the present study, histopathological material from a marine production site in the Scottish Highlands experiencing mortalities due to a seasonal gill disease with proliferative-type pathology was examined using light microscopy, special staining techniques and transmission electron microscopy (TEM). The microsporidian Desmozoon lepeophtherii Freeman et Sommerville, 2009 (syn. Paranucleospora theridion) was identified by staining using a Gram Twort method and TEM associated with distinctive proliferative and necrotic pathology confined to the interlamellar Malpighian cell areas of the primary filaments. Epitheliocystis was not a feature of the gill pathology observed. It is believed this is the first report of D. lepeophtherii being identified associated with pathology in a Scottish gill disease case, and supports anecdotal reports that a disease at least partly synonymous with PGI as described by Norwegian researchers is present in Scottish aquaculture. PMID- 23444901 TI - Ergonomic port placement in laparoscopic colorectal surgery: response to Muhlmann et al. PMID- 23444902 TI - The association of glutathione S-transferase gene mutations (including GSTT1 and GSTM1) with the prognostic factors and relapse in acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one fourth of all childhood cancers and approximately 75% of all childhood leukemias. Some prognostic factors determine the outcome of therapy [e.g. age, sex, initial white blood cell count (WBC), etc.]; however, it is believed that other mechanisms such as glutathione S-transferase (GST) gene mutation, the expression of lung resistance protein (LRP), and multidrug resistance-associated protein (MRP) also plays a role in treatment failure. In this study, GST gene mutations including GSTM1 and GSTT1 were evaluated in patients with leukemia. Thirty newly diagnosed ALL patients younger than 15 years of age participated in the present study. Bone marrow aspiration and biopsy were evaluated for immune phenotyping and DNA was extracted for GST genotyping. All data plus sex, age, initial WBC count, central nervous system (CNS) or testicular involvement, immune phenotype, and outcome (relapse or not) were analyzed statistically. Genotyping showed that 46% were double null, 50% were M1 null and 93.3% were T1 null for GST mutations. There was no statistically significant relationship between GSTT1 and GSTM1 mutations, or between double null status, prognostic factors and relapse (P > .05). So, although the results of GST mutations were consistent, it seems that these mutations are not statistically significant. PMID- 23444903 TI - HER2 amplification in squamous cell carcinomas of the vulva. PMID- 23444904 TI - BOND: Basic OligoNucleotide Design. AB - BACKGROUND: DNA microarrays have become ubiquitous in biological and medical research. The most difficult problem that needs to be solved is the design of DNA oligonucleotides that (i) are highly specific, that is, bind only to the intended target, (ii) cover the highest possible number of genes, that is, all genes that allow such unique regions, and (iii) are computed fast. None of the existing programs meet all these criteria. RESULTS: We introduce a new approach with our software program BOND (Basic OligoNucleotide Design). According to Kane's criteria for oligo design, BOND computes highly specific DNA oligonucleotides, for all the genes that admit unique probes, while running orders of magnitude faster than the existing programs. The same approach enables us to introduce also an evaluation procedure that correctly measures the quality of the oligonucleotides. Extensive comparison is performed to prove our claims. BOND is flexible, easy to use, requires no additional software, and is freely available for non-commercial use from http://www.csd.uwo.ca/~ilie/BOND/. CONCLUSIONS: We provide an improved solution to the important problem of oligonucleotide design, including a thorough evaluation of oligo design programs. We hope BOND will become a useful tool for researchers in biological and medical sciences by making the microarray procedures faster and more accurate. PMID- 23444905 TI - Enrichment of radon and carbon dioxide in the open atmosphere of an Australian coal seam gas field. AB - Atmospheric radon ((222)Rn) and carbon dioxide (CO2) concentrations were used to gain insight into fugitive emissions in an Australian coal seam gas (CSG) field (Surat Basin, Tara region, Queensland). (222)Rn and CO2 concentrations were observed for 24 h within and outside the gas field. Both (222)Rn and CO2 concentrations followed a diurnal cycle with night time concentrations higher than day time concentrations. Average CO2 concentrations over the 24-h period ranged from ~390 ppm at the control site to ~467 ppm near the center of the gas field. A ~3 fold increase in maximum (222)Rn concentration was observed inside the gas field compared to outside of it. There was a significant relationship between maximum and average (222)Rn concentrations and the number of gas wells within a 3 km radius of the sampling sites (n = 5 stations; p < 0.05). A positive trend was observed between CO2 concentrations and the number of CSG wells, but the relationship was not statistically significant. We hypothesize that the radon relationship was a response to enhanced emissions within the gas field related to both point (well heads, pipelines, etc.) and diffuse soil sources. Radon may be useful in monitoring enhanced soil gas fluxes to the atmosphere due to changes in the geological structure associated with wells and hydraulic fracturing in CSG fields. PMID- 23444907 TI - Self-recognition of structurally identical, rod-shaped macroions with different central metal atoms during their assembly process. AB - Two rod-shaped macroanions, ((C4H9)4N)7[Mo6O18NC(OCH2)3XMo6O18(OCH2)3CNMo6O18] (X = Mn(III) (1), Fe(III) (2)), with almost identical charge densities and morphologies except for their different encapsulated central metal atoms were each observed to self-assemble into "blackberry"-type supramolecular structures in their dilute solution, driven by the counterion-mediated attraction. Amazingly, the two macroions remained self-sorted and self-assembled into homogeneous assemblies in their mixed solutions, demonstrating a self-recognition behavior between two highly similar macroions during their assembly process, as confirmed by DLS, SLS, and TEM/EDS analysis. This self-recognition behavior can be explained by the slightly different charge distributions of the macroanions resulting from their different central atoms (confirmed by theoretical DFT calculations and dissociation experiments) and the high activation energy of the slow assembly process, which suppresses the formation of hybrid oligomers at the beginning of the self-assembly process. This work confirms that the long-range counterion-mediated electrostatic attraction is sensitive to the small difference in macroions and consequently offers the possibility for delicate selectivity and preference among different macroions. This phenomenon might be directly related to (and be the important reason for) some recognition behaviors in biological systems. PMID- 23444906 TI - Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and promoter methylation in cervical oncogenic lesions and cancer. AB - The aim of this study was to investigate the role of methylenetetrahydrofolate reductase (MTHFR) polymorphisms and MTHFR methylation pattern in cervical lesions development among women from Romania, a country with high prevalence of human papillomavirus (HPV) cervical infections. To achieve this goal, blood samples and cervical cytology specimens (n = 77)/tumour tissue specimens (n = 23) were investigated. As control, blood and negative cytological smears (n = 50) were used. A statistically significant association was found between T allele of C677T polymorphism and cervical lesions, heterozygote women presenting a threefold increased risk (normal/cervical lesions and tumours: wild homozygote 34/41 (0.68/0.41), heterozygote 14/51 (0.28/0.51), mutant homozygote 2/8 (0.04/0.08); OR = 3.081, P = 0.0035). Using chi square test for the control group, the HPV negative and HPV-positive patients with cervix lesions, a significant correlation between viral infection and T allele of C677T polymorphism (P = 0.0287) was found. The MTHFR promoter was methylated in all HGSIL and tumour samples, significant differences being noted between HPV-positive samples, control group and cases of cervical dysplastic lesions without HPV DNA (P < 0. 0001) and between samples from patients with high-risk (hr)HPV versus low-risk (lr)HPV (P = 0.0026). No correlations between polymorphisms and methylation were observed. In Romania, individuals carrying T allele are susceptible for cervical lesions. MTHFR promoter methylation is associated with cervical severity lesions and with hrHPV. PMID- 23444908 TI - Measurement of the energy dependence of X-ray-induced decomposition of potassium chlorate. AB - We report the first measurements of the X-ray induced decomposition of KClO3 as a function of energy in two experiments. KClO3 was pressurized to 3.5 GPa and irradiated with monochromatic synchrotron X-rays ranging in energy from 15 to 35 keV in 5 keV increments. A systematic increase in the decomposition rate as the energy was decreased was observed, which agrees with the 1/E(3) trend for the photoelectric process, except at the lowest energy studied. A second experiment was performed to access lower energies (10 and 12 keV) using a beryllium gasket; suggesting an apparent resonance near 15 keV or 0.83 A maximizing the chemical decomposition rate. A third experiment was performed using KIO3 to ascertain the anionic dependence of the decomposition rate, which was observed to be far slower than in KClO3, suggesting that the O-O distance is the critical factor in chemical reactions. These results will be important for more efficiently initiating chemical decomposition in materials using selected X-ray wavelengths that maximize decomposition to aid useful hard X-ray-induced chemistry and contribute understanding of the mechanism of X-ray-induced decomposition of the chlorates. PMID- 23444909 TI - A method of reflexive balancing in a pragmatic, interdisciplinary and reflexive bioethics. AB - In recent years there has been a wealth of literature arguing the need for empirical and interdisciplinary approaches to bioethics, based on the premise that an empirically informed ethical analysis is more grounded, contextually sensitive and therefore more relevant to clinical practice than an 'abstract' philosophical analysis. Bioethics has (arguably) always been an interdisciplinary field, and the rise of 'empirical' (bio)ethics need not be seen as an attempt to give a new name to the longstanding practice of interdisciplinary collaboration, but can perhaps best be understood as a substantive attempt to engage with the nature of that interdisciplinarity and to articulate the relationship between the many different disciplines (some of them empirical) that contribute to the field. It can also be described as an endeavour to explain how different disciplinary approaches can be integrated to effectively answer normative questions in bioethics, and fundamental to that endeavour is the need to think about how a robust methodology can be articulated that successfully marries apparently divergent epistemological and metaethical perspectives with method. This paper proposes 'Reflexive Bioethics' (RB) as a methodology for interdisciplinary and empirical bioethics, which utilizes a method of 'Reflexive Balancing' (RBL). RBL has been developed in response to criticisms of various forms of reflective equilibrium, and is built upon a pragmatic characterization of Bioethics and a 'quasi-moral foundationalism', which allows RBL to avoid some of the difficulties associated with RE and yet retain the flexible egalitarianism that makes it intuitively appealing to many. PMID- 23444910 TI - Intra-arterial waveform analysis: a study of senior nurse knowledge in a general intensive care unit. PMID- 23444911 TI - A broader basis for teaching reflection. PMID- 23444912 TI - Prevalence of pneumococcal vaccination in adult immune thrombocytopenia patients exposed to rituximab or to splenectomy. PMID- 23444914 TI - Erectile dysfunction, endothelium dysfunction, and microvascular damage in patients with systemic sclerosis. AB - INTRODUCTION: Erectile dysfunction (ED) prevalence in men with systemic sclerosis (SSc) is high and can be considered a manifestation of endothelium damage. AIM: This study aims to correlate ED with endothelial dysfunction and digital vascular damage in SSc patients. MAIN OUTCOME MEASURES: The main outcome measures were erectile function, Doppler indices of cavernous arteries, flow-mediated dilation (FMD), capillaroscopic damage, skin perfusion, and digital pulsatility. METHODS: In 23 SSc patients, erectile function was investigated using the International Index of Erectile Function-5 (IIEF-5). Doppler indices of cavernous arteries, peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were measured at the penoscrotal junction before and after pharmacostimulation with 20 mg prostaglandin E1. FMD and nailfold videocapillaroscopy (NVC) were used to evaluate endothelial dysfunction and capillaroscopic damage. Skin perfusion and digital sphygmic waves were measured by laser Doppler perfusion imaging (LDPI) and digital photoplethysmography (PPG), respectively. RESULTS: IIEF-5 score was reduced in 83% of patients. PSV was reduced in 96%, while EDV was increased in 48% of patients. A positive correlation was observed between IIEF-5 score and FMD (r = 0.71, P < 0.0001) and between the former and PSV (r = 0.76, P < 0.0001). A negative correlation was observed between EDV and FMD (r = -0.509, P < 0.01). FMD and Doppler indices were reduced with capillaroscopic damage progression. A positive correlation exists between LDPI perfusion and IIEF-5 score (r = 0.743, P < 0.0001) and between the former and PSV (r = 0.714, P < 0.0001), while a negative correlation is observed between LDPI perfusion and EDV (r = -0.677, P < 0.0001). A positive correlation exists between PPG pulsatility and IIEF-5 score (r = 0.752, P < 0.0001) and between the former and PSV (r = 0.747, P < 0.0001), while negative correlation is observed between PPG pulsatility and EDV (r = -0.689, P < 0.0001). CONCLUSION: In SSc patients, ED correlates with endothelial dysfunction and digital microvascular damage. PMID- 23444915 TI - "When diet and exercise are not enough": an examination of lifestyle change inefficacy claims in direct-to-consumer advertising. AB - Previous research suggests that direct-to-consumer (DTC) advertisements for pharmaceutical drugs have the potential to influence consumers' perceptions of whether symptoms should be treated medically and/or through behavior change. However, the relative frequency of messages emphasizing these approaches in pharmaceutical advertising remains largely unknown. A content analysis of print and television advertisements for cholesterol management medication between 1994 and 2005 (for print) and between 1999 and 2007 (for television) was conducted. First, the extent to which established theoretical constructs drawn from health communication scholarship are depicted in the content of DTC cholesterol advertisements is quantified. Second, specific claims about behavior change inefficacy when a pharmaceutical alternative is available are identified. Findings indicate that DTC ads offer many mixed messages about the efficacy of diet and exercise in reducing cholesterol and risk of heart disease. Theoretical and practical implications of this work are discussed. PMID- 23444913 TI - Synergistic antitumor activity from two-stage delivery of targeted toxins and endosome-disrupting nanoparticles. AB - Plant-derived Type I toxins are candidate anticancer therapeutics requiring cytosolic delivery into tumor cells. We tested a concept for two-stage delivery, whereby tumor cells precoated with an antibody-targeted gelonin toxin were killed by exposure to endosome-disrupting polymer nanoparticles. Co-internalization of particles and tumor cell-bound gelonin led to cytosolic delivery and >50-fold enhancement of toxin efficacy. This approach allows the extreme potency of gelonin to be focused on tumors with significantly reduced potential for off target toxicity. PMID- 23444916 TI - Analysis of serum and cerebrospinal fluid in clinically normal adult miniature donkeys. AB - AIM: To establish reference intervals for serum and cerebrospinal fluid (CSF) parameters in clinically healthy adult miniature donkeys. METHODS: Experiments were conducted on 10 female and 10 male clinically normal adult miniature donkeys, randomly selected from five herds. Lumbosacral CSF collection was performed with the sedated donkey in the standing position. Cell analysis was performed immediately after the samples were collected. Blood samples were obtained from the jugular vein immediately after CSF sample collection. Sodium, potassium, glucose, urea nitrogen, total protein, calcium, chloride, phosphorous and magnesium concentrations were measured in CSF and serum samples. A paired t test was used to compare mean values between female and male donkeys. RESULTS: The CSF was uniformly clear, colourless and free from flocculent material, with a specific gravity of 1.002. The range of total nucleated cell counts was 2-4 cells/MUL. The differential white cell count comprised only small lymphocytes. No erythrocytes or polymorphonuclear cells were observed on cytological examination. Reference values were obtained for biochemical analysis of serum and CSF. Gender had no effect on any variables measured in serum or CSF (p>0.05). CONCLUSION AND CLINICAL RELEVANCE: CSF analysis can provide important information in addition to that gained by clinical examination. CSF analysis has not previously been performed in miniature donkeys; this is the first report on the subject. In the present study, reference intervals for total nucleated cell count, total protein, glucose, urea nitrogen, sodium, potassium, chloride, calcium, phosphorous and magnesium concentrations of serum and CSF were determined for male and female miniature donkeys. PMID- 23444917 TI - Entry to beta-alkoxyacrylates via gold-catalyzed intermolecular coupling of alkynoates and allylic ethers. AB - The first gold-catalyzed intermolecular coupling of alkynoates and allylic ethers invoking alkoxy addition and [3,3]-sigmatropic rearrangement as the key mechanism has been developed. Remarkably, the reaction showed complete chemoselectivity toward the pathway initiated by the alkoxy addition to alkynes. This unprecedented reactivity led to a new access to diversely substituted beta alkoxyacrylates in a highly efficient manner. PMID- 23444918 TI - The effects of Porphyromonas gingivalis on the cell cycle progression of human gingival epithelial cells. AB - OBJECTIVE: Porphyromonas gingivalis is a major pathogen in the development and progression of periodontal disease. The interactions or cross-talk between bacteria and gingival epithelial cells drive bacteria to manipulate the cell cycle to favor bacterial survival and virulence expression within the host. This study aims to dissect the effects of P. gingivalis on the cell cycle in human gingival epithelial cells. MATERIALS AND METHODS: We established a model of P. gingivalis invading IHGE cells. The cell cycle distribution of human gingival epithelial cells was analyzed by flow cytometry. Cyclin D and cyclin E mRNA and protein were detected by real-time PCR and Western blot, respectively. RESULTS: Porphyromonas gingivalis-induced facilitation of cell growth was correlated with the acceleration of G1 phase of cell cycle. Cyclin D1 mRNA levels were significantly upregulated from 6 to 12 h after infection. Cyclin E protein and mRNA levels were elevated at 10 and 12 h after invasion. CONCLUSIONS: We confirmed that P. gingivalis significantly enhances IHGE cell proliferation by promoting the G1/S transition, involving the up-regulation of cyclin D and cyclin E. PMID- 23444919 TI - Does cooperation increase helpers' later success as breeders? A test of the skills hypothesis in the cooperatively displaying lance-tailed manakin. AB - Experience improves individual performance in many tasks. Pre-breeding cooperation may provide important experience that improves later success as a breeder, offering one compelling explanation for why some individuals delay reproduction to help others breed (the 'skills hypothesis'). However, confounding effects of age, quality and alternative selective benefits have complicated rigorous tests of this hypothesis. Male lance-tailed manakins perform cooperative courtship displays involving partnerships between unrelated alpha and beta males, and alphas monopolize resulting copulations. Beta males therefore do not receive immediate direct or indirect fitness benefits, but may gain skills during cooperation that increase their later success as an alpha. To date, however, the effect of cooperative experience on later success as a breeder has never been tested in any cooperatively displaying taxon. The effects of prior cooperative experience on reproductive success of alpha lance-tailed manakins were analysed in a mixed model framework using 12 years of information on cooperative experience and annual and lifetime genetic reproductive success for 57 alpha males. Models included previously identified effects of age and alpha tenure. Individual-level random effects controlled for quality differences to test for an independent influence of beta experience on success. Males accumulated up to 5 years of beta experience before becoming alphas, but 42.1% of alphas had no prior beta experience. Betas became alphas later in life, and experienced significantly lower reproductive success in their final year as alpha than males that were never beta, but did not have higher lifetime success or longer alpha tenures. Differences in patterns of annual siring success were best explained by age dependent patterns of reproductive improvement and senescence among alphas, not beta experience. Cooperative experience does not increase relative breeding success for male lance-tailed manakins. Importantly, beta cooperation seems to be an alternative reproductive tactic that yields fitness payoffs equivalent to a non-cooperative route to alpha status, if population growth rate is stable. PMID- 23444920 TI - Exploring the role of antithrombin replacement for the treatment of preeclampsia: a prospective randomized evaluation of the safety and efficacy of recombinant antithrombin in very preterm preeclampsia (PRESERVE-1). AB - PROBLEM: Antithrombin (AT) replacement has been described in patients with hereditary AT deficiency undergoing delivery; however, the kinetics of AT replacement in preeclampsia is not adequately understood. Therefore, the Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia (PRESERVE-1) study has been proposed. METHODS: Sixty women aged>=18 years at 24 0/7-28 0/7 weeks' gestation and with hypertension and proteinuria will be enrolled and randomly assigned to receive recombinant human AT or placebo until fetal and/or maternal indications cause cessation of expectant management or until 34 0/7 weeks' gestation. The primary endpoint is the increase in gestational age from randomization to delivery. Safety assessments and laboratory assays will also be performed. RESULTS: PRESERVE-1 study enrollment will begin during the second half of 2013. CONCLUSION: The PRESERVE-1 study will provide further insight into the pharmacokinetic activity and safety of AT therapy in preeclampsia. PMID- 23444921 TI - Morphology, seasonality and phylogeny of Zschokkella soleae sp. n. (Myxozoa, Myxosporea) parasite of Solea solea (L.) (Pleuronectiformes, Soleidae) from Ghar El Melh Lagoon, Tunisia. AB - A new Myxosporea, Zschokkella soleae sp. n., was found in the gall bladder and the bile of common sole, Solea solea (L.), from Ghar El Melh Lagoon in north-east Tunisia. This is the first record for the presence of Zschokkella species in Tunisian waters. The parasite's plasmodia are polysporic with variable size and shape. Some plasmodia appeared attached to the gall bladder epithelium while others were found free in bile. Mature spores are ellipsoidal in frontal view 13.8+/-0.38 MUm long and 10.86+/-0.40 MUm wide with two equal size spherical polar capsules 3.6+/-0.43 MUm in size. The prevalence of infection seems to correlate with host size and changes over the year with maximum percentage in summer. Based on the 18S rDNA sequence data, Z. soleae sp. n. is readily distinguishable from other myxozoan DNA sequences in GenBank. Phylogenetically, the new species is placed in the freshwater Myxidium clade including several Zschokkella spp. infecting the gall bladder. Morphology, histology as well as DNA sequence analysis indicate that the examined species differs from all previously described Zschokkella species. PMID- 23444922 TI - Comment on "Screening criteria for long-range transport potential of organic substances in water". PMID- 23444923 TI - Photodissociation dynamics of enolic 1,2-cyclohexanedione at 266, 248, and 193 nm: mechanism and nascent state product distribution of OH. AB - The photodissociation dynamics of 1,2-cyclohexanedione (CHD), which exists in enolic form in gas phase, is studied using pulsed laser photolysis (LP)-laser induced fluorescence (LIF) "pump-and-probe" technique at room temperature. The nascent state distribution of the OH radical, formed after initial photoexcitation of the molecule to it is (pi, pi*) and Rydberg states, is determined. The initial (pi, pi*) and Rydberg states are prepared by excitation with the fourth harmonic output of Nd:YAG (266 nm)/KrF (248 nm) and ArF (193 nm) lasers, respectively. The ro-vibrational distribution of the nascent OH photofragment is measured in collision-free conditions using LIF. The OH fragments are formed in the vibrationally cold state at all the above wavelengths of excitation but differ in rotational state distributions. At 266 nm photolysis, the rotational population of OH shows a curvature in Boltzmann plot, which is fairly described by two types of Boltzmann-like distributions characterized by rotational temperatures of 3100 +/- 100 and 900 +/- 80 K. However, at 248 nm photolysis, the rotational distribution is described by a single rotational temperature of 950 +/- 80 K. The spin-orbit and Lambda-doublets ratios of OH fragments formed in the dissociation process are also measured. The average translational energy in the center-of-mass coordinate, partitioned into the photofragment pairs of the OH formation channels, is determined to be 12.5 +/- 3.0, 12.7 +/- 3.0, and 12.0 +/- 3.0 kcal/mol at 266, 248, and 193 nm excitation, respectively. The energy partitioning into various degrees of freedom of products is interpreted with the help of different models, namely, statistical, impulsive, and hybrid models. To understand the nature of the dissociative potential energy surface involved in the OH formation channel, detailed ab initio calculations are performed using configuration interaction-singles (CIS) method. It is proposed that at 266 nm photolysis, the OH fragment is formed from two different excited state structures, one with a strong H bonding, similar to that in the ground state, and another without effective H bonding, whereas, at 248 nm photodissociation, it seems that the OH formation occurs mainly from the excited state, which lacks effective H-bonding. At 193 nm excitation, the initially prepared population in the Rydberg state crosses over to a nearby sigma* repulsive state along the C-O bond, from where the dissociation takes place. The exit barrier for the OH dissociation channel is estimated to be 14 kcal/mol. The existence of dynamical constraint due to strong hydrogen bond in the ground state is effectively present in the dissociation process at 266 and somewhat deficient at 248 nm photolysis. PMID- 23444924 TI - Podcasts made simple. PMID- 23444925 TI - Valuing interventions for localised prostate cancer. PMID- 23444926 TI - The need to devise a better means of training. PMID- 23444927 TI - Nerve growth factor (NGF): a potential urinary biomarker for overactive bladder syndrome (OAB)? AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The search for a biomarker in overactive bladder syndrome (OAB) is an emerging field of interest, as bladder dysfunction is a common complaint that causes significant morbidity. A biomarker may give us insight as a diagnostic tool, and also inform us about how severe the condition is, how it may progress and how it may best be treated. The protein of interest here is nerve growth factor (NGF) and it has been shown to be a dynamic molecule in the bladder of patients with OAB. Urinary levels have been seen to rise in patients with OAB and fall in those who respond to treatment. However, there have also been many studies that examine this trend in numerous other conditions, e.g. interstitial cystitis, bladder outflow obstruction, renal stone disease and patients with neurological impairment after stroke. As a result the specificity of this as a potential urinary biomarker for OAB is questioned. This is a review of published studies, which discusses the pros and cons of NGF as a potential urinary biomarker. The evidence is examined and the studies are summarised together in a Table. Questions remain about the reliability, practicality and specificity of NGF as a biomarker for OAB. These questions need to be addressed by further studies that could clarify the points raised. OBJECTIVE: To review the current literature on the use of urinary nerve growth factor (NGF) as a potential biomarker for overactive bladder syndrome (OAB). METHOD: A comprehensive electronic literature search was conducted using the PubMed database to identify publications relating to urinary NGF. RESULTS: There are a growing number of publications that have measured urinary NGF levels in different types of bladder dysfunction. These range from OAB, bladder pain syndrome, idiopathic and neurogenic detrusor overactivity, bladder oversensitivity and bladder outflow obstruction. Urinary NGF levels do appear to be raised in these pathological states when compared with healthy control samples. In patients with OAB, these raised urinary NGF levels appear to also reduce after successful treatment with antimuscarinics and botulinum toxin A, which indicates a potential use in monitoring responses to treatment. However, raised levels are not limited to OAB, which questions its specificity. Urinary NGF measurements are performed with an enzyme-linked immunosorbent assay using polyclonal antibodies to NGF. The technique requires standardisation, and the different antibodies to NGF require validating. Also a definition of what is the 'normal' range of NGF in urine is still required before it can be used as a diagnostic and prognostic tool. CONCLUSIONS: Whilst the evidence for an increased urinary NGF in OAB appears convincing, many questions about its validity remain including: specificity, sensitivity, cost- and time-effectiveness. Many criteria for what constitutes a biomarker still need to be evaluated and met before this molecule can be considered for this role. PMID- 23444928 TI - Seminoma stage 1: Patterns of care in Europe. PMID- 23444929 TI - Reply: Seminoma stage 1: Patterns of care in Europe. PMID- 23444930 TI - Landmarks in hormonal therapy for prostate cancer. PMID- 23444931 TI - Reply: Landmarks in hormonal therapy for prostate cancer. PMID- 23444932 TI - En bloc transurethral resection of bladder lesions: a trick to retrieve specimens up to 4.5 cm. PMID- 23444933 TI - Four-hundredfold overestimation of biopsy mortality. PMID- 23444934 TI - Reply: Four-hundredfold overestimation of biopsy mortality. PMID- 23444935 TI - Assessment of the histological damage to the testis after torsion: to puncture or not to puncture? PMID- 23444936 TI - Inflammatory prognostic markers in clear cell renal cell carcinoma - preoperative C-reactive protein does not improve predictive accuracy. PMID- 23444937 TI - Reply: Inflammatory prognostic markers in clear cell renal cell carcinoma - preoperative C-reactive protein does not improve predictive accuracy. PMID- 23444938 TI - Dependence and urinary symptoms among recreational ketamine users. PMID- 23444939 TI - Long-term survival after radical surgery for renal cell carcinoma with tumour thrombus. PMID- 23444940 TI - Metastatic castrate-resistant prostate cancer, dawn of a new age of management. PMID- 23444941 TI - Reply: Long-term survival after radical surgery for renal cell carcinoma with tumour thrombus. PMID- 23444942 TI - The moderating effect of nutritional status on depressive symptoms in veteran elders with dementia: a spaced retrieval combined with Montessori-based activities. AB - AIM: To examine the long-term effects of fixed/individualized spaced retrieval combined with Montessori-based activities on nutritional status and body mass index and nutritional improvement's moderating effect on depressive symptoms for people with dementia during a specific follow-up period. BACKGROUND: The decrease in food intake, often combined with poor nutrition, may induce depressive symptoms in people with dementia. DESIGN: A single-blind, quasi-experimental study with repeated measures. METHODS: Twenty-five fixed group participants received spaced retrieval combined with Montessori-based activities over 24 sessions. Thirty-eight individualized group participants received the same intervention with different sessions, which was adjusted according to each participant's learning response. Twenty-seven control group participants just received routine care. The Chinese version of the Mini-Nutritional Assessment and Cornell Scale for Depression in Dementia scores and body mass index were recorded at pre-test, posttest and 1-, 3- and 6-month follow-ups. Data were collected between July 2008-February 2010. RESULTS: The Mini-Nutritional Assessment scores and body mass index of the fixed and individualized groups could be significantly increased over time. Additionally, the Cornell Scale for Depression in Dementia scores could be significantly reduced as a result of the improvement of the Mini Nutritional Assessment scores arising from the individualized intervention. CONCLUSION: The depressive symptoms of residents with dementia could be moderated by the individualized intervention through nutritional improvement. Trained clinical nurse specialists can use this individualized intervention for residents with dementia who also have poor nutrition and depressive symptoms. PMID- 23444943 TI - Recent advances in design of immunogenic and effective naked DNA vaccines against cancer. AB - A variety of clinical trials for vaccines against cancer have provided evidence that DNA vaccines are well tolerated and have an excellent safety profile. DNA vaccines require much improvement to make them sufficiently effective against cancer in the clinic. Nowadays, it is clear that an increased antigen expression correlates with improved immunogenicity and it is critical to vaccine performance in large animals and humans. Similarly, additional strategies are required to activate effective immunity against poorly immunogenic tumour antigens. This review discusses very recent scientific references focused on the development of sophisticated DNA vaccines against cancer. We report a selection of novel and relevant patents employed to improve their immunogenicity through several strategies such as the use of tissue-specific transcriptional elements, nuclear localisation signalling, codon-optimisation and by targeting antigenic proteins to secretory pathway. Recent patents validating portions or splice variants of tumour antigens as candidates for cancer DNA vaccines with improved specificity, such as mesothelin and hTERT, are also discussed. Lastly, we review novel patents on the use of genetic immunomodulators, such as "universal" T helper epitopes derived from tetanus toxin, E. coli heat labile enterotoxin and vegetable proteins, as well as cytokines, chemokines or costimulatory molecules such as IL 6, IL-15, IL- 21 to amplify immunity against cancer. PMID- 23444944 TI - Your fate is in your hands? Handedness, digit ratio (2D:4D), and selection to a national talent development system. AB - Over the past decade a small evidence base has highlighted the potential importance of seemingly innocuous variables related to one's hands, such as hand dominance and the relative length of the second and fourth digits (2D:4D ratio), to success in sport. This study compared 2D:4D digit ratio and handedness among handball players selected to advance in a national talent development system with those not selected. Participants included 480 youth handball players (240 females and 240 males) being considered as part of the talent selection programme for the German Youth National team. Hand dominance and digit ratio were compared to age matched control data using standard t-tests. There was a greater proportion of left-handers compared to the normal population in males but not in females. There was also a lower digit ratio in both females and males. However, there were no differences between those selected for the next stage of talent development and those not selected on either handedness or digit ratio. These results add support for general effects for both digit ratio and handedness in elite handball; however, these factors seem inadequate to explain talent selection decisions at this level. PMID- 23444945 TI - Development and internal validation of an adrenal cortical carcinoma prognostic score for predicting the risk of metastasis and local recurrence. AB - OBJECTIVE: To develop and internally validate a prognostic score to predict the risk of metastases or recurrence in patients with adrenal cortical carcinomas (ACC). DESIGN: Clinical, laboratory and pathological data from 129 ACC patients, treated in a tertiary centre, were retrospectively reviewed. RESULTS: Using a multivariate binary logistic regression analysis, we developed a prognostic score with five covariates: a functional pattern other than isolated hyperandrogenism, a tumour size >7.5 cm, a primary tumour classified as T3/T4, the presence of microscopic venous invasion and a mitotic index >5/50 high-power fields. The prognostic score was calibrated according to the Hosmer-Lemeshow goodness-of-fit test (P = 0.9329) and exhibited excellent overall performance (Brier score = 0.0738). Finally, the discriminatory ability of the model, determined by the area under the ROC curve (AROC ), was near perfect (AROC , 0.9611; 95% CI, 0.92676 0.99552). The prediction model was internally validated with 200 bootstrap resamples and achieved excellent performance for estimating the risk of metastasis and recurrence in eight additional patients with apparently localized disease at diagnosis. CONCLUSION: We developed and internally validated a prognostic score based on the clinicopathological data that are readily available to any attending physician. Our model can be used to accurately estimate the risk of unfavourable outcomes in ACC patients. This score could be beneficial for both patient counselling and the identification of patients in whom adjuvant mitotane is justified. PMID- 23444946 TI - Sexual dysfunction and distress--development of a Polish version of the female sexual distress scale-revised. AB - INTRODUCTION: The concept of sexually related personal distress, central to the diagnosis of all female sexual dysfunction (FSD), is currently a subject of scientific debate. Several psychometric instruments have been used to measure sexually related personal distress in women, including the Female Sexual Distress Scale (FSDS) and its revised version (FSDS-R). AIM: To develop a Polish version of the FSDS-R (PL-FSDS-R). METHODS: In total, 210 women aged 18-55 years were included in the study. Seventy-five were diagnosed with hypoactive sexual desire disorder (HSDD), 31 were diagnosed with another FSD, and 104 were control. All subjects completed the PL-FSDS-R at baseline (day 0), day 7, and day 28. Internal consistencies were evaluated by Cronbach's alpha. Intraclass correlation coefficient was used to assess test-retest reliability. Discriminant validity was assessed by comparing mean scores of the FSD and control groups in a between groups analysis of variance. Receiver operating characteristic (ROC) analysis was performed to determine optimal cutoff values of the PL-FSDS-R. MAIN OUTCOME MEASURES: To measure the validity and reliability of the PL-FSDS-R and to determine optimal cutoff values. RESULTS: Mean total PL-FSDS-R score was statistically higher in women with HSDD and other FSD compared to healthy individuals, showing the test had discriminant validity. The frequency of sexual intercourse and quality of relationship with sexual partner but not other sexual behaviors were statistically correlated with the PL-FSDS-R score. ROC analysis confirmed these findings. All domains of the PL-FSDS-R demonstrated satisfactory internal consistencies, with a Cronbach's alpha-value of >0.70 for the entire sample. Test-retest coefficients were between 0.86-0.92, with the best reliability for a 7-day recall period. CONCLUSIONS: The PL-FSDS-R is a reliable questionnaire with good psychometric and discriminative validity, and can be used to measure sexually related personal distress in Polish women with FSD with a cutoff score of >=13. PMID- 23444947 TI - A comparison of the Cambridge Automated Neuropsychological Test Battery (CANTAB) with "traditional" neuropsychological testing instruments. AB - The Cambridge Neuropsychological Test Automated Battery (CANTAB) is frequently used in research protocols and increasingly in clinical practice. Despite the frequency of its use, important aspects of its measurement validity have yet to be established in healthy adults. Two hundred and fifty-five individuals completed the CANTAB and traditional neuropsychological tests commonly used in clinical practice, including selected subtests from the Wechsler Adult Intelligence Scale, Controlled Oral Word Association Test, Animal Naming, Trail Making Tests A and B, the Stroop test, and the Green Story Recall test. Results showed that CANTAB subtests were modestly correlated with traditional subtests. Correlations between CANTAB subtests and traditional subtests were less consistent when age and education were controlled for. In conclusion, the CANTAB shows modest associations with traditional neuropsychological test measures. PMID- 23444948 TI - Predictive biomarkers of clinical efficacy of allergen-specific immunotherapy: how to proceed. PMID- 23444949 TI - Failure of treatments based on the cytokine storm theory of sepsis: time for a novel approach. PMID- 23444951 TI - Tremelimumab: a review of development to date in solid tumors. AB - Tremelimumab is an investigational, fully human IgG monoclonal antibody directed against CTLA-4, a coinhibitory receptor that represses effector T-cell activity in cancer. Tremelimumab has produced promising anticancer responses in early clinical trials. However, a phase III trial of tremelimumab monotherapy versus chemotherapy in advanced melanoma was stopped early when no statistically significant difference in overall survival was observed between the two interventions. This article describes tremelimumab's putative mechanism of action, its preclinical pharmacology and clinical results to date across a range of cancer settings as monotherapy, as well as in combination with other therapies. The failure of the Phase III trial in melanoma is examined and factors affecting the possible future clinical development of tremelimumab are also explored. PMID- 23444952 TI - Does IL-15 have a causative role in large granular lymphocyte leukemia? AB - Evaluation of: Mishra A, Liu S, Sams GH et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell 22(5), 645-655 (2012). There is increasing evidence identifying a link between inflammation and cancer. A potent proinflammatory cytokine, IL-15, stimulates the proliferation and maintenance of both NK and T cells, and it is therefore likely that it may play a prominent role in certain hematologic malignancies. Previous studies have demonstrated that IL 15 overexpression can initiate leukemic transformation in murine models and that both NK- and T-cell malignancies can develop; the mechanism is explored in this article. The authors illustrate that IL-15 can cause chromosomal instability and DNA hypermethylation in large granular lymphocytes. These aberrations led to an aggressive acute large granular lymphocyte leukemia. Through studying the affected pathways, the authors were able to identify potential therapeutic targets and induce remission in a murine model. PMID- 23444953 TI - Homophilic antibodies as immunotherapeutics. AB - This review recalls the history of homophilic antibody discovery and adaptation for cancer immunotherapy. Homophilic antibodies are a rare type of murine monoclonal antibody produced by plasmacytomas. They are self-binding in solid phase assays and, in solution, are in an equilibrium of monomers and dimers. This equilibrium is controlled by antibody concentration and temperature, whereby low concentration and high temperature promote dimerization. The antibody domain that induces homophilic binding resides in the Vh region of the prototype T15 antibody. A peptide representing this domain can confer homophilicity to antibodies as a covalent conjugate. Homophilized antibodies have enhanced potency in target binding, induction of apoptosis, complement fixation and receptor mediated signal growth inhibition. Titration of homophilic antibodies reveals a dose response skewed toward lower concentrations. The immunotherapeutic utility of homophilized antibodies has been demonstrated in vitro and in animal models. Clinical studies are needed to establish homophilic antibodies as novel, potent, immunotherapeutic agents. PMID- 23444954 TI - The role of autoantibodies in autoimmune hepatitis type 2. AB - Antibodies play an important role in autoimmune liver diseases, such as autoimmune hepatitis (AIH). On the one hand, they are essential diagnostic markers to identify not only the presentation of AIH, but also the AIH subtype characterized by the presence of particular antibodies to target autoantigens in the liver. On the other hand, such autoantibodies might be directly involved in the etiology and/or pathogenesis of AIH. This review will reflect on the evidence of how specific autoantibodies influence AIH and will further provide insight into the necessities for generating therapeutic antibodies to treat AIH in the future. PMID- 23444955 TI - Sublingual immunotherapy for allergic rhinitis and conjunctivitis. AB - Sublingual immunotherapy (SLIT) for allergic respiratory diseases was first described in 1986 and immediately appeared as a viable alternative to the traditional subcutaneous route. Since then, more than 60 randomized controlled trials have been published, almost all with very favorable results. The average improvement over placebo in symptom score and medication use was always greater than 20%. The results of the clinical trials were pooled in several meta analyses, which consistently confirmed the efficacy of the treatment. SLIT is characterized by a satisfactory safety profile, its side effects being mainly limited to oral discomfort. Only six anaphylaxes and no fatalities have been so far reported. Due to the good risk:benefit ratio, SLIT is currently being investigated in diseases other than respiratory allergy, such as food allergy and atopic dermatitis. PMID- 23444957 TI - Update on the use of transgenic rice seeds in oral immunotherapy. AB - Rice seed provides an ideal production platform for pharmaceuticals in terms of high productivity and stability, as well as the scalability, safety and economy that are expected in plant production systems. Furthermore, these therapeutic products are bioencapsulated in protein bodies, which are seed-specific storage organelles that provide protection from digestion by gastrointestinal enzymes during delivery to the gut-associated lymphoid tissue. Thus, rice seed provides an ideal delivery system for the mucosal immune system. Oral immunotherapy using unprocessed transgenic rice seed containing therapeutic products has been demonstrated to induce effective mucosal immune tolerance and immune reactions against allergies and pathogens. PMID- 23444956 TI - Harms of TNF inhibitors in rheumatic diseases: a focused review of the literature. AB - A focused review of the risk of harms of anti-TNF inhibitors in adult rheumatic diseases was performed. An increased risk of serious infections, tuberculosis and other opportunistic infections has been reported across various studies, with etanercept appearing to have a modestly better safety profile in terms of tuberculosis and opportunistic infections, and infliximab posing a higher risk of serious infections. Evidence suggests no increase in risk of cancer with anti-TNF biologics, but there is an increased risk of non-melanoma skin cancer. Elderly patients appear to be at increased risk of incident or worsening heart failure with anti-TNF biologic use. PMID- 23444959 TI - Formation of guanine-6-sulfonate from 6-thioguanine and singlet oxygen: a combined theoretical and experimental study. AB - As an end metabolism product of the widely used thiopurine drugs, 6-thioguanine (6-TG) absorbs UVA and produces (1)O2 by photosensitization. This unusual photochemical property triggers a variety of DNA damage, among which the oxidation of 6-TG itself by (1)O2 to the promutagenic product guanine-6-sulfonate (G(SO3)) represents one of the major forms. It has been suspected that there exists an initial intermediate, G(SO), prior to its further oxidation to G(SO2) and G(SO3), but G(SO) has never been observed. Using density functional theory, we have explored the energetics and intermediates of 6-TG and (1)O2. A new mechanism via G(SOOH) -> G(SO2) -> G(SO4) -> G(SO3) has been discovered to be the most feasible energetically, whereas the anticipated G(SO) mechanism is found to encounter an inaccessibly high barrier and thus is prevented. The mechanism through the G(SOOH) and G(SO4) intermediates can be validated further by joint experimental measurements, where the fast rate constant of 4.9 * 10(9) M(-1) s( 1) and the reaction stoichiometry of 0.58 supports this low-barrier new mechanism. In addition to the dominant pathway of G(SOOH) -> G(SO2) -> G(SO4) -> G(SO3), a side pathway with higher barrier, G(SOOH) -> G, has also been located, providing a rationalization for the observed product distributions of G(SO2) and G(SO3) as major products and G as minor product. From mechanistic and kinetics points of view, the present findings provide new chemical insights to understand the high phototoxicity of 6-TG in DNA and point to methods of using 6-TG as a sensitive fluorescence probe for the quantitative detection of (1)O2, which holds particular promise for detecting (1)O2 in DNA-related biological surroundings. PMID- 23444960 TI - Temperature dependence of transport properties of spiro-MeOTAD as a hole transport material in solid-state dye-sensitized solar cells. AB - The internal transport and recombination parameters of solid-state dye-sensitized solar cells (ssDSCs) using the amorphous organic semiconductor 2,2',7,7' tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-MeOTAD) as a hole transport material (HTM) are investigated using electrical impedance spectroscopy. Devices were fabricated using flat and nanostructured TiO2 and compared to systems using nanostructured ZrO2 to differentiate between the transport processes within the different components of the ssDSC. The effect of chemically p-doping the HTM on its transport was investigated, and its temperature dependence was examined and analyzed using the Arrhenius equation. Using this approach the activation energy of the hole hopping transport within the undoped spiro-MeOTAD film was determined to be 0.34 +/- 0.02 and 0.40 +/- 0.02 eV for the mesoporous TiO2 and ZrO2 systems, respectively. PMID- 23444961 TI - Persistent pseudocowpox virus infection of the skin of a foot in a cat. PMID- 23444962 TI - In vivo genotoxicity and oxidative stress evaluation of an ethanolic extract from piquia (Caryocar villosum) pulp. AB - In this study, the ethanolic extract obtained from piquia pulp was assessed for genotoxicity and oxidative stress by employing the micronucleus test in bone marrow and peripheral blood cells in addition to comet, thiobarbituric-acid reactive substances (TBARS), and reduced glutathione assays in the liver, kidney, and heart. Additionally, phytochemical analyses were performed to identify and quantify the chemical constituents of the piquia extract. Wistar rats were treated by gavage with an ethanolic extract from piquia pulp (75 mg/kg body weight) for 14 days, and 24 h prior to euthanasia, they received an injection of saline or doxorubicin (15 mg/kg body weight, intraperoneally). The results demonstrated that piquia extract at the tested dose was genotoxic but not mutagenic, and it increased the TBARS levels in the heart. Further studies are required to fully elucidate how the properties of ethanolic extract of piquia pulp can affect human health. PMID- 23444963 TI - Kimchi, a fermented vegetable, improves serum lipid profiles in healthy young adults: randomized clinical trial. AB - Vegetable-based diets have generally focused on their health benefits including negative associations with the serum cholesterol concentrations. The aim of this study was to investigate whether serum lipid concentrations are influenced by the amount of kimchi intake. For the study, 100 volunteers were assigned to 2 dietary groups, low (15 g/day, n=50) and high (210 g/day, n=50) kimchi intake, and were housed together in a dormitory for 7 days. Identical meals except with different amount of kimchi were provided and subjects were instructed to maintain their normal physical activity. Concentrations of fasting blood glucose (FBG), total glucose, total cholesterol and low density lipoprotein (LDL)-C significantly decreased in both groups after 7 days of kimchi intake, but the effects were dose dependent. Lipid lowering effects of kimchi were more profound in the subjects with total cholesterol and LDL-C level over 190 and 130 mg/dL, respectively, in both groups. FBG was significantly decreased in the high kimchi intake as compared to the low intake group (P=.003). In conclusion, greater consumption of kimchi improved FBG and serum total cholesterol in young healthy adults. PMID- 23444964 TI - Chronic food administration of Salvia sclarea oil reduces animals' anxious and dominant behavior. AB - Recent studies indicate that an oil extract from Salvia sclarea may provide clinical benefits in various pathological conditions. In comparison to extracts from other Salvia species, S. sclarea oil contains twice as much omega-3 fatty acids, which are involved in eicosanoid synthesis pathways, and has been found to contain significant levels of the psychoactive monoterpane linalool. In the present study, we examined the mood stabilizing and anxiolytic-like effects of chronic food administration of S. sclarea oil extract on behavioral and physiological parameters of mice with prominent dominant and submissive features in behavioral assays used to test mood stabilizing and antidepressant drugs. Experimental animals received oil supplemented food from the age of 4 weeks or from conception via their pregnant dams. Each age group received either S. sclarea oil- or sunflower oil-enriched feed. Dominant animals, whose pregnant mothers received S. sclarea oil-enriched feed from the date of conception, showed a significant reduction of dominant and anxiety-like behavior, in comparison to their sunflower oil-treated counterparts. S. sclarea oil-treated submissive animals exhibited a similar tendency, and showed a significant reduction in blood corticosterone levels. These findings enforce the hypothesis that S. sclarea oil possesses anxiolytic properties. PMID- 23444965 TI - Effect of emulin on blood glucose in type 2 diabetics. AB - EmulinTM is a patented blend of chlorogenic acid, myricetin, and quercetin that has shown efficacy in reducing midday and post-oral glucose tolerance test (OGTT) area under the curve (AUC) glucose in streptozotocin-treated rats. The purpose of this study was to determine if similar effects would be evident in type 2 diabetic humans. Forty human subjects with confirmed type 2 diabetes (10 each in 4 groups: placebo/no medication, Emulin/no medication, placebo/metformin and Emulin/metformin) were evaluated. At the end of 1 week, fasting blood glucose, 2 h postprandial, actual peak glucose, and AUC (post-50 g OGTT) were determined. The placebo-only group had a large (5%-13%) increase in all parameters. The Emulin group and those on metformin performed similarly with reductions between 1% and 5%, with Emulin slightly outperforming the medication-alone group. The most significant reduction occurred in the Emulin/metformin group, with decreases in the parameters by up to 20%. These results suggest that Emulin, if consumed regularly, could not only have the acute effect of lowering the glycemic impact of foods, but chronically lower background blood glucose levels of type 2 diabetics. PMID- 23444966 TI - Polyphasic characterization of Aeromonas salmonicida isolates recovered from salmonid and non-salmonid fish. AB - Michigan's fisheries rely primarily upon the hatchery propagation of salmonid fish for release in public waters. One limitation on the success of these efforts is the presence of bacterial pathogens, including Aeromonas salmonicida, the causative agent of furunculosis. This study was undertaken to determine the prevalence of A. salmonicida in Michigan fish, as well as to determine whether biochemical or gene sequence variability exists among Michigan isolates. A total of 2202 wild, feral and hatchery-propagated fish from Michigan were examined for the presence of A. salmonicida. The examined fish included Chinook salmon, Oncorhynchus tshawytscha (Walbaum), coho salmon, O. kisutcha (Walbaum), steelhead trout, O. mykiss (Walbaum), Atlantic salmon, Salmo salar L., brook trout, Salvelinus fontinalis (Mitchill), and yellow perch, Perca flavescens (Mitchill). Among these, 234 fish yielded a brown pigment-producing bacterium that was presumptively identified as A. salmonicida. Further phenotypic and phylogenetic analyses identified representative isolates as Aeromonas salmonicida subsp. salmonicida and revealed some genetic and biochemical variability. Logistic regression analyses showed that infection prevalence varied according to fish species/strain, year and gender, whereby Chinook salmon and females had the highest infection prevalence. Moreover, this pathogen was found in six fish species from eight sites, demonstrating its widespread nature within Michigan. PMID- 23444968 TI - Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain. AB - The capsaicin 8% cutaneous patch is an emergent new treatment option for patients with peripheral neuropathic pain. In randomized controlled clinical studies relevant pain relief for 12 weeks was achieved in about one third of patients following a single application. The first part of this paper is a review of the pathophysiology, pharmacology, and published clinical trials with the capsaicin 8% cutaneous patch. The second part reports on outcomes of an interdisciplinary expert workshop, where new treatment results of three major German pain centers were presented and reviewed with the objectives of obtaining responder rates for different pain syndromes, assessing maintenance of effect under real-life conditions, and giving recommendations for practical care. The 12 week responder rates with pain relief of >= 30% were comparable in patients with mononeuropathies (37.9%) and postherpetic neuralgia (38.8%). Similar responder rates were seen in a subgroup of patients with cervical spine radiculopathy and back pain (46.7%). In HIV-associated neuropathy the responder rates were high (47.8%) but lower in patients with other polyneuropathies (17.6%). Response rates were nearly identical after 1 week (46.6%) and 4 weeks (43.3) and dropped only slightly at 12 weeks (37.4%). In a subgroup of 54 patients who underwent a second treatment, efficacy was maintained. Response rates in patients with or without lidocaine pretreatment were comparable. Treatment with the capsaicin 8% cutaneous patch was generally safe and well tolerated. The workshop panel recommended further investigation of opportunities to improve the application procedure and to perform studies on the skin penetration and distribution of capsaicin. A modified quantitative sensory testing (QST) should be developed for clinical practice in order to better understand the correlation of sensory profiles and response to capsaicin treatment. PMID- 23444967 TI - A novel method for cross-species gene expression analysis. AB - BACKGROUND: Analysis of gene expression from different species is a powerful way to identify evolutionarily conserved transcriptional responses. However, due to evolutionary events such as gene duplication, there is no one-to-one correspondence between genes from different species which makes comparison of their expression profiles complex. RESULTS: In this paper we describe a new method for cross-species meta-analysis of gene expression. The method takes the homology structure between compared species into account and can therefore compare expression data from genes with any number of orthologs and paralogs. A simulation study shows that the proposed method results in a substantial increase in statistical power compared to previously suggested procedures. As a proof of concept, we analyzed microarray data from heat stress experiments performed in eight species and identified several well-known evolutionarily conserved transcriptional responses. The method was also applied to gene expression profiles from five studies of estrogen exposed fish and both known and potentially novel responses were identified. CONCLUSIONS: The method described in this paper will further increase the potential and reliability of meta-analysis of gene expression profiles from evolutionarily distant species. The method has been implemented in R and is freely available at http://bioinformatics.math.chalmers.se/Xspecies/. PMID- 23444969 TI - Pegfilgrastim prophylaxis in patients at different levels of risk for chemotherapy-associated febrile neutropenia: an observational study. AB - BACKGROUND: Guidelines for using granulocyte colony-stimulating factor (G-CSF) in patients receiving chemotherapies with 10-20% (intermediate) risk for febrile neutropenia (FN) recommend additional assessment of patient-related FN risk factors. OBJECTIVE: The current study evaluated adherence to guideline recommendations and analysed modalities of pegfilgrastim use. METHODS: Adult cancer patients scheduled to receive a chemotherapy regimen assessed by the investigators as intermediate FN risk and who received pegfilgrastim were prospectively enrolled in this observational study from 2007-2010. Risk factors at study entry, treatment modalities and FN assessment were documented by investigators, whereas guideline adherence was centrally checked in a post-hoc analysis, according to guideline categorizations. RESULTS: Thirty-seven centres enrolled 335 evaluable patients with solid and hematologic neoplasias. Although physicians initially rated the FN risk of all chemotherapies as intermediate, after central re-assessment this applied only to 63.9% of regimens; 21.2% were reassessed as low risk and 14.9% as high risk. Pegfilgrastim was used as primary prophylaxis in 80.3% of all patients. The most frequent FN risk factors considered by physicians when deciding to use pegfilgrastim were female gender, advanced disease, age >= 65 years, and anaemia. FN incidence was higher in patients with >= 4 FN risk factors than those with <4 risk factors (10% vs. 4.3%; p = 0.055) and in patients with severe comorbidity than those without (13.6% vs. 4.5%; p = 0.014). Overall FN rate was 5.7%. LIMITATIONS: Due to the observational design of the study, findings are descriptive in nature. Post-hoc assessment of chemotherapy FN risk was determined by author's opinion in some cases. CONCLUSIONS: Overall, there was good adherence of Austrian physicians to guideline recommendations; however, there are chemotherapy regimens and clinical settings in which FN risk assignment is unclear in the literature. FN incidence with pegfilgrastim prophylaxis was similar to that reported in other observational and randomized studies. PMID- 23444970 TI - Prevalence of gastroprotective agent (GPA) use in adults with arthritis in the United States. AB - OBJECTIVE: The prevalence of non-steroidal anti-inflammatory drug (NSAID) and concurrent gastroprotective agent (GPA) use in the US is not known. As such, the prevalence of GPA use among arthritis patients taking NSAIDs was examined. METHODS: Men and women aged >= 40 with self-reported arthritis and members of a web-based community panel were invited via e-mail to participate in a web survey. Interested panelists consented and completed the survey. Participants using NSAIDs in the last 30 days were eligible. Questions regarding NSAID and GPA use were asked, likewise adherence to GPA (Morisky scale), comorbid conditions, gastrointestinal (GI) history, and other risk factors. Descriptive analyses and logistic regressions were performed to assess associations with GPA use and adherence. RESULTS: Invitations were sent to 7605 adults; 4108 (54%) responded; 2208 completed. Final sample was 1525 (76%) with osteoarthritis (OA), 354 (18%) with rheumatoid arthritis (RA), and 121 (6%) with both OA and RA. Mean age was 62.0; 64% were female; 83% white; 25% worked full-time, and 39% were retired. Mean duration with arthritis was 13.0 years; 47% and 19% experienced arthritis symptoms 'daily' and 'almost always', respectively. Nearly 43% reported using a GPA and 39% of daily NSAID users reported taking a GPA. Fifty-eight participants (2.9%) were classified as low GI risk, 342 (17.1%) were moderate risk, and 1600 (80.0%) were high risk. Variables significantly associated with GPA use included older age; male gender; being white (vs. Hispanic); taking an NSAID at least daily; taking fewer NSAIDs; taking a Cox-2 inhibitor or prescription NSAID; history of GI conditions; prescription antiplatelet use; and having GI symptoms. Similar variables were associated with GPA adherence. CONCLUSION: Less than half of adult men and women in the US taking a daily NSAID used GPAs and only 37% of high-risk participants were taking GPAs. PMID- 23444971 TI - Reactivity of surface species in heterogeneous catalysts probed by in situ X-ray absorption techniques. PMID- 23444972 TI - Nurses' knowledge and attitudes towards aged sexuality: validity and internal consistency of the Dutch version of the Aging Sexual Knowledge and Attitudes Scale. AB - AIM: This paper reports a study testing the content and face validity and internal consistency of the Dutch version of the Aging Sexual Knowledge and Attitudes Scale. BACKGROUND: The ability of older residents to sexually express themselves is known to be influenced by the knowledge and attitudes of nursing home staff towards later-life sexuality. Although the Aging Sexual Knowledge and Attitudes Scale is a widely used instrument to measure this, there is no validated, Dutch translation available. DESIGN: Instrument development. METHOD: Following a standard forward/backward translation into Dutch, the scale was further adapted for use in Flemish nursing home settings. Content and face validity and user-friendliness were assessed. The psychometric properties were determined by means of an exploratory study. Data were collected from March-April 2011 at eight Flemish nursing homes. Reliability was assessed using internal consistency and item-total correlations. RESULTS: Both subscales of the Flemish adaptation showed acceptable content validity. The face validity and user friendliness were deemed favourable with hardly any remarks given by the expert panel. The Cronbach's alpha was 0.80 and 0.88 for the knowledge and attitude subscales, respectively. The item-total correlations ranged from 0.21-0.48 for the knowledge section and from 0.09-0.68 for the attitude subscale. CONCLUSION: We conclude from our study that the Dutch version of the scale has acceptable to good psychometric properties. The Flemish adaptation therefore seems to be a valuable instrument for studying nursing staff's knowledge and attitudes towards aged sexuality in Flanders. PMID- 23444973 TI - Response to comment on "Screening criteria for long-range transport potential of organic substances in water". PMID- 23444974 TI - Immunogenicity and contraceptive efficacy of Escherichia coli-expressed recombinant porcine zona pellucida proteins. AB - PROBLEM: To overcome availability of the purified native zona pellucida (ZP) glycoproteins for immunocontraception, porcine ZP3, and ZP4 were expressed in E. coli. METHOD OF STUDY: Purified recombinant proteins were characterized by SDS PAGE and Western blot, and immunogenicity and contraceptive efficacy determined in FvB/J female mice. RESULTS: Purified ZP3, ZP3 with promiscuous T-cell epitope of tetanus toxoid, ZP4 and ZP4 incorporating promiscuous T-cell epitope of bovine RNase revealed ~44-, ~49-, ~53-, and ~55-kDa bands by SDS-PAGE and Western blot, respectively. Immunization of female mice with recombinant proteins elicited high antibody titers as well as T-cell responses. Immune sera recognized mouse oocyte ZP and also inhibited in vitro fertilization. Immunized mice showed significant decrease in fertility. Recombinant proteins were able to recall memory antibody response in female mice primed with porcine native ZP. CONCLUSION: Availability of recombinant porcine proteins will be useful in the development of contraceptive vaccine. PMID- 23444975 TI - Top-down and bottom-up influences on demographic rates of Antarctic fur seals Arctocephalus gazella. AB - Two major drivers in population dynamics are bottom-up processes, such as environmental factors that affect foraging success, and the top-down impacts of predation. Many populations of marine mammal and seabird species appear to be declining in response to reductions in prey associated with the bottom-up effects of climate change. However, predation, which usually occurs at sea and is difficult to observe, may also play a key role. We analysed drivers of population dynamics of Antarctic fur seals Arctocephalus gazella at Cape Shirreff from 1997 to 2009, including a predator that targets pre-weaned pups and bottom-up environmental effects in an ecosystem particularly sensitive to small changes in temperature. We use Bayesian mark-recapture analysis to demonstrate that although large-scale environmental variability affects annual adult survival and reproduction, first year survival appears to be driving the current decline in this population (as defined by a decline in the annual number of pups born). Although the number of pups increased during the first third of the study, first year survival and recruitment of those pups in later years was very low. Such low survival may be driven by leopard seal Hydrurga leptonyx predation, particularly prior to weaning. Our results suggest that without leopard seal predation, this population would most likely increase in size, despite the observed bottom-up effects of climate changes on adult vital rates. More broadly, our results show how age-targeted predation could be a major factor in population decline of K selected colonial breeders. PMID- 23444976 TI - Radio-protective effects of Nigella sativa oil on oxidative stress in tongue tissue of rats. AB - OBJECTIVE: The aim of this study was to evaluate the effects of Nigella sativa (N.S.) oil against radiation-induced oxidative stress in the rat tongue. MATERIAL AND METHODS: Thirty-two Sprague-Dawley rats were randomly divided into four equal groups. Group 1 [control group(C)] did not receive N.S. oil or irradiation. Group 2 [sham control group(CN)] did not receive N.S. oil or irradiation but received 1 ml saline orally, plus sham irradiation. Group 3 [irradiation group(R)] received irradiation, plus 1-ml saline orally. Group 4 [irradiation plus N.S. oil group(RN)] received irradiation plus 1 g kg(-1) per day of N.S. oil orally for 10 days. The animals were euthanized on day 10, and tongue tissues were collected for evaluating biochemical oxidative parameters. RESULTS: The oxidative stress index, total oxidant status and lipid hydroperoxides levels in the R group were statistically higher than those in the C, CN and RN groups. The paraoxonase levels in the R group were statistically lower than those in the C, CN and RN groups. No statistically significant differences were detected between any of the groups, in terms of total antioxidant status and the arylesterase, ceruloplasmin and total sulfhydryl group levels. CONCLUSION: Nigella sativa (N.S.) oil may be a beneficial agent in protecting against ionizing radiation-related tissue injury. PMID- 23444977 TI - Clitoral avulsion successfully repaired with 2-octylcyanoacrylate. AB - INTRODUCTION: Clitoral piercing is becoming more popular in the general populace, playing an aesthetic as well as likely sexual role. However, potential for injury also impacts future clitoral sexual function, thus highlighting the importance of proper repair. AIM: To report a 29-year-old woman presented to the emergency department after a clitoral piercing injury. Examination revealed avulsion of most of the clitoral body. After the patient refused expectant and surgical management, reapproximation was performed using 2-octylcyanoacrylate. METHODS: 2 Octylcyanoacrylate, commonly known as Dermabond((r)) (Ethicon Inc., Somerville, NJ, USA), was used to reapproximate the clitoral laceration for this patient. It is a cyanoacrylate tissue adhesive, forming a strong bond between wound edges to allow for normal healing to occur below. Benefits of use are decreased time of repair, water-resistant flexible coating, and no need for suture removal. RESULTS: The laceration was successfully reapproximated with 2 octylcyanoacrylate. The tissue held together satisfactorily and the patient was discharged to home. She was seen as an outpatient 3 days later, with a moderately tender and swollen clitoris, but with an intact repair and improved pain. A visit 8 weeks later showed a well-healed clitoris, and the patient reported resolution of pain and return of sexual function, with successful orgasms. CONCLUSIONS: The delicacy of clitoral anatomy and the potential impact of its injury on future sexual function make it an intimidating area of repair for the general physician. The method of repair must be tailored to the injury, patient, and physician; however, 2-octylcyanoacrylate is a viable alternative to traditional surgical or expectant management, offering strength and flexibility while avoiding further trauma with suture. PMID- 23444978 TI - Surgical correction of vesico-ureteric reflux for recurrent febrile urinary tract infections after kidney transplantation. AB - OBJECTIVE: To evaluate the outcome of anti-reflux revision surgery in patients diagnosed with at least a grade 3 reflux at voiding cysto-urethrography in patients with recurrent urinary tract infection (UTI) after renal transplantation. PATIENTS AND METHODS: We identified 60 patients with a diagnosis of recurrent febrile UTI and post-transplantation vesico-ureteric reflux (VUR) who underwent open surgical correction of reflux. Patient characteristics, including the aetiology of end-stage renal disease, age, time to VUR correction, type of VUR correction, serum creatinine levels, and number of UTIs before and after correction were documented. RESULTS: The median (range) age of the patients was 31.5 (9-65) years. A total of 30 patients underwent uretero-ureterostomy or pyelo-ureterostomy and 30 underwent extravesical or intravesical ureteric reimplantation. The median (range) creatinine levels before and after correction were 1.5 (0.8-4.5) mg/dL and 1.3 (0.7-4.5) mg/dL (P<0.05), respectively. The median (range) number of UTI episodes reported before the correction surgery was 4 (3-12), whereas number of UTI episodes after the surgery was 1 (0-12), the difference being significant (P<0.05). CONCLUSIONS: Open surgical correction of post-transplant VUR is an effective and safe method of decreasing UTI episodes and stopping reflux. Surgical correction of reflux may prolong the life of the renal graft. PMID- 23444980 TI - Protecting patient privacy and data security. PMID- 23444979 TI - Fatigue after myocardial infarction - a two-year follow-up study. AB - AIMS AND OBJECTIVES: To investigate changes in self-reported fatigue and depression from four months to two years following a myocardial infarction, as well as to explore gender differences, identify the incidence of fatigue without coexisting depression and finally predict health-related quality of life at a two year follow-up. BACKGROUND: Depression and fatigue are associated with decreased health-related quality of life after myocardial infarction. Although there is a close relationship between fatigue and depression, it has been shown that symptoms of fatigue can occur without coexisting depression. DESIGN: Quantitative and longitudinal design. METHODS: Participants (n = 155) were asked to complete the following questionnaires: the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Inventory-20 (MFI-20) and the Short Form Survey (SF-36) following myocardial infarction (after four months and two years). Descriptive statistics, paired t-tests and multiple regressions were carried out. RESULTS: In the entire group, self-reported fatigue had decreased from four months to two years after myocardial infarction. After two years, 18% of respondents reported depression together with fatigue and 30% reported fatigued without depression. Women scored higher than men on the fatigue dimensions reduced activity, reduced motivation and mental fatigue. Moreover, the physical dimension of health-related quality of life two years after myocardial infarction was predicted by experienced general fatigue at four months. CONCLUSION: Fatigue with or without coexisting possible/probable depression remains as a significant symptom two years after myocardial infarction in nearly half of the entire group. RELEVANCE TO CLINICAL PRACTICE: Fatigue is a problem following myocardial infarction. Therefore, systematic screening and early identification of patients experiencing symptoms of depression and fatigue after myocardial infarction are important for suitable care planning. In contemporary coronary care, strategies aimed at relieving fatigue should be developed. PMID- 23444981 TI - Ensuring public health neutrality. PMID- 23444982 TI - Adjuvanted influenza a (H1N1) 2009 vaccine in patients with hematological diseases: good safety and immunogenicity even in chemotherapy-treated patients. AB - BACKGROUND: Patients with hematological malignancies are more susceptible to viral infections including influenza. In 2009, the World Health Organization classified the novel influenza A (H1N1) virus as pandemic. The potential impact of this pandemic for patients with hematological disorders was unknown. Institutional guidelines recommended two doses of AS03-adjuvanted influenza A (H1N1) 2009 pandemic vaccine for these patients. OBJECTIVES: We aimed to determine the safety, immunogenicity, and clinical efficacy of this vaccine in patients with hematological diseases. Furthermore, we compared the immunological responses to that obtained by the non-adjuvanted trivalent seasonal influenza vaccine (TIV). METHODS: All included patients received adjuvanted pandemic vaccine and the majority received TIV. Serum for antibody analyses was collected at five time points. RESULTS: Thirty-one patients with different hematological diseases were included. After the second vaccine dose, a total of 25 (81%) reached both protective levels of antibodies and seroconversion response. Antibody titers >= 1 : 40 persisted for 50% of responding patients at 1 yr. Seroconversion was observed in 69% of 14 patients who had undergone hematopoietic stem cell transplantation and in all (9/9) patients with myeloma (five with ongoing treatment including high-dose corticosteroids). After vaccination with TIV, seroconversions against the three included strains were detected in 28%, 40%, and 20%. Response to the adjuvanted pandemic vaccine was superior (P < 0.009). CONCLUSIONS: A substantial proportion of patients with hematological malignancies including patients undergoing chemotherapy mounted a good response to the adjuvanted pandemic vaccine. This vaccine had superior immunogenicity as compared to the non-adjuvanted TIV. PMID- 23444984 TI - Waist-to-height ratio is the best indicator for undiagnosed type 2 diabetes. AB - AIMS: Early detection of diabetes is important for the prevention of diabetic complications. The best adiposity index for indicating Type 2 diabetes mellitus remains unclear. We aimed to identify the optimal adiposity measure among BMI, waist circumference, waist-hip ratio and waist-to-height ratio to indicate undiagnosed Type 2 diabetes and impaired fasting glucose in Chinese adults. METHODS: A total of 7567 participants aged 20-79 years were included in this study. Impaired fasting glucose was defined as a fasting plasma glucose level of 6.1-6.9 mmol/l in participants without diabetes. Undiagnosed Type 2 diabetes was identified as fasting plasma glucose >= 7.0 mmol/l when neither a history of diabetes nor use of hypoglycaemic drugs was present. Body weight, height, waist and hip circumferences were measured following standard procedures. Data were analysed using logistic regression and areas under the receiver operating characteristic curves. RESULTS: Of the 7567 participants, 536 were defined as having impaired fasting glucose and 690 were patients with Type 2 diabetes, including 290 (3.8%) persons with undiagnosed diabetes. In multivariate logistic regression, the odds ratios of waist-to-height ratio (>= 0.5) were stronger than BMI (>= 24 kg/m2), waist circumference (>= 85 cm in men and >= 80 cm in women) and waist-hip ratio (>= 0.85) for undiagnosed Type 2 diabetes and impaired fasting glucose. Among the four indices, waist-to-height ratio >= 0.5 showed the largest area under the receiver operating characteristic curve for diagnosing undiagnosed Type 2 diabetes (0.725, 95% CI 0.693-0.756) and impaired fasting glucose (0.662, 95% CI 0.638-0.687). CONCLUSIONS: By comparison with BMI, waist circumference and waist-hip ratio, waist-to-height ratio >= 0.5 may be the best indicator for undiagnosed Type 2 diabetes and impaired fasting glucose. PMID- 23444983 TI - Favourable metabolic effects of a eucaloric lower-carbohydrate diet in women with PCOS. AB - OBJECTIVE: Diet-induced reduction in circulating insulin may be an attractive nonpharmacological treatment for women with polycystic ovary syndrome (PCOS) among whom elevated insulin may exacerbate symptoms by stimulating testosterone synthesis. This study was designed to determine whether a modest reduction in dietary carbohydrate (CHO) content affects beta-cell responsiveness, serum testosterone concentration and insulin sensitivity in women with PCOS. DESIGN: In a crossover design, two diets ('Standard,' STD, 55:18:27% energy from carbohydrate/protein/fat; lower-carbohydrate, 41:19:40) were provided for 8 weeks in random order with a 4-week washout between. PATIENTS: Thirty women with PCOS. MEASUREMENTS: beta-cell responsiveness assessed as the C-peptide response to glucose during a liquid meal test; insulin sensitivity from insulin and glucose values throughout the test; insulin resistance (HOMA-IR); and total testosterone by immunoassay. RESULTS: Paired t-test indicated that the lower-CHO diet induced significant decreases in basal beta-cell response (PhiB), fasting insulin, fasting glucose, HOMA-IR, total testosterone and all cholesterol measures, and significant increases in insulin sensitivity and dynamic ('first-phase') beta cell response. The STD diet induced a decrease in HDL-C and an increase in the total cholesterol-to-HDL-C ratio. Across all data combined, the change in testosterone was positively associated with the changes in fasting insulin, PhiB and insulin AUC (P < 0.05). CONCLUSIONS: In women with PCOS, modest reduction in dietary CHO in the context of a weight-maintaining diet has numerous beneficial effects on the metabolic profile that may lead to a decrease in circulating testosterone. PMID- 23444986 TI - Communication: Structure, formation, and equilibration of ensembles of Ag-S complexes on an Ag surface. AB - We have utilized conditions of very low temperature (4.7 K) and very low sulfur coverage to isolate and identify Ag-S complexes that exist on the Ag(111) surface. The experimental conditions are such that the complexes form at temperatures above the temperature of observation. These complexes can be regarded as polymeric chains of varying length, with an Ag4S pyramid at the core of each monomeric unit. Steps may catalyze the formation of the chains and this mechanism may be reflected in the chain length distribution. PMID- 23444985 TI - Feasible concomitant treatment with eltrombopag and oral anticoagulation in a patient with chronic immune thrombocytopenia and severe cardiac comorbidities. PMID- 23444987 TI - Communication: Spectroscopic evidence for a planar cyclic CO trimer. AB - A high-resolution spectrum in the region of 2144 cm(-1) is assigned to the previously elusive CO trimer. In spite of interference from the CO dimer and some remaining unexplained details, there is strong evidence for a planar, cyclic, C bonded trimer structure, with C(3h) symmetry and 4.42 A intermolecular separation, in agreement with theoretical calculations. A modest vibrational blueshift of +0.85 cm(-1) is observed for the CO trimer, as compared to +0.71 cm( 1) for the C-bonded form of the dimer. PMID- 23444989 TI - Communication: One-photon phase control of cis-trans isomerization in retinal. AB - We computationally demonstrate the one-photon phase control of retinal isomerization under conditions of low laser intensity. The calculations, utilizing the multiconfigurational time dependent Hartree method, include coupling between the two modes that are active in isomerization and the background molecular vibrational environment. Noting previously unsuccessful computations highlights the significance of this result. PMID- 23444988 TI - Communication: Origin of the contributions to DNA structure in phages. AB - Cryo electron microscopy (cryo-EM) data of the interior of phages show ordering of the interior DNA that has been interpreted as a nearly perfectly ordered polymer. We show surface-induced correlations, excluded volume, and electrostatic forces are sufficient to predict most of the major features of the current structural data for DNA packaged within viral capsids without additional ordering due to elastic bending forces for the polymer. Current models assume highly ordered, even spooled, hexagonally packed conformations based on interpretation of cryo-EM density maps. We show herein that the surface induced packing of short (6mer), unconnected DNA polymer segments is the only necessary ingredient in creating ringed densities consistent with experimental density maps. This implies the ensemble of possible conformations of polymeric DNA within the capsid that are consistent with cryo-EM data may be much larger than implied by traditional interpretations where such rings can only result from highly-ordered spool-like conformations. This opens the possibility of a more disordered, entropically driven view of phage packaging thermodynamics. We also show the electrostatics of the DNA contributes a large portion of the internal hydrostatic and osmotic pressures of a phage virion, suggesting that nonlinear elastic anomalies might reduce the overall elastic bending enthalpy of more disordered conformations to have allowable free energies. PMID- 23444990 TI - Communication: Ab initio Joule-Thomson inversion data for argon. AB - The Joule-Thomson coefficient MU(H)(P, T) is computed from the virial equation of state up to seventh-order for argon obtained from accurate ab initio data. Higher order corrections become increasingly more important to fit the low-temperature and low-pressure regime and to avoid the early onset of divergence in the Joule Thomson inversion curve. Good agreement with experiment is obtained for temperatures T > 250 K. The results also illustrate the limitations of the virial equation in regions close to the critical temperature. PMID- 23444991 TI - Direct DeltaMBPT(2) method for ionization potentials, electron affinities, and excitation energies using fractional occupation numbers. AB - A direct method (D-DeltaMBPT(2)) to calculate second-order ionization potentials (IPs), electron affinities (EAs), and excitation energies is developed. The DeltaMBPT(2) method is defined as the correlated extension of the DeltaHF method. Energy differences are obtained by integrating the energy derivative with respect to occupation numbers over the appropriate parameter range. This is made possible by writing the second-order energy as a function of the occupation numbers. Relaxation effects are fully included at the SCF level. This is in contrast to linear response theory, which makes the D-DeltaMBPT(2) applicable not only to single excited but also higher excited states. We show the relationship of the D DeltaMBPT(2) method for IPs and EAs to a second-order approximation of the effective Fock-space coupled-cluster Hamiltonian and a second-order electron propagator method. We also discuss the connection between the D-DeltaMBPT(2) method for excitation energies and the CIS-MP2 method. Finally, as a proof of principle, we apply our method to calculate ionization potentials and excitation energies of some small molecules. For IPs, the DeltaMBPT(2) results compare well to the second-order solution of the Dyson equation. For excitation energies, the deviation from equation of motion coupled cluster singles and doubles increases when correlation becomes more important. When using the numerical integration technique, we encounter difficulties that prevented us from reaching the DeltaMBPT(2) values. Most importantly, relaxation beyond the Hartree-Fock level is significant and needs to be included in future research. PMID- 23444992 TI - Radial correlation effects on interconfigurational excitations at the end of the lanthanide series: a restricted active space second order perturbation study of Yb2+ and SrCl2:Yb2+. AB - At the end of the lanthanide series, 4f -> 5d and other interconfigurational transitions, in which one electron is excited from a tight 4f orbital to a much more diffuse one, occur with a break of many f-f pairs, which make the electron correlation effects dominant. For instance, the large energy gap of 25 000 cm(-1) (~29 500 cm(-1) without spin-orbit coupling) above the 4f(14) ground state of the SrCl2:Yb(2+) material is mostly due to electron correlation. In effect, a minimal multiconfigurational restricted active space (RASSCF) calculation that includes only the 4f(14) ground and 4f(13)5d and 4f(13)6s open-shell excited configurations gives a very small gap (5400 cm(-1)), whereas the correlation corrections to the 4f(14) -> 4f(13)5d(eg) transition energies at the second order perturbation theory (RASPT2) level are very large: 35 599 +/- 439 cm(-1), in average, for all excited states. These corrections are too large to be accurate at second order perturbation level. When a second f-shell is also included in the active space and single and double excitations to the 5d, 6s, and 5f shells are treated variationally, the (extended) RASSCF energy gap above the ground state and the electronic transitions increase by 22 038 +/- 120 cm(-1) and the RASPT2 correlation energy corrections become small (-721 +/- 571 cm(-1)), as it is desirable for a second order perturbation. A comparative analysis of both RASPT2 results reveals that the lack of the second f-shell accounts for 12 700 cm(-1) of the 14 223 +/- 80 cm(-1) overestimation of interconfigurational transitions energies by the minimal RASPT2 calculation, which indicates an inaccurate calculation of the differential radial correlation between the 4f(14) and 4f(13)5d configurations by second order perturbation theory. In order to establish practical and accurate procedures for the calculation of 4f -> 5d and other interconfigurational transitions at the end of the lanthanide series, the above and other RASSCF/RASPT2 calculations on the ionization potential of Yb(2+) in gas phase and in SrCl2 have been benchmarked in this paper against coupled cluster (coupled cluster singles and doubles and triples ) calculations, and RASSCF/RASPT2 calculations on the absorption spectrum of SrCl2:Yb(2+) have been compared with experiment. The results support that variational calculation of SD 4f -> 5f excitations prior to RASPT2 calculations can be a realistic, accurate, and feasible choice to model radial correlation effects at the end of the lanthanide series. PMID- 23444993 TI - Benchmarks of improved complete basis set extrapolation schemes designed for standard CCSD(T) atomization energies. AB - Simple modifications of complete basis set extrapolation formulas chosen from the literature are examined with respect to their abilities to reproduce a diverse set of 183 reference atomization energies derived primarily from very large basis set standard, frozen core coupled-cluster singles, doubles plus perturbative triples (CCSD(T)) with the aug-cc-pVnZ basis sets. This reference set was augmented with a few larger chemical systems treated with explicitly correlated CCSD(T)-F12b using a quadruple zeta quality basis set followed by extrapolation to complete basis set limit. Tuning the extrapolation formula parameters for the present reference set resulted in substantial reductions in the error metrics. In the case of the best performing approach, the aVnZ extrapolated results are equivalent to or better than results obtained from raw aV(n + 3)Z basis set calculations. To the extent this behavior holds for molecules outside the reference set, it represents an improvement of at least one basis set level over the original formulations and a further significant reduction in the amount of computer time needed to accurately approximate the basis set limit. PMID- 23444994 TI - Rigorously extensive orbital-invariant renormalized perturbative triples corrections from quasi-variational coupled cluster theory. AB - We show that, by making use of the linked tensor objects inherent to the approach, Orbital-optimised Quasi-Variational Coupled Cluster Theory (OQVCCD) leads naturally to a computationally-trivial, rigorously extensive, and orbital invariant renormalization of the standard (T) correction for the perturbative inclusion of the effects of connected triple excitations. The resulting prototype method, renormalized perturbative triple OQVCCD (R-OQVCCD(T)), is demonstrated to predict potential energy curves for single bond-breaking processes of significantly higher accuracy than OQVCCD with the standard perturbative triple excitation correction (OQVCCD(T)) itself, and to be in good numerical correspondence with the existing renormalized (R-CCSD(T)) and completely renormalized (CR-CCSD(T)) coupled-cluster singles doubles triples methods, while continuing to provide descriptions of multiple bond-breaking processes of OQVCCD(T) quality. PMID- 23444995 TI - Magnetohydrodynamic motion of a colloidal sphere with self-electrochemical surface reactions in a spherical cavity. AB - An analytical study is presented for the magnetic-field-induced motion of a colloidal sphere with spontaneous electrochemical reactions on its surface situated at the center of a spherical cavity filled with an electrolyte solution at the quasi-steady state. The zeta potential associated with the particle surface may have an arbitrary distribution, whereas the electric double layers adjoining the particle and cavity surfaces are taken to be thin relative to the particle size and the spacing between the solid surfaces. The electric current and magnetic flux density distributions are solved for the particle and fluid phases of arbitrary electric conductivities and magnetic permeabilities. Applying a generalized reciprocal theorem to the Stokes equations with a Lorentz force term resulting from these density distributions for the fluid motion, we obtain explicit formulas for the translational and angular velocities of the colloidal sphere valid for all values of the particle-to-cavity size ratio. The particle velocities decrease monotonically with an increase in this size ratio. For the limiting case of an infinitely large cavity, our result reduces to the relevant solution for an unconfined spherical particle. The boundary effect on the movement of the particle with interfacial self-electrochemical reactions induced by the magnetohydrodynamic force is equivalent to that in sedimentation and much stronger than that in general phoretic motions. PMID- 23444996 TI - Interatomic methods for the dispersion energy derived from the adiabatic connection fluctuation-dissipation theorem. AB - Interatomic pairwise methods are currently among the most popular and accurate ways to include dispersion energy in density functional theory calculations. However, when applied to more than two atoms, these methods are still frequently perceived to be based on ad hoc assumptions, rather than a rigorous derivation from quantum mechanics. Starting from the adiabatic connection fluctuation dissipation (ACFD) theorem, an exact expression for the electronic exchange correlation energy, we demonstrate that the pairwise interatomic dispersion energy for an arbitrary collection of isotropic polarizable dipoles emerges from the second-order expansion of the ACFD formula upon invoking the random-phase approximation (RPA) or the full-potential approximation. Moreover, for a system of quantum harmonic oscillators coupled through a dipole-dipole potential, we prove the equivalence between the full interaction energy obtained from the Hamiltonian diagonalization and the ACFD-RPA correlation energy. This property makes the Hamiltonian diagonalization an efficient method for the calculation of the many-body dispersion energy. In addition, we show that the switching function used to damp the dispersion interaction at short distances arises from a short range screened Coulomb potential, whose role is to account for the spatial spread of the individual atomic dipole moments. By using the ACFD formula, we gain a deeper understanding of the approximations made in the interatomic pairwise approaches, providing a powerful formalism for further development of accurate and efficient methods for the calculation of the dispersion energy. PMID- 23444997 TI - Molecular electrostatic potential at the atomic sites in the effective core potential approximation. AB - Considering calculations of the molecular electrostatic potential at the atomic sites (MEP@AS) in the presence of effective core potentials (ECP), we found that the consequent use of the definition of MEP@AS based on the energy derivative with respect to nuclear charge leads to a formula that differs by one term from the result of simple application of Coulomb's law. We have developed a general method to analytically treat derivatives of ECP with respect to nuclear charge. Benchmarking calculations performed on a set of simple molecules show that our formula leads to a systematic decrease in the error connected with the introduction of ECP when compared to all-electron results. Because of a straightforward implementation and relatively low costs of the developed procedure we suggest to use it by default. PMID- 23444998 TI - ACKS2: atom-condensed Kohn-Sham DFT approximated to second order. AB - A new polarizable force field (PFF), namely atom-condensed Kohn-Sham density functional theory approximated to second order (ACKS2), is proposed for the efficient computation of atomic charges and linear response properties of extended molecular systems. It is derived from Kohn-Sham density functional theory (KS-DFT), making use of two novel ingredients in the context of PFFs: (i) constrained atomic populations and (ii) the Legendre transform of the Kohn-Sham kinetic energy. ACKS2 is essentially an extension of the Electronegativity Equalization Method (EEM) [W. J. Mortier, S. K. Ghosh, and S. Shankar, J. Am. Chem. Soc. 108, 4315 (1986)] in which two major EEM shortcomings are fixed: ACKS2 predicts a linear size-dependence of the dipole polarizability in the macroscopic limit and correctly describes the charge distribution when a molecule dissociates. All ACKS2 parameters are defined as atoms-in-molecules expectation values. The implementation of ACKS2 is very similar to that of EEM, with only a small increase in computational cost. PMID- 23444999 TI - Density functionals for static, dynamical, and strong correlation. AB - In this work, our exact-exchange-based static + dynamical correlation density functional [A. D. Becke, J. Chem. Phys. 122, 064101 (2005)] is generalized to include "strong" correlation, i.e., accurate computations on dissociating chemical systems without breaking space or spin symmetries and without using multi-determinantal reference states. Also, we introduce a strong-correlation benchmark set composed of space- and spin-symmetrized open-shell atoms on which the generalized functional is tested. Initial results are very promising. PMID- 23445000 TI - Comparison of finite difference based methods to obtain sensitivities of stochastic chemical kinetic models. AB - Sensitivity analysis is a powerful tool in determining parameters to which the system output is most responsive, in assessing robustness of the system to extreme circumstances or unusual environmental conditions, in identifying rate limiting pathways as a candidate for drug delivery, and in parameter estimation for calculating the Hessian of the objective function. Anderson [SIAM J. Numer. Anal. 50, 2237 (2012)] shows the advantages of the newly developed coupled finite difference (CFD) estimator over the common reaction path (CRP) [M. Rathinam, P. W. Sheppard, and M. Khammash, J. Chem. Phys. 132, 034103 (2010)] estimator. In this paper, we demonstrate the superiority of the CFD estimator over the common random number (CRN) estimator in a number of scenarios not considered previously in the literature, including the sensitivity of a negative log likelihood function for parameter estimation, the sensitivity of being in a rare state, and a sensitivity with fast fluctuating species. In all examples considered, the superiority of CFD over CRN is demonstrated. We also provide an example in which the CRN method is superior to the CRP method, something not previously observed in the literature. These examples, along with Anderson's results, lead to the conclusion that CFD is currently the best estimator in the class of finite difference estimators of stochastic chemical kinetic models. PMID- 23445001 TI - Open-shell pair interaction energy decomposition analysis (PIEDA): formulation and application to the hydrogen abstraction in tripeptides. AB - An open-shell extension of the pair interaction energy decomposition analysis (PIEDA) within the framework of the fragment molecular orbital (FMO) method is developed. The open-shell PIEDA method allows the analysis of inter- and intramolecular interactions in terms of electrostatic, exchange-repulsion, charge transfer, dispersion, and optional polarization energies for molecular systems with a radical or high-spin fragment. Taking into account the low computational cost and scalability of the FMO and PIEDA methods, the new scheme provides a means to characterize the stabilization of radical and open-shell sites in biologically relevant species. The open-shell PIEDA is applied to the characterization of intramolecular interactions in capped trialanine upon hydrogen abstraction (HA) at various sites on the peptide. Hydrogen abstraction reaction is the first step in the oxidative pathway initiated by reactive oxygen or nitrogen species, associated with oxidative stress. It is found that HA results in significant geometrical reorganization of the trialanine peptide. Depending on the HA site, terminal interactions in the radical fold conformers may become weaker or stronger compared to the parent molecule, and often change the character of the non-covalent bonding from amide stacking to hydrogen bonding. PMID- 23445002 TI - Exploring the role of internal friction in the dynamics of unfolded proteins using simple polymer models. AB - Recent experiments showed that the reconfiguration dynamics of unfolded proteins are often adequately described by simple polymer models. In particular, the Rouse model with internal friction (RIF) captures internal friction effects as observed in single-molecule fluorescence correlation spectroscopy (FCS) studies of a number of proteins. Here we use RIF, and its non-free draining analog, Zimm model with internal friction, to explore the effect of internal friction on the rate with which intramolecular contacts can be formed within the unfolded chain. Unlike the reconfiguration times inferred from FCS experiments, which depend linearly on the solvent viscosity, the first passage times to form intramolecular contacts are shown to display a more complex viscosity dependence. We further describe scaling relationships obeyed by contact formation times in the limits of high and low internal friction. Our findings provide experimentally testable predictions that can serve as a framework for the analysis of future studies of contact formation in proteins. PMID- 23445003 TI - Total, elastic, and inelastic cross sections for positron and electron collisions with tetrahydrofuran. AB - We present total, elastic, and inelastic cross sections for positron and electron scattering from tetrahydrofuran (THF) in the energy range between 1 and 5000 eV. Total cross sections (TCS), positronium formation cross sections, the summed inelastic integral cross sections (ICS) for electronic excitations and direct ionization, as well as elastic differential cross sections (DCS) at selected incident energies, have been measured for positron collisions with THF. The positron beam used to carry out these experiments had an energy resolution in the range 40-100 meV (full-width at half-maximum). We also present TCS results for positron and electron scattering from THF computed within the independent atom model using the screening corrected additivity rule approach. In addition, we calculated positron-impact elastic DCS and the sum over all inelastic ICS (except rotations and vibrations). While our integral and differential positron cross sections are the first of their kind, we compare our TCS with previous literature values for this species. We also provide a comparison between positron and electron-impact cross sections, in order to uncover any differences or similarities in the scattering dynamics with these two different projectiles. PMID- 23445004 TI - Experimental and theoretical cross sections for positron collisions with 3 hydroxy-tetrahydrofuran. AB - Cross section results from a joint experimental and theoretical investigation into positron scattering from 3-hydroxy-tetrahydrofuran (3H-THF) are presented. Total and positronium (Ps) formation cross sections have been measured from 1 to 190 eV using the positron beamline at the Australian National University, which has an energy resolution between 60 and 100 meV. The total cross section (TCS) and the elastic and total inelastic integral cross sections in the energy range between 1 and 1000 eV have been computed within the Independent Atom Model using the Screening Corrected Additivity Rule approach. In addition, we have calculated elastic differential cross sections at selected incident energies. Our computations represent the first theoretical results reported for this target species, while our measured Ps formation cross sections are also novel. Comparison of the present TCS with the previous results from the University of Trento shows a good level of agreement at the lowest energies. We also provide a comparison between the present cross sections for 3H-THF and those from our earlier study on the parent molecule tetrahydrofuran. PMID- 23445005 TI - Classical dynamics of state-resolved hyperthermal O((3)P) + H2O((1)A1) collisions. AB - Classical dynamics calculations are performed for O((3)P) + H2O((1)A1) collisions from 2 to 10 km s(-1) (4.1-101.3 kcal mol(-1)), focusing on product internal energies. Several methods are used to produce ro-vibrationally state-resolved product cross sections and to enforce zero-point maintenance from analysis of the classical trajectories. Two potential energy surfaces are used: (1) a recently developed set of global reactive surfaces for the three lowest triplet states which model OH formation, H elimination to make H + OOH, O-atom exchange, and collisional excitation and (2) a non-reactive surface used in past classical and quantum collision studies. Comparisons to these previous studies suggest that for H2O vibrational excitation, classical dynamics which include gaussian binning procedures and/or selected zero-point maintenance algorithms can produce results which approximate quantum scattering cross sections fairly well. Without these procedures, the classical cross sections can be many orders of magnitude greater than the quantum cross sections for exciting the bending vibration of H2O, especially near threshold. The classical cross section over-estimate is due to energy borrowing from stretching modes which dip below zero-point values. For results on the reactive surfaces, the present calculations show that at higher velocities there is an unusually large amount of product internal excitation. For OOH, where 40% of available collision energy goes into internal motion, the excited product vibrational and rotational energy distributions are relatively flat and values of the OOH rotational angular momentum exceed J = 100. Other product channel distributions show an exponential fall-off with energy consistent with an energy gap law. The present detailed distributions and cross sections can serve as a guide for future hyperthermal measurements of this system. PMID- 23445006 TI - Coherent pi-electron dynamics of (P)-2,2'-biphenol induced by ultrashort linearly polarized UV pulses: angular momentum and ring current. AB - The results of a theoretical investigation of coherent pi-electron dynamics for nonplanar (P)-2,2'-biphenol induced by ultrashort linearly polarized UV pulses are presented. Expressions for the time-dependent coherent angular momentum and ring current are derived by using the density matrix method. The time dependence of these coherences is determined by the off-diagonal density matrix element, which can be obtained by solving the coupled equations of motion of the electronic-state density matrix. Dephasing effects on coherent angular momentum and ring current are taken into account within the Markov approximation. The magnitudes of the electronic angular momentum and current are expressed as the sum of expectation values of the corresponding operators in the two phenol rings (L and R rings). Here, L (R) denotes the phenol ring in the left (right)-hand side of (P)-2,2'-biphenol. We define the bond current between the nearest neighbor carbon atoms Ci and Cj as an electric current through a half plane perpendicular to the Ci-Cj bond. The bond current can be expressed in terms of the inter-atomic bond current. The inter-atomic bond current (bond current) depends on the position of the half plane on the bond and has the maximum value at the center. The coherent ring current in each ring is defined by averaging over the bond currents. Since (P)-2,2'-biphenol is nonplanar, the resultant angular momentum is not one-dimensional. Simulations of the time-dependent coherent angular momentum and ring current of (P)-2,2'-biphenol excited by ultrashort linearly polarized UV pulses are carried out using the molecular parameters obtained by the time-dependent density functional theory (TD-DFT) method. Oscillatory behaviors in the time-dependent angular momentum (ring current), which can be called angular momentum (ring current) quantum beats, are classified by the symmetry of the coherent state, symmetric or antisymmetric. The bond current of the bridge bond linking the L and R rings is zero for the symmetric coherent state, while it is nonzero for the antisymmetric coherent state. The magnitudes of ring current and ring current-induced magnetic field are also evaluated, and their possibility as a control parameter in ultrafast switching devices is discussed. The present results give a detailed description of the theoretical treatment reported in our previous paper [H. Mineo, M. Yamaki, Y. Teranish, M. Hayashi, S. H. Lin, and Y. Fujimura, J. Am. Chem. Soc. 134, 14279 (2012)]. PMID- 23445007 TI - Characteristic oxygen K-edge circular dichroism spectra of amino acid films by improved measurement technique. AB - Circular dichroism (CD) spectroscopy in the soft x-ray energy region is a new tool to study the local structure of chiral materials. In this paper, we introduce a method to measure high-quality CD spectra in the oxygen K-edge energy region. Characteristic CD spectra of thin films of the amino acids L-tyrosine and L-aspartic acid are reported and compared with those of films of L-alanine and L serine. The signals from the oxygen 1s -> pi* transitions of COO-, which is a common moiety in these amino acids, reflect the local geometry of each amino acid. PMID- 23445008 TI - Effect of geometrical orientation on the charge-transfer energetics of supramolecular (tetraphenyl)-porphyrin/C60 dyads. AB - The charge transfer (CT) excited state energies of donor-acceptor (D/A) pairs determine the achievable open-circuit voltage of D/A-based organic solar cell devices. Changes in the relative orientation of donor-acceptor pairs at the interface influence the frontier orbital energy levels, which impacts the dissociation of bound excitons at the D/A-interface. We examine the effect of relative orientation on CT excited state energies of porphyrin-fullerene dyads. The donors studied are base- and Zn-tetraphenyl porphyrin coupled to C60 as the acceptor molecule in an end-on configuration. We compare the energetics of a few low-lying CT states for the end-on geometry to our previously calculated CT energetics of a co-facial orientation. The calculated CT excitation energies are larger for the end-on orientation in comparison to the co-facial structure by about 0.7 eV, which primarily occurs due to a decrease in exciton binding energy in going from the co-facial to the end-on orientation. Furthermore, changes in relative donor-acceptor orientation have a larger impact on the CT energies than changes in donor-acceptor distance. PMID- 23445009 TI - Effect of length on the position of negative differential resistance and realization of multifunction in fused oligothiophenes based molecular device. AB - The length modulation of electron transport properties for molecular devices based on fused oligothiophenes has been investigated theoretically using a combination of non-equilibrium Green's functions and first-principles density functional theory. The results show that the lengths of the molecules have a distinct influence on the position of negative differential resistance (NDR) of the molecular devices. By exploring the effect on transmission properties of substituent groups, hexathieno[3,2-b:2',3'-d]thiophene with -NH2 and -NO2 substituents (model L) can be regard as a good candidate of multifunctional molecular device, which shows excellent rectifying performance (the largest rectification ration is 14.3 at 1.2 V) and clear NDR behavior (at 1.4 V). PMID- 23445010 TI - Classical calculations of radiative association in absence of electronic transitions. AB - A formula for the cross section of radiative association where no electronic transitions take place is derived and tested for diatomic molecules. The approach is based on classical mechanics and therefore it is valid for direct, i.e., non resonant, radiative association. For the formation of carbon monoxide (CO) and the cyano radical (CN), in the X1Sigma+ and A1Pi states, respectively, the treatment reproduces the baselines of the cross sections obtained using quantum mechanical perturbation theory. The method overestimates the formation cross section of potassium sodide (NaK) by about 8%. For the lower mass diatoms hydrogen fluoride (HF) and deuterium hydride (HD), the formula overestimates the cross sections by 12% and 60%, respectively. The formula can be used alone for estimates of radiative association rate constants, or in combination with Breit Wigner theory to include resonance contributions. PMID- 23445011 TI - Spin-orbit corrected full-dimensional potential energy surfaces for the two lowest-lying electronic states of FH2O and dynamics for the F + H2O -> HF + OH reaction. AB - The lowest two electronic states of FH2O both correlate adiabatically to the F(2P) + H2O and HF + OH(X2Pi) asymptotes, thus facilitating the title reaction. To understand the reaction dynamics, global potential energy surfaces (PESs) for the two electronic states are constructed based on more than 30,000 points at the Davidson corrected multi-state multi-reference configuration interaction level. Spin-orbit corrections at the complete active space self-consistent field level are included in both PESs. The spin-orbit corrected ground state PES retains a relatively deep pre-reaction van der Waals well and a "reactant-like" transition state with a classical barrier of 4.2 kcal/mol. The spin-orbit corrected excited state PES has, on the other hand, a very shallow pre-reaction van der Waals complex and a much higher (17.6 kcal/mol) classical barrier, also featuring a "reactant-like" transition state. The adiabatic F + H2O -> HF + OH reaction dynamics on these two PESs are investigated using both quasi-classical trajectory and full-dimensional wave packet methods. Both reaction pathways produce internally excited HF and relatively cold OH, consistent with a direct abstraction mechanism. In addition, the spin-orbit corrections on the ground electronic state have a limited impact on the dynamics. PMID- 23445012 TI - Infrared identification of the sigma-complex of Cl-C6H6 in the reaction of chlorine atom and benzene in solid para-hydrogen. AB - The reaction of a chlorine atom with benzene (C6H6) is important in organic chemistry, especially in site-selective chlorination reactions, but its product has been a subject of debate for five decades. Previous experimental and theoretical studies provide no concrete conclusion on whether the product is a pi or sigma-form of the Cl-C6H6 complex. We took advantage of the diminished cage effect of para-hydrogen (p-H2) to produce Cl in situ to react with C6H6 (or C6D6) upon photolysis of a Cl2/C6H6 (or C6D6)/p-H2 matrix at 3.2 K. The infrared spectrum, showing intense lines at 1430.5, 833.6, 719.8, 617.0, and 577.4 cm(-1), and several weaker ones for Cl-C6H6, and the deuterium shifts of observed new lines unambiguously indicate that the product is a 6-chlorocyclohexadienyl radical, i.e., the sigma-complex of Cl-C6H6. Observation of the sigma-complex rather than the pi-complex indicates that the sigma-complex is more stable in solid p-H2 at 3.2 K. The spectral information is crucial for further investigations of the Cl + C6H6 reaction either in the gaseous or solution phase. PMID- 23445013 TI - Adsorption of hydrogen on neutral and charged fullerene: experiment and theory. AB - Helium droplets are doped with fullerenes (either C60 or C70) and hydrogen (H2 or D2) and investigated by high-resolution mass spectrometry. In addition to pure helium and hydrogen cluster ions, hydrogen-fullerene complexes are observed upon electron ionization. The composition of the main ion series is (H2)(n)HC(m)(+) where m = 60 or 70. Another series of even-numbered ions, (H2)(n)C(m)(+), is slightly weaker in stark contrast to pure hydrogen cluster ions for which the even-numbered series (H2)(n)(+) is barely detectable. The ion series (H2)(n)HC(m)(+) and (H2)(n)C(m)(+) exhibit abrupt drops in ion abundance at n = 32 for C60 and 37 for C70, indicating formation of an energetically favorable commensurate phase, with each face of the fullerene ion being covered by one adsorbate molecule. However, the first solvation layer is not complete until a total of 49 H2 are adsorbed on C60(+); the corresponding value for C70(+) is 51. Surprisingly, these values do not exhibit a hydrogen-deuterium isotope effect even though the isotope effect for H2/D2 adsorbates on graphite exceeds 6%. We also observe doubly charged fullerene-deuterium clusters; they, too, exhibit abrupt drops in ion abundance at n = 32 and 37 for C60 and C70, respectively. The findings imply that the charge is localized on the fullerene, stabilizing the system against charge separation. Density functional calculations for C60 hydrogen complexes with up to five hydrogen atoms provide insight into the experimental findings and the structure of the ions. The binding energy of physisorbed H2 is 57 meV for H2C60(+) and (H2)2C60(+), and slightly above 70 meV for H2HC60(+) and (H2)2HC60(+). The lone hydrogen in the odd-numbered complexes is covalently bound atop a carbon atom but a large barrier of 1.69 eV impedes chemisorption of the H2 molecules. Calculations for neutral and doubly charged complexes are presented as well. PMID- 23445014 TI - Vibrational corrections to the first hyperpolarizability of the lithium salt of pyridazine Li-H3C4N2. AB - In this work we report results of vibrational corrections to the polarizability and first hyperpolarizability of the lithium salt of pyridazine Li-H3C4N2 obtained at the second-order Moller-Plesset theory level with the aug-cc-pVDZ basis set. The calculations were carried out by means of the perturbation theoretical method of Bishop and Kirtman and also using a variational approach proposed here. The results obtained show that at the static limit, the pure vibrational corrections for the polarizability and first hyperpolarizability have the same order of magnitude of the corresponding electronic contributions. Comparisons between the results obtained through the two methods show that the perturbation theoretical method is not suitable to treat the system studied, while the variational methodology presented seems to be an alternative approach to treat anharmonic systems. PMID- 23445015 TI - Application of smooth exterior scaling method to calculate the high harmonic generation spectra. AB - We have calculated the high harmonic generation spectra from Xe atom by imposing different kinds of absorbing potentials. Owing to the center of inversion of the model system, one should get odd harmonics only. However, using negative imaginary potentials as an absorbing boundary condition, we have also got even order harmonics along with the odd order harmonics. These non-odd order harmonics are generated due to the spurious reflections occurring at the grid boundary. On the contrary, when smooth exterior scaling methods are used as an absorbing boundary condition, only odd order harmonics are obtained. Hence, smooth exterior scaling methods impose proper absorbing boundary condition. PMID- 23445016 TI - Structural and spectroscopic study of the linear proton-bound complex of PN with HNP+. AB - This work reports the results of high level ab initio calculations of the PN HNP(+) complex and the corresponding hydrogen migration transition state. The geometries, rotational constants, harmonic vibrational frequencies, and energetics of each species involved in the complex are reported. A reduced dimensional 2D and 4D potential energy surface is constructed and used to obtain 2D and 4D vibrational states. The results of this study show excellent correlation to available experimental data for PN. The presented results can facilitate both laboratory and interstellar observations of this novel and strongly interacting linear proton-bound complex. PMID- 23445017 TI - Full-configuration-interaction study of the metal-insulator transition in model systems: Peierls dimerization in H(n) rings and chains. AB - The Peierls dimerization with associated metal-insulator transition is studied in a model systems with ab initio methods. These are chains and rings H(N) of hydrogen atoms treated by full CI using a minimal STO-3G atomic orbital basis for N = 6 to N = 14. We describe and discuss in some detail the potential energy surface governing Peierls' dimerization and study the localization tensor as the indicator of the metal-insulator transition. Results for linear chains and rings are compared. PMID- 23445018 TI - Fermi resonance in solid CO2 under pressure. AB - The symmetric-stretching fundamental (nu1) and the bending first overtone (2nu2) of CO2, which are accidentally degenerate with the same symmetry, undergo a Fermi resonance and give rise to two Raman bands with a frequency difference of 107 cm( 1) and an intensity ratio of 2.1. Both the frequency difference and intensity ratio can be varied by pressure applied to CO2 in condensed phases, which has been utilized as a spectroscopic geobarometer for minerals with CO2 inclusion. This study calculates the pressure dependence of the Fermi dyad frequency difference and intensity ratio by combining the embedded-fragment second-order Moller-Plesset perturbation calculations of harmonic frequencies of solid CO2 under pressure and the coupled-cluster singles and doubles with noniterative triples and vibrational configuration-interaction calculations of anharmonic frequencies of molecular CO2. It reproduces frequency difference quantitatively and intensity ratio qualitatively up to 10 GPa. The analysis of the results is shown to render strong support for one particular order of unperturbed frequencies, nu1 > 2nu2, in both the gas and solid phases, which has been a matter of controversy for decades. PMID- 23445019 TI - Effect of local structures on structural evolution during crystallization in undercooled metallic glass-forming liquids. AB - The effect of local structures on structural evolution during the crystallization of undercooled ZrCu metallic glass-forming liquid was studied via molecular dynamics simulations. It is found that body-centered-cubic (bcc)-like clusters play a key role in structural evolution during crystallization. In contrast to previous speculations, the number of bcc-like crystal nuclei does not change much before the onset of crystallization. Instead, the development of a bcc-like critical nucleus during annealing leads to a strong spatial correlation with other nuclei in its surroundings, forming a crystalline structure template. It is also found that the size distribution of bcc-like nuclei follows a power-law form with an exponential cutoff in the early stage of annealing, but changes to a pure power-law behavior just before the onset of crystallization. This implies that the crystalline structure template has fractal feature and the undercooled liquids evolve to a self-organized critical state before the onset of crystallization, which might trigger the subsequent rapid crystallization. According to the graph theory analysis, it is also found that the observed large scatter of the onset time of crystallization in different liquid samples results from the connectivity of the bcc-like clusters. PMID- 23445020 TI - Primary and secondary relaxation process in plastically crystalline cyanocyclohexane studied by 2H nuclear magnetic resonance. I. AB - We study the main (alpha-) and secondary (beta-) relaxation in the plastically crystalline (PC) phase of cyanocyclohexane by various 2H nuclear magnetic resonance (NMR) methods (line-shape, spin-lattice relaxation, stimulated echo, and two-dimensional spectra) above and below the glass transition temperature T(g) = 134 K. Our results regarding the alpha-process demonstrate that molecular motion is not governed by the symmetry of the lattice. Rather it is similar to the one reported for structural glass formers and can be modeled by a reorientation proceeding via a distribution of small and large angular jumps. A solid-echo line-shape analysis regarding the beta-process below T(g) yields again very similar results when compared to those of the structural glass formers ethanol and toluene. Hence we cannot confirm an intramolecular origin for the beta-process in cyanocyclohexane. The fast beta-process in the PC phase allows for the first time a detailed 2H NMR study of the process also at T > T(g): an additional minimum in the spin-lattice relaxation time reflecting the beta process is found. Furthermore the solid-echo spectra show a distinct deviation from the rigid limit Pake pattern, which allows a direct determination of the temperature dependent spatial restriction of the process. In Part II of this work, a quantitative analysis is carried out, where we demonstrate that within the model of a "wobbling in a cone" the mean cone angle increases above T(g) and the corresponding relaxation strength is compared to dielectric results. PMID- 23445021 TI - Primary and secondary relaxation process in plastically crystalline cyanocyclohexane studied by 2H nuclear magnetic resonance. II. Quantitative analysis. AB - We analyze the results of our previously reported 2H nuclear magnetic resonance (NMR) experiments in the plastically crystalline (PC) phase of cyanocyclohexane (Part I of this work) to study the fast secondary relaxation (or beta-process) in detail. Both, the occurrence of an additional minimum in the spin-lattice relaxation T1 and the pronounced effects arising in the solid-echo spectrum above the glass transition temperature T(g) = 134 K, allow for a direct determination of the restricting geometry of the beta-process in terms of the "wobbling-in-a cone" model. Whereas at temperatures below T(g) the reorientation is confined to rather small solid angles (below 10 degrees ), the spatial restriction decreases strongly with temperature above T(g), i.e., the distribution of cone angles shifts continuously towards higher values. The beta-process in the PC phase of cyanocyclohexane proceeds via the same mechanism as found in structural glass formers. This is substantiated by demonstrating the very similar behavior (for T < T(g)) of spin-lattice relaxation, stimulated echo decays, and spectral parameters when plotted as a function of (taken from dielectric spectroscopy). We do, however, not observe a clear-cut relation between the relaxation strength of the beta-process observed by NMR (calculated within the wobbling-in-a-cone model) and dielectric spectroscopy. PMID- 23445022 TI - Investigation of direct and indirect phonon-mediated bond excitation in alpha RDX. AB - We evaluate whether lattice or internal phonons dominate the thermal excitation of the N-N bonds in alpha-cyclotrimethylene trinitramine (alpha-RDX) by computing the fractional contributions of phonon modes to the excitation of all atomic interactions. We derive a method to compute these contributions, which we call mode energy fractions, from the phonon eigenvectors and a splitting of the dynamical matrix. This enables identification of phonon modes that most strongly excite the N-N bonds that play a key role in molecular decomposition of alpha RDX. Correlating these fractions with the mode populations and contributions to the specific heat and thermal conductivity, we analyze how thermal energy is distributed by phonons following a passing shock. Contrary to the common explanation that thermal energy is transferred to the N-N bonds indirectly, by internal phonons, we find that lattice phonons dominate this thermal energy transfer, implying that energy flow follows a direct route. We also comment on implications of these results for non-shock decomposition of alpha-RDX. PMID- 23445023 TI - Benchmark oxygen-oxygen pair-distribution function of ambient water from x-ray diffraction measurements with a wide Q-range. AB - Four recent x-ray diffraction measurements of ambient liquid water are reviewed here. Each of these measurements represents a significant development of the x ray diffraction technique applied to the study of liquid water. Sources of uncertainty from statistical noise, Q-range, Compton scattering, and self scattering are discussed. The oxygen-hydrogen contribution to the measured x-ray scattering pattern was subtracted using literature data to yield an experimental determination, with error bars, of the oxygen-oxygen pair-distribution function, g(OO)(r), which essentially describes the distribution of molecular centers. The extended Q-range and low statistical noise of these measurements has significantly reduced truncation effects and related errors in the g(OO)(r) functions obtained. From these measurements and error analysis, the position and height of the nearest neighbor maximum in g(OO)(r) were found to be 2.80(1) A and 2.57(5) respectively. Numerical data for the coherent differential x-ray scattering cross-section I(X)(Q), the oxygen-oxygen structure factor S(OO)(Q), and the derived g(OO)(r) are provided as benchmarks for calibrating force-fields for water. PMID- 23445024 TI - A DFT study of the NO dissociation on gold surfaces doped with transition metals. AB - The NO dissociation on a series of doped gold surfaces (type TM(n)@Au(111) or TM(n)@Au(110), with TM(n) = Ni, Ir, Rh, or Ag and referring n to the number of dopant atoms per unit cell) was investigated through periodic density functional theory calculations. Generally, doping of Au(111) and Au(110) matrices was found to strengthen the interaction with NO species, with the exception of Ag, and was found to increase the energy barrier for dissociation, with the exception of Ni on Au(111). The calculations suggest that the NO dissociation is only possible in the case of the Ir@Au(110) bimetallic surface but only at high temperatures. The increase of the contents of Ir on Au(110) was found to improve significantly the catalytic activity of gold towards the NO dissociation (E(act) = ~1 eV). Nevertheless, this energy barrier is almost the double of that calculated for NO dissociation on pure Ir(110). However, mixing the two most interesting dopant atoms resulted in a catalyst model of the type Ir@Ni(110) that was found to decrease the energy barrier to values close to those calculated for pure Ir surfaces, i.e., ~0.4 eV, and at the same time the dissociation reaction became mildly exothermic. PMID- 23445025 TI - Specific surface area of overlapping spheres in the presence of obstructions. AB - This study considers the random placement of uniform sized spheres, which may overlap, in the presence of another set of randomly placed (hard) spheres, which do not overlap. The overlapping spheres do not intersect the hard spheres. It is shown that the specific surface area of the collection of overlapping spheres is affected by the hard spheres, such that there is a minimum in the specific surface area as a function of the relative size of the two sets of spheres. The occurrence of the minimum is explained in terms of the break-up of pore connectivity. The configuration can be considered to be a simple model of the structure of a porous composite material. In particular, the overlapping particles represent voids while the hard particles represent fillers. Example materials are pervious concrete, metallurgical coke, ice cream, and polymer composites. We also show how the material properties of such composites are affected by the void structure. PMID- 23445026 TI - Imaging single electron spin in a molecule trapped within a nanocavity of tunable dimension. AB - Control of magnetism at the nanoscale is shown by a reversible transfer of an electron to and from a single molecule within the tunable gap of a scanning tunneling microscope. The addition of an electron to magnesium porphine changes the molecule from the diamagnetic state to the paramagnetic state. The existence of the single unpaired electron in the molecule is confirmed by spectroscopy and spatial imaging of the many body Kondo state and inelastic spin excitation between the Zeeman levels at 600 mK and up to 9 Tesla magnetic field. Here, we show that the spin is delocalized in an extended molecular orbital, in contrast to the spatially confined d and f states in atoms and magnetic centers in molecules. Furthermore, by tuning the dimension of the tunneling gap and visualizing the spectroscopic images, the inelastic spin-flip scatterings are shown to underlie the formation of the Kondo state. PMID- 23445027 TI - Many-body effects for critical Casimir forces. AB - Within mean-field theory we calculate the scaling functions associated with critical Casimir forces for a system consisting of two spherical colloids immersed in a binary liquid mixture near its consolute point and facing a planar, homogeneous substrate. For several geometrical arrangements and boundary conditions we analyze the normal and the lateral critical Casimir forces acting on one of the two colloids. We find interesting features such as a change of sign of these forces upon varying either the position of one of the colloids or the temperature. By subtracting the pairwise forces from the total force we are able to determine the many-body forces acting on one of the colloids. We have found that the many-body contribution to the total critical Casimir force is more pronounced for small colloid-colloid and colloid-substrate distances, as well as for temperatures close to criticality, where the many-body contribution to the total force can reach up to 25%. PMID- 23445028 TI - Exchange resonance in MDM nanolayer systems: experiment and theory. AB - Exchange resonance spectra of three sandwich devices containing nanolayers of Cr, Mn, Co, Ni, and Eu were recorded at 77 K. We found that these spectra are significantly different from those obtained earlier for Fe-SiO2-Au three-layer nanosandwich device. Detailed theoretical approach was developed to analyze the recorded spectra, g-factor values, and relaxation properties of the spin polarized states in the nanolayers. We found that the g-factor values and spin lattice relaxation rates may be adequately described by the spin-orbit scattering mechanism. Electric charge density fluctuations may also contribute to spin lattice relaxation in nanolayers. Second-order effects in the relaxation mechanism were also briefly considered. PMID- 23445029 TI - Phase behaviour and the random phase approximation for ultrasoft restricted primitive models. AB - Phase separation of the ultrasoft restricted primitive model (URPM) with gaussian charges is re-investigated in the random phase approximation (RPA)--the "Level A" approximation discussed by Nikoubashman, Hansen, and Kahl [J. Chem. Phys. 137, 094905 (2012)]. We find that the RPA predicts a region of low temperature vapour liquid coexistence, with a critical density much lower than that observed in either simulations or more refined approximations (we also remark that the RPA critical point for a related model with Bessel charges can be solved analytically). This observation suggests that the hierarchy of approximations introduced by Nikoubashman et al. should be analogous to those introduced by Fisher and Levin for the restricted primitive model [Phys. Rev. Lett. 71, 3826 (1993)], which makes the inability of these approximations to capture the observed URPM phase behaviour even more worthy of investigation. PMID- 23445030 TI - Symmetry effects in electrostatic interactions between two arbitrarily charged spherical shells in the Debye-Huckel approximation. AB - Inhomogeneous charge distributions have important repercussions on electrostatic interactions in systems of charged particles but are often difficult to examine theoretically. We investigate how electrostatic interactions are influenced by patchy charge distributions exhibiting certain point group symmetries. We derive a general form of the electrostatic interaction energy of two permeable, arbitrarily charged spherical shells in the Debye-Huckel approximation and apply it to the case of particles with icosahedral, octahedral, and tetrahedral inhomogeneous charge distributions. We analyze in detail how charge distribution symmetry modifies the interaction energy and find that local charge inhomogeneities reduce the repulsion of two overall equally charged particles, while sufficient orientational variation in the charge distribution can turn the minimum interaction energy into an attraction. Additionally, we show that larger patches and thus lower symmetries and wave numbers result in bigger attraction given the same variation. PMID- 23445031 TI - Study of the smecticA-hexaticB phase transition in homeotropic single domain samples of 65OBC liquid crystal by photopyroelectric calorimetry. AB - The smecticA-hexaticB phase transition was studied in a homeotropic single domain sample and in a non-aligned sample of n-hexyl-4'-n-pentyloxybiphenyl-4 carboxylate liquid crystal compound to probe the effect of different amount of defects on the phase transition. The specific heat, the thermal diffusivity and the enthalpy exchange were monitored over the transition and, at the same time, polarization microscopy observations could be carried out. The transition during the first cooling run was found to be accompanied by a considerably larger defect annealing in the non-aligned sample than in the homeotropic one, but the critical behaviour of the specific heat remained substantially the same. PMID- 23445032 TI - Kinetic pathways of sphere-to-cylinder transition in diblock copolymer melt under electric field. AB - Phase transition from body-centered-cubic spheres to cylinders in a diblock copolymer melt under an external electric field is investigated by means of real space dynamical self-consistent field theory. Different phase transition kinetic pathways and different cylindrical domains arrangements of the final phase are observed depending on the strength and direction of the applied electric field. Various transient states have been identified depending on the electric field being applied along [111], [100], and [110] directions. The electric field should be above a certain threshold value in order the transition to occur. A "dynamic critical exponent" of the transition is found to be about 3/2, consistent with other order-order transitions in diblock copolymers under electric field. PMID- 23445033 TI - Effects of the interaction range on structural phases of flexible polymers. AB - We systematically investigate how the range of interaction between non-bonded monomers influences the formation of structural phases of elastic, flexible polymers. Massively parallel replica-exchange simulations of a generic, coarse grained model, performed partly on graphics processing units and in multiple gaussian modified ensembles, pave the way for the construction of the structural phase diagram, parametrized by interaction range and temperature. Conformational transitions between gas-like, liquid, and diverse solid (pseudo) phases are identified by microcanonical statistical inflection-point analysis. We find evidence for finite-size effects that cause the crossover of "collapse" and "freezing" transitions for very short interaction ranges. PMID- 23445034 TI - Effects of compositional polydispersity on gradient copolymer melts. AB - The phase behavior of gradient copolymers is studied theoretically using random phase approximation (RPA) and self-consistent field theory (SCFT), focusing on the effects of monomer sequence distribution, or compositional polydispersity, of the polymer chains. The stability of the disordered phase is examined using RPA analysis, whereas the ordered phases of the system are studied using SCFT calculations. It is discovered that the critical domain spacing increases and the disorder-order transition temperature moves to higher values with the increase of the compositional polydispersity. SCFT results reveal that, depending on the value of the degree of segregation, structural change due to the different chain to-chain monomer sequence distribution is controlled by two different mechanisms. PMID- 23445035 TI - Comment on "The diatomic dication CuZn2+ in the gas phase" [J. Chem. Phys. 135, 034306 (2011)]. AB - In this Comment, the density functional theory (DFT) calculations carried out by Diez et al. [J. Chem. Phys. 135, 034306 (2011)] are revised within the framework of the coupled-cluster single double triple method. These more sophisticated calculations allow us to show that the (2)Sigma(+) electronic ground state of CuZn(2+), characterized as the metastable ground state by DFT calculations, is a repulsive state instead. The (2)Delta and (2)Pi metastable states of CuZn(2+), on the other hand, should be responsible for the formation mechanism of the dication through the near-resonant electron transfer CuZn(+) + Ar(+) -> CuZn(2+) + Ar reaction. PMID- 23445038 TI - Biomechanical engineering--year in review. PMID- 23445041 TI - Society awards. PMID- 23445039 TI - Acknowledgments for the special issue: "There is no I in BED". PMID- 23445042 TI - Journal of Biomechanical Engineering--legacy paper. PMID- 23445043 TI - 2011 Richard Skalak Award. PMID- 23445044 TI - 2012 Editors' choice papers. PMID- 23445046 TI - Evolving strategies in mechanobiology to more effectively treat damaged musculoskeletal tissues. AB - In this paper, we had four primary objectives. (1) We reviewed a brief history of the Lissner award and the individual for whom it is named, H.R. Lissner. We examined the type (musculoskeletal, cardiovascular, and other) and scale (organism to molecular) of research performed by prior Lissner awardees using a hierarchical paradigm adopted at the 2007 Biomechanics Summit of the US National Committee on Biomechanics. (2) We compared the research conducted by the Lissner award winners working in the musculoskeletal (MS) field with the evolution of our MS research and showed similar trends in scale over the past 35 years. (3) We discussed our evolving mechanobiology strategies for treating musculoskeletal injuries by accounting for clinical, biomechanical, and biological considerations. These strategies included studies to determine the function of the anterior cruciate ligament and its graft replacements as well as novel methods to enhance soft tissue healing using tissue engineering, functional tissue engineering, and, more recently, fundamental tissue engineering approaches. (4) We concluded with thoughts about future directions, suggesting grand challenges still facing bioengineers as well as the immense opportunities for young investigators working in musculoskeletal research. Hopefully, these retrospective and prospective analyses will be useful as the ASME Bioengineering Division charts future research directions. PMID- 23445047 TI - Methods for characterizing convective cryoprobe heat transfer in ultrasound gel phantoms. AB - While cryosurgery has proven capable in treating of a variety of conditions, it has met with some resistance among physicians, in part due to shortcomings in the ability to predict treatment outcomes. Here we attempt to address several key issues related to predictive modeling by demonstrating methods for accurately characterizing heat transfer from cryoprobes, report temperature dependent thermal properties for ultrasound gel (a convenient tissue phantom) down to cryogenic temperatures, and demonstrate the ability of convective exchange heat transfer boundary conditions to accurately describe freezing in the case of single and multiple interacting cryoprobe(s). Temperature dependent changes in the specific heat and thermal conductivity for ultrasound gel are reported down to -150 degrees C for the first time here and these data were used to accurately describe freezing in ultrasound gel in subsequent modeling. Freezing around a single and two interacting cryoprobe(s) was characterized in the ultrasound gel phantom by mapping the temperature in and around the "iceball" with carefully placed thermocouple arrays. These experimental data were fit with finite-element modeling in COMSOL Multiphysics, which was used to investigate the sensitivity and effectiveness of convective boundary conditions in describing heat transfer from the cryoprobes. Heat transfer at the probe tip was described in terms of a convective coefficient and the cryogen temperature. While model accuracy depended strongly on spatial (i.e., along the exchange surface) variation in the convective coefficient, it was much less sensitive to spatial and transient variations in the cryogen temperature parameter. The optimized fit, convective exchange conditions for the single-probe case also provided close agreement with the experimental data for the case of two interacting cryoprobes, suggesting that this basic characterization and modeling approach can be extended to accurately describe more complicated, multiprobe freezing geometries. Accurately characterizing cryoprobe behavior in phantoms requires detailed knowledge of the freezing medium's properties throughout the range of expected temperatures and an appropriate description of the heat transfer across the probe's exchange surfaces. Here we demonstrate that convective exchange boundary conditions provide an accurate and versatile description of heat transfer from cryoprobes, offering potential advantages over the traditional constant surface heat flux and constant surface temperature descriptions. In addition, although this study was conducted on Joule-Thomson type cryoprobes, the general methodologies should extend to any probe that is based on convective exchange with a cryogenic fluid. PMID- 23445049 TI - Biaxial tension of fibrous tissue: using finite element methods to address experimental challenges arising from boundary conditions and anisotropy. AB - Planar biaxial tension remains a critical loading modality for fibrous soft tissue and is widely used to characterize tissue mechanical response, evaluate treatments, develop constitutive formulas, and obtain material properties for use in finite element studies. Although the application of tension on all edges of the test specimen represents the in situ environment, there remains a need to address the interpretation of experimental results. Unlike uniaxial tension, in biaxial tension the applied forces at the loading clamps do not transmit fully to the region of interest (ROI), which may lead to improper material characterization if not accounted for. In this study, we reviewed the tensile biaxial literature over the last ten years, noting experimental and analysis challenges. In response to these challenges, we used finite element simulations to quantify load transmission from the clamps to the ROI in biaxial tension and to formulate a correction factor that can be used to determine ROI stresses. Additionally, the impact of sample geometry, material anisotropy, and tissue orientation on the correction factor were determined. Large stress concentrations were evident in both square and cruciform geometries and for all levels of anisotropy. In general, stress concentrations were greater for the square geometry than the cruciform geometry. For both square and cruciform geometries, materials with fibers aligned parallel to the loading axes reduced stress concentrations compared to the isotropic tissue, resulting in more of the applied load being transferred to the ROI. In contrast, fiber-reinforced specimens oriented such that the fibers aligned at an angle to the loading axes produced very large stress concentrations across the clamps and shielding in the ROI. A correction factor technique was introduced that can be used to calculate the stresses in the ROI from the measured experimental loads at the clamps. Application of a correction factor to experimental biaxial results may lead to more accurate representation of the mechanical response of fibrous soft tissue. PMID- 23445051 TI - 50 years of computer simulation of the human thermoregulatory system. AB - This paper presents an updated and augmented version of the Wissler human thermoregulation model that has been developed continuously over the past 50 years. The existing Fortran code is translated into C with extensive embedded commentary. A graphical user interface (GUI) has been developed in Python to facilitate convenient user designation of input and output variables and formatting of data presentation. Use of the code with the GUI is described and demonstrated. New physiological elements were added to the model to represent the hands and feet, including the unique vascular structures adapted for heat transfer associated with glabrous skin. The heat transfer function and efficacy of glabrous skin is unique within the entire body based on the capacity for a very high rate of blood perfusion and the novel capability for dynamic regulation of blood flow. The model was applied to quantify the absolute and relative contributions of glabrous skin flow to thermoregulation for varying levels of blood perfusion. The model also was used to demonstrate how the unique features of glabrous skin blood flow may be recruited to implement thermal therapeutic procedures. We have developed proprietary methods to manipulate the control of glabrous skin blood flow in conjunction with therapeutic devices and simulated the effect of these methods with the model. PMID- 23445052 TI - Mechanics of healthy and functionally diseased mitral valves: a critical review. AB - The mitral valve is a complex apparatus with multiple constituents that work cohesively to ensure unidirectional flow between the left atrium and ventricle. Disruption to any or all of the components-the annulus, leaflets, chordae, and papillary muscles-can lead to backflow of blood, or regurgitation, into the left atrium, which deleteriously effects patient health. Through the years, a myriad of surgical repairs have been proposed; however, a careful appreciation for the underlying structural mechanics can help optimize long-term repair durability and inform medical device design. In this review, we aim to present the experimental methods and significant results that have shaped the current understanding of mitral valve mechanics. Data will be presented for all components of the mitral valve apparatus in control, pathological, and repaired conditions from human, animal, and in vitro studies. Finally, current strategies of patient specific and noninvasive surgical planning will be critically outlined. PMID- 23445050 TI - Flexing computational muscle: modeling and simulation of musculotendon dynamics. AB - Muscle-driven simulations of human and animal motion are widely used to complement physical experiments for studying movement dynamics. Musculotendon models are an essential component of muscle-driven simulations, yet neither the computational speed nor the biological accuracy of the simulated forces has been adequately evaluated. Here we compare the speed and accuracy of three musculotendon models: two with an elastic tendon (an equilibrium model and a damped equilibrium model) and one with a rigid tendon. Our simulation benchmarks demonstrate that the equilibrium and damped equilibrium models produce similar force profiles but have different computational speeds. At low activation, the damped equilibrium model is 29 times faster than the equilibrium model when using an explicit integrator and 3 times faster when using an implicit integrator; at high activation, the two models have similar simulation speeds. In the special case of simulating a muscle with a short tendon, the rigid-tendon model produces forces that match those generated by the elastic-tendon models, but simulates 2 54 times faster when an explicit integrator is used and 6-31 times faster when an implicit integrator is used. The equilibrium, damped equilibrium, and rigid tendon models reproduce forces generated by maximally-activated biological muscle with mean absolute errors less than 8.9%, 8.9%, and 20.9% of the maximum isometric muscle force, respectively. When compared to forces generated by submaximally-activated biological muscle, the forces produced by the equilibrium, damped equilibrium, and rigid-tendon models have mean absolute errors less than 16.2%, 16.4%, and 18.5%, respectively. To encourage further development of musculotendon models, we provide implementations of each of these models in OpenSim version 3.1 and benchmark data online, enabling others to reproduce our results and test their models of musculotendon dynamics. PMID- 23445053 TI - Computational analysis of non-spherical particle transport and deposition in shear flow with application to lung aerosol dynamics--a review. AB - All naturally occurring and most man-made solid particles are nonspherical. Examples include air-pollutants in the nano- to micro-meter range as well as blood constituents, drug particles, and industrial fluid-particle streams. Focusing on the modeling and simulation of inhaled aerosols, theories for both spherical and nonspherical particles are reviewed to analyze the contrasting transport and deposition phenomena of spheres and equivalent spheres versus ellipsoids and fibers. PMID- 23445048 TI - Subject-specific analysis of joint contact mechanics: application to the study of osteoarthritis and surgical planning. AB - Advances in computational mechanics, constitutive modeling, and techniques for subject-specific modeling have opened the door to patient-specific simulation of the relationships between joint mechanics and osteoarthritis (OA), as well as patient-specific preoperative planning. This article reviews the application of computational biomechanics to the simulation of joint contact mechanics as relevant to the study of OA. This review begins with background regarding OA and the mechanical causes of OA in the context of simulations of joint mechanics. The broad range of technical considerations in creating validated subject-specific whole joint models is discussed. The types of computational models available for the study of joint mechanics are reviewed. The types of constitutive models that are available for articular cartilage are reviewed, with special attention to choosing an appropriate constitutive model for the application at hand. Issues related to model generation are discussed, including acquisition of model geometry from volumetric image data and specific considerations for acquisition of computed tomography and magnetic resonance imaging data. Approaches to model validation are reviewed. The areas of parametric analysis, factorial design, and probabilistic analysis are reviewed in the context of simulations of joint contact mechanics. Following the review of technical considerations, the article details insights that have been obtained from computational models of joint mechanics for normal joints; patient populations; the study of specific aspects of joint mechanics relevant to OA, such as congruency and instability; and preoperative planning. Finally, future directions for research and application are summarized. PMID- 23445055 TI - Review: the role of biomechanical modeling in the rupture risk assessment for abdominal aortic aneurysms. AB - AAA disease is a serious condition and a multidisciplinary approach including biomechanics is needed to better understand and more effectively treat this disease. A rupture risk assessment is central to the management of AAA patients, and biomechanical simulation is a powerful tool to assist clinical decisions. Central to such a simulation approach is a need for robust and physiologically relevant models. Vascular tissue senses and responds actively to changes in its mechanical environment, a crucial tissue property that might also improve the biomechanical AAA rupture risk assessment. Specifically, constitutive modeling should not only focus on the (passive) interaction of structural components within the vascular wall, but also how cells dynamically maintain such a structure. In this article, after specifying the objectives of an AAA rupture risk assessment, the histology and mechanical properties of AAA tissue, with emphasis on the wall, are reviewed. Then a histomechanical constitutive description of the AAA wall is introduced that specifically accounts for collagen turnover. A test case simulation clearly emphasizes the need for constitutive descriptions that remodels with respect to the mechanical loading state. Finally, remarks regarding modeling of realistic clinical problems and possible future trends conclude the article. PMID- 23445054 TI - System-level biomechanical approach for the evaluation of term and preterm pregnancy maintenance. AB - Preterm birth is the primary contributor to perinatal morbidity and mortality, with those born prior to 32 weeks disproportionately contributing compared to those born at 32-37 weeks. Outcomes for babies born prematurely can be devastating. Parturition is recognized as a mechanical process that involves the two processes that are required to initiate labor: rhythmic myometrial contractions and cervical remodeling with subsequent dilation. Studies of parturition tend to separate these two processes rather than evaluate them as a unified system. The mechanical property characterization of the cervix has been primarily performed on isolated cervical tissue, with an implied understanding of the contribution from the uterine corpus. Few studies have evaluated the function of the uterine corpus in the absence of myometrial contractions or in relationship to retaining the fetus. Therefore, the cervical-uterine interaction has largely been neglected in the literature. We suggest that a system-level biomechanical approach is needed to understand pregnancy maintenance. To that end, this paper has two main goals. One goal is to highlight the gaps in current knowledge that need to be addressed in order to develop any comprehensive and clinically relevant models of the system. The second goal is to illustrate the utility of finite element models in understanding pregnancy maintenance of the cervical-uterine system. The paper targets an audience that includes the reproductive biologist/clinician and the engineer/physical scientist interested in biomechanics and the system level behavior of tissues. PMID- 23445057 TI - Update on grand challenge competition to predict in vivo knee loads. AB - Validation is critical if clinicians are to use musculoskeletal models to optimize treatment of individual patients with a variety of musculoskeletal disorders. This paper provides an update on the annual Grand Challenge Competition to Predict in Vivo Knee Loads, a unique opportunity for direct validation of knee contact forces and indirect validation of knee muscle forces predicted by musculoskeletal models. Three competitions (2010, 2011, and 2012) have been held at the annual American Society of Mechanical Engineers Summer Bioengineering Conference, and two more competitions are planned for the 2013 and 2014 conferences. Each year of the competition, a comprehensive data set collected from a single subject implanted with a force-measuring knee replacement is released. Competitors predict medial and lateral knee contact forces for two gait trials without knowledge of the experimental knee contact force measurements. Predictions are evaluated by calculating root-mean-square (RMS) errors and R(2) values relative to the experimentally measured medial and lateral contact forces. For the first three years of the competition, competitors used a variety of methods to predict knee contact and muscle forces, including static and dynamic optimization, EMG-driven models, and parametric numerical models. Overall, errors in predicted contact forces were comparable across years, with average RMS errors for the four competition winners ranging from 229 N to 312 N for medial contact force and from 238 N to 326 N for lateral contact force. Competitors generally predicted variations in medial contact force (highest R(2 )= 0.91) better than variations in lateral contact force (highest R(2 )= 0.70). Thus, significant room for improvement exists in the remaining two competitions. The entire musculoskeletal modeling community is encouraged to use the competition data and models for their own model validation efforts. PMID- 23445058 TI - Dual-joint modeling for estimation of total knee replacement contact forces during locomotion. AB - Model-based estimation of in vivo contact forces arising between components of a total knee replacement is challenging because such forces depend upon accurate modeling of muscles, tendons, ligaments, contact, and multibody dynamics. Here we describe an approach to solving this problem with results that are tested by comparison to knee loads measured in vivo for a single subject and made available through the Grand Challenge Competition to Predict in vivo Tibiofemoral Loads. The approach makes use of a "dual-joint" paradigm in which the knee joint is alternately represented by (1) a ball-joint knee for inverse dynamic computation of required muscle controls and (2) a 12 degree-of-freedom (DOF) knee with elastic foundation contact at the tibiofemoral and patellofemoral articulations for forward dynamic integration. Measured external forces and kinematics were applied as a feedback controller and static optimization attempted to track measured knee flexion angles and electromyographic (EMG) activity. The resulting simulations showed excellent tracking of knee flexion (average RMS error of 2.53 deg) and EMG (muscle activations within +/-10% envelopes of normalized measured EMG signals). Simulated tibiofemoral contact forces agreed qualitatively with measured contact forces, but their RMS errors were approximately 25% of the peak measured values. These results demonstrate the potential of a dual-joint modeling approach to predict joint contact forces from kinesiological data measured in the motion laboratory. It is anticipated that errors in the estimation of contact force will be reduced as more accurate subject-specific models of muscles and other soft tissues are developed. PMID- 23445056 TI - Biochemomechanics of intraluminal thrombus in abdominal aortic aneurysms. AB - Most computational models of abdominal aortic aneurysms address either the hemodynamics within the lesion or the mechanics of the wall. More recently, however, some models have appropriately begun to account for the evolving mechanics of the wall in response to the changing hemodynamic loads. Collectively, this large body of work has provided tremendous insight into this life-threatening condition and has provided important guidance for current research. Nevertheless, there has yet to be a comprehensive model that addresses the mechanobiology, biochemistry, and biomechanics of thrombus-laden abdominal aortic aneurysms. That is, there is a pressing need to include effects of the hemodynamics on both the development of the nearly ubiquitous intraluminal thrombus and the evolving mechanics of the wall, which depends in part on biochemical effects of the adjacent thrombus. Indeed, there is increasing evidence that intraluminal thrombus in abdominal aortic aneurysms is biologically active and should not be treated as homogeneous inert material. In this review paper, we bring together diverse findings from the literature to encourage next generation models that account for the biochemomechanics of growth and remodeling in patient-specific, thrombus-laden abdominal aortic aneurysms. PMID- 23445059 TI - An electromyogram-driven musculoskeletal model of the knee to predict in vivo joint contact forces during normal and novel gait patterns. AB - Computational models that predict internal joint forces have the potential to enhance our understanding of normal and pathological movement. Validation studies of modeling results are necessary if such models are to be adopted by clinicians to complement patient treatment and rehabilitation. The purposes of this paper are: (1) to describe an electromyogram (EMG)-driven modeling approach to predict knee joint contact forces, and (2) to evaluate the accuracy of model predictions for two distinctly different gait patterns (normal walking and medial thrust gait) against known values for a patient with a force recording knee prosthesis. Blinded model predictions and revised model estimates for knee joint contact forces are reported for our entry in the 2012 Grand Challenge to predict in vivo knee loads. The EMG-driven model correctly predicted that medial compartment contact force for the medial thrust gait increased despite the decrease in knee adduction moment. Model accuracy was high: the difference in peak loading was less than 0.01 bodyweight (BW) with an R(2 )= 0.92. The model also predicted lateral loading for the normal walking trial with good accuracy exhibiting a peak loading difference of 0.04 BW and an R(2 )= 0.44. Overall, the EMG-driven model captured the general shape and timing of the contact force profiles and with accurate input data the model estimated joint contact forces with sufficient accuracy to enhance the interpretation of joint loading beyond what is possible from data obtained from standard motion capture studies. PMID- 23445060 TI - Fine tuning total knee replacement contact force prediction algorithms using blinded model validation. AB - The purpose of this study was to perform a blinded comparison of model predictions of total knee replacement contact forces to in vivo forces from an instrumented prosthesis during normal walking and medial thrust gait by participating in the "Third Grand Challenge Competition to Predict in vivo Knee Loads." We also evaluated model assumptions that were critical for accurate force predictions. Medial, lateral, and total axial forces through the knee were calculated using a previously developed and validated parametric numerical model. The model uses equilibrium equations between internal and external moments and forces to obtain knee joint contact forces and calculates a range of forces at instances during the gait cycle through parametric variation of muscle activity levels. For 100 instances during a normal over-ground gait cycle, model root mean square differences from eTibia data were 292, 248, and 281 for medial, lateral, and total contact forces, respectively. For 100 instances during a medial thrust gait cycle, model root mean square differences from eTibia data were 332, 234, and 470 for medial, lateral, and total contact forces, respectively. The percent difference between measured and predicted peak total axial force was 2.89% at the first peak and 9.36% at the second peak contact force for normal walking and 3.94% at the first peak and 14.86% at the second peak contact force for medial thrust gait. After unblinding, changes to model assumptions improved medial and lateral force predictions for both gait styles but did not improve total force predictions. Axial forces computed with the model compared well to the eTibia data under blinded and unblinded conditions. Knowledge of detailed knee kinematics, namely anterior-posterior translation, appears to be critical in obtaining accurate force predictions. PMID- 23445062 TI - Computational analysis of microstructure of ultra high molecular weight polyethylene for total joint replacement. AB - Ultra high molecular weight polyethylene (UHMWPE, or ultra high), a frequently used material in orthopedic joint replacements, is often the cause of joint failure due to wear, fatigue, or fracture. These mechanical failures have been related to ultra high's strength and stiffness, and ultimately to the underlying microstructure, in previous experimental studies. Ultra high's semicrystalline microstructure consists of about 50% crystalline lamellae and 50% amorphous regions. Through common processing treatments, lamellar percentage and size can be altered, producing a range of mechanical responses. However, in the orthopedic field the basic material properties of the two microstructural phases are not typically studied independently, and their manipulation is not computationally optimized to produce desired mechanical properties. Therefore, the purpose of this study is to: (1) develop a 2D linear elastic finite element model of actual ultra high microstructure and fit the mechanical properties of the microstructural phases to experimental data and (2) systematically alter the dimensions of lamellae in the model to begin to explore optimizing the bulk stiffness while decreasing localized stress. The results show that a 2D finite element model can be built from a scanning electron micrograph of real ultra high lamellar microstructure, and that linear elastic constants can be fit to experimental results from those same ultra high formulations. Upon altering idealized lamellae dimensions, we found that bulk stiffness decreases as the width and length of lamellae increase. We also found that maximum localized Von Mises stress increases as the width of the lamellae decrease and as the length and aspect ratio of the lamellae increase. Our approach of combining finite element modeling based on scanning electron micrographs with experimental results from those same ultra high formulations and then using the models to computationally alter microstructural dimensions and properties could advance our understanding of how microstructure affects bulk mechanical properties. This advanced understanding could allow for the engineering of next-generation ultra high microstructures to optimize mechanical behavior and increase device longevity. PMID- 23445061 TI - Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge. AB - Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest. PMID- 23445063 TI - The role of collagen synthesis in ventricular and vascular adaptation to hypoxic pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is typically due to right ventricular (RV) failure. An excellent predictor of mortality in PAH is proximal pulmonary artery stiffening, which is mediated by collagen accumulation in hypoxia-induced pulmonary hypertension (HPH) in mice. We sought to investigate the impact of limiting vascular and ventricular collagen accumulation on RV function and the hemodynamic coupling efficiency between the RV and pulmonary vasculature. Inbred mice were exposed to chronic hypoxia for 10 days with either no treatment (HPH) or with treatment with a proline analog that impairs collagen synthesis (CHOP-PEG; HPH + CP). Both groups were compared to control mice (CTL) exposed only to normoxia (no treatment). An admittance catheter was used to measure pressure-volume loops at baseline and during vena cava occlusion, with mice ventilated with either room air or 8% oxygen, from which pulmonary hemodynamics, RV function, and ventricular-vascular coupling efficiency (etavvc) were calculated. Proline analog treatment limited increases in RV afterload (neither effective arterial elastance Ea nor total pulmonary vascular resistance significantly increased compared to CTL with CHOP PEG), limited the development of pulmonary hypertension (CHOP-PEG reduced right ventricular systolic pressure by 10% compared to HPH, p < 0.05), and limited RV hypertrophy (CHOP-PEG reduced RV mass by 18% compared to HPH, p < 0.005). In an acutely hypoxic state, treatment improved RV function (CHOP-PEG increased end systolic elastance Ees by 43%, p < 0.05) and maintained etavvc at control, room air levels. CHOP-PEG also decreased lung collagen content by 12% measured biochemically compared to HPH (p < 0.01), with differences evident in large and small pulmonary arteries by histology. Our results demonstrate that preventing new collagen synthesis limits pulmonary hypertension development by reducing collagen accumulation in the pulmonary arteries that affect RV afterload. In particular, the proline analog limited structural and functional changes in distal pulmonary arteries in this model of early and somewhat mild pulmonary hypertension. We conclude that collagen plays an important role in small pulmonary artery remodeling and, thereby, affects RV structure and function changes induced by chronic hypoxia. PMID- 23445065 TI - Strategies utilized to transfer weight during knee flexion and extension with rotation for individuals with a total knee replacement. AB - Functional activities in daily life can require squatting and shifting body weight during transverse plane rotations. Stability of the knee can be challenging for people with a total knee replacement (TKR) due to reduced proprioception, nonconforming articular geometry, muscle strength, and soft tissue weakness. The objective of this study was to identify strategies utilized by individuals with TKR in double-stance transferring load during rotation and flexion. Twenty-three subjects were recruited for this study: 11 TKR subjects (age: 65 +/- 6 years; BMI 27.4 +/- 4.1) and 12 healthy subjects (age: 63 +/- 7; BMI 24.6 +/- 3.8). Each subject completed a novel crossover button push task where rotation, flexion, and extension of the knee were utilized. Each subject performed two crossover reaching tasks where the subject used the opposite hand to cross over their body and press a button next to either their shoulder (high) or knee (low), then switched hands and rotated to press the opposite button, either low or high. The two tasks related to the order they pressed the buttons while crossing over, either low-to-high (L2H) or high-to-low (H2L). Force platforms measured ground reaction forces under each foot, which were then converted to lead force ratios (LFRs) based on the total force. Knee flexion angles were also measured. No statistical differences were found in the LFRs during the H2L and L2H tasks for the different groups, although differences in the variation of the loading within subjects were noted. A significant difference was found between healthy and unaffected knee angles and a strong trend between healthy and affected subject's knee angles in both H2L and L2H tasks. Large variations in the LFR at mid-task in the TKR subjects suggested possible difficulties in maintaining positional stability during these tasks. The TKR subjects maintained more of an extended knee, which is a consistent quadriceps avoidance strategy seen by other researchers in different tasks. These outcomes suggest that individuals with a TKR utilize strategies, such as keeping an extended knee, to achieve rotary tasks during knee flexion and extension. Repeated compensatory movements could result in forces that may cause difficulty over time in the hip joints or low back. Early identification of these strategies could improve TKR success and the return to activities of daily living that involve flexion and rotation. PMID- 23445064 TI - Effect of age and proteoglycan deficiency on collagen fiber re-alignment and mechanical properties in mouse supraspinatus tendon. AB - Collagen fiber realignment is one mechanism by which tendon responds to load. Re alignment is altered when the structure of tendon is altered, such as in the natural process of aging or with alterations of matrix proteins, such as proteoglycan expression. While changes in re-alignment and mechanical properties have been investigated recently during development, they have not been studied in (1) aged tendons, or (2) in the absence of key proteoglycans. Collagen fiber re alignment and the corresponding mechanical properties are quantified throughout tensile mechanical testing in both the insertion site and the midsubstance of mouse supraspinatus tendons in wild type (WT), decorin-null (Dcn(-/-)), and biglycan-null (Bgn(-/-)) mice at three different ages (90 days, 300 days, and 570 days). Percent relaxation was significantly decreased with age in the WT and Dcn( /-) tendons, but not in the Bgn(-/-) tendons. Changes with age were found in the linear modulus at the insertion site where the 300 day group was greater than the 90 day and 570 day group in the Bgn(-/-) tendons and the 90 day group was smaller than the 300 day and 570 day groups in the Dcn(-/-) tendons. However, no changes in modulus were found across age in WT tendons were found. The midsubstance fibers of the WT and Bgn(-/-) tendons were initially less aligned with increasing age. The re-alignment was significantly altered with age in the WT tendons, with older groups responding to load later in the mechanical test. This was also seen in the Dcn(-/-) midsubstance and the Bgn(-/-) insertion, but not in the other locations. Although some studies have found changes in the WT mechanical properties with age, this study did not support those findings. However, it did show fiber re-alignment changes at both locations with age, suggesting a breakdown of tendon's ability to respond to load in later ages. In the proteoglycan-null tendons however, there were changes in the mechanical properties, accompanied only by location-dependent re-alignment changes, suggesting a site-specific role for these molecules in loading. Finally, changes in the mechanical properties did not occur in concert with changes in re alignment, suggesting that typical mechanical property measurements alone are insufficient to describe how structural alterations affect tendon's response to load. PMID- 23445066 TI - In vitro evaluation of a novel hemodynamically optimized trileaflet polymeric prosthetic heart valve. AB - Calcific aortic valve disease is the most common and life threatening form of valvular heart disease, characterized by stenosis and regurgitation, which is currently treated at the symptomatic end-stages via open-heart surgical replacement of the diseased valve with, typically, either a xenograft tissue valve or a pyrolytic carbon mechanical heart valve. These options offer the clinician a choice between structural valve deterioration and chronic anticoagulant therapy, respectively, effectively replacing one disease with another. Polymeric prosthetic heart valves (PHV) offer the promise of reducing or eliminating these complications, and they may be better suited for the new transcatheter aortic valve replacement (TAVR) procedure, which currently utilizes tissue valves. New evidence indicates that the latter may incur damage during implantation. Polymer PHVs may also be incorporated into pulsatile circulatory support devices such as total artificial heart and ventricular assist devices that currently employ mechanical PHVs. Development of polymer PHVs, however, has been slow due to the lack of sufficiently durable and biocompatible polymers. We have designed a new trileaflet polymer PHV for surgical implantation employing a novel polymer-xSIBS-that offers superior bio-stability and durability. The design of this polymer PHV was optimized for reduced stresses, improved hemodynamic performance, and reduced thrombogenicity using our device thrombogenicity emulation (DTE) methodology, the results of which have been published separately. Here we present our new design, prototype fabrication methods, hydrodynamics performance testing, and platelet activation measurements performed in the optimized valve prototype and compare it to the performance of a gold standard tissue valve. The hydrodynamic performance of the two valves was comparable in all measures, with a certain advantage to our valve during regurgitation. There was no significant difference between the platelet activation rates of our polymer valve and the tissue valve, indicating that similar to the latter, its recipients may not require anticoagulation. This work proves the feasibility of our optimized polymer PHV design and brings polymeric valves closer to clinical viability. PMID- 23445068 TI - A novel method for quantifying spatial correlations between patterns of atherosclerosis and hemodynamic factors. AB - Studies investigating the relation between the focal nature of atherosclerosis and hemodynamic factors are employing increasingly rigorous approaches to map the disease and calculate hemodynamic metrics. However, no standardized methodology exists to quantitatively compare these distributions. We developed a statistical technique that can be used to determine if hemodynamic and lesion maps are significantly correlated. The technique, which is based on a surrogate data analysis, does not require any assumptions (such as linearity) on the nature of the correlation. Randomized sampling was used to ensure the independence of data points, another basic assumption of commonly-used statistical methods that is often disregarded. The novel technique was used to compare previously-obtained maps of lesion prevalence in aortas of immature and mature cholesterol-fed rabbits to corresponding maps of wall shear stress, averaged across several animals in each age group. A significant spatial correlation was found in the proximal descending thoracic aorta, but not further downstream. Around intercostal branch openings the correlation was borderline significant in immature but not in mature animals. The results confirm the need for further investigation of the relation between the localization of atherosclerosis and blood flow, in conjunction with appropriate statistical techniques such as the method proposed here. PMID- 23445067 TI - Regional structural and biomechanical alterations of the ovine main pulmonary artery during postnatal growth. AB - The engineering foundation for novel approaches for the repair of congenital defects that involve the main pulmonary artery (PA) must rest on an understanding of changes in the structure-function relationship that occur during postnatal maturation. In the present study, we quantified the postnatal growth patterns in structural and biomechanical behavior in the ovine PA in the juvenile and adult stages. The biaxial mechanical properties and collagen and elastin fiber architecture were studied in four regions of the PA wall, with the collagen recruitment of the medial region analyzed using a custom biaxial mechanical multiphoton microscopy system. Circumferential residual strain was also quantified at the sinotubular junction and bifurcation locations, which delimit the PA. The PA wall demonstrated significant mechanical anisotropy, except in the posterior region where it was nearly isotropic. Overall, we observed only moderate changes in regional mechanical properties with growth. We did observe that the medial and lateral locations experience a moderate increase in anisotropy. There was an average of about 24% circumferential residual stain present at the luminal surface in the juvenile stage that decreased to 16% in the adult stage with a significant decrease at the bifurcation, implying that the PA wall remodels toward the bifurcation with growth. There were no measurable changes in collagen and elastin content of the tunica media with growth. On average, the collagen fiber recruited more rapidly with strain in the adult compared to the juvenile. Interestingly, the PA thickness remained constant with growth. When this fact is combined with the observed stable overall mechanical behavior and increase in vessel diameter with growth, a simple Laplace Law wall stress estimate suggests an increase in effective PA wall stress with postnatal maturation. This observation is contrary to the accepted theory of maintenance of homeostatic stress levels in the regulation of vascular function and suggests alternative mechanisms regulate postnatal somatic growth. Understanding the underlying mechanisms, incorporating important structural features during growth, will help to improve our understanding of congenital defects of the PA and lay the basis for functional duplication in their repair and replacement. PMID- 23445069 TI - Direct measurement of the permeability of human cervical tissue. AB - The mechanical integrity of the uterine cervix is critical for a pregnancy to successfully reach full term. It must be strong to retain the fetus throughout gestation and then undergo a remodeling and softening process before labor for delivery of the fetus. It is believed that cervical insufficiency (CI), a condition in pregnancy resulting in preterm birth (PTB), is related to a cervix with compromised mechanical strength which cannot resist deformation caused by external forces generated by the growing fetus. Such PTBs are responsible for infant developmental problems and in severe cases infant mortality. To understand the etiologies of CI, our overall research goal is to investigate the mechanical behavior of the cervix. Permeability is a mechanical property of hydrated collagenous tissues that dictates the time-dependent response of the tissue to mechanical loading. The goal of this study was to design a novel soft tissue permeability testing device and to present direct hydraulic permeability measurements of excised nonpregnant (NP) and pregnant (PG) human cervical tissue from women with different obstetric histories. Results of hydraulic permeability testing indicate repeatability for specimens from single patients, with an order of magnitude separating the NP and PG group means (2.1 +/- 1.4*10(-14) and 3.2 +/ 4.8*10(-13)m(4)/N[middle dot]s, respectively), and large variability within the NP and PG sample groups. Differences were found between samples with similar obstetric histories, supporting the view that medical history may not be a good predictor of permeability (and therefore mechanical behavior) and highlighting the need for patient-specific measurements of cervical mechanical properties. The permeability measurements from this study will be used in future work to model the constitutive material behavior of cervical tissue and to develop in vivo diagnostic tools to stage the progression of labor. PMID- 23445070 TI - Mechanical properties of viscoelastic media by local frequency estimation of divergence-free wave fields. AB - Magnetic resonance elastography (MRE) is an imaging modality with which mechanical properties can be noninvasively measured in living tissue. Magnetic resonance elastography relies on the fact that the elastic shear modulus determines the phase velocity and, hence the wavelength, of shear waves which are visualized by motion-sensitive MR imaging. Local frequency estimation (LFE) has been used to extract the local wavenumber from displacement wave fields recorded by MRE. LFE -based inversion is attractive because it allows material parameters to be estimated without explicitly invoking the equations governing wave propagation, thus obviating the need to numerically compute the Laplacian. Nevertheless, studies using LFE have not explicitly addressed three important issues: (1) tissue viscoelasticity; (2) the effects of longitudinal waves and rigid body motion on estimates of shear modulus; and (3) mechanical anisotropy. In the current study we extend the LFE technique to (1) estimate the (complex) viscoelastic shear modulus in lossy media; (2) eliminate the effects of longitudinal waves and rigid body motion; and (3) determine two distinct shear moduli in anisotropic media. The extended LFE approach is demonstrated by analyzing experimental data from a previously-characterized, isotropic, viscoelastic, gelatin phantom and simulated data from a computer model of anisotropic (transversely isotropic) soft material. PMID- 23445071 TI - Microscale fiber network alignment affects macroscale failure behavior in simulated collagen tissue analogs. AB - A tissue's microstructure determines its failure properties at larger length scales, however, the specific relationship between microstructure and macroscopic failure in native and engineered soft tissues (such as capsular ligaments, aortic aneurysms, or vascular grafts) has proven elusive. In this study, variations in the microscale fiber alignment in collagen gel tissue analogs were modeled in order to understand their effects on macroscale damage and failure outcomes. The study employed a multiscale finite-element (FE) model for damage and failure in collagen-based materials. The model relied on microstructural representative volume elements (RVEs) that consisted of stochastically-generated networks of discrete type-I collagen fibers. Fiber alignment was varied within RVEs and between layers of RVEs in a macroscopic FE model of a notched dogbone geometry. The macroscale stretch and the microscale response of fibers for each of the differently aligned cases were compared as the dogbone was uniaxially extended to failure. Networks with greater fiber alignment parallel to the direction of extension failed at smaller strains (with a 6-22% reduction in the Green strain at failure), however, at greater grip forces (a 28-60% increase) than networks with fibers aligned perpendicular to the extension. Alternating layers of crisscrossed network alignments (aligned +/-45 deg to the direction of extension) failed at smaller strains but at greater grip forces than those created using one fiber alignment type. In summary, variations in microscale structure via fiber alignment produced different macroscale failure trends. To conclude, these findings may be significant in the realm of tissue engineering and in soft tissue biomechanics. PMID- 23445073 TI - Exploring molecular and clinical management of patients in the follow up of the HPV related uterine lesions. PMID- 23445072 TI - Articular cartilage wear characterization with a particle sizing and counting analyzer. AB - Quantitative measurements of cartilage wear have been challenging, with no method having yet emerged as a standard. This study tested the hypothesis that latest generation particle analyzers are capable of detecting cartilage wear debris generated during in vitro loading experiments that last 24 h or less, by producing measurable content significantly above background noise levels otherwise undetectable through standard biochemical assays. Immature bovine cartilage disks (4 mm diameter, 1.3 mm thick) were tested against glass using reciprocal sliding under unconfined compression creep for 24 h. Control groups were used to assess various sources of contamination. Results demonstrated that cartilage samples subjected to frictional loading produced particulate volume significantly higher than background noise and contamination levels at all tested time points (1, 2, 6, and 24 h, p < 0.042). The particle counter was able to detect very small levels of wear (less than 0.02% of the tissue sample by volume), whereas no significant differences were observed in biochemical assays for collagen or glycosaminoglycans among any of the groups or time points. These findings confirm that latest-generation particle analyzers are capable of detecting very low wear levels in cartilage experiments conducted over a period no greater than 24 h. PMID- 23445074 TI - Evaluating the use of different positional strategies for sentence selection in biomedical literature summarization. AB - BACKGROUND: The position of a sentence in a document has been traditionally considered an indicator of the relevance of the sentence, and therefore it is frequently used by automatic summarization systems as an attribute for sentence selection. Sentences close to the beginning of the document are supposed to deal with the main topic and thus are selected for the summary. This criterion has shown to be very effective when summarizing some types of documents, such as news items. However, this property is not likely to be found in other types of documents, such as scientific articles, where other positional criteria may be preferred. The purpose of the present work is to study the utility of different positional strategies for biomedical literature summarization. RESULTS: We have evaluated three different positional strategies: (1) awarding the sentences at the beginning of the document, (2) preferring those at the beginning and end of the document, and (3) weighting the sentences according to the section in which they appear. To this end, we have implemented two summarizers, one based on semantic graphs and the other based on concept frequencies, and evaluated the summaries they produce when combined with each of the positional strategies above using ROUGE metrics. Our results indicate that it is possible to improve the quality of the summaries by weighting the sentences according to the section in which they appear (~17% improvement in ROUGE-2 for the graph-based summarizer and ~20% for the frequency-based summarizer), and that the sections containing the more salient information are the Methods and Material and the Discussion and Results ones. CONCLUSIONS: It has been found that the use of traditional positional criteria that award sentences at the beginning and/or the end of the document are not helpful when summarizing scientific literature. In contrast, a more appropriate strategy is that which weights sentences according to the section in which they appear. PMID- 23445075 TI - Negative ion photoelectron spectroscopy confirms the prediction that (CO)5 and (CO)6 each has a singlet ground state. AB - Cyclobutane-1,2,3,4-tetraone has been both predicted and found to have a triplet ground state, in which a b2g sigma molecular orbital (MO) and an a2u pi MO are each singly occupied. In contrast, (CO)5 and (CO)6 have each been predicted to have a singlet ground state. These predictions have been tested by generating the (CO)5(*-) and (CO)6(*-) radical anions in the gas phase, using electrospray vaporization of solutions of, respectively, the croconate (CO)5(2-) and rhodizonate (CO)6(2-) dianions. The negative ion photoelectron (NIPE) spectrum of the (CO)5(*-) radical anion gives an electron affinity of EA = 3.830 eV for formation of the singlet ground state of (CO)5. The triplet is found to be higher in energy by 0.850 eV (19.6 kcal/mol). The NIPE spectrum of the (CO)6(*-) radical anion gives EA = 3.785 eV for forming the singlet ground state of (CO)6, with the triplet state higher in energy by 0.915 eV (21.1 kcal/mol). (RO)CCSD(T)/aug-cc pVTZ//(U)B3LYP/6-311+G(2df) calculations give EA values that are only approximately 1 kcal/mol lower than those measured and DeltaE(ST) values that are 2-3 kcal/mol higher than those obtained from the NIPE spectra. Calculations of the Franck-Condon factors for transitions from the ground state of each radical anion, (CO)n(*-) to the lowest singlet and triplet states of the n = 4-6 neutrals, nicely reproduce all of the observed vibrational features in the low binding energy regions of all three NIPE spectra. Thus, the calculations of both the energies and vibrational structures of the two lowest energy bands in each of the NIPE spectra support the interpretation of the spectra in terms of a singlet ground state for (CO)5 and (CO)6 but a triplet ground state for (CO)4. PMID- 23445076 TI - Comparing daily versus less frequent blood glucose monitoring in patients with mild gestational diabetes. AB - OBJECTIVE: The prevalence of gestational diabetes mellitus (GDM) is increasing. This study was designed to determine if different frequencies in blood glucose (BG) monitoring, without regard to other variables, would allow timely detection of hyperglycemia requiring pharmacologic treatment in mild GDMs. METHODS: Retrospective chart review, limited to self-glucose monitoring values, of 120 mild GDM patients who required pharmacologic therapy. Three data sets were constructed from each patient's BG log: (1) all available BG; (2) every other day's BG blocked; (3) only every third day's BG available for review. The blocked BG datasets were compared with daily values. RESULTS: 95% and 97% of subjects were started on pharmacologic therapy before or within 7 d of the reference date using every other day and every third day BG logs, respectively. CONCLUSIONS: Based exclusively on BG values, without regard to other clinical information, every other day or every third day BG monitoring in mild GDM does not delay the initiation of pharmacologic therapy. PMID- 23445077 TI - Are yellow sticky traps an effective method for control of sweetpotato whitefly, Bemisia tabaci, in the greenhouse or field? AB - Yellow sticky traps are a common method for monitoring many pests, but it has not been shown whether they could be used as a control method. In this study the impact of yellow sticky traps on the population dynamics of the sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) was determined in the greenhouse and field. In the greenhouse, yellow sticky traps significantly suppressed the population increase of adult and immature whiteflies. The whitefly densities in the greenhouse with traps were significantly lower than the greenhouse without traps. In the field, traps did not have a significant impact on the population dynamics of adult and immature whiteflies. The densities in fields with traps were very similar to fields without traps. These results suggest that yellow sticky traps can be used as an effective method for the control of whiteflies in the greenhouse, but not in the field. This information will prove useful for the effective management of whiteflies in greenhouses. PMID- 23445079 TI - Phenolic composition analysis and gene expression in developing seeds of yellow- and black-seeded Brassica napus. AB - Breeders have focused on yellow-seeded Brassica napus (rapeseed) for its better quality compared with the black-seeded variety. Moreover, flavonoids have been associated with this kind of rapeseed. In this study, we applied lipid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS(n)) to compare flavonoids in developing seeds of natural black-seeded B. napus and yellow-seeded introgression lines selected from progenies of B. napus-Sinapis alba somatic hybrids. Aside from the most abundant phenolic compounds (sinapine and sinapic acid) and 1, 2-disinapoylglucose, 16 different flavonoids were identified and quantified, including (-)-epicatechin, five monocharged oligomers of (-)-epicatechin ([DP 2](-), [DP 3](-), [DP 4] [DP 2](-) B2 and [DP 2](-) B5), quercetin, kaempferol, isorhamnetin-dihexoside, kaempferol-sinapoyl-trihexoside, isorhamnetin-sinapoyl-trihexoside, isorhamnetin-hexoside-sulfate, and isorhamnetin-3-O-glucoside. Most of the flavonoids accumulated with seed development, whereas some rapidly decreased during maturation. The content of these flavonoids were lower in the yellow-seeded materials than in the black seeds. In addition, variations of insoluble procyanidin oligomers and soluble phenolic acids were observed among both rapeseed varieties. Transcriptome changes of genes participating in the flavonoid pathway were discovered by quantitative reverse transcription polymerase chain reaction analysis. Consistent with flavonoid changes identified by high performance liquid chromatography analysis, the expression of most genes in the flavonoid biosynthetic pathway was also downregulated. PMID- 23445080 TI - Sampling a biomarker of the human immunodeficiency virus across a synthetic nanopore. AB - One primary goal in nanobiotechnology is designing new methodologies for molecular biomedical diagnosis at stages much earlier than currently possible and without use of expensive reagents and sophisticated equipment. In this work, we show the proof of principle for single-molecule detection of the nucleocapsid protein 7 (NCp7), a protein biomarker of the HIV-1 virus, using synthetic nanopores and the resistive-pulse technique. The biosensing mechanism relied upon specific interactions between NCp7 and aptamers of stem-loop 3 (SL3) in the packaging domain of the retroviral RNA genome. One critical step of this study was the choice of the optimal size of the nanopores for accurate, label-free determinations of the dissociation constant of the NCp7 protein-SL3 RNA aptamer complex. Therefore, we systematically investigated the NCp7 protein-SL3 RNA aptamer complex employing two categories of nanopores in a silicon nitride membrane: (i) small, whose internal diameter was smaller than 6 nm, and (ii) large, whose internal diameter was in the range of 7 to 15 nm. Here, we demonstrate that only the use of nanopores with an internal diameter that is smaller than or comparable with the largest cross-sectional size of the NCp7-SL3 aptamer complex enables accurate measurement of the dissociation constant between the two interacting partners. Notably, this determination can be accomplished without the need for prior nanopore functionalization. Moreover, using small solid-state nanopores, we demonstrate the ability to detect drug candidates that inhibit the binding interactions between NCp7 and SL3 RNA by using a test case of N-ethylmaleimide. PMID- 23445081 TI - Dementia behavioural and psychiatric symptoms: effect on caregiver's sleep. AB - AIMS AND OBJECTIVES: To examine caregiver sleep quality, especially in relation to the daytime and night-time behaviours and psychological symptoms exhibited by persons with dementias. BACKGROUND: Caregivers of persons with dementias experience poorer sleep in comparison with noncaregivers, and poor sleep is related to negative health outcomes. The reasons for caregivers' poor sleep are complex, and it is known that the night-time behaviours of the persons with dementia contribute to caregiver sleep disruption. However, the frequency of behavioural and psychological symptoms of dementia has hitherto not been sufficiently explored as a contributing factor to poor caregiver sleep. DESIGN: A nonexperimental cross-sectional design. METHODS: Eighty caregivers completed questionnaires on the frequency of behavioural and psychological symptoms of the persons with dementia, the Dementia Severity Rating Scale, the Pittsburgh Sleep Quality Index and the Center for Epidemiologic Studies Depression Scale. RESULTS: Poor sleep was reported with awakenings by the persons with dementia occurring for more than half of the caregivers. The frequency of behaviours and symptoms did not make a unique contribution to the variance of caregivers' global sleep. The frequency of behaviours, and specifically of agitation and apathy, contributed to the variance in subjective sleep quality, as defined by the caregivers' appraisal of their sleep. CONCLUSIONS: The findings demonstrate the relationship between (1) daytime and night-time behaviours of persons with dementias and (2) their caregivers' sleep quality and emphasise the complexity of the factors that contribute to caregiver sleep quality. RELEVANCE TO CLINICAL PRACTICE: These findings suggest that nurses should be cognizant of the relationship between daytime behaviours of the persons with dementia and the caregivers' appraisal of their sleep, realising that appraising one's sleep as poor can be a contributing factor to perpetuating sleep problems. Interventions aimed at helping the caregiver manage the persons with dementia's agitation or the caregiver's emotional response to persons with dementia apathy may improve caregivers' perception of their sleep. PMID- 23445082 TI - Construction of predictive models for recurrence and progression in >1000 patients with non-muscle-invasive bladder cancer (NMIBC) from a single centre. AB - OBJECTIVE: To construct predictive models based on the objectively calculated risks of progression and recurrence of non-muscle-invasive bladder cancer (NMIBC) in a large cohort of patients from a single centre. PATIENTS AND METHODS: Between October 1984 and March 2009 a cohort of 1019 patients (877 males; 142 females; median age 44 years) with histologically confirmed NMIBC was included in this study. Among these patients, 74% received bacillus Calmette-Guerin (BCG)-based therapy. Complete transurethral resection of bladder tumour of all visible tumours was carried out in all patients, and the stage and grade were determined. Univariate analysis and multivariate Cox regression were used to identify predictors of recurrence and progression. The studied predictors included age, sex, stage, grade, associated carcinoma in situ, tumour size, multiplicity, macroscopic appearance of the tumour, history of recurrence and type of adjuvant intravesical therapy. Multivariate logistic regression models were used to develop the 12- and 60-month recurrence and progression predictive models. The predictive accuracy of the models was assessed for discrimination as well as calibration. RESULTS: The median (range) follow-up was 44 (6-254) months. On multivariate analysis, stage, multiplicity, history of recurrence and adjuvant intravesical therapy were significantly associated with recurrence, whereas for progression only tumour grade and size were significant independent predictors. The constructed nomograms had a 64.9% and 69.4% chance of correctly distinguishing between two patients, one destined to have a recurrence and one not at 12 and 60 months, respectively. The constructed nomograms had a 70.2% and 73.5% chance of correctly distinguishing between two patients, one destined to progress and one not at 12 and 60 months, respectively. All predictive models were well calibrated. CONCLUSIONS: Based on multivariate analysis of the studied prognostic factors nomograms for predicting recurrence and progression in NMIBC were constructed. Most of the studied patients had received BCG-based therapy, making these models more closely applicable to contemporary practice than others. These predictive models have reasonable discriminative ability and are well calibrated, but require external validation before they can be applied to other populations. PMID- 23445083 TI - Hydrogen peroxide alters sternohyoid muscle function. AB - Upper airway (UA) dilator muscles are critical for the maintenance of airway patency. Injury or fatigue to this group of muscles, as observed in patients with obstructive sleep apnoea (OSA) and animal models of OSA, may leave the UA susceptible to collapse. Although the mechanisms underlying respiratory muscle dysfunction are not completely understood, there is strong evidence suggesting a link between increased production of reactive oxygen species and altered muscle function. The aim of this study was to examine the effects of H2O2 on rat sternohyoid muscle function in vitro. Sternohyoid contractile and endurance properties were examined at 35 degrees C under control or hypoxic conditions. Studies were conducted in the presence of varying concentrations of H2O2 (0, 0.01, 0.1 and 1 mM). Muscle function was also examined in the presence of antioxidants [desferoxamine (DFX), catalase] and the reducing agent dithiothreitol (DTT). H2O2 decreased muscle endurance in a concentration dependent manner. This was partially reversed by catalase, DFX and DTT. Our results suggest that oxidants may contribute to UA respiratory muscle dysfunction with implications for the control of UA patency in vivo. PMID- 23445085 TI - Addressing geographic variability in the comparative toxicity potential of copper and nickel in soils. AB - Comparative toxicity potentials (CTP), in life cycle impact assessment also known as characterization factors (CF), of copper (Cu) and nickel (Ni) were calculated for a global set of 760 soils. An accessibility factor (ACF) that takes into account the role of the reactive, solid-phase metal pool in the soil was introduced into the definition of CTP. Geographic differences in fate, accessibility, bioavailability, and terrestrial toxicity were assessed by combining the USEtox characterization model, empirical regression models, and terrestrial biotic ligand models. The median CTPs for Cu and Ni with 95% geographic variability intervals are 1.4 * 10(3) (1.7 * 10(2) to 2.0 * 10(4)) and 1.7 * 10(3) (2.1 * 10(2) to 1.1 * 10(4)) m(3)/kg . day, respectively. The geographic variability of 3.5 orders of magnitude in the CTP of Cu is mainly associated with the variability in soil organic carbon and pH. They largely influence the fate and bioavailability of Cu in soils. In contrast, the geographic variability of 3 orders of magnitude in the CTP of Ni can mainly be explained by differences in pore water concentration of magnesium (Mg(2+)). Mg(2+) competes with Ni(2+) for binding to biotic ligands, influencing the toxicity. Our findings stress the importance of dealing with geographic variability in the calculation of CTPs for terrestrial ecotoxicity of metals. PMID- 23445084 TI - Detection of influenza C virus by a real-time RT-PCR assay. AB - BACKGROUND: Influenza C virus can cause both upper and lower respiratory tract infections and has been reported to be prevalent in children. However, these infections have been under-diagnosed, and epidemiological data available are limited due to the lack of convenient detection assays. OBJECTIVE: Design and validate a real-time reverse-transcriptase PCR (rt RT-PCR) assay for the detection of influenza C. STUDY DESIGN: Respiratory samples from two primary settings, namely, children who were hospitalized or seen in the emergency department, and respiratory outbreaks for which no other viral etiology was found were used for the detection of influenza C. RESULTS AND CONCLUSIONS: The assay was sensitive and specific for the detection of influenza C. Eleven of 474 (2.32%) patients, all less than 10 years of age, were positive for influenza C. The strains clustered into two lineages, namely C/Kanagawa and C/Sao Paulo, based upon sequencing of the hemagglutinin-esterase gene. Epidemiological data showed that a higher proportion of influenza C infections occur in younger children and during the winter months. This is the first report of the detection of influenza C in Alberta, Canada, and suggests that the detection of this virus should be included in respiratory virus testing panels. PMID- 23445086 TI - Maternal thyroid parameters, body mass index and subsequent weight gain during pregnancy in healthy euthyroid women. AB - CONTEXT: Obesity and too much weight gain during gestation have a negative effect on obstetric and neonatal outcomes. OBJECTIVE: To determine the relationship between thyroid hormone parameters, body mass index (BMI) and weight gain during gestation. DESIGN: Prospective follow-up study of thyroid parameters and gestational weight gain. SETTING: Healthy pregnant women, included at first antenatal consultation. PATIENTS: Thyroid function (TSH, FT4 and TPO-Ab) was assessed at 12, 24 and 36 weeks' gestation in 1035 Dutch Caucasian women who delivered at >=37 weeks. BMI (WHO criteria) was assessed at eight weeks, and weight gain throughout gestation was also assessed using the US Institute of Medicine (IOM) criteria. MEASUREMENTS: PRIMARY OUTCOME MEASURE: a possible relationship between maternal thyroid parameters and BMI at the first trimester. SECONDARY OUTCOME MEASURE: the relationship between thyroid parameters and weight gain throughout gestation. RESULTS: At 12 weeks' gestation, BMI correlated with FT4 (r = -0.14, P < 0.001), but not with TSH (r = 0.04, P = 0.89). 415 (40%) of the women met the IOM criteria for appropriate weight gain, 326 (32%) showed less weight gain and 294 (28%) gained too much weight. At all trimesters, the latter group of women showed higher median TSH and lower median FT4 compared with those with normal weight gain. FT4 at 24 weeks' gestation (OR: 0.84, 95% CI: 0.77 0.91), younger age (OR: 0.97, 95% CI: 0.95-0.99) and primiparity (OR: 0.51, 95% CI: 0.38-0.68) were independently related to too much weight gain. CONCLUSIONS: Maternal thyroid parameters are related to both prepregnancy BMI and weight gain throughout gestation. PMID- 23445087 TI - Medical strategies to reduce amputation in patients with type 2 diabetes. AB - Lower extremity amputation is a common and disabling complication of Type 2 diabetes. Whilst the introduction of specialist multidisciplinary teams has led to a reduction in the incidence of lower extremity amputation in some centres, the overall prevalence of diabetes-related amputation has actually increased in recent decades. The aetiology of diabetes-related amputation is complex, with neuropathy, macrovascular and microvascular disease contributing significantly. Ulceration, previous amputation, increasing diabetes duration and poor long-term control of glycaemia and lipids are important risk factors for amputation in populations with diabetes. Major randomized intervention trials of blood glucose lowering or anti-hypertensive therapies in populations with diabetes have shown limited reductions in neuropathy and/or macrovascular disease, and no benefit on amputation rates. In contrast, a recent analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed a significantly reduced rate of minor, but not major amputations in patients with Type 2 diabetes treated with fenofibrate. Mechanistic studies are clearly needed to understand the basis of this benefit. PMID- 23445088 TI - For the sake of inquiry and knowledge--the inevitability of open access. PMID- 23445089 TI - Open but not free--publishing in the 21st century. PMID- 23445090 TI - Creative Commons and the openness of open access. PMID- 23445091 TI - The downside of open-access publishing. PMID- 23445092 TI - Ondansetron in pregnancy and risk of adverse fetal outcomes. AB - BACKGROUND: Ondansetron is frequently used to treat nausea and vomiting during pregnancy, but the safety of this drug for the fetus has not been well studied. METHODS: We investigated the risk of adverse fetal outcomes associated with ondansetron administered during pregnancy. From a historical cohort of 608,385 pregnancies in Denmark, women who were exposed to ondansetron and those who were not exposed were included, in a 1:4 ratio, in propensity-score-matched analyses of spontaneous abortion (1849 exposed women vs. 7396 unexposed women), stillbirth (1915 vs. 7660), any major birth defect (1233 vs. 4932), preterm delivery (1792 vs. 7168), and birth of infants at low birth weight and small for gestational age (1784 vs. 7136). In addition, estimates were adjusted for hospitalization for nausea and vomiting during pregnancy (as a proxy for severity) and the use of other antiemetics. RESULTS: Receipt of ondansetron was not associated with a significantly increased risk of spontaneous abortion, which occurred in 1.1% of exposed women and 3.7% of unexposed women during gestational weeks 7 to 12 (hazard ratio, 0.49; 95% confidence interval [CI], 0.27 to 0.91) and in 1.0% and 2.1%, respectively, during weeks 13 to 22 (hazard ratio, 0.60; 95% CI, 0.29 to 1.21). Ondansetron also conferred no significantly increased risk of stillbirth (0.3% for exposed women and 0.4% for unexposed women; hazard ratio, 0.42; 95% CI, 0.10 to 1.73), any major birth defect (2.9% and 2.9%, respectively; prevalence odds ratio, 1.12; 95% CI, 0.69 to 1.82), preterm delivery (6.2% and 5.2%; prevalence odds ratio, 0.90; 95% CI, 0.66 to 1.25), delivery of a low-birth weight infant (4.1% and 3.7%; prevalence odds ratio, 0.76; 95% CI, 0.51 to 1.13), or delivery of a small-for-gestational-age infant (10.4% and 9.2%; prevalence odds ratio, 1.13; 95% CI, 0.89 to 1.44). CONCLUSIONS: Ondansetron taken during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes. (Funded by the Danish Medical Research Council.). PMID- 23445093 TI - Nocturnal glucose control with an artificial pancreas at a diabetes camp. AB - BACKGROUND: Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS: In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS: On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS: Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.). PMID- 23445094 TI - Clinical practice. Idiopathic scoliosis in adolescents. PMID- 23445095 TI - The implications of clonal genome evolution for cancer medicine. PMID- 23445096 TI - Images in clinical medicine. Talc retinopathy. PMID- 23445097 TI - Case records of the Massachusetts General Hospital. Case 7-2013. A 77-year-old woman with long-standing unilateral thoracic pain and incontinence. PMID- 23445098 TI - Dalcetrapib in patients with an acute coronary syndrome. PMID- 23445099 TI - Dalcetrapib in patients with an acute coronary syndrome. PMID- 23445100 TI - Bedside monitoring of antiplatelet therapy for coronary stenting. PMID- 23445101 TI - Bedside monitoring of antiplatelet therapy for coronary stenting. PMID- 23445102 TI - Bedside monitoring of antiplatelet therapy for coronary stenting. PMID- 23445103 TI - Fracture risk and zoledronic acid in men with osteoporosis. PMID- 23445104 TI - Fracture risk and zoledronic acid in men with osteoporosis. PMID- 23445105 TI - Case 35-2012: A man with weakness, anorexia, and diffuse pain. PMID- 23445106 TI - Case 35-2012: A man with weakness, anorexia, and diffuse pain. PMID- 23445107 TI - Case 35-2012: A man with weakness, anorexia, and diffuse pain. PMID- 23445108 TI - Case 35-2012: A man with weakness, anorexia, and diffuse pain. PMID- 23445109 TI - ERBB2 inhibition and heart failure. PMID- 23445110 TI - ERBB2 inhibition and heart failure. PMID- 23445111 TI - Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia. PMID- 23445112 TI - Images in clinical medicine. Torus mandibularis. PMID- 23445113 TI - Clinical decisions. Mammography screening--polling results. PMID- 23445114 TI - Operant conditioning of autobiographical memory retrieval. AB - Functional avoidance is considered as one of the key mechanisms underlying overgeneral autobiographical memory (OGM). According to this view OGM is regarded as a learned cognitive avoidance strategy, based on principles of operant conditioning; i.e., individuals learn to avoid the emotionally painful consequences associated with the retrieval of specific negative memories. The aim of the present study was to test one of the basic assumptions of the functional avoidance account, namely that autobiographical memory retrieval can be brought under operant control. Here 41 students were instructed to retrieve personal memories in response to 60 emotional cue words. Depending on the condition, they were punished with an aversive sound for the retrieval of specific or nonspecific memories in an operant conditioning procedure. Analyzes showed that the course of memory specificity significantly differed between conditions. After the procedure participants punished for nonspecific memories retrieved significantly more specific memories compared to participants punished for specific memories. However, whereas memory specificity significantly increased in participants punished for specific memories, it did not significantly decrease in participants punished for nonspecific memories. Thus, while our findings indicate that autobiographical memory retrieval can be brought under operant control, they do not support a functional avoidance view on OGM. PMID- 23445116 TI - Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women. AB - PROBLEM: This study compares the frequencies of plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and its relationship with eight antiphospholipid antibodies (aPLs) in serum of 157 patients with repeated pregnancy loss (RPL). METHOD OF STUDY: PAI-1 (-675) 4G/5G polymorphism was determined using standard PCR-RFLP method. Enzyme-linked immunosorbent assay was used for the detection of aPLs against ph-serine, ph-ethanolamine, ph-inositol, ph-DL-glycerol, phosphatidic acid, annexin V, cardiolipin, and beta2-GPI. Allelic frequency and distribution of genotypes were calculated. The prevalence of the risk conferring 4G allele and 4G/4G homozygous genotype in patients and controls was compared, and the correlation between aPLs positivity and PAI-1 4G/4G genotype was tested by chi-square test. RESULTS: Statistically highly significant correlation between RPL and PAI-1 (-675) 4G/4G genotype was found. No correlation between PAI-1 ( 675) 4G/5G polymorphism and the presence of antiphospholipid antibodies in RPL patients was observed. CONCLUSIONS: PAI-1 (-675) 4G/4G homozygous genotype increases the risk of RPL independently from the aPLs positivity. PMID- 23445117 TI - Bisphenol A in relation to behavior and learning of school-age children. AB - BACKGROUND: Bisphenol A (BPA) has been shown to affect brain and behavior in rodents and nonhuman primates, but there are few studies focusing on its relationship to human neurobehavior. We aimed to investigate the relationship between environmental exposure to BPA and childhood neurobehavior. METHODS: Urinary BPA concentrations and behavioral and learning characteristics were assessed in a general population of 1,089 children, aged 8-11 years. The main outcome measures were the Child Behavior Checklist (CBCL) and the Learning Disability Evaluation Scale (LDES). RESULTS: Urinary levels of BPA were positively associated with the CBCL total problems score and negatively associated with the learning quotient from the LDES. The linear association with the CBCL anxiety/depression score and the quadratic association with the LDES listening score were significant after correction for multiple comparisons. CONCLUSIONS: Environmental exposure to BPA might be associated with childhood behavioral and learning development. The results suggest possible nonmonotonic relationships. PMID- 23445118 TI - Striated muscle involvement in experimental oral infection by herpes simplex virus type 1. AB - Herpes simplex virus type 1 is one of the most frequent causes of oral infection in humans, especially during early childhood. Several experimental models have been developed to study the pathogenesis of this virus but all of them employed adult animals. In this work, we developed an experimental model that uses mice younger than 4 days old, to more closely resemble human infection. Mice were infected subcutaneously with the prototype strain McIntyre of Herpes simplex-1, and the progression of infection was studied by immunoperoxidase. All animals died within 24-72 h post-infection, while viral antigens were found in the oral epithelium, nerves and brain. The most striking result was the finding of viral antigens in the nucleus and cytoplasm of cells belonging to striated muscles. Organotypic cultures of striated muscles were performed, and viral replication was observed in them by immunocytochemistry, electron microscopy and viral isolation. We conclude that the infection of striated muscles is present from the onset of oral infection and, eventually, could explain some clinical observations in humans. PMID- 23445119 TI - Avian polyomavirus identified in a nestling Gouldian finch (Erythrura gouldiae) in New Zealand. AB - Abstract CASE HISTORY: Four 4-5-month-old nestlings and one adult in a commercial aviary of 53 Gouldian finches (Erythrura gouldiae) died over a 2-week period in July 2000. PATHOLOGICAL FINDINGS: One nestling was necropsied and showed bronze tinged skeletal muscles, a swollen liver with haemorrhagic margins and numerous haemorrhages on serosal surfaces. The histological lesions included multifocal hepatic necrosis and haemorrhage associated with the presence of large clear or basophilic intranuclear inclusions in hepatocytes and Kupffer cells suggestive of avian polyomavirus infection. Similar inclusion bodies were present in splenic histiocytes. MOLECULAR BIOLOGY: DNA was subsequently extracted from archived portions of liver, spleen, gizzard, heart, lung and kidney. A broad spectrum nested PCR was used to detect polyomavirus which sequence analysis confirmed as finch polyomavirus. DIAGNOSIS: Avian polyomavirus. CLINICAL RELEVANCE: Avian virus infections such as polyomavirus should be suspected in cases of sudden death in nestlings, particularly in susceptible species such as psittacine and passerine birds. The archiving of tissues from unconfirmed disease outbreaks provides a valuable resource for retrospective investigations. PMID- 23445120 TI - Identification of germ cell-specific genes in mammalian meiotic prophase. AB - BACKGROUND: Mammalian germ cells undergo meiosis to produce sperm or eggs, haploid cells that are primed to meet and propagate life. Meiosis is initiated by retinoic acid and meiotic prophase is the first and most complex stage of meiosis when homologous chromosomes pair to exchange genetic information. Errors in meiosis can lead to infertility and birth defects. However, despite the importance of this process, germ cell-specific gene expression patterns during meiosis remain undefined due to difficulty in obtaining pure germ cell samples, especially in females, where prophase occurs in the embryonic ovary. Indeed, mixed signals from both germ cells and somatic cells complicate gonadal transcriptome studies. RESULTS: We developed a machine-learning method for identifying germ cell-specific patterns of gene expression in microarray data from mammalian gonads, specifically during meiotic initiation and prophase. At 10% recall, the method detected spermatocyte genes and oocyte genes with 90% and 94% precision, respectively. Our method outperformed gonadal expression levels and gonadal expression correlations in predicting germ cell-specific expression. Top-predicted spermatocyte and oocyte genes were both preferentially localized to the X chromosome and significantly enriched for essential genes. Also identified were transcription factors and microRNAs that might regulate germ cell-specific expression. Finally, we experimentally validated Rps6ka3, a top-predicted X linked spermatocyte gene. Protein localization studies in the mouse testis revealed germ cell-specific expression of RPS6KA3, mainly detected in the cytoplasm of spermatogonia and prophase spermatocytes. CONCLUSIONS: We have demonstrated that, through the use of machine-learning methods, it is possible to detect germ cell-specific expression from gonadal microarray data. Results from this study improve our understanding of the transition from germ cells to meiocytes in the mammalian gonad. Further, this approach is applicable to other tissues for which isolating cell populations remains difficult. PMID- 23445121 TI - Immersing undergraduates into an interprofessional longitudinal rural placement. AB - INTRODUCTION: An Integrated Multidisciplinary Model of Education in Rural Settings (IMMERSe) program was piloted in 2010 in a rural region of South Australia. The aim of the program was to place students from different health programs together, in a rural environment, for one or two semesters of the academic year to promote interprofessional learning. Students were given the opportunity to participate in joint fortnightly education sessions with an emphasis on interprofessional relations and teamwork, undertaking activities such as case studies, role plays, journal club, work shadowing and invited speakers. METHODS: A qualitative approach was used to explore student perspectives of a rural interprofessional clinical placement. Students were invited to participate in focus groups and reflective writing exercises. This data was analysed in relation to the students' thoughts and reflections around professionalism, teamwork and collegial relationships. RESULTS: The analysis resulted in three major themes: (1) interprofessional interactions with other students; (2) interprofessional interactions with other health professionals; and (3) interprofessional interactions with the community. Students in our study demonstrated a new level of respect for health professionals outside of their discipline, and gained a sense of how their own independent roles can blend or partner with others' roles, to draw on each other's expertise. CONCLUSIONS: Student learning experiences can be enhanced through engagement and integration in a rural community context. Interprofessional learning in a rural community placement can increase students' understanding of professionalism, teamwork and collegiality, which are all important components of collaborative practice. Reflective journaling is a useful method for evaluating the student experience. PMID- 23445122 TI - Ant distribution in relation to ground water in north Florida pine flatwoods. AB - Longleaf pine savannas are one of the most threatened ecosystems in the world, yet are understudied. Ants are a functionally important and diverse group of insects in these ecosystems. It is largely unknown how local patterns of species diversity and composition are determined through the interaction of this dominant animal group with abiotic features of longleaf pine ecosystems. Here we describe how an important abiotic variable, depth to water table, relates to ant species distributions at local scales. Pitfall trapping studies across habitat gradients in the Florida coastal plains longleaf pine flatwoods showed that the ant community changed with mild differences in habitat. In this undulating landscape, elevation differences were less than 2 m, and the depth to the water table ranged from < 20 cm to 1.2 m. The plant species composing the ground cover were zoned in response to depth to water, and shading by canopy trees increased over deeper water tables. Of the 27 ant species that were analyzed, depending on the statistical test, seven or eight were significantly more abundant over a deep water table, eight to ten over a shallow one, and nine to eleven were not significantly patterned with respect to depth to water. Ant species preferring sites with shallow groundwater also preferred the shadier parts of the sites, while those preferring sites with deeper groundwater preferred the sunnier parts of the sites. This suggests that one group of species prefers hot-dry conditions, and the other cooler-moist. Factor analysis and abundance-weighted mean site characteristics generally confirmed these results. These results show that ant communities in this region respond to subtle differences in habitat, but whether these differences arise from founding preferences, survival, competition, or some combination of these is not known. PMID- 23445123 TI - Relationship of trauma centre characteristics and patient outcomes: a systematic review. AB - AIMS AND OBJECTIVES: To systematically review the relationship of trauma centre characteristics and trauma patient outcomes. BACKGROUND: Numerous studies have documented the impact of trauma centre level, trauma centre verification, volume per centre and per surgeon or resource availability on outcomes among trauma patients. However, there continues to be debated about whether trauma care is comparable by these trauma centre characteristics. DESIGN: Systematic review. METHODS: Eligible studies were identified via electronic database searches, footnote chasing and contact with clinical experts. Quality of selected studies was assessed in terms of internal and external validity using 14 questions. Two reviewers independently examined titles, abstracts and whether each met the predefined criteria. RESULTS: A total of 50 studies which met criteria were selected. Ten of 17 articles showed that level I trauma centres had better patient outcomes than level II centres. The achievement of trauma centre verification by American College of Surgeons or State was beneficial to decreasing mortality and length of stay in 9 of 11 studies. High trauma admission volume was beneficial in 8 of 16 studies. The volume per trauma surgeon did not contribute to better patient outcomes in 4 of 5 studies. The availability of in house trauma surgeon was beneficial to lower mortality and shorter length of stay in only 2 of 9 studies. CONCLUSION: This review supports that achieving the trauma centre verification by American College of Surgeons or State is definitely beneficial to patient outcomes. However, the benefit of level I centres compared with level II centres, and volume of annual trauma patients to outcomes is still debating. Further prospective study examining this relationship is required. RELEVANCE TO CLINICAL PRACTICE: Understanding which characteristics of trauma centre provides the best prospect for improved outcomes depending on patient need and resource availability would allow further appreciation of the processes that foster such enhancement. PMID- 23445124 TI - Early intervention and evaluation for adult-onset psychosis: the JCEP study rationale and design. AB - AIM: Psychotic disorders incur substantial long-term burdens to patients and society. Early intervention (EI) during the initial years of psychotic disorders can improve long-term outcome. In Hong Kong, a pilot EI programme (EASY, Early Assessment Service for Young people with psychosis) had been set up since 2001 to serve clients under 25 years of age. Although EASY has been effective in improving outcome, consolidation of early psychosis work requires further development. METHODS: The present paper describes a new EI development which targets adult patients with psychosis in Hong Kong. The Jockey Club Early Psychosis (JCEP) project was launched in 2009. Expanding the service to patients above 25 years old, JCEP aims to deliver a territory-wide specialized EI service to adult-onset psychosis patients, to promote public awareness on early psychosis, and to research on the optimal intervention model and duration for early psychosis in a 4-year randomized controlled trial (RCT). Participants were randomly assigned to receive either 4 years of EI service, 2 years of EI service, or 4 years of standard care. Their symptoms, neurocognitive functions, psychosocial well-being and health economics were regularly assessed. RESULTS: To date, 360 patients were recruited into the RCT, and 740 patients were recruited in a 2-year naturalistic study. Prospective, longitudinal follow-up assessments of these patients are still underway. CONCLUSIONS: JCEP is the first EI project to provide adult early psychosis service in Chinese population. Future data would help to address the optimal duration of EI and its cost-effectiveness. This would also assist regional and international mental health development. PMID- 23445125 TI - Vectorization efforts to increase Gram-negative intracellular drug concentration: a case study on HldE-K inhibitors. AB - In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies. PMID- 23445126 TI - Development and bottlenecks of renewable electricity generation in China: a critical review. AB - This review provides an overview on the development and status of electricity generation from renewable energy sources, namely hydropower, wind power, solar power, biomass energy, and geothermal energy, and discusses the technology, policy, and finance bottlenecks limiting growth of the renewable energy industry in China. Renewable energy, dominated by hydropower, currently accounts for more than 25% of the total electricity generation capacity. China is the world's largest generator of both hydropower and wind power, and also the largest manufacturer and exporter of photovoltaic cells. Electricity production from solar and biomass energy is at the early stages of development in China, while geothermal power generation has received little attention recently. The spatial mismatch in renewable energy supply and electricity demand requires construction of long-distance transmission networks, while the intermittence of renewable energy poses significant technical problems for feeding the generated electricity into the power grid. Besides greater investment in research and technology development, effective policies and financial measures should also be developed and improved to better support the healthy and sustained growth of renewable electricity generation. Meanwhile, attention should be paid to the potential impacts on the local environment from renewable energy development, despite the wider benefits for climate change. PMID- 23445127 TI - Fallopius: the great anatomist, surgeon and botanist. PMID- 23445128 TI - Pregnancy management following bariatric surgery. AB - Bariatric surgery is gaining in popularity, due to globally increasing rates of obesity. In the UK, this has manifested as a 14-fold increase in bariatric surgery between 2004 and 2010, making it necessary to develop strategies to manage women who become pregnant following bariatric surgery. This review paper has explored all the current evidence in the literature and provided a comprehensive management strategy for pregnant women following bariatric surgery. The emphasis is on a multidisciplinary team approach to all aspects of care. Adequate pre-conception and antenatal and postnatal care is essential to good pregnancy outcomes with emphasis on appropriate nutritional supplementation. This is especially important following malabsorptive procedures. There is no evidence to suggest that pregnancy outcome is worse after bariatric surgery, though women who remain obese are prone to obesity-related risks in pregnancy. Neonatal outcome post-bariatric surgery is no different from the general population. PMID- 23445129 TI - The impact of strenuous physical activity on the development of pelvic organ prolapse. AB - Pelvic organ prolapse is a common gynaecological problem and the mechanisms underlying prolapse development are not yet clear but it is thought that increases in abdominal pressure, such as those routinely involved in heavy lifting and long periods of standing, may cause progressive pelvic floor damage over time. The aim of this study was to investigate the effects of strenuous physical activity on the development of prolapse. A narrative literature review was carried out to investigate the effects of occupation and recreational activity on the pathogenesis of pelvic organ prolapse. A marked paucity of literature relevant to the research question makes it difficult to draw firm conclusions. Further research is greatly needed to explore potentially preventable factors in this frequently occurring condition. The review reveals some evidence linking strenuous physical activity with pelvic organ prolapse but this is neither consistent nor adequately powered to reach any firm conclusions. PMID- 23445130 TI - Mature cystic teratoma of the fallopian tube. AB - Teratoma of the fallopian tube (cystic or solid) is a rarely encountered tumour and, to date, only 73 cases have been reported in the literature. A comprehensive review has not been done since 1972, when Mazzarella and colleagues reviewed 44 cases of tubal teratomas. This situation has prompted us to survey the literature to update the data on tubal teratoma cases. The majority of the tumours were benign. The tumour was cystic in nature in 50 cases. Patients' ages ranged between 17 and 67 years. None of them was diagnosed preoperatively. Half of the tumours were <= 5 cm, whereas the other half were > 5 cm in diameter. About two thirds of the patients were associated with two or fewer gravidity. To the best of our knowledge, the present case included in our paper is the first tubal cystic teratoma reported from Turkey. PMID- 23445131 TI - Personal professional indemnity and contractual issues for trainees in obstetrics and gynaecology. AB - Over the last few decades, more healthcare professionals have faced investigation into complaints about medical care and healthcare outcomes (Department of Health 2003). With increasing medical negligence cases being brought against doctors, it is time to carefully consider the implications of such actions to ensure appropriate safeguards (Ferner and McDowell 2006). At a time when the culture of 'no win, no fee' is rampant, the jobbing frontline doctor is on the back-foot trying to untangle the legalities of a malpractice claim (Ferner and McDowell 2006). Reassuringly, the numbers of doctors referred to the GMC or having to face legal procedures or claims for compensation are still very small (National Audit Office 2001). An essential issue for all doctors is having appropriate indemnity cover in the event that their practice is challenged. The opt-out for the European Working Time Regulations (EWTR) has caused further confusion as to what is covered for junior doctors by individual indemnity policies and the employer's liability scheme. Recently, the RCOG Trainees committee and the BMA Junior Doctors Association issued a joint advice regarding this issue (RCOG 2010). In this paper, we consider the differences in cover provided by the employer's liability scheme, individual professional indemnity schemes and the role of professional bodies. We also seek to clarify the understanding of these surrounding EWTR and the voluntary opt-out clause and provide up-to-date information on medico-legal issues and protection schemes regarding legal liabilities. PMID- 23445132 TI - Early prophylactic treatment in pregnant women during the 2009-2010 H1N1 pandemic: obstetric and neonatal outcomes. AB - The aim of the study was to estimate the risk factors associated with the 2009 H1N1 influenza infection, during pregnancy; to describe complications and obstetric and perinatal outcomes of pregnancies during the H1N1 pandemic in 2009; to identify if there is teratogenicity at birth after antiviral treatment. Medical records of 168 pregnant women treated in Reina Sofia University Hospital (Cordoba, Spain) for suspected influenza A H1N1 from September 2009 to February 2010 were analysed. Using the PCR test, 76 pregnant women were diagnosed with H1N1 + infection, and infection was ruled out in the remaining 92. To manage the pandemic, recommendations of the Centres for Disease Control and Prevention were followed. Results showed that the majority of pregnant women were attended at the hospital between October and December 2009 (91.27%). Most of them were in the third-quarter of pregnancy (42.9%). In our sample, being aged between 29 and 37 years reduces the risk of acquiring infection (odds ratio, OR 0.379, 95% confidence interval, CI 0.188-0.763). However, in pregnant women who have required hospitalisation, the risk of infection increased five-fold (OR = 4.999; 95% CI = 1.178-21.212). No differences were found between obstetric and perinatal outcomes of both affected and unaffected or treated and untreated cohorts. No teratogenicity was observed at birth. It was concluded that maternal age and 3rd trimester pregnancy were found related to the risk of acquiring H1N1. No differences in obstetric outcomes or worse perinatal outcomes were found in patients affected by the pandemic. Early prophylactic treatment may be related to better maternal-fetal results. PMID- 23445133 TI - Serum levels of adrenomedullin and inflammatory cytokines in women with term idiopathic intrauterine growth restriction. AB - This study aimed to determine the concentrations of adrenomedullin (AM), tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 in maternal circulation of full-term idiopathic intrauterine growth restriction (IUGR) in relation to appropriate-for-gestational-age (AGA) and the possible correlation of AM to these cytokines. A case-control study included 50 idiopathic IUGR mothers and 25 AGA, who were evaluated regarding their serum levels of AM, TNF-alpha and IL-6. We found that women with idiopathic IUGR have significantly higher serum levels of AM, TNF-alpha and IL-6 (p = 0.008; 0.016; 0.029, respectively) and the level of AM was significantly correlated to serum level of TNF-alpha (r = 0.417, p = 0.003) but not significantly correlated to IL-6 compared with the AGA group. In conclusion, the significant increase of AM, TNF-alpha and IL-6 in the idiopathic IUGR group might contribute to the uteroplacental haemodynamic alterations and can serve as a useful biochemical marker. Significant correlation between AM and TNF-alpha could hypothesise the existence of a complex interaction between AM and this inflammatory cytokine. PMID- 23445134 TI - Epidemiology of early pre-term delivery: relationship with clinical and histopathological infective parameters. AB - In this study, we want to evaluate which are the risk factors involved in early pre-term delivery (PTD). Spontaneous PTD results from two clinical conditions: (1) spontaneous pre-term labour (PTL) leading to PTD (idiopathic) and (2) pre term premature rupture of membranes (pPROM). This is a multicentric, observational, retrospective, cross-sectional study, which includes 7,631 women admitted in the Obstetric units of Siena, Perugia, Torino, Trieste, Milano, Modena, Ancona, Foggia and Catania. Data were obtained from all patients having delivered spontaneously, pre-term or at term. The present study reveals the involvement of inflammation/infection in pathogenetic mechanisms leading to early PTD in the Italian population. A higher incidence of both clinical and pathological parameters of inflammation/infection - pPROM, genitourinary tract infections, placenta histopathological inflammation, WBC and C-reactive protein (CRP) - in early pre-term delivery in respect to late pre-term delivery and delivery at term, were shown. PMID- 23445135 TI - Vaginal lactoferrin in asymptomatic patients at low risk for pre-term labour for shortened cervix: cervical length and interleukin-6 changes. AB - A total of 3,324 singleton pregnant women were screened for pre-term delivery and 128 women were finally randomised and analysed for outcome showing borderline cervical length (25-29 mm) and elevated cervico-vaginal interleukin 6 levels. To verify if vaginal administration of lactoferrin might have an influence on these variables, two groups of 64 patients were formed. Study cases were submitted to lactoferrin for 21 days; controls received no treatment. An inverse relation was found between interleukin 6 levels and cervical length. On day 30 from the beginning of the treatment, study cases showed a decrease in interleukin 6 levels and an increase in cervical length. A greater number of women with regular uterine contractions and reduced cervical consistency before the 37th week of gestation were found in the controls. Our data show that lactoferrin could play a role in reducing the number of women at risk for pre-term birth for shortened cervical length and elevated interleukin 6 levels. PMID- 23445136 TI - Estimating risk factors and causes for postpartum febrile morbidity in teenage mothers. AB - In this cohort study, our objective was to identify potentially modifiable risk factors and causes for febrile morbidity in teenage mothers. We identified all cases of febrile morbidity using the United States Joint Commission on Maternal Welfare definition in a cohort of teenage deliveries over a 4-year period at one institution. Of the 730 included teenage deliveries, 49 (7%) women suffered postpartum febrile morbidity. Higher maternal pre-pregnancy body mass index (BMI: 34.0 +/- 8.6 vs 30.3 +/- 6.0 kg/m(2), p = 0.0001), caesarean delivery (RR 21.3, 95% CU 8.9-54.9) and postpartum haemorrhage (RR 3.0, 95% CI 1.1-6.7) were associated with postpartum febrile morbidity. Risk factors for febrile morbidity in the teenage parturient include obesity, caesarean delivery and postpartum haemorrhage. Considering the increasing rates of teenage obesity and overall caesarean delivery rates, attention must be focused on these modifiable risk factors to avoid this complication during a tenuous time for the teenage parent. PMID- 23445137 TI - Knowledge of symptoms and signs of puerperal sepsis in a community in north eastern Nigeria: a cross-sectional study. AB - Puerperal sepsis is a leading cause of mortality in developing countries. The objective of this study is to determine the knowledge of symptoms and signs of puerperal sepsis. It was a cross-sectional community-based study. Of the 400 respondents interviewed, 289 (72.2%) were between the ages of 20 and 39 years, and most, 374 (93.5%), were married. Only 14 (3.5%) had tertiary education. Most respondents, 224 (56.0%) were farmers and grandmultiparae accounted for 187 (46.7%). A reassuring number of respondents, 265 (66.3%), knew that fever with abnormal vaginal discharge; 252 (63%) fever with foul smelling lochia; 346 (86.4%) fever occurring with lower abdominal pain and 182 (45.5%) knew that fever occurring with prolonged flow of lochia, are all indicators of puerperal sepsis. A total of 53% of respondents were not aware of the causes of puerperal sepsis; 10% believed it is caused by evil spirits. The knowledge of the causes of puerperal sepsis is poor. There is the need to put more emphasis on the causes of puerperal sepsis during antenatal health talks. This could help reduce morbidity and mortality associated with puerperal sepsis. PMID- 23445138 TI - Knowledge of hepatitis B virus infection, access to screening and vaccination among pregnant women in Ibadan, Nigeria. AB - The knowledge of pregnant women about Hepatitis B virus infection at three different levels of healthcare and their access to screening and vaccination was evaluated by a questionnaire-based cross-sectional study. There were 643 respondents with a mean age of 30.2 +/- 5.2 years and mean gestational age of 26.1 +/- 8.4 weeks. The distribution of respondents was 55 (8.6%, primary), 204 (31.7%, secondary) and 383 (59.6%, tertiary) women. The majority of respondents were traders (36%) or civil servants/professionals (28.6%). Overall, 76% of all women had inadequate knowledge about hepatitis B infection; 19.5% had been screened, while 9.7% had been vaccinated. There was an increased likelihood of adequate knowledge, previous screening and vaccination among health workers (p = 0.00). Other positive predictors of knowledge and vaccination were tertiary education (p = 0.04) and tertiary care (p = 0.00). There is inadequate knowledge among pregnant women in Ibadan about Hepatitis B infection, with significant differences at the various levels of care, particularly in non-tertiary settings where screening and vaccination is also sub-optimal. Information dissemination, universal screening and vaccination services for pregnant women in Nigeria require urgent consideration. PMID- 23445139 TI - Fetal and neonatal outcomes in women taking domperidone during pregnancy. AB - The safety of domperidone in pregnancy remains unknown. Therefore, the study aimed to prospectively evaluate the fetal outcomes of women who were taking domperidone during pregnancy. In a prospective cohort study design, 120 1st- trimester pregnant women who were taking domperidone for controlling gastrointestinal tract symptoms and 212 age-matched pregnant women not exposed to any potential teratogenic agent, were followed-up until delivery. In the case group, domperidone was indicated for control of functional gastrointestinal disorders in 59.2%, the maximum dose was 30 mg/day and exposure occurred between 2(+4) and 20 weeks' gestation. Fetal outcomes including gestational age at birth, birth weight and length, head circumference at birth, and 1- and 5-min Apgar score were similar in the two study groups. There were three babies born with malformations in each group (OR = 0.6; 95% CI 0.1, 2.8). In conclusion, domperidone does not appear to be a major human teratogen. However, our findings require further confirmation in larger studies. PMID- 23445140 TI - Caesarean hysterectomy for placenta praevia accreta: filling the bladder technique to identify an appropriate bladder separation site. PMID- 23445141 TI - Effects of low-dose metformin and rosiglitazone on biochemical, clinical, metabolic and biophysical outcomes in polycystic ovary syndrome. AB - The aim of this study was to compare the effect of low-dose metformin and rosiglitazone on clinical, biochemical, ultrasound features and endothelial function in patients with polycystic ovary syndrome (PCOS). After randomisation, a group of 17 women received metformin 500 mg b.d. (MG) and a group of 18 received rosiglitazone 4 mg o.d. (RG) for 3 months. Serum FSH, LH, testosterone, fasting glucose, insulin, IGF-1, IGFBP-3, CRP were measured at baseline and follow-up. Ovarian scan and microcirculation studies were also performed. It was found that there was a reduction in hyperandrogenaemia, insulin resistance, lipidaemia, CRP levels, ovarian volume and number of follicles in both groups. No improvement in endothelial- dependent function was noted but a significant improvement in endothelial-independent function in rosiglitazone group. It was concluded that low-dose therapeutic regimen with rosiglitazone and metformin, has comparable beneficial impacts on metabolic, hormonal and morphological features of PCOS but no obvious effect on vascular parameters in a population of predominantly mild PCOS. PMID- 23445142 TI - Possible improvement of depression after systematic examination and explanation of live birth rates among women with recurrent miscarriage. AB - We conducted a prospective study to determine whether systematic examinations and provision of explanation regarding the successful birth rates might improve mood or anxiety disorders among childless women with recurrent miscarriages. A total of 305 first-visit patients with a history of 2-12 miscarriages completed a first questionnaire battery, including: 'K6', a new screening instrument for mood and anxiety disorders, the 'Symptom Checklist-90 Revised' (SCL-90-R) and the 'Emotional Impact' questionnaire. Of these, 170 patients who underwent routine examinations and received an explanation about successful live birth rates responded to the second questionnaire. A total of 15.4% of the patients were estimated to suffer from diagnosable depression or anxiety disorders. Patients with high scores on K6 also showed elevated scores on all the subscales of SCL-90 R, including depression and anxiety. The K6 of patients with translocation was significantly higher than that of patients with antiphospholipid antibodies. The K6 and depression scores in the 2nd questionnaire survey were significantly lower than those in the 1st survey in the 170 patients. Improvement in depression was found in patients who underwent routine examination and received an explanation. PMID- 23445143 TI - Duration and determinants of inter-birth interval among women in Enugu, south eastern Nigeria. AB - The difference in fertility levels of any given two societies has a relationship with the interval between births. We determined the duration of inter-birth interval and the determinants of short inter-birth interval in Enugu, Nigeria. Questionnaires were administered to a cross-section of 420 women consecutively recruited from the family planning and antenatal clinics of two hospitals in Enugu metropolis. The mean age was 30.9 +/- 5.1 (range 20-44) years. The median inter-birth interval was 21.5 months and the prevalence of modern contraceptive use among respondents was 18.1%. Women's age of 25 years or less, duration of breast-feeding of 10 months or less, and non-use of modern contraceptives had strong association (p < 0.05) with short inter-birth interval. The mean inter birth interval in Enugu is short. Future child spacing campaign in Enugu should target the encouragement of longer breast-feeding practices and increased uptake of modern contraception among our women. PMID- 23445144 TI - Gender attitude to the empowerment of women: an independent right to contraceptive acceptance, choice and practice. AB - Multiple factors influence the acceptance, choice and utilisation of contraceptive. The objective of the study is to identify individual attitude towards the empowerment of women to an independent right to accept, choose and utilise a contraceptive method of their choice without recourse to their male partners. This is a cross sectional study of men and women of different socio cultural background working or utilising the services of the Federal Medical Centre Gombe, Nigeria. There were 554 respondents. Only 187 (34.4%) respondents thought that all women, irrespective of marital status, should have an independent right to contraceptive acceptance, choice and practice. Significantly more men (85.4%) than women (61.8%) rejected that women should have an independent right to contraceptive acceptance, choice and practice. Majority of both gender favoured male influence in the acceptance and choice of method of contraception. Our study has re-echoed the importance of male involvement in contraception decision-making. PMID- 23445145 TI - Experiences of women referred for urgent assessment of postmenopausal bleeding (PMB). AB - Women with postmenopausal bleeding (PMB) are referred for specialist assessment within 2 weeks of presentation to their GP. No research has previously examined women's experiences of expedited referral. This was investigated in the present study using questionnaires (6-item State Anxiety Inventory (6-STAI)) and focus groups. A total of 55 women completed questionnaires. Results showed high levels of anxiety at first hospital visit (mean 47.0 (SD 14.27); 95% CI 43.14-50.93). Scores declined by 90 days, but were higher in those not undergoing hysteroscopy. Fifteen women who underwent hysteroscopy attended focus groups. Women recalled fear of cancer from symptom onset until receipt of results. Anxiety was exacerbated by poor knowledge of PMB and lack of awareness of expedited referral. Post-discharge, those with unexplained or recurrent symptoms expressed frustration and upset. Effective strategies to raise awareness of PMB and its causes are needed, including reasons for expedited referral. Women without cancer may also need more support. PMID- 23445146 TI - Examiners' perceptions of the objective structured clinical examination in colposcopy. AB - Certification in Colposcopy by the British Society for Colposcopy and Cervical Pathology (BSCCP) and the Royal College of Obstetricians and Gynaecologists is a formal pre- requisite to the practice of colposcopy within the UK. This certification is awarded after passing an Objective Structured Clinical Examination (OSCE). The aim of the project is to explore examiners' perceptions of the OSCE examination in colposcopy and consider whether it is the right tool to differentiate between safe and unsafe practice in colposcopy. A case study research methodology was employed for the project, and questionnaires were sent to 30 examiners for OSCE in Colposcopy. The project also included conducting semi structured interviews with two examiners, two trainees and a senior manager of the BSCCP. The questionnaire had a response rate of 28 (94%). The satisfaction rate among the examiners about the standard of questions in OSCE in Colposcopy was 93%, and 89% of the examiners would allow a candidate passing the examination to carry out a clinic in their absence. A total of 26 (94%) examiners thought that the examination was fit for purpose. It was suggested that testing of practical skills should also be made part of the examination. It seems OSCE in Colposcopy is perceived well both by the examiners and the candidates. PMID- 23445147 TI - Outcome of molar pregnancies in Malaysia: a tertiary centre experience. AB - Gestational trophoblastic disease (GTD) is a common problem among Asian ethnics. A total of 102 women with molar pregnancies between 1 January 2005 and 31 December 2010, were analysed. The aim of the study was to determine the outcome of all molar pregnancies in our institution. The local incidence of molar pregnancy was 2.6 per 1,000 deliveries. A total of 48 women (47.1%) had complete hydatidiform mole and another 54 (52.9%) had partial mole. The mean age of the women with molar pregnancies was 32.0 +/- 7.9 years. The mean gestational age at initial diagnosis was 11 weeks +/- 3 days. The majority (97 women, 95.1%) had symptoms of vaginal bleeding and 18 (17.6%) women had a uterus larger than dates. A total of 48 (47.1%) women had ultrasound scan findings of 'snow-storm' appearance. None of the women with uncomplicated molar pregnancy had evidence of relapse following one undetectable serum beta-hCG level. Four out of the 102 women (3.9%) developed persistent trophoblastic disease before attaining one undetectable serum beta-hCG level. All four women required single agent methotrexate and they remained in remission. The prognosis for uncomplicated molar pregnancy is good. Establishment of a National Trophoblastic Centre is recommended to maintain optimal outcome. PMID- 23445148 TI - Pattern of gynaecological malignancies at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. AB - Gynaecological malignancies contribute to the global burden of diseases and are of public health interest. The objective of this study was to determine the pattern of distribution of gynaecological malignancies seen between 1 January 2002 and 31 December 2006, at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. It was a retrospective descriptive study. A total of 166 cases of gynaecological malignancies were encountered, cervical cancer was the most common (59.6%). This was followed by ovarian cancer (21.1%), trophoblastic tumour (7.8%) and corpus uteri cancer (6.0%). Others included cancer of the vulva (3.6%) and cancer of the vagina (1.8%). Squamous cell carcinoma accounted for 96.0% of cervical cancers. Epithelial tumours represented 60.0% of ovarian cancers, and serous cyst adenocarcinoma was the most common histological variety. All the vulval and vaginal cancers were of squamous cell type. In conclusion, genital malignancies are common and cervical cancer remains the leading gynaecological malignancy in this centre. PMID- 23445149 TI - Myomectomy: a suturing technique for the open procedure. AB - Uterine fibroids are common among women of reproductive age. In women who have not completed their family, a myomectomy is often suggested to preserve and improve fertility. Here, we would like to describe our technique of myomectomy in an open laparotomy procedure. PMID- 23445150 TI - Antenatal identification of isolated anophthalmia. PMID- 23445151 TI - Early prenatal diagnosis of iniencephaly associated with holoprosencephaly and cyclops. PMID- 23445152 TI - Caudal regression syndrome. PMID- 23445153 TI - Trisomy 8 mosaicism a controversial prenatal diagnosis. PMID- 23445154 TI - The protective effect of oligohydramnios in a case of missed diagnosis of spontaneous septostomy in monochorionic diamniotic twins. PMID- 23445155 TI - Ectopic decidua in pregnancy discovered incidentally during caesarean delivery. PMID- 23445156 TI - Ruptured heterotopic pregnancy after assisted reproduction in a patient who underwent bilateral salpingectomy. PMID- 23445157 TI - Vulval epithelioid leiomyoma in a pregnant woman. PMID- 23445158 TI - A rare case of vulval pilonidal sinus diagnosed on ultrasound. PMID- 23445159 TI - Pelvic actinomycosis: a disease that should not be overlooked in cases with suspected advanced ovarian cancer. PMID- 23445160 TI - Sister Mary Joseph's nodule in advanced ovarian cancer. PMID- 23445161 TI - Ovarian serous cystadenocarcinoma metastasising to the breast. PMID- 23445162 TI - Change in paternity, pre-eclampsia, fetal growth retardation and maternal testosterone concentration. PMID- 23445164 TI - Statement of retraction. PMID- 23445165 TI - Retracted: Advances in the physiological and pathological implications of cholesterol. AB - Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco- and mineralo-corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high-impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol-related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades. PMID- 23445166 TI - Development of an in vitro dendritic cell-based test for skin sensitizer identification. AB - The sensitizing potential of chemicals is currently assessed using animal models. However, ethical and economic concerns and the recent European legislative framework triggered intensive research efforts in the development and validation of alternative methods. Therefore, the aim of this study was to develop an in vitro predictive test based on the analysis and integration of gene expression and intracellular signaling profiles of chemical-exposed skin-derived dendritic cells. Cells were treated with four known sensitizers and two nonsensitizers, and the effects on the expression of 20 candidate genes and the activation of MAPK, PI3K/Akt, and NF-kappaB signaling pathways were analyzed by real-time reverse transcription polymerase chain reaction and Western blotting, respectively. Genes Trxr1, Hmox1, Nqo1, and Cxcl10 and the p38 MAPK and JNK signaling pathways were identified as good predictor variables and used to construct a dichotomous classifier. For validation of the model, 12 new chemicals were then analyzed in a blind assay, and from these, 11 were correctly classified. Considering the total of 18 compounds tested here, 17 were correctly classified, representing a concordance of 94%, with a sensitivity of 92% (12 of 13 sensitizers identified) and a specificity of 100% (5 of 5 nonsensitizers identified). Additionally, we tested the ability of our model to discriminate sensitizers from nonallergenic but immunogenic compounds such as lipopolysaccharide (LPS). LPS was correctly classified as a nonsensitizer. Overall, our results indicate that the analysis of proposed gene and signaling pathway signatures in a mouse fetal skin-derived dendritic cell line represents a valuable model to be integrated in a future in vitro test platform. PMID- 23445167 TI - Abstinence duration modulates striatal functioning during monetary reward processing in cocaine patients. AB - Pre-clinical and clinical studies in cocaine addiction highlight alterations in the striatal dopaminergic reward system that subserve maintenance of cocaine use. Using an instrumental conditioning paradigm with monetary reinforcement, we studied striatal functional alterations in long-term abstinent cocaine-dependent patients and striatal functioning as a function of abstinence and treatment duration. Eighteen patients and 20 controls underwent functional magnetic resonance imaging during a Monetary Incentive Delay task. Region of interest analyses based on masks of the dorsal and ventral striatum were conducted to test between-group differences and the functional effects in the cocaine group of time (in months) with no more than two lapses from the first time patients visited the clinical service to seek treatment at the scanning time (duration of treatment), and the functional effects of the number of months with no lapses or relapses at the scanning session time (length of abstinence). We applied a voxel-wise and a cluster-wise FWE-corrected level (pFWE) at a threshold of P < 0.05. The patient group showed lower activation in the right caudate during reward anticipation than the control group. The regression analyses in the patients group revealed a positive correlation between duration of treatment and brain activity in the left caudate during reward anticipation. Likewise, length of abstinence negatively correlated with brain activity in the bilateral nucleus accumbens during monetary outcome processing. In conclusion, caudate and nucleus accumbens show a different brain response pattern to non-drug rewards during cocaine addiction, which can be modulated by treatment success. PMID- 23445168 TI - Concentrations of clindamycin hydrochloride in homogenates of normal dog skin when administered at two oral dosage regimens. AB - BACKGROUND: Clindamycin is frequently used for the treatment of bacterial pyoderma. OBJECTIVE: To compare the pharmacokinetics of clindamycin in whole skin homogenates of normal dogs when administered orally at two dosage regimens (5.5 mg/kg BW, twice daily and 11 mg/kg BW, once daily). ANIMALS AND METHODS: Skin biopsies were obtained from six laboratory beagles before, 3, 6 and 12 h after the first and the fifth dose of clindamycin at the former regimen, as well as before, 3, 6, 12 and 24 h after the first and third dose at the latter regimen. Tissue was homogenized and clindamycin concentrations were measured by reverse phase high-performance liquid chromatography coupled with mass spectrometry. Results were analyzed using Student's t-test at a level of significance of 0.05. RESULTS: Maximal concentration and area under the concentration-time curve, but not their relevant dose-normalized values, were higher at the dosage regimen of 11 mg/kg BW, once daily than at 5.5 mg/kg BW twice daily. CONCLUSIONS: The pharmacokinetic profile of clindamycin is at least equal, if not better, when this antimicrobial is administered at 11 mg/kg BW, once daily. PMID- 23445169 TI - IL-22 levels are associated with Trichomonas vaginalis infection in the lower genital tract. AB - PROBLEM: IL-22 has important functions at mucosal surfaces, including the induction of antimicrobial peptides and maintenance of epithelium. However, IL-22 has not been investigated in the genital tract during TV infection. METHODS OF STUDY: Women who visited an STD clinic and women from a cohort with frequent Trichomoniasis were studied. IL-22, IL-17, and antimicrobial peptides were measured in cervicovaginal lavage by ELISA. RESULTS: In women visiting the STD clinic, those without STDs (n = 10) had a median IL-22 of 0 pg/mL, while women with infections (n = 30) had 27 pg/mL (P = 0.04). In the cohort, women with Trichomoniasis (n = 19) had significantly higher IL-22 than women with no infections (n = 21, 74 versus 0 pg/mL, P = 0.0001). IL-17 was also significantly increased in Trichomoniasis, and there was a correlation between IL-22 and IL-17 (P = 0.001). CONCLUSION: IL-22 is increased in STDs generally and in Trichomoniasis specifically suggesting an antimicrobial response of the mucosa and an epithelial repair process induced by the STDs. PMID- 23445170 TI - Accuracy of continuous glucose monitoring during exercise in type 1 diabetes pregnancy. AB - BACKGROUND: Performance of continuous glucose monitors (CGMs) may be lower when glucose levels are changing rapidly, such as occurs during physical activity. Our aim was to evaluate accuracy of a current-generation CGM during moderate intensity exercise in type 1 diabetes (T1D) pregnancy. SUBJECTS AND METHODS: As part of a study of 24-h closed-loop insulin delivery in 12 women with T1D (disease duration, 17.6 years; glycosylated hemoglobin, 6.4%) during pregnancy (gestation, 21 weeks), we evaluated the Freestyle Navigator((r)) sensor (Abbott Diabetes Care, Alameda, CA) during afternoon (15:00-18:00 h) and morning (09:30 12:30 h) exercise (55 min of brisk walking on a treadmill followed by a 2-h recovery), compared with sedentary conditions (18:00-09:00 h). Plasma (reference) glucose, measured at regular 15-30-min intervals with the YSI Ltd. (Fleet, United Kingdom) model YSI 2300 analyzer, was used to assess CGM performance. RESULTS: Sensor accuracy, as indicated by the larger relative absolute difference (RAD) between paired sensor and reference glucose values, was lower during exercise compared with rest (median RAD, 11.8% vs. 18.4%; P<0.001). These differences remained significant when correcting for plasma glucose relative rate of change (P<0.001). Analysis by glucose range showed lower accuracy during hypoglycemia for both sedentary (median RAD, 24.4%) and exercise (median RAD, 32.1%) conditions. Using Clarke error grid analysis, 96% of CGM values were clinically safe under resting conditions compared with only 87% during exercise. CONCLUSIONS: Compared with sedentary conditions, accuracy of the Freestyle Navigator CGM was lower during moderate-intensity exercise in pregnant women with T1D. This difference was particularly marked in hypoglycemia and could not be solely explained by the glucose rate of change associated with physical activity. PMID- 23445171 TI - Versatile fluorescence resonance energy transfer-based mesoporous silica nanoparticles for real-time monitoring of drug release. AB - We describe the development of a versatile fluorescence resonance energy transfer (FRET)-based real-time monitoring system, consisting of (a) coumarin-labeled cysteine tethered mesoporous silica nanoparticles (MSNs) as the drug carrier, (b) a fluorescein isothiocyanate-beta-cyclodextrin (FITC-beta-CD) as redox-responsive molecular valve blocking the pores, and (c) a FRET donor-acceptor pair of coumarin and FITC integrated within the pore-unlocking event, thereby allowing for monitoring the release of drugs from the pores in real-time. Under nonreducing conditions, when the disulfide bond is intact, the close proximity between coumarin and FITC on the surface of MSNs results in FRET from coumarin to FITC. However, in the presence of the redox stimuli like glutathione (GSH), the disulfide bond is cleaved which leads to the removal of molecular valve (FITC beta-CD), thus triggering drug release and eliminating FRET. By engineering such a FRET-active donor-acceptor structure within the redox-responsive molecular valve, we can monitor the release of the drugs entrapped within the pores of the MSN nanocarrier, following the change in the FRET signal. We have demonstrated that, any exogenous or endogenous change in the GSH concentration will result in a change in the extent of drug release as well as a concurrent change in the FRET signal, allowing us to extend the applications of our FRET-based MSNs for monitoring the release of any type of drug molecule in real-time. PMID- 23445173 TI - Chewing efficiency and electromyographic activity of masseter muscle with three designs of implant-supported mandibular overdentures. A cross-over study. AB - PURPOSE: The aim of this study was to compare the effect of three designs for implant-supported mandibular overdenture on the chewing efficiency and electromyographic (EMG) activity of masseter muscles. MATERIAL AND METHODS: Eighteen edentulous patients received new maxillary and mandibular dentures (control, CD) before implant placement. After using the dentures for 3 months, patients were randomly divided into six blocks (three patients/block) and received four implants in canine and first molar areas of the mandible. Following osseointegration period, new duplicate mandibular overdentures were successively connected to the implants with: (i) ball attachment on two implants (2BOD), (ii) bar attachment on two implants (2ROD), and (iii) bar attachments on four implants (4ROD) in a random order. Chewing efficiency was measured using chewing gum, and EMG was recorded during clenching (with or without food). Evaluations were made 3 months after using each of the following prostheses: CD, 2BOD, 2ROD, and 4ROD. RESULTS: All implant-supported overdentures showed a significant increase in chewing efficiency and EMG values when compared to CD. These values increased significantly with 4ROD when compared to 2BOD or 2ROD prostheses. There was no significant difference in chewing efficiency and EMG between 2BOD and 2ROD prostheses. CONCLUSION: Four-implant-supported overdentures seem to present a functional advantage vs. two-implant-supported overdentures, independent of the chosen attachment system. PMID- 23445174 TI - Is boundary extension emotionally selective? AB - When they have to memorize a picture, people usually build a memory trace including more extensive boundaries than the original picture, a phenomenon known as boundary extension or BE. This article looks at whether the emotion category expressed (i.e., happiness, pleasure, irritation, or anger) by actors in short films could have an influence on the BE effect. The results showed that positively valenced emotions (happiness, pleasure) led to an extension effect, while the negatively valenced ones (anger, irritation) did not produce any significant memory distortion. The arousal dimension of emotions had no significant effect on BE. The current results were discussed in the light of previous studies on the links between BE and emotions. PMID- 23445175 TI - Membrane topology of yeast alkaline ceramidase YPC1. AB - Ypc1p (yeast phyto-ceramidase 1) and Ydc1p (yeast dihydroceramidase 1) are alkaline ceramide hydrolases that reside in the ER (endoplasmic reticulum). Ypc1p can catalyse the reverse reaction, i.e. the condensation of non-esterified fatty acids with phytosphingosine or dihydrosphingosine and overexpression of YPC1 or YDC1 can provide enough ceramide synthesis to rescue the viability of cells lacking the normal acyl-CoA-dependent ceramide synthases. To better understand the coexistence of acyl-CoA-dependent ceramide synthases and ceramidases in the ER we investigated the membrane topology of Ypc1p by probing the cysteine residue accessibility of natural and substituted cysteines with membrane non-permeating mass-tagged probes. The N- and C-terminal ends of Ypc1p are oriented towards the lumen and cytosol respectively. Two of the five natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge. The data allow the inference that all of the amino acids of Ypc1p that are conserved in the Pfam PF05875 ceramidase motif and the CREST {alkaline ceramidase, PAQR [progestin and adipoQ (adiponectin) receptor] receptor, Per1 (protein processing in the ER 1), SID-1 (sister disjunction 1) and TMEM8 (transmembrane protein 8)} superfamily are located in or near the ER lumen. Microsomal assays using a lysine residue-specific reagent show that the reverse ceramidase activity can only be blocked when the reagent has access to Ypc1p from the lumenal side. Overall the data suggest that the active site of Ypc1p resides at the lumenal side of the ER membrane. PMID- 23445178 TI - The three-dimensional image analysis of the chromocenter in motile and immotile human sperm. AB - Chromosomes in human spermatozoa are arranged non-randomly with the centromeres of non-homologous chromosomes forming a chromocenter. We have compared motile and immotile sperm populations in normozoospermic patients to determine if there is any dissimilarity in the formation of the chromocenter and the nuclear position of chromosome 17. Based on the differences between motile and immotile populations, we propose for the 'optimal' nuclear organization to be defined as containing 1 to 3 chromocenter(s) with central radial and median longitudinal position for the centromere of chromosome 17. By this definition, 42% of motile spermatozoa had 'optima' nuclei, in comparison to 25% of immotile spermatozoa (P < 0.05). Immotile spermatozoa exhibited a greater disruption in the formation of the chromocenter, altered position of the centromere of chromosome 17, and were more prone to chemical decondensation, resulting in higher nuclear and chromocenter volumes. The altered topology of the chromosomes might lead to the disruption of the sequence of events involved in fertilization and early embryonic development. PMID- 23445176 TI - Alstrom syndrome is associated with short stature and reduced GH reserve. AB - INTRODUCTION: Alstrom syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called 'ciliopathies' and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population. MATERIAL AND METHODS: Twenty three patients with ALMS (age, 1-52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone-releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic-pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. RESULTS: The length-for-age measurements from birth to 36 months showed normal growth with most values falling within -0.67 SDS to +1.28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16-20 years; mean SDS, -2.22 +/- 1.16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154.7 +/- 10.6 cm vs 162.9 +/- 4.8 cm, P = 0.009) and a mild increase in BMI (Kg/m(2) ) (27.8 +/- 4.8 vs 24.1 +/- 2.5, P = 0.007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11.9 +/- 6.9 MUg/l vs 86.1 +/- 33.2 MUg/l, P < 0.0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149.7 +/- 6.2 cm vs 161.9 +/- 9.2 cm, P = 0.04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. CONCLUSIONS: Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion. PMID- 23445179 TI - The effect of functional movement ability on the quality of life after total hip replacement. AB - AIMS AND OBJECTIVES: To analyse in detail the relationship between the movement and generic health-related quality of life (HRQoL) indicators and the subjective feeling of health of the patients, as well as the objective movement parameters measured by the surgeon and the patient's opinion about the success of the total hip replacement (THR). BACKGROUND: We have only limited information about the effect of mobility function improvement on the HRQoL several years after THR. We have recently found that after THR postoperative health awareness is influenced mainly by cardiovascular diseases, but the effects of the movement parameters on the subsequent feelings of well-being were not examined. DESIGN: Retrospective longitudinal study. METHODS: This study involved 109 patients who had had THR. The patients' health status and objective and subjective mobility function at the time of operation and five years later were evaluated using questionnaires (including EQ-5D and WOMAC scores) and the hospital database. RESULTS: All components of EQ-5D and WOMAC had significantly improved by Year 5 in patients who experienced a complete recovery after the operation, but not the mobility and pain components of EQ-5D for those patients who felt an improvement only in their subjective mobility function. The surgeon-assessed parameters and use of walking aids showed a similar distribution in patients who considered themselves to be healthy or only moderately sick five years after THR. CONCLUSION: Successful THR significantly improves the feeling of well-being and the mobility function of patients even five years after the operation. In individual cases, however, other subjective and objective factors, but not the mobility function, have a major influence on the HRQoL. RELEVANCE TO CLINICAL PRACTICE: Five years after successful THR, nursing care has to focus not only on the further improvement of the mobility but on strengthening the subjective feeling of the patient's well being and health. PMID- 23445180 TI - Biogeographical origin and speciation of the Anthocoris nemorum group. AB - The Anthocoris nemorum group belongs to the Anthocoridae (Hemiptera), and is an important group of predators of agricultural pests. A phylogeny was constructed in conjunction with dispersal-vicariance analysis of the Anthocoris nemorum group species in order to discern the relationships between the phylogeographical structuring of A. nemorum group species, and the effects of the Qinghai-Tibet plateau uplift. The divergence times were estimated using Bayesian inference as implemented in BEAST. A portion of the mitochondrial COI gene (1406 bp) and 16S rDNA (932 bp) were chosen as molecular markers to reconstruct evolutionary relationships among 10 species in this group. The combined approach, based on phylogeny, estimation of node dates, and dispersal-vicariance analyses, indicated that the phylogeographical structuring of A. nemorum has been primarily shaped by the two main periods of the Qinghai-Tibet plateau uplift. The DIVA optimal reconstructions suggest that A. nemorum diversified from the Miocene to the Pleistocene from a center of origin in the Hengduan Mountains. The rapid uplift of Mountain ranges associated with the uplift of the entire Qinghai-Tibet plateau may have promoted rapid divergence in the A. nemorum group. Vicariance and dispersal were both essential in shaping the present distribution patterns of A. nemorum. PMID- 23445172 TI - MtDNA control region variation affirms diversity and deep sub-structure in populations from southern Africa. AB - BACKGROUND: The current San and Khoe populations are remnant groups of a much larger and widely dispersed population of hunter-gatherers and pastoralists, who had exclusive occupation of southern Africa before the influx of Bantu-speakers from 2 ka (ka = kilo annum [thousand years] old/ago) and sea-borne immigrants within the last 350 years. Here we use mitochondrial DNA (mtDNA) to examine the population structure of various San and Khoe groups, including seven different Khoe-San groups (Ju/'hoansi, !Xun, /Gui+//Gana, Khwe, ?Khomani, Nama and Karretjie People), three different Coloured groups and seven other comparative groups. MtDNA hyper variable segments I and II (HVS I and HVS II) together with selected mtDNA coding region SNPs were used to assign 538 individuals to 18 haplogroups encompassing 245 unique haplotypes. Data were further analyzed to assess haplogroup histories and the genetic affinities of the various San, Khoe and Coloured populations. Where possible, we tentatively contextualize the genetic trends through time against key trends known from the archaeological record. RESULTS: The most striking observation from this study was the high frequencies of the oldest mtDNA haplogroups (L0d and L0k) that can be traced back in time to ~100 ka, found at high frequencies in Khoe-San and sampled Coloured groups. Furthermore, the L0d/k sub-haplogroups were differentially distributed in the different Khoe-San and Coloured groups and had different signals of expansion, which suggested different associated demographic histories. When populations were compared to each other, San groups from the northern parts of southern Africa (Ju speaking: !Xun, Ju/'hoansi and Khoe-speaking: /Gui+//Gana) grouped together and southern groups (historically Tuu speaking: ?Khomani and Karretjie People and some Coloured groups) grouped together. The Khoe group (Nama) clustered with the southern Khoe-San and Coloured groups. The Khwe mtDNA profile was very different from other Khoe-San groups with high proportions of Bantu-speaking admixture but also unique distributions of other mtDNA lineages. CONCLUSIONS: On the whole, the research reported here presented new insights into the multifaceted demographic history that shaped the existing genetic landscape of the Khoe-San and Coloured populations of southern Africa. PMID- 23445181 TI - A perspective on free radical autoxidation: the physical organic chemistry of polyunsaturated fatty acid and sterol peroxidation. AB - This Perspective describes advances from the author's laboratory on the free radical reactions of organic compounds with molecular oxygen. Polyunsaturated fatty acids (PUFAs) and sterols are particularly prone to undergo radical chain oxidation, and evidence suggests that this process, known as lipid peroxidation, occurs in vivo under a variety of conditions that are the result of an oxidative stress. Cyclic peroxides, hydroperoxides, and epoxy alcohols are major products formed from peroxidation, and the basic mechanisms of product formation are now reasonably well understood. These mechanisms include reversible addition of oxygen to carbon radicals, rearrangement and cyclization of allyl and pentadienyl peroxyl radicals, and homolytic substitution of carbon radicals on the peroxide bond. A physical organic approach to the problem of free radicals in biology and medicine is highlighted in this Perspective with stereochemical, kinetic, and extrathermodynamic probes applied to the study of mechanism. A radical clock permits the determination of free radical propagation rate constants, and 7 dehydrocholesterol, the immediate biosynthetic precursor of cholesterol, is found by this clock to be one of the most oxidizable lipids known. The consequences of the extreme reactivity of 7-dehydrocholesterol on human health is the focus of a current research theme in the author's laboratory. PMID- 23445182 TI - Pain medication management in nursing homes and nursing scope of practice. AB - Inadequate pain medication management is pervasive in nursing homes (NHs). Licensed practical nurses (LPNs) deliver the majority of licensed nursing care, but LPNs are neither trained nor licensed to provide comprehensive pain assessment and medication management. In this study, we describe how pain medication management occurs in NHs by exploring LPNs' management approaches, while considering scope-of-practice differences between RNs and LPNs. Using comparative case studies of 10 NHs in North Carolina and Minnesota, we found practice variations in pain detection, assessment, and medication administration. Differences clustered in three areas: (a) the extent to which RNs and LPNs connected formally and informally to provide pain care, (b) the degree to which RNs and LPNs were considered interchangeable with one another, and (c) the RN-to LPN ratio. Results highlight quality issues and suggest ways to improve pain medication management in NHs. PMID- 23445183 TI - Improving comprehension of medication information: implications for nurse-patient communication. AB - Older adults with chronic illness have complex medication regimens that require an understanding of a wide range of information. The impact of patient characteristics (e.g., cognitive ability), health documents (language and multimedia), and the communication context (available time to communicate) in which older adults understand the information needed to take medication safely are considered to identify recommendations for nurses to communicate effectively with older adults. This article focuses on visually presented information (text and graphics) to motivate suggestions for improving patient education materials. Information communicated during provider-patient encounters is also considered, with implications for improving nurse-patient collaboration. PMID- 23445184 TI - Characterizing caregiver-mediated medication management in patients with memory loss. AB - Increasingly, family members are assisting with the complex task of medication management when patients are experiencing cognitive decline. To date, limited published research addresses caregiver-mediated medication management of patients with impaired cognition. Thus, the purpose of this study was to describe the characteristics and correlates of caregiver-mediated medication management in community-dwelling patients with memory loss. We used baseline data from the 91 patient-caregiver dyads participating in a randomized controlled trial designed to assist caregivers of patients with memory loss with medication management. The patient's level of cognitive impairment was not related to medication errors; however, the number of medications that patients were prescribed and taking was related to medication errors. Important factors to consider when discussing medication management with caregivers of patients with memory loss include the caregiver's age, cognitive ability, and depressive symptoms, as well as the caregiver's perception of the impact of the patient's behavioral problems. PMID- 23445185 TI - Treatment of insomnia in older adults: re-evaluating the benefits and risks of sedative hypnotic agents. AB - Insomnia and sleep complaints are common among older adults. Although once considered safer than benzodiazepine drugs, recent data on non-benzodiazepine drugs, such as zolpidem (Ambien((r))), have revealed similar negative effects. This issue, as well as others, has been included in the recent updated 2012 American Geriatrics Society Beers Criteria. This article describes the risks and benefits associated with sedative hypnotic agents in older adults and discusses the conundrum facing practitioners as well as patients. PMID- 23445186 TI - Risk evaluation and mitigation strategies for older adults with persistent pain. AB - The U.S. Food and Drug Administration issued Risk Evaluation and Mitigation Strategies for certain analgesic agents, but all medicines for older adults warrant risk-reduction considerations. Although not all older adults have pain, a higher prevalence of persistent pain exists in this population. Nursing actions are needed to minimize the negative impact persistent pain, analgesic agents, or both have on physical, mental, and social functioning. Practices vary considerably, ranging from failing to use analgesic agents for older adults with considerable pain to exposing them to potentially life-threatening toxicities, overdoses, or drug interactions. Older adults tend to be more vulnerable to side effects and drug interactions due to differences in drug distribution, metabolism, and elimination; thus, vigilant assessment and monitoring is needed to mitigate risks whenever analgesic agents are used. This review delineates these vulnerabilities while informing clinicians of the strategies needed to promote safe, effective use of medications when treating pain in older adults. PMID- 23445187 TI - Cobalt corrole catalyst for efficient hydrogen evolution reaction from H2O under ambient conditions: reactivity, spectroscopy, and density functional theory calculations. AB - The feasibility of a hydrogen-based economy relies very much on the availability of catalysts for the hydrogen evolution reaction (HER) that are not based on Pt or other noble elements. Significant breakthroughs have been achieved with certain first row transition metal complexes in terms of low overpotentials and large turnover rates, but the majority of reported work utilized purified and deoxygenated solvents (most commonly mixtures of organic solvents/acids). Realizing that the design of earth abundant metal catalysts that operate under truly ambient conditions remains an unresolved challenge, we have now developed an electronically tuned Co(III) corrole that can catalyze the HER from aqueous sulfuric acid at as low as -0.3 V vs NHE, with a turnover frequency of 600 s(-1) and ?10(7) catalytic turnovers. Under aerobic conditions, using H2O from naturally available sources without any pretreatment, the same complex catalyzes the reduction of H(+) with a Faradaic Yield (FY) of 52%. Density functional theory (DFT) calculations indicate that the electron density on a putative hydride species is delocalized off from the H atom into the macrocycle. This makes the protonation of a [Co(III)-H](-) species the rate determining step (rds) for the HER consistent with the experimental data. PMID- 23445188 TI - CD40, CD80, and CD86 costimulatory molecules are differentially expressed on murine splenic antigen-presenting cells during the pre-implantation period of pregnancy, and they modulate regulatory T-cell abundance, peripheral cytokine response, and pregnancy outcome. AB - PROBLEM: The object of the study was to investigate the costimulatory phenotype of spleen antigen-presenting cells (APCs) in mice after mating and the influence of costimulatory signal blocking on pregnancy outcome, cytokine production, and Treg cell concentration. METHOD OF STUDY: The levels of CD40, CD80, and CD86 on spleen APCs at day 0.5 and 3.5 after mating (C57BL/6Jx DBA/2J and C57BL/6JxBalb/c) were assessed by flow cytometry and RT-PCR. Blocking antibodies against costimulatory molecules were given i.p. at day 3.5 after mating. Pregnancy outcomes, blood cytokine (ELISA), and spleen Treg (flow cytometry) concentrations were examined at day 10.5 after mating. RESULTS: Differential expression of costimulatory molecules on spleen APCs of mated v. pseudopregnant mice was observed mainly at day 3.5 after conception. Administration of anti-CD86 antibody lowered pregnancy outcome. Cytokine expression was modulated after administration of anti-CD86, anti-CD80 and anti-CD40 antibodies, whereas only anti-CD40 antibody changed the concentration of Treg lymphocytes and the level of Foxp3 protein expression. CONCLUSION: Costimulatory phenotype of female spleen APCs is distinctly modulated after mating. Alteration of costimulatory signal derived from APCs during pre-implantation period of pregnancy may have an adverse effect on pregnancy outcome and the tolerogenic immune response. PMID- 23445189 TI - Optoelectronic functional materials based on alkylated-pi molecules: self assembled architectures and nonassembled liquids. AB - The engineering of single molecules into higher-order hierarchical assemblies is a current research focus in molecular materials chemistry. Molecules containing pi-conjugated units are an important class of building blocks because their self assembly is not only of fundamental interest, but also the key to fabricating functional systems for organic electronic and photovoltaic applications. Functionalizing the pi-cores with "alkyl chains" is a common strategy in the molecular design that can give the system desirable properties, such as good solubility in organic solvents for solution processing. Moreover, the alkylated pi system can regulate the self-assembly behavior by fine-tuning the intermolecular forces. The optimally assembled structures can then exhibit advanced functions. However, while some general rules have been revealed, a comprehensive understanding of the function played by the attached alkyl chains is still lacking, and current methodology is system-specific in many cases. Better clarification of this issue requires contributions from carefully designed libraries of alkylated-pi molecular systems in both self-assembly and nonassembly materialization strategies. Here, based on recent efforts toward this goal, we show the power of the alkyl chains in controlling the self-assembly of soft molecular materials and their resulting optoelectronic properties. The design of alkylated-C60 is selected from our recent research achievements, as the most attractive example of such alkylated-pi systems. Some other closely related systems composed of alkyl chains and pi-units are also reviewed to indicate the universality of the methodology. Finally, as a contrast to the self-assembled molecular materials, nonassembled, solvent-free, novel functional liquid materials are discussed. In doing so, a new journey toward the ultimate organic "soft" materials is introduced, based on alkylated-pi molecular design. PMID- 23445190 TI - Involving the cerebellum in cocaine-induced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine. AB - Because of its primary role in drug-seeking, consumption and addictive behaviour, there is a growing interest in identifying the neural circuits and molecular mechanisms underlying the formation, maintenance and retrieval of drug-related memories. Human studies, which focused on neuronal systems that store and control drug-conditioned memories, have found cerebellar activations during the retrieval of drug-associated cue memory. However, at the pre-clinical level, almost no attention has been paid to a possible role of the cerebellum in drug-related memories. In the present study, we ought to fill this gap by aiming to investigate the pattern of neuronal activation (as revealed by cFos expression) in different regions of the prefrontal cortex and cerebellum of mice trained to develop conditioned preference for an olfactory stimulus (CS+) paired with cocaine. Our results indicate that CS+ preference was directly associated with cFos expression in cells at the apical region of the granule cell layer of the cerebellar vermis; this relationship being more prominent in some specific lobules. Conversely, cFos+ immunostaining in other cerebellar regions seems to be unrelated to CS+ preference but to other aspects of the conditioning procedure. At the prefrontal cortex, cFos expression seemed to be related to cocaine administration rather than to its ability to establish conditioned preference. The present results suggest that as it has been observed in some clinical studies, the cerebellum might be an important and largely overlooked part of the neural circuits involved in generating, maintaining and/or retrieving drug memories. PMID- 23445191 TI - Inactivation of Pseudomonas aeruginosa by direct sunlight. AB - We determined the sensitivity of Pseudomonas aeruginosa to direct sunlight radiation, while maintaining the experimental temperature below levels harmful to the bacterium. The results presented here were similar to previous data on solar sensitivity obtained half a world away on another related bacterial species. The findings presented in this study suggest that related bacteria have a characteristic sensitivity to sunlight with their survival depending mainly on the fluence (photons) received in a dose-dependent manner that is otherwise relatively independent from latitude, atmospheric ozone and other local conditions. Conditions that inactivated P. aeruginosa did not result in measurable impairment of specific polymerase chain reaction (PCR) or enzyme linked immunoassays (ELISA) tests suggesting that this germ could still be amenable to detection after inactivation by sunlight. The results presented in this study should assist in predicting the survival of P. aeruginosa outdoors and in monitoring the risk posed by this widespread organism in a variety of environmental settings. PMID- 23445192 TI - The benefits and risks of alemtuzumab in multiple sclerosis. PMID- 23445193 TI - Infections during treatment with biological agents and possible treatment in clinical practice. PMID- 23445196 TI - Immunopathogenesis of allergic disorders: current concepts. AB - Allergic disorders are a group of immune-mediated disorders that are associated with considerable morbidity and ill health. There has been significant rise in the prevalence of allergy in the last few years. This has heightened interest in uncovering the novel mechanisms involved in etiopathogenesis of allergic disorders. Understanding the pathways underlying allergy will help in developing effective modalities for its prevention and treatment. This review focuses primarily on common IgE-mediated allergic conditions and recent developments in their immunopathogenesis, especially those involving respiratory mucosa. PMID- 23445197 TI - Allergy to ortho-phthalaldehyde in the healthcare setting: advice for clinicians. AB - This study summarizes and reviews the available health information on ortho phthalaldehyde (OPA), a recently introduced and widespread disinfectant for heat sensitive medical equipment, particularly focusing on its possible immunological effects in the healthcare setting. OPA properties derived from laboratory and clinical studies, and in vivo and in vitro tests for the diagnosis of OPA allergy are described. The available evidence suggests the spreading of OPA as disinfectant in endoscopy units despite the little available scientific evidence on its safety. Indeed, some papers reported on serious adverse reactions to OPA in patients and, to a lesser extent, in exposed workers, and in vivo studies suggested that OPA is a dermal and respiratory sensitizer. Finally, until more definite safety data become available only suggestions on possible preventive measures can be provided. PMID- 23445195 TI - Fueling autoimmunity: type I interferon in autoimmune diseases. AB - In recent years, active research using genomic, cellular and animal modeling approaches has revealed the fundamental forces driving the development of autoimmune diseases. Type I interferon imprints unique molecular signatures in a list of autoimmune diseases. Interferon is induced by diverse nucleic acid containing complexes, which trigger innate immune activation of plasmacytoid dendritic cells. Interferon primes, activates or differentiates various leukocyte populations to promote autoimmunity. Accordingly, interferon signaling is essential for the initiation and/or progression of lupus in several experimental models. However, the heterogeneous nature of systemic lupus erythematosus requires better characterization on how interferon pathways are activated and subsequently promote the advancement of autoimmune diseases. Given the central role of type I interferon, various strategies are devised to target these cytokines or related pathways to curtail the progression of autoimmune diseases. PMID- 23445198 TI - Role of IgG antibodies in association with placental function and immunologic diseases in human pregnancy. AB - During human pregnancy, the maternal immune system develops and changes, providing protection for the growing placenta and fetus. These protective changes provide mechanisms allowing two genetically different individuals to interact with each other without allograft rejection. In addition to normal pregnancy, some pregnancies may develop under immunologic diseases, during which specific monitoring and medical treatments are essential. The aim of this current review is to provide information regarding the development of human placental function during pregnancy, the immunology of human pregnancy and the role of the placenta in providing the fetal tissue with antibodies (IgG and its subclasses 1-4), which are required for the passive immunization of the newborn. In addition, the available methods for the determination of placental function will be explored. Furthermore, immunologic diseases observed during pregnancy and the possible therapies for these diseases will be assessed. PMID- 23445199 TI - Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults. AB - Idiopathic focal and segmental glomerular sclerosis is a frequent cause of nephrotic syndrome and end-stage renal disease. The pathogenesis is still unknown, although the body of evidence suggests that focal and segmental glomerular sclerosis is caused by a not clearly identified circulating factor that alters the permselectivity of the glomerular barrier. Proteinuria is followed by podocyte injury. Glucocorticoids, calcineurin inhibitors, cytotoxic agents and mycophenolate mofetil, either given alone or in combination, may obtain complete or partial remission of proteinuria in 50-60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to the available drugs. A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation. PMID- 23445200 TI - Leptospirosis: current situation and trends of specific laboratory tests. AB - Leptospirosis is re-emerging as a worldwide zoonosis and is caused by bacteria of the genus Leptospira. Human leptospirosis is associated with high temperature and humidity. Laboratory tests are indispensible for the early diagnosis and proper disease management. The demand for suitable leptospirosis point-of-care diagnostic tests grows with the awareness and number of incidences. Confirmation is achieved by the microscopic agglutination test, bacterial cultivation, PCR or histopathologic methods. However, high costs, poor standardization and/or elaborate sample preparation prevent routine use at the point of care. Cost efficient, but insensitive serological methods dominate the diagnostic landscape and, likewise, urgently need improvement toward greater compliance with some of the point-of-care criteria. Combined application of antigen and antibody detection methods increases accuracy, but also new development or transfer of diagnostic technologies should be considered useful. Nano- and microparticle technology may play a key role in improving future antigen detection methods. PMID- 23445204 TI - The role of fecundity and reproductive effort in defining life-history strategies of North American freshwater mussels. AB - Selection is expected to optimize reproductive investment resulting in characteristic trade-offs among traits such as brood size, offspring size, somatic maintenance, and lifespan; relative patterns of energy allocation to these functions are important in defining life-history strategies. Freshwater mussels are a diverse and imperiled component of aquatic ecosystems, but little is known about their life-history strategies, particularly patterns of fecundity and reproductive effort. Because mussels have an unusual life cycle in which larvae (glochidia) are obligate parasites on fishes, differences in host relationships are expected to influence patterns of reproductive output among species. I investigated fecundity and reproductive effort (RE) and their relationships to other life-history traits for a taxonomically broad cross section of North American mussel diversity. Annual fecundity of North American mussel species spans nearly four orders of magnitude, ranging from < 2000 to 10 million, but most species have considerably lower fecundity than previous generalizations, which portrayed the group as having uniformly high fecundity (e.g. > 200000). Estimates of RE also were highly variable, ranging among species from 0.06 to 25.4%. Median fecundity and RE differed among phylogenetic groups, but patterns for these two traits differed in several ways. For example, the tribe Anodontini had relatively low median fecundity but had the highest RE of any group. Within and among species, body size was a strong predictor of fecundity and explained a high percentage of variation in fecundity among species. Fecundity showed little relationship to other life-history traits including glochidial size, lifespan, brooding strategies, or host strategies. The only apparent trade-off evident among these traits was the extraordinarily high fecundity of Leptodea, Margaritifera, and Truncilla, which may come at a cost of greatly reduced glochidial size; there was no relationship between fecundity and glochidial size for the remaining 61 species in the dataset. In contrast to fecundity, RE showed evidence of a strong trade-off with lifespan, which was negatively related to RE. The raw number of glochidia produced may be determined primarily by physical and energetic constraints rather than selection for optimal output based on differences in host strategies or other traits. By integrating traits such as body size, glochidial size, and fecundity, RE appears more useful in defining mussel life-history strategies. Combined with trade-offs between other traits such as growth, lifespan, and age at maturity, differences in RE among species depict a broad continuum of divergent strategies ranging from strongly r-selected species (e.g. tribe Anodontini and some Lampsilini) to K selected species (e.g. tribes Pleurobemini and Quadrulini; family Margaritiferidae). Future studies of reproductive effort in an environmental and life-history context will be useful for understanding the explosive radiation of this group of animals in North America and will aid in the development of effective conservation strategies. PMID- 23445203 TI - Evaluation of adverse events in self-reported sulfa-allergic patients using topical carbonic anhydrase inhibitors. AB - PURPOSE: To investigate whether a self-reported history of allergy to sulfa-based drugs is a predictor for subsequent adverse reactions to topical carbonic anhydrase inhibitors (CAIs). METHODS: A retrospective case-controlled cohort study via chart review was performed on 1,287 patients with a diagnosis of glaucoma. The outcome measure was the development of an adverse reaction (either ocular, systemic, or both) within at least 30 days after receipt of 1 of 4 classes of topical glaucoma medications: CAIs (dorzolamide and brinzolamide), prostaglandin analogues, beta-adrenergic blockers, and alpha2-adrenergic agonists. RESULTS: Patients with a self-reported history of sulfa allergy had significantly more ocular adverse reactions after the initiation of any of the topical antiglaucoma medications when compared to those patients with no reported allergies. Patients with a self-reported sulfa allergy and patients who self reported other, nonsulfa-related allergies had similar rates of adverse reactions to most of the topical medications. The patients reporting a sulfa allergy who used topical CAIs did not have more adverse reactions compared with patients who reported having other, nonsulfa-related allergies who used topical CAIs. Self reported sulfa-allergic patients had similar rates of adverse reactions to topical CAIs compared with topical prostaglandin analogues. CONCLUSION: It may be safe to use a topical CAI in patients who report a history of a sulfa allergy. Patients with medication allergies of any kind may be more likely to develop allergic reactions to other, unrelated drug classes. PMID- 23445206 TI - Method for the preparation of derivatives of heptiptycene: toward dual-cavity baskets. AB - We have developed a novel synthetic method that enables the preparation of functional derivatives of heptiptycene, i.e., cavitands with two juxtaposed cavities. The homocoupling of bicyclic dibromoalkenes is promoted by Pd(OAc)2 (10%) in dioxane (100 degrees C) to give cyclotrimers in 27-77% yield under optimized reaction conditions (Ph3P, K2CO3, n-Bu4NBr, N2, 4 A MS). These dual cavity baskets show a strong pi -> pi* absorption at 241 nm (epsilon = 939,000 M( 1) cm(-1)), along with a subsequent fluorescence emission at 305 nm. PMID- 23445205 TI - Pathway-focused bioassays and transcriptome analysis contribute to a better activity monitoring of complex herbal remedies. AB - BACKGROUND: Transcriptome analysis in combination with pathway-focused bioassays is suggested to be a helpful approach for gaining deeper insights into the complex mechanisms of action of herbal multicomponent preparations in living cells. The polyherbalism based concept of Tibetan and Ayurvedic medicine considers therapeutic efficacy through multi-target effects. A polyherbal Indo Tibetan preparation, Padma 28, approved by the Swiss drug authorities (Swissmedic Nr. 58436), was applied to a more detailed dissection of mechanism of action in human hepatoma HepG2 cells. Cell-free and cell-based assays were employed to evaluate the antioxidant capacity. Genome-wide expression profiling was done by applying Human Genome U133 Plus 2.0 Affymetrix arrays. Pathway- and network oriented analysis elucidated the affected biological processes. The results were validated using reporter gene assays and quantitative real-time PCR. RESULTS: To reveal the direct radical scavenging effects of the ethanolic extract of the Indo Tibetan polyherbal remedy Padma 28, an in vitro oxygen radical absorbance capacity assay (ORAC) was employed, which resulted in a peroxyl-radical scavenging activity of 2006 +/- 235 MUmol TE/g. Furthermore, the antioxidant capacity of Padma 28 was analysed in living HepG2 cells, by measuring its scavenging potential against radical induced ROS. This formulation showed a considerable antioxidant capacity by significantly reducing ROS levels in a dose dependent manner.Integrated transcriptome analysis revealed a major influence on phase I and phase II detoxification and the oxidative stress response. Selected target genes, such as heme oxygenase 1, were validated in qPCR experiments. Network analysis showed 18 interrelated networks involved in important biological functions such as drug and bio-molecule metabolism, molecular transport and cellular communication. Some molecules are part of signaling cascades that are active during development and morphogenesis or are involved in pathological conditions and inflammatory response. CONCLUSIONS: The identified molecular targets and pathways suggest several mechanisms that underlie the biological activity of the preparation. Although extrapolation of these findings to the in vivo situation is not possible, the results obtained might be the basis for further investigations and new hypotheses to be tested. This study demonstrates the potential of the combination of focused and unbiased research strategies in the mode of action analysis of multicomponent herbal mixtures. PMID- 23445207 TI - Proconiini sharpshooters of Argentina, with notes on its distribution, host plants, and natural enemies. AB - The American tribe Proconiini (Hemiptera: Cicadellidae: Cicadellinae) is one of the largest groups of xylem-feeding insects and includes the majority of the known vectors of xylem-born phytopathogenic organisms. The significance of the pathogens that this group transmits gives them an important role as pests, mostly for citrus fruit, grapes, and almonds. Knowledge of these Hemiptera in Argentina is insufficient and fragmentary. Thus one of the aims of this paper is to summarize the available information of the Proconiini sharpshooters in Argentina. In addition, 14 species are mentioned for the first time in the country, and new distributional data are given for 18 species. Thirty-four new associations between sharpshooters and host plants are recorded. New records of egg parasitoids are given for Dechacona missionum, Molomea consolida, M. lineiceps, and Tapajosa similis. PMID- 23445208 TI - Identifying refugia from climate change using coupled ecological and genetic data in a transitional Mediterranean-temperate tree species. AB - Populations occurring in areas of overlap between the current and future distribution of a species are particularly important because they can represent "refugia from climate change". We coupled ecological and range-wide genetic variation data to detect such areas and to evaluate the impacts of habitat suitability changes on the genetic diversity of the transitional Mediterranean temperate tree Fraxinus angustifolia. We sampled and genotyped 38 natural populations comprising 1006 individuals from across Europe. We found the highest genetic diversity in western and northern Mediterranean populations, as well as a significant west to east decline in genetic diversity. Areas of potential refugia that correspond to approximately 70% of the suitable habitat may support the persistence of more than 90% of the total number of alleles in the future. Moreover, based on correlations between Bayesian genetic assignment and climate, climate change may favour the westward spread of the Black Sea gene pool in the long term. Overall, our results suggest that the northerly core areas of the current distribution contain the most important part of the genetic variation for this species and may serve as in situ macrorefugia from ongoing climate change. However, rear-edge populations of the southern Mediterranean may be exposed to a potential loss of unique genetic diversity owing to habitat suitability changes unless populations can persist in microrefugia that have facilitated such persistence in the past. PMID- 23445209 TI - Single cell antimicrobial susceptibility testing by confined microchannels and electrokinetic loading. AB - Multidrug-resistant pathogens are an emerging global health problem. In addition to the need of developing new antibiotics in the pipeline, the ability to rapidly determine the antibiotic resistance profiles of bacteria represents one of the most crucial steps toward the management of infectious diseases and the prevention of multidrug-resistant pathogens. Here, we report a single cell antimicrobial susceptibility testing (AST) approach for rapid determination of the antibiotic resistance of bacterial pathogens. By confining individual bacteria in gas permeable microchannels with dimensions comparable to a single bacterium, the antibiotic resistance of the bacteria can be monitored in real time at the single cell level. To facilitate the dynamic loading of the bacteria into the confined microchannels for observation, AC electrokinetics is demonstrated for capturing bacteria to defined locations in high-conductivity AST buffer. The electrokinetic technique achieves a loading efficiency of about 75% with a negligible effect on the bacterial growth rate. To optimize the protocol for single cell AST, the bacterial growth rate of individual bacteria under different antibiotic conditions has been determined systematically. The applicability of single cell AST is demonstrated by the rapid determination of the antimicrobial resistant profiles of uropathogenic clinical isolates in Mueller-Hinton media and in urine. The antibiotic resistance profiles of bacteria can be determined in less than 1 h compared to days in standard culture-based AST techniques. PMID- 23445210 TI - Dangerous combinations: Ingestible CAM supplement use during chemotherapy in patients with ovarian cancer. AB - OBJECTIVE: Some ingestible complementary and alternative medicine (CAM) supplements, including herbal remedies, teas, and vitamins, have biological activities that make them likely to interact poorly with conventional chemotherapeutic treatments. This study surveyed women with ovarian cancer to document the extent to which women use ingestible CAM supplements and conventional chemotherapeutic treatments that are believed to be of potential concern when used together. METHODS: A total of 219 patients with ovarian cancer who received care from 1 of 2 participating conventional oncology practices were surveyed about CAM use during and after ovarian cancer treatment. RESULTS: A total of 200 women reported having chemotherapy to treat their ovarian cancer. Of those, 79 (40%) reported using 1 or more CAM supplements that could be cause for concern when taken with 1 or more of the chemotherapy medications they were receiving. Many patients took multiple supplements of potential concern. Of these women, 42% (n=33) consulted with a conventional provider and 24% (n=19) consulted with a CAM provider about the contraindicated supplements they used. CONCLUSION: Although it is not clear that any of these contraindicated combinations of CAM and conventional therapy actually caused adverse outcomes, increased toxicities, or reduced the effectiveness of primary therapies, all these effects are possible given the substances being used in combination. Research is needed to understand the real risk associated with CAM and conventional polypharmacy. If risks associated with CAM use prove substantial, then improved systems to assure that all women get advice regarding supplement use during ovarian cancer treatment will be needed. PMID- 23445211 TI - Effectiveness of Chinese herbal medicine as an adjunctive treatment for dilated cardiomyopathy in patients with heart failure. AB - OBJECTIVES: To evaluate the effectiveness and safety of Chinese herbal medicine (CHM) as an adjunctive treatment for patients with dilated cardiomyopathy (DCM) and heart failure. DESIGN: Studies on biomedical treatment plus CHM versus biomedical treatment alone in treating patients with DCM and heart failure were retrieved from PubMed and other major databases (1980-2011). Meta-analysis was performed on the overall effects on effective rate, left ventricular ejection fraction, left ventricular diastolic end diameter, and other outcome measures. RESULTS: Twenty-seven studies with 1887 patients were included. Compared with biomedical treatment alone, biomedical treatment plus CHM showed significant improvement in effective rate (relative risk, 1.26; 95% confidence interval [CI], 1.19-1.34), left ventricular ejection fraction (%) (mean difference, 5.88; 95% CI, 3.92-7.85), left ventricular diastolic end diameter (mm) (mean difference, 2.78; 95% CI, -5.15 to -0.42), and other outcome measures. Most adverse events observed in the studies were not severe and resolved without special treatment. CONCLUSIONS: This meta-analysis indicated that biomedical treatment plus CHM is more effective than biomedical treatment alone in treating patients with DCM and heart failure. However, further studies with long-term follow-up, systemic adverse events evaluation, and other ethnic groups are still required to verify the efficacy and safety of CHM as an adjunctive treatment in all patients with DCM and heart failure. PMID- 23445212 TI - It is time to define metabolically obese but normal-weight (MONW) individuals. PMID- 23445214 TI - Knowledge of ethical guidelines: a survey of the Danish Psychiatric Association. PMID- 23445215 TI - After the flood: resilience among tsunami-afflicted adolescents. AB - BACKGROUND: About 7000 Swedish citizens were on Christmas holiday in the disaster area at the time of the South-east Asian tsunami in 2004, in many cases with children and adolescents in their families. AIMS: To investigate how adolescents experience a traumatic exposure to a natural disaster. METHOD: Twenty adolescents aged 16-19 years, who had experienced the 2004 tsunami and participated in a follow-up study 19 months post-disaster, were randomly selected and interviewed about their reactions, their life afterwards and their families. The study combines the face-to-face, semi-structured interviews with questionnaire data on mental health for 4910 Swedish adolescents and adults. RESULTS: The themes that emerged inductively during the analysis of the interviews were psychological reactions during the catastrophe, the coping after, changes in self-image, worldview, role in the family, risk interpretation and altruism. The disaster had profound impact on family relations, social networks and plans for the future. Many felt strengthened by the experience and by their ability to cope in comparison with other family members, but also perceived isolation and lack of understanding. The general mental health status among the adolescents did not differ significantly from those of older age at the 19-month follow-up. CONCLUSIONS: According to the adolescents', they experienced the tsunami-disaster differently than others around them. Their subjective interpretation of the event and its aftermath indicates resilience, especially among the young men. Future follow-up studies in larger samples of both symptoms and psychological functioning are warranted. PMID- 23445217 TI - Considerations for the development of health-based surface dust cleanup criteria for beryllium. AB - The exposure-response patterns with beryllium sensitization (BeS), chronic beryllium disease (CBD) and lung cancer are influenced by a number of biological and physicochemical factors. Recent studies have suggested dermal exposure as a pathway for BeS. In light of the current non-health-based DOE Beryllium Rule surface criteria, the feasibility of deriving a human health-based surface dust cleanup criteria (SDCC) for beryllium was assessed based on toxicology and health risk factors via all potential routes of exposure. Beryllium-specific and general exposure factors were evaluated, including (1) beryllium physicochemical characteristics, bioavailability and influence on disease prevalence, and (2) chemical dissipation, resuspension and transfer. SDCC for non-cancer (SDCC) and cancer (SDCC) endpoints were derived from a combination of modern methods applied for occupational, residential and building reentry surface dust criteria. The most conservative SDCC estimates were derived for dermal exposure (5-379 MUg/100 cm for 0.1-1% damaged skin and 17-3337 MUg/100 cm for intact skin), whereas the SDCC for inhalation exposure ranged from 51 to 485 MUg/100 cm. Considering this analysis, the lowest DOE surface criterion of 0.2 MUg/100 cm is conservative for minimizing exposure and potential risks associated with beryllium-contaminated surfaces released for non-beryllium industrial or public sector use. Although methodological challenges exist with sampling and analysis procedures, data variability and interpretation of surface dust information in relation to anthropogenic and natural background concentrations, this evaluation should provide useful guidance with regard to cleanup of manufacturing equipment or remediation of property for transfer to the general public or non-beryllium industrial facilities. PMID- 23445216 TI - Clinical, microbiological, and salivary biomarker profiles of dental implant patients with type 2 diabetes. AB - OBJECTIVE: Regulators of peri-implant bone loss in patients with diabetes appear to involve multiple risk factors that have not been clearly elucidated. This study was conducted to explore putative local etiologic factors on implant bone loss in relation to type 2 diabetes mellitus, including clinical, microbial, salivary biomarker, and psychosocial factors. MATERIALS AND METHODS: Thirty-two subjects (divided into type 2 diabetes mellitus and non-diabetic controls), having at least one functional implant and six teeth, were enrolled in a 1-year longitudinal investigation. Analyses of clinical measurements and standardized intra-oral radiographs, saliva and serum biomarkers (via protein arrays for 20 selected markers), and plaque biofilm (via qPCR for eight periodontal pathogens) were performed at baseline and 1 year. In addition, the subjects were asked to respond to questionnaires to assess behavioral and psychosocial variables. RESULTS: There was a significant increase from baseline to 1 year in the probing depth of implants in the diabetes group (1.95 mm to 2.35 mm, P = 0.015). The average radiographic bone loss during the study period marginally increased at dental implants compared to natural teeth over the study period (0.08 mm vs. 0.05 mm; P = 0.043). The control group harbored higher levels of Treponema denticola at their teeth at baseline (P = 0.046), and the levels of the pathogen increased significantly over time around the implants of the same group (P = 0.003). Salivary osteoprotegerin (OPG) levels were higher in the diabetes group than the control group at baseline only; in addition, the salivary levels of IL-4, IL-10, and OPG associated with host defense were significantly reduced in the diabetes group (P = 0.010, P = 0.019, and P = 0.024), while controls showed an increase in the salivary OPG levels (P = 0.005). For psychosocial factors, there were not many significant changes over the observation period, except for some findings related to coping behaviors at baseline. CONCLUSIONS: The study suggests that the clinical, microbiological, salivary biomarker, and psychosocial profiles of dental implant patients with type 2 diabetes who are under good metabolic control and regular maintenance care are very similar to those of non-diabetic individuals. Future studies are warranted to validate the findings in longer-term and larger clinical trials (ClinicalTrials.gov # NCT00933491). PMID- 23445219 TI - Rapid method for the separation and recovery of endocrine-disrupting compound bisphenol AP from wastewater. AB - The removal of bisphenol AP (BPAP) by a multiwalled carbon nanotube (MWCNT) was investigated. BPAP, representing typical scenarios for the BPAP-MWCNT interactions, was employed as a probe molecule. It was found that BPAP exhibited great adsorptive affinity to MWCNT, and the adsorption kinetics equilibrium was arrived within 4.0 min following the pseudo-second-order model. The overall rate process was mainly controlled by the external mass transfer. The hydrogen bond, hydrophobic, and pi-pi stacking interactions were dominant factors for the strong adsorption of BPAP, instead of the pH ionic strength and other ionic species in contaminated water. The MWCNT has higher stability within 8 removal-regeneration recycles, and up to 95% of recovery could be obtained by eluting the adsorbed BPAP on MWCNT adsorbent using ethanol/sodium hydrate solution. The results of the experiment on real samples verified the effectiveness for the recovery and removal of BPAP from wastewater samples. PMID- 23445221 TI - RegulatING chromatin regulators: post-translational modification of the ING family of epigenetic regulators. AB - The five human ING genes encode at least 15 splicing isoforms, most of which affect cell growth, differentiation and apoptosis through their ability to alter gene expression by epigenetic mechanisms. Since their discovery in 1996, ING proteins have been classified as type II tumour suppressors on the basis of reports describing their down-regulation and mislocalization in a variety of cancer types. In addition to their regulation by transcriptional mechanisms, understanding the range of PTMs (post-translational modifications) of INGs is important in understanding how ING functions are fine-tuned in the physiological setting and how they add to the repertoire of activities affected by the INGs. In the present paper we review the different PTMs that have been reported to occur on INGs. We discuss the PTMs that modulate ING function under normal conditions and in response to a variety of stresses. We also describe the ING PTMs that have been identified by several unbiased MS-based PTM enrichment techniques and subsequent proteomic analysis. Among the ING PTMs identified to date, a subset has been characterized for their biological significance and have been shown to affect processes including subcellular localization, interaction with enzymatic complexes and ING protein half-life. The present review aims to highlight the emerging role of PTMs in regulating ING function and to suggest additional pathways and functions where PTMs may effect ING function. PMID- 23445220 TI - Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. AB - Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in cancer via interaction with the DAL-1 tumor suppressor protein. However, few selective inhibitors of PRMTs have been discovered. We recently disclosed the first selective PRMT3 inhibitor, which occupies a novel allosteric binding site and is noncompetitive with both the peptide substrate and cofactor. Here we report comprehensive structure-activity relationship studies of this series, which resulted in the discovery of multiple PRMT3 inhibitors with submicromolar potencies. An X-ray crystal structure of compound 14u in complex with PRMT3 confirmed that this inhibitor occupied the same allosteric binding site as our initial lead compound. These studies provide the first experimental evidence that potent and selective inhibitors can be created by exploiting the allosteric binding site of PRMT3. PMID- 23445222 TI - G-protein-coupled receptor structure, ligand binding and activation as studied by solid-state NMR spectroscopy. AB - GPCRs (G-protein-coupled receptors) are versatile signalling molecules at the cell surface and make up the largest and most diverse family of membrane receptors in the human genome. They convert a large variety of extracellular stimuli into intracellular responses through the activation of heterotrimeric G proteins, which make them key regulatory elements in a broad range of normal and pathological processes, and are therefore one of the most important targets for pharmaceutical drug discovery. Knowledge of a GPCR structure enables us to gain a mechanistic insight into its function and dynamics, and further aid rational drug design. Despite intensive research carried out over the last three decades, resolving the structural basis of GPCR function is still a major activity. The crystal structures obtained in the last 5 years provide the first opportunity to understand how protein structure dictates the unique functional properties of these complex signalling molecules. However, owing to the intrinsic hydrophobicity, flexibility and instability of membrane proteins, it is still a challenge to crystallize GPCRs, and, when this is possible, it is no longer in its native membrane environment and no longer without modification. Furthermore, the conformational change of the transmembrane alpha-helices associated with the structure activation increases the difficulty of capturing the activation state of a GPCR to a higher resolution by X-ray crystallography. On the other hand, solid-state NMR may offer a unique opportunity to study membrane protein structure, ligand binding and activation at atomic resolution in the native membrane environment, as well as described functionally significant dynamics. In the present review, we discuss some recent achievements of solid-state NMR for understanding GPCRs, the largest mammalian proteome at ~1% of the total expressed proteins. Structural information, details of determination, details of ligand conformations and the consequences of ligand binding to initiate activation can all be explored with solid-state NMR. PMID- 23445218 TI - Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans. AB - Abstract Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors. PMID- 23445224 TI - How Sox2 maintains neural stem cell identity. AB - The transcription factor Sox2 [SRY (sex-determining region Y)-box 2] is expressed at the earliest developmental stages in the nervous system and functions as a marker protein for neural development. Sox2 is found in embryonic neural stem cells as well as in virtually all adult neural stem cells of the subventricular region and the subgranular zone of the hippocampus. Gain-of-function and loss-of function experiments in transgenic animals revealed a key role for Sox2 in the maintenance of neural stem cell properties, including proliferation/survival, self-renewal and neurogenesis. A limited set of Sox2-responsive target genes have been identified, including the genes encoding the neural stem cell marker nestin and the signalling molecule sonic hedgehog. In this issue of the Biochemical Journal, Feng et al. identified the survivin gene as a target for Sox2 in neural stem cells. Survivin protects cells from programmed cell death and functions as a regulator of cell division. The regulation of survivin expression by Sox2 explains why the reduction of the Sox2 concentration in neural stem cells is accompanied by a reduced proliferation of the cells and an induction of apoptosis. It would be of interest to know whether the Sox2-survivin connection is a common scheme to maintain the 'stemness' identity of other stem/progenitor cells. PMID- 23445225 TI - Incorporation of T4 bacteriophage in electrospun fibres. AB - AIMS: Antibacterial food packaging materials, such as bacteriophage-activated electrospun fibrous mats, may address concerns triggered by waves of bacterial food contamination. To address this, we investigated several efficient methods for incorporating T4 bacteriophage into electrospun fibrous mats. METHODS AND RESULTS: The incorporation of T4 bacteriophage using simple suspension electrospinning led to more than five orders of magnitude decrease in bacteriophage activity. To better maintain bacteriophage viability, emulsion electrospinning was developed where the T4 bacteriophage was pre-encapsulated in an alginate reservoir via an emulsification process and subsequently electrospun into fibres. This resulted in an increase in bacteriophage viability, but there was still two orders of magnitude drop in activity. Using a coaxial electrospinning process, full bacteriophage activity could be maintained. In this process, a core/shell fibre structure was formed with the T4 bacteriophage being directly incorporated into the fibre core. The core/shell fibre encapsulated bacteriophage exhibited full bacteriophage viability after storing for several weeks at +4 degrees C. CONCLUSIONS: Coaxial electrospinning was shown to be capable of encapsulating bacteriophages with high loading capacity, high viability and long storage time. SIGNIFICANCE AND IMPACT OF THE STUDY: These results are significant in the context of controlling and preventing bacterial infections in perishable foods during storage. PMID- 23445226 TI - Implanted electrical devices and gastroesophageal reflux disease: an effective approach to treatment. PMID- 23445227 TI - Triglyceride levels, pancreatitis and choice of lipid-modifying therapy. PMID- 23445228 TI - The novel use of peptide analogs in short bowel syndrome. PMID- 23445230 TI - The predictive value of steatosis in hepatitis C virus infection. AB - Steatosis is a complication of hepatitis C virus (HCV) infection and the mechanisms of its development are complex, involving viral and host factors. Steatosis that is prevalently viral is associated with HCV genotype 3, and steatosis that is prevalently metabolic is associated with non-3 genotypes. Viral steatosis is correlated with the level of HCV replication, whereas metabolic steatosis is related to insulin resistance. The two types of steatosis have a different impact on HCV disease and may have an additive effect. HCV infection is a multifaceted disease with hepatic and extrahepatic manifestations. There is a body of evidence indicating that HCV-related steatosis plays a role in many HCV manifestations and, thus, the presence of steatosis is a predictive factor for the development of such events. The current data show that HCV-related steatosis predicts an advanced liver disease and a more rapid progression of fibrosis, as well as an increased risk of development of hepatocellular carcinoma. Moreover, the presence of steatosis in a HCV patient has a high predictive value that the subject may have or may develop insulin resistance, diabetes and metabolic syndrome. Recently, a strict association between HCV-related steatosis and development of atherosclerosis has been demonstrated. In addition, steatosis negatively impacts response rate to interferon-based treatment, even in HCV genotype-3 infection. Therapeutic strategies to improve steatosis and, consequently, response to standard antiviral therapy and outcome of disease are wanted. The authors summarize current knowledge of impact of steatosis on the above reported clinical conditions associated with HCV infection. PMID- 23445231 TI - The pediatric pouch in inflammatory bowel disease: a primer for the gastroenterologist. AB - Pediatric severe ulcerative colitis that is resistant to current medical treatment can successfully be managed surgically with a colectomy, ileal pouch creation and pouch-anal anastomosis. Key issues that should be considered and discussed before the pouch option can be offered include alternative surgical procedures, pouch function expectations, risk of surgical leak, pelvic sepsis, anastomotic strictures, acute and chronic pouch inflammation, Crohn's disease of the pouch and risk of reduced fertility for females. A long-term risk is malignancy of the residual colonic tissue. The decision to proceed with a pouch or not poses a substantial emotional burden to the child and family. Despite the risk of surgical complications and pouch inflammatory and functional challenges, the overwhelming majority of children and their families are satisfied with their pouch surgery outcomes. Further study is needed to assess preoperative risk predictors, prevention and treatment of complications. PMID- 23445232 TI - Psychological factors and stress in inflammatory bowel disease. AB - The role of psychological distress and personality as predisposing factors for the development of inflammatory bowel disease (IBD) remains controversial. Attempts to investigate the role of psychological factors in IBD exhibited rather conflicting results. Among the studies concerning the effects of stress or depression on the course of IBD, the majority suggest that stress worsened IBD, the rest giving either negative or inconclusive results. However, application of strategies, including avoidance of coping and training patients in problem solving or emotion-oriented, could influence the course of IBD. Large controlled clinical trials are needed in order to clarify the impact of psychological interventions on the quality of life and the course of disease. PMID- 23445233 TI - Evaluation of the small bowel in inflammatory bowel disease. AB - Crohn's disease is a chronic inflammatory bowel disease (IBD) that can affect the entire GI tract, and adequate visualization of the small bowel is imperative for both diagnosis and management. Magnetic resonance and computed tomography enterography have gradually replaced barium-based studies. Magnetic resonance enterography has the distinct advantage of avoiding ionizing radiation to which many patients with IBD are overexposed. Endoscopy-based techniques, including capsule endoscopy and device-assisted enteroscopy, allow direct visualization of the small bowel mucosa. Deep enteroscopy has the additional benefit of allowing sampling of the mucosa for histological analysis. Small intestine contrast ultrasound is rapidly gaining credence as an excellent, radiation-free imaging technique, but is not available in all countries. Other imaging modalities, such as positron emission tomography and leucocyte scintigraphy, continue to be studied and may have a role in specific circumstances. This review summarizes the evidence for the various techniques for evaluating the small bowel in IBD. PMID- 23445234 TI - Gut-liver axis: an immune link between celiac disease and primary biliary cirrhosis. AB - The association between celiac disease and primary biliary cirrhosis is well established. The breakdown of gut-liver axis equilibrium plays a central role in the development of immune disorders involving the small bowel and liver. In celiac disease, immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens reach the liver through the portal circulation owing to the increased intestinal permeability. A molecular mimicry between bacterial antigens and the pyruvate dehydrogenase E2 component, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis. An aberrant intestinal T lymphocyte homing to the liver may contribute to trigger immune hepatic damage. Both celiac disease and primary biliary cirrhosis share several features, including a higher prevalence in females, autoimmune comorbidities and specific autoantibodies. Reciprocal screening for both diseases is recommended, as an early diagnosis with the appropriate treatment can improve the outcome of these patients. PMID- 23445235 TI - Management of giant liver hemangiomas: an update. AB - Liver hemangiomas are the most common benign liver tumors and are usually incidental findings. Liver hemangiomas are readily demonstrated by abdominal ultrasonography, computed tomography or magnetic resonance imaging. Giant liver hemangiomas are defined by a diameter larger than 5 cm. In patients with a giant liver hemangioma, observation is justified in the absence of symptoms. Surgical resection is indicated in patients with abdominal (mechanical) complaints or complications, or when diagnosis remains inconclusive. Enucleation is the preferred surgical method, according to existing literature and our own experience. Spontaneous or traumatic rupture of a giant hepatic hemangioma is rare, however, the mortality rate is high (36-39%). An uncommon complication of a giant hemangioma is disseminated intravascular coagulation (Kasabach-Merritt syndrome); intervention is then required. Herein, the authors provide a literature update of the current evidence concerning the management of giant hepatic hemangiomas. In addition, the authors assessed treatment strategies and outcomes in a series of patients with giant liver hemangiomas managed in our department. PMID- 23445236 TI - Toward a standardized system for hepatocellular carcinoma diagnosis using computed tomography and MRI. AB - Contrast-enhanced computed tomography and MRI are frequently used for the noninvasive diagnosis of hepatocellular carcinoma (HCC). Despite their important role in diagnosis and management of HCC, until recently, there has been no standardized system for their interpretation, reporting and data collection. In 2008, the American College of Radiology convened a committee to develop such a standardized system. This article reviews the role of computed tomography and MRI in the diagnosis and management of HCC; the need for a standardized imaging interpretation system; current HCC imaging criteria included in management guidelines endorsed by the European Association for the Study of Liver, American Association for Study of Liver Diseases, United Network for Organ Sharing and Asian Pacific Association for the Study of the Liver; and the limitations of these criteria. The article then provides an overview of the Liver Imaging Reporting and Data System and discusses future directions. PMID- 23445237 TI - The role of antimicrobials in Crohn's disease. AB - This review summarizes literature regarding the role of antimicrobials for induction and maintenance of Crohn's disease (CD) remission. PubMed was searched (1966 to October 2012) for controlled trials involving adults and written in English. Five of the 13 identified studies showed benefit with the use of ciprofloxacin, metronidazole and rifaximin for induction of remission. Eight studies showed no benefit using ciprofloxacin, metronidazole, combination of metronidazole and ciprofloxacin or clarithromycin and rifaximin. Four of the five studies showed benefit based on colonic location. Perianal CD with draining fistulas responded in one of two studies. Two studies in postileocolonic resection demonstrated benefit of metronidazole or ornidazole in reducing CD recurrence. Antimicrobials, especially metronidazole, are promising for inducing remission in patients with colonic CD and preventing recurrence in postileocolonic resection. PMID- 23445238 TI - Organocatalytic C-H bond arylation of aldehydes to bis-heteroaryl ketones. AB - An organocatalytic aldehyde C-H bond arylation process for the synthesis of complex heteroaryl ketones has been developed. By exploiting the inherent electrophilicity of diaryliodonium salts, we have found that a commercial N heterocyclic carbene catalyst promotes the union of heteroaryl aldehydes and these heteroaromatic electrophile equivalents in good yields. This straightforward catalytic protocol offers access to ketones bearing a diverse array of arene and heteroarene substituents that can subsequently be converted into molecules displaying structural motifs commonly found in medicinal agents. PMID- 23445239 TI - PACE DATA CARD* PMID- 23445240 TI - STIMAREC Report of July, August, 1983. PMID- 23445241 TI - Performance of Cardiac Pacemaker Pulse Generators. PMID- 23445242 TI - Neutron diffraction study of the Li-ion battery cathode Li2FeP2O7. AB - With a combination of magnetic susceptibility measurements and low-temperature neutron diffraction analyses, the magnetic structure of Li2FeP2O7 cathode has been solved. This pyrophosphate Li2FeP2O7 compound stabilizes into a monoclinic framework (space group P2(1)/c), having a pseudolayered structure with the constituent Li/Fe sites distributed into MO6 and MO5 building units. The magnetic susceptibility follows a Curie-Weiss behavior above 50 K. Li2FeP2O7 shows a long range antiferromagnetic ordering at T(N) = 9 K, as characterized by the appearance of distinct additional peaks in the neutron diffraction pattern below T(N). Its magnetic reflections can be indexed with a propagation vector k = (0,0,0). The magnetic moments inside the FeO6-FeO5 clusters are ferromagnetic, whereas these clusters are antiferromagnetic along the chains. The adjacent chains are in turn ferromagnetically arranged along the a-axis. The magnetic structure of Li2FeP2O7 cathode material is described focusing on their localized spin-spin exchange. The magnetic structure and properties have been generalized for Li2FeP2O7-Li2CoP2O7 binary solid solutions. PMID- 23445243 TI - Latest progress in microsporidian genome research. AB - Microsporidia are obligate intracellular pathogens of medical and ecological importance whose genomes have been studied extensively over the last decade. Such studies have focused on the remarkably reduced gene content that characterizes all known species, and some have unraveled the mechanisms that are involved in their extreme genome compaction. In the last year, a large number of new genome sequences from several divergent members of the group have been finally released and analyzed, and these have revealed the presence of many features that were previously unsuspected to exist within the group. This study aims to shortly review the most recent progress in the field of microsporidian genomics, highlighting the importance of the most recently released genome data for our understanding of the biology and evolution of this important group of parasites. PMID- 23445244 TI - Suicidal ideations and sleep-related problems in early adolescence. AB - AIMS: Suicidal ideation and sleep-related problems are associated with many common psychopathological entities in early adolescence. This study examined possible association between suicidal ideation and sleep-related problems. METHODS: A cross-sectional study was performed in classroom settings at 840 early adolescents 11-13 years of age. Of those, 791 adolescents fully completed the data and thus represent an actual sample. Suicidal ideations were assessed with three dichotomous (yes/no) items: 'I often think about death'; 'I wish I was dead'; 'I often think about suicide.' A composite measure of perceived sleep related problems was formed by combining items from the Junior Eysenck Personality Questionnaire (Do you find it hard to sleep at night because you are worrying about things?), Children Depression Inventory (It is hard for me to fall asleep at night), and two additional dichotomous questions (I often was not able to fall asleep because of worrying; At times I was not able to stay asleep because of worrying). This score mainly assessed difficulties in initiating or maintaining sleep. RESULTS: A total of 7.1% adolescents reported suicidal ideation and 86.7% of them had sleep problems. Sleep-related problems were associated with any suicidal ideation and each type of ideation separately. CONCLUSION: This study suggests association of sleep problems and suicidal ideations in early adolescence. Therefore, clinicians should evaluate this population for sleep disturbances, as they might be a marker of increased risk for suicidality. PMID- 23445245 TI - Thermo-mechanical degradation of composite restoration photoactivated by modulated methods-a SEM study of marginal and internal gap formation. AB - OBJECTIVE: To evaluate the influence of thermal-mechanical degradation on superficial and internal gap formation of composite restorations photoactivated using modulated methods. MATERIALS AND METHODS: An experimental composite was prepared using a resin matrix containing 65wt% Bis-GMA and 35wt% TEGDMA. Camphorquinone (0.5wt%) and dimethylaminoethyl-methacrylate (0.5wt%) were dissolved in the resin as a photo-initiator system and 65wt.% silanized glass fillers were added to the matrix. Ground buccal surfaces of bovine lower incisors were used to make 160 preparations (3 mm * 3 mm * 2 mm in depth). An adhesive system (Adper Single Bond 2) was applied and the specimens were assigned into 16 groups (n = 10), according to the photoactivation method [high intensity (HI), low intensity (LI), soft-start (SS) and pulse-delay (PD)] and the degradation protocol [(control/no degradation; thermal cycling (TC); mechanical loading (ML); thermo-mechanical loading (TC+ML)]. Marginal and internal interfaces of bonded restorations were replicated in epoxy resin and analyzed by SEM. Gaps were expressed as a percentage of the total length of the margins. Data were submitted to 2-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: For the control group no significance was noted among the photoactivation methods. TC had no effect in gap formation. ML and TC+ML increased the incidence of superficial gaps for both HI and SS groups as well as increased the internal gaps for all groups. CONCLUSION: Although photoactivation methods do not influence gap formation at first, composite restoration photoactivated by low intensity or modulated methods showed improved resistance to thermo-mechanical degradation. Mechanical loading is determinant for interfacial degradation of composite restorations, while thermal cycling has no effect on gap formation. PMID- 23445246 TI - Histological findings on jaw osteonecrosis associated with bisphosphonates (BONJ) or with radiotherapy (ORN) in humans. AB - OBJECTIVE: To describe the histological features of bone tissue harvested from patients affected by jaw osteonecrosis associated with bisphoshponates (BONJ) or with radiotherapy (ORN), in undecalcified ground sections. MATERIALS AND METHODS: Sixteen bone tissue samples from 14 patients with BONJ and two patients with ORN were processed in order to obtain both ground, undecalcified sections and decalcified sections. The sections underwent histometric and morphometric analysis. RESULTS: Bone tissue samples obtained from patients with BONJ or ORN of the jaws shared some histological characteristics. Common histological features included the loss of bone architecture, the absence of a proper Haversian system and proper marrow spaces, the presence of necrotic spots of non-mineralized tissue, areas of empty osteocytic lacunae next to areas of hypercellularity, the presence of resorption pits with rare osteoclast-like cells and the presence of bacteria and of an inflammatory infiltrate. A violet rib of tissue characterized by large resorption pits facing was frequently observed between the mineralized bone and the inflammatory infiltrate. CONCLUSIONS: The histological features of BONJ and ORN are similar and resemble those of osteomyelitis. Even though it is not clear whether infection is the cause or consequence of bone exposure, inflammatory cells, bacteria or their products may have a massive, direct lytic effect on bone tissue challenged by bisphosphonates. PMID- 23445247 TI - A comparison of residual smear layer and erosion following different endodontic irrigation protocols tested under clinical and laboratory conditions. AB - OBJECTIVE: To compare the smear layer removal efficacy and erosive effects of different irrigation protocols under clinical and laboratory conditions. MATERIALS AND METHODS: Mandibular third molars (n = 32) of 30-45 year-old patients were instrumented with rotary files and were randomly assigned to one of the following groups for final irrigation: (1) 5.25% NaOCl; (2) 17% EDTA; and (3) BioPure MTAD. Thereafter, the teeth were immediately extracted and processed for micromorphological investigation. In vitro specimen pairs were prepared by repeating the clinical experiments on freshly-extracted mandibular third molars. To compare open and closed systems, laboratory experiments were repeated on 32 additional teeth with enlarged apical foramen. The cleanliness of the root canals and the extent of erosion were assessed by environmental scanning electron microscopy. RESULTS: Specimens prepared under clinical and laboratory conditions had similar cleanliness and erosion scores (p > 0.05). Under both conditions, the tested solutions were more effective in removing the smear layer in the coronal and middle regions than in the apical one. Comparison of closed and open systems showed similar levels of cleanliness and erosion in all regions (p > 0.05), with the exception of 17% EDTA showing significantly higher levels of cleanliness and erosion in the apical third of open-end specimens. CONCLUSIONS: Based on clinical correlates of in vitro root canal cleanliness and erosion, laboratory testing of root canal irrigants on extracted teeth with closed apices can serve as a reliable method to simulate the clinical condition. EDTA was the most effective final irrigation solution in removing the smear layer at the expense of yielding the greatest erosive effect. PMID- 23445248 TI - A pilot study to investigate adherence to long-acting opioids among patients with advanced lung cancer. AB - BACKGROUND: Uncontrolled pain remains prevalent in patients with advanced cancer and has been associated with worse quality of life and greater health care utilization. Poor adherence to analgesics may represent a modifiable barrier to pain management. OBJECTIVE: This pilot study aimed to establish feasibility/utility of evaluating self-reported adherence to long-acting (LA) opioids in patients with advanced lung cancer, and to explore rates and correlates of adherence. METHODS: Consecutive patients attending an ambulatory thoracic oncology clinic with a diagnosis of advanced lung cancer and a current LA opioid regimen were approached to complete a brief questionnaire during their clinic visit. Participants reported LA opioid adherence during the past 4 weeks (0%-100%) and knowledge of their LA opioid regimen, and completed the Patient Health Questionnaire-2 (PHQ-2) depression screen. Demographic and clinical information were confirmed via electronic health record review. RESULTS: Fifty four eligible patients were approached to reach our target sample (n=50; enrollment=92.6%). Self-reported adherence to LA opioids was 85.4% (standard deviation [SD]=21.0). Twenty-eight percent reported a frequency of medication use that did not match the prescribed daily frequency. Lower adherence was associated with inaccurate frequency (p=0.004), positive depression screen (p=0.005), and older age (p=0.04). CONCLUSIONS: Our results demonstrate the feasibility of integrating self-report assessments of LA opioid adherence into a thoracic oncology clinic. Patients reported high adherence, but more than one-quarter did not accurately report the prescribed frequency of daily doses. Understanding of LA opioid regimens may be a critical indicator of adherence in patients with advanced cancer. PMID- 23445249 TI - Not just little adults: palliative care physician attitudes toward pediatric patients. AB - BACKGROUND: Palliative care physicians are increasingly being asked to provide end-of-life (EOL) care for children. Yet very little is known about physicians' level of comfort and willingness to do so. OBJECTIVES: This study assessed the attitudes of palliative care physicians toward providing care for pediatric patients and to describe the supports they desire in order to do so. METHODS: An online questionnaire was e-mailed to all physicians in the Division of Palliative Care at the University of Toronto. The questionnaire explored perceptions, attitudes, and level of comfort caring for pediatric patients. Results are reported using frequencies, ratios, and other descriptive analyses. RESULTS: Forty-four physicians of the 74 (59%) surveyed responded. On average, physicians cared for fewer than one child per each year of practice. Although the majority of respondents perceived their pediatric training to be inadequate, 70% were willing to provide care to children. Respondents felt at ease applying their knowledge and skills in some aspects of pediatric care (e.g., principles of pain and symptom management, communication about EOL issues) but less so in others (e.g., medication dosing, ethical issues unique to pediatrics). All respondents welcomed opportunities for additional training, but a third felt it was not essential. In particular, the most frequently expressed need was for mentorship by pediatric palliative care specialists. CONCLUSIONS: Palliative physicians tend to be willing to care for children, but perceive their level of training to be insufficient. Although additional training is endorsed, physicians favored real time support and mentorship from a pediatric expert. PMID- 23445250 TI - Palliative medicine and psychiatry. PMID- 23445251 TI - Hospice emergency kit for veterans: a pilot study. AB - BACKGROUND: Although the provision of hospice emergency kits (HEKs) by home hospice agencies is thought to be widespread, little is known about their use, safety, and impact. OBJECTIVE: This study evaluated HEK medication utilization, safety, diversion, and perceived impact. DESIGN: Evaluation consisted of a retrospective patient chart abstraction and an anonymous questionnaire for home hospice nurses. SETTING/SUBJECTS: Chart abstraction examined the computerized records of deceased veterans discharged to home hospice in 2009 (N=76). The questionnaire was completed by 78 home hospice nurses from 16 agencies. MEASUREMENTS: Chart abstraction examined HEK medication utilization, symptoms addressed, and safety/diversion concerns. The hospice nurse questionnaire assessed their perceptions of HEK utilization, safety, and impact, including efficacy for preventing emergency department (ED) visits and hospitalizations. RESULTS: Of patients who received an HEK, its use was documented in 50% of cases. The most used items were morphine concentrate and antibiotics. Nurses estimated that the HEK was utilized in 66.3% of cases, with the most frequently used medications being morphine, lorazepam, promethazine, and haloperidol. Fifty-nine percent of nurses felt HEKs were helpful 100% of the time (mean=84.2%; median=100% of the time) and 93% felt that an emergency department (ED) visit or hospitalization was avoided by having the kit in the home. Eighteen percent believed that medications in the kit are used by someone other than the patient. CONCLUSIONS: HEKs have value as a means to alleviate many symptoms that emerge predictably in home hospice patients and may avoid unwanted hospitalizations and ED visits. PMID- 23445252 TI - Regression model for estimating inactivation of microbial aerosols by solar radiation. AB - The inactivation of pathogenic aerosols by solar radiation is relevant to public health and biodefense. We investigated whether a relatively simple method to calculate solar diffuse and total irradiances could be developed and used in environmental photobiology estimations instead of complex atmospheric radiative transfer computer programs. The second-order regression model that we developed reproduced 13 radiation quantities calculated for equinoxes and solstices at 35( degrees ) latitude with a computer-intensive and rather complex atmospheric radiative transfer program (MODTRAN) with a mean error <6% (2% for most radiation quantities). Extending the application of the regression model from a reference latitude and date (chosen as 35 degrees latitude for 21 March) to different latitudes and days of the year was accomplished with variable success: usually with a mean error <15% (but as high as 150% for some combination of latitudes and days of year). This accuracy of the methodology proposed here compares favorably to photobiological experiments where the microbial survival is usually measured with an accuracy no better than +/-0.5 log10 units. The approach and equations presented in this study should assist in estimating the maximum time during which microbial pathogens remain infectious after accidental or intentional aerosolization in open environments. PMID- 23445253 TI - Pressure ulcer on toe because of attaching patient's toe to bolt of ICU bed. PMID- 23445254 TI - Palladium-catalyzed decarboxylative cross-coupling reactions: a route for regioselective functionalization of coumarins. AB - A straightforward, regioselective, and step-economical ligand-free palladium catalyzed decarboxylative functionalization of coumarin-3-carboxylic acids is devised. This protocol is compatible with a wide variety of electron-donating and -withdrawing substituents and allows for construction of various biologically important pi-electron extended coumarins. PMID- 23445255 TI - Understanding tobacco industry pricing strategy and whether it undermines tobacco tax policy: the example of the UK cigarette market. AB - AIMS: Tobacco tax increases are the most effective means of reducing tobacco use and inequalities in smoking, but effectiveness depends on transnational tobacco company (TTC) pricing strategies, specifically whether TTCs overshift tax increases (increase prices on top of the tax increase) or undershift the taxes (absorb the tax increases so they are not passed onto consumers), about which little is known. DESIGN: Review of literature on brand segmentation. Analysis of 1999-2009 data to explore the extent to which tax increases are shifted to consumers, if this differs by brand segment and whether cigarette price indices accurately reflect cigarette prices. SETTING: UK. PARTICIPANTS: UK smokers. MEASUREMENTS: Real cigarette prices, volumes and net-of-tax- revenue by price segment. FINDINGS: TTCs categorise brands into four price segments: premium, economy, mid and 'ultra-low price' (ULP). TTCs have sold ULP brands since 2006; since then, their real price has remained virtually static and market share doubled. The price gap between premium and ULP brands is increasing because the industry differentially shifts tax increases between brand segments; while, on average, taxes are overshifted, taxes on ULP brands are not always fully passed onto consumers (being absorbed at the point each year when tobacco taxes increase). Price indices reflect the price of premium brands only and fail to detect these problems. CONCLUSIONS: Industry-initiated cigarette price changes in the UK appear timed to accentuate the price gap between premium and ULP brands. Increasing the prices of more expensive cigarettes on top of tobacco tax increases should benefit public health, but the growing price gap enables smokers to downtrade to cheaper tobacco products and may explain smoking-related inequalities. Governments must monitor cigarette prices by price segment and consider industry pricing strategies in setting tobacco tax policies. PMID- 23445256 TI - A new fossil from the Jurassic of Patagonia reveals the early basicranial evolution and the origins of Crocodyliformes. AB - Extant crocodylians have a limited taxonomic and ecological diversity but they belong to a lineage (Crocodylomorpha) that includes basal and rather generalized species and a highly diverse clade, Crocodyliformes. The latter was among the most successful groups of Mesozoic tetrapods, both in terms of taxonomic and ecological diversity. Crocodyliforms thrived in terrestrial, semiaquatic, and marine environments, and their fossil diversity includes carnivorous, piscivorous, insectivorous, and herbivorous species. This remarkable ecological and trophic diversity is thought only to occur in forms with a completely akinetic skull, characterized by a functionally integrated and tightly sutured braincase-quadrate-palate complex. However, the patterns of evolutionary change that led to the highly modified skull of crocodyliforms and that likely enabled their diversification remain poorly understood. Herein, a new basal crocodylomorph from the Late Jurassic of Patagonia is described, Almadasuchus figarii gen. et sp. nov. The new taxon is known from a well-preserved posterior region of the skull as well as other craniomandibular and postcranial remains. Almadasuchus figarii differs from all other crocodylomorphs in the presence of six autapomorphic features, including the presence of a large lateral notch on the upper temporal bar, an otic shelf of the squamosal that is wider than long, a deep subtriangular concavity on the posterolateral surface of the squamosal, and an elongated pneumatopore on the ventral surface of the quadrate. Phylogenetic analysis focused on the origin of Crocodyliformes places Almadasuchus as the sister group of Crocodyliformes, supported by synapomorphic features of the skull (e.g. subtriangular basisphenoid, absence of basipterygoid process, absence of a sagittal ridge on the frontal, and a flat anterior skull roof with an ornamented dorsal surface). New braincase information provided by Almadasuchus and other crocodylomorphs indicates that most of the modifications on the posterior region of the skull of crocodyliforms, including the strongly sutured braincase, quadrate, and the extensive secondary palate appeared in a stepwise manner, and pre-dated the evolutionary changes in the snout, jaws, and dentition. This indicates that the progressively increased rigidity of the skull provided the structural framework that allowed the great ecological diversification of crocodyliforms during the course of the Mesozoic. The phylogenetic pattern of character acquisition inferred for the strongly sutured (akinetic) skull and the appearance of more diverse feeding behaviours that create high mechanical loads on the skull provides another interesting parallel between the evolution of Mesozoic crocodyliforms and the evolutionary origins of mammals. PMID- 23445257 TI - Prevalence of hyperprolactinaemia in female premenopausal blood donors. AB - OBJECTIVE: The prevalence of asymptomatic hyperprolactinaemia has been widely studied in certain populations such as antipsychotic drugs users, infertile women or patients with primary hypothyroidism, but data on the prevalence of hyperprolactinaemia and macroprolactinaemia in the healthy population are very scarce in the literature. We aimed to obtain an unbiased estimation of the prevalence in premenopausal women of: (i) hyperprolactinaemia and (ii) its aetiology, including macroprolactinaemia and stress-related hyperprolactinaemia, while considering simultaneously the use of hormonal contraceptives. DESIGN: Prevalence survey. SUBJECTS: Three-hundred and ninety-three consecutive premenopausal women reporting spontaneously for blood donation. MEASUREMENTS: We performed an exhaustive clinical history and physical examination, establishing the presence of hirsutism, acne, alopecia, menstrual dysfunction and reproductive history. We also measured serum prolactin (PRL) (ruling out macroprolactinaemia when indicated), thyrotrophin, total testosterone, androstendione, sex hormone binding globulin and dehydroepiandrosterone sulphate concentrations. RESULTS: Serum PRL concentrations were increased in 16 of 393 women (4.1% prevalence, 95% CI: 2.1-6.0). The prevalence of macroprolactinaemia was 0.6% (95% CI: 0-1) in the total female blood donor population and was 12.5% (95% CI: 6-31) among hyperprolactinaemic patients. The remaining hyperprolactinaemic women had stress related hyperprolactinaemia as the more likely aetiology. Finally, the frequency of hyperprolactinaemia was similar in users and nonusers of hormonal contraceptives (4.5% and 3.9% respectively, P = 0.209). CONCLUSIONS: The prevalence of hyperprolactinaemia in healthy female blood donors is low and is not influenced by the use of hormonal contraceptives. Pathological causes are very rare with stress-related hyperprolactinaemia and macroprolactinaemia being the most frequent causes of hyperprolactinaemia in these women. PMID- 23445258 TI - Amyotrophic lateral sclerosis progression and stability of brain-computer interface communication. AB - Our objective was to investigate the relationship between brain-computer interface (BCI) communication skill and disease progression in amyotrophic lateral sclerosis (ALS). We sought also to assess stability of BCI communication performance over time and whether it is related to the progression of neurological impairment before entering the locked-in state. A three years follow up, BCI evaluation in a group of ALS patients (n = 24) was conducted. For a variety of reasons only three patients completed the three years follow-up. BCI communication skill and disability level, using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, were assessed at admission and at each of the three follow-ups. Multiple non-parametric statistical methods were used to ensure reliability of the dependent variables: correlations, paired test and factor analysis of variance. Results demonstrated no significant relationship between BCI communication skill (BCI-CS) and disease evolution. The patients who performed the follow-up evaluations preserved their BCI-CS over time. Patients' age at admission correlated positively with the ability to achieve control over a BCI. In conclusion, disease evolution in ALS does not affect the ability to control a BCI for communication. BCI performance can be maintained in the different stages of the illness. PMID- 23445259 TI - A new species of Scirtothrips infesting Ginkgo biloba in eastern China. AB - A new thrips species, Scirtothrips ginkgoe Mirab-balou, Tong, and Chen, sp. n. (Thripidae: Thripinae) from Eastern China, collected on the leaves of Ginkgo biloba L. (Ginkgoaceae), is described and illustrated based on the male and female adult stage and the larva. PMID- 23445260 TI - Horizontal transfer of OC1 transposons in the Tasmanian devil. AB - BACKGROUND: There is growing recognition that horizontal DNA transfer, a process known to be common in prokaryotes, is also a significant source of genomic variation in eukaryotes. Horizontal transfer of transposable elements (HTT) may be especially prevalent in eukaryotes given the inherent mobility, widespread occurrence, and prolific abundance of these elements in many eukaryotic genomes. RESULTS: Here, we provide evidence for a new case of HTT of the transposon family OposCharlie1 (OC1) in the Tasmanian devil, Sarcophilus harrisii. Bioinformatic analyses of OC1 sequences in the Tasmanian devil genome suggest that this transposon infiltrated the common ancestor of the Dasyuridae family ~17 million years ago. This estimate is corroborated by a PCR-based screen for the presence/absence of this family in Tasmanian devils and closely-related species. CONCLUSIONS: This case of HTT is the first to be reported in dasyurids. It brings the number of animal lineages independently invaded by OC1 to 12, and adds a fourth continent to the pandemic-like pattern of invasion of this transposon. In the context of these data, we discuss the evolutionary history of this transposon family and its potential impact on the diversification of marsupials. PMID- 23445261 TI - Two-photon microscopy of dermal innervation in a human re-innervated model of skin. AB - When skin is injured, innervation can be severely disrupted. The subsequent re innervation processes are poorly understood notably because of the inability to image the full meandering course of nerves with their ramifications and endings from histological slices. In this letter, we report on two-photon excitation fluorescence (TPEF) microscopy of entire human skin explants re-innervated by rodent sensory neurons labelled with the styryl dye FM1-43. TPEF imaging of nerve fibres to a depth up to roughly 300 MUm within the dermis was demonstrated, allowing three-dimensional reconstruction of the neural tree structure. Endogenous second-harmonic imaging of type I fibrillar collagen was performed in parallel to TPEF imaging using the same nonlinear microscope, revealing the path of the nerves through the dermis. PMID- 23445262 TI - Modification of tethered bilayers by phospholipid exchange with vesicles. AB - Phosphatidylcholine and cholesterol exchange between vesicles and planar tethered bilayer lipid membranes (tBLMs) was demonstrated from electrochemical impedance spectroscopy (EIS), fluorescence microscopy (FM), and neutron reflectometry (NR) data. Cholesterol is incorporated into the tBLMs, as determined by the functional reconstitution of the pore forming toxin alpha-hemolysin (EIS data), attaining cholesterol concentrations nearly equal to that in the donor vesicles. Using fluorescently labeled lipids and cholesterol, FM indicates that the vesicle-tBLM exchange is homogeneous for the lipids but not for cholesterol. NR data with perdeuterated lipids indicates lipid exchange asymmetry with two lipids exchanged in the outer leaflet for every lipid in the inner leaflet. NR and EIS data further show different exchange rates for cholesterol (t1/2 < 60 min) and phosphatidylcholine (t1/2 > 4 h). This work lays the foundation for the preparation of robust, lower defect, more biologically relevant tBLMs by essentially combining the two methods of tBLM formation-rapid solvent exchange and vesicle fusion. PMID- 23445265 TI - Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes. AB - OBJECTIVE: To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O methyltransferase) gene. METHOD: Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. RESULTS: Childhood abuse showed a significant main effect on both positive (beta = 0.09; SE = 0.04; P = 0.047) and negative PEs (beta = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (beta = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. CONCLUSION: Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis. PMID- 23445264 TI - A qualitative natural history study of ME/CFS in the community. AB - In previous qualitative research on Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS), researchers have focused on the experiences of patients with ME/CFS in tertiary care samples. This qualitative study examined the natural history of people with ME/CFS (n = 19) from a community-based sample. Findings highlighted multilayered themes involving the illness experience and the physical construction of ME/CFS. In addition, this study further illuminated unique subthemes regarding community response and treatment, which have implications for understanding the progression of ME/CFS as well as experiences of those within patient networks. There is a need for more longitudinal qualitative research on epidemiological samples of patients with ME/CFS. PMID- 23445266 TI - A randomized, double-blinded, placebo-controlled trial of intercostal nerve block after percutaneous nephrolithotomy. AB - BACKGROUND AND PURPOSE: The optimal method of pain control after percutaneous nephrolithotomy (PCNL) remains controversial. We sought to determine whether intercostal nerve block with bupivicaine provided superior pain control, when compared with placebo, with a lower need for narcotics and improved health related quality of life (HRQL) in the immediate postoperative period. PATIENTS AND METHODS: Sixty-three patients were randomized to receive intercostal blockade with either 20 mL of 0.5% bupivacaine with epinephrine or 20 mL physiologic saline. All patients received intravenous narcotic patient-controlled analgesia (PCA) postoperatively. Data were collected on stone parameters, demographics, analgesic usage, length of stay, and HRQL as assessed by the Postoperative Recovery Scale. RESULTS: The mean age was 47.7+/-1.2 years; mean body mass index was 28.0+/-5.0 kg/m(2); mean stone diameter was 29.2+/-15.8 mm. Within the first 3 to 6 hours after surgery, there was a significant reduction in narcotic use for the group receiving intercostal nerve blockade with bupivacaine compared with placebo. At 3 hours, narcotic use was 2.4+/-3.1 mg vs 4.3+/-3.8 mg morphine equivalents (P=0.034), and within 6 hours of surgery, narcotic use was 5.9+/-6.1 mg vs 8.8+/-7.4 mg (P=0.096). Durable improvement in HRQL was also observed in patients receiving intercostal nerve blockade with bupivacaine compared with placebo (P=0.034). No complications were attributable to the intercostal nerve blocks in either group. CONCLUSIONS: Intercostal blockade with bupivacaine significantly improves both pain control and HRQL in the early postoperative period. The effectiveness of bupivacaine disappears within 6 hours of surgery, after which narcotic use becomes indistinguishable. Intercostal nerve blockade is an easy, safe, and inexpensive method that can be used to optimize pain control after PCNL. PMID- 23445267 TI - In vitro biomechanical comparison of a 4.5 mm narrow locking compression plate construct versus a 4.5 mm limited contact dynamic compression plate construct for arthrodesis of the equine proximal interphalangeal joint. AB - OBJECTIVES: To compare the in vitro biomechanical properties of a 4.5 mm narrow locking compression plate (PIP-LCP) with 2 abaxially located transarticular screws and a 4.5 mm limited contact dynamic compression plate (LC-DCP) with 2 abaxially located transarticular screws using equine pasterns. STUDY DESIGN: Experimental. Paired in vitro biomechanical testing of 2 methods for stabilizing adult equine forelimb PIP joints. ANIMAL: Adult equine forelimbs (n = 8 pairs). METHODS: Each pair of PIP joints were randomly instrumented with either a PIP-LCP or LC-DCP plate axially and 2 parasagitally positioned 5.5 mm transarticular screws. The proximal aspect of the proximal phalanx (P1) and the distal aspect of the middle phalanx (P2) were embedded to allow for mounting on a mechanical testing machine. Each construct was tested in both cyclic and subsequently single cycle to failure in 4-point bending. The displacement required to maintain a target load of 1 kN over 3600 cycles at 1 Hz was recorded. Maximum bending moment at failure and construct stiffness was calculated from the single cycle to failure testing. RESULTS: In cyclic testing, significantly more displacement occurred in the LC-DCP (0.46 +/- 0.10 mm) than for the PIP-LCP (0.17 +/- 0.11 mm) constructs (P = .016). During single cycle testing there was no significant difference in the bending moment between the LC-DCP (148.7 +/- 19.4 N m) and the PIP-LCP (164.6 +/- 17.6 N m) constructs (P = .553) and the stiffness of the LC DCP (183.9 +/- 26.9 N mm) was significantly lower than for the PIP-LCP (279.8 +/- 15.9 N/mm) constructs (P = .011). All constructs failed by fracture of the bone associated with the transarticular screws and subsequently bending of the plates at the middle hole. CONCLUSIONS: Use of the PIP-LCP resulted in a stiffer construct of the same strength as the LC-DCP in vitro using this 4-point bending model. PMID- 23445268 TI - Social cognition training as an intervention for improving functional outcome in first-episode psychosis: a feasibility study. AB - BACKGROUND: Social cognitive deficits have a detrimental effect on social and role functioning at both early and late stages of psychotic illness. AIM: To assess the feasibility of social cognition and interaction training (SCIT) in first-episode psychosis (FEP). METHODS: A total of 12 FEP participants were sequentially allocated to one of two SCIT groups, each of which met once per week for 10 consecutive weeks. Social cognition and functioning was assessed at baseline and post-intervention. RESULTS: SCIT was well-tolerated and retention was good. FEP participants improved significantly on measures of emotion recognition and social and occupational functioning. CONCLUSIONS: This study extends previous research by applying SCIT early in the course of illness, with the rationale that there is greater brain plasticity in this developmental phase of life, and greater scope to reduce or prevent disability. Results suggest SCIT is acceptable to and potentially helpful for this young population, thus a large randomized controlled trial is warranted. PMID- 23445269 TI - Use of varenicline versus bupropion and risk of psychiatric adverse events. AB - AIM: To investigate whether varenicline use was associated with increased risk of psychiatric adverse events, compared with bupropion, another drug used for smoking cessation. DESIGN, SETTING AND PARTICIPANTS: We conducted a registry based cohort study in Denmark, 2007-10, comparing new users of varenicline and bupropion in unmatched and 1 : 1 propensity score-matched analyses. MEASUREMENTS: Using Cox regression, we estimated the hazard ratio (HR) of any psychiatric adverse event (emergency department visit or in-patient admission with a psychiatric diagnosis) within 30 days following treatment initiation. The unmatched and matched analyses correspond to conventional crude and fully adjusted analyses, respectively. FINDINGS: In unmatched analyses, there were 106 (0.18%) psychiatric adverse events among 59 790 varenicline users (rate 22 events per 1000 person-years), compared with 46 (0.26%) events among 17 936 bupropion users (rate 31 per 1000); the HR was 0.69 [95% confidence interval (CI): 0.49 0.98]. In propensity score-matched analyses, 39 (0.22%) events occurred among 17 935 varenicline users (rate 27 per 1000), compared with 46 (0.26%) events among 17 935 bupropion users (rate 31 per 1000); varenicline was not associated with increased risk of psychiatric adverse events (HR 0.85, 95% CI: 0.55-1.30). The overall rate of psychiatric adverse events was substantially higher among participants with a history of psychiatric disorder than in patients without such history; the risk associated with varenicline did not differ significantly by history of psychiatric disorder. CONCLUSIONS: In Denmark, the risk of psychiatric adverse events diagnosed during an emergency department visit or in-patient admission was not significantly higher with varenicline use compared with bupropion. PMID- 23445270 TI - Salivary innate defense system in type 1 diabetes mellitus in children with mixed and permanent dentition. AB - OBJECTIVE: It should be expected that type 1 diabetes mellitus may disturb innate and acquired immunity. There are no data on type 1 diabetes mellitus-related changes in the salivary flow and the protein output responsible for the innate immunity of saliva depending on the quality of dentition reflecting the age of child. The aim of this work was the evaluation of parameters responsible for the innate immunity of saliva in children and adolescents with type 1 diabetes mellitus. MATERIALS AND METHODS: In diabetic children, adolescent and healthy volunteers, the salivary flow, the output and the concentration of the activity of peroxidase (colorimetry), lysozyme (radial immunodiffusion) and lactoferrin (ELISA) were determined. RESULTS: In children with mixed and permanent dentition, type 1 diabetes mellitus significantly decreases (as compared with the appropriate controls) the unstimulated salivary flow, the output, concentration of peroxidase and the output of the lysozyme and lactoferrin. CONCLUSION: In conclusion, it may be stated that type 1 diabetes mellitus causes functional changes in the salivary glands, resulting in a decrease of the salivary flow and weakening of the salivary innate defense system, thus creating a threat to the oral and general health of type 1 diabetes mellitus children. The results showed that the salivary glands of younger children, when compared to adolescents with type 1 diabetes mellitus, are more susceptible to the injurious effects of the disease. PMID- 23445271 TI - Synthesis of heteroarylated polyfluorobiphenyls via palladium-catalyzed sequential sp2 C-H bonds functionalizations. AB - The higher reactivity of C5-H bonds of heteroarenes as compared to C-H bonds of bromopolyfluorobenzenes for palladium-catalyzed direct arylation allows the selective synthesis of the polyfluoroaryl-heteroarenes in moderate to high yields, without C-H bond functionalization of the polyfluorobenzene ring. In most cases, low loading of Pd(OAc)2 catalyst (0.5-1 mol %) was employed. Then, from these heteroarylated polyfluorobenzenes, the palladium-catalyzed C-H bond functionalization of the polyfluorobenzene ring allows the synthesis of heteroarylated polyfluorobiphenyls. PMID- 23445272 TI - A new endotracheal tube for infants--laboratory and clinical assessment: a preliminary study. AB - BACKGROUND: Conventional endotracheal pediatric tubes offer high resistance due to their small diameters and relatively high flow during ventilation. Any increase of the diameter of the tube lumen decreases the airway resistance and subsequently, the work of breathing (WOB). We compared ventilation mechanics using a new, cone-shaped endotracheal tube of our design to the Cole and standard tubes. METHODS: The study has been divided into three parts: (i) preliminary laboratory tests, (ii) in vitro study with infant lung model, and (iii) clinical study in infants. Flow resistance and WOB were compared, using standard, Cole (in experimental phase only) and cone tubes. RESULTS: We proved that inspiratory (Ri ) and expiratory (Re ) resistance, and WOB, were significantly lower in patients ventilated via a cone tube. Mean Ri decreased by 37%, compared with the baseline values, Re - by 35%, and total WOB - by 12%. CONCLUSION: The cone tube offers lower resistance to gas flow than the standard, used nowadays in clinical practice. It can be especially beneficial to spontaneously breathing patients reducing WOB and improving gas exchange. PMID- 23445273 TI - Comparison of human immunodeficiency virus assays in window phase and elite controller samples: viral load distribution and implications for transmission risk. AB - BACKGROUND: After 3 years of individual-donation nucleic acid test (ID-NAT) screening by the South African National Blood Service (SANBS), a repository of 73 human immunodeficiency virus antibody (anti-HIV)-negative window period (WP) yield samples and 28 anti-HIV-positive, HIV-RNA-negative elite controllers (ECs) became available for comparison of a p24 antigen (p24 Ag) assay (Innogenetics), two viral load assays (Siemens branch DNA [bDNA] 3.0 and Abbott real-time polymerase chain reaction [RT-PCR]), and three triplex NAT assays (Novartis Diagnostics Ultrio and Ultrio-Plus and Roche TaqScreen) by replicate testing of dilutions. STUDY DESIGN AND METHODS: Viral loads were assessed by bDNA and RT-PCR assays and if below 100 copies (cps)/mL, by Ultrio limiting dilution probit analysis. The probability of virus transmission by WP and EC donations was estimated for different levels of the 50% minimum infectious dose (ID50 ) using Poisson distribution statistics. RESULTS: The equal distribution of WP donations plotted by log HIV-RNA levels indicated a random appearance of donors in the ramp up phase. The HIV p24 Ag assay detected 45% of WP samples and the cutoff crossing point was estimated at 8140 (bDNA)/22,710 (RT-PCR) cps/mL. On replicate retesting of 40 HIV p24 Ag-negative ID-NAT WP-yield samples Ultrio minipool (MP)8, Ultrio Plus MP8, and TaqScreen MP6 detected 79, 81, and 78%, respectively. Modeling with an estimated ID50 of 31.6 virions/RBC indicated that 15% of p24 Ag-negative ID NAT WP-yield donations would have transmitted HIV if MP6-8 NAT had been used. Only 2% of RBC transfusions from ECs are estimated to be infectious with a worst case ID50 estimate of 316 virions. CONCLUSION: Our analysis of viremia and infectivity of WP and EC donations enables comparison of the efficacy of NAT options in preventing HIV transmission risk. PMID- 23445274 TI - Reactions of a cyclodimethylsiloxane (Me2SiO)6 with silver salts of weakly coordinating anions; crystal structures of [Ag(Me2SiO)6][Al] ([Al] = [FAl{OC(CF3)3}3], [Al{OC(CF3)3}4]) and their comparison with [Ag(18-crown 6)]2[SbF6]2. AB - Two silver-cyclodimethylsiloxane cation salts [AgD6][Al] ([Al] = [Al(ORF)4](1) or [FAl(OR(F))3](2), R(F) = C(CF3)3, D = Me2SiO) were prepared by the reactions of Ag[Al] with D6 in SO2(l). For a comparison the [Ag(18-crown-6)]2[SbF6]2(3) salt was prepared by the reaction of Ag[SbF6] and 18-crown-6 in SO2(l). The compounds were characterized by IR, multinuclear NMR, and single crystal X-ray crystallography. The structures of 1 and 2 show that D6 acts as a pseudo crown ether toward Ag(+). The stabilities and bonding of [MDn](+) and [M(18-crown 6)](+) (M = Ag, Li, n = 4-8) complexes were studied with theoretical calculations. The calculations predicted that D6 adopts a puckered C(i) symmetric structure in the gas phase in contrast to previous reports. 18-Crown-6 was calculated to bind more strongly to Li(+) and Ag(+) than D6. (29)Si[(1)H] NMR results in solution, and calculations in the gas phase established that a hard Lewis acid Li(+) binds more strongly to D6 than Ag(+). A comparison of the [MD(n)](+) complex stabilities showed D7 to form the most stable metal complexes in the gas phase and the solid state and explained why [AgD7][SbF6] was isolated in a previous reaction where ring transformations resulted in an equilibrium of [AgD(n)](+) complexes. In contrast, the isolations of 1 and 2 were possible because the corresponding equilibrium of [AgD(n)](+) complexes was not observed with [Al](-) anions. The formation of the dinuclear complex salt 3 instead of the corresponding mononuclear complex salt was shown to be driven by the gain in lattice enthalpy in the solid state. The bonding to Li(+) in D6 and 18-crown-6 metal complexes was described by a quantum theory of atoms in molecules (QTAIM) analysis to be mostly electrostatic while the bonding to Ag(+) also had a significant charge transfer component. The charge transfer from both D6 and 18 crown-6 to Ag(+) and Li(+) metal ions was depicted by the QTAIM analysis to be of similar strength, and the difference in the stabilities of the complexes was attributed mostly to more attractive electrostatic interactions between 18-crown 6 and the metal ions despite the more negative oxygen atomic charges calculated for D6. PMID- 23445275 TI - Does cow's milk protein elimination diet have a role on induction and maintenance of remission in children with ulcerative colitis? AB - AIM: Aims of this study were to evaluate the efficacy of a cow's milk protein (CMP) elimination diet on induction and maintenance of remission and to define association with atopy in children with ulcerative colitis (UC). METHODS: Twenty nine consecutive patients (mean age: 11.2 years; range: 4.6-17 years; F/M: 15/14) with newly diagnosed UC were randomized either to receive a CMP elimination diet (n = 14) or to continue a free diet (n = 15) associated with concomitant steroid induction and mesalazine maintenance treatment. Children were prospectively evaluated at four time points: within 1 month, 6 months and 1 year after diagnosis or at the time of relapse. RESULTS: Twenty-five of the 29 enrolled patients responded to the UC induction therapy with a complete remission (86.2%), 13 belonging to CMP elimination diet group and 12 to free diet group (p = 0.59). Overall, our data showed that 7 of 13 (53.8%) patients treated with CMP elimination diet and 8 of 15 (53.3%) patients on free diet and UC therapy relapsed within 1 year of follow-up (p = 1). CONCLUSIONS: In conclusion, data of this paediatric, randomized trial suggest that CMP elimination has no role in the management of UC in non-sensitized children. PMID- 23445276 TI - The effect of bone morphometric changes on orthodontic tooth movement in an osteoporotic animal model. AB - OBJECTIVE: To elucidate the effect of bone morphometric changes on orthodontic tooth movement (OTM) in zoledronic acid-treated ovariectomized rats. MATERIALS AND METHODS: Twenty-one 10-week-old female Wistar rats were divided into ovariectomy (OVX), OVX with zoledronic acid administration (OVX + ZOL), and sham operation (control) groups. Two weeks after OVX, ZOL administration was initiated. Twelve weeks after OVX, a nickel-titanium closed-coil spring of 25-g force was applied mesially to the maxillary left first molar. In vivo micro computed tomography (CT) of the left proximal tibia was performed for bone morphometric analysis every 2 weeks after OVX. In addition, OTM was investigated using micro-CT at 0, 12, and 14 weeks after OVX. RESULTS: There were significant differences in the bone mineral content (BMC), bone volume (BV), BMC to tissue volume ratio (BMC/TV), and BV to TV ratio of trabecular bone between the control and OVX groups and also between the OVX + ZOL and OVX groups. In the OVX + ZOL group, increased BMC and BV in the cortical bone and increased bone mineral density (BMD) in the trabecular bone were observed. Interestingly, OTM in the OVX group was almost two times more than that in the control and OVX + ZOL groups. Moreover, OTM was correlated with BMD, BMC, BV, and BMC/TV in the trabecular bone. CONCLUSIONS: OVX accelerated OTM, while ZOL suppressed it. OTM demonstrated a significant negative relationship with trabecular bone mass. PMID- 23445278 TI - Providing a humane death: expanded euthanasia guidelines add species, process, technique considerations. PMID- 23445279 TI - Parasitology practice guidelines. PMID- 23445280 TI - One health, food security, and veterinary medicine. PMID- 23445281 TI - What is your diagnosis? Cryptococcal patellar osteomyelitis. PMID- 23445282 TI - ECG of the month. Liver lobe torsion. PMID- 23445283 TI - Anesthesia case of the month. Methemoglobinemia. PMID- 23445284 TI - Pathology in practice. Uveodermatologic syndrome. PMID- 23445285 TI - Pathology in practice. Tyzzer's disease. PMID- 23445288 TI - Evaluation of coagulation in dogs with partial or complete extrahepatic biliary tract obstruction by means of thromboelastography. AB - OBJECTIVE: To characterize in vitro coagulation status in a cohort of dogs with extrahepatic biliary tract obstruction (EHBO) and to evaluate these patients for hypercoagulability by means of thromboelastography. DESIGN: Prospective cohort study. Animals-10 dogs with EHBO and 19 healthy control dogs. PROCEDURES: Partial or complete EHBO was confirmed via exploratory celiotomy. Venous blood samples were collected for evaluation of prothrombin time (PT) and activated partial thromboplastin time (APTT); fibrinogen and D-dimer concentrations; protein C and antithrombin activities; and factor VII, VIII, and XI coagulant activities in plasma as well as thromboelastography in whole blood. Thromboelastography variables were measured from the thromboelastography tracing, and a coagulation index was calculated. Thromboelastography results were compared with those of healthy control dogs previously evaluated by the same laboratory. RESULTS: Hypercoagulability was diagnosed in all dogs with EHBO on the basis of a high coagulation index. Thromboelastography variables, including maximal amplitude, alpha-angle, and coagulation index, were significantly higher, and K (clot formation time) and R (reaction time) were significantly lower in these dogs than in control dogs. All dogs with EHBO had PT and APTT within respective reference ranges. Plasma D-dimer and fibrinogen concentrations were above reference ranges in 8 and 7 dogs, respectively, and protein C and antithrombin activities were below reference ranges in 3 and 1 dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro hypercoagulability was commonly detected in dogs with naturally occurring EHBO. The traditional view of EHBO as a disease that causes hypocoagulability may need to be reconsidered. PMID- 23445289 TI - Relationship between dynamin 1 mutation status and characteristics of recurrent episodes of exercise-induced collapse in Labrador Retrievers. AB - OBJECTIVE: To identify characteristics of exercise-induced collapse in Labrador Retrievers and compare characteristics for dogs with various dynamin 1 gene (DNM1) mutation statuses. DESIGN: Retrospective cross-sectional study. ANIMALS: 109 Labrador Retrievers with a history of recurrent exercise-induced collapse, clinically normal behavior and gait between episodes, and no reason for collapse identified via medical evaluation. PROCEDURES: Data were collected via surveys from owners of dogs that were tested for an autosomal recessive DNM1 mutation causing DNM1-associated exercise-induced collapse (d-EIC). Dogs were identified as having d-EIC (homozygous for the mutation) or not having d-EIC (heterozygous for or without the mutation). Survey data were reviewed by an investigator unaware of the genotypes of dogs, and collapse characteristics were compared between groups. RESULTS: 74 dogs had d-EIC; 35 dogs did not have d-EIC. Dogs with d-EIC were young (median age, 12 months) at the time of the first collapse episode; collapse in such dogs typically originated in the hind limbs and was characterized by low muscle tone, clinically normal mentation, and rapid recovery. Dogs without d-EIC were older (median age, 23 months) than dogs with d EIC; such dogs had various characteristics of collapse that were not consistent with a single disease. CONCLUSIONS AND CLINICAL RELEVANCE: Characteristics of exercised-induced collapse in Labrador Retrievers with various DNM1 genotypes were identified in this study; findings may help distinguish dogs with d-EIC from those with other types of collapse conditions. Characteristics of collapse in Labrador Retrievers that were not homozygous for the DNM1 mutation differed substantially among dogs and may have been attributable to multiple causes. PMID- 23445290 TI - Treatment of pyloric stenosis in a cat via pylorectomy and gastroduodenostomy (Billroth I procedure). AB - CASE DESCRIPTION: A 5-month-old 1.9-kg (4.2-lb) spayed female Siamese cat was evaluated because of a history of decreased appetite, regurgitation, vomiting, and lack of weight gain. CLINICAL FINDINGS: Radiographic findings included a fluid- and gas-distended stomach with a small accumulation of mineral opacities. Ultrasonographic examination confirmed severe fluid distention of the stomach with multiple hyperechoic structures present and revealed protrusion of the thickened pylorus into the gastric lumen, with normal pylorogastric serosal continuity. Endoscopy of the upper gastrointestinal tract revealed an abnormally shortened pyloric antrum and stenotic pyloric outflow orifice. Pyloric stenosis resulting in pyloric outflow obstruction was diagnosed. TREATMENT AND OUTCOME: A pylorectomy with end-to-end gastroduodenostomy (Billroth I procedure) was successfully performed, and a temporary gastrostomy tube was placed. Six days after surgery, the cat was eating and drinking normally, with the tube only used for administration of medications. The gastrostomy tube was removed 12 days after surgery. Results of follow-up examination by the referring veterinarian 3 weeks after surgery were normal. Occasional vomiting approximately 2 months after surgery was managed medically. Fifteen months after surgery, the owners reported that the cat seemed completely normal in appearance and behavior. CLINICAL RELEVANCE: Pyloric stenosis should be considered a differential diagnosis for young cats with pyloric outflow obstruction. The cat of this report was treated successfully with a Billroth I procedure. Histologic examination and immunohistochemical analysis of the excised tissue showed the stenosis to be associated with hypertrophy of the tunica muscularis. PMID- 23445291 TI - Successful treatment of encrusted cystitis associated with Staphylococcus pseudintermedius infection in the urinary bladder of a dog. AB - CASE DESCRIPTION: A 5-year-old female spayed mixed-breed dog was examined because of signs of persistent stranguria following treatment for urethral obstruction. CLINICAL FINDINGS: Radiographic, ultrasonographic, cystoscopic, and histologic findings were consistent with encrusted cystitis. Results of bacteriologic culture of urine and bladder wall biopsy samples indicated growth of Staphylococcus pseudintermedius. Treatment and Outcome-The dog was initially treated via IV administration of fluids, placement of an indwelling urinary catheter, lavage of the bladder with sterile saline (0.9% NaCl) solution, and administration of antimicrobial drugs and bethanechol (to improve voiding of urine from the bladder). Antimicrobial drugs were administered for 3 months, and a commercially available diet for dissolution of urinary calculi was fed. Clinical signs of encrusted cystitis gradually resolved during the 3 months after the initial examination. Results of urinalysis and abdominal ultrasonographic examination performed 4 months after the initial examination indicated resolution of the disease. CLINICAL RELEVANCE: Encrusted cystitis is extremely rare in small animals and has previously only been associated with Corynebacterium spp infection of the urinary bladder. Resolution of encrusted cystitis has previously been achieved via surgical debridement of the bladder and treatment with antimicrobial drugs. The clinical findings and successful resolution of clinical signs in the dog of the present report suggested that urease-positive bacteria other than Corynebacterium spp can cause encrusted cystitis and that feeding of a diet for dissolution of urinary calculi in conjunction with antimicrobial treatment may result in resolution of urinary bladder lesions and clinical signs attributable to the disease without the need for surgical debridement of encrusted plaques. PMID- 23445292 TI - Spinal cord compression secondary to extramedullary hematopoiesis in a dog. AB - CASE DESCRIPTION: An 11-year-old spayed female Siberian Husky was evaluated because of a 2-week history of progressive paraparesis. CLINICAL FINDINGS: Results of neurologic examination were consistent with a T3-L3 myelopathy. There were no abnormalities on CBC, and hypercalcemia was noted on serum biochemical analysis. Several hypoechoic splenic nodules were evident on abdominal ultrasonography, and results of fine-needle aspiration cytology were consistent with splenic extramedullary hematopoiesis (EMH). Two compressive, extradural masses in the dorsal epidural space of the thoracolumbar region of the spinal cord were seen on MRI images. TREATMENT AND OUTCOME: A dorsal laminectomy was performed to remove the extradural spinal masses. Results of histologic examination of tissue samples were consistent with EMH. Following surgery, clinical signs of paraparesis resolved, and there was no recurrence of the masses 24 months after surgery. CLINICAL RELEVANCE: Extramedullary hematopoesis should be considered as a differential diagnosis in dogs in which results of diagnostic imaging indicate a epidural mass. In human patients, spinal EMH usually occurs secondary to an underlying hematologic disease, but it can also occur spontaneously. Treatment options reported for humans include surgical decompression, radiation therapy, chemotherapy, and blood transfusion. The dog of this report responded favorably to surgical decompression and was clinically normal 2 years after surgery. PMID- 23445293 TI - Surgical stabilization of shoulder luxation in a pot-bellied pig. AB - Case Description-A 4.6-month-old pot-bellied pig was evaluated because of non weight-bearing lameness (grade 5/5) in the right forelimb of 4 days' duration. Clinical Findings-Clinical and radiographic examination revealed a closed, lateral luxation of the right shoulder joint. Treatment and Outcome-Initial attempts at closed reduction failed to provide adequate stability of the shoulder joint. Open reduction and internal fixation by placement of 2 lateral tension sutures with a system designed for canine cranial cruciate ligament repair provided adequate joint stability and a successful outcome. Conclusions and Clinical Relevance-Stabilization of the shoulder joint with lateral tension sutures after open reduction should be considered for management of lateral shoulder luxation in pot-bellied pigs. PMID- 23445294 TI - Evaluation of a point-of-care portable analyzer for measurement of plasma immunoglobulin G, total protein, and albumin concentrations in ill neonatal foals. AB - OBJECTIVE: To compare the diagnostic performance of a point-of-care (POC) analyzer with that of established methods for the measurement of plasma IgG, total protein, and albumin concentrations in neonatal foals. DESIGN: Evaluation study. ANIMALS: 100 neonatal foals < 7 days of age. Procedures-Plasma IgG, total protein, and albumin concentrations were measured with a POC analyzer via an immunoturbidimetric method. Corresponding measurements of plasma IgG, total protein, and albumin concentrations were measured by means of automated biochemical analyzers via automated immunoturbidimetric, biuret, and bromocresol green dye-binding assays, respectively (standard laboratory methods). RESULTS: The sensitivity and specificity of the POC analyzer for detection of failure of passive transfer of immunity (FPTI) in foals were 80.7% and 100%, respectively, when FPTI was defined as a plasma IgG concentration < 400 mg/dL and were 75.9% and 100%, respectively, when FPTI was defined as a plasma IgG concentration < 800 mg/dL. The POC analyzer overestimated plasma albumin concentrations and, to a lesser extent, plasma total protein concentrations, compared with values determined with the standard laboratory methods. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested the POC analyzer was acceptable for determination of plasma IgG and total protein concentrations in ill foals. The POC analyzer overestimated plasma albumin concentration such that its use was clinically unacceptable for the determination of that concentration. The POC analyzer provided timely measurements of plasma IgG concentrations, which is necessary information for the assessment of passive transfer of maternal antibodies to neonatal foals. PMID- 23445295 TI - Incidence, management, and outcome of complications of castration in equids: 324 cases (1998-2008). AB - OBJECTIVE: To determine the incidence of complications and identify risk factors associated with development of complications following routine castration of equids. DESIGN: Retrospective case series. Animals-311 horses, 10 mules, and 3 donkeys. PROCEDURES: Medical records of equids undergoing routine castration were reviewed. Age, breed, surgical techniques (closed vs semiclosed castration and use of ligatures), anesthesia method (general IV anesthesia vs standing sedation with local anesthesia) and repeated administration of IV anesthetic agents, administration of antimicrobials and anti-inflammatory drugs, and details regarding development, management, and outcome of complications were recorded. Odds ratios and 95% confidence intervals were determined. Associations between additional doses of anesthetic agents during surgery and development of complications were analyzed with a Jonckheere-Terpstra test. RESULTS: 33 of 324 (10.2%) equids developed a complication after surgery; 32 recovered and 1 was euthanized because of eventration. Equids that underwent semiclosed castration had significantly higher odds of developing a complication (OR, 4.69; 95% confidence interval, 2.09 to 10.6) than did those that underwent closed castration. Equids that received additional doses of anesthetic agents to maintain adequate general anesthesia developed complications more frequently than those that did not require this treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Incidence of complications was low, and most evaluated variables were not significantly associated with development of complications following castration in equids. However, findings suggested that the choice of surgical technique (closed vs semiclosed) is an important factor in this regard. Future studies should investigate whether duration of surgery is associated with complications following castration in equids. PMID- 23445296 TI - Clinicopathologic variables associated with hypokalemia in lactating dairy cows with abomasal displacement or volvulus. AB - OBJECTIVE: To identify potential mechanisms for hypokalemia in dairy cows with left-displaced abomasum (LDA), right-displaced abomasum (RDA), or abomasal volvulus (AV). DESIGN: Retrospective analysis of clinicopathologic data from 2 convenience samples of cows. SAMPLE: 112 lactating dairy cows with AV (group 1); 1,332 lactating dairy cows (group 2) with LDA (n = 1,160) or RDA or AV (172). PROCEDURES: Data were analyzed via Spearman rho and multivariate stepwise regression. RESULTS: 78 of 112 (70%) group 1 cows were hypokalemic (mean serum potassium concentration, 3.5 mEq/L; reference range, 3.9 to 5.8 mEq/L). For group 1 cows, serum chloride concentration had the strongest positive association with serum potassium concentration, and serum potassium concentration was negatively associated with plasma bicarbonate and serum glucose, creatinine, and urea concentrations. Six hundred thirty-six of 1,160 (55%) of group 2 cows with LDA were hypokalemic (mean serum potassium concentration, 3.7 mEq/L). Ninety-two of 172 (53%) group 2 cows with RDA or AV were hypokalemic (mean serum potassium concentration, 3.8 mEq/L). For group 2 cows, serum chloride concentration had the strongest positive association with serum potassium concentration, and serum potassium concentration was negatively associated with indices of feed intake (serum bilirubin concentration) and hydration status. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested hypokalemia was associated with hypochloremia, alkalemia, low feed intake with high amount of milk produced, hypovolemia, and hyperglycemia in lactating dairy cows. Treatment of hypokalemia should include surgical correction of abomasal displacement, increased dietary potassium intake via dietary dry matter intake or oral administration of KCl, and correction of hypochloremia, alkalemia, metabolic alkalosis, and dehydration. PMID- 23445297 TI - Gangrenous mastitis caused by Bacillus species in six goats. AB - CASE DESCRIPTION: 6 lactating dairy goats were examined because of acute mastitis. CLINICAL FINDINGS: Goats were considered to have endotoxemia on the basis of physical examination and clinicopathologic findings. The affected udder halves had gangrenous discolored distal portions with sharp demarcations from grossly normal tissue proximally. Udder secretions from the affected sides were serosanguineous in all cases. A Bacillus sp was isolated in pure cultures in all cases. In 1 case, the Bacillus sp was identified as Bacillus cereus. TREATMENT AND OUTCOME: Goats were treated for mastitis and endotoxemia with polyionic IV fluid therapy, systemic and intramammary antimicrobial administration, anti inflammatory drug administration, and other supportive treatment. All goats survived to discharge. All except 1 goat had follow-up information available. The affected udder halves sloughed in 1 to 2 months following discharge. In subsequent lactations after the mastitis episodes, milk production in 2 of 5 goats was above the mean, as determined on the basis of Dairy Herd Improvement records, and 3 of 5 goats were voluntarily withdrawn from lactation. All 5 goats had successful kiddings after the Bacillus mastitis episode. CONCLUSIONS AND CLINICAL RELEVANCE: Bacillus sp should be considered as a causative agent in goats with gangrenous mastitis, especially when the Bacillus sp is isolated in a pure culture. Antimicrobial sensitivity testing is recommended for selection of an appropriate antimicrobial for treatment. Prognosis for survival appears to be good, although milk production may be decreased. PMID- 23445298 TI - Prolactin in obese children: a bridge between inflammation and metabolic endocrine dysfunction. AB - OBJECTIVE: Adipocytes, regulated by insulin, represent the major peripheral source of prolactin (PRL), which play a pivotal role in energy balance, acting on adipogenesis and lipolysis. The aim of this study was to investigate whether PRL was associated with obesity-related inflammatory status and metabolic parameters. The diagnostic and prognostic role of PRL for metabolic syndrome (MS) was assessed. The effects of short-term lifestyle therapy on PRL levels were evaluated. SUBJECTS: Prolactin was assessed in 94 obese patients and compared with 40 healthy children (HS).Patients were followed up for 1 year. Receiver operating characteristics (ROC) analysis was employed to find the best cut-off values capable of identifying MS in obese children for PRL, IL-6 and TNF-alpha. Kaplan-Meier curves were also generated. Adjusted risk estimates for MS were calculated using Cox proportional hazard regression analysis. An obesity intervention programme was administered for 12 months. RESULTS: Prolactin levels were lower in obese patients than controls (P < 0.0001). PRL was found to be inversely correlated with BMI, IL-6 and HOMA-IR, whereas a direct correlation was found with HDL values. At ROC analysis, PRL showed higher sensitivity and specificity than IL-6 and TNF-alpha in identifying MS in obese children. Cox proportional hazard regression analysis showed that PRL predicted MS independently of other potential confounders. The lifestyle intervention improved PRL and metabolic parameters. CONCLUSIONS: Prolactin represents a prognostic marker for obese children and a predictive factor for progression to MS. PRL measurement may be useful as part of the endocrine work-up of obese children. PMID- 23445299 TI - Reasons why women in Turkey prefer short-term use of hormone replacement therapy (HRT). AB - The research was conducted as an epidemiological study with a before-after interference. Ninety-three women who regularly visited a menopausal clinic in Kayseri and who had begun hormone replacement therapy (HRT) made up the study sample. Seventy-five women were involved in the second step, carried out 18 months after the first interview. It was concluded that 25.3% of the women who began HRT had more menopausal complaints before HRT, while these complaints were generally reduced after the 18 months (p < .05). There was no important change in their quality of life (QOL; p > .05), but there was a positive change seen in emotional reactions (p < .05). PMID- 23445300 TI - Constructing metal nanoparticle multilayers with polyphenylene dendrimer/gold nanoparticles via "click" chemistry. AB - Multilayer films composed of azide-functional polymer and polyphenylene dendrimer stabilized gold nanoparticles with alkynes in their peripheries have been fabricated using a layer-by-layer (LBL) approach via "click" chemistry. This method permits facile covalent linking of the polymer/nanoparticle interlayers in the mixture of DMF and water, which provides a general and powerful technique for preparing uniform nanoparticle (NP) thin films. The deposition process is linearly related to the number of bilayers as monitored by UV-vis spectroscopy. The multilayer structure and morphology have been characterized by X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and contact angle. PMID- 23445301 TI - Incidence trends of cannabis and cocaine use from periodic Spanish general population surveys: effect of standardizing results by age structure. AB - AIMS: This study estimates life-time incidence trends of cannabis and cocaine use over 38 years from general population surveys of drug use (GPSDU) in Spain, taking into account changes of population age structure. DESIGN: Periodic cross sectional studies. SETTING: Eight biennial GPSDU from 1995 to 2009 in Spain. PARTICIPANTS: Interviewees aged 15-64 years who reported age of first ever cannabis and/or cocaine use between 10 and 64 years between 1971 and 2008. MEASUREMENTS: Estimates of raw and standardized incidences were calculated as a weighted mean of the incidences from all surveys. Standardization was conducted to take into account changes of population age structure. Incidence trends were extracted applying weighted cubic smoothing splines to incidence estimates. FINDINGS: For both substances, estimated raw incidence trends increased up until 2000 (rates of 11.5 +/- 0.7 and 3.6 +/- 0.5 per 1000, respectively, for cannabis and cocaine), and then decreased significantly (in 2008, 9.6 +/- 1.2 and 2.7 +/- 0.6, respectively). In contrast, standardized rates exhibit a steadily increasing trend up to 2000 (9.0 +/- 0.6 and 2.8 +/- 0.4), followed by a statistically non significant increasing trend afterwards (in 2008, 9.5 +/- 1.2 and 2.8 +/- 0.6). The largest increases of incidence were observed in both male and female subjects aged 15-19 years. CONCLUSIONS: Using data from Spanish general population surveys of drug use, an apparently decreasing trend of raw incidence rates in both cannabis and cocaine use from 2000 became non-decreasing trends when these rates were standardized. First experiences of cannabis and cocaine use in Spain occur mainly in younger ages (15-19 years). PMID- 23445302 TI - The use of a non cultured autologous cell suspension to repair chronic ulcers. AB - The purpose of this uncontrolled study was to evaluate the clinical effectiveness of ReCell((r)) system in the treatment of chronic ulcers. From October 2011 to July 2012, 20 patients, 8 men and 12 women with a mean age of 70 years, with chronic ulcers of different aetiology that were unresponsive to conventional therapies were recruited and treated using the ReCell((r)) system. Patient pain rate, scar aesthetics and patient satisfaction were assessed using a Visual Analogue Scale, Manchester Scar Scale and the Rosenberg Self-Esteem Scale, respectively. Complete ulcer healing, defined as 100% reepithelialisation was observed between 40 and 60 days in 14 patients (70%) depending on the type of ulcer and comorbidity. At day 60 postprocedure, 80% reepithelialisation was present in five patients (25%), while one patient with concomitant psoriasis had 50% reepithelialisation. Pain scores improved by day 7 postprocedure. The function and aesthetics of the ReCell-treated patients were good. It is concluded that the ReCell technique may have provided the regenerative tissue stimulation necessary for the rapid healing of chronic ulcers, including those not responsive to more traditional methods. PMID- 23445303 TI - Deregulation of glycolysis in cancer: glyceraldehyde-3-phosphate dehydrogenase as a therapeutic target. AB - INTRODUCTION: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme, but recent studies have shown its non-glycolytic role in cell death, survival mechanisms and diseases. Increase in glycolysis, in particular overexpression of GAPDH, has been considered an important feature of many types of cancer cells. This review focuses on the role of GAPDH in carcinogenesis and the possibility of using this target for anticancer therapy. AREAS COVERED: In this review, the studies targeting GAPDH in human cancer as well as its functions in normal and cancer cells are described and discussed. EXPERT OPINION: GAPDH is an essential component of the glycolysis energy system, which is actively employed in cancer cells. Analysis of the so-called bioenergetics signature (the ratio of beta-F1-ATPase and GAPDH proteins) of different cancer types can be used for estimation of the cell metabolic activity, cancer aggressiveness and response to chemotherapy. Recent studies suggest GAPDH as a promising target for therapy of some carcinomas. Incidentally, limitations of this approach may come from the versatility of the GAPDH enzyme, since it combines glycolytic, pro-apoptotic and other activities. Hence, targeting GAPDH may lead to unexpected results concerning normal cells and therefore requires further research. PMID- 23445304 TI - Quantitative evaluation of myofibroblast apoptosis during wound healing in rat palate after post-operative administration of basic fibroblast growth factor (bFGF). AB - OBJECTIVE: Excessive wound contraction apparently inhibits maxillary growth; thus, myofibroblast apoptosis needs to be accelerated in mucoperiosteal denudation after palatoplasty. The aim of this study was to evaluate myofibroblast apoptosis during wound healing in mucoperiosteal denudation of rat palates immediately after post-operative administration of basic fibroblast growth factor (bFGF). MATERIALS AND METHODS: A total of 100 male Wistar rats aged 20 days were divided into control, scar, sham and bFGF groups (n = 25 each). In the scar, sham and bFGF groups, mucoperiosteum was removed from the palate and fibrin glue was applied to the exposed bone surface immediately after surgery. In the bFGF group, 10 MUL of 2 MUg/MUL bFGF solution was injected into the operated area beneath the fibrin glue. At 2, 5, 7, 14 and 28 days post-operatively, myofibroblast apoptosis during the wound healing process was investigated by double immunofluorescence staining. The apoptotic area of myofibroblasts was measured using image software. RESULTS: In the bFGF group, at 2 days, apoptosis of myofibroblasts in the lamina propria and submucosa was marked, as compared with the other three groups and apoptosis of myofibroblasts was scarcely seen at 5 days. At 5 and 7 days, the apoptotic area of myofibroblasts in the bFGF group was statistically significantly smaller when compared to the scar and sham groups. CONCLUSION: The results confirmed that bFGF injection immediately after surgery accelerated apoptosis of myofibroblasts in mucoperiosteal denudation of rats. This may reduce maxillary growth retardation due to excessive wound contraction. PMID- 23445306 TI - Treatment of severe psoriasis with biological therapies in patients with viral hepatitis B and C. PMID- 23445307 TI - Allergy workup of severe cutaneous adverse drug reactions: a light at the end of the tunnel? PMID- 23445308 TI - Supra-ultraviolet hits sunbed seekers. PMID- 23445309 TI - Photodynamic therapy of infected ulcers. PMID- 23445310 TI - A costly revolution for a subgroup of patients with metastatic melanoma. PMID- 23445312 TI - Commentary: BRAF inhibitors for metastatic melanoma. PMID- 23445313 TI - Proteasome inhibition as a novel mechanism of the proapoptotic activity of gamma secretase inhibitor I in cutaneous T-cell lymphoma. AB - BACKGROUND: We have previously discovered that Notch1 is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL), and is required for survival of CTCL cell lines. Notch can be inhibited by gamma-secretase inhibitors (GSIs), which differ widely in their ability to induce apoptosis in CTCL. OBJECTIVES: To investigate whether GSI-I, in addition to inhibiting Notch, induces apoptosis in CTCL by proteasome inhibition, as GSI-I is very potent and has structural similarity to the proteasome inhibitor MG-132. METHODS: Cell lines derived from CTCL (MyLa, SeAx, JK, Mac1 and Mac2a) were treated with GSI-I and two other proteasome inhibitors (MG-132 and bortezomib). The effects on cell viability, apoptosis and proteasome activity were measured, as was the impact on the prosurvival, nuclear factor kappaB (NF-kappaB) pathway. RESULTS: In CTCL, GSI-I had proteasome-blocking activity with a potency comparable to the proteasome inhibitors MG-132 and bortezomib. Proteasome inhibition was the main mechanism responsible for GSI-I-induced cell death, as tiron, a compound known to reverse the effect of MG-132, restored proteasome activity and largely abrogated the cytotoxic effect of GSI-I. Although inactivation of NF-kappaB is an important mechanism of action for proteasome inhibitors, we demonstrated an apparent activation of NF-kappaB. Furthermore, we showed that while the tumour suppressor protein p53 was induced during proteasome inhibition, it was dispensable for CTCL apoptosis, as both SeAx cells, which harbour p53 mutations that attenuate the apoptotic capacity, and HuT-78 cells, which have a deleted p53 gene, demonstrated potent apoptotic response. CONCLUSIONS: GSI-I represents an interesting drug with a dual mechanism of action comprising inhibition of both Notch and the proteasome. PMID- 23445314 TI - Assessment of skin barrier function in podoconiosis: measurement of stratum corneum hydration and transepidermal water loss. AB - BACKGROUND: Podoconiosis is a common cause of lymphoedema in barefoot workers in Ethiopia and other countries. It has severe consequences for patients' physical function, quality of life and economic status. AIMS: To investigate stratum corneum (SC) hydration and transepidermal water loss (TEWL) in patients with podoconiosis compared with controls. METHODS: In total, 55 patients and 20 controls were recruited. For each study subject, SC and TEWL measurements were taken, along with foot and lower leg circumferences. Measurements were compared between the patient and control groups. RESULTS: Foot circumferences tended to be higher in patients with podoconiosis, with the mean foot:leg circumference ratio being 1.19 (95% confidence interval 1.11-1.28) times that for controls (P = 0.001). There was no detectable difference between patients and controls in TEWL values (P > 0.05); however, SC hydration was significantly lower in patients vs. controls for the foot (P = 0.004) and lower leg (P = 0.046) sites. CONCLUSIONS: Patients with podoconiosis have significantly lower SC hydration in the skin of their lower legs and feet than controls, which may lead to cracking and splitting, and increased risk of lymphoedema and infection. PMID- 23445305 TI - Why so many unknown genes? Partitioning orphans from a representative transcriptome of the lone star tick Amblyomma americanum. AB - BACKGROUND: Genomic resources within the phylum Arthropoda are largely limited to the true insects but are beginning to include unexplored subphyla, such as the Crustacea and Chelicerata. Investigations of these understudied taxa uncover high frequencies of orphan genes, which lack detectable sequence homology to genes in pre-existing databases. The ticks (Acari: Chelicerata) are one such understudied taxon for which genomic resources are urgently needed. Ticks are obligate blood feeders that vector major diseases of humans, domesticated animals, and wildlife. In analyzing a transcriptome of the lone star tick Amblyomma americanum, one of the most abundant disease vectors in the United States, we find a high representation of unannotated sequences. We apply a general framework for quantifying the origin and true representation of unannotated sequences in a dataset and for evaluating the biological significance of orphan genes. RESULTS: Expressed sequence tags (ESTs) were derived from different life stages and populations of A. americanum and combined with ESTs available from GenBank to produce 14,310 ESTs, over twice the number previously available. The vast majority (71%) has no sequence homology to proteins archived in UniProtKB. We show that poor sequence or assembly quality is not a major contributor to this high representation by orphan genes. Moreover, most unannotated sequences are functional: a microarray experiment demonstrates that 59% of functional ESTs are unannotated. Lastly, we attempt to further annotate our EST dataset using genomic datasets from other members of the Acari, including Ixodes scapularis, four other tick species and the mite Tetranychus urticae. We find low homology with these species, consistent with significant divergence within this subclass. CONCLUSIONS: We conclude that the abundance of orphan genes in A. americanum likely results from 1) taxonomic isolation stemming from divergence within the tick lineage and limited genomic resources for ticks and 2) lineage-specific genes needing functional genomic studies to evaluate their association with the unique biology of ticks. The EST sequences described here will contribute substantially to the development of tick genomics. Moreover, the framework provided for the evaluation of orphan genes can guide analyses of future transcriptome sequencing projects. PMID- 23445315 TI - Eczema severity in preadolescent children and its relation to sex, filaggrin mutations, asthma, rhinitis, aggravating factors and topical treatment: a report from the BAMSE birth cohort. AB - BACKGROUND: Filaggrin (FLG) mutations are major genetic determinants for eczema, but their role in eczema severity needs further investigation. Children with eczema are at higher risk of having asthma and rhinitis but it is not known if this risk is associated with the severity of eczema. OBJECTIVES: To investigate eczema severity in relation to sex, FLG mutations, asthma, rhinitis and topical treatment among preadolescent children in a population-based cohort. METHODS: Parental questionnaires were used to obtain data on symptoms of eczema, asthma, and rhinitis among 3301 preadolescent children. Eczema severity was evaluated based on sleep disturbance, extent of disease and total time with eczema the previous year. Genotyping was performed in 1854 individuals for three common FLG mutations (R501X, R2447X and 2282del4). Results Eczema was more prevalent among girls (14.5%) than boys (9.4%). FLG mutations were detected in 13.1% of children with mild eczema and 12.5% with moderate-to-severe eczema. Of children with moderate-to-severe eczema, 45.1% had rhinitis and 22.0% had asthma compared with 32.7% and 13.8% of children with mild eczema, respectively. Children with moderate-to-severe eczema used moisturizers and topical glucocorticoids more frequently than children with mild eczema. Boys used moisturizers less frequently than girls. CONCLUSIONS: More preadolescent girls than boys had eczema. FLG mutations did not influence eczema severity in our population-based cohort. Prevalence of rhinitis and asthma was associated with eczema severity, with the highest prevalence among boys with moderate-to-severe eczema. PMID- 23445316 TI - Incidence and survival in patients with cutaneous malignant melanoma: experience in a U.K. population, 1984-2009. PMID- 23445318 TI - Treatment and early intervention in psychosis program (TIPP-Lausanne): Implementation of an early intervention programme for psychosis in Switzerland. AB - AIM: In a survey conducted in the Lausanne catchment area in 2000, we could estimate on the basis of file assessment that first-episode psychosis (FEP) patients had psychotic symptoms for more than 2 years before treatment and that 50% did not attend any outpatient appointment after discharge from hospital. In this paper, we describe the implementation of a specialized programme aimed at improving engagement and quality of treatment for early psychosis patients in the Lausanne catchment area in Switzerland. METHOD: The Treatment and Early Intervention in Psychosis Program-Lausanne is a comprehensive 3-year programme composed of (i) an outpatient clinic based on assertive case management; (ii) a specialized inpatient unit; and (iii) an intensive mobile team, connected for research to the Center for Psychiatric Neuroscience. RESULTS: Eight years after implementation, the programme has included 350 patients with a disengagement rate of 9% over 3 years of treatment. All patients have been assessed prospectively and 90 participated in neurobiological research. Based on this experience, the Health Department funded the implementation of similar programmes in other parts of the state, covering a total population of 540,000 people. CONCLUSION: Programmes for early intervention in psychosis have a major impact on patients' engagement into treatment. While development of mobile teams and assertive case management with specific training are crucial, they do not necessitate massive financial support to be started. Inclusion of a research component is important as well, in terms of service planning and improvement of both quality of care and impact of early intervention strategies. PMID- 23445319 TI - A double-enzyme-coupled assay for high-throughput screening of succinic acid producing strains. AB - AIMS: To develop a microplate-based high-throughput assay for the detection of succinic acid, which is widely used in many fields of industry. The assay can also be applied to screen high succinic acid-producing strains. METHODS AND RESULTS: Here, we developed a double-enzyme-based succinic acid detection assay using fumarate reductase and peroxidase (named FRDP assay) to screen and isolate high succinic acid-producing bacteria. The assay was performed in 96-well microplate in a high-throughput and had a well linear detection range of succinic acid from 0.05 mmol l(-1) to 0.2 mmol l(-1) . Interference analysis results showed the complex media (LB),the by-products (formic acid and acetic acid) of fermentation and a longer fermentation time interfere with the FRDP assay, while the mineral media (M9) and short fermentation time (<12 h) could minimize the interference. CONCLUSIONS: The developed double-enzyme-coupled FRDP assay can be used in quick screening of succinic acid production. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, a novel high-throughput screening method to detect succinic acid was developed. This screening method is useful to screen succinic acid-producing bacteria and can be easily adjusted to screen different strains for the production of many other metabolites. PMID- 23445320 TI - A randomized study of surgical site infiltration with bupivacaine or ketamine for pain relief in children following cleft palate repair. AB - BACKGROUND: Wound infiltration with ketamine reduces postoperative pain after tonsillectomy by NMDA receptor blockade and local anesthetic effect. OBJECTIVES: To evaluate the postoperative analgesia after surgical site infiltration with bupivacaine or ketamine in children undergoing cleft palate surgery. MATERIALS AND METHODS: After institutional ethics committee approval and parental consent, 50 ASA-1 children of age 1-6 years undergoing palatoplasty were included in this prospective randomized double-blind study. A standardized technique of general anesthesia was used. The surgical site was infiltrated with either 2 mg.kg(-1) of bupivacaine (Group B) or 0.5 mg.kg(-1) of ketamine (Group K). Pain (Children Hospital Eastern Ontario Pain Score), sedation, dysphagia, nausea, vomiting, and sleep pattern were assessed postoperatively up to 24 h. RESULTS: CHEOPS scores were similar in both the groups up to 12 h but were lower with ketamine compared with bupivacaine at 24 h postoperatively (P = 0.01). Fewer children required rescue analgesics in Group K (28%) than in Group B (64%; P < 0.01). The time to first rescue analgesic and the amount of analgesics used in 24 h were similar in the two groups. Fewer children suffered from dysphagia in Group K (52%) than in Group B (88%; P < 0.01). More children in Group B had disturbed sleep than in Group K at 6 (88% vs 56%; P = 0.012) and 12 h (60% vs 24%; P = 0.01) postoperatively. None of the children had deep sedation, desaturation or respiratory depression. CONCLUSION: Surgical site infiltration with either bupivacaine or ketamine provides adequate analgesia and is devoid of major side effects. Ketamine is superior to bupivacaine in terms of requirement of rescue analgesic, peaceful sleep pattern and early resumption of feeding. PMID- 23445321 TI - Hydrogen bond-assisted 6pi-azaelectrocyclization of penta-2,4-dienamides: synthesis of dihydropyridin-2(3H)-ones. AB - A facile and efficient synthesis of substituted dihydropyridin-2(3H)-ones is developed from penta-2,4-dienamides, in which an intramolecular C-N bond was formed through thermal 6pi-azaelectrocyclization. The intramolecular hydrogen bonding-assisted cyclization reaction opens access to a variety of dihydropyridin 2(3H)-ones. PMID- 23445322 TI - Babesia microti real-time polymerase chain reaction testing of Connecticut blood donors: potential implications for screening algorithms. AB - BACKGROUND: Babesia microti, an intraerythrocytic parasite, has been implicated in transfusion transmission. B. microti seroprevalence in Connecticut (CT) blood donors is approximately 1%; however, it is not known what percentage of donors is parasitemic and poses a risk for transmitting infection. Therefore, we determined the prevalence of demonstrable B. microti DNA in donors from a highly endemic area of CT and compared observed rates with concurrent immunofluorescence assay (IFA) testing results. STUDY DESIGN AND METHODS: Blood samples from consenting donors in southeastern CT were collected from mid-August through early October 2009 and tested by IFA for immunoglobulin G antibodies and real-time polymerase chain reaction (PCR) for B. microti DNA. IFA specificity was determined using blood donor samples collected in northwestern Vermont (VT), an area nonendemic for Babesia. RESULTS: Of 1002 CT donors, 25 (2.5%) were IFA positive and three (0.3%) were real-time PCR positive. Among the three real-time PCR-positive donors, two were also IFA positive, while one was IFA negative and may represent a window period infection. The two IFA- and real-time PCR-positive donors appeared to subsequently clear infection. The other real-time PCR-positive donor did not provide follow-up samples. Of 1015 VT donors tested by IFA, only one (0.1%) was positive, but may have acquired infection during travel to an endemic area. CONCLUSION: We prospectively identified several real-time PCR-positive blood donors, including an IFA-negative real-time PCR-positive donor, in an area highly endemic for B. microti. These results suggest the need to include nucleic acid testing in planned mitigation strategies for B. microti. PMID- 23445324 TI - Relationship between the electron density of the heme Fe atom and the vibrational frequencies of the Fe-bound carbon monoxide in myoglobin. AB - We analyzed the vibrational frequencies of the Fe-bound carbon monoxide (CO) of myoglobin reconstituted with a series of chemically modified heme cofactors possessing a heme Fe atom with a variety of electron densities. The study revealed that the stretching frequency of Fe-bound CO (nu(CO)) increases with decreasing electron density of the heme Fe atom (rho(Fe)). This finding demonstrated that the nu(CO) value can be used as a sensitive measure of the rho(Fe) value and that the pi back-donation of the heme Fe atom to CO is affected by the heme pi-system perturbation induced through peripheral side chain modifications. PMID- 23445323 TI - Solution NMR and computational methods for understanding protein allostery. AB - Allosterism is an essential biological regulatory mechanism. In enzymes, allosteric regulation results in an activation or inhibition of catalytic turnover. The mechanisms by which this is accomplished are unclear and vary significantly depending on the enzyme. It is commonly the case that a metabolite binds to the enzyme at a site distant from the catalytic site, yet its binding is coupled to and sensed by the active site. This coupling can manifest in changes in structure, dynamics, or both at the active site. These interactions between the allosteric and active site, which are often quite distant from one another, involve numerous atoms as well as complex conformational rearrangements of the protein secondary and tertiary structure. Interrogation of this complex biological phenomenon necessitates multiple experimental approaches. In this article, we outline a combined solution NMR spectroscopic and computational approach using molecular dynamics and network models to uncover mechanistic aspects of allostery in the enzyme imidazole glycerol phosphate synthase. PMID- 23445325 TI - Peptide-bacteria interactions using engineered surface-immobilized peptides from class IIa bacteriocins. AB - Specificity of the class IIa bacteriocin Leucocin A (LeuA), an antimicrobial peptide active against Gram-positive bacteria, including Listeria monocytogenes , is known to be dictated by the C-terminal amphipathic helical region, including the extended hairpin-like structure. However, its specificity when attached to a substrate has not been investigated. Exploiting properties of LeuA, we have synthesized two LeuA derivatives, which span the amphipathic helical region of the wild-type LeuA, consisting of 14- (14AA LeuA, CWGEAFSAGVHRLA) and 24-amino acid residues (24AA LeuA, CSVNWGEAFSAGVHRLANGGNGFW). The peptides were purified to >95% purity, as shown by analytical RP-HPLC and mass spectrometry. By including an N-terminal cysteine group, the tailored peptide fragments were readily immobilized at the gold interfaces. The resulting thickness and molecular orientation, determined by ellipsometry and grazing angle infrared spectroscopy, respectively, indicated that the peptides were covalently immobilized in a random helical orientation. The bacterial specificity of the anchored peptide fragments was tested against Gram-positive and Gram-negative bacteria. Our results showed that the adsorbed 14AA LeuA exhibited no specificity toward the bacterial strains, whereas the surface-immobilized 24AA LeuA displayed significant binding toward Gram-positive bacteria with various binding affinities from one strain to another. The 14AA LeuA did not show binding as this fragment is most likely too short in length for recognition by the membrane-bound receptor on the target bacterial cell membrane. These results support the potential use of class IIa bacteriocins as molecular recognition elements in biosensing platforms. PMID- 23445326 TI - Healthy hospital food initiatives in the United States: time to ban sugar sweetened beverages to reduce childhood obesity. AB - While childhood obesity is a global problem, the extent and severity of the problem in United States, has resulted in a number of new initiatives, including recent hospital initiatives to limit the sale of sweetened beverages and other high calorie drinks in hospital vending machines and cafeterias. These proposed policy changes are not unique to United States, but are more comprehensive in the number of proposed hospitals that they will impact. Meanwhile, however, it is advised, that these initiatives should focus on banning sugar sweetened beverages, including sodas, 100% fruit juice and sports drinks, from hospital cafeterias and vending machines instead of limiting their presence, so as to ensure the success of these programs in reducing the prevalence of childhood obesity. If US hospitals comprehensively remove sugar sweetened beverages from their cafeterias and vending machines, these programs could subsequently become a model for efforts to address childhood obesity in other areas of the world. CONCLUSION: Hospitals should be a model for health care reform in their communities and removing sugar sweetened beverages is a necessary first step. PMID- 23445327 TI - Visceral adipose tissue is significantly associated with hearing thresholds in adult women. AB - OBJECTIVE: Metabolic syndrome is a risk factor for age-related hearing impairment (ARHI). There are metabolic differences between abdominal adipose tissue present in subcutaneous and visceral areas. In this study, we investigated the association between abdominal fat composition, measured by computerized tomography (CT), and hearing thresholds. PATIENTS AND METHODS: We recruited 662 adults aged 40-82 years with normal or symmetrical sensorineural hearing loss who underwent fat measurement by CT. Linear regression models were used to address the association between risk factors, including abdominal fat composition, and average hearing levels at low and high frequencies. RESULTS: After adjusting for age, systemic disease and other variables, a positive association between visceral adipose tissue (VAT) area and average hearing threshold was observed in women. In men, there was no significant association between abdominal fat composition and hearing threshold. CONCLUSION: Our findings show an association between VAT and hearing impairment in women. A reduction in visceral adiposity may help to prevent hearing loss in women. PMID- 23445328 TI - The ventriculocholecystic shunt: two case reports and a review of the literature. AB - We describe the re-siting of ventriculoperitoneal shunts to the gallbladder in two children. The first child had a rare case of hydrocephalus associated with plasminogen deficiency. She had had multiple VP shunt revisions due to non absorption of CSF from the peritoneum. The second had craniopharyngioma-related hydrocephalus with once again a non-absorbing peritoneum. We report no surgical complications in the revisions for both the cases, and there has been a subsequent follow-up of 46 and 28 months, respectively, without incident. A review of the relevant literature describing the use and the performance of ventriculocholecystic shunts in comparison with other ventricular shunts is considered. PMID- 23445329 TI - Getting the basics right: opportunities for developing neurosurgical procedural skills in ENT surgery. PMID- 23445330 TI - Operative treatment of paediatric penetrating head injuries in southern Afghanistan. AB - The operative management and early post-operative outcome of 16 consecutive cases of paediatric penetrating head injury treated by a single surgeon at a military trauma centre in Southern Afghanistan are retrospectively analysed. The majority of cases of injury were caused by fragments from exploding munitions. The aim of neurosurgical intervention in penetrating head injury is the prevention of wound infection and treatment or prevention of a critical rise in intracranial pressure. In 14 cases in this study, these aims were fulfilled without resort to brain resection, although a delayed cranioplasty procedure was required in 6 patients. Despite the ongoing conflict, families, local communities and coalition forces transport teams combine to make the latter a viable option in Southern Afghanistan, with an excellent short-term outcome. PMID- 23445331 TI - Diffusion tensor invasive phenotypes can predict progression-free survival in glioblastomas. AB - INTRODUCTION: Glioblastomas multiformes (GBM) remain incurable in most cases. Their invasion into normal brain makes current therapies ineffective. Post-mortem studies suggest about a 25% of GBMs invade less than 1 cm from the tumour bulk and 20% invade more than 3 cm. AIM OF STUDY: The study aims to use DTI to assess tumour extension and determine how previously reported patterns relate to the progression-free survival (PFS). MATERIALS AND METHODS: Twenty-five patients with GBM treated according to the EORTC/NCIC protocol were retrospectively analysed. Patients were imaged post-operatively at 1.5 T. The sequences were composed of standard anatomical and a standard DTI sequence. As described earlier p and q maps were constructed. For each of the p and q maps, regions of interest were drawn around the visible abnormality. Patients were assigned a diffuse, localised or minimally invasive pattern. Progression was defined according to the RANO criteria (4) and PFS determined in days. Kaplan-Meier plots of survival for the three groups were plotted as were the proportion of patients who had not progressed at 24 months. RESULTS: The median PFS for the diffuse group was 278 days, for the localised group 605 days and 820 days for the minimally invasive group. Three-fourth of the minimally invasive group were progression-free at 24 months (LOG RANK 9.25; p = 0.010). CONCLUSION: It is possible to identify three invasive phenotypes in GBMs using Diffusion tensor imaging , and these three phenotypes have different progression free survival. A minimal phenotype (20% of patients) predicts a greater delay to progression. PMID- 23445332 TI - Dumbbell ganglioneuroma mimicking lumbar neurofibroma: a case report and review of the literature. AB - Spinal ganglioneuromas may grow in a dumbbell fashion. We report the first case of an intradural, extramedullary ganglioneuroma in the lumbar spine and review the pertinent literature. Although rare, we propose that ganglioneuroma be considered a differential diagnosis in patients presenting with a large mass occupying both intraspinal and extraspinal compartments. PMID- 23445333 TI - The role of neuroscience societies in widening undergraduate awareness of neurosurgery. PMID- 23445334 TI - Tumour infiltrating T-cell subpopulations in glioblastomas: what is the significance of natural killer T-cells? PMID- 23445335 TI - Efficacy of antiseptics containing povidone-iodine, octenidine dihydrochloride and ethacridine lactate against biofilm formed by Pseudomonas aeruginosa and Staphylococcus aureus measured with the novel biofilm-oriented antiseptics test. AB - Increasing data suggesting that microorganisms in the biofilm form are among the leading agents of persistent infections of chronic wounds require the development of new approaches to treatment. The aim of this article was to compare the efficacy of three commonly used antiseptics using a biofilm-oriented approach. Biofilm-oriented antiseptics test (BOAT), the innovative method, allows to estimate, in a quick and reliable manner, the in vitro activity of working solutions of antiseptics in real contact times against bacteria in the biofilm form and to use the results in the selection of an appropriate antiseptic to treat local infections in the clinical practice. PMID- 23445336 TI - The contribution of self-help/mutual aid groups to mental well-being. AB - This article explores the contribution of self-help/mutual aid groups to mental well-being. Self-help/mutual aid groups are self-organising groups where people come together to address a shared a health or social issue through mutual support. They are associated with a range of health and social benefits, but remain poorly understood. This article draws on data from stage one of ESTEEM, a project which runs from 2010 to 2013. Stage one ran from 2010 to 2011 and involved participatory, qualitative research carried out in two UK sites. Twenty one groups were purposively selected to include a range of focal issues, longevity, structures and ethnic backgrounds. Researchers carried out 21 interviews with group coordinators and twenty group discussions with members to explore the groups' purpose, nature and development. Preliminary analysis of the data suggested that mental well-being was a common theme across the groups. Subsequently the data were re-analysed to explore the groups' contribution to mental well-being using a checklist of protective factors for mental well-being as a coding framework. The findings showed that groups made a strong contribution to members' mental well-being by enhancing a sense of control, increasing resilience and facilitating participation. Group members were uplifted by exchanging emotional and practical support; they gained self-esteem, knowledge and confidence, thereby increasing their control over their situation. For some groups, socio-economic factors limited their scope and threatened their future. The article provides an evidence-base which illustrates how self-help/mutual aid groups can enhance mental well-being. If supported within a strategy for social justice, these groups enable people with varied concerns to develop a tailored response to their specific needs. The authors suggest that policy-makers engage with local people, investing in support proportionate to the needs of different populations, enabling them to develop their own self-help/mutual aid groups to enhance their sense of mental well-being. PMID- 23445337 TI - Comment and reply on: pegfilgrastim is safe and effective in the prevention of neutropenia and treatment delays in biweekly regimens. PMID- 23445338 TI - Safety and efficacy of neoadjuvant FOLFIRINOX treatment in a series of patients with borderline resectable pancreatic ductal adenocarcinoma. PMID- 23445340 TI - Sociodemographic variables and depression in Turkish women from polygamous versus monogamous families. AB - In this study, we aimed to determine the different sociodemographic variables of polygamous and monogamous wives, and the relationship between depression and polygamous marriage. Seventy-nine polygamous wives and 73 monogamous wives from Kahramanmaras, located in southern Turkey, were interviewed. After reviewing the data, we suggest that there is a statistically significant difference between polygamous wives and monogamous wives in terms of Beck Depression Inventory (BDI) scores. The results highlighted many implications for clinical practice and for future research. Additional research needs to be conducted in order to investigate the effects of polygamy on women's mental health. PMID- 23445339 TI - Connective tissue of cervical carcinoma xenografts: associations with tumor hypoxia and interstitial fluid pressure and its assessment by DCE-MRI and DW-MRI. AB - Abstract Background. A high fraction of stroma in malignant tissues is associated with tumor progression, metastasis, and poor prognosis. Possible correlations between the stromal and physiologic microenvironments of tumors and the potential of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in quantification of the stromal microenvironment were investigated in this study. Material and methods. CK-160 cervical carcinoma xenografts were used as preclinical tumor model. A total of 43 tumors were included in the study, and of these tumors, 17 were used to search for correlations between the stromal and physiologic microenvironments, 11 were subjected to DCE-MRI, and 15 were subjected to DW-MRI. DCE-MRI and DW-MRI were carried out at 1.5 T with a clinical MR scanner and a slotted tube resonator transceiver coil constructed for mice. Fraction of connective tissue (CTFCol) and fraction of hypoxic tissue (HFPim) were determined by immunohistochemistry. A Millar SPC 320 catheter was used to measure tumor interstitial fluid pressure (IFP). Results. CTFCol showed a positive correlation to IFP and an inverse correlation to HFPim. The apparent diffusion coefficient assessed by DW-MRI was inversely correlated to CTFCol, whereas no correlation was found between DCE-MRI-derived parameters and CTFCol. Conclusion. DW-MRI is a potentially useful method for characterizing the stromal microenvironment of tumors. PMID- 23445341 TI - Pigmentation: selective photothermolysis or non-specific skin necrosis using different intense pulsed light systems? AB - BACKGROUND AND OBJECTIVE: This study considers end point tissue responses and side effects to determine whether 'square pulse' IPL is more or less effective than the traditional IPL. Supporting histological data and computational modelling results are provided. It provides guidance for IPL users unfamiliar with constant spectrum IPL devices and redirects attention to treatment end points. MATERIALS AND METHODS: Twenty subjects of Fitzpatrick Skin Types I-III, presenting with various epidermal pigmented lesions, were treated 1-3 times with two different IPLs. Coupling gel was used and firm pressure was applied to exclude blood from the treatment area. Immediate and post-treatment side effects, degree of discomfort and end results at fourteen and thirty days were evaluated by professional observation, digital photography and a patient questionnaire. RESULTS: Both IPLs showed a mean clearance of over 80% after 1-3 treatments but the free discharge IPL demonstrated a greater side effect profile with a higher incidence of ulceration, crusting and erythema. CONCLUSIONS: Clinical observation and mathematical modelling suggests that the square pulse, partial discharge IPL system may provide the IPL operator with greater control over the coagulation of pigment and is therefore the more efficient device for effective pigment lightening with fewer side effects. PMID- 23445343 TI - Memory-guided saccades in youth-onset psychosis and attention deficit hyperactivity disorder (ADHD). AB - AIM: Working memory deficits have been shown to be present in children and adolescents with schizophrenia and attention deficit hyperactivity disorder. Considering the differences in clinical characteristics between these disorders, it was the goal of this study to assess differences in the specific components of working memory in children and adolescents with psychosis and attention deficit hyperactivity disorder. METHODS: Children and adolescents (age range 8-20 years) with either a non-affective psychotic disorder (n = 25), attention deficit hyperactivity disorder (n = 33) and controls (n = 58) were administered an oculomotor delayed-response task using both a recall and a control condition. Memory-guided saccades were measured during delay periods of 2, 8 and 20 s. RESULTS: Although both clinical groups were less accurate than controls, there was no evidence of a disproportionate impairment in recall. In addition, there was no evidence of a delay-dependent impairment in psychosis; however, there was a delay-dependent impairment in attention deficit hyperactivity disorder when corrective saccades were included. Speed of information processing was correlated with distance errors in psychosis, suggesting that speed of encoding the stimulus location may have constrained the accuracy of the saccades. CONCLUSIONS: Our findings support impairments during encoding in the psychosis group and a delay dependent deficit in the attention deficit hyperactivity disorder group. PMID- 23445344 TI - Design of superbasic guanidines: the role of multiple intramolecular hydrogen bonds. AB - New organic superbases have been designed using the concept of multiple intramolecular hydrogen bonds. Substituents capable of forming strong intramolecular H-bonds were selected on the basis of the energy of stabilization that occurs upon the formation of a complex between N,N',N"-trimethylguanidine and small model molecules. The proton affinities and the corresponding pK(a) values in acetonitrile of the new superbases are examined by Density Functional Theory (DFT). It is shown that N,N',N"-substitution of guanidine with appropriate substituents results in new organic superbases with gas phase proton affinities between 286 and 293 kcal mol(-1), thus being 15 to 20 kcal mol(-1) more basic than parental superbase N,N',N"-tris[(3-dimethylamino)propyl]-guanidine (tris DMPG), whereas estimated pK(a) values in acetonitrile range between 29.5 and 33.2. PMID- 23445342 TI - A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX. AB - BACKGROUND: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits. RESULTS: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity. CONCLUSION: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system. PMID- 23445345 TI - Isolation, molecular characterization and antimicrobial susceptibilities of isolates of Mycoplasma agalactiae from bulk tank milk in an endemic area of Spain. AB - AIM: To isolate and characterize strains of Mycoplasma agalactiae from bulk tank and silo ewes' milk. METHODS AND RESULTS: Thirteen mycoplasma isolates were obtained from samples of sheep milk taken from bulk tank and large silos and identified as Myc. agalactiae by PCR-DGGE. The isolates were typed by pulsed field gel electrophoresis (PFGE), SDS-PAGE and immunoblot. The in vitro activity of 13 antimicrobials of veterinary interest was tested against these isolates. Results showed that the most effective compounds against Myc. agalactiae in vitro were clindamycin, an antibiotic not previously described as a suitable contagious agalactia (CA) treatment, with Minimum Inhibitory Concentration (MIC) values of <0.12 MUg ml(-1) , and quinolones, with MIC values <0.12-0.5 MUg ml(-1) , which are used as standard treatments against CA. CONCLUSIONS: Based on the in vitro assay, clindamycin, quinolones, tylosin and tilmicosin would be appropriate antimicrobials for CA treatment. The isolates were mostly resistant to erythromycin, indicating that it would not be a suitable choice for therapy. The isolates showed common molecular and protein profiles by PFGE and SDS-PAGE, with minor differences observed by immunoblot analysis, suggesting a clonal relationship among them. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated the importance of the appropriate selection of antimicrobials for treatment of CA. PMID- 23445346 TI - Single-molecule spectroscopy on RC-LH1 complexes of Rhodopseudomonas acidophila strain 10050. AB - We have revisited the RC-LH1 complex from Rhodopseudomonas (Rps.) acidophila for single-molecule spectroscopy. For the current study the pigment-protein complexes were stabilized in the detergent buffer solution using a relatively mild detergent (dodecyl-beta-D-maltoside (DDM) instead of lauryldimethylamine N-oxide (LDAO)). This leads to a significant reduction of the fraction of broken/dissociated RC-LH1 complexes with respect to previous studies and has allowed us to investigate a sufficiently large sample of individual RC-LH1 complexes. For most of the complexes the fluorescence-excitation spectra exhibit a narrow spectral feature at the red end of the spectrum. Analysis of the statistics of the spectral properties yields a close resemblance with the results obtained on RC-LH1 complexes from Rps. palustris for which a low-resolution X-ray structure is available. Based on this comparison we come to the conclusion that for both species the RC-LH1 complex can be described by the same structural model, that is, an overall elliptical assembly of pigments that features a gap. PMID- 23445347 TI - Normal spermatogenesis and sperm function in a subject affected by cerebellar ataxia due to congenital vitamin E deficiency. AB - Vitamin E possesses potent beneficial effects on mammalian spermatogenesis and sperm quality. Subjects affected by cerebellar ataxia due to congenital isolated vitamin E deficiency (AVED) show vitamin E deficiency caused by a selective impaired gastrointestinal absorption of vitamin E for a mutation in the gene for alpha-tocopherol transfer protein leading to impairment of vitamin E absorption and decreased vitamin E plasma levels. Here, we present a 34-year-old male patient with AVED showing normal seminal parameters and normal gonadotrophins, testosterone and inhibin B plasma levels. The normal standard seminal parameters of this patient with AVED possibly question the role of vitamin E in human spermatogenesis. PMID- 23445348 TI - Influence of calcium ions on rhamnolipid and rhamnolipid/anionic surfactant adsorption and self-assembly. AB - The impact of Ca(2+) counterions on the adsorption at the air-water interface and self-assembly in aqueous solution of the rhamnolipid biosurfactant and its mixture with the anionic surfactant sodium dodecylbenzenesulfonate, LAS, has been studied using neutron reflectometry and small-angle neutron scattering. The results illustrate how rhamnolipids are calcium tolerant and how their blending with conventional anionic surfactants improves the calcium tolerance of the anionic surfactant. Ca(2+) has relatively little effect upon the adsorption and self-assembly of the monorhamnose, R1, and dirhamnose, R2, rhamnolipids, even at high pH, due to their predominantly nonionic nature. For R1/R2 mixtures the addition of Ca(2+) has little impact upon the adsorbed amount or the surface composition. For R2/LAS mixtures the addition of Ca(2+) results in an increased adsorption and a surface slightly richer in R2. The weak binding of Ca(2+) to R1 and R2 does result in a change to the degree of ionization of the micelles and especially for mixed R1/R2 micelles at R1-rich solution compositions. The stronger binding of Ca(2+) to LAS results in the addition of Ca(2+) having a much greater impact on the self-assembly of R1/LAS and R2/LAS mixtures. For R1/LAS mixtures the addition of Ca(2+) promotes the formation of more planar structures, even at low surfactant concentrations where in the absence of Ca(2+) mixed globular micelle formation dominates. In R2/LAS mixtures, where there is a greater contrast between the high and low preferred curvatures associated with R2 and LAS, the addition of Ca(2+) results in a more complex evolution in micellar aggregation and the degree of ionization of the micelles. This results in variations in Ca(2+) binding that promotes micellar structures in which a spatial segregation of the two surfactant components within the micelle occurs. PMID- 23445349 TI - High-frequency micro-ultrasound for vascular access in young children--a feasibility study by the High-frequency UltraSound in Kids studY (HUSKY) group. AB - BACKGROUND: Cannulation of small arteries and veins in young children can be challenging. Although anesthesiologists frequently use ultrasound for placement of central venous lines and nerve blocks, its use for cannulation of small, peripheral vessels is less helpful. Ultrasound systems (7-15 MHz) currently used in clinical practice focus poorly at the sub-10-mm space and thus lack the resolution to allow accurate ultrasound-guided cannulation of small vessels. High frequency micro-ultrasound (HFMU) is a new technology that allows higher resolution (15-50 MHz) compared with conventional ultrasound. Limited human studies have been performed thus far with HFMU, and none have been performed in young children or for vascular access. METHODS: This study was conducted to determine the feasibility of using HFMU to visualize and cannulate peripheral arteries and central veins in children under the age of 6 years old. The diameter of radial and ulnar arteries was also measured. RESULTS: The anesthesiologists involved in this study found the 50 MHz HFMU probe useful for cannulation of peripheral arteries, especially in the youngest children. The higher-frequency probes were less helpful for internal jugular vein cannulation because it was not always possible to view the carotid artery while cannulating the vein. CONCLUSIONS: The experience gained in this feasibility study suggests that HFMU could be a valuable addition to our armamentarium for difficult vascular access in the future. PMID- 23445350 TI - Healthcare utilization and health-related quality of life of adult survivors of preterm birth complicated by bronchopulmonary dysplasia. AB - AIM: This study aims to characterize the impact of preterm birth, respiratory distress syndrome and bronchopulmonary dysplasia on quality of life and healthcare utilization in adulthood. METHODS: A mail survey on quality of life and respiratory health was sent to a list of potential subjects identified using the databases of the Regie de l'asssurance maladie du Quebec. Four groups of adults born between 1987 and 1993 were compared: (i) preterm with bronchopulmonary dysplasia, (ii) preterm with respiratory distress syndrome, (iii) preterm without respiratory complications and (iv) term controls. As a complement, data from the governmental healthcare administrative databases were extracted for responders. RESULTS: Although the groups differed in their use of healthcare services and prescription drugs, no clinically significant difference was observed for Saint George's Respiratory Questionnaire (SGRQ), SF-36v2 and Medical Research Council (MRC) Dyspnea Scale scores. However, compared to term subjects, bronchopulmonary dysplasia subjects were less likely to access higher education and more likely to be either invalid or unemployed. CONCLUSION: Compared to term subjects, subjects with a history of prematurity and respiratory distress syndrome or bronchopulmonary dysplasia had similar health-related quality of life and respiratory symptoms despite greater use of healthcare services and prescription drugs. PMID- 23445351 TI - 'I'm actually being the grown-up now': leadership, maturity and professional identity development. AB - AIM: This study reports on an evaluation of an in-house nursing and midwifery leadership programme within a New Zealand District Health Board aimed at improving leadership capacity within clinical environments. BACKGROUND: The programme associated with this study is based on Practice Development concepts which aim to improve patient care and service delivery as well as empower practitioners to foster and support a transformational culture. METHODS: Mixed methods were used. RESULTS: Evidence indicated participants' self-confidence improved leading to a 'growing up'. This was demonstrated in a number of ways: taking more responsibility for individual clinical practice, undertaking quality and safety roles as well as postgraduate study. These findings can be constructed in terms of linking leadership training with the development of professional identity. CONCLUSIONS: This study provides evidence that in-house leadership programmes can provide front-line nurses and midwives with opportunities to enhance their professional identity and expand their skills in a variety of ways. IMPLICATIONS FOR NURSING MANAGEMENT: Organisational investment in in-house programmes aimed at leadership skills have the potential to enhance patient care as well as improve the work environment for nurses and midwives. However, in house programmes should be considered as augmenting rather than replacing tertiary education institutions' leadership courses and qualifications. PMID- 23445352 TI - Intraoperative cell salvage is associated with reduced postoperative blood loss and transfusion requirements in cardiac surgery: a cohort study. AB - BACKGROUND: This study investigated whether implementation of cell salvage of shed mediastinal and residual blood in all patients undergoing low-to-moderate risk cardiac surgery reduces the need for allogeneic red blood cell (RBC) transfusion compared to patients not subjected to cell salvage. STUDY DESIGN AND METHODS: This retrospective cohort study included patients undergoing low-to moderate-risk cardiac surgery with cardiopulmonary bypass without (control; n = 531) or with cell salvage (n = 433; Autolog, Medtronic). Study endpoints, including 24-hour blood loss and RBC requirements, were evaluated using adjusted logistic regression. RESULTS: Baseline characteristics were similar between groups. The cell saver group received 568 +/- 267 mL of autologous blood. Median number of allogeneic RBC transfusions was higher in the control group (2 [1-5]) compared with the cell salvage group (1 [0-3]; p < 0.001). There were no clinically relevant differences in postoperative coagulation test results between groups. The relative risk (RR) for postoperative RBC transfusion was reduced to 0.76 (95% confidence interval [CI], 0.70-0.83; p < 0.0001) in the cell salvage group. Moreover, patients in the cell salvage group had a lower chance for myocardial infarction (RR, 0.26; 95% CI, 0.08-0.91; p = 0.035), whereas the cell salvage group was associated with a higher probability for intensive care discharge within 24 hours after surgery (RR, 1.08; 95% CI, 1.02-1.14; p = 0.009). CONCLUSION: The use of cell salvage throughout the entire procedure reduces postoperative blood loss and allogeneic RBC transfusion. These findings advocate implementation of cell salvage in all patients undergoing on-pump cardiac surgery, irrespective of anticipated surgery-related blood loss. PMID- 23445353 TI - Tunable color of Ce3+/Tb3+/Mn(2+)-coactivated CaScAlSiO6 via energy transfer: a single-component red/white-emitting phosphor. AB - A series of single-component red/white-emitting CaScAlSiO6:Ce(3+),Tb(3+),Mn(2+) phosphors have been synthesized by a solid-state reaction. It is observed that CaScAlSiO6:Ce(3+),Tb(3+) phosphors exhibit two dominating bands situated at 380 and 542 nm, originating from the allowed 5d -> 4f transition of the Ce(3+) ion and the (5)D4 -> (7)F(J) = (J = 6, 5, 4, 3) transition of the Tb(3+) ion, respectively. As for CaScAlSiO6:Ce(3+),Mn(2+), our results indicate that Mn(2+) may occupy not only a Ca(2+) site to generate an orange emission [Mn(2+)(I)] at 590 nm but also a Sc(3+) site to generate a red emission [Mn(2+)(II)] at 670 nm. Both energy transfers from Ce(3+) to Tb(3+) and from Ce(3+) to Mn(2+) in the CaScAlSiO6 host are investigated and have been demonstrated to be of the resonant type via a dipole-dipole mechanism. By proper tuning of the relative composition of Tb(3+)/Mn(2+), white light can also be achieved upon excitation of UV light, indicating that the developed phosphor may potentially be used as a single component red/white-emitting phosphor for UV-light-emitting diodes. PMID- 23445354 TI - Changes in sexual functioning in women after neuromodulation for voiding dysfunction. AB - INTRODUCTION: Sacral neuromodulation is a well-established treatment for urinary and bowel disorders with potential use for other disorders such as sexual dysfunction. AIM: To evaluate changes in sexual functioning in women undergoing neuromodulation for voiding symptoms. METHODS: Patients enrolled in our prospective, observational neuromodulation database study were evaluated. Data were collected from medical records, and patient-completed Female Sexual Function Index (FSFI) and Interstitial Cystitis Symptom-Problem Indices (ICSI-PI) at baseline, 3, 6, and 12 months post-implant. Patients rated overall change in sexual functioning on scaled global response assessments (GRA) at 3, 6, and 12 months post-implant. We grouped women by baseline FSFI scores: less (score<26) and more sexually functional (score>=26). Data were analyzed with Pearson's Chi square or Fisher's Exact test and repeated measures. MAIN OUTCOMES MEASURES: Changes in FSFI and ICSI-PI scores in women grouped by baseline FSFI score<26 and >=26. RESULTS: Of 167 women evaluated, FSFI scores improved overall from preimplant (mean 13.5+/-8.5) to 12 months (N=72; mean 15.9+/-8.9, P=0.004). At baseline and each follow-up point, ICSI-PI scores were similar between groups and improved through time. For patients in the FSFI<26 group there was improvement from baseline to 12-month scores (N=63; 11.9+/-6.9 to 14.8+/-8.7; P=0.0006). Improved FSFI domains included desire, orgasm, satisfaction, and pain. Furthermore, of the 74 subjects in this group not sexually active at baseline, 10 became sexually active during follow-up. In the FSFI>=26 group there was slight but statistically significant decline in mean scores between baseline and 12 months (N=9; 27.4+/-1.1 to 24.5+/-3.4; P=0.0302); however one had become sexually inactive. A significant decrease was seen in the satisfaction domain. CONCLUSIONS: Many factors affect sexual functioning in women; however sexual function may improve along with urinary symptoms after neuromodulation. PMID- 23445355 TI - A SNP resource for Douglas-fir: de novo transcriptome assembly and SNP detection and validation. AB - BACKGROUND: Douglas-fir (Pseudotsuga menziesii), one of the most economically and ecologically important tree species in the world, also has one of the largest tree breeding programs. Although the coastal and interior varieties of Douglas fir (vars. menziesii and glauca) are native to North America, the coastal variety is also widely planted for timber production in Europe, New Zealand, Australia, and Chile. Our main goal was to develop a SNP resource large enough to facilitate genomic selection in Douglas-fir breeding programs. To accomplish this, we developed a 454-based reference transcriptome for coastal Douglas-fir, annotated and evaluated the quality of the reference, identified putative SNPs, and then validated a sample of those SNPs using the Illumina Infinium genotyping platform. RESULTS: We assembled a reference transcriptome consisting of 25,002 isogroups (unique gene models) and 102,623 singletons from 2.76 million 454 and Sanger cDNA sequences from coastal Douglas-fir. We identified 278,979 unique SNPs by mapping the 454 and Sanger sequences to the reference, and by mapping four datasets of Illumina cDNA sequences from multiple seed sources, genotypes, and tissues. The Illumina datasets represented coastal Douglas-fir (64.00 and 13.41 million reads), interior Douglas-fir (80.45 million reads), and a Yakima population similar to interior Douglas-fir (8.99 million reads). We assayed 8067 SNPs on 260 trees using an Illumina Infinium SNP genotyping array. Of these SNPs, 5847 (72.5%) were called successfully and were polymorphic. CONCLUSIONS: Based on our validation efficiency, our SNP database may contain as many as ~200,000 true SNPs, and as many as ~69,000 SNPs that could be genotyped at ~20,000 gene loci using an Infinium II array-more SNPs than are needed to use genomic selection in tree breeding programs. Ultimately, these genomic resources will enhance Douglas fir breeding and allow us to better understand landscape-scale patterns of genetic variation and potential responses to climate change. PMID- 23445356 TI - Does the 9p region affect arterial stiffness? Results from a cohort of hypertensive individuals. AB - OBJECTIVE: Evidence exists that arterial stiffness, i.e. an independent predictor of cardiovascular and all-causes mortality, has a genetic component. The 9p21 region is associated with a greater susceptibility to coronary disease. Whether this can be ascribed to the fact that genes located on chromosome 9p may also regulate arterial stiffness is largely unknown, however. We evaluate the influence of single nucleotide polymorphisms (SNPs) from 9p on carotid-femoral pulse wave velocity (C-F PWV), measured via the Complior method, in a cohort of 821 hypertensive subjects. DESIGN: The selected tagSNPs were screened with a custom-designed 384-plex VeraCode GoldenGate Genotyping assay on Illumina BeadXpress Reader platform. Association analysis was done using PLINK considering C-F PWV as a quantitative trait (linear regression assuming an additive model) adjusting for sex, age, systolic blood pressure and body mass index (BMI). We used false discovery rate (FDR) to account for multiple testing. RESULTS: Although none of the 384 SNPs was significant after adjusting for multiple testing, probably due to the small sample size of the study population, a trend of association with C-F PWV was observed for rs300622 and rs2381640. CONCLUSIONS: These data suggest that SNPs located on chromosome 9p may affect arterial stiffness. Further studies are needed to confirm our finding on a larger sample and define the physiopathological link of the present results. PMID- 23445357 TI - Large-scale road safety programmes in low- and middle-income countries: an opportunity to generate evidence. AB - The growing burden of road traffic injuries, which kill over 1.2 million people yearly, falls mostly on low- and middle-income countries (LMICs). Despite this, evidence generation on the effectiveness of road safety interventions in LMIC settings remains scarce. This paper explores a scientific approach for evaluating road safety programmes in LMICs and introduces such a road safety multi-country initiative, the Road Safety in 10 Countries Project (RS-10). By building on existing evaluation frameworks, we develop a scientific approach for evaluating large-scale road safety programmes in LMIC settings. This also draws on '13 lessons' of large-scale programme evaluation: defining the evaluation scope; selecting study sites; maintaining objectivity; developing an impact model; utilising multiple data sources; using multiple analytic techniques; maximising external validity; ensuring an appropriate time frame; the importance of flexibility and a stepwise approach; continuous monitoring; providing feedback to implementers, policy-makers; promoting the uptake of evaluation results; and understanding evaluation costs. The use of relatively new approaches for evaluation of real-world programmes allows for the production of relevant knowledge. The RS-10 project affords an important opportunity to scientifically test these approaches for a real-world, large-scale road safety evaluation and generate new knowledge for the field of road safety. PMID- 23445358 TI - Effect of glacial acetic acid treatment of cervical ThinPrep specimens on HPV DNA detection with the cobas 4800 HPV test. AB - BACKGROUND: Cytology laboratories in the UK routinely treat unsatisfactory cervical liquid-based cytology (LBC) specimens with glacial acetic acid (GAA) to reduce the unsatisfactory rate. However, there is limited published data on the effect of GAA reprocessing on the molecular detection of human papillomavirus (HPV). The aim of this study was to assess the impact of GAA treatment of cervical ThinPrep((r)) samples on HPV detection with the cobas((r)) 4800 HPV Test (Roche Molecular Systems, Pleasanton, CA, USA). METHODS: Residual ThinPrep samples (n = 121) were selected to provide a range of typical cytology results and enrich the study samples for HPV positivity. Specimens were equally split into two fractions: one part treated with 10% GAA and the other part left untreated. All samples were HPV tested using the cobas 4800 HPV Test, which simultaneously detects a total of 14 high-risk HPV (hrHPV) genotypes and individually identifies HPV16 and HPV18. The HPV positive/negative status of tested samples determined the level of agreement between treated and untreated fractions; one sample failed owing to detection of a clot by the instrument during pipetting, leaving 120 samples in the study. Statistical analysis was performed using an unweighted kappa. RESULTS: Analysis of overall HPV positivity showed 97.5% (117/120) agreement between the treated and untreated fractions with a kappa value of 0.95. There were 63/65 (96.9%) concordant HPV positive and 54/55 (98.2%) concordant HPV negative results. In addition to the three discordant results for overall HPV positivity, there were three HPV type-specific discrepancies giving a total of 114/120 concordant HPV results (95% agreement). CONCLUSIONS: Glacial acetic acid (GAA) treatment of cervical ThinPrep specimens does not have significant adverse affects on HPV detection with the cobas 4800 HPV Test. PMID- 23445359 TI - Development of the S3Pvac vaccine against porcine Taenia solium cysticercosis: a historical review. AB - Herein we present a review of our research dealing with vaccination against experimental and naturally acquired porcine Taenia solium cysticercosis using Taenia crassiceps-derived antigens. Results strongly support that the different versions of S3Pvac vaccine are indeed effective against porcine T. solium cysticercosis. Immunological results related to vaccination prove that protection is at least partially mediated by specific immunity. The data also support the validity of T. crassiceps murine cysticercosis as an effective tool to identify vaccine candidates against some metacestode infections. PMID- 23445360 TI - Different diversity-functioning relationship in lake and stream bacterial communities. AB - Biodiversity patterns have been successfully linked to many ecosystem functions, and microbial communities have been suspected to harbour a large amount of functionally redundant taxa. We manipulated the diversity of stream and lake water column bacterial communities and investigated how the reduction in diversity affects the activities of extracellular enzymes involved in dissolved organic carbon degradation. Dissimilar communities established in cultures inoculated with stream or lake bacteria and utilized different organic matter compounds as indicated by the different extracellular enzyme activities. Stream bacterial communities preferentially used plant-derived organic material such as cellulose and hemicellulose. Communities obtained from the lake, where the longer residence time might permit the organic matter to age, efficiently degraded lignin-like material and also showed higher peptide degradation capacities. The results highlight a stronger negative effect of decreasing diversity on ecosystem multifunctionality for stream than for lake bacterial communities. We found a relatively higher multifunctional redundancy in the lake as compared to the stream-derived cultures and suggest that community assembly might shape diversity functioning relationships in freshwater bacterial communities. PMID- 23445361 TI - Recombinant PTD-Cu/Zn SOD attenuates hypoxia-reoxygenation injury in cardiomyocytes. AB - BACKGROUND: Oxidative stress plays a pivotal role in myocardial ischemia reperfusion injury. Increasing the protein expression of intracellular Cu/Zn SOD, which is the major endogenous antioxidant enzyme, may attenuate or prevent hypoxia-reoxygenation injury (HRI) in cultured cardiomyocytes. However, ectogenic Cu/Zn-SOD can hardly be transferred into cells to exert biological effects. In this study, we constructed PTD-Cu/Zn SOD plasmid with a kind of translocation structure-Protein transduction domain (PTD) and detected its transmembrane ability and antioxidant effects in H9c2 rat cardiomyocytes subjected to hypoxia/reoxygenation injury (HRI). METHODS: We constructed the pET-PTD-Cu/Zn SOD (CDs) prokaryotic expression vectors in plasmid that were inserted into E. coli BL21 to induce the protein expression of PTD-Cu/Zn SOD. H9c2 cardiomyocyte HRI was achieved by exposing cardiomyocytes to 12 h hypoxia followed by 2 h reoxygenation. Protein expression of PTD-Cu/Zn SOD in cardiomyocytes was assayed by Western blot and their enzyme activities were investigated by immunohistochemistry and flow cytometry. RESULTS: In cultured cardiomyocytes hypoxia-reoxygenation injury model, exogenous PTD-Cu/Zn SOD could penetrate cell membrane to clear superoxide anion and decrease hydrogen peroxide level in H9c2 cardiomyocytes subjected to HRI. The level of mitochondrial membrane potential was restored to normal, and the cell apoptosis was reduced in cardiomyocytes with PTD-Cu/Zn SOD treatment during HRI. CONCLUSION: Recombinant PTD-Cu/Zn SOD could scavenge intracellular-free superoxide anion, protect mitochondria from damages, and attenuate the hypoxia-reoxygenation injury in cultured cardiomyocytes. PMID- 23445362 TI - Arylazanylpyrazolone derivatives as inhibitors of mutant superoxide dismutase 1 dependent protein aggregation for the treatment of amyotrophic lateral sclerosis. AB - The arylsulfanylpyrazolone and aryloxanylpyrazolone scaffolds previously were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein aggregation and to extend survival in the ALS mouse model. However, further evaluation of these compounds indicated weak pharmacokinetic properties and a relatively low maximum tolerated dose. On the basis of an ADME analysis, a new series of compounds, the arylazanylpyrazolones, has been synthesized, and structure activity relationships were determined. The SAR results showed that the pyrazolone ring is critical to cellular protection. The NMR, IR, and computational analyses suggest that phenol-type tautomers of the pyrazolone ring are the active pharmacophore with the arylazanylpyrazolone analogues. A comparison of experimental and calculated IR spectra is shown to be a valuable method to identify the predominant tautomer. PMID- 23445363 TI - Optimal place of a foreign gene in the genome of viral haemorrhagic septicaemia virus (VHSV) for development of VHSV-based viral-vectored vaccines. AB - AIM: As the strength and duration of immune responses can be regulated by the antigen dose, higher expression of foreign antigens in the viral-vectored vaccines would be an important factor for inducing effective immune responses. The aim of this study was to determine the optimal insertion place of a foreign antigen gene in the genome of viral haemorrhagic septicaemia virus (VHSV) for development of VHSV-based viral-vectored vaccines. METHODS AND RESULTS: Recombinant VHSVs (rVHSVs) harbouring the red fluorescent protein (RFP) gene between N and P (rVHSV-A-RFP), P and M (rVHSV-B-RFP), or M and G genes (rVHSV-C RFP) in the genome were rescued by reverse genetics. Their replication ability and expression level of RFP were compared according to the inserted locations. The viral titres of each rVHSV were not significantly different. However, Epithelioma papulosum cyprini (EPC) cells infected with rVHSV-A-RFP or rVHSV-B RFP showed clearly higher fluorescence than cells infected with rVHSV-C-RFP. There was no significant difference in RFP expression between cells infected with rVHSV-A-RFP and rVHSV-B-RFP. CONCLUSIONS: The present results indicate that insertion of a foreign gene between N and P, or P and M genes of VHSV genome would be advantageous for development of VHSV-based viral-vectored vaccines. SIGNIFICANCE AND IMPACT OF THE STUDY: The present work is the first report on the optimal location of a foreign gene in VHSV genome for high expression, and the locations identified in this study would be suitable for the development of VHSV based viral-vectored vaccines. PMID- 23445364 TI - Tight coupling of polymerization and depolymerization of polyhydroxyalkanoates ensures efficient management of carbon resources in Pseudomonas putida. AB - Environmental microbes oscillate between feast and famine and need to carefully manage utilization, storage and conversion of reserve products to exploitable sources of carbon and energy. Polyhydroxyalkanoates (PHAs) are storage polymers that serve bacteria as sources of food materials under physiological conditions of carbon demand. In order to obtain insights into the role of PHA depolymerase (PhaZ) and its relationship to a PHA polymerase (PhaC2) in the carbon management activity of Pseudomonas putida strain U, we created a polymerase hyperexpression strain and a depolymerase knockout mutant of this strain, and examined their synthesis of PHA and expression of their PHA genes. This study revealed that hyperexpression of PhaC2 led to the accumulation of higher amounts of PHA (44%wt) than in the wild-type strain (24%wt) after 24 h of cultivation, which then returned to wild-type levels by 48 h, as a result of elevated depolymerization. The phaZ mutant, however, accumulated higher levels of PHA than the parental strain (62%wt), which were maintained for at least 96 h. Transcriptional analysis of the pha cluster by RT-PCR revealed that PHA operon proteins, including depolymerase, are expressed from the beginning of the growth phase. Hyperexpression of the PhaC2 polymerase was accompanied by an increase in the expression of the PhaZ depolymerase and a decrease in expression of another PHA polymerase, PhaC1. This suggests tight regulatory coupling of PHA polymerase and depolymerase activities that act in synergy, and in concert with other PHA proteins, to provide dynamic PHA granule synthesis and remodelling that rapidly and sensitively respond to changes in availability of carbon and the physiological-metabolic needs of the cell, to ensure optimal carbon resource management. PMID- 23445365 TI - Aging-associated enzyme human clock-1: substrate-mediated reduction of the diiron center for 5-demethoxyubiquinone hydroxylation. AB - The mitochondrial membrane-bound enzyme Clock-1 (CLK-1) extends the average longevity of mice and Caenorhabditis elegans, as demonstrated for Deltaclk-1 constructs for both organisms. Such an apparent impact on aging and the presence of a carboxylate-bridged diiron center in the enzyme inspired this work. We expressed a soluble human CLK-1 (hCLK-1) fusion protein with an N-terminal immunoglobulin binding domain of protein G (GB1). Inclusion of the solubility tag allowed for thorough characterization of the carboxylate-bridged diiron active site of the resulting GB1-hCLK-1 by spectroscopic and kinetic methods. Both UV visible and Mossbauer experiments provide unambiguous evidence that GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase, utilizing its carboxylate bridged diiron center. The binding of DMQn (n = 0 or 2) to GB1-hCLK-1 mediates reduction of the diiron center by nicotinamide adenine dinucleotide (NADH) and initiates O2 activation for subsequent DMQ hydroxylation. Deployment of DMQ to mediate reduction of the diiron center in GB1-hCLK-1 improves substrate specificity and diminishes consumption of NADH that is uncoupled from substrate oxidation. Both Vmax and kcat/KM for DMQ hydroxylation increase when DMQ0 is replaced by DMQ2 as the substrate, which demonstrates that an isoprenoid side chain enhances enzymatic hydroxylation and improves catalytic efficiency. PMID- 23445366 TI - Pericardial neo-aorta to bridge long segment defects after infected aortic reconstructions. AB - Aortic prosthetic graft infection is a rare, potentially fatal complication. Surgical explantation of the infected native and prosthetic material with sufficient debridement has sometimes been limited by the lack of a suitable conduit to bridge the residual long segment defect. We describe the implantation of a bovine pericardial fashioned neo-aorta to manage this problem. PMID- 23445367 TI - Renewed interest in the role of consolidative radiotherapy in advanced stage diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non Hodgkin lymphoma (NHL) in the United States, and two-thirds of these patients will present with advanced stage (stage III-IV) disease. Although radiation therapy (RT) alone was the first curative therapy for limited stage DLBCL, the advancement of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with the addition of the anti-CD20 antibody rituximab became the cornerstone of current management. The role of consolidative RT as part of first-line therapy in the management of patients with advanced stage DLBCL remains unclear, and represents an area of controversy with considerable differences in patterns of practice across different institutions. Emerging data now challenge the National Comprehensive Cancer Network (NCCN) guidelines, and give support to the use of consolidative RT in patients with advanced stage DLBCL. This review summarizes the major studies as reflected in our current practice and provides further insight into future directions for randomized trials which would help better define the role of consolidative RT in such a cohort. PMID- 23445368 TI - Bortezomib salvage therapy in refractory acute adult T-cell leukemia/lymphoma. PMID- 23445369 TI - Patterns of appearance and risk of misdiagnosis of intrahepatic cholangiocarcinoma in cirrhosis at contrast enhanced ultrasound. AB - AIM: Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC. METHODS: All ICC on cirrhosis seen in three Italian centres (Bologna, Milan and Pavia) between 2003 and 2011, in which CEUS and at least another imaging technique (CT or MRI) had been performed, were retrospectively identified. Those patients with ICC size comparable to the early HCC stage (Milan criteria, considered as small ICC) were enrolled for this study. The enhancement pattern at CEUS was analysed and compared with CT or MRI. RESULTS: A total of 25 small ICC made this study group. CEUS was at risk of misdiagnosis of ICC for HCC in a significantly higher number of cases than in CT (performed in 24 ICC) (52% vs. 4.2%, P = 0.009) and MRI (11 ICC) (52% vs. 9.1%, P = 0.02). A different contrast pattern among all techniques was found in 6 of 10 ICC lesions submitted to the three imaging methods. In the arterial phase, ICC lacked global hyperenhacement in approximately 50% of cases at CEUS and the degree of intensity of wash-out in the late phase was marked in 24% of nodules. CONCLUSIONS: CEUS misdiagnosed as HCC a significantly higher number of ICC lesions in cirrhotic patients than CT and MRI. However, some CEUS contrast features can help suspect ICC, especially in some cases with inconclusive CT or MRI. PMID- 23445370 TI - CO(2) capture and geologic storage: the possibilities. AB - Carbon dioxide (CO(2)) capture and geologic storage has been postulated as one possible method to stabilize the atmospheric concentration of CO(2) by injecting and storing it in deep geologic formations. This issue paper analyzes the viability of capture and geologic storage of becoming an effective method to aid in stabilizing the atmospheric concentration of CO(2). It is herein shown that such viability is contingent on overcoming major obstacles that are hydrogeological, technical, and economic in nature. Our analysis indicates that capture and geologic storage is likely to have negligible success in reducing the atmospheric buildup of CO(2) in the coming decades. The magnitude of the anthropogenic emissions of CO(2) indicates that a transition of the world economy away from reliance on fossil fuels might be the only path to stabilize its atmospheric concentration. PMID- 23445371 TI - Single-nucleotide polymorphisms in the LRWD1 gene may be a genetic risk factor for Japanese patients with Sertoli cell-only syndrome. AB - Genetic mechanisms have been implicated as a cause of some cases of male infertility. Recently, ten novel genes involved in human spermatogenesis, including human LRWD1, have been identified by expression microarray analysis of human testictissue. The human LRWD1 protein mediates the origin recognition complex in chromatin, which is critical for the initiation of pre-replication complex assembly in G1 and chromatin organization in post-G1 cells. The Lrwd1 gene expression is specific to the testis in mice. Therefore, we hypothesized that mutation or polymorphisms of LRWD1 participate in male infertility, especially azoospermia. To investigate whether LRWD1 gene defects are associated with azoospermia caused by SCOS and meiotic arrest (MA), mutational analysis was performed in 100 and 30 Japanese patients by direct sequencing of the coding regions, respectively. Statistical analysis was performed for patients with SCOS and MA and in 100 healthy control men. No mutations were found in LRWD1; however, three coding single-nucleotide polymorphisms (SNP1-SNP3) could be detected in the patients. The genotype and allele frequencies in SNP1 and SNP2 were notably higher in the SCOS group than in the control group (P < 0.05). These results suggest the critical role of LRWD1 in human spermatogenesis. PMID- 23445372 TI - African American women and breastfeeding: an integrative literature review. AB - The purpose of this article is to present a review of literature regarding factors that influence breastfeeding intentions, initiation, and duration in the African American population. Research related to health disparities experienced by African Americans in the United States, as well as research regarding the protective benefits of breastfeeding for those specific health disparities, are also presented. Community and institutional interventions and promotional campaigns aimed at increasing initiation and duration of breastfeeding in the African American population are discussed. Future research regarding African American women's breastfeeding experiences using Black feminist thought as a theoretical foundation is recommended. PMID- 23445373 TI - Angle-resolved XPS analysis and characterization of monolayer and multilayer silane films for DNA coupling to silica. AB - We measure silane density and Sulfo-EMCS cross-linker coupling efficiency on aminosilane films by high-resolution X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) measurements. We then characterize DNA immobilization and hybridization on these films by (32)P-radiometry. We find that the silane film structure controls the efficiency of the subsequent steps toward DNA hybridization. A self-limited silane monolayer produced from 3 aminopropyldimethylethoxysilane (APDMES) provides a silane surface density of ~3 nm(-2). Thin (1 h deposition) and thick (19 h deposition) multilayer films are generated from 3-aminopropyltriethoxysilane (APTES), resulting in surfaces with increased roughness compared to the APDMES monolayer. Increased silane surface density is estimated for the 19 h APTES film, due to a ~32% increase in surface area compared to the APDMES monolayer. High cross-linker coupling efficiencies are measured for all three silane films. DNA immobilization densities are similar for the APDMES monolayer and 1 h APTES. However, the DNA immobilization density is double for the 19 h APTES, suggesting that increased surface area allows for a higher probe attachment. The APDMES monolayer has the lowest DNA target density and hybridization efficiency. This is attributed to the steric hindrance as the random packing limit is approached for DNA double helices (dsDNA, diameter >= 2 nm) on a plane. The heterogeneity and roughness of the APTES films reduce this steric hindrance and allow for tighter packing of DNA double helices, resulting in higher hybridization densities and efficiencies. The low steric hindrance of the thin, one to two layer APTES film provides the highest hybridization efficiency of nearly 88%, with 0.21 dsDNA/nm(2). The XPS data also reveal water on the cross-linker-treated surface that is implicated in device aging. PMID- 23445375 TI - The prospect of selective recognition of nerve agents with modular basket-like hosts. A structure-activity study of the entrapment of a series of organophosphonates in aqueous media. AB - We designed, prepared, and characterized three cup-shaped cavitands 1-3 for trapping organophosphonates (O?PR(OR')2, 118-197 A(3)) whose shape and size correspond to G-type chemical warfare agents (132-186 A(3)). With the assistance of computational (molecular dynamics) and experimental ((1)H NMR spectroscopy) methods, we found that host [1-H3](3+) orients its protonated histamine residues at the rim outside the cavity, in bulk water. In this unfolded form, the cavitand traps a series of organophosphonates 5-13 (K(app) = 87 +/- 1 to 321 +/- 6 M(-1) at 298.0 K), thereby placing the P-CH3 functional group in the inner space of the host. A comparison of experimental and computed (1)H NMR chemical shifts of both hosts and guests allowed us to derive structure-activity relationships and deduce that, upon the complexation, the more sizable P-OR functional groups in guests drive organophosphonates to the northern portion of the basket [1-H3](3+). This, in turn, causes a displacement of the guest's P-CH3 group and a contraction of the cup-shaped scaffold. The proposed induced-fit model of the recognition is important for turning these modular hosts into useful receptors capable of a selective detection/degradation of organophosphorus nerve agents. PMID- 23445374 TI - PacC and pH-dependent transcriptome of the mycotrophic fungus Trichoderma virens. AB - BACKGROUND: In fungi, environmental pH is an important signal for development, and successful host colonization depends on homeostasis. Surprisingly, little is known regarding the role of pH in fungal-fungal interactions. Species of Trichoderma grow as soil saprobes but many are primarily mycotrophic, using other fungi as hosts. Therefore, Trichoderma spp. are studied for their potential in biocontrol of plant diseases. Particularly in alkaline soil, pH is a critical limiting factor for these biofungicides, whose optimal growth pH is 4-6. Gaining an understanding of pH adaptability is an important step in broadening the activity spectrum of these economically important fungi. RESULTS: We studied the pH-responsive transcription factor PacC by gene knockout and by introduction of a constitutively active allele (pacCc). DeltapacC mutants exhibited reduced growth at alkaline pH, while pacCc strains grew poorly at acidic pH. In plate confrontation assays DeltapacC mutants showed decreased ability to compete with the plant pathogens Rhizoctonia solani and Sclerotium rolfsii. The pacCc strain exhibited an overgrowth of R. solani that was comparable to the wild type, but was unable to overgrow S. rolfsii. To identify genes whose expression is dependent on pH and pacC, we designed oligonucleotide microarrays from the transcript models of the T. virens genome, and compared the transcriptomes of wild type and mutant cultures exposed to high or low pH. Transcript levels from several functional classes were dependent on pacC, on pH, or on both. Furthermore, the expression of a set of pacC-dependent genes was increased in the constitutively-active pacCc strain, and was pH-independent in some, but not all cases. CONCLUSIONS: PacC is important for biocontrol-related antagonism of other fungi by T. virens. As much as 5% of the transcriptome is pH-dependent, and of these genes, some 25% depend on pacC. Secondary metabolite biosynthesis and ion transport are among the relevant gene classes. We suggest that DeltapacC mutants may have lost their full biocontrol potential due to their inability to adapt to alkaline pH, to perceive ambient pH, or both. The results raise the novel possibility of genetically manipulating Trichoderma in order to improve adaptability and biocontrol at alkaline pH. PMID- 23445376 TI - Proficiency tests reveal the need to improve laboratory assays for fetomaternal hemorrhage for Rh immunoprophylaxis. PMID- 23445377 TI - Overview of differences between microbial feed additives and probiotics for food regarding regulation, growth promotion effects and health properties and consequences for extrapolation of farm animal results to humans. AB - For many years, microbial adjuncts have been used to supplement the diets of farm animals and humans. They have evolved since the 1990s to become known as probiotics, i.e. functional food with health benefits. After the discovery of a possible link between manipulation of gut microflora in mice and obesity, a focus on the use of these beneficial microbes that act on gut microflora in animal farming was undertaken and compared with the use of probiotics for food. Beneficial microbes added to feed are classified at a regulatory level as zootechnical additives, in the category of gut flora stabilizers for healthy animals and are regulated up to strain level in Europe. Intended effects are improvement of performance characteristics, which are strain dependent and growth enhancement is not a prerequisite. In fact, increase of body weight is not commonly reported and its frequency is around 25% of the published data examined here. However, when a Body Weight Gain (BWG) was found in the literature, it was generally moderate (lower than or close to 10%) and this over a reduced period of their short industrial life. When it was higher than 10%, it could be explained as an indirect consequence of the alleviation of the weight losses linked to stressful intensive rearing conditions or health deficiency. However, regulations on feed do not consider the health effects because animals are supposed to be healthy, so there is no requirement for reporting healthy effects in the standard European dossier. The regulations governing the addition of beneficial microorganisms to food are less stringent than for feed and no dossier is required if a species has a Qualified Presumption of Safety status. The microbial strain marketed is not submitted to any regulation and its properties (including BWG) do not need to be studied. Only claims for functional or healthy properties are regulated and again growth effect is not included. However, recent studies on probiotic effects showed that BWG could also be observed in humans, or not, according to species and strains. Determining the significance of farm animal results for extrapolation to humans, especially regarding body weight improvement, was not easy because they do not use the same microbial strains nor always the same species. Furthermore, the framework for the management of microbials added to feed or to food differ, especially with regard to goal, timescale and lifestyle. So no one can exclude the possibility that beneficial microorganisms having probiotic effects may have long-term effects in humans that cannot be seen to date in animals, where short-term use is the rule. A possible link to obesity cannot be excluded in relation to timescale, species and strain specificity. To conclude, beneficial microorganisms added in feed are key factors stringently regulated for short-term improvement of zootechnical performances in animals and their use does not entirely parallel that of human probiotics. So extrapolation of farm animal results to humans is biased and not sufficient to be conclusive regarding the existence or not of a link between probiotics and obesity. From a toxicological and nutritional point of view and considering recent findings on a link between antibiotic use in early life and excessive risk of becoming overweight, one suggestion is to study the at-risk population in Europe, pregnant women and their babies before and after birth and during early childhood, in an epidemiological long-term cohort survey. PMID- 23445378 TI - The modulated structure of Co3Al4Si2: incommensurability and Co-Co interactions in search of filled octadecets. AB - Incommensurate modulations are increasingly being recognized as a common phenomenon in solid-state compounds ranging from inorganic materials to molecular crystals. The origins of such modulations are often mysterious, but appear to be as diverse as the compounds in which they arise. In this Article, we describe the crystal structure and bonding of Co3Al4Si2, the delta phase of the Co-Si-Al system, whose modulated structure can be traced to a central concept of inorganic chemistry: the 18 electron rule. The structure is monoclinic, conforming to the 3 + 1D superspace group C/2m(0beta0)s0. The basis of the crystal structure is a rod packing of columns of the fluorite (CaF2) type, a theme that is shared by the recently determined structure of Fe8Al(17.4)Si(7.6). The columns are arranged into sheets, within which the fluorite structure's primitive cubic network of Si/Al atoms continues uninterrupted from column to column. Between the sheets, layers of interstitial Si/Al atoms occur, some of which are arranged with a periodicity incommensurate with that of the fluorite-type columns. Strong modulations in the interstitial layers result. Electronic structure calculations, using a DFT-calibrated Huckel model on a commensurate approximate structure, reveal that the complex pattern of atoms within these interstitial layers serves to distribute Si/Al atoms around the Co atoms in order to reach 18 electron counts (filled octadecets). Central to this bonding scheme is the covalent sharing of electron pairs between Co atoms. The shared electron pairs occupy orbitals that are isolobal to classical Co-Co sigma and pi bonds, but whose stability is tied to multicenter character involving bridging Si/Al atoms. Through these features, Co3Al4Si2 expands the structural and electronic manifestations of the 18 electron rule in solid-state inorganic compounds. PMID- 23445379 TI - A psychophysiological investigation of sexual arousal in women with lifelong vaginismus. AB - INTRODUCTION: Relatively little is known about the subjective reactions of women with lifelong vaginismus to erotic stimuli and genital arousal has never been investigated. Reports of maladaptive cognitions and fears regarding sexuality and intercourse suggest that anxiety may interfere with sexual arousal in women with vaginismus. AIMS: To examine the genital and subjective responses to sexually explicit film stimuli of women with lifelong vaginismus compared with women with lifelong dyspareunia and women with no pain. METHODS: Forty-five women (15 vaginismus, 15 dyspareunia, and 15 no pain) viewed two neutral and two erotic film sets, one depicting sexual activity without vaginal penetration and the other depicting intercourse, over two testing sessions. MAIN OUTCOME MEASURES: Vulvar temperature was recorded using an infrared camera. Participants completed a measure of subjective responses after viewing each film. RESULTS: All groups experienced increased vulvar temperature during the erotic films regardless of activity depicted. In response to the erotic films, the vaginismus group reported less mental arousal than the no-pain group and a range of negative subjective responses, including threat and disgust. Overall, participants showed concordance between peak subjective sexual arousal and temperature change from baseline to peak arousal. CONCLUSION: Despite negative subjective responses, women with vaginismus responded with increased genital sexual arousal to erotic films. The resilience of genital arousal may have resulted from moderate levels of anxiety experienced in the laboratory setting facilitating sexual response regardless of subjective appraisal; however, anxiety experienced in a dyadic context may interfere more substantially. PMID- 23445380 TI - Nurse retention and satisfaction in Ecuador: implications for nursing administration. AB - AIM: This study explores the characteristics of professional nursing work environments that may affect nursing turnover and satisfaction within a large Ecuadorian hospital. BACKGROUND: Nursing turnover is a challenge and may compromise patient care. Work dissatisfaction contributes to high turnover. Improving nurse satisfaction can contribute to better patient outcomes. METHOD: Eighty-eight nurses participated in a quantitative and qualitative survey focusing on nursing satisfaction, turnover and selected organisation characteristics. RESULTS: Issues that may affect nurse satisfaction and turnover were identified using questions from the Nursing Work Index: pay, insufficient number of nurses, undervaluing of nurses by public and the medical team, limited advancement opportunities, lack of autonomy and inflexibility in schedule. Other themes identified from qualitative data are reported. CONCLUSIONS: The top factor of decreased satisfaction was low pay as indicated by the Nursing Work Index. The qualitative results showed that low pay was the factor for nurse turnover. Additional factors related to nursing satisfaction can be addressed to improve nurse retention. IMPLICATIONS FOR NURSING MANAGEMENT: Along with increasing nursing pay, strategies to consider in decreasing turnover and increasing satisfaction included: providing opportunities for nursing advancement, promoting the value of nursing, creating clinical protocols and enhancing autonomy. This study adds to knowledge about nursing needs and satisfaction in South America. PMID- 23445384 TI - Statement of retraction. Complex care needs of patients with late-stage HIV disease: a retrospective study. PMID- 23445385 TI - Victoria has a developmental disability. PMID- 23445390 TI - Human maternal placentophagy: a survey of self-reported motivations and experiences associated with placenta consumption. AB - Maternal placentophagy, although widespread among mammals, is conspicuously absent among humans cross-culturally. Recently, however, advocates for the practice have claimed it provides human postpartum benefits. Despite increasing awareness about placentophagy, no systematic research has investigated the motivations or perceived effects of practitioners. We surveyed 189 females who had ingested their placenta and found the majority of these women reported perceived positive benefits and indicated they would engage in placentophagy again after subsequent births. Further research is necessary to determine if the described benefits extend beyond those of placebo effects, or are skewed by the nature of the studied sample. PMID- 23445391 TI - Individuals' knowledge and practices of the cold chain. AB - This study aims to identify the influence of education on the practices and knowledge of consumers to protect or maintain the cold chain in the Turkish capital of Ankara. Data were gathered by using a questionnaire. Participants were 700 randomly selected volunteering adults. The majority of the participants had a university degree (69.0%) and did not know the definition of cold chain but had some knowledge about it, and differences existed between primary school and university graduates. The scores of consumers' attitudes to maintain cold chain were determined to increase in parallel with education level. The rate of people knowing refrigerator temperature, the coldest part of refrigerator, and controlling whether shops correctly store the products was highest in university graduates. Adults were observed to believe that shop assistants were responsible for maintaining a cold chain. However, the actual importance of consumers in this process reveals the importance of education for individuals. PMID- 23445392 TI - Lodgepole Pine Cambium (Pinus contorta Dougl. ex Loud. var. latifolia Engelm. ex S. Wats.): a springtime first peoples' food in British Columbia. AB - Lodgepole pine (Pinus contorta var. latifolia) is a tree species utilized for succulent edible cambium and secondary phloem in the spring by Interior First Peoples of the Pacific Northwest. In this article we present a nutritional analysis of this food based on a pooled sample of 17 trees harvested in the Chilcotin region of British Columbia. We also present enzymatic sugar analysis of raw, dried, and cooked lodgepole pine cambium harvested from the Chilcotin and Okanagan regions in British Columbia. In the discussion we interpret the nutrient values of raw lodgepole pine cambium in comparison to dried and cooked cambium, results from other nutritional studies of pine cambium, and nutrients in some other traditional and nontraditional foods. PMID- 23445393 TI - Genetic diversity of mungbean (Vigna radiata L.) in iron and zinc content as impacted by farmers' varietal selection in Northern India. AB - From the last few years a debate has been continuing over the issue of malnutrition and hunger in the developing countries. The present article investigates the importance of participatory varietal selection in the development of a suitable cultivar of mungbean along with the nutritional content and the agronomic traits of the cultivars selected by farmers in participatory varietal selection. A combination of the conventional survey strategy, participatory varietal selection, molecular markers, and chemical analysis were used to carry out the study, and results revealed that the farmers have the capacity to utilize available genetic resources to manage disease, and they can identify the disease at early stages of plant development. The genetic diversity was studied using 23 inter-simple sequence repeat marker, which shows that the extent of genetic diversity ranges from 65% to 87%, while chemical analysis of selected mungbean cultivars shows a moderate amount of iron (3.9 mg/100 g) and zinc (2.5 mg/100 g). PMID- 23445394 TI - Impact of roasting time on the sensory profile of arabica and robusta coffee. AB - Roasted coffee samples of the two major trade species (Coffea arabica and C. canephora) were studied to identify sensory descriptors that might be used to determine blends production and evaluation, following the expectations of consumers. Coffee beans were roasted at 220 + 10 degrees C, for 7, 9, and 11 min, and the sensory profiles of the beverages were assessed. From descriptive analysis the eigenvalues allowed the identification of two principal components (PCs), being the variance between samples 68.9% and 21.1%. In the first PC the characteristic odor, astringency, body, bitter flavor, burned aroma, and residual, typical, and burned tastes prevailed. The correlation coefficient between the second PC and citric acid flavor and aroma reached 0.96 and 0.78, respectively. It was concluded that in beverages of these species, the descriptors of both components can be separated according to bean roasting time. Considering roasting time, the overall quality was also rated. PMID- 23445395 TI - Wild leafy vegetables consumed in Buhera District of Zimbabwe and their phenolic compounds content. AB - A questionnaire was used to gather information on the wild leafy vegetables consumed. The phenolic concentrations were determined by the vanillin, butanol, and tannin binding assays. Seventy-nine traditional vegetables were mentioned by the respondents and 20 of these were classified according to their species. The contents of flavonoids varied from 1.2 mg/g for Cleome gynandra to 8.0 mg/g for Bidens pilosa. The levels of proanthocyanidins ranged from 1.9 mg/g for lettuce to 11.2 mg/g for Bidens pilosa. The tannin contents of the vegetables ranged from 5.7 mg/g for Cleome gynandra to 8.3 mg/g for Bidens pilosa. The present study showed that these vegetables are valuable sources of phenolic compounds as compared to some exotic species. PMID- 23445396 TI - Mass spectrometric analysis of sialylated glycans with use of solid-phase labeling of sialic acids. AB - The analysis of sialylated glycans is critical for understanding the role of sialic acid in normal biological processes as well as in disease. However, the labile nature of sialic acid typically renders routine analysis of this monosaccharide by mass spectrometric methods difficult. To overcome this difficulty we pursued derivatization methodologies, extending established acetohydrazide approaches to aniline-based methods, and finally to optimized p toluidine derivatization. This new quantitative glycoform profiling method with use of MALDI-TOF in positive ion mode was validated by first comparing N-glycans isolated from fetuin and serum and was then exploited to analyze the effects of increased metabolic flux through the sialic acid pathway in SW1990 pancreatic cancer cells by using a colabeling strategy with light and heavy toluidine. The latter results established that metabolic flux, in a complementary manner to the more well-known impact of sialyltransferase expression, can critically modulate the sialylation of specific glycans while leaving others virtually unchanged. PMID- 23445397 TI - Antibiotic adjuvants: identification and clinical use. PMID- 23445398 TI - Social cognition and social functioning in nonclinical paranoia. AB - INTRODUCTION: Persons with nonclinical paranoia show many of the same biases as those with clinical paranoia, suggesting that paranoia exists on a continuum. However, little is known about the various social cognitive processes found in paranoia and how these relate to social functioning and social behaviours in general. This study will examine performance on emotion perception and attributional style measures and their relationship to social functioning, social problem solving, and social skill. A key element in this study will be the incorporation of ambiguity in the perception of emotional expressions and the assignment of attributional blame, which appears to be an important, yet neglected, construct in paranoia. METHODS: Twenty-six persons with high levels of nonclinical paranoia and 31 persons with low levels of paranoia completed measures of emotion perception, attributional style, social functioning, and social problem solving. Salient and subtle emotional expressions were used to examine how ambiguity impacts emotion perception in paranoia. RESULTS: The group high in nonclinical paranoia showed reduced accuracy for subtle negative emotional expressions and showed more perceived hostility and blame for ambiguous social situations as compared to the group low in nonclinical paranoia. Also, the high nonclinical paranoia group reported less social engagement, fewer social contacts, and more problems in social perception and social skill than the group low in nonclinical paranoia. CONCLUSION: Social cognitive and social functioning biases are found in persons with high levels of nonclinical paranoia. Possible mechanisms of these biases and relevance for treatment approaches are discussed. PMID- 23445399 TI - Oral hairy leukoplakia diagnosis by Epstein-Barr virus in situ hybridization in liquid-based cytology. AB - OBJECTIVE: To establish a definitive diagnosis of oral hairy leukoplakia (OHL) by in situ hybridization for Epstein-Barr virus (EBV) detection with liquid-based cytology (LBC), using the ThinPrep(r) Pap Test, and to compare its efficacy with the traditional method of performing biopsy. METHODS: Thirty-three individuals divided into three groups were included in this study. Group 1 consisted of 15 human immunodeficiency virus (HIV)-positive patients with a clinical and histopathological diagnosis of OHL on the lateral border of the tongue. Group 2 consisted of 10 HIV-positive individuals with neither OHL nor other oral lesions. Group 3 consisted of 10 immunocompetent HIV-negative individuals with neither OHL nor other oral lesions. For each patient from the three groups, exfoliative LBC was performed on the lateral border of the tongue using ThinPrep. For the patients from group 1, a 6-mm-diameter punch biopsy was obtained from the same anatomic site as the brush collection to confirm the diagnosis of OHL by histopathology with in situ hybridization. Slides were prepared for morphological cellular analysis using Papanicolaou (Pap) staining, and for EBV detection using in situ hybridization. RESULTS: Thirteen of the 15 patients from group 1 were confirmed on punch biopsy as OHL, providing the gold standard for the study. The sensitivity of LBC followed by a Pap-stained smear was 62% and the specificity was 90%. The sensitivity of LBC followed by in situ hybridization was 100% and the specificity was 100%. CONCLUSIONS: Exfoliative LBC associated with EBV in situ hybridization is a simple, effective and non-invasive diagnostic tool for OHL. PMID- 23445401 TI - Cost-per-remission analysis of infliximab compared to adalimumab among adults with moderate-to-severe ulcerative colitis. AB - OBJECTIVE: To compare cost per remission (CPR) of infliximab (IFX) versus adalimumab (ADA) for the treatment of moderately-to-severely active UC. METHODS: This is CPR model comparing IFX and ADA in the treatment of UC using clinical trial data. Clinical outcome measures include clinical remission and sustained clinical remission (SCR). Economic endpoints were modeled as medication costs. CPR ratios and number needed to treat (NNT) costs were computed at 8, 52, and 54 weeks. RESULTS: CPR for bio-naive patients for IFX and ADA at weeks 8, 52, and 54 was $42,086 vs. $79,558: $147,379 vs. $320,097; $147,379 vs. $330,767, respectively. CPR for all patients for IFX and ADA at weeks 8, 52, and 54 was $42,086 vs. $113,812; $147,379 vs. $349,197; $147,379 vs. $360,836, respectively. Cost per SCR for bio-naive patients and all patients for IFX and ADA was $203,205 vs. $682,873 and $203,205 vs. $698,393, respectively. NNT and NNT costs for clinical remission for bio-naive patients at weeks 8, 52, and 54 were lower for IFX (4 vs.10, $40,235 vs. $81,945; 5 vs.10, $134,115 vs. $307,293; 5 vs. 10, $134,115 vs. $317,536, respectively) than for ADA. NNT and NNT costs for clinical remission for all patients at weeks 8, 52, and 54 were lower for IFX (4 vs.14, $40,235 vs. $114,723; 5 vs.11, $134,115 vs. $338,022; 5 vs. 11, $134,115 vs. $349,290, respectively) than for ADA. NNT and NNT costs for SCR for bio-naive and all patients were lower for IFX (8 vs. 22, $214,584 vs. $676,045; 8 vs.23, $214,584 vs. $706,774) than for ADA. Study limitations include lack of head-to head trial data, different primary endpoints between the two clinical trials, and indirect costs were not included. CONCLUSION: IFX had lower CPR and cost per SCR than ADA in the treatment of moderately to severely active UC. PMID- 23445400 TI - Resolution of oligomeric species during the aggregation of Abeta1-40 using (19)F NMR. AB - In the commonly used nucleation-dependent model of protein aggregation, aggregation proceeds only after a lag phase in which the concentration of energetically unfavorable nuclei reaches a critical value. The formation of oligomeric species prior to aggregation can be difficult to detect by current spectroscopic techniques. By using real-time (19)F NMR along with other techniques, we are able to show that multiple oligomeric species can be detected during the lag phase of Abeta1-40 fiber formation, consistent with a complex mechanism of aggregation. At least six types of oligomers can be detected by (19)F NMR. These include the reversible formation of large beta-sheet oligomer immediately after solubilization at high peptide concentration, a small oligomer that forms transiently during the early stages of the lag phase, and four spectroscopically distinct forms of oligomers with molecular weights between ~30 and 100 kDa that appear during the later stages of aggregation. The ability to resolve individual oligomers and track their formation in real-time should prove fruitful in understanding the aggregation of amyloidogenic proteins and in isolating potentially toxic nonamyloid oligomers. PMID- 23445402 TI - Iodine effects on phenolic metabolism in lettuce plants under salt stress. AB - Iodine, applied as iodate in biofortification programs (at doses of <=80 MUM), has been confirmed to improve the foliar biomass, antioxidant response, and accumulation of phenol compounds in lettuce plants. The changes in phenolic compounds induced by the iodate application appear to have functional consequences in the response of salt-stressed plants. Thus, the aim of the present study was to determine whether the application of iodate can improve the response of severe salinity stress and whether the resistance can be attributed to the phenolic metabolism in lettuce ( Lactuca sativa cv. Philipus), a glycophyte cultivated for food and consumed year round. In this work, the application of iodate, especially at 20 and 40 MUM, in lettuce plants under salinity stress (100 mM NaCl) exerted a significantly positive effect on biomass and induced higher activity in the enzymes shikimate dehydrogenase and phenylalanine ammonia-lyase as well as the lower MW phenol-degrading enzyme polyphenol oxidase. This increased hydroxycinnamic acids and derivatives in addition to total phenols, which appear to act as protective compounds against salinity. This study reveals that in agricultural areas affected by this type of stress, the application of iodate may be an effective strategy, as it not only improves lettuce plant growth but also supplements the human diet with phenolic compounds and the trace element iodine. PMID- 23445403 TI - The Bentall procedure without the use of a prepared valved-conduit: a step backwards? AB - A repeat Bentall procedure or a Bentall procedure in an immobile aortic root such as a prior homograft that has calcified can be problematic. Separating the valve from the conduit and with a modified elephant trunk concept we have simplified the proximal graft anastomosis using a running suture technique. This is followed by coronary ostia implantation and then by lowering the aortic valve onto the aortic annulus using a running suture technique. PMID- 23445404 TI - Fungi and mycotoxins in silage: an overview. AB - The present revision shows the early and current knowledge in the field of silage fungi and mycotoxins explaining the relevance of fungi and mycotoxins in silage. The problem does not end in animal disease or production losses as mycotoxins in feed can lead to the presence of their metabolic products in dairy products, which will be eventually affecting human health, mainly infants. Silage is green forage preserved by lactic fermentation under anaerobic conditions. This ecosystem maintains its quality and nutritional value depending on interactions among physical, chemical and biological agents. Forages used for ensilage are naturally in contact with yeasts and filamentous fungi, and the contamination often occurs in the field and can also occur during harvesting, transport, storage. Moreover, postharvest poor management can lead to a rapid spoilage. Studies on fungal contamination of dairy cattle feed have shown how corn silage influences the contamination degree of feed supplied to livestock. Increasing knowledge in this area will help elucidate the influence that this microbiota exerts on production and/or degradation of mycotoxins present in silage. Some of these fungi, although opportunist pathogens, are relevant epidemiologically and represent a high risk of contamination to farm workers who handle them improperly. PMID- 23445405 TI - A synthetic dolastatin 10 analogue suppresses microtubule dynamics, inhibits cell proliferation, and induces apoptotic cell death. AB - We have synthesized eight analogues (D1-D8) of dolastatin 10 containing several unique amino acid subunits. Of these agents, D5 was found to be most effective in inhibiting both HeLa cell proliferation and microtubule assembly in vitro. At low nanomolar concentrations, D5 inhibited the proliferation of several types of cancer cells in culture. D5 bound to tubulin with a dissociation constant of 29.4 +/- 6 MUM. D5 depolymerized microtubules in cultured cells and produced mulitpolar spindles. At its half-maximal inhibitory concentration (15 nM), D5 strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. D5 increased the accumulation of checkpoint proteins BubR1 and Mad2 at the kinetochoric region and caused G2/M block in these cells. The blocked cells underwent apoptosis with the activation of Jun N-terminal kinase. The results suggested that D5 exerts its antiproliferative action by dampening microtubule dynamics. PMID- 23445406 TI - Scoring satisfaction among patients, attending ART Centre of a medical college in North-West India. AB - Patient satisfaction is a measurable concept comprising multidimensional elements such as access to care, quality of the provider patient interpersonal relationship and affordability of care. This further influences the decisions to seek care and outcomes of diseases. Although stigma and discrimination are potential barriers to effective implementation of the antiretroviral therapy (ART) programme, higher satisfaction levels of patients are also crucial for treatment adherence. A hospital-based cross-sectional study was conducted at the ART centre of IG Medical College, Shimla from November 2008 through May 2009. Three hundred and eighty four consecutive adult (>=18 years) patients attending the ART centre and on ART who consented to participate in the study were enrolled. Of the 384 patients, 209 (54.4%) were males. Majority were in the age bracket of 25-44 years. About 61.6% of the patients were satisfied to the services being provided. Mean Patient Satisfaction Questionnaire (PSQ) scores were the highest for technical quality of care and lowest for financial aspects. About 69.4% of the patients were satisfied towards their care provider. Although a majority of the patients were satisfied, several areas of patient care need improvement. PMID- 23445407 TI - MicroRNA miR-30 family regulates non-attachment growth of breast cancer cells. AB - BACKGROUND: A subset of breast cancer cells displays increased ability to self renew and reproduce breast cancer heterogeneity. The characterization of these so called putative breast tumor-initiating cells (BT-ICs) may open the road for novel therapeutic strategies. As microRNAs (miRNAs) control developmental programs in stem cells, BT-ICs may also rely on specific miRNA profiles for their sustained activity. To explore the notion that miRNAs may have a role in sustaining BT-ICs, we performed a comprehensive profiling of miRNA expression in a model of putative BT-ICs enriched by non-attachment growth conditions. RESULTS: We found breast cancer cells grown under non-attachment conditions display a unique pattern of miRNA expression, highlighted by a marked low expression of miR 30 family members relative to parental cells. We further show that miR-30a regulates non-attachment growth. A target screening revealed that miR-30 family redundantly modulates the expression of apoptosis and proliferation-related genes. At least one of these targets, the anti-apoptotic protein AVEN, was able to partially revert the effect of miR-30a overexpression. Finally, overexpression of miR-30a in vivo was associated with reduced breast tumor progression. CONCLUSIONS: miR30-family regulates the growth of breast cancer cells in non attachment conditions. This is the first analysis of target prediction in a whole family of microRNAs potentially involved in survival of putative BT-ICs. PMID- 23445408 TI - The health burden of orphan zoonotic disease in the United Kingdom, 2005-2009. AB - 'Orphan' zoonotic diseases attract disproportionately low scientific and public health attention for the impact that they can have. This article pulls together information on their health burden in the UK from routine and enhanced data sources. These diseases are heterogeneous in nature; some have very low case numbers (e.g. hydatid disease), whilst others affect hundreds of patients each year (e.g. toxoplasmosis). The number of deaths attributed to orphan zoonoses is relatively low, and the majority recorded in this article were caused by toxoplasmosis. There is a clear issue of under-reporting and under-diagnosis in the data sets presented, and further work should be carried out to obtain more accurate estimates of the prevalence of zoonotic infections. Joint human and veterinary studies are especially important for these diseases. PMID- 23445409 TI - Clinical implication of hypovascular hepatocellular carcinoma studied in 4,474 patients with solitary tumour equal or less than 3 cm. AB - BACKGROUND & AIMS: To clarify the biological behaviour of small hypovascular hepatocellular carcinoma (HCC) because of insufficient evidence even though frequently encountered. METHODS: The study covered naive 4,474 patients who met solitary HCC <= 3 cm (mean, 2.1 cm), histopathologically proven and Child Pugh A or B. Macroscopic vascular invasion and distant metastasis were excluded. The hypovascularity of tumour was defined as hypo- or iso-enhancement in arterial phase of multiple dynamic imaging techniques. RESULTS: Of them, 802 (18%) were hypovascular. The ratio of hypovascular HCC decreased as tumour size increased (P < 0.001) and most of them developed to hypervascular type when they grew over 1.5 cm. Hypovascular group showed a significantly higher ratio of well differentiated grade (P < 0.001) and marginally less incidence of microvascular invasion and metastases compared with hypervascular group. The histologic dedifferentiation (less differentiation) developed step-by-step as tumour size increased in hyper- and even hypovascular group. The des-gamma-carboxy prothrombin (DCP) value >= 300 mAU/ml was closely correlated with increase of tumour size in both groups. Logistic regression analysis revealed five variables were independent predictors for hypovascular HCC; tumour size <= 1.5 cm, alpha-fetoprotein < 200 ng/ml, DCP < 40 mAU/ml, well differentiated grade, and positivity for hepatitis C virus antibody. CONCLUSIONS: Hypovascular HCC was biologically less aggressive and developed with stepwise dedifferentiation and transformation to hypervascular appearance along with tumour growth. These results will help in leading correct diagnosis of small hypovascular tumour and assessing optimal treatment for hypovascular HCC <= 3 cm. PMID- 23445410 TI - Combustion of volatile organic compounds over composite catalyst of Pt/gamma Al2O3 and beta zeolite. AB - Catalytic oxidation of volatile organic compounds (VOCs) was carried out over a composite catalyst comprising Pt/gamma-Al2O3 and protonated beta zeolite. The conversion of several VOCs such as ethyl acetate, butyl acetate, 2-propanol, 1,2 dichloroethane, and chloroethane over the composite catalyst was higher than the conversion over the conventional Pt/gamma-Al2O3 catalyst, indicating a remarkable improvement in the oxidation activity of the composite. On the other hand, no difference in the conversion of methyl ethyl ketone, methyl isobutyl ketone, toluene, benzene, and chloroethylene was observed for the composite catalyst versus the Pt/gamma-Al2O3 catalyst. To clarify the role of the zeolite component, the reaction products obtained using the composite catalyst were compared with those obtained using the Pt/gamma-Al2O3 catalyst. For the cases in which considerable improvement in the oxidation activity was observed with the composite, it was revealed that the conversion of VOCs to intermediate compounds took place over the acidic sites of the zeolite; the intermediates tended to be easily oxidized to CO2 on the Pt/gamma-Al2O3 catalyst. In addition, the composite catalyst also exhibited high durability. High catalytic activity was maintained even after aging at 600 degrees C for more than 1000 h. PMID- 23445411 TI - Simulation model to predict the fate of ciprofloxacin in the environment after wastewater treatment. AB - The extent hospital effluent contributes to antimicrobial presence in the environment and its impact on resistance dissemination remains unknown. To investigate the fate of the antimicrobial ciprofloxacin in hospital effluent a Monte Carlo simulation model was developed to model levels from hospital use to wastewater treatment plant (WWTP) effluent release, in addition to modeling resistance formation potential, hazard quotient (HQ) and swimmer exposure. The mean predicted concentration (PC) of ciprofloxacin in hospital effluent, urban effluent, WWTP effluent, sludge, soil and sea water was 579, 6.06, 2.59, 3.48, 0.006 and 0.15 mg/m(3), respectively. A parallel surveillance study confirmed levels of ciprofloxacin above or below the limit of detection. The model predicted levels would never exceed the ECOSAR toxicity value. The model predicted a 98% probability of ciprofloxacin exhibiting a HQ > 1 (low toxicity concern). The mean ciprofloxacin PC in WWTP effluent was less than the minimum inhibitory concentration (MIC). The probability of conditions in WWTP effluent being favorable for resistance at 20% and 80% of the MIC was 3% and 72%, respectively. In all instances, when the MIC was bound, the probability for resistance formation within soil and sea water was < 1%. The probability of a swimmer being exposed to a level of ciprofloxacin greater than the acceptable daily intake was negligible. The study concluded that release of hospital effluent into the environment may lead to concentrations of ciprofloxacin which are of low toxicity concern but may be conducive to resistance formation and allow for the dissemination of resistance. PMID- 23445412 TI - Andromeda polifolia and Oxycoccus microcarpus as pollution indicators for ombrotrophic bogs in the Western Sudety Mountains (SW Poland). AB - Concentrations of the elements Cd, Cr, Cu, Fe, Li, Mn, N, Ni, Pb and Zn in Andromeda polifolia, Oxycoccus microcarpus and in the peat in which these plants grew were measured in the Western Sudety (Karkonosze and Izerskie Mts., SW Poland). Of both the investigated plant fruit, O. microcarpus harvested from wild populations are commonly used as medicines. Samples from ombrotrophic bogs were investigated within the area influenced by exhausts of the former Black Triangle, one of the most heavily industrialized and polluted areas in Europe. A. polifolia and O. microcarpus growing at the highest elevations contained the highest Cu, Li, Ni, Mn and Zn concentrations and in addition O. microcarpus also contained the highest Cr concentrations. Both the investigated species have wide circumpolar distribution in ombrotrophic mires of the Northern hemisphere. As this type of mires is nourished solely by atmospheric deposition, the increased metal concentrations in A. polifolia and O. microcarpus may be an indication that their habitats receive an atmospheric input of long-range transported pollution. Our investigation proves that both species are able to accumulate elevated metal levels and may be used in the bioindication of the metal status in ombrotrophic mires. Controlling the collection of O. microcarpus fruit for consumption and medicinal purposes is recommended as this species can accumulate increased metal levels. However, further more detailed studies are necessary to verify the inner translocation of metals into fruit. PMID- 23445413 TI - Application of statistical experimental design to optimize the photocatalytic degradation of a thiazin dye using silver ion-doped titanium dioxide. AB - A three-factor, three-levels Box-Behnken design combined with response surface methodology (RSM) was used to optimize the photocatalytic degradation process of Methylene blue (MB), a cationic thiazin dye, using Agdoped TiO2 under UV irradiation in a batch reactor. The individual and interaction effects of three operational parameters, photocatalyst dose (1.5-2.5 g/L), initial dye concentration (10-50 ppm) and pH (5-9), selected based on single factor study, on the colour removal (decolourization) and COD removal (mineralization) of the dye were determined by fitting the results of the experiments to two quadratic polynomial models relating the parameters to the response variables. Design Expert software version 8.0.6.1 was used to determine the effects of the parameters on the two responses and the optimum values of the parameters. The initial dye concentration was found to have a higher negative effect on the two responses, while photocatalyst dose and pH had lower positive effect. Under the optimum conditions (dose of Ag+ doped TiO2 1.97 g/L, initial concentration of MB 22.86 ppm and pH of reaction mixture 6.68) the decolourization and mineralization rate of MB were predicted as more than 96% and 71%, respectively. The high correlation between adjusted and predicted R values indicates goodness of fit of the model. PMID- 23445414 TI - Potential of biosorbent developed from fruit peel of Trewia nudiflora for removal of hexavalent chromium from synthetic and industrial effluent: Analyzing phytotoxicity in germinating Vigna seeds. AB - Chromium (VI) removal efficiency of a biosorbent prepared from fruit peel of Trewia nudiflora plant was studied. The effect of pH, sorbent dose, initial metal concentration and temperature was studied with synthetic Cr+6 solution in batch mode. About 278 mg/g of Cr+6 sorption was obtained at 293 K at an optimum pH of 2.0 and biosorbent dose of 0.75 g/L. Equilibrium sorption data with varying initial concentration of Cr+6 (22-248 mg/L) at three different temperatures (293 313 K) were analyzed by various isotherms. Biosorption kinetics and thermodynamics were described using standard model equations. Encouraging results were obtained by the application of the biosorptive treatment for removal of Cr+6 from wastewater collected from common effluent treatment plant of tannery industry. In addition, C+6r desorption behavior was studied on different systems. Biosorbent was characterized by FESEM, FT-IR and XRD, etc. Effect of the biosorptive treatement with respect to the phytotoxicity of Cr+6 was analyzed by studying the seed germination behavior and enzyme activity of a pulse seed (Vigna radiata L.). Different concentrations of Cr+6 solution in both synthetic medium, as well as, in tannery effluent was employed and the results were compared with that of biosorbent treated medium. The study showed that due to efficient removal of Cr+6 from aqueous phase, considerable enhancement of seed germination, as well as, increase in root length was obtained for the biosorbent treated solutions which were close to that of the control values. Significant decrease (P < 0.01) in POD activity was observed in seeds irrigated with biosorbent treated wastewater compared to untreated wastewater. The study showed that the novel biosorbent prepared might be utilized for abatement of heavy metal toxicity, i.e., Cr+6 from industrial effluent. PMID- 23445415 TI - Optimization of semi-aerobic stabilized leachate treatment using ozone/Fenton's reagent in the advanced oxidation process. AB - The objective of this study was to investigate the performance of employing Fenton's reagent in the advanced oxidation of ozone to treat stabilized landfill leachate in an ozone reactor. A central composite design (CCD) with response surface methodology (RSM) was applied to evaluate the relationships between operating variables, such as ozone and Fenton dosage, pH, and reaction time, to identify the optimum operating conditions. Quadratic models for the following four responses proved to be significant with very low probabilities (<0.0001): chemical oxygen demand (COD), color, NH-N, and ozone consumption (OC). The obtained optimum conditions included a reaction time of 90 min, 30 g/m3 ozone, 0.01 mol/L2H2O,0.02 mol/L Fe2+, and pH 5. COD, color, and NH3-N removal rates of 79%, 100%, and 20%, respectively, and 0.18 kg O3/kg COD OC were obtained. The predictions correspond well with experimental results (COD, color, and NH-N removal rates of 78%, 98.5%, and 19%, respectively, and 0.29 kg O3/kg COD OC). This method reduces the treatment time and improves the treatment efficiency relative to a previously published method that used Fenton's reagent prior to ozonation. PMID- 23445416 TI - Temporal distribution of fine particulates (PM2.5:PM10), potentially toxic metals, PAHs and Metal-bound carcinogenic risk in the population of Lucknow City, India. AB - Ubiquitous fine particulates can readily be bound to toxic metals and polycyclic aromatic hydrocarbons and are considered to be a great threat to human health. The purpose of this study was to assess the magnitude of air pollution risks to public health by determining four crucial parameters- inhalable particulates, metals in particulates and PAHs which are associated with PM10 in the air environment of Lucknow, India during 2007-09. The values of PM10 and PM2.5 ranged between 102.3-240.5 and 28.0-196.9 MUg/m3 whilst the average PM10 was 1.7 times and PM was 1.5 times higher than their respective NAAQS of 100 and 60 MUg/m3 respectively. The estimated relative death rate and hospital admissions for each increase in the PM10 levels of 10 MUg/m3 ranged from 1.5-8% and from 3.9-8.0% (as per APHEA2 1990) respectively in persons > 65 yrs. Among the locations; AQ, AQ and AQ (with diversified activities and heavy traffic) recorded higher concentrations of both the particulate fractions than the AQ (residential area with low traffic). The average concentrations of Fe, Pb, Ni, Cu, Cr, Cd in PM10 were 219.4, 40.6, 35.1, 27.3, 22.2 and 16.2 ng/m3 and that in PM2.5 were 54.3, 33.9, 38.5, 29.4, 8.4, and 1.17 ng/m3 respectively Regression analysis revealed that correlation of metals with PM2.5 was stronger than PM. The ratio of metals adsorbed on surface of particles (PM2.5:PM10) reveals that PM2.5 has more affinity for Ni, Cu and Pb and PM10 for Cd, Fe and Cr. Health risk due to carcinogenic metals bound to respirable particulates was predicted by estimating excess cancer risk (ECR). The highest ECR value was estimated for Cr, 266.70 * 10 6, which was associated with PM10 and 100.92 * 10-6 which was associated with PM2.5, whereas lead has the lowest ECR value. Amongst PAHs, benzo(a)pyrene (51.96 +/- 19.71 ng/m) was maximum in PM10 samples. Maximum concentrations of PM10, PM2.5, metals and PAHs were detected during winter, and the lowest was during monsoon. The higher prevalence of diseases among the population may be due to high concentration of particulates coated with toxic metals and PAHs present in air environment. PMID- 23445417 TI - Complexes of potentially pathogenic microscopic fungi in anthropogenic polluted soils. AB - This study was undertaken to investigate the species' diversity and structure of potentially pathogenic microscopic fungal complexes in podzolic soils polluted by fluorine, heavy metals (Cu, Ni, Co), oil products (diesel fuel, gas condensate, mazut). Lists of potentially pathogenic fungi isolated from soils are made specifically for north-western part of Russia (Kola Peninsula). The majority of studied fungus species belong to the following genera: Penicillium, Aspergillus, Mucor, Lecanicillium and Phoma. Penicillium miczynskii was identified as the most stable type of fungus with respect to all studied types of oil products. Mucor hiemalis was identified as the most sensitive type. An increase of 15% portion of potentially pathogenic fungi as compared to the background soil in zones of aluminum and copper-nickel plants was revealed. The results indicate an increase of 20-25% of potentially pathogenic fungi in pollution of soil with oil products. The structure of fungal complexes was observed to have changed in the polluted soils and the species number and frequency of occurrence of potentially pathogenic fungi were also increased. PMID- 23445418 TI - Assessing an intermittently operated household scale slow sand filter paired with household bleach for the removal of endocrine disrupting compounds. AB - Endocrine disrupting compounds (EDCs) are a contaminant of emerging concern throughout the world, including developing countries where centralized water and wastewater treatment plants are not common. In developing countries, household scale water treatment technologies such as the biosand filter (BSF) are used to improve drinking water quality. No studies currently exist on the ability of the BSF to remove EDCs. In this experiment, the BSF was evaluated for the removal of three EDCs, estrone (E1), estriol (E3), and 17alpha-ethinyl estradiol (EE2). Removal results were compared to the slow sand filter (SSF) from the literature, which is similar to the BSF in principal but comparisons have revealed differences in removal of other water quality parameters between SSF and BSF. In general, the BSF minimally removed the compounds from spiked lake water as removal was less than 15% for all three compounds, though mass removal much higher than other studies in which the SSF was used. Household bleach was added to the rate was BSF effluent as suggested in order to achieve different Cl- concentrations (0.67, 2.0, 5.0, and 10.0 mg/L) and subsequent removal of EDCs by oxidation was examined. Concentrations were reduced > 98% for all compounds when the Cl- concentration was greater than 5 mg/L. Removal efficiency was > 50% at the 0.67 mg/L Cl- concentration, while almost 70% removal was observed for all compounds at the 2.0 mg/L Cl- concentration. PMID- 23445419 TI - Identification of dissolved organic matter in raw water supply from reservoirs and canals as precursors to trihalomethanes formation. AB - The characteristic and quantity of dissolved organic matter (DOM) as trihalomethanes precursors in water from the U-Tapao Basin, Songkhla, Thailand was investigated. The sources of water in the basin consisted of two reservoirs and the U-Tapao canal. The canal receives water discharge from reservoirs, treated and untreated wastewater from agricultural processes, communities and industries. Water downstream of the canal is utilized as a raw water supply. Water samples were collected from two reservoirs, upstream and midstream of the canal, and the raw water supply in the rainy season and summer. The DOM level in the canal water was higher than that of the reservoir water. The highest trihalomethane formation potential (THMFP) was formed in the raw water supply. Fourier-transform infrared peaks of the humic acid were detected in the reservoir and canal waters. Aliphatic hydrocarbon and organic nitrogen were the major chemical classes in the reservoir and canal water characterized by a pyrolysis gas chromatography mass spectrometer. The optimal condition of the poly aluminum chloride (PACl) coagulation was obtained at a dosage of 40 mg/L at pH 7. This condition could reduce the average UV-254 to 57%, DOC to 64%, and THMFP to 42%. In the coagulated water, peaks of O-H groups or H-bonded NH, C?O of cyclic and acyclic compounds, ketones and quinines, aromatic C?C, C-O of alcohols, ethers, and carbohydrates, deformation of COOH, and carboxylic acid salts were detected. The aliphatic hydrocarbon, organic nitrogen and aldehydes and ketones were the major chemical classes. These DOM could be considered as the prominent DOM for the water supply plant that utilized PACl as a coagulant. PMID- 23445420 TI - Effect of different buffer agents on in-vessel composting of food waste: performance analysis and comparative study. AB - This study investigated the performance and feasibility for application of different buffer agent combinations, including K2HPO4/MgSO4, KH2PO4/MgSO4 and NaAc, in composting of food waste. The variations of temperature, pH, O2 consumption, organic mass and ammonia release were monitored. The results showed that addition of all these three types of agents could prolong the thermophilic stage during composting. The amendments of KH2PO4/MgSO4 and NaAc could increase and decrease the final pH levels, respectively. Application of K2HPO4/MgSO4 and NaAc would lead to a peak daily oxygen uptake rate of 10.0 and 12.4 mg/(g.h) respectively, which were all higher than that with KH2PO4/MgSO4 amendment. Similarly, the reactors with K2HPO4/MgSO4 and NaAc were also associated with a higher cumulative oxygen uptake and total organic degradation rate. The amendment of NaAc resulted in a higher ammonia loss than the other two agents. More inorganic nitrogen contents were observed in the series with K2HPO4/MgSO4 and NaAc. It can be concluded that K2HPO4/MgSO4 additive showed the most favorable influence on composting performance. The results of this study will have important implications for developing appropriate treatment approach for food waste composting. PMID- 23445421 TI - Microbial contamination associated with consumption and the growth in plastic bottled beverage. AB - Plastic bottles enable the storage of unfinished beverages, and most of microbial contamination has occurred in the unfinished beverage that was left. Therefore, we investigated microorganisms in various beverages contaminated by pouring and drinking directly by mouth from the bottle, and analyzed the growth of microorganisms in the beverages at room temperature. In the pouring test, microbial growth was detected in 60 of 320 samples, and 13 bacterial strains, 49 mold strains, and 8 yeast strains were isolated. Molds including Cladosporium spp., Tramets spp., Bjerkandera spp., and Penicillium spp. accounted for the majority of isolated microorganisms. In the drinking test, microbial growth was detected in 181 of 352 samples, and 225 bacterial strains, 27 mold strains and 77 yeast strains were isolated. Bacteria including Streptococcus spp. such as S. salivarius and Staphylococcus spp. such as S. aureus accounted for the majority of isolated microorganisms. Enterotoxin-producing S. aureus and Bacillus cereus were also isolated. The pH of the beverage influenced the growth of bacteria. The Brix values of the beverage did not correlate with the growth of microorganisms. These results revealed that various microorganisms including foodborne pathogens were able to grow in numerous types of beverages and that the storage of unfinished beverage in inappropriate condition, such as the storage at room temperature led microorganism to grow easily in beverage. Therefore, it is necessary to consume beverages as soon as possible after opening the bottle. PMID- 23445422 TI - Degradation of paracetamol by Pseudomonas aeruginosa strain HJ1012. AB - Pseudomonas aeruginosa strain HJ1012 was isolated on paracetamol as a sole carbon and energy source. This organism could completely degrade paracetamol as high as 2200 mg/L. Following paracetamol consumption, a CO2 yield rate up to 71.4% proved that the loss of paracetamol was mainly via mineralization. Haldane's equation adequately described the relationship between the specific growth rate and substrate concentration. The maximum specific growth rate and yield coefficient were 0.201 g-Paracetamol/g-VSS.h and 0.101 mg of biomass yield/mg of paracetamol consumed, respectively. A total of 8 metabolic intermediates was identified and classified into aromatic compounds, carboxylic acids, and inorganic species (nitrite and nitrate ions). P-aminophenol and hydroquinone are the two key metabolites of the initial steps in the paracetamol catabolic pathway. Paracetamol is degraded predominantly via p-aminophenol to hydroquinone with subsequent ring fission, suggesting partially new pathways for paracetamol degrading bacteria. PMID- 23445423 TI - Levels and sources of polychlorinated biphenyls in Ankara creek sediments, Turkey. AB - The spatial distribution, degree of pollution and major sources of polychlorinated biphenyls (PCBs) were evaluated in surficial sediments of Ankara Creek, located in the capital of Turkey and serving as one of the tributaries in the third largest watershed in Turkey. Sediment SigmaPCB concentrations analyzed on Aroclor and congener basis (seven indicator congeners) range from 5.5 to 777.6 ng g(-1) and 3.7 to 743.3 ng g(-1) dw as Aroclor and congener based concentrations, respectively. High concentrations of SigmaPCBs were observed in the samples located at the downstream sections of the Creek, after discharge from Ankara municipal wastewater treatment plant. Using a chemical mass balance receptor model (CMB), major sources of PCBs affecting the sediments were investigated. The CMB model identified Aroclor 1254 and 1260 to be the major PCB sources affecting sediments. The potential sources for the PCBs were briefly discussed in terms of their use in various industrial applications. PMID- 23445424 TI - The effect of volatile fatty acids (VFAs) on nutrient removal in SBR with biomass adapted to dairy wastewater. AB - This study aims to determine the effect of volatile fatty acids on nitrates and orthophosphate removal in a sequencing batch reactor (SBR) with activated sludge biomass adapted to process dairy wastewater. The research also determine whether it is the type of fatty acid applied that is responsible for the effectiveness of denitrification and dephosphatation at varying nitrate:orthophosphate ratios, or whether these processes are additionally affected by the presence of microorganisms that have adapted to the specific carbon composition of the wastewater being treated. At the beginning of an operating cycle SBRs were dosed with VFAs to provide a source of carbon. A comparative analysis was performed of nitrate and orthophosphate removal at initial nitrate concentrations of 1.22, 7.3 and 15.2 mgN(NO3)L-1. Doses of fatty acids were approximately 10.5 mg 1COD.mgP(PO4). They consisted of acetic, propionic, butyric, isobutyric, valeric, isovaleric and caproic acids. Increases of nitrate concentration from 1.22 to 15.2 mg N(NO3)L-1 were observed to reduce the quantity of removed orthophosphate depending on the fatty acid applied, from 7.2-9.2 mgP(PO4)L to 4.5 - 6.7 mgP(PO4)L. Every increase in the removed nitrates by 5.0 mgN(NO3)L-1 was accompanied by a decrease in the removed orthophosphate of around 1 mgP(PO4)L-1. The reactor containing acetic acid was found to remove the highest amount of orthophosphate irrespective of the nitrates concentration. Acids present in significant amount in dairy wastewaters (i.e. acetic, propionic and butyric) were more effective source of carbon in the denitrification process compared to low concentration acids. PMID- 23445425 TI - Novel route for silylation of silica gel and aliphatic amines immobilization based on microwave-assisted solvent free synthesis and their applications for Cu(II) and Fe(III) removal from natural water samples. AB - This article describes a new route for silica gel silylation and immobilization of aliphatic amines based on microwave-assisted solvent free synthesis to produce new solid phase extractors. The mode of synthesis was optimized under microwave conditions and achieved in a short time without using solvents. The produced phases named: silica gel- monoamine (SG-MA), silica gel- ethylenediamine (SG-EDA) and silica gel- diethylenetriamine (SG-DETA). The selectivity of these phases towards the uptake of Cu(II) and Fe(III) was checked using batch equilibration technique. Microwave radiation power and time of radiation were optimized to obtain the highest metal uptake values. The novel synthesized silica amine phases were characterized using Fourier transform infrared spectra and scanning electron microscope. The effects of different parameters including, hydrogen ion concentration, initial metal ion concentration, mass of the phase and shaking time on binding capacities of both Cu(II) and Fe(III) were explored. Results of sorption isotherms of the phases were better fitted with the Langmuir model (r2 >= 0.950). In addition, the kinetics data were best fitted with the pseudo-second order type (r2 = 0.999). Application of SG-MA for removal of Cu(II)- and Fe(III) spiked natural water samples was achieved satisfactorily using batch experiments. The results were found to refer to superior recovery percentages (90.0-97.01 +/- 0.010-0.521%) with no significant matrix interferences. PMID- 23445426 TI - Moss biomonitoring of air pollution with chromium in Croatia. AB - The purpose of this study was to determine the atmospheric deposition of chromium in Croatia by using moss biomonitoring technique and atomic emission spectrometry with inductively coupled plasma (ICP-AES). Moss samples (Hylocomium splendens, Hypnum cupressiforme, Brachythecium rutabulum and Homalothecium Sericeum) were collected from 121 sampling sites evenly distributed over the country, during the summer and autumn of 2010. Collected samples were air dried, then cleaned and digested by using microwave digestion system. The median value obtained in this study (1.94 mg kg-1) compared with the median value of previous investigation performed in 2006 (2.75 mg kg-1) shows that the content of chromium decreased. Higher contents of chromium were found in moss samples collected in the regions of Central Croatia, in/near the cities of Zagreb, Sisak and Kutina, which, in the most of the cases, are result of anthropogenic activities. In Costal Croatia, higher values have a natural origin due to the significantly higher content of Cr in soil from this region. The results were compared with those from similar studies in neighboring and other Balkan countries. It was established that the content of chromium in Croatia is lower than in the most of these countries. PMID- 23445427 TI - (Meta)cognitive beliefs in posttraumatic stress disorder following forced displacement at the end of the Second World War in older adults and their offspring. AB - INTRODUCTION: The aim of the present study was to investigate (meta)cognitive beliefs related to posttraumatic stress disorder (PTSD) in a sample of individuals displaced as children at the end of the Second World War as well as transgenerational effects of trauma and PTSD on the offspring. METHODS: Displaced individuals with (n=20) and without PTSD (n=24) and nondisplaced healthy controls (n=11), as well as one of their adult offspring, were assessed with the Metacognitions Questionnaire (MCQ-30). Older adults, formerly displaced in childhood, were additionally assessed with the Posttraumatic Cognitions Inventory (PTCI). RESULTS: Dysfunctional beliefs (MCQ-30, PTCI) were particularly pronounced in formerly displaced individuals with PTSD, but not in the offspring generation. CONCLUSIONS: The findings suggest that in an aging group of displaced individuals with PTSD dysfunctional beliefs are associated with the disorder. Bias modification may help to attenuate symptomatology. No evidence was found for a transgenerational effect. PMID- 23445428 TI - In vitro neutralization of viral hemorrhagic septicemia virus by plasma from immunized zebrafish. AB - We studied humoral long-term adaptive viral neutralization responses in zebrafish (Danio rerio), an increasingly useful vertebrate model for viral diseases actually limited by the absence of standardized anti-zebrafish immunoglobulin M (IgM) antibodies. We established an alternative method, similar to those used in other fish, to achieve a first estimation of zebrafish anti-viral antibody-like responses. We used the viral hemorrhagic septicemia virus (VHSV) model because, although protection after this non-natural infection was demonstrated in cold acclimatized zebrafish, little is known about their induced anti-VHSV antibody like responses. Therefore, we first optimized a micro-neutralization method based on immunostaining VHSV-infected fish cell monolayers to detect zebrafish neutralizing activity in plasma samples in one day. We then used the method to measure the specific anti-VHSV neutralization in plasma obtained from individual zebrafish under various VHSV challenges or immunization protocols. The neutralizing activity was inhibited by protein A-sepharose and rabbit anti zebrafish IgM antibodies, suggesting the implication of IgM zebrafish antibodies in such responses. To our knowledge, this is the first report to demonstrate detectable and significant VHSV neutralization titers in zebrafish surviving VHSV infections. This micro-method might be useful, not only for the follow-up of infection/vaccine development in the zebrafish/VHSV model in particular, but also for similar work involving other in vitro neutralizable zebrafish pathogens. This technique might also further the development of alternative ELISA assay methods to measure specific immunoglobulins in zebrafish. PMID- 23445429 TI - Noninvasive measurement of steroid hormones in zebrafish holding-water. AB - Zebrafish (Danio rerio) has recently emerged as a new animal model in neuroendocrinology and behavior (e.g., stress physiology and ecotoxicology studies). In these areas, the concentrations of steroid hormones in the blood are often used to study the endocrinological status of individuals. However, due to the small body size of zebrafish, blood sampling is difficult to perform and the amount of plasma obtained per sample for assaying hormones is very small (ca. 1-5 MUL), and therefore most studies have been using whole-body hormone concentrations, which implies sacrificing the individuals and hampers sequential sampling of the same individual. Here a noninvasive method to assay steroid hormones from zebrafish holding-water, based on the fact that steroids are released into the fish holding-water through the gills by passive diffusion, is validated. Cortisol and the androgen 11-ketotestosterone (KT) were measured in water samples and compared to plasma levels in the same individuals. Cortisol released to holding-water correlates positively with plasma concentrations, but there was a lack of correlation between KT water and circulating levels. However, KT levels showed a highly significant sex difference that can be used to noninvasively sex individuals. An ACTH challenge test demonstrated that an induced increase in circulating cortisol concentration can be reliably detected in holding-water levels, hence attesting the responsiveness of holding-water levels to fluctuations in circulating levels. PMID- 23445430 TI - Effect of DHEA therapy on sexual behavior in female rats. AB - Delta-5 androgen therapies seem to enhance the sexual response in experimental animal models and in clinical trial. This study analyzed the influence of dehydroepiandrosterone (DHEA) administration on receptive and proceptive components of female rat sexual behavior. Ovariectomized (OVX) adult rats were divided in six groups submitted to the following treatments for 4 weeks: DHEA 0.5 and 5 mg/kg, by oral gavage, alone or in combination with estradiol benzoate 3 ug/rat; EB 3 and 10 ug/rat as control groups. All animals received progesterone (500 ug/rat) 4 h before the behavioral tests. All animals were tested for the following: receptivity and proceptivity weekly for 4 weeks; partner preference and paced mating behavior at the end of the treatments. Oral administration of DHEA at 5 mg/kg in EB primed rats was able to significantly increase proceptive behaviors, already after 1 week of treatment. The increase was more marked after 3 and 4 weeks of treatment. Behavioral changes were associated to modifications of circulating and brain level of allopregnanolone and beta-endorphin, although circulating hormonal levels were within a physiological range. Hormonal treatment using physiological doses of delta-5 androgens (DHEA) positively affects sexual motivation in OVX rats. PMID- 23445433 TI - Dark-coloured semen in nonobstructive azoospermia: a report of four cases. AB - Dark-coloured semen is rarely observed in men with nonobstructive azoospermia in absence of genital tract bleeding. Dark-coloured semen is also observed rarely in men with spinal cord injury with or without genital tract bleeding. However, this condition has not been reported in the literature in absence of genital tract bleeding or spinal cord injury. Here, we report men with nonobstructive azoospermia with dark-coloured semen and without genital tract bleeding or spinal cord injury. The study included four subjects with dark-coloured semen. All the samples first investigated for the presence of red blood cells as well as haemoglobin. All the cases were examined in details with seminal, hormonal and genetic parameters. In addition, an elemental electron microscopy and inductively coupled plasma-atomic emission spectrometry evaluation for heavy metals was performed. The semen parameters showed normal volume, pH, leucocyte count and azoospermia or oligoazoospermia. Dark-coloured semen specimens contained neither red blood cells nor haeme pigment. Electron microscopy showed presence of platinum in all the cases, whereas inductively coupled plasma-atomic emission spectrometry revealed increased levels of lead, manganese and nickel in serum as compared to controls. The results indicate dark-coloured semen may be linked with heavy metals found in seminal cells. PMID- 23445431 TI - Barriers to use of workers' compensation for patient care at Massachusetts community health centers. AB - OBJECTIVES: To examine barriers community health centers (CHCs) face in using workers' compensation insurance (WC). DATA SOURCES/STUDY SETTING: Leadership of CHCs in Massachusetts. STUDY DESIGN: We used purposeful snowball sampling of CHC leaders for in-depth exploration of reimbursement policies and practices, experiences with WC, and decisions about using WC. We quantified the prevalence of perceived barriers to using WC through a mail survey of all CHCs in Massachusetts. DATA COLLECTION/EXTRACTION METHODS: Emergent coding was used to elaborate themes and processes related to use of WC. Numbers and percentages of survey responses were calculated. PRINCIPAL FINDINGS: Few CHCs formally discourage use of WC, but underutilization emerged as a major issue: "We see an awful lot of work-related injury, and I would say that most of it doesn't go through workers' comp." Barriers include lack of familiarity with WC, uncertainty about work-relatedness, and reliance on patients to identify work-relatedness of their conditions. Reimbursement delays and denials lead patients and CHCs to absorb costs of services. CONCLUSION: Follow-up studies should fully characterize barriers to CHC use of WC and experiences in other states to guide system changes in CHCs and WC agencies. Education should target CHC staff and workers about WC. PMID- 23445432 TI - Effects of supraphysiological testosterone treatment and orchiectomy on ischemia/reperfusion-induced bladder dysfunction in male rabbits. AB - INTRODUCTION: The roles of testosterone and orchiectomy on male bladder subjected to ischemic/reperfusion (I/R) injuries received little attention. To fill this gap, the present study intended to examine testosterone and orchiectomy effects on male rabbits subjected to I/R damages. AIM: To elucidate the effects of testosterone and orchiectomy on contractile response, bladder morphology, interstitial fibrosis, and oxidative stress in male rabbit bladder subjected to I/R surgery. METHODS: Male New Zealand rabbits were distributed into five groups as follows: Group 1 received sham surgical procedure. In group 2, I/R surgery was performed. In group 3, testosterone (100 MUg/kg/day) was intramuscularly injected prior to I/R surgery. In group 4, orchiectomy was performed prior to I/R surgery. In group 5, orchiectomy was performed with subsequent testosterone administration, followed by I/R surgery. All the rabbits were euthanized 7 days after I/R. Comparative studies were analyzed to elucidate the effects of testosterone and orchiectomy on bladder dysfunction subjected to I/R injuries. MAIN OUTCOME MEASURES: Bladder contractile function was evaluated. Masson's trichrome staining and immunohistochemical studies were performed to evaluate bladder morphology and intramural nerve terminals. Western blotting was examined to investigate the expressions of fibrosis and oxidative stress markers. RESULTS: I/R surgery significantly decreased bladder contractility in response to various stimulations with and without testosterone treatment. I/R damages decreased bladder nerve density with and without testosterone. The expressions of fibrosis and oxidative stress-related proteins were increased by I/R injuries with or without testosterone treatment. Testosterone depletion significantly decreased the expressions of transforming growth factor-beta and fibronectin expressions after I/R injury. Supraphysiological testosterone treatment after orchiectomy greatly increased the expressions of these fibrosis proteins; however, orchiectomy alone ameliorated I/R injuries. CONCLUSIONS: Testosterone treatment or orchiectomy affected I/R-induced bladder damages in male rabbits. Orchiectomy decreased the level of fibrosis and oxidative stress markers and increased neurofilament densities. Supraphysiological exogenous testosterone administration after orchiectomy further exacerbated such detrimental effects of I/R. PMID- 23445434 TI - A novel ionic liquid-in-oil microemulsion composed of biologically acceptable components: an excitation wavelength dependent fluorescence resonance energy transfer study. AB - In this work we have reported the formulation of a novel ionic liquid-in-oil (IL/O) microemulsion where the polar core of the ionic liquid, 1-ethyl-3 methylimidazolium n-butylsulfate ([C2mim][C4SO4]), is stabilized by a mixture of two nontoxic nonionic surfactants, polyoxyethylene sorbitan monooleate (Tween-80) and sorbitan laurate (Span-20), in a biological oil phase of isopropyl myristate (IPM). The formation of the microemulsion droplets has been confirmed from the dynamic light scattering (DLS) and phase behavior study. To assess the dynamic heterogeneity of this tween-based IL/O microemulsion, we have performed an excitation wavelength dependent fluorescence resonance energy transfer (FRET) from coumarin 480 (C480) to rhodamine 6G (R6G). The multiple donor-acceptor (D-A) distances, ~15, 30, and 45 A, obtained from the rise times of the acceptor emission in the presence of a donor can be rationalized from the varying distribution of the donor, C480, in the different regions of the microemulsion system. With increasing the excitation wavelength from 375 to 408 nm, the contribution of the rise component of ~240 ps which results the D-A distance of ~30 A increases significantly due to the enhanced contribution of the C480 probe molecules closer to the acceptor in the ionic liquid pool of the microemulsion. PMID- 23445435 TI - X-ray absorption spectroscopy of a quantitatively Mo(V) dimethyl sulfoxide reductase species. AB - Molybdenum K-edge X-ray absorption spectroscopy (XAS) has been used to probe the structure of a Mo(V) species that has been suggested to be a catalytic intermediate in the reaction of dimethyl sulfoxide (DMSO) reductase with the alternative substrate trimethylamine N-oxide (Bennet et al. Eur. J. Biochem. 1994, 255, 321-331; Cobb et al. J. Biol. Chem. 2005, 280, 11007-11017; Mtei, et al. J. Am. Chem. Soc. 2011, 133, 9672-9774). The oxidized Mo(VI) state of DMSO reductase has previously been structurally characterized as being six coordinate, with four sulfurs from pyranopterin dithiolene molybdenum cofactors, a terminal oxygen ligand, and an additional oxygen coordination from a serine residue. We find the most plausible structure for the Mo(V) active site is a five-coordinate species with four sulfur donors from the two pyranopterin dithiolene ligands, with an average Mo-S bond-length of 2.35 A, plus a single oxygen donor at 1.99 A, very likely from an Mo-OH ligand. Our results thus suggest that the oxygen of the serine residue has dissociated from the metal ion, suggesting hitherto unsuspected flexibility of the active site, and calling into question whether this putative intermediate is catalytically relevant. The relevance to previous Mo(V) electron paramagnetic resonance and other spectroscopic studies on DMSO reductase is discussed. XAS of an extensively studied Mo(V) form of Rhodobacter sphaeroides DMSO reductase (the high-g split species) shows that previously suggested structures for the active site are likely incorrect. PMID- 23445436 TI - Pharmacological therapies and major gastrointestinal bleeding in patients with atrial fibrillation. PMID- 23445438 TI - All-integrated and highly sensitive paper based device with sample treatment platform for Cd2+ immunodetection in drinking/tap waters. AB - Nowadays, the development of systems, devices, or methods that integrate several process steps into one multifunctional step for clinical, environmental, or industrial purposes constitutes a challenge for many ongoing research projects. Here, we present a new integrated paper based cadmium (Cd(2+)) immunosensing system in lateral flow format, which integrates the sample treatment process with the analyte detection process. The principle of Cd(2+) detection is based on competitive reaction between the cadmium-ethylenediaminetetraacetic acid-bovine serum albumin-gold nanoparticles (Cd-EDTA-BSA-AuNP) conjugate deposited on the conjugation pad strip and the Cd-EDTA complex formed in the analysis sample for the same binding sites of the 2A81G5 monoclonal antibody (mAb), specific to Cd EDTA but not Cd(2+) free, which is immobilized onto the test line. This platform operates without any sample pretreatment step for Cd(2+) detection thanks to an extra conjugation pad that ensures Cd(2+) complexation with EDTA and interference masking through ovalbumin (OVA). The detection and quantification limits found for the device were 0.1 and 0.4 ppb, respectively, these being the lowest limits reported up to now for metal sensors based on paper. The accuracy of the device was evaluated by addition of known quantities of Cd(2+) to different drinking water samples and subsequent Cd(2+) content analysis. Sample recoveries ranged from 95 to 105% and the coefficient of variation for the intermediate precision assay was less than 10%. In addition, the results obtained here were compared with those obtained with the well-established inductively coupled plasma emission spectroscopy (ICPES) and the analysis of certificate standard samples. PMID- 23445439 TI - 5-HTTLPR and anxiety modulate brain-heart covariation. AB - To date, little is known about genes affecting the interplay of brain and heart activity. Because serotonin (5-HT) is involved in corticovagal neurotransmission, we tested whether the 5-HT transporter polymorphism 5-HTTLPR affects brain-heart covariation. Further, associations with neuroticism/anxiety (NANX) were tested, as anxiety is related to 5-HT and neurogenic changes of heart period (HP). N = 168 participants performed a time-estimation task while EEG and HP were recorded. Brain-heart covariation was measured using time-lagged within-subject correlations of centromedial feedback-evoked single-trial EEG at 300 ms and subsequent changes of HP. EEG-HP correlations were higher in 5-HTTLPR long allele carriers. Moreover, after negative feedback, EEG-HP correlations and feedback related negativity amplitudes independently correlated with NANX. The results indicate that individual differences in brain-heart covariation relate to 5-HT and NANX. PMID- 23445440 TI - New enumeration algorithm for protein structure comparison and classification. AB - BACKGROUND: Protein structure comparison and classification is an effective method for exploring protein structure-function relations. This problem is computationally challenging. Many different computational approaches for protein structure comparison apply the secondary structure elements (SSEs) representation of protein structures. RESULTS: We study the complexity of the protein structure comparison problem based on a mixed-graph model with respect to different computational frameworks. We develop an effective approach for protein structure comparison based on a novel independent set enumeration algorithm. Our approach (named: ePC, efficient enumeration-based Protein structure Comparison) is tested for general purpose protein structure comparison as well as for specific protein examples. Compared with other graph-based approaches for protein structure comparison, the theoretical running-time O(1.47 rnn2) of our approach ePC is significantly better, where n is the smaller number of SSEs of the two proteins, r is a parameter of small value. CONCLUSION: Through the enumeration algorithm, our approach can identify different substructures from a list of high-scoring solutions of biological interest. Our approach is flexible to conduct protein structure comparison with the SSEs in sequential and non-sequential order as well. Supplementary data of additional testing and the source of ePC will be available at http://bioinformatics.astate.edu/. PMID- 23445441 TI - Both the sera of patients with Behcet's disease and Streptococcus sanguis stimulate membrane expression of hnRNP A2/B1 in endothelial cells. AB - OBJECTIVES: Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 has been identified as a target antigen of anti-endothelial cell immunglobulin (Ig)A antibodies in patients with Behcet's disease (BD). The aim was to investigate the effects of the sera from BD patients and Streptococcus sanguis on the subcellular expression of hnRNP A2/B1 in human dermal microvascular endothelial cells (HDMECs). METHOD: The sera of BD patients and healthy controls (HC) as well as cultured S. sanguis were used to stimulate HDMECs. Subcellular fractions were obtained from stimulated HDMECs and were subjected to immunoblot analyses. The distribution of hnRNP A2/B1 was investigated by immunocytochemistry and direct immunofluorescence study was performed in biopsy specimens of mucosal ulcers from BD patients. RESULTS: BD patients' sera increased the membrane expression of hnRNP A2/B1 in HDMECs after 12 and 24 h of incubation compared with HDMECs incubated with endothelial cell culture media and HC sera. S. sanguis also increased hnRNP A2/B1 in the cellular membrane. hnRNP A2/B1 mRNA level was also significantly upregulated in HDMECs incubated with BD patients' sera and S. sanguis. Immunocytochemistry demonstrated marked expression of hnRNP A2/B1 in the cytoplasm and cellular membrane of HDMECs incubated with BD patients' sera or S. sanguis. In addition, direct immunofluorescence experiments revealed the co localization of serum IgA antibodies and monoclonal antibodies (mAbs) against hnRNP A2/B1 in tissue sections from ulcers of BD patients. CONCLUSIONS: Our data indicate that both the sera of BD patients with active disease and S. sanguis infection are inflammatory stimuli that can induce membranous hnRNP A2/B1 expression in HDMECs. PMID- 23445442 TI - Structure of human telomeric RNA (TERRA): stacking of two G-quadruplex blocks in K(+) solution. AB - Telomeric repeat-containing RNAs (TERRA) are transcription products of the telomeres. Human TERRA sequences containing UUAGGG repeats can form parallel stranded G-quadruplexes. The stacking interaction of such structures was shown to be important for ligand targeting and higher-order arrangement of G-quadruplexes in long TERRA sequences. Here we report on the first high-resolution structure of a stacked G-quadruplex formed by the 10-nucleotide human TERRA sequence r(GGGUUAGGGU) in potassium solution. This structure comprises two dimeric three layer parallel-stranded G-quadruplex blocks, which stack on each other at their 5'-ends. The adenine in each UUA loop is nearly coplanar with the 5'-end G-tetrad forming an A.(G.G.G.G).A hexad, thereby increasing the stacking contacts between the two blocks. Interestingly, this stacking and loop conformation is different from all structures previously reported for the free human TERRA but resembles the structure previously determined for a complex between a human TERRA sequence and an acridine ligand. This stacking conformation is a potential target for drugs that recognize or induce the stacking interface. PMID- 23445443 TI - Occult coronary ostial obstruction late after arterial switch operation. AB - Occult coronary artery obstruction can be a late source of morbidity and mortality following the arterial switch operation for transposition of the great arteries. We describe a case of undiagnosed left coronary ostial obstruction in a teenager which may have contributed to perioperative ventricular dysfunction and subsequent mortality following a reoperation many years after arterial switch. PMID- 23445444 TI - Molecular surface structural changes of plasticized PVC materials after plasma treatment. AB - In this research, a variety of analytical techniques including sum frequency generation vibrational spectroscopy (SFG), coherent anti-Stokes Raman spectroscopy (CARS), and X-ray photoelectron spectroscopy (XPS) have been employed to investigate the surface and bulk structures of phthalate plasticized poly(vinyl chloride) (PVC) at the molecular level. Two types of phthalate molecules with different chain lengths, diethyl phthalate (DEP) and dibutyl phthalate (DBP), mixed with PVC in various weight ratios were examined to verify their different surface and bulk behaviors. The effects of oxygen and argon plasma treatment on PVC/DBP and PVC/DEP hybrid films were investigated on both the surface and bulk of films using SFG and CARS to evaluate the different plasticizer migration processes. Without plasma treatment, SFG results indicated that more plasticizers segregate to the surface at higher plasticizer bulk concentrations. SFG studies also demonstrated the presence of phthalates on the surface even at very low bulk concentration (5 wt %). Additionally, the results gathered from SFG, CARS, and XPS experiments suggested that the PVC/DEP system was unstable, and DEP molecules could leach out from the PVC under low vacuum after several minutes. In contrast, the PVC/DBP system was more stable; the migration process of DBP out of PVC could be effectively suppressed after oxygen plasma treatment. XPS results indicated the increase of C?O/C-O groups and decrease of C-Cl functionalities on the polymer surface after oxygen plasma treatment. The XPS results also suggested that exposure to argon plasma induced chemical bond breaking and formation of cross-linking or unsaturated groups with chain scission on the surface. Finally, our results indicate the potential risk of using DEP molecules in PVC since DEP can easily leach out from the polymeric bulk. PMID- 23445445 TI - Fermentative 2-carbon metabolism produces carcinogenic levels of acetaldehyde in Candida albicans. AB - Acetaldehyde is a carcinogenic product of alcohol fermentation and metabolism in microbes associated with cancers of the upper digestive tract. In yeast acetaldehyde is a by-product of the pyruvate bypass that converts pyruvate into acetyl-Coenzyme A (CoA) during fermentation. THE AIMS OF OUR STUDY WERE: (i) to determine the levels of acetaldehyde produced by Candida albicans in the presence of glucose in low oxygen tension in vitro; (ii) to analyse the expression levels of genes involved in the pyruvate-bypass and acetaldehyde production; and (iii) to analyse whether any correlations exist between acetaldehyde levels, alcohol dehydrogenase enzyme activity or expression of the genes involved in the pyruvate bypass. Candida albicans strains were isolated from patients with oral squamous cell carcinoma (n = 5), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients with chronic oral candidosis (n = 5), and control patients (n = 5). The acetaldehyde and ethanol production by these isolates grown under low oxygen tension in the presence of glucose was determined, and the expression of alcohol dehydrogenase (ADH1 and ADH2), pyruvate decarboxylase (PDC11), aldehyde dehydrogenase (ALD6) and acetyl-CoA synthetase (ACS1 and ACS2) and Adh enzyme activity were analysed. The C. albicans isolates produced high levels of acetaldehyde from glucose under low oxygen tension. The acetaldehyde levels did not correlate with the expression of ADH1, ADH2 or PDC11 but correlated with the expression of down-stream genes ALD6 and ACS1. Significant differences in the gene expressions were measured between strains isolated from different patient groups. Under low oxygen tension ALD6 and ACS1, instead of ADH1 or ADH2, appear the most reliable indicators of candidal acetaldehyde production from glucose. PMID- 23445447 TI - Lab in a tube: ultrasensitive detection of microRNAs at the single-cell level and in breast cancer patients using quadratic isothermal amplification. AB - Through rational design of a functional molecular probe with high sequence specificity that takes advantage of sensitive isothermal amplification with simple operation, we developed a one-pot hairpin-mediated quadratic enzymatic amplification strategy for microRNA (miRNA) detection. Our method exhibits ultrahigh sensitivity toward miR-21 with detection limits of 10 fM at 37 degrees C and 1 aM at 4 degrees C, which corresponds to nine strands of miR-21 in a 15 MUL sample, and it is capable of distinguishing among miRNA family members. More importantly, the proposed approach is also sensitive and selective when applied to crude extractions from MCF-7 and PC3 cell lines and even patient tissues from intraductal carcinoma and invasive ductal carcinoma of the breast. PMID- 23445448 TI - Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8 Triazaspiro[4.5]decane Core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells. AB - An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells. PMID- 23445449 TI - Mesangial cells are responsible for orchestrating the renal podocytes injury in the context of malignant hypertension. AB - AIM: Two populations of renal cells fully possess functional contractile cell apparatus: mesangial cells and podocytes. Previous studies demonstrated that in the context of malignant hypertension overproduction of Angiotensin-II by the contracting mesangial cells aggravated hypercellularity and apoptosis of adjacent cell populations. The role of podocytes in pathogenesis of malignant hypertension is unclear. We investigated responsiveness of normal vs. hyperglycaemic podocytes to pressure in a model of malignant hypertension. METHODS: Rat renal podocytes and mesangial cells were subjected to high hydrostatic pressure, using an in vitro model of malignant hypertension. Part of them was pre-exposed to hyperglycaemic medium. Alternatively, the cells were cultured in conditioned medium collected from mesangial cells pre-exposed to pressure. RESULTS: Angiotensin-II was significantly increased in normoglycaemic mesangial cells subjected to pressure, triggering enhanced proliferation and apoptosis. No augmented Angiotensin-II, proliferation or apoptosis were evident in pressure exposed normoglycaemic podocytes. In hyperglycaemic mesangial cells, but not podocytes, basal Angiotensin-II and apoptosis were augmented, along with abrogated proliferation. Challenge with exogenous Angiotensin-II or Angiotensin II-containing conditioned medium, induced apoptosis both in podocytes and mesangial cells. CONCLUSIONS: 1. Unlike mesangial cells, podocytes do not respond to high pressure or hyperglycaemia per se. Resultantly, neither high pressure nor hyperglycaemia, trigger apoptosis of podocytes in vitro. However, surplus of Angiotensin-II, amply produced in vivo by the adjacent mesangial cells, would seem to be sufficient for initiating apoptosis of both mesangial cells and podocytes. 2. Hyperglycaemia abrogates cell replication. Resultantly, in diabetic patients regeneration of renal tissue damaged by the incidence of malignant hypertension may become compromised or completely lost. PMID- 23445450 TI - Functional, biochemical and 3D studies of Mycobacterium tuberculosis protein peptides for an effective anti-tuberculosis vaccine. AB - Tuberculosis (TB) is an air-born, transmissible disease, having an estimated 9.4 million new TB cases worldwide in 2009. Eventual control of this disease by developing a safe and efficient new vaccine able to detain its spread will have an enormous impact on public health policy. Selecting potential antigens to be included in a multi-epitope, minimal subunit-based, chemically-synthesized vaccine containing the minimum sequences needed for blocking mycobacterial interaction with host cells is a complex task due to the multiple mechanisms involved in M. tuberculosis infection and the mycobacterium's immune evasion mechanisms. Our methodology, described here takes into account a highly robust, specific, sensitive and functional approach to the search for potential epitopes to be included in an anti-TB vaccine; it has been based on identifying short mycobacterial protein fragments using synthetic peptides having high affinity interaction with alveolar epithelial cells (A549) and monocyte-derived macrophages (U937) which are able to block the microorganism's entry to target cells in in vitro assays. This manuscript presents a review of the results obtained with some of the MTB H37Rv proteins studied to date, aimed at using these high activity binding peptides (HABPs) as platforms to be included in a minimal subunit-based, multiepitope, chemically-synthesized, antituberculosis vaccine. PMID- 23445451 TI - Epstein-Barr virus associated smooth muscle tumors in post transplant pediatric patients two cases of rare locations, and review of the literature. AB - Epstein-Barr virus (EBV) may present few or no symptoms in immunocompetent individuals; however, in immunocompromised patients as in the case of AIDS and post-transplant patients, the virus occasionally stimulates neoplastic transformations. Epstein-Barr virus may play a role in the development of smooth muscle tumors (SMT). In the case of Epstein-Barr associated smooth muscle tumors (EBV+SMT), the virus is thought to be the leading factor to the tumorigenic pathway. We report two pediatric patients (6 and 13 years old) who underwent liver transplantation and developed EBV+SMT in the colon and orbit. These two cases represent rare locations for this kind of lesion. PMID- 23445452 TI - Fetal autopsy of Meckel Gruber syndrome -a case report. AB - Meckel Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post-axial polydactyly. One such rare case at 28 weeks of gestation was terminated and its case report with the phenotypic features, fetal autopsy and histo-pathological examination are discussed. PMID- 23445453 TI - A dual mode pulsed electro-magnetic cell stimulator produces acceleration of myogenic differentiation. AB - This paper presents the design and test of a dual-mode electric and magnetic biological stimulator (EM-Stim). The stimulator generates pulsing electric and magnetic fields at programmable rates and intensities. While electric and magnetic stimulators have been reported before, this is the first device that combines both modalities. The ability of the dual stimulation to target bone and muscle tissue simultaneously has the potential to improve the therapeutic treatment of osteoporosis and sarcopenia. The device is fully programmable, portable and easy to use, and can run from a battery or a power supply. The device can generate magnetic fields of up to 1.6 mT and output voltages of +/- 40 V. The EM-Stim accelerated myogenic differentiation of myoblasts into myotubes as evidenced by morphometric, gene expression, and protein content analyses. Currently, there are many patents concerned with the application of single electrical or magnetic stimulation, but none that combine both simultaneously. However, we applied for and obtained a provisional patent for new device to fully explore its therapeutic potential in pre-clinical models. PMID- 23445454 TI - Social Communication Impairs Working-Memory Performance. AB - Performance on working-memory tests is frequently used in experimental psychology and neuroscience, as well as in neuropsychological testing and clinical screening. It can be strongly affected by the social context and the communication style of the experimenter. We tested this hypothesis in two experiments, examining standardized neuropsychological working-memory tests in different social communication contexts. Our results show that the more ostensive communication context (eye contact, exaggerated intonation contours) impairs working-memory performance. These results draw attention to the fact that the communication style of the examiner could have a robust effect on working-memory performance and could even modify clinical diagnosis. PMID- 23445455 TI - Nursing home staffing requirements and input substitution: effects on housekeeping, food service, and activities staff. AB - OBJECTIVE: To study the effect of minimum nurse staffing requirements on the subsequent employment of nursing home support staff. DATA SOURCES: Nursing home data from the Online Survey Certification and Reporting (OSCAR) System merged with state nurse staffing requirements. STUDY DESIGN: Facility-level housekeeping, food service, and activities staff levels are regressed on nurse staffing requirements and other controls using fixed effect panel regression. DATA EXTRACTION METHOD: OSCAR surveys from 1999 to 2004. PRINCIPAL FINDINGS: Increases in state direct care and licensed nurse staffing requirements are associated with decreases in the staffing levels of all types of support staff. CONCLUSIONS: Increased nursing home nurse staffing requirements lead to input substitution in the form of reduced support staffing levels. PMID- 23445456 TI - The effects of cryosolvents on DOPC-beta-sitosterol bilayers determined from molecular dynamics simulations. AB - Polyhydroxylated alcohols and DMSO are common cryosolvents that can damage cell membranes at sufficiently high concentrations. The interaction of representative plant cell membranes composed of mixed 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)-beta-sitosterol bilayers, at a range of compositions, with a variety of cryosolvent molecules (DMSO, propylene glycol, ethylene glycol, glycerol, and methanol) has been investigated using molecular dynamics simulations. All the cryosolvents cause the bilayers to thin and become disordered; however, DMSO and propylene glycol have a greater disordering effect on the bilayer. Propylene glycol is shown to have the ability to cause the formation of pores in pure DOPC bilayers in a manner similar to that previously shown for DMSO. As the concentration of beta-sitosterol within the bilayer increases, the membranes become more resistant to the deleterious effects of the cryosolvents. All three polyhydroxylated species are observed to form hydrogen bonds to multiple phospholipid molecules, effectively acting as cross-linkers, with glycerol being the most effective cross-linker. Increases in the concentration of beta sitosterol reduce overall hydrogen bonding of the bilayer with the cryosolvents as well as cross-linking, with glycerol and ethylene glycol being the most affected. The ability of all of these cryosolvents to affect the integrity of cell membranes appears to be the result of the balance of their ability to disorder lipid bilayers, to diffuse across them, and to interact with the lipid head groups. PMID- 23445457 TI - Conscientious refusals and reason-giving. AB - Some philosophers have argued for what I call the reason-giving requirement for conscientious refusal in reproductive healthcare. According to this requirement, healthcare practitioners who conscientiously object to administering standard forms of treatment must have arguments to back up their conscience, arguments that are purely public in character. I argue that such a requirement, though attractive in some ways, faces an overlooked epistemic problem: it is either too easy or too difficult to satisfy in standard cases. I close by briefly considering whether a version of the reason-giving requirement can be salvaged despite this important difficulty. PMID- 23445459 TI - Three-dimensional chemical mapping with a confocal XRF setup. AB - A new approach for the nondestructive reconstruction of stratified systems with constant elemental composition but with varying chemical compounds has been developed. The procedure is based on depth scans with a confocal X-ray fluorescence setup at certain energies near absorption edges. These so-called marker energies, where XAFS signals of the involved chemical compounds differ significantly, can also be used to uncover the chemical composition and its topology. A prominent field of application is homogeneous material that is degraded due to chemical reactions like oxidation or reduction. A procedure for the semiquantitative reconstruction of stratified material by means of depth scans at marker energies is elaborated and validated and a three-dimensional mapping is presented. PMID- 23445458 TI - A highly accurate heuristic algorithm for the haplotype assembly problem. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation in human DNA. The sequence of SNPs in each of the two copies of a given chromosome in a diploid organism is referred to as a haplotype. Haplotype information has many applications such as gene disease diagnoses, drug design, etc. The haplotype assembly problem is defined as follows: Given a set of fragments sequenced from the two copies of a chromosome of a single individual, and their locations in the chromosome, which can be pre-determined by aligning the fragments to a reference DNA sequence, the goal here is to reconstruct two haplotypes (h1, h2) from the input fragments. Existing algorithms do not work well when the error rate of fragments is high. Here we design an algorithm that can give accurate solutions, even if the error rate of fragments is high. RESULTS: We first give a dynamic programming algorithm that can give exact solutions to the haplotype assembly problem. The time complexity of the algorithm is O(n * 2t * t), where n is the number of SNPs, and t is the maximum coverage of a SNP site. The algorithm is slow when t is large. To solve the problem when t is large, we further propose a heuristic algorithm on the basis of the dynamic programming algorithm. Experiments show that our heuristic algorithm can give very accurate solutions. CONCLUSIONS: We have tested our algorithm on a set of benchmark datasets. Experiments show that our algorithm can give very accurate solutions. It outperforms most of the existing programs when the error rate of the input fragments is high. PMID- 23445460 TI - Magnetic resonance laparoscopy: A new non-invasive technique for the assessment of chronic viral liver disease. AB - AIM: Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus. METHODS: We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis. RESULTS: The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child Pugh classification. CONCLUSION: Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis. PMID- 23445462 TI - To err or to guess: an ERP study on the source of errors. AB - Given the large contribution of human error in the failure of complex systems, understanding the source of errors is an important issue. It has been proposed that, in speeded situations, responses biases induce subjects to guess which response will be required. When the guess turns out to be wrong, a fast guess error occurs. In unbiased conditions the possible contribution of fast guess errors remains an open question. We used a response-locked event-related potential (N-40), assumed to reveal the presence of a response selection process during the reaction time, to probe the presence of a response selection in biased and unbiased situations. The N-40 was present without response bias but absent in biased situations. This lends physiological support to the idea that, in a priming paradigm as used here, most errors in biased conditions are fast guesses whereas most errors result from inappropriate response selections in unbiased conditions. This reveals different sources of errors. PMID- 23445461 TI - Vacuum assisted vegetation extraction for the management of large lead vegetations. AB - BACKGROUND: Complete device and lead removal is recommended for management of infected implantable cardiac device. Management of large lead vegetation (2 cm) is still in debate. METHODS: We report a series of patients involving percutaneous extraction of large vegetations (>2 cm) from ICD/pacing leads using the AngioVac Cannula in patients with infective endocarditis. This approach was used to debulk the ICD/pacing lead vegetations in order to minimize the risk of septic pulmonary embolism during lead explantation. CONCLUSION: AngioVac Cannula can be used safely and effectively as an adjunctive method for patients with large lead vegetation. PMID- 23445463 TI - Risk factors of erectile dysfunction in patients receiving methadone maintenance therapy. AB - INTRODUCTION: While methadone effectively treats opiate dependence, the side effect of erectile dysfunction (ED) may interfere with treatment adherence and benefits. AIM: To determine the rate of ED and the associated factors which predict ED in male patients on methadone maintenance therapy (MMT) in a Malaysian population. MAIN OUTCOME MEASURES: The main outcome measures were the International Index of Erectile Function-15 (IIEF-15) and the Beck Depression Inventory (BDI). METHODS: A total of 108 participants diagnosed with heroin dependence were assessed. We used the Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) on subjects who received MMT, and they were assessed using the IIEF-15, the BDI, and measures of other clinical and sociodemographic variables. RESULTS: The rate of ED among men on MMT was 68.5% (mild ED, 36.1%; mild to moderate ED, 22.2%; severe ED, 3.7%). The mean age of the participants was 43.45 years. Older age (P = 0.002), concurrent illicit heroin use (P = 0.024), and having an older partner (P = 0.039) were significantly associated with ED. Following multivariate analysis, it was found that older age was the only significant predictor of ED, with an adjusted odds ratio of 1.07 (95% CI = 1.02-1.16). Methadone dose and duration of methadone treatment were not significantly associated with ED. CONCLUSION: ED was highly prevalent among male patients on MMT. This suggests that there is a need for routine assessment of sexual function in patients on methadone. Among the risk factors, age was the only factor that was significantly associated with ED. The current use of MMT in Malaysia in terms of dosage and duration did not pose a significant risk for ED. PMID- 23445464 TI - Assessment of mastication in healthy children and children with cerebral palsy: a validity and consistency study. AB - The aim of this study was to develop the Mastication Observation and Evaluation instrument for observing and assessing the chewing ability of children eating solid and lumpy foods. This study describes the process of item definition and item selection and reports the content validity, reproducibility and consistency of the instrument. In the developmental phase, 15 experienced speech therapists assessed item relevance and descriptions over three Delphi rounds. Potential items were selected based on the results from a literature review. At the initial Delphi round, 17 potential items were included. After three Delphi rounds, 14 items that regarded as providing distinctive value in assessment of mastication (consensus >75%) were included in the Mastication Observation and Evaluation instrument. To test item reproducibility and consistency, two experts and five students evaluated video recordings of 20 children (10 children with cerebral palsy aged 29-65 months and 10 healthy children aged 11-42 months) eating bread and a biscuit. Reproducibility was estimated by means of the intraclass correlation coefficient (ICC). With the exception of one item concerning chewing duration, all items showed good to excellent intra-observer agreement (ICC students: 0.73-1.0). With the exception of chewing duration and number of swallows, inter-observer agreement was fair to excellent for all items (ICC experts: 0.68-1.0 and ICC students: 0.42-1.0). Results indicate that this tool is a feasible instrument and could be used in clinical practice after further research is completed on the reliability of the tool. PMID- 23445465 TI - Osteonecrosis of the jaw after implant surgery in patients treated with bisphosphonates--a presentation of six consecutive cases. AB - BACKGROUND: Osteonecrosis of the jaws in patients treated with bisphosphonates is mostly associated with intravenous bisphosphonates while the incidence associated with oral bisphosphonates is not significant. PURPOSE: The purpose of this paper is to describe a series of cases of jaw osteonecrosis that may be associated with dental implant placement in patients who had taken nitrogen containing bisphosphonates via oral and/or intravenous route. PATIENTS: Six female patients were treated for osteonecrosis of the jaw after implant placement. An average age was 71.8 +/- 6.5 years old and they had a history of bisphosphonate use. Two patients suffered from cancer and the other patients had osteoporosis. Two osteoporosis patients had taken only oral bisphosphonate and the other patients received intravenous bisphosphonates. RESULTS: Resection of necrotized bone, implant removal, and primary closure were performed in five patients and four patients showed uneventful healing. One patient presented recurrence at the maxilla and underwent further extraction and resection. One patient presented with an exposure of the bone after implant placement was treated with an advanced flap closure, and the implants were preserved. CONCLUSION: Unusual jaw necrosis after dental implant surgery might be related with oral and/or intravenous bisphosphonates. Wide resection of necrotic bone, collagen graft, and primary closure are key factors for successful healing. PMID- 23445466 TI - Dehydrogenation of benzene on liquid Al100(+). AB - The reactions of benzene on Al100(+) have been investigated as a function of cluster temperature (300-1100 K) and relative kinetic energy (1-14 eV) by low energy ion-beam methods and mass spectrometry. Benzene chemisorbs on both solid and liquid aluminum clusters to generate Al100C6D6(+). A series of Al(100-n)(+) (n = 1, 2, 3, ...) products was also observed. As the cluster temperature was raised above the melting temperature of Al100(+), the Al100C6D6(+) product dehydrogenates to form Al100C6D4(+), Al100C6D2(+), and Al100C6(+). The degree of dehydrogenation was measured as a function of temperature. Very little Al100C6D2(+) was observed, suggesting that the losses of the second and third D2 molecules are coordinated. PMID- 23445467 TI - Phase inversion of emulsions containing a lipophilic surfactant induced by clay concentration. AB - Emulsions stabilized by clay particles and sorbitan monooleate (Span 80) were investigated, and an abnormal phase inversion was observed by increasing the concentration of clay particles in the aqueous phase. At a fixed concentration of Span 80 in the oil phase, the emulsions were oil-in-water (o/w) when the concentration of clay particles in the aqueous phase was low. Surprisingly, the emulsion inverted to water-in-oil (w/o) when the concentration of the hydrophilic clay particles was increased. On the basis of the results of rheological measurements and laser-induced fluorescent confocal microscopy observation, we suggest that this phase inversion is induced by the gel structures formed at high concentration of clay particles. The effects of clay concentration on the stability and the droplet size of these emulsions were also investigated. PMID- 23445468 TI - Photo-initiated thiol-ene click reactions as a potential strategy for incorporation of [M(I)(CO)3]+ (M = Re, (99m)Tc) complexes. AB - Click reactions offer a rapid technique to covalently assemble two molecules. In radiopharmaceutical construction, these reactions can be utilized to combine a radioactive metal complex with a biological targeting molecule to yield a potent tool for imaging or therapy applications. The photo-initiated radical thiol-ene click reaction between a thiol and an alkene was examined for the incorporation of [M(I)(CO)3](+) (M = Re, (99m)Tc) systems for conjugating biologically active targeting molecules containing a thiol. In this strategy, a potent chelate system, 2,2'-dipicolylamine (DPA), for [M(I)(CO)3](+) was functionalized at the central amine with a terminal alkene linker that was explored with two synthetic approaches, click then chelate and chelate then click, to determine the flexibility and applicability of the thiol-ene click reaction to specifically incorporate ligand systems and metal complexes with a thiol containing molecule. In the click then chelate approach, the thiol-ene click reaction was carried out with the DPA chelate followed by complexation with [M(I)(CO)3](+). In the chelate then click approach, the alkene functionalized DPA chelate was first complexed with [M(I)(CO)3](+) followed by the conduction of the thiol-ene click reaction. Initial studies utilized benzyl mercaptan as a model thiol for both strategies to generate the identical product from either route to provide information on reactivity and product formation. DPA ligands functionalized with two unique linker systems (allyl and propyl allyl ether) were prepared to examine the effect of the proximity of the chelate or complex on the thiol-ene click reaction. Both the thiol-ene click and coordination reactions with Re, (99m)Tc were performed in moderate to high yields demonstrating the potential of the thiol-ene click reaction for [M(I)(CO)3](+) incorporation into thiol containing biomolecules. PMID- 23445469 TI - Feline sarcoma-related protein expression correlates with malignant aggressiveness and poor prognosis in renal cell carcinoma. AB - Feline sarcoma-related protein (Fer) is a ubiquitously expressed non-receptor protein tyrosine kinase associated with proliferation in various cancer cells. However, no reports have described the pathological roles and prognostic value of Fer expression in renal cell carcinoma (RCC). We investigated Fer expression in three RCC cell lines (ACHN, Caki-1, and Caki-2) and in normal tubule cells (HK-2) by immunoblotting. Fer expression was highest in ACHN cells, with Caki-1 showing intermediate levels and Caki-2 showing low levels, and was undetectable in HK-2. RNA interference was therefore used to assess the effects of Fer knockdown in ACHN. Knockdown of Fer expression was found to inhibit RCC cell proliferation and colony formation. Immunohistochemical analysis of 131 human RCC tissues (110 conventional, 11 chromophobe, and 10 papillary) investigated relationships between Fer expression and clinicopathological features, including cancer cell proliferation, apoptosis, and prognostic value for survival. In human tissues, Fer expression was significantly higher in cancer cells than in normal tubules. In addition, expression levels correlated with cancer cell proliferation, but not with apoptosis. Multivariate analysis indicated associations of Fer expression with pT stage, tumor grade, and metastasis (P < 0.001). Fer expression was also prognostic for cause-specific survival according to multivariate analysis (hazard ratio, 3.89; 95% confidence interval, 1.02-14.84, P = 0.047). Fer expression correlates with RCC cell proliferation both in vitro and in vivo, and with tumor progression and survival. This represents useful information for discussing the pathological and clinical significance of Fer in RCC. PMID- 23445470 TI - Synergy between essential oil components and antibiotics: a review. AB - With the increase in antibiotic-resistant bacteria and the lack of new antibiotics being brought onto the market, alternative strategies need to be found to cope with infections resulting from drug-resistant bacteria. A possible solution may be to combine existing antibiotics with phytochemicals to enhance the efficacy of antibiotics. A group of phytochemicals that is said to have such effects, according to in vitro studies, is essential oils (EOs) and their components. Amongst others, EOs containing carvacrol, cinnamaldehyde, cinnamic acid, eugenol and thymol can have a synergistic effect in combination with antibiotics. Several modes of action have been put forward by which antibiotics and the essential oil components may act synergistically, such as by affecting multiple targets; by physicochemical interactions and inhibiting antibacterial resistance mechanisms. Many reported assays show additivity or moderate synergism, indicating that EOs may offer possibilities for reducing antibiotic use. PMID- 23445472 TI - Social perception in borderline personality disorder: the role of context. AB - The purpose of this study was to examine social and nonsocial context processing in persons with borderline personality disorder (BPD). A secondary goal was to examine social perception in this population. The performance of 23 individuals with DSM-IV-diagnosed BPD was compared to a nonclinical control sample of 40 individuals. The participants were asked to perform both a social perceptual task that requires social context processing and a nonsocial context processing task. Social perception was examined using the Profile of Nonverbal Sensitivity (PONS). The results demonstrate that the group with BPD was impaired on all tasks relative to the control group. Yet their reaction time improved when provided with social context. Implications for future research are discussed. PMID- 23445471 TI - Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction. AB - On the basis of an initial molecular modeling study suggesting the favorable binding of the "privileged" fragment 8-hydroxyquinoline with HIV-1 integrase (IN) at the IN-lens epithelium-derived growth factor/p75 (LEDGF/p75) interface , we developed a set of modified 8-hydroxyquinoline fragments demonstrating micromolar IC50 values for inhibition of the IN-LEDGF/p75 interaction, but significant cytotoxicity was associated with these initial compounds. Diverse modifications at the C5 and C7 carbons of the 8-hydroxyquinoline core improved potency, but reduction of diversity to only modifications at the C5 position ultimately yielded potent inhibitors with low cytotoxicity. Two of these particular compounds, 5-((p-tolylamino)methyl)quinolin-8-ol and 5-(((3,4 dimethylphenyl)amino)methyl)quinolin-8-ol, inhibited viral replication in MT-4 cells with low micromolar EC50. This is the first study providing evidence for 8 hydroxyquinolines as novel inhibitors of the IN-LEDGF/p75 interaction. Our lead compounds are druglike, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity. PMID- 23445474 TI - How to measure quality of life for cost-effectiveness analyses of personality disorders: a systematic review. AB - A systematic review was undertaken to assess the construct validity and responsiveness of four generic health-related quality of life (HRQL) measures in personality disorders (PDs). Ten databases were searched and reference lists scrutinized to identify relevant studies. Relevant data were extracted accordingly. A narrative synthesis was performed of the evidence on construct validity, including known groups validity (detecting differences in HRQL scores between two different groups), convergent validity (strength of association between generic HRQL), and other measures (e.g., symptom) and responsiveness (differences in generic HRQL measure scores in responders/nonresponders or correlation with changes in other measures). Ten studies were identified: six of the EQ-5D, two involving the SF-36, and another two the SF-12, but none with the SF-6D. Evidence indicated that the EQ-5D, SF-36, and SF-12 were probably valid measures with PDs. Four studies demonstrated that the EQ-5D Index was able to detect changes in patients. The authors conclude that generic HRQL measures appear appropriate for use with people with PDs in terms of psychometric performance. However, qualitative concerns remain as to whether they fully reflect the impact of the condition. PMID- 23445476 TI - Executive functioning in people with obsessive-compulsive personality traits: evidence of modest impairment. AB - Investigations of executive dysfunctions among people with obsessive-compulsive personality disorders (OCPD) have yielded inconsistent results. The authors speculate that obsessive-compulsive personality traits (OCPT) from a nonclinical population may be associated with specific executive dysfunctions relative to working memory, attentional set-shifting, and planning. A sample consisting of 79 adults (39 females, 40 males) was divided into high and low scorers on the Personality Diagnostic Questionnaire-4 (PDQ-4; Hyler, 1994). In addition, these participants were interviewed using the SCID-II (First, Spitzer, Gibbon & Williams, 1997) to confirm the presence of symptoms of obsessive-compulsive personality. Participants completed a battery of executive tasks associated with the Cambridge Neuropsychological Test Automated Battery (CANTAB), including Spatial Working Memory, Intradimensional/Extradimensional (ID/ED), Attentional Set-Shifting, and Stockings of Cambridge. Also, self-report measures of executive functions as well as of anxiety and depressive symptoms were administered. The analysis of covariance revealed significant differences between participants with OCPT and controls on the Spatial Working Memory tasks, ID/ED tasks, Stockings of Cambridge, and the Dysexecutive Questionnaire (DEX). Nevertheless, there were no significant differences in the number of problems solved in minimum movements. These results suggest that executive dysfunctions are present in people with prominent OCPT and that there is a high convergence between clinical and ecological measures of executive functions in people with obsessive personality traits. PMID- 23445475 TI - The relationship between childhood adversity and dysphoric inner states among borderline patients followed prospectively for 10 years. AB - Childhood experiences of abuse and neglect were assessed in relation to dysphoric states among patients with borderline personality disorder (BPD) over a 10-year course of prospective follow-up. The Revised Childhood Experiences Questionnaire was administered at baseline to 290 patients meeting DIB-R and DSM-III-R criteria for BPD. The Dysphoric Affect Scale--a 50-item self-report measure of affective and cognitive states thought to be common among and specific to borderline patients--was administered at fives waves of prospective follow-up. Significant predictors of dysphoric states included emotional abuse, verbal abuse, physical abuse, sexual abuse, emotional withdrawal, inconsistent treatment, denial of patient's feelings, lack of a real relationship, placing patient in parental role, and failure to protect patient. This suggests that abusive and neglectful childhood experiences are significant risk factors for severe affective and cognitive difficulties reported by borderline patients and that sexual abuse is neither necessary nor sufficient for the development of these troubling inner states. PMID- 23445477 TI - Food consumption as affect modulation in borderline personality. AB - The present study examined relationships among negative affect, borderline personality features, and eating behavior through the experimental manipulation of mood. Undergraduate women (N = 307) completed a baseline mood assessment, viewed a 39-minute sad film either with or without concurrent food presentation, then completed a second mood assessment and questionnaires assessing personality and eating attitudes/behaviors. Women reporting more borderline personality features exhibited greater negative affect across time and were more reactive to the sad film. Food presentation appeared to have a small ameliorative effect on sadness and general negative affect. However, quantity of food consumption was associated with improvements in mood only for women reporting higher levels of borderline personality features. These data suggest that women with borderline personality characteristics may be at elevated risk for developing problems with binge eating, because consuming larger quantities of food appeared to have a tempering effect on their negative mood and feelings of sadness. PMID- 23445478 TI - Radiation therapy resources and guideline-concordant radiotherapy for early-stage breast cancer patients in an underserved region. AB - OBJECTIVE: To examine the relationship between radiation therapy resources and guideline-concordant radiotherapy after breast-conserving surgery (BCS) in Kentucky. DATA SOURCES: The SEER registry and Area Resource File provided county level data describing cancer care resources and socioeconomic conditions of Kentucky residents. STUDY DESIGN: The outcome variable was rate of BCS without radiotherapy in each county for 2000-2007. Eight-year weighted average rates of radiation therapy providers and hospitals per 100,000 residents were explanatory variables of interest. Exploratory spatial data analyses and spatial econometric models were estimated. PRINCIPAL FINDINGS: Appalachian counties in Kentucky had significantly fewer radiation oncologists, hospitals with radiation therapy facilities, and surgeons per 100,000 residents than non-Appalachian counties. The likelihood of BCS without radiation was significantly higher among Appalachian compared to non-Appalachian women (42.5 percent vs. 29.0 percent, p < .001). Higher proportions of women not receiving recommended radiotherapy after BCS were clustered in Eastern Kentucky around Lexington. This geographic disparity was partially explained by significantly fewer radiation therapy facilities in Appalachian Kentucky in adjusted analyses. CONCLUSIONS: Scarce radiation therapy resources in Appalachian Kentucky are associated with disparities in receipt of guideline-concordant radiotherapy, suggesting that policy action is needed to improve the cancer treatment infrastructure in disadvantaged mountainous areas. PMID- 23445479 TI - Monoclonal antibody-based fluorescence polarization immunoassay for high throughput screening of furaltadone and its metabolite AMOZ in animal feeds and tissues. AB - A simple and fast homogeneous fluorescent polarization immunoassay (FPIA) was developed for the determination of furaltadone and its metabolite 3-amino-5 methylmorpholino-2-oxazolidinone (AMOZ). Monoclonal antibody with high cross reactivity to furaltadone and the nitrophenyl derivative of AMOZ (NPAMOZ) were produced against a novel immunogen and the effects of several synthesized tracers on FPIA sensitivity studied. The proposed FPIA, using an optimum antibody and tracer pair, had an IC50 of 4.3 ug L-1 and limit of detection at 0.6 ug L-1 for furaltadone, and 2.7 ugL-1 and 0.3 ug L-1 for NPAMOZ. Recoveries of furaltadone from animal feeds by FPIA ranged from 79.6 to 87.7%, while recoveries of AMOZ from animal tissues ranged from 72.9 to 83.1%. Good correlation (R>0.99) between the results of this FPIA and a standard analytical method was obtained. The FPIA does not require separation or washing steps and the total time required for equilibrium of the antibody-tracer interaction is only 10 min. These results indicated that the proposed FPIA offers great potential and utility for the high throughput screening of furaltadone residues in animal feed and its metabolite AMOZ residues in animal tissues. PMID- 23445481 TI - Thirty-day mortality after coronary artery bypass surgery in patients aged <50 years: results of a multicenter study and meta-analysis of the literature. AB - BACKGROUND: Young patients requiring myocardial revascularization are considered at low operative risk, but data on their outcome are scarce. This study was undertaken to evaluate the prevalence and 30-day mortality of patients aged <50 years after isolated coronary artery bypass surgery (CABG). MATERIALS AND METHODS: This is a multicenter study including 2207 patients aged <50 years undergoing isolated CABG at 68 Italian hospitals. RESULTS: The proportion of patients aged <50 years in this series was 5.3% and varied significantly from 0% to 9.9% in different institutions (p < 0.0001). The 30-day mortality rate was 0.9%. One-to-one propensity score matching of patients aged <50 years versus older patients resulted in 2013 pairs whose 30-day mortality was 0.9% and 2.2%, respectively (p = 0.001). Logistic regression showed that left ventricular ejection fraction <30% (OR 5.5, 95% CI 1.6-18.6), peripheral vascular disease (OR 3.6, 95% CI 1.1-12.0), pulmonary hypertension (OR 18.1, 95% CI 1.8-187.0), critical preoperative state (OR 4.7, 95% CI 1.5-14.3), and emergency operation (OR 3.8, 95% CI 1.1-12.9) were independent predictors of 30-day mortality. Meta analysis of five studies reporting on patients aged <50 years who underwent isolated CABG showed that operative mortality in these patients was 0.9% (95% CI, 0.8-1.1%, I(2) 0%, 135/14,316 patients). CONCLUSIONS: The proportion of patients aged <50 years undergoing CABG is low and varies significantly among institutions. The results of this study and a meta-analysis of the literature data showed that CABG can be carried out in young patients with an extremely low risk of operative mortality. PMID- 23445483 TI - Examining Cognitive Status of Elderly Iranians: Farsi Version of the Modified Mini-Mental State Examination. AB - The Modified Mini-Mental State Examination (3MS) is an expanded and modified version of the Mini-Mental State Examination (MMSE). Research demonstrates that the reliability, validity, specificity, and sensitivity of the 3MS are superior to that of the MMSE in detecting cognitive impairment. The Farsi version of the 3MS (F-3MS) was examined as a screening tool for dementia among elderly Iranians. The F-3MS and the Clock Drawing Test (CDT) were administered to 58 patients with dementia and 145 control subjects with normal cognition, aged 60 to 85 years. The difference between groups on the mean total scores of the F-3MS was statistically significant (dementia = 60.65 +/- 9.89, control = 80.73 +/- 8.26; df = 201, t = 14.75, p < .001). The receiver-operating characteristic curve showed 78 as the optimal cutoff point for detecting dementia, with a sensitivity of 98% and specificity of 81%. Interrater reliability was high (n = 50, r = .91, p < .001), as were test-retest reliability (n = 50, r = .89, p < .001) and internal consistency (a = .85). The F-3MS correlated strongly with the CDT, supporting convergent validity of the F-3MS. The F-3MS can be used as a valid and reliable measure for dementia screening among elderly Iranians. PMID- 23445482 TI - Synthesis and characterization of a novel inhibitor of C-reactive protein mediated proinflammatory effects. AB - BACKGROUND: Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead-one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP. METHODS: Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase "split/mix" approach. RESULTS: By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-kappaB (NFkappaB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca(2+) ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding. CONCLUSIONS: Future studies will examine the utility of this inhibitor in animal models and clinical trials. PMID- 23445484 TI - Paediatricians' decision making about prescribing stimulant medications for children with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is now the most common reason for a child to present to a paediatrician in Australia. Stimulant medications are commonly prescribed for children with ADHD, to reduce symptoms and improve function. In this study we investigated the factors that influence paediatricians' decisions about prescribing stimulant medications. METHOD: In depth, semi-structured interviews were conducted with paediatricians (n = 13) who were purposively recruited so as to sample a broad demographic of paediatricians working in diverse clinical settings. Paediatricians were recruited from public outpatient and private paediatrician clinics in Victoria, Australia. The interviews were audio-recorded and transcribed verbatim for thematic analysis. Paediatricians also completed a questionnaire describing their demographic and practice characteristics. RESULTS: Our findings showed that the decision to prescribe is a dynamic process involving two key domains: (1) weighing up clinical factors; and (2) interacting with parents and the patient along the journey to prescribing. Five themes relating to this process emerged from data analysis: comprehensive assessments that include history, examination and information from others; influencing factors such as functional impairment and social inclusion; previous success; facilitating parental understanding including addressing myths and parental confusion; and decision-making model. CONCLUSIONS: Paediatricians' decisions to prescribe stimulant medications are influenced by multiple factors that operate concurrently and interdependently. Paediatricians do not make decisions about prescribing in isolation; rather, they actively involve parents, teachers and patients, to arrive at a collective, well-informed decision. PMID- 23445485 TI - Ataxia-telangiectasia mutated kinase-mediated upregulation of NKG2D ligands on leukemia cells by resveratrol results in enhanced natural killer cell susceptibility. AB - The powerful activating receptor NKG2D is expressed by natural killer (NK) cells and promotes cytotoxic lysis of cancer cells expressing NKG2D ligands (NKG2D-Ls). We report the effective induction of NKG2D-Ls, achieved with the naturally occurring polyphenol resveratrol, in a broad range of leukemia cells. In this study, resveratrol upregulated the NKG2D-Ls MHC class I chain-related proteins MICA and MICB, and UL16-binding proteins ULBP1, ULBP2, and ULBP3 in most of the leukemia cells analyzed. Ligand upregulation induced by resveratrol was impaired by pharmacological and genetic disruption of ataxia-telangiectasia mutated kinase, the main regulator of NKG2D-L expression. Leukemia cells treated with resveratrol were more susceptible to killing by NK cells than untreated cells, and the enhanced cytotoxicity of NK cells was blocked by treatment of NK cells with anti-NKG2D mAbs. Interestingly, resveratrol consistently upregulated the NKG2D receptor expression and enhanced NKG2D-mediated functions in resting NK cells obtained from healthy individuals. Therefore, resveratrol has attractive immunotherapeutic potential. PMID- 23445486 TI - The effect of whole-body cooling on hematological and coagulation parameters in asphyxic newborns. AB - Although moderate therapeutic hypothermia is the only proven neuroprotective therapy in neonatal hypoxic ischemic encephalopathy secondary to perinatal asphyxia (PA), there is lack of data for its effect on hemostasis. To investigate the effect of neonatal asphyxia on hemostasis and to evaluate the effect of whole body cooling on hematological parameters. Hematological parameters evaluated on the first day of patients with PA before start of hypothermia were compared with those of healthy controls. The effects of whole body cooling on the same parameters were also evaluated on the fourth day. A total of 17 neonates with PA and 15 healthy controls were included. Mean values for prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and d-dimer obtained on the first day were significantly higher in the PA group compared to healthy controls (P <= .001 for all comparisons), whereas platelet count, levels of fibrinogen, factors II, V, VII, IX, X, and XI were significantly lower (P <= .005 for all comparisons). Levels of factor XIII were normal in both groups. In the study group, mean values for PT, INR, aPTT, and d dimer evaluated on postnatal day 4 were significantly lower compared to values obtained on the first day of birth in PA group (P < .05 for all comparisons), with statistically significant increases in mean levels of fibrinogen, factor II, V, VII, IX, X, and XII (P < .05 for all comparisons). PA results in significant reductions in levels of factors of the extrinsic pathway and has been associated with thrombocytopenia and disseminated intravascular coagulation. Hypothermia may actually improve the clinical picture in such patients rather than aggravating the hemostatic disturbance, particularly with the implementation of supportive treatment. PMID- 23445487 TI - The Ca(2+) -binding protein PCaP2 located on the plasma membrane is involved in root hair development as a possible signal transducer. AB - Plasma membrane-associated Ca(2+) -binding protein-2 (PCaP2) of Arabidopsis thaliana is a novel-type protein that binds to the Ca(2+) /calmodulin complex and phosphatidylinositol phosphates (PtdInsPs) as well as free Ca(2+) . Although the PCaP2 gene is predominantly expressed in root hair cells, it remains unknown how PCaP2 functions in root hair cells via binding to ligands. From biochemical analyses using purified PCaP2 and its variants, we found that the N-terminal basic domain with 23 amino acids (N23) is necessary and sufficient for binding to PtdInsPs and the Ca(2+) /calmodulin complex, and that the residual domain of PCaP2 binds to free Ca(2+) . In mutant analysis, a pcap2 knockdown line displayed longer root hairs than the wild-type. To examine the function of each domain in root hair cells, we over-expressed PCaP2 and its variants using the root hair cell-specific EXPANSIN A7 promoter. Transgenic lines over-expressing PCaP2, PCaP2(G2A) (second glycine substituted by alanine) and ?23PCaP2 (lacking the N23 domain) exhibited abnormal branched and bulbous root hair cells, while over expression of the N23 domain suppressed root hair emergence and elongation. The N23 domain was necessary and sufficient for the plasma membrane localization of GFP-tagged PCaP2. These results suggest that the N23 domain of PCaP2 negatively regulates root hair tip growth via processing Ca(2+) and PtdInsP signals on the plasma membrane, while the residual domain is involved in the polarization of cell expansion. PMID- 23445488 TI - Correlates of frequency of HIV testing among men who have sex with men in Washington, DC. AB - In Washington, DC, the leading mode of HIV transmission is through men who have sex with men (MSM) behavior. This study explored differences between frequent HIV testers (men testing at least twice a year) and annual or less frequent testers (men testing once a year or less) in DC. Nearly, one-third of MSM reported testing for HIV at least four times in the prior two years. In the multivariable model, frequent testers had significantly higher odds of being aged 18-34 (aOR =1.94), knowing their last partner's HIV status (aOR=1.86), having 5+ partners in the last year (aOR=1.52), and having seen a health-care provider in the last year (aOR=2.28). Conversely, frequent testers had significantly lower odds of being newly HIV positive (aOR=0.27), and having a main partner at last sex (vs. casual/exchange partner; aOR=0.59). Medical providers need to be encouraged to consistently offer an HIV test to their patients, especially those who are sexually active and who have not tested recently. PMID- 23445489 TI - miRNA-target prediction based on transcriptional regulation. AB - BACKGROUND: microRNAs (miRNAs) are tiny endogenous RNAs that have been discovered in animals and plants, and direct the post-transcriptional regulation of target mRNAs for degradation or translational repression via binding to the 3'UTRs and the coding exons. To gain insight into the biological role of miRNAs, it is essential to identify the full repertoire of mRNA targets (target genes). A number of computer programs have been developed for miRNA-target prediction. These programs essentially focus on potential binding sites in 3'UTRs, which are recognized by miRNAs according to specific base-pairing rules. RESULTS: Here, we introduce a novel method for miRNA-target prediction that is entirely independent of existing approaches. The method is based on the hypothesis that transcription of a miRNA and its target genes tend to be co-regulated by common transcription factors. This hypothesis predicts the frequent occurrence of common cis-elements between promoters of a miRNA and its target genes. That is, our proposed method first identifies putative cis-elements in a promoter of a given miRNA, and then identifies genes that contain common putative cis-elements in their promoters. In this paper, we show that a significant number of common cis-elements occur in ~28% of experimentally supported human miRNA-target data. Moreover, we show that the prediction of human miRNA-targets based on our method is statistically significant. Further, we discuss the random incidence of common cis-elements, their consensus sequences, and the advantages and disadvantages of our method. CONCLUSIONS: This is the first report indicating prevalence of transcriptional regulation of a miRNA and its target genes by common transcription factors and the predictive ability of miRNA-targets based on this property. PMID- 23445490 TI - Asymmetric dearomatizing spirolactonization of naphthols catalyzed by spirobiindane-based chiral hypervalent iodine species. AB - This report details the development of a spirobiindane-based chiral hypervalent iodine reagent, especially focusing on its structural elucidation for effective asymmetric induction of the chiral spiro center during the oxidative dearomatizing spirolactonization of naphthols. In this study we synthesized a new series of ortho-functionalized spirobiindane catalysts and demonstrated that the enantioselectivity can be dramatically improved by the presence of the substituents ortho to the iodine atom. The structural elucidation of a spirobiindane-based hypervalent iodine catalyst has led to further improvement in the stereoselective construction of the spiro center during the oxidative dearomatizing spirolactonization of naphthols. Thus, catalytic oxidation with the highest reported level of enantioselectivity in hypervalent iodine chemistry has been achieved with also an excellent level of asymmetric induction (92% ee for substrate 3a). As a result, this study, dealing with a series of modified iodine catalysts, can provide important clues about the transition state and reaction intermediate to help scientists understand the origin of the stereoselectivity. A plausible transition-state model and intermediate in the reaction for the stereoselective formation of spirolactone products are postulated by considering the ortho-substituent effect and the results of X-ray analysis. In this reaction model, the high enantiomeric excess obtained by using the spirobiindane catalysts could be well explained by the occupation of the equatorial site and extension of the surroundings around the hypervalent iodine bonds by the introduced ortho substituent. Thus, this study would contribute to estimation of the chiral hypervalent iodine compounds in asymmetric reactions. PMID- 23445491 TI - Sculpting the analytical volume in and around nanoparticle sensors using a multilayer geometry. AB - The use of structured nanoparticles as optical contrast agents has led to new sensing opportunities in localizing the analytical volume within or outside the particle. Here we examine the use of structured nanoparticles for controlling the sensed analytical volume and figures of merit for their use. Nanolayered alternating metal-dielectric particles (nanoLAMPs), consisting of metal dielectric nanospheres, are a flexible and highly tunable structure and used here to illustrate the concept of sculpting the analytical volume associated with a nanoparticle. The alternating metal and dielectric shells in LAMPs are designed such that, when illuminated, the plasmonic coupling of metal shells results in amplified electric fields in specific volumes. The strength and extent of regions with amplified fields (hot spots) in and around a LAMP are at the expense of other regions with depleted fields. A rigorous Mie theory formulation is used to model electric field redistributions. A genetic algorithm-based strategy is then employed to design LAMPs that selectively enhance the response of analyte molecules located either outside or in various dielectric layers through electric field redistribution. We demonstrate that it is possible to localize the analytical volume to within or outside the particle quite efficiently. Further, the analytical figures of merit (localization and amplification of signal as well as contrast between sensed species and background) are optimized and limits to the same are described. The strategy proposed here is a general route to engineer a palette of probes with highly specific detection capabilities using spectroscopy techniques based on surface-enhanced scattering, absorption, or emission processes. PMID- 23445492 TI - Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65. AB - BACKGROUND: In Oncology, the resistance of the cancerous cells to chemotherapy continues to be the principal limitation. The nuclear factor-kappa B (NF-kappaB) transcription factor plays an important role in tumor escape and resistance to chemotherapy and this factor regulates several pathways that promote tumor survival including some antiapoptotic proteins such as Bcl-2 and Bcl-XL. In this study, we investigated, in U937 human leukemia cells, the effects of PTX and the MG132 proteasome inhibitor, drugs that can disrupt the NF-kappaB pathway. For this, we evaluated viability, apoptosis, cell cycle, caspases-3, -8, -9, cytochrome c release, mitochondrial membrane potential loss, p65 phosphorylation, and the modification in the expression of pro- and antiapoptotic genes, and the Bcl-2 and Bcl-XL antiapoptotic proteins. RESULTS: The two drugs affect the viability of the leukemia cells in a time-dependent manner. The greatest percentage of apoptosis was obtained with a combination of the drugs; likewise, PTX and MG132 induce G1 phase cell cycle arrest and cleavage of caspases -3,-8, 9 and cytochrome c release and mitochondrial membrane potential loss in U937 human leukemia cells. In these cells, PTX and the MG132 proteasome inhibitor decrease p65 (NF-kappaB subunit) phosphorylation and the antiapoptotic proteins Bcl-2 and Bcl-XL. We also observed, with a combination of these drugs overexpression of a group of the proapoptotic genes BAX, DIABLO, and FAS while the genes BCL-XL, MCL-1, survivin, IkappaB, and P65 were downregulated. CONCLUSIONS: The two drugs used induce apoptosis per se, this cytotoxicity was greater with combination of both drugs. These observations are related with the caspases -9, -3 cleavage and G1 phase cell cycle arrest, and a decrease in p65 phosphorylation and Bcl-2 and Bcl-XL proteins. As well as this combination of drugs promotes the upregulation of the proapoptotic genes and downregulation of antiapoptotic genes. These observations strongly confirm antileukemic potential. PMID- 23445493 TI - Frequency of inappropriate therapy in patients implanted with dual- versus single chamber ICD devices in the ICD arm of MADIT-CRT. AB - BACKGROUND: The majority of implantable cardioverter defibrillators (ICDs) are dual-chamber devices, but studies on the frequency of inappropriate therapy in dual- versus single-chamber devices have shown conflicting results. The aim of this study is to determine whether implantation of dual-chamber ICD devices decrease the incidence of inappropriate therapy without an unacceptable increase in complications. METHODS: In the ICD arm of the MADIT-CRT study (N = 704), comparisons of single- versus dual-chamber ICD devices were investigated on the endpoints of inappropriate therapy (antitachycardia pacing [ATP] and shocks) and device- and procedure-related complications by use of multivariate Cox proportional hazard regression analysis (hazard ratio dual:single chamber) adjusting for relevant covariates. RESULTS: The frequency of inappropriate therapies in single- and dual-chamber recipients was 41/294 (14%) and 50/410 (12%), respectively. There was no significant difference in overall inappropriate therapy (hazard ratio [HR] = 0.95 [CI: 0.63-1.45], P = 0.95) or inappropriate ATP (HR = 0.98 [CI: 0.61-1.58], P = 0.94), between single- and dual-chamber devices, using single-chamber as a reference (Dual:Single). However, there was a trend toward a decrease in inappropriate shocks (HR = 0.60 [CI: 0.34-1.08], P = 0.09) in the dual-chamber group. The same was evident when only analyzing inappropriate therapy for atrial tachyarrhythmias (HR = 0.88 [CI: 0.56-1.38], P = 0.58). There was no significant difference between the groups in device- or procedure-related complications (HR = 1.54 [CI: 0.82-2.90], P = 0.18). CONCLUSION: No significant difference was found in inappropriate therapy or complications in patients treated with single- versus dual-chamber ICD devices. PMID- 23445494 TI - The utility of low frequency heart rate variability as an index of sympathetic cardiac tone: a review with emphasis on a reanalysis of previous studies. AB - This article evaluates the suitability of low frequency (LF) heart rate variability (HRV) as an index of sympathetic cardiac control and the LF/high frequency (HF) ratio as an index of autonomic balance. It includes a comprehensive literature review and a reanalysis of some previous studies on autonomic cardiovascular regulation. The following sources of evidence are addressed: effects of manipulations affecting sympathetic and vagal activity on HRV, predictions of group differences in cardiac autonomic regulation from HRV, relationships between HRV and other cardiac parameters, and the theoretical and mathematical bases of the concept of autonomic balance. Available data challenge the interpretation of the LF and LF/HF ratio as indices of sympathetic cardiac control and autonomic balance, respectively, and suggest that the HRV power spectrum, including its LF component, is mainly determined by the parasympathetic system. PMID- 23445495 TI - Proteomic analysis of two metabolic proteins with potential to translocate to plasma membrane associated with tumor metastasis development and drug targets. AB - Metastasis is the main cause for death of breast cancer patients. However, the underlying mechanism is still poorly understood. Plasma membrane (PM) proteins play a key role in various biological processes, especially for cell migration. In this study, we used a set of well-characterized mammary mouse cell lines, 67NR, 168FARN, 4T1, representing the metastatic progression, to study the differentially expressed membrane proteins. These proteins were analyzed by a linear ion trap tandem mass spectrometry (LTQ-MS/MS) following cell surface biotinylation and streptavidin purification. A total of 1667 membrane proteins were identified, out of which 472 were characterized as differentially expressed with at least 2-fold change and p-value < 0.01. Functional clustering of the 472 proteins revealed that 178 of them were metabolic proteins. Finally, we focused on two metabolic proteins, fatty acid synthase (FASN) and NAD(P)H steroid dehydrogenase-like protein (NSDHL), which were validated by Western blot and immunofluorescence. We found that FASN and NSDHL translocated to the plasma membrane from the intracellular compartment, and their expressions increased from 67NR to 4T1. This alteration of localization along with differential expressions might be necessary for metastasis development. Potentially, FASN and NSDHL could serve as drug targets in new antimetastasis therapy. PMID- 23445496 TI - Synthesis and biological evaluation of 2-(alkoxycarbonyl)-3 anilinobenzo[b]thiophenes and thieno[2,3-b]pyridines as new potent anticancer agents. AB - Two new series of inhibitors of tubulin polymerization based on the 2 (alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene and thieno[2,3 b]pyridine molecular skeletons were synthesized and evaluated for antiproliferative activity on a panel of cancer cell lines, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. Antiproliferative activity was strongly dependent on the position of the methyl group on the benzene portion of the benzo[b]thiophene nucleus, with the greatest activity observed when the methyl was located at the C-6 position. Also, in the smaller thieno[2,3-b]pyridine series, the introduction of the methyl group at the C-6 position resulted in improvement of antiproliferative activity to the nanomolar level. The most active compounds (4i and 4n) did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. Compound 4i significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice. PMID- 23445497 TI - Drug-initiated ring-opening polymerization of O-carboxyanhydrides for the preparation of anticancer drug-poly(O-carboxyanhydride) nanoconjugates. AB - We report a novel synthetic strategy of polymer-drug conjugates for nanoparticulate drug delivery: hydroxyl-containing drug (e.g., camptothecin, paclitaxel, doxorubicin and docetaxel) can initiate controlled polymerization of phenyl O-carboxyanhydride (Phe-OCA) to afford drug-poly(Phe-OCA) conjugated nanoparticles, termed drug-PheLA nanoconjugates (NCs). Our new NCs have well controlled physicochemical properties, including high drug loading, quantitative drug loading efficiency, controlled particle size with narrow particle size distribution, and sustained drug release profile over days without "burst" release effect as observed in conventional polymer/drug encapsulates. Compared with polylactide NCs, the PheLA NCs have increased noncovalent hydrophobic interchain interactions and thereby result in remarkable stability in human serum with negligible particle aggregation. Such distinctive properties can reduce the premature disassembly of NCs upon dilution in the bloodstream and prolong NCs' in vivo circulation with the enhancement of intratumoral accumulation of NCs, which has a bearing on therapeutic effectiveness. PMID- 23445499 TI - Embryos, the principle of proportionality, and the shaky ground of moral respect. AB - The debate concerning the moral permissibility of using human embryos in human embryonic stem cell (hESC) research has long centred on the question of the embryo's supposed right to life. However, in focussing only on this question, many opponents to hESC research have escaped rigorous scrutiny by making vague and unfounded appeals to the concept of moral respect in order to justify their opposition to certain hESC practices. In this paper, I offer a critical analysis of the concept of moral respect, and its use to support the intuitively appealing principle of proportionality in hESC research. I argue that if proponents of this principle are to justify its adoption by appealing to the concept of moral respect, they must explain two things concerning the nature of the moral respect owed to embryos. First, they must explain which particular aspect of the embryo is morally relevant, and why. Second, they must explain why some uses of embryos in research fail to acknowledge what is morally relevant about the embryo, and thereby involve a violation of the moral respect that they are due. I shall show that providing such explanations may be more difficult than it first appears. PMID- 23445498 TI - Do clinical standards for diabetes care address excess risk for hypoglycemia in vulnerable patients? A systematic review. AB - OBJECTIVE: To determine whether diabetes clinical standards consider increased hypoglycemia risk in vulnerable patients. DATA SOURCES: MEDLINE, the National Guidelines Clearinghouse, the National Quality Measures Clearinghouse, and supplemental sources. STUDY DESIGN: Systematic review of clinical standards (guidelines, quality metrics, or pay-for-performance programs) for glycemic control in adult diabetes patients. The primary outcome was discussion of increased risk for hypoglycemia in vulnerable populations. DATA COLLECTION/EXTRACTION METHODS: Manuscripts identified were abstracted by two independent reviewers using prespecified inclusion/exclusion criteria and a standardized abstraction form. PRINCIPAL FINDINGS: We screened 1,166 titles, and reviewed 220 manuscripts in full text. Forty-four guidelines, 17 quality metrics, and 8 pay-for-performance programs were included. Five (11 percent) guidelines and no quality metrics or pay-for-performance programs met the primary outcome. CONCLUSIONS: Clinical standards do not substantively incorporate evidence about increased risk for hypoglycemia in vulnerable populations. PMID- 23445500 TI - The loss of indirect interactions leads to cascading extinctions of carnivores. AB - Species extinctions are biased towards higher trophic levels, and primary extinctions are often followed by unexpected secondary extinctions. Currently, predictions on the vulnerability of ecological communities to extinction cascades are based on models that focus on bottom-up effects, which cannot capture the effects of extinctions at higher trophic levels. We show, in experimental insect communities, that harvesting of single carnivorous parasitoid species led to a significant increase in extinction rate of other parasitoid species, separated by four trophic links. Harvesting resulted in the release of prey from top-down control, leading to increased interspecific competition at the herbivore trophic level. This resulted in increased extinction rates of non-harvested parasitoid species when their host had become rare relative to other herbivores. The results demonstrate a mechanism for horizontal extinction cascades, and illustrate that altering the relationship between a predator and its prey can cause wide-ranging ripple effects through ecosystems, including unexpected extinctions. PMID- 23445501 TI - Assessment of female sexual function in pregnant women with gestational diabetes mellitus. AB - INTRODUCTION: Female sexual dysfunction is a frequent problem that may be caused by several factors, such as pregnancy and diabetes, and that can affect the woman's quality of life. AIM: The aim of this study was to assess the sexual function of pregnant women with gestational diabetes. METHODS: This is a cross sectional clinical study involving 88 women, among which 33 were pregnant with gestational diabetes mellitus (GDM) and 55 were with low-risk pregnancy (LRP). MAIN OUTCOME MEASURES: Sexual function was assessed using the Female Sexual Function Index (FSFI), a self-applicable questionnaire validated in Portuguese. All the pregnant women answered the questionnaire between the 20th and 25th week of gestation. Data were submitted to descriptive analysis by using the SAS version 9.2 procedure PROC MEANS (SAS Institute Inc., Cary, NC, USA), whereas Student's t-test was applied by using the procedure PROC TTEST (SAS Institute Inc.) at a significance level of <=5% for all analyses. RESULTS: The percentage of women presenting sexual dysfunction in each group was the following: 66.7% in Group GDM and 38.9% in the Group LRP, with significant difference between the groups (P = 0.03). However, no significant differences were found between the groups regarding sexual desire, excitement, lubrication, and pain. On the total score of FSFI, Group GDM had a score <=26.55 (P = 0.03). CONCLUSION: Diabetic pregnant women were found to have a higher incidence of sexual dysfunction as their scores were lower for all FSFI domains compared with LRP females. PMID- 23445502 TI - Modified pulsincap of ibuprofen--a novel approach for chronotherapy. AB - The aim of the present work was to develop colon specific drug delivery system for ibuprofen using natural polymers as carriers. We have investigated colon specific, pulsatile device to achieve time and site specific release of ibuprofen based on chronopharmaceutical considerations. The basic design consists of an insoluble hard gelatin capsule body, filled with ibuprofen surface solid dispersions and sealed with guar gum hydrogel plug. The entire capsule was coated with ethyl cellulose, so that the variability in gastric emptying time can be overcome and a colon specific release can be achieved. Surface solid dispersions (SSDs) of ibuprofen were prepared using natural polymers such as Guar gum (GG), Hupu gum (HG) and Xanthan gum (XG) in the weight ratios of 1:0.5, 1:1 and 1:2 by using solvent evaporation method. Physicochemical properties of the prepared SSD were characterized by FTIR and DSC. Optimized SSD were obtained by practical yield, drug content, solubility and dissolution studies and were selected for further fabrication of pulsincaps. Guar gum was used as hydrogel plug material to maintain a suitable lag period. The prepared pulsincaps were evaluated for in vitro release. Pulsincap formulated with Ibuprofen-Hupu gum (PF3) at 1:2 ratio of surface solid dispersions showed highest drug release over the period of 12 hr and release was found to be Higuchi model kinetics. The present research study results have confirmed that the modified pulsincap of ibuprofen is a suitable device for the time dependent and site specific delivery to the colon segment of GIT. PMID- 23445503 TI - The Evolution of the Wechsler Memory Scale: A Selective Review. AB - In clinical use since 1940, the Wechsler Memory Scale was formally introduced to the psychological community in 1945. By 1946, it ranked 90th out of the 100 most frequently used psychological tests. By 1969, it was the 19th most used psychological test and the 2nd most used test of memory. By 1982, it was the 12th most used test and the most used memory test-a popularity it continues to enjoy. The present article will briefly trace the origin of the Wechsler Memory Scale and examine its evolution across the revisions that appeared in 1987, 1997, and 2009. Issues with norming and standardization, as well as reliability and validity, will be summarized. It is argued that the test continues to have several serious shortcomings, including a lack of anchoring in an explicit neuroanatomical theory of memory and an underlying factor structure that appears to have changed little despite changes in the manifest structure and content of the test. PMID- 23445504 TI - Role of sodium doping in lead chalcogenide thermoelectrics. AB - The solubility of sodium and its effects on phonon scattering in lead chalcogenide PbQ (Q = Te, Se, S) family of thermoelectric materials was investigated by means of transmission electron microscopy and density functional calculations. Among these three systems, Na has the highest solubility limit (~2 mol %) in PbS and the lowest ~0.5 mol %) in PbTe. First-principles electronic structure calculations support the observations, indicating that Na defects have the lowest formation energy in PbS and the highest in PbTe. It was also found that in addition to providing charge carriers (holes) for PbQ, Na introduces point defects (solid solution formation) and nanoscale precipitates; both reduce the lattice thermal conductivity by scattering heat-carrying phonons. These results explain the recent reports of high thermoelectric performance in p-type PbQ materials and may lead to further advances in this class of materials. PMID- 23445505 TI - Recovery education: a tool for psychiatric nurses. AB - Patient teaching is vital for nursing care of psychiatric patients. This paper describes the process of developing Recovery Education as a tool for nurses who lead daily patient education groups. Gundersen Lutheran's Recovery Model developed for the Inpatient Psychiatric Unit includes seven Elements of Recovery- Hope, Security, Support/Managing Symptoms, Empowerment, Relationships, Coping and Finding Meaning. Concepts of cognitive behavioural therapy, mindfulness and case based education were woven through recovery lessons in ready-to-use folders. Statistics on patient satisfaction and patient outcome data were positive. Education for self-management can move patients forward to improve health and healing on their recovery journey. PMID- 23445506 TI - How far in-silico computing meets real experiments. A study on the structure and dynamics of spin labeled vinculin tail protein by molecular dynamics simulations and EPR spectroscopy. AB - BACKGROUND: Investigation of conformational changes in a protein is a prerequisite to understand its biological function. To explore these conformational changes in proteins we developed a strategy with the combination of molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy. The major goal of this work is to investigate how far computer simulations can meet the experiments. METHODS: Vinculin tail protein is chosen as a model system as conformational changes within the vinculin protein are believed to be important for its biological function at the sites of cell adhesion. MD simulations were performed on vinculin tail protein both in water and in vacuo environments. EPR experimental data is compared with those of the simulated data for corresponding spin label positions. RESULTS: The calculated EPR spectra from MD simulations trajectories of selected spin labelled positions are comparable to experimental EPR spectra. The results show that the information contained in the spin label mobility provides a powerful means of mapping protein folds and their conformational changes. CONCLUSIONS: The results suggest the localization of dynamic and flexible regions of the vinculin tail protein. This study shows MD simulations can be used as a complementary tool to interpret experimental EPR data. PMID- 23445507 TI - Genome-wide investigation of cellular targets and mode of action of the antifungal bacterial metabolite 2,4-diacetylphloroglucinol in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae is a proven model to investigate the effects of small molecules and drugs on fungal and eukaryotic cells. In this study, the mode of action of an antifungal metabolite, 2,4-diacetylphloroglucinol (DAPG), was determined. Applying a combination of genetic and physiological approaches, it was established that this bacterial metabolite acts as a proton ionophore and dissipates the proton gradient across the mitochondrial membrane. The uncoupling of respiration and ATP synthesis ultimately leads to growth inhibition and is the primary toxic effect of DAPG. A genome-wide screen identified 154 DAPG-tolerant mutants and showed that there are many alterations in cellular metabolism that can confer at least some degree of tolerance to this uncoupler. One mutant, ydc1, was studied in some more detail as it displayed increased tolerance to both DAPG and the uncoupler carbonylcyanide m-chlorophenylhydrazone (CCCP) and appears to be unconnected to other tolerant mutant strains. Deleting YDC1 alters sphingolipid homoeostasis in the cell, and we suggest here that this may be linked to reduced drug sensitivity. Sphingolipids and their derivatives are important eukaryotic signal molecules, and the observation that altering homoeostasis may affect yeast response to metabolic uncoupling agents raises some intriguing questions for future studies. PMID- 23445508 TI - Human chronotype is determined in bodily cells under real-life conditions. AB - Individuals differ in their preferred timing of sleep and activity, which is referred to as a chronotype. The timing shows a wide distribution; extremely early chronotypes may wake up when the extremely late chronotypes fall asleep. The chronotype is supposed to be determined by the central circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus because the phasing of the pineal melatonin rhythm, which is driven by the SCN, correlates with the sleep timing preference. In addition to the SCN, circadian oscillators are also present in most if not all bodily cells. These peripheral clocks are synchronized by the central SCN clock and by other tissue-specific entraining cues. At the molecular level, the circadian oscillations are based on a complex, self-sustaining mechanism that drives the rhythmical expression of clock genes and their proteins. The aim of the present field study was to elucidate whether the changes in the internal timing of early and late chronotypes, as expressed by changes in the phases of their mid-sleep and melatonin secretion, can also be detected at the molecular clockwork level in subjects examined under real-life conditions. Ninety-five adult volunteers were chronotyped using an adapted Munich chronotype questionnaire to assess their mid-sleep phase, and 6 subjects with early chronotypes and 6 with late chronotypes were chosen for the study. For the assessment of the circadian phase, the subjects provided samples of saliva for the melatonin assay and samples of oral mucosa for the determination of clock gene Per1, Per2, and Rev-erbalpha mRNA levels every 4 h during a 24-h period. The significant correlation between the phase of the melatonin profile and timing of mid-sleep confirmed the classification of the subjects according to their chronotype. The circadian phases of the Per1, Per2, and Rev-erbalpha expression profiles in the oral mucosa were advanced in the early chronotypes compared with those in the late chronotypes (p < .001) and correlated significantly with the mid-sleep phase of the individual subjects. Moreover, the circadian phases of the Per1 expression profiles of individual subjects correlated significantly with the phases of their melatonin profiles (p < .05), whereas the correlation for the Per2 and Rev-erbalpha phases was nonsignificant, although the trend was the same. Our results demonstrate that the individual chronotype in humans living in real life conditions affects not only the phasing of the daily melatonin rhythm in saliva but also the phasing of Per1, Per2, and Rev-erbalpha clock gene expression profiles in buccal mucosa cells. This report represents the first demonstration that the human peripheral circadian clock may sense the individual's chronotype under field study conditions. The data contribute to our understanding of the mechanisms underlying human chronotypes in real life. PMID- 23445509 TI - Association between phase shifts, expression levels, and amplitudes in peripheral circadian clocks. AB - Data analyses examining the relationship between circadian phase shifts and amplitudes are scarce. The aim of this data analysis was to explore the association between the phase shifts of gene expression, their amplitudes, and daily levels as a result of a given treatment under ad libitum or restricted feeding (RF) conditions. Two hundred forty data sets of gene expression (clock and metabolic genes) from various tissues and treatments were statistically analyzed. The data revealed a significant association between phase delays and increased amplitudes. Moreover, upon subgroup analyses, separating the RF from the non-RF groups, phase delays were significantly correlated with increased amplitudes and phase advances with decreased amplitudes. This picture was also achieved when clock genes, but not metabolic genes, were analyzed. In contrast, under RF, increased amplitude of metabolic genes correlated with phase advances. Moreover, phase advances under RF led to increased average daily levels in clock genes, but not in metabolic genes. In summary, these data demonstrated statistically significant association between phase shifts, daily levels, and amplitudes in circadian gene expression in peripheral tissues under timed versus ad libitum feeding conditions. PMID- 23445510 TI - Factors associated with shift work disorder in nurses working with rapid-rotation schedules in Japan: the nurses' sleep health project. AB - Workers who meet the criteria for shift work disorder (SWD) have elevated levels of risk for various health and behavioral problems. However, the impact of having SWD on shiftworkers engaged in rapid-rotation schedules is unknown. Moreover, the risk factors for the occurrence of SWD remain unclear. To clarify these issues, we conducted a questionnaire-based, cross-sectional survey on a sample of shiftworking nurses. Responses were obtained from 1202 nurses working at university hospitals in Tokyo, Japan, including 727 two-shift workers and 315 three-shift workers. The questionnaire included items relevant to age, gender, family structure, work environment, health-related quality of life (QOL), diurnal type, depressive symptoms, and SWD. Participants who reported insomnia and/or excessive sleepiness for at least 1 mo that was subjectively relevant to their shiftwork schedules were categorized as having SWD. The prevalence of SWD in the sampled shiftworking nurses was 24.4%; shiftworking nurses with SWD showed lower health-related QOL and more severe depressive symptoms, with greater rates of both actual accidents/errors and near misses, than those without SWD. The results of logistic regression analyses showed that more time spent working at night, frequent missing of nap opportunities during night work, and having an eveningness-oriented chronotype were significantly associated with SWD. The present study indicated that SWD might be associated with reduced health-related QOL and decreased work performance in shiftworking nurses on rapid-rotation schedules. The results also suggested that missing napping opportunities during night work, long nighttime working hours, and the delay of circadian rhythms are associated with the occurrence of SWD among shiftworking nurses on rapid-rotation schedules. PMID- 23445511 TI - Effect of experimental diabetic retinopathy on the non-image-forming visual system. AB - Diabetic retinopathy is a leading cause of blindness. Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are involved in non-image-forming visual responses such as photoentrainment of circadian rhythms and pupillary light reflex. Since several reports indicate that retinal ganglion cells are affected by diabetes, we investigated the non-image-forming visual system in an advanced stage of experimental diabetes in rats induced by streptozotocin. After 15 wks of diabetes induction, clear alterations in the visual function were observed and all animals developed mature cataracts. At this time point, concomitantly with a significant decrease in the number of Brn3a(+) retinal ganglion cells, no differences in the number of melanopsin-containing cells, melanopsin levels, and retinal projections to the suprachiasmatic nuclei and the olivary pretectal nucleus were observed. At high light intensity, afferent pupil light reflex appears to be conserved in diabetic animals. After 15 wks of diabetes induction, a significant decrease in light-induced c-Fos expression in the suprachiasmatic nuclei was found. In diabetic animals, the locomotor activity pattern was conserved, although a delay in the time needed for re-entrainment after a phase delay was observed. In diabetic animals, lensectomy reversed the alterations in c-Fos expression and in the locomotor activity rhythm. These results suggest that the neuronal substrate of the non-image-forming visual system remained largely unaffected at advanced stages of diabetes, and that lensectomy, a relatively easy and safe surgery, could partially restore circadian alterations induced by diabetes. PMID- 23445512 TI - Delayed sleep timing and symptoms in adults with attention-deficit/hyperactivity disorder: a controlled actigraphy study. AB - Patients with attention-deficit/hyperactivity disorder (ADHD) often exhibit disrupted sleep and circadian rhythms. Determination of whether sleep disturbance and/or circadian disruption are differentially associated with symptom severity is necessary to guide development of future treatment strategies. Therefore, we measured sleep and ADHD symptoms in participants aged 19-65 who met the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria for ADHD and insomnia without psychiatric comorbidities by monitoring actigraphy and daily sleep logs for 2 wks, as well as the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), the ADHD Rating Scale (ADHD-RS), and a clinic-designed sleep behavior questionnaire. Principal components analysis identified correlated circadian- and sleep-related variables in all participants with ADHD who completed the study (n = 24). The identified components were entered into a backwards stepwise linear regression analysis, which indicated that delayed sleep timing and increased sleepiness (ESS) (but not sleep duration or sleep efficiency) significantly predicted greater severity of both hyperactive-impulsive and inattentive ADHD symptoms (p < .05 for partial regression coefficients). In addition, combined subtypes had the most impaired age-adjusted sleep quality (PSQI scores; p < .05 compared with healthy controls; n = 13), and 91.7% of them reported going to bed late due to being "not tired/too keyed up to sleep" compared with 57.2% and 50% of inattentive and symptom controlled participants, respectively (p < .05). In conclusion, the results of this study suggest that ADHD symptom severity correlates with delayed sleep timing and daytime sleepiness, suggesting that treatment interventions aimed at advancing circadian phase may improve daytime sleepiness. In addition, ADHD adults with combined hyperactive-impulsive and inattentive symptoms have decreased sleep quality as well as the delayed sleep timing of predominately inattentive subtypes. PMID- 23445514 TI - Expression of OV-6 in primary colorectal cancer and rectal cancer with preoperative chemoradiotherapy: a clinicopathological study. AB - AIMS: OV-6 is among the best available markers of liver stem cells. The aim of this study was to investigate OV-6 expression and its clinical implications in colorectal cancer. METHODS AND RESULTS: Expression of OV-6 and its clinical implications were investigated in 94 patients with American Joint Committee on Cancer (AJCC) stage I-III primary colorectal cancer and in 37 rectal cancer patients who had received preoperative chemoradiotherapy. The two main expression patterns of OV-6 were cytoplasmic and membranous. Overexpression of OV-6, which was identified on the basis of overall staining intensity, was associated with perineural invasion, lymphovascular invasion, and early relapses. Membranous OV-6 overexpression was also significantly associated with depth of tumour invasion, AJCC stage, lymphovascular and perineural invasion, and postoperative early relapse. Disease-free survival and overall survival were significantly poorer in patients with high overall OV-6 expression than in those with low overall OV-6 expression (P = 0.015 and P = 0.029, respectively), and significantly poorer in patients with high membranous OV-6 expression than in those with low membranous OV-6 expression (P < 0.001 and P < 0.001, respectively). Membranous OV-6 expression was a more reliable prognostic marker than overall expression. CONCLUSIONS: OV-6 is not unique to the hepatobiliary system, and may be a novel prognostic marker in colorectal cancer. PMID- 23445513 TI - Season of birth is associated with adult body mass index in patients with bipolar disorder. AB - Cardiovascular risk factors, such as abdominal obesity and obesity in general, are very prevalent among patients with bipolar disorder (BD). Although long-term use of psychotropic medications is an important determinant of these risk factors, other evidence suggests that early development may interact with the mood disorder diathesis to exponentially increase the risk of obesity. The goal of our study was to test whether season of birth is associated with adult body mass index (BMI) and abdominal obesity in individuals with bipolar disorder. We compared season of birth effects on BMI in 375 adult patients with bipolar disorder and 196 adult patients with unipolar major depression. We found a significant season of birth effect on BMI in patients with bipolar disorder, but not unipolar. In patients with bipolar disorder, season of birth was also associated with waist circumference, with a stronger effect in males. Season of birth affects adult BMI and waist circumference in patients with bipolar disorder, but not in patients with unipolar depression. Our results suggest that early environmental factors, yet to be identified, interact with specific neurobiological features of bipolar disorder to determine stable traits and disease risk factors in adult life. PMID- 23445515 TI - Anion-exchange-based amperometric assay for heparin using polyimidazolium as synthetic receptor. AB - This study demonstrates a facile yet effective strategy for amperometric assay of electrochemically inactive heparin based on an anion-exchange mechanism with polyimidazolium (Pim) as the synthetic receptor. The rationale for the amperometric heparin assay is essentially based on the different binding affinity of the synthetic Pim receptor toward electrochemically active ferricyanide (Fe(CN)6(3-)) and electrochemically inactive heparin. To accomplish the amperometric assay, Pim is first synthesized and used as the artificial receptor to recognize the anions (i.e., Fe(CN)6(3-) and heparin). The stronger binding affinity of the synthetic Pim receptor toward heparin than toward Fe(CN)6(3-) essentially validates the amperometric heparin assay through an anion-exchange mechanism with the decrease in the redox peak current of Fe(CN)6(3-) adsorbed onto the Pim film as the signal readout. The anion exchange between Fe(CN)6(3-) and heparin on the Pim receptor is verified by cyclic voltammetry and Fourier transform IR and UV-visible spectroscopies. The ratio of the current decrease shows a linear relationship with heparin concentration with a concentration range from 0.5 to 10 MUM. With animal experiments by dosing intraperitoneally and collecting the serum sample, the method is demonstrated to be potentially useful for investigating heparin metabolism in the biological system. This study not only provides a simple yet effective route to a heparin assay but also opens a new way to developing amperometric methods for electrochemically inert species by fully utilizing the supramolecular principles. PMID- 23445516 TI - A variant of LEAFY reveals its capacity to stimulate meristem development by inducing RAX1. AB - In indeterminate inflorescences, floral meristems develop on the flanks of the shoot apical meristem, at positions determined by auxin maxima. The floral identity of these meristems is conferred by a handful of genes called floral meristem identity genes, among which the LEAFY (LFY) transcription factor plays a prominent role. However, the molecular mechanism controlling the early emergence of floral meristems remains unknown. A body of evidence indicates that LFY may contribute to this developmental shift, but a direct effect of LFY on meristem emergence has not been demonstrated. We have generated a LFY allele with reduced floral function and revealed its ability to stimulate axillary meristem growth. This role is barely detectable in the lfy single mutant but becomes obvious in several double mutant backgrounds and plants ectopically expressing LFY. We show that this role requires the ability of LFY to bind DNA, and is mediated by direct induction of REGULATOR OF AXILLARY MERISTEMS1 (RAX1) by LFY. We propose that this function unifies the diverse roles described for LFY in multiple angiosperm species, ranging from monocot inflorescence identity to legume leaf development, and that it probably pre-dates the origin of angiosperms. PMID- 23445517 TI - Elevated T-wave alternans predicts nonsustained ventricular tachycardia in association with percutaneous coronary intervention in ST-segment elevation myocardial infarction (STEMI) patients. AB - INTRODUCTION: Successful reperfusion with primary percutaneous coronary intervention (PCI) can paradoxically elicit temporary vulnerability to ventricular arrhythmia. We examined whether T-wave alternans (TWA) level is correlated with nonsustained ventricular tachycardia (NSVT) incidence in association with PCI in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: We analyzed continuous 24-hour ambulatory electrocardiograms in 48 STEMI patients during and after successful primary PCI, achieving Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow. TWA was measured using modified moving average method. Maximum TWA was elevated in patients with (N = 22) compared to without (N = 26) NSVT (75.1 +/- 6.3 vs 49.9 +/- 3.6 MUV, P < 0.005) during the 22-hour monitoring period. TWA >= 60MUV predicted NSVT with sensitivity of 77%; specificity, 73%; positive predictive value, 71%; and negative predictive value, 79%. Area under receiver operator characteristic curve (AUC) was 0.87 for maximum TWA in predicting NSVT. By comparison, ST-segment levels did not differ in patients with versus without NSVT and were not predictive (AUC = 0.52). TWA was elevated prior to PCI and remained elevated at 30 minutes after balloon inflation despite restoration of TIMI grade 3 flow in all patients, declining by 22 hours (P < 0.05). Maximum ST-segment levels decreased from before PCI to 30 minutes after balloon inflation. TWA is regionally specific, with higher values prior to PCI in precordial lead V5 than in V1 for left coronary lesions. CONCLUSIONS: TWA may be useful in identifying individuals at heightened risk for arrhythmia in association with primary PCI and can potentially signal time-dependent changes in arrhythmia vulnerability. PMID- 23445518 TI - Experience of childbirth in first-time mothers of advanced age - a Norwegian population-based study. AB - BACKGROUND: Delaying the first childbirth to an advanced age has increased significantly during the last decades, but little is known about older first time mothers' experience of childbirth. This study investigates the associations between advanced maternal age in primiparous women and the postnatal assessment of childbirth. METHODS: The study was based on the National Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Data on 30 065 nulliparous women recruited in the second trimester 1999-2008 were used. Three questionnaires were completed: around gestational week 17 and 30, and at 6 months postpartum. Medical data were retrieved from the national Medical Birth Register. Advanced age was defined as >=32 years and the reference group as 25-31 years. Descriptive and multiple logistic regression analyses were conducted. RESULTS: Primiparous women aged 32 years and above expressed more worry about the upcoming birth than the younger women (adjusted OR 1.13; 95% CI 1.06-1.21), and 6 months after the birth they had a slightly higher risk of having experienced childbirth as 'worse than expected' (adjusted OR 1.09; 95% CI 1.02-1.16). The difference in birth experience was explained by mode of delivery. Comparisons within subgroups defined by the same mode of delivery showed that the risk of a more negative birth experience in the older women only applied to those with a spontaneous vaginal birth (adjusted OR 1.12; 95% CI 1.02-1.22). In women delivered by cesarean section, the older more often than younger women rated childbirth as 'better than expected' (elective cesarean delivery: adjusted OR 1.36; 95% CI 1.01-1.85, emergency cesarean delivery: adjusted OR 1.38; 95% CI 1.03-1.84). CONCLUSION: Postponing childbirth to >=32 years of age only marginally affected the experience of childbirth. Older women seemed to manage better than younger with having an operative delivery. PMID- 23445519 TI - MixSIH: a mixture model for single individual haplotyping. AB - BACKGROUND: Haplotype information is useful for various genetic analyses, including genome-wide association studies. Determining haplotypes experimentally is difficult and there are several computational approaches that infer haplotypes from genomic data. Among such approaches, single individual haplotyping or haplotype assembly, which infers two haplotypes of an individual from aligned sequence fragments, has been attracting considerable attention. To avoid incorrect results in downstream analyses, it is important not only to assemble haplotypes as long as possible but also to provide means to extract highly reliable haplotype regions. Although there are several efficient algorithms for solving haplotype assembly, there are no efficient method that allow for extracting the regions assembled with high confidence. RESULTS: We develop a probabilistic model, called MixSIH, for solving the haplotype assembly problem. The model has two mixture components representing two haplotypes. Based on the optimized model, a quality score is defined, which we call the 'minimum connectivity' (MC) score, for each segment in the haplotype assembly. Because existing accuracy measures for haplotype assembly are designed to compare the efficiency between the algorithms and are not suitable for evaluating the quality of the set of partially assembled haplotype segments, we develop an accuracy measure based on the pairwise consistency and evaluate the accuracy on the simulation and real data. By using the MC scores, our algorithm can extract highly accurate haplotype segments. We also show evidence that an existing experimental dataset contains chimeric read fragments derived from different haplotypes, which significantly degrade the quality of assembled haplotypes. CONCLUSIONS: We develop a novel method for solving the haplotype assembly problem. We also define the quality score which is based on our model and indicates the accuracy of the haplotypes segments. In our evaluation, MixSIH has successfully extracted reliable haplotype segments. The C++ source code of MixSIH is available at https://sites.google.com/site/hmatsu1226/software/mixsih. PMID- 23445520 TI - Imagining the truth and the moon: an electrophysiological study of abstract and concrete word processing. AB - Previous event-related potential studies have indicated that both a widespread N400 and an anterior N700 index differential processing of concrete and abstract words, but the nature of these components in relation to concreteness and imagery has been unclear. Here, we separated the effects of word concreteness and task demands on the N400 and N700 in a single word processing paradigm with a within subjects, between-tasks design and carefully controlled word stimuli. The N400 was larger to concrete words than to abstract words, and larger in the visualization task condition than in the surface task condition, with no interaction. A marked anterior N700 was elicited only by concrete words in the visualization task condition, suggesting that this component indexes imagery. These findings are consistent with a revised or extended dual coding theory according to which concrete words benefit from greater activation in both verbal and imagistic systems. PMID- 23445521 TI - Improved detection of quantitative differences using a combination of spectral counting and MS/MS total ion current. AB - Label-free quantitative strategies are commonly used in shotgun proteomics to detect differences in protein abundance between biological sample groups. Here, we have employed a combination of two such approaches, spectral counting (SpC) and average MS/MS total ion current (MS(2) TIC), for the analysis of rat kidney mitochondria in response to metabolic acidosis. In total, 49 proteins were observed to be significantly altered in response to metabolic acidosis (p-value < 0.05). Of these, 32 proteins were uniquely observed as significantly different by SpC, 14 by MS(2) TIC, and only 3 by both approaches. Western blot analysis was performed on a subset of these proteins to validate the observed abundance differences. This study illustrates the utility and ease of combining these two label-free quantitative approaches to increase the number of detected protein abundance differences in the shotgun analysis of complex biological samples. PMID- 23445522 TI - Examination of the mode of action of the almiramide family of natural products against the kinetoplastid parasite Trypanosoma brucei. AB - Almiramide C is a marine natural product with low micromolar activity against Leishmania donovani, the causative agent of leishmaniasis. We have now shown that almiramide C is also active against the related parasite Trypanosoma brucei, the causative agent of human African trypanosomiasis. A series of activity-based probes have been synthesized to explore both the molecular target of this compound series in T. brucei lysates and site localization through epifluorescence microscopy. These target identification studies indicate that the almiramides likely perturb glycosomal function through disruption of membrane assembly machinery. Glycosomes, which are organelles specific to kinetoplastid parasites, house the first seven steps of glycolysis and have been shown to be essential for parasite survival in the bloodstream stage. There are currently no reported small-molecule disruptors of glycosome function, making the almiramides unique molecular probes for this understudied parasite-specific organelle. Additionally, examination of toxicity in an in vivo zebrafish model has shown that these compounds have little effect on organism development, even at high concentrations, and has uncovered a potential side effect through localization of fluorescent derivatives to zebrafish neuromast cells. Combined, these results further our understanding of the potential value of this lead series as development candidates against T. brucei. PMID- 23445523 TI - Exploring knowledge, attitudes, and practices related to alcohol in Mongolia: a national population-based survey. AB - BACKGROUND: The leading cause of mortality in Mongolia is Non-Communicable Disease. Alcohol is recognised by the World Health Organization as one of the four major disease drivers and so, in order to better understand and triangulate recent national burden-of-disease surveys and to inform policy responses to alcohol consumption in Mongolia, a national Knowledge, Attitudes and Practices survey was conducted. Focusing on Non-Communicable Diseases and their risk factors, this publication explores the alcohol-related findings of this national survey. METHODS: A door-to-door, household-based questionnaire was conducted on 3450 people from across Mongolia. Participants were recruited using a multi-stage random cluster sampling technique, and eligibility was granted to permanent residents of households who were aged between 15 and 64 years. A nationally representative sample size was calculated, based on methodologies aligned with the WHO STEPwise approach to Surveillance. RESULTS: Approximately 50% of males and 30% of females were found to be current drinkers of alcohol. Moreover, nine in ten respondents agreed that heavy episodic drinking of alcohol is common among Mongolians, and the harms of daily alcohol consumption were generally perceived to be high. Indeed, 90% of respondents regarded daily alcohol consumption as either 'harmful' or 'very harmful'. Interestingly, morning drinking, suggestive of problematic drinking, was highest in rural men and was associated with lower levels of education and unemployment. CONCLUSION: This research suggests that Mongolia faces an epidemiological challenge in addressing the burden of alcohol use and related problems. Males, rural populations and those aged 25-34 years exhibited the highest levels of risky drinking practices, while urban populations exhibit higher levels of general alcohol consumption. These findings suggest a focus and context for public health measures addressing alcohol-related harm in Mongolia. PMID- 23445524 TI - Dire necessity and transformation: entry-points for modern science in Islamic bioethical assessment of porcine products in vaccines. AB - The field of medicine provides an important window through which to examine the encounters between religion and science, and between modernity and tradition. While both religion and science consider health to be a 'good' that is to be preserved, and promoted, religious and science-based teachings may differ in their conception of what constitutes good health, and how that health is to be achieved. This paper analyzes the way the Islamic ethico-legal tradition assesses the permissibility of using vaccines that contain porcine-derived components by referencing opinions of several Islamic authorities. In the Islamic ethico-legal tradition controversy surrounds the use of proteins from an animal (pig) that is considered to be impure by Islamic law. As we discuss the Islamic ethico-legal constructs used to argue for or against the use of porcine-based vaccines we will call attention to areas where modern medical data may make the arguments more precise. By highlighting areas where science can buttress and clarify the ethico legal arguments we hope to spur an enhanced applied Islamic bioethics discourse where religious scholars and medical experts use modern science in a way that remains faithful to the epistemology of Islamic ethics to clarify what Islam requires of Muslim patients and healthcare workers. PMID- 23445525 TI - Use of echocardiographic pulmonary acceleration time and estimated vascular resistance for the evaluation of possible pulmonary hypertension. AB - BACKGROUND: During ultrasound examination, tricuspid regurgitation may be absent or gives a signal that is not reliable for the estimation of systolic pulmonary pressure. The aim of this study was to evaluate the usefulness of acceleration time (AT) from the right ventricular outflow tract (RVOT) as an estimation of the trans-tricuspid valve gradient (TTVG) and to investigate the correlation between estimated and invasive pulmonary vascular resistance (PVR). METHODS: The AT was correlated to the TTVG measured with routine standard echocardiography in 121 patients. In a subgroup of 29 patients, systolic pulmonary pressure (SPAP) and mean pulmonary arterial pressure (MPAP) were obtained from recent right heart catheterization (RHC). RESULTS: We found no significant correlation between the estimation of right atrial pressure (RAP) by echocardiography and the RAP obtained by RHC. Estimated SPAP (TTGV + RAP mean from RHC) showed a good linear relation to invasively measured SPAP. TTVG and AT showed a non-linear relation, similar to SPAP and MPAP measured by catheterization and AT. For detection of SPAP above 38 mmHg a cut-off for AT of 100 ms resulted in a sensitivity of 89% and a specificity of 84%. For detection of MPAP above 25 mmHg a cut-off for AT of 100 ms resulted in similar sensitivity and specificity. Invasive PVR and the ratio of TTVG and the time velocity integral of the RVOT (TVI (RVOT) ) had a strong linear relation. CONCLUSIONS: Our study confirms that AT appears to be useful for the evaluation of pulmonary hypertension. In high risk patients, an AT of less than 100 ms indicates a high probability of pulmonary hypertension. Furthermore, PVR estimation by ultrasound seems preferably be done by using the ratio of TTVG and TVI RVOT. PMID- 23445526 TI - Surgical management of penile fracture and long-term outcome on erectile function and voiding. AB - INTRODUCTION: Penile fracture is an emergency in urology. Surgical management is recommended, but objective data of postoperative long-term effects, especially regarding voiding and erectile function, vary. AIM: To assess long-term results of patients undergoing surgical therapy for penile fracture. METHODS: Patients presenting with suspicion of penile fracture were included in this study. Diagnosis of penile fracture was made by clinical assessment and surgery performed thereafter. The defect of the tunica albuginea was closed by absorbable suture. In case of concomitant urethral lesion, the defect was repaired simultaneously. Voiding and erectile function were evaluated at long-term follow up by mail. Patients' status before penile fracture was assessed retroactively. MAIN OUTCOME MEASURES: Erectile function was assessed by the International Index of Erectile Function questionnaire and voiding function by the International Prostate Symptom Score questionnaire. RESULTS: N = 34 patients were included. Penile fracture was suspected in 28/34 (82.4%) patients. Twenty-six of the 28 (92.9%) patients underwent surgery. Only less than half of confirmed fracture patients presented with the classical triad of an audible crack, detumescense, and hematoma. Fourteen of the 26 (53.8%) patients after surgery were available for follow-up. Mean follow-up was 45.6 months (range: 3.6-128.4). In 13/14 (92.9%) patients, penile fracture was confirmed by surgery. At follow-up, 7/13 (53.8%) patients had impaired erectile function, with 3/13 (23.1%) patients needing medical treatment. Four of the 13 (30.8%) patients showed deterioration of voiding including occurrence of urethral fistula. CONCLUSIONS: Penile fracture is an emergency for which surgery should be offered. Clinical suspicion of fracture should be high even with hematoma alone. Concomitant urethral injury is common, particularly with bilateral corporal rupture and/or initial hematuria. Preoperative counseling should include discussion of long-term erectile and voiding dysfunction, penile deformity, and urethral fistula both with and without surgery. Close patient follow-up is required. PMID- 23445527 TI - Primary rhabdoid adrenocortical carcinoma: a clinicopathological and immunohistochemical study of three cases. AB - AIMS: We describe three cases of primary adrenocortical carcinoma (ACC) with prominent rhabdoid features and study their clinicopathological and immunohistochemical properties. METHODS AND RESULTS: The patients were three females aged 45-55 years (mean 49 years), none of whom had any hormone-related symptoms. Histologically, the characteristic features were rhabdoid tumour cells with prominent eosinophilic cytoplasmic inclusions, eccentric vesicular nuclei and prominent nucleoli. Areas of more conventional ACC were present in all cases. Immunohistochemically, the rhabdoid component showed a similar staining pattern to conventional ACC, being positive for steroid receptor cofactor 1, inhibin, melan A, calretinin and synaptophysin, while negative for high molecular weight cytokeratin and Pax8. In addition, antimitochondrial antibodies showed a weak reaction and nuclear expression of integrase interactor 1 (INI1) was preserved. Clinical follow-up information for two patients demonstrated that one patient was alive 237 months after diagnosis, and one patient had died of disease 4 months after diagnosis. CONCLUSIONS: ACC with rhabdoid features are rare tumours that seem to mirror the clinical and immunohistochemical features of conventional ACC. In addition, they appear to display similar biological behaviour. Adrenocortical carcinoma should be included in the differential diagnosis when evaluating tumours of unknown origin with rhabdoid morphology. PMID- 23445528 TI - TSG: a new algorithm for binary and multi-class cancer classification and informative genes selection. AB - BACKGROUND: One of the challenges in classification of cancer tissue samples based on gene expression data is to establish an effective method that can select a parsimonious set of informative genes. The Top Scoring Pair (TSP), k-Top Scoring Pairs (k-TSP), Support Vector Machines (SVM), and prediction analysis of microarrays (PAM) are four popular classifiers that have comparable performance on multiple cancer datasets. SVM and PAM tend to use a large number of genes and TSP, k-TSP always use even number of genes. In addition, the selection of distinct gene pairs in k-TSP simply combined the pairs of top ranking genes without considering the fact that the gene set with best discrimination power may not be the combined pairs. The k-TSP algorithm also needs the user to specify an upper bound for the number of gene pairs. Here we introduce a computational algorithm to address the problems. The algorithm is named Chisquare-statistic based Top Scoring Genes (Chi-TSG) classifier simplified as TSG. RESULTS: The TSG classifier starts with the top two genes and sequentially adds additional gene into the candidate gene set to perform informative gene selection. The algorithm automatically reports the total number of informative genes selected with cross validation. We provide the algorithm for both binary and multi-class cancer classification. The algorithm was applied to 9 binary and 10 multi-class gene expression datasets involving human cancers. The TSG classifier outperforms TSP family classifiers by a big margin in most of the 19 datasets. In addition to improved accuracy, our classifier shares all the advantages of the TSP family classifiers including easy interpretation, invariant to monotone transformation, often selects a small number of informative genes allowing follow-up studies, resistant to sampling variations due to within sample operations. CONCLUSIONS: Redefining the scores for gene set and the classification rules in TSP family classifiers by incorporating the sample size information can lead to better selection of informative genes and classification accuracy. The resulting TSG classifier offers a useful tool for cancer classification based on numerical molecular data. PMID- 23445529 TI - Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns. AB - Aliphatic N,N'-linked oligoureas are peptidomimetic foldamers that adopt a well defined helical secondary structure stabilized by a collection of remote three center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO- residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., -NH-CH2 CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, and -NH-CH(R(1))-CH(R(2))-NH-CO-], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2-diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers. PMID- 23445530 TI - A novel coronavirus capable of lethal human infections: an emerging picture. AB - In September 2012, a novel coronavirus was isolated from a patient in Saudi Arabia who had died of an acute respiratory illness and renal failure. The clinical presentation was reminiscent of the outbreak caused by the SARS coronavirus (SARS-CoV) exactly ten years ago that resulted in over 8000 cases. Sequence analysis of the new virus revealed that it was indeed a member of the same genus as SARS-CoV. By mid-February 2013, 12 laboratory-confirmed cases had been reported with 6 fatalities. The first 9 cases were in individuals resident in the Middle East, while the most recent 3 cases were in family members resident in the UK. The index case in the UK family cluster had travel history to Pakistan and Saudi Arabia. Although the current evidence suggests that this virus is not highly transmissible among humans, there is a real danger that it may spread to other parts of the world. Here, a brief review of the events is provided to summarize the rapidly emerging picture of this new virus. PMID- 23445531 TI - Premenstrual syndrome and premenstrual dysphoric disorder among Jordanian women. AB - The objectives of this study were to detect the prevalence, severity and factors associated with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) among Jordanian women, and to identify the most common self-treatment strategies used by women to alleviate the symptoms associated with PMS and/or PMDD. Data were collected from 254 women studying or working at one of the largest Jordanian governmental university using Shortened Premenstrual Assessment Form (SPAF), Perceived Stress Scale (PSS) and Diagnostic and Statistical Manual of Mental Disorders 4th Edition-Text Revision (DSM-IV-TR) research criteria for diagnosis of PMDD. The findings indicated that the prevalence of PMS and PMDD were 80.2%, 10.2% respectively. Abdominal cramp, lower back pain and breast pain were reported to be the most severe symptoms associated with PMS and PMDD. Significant correlations were found between severity of premenstrual symptoms and perceived stress level, age, body mass index, marital status, perception of health in general and absent from work. The most frequently reported self treatment strategies used by women to alleviate PMS and PMDD symptoms were: taking analgesics, increasing hot fluids intake, wearing heavy and warm clothes, and lying down on the abdomen. Understanding the prevalence, severity and self treatment strategies for women experiencing PMS and PMDD symptoms help in improving women's quality of life and decrease their suffering from these symptoms. PMID- 23445532 TI - Toward single-cell analysis by plume collimation in laser ablation electrospray ionization mass spectrometry. AB - Ambient ionization methods for mass spectrometry have enabled the in situ and in vivo analysis of biological tissues and cells. When an etched optical fiber is used to deliver laser energy to a sample in laser ablation electrospray ionization (LAESI) mass spectrometry, the analysis of large single cells becomes possible. However, because in this arrangement the ablation plume expands in three dimensions, only a small portion of it is ionized by the electrospray. Here we show that sample ablation within a capillary helps to confine the radial expansion of the plume. Plume collimation, due to the altered expansion dynamics, leads to greater interaction with the electrospray plume resulting in increased ionization efficiency, reduced limit of detection (by a factor of ~13, reaching 600 amol for verapamil), and extended dynamic range (6 orders of magnitude) compared to conventional LAESI. This enhanced sensitivity enables the analysis of a range of metabolites from small cell populations and single cells in the ambient environment. This technique has the potential to be integrated with flow cytometry for high-throughput metabolite analysis of sorted cells. PMID- 23445533 TI - Multiclass relevance units machine: benchmark evaluation and application to small ncRNA discovery. AB - BACKGROUND: Classification is the problem of assigning each input object to one of a finite number of classes. This problem has been extensively studied in machine learning and statistics, and there are numerous applications to bioinformatics as well as many other fields. Building a multiclass classifier has been a challenge, where the direct approach of altering the binary classification algorithm to accommodate more than two classes can be computationally too expensive. Hence the indirect approach of using binary decomposition has been commonly used, in which retrieving the class posterior probabilities from the set of binary posterior probabilities given by the individual binary classifiers has been a major issue. METHODS: In this work, we present an extension of a recently introduced probabilistic kernel-based learning algorithm called the Classification Relevance Units Machine (CRUM) to the multiclass setting to increase its applicability. The extension is achieved under the error correcting output codes framework. The probabilistic outputs of the binary CRUMs are preserved using a proposed linear-time decoding algorithm, an alternative to the generalized Bradley-Terry (GBT) algorithm whose application to large-scale prediction settings is prohibited by its computational complexity. The resulting classifier is called the Multiclass Relevance Units Machine (McRUM). RESULTS: The evaluation of McRUM on a variety of real small-scale benchmark datasets shows that our proposed Naive decoding algorithm is computationally more efficient than the GBT algorithm while maintaining a similar level of predictive accuracy. Then a set of experiments on a larger scale dataset for small ncRNA classification have been conducted with Naive McRUM and compared with the Gaussian and linear SVM. Although McRUM's predictive performance is slightly lower than the Gaussian SVM, the results show that the similar level of true positive rate can be achieved by sacrificing false positive rate slightly. Furthermore, McRUM is computationally more efficient than the SVM, which is an important factor for large-scale analysis. CONCLUSIONS: We have proposed McRUM, a multiclass extension of binary CRUM. McRUM with Naive decoding algorithm is computationally efficient in run-time and its predictive performance is comparable to the well-known SVM, showing its potential in solving large-scale multiclass problems in bioinformatics and other fields of study. PMID- 23445535 TI - Promoting the health, safety and welfare of adults with learning disabilities in acute care settings: a structured literature review. AB - AIMS AND OBJECTIVES: To present the findings of a structured literature review that aimed to identify the influences on the health, safety and welfare of adults with learning disabilities in acute hospitals. BACKGROUND: There is increasing evidence regarding the inadequacy of care for people with learning disabilities in acute care settings. However, few studies have specifically addressed their health, safety and welfare in such contexts. DESIGN: Four key electronic databases (Medline; PsycINFO; British Nursing Index and archive; Cumulative Index to Nursing and Allied Health Literature) were searched for relevant literature published between 2000 and 2011. METHODS: Publications assessed as meeting the inclusion criteria were retrieved in full. Data were extracted regarding methods used; primary aims of the study being reported; and key findings. RESULTS: Of the 3505 papers identified in the initial search, eight met the inclusion criteria. Analysis revealed six areas of influence on the health, safety and welfare of adults with learning disabilities in acute hospitals: care provision (meeting health and personal needs); communication; staff attitudes; staff knowledge; supporters; and carers (valuing their role); physical environment. CONCLUSIONS: We represent these six areas diagrammatically, as concentric rings. These influence on health, safety and welfare form an inner (direct) layer and an outer (indirect) layer consisting of liaison services and education/training. This new conceptualisation of influences as being multi-layered assists in the identification of similarly multi-layered improvement strategies. RELEVANCE TO CLINICAL PRACTICE: Adults with learning disabilities can exert their own influence on health, safety and welfare and should be supported to make decisions about their own care. More broadly they should be involved with policy development, nurse education and research. This can be achieved through inclusive approaches, for example, inviting people with learning disabilities to input into nursing curricula or to engage in research as coinvestigators. PMID- 23445534 TI - Transition to motherhood in type 1 diabetes: design of the pregnancy and postnatal well-being in transition questionnaires. AB - BACKGROUND: Life transitions are associated with high levels of stress affecting health behaviours among people with Type 1 diabetes. Transition to motherhood is a major transition with potential complications accelerated by pregnancy with risks of adverse childbirth outcomes and added anxiety and worries about pregnancy outcomes. Further, preparing and going through pregnancy requires vigilant attention to a diabetes management regimen and detailed planning of everyday activities with added stress on women. Psychological and social well being during and after pregnancy are integral for good pregnancy outcomes for both mother and baby. The aim of this study is to establish the face and content validity of two novel measures assessing the well-being of women with type 1 diabetes in their transition to motherhood, 1) during pregnancy and 2) during the postnatal period. METHODS: The approach to the development of the Pregnancy and Postnatal Well-being in T1DM Transition questionnaires was based on a four-stage pre-testing process; systematic overview of literature, items development, piloting testing of questionnaire and refinement of questionnaire. The questionnaire was reviewed at every stage by expert clinicians, researchers and representatives from consumer groups. The cognitive debriefing approach confirmed relevance of issues and identified additional items. RESULTS: The literature review and interviews identified three main areas impacting on the women's postnatal self-management; (1) psychological well-being; (2) social environment, (3) physical (maternal and fetal) well-being. The cognitive debriefing in pilot testing of the questionnaire identified that immediate postnatal period was difficult, particularly when the women were breastfeeding and felt depressed. CONCLUSIONS: The questionnaires fill an important gap by systematically assessing the psychosocial needs of women with type 1 diabetes during pregnancy and in the immediate postnatal period. The questionnaires can be used in larger data collection to establish psychometric properties. The questionnaires potentially play a key role in prospective research to determine the self-management and psychological needs of women with type 1 diabetes transitioning to motherhood and to evaluate health education interventions. PMID- 23445537 TI - Urinary CD8+ T-cell counts discriminate between active and inactive lupus nephritis. AB - INTRODUCTION: Lupus nephritis (LN) is a severe and frequent manifestation of systemic lupus erythematosus (SLE). Early detection of initial renal manifestations and relapses during follow-up is pivotal to prevent loss of renal function. Apart from renal biopsies, current urinary and serological diagnostic tests fail to accurately demonstrate the presence of active LN. Previously, we demonstrated that effector memory T-cells (CD45RO+CCR7-;TEM) migrate into the urine during active LN. The objective of this study was to assess the diagnostic value of urinary T-cells in comparison with traditional markers of active LN. METHODS: T-cells in the urine during active LN and remission were investigated. Twenty-two, in most cases biopsy-proven, active LN patients and 24 SLE patients without active LN were enrolled and serial measurements were performed in 16 patients. RESULTS: Analysis of the urinary sediment in active renal disease showed an increased number of CD8+ T-cells and absence of these cells during remission. Enumerating T-cell counts in LN patients with a history of renal involvement was a superior marker of active LN in comparison to traditional markers, such as proteinuria and s-creatinine. CONCLUSIONS: In conclusion, urinary T-cells, in particular CD8+ T cells, are a promising marker to assess renal activity in LN patients, in particular in those with prior renal involvement. PMID- 23445538 TI - Depression prevention and mental health promotion interventions: is stigma taken into account? An overview of the Italian initiatives. PMID- 23445536 TI - Retrospective attention enhances visual working memory in the young but not the old: an ERP study. AB - Behavioral evidence from the young suggests spatial cues that orient attention toward task-relevant items in visual working memory (VWM) enhance memory capacity. Whether older adults can also use retrospective cues ("retro-cues") to enhance VWM capacity is unknown. In the current event-related potential (ERP) study, young and old adults performed a VWM task in which spatially informative retro-cues were presented during maintenance. Young but not older adults' VWM capacity benefited from retro-cueing. The contralateral delay activity (CDA) ERP index of VWM maintenance was attenuated after the retro-cue, which effectively reduced the impact of memory load. CDA amplitudes were reduced prior to retro-cue onset in the old only. Despite a preserved ability to delete items from VWM, older adults may be less able to use retrospective attention to enhance memory capacity when expectancy of impending spatial cues disrupts effective VWM maintenance. PMID- 23445539 TI - Effect of long-term wastewater irrigation on potential denitrification and denitrifying communities in soils at the watershed scale. AB - Wastewater irrigation mitigates the problem of water shortage but leads to the potential accumulation of pollutants and causes corresponding changes in denitrifying communities and denitrification, hence the potential ecological risk of long-term wastewater irrigation should not be overlooked. We investigated the relative contributions of different environmental factors to the abundance and diversity of denitrifying communities harboring nirK, nirS, and nosZ genes and the relative importance of these biotic and abiotic variables in potential denitrification activity (PDA) in soils with wastewater irrigation for around 25 years at a large watershed scale. Results showed that soil physicochemical properties, pollutants, including heavy metals and PAHs, and vegetation are the major factor groups influencing the abundance and structure of the three denitrifying communities and PDA. NirK-, nirS-, or nosZ-harboring denitrifiers responded in different manners to environmental changes, and were mainly influenced by substrate concentration, carbon source, or pollutants, respectively. The structure of the three denitrifying communities was more relevant to the environmental changes than their abundance. Conversely, the abundance, rather than diversity, was correlated with PDA. Pollutants and vegetation could affect PDA by both direct and indirect paths through soil physicochemical properties including pH, carbon and nitrogen sources, or through the abundance of denitrifying functional genes. The abundance of denitrifying functional genes is a valuable index that integrates potential activity and various environmental factors, and is therefore a good predictor of denitrification in the presence of environmental changes. PMID- 23445540 TI - Associations between dietary variety and measures of body adiposity: a systematic review of epidemiological studies. AB - Dietary variety is positively correlated with energy intake in most studies. However, the associations between dietary variety and measures of body adiposity are inconsistent in the literature, which limits the development of clear national nutrition recommendations regarding dietary variety. In the present systematic review, we critically evaluate the associations between dietary variety and measures of body adiposity among healthy adults within the existing literature. We conducted a systematic search of the MEDLINE and Web of Science databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to examine these associations. We identified twenty six studies in total that investigated the associations between dietary variety and body adiposity measures. Total variety was non-significantly associated with body adiposity in most studies, while variety in recommended foods was either inversely associated (six out of ten studies) or non-significantly associated (three out of ten studies) with body adiposity. Conversely, variety in non recommended foods (i.e. sources of added sugars and solid fats) increased the likelihood of excess adiposity in most studies (six out of nine studies). Definitions and measurement of dietary variety were inconsistent across studies and contributed to some of the discrepancies noted in the literature. In conclusion, among the studies that met the inclusion criteria for the present review, dietary variety was inconsistently associated with body adiposity in diverse populations. Using consistent and specific definitions of dietary variety may help provide further insight into the associations between dietary variety and excess adiposity before definitive public health messages are ma PMID- 23445541 TI - Health literacy of Dutch adults: a cross sectional survey. AB - BACKGROUND: Relatively little knowledge is available to date about health literacy among the general population in Europe. It is important to gain insights into health literacy competences among the general population, as this might contribute to more effective health promotion and help clarify socio-economic disparities in health. This paper is part of the European Health Literacy Survey (HLS-EU). It aims to add to the body of theoretical knowledge about health literacy by measuring perceived difficulties with health information in various domains of health, looking at a number of competences. The definition and measure of health literacy is still topic of debate and hardly any instruments are available that are applicable for the general population. The objectives were to obtain an initial measure of health literacy in a sample of the general population in the Netherlands and to relate this measure to education, income, perceived social status, age, and sex. METHODS: The HLS-EU questionnaire was administered face-to-face in a sample of 925 Dutch adults, during July 2011. Perceived difficulties with the health literacy competences for accessing, understanding, appraising and applying information were measured within the domains of healthcare, disease prevention and health promotion. Multiple linear regression analyses were applied to explore the associations between health literacy competences and education, income, perceived social status, age, and sex. RESULTS: Perceived difficulties with health information and their association with demographic and socio-economic variables vary according to the competence and health domain addressed. Having a low level of education or a low perceived social status or being male were consistently found to be significantly related to relatively low health literacy scores, mainly for accessing and understanding health information. CONCLUSIONS: Perceived difficulties with health information vary between competences and domains of health. Health literacy competences are associated with indicators of socio-economic position and with the domain in which health information is provided. PMID- 23445542 TI - CognitionMaster: an object-based image analysis framework. AB - BACKGROUND: Automated image analysis methods are becoming more and more important to extract and quantify image features in microscopy-based biomedical studies and several commercial or open-source tools are available. However, most of the approaches rely on pixel-wise operations, a concept that has limitations when high-level object features and relationships between objects are studied and if user-interactivity on the object-level is desired. RESULTS: In this paper we present an open-source software that facilitates the analysis of content features and object relationships by using objects as basic processing unit instead of individual pixels. Our approach enables also users without programming knowledge to compose "analysis pipelines" that exploit the object-level approach. We demonstrate the design and use of example pipelines for the immunohistochemistry based cell proliferation quantification in breast cancer and two-photon fluorescence microscopy data about bone-osteoclast interaction, which underline the advantages of the object-based concept. CONCLUSIONS: We introduce an open source software system that offers object-based image analysis. The object-based concept allows for a straight-forward development of object-related interactive or fully automated image analysis solutions. The presented software may therefore serve as a basis for various applications in the field of digital image analysis. PMID- 23445543 TI - Sirtuins as possible drug targets in type 2 diabetes. AB - The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem in industrialized countries, and new therapeutic strategies to prevent T2DM are urgently needed worldwide. It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related diseases, including diabetes. Molecules that mimic CR metabolically may therefore represent new therapeutic targets for T2DM. Sirtuin1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a NAD+-dependent histone deacetylase, and its activity is closely associated with longevity under CR. Growing evidence suggests that SIRT1 regulates glucose lipid metabolism through its deacetylase activity for many known substrates and has many roles in the metabolic pathway through its direct or indirect involvement in insulin signaling in insulin-sensitive organs, including adipose tissue, liver and skeletal muscle. In addition, SIRT1 regulates insulin secretion, and adiponectin production, inflammation, gluconeogenesis, circadian rhythms and oxidative stress, which together contribute to the development of insulin resistance. Moreover, the overexpression of SIRT1 and several SIRT1 activators have beneficial effects on glucose homeostasis and insulin sensitivity in diabetic animal models and humans. Therefore, SIRT1 may represent a new therapeutic target for the prevention of diseases related to insulin resistance and T2DM. In addition, SIRT3 and SIRT6 play crucial roles in glucose and lipid metabolism. In this review, we summarize the current understanding of the biological functions of SIRT1, SIRT3 and SIRT6 in metabolism and discuss their potential role as therapeutic targets in T2DM. PMID- 23445544 TI - Cross cultural evaluation of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) --a mixed methods study. AB - BACKGROUND: We aimed to validate the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) among English speaking adults representing two of the minority ethnic groups living in the UK, self-identified as Chinese or Pakistani by background, in a mixed methods study. METHODS: Quantitative data were collected in two cities in the West Midlands, UK. Item response, dimensionality, internal consistency, and construct validity of the WEMWBS were assessed in Chinese and Pakistani groups separately, using data from both cities combined.Qualitative data were collected in the first city in eight focus groups of different ages recruited by the community workers. Three mixed sex Chinese and five single sex Pakistani groups discussed ease of completion and comprehension of items, together with overall reactions to the scale and underlying concept.Results of quantitative and qualitative analysis were examined for commonalities and differences. RESULTS: Item completion and item total correlations were satisfactory in both groups. In the Chinese data, Exploratory Factor Analysis showed a single factor with loadings ranging from 0.60 to 0.82 for all 14 items. In the Pakistani data, three factors reached statistical significance; however, a substantial drop in eigenvalues between the first and second factors and the limited variance explained by the second and third factors supported a one-factor model. All items loaded on this factor from 0.51 to 0.83.In the Chinese and Pakistani data respectively, Cronbach's alpha was 0.92 (0.89 - 0.94) and 0.91 (0.88 - 0.94); Spearman's correlation with GHQ-12 was - 0.63 (-0.73 to -0.49) and -0.55 (-0.70 to -0.36), and with the WHO-5 0.62 (0.46-0.75) and 0.64 (0.50 to 0.76).Qualitative analysis revealed good comprehension and ease of completion of almost all items. Some culturally determined differences in understanding of mental well-being, which varied both between and within communities, emerged. CONCLUSIONS: The WEMWBS was well received by members of both Pakistani and Chinese communities. It showed high levels of consistency and reliability compared with accepted criteria. Data were sufficiently strong to recommend the WEMWBS for use in general population surveys. PMID- 23445545 TI - The illusion of specific capture: surface and solution studies of suboptimal oligonucleotide hybridization. AB - BACKGROUND: Hybridization based assays and capture systems depend on the specificity of hybridization between a probe and its intended target. A common guideline in the construction of DNA microarrays, for instance, is that avoiding complementary stretches of more than 15 nucleic acids in a 50 or 60-mer probe will eliminate sequence specific cross-hybridization reactions. Here we present a study of the behavior of partially matched oligonucleotide pairs with complementary stretches starting well below this threshold complementarity length - in silico, in solution, and at the microarray surface. The modeled behavior of pairs of oligonucleotide probes and their targets suggests that even a complementary stretch of sequence 12 nt in length would give rise to specific cross-hybridization. We designed a set of binding partners to a 50-mer oligonucleotide containing complementary stretches from 6 nt to 21 nt in length. RESULTS: Solution melting experiments demonstrate that stable partial duplexes can form when only 12 bp of complementary sequence are present; surface hybridization experiments confirm that a signal close in magnitude to full strength signal can be obtained from hybridization of a 12 bp duplex within a 50mer oligonucleotide. CONCLUSIONS: Microarray and other molecular capture strategies that rely on a 15 nt lower complementarity bound for eliminating specific cross-hybridization may not be sufficiently conservative. PMID- 23445546 TI - iSeeRNA: identification of long intergenic non-coding RNA transcripts from transcriptome sequencing data. AB - BACKGROUND: Long intergenic non-coding RNAs (lincRNAs) are emerging as a novel class of non-coding RNAs and potent gene regulators. High-throughput RNA sequencing combined with de novo assembly promises quantity discovery of novel transcripts. However, the identification of lincRNAs from thousands of assembled transcripts is still challenging due to the difficulties of separating them from protein coding transcripts (PCTs). RESULTS: We have implemented iSeeRNA, a support vector machine (SVM)-based classifier for the identification of lincRNAs. iSeeRNA shows better performance compared to other software. A public available webserver for iSeeRNA is also provided for small size dataset. CONCLUSIONS: iSeeRNA demonstrates high prediction accuracy and runs several magnitudes faster than other similar programs. It can be integrated into the transcriptome data analysis pipelines or run as a web server, thus offering a valuable tool for lincRNA study. PMID- 23445547 TI - The prolyl isomerase SlyD is a highly efficient enzyme but decelerates the conformational folding of a client protein. AB - Folding enzymes often use distinct domains for the interaction with a folding protein chain and for the catalysis of intrinsically slow reactions such as prolyl cis/trans isomerization. Here, we investigated the refolding reaction of ribonuclease T1 in the presence of the prolyl isomerase SlyD from Escherichia coli to examine how this enzyme catalyzes the folding of molecules with an incorrect trans proline isomer and how it modulates the conformational folding of the molecules with the correct cis proline. The kinetic analysis suggests that prolyl cis -> trans isomerization in the SlyD-bound state shows a rate near 100 s(-1) and is thus more than 10(4)-fold accelerated, relative to the uncatalyzed reaction. As a consequence of its fast binding and efficient catalysis, SlyD retards the conformational folding of the protein molecules with the correct cis isomer, because it promotes the formation of the species with the incorrect trans isomer. In the presence of >=1 MUM SlyD, protein molecules with cis and trans prolyl isomers refold with identical rates, because SlyD-catalyzed cis/trans equilibration is faster than conformational folding. The cis or trans state of a particular proline is thus no longer a determinant for the rate of folding. PMID- 23445548 TI - The Swiss bus accident on 13 March 2012: lessons for pre-hospital care. PMID- 23445549 TI - Molecular characterization and expression analysis of soluble trehalase gene in Aphis glycines, a migratory pest of soybean. AB - In insects, the enzyme trehalase plays a crucial role in energy metabolism, chitin synthesis and possibly during plant-insect interactions. We have characterized a soluble trehalase gene (Tre-1) from cDNA of Aphis glycines, a serious migratory pest of soybean. The full-length cDNA of Tre-1 in A. glycines (AyTre-1) was 2550 bp long with an open reading frame of 1770 bp that encoded for a 589 amino acid residues protein. Sequence assessment and phylogenetic analysis of the putative protein suggested that the selected cDNA belongs to soluble trehalase group. Quantitative PCR (qPCR) analysis in different tissues and developmental stages revealed peak mRNA levels of AyTre-1 in the gut (compared with other tissues assayed) and highest expression in the second instar compared with the other developmental stages assayed. Interestingly, a significantly increased expression of AyTre-1 (1.9-fold, P < 0.05) was observed in the alate morphs compared with that in apterate morphs. However, there was no significant difference in AyTre-1 expression in A. glycines-nymphs fed with resistant and susceptible plants. Expression patterns identified in this study provide a platform to investigate the role of AyTre-1 in physiological activities such as flight and feeding in A. glycines. The characterization of soluble trehalase gene may help to develop novel strategies to manage A. glycines using trehalase inhibitors and using RNA interference for knock-down of AyTre-1 expression. PMID- 23445550 TI - Preterm Birth and Healthy Outcomes Team: the science and strategy of team-based investigation. PMID- 23445551 TI - Endothelial heterogeneity and adhesion molecules N-glycosylation: implications in leukocyte trafficking in inflammation. AB - Inflammation is a major contributing element to a host of diseases with the interaction between leukocytes and the endothelium being key in this process. Much is understood about the nature of the adhesion molecule proteins expressed on any given leukocyte and endothelial cell that modulates adhesive interactions. Although it is appreciated that these proteins are heavily glycosylated, relatively little is known about the roles of these posttranslational modifications and whether they are regulated, and if so how during inflammation. Herein, we suggest that a paucity in this understanding is one major reason for the lack of successful therapies to date for modulating leukocyte-endothelial interactions in human inflammatory disease and discuss developing paradigms of (i) how endothelial adhesion molecule glycosylation (with a focus on N glycosylation) maybe a critical element in understanding endothelial heterogeneity between different vascular beds and species, (ii) how adhesion molecule N-glycosylation may be under distinct, and as yet, unknown modes of regulation during inflammatory stress to affect the inflammatory response in a vascular bed- and disease-specific manner (analogous to a "zip code" for inflammation) and finally (iii) to underscore the concept that a fuller appreciation of the role of adhesion molecule glycoforms is needed to provide foundations for disease and tissue-specific targeting of inflammation. PMID- 23445552 TI - The importance of preoperative information for patient participation in colorectal surgery care. AB - AIMS AND OBJECTIVES: To identify and describe patients' experiences of a preoperative information session with a nurse, as part of the enhanced recovery after surgery (ERAS) concept, and its impact on patient participation in their own care. BACKGROUND: Enhanced recovery after surgery is a standardised, multimodal treatment programme for elective colorectal surgery, leading to faster recovery and shorter hospital stays via interprofessional collaboration. The ERAS concept is initiated for patients a week before surgery when the patient receives detailed information about the care process during a meeting with a nurse. DESIGN: The study is a qualitative interpretive study based on interviews. METHODS: Twelve patients, nine men and three women, were interviewed. The interviews were transcribed verbatim and analysed using interpretive phenomenological analysis (IPA). RESULTS: The analysis identified and formulated five themes: being seen, security, trust, responsibility and participation. All themes are closely related and illustrate positive and negative sides of the patient's experience. They hang together and form a complete set of experiences: ERAS conversation and its impact on patients' participation. CONCLUSIONS: The results show that patients feel confirmed in the ERAS conversation. Healthcare professionals need to be bonding more information call during hospitalisation. It is important to confirm the patient in order for them to participate and take responsibility. Reliance on caregivers is important for patients to feel safe and to participate in their own care. This study shows that the ERAS conversation was experienced as being structured and individually tailored, but the information must apply to the patients throughout the period of care. RELEVANCE TO CLINICAL PRACTICE: Some shortcomings have been revealed, which should enable improvement in the care of patients. Healthcare professionals need to raise awareness of patients' responsibilities for participation in their own recovery and care. Healthcare professionals and patients need to be aware of each other's responsibilities. PMID- 23445553 TI - Follow up of lung transplant recipients using an electronic nose. AB - Lung transplantation is the only available treatment for some end-stage lung diseases. However, patients following lung transplantation need tight control to prevent serious complications, but mainly invasive techniques are available. An electronic nose is a non-invasive way to measure exhaled volatiles. In this study we investigated the potential of electronic nose measurements in lung transplant patients and compared the 'breathprint' with clinical parameters. Sixteen patients with lung transplant and 33 healthy subjects participated in the study. Exhaled breath was collected; laboratory tests and lung function measurements were carried out. Breath samples were processed by an electronic nose, analysed using principal component analysis and compared to blood (CRP, tacrolimus) and lung function parameters. Significant differences were found in exhaled breath volatile compound pattern between healthy subjects and lung transplant recipients. The plasma level of tacrolimus showed significant relationship with 'breathprint' in lung transplanted patients. Patients living with transplanted lungs can be discriminated from healthy subjects by exhaled breath volatile organic compounds' profile. Treatment after lung transplantation needs to be taken into consideration when using an electronic nose as medication may have profound influence on breathprints. PMID- 23445554 TI - Solid pseudopapillary tumor of the pancreas and concomitant urogenital malformations in a young woman. AB - Solid pseudopapillary tumor (SPT) of the pancreas is a rare pancreatic tumor with low malignant potential. It occurs characteristically more often in young women. SPT associated with extra- and pancreatic anomalies are occasionally reported. Here we report a case of pancreatic SPT with concomitant urogenital malformations including solitary kidney and uterus didelphys in a 25-year-old woman. The patient underwent central pancreatectomy, and SPT was confirmed with pathological results. Recurrence or metastasis was not found after 14 months of follow-up. PMID- 23445555 TI - Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study. AB - AIM: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD. METHODS: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [(18)F]fluorodeoxyglucose positron emission computed tomography (FDG PET) and magnetic resonance imaging, and a complete neuropsychological battery. RESULTS: FDG-PET of subjects with PD revealed significant metabolic elevations in the bilateral posterior lentiform nucleus, posterior cingulate, and parahippocampus, and metabolic reductions in the bilateral temporoparietal association cortex and occipital lobe versus controls. PD subjects had significant reductions in executive/attention function, memory/verbal learning, and speed of thinking, and significantly increased depression, anxiety and apathy scores compared with controls. Motor dysfunction correlated with increased metabolism in the posterior lentiform nucleus, pons, and cerebellum, and decreased metabolism in the temporoparietal lobe. Cognitive dysfunction correlated with increased posterior cingulate metabolism and decreased temporoparietal lobe metabolism. Depressive symptoms correlated with increased amygdala metabolism; anxiety scores correlated with decreased caudate metabolism, and apathy scores correlated with increased metabolism in the anterior cingulate and orbitofrontal lobe and decreased metabolism in the temporoparietal association cortex. CONCLUSIONS: Our findings showed that motor, cognitive, and emotional dysfunction in PD are associated with distinct patterns of cerebral metabolic changes. PMID- 23445556 TI - Imprinted genes in mouse placental development and the regulation of fetal energy stores. AB - Imprinted genes, which are preferentially expressed from one or other parental chromosome as a consequence of epigenetic events in the germline, are known to functionally converge on biological processes that enable in utero development in mammals. Over 100 imprinted genes have been identified in the mouse, the majority of which are both expressed and imprinted in the placenta. The purpose of this review is to provide a summary of the current knowledge regarding imprinted gene function in the mouse placenta. Few imprinted genes have been assessed with respect to their dosage-related action in the placenta. Nonetheless, current data indicate that imprinted genes converge on two key functions of the placenta, nutrient transport and placental signalling. Murine studies may provide a greater understanding of certain human pathologies, including low birth weight and the programming of metabolic diseases in the adult, and complications of pregnancy, such as pre-eclampsia and gestational diabetes, resulting from fetuses carrying abnormal imprints. PMID- 23445557 TI - A systematic review of measures of shoulder pain and functioning using the International classification of functioning, disability and health (ICF). AB - BACKGROUND: Shoulder pain is a common condition with prevalence estimates of 7 26% and the associated disability is multi-faceted. For functional assessments in clinic and research, a number of condition-specific and generic measures are available. With the approval of the ICF, a system is now available for the analysis of health status measures. The aims of this systematic literature review were to identify the most frequently addressed aspects of functioning in assessments of shoulder pain and provide an overview of the content of frequently used measures. METHODS: Meaningful concepts of the identified measures were extracted and linked to the most precise ICF categories. Second-level categories with a relative frequency above 1% and the content of measures with at least 5 citations were reported. RESULTS: A set of 40 second-level ICF categories were identified in 370 single-item measures and 105 multi-item measures, of these, 28 belonged to activities and participation, 11 to body functions and structures and 1 to environmental factors. The most frequently addressed concepts were: pain; movement-related body functions and structures; sleep, hand and arm use, self care, household tasks, work and employment, and leisure. Concepts of psycho social functions and environmental factors were less frequently included. The content overview of commonly used condition-specific and generic measures displayed large variations in the number of included concepts. The most wide ranging measures, the DASH and ASES were linked to 23 and 16 second-level ICF categories, respectively, whereas the Constant were linked to 7 categories and the SST and the SPADI to 6 categories each. CONCLUSIONS: This systematic review displayed that measures used for shoulder pain included more than twice as many concepts of activities and participation than concepts of body functions and structures. Environmental factors were scarcely addressed. The huge differences in the content of the condition-specific multi-item measures demonstrates the importance of clarifying the content to select the most appropriate measure both in research and in clinical work. For clinical situations, we propose use of a wide-ranging condition-specific measure that conceptualizes assessments of shoulder pain from a bio-psycho-social perspective. Further research is needed to assess how patient-reported problems in functioning are captured in the commonly used measures. PMID- 23445558 TI - Breath analysis--past, present and future: a special issue in honour of Michael Phillips' 70th birthday. PMID- 23445561 TI - Maternal exposure to lipopolysaccharide leads to transient motor dysfunction in neonatal rats. AB - Epidemiological and experimental data implicate maternal infection and inflammation in the etiology of brain white matter injury, which may lead to cerebral palsy in preterm newborns. Our aim was to investigate motor development of the offspring after maternal administration of lipopolysaccharide (LPS). Wistar rats were intraperitoneally injected with Escherichia coli LPS or saline on gestational days 19 and 20. From birth to 3 weeks, pups were tested for neurobehavioral development, neurological signs and reflexes. From 3 to 6 weeks, motor coordination was investigated. At 4 months, animals were tested for locomotion. Brain myelination was assessed by myelin basic protein immunohistochemistry. Days of appearance of several neurological reflexes were significantly delayed, and neonate LPS pups displayed retarded performance in righting, gait and negative geotaxis. At the juvenile stage, LPS animals showed important impairment in coordination. However, although the LPS group performed worse in most tests, they reached vehicle levels by 5 weeks. At 4 months, LPS animals did not show variations in locomotion performances compared to vehicle. No myelination differences have been observed in the brains at adulthood. Maternal LPS administration results in delayed motor development even though these alterations fade to reach control level by 5 weeks. Motor impairments observed at the early stage in this study could be linked to previously reported hypomyelination of the white matter induced by maternal LPS challenge in the neonates. Finally, the normal myelination shown here at adulthood may explain the functional recovery of the animals and suggest either a potential remyelination of the brain or a delayed myelination in LPS pups. PMID- 23445560 TI - Key components of early intervention programs for preterm infants and their parents: a systematic review and meta-analysis. AB - BACKGROUND: Preterm infants are at greater risk for neurodevelopmental disabilities than full term infants. Interventions supporting parents to improve the quality of the infant's environment should improve developmental outcomes for preterm infants. Many interventions that involve parents do not measure parental change, nor is it clear which intervention components are associated with improved parental outcomes. The aim of this review was to categorize the key components of early intervention programs and determine the direct effects of components on parents, as well as their preterm infants. METHODS: MEDLINE, EMBASE, CINAHL, ERIC, and Cochrane Database of Systematic Reviews were searched between 1990 and December 2011. Eligible randomized controlled trials (RCTs) included an early intervention for preterm infants, involved parents, and had a community component. Of 2465 titles and abstracts identified, 254 full text articles were screened, and 18 met inclusion criteria. Eleven of these studies reported maternal outcomes of stress, anxiety, depressive symptoms, self efficacy, and sensitivity/responsiveness in interactions with the infant. Meta analyses using a random effects model were conducted with these 11 studies. RESULTS: Interventions employed multiple components categorized as (a) psychosocial support, (b) parent education, and/or (c) therapeutic developmental interventions targeting the infant. All interventions used some form of parenting education. The reporting quality of most trials was adequate, and the risk of bias was low based on the Cochrane Collaboration tool. Meta-analyses demonstrated limited effects of interventions on maternal stress (Z = 0.40, p = 0.69) and sensitivity/responsiveness (Z = 1.84, p = 0.07). There were positive pooled effects of interventions on maternal anxiety (Z = 2.54, p = 0.01), depressive symptoms (Z = 4.04, p <.0001), and self-efficacy (Z = 2.05, p = 0.04). CONCLUSIONS: Positive and clinically meaningful effects of early interventions were seen in some psychosocial aspects of mothers of preterm infants. This review was limited by the heterogeneity of outcome measures and inadequate reporting of statistics. IMPLICATIONS OF KEY FINDINGS: Interventions for preterm infants and their mothers should consider including psychosocial support for mothers. If the intervention involves mothers, outcomes for both mothers and preterm infants should be measured to better understand the mechanisms for change. PMID- 23445562 TI - Achievement of pregnancies in women with primary ovarian insufficiency using close monitoring of follicle development: case reports. AB - Women with primary ovarian insufficiency (POI)/premature ovarian failure exhibit hypergonadotropic hypogonadism due to follicle dysfunction and depletion before the age of 40 years. Because ovulation is extremely rare and thought to be unpredictable in women with POI and because no ovulation induction regimens have been shown to be efficacious, oocyte donation is the only evidence-based treatment for women with POI with desired fertility. Oocyte donation is, however, extremely limited in several countries including Japan. Here, we report four women with POI who achieved pregnancies resulting from timed intercourse or intrauterine insemination in combination with cyclic estrogen/progesterone therapy and close monitoring of follicle development. These four patients were diagnosed with POI at the mean age of 27.5 +/- 8.5 (mean +/- SD; range, 19-35), subjected to follicle monitoring at the mean age of 29.8 +/- 5.7 (23-35), and conceived at the mean age of 34.5 +/- 3.9 (29-38). The interval between the initiation of follicle monitoring and pregnancy was 4.8 +/- 2.8 (2-8) years. In one of the patients, her most recent ovulation occurred after a three-year interval. All four patients had uncomplicated pregnancies with term deliveries. In the event that oocyte donation and adoption are not available and/or various treatments with intensive ovulation induction have been unsuccessful, close and continuous monitoring of follicle growth to identify very rare ovulatory events might be considered for patients with POI and desired fertility. PMID- 23445563 TI - Analysis of ventilatory ratio as a novel method to monitor ventilatory adequacy at the bedside. AB - INTRODUCTION: Due to complexities in its measurement, adequacy of ventilation is seldom used to categorize disease severity and guide ventilatory strategies. Ventilatory ratio (VR) is a novel index to monitor ventilatory adequacy at the bedside. VR=(VEmeasured * PaCO2measured)/(VEpredicted * PaCO2ideal). VEpredicted is 100 mL.Kg-1.min-1 and PaCO2ideal is 5 kPa. Physiological analysis shows that VR is influenced by dead space (VD/VT) and CO2 production (VCO2). Two studies were conducted to explore the physiological properties of VR and assess its use in clinical practice. METHODS: Both studies were conducted in adult mechanically ventilated ICU patients. In Study 1, volumetric capnography was used to estimate daily VD/VT and measure VCO2 in 48 patients. Simultaneously, ventilatory ratio was calculated using arterial blood gas measurements alongside respiratory and ventilatory variables. This data was used to explore the physiological properties of VR. In Study 2, 224 ventilated patients had daily VR and other respiratory variables, baseline characteristics, and outcome recorded. The database was used to examine the prognostic value of VR. RESULTS: Study 1 showed that there was significant positive correlation between VR and VD/VT (modified r = 0.71) and VCO2 (r = 0.14). The correlation between VR and VD/VT was stronger in mandatory ventilation compared to spontaneous ventilation. Linear regression analysis showed that VD/VT had a greater influence on VR than VCO2 (standardized regression coefficient 1/1-VD/VT: 0.78, VCO2: 0.44). Study 2 showed that VR was significantly higher in non-survivors compared to survivors (1.55 vs. 1.32; P < 0.01). Univariate logistic regression showed that higher VR was associated with mortality (OR 2.3, P < 0.01), this remained the case after adjusting for confounding variables (OR 2.34, P = 0.04). CONCLUSIONS: VR is an easy to calculate bedside index of ventilatory adequacy and appears to yield clinically useful information. PMID- 23445564 TI - HIV+ children and their families in the UK: results from a family-clinic based 'look-back' exercise in London. AB - Advances in antiretroviral treatment have resulted in a growing number of HIV+ children surviving into adolescence and adulthood. However, HIV remains a chronic condition compounded by additional psychosocial stressors associated with living with HIV. The gold standard for treatment of HIV+ children and young people is within a family context. This 'look-back' exercise was conducted within an HIV family clinic context in London. HIV+ children's clinical notes were examined with the aim of describing the medical and social context of the families attending the clinic. Results showed that families are living with many psychosocial challenges that may have an impact on their ability to respond effectively to the challenge of living with HIV disease. PMID- 23445565 TI - Fast probabilistic file fingerprinting for big data. AB - BACKGROUND: Biological data acquisition is raising new challenges, both in data analysis and handling. Not only is it proving hard to analyze the data at the rate it is generated today, but simply reading and transferring data files can be prohibitively slow due to their size. This primarily concerns logistics within and between data centers, but is also important for workstation users in the analysis phase. Common usage patterns, such as comparing and transferring files, are proving computationally expensive and are tying down shared resources. RESULTS: We present an efficient method for calculating file uniqueness for large scientific data files, that takes less computational effort than existing techniques. This method, called Probabilistic Fast File Fingerprinting (PFFF), exploits the variation present in biological data and computes file fingerprints by sampling randomly from the file instead of reading it in full. Consequently, it has a flat performance characteristic, correlated with data variation rather than file size. We demonstrate that probabilistic fingerprinting can be as reliable as existing hashing techniques, with provably negligible risk of collisions. We measure the performance of the algorithm on a number of data storage and access technologies, identifying its strengths as well as limitations. CONCLUSIONS: Probabilistic fingerprinting may significantly reduce the use of computational resources when comparing very large files. Utilisation of probabilistic fingerprinting techniques can increase the speed of common file related workflows, both in the data center and for workbench analysis. The implementation of the algorithm is available as an open-source tool named pfff, as a command-line tool as well as a C library. The tool can be downloaded from http://biit.cs.ut.ee/pfff. PMID- 23445566 TI - Impact on quality of life in teachers after educational actions for prevention of voice disorders: a longitudinal study. AB - BACKGROUND: Voice problems are more common in teachers due to intensive voice use during routine at work. There is evidence that occupational disphonia prevention programs are important in improving the quality voice and consequently the quality of subjects' lives. AIM: To investigate the impact of educational voice interventions for teachers on quality of life and voice. METHODS: A longitudinal interventional study involving 70 teachers randomly selected from 11 public schools, 30 to receive educational intervention with vocal training exercises and vocal hygiene habits (experimental group) and 40 to receive guidance on vocal hygiene habits (control group control). Before the process of educational activities, the Voice-Related Quality of Life instrument (V-RQOL) was applied, and 3 months after conclusion of the activities, the subjects were interviewed again, using the same instrument. For data analysis, Prox MIXED were applied, with a level of significance alpha < 0.05. RESULTS: Teachers showed significantly higher domain and overall V-RQOL scores after preventive intervention, in both control and experimental groups. Nevertheless, there was no statistical difference in scores between the groups. CONCLUSION: Educational actions for vocal health had a positive impact on the quality of life of the participants, and the incorporation of permanent educational actions at institutional level is suggested. PMID- 23445567 TI - Genetic ancestry modifies fatty acid concentrations in different adipose tissue depots and milk fat. AB - The objective of this study was to determine the effect of cow genetic strain on fatty acid (FA) profiles in adipose tissue and milk. Adipose samples from two subcutaneous (shoulder and tail-head) and three visceral (kidney channel, mesenteric and omental) depots were obtained post mortem from New Zealand (NZ; n = 8) and North American (NA; n = 8) Holstein-Friesian cows. At the time of slaughter cows were in similar body condition (NZ: 4.0 +/- 0.03, NA: 4.0 +/- 0.02; +/- SD) and stage of lactation (NZ: 90 +/- 11.2 d; NA: 83 +/- 4.3 d; +/- SD). Milk was collected during the a.m. milking prior to slaughter and milk fat was extracted. Adipose and milk fat FA were quantified using gas chromatography. NZ cows had a lower proportion of saturated FA in shoulder, tail-head and omental adipose tissue and a greater proportion of mono-unsaturated FA and an elevated Delta9-desaturase index in shoulder and tail-head adipose tissue. The proportions of individual FA differed between adipose depots, with proportions of de-novo FA greater in subcutaneous compared with visceral adipose depots. Milk from NZ cows contained greater concentrations of short chain FA (C8 : 0-12 : 0) and CLA, and less cis-9 18 : 1 than milk from NA cows. Regression analysis identified moderate associations between milk FA and shoulder adipose tissue FA for 18 : 2 (R(2) = 0.24), 18 : 3 n - 3 (R(2) = 0.39), and polyunsaturated fatty acids (R(2) = 0.38). Results from this study support the hypothesis that genetic strain dictates FA profiles in adipose tissue and milk and may alter the metabolic status of the various adipose depots differently. The data further support the premise that genetic strain affects the metabolic status of the various adipose depots differently. Elucidating the mechanisms that regulate the different adipose depots in the NZ and NA strains will increase our understanding of tissue mobilization and replenishment. PMID- 23445568 TI - De novo transcriptomic resources for two sibling species of moths: Ostrinia nubilalis and O. scapulalis. AB - BACKGROUND: This study aimed at enhancing the transcriptomic resources for two sibling species of moths, Ostrinia scapulalis (Adzuki bean borer) and Ostrinia nubilalis (European corn borer), as a foundation for future researches on their divergence history. Previous works on these species had shown that their genetic divergence was low, while they were reproductively isolated in natura and specialized on different host plants. Comparative genomic resources will help facilitate the understanding of the mechanisms involved in this isolation and adaptation to the host plants. Despite their fundamental interest, these species still lack the genomic resources to thoroughly identify candidate genes for functions of interest. We present here a high throughput sequencing and de novo transcriptome assembly for these two sibling species in line with this objective of comparative genomics. RESULTS: Based on 322,504 and 307,622 reads of 454 sequencing for O. scapulalis and O. nubilalis respectively, we reconstructed 11,231 and 10,773 transcripts, of which 40% were functionally annotated by BLAST analyzes. We determined the level of completeness of both assemblies as well as the recovery level of published Ostrinia genomic resources. Gene ontology (GO) of common and species-specific de novo transcripts did not reveal GO terms significantly enriched in one or the other species. By applying stringent homology searches on transcripts common to O. scapulalis and O. nubilalis, we identified a set of homologous transcripts, with a mean nucleotide identity value of 98.1%. In this set, the most divergent transcripts revealed candidate genes involved in developmental, sensorial and pathogen defense processes. CONCLUSIONS: This data greatly increases the genomic resources of Ostrinia species and constitute a solid skeleton for future comparative analyzes of expression or diversity, despite we show that the transcriptomes for both species have not been assembled at full completion. In addition, we provide a set of homologous transcripts together with their annotation as a source of candidate genes for comparative analyzes. PMID- 23445569 TI - Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by L-Deprenyl. AB - BACKGROUND: Development of mammary tumors is an age-associated phenomenon that is likely due to deficits in the neuroendocrine-immune interactions. Previously, we demonstrated that L-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, can enhance immune responses and restore noradrenergic (NA) innervation in the spleens of rats with carcinogen-induced and spontaneously developing mammary tumors. OBJECTIVES: To investigate whether (1) treatment of early middle-aged female rats would prevent the spontaneous development of mammary tumors accompanied by restoration of immunity in the spleen and draining lymph nodes (DLN) and sympathetic NA innervation in the spleen and (2) deprenyl can influence the proliferation of estrogen receptor (ER)-positive (MCF-7 and T47D) and ER negative (MDA-MB-231 and Hs 578T) human breast cancer cells. METHODS: Early middle-aged (8- to 9-month-old) female Sprague-Dawley rats were treated with 0, 1.0 or 2.5 mg of deprenyl/kg body weight (BW) daily i.p. for 12 months. Cells of ER-positive (ER+) and ER-negative (ER-) human breast cancer cell lines were incubated with media or 10(-3) to 10(-8) M deprenyl for 1, 2, 4 or 6 days to examine the proliferation of cells. RESULTS: Tumor incidence increased in saline treated old female rats, while deprenyl treatment significantly reduced the incidence of mammary tumors in these rats. Saline-treated tumor-bearing rats exhibited reduced splenic NA innervation and norepinephrine (NE) content, splenic interleukin (IL)-2 and interferon (IFN)-gamma levels and NK cell activity as well as DLN IL-2 and IFN-gamma levels compared to young female rats without tumors. In contrast, treatment with 2.5 mg/kg of deprenyl enhanced IL-2 and IFN-gamma production in both the spleen and DLN as well as splenic natural killer (NK) cell activity. Deprenyl treatment also increased concanavalin A (Con A)-induced proliferation of T lymphocytes in the DLN. Deprenyl-induced changes in immune responses were accompanied by enhanced NA innervation and NE content in the spleen. In vitro incubation of various concentrations of deprenyl with ER+ human breast cancer cell lines partly inhibited the proliferation of cells, while it had no effect on the ER- breast cancer cells. CONCLUSIONS: These results suggest that (1) development of mammary tumors is mediated through the loss of immunity and sympathetic NA nerve fibers accompanied by reduced NE levels in the spleen, (2) the prevention of mammary tumor development by deprenyl may involve the reversal of the tumor-associated decline in sympathetic NA activity and cell mediated immune responses in the spleen and DLN and (3) the antitumor effects of deprenyl may be partially mediated through ER-dependent intracellular signaling pathways. PMID- 23445570 TI - Exhaled nitric oxide as biomarker of acute lung injury: an unfulfilled promise? AB - The discovery of nitric oxide (NO) as a signalling and regulatory molecule and its subsequent detection in the exhaled breath has not only yielded new mechanistic insights but also diagnostic opportunities and therapeutic targets in several important medical conditions. In diseases involving chronic pulmonary inflammation such as asthma that affects millions worldwide, exhaled NO has achieved spectacular successes with patients currently owning handheld devices and monitoring inflammatory aspects of their conditions in their own homes. This has been facilitated by recognition by regulatory bodies, scientific and clinical societies and insurance companies. While characteristic changes in exhaled NO have also been observed in acute lung injury (ALI), the promise of exhaled NO as a surrogate biomarker of this life-threatening disease has not been achieved. In this work, we have analysed factors contributing to successes of exhaled NO in the asthma field and contrasted these on the ALI field. We provide a snapshot of current status of exhaled NO field in ALI and propose a framework for definite evaluation of exhaled NO as a clinically useful biomarker. PMID- 23445572 TI - Pseudobulbar dysarthria in the initial stage of motor neuron disease with dementia: a clinicopathological report of two autopsied cases. AB - We retrospectively analyzed the clinical features of two cases of neurodegenerative disease, whose initial symptoms were motor speech disorder and dementia, brought to autopsy. We compared the distributions of pathological findings with the clinical features. The main symptom of speech disorder was dysarthria, involving low pitch, slow rate, hypernasality and hoarseness. Other than these findings, effortful speech, sound prolongation and initial difficulty were observed. Moreover, repetition of multisyllables was severely impaired compared to monosyllables. Repetition and comprehension of words and sentences were not impaired. Neither atrophy nor fasciculation of the tongue was observed. Both cases showed rapid progression to mutism within a few years. Neuropathologically, frontal lobe degeneration including the precentral gyrus was observed. The bilateral pyramidal tracts also showed severe degeneration. However, the nucleus of the hypoglossal nerve showed only mild degeneration. These findings suggest upper motor neuron dominant motor neuron disease with dementia. We believe the results indicate a subgroup of motor neuron disease with dementia whose initial symptoms involve pseudobulbar palsy and dementia, and which shows rapid progression to mutism. PMID- 23445571 TI - A rare primary tumor of the thyroid gland: report a new case of leiomyosarcoma and literature review. AB - Primary leiomyosarcomas of the thyroid gland are extremely rare. we report a case of a 72 year-old women with a painful growing mass of the left neck with skin fistula. The patient underwent a lobectomy. The tumor histology showed spindle shaped cells arranged in interlacing fascicles that expressed desmine and H caldesmone, but were negative for cytokeratins and thyroglobulin. Total body CT scan didn't show any other tumor. The patient died two months after surgery. Primary thyroid leiomyosarcoma may be mistaken for other tumors, such as anaplastic or medullary carcinomas. Therefore, the diagnosis is difficult and requires numerous clinical, radiological, and pathological investigations. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1917621950869224. PMID- 23445573 TI - Concentration of exhaled breath condensate biomarkers after fractionated collection based on exhaled CO2 signal. AB - A standard procedure for exhaled breath condensate (EBC) collection is still lacking. The aim of this study was to compare the concentration of several biomarkers in whole (W-EBC) and fractionated EBC (A-EBC), the latter collected starting from CO2 >= 50% increase during exhalation. Forty-five healthy non smokers or asymptomatic light smokers were enrolled. Total protein concentrations in W-EBC and A-EBC were overlapping (median: 0.7 mg l(-1) in both cases), whereas mitochondrial DNA was higher in A-EBC (0.021 versus 0.011 ng ml(-1)), indicating a concentration rather than a dilution of lining fluid droplets in the last portion of exhaled air. H2O2 (0.13 versus 0.08 uM), 8-isoprostane (4.9 versus 4.4 pg ml(-1)), malondialdehyde (MDA) (4.2 versus 3.2 nM) and 4-hydroxy-2-nonhenal (HNE) (0.78 versus 0.66 nM) were all higher in W-EBC, suggesting a contribution from the upper airways to oxidative stress biomarkers in apparently healthy subjects. NH4(+) was also higher in W-EBC (median: 590 versus 370 uM), with an estimated increase over alveolar and bronchial air by a factor 1.5. pH was marginally, but significantly higher in W-EBC (8.05 versus 8.01). In conclusion, the fractionation of exhaled air may be promising in clinical and occupational medicine. PMID- 23445574 TI - A mutualistic approach to morality: the evolution of fairness by partner choice. AB - What makes humans moral beings? This question can be understood either as a proximate "how" question or as an ultimate "why" question. The "how" question is about the mental and social mechanisms that produce moral judgments and interactions, and has been investigated by psychologists and social scientists. The "why" question is about the fitness consequences that explain why humans have morality, and has been discussed by evolutionary biologists in the context of the evolution of cooperation. Our goal here is to contribute to a fruitful articulation of such proximate and ultimate explanations of human morality. We develop an approach to morality as an adaptation to an environment in which individuals were in competition to be chosen and recruited in mutually advantageous cooperative interactions. In this environment, the best strategy is to treat others with impartiality and to share the costs and benefits of cooperation equally. Those who offer less than others will be left out of cooperation; conversely, those who offer more will be exploited by their partners. In line with this mutualistic approach, the study of a range of economic games involving property rights, collective actions, mutual help and punishment shows that participants' distributions aim at sharing the costs and benefits of interactions in an impartial way. In particular, the distribution of resources is influenced by effort and talent, and the perception of each participant's rights on the resources to be distributed. PMID- 23445575 TI - Intertemporal bargaining predicts moral behavior, even in anonymous, one-shot economic games. AB - To the extent that acting fairly is in an individual's long-term interest, short term impulses to cheat present a self-control problem. The only effective solution is to interpret the problem as a variant of repeated prisoner's dilemma, with each choice as a test case predicting future choices. Moral choice appears to be the product of a contract because it comes from self-enforcing intertemporal cooperation. PMID- 23445576 TI - Cooperation and fairness depend on self-regulation. AB - Any evolved disposition for fairness and cooperation would not replace but merely compete with selfish and other antisocial impulses. Therefore, we propose that human cooperation and fairness depend on self-regulation. Evidence shows reductions in fairness and other prosocial tendencies when self-regulation fails. PMID- 23445577 TI - Partner selection, coordination games, and group selection. AB - The process of partner selection reflects ethnographic realities where cooperative rewards obtain that would otherwise be lost to loners. Baumard et al. neglect frequency-dependent processes exemplified by games of coordination. Such games can produce multiple equilibria that may or may not include fair outcomes. Additional, group-selection processes are required to produce the outcomes predicted by the models. PMID- 23445578 TI - From mutualism to moral transcendence. AB - Baumard et al. attribute morality to a naturally selected propensity to share costs and benefits of cooperation fairly. But how does mundane mutualism relate to transcendent notions of morality critical to creating cultures and civilizations? Humans often make their greatest exertions for an idea they form of their group. Primary social identity is bounded by sacred values, which drive individuals to promote their group through non-rational commitment to actions independently of likely risks and rewards. PMID- 23445579 TI - Modeling justice as a natural phenomenon. AB - Among other things, Baumard et al.'s "A Mutualistic Approach to Morality" considers the enforcement and establishment of moral norms, the interpersonal comparison of welfare, and the structure of fairness norms. This commentary draws attention to the relevance of the game theory literature to the first and second topic, and the social psychology literature to the third topic. PMID- 23445580 TI - Can mutualistic morality predict how individuals deal with benefits they did not deserve? AB - An individual obtains an unfair benefit and faces the dilemma of either hiding it (to avoid being excluded from future interactions) or disclosing it (to avoid being discovered as a deceiver). In line with the target article, we expect that this dilemma will be solved by a fixed individual strategy rather than a case-by case rational calculation. PMID- 23445581 TI - "Fair" outcomes without morality in cleaner wrasse mutualism. AB - Baumard et al. propose a functional explanation for the evolution of a sense of fairness in humans: Fairness preferences are advantageous in an environment where individuals are in strong competition to be chosen for social interactions. Such conditions also exist in nonhuman animals. Therefore, it remains unclear why fairness (equated with morality) appears to be properly present only in humans. PMID- 23445582 TI - Heterogeneity in fairness views: a challenge to the mutualistic approach? AB - This commentary argues that the observed heterogeneity in fairness views, documented in many economic experiments, poses a challenge to the partner choice theory developed by Baumard et al. It also discusses the extent to which their theory can explain how people consider inequalities due to pure luck. PMID- 23445583 TI - A strange(r) analysis of morality: a consideration of relational context and the broader literature is needed. AB - Baumard et al.'s definition of morality is narrow and their review of empirical work on human cooperation is limited, focusing only on economic games, almost always involving strangers. We suggest that theorizing about mutualisms will benefit from considering extant empirical behavioral research far more broadly and especially from taking relational context into account. PMID- 23445584 TI - The emotional shape of our moral life: anger-related emotions and mutualistic anthropology. AB - The evolutionary hypothesis advanced by Baumard et al. makes precise predictions on which emotions should play the main role in our moral lives: morality should be more closely linked to "avoidance" emotions (like contempt and disgust) than to "punitive" emotions (like anger). Here, we argue that these predictions run contrary to most psychological evidence. PMID- 23445585 TI - Does market competition explain fairness? AB - The target article by Baumard et al. uses their previous model of bargaining with outside options to explain fairness and other features of human sociality. This theory implies that fairness judgments are determined by supply and demand but humans often perceive prices (divisions of surplus) in competitive markets to be unfair. PMID- 23445586 TI - Evidence for partner choice in toddlers: considering the breadth of other oriented behaviours. AB - When do humans become moral beings? This commentary draws on developmental psychology theory to expand the understanding of early moral behaviours. We argue that by looking at a broader range of other-oriented acts than what has been considered by Baumard et al., we can find support for the mutualistic approach to morality even in early instances of other-oriented behaviours. PMID- 23445587 TI - Baumard et al.'s moral markets lack market dynamics. AB - Market models are indeed indispensable to understanding the evolution of cooperation and its emotional substrates. Unfortunately, Baumard et al. eschew market thinking in stressing the supposed invariance of moral/cooperative behavior across circumstances. To the contrary, humans display contingent morality/cooperation, and these shifts are best accounted for by market models of partner choice for mutually beneficial collaboration. PMID- 23445588 TI - More to morality than mutualism: consistent contributors exist and they can inspire costly generosity in others. AB - Studies of economic decision-making have revealed the existence of consistent contributors, who always make contributions to the collective good. It is difficult to understand such behavior in terms of mutualistic motives. Furthermore, consistent contributors can elicit apparently altruistic behavior from others. Therefore, although mutualistic motives are likely an important contributor to moral action, there is more to morality than mutualism. PMID- 23445589 TI - Mutualism is only a part of human morality. AB - Baumard et al. mischaracterize our model of individual and social choice behavior. We model individuals who maximize preferences given their beliefs, and subject to their informational and material constraints (Fehr & Gintis 2007). Individuals thus must make trade-offs among self-regarding, other-regarding, and character virtue goals. Two genetic predispositions are particularly crucial. The first is strong reciprocity. The second is the capacity to internalize norms through the socialization process. Our model includes the authors' model as a subset. PMID- 23445590 TI - Beyond economic games: a mutualistic approach to the rest of moral life. AB - Mutualism provides a compelling account of the fairness intuitions on display in economic games. However, it is not yet clear how well the approach holds up as an explanation of all human morality. The theory needs to be tested outside the methodological neighborhood it was born in; such testing has the potential to greatly improve our understanding of morality in general. PMID- 23445591 TI - Bargaining power and the evolution of un-fair, non-mutualistic moral norms. AB - Mutualistic theory explains convincingly the prevalence of fairness norms in small societies of foragers and in large contemporary democratic societies. However, it cannot explain the U-shaped curve of egalitarianism in human history. A theory based on bargaining power is able to provide a more general account and to explain mutualism as a special case. According to this approach, social norms may be more variable and malleable than Baumard et al. suggest. PMID- 23445592 TI - The paradox of the missing function: How similar is moral mutualism to biofunctional understanding? AB - We explain here how the natural selection theory of people's mutualistic sense of fairness and the biofunctional theory of human understanding are made for each other. We welcome the stage that the target article has already set for this convergence, and invite the authors to consider moving the two independently developed approaches a step closer to the natural selection level of biofunctional understanding. PMID- 23445593 TI - Your theory of the evolution of morality depends upon your theory of morality. AB - Baumard et al. attribute to humans a sense of fairness. However, the properties of this sense are so underspecified that the evolutionary account offered is not well-motivated. We contrast this with the framework of Universal Moral Grammar, which has sought a descriptively adequate account of the structure of the moral domain as a precondition for understanding the evolution of morality. PMID- 23445594 TI - You can't have it both ways: what is the relation between morality and fairness? AB - Baumard and colleagues put forward a new hypothesis about the nature and evolution of fairness. In this commentary, we discuss the relation between morality and their views about fairness. PMID- 23445595 TI - Biological evolution and behavioral evolution: two approaches to altruism. AB - Altruism may be learned (behavioral evolution) in a way similar to that proposed in the target article for its biological evolution. Altruism (over social space) corresponds to self-control (over time). In both cases, one must learn to ignore the rewards to a particular (person or moment) and behave to maximize the rewards to a group (of people or moments). PMID- 23445596 TI - Sense of fairness: not by itself a moral sense and not a foundation of a lot of morality. AB - Baumard et al. make a good case that a sense of fairness evolved and that showing this requires reciprocity games with choice of partner. However, they oversimplify both morality and the evolution of morality. Where fairness is involved in morality, other things are, too, and fairness is often not involved. In the evolution of morality, other things played a role. Plus, the motive for being fair originally was self-interest, not anything moral. PMID- 23445597 TI - Competitive morality. AB - Baumard et al. argue that partner choice leads to fairness and mutualism, which then form the basis for morality. I comment that mutualism takes us only so far, and I apply the theory of competitive altruism in arguing how strategic investment in behaviours which make one a desirable partner may drive moral conduct. PMID- 23445598 TI - Ego function of morality and developing tensions that are "within". AB - We applaud Baumard et al.'s mutualistic account of morality but detect circularity in their articulation of how morality emerged. Contra the authors, we propose that mutualism might account for a sensitivity to convention (the ways things are done within a group) rather than for a sense of fairness. An ontogenetic perspective better captures the complexity of what it means to be moral. PMID- 23445599 TI - Non-mutualistic morality. AB - Although mutually advantageous cooperative strategies might be an apt account of some societies, other moral systems might be needed among certain groups and contexts. In particular, in a duty-based moral system, people do not behave morally with an expectation for proportional reward, but rather, as a fulfillment of debt owed to others. In such systems, mutualistic motivations are not necessarily a key component of morality. PMID- 23445600 TI - Not all mutualism is fair, and not all fairness is mutualistic. AB - The target article convincingly argues that mutualistic cooperation is supported by partner choice. However, we will suggest that mutualistic cooperation is not the basis of fairness; instead, fairness is based on impartiality. In support of this view, we show that adults are willing to destroy others' resources to avoid inequality, a result predicted by impartiality but not by mutualistic cooperation. PMID- 23445601 TI - Disentangling the sense of ownership from the sense of fairness. AB - Both evolutionary and developmental research indicate that humans are adapted to respecting property rights, independently (and possibly orthogonally) of considerations of fairness. We offer evidence from psychological experiments suggesting that enforcing one's rights and respecting others' possessions are basic cognitive mechanisms automatically activated and grounded in humans' sensory-motor system. This may entail an independent motivation that is more profound than considerations of fairness and impartiality. PMID- 23445602 TI - From partner choice to equity - and beyond? AB - Baumard et al. provide an intriguing model where morality emerges from the dynamics of partner choice in mutualistic interactions. I discuss evidence from human and nonhuman primates that supports the overall approach, but highlights a gap in explaining the human specificity of moral cognition. I suggest that an essential characteristic of human fairness is to override concerns about merit in favor of promoting the welfare in others who are needy. PMID- 23445603 TI - Building a larger tent for public health: implications of the SOPHE-AAHE unification. AB - The unification of the American Association for Health Education (AAHE) and the Society for Public Health Education (SOPHE) generates a long-desired synergy, a ramping up of our leadership influence in promoting health. It also serves as an ongoing opportunity to reflect on how we synergize the distinct philosophic, scientific, and practical approaches that our AAHE colleagues bring in constructing a larger tent for public health education. Running parallel to our union with AAHE is the undertaking by several schools of health, physical education, and recreation (HPER) to become schools of public health. The unification between AAHE and SOPHE can be of enormous benefit to such a process. Just as the harmonious integration of two organizations with similar but distinct perspectives depends on compromise and transcendence, the schools that they embody-both public health and HPER-might consider ways to engage in continued dialogue to assure a more expansive paradigm for public health. SOPHE has an important role to play in this process, and with the additional insight and influence that our AAHE colleagues bring, we can become more instrumental as a boundary spanner. Mechanisms for such integration are discussed. PMID- 23445604 TI - The hepatitis C self-management program: sustainability of primary outcomes at 1 year. AB - OBJECTIVE: Chronic hepatitis C infection afflicts millions of people worldwide. Although antiviral treatments are increasingly effective, many hepatitis C virus (HCV) patients avoid treatment, do not complete or respond to treatment, or have contraindications. Self-management interventions are one option for promoting behavioral changes leading to liver wellness and improved quality of life. Our objective was to evaluate whether the effects of the HCV self-management program were sustained at the 12-month follow-up assessment. METHODS: Veteran Affairs patients with hepatitis C (N = 134; mean age = 54.6 years, 95% male, 41% ethnic minority, 48% homeless in last 5 years) were randomized to either a 6-week self management workshop or an information-only intervention. The weekly 2-hour self management sessions were based on a cognitive-behavioral program with hepatitis C specific modules. Outcomes including hepatitis C knowledge, depression, energy, and health-related quality of life were measured at baseline, 6 weeks, 6 months, and 12 months later. Data were analyzed using repeated measures ANOVA. RESULTS: Compared with the information-only group, participants attending the self management workshop improved more on HCV knowledge (p < .005), SF-36 energy/vitality (p = .016), and the Quality of Well-Being Scale (p = .036). Similar trends were found for SF-36 physical functioning and Center for Epidemiologic Studies Short Depression Scale. CONCLUSION: Better outcomes were sustained among self-management participants at the 12-month assessment despite the intervention only lasting 6 weeks. HCV health care providers should consider adding self-management interventions for patients with chronic HCV. PMID- 23445605 TI - Children's school readiness: implications for eliminating future disparities in health and education. AB - BACKGROUND: School-entry characteristics predict adult educational attainment, which forecasts dispositions toward disease prevention. Health and education risks can also be transmitted from one generation to the next. As such, school readiness forecasts a set of intertwined biopsychosocial trajectories that can influence the developmental antecedents to health and disease prevalence in society. PURPOSE: To predict children's health behaviors and academic adjustment at the end of fourth grade from their kindergarten entry math, vocabulary, and attention skills. METHOD: We use a subsample of 614 girls and 541 boys from the Quebec Longitudinal Study of Child Development (Canada). Children were individually assessed for cognitive skills and teachers rated their classroom attention skills at 65 months. Outcome measures include health behaviors, psychosocial, and academic outcomes at 122 months. Multiple regression analyses were used. RESULTS: Receptive vocabulary in kindergarten exclusively predicted fourth-grade dietary habits. Unstandardized coefficients predicted decreases in sweet snack intake (beta = -.009, 95% confidence interval [CI] = -.011 to -.006) and dairy product intake (beta = .009, 95% CI = .005 to .013). Conversely, higher kindergarten math skills predicted increases in activities requiring physical effort (beta = .030, 95% CI = .011 to .056). Although vocabulary and attention skills were found important, kindergarten math skills were stronger and more consistent predictors of later academic outcomes. CONCLUSIONS: From a population health perspective, the skills children bring to the kindergarten classroom might reduce a host of lifestyle risks from childhood through adulthood. Early promotion of such skills also offers possibilities for ultimately reducing later disparities in health and education. PMID- 23445606 TI - Depressive symptoms among immigrant and Canadian born mothers of preterm infants at neonatal intensive care discharge: a cross sectional study. AB - BACKGROUND: Mothers of preterm infants are considered at higher risk for depressive symptoms, higher than for mothers of healthy term infants. Predictors of depressive symptoms in mothers of preterm infants are not yet well established. Immigrant mothers of term infants have higher prevalence of depressive symptoms than Canadian born mothers but the relative prevalence for immigrant mothers of preterm infants is unknown. This study had two aims: (i) to investigate the prevalence of depressive symptoms in immigrant as compared to Canadian born mothers of preterm infants, and (ii) to determine what factors are associated with depressive symptoms in mothers of preterm infants. METHODS: This is a multi-site, cross sectional study of mothers whose preterm infants required hospitalization in neonatal intensive care unit (NICU). Consecutive eligible mothers (N = 291) were recruited during the week prior to their infant's NICU discharge. Mothers completed a self-administered questionnaire booklet of validated psychosocial/cultural measures including the Center for Epidemiological Studies Depression Scale (CES-D), Parental Stressor Scale:NICU, General Functioning Subscale of the McMaster Family Assessment Device, Social Support Index, and Vancouver Index of Acculturation; and demographic characteristics questions. Infant characteristics included gestational age, birth weight, sex, singleton/multiple birth, and Score for Neonatal Acute Physiology-II. RESULTS: Immigrant mothers (N = 107), when compared to Canadian born mothers (N = 184), reported more depressive symptoms, poorer family functioning, less social support, and less mainstream acculturation. Hierarchical regression for a subsample of 271 mothers indicated that single parent status, high stress, poorer family functioning, and less social support were associated with increased depressive symptoms and accounted for 39% of the variance on the CES-D. Immigrant status did not contribute significantly to the final regression model. CONCLUSIONS: Immigrant mothers of preterm infants are at increased risk for depressive symptoms. For immigrant and Canadian born mothers of preterm infants hospitalized in NICU and particularly for single mothers, interventions to reduce stress and increase family functioning and social support may reduce depressive symptoms. Given the effects of depression on maternal health and functioning, such an intervention may improve child outcomes. PMID- 23445608 TI - Taking a fresh look at the pediatric clinical experience. PMID- 23445607 TI - Safe digital isolation of the santorini plexus during radical retropubic prostatectomy. AB - BACKGROUND: We describe a safe and easily reproducible technique to control Santorini plexus during radical retropubic prostatectomy (RRP) which uses simple digital dissection. METHODS: We retrospectively reviewed 56 consecutive patients who underwent RRP for clinically localised prostate cancer from November 2008 to November 2010. Santorini plexus was isolated and secured in all patients using a new technique of simple digital dissection in which the index finger is used not to only localize the catheter inside the urethra, but also to develop the right plane between Santorini plexus and urethra. This is obtained by gentle bilateral digital dissection through the lateral aspects of periprostatic fascia which are eventually breached by the fingers, developing a right plane just above the urethra. Santorini plexus is then easily ligated and divided. Indicators of outcomes included estimated blood loss, transfusion requirements, operative time, positive margins and complication rates of the technique. RESULTS: The maneuver was successful in 53/56 (95%) patients. Mean (range) blood loss and overall operative time for RRP were 620 ml (100-1500) and 130 min. (80-190), respectively. Transfusion rate was 8,9% (5/56). Positive surgical margin rate was 14% (8/56). No complication related to the employed technique was recorded. CONCLUSIONS: Digital dissection of Santorini plexus during RRP is simple and easily feasible. It speeds up the process of finding the right plane just above the urethra allowing good haemostasis in the surgical field and proper apical dissection. PMID- 23445609 TI - The use of film in teaching concepts of qualitative inquiry to graduate nursing students. PMID- 23445610 TI - Connecting academia to practice: giving tomorrow's nursing leaders a head start. PMID- 23445611 TI - Tumor-initiating cells and FZD8 play a major role in drug resistance in triple negative breast cancer. AB - Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially conducted gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of Wnt receptors, and its downstream targets LEF1 and TCF in residual CRL2335 tumor cells after treatment with cisplatin plus TRAIL. Increased FZD8 levels were further confirmed in other TNBC cell lines. Inhibition of FZD8 by siRNA in CRL2335 cells in the presence of cisplatin plus TRAIL reduced beta-catenin and survivin levels and increased apoptosis compared with scrambled siRNA-treated cells. In vivo data show that cisplatin plus TRAIL treatment significantly reduces tumor volume in NOD/SCID mice. However, we found that cisplatin plus TRAIL treatment predominantly eliminated non-tumor-initiating cells, as shown by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells stably transfected with DsRed. This led to TIC enrichment in residual tumors, as confirmed by immunostaining for TIC markers. Moreover, an increase in FZD8 expression was observed in residual tumors treated with cisplatin and TRAIL. Taken together, our findings suggest that FZD8-mediated Wnt signaling may play a major role in mediating resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBCs. PMID- 23445612 TI - Y-box binding protein-1 contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells. AB - Gene amplification of HER2/ErbB2 occurs in gastric cancer and the therapeutic efficacy of the HER2-targeted antibody, trastuzumab, has recently been improved against HER2-positive advanced stomach cancer. Here, we examined whether Y-box binding protein-1 (YB-1) could selectively control HER2 gene expression and cellular sensitivity to EGF receptor (EGFR) family protein-targeted drugs in human gastric cancer cells. HER2 expression was specifically downregulated by YB 1 silencing using its cognate siRNA, whereas there was less change in the expression of EGFR and HER3. A chromatin immunoprecipitation assay revealed the specific binding of YB-1 to its consensus sequence on the 5'-regulatory region of HER2. YB-1 knockdown induced drug resistance to lapatinib, a dual EGFR and HER2 kinase inhibitor, and also to erlotinib, an EGFR kinase inhibitor. Moreover, phosphorylation of protein kinase B (Akt) was not markedly affected by lapatinib or erlotinib when YB-1 was silenced. Nuclear YB-1 expression was significantly (P = 0.026) associated with HER2 expression, but not with EGFR or HER3, in patients with gastric cancer (n = 111). The YB-1-HER2 axis may therefore be useful for the further development of personalized therapeutics against gastric cancer by HER2 targeted drugs. PMID- 23445613 TI - Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. AB - Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2 mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs. PMID- 23445615 TI - Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease. AB - We examined executive functioning in patients with Parkinson's disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson's disease. However, since some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved. PMID- 23445614 TI - Ischemia-induced neuroinflammation is associated with disrupted development of oligodendrocyte progenitors in a model of periventricular leukomalacia. AB - Microglial activation in crossing white matter tracts is a hallmark of noncystic periventricular leukomalacia (PVL), the leading pathology underlying cerebral palsy in prematurely born infants. Recent studies indicate that neuroinflammation within an early time window can produce long-lasting defects in oligodendroglial maturation, myelination deficit, as well as disruption of transcription factors important in oligodendroglial maturation. We recently reported an ischemic mouse model of PVL, induced by unilateral neonatal carotid artery ligation, leading to selective long-lasting bilateral myelination deficits, ipsilateral thinning of the corpus callosum, ventriculomegaly, as well as evidence of axonopathy. Here, we report that permanent unilateral carotid ligation on postnatal day 5 in CD-1 mice induces an inflammatory response, as defined by microglial activation and recruitment, as well as significant changes in cytokine expression (increased IL 1beta, IL-6, TGF-beta1, and TNF-alpha) following ischemia. Transient reduction in counts of oligodendrocyte progenitor cells (OPCs) at 24 and 48 h after ischemia, a shift in OPC cell size and morphology towards the more immature form, as well as likely migration of OPCs were found. These OPC changes were topographically associated with areas showing microglial activation, and OPC counts negatively correlated with increased microglial staining. The presented data show a striking neuroinflammatory response in an ischemia-induced model of PVL, associated with oligodendroglial injury. Future studies modulating the neuroinflammatory response in this model may contribute to a better understanding of the interaction between microglia and OPCs in PVL and open opportunities for future therapies. PMID- 23445616 TI - Nucleospora cyclopteri n. sp., an intranuclear microsporidian infecting wild lumpfish, Cyclopterus lumpus L., in Icelandic waters. AB - BACKGROUND: Commercial fisheries of lumpfish Cyclopterus lumpus have been carried out in Iceland for centuries. Traditionally the most valuable part is the eggs which are harvested for use as a caviar substitute.Previously reported parasitic infections from lumpfish include an undescribed intranuclear microsporidian associated with abnormal kidneys and mortalities in captive lumpfish in Canada. During Icelandic lumpfish fisheries in spring 2011, extensive enlargements to the kidneys were observed in some fish during processing. The aim of this study was to identify the pathogen responsible for these abnormalities. METHODS: Lumpfish from the Icelandic coast were examined for the causative agent of kidney enlargement. Fish were dissected and used in histological and molecular studies. RESULTS: Lumpfish, with various grades of clinical signs, were observed at 12 of the 43 sites sampled around Iceland. From a total of 77 fish examined, 18 had clear clinical signs, the most prominent of which was an extensive enlargement and pallor of the kidneys. The histopathology of the most severely affected fish consisted of extensive degeneration and necrosis of kidney tubules and vacuolar degeneration of the haematopoietic tissue. Intranuclear microsporidians were detected in all organs examined in fish with prominent clinical signs and most organs of apparently healthy fish using the new PCR and histological examination. One or multiple uniformly oval shaped spores measuring 3.12 +/- 0.15 * 1.30 +/- 0.12 MUm were observed in the nucleus of affected lymphocytes and lymphocyte precursor cells. DNA sequencing provided a ribosomal DNA sequence that was strongly supported in phylogenetic analyses in a clade containing other microsporidian parasites from the Enterocytozoonidae, showing highest similarity to the intranuclear microsporidian Nucleospora salmonis. CONCLUSIONS: Intranuclear microsporidian infections are common in wild caught lumpfish from around the Icelandic coast. Infections can cause severe clinical signs and extensive histopathological changes, but are also present, at lower levels, in fish that do not show clinical signs. Some common features exist with the intranuclear microsporidian previously reported from captive Canadian lumpfish, but DNA sequence data is required from Canadian fish to confirm conspecificity.Based on phylogenetic analysis and the intranuclear location of the parasite, the name Nucleospora cyclopteri n. sp. is proposed. PMID- 23445617 TI - Occupational exposure to organophosphate and carbamate pesticides affects sperm chromatin integrity and reproductive hormone levels among Venezuelan farm workers. AB - OBJECTIVES: Several reports suggest that chronic pesticide exposure may affect semen quality and male fertility in humans. The objective of this study was to evaluate the association between occupational exposure to organophosphate (OP) and carbamate (CB) pesticides and semen quality, as well as levels of reproductive and thyroid hormones of Venezuelan farm workers. METHODS: Thirty five healthy men (unexposed group) and 64 male agricultural workers (exposed group) were recruited for clinical evaluation of fertility status. Fresh semen samples were evaluated for sperm quality and analyzed for DNA fragmentation index (DFI) by flow cytometry. Pesticide exposure was assessed by measuring erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) with a Test mate ChE field kit. Serum levels of total testosterone (Tt), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH) and free thyroxine (FT4) were analyzed using enzyme immunoassay kits. RESULTS: Evidence of pesticide exposure was found in 87.5% of farmers based on AChE and BuChE inhibition. Significant increments were observed in sperm DFI with significant decreases in some semen parameters. DFI was negatively correlated with BuChE, sperm concentration, morphology and vitality in these workers. The levels of Tt, PRL, FT4 and TSH appeared to be normal; however, there was a tendency for increased LH and FSH levels in exposed workers. CONCLUSIONS: Our results confirm the potential impact of chronic occupational exposure to OP/CB pesticides on male reproductive function, which may cause damage to sperm chromatin, decrease semen quality and produce alterations in reproductive hormones, leading to adverse reproductive health outcomes. PMID- 23445618 TI - Netrin-1 regulates colon-kidney cross talk through suppression of IL-6 function in a mouse model of DSS-colitis. AB - Organ cross talk is increasingly appreciated in human disease, and inflammatory mediators are shown to mediate distant organ injury in many disease models. Colitis and intestinal injury are known to be mediated by infiltrating immune cells and their secreted cytokines. However, its effect on other organs, such as the kidney, has never been studied. In the current study, we examined the effect of dextran sulfate sodium (DSS)-colitis on kidney injury and inflammation. In addition, we hypothesized that netrin-1 could modulate colon-kidney cross talk through regulation of inflammation and apoptosis. Consistent with our hypothesis, DSS-colitis induced acute kidney injury in mice. Epithelial-specific overexpression of netrin-1 suppressed both colitis and colitis-induced acute kidney injury, which was associated with reduced weight loss, neutrophil infiltration into colon mucosa, intestinal permeability, epithelial cell apoptosis, and cytokine and chemokine production in netrin-1 transgenic mice colon and kidney. To determine whether netrin-1-protective effects were mediated through suppression of IL-6, IL-6 knockout mice were treated with DSS and acute kidney injury was determined. IL-6 knockout was resistant to colitis and acute kidney injury. Moreover, administration of IL-6 to netrin-1 transgenic mice did not affect the netrin-1-protective effects on the colon and kidney, suggesting that netrin-1 may reduce both IL-6 production and its activity. The present study identifies previously unrecognized cross talk between the colon and kidney, and netrin-1 may limit distant organ injury by suppressing inflammatory mediators and apoptosis. PMID- 23445619 TI - Inhibition of diuretic stimulation of an insect secretory epithelium by a cGMP dependent protein kinase. AB - The rate of urine secretion by insect Malpighian tubules (MTs) is regulated by multiple diuretic and antidiuretic hormones, often working either synergistically or antagonistically. In the Drosophila melanogaster MT, only diuretic factors have been reported. Two such agents are the biogenic amine tyramine (TA) and the peptide drosokinin (DK), both of which act on the stellate cells of the tubule to increase transepithelial chloride conductance. In the current study, TA and DK signaling was quantified by microelectrode recording of the transepithelial potential in isolated Drosophila MTs. Treatment of tubules with cGMP caused a significant reduction in the depolarizing responses to both TA and DK, while cAMP had no effect on these responses. To determine whether a specific cGMP-dependent protein kinase (PKG) was mediating this inhibition, PKG expression was knocked down by RNAi in either the principal cells or the stellate cells. Knockdown of Pkg21D in the stellate cells eliminated the modulation of TA and DK signaling. Knockdown of Pkg21D with a second RNAi construct also reduced the modulation of TA signaling. In contrast, knockdown of the expression of foraging or CG4839, which encodes a known and a putative PKG, respectively, had no effect. These data indicate that cGMP, acting through the Pkg21D gene product in the stellate cells, can inhibit signaling by the diuretic agents TA and DK. This represents a novel function for cGMP and PKG in the Drosophila MT and suggests the existence of an antidiuretic hormone in Drosophila. PMID- 23445620 TI - Direct assessment of tubuloglomerular feedback responsiveness in connexin 40 deficient mice. AB - Participation of connexin 40 (Cx40) in the regulation of renin secretion and in the tubuloglomerular feedback (TGF) component of renal autoregulation suggests that gap junctional coupling through Cx40 contributes to the function of the juxtaglomerular apparatus. In the present experiments, we determined the effect of targeted Cx40 deletion in C57BL/6 and FVB mice on TGF responsiveness. In C57BL/6 mice, stop-flow pressure (PSF) fell from 40.3 +/- 2 to 34.5 +/- 2 mmHg in wild-type (WT) and from 31 +/- 1.06 to 26.6 +/- 0.98 mmHg in Cx40-/- mice. PSF changes of 5.85 +/- 0.67 mmHg in WT and of 4.3 +/- 0.55 mmHg in Cx40-/- mice were not significantly different (P = 0.08). In FVB mice, PSF fell from 37.4 +/- 1.5 to 31.6 +/- 1.5 mmHg in WT and from 28.1 +/- 1.6 to 25.4 +/- 1.7 mmHg in Cx40-/-, with mean TGF responses being significantly greater in WT than Cx40-/- (5.5 +/- 0.55 vs. 2.7 +/- 0.84 mmHg; P = 0.002). In both genetic backgrounds, PSF values were significantly lower in Cx40-/- than WT mice at all flow rates. Arterial blood pressure in the animals prepared for micropuncture was not different between WT and Cx40-/- mice. We conclude that the TGF response magnitude in superficial cortical nephrons is reduced by 30-50% in mice without Cx40, but that with the exception of a small number of nephrons, residual TGF activity is maintained. Thus gap junctional coupling appears to modulate TGF, perhaps by determining the kinetics of signal transmission. PMID- 23445621 TI - Two-way AIC: detection of differentially expressed genes from large scale microarray meta-dataset. AB - BACKGROUND: Detection of significant differentially expressed genes (DEGs) from DNA microarray datasets is a common routine task conducted in biomedical research. For the detection of DEGs, numerous methods are proposed. By such conventional methods, generally, DEGs are detected from one dataset consisting of group of control and treatment. However, some DEGs are easily to be detected in any experimental condition. For the detection of much experiment condition specific DEGs, each measurement value of gene expression levels should be compared in two dimensional ways, or both with other genes and other datasets simultaneously. For this purpose, we retrieve the gene expression data from public database as possible and construct "meta-dataset" which summarize expression change of all genes in various experimental condition. Herein, we propose "two-way AIC" (Akaike Information Criteria), method for simultaneous detection of significance genes and experiments on meta-dataset. RESULTS: As a case study of the Pseudomonas aeruginosa, we evaluate whether two-way AIC method can detect test data which is the experiment condition specific DEGs. Operon genes are used as test data. Compared with other commonly used statistical methods (t-rank/F-test, RankProducts and SAM), two-way AIC shows the highest specificity of detection of operon genes. CONCLUSIONS: The two-way AIC performs high specificity for operon gene detection on the microarray meta-dataset. This method can also be applied to estimation of mutual gene interactions. PMID- 23445623 TI - Food for thought from plant and animal genomes. PMID- 23445622 TI - Differentiated embryonic chondrocyte-expressed gene 1 is associated with hypoxia inducible factor 1alpha and Ki67 in human gastric cancer. AB - BACKGROUND: Gastric cancer is a leading causes of cancer-related deaths ,but the underlying molecular mechanisms of its progression are largely unknown. Differentiated embryonic chondrocyte-expressed gene 1 (DEC1), is an important transcription factor involved in the progression of tumors and has recently been identified to be strongly inducible by hypoxia. Little is known about the contribution of DEC1 to the intracellular hypoxia and proliferation signaling events in gastric cancer. METHODS: Immunohistochemistry was used to detect the expression of DEC1, hypoxia-inducible factor 1(HIF-1alpha) and Ki67 in 173 human gastric cancer samples and adjacent non-tumor tissues samples. The relationship between DEC1, HIF-1alpha and Ki67 was evaluated. RESULTS: DEC1 protein was persistently expressed in the nucleus and cytoplasm of gastric cancer tissue. The protein expression of DEC1 and HIF-1alpha in tumour tissues was 83.8% and 54.3%, respectively, and was significantly higher than that in adjacent normal tissues (83.8% vs 23.7%, P < 0.001; 54.3% vs 12.7%, P < 0.001). The expression of DEC1 and HIF-1alpha was associated with poor histological differentiation. (P < 0. 01). Furthermore, DEC1 level was positively correlated with HIF-1alpha (P < 0. 01, r=0.290) and Ki67 expression (P < 0. 01, r=0.249). CONCLUSION: The upregulation of DEC1 may play an important role in hypoxia regulation and cell proliferation in gastric cancer. The relevant molecular mechanism requires further investigation. PMID- 23445624 TI - The association between bedding material and the bacterial counts of Staphylococcus aureus, Streptococcus uberis and coliform bacteria on teat skin and in teat canals in lactating dairy cattle. AB - Several mastitis-causing pathogens are able to colonize the bovine teat canal. The objective of this study was to investigate the association between the treatment of sawdust bedding with a commercial alkaline conditioner and the bacterial counts on teat skin and in the teat canal. The study used a crossover design. Ten lactating Holstein cows that were free of udder infections and mastitis were included in the study. The animals were bedded on either untreated sawdust or sawdust that had been treated with a hydrated lime-based conditioner. Once a day, fresh bedding material was added. After 3 weeks, the bedding material was removed from the cubicles, fresh bedding material was provided, and the cows were rotated between the two bedding material groups. Teat skin and teat canals were sampled using the wet and dry swab technique after weeks 1, 2, 3, 4, 5 and 6. Staphylococcus aureus, Streptococcus uberis, Escherichia coli and other coliform bacteria were detected in the resulting agar plate cultures. The treatment of the bedding material was associated with the teat skin bacterial counts of Str. uberis, Esch. coli and other coliform bacteria. An association was also found between the bedding material and the teat canal bacterial counts of coliform bacteria other than Esch. coli. For Staph. aureus, no associations with the bedding material were found. In general, the addition of a hydrated lime based conditioner to sawdust reduces the population sizes of environmental pathogens on teat skin and in teat canals. PMID- 23445625 TI - Routine use of positron-emission tomography/computed tomography for staging of primary colorectal cancer: does it affect clinical management? AB - BACKGROUND: The use of positron emission tomography-computed tomography (PET/CT) for the preoperative staging of patients with colon and rectal cancer has increased steadily over the last decade. The aim of this study was to evaluate the effect of PET/CT on the preoperative staging and clinical management of patients with colorectal cancer. METHODS: Between December 2010 and February 2012, 64 consecutive patients with colorectal cancer were evaluated with both PET/CT scans and conventional preoperative imaging studies. We prospectively recorded the medical reports of these patients. The PET/CT findings were compared with conventional imaging studies and the rate of over-staging or down-staging and changes in clinical management were evaluated. The correlation of the PET/CT with the conventional imaging was compared by a kappa agreement coefficient. Differences in the accuracy for N and T staging were assessed by chi2 and related samples marginal homogeneity tests. RESULTS: Thirty-nine (60.9%) patients had rectal cancer and 25 (39.1%) had colon cancer. Based on PET/CT, additional lesions were found in 6 (9.4%) of the patients: hilar and paratracheal lesions in 4 patients, hepatic in 1 and supraclavicular in 1 patient. In four of six patients, detailed imaging studies or biopsies revealed chronic inflammatory changes. Hepatic and supraclavicular involvement was confirmed in two patients. Therefore, the false positivity rate of PET/CT was 6.25%. Based on the additional PET/CT, 2 (3.2%) patients had a change in surgical management. A chemotherapy regimen was administered to the patient with a 1.5 cm hepatic metastasis near the right hepatic vein; for another patient with an identified supraclavicular lymph node metastasis, a simultaneous excision was performed. CONCLUSIONS: Routine use of PET/CT for preoperative staging did not impact disease management for 96.8% of our patients. The results of our study conclude that PET/CT should not be routinely used for primary staging of colorectal cancer. More studies are required for identifying the subgroup of patients who might benefit from a PET/CT in their initial staging. PMID- 23445626 TI - Influence of radiographic contrast media on the nitric oxide release from human arterial and venous endothelial cells on extracellular matrix. AB - Radiographic contrast media (RCM) can vary widely in their physicochemical properties, e.g. the iodine concentration, osmolality, molecule structure, chemotoxicity, hydrophilicity, electric charge and viscosity. Besides the necessary effect of Roentgen ray absorption, which provides contrast-rich images of vessels, RCMs can have varying adverse effects. As one possible cause of microcirculatory disorders, changes in morphology and function of endothelial cells are discussed. Therefore, RCM media-induced release of nitric oxide from arterial as well as from venous endothelial cells in contact with two commercially available RCMs (Iodixanol and Iomeprol) was investigated. NO concentrations started to increase slightly in the HUVEC control cultures after 3 min incubation time, however, NO concentrations in the cultures incubated with Iomeprol 350 and Iodixanol 320 did not change over time (Iomeprol 350: p = 0.4905; Iodixanol 320: p = 0.784). On the whole, the time-dependent NO release differed for the three groups (RCM * time: p = 0.00224). This difference was due to the fact that, after incubation with the two contrast agents (Iodixanol 320: p = 0.0003; Iomeprol 350: p = 0.0168), less NO was released by the exposed HUVEC at 3 minutes and after 12 hours than by the control cells. In the control cultures of arterial endothelial cells as well as in cultures incubated with 30% v/v Iodixanol supplemented culture medium the NO release did not change. In those cultures of arterial endothelial cells supplemented with 30% v/v Iomeprol the NO release was significantly less than in control cultures and in cultures supplemented with Iodixanol (p = 0.021; p = 0.043). Inspite of a missing shear stress in our static plane vessel wall model there was a RCM-dependent difference in NO release from endothelial cells in vitro. The NO release from venous endothelial cells differed significantly from the NO release from arterial endothelial cells. While the administration of Iomeprol induced a decrease in NO release no changes occurred after Iodixanol administration. PMID- 23445627 TI - Red blood cell mechanical stability test. AB - Red blood cells (RBC) are exposed to various levels of shear stress (SS) during their flow in the circulatory system, yet no significant damage occurs if their mechanical stability is not impaired. Alternatively, normal RBC may be damaged during flow in non-physiological environments and under extreme SS (e.g., extracorporeal circulation, ventricular assist devices). The shear-induced damage may result in hemolysis or in altered mechanical properties of RBC that, in turn, reduces the ability of RBC to withstand further damage by SS. An ektacytometer employing a Couette shearing system was used to apply SS at a constant level of 100 Pa for 300 seconds as a model of sub-hemolytic mechanical stress. The degree of cellular damage during and after the application was assessed by diffraction pattern analysis. The area of the diffraction pattern was found to correlate with the number of RBC in the sheared suspension. Monitoring the ellipse area during the application of gradually increasing SS provides the concentration of the remaining intact RBC and can therefore be used to estimate the hemolytic threshold as a measure of RBC mechanical stability. The hemolytic threshold determined after the mechanical stress application was found to be ~150 Pa, while it was ~250 Pa in the same samples before the SS application. Additionally, SS elongation index curves recorded before and after the application of the sub hemolytic SS significantly differed from each other, indicating the impairment in deformability following the mechanical stress. The Couette type ektacytometer can be used as a tool to assess the sub-hemolytic damage to RBC in testing the biomedical equipment. PMID- 23445628 TI - The role of critical shear stress on acute coronary syndrome. AB - Increased aggregation of RBC is associated with many vascular diseases, including acute coronary syndrome (ACS). Critical shear-stress (CSS) as in index of red cell aggregation is defined as either the minimum shear-stress required dispersing the aggregates. The objective of this study is to access the role of CSS in ACS comparing to SA, and to evaluate the correlation with usual biomarkers for atherosclerosis such as fibrinogen, hs-CRP. 169 SA and 223 ACS patients were finally enrolled. A detailed medical history and laboratory data were obtained for each participant from clinical records. CSS is measured by simultaneous measurement of shear stress and light backscattering using a small disposable kit with a microfluidic hemorheometer. We hypothesized that higher value of CSS might be associated increased thrombosis in ACS. As results, relatively younger age was shown and more male in ACS patients, and inflammatory markers (WBC, hs-CRP) were higher in ACS. Whole blood viscosities were significantly higher in ACS than SA along at all shear rates. CSS was 25.7% higher in ACS (333.8 +/- 147.8) than in SA (265.4 +/- 149.9 mPa) (p < 0.001). CSS was highly correlated white blood cell counts, hs-CRP, fibrinogen, and erythrocyte sedimentation rate (ESR). Among those variables, fibrinogen, and ESR were strongly correlated with CSS. We may suggest that CSS could be used as a novel risk marker for ACS. PMID- 23445629 TI - The role of hemorheological factors in cardiovascular medicine. AB - Cardiovascular diseases (CVD) are the most frequent cause of death throughout the world. The coronary vessel system is a special part of the circulation since there is a continuous change in blood flow, perfusion pressure and shear rate during each cardiac cycle. It is also the place of the narrowest capillaries in the human body, therefore the role of rheological alterations may be of greater importance than in the other parts of the circulatory system. During the past decades, our group has investigated hemorheological parameters (HP) in over 1,000 patients diagnosed with various forms of ischemic heart disease (IHD). In one prospective study, we measured the HP of patients with acute coronary syndrome (ACS). On admission, all examined variables were significantly worse than those of control subjects. During the hospital phase, some of the HP showed further deterioration, and HP remained in the pathologic range during the follow-up period. In another study, we showed that HP are in close correlation with the severity of coronary artery disease. In patients treated with percutaneous coronary intervention, changes in HP were very similar to those observed in subjects with ACS. In a recent study, we analyzed HP in patients undergoing CABG surgery. Our data suggest a hemorheological advantage of off-pump surgery. In another study low Hct/WBV ratio can be regarded as a risk factor of cardiac death in IHD. Our data indicate that rheological parameters are significantly altered in patients with IHD: the extent of the alterations is in excellent correlation with the clinical severity of the disease. Our findings prove that HP play a critical role in the pathogenesis of myocardial ischemia. In recent in vitro and in vivo studies we have investigated the effects of red wine on hemorheological parameters. Our results show that moderate red wine consumption has beneficial effects on hemorheological parameters which may contribute to the French paradox. PMID- 23445630 TI - Elevated coronary whole blood viscosity in acute coronary syndrome patients. AB - OBJECTIVES: As most clinical studies measure whole blood viscosity (WBV) from peripheral samples, potential differences in WBV obtained from the coronary arteries are often ignored. This study investigated differences in WBV measured from coronary artery specimens in patients with and without acute coronary syndrome (ACS). METHODS AND RESULTS: Consecutive patients with chest pain who underwent diagnostic coronary angiography were divided into two groups [non-ACS (n = 16), ACS (n = 22)]. The ACS group consisted of unstable angina (n = 13) and acute myocardial infarction (n = 9) patients. Two blood samples were obtained from each patient at the both coronary artery ostia prior to coronary angiography. Low-shear and high-shear blood viscosities (BVs) were measured at shear rates of 1 and 300 s-1, respectively, by a scanning capillary tube viscometer (Bio-Visco Inc., South Korea). Both low-shear and high-shear BVs obtained from peripheral, left and right coronary arteries were not different in both groups. Mean coronary low-shear WBV values obtained in ACS group were 29.2% higher than those in non-ACS group (295.3 +/- 87.2 mP vs. 228.5 +/- 69.2 mP, p = 0.016). Mean coronary high-shear WBV values obtained in ACS group were 15.6% higher than those in non-ACS group (42.9 +/- 10.0 mP vs. 37.1 +/- 4.6 mP, p = 0.036). CONCLUSIONS: Direct measurement of WBV from the coronary artery showed no differences with peripheral samples. Future larger studies are needed to clarify our results. PMID- 23445632 TI - Interaction of human umbilical vein endothelial cells (HUVEC) with platelets in vitro: Influence of platelet concentration and reactivity. AB - Endothelialisation of polymer-based cardiovascular implants is one strategy to render biomaterials hemocompatible. The evaluation of the functionality and the confluence of an endothelial cell (EC) monolayer in vitro is therefore of crucial importance, because a non-functional or non-confluent EC monolayer can contribute to the failure of vascular grafts. Moreover, the comparison of different potential biomaterials regarding their ability to induce the formation of a functional confluent EC monolayer is of great value. Most of the currently reported in vitro studies focus on direct or indirect markers of EC behaviour. However, these studies still lack the final proof that the EC monolayer, which can be developed on polymers is confluent and functional. In this study, we investigated the suitability of an in vitro co-culture of human umbilical vein endothelial cells (HUVEC) with platelets to predict the functionality of an EC monolayer. The interaction of platelets with HUVEC was evaluated depending on the concentration of the platelets in the added plasma and of the reactivity of the platelets to pharmacological stimuli. For this purpose, HUVEC were seeded in a 24 well plate. After three days of cultivation, platelets were added to the HUVEC cell culture medium to final concentrations of 200, 2,000 or 20,000 platelets/MUl (n = 7 each). The platelets were processed immediately after blood collection and added to the HUVEC culture after a 30 minutes resting period. As a first control, an EC monolayer just cultured with EC medium was used. As a second control EC supplemented with plasma without platelets were applied. The HUVEC monolayer was investigated microscopically after 1 hour of platelet exposition. The addition of thrombocytes to EC affected the EC adherence dependent on the initial cell seeding number of HUVEC, the platelet concentration and also on the reactivity of platelets added. In both controls no significant EC detachment was detected. The results demonstrated a significant influence of platelet concentration and reactivity on the adherence of EC in a static model. PMID- 23445631 TI - Nutritional and metabolic determinants of blood rheology differ between trained and sedentary individuals. AB - Body composition and nutrition have been reported to be correlated with blood rheology. However, in sedentary and in physically active individuals these relationships seem to be not exactly similar. This study investigated whether exercise training status influences these relationships. 32 athletes (ATH) (age: 25 +/- 0.7 yr; body mass index (BMI): 23.75 +/- 0.23 kg/m2) were compared to 21 sedentary subjects (SED) (age: 45.19 +/- 2.90; BMI = 33.41 +/- 1.33) with nutritional assessment (autoquestionnaire), bioelectrical impedancemetry, viscometry at high shear rate (MT90) and Myrenne aggregometer. Subjects differ according to age, weight and adiposity parameters. Their eating behavior is different: ATH eat a higher percentage of protein (p < 0.005), a lower percentage of lipid (p < 0.05), and a higher total amount of carbohydrate (+31% p < 0.02). Their viscosity factors are similar except plasma viscosity which is higher in SED than ATH (1.51 +/- 0.03 vs 1.43 +/- 0.02 mPa.s, p < 0.05). In both ATH and SED, abdominal obesity (waist-to-hip ratio or WHR) is associated with impairments in blood rheology, but not exactly the same. In ATH, WHR is associated with an increase in hematocrit (r = 0.647; p = 0.009), plasma viscosity (r = 0.723; p = 0.002), and caloric (and CHO) intake moderately increase RBC rigidity (r = 0.5405; p = 0.0251) and aggregability (r = 0.3366 p = 0.0596). In SED the picture is different, adiposity increases hematocrit (r = 0.460; p = 0.048), abdominal fatness increases blood viscosity independent of hematocrit, and CHO intake is associated with lower RBC aggregability (r = -0.493; p = 0.0319). PMID- 23445633 TI - Influence of physically crosslinked gelatins on the vasculature in the avian chorioallantoic membrane. AB - Gelatins functionalized with desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT) form physically crosslinked hydrogels, due to the interactions between the introduced aromatic moieties and gelatin triple helices, whose extent depends on the thermal treatment of the material. The G-modulus of these hydrogels can be tailored to the range of the natural extracellular matrix by adjusting the degree of crosslinking. While these gelatin-based materials have been shown to be not angiogenic, the aim of the study was to evaluate whether these biomaterials influence the regulation of blood vessels when positioned on the chorionallantoic membrane (CAM) of fertilized eggs. The results clearly indicate that the DAT functionalized gelatin led to an increase of the diameter of the blood vessels in the CAM, which at the same time is probably associated with an increased blood flow in these CAM vessels. The vessel diameters of the four groups (DAT functionalized gelatin, DATT-functionalized gelatin, plain gelatin, control group without gelatin, each n = 10) differed significantly (p < 0.0001). Vessels in the CAM exposed to the DAT-functionalized gelatin showed with 36.4 MUm +/- 3.4 MUm the largest mean diameters compared to the mean diameters of the samples exposed to DATT gelatin (16.0 MUm +/- 0.8 MUm; p < 0.05) and the plain gelatin (21.2 MUm +/- 1.0 MUm; p < 0.05), which both did not differ significantly from the vessels of the control group. The biocompatibility of the materials in vitro motivates the exploration of their application as matrix in local drug-release systems with short half-life times (one hour up to several days). PMID- 23445634 TI - Substrate stiffness influences the outcome of antitumor drug screening in vitro. AB - Substrate stiffness has been proven to play a critical role in vitro tumor proliferation; however, pharmacological studies on antitumor drug screening are still routinely carried out in regular plastic culture plates. In the article, polydimethylsiloxane (PDMS) substrates with different stiffness (mimicking articular cartilage, collagenous bone and mammary tumor respectively) and plastic substrate were employed to establish the mechanical microenvironment for the in vitro drug screening platform. We studied the influences of stiffness on the responses of MCF-7 cells to typical antitumor drugs, cisplatin and taxol. Results showed that for both the treatment IC50 value to MCF-7 cells decreased significantly (p < 0.01) on the rigid substrate, indicating that MCF-7 cells on soft substrate have a resistance to cytotoxicity of antitumor drugs. The sensitivity of MCF-7 cells on rigid substrate to drug cytotoxicity was attributed to the increased cell cycle progression, implying that agents proven to be effective in vitro by conventional screening approach might be inefficient in a soft microenvironment in vivo. We conclude that stiffness of the substrates, as a critical mechanical factor, should be concerned for screening antitumor agents in vitro. As an extrapolation, the extensively used drug screening system needs to be revalued and redesigned. PMID- 23445635 TI - Influence of blood lipids on plasma and blood viscosity. AB - BACKGROUND AND AIM: The relationship between hyperlipidemia and blood and plasma viscosity is not completely clear. While increasing viscosity is often reported with increasing blood lipids, lipid-lowering treatments are often unable to normalize the viscosity values. Aim of this study is to try to clarify the relationship between blood lipids and viscosity. METHODS AND RESULTS: Apparently healthy subjects were enrolled (n = 410). Smokers, diabetics, obese, and hypertriglyceridemic (above 400 mg/dl) were excluded. Blood (at shear rate 225/s) and plasma viscosity were measured at 37 degrees C. Erythrocyte rigidity (Tk) was calculated according to Dintenfass. Blood lipids and glucose were measured by routine methods. Hyperlipidemic subjects (n = 315) had higher values of plasma viscosity (1.44 +/- 0.13 vs. 1.40 +/- 0.12 cP, p = 0.007), and blood viscosity (4.51 +/- 0.54 vs. 4.35 +/- 0.55 cP, p = 0.013), compared to normolipidemic subjects (n = 95). In simple correlation analysis, plasma viscosity was directly associated with LDL cholesterol, and inversely with Tk and HDL cholesterol. In multiple regression analysis the association with LDL and HDL was strengthened, though these two variables as a whole accounted for only 5% (adjusted R2) of the variability of plasma viscosity. Blood viscosity was significantly associated with haematocrit, plasma viscosity, Tk and all considered variables but age in simple correlation analysis, but only with haematocrit, plasma viscosity and Tk in multiple regression analysis. CONCLUSIONS: LDL cholesterol and HDL cholesterol influence plasma viscosity, but not blood viscosity. Triglycerides up to values of 400 mg/dl do not seem to have important effects, at least in apparently healthy subjects and at the shear rates used in the present study. The contribution of LDL and HDL cholesterol to plasma viscosity seems however quite limited. PMID- 23445636 TI - Blood characteristics effect on pulse wave velocity. AB - PWV, a surrogate marker for vascular stiffness, can be also expressed by the Bramwell-Hill equation. The effect of blood density to PWV has been ignored, because variation of blood density is assumed to be negligible. In some clinical situation, blood density could be changed, and blood density as a mechanical property of blood flow might affect to PWV. While the elastic property plays an important role in determining the wave propagation in an elastic tube, our assumption is that there might be some relation between blood flow and vascular wall, and that the characteristics of blood flow might influence PWV. This study was objected to investigate the role of mechanical and hemorheologic parameters on PWV in subjects with cardiovascular disease. We have measured and analyzed the PWV, hemorheologic parameters, and other clinical parameters in 814 patients with coronary arterial disease scheduled for coronary angiography. There is no commercial method for measuring whole blood density. So, we defined the density score, which is sum of hemoglobin and total protein. And the hemorheologic parameters were measured within 4 hours after sampling by automated microfluidic hemorheometer. And the effect of all the clinical and hemorheologic parameter on PWV was analyzed by multiple linear regression analysis. Many clinical parameters including age and blood pressure, high shear WBV and ESR as hemorheologic parameters, and density score were correlated well with ba-PWV. However, many clinical variables, high shear WBV and ESR lost the independent significance on multivariable regression analysis. Only age, SBP, and density score were independent variables (p < 0.001). In conclusion, density score as a mechanical property of blood might be suggested as an independent variable influencing PWV in addition to age and blood pressure, but hemorheologic parameters, such as RBC deformability, aggregation, and whole blood viscosity do not affect PWV independently. PMID- 23445638 TI - Chemotherapy +/- cetuximab modulates peripheral immune responses in metastatic colorectal cancer. AB - OBJECTIVE: To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5 fluorouracil/leucovorin (IFL) alone or in combination with cetuximab (C-IFL). METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment. RESULTS: PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-gamma, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-gamma, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-gamma, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency. CONCLUSION: The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome. PMID- 23445637 TI - Anti-protozoal activity of aporphine and protoberberine alkaloids from Annickia kummeriae (Engl. & Diels) Setten & Maas (Annonaceae). AB - BACKGROUND: Malaria, trypanosomiasis and leishmaniasis have an overwhelming impact in the poorest countries in the world due to their prevalence, virulence and drug resistance ability. Currently, there is inadequate armory of drugs for the treatment of malaria, trypanosomiasis and leishmaniasis. This underscores the continuing need for the discovery and development of new anti-protozoal drugs. Consequently, there is an urgent need for research aimed at the discovery and development of new effective and safe anti-plasmodial, anti-trypanosomal and anti leishmanial drugs. METHODS: Bioassay-guided chromatographic fractionation was employed for the isolation and purification of antiprotozoal alkaloids. RESULTS: The methanol extract from the leaves of Annickia kummeriae from Tanzania exhibited a strong anti-plasmodial activity against the multi-drug resistant Plasmodium falciparum K1 strain (IC50 0.12 +/- 0.01 MUg/ml, selectivity index (SI) of 250, moderate activity against Trypanosoma brucei rhodesiense STIB 900 strain (IC50 2.50 +/- 0.19 MUg/ml, SI 12) and mild activity against Leishmania donovani axenic MHOM-ET-67/82 strain (IC50 9.25 +/- 0.54 MUg/ml, SI 3.2). Bioassay-guided chromatographic fractionation led to the isolation of four pure alkaloids, lysicamine (1), trivalvone (2), palmatine (3), jatrorrhizine (4) and two sets of mixtures of jatrorrhizine (4) with columbamine (5) and palmatine (3) with (-)-tetrahydropalmatine (6). The alkaloids showed low cytotoxicity activity (CC50 30 - >90 MUg/ml), strong to moderate anti-plasmodial activity (IC50 0.08 +/ 0.001 - 2.4 +/- 0.642 MUg/ml, SI 1.5-1,154), moderate to weak anti-trypanosomal (IC50 2.80 +/- 0.001 - 14.3 +/- 0.001 MUg/ml, SI 2.3-28.1) and anti-leishmanial activity IC50 2.7 +/- 0.001 - 20.4 +/- 0.003 MUg/ml, SI 1.7-15.6). CONCLUSION: The strong anti-plasmodial activity makes these alkaloids good lead structures for drug development programs. PMID- 23445640 TI - [Left atrial posterior wall flap method for II a type of the isolated total anomalous pulmonary venous drainage]. AB - We address the left atrial posterior wall flap (LAPF) method for the isolated total anomalous pulmonary venous drainage( TAPVD) II a. The postoperative pulmonary venous obstruction( PVO) is a serious complication and is not rare after repair of the isolated TAPVD II a by the conventional surgical techniques. The LAPF method contains superiorities to prevent PVO to the conventional surgical techniques by wider left atrium(LA) - pulmonary vein(PV) communication, less risk of turbulence and no need of a prosthetic patch or an autologous pericardial patch. Furthermore, from a hemodynamic point of view, it makes LA-PV communication a functional preloading chamber which leads the postoperative hemodynamics stable. So, we think that the LAPF method is able to be a standard operative technique for the isolated TAPVD II a. PMID- 23445641 TI - [Aortic valve surgery in a patient with cold agglutinin disease; effectiveness of continuous retrograde cardioplegia]. AB - A 76-year-old female was hospitalized because of congestive heart failure and anemia. A thorough examination led to a diagnosis of severe aortic stenosis and cold agglutinin disease. The critical temperature for hemagglutination was 27 degrees C, which caused particular problems with regard to the myocardial protection temperature during surgery. Aortic valve replacement was performed safely by increasing the normal myocardial protection temperature from 15 degrees C to 32 degrees C and using 3 times the normal volume of cardioplagic fluid. As a result of strict perioperative thermal management, the operation was completed without any complications. PMID- 23445639 TI - A pilot cohort analytic study of Family Integrated Care in a Canadian neonatal intensive care unit. AB - BACKGROUND: We have developed a Family Integrated Care (FIC) model for use in a neonatal intensive care unit (NICU) where parents provide most of the care for their infant, while nurses teach and counsel parents. The objective of this pilot prospective cohort analytic study was to explore the feasibility, safety, and potential outcomes of implementing this model in a Canadian NICU. METHODS: Infants born <= 35 weeks gestation, receiving continuous positive airway pressure or less respiratory support, with a primary caregiver willing and able to spend >= 8 hours a day with their infant were eligible. Families attended daily education sessions and were mentored at the bedside by nurses. The primary outcome was weight gain, as measured by change in z-score for weight 21 days after enrolment. For each enrolled infant, we identified two matched controls from the previous year's clinical database. Differences in weight gain between the two groups were analyzed using a linear mixed effects multivariable regression model. We also measured parental stress levels using the Parental Stress Survey: NICU, and interviewed parents and nurses regarding their experiences with FIC. RESULTS: This study included 42 mothers and their infants. Of the enrolled infants, matched control data were available for 31 who completed the study. The rate of change in weight gain was significantly higher in FIC infants compared with control infants (p < 0.05). There was also a significant increase in the incidence of breastfeeding at discharge (82.1 vs. 45.5%, p < 0.05). The mean Parental Stress Survey: NICU score for FIC mothers was 3.06 +/- 0.12 at enrolment, which decreased significantly to 2.30 +/- 0.13 at discharge (p < 0.05). Feedback from the parents and nurses indicated that FIC was feasible and appropriately implemented. CONCLUSIONS: This study suggests that the FIC model is feasible and safe in a Canadian healthcare setting and results in improved weight gain among preterm infants. In addition, this innovation has the potential to improve other short and long-term infant and family outcomes. A multi-centre randomized controlled trial is needed to further evaluate the efficacy of FIC in the Canadian context. PMID- 23445642 TI - [Redo coronary artery bypass grafting after pneumonectomy]. AB - A 77-year-old man who had undergone left pneumonectomy 16 years and quadruple coronary artery bypass grafting (CABG) 4 years previously presented with unstable angina pectoris. Coronary angiography revealed severe stenosis of the left main trunk and the proximal left anterior descending artery(LAD), and the severely narrowed left internal thoracic artery (LITA)-LAD graft. Computed tomography(CT) presented a marked shift of the heart and great vessels into the left hemithorax with a hyperinflated right lung crossing the midline. The LAD would not seem to be accessible by median sternotomy. Off-pump coronary artery bypass grafting (OPCAB) with a saphenous vein graft to LAD was performed through a rib-cross left thoracotomy. The patient's postoperative course was uneventful, and postoperative CT revealed a patent graft. OPCAB through rib-cross thoracotomy is safe and useful and can be an option for redo CABG, particularly in instances of previous pneumonectomy. PMID- 23445643 TI - [Ectopic mediastinal parathyroid adenoma resected by video-assisted thoracic surgery with intraoperative methylene blue infusion]. AB - We report a case of 26-year-old man treated for ectopic mediastinal parathyroid adenoma with videoassisted thoracic surgery and perioperative methylene blue intravenous injection. The patient had elevated serum calcium levels, and a history of recurrent urinary stone seizures from 8 years ago. Hypercalcemiadue to the hyperparathyroidism was suspected and am ectopic parathyroid adenoma in the mediastinum was identified by computed tomography (CT) and magnetic resonance imaging(MRI).Thoracoscopic extirpation of mediastinal parathyroid adenoma was scheduled with the help of tumor staining by methylene blue intravenous injection. The lesion was identified easily during surgery, andthe thoracoscopic surgery could be safely performed. The postoperative course is well, and hypercalcemia was improved. The ureteral stone seizures did not occur subsequently. PMID- 23445644 TI - [Anomalous systemic arterial supply to normal basal segments of the left lung (Pryce type I)]. AB - Patient 1 was a 54-year-old female diagnosed with anomalous systemic arterial supply to normal basal segments of the left lung discovered as an abnormality on chest X-ray radiography. Patient 2 was a 47-year-old male in whom the disease was diagnosed by close examination of bloody sputum. Division of the abnormal artery and left lower lobectomy were performed in patient 1. Arterial congestion and serpentine distribution were noted in the basal segments of the lung, which was the region perfused by the abnormal artery, on histopathological examination. Arteriosclerotic changes were noted in the vascular wall, but no abnormal vascular wall or alveolar structure was noted in S6, which was not included in theperfused region. Based on the above findings, division of the abnormal artery and left basal segmentectomy were performed in patient 2. Bloody sputum disappeared, and activity of daily living( ADL) were not impaired after surgery. PMID- 23445645 TI - [Modified infarct exclusion technique of postinfarction ventricular septal perforation]. AB - Ventricular septal perforation is one of the most serious complications of acute myocardial infarction, and is often fatal unless treated surgically. Despite the development of various surgical techniques for repair of postinfarction ventricular septal perforation, the operative mortality remains high. We report 3 consecutive cases in which a modified infarct exclusion technique was used to repair ventricular septal rupture after anterior myocardial infraction. The septal rupture was closed by the 1st pericardial patch with buttressed mattress sutures. Then buttressed mattress sutures were passed sequentially through the septal portion of the 2nd patch, the ventricular septum, and the free wall of the right ventricle to exclude the infarcted myocardium and septal perforation. The pericardial patch was sutured to the free wall of the left ventricle with a continuous suture for reconstruction of the left ventricular cavity. The ventriculotomy was closed with buttressed mattress sutures and a continuous suture. All 3 patients had an acceptable postoperative course and were discharged in satisfactory conditions. This technique seems to achieve satisfactory early results when used in the acute phase of myocardial infarction. PMID- 23445646 TI - [Evaluation of 2 ports video-assisted thoracoscopic surgery (VATS) using endo close for primary spontaneous pneumothorax]. AB - We aimed to assess the perioperative outcomes of 2 ports video-assisted thoracoscopic surgery(VATS) using Endo-Close (2 ports VATS) in patient for the primary spontaneous pneumothorax(PSP) compared to conventional 3 ports VATS in our hospital. 31 consecutive patients(11;2 ports VATS and 20;3 ports VATS) since 2009 were enrolled in this study. Endo-Close is a device that for pulling the anchoring thread by puncture 1.5 cm incision at the level of the 7th intercostal space( ICS) at the median axillary line( MAL) for camera port, a 1.5 cm incision at the level of the 4th ICS at the anterior axillary line for working port, and 2 mm puncture at the level of the 5th ICS at the MAL using the Endo-Close were placed for this procedure. Compared with 3 ports VATS, equivalent results were obtained by the present procedure;operation time(58.6+/-18.3 minutes vs 63.0+/ 15.1 minutes, NS), duration of drainage after operation(1.0+/-0 days vs 1.3+/-0.5 days, NS), postoperative hospital stay(3.0+/-1.5 days vs 3.7+/-1.4 days, NS) significantly.Blood loss was minimal in both cases. In conclusion, 2 port VATS using Endo-Close proved to be feasible method in surgical treatment for PSP. PMID- 23445647 TI - [Successful treatment of the intracranial hemorrhage after the cardiac surgery for infective endocarditis]. AB - We report an extremely rare case of a successful treatment of the intracranial hemorrhage after the cardiac surgery for infective endocarditis(IE). A 34-year old woman was admitted to our hospital with a diagnosis of active IE due to Staphylococcus aureus, complicated with cerebral infarctions. Preoperative echocardiography showed mobile vegetations on both leaflets of the mitral valve with 15 and 6 mm diameters. Mitral valve repair was performed on hospital day 10. There were mobile vegetations on the A2 and P3. Five days after the cardiac surgery, brain magnetic resonance imaging(MRI) and angiography demonstrated intracranial hemorrhage due to the rupture of the intracranial aneurysm, which was urgently clipped. No neurological sequel has been noted since the successful treatment. PMID- 23445648 TI - [Pulmonary abscess caused by fish bone]. AB - We describe an extremely rare case of pulmonary abscess caused by fish bone which stabbed the lung from transesophageal route. A 60-year-old woman referred to our hospital complaining of fever. Three days before, she had swallowing pain while eating the bony parts of a fish. An examination on admission showed that C reactive protein (CRP) is 9.70 mg/dl. Chest computed tomography (CT)revealed, 4 cm mass shadow in the right upper lobe and fish bone material in the mass shadow. Esophagography showed no abnormal findings. Right upper lobectomy was performed under the diagnosis of pulmonary abscess by fish bone. Post operative course was uneventful. The cause was suspected of migration of a fish bone into the right upper lobe via mediasinum and thoracic cavity from esophagus. PMID- 23445649 TI - [Resected case of pulmonary mucormycosis]. AB - A 62-year-old man, with chronic renal failure and receiving hemodialysis, pointed out to have an abnormal shadow on a chest X-ray. A chest computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (FDG-PET) examination showed a 6 cm size mass lesion in the middle of left thoracic cavity. Confirmed diagnosis was not obtained by needle biopsies. Left upper lobectomy was performed on suspicion of a lung cancer. Histopathologically, fungal hyphae were detected in these surgical specimens and it was diagnosed as pulmonary mucormycosis caused by Rhizopus species. PMID- 23445650 TI - [Lung cancer occurring in a left upper division which is mirror imaged to a right upper lobe]. AB - A 55-year-old man was admitted to our hospital because of an abnormal shadow in the left upper division on chest computed tomography(CT). Virtual bronchoscopy revealed a displaced anomalous bronchus. Thin sliced CT revealed complete lobulation between the upper division and the lingula. Three dimensional (3D)-CT revealed abnormal distribution of the left pulmonary artery which descended without passing over the left main bronchus. The left upper division was evaluated to be mirror imaged to a right upper lobe. Video assisted thoracoscopic left upper divisionectomy was performed. The tumor was diagnosed as adenocarcinoma( pT1aN0M0:p-stage I A). PMID- 23445651 TI - [Acute Type A aortic dissection with superior mesenteric arterial dissection; report of a case]. AB - We report a case of acute type A dissection with acute abdomen due to blood flow insufficiency in the superior mesenteric artery. A 73-year-old man was presented to hospital complaining sudden onset of chest pain. Contrast-enhanced computed tomography revealed a type A aortic dissection, that extended from the ascending aorta to the left common iliac atery. Superior mesenteric artery was compressed by the thrombosed false lumen. Epigastric pain was exacerbated acutely, we decided to treat the bowel ischemia 1st, and after that, if bowel ischemia was reversible, central repair operation performed. Emergent saphenous vein bypass was performed from the right external iliac artery to the superior mesenteric artery. Then total arch replacement was performed using cardiopulmonary bypass. The patient complicated with postoperative paralytic ileus, he completely recovered without bowel resection. PMID- 23445652 TI - [Extra cardiac unruptured aneurysm of the right sinus of Valsalva with aortic regurgitation and right coronary ostial stenosis; report of a case]. AB - A 78-year-old female presented with a chief complaint of palpitations. She was diagnosed with a large unruptured aneurysm of the sinus of Valsalva accompanying aortic regurgitation and right coronary artery ostial stenosis. When the aneurysm was resected following cardiac arrest, it was found to be an aneurysm with the right Valsalva sinus at the orifice. Root replacement was not required because there was no aortic annular dilatation. Patch closure as well as aortic valve replacement were conducted. The right coronary artery was diverged from the aneurysm and the aperture thereof was severely stenosed. Therefore, bypass surgery was additionally conducted. Postoperative course was uneventful. An unruptured aneurysm of the sinus of Valsalva, which is a relatively rare disease, is asymptomatic in many cases and tends to have grown large when found. Because the postoperative results were relatively good, we believe that surgery should be performed at an early stage in order to avoid rupture. PMID- 23445653 TI - [Successful repair of isolated extracardiac unruptured sinus of Valsalva aneurysm; report of a case]. AB - We report a case of isolated, unruptured extracardiac aneurysm of the right coronary sinus of Valsalva. The aneurysm was detected incidentally in a 75-years old woman during the treatment of angina pectoris. A 30*35 mm sized aneurysm was located in the right sinus of Valsalva with extracardiac protrusion. It was repaired by obliterating its orifice with an autologous pericardial patch reinforced by a polytetrafluoroethylene (PTFE) patch. Early surgical repair should be a treatment of choice for this entity to prevent catastrophic event. PMID- 23445654 TI - [Pericardial defect incidentaly noticed during off-pump coronary artery bypass grafting; report of a case]. AB - We experienced a rare case of congenital pericardial defect incidentally found during off-pump coronary artery bypass grafting (CABG)[OPCAB]. We performed off pump for a 61-year-old man. He was asymptomatic but was noted to have an abnormal chest X-ray showing the enlarged heart. He had right ventricule lifting upward and apex shifting far to left side. Partial absence of the left pericardium was found. The surgery was technically more demanding than usual, because of heart rotation and inadequate pericardial stitch. PMID- 23445655 TI - [Tricuspid valve endocarditis following osteomyelitis; report of a case]. AB - A 71-year-old man was admitted with complaints of high fever and lumbago. Echocardiography showed vegetation about 16*7 mm in size attached to the tricuspid valve. Magnetic resonance imaging showed osteomyelitis. As serial echocardiography showed the progression of valvular lesion despite antibiotic therapy, the patient underwent endoscopic removal of intervertebral disc 1st, and then tricuspid valve plasty was performed 3 days later. As of the last follow-up observation at 3 years, the patient has been doing well. PMID- 23445656 TI - [Solitary ectopic thymoma at ligamentum arteriosum; report of a case]. AB - We report a case of solitary ectopic thymoma at the ligamentum arteriosum, which was resected with thoracoscopic surgery. A 62-year-old male patient received chemoradiation therapy for laryngeal cancer approximately 1 year before. The present computed tomography scan indicated a mass (diameter, 2 cm) at the ligamentum arteriosum. Furthermore, positron emission tomography showed an abnormal accumulation on the mass. Malignant lymphoma and laryngeal cancer with lymph node metastasis were suspected, and thoracoscopic surgery was performed. The tumor had a clear margin;therefore, it could be extirpated easily. The results of the postoperative pathological examination indicated that the tumor was an ectopic thymoma. The patient was discharged 3 days after the surgery because he showed good clinical course and was kept under careful observation. PMID- 23445657 TI - [Plication of diaphragm for eventration of diaphragm caused by megacolon; report of a case]. AB - A 70-year-old woman with severe respiratory distress was admitted to our hospital by ambulance. Chest X-ray revealed marked elevation of left diaphragm and invagination of megacolon. Colectomy was performed to improve the respiratory distress, but continuous mechanical ventilation was necessary after operation due to hypoxia and hypercapnea. Therefore, plication of diaphragm was additionally performed. With 10 rows of nonabsorbable sutures, 6 to 8 pleats were formed. The following day of operation, she was successfully relieved from the ventilator. PMID- 23445658 TI - [Successful thoracoscopic surgery for mediastinal parathyroid tumor with preoperative intravenous methylene blue infusion; report of a case]. AB - A 56-year-old woman was referred to our hospital presenting high serum levels of calcium (Ca) and intact-parathyroid hormone (PTH) and an anterior mediastinal nodule of 18*13 mm in size on chest computed tomography (CT). Tumor was suspected of a parathyroid tumor. 99mTc-methoxy-isobutylisonitrile( MIBI) scintigram showed abnormal radioactive tracer accumulation in the lesion. 3 ml/kg of methylene blue was administered intravenously an hour before surgery, and the stained tumor was successfully resected by thoracoscopic surgery. Pathological diagnosis was parathyroid hyperplasia. Postoperative course was uneventful and serum levels of Ca and intact-PTH returned to normal ranges. PMID- 23445659 TI - Blomia tropicalis Blo t 5 and Blo t 21 recombinant allergens might confer higher specificity to serodiagnostic assays than whole mite extract. AB - BACKGROUND: Blomia tropicalis is a dust mite and an important source of allergens in tropical regions. Up to now, the assays to diagnose atopy to this mite use whole body extract as antigens. However, anti-B. tropicalis IgE antibodies cross react with Ascaris lumbricoides antigens, hindering the diagnosis of allergy to this mite. In this study, B. tropicalis recombinant allergens were evaluated with the purpose of developing an immunodiagnostic assay for allergy to this mite with greater specificity than those commercially available. METHODS: Two B. tropicalis allergens (Blo t 5 and Blo t 21) were cloned into a plasmidial expression vector, expressed in Escherichia coli and purified by affinity chromatography. Sixty three sera containing anti-B. tropicalis extract (BtE) IgE antibodies were used to investigate IgE reactivity to the recombinant Blot 5 and 21 allergens. Inhibition assays with 20 sera pre-adsorbed with A. lumbricoides extract were performed using rBlo t 5, rBlo t 21, and BtE as antigens. All the assays were carried using indirect ELISA. RESULTS: Eighty-two point nine percent and 80.0% of the sera with anti-BtE antibodies from 35 children reacted with rBlo t 5 and rBlo t 21, respectively, whereas 92.8% and 89.3% of the 28 sera with anti-BtE antibodies from adult asthma patients reacted with the same allergens, and 96.4% of these sera reacted with a mixture of rBlo t 5 and rBlo t 21. In an inhibition ELISA, the absorption of sera by A. lumbricoides extract affected less the reaction with rBlo t 5 and rBlo t 21 than with BtE. CONCLUSIONS: The rBlo t 5 and rBlo t 21 allergens contain important epitopes recognized by IgE antibodies of individuals allergic to B. tropicalis antigens. Moreover, the assays using the recombinant allergens had lower IgE cross-reactivity with A. lumbricoides antigens, a fact which would confers higher specificity to serodiagnostic assays than the crude mite extract. However, additional recombinant allergens should be evaluated in order to reach the same sensitivity of the commercially available assays based on mite extract. PMID- 23445660 TI - Highly pathogenic influenza viruses inhibit inflammatory response in monocytes via activation of rar-related orphan receptor RORalpha. AB - Infections with highly pathogenic avian influenza viruses (HPAIV) in humans lead to systemic disease associated with cytokine storm and multiorgan failure. In this study we aimed to identify the role of monocytes for the host response to HPAIV infection. Using genome-wide microarray analysis, we surprisingly demonstrate a reduced immune response of human monocytes to HPAIV H5N1 compared to human influenza A viruses. In bioinformatic analyses we could reveal a potential role of the Rar-related orphan receptor alpha (RORalpha) for the gene expression pattern induced by H5N1. RORalpha is known as an inhibitor of NF kappaB signaling. We provide evidence that in monocytes RORalpha is activated by H5N1, resulting in inhibited NF-kappaB signaling. Using murine Hoxb8-immortalized RORalpha-/-, monocytes rescued NF-kappaB signaling upon H5N1 infection, confirming the biological relevance of RORalpha as an H5N1-induced mediator of monocytic immunosuppression. In summary, our study reveals a novel RORalpha dependent escape mechanism by which H5N1 prevents an effective inflammatory response of monocytes blocking NF-kappaB-dependent gene expression. PMID- 23445661 TI - Trypsin-like serine peptidase profiles in the egg, larval, and pupal stages of Aedes albopictus. AB - BACKGROUND: Aedes albopictus, a ubiquitous mosquito, is one of the main vectors of dengue and yellow fever, representing an important threat to public health worldwide. Peptidases play key roles in processes such as digestion, oogenesis, and metamorphosis of insects. However, most of the information on the proteolytic enzymes of mosquitoes is derived from insects in the adult stages and is often directed towards the understanding of blood digestion. The aim of this study was to investigate the expression of active peptidases from the preimaginal stages of Ae. albopictus. METHODS: Ae. albopictus eggs, larvae, and pupae were analyzed using zymography with susbtrate-SDS-PAGE. The pH, temperature and peptidase inhibitor sensitivity was evaluated. In addition, the proteolytic activities of larval instars were assayed using the fluorogenic substrate Z-Phe-Arg-AMC. RESULTS: The proteolytic profile of the larval stage was composed of 8 bands ranging from 17 to 130 kDa. These enzymes displayed activity in a broad range of pH values, from 5.5 to 10.0. The enzymatic profile of the eggs was similar to that of the larvae, although the proteolytic bands of the eggs showed lower intensities. The pupal stage showed a complex proteolytic pattern, with at least 6 bands with apparent molecular masses ranging from 30 to 150 kDa and optimal activity at pH 7.5. Peptidases from larval instars were active from 10 degrees C to 60 degrees C, with optimal activity at temperatures between 37 degrees C and 50 degrees C. The proteolytic profile of both the larval and pupal stages was inhibited by phenyl-methyl sulfonyl-fluoride (PMSF) and Nalpha-Tosyl L-lysine chloromethyl ketone hydrochloride (TLCK), indicating that the main peptidases expressed during these developmental stages are trypsin-like serine peptidases. CONCLUSION: The preimaginal stages of Ae. albopictus exhibited a complex profile of trypsin-like serine peptidase activities. A comparative analysis of the active peptidase profiles revealed differential expression of trypsin-like isoforms among the preimaginal stages, suggesting that some of these enzymes are stage specific. Additionally, a comparison of the peptidase expression between larvae from eggs collected in the natural environment and larvae obtained from the eggs of female mosquitoes maintained in colonies for a long period of time demonstrated that the proteolytic profile is invariable under such conditions. PMID- 23445663 TI - Diagnostic distribution of 100 unilateral, side-locked headaches consulting a specialized clinic. AB - OBJECTIVES: We analyzed the diagnoses of patients consulting due to strictly unilateral headaches. METHODS: We prospectively collected data from 100 consecutive patients. Diagnosis followed the ICHD-II criteria. RESULTS: They accounted for 18.9% of the 528 patients seen in the study period. They were more frequent in males (58%). Age ranged from 19 to 81 years. Diagnostic distribution was: cluster headache (38 cases), a variety of secondary headaches (14 cases), migraine (11 cases), cervicogenic headaches (9 cases), hemicrania continua (8 cases), nummular headache (6 cases), psychiatric headache (5 cases), paroxysmal hemicranias (4 cases), short-lasting unilateral neuralgiform headache attacks syndrome (3 cases), stabbing headache (1 case), and hypnic headache (1 case). Mean ages at onset fell between 47 and 58 years for several diagnoses (cervicogenic, nummular, psychiatric, hemicrania continua and paroxysmal hemicrania headaches), and were 22 years for migraine, 32 for cluster and in general older than 55 years for secondary headaches. CONCLUSIONS: Strictly unilateral headaches account for almost 20% of headaches in subjects attending a headache clinic. Trigeminal-autonomic cephalgias in general (52%) and cluster headache in particular (38%) are the most frequent diagnoses, but secondary headaches account for 1 of 5 cases. Age at onset can be of help in their presumptive diagnosis. PMID- 23445664 TI - The 3.5 angstrom X-ray structure of the human connexin26 gap junction channel is unlikely that of a fully open channel. AB - The permeability of gap junction channels to metabolites, and not simply to small inorganic ions, is likely to play an important role in development, physiology as well as in etiology of several diseases. Here, we combined dual patch clamp and fluorescence imaging techniques with molecular dynamics (MD) simulations to investigate the permeation of calcein, a relatively large fluorescent tracer (MW 622 Da) through homomeric gap junction channels formed by wild type human connexin26 (hCx26wt) protomers. Our experimental data indicate that the unitary flux of calcein driven by a 125 MUM concentration difference is Jpore = 226 molecule/s per channel. In the light of Eyring transition state theory adapted for the liquid phase, this value corresponds to an energy barrier of ~20 kBT (where kB is the Boltzmann constant and T is absolute temperature). The barrier predicted by our MD simulations, based on the 3.5 A X-ray structural model of the hCx26wt gap junction channel, is ~45 kBT. The main contributions to the energetics of calcein permeation originated from the interaction between the permeating molecule and the charged aminoacids lining the channel pore. Assigning a fake zero total charge to the calcein molecule yielded a value for the barrier height compatible with the experimental data. These results can be accounted for by two different (although not mutually exclusive) hypotheses: (1) the X-ray model of the hCx26wt gap junction channel is not representative of a fully open state; (2) post translational modifications affecting the hCx26wt protein in our expression system differed from the modifications undergone by the proteins in the conditions used to obtain the crystal structure. Hypothesis (1) is compatible with data indicating that, only 10% or less of the channels forming a gap junction plaque are in the open state, and therefore the averaging procedure intrinsic in the generation of the crystal structure data more closely reflects that of a closed channel. Hypothesis (2) is compatible with recent mass spectrometry data and implies that the charge of several amino acid side chains may have been altered, thus modifying substantially the permeation properties of the channels in living cells. PMID- 23445662 TI - Friend or foe: high bone mineral density on routine bone density scanning, a review of causes and management. AB - A finding of high BMD on routine DXA scanning is not infrequent and most commonly reflects degenerative disease. However, BMD increases may also arise secondary to a range of underlying disorders affecting the skeleton. Although low BMD increases fracture risk, the converse may not hold for high BMD, since elevated BMD may occur in conditions where fracture risk is increased, unaffected or reduced. Here we outline a classification for the causes of raised BMD, based on identification of focal or generalized BMD changes, and discuss an approach to guide appropriate investigation by clinicians after careful interpretation of DXA scan findings within the context of the clinical history. We will also review the mild skeletal dysplasia associated with the currently unexplained high bone mass phenotype and discuss recent advances in osteoporosis therapies arising from improved understanding of rare inherited high BMD disorders. PMID- 23445665 TI - Evaluating the clinical and economic burden of healthcare-associated infections during hospitalization for surgery in France. AB - Over 4 million patients suffer nosocomial infections annually in the European Union. This study aimed to estimate the healthcare burden associated with healthcare-associated infections (HAIs) following surgery in France, and explore the potential impact of infection control strategies and interventions on the clinical and economic burden of disease. Data on the frequency of HAIs were gathered from the 2010 Programme de Medicalisation des Systemes d'Information (PMSI), and cost data were taken from the 2009 Echelle Nationale de Couts a Methodologie Commune (ENCC). It was estimated that 3% of surgical procedures performed in 2010 in France resulted in infection, resulting in an annual cost of ?57 892 715. Patients experiencing a HAI had a significantly increased mortality risk (4.15-fold) and an increased length of hospital stay (threefold). Scenario analysis in which HAI incidence following surgery was reduced by 8% (based on a study of the effectiveness of triclosan-coated sutures), suggested that, annually, 20 205 hospital days and ?4 588 519 could be saved. Analyses of 20% and 30% reductions in incidence (based on an estimate of the number of preventable nosocomial infections) suggested that annual savings of ?11 548 057 and ?17 334 696, respectively, could be made. New infection control interventions which reduce HAI incidence during hospitalization for surgery have the potential to provide valuable cost savings to healthcare providers. PMID- 23445667 TI - The 40th Annual Meeting of the Japan Society for Clinical Immunology. PMID- 23445666 TI - The effect of a paced auditory serial addition test (PASAT) intervention on the profile of volatile organic compounds in human breath: a pilot study. AB - This study sought to identify if detectable changes in human breath profiles may be observed following a psychological intervention designed to induce stress, a paced auditory serial addition test (PASAT). Breath samples were collected from 22 participants (10 male and 12 female) following a double cross-over randomized design with two experimental interventions. One intervention required participants to listen to classical music chosen to be neutral. The other intervention required participants to undertake a PASAT that induced cardiovascular responses consistent with acute stress. Both interventions also involved two sequences of cognitive function tests. Blood-pressure and heart-rate were recorded throughout each intervention and distal breath samples were collected onto Tenax(r) TA/Carbograph 1 thermal desorption tubes, using an adaptive breath sampler. Samples were collected before and after the PASAT. Breath samples were analysed by thermal desorption gas chromatography-mass spectrometry. Data registration using retention indexing and peak deconvolution followed by partial least-squares discriminant analysis identified six stress sensitive compounds. A principal components analysis model based on these components generated a model that predicted post-PASAT versus post-neutral intervention samples with a sensitivity of 83.3% and a selectivity of 91.6% for females, compared to 100% sensitivity and 90% selectivity for males. Of the six compounds indole, 2-hydroxy-1-phenylethanone, benzaldehyde, and 2-ethylhexan-1-ol were identified on the basis of mass spectral, retention indexing and confirmation against pure standards. 2-methylpentadecane was tentatively identified from mass spectral and retention indexing, whilst one component has yet to be assigned, although the mass spectrum is indicative of a terpene. Indole and 2-methylpentadecane concentrations increased in response to the PASAT intervention, while the other compounds reduced in their abundance in human breath, possibly as a result of ventilation effects. PMID- 23445683 TI - Infarcted fibroadenoma of the breast: report of two new cases with review of the literature. AB - INTRODUCTION: Fibroadenomas are the most common benign breast tumors in young women. Infarction is rarely observed in fibroadenomas and when present, it is usually associated with pregnancy or lactation. Infarction can exceptionally occur as a complication of previous fine-needle aspiration biopsy or during lactation and pregnancy. MATERIALS AND METHODS: Retrospective review of 650 cases of fibroadenomas diagnosed at our institution during the 8-years period identified two cases of fibroadenomas with infarction (rate ~0.3%). RESULTS: Two partially infarcted fibroadenomas were diagnosed on core biopsy and frozen section in an adolescent girl (13 years old) and in a young woman (25 years old), respectively. No preceding fine-needle aspiration biopsy was performed in these cases, nor were the patients pregnant or lactating at the time of the diagnosis. CONCLUSION: Spontaneous infarction within fibroadenoma is a rare phenomenon in younger patients. The presence of necrosis on core biopsy or frozen section should be cautiously interpreted and is not a sign of malignancy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1556060549847356. PMID- 23445684 TI - Proteomics: improving biomarker translation to modern medicine? PMID- 23445686 TI - Diagnostic classification past, present, and future: implications for pharmacotherapy. AB - Making a diagnosis is a key step in understanding the natural course of a disorder, selecting an appropriate treatment for the disorder, and predicting its response to treatment. Diagnostic proposals can be evaluated in two ways: reliability and validity. The reliability and validity of diagnoses are not one and the same, although establishing reliability is usually a necessary step before being able to evaluate and determine validity. There is little evidence that most psychiatric diagnoses are valid, but the reliability of diagnoses using classification systems developed since 1970 have greatly improved and are important for clinical practice and research. Past and current diagnostic systems have not optimally assisted the search for disorder-specific pathophysiological mechanisms, and they do not provide the specificity that clinicians would like when selecting medication. The Research Domain Criteria project is intended to shift research away from categorical diagnoses to focus on dysregulated neurobiological systems, and this approach ultimately may be more useful for understanding the pathophysiology of mental disorders and improving the development and use of treatment interventions. PMID- 23445685 TI - DSM-5 changes in the diagnosis of autism spectrum disorder. AB - The long-awaited fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is about to be published. The changes in the criteria for diagnosis of autism spectrum disorder are of particular interest to psychiatric nurses. This article describes the changes and the new criteria. Implications for patients and nurses, both positive and negative, are also discussed. PMID- 23445688 TI - The usefulness of a Trauma Registry and the role of the general surgeon in the multidisciplinary approach to trauma patients: 3-year experience at Sant'Andrea University Hospital in Rome. AB - The purpose of this study is to verify the usefulness of a multidisciplinary Trauma Registry in the evaluation of trauma, particularly in relation to the number of specialists involved, and to analyze the effective role of the general trauma surgeon in an integrated trauma care system. The present study was performed by analyzing data from the Trauma Registry of the University Hospital Sant'Andrea in Rome, which was set up in March 2006. Data recorded between March 2006 and March 2009 was considered for the present study. The severity of trauma was categorized by dividing patients into 4 subgroups based on the value of ISS: minor injuries (ISS 1-8), moderate (ISS 9-15), severe (ISS 16-24) and very severe (ISS> 24). Patients who had an ISS greater than 9 were taken into account for further analysis and comparison. To evaluate the significance of the multidisciplinarity the patients were stratified in subgroups considering the number of specialists involved in relation to the anatomic location of injuries. In the 1386 trauma patients entered in the registry, the mean and median ISS value were 10.7 +/- 8.4 and 9 respectively. The overall mortality and morbidity were 4.1% and 7.4% respectively. There was a statistically significant linear relationship between the number of specialists involved and the ISS (multidisciplinarity / ISS r = 0.493, p <0.001). Patients with ISS greater than 9 were 358, 25.8% of all cases. The mean ISS was 21.4 +/- 10.3. Mortality and morbidity rates were 9.8% (35 patients) and 22.1% (79 patients) respectively. The average number of specialists involved was 2.4 +/- 1.1, median 2 (range 1- 6). Results confirmed the significance of the multidisciplinary treatment for patients with trauma and the central role played by the general surgeon. PMID- 23445687 TI - Photoprotective and antioxidant effects of Rhubarb: inhibitory action on tyrosinase and tyrosine kinase activities and TNF-alpha, IL-1alpha and alpha-MSH production in human melanocytes. AB - BACKGROUND: Exposure to ultraviolet (UV) radiation causes various forms of acute and chronic skin damage, including immunosuppression, inflammation, premature aging and photodamage. Furthermore, it induces the generation of reactive oxygen species, produces proinflammatory cytokines and melanocyte-stimulating hormone (MSH) and increases tyrosinase activity. The aim of this study was to evaluate the potential photoprotective effects of Rheum rhaponticum L. rhizome extract on human UV-stimulated melanocytes. METHODS: The effects of Rheum rhaponticum rhizome extract on tyrosine kinase activity, and on interleukin-1alpha (IL 1alpha), tumour necrosis factor alpha (TNF-alpha), and alpha-MSH production in human epidermal melanocytes were evaluated under UV-stimulated and non-stimulated conditions. Antioxidant activity was evaluated by lipid peroxidation and 1,1 dyphenyl-2-picryl-hydrazyl (DPPH) assays, while anti-tyrosinase activity was evaluated by the mushroom tyrosinase method. RESULTS: Rheum rhaponticum L. rhizome extract showed in vitro antioxidant properties against lipid peroxidation, free radical scavenging and anti-tyrosinase activities, and inhibited the production of IL-1alpha, TNF-alpha, alpha-MSH, and tyrosine kinase activity in melanocytes subjected to UV radiation. CONCLUSIONS: These results support the inclusion of Rheum rhaponticum L. rhizome extract into cosmetic, sunscreen and skin care products for the prevention or reduction of photodamage. PMID- 23445689 TI - Emergency treatment of violent trauma: clinical cases and surgical treatment of penetrating thoracoabdominal, perineal and anorectal trauma. AB - AIM: The authors analyse clinical cases of penetrating thoracic, abdominal, perineal and anorectal injury and describe the traumatic event and type of lesion, the principles of surgical treatment, the complication rate and follow up. MATERIALS AND METHODS: In the last 24 months, we analyzed 10 consecutive cases of penetrating thoracic and abdominal wounds [stab wound (n=7), with evisceration (n=4), gunshot wound (n=1)], and penetrating perineal and anorectal wounds (impalement n=4). In addition, we report an unusual case of neck injury from a stab wound. All the patients underwent emergency surgery for the lesions reported. RESULTS: In 7 cases of perforating vulnerant thoracoabdominal trauma from stab wounds there was hemoperitoneum due to bleeding from the abdominal wall (n=3), the omentum (n=1), the vena cava (n=1) and the liver (n=2). Evisceration of the omentum was observed in 4 cases. In 2 cases laparoscopy was performed. In one case laparotomy and thoracoscopy was performed. In a patient with an abdominoperineal gunshot wound, exploration was extraperitoneal. The 4 cases of perineal and anorectal impalement were treated with primary reconstruction, while in one case a laparotomy was needed to suture the rectum and fashion a temporary colostomy. In one case of anorectal injury rehabilitation resulted in a gradual improvement of fecal continence, while in the patient with the colostomy follow up at 2 months was scheduled to plan colostomy closure. CONCLUSIONS: Based on the our clinical experience and the literature, in penetrating abdominal trauma laparotomy may be required if patients are hemodynamically unstable (or in hemorrhagic shock), in patients with evisceration and peritonitis, or for exploration of penetrating thoracoabdominal and epigastric lesions. In anterior injuries of the abdominal wall from gunshot or stab wounds, laparotomy is indicated when there is peritoneal violation and significant intraperitoneal damage. In patients with actively bleeding wounds of the abdominal wall muscles minimal laparotomy is often necessary for control of hemorrhage and abdominal wall reconstruction to avoid herniation. If patients are asymptomatic, in cases of anterior lesions the indications for diagnostic laparoscopy are uncertain. Selective conservative treatment is reserved for asymptomatic patients who are hemodynamically stable. Further controlled studies are needed. Early surgery for perineal and anorectal trauma, and also for complex injuries, is the gold standard for treatment. PMID- 23445690 TI - The impact of etiological factors on mortality in retroperitoneal hematomas. AB - AIM: Retroperitoneal hematomas (RPH) mostly occur after blunt and penetrating traumas. However, these hematomas may develop spontaneously in the elderly and the patients who use anticoagulants. Between January 2006 and December 2011, 31 patients with RPH were evaluated retropectively. The patients were allocated into three groups according to the underlying etiological factor: Group I; spontaneous RPH, group II; RPH caused by penetrating trauma, group III; RPH caused by blunt trauma. RESULTS: There were 22 (71%) male and 9 (29%) female patients with a mean age of 35.7 +/- 18.7 (range: 15-88 years). Spontaneous RPH was diagnosed in eight patients (25.8%) while RPH caused by penetrating trauma in 13 patients (41.9%) and RPH induced by blunt trauma in 10 (32.3%) patients. Retroperitoneal hematomas were located at zone I in 2 patients (6.5%) whereas zone II in 19 patients (61.3%) and zone III in 9 patients (29%). On the other hand, RPH was regarded to be at zone II-III in 1 patient (3.2%). Additional organ injury was defined in 18 patients (58.1%). Twenty patients (65%) were treated surgically. The morbidity rates were 12.5%, 7.7% and 20% and the mortality rates were denoted as 12.5%, 15.4% and 50%, for group I, group II and group III, respectively. DISCUSSION: Additional organ injury, massive blood transfusion, the route of injury and the need for surgery are defined as the most significant factors associated with increased mortality. PMID- 23445691 TI - Risk assessment of exposure to lead in tap water among residents of Seri Kembangan, Selangor state, Malaysia. AB - INTRODUCTION: A cross sectional study was conducted to estimate risk of exposure to lead via tap water ingestion pathway for the population of Seri Kembangan (SK). METHODOLOGY: By using purposive sampling method, 100 respondents who fulfilled the inclusive criteria were selected from different housing areas of SK based on geographical population distribution. Residents with filtration systems installed were excluded from the study. Questionnaires were administered to determine water consumption-related information and demographics. Two water samples (first-flushed and fully-flushed samples) were collected from kitchen tap of each household using HDPE bottles. A total of 200 water samples were collected and lead concentrations were determined using a Graphite Furnace Atomic Absorption Spectrophotometer (GFAAS). RESULTS: Mean lead concentration in first flushed samples was 3.041+/- SD 6.967ug/L and 1.064+/- SD 1.103ug/L for fully flushed samples. Of the first-flushed samples, four (4) had exceeded the National Drinking Water Quality Standard (NDWQS) lead limit value of 10ug/L while none of the fully-flushed samples had lead concentration exceeded the limit. There was a significant difference between first-flushed samples and fully-flushed samples and flushing had elicited a significant change in lead concentration in the water (Z = -5.880, p<0.05). It was also found that lead concentration in both first flushed and fully flushed samples was not significantly different across nine (9) areas of Seri Kembangan (p>0.05). Serdang Jaya was found to have the highest lead concentration in first-flushed water (mean= 10.44+/- SD 17.83ug/L) while Taman Universiti Indah had the highest lead concentration in fully-flushed water (mean=1.45+/- SD 1.83ug/L). Exposure assessment found that the mean chronic daily intake (CDI) was 0.028+/- SD 0.034ugday-1kg-1. None of the hazard quotient (HQ) value was found to be greater than 1. CONCLUSION: The overall quality of water supply in SK was satisfactory because most of the parameters tested in this study were within the range of permissible limit and only a few samples had exceeded the standard values for lead and pH. Non-carcinogenic risk attributed to ingestion of lead in SK tap water was found to be negligible. PMID- 23445692 TI - The effect of dietary supplements on the quality of life of retired professional football players. AB - Professional football players may experience negative health consequences when they retire such as chronic pain, cognitive problems as well as other consequences of sports-related injuries. The purpose of this pilot study is to determine the effects of dietary supplementation with multiple nutrients on the quality of life of retired football players. Fifteen retired players received daily supplementation of fish oil with cholecalciferol, antioxidants, natural vitamins and minerals, polysaccharides and phytosterol-amino acid complex for 6 months. Using an open-labeled repeated measures design, volunteers completed self report assessment measures at baseline, 1, 3 and 6 months. Outcome measures were CDC HRQOL-4, WHOQOL-BREF, POMS, MFQ and pain self-assessment. General health rating improvement on CDC HRQOL-4 from month 1 was sustained to month 6 (p<0.0001). Mental health days improved at 6 months (p<0.05). WHOQOL-BREF showed increased health satisfaction at all measurement points (p<0.05) and the Physical and Psychological Domain Scores at 6 months (p<0.05). MFQ General Rating of Memory improved at 3 and 6 months (p<0.05). Vigor scale in POMS was significant at 3 months (p<0.05). Decreased pain was noted only for the elbow at month 1 and the knee at month 3 (p<0.05). No adverse events were reported. Results of this study offer preliminary insight into using dietary supplements to support and optimize quality of life in retired football players. Further research using a placebo-controlled design is needed to characterize the potential benefit to physical and psychological well-being of multiple dietary supplementations for this cohort. PMID- 23445693 TI - The effectiveness and efficiency of disease management programs for patients with chronic diseases. AB - OBJECTIVE: Disease management (DM) approach is increasingly advocated as a means of improving effectiveness and efficiency of healthcare for chronic diseases. To evaluate the evidence on effectiveness and efficiency of DM, evidence synthesis was carried out. METHODS: To locate eligible meta-analyses and systematic reviews, we searched Medline, EMBASE, the Cochrane Library, SCI-EXPANDED, SSCI, A&HCI, DARE, HTA and NHS EED from 1995 to 2010. Two reviewers independently extracted data and assessed a study quality. RESULTS: Twenty-eight meta-analyses and systematic reviews were included for synthesizing evidence. The proportion of articles which observed improvement with a reasonable amount of evidence was the highest at process (69%), followed by health services (63%), QOL (57%), health outcomes (51%), satisfaction (50%), costs (38%) and so on. As to mortality, statistically significant results were observed only in coronary heart disease. Important components in DM, such as a multidisciplinary approach, were identified. CONCLUSION: The evidence synthesized shows considerable evidence in the effectiveness and efficiency of DM programs in process, health services, QOL and so on. The question is no longer whether DM programs work, but rather which type or component of DM programs works best and efficiently in the context of each healthcare system or country. PMID- 23445694 TI - The impact of fear, secrecy, and stigma on parental disclosure of HIV status to children: a qualitative exploration with HIV positive parents attending an ART clinic in South Africa. AB - South Africa is one of the sub Saharan countries where considerable progress in providing antiretroviral treatment (ART) has been made. The increased access to ART contributes to improvements in the prognosis of HIV and parents are more likely to raise their children than ever before. The study examined the social context influencing disclosure of parental HIV status to children from the perspectives of fathers and mothers accessing ART from an academic hospital in South Africa. Three focus group interviews were conducted with 26 non-disclosed biological parents of children aged between 7 and 18 years. Their ages ranged between 20-60 years and they cared for a total of 60 children. Parental decision not to disclose their HIV status to children was influenced by the fear of death and dying, the influence of television and media, stigma and discrimination. Parents delayed disclosure of their HIV status to children because children believed that AIDS kills. Parents also feared that the child may not be able to keep the parent's HIV status secret and might result in the family being subjected to stigma, discrimination, and isolation. Fear of stigma and discrimination were also responsible for the continuous efforts by parents to protect their HIV status from their children, family and neighbour's. Parents also delayed disclosure to children because they lacked disclosure skills and needed support for disclosure from health care providers. Healthcare providers are in a unique position to provide such support and guidance and assist parents to disclose and children to cope with parental HIV infection. PMID- 23445695 TI - The plight of parents/caregivers of children with heart disease in the rural areas of Namibia: a problem of coping. AB - Providing care for a child with heart disease is a daunting task for any parent/caregiver, particularly for those living in poor conditions in rural Namibia. A qualitative, exploratory, phenomenological and contextual study was conducted to describe such parents'/caregivers' experiences of providing care for a child with a heart disease. The study also examined the children's experiences of living with the burden of disease at home. The findings revealed experiences of emotional turmoil, disruptive social functioning and social relations, lack of support from the family, lack of organised forms of support from societal organisations, as well as experiences of low vitality among the children. These experiences together signify the overall poor coping by the parents/caregivers and the children. This paper presents the findings of a situational analysis of the experiences of caring for a child with heart disease and of living with heart disease. PMID- 23445696 TI - Empowerment of the rural parents/caregivers of children with heart diseases in Namibia to facilitate coping with the demands of caring at home. AB - AIM: The purpose of this study was to describe how the parents/caregivers of children with heart diseases cope with the demands of caring for these children at home, with the purpose to develop a home-based health care programme to facilitate the parents/caregivers' coping with the demands of care. METHODS: A qualitative, exploratory, descriptive, and contextual study was conducted. Phenomenological data on the lived experiences of coping with the demands to care by the parents/caregivers and of living with the burden of the disease by the children were gathered and interpreted from a purposefully selected sample of 5 multiple cases of parents/caregivers and children with heart disease from the rural areas. RESULTS: The findings have revealed poor coping with the demands of caring among the parents/caregivers, as characterized by the experiences of emotional challenges, disruptive social functioning and social relations, lack of support from the family and societal organizations, financial difficulties and of course the experiences of decreased vitality by the children. As a result, the need to empower the parents/caregivers for them to cope with providing a continuum care to their children who have heart disease was identified. The dynamics to mitigate the negative experiences were conceptualized. Therefore, the interventions of a home-based health care programme as an interface to facilitate the parents/caregivers to cope with the challenges caused by the demands to care were developed. CONCLUSIONS: The need for empowerment of these parents/caregivers can be met through the implementation of multi-component interventions, which draw together all the possible determinants factors and the coping methods to facilitate coping. PMID- 23445697 TI - Myths and fallacies about male contraceptive methods: a qualitative study amongst married youth in slums of Karachi, Pakistan. AB - Pakistan presently has one of the largest cohorts of young people in its history, with around 36 million people between the ages of 15 and 24 years. One of the main reasons for high population growth in Pakistan is almost stagnant contraceptive prevalence rate of 30% nationally and 17.4% amongst youth. The study was conducted to explore the perceptions regarding myths and fallacies related to male contraceptive methods among married youth aged 18-24 year in Karachi, Pakistan. Qualitative exploratory study design was adopted and a total of eight Focus Group Discussions (FGDs) were conducted. Study was conducted in two Union Councils of Korangi Town in the squatter settlement of Karachi, Pakistan from July to September 2010. Thematic analysis was done manually. General, physical, sexual, psychological, socio-cultural and religious were the common categories which lead to myths and fallacies related to condoms use and vasectomy among the married youth. The foremost myth amongst male and female youth was that use of both condoms and vasectomy cause impotence in males. Additionally, condoms were thought to cause infections, backache and headache in males. Some youth of the area think that vasectomy is meant for prisoners only. In conclusion our findings suggest that the potential reasons behind low use of male contraceptive methods among youth of squatter settlement of Karachi were myths and fallacies about male contraceptive methods. There are some important policy implications like counseling of the couple through peers and well trained family planning service providers to address these myths and misconceptions from the minds of youth. PMID- 23445698 TI - Dyspnea in Chronic Fatigue Syndrome (CFS): comparison of two prospective cross sectional studies. AB - Chronic Fatigue Syndrome (CFS) subjects have many systemic complaints including shortness of breath. Dyspnea was compared in two CFS and control cohorts to characterize pathophysiology. Cohort 1 of 257 CFS and 456 control subjects were compared using the Medical Research Council chronic Dyspnea Scale (MRC Score; range 0-5). Cohort 2 of 106 CFS and 90 controls answered a Dyspnea Severity Score (range 0-20) adapted from the MRC Score. Subsets of both cohorts completed CFS Severity Scores, fatigue, and other questionnaires. A subset had pulmonary function and total lung capacity measurements. Results show MRC Scores were equivalent between sexes in Cohort 1 CFS (1.92 [1.72-2.16]; mean [95% C.I.]) and controls (0.31 [0.23-0.39]; p<0.0001). Receiver-operator curves identified 2 as the threshold for positive MRC Scores in Cohort 1. This indicated 54% of CFS, but only 3% of controls, had significant dyspnea. In Cohort 2, Dyspnea Score threshold of 4 indicated shortness of breath in 67% of CFS and 23% of controls. Cohort 2 Dyspnea Scores were higher for CFS (7.80 [6.60-9.00]) than controls (2.40 [1.60-3.20]; p<0.0001). CFS had significantly worse fatigue and other complaints compared to controls. Pulmonary function was normal in CFS, but Borg scores and sensations of chest pain and dizziness were significantly greater during testing than controls. General linear model of Cohort 2 CFS responses linked Dyspnea with rapid heart rate, chest pain and dizziness. In conclusion, sensory hypersensitivity without airflow limitation contributed to dyspnea in CFS. Correlates of dyspnea in controls were distinct from CFS suggesting different mechanisms. PMID- 23445699 TI - Parental perspectives of a 4-week family-based lifestyle intervention for children with obesity. AB - OBJECTIVES: The childhood obesity epidemic is now recognized as one of the most serious public health challenges of the 21st century. Community-based behaviour modification treatment programs involving both children and their families are warranted. The purpose of this study was to explore the experiences of parents whose children participated in the Children's Health and Activity Modification Program (C.H.A.M.P.): a 4-week lifestyle program delivered as a day-camp for obese children at risk for type II diabetes and their families. Parents were required to attend four half-day education sessions during the intervention period. METHODS: Seven focus groups were conducted immediately following the 4 week interventions offered in August 2008 and 2009. The perspectives of 38 parents representing 32 children aged 8-14 with obesity (i.e., body mass index > the 95th percentile) were shared. RESULTS: Overall, parents were pleased with the impact of the program and proud of their children's accomplishments (e.g., increased physical activity levels, enhanced self-esteem, weight loss). Several facilitators to success (e.g., social support; a positive environment) and barriers to its maintenance (e.g., time management; unsupportive family members) were identified, and recommendations were made for future programs. Although parents found the half-day sessions valuable, post-programmatic bi-monthly booster session adherence declined over the one-year follow-up period. CONCLUSION: Delivered as a 4-week day-camp, C.H.A.M.P. represents a unique approach to the treatment of childhood obesity. Future family-based interventions should consider avenues for intensifying the parental program component whilst employing strategies to promote parental adherence in service of enhancing long term sustainability of health behaviour changes. PMID- 23445700 TI - Patterns of daily duration and frequency of breastfeeding among exclusively breastfed infants in Shiraz, Iran, a 6-month follow-up study using Bayesian generalized linear mixed models. AB - INTRODUCTION: Despite numerous studies on the benefits of exclusive breastfeeding during the first half year of life, little information is available on actual breastfeeding practices in terms of daily duration and frequency of suckling. This study proposes to determine daily breastfeeding patterns among exclusively breastfed infants from birth to six months. SUBJECT AND METHODS: An observational prospective follow-up study of daily feeding practices among exclusively breastfed infants was conducted in 2007/2008. Mothers were recruited and interviewed during their first month postpartum health center visit. A total of 287 mothers were recruited into the study. Primary outcome measures were suckling duration and frequency of breastfeeding during daytime and nighttime. Mothers were asked at each healthcare visit to report the daily duration in minutes and the daily number of breastfeeding sessions. Mixed models were used to determine breastfeeding patterns and predictors. RESULTS: Of 287 mothers selected for this study, 174 (61%) exclusively breastfeeding until six months after delivery. Mixed modeling showed that as the infant's age increased duration of one suckling, cumulative duration and frequency of breastfeeding during daytime, nighttime and a twenty four hour period all gradually decreased. Infants gender and receiving professional advice about breastfeeding were also significant factors in breastfeeding patterns (p<0.05). CONCLUSIONS: The one suckling duration and frequency of feeds in this study population were considerably higher than values reported in other populations. The variation of feeding patterns between exclusively breastfed infants was very wide. The distributions of one suckling duration, frequency of breastfeeding and cumulative duration of feeds were right skewed. The current professional advices about breastfeeding are not appropriate because they do not consider unique condition within specific populations. PMID- 23445701 TI - Measuring burden of diseases in a rapidly developing economy: state of Qatar. AB - BACKGROUND: The Global Burden of Disease (GBD) study has provided a conceptual and methodological framework to quantify and compare the health of populations. AIM: The objective of the study was to assess the national burden of disease in the population of Qatar using the disability-adjusted life year (DALYs) as a measure of disability. METHODS: We adapted the methodology described by the World Health Organization for conducting burden of disease to calculate years of life lost due to premature mortality (YLL), years lived with disability (YLD) and disability adjusted life years (DALYs). The study was conducted during the period from November 2011 to October 2012. RESULTS: The study findings revealed that ischemic heart disease (11.8%) and road traffic accidents (10.3%) were the two leading causes of burden of diseases in Qatar in 2010. The burden of diseases among men (222.04) was found three times more than of women's (71.85). Of the total DALYs, 72.7% was due to non fatal health outcomes and 27.3% was due to premature death. For men, chronic diseases like ischemic heart disease (15.7%) and road traffic accidents (13.7%) accounted great burden and an important source of lost years of healthy life. For women, birth asphyxia and birth trauma (12.6%) and abortion (4.6%) were the two leading causes of disease burden. CONCLUSION: The results of the study have shown that the national health priority areas should cover cardiovascular diseases, road traffic accidents and mental health. The burden of diseases among men was three times of women's. PMID- 23445702 TI - Effects of the comprehensive cardiac rehabilitation program on psychological factors and quality of life among coronary heart disease patients. AB - The Comprehensive Lifestyle Intervention, which integrates psychological and educational intervention, is a program to improve self-efficacy, self-regulation, self-care, body mass index and quality of life of the patients with coronary heart disease during early stages following hospitalization. The purpose of this study was to investigate the effects of the Comprehensive Cardiac Rehabilitation Program affecting psychological factors including self-efficacy, self-regulation, self-care, quality of life (QoL), and body mass index (BMI). This study was a quasi-experimental research with a repeated one group design. Eighty patients with coronary artery disease were recruited from either the Medicine or Surgical Ward at the Phramongkutklao Hospital where the patients joined the Comprehensive Cardiac Rehabilitation Program, which included attending exercising practice and receiving face-to-face counseling while being admitted to the hospital. Telephone counseling was thereafter performed one week after being discharged from the hospital, followed by undergoing individual or group counseling at the Cardiac Rehabilitation Clinic the following week. The follow-up period was performed within six weeks after hospitalization. Data was collected on two occasions before discharging from the hospital (pretest) and six weeks after (post-test) by using the self-efficacy, self-regulation, and self-care questionnaires, as well as the Short Form(SF) -36 (Thai version). The results indicated that by six weeks, 50%, 58.80%, 46.20%, and 72.50% of patients, respectively, had experienced increases with self-efficacy, self-regulation, self-care, and quality of life scores, while 12.50% of patients had decreased their body mass index in comparison with the pretest score. From the paired t-test, the self-efficacy, self-regulation and quality of life scores were statistically significant, having increased to the p<0.01 level; self-care was statistically significant, having increased to the p<0.05 level along with body mass index, which was statistically significant having experienced a decrease to the p<0.01 level. PMID- 23445703 TI - Sensationalising the female pudenda: an examination of public communication of aesthetic genital surgery. AB - We live in a society where beauty and sensations are important. Advances in medical technologies have brought on waves of new notions of beauty where commercial interests both in the media and the health industry spurred by fashion, advertising and celebrity promotion have tended to popularise body modifications and enhancements. In recent times, through offerings on cable television channels and glossy consumer magazines, medical procedures hitherto only in the precincts of medical schools, gyneacological clinics and medical journals have now pervaded the population. More seriously, on the Internet particularly, medical experts now offer services and graphic details of labiaplasty, clitoral hood reduction or enhancement, vaginal rejuvenation, etc. Here, we examine the public communication of the phenomenon of aesthetic genital surgery and interrogate thus; is it decent, honest, balanced and ethical? Relying on textual analysis, personal observation and literature review for data gathering, we observe that besides tending to commercialise and medicalise the female genitalia, a coalescence of medical, advertising and fashion interests as played out in the media sensationalises the benign science of plastic surgery and robs it of its truthfulness, genuineness, and purposefulness. The conclusion is that in Africa, where the effect of the development crises is telling, the hype surrounding cosmetic or aesthetic genital surgery is a damaging distraction particularly when the continent is waging a battle against female genital mutilation. The recommendations are that media and medical regulatory bodies should impress it upon media and medical industry operators that glaring commercial promotions of cosmetic genital surgery in the public media be checked, and that such communication should bear equal weight of facts related to risks, short comings, complications, and threats; in physical, social, and psychological terms. PMID- 23445705 TI - Parallel NGO networks for HIV control: risks and opportunities for NGO contracting. AB - Policy measures for preventive and promotive services are increasingly reliant on contracting of NGOs. Contracting is a neo-liberal response relying on open market competition for service delivery tenders. In contracting of health services a common assumption is a monolithic NGO market. A case study of HIV control in Pakistan shows that in reality the NGO market comprises of parallel NGO networks having widely different service packages, approaches and agendas. These parallel networks had evolved over time due to vertical policy agendas. Contracting of NGOs for provision of HIV services was faced with uneven capacities and turf rivalries across both NGO networks. At the same time contracting helped NGO providers belonging to different clusters to move towards standardized service delivery for HIV prevention. Market based measures such as contracting need to be accompanied with wider policy measures that facilitate in bringing NGOs groups to a shared understanding of health issues and responses. PMID- 23445704 TI - Small airways involvement in patients with rheumatoid arthritis. AB - OBJECTIVES: One of the common causes of morbidity in patients with RA is pulmonary involvement. Some studies have shown that the possible abnormal results of pulmonary function tests in rheumatoid disease are higher than usual. We aimed to evaluate the prevalence of spirometric abnormalities in patients with RA. MATERIALS & METHODS: This case-control study was conducted on 99 patients with RA who referred to a rheumatology clinic in Qazvin, northwest Iran. Sixty five age- and sex-matched healthy controls were recruited as well. History taking, physical examination, laboratory tests and spirometry were performed for the participants. RA severity was assessed according to Disease Activity Score 28 (DAS28). The data were processed using SPSS software version 16. Chi square and student's t test and multiple logistic regressions were used as appropriated. RESULTS: The mean (+/-SD) age of the patients was 46 (+/-10.5) years. The mean (+/-SD) duration of disease was 4.8 (+/-5.4) years, and the mean (+/-SD) DAS28 was 2.5 (+/-1.1). Dyspnea was the most common respiratory complaint (6.1%). Three (3%) patients had mild restrictive, 2 (2%) patients mild obstructive, and one (1%) patient moderate obstructive diseases. In the control group, only one participant had mild restrictive pulmonary disease (P<0.05). A significant decrease of FEF25 [OR=3.2; 95%CI (1.9-4.5)], FEF50 [OR=2.5; 95% CI (1.7-3.1)], FEF75 [OR=2.3; 95% CI (1.4 2.7)] and FEF25-75 [OR=2.7; 95% CI (1.7-3.5)] was observed in patients compared with the control group. We found no correlation between the patients' age, duration and severity of the disease, and laboratory tests with spirometric indices. CONCLUSION: It is recommended that patients with RA be visited on a regular basis and PFT be done for them for the early diagnosis of pulmonary involvement. PMID- 23445706 TI - A diagnostic electronic reporting framework proposal using preassigned automated coded phrases. AB - Radiologists daily diagnose a large number of Chest X-rays and it is crucial that these reports are appropriately recorded, meaningfully indexed, carefully stored, easily retrieved, shared and printed. The absence of organized reports' storage does not permit their direct and easy retrieval, while after almost a year the report is perished and not even readable (handwritten or typed). The scope of this paper is to evaluate and propose the use of preassigned automated-coded phrases for the chest X-ray electronic reporting in a Radiology Department. The research included 9,252 typed reports, using the proposed method and 949 hand written reports (later typed or not), which were used to compare between the time being spent in reporting with either method. The results proved that even if the method could not be applied fully, there was a 90% reduction of the time being spent by the radiologists and secretarial staff in a Radiology Department, thereby facilitating the typing and management of the electronic archives. In addition, it was found that the reprinting due to addendums/discrepancies, when the proposed method was used, was reduced fourfold, when compared to the previously used methods. In conclusion, the consistent application of preassigned automated-coded reporting can be time saving, cost effective and environmentally friendly saving paper and ink. PMID- 23445707 TI - Dietary diversity and its related factors among adolescents: a survey in Ahvaz Iran. AB - INTRODUCTION: Healthy growth and development essentially need a balanced diet of nutrients and vitamins which includes a variety of foods from different food groups. The primary aim of this study was to assess the dietary diversity (DD) and its related factors among adolescents' high school girls in Ahvaz-Iran. METHODOLOGY: This was a cross-sectional study which it was structured based on the WHO & FAO's dietary diversity questionnaire. The study population consisted of 506 high school girls aged 15 to 18. Data about diet, socio-demographic and anthropometric characteristics were gathered. A dietary diversity score (DDS) and anthropometric of girls were measured. The relation of DDS with anthropometric measures and economic situation were assessed. RESULTS: The mean DDS was 6.81+/ 1.75. A total of 18.85% and 8.3% of participants were overweight and obese respectively. In participants with scores ? six, Body Mass Index, waist circumference and waist-hip ratio were slightly greater than in individuals with scores less than six, however it was not significant except for waist hip ratio. The Logistic Regression showed that; weak economical situation was a risk for poor DDS (OR= 3.5, CI= 1.06-10.6, p=0.03). CONCLUSION: The FAO's third version of guidelines is a good indicator for measuring DDS. The results of this study indicate that high school girls' knowledge and practice about dietary diversity are not good and need to be improved by educational classes. PMID- 23445708 TI - Urinary tract infection among symptomatic outpatients visiting a tertiary hospital based in midwestern Nigeria. AB - Microbial pathogens implicated in urinary tract infection and their antibiotic susceptibility patterns as prevalent in UTI symptomatic outpatients resident in Benin City, Nigeria was the focus of this study. One hundred (100) midstream urine samples were collected into sterile plastic universal bottles from outpatients who visited the University of Benin Teaching Hospital, Nigeria and who were tentatively diagnosed as manifesting symptoms of UTI. Patients were referred to the Medical Microbiology department by the consulting doctors. Significant bacterial counts and neutrophil (pus cells) counts were carried out on samples by standard methods. Positive samples for both counts were inoculated aseptically on sterile MacConkey agar, Cystine Lactose Electrolyte Deficient (CLED) agar and Sabouraud Dextrose agar plates and incubated appropriately. Microbial isolates were identified and antibiotic sensitivity testing was carried out on isolates by standard methods. Thirty nine (39.0%) and 61 (61.0%) samples recorded significant microbial growth and no growth respectively. Gram negative bacilli constituted 86.1% (of which enterobacteriaceae made up 49.9%) while gram positive cocci made up 13.9%. Strains of uropathogens isolated were Alcaligenes spp (19.4%), Klebsiella aerogenes (16.7%), Escherichia coli (13.9%), Staphylococcus aureus (13.9%), Candida albicans (11.1%), Proteus mirabilis (8.3%), Pseudomonas aeruginosa (5.5%), Enterobacter spp (5.5%) and Providencia spp (5.5%). Occurrence of UTI in male and female patients were 58.3% and 41.7% respectively of which UTI occurred highest in the 25-46, 15-54 and 27-54 age groups in that decreasing order. Alcaligenes spp occurred most in very old female patients. Candida albicans (the only fungal uropathogen) occurred in an 8day old male patient. Other isolates occurred in much older patients. A significantly high microscopic neutrophil count or pyuria was recorded from deposits of UTI positive patients (i.e. < 5/HPF). Eighteen (representing 50.5%) and 15 (47.8%) of total microbial strains isolated were sensitive to nitrofurantoin and ceftriaxone respectively. Antibiotic susceptibility profile also showed 13(41.6%), 13(41.6%), 13(41.6%) for ciprofloxacin, cefuroxime and ofloxacin respectively suggesting moderate sensitivity of the fluoroquinolones and second/third generation cephalosporins. Gentamicin, ampicillin and augmentin recorded over 70.0% resistance level each. A total of nineteen bacterial strains made of E.coli, Enterobacter spp, Proteus mirabilis, Providencia spp, Staph. aureus and Pseudomonas aeruginosa were multi drug resistant as they resisted 3, 3, 4, 4, 5 and 8 antibiotics respectively. PMID- 23445709 TI - Antecedents of elderly home residency in cognitive healthy elders: a qualitative study. AB - Admission to elderly homes brings with itself fear of losing home and many other mental consequences to both the elder and family members. The aim of this study was to explore the experiences of elders about factors influencing living in the elderly home. Using a qualitative design, 14 elder people living in elderly homes were chosen through purposive sampling based on defined criteria. Semi-structured interviews were held with the participants and field noting was taken during the interviews. Collected data was analyzed using thematic analysis, which resulted in the development of three main themes: "basic Predictors", "self-care crisis", and "role crisis", which were consisted of a couple of subthemes. We conclude that nurses to better care in community and elderly homes, need to know that living in elderly homes has universal predictors; Of course their weight and position are different on different contexts. PMID- 23445710 TI - Prevalence of malnutrition among preschool children in northeast of Iran, a result of a population based study. AB - INTRODUCTION: Malnutrition in preschool children is a significant problem and has been identified by the World Health Organization (WHO) as the most lethal form of malnutrition, indirectly or directly causes an annual death of at least 5 million children worldwide. The object of this study was to estimated the rate of underweight, stunting and wasting among preschool children in northeast of Iran. METHODS: A cross sectional population based study was conducted and 70339 children; 35792 males and 34547 females were recruited. The primary outcome variables were; weight, height, age and gender of the children. The sex and age specific rate and overall rate of underweight, stunting, and wasting were calculated. RESULTS: The rate of underweight, stunting, and wasting were 7.5%, 12.5% and 4.4% respectively. There were significant differences in stunting and wasting rate between boys and girls. The overall rate of stunting was significantly higher than the overall rates of underweight and wasting. The rate of malnutrition increased with child's age. CONCLUSION: In compare to WHO criteria, the rate of malnutrition among this study population was low. According to the higher rate of stunting, the main goal of future research and interventions must be finding the causes of deficiency in height growth and improving it. PMID- 23445711 TI - The relationship between demographic variables and diabetes self-management in diabetic patients in Amman city/Jordan. AB - BACKGROUND: Diabetes is a chronic disease that requires routine and complicated self care. Although self care can be managed by most diabetes patients, there are many variables that may make diabetes self-management difficult. AIM: The study examined the relationship between clients' demographic variables and diabetes self-management in diabetic clients in Amman city/Jordan. METHOD: The data were collected through a self-completed questionnaire developed by the researchers and combined with the perceived diabetes self-management scale (PDSMS). The sampling of the investigation comprised 178 diabetes clients from Amman city/Jordan. FINDINGS: There was proportional little relationship between income level and diabetes self management, and reversely proportional low relationship between duration of diabetes and diabetes self management. Other variables had no relationship with diabetes self management. CONCLUSION: The demographic variables related to diabetes self-management in this study are income level and duration of diabetes. As income level increases, diabetes self-management become better, and the longer the duration of diabetes, the worse is diabetes self-management. PMID- 23445712 TI - Safety and effectiveness of an endoscopic suturing device in a human colonic treat-and-resect model. AB - BACKGROUND: Despite advances in many areas of therapeutic endoscopy, the development of an effective endoscopic suturing device has been elusive. The purpose of this trial was to evaluate the safety and effectiveness of a suturing device to place and secure sutures within normal, in vivo human colonic tissue prior to surgical resection. METHODS: Patients undergoing elective colectomy were enrolled in this treat-and-resect model. The Overstitch endoscopic suturing device (Apollo Endosurgery, Austin, TX) was used to place sutures in healthy colonic tissue during a 15-minute, time-limited period. Following colectomy, the explanted tissue was evaluated to determine the depth of suture penetration and the effectiveness of the suture/cinch element. Clinical and operative data were recorded. RESULTS: Four patients (50% female) were enrolled. Seven sutures were successfully placed, incorporating a total of 10 tissue bites in a mean of 13.5 minutes. On inspection of the explanted tissue, all sutures were found to be located subserosal (no full thickness bites were taken). The suture and cinch elements were judged to be effective in the majority of cases. One device-related issue did not inhibit the ability to oppose tissue or place the cinch. There were no intraoperative or postoperative complications. CONCLUSIONS: The Overstitch permitted safe and effective suturing in an in vivo human colon model. The sutures were placed at a consistent subserosal depth and at no point risked iatrogenic injury to adjacent structures. Technical issues with the device were infrequent and did not inhibit the ability to place sutures effectively. PMID- 23445713 TI - Conversion from cephalic vein to external jugular vein: success rate increased on totally implantable access ports with cut-down method. AB - BACKGROUND: Totally implantable access ports (Port-A) can be inserted using 2 techniques: cut-down and percutaneous. The cut-down method is safer than the percutaneous method. However, the cut-down method has a higher failure rate. We report an alternative method to decrease the failure rate of the cut-down method. PATIENTS AND METHODS: In all, 758 cases of Port-A implantation with cephalic vein cut-down were tried, and 56 cases failed. Of the 56 cases, 29 cases were converted to the percutaneous subclavian method (group A), and 27 cases were converted to the external jugular vein cut-down method (group B). The patient's characteristics, causes of failure of cephalic vein cut-down, operating time, and complications were compared. RESULTS: The failure rate of cephalic vein cut-down was 7.4%. The causes of failure of cephalic vein cut-down are described. There were 4 complications in group A, including one pneumothorax (1/29), one fracture of the catheter (1/29), one embolization of the catheter (1/29), and one hematoma formation in the port site (1/29); 2 complications occurred in group B, including one embolization of the catheter (1/27) and one hematoma in the port site (1/27). The total complications were 17.7%. CONCLUSION: Conversion to external jugular vein cut-down is safely and easily applied in cases of cephalic vein cut-down failure. This method did not take more time than the percutaneous subclavian method. However, placement of the port should be made more carefully to prevent angulation of the catheter. We provide an alternative method to deal with failure of cephalic vein cut-down. PMID- 23445714 TI - Elastic rubber strips to heal large wounds of the body wall. AB - BACKGROUND/PURPOSE: Closure of large wounds is a difficult surgical challenge. This article reports on the effective closure of large surgical wounds using elastic rubber strips. METHODS: One to 3 circular elastic rubber strips were sutured by applying moderate tension to the opposite edges of 30 large wounds in 28 patients. The strips were sutured in a successive "X" fashion by crossing one over the other. These rubber strips were replaced when they ruptured or after their tension had reduced because of the closure of the wounds. RESULTS: Complete closure of the wounds was achieved with no further need for any surgical procedure or device. One patient with laparostomy and colostomy presented with difficulty on adapting the colostomic bag, and the rubber strips were removed. The rubber strip had little effect on a large wound of the skull. In the late postoperative follow-up, 3 of the 15 closed laparostomies developed incisional hernias, and all these patients were subjected to hernioplasties with good results. CONCLUSION: The use of circular elastic rubber strips maintained at moderate tension is a simple, effective, and inexpensive surgical option for healing large wounds. It is readily available at any hospital and requires no extensive surgical experience. PMID- 23445715 TI - Unexpected: an interpretive description of parental traumas' associated with preterm birth. AB - BACKGROUND: Preterm birth (PTB) places a considerable emotional, psychological, and financial burden on parents, families, health care resources, and society as a whole. Efforts to estimate these costs have typically considered the direct medical costs of the initial hospital and outpatient follow-up care but have not considered non-financial costs associated with PTB such as adverse psychosocial and emotional effects, family disruption, strain on relationships, alterations in self-esteem, and deterioration in physical and mental health. The aim of this inquiry is to understand parents' experience of PTB to inform the design of subsequent studies of the direct and indirect cost of PTB. The study highlights the traumatic nature of having a child born preterm and discusses implications for clinical care and further research. METHOD: Through interviews and focus groups, this interpretive descriptive study explored parents' experiences of PTB. The interviews were audiotaped, transcribed, and analyzed for themes. Analysis was ongoing throughout the study and in subsequent interviews, parents were asked to reflect and elaborate on the emerging themes as they were identified. RESULTS: PTB is a traumatic event that shattered parents' taken-for-granted expectations of parenthood. For parents in our study, the trauma they experienced was not related to infant characteristics (e.g., gestational age, birth weight, Apgar scores, or length of stay in the NICU), but rather to prolonged uncertainty, lack of agency, disruptions in meaning systems, and alterations in parental role expectations. Our findings help to explain why things like breast feeding, kangaroo care, and family centered practices are so meaningful to parents in the NICU. As well as helping to (re)construct their role as parents, these activities afford parents a sense of agency, thereby moderating their own helplessness. CONCLUSION: These findings underscore the traumatic nature and resultant psychological distress related to PTB. Obstetrical and neonatal healthcare providers need to be educated about the symptoms of Acute Stress Disorder (ASD) and Posttraumatic Stress Disorder (PTSD) to better understand and support parents' efforts to adapt and to make appropriate referrals if problems develop. Longitudinal economic studies must consider the psychosocial implications of PTB to in order to determine the total related costs. PMID- 23445717 TI - The efficacy of incretin therapy in patients with type 2 diabetes undergoing hemodialysis. AB - BACKGROUND: Although incretin therapy is clinically available in patients with type 2 diabetes undergoing hemodialysis, no study has yet examined whether incretin therapy is capable of maintaining glycemic control in this group of patients when switched from insulin therapy. In this study, we examined the efficacy of incretin therapy in patients with insulin-treated type 2 diabetes undergoing hemodialysis. METHODS: Ten type 2 diabetic patients undergoing hemodialysis received daily 0.3 mg liraglutide, 50 mg vildagliptin, and 6.25 mg alogliptin switched from insulin therapy on both the day of hemodialysis and the non-hemodialysis day. Blood glucose level was monitored by continuous glucose monitoring. After blood glucose control by insulin, patients were treated with three types of incretin therapy in a randomized crossover manner, with continuous glucose monitoring performed for each treatment. RESULTS: During treatment with incretin therapies, severe hyperglycemia and ketosis were not observed in any patients. Maximum blood glucose and mean blood glucose on the day of hemodialysis were significantly lower after treatment with liraglutide compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. The standard deviation value, a marker of glucose fluctuation, on the non-hemodialysis day was significantly lower after treatment with liraglutide compared with treatment with insulin and alogliptin (p < 0.05), but not with vildagliptin. Furthermore, the duration of hyperglycemia was significantly shorter after treatment with liraglutide on both the hemodialysis and non-hemodialysis days compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. CONCLUSIONS: The data presented here suggest that patients with type 2 diabetes undergoing hemodialysis and insulin therapy could be treated with incretin therapy in some cases. PMID- 23445716 TI - Secretory versus degradative autophagy: unconventional secretion of inflammatory mediators. AB - Autophagy (macroautophagy) is often defined as a degradative process and a tributary of the lysosomal pathway. In this context, autophagy carries out cytoplasmic quality control and nutritional functions by removing defunct or disused organelles, particulate targets and invading microbes, and by bulk digestion of the cytoplasm. However, recent studies indicate that autophagy surprisingly affects multiple secretory pathways. Autophagy participates in extracellular delivery of a number of cytosolic proteins that do not enter the conventional secretory pathway via the Golgi apparatus but are instead unconventionally secreted directly from the cytosol. In mammalian cells, a prototypical example of this manifestation of autophagy is the unconventional secretion of a major proinflammatory cytokine, IL-1beta. This review examines the concept of secretory autophagy and compares and contrasts the role of autophagy in the secretion of IL-1alpha and IL-1beta. Although IL-1alpha and IL-1beta have closely related extracellular inflammatory functions, they differ in intracellular activation, secretory mechanisms and how they are affected by autophagy. This example indicates that the role of autophagy in secretion is more complex, at least in mammalian cells, than the simplistic view that autophagosomes provide carriers for unconventional secretion of cytosolic proteins. PMID- 23445718 TI - Phase II study of cetuximab in combination with docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck after platinum-containing therapy: a multicenter study of the Arbeitsgemeinschaft Internistische Onkologie. AB - BACKGROUND: Cetuximab and docetaxel have single-agent activity in squamous cell carcinoma of the head and neck (SCCHN). The efficacy of their combination was evaluated in platinum-pretreated patients with recurrent and/or metastatic SCCHN. PATIENTS AND METHODS: A total of 84 patients were treated with docetaxel 35 mg/m(2) weekly for a maximum of 6 cycles and concomitant cetuximab 250 mg/m(2) weekly until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate and secondary endpoints included the response rate in relation to platinum sensitivity, progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Nine (11%) patients achieved a partial response and 34 (40%) stable disease, resulting in a disease control rate of 51%. Response to treatment was 49% in previously platinum-sensitive and 50% in previously platinum-resistant disease. The median PFS was 3.1 months and the median OS 6.7 months. The most common grade 3 or 4 adverse events were mucositis (8%), pneumonia (8%), fatigue (8%) and skin reactions (14%). Sepsis occurred in 3 patients. CONCLUSION: Cetuximab plus docetaxel is an active treatment regimen with moderate toxicity in SCCHN patients. However, no superiority in comparison with monotherapy could be shown. Responsiveness and survival were independent of previous platinum sensitivity. PMID- 23445719 TI - The neuroanatomy of herophilus. AB - Herophilus (ca. 330 to ca. 260 BC) was one of Hellenistic -Alexandria's renowned scholars, a leading physician, often named the 'Father of Anatomy'. From cadaveric dissections and possibly vivisection Herophilus considered the ventricles to be the seat of the soul, intelligence and mental functions. Herophilus introduced the term rete mirabile found in ungulates but not in man, as opposed to Galen, who erroneously believed it a vital human network. A founder of the principles of observations in science, and an exponent of measurements in medicine, his accurate dissections resulted in original anatomical discoveries. He distinguished nerves that produce voluntary motion from blood vessels, and motor from sensory nerves; the nerves of the spinal cord were directly linked to the brain. He identified at least seven pairs of cranial nerves. Herophilus demonstrated the meninges, and ventricles, regarding the fourth as most important. His name is perpetuated by his accounts of the calamus scriptorius and the confluence of venous sinuses the torcular Herophili. PMID- 23445722 TI - Ethics in surgery. PMID- 23445723 TI - An epidemiological survey of Mycoplasma hominis and Ureaplasma urealyticum in gynaecological outpatients, Rome, Italy. AB - The objective of this study was to assess the prevalence of Ureaplasma urealyticum and Mycoplasma hominis infections and to investigate associations between their presence in the lower female genital tract and lifestyle characteristics. The study was performed on a population of 3115 women, comparing the demographic and behavioural characteristics of 872 women with U. urealyticum infection and 142 women with M. hominis with uninfected women, using univariate and multiple logistic regression analysis. The prevalence of infection with U. urealyticum was 28% and M. hominis was 4.6%. In multivariate logistic regression analysis, intrauterine device, number of sexual partners and age (<35 years) were significantly associated with U. urealyticum while previous induced abortion, condom use and young age at first intercourse (<16 years) were associated with M. hominis infection. U. urealyticum infection presents the same demographic and behavioural characteristics of a sexually transmitted disease. The unprotective role of condom use suggests a non-sexual mode of transmission of M. hominis infection. PMID- 23445724 TI - Change in active travel and changes in recreational and total physical activity in adults: longitudinal findings from the iConnect study. AB - BACKGROUND: To better understand the health benefits of promoting active travel, it is important to understand the relationship between a change in active travel and changes in recreational and total physical activity. METHODS: These analyses, carried out in April 2012, use longitudinal data from 1628 adult respondents (mean age 54 years; 47% male) in the UK-based iConnect study. Travel and recreational physical activity were measured using detailed seven-day recall instruments. Adjusted linear regression models were fitted with change in active travel defined as 'decreased' (<-15 min/week), 'maintained' (+/- 15 min/week) or 'increased' (>15 min/week) as the primary exposure variable and changes in (a) recreational and (b) total physical activity (min/week) as the primary outcome variables. RESULTS: Active travel increased in 32% (n=529), was maintained in 33% (n=534) and decreased in 35% (n=565) of respondents. Recreational physical activity decreased in all groups but this decrease was not greater in those whose active travel increased. Conversely, changes in active travel were associated with commensurate changes in total physical activity. Compared with those whose active travel remained unchanged, total physical activity decreased by 176.9 min/week in those whose active travel had decreased (adjusted regression coefficient -154.9, 95% CI -195.3 to -114.5) and was 112.2 min/week greater among those whose active travel had increased (adjusted regression coefficient 135.1, 95% CI 94.3 to 175.9). CONCLUSION: An increase in active travel was associated with a commensurate increase in total physical activity and not a decrease in recreational physical activity. PMID- 23445725 TI - Within-day and between-day repeatability of measurements with an electronic nose in patients with COPD. AB - Electronic noses (e-noses), artificial sensor systems generally consisting of chemical sensor arrays for the detection of volatile compound profiles, have potential applications in respiratory medicine. We assessed within-day and between-day repeatability of an e-nose made from 32 sensors in patients with stable chronic obstructive pulmonary disease (COPD). We also compared between-day repeatability of an e-nose, fraction of exhaled nitric oxide (FENO) and pulmonary function testing. Within-day and between-day repeatability for the e-nose was assessed in two breath samples collected 30 min and seven days apart, respectively. Repeatability was expressed as an intraclass correlation coefficient (ICC). All sensors had ICC above 0.5, a value that is considered acceptable for repeatability. Regarding within-day repeatability, ICC ranged from 0.75 to 0.84 (mean = 0.80 +/- 0.004). Sensors 6 and 19 were the most reproducible sensors (both, ICC = 0.84). Regarding between-day repeatability, ICC ranged from 0.57 to 0.76 (mean = 0.68 +/- 0.01). Sensor 19 was the most reproducible sensor (ICC = 0.76). Within-day e-nose repeatability was greater than between-day repeatability (P < 0.0001). Between-day repeatability of FENO (ICC = 0.91) and spirometry (ICC range = 0.94-0.98) was greater than that of e-nose (mean ICC = 0.68). In patients with stable COPD, the e-nose used in this study has acceptable within-day and between-day repeatability which varies between different sensors. PMID- 23445726 TI - [Involvement of myeloid derived immunosuppressive cells in progressive renal diseases]. AB - Immunosuppressive cells have been reported to contribute to the inflammatory diseases in various organs. Interferon (IFN)-gamma stimulations skew macrophages (Mpsi) toward classically activated (M1) phenotype and interleukin (IL)-4, IL-13, IL-10 skew toward alternatively activated (M2) phenotypes. M2 polarized Mpsi has immune regulatory function via various mechanisms, such as cytokine/chemokine expression, high activity of scavenging and interaction with other type of cells. Recently, another type of immunosuppressive myeloid cells, myeloid derived suppressor cells (MDSC), have been explored not only in tumor immunology, but also in inflammatory diseases. Orchestration of inflammation by these immunosuppressive cells with inflammatory cells has impact on progressive kidney diseases as well as inflammatory diseases. PMID- 23445727 TI - [Roles of RORgammat+ innate lymphoid cells in mucosal tissues of mouse and human]. AB - Innate Lymphoid cells (ILCs) are recently defined lymphocytes composed of several subsets such as Natural Killer (NK), Natural Helper (NH) and RORgammat(+) cells, which have no antigen receptors but exhibit rapid cytokine production after stimulation. Murine RORgammat(+) ILCs can be classified either as CCR6(+)c kit(high)IL-7Ralpha(high) or CCR6NK(-)p46(+) cells. The former ones play roles on the formation of secondary lymphoid tissues and the later ones contribute to the maintenance of intestinal epithelial integrity by producing IL-22. Human fetal intestine, tonsil and lympho nodes harbor both NKp44 positive and negative RORgammat(+) ILC subsets. Since human Crohn's disease patients have increased number of RORgammat(+) ILCs in the inflamed intestine, roles of RORgammat(+) ILCs on the pathogenesis of Crohn's disease became of great interest. PMID- 23445728 TI - [Roles of aberrant endothelial progenitor cells in pathogenesis of systemic sclerosis]. AB - Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by excessive fibrosis and microvasculopathy, along with poor vascular formation and repair. The maintenance of the postnatal vascular system requires constant remodeling through vasculogenesis, which is mediated by the de novo differentiation of mature endothelial cells from endothelial progenitor cells (EPCs). However, a great deal of controversy about EPCs and their roles in postnatal vascular formation has arisen because of discrepancies in how EPCs are defined. The current consensus is that EPCs are heterogeneous cell population containing an extremely small count of "true EPCs", and pro-angiogenic hematopoietic cells (PHCs) that promotes vascular formation and repair through secretion of pro-angiogenic factors, and differentiation into endothelial cells and mural cells. In 2004, we reported a reduced number and impaired function of circulating CD34(+)CD133(+)CD309(+)CD45(dim)CD14(-) EPCs, which are now regarded as an immature subset of PHCs, in patients with SSc, and proposed a theory that defective vascular repair machinery as one of important mechanisms contributing to SSc vasculopathy. In addition, we showed that in SSc patients, circulating monocytic PHCs were increased and have enhanced angiogenic potency and differentiation potential to fibroblast-like cells. In summary, EPCs are involved in the pathogenesis of SSc by participating in two major pathological features, microvasculopathy and excessive fibrosis. Understanding the roles of EPCs in disease process of SSc may be key to dissecting its pathogenesis and to developing novel therapeutic strategies for this intractable condition. PMID- 23445729 TI - [Biomarkers associated with unresponsiveness to IVIG in children with Kawasaki disease]. AB - We have adopted DNA-microarray technology to analyze gene expression profiles in patients with Kawasaki Disease (KD). The results demonstrated that neutrophils in acute KD patients were not only expanded in number but also activated through the expression of a variety of late-stage granulocyte-specific genes such as polycythemia rubra vera 1 (PRV-1) and haptoglobin compared with febrile controls. In accordance with these findings, serum granulocyte colony-stimulating factor (G CSF) levels were also higher in IVIG-resistant patients than those in responsive patients. These results might indicate evidences for dysregulated immunological pathways in KD patients and provide possible tools for diagnosis and prognostics of KD. We also found that high-dose IgG specifically and completely inhibited accelerated expression of KD-related cytokines such as G-CSF, IL-6 and IL-1beta by HCAEC in response to TNF-alpha. The suppression of these cytokine genes correlated closely with functional inhibition of a transcription factor, C/EBP delta. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD. PMID- 23445730 TI - [Dopamine receptor signaling regulates human osteoclastogenesis]. AB - Although the central nervous system and the neurotransmitters are known to control not only the immune system but also the homeostasis of bone mass, their pathological relevance to bone disorders remains unclear. Osteoclasts in the synovium of rheumatoid arthritis (RA) play an important role in bone destruction. It is known that increased sympathetic nervous activity increases both differentiation and function of osteoclasts, which leads to bone loss. Dopamine, a major neurotransmitter, transmits signals via five different seven transmembrane G protein-coupled receptors termed D1 to D5. We previously reported that dopamine plays an important role in IL-6-IL-17 axis and subsequent joint destruction in RA. The major source of dopamine in the synovial tissue of RA was dendritic cells (DCs) that stored and secreted dopamine. Dopamine released by DCs bounded to D1-like dopamine receptors on T cells and induced activation of cAMP and differentiation to Th17 cells via IL-6 production We here overview the interplay among the immune system, bone metabolism and neurologic system shedding light upon dopaminergic signals upon osteoclastogenesis. PMID- 23445731 TI - [Toward therapeutic application of IL-10-producing regulatory T cells]. AB - IL-10 is an anti-inflammatory cytokine with an important role in preventing inflammatory and autoimmune responses. IL-10 is also important for suppressive function of inducible regulatory T (iTreg) cells, several types of which were reported in succession. Type1 regulatory T (Tr1) cell is a representative of IL 10-prroducing regulatory T cells. Although specific surface markers or origin of Tr1 cells have not fully been clarified yet, IL-27 was recently reported to induce IL-10 production in T cells and be an inducer of Tr1 cells. We previously reported that CD4(+)CD25(-)lymphocyte activation gene (LAG-3)(+) Treg (LAG3(+) Treg) is one of the peripherally inducible Tregs and functions as an immune regulator through IL-10 production. We found that the expression level of Egr-2, a transcription factor required for T cell anergy induction, is elevated in LAG3(+) Treg and that forced expression of Egr-2 induces LAG-3 expression and IL 10 production. Egr-2 has been suggested to be a key player of regulatory function in LAG3(+) Treg. In this study, we review Tr1 cells and the mechanism of IL-10 induction by IL-27 in T cells. Also, we introduce LAG3(+) Treg and discuss the therapeutic potential of these regulatory T cells. PMID- 23445732 TI - [Case of successful pregnancy and childbirth in a rheumatoid arthritis patient treated with etanercept]. AB - The patient was a 34-year-old woman who, at age 23, was diagnosed with rheumatoid arthritis (RA) presenting with morning stiffness, swelling and tenderness of bilateral knee joints and metacarpophalangeal (MP) joints of the right second and third fingers, increased C-reactive protein (CRP) levels, and a high level of rheumatoid factor (RF). The patient was maintaining remission with oral dose of bucillamine (BUC; 300 mg/day); however, due to the deterioration of arthralgia at age 26, she was additionally administered 8 mg/week of methotrexate (MTX), which improved the symptoms. Thereafter, the prescription of BUC was discontinued. At age 31, she experienced onsets of swelling and tenderness in both the knee joints and wrists and in MP joints of the right second and third fingers; further, CRP levels increased to 5.44 mg/dL, resulting in increased RA activity. The concomitant administration of infliximab was started at a dose of 3 mg/kg, which helped achieve favorable RA control. At age 32, approximately 2 years before childbirth, the prescription of infliximab was changed to 25 mg/dose of etanercept administered twice a week because the patient wished to conceive. Remission was maintained even after the drug change; therefore, MTX was discontinued and the patient was treated with etanercept alone. After she was confirmed to be pregnant in March of the following year, administration of etanercept was continued for treating of RA even during pregnancy. During that time, RA was favorably controlled, and the patient gave birth to a baby boy weighing 3192 g in October of the same year. The Apgar score of the baby was favorable. This case is considered important because, to the best of our knowledge, this may be the first report of a planned pregnancy and childbirth in a patient under administration of a biological preparation. PMID- 23445733 TI - [Chronic recurrent multifocal osteomyelitis with interstitial myositis]. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non infectious disorder of skeletal system mainly seen in children. We report a case of CRMO presenting with fever and leg pain. The patient was an 11-year-old boy complaining of a fever, swelling and pain on his right foot, and pain on both legs. Although serum levels of CK and aldolase were not increased, MRI imaging suggested polymyositis. Muscle biopsy showed interstitial infiltration of inflammatory cells without any evidences of dermatomyositis or polymyositis. One month later, he complained of a swelling, pain and redness of his left clavicle as recurrently experienced during the recent 6 months, and MRI investigation indicated the diagnosis of osteomyelitis. Bone biopsy was performed and showed chronic inflammatory changes with negative bacterial culture. Multiple bone lesions and muscle uptake of FDG in his legs were revealed by whole body FDG PET/CT, and he was diagnosed as having CRMO with interstitial myositis. The combinatorial administration of non-steroidal anti-inflammatory drugs and bisphosphonate successfully improved his clinical symptoms and laboratory abnormalities. To our knowledge, there is no report of a patient of CRMO associated with interstitial myositis. PMID- 23445734 TI - Case of granulomatosis with polyangiitis (Wegener's granulomatosis) manifested with asymptomatic intracerebral hemorrhage. AB - A 46-year-old man, who had had sinusitis, developed bilateral omalgia, petechiae on his lower extremities and a congested right eye. A blood test detected elevated serum C-reactive protein level. Computed tomography incidentally found an acute lesion of thalamic hemorrhage without neurological symptoms and no specific therapy was given at the time. Thereafter, he developed vertigo, vomiting and pneumonia for which antibiotics were ineffective. He was referred and admitted to our hospital. Further, aural and renal lesions, and presence of serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) confirmed his diagnosis of granulomatosis with polyangiitis (Wegener's) (GPA). With corticosteroid and cyclophosphamide therapy, his symptoms disappeared in two months along with faded PR3-ANCA. Afterward he showed neither new cerebral lesion nor symptom. This is a rare case of GPA manifested with asymptomatic intracerebral hemorrhage. It should be noted that GPA could cause various manifestations in central nervous system such as a fatal or an asymptomatic hemorrhagic lesion, which might respond to immunosuppressive therapy. PMID- 23445735 TI - Community-acquired pneumonia among children in Taiwan. PMID- 23445736 TI - Medication errors in pediatrics. PMID- 23445737 TI - Influence and mechanisms of maternal and infant diets on the development of childhood asthma. AB - Perinatal nutrition has been implicated in the programming of diseases in children and adults. The prevalence of asthma has dramatically increased in the past few decades, particularly in children. This suggests that the perinatal environment, including maternal and infant diets, may be involved in the increase in the prevalence of asthma. Recent studies have demonstrated that certain maternal and infant diets have a protective or augmentative effect on the development of asthma. Maternal diets with higher vitamin D, vitamin E, or/and probiotics are related to asthma prevention. Infants with breast feeding for at least 4 months and/or complementary diets between 4 and 6 months may have regulatory effects on the prevention of asthma. In summary, diets may have epigenetic or immune regulatory effects on the promotion or prevention of asthma. This article analyzes recent reports on the potential mechanism and mechanism driven early prevention of childhood asthma by modification of maternal and infant diets. PMID- 23445738 TI - Long-term management of Kawasaki disease: implications for the adult patient. AB - Coronary artery complications from Kawasaki disease (KD) range from no involvement to giant coronary artery aneurysms (CAA). Current long-term management protocols are calibrated to the degree of maximal and current coronary artery involvement reflecting the known likelihood of severe long-term cardiac complications. It has recently been suggested that all KD patients may be at potential risk of severe long-term cardiac complications. If this assertion was to be confirmed, current follow-up protocols would need to be extensively modified, with important implications both for the growing adult population with a previous history of KD and for the healthcare system. Based on the available evidence, patients with multiple large and/or giant CAA are at substantial risk of severe long-term cardiac complications and should have regular specialized follow-up. Patients with transient or no CAA have not been reported to be at risk of severe long-term cardiac complications. The influence of KD on the atherosclerotic process remains suboptimally defined, and should be the focus of future studies. Heightened cardiovascular risk factor surveillance and management is recommended regardless of coronary artery involvement. Based on the currently available evidence, existing long-term management protocols seem to be appropriately calibrated to the level of risk. Revised long-term management protocols should incorporate newer, noninvasive imaging methods and intensive management of atherosclerotic risk. There is insufficient evidence at this time to mandate long-term specialized follow-up and invasive testing for patients who have not had CAA. PMID- 23445739 TI - Fatal community-acquired pneumonia: 18 years in a medical center. AB - BACKGROUND: Community-acquired pneumonia (CAP) remains a significant cause of childhood morbidity worldwide. We analyzed the etiologies and the clinical characteristics of children who died from CAP. This study aimed at early identification of the poor prognostic factors in order to improve the efficiency of pneumonia management and prevent deaths. METHODS: A retrospective chart review was performed for children younger than 18 years admitted to Shin Kong Wu Ho-Su Memorial Hospital between September 1992 and August 2010 with a diagnosis of pneumonia on admission. Twenty-one patients who died with the diagnosis of pneumonia and its complications were included in the study, along with 63 age- and year-matched survival controls. RESULTS: Twelve patients (57.1%) were younger than 2 years. Gram-negative bacteria (7 patients) were the most frequently identified pathogen, followed by Mycoplasma pneumoniae (6 patients). Four of these six M. pneumoniae infected patients were co-infected with other pathogens. Among the clinical characteristics, fatal CAP was associated mainly with initial presentations of anemia, lymphopenia, thrombocytopenia, bandemia, hyponatremia, sepsis, meningitis, metabolic acidosis, disseminated intravenous coagulopathy, and underlying congenital diseases. In multivariate logistic regression analysis, metabolic acidosis (odds ratio = 8.50; 95% confidence interval = 2.82-25.60; p < 0.001) was a prognostic risk factor for fatality. CONCLUSION: For patients with CAP, blood gas should be included in the routine blood test on admission. Once the initial blood test associated with the aforementioned poor prognostic factors has been identified, an immediate treatment including Gram-negative bacilli antibiotics should be started aggressively in order to prevent deaths. PMID- 23445740 TI - Characteristics of the first human milk bank in Taiwan. AB - BACKGROUND: The benefits of feeding human milk to infants, even in prematurity, have been well documented. Well-organized donor milk processing has made the milk bank a good source of nutrition for premature or sick infants if their own mother's milk is not sufficient or suitable. The Taipei City Hospital Milk Bank was established in 2005 and is the first nonprofit human milk bank to operate in Taiwan. METHODS: The milk bank has adopted standards of practice laid down by the Human Milk Banking Association of North America and United Kingdom Association for Milk Banking. The clinical characteristics of the eligible milk donors, the recipients, and the donor milk were reviewed retrospectively. RESULTS: In the past 6 years, 816 eligible donors donated a total or 13,900 L (mean 17.03 L/donor) of breast milk. The mean age of these donors was 31.3 years, and 79.7% of them had college education. Most had term delivery (91.2%), with mean birth weight of their babies being 3120 g; 68.9% of the donors were primiparas. A total of 551 infants had received bank milk, with these indications: prematurity (65.4%), malabsorption (7.6%), feeding intolerance (7.2%), maternal illness (5.1%) and post-surgery (4.6%). The pass rate of raw donor milk was around 72.1%. The most common reasons to discard raw milk were Gram-negative rods contamination (72.8%) and >=10 colony-forming units/mL of coagulase-negative Staphylococcus (62.3%). Only 0.63% of donor milk post pasteurization showed bacterial growth. CONCLUSION: Proper management and operation of a human milk bank can support breastfeeding, and provide a safe alternative to artificial formula for feeding preterm or ill infants in Taiwan. Sustainability of the milk bank needs more propagation and financial support by health authorities. PMID- 23445741 TI - Effectiveness of education programs about oral antibiotic suspensions in pediatric outpatient services. AB - BACKGROUND: The effectiveness of education programs for pediatric patients receiving oral antibiotic suspension was unclear. METHODS: When pediatric patients were prescribed antibiotics in powder form for suspension at the outpatient clinic of a university hospital, the responsible 150 caregivers were consecutively allocated into three education programs: Group 1 subjects read the package insert; Group 2 read a photograph-designed educational sheet; and Group 3 received a face-to-face medication education from a pharmacist with the photograph-designed educational sheet. The effectiveness of the three education programs for pediatric patients' caregivers was evaluated using a questionnaire comprised of 12 questions. RESULTS: The proportions of the caregivers in Groups 1, 2 and 3 who answered the questionnaire perfectly with 100% accuracy were 2%, 14% and 74%, respectively (p < 0.001). The means +/- standard deviations of the overall time spent by the caregivers in Groups 1, 2 and 3 were 353 +/- 135, 334.2 +/- 115.1, and 281.4 +/- 114 seconds, respectively (p = 0.013). Clearly, the pharmacist's face-to-face mediation education program provided effective and time saving medication instructions for pediatric oral antibiotics. The specific questions regarding easy-to-make errors related to the reconstitution step (p < 0.001), water volume for reconstitution (p < 0.001), storage temperature (p = 0.004) and shelf life (p = 0.002) of stock powder, whether the drug should be taken before or after a meal (p < 0.001), and the method and volume for syrup measurement (p < 0.001). CONCLUSION: This study demonstrated that when compared to reading a package insert or education sheet, a pharmacist's verbal education with photographic education materials was significantly more effective and time saving in providing caregivers with the correct knowledge of oral antibiotic suspensions in pediatrics. PMID- 23445742 TI - Reaction at the bacillus Calmette--Guerin inoculation site in patients with Kawasaki disease. AB - BACKGROUND: The bacillus Calmette-Guerin (BCG) reaction is not included in the classical clinical criteria for Kawasaki disease (KD). However, a reaction at the BCG inoculation site has been mentioned among the "other clinical findings" that are present in about 30-50% of KD patients. The objective of this study was to investigate the clinical characteristics of KD patients with reactions at the BCG inoculation site. METHODS: A retrospective study of all patients diagnosed with KD between September 2000 and August 2010 was performed. The clinical presentations, laboratory results, treatment outcomes, and coronary artery abnormalities in the BCG-reactive [BCG(+)] and BCG-nonreactive [BCG(-)] groups were analyzed and compared. RESULTS: In total, 145 patients with KD diagnosed at our institution were included; 46 (31.7%) had a reaction at the BCG inoculation site. The BCG(+) group was younger than the BCG(-) group. Laboratory results showed higher white blood cell counts, platelet counts, and serum potassium levels, and lower low-density lipoprotein levels in the BCG(+) group. The BCG(+) group had a shorter fever duration before intravenous immunoglobulin treatment and a shorter total fever duration than the BCG(-) group. Multivariable logistic regression analysis showed that the age at diagnosis was the only factor significantly associated with a reaction at the BCG inoculation site in KD patients. CONCLUSIONS: In countries with a national BCG vaccination program, a reaction at the BCG inoculation site could be a useful and early diagnostic sign of KD among younger patients, especially those younger than 6 months. PMID- 23445743 TI - Allergic colitis in infants related to cow's milk: clinical characteristics, pathologic changes, and immunologic findings. AB - BACKGROUND: Allergic colitis (AC) is an inflammatory condition characterized by eosinophils infiltrating the colonic wall. It can be a benign and/or severe illness among gastrointestinal diseases in infants. METHODS: We report five infants who, since January 2009, in whom AC under fibrotic endoscopic examinations has been diagnosed. The criterion for histopathologic diagnosis of AC in this study was five or more eosinophils per high-power field. Patients' clinical symptoms, pathologic findings, and immunologic studies, such as specific antibodies against component of cow's milk protein, were compared with those of allergic children without AC and those of nonatopic control children. RESULTS: Histopathologic examinations of biopsy specimens revealed acute inflammation with characteristic eosinophilic infiltration of lamina propria (5-15 eosinophils per high-power field) in all five patients. They all had strongly positive skin prick tests against milk protein, which were not correlated with in vitro allergen specific immunoglobulin (Ig) E levels. In contrast, there were significantly higher levels of IgE antibodies, and lower specific IgG4 and IgA levels to components and whole milk proteins in AC, as compared to control children without AC. CONCLUSION: Endoscopic biopsy specimens of intestine confirm the diagnosis of AC. However, allergen skin prick test and IgE antibody to milk protein components also provide helpful diagnostic tools for this rare disease in children. PMID- 23445744 TI - Eosinophilic meningitis caused by Angiostrongylus cantonensis in an adolescent with mental retardation and pica disorder. AB - Eosinophilic meningitis or encephalitis is a rare disorder and is most commonly caused by Angiostrongylus cantonensis. Humans are accidentally infected when they ingest raw snails or vegetables contaminated with the parasite larvae. Because of the improvement in sanitary food handling practices, the occurrence of A. cantonensis eosinophilic meningitis has been decreasing in Taiwan in recent decades. The common symptoms and signs of eosinophilic meningitis are severe headache, neck stiffness, paresthesia, vomiting, nausea, and fever. Acute urinary retention is a rare presentation. We report a case of A. cantonensis eosinophilic meningitis in an intellectually disabled patient who presented with acute urinary retention without any other meningeal signs. The patient received supportive treatment with corticosteroid therapy and was discharged and received urinary rehabilitation at home. PMID- 23445745 TI - Successful treatment of arterial thrombus in an extremely low-birth-weight preterm neonate. AB - Arterial thromboembolism in the pediatric population frequently occurs secondary to arterial catheterization. Catheterization-related complications are more common in smaller and sicker infants, due to high prothrombotic activity, low levels of natural anticoagulants, and various fibrinolytic imbalances. Arterial thrombus management in neonates remains controversial. Recombinant tissue plasminogen activator is the most commonly used thrombolytic agent in children, however there is very little experience with recombinant tissue plasminogen activator therapy in small prematures, especially in the first week of life. This case study reports catheter-related femoral artery occlusion in an extremely low birth-weight preterm infant. Despite continuous heparin infusion for 6 hours, no resolution of the thrombus was seen by clinicians. Heparin was stopped, and recombinant tissue plasminogen activator therapy enabled complete recovery from the thrombus. The risk of bleeding (including intracranial hemorrhage) with recombinant tissue plasminogen activator treatment, especially in small preterm neonates is unknown. However, in this extremely low-birth-weight preterm infant, recombinant tissue plasminogen activator therapy was effective, and limiting the infusion rate to <=0.4 mg/kg/hour was safe. PMID- 23445746 TI - Late-onset invasive group B Streptococcal infection with serotype VIII in a neonate having congenital biliary atresia. AB - A female newborn was admitted to our department 15 days after birth for insufficient sucking and jaundice. The patient's blood and urine cultures were both positive for group B streptococcal (GBS) infection. A maternal vaginal sample at 35 weeks' gestation was negative for GBS in culture-based microbiologic screening. The patient recovered shortly after receiving systemic antibiotic therapy. On the basis of clinical evidence of white stool and progressive jaundice, we suspected that the newborn had complications related to congenital biliary atresia (CBA); surgery was performed. Isolates from the mother's vaginal sample obtained when the patient was 25 days old, along with neonatal blood, revealed identical patterns (serotype VIII and sequence type 1) of GBS capsular and multilocus sequence typing, suggestive of maternal transmission. Molecular epidemiologic examination may be useful to clarify the transmission route and etiology; culture-based microbiologic screening appears to have limitations for detecting the route of transmission. PMID- 23445747 TI - The All Our Babies pregnancy cohort: design, methods, and participant characteristics. AB - BACKGROUND: The prospective cohort study design is ideal for examining diseases of public health importance, as its inherent temporal nature renders it advantageous for studying early life influences on health outcomes and research questions of aetiological significance. This paper will describe the development and characteristics of the All Our Babies (AOB) study, a prospective pregnancy cohort in Calgary, Alberta, Canada designed to examine determinants of maternal, infant, and child outcomes and identify barriers and facilitators in health care utilization. METHODS: Women were recruited from health care offices, communities, and through Calgary Laboratory Services before 25 weeks gestation from May 2008 to December 2010. Participants completed two questionnaires during pregnancy, a third at 4 months postpartum, and are currently being followed-up with questionnaires at 12, 24, and 36 months. Data was collected on pregnancy history, demographics, lifestyle, health care utilization, physical and mental health, parenting, and child developmental outcomes and milestones. In addition, biological/serological and genetic markers can be extracted from collected maternal and cord blood samples. RESULTS: A total of 4011 pregnant women were eligible for recruitment into the AOB study. Of this, 3388 women completed at least one survey. The majority of participants were less than 35 years of age, Caucasian, Canadian born, married or in a common-law relationship, well-educated, and reported household incomes above the Calgary median. Women who discontinued after the first survey (n=123) were typically younger, non-Caucasian, foreign born, had lower education and household income levels, were less likely to be married or in a common-law relationship, and had poor psychosocial health in early pregnancy. In general, AOB participants reflect the pregnant and parenting population at local and provincial levels, and perinatal indicators from the study are comparable to perinatal surveillance data. CONCLUSIONS: The extensive and rich data collected in the AOB cohort provides the opportunity to answer complex questions about the relationships between biology, early experiences, and developmental outcomes. This cohort will contribute to the understanding of the biologic mechanisms and social/environmental pathways underlying associations between early and later life outcomes, gene-environment interactions, and developmental trajectories among children. PMID- 23445748 TI - Haplotype-assisted accurate non-invasive fetal whole genome recovery through maternal plasma sequencing. AB - BACKGROUND: The applications of massively parallel sequencing technology to fetal cell-free DNA (cff-DNA) have brought new insight to non-invasive prenatal diagnosis. However, most previous research based on maternal plasma sequencing has been restricted to fetal aneuploidies. To detect specific parentally inherited mutations, invasive approaches to obtain fetal DNA are the current standard in the clinic because of the experimental complexity and resource consumption of previously reported non-invasive approaches. METHODS: Here, we present a simple and effective non-invasive method for accurate fetal genome recovery-assisted with parental haplotypes. The parental haplotype were firstly inferred using a combination strategy of trio and unrelated individuals. Assisted with the parental haplotype, we then employed a hidden Markov model to non invasively recover the fetal genome through maternal plasma sequencing. RESULTS: Using a sequence depth of approximately 44X against a an approximate 5.69% cff DNA concentration, we non-invasively inferred fetal genotype and haplotype under different situations of parental heterozygosity. Our data show that 98.57%, 95.37%, and 98.45% of paternal autosome alleles, maternal autosome alleles, and maternal chromosome X in the fetal haplotypes, respectively, were recovered accurately. Additionally, we obtained efficient coverage or strong linkage of 96.65% of reported Mendelian-disorder genes and 98.90% of complex disease associated markers. CONCLUSIONS: Our method provides a useful strategy for non invasive whole fetal genome recovery. PMID- 23445750 TI - Salinity tolerance, Na+ exclusion and allele mining of HKT1;5 in Oryza sativa and O. glaberrima: many sources, many genes, one mechanism? AB - BACKGROUND: Cultivated rice species (Oryza sativa L. and O. glaberrima Steud.) are generally considered among the crop species most sensitive to salt stress. A handful of lines are known to be tolerant, and a small number of these have been used extensively as donors in breeding programs. However, these donors use many of the same genes and physiological mechanisms to confer tolerance. Little information is available on the diversity of mechanisms used by these species to cope with salt stress, and there is a strong need to identify varieties displaying additional physiological and/or genetic mechanisms to confer higher tolerance. RESULTS: Here we present data on 103 accessions from O. sativa and 12 accessions from O. glaberrima, many of which are identified as salt tolerant for the first time, showing moderate to high tolerance of high salinity. The correlation of salinity-induced senescence (as judged by the Standard Evaluation System for Rice, or SES, score) with whole-plant and leaf blade Na+ concentrations was high across nearly all accessions, and was almost identical in both O. sativa and O. glaberrima. The association of leaf Na+ concentrations with cultivar-groups was very weak, but association with the OsHKT1;5 allele was generally strong. Seven major and three minor alleles of OsHKT1;5 were identified, and their comparisons with the leaf Na+ concentration showed that the Aromatic allele conferred the highest exclusion and the Japonica allele the least. A number of exceptions to this association with the Oryza HKT1;5 allele were identified; these probably indicate the existence of additional highly effective exclusion mechanisms. In addition, two landraces were identified, one from Thailand and the other from Senegal, that show high tissue tolerance. CONCLUSIONS: Significant variation in salinity tolerance exists within both cultivated Oryza species, and this is the first report of significant tolerance in O. glaberrima. The majority of accessions display a strong quantitative relationship between tolerance and leaf blade Na+ concentration, and thus the major tolerance mechanisms found in these species are those contributing to limiting sodium uptake and accumulation in active leaves. However, there appears to be genetic variation for several mechanisms that affect leaf Na+ concentration, and rare cases of accessions displaying different mechanisms also occur. These mechanisms show great promise for improving salt tolerance in rice over that available from current donors. PMID- 23445749 TI - Immunohistochemical expression of CD44s in human neuroblastic tumors: Moroccan experience and highlights on current data. AB - BACKGROUND: Peripheral neuroblastic tumors (pNTs), including neuroblastoma (NB), ganglioneuroblastoma (GNB) and ganglioneuroma (GN), are extremely heterogeneous pediatric tumors responsible for 15 % of childhood cancer death. The aim of the study was to evaluate the expression of CD44s ('s': standard form) cell adhesion molecule by comparison with other specific prognostic markers. METHODS: An immunohistochemical profile of 32 formalin-fixed paraffin-embedded pNTs tissues, diagnosed between January 2007 and December 2010, was carried out. RESULTS: Our results have demonstrated the association of CD44s negative pNTs cells to lack of differentiation and tumour progression. A significant association between absence of CD44s expression and metastasis in human pNTs has been reported. We also found that expression of CD44s defines subgroups of patients without MYCN amplification as evidenced by its association with low INSS stages, absence of metastasis and favorable Shimada histology. DISCUSSION: These findings support the thesis of the role of CD44s glycoprotein in the invasive growth potential of neoplastic cells and suggest that its expression could be taken into consideration in the therapeutic approaches targeting metastases. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1034403150888863 PMID- 23445751 TI - Inhaled corticosteroids and the increased risk of pneumonia. AB - Recently it has been suggested that there is a causal association between the use of inhaled corticosteroids (ICSs) and the risk of developing pneumonia in patients with chronic obstructive pulmonary disease (COPD). An increased risk of pneumonia associated with ICS use has been seen in trials with different design, different study populations and with evidence of a dose-response relationship. However, as none of these clinical trials were originally designed to assess pneumonia risk, radiographic confirmation of pneumonia was not always obtained. The extent to which pneumonia events have been confounded with acute exacerbations of COPD is unclear. As increased pneumonia events were not associated with increased mortality it remains unclear what the clinical significance of these findings are. Further complicating the association between ICSs and pneumonia is that meta-analyses restricted to budesonide trials have not shown an increased risk of pneumonia, and no association has been seen in patients with asthma. A number of mechanisms by which ICSs could increase the risk of pneumonia have been proposed, principally related to their immunosuppressive effect. Well-designed clinical trials with predefined endpoints and objective pneumonia definitions are needed before the real risk of pneumonia conferred by ICSs can be established. In the meantime, it seems reasonable to reduce ICSs given to COPD patients to the lowest effective doses, reduce the risk in individual patients by ensuring appropriate vaccination and to be vigilant for the possibility of pneumonia in patients with COPD on ICSs as they largely overlap with those of an acute exacerbation. PMID- 23445753 TI - Oxygen toxicity is reduced by acetylcholinesterase inhibition in the developing rat brain. AB - The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation employing acetylcholine as the key endogenous mediator. In this study, we investigated the effects of the cholinergic agonists, physostigmine and donepezil, on neurodegeneration, inflammation and oxidative stress during oxygen toxicity in the developing rat brain. The aim of this study was to investigate the level of neurodegeneration, expression of proinflammatory cytokines, glutathione and lipid peroxidation after hyperoxia and treatment with the acetylcholinesterase (AChE) inhibitors, physostigmine and donepezil in the brain of neonatal rats. Six-day old Wistar rats were exposed to 80% oxygen for 12-24 h and received 100 MUg/kg physostigmine or 200 MUg/kg donepezil intraperitoneally. Sex-matched littermates kept in room air and injected with normal saline, physostigmine or donepezil served as controls. Treatment with both inhibitors significantly reduced hyperoxia-triggered activity of AChE, neural cell death and the upregulation of the proinflammatory cytokines IL-1beta and TNF-alpha in the immature rat brain on the mRNA and protein level. In parallel, hyperoxia-induced oxidative stress was reduced by concomitant physostigmine and donepezil administration, as shown by an increased reduced/oxidized glutathione ratio and attenuated malondialdehyde levels, as a sign of lipid peroxidation. Our results suggest that a single treatment with AChE inhibitors at the beginning of hyperoxia attenuated the detrimental effects of oxygen toxicity in the developing brain and may pave the way for AChE inhibitors, which are currently used for the treatment of Alzheimer's disease, as potential candidates for adjunctive neuroprotective therapies to the immature brain. PMID- 23445754 TI - Genetic characteristics of Shiga toxin-producing E. coli O157, O26, O103, O111 and O145 isolates from humans, food, and cattle in Belgium. AB - In this study, we characterized 272 Shiga toxin-producing Escherichia coli (STEC) isolates from humans, food, and cattle in Belgium [O157 (n = 205), O26 (n = 31), O103 (n = 15), O111 (n = 10), O145 (n = 11)] for their virulence profile, whole genome variations and relationships on different genetic levels. Isolates of O157 displayed a wide variation of stx genotypes, heterogeneously distributed among pulsogroups (80% similarity), but with a concordance at the pulsosubgroup level (90% similarity). Of all serogroups evaluated, the presence of eae was conserved, whereas genes encoded on the large plasmid (ehx, espP, katP) occurred in variable combinations in O26, O103, and O145. The odds of having haemolytic uraemic syndrome was less for all genotypes stx2a, stx2c, stx1/stx2c, and stx1 compared to genotype stx2a/stx2c; and for patients aged >5 years compared to patients aged <= 5 years. Based on the genetic typing and by using epidemiological data, we could confirm outbreak isolates and suggest epidemiological relationships between some sporadic cases. Undistinguishable pulsotypes or clones with minor genotypic variations were found in humans, food, and cattle in different years, which demonstrated the important role of cattle as a reservoir of STEC O157, and the circulation and persistence of pathogenic clones. PMID- 23445752 TI - Energy deprivation by silibinin in colorectal cancer cells: a double-edged sword targeting both apoptotic and autophagic machineries. AB - Small molecules with the potential to initiate different types of programmed cell death could be useful 'adjunct therapy' where current anticancer modalities fail to generate significant activity due to a defective apoptotic machinery or resistance of cancer cells to the specific death mechanism induced by that treatment. The current study identified silibinin, for the first time, as one such natural agent, having dual efficacy against colorectal cancer (CRC) cells. First, silibinin rapidly induced oxidative stress in CRC SW480 cells due to reactive oxygen species (ROS) generation with a concomitant dissipation of mitchondrial potential (DeltaPsim) and cytochrome c release leading to mild apoptosis as a biological effect. However, with increased exposure to silibinin, cytoplasmic vacuolization intensified within the cells followed by sequestration of the organelles, which inhibits the further release of cytochrome c. Interestingly, this decrease in apoptotic response correlated with increased autophagic events as evidenced by tracking the dynamics of LC3-II within the cells. Mechanistic studies revealed that silibinin strongly inhibited PIK3CA-AKT MTOR but activated MAP2K1/2-MAPK1/3 pathways for its biological effects. Corroborating these effects, endoplasmic reticulum stress was generated and glucose uptake inhibition as well as energy restriction were induced by silibinin, thus, mimicking starvation-like conditions. Further, the cellular damage to tumor cells by silibinin was severe and irreparable due to sustained interference in essential cellular processes such as mitochondrial metabolism, phospholipid and protein synthesis, suggesting that silibinin harbors a deadly 'double-edged sword' against CRC cells thereby further advocating its clinical effectiveness against this malignancy. PMID- 23445755 TI - Predictors of shunt-dependent chronic hydrocephalus after aneurysmal subarachnoid haemorrhage. AB - INTRODUCTION: Chronic hydrocephalus is a common complication that can occur after aneurysmal subarachnoid haemorrhage (SAH). The purpose of this study was to investigate clinical risk factors that could predict the occurrence of shunt dependent chronic hydrocephalus after aneurysmal SAH. METHODS: Eighty-eight consecutive patients who underwent either surgery or transarterial endovascular embolization as a treatment for cerebral aneurysm within 72 h -after experiencing SAH from March 2005 to July 2006 were studied retrospectively to assess the risk factors that might predict shunt-dependent chronic hydrocephalus. Clinical and demographic factors were examined, including age, sex, initial admission mean arterial blood pressure (MABP), blood sugar level at admission, fever frequency, initial external ventricular drainage (EVD), Fisher grade, Hunt and Hess grade, intraventricular haemorrhage (IVH) and treatment methods to define predictors of shunt-dependent hydrocephalus. The length of hospital stay and modified Rankin scale recorded 6 months after SAH were also evaluated; these parameters were compared between the shunt-dependent and non-shunt-dependent groups. RESULTS: Of the 88 patients, 22 (25%) underwent shunt placement to treat their chronic hydrocephalus. The average length of hospital stay was 33.9 days for the shunt treated group and 14 days for the non-shunt-treated group. The non-shunt-treated group scored an average of 1.05 on the modified Rankin scale compared with 2.77 for the shunt-treated group. A univariate analysis revealed that several admission variables were associated with long-term shunt-dependent hydrocephalus: (1) increased age (p = 0.023); (2) initial admission MABP (p = 0.027); (3) a high Fisher grade (p = 0.031); (4) a poor admission Hunt and Hess grade (p = 0.030); (5) the presence of IVH (p = 0.029), and (6) initial EVD (p < 0.0001). The factor most commonly associated with shunt-dependent hydrocephalus over the course of hospital days was fever frequency (p < 0.0001). CONCLUSIONS: Chronic hydrocephalus after aneurysmal SAH has a multifactorial aetiology. Understanding the risk factors that predict the occurrence of chronic hydrocephalus may help neurosurgeons to expedite permanent cerebrospinal fluid diversion, which could decrease both the cost and length of hospital stay and prevent further complications. PMID- 23445756 TI - Ethnobotanical appraisal and medicinal use of plants in Patriata, New Murree, evidence from Pakistan. AB - BACKGROUND: This paper reflects the empirical findings of an ethnobotanical survey which was undertaken in Patriata (New Murree) of district Rawalpindi in Pakistan. The aims and objectives of the study were to document indigenous knowledge of plants particularly of medicinal, veterinary, fruit, vegetable, fodder, fuel etc. METHODS: For this purpose, the whole area was surveyed for documenting folk knowledge using a semi-structured questionnaire. A total of 93 plants species belonging to 80 genera and 56 families were found in a variety of uses by the local people for the accomplishment of their basic needs. The study further employs binary logit regression model of medicinal uses of these plants so as to identify the probability of occurrence of medicinal use of woody or non woody plants keeping other plant characteristics in view. RESULTS: Ethnobotanical data shows that most plants are used for medicinal and fodder purposes (27.93% each), followed by fuel (16.90%), fruit (6.55%), vegetable (5.52%) and ethno veterinary (3.79%). There is also an established association of medicinal use of plants to the fruits use. Non-woody plants have high tendency towards medicinal use of the plants as compared to woody plants. Annual plants are less likely to be directly associated with medicinal use of plants in the surveyed vegetation. Underground plant parts are more likely to be used for medicinal purposes as revealed from the Logit expressions. CONCLUSIONS: The study revealed that most of the plants are used for medicinal and fodder purposes. The results of Logit Model showed that the probabilities of plant species for their medicinal use are associated to the woody or non-woody, aerial or underground, perennial or annual characteristics of plants. One should be careful in completely generalizing the results as the survey findings are sensitive to the plant species and the vegetation under consideration. But it can be specified that there exists either some positive or negative association of medicinal use of plants to the various characteristics of plant species. PMID- 23445757 TI - [Developmental history: bendamustine yesterday, today, tomorrow]. PMID- 23445758 TI - [Current and future indications for bendamustine: chronic lymphocytic leukemia, indolent lymphoma, mantle cell lymphoma and diffuse large B-cell lymphomas]. PMID- 23445759 TI - [Therapeutic strategies in multiple myeloma: the future role of bendamustine]. PMID- 23445760 TI - [Health services research: tumor registry for lymphatic neoplasia]. PMID- 23445761 TI - Lack of clinically evident signs of organ failure affects ED treatment of patients with severe sepsis. AB - BACKGROUND: It is not known whether lack of recognition of organ failure explains the low compliance with the "Surviving Sepsis Campaign" (SSC) guidelines. We evaluated whether compliance was higher in emergency department (ED) sepsis patients with clinically recognizable signs of organ failure compared to patients with only laboratory signs of organ failure. METHODS: Three hundred twenty-three ED patients with severe sepsis and septic shock were prospectively included. Multivariable binary logistic regression was used to assess if clinical and biochemical signs of organ failure were associated with compliance to a SSC-based resuscitation bundle. In addition, two-way analysis of variance was used to investigate the relation between the predisposition, infection, response and organ failure (PIRO) score (3 groups: 1-7, 8-14, 15-24) as a measure of illness severity and time to antibiotics with disposition to ward or ICU as effect modifier. RESULTS: One hundred twenty-five of 323 included sepsis patients with new-onset organ failure were admitted to the ICU, and in all these patients the SSC resuscitation bundle was started. Respiratory difficulty, hypotension and altered mental status as clinically recognizable signs of organ failure were independent predictors of 100% compliance and not illness severity per se. Corrected ORs (95% CI) were 3.38 (1.08-10.64), 2.37 (1.07-5.23) and 4.18 (1.92 9.09), respectively. Septic ED patients with clinically evident organ failure were more often admitted to the ICU compared to a ward (125 ICU admissions, P < 0.05), which was associated with shorter time to antibiotics [ward: 127 (113-141) min; ICU 94 (80-108) min (P = 0.005)]. CONCLUSIONS: The presence of clinically evident compared to biochemical signs of organ failure was associated with increased compliance with a SSC-based resuscitation bundle and admission to the ICU, suggesting that recognition of severe sepsis is an important barrier for successful implementation of quality improvement programs for septic patients. In septic ED patients admitted to the ICU, the time to antibiotics was shorter compared to patients admitted to a normal ward. PMID- 23445762 TI - Quantifying nisin adsorption behavior at pendant PEO layers. AB - The antimicrobial peptide nisin shows potent activity against Gram-positive bacteria including the most prevalent implant-associated pathogens. Its mechanism of action minimizes the opportunity for the rise of resistant bacteria and it does not appear to be toxic to humans, suggesting good potential for its use in antibacterial coatings for selected medical devices. A more quantitative understanding of nisin loading and release from polyethylene oxide (PEO) brush layers will inform new strategies for drug storage and delivery, and in this work optical waveguide lightmode spectroscopy was used to record changes in adsorbed mass during cyclic adsorption-elution experiments with nisin, at uncoated and PEO coated surfaces. PEO layers were prepared by radiolytic grafting of Pluronic(r) surfactant F108 or F68 to silanized silica surfaces, producing long- or short chain PEO layers, respectively. Kinetic patterns were interpreted with reference to a model accounting for history-dependent adsorption, in order to evaluate rate constants for nisin adsorption and desorption, as well as the effect of pendant PEO on the lateral clustering behavior of nisin. Nisin adsorption was observed at the uncoated and F108-coated surfaces, but not at the F68-coated surfaces. Nisin showed greater resistance to elution by peptide-free buffer at the uncoated surface, and lateral rearrangement and clustering of adsorbed nisin was apparent only at the uncoated surface. We conclude peptide entrapment at the F108-coated surface is governed by a hydrophobic inner region of the PEO brush layer that is not sufficient for nisin entrapment in the case of the shorter PEO chains of the F68-coated surface. PMID- 23445764 TI - Fabrication and characterization of La2Zr2O7 films on different buffer architectures for YBa2Cu3O7-delta coated conductors by RF magnetron sputtering. AB - La2Zr2O7 (LZO) films were grown on different buffer architectures by radio frequency magnetron sputtering for the large-scale application of YBa2Cu3O7-x (YBCO)-coated conductors. The three different buffer architectures were cerium oxide (CeO2), yttria-stabilized zirconia (YSZ)/CeO2, and CeO2/YSZ/CeO2. The microstructure and surface morphology of the LZO film were studied by X-ray diffraction, optical microscopy, field emission scanning electron microscopy, and atomic force microscopy. The LZO films prepared on the CeO2, YSZ/CeO2, and CeO2/YSZ/CeO2 buffer architectures were preferentially c-axis-oriented and highly textured. The in-plane texture of LZO film on CeO2 single-buffer architecture was ? phi = 5.5 degrees and the out-of-plane texture was ? omega = 3.4 degrees . All the LZO films had very smooth surfaces, but LZO films grown on YSZ/CeO2 and CeO2/YSZ/CeO2 buffer architectures had cracks. The highly textured LZO film grown on CeO2-seed buffered NiW tape was suitable for the epitaxial growth of YBCO film with high currents. PMID- 23445763 TI - Propolis changes the anticancer activity of temozolomide in U87MG human glioblastoma cell line. AB - BACKGROUND: Propolis is a honey bee product which contains many active compounds, such as CAPE or chrysin, and has many beneficial activities. Recently, its anti tumor properties have been discussed. We have tested whether the ethanolic extract of propolis (EEP) interferes with temozolomide (TMZ) to inhibit U87MG cell line growth. METHODS: The U87MG glioblastoma cell line was exposed to TMZ (10-100 MUM), EEP (10-100 MUg/ml) or a mixture of TMZ and EEP during 24, 48 or 72 hours. The cell division was examined by the H3-thymidine incorporation, while the western blot method was used for detection of p65 subunit of NF-kappaB and ELISA test to measure the concentration of its p50 subunit in the nucleus. RESULTS: We have found that both, TMZ and EEP administrated alone, had a dose- and time-dependent inhibitory effect on the U87MG cell line growth, which was manifested by gradual reduction of cell viability and alterations in proliferation rate. The anti-tumor effect of TMZ (20 MUM) was enhanced by EEP, which was especially well observed after a short time of exposition, where simultaneous usage of TMZ and EEP resulted in a higher degree of growth inhibition than each biological factor used separately. In addition, cells treated with TMZ presented no changes in NF-kappaB activity in prolonged time of treatment and EEP only slightly reduced the nuclear translocation of this transcription factor. In turn, the combined incubation with TMZ and EEP led to an approximately double reduction of NF-kappaB nuclear localization. CONCLUSIONS: We conclude that EEP presents cytotoxic properties and may cooperate with TMZ synergistically enhancing its growth inhibiting activity against glioblastoma U87MG cell line. This phenomenon may be at least partially mediated by a reduced activity of NF-kappaB. PMID- 23445765 TI - Novel cancer drivers: mining the kinome. AB - Large-scale cancer genome studies are unveiling significant complexity and heterogeneity even in histopathologically indistinguishable cancers. Differentiating 'driver' mutations that are functionally relevant from 'passenger' mutations is a major challenge in cancer genomics. While recurrent mutations in a gene provides supporting evidence of 'driver' status, novel computational methods and model systems are greatly improving our ability to identify genes important in carcinogenesis. Reimand and Bader have recently shown that driver gene discovery in discrete gene classes (in this case the kinome) is possible across multiple cancer types and has the potential to yield new druggable targets and clinically relevant leads. PMID- 23445766 TI - Methods of NO detection in exhaled breath. AB - There is still an unexplored potential for exhaled nitric oxide (NO) in many clinical applications. This study presents an overview of the currently available methods for monitoring NO in exhaled breath and the use of the modelling of NO production and transport in the lung in clinical practice. Three technologies are described, namely chemiluminescence, electrochemical sensing and laser-based detection with their advantages and limitations. Comparisons are made in terms of sensitivity, time response, size, costs and suitability for clinical purposes. The importance of the flow rate for NO sampling is discussed from the perspective of the recent recommendations for standardized procedures for online and offline NO measurement. The measurement of NO at one flow rate, such as 50 ml s(-1), can neither determine the alveolar site/peripheral contribution nor quantify the difference in NO diffusion from the airways walls. The use of NO modelling (linear or non-linear approach) can solve this problem and provide useful information about the source of NO. This is of great value in diagnostic procedures of respiratory diseases and in treatment with anti-inflammatory drugs. PMID- 23445767 TI - Low serum LDL cholesterol levels are associated with elevated mortality from liver cancer in Japan: the Ibaraki Prefectural health study. AB - Liver cancer a global public health concern and well known for poor prognosis. The association between low total cholesterol level and liver cancer has been reported. However, the association between low low-density lipoprotein (LDL) cholesterol levels and liver cancer is still unclear. The aim of this study was to examine the relationship between LDL cholesterol level and liver cancer mortality. A total of 16,217 persons (5,551 men and 10,666 women) aged 40-79 years in 1993 were followed until 2008. LDL cholesterol levels were divided into four categories (<80 mg/dl, 80-99 mg/dl, 100-119 mg/dl, and >=120 mg/dl). Hazard ratio of LDL cholesterol level for liver cancer mortality was calculated using a multivariable Cox proportional hazards model. Covariates were age, sex, alanine transaminase, body mass index, alcohol intake and smoking status, all of which were correlated with LDL cholesterol levels. There were 51 deaths (32 men and 19 women) from liver cancer. Multivariable hazard ratios of liver cancer deaths for LDL cholesterol levels of <80 mg/dl was 4.33 (95% confident interval [CI]: 1.94, 9.68), for LDL cholesterol levels of 80-99 mg/dl was 1.03 (95% CI: 0.42, 2.53), and for LDL cholesterol levels of >=120 mg/dl was 0.43 (95% CI: 0.20, 0.92) compared with LDL cholesterol levels of 100-199 mg/dl (p for trend<0.01). Therefore, low LDL cholesterol levels are associated with elevated risk of liver cancer mortality. Low LDL cholesterol may be a predictive marker for death due to liver cancer. PMID- 23445768 TI - Validation of Canadian mothers' recall of events in labour and delivery with electronic health records. AB - BACKGROUND: Maternal report of events that occur during labour and delivery are used extensively in epidemiological research; however, the validity of these data are rarely confirmed. This study aimed to validate maternal self-report of events that occurred in labour and delivery with data found in electronic health records in a Canadian setting. METHODS: Data from the All Our Babies study, a prospective community-based cohort of women's experiences during pregnancy, were linked to electronic health records to assess the validity of maternal recall at four months post-partum of events that occurred during labour and delivery. Sensitivity, specificity and kappa scores were calculated. Results were stratified by maternal age, gravidity and educational attainment. RESULTS: Maternal recall at four months post-partum was excellent for infant characteristics (gender, birth weight, gestational age, multiple births) and variables related to labour and delivery (mode of delivery, epidural, labour induction) (sensitivity and specificity >85%). Women who had completed a university degree had significantly better recall of labour induction and use of an epidural. CONCLUSION: Maternal recall of infant characteristics and events that occurred during labour and delivery is excellent at four months post-partum and is a valid source of information for research purposes. PMID- 23445769 TI - Ethno-ornithology and conservation of wild birds in the semi-arid Caatinga of northeastern Brazil. AB - The utilization of birds as pets has been recognized as one of the principal threats to global avifauna. Most of the information about the use and sale of birds as pets has been limited to areas of high biodiversity and whose impacts of anthropic actions have been widely broadcast internationally, for example for the Amazon Forest and forest remnants of Southeast Asia. The Caatinga predominates in the semi-arid region of Brazil, and is one of the semi-arid biomes with the greatest biological diversity in the world, where 511 species of birds exist. Many of these birds are used as pets, a common practice in the region, which has important conservationist implications but has been little studied. Therefore, the aim of the present study was to detail aspects of the use of birds as pets in a locality in the semi-arid region of Northeast Brazil. Information on the use of avifauna was obtained through interviews and visits to the homes of 78 wild bird keepers. A total of 41 species of birds were recorded, mostly of the families Emberizidae (n = 9 species), Columbidae (n = 7 species), Icteridae (n = 6 species) and Psittacidae (n = 3 species). The birds that were most often recorded were Paroaria dominicana (n = 79 especimens), Sporophila albogularis (n = 67), Aratinga cactorum (n = 49), Sporophila lineola (n = 36), Sicalis flaveola (n = 29) and Sporophila nigricollis (n = 27). The use of wild birds in the area studied, as an example of what occurs in other places in the semi-arid Northeast, demonstrates that such activities persist in the region, in spite of being illegal, and have been happening in clandestine or semi-clandestine manner. No statistically significant correlation were found between socioeconomic factors and keeping birds as pets reflects the cultural importance of this practice of rearing wild birds for pets in the region, which is widespread among the local population, independent of socioeconomic factors. Obviously, human pressure on the avifauna exploited has ecological implications and makes it clear that conservationist measures should consider the cultural, economic and social aspects of these practices. These measures should be carried out by both directly combating the illegal traffic of animals and promoting educational campaigns aimed at all the players involved, from the collectors up to the consumer and wild bird keepers. PMID- 23445770 TI - CRISPR-spacer integration reporter plasmids reveal distinct genuine acquisition specificities among CRISPR-Cas I-E variants of Escherichia coli. AB - Prokaryotes immunize themselves against transmissible genetic elements by the integration (acquisition) in clustered regularly interspaced short palindromic repeats (CRISPR) loci of spacers homologous to invader nucleic acids, defined as protospacers. Following acquisition, mono-spacer CRISPR RNAs (termed crRNAs) guide CRISPR-associated (Cas) proteins to degrade (interference) protospacers flanked by an adjacent motif in extrachomosomal DNA. During acquisition, selection of spacer-precursors adjoining the protospacer motif and proper orientation of the integrated fragment with respect to the leader (sequence leading transcription of the flanking CRISPR array) grant efficient interference by at least some CRISPR-Cas systems. This adaptive stage of the CRISPR action is poorly characterized, mainly due to the lack of appropriate genetic strategies to address its study and, at least in Escherichia coli, the need of Cas overproduction for insertion detection. In this work, we describe the development and application in Escherichia coli strains of an interference-independent assay based on engineered selectable CRISPR-spacer integration reporter plasmids. By using this tool without the constraint of interference or cas overexpression, we confirmed fundamental aspects of this process such as the critical requirement of Cas1 and Cas2 and the identity of the CTT protospacer motif for the E. coli K12 system. In addition, we defined the CWT motif for a non-K12 CRISPR-Cas variant, and obtained data supporting the implication of the leader in spacer orientation, the preferred acquisition from plasmids harboring cas genes and the occurrence of a sequential cleavage at the insertion site by a ruler mechanism. PMID- 23445771 TI - TBI surveillance using the common data elements for traumatic brain injury: a population study. AB - BACKGROUND: To characterize the patterns of presentation of adults with head injury to the Emergency Department. METHODS: This is a cohort study that sought to collect injury and outcome variables with the goal of characterizing the very early natural history of traumatic brain injury in adults. This IRB-approved project was conducted in collaboration with our Institution's Center for Translational Science Institute. Data were entered in REDCap, a secure database. Statistical analyses were performed using JMP 10.0 pro for Windows. RESULTS: The cohort consisted of 2,394 adults, with 40% being women and 79% Caucasian. The most common mechanism was fall (47%) followed by motor vehicle collision (MVC) (36%). Patients sustaining an MVC were significantly younger than those whose head injury was secondary to a fall (P < 0.0001). Ninety-one percent had CT imaging; hemorrhage was significantly more likely with worse severity as measured by the Glasgow Coma Score (chi-square, P < 0.0001). Forty-four percent were admitted to the hospital, with half requiring ICU admission. In-hospital death was observed in 5.4%, while neurosurgical intervention was required in 8%. For all outcomes, worse TBI severity per GCS was significantly associated with worse outcomes (logistic regression, P < 0.0001, adjusted for age). CONCLUSION: These cohort data highlight the burden of TBI in the Emergency Department and provide important demographic trends for further research. PMID- 23445772 TI - Leydig cell tumour in a 46,XX child with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. AB - CASE REPORT: A 10-year-old male was referred to our institution due to short stature and bilateral cryptorchidism and reported pubic hair development and acne since the age of 4 years. Laboratory and molecular genetic tests indicated congenital adrenal hyperplasia due to 21-hydroxylase deficiency. After treatment with prednisone, adrenal hormones normalised but testosterone remained elevated. Magnetic resonance imaging of the abdomen due to cryptorchidism revealed uterus and adnexal attachments, a prostate and poorly defined nodules on the iliac chains. Upon exploratory laparotomy, a hysterectomy, bilateral oophorectomy and resection of a peri-adnexal nodular lesion on the patient's right side were performed. Histopathology of the nodule mass was compatible with a Leydig cell tumour with a low proliferation rate according to Ki67. PMID- 23445774 TI - Effects of the electrical conductivity and orientation of silicon substrate on the synthesis of multi-walled carbon nanotubes by thermal chemical vapor deposition. AB - We studied the effects of the electrical conductivity and orientation of silicon substrate on both catalytic Fe thin film and the structure and morphology of multi-walled carbon nanotube (MWNT) grown by low-pressure chemical vapor deposition. Both p-type Si(100) and Si(111) substrates with three different doping concentrations (high, low, undoped) were used to evaluate the formation of catalytic nanoparticles and the growth of MWNTs. The morphology of catalytic nanoparticles such as size and density was characterized by field-emission scanning electron microscopy, Cs-corrected energy-filtered transmission electron microscopy, and X-ray photoelectron spectroscopy. Structural characteristics of MWNTs grown on different combinations of silicon substrate orientation and electrical conductivities (sigma) were also systematically analyzed. Based on the experimental results, growth modes of MWNTs could be controlled by choosing an appropriate combination of sigma and orientation of Si substrates. PMID- 23445773 TI - Impact of care management processes and integration of care on blood pressure control in diabetes. AB - BACKGROUND: Fragmentation within health care systems may negatively impact the quality of chronic disease patient care. We sought to evaluate the relationship between care management processes (CMP), integration of services, and blood pressure (BP) control among diabetic patients. METHODS: Retrospective chart reviews were performed for a random sample of adult diabetic hypertensive patients (n = 2,162) from 28 physician organizations in the United States (US). A modified version of the Physician Practice Connection Readiness Survey (PPC-RS) was completed by the chief medical officer at each site. The PPC-RS measured health system organization, delivery system redesign, decision support, clinical information systems, and self-management support, and an integration scale measured structure, functions, and financial risk. Correlations between PPC and integration scores and BP outcomes were assessed using Spearman correlation coefficients. RESULTS: Approximately 39.9% of diabetic patients had controlled BP. Mean total PPC score across sites was 55, with highest mean scores for health system organization (81), followed by design support (60), clinical information systems (57), self-management support (39), and delivery system redesign (39). Mean integration score was 46 (SD 27, range 4-93), and means of subscores were 64 for structure, 33 for financial risk, and 42 for function. Clinical information systems subscore was correlated with uncontrolled BP (r = -0.38, p < 0.05), while association with total PPC score was strong but not significant at p < 0.05 (r = 0.32). Total integration score and the structure subscore were significantly correlated with BP control (r = 0.38, p < 0.05, and r = 0.49, p < 0.01). CONCLUSIONS: This study suggests that CMP and service integration may be associated with better outcomes in diabetes, though results were mixed and limited by a small number of participating sites. Primary care implementation of integrated electronic medical records may have a beneficial effect on patient outcomes for diabetes and other chronic diseases. PMID- 23445775 TI - Prevalence and distribution of different diarrhoeagenic Escherichia coli virulotypes in major water bodies in Bangladesh. AB - Escherichia coli, a prominent waterborne pathogen, causes a variety of gastrointestinal and extraintestinal infections that depend on virulence determinants. To monitor natural aquatic systems for virulence-associated genes of E. coli, multiplex PCR was used in a survey covering 46 major natural water bodies in Bangladesh. DNA was extracted directly from water samples as well as from pre-enriched and enriched cultures during three successive seasons and assessed for E. coli virulotype distribution. From the five virulotypes, genes from the enterotoxigenic (ETEC), enteropathogenic (EPEC), and enterohaemorrhagic (EHEC) virulotypes were detected consistently, but genes from the enteroinvasive (EIEC) and enteroaggregative (EAEC) virulotypes were traced only occasionally. ETEC was the most prevalent virulotype, followed by EPEC. However, EIEC and EAEC virulotypes could not be detected in winter or the rainy season, respectively. Specific regional distribution patterns of different E. coli virulotypes and their temporal fluctuations were identified. These observations may assist with assessing seasonal risk and identifying vulnerable areas of the country prone to E. coli-associated outbreaks. PMID- 23445777 TI - The emerging role of MicroRNAs in the regulation of gene expression by nutrients. AB - MicroRNAs (miRNAs) are a class of evolutionarily conserved, small non-coding RNAs of 19-24 nucleotides in length that regulate gene expression mostly at the posttranscriptional level. They are known to be involved in the control of different processes such as cell cycling, programmed cell death, cell differentiation, tumor development, metastasis, and sensing of nutrient stress. This review summarizes the evidence regarding the changes in miRNA expression that are caused by diets with a deficiency or augmented intake of nutrients such as amino acids, carbohydrates, fatty acids, vitamins, and phytochemicals. As diet is known to influence the expression of miRNAs, miRNA profiling has the potential to be useful in the assessment of nutritional status in dietary intervention studies. Additionally, as it can change miRNA expression, diet may be used as a therapeutic agent to treat many different diseases. Also, we explored here some ideas on therapeutics based on the manipulation of miRNA expression levels for dietary-derived diseases as well as the putative effect of food-derived miRNAs on host gene expression. PMID- 23445776 TI - Genome-wide association studies in preterm birth: implications for the practicing obstetrician-gynaecologist. AB - Preterm birth has the highest mortality and morbidity of all pregnancy complications. The burden of preterm birth on public health worldwide is enormous, yet there are few effective means to prevent a preterm delivery. To date, much of its etiology is unexplained, but genetic predisposition is thought to play a major role. In the upcoming year, the international Preterm Birth Genome Project (PGP) consortium plans to publish a large genome wide association study in early preterm birth. Genome-wide association studies (GWAS) are designed to identify common genetic variants that influence health and disease. Despite the many challenges that are involved, GWAS can be an important discovery tool, revealing genetic variations that are associated with preterm birth. It is highly unlikely that findings of a GWAS can be directly translated into clinical practice in the short run. Nonetheless, it will help us to better understand the etiology of preterm birth and the GWAS results will generate new hypotheses for further research, thus enhancing our understanding of preterm birth and informing prevention efforts in the long run. PMID- 23445778 TI - Quantification of hydrogen cyanide (HCN) in breath using selected ion flow tube mass spectrometry--HCN is not a biomarker of Pseudomonas in chronic suppurative lung disease. AB - Hydrogen cyanide (HCN) in exhaled breath has been proposed as a biomarker for airway inflammation, and also a marker of the presence in the airways of specific organisms, especially Pseudomonas aeruginosa. However the production of HCN by salivary peroxidase in the oral cavity increases orally exhaled concentrations, and may not reflect the condition of the lower airways. Using SIFT-MS we aimed to determine an appropriate single-exhalation breathing maneuver which avoids the interference of HCN produced in the oral cavity. We have established that the SIFT-MS Voice200TM is suitable for the online measurement of HCN in exhaled breath. In healthy volunteers a significantly higher end exhaled HCN concentration was measured in oral exhalations compared to nasal exhalations (mean +/- SD) 4.5 +/- 0.6 ppb versus 2.4 +/- 0.3 ppb, p < 0.01. For the accurate and reproducible quantification of end exhaled HCN in breath a nasal inhalation to full vital capacity and nasal exhalation at controlled flow is recommended. This technique was subsequently used to measure exhaled HCN in a group of patients with chronic suppurative lung disease (CSLD) and known microbiological colonization status to determine utility of HCN measurement to detect P. aeruginosa. Median nasal end exhaled HCN concentrations were higher in patients with CSLD (3.7 ppb) than normal subjects (2.0 ppb). However no differences between exhaled HCN concentrations of subjects colonized with P. aeruginosa and other organisms were identified, indicating that breath HCN is not a suitable biomarker of P. aeruginosa colonization. PMID- 23445779 TI - Phase I trial of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma - GORTEC 2004-02. AB - PURPOSE: This study sought to determine the maximum tolerated dose (MTD) of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Phase I, multicenter, open-labelled, non comparative and dose escalating trial. Patients with locally advanced HNSCC were enrolled onto cohorts of escalating dose of etoposide. Oral etoposide was administered on five consecutive days every week for 7 weeks (7 treatment cycles) in combination with daily radiotherapy (70 Gy /35 fractions). Two dose levels (25 mg/day and 50 mg/day) of etoposide were planned and three to six patients were to be enrolled at each level according to the potential DLTs. RESULTS: Fourteen patients were allocated to two dose levels: 25 mg/day (3) and 50 mg/day (11). Cisplatin was contra-indicated in all the patients included. Only one patient (50 mg/day) presents a grade 4 neutropenia (DLT), no other DLTs were observed. The most frequently adverse events (AEs) were radiomucositis. Two deaths before 3 months of end of treatment were not related to treatment. Seven patients were still alive with a median follow-up of 30 months (12-58 months). Nine patients had a complete response (CR) at 3 months after the radiotherapy; Among the 9 patients, 3 patients had a local relapse; one patient with local and distant relapse. CONCLUSION: Due to only one DLT experienced, it is possible to a dose of 50 mg/day for phase II studies, however this should be considered with caution. PMID- 23445780 TI - Tear film osmolarity in patients with diabetes mellitus. AB - PURPOSE: To compare tear film osmolarity (TFO) between patients with diabetes mellitus (DM) and normal healthy individuals. METHODS: In this prospective case controlled study, the TFO in 46 normal subjects (control group) and 55 patients with DM (study group) was evaluated. TFO in milliosmole (mOsm) was measured by using an auto-osmometer. The serum levels of glycosylated hemoglobin (HbA1c) and blood glucose in all participants were also measured. Mean outcome measures were TFO and its relationship with HbA1c level and duration of DM. RESULTS: Mean TFO was 320.40 +/- 21.80 mOsm/l in the study group and 308.22 +/- 18.16 mOsm/l in the control group (p < 0.001). The TFO values were significantly associated with duration of DM (r = 0.476, p < 0.001), but no significant correlation was found with HbA1c level (r = 0.225, p = 0.114). CONCLUSIONS: The study shows a significantly higher TFO in patients with DM than in the healthy controls. TFO also correlates with the duration of DM. PMID- 23445781 TI - Reconstruction of the traumatic eyelid injuries: a 6-years experience. AB - AIM: Our aim is focused on the management of eyelid injuries and on the chose different techniques for the reconstruction. The reconstructions of the upper eyelid and lower eyelid should be based on both functional and cosmetic aspects. MATERIAL OF STUDY: We looked at 47 patients from 2005 to 2011 with eyelid injuries. All patients were subjected to a surgical treatment. RESULTS: After a median follow-up from one to five years, in all cases the skin coverage was reinstated and mobility was restored, thereby adhering to the principles of both morphological and functional reconstruction. DISCUSSION: Eyelids are complex structures and pose a challenge for reconstruction. They play an important role in protecting the globe from trauma, excessive light and in maintaining the integrity of tear films and moving the tears toward the lacrimal drainage system. Concerning reconstruction by means of flap, the main principles dictate that with this procedure the new coverage will appear as much as possible, "like" the original tissue. CONCLUSIONS: There are different techniques available for reconstructions of defects of eyelids. The availability of tissues, technical expertise and the specific needs of the patient have to kept in mind before choosing a particular method. Compared with other frequently used techniques, the nasal chondromucosal flap is a one-stage operation, does not damage the lower lid, and provides a thin, mobile eyelid with an anatomically complete reconstruction. PMID- 23445782 TI - Carcinoma showing thymus-like differentiation (CASTLE): a case report. AB - INTRODUTION: Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant thyroid cancer. We report a case of CASTLE treated with surgery and adjuvant external neck radiation therapy. MATERIALS AND METHODS: We experienced a case of CASTLE in a 63-year-old man, who presented with a neck mass due to enlarged and hard thyroid gland, most notably in the right lobe, without palpable cervical nodes. RESULTS: Total thyroidectomy was performed for both diagnostic and therapeutic purposes. Histologic examination of the specimen showed a "thymus like" thyroid cancer; the tumor, partially circumscribed, lobulated, involved both lobes, and in more points reached the capsule of the organ and infiltrated perithyroid muscle tissue. After immunohistochemical assay (CK19 +, CK20 -, thyroglobulin -, calcitonin -, CD5 +, CD117 +), a diagnosis of CASTLE was made. DISCUSSION: CASTLE is a rare, malignant tumour of the thyroid gland, with histopathological features similar to squamous cell carcinoma, but with a more favourable prognosis. Preoperative diagnosis is difficult. CASTLE is usually cured surgically with total thyroidectomy and selective neck dissection, followed by radiotherapy. CONCLUSIONS: Surgery and radiotherapy are effective to manage thyroid CASTLE tumors. PMID- 23445783 TI - Treatment of congenital liver cysts. A surgical technique tailored through a 35 year experience. AB - BACKGROUND: The most important aims of the treatment of CLC are long-term relief of symptoms and elimination of cysts. Treatment of choice is yet debated. METHODS: Data of patients treated for CLC during a 35-years experience were retrospectively analyzed. Variables analyzed were: age, sex, hepatic cyst location, cyst diameter, symptoms, surgical procedure, short and long-term outcomes. RESULTS: We examined 49 consecutive patients treated for CLC (mean follow-up, 76 months). The study was divided into two periods: 1975-1999 and 2000 2010. Procedures performed in the first period were needle aspiration and sclerotherapy (n= 6), hepatic resections (9), cystojejunostomy (4), open unroofing (10), and laparoscopic unroofing (8). Omentopexy within the residual cystic cavity was associated with seven open and two laparoscopic unroofing cases. Rates of morbidity and recurrence were 23.5% and 44.1%, respectively. One patient died in the peri-operative period. Procedures performed in the second period were open unroofing (9), laparoscopic unroofing (5), and hepatic resection (1). Omentopexy was associated with all open procedures and two laparoscopic procedures. Overall morbidity in this group was 16.6%, and recurrence occurred in one patient (6.7%). CONCLUSIONS: Cyst unroofing and omentopexy is a safe and highly effective procedure for the treatment of CLC. Laparoscopy is confirmed as the procedure of choice except for cases in which the cysts are in the posterior right liver, where a wide mobilization of the liver is necessary. PMID- 23445785 TI - Ab initio calculation of valley splitting in monolayer delta-doped phosphorus in silicon. AB - : The differences in energy between electronic bands due to valley splitting are of paramount importance in interpreting transport spectroscopy experiments on state-of-the-art quantum devices defined by scanning tunnelling microscope lithography. Using vasp, we develop a plane-wave density functional theory description of systems which is size limited due to computational tractability. Nonetheless, we provide valuable data for the benchmarking of empirical modelling techniques more capable of extending this discussion to confined disordered systems or actual devices. We then develop a less resource-intensive alternative via localised basis functions in siesta, retaining the physics of the plane-wave description, and extend this model beyond the capability of plane-wave methods to determine the ab initio valley splitting of well-isolated delta-layers. In obtaining an agreement between plane-wave and localised methods, we show that valley splitting has been overestimated in previous ab initio calculations by more than 50%. PMID- 23445786 TI - Tracking sickness through social networks - the practical use of social network mapping in supporting the management of an E. coli O157 outbreak in a primary school in London. AB - This paper describes the practical use of social network diagrams in the management of an outbreak of Escherichia coli O157 (VTEC) in a primary school in London. The diagrams were created during the outbreak to establish the extent and nature of person-to-person transmission in the cases and their contacts. The diagrams supported a tailored public health action, and hence aided in the control of the outbreak. We conclude that for selected infectious diseases, social network diagrams can provide a valuable tool in the management of an outbreak. PMID- 23445787 TI - Neurilemmoma showing a unique growth pattern in the lateral chest wall: both inside and outside the thoracic cavity. AB - We report the first case of the intercostal neurilemmoma showing a unique growth pattern in the lateral chest wall (both inside and outside the thoracic cavity). Usually, intrathoracic neurilemmoma is found in the posterior mediastinum and bulge from the inner surface of the bony thorax toward the thoracic cavity. This unique growing pattern of neurilemmoma arising from intercostal nerve was clearly demonstrated by computed tomography and ultrasonography. PMID- 23445784 TI - Functional decorations: post-translational modifications and heart disease delineated by targeted proteomics. AB - The more than 300 currently identified post-translational modifications (PTMs) provides great scope for subtle or dramatic alteration of protein structure and function. Furthermore, the rapid and transient nature of many PTMs allows efficient signal transmission in response to internal and environmental stimuli. PTMs are predominantly added by enzymes, and the enzymes responsible (such as kinases) are thus attractive targets for therapeutic interventions. Modifications can be grouped according to their stability or transience (reversible versus irreversible): irreversible types (such as irreversible redox modifications or protein deamidation) are often associated with aging or tissue injury, whereas transient modifications are associated with signal propagation and regulation. This is particularly important in the setting of heart disease, which comprises a diverse range of acute (such as ischemia/reperfusion), chronic (such as heart failure, dilated cardiomyopathy) and genetic (such as hypertrophic cardiomyopathy) disease states, all of which have been associated with protein PTM. Recently the interplay between diverse PTMs has been suggested to also influence cellular function, with cooperation or competition for sites of modification possible. Here we discuss the utility of proteomics for examining PTMs in the context of the molecular mechanisms of heart disease. PMID- 23445788 TI - Hybrid procedure for a Kommerell's diverticulum in a right-sided aortic arch. AB - A rare case of an aneurysmal Kommerell's diverticulum in a right-sided aortic arch was successfully treated using a hybrid procedure comprising total arch replacement and percutaneous stent grafting. A 65-year-old man with dysphagia was diagnosed with an ectatic right-sided aortic arch and a saccular aneurysm of the Kommerell's diverticulum. Since its radical resection during a single surgery was unfeasible because of its complex configuration, a 2-stage procedure was adopted. PMID- 23445789 TI - Extracorporeal membrane oxygenation with double venous drainage. AB - We report on a successful configuration strategy of extracorporeal membrane oxygenation(ECMO) in two consecutive cases of acute lung injury. A 60-year-old woman with Streptococcus pneumoniae infection and a 22-year-old man with hemothorax were admitted to our hospital with failing lungs. Although treatment with a ventilator was started, oxygenation could not be maintained. ECMO with a femoro-femoral circuit was performed, which showed a slight improvement in oxygenation. However, not enough oxygen support was provided. To minimize the venous mixture at the right atrium, we added venous drainage from the right jugular vein which resulted in better oxygenation and patient survival. PMID- 23445790 TI - A case of an acute cervicomediastinal hematoma secondary to the spontaneous rupture of a parathyroid adenoma. AB - We herein report the case of a patient with an acute cervicomediastinal hematoma secondary to the spontaneous rupture of a parathyroid adenoma. A 47-year-old female presented with swelling and pain in the neck. She had no history of trauma or of having undergone any medical or odontological procedures. An ultrasound examination revealed the presence of an obscure mass located behind the right lobe of the thyroid gland. A computed tomography scan showed the presence of a low-density lesion extending from the retropharynx to the mediastinum, a high density lesion located behind the right lobe of the thyroid gland and a right pleural effusion. Because the patient's neck swelling and anemia gradually worsened, she underwent emergency surgery. The neck was found to be swollen due to a hematoma; however, no abscesses were detected in the operative field.Thoracoscopy of the right chest showed no active bleeding. The fragmented mass was histopathologically diagnosed as a parathyroid adenoma with acute hemorrhage, which is quite rare. Our experience suggests that, in patients with severe cervicomediastinal hematomas without any trauma or trigger, a diagnosis of spontaneous rupture of a parathyroid gland lesion should be considered. PMID- 23445791 TI - Intrathoracic thyroid solitary fibrous tumor presenting with respiratory failure. AB - Solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm that arises primarily from the pleura, but recognized also in other tissues. SFT in the thyroid gland is extremely rare. Here we presented the second reported SFT arising in an intrathoracic goiter. The88-year-old woman was referred with a huge goiter involving upper mediastinum accompanied by airway obstruction and tracheostomy. The patient underwent a left subtotal thyroidectomy, which revealed a SFT. No recurrence was noted during 3 years of follow-up. PMID- 23445792 TI - Iliac leg and abdominal aortic cuff stent-graft for blunt thoracic aortic injury in young patient. AB - Thoracic endovascular aortic repair for blunt thoracic aortic injury in young adults with small aortic diameter often encounters high difficulty. We report, to our knowledge, the first case of successful treatment using combination of iliac leg and abdominal aortic cuff stent-graft. PMID- 23445793 TI - A recurrent vagal schwannoma in the middle mediastinum after surgical enucleation. AB - A 50-year-old man underwent repeat surgery for a benign vagal schwannoma in the middle mediastinum. He had undergone tumor enucleation at another hospital 4 months before presentation. The tumor (99 * 88 * 76 mm) was located in the aortopulmonary window and arose from the left vagus nerve. It had been enucleated, leaving its sheath behind to preserve the nerve. Imaging studies showed tumor regrowth without distant metastasis, and the tumor was extirpated along with the involved nerve during cardiopulmonary bypass. There was no nerve dysfunction, recurrence, or metastasis 6 months after the operation. A benign vagal schwannoma can be excised with nerve transection or enucleated without nerve transection. The present case suggests that a vagal mediastinal schwannoma should be extirpated along with the nerve because insufficient enucleation might lead to tumor regrowth. PMID- 23445794 TI - Successful sleeve lobectomy of inflammatory myofibroblastic tumor in a 4-year-old child. AB - Primary pulmonary tumors in small children have remained a challenge for pediatric surgeons. Pneumonectomy and radical lobectomy are limitedly indicated due to surgical difficulties and sequelae. Here, we present our experience with a 4-year-old patient who suffered from an inflammatory myofibroblastic tumor. A left lower sleeve lobectomy was performed, and the patient recovered significantly after surgery. At the last follow-up, the child was growing well without any sequel, which supports our hypothesis that in small children, sleeve resection is the preferred treatment for tumors on the main stem bronchus and presents an alternative to an otherwise unavoidable pneumonectomy. PMID- 23445795 TI - Double atrial septum with interatrial chamber formation and recurrent paradoxical embolism. AB - Paradoxical embolism is a common cause of cryptogenic stroke. Cardiogenic origin is often the real culprit of unexplained stroke. We report a rare case of double atrial septum with an interatrial chamber and stenosis of the inferior vena cava orifice, which lead to recurrent paradoxical embolism, and then highlight the clinical importance of this rare type of congenital heart disease. PMID- 23445796 TI - Non-obstructive mesenteric ischemia after cardiovascular surgery: not so uncommon. PMID- 23445797 TI - Prevention of atrial fibrillation with ultra-low dose landiolol after off-pump coronary artery bypass grafting. AB - PURPOSE: Postoperative atrial fibrillation (AF) is a common complication of cardiac surgery that is associated with an increased incidence of other complications. The goal of this prospective randomized study was to evaluate the effect of ultra-low dose landiolol hydrochloride for prevention of AF after off pump coronary artery bypass grafting (CABG). METHODS: The subjects were 47 patients who underwent isolated CABG and were randomly divided into those who received landiolol from ICU admission until the beginning of oral drug intake (Group L) and those administered diltiazem hydrochloride over the same period (Group D). The incidence of AF within one week after surgery was examined as the primary endpoint. Heart rate, blood pressure, cardiac output, and other hemodynamic parameters were used as secondary endpoints. The rates of adverse events were also recorded. RESULTS: The incidences of AF in the first postoperative week were 4.8% and 27% in Groups L and D, respectively (p = 0.046). There were no differences in hemodynamic parameters between the Groups. In multivariate analysis, no factor emerged as a significant risk factor for postoperative AF. Two patients had adverse events of asthma and hypotension, respectively, in Group L. CONCLUSION: Ultra-low dose landiolol is effective for preventing AF after CABG without worsening hemodynamics. PMID- 23445798 TI - Bronchial stump coverage with fibrin glue-coated collagen fleece in lung cancer patients who underwent pneumonectomy. AB - PURPOSE: Bronchopleural fistula (BPF) is a serious complication following pneumonectomy in lung cancer patients. The aim of this retrospective study is to investigate the efficacy of bronchial stump reinforcement with a collagen fleece coated with fibrin glue(TachoComb(r)). METHODS: The bronchial stumps of 43 lung cancer patients who underwent pneumonectomy between January 1998 and January 2003 were covered with pericardial fat pad.From February 2003 to the March 2011, we used TachoComb to cover the bronchial stumps of all lung cancer patients undergoing pneumonectomy (20 cases). Several preoperative, intraoperative, and postoperative variables were recorded retrospectively. RESULTS: Univariate analysis of comorbidities and risk factors did not show any significant differences between the two groups except for neoadjuvant chemotherapy. Postpneumonectomy BPF occurred in three of the 43 (7%) patients who had pericardial fat pad coverage and in none of the patients treated by TachoComb. CONCLUSION: Reinforcement of the bronchial stump with TachoComb is a simple procedure, comparable to coverage with viable tissue, and should be considered in the prevention of postpneumonectomy BPF. PMID- 23445799 TI - Management of concomitant large aortic aneurysm and severe stenosis of aortic arc. AB - Primary large saccular aortic aneurysm with high grade stenosis of aortic arc is rare, and no standard therapy is available. We have encountered one case and successfully treated using a hybrid interventional approach. A 59-year-old woman with a 7-day history of headache, dizziness and chest pain, and a 5-year history of hypertension admitted and was diagnosed with transverse aortic aneurysm with sever aortic stenosis, the huge saccular aneurysm was located behind the transverse aortic arc. During surgery, a bypass with graft from ascending aorta to left external iliac artery was made initially in order to ensure the blood supply to the left leg, afterward, a 40 mm * 160 mm covered stent was implanted to cover the orifice of aneurysm and was used as a supporting anchorage in the descending aorta, a second covered stent (20 mm * 100 mm) was implanted to expand the stenosis of aortic arc. Follow-up at 1.5-year after surgery, the patient has been doing well without any surgical complication. A collateral pathway between internal mammary artery and inferior epigastric artery via the superior epigastric artery was found on3-dimensional reconstruction before surgery. Interruption of the compensatory arterial collateral pathway in the patient with severe stenosis of aortic arc should be prevented if possible in order to ensure the satisfactory perfusion of the lower limbs of the body.In conclusion, a patient with transverse aortic aneurysm accompanied with severe aortic stenosis can be treated by hybrid surgery. PMID- 23445800 TI - A resected melanoma of the lung metastasized from an occult skin lesion: a case report. AB - An 86-year-old woman with a history of right breast cancer resected seven years ago had a small pulmonary nodule located in left S5. Diagnosis was made by bronchoscopy using the endobronchial ultrasonography-guided sheath (EBUS-GS) method, but a histological diagnosis was not obtained. Wedge resection was performed due to suspicion of a metastatic lesion from breast cancer based on radiological findings. The tumor was subsequently found to be malignant melanoma of the lung. An initial diagnosis of primary melanoma of the lung was made because a melanoma lesion at another site was not seen despite a detailed work up. However, 8 months after surgery, a malignant melanoma appeared at the tip of the right index finger. We rediagnosed the lung lesion as a metastatic malignant melanoma based on the low incidence of primary melanoma of the lung and on the pathological features. PMID- 23445801 TI - Temporary extracorporeal brachio-femoral vascular prosthesis shunt for ischemia prevention in an operation for abdominal aortic and iliac aneurysms in a patient with Marfan's syndrome. AB - In open vascular repair, when prolonged infrarenal aortic clamping can be expected, and collateral perfusion is reduced, the use of a temporary shunt may reduce the risk of ischemic complications. In a patient with Marfan's syndrome and aortic dissection who had developed infrarenal aneurysms, segmental arteries had been occluded by prior aortic surgery and collateral arteries in the anterior torso could have been damaged by previous pectus excavatum, muscle flap, sternotomy, and ventral hernia operations. The axillary artery was dilated. For the prevention of ischemia during open repair with a bifurcated graft, a temporary extracorporeal brachio-femoral vascular prosthesis shunt was constructed. Ischemia was not observed. The use of a temporary extracorporeal brachio-femoral shunt with a vascular prosthesis is a feasible method for ischemia prevention. PMID- 23445802 TI - Left coronary ostial stenosis after the modified bentall using a long interposed coronary graft in a patient with pectus excavatum. AB - A 26-year-old man presented chest oppression. He had pectus excavatum associated with Loeys-Dietz syndrome and a history of redo aortic root replacement with the modified Bentall technique using an 8-mm long interposed graft to the left coronary ostium. Coronary angiography revealed severe stenosis of both left coronary ostium and proximal left anterior descending artery, which was supposed to be resulted from thrombosis in the interposed graft. The left coronary system was bypassed through a left thoracotomy, which was suitable in this patient because the pectus excavatum would prevent harvest of the left internal thoracic artery through re-median sternotomy and to avoid potential sternal reentry injury of the heart. Although the left anterior descending artery was easily accessed under off-pump technique, exposure and anastomosis of the circumflex coronary artery was more difficult than expected without cardiopulmonary bypass as the pectus excavatum and adhesion of the heart prevented anterior shift and rotation of the heart. PMID- 23445803 TI - Modified perfusion strategy and aortic arch debranching in complicated acute aortic dissection type A: a bridge to definitive endovascular therapy. AB - INTRODUCTION: Patients with acute aortic dissection type A (AADA) with aortic arch and supra-aortic vessel involvement have a higher postoperative stroke prevalence and risk of later aortic arch aneurysm development. CASE REPORT: We report a case of AADA with involvement of supraaortic arteries, complicated by cerebral malperfusion. The ascending aorta was replaced using bilateral antegrade cerebral perfusion through side-grafts attached to both carotid arteries, which were subsequently used as aorto-bi-carotid bypass. One year later, the diameter of aortic arch increased to 5 cm. The endovascular treatment of aortic arch was easily performed since debranching was already almost complete. CONCLUSIONS: Immediate bilateral carotid artery inflow and subsequent aorto-bi-carotid bypass is a safe way to prevent cerebral malperfusion in the setting of complicated AADA.A potential benefit of this technique is almost complete debranching that facilitates an endovascular arch replacement. PMID- 23445804 TI - Paravertebral block as a promising analgesic modality for managing post thoracotomy pain. AB - PURPOSE: Analgesia following thoracotomy is routinely accomplished using epidural blockage performed by anesthesiologists. More effective pain control can be achieved with continuous paravertebral blockage performed by thoracic surgeons. We aimed to retrospectively analyze the efficacy of paravertebral blockage for managing post-thoracotomy pain. METHODS: The study included 125 patients who underwent continuous paravertebral blockage for the following types of thoracic surgery: video-assisted thoracoscopic surgery(n = 87), anterior axillary thoracotomy (n = 21), posterolateral thoracotomy (n = 16), and median sternotomy with additional left thoracotomy (n = 1). We retrospectively evaluated the analgesic effects of continuous paravertebral blockage by assessing whether a good cough effort could be performed and whether an additional painkiller was given as a rescue medication. RESULTS: About 115 patients could perform a good cough effort to expectorate sputum immediately after extubation in the operating room. Six patients tolerated postoperative pain well without any oral or rectal non-steroidal anti-inflammatory drugs (NSAIDs). For97 patients postoperative NSAIDs could control thoracotomy pain well. Twenty-two patients were given an additional painkiller stronger than NSAIDs. Three patients complained of nausea postoperatively. CONCLUSION: Adequate post-thoracotomy pain control was accomplished by continuous paravertebral blockage, with few complications. PMID- 23445805 TI - Surgery for elderly lung cancer. AB - OBJECTIVE: There are still controversies about the surgical benefits for elderly lung cancer.The aims of this study were to assess impacts of aging for non-small cell lung cancer(NSCLC) following pulmonary resection. METHODS: A retrospective study was undertaken for patients operated at a curative intent from January 1998 to October 2008. Patients were divided into two groups: Group 1 consisted of patients aged at least 75 years old, and group 2 were patients less than 75 years old. Perioperative characteristics and details, hospital courses, surgery-related morbidities, surgical mortality, and survival were compared between groups. RESULTS: Of 442 eligible patients, 73 patients (16.5%) were in group 1 (mean age 78.3 years) and 369 (83.5%) patients were in group 2 (mean age 62.5 years). The following data were compared with statistical significance: hospital stay (17.8 vs. 8.9 days), mortality rate (8.2 vs. 2.2%), morbidity rate (26.0 vs. 13.3%), and length in intensive care unit (5.7 vs. 3.2 days). The main causes for morbidities in group 1 showed cardiopulmonary-related. Tumor stage without considering age had statistically significant influence on survival. Survivals of two groups were comparative. (p= 0.10) Intriguingly, the disease-related survival (28.3 months; p= 0.008) and progression-free survival (25.0 months; p<0.001) in group 1 were significantly better than group 2 (20.2 and 12.2 months). CONCLUSIONS: Although operation for NSCLC in the elderly patients causes more complications, especially in the cardiopulmonary system, their outcome showed better than their younger counterparts. Pulmonary resection for elderly patients may get longer disease control. Elderly patients with physical fit for surgery should not be considered as a contraindication to pulmonary resection based on age alone. PMID- 23445806 TI - Predictors of postoperative atrial fibrillation after on-pump coronary artery bypass grafting: is duration of mechanical ventilation time a risk factor? AB - PURPOSE: This study aimed to establish the role of risk factors in the etiology of postoperative atrial fibrillation (AF) after coronary artery bypass grafting (CABG). METHODS: Between September 2001 and March 2008, 1040 patients underwent isolated CABG at our clinic. Nine hundred and eleven of these patients did not have any AF(Non-AF Group) and the other one hundred and twenty-nine had AF (AF Group). A retrospective study was performed for patient, disease and treatment related factors and multivariate analysis was used to identify independent clinical predictors of postoperative AF. RESULTS: Postoperative AF was identified in 129 (12.4%) of the patients, and those were significantly older and had significantly higher additive EuroSCORE score as compared with patients without AF. During the postoperative course, patients with postoperative AF also had significantly higher and prolonged (>=6 hours) mechanical ventilation time, longer and prolonged intensive care unit stay and longer hospital stay. Logistic regression analysis revealed that postoperative AF development ratio was 1.690 times higher when the ventilation time was over 6 hours (OR 1.690, 95% CI 1.092 2.615, p = 0.018); 1.240 times higher in the presence of elevated additive EuroSCORE score (OR 1.240, 95% CI1.109-1.385, p = 0.0001); 1.052 times higher in the presence of advanced age (OR 1.052,95% CI 1.031-1.0741, p = 0.0001). CONCLUSION: Analysis of our data reveals that, patient's age, additive EuroSCORE score, and prolonged ventilation are predictors of postoperative AF. Identification of risk factors might lead to better prevention of this problem and its potential consequences. However, to support our investigation and obtain more reliable evidence, prospective randomized controlled trials are needed. PMID- 23445807 TI - Control of actin dynamics by allosteric regulation of actin binding proteins. AB - The regulated assembly and organization of actin filaments allows the cell to construct a large diversity of actin-based structures specifically suited to a range of cellular processes. A vast array of actin regulatory proteins must work in concert to form specific actin networks within cells, and spatial and temporal requirements for actin assembly necessitate rapid regulation of protein activity. This chapter explores a common mechanism of controlling the activity of actin binding proteins: allosteric autoinhibition by interdomain head-tail interactions. Intramolecular interactions maintain these proteins in a closed conformation that masks protein domains needed to regulate actin dynamics. Autoinhibition is typically relieved by two or more ligand binding and/or posttranslational modification events that expose key protein domains. Regulation through multiple inputs permits precise temporal and spatial control of protein activity to guide actin network formation. PMID- 23445808 TI - Dynamics and regulation of epithelial adherens junctions: recent discoveries and controversies. AB - Adherens junctions (AJs) are evolutionarily conserved plasma-membrane structures that mediate cell-cell adhesions in multicellular organisms. They are organized by several types of adhesive integral membrane proteins, most notably cadherins and nectins that are clustered and stabilized by a number of cytoplasmic scaffolds. AJs are key regulators of tissue architecture and dynamics via control of cell proliferation, polarity, shape, motility, and survival. They are absolutely critical for normal tissue morphogenesis and their disruption results in pathological abnormalities in different tissues. Although the field of adherens-junction research dramatically progressed in recent years, a number of important questions remain controversial and poorly understood. This review outlines basic principles that regulate organization of AJs in mammalian epithelia and discusses recent advances and standing controversies in the field. A special attention is paid to the regulation of AJs by vesicle trafficking and the intracellular cytoskeleton as well as roles and mechanisms of adherens junction disruption during tumor progression and tissue inflammation. PMID- 23445809 TI - Regulation of cilium length and intraflagellar transport. AB - Primary cilia are highly conserved sensory organelles that extend from the surface of almost all vertebrate cells. The importance of cilia is evident from their involvement in many diseases, called ciliopathies. Primary cilia contain a microtubular axoneme that is used as a railway for transport of both structural components and signaling proteins. This transport machinery is called intraflagellar transport (IFT). Cilia are dynamic organelles whose presence on the cell surface, morphology, length and function are highly regulated. It is clear that the IFT machinery plays an important role in this regulation. However, it is not clear how, for example environmental cues or cell fate decisions are relayed to modulate IFT and cilium morphology or function. This chapter presents an overview of molecules that have been shown to regulate cilium length and IFT. Several examples where signaling modulates IFT and cilium function are used to discuss the importance of these systems for the cell and for understanding of the etiology of ciliopathies. PMID- 23445811 TI - Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: intentionally or unintentionally. AB - Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17 demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of "eHsp90 dependent" cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90. PMID- 23445813 TI - New insights into the developmental mechanisms of coronary vessels and epicardium. AB - During heart development, the epicardium, which originates from the proepicardial organ (PE), is a source of coronary vessels. The PE develops from the posterior visceral mesoderm of the pericardial coelom after stimulation with a combination of weak bone morphogenetic protein and strong fibroblast growth factor (FGF) signaling. PE-derived cells migrate across the heart surface to form the epicardial sheet, which subsequently seeds multipotent subepicardial mesenchymal cells via epithelial-mesenchymal transition, which is regulated by several signaling pathways including retinoic acid, FGF, sonic hedgehog, Wnt, transforming growth factor-beta, and platelet-derived growth factor. Subepicardial endothelial progenitors eventually generate the coronary vascular plexus, which acquires an arterial or venous phenotype, connects with the sinus venosus and aortic sinuses, and then matures through the recruitment of vascular smooth muscle cells under the regulation of complex growth factor signaling pathways. These developmental programs might be activated in the adult heart after injury and play a role in the regeneration/repair of the myocardium. PMID- 23445814 TI - New insights into roles of tubulobulbar complexes in sperm release and turnover of blood-testis barrier. AB - Tubulobulbar complexes are actin-filament-related structures that form at intercellular junctions in the seminiferous epithelium of mammalian testis. The structures occur both at adhesion junctions between Sertoli cells and the maturing spermatids in apical regions of the epithelium, and at junction complexes between neighboring Sertoli cells near the base of the epithelium. Here, we review the general morphology and molecular composition of tubulobulbar complexes, and also include a description of tubulobulbar complex structure in the human seminiferous epithelium. Although tubulobulbar complexes are unique to the seminiferous epithelium, they have the molecular signature of clathrin-based endocytosis machinery present generally in cells. We review the evidence that tubulobulbar complexes internalize intact intercellular junctions and are significant components of the sperm-release mechanism and the process by which spermatocytes translocate from basal to adluminal compartments of the epithelium. PMID- 23445812 TI - New insights into the mechanism for chromosome alignment in metaphase. AB - During mitosis, duplicated sister chromatids are properly aligned at the metaphase plate of the mitotic spindle before being segregated into two daughter cells. This requires a complex process to ensure proper interactions between chromosomes and spindle microtubules. The kinetochore, the proteinaceous complex assembled at the centromere region on each chromosome, serves as the microtubule attachment site and powers chromosome movement in mitosis. Numerous proteins/protein complexes have been implicated in the connection between kinetochores and dynamic microtubules. Recent studies have advanced our understanding on the nature of the interface between kinetochores and microtubule plus ends in promoting and maintaining their stable attachment. These efforts have demonstrated the importance of this process to ensure accurate chromosome segregation, an issue which has great significance for understanding and controlling abnormal chromosome segregation (aneuploidy) in human genetic diseases and in cancer progression. PMID- 23445810 TI - Cellular and molecular biology of airway mucins. AB - Airway mucus constitutes a thin layer of airway surface liquid with component macromolecules that covers the luminal surface of the respiratory tract. The major function of mucus is to protect the lungs through mucociliary clearance of inhaled foreign particles and noxious chemicals. Mucus is comprised of water, ions, mucin glycoproteins, and a variety of other macromolecules, some of which possess anti-microbial, anti-protease, and anti-oxidant activities. Mucins comprise the major protein component of mucus and exist as secreted and cell associated glycoproteins. Secreted, gel-forming mucins are mainly responsible for the viscoelastic property of mucus, which is crucial for effective mucociliary clearance. Cell-associated mucins shield the epithelial surface from pathogens through their extracellular domains and regulate intracellular signaling through their cytoplasmic regions. However, neither the exact structures of mucin glycoproteins, nor the manner through which their expression is regulated, are completely understood. This chapter reviews what is currently known about the cellular and molecular properties of airway mucins. PMID- 23445816 TI - Status of human germ cell differentiation from pluripotent stem cells. AB - Historically, the quality of life of infertile couples has been greatly diminished by the loss of opportunity to conceive. However, beginning with the advent of IVF in the late 1970s, novel clinical interventions have greatly changed the outlook for those with severe forms of infertility. Yet, in cases in which the quality and quantity of germ cells are most compromised, there are few options. In the present paper, the current status of germ cell development from stem cells is reviewed in light of potential utility for basic science and clinical applications. PMID- 23445817 TI - Altered pregnancy outcomes in mice following treatment with the hyperglycaemia mimetic, glucosamine, during the periconception period. AB - Exposure of cumulus-oocyte complexes to the hyperglycaemia mimetic, glucosamine, during in vitro maturation impairs embryo development, potentially through upregulation of the hexosamine biosynthesis pathway. This study examined the effects of in vivo periconception glucosamine exposure on reproductive outcomes in young healthy mice, and further assessed the effects in overweight mice fed a high-fat diet. Eight-week-old mice received daily glucosamine injections (20 or 400mgkg(-1)) for 3-6 days before and 1 day after mating (periconception). Outcomes were assessed at Day 18 of gestation. Glucosamine treatment reduced litter size independent of dose. A high-fat diet (21% fat) for 11 weeks before and during pregnancy reduced fetal size. No additional effects of periconception glucosamine (20mgkg(-1)) on pregnancy outcomes were observed in fat-fed mice. In 16-week-old mice fed the control diet, glucosamine treatment reduced fetal weight and increased congenital abnormalities, but did not alter litter size. As differing effects of glucosamine were observed in 8-week-old and 16-week-old mice, maternal age effects were assessed. Periconception glucosamine at 8 weeks reduced litter size, whereas glucosamine at 16 weeks reduced fetal size. Thus, in vivo periconception glucosamine exposure perturbs reproductive outcomes in mice, with the nature of the outcomes dependent upon maternal age. PMID- 23445815 TI - Role of microRNA-138 as a potential tumor suppressor in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is an aggressive life-threatening disease associated with high mortality rates. While efforts have been made to explore the molecular mechanisms that contribute to the initiation and progression of HNSCC, most studies focus on protein-coding genes. Understanding of the genomic aberrations associated with noncoding genes (such as microRNAs) and their effects on HNSCC is still relatively limited. Recent evidence suggests that deregulation of microRNA genes (such as downregulation of miR-138) plays an important role in HNSCC. While deregulation of miR-138 has been frequently observed in HNSCC and other cancer types, the precise roles of miR-138 in tumorigenesis remain elusive. Recent bioinformatics analyses and functional studies using in vitro and in vivo systems have identified a number of functional targets for miR-138. These include genes that participate in essential biological processes that are highly relevant to the initiation and progression of HNSCC, including cell migration, epithelial to mesenchymal transition, cell cycle progression, DNA damage response and repair, senescence, and differentiation. However, the biological systems, study design, and data interpretation from these studies are highly variable, which hinder our understanding of the role of miR 138 in tumorigenesis at molecular level. In this review, we will first introduce the significance of microRNA deregulation in HNSCC. We will then provide a comprehensive review and integrative analysis of the existing studies on miR-138, and aim to define its molecular mechanisms that contribute to the initiation and progression of HNSCC. PMID- 23445818 TI - Sex determination of porcine embryos using a new developed duplex polymerase chain reaction procedure based on the amplification of repetitive sequences. AB - Polymerase chain reaction (PCR)-based assays have become increasingly prevalent for sexing embryos. The aim of the present study was to develop a suitable duplex PCR procedure based on the amplification of porcine repetitive sequences for sexing porcine tissues, embryos and single cells. Primers were designed targeting the X12696 Y chromosome-specific repeat sequence (SUSYa and SUSYb; sex-related primer sets), the multicopy porcine-specific mitochondrial 12S rRNA gene (SUS12S; control primer set) and the X51555 1 chromosome repeat sequence (SUS1; control primer set). The specificity of the primer sets was established and the technique was optimised by testing combinations of two specific primer sets (SUSYa/SUS12S; SUSYb/SUS12S), different primer concentrations, two sources of DNA polymerase, different melting temperatures and different numbers of amplification cycles using genomic DNA from porcine ovarian and testicular tissue. The optimised SUSYa/SUS12S- and SUSYb/SUS12S-based duplex PCR procedures were applied to porcine in vitro-produced (IVP) blastocysts, cell-stage embryos and oocytes. The SUSYb/SUS12S primer-based procedure successfully sexed porcine single cells and IVP cell-stage embryos (100% efficiency), as well as blastocysts (96.6% accuracy; 96.7% efficiency). This is the first report to demonstrate the applicability of these repetitive sequences for this purpose. In conclusion, the SUSYb/SUS12S primer-based duplex PCR procedure is highly reliable and sensitive for sexing porcine IVP embryos. PMID- 23445819 TI - Genotype and fetal size affect maternal-fetal amino acid status and fetal endocrinology in Large White * Landrace and Meishan pigs. AB - This study compared maternal plasma amino acid concentrations, placental protein secretion in vitro and fetal body composition and plasma amino acid and hormone concentrations in feto-placental units from the smallest and a normally-sized fetus carried by Large White * Landrace or Meishan gilts on Day 100 of pregnancy. Compared with Large White * Landrace, Meishan placental tissue secreted more protein and Meishan fetuses contained relatively more fat and protein, but less moisture. Fetal plasma concentrations of insulin, triiodothryonine, thyroxine and insulin-like growth factor (IGF)-II were higher in Meishan than Large White * Landrace fetuses. In both breeds, fetal cortisol concentrations were inversely related to fetal size, whereas concentrations of IGF-I were higher in average sized fetuses. Concentrations of 10 amino acids were higher in Large White * Landrace than Meishan gilts, while glutamine concentrations were higher in Meishan gilts. Concentrations of alanine, aspartic acid, glutamic acid and threonine were higher in Meishan than Large White * Landrace fetuses. Average sized fetuses had higher concentrations of asparagine, leucine, lysine, phenylalanine, threonine, tyrosine and valine than the smallest fetus. This study revealed novel genotype and fetal size differences in porcine maternal-fetal amino acid status and fetal hormone and metabolite concentrations. PMID- 23445820 TI - The critical importance of ovarian angiogenesis. PMID- 23445821 TI - Clinical significance of treatment delay in status epilepticus. AB - BACKGROUND: Status epilepticus (SE) is a medical emergency that requires immediate action. The clinical and demographic features of SE are known to be highly variable. The objective of this study was to analyze the effect of treatment delays on patient recovery and different clinical factors that are important in the determination of the acute prognosis in SE. METHODS: This population-based study included 109 consecutive visits of patients with the diagnosis of SE in the emergency department (ED) of Tampere University Hospital. The clinical features of SE were compared with the discharge condition. RESULTS: The treatment delays were long; in half of the patients, the delay for paramedic arrival was over 30 min, and in one-third of the cases, the delay was over 24 h. ED patients who had less than 1 h of delay before the administration of an antiepileptic drug (AED) had better outcomes compared to patients with a greater than 1 h delay (p < 0.05). The two major etiologies for the SE were cerebrovascular disease and alcohol misuse. A good immediate outcome was found in 46% of the patients. Epileptiform activity on the EEG, a history of epilepsy or SE, presence of cardiovascular disease, and alcohol misuse were associated with a poor outcome. CONCLUSIONS: The results of this study emphasize the importance of an urgent response by emergency services and proper recognition of atypical phenotypes of SE. PMID- 23445823 TI - Land plant evolutionary timeline: gene effects are secondary to fossil constraints in relaxed clock estimation of age and substitution rates. AB - PREMISE OF THE STUDY: Land plants play an essential role in the evolution of terrestrial life. Their time of origin and diversification is fundamental to understanding the evolution of life on land. We investigated the timing and the rate of molecular evolution of land plants, evaluating the effects of different types of molecular data, including temporal information from fossils, and using different molecular clock methods. * METHODS: Ages and absolute rates were estimated independently with two substitutionally different data sets: a highly conserved 4-gene data set and matK, a fast-evolving gene. The vascular plant backbone and the crown nodes of all major lineages were calibrated with fossil derived ages. Dates and absolute rates were estimated while including or excluding the calibrations and using two relaxed clocks that differ in their implementation of temporal autocorrelation. * KEY RESULTS: Land plants diverged from streptophyte alga 912 (870-962) million years ago (Mya) but diversified into living lineages 475 (471-480) Mya. Ages estimated for all major land-plant lineages agree with their fossil record, except for angiosperms. Different genes estimated very similar ages and correlated absolute rates across the tree. Excluding calibrations resulted in the greatest age differences. Different relaxed clocks provided similar ages, but different and uncorrelated absolute rates. * CONCLUSIONS: Whole-genome rate accelerations or decelerations may underlie the similar ages and correlated absolute rates estimated with different genes. We suggest that pronounced substitution rate changes around the angiosperm crown node may represent a challenge for relaxed clocks to model adequately. PMID- 23445822 TI - Fluorescent triplex-forming DNA oligonucleotides labeled with a thiazole orange dimer unit. AB - Fluorescent probes for the detection of a double-stranded DNA were prepared by labeling a triplex-forming DNA oligonucleotide with a thiazole orange (TO) dimer unit. They belong to ECHO (exciton-controlled hybridization-sensitive fluorescent oligonucleotide) probes which we have previously reported. The excitonic interaction between the two TO molecules was expected to effectively suppress the background fluorescence of the probes. The applicability of the ECHO probes for the detection of double-stranded DNA was confirmed by examining the thermal stability and photophysical and kinetic properties of the DNA triplexes formed by the ECHO probes. PMID- 23445824 TI - Sexual stability in the nearly dioecious Pinus johannis (Pinaceae). AB - PREMISE OF THE STUDY: Even though dioecy is a dominant sexual system among gymnosperms, little is known about its evolutionary history. Pinus johannis may represent a model system because unisexual and monoecious individuals compose its populations. The presence of unisexual individuals in other Pinus species is a consequence of sexual lability. Here we determined whether P. johannis represents the first example of a dioecious or nearly dioecious reproductive system in conifers by evaluating its sexual stability. * METHODS: To assess the stability of sexual expression, we quantified the proportion of male vs. female reproductive structures produced by trees over multiple years and tested for the presence of sexual dimorphism. Sexual lability hypotheses were also examined by looking at the relationship between environmental factors and sexual expression and by comparing the reproductive behavior of P. johannis with its closest labile relative, P. edulis. * KEY RESULTS: Pinus johannis is nearly dioecious: ~99% of individuals are unisexual or express a low proportion of the opposite gender with few changes in sexual expression through time. We found sexual dimorphism consistent with sexual stability. Sexual expression did not vary with tree size/age, abiotic environment, or herbivore removal, providing evidence against sexual lability. Individuals of P. johannis tended to produce only male or female strobili, whereas those of P. edulis were mainly monoecious with a gradient in the female to male strobili ratio. * CONCLUSIONS: This study represents the first report of a nearly stable dioecious Pinus species. The variety of sexual morphs coexisting in the same population makes P. johannis a model for studying the evolution of dioecy in gymnosperms. PMID- 23445825 TI - Emasculation increases seed set in the bird-pollinated hermaphrodite Kniphofia linearifolia (Xanthorrhoeaceae): evidence for sexual conflict? AB - PREMISE OF THE STUDY: Hermaphroditism in plants can lead to gender conflicts, such as pollen discounting-the loss of siring opportunities following self pollination, and ovule discounting-the loss of seed production opportunities when self-pollen tubes disable ovules through early inbreeding depression or late acting self-incompatibility. If ovules are discounted by self-pollination, it can be predicted that emasculation (removal of self-pollen) should increase seed production, as long as pollinators are not deterred by emasculation. * METHODS: Using the hermaphroditic Kniphofia linearifolia, which belongs to a lineage known to possess late-acting self-incompatibility, we performed hand-pollinations with either self- or cross-pollen and recorded pollen tube growth and seed production. We paired experimentally emasculated plants with non-emasculated controls and quantified pollinator visitation rates, fruit, and seed set in both groups. * KEY RESULTS: Ovules penetrated by tubes from self-pollen uniformly failed to develop into seeds, as expected from ovarian self-incompatibility (or strong early inbreeding depression). Experimental emasculation had no effect on the rate of visitation by birds, the primary pollinators of this species, but led to increased rejection by bees, which are secondary pollinators. Despite reducing visitation by some pollinators, emasculation led to increased seed production and reduced rates of seed abortion. * CONCLUSIONS: These results show that female performance in hermaphroditic flowers can be enhanced when flowers are emasculated, even if the overall number of pollinator visits is decreased. The most likely explanation for this effect of emasculation is that it reduces ovule discounting arising from pollinator-mediated self-pollination. PMID- 23445826 TI - Modified leaves with disk-shaped nectaries of Macaranga sinensis (Euphorbiaceae) provide reward for pollinators. AB - PREMISE OF THE STUDY: Nectar is the most common reward provided by animal pollinated flowers. Diversity in position and structure of floral nectaries suggests that floral nectar production evolved repeatedly, but the evolutionary origins are not well known. Flowers of the genus Macaranga (Euphorbiaceae) are apetalous and lack floral nectar. Nevertheless, many Macaranga species possess disk-shaped nectaries on their leaves, sought by ants that defend plants from herbivory. In some Macaranga species, similar glands also occur on the bracteoles modified leaves subtending the flowers. We investigated whether these glands on the bracteoles of M. sinensis are involved in pollination. * METHODS: Flower visitors were captured, and body pollen was examined. The behavior of flower visitors on inflorescences was also observed. Sugar composition of the nectar from bracteoles and leaves was collected and analyzed using high-performance liquid chromatography. * KEY RESULTS: Various bees and flies with body pollen visited both male and female inflorescences, feeding on nectar from the bracteoles and touching anthers and stigmas in the process. Sugar composition of nectar from the bracteoles and the leaves did not differ. * CONCLUSIONS: Macaranga sinensis was pollinated by insects foraging on the disk-shaped nectaries on bracteoles. The similar appearance, position, and sugar composition of nectar suggest that disk-shaped nectaries on bracteoles and leaves are homologous and that nectaries on leaves were recruited to inflorescences to serve floral function in M. sinensis. Having protective mutualism with ants has likely opened an unusual route for the evolution of floral nectar in otherwise non nectar-producing flowers of M. sinensis. PMID- 23445827 TI - Inbreeding depression and partitioning of genetic load in the invasive biennial Alliaria petiolata (Brassicaceae). AB - PREMISE OF THE STUDY: Invasive species are nonnative species that enter novel environments, establish sustained populations, and can negatively impact native species. Here we assess a potential weakness of invasive species (genetic load) and show how species might overcome genetic barriers. Colonization of novel habitats by invasive species typically involves few individuals, exposing populations to founder effects. We empirically tested a central Illinois population of an invasive biennial plant, Alliaria petiolata, for evidence of a founder effect by assessing the pattern of genetic load. * METHODS: To estimate genetic load, we assayed offspring from three cross types (self-pollinated, outcrossed within- and between-populations) in a greenhouse. Vegetative and reproductive traits were measured on first-year plants grown with or without intraspecific competition. * KEY RESULTS: We found substantial genetic load in this population of A. petiolata, which can mostly be attributed to genetic drift (founder effect) and not inbreeding depression. Between-population heterosis was expressed more than inbreeding depression under intraspecific competition. * CONCLUSIONS: Inbreeding may be adaptive for A. petiolata in its introduced range by providing reproductive assurance, with limited inbreeding load. Nevertheless, most of the genetic load in this population of A. petiolata is due to fixation of deleterious alleles. Drift load is expected, given that this population is near the edge of its continuous geographic range in highly fragmented habitats, and gene flow between isolated populations is likely highly limited. Preventing additional introduction and movement of propagules between isolated local populations should reduce heterosis and A. petiolata competitiveness. PMID- 23445828 TI - Winged fruits and associated leaves of Shorea (Dipterocarpaceae) from the Late Eocene of South China and their phytogeographic and paleoclimatic implications. AB - PREMISE OF THE STUDY: Dipterocarps are the representative component of tropical rain forests in Southeast Asia and hold important economic and ecological significance, but their origin and migration are controversial. Information on dipterocarpaceous fossils, particularly the more convincing reproductive structures, not only can improve the phylogenetic and phytogeographic studies of this family, but also provide important information for reconstructing paleoclimate. * METHODS: Morphologically preserved winged fruits and associated leaves were collected from the Late Eocene Huangniuling Formation, Maoming Basin, South China. We determined their taxonomic positions based on comparative morphology with similar extant and fossil specimens and discuss their phytogeographic and paleoclimatic implications by consulting the distribution and habitat of fossil and modern populations. * KEY RESULTS: The Late Eocene winged fruits are attributed to Shorea Roxburgh ex Gaertner (Dipterocarpaceae) as Shorea maomingensis sp. nov. The associated leaves are recognized as Shorea sp. based on leaf architecture, and they are likely to be conspecific with the winged fruits. * CONCLUSIONS: The discovery of dipterocarps indicates that they had arrived in tropical and humid South China by the Late Eocene. Dipterocarps including Shorea exhibit a wide range of physiological tolerance to climate; palynological analysis suggests an increase in aridity and seasonality in the Maoming Basin from the Late Eocene. Dipterocarps became adapted to this seasonal climate from the Late Eocene to Early Miocene, expanded northward in the climatic optimum of the Middle Miocene, and declined and gradually disappeared from the southeastern part of the continent from the Late Miocene. PMID- 23445829 TI - Variation in presentation and presence of DNA adducts and p53 mutations in patients with endemic nephropathy--an environmental form of the aristolochic acid nephropathy. AB - BACKGROUND: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. METHODS: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL) DNA adducts were performed. RESULTS: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T-> T:A transversion) were found in tissues of cases 1 and 2. CONCLUSION: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms. PMID- 23445830 TI - Comparing CenteringPregnancy(r) to standard prenatal care plus prenatal education. AB - BACKGROUND: There is significant evidence to support the importance of prenatal care in preventing adverse outcomes such as preterm birth and low infant birth weight. Previous studies have indicated that the benefits of prenatal care are not evenly distributed throughout the social strata. In addition, emerging evidence suggests that among particular populations, rates of preterm birth are unchanged or increasing. This suggests that an alternate care model is necessary, one that seeks to addresses some of the myriad of social factors that also contribute to adverse birth outcomes. In previous studies, the group prenatal care model CenteringPregnancy(r) had been shown to reduce adverse birth outcomes, but to date, no comparison had been made with a model that included prenatal education. This study sought to investigate whether any significant difference remained within the comparison groups when both models accounted for social factors. METHODS: This analysis was based on survey data collected from a prospective cohort of pregnant women through the All Our Babies Study in Calgary, Alberta. RESULTS: At baseline, there were significant differences between the comparison groups in their psychosocial health, with the women in the CenteringPregnancy(r) group scoring higher levels of depressive symptoms, stress and anxiety. At four months postpartum, the differences between the groups were no longer significant. CONCLUSIONS: These results suggest that CenteringPregnancy(r) can recruit and retain a demographically vulnerable group of women with a constellation of risk factors for poor pregnancy and birth outcomes, including poverty, language barriers and poor mental health. Post program, the rates of stress, anxiety and depression were similar to other women with more social and financial advantage. These findings suggest that CenteringPregnancy(r) may be a community based care strategy that contributes to improved mental health, knowledge, and behaviours to optimize outcomes for mothers and children. PMID- 23445831 TI - Comparison of left ventricular geometry after HeartMate II and HeartWare left ventricular assist device implantation. AB - BACKGROUND: HeartMate II (HM II) and HeartWare (HW) Left Ventricular Assist Devices have been successfully used in end-stage heart failure patients as a bridge to transplantation, recovery, or decision. We set out to compare their effect in off-loading the left ventricle and its geometry. METHODS: The left ventricular end diastolic (LVEDD) and end systolic (LVESD) diameters were compared between first time HM II (n = 25) and HW implantations (n = 24) before and after the operation at 1, 3, and 6 months. A p value of less than 0.05 was considered as significant. RESULTS: Post-operative LVEDD and LVESD at 1, 3, and 6 months were significantly reduced in comparison with pre-operative values in both HM II and HW groups. No significant difference was found comparing HM II and HW groups together before and after the operation. CONCLUSIONS: Our study shows that both HM II and HW can significantly reduce the left ventricular systolic and diastolic dimensions and off-load the left ventricle. The miniaturized nature of HW does not affect its performance and it could be as effective as HM II. PMID- 23445832 TI - A quantitative study of the influence of inhaled compounds on their concentrations in exhaled breath. AB - Throughout the development of breath analysis research, there has been interest in how the concentrations of trace compounds in exhaled breath are related to their concentrations in the ambient inhaled air. In considering this, Phillips introduced the concept of 'alveolar gradient' and judged that the measured exhaled concentrations of volatile organic compounds should be diminished by an amount equal to their concentrations in the inhaled ambient air. The objective of the work described in this paper was to investigate this relationship quantitatively. Thus, experiments have been carried out in which inhaled air was polluted by seven compounds of interest in breath research, as given below, and exhaled breath has been analysed by SIFT-MS as the concentrations of these compounds in the inhaled air were reduced. The interesting result obtained is that all the exogenous compounds are partially retained in the exhaled breath and there are close linear relationships between the exhaled and inhaled air concentrations for all seven compounds. Thus, retention coefficients, a, have been derived for the following compounds: pentane, 0.76 +/- 0.09; isoprene, 0.66 +/- 0.04; acetone, 0.17 +/- 0.03; ammonia, 0.70 +/- 0.13, methanol, 0.29 +/- 0.02; formaldehyde, 0.06 +/- 0.03; deuterated water (HDO), 0.09 +/- 0.02. From these data, correction to breath analyses for inhaled concentration can be described by coefficients specific to each compound, which can be close to 1 for hydrocarbons, as applied by Phillips, or around 0.1, meaning that inhaled concentrations of such compounds can essentially be neglected. A further deduction from the experimental data is that under conditions of the inhalation of clean air, the measured exhaled breath concentrations of those compounds should be increased by a factor of 1/(1 - a) to correspond to gaseous equilibrium with the compounds dissolved in the mixed venous blood entering the alveoli. Thus, for isoprene, this is a factor of 3, which we have confirmed experimentally by re-breathing experiments. PMID- 23445833 TI - Increased risk for Campylobacter jejuni and C. coli infection of pet origin in dog owners and evidence for genetic association between strains causing infection in humans and their pets. AB - We compared Campylobacter jejuni/coli multilocus sequence types (STs) from pets (dogs/cats) and their owners and investigated risk factors for pet-associated human campylobacteriosis using a combined source-attribution and case-control analysis. In total, 132/687 pet stools were Campylobacter-positive, resulting in 499 strains isolated (320 C. upsaliensis/helveticus, 100 C. jejuni, 33 C. hyointestinalis/fetus, 10 C. lari, 4 C. coli, 32 unidentified). There were 737 human and 104 pet C. jejuni/coli strains assigned to 154 and 49 STs, respectively. Dog, particularly puppy, owners were at increased risk of infection with pet-associated STs. In 2/68 cases vs. 0.134/68 expected by chance, a pet and its owner were infected with an identical ST (ST45, ST658). Although common sources of infection and directionality of transmission between pets and humans were unknown, dog ownership significantly increased the risk for pet-associated human C. jejuni/coli infection and isolation of identical strains in humans and their pets occurred significantly more often than expected. PMID- 23445834 TI - Establishing a Southern Swedish Malignant Melanoma OMICS and biobank clinical capability. AB - BACKGROUND: The objectives and goals of the Southern Swedish Malignant Melanoma (SSMM) are to develop, build and utilize cutting edge biobanks and OMICS platforms to better understand disease pathology and drug mechanisms. The SSMM research team is a truly cross-functional group with members from oncology, surgery, bioinformatics, proteomics, and genomics initiatives. Within the research team there are members who daily diagnose patients with suspect melanomas, do follow-ups on malignant melanoma patients and remove primary or metastatic lesions by surgery. This inter-disciplinary clinical patient care ensures a competence build as well as a best practice procedure where the patient benefits. METHODS: Clinical materials from patients before, during and after treatments with clinical end points are being collected. Tissue samples as well as bio-fluid samples such as blood fractions, plasma, serum and whole blood will be archived in 384-high density sample tube formats. Standardized approaches for patient selections, patient sampling, sample-processing and analysis platforms with dedicated protein assays and genomics platforms that will hold value for the research community are used. The patient biobank archives are fully automated with novel ultralow temperature biobank storage units and used as clinical resources. RESULTS: An IT-infrastructure using a laboratory information management system (LIMS) has been established, that is the key interface for the research teams in order to share and explore data generated within the project. The cross-site data repository in Lund forms the basis for sample processing, together with biological samples in southern Sweden, including blood fractions and tumor tissues. Clinical registries are associated with the biobank materials, including pathology reports on disease diagnosis on the malignant melanoma (MM) patients. CONCLUSIONS: We provide data on the developments of protein profiling and targeted protein assays on isolated melanoma tumors, as well as reference blood standards that is used by the team members in the respective laboratories. These pilot data show biobank access and feasibility of performing quantitative proteomics in MM biobank repositories collected in southern Sweden. The scientific outcomes further strengthen the build of healthcare benefit in the complex challenges of malignant melanoma pathophysiology that is addressed by the novel personalized medicines entering the market. PMID- 23445835 TI - Open questions: what is there left for cell biologists to do? PMID- 23445836 TI - Unusual presentation and treatment of biliary ileus with long term follow up: case report and review of the literature. AB - Gallstone ileus is a rare complication of cholelithiasis. It accounts for 25% of nonstrangulated small bowel obstructions in patients over the age of 65 years. The morbidity and mortality rate of gallstone ileus remains very high, partly because of misdiagnosis or delayed diagnosis. The two surgical options are: a) enterolithotomy with removal of impacted stone, cholecystectomy, and fistula repair at the same surgical operation (i.e., "one-stage" procedure) and b) enterolithotomy with stone extraction followed or not by elective biliary surgery. The latter is the most popular surgical approach, whereas enterolithotomy combined with cholecistectomy and fistulectomy is indicated only in selected cases. In this article, a case of biliary ileus with unusual presentation treated by entherolithotomy alone with long term follow up is described, and the literature on this subject is reviewed and discussed. PMID- 23445837 TI - Necrotizing soft tissue infections (NSTIs): literary review and description of a Fournier syndrome case. AB - A 62 y.o. male with tight fimosis, swelling, redness, pain on palpating and necrosis of the penis and scrotum was admitted in our clinic, (FGSI = 6) with periferic vasculopathy; and diabetes mellitus type II and he was in dialysis treatment before the hospitalization. The patient was HCV affected. In 24 hours he underwent radical surgical debridement with excision of all necrotic material from penis and scrotum up to the subdermal layer and tissue of doubtful viability for about 75% of the skin and circumcision. In third, fifth and seventh postoperative days he underwent to local infusion of autologous PLT growth factors. The patient was discharged in 9th postoperative day and FGSI was still 6; the skin and subdermal tissue was barely reskined, with low homogeneous granulation, edema was heavely reduced. In our case, deviation from homeostasis status at admission was the main worrying factor. We found that diabetes mellitus and renal dysfunction at admission was also important risk factor for FG. "E.Coli" was the most common organism isolated from patient wound cultures. The FGSI is an objective and easy to apply score method to quantify the metabolic status and can be used to evaluate therapeutic options and assess results. PMID- 23445838 TI - Evaluation of inflammatory markers after orthopedic surgical intervention in children. AB - OBJECTIVE: The study aim was to evaluate inflammation markers values (C-reactive protein (CRP), Erythrocite sedimentation (ES), White blood cells count (WBC)) in surgically treated pediatric patients with diagnosed developmental displasia of the hip or Perthes disease before and after operation. METHODS: We have evaluated 43 children (20 patients were with diagnosed unilateral developmental displasia of the hip while 23 had Perthes disease). Blood samples were drown at the admission and 5 days after admission, and further inflammatory parameters were analyzed: ES (mm/hour), CRP (mg/L) and WBC (x1000/mm3) count. RESULTS: Elevated erythrocite sedimentation (ESR) was significantly frequent than elevated CRP (p<0.01) and elevated WBC as well (p<0.01). Values of ESR and WBC do not correlate closely with age (FESR= 1.805; FWBC= 0.130; p>0.05) while CRP values correlate significantly with the age of the patients (FCRP= 4.948; p<0.05). The most frequently isolated marker was ESR (34.88%). The most frequent elevated two markers were ESR and CRP (44.19%). CONCLUSION: Surgical procedure could alter the values of inflammatory markers leading to the increasement even though there is no other clinical signs of infection. For estimation of the possible presence of the infection, clinical signs and patients intensive clinical follow-up after the surgery, should be done along with the evaluation of inflammatory markers. PMID- 23445839 TI - Introduction to the symposium on nutrition of the preterm infant. PMID- 23445840 TI - Feeding the preterm infant: opportunities and challenges of bringing science to the bedside. AB - Designing an optimal feeding program for preterm infants is particularly challenging. These infants require individualized feeding plans and frequent medical interventions, and their health status and physical limitations necessitate specialized products. This review highlights the challenges of translating new understandings into practical application and, specifically, the challenges of translating scientific knowledge into available nutritional products that can be used to meet the special needs of preterm infants. All infant formula products are developed for use in a heavily regulated environment, which is not integrated internationally. The regulatory framework for preterm nutrition products can be particularly complex in the areas of composition and the degree of scientific and clinical support required across countries. Registration and approval of products for preterm infants in most countries must address the complexities for a population for which no well-recognized nonclinical safety or efficacy models exist. Mandatory regulatory review for science-based innovative product improvements may require two or more years. In addition, throughout years of development, industry must justify the financial support of programs that serve a small specialty segment of the market. These industry-specific challenges may be neither visible nor appreciated by the general public or health care professionals, and, yet, they are integral to the development process. Effective collaborations among academic scientists, regulatory authorities, and the industry are essential to bring science to the bedside. Without such collaborations, preterm infants, and particularly very low birth weight infants, in the neonatal intensive care unit will not be able to benefit from innovative nutrition interventions designed to improve short- and long-term clinical outcomes. PMID- 23445841 TI - Nutritional management of the low birth weight/preterm infant in community settings: a perspective from the developing world. AB - Globally, about 20 million infants are born with low birth weight (LBW; <2500 g). Of all LBW infants, approximately 95% are born in developing countries. The greatest incidence of LBW occurs in South-Central Asia; the second greatest is in Africa. The two main reasons for LBW are preterm birth (<37 weeks) and intrauterine growth restriction (IUGR), which are risk factors for increased morbidity and mortality in newborn infants. Maternal nutrition status is one of the most important risk factors for LBW/IUGR. Providing balanced protein energy and multiple micronutrient supplements to pregnant women will reduce incidence of IUGR. Calcium supplementation during pregnancy will reduce the incidence of pre eclampsia and preterm birth in developing countries. Exclusive breastfeeding is protective for a mother and her infant and has been shown to reduce morbidity and mortality in infancy. Kangaroo mother care for preterm infants will reduce severe morbidity and mortality as well. Community-based intervention packages are among the most effective methods of reducing morbidity and mortality in mothers and children. Future research should focus on improving triage of preterm and IUGR infants. Exclusive breastfeeding should be promoted, and appropriate alternative food supplements should be provided when breastfeeding is not possible. PMID- 23445842 TI - Symposium summary: looking back and looking forward. PMID- 23445843 TI - Human milk and the nutritional needs of preterm infants. AB - Key principles underpinning feeding guidelines for preterm infants include support for developmental care, breastfeeding, milk expression, and creating feeding plans. Early trophic feeding with colostrum and transitional milk improves immune protection and promotes gut maturation. Studies of preterm infants demonstrate that feeding mother's milk (MM) decreases the incidence of infection and necrotizing enterocolitis and improves neurodevelopmental outcome but may decrease ponderal and linear growth. Standard practice in neonatal units is to promote mother's own milk as the feed of choice for all infants. However, it is not feasible or prudent to do so for all preterm infants. Mothers of preterm infants have lower rates of successful breastfeeding compared with those of term infants. MM can contain harmful bacterial or viral pathogens. Although preterm human milk (HM) contains higher concentrations of protein, sodium, zinc, and calcium than mature HM, it falls short of supplying adequate quantities of nutrients required by preterm infants. Therefore, HM supplemented with nutrients is recommended for all infants born before 32 weeks gestation and for certain infants born at 32-36 weeks of gestation. HM is the preferred feed, but preterm formula is an appropriate option when there is an inadequate supply of MM. PMID- 23445844 TI - Growth curves: how to best measure growth of the preterm infant. AB - Birth weight is one of the most important anthropometric measures in the evaluation of an infant. For the full-term infant, birth weight is compared with reference or standard growth curves that are constructed by plotting weight, length, and head circumference against postnatal age. Following a similar approach for preterm infants is less effective for a variety of reasons. Birth weight and other anthropometric measures used to evaluate an infant at birth are influenced by various maternal characteristics, the intrauterine milieu, and duration of gestation. Second, the causes of premature birth and their impact on birth weight are largely unknown. Third, gestational age is difficult to determine with full certainty. One approach that has been used to circumvent these issues is to use intrauterine growth reference curves. However, these curves do not really reflect "normal" growth because they were constructed using cross-sectional data from infants born prematurely and, as such, do not reflect the normal condition. Thus, there is a need to develop normative growth curves derived from "healthy" preterm infants that can be applied to neonates born prematurely. These should be updated periodically to reflect secular trends in maternal body weight, height, and overall health. PMID- 23445845 TI - Vitamin D, vitamin A, maternal-perinatal considerations: old concepts, new insights, new questions. AB - Vitamins A and D are essential nutrients that play important roles in growth and development. Preterm and low birth weight infants have low levels of these nutrients and are at risk for developing detrimental health consequences associated with vitamin A and vitamin D deficiencies. Preliminary data suggest that vitamin A and D supplementation is needed to prevent deficiency. More work is needed to define optimal doses, timing, and modes of administration to ensure that an adequate supply of these vitamins is available to meet the critical needs during pregnancy and in high-risk neonates. PMID- 23445846 TI - Evaluation of adequacy of protein and energy. AB - Growth assessment is the most common measure of nutritional adequacy in pediatrics, especially when evaluating nutrition of preterm neonates. The American Academy of Pediatrics defines postnatal nutrient intake to promote growth as one that "approximates the rate of growth...for a normal fetus of the same post-menstrual age." It is known that in the fetus, fat and lean body mass are accreted progressively as gestation progresses, whereas postnatal growth and observed accretion of fat and lean body mass differ. This review discusses anthropometric measures used to assess growth, biochemical markers used to monitor nutritional sufficiency, and the effect of growth trajectory in preterm infants on health outcomes later in life. PMID- 23445847 TI - Lipid needs of preterm infants: updated recommendations. AB - Long-chain polyunsaturated fatty acids (LCPUFAs) are of nutritional interest because they are crucial for normal development of the central nervous system and have potential long-lasting effects that extend beyond the period of dietary insufficiency. Here we review the recent literature and current recommendations regarding LCPUFAs as they pertain to preterm infant nutrition. In particular, findings that relate to fetal accretion, LCPUFA absorption and metabolism, effects on development, and current practices and recommendations have been used to update recommendations for health care providers. The amounts of long-chain polyunsaturated fatty acids (LCPUFAs) used in early studies were chosen to produce the same concentrations as in term breast milk. This might not be a wise approach for preterm infants, however, particularly for very and extremely preterm infants, whose requirements for LCPUFAs and other nutrients exceed what is normally provided in the small volumes that they are able to tolerate. Recent studies have reported outcome data in preterm infants fed milk with a docosahexaenoic acid (DHA) content 2-3 times higher than the current concentration in infant formulas. Overall, these studies show that providing larger amounts of DHA supplements, especially to the smallest infants, is associated with better neurologic outcomes in early life. We emphasize that current nutritional management might not provide sufficient amounts of preformed DHA during the parenteral and enteral nutrition periods and in very preterm/very low birth weight infants until their due date, and that greater amounts than used routinely likely will be needed to compensate for intestinal malabsorption, DHA oxidation, and early deficit. Research should continue to address the gaps in knowledge and further refine adequate intake for each group of preterm infants. PMID- 23445848 TI - Selected macro/micronutrient needs of the routine preterm infant. AB - Requirements for optimal nutrition, especially for micronutrients, are not well defined for premature infants. The "reference fetus," developed by Ziegler et al,(1) has served as a model to define nutritional needs and studies designed to determine nutrient requirements. Revision of nutrient requirements and provision of optimal nutrition may lead to improved outcomes in preterm infants. Appropriate provision of nutrients also may help prevent nutritional disorders, such as metabolic bone disease and anemia. In this review, we discuss calcium, phosphorus, magnesium, vitamin D, iron, and copper, and define optimal intakes based on the available published data. PMID- 23445849 TI - Intestinal mucosal defense system, Part 1. Consensus recommendations for immunonutrients. AB - When microbial communities colonize in the developing intestinal tract after birth, microorganisms interact with specific apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inflammatory cytokines, thus providing protection from pathogen-induced mucosal damage. Multiple immune modulatory factors in human milk and innate humoral factors also control inflammatory responses, providing additional protective effects. Our understanding of the role of the luminal microbial communities or microbiota is growing rapidly as novel technologies provide new insights into their taxonomy, function during early development, and impact on life-long health. Multiple studies have evaluated the effects of the specific nutrients, glutamine, arginine, nucleotides, polyunsaturated fatty acids, and lactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to modulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is yet known to design specific clinical care practices that support a healthy microbiota. PMID- 23445850 TI - Intestinal mucosal defense system, Part 2. Probiotics and prebiotics. AB - The interplay between microorganisms and the intestine of newborn infants is associated with diverse functional and clinical outcomes that result from the specific interactions among microbial communities, their products, and the unique characteristics of the gastrointestinal tract. Multiple mechanisms of action for infant formula ingredients with probiotic activity appear to exist. These mechanisms are thought to protect the host not only from intestinal diseases but also from systemic infection. However, questions about the safety of probiotics for preterm infants remain unanswered, particularly with regard to sepsis, immunomodulatory effects, and microbial resistance. Few well-designed studies have been conducted to evaluate the effects of probiotic, prebiotic, and synbiotic ingredients on relevant clinical outcomes in preterm infants. Although existing data are encouraging, there is insufficient evidence to recommend the routine use of these ingredients in all preterm infants. PMID- 23445851 TI - Feeding preterm infants today for later metabolic and cardiovascular outcomes. AB - Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known whether the influence of infant and childhood growth rates and early nutrition on long-term outcomes is the same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic outcomes in preterm infants. Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of development have significant adverse effects on later development. Our review suggests that growth between birth and expected term and 12-18 months post term has no significant effect on later blood pressure and metabolic syndrome, whereas reduced growth during hospitalization significantly impacts later neurodevelopment. In contrast, growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular well being, which suggests that nutritional interventions during this period are worthy of more study. Our review also highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hospitalization and after discharge on development, the risk of developing hypertension, or insulin resistance. PMID- 23445852 TI - Nutritional needs of the micropreterm infant. AB - We have used an expansive definition of a micropreterm infant as <30 weeks' gestation to provide a global perspective to a "high risk" group of preterm infants for which there are little published data to guide nutritional management. Consensus nutritional guidelines for preterm infants have been developed for infants >1000 g birth weight and >28 weeks' gestational age. Micropreterm infants have greater nutritional deficits at birth than more mature preterm infants and accumulate greater postnatal deficits. Nutritional guidelines based on the needs of preterm infants born >28 weeks' gestation are unlikely, on a theoretical basis, to meet nutritional requirements of micropreterm infants. Unfortunately, very few good quality studies have addressed the nutritional requirements of this group specifically; this makes it difficult to formulate solid, evidence-based nutritional recommendations for these neonates. Nutritional management of micropreterm infants is based on recommendations established for preterm infants, which are adjusted after considering an infant's gestational age, birth weight, and clinical status. Minimal enteral feeding should commence on the first or second day of life, with incremental advancement and fortification of human milk when 100 mL/kg is tolerated. Early use of parenteral nutrition is recommended, ideally initiated within the first hours of life and enteral feeds are being established; this will help prevent the accumulation of nutritional deficits and incidence of growth failure. Fortified human milk should be given in order to meet nutritional requirements. When human milk is not available in sufficient quantity, a preterm formula should be given. PMID- 23445853 TI - Nutritional requirements and feeding recommendations for small for gestational age infants. AB - We define the small for gestational age (SGA) infant as an infant born >= 35 weeks' gestation and <10th percentile on the Fenton Growth Chart. Policy statements from many organizations recommend mother's own milk for SGA infants because it meets most of their nutritional requirements and provides short- and long-term benefits. Several distinct patterns of intrauterine growth restriction are identified among the heterogeneous grouping of SGA infants; each varies with regard to neonatal morbidities, requirements for neonatal management, postnatal growth velocities, neurodevelopmental progress, and adult health outcomes. There is much we do not know about nutritional management of the SGA infant. We need to identify and define: infants who have "true" growth restriction and are at high risk for adverse metabolic outcomes in later life; optimal growth velocity and "catch-up" growth rates that are conducive with life-long health and well being; global approaches to management of hypoglycemia; and an optimal model for postdischarge care. Large, rigorously conducted trials are required to determine whether aggressive feeding of SGA infants results in improved nutritional rehabilitation, growth, and neurodevelopmental outcomes. Before birth, maternal supplementation with specific nutrients reduces the rate and severity of growth restriction and may prevent nutrient deficiency states if infants are born SGA. After birth, the generally accepted goal is to provide enough nutrients to achieve postnatal growth similar to that of a normal fetus. In addition, we recommend SGA infants be allowed to "room in" with their mothers to promote breastfeeding, mother-infant attachment, and skin-to-skin contact to assist with thermoregulation. PMID- 23445854 TI - Nutritional recommendations for the late-preterm infant and the preterm infant after hospital discharge. AB - Early nutritional support of preterm infants is critical to life-long health and well being. Numerous studies have demonstrated that preterm infants are at increased risk of mortality and morbidity, including disturbances in brain development. To date, much attention has focused on enhancing the nutritional support of very low and extremely low birth weight infants to improve survival and quality of life. In most countries, preterm infants are sent home before their expected date of term birth for economic or other reasons. It is debatable whether these newborns require special nutritional regimens or discharge formulas. Furthermore, guidelines that specify how to feed very preterm infants after hospital discharge are scarce and conflicting. On the other hand, the late preterm infant presents a challenge to health care providers immediately after birth when decisions must be made about how and where to care for these newborns. Considering these infants as well babies may place them at a disadvantage. Late preterm infants have unique and often-unrecognized medical vulnerabilities and nutritional needs that predispose them to greater rates of morbidity and hospital readmissions. Poor or inadequate feeding during hospitalization may be one of the main reasons why late-preterm infants have difficulty gaining weight right after birth. Providing optimal nutritional support to late premature infants may improve survival and quality of life as it does for very preterm infants. In this work, we present a review of the literature and provide separate recommendations for the care and feeding of late-preterm infants and very preterm infants after discharge. We identify gaps in current knowledge as well as priorities for future research. PMID- 23445855 TI - Sports activity after total joint arthroplasty: recommendations for the counseling physician. AB - Sports activity after total joint arthroplasty (TJA) has become an increasingly important topic, as many younger patients seeking TJA have higher postoperative expectations with regard to return to athletic activity. Our current knowledge of this area is largely based on retrospective clinical studies and surveys of surgeon recommendations. The decision to participate in sports after TJA depends on the patient's general health, prior athletic experience, type of TJA, and desired sporting activity. Ultimately, patients should discuss these factors with their physician in order to make an educated decision regarding sports activity after TJA. This article summarizes the best available evidence to help guide physicians in their conversation with patients regarding safe and appropriate sports activity after TJA. PMID- 23445856 TI - Arthroscopic rotator cuff repair: impact of diabetes mellitus on patient outcomes. AB - INTRODUCTION: Arthroscopic repair of rotator cuff tears has been associated with satisfactory improvement in pain and function. The goal of this study was to compare the results of patients with diabetes and patients without diabetes after the 2 cohorts underwent arthroscopic rotator cuff repair (RCR). METHODS: We performed a retrospective review of 56 patients with type 1 diabetes mellitus or type 2 diabetes mellitus and 67 patients without diabetes, all of whom underwent arthroscopic RCR with 1 year of follow-up. Changes in range of motion (ROM), American Shoulder and Elbow Surgeons (ASES) score, and Penn Shoulder Score (PSS) were compared between both groups at 1 year postoperatively. RESULTS: There was a statistically significant improvement in ROM for both groups. However, patients without diabetes had greater forward flexion (P = 0.02), abduction (P = 0.04), and external rotation (P = 0.004). Both groups noted significant improvement in their respective ASES score and PSS. However, patients with diabetes had a lower ASES score (P < 0.01) and PSS (P < 0.01). There were no differences in recurrent tears or complications. CONCLUSION: Arthroscopic RCR in patients with diabetes resulted in improved postoperative ROM and function. PMID- 23445857 TI - Anterior cruciate ligament reconstruction in patients aged > 40 years: a case control study. AB - PURPOSE: To determine the outcomes of isolated anterior cruciate ligament (ACL) reconstruction in physically active patients aged > 40 years, and to compare these results with those of a younger patient cohort who underwent the same procedure. METHODS: A retrospective review was performed on all patients aged > 40 years who underwent ACL reconstruction between 2000 and 2008. A consecutive series of patients aged <= 25 years who underwent the same procedure during this same time period were selected as a control group. Age, sex, graft type, concomitant injuries, complications, and a validated outcome measure (Lysholm Knee Scoring Scale) were assessed at final follow-up. RESULTS: Forty-six patients (average age, 44.9 years; 28 men, 18 women) in the older group were identified and compared with 48 patients (average age, 21 years; 23 men, 25 women) in the younger group, with an average follow-up period of 5.4 and 5.1 years, respectively. There was no statistically significant difference between the groups in terms of associated injuries. The older group had a higher degree of cartilage degeneration (P = 0.0001). Lysholm scores averaged 90.3 in the older cohort compared with 88.7 in the younger cohort, with no statistical difference between groups. CONCLUSION: The older patients had outcomes comparable with the younger patients. Age alone should not exclude ACL-deficient patients from undergoing reconstructive surgery. PMID- 23445859 TI - Shoulder and elbow arthroplasty in younger patients. AB - Joint arthroplasty is common in elderly patients with arthritis. The success of joint arthroplasty in the elderly population has increased the indications for joint arthroplasty in younger patients. The success and increased indications are due to advances in technology and joint arthroplasty design and materials, as well as to bone-conserving approaches that are more applicable to younger patients. Although most joint arthroplasty procedures are for the hip and knee, the upper extremity (shoulder and elbow) is the fastest-growing segment of joint arthroplasty procedures. This article presents innovative approaches to shoulder and elbow arthroplasty that are designed to treat younger patients with arthritis of the shoulder and elbow. PMID- 23445858 TI - Current recommendations for anterior cruciate ligament bracing: when to use. AB - Braces are often used during various stages of recovery from an anterior cruciate ligament tear despite there being sparse definitive research supporting their use. This article reviews the literature on brace use for patients with anterior cruciate ligament tears in order to provide a guide for clinicians. There is evidence to support immediate postoperative bracing, with the goals of maintaining full extension and decreasing effusion. There may be a psychological benefit for its use in return to sport; however, this should be weighed against decreased performance. In the context of modern graft-fixation techniques and early mobilization protocols, empiric functional brace prescription is not required for successful long-term clinical outcomes and return to sport. PMID- 23445860 TI - Exercise for patients with COPD: an integral yet underutilized intervention. AB - Chronic obstructive pulmonary disease (COPD) was the third leading cause of mortality in the United States in 2009 and accounts for millions of dollars in health care expenses annually. It is characterized by slow declines in functional ability and exercise tolerance, which are strongly predictive of poor health related quality of life and survival. The cycle of physical, social, and psychosocial consequences of COPD is more easily prevented than remedied; therefore, maintaining baseline respiratory function is a key goal of early treatment. Although medical management of COPD is generally well understood and implemented by most primary care physicians, multidisciplinary approaches that include nonpharmacologic modalities (eg, exercise training) are not often used. Exercise training can alleviate dyspnea and improve exercise tolerance and health related quality of life in patients with mild-to-severe COPD. Pulmonary rehabilitation, which includes exercise training, nutritional and psychological counseling, and patient education, is an important component of COPD treatment and management programs, and is currently underutilized in the United States. This article addresses the role of exercise as part of a multidisciplinary approach to the management of COPD, especially with regard to pulmonary rehabilitation. PMID- 23445861 TI - Evidence for determining the exercise prescription in patients with osteoarthritis. AB - Osteoarthritis (OA) is a chronic joint disease that affects more than one-third of older adults (age > 65 years), most often involving the hip and knee. Osteoarthritis causes pain and limits mobility, thereby reducing patient quality of life. Conservative, nonsurgical, nonpharmacologic treatment strategies include weight reduction, orthotics, physical therapy modalities, acupuncture, massage, and exercise. The breadth of the current literature on OA can make determining the appropriate exercise prescription challenging. Aerobic exercise, strengthening exercise, Tai chi, and aquatic exercise can all alleviate pain and improve function in patients with OA. The choice of the specific type and mode of delivery of the exercise should be individualized and should consider the patient's preferences. Ongoing monitoring and supervision by a health care professional are essential for patients to participate in and benefit from exercise. PMID- 23445862 TI - Exercise and COPD: therapeutic responses, disease-related outcomes, and activity promotion strategies. AB - Chronic obstructive pulmonary disease (COPD) reduces patients' exercise capacities and their abilities to perform daily physical activities, thereby increasing morbidity and mortality rates. The cycle of dyspnea, deconditioning, and declining physical activity not only accelerates the progression of COPD but also increases the risk for developing or aggravating metabolic and cardiovascular diseases. Cardiovascular and metabolic comorbidities also limit physical function, and their disabling effects in combination with COPD may be greater than the effects of each disease alone. The impact of COPD and its treatment on the ability to exercise, and the degree of physical activity in daily life, can be measured by field-based tests (eg, the 6-minute walk test or incremental and endurance shuttle-walk test), laboratory-based tests (eg, incremental or constant work-rate treadmill and cycle-ergometer tests), and physical activity assessments (eg, questionnaires and accelerometers). Walking tests increase oxygen consumption and desaturation in patients with COPD more than cycling tests with similar work-rate profiles and may more closely resemble patients' normal activities. Despite the questionable relevance of exercise testing to patients' daily functionality, exercise parameters remain important predictors of survival in patients with COPD. Treatment of COPD (pharmacotherapy, pulmonary rehabilitation, or both) can increase exercise capacity and physical activity in daily life, which potentially slows the decline of lung function, reduces the frequencies of exacerbations and hospitalizations, decreases mortality, slows the progression of comorbidities, improves health-related quality of life, and increases the activity reserve for routine function. This article examines the interactions of reduced physical activity and decreased exercise capacity with the progression of COPD, comorbidities, and mortality. The article also describes the available exercise tests for patients with COPD and reviews the evidence indicating that treating COPD improves exercise capacity. Notably, it appears that even mild COPD reduces exercise capacity and daily physical activity, indicating the need for early intervention. PMID- 23445863 TI - Sudden cardiac death in young athletes: preparticipation screening for underlying cardiovascular abnormalities and approaches to prevention. AB - The study of sudden cardiac death (SCD) in athletes has received more interest in the medical and lay press over the past few years. Professional athletes represent ideals of fitness and health, and the sudden death of prominent athletes can come as a shock. Underlying occult cardiovascular disorders are the most common cause of SCD in athletes. Unfortunately, because these disorders rarely present clinically, their initial manifestation is often a fatal event. Due to this, much attention has turned to both primary and secondary prevention. Primary prevention includes preparticipation screening and secondary prevention includes having automatic external defibrillators available at sporting events. This article summarizes the most common causes of athletic-related cardiac arrest and evaluates the screening methods used to screen for these conditions. The general sentiment is that we need to more effectively identify athletes who are at risk for SCD, but how to do so using an efficient screening system and in a cost-effective manner have not been determined. PMID- 23445864 TI - Exercise-deficit disorder in children: are we ready to make this diagnosis? AB - Primary care physicians, particularly pediatricians, are expected to promote physical activity and prescribe exercise to patients. Unfortunately, many health care professionals do not have adequate skills or experience in this area, making exercise intervention logistically and psychologically challenging. Exercise deficit disorder (EDD), which is a new term to the literature, is defined as reduced levels of moderate-to-vigorous physical activity, inconsistent with public health recommendations. Physicians are in a unique position to identify children who are deficient in exercise and initiate prevention strategies. To aid physicians in the diagnosis and treatment of children with EDD, we propose integrating exercise assessment into primary care practice, and, when appropriate, referral to a pediatric exercise specialist. This approach should ensure adequate development of muscle strength and motor skills that are required for successful physical activity participation. The timely identification of children with EDD is essential in preventing resistance to intervention. Connecting pediatric health care professionals with pediatric exercise specialists, culminating in an established professional collaborative system, is critical for promoting healthy behaviors throughout childhood and adolescence. PMID- 23445865 TI - Eminence-based medicine versus evidence-based medicine: is anterior cruciate ligament reconstruction optimally performed with the double-bundle technique? AB - The anterior cruciate ligament (ACL) comprises 2 distinct bands or bundles-the anteromedial bundle, which is tighter in flexion, and the posterolateral bundle, which is tighter in extension. Traditional ACL reconstruction uses 1 graft. A new technique, known as the double-bundle technique, uses 2 tendon grafts to more closely approximate normal anatomy. Because the medical literature does not provide a definitive answer as to which reconstruction method is better, we surveyed 500 experts in sports medicine in a previous study to determine whether they agreed with the statement "ACL reconstruction is optimally performed with the double-bundle technique." Respondents were inclined to answer "This statement is probably false." Our article interprets the expert responses by reviewing the basic and clinical sciences implicit in the question and reviewing the literature regarding outcomes. We found that double-bundle ACL reconstruction is theoretically appealing, but evidence proving that it improves clinical outcomes is unavailable. High-quality studies are under way on the topic, which may provide a definitive answer. However, until such data are available, the expert consensus from our survey was that the double-bundle technique is not necessarily the optimal approach. PMID- 23445866 TI - Q&A: Re-review opt-out and painless publishing. PMID- 23445867 TI - A qualitative study of the experience of CenteringPregnancy group prenatal care for physicians. AB - BACKGROUND: This study sought to understand the central meaning of the experience of group prenatal care for physicians who were involved in providing CenteringPregnancy through a maternity clinic in Calgary, Canada. METHOD: The study followed the phenomenological qualitative tradition. Three physicians involved in group prenatal care participated in a one-on-one interview between November and December 2009. Two physicians participated in verification sessions. Interviews followed an open ended general guide and were audio recorded and transcribed. The purpose of the analysis was to identify meaning themes and the core meaning experienced by the physicians. RESULTS: Six themes emerged: (1) having a greater exchange of information, (2) getting to knowing, (3) seeing women get to know and support each other, (4) sharing ownership of care, (5) having more time, and (6) experiencing enjoyment and satisfaction in providing care. These themes contributed to the core meaning for physicians of "providing richer care." CONCLUSIONS: Physicians perceived providing better care and a better professional experience through CenteringPregnancy compared to their experience of individual prenatal care. Thus, CenteringPregnancy could improve work place satisfaction, increase retention of providers in maternity care, and improve health care for women. PMID- 23445868 TI - TiO2-graphene oxide nanocomposite as advanced photocatalytic materials. AB - BACKGROUND: Graphene oxide composites with photocatalysts may exhibit better properties than pure photocatalysts via improvement of their textural and electronic properties. RESULTS: TiO2-Graphene Oxide (TiO2 - GO) nanocomposite was prepared by thermal hydrolysis of suspension with graphene oxide (GO) nanosheets and titania peroxo-complex. The characterization of graphene oxide nanosheets was provided by using an atomic force microscope and Raman spectroscopy. The prepared nanocomposites samples were characterized by Brunauer-Emmett-Teller surface area and Barrett-Joiner-Halenda porosity, X-ray Diffraction, Infrared Spectroscopy, Raman Spectroscopy and Transmission Electron Microscopy. UV/VIS diffuse reflectance spectroscopy was employed to estimate band-gap energies. From the TiO2 - GO samples, a 300 MUm thin layer on a piece of glass 10*15 cm was created. The photocatalytic activity of the prepared layers was assessed from the kinetics of the photocatalytic degradation of butane in the gas phase. CONCLUSIONS: The best photocatalytic activity under UV was observed for sample denoted TiGO_100 (k = 0.03012 h-1), while sample labeled TiGO_075 (k = 0.00774 h-1) demonstrated the best activity under visible light. PMID- 23445870 TI - An exceptional cause of progressive dyspnoea in a renal transplant recipient: hemangioma of the mitral valve. AB - Primary cardiac hemangioma is a very rare benign vascular tumor, with valvular hemangiomas being even less frequent as valves are generally avascular structures. We present the first case of mitral valve hemangioma in a renal transplant recipient. Patient presented with progressive dyspnea. Transesophageal echocardiogram (TEE) demonstrated a 0.8x0.9-cm pedunculated tumor mass on the posterior leaflet of the mitral valve. Coronary angiography identified a small artery which filled from the circumflex artery and fed the tumor. The tumor was surgically removed. Histopathological examination revealed a hemangioma. The postoperative course was uneventful with stable graft function. PMID- 23445869 TI - Shaping up for action: the path to physiological maturation in the renal tubules of Drosophila. AB - The Malpighian tubule is the main organ for excretion and osmoregulation in most insects. During a short period of embryonic development the tubules of Drosophila are shaped, undergo differentiation and become precisely positioned in the body cavity, so they become fully functional at the time of larval hatching a few hours later. In this review I explore three developmental events on the path to physiological maturation. First, I examine the molecular and cellular mechanisms that generate organ shape, focusing on the process of cell intercalation that drives tubule elongation, the roles of the cytoskeleton, the extracellular matrix and how intercalation is coordinated at the tissue level. Second, I look at the genetic networks that control the physiological differentiation of tubule cells and consider how distinctive physiological domains in the tubule are patterned. Finally, I explore how the organ is positioned within the body cavity and consider the relationship between organ position and function. PMID- 23445871 TI - O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity. AB - 7,8-Dihydroxyflavone (7,8-DHF) acts as a TrkB receptor-specific agonist. It mimics the physiological actions of brain-derived neurotrophic factor (BDNF) and demonstrates remarkable therapeutic efficacy in animal models of various neurological diseases. Nonetheless, its in vivo pharmacokinetic profiles and metabolism remain unclear. Here we report that 7,8-DHF and its O-methylated metabolites distribute in mouse brain after oral administration. Both hydroxy groups can be mono-methylated, and the mono-methylated metabolites activate TrkB in vitro and in vivo. Blocking methylation, using COMT inhibitors, diminishes the agonistic effect of TrkB activation by 7,8-DHF or 4'-dimethylamino-7,8-DHF, supporting the contribution of the methylated metabolite to TrkB activation in mouse brain. Moreover, we have synthesized several methylated metabolite derivatives, and they also potently activate the TrkB receptor and reduce immobility in both forced swim test and tail suspension test, indicating that these methylated metabolites may possess antidepressant activity. Hence, our data demonstrate that 7,8-DHF is orally bioavailable and can penetrate the brain-blood barrier. The O-methylated metabolites are implicated in TrkB receptor activation in the brain. PMID- 23445872 TI - Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas. AB - Pediatric follicular lymphoma is a rare disease that differs genetically and clinically from its adult counterpart. With the exception of pediatric follicular lymphoma with IRF4-translocation, the genetic events associated with these lymphomas have not yet been defined. We applied array-comparative genomic hybridization and molecular inversion probe assay analyses to formalin-fixed paraffin-embedded tissues from 18 patients aged 18 years and under with IRF4 translocation negative follicular lymphoma. All evaluable cases lacked t(14;18). Only 6 of 16 evaluable cases displayed chromosomal imbalances with gains or amplifications of 6pter-p24.3 (including IRF4) and deletion and copy number neutral-loss of heterozygosity in 1p36 (including TNFRSF14) being most frequent. Sequencing of TNFRSF14 located in the minimal region of loss in 1p36.32 showed nine mutations in 7 cases from our series. Two subsets of pediatric follicular lymphoma were delineated according to the presence of molecular alterations, one with genomic aberrations associated with higher grade and/or diffuse large B-cell lymphoma component and more widespread disease, and another one lacking genetic alterations associated with more limited disease. PMID- 23445873 TI - Age and organ damage correlate with poor survival in myeloma patients: meta analysis of 1435 individual patient data from 4 randomized trials. AB - Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46 60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects. PMID- 23445874 TI - Hematopoietic stem cell transplantation for children with high-risk acute lymphoblastic leukemia in first complete remission: a report from the AIEOP registry. AB - Children with high-risk acute lymphoblastic leukemia in first complete remission can benefit from allogeneic hematopoietic stem cell transplantation. We analyzed the outcome of 211 children with high-risk acute lymphoblastic leukemia in first complete remission who were given an allogeneic transplant between 1990 and 2008; the outcome of patients who, despite having an indication for transplantation and a suitable donor, did not receive the allograft for different reasons in the same time period was not analyzed. Sixty-nine patients (33%) were transplanted between 1990 and 1999, 58 (27%) between 2000 and 2005, and 84 (40%) between 2005 and 2008. A matched family donor was employed in 138 patients (65%) and an unrelated donor in 73 (35%). The 10-year probabilities of overall and disease-free survival were 63.4% and 61%, respectively. The 10-year cumulative incidences of transplantation-related mortality and relapse were 15% and 24%, respectively. After 1999, no differences in either disease-free survival or transplant-related mortality were observed in patients transplanted from unrelated or matched family donors. In multivariate analysis, grade IV acute graft-versus-host disease was an independent factor associated with worse disease-free survival. By contrast, grade I acute graft-versus-host disease and age at diagnosis between 1 and 9 years were favorable prognostic variables. Our study, not intended to evaluate whether transplantation is superior to chemotherapy for children with acute lymphoblastic leukemia in first complete remission and high-risk features, shows that the allograft cured more than 60% of these patients; in the most recent period, the outcome of recipients of grafts from matched family and unrelated donors was comparable. PMID- 23445875 TI - Hepcidin level predicts hemoglobin concentration in individuals undergoing repeated phlebotomy. AB - Dietary iron absorption is regulated by hepcidin, an iron regulatory protein produced by the liver. Hepcidin production is regulated by iron stores, erythropoiesis and inflammation, but its physiology when repeated blood loss occurs has not been characterized. Hepcidin was assayed in plasma samples obtained from 114 first-time/reactivated (no blood donations in preceding 2 years) female donors and 34 frequent (>=3 red blood cell donations in preceding 12 months) male donors as they were phlebotomized >=4 times over 18-24 months. Hepcidin levels were compared to ferritin and hemoglobin levels using multivariable repeated measures regression models. Hepcidin, ferritin and hemoglobin levels declined with increasing frequency of donation in the first time/reactivated females. Hepcidin and ferritin levels correlated well with each other (Spearman's correlation of 0.74), but on average hepcidin varied more between donations for a given donor relative to ferritin. In a multivariable repeated measures regression model the predicted inter-donation decline in hemoglobin varied as a function of hepcidin and ferritin; hemoglobin was 0.51 g/dL lower for subjects with low (>45.7 ng/mL) or decreasing hepcidin and low ferritin (>26 ng/mL), and was essentially zero for other subjects including those with high (>45.7 ng/mL) or increasing hepcidin and low ferritin (>26 ng/mL) levels (P<0.001). In conclusion, hepcidin levels change rapidly in response to dietary iron needed for erythropoiesis. The dynamic regulation of hepcidin in the presence of a low levels of ferritin suggests that plasma hepcidin concentration may provide clinically useful information about an individual's iron status (and hence capacity to tolerate repeated blood donations) beyond that of ferritin alone. Clinicaltrials.gov identifier: NCT00097006. PMID- 23445876 TI - A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia. AB - Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists with demonstrated efficacy against immune thrombocytopenia in prospective controlled studies, were recently authorized in most countries for adults with chronic immune thrombocytopenia. So far, no data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles were evaluated for 46 patients who sequentially received both drugs, switching from one to the other. The reasons for switching were: lack of efficacy for 23 patients, platelet-count fluctuations for 11, side effects for 4, and 8 patients' preferences. For 50-80% of the patients, switching from romiplostim to eltrombopag or eltrombopag to romiplostim effectively impacted the platelet count, with fluctuations disappearing in 54% and side effects resolved in 100%. In 80% of the patients, the 2 thrombopoietic receptor-agonists achieved similar response patterns. Our results confirmed that switching from one thrombopoietic receptor-agonist to the other could be beneficial in clinical practice for patients with severe chronic immune thrombopenia who failed to respond or experienced adverse events to the first. (Clinical Trials.gov identifier: NCT01618734). PMID- 23445877 TI - Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor. AB - The Wiskott-Aldrich syndrome protein is an essential cytoskeleton regulator found in cells of the hematopoietic lineage and controls the motility of leukocytes. The impact of WAS gene deficiency on the mobilization of hematopoietic progenitor/stem cells in circulation has remained unexplored but information would be pertinent in the context of autologous gene therapy of Wiskott-Aldrich syndrome. The response to granulocyte-colony stimulating factor mobilization was investigated in a murine WAS knock-out model of the disease, by measuring hematologic parameters, circulation and engraftment of hematopoietic progenitor/stem cells. In the steady-state, adult WAS knock-out mice have B-cell lymphopenia, marked neutrophilia, increased counts of circulating hematopoietic progenitor cells and splenomegaly, presumably caused by the retention of hematopoietic progenitor cells due to high levels of splenic CXCL12. In spite of these anomalies, the administration of granulocyte-colony-stimulating factor mobilizes progenitor/stem cells in WAS knock-out mice to the same level and with the same kinetics as in wild-type control mice. Mobilized peripheral blood cells from WAS knock-out mice can be transduced and are able to engraft into lethally irradiated hosts reconstituting multiple lineages of cells and providing more effective radio-protection than mobilized cells from wild-type control mice. Surprisingly, the homing and the peripheral blood recovery of B lymphocytes was influenced by the background of the host. Thus, in the absence of Wiskott-Aldrich syndrome protein, effective mobilization is achieved but partial correction may occur as a result of an abnormal hematopoietic environment. PMID- 23445878 TI - Transcription factor nuclear factor erythroid-2 mediates expression of the cytokine interleukin 8, a known predictor of inferior outcome in patients with myeloproliferative neoplasms. AB - The transcription factor nuclear factor erythroid-2 is over-expressed in patients with myeloproliferative neoplasms irrespective of the presence of the JAK2(V617F) mutation. Our transgenic mouse model over-expressing nuclear factor erythroid-2, which recapitulates many features of myeloproliferative neoplasms including transformation to acute myeloid leukemia, clearly implicates this transcription factor in the pathophysiology of myeloproliferative neoplasms. Because the targets mediating nuclear factor erythroid-2 effects are not well characterized, we conducted microarray analysis of CD34(+) cells lentivirally transduced to over express nuclear factor erythroid-2 or to silence this transcription factor via shRNA, in order to identify novel target genes. Here, we report that the cytokine interleukin 8 is a novel target gene. Nuclear factor erythroid-2 directly binds the interleukin 8 promoter in vivo, and these binding sites are required for promoter activity. Serum levels of interleukin 8 are known to be elevated in both polycythemia vera and primary myelofibrosis patients. Recently, increased interleukin 8 levels have been shown to be predictive of inferior survival in primary myelofibrosis patients in multivariate analysis. Therefore, one of the mechanisms by which nuclear factor erythroid-2 contributes to myeloproliferative neoplasm pathology may be increased interleukin 8 expression. PMID- 23445879 TI - Protein-losing enteropathy following the Fontan procedure in a child with intestinal lactase deficiency treated with lactose-free diet. AB - A 12-year-old girl presented with a protein-losing enteropathy. Symptoms started 4 weeks after undergoing the Fontan procedure at the age of 1.5 years for mitral atresia, ventricular septal defect, and double-outlet right ventricle. Upon referral for 3 weeks of rehabilitation after multiple interventional measures and drug treatments, she appeared in a dystrophic state, with decreased plasma protein and electrolyte levels along with occasional tetanic convulsions. Blood glucose levels after a lactose tolerance test were markedly reduced. The introduction of a lactose-free diet was quickly effective, with plasma protein and electrolyte levels raised to normal levels, and the girl's body weight increased without ascites or oedema. Molecular genetic examination revealed a homozygous C/C13910 polymorphism in the LCT gene. CONCLUSION: Protein-losing enteropathy in the Fontan circulation may be provoked by lactase deficiency and should therefore be ruled out to exclude this rather common condition. PMID- 23445880 TI - Clinical breath analysis: discriminating between human endogenous compounds and exogenous (environmental) chemical confounders. AB - Volatile organic compounds (VOCs) in exhaled breath originate from current or previous environmental exposures (exogenous compounds) and internal metabolic (anabolic and catabolic) production (endogenous compounds). The origins of certain VOCs in breath presumed to be endogenous have been proposed to be useful as preclinical biomarkers of various undiagnosed diseases including lung cancer, breast cancer, and cardio-pulmonary disease. The usual approach is to develop difference algorithms comparing VOC profiles from nominally healthy controls to cohorts of patients presenting with a documented disease, and then to apply the resulting rules to breath profiles of subjects with unknown disease status. This approach to diagnosis has a progression of sophistication; at the most rudimentary level, all measurable VOCs are included in the model. The next level corrects exhaled VOC concentrations for current inspired air concentrations. At the highest level, VOCs exhibiting discriminatory value also require a plausible biochemical pathway for their production before inclusion. Although these approaches have all shown some level of success, there is concern that pattern recognition is prone to error from environmental contamination and between subject variance. In this paper, we explore the underlying assumptions for the interpretation and assignment of endogenous compounds with probative value for assessing changes. Specifically, we investigate the influence of previous exposures, elimination mechanisms and partitioning of exogenous compounds as confounders of true endogenous compounds. We provide specific examples based on a simple classical pharmacokinetic approach to identify potential misinterpretations of breath data and propose some remedies. PMID- 23445882 TI - Uterine artery Doppler at 30-33 weeks' gestation in the prediction of preeclampsia. AB - OBJECTIVE: To investigate the potential value of measuring uterine artery pulsatility index (PI) at 30-33 weeks' gestation in the prediction of preeclampsia (PE) developing at or after 34 weeks. METHODS: Screening study in singleton pregnancies at 30-33 weeks' gestation including 4,294 cases that were unaffected by PE, gestational hypertension (GH) or delivery of small for gestational age neonates (normal group), 145 that subsequently developed PE, with 37 cases requiring delivery at 34-37 weeks (intermediate-PE) and 108 delivering at or after 38 weeks (late-PE) and 161 that developed GH. The a priori risks for intermediate- and late-PE from maternal demographic characteristics and medical history were derived by logistic regression analysis. The a posteriori risks were calculated by combining the a priori risks with the likelihood ratios for uterine artery PI, which were calculated from fitted bivariate gaussian distributions. RESULTS: In screening for PE by a combination of maternal characteristics and uterine artery PI, the estimated detection rates of intermediate- and late-PE, at a false-positive rate of 10%, were 70.3 and 54.6%, respectively. CONCLUSION: Combined testing by maternal characteristics and uterine artery PI at 30-33 weeks could effectively identify women at high risk for subsequent development of PE. PMID- 23445881 TI - 5,6-Dimethoxybenzofuran-3-one derivatives: a novel series of dual Acetylcholinesterase/Butyrylcholinesterase inhibitors bearing benzyl pyridinium moiety. AB - BACKGROUND: Several studies have been focused on design and synthesis of multi target anti Alzheimer compounds. Utilizing of the dual Acetylcholinesterase/Butyrylcholinesterase inhibitors has gained more interest to treat the Alzheimer's disease. As a part of a research program to find a novel drug for treating Alzheimer disease, we have previously reported 6 alkoxybenzofuranone derivatives as potent acetylcholinesterase inhibitors. In continuation of our work, we would like to report the synthesis of 5,6-dimethoxy benzofuranone derivatives bearing a benzyl pyridinium moiety as dual Acetylcholinesterase/Butyrylcholinesterase inhibitors. METHODS: The synthesis of target compounds was carried out using a conventional method. Bayer-Villiger oxidation of 3,4-dimethoxybenzaldehyde furnished 3,4-dimethoxyphenol. The reaction of 3,4-dimethoxyphenol with chloroacetonitrile followed by treatment with HCl solution and then ring closure yielded the 5,6-dimethoxy benzofuranone. Condensation of the later compound with pyridine-4-carboxaldehyde and subsequent reaction with different benzyl halides afforded target compounds. The biological activity was measured using standard Ellman's method. Docking studies were performed to get better insight into interaction of compounds with receptor. RESULTS: The in vitro anti acetylcholinesterase/butyrylcholinesterase activity of compounds revealed that, all of the target compounds have good inhibitory activity against both Acetylcholinesterase/Butyrylcholinesterase enzymes in which compound 5b (IC50 = 52 +/- 6.38nM) was the most active compound against acetylcholinesterase. The same binding mode and interactions were observed for the reference drug donepezil and compound 5b in docking study. CONCLUSIONS: In this study, we presented a new series of benzofuranone-based derivatives having pyridinium moiety as potent dual acting Acetylcholinesterase/Butyrylcholinesterase inhibitors. PMID- 23445883 TI - [Advances in bone densitometry equipment]. AB - Techniques in bone densitometry have made remarkable progress in the past quarter century and are now widely used in the daily practice of osteoporosis. Since the skeletal site and the method of measurement differ among the type of equipments, several types are adopted to suit the situation of each medical institute. Central DXA is used to provide a thorough examination of osteoporosis in large hospitals, whereas in general clinics the radial DXA or radiographic photodensitometry of metacarpus is mainly used. Quantitative ultrasound of calcaneus is mostly used for screening osteoporosis. DXA is also going to be applied to vertebral fracture assessment, hip structural analysis and micro architectural analysis of vertebral trabecular bone. PMID- 23445884 TI - [Evaluation of bone for using of bone metabolic markers in the diagnosis and treatment of osteoporosis]. AB - Quantification of BMD is being used as the main method to diagnose osteoporosis and measurement accuracy has dramatically improved. However, essential clinical parameters of osteoporosis include more dynamic markers such as bone metabolic markers. Bone metabolism undergoes daily dynamic changes, and even with the same BMD, the metabolic state differs and the pathologic significance also differs. Therefore, to use BMD measurement as a dynamic marker, one must wait for an observation period of 6 months to 1 year before remeasurement, whereas bone metabolic markers accurately reflect the state of bone metabolism at the point in time of the measurement. Bone metabolic markers can also be used as a guide to selecting pharmacotherapy. When there is doubt about choosing a drug, the use of bone metabolic markers can enable more appropriate selection. Furthermore, to evaluate the effects of drug therapy on disease improvement, assessing the state of bone metabolism at the time of diagnosis is recommended whenever possible. However, if a decision is made to select treatment with little influence on bone metabolism, then measuring bone metabolic markers to monitor drug treatment effects has little clinical significance. Recently the clinical application of bone metabolic markers have been achieved significant progress and the measurements of these indices give us better understanding of pathological of osteoporosis. Therefore, it is very important to guide the proper application and assessment of bone metabolic markers in clinical practice. PMID- 23445885 TI - [Progress in clinical bone assessment using CT]. AB - Clinical computed tomography (CT) provides the information of bone structure and mineral density in vivo . Based on three-dimensional bone structure, voluntary two-dimensional sections are available, as well as trabecular and cortical data separately. However, the trabecular structure, which size is smaller than the spatial resolution, cannot be measured precisely. A recently system, high resolution peripheral quantitative CT (HR-pQCT) , can visualize and quantify the trabecular and cortical microstructure in vivo . Because of low radiation dose and high reproducibility, HR-pQCT system is expected to be a useful tool to assess the pathophysiological changes or the efficacy of anti-osteoporotic agents on bone. PMID- 23445886 TI - [Bone histology after intermittent PTH treatment - animal models -]. AB - Intermittent administration of parathyroid hormone, PTH, appears to promote preosteoblastic proliferation and osteoblastic bone formation, giving rise to anabolic effect in bone. We investigated the behavior of osteoblastic cells after intermittent PTH treatment and attempted to elucidate the role of osteoclasts on the mediation of PTH-driven bone anabolism. As a consequence, bone formation was increased in PTH-treated wild-type mice, whereas in the osteoclast-deficient c fos - / - mice, there was no significant increase in bone formation, despite the highly-increased population of preosteoblasts. It seems likely that the absence of osteoclasts might hinder PTH-driven bone anabolism, and also that osteoclastic presence may be necessary for full osteoblastic differentiation and enhanced bone formation seen after intermittent PTH administration. We will also discuss the pivotal role of osteocytes in PTH-mediated anabolic effect. PMID- 23445887 TI - [Analysis of bone tissues by using fluorescent imaging]. AB - Rapid development of fluorescent imaging techniques enables us to understand cellular dynamics in vivo . We have originally established an advanced imaging system for visualizing live bone tissues with intravital multiphoton microscopy. By means of the system we have recently succeeded in visualization of mature osteoclasts in live bones and revealed that RANKL regulates bone-resorptive functions of mature osteoclasts in vivo . We also developed new image analysis software for tracking morphological changes of mature osteoclasts and generated pH-sensing chemical fluorescent probes for detecting bone resorption at local sites on the bone surface. Here we show the latest data and the detailed methodology of intravital imaging of bone tissues, and also discuss its further application. PMID- 23445888 TI - [Evaluation of muscle mass using Dual energy X-ray absorptiometry]. AB - DXA can accurately calculate bone mass, fat mass, and lean body mass, and so is considered the gold standard among methods of measuring skeletal muscle mass. Skeletal muscle mass is an essential item in the diagnosis of sarcopenia. Since the appendicular lean mass nearly corresponds to muscle mass, the appendicular skeletal muscle mass corrected for body height has been proposed as an indicator of muscle mass, and is the basis for a diagnosis of sarcopenia. PMID- 23445889 TI - [SSBT (severely suppressed bone turnover) ]. AB - Atypical fractures of femoral shaft and pelvis occurred on the long-term bisphosphonate treatment patients have been first reported in 2005. Since then many cases have been reported, while the number of atypical fractures is small compared with that of bisphosphonate treatment patients. It is speculated that accumulation of microdamage induced by severely suppressed bone turnover causes clinical fatigue fracture. PMID- 23445890 TI - [Assessment of fracture risk using quantitative ultrasound (QUS) ]. AB - Previous studies have demonstrated close associations between QUS parameters and osteoporotic status. However, due to the ambiguities in assessing accuracy of QUS and the moderate correlation of DXA and QUS results, currently there is no agreement on how results of QUS devices should be interpreted in order to diagnose osteoporosis. However, I could recommend for clinical application that QUS should be used as the predictor of the risk of osteoporotic fractures. Good portability and low cost of QUS technique might make QUS an attractive technology for assessing risk of fractures in large populations. PMID- 23445891 TI - [Clinical application of serum 25OHD]. AB - Serum 25OHD concentration is considered to be an appropriate measure for judging vitamin D insufficiency/sufficiency. It is hard to set its reference value. Nowadays, two reference values, namely 50 nmol/L for prevention of bone fracture and 75 nmol/L for lowering serum PTH concentration have been proposed. In the elderly, if the former value is used for the assessment, almost half of the population will be classified as insufficient, while the latter is used, almost all the population will be classified as insufficient. Precise and reliable measurements for serum 25OHD are critical for the clinical use of the reference value and the reimbursement of serum 25OHD measurement with the national health care system are required in the treatment of osteoporosis. PMID- 23445892 TI - [Clinical nuclear medicine in bone metastases]. AB - (99m)Tc-hydroxymethylene diphosphonate is not directly to Calcium of the bone matrix, but is binding to hydroxyapatite within the bone matrix. Strontium-89 is a member of family II A of the periodic table, same as Calcium, and is incorporated into bone matrix directly. It is very important that the the regions of the pain from bone metastases are present in the site of the abnormal uptake by bone metastases. PMID- 23445893 TI - [Bone metabolic markers for evaluation of bone metastases]. AB - Bone metabolic markers consist of bone formation markers, which are secreted from osteoblasts (BAP, OC, P1CP, P1NP) , and bone resorption markers, which are metabolites of bone type 1 collagen or secreted from osteoclasts (PYD, DPD, NTX, CTX, 1CTP, TRACP) . Those bone metabolic markers are useful for : (1) diagnosis of bone metastases, (2) follow-up during treatment of bone metastases, and (3)predicting prognosis of bone metastases. PMID- 23445894 TI - [Assessment of the treatment of glucocorticoid-induced osteoporosis]. AB - Glucocorticoid-induced osteoporosis (GIOP) is known as a serious adverse side effect during long-term glucocorticoid treatment. Several clinical guidelines are available to whom and how we should start to treat GIOP. However, the assessment of the treatment of GIOP is still controversial. Accumulating evidences suggest us that both bone mineral density and bone turn over markers could reflect the effect of some pharmacological agents on bone metabolism. However, further studies would be required for precise assessment of the efficacy of drugs on fracture prevention in GIOP. PMID- 23445895 TI - [Assessment of joint structure in patients with rheumatoid arthritis]. AB - Recent progress in the treatment of rheumatoid arthritis (RA) with TNF-inhibitors has brought a paradigm shift, in which clinical and structural remission is now a target to be approached. However, joint damage already develops in a majority of patients before appropriate treatments are provided. Joint damage results from the destruction of bone and cartilage, which can be visualized via radiography as joint erosion (JE) and joint space narrowing (JSN) , respectively. JSN is a surrogate marker for loss of cartilage and it also reflects damage to tissues causing joint dislocation, a phenomenon that is less prevalent among patients with early RA. JE has been perceived to be the most critical indicator of permanent disability in RA. The combination of TNF-inhibitor and MTX reduces the risk of joint damage, measured by radiographic modified total Sharp score (mTSS) . Biologics targeting cytokines and lymphocytes not only expand the array of treatments for RA but also provide important insights into pathogenesis of this disease. PMID- 23445897 TI - Matrix Gla protein is involved in crystal formation in kidney of hyperoxaluric rats. AB - BACKGROUND: Matrix Gla protein (MGP) is a molecular determinant regulating vascular calcification of the extracellular matrix. However, it is still unclear how MGP may be involved in crystal formation in the kidney of hyperoxaluric rats. METHODS: Male Sprague-Dawley rats were divided into the hyperoxaluric group and control group. Hyperoxaluric rats were administrated by 0.75% ethylene glycol (EG) for up to 8 weeks. Renal MGP expression was detected by the standard avidin biotin complex (ABC) method. Renal crystal deposition was observed by a polarizing microscope. Total RNA and protein from the rat kidney tissue were extracted. The levels of MGP mRNA and protein expression were analyzed by the real-time polymerase chain reaction (RT-PCR) and Western blot. RESULTS: Hyperoxaluria was induced successfully in rats. The MGP was polarly distributed, on the apical membrane of renal tubular epithelial cells, and was found in the ascending thick limbs of Henle's loop (cTAL) and the distal convoluted tubule (DCT) in hyperoxaluric rats, its expression however, was present in the medullary collecting duct (MCD) in stone-forming rats. Crystals with multilaminated structure formed in the injurious renal tubules with lack of MGP expression.MGP mRNA expression was significantly upregulated by the crystals' stimulations. CONCLUSION: Our results suggested that the MGP was involved in crystals formation by the continuous expression, distributing it polarly in the renal tubular cells and binding directly to the crystals. PMID- 23445896 TI - Brain functional networks in syndromic and non-syndromic autism: a graph theoretical study of EEG connectivity. AB - BACKGROUND: Graph theory has been recently introduced to characterize complex brain networks, making it highly suitable to investigate altered connectivity in neurologic disorders. A current model proposes autism spectrum disorder (ASD) as a developmental disconnection syndrome, supported by converging evidence in both non-syndromic and syndromic ASD. However, the effects of abnormal connectivity on network properties have not been well studied, particularly in syndromic ASD. To close this gap, brain functional networks of electroencephalographic (EEG) connectivity were studied through graph measures in patients with Tuberous Sclerosis Complex (TSC), a disorder with a high prevalence of ASD, as well as in patients with non-syndromic ASD. METHODS: EEG data were collected from TSC patients with ASD (n = 14) and without ASD (n = 29), from patients with non syndromic ASD (n = 16), and from controls (n = 46). First, EEG connectivity was characterized by the mean coherence, the ratio of inter- over intra-hemispheric coherence and the ratio of long- over short-range coherence. Next, graph measures of the functional networks were computed and a resilience analysis was conducted. To distinguish effects related to ASD from those related to TSC, a two-way analysis of covariance (ANCOVA) was applied, using age as a covariate. RESULTS: Analysis of network properties revealed differences specific to TSC and ASD, and these differences were very consistent across subgroups. In TSC, both with and without a concurrent diagnosis of ASD, mean coherence, global efficiency, and clustering coefficient were decreased and the average path length was increased. These findings indicate an altered network topology. In ASD, both with and without a concurrent diagnosis of TSC, decreased long- over short-range coherence and markedly increased network resilience were found. CONCLUSIONS: The altered network topology in TSC represents a functional correlate of structural abnormalities and may play a role in the pathogenesis of neurological deficits. The increased resilience in ASD may reflect an excessively degenerate network with local overconnection and decreased functional specialization. This joint study of TSC and ASD networks provides a unique window to common neurobiological mechanisms in autism. PMID- 23445898 TI - Elderly patients' participation in emergency medical services when offered an alternative care pathway. AB - As organizational changes in the healthcare system are in progress, to enhance care quality and reduce costs, it is important to investigate how these changes affect elderly patients' experiences and their rights to participate in the choice of healthcare. The aim of this study is to describe elderly patients' lived experience of participating in the choice of healthcare when being offered an alternative care pathway by the emergency medical services, when the individual patient's medical needs made this choice possible. This study was carried out from the perspective of caring science, and a phenomenological approach was applied, where data were analysed for meaning. Data consist of 11 semi-structured interviews with elderly patients who chose a healthcare pathway to a community-based hospital when they were offered an alternative level of healthcare. The findings show that the essence of the phenomenon is described as "There was a ray of hope about a caring encounter and about being treated like a unique human being". Five meaningful constituents emerged in the descriptions: endurable waiting, speedy transference, a concerned encounter, trust in competence, and a choice based on memories of suffering from care. The conclusion is that patient participation in the choice of a healthcare alternative instead of the emergency department is an opportunity of avoiding suffering from care and being objectified. PMID- 23445899 TI - Laser therapy treatment of phacomatosis pigmentovascularis type II: two case reports. AB - INTRODUCTION: Phacomatosis pigmentovascularis is a rare congenital condition characterized by vascular malformation associated with extensive pigmented nevi. Even though it forms a large, prominent skin lesion, therapy for phacomatosis pigmentovascularis is rarely discussed. To the best of our knowledge, this is the first report of phacomatosis pigmentovascularis type II treated with combined laser therapy using Q-switched alexandrite and long-pulsed dye lasers. CASE PRESENTATIONS: In the first of two cases reported here, a 2-week-old Japanese baby girl was given a diagnosis of phacomatosis pigmentovascularis type II and Klippel-Trenaunay syndrome because of port-wine stains, cutis marmorata telangiectatica congenita, and aberrant Mongolian spots over her trunk and limbs. After five laser therapy sessions under general anesthesia, her aberrant Mongolian spots and port-wine stains have improved. But interestingly, the cutis marmorata telangiectatica congenita on the patient's back has improved without laser therapy.In the second case, a 4-month-old Japanese baby boy was referred to us because of port-wine stains, cutis marmorata telangiectatica congenita, and aberrant Mongolian spots over his face, trunk and limbs. Phacomatosis pigmentovascularis type II was diagnosed and laser therapy was started. After three laser therapy sessions under general anesthesia, the aberrant Mongolian spots and port-wine stains have improved. The cutis marmorata telangiectatica congenita on the baby's back, buttocks, and arms has faded somewhat without laser therapy. CONCLUSIONS: Combined laser therapy improved the phacomatosis pigmentovascularis skin lesions, but was not effective for the cutis marmorata telangiectatica congenita with hemiatrophy. Cutis marmorata telangiectatica congenita without atrophy can be expected to improve on its own. Our results will assist physicians considering how best to treat patients with phacomatosis pigmentovascularis. PMID- 23445900 TI - The new "snippets from the past" and a new section about "epidemiology in history". PMID- 23445902 TI - A framework for multiple imputation in cluster analysis. AB - Multiple imputation is a common technique for dealing with missing values and is mostly applied in regression settings. Its application in cluster analysis problems, where the main objective is to classify individuals into homogenous groups, involves several difficulties which are not well characterized in the current literature. In this paper, we propose a framework for applying multiple imputation to cluster analysis when the original data contain missing values. The proposed framework incorporates the selection of the final number of clusters and a variable reduction procedure, which may be needed in data sets where the ratio of the number of persons to the number of variables is small. We suggest some ways to report how the uncertainty due to multiple imputation of missing data affects the cluster analysis outcomes-namely the final number of clusters, the results of a variable selection procedure (if applied), and the assignment of individuals to clusters. The proposed framework is illustrated with data from the Phenotype and Course of Chronic Obstructive Pulmonary Disease (PAC-COPD) Study (Spain, 2004-2008), which aimed to classify patients with chronic obstructive pulmonary disease into different disease subtypes. PMID- 23445901 TI - Characterizing durations of heroin abstinence in the California Civil Addict Program: results from a 33-year observational cohort study. AB - In accordance with the chronic disease model of opioid dependence, cessation is often observed as a longitudinal process rather than a discrete endpoint. We aimed to characterize and identify predictors of periods of heroin abstinence in the natural history of recovery from opioid dependence. Data were collected on participants from California who were enrolled in the Civil Addict Program from 1962 onward by use of a natural history interview. Multivariate regression using proportional hazards frailty models was applied to identify independent predictors and correlates of repeated abstinence episode durations. Among 471 heroin-dependent males, 387 (82.2%) reported 932 abstinence episodes, 60.3% of which lasted at least 1 year. Multivariate analysis revealed several important findings. First, demographic factors such as age and ethnicity did not explain variation in durations of abstinence episodes. However, employment and lower drug use severity predicted longer episodes. Second, abstinence durations were longer following sustained treatment versus incarceration. Third, individuals with multiple abstinence episodes remained abstinent for longer durations in successive episodes. Finally, abstinence episodes initiated >10 and <=20 years after first use lasted longer than others. Public policy facilitating engagement of opioid-dependent individuals in maintenance-oriented drug treatment and employment is recommended to achieve and sustain opioid abstinence. PMID- 23445903 TI - Wireless neurochemical monitoring in humans. AB - Electrochemical techniques have long been utilized to investigate chemical changes in the neuronal microenvironment. Preclinical models have demonstrated the successful monitoring of changes in various neurotransmitter systems in vivo with high temporal and spatial resolution. The expansion of electrochemical recording to humans is a critical yet challenging goal to elucidate various aspects of human neurophysiology and to create future therapies. We have designed a novel device named the WINCS (Wireless Instantaneous Neurotransmitter Concentration Sensing) system that combines rapid scan voltammetry with wireless telemetry for highly resolved electrochemical recording and analysis. WINCS utilizes fast-scan cyclic voltammetry and fixed potential amperometry for in vivo recording and has demonstrated high temporal and spatial resolution in detecting changes in extracellular levels of a wide range of analytes including dopamine, adenosine, glutamate, serotonin, and histamine. Neurochemical monitoring in humans represents a new approach to understanding the neurophysiology of the central nervous system, the neurobiology of numerous diseases, and the underlying mechanism of various neurosurgical therapies. This article addresses the current understanding of electrochemistry, its application in humans, and future directions. PMID- 23445904 TI - Development and validation of primary human myometrial cell culture models to study pregnancy and labour. AB - BACKGROUND: The development of the in vitro cell culture model has greatly facilitated the ability to study gene expression and regulation within human tissues. Within the human uterus, the upper (fundal) segment and the lower segment may provide distinct functions throughout pregnancy and during labour. We have established primary cultured human myometrial cells, isolated from both upper and lower segment regions of the pregnant human uterus, and validated them for the purpose of studying human pregnancy and labour. The specific objectives of this study were to monitor the viability and characterize the expression profile using selected cellular, contractile and pregnancy associated markers in the primary cultured human myometrial cells. Labour has been described as an inflammatory process; therefore, the ability of these cells to respond to an inflammatory stimulus was also investigated. METHODS: Myometrial cells isolated from paired upper segment (US) and lower segment (LS) biopsies, obtained from women undergoing Caesarean section deliveries at term prior to the onset of labour, were used to identify expression of; alpha smooth muscle actin, calponin, caldesmon, connexin 43, cyclo-oxygenase-2 (COX-2), oxytocin receptor, tropomyosin and vimentin, by RT-PCR and/or immunocytochemistry. Interleukin (IL)-1beta was used to treat cells, subsequently expression of COX-2 mRNA and release of interleukin-8 (CXCL8), were measured. ANOVA followed by Bonferroni's multiple comparisons test was performed. RESULTS: We demonstrate that US and LS human myometrial cells stably express all markers examined to at least passage ten (p10). Connexin 43, COX-2 and vimentin mRNA expression were significantly higher in LS cells compared to US cells. Both cell populations respond to IL-1beta, demonstrated by a robust release of CXCL8 and increased expression of COX-2 mRNA from passage one (p1) through to p10. CONCLUSIONS: Isolated primary myometrial cells maintain expression of smooth muscle and pregnancy-associated markers and retain their ability to respond to an inflammatory stimulus. These distinct myometrial cell models will provide a useful tool to investigate mechanisms underlying the process of human labour and the concept of functional regionalization of the pregnant uterus. PMID- 23445906 TI - Forced expiratory capnography and chronic obstructive pulmonary disease (COPD). AB - This report proposes a potentially sensitive and simple physiological method to detect early changes and to follow disease progression in obstructive pulmonary disease (COPD) based upon the usual pulmonary function test. Pulmonary function testing is a simple, although relatively insensitive, method to detect and follow COPD. As a proof-of-concept, we have examined the slope of the plateau for carbon dioxide during forced expiratory capnography in healthy (n = 10) and COPD subjects (n = 10). We compared the change in the rate of exhalation of carbon dioxide over time as a marker of heterogeneous ventilation of the lung. All subjects underwent pulmonary function testing, body-plethysmography, and forced exhalation capnography. The subjects with COPD also underwent high-resolution computed tomography of the chest. Regression lines were fitted to the slopes of the forced exhalation capnogram curves. There was no difference in the mean levels of exhaled carbon dioxide between the COPD and the healthy groups (p > 0.48). We found a significant difference in the mean slope of the forced exhalation capnogram for the COPD subjects compared to the healthy subjects (p = 0.01). Most important, for the COPD subjects, there was a significant positive correlation between the slope of the forced exhaled capnogram and a defined radiodensity measurement of the lung by high-resolution computed tomography (r(2) = 0.49, p = 0.02). The slope of the forced exhalation capnogram may be a simple way to determine physiological changes in the lungs in patients with COPD that are not obtainable with standard pulmonary function tests. Forced exhalation capnography would be of great clinical benefit if it can identify early disease changes and at-risk individuals. PMID- 23445907 TI - Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder, characterized clinically by insidious onset of memory and cognition impairment, emergence of psychiatric symptoms and behavioral disorder, and impairment of activities of daily living (ADL). Traditional Chinese medicine (TCM) is practiced in the Chinese health care system for more than 2,000 years. In recent years, scientists have isolated many novel compounds from herbs, some of which improve dementia with fewer side effects than conventional drugs and are regarded as potential anti-AD drugs. In this review, we summarize the latest research progress on TCM showing their possible role of treatment of AD and other demented diseases and possible pharmacological actions. PMID- 23445908 TI - Maternal serum placental growth factor, pregnancy-associated plasma protein-a and free beta-human chorionic gonadotrophin at 30-33 weeks in the prediction of pre eclampsia. AB - OBJECTIVE: To investigate the potential value of maternal serum concentrations of free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 30-33 weeks of gestation in the prediction of pre-eclampsia (PE) developing at or after 34 weeks. METHODS: Serum free beta-hCG, PAPP-A and PlGF were measured at 11-13 and at 30-33 weeks of gestation in a case-control study of 50 cases that developed PE at or after 34 weeks and 250 unaffected controls. The measured concentration of metabolites was converted into multiples of the unaffected median (MoM) and the MoM values in the PE and control groups were compared. RESULTS: At 11-13 weeks, serum PlGF and PAPP A, but not free beta-hCG, were significantly lower in the PE group than in the controls (0.824, 0.748 and 0.857 vs. 1.000 MoM). At 30-33 weeks in the PE group, PlGF was reduced (0.356 MoM), free beta-hCG was increased (1.750 MoM), but PAPP-A was not significantly different (0.991 MoM) from control (1.000 MoM). In screening for PE at 30-33 weeks by a combination of maternal characteristics and serum PlGF, the estimated detection rates, at a false-positive rate of 10%, of intermediate PE (requiring delivery at 34-37 weeks) and late PE (with delivery after 37 weeks) were 85.7 and 52.8%, respectively. The performance of screening was not improved by the addition of free beta-hCG or the free beta-hCG/PlGF ratio. CONCLUSION: Screening by maternal characteristics and serum PlGF at 30-33 weeks could identify most pregnancies that will subsequently develop PE. PMID- 23445909 TI - Can local muscles augment stability in the hip? A narrative literature review. AB - Hip pain and dysfunction are increasingly recognised as important causes of morbidity in younger and older adults. Pathology compromising the passive stability of the hip joint, including acetabular labral injury, may lead to increased femoral head translation, greater joint contact pressures and ultimately degenerative hip disease. Activation of hip muscles may play an important role in augmenting the stability in the normal and the passively unstable hip. Research at other joints suggests that the local, rather than global, muscles are well suited to provide subtle joint compression, limiting translation, with minimal metabolic cost. Based on the known characteristics of local muscles and the limited research available on hip muscles, it is proposed that the local hip muscles; quadratus femoris, gluteus minimus, gemelli, obturator internus and externus, iliocapsularis and the deep fibres of iliopsoas, may be primary stabilisers of the hip joint. Interventions aimed at restoring isolated neuromuscular function of the primary hip stabilisers may be considered when treating people with passive hip instability prior to commencing global muscle rehabilitation. Finally, further research is needed to investigate the potential association between function of the hip muscles (including muscles likely to have a role in stabilising the hip) and hip pathology affecting hip stability such as acetabular labral lesions. PMID- 23445910 TI - Whole body vibration therapy in patients with Duchenne muscular dystrophy--a prospective observational study. AB - OBJECTIVES: To study the tolerability of whole body vibration (WBV) exercise in patients with Duchenne muscular dystrophy (DMD) and its effects on muscle and bone. METHODS: WBV was performed two to three times a week for three months. Motor function, muscle strength, bone mass and biochemical markers of bone and mineral metabolism were analyzed before and after the WBV period at 0, 3, 6 and 12 months. RESULTS: Six ambulatory patients with DMD aged 5.7-12.5 years completed the study. No changes in creatine kinase activity were found, indicating that the WBV exercise did not further damage the skeletal muscle. No significant changes in bone mass, muscle strength or bone markers were found. However, there was a non-significant trend for the bone formation marker, bone specific alkaline phosphate, to increase from a mean of 59 U/L to 73 U/L after three months of WBV. The bone formation marker levels returned to baseline three months after discontinuing WBV and were still at that level after nine months. CONCLUSIONS: WBV therapy appears to be safe and well tolerated among ambulatory DMD patients. The potential benefits of WBV on bone and muscle in DMD remain to be elucidated. PMID- 23445911 TI - The acute effects of whole-body vibration on gait parameters in adults with cerebral palsy. AB - OBJECTIVES: As adults with cerebral palsy (CP) are surviving longer, interventions are needed to reduce spasticity and increase strength to improve mobility and life quality. Adults with CP are lacking a form of independent exercise that allows them to maintain or improve their ambulation skills. A new approach to increase muscle strength and flexibility called whole-body vibration (WBV) was assessed. METHODS: Using an individualized frequency (I-Freq) approach to WBV therapy the acute effects on gait in adults with CP was measured. In this study, eight adults with CP (age 20-51 years, two female) participated in two testing sessions: session one determined each individual's I-Freq; and session two included a 3D gait analysis before and after a WBV treatment. The WBV was administered in five, one minute bouts of vibration followed by one minute of rest. RESULTS: Following WBV exposure subjects experienced a significant increase in walking speed (P=0.047), stride length (P=0.017) and dynamic ankle range of motion (P=0.042). CONCLUSIONS: These data show that acute WBV treatments at I Freq can improve measures of gait and mobility in adults with CP, however, future should assess potential long-term improvements. PMID- 23445912 TI - Disuse induced by botulinum toxin affects the bone marrow expression profile of bone genes leading to a rapid bone loss. AB - OBJECTIVES: Molecular events occurring in the bone marrow microenvironment of an immobilized mouse limb after Botulinum toxin (BTX) injection haven't been characterized. BTX injection induces a localized disuse in which the tissue events have well been characterized. METHODS: BTX injection was performed in the right quadriceps; saline injection in the left side was used as control. Mice were sacrificed at 0, 7, 14, 21 and 28 days; tibias were used for microCT analysis; bone marrow from femurs for RT-PCR analysis. RESULTS: MicroCT revealed bone loss and microarchitectural damages on the immobilized side as from 7d; cortical area tended to be lower on the immobilized limb at 28d. Gene expression of formation factors was altered as from 7 days post-BTX: alkaline phosphatase, Tgfbeta1, Lrp5, Sfrp2. Only Sfrp2 and Lrp5 were maintained altered until 28d. Expression of Dkk1 increased from 21d and represented a late inhibitor of formation. Gene expression of resorption markers increased as from 7d (Rankl, Tracp, Il1alpha, Il1beta and Il6) and was maintained until 28d for Tracp and Il6. CONCLUSION: A localized disuse induces rapid modifications in the bone marrow gene expression leading to bone loss due to an early decrease of formation associated with an increase in resorption. PMID- 23445913 TI - Electrical impedance alterations in the rat hind limb with unloading. AB - OBJECTIVES: Methods are needed for quantifying muscle deconditioning due to immobilization, aging, or spaceflight. Electrical impedance myography (EIM) is one technique that may offer easy-to-follow metrics. Here, we evaluate the time course and character of the change in single- and multi-frequency EIM parameters in the hind-limb suspension model of muscle deconditioning in rats. METHODS: Sixty-two rats were studied with EIM during a two-week period of hind limb unloading followed by a two-week recovery period. Random subsets of animals were sacrificed at one-week time intervals to measure muscle fiber size. RESULTS: Significant alterations were observed in nearly all impedance parameters. The 50 kHz phase and multi-frequency phase-slope, created by taking the slope of a line fitted to the impedance values between 100-500 kHz, appeared most sensitive to disuse atrophy, the latter decreasing by over 33.0+/-6.6% (p<0.001), a change similar to the maximum reduction in muscle fiber size. Impedance alterations, however, lagged changes in muscle fiber size. CONCLUSIONS: EIM is sensitive to disuse change in the rat, albeit with a delay relative to alterations in muscle fiber size. Given the rapidity and simplicity of EIM measurements, the technique could prove useful in providing a non-invasive approach to measuring disuse change in animal models and human subjects. PMID- 23445914 TI - Sclerostin and DKK1 levels during 14 and 21 days of bed rest in healthy young men. AB - OBJECTIVES: Wnt signaling pathway may be crucial in the pathogenesis of disuse induced bone loss. Sclerostin and DKK1, antagonists of the Wnt signaling pathway, were assessed during immobilization by bed rest in young, healthy people. METHODS: Two bed rest studies were conducted at the German Aerospace Center in Cologne. 14 days of 6 degrees head-down-tilt bed rest were applied to eight healthy young male test subjects in study 1 and 21 days of head-down-tilt bed rest to seven healthy male subjects in study 2. RESULTS: Sclerostin levels increased in both studies during bed rest (study 1, 0.64+/-0.05 ng/ml to 0.69+/ 0.04 ng/ml, P=0.014; study 2, 0.42+/-0.04 ng/ml to 0.47+/-0.04 ng/ml, P=0.008) and they declined at the end of the 14- and 21-day bed rest periods. DKK1 decreased during the bed rest period in study 1 (P<0.001) but increased during bed rest in study 2 (P=0.006). As expected, bone formation marker PINP decreased (study 1, P=0.013; study 2, P<0.001) and bone resorption marker NTX increased during bed rest (P<0.001). CONCLUSION: Data suggest that the Wnt signaling pathway is involved in disuse-induced bone loss in young, healthy humans. PMID- 23445915 TI - Bone geometry and strength are adapted to muscle force in children and adolescents perinatally infected with HIV. AB - OBJECTIVES: To determine if bone health is compromised in perinatally HIV infected youth. METHODS: We assessed BMC at the proximal femur, lumbar spine and total body using DXA in perinatally HIV-infected youth (n=31; 9-18y). Using pQCT, we assessed muscle CSA, total and cortical bone area, cortical BMD and thickness and strength strain index at the tibial shaft. Thirty and 18 participants returned at 12- and 24-months, respectively. We calculated age- and sex-specific z-scores for the HIV-infected youth using data from a healthy cohort (n=883; 9 18y). RESULTS: At baseline, height and MCSA were reduced in HIV-infected youth ( 0.79 to -0.23, p<0.05). BMC z-scores adjusted for height and lean mass were lower than controls at all sites except the lumbar spine (-0.57 to -0.27, p<0.05). Bone area and strength z-scores were not different from zero after adjusting for tibial length and MCSA. In contrast, cortical BMD z-scores were greater in HIV infected youth (0.46, p=0.011). Z-scores for all bone outcomes showed positive trends over time in HIV-infected youth. CONCLUSION: Although HIV infection may be associated with bone mass deficits during growth, bone geometry and strength appear adapted to muscle force. Further, deficits in bone mass may dissipate over time in this population. PMID- 23445916 TI - Bone strength and density via pQCT in post-menopausal osteopenic women after 9 months resistive exercise with whole body vibration or proprioceptive exercise. AB - OBJECTIVES: In order to better understand which training approaches are more effective for preventing bone loss in post-menopausal women with low bone mass, we examined the effect of a nine-month resistive exercise program with either an additional whole body vibration exercise (VIB) or balance training (BAL). METHODS: 68 post-menopausal women with osteopenia were recruited for the study and were randomised to either the VIB or BAL group. Two training sessions per week were performed. 57 subjects completed the study (VIB n=26; BAL n=31). Peripheral quantitative computed tomography (pQCT) measurements of the tibia, fibula, radius and ulna were performed at baseline and at the end of the intervention period at the epiphysis (4% site) and diaphysis (66% site). Analysis was done on an intent-to-treat approach. RESULTS: Significant increases in bone density and strength were seen at a number of measurement sites after the intervention period. No significant differences were seen in the response of the two groups at the lower-leg. CONCLUSIONS: This study provided evidence that a twice weekly resistive exercise program with either additional balance or vibration training could increase bone density at the distal tibia after a nine month intervention period in post-menopausal women with low bone mass. PMID- 23445917 TI - Changes in bone density and geometry of the radius in chronic stroke and related factors: a one-year prospective study. AB - OBJECTIVES: To describe the changes in bone density and geometry of the radius after chronic stroke and the associated clinical factors. METHODS: Twenty stroke patients (12 men and 8 women, age=42-78 years, time post-stroke=12-166 months) and 23 control participants (14 men and 9 women, age=53-77 years) were assessed at the time of enrolment and one year later. Peripheral quantitative computed tomography was used to scan the radius epiphysis (4% site) and diaphysis (33% site). Grip strength, spasticity, paretic arm disuse, physical activity, and vascular health were also evaluated. RESULTS: During the follow-up period, only the cortical thickness and cortical bone mineral content (BMC) in the paretic radius diaphysis showed a decline that exceeded the least significant change value (p=0.002). Paretic arm disuse, lower vascular elasticity and physical activity level at initial assessment were significantly related to more decline in cortical thickness at this site (p<0.01). CONCLUSIONS: The paretic radius diaphysis sustained significant reduction in cortical thickness and cortical BMC over time in chronic stroke, but these changes were less pronounced than those previously reported in sub-acute stroke. Strategies to modify vascular health, disuse, and physical activity may be important in improving upper limb bone health but will need further investigations. PMID- 23445918 TI - Variation in cortical density within the cortical shell of individuals across a range in densities and ages. AB - OBJECTIVES: The purpose of this study was to determine variability in cortical volumetric bone density (vBMD) from a single slice tibia image over a range of vBMD readings and ages. METHODS: Males and females (N=80; aged 6-80) were randomly selected from a previous study. Cortical vBMD at the anterior, posterior, medial, and lateral regions as well as the endocortical, mid-cortical, and pericortical regions of the cortical shell were determined using pQCT. RESULTS: Mean anterior ROI cortical vBMD (1111+/-11 mg/cm(3)) was lower than the posterior and lateral ROIs (1169+/-7 mg/cm(3) and 1151+/-9 mg/cm(3), respectively), (p<0.05). Individuals with lower overall cortical vBMD and younger individuals had greater vBMD variability within the shell (r=0.37, p=0.004). Difference between anterior and posterior regions was inversely associated with cortical vBMD and jump power (r=0.46, p=0.001). Endocortical vBMD (1080+/-6 mg/cm) was lower than the mid-cortical and pericortical regions (1152+/-5 mg/cm(3) and 1147+/-5 mg/cm, respectively). CONCLUSIONS: Variability in cortical vBMD was higher among young individuals and those with lower overall cortical vBMD, while lowest in older individuals and men. The anterior ROI had lower mean cortical vBMD than posterior or lateral regions, and endocortical vBMD was lower than the mid- and pericortical regions. PMID- 23445919 TI - The effect of the oral contraceptive pill on the passive stiffness of the human gastrocnemius muscle in vivo. AB - The aim of this investigation was to determine the effect of sustained monophasic oral contraceptive pill (MOCP) use on the in vivo passive stiffness of the gastrocnemius medialis (GM) muscle-tendon unit. Twenty four females volunteered for this study (age range 20-25 yrs); twelve participants had been taking the combined MOCP for a minimum of 12 months, and twelve participants, who had never taken the MOCP, formed a control group. Distal displacement of the GM myotendinous junction (MTJ) was measured during passive dorsiflexion at 2 Nm increments to 20 Nm, and at end range of motion using ultrasonography. In addition, GM MTJ displacement was measured at passive torques equivalent to 5, 10 and 15% of plantarflexion maximal voluntary contraction (MVC) torque, and relative to GM length. MOCP users had significantly greater GM MTJ displacement at all passive torques (P<0.01), reaching 40% more at 20 Nm; these displacements remained significantly different when MVC and GM length were accounted for (P<0.01). Passive muscle stiffness from 0-20 Nm was 31% less in MOCP users compared to non-users (P<0.01). In conclusion, based on the in vivo assessment of GM MTJ displacement, passive muscle stiffness is less in MOCP using females, compared to non-pill users. PMID- 23445920 TI - Is exercise-induced muscle damage susceptibility body segment dependent? Evidence for whole body susceptibility. AB - OBJECTIVE: The current study examined serum CK activity following bench press (BP) and leg press (LP) exercise-induced muscle damage to evaluate agreement of subjects classification as either high (HiR) or normal responders (NoR) between upper and lower body muscle groups. METHODS: Forty-two men performed two resistance exercise bouts (BP and LP) of four sets of maximum repetitions to concentric failure at 10RM, following a random design. RESULTS: Fourteen subjects were classified as HiR after the BP and thirteen subjects after LP, while nine subjects were classified as HiR for both exercises. The analysis revealed good agreement (Kappa=0.528, with SE=0.137 and 95% confidence interval: from 0.259 to 0.798). Additionally, we found a significant moderate correlation (r=0.65, p<0.001) between CK peaks obtained following LP and BP. CONCLUSION: Our results suggest that exercise-induced muscle damage susceptibility is a whole body characteristic and is not body segment dependent. Thus, it may be that genetic or systemic mechanisms explain individual variation in muscle damage susceptibility. PMID- 23445921 TI - Vitamin D status and muscle function in children with neurofibromatosis type 1 (NF1). AB - OBJECTIVES: The aim of this cross-sectional study was to assess the vitamin D status and muscle function in children with NF1 compared with their unaffected siblings. METHODS: NF1 children between 5 and 18 years of age and who had at least one unaffected sibling were identified. Serum concentrations of 25 hydroxyvitamin D (25(OH)D), calcium, inorganic phosphate, alkaline phosphate, parathyroid hormone and 1,25-dihydroxyvitamin D were measured. The Leonardo Mechanography Ground Reaction Force Platform (GRFP) was used to measure EFI, jump power, force and height. RESULTS: There was no significant difference in 25(OH)D between NF1 subjects and unaffected siblings. Relative jump power and force were found to be significantly different. The adjusted means (95% confidence limits) of non-NF1 and NF1 children for relative jump power (W/kg), controlling for body mass and age, were 37.31 (34.14, 40.49) and 32.51 (29.34, 35.68), respectively (P=0.054); and force (N/kg), controlling for body mass, age and gender, were 25.79 (24.28, 27.30) and 21.12 (19.61, 22.63), respectively (P<0.0001). Jumping parameters were not related to serum 25(OH)D. CONCLUSIONS: There was no significant relationship between vitamin D status and NF1 status in children. NF1 children had significantly impaired jumping power and force, when compared to their unaffected siblings. PMID- 23445922 TI - Fibrous dysplasia; confirmation of clinical diagnosis by DNA tests instead of biopsy. PMID- 23445923 TI - Dissociative paraplegia after epidural anesthesia: a case report. AB - INTRODUCTION: Clinicians are confronted with considerable difficulties in diagnosing conversion disorders such as dissociative paraplegia. In the literature, there is still no sufficient evidence regarding a typical pattern or general characteristics for this neuropsychiatric syndrome. Over the last decades case reports have described patients with similar personality traits, psychopathological characteristics, history and symptoms. CASE PRESENTATION: We present the case of a 67-year-old Caucasian woman of high economic status and educational level with no psychopathological symptoms and no history of mental disorders who developed dissociative paraplegia after epidural anesthesia. The neurological examination revealed incongruous features, and repeated spine magnetic resonance imaging was normal. Three years earlier the patient had transient paralysis of her left lower limb without detectable cause. CONCLUSION: We identified an association between stressful life events and neurological anomalies. Crucial for the diagnosis of dissociative paraplegia is the neurological examination. Our case demonstrates that lack of psychopathological features and previous psychiatric diagnosis are not sufficient to exclude dissociative paraplegia. In patients with incongruous neurological findings and absent neurobiological correlates, clinicians should consider the presence of conversion disorders such as dissociative paraplegia. PMID- 23445924 TI - Qualitative and quantitative characterization of protein-phosphoinositide interactions with liposome-based methods. AB - We characterized phosphoinositide binding of the S. cerevisiae PROPPIN Hsv2 qualitatively with density flotation assays and quantitatively through isothermal titration calorimetry (ITC) measurements using liposomes. We discuss the design of these experiments and show with liposome flotation assays that Hsv2 binds with high specificity to both PtdIns3P and PtdIns(3,5)P 2. We propose liposome flotation assays as a more accurate alternative to the commonly used PIP strips for the characterization of phosphoinositide-binding specificities of proteins. We further quantitatively characterized PtdIns3P binding of Hsv2 with ITC measurements and determined a dissociation constant of 0.67 uM and a stoichiometry of 2:1 for PtdIns3P binding to Hsv2. PtdIns3P is crucial for the biogenesis of autophagosomes and their precursors. Besides the PROPPINs there are other PtdIns3P binding proteins with a link to autophagy, which includes the FYVE domain containing proteins ZFYVE1/DFCP1 and WDFY3/ALFY and the PX-domain containing proteins Atg20 and Snx4/Atg24. The methods described could be useful tools for the characterization of these and other phosphoinositide-binding proteins. PMID- 23445927 TI - [Towards new diagnostic systems: Process, questions, and dilemmas]. PMID- 23445925 TI - Adiposity and cognitive decline in the cardiovascular health study. AB - BACKGROUND: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study. METHODS: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline. RESULTS: The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 +/- 5.2 and 73.9 +/- 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow up, poor self-reported health, or persons with cardiovascular disease. CONCLUSIONS: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions. PMID- 23445926 TI - Effect of data normalization on the creation of neuro-probabilistic atlases. AB - In the past 15 years, rapid improvements in imaging technology and methodology have had a tremendous impact on how we study the human brain. During deep brain stimulation surgeries, detailed anatomical images can be combined with physiological data obtained by microelectrode recordings and microstimulations to address questions relating to the location of specific motor or sensorial functions. The main advantage of techniques such as microelectrode recordings and microstimulations over brain imaging is their ability to localize patient physiological activity with a high degree of spatial resolution. Aggregating data acquired from large populations permits to build what are commonly referred to as statistical atlases. Data points from statistical atlases can be combined to produce probabilistic maps. A crucial step in this process is the intersubject spatial normalization that is required to relate a position in one subject's brain to a position in another subject's brain. In this paper, we study the impact of spatial normalization techniques on building statistical atlases. We find that the Talairach or anterior-posterior commissure coordinate system commonly used in the medical literature produces atlases that are more dispersed than those obtained with normalization methods that rely on nonlinear volumetric image registration. We also find that the maps produced using nonlinear techniques correlate with their expected anatomic positions. PMID- 23445928 TI - [Attention deficits and response to drug therapy in patients with treatment resistant schizophrenia: results through confirmatory factor analysis]. AB - INTRODUCTION: There are no experimental data that demonstrate whether patients with neuroleptic-resistant schizophrenia differ or not in their pattern of neuropsychological functioning from patients with adequate drug response. METHOD: Fifty-two patients with drug-resistant psychosis (DRP) and 42 patients with schizophrenia not resistant to treatment (NDRP) were recruited following the criteria of Kane et al (1988). A sample of 45 healthy controls matched by age, sex and educational level was also recruited. The clinical evaluations used were the Positive and Negative Symptom Scale (PANSS), functional disability (WHO-DAS) and the Clinical Global Impression (CGI) scale. RESULTS: Through the use of confirmatory factor analysis, we obtained a latent cognitive structure of six cognitive factors: attention, processing speed, verbal memory, working memory, verbal fluency and executive functions. As expected, the control group performed better than the two patient groups (both DRP and NDRP) in all neuropsychological domains. Additionally, the DRP group scored significantly worse in attention than the NDRP group even though no differences between these two groups were found in age of disease onset, number of hospitalizations or length of hospitalization. From a clinical point of view, the DRP group showed greater severity of positive symptoms (p<0.01) and higher global deterioration (p<0.01), which did not translate into greater functional disability. CONCLUSIONS: The results obtained do not allow us to conclude that there is a specific neuropsychological profile in neuroleptic-resistant patients. The only differential parameter was performance in the attentional domain. Our findings better fit the hypothesis of a "clinical continuum" and differ from the categoric classification of this mental disorder. PMID- 23445929 TI - [Evaluation of the efficacy of involuntary outpatient treatment in reducing the use of mental health services in hospital]. AB - OBJECTIVE: To determine whether psychiatric patients in involuntary outpatient treatment (IOT) show reduced use of mental health services in hospital compared with a control group not subject to a judicial order. METHOD: We compared a group of patients in IOT (n=38) with a control group (n=38), selected from involuntarily hospitalized patients during the same period. Patients in the control group had similar sociodemographic, clinical and psychiatric characteristics to the group with IOT. We analyzed the number of emergencies, inpatient admissions and length of hospital stay during a follow-up period of 6 months after the beginning of the judicial order in the IOT group or after hospital discharge in the control group. RESULTS: No significant differences were found between the IOT and the control group in hospital use (number of emergencies, inpatient admissions and mean length of hospital stay). CONCLUSIONS: These results question the efficacy of IOT to reduce the use of hospital services. PMID- 23445930 TI - [Cognitive complaints in schizophrenia: relationship with insight and other cognitive measures]. AB - INTRODUCTION: Individuals diagnosed with schizophrenia have significant cognitive deficits. However, the subjective perception of these deficits do not always coincide with the neuropsychological test and clinical ratings. METHODOLOGY: This study evaluates the cognitive performance of 46 outpatients with schizophrenia, in a Psychosocial Rehabilitation Program, by three different measures: neuropsychological tests (objective assessment), cognitive factor of PANSS (clinical ratings), and subjective scale of cognition, SSTICS (patient self report). Also studies the possible relationship between subjective assessment of cognitive symptoms and insight of the mental disorder (SUMD). RESULTS: SSTICS total score correlated only with some neuropsychological subtest, but not with cognitive factor of PANSS. The clinical ratings is more consistent with neuropsychological test than the cognitive complaints. No relationship between SUMD and SSTICS. CONCLUSIONS: Because of the lack of correspondence among several measures, it is possible to think that have been evaluated different cognitive areas. So, it is important to consider all options of assessment in order to create cognitive rehabilitation programs. Cognitive complaints seems to be an independent variable of insight. PMID- 23445931 TI - [Violence against women in mental health departments: Is it relevant for mental health professionals?]. AB - INTRODUCTION: Violence against women (VaW) directly influences their quality of life and mental health. Unfortunately, its influence may be ignored or underestimated by professionals attending these women. OBJECTIVES: To describe a hospitalized sample of women suffering from emergent VaW who visited the mental health department for other reasons. To evaluate the degree of knowledge about VaW and interventions for VaW taken by health professionals. METHODS: We performed an observational, prospective study with systematic data collection on all cases of emergent and/or urgent VaW at the Corporacio Sanitaria Parc Tauli (Sabadell, Spain) from January-December 2004 and January-December 2006. The reference population consisted of 390,000 inhabitants, mostly urban and from the industrial and service economic sectors. A descriptive statistical analysis was performed. RESULTS: In the two study periods, 218 and 194 women, respectively, were attended for emergent and/or urgent VaW resulting in severe injures and/or medical and/or social assistance. Of these, up to 53 received or had received specialized mental health treatment. Most of these women (69.7%) withdrew from follow-up. We detected a high rate of comorbid abuse or dependence on alcohol (27.3%), benzodiazepines (33.3%) or other drugs of abuse and a high rate of suicide attempts (41.9%) and successful suicides in these periods. VaW was explicitly registered in only 51.1% of the cases and a specific intervention for VaW was documented in only 15.2% of the cases. CONCLUSIONS: The prevalence of psychiatric and/or psychological disorders was very high in our sample, but the presence of VaW was not always specifically documented or treated. PMID- 23445932 TI - [Pyschotherapygenetics. Do genes influence psychotherapy adherence?]. AB - OBJECTIVE: There is probably an association between genetic factors, personality traits and response to psychotherapy. We propose the new concept of "psychotherapygenetics" as a strategy to study how genetic factors may influence psychotherapeutic response. The aim was to examine the association between polymorphisms of the serotonin transporter gene (SERT) and the dopamine 4 receptor gene (DRD4) with adherence to psychotherapy. METHOD: We performed a prospective study of 110 patients with borderline personality disorder (BPD) who participated in dialectical behavioral therapy (DBT). Three polymorphisms were examined: the 5-HTTLPR and the VNTR on the SERT gene and the 7-repeat allele (D4.7) on the DRD4 gene. The dropout rate and the mean number of sessions attended were used as an adherence index. RESULTS: The presence of the 12-repeat allele on the VNTR polymorphism of SERT was associated with higher adherence to psychotherapy. There was no significant association between the 5-HTTLPR or D4.7 polymorphisms and adherence. CONCLUSIONS: Our preliminary results show a correlation between certain genetic variations and adherence to DBT in patients with BPD. A "psychotherapygenetics" approach could be useful to study how genetic variables may influence patients' psychotherapy response. PMID- 23445933 TI - Neural connectivity abnormalities in autism: insights from the Tuberous Sclerosis model. AB - Autism Spectrum Disorder (ASD) is a behavioral syndrome caused by complex genetic and non-genetic risk factors. It has been proposed that these risk factors lead to alterations in the development and 'wiring' of brain circuits and hence, the emergence of ASD. Although several lines of research lend support to this theory, etiological and clinical heterogeneity, methodological issues and inconsistent findings have led to significant doubts. One of the best established, albeit rare, causes of ASD is the genetic condition Tuberous Sclerosis Complex (TSC), where 40% of individuals develop ASD. A recent study by Peters and Taquet et al. analyzed electroencephalography (EEG) data using graph theory to model neural 'connectivity' in individuals with TSC with and without ASD and cases with 'idiopathic' ASD. TSC cases exhibited global under-connectivity and abnormal network topology, whereas individuals with TSC + ASD demonstrated similar connectivity patterns to those seen in individuals with idiopathic ASD: decreased long- over short-range connectivity. The similarity in connectivity abnormalities in TSC + ASD and ASD suggest a common final pathway and provide further support for 'mis-wired' neural circuitry in ASD. The origins of the connectivity changes, and their role in mediating between the neural and the cognitive/behavioral manifestations, will require further study.Please see related research article here http://www.biomedcentral.com/1741-7015/11/54. PMID- 23445934 TI - Cerebral basis of posttraumatic stress disorder following the Chernobyl disaster. AB - BACKGROUND: Whether posttraumatic stress disorder (PTSD) following radiation emergency has psychopathological, neurocognitive, and neurophysiological peculiarities is at issue. OBJECTIVE: The goal was to explore the features and cerebral basis of "radiation" PTSD in the survivors of the Chernobyl accident. Subjects and Methods The cross-sectional study included 241 people, 219 of whom have been diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, among them 115 clean-up workers of the Chernobyl accident (34 with acute radiation sickness), 76 evacuees from the Chernobyl exclusion zone, 28 veterans of the war in Afghanistan, and 22 healthy unexposed individuals. Psychometric examinations, neurocognitive assessments, computerized electroencephalography, and cerebral vascular Doppler were used. RESULTS: "Radiation" PTSD includes "flashforward" phenomena and anticipating stress (projection of fear and danger to the future); somatoform disorders (depression, trait and state anxiety); and neurocognitive deficit (impaired memory and attention, auditory-verbal memory and learning, proactive and retroactive interference, cerebellar and stem symptoms, intellectual changes). The intima-media component, thickness of common carotid arteries, and common and left internal carotid arteries stenosis rates are increased in the liquidators. Changes of bioelectrical brain activity as a decrease of beta- and theta-power, together with an increase of alpha-power, were found in the Chernobyl accident survivors with PTSD. CONCLUSIONS: PTSD following radiation emergency is characterized by comorbidity of psychopathology, neurocognitive deficit, and cerebrovascular pathology with increased risk of cerebral atherosclerosis and stroke. The cerebral basis of this PTSD is proposed to be an abnormal communication between the pyramidal cells of the neocortex and the hippocampus, and deep brain structures. It is recommended that a system of emergency and long-term psychological and psychiatric care be organized for the survivors in Fukushima Daichi, Japan. PMID- 23445935 TI - Maternal circulating leukocytes display early chemotactic responsiveness during late gestation. AB - BACKGROUND: Parturition has been widely described as an immunological response; however, it is unknown how this is triggered. We hypothesized that an early event in parturition is an increased responsiveness of peripheral leukocytes to chemotactic stimuli expressed by reproductive tissues, and this precedes expression of tissue chemotactic activity, uterine activation and the systemic progesterone/estradiol shift. METHODS: Tissues and blood were collected from pregnant Long-Evans rats on gestational days (GD) 17, 20 and 22 (term gestation). We employed a validated Boyden chamber assay, flow cytometry, quantitative real time-polymerase chain reaction, and enzyme-linked immunosorbent assays. RESULTS: We found that GD20 maternal peripheral leukocytes migrated more than those from GD17 when these were tested with GD22 uterus and cervix extracts. Leukocytes on GD20 also displayed a significant increase in chemokine (C-C motif) ligand 2 (Ccl2) gene expression and this correlated with an increase in peripheral granulocyte proportions and a decrease in B cell and monocyte proportions. Tissue chemotactic activity and specific chemokines (CCL2, chemokine (C-X-C motif) ligand 1/CXCL1, and CXCL10) were mostly unchanged from GD17 to GD20 and increased only on GD22. CXCL10 peaked on GD20 in cervical tissues. As expected, prostaglandin F2alpha receptor and oxytocin receptor gene expression increased dramatically between GD20 and 22. Progesterone concentrations fell and estradiol 17beta concentrations increased in peripheral serum, cervical and uterine tissue extracts between GD20 and 22. CONCLUSION: Maternal circulating leukocytes display early chemotactic responsiveness, which leads to their infiltration into the uterus where they may participate in the process of parturition. PMID- 23445936 TI - Towards an ontogenetic understanding of inflorescence diversity. AB - BACKGROUNDS AND AIMS: Conceptual and terminological conflicts in inflorescence morphology indicate a lack of understanding of the phenotypic diversity of inflorescences. In this study, an ontogeny-based inflorescence concept is presented considering different meristem types and developmental pathways. By going back to the ontogenetic origin, diversity is reduced to a limited number of types and terms. METHODS: Species from 105 genera in 52 angiosperm families are investigated to identify their specific reproductive meristems and developmental pathways. Based on these studies, long-term experience with inflorescences and literature research, a conceptual framework for the understanding of inflorescences is presented. KEY RESULTS: Ontogeny reveals that reproductive systems traditionally called inflorescences fall into three groups, i.e. 'flowering shoot systems' (FSS), 'inflorescences' sensu stricto and 'floral units' (FUs). Our concept is, first, based on the identification of reproductive meristem position and developmental potential. The FSS, defined as a seasonal growth unit, is used as a reference framework. As the FSS is a leafy shoot system bearing reproductive units, foliage and flowering sequence play an important role. Second, the identification of two different flower-producing meristems is essential. While 'inflorescence meristems' (IMs) share acropetal primordia production with vegetative meristems, 'floral unit meristems' (FUMs) resemble flower meristems in being indeterminate. IMs produce the basic inflorescence types, i.e. compound and simple racemes, panicles and botryoids. FUMs give rise to dense, often flower-like units (e.g. heads). They occur solitarily at the FSS or occupy flower positions in inflorescences, rendering the latter thyrses in the case of cymose branching. CONCLUSIONS: The ontogenetic concept differs from all existing inflorescence concepts in being based on meristems and developmental processes. It includes clear terms and allows homology statements. Transitional forms are an explicit part of the concept, illustrating the ontogenetic potential for character transformation in evolution. PMID- 23445937 TI - Biochemical and physiological bases for utilization of dietary amino acids by young Pigs. AB - Protein is quantitatively the most expensive nutrient in swine diets. Hence it is imperative to understand the physiological roles played by amino acids in growth, development, lactation, reproduction, and health of pigs to improve their protein nutrition and reduce the costs of pork production. Due to incomplete knowledge of amino acid biochemistry and nutrition, it was traditionally assumed that neonatal, post-weaning, growing-finishing, and gestating pigs could synthesize sufficient amounts of all "nutritionally nonessential amino acids" (NEAA) to support maximum production performance. Therefore, over the past 50 years, much emphasis has been placed on dietary requirements of nutritionally essential amino acids as building blocks for tissue proteins. However, a large body of literature shows that NEAA, particularly glutamine, glutamate, arginine and proline regulate physiological functions via cell signaling pathways, such as mammalian target of rapamycin, AMP-activated protein kinase, extracellular signal-related kinase, Jun kinase, mitogen-activated protein kinase, and NEAA-derived gaseous molecules (e.g., nitric oxide, carbon monoxide, and hydrogen sulfide). Available evidence shows that under current feeding programs, only 70% and 55% of dietary amino acids are deposited as tissue proteins in 14-day-old sow-reared piglets and in 30 day-old pigs weaned at 21 days of age, respectively. Therefore, there is an urgent need to understand the roles and dietary requirements of NEAA in swine nutrition. This review highlights the basic biochemistry and physiology of absorption and utilization of amino acids in young pigs to enhance the efficacy of utilization of dietary protein and to minimize excretion of nitrogenous wastes from the body. PMID- 23445938 TI - Caspases playing in the field of neuroinflammation: old and new players. AB - Neuroinflammation is a complex immune response against the harmful effects of diverse stimuli within the central nervous system. Caspases are a family of intracellular cysteine proteases that mediate proteolytic events indispensable for transduction of signaling pathway-controlling biological phenomena such as apoptosis and inflammation. To date, 14 players have been identified in mammals. For many years, caspases were simply divided into 'apoptotic' and 'proinflammatory' caspases and this classification remains useful to some extent. However, increasing evidence indicates that many of these so-called apoptotic caspases also exert nonapoptotic functions. In addition, the role of certain members of the supposed inflammatory caspases in the inflammatory process per se has also been discussed. In this review, we highlight the role for 'apoptotic' and 'proinflammatory' caspases in the regulation of the inflammation response with a special focus on the central nervous system. PMID- 23445940 TI - Evaluation of a health literacy screening tool in primary care patients: evidence from Serbia. AB - Improving health literacy skills is important for patient comprehension of health related topics and their ability to attend to their medical problems. Promoting health literacy is a pivotal policy for maintaining and promoting health. The objective of the present study was to translate the Test of Functional Health Literacy in Adults (TOFHLA; long and short versions) into Serbian and evaluate the translated and cross-culturally adapted questionnaires in Serbian primary care patients. The translated TOFHLA questionnaires were administered to 120 patients. Additionally, a self-completed questionnaire was used. Both descriptive and inferential statistics were measured. The mean score for the TOFHLA was 73.49 (median, 78; SD = 17.94; range, 0-100) and the mean score for the Short Test of Functional Health Literacy in Adults (STOFHLA) was 29.28 (median, 32; SD = 6.16; range, 0-36). Sex, age, education, self-perceived health and presence of any chronic disease were associated with health literacy scores. The internal consistency (Cronbach's alpha) was 0.73 for the TOFHLA numeracy subset, 0.95 for reading comprehension, 0.94 for the TOFHLA and 0.90 for the STOFHLA. The Pearson correlation between the TOFHLA and STOFHLA was 0.89. The area under the curve of these two tests was 0.79 (95% CI, 0.602-0.817). The Serbian translated versions of the TOHFLA questionnaires offer valid measures of functional health literacy. There were no differences between the reliability and validity of the short and long TOFHLA forms. PMID- 23445939 TI - Combinations of social participation and trust, and association with health status-an Australian perspective. AB - A limited number of studies have examined the 'miniaturization of community' model which is based on belief that 'new' individualistic, and narrower forms of social participation, do not promote generalized trust in others. Little is known about miniaturization of community and self-reported health, physical health and psychological health in Australia. Data from a 2009 computer-assisted-telephone interview survey was used to investigate generalized trust, social participation and health-related quality of life in a regional Australian population (n = 1273; mean age 51.2 years). Logistic regression analyses were performed to investigate the associations between generalized trust, social participation and poor self reported health (global self-rated, psychological and physical), and included four social participation/trust categories. A majority (67%) reported high generalized trust of others, 54% were categorized as high social participators. Miniaturization of community was a risk factor for poor self-rated psychological health across genders, and a risk factor for poor self-rated health for males. For women, low social participation (irrespective of trust level) was associated with poor self-reported health. Given current and previous findings, there is a need for further research in a range of contexts which explores the underlying concept of miniaturization of community, that is, the changes in social participation and social networks which may negatively impact community health. PMID- 23445941 TI - Exploring the process of capacity-building among community-based health promotion workers in Alberta, Canada. AB - Community capacity-building is a central element to health promotion. While capacity-building features, domains and relationships to program sustainability have been well examined, information on the process of capacity-building as experienced by practitioners is needed. This study examined this process as experienced by coordinators working within a community-based chronic disease prevention project implemented in four communities in Alberta (Canada) from 2005 2010 using a case study approach with a mixed-method design. Data collection involved semi-structured interviews, a focus group and program documents tracking coordinator activity. Qualitative analysis followed the constant comparative method using open, axial and selective coding. Quantitative data were analyzed for frequency of major activity distribution. Capacity-building process involves distinct stages of networking, information exchange, partnering, prioritizing, planning/implementing and supporting/ sustaining. Stages are incremental though not always linear. Contextual factors exert a great influence on the process. Implications for research, practice and policy are discussed. PMID- 23445942 TI - Effects of magnolol on impairment of learning and memory abilities induced by scopolamine in mice. AB - Alzheimer's disease (AD), one of the most common forms of dementia, is primarily ascribed to the cholinergic deficits and neuronal dysfunction. Magnolol (Mag), a bioactivator extracted from Magnolia officinalis, has protective effects on cholinergic neurons, but the specific mechanism remains unknown. To further evaluate the therapeutic effects of Mag on the learning and memory impairment in a scopolamine (Scop)-induced mouse model, the passive avoidance and the Morris water maze tests, the measurement of the ratio of brain/hippocampus to body weight, activities of acetyl cholinesterase (AChE), superoxide dismutase (SOD), total nitric oxide synthase (total NOS) and the content of methane dicarboxylic aldehyde (MDA) in hippocampus homogenate as well as the immunefluorescence staining of the AChE positive nerve fibers were performed. Therapeutically treated with Mag, the impaired abilities of learning and memory of the Scop induced mice were almost restored to the native levels. The restored AChE, total NOS and SOD activities and the MDA level were observed, with a relatively normal density of AChE positive nerve fibers in hippocampus CA3 molecular layer. The improving efficacy of Mag on learning and memory impairment induced by Scop is dose-dependent, indicating that Mag has potential neuroprotective effects against neuronal impairment and memory dysfunction induced by Scop in mice. The underlying mechanisms may be associated with the anti-oxidative effects of Mag and its protective effects on hippocampus cholinergic neurons. PMID- 23445943 TI - Migration confers survival benefits against avian predators for partially migratory freshwater fish. AB - The importance of predation risk in shaping patterns of animal migration is not well studied, mostly owing to difficulties in accurately quantifying predation risk for migratory versus resident individuals. Here, we present data from an extensive field study, which shows that migration in a freshwater fish (roach, Rutilus rutilus) that commonly migrates from lakes to streams during winter confers a significant survival benefit with respect to bird (cormorant, Phalacrocorax carbo spp.) predation. We tagged over 2000 individual fish in two Scandinavian lakes over 4 years and monitored migratory behaviour using passive telemetry. Next, we calculated the predation vulnerability of fish with differing migration strategies, by recovering data from passive integrated transponder tags of fish eaten by cormorants at communal roosts close to the lakes. We show that fish can reduce their predation risk from cormorants by migrating into streams, and that probability of being preyed upon by cormorants is positively related to the time individuals spend in the lake during winter. Our data add to the growing body of evidence that highlights the importance of predation for migratory dynamics, and, to our knowledge, is one of the first studies to directly quantify a predator avoidance benefit to migrants in the field. PMID- 23445944 TI - Exposure to sperm competition risk improves survival of virgin males. AB - Sperm competition between the ejaculates of multiple males for the fertilization of a given set of ova is taxonomically widespread. Males have evolved remarkable adaptations to increase their reproductive success under postcopulatory sexual selection, which in many species includes the ability to modify behaviour and ejaculate characteristics plastically to match the perceived level of sperm competition. Males of the model species Drosophila melanogaster increase mating duration and modify seminal fluid composition in response to short-term changes in sperm competition risk. If these responses increase a male's total investment in reproduction, he must either trade-off this cost against other life-history traits or suffer reduced survival. We tested whether mounting a plastic sperm competition response bears an instantaneous survival cost, and instead found that male D. melanogaster exposed to a high risk of sperm competition survive 12 per cent longer than those at low risk, equating to a 49 per cent reduction in the hourly hazard of death. This striking effect was found only among virgins: the high cost of mating in this species eliminates any such benefit among non-virgin males. Our results suggest that the improvement in survival found among virgins may be a product of males' tactical responses to sperm competition. PMID- 23445945 TI - Size-dependent physiological responses of shore crabs to single and repeated playback of ship noise. AB - Anthropogenic noise has fundamentally changed the acoustics of terrestrial and aquatic environments, and there is growing empirical evidence that even a single noise exposure can affect behaviour in a variety of vertebrate organisms. Here, we use controlled experiments to investigate how the physiology of a marine invertebrate, the shore crab (Carcinus maenas), is affected by both single and repeated exposure to ship-noise playback. Crabs experiencing ship-noise playback consumed more oxygen, indicating a higher metabolic rate and potentially greater stress, than those exposed to ambient-noise playback. The response to single ship noise playback was size-dependent, with heavier crabs showing a stronger response than lighter individuals. Repeated exposure to ambient-noise playback led to increased oxygen consumption (probably due to handling stress), whereas repeated exposure to ship-noise playback produced no change in physiological response; explanations include the possibility that crabs exhibited a maximal response on first exposure to ship-noise playback, or that they habituated or become tolerant to it. These results highlight that invertebrates, like vertebrates, may also be susceptible to the detrimental impacts of anthropogenic noise and demonstrate the tractability for more detailed investigations into the effects of this pervasive global pollutant. PMID- 23445946 TI - Butterfly survival on an isolated island by improved grip. AB - On small isolated islands, natural selection is expected to reduce the dispersal capacity of organisms, as short distances do not require a high rate of dispersal, which might lead to accidental emigration from the population. In addition, individuals foregoing the high cost of maintaining flight capacity may instead allocate resources to other functions. However, in butterflies and many other insects, flight is necessary not only for dispersal but also for most other activities. A weakly flying individual would probably do worse and have an elevated rather than reduced probability of accidental emigration. Here, we report results consistent with the hypothesis that a butterfly population on an isolated island, instead of having lost its flight capacity, has evolved better grip to resist the force of wind and to avoid being blown off the island. Our study suggests that local adaptation has occurred in this population in spite of its very small size (Ne ~ 100), complete isolation, low genetic variation and high genetic load. PMID- 23445947 TI - Repeated evolution of salt-tolerance in grasses. AB - The amount of salt-affected agricultural land is increasing globally, so new crop varieties are needed that can grow in salt-affected soils. Despite concerted effort to develop salt-tolerant cereal crops, few commercially viable salt tolerant crops have been released. This is puzzling, given the number of naturally salt-tolerant grass species. To better understand why salt-tolerance occurs naturally but is difficult to breed into crop species, we take a novel, biodiversity-based approach to its study, examining the evolutionary lability of salt-tolerance across the grass family. We analyse the phylogenetic distribution of naturally salt-tolerant species on a phylogeny of 2684 grasses, and find that salt-tolerance has evolved over 70 times, in a wide range of grass lineages. These results are confirmed by repeating the analysis at genus level on a phylogeny of over 800 grass genera. While salt-tolerance evolves surprisingly often, we find that its evolution does not often give rise to a large clade of salt-tolerant species. These results suggest that salt-tolerance is an evolutionarily labile trait in grasses. PMID- 23445948 TI - A trade-off between having many sons and shorter maternal post-reproductive survival in pre-industrial Finland. AB - A bias in reproduction towards sons, which are energetically more costly than daughters, has been suggested to shorten parental lifespan, but previous results have been mixed. Reproductive costs should be most evident in low rather than high resource settings, and are not expected to be severe in men, because women pay higher direct costs of reproduction. We, therefore, used demographic data from pre-industrial Finland to investigate whether the number of sons and daughters born affected their parents' post-reproductive survival and whether this was related to parent's resource availability. Irrespective of access to resources, mothers, but not fathers, with many sons suffered from reduced post reproductive survival, and this association decreased as mothers aged. Our results provide evidence that Finnish mothers traded long post-reproductive lifespan for giving birth to many sons. PMID- 23445949 TI - Low second-to-fourth digit ratio predicts indiscriminate social suspicion, not improved trustworthiness detection. AB - Testosterone administration appears to make individuals less trusting, and this effect has been interpreted as an adaptive adjustment of social suspicion, that improved the accuracy of trusting decisions. Here, we consider another possibility, namely that testosterone increases the subjective cost of being duped, decreasing the propensity to trust without improving the accuracy of trusting decisions. In line with this hypothesis, we show that second-to-fourth digit ratio (2D:4D, a proxy for effects of testosterone in the foetus) correlates with the propensity to trust, but not with the accuracy of trusting decisions. Trust game players (n = 144) trusted less when they had lower 2D:4D (high prenatal testosterone), but their ability to detect the strategy of other players was constant (and better than chance) across all levels of digit ratio. Our results suggest that early prenatal organizing effects of testosterone in the foetus might impair rather than boost economic outcomes, by promoting indiscriminate social suspicion. PMID- 23445950 TI - Optimal digestion theory does not predict the effect of pathogens on intestinal plasticity. AB - One prediction of optimal digestion theory is that organisms will increase the relative length of their digestive tracts when food resources become limited. We used theory of optimal digestion to test whether tadpoles can adjust the relative length of their intestines when challenged with the fungal pathogen Batrachochytrium dendrobatidis (Bd). The degree of tadpole mouthpart damage, a symptom of Bd infections that reduces food consumption, was associated positively with the length of tadpole intestines relative to their body size, consistent with optimal digestion theory. After controlling for mouthpart damage, tadpoles exposed to Bd had shorter intestines relative to their body size, opposite to the predictions of optimal digestion theory. One explanation of why tadpoles with higher Bd loads have shorter relative intestinal lengths is that they divert energy from maintaining intestinal and overall growth towards anti-parasite defences. PMID- 23445951 TI - Absence of major histocompatibility complex class II mediated immunity in pipefish, Syngnathus typhle: evidence from deep transcriptome sequencing. AB - The major histocompatibility complex (MHC)-mediated adaptive immune system is the hallmark of gnathostome immune defence. Recent work suggests that cod-like fishes (Gadidae) lack important components of the MHC class II mediated immunity. Here, we report a putative independent loss of functionality of this pathway in another species, the pipefish Syngnathus typhle, that belongs to a distantly related fish family (Syngnathidae). In a deep transcriptome sequencing approach comprising several independent normalized and non-normalized expressed sequence tag (EST) libraries with approximately 7.5 * 10(8) reads, sequenced with two next generation platforms (454 and Illumina), we were unable to identify MHC class IIalpha/beta genes as well as genes encoding associated receptors. Along with the recent findings in cod, our results suggest that immune systems of the Euteleosts may be more variable than previously assumed. PMID- 23445952 TI - Jaws for a spiral-tooth whorl: CT images reveal novel adaptation and phylogeny in fossil Helicoprion. AB - New CT scans of the spiral-tooth fossil, Helicoprion, resolve a longstanding mystery concerning the form and phylogeny of this ancient cartilaginous fish. We present the first three-dimensional images that show the tooth whorl occupying the entire mandibular arch, and which is supported along the midline of the lower jaw. Several characters of the upper jaw show that it articulated with the neurocranium in two places and that the hyomandibula was not part of the jaw suspension. These features identify Helicoprion as a member of the stem holocephalan group Euchondrocephali. Our reconstruction illustrates novel adaptations, such as lateral cartilage to buttress the tooth whorl, which accommodated the unusual trait of continuous addition and retention of teeth in a predatory chondrichthyan. Helicoprion exemplifies the climax of stem holocephalan diversification and body size in Late Palaeozoic seas, a role dominated today by sharks and rays. PMID- 23445954 TI - Epidemiological and clinical features of moyamoya disease in the USA. AB - BACKGROUND: An increasing number of cases of Moyamoya disease have been reported in the Japanese and US literature. We performed this study to quantify the rise in the prevalence of Moyamoya disease and to study the unique epidemiological and clinical features in the USA that may explain a change in incidence. METHODS: We analyzed data derived from patients entered in the Nationwide Inpatient Sample between 2005 and 2008, using ICD-9 codes for Moyamoya disease. Data including patient age, gender, ethnicity, secondary diagnosis, medical complications, and hospital costs were obtained. RESULTS: From 2005 to 2008 in the USA, there were an estimated 7,473 patients admitted with a primary or secondary diagnosis of Moyamoya disease. Patients admitted with Moyamoya disease were most frequently women and Caucasian. Overall, ischemic stroke was the most common reason for admission. Hemorrhagic stroke was more frequent in adults compared with children, 18.1 versus 1.5% (p < 0.05). CONCLUSION: The number of patients identified and admitted with Moyamoya disease has risen dramatically in the last decade. This study can lead to a better understanding of the disease pattern and healthcare consequences in the USA and suggests that pathophysiologic differences in Moyamoya disease may exist. PMID- 23445953 TI - Internalizing and externalizing problems, depression, and self-esteem in non detained male juvenile offenders. AB - BACKGROUND: High rates of mental disorders have been found in detained juvenile offenders, whereas the role of psychopathology in non-detained offenders is less clear. Therefore, the present study compared psychopathology in male non-detained delinquent juveniles and two matched samples from the community and an adolescent psychiatric clinic. METHODS: 125 male adolescents aged 11 to 19 years (m = 16.2 years, SD = 1.5 years) from an outpatient adolescent forensic clinic were compared to a community sample from the Zurich Adolescent Psychology and Psychopathology Study (ZAPPS) and a referred sample from a psychiatric clinic matched for age and nationality. All subjects responded to questionnaires measuring internalizing and externalizing problems, depressive symptoms and self esteem. RESULTS: The sample of non-detained juvenile offenders showed similar rates of self-reported internalizing and externalizing problems when compared to the community sample, whereas the clinic sample displayed an increased rate of various disturbances. Similar results were found also for self-esteem. In agreement with these findings, non-detained juvenile offenders less frequently had a psychiatric diagnosis after full clinical assessment when compared to the clinical sample. However, a diagnosis of conduct disorders and a lower IQ range was found more frequently in non-detained juvenile offenders. Offenders with serious delinquent acts and involving weapons showed higher depression scores than the rest of the offenders. CONCLUSION: In non-detained assessment situations before court examination, juvenile offenders present rather normal behaviour. Their lack of awareness of potential behavioural problems should be considered during assessment and treatment of this group of offenders. PMID- 23445955 TI - Ammonia in breath and emitted from skin. AB - Ammonia concentrations in exhaled breath (eNH3) and skin gas of 20 healthy subjects were measured on-line with a commercial cavity ring-down spectrometer and compared to saliva pH and plasma ammonium ion (NH(+)4), urea and creatinine concentrations. Special attention was given to mouth, nose and skin sampling procedures and the accurate quantification of ammonia in humid gas samples. The obtained median concentrations were 688 parts per billion by volume (ppbv) for mouth-eNH3, 34 ppbv for nose-eNH3, and 21 ppbv for both mouth- and nose-eNH3 after an acidic mouth wash (MW). The median ammonia emission rate from the lower forearm was 0.3 ng cm(-2) min(-1). Statistically significant (p < 0.05) correlations between the breath, skin and plasma ammonia/ammonium concentrations were not found. However, mouth-eNH3 strongly (p < 0.001) correlated with saliva pH. This dependence was also observed in detailed measurements of the diurnal variation and the response of eNH3 to the acidic MW. It is concluded that eNH3 as such does not reflect plasma but saliva and airway mucus NH(+)4 concentrations and is affected by saliva and airway mucus pH. After normalization with saliva pH using the Henderson-Hasselbalch equation, mouth-eNH3 correlated with plasma NH(+)4, which points to saliva and plasma NH(+)4 being linked via hydrolysis of salivary urea. PMID- 23445956 TI - A grassroots movement sounds the call. PMID- 23445957 TI - Advance care planning. PMID- 23445958 TI - Adequate staffing. PMID- 23445959 TI - True nursing. PMID- 23445960 TI - The elderly and depression. PMID- 23445961 TI - The elderly and depression. PMID- 23445962 TI - Unity among nurses. PMID- 23445963 TI - Global burden of disease study uncovers new challenges of longevity. PMID- 23445965 TI - Overcoming state hurdles to independent NP practice. PMID- 23445970 TI - Tobacco-use prevention goes up in smoke. PMID- 23445971 TI - The economy's effect on nursing employment. PMID- 23445979 TI - Pray, let us wash our hands. 1932. PMID- 23445980 TI - The Campaign for Action: an update. PMID- 23445981 TI - Sexuality in nursing care facilities. PMID- 23445982 TI - The timed up and go test. PMID- 23445983 TI - Creating an online journal club using WordPress.com. PMID- 23445989 TI - Nurse develops successful evidence-based parenting program. PMID- 23445991 TI - Strategies for the delivery of multiple collinear infusion clouds in convection enhanced delivery in the treatment of Parkinson's disease. AB - BACKGROUND: Delivery of multiple collinear payloads utilizing convection-enhanced delivery (CED) has historically been performed by retraction of a needle or catheter from the most distal delivery site. Few studies have addressed end infusion morphology and associated payload reflux in stacked and collinear infusions, and studies comparing the advancement with the retraction mode are lacking. OBJECTIVE: To compare advancement versus retraction mode infusion results. METHODS: Infusion cloud pairs were created with the advancement and retraction technique in agarose gel using both open end-port SmartFlow (SF) and valve tip (VT) catheter infusion systems. Backflow, radius of infusion, and morphology were assessed. RESULTS: Infusions with the SF catheter, in contrast to the VT catheter, exhibited significantly more backflow in retraction mode at the shallow infusion site. Infusion morphology differed with the second infusion after retraction: the infusate at the proximal site first filling the channel left by the retraction and then being convected into gel in a pronouncedly non spherical shape during the second infusion. CONCLUSIONS: Significant differences in cloud morphology were noted with respect to external catheter geometry with retraction versus penetration between infusions in an agarose gel model of the brain. Further study is warranted to determine optimal protocols for human clinical trials employing CED with multiple collinear payloads. PMID- 23445992 TI - [A genetic signature for complex psychiatric diseases]. PMID- 23445993 TI - [Diagnostic delay and differences by sex and clinical subtype in a cohort of outpatients with bipolar disorder]. AB - INTRODUCTION: We describe the clinical and sociodemographic features at baseline of a cohort of bipolar patients included in a prospective study. METHODS: A total of 296 consecutive outpatients with bipolar disorder were recruited. Diagnosis relied on clinical judgment according to DSM-IV-TR criteria and the semi structured MINI Interview. Retrospective data on the course of the disease and cross-sectional data on social adaptation (Social Adaptation Adjustment Self Assessment Scale (SASS) and affective symptoms were collected. Affective symptomatology (euthymia, subsyndromal symptoms and episodes) was studied according to clinical criteria and the Hamilton Depression and Young rating scales. Differences between type I and II bipolar patients and between men and women were analyzed. RESULTS: The mean age was 48.8 years (95% CI 47.2-50.4); 56.8% were women and 43.2% were men. A total of 65.2% had a diagnosis of type I bipolar disorder and 23.3% of type II; 49.8% of the sample were euthymic, 32.7% had subsyndromal symptoms and 17.5% had had an affective episode. Diagnostic delay was 9.3 years (95% CI 8.2-10.3). In patients with type II bipolar disorder, the mean age (54.4 years; 95% CI 50.9-57.9 vs. 47.7 years; 95% CI 45.8-49.7, p=0.007), age at onset of illness (35.7 years; 95% CI 31.8-39.7 vs. 29.8 years; 95% CI 28-31.6, p=0.008) and age at diagnosis (47.7 years; 95% CI 44-51.3 vs. 37.9; 95% CI 35.9-39.8, p<0.0001) were higher than in patients with type I bipolar disorder. Manic polarity in the initial episode and psychotic episodes were more frequent in men, while depressive episodes and hypothyroidism were more frequent in women. CONCLUSIONS: Our results confirm data published in our environment on sociodemographic and clinical variables but diagnostic delay in our study was longer. Compared with American samples, age at onset and at diagnosis were higher in our sample but comorbidity was much lower. PMID- 23445994 TI - [Antipsychotic polypharmacy in a general hospital in-patient psychiatric unit]. AB - INTRODUCTION: The association of antipsychotics is common in clinical practice despite the lack of scientific evidence to support this practice. There are few data on these patterns of use in hospitals in Spain. However, such data are required for the development of indicators of quality of care. AIMS: To collect information on prescription of antipsychotics in a psychiatric inpatient unit. METHODS: We performed a retrospective observational study of inpatients under treatment with antipsychotic drugs in 2006. RESULTS: We reviewed 136 patients with a mean age of 38 years and a mean length of stay of 22 days. Antipsychotics were used primarily in schizophrenic disorder (44.9%). At admission, atypical antipsychotics (second or third generation) were the most frequently used drugs in monotherapy (41.2%), a combination of two or more antipsychotics was used in 43% of the patients and the use of additional medication (not antipsychotics) was very high (84.6%). At discharge, the results were similar, but a notable finding was the increase in the combination of an atypical antipsychotic with extended release drugs (from 2% to 11%). CONCLUSIONS: The use of atypical antipsychotics as the first therapeutic option is becoming established, confirming the phenomenon of polypharmacy in the treatment of psychoses. The study design did not allow directional relations to be established but some trends, such as the possibility that polypharmacy is more common in patients with schizophrenia and is associated with the use of depot antipsychotics, were confirmed. PMID- 23445995 TI - [Longitudinal study comparing depressive female patients with and without premenstrual exacerbation]. AB - INTRODUCTION: The aim of this study was to evaluate whether there are any differences in the clinical features of depression, personality and the G factor among women with and without premenstrual exacerbation (PE) of depression. MATERIAL AND METHODS: Ninety-nine outpatients diagnosed with major depression (DSM-IV) were interviewed twice. At baseline, the patients were not taking medication. The 74 patients who achieved remission (Hamilton rating scale for depression <=7) after 16 weeks were evaluated again through the 16-personality factor (16-PF) questionnaire (5(th) edition) and the D48 (or Dominos) test. RESULTS: No differences in clinical characteristics or prognosis were found between the two groups of women, except for the greater presence of seasonal features among women with PE. Women with PE also scored higher for self-control on the 16-PF and scored lower on the D48 (Domino) test. The logistic analysis showed that higher self-control scores increased the risk for PE in 51.3% of the sample, while higher scores on the D48 test decreased the risk in 8.6%. CONCLUSIONS: There were no differences between the two groups in the clinical features or prognosis of depression, except for the higher rates of seasonal features in the PE group. In contrast, differences were found in personality traits and the D48 between the two groups. PMID- 23445996 TI - [X tetrasomy (48,XXXX karyotype) in a girl with altered behavior]. AB - INTRODUCTION: We report the case of a 14-year-old girl with mental retardation and dysmorphic features referred to child psychiatry because of altered behavior at school. MATERIAL AND METHODS: Karyotyping (GTG banding), in situ fluorescent hybridization (FISH) and molecular study of parental origin by polymorphic STS were performed. RESULTS: Genetic study revealed a 48,XXXX karyotype with a maternal origin of the X-tetrasomy. The mechanism was successive non-dysjunction at meiosis I and II. CONCLUSIONS: The interest of this case lies in the rarity of the chromosomal anomaly and its late diagnosis, leading to a failure to adapt the girl's education to her needs, with consequences for her psyche. PMID- 23445997 TI - [Quetiapine treatment in adolescents: A 6-month naturalistic study]. AB - INTRODUCTION: The aim of this study was to evaluate discontinuation of quetiapine treatment in adolescents (12-18 years) in a 6-month naturalistic follow-up study and to assess the influence of distinct demographic and clinical factors on quetiapine discontinuation. MATERIAL AND METHODS: We performed a naturalistic 6 month follow-up study in 61 antipsychotic-naive patients [39 boys (64%)] who initiated quetiapine treatment. The dependent variable was treatment discontinuation for any cause (continuation/discontinuation was a dichotomic variable). The independent variables were age, gender, race, duration of mental illness, Global Assessment of Functioning (GAF) score at treatment initiation, adverse effects in the first 16 days of treatment, the presence of involuntary movements before starting treatment, and abusive consumption or toxic dependency. RESULTS: Of the 61 patients participating in the study, 42 (68.9%) complied with quetiapine treatment for 6 months, while 19 (31.1%) discontinued the treatment (for any cause). The presence of Parkinson-like symptoms before starting treatment was a risk factor for discontinuation (Hazard Ratio=8.3, p=0.007). CONCLUSIONS: Continuation/discontinuation of quetiapine was influenced by the presence of motor symptoms before treatment initiation, which therefore affected the patient's overall prognosis. Consequently, we recommend that the presence of motor symptoms be evaluated before treatment with antipsychotic drugs is started. PMID- 23445998 TI - [Myxedema psychosis as the first manifestation of hypothyroidism]. PMID- 23445999 TI - Maternal plasma sequencing: a powerful tool towards fetal whole genome recovery. AB - Noninvasive prenatal diagnosis of chromosomal aneuploidies, although challenging, has been achieved through the implementation of novel methodologies such as methylated DNA immunoprecipitation and next generation sequencing technologies. Nevertheless, additional developments are required towards the interpretation of other fetal abnormalities of higher complexity, such as de novo mutations including microdeletion and microduplication syndromes as well as complex diseases. The application of next generation sequencing technologies towards fetal whole genome recovery has demonstrated great potential to achieve the above goal. In a research article published in Genome Medicine, Chen et al. presented a novel approach that allowed more robust and accurate characterization of parental alleles compared with previous studies. This was achieved through a revolutionary strategy based on the use of trios and unrelated individuals that simultaneously targets the interpretation of the fetal haplotype and phenotype in one step. It is hereby shown that the implementation of a more accurate experimental design in combination with proper analytical tools can provide robust noninvasive fetal whole genome recovery with the potential for further developments beyond the DNA level. PMID- 23446001 TI - A graded exposure intervention for distressing visual hallucinations in schizophrenia. AB - BACKGROUND: Distressing visual hallucinations (VH) are frequently present in schizophrenia. Despite their prevalence, limited research exists regarding effective clinical interventions. Cognitive models of VH state that distress results from threat appraisals of the hallucination. METHOD: This individual case study describes the use of a graded exposure approach following the discovery of phobic anxiety associated with visual hallucinatory content. Treatment involved 20 sessions of individual cognitive behaviour therapy (CBT), of which 12 sessions focused on graded exposure. RESULTS: A reduction in frequency of visions and associated distress was reported and these changes were maintained at a 3-month follow-up. CONCLUSIONS: The findings are consistent with the cognitive model of VH. Through exposure to the hallucinatory content, the client re-appraised her VH as non-threatening, and her fear of them reduced. This reduction in anxiety led to a decrease in the occurrence of the VH. PMID- 23446000 TI - Transgenerational programming of maternal behaviour by prenatal stress. AB - Peripartum events hold the potential to have dramatic effects in the programming of physiology and behaviour of offspring and possibly subsequent generations. Here we have characterized transgenerational changes in rat maternal behaviour as a function of gestational and prenatal stress. Pregnant dams of the parental generation were exposed to stress from days 12-18 (F0-S). Their daughters and grand-daughters were either stressed (F1-SS, F2-SSS) or non-stressed (F1-SN, F2 SNN). Maternal antepartum behaviours were analyzed at a time when pregnant dams usually show a high frequency of tail chasing behaviours. F1-SS, F2-SNN and F2 SSS groups showed a significant reduction in tail chasing behaviours when compared with controls. The effects of multigenerational stress (SSS) slightly exceeded those of transgenerational stress (SNN) and resulted in absence of tail chasing behaviour. These findings suggest that antepartum maternal behaviour in rats is programmed by transgenerational inheritance of stress responses. Thus, altered antepartum maternal behaviour may serve as an indicator of an activated stress response during gestation. PMID- 23446002 TI - Cumulative lactate and hospital mortality in ICU patients. AB - BACKGROUND: Both hyperlactatemia and persistence of hyperlactatemia have been associated with bad outcome. We compared lactate and lactate-derived variables in outcome prediction. METHODS: Retrospective observational study. Case records from 2,251 consecutive intensive care unit (ICU) patients admitted between 2001 and 2007 were analyzed. Baseline characteristics, all lactate measurements, and in hospital mortality were recorded. The time integral of arterial blood lactate levels above the upper normal threshold of 2.2 mmol/L (lactate-time-integral), maximum lactate (max-lactate), and time-to-first-normalization were calculated. Survivors and nonsurvivors were compared and receiver operating characteristic (ROC) analysis were applied. RESULTS: A total of 20,755 lactate measurements were analyzed. Data are srpehown as median [interquartile range]. In nonsurvivors (n = 405) lactate-time-integral (192 [0-1881] min.mmol/L) and time-to-first normalization (44.0 [0-427] min) were higher than in hospital survivors (n = 1846; 0 [0-134] min.mmol/L and 0 [0-75] min, respectively; all p < 0.001). Normalization of lactate <6 hours after ICU admission revealed better survival compared with normalization of lactate >6 hours (mortality 16.6% vs. 24.4%; p < 0.001). AUC of ROC curves to predict in-hospital mortality was the largest for max-lactate, whereas it was not different among all other lactate derived variables (all p > 0.05). The area under the ROC curves for admission lactate and lactate-time-integral was not different (p = 0.36). CONCLUSIONS: Hyperlactatemia is associated with in-hospital mortality in a heterogeneous ICU population. In our patients, lactate peak values predicted in-hospital mortality equally well as lactate-time-integral of arterial blood lactate levels above the upper normal threshold. PMID- 23446003 TI - Potential benefit of final kissing balloon inflation after single stenting for the treatment of bifurcation lesions--insights from optical coherence tomography observations. AB - BACKGROUND: Treatment of coronary bifurcation lesions using a single stenting strategy is preferable over that using a 2-stent technique. The benefit of final kissing inflation (FKI), however, has not been established. METHODS AND RESULTS: Seventy-two patients (76 lesions) with true bifurcation lesions treated with a single drug-eluting stent with FKI (n=33 lesions) or without FKI (non-FKI, n=43 lesions) were enrolled in this study. Optical coherence tomography (OCT) was performed at 6-12 months after implantation. Based on the OCT findings, the percentage of jailing struts (number of jailing struts/total number of struts at the bifurcation lesion) was calculated. Percentage of uncovered struts and frequency of thrombus attachment were each evaluated at the proximal, bifurcation, and distal segments. Major adverse cardiac events (MACE) were also evaluated. The percentage of jailing struts was significantly lower in the FKI than in the non-FKI group (5.8+/-6.2% vs. 17.3+/-6.1%, P<0.01). Thrombus attachment was less frequent in the FKI group (24.2% vs. 46.5%, P=0.046), especially at side-branch orifices (3.0% vs. 27.9%, P<0.001). The percentage of uncovered struts was lower in the FKI than non-FKI group at the proximal, bifurcation, and distal segments. The incidence of MACE was not different in this small cohort. CONCLUSIONS: FKI might reduce the frequency of subclinical thrombus possibly by reducing the number of jailing struts. PMID- 23446004 TI - Measurement of heart-type fatty acid-binding protein before discharge. PMID- 23446005 TI - The association between academic engagement and achievement in health sciences students. AB - BACKGROUND: Educational institutions play an important role in encouraging student engagement, being necessary to know how engaged are students at university and if this factor is involved in student success point and followed.To explore the association between academic engagement and achievement. METHODS: Cross-sectional study. The sample consisted of 304 students of Health Sciences. They were asked to fill out an on-line questionnaire. Academic achievements were calculated using three types of measurement. RESULTS: Positive correlations were found in all cases. Grade point average was the academic rate most strongly associated with engagement dimensions and this association is different for male and female students. The independent variables could explain between 18.9 and 23.9% of the variance (p < 0.05) in the population of university students being analyzed. CONCLUSIONS: Engagement has been shown to be one of the many factors, which are positively involved, in the academic achievements of college students. PMID- 23446006 TI - Morphological study of progressive glomerulonephropathy in common marmosets (Callithrix jacchus). AB - Spontaneous progressive glomerulonephropathy often occurs in common marmosets. However, there are few detailed reports concerning the age-related progressive process of glomerular changes. We discuss the glomerular changes in the early stage and the progressive changes in the advanced stage of nephropathy. We investigated the kidneys of common marmosets (2-11 years old; 9 males and 12 females) using hematoxylin and eosin, periodic acid-Schiff, periodic acid methenamine-silver, and Masson's trichrome (MT) stains and a transmission electron microscope. There was no remarkable change in urine cytology, hematology, or blood chemistry. In the early stage of nephropathy, effacement of podocyte foot processes was observed ultrastructurally even though there were no marked glomerular lesions in the light microscopy. Subsequently, mesangial proliferation occurred from the hilar to peripheral side along the tuft. In the middle stage, red deposits were visible at the glomerular basement membrane (GBM) and the mesangial region directly under the GBM (paramesangial area) with the MT stain. Electron dense deposits were seen at the same area. In the advanced stage, the irregularity became prominent with or without dense deposits. It is necessary to investigate in detail whether the change of podocyte in the early stage was immuno-mediated or due to podocyte failure. PMID- 23446008 TI - Glomerular repair retardation via blocking of angiotensin II type 1a receptor pathway in a mouse glomerulonephritis model. AB - BACKGROUND/AIMS: To examine the role of the angiotensin II (ATII) type 1a receptor (AT1-R) pathway in renal tissue damage and repair, we investigated reversible glomerular injury in a mouse model of habu snake venom (HSV)-induced glomerulonephritis using AT1-R-deficient (AT1a-/-) mice and AT1-R antagonist treated mice. METHODS: Experimental glomerulonephritis was induced by single administration of HSV to AT1a(+/+) mice (HSV group) and AT1a(-/-) mice (KO-HSV group) and AT1-R antagonist-treated BL6 mice (HSV-ARB group). Morphological change and expression levels of type IV collagen, CD31, and vascular endothelial growth factor (VEGF) were analyzed. RESULTS: The HSV group showed increased mesangial matrix expansion on day 7, which returned to preinjection levels by day 56, while mes-angial matrix expansion and increased type IV collagen expression were seen throughout days 7 to 56 in the KO-HSV group. The KO-HSV group showed fewer CD31-positive capillary loops and a marked decrease in the number of VEGF positive cells in the glomeruli than the HSV group. VEGF administration to the KO HSV group facilitated glomerular capillary repair and reconstruction. The HSV-ARB group showed the same delay in glomerular repair as that seen in the KO-HSV group. CONCLUSION: Our results indicate that blocking of the ATII-AT1R pathway delays glomerular repair via angiogenesis inhibition, followed by reduced induction of VEGF. PMID- 23446009 TI - Distortions of iris and anterior lens capsule OCT images by ICRS. PMID- 23446007 TI - Neonatal systemic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. AB - Brain inflammation via intracerebral injection with lipopolysaccharide (LPS) in early life has been shown to increase risks for the development of neurodegenerative disorders in adult rats. To determine if neonatal systemic LPS exposure has the same effects on enhancement of adult dopaminergic neuron susceptibility to rotenone neurotoxicity as centrally injected LPS does, LPS (2 MUg/g body weight) was administered intraperitoneally into postnatal day 5 (P5) rats and when grown to P70, rats were challenged with rotenone, a commonly used pesticide, through subcutaneous minipump infusion at a dose of 1.25 mg/kg/day for 14 days. Systemically administered LPS can penetrate into the neonatal rat brain and cause acute and chronic brain inflammation, as evidenced by persistent increases in IL-1beta levels, cyclooxygenase-2 expression and microglial activation in the substantia nigra (SN) of P70 rats. Neonatal LPS exposure resulted in suppression of tyrosine hydroxylase (TH) expression, but not actual death of dopaminergic neurons in the SN, as indicated by the reduced number of TH+ cells and unchanged total number of neurons (NeuN+) in the SN. Neonatal LPS exposure also caused motor function deficits, which were spontaneously recoverable by P70. A small dose of rotenone at P70 induced loss of dopaminergic neurons, as indicated by reduced numbers of both TH+ and NeuN+ cells in the SN, and Parkinson's disease (PD)-like motor impairment in P98 rats that had experienced neonatal LPS exposure, but not in those without the LPS exposure. These results indicate that although neonatal systemic LPS exposure may not necessarily lead to death of dopaminergic neurons in the SN, such an exposure could cause persistent functional alterations in the dopaminergic system and indirectly predispose the nigrostriatal system in the adult brain to be damaged by environmental toxins at an ordinarily nontoxic or subtoxic dose and develop PD like pathological features and motor dysfunction. PMID- 23446011 TI - Anatomy of a manuscript. PMID- 23446010 TI - SMILE blinks! PMID- 23446012 TI - One-year safety and efficacy results of a hydrogel inlay to improve near vision in patients with emmetropic presbyopia. AB - PURPOSE: To conduct a feasibility study of the safety and efficacy of a corneal contouring inlay as a treatment for emmetropic presbyopia. METHODS: The Raindrop corneal inlay (ReVision Optics, Inc., Lake Forest, CA) was implanted on the corneal stromal bed beneath a keratotomy flap in 20 nondominant eyes of 20 patients. The implant is designed to cause a change in the curvature of the overlying cornea, with a subsequent multifocal change in refractive power. Efficacy outcome was defined as at least 75% of eyes with uncorrected near visual acuity of 0.3 logMAR (20/40 Snellen) or better at 6 months. Main safety outcomes were retention of preoperative best-corrected distance visual acuity and reports of adverse events. Other outcome measures included contrast sensitivity; near, intermediate, and distance visual acuities; patient satisfaction; spectacle use; and complications. RESULTS: All implanted eyes achieved uncorrected near visual acuity of 0.3 logMAR (20/40 Snellen) or better by the 1-week postoperative examination and remained so throughout the 1-year follow-up period, also averaging less than 0.1 logMAR (20/25 Snellen) monocularly and binocularly throughout that period. Mean binocular uncorrected distance visual acuity remained within 0.02 logMAR of the preoperative mean throughout the study. One patient who was dissatisfied with the resulting vision underwent explantation. At 1 year, 16 of 19 patients seldom or never wore glasses and all 19 were satisfied or very satisfied with their overall vision. CONCLUSIONS: The hydrogel corneal inlay improved uncorrected near and intermediate visual acuity in patients with emmetropic presbyopia, with high patient satisfaction and little effect on distance visual acuity. PMID- 23446013 TI - SD-OCT analysis of regional epithelial thickness profiles in keratoconus, postoperative corneal ectasia, and normal eyes. AB - PURPOSE: To assess corneal microarchitecture and regional epithelial thickness profile in eyes with keratoconus, postoperative corneal ectasia (ectasia), and normal unoperated eyes (controls) using spectral-domain optical coherence tomography (SD-OCT). METHODS: Regional corneal epithelial thickness profiles were measured with anterior segment SD-OCT (Optovue RTVue-100, Optovue Inc., Fremont, CA). Epithelial thickness was assessed at 21 points, 0.5 mm apart, across the central 6-mm of the corneal apex in the horizontal and vertical meridians. RESULTS: One hundred twenty eyes were evaluated, including 49 eyes from 29 patients with keratoconus, 32 eyes from 16 patients with ectasia, and 39 eyes from 21 control patients. Average epithelial thickness at the corneal apex was 41.18 +/- 6.47 MUm (range: 30 to 51 MUm) for keratoconus, 46.5 +/- 6.72 MUm for ectasia (range: 34 to 60 MUm), and 50.45 +/- 3.92 MUm for controls (range: 42 to 55 MUm). Apical epithelial thickness was significantly thinner in eyes with keratoconus (P < .0001) and ectasia (P = .0007) than in controls. Epithelial thickness ranges in all other areas varied widely for keratoconus (range: 21 to 101 MUm) and ectasia (range: 30 to 82 MUm) compared to controls (range: 43 to 64) (P = .0063). CONCLUSION: SD-OCT demonstrated significant central and regional epithelial thickness profile differences between keratoconus, ectasia, and control eyes, with significant variability and unpredictability in ectatic eyes. This regional irregularity may necessitate direct epithelial thickness measurement for treatments where underlying stromal variations may be clinically relevant, including corneal collagen cross-linking or topography-guided ablations. PMID- 23446014 TI - Non-penetrating femtosecond laser intrastromal astigmatic keratotomy in patients with mixed astigmatism after previous refractive surgery. AB - PURPOSE: To report the outcomes of the correction of mixed astigmatism with non penetrating femtosecond laser intrastromal astigmatic keratotomy in patients with previous refractive surgery. METHODS: One hundred twelve eyes that had low mixed astigmatism after excimer laser surgery, refractive lens exchange, or phakic intraocular lens implantation underwent intrastromal astigmatic keratotomy using paired symmetrical non-penetrating intrastromal arcuate keratotomies created 60 MUm from the surface to 80% depth at 7 mm diameter. Outcome measures included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), subjective refraction, and keratometry. A coupling ratio was calculated to assess the change in spherical equivalent. Average follow-up was 7.6 +/- 2.9 months. Patients were divided into two groups: no excimer laser corneal ablation and previous excimer laser surgery. Preoperative and postoperative data were compared between groups and analyses were performed on the whole group of eyes. RESULTS: Overall, the mean UDVA improved significantly from 0.18 +/- 0.14 to 0.02 +/- 0.12 logMAR (6/9 to ~6/6 Snellen) (P < .01). The mean absolute subjective cylinder decreased significantly from 1.20 +/- 0.47 diopters (D) preoperatively to 0.55 +/- 0.40 D postoperatively (P < .01). Subjective sphere decreased significantly from +0.61 +/- 0.33 to +0.17 +/- 0.36 D (P < 0.01). The mean CDVA was -0.03 +/- 0.08 logMAR (~ 6/6 Snellen) preoperatively and -0.05 +/- 0.09 logMAR (~ 6/5 Snellen) postoperatively (P = .06). The coupling ratio was 0.92 +/- 0.45. There was no statistically significant difference in the preoperative and postoperative sphere, cylinder, UDVA, CDVA, and coupling ratio between groups. No surgical complications occurred. CONCLUSIONS: Femtosecond laser intrastromal astigmatic keratotomy was effective at reducing refractive error in patients where other surgical options were exhausted. Predictability and efficacy could be improved with nomogram refinement. PMID- 23446015 TI - Implantation of three-piece silicone toric additive IOLs in challenging clinical cases with high astigmatism. AB - PURPOSE: To analyze the refractive outcomes and safety of three-piece silicone toric sulcus-fixated add-on intraocular lenses (IOLs) (HumanOptics/Dr.Schmidt Intraocularlinsen, Erlangen, Germany) in complex clinical cases with high astigmatism such as in cases with previous penetrating keratoplasty. METHODS: Interventional case series of 21 eyes of 20 patients enrolled at two German centers. Functional results including power vector analysis, accuracy of IOL power calculation, rotational stability, and postoperative complications were evaluated from 2 months to 6 years postoperatively. RESULTS: The preoperative subjective cylinder exceeded or was equal to -6.00 diopters (D) in 81% of eyes (range: -2.00 to -17.00 D). The median follow-up period was 7.6 months (range: 57 days to 6 years). The efficacy analysis focused on the 2 to 6 months follow-up visit. Postoperatively, there was a median reduction of astigmatism by 70.59% (subjective cylinder range: 0.00 to -5.00 D), improvement of uncorrected distance visual acuity, and unchanged median corrected distance visual acuity. The attempted spherical equivalent was achieved within +/- 0.50 D in 45% and within +/- 1.00 D in 65% of cases. Five eyes received secondary surgical alignment of axis. Other complications related to the surgical procedure were mainly transient shortly after implantation, such as intraocular pressure elevation (2 of 21 eyes) or corneal edema (2 of 21 eyes). Persisting changes were seen only in rare cases and included pigment dispersion (1 of 21 eyes) or corneal edema requiring a second keratoplasty within 9 months after surgery (2 of 21 eyes). CONCLUSIONS: Toric add-on IOLs may be useful in reducing high astigmatism and anisometropia and increasing spectacle independence even in complex clinical conditions with high refractive errors. PMID- 23446016 TI - Efficacy and stability of AT TORBI 709 M toric IOL. AB - PURPOSE: To describe the intraocular rotational stability and refractive results of the toric AT TORBI 709 M (former AT.Comfort 464 TLC) intraocular lens (IOL) (Carl Zeiss Meditec AG, Jena, Germany). METHODS: Forty-eight eyes of 32 consecutive patients with cataract and greater than 1 diopter of corneal astigmatism were included. Implantation of the toric IOL was performed after phacoemulsification. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), residual refractive sphere, residual keratometric and refractive cylinders, and toric IOL axis were measured before and 1, 3, and 6 months after surgery. RESULTS: Mean logMAR UDVA and CDVA improved significantly after surgery (P < .05). UDVA was 20/40 or better in 88.1% of eyes and 20/25 or better in 61.9%. CDVA was 20/40 or better in 100% of eyes and 20/25 or better in 90.2%. Mean refractive cylinder decreased significantly from -2.23 +/- 1.72 before to -0.43 +/- 0.53 after surgery (P < .05). Vector analysis of attempted versus achieved correction showed 100% of eyes within +/- 1.00 D and 95.2% within +/- 0.50 D for J and 100% of eyes were within +/- 1.00 D and 95.2% within +/- 0.50 D for J. Mean toric IOL axis rotation was 4.42 +/- 4.31 degrees (range: 0 to 16 degrees) and 86% of the lenses rotated less than 10 degrees. CONCLUSIONS: The AT TORBI 709 M IOL has proved to be a predictable and effective device with good rotational stability for the correction of preexisting astigmatism during cataract surgery. PMID- 23446017 TI - Factors affecting near vision after monofocal intraocular lens implantation. AB - PURPOSE: To identify factors that influence near vision after monofocal intraocular lens (IOL) implantation for distance vision. METHODS: A retrospective review was conducted of patients who underwent cataract surgery with monofocal IOL implantation from October 2009 to April 2010 at Samsung Medical Center. Eyes were classified as having good (? J4) or poor (< J4) near vision. Factors analyzed included age, sex, intraocular lens (IOL) movement, axial length, pupil size, degree and type of astigmatism, IOL type, total aberration, and higher order aberrations. Binary logistic regression and odds ratios with 95% confidence intervals were determined. RESULTS: This retrospective study involved 84 eyes of 84 patients. Thirty-four eyes were classified as having good near vision and 50 eyes as having poor near vision. All groups had a postoperative uncorrected visual acuity greater than 0.2 logMAR (Snellen 20/32) and a refractive error within +/- 0.5 diopter of spherical equivalent. Pupil size and axial length were inversely associated with good near vision (P = .034 and .039, respectively). A pupil size smaller than 2.6 mm and an axial length less than 23.0 mm resulted in better near vision than larger measurements after monofocal IOL implantation for distant target. CONCLUSIONS: Among the factors analyzed, small pupil size and short axial length predicted good near vision after phacoemulsification and monofocal IOL implantation. PMID- 23446018 TI - Refractive error assessment: influence of different optical elements and current limits of biometric techniques. AB - PURPOSE: To identify and quantify sources of error on refractive assessment using exact ray tracing. METHODS: The Liou-Brennan eye model was used as a starting point and its parameters were varied individually within a physiological range. The contribution of each parameter to refractive error was assessed using linear regression curve fits and Gaussian error propagation analysis. A MonteCarlo analysis quantified the limits of refractive assessment given by current biometric measurements. RESULTS: Vitreous and aqueous refractive indices are the elements that influence refractive error the most, with a 1% change of each parameter contributing to a refractive error variation of +1.60 and -1.30 diopters (D), respectively. In the phakic eye, axial length measurements taken by ultrasound (vitreous chamber depth, lens thickness, and anterior chamber depth [ACD]) were the most sensitive to biometric errors, with a contribution to the refractive error of 62.7%, 14.2%, and 10.7%, respectively. In the pseudophakic eye, vitreous chamber depth showed the highest contribution at 53.7%, followed by postoperative ACD at 35.7%. When optic measurements were considered, postoperative ACD was the most important contributor, followed by anterior corneal surface and its asphericity. A MonteCarlo simulation showed that current limits of refractive assessment are 0.26 and 0.28 D for the phakic and pseudophakic eye, respectively. CONCLUSIONS: The most relevant optical elements either do not have available measurement instruments or the existing instruments still need to improve their accuracy. Ray tracing can be used as an optical assessment technique, and may be the correct path for future personalized refractive assessment. PMID- 23446019 TI - Effect of platelet-rich plasma in nerve regeneration after LASIK. AB - PURPOSE: To investigate the effect of topical eye application of platelet-rich plasma (E-PRP) on the recovery of corneal sensitivity after LASIK and the anatomical recovery of the sub-basal corneal plexus as studied by confocal microscopy. METHODS: This was a randomized, consecutive, controlled, prospective and masked study on 108 myopic eyes receiving LASIK. The main variables of the study were the increase in corneal sensitivity (Cochet-Bonet aesthesiometer; Luneau, Paris, France) and the aspect of the sub-basal nerve plexus (confocal microscope). Additionally, a biomicroscopic study of the epithelial status of the cornea and a subjective questionnaire were completed. Each eye of each patient was assigned to one of two groups: 54 eyes treated with balanced saline solution and 54 fellow eyes receiving PRP drops for 3 months. RESULTS: No significant differences were detected when the corneal sensitivity thresholds were compared at any postoperative visit in both groups (P > .05 for all comparisons). Almost identical sub-basal fiber densities were estimated for both groups before LASIK (t test, P = .66). However, the type and severity of staining detected during the slit-lamp examinations at the first and third month postoperatively were significantly less evident in the E-PRP treatment group (Wilcoxon test, P < .05). CONCLUSIONS: PRP drops have beneficial effects for promoting epithelial status after LASIK but have no positive effect on recovery of corneal sensitivity, probably due to the limited bioavailability of growth factors in corneal stroma when the substance is topically administered. PMID- 23446020 TI - Scleral fixation underneath an intact conjunctiva. AB - PURPOSE: To describe a technique for the fixation of intraocular lenses or capsular tension rings through the ciliary sulcus or pars plana. METHODS: This alternative technique allows burial of the knot and the free suture ends within the sclera, without using a scleral flap or pocket or even a conjunctival opening. RESULTS: No suture exposure has occurred with the use of the suture burial technique in approximately 25 eyes in 4 years. Additional benefits include less patient discomfort and an improved anatomic and cosmetic outcome starting from the first postoperative day. CONCLUSIONS: This technique causes minimal tissue damage and scarring with almost no postoperative discomfort. PMID- 23446023 TI - Bartonella henselae infection associated with autoimmune thyroiditis in a child. AB - BACKGROUND: Bartonella henselae was discovered a quarter of a century ago as the causative agent of cat-scratch disease. More recently, Bartonella has been found to be responsible for a broad range of clinical syndromes (prolonged fever, hepatosplenic disease, encephalopathies, ocular disease) and associated with autoimmune conditions. CASE: This is the first report of autoimmune thyroiditis related to B. henselae infection. We describe an 11-year-old boy who presented with goiter and weight loss. At the time of admission a 2 * 1 cm mildly tender right supraclavicular lymph node was noted in association with an erythematous papule at the same side of the neck. We describe an association of autoimmune hyperthyroidism (Hashitoxicosis) with B. henselae infection (cat-scratch disease) in a pediatric patient. CONCLUSION: Different types of infections are implicated in the pathogenesis of autoimmune thyroid disease through molecular mimicry or other mechanisms, despite their role is disputed. We speculated that autoimmune thyroiditis should be added to the spectrum of clinical syndromes that can be triggered by B. henselae. PMID- 23446022 TI - Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision. AB - BACKGROUND: There is uncertainty on the benefit of adjuvant chemotherapy in patients with stage II colorectal cancers. The aim of this study is to investigate the combined role of clinical, pathological and molecular parameters to identify those stage II patients who better benefit from adjuvant therapy. METHODS: We examined 120 stage II colon cancer patients. Of these, 60 patients received adjuvant 5-FU chemotherapy after surgery and the other 60 did not receive therapy. Immunohistochemical (IHC) analyses were performed to evaluate the expressions of Thymidylate synthetase (TYMS), TP53 (p53), beta-catenin (CTNNB1) and CD8. For TYMS, its mRNA expression levels were also investigated by real time qRT-PCR. The entire case study was characterized by the presence of a defect in the MMR (mismatch repair) system, the presence of the CpG island methylator phenotype (CIMP or CIMP-High) and for the V600E mutation in the BRAF gene. At the histo-pathological level, the depth of tumour invasion, lymphovascular invasion, invasion of large veins, host lymphocytic response and tumour border configuration were recorded. RESULTS: The presence of the V600E mutation in the BRAF gene was a poor prognostic factor for disease free and overall survival (DFS; hazard ratio [HR], 2.57; 95% CI: 1.03 -6.37; p = 0.04 and OS; HR, 3.68; 95% CI: 1.43-9.47; p < 0.01 respectively), independently of 5-FU treatment. Adjuvant therapy significantly improved survival in patients with high TYMS levels (p = 0.04), while patients with low TYMS had a better outcome if treated by surgery alone (DFS; HR, 6.07; 95% CI, 0.82 to 44.89; p = 0.04). In patients with a defect in the MMR system (dMMR), 5-FU therapy was associated to reduced survival (DFS; HR, 37.98; 95% CI, 1.04 to 1381.31; p = 0.04), while it was beneficial for CIMP-High associated tumours (DFS; HR, 0.17; 95% CI, 0.02 to 1.13; p = 0.05). CONCLUSIONS: Patients' characterization according to MMR status, CIMP phenotype and TYMS mRNA expression may provide a more tailored approach for adjuvant therapy in stage II colon cancer. PMID- 23446024 TI - Preoperative three-dimensional model creation of magnetic resonance brain images as a tool to assist neurosurgical planning. AB - BACKGROUND: Neurosurgeons regularly plan their surgery using magnetic resonance imaging (MRI) images, which may show a clear distinction between the area to be resected and the surrounding healthy brain tissue depending on the nature of the pathology. However, this distinction is often unclear with the naked eye during the surgical intervention, and it may be difficult to infer depth and an accurate volumetric interpretation from a series of MRI image slices. OBJECTIVES: In this work, MRI data are used to create affordable patient-specific 3-dimensional (3D) scale models of the brain which clearly indicate the location and extent of a tumour relative to brain surface features and important adjacent structures. METHODS: This is achieved using custom software and rapid prototyping. In addition, functionally eloquent areas identified using functional MRI are integrated into the 3D models. RESULTS: Preliminary in vivo results are presented for 2 patients. The accuracy of the technique was estimated both theoretically and by printing a geometrical phantom, with mean dimensional errors of less than 0.5 mm observed. CONCLUSIONS: This may provide a practical and cost-effective tool which can be used for training, and during neurosurgical planning and intervention. PMID- 23446025 TI - A case of heterotopic pancreas in the stomach. PMID- 23446026 TI - Worldwide burden of cancer incidence below the age of 40 in 2002 extrapolated from the Cancer Incidence in Five Continents Vol. IX. PMID- 23446027 TI - Minimizing cytosol dilution in whole-cell patch-clamp experiments. AB - During a conventional whole-cell patch clamp experiment, diffusible cytosolic ions or molecules absent in the pipette solution can become diluted by a factor of one million or more, leading to diminished current or fluorescent signals. Existing methods to prevent or limit cytosol diffusion include reducing the diameter of the pipette's orifice, adding cytosolic extract or physiological entities to the pipette solution, and using the perforated patch clamp configuration. The first method introduces measurement error in recorded signals from increased series resistance and the latter two are cumbersome to perform. In addition, most perforated patch configurations, prevent investigators from using test compounds in the pipette solution. We present a method to overcome these limitations by minimizing cytosol dilution using a novel pipette holder. Cell attached configuration is obtained with the pipette filled with pipette solution. Most of the pipette solution is then replaced with mineral oil so that cytosol dilution can be minimized in whole-cell configuration. To accomplish this requires a suction line and two Ag/AgCl electrodes inside the pipette. Testing our novel pipette holder with Chinese Hamster Ovarian cells, we demonstrate cytosol dilution factors between 76 and 234. For large cells with somas greater than 40 MUm, cytosol dilution factors of 10 or less are achievable. PMID- 23446029 TI - EEG-based classification of fast and slow hand movements using Wavelet-CSP algorithm. AB - A brain-computer interface (BCI) acquires brain signals, extracts informative features, and translates these features to commands to control an external device. This paper investigates the application of a noninvasive electroencephalography (EEG)-based BCI to identify brain signal features in regard to actual hand movement speed. This provides a more refined control for a BCI system in terms of movement parameters. An experiment was performed to collect EEG data from subjects while they performed right-hand movement at two different speeds, namely fast and slow, in four different directions. The informative features from the data were obtained using the Wavelet-Common Spatial Pattern (W-CSP) algorithm that provided high-temporal-spatial-spectral resolution. The applicability of these features to classify the two speeds and to reconstruct the speed profile was studied. The results for classifying speed across seven subjects yielded a mean accuracy of 83.71% using a Fisher Linear Discriminant (FLD) classifier. The speed components were reconstructed using multiple linear regression and significant correlation of 0.52 (Pearson's linear correlation coefficient) was obtained between recorded and reconstructed velocities on an average. The spatial patterns of the W-CSP features obtained showed activations in parietal and motor areas of the brain. The results achieved promises to provide a more refined control in BCI by including control of movement speed. PMID- 23446028 TI - Hierarchical information fusion for global displacement estimation in microsensor motion capture. AB - This paper presents a novel hierarchical information fusion algorithm to obtain human global displacement for different gait patterns, including walking, running, and hopping based on seven body-worn inertial and magnetic measurement units. In the first-level sensor fusion, the orientation for each segment is achieved by a complementary Kalman filter (CKF) which compensates for the orientation error of the inertial navigation system solution through its error state vector. For each foot segment, the displacement is also estimated by the CKF, and zero velocity update is included for the drift reduction in foot displacement estimation. Based on the segment orientations and left/right foot locations, two global displacement estimates can be acquired from left/right lower limb separately using a linked biomechanical model. In the second-level geometric fusion, another Kalman filter is deployed to compensate for the difference between the two estimates from the sensor fusion and get more accurate overall global displacement estimation. The updated global displacement will be transmitted to left/right foot based on the human lower biomechanical model to restrict the drifts in both feet displacements. The experimental results have shown that our proposed method can accurately estimate human locomotion for the three different gait patterns with regard to the optical motion tracker. PMID- 23446030 TI - Controlling a human-computer interface system with a novel classification method that uses electrooculography signals. AB - Electrooculography (EOG) signals can be used to control human-computer interface (HCI) systems, if properly classified. The ability to measure and process these signals may help HCI users to overcome many of the physical limitations and inconveniences in daily life. However, there are currently no effective multidirectional classification methods for monitoring eye movements. Here, we describe a classification method used in a wireless EOG-based HCI device for detecting eye movements in eight directions. This device includes wireless EOG signal acquisition components, wet electrodes and an EOG signal classification algorithm. The EOG classification algorithm is based on extracting features from the electrical signals corresponding to eight directions of eye movement (up, down, left, right, up-left, down-left, up-right, and down-right) and blinking. The recognition and processing of these eight different features were achieved in real-life conditions, demonstrating that this device can reliably measure the features of EOG signals. This system and its classification procedure provide an effective method for identifying eye movements. Additionally, it may be applied to study eye functions in real-life conditions in the near future. PMID- 23446031 TI - Loss-of-function of a ubiquitin-related modifier promotes the mobilization of the active MITE mPing. AB - Miniature inverted-repeat transposable elements (MITEs) are widespread in both prokaryotic and eukaryotic genomes, where their copy numbers can attain several thousands. Little is known, however, about the genetic factor(s) affecting their transpositions. Here, we show that disruption of a gene encoding ubiquitin-like protein markedly enhances the transposition activity of a MITE mPing in intact rice plants without any exogenous stresses. We found that the transposition activity of mPing is far higher in the lines harboring a non-functional allele at the Rurm1 (Rice ubiquitin-related modifier-1) locus than in the wild-type line. Although the alteration of cytosine methylation pattern triggers the activation of transposable elements under exogenous stress conditions, the methylation degrees in the whole genome, the mPing-body region, and the mPing-flanking regions of the non-functional Rurm1 line were unchanged. This study provides experimental evidence for one of the models of genome shock theory that genetic accidents within cells enhance the transposition activities of transposable elements. PMID- 23446033 TI - [A paradigm shift in modern psychiatric diagnosis? Neural network dysfunction as a pathophysiological concept and novel diagnostic tool]. PMID- 23446032 TI - The ULT1 and ULT2 trxG genes play overlapping roles in Arabidopsis development and gene regulation. AB - The epigenetic regulation of gene expression is critical for ensuring the proper deployment and stability of defined genome transcription programs at specific developmental stages. The cellular memory of stable gene expression states during animal and plant development is mediated by the opposing activities of Polycomb group (PcG) factors and trithorax group (trxG) factors. Yet, despite their importance, only a few trxG factors have been characterized in plants and their roles in regulating plant development are poorly defined. In this work, we report that the closely related Arabidopsis trxG genes ULTRAPETALA1 (ULT1) and ULT2 have overlapping functions in regulating shoot and floral stem cell accumulation, with ULT1 playing a major role but ULT2 also making a minor contribution. The two genes also have a novel, redundant activity in establishing the apical-basal polarity axis of the gynoecium, indicating that they function in differentiating tissues. Like ULT1 proteins, ULT2 proteins have a dual nuclear and cytoplasmic localization, and the two proteins physically associate in planta. Finally, we demonstrate that ULT1 and ULT2 have very similar overexpression phenotypes and regulate a common set of key development target genes, including floral MADS-box genes and class I KNOX genes. Our results reveal that chromatin remodeling mediated by the ULT1 and ULT2 proteins is necessary to control the development of meristems and reproductive organs. They also suggest that, like their animal counterparts, plant trxG proteins may function in multi-protein complexes to up regulate the expression of key stage- and tissue-specific developmental regulatory genes. PMID- 23446035 TI - [Early markers of endothelial dysfunction posttraumatic stress disorder. Role in atherogenesis]. AB - There is a strong association between cardiovascular diseases, thromboembolism, and atherosclerosis with endothelial dysfunction. The relationship of the latter with neuropsychiatric diseases such as the post traumatic stress disorder (PTSD) stands as a risk factor for the development of atherosclerotic phenomena. OBJECTIVE: To disclose a meaningful association between PTSD and higher values of endothelial dysfunction molecules like e-Selectin, s-ICAM-1 and v-CAM-1, in comparison with healthy subjects without PTSD. METHODS: 24 patients with PTSD and 24 healthy subjects were selected e-Selectin, v-CAM-1 e soluble ICAM-1 levels were measured in plasma. The PTSD severity symptoms scale and the Trauma Symptom Checklist were administered to both samples. RESULTS: A meaningful and robust correlation between endothelial dysfunction markers e-Selectin, s-ICAM-1 y v-CAM 1 plasma levels and the severity of the PTSD was disclosed. CONCLUSION: There is a continual relationship between PTSD symptoms severity and plasmatic levels of endothelial dysfunction markers. This relationship can explain the probability of developing cardiovascular diseases and atherogenesis and traumatic life events which ends up as PTSD at common grounds with inflammatory vascular response. PMID- 23446034 TI - [Impact of the spanish consensus on physical health of patients with schizophrenia]. AB - INTRODUCTION: This study evaluates the physical health of patients with schizophrenia and analyzes the change in the percentage of patients with evaluations in the known diabetes and cardiovascular risk predictors before and 6 months after the dissemination of the "Consensus on Physical Health in Schizophrenia Patients". MATERIAL AND METHODS: This is an epidemiological non interventional and transversal study, in which 229 psychiatrists evaluated 1,193 clinical records of patients with a diagnose of schizophrenia according to ICD 10, attended in the psychiatry consultations planned in January and September of 2007. Study results were analyzed using descriptive statistics. RESULTS: 1,193 evaluable patients were included, with a mean age of 39.7+/-11.6 years, diagnosed of schizophrenia 15.0+/-10.3 years ago, and a 65.90% were men. The presence of concomitant diseases was 39.98%, being hypercholesterolemia (46.33%), hypertriglyceridaemia (33.54%) and arterial hypertension (26.00%) the most frequent. After the dissemination of the Consensus, the percentage of patients who had all the physical measurements taken increased by 13.75%. Forty eight per cent of the psychiatrists were considered as being aware of the Consensus. The percentage of measurements taken was higher within the psychiatrists who were aware of the Consensus (17.32%) than within those who were not aware of it (10.33%). CONCLUSIONS: The results of this study show an increase of the physical health control from patients with schizophrenia after the dissemination of the Consensus, which should improve an integral approach of these patients to ensure a similar life expectancy, quality of life and function to the general population. PMID- 23446036 TI - [The use of "cognitive" in health terminology. A latent controversy]. AB - BACKGROUND: The adjective "cognitive" has a double meaning and it is used for naming two disciplines with separate activities: Cognitive neuroscience and cognitive psychotherapy. This has an unrecognised impact on the health terminology and the classification systems. METHOD: The current use of this term is reviewed in a series of key dictionaries, scientific books, databases (OldMedline and PsycINFO) and specific web searchers (Google Scholar). The history of this term and its etymology is also reviewed and compared to other alternatives (i.e. noetic) as well as its use in international classifications (e.g. the International Classification of Functioning - ICF). RESULTS: The modern use of the term "cognitive" in Neurosciences can be traced back to Hebb in a 1955 one year before that recorded at official version. The different meaning of this term in psychology can be traced back to the same decade. Departing from the ICF framework of mental functions, "cognitive" can be regarded as a generic term that encompasses both neurocognitive and meta-cognitive functions and should not be used for classification purposes. A hierarchy is suggested for the use of "neurocognitive" in the classification of mental functions. COMMENTS: The polysemic use of this name reveals a latent controversy in health sciences which has implications for its use in the international classification systems. There is an need to improve the standard definition and the semantic hierarchy of the term "cognitive", "neurocognitive" and other related terms within the context of International Health Terminology Standards Development Organisation (IHTSO). PMID- 23446037 TI - [Resilience: An approach to the concept]. AB - The capacity to recover from extremes of trauma and stress is termed resilience. Resilience reflects a dynamic confluence of factors that promotes positive adaptation despite exposure to adverse life experiences. Resilience is thought to be important as a component of successful psychosocial adjustment and is associated with mental health. In recent years, increasing attention has been drawn to the potential role that personality and neurobiology might play in determining resilience. This paper presents, from de current knowledge, an overview of the concept of resilience and its implications to the healthcare. PMID- 23446038 TI - [Differential characteristics of the efficacy and tolerability of second generation antipsychotics in the treatment of psychotic disorders in children and adolescents]. AB - Over the last few years, there has been a marked increase in the prescription of second-generation antipsychotics (SGA) for the treatment of psychotic disorders and other psychiatric conditions in children and adolescents. However, few reports compare the tolerability and efficacy of the different SGAs in this population. We review the literature on the differential characteristics of efficacy and tolerability of SGA in the pediatric population. Our results show that SGAs are not a homogeneous group, but that each drug has a distinct profile, particularly with respect to side effects, especially metabolic complications. Comparisons between SGAs have shown that treatment with olanzapine was associated with greater weight gain and increased cholesterol levels, and that treatment with risperidone was associated with a greater increase in prolactin levels. Therefore, the specific profile of an SGA should be taken into consideration when prescribing these drugs. PMID- 23446040 TI - Predictors of skin self-examination before and after a melanoma diagnosis: the role of medical advice and patient's level of education. AB - BACKGROUND: Cutaneous melanoma is the fastest growing tumor of the skin and the median life span of patients with advanced disease is less than a year. Melanoma related mortality can be reduced through early detection via clinical skin exams and patient self-examination. Despite the potential to reducing the medical burden associated with clinical skin exams, systematic and regular skin self examinations (SSE) are rarely performed. The current study examined psychosocial predictors of SSE and changes in SSE behavior from pre- to post-diagnosis in order to guide future melanoma prevention initiatives. FINDINGS: A consecutive sample of 47 melanoma survivors was drawn from a tertiary care clinic. Most melanomas had been detected by patients, spouses and other laypersons. Higher education was related to more frequent SSE at pre-diagnosis, more thorough SSE at post-diagnosis, and more frequent reports of having been advised to perform SSE at post-diagnosis. SSE behaviors increased significantly from pre- to post diagnosis. CONCLUSIONS: These findings suggest that different patient subgroups display varied knowledge base, readiness for change, and receptiveness for medical advice. Thus, interventions seeking to enhance skin self-exam practice may be most effective when the individual's psychosocial characteristics are taken into account. PMID- 23446039 TI - CoRSeqV3-C: a novel HIV-1 subtype C specific V3 sequence based coreceptor usage prediction algorithm. AB - BACKGROUND: The majority of HIV-1 subjects worldwide are infected with HIV-1 subtype C (C-HIV). Although C-HIV predominates in developing regions of the world such as Southern Africa and Central Asia, C-HIV is also spreading rapidly in countries with more developed economies and health care systems, whose populations are more likely to have access to wider treatment options, including the CCR5 antagonist maraviroc (MVC). The ability to reliably determine C-HIV coreceptor usage is therefore becoming increasingly more important. In silico V3 sequence based coreceptor usage prediction algorithms are a relatively rapid and cost effective method for determining HIV-1 coreceptor specificity. In this study, we elucidated the V3 sequence determinants of C-HIV coreceptor usage, and used this knowledge to develop and validate a novel, user friendly, and highly sensitive C-HIV specific coreceptor usage prediction algorithm. RESULTS: We characterized every phenotypically-verified C-HIV gp120 V3 sequence available in the Los Alamos HIV Database. Sequence analyses revealed that compared to R5 C-HIV V3 sequences, CXCR4-using C-HIV V3 sequences have significantly greater amino acid variability, increased net charge, increased amino acid length, increased frequency of insertions and substitutions within the GPGQ crown motif, and reduced frequency of glycosylation sites. Based on these findings, we developed a novel C-HIV specific coreceptor usage prediction algorithm (CoRSeqV3-C), which we show has superior sensitivity for determining CXCR4 usage by C-HIV strains compared to all other available algorithms and prediction rules, including Geno2pheno[coreceptor] and WebPSSMSINSI-C, which has been designed specifically for C-HIV. CONCLUSIONS: CoRSeqV3-C is now openly available for public use at http://www.burnet.edu.au/coreceptor. Our results show that CoRSeqV3-C is the most sensitive V3 sequence based algorithm presently available for predicting CXCR4 usage of C-HIV strains, without compromising specificity. CoRSeqV3-C may be potentially useful for assisting clinicians to decide the best treatment options for patients with C-HIV infection, and will be helpful for basic studies of C-HIV pathogenesis. PMID- 23446041 TI - Negative impact of cardiovascular risk factors on left atrial and left ventricular function related to aortic stiffness--new application of 2 dimensional speckle-tracking echocardiography. AB - BACKGROUND: The aim of the present study was to detect earlier the negative effect of cardiovascular risk (CVR) factors on left atrial (LA) and left ventricular (LV) function related to abdominal aortic (AAO) stiffness using 2 dimensional speckle-tracking echocardiography (2DSTE) in asymptomatic patients. METHODS AND RESULTS: One hundred and twelve patients with CVR factors and 56 healthy individuals were studied. 2DSTE data were acquired for determination of LA and LV myocardial and AAO wall deformations. LA volume index, LV mass index, ratio of early diastolic transmitral flow to mitral annular velocity (E/e')/peak systolic LA strain (S-LAs), and AAO stiffness were greater, and peak early diastolic LV longitudinal strain rate (SR-LVe) was lower in the patient group. Among the significantly correlated variables with AAO stiffness on univariate analysis, multivariate linear regression analysis identified SR-LVe and (E/e')/S LAs in the patient group, and only age in the healthy group, as independent predictor of AAO stiffness. CONCLUSIONS: Structural and functional changes in the LA and LV and AAO stiffening were accelerated with CVR factors, and higher AAO stiffness was associated with deteriorated LA compliance and impaired LV relaxation in asymptomatic patients with CVR factors. 2DSTE has a potential for earlier detection of abnormal LA and LV function related to increased AAO stiffness. PMID- 23446042 TI - First observation of a potential non-invasive breath gas biomarker for kidney function. AB - We report on the search for low molecular weight molecules-possibly accumulated in the bloodstream and body-in the exhaled breath of uremic patients with kidney malfunction. We performed non-invasive analysis of the breath gas of 96 patients shortly before and several times after kidney transplantation using proton transfer-reaction mass spectrometry (PTR-MS), a very sensitive technique for detecting trace amounts of volatile organic compounds. A total of 642 individual breath analyses which included at least 41 different chemical components were carried out. Correlation analysis revealed one particular breath component with a molecular mass of 114 u (unified atomic mass units) that clearly correlated with blood serum creatinine, which is the currently accepted marker for assessing the function of the kidney. In particular, daily urine production showed good correlation with the identified breath marker. An independent set of seven samples taken from three patients at the onset of dialysis and three controls with normal kidney function confirmed a significant difference in concentration between patients and controls for a compound with a molecular mass of 114.1035 u using high mass resolving proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS). A chemical composition of C7H14O was derived for the respective component. Fragmentation experiments on the same samples using proton transfer-reaction triple-quadrupole tandem mass spectrometry (PTR-QqQ-MS) suggested that this breath marker is a C7-ketone or a branched C7-aldehyde. Non invasive real-time monitoring of the kidney function via this breath marker could be a possible future procedure in the clinical setting. PMID- 23446043 TI - 3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer related death. It is lethal in nearly all patients, due to an almost complete chemoresistance. Most if not all drugs that pass preclinical tests successfully, fail miserably in the patient. This raises the question whether traditional 2D cell culture is the correct tool for drug screening. The objective of this study is to develop a simple, high-throughput 3D model of human PDAC cell lines, and to explore mechanisms underlying the transition from 2D to 3D that might be responsible for chemoresistance. METHODS: Several established human PDAC and a KPC mouse cell lines were tested, whereby Panc-1 was studied in more detail. 3D spheroid formation was facilitated with methylcellulose. Spheroids were studied morphologically, electron microscopically and by qRT-PCR for selected matrix genes, related factors and miRNA. Metabolic studies were performed, and a panel of novel drugs was tested against gemcitabine. RESULTS: Comparing 3D to 2D cell culture, matrix proteins were significantly increased as were lumican, SNED1, DARP32, and miR-146a. Cell metabolism in 3D was shifted towards glycolysis. All drugs tested were less effective in 3D, except for allicin, MT100 and AX, which demonstrated effect. CONCLUSIONS: We developed a high-throughput 3D cell culture drug screening system for pancreatic cancer, which displays a strongly increased chemoresistance. Features associated to the 3D cell model are increased expression of matrix proteins and miRNA as well as stromal markers such as PPP1R1B and SNED1. This is supporting the concept of cell adhesion mediated drug resistance. PMID- 23446044 TI - Comparison of Kasai autocorrelation and maximum likelihood estimators for Doppler optical coherence tomography. AB - In optical coherence tomography (OCT) and ultrasound, unbiased Doppler frequency estimators with low variance are desirable for blood velocity estimation. Hardware improvements in OCT mean that ever higher acquisition rates are possible, which should also, in principle, improve estimation performance. Paradoxically, however, the widely used Kasai autocorrelation estimator's performance worsens with increasing acquisition rate. We propose that parametric estimators based on accurate models of noise statistics can offer better performance. We derive a maximum likelihood estimator (MLE) based on a simple additive white Gaussian noise model, and show that it can outperform the Kasai autocorrelation estimator. In addition, we also derive the Cramer Rao lower bound (CRLB), and show that the variance of the MLE approaches the CRLB for moderate data lengths and noise levels. We note that the MLE performance improves with longer acquisition time, and remains constant or improves with higher acquisition rates. These qualities may make it a preferred technique as OCT imaging speed continues to improve. Finally, our work motivates the development of more general parametric estimators based on statistical models of decorrelation noise. PMID- 23446045 TI - Adenoid cystic carcinoma of hard palate with coincidental metastases to lung and liver. AB - Adenoid cystic carcinoma is the most frequent pathology occurring in the minor salivary glands .It is usually slow growing; however, it can spread via perineural invasion, haematogenous and lymphatogenous metastasis. Most common sites of metastasis are lung and bone. Involvement of the other sites is not common. In this article, we present a woman with coincident lung and liver metastases. PMID- 23446046 TI - Osgood-Schlatter disease. PMID- 23446047 TI - Endoscopic management of a major bile duct stricture from surgical clips following laparoscopic hemicolectomy. AB - Benign postoperative bile duct strictures are usually complications of cholecystectomies. However, development of obstructive jaundice and biliary stricture as a result of surgical clips after laparoscopic right hemicolectomy is rare and has not been reported in the literature. We present a case of a 64-year old woman who presented with sudden onset jaundice and abdominal pain, 1 week following right hemicolectomy. Laboratory reports suggested obstructive jaundice. Subsequent imaging studies showed biliary dilation of both intrahepatic and extrahepatic ducts with no evidence of bile duct stones. The endoscopic retrograde cholangiopancreatography (ERCP) showed an abrupt, complete obstruction of the common bile duct at the level of the surgical clips. The bile duct stricture formed at the site of surgical clips improved significantly after serial incremental biliary dilations with successive placement of increasing number of endoprostheses side-by-side at repeat ERCP sessions. PMID- 23446049 TI - Hypertriglyceridaemia-induced pancreatitis. AB - Hypertriglyceridaemia is the third most common cause of acute pancreatitis but is relatively rare and therefore requires a high level of clinical suspicion to be diagnosed. We discuss the case of a 46-year-old man who initially presented to the accident and emergency department with suspected first presentation of diabetic ketoacidosis (DKA) and a normal amylase but who did not respond to DKA treatment. Further history revealed significant cardiovascular risk factors, examination showed an evidence of hyperlipidaemia and investigations revealed acute pancreatitis secondary to hypertriglyceridaemia. We discuss the causes of hypertriglyceridaemia, the difficulty in differentiating primary versus secondary hypertriglyceridaemia, possible pathogenesis and current evidence-based treatments. PMID- 23446048 TI - Intra-abdominal bleeding during treprostinil infusion in a patient with pulmonary arterial hypertension. AB - Medical treatment of pulmonary arterial hypertension (PAH) is increasingly common. Prostacyclins were introduced in the early 90s, and treprostinil is one of the most frequently used drugs of this class today, owing to its long half life and to the possibility to administer the molecule through several routes. Treprostinil is considered a safe drug and is associated with a significant improvement of exercise capacity, especially in patients with idiopathic PAH (iPAH). Systemic sclerosis-associated PAH (sc-PAH) correlates to a worse prognosis compared with that of iPAH. Despite these considerations, safety data on treprostinil are still limited and mainly derived from randomised controlled trials and retrospective studies with relatively small and heterogeneous cohorts of patients with PAH. We report the occurrence of a severe intra-abdominal bleeding during treprostinil infusion in a patient with sc-PAH. PMID- 23446050 TI - Hiding in plain sight; constrictive pericarditis. AB - We present a case of constrictive pericarditis that was especially difficult to diagnose. The patient presented with generalised oedema, dyspnoea and pleural effusions. History was significant for prior polysubstance abuse but was otherwise unremarkable. Physical examination revealed only jugular venous distention. CT demonstrated a normal pericardium with pleural effusions. Echocardiography showed mildly elevated right ventricular pressures with dyssynergic motion of the ventricular septum. No intervention was being carried out, but 1 month later further evaluation with a right and left heart catheterisation showed the classical square-root sign with equalisation of diastolic pressures in both ventricles as well as ventricular interdependence. Idiopathic constrictive pericarditis was thus diagnosed with a subsequent pericardial stripping which confirmed a thickened pericardium encasing the heart. PMID- 23446051 TI - Liquid hyper-absorption as a cause of increased DTPA clearance in the cystic fibrosis airway. AB - BACKGROUND: Airway liquid hyper-absorption is a key pathophysiological link between the genetic mutations of cystic fibrosis (CF) and the development of lung disease. Here we consider whether the clearance of radiolabeled diethylene triamine pentaacetic acid (DTPA) might be used to detect changes in airway liquid absorption. METHODS: Tc99m-DTPA was added to the apical (luminal) surface of primary human bronchial epithelial cell cultures from CF and non-CF lungs. Liquid absorption rates were assessed using an optical method and compared to DTPA absorption rates. Measurements of transepithelial electrical resistance (TER) were made to determine the effect of epithelial permeability. DTPA absorption was assessed after stimuli known to influence liquid absorption (volume addition and osmotic gradients) and in cultures containing different proportions of CF and non CF cells. RESULTS: DTPA absorption rate was increased in CF cultures matching previous in vivo studies in individuals with CF. DTPA and liquid absorption rates were proportional. There was no relationship between TER and DTPA absorption rate when measured in individual cultures. Apical volume addition increased both DTPA and liquid absorption rates. DTPA absorption increased in a dose-dependent manner after basolateral mannitol addition was used to create transepithelial osmotic gradients favoring liquid absorption. Conversely, apical mannitol (a candidate therapy) slowed DTPA absorption in CF cultures. CONCLUSIONS: These results imply that DTPA absorption is directly related to liquid absorption, consistent with increased rates of airway surface liquid absorption in the CF airway, and that modification of liquid absorption from osmotic therapies might be detectable through DTPA absorption measurements in vivo. TRIAL REGISTRATION: none. PMID- 23446052 TI - The role of the nucleosome acidic patch in modulating higher order chromatin structure. AB - Higher order folding of chromatin fibre is mediated by interactions of the histone H4 N-terminal tail domains with neighbouring nucleosomes. Mechanistically, the H4 tails of one nucleosome bind to the acidic patch region on the surface of adjacent nucleosomes, causing fibre compaction. The functionality of the chromatin fibre can be modified by proteins that interact with the nucleosome. The co-structures of five different proteins with the nucleosome (LANA, IL-33, RCC1, Sir3 and HMGN2) recently have been examined by experimental and computational studies. Interestingly, each of these proteins displays steric, ionic and hydrogen bond complementarity with the acidic patch, and therefore will compete with each other for binding to the nucleosome. We first review the molecular details of each interface, focusing on the key non covalent interactions that stabilize the protein-acidic patch interactions. We then propose a model in which binding of proteins to the nucleosome disrupts interaction of the H4 tail domains with the acidic patch, preventing the intrinsic chromatin folding pathway and leading to assembly of alternative higher order chromatin structures with unique biological functions. PMID- 23446053 TI - Neutron scattering: a tool to detect in vivo thermal stress effects at the molecular dynamics level in micro-organisms. AB - In vivo molecular dynamics in Halobacterium salinarum cells under stress conditions was measured by neutron scattering experiments coupled with microbiological characterization. Molecular dynamics alterations were detected with respect to unstressed cells, reflecting a softening of protein structures consistent with denaturation. The experiments indicated that the neutron scattering method provides a promising tool to study molecular dynamics modifications in the proteome of living cells induced by factors altering protein folds. PMID- 23446055 TI - Perceptions of UK medical graduates' preparedness for practice: a multi-centre qualitative study reflecting the importance of learning on the job. AB - BACKGROUND: There is evidence that graduates of different medical schools vary in their preparedness for their first post. In 2003 Goldacre et al. reported that over 40% of UK medical graduates did not feel prepared and found large differences between graduates of different schools. A follow-up survey showed that levels of preparedness had increased yet there was still wide variation. This study aimed to examine whether medical graduates from three diverse UK medical schools were prepared for practice. METHODS: This was a qualitative study using a constructivist grounded theory approach. Prospective and cross-sectional data were collected from the three medical schools.A sample of 60 medical graduates (20 from each school) was targeted. They were interviewed three times: at the end of medical school (n = 65) and after four (n = 55) and 12 months (n = 46) as a Year 1 Foundation Programme doctor. Triangulated data were collected from clinicians via interviews across the three sites (n = 92). In addition three focus groups were conducted with senior clinicians who assess learning portfolios. The focus was on identifying areas of preparedness for practice and any areas of lack of preparedness. RESULTS: Although selected for being diverse, we did not find substantial differences between the schools. The same themes were identified at each site. Junior doctors felt prepared in terms of communication skills, clinical and practical skills and team working. They felt less prepared for areas of practice that are based on experiential learning in clinical practice: ward work, being on call, management of acute clinical situations, prescribing, clinical prioritisation and time management and dealing with paperwork. CONCLUSIONS: Our data highlighted the importance of students learning on the job, having a role in the team in supervised practice to enable them to learn about the duties and responsibilities of a new doctor in advance of starting work. PMID- 23446057 TI - Gamma knife surgery for refractory insular cortex epilepsy. AB - BACKGROUND: Resection of the epileptogenic insular cortex is surgically challenging. We sought to evaluate the potential of Gamma Knife surgery (GKS) for the treatment of pharmacoresistant insular cortex epilepsy (ICE) in patients who underwent GKS between 2005 and 2010. Adverse events and effects on seizure frequency were assessed. METHODS: Three cases of refractory ICE were treated by GKS between 2005 and 2010. RESULTS: Case 1 had refractory nonlesional ICE, proven by depth electrodes only partially helped by a left posterior insulectomy. Case 2 had refractory ICE due to a left insular cavernoma. Case 3 had refractory ICE, confirmed by an invasive study but complicated by transient dysphasia from contusion of Wernicke's area. The marginal and maximum radiation doses delivered were 20 and 40 Gy, respectively. Treatment volume ranged from 1.2 to 3.2 cm3. Two out of 3 patients experienced significant seizure reduction and the third had a worthwhile improvement (follow-up 30-76 months). Complete antiepileptic drug withdrawal was un-fortunately not possible. Complications included transient lightheadedness and new-onset seizures responsive to medical treatment, both in the same patient. CONCLUSION: GKS is a promising technique for selected drug resistant ICE patients. Additional observations are necessary. PMID- 23446056 TI - Isolating cognitive and neurologic HIV effects in substance-dependent, confounded cohorts: a pilot study. AB - Controversy exists as to whether effects of HIV infection can be detected in the cognitive profiles of substance users, with methodological differences in degree of control for confounding factors a major contributor to empirical discrepancies. To address this shortcoming, we conducted a small but well controlled study aimed at isolating HIV neurocognitive (NC) effects in a group of chronic substance users. Thirty HIV-negative substance users were individually matched to 30 HIV-positive substance users on relevant medical and demographic factors, including reading level and methadone therapy status. Results revealed that reading level, methadone maintenance therapy, and positive urine toxicology each exerted significant influence on NC function, and that HIV status was a significant predictor of learning and speeded processing after these control factors were considered. The HIV-positive group also displayed significantly more neurologically assessed motor impairment (p < .05), which was specifically related to impaired cognition in this group and independent of degree of immunocompromise. These data demonstrate the need for increased attention to clinical/demographic characteristics of groups under study. They also show that with applied methodological rigor, the deleterious effects of HIV on cognition can be parsed from substance use, even in small samples with chronic and active use histories. PMID- 23446058 TI - Attenuated antigen-specific T cell responses in cirrhosis are accompanied by elevated serum interleukin-10 levels and down-regulation of HLA-DR on monocytes. AB - BACKGROUND: Advanced liver disease predisposes to bacterial translocation and endotoxaemia which can contribute to elevated circulating levels of IL-10 and down-regulation of MHC class II on antigen-presenting cells. We sought to evaluate antigen-specific T-cell responses toward common viral antigens in order to investigate defects in cellular immunity in cirrhosis. METHODS: Peripheral blood was obtained from 22 cirrhotic patients with systemic inflammation, 13 cirrhotic patients without systemic inflammation and 14 healthy controls. C reactive protein was used as an indicator for systemic inflammation using a cut off of 10 mg/l. Intracellular Th1 cytokines were quantified after T cell stimulation with the viral peptides EBNA1 and BZLF1 or the bacterial superantigen SEB by flow cytometry. Serum levels of lipopolysaccharide-binding protein (LBP) and IL-10 were quantified by ELISA. RESULTS: Compared to healthy controls, patients with cirrhosis had higher circulating levels of LBP and IL-10, an expansion of peripheral blood CD14+ monocytes with low HLA-DR expression and an increased fraction of CD25-positive CD4+ and CD8+ T cells. These findings were most pronounced in cirrhotic patients with systemic inflammation but fell short of reaching statistical significance when comparing against cirrhotic patients without systemic inflammation. In the former group TNF-alpha production in CD4+ and CD8+ T cells was reduced after stimulation with SEB, whereas there was no significant difference between the total cohort of cirrhotic patients and controls. After stimulation with the overlapping peptide pools for viral antigens EBNA1 and BZLF1, the number of responding T cells and the amount of TNF-alpha or IFN-gamma production did not differ between the three pre-defined groups. However, cirrhotic patients with null-responses to EBV peptides had significantly higher serum IL-10 levels than responders to EBV peptides. Furthermore, TNF-alpha production in responding T cells was attenuated in patients with a high frequency of CD14+ HLA-DR- monocytes. CONCLUSION: Our data suggest that bacterial translocation, endotoxaemia, inflammation and T cell activation in cirrhosis are accompanied by an increase in circulating anti-inflammatory cytokines, reduced monocytic MHC class II expression and attenuated cytokine production in T cells. These changes are likely to contribute to altered adaptive immune responses during infection or after vaccination. PMID- 23446059 TI - Lessons learned from field-testing a brief behavioral intervention package for African American women at risk for HIV/STDs. AB - This article describes how Sister to Sister, an evidence-based HIV/STD intervention for African American women in clinical settings, was prepared for national dissemination using the Centers for Disease Control and Prevention's Replicating Effective Programs research translation process. To test the feasibility of the intervention in the "real world," Sister to Sister's original research team collaborated with community partners to field-test the intervention in three clinical settings. Experiences from field-testing and input from a community advisory board were used to translate research protocols into a package of user-friendly materials that could be easily adopted by frontline clinic staff throughout the nation. Process monitoring and evaluation data demonstrated that Sister to Sister could be implemented successfully by a variety of practitioners including nurses, health educators, and HIV test counselors. "Buy-in" from clinic administrators and providers was a prerequisite to the success of the intervention. Replicating Effective Programs provided a useful process that can be applied by others to successfully prepare evidence-based interventions such as Sister to Sister for national dissemination. PMID- 23446061 TI - Less invasive surfactant administration in extremely preterm infants: impact on mortality and morbidity. AB - BACKGROUND: A new mode of surfactant administration without intubation - less invasive surfactant administration (LISA) - has recently been described for premature infants. OBJECTIVE: We report single-center outcome data of extremely premature infants who have been managed by LISA in our department. Mortality and morbidity rates of the cohort were compared to historical controls from our own center and to data of the Vermont-Oxford Neonatal Network (VONN). PATIENTS AND METHODS: All infants born at 23-27 weeks' gestational age during 01/2009 and 06/2011 (n = 224) were managed by LISA and included in the study group. RESULTS: LISA was tolerated by 94% of all infants. 68% of infants stayed on continuous positive airway pressure on day 3. The rate of mechanical ventilation was 35% within the first week and 59% during the entire hospital stay. Compared to historical controls, we found significantly higher survival rates (75.8 vs. 64.1%) and significantly less intraventricular hemorrhage (IVH) (28.1 vs. 45.9%), severe IVH (13.1 vs. 23.9%) and cystic periventricular leukomalacia (1.2 vs. 5.6%); only persistent ductus arteriousus (PDA) (74.7 vs. 52.6%) and retinopathy of prematurity (ROP) (40.5 vs. 21.1%) occurred significantly more often. Compared to VONN data, we found significantly less chronic lung disease (20.6 vs. 46.4%), severe cerebral lesions (IVH 3/4 + cystic PVL; 9.4 vs. 16.1%) and ROP (all grades) (40.5 vs. 56.5%); only PDA (74.7 vs. 63.1%) and severe ROP (> grade 2) (24.1 vs. 14.1%) occurred significantly more often in our cohort. CONCLUSION: Surfactant can be effectively and safely delivered via LISA and this is associated with low rates of mechanical ventilation and various adverse outcomes in extremely premature infants. PMID- 23446062 TI - Towards optimal treatment with growth hormone in short children and adolescents: evidence and theses. AB - Treatment with growth hormone (GH) has become standard practice for replacement in GH-deficient children or pharmacotherapy in a variety of disorders with short stature. However, even today, the reported adult heights achieved often remain below the normal range. In addition, the treatment is expensive and may be associated with long-term risks. Thus, a discussion of the factors relevant for achieving an optimal individual outcome in terms of growth, costs, and risks is required. In the present review, the heterogenous approaches of treatment with GH are discussed, considering the parameters available for an evaluation of the short- and long-term outcomes at different stages of treatment. This discourse introduces the potential of the newly emerging prediction algorithms in comparison to other more conventional approaches for the planning and evaluation of the response to GH. In rare disorders such as those with short stature, treatment decisions cannot easily be deduced from personal experience. An interactive approach utilizing the derived experience from large cohorts for the evaluation of the individual patient and the required decision-making may facilitate the use of GH. Such an approach should also lead to avoiding unnecessary long-term treatment in unresponsive individuals. PMID- 23446064 TI - Estimating HIV prevalence from surveys with low individual consent rates: annealing individual and pooled samples. AB - : Many HIV prevalence surveys are plagued by the problem that a sizeable number of surveyed individuals do not consent to contribute blood samples for testing. One can ignore this problem, as is often done, but the resultant bias can be of sufficient magnitude to invalidate the results of the survey, especially if the number of non-responders is high and the reason for refusing to participate is related to the individual's HIV status. One reason for refusing to participate may be for reasons of privacy. For those individuals, we suggest offering the option of being tested in a pool. This form of testing is less certain than individual testing, but, if it convinces more people to submit to testing, it should reduce the potential for bias and give a cleaner answer to the question of prevalence. This paper explores the logistics of implementing a combined individual and pooled testing approach and evaluates the analytical advantages to such a combined testing strategy. We quantify improvements in a prevalence estimator based on this combined testing strategy, relative to an individual testing only approach and a pooled testing only approach. Minimizing non-response is key for reducing bias, and, if pooled testing assuages privacy concerns, offering a pooled testing strategy has the potential to substantially improve HIV prevalence estimates. PMID- 23446060 TI - Oligodendroglial alterations and the role of microglia in white matter injury: relevance to schizophrenia. AB - Schizophrenia is a chronic and debilitating mental illness characterized by a broad range of abnormal behaviors, including delusions and hallucinations, impaired cognitive function, as well as mood disturbances and social withdrawal. Due to the heterogeneous nature of the disease, the causes of schizophrenia are very complex; its etiology is believed to involve multiple brain regions and the connections between them, and includes alterations in both gray and white matter regions. The onset of symptoms varies with age and severity, and there is some debate over a degenerative or developmental etiology. Longitudinal magnetic resonance imaging studies have detected progressive gray matter loss in the first years of disease, suggesting neurodegeneration; but there is also increasing recognition of a temporal association between clinical complications at birth and disease onset that supports a neurodevelopmental origin. Presently, neuronal abnormalities in schizophrenia are better understood than alterations in myelin producing cells of the brain, the oligodendrocytes, which are the predominant constituents of white matter structures. Proper white matter development and its structural integrity critically impacts brain connectivity, which affects sensorimotor coordination and cognitive ability. Evidence of defective white matter growth and compromised white matter integrity has been found in individuals at high risk of psychosis, and decreased numbers of mature oligodendrocytes are detected in schizophrenia patients. Inflammatory markers, including proinflammatory cytokines and chemokines, are also associated with psychosis. A relationship between risk of psychosis, white matter defects and prenatal inflammation is being established. Animal models of perinatal brain injury are successful in producing white matter damage in the brain, typified by hypomyelination and/or dysmyelination, impaired motor coordination and prepulse inhibition of the acoustic startle reflex, recapitulating structural and functional characteristics observed in schizophrenia. In addition, elevated expression of inflammation-related genes in brain tissue and increased production of cytokines by blood cells from patients with schizophrenia indicate immunological dysfunction and abnormal inflammatory responses, which are also important underlying features in experimental models. Microglia, resident immune defenders of the central nervous system, play important roles in the development and protection of neural cells, but can contribute to injury under pathological conditions. This article discusses oligodendroglial changes in schizophrenia and focuses on microglial activity in the context of the disease, in neonatal brain injury and in various experimental models of white matter damage. These include disorders associated with premature birth, and animal models of perinatal bacterial and viral infection, oxygen deprivation (hypoxia) and excess (hyperoxia), and elevated systemic proinflammatory cytokine levels. We briefly review the effects of treatment with antipsychotic and anti-inflammatory agents in models of perinatal brain injury, and comment on the therapeutic potential of these strategies. By understanding the neurobiological basis of oligodendroglial abnormalities in schizophrenia, it is hoped that patients will benefit from the availability of targeted and more efficacious treatment options. PMID- 23446065 TI - Combining cognitive-behavioral therapy and milnacipran for fibromyalgia: a feasibility randomized-controlled trial. AB - OBJECTIVES: To evaluate the feasibility of a randomized-controlled trial and to obtain estimates of the effects of combined cognitive-behavioral therapy (CBT) and milnacipran for the treatment of fibromyalgia. METHODS: Fifty-eight patients with fibromyalgia were randomized to 1 of the 3 treatment arms: (1) combination therapy (n = 20); (2) milnacipran+education (n = 19); and (3) placebo+CBT (n = 19). Patients received either milnacipran (100 mg/d) or placebo. Patients also received 8 sessions of phone-delivered CBT or educational instructions, but only from baseline to week 9. Assessments were conducted at baseline, week 9, and 21. The primary endpoints were baseline to week 21 changes in weekly average pain intensity and physical function (SF-36 physical function scale). RESULTS: Compared with milnacipran, combination therapy demonstrated a moderate effect on improving SF-36 physical function (SE = 9.42 [5.48], P = 0.09, effect size = 0.60) and in reducing weekly average pain intensity (mean difference [SE] = -1.18 [0.62], P = 0.07, effect size = 0.67). Compared with milnacipran, CBT had a moderate to large effect in improving SF-36 physical function (mean difference [SE] = 11.0 [5.66], P = 0.06, effect size = 0.70). Despite the presence of concomitant centrally acting therapies, dropout rate was lower than anticipated (15% at week 21). Importantly, at least 6 out of the 8 phone-based therapy sessions were successfully completed by 89% of the patients; and adherence to the treatment protocols was > 95%. CONCLUSIONS: In this pilot study, a therapeutic approach that combines phone-based CBT and milnacipran was feasible and acceptable. Moreover, the preliminary data supports conducting a fully powered randomized-controlled trial. PMID- 23446063 TI - Carbon monoxide in exhaled breath testing and therapeutics. AB - Carbon monoxide (CO), a low molecular weight gas, is a ubiquitous environmental product of organic combustion, which is also produced endogenously in the body, as the byproduct of heme metabolism. CO binds to hemoglobin, resulting in decreased oxygen delivery to bodily tissues at toxicological concentrations. At physiological concentrations, CO may have endogenous roles as a potential signaling mediator in vascular function and cellular homeostasis. Exhaled CO (eCO), similar to exhaled nitric oxide (eNO), has been evaluated as a candidate breath biomarker of pathophysiological states, including smoking status, and inflammatory diseases of the lung and other organs. eCO values have been evaluated as potential indicators of inflammation in asthma, stable COPD and exacerbations, cystic fibrosis, lung cancer, or during surgery or critical care. The utility of eCO as a marker of inflammation and its potential diagnostic value remain incompletely characterized. Among other candidate 'medicinal gases' with therapeutic potential, (e.g., NO and H2S), CO has been shown to act as an effective anti-inflammatory agent in preclinical animal models of inflammatory disease, acute lung injury, sepsis, ischemia/reperfusion injury and organ graft rejection. Current and future clinical trials will evaluate the clinical applicability of this gas as a biomarker and/or therapeutic in human disease. PMID- 23446067 TI - Long-term results of percutaneous lumbar decompression for LSS: two-year outcomes. AB - OBJECTIVE: The aim of this report was to evaluate the long-term effectiveness and safety of mild lumbar decompression for the treatment of neurogenic claudication associated with lumbar spinal stenosis. This technique uses a percutaneous dorsal approach to remove small portions of ligament and lamina, thereby restoring space and decompressing the spinal canal. MATERIALS AND METHODS: Two-year data are reported for 45 patients treated with mild decompression at 11 US sites. Outcome measures included the Visual Analog Scale (VAS), Oswestry Disability Index, and Zurich Claudication Questionnaire. Safety was monitored throughout the procedural and follow-up period for all patients. Interim data are included for these patients at 1 week, 6 months, and 1-year follow-up. RESULTS: Seventy-one percent of patients reported improvement in VAS at the end of the reporting period. At 2 years, patients demonstrated a statistically significant reduction of pain as measured by VAS, and improvement in physical function and mobility was significant as measured by Zurich Claudication Questionnaire and Oswestry Disability Index. Tukey honestly significant different test found significant improvement in all outcome measures from baseline to each follow-up interval. Further, major improvement occurred by 1-week follow-up and showed no difference between each subsequent follow-up, signifying considerable stability and durability of the initial result over time. No major device or intraprocedural adverse events were reported. DISCUSSION: In this report of 2-year follow-up on 45 patients treated with mild percutaneous lumbar decompression, patients experienced statistically significant pain relief and improved functionality. PMID- 23446066 TI - Pedometer-driven walking for chronic low back pain: a feasibility randomized controlled trial. AB - OBJECTIVES: To evaluate the feasibility of an RCT of a pedometer-driven walking program and education/advice to remain active compared with education/advice only for treatment of chronic low back pain (CLBP). METHODS: Fifty-seven participants with CLBP recruited from primary care were randomly allocated to either: (1) education/advice (E, n=17) or (2) education/advice plus an 8-week pedometer driven walking program (EWP, n=40). Step targets, actual daily step counts, and adverse events were recorded in a walking diary over the 8 weeks of intervention for the EWP group only. All other outcomes (eg, functional disability using the Oswestry Disability Questionnaire (ODQ), pain scores, physical activity (PA) measurement etc.) were recorded at baseline, week 9 (immediately post intervention), and 6 months in both groups. RESULTS: The recruitment rate was 22% and the dropout rate was lower than anticipated (13% to 18% at 6 mo). Adherence with the EWP was high, 93% (n=37/40) walked for >= 6 weeks, and increased their steps/day (mean absolute increase in steps/d, 2776, 95% confidence interval [CI], 1996-3557) by 59% (95% CI, 40.73%-76.25%) from baseline. Mean percentage adherence with weekly step targets was 70% (95% CI, 62%-77%). Eight (20%) minor related adverse events were observed in 13% (5/40) of the participants. The EWP group participants demonstrated an 8.2% point improvement (95% CI, -13 to -3.4) on the ODQ at 6 months compared with 1.6% points (95% CI, -9.3 to 6.1) for the E group (between group d=0.44). There was also a larger mean improvement in pain (d=0.4) and a larger increase in PA (d=0.59) at 6 months in EWP. DISCUSSION: This preliminary study demonstrated that a main RCT is feasible. EWP was safe and produced a real increase in walking; CLBP function and pain improved, and participants perceived a greater improvement in their PA levels. These improvements require confirmation in a fully powered RCT. PMID- 23446068 TI - A 3-year, open-label, flexible-dosing study of milnacipran for the treatment of fibromyalgia. AB - OBJECTIVES: To evaluate the effects of long-term milnacipran treatment in fibromyalgia patients. METHODS: Patients completing a previous milnacipran study were eligible to participate in this long-term (up to 3.25 y), open-label study. After washout, dose escalation, and 8 weeks of stable-dose treatment (100 mg/d), patients received flexible doses of milnacipran (50 to 200 mg/d) for the remainder of the study. Safety evaluations included adverse events and vital signs. Clinical measures included weekly recall pain (visual analog scale [VAS]), Patient Global Disease Status (PGDS), and the Short Form-36 Health Survey (SF-36, including the Physical Component Summary [PCS] and Mental Component Summary scores). Cohort analyses were conducted to assess the effects of milnacipran over varying periods of time. RESULTS: Of 1227 patients entering the study, 585 (47.7%) were classified as completers, including 379 (30.9%) patients who were currently enrolled when the study was administratively terminated. Mean duration of treatment was 19 months, with 206 patients reaching the final visit and receiving 36 to 38 months of study treatment. The percentage of patients with >=1 treatment-emergent adverse event was 88.3%, with nausea (25.9%) and headache (13.4%) being the most common events. Discontinuations due to adverse events occurred in 20.9% of patients. Potentially clinically significant increases in blood pressure or heart rate occurred in <=1.1% of patients. Mean improvement from baseline in weekly recall VAS pain was 17.6; improvements in global status (PGDS) and physical functioning (SF-36 PCS) were also observed. In all patient cohorts, these improvements were observed by month 3 and remained relatively constant over time. At final study visit in the 3-year cohort, 70.3% of patients rated their overall fibromyalgia as "much improved" or "very much improved." DISCUSSION: No new safety concerns were identified in this long-term study. Sustained symptom improvements were found in fibromyalgia patients who received up to 3.25 years of milnacipran treatment. PMID- 23446069 TI - A systematic review and meta-analysis of medical leech therapy for osteoarthritis of the knee. AB - OBJECTIVES: Osteoarthritis of the knee is a common chronic disease among older adults. Therapeutic approaches mainly consist of physiotherapy or pharmacological therapy, but these approaches are limited over time by their cost and/or side effects. This paper presents a systematic review and meta-analysis of the effectiveness of medical leech therapy for osteoarthritis of the knee. METHODS: The PubMed/MEDLINE, Cochrane Library, EMBASE, Scopus, and CAMBASE databases were screened in August 2012 to identify randomized (RCTs) and nonrandomized controlled clinical trials (CCTs) comparing leech therapy to control conditions. Main outcome measures were pain, functional impairment, and joint stiffness. For each outcome, standardized mean differences (SMD) and 95% confidence intervals were calculated. RESULTS: Three RCTs and 1 CCT were found, in which a total of 237 patients with osteoarthritis were included. Three trials had a low risk of bias. There was strong overall evidence for immediate (SMD=-1.05; P<0.01) and short-term pain reduction (SMD=-1.00; P<0.01), immediate improvement in patients' physical function (SMD=-0.72; P<0.01), and both immediate (SMD=-0.88; P=0.04) and long-term improvement in their joint stiffness (SMD=-0.62; P<0.01). Moderate evidence was found for leech therapy's short-term effects on physical function (SMD=-0.46; P<0.01) and long-term effects on pain (SMD=-0.45; P<0.01). Leech therapy was not associated with any serious adverse events. DISCUSSION: This systematic review found moderate to strong evidence for the reduction of pain, functional impairment, and joint stiffness after medical leech therapy in patients with osteoarthritis of the knee. Given the low number of reported adverse events, leech therapy may be a useful approach in treating this condition. Further high-quality RCTs are required for the conclusive judgment of its effectiveness and safety. PMID- 23446070 TI - The effectiveness of conservative treatment for patients with cervical radiculopathy: a systematic review. AB - OBJECTIVES: The aim of this systematic review is to assess the effectiveness of conservative treatments for patients with cervical radiculopathy, a term used to describe neck pain associated with pain radiating into the arm. Little is known about the effectiveness of conservative treatment for patients with cervical radiculopathy. METHODS: We electronically searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, and CINAHL for randomized clinical trials. Conservative therapies consisted of physiotherapy, collar, traction etc. Two authors independently assessed the risk of bias using the criteria recommended by the Cochrane Back Review Group and extracted the data. If studies were clinically homogenous, a meta-analysis was performed. The overall quality of the body of evidence was evaluated using the GRADE method. RESULTS: Fifteen articles were included that corresponded to 11 studies. Two studies scored low risk of bias. There is low-level evidence that a collar is no more effective than physiotherapy at short-term follow-up and very low-level evidence that a collar is no more effective than traction. There is low-level evidence that traction is no more effective than placebo traction and very low level-evidence that intermittent traction is no more effective than continuous traction. DISCUSSION: On the basis of low-level to very low-level evidence, no 1 intervention seems to be superior or consistently more effective than other interventions. Regardless of the intervention assignment, patients seem to improve over time, indicating a favorable natural course. Use of a collar and physiotherapy show promising results at short-term follow-up. PMID- 23446071 TI - Electroencephalographic activity in response to procedural pain in preterm infants born at 28 and 33 weeks gestational age. AB - OBJECTIVES: Preterm infants undergo frequent painful procedures in the neonatal intensive care unit. Electroencephalography (EEG) changes in reaction to invasive procedures have been reported in preterm and full-term neonates. Frontal EEG asymmetry as an index of emotion during tactile stimulation shows inconsistent findings in full-term infants, and has not been examined in the context of pain in preterm infants. Our aim was to examine whether heel lance for blood collection induces changes in right-left frontal asymmetry, suggesting negative emotional response, in preterm neonates at different gestational age (GA) at birth and different duration of stay in the neonatal intensive care unit. MATERIALS AND METHODS: Three groups of preterm infants were compared: set 1: group 1 (n=24), born and tested at 28 weeks GA; group 2 (n=22), born at 28 weeks GA and tested at 33 weeks; set 2: group 3 (n=25), born and tested at 33 weeks GA. EEG power was calculated for 30-second artifact-free periods, in standard frequency bandwidths, in 3 phases (baseline, up to 5 min after heel lance, 10 min after heel lance). RESULTS: No significant differences were found in right-left frontal asymmetry, or in ipsilateral or contralateral somatosensory response, across phases. In contrast, the Behavioral Indicators of Infant Pain scores changed across phase (P<0.0001). Infants in group 1 showed lower Behavioral Indicators of Infant Pain scores (P=0.039). DISCUSSION: There are technical challenges in recording EEG during procedures, as pain induces motor movements. More research is needed to determine the most sensitive approach to measure EEG signals within the context of pain in infancy. PMID- 23446072 TI - Quality of life and emotional functioning in youth with chronic migraine and juvenile fibromyalgia. AB - SUMMARY: Chronic pain in children is associated with significant negative impact on social, emotional, and school functioning. Previous studies on the impact of pain on children's functioning have primarily used mixed samples of pain conditions or single pain conditions (eg, headache and abdominal pain) with relatively small sample sizes. As a result, the similarities and differences in the impact of pain in subgroups of children with chronic pain have not been closely examined. OBJECTIVE: To compare pain characteristics, quality of life, and emotional functioning among youth with pediatric chronic migraine (CM) and juvenile fibromyalgia (JFM). METHODS: We combined data obtained during screening of patients for 2 relatively large intervention studies of youth (age range, 10 to 18 y) with CM (N=153) and JFM (N=151). Measures of pain intensity, quality of life (Pediatric Quality of Life; PedsQL, child and parent-proxy), depressive symptoms (Children's Depression Inventory), and anxiety symptoms (Adolescent Symptom Inventory-4-Anxiety subscale) were completed by youth and their parent. A multivariate analysis of covariance controlling for effects of age and sex was performed to examine differences in quality of life and emotional functioning between the CM and JFM groups. RESULTS: Youth with JFM had significantly higher anxiety and depressive symptoms, and lower quality of life in all domains. Among children with CM, overall functioning was higher but school functioning was a specific area of concern. DISCUSSION: Results indicate important differences in subgroups of pediatric pain patients and point to the need for more intensive multidisciplinary intervention for JFM patients. PMID- 23446073 TI - Biofeedback-based cognitive-behavioral treatment compared with occlusal splint for temporomandibular disorder: a randomized controlled trial. AB - OBJECTIVES: Cognitive-behavioral treatment has proven efficacy for chronic temporomandibular disorder (TMD). However, most patients receive dental treatment that may not address psychological comorbidities often present in TMD. The aim of the present study was to evaluate the efficacy of biofeedback-based cognitive behavioral treatment (BFB-CBT) versus dental treatment with occlusal splint (OS). Moreover, changes in nocturnal masseter muscle activity (NMMA) were investigated. METHODS: Fifty-eight patients with chronic TMD were randomly assigned to receive either 8 weekly sessions of BFB-CBT or 8 weeks of OS treatment. Diagnoses were established using Research Diagnostic Criteria for TMD. Pain intensity and disability were defined as primary outcomes. Secondary outcomes included emotional functioning, pain coping, somatoform symptoms, treatment satisfaction, and adverse events. NMMA was assessed during 3 nights pretreatment and posttreatment with portable devices. Follow-up assessment took place 6 months after the treatment. RESULTS: Both treatments resulted in significant reductions in pain intensity and disability, with similar amounts of clinically meaningful improvement (45% for BFB-CBT and 48% for OS). Patients receiving BFB-CBT showed significantly larger improvements in pain coping skills. Satisfaction with treatment and ratings of improvement were higher for BFB-CBT. Effects were stable over 6 months, and tended to be larger in the BFB-CBT group for all outcomes. No significant changes were observed in NMMA. DISCUSSION: The fact that BFB-CBT resulted in larger improvements in pain coping skills, and was well accepted by the patients, underlines the importance and feasibility of psychological treatments in the clinical management of TMD. PMID- 23446074 TI - An alternative to traditional mirror therapy: illusory touch can reduce phantom pain when illusory movement does not. AB - OBJECTIVES: There is evidence that amputation leads to cortical reorganization, and it has been suggested that phantom pain might be related to a consequently emerging incongruence of motor intention, somatosensation and visual feedback. One therapeutic approach that has the potential to temporarily resolve this visuo proprioceptive dissociation is mirror therapy, during which amputees typically move their intact limb while observing its reflection in a mirror, which in turn evokes the illusory perception of movement of their phantom limb. However, while the action of moving the phantom relieves pain for some patients, it can actually increase cramping sensations in others. In the current study we therefore implemented an alternative version of the mirror therapy involving a visuotactile illusion, to explore whether it might be effective with amputees for whom the action of moving the phantom increases phantom pain. METHODS: We recruited six upper limb amputees who had been previously exposed to the classical mirror therapy with no or limited success, and exposed them to two differential experimental conditions involving visualization paired with either illusory movement or illusory touch of the phantom hand. RESULTS: While none of the participants benefitted from the movement condition, five participants showed a significant pain reduction during the stroking condition. DISCUSSION: Albeit preliminary, our results represent an encouraging finding of possible future clinical relevance, and indicate that the type of multisensory stimulation that most efficiently reduces phantom pain can vary in different sub-populations of amputees. PMID- 23446075 TI - Treatment expectations among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation. AB - OBJECTIVES: To understand expectations regarding treatment recommendations among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. METHODS: A total of 102 adolescent-parent dyads were recruited at the time of initial contact with a multidisciplinary pain management clinic. Each participant completed reports of adolescent pain intensity and disability, biopsychosocial perspective of pain, and treatment expectations related to recommendations and feedback for a vignette description of an adolescent presenting at an initial multidisciplinary pain clinic evaluation. RESULTS: Descriptive findings for individual treatment expectations and adolescent-parent dyad agreement statistics were examined. Slight to fair levels of agreement occurred for 50% of the expectations assessed. The strongest shared expectations were for recommendations to return to school, pursue psychological counseling, and pursue PT/OT treatment. Stronger agreement occurred for items reflecting alternative, emotional, behavioral, and activity recommendations with weaker agreement for medical interventions (eg, medication and surgery). Correlations emerged between individual expectations and adolescent pain intensity, disability, with the greatest number of significant relationships found for adolescent and parent expectations and biopsychosocial perspectives of pain. DISCUSSION: Our results document that adolescents and parents show modest levels of agreement on expectations for treatment at the time of an initial pain clinic evaluation. This may relate to expectations being internal perspectives not clearly expressed within families; thus, the initial treatment consultation may provide an important opportunity to create and align appropriate expectations. Implications of our findings are considered with respect to education, treatment, and future research to understand factors that contribute to treatment adherence and outcomes. PMID- 23446076 TI - The effect of repeated intramuscular alfentanil injections on experimental pain and abuse liability indices in healthy males. AB - OBJECTIVE: Opioid-induced hyperalgesia (OIH), increased sensitivity to noxious stimuli after repeated opioid exposures, has been demonstrated in preclinical studies. However, there is no accepted, prospective model of OIH after repeated opioid exposures currently available in humans. This study assessed a potential prospective OIH model. METHODS: Double-blind intramuscular injections of a short acting opioid (alfentanil 15 mcg/kg; N=8) were compared to active placebo (diphenhydramine 25 mg; N=3) on cold and pressure pain testing and standard abuse liability measures in eight 10-hour sessions (1 injection/session) over 4 to 5 weeks in healthy, pain-free males. Decreases from session baseline pain threshold (PThr) and tolerance (PTol) were calculated to represent hyperalgesia, and were assessed both within and across sessions. RESULTS: Mean decreases in cold PTol were seen in the alfentanil group at 180 minutes (-3.8 s, +/-26.5) and 480 minutes (-1.63 s, +/-31.5) after drug administration. There was a trend for differences between conditions on cold PThr hyperalgesia but not for pressure PThr. Alfentanil participants had greater mean ratings on Liking and High visual analog scales at peak effects (30 min), but these scores did not change across sessions. DISCUSSION: Repeated alfentanil exposures over 4 to 5 weeks resulted in within session decreases in cold pain tolerance from baseline but these differences were not substantially different from diphenhydramine controls. The results did not support the phenomenon of OIH in this model, although definitive conclusions regarding the existence of OIH in humans likely requires a larger sample size or an alternative model. PMID- 23446078 TI - Phonophoresis versus placebo for carpal tunnel syndrome. PMID- 23446077 TI - Pain beliefs and readiness to change among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation. AB - OBJECTIVES: To understand relationships between pain-related beliefs and readiness to change among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. METHODS: A total of 102 adolescent-parent dyads were recruited at the time of initial evaluation at a multidisciplinary pain management clinic. Dyads completed self-report measures to assess pain, catastrophizing, endorsement of a biopsychosocial perspective of pain, and readiness to change/motivation to adopt a self-management approach to pain coping. RESULTS: Agreement between adolescent-parent dyad reports of pain catastrophizing and readiness to change was found; however, adolescents were less likely to view pain as "affected by feelings and emotions" than parents. The hypothesis that greater pain catastrophizing would be correlated with less readiness to change was partially supported. Adolescent and parents who reported lower levels of endorsement of a biopsychosocial perspective were less willing to adopt a self-management approach to pain coping. Endorsement of a biopsychosocial perspective of pain aligned with readiness to change stages more consistently for parents. DISCUSSION: This study documents initial relationships among pain catastrophizing, biopsychosocial perspectives of pain, and readiness to engage in a self-management approach to pain coping for adolescents with chronic pain and their parents. Although agreement exists between dyads regarding catastrophizing and readiness to change, differences were noted in biopsychosocial perspective and dominant readiness to change stage before an initial pain clinic encounter. Findings are considered in terms of future research to advance knowledge regarding the role these factors may play in treatment adherence and outcomes. PMID- 23446079 TI - Percutaneous trigeminal rhizotomy for facial pain secondary to head and neck malignancy. AB - BACKGROUND: Nearly 80% of patients with head and neck cancers experience facial pain related to their tumor or treatment. The majority obtain pain relief with appropriate medical treatment. Occasionally some remain refractory to all analgesics or cannot tolerate the accompanying side effects. They may benefit from surgical intervention. OBJECTIVES: We report a case of medically intractable facial pain secondary to squamous cell carcinoma of the tongue that was successfully treated with percutaneous trigeminal rhizotomy. METHODS: Percutaneous trigeminal radiofrequency rhizotomy involves thermoablation of the trigeminal nerve within Meckel's cave by an electrode inserted through the cheek and foramen ovale. RESULTS: Facial pain was successfully controlled postoperatively. DISCUSSION: Percutaneous trigeminal rhizotomy is a surgical option for managing nociceptive pain secondary to a head and neck malignancy. This technique, last reported in the literature almost 30 years ago, must not be forgotten by the next generation of oncologists, pain specialists, and neurosurgeons. PMID- 23446080 TI - Topical treatment of neuropathic pain using compounded medications. AB - BACKGROUND: The current medical treatment of neuropathic pain (NP) is inadequate with more than two thirds of patients having no suitable solution for their morbid disease and deteriorating quality of life. Currently, medications for the treatment of NP are mostly systemic (affecting the central nervous system) and are dose limited because of serious and debilitating adverse effects. Scientific evidence suggests that localized cutaneous NP can be treated effectively and safely by topical medications; however, only a few topical medications are indicated for NP. This lack of topica medications stems from the limited resources that have been dedicated to exploring the role of the peripheral nervous system in NP or to the development of peripherally active topical analgesics. OBJECTIVES: To explore the evidence supporting the role of topical medications and the role of an expert compounding pharmacist in compounding effective and safe topical preparations to treat NP. METHODS: A narrative review. RESULTS: Well-designed randomized control trials and increasing number of case reports have shown positive results regarding a few topical compounded medications for the treatment of various pathologies of NP. This review summarizes the relevant scientific data supporting the use of topical medication in treating certain types of NP. DISCUSSION: This article discusses the role of topical medications in treating localized cutaneous NP and the role of the compounding pharmacists in applying this therapeutic approach (eg, the scientific considerations that the pharmacist should take into account). PMID- 23446081 TI - The impact of socioeconomic and clinical factors on purchase of prescribed analgesics before and after hysterectomy on benign indication. AB - OBJECTIVE: Pelvic pain is a primary symptom of women referred for hysterectomy. This study identified risk factors for purchase of prescribed analgesics before and after hysterectomy and examined purchase changes after hysterectomy, specifically focusing on socioeconomic effects. METHODS: Nearly all Danish women (n=13,420) with a hysterectomy on benign indication between 2004 and 2006 were included in a registry-based follow-up study. Information on prescription analgesic purchase was from the Danish National Prescription Registry. Factors associated with a purchase and associations between socioeconomic factors and changes in analgesic purchase were assessed. RESULTS: Analgesic purchase after hysterectomy was independently predicted by age below 35 or above 65 years, body mass index >29.9, high American Society of Anesthesiologists (ASA) score, uterus weight <300 g, comorbidity, and less than high school education. In this study, 15% of women initiated or increased analgesic purchase after hysterectomy, whereas 50% with a purchase before hysterectomy ceased buying afterward. Women with low socioeconomic status (SES) (assessed by education, employment, and income) were more likely to increase purchase of analgesics than women with high SES (odds ratio for less than high school vs. more than high school=1.58; 95% confidence interval, 1.31-1.91) and less likely to cease use than women with high SES (odds ratio=0.67; confidence interval, 0.52-0.86 for low vs. high education). DISCUSSION: These results suggest that purchase of analgesics after hysterectomy is related to preoperative factors. Compared with women with high SES, women with low SES had less favorable changes in analgesic purchase after hysterectomy. PMID- 23446082 TI - Coping and recovery in whiplash-associated disorders: early use of passive coping strategies is associated with slower recovery of neck pain and pain-related disability. AB - OBJECTIVE: Coping is shown to affect outcomes in chronic pain patients; however, few studies have examined the role of coping in the course of recovery in whiplash-associated disorders (WAD). The purpose of this study was to determine the predictive value of coping style for 2 key aspects of WAD recovery, reductions in neck pain, and in disability. METHODS: A population-based prospective cohort study design was used to study 2986 adults with traffic related WAD. Participants were assessed at baseline, 6 weeks, and 4, 8, and 12 months postinjury. Coping was measured at 6 weeks using the Pain Management Inventory, and neck pain recovery was assessed at each subsequent follow-up, using a 100 mm visual analogue scale (VAS). Disability was assessed at each follow-up using the Pain Disability Index (PDI). Pain recovery was defined as a VAS score of 0 to 10; disability recovery was defined as a PDI score of 0 to 4. Data analysis used multivariable Cox proportional hazards models. RESULTS: Those using high versus low levels of passive coping at 6 weeks postinjury experienced 28% slower pain recovery and 43% slower disability recovery. Adjusted hazard rate ratios for pain recovery and disability recovery were 0.72 (95% CI, 0.59-0.88) and 0.57 (95% CI, 0.41-0.78), respectively. Active coping was not associated with recovery of neck pain or disability. CONCLUSIONS: Passive coping style predicts neck pain and self-assessed disability recovery. It may be beneficial to assess and improve coping style early in WAD. PMID- 23446083 TI - Factors associated with outcome after superior hypogastric plexus neurolysis in cancer patients. AB - OBJECTIVE: Superior hypogastric plexus neurolysis (SHP-N) has been shown in uncontrolled studies to provide intermediate-term benefit in a majority of patients with pain secondary to genitourinary, gynecologic, and colorectal cancers. The purpose of this is to determine factors associated with treatment outcome. MATERIALS AND METHODS: Patients who underwent SHP-N after a positive prognostic block were identified based on diagnostic classification and procedural codes from databases at 2 large teaching hospitals. A host of demographic, clinical, and treatment factors were examined for their association with treatment success, which was defined as >=50% pain relief lasting >=1 month. RESULTS: A total of 53.1% of 32 patients with sufficient medical records for analysis experienced a positive outcome. Those with a positive outcome were older (mean age 59.6 y, SD 13.1 vs. 47.8, SD 15.6; P=0.03), less likely to have pelvic pain (36.8% success rate, P=0.04), and more likely to have bladder cancer (88.9% success rate; P=0.01) than those with a negative outcome. In stratified analysis, female were more likely to have positive outcome if they did not have pelvic pain compared to those that did (P=0.008). This difference was not significant for males. DISCUSSION: Selecting patients based on demographic and clinical variables may improve treatment outcomes for SHP-N. Larger, prospective studies are needed to confirm our results and better refine selection criteria better. PMID- 23446084 TI - Is mild persisting pain too insignificant to be considered a chronic pain condition? PMID- 23446085 TI - Mindfulness-based cognitive therapy for the treatment of headache pain: a pilot study. AB - OBJECTIVE: This pilot study reports the findings of a randomized controlled trial (RCT) investigating the feasibility, tolerability, acceptability, and initial estimates of efficacy of mindfulness-based cognitive therapy (MBCT) compared to a delayed treatment (DT) control for headache pain. It was hypothesized that MBCT would be a viable treatment approach and that compared to DT, would elicit significant improvement in primary headache pain-related outcomes and secondary cognitive-related outcomes. MATERIALS AND METHODS: RCT methodology was employed and multivariate analysis of variance models were conducted on daily headache diary data and preassessment and postassessment data for the intent-to-treat sample (N=36), and on the completer sample (N=24). RESULTS: Patient flow data and standardized measures found MBCT for headache pain to be feasible, tolerable, and acceptable to participants. Intent-to-treat analyses showed that compared to DT, MBCT patients reported significantly greater improvement in self-efficacy (P=0.02, d=0.82) and pain acceptance (P=0.02, d=0.82). Results of the completer analyses produced a similar pattern of findings; additionally, compared to DT, MBCT completers reported significantly improved pain interference (P<0.01, d= 1.29) and pain catastrophizing (P=0.03, d=-0.94). Change in daily headache diary outcomes was not significantly different between groups (P's>0.05, d's<=-0.24). DISCUSSION: This study empirically examined MBCT for the treatment of headache pain. Results indicated that MBCT is a feasible, tolerable, acceptable, and potentially efficacious intervention for patients with headache pain. This study provides a research base for future RCTs comparing MBCT to attention control, and future comparative effectiveness studies of MBCT and cognitive-behavioral therapy. PMID- 23446086 TI - The reciprocal effects of pain intensity and activity limitations: implications for outcomes assessment in clinical trials. AB - OBJECTIVES: To examine the reciprocal effects of pain intensity and limitations in physical functioning over time. METHODS: This study presents findings from a reanalysis of a 7-center trial conducted in Ontario, Canada, included 209 adults with chronic knee pain secondary to osteoarthritis. Patients were randomized to receive 28 days of therapy with an active solution (1.5% w/w diclofenac sodium in dimethyl sulfoxide) or 1 of 2 control solutions containing no diclofenac. The key outcome measures used in the current analyses were administered throughout the study period and assessed pain intensity, perceived activity limitations, and a composite score measuring both domains. A structural cross-lagged regression approach was used to determine the reciprocal effects of pain and activity limitations over time. RESULTS: In both study groups, participants (N=209) experienced significant reductions in mean pain intensity and activity limitations from baseline to weeks 1, 2, 3, and 4 (P<0.001 for both variables). Similarly, there were significant reductions in the activity limitations outcome at weeks 1 and 4 for the active versus control group (P<0.05 for both). Higher levels of perceived activity limitations predicted more future pain at all time points. Cross-lagged associations in which pain predicted subsequent perceived activity limitations were not significant at any time point. All 3 outcome measures evidenced similar responsiveness to the treatment. CONCLUSION: These analyses showed that a decrease in activity limitations results in a decrease in pain intensity. However, changes in pain intensity had no effect on subsequent activity limitations in the study sample. None of the 3 outcome variables emerged as being more responsive to treatment than the others. PMID- 23446089 TI - Catechol-O-methyltransferase (COMT) gene polymorphisms as risk factor in temporomandibular disorders patients from Southern Italy. AB - OBJECTIVES: To evaluate the role of COMT gene variants as potential risk factors in a group of patients affected with chronic temporomandibular disorder (TMD) pain. METHODS: We sequenced COMT gene in 182 Italian subjects (50 affected by TMD and 132 controls). The study population consisted of patients affected by myogenous and/or arthrogenous pain (RDC/TMD: Ia, Ib, IIIa, IIIb diagnostic categories). RESULTS: We detected 40 single nucleotide polymorphisms (SNPs) variants (18 novel). Three SNPs, all located in the promoter regions, were more frequently present in cases than in controls (rs 4646310 P=0.018, rs165656 P=0.001, rs 165722 P=0.007). After the False Discovery Rate (FDR) correction rs165656 remained significantly associated with TMD (P=0.049). In addition, the rs 4646310 (AG vs GG, P=0.015) and rs 165656 (GG vs CC, P=0.001) were at binary logistic regression analysis independently associated with TMD, conferring a risk disease of 2.6 (CI= 1.2-5.6) and of 5.3 (CI= 2.0-13.7) respectively. DISCUSSION: Our data extend the number of SNPs present in the promoter region that could play a regulatory role in COMT gene and suggest that the genetic polymorphisms rs 165656 and rs 4646310 exert a role in TMD susceptibility. PMID- 23446088 TI - NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV associated distal sensory polyneuropathy: results of a 52-week open-label study. AB - OBJECTIVES: To evaluate the efficacy, safety, and tolerability of repeated NGX 4010 treatments in the open-label extension phase of a 52-week study in patients with neuropathic pain due to HIV-associated distal sensory polyneuropathy (HIV DSP). METHODS: Patients completing the 12-week, randomized, double-blind phase of the study could enter a 40-week, open-label phase, and receive up to 3, 60-minute NGX-4010 treatments. Patients recorded their "average pain for the past 24 hours" daily using the Numeric Pain Rating Scale (NPRS). Efficacy assessment included the percentage NPRS score reduction from baseline to weeks 2 to 12 after the final treatment, and Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) questionnaires at study termination. RESULTS: Of 307 patients randomized, 272 entered the open-label phase; 81, 90, 55, and 46 received 0, 1, 2, and 3 retreatments, respectively. The mean percentage decrease in NPRS score from baseline to weeks 2 to 12 after the final treatment was similar in patients receiving single or multiple NGX-4010 treatments (-25.8%, 27.1%, -24.6%, and -22.7% for 1, 2, 3, and 4 NGX-4010 treatments, respectively). PGIC and CGIC results demonstrated a benefit of NGX-4010 treatment through to the end of the study regardless of the number of treatments received. Transient local application site reactions were the most frequently reported adverse events, and were mainly mild to moderate, nonserious, and did not increase with repeated treatment. DISCUSSION: Repeated NGX-4010 treatments were generally well tolerated and resulted in consistent reductions in HIV-DSP-associated pain and improvement in patient-reported outcomes. PMID- 23446090 TI - The safety of liposome bupivacaine, a novel local analgesic formulation. AB - OBJECTIVE: Pooled safety data from 10 randomized, double-blind studies of liposome bupivacaine, a novel local analgesic formulation, were examined. METHODS: Eight hundred twenty-three patients received liposome bupivacaine (dose, 66 to 532 mg) given locally at the surgical site in 5 different settings (hemorrhoidectomy, bunionectomy, breast augmentation, total knee arthroplasty, and hernia repair); 446 received bupivacaine HCl (dose, 75 to 200 mg) and 190 received placebo. Adverse events (AEs) were monitored for up to 36 days after administration. RESULTS: Overall, 48% of patients were men and 21% were 65 years and older. Incidence of AEs was 62% for patients receiving liposome bupivacaine, versus 75% and 43% for patients receiving bupivacaine HCl and placebo, respectively. The most common AEs (incidence >10%) in the liposome bupivacaine arms were nausea, constipation, and vomiting. One death was reported in the liposome bupivacaine group and 1 in the bupivacaine HCl group; both deemed unrelated to study drug. Serious AEs were reported in 2.7% of patients receiving liposome bupivacaine, versus 5.4% and 1.1% of those receiving bupivacaine HCl and placebo, respectively. In both the liposome bupivacaine and bupivacaine HCl groups, 6% of patients experienced a cardiac AE; these were primarily tachycardia (4% vs. 5%, respectively) and bradycardia (2% vs. 1%, respectively). Overall incidence of treatment-related cardiac AEs was <1%; all were associated with liposome bupivacaine. All of these events were assessed by investigators as possibly related to study drug; all were mild or moderate in severity, and none required therapeutic intervention. DISCUSSION: Liposome bupivacaine exhibited acceptable tolerability across 823 patient exposures. PMID- 23446091 TI - AIB1 and its significant role in tumor pathogenesis in systemic malignancies: beyond breast carcinomas. PMID- 23446092 TI - Adherence to treatment guidelines for primary sarcomas affects patient survival: a side study of the European CONnective TIssue CAncer NETwork (CONTICANET). AB - BACKGROUND: The impact of adherence to clinical practice guidelines (CPGs) for loco-regional treatment (i.e. surgery and radiotherapy) and chemotherapy on local disease control and survival in sarcoma patients was investigated in a European study conducted in an Italian region (Veneto). PATIENTS AND METHODS: The completeness of the adherence to the Italian CPGs for sarcomas treatment was assessed by comparing the patient's charts and the CPGs. Propensity score adjusted multivariate survival analysis was used to assess the impact of CPGs adherence on patient clinical outcomes. RESULTS: A total of 151 patients were included. Adherence to CPGs for loco-regional therapy and chemotherapy was observed in 106 out of 147 (70.2%) and 129 out of 139 (85.4%) patients, respectively. Non-adherence to CPGs for loco-regional treatment was independently associated with AJCC stage III disease [odds ratio (OR) 1.77, P = 0.011] and tumor-positive excision margin (OR 3.55, P = 0.003). Patients not treated according to the CPGs were at a higher risk of local recurrence [hazard ratio (HR) 5.4, P < 0.001] and had a shorter sarcoma-specific survival (HR 4.05, P < 0.001), independently of tumor stage. CONCLUSIONS: Incomplete adherence to CPGs for loco-regional treatment of sarcomas was associated with worse prognosis in patients with non-metastatic tumors. PMID- 23446093 TI - Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: a retrospective population-based study from the Nordic Lymphoma Group. AB - BACKGROUND: Standard treatment of adult Burkitt lymphoma is not defined due to the lack of randomised trials. In this situation, population-based data may represent a useful contribution in order to identify an optimal treatment strategy. PATIENTS AND METHODS: The aims of this study were to investigate the outcome for adult HIV-negative BL with different chemotherapy regimens, and to assess possible improvement within the time frame of the study. The study population was identified through the Swedish and Danish lymphoma registries 2000 2009. RESULTS: A total of 258 patients were identified. Since 2000, overall survival (OS) improved significantly only for younger patients (<65 years). Intensive regimens such as the Berlin-Frankfurt-Munster, hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) were associated with a favourable 2-year OS of 82%, 83%, and 69%, respectively. The low-intensive CHOP/CHOEP regimens achieved a 2 year OS of 38.8%, confirming their inadequacy for the treatment of BL. In a multivariate analysis, rituximab was not significantly associated with improved OS. CONCLUSIONS: In this population-based retrospective series of adult BL, intensive chemotherapy regimens were associated with favourable outcome. The impact of the addition of rituximab remains uncertain and warrants further investigation. PMID- 23446094 TI - Families' experiences with patients who died after assisted suicide: a retrospective interview study in southern Switzerland. AB - BACKGROUND: In Switzerland, if certain conditions are met, assisted suicide is not prosecuted. International debate suggests that requests for hasten death are often altered by the provision of palliative care. Aims of the study were to explore patients' reasons for choice of assisted suicide and family perceptions of the interactions with health care professionals. PATIENTS AND METHODS: This is a qualitative study upon 11 relatives of 8 patients cared for by a palliative care team, deceased of assisted suicide. RESULTS: Pain and symptom burden were not regarded by patients as key reasons to seek assisted suicide: existential distress and fear of loss of control were the determinants. Most patients had made pre-illness decisions to use assisted suicide. A general need for perceived control and fear of dependency were reported as a common characteristic of these patients. Patients held misunderstandings about the nature and purpose of palliative care, and the interviewed indicated that patients did not regard provision of palliative care services as influential in preventing their decision. CONCLUSIONS: Assisted suicide was preferred despite provision of palliative care. Better understanding of the importance placed on perceived control and anticipated dependency is needed. Further research is needed to develop appropriate support for patients contemplating assisted suicide. PMID- 23446095 TI - Tertiarism in psychiatry: the barcelona clinic bipolar disorders programme. PMID- 23446096 TI - Commentary: the current state of psychopharmacology and psychiatry. PMID- 23446097 TI - Validation of the Spanish Personal and Social Performance scale (PSP) in outpatients with stable and unstable schizophrenia. AB - INTRODUCTION: The main long-term therapeutic goals of schizophrenia should go beyond the symptoms and include the improvement of patients' psychosocial functioning and quality of life. The aim of this study was to validate the Personal and Social Performance (PSP) scale in Spanish outpatients with schizophrenia. MATERIALS AND METHODS: Naturalistic, 6-month follow-up, multicentre study. 244 patients and 76 controls were evaluated using the PSP, the Social and Occupational Functioning Assessment Scale (SOFAS), and the Clinical Global Impression - Severity (CGI-S) and Change (CGI-C) scales. RESULTS: Internal reliability=0.87. Test-retest reliability=0.98. Construct validity=1 component that explained 73.2% of the variance. Convergent validity: Pearson correlation coefficient between PSP and SOFAS=0.95 (p<0.0001), between PSP and CGI-S=-0.88 (p<0.0001). Discriminant validity: the PSP discriminates between patients and controls [50.3 versus 91.9, p<0.0001] and among patients with mild, moderate, and severe schizophrenia according to CGI-S scores [73 versus 56.6 versus 37.5, p<0.0001]. Area under the curve=0.986. A cut-off point of 79 on the PSP scale provided good sensitivity (94.3%) and specificity (96.1%) for identifying patients and controls according to their level of functioning. At month 6 significant improvements (p<0.0001) were seen in PSP, SOFAS, and CGI-C scores. The PSP was sensitive to improvement; a score of very much improved in the CGI-C corresponds to a improvement of 34 points in the PSP. CONCLUSION: The Spanish PSP is a reliable, valid and sensitive instrument for measuring functioning in outpatients with schizophrenia. As a brief, clinician-rated instrument, the PSP scale seems to be appropriate for use in everyday clinical practice as a mean of identifying and monitoring changes in patient's functioning. PMID- 23446098 TI - Depressive symptoms associated with changes in circadian rhythms. Concordance in perception between doctor and patient, clinical impact and its response to current antidepressant drugs. AB - This is a descriptive, transversal and multicenter study using self-administered surveys concurrently to collect the opinions of two groups (psychiatrists and patients) and discuss their disagreements. The scope of study are hospital services, outpatient centers, individual professional consultation and other assistance system, public or private, which provides psychiatric care in Spain. Participated in this study 319 psychiatrists and 957 patients with the diagnosis of depression, stratified by autonomous communities. The populations they are intended to infer the results of this study were all patients diagnosed with depression and antidepressant treatment, and the group of specialists in psychiatry responsible for clinical monitoring at the national level. In the study sample, depressive symptoms related to circadian rhythms are very common: they are perceived by more than 65% of patients surveyed, except the "early morning awakening insomnia" (54%) and "fatigue, anergy and unresponsiveness" (37%). In general, and endorsing the study hypothesis, the prevalence of almost all analyzed depressive symptoms is significantly underestimated by psychiatrists about the perception of the patients themselves. Only the presence of "fatigue, anergy and unresponsiveness" is more often observed by professionals than by patients, perhaps by nature be of particular somatic symptoms that may suggest to the clinician to rule out underlying organic pathology. In light of the results presented it is concluded that disturbances in circadian rhythms are core aspects of depression and frequent cause of key symptoms and residual symptoms of patients in treatment. These disorders appear to be underestimated by professionals and only partially solved with existing antidepressant drugs. PMID- 23446099 TI - Theory of mind, facial recognition and emotional processing in schizophrenia. AB - Social cognition can be understood as "the mental operations underlying social interactions, which include the human ability to perceive the intentions and dispositions of others" (Brothers, 1990). Theory of mind, atributtional style, social perception are involved in social cognition. It is wellknown that social cognition is impaired in individuals with schizophrenia. Recent investigations for social cognition in schizophrenia has showed that there is a relationship among social cognition, neurocognition and psychosocial functioning. The purpose of this article is to provide a review of social cognition in schizophrenia focusing on the deficit in Theory of mind described by Frith and recent neuroimaging studies. In fact neuroimaging research has demonstrated specific brain regions consistently engaged during theory of mind tasks.We also present some of the instruments avalaible to evaluate social cognition and to review and improve the main intervention programs. Social cognition may be an important target for pharmacological and psychosocial treatments in the future. PMID- 23446100 TI - Oxytocin and autism: a hypothesis to research. Can perinatal oxitocinergic manipulation facilitate autism? AB - The study of the neurohormonal and behavioral processes and neural mechanisms involved in the development of attachment between the infant and the mother has received increased attention over the last years. Oxytocin has been shown to play a central role in the regulation of affiliate social behavior, including sexual behavior, mother infant bonding and social memory and recognition. Following normal physiological vaginal birth highest levels plasmatic endogenous oxytocin are achieved, which has been related to the presence of a sensitive period which seems to facilitate bonding and initial mother and newborn attachment. Perinatal manipulation of peptidic hormones like oxytocin can have life long lasting effects on social and sexual behaviors in animal models. Disregulation of oxytocinergic system has been observed in individuals with autistic disorders. A review of the possible effects of oxytocinergic perinatal manipulation in human newborns is discussed in the present review article. The hypothesis of the possible effect of perinatal oxytocin manipulation on the ethiology of autism is discussed. PMID- 23446101 TI - Effectiveness and risks of combining antipsychotic drugs with electroconvulsive treatment. AB - INTRODUCTION: The simultaneous application of electroconvulsive therapy (ECT) and psychotropic drugs is based on sparse data. Despite this, and the restrictive approach of the Guidelines and Consensus is widespread in the usual care, it is widely practiced in routine clinical. METHOD: We reviewed the results of search on the topic in MEDLINE, PsychINFO, EMBASE and Cochrane, and the main guidelines on the subject and analyzed for drug groups. RESULTS: Except some reservation with regard to classical MAOIs, antidepressants are safe and effective enhancers of the TEC. It is desirable to discontinuation of BZD whenever clinically possible before the course of ECT for risk of interference, if not possible will have to use proper technique to ensure effective incentives. It is advisable to stop or reduce the dose of lithium prior to ECT based on a cost-benefit analysis of the risk of relapse, if maintained will be adjusted lower levels and cognitive effects minimizing techniques. The combination with "classic" and "atypical" antipsychotics power positive clinical effects and the risk of combined use is low. The positive data are collected with clozapine and ECT-resistant psychosis, with little presence of effects of the decrease of seizure threshold by clozapine, and important effect of empowerment, but of limited duration. CONCLUSIONS: Although it is strictly necessary to identify situations in terms of drugs, patient and ECT technique, and care necessary to develop tests that provide methodologically sound data, the combined use of ECT and psychotropic drugs in general presents an acceptable risk level and efficacy data by encouraging empowerment. PMID- 23446102 TI - Clinical meaningful outcomes in schizophrenia: remission and recovery. AB - The traditional view of schizophrenia as a disabling and irremediably progressive disease is being reconsidered because of the evidences arising from long-term follow-up studies. On the other hand, recent advances of therapies have yielded significant functional improvements for some patients. Together, these facts are serving to raise treatment prospects, placing the focus on functional recovery. Although the availability of a valid set of consensus remission criteria has been an important step toward the definition of therapeutic objectives and the conceptualization of recovery, remission and recovery still are rare concepts in the setting of routine clinical practice. The present article includes a brief review of these concepts, and presents the results from two observational European studies that provide empirical data about the actual situation of ambulatory patients with schizophrenia in terms of symptomatic remission, and that help in advancing the conceptualization of recovery, contributing to the development of clinical and research definitional criteria. Such results indicate that remission of symptoms constitutes a realistic therapeutic goal in a number of patients, with a considerable temporal stability; on the other hand, recovery definitions should include functional and subjective dimensions. In conclusion, remission is a tenable and clinically valid concept, with a significant contribution to functional improvement. Meanwhile, the recovery construct still requires substantial development. PMID- 23446103 TI - Venlafaxine and inappropriate antidiuretic hormone excretion. PMID- 23446105 TI - Power and control in the legal system: from marriage/relationship to divorce and custody. AB - The purpose of this study was to examine the ways in which abuse that occurred during marriage/relationship continued within divorce and custody-related legal proceedings. Twenty-seven women participated in semistructured interviews. Interviews were analyzed utilizing a grounded theory approach in order to inductively arrive at a theory explaining how abuse dynamics may continue during legal proceedings. Participants identified child support litigation, custody and visitation battles, intimidation/harassment, deliberately prolonging the case, manipulating finances, and distortions of information as methods by which their exes sought to maintain power and control. Counseling implications are described. PMID- 23446104 TI - Exercise and obesity in fibromyalgia: beneficial roles of IGF-1 and resistin? AB - INTRODUCTION: Severe fatigue is a major health problem in fibromyalgia (FM). Obesity is common in FM, but the influence of adipokines and growth factors is not clear. The aim was to examine effects of exercise on fatigue, in lean, overweight and obese FM patients. METHODS: In a longitudinal study, 48 FM patients (median 52 years) exercised for 15 weeks. Nine patients were lean (body mass index, BMI 18.5 to 24.9), 26 overweight (BMI 25 to 29.9) and 13 obese. Fatigue was rated on a 0 to 100 mm scale (fibromyalgia impact questionnaire [FIQ] fatigue) and multidimensional fatigue inventory (MFI-20) general fatigue (MFIGF). Higher levels in FIQ fatigue and MFIGF indicate greater degree of fatigue. Free and total IGF-1, neuropeptides, adipokines were determined in serum and cerebrospinal fluid (CSF). RESULTS: Baseline FIQ fatigue correlated negatively with serum leptin (r=-0.345; P=0.016) and nerve growth factor (NGF; r=-0.412; P=0.037). In lean patients, baseline MFIGF associated negatively with serum resistin (r=-0.694; P=0.038). FIQ Fatigue associated negatively with CSF resistin (r=-0.365; P=0.073). Similarly, FIQ fatigue (r=-0.444; P=0.026) and MFIGF correlated negatively with CSF adiponectin (r=-0.508; P=0.01). In lean patients, FIQ fatigue (P=0.046) decreased after 15 weeks. After 30 weeks, MFIGF decreased significantly in lean (MFIGF: P=0.017), overweight (MFIGF: P=0.001), and obese patients (MFIGF: P=0.016). After 15 weeks, total IGF-1 increased in lean (P=0.043) patients. ?Total IGF-1 differed significantly between lean and obese patients (P=0.010). ?Total IGF-1 related negatively with ?MFIGF after 15 weeks (r=-0.329; P=0.050). After 30 weeks, ?FIQ fatigue negatively correlated with ?NGF (r=-0.463; P=0.034) and positively with ?neuropeptide Y (NPY) (r=0.469; P=0.032). Resistin increased after 30 weeks (P=0.034). ?MFIGF correlated negatively with ?resistin (r=-0.346; P=0.031), being strongest in obese patients (r=-0.815; P=0.007). In obese patients, ?FIQ fatigue after 30 weeks correlated negatively with ?free IGF-1 (r=-0.711; P=0.032). CONCLUSIONS: Exercise reduced fatigue in all FM patients, this effect was achieved earlier in lean patients. Baseline levels of resistin in both serum and CSF associated negatively with fatigue. Resistin was increased after the exercise period which correlated with decreased fatigue. Changes in IGF-1 indicate similar long-term effects in obese patients. This study shows reduced fatigue after moderate exercise in FM and indicates the involvement of IGF-1 and resistin in these beneficial effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00643006. PMID- 23446106 TI - Incomplete data in randomized dermatology trials: consequences and statistical methodology. AB - Randomized clinical trials can provide the highest level of evidence regarding the effectiveness of therapeutic interventions. When individuals in trials do not complete the planned treatment period it is often not possible to observe the desired outcomes, which results in incomplete data. Here we review various mechanisms which can lead to incomplete data, discuss the impact of these mechanisms, and present strategies for dealing with incomplete data. We discuss these issues in the context of clinical trials in dermatology and provide practical recommendations for planning and drawing conclusions from studies which could involve incomplete data. PMID- 23446107 TI - Epitope mapping of the nucleocapsid protein of sendai virus and application of antigenic epitopes for the ELISA-based diagnosis of sendai virus infection. AB - Sendai virus (SeV) is one of the most prevalent viral pathogens infecting laboratory mice and rats. To date, mature SeV virions have been used as antigens for serological diagnosis. To develop antigens that are more specific and easier to prepare for diagnosis, we examined the antigenic sites in the nucleocapsid protein (NP) of SeV with antisera from experimentally SeV-infected mice and a peptide array membrane containing overlapping 10-mer peptides covering the entire NP. We found antigenic linear sequences in two regions, amino acids 120-160 and 420-500, of the SeV-NP. From these antigenic sequences, we applied two synthesized peptides, IVKTRDMEYERTTEWL and FVTLHGAERLEEETNDE, which correspond to positions 119-134 and 458-474 of the SeV-NP, respectively, as antigens in an enzyme-linked immunosorbent assay (ELISA). Evaluation of the ELISAs using these peptides revealed that they were specific to anti-SeV antisera. Furthermore, the ELISAs using these peptides were able to distinguish between SeV-positive and SeV negative mouse sera to the same extent as a commercial ELISA kit. These results indicate that these peptides are useful for the serological diagnosis of SeV infection. PMID- 23446108 TI - Analysis of bacterial community shifts in the gastrointestinal tract of pigs fed diets supplemented with beta-glucan from Laminaria digitata, Laminaria hyperborea and Saccharomyces cerevisiae. AB - This study was designed to evaluate the effects of algal and yeast beta-glucans on the porcine gastrointestinal microbiota, specifically the community of Lactobacillus, Bifidobacterium and coliforms. A total of 48 pigs were fed four diets over a 28-day period to determine the effect that each had on these communities. The control diet consisted of wheat and soya bean meal. The remaining three diets contained wheat and soya bean meal supplemented with beta glucan at 250 g/tonne from Laminaria digitata, Laminaria hyperborea or Saccharomyces cerevisiae. Faecal samples were collected from animals before feeding each diet and after the feeding period. The animals were slaughtered the following day and samples were collected from the stomach, ileum, caecum, proximal colon and distal colon. Alterations in Lactobacillus in the gastrointestinal tract (GIT) were analysed using denaturing gradient gel electrophoresis (DGGE) profiles generated by group-specific 16S rRNA gene PCR amplicons. Plate count analysis was also performed to quantify total coliforms. DGGE profiles indicated that all beta-glucan diets provoked the emergence of a richer community of Lactobacillus. The richest community of lactobacilli emerged after feeding L. digitata (LD beta-glucan). Plate count analysis revealed that the L. hyperborea (LH beta-glucan) diet had a statistically significant effect on the coliform counts in the proximal colon in comparison with the control diet. beta-glucan from L. digitata and S. cerevisiae also generally reduced coliforms but to a lesser extent. Nevertheless, the beta-glucan diets did not significantly reduce levels of Lactobacillus or Bifidobacterium. DGGE analysis of GIT samples indicated that the three beta-glucan diets generally promoted the establishment of a more varied range of Lactobacillus species in the caecum, proximal and distal colon. The LH beta-glucan had the most profound reducing effect on coliform counts when compared with the control diet and diets supplemented with L. digitata and S. cerevisiae beta-glucans. PMID- 23446109 TI - Methylphenidate in mania project (MEMAP): study protocol of an international randomised double-blind placebo-controlled study on the initial treatment of acute mania with methylphenidate. AB - BACKGROUND: Treatment of patients with acute mania remains a considerable medical challenge since onset of action of antimanic medication is delayed for several days. Psychostimulants could have an earlier onset of action. This assumption is based on the 'vigilance regulation model of mania' which postulates that vigilance is unstable in manic patients. Accordingly, vigilance-stabilising psychostimulants could be more useful than conventional treatment in acute mania. We present here the study protocol of a trial intended to study the efficacy and safety of methylphenidate in the initial treatment of acute mania. METHODS/DESIGN: A multi-centre, randomised, double-blind, placebo-controlled clinical trial will be conducted in 88 bipolar inpatients with acute mania. Male and female patients older than 18 years will be randomised to treatment with either methylphenidate (20 to 40 mg/day) or placebo for 2.5 days, given once or twice daily. The main outcome measure is the reduction in the Young Mania Rating Scale (YMRS) after 2.5 days of treatment. Other outcome measures include the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) the Clinical Global Impression-Bipolar Scale (CGI-BP), the Screen for Cognitive Impairment in Psychiatry (SCIP), actigraphy and the EEG-'Vigilance Algorithm Leipzig' (VIGALL). DISCUSSION: A positive study outcome of the proposed study could substantially impact our understanding of the etiopathogenesis of mania and open new treatment perspectives. PMID- 23446111 TI - p-Channel field-effect transistors based on C60 doped with molybdenum trioxide. AB - Fullerene (C60) is a well-known n-channel organic semiconductor. We demonstrate that p-channel C60 field-effect transistors are possible by doping with molybdenum trioxide (MoO3). The device performance of the p-channel C60 field effect transistors, such as mobility, threshold voltage, and on/off ratio is varied in a controlled manner by changing doping concentration. This work demonstrates the utility of charge transfer doping to obtain both n- and p channel field-effect transistors with a single organic semiconductor. PMID- 23446110 TI - PET/MR: a paradigm shift. AB - More than a decade ago, multimodality imaging was introduced into clinical routine with the development of the positron emission tomography (PET)/computed tomography (CT) technique. Since then, PET/CT has been widely accepted in clinical imaging and has emerged as one of the main cancer imaging modalities. With the recent development of combined PET/magnetic resonance (MR) systems for clinical use, a promising new hybrid imaging modality is now becoming increasingly available. The combination of functional information delivered by PET with the morphologic and functional imaging of MR imaging (e.g., diffusion weighted imaging, dynamic contrast-enhanced MR imaging and MR spectroscopy) offers exciting possibilities for clinical applications as well as basic research. However, the differences between CT and MR imaging are fundamental. This also leads to distinct differences between PET/CT and PET/MR not only regarding image interpretation but also concerning data acquisition, data processing and image reconstruction. This article provides an overview of the principal differences between PET/CT and PET/MR in terms of scanner design and technology, attenuation correction, speed, acquisition protocols, radiation exposure and safety aspects. PET/MR is expected to show advantages over PET/CT in clinical applications in which MR is known to be superior to CT due to its high intrinsic soft tissue contrast. However, as of now, only assumptions can be made about the future clinical role of PET/MR, as data about the performance of PET/MR in the clinical setting are still limited. The possible future clinical use of PET/MR in oncology, neurology and neurooncology, cardiology and imaging of inflammation is discussed. PMID- 23446112 TI - Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds. AB - We have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite targets to be assayed in parallel owing to the strains' expression of different fluorescent proteins. A strain expressing the human target is included in the multiplexed screen to exclude compounds that do not discriminate between host and parasite enzymes. This form of assay has the advantages of using known targets and not requiring the in vitro culture of parasites. We performed automated screens for inhibitors of parasite dihydrofolate reductases, N-myristoyltransferases and phosphoglycerate kinases, finding specific inhibitors of parasite targets. We found that our 'hits' have significant structural similarities to compounds with in vitro anti-parasitic activity, validating our screens and suggesting targets for hits identified in parasite-based assays. Finally, we demonstrate a 60 per cent success rate for our hit compounds in killing or severely inhibiting the growth of Trypanosoma brucei, the causative agent of African sleeping sickness. PMID- 23446114 TI - A left-to-right shunt via the ductus arteriosus is associated with increased regional cerebral oxygen saturation during neonatal transition. AB - BACKGROUND: Oxygen delivery to the brain is dependent on cardiac output and arterial oxygen content. OBJECTIVES: The study was designed to investigate the influence of a left-to-right shunt via the ductus arteriosus (DA) on regional oxygen saturation (rSO2) of the brain and peripheral tissue during postnatal transition. METHODS: Nested case-control study. In term neonates after elective cesarian section, rSO2 of the brain and pre- and postductal peripheral tissue were measured 15 min after uncomplicated postnatal transition. Two groups were formed according to shunt flow characteristics via the DA: shunt group (with a left-to-right shunt), and nonshunt group (no shunt). RESULTS: Of 80 infants, in 58 (72%) a left-to-right shunt was identified, and in 22 (28%) no flow was seen via the DA. The 22 infants formed the nonshunt group. They were matched with 22 newborn infants with a left-to-right shunt via the DA (shunt group). Infants in the nonshunt group had significantly lower cerebral rSO2 values and higher fractional tissue oxygen extraction and heart rate values. There were no significant differences in regard to peripheral rSO2 values. CONCLUSION: During postnatal transition, term infants with a left-to-right shunt via the DA have significantly higher cerebral rSO2 values compared to infants without shunt flow. PMID- 23446115 TI - Bioethics in popular science: evaluating the media impact of The Immortal Life of Henrietta Lacks on the biobank debate. AB - BACKGROUND: The global expansion of biobanks has led to a range of bioethical concerns related to consent, privacy, control, ownership, and disclosure. As an opportunity to engage broader audiences on these concerns, bioethicists have welcomed the commercial success of Rebecca Skloot's 2010 bestselling book The Immortal Life of Henrietta Lacks. To assess the impact of the book on discussion within the media and popular culture more generally, we systematically analyzed the ethics-related themes emphasized in reviews and articles about the book, and in interviews and profiles of Skloot. METHODS: We conducted a content analysis of a population of relevant English-language articles and transcripts (n = 125) produced by news organizations and publications in the U.S., Canada, Great Britain/Ireland, and Australia/New Zealand. We scored each article for the emphasis and appearance of 9 ethics-related themes. These were informed consent, welfare of the vulnerable, compensation, scientific progress, control/access, accountability/oversight, privacy, public education, and advocacy. RESULTS: The informed consent theme dominated media discussion, with almost 39.2 percent of articles/transcripts featuring the theme as a major focus and 44.8 percent emphasizing the theme as a minor focus. Other prominent themes and frames of reference focused on the welfare of the vulnerable (18.4 percent major emphasis; 36.0 percent minor emphasis), and donor compensation (19.2 percent major; 52.8 percent minor). Ethical themes that comprised a second tier of prominence included those of scientific progress, control/access, and accountability/oversight. The least prominent themes were privacy, public education, and advocacy. CONCLUSIONS: The book has been praised as an opportunity to elevate media discussion of bioethics, but such claims should be re considered. The relatively narrow focus on informed consent in the media discussion generated by Skloot's book may limit the ability of ethicists and advocates to elevate attention to donor control, compensation, patenting, privacy, and other ethical issues. Still, ethicists should view the book and a pending major TV film translation as opportunities to highlight through media outreach, consultation exercises and public forums a broader range of bioethical concerns that would otherwise be under-emphasized in news coverage. Such efforts, however, need to be carefully planned and evaluated. PMID- 23446116 TI - Real-time multi-marker measurement of organic compounds in human breath: towards fingerprinting breath. AB - The prospects for exploiting proton transfer reaction-time of flight-mass spectrometry (PTR-ToF-MS) in medical diagnostics are illustrated through a series of case studies. Measurements of acetone levels in the breath of 68 healthy people are presented along with a longitudinal study of a single person over a period of 1 month. The median acetone concentration across the population was 484 ppbV with a geometric standard deviation (GSD) of 1.6, whilst the average GSD during the single subject longtitudinal study was 1.5. An additional case study is presented which highlights the potential of PTR-ToF-MS in pharmacokinetic studies, based upon the analysis of online breath samples of a person following the consumption of ethanol. PTR-ToF-MS comes into its own when information across a wide mass range is required, particularly when such information must be gathered in a short time during a breathing cycle. To illustrate this property, multicomponent breath analysis in a small study of cystic fibrosis patients is detailed, which provides tentative evidence that online PTR-ToF-MS analysis of tidal breath can distinguish between active infection and non-infected patients. PMID- 23446117 TI - Pulmonary neuroendocrine tumor incidentally detected by (18)F-CH PET/CT. AB - We report the case of a pulmonary neuroendocrine tumor (NET) incidentally detected by F-CH PET/CT performed during restaging in a 68-year-old patient affected by prostate cancer. To clarify the nature of the pulmonary lesion, the patient underwent a CT-guided biopsy which revealed the presence of a pulmonary NET. A subsequent Ga-DOTANOC PET/CT demonstrated the somatostatin receptor expression in the pulmonary lesion. The patient underwent a right lung lobectomy; at pathology, a well-differentiated NET was confirmed. Our case highlights that pulmonary NETs should be considered in the differential diagnosis of pulmonary lesions showing uptake of radiolabeled choline. PMID- 23446118 TI - (18)F-FDG PET/CT imaging of critical ischemia in the diabetic foot. AB - A 72-year-old patient with type 2 diabetes mellitus underwent F-FDG PET/CT for diabetic foot infection. No increased focal uptake was seen. F-FDG uptake was absent in the second, third, and fourth toes of the right foot. Angiography demonstrated severe stenosis in the proximal anterior tibial artery and segmental stenosis on the posterior tibial artery. The patient was diagnosed as having dry gangrene of the second to fourth toes of the right foot due to ischemia. He underwent a selective amputation because of the lack of revascularization possibilities. PMID- 23446119 TI - A proposed method to comprehensively define outcomes in acoustic tumor patients undergoing CyberKnife management. AB - BACKGROUND: Vestibular assessment in patients with acoustic tumor (so-called vestibular schwannoma, VS) via ocular vestibular-evoked myogenic potential (oVEMP) and cervical VEMP (cVEMP) tests are not often discussed in the neurosurgical literature. OBJECTIVES: This study conducted physiological and morphological assessments for VS patients before and after CyberKnife radiosurgery. METHODS: Twenty patients with unilateral VS underwent a battery of tests comprising facial nerve function test, audiometry, and caloric, oVEMP and cVEMP tests before and 2 years after CyberKnife treatment at a mean dosage of 18 Gy in 3 fractions. RESULTS: The abnormal percentages of caloric, oVEMP and cVEMP tests did not significantly differ before and after Cyberknife treatment, indicating that preservation of the superior and inferior vestibular nerves can be achieved after radiosurgery. Median tumor volumes, 1.49 cm3 before treatment versus 0.97 cm3 at 2 years after treatment, differed significantly. CONCLUSIONS: The use of oVEMP and cVEMP tests in VS patients before stereotactic radiosurgery may help to evaluate the tumor origin from the superior or inferior vestibular nerve. It takes a short time and costs less, and it would be practical to make this a routine examination in VS patients having stereotactic radiosurgery. PMID- 23446120 TI - Same-sex cohabitors and health: the role of race-ethnicity, gender, and socioeconomic status. AB - A legacy of research finds that marriage is associated with good health. Yet same sex cohabitors cannot marry in most states in the United States and therefore may not receive the health benefits associated with marriage. We use pooled data from the 1997 to 2009 National Health Interview Surveys to compare the self-rated health of same-sex cohabiting men (n = 1,659) and same-sex cohabiting women (n = 1,634) with that of their different-sex married, different-sex cohabiting, and unpartnered divorced, widowed, and never-married counterparts. Results from logistic regression models show that same-sex cohabitors report poorer health than their different-sex married counterparts at the same levels of socioeconomic status. Additionally, same-sex cohabitors report better health than their different-sex cohabiting and single counterparts, but these differences are fully explained by socioeconomic status. Without their socioeconomic advantages, same sex cohabitors would report similar health to nonmarried groups. Analyses further reveal important racial-ethnic and gender variations. PMID- 23446121 TI - The significance of cervical ribs in thoracic outlet syndrome. AB - OBJECTIVE: The purpose of this study was to review our operative experience in patients with thoracic outlet syndrome (TOS) resulting from cervical ribs causing clinical symptoms. METHODS: This study is a retrospective review of a prospectively acquired database of patients with TOS treated with first rib resection and scalenectomy with or without cervical rib resection at the Johns Hopkins Medical Institutions. RESULTS: Between October 2003 and June 2011, a total of 23 cervical rib resections were performed on 20 patients, three of whom had bilateral cervical ribs resected during separate operations. Seven patients presented with subclavian artery thrombosis. Three of seven patients had subclavian artery aneurysms and underwent cervical rib resection through a supraclavicular approach to facilitate subclavian artery bypass. Five patients presented with an ischemic upper extremity without thrombosis and underwent transaxillary first rib and cervical rib resection. Three patients presented with subclavian vein thrombosis; two of the three patients underwent balloon dilation 2 weeks postoperatively for stenosis. Additionally, five patients presented with neurogenic TOS evidenced by pain, numbness, and weakness without vascular compromise in the affected arm. Cervical ribs with bony fusion to the first rib were found in 17 of 23 cases (74%). CONCLUSIONS: Cervical ribs causing clinical symptoms are large and frequently fused to the first rib, and can result in aneurysm formation or thrombosis. In our experience, both the cervical rib and the first rib must be removed to relieve arterial compression and can usually be done through a transaxillary approach. Only patients with aneurysms needing arterial reconstruction require resection of the artery from a supraclavicular approach. PMID- 23446122 TI - Application of Investigational Device Exemptions regulations to endograft modification. AB - For patients with complex aortic aneurysms that cannot be treated effectively with currently approved endografts, physicians have made fenestrations in marketed devices and constructed branched grafts by creatively implanting available endograft components. For the most part, these procedures are being done outside of clinical studies by individual physicians. Although these novel approaches may be useful in the treatment of individual patients, the current ad hoc use of physician-created fenestrated and branched devices may not result in the unbiased capture and reporting of data regarding short- and longer-term outcomes. As a result, unsubstantiated conclusions regarding the safety and effectiveness of these procedures may be drawn. Well-designed and executed clinical studies are necessary to adequately assess the benefits and risks of these techniques. Because these interventions involve the use of significant risk devices, these studies need to be conducted under United States Food and Drug Administration-approved Investigational Device Exemptions (IDE) applications. Although this regulatory process adds complexity to the application of these creative techniques, the IDE regulations assure that patient protection measures are followed and data are captured to assess safety and effectiveness. This approach creates opportunities to advance the development of innovative, beneficial devices and procedures to treat complex aortic aneurysms. PMID- 23446123 TI - Manufacturer evaluations of endograft modifications. AB - The motivation to modify the design of a vascular device can arise from a number of sources. Clinical experience with the unmodified device could suggest new design modifications to improve device performance or clinical outcomes. Similarly, clinical success with a device often suggests modifications that could broaden the applicability of the device to enable treatment of different or more advanced disease states. As a specific example, both of these scenarios have arisen during the last decade in the evolution of endovascular grafts for the treatment of abdominal aortic aneurysms, with modifications enabling the treatment of patients with shorter infrarenal necks, more angulated anatomy, and smaller access vessels. These modifications have been made by manufacturers and additionally by physicians who create branched and fenestrated devices. The experience to date with the use of fenestrated devices and the development of chimney, snorkel, and periscope techniques suggests that modifications to off-the shelf devices may provide some clinical benefit. This experience provides additional motivation for manufacturers to develop devices to address the clinical needs not met with their current product lines. For manufacturers, the device development process includes an assessment of the new device design to determine the appropriate evaluation strategy to support the safety and effectiveness of the modified device. This report provides a high-level overview of the process generally followed by device manufacturers to evaluate a proposed device modification before market release, in accordance with local country regulations and recognized international standards such as the International Organization of Standardization (ISO) standards for endovascular grafts (ISO 25539 Part 1). PMID- 23446124 TI - A surgeon's perspective regarding the regulatory, compliance, and legal issues involved with physician-modified devices. AB - Physician-modified endovascular devices are becoming commonplace in a modern climate where innovation outpaces regulated technological advancement. Off-label use of medical devices occurs on a daily basis throughout many institutions across the United States and when performed by physicians, is both legal and unregulated. The purpose of this invited commentary is to review the regulatory, compliance, and legal issues regarding the practice of medical device modification. PMID- 23446125 TI - Advisory statement on clinical use of modified aortic endografts from the Society for Vascular Surgery(r). PMID- 23446126 TI - Gigantic clavicle osteochondroma with carotid compression as a rare cause of stroke. AB - We report the case of a 26-year-old woman who presented with embolic stroke from left common carotid artery compression by a gigantic clavicular osteochondroma. To our knowledge, this is the only such case described in the literature. The other particularity of this case is the delayed appearance of this childhood tumor. Surgery was successful, with a satisfying outcome. PMID- 23446127 TI - Surgical repair of a coeliac artery aneurysm. PMID- 23446128 TI - Ureteroarterial fistula. PMID- 23446129 TI - Iliocaval and aortoiliac reconstruction following en bloc retroperitoneal leiomyosarcoma resection. PMID- 23446130 TI - Debate: whether fenestrated endografts should be limited to a small number of specialized centers. AB - Until fairly recently, experience with advanced endovascular technologies, including fenestrated endovascular repair (FEVAR), has been limited to a relatively small number of practitioners worldwide. Excellent outcomes have been achieved by these accomplished surgeons who, at least initially, have primarily used custom-made devices constructed by a single endograft manufacturer. Access to this technology has been limited by the skills necessary for such procedures and by the customization process with industry partners. However, several issues are changing rapidly with FEVAR. Increasing numbers of surgeons now have the necessary endovascular skills, and off-the-shelf endografts from several manufacturers have become, or are becoming, available. Also, the regulatory landscape is changing with device approval in the United States. Surgeons and patients alike are anticipating the widespread adoption of this advanced technology that will surely benefit increasing numbers of patients. Or will it? Will widespread adoption in a larger number of smaller-volume hospitals, by less experienced surgeons, result in poor patient outcomes, or will excellent results continue with more patients benefitting from these technologic advances? These are important questions to ask before such adoption and are the subject of this debate. PMID- 23446131 TI - Editors' commentary. PMID- 23446133 TI - Regarding "endovascular vs open repair for ruptured abdominal aortic aneurysm". PMID- 23446134 TI - Reply: To PMID 22626871. PMID- 23446135 TI - Regarding "patient outcomes and thoracic aortic volume and morphologic changes following thoracic endovascular aortic repair in patients with complicated chronic type B aortic dissection". PMID- 23446136 TI - Analysis and mapping of a 3' coterminal transcription unit derived from human cytomegalovirus open reading frames UL30-UL32. AB - BACKGROUND: It has been predicted that the UL31 gene originates from the positive strand of the human cytomegalovirus (HCMV) genome, whereas the UL30 and UL32 genes originate from the complementary strand. Except for the UL32 gene, the transcription of this gene region has not been investigated extensively. METHODS: Northern blotting, cDNA library screening, RACE-PCR,and RT-PCR were used. RESULTS: At least eight transcripts of the antisense orientation of UL31 were transcribed from the UL30-UL32 region during the late phase of HCMV infection. The 3' coterminus of these transcripts was located within the predicted UL30 gene. The longest 6.0-kb transcript was initiated upstream of the predicted UL32 gene. Other transcripts were derived from the predicted UL30 and UL31 gene region. Except for the previously predicted UL32 open reading frame (ORF), three novel ORFs, named UL31anti-1, UL31anti-2 and UL31anti-3, were located in the transcripts from the UL31anti-UL32 transcription unit. No transcription was found in UL31. CONCLUSION: A family of novel 3' coterminal transcripts was transcribed from the UL30-UL32 gene region. PMID- 23446138 TI - Combined approaches for HIV cure. AB - PURPOSE OF REVIEW: A serious effort has begun to develop therapies that may be capable of eradicating established HIV infection in man. Because of the biological complexity of HIV infection that persists despite potent antiretroviral therapy, it is widely believed that if such therapies can be developed they will involve complex, multimodality approaches. We highlight some of the recent studies in this effort. RECENT FINDINGS: An inhibitor of histone deacetylase has been demonstrated to disrupt latency in man, and new histone deacetylase inhibitors have been identified. Other potential targets, such as histone methyltransferase, protein kinase C, and BRD4, have been recently studied. Model systems, both in primary cells and in animal models, are beginning to be validated. In the clinic, immune-based therapies to aid in the clearance of persistent infection are also being tested. SUMMARY: It is too early to know what combination eradication therapies for HIV infection will look like in the future, but candidate therapies and model systems to perform preclinical validation are beginning to take shape. PMID- 23446137 TI - Neck muscle cross-sectional area, brain volume and cognition in healthy older men: a cohort study. AB - BACKGROUND: Two important consequences of the normal ageing process are sarcopenia (the age-related loss of muscle mass and function) and age-related cognitive decline. Existing data support positive relationships between muscle function, cognition and brain structure. However, studies investigating these relationships at older ages are lacking and rarely include a measure of muscle size. Here we test whether neck muscle size is positively associated with cognition and brain structure in older men. METHODS: We studied 51 healthy older men with mean age 73.8 (sd 1.5) years. Neck muscle cross-sectional area (CSA) was measured from T1-weighted MR-brain scans using a validated technique. We measured multiple cognitive domains including verbal and visuospatial memory, executive functioning and estimated prior cognitive ability. Whole brain, ventricular, hippocampal and cerebellar volumes were measured with MRI. General linear models (ANCOVA) were performed. RESULTS: Larger neck muscle CSA was associated with less whole brain atrophy (t = 2.86, p = 0.01, partial eta squared 17%). Neck muscle CSA was not associated with other neuroimaging variables or current cognitive ability. Smaller neck muscle CSA was unexpectedly associated with higher prior cognition (t = -2.12, p < 0.05, partial eta squared 10%). CONCLUSIONS: In healthy older men, preservation of whole brain volume (i.e. less atrophy) is associated with larger muscle size. Longitudinal ageing studies are now required to investigate these relationships further. PMID- 23446140 TI - Influence of general anesthesia with isoflurane following propofol-induction on natural killer cell cytotoxic activities of peripheral blood lymphocytes in dogs. AB - To investigate influence of general anesthesia on immunological anti-tumor activity, the natural killer (NK) cytotoxic activity of peripheral lymphocytes (PBLs) was measured in 7 dogs anesthetized for 3 hr with isoflurane following propofol-induction (anesthesia group) and 6 dogs without anesthesia (control group). Blood samples were collected before (baseline) and 24, 120 and 192 hr after the anesthesia. The PBLs were isolated via centrifugation with Ficoll Hypaque solution (density, 1.073), and adherent cells were removed. The NK cytotoxic activity of the isolated PBLs against canine thyroid cancer cells was detected by the colorimetric rose Bengal assay. Significant decrease in the NK cytotoxic activity was observed at 24 hr after the anesthesia, compared with the baseline values and the control group. The NK cytotoxic activities were recovered to the baseline values until 120 hr after the anesthesia. The general anesthesia with isoflurane following propofol-induction decreased the NK cytotoxic activities of PBLs in dogs. This finding has a clinical relevance to the risk of tumor recurrence or metastasis induced by the suppression of immunological anti tumor activity after general anesthesia in dogs. The results further emphasized the importance of the need to evaluate immune suppression following general anesthesia in animals. PMID- 23446139 TI - CD4+Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZBxNZW) F1 lupus mice. AB - INTRODUCTION: The ability to ameliorate murine lupus renders regulatory T cells (Treg) a promising tool for the treatment of systemic lupus erythematosus (SLE). In consideration to the clinical translation of a Treg-based immunotherapy of SLE, we explored the potential of CD4+Foxp3+ Treg to maintain disease remission after induction of remission with an established cyclophosphamide (CTX) regimen in lupus-prone (NZBxNZW) F1 mice. As a prerequisite for this combined therapy, we also investigated the impact of CTX on the biology of endogenous Treg and conventional CD4+ T cells (Tcon). METHODS: Remission of disease was induced in diseased (NZBxNZW) F1 mice with an established CTX regimen consisting of a single dose of glucocorticosteroids followed by five day course with daily injections of CTX. Five days after the last CTX injection, differing amounts of purified CD4+Foxp3+CD25+ Treg were adoptively transferred and clinical parameters, autoantibody titers, the survival and changes in peripheral blood lymphocyte subsets were determined at different time points during the study. The influence of CTX on the numbers, frequencies and proliferation of endogenous Treg and Tcon was analyzed in lymphoid organs by flow cytometry. RESULTS: Apart from abrogating the proliferation of Tcon, we found that treatment with CTX induced also a significant inhibition of Treg proliferation and a decline in Treg numbers in lymphoid organs. Additional adoptive transfer of 1.5*106 purified Treg after the CTX regimen significantly increased the survival and prolonged the interval of remission by approximately five weeks compared to mice that received only the CTX regimen. The additional clinical amelioration was associated with an increase in the Treg frequency in the peripheral blood indicating a compensation of CTX induced Treg deficiency by the Treg transfer. CONCLUSIONS: Treg were capable to prolong the interval of remission induced by conventional cytostatic drugs. This study provides valuable information and a first proof-of-concept for the feasibility of a Treg-based immunotherapy in the maintenance of disease remission in SLE. PMID- 23446141 TI - Strategies, strengths and limitations in pharmacogenetic studies of antipsychotics. PMID- 23446142 TI - Impact of a social and employment crisis on the demand for mental health care (Footwear Crisis, Elche 2004). AB - INTRODUCTION: Between December 1999 and December 2004 the footwear manufacturing industry in Elche suffered a 24% fall in employment. In this context, it was decided to conduct study to detect possible changes in the demand for mental health care. MATERIAL AND METHODS: The first-time consultations between December 2001 and June 2002 were compared with those seen between October 2004 and April 2005. Differences were looked for in the percentage of referrals for work-related stress factors. The role of these work-related stress factors in the changes detected in the sociodemographic profile of the patients was also evaluated. RESULTS AND CONCLUSIONS: Changes were detected in the sociodemographic profile (gender and education level), employment status and reason for consultation. First consultations increased in the following groups: males, with a higher education level, unemployed, on sick leave or pensioners, and also those with employment problems as the main reason for consultation or a worsening of other health conditions. PMID- 23446143 TI - Psychiatric comorbidity in a sample of opiate-dependent patients treated with sublingual buprenorphine in a therapeutic community regime. AB - INTRODUCTION: The purpose of this work is to estimate the prevalence of psychiatric cases in a sample of opiate-dependent patients treated with sublingual buprenorphine in a therapeutic community regime, and to describe their progress during the first month of treatment. METHODS: An observational, longitudinal, prospective study was conducted. Of the 119 opiate-dependent patients selected, 46 agreed to start treatment with buprenorphine. For organisational reasons, the psychopathological assessment was carried out on 36 of these patients. The measurement tools used were the MINI, GHQ-28, IPDE and Assessment of the Quality of Life in Psychoactive Substance Addicts (TEQLASP). RESULTS: The prevalence rate of any psychiatric disorder was 78%. The prevalence of Axis I diagnoses was 69.4%. The prevalence of cases in Axis II was 58.3%, and 50% of patients had concomitant Axis I and Axis II disorders. The patients with Axis I psychiatric disorders showed a significant reduction in the mean scores of the GHQ-28 scale, and in the B (anxiety/unease), C (social dysfunction), and D (depression) subscales of the GHQ-28. The differences observed between the patients with no psychiatric disorders after one month of treatment were not significant. An improvement in the quality of life wad observed in both groups, although these changes were of a lower magnitude in the group with psychiatric disorders. DISCUSSION: The results of this study show a very high frequency of psychiatric disorders. For this reason, psychiatric illness must be actively looked for whenever we assess a drug-dependent patient. PMID- 23446144 TI - Bulimia nervosa: emotions and making decisions. AB - OBJECTIVE: The purpose of this article is to add to the knowledge of the neurobiology and aetiopathogenesis of bulimia nervosa, a common disorder in routine clinical practice. To do this, we will study decision making in low risk and low uncertainty patients. MATERIAL AND METHODS: The study consisted of 19 females who fulfilled the diagnostic criteria of bulimia nervosa according to the DSM-IV and a control group of 28 healthy female students from the Faculty of Psychology. They performed two tasks: one a "cups task" risk and the other an "ambiguity task", both associated with emotions and decision making. RESULTS: The patients with bulimia took more risks in the win domain than in the lose domain, whereas the reverse was observed in the control group. In the decision making task, low ambiguity, and the number of decisions risked, was similar in both bulimia nervosa and the control group. CONCLUSIONS: Our results support those of previous investigations and theories that postulate that the making of decisions is not only mediated by cognitive processes, but the emotions also play an important role in these processes. PMID- 23446145 TI - Capgras Syndrome associated with the use of psychoactive substances. AB - INTRODUCTION: Capgras syndrome has originally been described as psychiatric syndrome. However, in the last few years reports of patients with this syndrome has significantly increased in patients with neurological, metabolic, and infectious diseases and those who consume alcohol. Different hypotheses have been proposed to explain the neurobiology of this very unusual symptom, such as changes in the dopamine circuit and specific dysfunctions in facial processing. CASE: In this work we present a new case of Capgras syndrome, associated with an acute cocaine overdose, which was transient and reversible. DISCUSSION: The neurobiological bases of this syndrome are analysed, along with their relationship with the changes induced by cocaine use. Thus, Capgras syndrome could be the expression of functional changes at frontal-temporal level, and the paralimbic region secondary to the consumption of psychoactive substances such as cocaine. PMID- 23446146 TI - Asenapine: a new focus on the treatment of mania. AB - DEVELOPMENT: Asenapine, recently marketed in United States and ready to be so in Europe, is a multimodal action second-generation antipsychotic, with high affinity for multiple dopaminergic (D2, D3 y D4), serotonergic (5HT2A, 5HT2B, 5HT2C, 5HT6 and 5HT7) and adrenergic (alpha1A, alpha2A, alpha2B and alpha2C) receptors. Asenapine has to be administered sublingually. After going through succesfully the preliminary phases of development, several clinical trials have been completed in two main indications: schizophrenia and mania. This article summarizes the available evidence on its safety and efficacy in acute mania and provides some prospect on its clinical immediate and future applications. CONCLUSIONS: Asenapine is effective and generally well tolerated in the treatment of moderate-to-severe acute mania associated to bipolar I disorder. The sublingual administration may be a challenge (coadministration with food or other drugs needs to be avoided) but also an opportunity (improved treatment adherence). Due to its multimodal receptor profile, it may cause several side effects, but most of those are relatively mild, with none being particularly outstanding. In Europe, asenapine is indicated for the treatment of acute mania only, but several trials are being conducted in schizophrenia and bipolar depression. PMID- 23446147 TI - Tentative suicide in a psychotic patient admitted to a general hospital: presentation of a case. PMID- 23446148 TI - The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. AB - HMGB1 is a ubiquitous nuclear protein present in almost all cell types. In addition to its intracellular functions, HMGB1 can be extracellularly released, where it mediates activation of innate immune responses, including chemotaxis and cytokine release. HMGB1 contains three conserved redox-sensitive cysteines (C23, C45, and C106); modification of these cysteines determines the bioactivity of extracellular HMGB1. Firstly, the cytokine-stimulating activity of HMGB1 requires C23 and C45 to be in a disulfide linkage, at the same time that C106 must remain in its reduced form as a thiol. This distinctive molecular conformation enables HMGB1 to bind and signal via the TLR4/MD-2 complex to induce cytokine release in macrophages. Secondly, for HMGB1 to act as a chemotactic mediator, all three cysteines must be in the reduced form. This all-thiol HMGB1 exerts its chemotactic activity to initiate inflammation by forming a heterocomplex with CXCL12; that complex binds exclusively to CXCR4 to initiate chemotaxis. Thirdly, binding of the HMGB1 to CXCR4 or to TLR4 is completely prevented by all-cysteine oxidation. Also, the initial post-translational redox modifications of HMGB1 are reversible processes, enabling HMGB1 to shift from acting as a chemotactic factor to acting as a cytokine and vice versa. Lastly, post-translational acetylation of key lysine residues within NLSs of HMGB1 affects HMGB1 to promote inflammation; hyperacetylation of HMGB1 shifts its equilibrium from a predominant nuclear location toward a cytosolic and subsequent extracellular presence. Hence, post translational modifications of HMGB1 determine its role in inflammation and immunity. PMID- 23446150 TI - Leukocyte-specific protein 1 links TNF receptor-associated factor 1 to survival signaling downstream of 4-1BB in T cells. AB - 4-1BB is a member of the TNFR superfamily, which contributes to the activation of signaling pathways required for the survival of activated and memory T cells. We have shown previously that TRAF1, an adaptor protein recruited to 4-1BB, is required for 4-1BB-mediated CD8 T cell survival in vivo. With the use of a proteomics approach in primary T cells, we have identified LSP1 as a novel protein recruited to the 4-1BB signaling complex in a TRAF1-dependent manner. Further characterization of the interaction between TRAF1 and LSP1 revealed that LSP1 requires the TRAF-N domain of TRAF1 for direct association. Similarly to TRAF1(-/-) T cells, LSP1(-/-) T cells exhibit impaired ERK activation following stimulation through 4-1BB and consequently, are unable to down-modulate expression of the proapoptotic Bcl-2 family member Bim. Moreover, we demonstrate that the absence of LSP1 expression leads to defective expansion and survival of T cells in response to 4-1BB stimulation. Thus, we have identified LSP1 as a new mediator involved in 4-1BB signaling and T cell survival. Collectively, our work shows that TRAF1 and LSP1 cooperate downstream of 4-1BB to activate ERK signaling and down-modulate the levels of Bim leading to enhanced T cell survival. PMID- 23446151 TI - [A toddler with traumatic brain injury]. AB - A 14-month-old boy presented with a haematoma and an oedematous swelling in the left parieto-occipital region after sustaining a fall from 3 meters. CT images of the brain showed a multifragmentary fracture in the parietotemporal region. Because the swelling progressed during admission, an MRI of the brain was performed, which revealed extrusion of brain tissue through a skull defect into the subgaleal space. Resultantly, the diagnosis of 'cranial burst fracture' was established. After neurosurgical resection and dural repair, the boy was discharged from the hospital without neurological symptoms. PMID- 23446149 TI - TLR2 deletion promotes arthritis through reduction of IL-10. AB - RA is a chronic inflammatory disease characterized by the persistent expression of inflammatory cytokines from macrophages, which may be mediated, in part, through TLR2 signaling. Earlier studies demonstrate a role for TLR2 signaling in dampening the arthritis in IL-1Ra-/- mice, which was mediated through T cells. This study was performed to determine whether TLR2 signaling plays a role in the pathogenesis of T cell-independent arthritis triggered by transferring serum from K/BxN mice. We documented more severe arthritis in Tlr2-/- mice compared with WT controls. The Tlr2-/- mice also demonstrated increased inflammation, erosion, pannus formation, and osteoclastogenesis, as well as increased IL-1beta and decreased IL-10 within the joints. In vitro bone marrow-differentiated macrophages expressed comparable levels of activating and inhibitory FcgammaRs, however when stimulated with immune complexes, the Tlr2-/- macrophages expressed decreased IL-10 and reduced activation of Akt and ERK. Our findings indicate that Tlr2-/- promotes the effector phase of arthritis through decreased IL-10 by macrophages, which is important, not only as an anti-inflammatory cytokine but also in restraining the differentiation and activation of osteoclasts. PMID- 23446152 TI - [A chance finding in a woman with abdominal pain]. AB - A 73-year-old woman was presented to the emergency department with severe abdominal pain. A CT-scan of the abdomen showed coprostasis and a visceral abdominal aneurysm of the splenic artery. Subsequently, the aneurysm was treated with endovascular coiling. PMID- 23446153 TI - [A woman with a palpable abnormality in the breast]. AB - Mondor's disease is a rare benign condition characterized by thrombophlebitis of superficial veins of the chest and the breast. Typically, there is a spontaneous onset of tenderness and redness due to a cord-like induration on the lateral thoracic wall. It is a self-limiting disease that should be distinguished from breast cancer. In general, the combination of clinical symptoms and mammography confirms the diagnosis. PMID- 23446154 TI - [Peripheral circulation in critically ill patients: non-invasive methods for the assessment of the peripheral perfusion]. AB - Peripheral tissues, such as skin and muscles, are sensitive to alterations in perfusion. During circulatory shock, these tissues are the first to receive less blood and the last to recover after treatment. By monitoring peripheral circulation, disturbance of the systemic circulation can be detected at an early stage. Peripheral perfusion is often disturbed in critically ill patients. Peripheral perfusion may remain disturbed, even if conventional hemodynamic parameters such as blood pressure and heart frequency normalize after treatment. Persistent abnormal peripheral perfusion is related to a poorer clinical course. With current non-invasive methods, peripheral circulation in critically ill patients can easily be assessed at the bedside. Interventions that improve peripheral circulation may speed up recovery in critically ill patients. PMID- 23446155 TI - [A boy with a cough and shoulder pain]. AB - A 15-year-old boy reported to the Accident and Emergency Department with excessive coughing, shortness of breath and pain in the area of his left shoulder blade. Methicillin-resistant Staphylococcus aureus (MRSA) was cultured from his sputum. The boy was otherwise healthy, and had no immune deficiency or underlying anatomic abnormality. He probably contracted the MRSA infection at the international school he attends. PMID- 23446156 TI - [Neonatal abstinence syndrome after maternal use of tramadol]. AB - BACKGROUND: Tramadol is an opioid with lipophilic characteristics that freely crosses the placenta. Due to the placental transfer, there is a risk of neonatal withdrawal symptoms. Therefore, chronic use during pregnancy is not advised. CASE DESCRIPTION: A 25-year-old pregnant woman, gravida 3, para 1, used tramadol 100 mg 3 times a day for chronic headache and migraine during this pregnancy. Because of the risk for neonatal abstinence syndrome, delivery took place in the hospital and the neonate had to stay at least 3 days for observation. The newborn developed neonatal withdrawal symptoms 36 hours after delivery. Treatment with phenobarbital was effective; 9 days after delivery the newborn was discharged without further treatment. CONCLUSION: When tramadol is used during pregnancy, there is a serious risk for neonatal abstinence syndrome. Phenobarbital proved to be effective for the treatment of neonatal tramadol withdrawal. PMID- 23446157 TI - [Prevention of psychotic disorders; is the time ripe for intervention?]. AB - A growing number of research papers focus on the identification of young individuals meeting 'ultra-high risk criteria' for developing a first episode of psychosis. Intervention in this early phase might possibly prevent or postpone the development of a full-blown psychosis. Different detection and treatment strategies within this target group are being discussed. This is illustrated using three cases. The first is a 20-year-old female with subclinical psychotic symptoms and recent functional decline; however, as her symptoms only presented following drug abuse, she was not considered to be at ultra-high risk for developing a first episode of psychosis. The second case involves a 17-year-old student who did meet at-risk criteria; after seeking help for subclinical psychotic symptoms and increasing social withdrawal behaviour his symptoms decreased with help of CBT. The third case, an 18-year-old male, illustrates that specialized investigation into high-risk symptoms of psychosis are sometimes needed to reveal frank psychotic symptoms. PMID- 23446158 TI - [A smoker with progressive knee complaints]. AB - A 70-year-old smoker was referred for X-rays of both painful knees. Both femora showed signs of hypertrophic osteoarthropathy. Chest radiography demonstrated a tumour in the upper lobe of the right lung. The patient was diagnosed with hypertrophic pulmonary osteoarthropathy (Marie-Bamberger syndrome). PMID- 23446159 TI - [Informed choice: a challenge for the Dutch national breast cancer screening programme]. AB - Debates about the Dutch national breast cancer screening programme sometimes lead to polarised opinions as to its usefulness. This article aims to clarify the perspectives related to this discussion. Supporters and opponents agree that the screening programme has advantages for the general population, but inevitably also disadvantageous aspects. They differ in the weighting of collective advantages and disadvantages. More importantly, every woman who is invited is free to accept the invitation to participate or not. Ideally, she makes a deliberate, informed choice based on sufficient knowledge. The real challenge for professionals is to provide good, honest, balanced information and adequate support to women when making their decision whether or not to participate in breast cancer screening. PMID- 23446161 TI - Short-term effects of hypothermia on axonal injury, preoligodendrocyte accumulation and oligodendrocyte myelination after hypoxia-ischemia in the hippocampus of immature rat brain. AB - Hypothermia is known to improve neurological recovery of animals and humans exposed to hypoxic-ischemic (HI) injury. However, the underlying mechanisms of the neuroprotective effects of hypothermia are only partially understood, including decreased excitotoxicity and apoptosis, and suppressed inflammation. There are few studies about the hypothermic effects on axonal injury and oligodendrocyte (OL) lineage degeneration, which are important components of neonatal brain injuries that cause cognitive disability. We hypothesized that mild hypothermia would reduce axonal injury and increase myelination in the hippocampus after HI. We performed left carotid artery ligation followed by 8% oxygen for 2 h in 7-day-old rats. Animals were divided into a hypothermic group (rectal temperature 32-33 degrees C for 24 h) and a normothermic group (36-37 degrees C for 24 h) immediately after HI. Animals were sacrificed at 1, 3 and 7 days for immunohistochemistry or Western blot analysis. We detected neuron loss by microtubule-associated protein 2 labeling and axonal injury by non phosphorylated neurofilament (SMI32) with neurofilament 200 (NF200) double staining. We examined early OL progenitors by A2B5 or NG2, preoligodendrocytes (preOLs) by O4, and mature OLs by 2,3-cyclic nucleotide 3-phosphodiesterase (CNPase) and glutathione S-transferase (GST)-pi staining. Apoptosis was studied by active caspase-3. Hypothermia was associated with a significant elevation of neurons and axons in the hippocampal CA1 region after HI. Early OL progenitors (A2B5(+)) were elevated, but preOLs (O4(+)) and active caspase-3 were dramatically reduced in the hypothermic rat brain. Further study showed that the apoptotic rate of preOLs (caspase-3(+)-O4(+)/O4(+)) was markedly attenuated by hypothermic treatment compared to normothermic animals. The immunoreactivity of CNPase and GST-pi and the protein level of the myelin basic protein significantly increased in the hippocampus of hypothermia-treated rat brain. Axonal myelination also increased in hypothermic animals, which were tested by myelin basic protein and NF200 double staining and electron microscopy. These results showed that hypothermia reduced HI damage to axons and OL myelination coincided with increased early OL progenitor proliferation and decreased preOL accumulation and apoptosis. This study suggested new aspects that may contribute to elucidate the mechanism of hypothermic neuroprotection in neonatal rat brain. PMID- 23446162 TI - Sex effect on meat quality and carcass traits of foals slaughtered at 15 months of age. AB - The effect of sex on carcass measurement, physico-chemical properties, nutritional value and sensory characteristics of foal meat slaughtered at 15 months was investigated. Twelve foals (six females and six males) from an extensive production system in freedom regimen were used for this study. Sex had no statistical influence on carcass measurements, chemical composition, colour parameters, textural properties, amino acid content and sensory characteristics. In contrast, there was a clear effect on the fatty acid profile of longissimus dorsi. Slaughter weight was not significantly (P > 0.05) different between sexes, although higher values were observed in male group compared with female group (194 v. 184 kg). As a consequence, this trend affected carcass weight being slightly (P > 0.05) heavier in the male group than in the female group. On the other hand, cooking loss samples from males showed significantly higher values than those from females (21.50% v. 14.96%, P < 0.05). From a nutritional point of view, the n-6/n-3 ratio in both sexes was within the recommended range for the human diet and this ratio was ostensibly different between the sexes (1.83 v. 1.36, P < 0.05, for male and female, respectively) and it showed a strong correlation (r = -0.91, P < 0.01) with C18:3n-3 content. PMID- 23446163 TI - How did morality originate? A review of Christopher Boehm, Moral Origins: The Evolution of Virtue, Altruism, and Shame. PMID- 23446165 TI - We are unique when we cry: A review of Michael Trimble, Why Humans Like to Cry: Tragedy, Evolution, and the Brain. PMID- 23446167 TI - The Right Person, In the Right Place, At the Right Time: A review of Napoleon A. Chagnon, Noble Savages: My Life Among Two Dangerous Tribes-The Yanomamo and the Anthropologists. PMID- 23446166 TI - A personality for modern living: A review of Kevin Dutton, The Wisdom of Psychpaths: What Saints, Spies, and Serial Killers Can Teach Us About Success. PMID- 23446173 TI - Practical blood flow restriction training increases acute determinants of hypertrophy without increasing indices of muscle damage. AB - Vascular blood flow restriction (BFR) training stimulates muscle hypertrophy by increasing muscle activation and muscle swelling. Previous studies used expensive pneumatic cuffs, which may not be practical for regular use. The aim was to investigate the acute effects of low-intensity practical BFR (LI-pBFR) on muscle activation, muscle swelling, and damage. Twelve trained male participants completed a 30-, 15-, 15-, 15-repetition scheme at 30% of their leg press 1 repetition maximum under control and LI-BFR conditions. Under the LI-BFR trial, knee wraps were applied to the thighs at a pressure that resulted in venous, not arterial, occlusion. In the control trial, wraps were applied with zero pressure. Ultrasound-determined muscle thickness was recorded at baseline; 0 minutes post with wraps; 0, 5, and 10 minutes post without wraps. Muscle activation was recorded during warm-ups and on the final set of 15 repetitions. Indices of muscle damage (soreness, power, and muscle swelling) were also recorded. There was a condition by time effect for muscle thickness (p < 0.0001, effect size [ES] = 0.5), in which muscle thickness increased in the LI-pBFR condition 0 minutes post with wraps and through 5 minutes post without wraps. No changes occurred in the control. There was a condition by time effect for muscle activation (p < 0.05, ES = 0.2). The LI-pBFR had greater activation than the control did. There were no condition by time effects on indices of muscle damage. Our data indicate that practical BFR significantly increases muscle activation and muscle thickness without increasing indices of damage. PMID- 23446174 TI - RE: Insensitivity of the in vitro cytokinesis-block micronucleus assay with human lymphocytes for the detection of DNA damage present at the start of the cell culture (Mutagenesis, 27, 743-747, 2012). PMID- 23446175 TI - Malondialdehyde-deoxyguanosine and bulky DNA adducts in schoolchildren resident in the proximity of the Sarroch industrial estate on Sardinia Island, Italy. AB - Air quality is a primary environmental concern in highly industrialised areas, with potential health effects in children residing nearby. The Sarroch industrial estate in Cagliari province, Sardinia Island, Italy, hosts the world's largest power plant and the second largest European oil refinery and petrochemical park. This industrial estate produces a complex mixture of air pollutants, including benzene, heavy metals and polycyclic aromatic hydrocarbons. Thus, we conducted a cross-sectional study to evaluate the prevalence of malondialdehyde deoxyguanosine adducts in the nasal epithelium of 75 representative children, aged 6-14 years, attending primary and secondary schools in Sarroch in comparison with 73 rural controls. Additionally, the levels of bulky DNA adducts were analysed in a subset of 62 study children. DNA damage was measured by (32)P postlabelling methodologies. The air concentrations of benzene and ethyl benzene were measured in the school gardens of Sarroch and a rural village by diffusive samplers. Outdoor measurements were also performed in other Sarroch areas and in the proximity of the industrial estate. The outdoor levels of benzene and ethyl benzene were significantly higher in the school gardens of Sarroch than in the rural village. Higher concentrations were also found in other Sarroch areas and in the vicinity of the industrial park. The mean levels of malondialdehyde deoxyguanosine adducts per 10(8) normal nucleotides +/- standard error (SE) were 74.6+/-9.1 and 34.1+/-4.4 in the children from Sarroch and the rural village, respectively. The mean ratio was 2.53, 95% confidence interval (CI): 1.71-2.89, P < 0.001, versus rural controls. Similarly, the levels of bulky DNA adducts per 10(8) normal nucleotides +/- SE were 2.9+/-0.4 and 1.6+/-0.2 in the schoolchildren from Sarroch and the rural village, respectively. The means ratio was 1.90, 95% CI: 1.25-2.89, P = 0.003 versus rural controls. Our study indicates that children residing near the industrial estate have a significant increment of DNA damage. PMID- 23446176 TI - An ECVAG inter-laboratory validation study of the comet assay: inter-laboratory and intra-laboratory variations of DNA strand breaks and FPG-sensitive sites in human mononuclear cells. AB - The alkaline comet assay is an established, sensitive method extensively used in biomonitoring studies. This method can be modified to measure a range of different types of DNA damage. However, considerable differences in the protocols used by different research groups affect the inter-laboratory comparisons of results. The aim of this study was to assess the inter-laboratory, intra laboratory, sample and residual (unexplained) variations in DNA strand breaks and formamidopyrimidine DNA glycosylase (FPG)-sensitive sites measured by the comet assay by using a balanced Latin square design. Fourteen participating laboratories used their own comet assay protocols to measure the level of DNA strand breaks and FPG-sensitive sites in coded samples containing peripheral blood mononuclear cells (PBMC) and the level of DNA strand breaks in coded calibration curve samples (cells exposed to different doses of ionising radiation) on three different days of analysis. Eleven laboratories found dose response relationships in the coded calibration curve samples on two or three days of analysis, whereas three laboratories had technical problems in their assay. In the coded calibration curve samples, the dose of ionising radiation, inter-laboratory variation, intra-laboratory variation and residual variation contributed to 60.9, 19.4, 0.1 and 19.5%, respectively, of the total variation. In the coded PBMC samples, the inter-laboratory variation explained the largest fraction of the overall variation of DNA strand breaks (79.2%) and the residual variation (19.9%) was much larger than the intra-laboratory (0.3%) and inter subject (0.5%) variation. The same partitioning of the overall variation of FPG sensitive sites in the PBMC samples indicated that the inter-laboratory variation was the strongest contributor (56.7%), whereas the residual (42.9%), intra laboratory (0.2%) and inter-subject (0.3%) variations again contributed less to the overall variation. The results suggest that the variation in DNA damage, measured by comet assay, in PBMC from healthy subjects is assay variation rather than variation between subjects. PMID- 23446177 TI - Distinct pathways for repairing mutagenic lesions induced by methylating and ethylating agents. AB - DNA alkylation damage can be repaired by nucleotide excision repair (NER), base excision repair (BER) or by direct removal of alkyl groups from modified bases by O(6)-alkylguanine DNA alkyltransferase (AGT; E.C. 2.1.1.63). DNA mismatch repair (MMR) is also likely involved in this repair. We have investigated alkylation induced mutagenesis in a series of NER- or AGT-deficient Escherichia coli strains, alone or in combination with defects in the MutS, MutL or MutH components of MMR. All strains used contained the F'prolac from strain CC102 (F'CC102) episome capable of detecting specifically lac GC to AT reverse mutations resulting from O(6)-alkylguanine. The results showed the repair of O(6) methylguanine to be performed by AGT ? MMR > NER in order of importance, whereas the repair of O(6)-ethylguanine followed the order NER > AGT > MMR. Studies with double mutants showed that in the absence of AGT or NER repair pathways, the lack of MutS protein generally increased mutant frequencies for both methylating and ethylating agents, suggesting a repair or mutation avoidance role for this protein. However, lack of MutL or MutH protein did not increase alkylation induced mutagenesis under these conditions and, in fact, reduced mutagenesis by the N-alkyl-N-nitrosoureas MNU and ENU. The combined results suggest that little or no alkylation damage is actually corrected by the mutHLS MMR system; instead, an as yet unspecified interaction of MutS protein with alkylated DNA may promote the involvement of a repair system other than MMR to avoid a mutagenic outcome. Furthermore, both mutagenic and antimutagenic effects of MMR were detected, revealing a dual function of the MMR system in alkylation-exposed cells. PMID- 23446178 TI - A de novo T73I mutation in PTPN11 in a neonate with severe and prolonged congenital thrombocytopenia and Noonan syndrome. AB - We observed a neonate with severe congenital thrombocytopenia and features of Noonan syndrome where evaluations were negative for immune-mediated thrombocytopenia, congenital infections, and Fanconi anemia. The marrow findings and a significantly elevated plasma thrombopoietin (Tpo) level were consistent with congenital amegakaryocytic thrombocytopenia; we sought a genetic mutation that could explain this phenotype. No mutations were identified in c-MPL (the Tpo receptor gene). Microarray analysis of peripheral blood did not reveal an abnormality. DNA sequencing of the PTPN11 gene showed a heterozygous C>T nucleotide substitution in exon 3 (c.218C>T) predicted to result in a threonine to-isoleucine change at residue 73 (T73I). A 6-week trial of eltrombopag (an agonist of the Tpo receptor) failed to increase the platelet count. We propose this specific PTPN11 mutation results in abnormalities of the protein product SHP 2, which, because of its role in signal transduction, results in severe congenital thrombocytopenia refractory to c-MPL agonists. PMID- 23446179 TI - A retrospective study of secondary bacteraemia in hospitalised adults with community acquired non-typhoidal Salmonella gastroenteritis. AB - BACKGROUND: The clinical significance of bacteraemia secondary to non-typhoidal Salmonella (NTS) gastroenteritis in hospitalised adults is uncertain. METHODS: Adults admitted to a hospital in Liverpool, UK, with NTS gastroenteritis were identified using hospital discharge data and laboratory records. Patients with known HIV infection were excluded. Risk factors for a complicated or fatal course were determined. RESULTS: Between 1982 and 2006 inclusive, 633 adults were identified. Serovars causing infection included Enteritidis (46.6%), Typhimurium (27.6%) and Virchow (4.9%). A blood culture was taken in 364 (57.5%) patients who were generally sicker than those who were not cultured. Bacteraemia was detected in 63 (17.3%) patients who had blood cultures taken (63/633 (10.0%) of all patients). Bacteraemia was more common in those aged >= 65 years (p < 0.001) and in those aged < 65 years who had an underlying chronic disease. A complicated course occurred in 91 (25.0%) patients who had had a blood culture taken (148/633 (23.4%) of all patients). Independent factors associated with a complicated or fatal course among the patients investigated with a blood culture were bacteraemia (Adjusted Odds Ratio 5.34, 95% CI 2.86-9.95); new onset confusion or coma (AOR 4.80, 95% CI 1.91-12.07); prolonged symptoms prior to admission (AOR 2.48, 95% CI 1.44-4.27); dehydration (AOR1.90, 95% CI 1.07-3.38); and absence of fever (AOR 0.56, 95% CI 0.32-0.95). The 30 day attributable case fatality for all patients was 1.5%. CONCLUSIONS: In this study secondary bacteraemia, as well as other clinical factors, was independently associated with a complicated or fatal course in non-HIV infected adults admitted to hospital with NTS gastroenteritis. PMID- 23446180 TI - Cost effectiveness of a computer-delivered intervention to improve HIV medication adherence. AB - BACKGROUND: High levels of adherence to medications for HIV infection are essential for optimal clinical outcomes and to reduce viral transmission, but many patients do not achieve required levels. Clinician-delivered interventions can improve patients' adherence, but usually require substantial effort by trained individuals and may not be widely available. Computer-delivered interventions can address this problem by reducing required staff time for delivery and by making the interventions widely available via the Internet. We previously developed a computer-delivered intervention designed to improve patients' level of health literacy as a strategy to improve their HIV medication adherence. The intervention was shown to increase patients' adherence, but it was not clear that the benefits resulting from the increase in adherence could justify the costs of developing and deploying the intervention. The purpose of this study was to evaluate the relation of development and deployment costs to the effectiveness of the intervention. METHODS: Costs of intervention development were drawn from accounting reports for the grant under which its development was supported, adjusted for costs primarily resulting from the project's research purpose. Effectiveness of the intervention was drawn from results of the parent study. The relation of the intervention's effects to changes in health status, expressed as utilities, was also evaluated in order to assess the net cost of the intervention in terms of quality adjusted life years (QALYs). Sensitivity analyses evaluated ranges of possible intervention effectiveness and durations of its effects, and costs were evaluated over several deployment scenarios. RESULTS: The intervention's cost effectiveness depends largely on the number of persons using it and the duration of its effectiveness. Even with modest effects for a small number of patients the intervention was associated with net cost savings in some scenarios and for durations greater than three months and longer it was usually associated with a favorable cost per QALY. For intermediate and larger assumed effects and longer durations of intervention effectiveness, the intervention was associated with net cost savings. CONCLUSIONS: Computer delivered adherence interventions may be a cost-effective strategy to improve adherence in persons treated for HIV. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01304186. PMID- 23446181 TI - Fertility after complete uterine rupture. AB - PURPOSE OF REVIEW: This review will address fertility and pregnancy outcome in women with history of uterine rupture. RECENT FINDINGS: Increasing rates of primary Cesarean delivery and vaginal birth after one or more Cesarean sections will lead to higher rates of uterine rupture. Recent advances in reproductive medicine, open fetal surgery and gynecological surgery may also play a role in increasing uterine rupture rate. The implementation of the American College of Obstetricians and Gynecologists and Royal College of Obstetricians and Gynecologists guidelines on birth after Cesarean section will decrease the Cesarean section rate but may transiently increase the rate of uterine rupture. The maternal and perinatal risks of multiple Cesarean birth are much higher than those of uterine rupture. Women with prior uterine rupture are fertile. They have higher risk of recurrent uterine rupture. SUMMARY: Every obstetrician is bound to face the challenge of uterine rupture or women with prior uterine rupture. Those women should have a favorable maternal and perinatal outcome when managed in a tertiary center. PMID- 23446182 TI - Stereotactic radiosurgery of a papillary tumor of the pineal region: case report and review of the literature. AB - BACKGROUND/AIMS: Papillary tumors of the pineal region are a recently described very rare group of primary CNS neoplasms. Because of their rarity, it has proven to be difficult to establish the optimal therapy. Furthermore, microsurgical resection of pineal region neoplasms is associated with quite a high morbidity. We report the first case of stereotactic radiosurgery of a histologically confirmed papillary tumor of the pineal region. METHODS: After establishing the diagnosis by stereotactic biopsy, the patient was treated with stereotactic radiosurgery in a Gamma Knife unit. RESULTS: Five years after treatment, the tumor size is still decreasing, showing a good response to the treatment. CONCLUSIONS: Stereotactic radiosurgery should be considered a treatment option in these surgically challenging tumors. PMID- 23446183 TI - Implications of combined ovariectomy/multi-deficiency diet on rat bone with age related variation in bone parameters and bone loss at multiple skeletal sites by DEXA. AB - BACKGROUND: Osteoporosis is a multi-factorial, chronic, skeletal disease highly prevalent in post-menopausal women and is influenced by hormonal and dietary factors. Because animal models are imperative for disease diagnostics, the present study establishes and evaluates enhanced osteoporosis obtained through combined ovariectomy and deficient diet by DEXA (dual-energy X-ray absorptiometry) for a prolonged time period. MATERIAL/METHODS: Sprague-Dawley rats were randomly divided into sham (laparotomized) and OVX-diet (ovariectomized and fed with deficient diet) groups. Different skeletal sites were scanned by DEXA at the following time points: M0 (baseline), M12 (12 months post-surgery), and M14 (14 months post-surgery). Parameters analyzed included BMD (bone mineral density), BMC (bone mineral content), bone area, and fat (%). Regression analysis was performed to determine the interrelationships between BMC, BMD, and bone area from M0 to M14. RESULTS: BMD and BMC were significantly lower in OVX-diet rats at M12 and M14 compared to sham rats. The Z-scores were below -5 in OVX-diet rats at M12, but still decreased at M14 in OVX-diet rats. Bone area and percent fat were significantly lower in OVX-diet rats at M14 compared to sham rats. The regression coefficients for BMD vs. bone area, BMC vs. bone area, and BMC vs. BMD of OVX diet rats increased with time. This is explained by differential percent change in BMD, BMC, and bone area with respect to time and disease progression. CONCLUSIONS: Combined ovariectomy and deficient diet in rats caused significant reduction of BMD, BMC, and bone area, with nearly 40% bone loss after 14 months, indicating the development of severe osteoporosis. An increasing regression coefficient of BMD vs. bone area with disease progression emphasizes bone area as an important parameter, along with BMD and BMC, for prediction of fracture risk. PMID- 23446185 TI - Logistics of transfusion support for patients with massive hemorrhage. AB - PURPOSE OF REVIEW: Traditionally, trauma resuscitation protocols have advocated sequential administration of therapeutic components, beginning with crystalloid solutions infused to replace lost intravascular volume. However, rapid restoration of the components of blood is essential for ensuring adequate tissue perfusion and for preventing acidosis, coagulopathy, and hypothermia, referred to as the 'lethal triad' in trauma settings. The review summarizes practical approaches for transfusion support of patients with massive hemorrhage. RECENT FINDINGS: Massive transfusion protocols for blood transfusion support are reviewed, including practical considerations from our own. We maintain an inventory of thawed, previously frozen plasma (four units each of blood group O and A), which can be issued immediately for patients in whom the blood type is known. As frozen plasma requires 45 min to thaw, liquid AB plasma (26 day outdate) functions as an excellent alternative, particularly for patients with unknown or blood group B or AB types. SUMMARY: Close monitoring of bleeding and coagulation in trauma patients allows goal-directed transfusions to optimize patients' coagulation, reduce exposure to blood products, and to improve patient outcomes. Future studies are needed to understand and demonstrate improved patient outcomes. PMID- 23446186 TI - Current world literature. PMID- 23446184 TI - A mobile instrumentation platform to distinguish airway disorders. AB - Asthma and chronic obstructive pulmonary disease (COPD) are distinct but clinically overlapping airway disorders which often create diagnostic and therapeutic dilemmas. Current strategies to discriminate these diseases are limited by insensitivity and poor performance due to biologic variability. We tested the hypothesis that a gas chromatograph/differential mobility spectrometer (GC/DMS) sensor could distinguish between clinically well-defined groups with airway disorders based on the volatile organic compounds (VOCs) obtained from exhaled breath. After comparing VOC profiles obtained from 13 asthma, 5 COPD and 13 healthy control subjects, we found that VOC profiles distinguished asthma from healthy controls and also a subgroup of asthmatics taking the drug omalizumab from healthy controls. The VOC profiles could not distinguish between COPD and any of the other groups. Our results show a potential application of the GC/DMS for non-invasive and bedside diagnostics of asthma and asthma therapy monitoring. Future studies will focus on larger sample sizes and patient cohorts. PMID- 23446188 TI - Never in neutral: a systems biology and evolutionary perspective on how aneuploidy contributes to human diseases. AB - Whereas germline-inherited whole-chromosome aneuploidy has long been known to cause miscarriages and developmental abnormalities, somatically acquired aneuploidies have been observed in cancer cells and more recently also in cells of the normal liver and brain. Furthermore, aneuploidy is being increasingly reported in clinical isolates of pathogenic microbes such as fungi and parasites. Whereas many efforts have been devoted to the dissection of the molecular mechanisms that lead to aneuploidy, we have only recently started to investigate how aneuploidy alters the phenotypic makeup of a cell. Here we review recent evidence supporting the idea that aneuploidy is a large-effect mutation that introduces large changes in the cellular phenome. From a systems biology perspective, this can be explained by the extensive changes that aneuploidy brings about in both the transcriptome and the proteome of a cell. We further provide an evolutionary perspective on how aneuploidy-induced phenotypic variation may contribute to the exacerbation of human pathologies such as cancer and infectious diseases, by conferring selectable traits such as increased virulence and drug resistance. PMID- 23446189 TI - Evidence for M2 and M3 muscarinic receptor involvement in cholinergic excitatory junction potentials through synergistic activation of cation channels in the longitudinal muscle of mouse ileum. AB - Cholinergic nerve-mediated excitatory junction potentials (EJPs) in the longitudinal muscle of mouse ileum were characterized by using M2 or M3 muscarinic receptor-knockout (KO) mice and 1-[beta-[3-(4-methoxyphenyl) propoxy] 4-methoxyphenethyl]-1H-imidazole hydrochloride (SK&F 96365) and pertussis toxin (PTX). EJPs evoked by electrical field stimulation (EFS) in wild-type preparations, initially determined to be cholinergic in origin using tetrodotoxin, atropine, and eserine, were profoundly depressed after SK&F 96365 treatment known to block muscarinic receptor-operated cation channels. A similar depression of the EJPs was also observed by PTX treatment, which is predicted to disrupt M2-mediated pathways linked to cation channel activation. In M2-KO mouse preparations, cholinergic EJPs were evoked by EFS with their relative amplitude of 20%-30% to the wild-type EJP and strongly inhibited by SK&F 96365. No cholinergic EJP was seen in M3-KO as well as M2/M3 double-KO preparations. The results suggest that the wild-type cholinergic EJP is not a simple mixture of M2 and M3 responses, but due to synergistic activation of cation channels by both M2 and M3 receptors in the murine ileal longitudinal muscle. PMID- 23446191 TI - Pharmacogenetics in psychiatry: the need to prove its benefits. PMID- 23446190 TI - Towards a more clinically useful International World Health Organisation classification of mental disorders. PMID- 23446192 TI - Are obesity and other physical comorbidities related to mental illness? AB - BACKGROUND: Several studies have shown that patients with persistent or severe mental illness are at increased risk for obesity, both from the illness itself and from its treatment. Nevertheless, obesity in these patients could be related to other sociodemographic, psychosocial, and genetic factors. AIM: To explore whether obesity, and other physical comorbidity, are more prevalent in long-term psychiatric outpatients as compare to standard population. DESIGN: Cross sectional study in a rural Community Mental Health Setting, comparing physical and demographic data from psychiatric outpatients with data from the general population of the region, controlling for age, gender, body mass index (BMI) and physical comorbidity. RESULTS: Psychiatric patients were older, with higher BMIs and more chronic diseases. They are more frequently diagnosed with hypertension and hyperlipidemia. However, obesity is related to age, gender and comorbidity, but not to the presence or absence of psychiatric illnesses. CONCLUSIONS: Psychiatric patients are more obese than the general population, but it might be related to physical and demographic correlates: age, chronic illness and lifestyle. These factors can be also responsible for their increase risk of hypertension and hyperlipidemia. All those factors could be more relevant than the presence of mental illness itself or its treatment. PMID- 23446193 TI - Efficacy of second-generation-antipsychotics in the treatment of negative symptoms of schizophrenia: a meta-analysis of randomized clinical trials. AB - OBJECTIVES: To determine whether second-generation-antipsychotics (SGAs) are effective for negative symptoms treatment in schizophrenia. METHODS: Two meta analyses were carried out using placebo or haloperidol as comparators. The search included the following databases: Pubmed, The Cochrane Central Register of Controlled Trials, Proquest Health and Medical Complete, Science Citation Index Expanded, and Current Contents Connect. The outcome measure used was the change in negative symptoms, choosing a standardized statistic (Cohen's d) to synthesize the data. RESULTS: In the placebo-controlled meta-analysis, the effect sizes (Cohen's d) obtained for amisulpride, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone were 0.52, 0.34, 0.43, 0.36, 0.40 and 0.46, respectively, favoring active treatment against placebo (P<0.001 in all cases). The haloperidol-controlled meta-analysis only showed a statistically significant trend favoring antipsychotics over haloperidol (Cohen's d=0.15). CONCLUSIONS: Most antipsychotics (amisulpride, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone) are effective in the treatment of negative symptoms. Amisulpride and ziprasidone showed higher effect sizes. PMID- 23446194 TI - Subclinical depression in Spain: prevalence and health impact. AB - INTRODUCTION: Subclinical depression is a prevalent condition with important implications for patients' functioning and wellbeing. However, there is a lack of studies operationalising its definition and studying its clinical significance and health impact in depth. This work analyses subclinical depression impact on a health satus score derived from eight heath domains, and its prevalence in Spanish population. METHODS: The sample was selected from World Health Survey database, choosing the answers for Spain of people with a dignosis of subclinical depression and no depressive disorders. RESULTS: Controlling the interaction of the different demographic variables, being female was the only significant predictor for the presence of subclinical depression. A worse health status is associated with subclinical depression, being female, a higher age, lower incomes, less years of formal education and being widowed. The decrease is significant in the eight health domains composing the score. CONCLUSIONS: The necessity of a better conceptualization of the nature of clinical depression is highlighted, going in depth in different proposals defending a definition based on clinical signification rather than in the number of depressive symptoms, with the goal of avoiding the pathologization of human suffering and inherent distress to several vital situations. PMID- 23446195 TI - Recommendations for switching antipsychotics. A position statement of the Spanish Society of Psychiatry and the Spanish Society of Biological Psychiatry. AB - Switching antipsychotics is common in the clinical practice setting and is associated with potential clinically relevant complications. An expert group selected by Spanish Society of Psychiatry and the Spanish Society of Biological Psychiatry has reviewed the evidence provided by randomized clinical trials and other relevant information to reach consensus recommendations for switching antipsychotics. In this article, we will review all the information that has led to those recommendations and which includes: indications and contraindications for switching antipsychotics, pharmacological issues, switching strategies, switching antipsychotics due to efficacy problems, switching antispychotics due to tolerability issues (including extrapyramidal symptoms and tardive dyskinesia, weight gain, metabolic disorders, hyperprolactinemia, sexual dysfunction, persistent sedation, and QT prolongation), switching antypsychotics due to lack of treatment compliance, and switching antipsychotics in patients with bipolar disorders. PMID- 23446196 TI - Electroconvulsive therapy as treatment for malignant neuroleptic syndrome. AB - In the era of new antipsychotic drugs the severe symptomatology known by the name of neuroleptic malignant syndrome (NMS) continues to have a high incidence and mortality. We review its origin, pathophysiology, diagnostic criteria and staging, particularly with electroconvulsive therapy (ECT), and proposing a less restrictive use and more adjusted to the updated knowledge of this technique. In particular, we consider the justified use of bilateral lead placement, a frequency of three sessions per week, and loads calculated for age, which would ensure effective seizures with an early response, thus avoiding the use of repeated sub-seizure stimuli to calculate the threshold by titration. We believe there is little evidence on the fear of the risk of increasing malignant hyperthermia in NMS due to the substances used in anaesthesia, but is justified to use non-depolarising relaxants due to the risk of hyperkalaemia on being exposed to succinylcholine. Finally we believe it is essential to familiarise the other specialists involved in the treatment with ECT, to increase the availability of the technique and our training in this to the currently available complexity. PMID- 23446197 TI - Paliperidone palmitate versus risperidone long-acting injection in markedly-to severely ill schizophrenia subjects: onset of efficacy with recommended initiation regimens. AB - OBJECTIVE: To examine onset of efficacy of two long-acting injectable atypical antipsychotics in markedly-to-severely ill schizophrenia subjects. METHODS: This subgroup analysis included 292 subjects with baseline Clinical Global Impressions Severity scores of markedly ill or worse from a 13-week, randomized, double-dummy noninferiority study (NCT00589914). Subjects received either: 1) paliperidone palmitate (PP; 234 mg day 1 and 156 mg day 8 [corresponding to 150 and 100 milligram equivalents of paliperidone, respectively], both administered in deltoid muscle, followed by once-monthly flexible dosing in deltoid or gluteal muscle) and risperidone long-acting injection (RLAI)-matched placebo injections; or, 2) RLAI (25 mg, days 8 and 22; followed by biweekly flexible dosing) and PP matched placebo injections. RLAI subjects received oral risperidone days 1-28; PP subjects received oral placebo. Because of RLAI's release profile, data through day 22 correspond to oral risperidone. Assessments included Positive and Negative Syndrome Scale (PANSS) and adverse event (AE) reports. Paired t-tests assessed within-group changes. RESULTS: LS mean (SE) PANSS total scores improved significantly (both p<.001) with PP and oral risperidone by day 4 (-5.0 [0.6] and -3.4 [0.6], respectively) through day 22; and with PP and RLAI through end point (-21.5 [1.9] and -18.6 [1.9], respectively). The between-group difference was significant only at day 4 (p=.006). Proportion of subjects with a .30% reduction in PANSS total score was not significantly different between the two groups at day 4 and was significantly greater with paliperidone palmitate than oral risperidone at days 15 and 22 (26.1% versus 12.7%, p=.013; 41.6% versus 32.0%, p=.048, respectively). Most common AEs (.5% in either treatment group): headache (PP 6.3% and RLAI 14.0%), insomnia (10.6% and 10.7%), somnolence (7.8% and 1.3%), akathisia (7.0% and 5.3%), schizophrenia (8.5% and 5.3%), agitation (5.6% and 2.0%), and injection site pain (5.6% and 1.3%). CONCLUSIONS: Using the recommended dosing regimens for PP and RLAI, both PP and oral risperidone (used during RLAI initiation) improved symptoms of schizophrenia in markedly-to severely ill subjects at days 4-22. PMID- 23446198 TI - Early perception of medication benefit predicts subsequent antipsychotic response in schizophrenia: "the consumer has a point" revisited. AB - BACKGROUND: An easy-to-administer tool for predicting response to antipsychotic treatment could improve the acute management of patients with schizophrenia. We assessed whether a patient's perception of medication benefit early in treatment could predict subsequent response or nonresponse to continued use of the same treatment. METHOD: This post hoc analysis used data from a randomized, open-label trial of antipsychotics for treatment of schizophrenia in which attitudes about medication adherence were assessed after two weeks of antipsychotic treatment using the Rating of Medication Influences (ROMI) scale. The analysis included 439 patients who had Positive and Negative Syndrome Scale (PANSS) and ROMI scale data at Weeks 2 and 8. Scores on the ROMI subscale Perceived Medication Benefit factor were used to predict subsequent antipsychotic response at Week 8, defined as a .20% reduction from baseline on the PANSS. Logistic regression was used to identify a cut-off score for the Perceived Medication Benefit factor that could accurately identify antipsychotic responders vs. nonresponders at Week 8. RESULTS: A score of .2.75 (equal to a mean subscale score of .11.00) on the ROMI scale Perceived Medication Benefit factor at Week 2 predicted response at Week 8 with high specificity (72%) and negative predictive value (70%), moderate sensitivity (44%) and positive predictive value (47%), and with a 38% misclassification rate. CONCLUSIONS: A brief assessment of the patient's perception of medication benefit at two weeks into treatment appears to be a good predictor of subsequent response and nonresponse after eight weeks of treatment with the same antipsychotic. PMID- 23446199 TI - Cerumen impaction in patients with schizophrenia. AB - Cerumen impaction may cause hearing loss and pain. We investigated the prevalence of cerumen impaction in a population of outpatients with schizophrenia spectrum psychoses and studied factors contributing to it. As a part of our study--"The Living Conditions and Physical Health of Outpatients with Schizophrenia"--we performed a thorough medical examination including otoscopy of the ear canal for patients treated in the community mental health center of one Finnish municipality. Out of a total of 61 patients, cerumen impaction was found in 12 (19.7%). In a logistic regression model, living in a group home (OR 13.7, 95% confidence interval 3.0-64.0, p=0.0008) significantly predicted cerumen impaction. Cerumen impaction was also associated with male gender and lower GAF scores. Cerumen impaction is common in patients with schizophrenia, and is associated with low level of functioning. Diagnosis and treatment of cerumen impaction among schizophrenia patients is essential in avoiding this easily treatable cause of hearing loss and its consequences such as difficulties in cognition and social interaction. PMID- 23446200 TI - Psychotic disorder after contact with a potentially rabid animal and post exposure prophylactic anti-rabies treatment. AB - We present the case of a 19-year-old who developed psychotic symptoms after exposure to a potentially rabid animal and post-exposure prophylactic treatment. This case serves to remind physicians to fully explore the possibility of a nonpsychiatric origin of de novo psychotic symptoms and provides indirect evidence in favor of the possible involvement of the immune system in the development of psychotic disorders. PMID- 23446201 TI - Prolonged reaction to mental arithmetic stress in first-degree relatives of schizophrenia patients. AB - OBJECTIVE: Several studies have reported abnormal heart rate variability (HRV) in schizophrenia patients, suggesting a pathophysiological link between central autonomic dysfunction and symptoms of schizophrenia and that these could be heritable. This study aimed at evaluating cardiac autonomic response to mental arithmetic stress in first-degree relatives of schizophrenia patients (FDRS) employing HRV analysis. METHODS: HRV measures were computed for 25 healthy FDRS and 25 age- and gender-matched controls during rest, mental arithmetic stress task and recovery period. Subtracting serial sevens from 700 for five minutes formed the stress task. Recovery period lasted five minutes starting from the termination of the stress task. RESULTS: Both groups showed similar alterations during the stress task. After stress termination, recovery to the basal values was observed in controls but not in patients' relatives, maintaining a pattern similar to that during the stress task. CONCLUSIONS: Poor recovery from cardiac autonomic functions (CAF) alterations induced by arithmetic stress may be a heritable trait marker of schizophrenia. Our report supports endophenotypic potential of HRV in schizophrenia research. PMID- 23446202 TI - The effect of provider density on lung cancer survival among blacks and whites in the United States. AB - INTRODUCTION: Lung cancer mortality rates may vary with access to specialty providers and local resources. We sought to examine the effect of access to care, using density of lung cancer care providers, on lung cancer mortality among blacks and whites in the United States. METHODS: We examined U.S. county-level data for age-adjusted lung cancer mortality rates from 2003 to 2007. Our primary independent variable was per capita number of thoracic oncologic providers, adjusting for county-level smoking rates, socioeconomic status, and other geographic factors. Data were obtained from 2009 Area Resource File, National Center for Health Statistics, and the County Health Rankings Project. RESULTS: Providers of lung cancer care were unevenly distributed among the U.S. counties. For example, 41.4% of the U.S. population reside in counties with less than four thoracic surgeons per 100,000 people, 23.4% in counties with 4 to 15 surgeons per 100,000 people, and 35.3% in counties with more than 15 surgeons per 100,000 people. Geographically, 4.3% of whites compared with 11.2% of blacks lived in high lung cancer mortality zones. Lung cancer mortality did not vary by density of thoracic surgeons or oncology services; however, higher primary care provider density was associated with lung cancer mortality reduction of 4.1 per 100,000 for whites. CONCLUSION: Variation in provider density for thoracic oncology in the United States was not associated with a difference in lung cancer mortality. Lower mortality associated with higher primary care provider density suggests that equitable access to primary care may lead to reduced cancer disparities. PMID- 23446203 TI - Prognostic factors and outcome for patients with esophageal squamous cell carcinoma underwent surgical resection alone: evaluation of the seventh edition of the American Joint Committee on Cancer staging system for esophageal squamous cell carcinoma. AB - INTRODUCTION: More data are essential to test the efficacy of the seventh edition of the American Joint Committee on Cancer (AJCC) staging system for esophageal squamous cell carcinoma (ESCC). This retrospective study was designed to identify the prognostic factors for survival of patients with ESCC who underwent surgical resection alone and to evaluate the new AJCC staging system for ESCC. METHODS: Data of a single-center cohort of 2011 patients with ESCC who underwent surgical resection alone according to the new staging system were reviewed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: The 1-, 3-, and 5-year overall survival rates were 83.5, 57.4, and 47.4%, respectively, with a median survival time of 51.0 months. Age, histologic grade, R-category, pT category, pN category, pM category, pTNM stage, and the extent of lymph node metastasis were independent prognostic factors (p < 0.05). In separate subgroup analyses, the survival differences were not significant for pN2 versus pN3 category (p = 0.159) and stages IA versus IB (p = 0.922). Subdivisions by depth of infiltration rather than tumor grade for pT1N0M0 cancers and modified nodal categories (0, 1, 2-3, and >=4 positive lymph nodes) better represented a survival advantage. CONCLUSIONS: The seventh edition of the AJCC staging system for ESCC is acceptable in predicting survival. However, tumor location does not influence survival in our study. Subdivisions of pT1N0M0 cancers and the N classification may need to be modified. PMID- 23446204 TI - FDG PET-CT aids in the preoperative assessment of patients with newly diagnosed thymic epithelial malignancies. AB - INTRODUCTION: Advanced thymoma (stage III and IV) is difficult to detect by computed tomography (CT), yet it is important to distinguish between early (stage I and II) and advanced disease before surgery, as patients with locally advanced tumors require neoadjuvant chemotherapy to enable effective resection. This study assessed whether the amount of fluorodeoxyglucose (FDG) uptake can predict advanced thymoma and whether it can separate thymoma from thymic cancer. METHODS: We retrospectively reviewed FDG positron emission tomography (PET)-CT scans of 51 consecutive newly diagnosed patients with thymic epithelial malignancy. PET-CT findings documented focal FDG activity: SUVmax, SUVmean, SUVpeak, and total body volumetric standardized uptake value (SUV) measurements. These were correlated with Masaoka-Koga staging and World Health Organization classification. Wilcoxon ranked sum tests were used to assess association between SUV and pathological stage, cancer type, and classification. RESULTS: Among the study patients, 37 had thymoma, 12 thymic carcinoma, and 2 thymic carcinoid. Higher focal FDG uptake was seen in patients with type B3 thymoma than in those with type A, AB, B1, or B2 thymoma (p < 0.006). FDG uptake was higher in patients with thymic carcinoma or carcinoid than in patients with thymoma (p < 0.0003), with more variable associations with volumetric SUV measurements. There was no significant association observed between higher focal FDG uptake and advanced-stage disease in thymoma patients (p > 0.09), although greater FDG-avid tumor volume was significantly associated with advanced disease (p < 0.03). CONCLUSIONS: Focal FDG uptake cannot predict advanced thymoma but is helpful in distinguishing thymoma from thymic carcinoma, or the more aggressive thymoma, type B3. PMID- 23446205 TI - Quantitative estimation of AgNORs in normal, dysplastic and malignant oral mucosa. AB - AIMS: Silver stainable nucleolar organizer regions (AgNORs) have received a great deal of attention recently as their frequency within the nuclei is significantly higher in malignant cells than in normal, reactive or benign neoplastic cells. The objective of this study was to carry out a quantitative assessment of large and small AgNORs in oral normal mucosa, precancerous lesions and infiltrating squamous cell carcinomas. METHODS: The study comprised 110 formalin-fixed, paraffin-embedded oral mucosal biopsies consisting of 30 oral dysplasia, 60 oral squamous cell carcinomas and 20 normal oral mucosa. AgNORs were counted in each nucleus, categorized as small, large and total number of AgNORs in each cell and their means were calculated. RESULTS: The mean value of small AgNORs, large AgNORs and total AgNORs increased gradually from normal mucosa to dysplastic lesions to squamous cell carcinomas. The study clearly indicates that in oral squamous cell carcinomas, AgNORs diminish in size as they increase in number. Further, AgNOR counts increase as the degree of malignant potential of the cell increases. CONCLUSIONS: By combining both the enumeration of AgNORs and their size, good distinction can be made between normal, dysplastic and infiltrating squamous cell carcinomas. This could help in the early diagnosis and prognosis of dysplastic mucosal lesions and their malignant transformation. PMID- 23446206 TI - Lipophilic fluorescent products of free radicals. AB - BACKGROUND: Fluorescent pigments are the end-products of reactions involving free radical attack on biological molecules and can be formed, for example, in reactions between lipid peroxidation products, mainly unsaturated aldehydes, with free amino groups. Their characteristic emission maximum was found to be at 420 470 nm after being excited at 340-390 nm. The mechanism of their formation and chemical identity has been revealed in many in vitro studies, in which reactive aldehydes were incubated with amino group-containing molecules. Owing to their intrinsic fluorescent properties and molecular stability these products are easily measured by means of spectrofluorimetry and are used as biomarkers of oxidative stress caused by various triggers. It has been found that the fluorescent products are formed in excess in conditions linked with increased free radical production, such as atherosclerosis, Alzheimer's disease and multiple sclerosis. METHODS: We searched the literature using "MEDLINE" and "Web of Science" in order to get an overview of the state of knowledge about fluorescent products of free radicals, that is, their analysis from in vitro studies, animal and human studies and their use as markers of oxidative damage. CONCLUSIONS: Although their chemical structure may not have been elucidated, the fluorophores formed in this way have found application as markers of oxidative stress in many animal and human studies. In vitro experiments using model reactions have given some clues as to how certain fluorescent pigments arise during oxidative reactions in vivo. Advances in analytical techniques should lead the chemical characterization of pigments of different origin to completeness. PMID- 23446207 TI - Can markers of collagen turnover or other biomarkers contribute to the diagnostics of heart failure with normal left ventricular ejection fraction? AB - AIMS: Plasma levels of some biomarkers and markers of collagen turnover may reflect myocardial structural abnormalities associated with diastolic dysfunction. The aim of this study was to determine whether these markers could contribute to the diagnostics of heart failure with normal ejection fraction (HFNEF). METHODS AND RESULTS: 91 patients with exertional dyspnea and normal left ventricular ejection fraction and 20 healthy controls underwent plasma analysis of markers of collagen turnover and other biomarkers, spirometry, and resting and exercise echocardiography. 38 patients with dyspnea had evidence of HFNEF, diagnosed at the early stage. Compared to the remaining patients, those with HFNEF had a significantly higher plasma levels of carboxy-terminal telopeptide of collagen type I (median 4.5 ug/L vs. 3.5 ug/L, P<0.05) and big endothelin (median 1.1 pmol/L vs 0.9 pmol/L, P<0.05). Univariate logistic regression analysis revealed a significant association between HFNEF and the following biomarkers: big endothelin, amino-terminal propeptide of type III procollagen (PIIINP), and matrix metalloproteinase-2 (MMP-2). However, none of these biomarkers independently contributed to the HFNEF diagnostics in a multivariate logistic regression analysis. CONCLUSION: Plasma levels of big endothelin, PIIINP, and MMP 2 were found to be associated with the presence of early diagnosed HFNEF. However, none of these biomarkers contributed independently to current noninvasive HFNEF diagnostics recommended by the European Society of Cardiology guidelines. PMID- 23446208 TI - The safety and efficacy of bridging full-dose IV-IA thrombolysis in acute ischemic stroke patients with MCA occlusion: a comparison with IV thrombolysis alone. AB - AIMS: Early recanalization of the occluded cerebral artery is substantial for clinical improvement in acute ischemic stroke (IS) patients. The rate of achieved recanalizations using IVT is low. The aim of this study was to compare the safety and efficacy of bridging full-dose intravenous-intraarterial (IV-IA) thrombolysis to IVT alone in acute IS patients with occluded MCA. METHODS: Seventy-nine consecutive IS patients with MCA occlusion were treated either with IVT alone (historic controls, Group 1) or with full-dose IV-IA thrombolysis (Group 2). Stroke severity was evaluated using NIHSS, achieved recanalizations using transcranial Doppler (Group 1) or angiography (Group 2). Occurrence of ICH including SICH was evaluated after 24 hours. 90-day clinical outcome was evaluated using modified Rankin Scale (mRS). RESULTS: Group 1 consisted of 50 patients (24 males, mean age 70.8+/-10.2 years) and Group 2 of 29 patients (14 males, mean age 67.8+/-10.0 years). No difference was found in the initial NIHSS (median 16 vs. 17) and other baseline parameters including time from stroke onset to IVT. Patients treated with bridging therapy had a higher number of achieved MCA recanalization (75.9 vs. 32.0%, P=0.0002), similar number of SICH (6.0 vs. 6.9%, P=1.000) and 34.5% of them achieved mRS 0-2 versus 28.0% of patients treated with IVT (P=0.546). Patients with shorter TR had significantly better clinical outcome (P=0.019). CONCLUSION: Bridging IV-IA thrombolysis seems to be safe and more effective than IVT alone in acute stroke patients with MCA occlusion. PMID- 23446209 TI - Dehiscent scar in the lower uterine segment after Caesarean section and IVF infertility treatment: a case report. AB - AIMS: Caesarean section is the most common obstetric operation associated with short and long term risks, one of which is uterine scar dehiscence. In this case report we describe four cases of in vitro fertilization and embryo transfer (IVF+ET) treatment where the embryo was transferred into the uterus with known scar dehiscence in the lower uterine segment after a previous Caesarean section (SC). METHODS: All transfers of embryos were ultrasound guided directly into the middle of uterine cavity. All resulting pregnancies continued without problems related to the dehiscent scar and babies were delivered in the third trimester by elective/emergency SC. RESULTS: Our cases suggest that IVF+ET can be offered as an infertility treatment option despite a dehiscent scar in the lower uterine segment after previous SC. PMID- 23446210 TI - Biological properties of a novel coladerm-beta glucan membrane.In vitro assessment using human fibroblasts. AB - AIM: The purpose of this study was to prepare a coladerm-beta glucan membrane (CBGM) and to evaluate its biocompatibility, cytotoxicity, antimicrobial activity, genotoxicity and mutagenicity. METHODS: The biocompatibility of the membrane was studied on the base of cell adhesion and colonization of human fibroblasts on the biomaterial surface by light microscopy. The MTT test and LDH level determination in the culture medium removed from the control and cells treated on the membrane, were used for viability and cytotoxic evaluations. Flow cytometry and gel electrophoresis were used for analysis of cell cycle and death. The antimicrobial activity of CBGM was tested using the qualitative dilution method. Ames bacteria gene mutation test and Comet assay were used for mutagenic and genotoxic studies. RESULTS: MTT and LDH tests confirmed that CBGM is a non toxic biomaterial. Flow cytometry and gel electrophoresis demonstrated that the membrane did not affect the cell cycle and did not induce either necrotic or apoptotic cell death. CBGM exhibited antibacterial activity against G(-) bacteria E. sakazakii, S. marcescens, E. coli and agains G(+) sporogenic bacteria B. cereus. No antifungal activity was detected. The membrane did not induce mutagenicity in the bacterial reverse mutation test in Salmonella Typhimurium strains. Similarly, the comet assay showed that the tested fibroblast cells growing with/without the membrane did not show any statistically significant DNA damage. CONCLUSIONS: The CBGM has good biocompatibility, no cytotoxicity/genotoxicity/mutagenicity and it can be included as a potential scaffold for tissue engineering. PMID- 23446211 TI - Lycopene improves the distorted ratio between AA/DHA in the seminal plasma of infertile males and increases the likelihood of successful pregnancy. AB - AIMS: Male infertility has been associated with imbalance in the polyunsaturated fatty acids arachidonic acid/docosahexaenoic acid (AA/DHA) ratio. This study aimed to assess whether use of the potent antioxidant, lycopene, would affect this imbalance in seminal plasma and to test whether modulation of the AA/DHA ratio correlates with male fertility. METHODS: The study included 44 males from infertile couples who were treated with lycopene for three months before scheduled IVF treatment. The control group was 13 fertile males who were also treated with lycopene for three months. AA and DHA levels were measured in seminal plasma before and after treatment. The outcome of IVF treatment after lycopene use in of males from infertile couples was recorded. RESULTS: The subjects were subdivided into 21 normozoospermic males from couples with idiopathic infertility and 23 males with semen abnormalities. Prior to the treatment with lycopene, the AA/DHA ratios in both subgroups of patients were significantly higher than in fertile controls and improved following treatment with lycopene. Improvement was more marked in the normospermic males. Seven spontaneous pregnancies (16%) occurred before the scheduled IVF treatment and 15 couples (42%) achieved pregnancy after IVF. CONCLUSIONS: Three months of treatment with lycopene led to a significant improvement in the AA/DHA ratio in seminal plasma of males from infertile couples and facilitated the spontaneous as well as IVF conception. PMID- 23446212 TI - Acute effects of right ventricular pacing on cardiac haemodynamics and transvalvular impedance. AB - AIMS: To assess the acute side-effects of right ventricular (RV) stimulation applied in apex and mid-septum, in order to establish the optimal lead location in clinical practice. METHODS: During pacemaker implantation, the ventricular lead was temporarily fixed in the apex and then moved to mid-septum. In both positions, surface and endocardial electrograms and transvalvular impedance (32 cases), left ventricular (LV) pressure (23), and transthoracic echocardiography (10) were acquired with intrinsic activity and VDD pacing. RESULTS: A larger increase in QRS duration was noticed with apical than septal pacing (65+/-25 vs. 45+/-29 ms; P<10(-4)). The proportion of cases where RV stimulation affected the transvalvular impedance waveform was higher with apical lead location (56% vs. 20%; P<0.02). VDD pacing at either site reduced the maximum dP/dt by 6% with respect to intrinsic AV conduction (IAVC; P<0.005). The maximum pressure drop taking place in 100 ms was reduced by 6 and 8%, respectively, with apical and septal pacing (P<0.01 vs. IAVC). Apical VDD decreased mitral annulus velocity in early diastole (E') from 7.5+/-1.4 to 5.9+/-0.9 cm/s (P<0.02) and prolonged the E wave deceleration time (DT) from 156+/-33 to 199+/-54 ms (P<0.02), while septal pacing induced non-significant modifications in E' and DT. CONCLUSION: Ventricular stimulation acutely impairs LV systolic and diastolic performance, independent of the pacing site. Septal lead location preserves RV contraction mechanics and reduces the electrical interventricular delay. PMID- 23446213 TI - HLA compatibility index: does it have a role in patients after heart transplantation? AB - AIMS: To determine the impact of HLA compatibility measured by the Compatibility Index, on survival, rate of rejections, malignancies and infections in patients after heart transplantation (HTx). METHODS: We carried out a retrospective analysis of 182 consecutive patients who underwent heart transplantation in our center from January 2001 to April 2010. According to degree of HLA-A, B and DR matching (Compatibility Index, CI) the patients were divided in two groups, Group A (n=83) with an IC 0-17 and group B (n=99) with an IC 18-26. There was no significant difference in demographic parameters between recipients and donors. RESULTS: We found no difference in rates of rejections or infections between Group A and Group B (AR: 22 (26.5%) vs. 34 (34.3%), P=0.2539; infections: 21 (25.3%) vs. 27 (27%) P=0.7637). The distribution of infections in terms of type (bacterial, viral, fungal, including Aspergillus) was similar in both groups. The incidence of malignant tumours was infrequent (3 (3.6%) vs. 4 (4.0%), P=0.8817). We found trend toward lower level of tacrolimus in Group A. Long term survival was similar in both groups. CONCLUSIONS: Based on the results of our single center trial, we found no impact of higher degree of HLA-A,-B, and -DR matching on survival, rejection episodes or infection. Further large studies are necessary to confirm our hypothesis that subjects with better HLA compatibility could require lower dose immunosuppression. PMID- 23446214 TI - Influencing factors on cardiac structure and function beyond glycemic control in patients with type 2 diabetes mellitus. AB - BACKGROUND: We hypothesized that clinical factors other than glycemic control may influence abnormal cardiac function in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the independent factors for abnormal cardiac function among clinical factors in T2DM. METHODS: We studied 148 asymptomatic patients with T2DM without overt heart disease. Echocardiographic findings were compared between diabetic patients and 68 age-matched healthy subjects. Early (E) and late (A) diastolic mitral flow velocity and early diastolic mitral annular velocity (e') were measured for assessing left ventricular (LV) diastolic function. We evaluated insulin resistance, non-esterified fatty acid, high sensitive CRP, estimated glomerular filtration rate, waist/hip ratio, abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and other clinical characteristics in addition to glycemic control. VAT and SAT were quantified by computed tomography. RESULTS: In T2DM, E/A and e' were significantly lower, and E/e', left atrial volume and LV mass were significantly greater than in control subjects. In multivariate liner regression analysis, VAT was an independent determinant of left atrial volume (beta =0.203, p=0.011), E/A (beta =-0.208, p=0.002), e' (beta =-0.354, p<0.001) and E/e' (beta=0.220, p=0.003). Age was also an independent determinant, whereas fasting plasma glucose and hemoglobin A1c levels were not. In addition to systolic blood pressure, waist hip ratio (beta=0.173, p=0.024) and VAT/SAT ratio (beta=0.162, p=0.049) were independent determinants of LV mass. CONCLUSION: Excessive visceral fat accompanied by adipocyte dysfunction may play a greater role than glycemic control in the development of diastolic dysfunction and LV hypertrophy in T2DM. PMID- 23446216 TI - Linkage between Anaplasma marginale outer membrane proteins enhances immunogenicity but is not required for protection from challenge. AB - The prevention of bacterial infections via immunization presents particular challenges. While outer membrane extracts are often protective, they are difficult and expensive to isolate and standardize and thus are often impractical for development and implementation in vaccination programs. In contrast, individual proteins, which are easily adapted for use in subunit vaccines, tend to be poorly protective. Consequently, identification of the specific characteristics of outer membrane-based immunogens, in terms of the antigen contents and contexts that are required for protective immunity, represents a major gap in the knowledge needed for bacterial vaccine development. Using as a model Anaplasma marginale, a persistent tick-borne bacterial pathogen of cattle, we tested two sets of immunogens to determine whether membrane context affected immunogenicity and the capacity to induce protection. The first immunogen was composed of a complex of outer membrane proteins linked by covalent bonds and known to be protective. The second immunogen was derived directly from the first one, but the proteins were individualized rather than linked. The antibody response induced by the linked immunogen was much greater than that induced by the unlinked immunogen. However, both immunogens induced protective immunity and an anamnestic response. These findings suggest that individual proteins or combinations of proteins can be successfully tested for the ability to induce protective immunity with less regard for overall membrane context. Once protective antigens are identified, immunogenicity could be enhanced by cross linking to allow a reduced immunogen dose or fewer booster vaccinations. PMID- 23446215 TI - The spectrum of acute bacterial meningitis in elderly patients. AB - BACKGROUND: We conducted a prospective, observational study in Barcelona to determine the epidemiology, clinical features, and outcome of elderly patients with acute bacterial meningitis (ABM) compared with younger adults. METHODS: During 1982-2010, all patients with ABM were prospectively evaluated. There were two groups: I (15-64 years) and II (>= 65 years). All patients underwent clinical examination on admission and at discharge following a predefined protocol. RESULTS: We evaluated 635 episodes of ABM. The incidence was 4.03/100,000 (Group I) and 7.40 /100,000 inhabitants/year (Group II) (RR = 1.84; 95%CI: 1.56-2.17, P < 0.0001). Elderly patients had co-morbid conditions more frequently (P < 0.0001) and more frequently lacked fever (P = 0.0625), neck stiffness (P < 0.0001) and skin rash (P < 0.0001), but had an altered level of consciousness more often (P < 0.0001). The interval admission-start of antibiotic therapy was longer for elderly patients (P < 0.0001). Meningococcal meningitis was less frequent in elderly patients (P < 0.0001), whereas listerial (P = 0.0196), gram-negative bacillary (P = 0.0065), and meningitis of unknown origin (P = 0.0076) were more frequent. Elderly patients had a higher number of neurologic (P = 0.0009) and extra-neurologic complications (P < 0.0001). The overall mortality ratio was higher in elderly patients (P < 0.0001). CONCLUSIONS: Elderly people are at higher risk of having ABM than younger adults. ABM in the elderly presents with co-morbid conditions, is clinically subtler, has a longer interval admission antibiotic therapy, and has non-meningococcal etiology. It is associated with an earlier and higher mortality rate than in younger patients. PMID- 23446217 TI - Role of gluten intake at the time of hepatitis B virus vaccination in the immune response of celiac patients. AB - Some reports have demonstrated an inadequate response to hepatitis B vaccination in patients affected by celiac disease. The aim of our study was to evaluate hepatitis B vaccination response in relation to gluten exposure status in patients with celiac disease. To measure the gluten exposure status at the time of vaccination, we considered three groups: group A (exposed to gluten), including patients vaccinated as 12-year-old adolescents (the celiac disease diagnosis was established after vaccination); group B (not exposed to gluten), including patients vaccinated as 12-year-old adolescents on a gluten-free diet at the time of vaccination; and group C (infants), including patients vaccinated at birth. The response of celiac patients to hepatitis B vaccination was compared to that of healthy subjects, i.e., those in the control group (group D). This study included 163 celiac patients (group A, 57 patients; group B, 46 patients; and group C, 60 patients) and 48 controls (group D). An inadequate response to hepatitis B immunization was present in 43.9% of patients in group A, 34.8% of patients in group B, 58.3% of patients in group C, and 8.3% of patients in group D (group A versus group D, P < 0.001; group B versus group D, P = 0.002; group C versus group D, P = 0.001) (no significant difference for group A versus group B and group A versus group C was evident). Our data suggest that gluten exposure does not influence the response to hepatitis B immunization and that the human leukocyte antigen probably plays the main immunological role in poor responses to hepatitis B-vaccinated celiac patients. PMID- 23446218 TI - Evaluation of a rapid device for serological diagnosis of Leishmania infantum infection in dogs as an alternative to immunofluorescence assay and Western blotting. AB - In this study, we compared a rapid immunochromatographic test (Speed Leish K; BVT Groupe Virbac, La Seyne sur Mer, France) with an indirect immunofluorescence assay (IFAT) and Western blotting (WB) for the detection of Leishmania infantum antibodies in dogs. A total of 250 serum samples were collected from 125 L. infantum-positive and 125 L. infantum-negative dogs. Among the positive samples, 81 were strongly positive at low IFAT dilutions, while 44 were low-reactivity sera (IFAT titers, 1:40 to 1:80). The sensitivity and specificity of the Speed Leish K were 96.3% and 100%, respectively, compared with those of the IFAT. When IFAT low-reactivity sera (titers, 1:40 or 1:80) were tested with the Speed Leish K, using WB results as a reference, the sensitivities were 93.75% for sera with a 1:80 titer and 73.33% for sera with a 1:40 titer, and the specificity was 100%. The Speed Leish K is easy to use and performs well, so it can be considered a quick and reliable tool for the diagnosis of L. infantum infection in dogs. PMID- 23446219 TI - Evaluation of the safety and immunogenicity of a candidate tuberculosis vaccine, MVA85A, delivered by aerosol to the lungs of macaques. AB - Tuberculosis (TB) is a reemerging disease. The only available vaccine, Mycobacterium bovis BCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-of-concept data for further evaluation of this route of immunization for use in human clinical trials. PMID- 23446220 TI - Lsr2 of Mycobacterium leprae and its synthetic peptides elicit restitution of T cell responses in erythema nodosum leprosum and reversal reactions in patients with lepromatous leprosy. AB - The Lsr2 protein of Mycobacterium leprae and its synthetic peptides have been shown to elicit lymphoproliferation and gamma interferon (IFN-gamma) release by peripheral blood mononuclear cells (PBMCs) of patients with lepromatous leprosy (M. Chaduvula, A. Murtaza, N. Misra, N. P. Narayan, V. Ramesh, H. K. Prasad, R. Rani, R. K. Chinnadurai, I. Nath, Infect. Immun. 80:742-752, 2012). PBMCs from 16 patients with lepromatous leprosy who were undergoing erythema nodosum leprosum (ENL) (type 2) and 5 patients with reversal reactions (RR) (type 1) were stimulated with M. leprae, recombinant Lsr2, and six end-to-end synthetic peptides (A through F) spanning the Lsr2 sequence. During the reaction all patients with ENL showed lymphoproliferation (stimulation index, >2) in response to peptides A and F, with other peptides eliciting responses in 75 to 88% of the subjects. In PBMC cultures, both lymphoproliferation and IFN-gamma release for peptide E were significantly higher than for peptides B and C and recombinant Lsr2 (P < 0.05, Wilcoxon signed-rank test). Five patients with RR also showed enhanced lymphoproliferative responses and IFN-gamma release in response to Lsr2, M. leprae, and peptide E. Six months postreaction, 14 patients with ENL continued to exhibit responses to Lsr2 and its peptides, with the highest responses being elicited by peptide E. However, 5 subjects showed no lymphoproliferation and had reduced IFN-gamma release in response to Lsr2 peptides (P < 0.001, Kruskal-Wallis test) but responded to recombinant Lsr2. Six patients with ENL had HLA-A*68.01, which the STFPEITHI program showed to have high peptide-binding scores of 20 to 21 for peptides E, B, and C. Eleven patients had HLA-DRB1*1501 and HLA-DRB1*1502, which had high binding scores for peptides C and E. Thus, Lsr2 and its peptides are recognized in leprosy reactions during and well after the subsidence of clinical signs. PMID- 23446221 TI - Volatiles from oral anaerobes confounding breath biomarker discovery. AB - The levels of compounds in exhaled mouth air do not necessarily reflect levels in the systemic circulation as bacteria can bio-transform substrates to produce compounds within the mouth. This should be of concern to researchers measuring breath volatiles with the aim of diagnosing systemic or metabolic conditions as very little is known about the origin of many compounds detected on the breath. This pilot study investigated the production of volatile compounds by bacterial communities present within the mouth. Solid-phase micro-extraction was used to extract volatiles from the headspace gas of two Gram-positive and two Gram negative bacterial cultures known to be present within the mouth and from tongue biofilm microflora. Analyses were undertaken using gas chromatography mass spectrometry. Between 64 and 82 volatile compounds were detected from sampling the headspace gas above each of the cultures. Gram-negative anaerobes were found to produce more volatile sulfur compounds (VSCs) and amines. Solobacterium moorei, a Gram-positive species was however found to produce higher levels of acids, hydrocarbons, alcohols and aldehydes than the other species studied. Tongue-scrape biofilm systems at lower pH gave more hydrocarbons, ketones and fatty acids whilst at higher pH more alcohols, aldehydes, VSCs and amines were detected in the headspace. The results show that a number of compounds detected in mouth breath are produced by anaerobic bacteria in tongue biofilms. Thus, the contribution of volatiles from oral anaerobes cannot be ignored and more research is required to identify the major source of breath compounds as this will help determine their clinical significance as indicators of systemic disease or metabolic disorders in the body. PMID- 23446225 TI - Cochlear implantation with hearing preservation yields significant benefit for speech recognition in complex listening environments. AB - OBJECTIVE: The aim of this study was to assess the benefit of having preserved acoustic hearing in the implanted ear for speech recognition in complex listening environments. DESIGN: The present study included a within-subjects, repeated measures design including 21 English-speaking and 17 Polish-speaking cochlear implant (CI) recipients with preserved acoustic hearing in the implanted ear. The patients were implanted with electrodes that varied in insertion depth from 10 to 31 mm. Mean preoperative low-frequency thresholds (average of 125, 250, and 500 Hz) in the implanted ear were 39.3 and 23.4 dB HL for the English- and Polish speaking participants, respectively. In one condition, speech perception was assessed in an eight-loudspeaker environment in which the speech signals were presented from one loudspeaker and restaurant noise was presented from all loudspeakers. In another condition, the signals were presented in a simulation of a reverberant environment with a reverberation time of 0.6 sec. The response measures included speech reception thresholds (SRTs) and percent correct sentence understanding for two test conditions: CI plus low-frequency hearing in the contralateral ear (bimodal condition) and CI plus low-frequency hearing in both ears (best-aided condition). A subset of six English-speaking listeners were also assessed on measures of interaural time difference thresholds for a 250-Hz signal. RESULTS: Small, but significant, improvements in performance (1.7-2.1 dB and 6-10 percentage points) were found for the best-aided condition versus the bimodal condition. Postoperative thresholds in the implanted ear were correlated with the degree of electric and acoustic stimulation (EAS) benefit for speech recognition in diffuse noise. There was no reliable relationship among measures of audiometric threshold in the implanted ear nor elevation in threshold after surgery and improvement in speech understanding in reverberation. There was a significant correlation between interaural time difference threshold at 250 Hz and EAS-related benefit for the adaptive speech reception threshold. CONCLUSIONS: The findings of this study suggest that (1) preserved low-frequency hearing improves speech understanding for CI recipients, (2) testing in complex listening environments, in which binaural timing cues differ for signal and noise, may best demonstrate the value of having two ears with low-frequency acoustic hearing, and (3) preservation of binaural timing cues, although poorer than observed for individuals with normal hearing, is possible after unilateral cochlear implantation with hearing preservation and is associated with EAS benefit. The results of this study demonstrate significant communicative benefit for hearing preservation in the implanted ear and provide support for the expansion of CI criteria to include individuals with low-frequency thresholds in even the normal to near-normal range. PMID- 23446226 TI - The effects of limited bandwidth and noise on verbal processing time and word recall in normal-hearing children. AB - OBJECTIVES: Understanding speech in acoustically degraded environments can place significant cognitive demands on school-age children who are developing the cognitive and linguistic skills needed to support this process. Previous studies suggest the speech understanding, word learning, and academic performance can be negatively impacted by background noise, but the effect of limited audibility on cognitive processes in children has not been directly studied. The aim of the present study was to evaluate the impact of limited audibility on speech understanding and working memory tasks in school-age children with normal hearing. DESIGN: Seventeen children with normal hearing between 6 and 12 years of age participated in the present study. Repetition of nonword consonant-vowel consonant stimuli was measured under conditions with combinations of two different signal to noise ratios (SNRs; 3 and 9 dB) and two low-pass filter settings (3.2 and 5.6 kHz). Verbal processing time was calculated based on the time from the onset of the stimulus to the onset of the child's response. Monosyllabic word repetition and recall were also measured in conditions with a full bandwidth and 5.6 kHz low-pass cutoff. RESULTS: Nonword repetition scores decreased as audibility decreased. Verbal processing time increased as audibility decreased, consistent with predictions based on increased listening effort. Although monosyllabic word repetition did not vary between the full bandwidth and 5.6 kHz low-pass filter condition, recall was significantly poorer in the condition with limited bandwidth (low pass at 5.6 kHz). Age and expressive language scores predicted performance on word recall tasks, but did not predict nonword repetition accuracy or verbal processing time. CONCLUSIONS: Decreased audibility was associated with reduced accuracy for nonword repetition and increased verbal processing time in children with normal hearing. Deficits in free recall were observed even under conditions where word repetition was not affected. The negative effects of reduced audibility may occur even under conditions where speech repetition is not impacted. Limited stimulus audibility may result in greater cognitive effort for verbal rehearsal in working memory and may limit the availability of cognitive resources to allocate to working memory and other processes. PMID- 23446227 TI - Improving the diagnosis and management of neuroendocrine tumors: utilizing new advances in biomarker and molecular imaging science. AB - Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Oberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions. PMID- 23446228 TI - Unilateral favre-racouchot disease: evidence for the etiological role of chronic solar damage. AB - Favre-Racouchot disease commonly presents as comedones, cysts and elastosis in the periocular region of older men. Its etiology has been linked to several exogenous factors. Here we present 2 patients with strictly unilateral manifestation of the disease and a corresponding history of predominantly one sided chronic occupational sun exposure and smoking, making the case for the causative role of these two factors. PMID- 23446229 TI - Pallidal deep brain stimulation for a case of hemidystonia secondary to a striatal stroke. AB - BACKGROUND: The efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for medically refractory idiopathic generalized dystonia has been demonstrated repeatedly. More variable outcomes have been reported in the treatment of secondary dystonia with GPi DBS. OBJECTIVES: The present study seeks to examine the pallidal physiology and clinical outcome of GPi DBS in a case of secondary dystonia. METHODS: We report on a 43-year-old man who at the age of 9 suffered a left basal ganglia stroke and at the age of 21 developed severe disabling hemidystonia. Following unsuccessful medical management for many years and an axial involvement of the dystonia, he underwent bilateral GPi DBS with dual microelectrode mapping of cell firing and evoked field potentials (fEP). RESULTS: On the intact side we found regular firing of pallidal neurons and normal fEP indicative of functioning striatopallidal pathways. The affected side was found to include a higher frequency of bursting pallidal neurons. fEP could not be evoked on the affected side, suggesting their origin to be striatal GABAergic afferents. CONCLUSIONS: The patient had marked benefit from bilateral GPi DBS, which suggests that the therapeutic effects of DBS were mediated by the intact pathways in this case of hemidystonia. PMID- 23446230 TI - CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice. AB - Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE deficient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic inflammation and macrophage infiltration. In cultured vascular smooth muscle cells (VSMCs), rAAV-mediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced inflammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferator activated receptor (PPAR)gamma activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPARgamma activation and anti-inflammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA. PMID- 23446233 TI - [Letter about editorial]. PMID- 23446232 TI - [Ethics and transparency please!]. PMID- 23446231 TI - LXR activation by GW3965 alters fat tissue distribution and adipose tissue inflammation in ob/ob female mice. AB - To investigate the role of liver X receptor (LXR) in adipose tissue metabolism during obesity, ob/ob mice were treated for 5 weeks with the synthetic LXR agonist GW3965. MRI analysis revealed that pharmacological activation of LXR modified fat distribution by decreasing visceral (VS) fat and inversely increasing subcutaneous (SC) fat storage without affecting whole body fat content. This was concordant with opposite regulation by GW3965 of the lipolytic markers hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in the two fat depots; moreover, the expression of genes involved in lipogenesis was significantly induced in SC fat. Lipidomic analysis suggested that changes in lipid composition in response to GW3965 also varied between VS and SC fat. In both depots, the observed alteration in lipid composition indicated an overall change toward less lipotoxic lipids. Flow cytometry analysis showed decreased immune cell infiltration in adipose tissue of ob/ob mice in response to GW3965 treatment, which in VS fat mainly affected the macrophage population and in SC fat the lymphocyte population. In line with this, the expression and secretion of proinflammatory markers was decreased in both fat deposits with GW3965 treatment. PMID- 23446234 TI - [Publish your case report]. PMID- 23446236 TI - [Pecutaneous mitral valve repair]. AB - Over four million Europeans and a similar number Americans suffer from significant mitral regurgitation (MR). Approximately 250,000 new patients are diagnosed with the disease annually. The disorder generally evolves insidiously over many years because the heart compensates for the regurgitant volume by left atrial enlargement, left ventricular (LV) volume overload, and progressive (LV) dilatation. The most common causes of MR include ischemic heart disease, non ischemic heart disease, and valve degeneration. Mitral valve surgery has long been the only treatment available with proven efficacy for MR. It alleviates clinical symptoms and prevents ventricular dilatation and heart failure, or attenuates further progression of this process. Surgical valve repair significantly improves clinical outcomes compared with valve replacement, reducing mortality by approximately 70%. However, patients with heart failure have both higher acute risk and significant rates of late MR recurrence after surgical repair of ischemic MR. Recently, a number of percutaneous modalities of mitral valve repair have been developed. Most of these techniques are still at early stages of clinical evaluation. The MitraClip System consists of a percutaneous edge-to-edge attachemnt system that mimics the surgical procedure. This technique creates a bridge between the anterior and posterior leaflet by means of a clip deployed through trans-septal catheterization. The growing experience show that percutaneous edge-to-edge repair using the MitraClip system is feasible, safe and, in overall, effective, with very promising clinical results when performed in carefully selected patients, The new technique does not represent a general alternative to conventional surgical valve repair, which remains the gold standard particularly in the patients with degenerative MR. However, it offers a valid option in patients unsuitable for surgery and those with functional MR secondary to advanced heart failure, where the surgical approach still remains empiric. PMID- 23446237 TI - [Sexually transmitted infections: update 2013]. AB - Although there have been significant advances in diagnosis, treatment, and education, the occurence of STI continues to increase worldwide as well as in Switzerland. The most common STI include human papillomavirus (HPV), chlamydia, herpes, simplex virus types 1 and 2, gonorrhea, syphilis, hepatitis B and trichomoniasis. Diagnosis and treatment continue to be major public health challenges because of the asymptomatic nature of many of these infections. Recent studies showed favorable epidemiologic trends for HPV infection in vaccinated females as well as in some males. On the other hand we are confronted with rising incidences e.g. in urethritis with various causative agents and in syphilis cases. Alarmingly during the last 3 years gonococci have become less susceptible to our remaining antibiotics, necessitating strict adherence to updated treatment guidelines. Other trends in STIs and their consequences are discussed. PMID- 23446238 TI - [Acute kidney injury-emergency or coincidence?]. AB - An unifying definition of acute kidney injury as a precursor of acute renal failure has been published in march last year. Its remarkable mortality makes an early diagnosis an important goal. New biomarkers will be an important step to reach this goal in the near future. Depending on the underlying cause, therapeutic actions should be realized as soon as possible to diminish in hospital mortality and chronic nephropathy. Intensive care units often are the first to test for new active substances. PMID- 23446239 TI - [Pediatric supracondylar fractures of the humerus]. AB - Supracondylar fractures are on the of the most common injuries in paediatric patients. Therapeutic consequences depend on the one hand on the degree of the osseous displacement according to the Gartland classification. On the other hand, the diagnosis of concomitant neuro-vascular injuries is crucial to prevent long term impairment. Never the less, clinical diagnosis can be challenging. In-depth knowledge of pediatric supracondylar humerus fractures is a prerequisite to achieve a functionally and cosmetically satisfactory long-term outcome. PMID- 23446240 TI - [Cholesterol inhibitor and memantine in symptomatic dementia therapy]. PMID- 23446241 TI - [Positive effect of amoxicillin/clavulanic acid for exacerbations of mild to moderate copd]. PMID- 23446242 TI - [Modest effect of mammography screenings]. PMID- 23446244 TI - [CME ECG 40. Vertigo with ST elevation in V2. Brugada syndrome]. PMID- 23446247 TI - Discriminant ratio and biometrical equivalence of measured vs. calculated apolipoprotein B100 in patients with T2DM. AB - BACKGROUND: Apolipoprotein B100 (ApoB100) determination is superior to low density lipoprotein cholesterol (LDL-C) to establish cardiovascular (CV) risk, and does not require prior fasting. ApoB100 is rarely measured alongside standard lipids, which precludes comprehensive assessment of dyslipidemia. OBJECTIVES: To evaluate two simple algorithms for apoB100 as regards their performance, equivalence and discrimination with reference apoB100 laboratory measurement. METHODS: Two apoB100-predicting equations were compared in 87 type 2 diabetes mellitus (T2DM) patients using the Discriminant ratio (DR). Equation 1: apoB100 = 0.65*non-high-density lipoprotein cholesterol + 6.3; and Equation 2: apoB100 = 33.12 + 0.675*LDL-C + 11.95*ln[triglycerides]. The underlying between-subject standard deviation (SDU) was defined as SDU = ? (SD2B - SD2W/2); the within subject variance (Vw) was calculated for m (2) repeat tests as (Vw) = Sigma(xj xi)2/(m-1)), the within-subject SD (SDw) being its square root; the DR being the ratio SDU/SDW. RESULTS: All SDu, SDw and DR's values were nearly similar, and the observed differences in discriminatory power between all three determinations, i.e. measured and calculated apoB100 levels, did not reach statistical significance. Measured Pearson's product-moment correlation coefficients between all apoB100 determinations were very high, respectively at 0.94 (measured vs. equation 1); 0.92 (measured vs. equation 2); and 0.97 (equation 1 vs. equation 2), each measurement reaching unity after adjustment for attenuation. CONCLUSION: Both apoB100 algorithms showed biometrical equivalence, and were as effective in estimating apoB100 from routine lipids. Their use should contribute to better characterize residual cardiometabolic risk linked to the number of atherogenic particles, when direct apoB100 determination is not available. PMID- 23446250 TI - Therapy of relapsing minimal-change disease in adults: a new approach? AB - Multiple-relapsing minimal-change disease (MCD) often requires exposure to potentially toxic agents in an attempt to achieve a lasting remission of nephrotic syndrome. Munyentwali and co-workers describe an experience using rituximab in adults with multiple-relapsing MCD that supports both efficacy and safety of this agent. However, the optimal dosing regimen and mechanism of action remain unclear. Thus, randomized controlled trials are warranted in both adults and children to better define the role of rituximab in multiple-relapsing MCD. PMID- 23446251 TI - Intensive glycemic control in type 2 diabetics at high cardiovascular risk: do the benefits justify the risks? AB - Perkovic et al. use novel data from the ADVANCE study to report on the potential renal benefits of standard glycemic control, compared with intensive glycemic control (mean hemoglobin A1c 7.3 and 6.5%, respectively). Intensive glycemic control reduced the risk of new-onset microalbuminuria, new-onset macroalbuminuria, and progression of albuminuria. The risk of end-stage renal disease was also reduced in patients treated with intensive glycemic control, although the number of events was small. PMID- 23446252 TI - IgG4: a tantalizing link between causes of membranous glomerulonephritis and systemic disease. AB - Alexander et al. give a detailed description of IgG4-related membranous glomerulonephritis (MGN). Their data delineate for the first time in IgG4-related disease (IgG4-RD) a second pattern of tissue injury occurring within the same organ. The paper highlights that MGN can occur alone or simultaneously with IgG4 related tubulointerstitial nephritis. Thus, it extends our understanding of IgG4 RD and illuminates potential pathways for new investigations into its pathophysiology. PMID- 23446253 TI - What can tubular progenitor cultures teach us about kidney regeneration? AB - Cultures of stem or progenitor cells have made critical contributions to the comprehension of tissue regeneration. In the kidney, primary cultures of human tubular progenitors became available only recently and allow dissection of the functional properties of tubular progenitors vs. differentiated tubular epithelia. Toll-like receptor-mediated activation now appears as a previously unknown mechanism of progenitor-mediated tubular regeneration, implying that proinflammatory factors activate regenerative processes in the kidney. PMID- 23446254 TI - Non-light-chain immunoglobulin amyloidosis: time to expand or refine the spectrum to include light+heavy chain amyloidosis? AB - Among the various systemic amyloidoses, deposits derived from the immunoglobulin light chain (AL) account for 85% of cases. In this issue, Nasr et al. report 16 cases of renal heavy and light+heavy chain amyloidosis and compare them with renal light chain amyloidosis. While additional studies are needed to shed light on the heavy and light+heavy chain amyloidoses, several observations by the authors suggest important practical implications, including differences in clinical picture, prognosis and pathologic diagnosis. PMID- 23446255 TI - Choices in kidney transplantation in type 1 diabetes: are there skeletal benefits of the endocrine pancreas? AB - Previously, recipients of a simultaneous pancreas-kidney transplant versus a kidney transplant alone were thought to have higher fracture risk. Using a large US registry, Nikkel et al. observed lower rates of fracture hospitalization among patients with type 1 diabetes after simultaneous pancreas-kidney compared with kidney transplantation alone, particularly among men. It is not known whether the apparent benefit of simultaneous pancreas-kidney transplantation is due to improved bone strength or fewer falls, but these findings may influence transplant decision making. PMID- 23446256 TI - Non-apoptotic effects of antiapoptotic agent zVAD-fmk in renal injury. PMID- 23446257 TI - Fistula versus catheter outcomes: the importance of surgical training. PMID- 23446258 TI - The authors reply. PMID- 23446259 TI - Progression of polycystic kidney disease in a kidney transplant. PMID- 23446260 TI - The Case | Visual loss and bilateral dilated nonreactive pupils in a uremic patient. PMID- 23446261 TI - The neonatal intubation causes defects in primary teeth of premature infants. AB - AIM: This study aimed to evaluate the relationship between intubation during the neonatal period and enamel defects in primary teeth of preterm infants. It was an observational, prospective, analytical and sampling of convenience. We selected 157 children who had average birth weight of 1656.3+/-627.8 g, gestational age of 31.7+/-2.7 weeks and the examination of chronological age 2.2+/-0.6 years old. METHODS: Clinical examination of the oral cavity showed that the frequency of enamel defects was higher (86.3%) among children intubated when compared to non intubated children (13.7%). The enamel defects was found to be inversely proportional to gestational age. The intubation time was related to the probability of occurrence of DDE (P<0.001), in other words, the greater the number of days intubated, the greater the chance of DDE. In children intubated, hypoplasia mainly affected the upper teeth on the left side of the mouth. CONCLUSION: Tracheal intubation in the neonatal period is the main cause of enamel defects in primary teeth of children born preterm. The longer the duration of intubation, the greater the chance of developing dental enamel defect. The area of action during movement of the laryngoscope toggle corresponds to the region most affected by tooth enamel hypoplasia in children intubated, upper right central incisor, lateral incisor and upper left. PMID- 23446262 TI - [Psychiatry and its objects]. PMID- 23446263 TI - [Glutamatergic antidepressants? The intriguing antidepressant properties of ketamine]. PMID- 23446264 TI - [The Spanish version of two olfactory scales: reliability and validity]. AB - BACKGROUND: It is well known that smells have marked effects on behavior, cognition and on emotional responses. Therefore, it is very useful to have at our disposal instruments that allow us the measure these effects. OBJECTIVE: The aim of this study was to translate and validate the Spanish version of the Affective Impact of Odors scale (AIO) and the Odor Awareness Scale (OAS). MATERIAL AND METHODS: This study was carried out on a sample of 100 participants from the general population. The internal consistency was measured by Cronbach's alpha and the test-retest reliability, by the intraclass correlation coefficient (ICC). Convergent validity was assessed by means of Pearson correlation coefficient between the scales and three olfactory measures used as external criteria. As an additional measure of convergent validity, the relationship between AIO and OAS was also assessed. An exploratory factor analysis was carried out to determine the internal structure of the scales. RESULTS: The Spanish version of AIO and OAS showed a good internal consistency level with Cronbach's alpha of 0.727 and 0.906, respectively. ICC values pointed out a high test-retest reliability (AIO=0.780; OAS=0.895). Convergent validity of these measures was overall satisfactory. A one-factor solution was found for every scale. CONCLUSIONS: The Spanish version of OAS and AIO scales meets psychometric criteria for establishing satisfactory reliability and validity. Thus, they could be considered as suitable research tools for the assessment of the olfactory function in Spanish general population. PMID- 23446265 TI - [Impulsivity, sensation seeking and aggressiveness in patients with bipolar I and II disorder]. AB - OBJECTIVE: Although impulsivity may seem to be strongly linked to bipolar disorder, few studies have directly measured this phenomenon. To determine its implications for the prognosis of this illness, we studied the relationship between impulsivity and other aspects that are probably related, such as sensation seeking and aggressiveness, and different clinical variables of bipolar disorder. METHOD: Sixty-nine (type I, n=42; type II, n=27) outpatients from a unit specifically for bipolar patients in remission completed the Barratt Impulsiveness Scale (BIS), the Sensation Seeking Scale (SSS), the Buss-Durkee Hostility Inventory (BDHI) and the Bipolar Eating Disorder Scale (BEDS). Sociodemographic and clinical data were obtained. RESULTS: Type II bipolar patients scored significantly higher on the BIS and the BDHI physical aggression subscale. Patients with predominant depressive polarity also obtained significantly higher global scores on the BDHI. No differences were found relating to prior suicide attempts or psychiatric admissions. Smoking patients scored significantly higher on the BIS non-planning subscale and the SSS disinhibition subscale. LIMITATIONS: As patients with substance use disorder (SUD) were excluded, the sample of this study may represents a subgroup of patients with bipolar disorder with probably low levels of impulsivity. CONCLUSIONS: Impulsivity and aggressiveness are relevant aspects of bipolar disorders that could significantly increase comorbidity, especially in type II bipolar patients. Adequate diagnosis and treatment are, therefore, important factors in improving the clinical course of this illness. PMID- 23446266 TI - [Psychopharmacological treatment of bipolar disorder in Latin American]. AB - OBJECTIVE: This study assessed the treatment preferences among Latin-American psychiatrists for their bipolar disorder patients and if these preferences reflect the current guidelines. METHODS: We designed a survey comprised of fourteen questions. All the questions were aimed at the treatment of bipolar I patients only. We distributed the survey by hand or e-mail to psychiatrists in eight different countries: Argentina, Brasil, Colombia, Costa Rica, Ecuador, Mexico, Peru and Venezuela. Between May 2008 and June 2009, we were able to gather 1143 surveys. RESULTS: As the initial choice of treatment for a bipolar patient who debuts with mania, 61.3% choose a combination of an atypical antipsychotic and a mood stabilizer. Lithium Carbonate (50%) was the first choice for a mood stabilizer in a manic episode. Olanzapine (55.4%) was the initial antipsychotic of choice for the treatment of acute mania. For the treatment of acute bipolar depression, 27% choose Lamotrigineas their first choice. Most of the psychiatrists (74.8%) prescribe antidepressants for the treatment of bipolar depression. For maintenance treatment of bipolar depression most psychiatrists first choice would be Lamotrigine (50.3%). Most of the psychiatrists (89.1%) prescribed two or more psychotropic drugs for the maintenance treatment of their bipolar patients. CONCLUSIONS: There were some similarities with the studies previously done in the US. It seems that for the most part the Latin-American psychiatrists don't strictly follow the literature guidelines that are published, but rather adapt the treatment to the specific case. More longitudinal studies of prescribing patterns in bipolar disorder are needed to corroborate these findings. PMID- 23446267 TI - [Report of the 3(rd) European Brain Policy Forum]. PMID- 23446268 TI - [Systematic review of the Genomewide Association Studies (GWAS) in schizophrenia]. AB - INTRODUCTION: Heritability in schizophrenia can reach up to 80% and the risk in families is 5-10 times higher than in the general population. The large contribution of genetics in this disorder has led to a growing interest in its study. OBJECTIVES: To review the findings of genetic studies known as Genomewide Association Studies (GWAS) on schizophrenia. METHOD: Systematic search using Pubmed with the key words GWAS and (psychosis) or (schizophrenia). The following web pages have been reviewed: http://www.szgene.org/largescale.asp and www.genome.gov/gwastudies/. RESULTS: The GWAS have focused on causal biological aspects, such as the histocompatibility complex, glutamate metabolism, apoptosis and inflammatory processes, and the immune system (TNF-beta, TNFR1). Also focused in the search were the genes that modulate the appearance of secondary metabolic and cardiac effects and secondary effects in subjects with schizophrenia and on anti-psychotic treatment. In neurorecognition, over-expression of the MET proto oncogene (MET) has been associated with a low susceptibility for schizophrenia and a better cognitive performance, as well as a lower susceptibility for the incidence of cancer. Mention is also made of the different genes that mediate in cognitive functioning depending on the anti-psychotic treatment received. CONCLUSIONS: The main interests of the GWAS during the last few years have been the neurobiological pathways involved in schizophrenia. The discoveries arising from these studies have been limited. This has led to an innovative approach on the aetiological study of the disorder by studying gene-environment interactions. PMID- 23446269 TI - Survey of human papillomavirus types and their vertical transmission in pregnant women. AB - BACKGROUND: The prevalence, genotypes, and vertical transmission characteristics of human papillomavirus (HPV) among pregnant women from Nanjing, China was investigated. METHODS: Cervical cells were collected from healthy pregnant women (n = 3139; stage of gestation, 24.6 +/- 2.1 weeks) for cytological evaluation and determination of HPV infection status. Exfoliated oral and genital cells were collected from neonates (<1-day-old, n = 233) whose mothers were positive for HPV DNA. We used HPV Gene Chip technology with 23 HPV genotype probes to conduct our analysis. RESULTS: Overall prevalence of HPV DNA among pregnant women was 13.4% (422/3139). The most frequently detected HPV genotypes were HPV-16 (29.6%, 125/422), -18 (14.7%, 62/422), and -58 (14.2%, 60/422). The rate of concordance for HPV DNA in maternal-neonatal pairs was 23.6% (55/233), with HPV type-specific concordance occurring in 26 cases. A higher prevalence of HPV DNA was apparent in female neonates compared with males (17.7 vs. 11.6%). CONCLUSIONS: The prevalence of cervical HPV DNA in pregnant women from Nanjing was low, with vertical transmission rates slightly higher. From our findings, we concluded that there was efficient vertical transmission of three HPV genotypes, with HPV-16 the most prevalent type in pregnant women and newborn babies. PMID- 23446273 TI - Monitoring breath during oral glucose tolerance tests. AB - The evolution of breath composition during oral glucose tolerance tests (OGTTs) was analysed by thermal desorption/gas chromatography/mass spectrometry in 16 subjects and correlated to blood glucose levels. The glucose tolerance tests classified five of the subjects as diabetics, eight as affected by impaired glucose tolerance and three as normoglycaemic. Acetone levels were generally higher in diabetics (average concentration values: diabetics, 300 +/- 40 ppbv; impaired glucose tolerance, 350 +/- 30 ppbv; normoglycaemic, 230 +/- 20 ppbv) but the large inter-individual variability did not allow us to identify the three groups by this parameter alone. The exhalation of 3-hydroxy-butan-2-one and butane-2,3-dione, likely due to the metabolization of glucose by bacteria in the mouth, was also observed. Future work will involve the extension of the analyses to other volatile compounds by attempting to improve the level of discrimination between the various classes of subjects. PMID- 23446275 TI - Switching from single-stranded to double-stranded DNA limits the unwinding processivity of ring-shaped T7 DNA helicase. AB - Phage T7 helicase unwinds double-stranded DNA (dsDNA) by encircling one strand while excluding the complementary strand from its central channel. When T7 helicase translocates on single-stranded DNA (ssDNA), it has kilobase processivity; yet, it is unable to processively unwind linear dsDNA, even 60 base pairs long. Particularly, the GC-rich dsDNAs are unwound with lower amplitudes under single-turnover conditions. Here, we provide evidence that T7 helicase switches from ssDNA to dsDNA during DNA unwinding. The switching propensity is higher when dsDNA is GC-rich or when the 3'-overhang of forked DNA is <15 bases. Once helicase encircles dsDNA, it travels along dsDNA and dissociates from the end of linear DNA without strand separation, which explains the low unwinding amplitude of these substrates. Trapping the displaced strand with ssDNA binding protein or changing its composition to morpholino oligomer that does not interact with helicase increases the unwinding amplitude. We conclude that the displaced strand must be continuously excluded and kept away from the central channel for processive DNA unwinding. The finding that T7 helicase can switch from ssDNA to dsDNA binding mode during unwinding provides new insights into ways of limiting DNA unwinding and triggering fork regression when stalled forks need to be restarted. PMID- 23446274 TI - Translocation of Saccharomyces cerevisiae Pif1 helicase monomers on single stranded DNA. AB - In Saccharomyces cerevisiae Pif1 participates in a wide variety of DNA metabolic pathways both in the nucleus and in mitochondria. The ability of Pif1 to hydrolyse ATP and catalyse unwinding of duplex nucleic acid is proposed to be at the core of its functions. We recently showed that upon binding to DNA Pif1 dimerizes and we proposed that a dimer of Pif1 might be the species poised to catalysed DNA unwinding. In this work we show that monomers of Pif1 are able to translocate on single-stranded DNA with 5' to 3' directionality. We provide evidence that the translocation activity of Pif1 could be used in activities other than unwinding, possibly to displace proteins from ssDNA. Moreover, we show that monomers of Pif1 retain some unwinding activity although a dimer is clearly a better helicase, suggesting that regulation of the oligomeric state of Pif1 could play a role in its functioning as a helicase or a translocase. Finally, although we show that Pif1 can translocate on ssDNA, the translocation profiles suggest the presence on ssDNA of two populations of Pif1, both able to translocate with 5' to 3' directionality. PMID- 23446277 TI - Reply to: Anaesthetic management in patients with Duchenne muscular dystrophy. PMID- 23446278 TI - RNA-templated DNA origami structures. AB - Using the RNA transcript as a template, RNA-templated DNA origami structures were constructed by annealing with designed DNA staple strands. RNA-templated DNA origami structures were folded to form seven-helix bundled rectangular structures and six-helix bundled tubular structures. The chemically modified RNA-DNA hybrid origami structures were prepared by using RNA templates containing modified uracils. PMID- 23446276 TI - Single-molecule chemical denaturation of riboswitches. AB - To date, single-molecule RNA science has been developed almost exclusively around the effect of metal ions as folding promoters and stabilizers of the RNA structure. Here, we introduce a novel strategy that combines single-molecule Forster resonance energy transfer (FRET) and chemical denaturation to observe and manipulate RNA dynamics. We demonstrate that the competing interplay between metal ions and denaturant agents provides a platform to extract information that otherwise will remain hidden with current methods. Using the adenine-sensing riboswitch aptamer as a model, we provide strong evidence for a rate-limiting folding step of the aptamer domain being modulated through ligand binding, a feature that is important for regulation of the controlled gene. In the absence of ligand, the rate-determining step is dominated by the formation of long-range key tertiary contacts between peripheral stem-loop elements. In contrast, when the adenine ligand interacts with partially folded messenger RNAs, the aptamer requires specifically bound Mg(2+) ions, as those observed in the crystal structure, to progress further towards the native form. Moreover, despite that the ligand-free and ligand-bound states are indistinguishable by FRET, their different stability against urea-induced denaturation allowed us to discriminate them, even when they coexist within a single FRET trajectory; a feature not accessible by existing methods. PMID- 23446279 TI - [Renal adaptation after experimental nephrectomy in animals: a review]. AB - OBJECTIVE AND DATA-GATHERING: We reviewed experimental litterature about kidney adaptation after nephrectomy in mammals. KNOWLEDGE SYNTHESIS: Renal mass increases after nephrectomy thanks to two components, one is immediately due to the rise of glomulary capillary vascular flow, other is linked to cellular modifications with hyperplasia stage which precedes hypertrophy stage. After nephrectomy, young animals show higher renal adaptability than adults. Similarly, the sex influences the remnant kidney parenchyma volume, the increase of glomerular filtration, the hyperplasia's intensity or length, the hypertrophy's metabolic pathways and the glomerular and tubular cells' injury. There is no question that renal compensatory is regulated by hormones such as IGF-1, TGFbeta 1 and Ang-II. PMID- 23446280 TI - [Prognostic influence of prostate gland invasion by bladder tumour and/or prostate cancer in cystoprostatectomy specimen: a review]. AB - INTRODUCTION: Cystoprostatectomy (CPT) is the gold standard surgical treatment for muscle invasive bladder cancer (MIBC). In certain cases, MIBC can invade the prostate gland and/or a prostate cancer (PCa) can be discovered fortuitously on the pathologic specimen. The aim of the current study was to report the prognostic influence of PCa in patients who underwent a CPT for MIBC. MATERIALS AND METHODS: A systematic review of the scientific literature was achieved in the Pubmed database, using the following keywords: prostatic neoplasm; urinary bladder neoplasm; cystectomy; surgery; recurrence; prognosis; survival. Clinical cases and series of less than five cases were deliberately excluded herein. RESULTS: Overall, ten studies published between 2004 and 2011 and involving 2196 patients were selected. Only retrospective studies of low level of evidence (NP 4) were available. The incidence of neoplastic invasion of the prostate gland by MIBC ranged from 25 to 48%. Preoperative predictors were multiple BC, recurrent, location in the trigone and existence of CIS. Overall survival at 3 years was significantly affected by the invasion of the prostate gland (pT4a) in these patients. The incidence of PCa discovered incidentally pathologic specimen CPT ranged from 14 to 49%. Only age was found as a positive predictor. The diagnosis of PCa did not influence survival of patients with MIBC and no specific PCa adjuvant treatment was systematically advocated. CONCLUSION: Fortuitous diagnosis of PCa and/or neoplastic invasion of the prostatic gland by BC on CPT specimen is not uncommon but this is variable across studies, depending on the quality of the pathological analysis. The invasion of the prostate gland by MIBC is a serious situation (pT4a) and linked with a poor prognosis. In case of concomitant PCa and MIBC, the prognosis is much more related to the natural history of the bladder tumour. PMID- 23446281 TI - [Urothelial carcinoma in patients under 40 years. Review of the cancer committee of the French Association of Urology]. AB - INTRODUCTION: Urothelial carcinoma in young patients (<40 years) is rare. The only known risk factor is exposure to tobacco smoking and/or early active tobacco intoxication. No genetic predisposing factor seems to exist. MATERIAL AND METHODS: A review of the literature was performed using PubMed database with a combination of the following keywords: urothelial carcinoma, young patients/adults, children, pediatrics, urothelium and neoplasm prognosis. DISCUSSION: Urothelial carcinomas before the age of 20 years are non-invasive papillary lesions (papillary urothelial neoplasm of low malignant potential and non-invasive papillary urothelial carcinoma low grade or high grade) of excellent prognosis. Rare cases of infiltrating carcinomas have been described between 20 to 40 years; their histological and clinical aspects are close to those observed in usual urothelial carcinomas. CONCLUSION: The management of urothelial carcinomas of patients under 40 years relies on the tumor grade and stage. Treatment of aggressive cases has to be curative from a clinical point of view, nevertheless conserving vital and reproducing functions. PMID- 23446282 TI - [Robot-assisted partial nephrectomy versus laparoscopic partial nephrectomy: a single institution experience]. AB - OBJECTIVE: To compare perioperative outcomes of robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN) in a single French institution. PATIENTS: Between February 2008 and April 2012, 98 patients underwent RAPN (n=54) or NPL (n=44) for a kidney tumor. Demographic data, perioperative and pathological outcomes were compared using Student's test and chi2 for continuous and categorical variables, respectively. RESULTS: Both groups were comparable for age, BMI, American Society of Anesthesiologists classification (ASA) and preoperative renal function (MDRD clearance). Tumor complexity was increased in the RAPN group (55.5 % vs. 29.5 % RENAL score>=2, P=0.05). There was no significant difference in terms of operative time (191 vs. 202 min, P=0.2), tumor size (35 vs. 30mm, P=0.1) or positive margins (2 vs. 5, P=0.14). However, there was a significant decrease in warm ischemia time (18 vs. 25.6 min, P=0.004) and hospital stay (5.1 vs. 6.9 days, P=0.003) for RAPN. Estimated blood loss was greater in the RAPN group (490 vs. 280mL, P=0.003), but the numbers of transfusions were similar (5 vs. 4 patients, P=0.96). Urinary tract was more frequently entered in the RAPN group (28 vs. 12, P=0.009). The complication rate was similar in both groups (28 % vs. 32 %, P=0.66). CONCLUSION: RAPN is feasible and reproducible. As in previous publications, our study confirms a potential benefit of RAPN concerning warm ischemia. PMID- 23446283 TI - [Evaluation of the management of metastatic renal cell carcinoma in the era of targeted therapies. retrospective clinical study over six years]. AB - OBJECTIVE: To evaluate the outcomes following targeted therapies in the management of metastatic renal cell carcinoma (mRCC), through the study of overall survival (OS) and progression-free (PFS). PATIENTS AND METHODS: We retrospectively included 78 patients treated with targeted therapies for mRCC at the Paul Papin Cancer Institute from 2004 to 2009. Overall survival (OS), progression free survival (PFS), response to treatment, occurrence of grade III and IV side effects, were analyzed following first and second line treatments. RESULTS: Median follow-up was 33 months [5-236], and 41 patients died (52.6%). Median OS was 36 months [95% CI 29-43]. The median PFS was 14 months [95% CI 6.71 21.29] for sunitinib, 38 months [95% CI 11.41-64.59] for bevacizumab with interferon (IFN), and 8 months [95% CI 0-17.03] for IFN alone. A partial reduction, stabilization or increase in tumor size was observed for 19.2%, 47.4% and 25.6% of cases. A second line treatment was given for 53 patients. They received either sunitinib (n=20, 37.8%), bevacizumab with IFN (n=7, 13.2%), sorafenib (n=17, 32.2%), temsirolimus (n=3, 5.6%) or other molecules (n=6 11.2%). Grade III or IV side effects were observed for 14.1%, 28.3% and 18.2% of the patients following first, second and third line treatment, respectively. CONCLUSION: Outcomes of targeted therapies in our center upheld the literature data. These therapies allow a benefit survival versus immunotherapy, with sometimes large side-effect. PMID- 23446284 TI - [Bladder tumor targeting by Hexvix((r)) fluorescence: 4 years results after prospective monocentric evaluation]. AB - PURPOSE: Prospective evaluation of bladder tumor targeting by Hexvix((r)) fluorescence. PATIENTS AND METHODS: From September 2008 to April 2012, 107 patients have been evaluated using Hexvix((r)) technique (blue light) for typically papillary bladder tumor or suspected bladder tumor. Clinical and pathological data have been collected prospectively and patients have been classified using EORTC score. RESULTS: From the 107 patients, 67 have been identified with bladder cancer and 328 samples have shown positive fluorescence in blue light. Compared to white light, 13 additional tumors have been diagnosed by Hexvix((r)) for 11 patients: Cis (n=6), LMP (n=3), pTa low grade (n=3), pT1 low grade (n=1) (P=0.003). The false positive rate for Hexvix((r)) was 53.4% versus 52% for white light. Previous TCC history, multifocality and EORTC score for recurrence and progression have been associated with better bladder cancer targeting by Hexvix((r)) (P=0.007; P=0.01; P=0.03; P=0.04). CONCLUSION: In our experience, Hexvix((r)) targeting was associated with better diagnosis for bladder cancer with 9% (13/144) of new positive samples (P=0.003). In our study, false positive rate is a critical point (53.4%). Multifocality, previous TCC, and EORTC score for recurrence and progression might allow selecting patients to be targeted by Hexvix((r)). PMID- 23446285 TI - [Functional MRI by general radiologists in prediction of side-specific extracapsular extension after radical prostatectomy: what value in daily practice?]. AB - OBJECTIVE: To evaluate the performance of functional MRI (FMRI) performed by general radiologists (GR) in detection of side-specific extracapsular extension (SSECE) prostate cancer (PCa). METHODS: We retrospectively analyzed 79 patients who underwent FMRI with pelvic phased array coil before radical prostatectomy (RP) performed at University Hospital (UH) of Nimes. Twelve GR (including three from UH) interpreted the images during their daily practice. FMRI results were dichotomized as positive or negative and confronted to pathological reports for SSECE and side-specific seminal vesicle invasion (SSSVI), with calculation of diagnostic values. The influence of interval between biopsy and FMRI, diffusion weighted sequence (DWS) and intensity of FMRI, on the diagnostic performance were assessed by Fisher's exact test. RESULTS: A SSECE and a SSSVI were observed at FMRI and pathology respectively on 14 (8.8%) and 38 (24.1%) prostate lobes, and on six (3.8%) and seven (4.4%) prostate lobes. The sensitivity, specificity, positive and negative predictive values of FMRI for SSECE were respectively 24%, 96%, 64% and 80%; and for SSSVI were 14%, 97%, 17% and 96% respectively. The time between biopsy and FMRI, intensity of FMRI and DWS, did not influence the sensitivity and specificity of fMRI at Fisher test. CONCLUSION: This study found that preoperative prostate FMRI performed by GR has good specificity but poor sensitivity in predicting SSECE on pathological reports. PMID- 23446286 TI - [Construction and validation of an evaluation tool of sexual health using self administered questionnaires for an application to metabolic diseases]. AB - AIM: To elaborate and validate in general population a survey built with self administered questionnaires in French about evaluation of sexual health for an application to men and women with metabolic disease. MATERIALS AND METHODS: Study built with four questionnaires (socio-familial environment [MSPSS scale], self esteem [Rosenberg scale], anxiety and depression scale [Sigmund and Snaith scale], and male [BISF-M] or female [BISF-W] sexuality) translated in French and distributed to 232 men and 260 women. RESULTS: Hundred and eleven men aged 18 to 56 years and 142 women aged 20 to 60 years answered the self-administered questionnaire. Analysis showed several links between self-esteem, anxiety and depression and the different domains of male sexuality, justifying their association. Comparison between men and women confirmed the differences of sexual approach between the two sexes. CONCLUSION: Results in our population were concordant with those already reported in literature, indicating the validity and the reliability of our questionnaire and its multiparametric approach. Data obtained in this population will allow to use this multiparametric tool with patients affected by a metabolic disease. PMID- 23446287 TI - [Acute renal failure following rectosigmoidoscopy]. AB - We report the case of a 24-year old man with a past history of vesical extrophy and ureterosigmoidostomy in childhood, admitted with acute left flank pain and acute renal failure. The complaints started the day following the endoscopic resection of a sigmoid polyp. The stricture of the ureterosigmoid junction was diagnosed by intravenous urography. Conservative treatment with endo-ureteral dilatation was successfully performed. At 2 years of follow-up, the patient is still asymptomatic, without any residual hydronephrosis. PMID- 23446288 TI - [A case of hepatitis C virus possible transmission following a transrectal ultrasound guided prostate biopsy]. AB - The prostate biopsy is a current and well-codified act. To date, there have been no reported risks of viral transmission between patients linked to contaminated ultrasound probe. We report the case of a patient having contracted the virus of hepatitis C after transrectal prostate biopsy during an individual screening of prostate cancer. PMID- 23446289 TI - Development and validation of a sensitive LC-MS-MS assay for the quantification of betulonic acid in rat plasma. AB - A rapid, sensitive and reliable liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of betulonic acid in rat plasma. The plasma samples were prepared by protein precipitation. Chromatographic separation was achieved on an Agela MG-C18 analytical column (50 * 2.1 mm, 5 um) using methanol-water-formic acid (80:20:0.1, v/v/v) as the mobile phase with a constant flow rate of 0.6 mL/min. Mass detection was conducted by electrospray ionization in positive ion multiple reaction monitoring mode. The calibration curves were linear over a concentration range of 3.00-3,000 ng/mL for the analyte. The intra-day and inter-day accuracy and precision were within the acceptable limits of +/-15% at all concentrations. The method was successfully applied for the estimation of betulonic acid in rat plasma from a preclinical pharmacokinetics study. PMID- 23446290 TI - Impetigo Herpetiformis during pregnancy: a case report and literature review. AB - BACKGROUND: Impetigo herpetiformis (IH) is a rare pustular dermatosis that typically occurs in pregnant women with unknown etiology. CASE REPORT: We report an 18-year-old primigravida who presented with IH at nearly 30 weeks' gestation and was the first patient reported in mainland China. The patient's condition deteriorated rapidly in spite of treatment with corticosteroids and antibiotics, so we decided to terminate the pregnancy by induction of labor. After vaginal delivery she developed fever and her skin lesions did not disappear naturally. Fortunately her symptoms were resolved with the treatment of antibiotics and acitretin, and at day 60 postpartum her skin lesions had completely disappeared. CONCLUSION: Although IH is associated with high mortality and morbidity in both fetus and mother, a better prognosis could be achieved with an immediate diagnosis and proper treatment. The etiology of IH needs to be further explored and the process of diagnosis and therapy should be standardized. PMID- 23446291 TI - Tetramethylpyrazine prevents contrast-induced nephropathy by inhibiting p38 MAPK and FoxO1 signaling pathways. AB - BACKGROUND: Apoptosis is recognized as an important mechanism in contrast-induced nephropathy (CIN). As tetramethylpyrazine (TMP) has been recently found to be renoprotective and anti-apoptotic in multiple kidney injuries, we hypothesized that TMP would prevent CIN. METHODS: An experimental model of CIN was established in rats. Serum creatinine, blood urea nitrogen, plasma cystatin C, urinary N acetyl-beta-glucosaminidase, and urinary gamma-glutamyl transpeptidase were measured to evaluate kidney function. Apoptosis was assessed by transmission electron microscopy, transferase-mediated deoxyuridine triphosphate nick end labeling staining, and poly-ADP-ribose polymerase cleavage. Fork-head box O1 transcriptional factor (FoxO1) mRNA expression was evaluated by quantitative real time PCR. Phospho-p38 mitogen-activated protein kinase (MAPK) protein expression was assessed by immunohistochemistry and Western blotting. RESULTS: TMP significantly attenuated the resulting renal dysfunction and renal tubular cell apo-ptosis. Mechanistically, TMP decreased the expression of phospho-p38 MAPK protein and attenuated the increased FoxO1 mRNA and nuclear protein expression. In addition, TMP inhibited inducible nitric oxide synthase and Bax protein expression while it upregulated Bcl-2. CONCLUSION: In summary, this study demonstrated the protective role of TMP against CIN and indicated the effects of TMP may be mediated by the inhibition of p38 MAPK and FoxO1 pathways. Thus, TMP may be a new potential therapeutic agent to prevent CIN. PMID- 23446292 TI - Surgery for aggressive behavior disorder. PMID- 23446294 TI - Effectively addressing complex proteomic search spaces with peptide spectrum matching. AB - SUMMARY: Protein identification by mass spectrometry is commonly accomplished using a peptide sequence matching search algorithm, whose sensitivity varies inversely with the size of the sequence database and the number of post translational modifications considered. We present the Spectrum Identification Machine, a peptide sequence matching tool that capitalizes on the high-intensity b1-fragment ion of tandem mass spectra of peptides coupled in solution with phenylisotiocyanate to confidently sequence the first amino acid and ultimately reduce the search space. We demonstrate that in complex search spaces, a gain of some 120% in sensitivity can be achieved. AVAILABILITY: All data generated and the software are freely available for academic use at http://proteomics.fiocruz.br/software/sim. CONTACT: paulo@pcarvalho.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23446293 TI - Batch production of a silk-elastin-like protein in E. coli BL21(DE3): key parameters for optimisation. AB - BACKGROUND: Silk-elastin-like proteins (SELPs) combining the physicochemical and biological properties of silk and elastin have a high potential for use in the pharmaceutical, regenerative medicine and materials fields. Their development for use is however restrained by their production levels. Here we describe the batch production optimisation for a novel recently described SELP in the pET-E. coli BL21(DE3) expression system. Both a comprehensive empirical approach examining all process variables (media, induction time and period, temperature, pH, aeration and agitation) and a detailed characterisation of the bioprocess were carried out in an attempt to maximise production with this system. RESULTS: This study shows that maximum SELP volumetric production is achieved at 37 degrees C using terrific broth at pH 6-7.5, a shake flask volume to medium volume ratio of 10:1 and an agitation speed of 200 rpm. Maximum induction is attained at the beginning of the stationary phase with 0.5 mM IPTG and an induction period of at least 4 hours. We show that the selection agents ampicillin and carbenicillin are rapidly degraded early in the cultivation and that plasmid stability decreases dramatically on induction. Furthermore, acetate accumulates during the bioprocess to levels which are shown to be inhibitory to the host cells. Using our optimised conditions, 500 mg/L of purified SELP was obtained. CONCLUSIONS: We have identified the optimal conditions for the shake flask production of a novel SELP with the final production levels obtained being the highest reported to date. While this study is focused on SELPs, we believe that it could also be of general interest to any study where the pET (ampicillin selective marker)-E. coli BL21(DE3) expression system is used. In particular, we show that induction time is critical in this system with, in contrast to that which is generally believed, optimal production being obtained by induction at the beginning of the stationary phase. Furthermore, we believe that we are at or near the maximum productivity for the system used, with rapid degradation of the selective agent by plasmid encoded beta-lactamase, plasmid instability on induction and high acetate production levels being the principal limiting factors for further improved production. PMID- 23446295 TI - Multidisciplinary management of primary adenoid cystic carcinoma of the eyelid with perineural invasion. AB - Primary cutaneous adenoid cystic carcinoma of the eyelid is an extremely rare entity with the propensity to recur locally, spread to regional lymph nodes, and invade perineural spaces. Of the 8 cases previously reported in the literature, only 2 were noted to be associated with perineural invasion, and neither of these was treated with radiation therapy. The authors report the case of a 35-year-old woman who presented with a progressively enlarging left lower eyelid lesion. An excisional biopsy with wide margins revealed a diagnosis of primary adenoid cystic carcinoma of the eyelid with perineural invasion. Because of the high risk of recurrence associated with perineural invasion, the patient received postoperative adjuvant radiation in the form of 50 Gy relative biological effectiveness of proton beam therapy to the postoperative tumor bed and to the infraorbital nerve tracking back to the apex of the orbit, followed by a 10-Gy boost to the lower eyelid tumor bed with orthovoltage x-rays. PMID- 23446296 TI - Superior ophthalmic vein enlargement and increased muscle index in dysthyroid optic neuropathy. AB - PURPOSE: To compare superior ophthalmic vein diameter and extraocular muscle index in patients with thyroid eye disease with or without optic neuropathy. METHODS: High-resolution CT scan images of 40 orbits of 20 patients with history of thyroid eye disease (with or without optic neuropathy), who underwent orbital decompression surgery from January 2007 to November 2009, were retrospectively reviewed. Superior ophthalmic vein diameter was measured in coronal and axial planes. Extraocular muscle index was calculated according to the method proposed by Barrett et al. The clinical diagnosis of optic neuropathy was based on characteristic signs that included afferent pupillary defect, decreased visual acuity, visual field defects, and dyschromatopsia. Orbits were divided in 2 groups based on presence or absence of optic neuropathy. RESULTS: Superior ophthalmic vein diameter was significantly higher in orbits with concomitant optic neuropathy (mean 2.4 +/- 0.4mm, p < 0.0001). Increased muscle index was also related to optic neuropathy (mean 57.9% +/- 5.7%, p = 0.0002). Muscle index greater than 50% was present in all patients with dysthyroid optic neuropathy. CONCLUSIONS: This study suggests that patients with thyroid eye disease with enlarged superior ophthalmic vein and increased extraocular muscle index are more likely to have concomitant optic neuropathy. PMID- 23446297 TI - Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma. AB - PURPOSE: To review the literature on targeted therapy for orbital and periocular basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) and provide examples of patients recently treated with such therapy. METHODS: The authors reviewed the literature on clinical results of targeted therapy and the molecular basis for targeted therapy in orbital and periocular BCC and cutaneous SCC. The authors also present representative cases from their practice. RESULTS: Mutation in the patched 1 gene (PTCH1) has been implicated in BCC, and overexpression of epidermal growth factor receptor (EGFR) has been shown in SCC. Vismodegib, an inhibitor of smoothened, which is activated upon binding of hedgehog to Ptc, has been shown to significantly decrease BCC tumor size or even produce complete resolution, especially in cases of basal cell nevus syndrome. Similarly, EGFR inhibitors have been shown to significantly decrease SCC tumor size in cases of locally advanced and metastatic disease. The authors describe successful outcomes after vismodegib treatment in a patient with basal cell nevus syndrome with numerous bulky lesions of the eyelid and periocular region and erlotinib (EGFR inhibitor) treatment in a patient with SCC who was deemed not to be a good surgical candidate because of advanced SCC of the orbit with metastasis to the regional lymph nodes, advanced age, and multiple medical comorbidities. CONCLUSIONS: Targeted therapy using hedgehog pathway and EGFR inhibitors shows significant promise in treatment of orbital and periocular BCC and cutaneous SCC, respectively. Such targeted therapy may be appropriate for patients who are not good candidates for surgery. PMID- 23446298 TI - Eyelid lymphedema following neck dissection and radiotherapy. AB - Chronic eyelid lymphedema following neck dissection and radiotherapy is rare with 1 report in the literature. The authors report 3 cases and review the literature. Two cases had bilateral neck dissection and developed bilateral eyelid lymphedema and 1 case had unilateral neck dissection (left side) and developed ipsilateral lymphedema. Two patients underwent surgical debulking of lymphedema with significant improvement in symptoms. One patient declined surgical intervention, and the lymphedema remained unchanged. Chronic eyelid lymphedema following neck dissection and radiotherapy occurs where predominant lymphatic drainage to the submandibular and deep cervical lymph node basin is removed. Lymphedema tends to persist when it occurs and in selected cases appearance can be effectively improved by debulking and excision of festoons. PMID- 23446299 TI - Secondary tarsoconjunctival graft: a modification to the Cutler-Beard procedure. AB - PURPOSE: The Cutler-Beard procedure is a commonly used technique to reconstruct large upper eyelid defects. Eyelid retraction and entropion are common complications. To prevent these problems, the authors modified the traditional Cutler-Beard procedure with secondary placement of an autologous tarsoconjunctival graft. METHODS: This is a retrospective review of 2 patients with large upper eyelid defects necessitating upper eyelid reconstruction. The initial stage is unaltered. At the time of flap division, a tarsoconjunctival graft from the contralateral upper eyelid is sutured to the posterior surface of the newly constructed upper eyelid. Two patients underwent this procedure, and follow up was 4 and 23 months, respectively. Patients developed no postoperative complications, including entropion or retraction. CONCLUSIONS: This modification to the Cutler-Beard operation is a technically simple procedure that can restore a more anatomically correct eyelid and can prevent subsequent entropion or retraction. This technique is unique, offering 3 major advances: first, placing the graft at the second surgical stage; second, replacing the tarsus and conjunctiva with like tissue; and third, preserving a lip of conjunctiva to cover the edge of the newly reconstructed upper eyelid. PMID- 23446300 TI - Orbital follicular hyperplasia in common variable immune deficiency syndrome. AB - Common variable immune deficiency (CVID) is characterized by reduced serum immune globulins and impaired or absent antibody responses. Patients become more susceptible to infections and to lymphoproliferation and granulomatous inflammation. Ophthalmic manifestations of CVID are rare. The authors describe a case of orbital follicular hyperplasia in a 15-year-old girl with CVID syndrome causing proptosis and exposure keratopathy. PMID- 23446301 TI - Tissue ingrowth into perforated polymethylmethacrylate orbital implants: an experimental study. AB - PURPOSE: To evaluate the clinical response and fibrovascular ingrowth into perforated acrylic orbital implants in a rabbit model. METHODS: Perforated implants were manufactured by drilling channels interconnected at the center in conventional 12- to 13-mm acrylic spheres. The implants were placed in 16 eviscerated eyes with posterior sclerotomy of 16 New Zealand white rabbits. Clinical evaluation was performed daily for the first 14 days after surgery and at 7-day intervals until the end of the study (180 days). Histopathologic analysis was performed at 14, 45, 90, and 180 days after implantation. Hematoxylin-eosin and picrosirius red staining was used to assess the inflammatory reaction and collagen formation. RESULTS: There were no signs of infection, implant exposure, or extrusion in any animal during the study. Tissue ingrowth in the implant center was already detected by 14 days. At the end of the study, there was a dense collagen ingrowth with just a few inflammatory cells inside the implant. No multinucleated giant cells were found in any implant. CONCLUSIONS: Similar to porous implants, perforated acrylic implants permit fibrovascular ingrowth from surrounding orbital tissues. PMID- 23446302 TI - Gaze-evoked amaurosis from orbital breast carcinoma metastasis. AB - Gaze-evoked amaurosis (GEA) is a transient monocular vision loss provoked by eccentric gaze. Gaze-evoked amaurosis has been associated with a variety of orbital lesions, most commonly optic nerve sheath meningiomas and cavernous hemangiomas. The authors describe the first report in the literature of GEA as the presenting symptom of an orbital metastasis. The patient was a 47-year-old woman with a history of breast cancer with no known history of metastasis or active disease who presented with several weeks of vision loss in the OD upon rightward gaze. She was found to have enophthalmos and optic disc edema of the OD. Imaging revealed an intraorbital lesion, and a biopsy was consistent with a scirrhous metastasis of her breast carcinoma. This case highlights the importance of considering orbital metastases among the differential for gaze-evoked amaurosis. PMID- 23446303 TI - Collagenous fibroma (desmoplastic fibroblastoma) of the orbital rim. AB - A 40-year-old woman with left periorbital swelling for 1 month presented without diplopia or change in vision. Imaging studies revealed a 1-cm mass at the frontozygomatic junction at the orbital rim with slight bony erosion and spiculation. The lesion was applied to the periosteum and was excised along with a portion of the bony orbital rim. Histopathology revealed elongated and stellate fibroblasts within a dense collagenous matrix. Vimentin and Masson trichrome staining was consistent with a collagenous fibroma, a rare tumor that has, only once before, been reported in the orbit in the lacrimal fossa region. The current collagenous fibroma arose from the periosteum to grow exophytically, causing minimal bone changes. A literature review shows that this condition predominantly affects middle-aged and older adults rather than children. PMID- 23446305 TI - Rhinotillexomania: a rare cause of medial orbital wall erosion. AB - The authors report a rare case of medial orbital wall erosion with an orbital inflammatory mass and resultant lacrimal obstruction secondary to rhinotillexomania. A 67-year-old male with known history of compulsive nose picking (rhinotillexomania) sought treatment for complaints of watering in his OD. Examination revealed a blocked right inferior canaliculus. Nasal endoscopy showed a large nasal septal defect with multiple areas of crusting and bleeding. Hematologic investigations were normal. CT scan confirmed a large nasal septal and right medial orbital wall defect with an adjacent soft tissue mass in the medial orbit. Investigations ruled out systemic pathology. Histologic examination of medial orbital mass, sinus, and nasal mucosa revealed a reactive inflammatory infiltrate with surface Gram-positive cocci. The authors hypothesized that the patient had enlarged an existing nasal septal defect due to repetitive nose picking resulting in recurrent infection and inflammation of sinuses, leading to erosion of his medial orbital wall. PMID- 23446304 TI - Patient-reported benefit from botulinum toxin treatment for essential blepharospasm: using 2 assessment scales. AB - PURPOSE: To assess and compare the change in quality-of-life and function following treatment with botulinum toxin (BTX) using the Glasgow Benefit Inventory (GBI) and Blepharospasm Disability Index (BSDI) scores. METHODS: A cross-sectional study of 62 consecutive patients treated with BTX for blepharospasm conducted during a postinterventional telephone interview. Post hoc analysis converts the GBI to a score from -100 (maximum harm) through 0 (no effect) to +100 (maximum benefit). The BSDI is converted to a score on a scale from -4 (maximum harm) through 0 (no effect) to +4 (maximum benefit). A Wilcoxon signed-rank test and linear regression analysis were performed. RESULTS: A statistically significant benefit (Wilcoxon signed-rank test) from treatment of 31.36 (95% confidence interval = 26.22-36.50; p < 0.001) and 1.04 (95% confidence interval = 0.80-1.27; p < 0.001) using the GBI and BSDI scores, respectively. Regression analysis was performed demonstrating a strong positive correlation between both scales (r = 0.637). CONCLUSIONS: BTX treatment for blepharospasm is associated with significant patient-reported improvements in quality-of-life (GBI) and functional ability (BSDI) with a strong positive correlation between both scores. PMID- 23446306 TI - Effects of local anesthesia with bupivacaine plus epinephrine on blepharoptosis and levator palpebrae muscle function. AB - PURPOSE: To evaluate the effect of local anesthesia with bupivacaine plus epinephrine on the extent of blepharoptosis and levator palpebrae muscle function. METHODS: : In this prospective interventional case series, patients with blepharoptosis who were candidates for aponeurotic surgery were included. After initial preparations in the operating room, a total of 1 ml of a mixture of bupivacaine 0.5% plus epinephrine 1:100,000 were injected into the upper eyelid. The margin reflex distance 1 (MRD1) and the extent of levator muscle function were measured before and 2, 5, 10, and 15 minutes after injection. RESULTS: A total of 36 eyes including 21 men (58.3%) and 15 women (41.7%) with an average age of 41.81 +/- 23.09 (17-83 years) were studied. There were 21 eyes with myogenic and 15 eyes with aponeurotic blepharoptosis. The mean MRD1 was 1.18 +/- 1.06 mm before injection and -0.02 +/- 0.85, 0.52 +/- 0.98, 0.98 +/- 1.05, and 1.02 +/- 1.06 mm at 2, 5, 10, and 15 minutes after injections, respectively. The changes in the MRD1 measurements were statistically significant at all time points. The MRD1 values decreased during the first 2 minutes after injection in 88.8% of eyes, but returned to initial value after 15 minutes in 84.3%. The change in the levator muscle function measurements was statistically significant at 2 and 5 minutes after injections; however, the differences were clinically negligible. CONCLUSIONS: : The local anesthesia of the eyelid with 1 ml bupivacaine plus epinephrine causes a temporary increase of blepharoptosis within the first few minutes with minimal effect on levator muscle function measurements. PMID- 23446307 TI - Bloody epiphora secondary to a lacrimal sac varix. AB - This is a report of a 57-year-old female patient who sought treatment for multiple episodes of bloody epiphora. A CT of her orbits revealed enhancement and enlargement of her left lacrimal sac and duct. A biopsy was then performed, which showed a varix involving the wall of the lacrimal sac. To the authors' knowledge, this is the first reported case of a lacrimal sac varix causing bloody epiphora. PMID- 23446308 TI - Linear IgA bullous dermatosis: an unusual cause of upper eyelid cicatricial entropion. AB - Chronic cicatrizing conjunctivitis is a relatively uncommon condition resulting in significant ophthalmic morbidity, including keratoconjunctivitis sicca, cicatricial entropion, trichiasis, corneal scarring, significant discomfort, and visual loss. The potential causes of cicatrizing conjunctivitis are varied and include commonly encountered entities such as ocular cicatricial pemphigoid, Stevens-Johnson syndrome, and trachoma and many more rare causes which are particularly difficult to diagnose and treat and may not be familiar to the ophthalmologist. The authors herein present a case of chronic cicatrizing conjunctivitis, cicatricial entropion, and trichiasis caused by a rare entity called linear IgA bullous dermatosis. The case presentation conforms to the tenets of the Declaration of Helsinki and is Health Insurance Portability and Accountability Act compliant. This chronic dermatosis has a varied presentation, and the ophthalmic manifestations in particular have been infrequently described. This case demonstrates the benefits of immunohistochemistry in diagnosis and the difficulties in medical and surgical management of linear IgA bullous dermatosis while underscoring the lifelong difficulties in managing chronic inflammatory conditions causing ocular cicatrization. PMID- 23446309 TI - Volatile breath biomarkers for patient monitoring during haemodialysis. AB - Patients with end-stage renal disease (ESRD) are at risk for a numerous complications. This study was intended to evaluate breath analysis for monitoring and therapy initiation under haemodialysis (HD). Exhaled alveolar air from 30 ESRD patients during 4 h thrice-weekly HD was analysed by means of HS-SPME-GC-MS. Venous blood samples were taken for determination of conventional serum parameters. Exhaled concentrations of isoprene (10-589 ppbV) were dropped at initiation of HD and increased at the end of HD. Isoprene concentration changes were similar to changes of serum LDH activities. Variation of exhaled acetone concentrations (59 to 8509 ppbV) was significantly lower in diabetic patients when compared to non-diabetics. Exhaled pentane (0.3 to 12 ppbV) increased at onset of HD and returned to baseline levels afterwards. Benzene concentrations showed typical washout characteristics. Ethanol and DMS concentrations remained constant during HD. Breath analysis can be used to recognize oxidative stress, metabolic conditions and haemolysis during HD. Hence, non-invasive breath testing could be used to monitor ESRD patients under HD and prevent them from being affected by well-known detrimental side effects of renal replacement therapy. PMID- 23446310 TI - Highly reversible lithium storage in Si (core)-hollow carbon nanofibers (sheath) nanocomposites. AB - A favorable Si (core)-hollow carbon nanofiber (sheath) nanocomposite, was synthesized by a coaxial electrospinning technique. As a potential anode material for LIBs, this composite displays a high reversible capacity of 1300 mA h g(-1) even after 80 cycles at 0.5 C. It also exhibits a reversible discharge capacity as high as 700 mA h g(-1) when cycled at 3 C. This makes the Si-C composite a promising candidate for use as an anode material in lithium ion batteries. Beyond that, coaxial electrospinning has proved itself as a powerful technique to prepare nanomaterials with hollow core-shell architectures. PMID- 23446311 TI - Bortezomib and vorinostat in refractory acute myelogenous leukemia and high-risk myelodysplastic syndromes: produces stable disease but at the cost of high toxicity. PMID- 23446312 TI - MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenstrom's macroglobulinemia. AB - We evaluated the MYD88 L265P mutation in Waldenstrom's macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity ~10(-3)). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P=0.022), more lymphocytosis (24 vs 5%, P=0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P=0.002), atypical immunophenotype (CD23-CD27+ +FMC7+ +), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P=0.012) and less IGHV3-23 gene selection (9 vs 27%, P=0.014). These small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival. PMID- 23446313 TI - The war against dementia: are we battle weary yet? AB - Recently, the use of military metaphors when discussing dementia and in particular Alzheimer's disease has increased, both in medical literature and mainstream media. While military metaphors are a recent adoption when used to describe dementia, in oncology there has been longstanding debate about the usefulness of such metaphors. This article reviews the history of military metaphors in medicine, literature discussing their use, and considers their use in describing dementia. While military metaphors are widely used in medicine, consideration should be taken in their use as they have the potential to influence the way we and our patients conceptualise and experience illness and treatment. PMID- 23446314 TI - A sign of superspreading in tuberculosis: highly skewed distribution of genotypic cluster sizes. AB - BACKGROUND: Molecular typing is a valuable tool for gaining insight into spread of Mycobacterium tuberculosis. Typing allows for clustering of cases whose isolates share an identical genotype, revealing epidemiologic relatedness. Observed distributions of genotypic cluster sizes of tuberculosis (TB) are highly skewed. A possible explanation for this skewness is the concept of "superspreading": a high heterogeneity in the number of secondary cases caused per infectious individual. Superspreading has been previously found for diseases such as severe acute respiratory syndrome and smallpox, where the entire transmission tree is known. So far, no method exists to relate superspreading to the distribution of genotypic cluster sizes. METHODS: We quantified heterogeneity in secondary infections per infectious individual by describing this number as a negative binomial distribution. The dispersion parameter k is a measure of superspreading; standard (homogeneous) models use values of k >= 1, whereas small values of k imply superspreading. We estimated this negative binomial dispersion parameter for TB in the Netherlands, using the genotypic cluster size distribution for all 8330 cases of culture confirmed, pulmonary TB diagnosed between 1993 and 2007 in the Netherlands. RESULTS: The dispersion parameter k was estimated at 0.10 (95% confidence interval = 0.09-0.12), well in the range of values consistent with superspreading. Simulation studies showed the method reliably estimates the dispersion parameter across a range of scenarios and parameter values. CONCLUSION: Heterogeneity in the number of secondary cases caused per infectious individual is a plausible explanation for the observed skewness in genotypic cluster size distribution of TB. PMID- 23446315 TI - Kallikrein-related peptidases (KLKs) in gastrointestinal cancer: mechanistic and clinical aspects. AB - The human tissue kallikrein (KLK1) and kallikrein-related peptidases (KLKs) are secreted serine proteases with diverse expression patterns and physiological roles in different systems, including the digestive system. The aberrant expression of KLKs in gastrointestinal malignancies as well as their implication in carcinogenesis including cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with various clinic pathological parameters of patients with gastric, colorectal, pancreatic, hepatic, and esophageal cancer. Moreover, several KLKs possess significant favourable or unfavourable prognostic value in these human malignancies. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making, since early diagnosis of gastrointestinal cancer and early detection of recurrence following surgery are critical for the effective treatment of patients and for a positive clinical outcome. The current review provides a brief overview of the functional role of KLKs in gastric, colorectal, pancreatic, hepatic, and esophageal cancer, and describes the current status of KLKs as potential tumour biomarkers in these human malignancies. PMID- 23446316 TI - Novel synthesis of super peroxidase mimetic polycrystalline mixed metal hexacyanoferrates nanoparticles dispersion. AB - Mixed metal-hexacyanoferrates (MHCF) have shown promising applications for technological development particularly in energy storage technologies, ferromagnetic materials, and electrode materials. However, the challenge of controlling their chemical synthesis, solubility, polycrystallinity and nanogeometry have restricted the practical implementation of MHCF in commercial designs. Further, MHCFs have shown potential as peroxidase mimetics. There is still challenging demand to enhance the catalytic efficiency of such materials to the equivalent of biocatalytic activity thereby allowing the precise control of the mimetic character and ultimately leading to the development of new materials as powerful peroxidases i.e. Horseradish peroxidase (HRP) replacement during enzyme and immuno-sensors development. We report herein a new process that allows the controlled synthesis of biocompatible mixed MHCF nanoparticles with a variety of transition metal ions. The resulting polycrystalline mixed MHCF shows enhanced catalytic efficiency to hydrogen peroxide (H2O2) as compared to that of polycrystalline Prussian blue (PB) made under similar conditions with significant increase in catalytic efficiency as a function of respective hetero-transition metal ion of mixed FeHCF in the order of FeHCF < Mn-FeHCF < Ni-FeHCF < Cu-FeHCF justifying as perfect peroxidase replacement. PMID- 23446317 TI - Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data. AB - BACKGROUND: Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of whole genome sequencing particularly attractive for clinical and epidemiological investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the genome over relevant timescales is required. METHODS: We attempted to estimate a molecular clock by sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years. RESULTS: Multiple analyses support an average mutation rate of ~0.3 SNPs per genome per year. However, all analyses revealed a very high degree of variation around this mean, making the confirmation of links proposed by epidemiology, and inference of novel links, difficult. Despite this, in some cases, the phylogenetic context of other strains provided evidence supporting the confident exclusion of previously inferred epidemiological links. CONCLUSIONS: This in depth analysis of the molecular clock revealed that it is slow and variable over short time scales, which limits its usefulness in transmission studies. However, the superior resolution of whole genome sequencing can provide the phylogenetic context to allow the confident exclusion of possible transmission events previously inferred via traditional DNA fingerprinting techniques and epidemiological cluster investigation. Despite the slow generation of variation even at the whole genome level we conclude that the investigation of tuberculosis transmission will benefit greatly from routine whole genome sequencing. PMID- 23446318 TI - Association of uric acid with obesity and endothelial dysfunction in children and early adolescents. AB - BACKGROUND: Hyperuricemia in adults is known to be associated with hypertension, the metabolic syndrome and cardiovascular disease. The purpose of this study was to elucidate the factors associated with hyperuricemia in obese children and early adolescents and to investigate the threshold serum level of uric acid (UA) for the metabolic syndrome in children. METHODS: We assessed anthropometric measurements, blood pressure, body composition and biochemical data in 1,559 obese children. To assess endothelial dysfunction, flow-mediated dilatation (FMD) was measured in 92 children. The correlations between serum UA levels and various parameters were examined. The threshold serum UA level for the metabolic syndrome was calculated by receiver-operating characteristic (ROC) curve analysis. RESULTS: Serum UA levels were positively correlated with lipids in both boys and girls, and they were inversely correlated with FMD in the boys but not the girls. The threshold serum UA level for the metabolic syndrome was 5.25 mg/dl in boys and 5.05 mg/dl in girls. However, the specificity and sensitivity of ROC curve analysis are not so striking. CONCLUSION: The correlation between UA and FMD showed gender differences and might be affected by the hormonal status. The cutoff level of serum UA as a marker of the metabolic syndrome in obese children was affected by both age and gender. PMID- 23446320 TI - Cardiac implantable electronic devices: prevention starts from ethics-reply. PMID- 23446321 TI - Answer to the comment by Leveque et al. on 'Bilateral cingulotomy and anterior capsulotomy applied to patients with aggressiveness'. PMID- 23446319 TI - Diversity of the var gene family of Indonesian Plasmodium falciparum isolates. AB - BACKGROUND: The large polymorphic protein PfEMP1 is encoded by the var gene family. PfEMP1 has been shown to play an important role as cytoadherence ligand on the surface of infected erythrocytes and thereby contributes to the distinct pathogenesis of malaria. The study explored the diversity of the DBL1alpha and DBL2beta-C2 domains of the protein from Indonesian Plasmodium falciparum field isolates. METHODS: Samples of patients with severe and uncomplicated malaria from two different malaria-endemic areas in Indonesia were collected and DNA directly extracted. Dried blood on filter paper was prepared for RNA extraction. PCR amplicons were either cloned and subsequently sequenced or directly sequenced for analysis on nucleotide and amino acid level. Recently published as well as self designed primers were used for amplification. RESULTS: Blood from eight patients was finally used for analysis. Seventy-one different sequences out of over 500 DBL1alpha sequenced clones were observed, resulting in an average of 8.9 different DBL1alpha sequences per isolate. The average DBL1alpha sequence similarity within isolates was similar to between isolates. Phylogenetic analysis demonstrated no clustering of sequences regarding strain or geographical origin. The DBL1alpha sequences were analysed by distribution of semi-conserved features (cysteine/PoLV1-4 grouping) and classified into six sequence groups. The DBL1alpha cys2 type was observed in all expressed sequences in vivo. Expression of certain DBL sequences implied potential involvement in the pathogenesis. As expected, the DBL2beta-C2 domains showed high to moderate homology among each other. CONCLUSION: The DBL1alpha domains of PfEMP1 from clinical Indonesian isolates showed high divergence among same isolates and some similarities with other Asia-Pacific strains. Further investigations of important var gene domains with a larger sample size are required to confirm with statistical significance observed associations with severe malaria in Indonesian samples. PMID- 23446322 TI - Acinic cell carcinoma and petrous bone metastasis. PMID- 23446323 TI - Sudden sensorineural hearing loss as first presenting symptom of unifocal Langerhans cell histiocytosis in the temporal bone. PMID- 23446324 TI - In memoriam: William F. House, D.D.S., M.D., the "father of neurotology" 1923 2012. PMID- 23446325 TI - Unusual association of bilateral persistent stapedial arteries and microtia with bilateral ossicular anomalies resulting in conductive hearing loss. PMID- 23446326 TI - Evolution of pediatric cochlear implantation. PMID- 23446327 TI - Outcomes for children with deaf-blindness with cochlear implants: a multisite observational study. AB - INTRODUCTION: Children with dual sensory impairments are receiving cochlear implants; however, little is known regarding their language outcomes. MATERIALS AND METHODS: Children between the ages of 6 months and 8 years with dual sensory impairment and cochlear implant(s) were recruited from across the United States to participate in an evaluation of language skills using the Reynell-Zinkin Developmental Scales, a tool validated on children with vision impairment and adapted for children with hearing loss. Basic demographic information was also collected from care givers. RESULTS: Ninety-one children completed assessments after implantation. For receptive language abilities, 32% of children obtained a level of sound detection, 15% obtained the ability to understand simple words, 21% could identify words, 5% could follow simple directions, and 22% could follow directions related to the functional use of objects. Four children had no response to sound after cochlear implantation. For expressive language abilities, 49% only had sound production skills, 9% could jargon, 18% could communicate with some words, 12% could communicate with simple sentences, and 12% could communicate with complex sentences. Children with lower developmental ages (or quotients) tended to obtain lower level expressive language skills such as sound production and jargoning. Developmental abilities, rather than age at implant, were the most robust predictor associated with outcomes. DISCUSSION: This information can guide cochlear implant centers when discussing outcomes with families in the cochlear implant candidacy process. There is great heterogeneity in outcomes and caution should be used in discussing possible language outcomes for children with dual sensory impairments. PMID- 23446329 TI - In vitro hypertrophy and calcification of human fracture haematoma-derived cells in chondrogenic differentiation. AB - PURPOSE: The haematoma at a fracture site plays an important role in fracture healing. Previously, we demonstrated that a fracture haematoma contains multilineage mesenchymal progenitor cells. We postulated that the haematoma provided a source of chondrogenic cells for endochondral ossification during fracture healing and preservation of the cells contributed to biological fracture healing. In this study, we investigated whether haematoma-derived cells (HCs) could differentiate into hypertrophic chondrocytes and finally induce calcification of the extracellular matrix in vitro. METHODS: Fracture haematomas were obtained from four patients. HCs were cultured for five weeks under conditions that induce chondrogenic differentiation, followed by two weeks of hypertrophic induction using a pellet culture system. The pellets were analysed histologically and immunohistochemically. The gene expression levels of chondrogenic, hypertrophic, osteogenic, and angiogenic markers were measured by real-time PCR. RESULTS: The histological and immunohistochemical analyses revealed that HCs differentiated into chondrocytes and hypertrophic chondrocytes, followed by calcification of the extracellular matrix. This sequential differentiation was also reflected in the gene expression profiles. After chondrogenic induction, expression of osteogenic and angiogenic markers was not significantly upregulated. However, the expression of these markers was significantly upregulated following hypertrophic induction. These in vitro observations mimicked the process of endochondral ossification during fracture healing. CONCLUSIONS: Our results suggest that the fracture haematoma may offer a source of cells with chondrogenic potential that play key roles in endochondral ossification during fracture healing. These findings support the opinion that the haematoma should be preserved for biological fracture healing. PMID- 23446330 TI - A minimally invasive approach for total hip arthroplasty does not diminish early post-operative outcome in obese patients: a prospective, randomised trial. AB - PURPOSE: The benefits of minimally invasive surgical techniques in total hip arthroplasty (THA) are well known, but concerns about applying those techniques in obese patients are controversial. We prospectively compared patients with increased body mass index (BMI >= 30) undergoing THA with normal weight patients. METHODS: A total of 134 patients admitted for unilateral THA were randomised to have surgery through either a transgluteal or a minimally invasive approach (MicroHip). In each group a BMI >= 30 was used to define obese patients. Pre- and early post-operative demographics, intraoperative data, baseline haematological values, hip function (Harris Hip Score, Oxford Hip Score) and quality of life (EQ 5D) were assessed with follow-up at three months. RESULTS: Duration of surgery, blood loss, C-reactive protein levels, radiographic measurements and complication rates were comparable in all groups. There was a tendency for lower serum creatine kinase levels in the MicroHip group. Intraoperative fluoroscopic time and dose area products were significantly elevated in patients with a BMI exceeding 30 regardless of the approach used. Time points of mobilisation, length of hospital stay and functional outcome measurements were similar in the different weight groups. CONCLUSIONS: Our data suggest that obese patients gain similar benefit from MicroHip THA as do non-obese patients. The results of this study should be further investigated to assess long-term survivorship. PMID- 23446331 TI - A highly efficient microfluidic nano biochip based on nanostructured nickel oxide. AB - We present results of the studies relating to fabrication of a microfluidic biosensor chip based on nickel oxide nanorods (NRs-NiO) that is capable of directly measuring the concentration of total cholesterol in human blood through electrochemical detection. Using this chip we demonstrate, with high reliability and in a time efficient manner, the detection of cholesterol present in buffer solutions at clinically relevant concentrations. The microfluidic channel has been fabricated onto a nickel oxide nanorod-based electrode co-immobilized with cholesterol esterase (ChEt) and cholesterol oxidase (ChOx) that serves as the working electrode. Bare indium tin oxide served as the counter electrode. A Ag/AgCl wire introduced to the outlet of the microchannel acts as a reference electrode. The fabricated NiO nanorod-based electrode has been characterized using X-ray diffraction, Raman spectroscopy, HR-TEM, FT-IR, UV-visible spectroscopy and electrochemical techniques. The presented NRs-NiO based microfluidic sensor exhibits linearity in the range of 1.5-10.3 mM, a high sensitivity of 0.12 mA mM(-1) cm(-2) and a low value of 0.16 mM of the Michaelis Menten constant (Km). PMID- 23446332 TI - Effectiveness of systemic high-dose dexamethasone therapy for idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: To evaluate the effectiveness of systemic high-dose dexamethasone therapy for sudden sensorineural hearing loss in comparison to the previous treatment regimen at our clinic with systemic prednisone 100 mg daily for 7 days analyzed in a previous study. METHODS: We conducted a retrospective review of an electronic patient data base of 79 patients with idiopathic sudden sensorineural hearing loss. The standard treatment was orally applied dexamethasone (1st to 3rd day: 40 mg daily, 4th to 6th day: 10 mg daily) in an ambulant setting. The primary endpoint was change in hearing threshold from the initial audiogram to an audiogram at least 4 weeks later. Factors that were analyzed included patient's age, interval between onset of symptoms and start of treatment, presence or absence of dizziness and tinnitus, the audiogram pattern, severity of hearing loss and hearing in the opposite ear. Hearing gain was expressed either as absolute or relative hearing gain. Functionally relevant recovery of hearing was defined as the final pure-tone average (PTA) of 30 dB or less (or the same as the PTA of the opposite ear +/- 10 dB). Furthermore, we calculated the percentage of patients with complete, partial and no recovery as defined in the recently published Clinical Practice Guideline of the American Academy of Otolaryngology - Head and Neck Surgery Foundation. We then compared our results with the previous treatment regimen carried out at our clinic. RESULTS: The average initial PTA hearing loss in the affected ear compared to baseline PTA of the unaffected ear was 51.5 +/- 20.9 dB (mean +/- SD). The mean absolute hearing gain was 44.4 +/- 18.1 dB. The mean relative hearing gain was 86 +/- 19%. Of the total, 87% had functionally relevant recovery of hearing. All of our patients showed partial (24%) or complete recovery (76%). No difference in recovery rate could be detected between patients with start of therapy within 24 h and patients with beginning of therapy within 7 days. We found a correlation between the severity of hearing loss and functionally relevant recovery. A mild hearing loss was noted in 34% of patients, with an average relative hearing gain of 89% and a functionally relevant recovery in 96% of them; the 9% of patients with initial deafness showed a mean relative hearing gain of 69% and a functionally relevant recovery in 43%. The audiogram pattern with low- or high-frequency hearing loss showed the best recovery rate; the poorest recovery rate was found in patients with initial deafness. CONCLUSION: Application of high-dose orally applied dexamethasone seems to improve the recovery outcomes in comparison to prednisone 100 mg p.o. for 7 days. PMID- 23446334 TI - BTB and CNC homolog 1 (Bach1) deficiency ameliorates TNBS colitis in mice: role of M2 macrophages and heme oxygenase-1. AB - BACKGROUND: BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1), which plays an important role in the protection of cells and tissues against acute and chronic inflammation. However, the role of Bach1 in the gastrointestinal mucosal defense system remains little understood. HO-1 supports the suppression of experimental colitis and localizes mainly in macrophages in colonic mucosa. This study was undertaken to elucidate the Bach1/HO-1 system's effects on the pathogenesis of experimental colitis. METHODS: This study used C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice in which colonic damage was induced by the administration of an enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Subsequently, they were evaluated macroscopically, histologically, and biochemically. Peritoneal macrophages from the respective mice were isolated and analyzed. Then, wild-type mice were injected with peritoneal macrophages from the respective mice. Acute colitis was induced similarly. RESULTS: TNBS-induced colitis was inhibited in Bach1-deficient mice. TNBS administration increased the expression of HO-1 messenger RNA and protein in colonic mucosa in Bach1-deficient mice. The expression of HO-1 mainly localized in F4/80-immunopositive and CD11b-immunopositive macrophages. Isolated peritoneal macrophages from Bach1-deficient mice highly expressed HO-1 and also manifested M2 macrophage markers, such as Arginase-1, Fizz-1, Ym1, and MRC1. Furthermore, TNBS-induced colitis was inhibited by the transfer of Bach1-deficient macrophages into wild-type mice. CONCLUSIONS: Deficiency of Bach1 ameliorated TNBS-induced colitis. Bach1-deficient macrophages played a key role in protection against colitis. Targeting of this mechanism is applicable to cell therapy for human inflammatory bowel disease. PMID- 23446333 TI - Predictors of temporary and permanent work disability in patients with inflammatory bowel disease: results of the swiss inflammatory bowel disease cohort study. AB - BACKGROUND: Inflammatory bowel disease can decrease the quality of life and induce work disability. We sought to (1) identify and quantify the predictors of disease-specific work disability in patients with inflammatory bowel disease and (2) assess the suitability of using cross-sectional data to predict future outcomes, using the Swiss Inflammatory Bowel Disease Cohort Study data. METHODS: A total of 1187 patients were enrolled and followed up for an average of 13 months. Predictors included patient and disease characteristics and drug utilization. Potential predictors were identified through an expert panel and published literature. We estimated adjusted effect estimates with 95% confidence intervals using logistic and zero-inflated Poisson regression. RESULTS: Overall, 699 (58.9%) experienced Crohn's disease and 488 (41.1%) had ulcerative colitis. Most important predictors for temporary work disability in patients with Crohn's disease included gender, disease duration, disease activity, C-reactive protein level, smoking, depressive symptoms, fistulas, extraintestinal manifestations, and the use of immunosuppressants/steroids. Temporary work disability in patients with ulcerative colitis was associated with age, disease duration, disease activity, and the use of steroids/antibiotics. In all patients, disease activity emerged as the only predictor of permanent work disability. Comparing data at enrollment versus follow-up yielded substantial differences regarding disability and predictors, with follow-up data showing greater predictor effects. CONCLUSIONS: We identified predictors of work disability in patients with Crohn's disease and ulcerative colitis. Our findings can help in forecasting these disease courses and guide the choice of appropriate measures to prevent adverse outcomes. Comparing cross-sectional and longitudinal data showed that the conduction of cohort studies is inevitable for the examination of disability. PMID- 23446335 TI - Early life stress triggers persistent colonic barrier dysfunction and exacerbates colitis in adult IL-10-/- mice. AB - BACKGROUND: It has become increasingly evident that disease flares in the human inflammatory bowel diseases are influenced by life stress. It is known that life stress can trigger disturbances in intestinal barrier function and activate proinflammatory signaling pathways, which are important contributors to intestinal inflammation and clinical disease; however, the exact mechanisms of stress-induced inflammatory bowel disease exacerbations remain to be elucidated. Here, we presented a model of early life stress-induced exacerbation of colitis in interleukin (IL)-10 mice. METHODS: C57Bl/6 wild-type and IL-10 mice were exposed to neonatal maternal separation (NMS) stress on postnatal days 1 to 18 and reared under normal conditions until 10 to 12 weeks of age. At this time, histopathology, colitis scores, intestinal barrier function, proinflammatory cytokine expression, and mast cell activity were evaluated. RESULTS: NMS increased the severity of colitis IL-10 mice indicated by greater colitis scores and colonic proinflammatory cytokine concentrations. NMS and IL-10 increased colonic permeability; however, NMS alone did not induce colitis. Increased mast cell activation and colonic tryptase release were observed in IL-10 mice exposed to NMS, indicating mast cell activation. CONCLUSIONS: This study demonstrates that colitis in IL-10 mice can be exacerbated by NMS stress. The precise mechanisms of enhanced colitis severity in NMS IL10 mice are unclear but persistent defects in intestinal barrier function likely play a contributing role. NMS serves as a novel model to investigate the mechanisms by which early life stress influences the development and course of inflammatory bowel disease in adulthood. PMID- 23446337 TI - Elective switching from infliximab to adalimumab in stable Crohn's disease. AB - BACKGROUND: Elective switching of biological therapy in patients with Crohn's disease (CD) in remission is generally discouraged, given the theoretical risk of antibody formation and loss of response. The aim of this study was to assess efficacy and tolerability of adalimumab (ADA) therapy after an elective switch from infliximab (IFX) in patients with stable CD. METHODS: Patients with CD with stable disease for >6 months (Harvey-Bradshaw Index <= 8) on IFX were eligible for this prospective, open-label single-center study. The primary endpoint was termination of ADA therapy. Disease activity (Harvey-Bradshaw Index, laboratory results) and adverse events were documented during the follow-up. RESULTS: We enrolled 29 patients with CD (19 women, mean age, 39 years; interquartile range, 23-58 years) who switched from IFX to ADA. At the end of the 54-week follow-up period, 72% of patients continued ADA therapy. Eight patients discontinued ADA therapy due to disease activity (n = 3), side effects (n = 4), or general symptoms (n = 1). After discontinuation of ADA, 4 patients switched back to IFX, and no infusion reactions occurred. No significant changes were observed in Harvey-Bradshaw Index scores, C-reactive protein, and leukocyte counts at 0 versus 54 weeks. Half of the patients who discontinued ADA showed an elevated baseline C-reactive protein. CONCLUSIONS: The majority of patients with CD (72%) continued therapy and maintained remission after an elective switch from IFX to ADA, although switching back to IFX, if required, was well tolerated. However, elective switching of anti-tumor necrosis factor therapy in stable CD should be carefully considered, given the risk of loss of response and the limited options for alternative maintenance therapies. PMID- 23446336 TI - Rates and predictors of oral medication adherence in pediatric patients with IBD. AB - BACKGROUND: Symptoms of inflammatory bowel disease (IBD) include bloody diarrhea, fatigue, abdominal pain, and weight loss. Long-term management of remission for most patients requires adherence to taking 1 or more oral medications daily, in the absence of symptoms. We investigated whether disease characteristics and behavioral characteristics predict adherence to prescribed medical regimens. METHODS: : Patients aged 8 to 17.5 years, newly diagnosed with IBD, and a matched cohort previously diagnosed were studied over a 6-month period. Adherence was assessed using medication electronic monitoring devices (Medication Event Monitoring Systems); participants and parents completed questionnaires regarding emotional and behavioral functioning, and biological parameters were monitored. RESULTS: : Adherence was monitored for 45 newly and 34 previously diagnosed patients. In total, 16,478 patient-days (including 12,066 discrete days) were electronically monitored. Overall, 70.6% of 5-aminosalicylic acid and 65.4% of 6 mercaptopurine doses were taken. Only 25% and 15% of older adolescents took at least 80% of their 5-aminosalicylic acid and 6-mercaptopurine, respectively, compared with about 83% and 64% of 8-year-olds to 11-year-olds. Only age and behavioral issues were statistically linked to rates of adherence. CONCLUSIONS: Adherence to commonly prescribed oral medications for IBD is challenging for patients. Screening for emotional and behavioral problems, especially among older adolescents, would be important in identifying patients at risk of poor adherence, who might benefit from interventions. Biological solutions, although critical, when applied without attention to behavioral issues, are not likely to provide the level of therapeutic benefit that can be provided in a combined biobehavioral approach. PMID- 23446339 TI - Prevention of postoperative recurrence of Crohn's disease: what does the evidence support? AB - Patients who have undergone intestinal resection for Crohn's disease frequently develop endoscopic and clinical recurrence of their disease. Active smokers and those with perforating disease appear to be at a higher risk of this development. A number of agents have been shown in randomized controlled trials to reduce the risk of endoscopic and clinical recurrence, but international guidelines are currently ambiguous on which agent should be used. Because there are wide-ranging efficacy estimates, safety profiles, and costs for the various proven prophylactic agents, physicians should personalize the management of individual patients based on their estimated probability of clinical recurrence (low/high). Such risk stratification could be based on the patient's clinical profile with or without early postoperative endoscopic surveillance. Ongoing trials using this "tailored" strategy should provide answers on whether this approach allows optimal selection of proven therapies. PMID- 23446341 TI - Enantioselective separation of dansyl-DL-amino acids and some racemates on "click" functionalized native alpha-cyclodextrin based sub-2 MUm columns. AB - The current work demonstrates that native alpha-cyclodextrin, anchored onto sub-2 MUm silica particles via "click" reactions and packed into a 5 cm column, was found to be effective for the resolution of 11 pairs of dansyl-DL-amino acids (DAAs) using ultra-high performance liquid chromatography (UHPLC). All DAAs were completely or partially separated on the column and the resolution achieved for 7 pairs of DAAs was significantly greater than 1.5. It was found that the buffer type exerted a profound impact on the separation. The effects of analyte substituents adjacent to the chiral center of analytes as well as operation conditions with respect to the separation efficiency were discussed. Five racemic compounds with single or double rings also got resolved on this short alpha-CD column to some extent. PMID- 23446340 TI - Strategies for detecting colon cancer and dysplasia in patients with inflammatory bowel disease. AB - The risk of colorectal cancer in patients with long-standing ulcerative colitis or colonic Crohn's disease is increased. Patients with long-standing ulcerative colitis are offered enrollment into programs of endoscopic surveillance. Although direct evidence for a protective effect of surveillance against death from colorectal cancer is limited, colorectal cancer is detected at an earlier stage and the corresponding prognosis is better. Targeting biopsies using pancolonic chromoendoscopy is superior to taking multiple random biopsies for the detection of dysplasia at colonoscopy. PMID- 23446338 TI - Predictors of endoscopic inflammation in patients with ulcerative colitis in clinical remission. AB - BACKGROUND: Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of active endoscopic disease, and factors associated with it, in patients with UC who are in clinical remission. METHODS: Prospective observational study in a single center. Patients with UC in clinical remission (by Simple Clinical Colitis Activity Index) were enrolled prospectively at the time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo subscore), and histologic score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. RESULTS: Overall, 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for >6 months, and 86% were currently prescribed maintenance medications. At endoscopy, 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy subscore >0), and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for <6 months (P = 0.001), white blood count (P = 0.01), and C-reactive protein level (P = 0.009). A model combining these 3 variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-to-severe endoscopic activity in patients in clinical remission (area under the curve, 0.86). In an unselected subgroup of patients who had peripheral blood mononuclear cell messenger RNA profiling, GATA3 messenger RNA levels were significantly higher in patients with endoscopic activity. CONCLUSIONS: Duration of clinical remission, white blood count, and C-reactive protein level can predict the probability of ongoing endoscopic activity, despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing. PMID- 23446342 TI - Effects of the morphology of nanostructured ZnO and interface modification on the device configuration and charge transport of ZnO/polymer hybrid solar cells. AB - In an organic-based solar cell, the short exciton diffusion length of organic materials requires effective donor-acceptor heterojunction at the nanoscale. In this work, hybrid inorganic/polymer solar cells based on ZnO nanostructures and poly(3-hexylthiophene) (P3HT) are constructed to study the effects of ZnO morphologies and wettability of the surface on the P3HT infiltration ability and charge transport mechanisms. The P3HT infiltrates the ZnO nanorod (NR) more remarkably than ZnO nanoparticle (NP) substrates. Although surface modification with indoline D205 dye molecules improves the wettability (viz. enlarges the contact angle) of NP surface, the P3HT infiltration distance decreases in comparison with the pristine NP case. This leads to relatively low short-circuit current density (Jsc) of the NP devices in comparison with that of the NR devices, even though the surface area of NP layers is larger than that of NR ones. Moreover, surface modification with squaraine dye onto the NR surface shows more significant improvement in Jsc than the NP case. This is due to the well aligned morphology of the NRs, which facilitates dye modification, P3HT infiltration, and charge transport processes. These indicate that the NRs are more qualified as electron accepting substrates and transport pathway in hybrid solar cells than NPs. PMID- 23446343 TI - C2362F mutation gives rise to an ADAMTS13-resistant von Willebrand factor. AB - von Willebrand factor (VWF) multimers result from proteolysis by the metalloprotease ADAMTS13. Since C2362F-VWF features abnormally large multimers with their triplet oligomer structure replaced by a diffuse smear, we explored the susceptibility of C2362F-VWF to ADAMTS13. VWF-enriched blood samples, obtained by cryoethanol precipitation of plasma from a patient with von Willebrand disease (VWD) homozygous for the C2362F mutation and a normal subject, were submitted to cleavage by recombinant ADAMTS13 under static conditions in the presence of urea. C2362F-VWF proved completely ADAMTS13-resistant in vitro. At any concentration of recombinant ADAMTS13 (from 0.1 uM to 1 uM), there was no evidence of the abnormally large VWF multimers of C2362F-VWF disappearing, nor any increased representation of triplet multimer bands, unlike the situation seen in normal VWF. This is due partly to a defective ADAMTS13 binding to C2362F-VWF under static conditions, as seen in both the patient's and recombinant mutated VWF proteins. These findings were associated with a significantly shorter than normal survival of C2362F-VWF after DDAVP, demonstrating that proteolysis and VWF survival may be independent phenomena. Our findings clearly demonstrate that the loss of cysteine 2362 makes VWF resistant to proteolysis by ADAMTS13, at least partly due to an impaired ADAMTS13 binding to VWF. This suggests that the B2 domain of VWF is involved in modulating ADAMTS13 binding to VWF and the consequent proteolytic process. The C2362F-VWF mutation also enables a new abnormality to be identified in the VWF-ADAMTS13 relationship, i.e. an ADAMTS13 resistant VWF. PMID- 23446344 TI - Structural visualization of key steps in human transcription initiation. AB - Eukaryotic transcription initiation requires the assembly of general transcription factors into a pre-initiation complex that ensures the accurate loading of RNA polymerase II (Pol II) at the transcription start site. The molecular mechanism and function of this assembly have remained elusive due to lack of structural information. Here we have used an in vitro reconstituted system to study the stepwise assembly of human TBP, TFIIA, TFIIB, Pol II, TFIIF, TFIIE and TFIIH onto promoter DNA using cryo-electron microscopy. Our structural analyses provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions, including how TFIIF engages Pol II and promoter DNA to stabilize both the closed pre-initiation complex and the open-promoter complex, and to regulate start--initiation complexes, combined with the localization of the TFIIH helicases XPD and XPB, support a DNA translocation model of XPB and explain its essential role in promoter opening. PMID- 23446345 TI - Low-temperature aqueous-phase methanol dehydrogenation to hydrogen and carbon dioxide. AB - Hydrogen produced from renewable resources is a promising potential source of clean energy. With the help of low-temperature proton-exchange membrane fuel cells, molecular hydrogen can be converted efficiently to produce electricity. The implementation of sustainable hydrogen production and subsequent hydrogen conversion to energy is called "hydrogen economy". Unfortunately, its physical properties make the transport and handling of hydrogen gas difficult. To overcome this, methanol can be used as a material for the storage of hydrogen, because it is a liquid at room temperature and contains 12.6 per cent hydrogen. However, the state-of-the-art method for the production of hydrogen from methanol (methanol reforming) is conducted at high temperatures (over 200 degrees Celsius) and high pressures (25-50 bar), which limits its potential applications. Here we describe an efficient low-temperature aqueous-phase methanol dehydrogenation process, which is facilitated by ruthenium complexes. Hydrogen generation by this method proceeds at 65-95 degrees Celsius and ambient pressure with excellent catalyst turnover frequencies (4,700 per hour) and turnover numbers (exceeding 350,000). This would make the delivery of hydrogen on mobile devices--and hence the use of methanol as a practical hydrogen carrier--feasible. PMID- 23446346 TI - Natural RNA circles function as efficient microRNA sponges. AB - MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA. PMID- 23446347 TI - Stem Cells: A unifying theory for the crypt. PMID- 23446349 TI - Porous materials with optimal adsorption thermodynamics and kinetics for CO2 separation. AB - The energy costs associated with the separation and purification of industrial commodities, such as gases, fine chemicals and fresh water, currently represent around 15 per cent of global energy production, and the demand for such commodities is projected to triple by 2050 (ref. 1). The challenge of developing effective separation and purification technologies that have much smaller energy footprints is greater for carbon dioxide (CO2) than for other gases; in addition to its involvement in climate change, CO2 is an impurity in natural gas, biogas (natural gas produced from biomass), syngas (CO/H2, the main source of hydrogen in refineries) and many other gas streams. In the context of porous crystalline materials that can exploit both equilibrium and kinetic selectivity, size selectivity and targeted molecular recognition are attractive characteristics for CO2 separation and capture, as exemplified by zeolites 5A and 13X (ref. 2), as well as metal-organic materials (MOMs). Here we report that a crystal engineering or reticular chemistry strategy that controls pore functionality and size in a series of MOMs with coordinately saturated metal centres and periodically arrayed hexafluorosilicate (SiF(2-)(6)) anions enables a 'sweet spot' of kinetics and thermodynamics that offers high volumetric uptake at low CO2 partial pressure (less than 0.15 bar). Most importantly, such MOMs offer an unprecedented CO2 sorption selectivity over N2, H2 and CH4, even in the presence of moisture. These MOMs are therefore relevant to CO2 separation in the context of post-combustion (flue gas, CO2/N2), pre-combustion (shifted synthesis gas stream, CO2/H2) and natural gas upgrading (natural gas clean-up, CO2/CH4). PMID- 23446348 TI - Circular RNAs are a large class of animal RNAs with regulatory potency. AB - Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences. PMID- 23446350 TI - Catalysis: A step closer to a methanol economy. PMID- 23446351 TI - Molecular biology: Circles reshape the RNA world. PMID- 23446352 TI - Neuroscience: The units of a song. PMID- 23446353 TI - Intestinal label-retaining cells are secretory precursors expressing Lgr5. AB - The rapid cell turnover of the intestinal epithelium is achieved from small numbers of stem cells located in the base of glandular crypts. These stem cells have been variously described as rapidly cycling or quiescent. A functional arrangement of stem cells that reconciles both of these behaviours has so far been difficult to obtain. Alternative explanations for quiescent cells have been that they act as a parallel or reserve population that replace rapidly cycling stem cells periodically or after injury; their exact nature remains unknown. Here we show mouse intestinal quiescent cells to be precursors that are committed to mature into differentiated secretory cells of the Paneth and enteroendocrine lineage. However, crucially we find that after intestinal injury they are capable of extensive proliferation and can give rise to clones comprising the main epithelial cell types. Thus, quiescent cells can be recalled to the stem-cell state. These findings establish quiescent cells as an effective clonogenic reserve and provide a motivation for investigating their role in pathologies such as colorectal cancers and intestinal inflammation. PMID- 23446354 TI - Elemental gesture dynamics are encoded by song premotor cortical neurons. AB - Quantitative biomechanical models can identify control parameters that are used during movements, and movement parameters that are encoded by premotor neurons. We fit a mathematical dynamical systems model including subsyringeal pressure, syringeal biomechanics and upper-vocal-tract filtering to the songs of zebra finches. This reduces the dimensionality of singing dynamics, described as trajectories (motor 'gestures') in a space of syringeal pressure and tension. Here we assess model performance by characterizing the auditory response 'replay' of song premotor HVC neurons to the presentation of song variants in sleeping birds, and by examining HVC activity in singing birds. HVC projection neurons were excited and interneurons were suppressed within a few milliseconds of the extreme time points of the gesture trajectories. Thus, the HVC precisely encodes vocal motor output through activity at the times of extreme points of movement trajectories. We propose that the sequential activity of HVC neurons is used as a 'forward' model, representing the sequence of gestures in song to make predictions on expected behaviour and evaluate feedback. PMID- 23446355 TI - An exploratory study of the policy process and early implementation of the free NHIS coverage for pregnant women in Ghana. AB - BACKGROUND: Pregnant women were offered free access to health care through National Health Insurance (NHIS) membership in Ghana in 2008, in the latest phase of policy reforms to ensure universal access to maternal health care. During the same year, free membership was made available to all children (under-18). This article presents an exploratory qualitative analysis of how the policy of free maternal membership was developed and how it is being implemented. METHODS: The study was based on a review of existing literature - grey and published - and on a key informant interviews (n = 13) carried out in March-June 2012. The key informants included representatives of the key stakeholders in the health system and public administration, largely at national level but also including two districts. RESULTS: The introduction of the new policy for pregnant women was seen as primarily a political initiative, with limited stakeholder consultation. No costing was done prior to introduction, and no additional funds provided to the NHIS to support the policy after the first year. Guidelines had been issued but beyond collecting numbers of women registered, no additional monitoring and evaluation have yet been put in place to monitor its implementation. Awareness of the under-18 s policy amongst informants was so low that this component had to be removed from the final study. Initial barriers to access, such as pregnancy tests, were cited, but many appear to have been resolved now. Providers are concerned about the workload related to services and claims management but have benefited from increased financial resources. Users still face informal charges, and are reported to have responded differentially, with rises in antenatal care and in urban areas highlighted. Policy sustainability is linked to the survival of the NHIS as a whole. CONCLUSIONS: Ghana has to be congratulated for its persistence in trying to address financial barriers. However, many themes from previous evaluations of exemptions policies in Ghana have recurred in this study particularly, the difficulties of getting timely reimbursement to facilities, of controlling charging of patients, and of reaching the poorest. This suggests that providing free care through a national health insurance system has not solved systemic weaknesses. The wider concerns about raising the quality of care, and ensuring that all supply-side and demand-side elements are in place to make the policy effective will also take a longer term and bigger commitment. PMID- 23446358 TI - Recent advances in organic transistor printing processes. AB - Recent progress in organic field-effect transistor (OFET) printing processes is reviewed, and a perspective on the future of the field is discussed. The principles underlying the OFET printing techniques are introduced according to two categories: direct write printing and transfer printing. A comprehensive overview of the use of printing techniques in OFET production processes is also provided. Considerations for improving OFET device performance using printing processes are explored. Prior to OFET commercialization, the OFET printing techniques must satisfy several requirements, as discussed here. PMID- 23446356 TI - Imposing function down a (cupin)-barrel: secondary structure and metal stereochemistry in the alphaKG-dependent oxygenases. AB - The Fe(ii)/alphaketoglutarate (alphaKG) dependent oxygenases catalyze a diverse range of reactions significant in biological processes such as antibiotic biosynthesis, lipid metabolism, oxygen sensing, and DNA and RNA repair. Although functionally diverse, the eight-stranded beta-barrel (cupin) and HX(D/E)XnH facial triad motifs are conserved in this super-family of enzymes. Crystal structure analysis of 25 alphaKG oxygenases reveals two stereoisomers of the Fe cofactor, Anti and Clock, which differ in the relative position of the exchangeable ligand position and the primary substrate. Herein, we discuss the relationship between the chemical mechanism and the secondary coordination sphere of the alphaKG oxygenases, within the constraints of the stereochemistry of the Fe cofactor. Sequence analysis of the cupin barrel indicates that a small subset of positions constitute the second coordination sphere, which has significant ramifications for the structure of the ferryl intermediate. The competence of both Anti and Clock stereoisomers of Fe points to a ferryl intermediate that is 5 coordinate. The small number of conserved close contacts within the active sites of alphaKG oxygenases can be extended to chemically related enzymes, such as the alphaKG-dependent halogenases SyrB2 and CytC3, and the non-alphaKG dependent dioxygenases isopenicillin N synthase (IPNS) and cysteine dioxygenase (CDO). PMID- 23446357 TI - Impact of a modified data capture period on Liu comorbidity index scores in Medicare enrollees initiating chronic dialysis. AB - BACKGROUND: The Liu Comorbidity Index uses the United States Renal Data System (USRDS) to quantify comorbidity in chronic dialysis patients, capturing baseline comorbidities from days 91 through 270 after dialysis initiation. The 270 day survival requirement results in sample size reductions and potential survivor bias. An earlier and shorter time-frame for data capture could be beneficial, if sufficiently similar comorbidity information could be ascertained. METHODS: USRDS data were used in a retrospective observational study of 70,114 Medicare- and Medicaid-eligible persons who initiated chronic dialysis during the years 2000 2005. The Liu index was modified by changing the baseline comorbidity capture period to days 1-90 after dialysis initiation for persons continuously enrolled in Medicare. The scores resulting from the original and the modified comorbidity indices were compared, and the impact on sample size was calculated. RESULTS: The original Liu comorbidity index could be calculated for 75% of the sample, but the remaining 25% did not survive to 270 days. Among 52,937 individuals for whom both scores could be calculated, the mean scores for the original and the modified index were 7.4 +/- 4.0 and 6.4 +/- 3.6 points, respectively, on a 24-point scale. The most commonly calculated difference between scores was zero, occurring in 44% of patients. Greater comorbidity was found in those who died before 270 days. CONCLUSIONS: A modified version of the Liu comorbidity index captures the majority of comorbidity in persons who are Medicare-enrolled at the time of chronic dialysis initiation. This modification reduces sample size losses and facilitates inclusion of a sicker portion of the population in whom early mortality is common. PMID- 23446359 TI - Angiogenesis in villous chorangiosis observed by ultrastructural studies. AB - Chorangiosis is microscopically designated as more than ten terminal capillaries within the villous stroma of the placenta and is mostly related to chronic fetal hypoxia. However, the histogenetic relationship between increased number of terminal villous capillaries and chronic hypoxia has not yet been clarified. Of 665 placentas histologically examined at Saitama Medical University from 2003 to 2010, chorangiosis was found in 58 cases (8.7 %), which were mostly more than 35 gestational weeks. In addition, low birth weight (less than 2,500 g) infants (74.1 %) and those who suffered from cardiac anomalies, chromosome anomalies, and single umbilical artery comprised 32.7 % of cases. Placental lesions were associated with chorangiosis involved in infarct (46.6 %), intervillous thrombosis (20.7 %), and marginal hemorrhages (22.4 %). Scanning electron microscopic studies showed narrowing of vessel ostium and disorders of endothelium in the umbilical cord vessel complicated by chorangiosis. Furthermore, in transmission electron microscopic observation, not only the chorionic villi had multiple enlarged vessels within the villous stroma, but we also found that new capillaries were formed by angiogenesis with endothelial cells derived from fibroblasts under the chronic hypoxic state. PMID- 23446360 TI - Wetting behavior and activity of catalyst supports in carbon nanotube carpet growth. AB - A simple, reliable, and non-destructive approach based on contact angle measurements is described for predicting the activity of catalyst supports in carbon nanotube (CNT) carpet growth. The basic component of the surface free energy of different alumina supports - determined from the van Oss-Good-Chaudhury model and the Young-Dupre equation - was found to correlate with the activity of Fe catalyst during water-assisted CVD growth of CNT carpets. PMID- 23446361 TI - Acute ischemic brain lesions in infective endocarditis: incidence, related factors, and postoperative outcome. AB - BACKGROUND: Acute brain infarction affects the timing and regimen of cardiac surgery in patients with infective endocarditis (IE). We aimed to identify preoperative brain MRI characteristics, incidence, and related factors for acute ischemic lesions in left-sided IE patients undergoing cardiac surgery. Furthermore, we investigated whether preoperative acute ischemic lesions are associated with postoperative neurological complications in IE patients. METHODS: We retrospectively reviewed consecutive patients with a definite left-sided IE who underwent cardiac surgery in 6 university-affiliated hospitals from January 2004 to November 2011. Preoperative brain MRI evaluations were systematically performed on all patients without contraindications, regardless of neurological complications, with the aim of preventing perioperative complications. Patients were included if diffusion-weighted imaging and fluid-attenuated inversion recovery sequences were performed within 14 days after diagnosis. Associations between acute ischemic lesions and related factors were analyzed. Neurological complications within 30 days after surgery were evaluated for postoperative outcome analyses. RESULTS: Of 139 consecutive patients with left-sided IE who underwent cardiac surgery, 85 patients were evaluated in this study. The mean age was 58 +/- 16 years, and 22 patients (26%) were women. Preoperative MRI revealed acute ischemic lesions in 47 patients (55%), and 19 of these patients developed neurological symptoms. Among the patients with ischemic lesions, 24 (60%) had small lesions (<10 mm), 36 (77%) had multiple lesions, and 30 (64%) had lesions in multiple vascular territories. Compared to patients without ischemic lesions, patients with acute ischemic lesions were older and had significantly higher white blood cell counts and plasma C-reactive protein (CRP) levels, but lower hemoglobin levels. Logistic regression analyses showed that the white blood cell count and plasma CRP level were independently associated with acute ischemic lesions [adjusted OR per 1-SD increase were 2.21 (95% CI: 1.23-4.35) and 2.33 (95% CI: 1.27-4.96), respectively]. Three patients developed postoperative neurological complications, but preoperative acute ischemic lesions and postoperative complications were not associated. CONCLUSIONS: Preoperative MRI detected a high incidence of asymptomatic ischemic lesions in IE patients. Acute ischemic lesions were often small, multiple, and located in multiple vascular territories. Inflammatory reactions may play an important role in the development of ischemic lesions in IE patients. PMID- 23446362 TI - Increased skin inflammation and blood vessel density in human and experimental diabetes. AB - Systemic inflammation is associated with impaired wound healing in diabetes mellitus (DM) patients. Using immunohistochemistry techniques, the authors investigated changes in skin inflammation and skin blood vessels in human and experimental diabetes. Comparing to the non-DM human subjects, the total number of inflammatory cells per biopsy and the number of inflammatory cells around blood vessels, a strong indication of inflammation, were higher in DM subjects irrespective of their risk for developing diabetic foot ulcer. Inflammatory cell infiltration was robustly increased in all DM animal models compared with their non-DM controls. The number and density of blood vessels and CD31 positive proliferating endothelial cells around preexisting skin vessels was also higher in the DM patients. However, there were no differences in the skin blood flow between the non-DM and DM subjects. The number of skin blood vessels was also increased in the DM animals; however, these differences were less obvious than the ones observed for inflammatory cells. We conclude that skin inflammation and skin blood vessel density is increased in diabetic human subjects and in rodent and rabbit models of diabetes. PMID- 23446363 TI - Update on the diabetic foot 2012: the 14th biennial Malvern Diabetic Foot Conference, May 9-11, 2012. AB - The 14th biennial Malvern Diabetic Foot Conference was held in May 2012. Physicians, podiatrists, nurses, orthotists, surgeons, radiologists, and other professionals attended to reflect on the diabetic foot. The conference comprised interactive workshops, oral presentations of new research findings, and lectures from leading figures in the world of the diabetic foot. Over the 3 days, topics such as epidemiology, neuropathy, screening, vascular disease, prevention, and management among others were discussed. The conference has been an excellent platform from which to share new and ongoing research and it will without a doubt improve the treatment of the diabetic foot across the world. PMID- 23446364 TI - Leg ulcers associated with giant cell arteritis relapse. PMID- 23446365 TI - PICO: a revelation in topical negative pressure therapy? AB - The authors present the case of a 23-year-old paratrooper who was admitted to intensive therapy unit with florid meningococcal septicemia. Being young, fit, and well, he survived this acute episode with supportive therapy, antibiotics, and inotropes. He made a good recovery and was left with multiple wounds all over his body predominantly on the extensor aspects of his upper and lower limbs and torso. PMID- 23446366 TI - Super-oxidized solution (Dermacyn Wound Care) as adjuvant treatment in the postoperative management of complicated diabetic foot osteomyelitis: preliminary experience in a specialized department. AB - Surgery is usually used to treat diabetic foot osteomyelitis (DFO), whether primarily or in cases in which antibiotics are not able to control infection. In many cases, the bone is only partially removed, which means that residual infection remains in the bone margins, and the wound is left open to heal by secondary intent. The use of culture-guided postoperative antibiotic treatment and adequate management of the wound must be addressed. No trials exist dealing with local treatment in the postoperative management of these cases of complicated DFO. We decided to test a super-oxidized solution, Dermacyn Wound Care (DWC; Oculus Innovative Sciences Netherlands BV, Sittard, Netherlands) to obtain preliminary experience in patients in whom infected bone remained in the surgical wounds. Our hypothesis was that DWC could be useful to control infection in the residual infected bone and surrounding soft tissues and would thus facilitate healing. Fourteen consecutive patients who underwent conservative surgery for DFO, in whom clean bone margins could not be assured, were treated in the postoperative period with DWC. Eleven cases were located in the forefoot, 6 on the first ray and the rest in lesser toes, 1 in the Lisfranc joint, and 2 on the calcaneus. No side effects appeared during treatment. Neither allergies nor skin dermatitis were found. Limb salvage was successfully achieved in 100% of the cases. Healing was achieved in a median period of 6.8 weeks. PMID- 23446367 TI - A chronic leg ulcer presenting with Charcot-Marie-Tooth disease and type 2 diabetes: a case report. AB - Charcot-Marie-Tooth (CMT) disease is characterized by hereditary sensorimotor polyneuropathy with foot deformity, sensorineural hearing loss, moderate developmental delay, and gait disturbance. CMT presenting with type 2 diabetes and an ulcer has not been reported. This article reports a man who presented with the symptoms mentioned above and also with a leg ulcer and type 2 diabetes. He was diagnosed with CMT disease based on family history and genetic testing. A skin defect in the left leg had manifested for more than 1 year, and results of initial fasting plasma glucose revealed type 2 diabetes. The evolution of these manifestations, coupled with a slowly progressive weakness, numbness, muscular wasting, and sensory impairment, strongly suggested the co-occurrence of 3 different diseases in the same individual. PMID- 23446368 TI - Gram-negative diabetic foot osteomyelitis: risk factors and clinical presentation. AB - Osteomyelitis frequently complicates infections in the feet of patients with diabetes. Gram-positive cocci, especially Staphylococcus aureus, are the most commonly isolated pathogens, but gram-negative bacteria also cause some cases of diabetic foot osteomyelitis (DFO). These gram-negatives require different antibiotic regimens than those commonly directed at gram-positives. There are, however, few data on factors related to their presence and how they influence the clinical picture. We conducted a retrospective study to determine the variables associated with the isolation of gram-negative bacteria from bone samples in cases of DFO and the clinical presentation of these infections. Among 341 cases of DFO, 150 had a gram-negative isolate (alone or combined with a gram-positive isolate) comprising 44.0% of all patients and 50.8% of those with a positive bone culture. Compared with gram-positive infections, wounds with gram-negative organisms more often had a fetid odor, necrotic tissue, signs of soft tissue infection accompanying osteomyelitis, and clinically severe infection. By multivariate analysis, the predictive variables related to an increased likelihood of isolating gram-negatives from bone samples were glycated hemoglobin <7% (odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.1-3.5) and a wound caused by traumatic injury (OR = 2.0, 95% CI = 1.0-3.9). Overall, patients whose bone samples contained gram-negatives had a statistically significantly higher prevalence of leukocytosis and higher white blood cell counts than those without gram-negatives. In conclusion, gram-negative organisms were isolated in nearly half of our cases of DFO and were associated with more severe infections, higher white blood cell counts, lower glycated hemoglobin levels, and wounds of traumatic etiology. PMID- 23446370 TI - Factor V Leiden mutation-related chronic skin ulcers. AB - Chronic skin ulcers require extensive, systemic differential diagnosis; thus, they are difficult to diagnose and treat. Transient or persistent hypercoagulable states are among the rare causes of skin ulcers. Here, we present the case of a 27-year-old woman patient with recurrent, nonhealing skin ulcers of 8 years' duration, who had been treated unsuccessfully with various medications under different diagnoses at different clinics. On admission, a skin biopsy demonstrated occlusive vasculopathy, and the search for an inherited hypercoagulable state revealed a heterozygous factor V Leiden mutation. The patient was treated with anticoagulants and hyperbaric oxygen. On treatment, the skin lesions healed and did not recur. PMID- 23446371 TI - Skeletal tuberculosis following proximal tibia fracture. AB - Over the past several years, there has been a rise in incidence of tuberculosis in both developing and developed countries. Tuberculosis complicating a fracture is uncommon. In this article, we report the case of a 10-year-old patient with a proximal tibia fracture who developed discharging wound over the fracture site after 2 weeks of initial trauma. The fracture was showing no signs of healing. A diagnosis of tuberculosis of proximal tibia was made on the basis of polymerase chain reaction and histology. After antituberculous treatment was started, the sinus healed and the fracture united. To the best of our knowledge, such a presentation has not been documented. PMID- 23446369 TI - Calcific myonecrosis of the leg treated by debridement and limited access dressing. AB - Calcific myonecrosis is a rare late complication of limb trauma characterized by liquefaction and dystrophic calcification of muscles in the single compartment, usually in the leg. This occurs many years after the trauma and is probably due to chronic compartment syndrome. We report 2 cases of calcific myonecrosis involving the anterior compartment of the leg that presented to us in an advanced stage of multiple sinuses discharging calcific material. Incision and drainage had been attempted at a local hospital prior to presentation at our hospital resulting in a non healing wound. Both patients had a history of antecedent trauma to the leg a few years ago. Patients were treated by thorough debridement of the involved muscles in the anterior compartment. Limited access dressing (LAD) was used to manage the dead space left after debridement. After application of the LAD, the wound was covered with split skin grafting. In both patients, healing of the cavity following debridement was facilitated by application of limited access dressing. While the wound completely healed, the disability due to extensive debridement of anterior compartment of the leg persisted. At the latest follow-up, the patients were asymptomatic without any recurrence. Thorough debridement of the compartment involved and application of LAD may be another option of treating calcific myonecrosis of the leg, which was initially considered a "do not touch" lesion. Morbidity due to surgery and need of repeated surgeries for recurrences should be kept in mind and regular follow-up should be considered. PMID- 23446373 TI - Total hip replacement in an ipsilateral above-the-knee amputation: surgical technique, rehabilitation, and review of the literature. AB - In this article, we present a case report of a 62-year-old patient who previously underwent an above-the-knee amputation for vascular disease and we performed a total hip replacement on him because of hip osteoarthritis. As the only postoperative complication, the patient developed a methicillin-resistant Staphylococcus aureus surgical site infection, which was successfully treated. The surgical technique and the postoperative rehabilitation program are described in detail in an attempt to detect and face the challenges that patients with major lower limb amputations may present. The literature is reviewed and all known cases of hip replacements in amputees are presented. PMID- 23446372 TI - The application of distally pedicled peroneus brevis muscle flaps and retrograde neurocutaneous accompanying artery flaps for treatment of bony and soft-tissue 3 dimensional defects of the lower leg and foot. AB - To investigate the clinical effect of distally pedicled peroneus brevis muscle flaps and retrograde neurocutaneous flaps on treatment of bone and soft-tissue 3 dimensional defects of the lower leg and foot, the authors retrospectively studied all the patients admitted in their center in 3 consecutive years with bone and soft-tissue defects from March 2008 to February 2011; 21 patients suffering from traumatic and osteomyelitis were treated with peroneus brevis muscle flaps, for obliterating the hole-shaped bony defects after osteomyelitis debridement, and neurocutaneous flaps, for repairing associated soft-tissue defects. After thorough debridement, the average size of soft-tissue defects was 2 cm * 2 cm to 13 cm * 9 cm and that of bony defects was 2 cm * 2 cm * 2 cm to 6 cm * 3 cm * 3 cm. Neurocutaneous flaps completely survived in 20 cases, and the wounds healed at stage I; 1 case developed necrosis in the distal part of the peroneus brevis muscle flap and sural nerve flap, and the wound healed with a saphenous nerve flap. The flaps maintained good texture and shape during a follow up of 6 to 24 months. Recurrence of osteomyelitis was not observed in any of the patients. In conclusion, distally pedicled peroneus brevis muscle flaps and retrograde neurocutaneous flaps are simple, safe, reliable, and suitable for clinical treatment of hole-shaped bony defects and reconstruction of soft-tissue defects within a single stage, especially when the 2 defects are located in different 3-dimensional spaces. PMID- 23446374 TI - CD4+ T cells in atherosclerosis: regulation by platelets. AB - Atherosclerosis is an inflammatory and thrombotic disease, in which both CD4+ T cells and platelets play important roles throughout all stages of atherogenesis. CD4+ T cells are the most abundant T cells present in atherosclerotic lesions. They are primarily seen as type 1 T helper (Th1) cells, while the other CD4+ T cell subsets Th2, Th17, and regulatory T (Treg) cells are also found in the lesions with lower frequencies. CD4+ T effector cells release various cytokines, which exert paracrine or autocrine effects among different CD4+ T cell subsets and other lesional cells and subsequently modulate inflammatory processes in the lesions. Platelets are instrumental in thrombosis and haemostasis, but also play important regulatory roles in immune response, inflammation, and angiogenesis. The present review summarises the current knowledge and/or understanding on how platelets regulate recruitment, activation, differentiation, and cytokine production of different CD4+ T cell subsets, as well as impacts of the platelet- CD4+ T cell interactions on atherogenesis. The research perspectives of platelet CD4+ T cell interaction in atherosclerosis are also discussed. PMID- 23446375 TI - Analysis of single particle photodegradation using photothermal infrared microspectroscopy. AB - The increasing use of high throughput methods, coupled with the need to develop approaches to anticipate long term stability issues, has necessitated the introduction of testing approaches whereby extremely small samples may be rapidly analysed. A novel method is described whereby the UV light-induced degradation of single particles of a model drug, nifedipine, may be rapidly and simply monitored using photothermal infrared microspectroscopy (PTMS). The technique involves the contact attachment of individual particles to a heated probe tip composed of a modified Wollaston wire which enables temperature fluctuations to be measured. Application of a focused IR beam to excite the sample allows measurement and subsequent Fourier transformation of the resultant interferogram to produce an IR spectrum which is in good agreement with that obtained from conventional IR methods. By application of a UV source to the assembly for specified time periods, we demonstrate that it is possible to monitor the appearance of peaks associated with degradation products as a function of time. The technique is critically evaluated in terms of practical issues associated with volatilization, particle size effects and orientation to the light source as well as more general issues associated with the sensitivity, resolution and quantitative interpretation of data from the PTMS technique. Overall the method has been shown to be capable of rapid measurement of photo-instability on individual particles, with important implications for development of the approach as a rapid screening or high throughput technique, although there are practical and theoretical limitations to reliable quantitative analysis at the present time. PMID- 23446376 TI - Hemoglobin level in cervical cancer: a surrogate for an infiltrative phenotype. AB - OBJECTIVE: Hemoglobin (Hb) is a prognostic factor in cervical cancer, but the underlying mechanisms remain unknown. In this study, we hypothesized that low Hb level, either before or during radiotherapy (RT), is a surrogate for a more infiltrative and therefore aggressive disease, with uterine corpus invasion and nodal metastases. METHODS AND MATERIALS: Prospectively collected data of patients with locally advanced cervical cancer treated with curative intent using chemoradiation at a tertiary academic center was reviewed. All eligible patients had a positron emission tomographic scan and pelvic magnetic resonance imaging. Hemoglobin levels before RT and Hb nadir during RT were collected from the medical record. RESULTS: The median follow-up for 263 eligible patients was 38.7 months. Ninety-six patients (36.5%) had both uterine corpus invasion and positron emission tomography-positive nodal disease (C+N+). Patients with pretreatment Hb level of less than 120 g/L were more likely to have C+N+ disease (47%) compared with patients with a high pretreatment Hb level (32%; P = 0.034). The 3-year disease-free survival and overall survival (OS) were significantly lower in the C+N+ group compared with the remaining patients (40.1% vs 76.1%, P < 0.001, and 59.7% vs 83.1%, P < 0.001, respectively). Patients with low Hb nadir were more likely to have a C+N+ disease (P < 0.001), and low Hb nadir during RT was significantly an indicator of a higher recurrence rate (P = 0.002) and lower OS (P < 0.001). In multifactor analysis, statistically significant prognostic factors for OS included histology, high-echelon nodal involvement, tumor volume on magnetic resonance imaging, C+N+ status, and Hb nadir during treatment. Pretreatment Hb level was not an independent prognostic factor. CONCLUSIONS: The combination of corpus invasion and nodal metastases is associated with lower Hb level and inferior prognosis. Because C+N+ state is related to tumor growth from early invasion to the time of presentation, it is unlikely that the correction of Hb level during treatment will have a major impact on outcome. PMID- 23446377 TI - Pregnancy outcomes after treatment for cervical intraepithelial neoplasia in a single NHS hospital. AB - OBJECTIVE: The objective of this study was to assess the adverse pregnancy outcomes in women who had treatment for cervical intraepithelial neoplasia. METHODS: This was a retrospective cohort using data linkage. Pathology databases from Whipps Cross University Hospital were used to identify women with a histological sample taken at colposcopy between 1995 and 2009. Births for these women were identified through the hospitals' obstetric database. A total of 876 births (from 721 women) were identified. Logistic regression was used to assess the relationship between adverse pregnancy outcomes and treatment for cervical intraepithelial neoplasia before delivery. Results were adjusted by ethnicity, deprivation, and parity. RESULTS: After taking into account parity, socioeconomic status, and ethnicity, receiving any type of excisional treatment (single or multiple) before birth increased the risk of preterm labor compared with having a punch biopsy only (adjusted relative risk, 1.61; 95% confidence interval, 1.11 2.32). Preterm deliveries that occurred after a spontaneous onset of labor were found to be more likely after treatment for cervical disease (adjusted relative risk, 1.68; 95% confidence interval, 1.11-2.52). CONCLUSIONS: Women receiving any type of excisional treatment before delivery are at increased risk of preterm delivery when compared with women attending colposcopy but not treated. Although we took into account the effects of parity, socioeconomic status, and ethnicity, residual confounding factors may be unidentified. PMID- 23446378 TI - Reduced expression of NDUFS3 and its clinical significance in serous ovarian cancer. AB - OBJECTIVE: Expression of the mitochondrial protein, nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) Fe-S protein 3 (NDUFS3), down-regulates in some cancers including breast and kidney. This study evaluates NDUFS3 expression and its clinical significance in human serous ovarian adenocarcinoma. METHODS: 30 ovarian normal epithelium, 30 benign serous adenoma, and 100 serous carcinoma tissues were collected, and the expression of NDUFS3 protein and messenger RNA was evaluated by immunohistochemistry, Western blot, and real-time reverse transcription-polymerase chain reaction, respectively. Relationships between NDUFS3 protein expression and clinicopathologic parameters and disease free and overall survival were also studied. RESULTS: The expression of NDUFS3 messenger RNA and protein was significantly decreased in serous ovarian adenocarcinoma compared with normal ovarian epithelium and benign serous adenoma (both P < 0.001). Reduced NDUFS3 immunostaining correlated with advanced Federation of Gynecology and Obstetrics stage (P = 0.002) and suboptimal residual disease after primary surgery (P = 0.021). Reduced NDUFS3 expression also correlated with shorter disease-free (P = 0.002) and overall survival (P = 0.004). CONCLUSIONS: NDUFS3 expression is down-regulated in serous ovarian adenocarcinoma, suggesting that NDUFS3 may contribute to the development of serous ovarian cancer. PMID- 23446379 TI - Are the human papillomavirus genotypes different in cervical cancer and intraepithelial neoplasia in Jewish Israeli women, a low-risk population? AB - OBJECTIVES: Israel is traditionally considered to have the lowest prevalence of cervical cancer compared with that in other countries of the Western world. The aim of the present study was to establish the human papillomavirus (HPV) genotypes distribution among Israeli Jewish women with premalignant and cervical cancer. METHODS: Fifty-two specimens with invasive cervical cancer and 50 specimens with high-grade cervical intraepithelial neoplasia (CIN2/3) were identified. Human papillomavirus genotyping in paraffin-embedded specimens was performed by deparaffinization of the tissue sections and DNA extraction, followed by HPV genotype detection using a validated polymerase chain reaction (PCR)-based HPV GenoArray test kit, to simultaneously identify 21 HPV genotypes. RESULTS: Forty-eight (48/52; 92.3%) cervical cancer samples demonstrated PCR amplifiable DNA (non-HPV DNA). Forty (83.3%) of 48 samples were high-risk (HR) HPV positive. Six (12.5%) of 48 patients showed multiple HR HPV infections. Human papillomavirus types 16 and 18 dominated covering 28 (58.3%) and 14 (29.16%) of 48 samples. Human papillomavirus types 16 and 18 coinfected all 6 cases of multiple HR HPV infections. In CIN2/3 samples, 37 (78.7%) of 47 samples demonstrated PCR-amplifiable DNA (non-HPV DNA), and 20 (54.0%) of these 37 samples were infected by HPV. Human papillomavirus type 16 was found in 19 (95.0%) of 20 cases. Human papillomavirus type 18 was found in 3 (15.0%) of 20 cases; hence, HPV16 and HPV18 contributed to 100% of the cases. CONCLUSIONS: Human papillomavirus types 16 and 18 were responsible for the vast majority of invasive cervical cancer and CIN2/3 specimens (81.2% and 100%, respectively). Therefore, it is essential to include the HPV vaccine in the vaccine schedule of the Israeli population. PMID- 23446381 TI - Metabolism: Insulin's daily rhythm. PMID- 23446380 TI - Nuclear safety lies in greater transparency. PMID- 23446382 TI - Biogeochemistry: Carbon cycles Down Under. PMID- 23446383 TI - Nanomaterials: Solid carbon, springy and light. PMID- 23446384 TI - Medicine: Stem cells guide Alzheimer's drugs. PMID- 23446385 TI - Holography: Liquid crystal movies. PMID- 23446386 TI - Animal behaviour: How monarchs know where to go. PMID- 23446387 TI - Microbiology: Healthier prehistoric plaque. PMID- 23446388 TI - Ecology: Flower power guides bees. PMID- 23446389 TI - Neuroscience: Lonely teen rats choose drugs. PMID- 23446390 TI - Seven days: 22-28 February 2013. PMID- 23446391 TI - Physicist tipped for US energy post. PMID- 23446392 TI - Cholesterol limits lose their lustre. PMID- 23446393 TI - Tusk tracking will tackle illegal trade. PMID- 23446394 TI - Stem cells cruise to clinic. PMID- 23446396 TI - Correction. PMID- 23446395 TI - US science to be open to all. PMID- 23446397 TI - Circular RNAs throw genetics for a loop. PMID- 23446398 TI - Big biology: The 'omes puzzle. PMID- 23446399 TI - America's research adviser: Science's go-to guy. PMID- 23446400 TI - National Academy of Sciences: Move with the times. PMID- 23446401 TI - Brain training: Games to do you good. PMID- 23446403 TI - Arts: Reinventing Galileo. PMID- 23446402 TI - Urban planning: Monumental knock-offs. PMID- 23446406 TI - Philosophy: 'Antifragility' as a mathematical idea. PMID- 23446407 TI - Scientific genius: Will continue to thrive. PMID- 23446408 TI - Parental consent: Guarding children's genetic privacy. PMID- 23446409 TI - Energy efficiency: Don't belittle the rebound effect. PMID- 23446410 TI - Scientific genius: In different guises. PMID- 23446411 TI - Astrophysics: Black holes in a spin. PMID- 23446412 TI - Virology: Phages hijack a host's defence. PMID- 23446413 TI - Speech science: Tuned to the rhythm. PMID- 23446414 TI - Nutrition: When guests turn hostile. PMID- 23446415 TI - Cancer: Stress mixes chromosomes. PMID- 23446416 TI - A rapidly spinning supermassive black hole at the centre of NGC 1365. AB - Broad X-ray emission lines from neutral and partially ionized iron observed in active galaxies have been interpreted as fluorescence produced by the reflection of hard X-rays off the inner edge of an accretion disk. In this model, line broadening and distortion result from rapid rotation and relativistic effects near the black hole, the line shape being sensitive to its spin. Alternative models in which the distortions result from absorption by intervening structures provide an equally good description of the data, and there has been no general agreement on which is correct. Recent claims that the black hole (2 * 10(6) solar masses) at the centre of the galaxy NGC 1365 is rotating at close to its maximum possible speed rest on the assumption of relativistic reflection. Here we report X-ray observations of NGC 1365 that reveal the relativistic disk features through broadened Fe-line emission and an associated Compton scattering excess of 10-30 kiloelectronvolts. Using temporal and spectral analyses, we disentangle continuum changes due to time-variable absorption from reflection, which we find arises from a region within 2.5 gravitational radii of the rapidly spinning black hole. Absorption-dominated models that do not include relativistic disk reflection can be ruled out both statistically and on physical grounds. PMID- 23446417 TI - Giant osmotic energy conversion measured in a single transmembrane boron nitride nanotube. AB - New models of fluid transport are expected to emerge from the confinement of liquids at the nanoscale, with potential applications in ultrafiltration, desalination and energy conversion. Nevertheless, advancing our fundamental understanding of fluid transport on the smallest scales requires mass and ion dynamics to be ultimately characterized across an individual channel to avoid averaging over many pores. A major challenge for nanofluidics thus lies in building distinct and well-controlled nanochannels, amenable to the systematic exploration of their properties. Here we describe the fabrication and use of a hierarchical nanofluidic device made of a boron nitride nanotube that pierces an ultrathin membrane and connects two fluid reservoirs. Such a transmembrane geometry allows the detailed study of fluidic transport through a single nanotube under diverse forces, including electric fields, pressure drops and chemical gradients. Using this device, we discover very large, osmotically induced electric currents generated by salinity gradients, exceeding by two orders of magnitude their pressure-driven counterpart. We show that this result originates in the anomalously high surface charge carried by the nanotube's internal surface in water at large pH, which we independently quantify in conductance measurements. The nano-assembly route using nanostructures as building blocks opens the way to studying fluid, ionic and molecule transport on the nanoscale, and may lead to biomimetic functionalities. Our results furthermore suggest that boron nitride nanotubes could be used as membranes for osmotic power harvesting under salinity gradients. PMID- 23446418 TI - Specialized appendages in fuxianhuiids and the head organization of early euarthropods. AB - The organization of the head provides critical data for resolving the phylogenetic relationships and evolutionary history of extinct and extant euarthropods. The early Cambrian-period fuxianhuiids are regarded as basal representatives of stem-group Euarthropoda, and their anterior morphology therefore offers key insights for reconstructing the ancestral condition of the euarthropod head. However, the paired post-antennal structures in Fuxianhuia protensa remain controversial; they have been interpreted as both 'great appendages' and as gut diverticulae. Here we describe Chengjiangocaris kunmingensis sp. nov. and Fuxianhuia xiaoshibaensis sp. nov. from a new early Cambrian (Stage 3) fossil Lagerstatte in Yunnan, China. Numerous specimens of both species show a unique 'taphonomic dissection' of the anterodorsal head shield, revealing the cephalic organization in detail. We demonstrate the presence of a pair of specialized post-antennal appendages (SPAs) in the fuxianhuiid head, which attach at either side of the posteriorly directed mouth, behind the hypostome. Preserved functional articulations indicate a well-defined but restricted range of limb movement, suggestive of a simple type of sweep feeding. The organization of the SPAs in fuxianhuiids is incompatible with the (deutocerebral) anterior raptorial appendages of megacheirans, and argue against the presence of protocerebral limbs in the fuxianhuiids. The positions of the fuxianhuiid antennae and SPAs indicate that they are segmentally homologous to the deutocerebral and tritocerebral appendages of crown-group Euarthropoda respectively. These findings indicate that antenniform deutocerebral appendages with many podomeres are a plesiomorphic feature of the ancestral euarthropod head. PMID- 23446419 TI - Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle. AB - Biologists have long been concerned about what constrains variation in cell size, but progress in this field has been slow and stymied by experimental limitations. Here we describe a new method, ergodic rate analysis (ERA), that uses single-cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state. With this method, it is possible to calculate full time trajectories of any feature that can be labelled in fixed cells, for example levels of phosphoproteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell to-cell size variation. PMID- 23446420 TI - GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. AB - Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI. Although inhibitors of membrane protein smoothened (SMO) effectively suppress HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C iota/lambda (aPKC-iota/lambda) as a novel GLI regulator in mammals. aPKC-iota/lambda and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC-iota/lambda function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows that aPKC-iota/lambda and SMO control the expression of similar genes in tumour cells. aPKC-iota/lambda functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC-iota/lambda is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC-iota/lambda suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC-iota/lambda is critical for HH-dependent processes and implicates aPKC iota/lambda as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers. PMID- 23446421 TI - A bacteriophage encodes its own CRISPR/Cas adaptive response to evade host innate immunity. AB - Bacteriophages (or phages) are the most abundant biological entities on earth, and are estimated to outnumber their bacterial prey by tenfold. The constant threat of phage predation has led to the evolution of a broad range of bacterial immunity mechanisms that in turn result in the evolution of diverse phage immune evasion strategies, leading to a dynamic co-evolutionary arms race. Although bacterial innate immune mechanisms against phage abound, the only documented bacterial adaptive immune system is the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system, which provides sequence-specific protection from invading nucleic acids, including phage. Here we show a remarkable turn of events, in which a phage-encoded CRISPR/Cas system is used to counteract a phage inhibitory chromosomal island of the bacterial host. A successful lytic infection by the phage is dependent on sequence identity between CRISPR spacers and the target chromosomal island. In the absence of such targeting, the phage-encoded CRISPR/Cas system can acquire new spacers to evolve rapidly and ensure effective targeting of the chromosomal island to restore phage replication. PMID- 23446423 TI - Tumbleweeds and indelicate questions. PMID- 23446422 TI - Replication stress links structural and numerical cancer chromosomal instability. AB - Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity. CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance. Understanding a mechanistic basis for CIN is therefore paramount. Here we find evidence for impaired replication fork progression and increased DNA replication stress in CIN(+) colorectal cancer (CRC) cells relative to CIN(-) CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three new CIN-suppressor genes (PIGN (also known as MCD4), MEX3C (RKHD2) and ZNF516 (KIAA0222)) encoded on chromosome 18q that are subject to frequent copy number loss in CIN(+) CRC. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication associated damage, reduces the frequency of chromosome segregation errors after CIN-suppressor gene silencing, and attenuates segregation errors and DNA damage in CIN(+) cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity. PMID- 23446425 TI - Influence of the polymeric interphase design on the interfacial properties of (fiber-reinforced) composites. AB - In fiber-reinforced composites, the interphase nanostructure (i.e., the extended region between two phases in contact) has a pronounced influence on their interfacial adhesion. This work aims at establishing a link between the interphase design of PS-based polymeric fiber coatings and their influence on the micromechanical performance of epoxy-based composite materials. Thiol-ene photochemistry was utilized to introduce a polymeric gradient on silica-like surfaces following a two-step approach without additional photoinitiator. Two complementary grafting-techniques were adapted to modify glass fibers: "Grafting onto" deposition of PB-b-PS diblock copolymers for thin-film coatings (thickness<20 nm) at low grafting density (<0.1 chains/nm2)--and "grafting-from" polymerization for brush-like PS homopolymer coatings of higher thickness (up to 225 nm) and higher density. Polymer-coated glass fibers were characterized for polymer content using thermogravimetric analysis (TGA) and their nanostructural morphologies by scanning electron microscopy (SEM). Model substrates of flat glass and silicon were studied by atomic force microscopy (AFM) and spectroscopic ellipsometry (SE). The change in interfacial shear strength (IFSS) due to fiber modification was determined by a single fiber pull-out experiment. Thick coatings (>40 nm) resulted in a 50% decrease in IFSS. Higher shear strength occurred for thinner coatings of homopolymer and for lower grafting densities of copolymer. Increased IFSS (10%) was found upon dilution of the surface chain density by mixing copolymers. We show that the interfacial shear strength can be increased by tailoring of the interphase design, even for systems with inherently poor adhesion. Perspectives of polymeric fiber coatings for tailored matrix-fiber compatibility and interfacial adhesion are discussed. PMID- 23446424 TI - Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. AB - Acromegaly is frequently associated with alterations of glucose metabolism but factors predisposing these patients to exhibit impaired glucose tolerance or overt diabetes at diagnosis are poorly understood. This study included 148 patients with newly diagnosed acromegaly (80 men; mean age: 45 +/- 20 year). All patients underwent an oral glucose tolerance test (OGTT), unless already treated for diabetes. Insulin sensitivity (S) and beta-cell function (B) were also evaluated by homeostasis model assessment (HOMA). Normal glucose tolerance (NGT) was observed in 67 patients (46 %), impaired fasting glycaemia (IFG) or glucose tolerance (IGT) were found in 39 (26 %), and diabetes mellitus (DM) in 42 (28 %). NGT patients were 10 years younger than patients with abnormal glucose metabolism (p < 0.001) and diabetic patients had a higher BMI (p < 0.05). While HOMA-S was similar, HOMA-B was reduced in the IFG/IGT group (p < 0.05) and further in the DM group (p < 0.001). IGF-I z-score was higher in IFG/IGT (5.2 +/- 1.4) and DM patients (5.4 +/- 1.3) than in NGT patients (4.4 +/- 1.3; p < 0.05), but fasting and post-OGTT GH levels were not different between groups. In multivariate analyses, family history of diabetes and IGF-I were associated with hyperglycaemia, BMI and IGF-I predicted insulin resistance, and age was inversely correlated with beta-cell function. Impaired glucose metabolism is present in more than 50 % of patients at diagnosis of acromegaly, and is associated with an older age, a higher BMI, a family history of diabetes and a higher IGF-I z-score, but not with fasting or post-OGTT GH levels. PMID- 23446426 TI - Serum uric acid and outcome after acute ischemic stroke: PREMIER study. AB - BACKGROUND: Current evidence shows that uric acid is a potent antioxidant whose serum concentration increases rapidly after acute ischemic stroke (AIS). Nevertheless, the relationship between serum uric acid (SUA) levels and AIS outcome remains debatable. We aimed to describe the prognostic significance of SUA in AIS. METHODS: We studied 463 patients (52% men, mean age 68 years, 13% with glomerular filtration rate <60 ml/min at hospital arrival) with AIS pertaining to the multicenter registry PREMIER, who had SUA measurements at hospital presentation. Multivariate models were constructed to analyze the association of SUA with functional outcome as assessed by the modified Rankin scale (mRS) at 30-day, 3-, 6- and 12-month follow-up. A mRS 0-1 was regarded as a very good outcome. RESULTS: Mean SUA concentration at hospital arrival was 6.1 +/ 3.7 mg/dl (362.8 +/- 220.0 MUmol/l). Compared with cases with higher SUA levels at hospital admission, patients with <=4.5 mg/dl (<=267.7 MUmol/l; the lowest tertile of the sample) had more cases of a very good 30-day outcome (30.5 vs. 18.9%, respectively; p = 0.004). SUA was not associated with mortality or functional dependence (mRS >2) at 30 days, or with any outcome measure at 3, 6 or 12 months poststroke. After adjustment for age, gender, stroke type and severity (NIHSS <9), time since event onset, serum creatinine, hypertension, diabetes and smoking, a SUA <=4.5 mg/dl (<=267.7 MUmol/l) was positively associated with a very good short-term outcome (odds ratio: 1.76, 95% confidence interval: 1.05 2.95; negative predictive value: 81.1%), but not at 3, 6 or 12 months of follow up. When NIHSS was entered in the multivariate model as a continuous variable, the independent association of SUA with outcome was lost. Compared with cases with higher levels, patients with SUA <=4.5 mg/dl (<=267.7 MUmol/l) were more frequently younger than 55 years, women, with mild strokes, with normal serum creatinine and fewer had hypertension. The time since event onset to hospital arrival was not significantly associated with AIS severity or SUA levels; nevertheless, a nonsignificant tendency was observed for patients with severe strokes and high SUA levels arriving in <24 h. CONCLUSIONS: A low SUA concentration is modestly associated with a very good short-term outcome. Our findings support the hypothesis that SUA is more a marker of the magnitude of the cerebral infarction than an independent predictor of stroke outcome. PMID- 23446427 TI - Excessive urinary tract dilatation and proteinuria in pregnancy: a common and overlooked association? AB - BACKGROUND: Proteinuria and dilatation of the urinary tract are both relatively common in pregnancy, the latter with a spectrum of symptoms, from none to severe pain and infection. Proteinuria is a rare occurrence in acute obstructive nephropathy; it has been reported in pregnancy, where it may pose a challenging differential diagnosis with pre-eclampsia.The aim of the present study is to report on the incidence of proteinuria (>= 0.3; >= 0.5 g/day) in association with symptomatic-severe urinary tract dilatation in pregnancy. METHODS: Case series. SETTING: Nephrological-Obstetric Unit dedicated to pregnancy and kidney diseases (January 2000-April 2011). SOURCE: database prospectively updated since the start of the Unit. Retrospective review of clinical charts identified as relevant on the database, by a nephrologist and an obstetrician. RESULTS: From January 2000 to April 2011, 262 pregnancies were referred. Urinary tract dilatation with or without infection was the main cause of referral in 26 cases (predominantly monolateral in 19 cases): 23 singletons, 1 lost to follow-up, 1 twin and 1 triplet. Patients were referred for urinary tract infection (15 cases) and/or renal pain (10 cases); 6 patients were treated by urologic interventions ("JJ" stenting). Among them, 11 singletons and 1 triple pregnancy developed proteinuria >= 0.3 g/day (46.1%). Proteinuria was >= 0.5 g/day in 6 singletons (23.1%). Proteinuria resolved after delivery in all cases. No patient developed hypertension; in none was an alternative cause of proteinuria evident. No significant demographic difference was observed in patients with renal dilatation who developed proteinuria versus those who did not. An association with the presence of "JJ" stenting was present (5/6 cases with proteinuria >= 0.5 g/day), which may reflect both severer obstruction and a role for vescico-ureteral reflux, induced by the stent. CONCLUSIONS: Symptomatic urinary tract dilatation may be associated with proteinuria in pregnancy. This association should be kept in mind in the differential diagnosis with other causes of proteinuria in pregnancy, including pre-eclampsia. PMID- 23446428 TI - A case-control study of readmission to the intensive care unit after cardiac surgery. AB - BACKGROUND: The aim of this study was to identify predictors of repeated admission to the intensive care unit (ICU) of patients who underwent cardiac surgery procedures. MATERIAL/METHODS: This retrospective study analyzed 169 patients who underwent isolated coronary artery bypass grafting (CABG) between January 2009 and December 2010. The case group contained 54 patients who were readmitted to the ICU during the same hospitalization and the control group comprised 115 randomly selected patients. RESULTS: Logistic regression analysis revealed that independent predictors for readmission to the ICU after CABG were: older age of patients (odds ratio [OR] 1.04; CI 1.004-1.08); body mass index (BMI)>30 kg/m2 (OR 2.55; CI 1.31-4.97); EuroSCORE II>3.9% (OR 3.56; CI 1.59 7.98); non-elective surgery (OR 2.85; CI 1.37-5.95); duration of operation>4 h (OR 3.44; CI 1.54-7.69); bypass time>103 min (OR 2.5; CI 1.37-4.57); mechanical ventilation>530 min (OR 3.98; CI 1.82-8.7); and postoperative central nervous system (CNS) disorders (OR 3.95; CI 1.44-10.85). The hospital mortality of patients who were readmitted to the ICU was significantly higher compared to the patients who did not require readmission (17% vs. 3.8%, p=0.025). CONCLUSIONS: Identification of patients at risk of ICU readmission should focus on older patients, those who have higher BMI, who underwent non-elective surgery, whose operation time was more than 4 hours, and who have postoperative CNS disorders. Careful optimization of these high-risk patients and caution before discharging them from the ICU may help reduce the rate of ICU readmission, mortality, length of stay, and cost. PMID- 23446429 TI - Regulation of kallikrein-related peptidases in the skin - from physiology to diseases to therapeutic options. AB - Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases, which show a tissue-specific expression profile. This made them valuable tumour expression markers. It became evident that KLKs are involved in many physiological processes like semen liquefaction and skin desquamation. More recently, we have learnt that they are involved in many pathophysiological conditions and diseases making them promising target of therapeutic intervention. Therefore, regulation of KLKs raised the interest of numerous reports. Herein, we summarise the current knowledge on KLKs regulation with an emphasis on skin relevant KLKs regulation processes. Regulation of KLKs takes place on the level of transcription, on protease activation and on protease inactivation. A variety of protease inhibitors has been described to interact with KLKs including the irreversible serine protease inhibitors (SERPINs) and the reversible serine protease inhibitors of Kazal-type (SPINKs). In an attempt to integrate current knowledge, we propose that KLK regulation has credentials as targets for therapeutic intervention. PMID- 23446430 TI - Data Reporting Error in "Comment" Section in: Effect of MRI on Treatment Results or Decision Making in Patients With Lumbosacral Radiculopathy Referred for Epidural Steroid Injections. PMID- 23446431 TI - Downregulation of microRNA-138 enhances the proliferation, migration and invasion of cholangiocarcinoma cells through the upregulation of RhoC/p-ERK/MMP-2/MMP-9. AB - microRNAs (miRs) play an important role in tumor initiation and progression in many types of cancer, including cholangiocarcinoma (CC). miR-138 dysregulation is frequently observed in a variety of tumors. In the present study, miR-138 was found to be downregulated in CC tissues by quantitative real-time RT-PCR. Furthermore, its potential target molecule, Ras homolog gene family, member C (RhoC) protein, was found to be highly expressed in CC tissues examined by western blot analysis. Luciferase reporter assay further demonstrated that miR 138 directly targeted RhoC. We found that the introduction of miR-138 mimics to RBE and QBC939 CC cells could reduced RhoC mRNA and protein expression, and suppressed the proliferation, G1/S transition, migration and invasion of CC cells. However, transfection with a miR-138 inhibitor induced an inverse effect in CC cells. The expression of phosphorylated extracellular signal-regulated kinase (p-ERK), matrix metalloproteinase (MMP)-2 and MMP-9 decreased following transfection with miR-138, and increased following transfection with miR-138 inhibitor in CC cells. In conclusion, RhoC upregulation induced by miR-138 downregulation promotes the malignant progression of CC cells and the underlying mechanisms of this effect involve the increase in the expression of p-ERK/MMP 2/MMP-9. Consequently, miR-138/RhoC is a potential target for the clinical diagnosis and treatment of CC. PMID- 23446433 TI - Necrotizing meningoencephalitis in a cow. AB - An 18-month-old Charolais cow developed depression and drooling and was submitted for necropsy after euthanasia. The cow was 1 of 50 moved between 2 farms approximately 5 days before the onset of clinical disease. Gross findings included swollen and hemorrhagic areas of malacia in the frontal, temporal, and parietal lobes of the cerebral cortex. Microscopically there was a necrotizing meningoencephalitis with intranuclear astrocytic and neuronal eosinophilic viral inclusions in the frontal, temporal, and parietal cerebral cortex as well as in the basal nuclei and thalamus. The gross and microscopic findings were consistent with necrotizing meningoencephalitis caused by bovine herpesvirus (BHV-1 or BHV 5), and the diagnosis was confirmed by detection of bovine herpesviral antigen on fresh samples of brain via fluorescent antibody test using a monoclonal antibody against BHV-1 glycoprotein C. PMID- 23446432 TI - Salmonella enterica causes more severe inflammatory disease in C57/BL6 Nramp1G169 mice than Sv129S6 mice. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium) causes systemic inflammatory disease in mice by colonizing cells of the mononuclear leukocyte lineage. Mouse strains resistant to S. Typhimurium, including Sv129S6, have an intact Nramp1 (Slc11a1) allele and survive acute infection, whereas C57/BL6 mice, homozygous for a mutant Nramp1 allele, Nramp1(G169D) , develop lethal infections. Restoration of Nramp1 (C57/BL6 Nramp1(G169) ) reestablishes resistance to S. Typhimurium; mice survive at least 3 to 4 weeks postinfection. Since many transgenic mouse strains are on a C57/BL6 genetic background, C57/BL6 Nramp1(G169) mice provide a model to examine host genetic determinants of resistance to infection. To further evaluate host immune response to S. Typhimurium, we performed comparative analyses of Sv129S6 and C57/BL6 Nramp1(G169) mice 3 weeks following oral S. Typhimurium infection. C57/BL6 Nramp1(G169) mice developed more severe inflammatory disease with splenic bacterial counts 1000-fold higher than Sv129S6 mice and relatively greater splenomegaly and blood neutrophil and monocyte counts. Infected C57/BL6 Nramp1(G169) mice developed higher proinflammatory serum cytokine and chemokine responses (interferon-gamma, tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-2 and monocyte chemotactic protein-1 and chemokine [C-X-C motif] ligand 1, respectively) and marked decreases in anti-inflammatory serum cytokine concentrations (IL-10, IL-4) compared with Sv129S6 mice postinfection. Splenic dendritic cells and macrophages in infected compared with control mice increased to a greater extent in C57/BL6 Nramp1(G169) mice than in Sv129S6 mice. Overall, data show that despite the Nramp1 gene present in both strains, C57/BL6 Nramp1(G169) mice develop more severe, Th1-skewed, acute inflammatory responses to S. Typhimurium infection compared with Sv129S6 mice. Both strains are suitable model systems for studying inflammation in the context of adaptive immunity. PMID- 23446434 TI - Artificial leaf structures as a UV detector formed by the self-assembly of ZnO nanoparticles. AB - Artificial leaf structures have been fabricated by the self-assembly of ZnO nanoparticles. A hydrothermal method was used to synthesize the nanoparticles. The self-assembly patterns showed asymmetric dendritic morphologies, larger surface-to-volume ratios, a broad absorption band and high resistance. A non equilibrium two-stage-formation process included diffusion limited aggregation, and the phase-field model was introduced to explain the formation mechanism of the pattern. A high-performance ultraviolet detector was fabricated on the artificial leaf structures, which showed that the current under the irradiation of a UV lamp (1.21 mW cm(-2)) was about 10(4) times greater than in the dark. The various and functional properties of the pattern show us the vast prospects of potential applications for light harvesting systems and other optical-electric devices. PMID- 23446435 TI - Exploring barriers and facilitators to participation of male-to-female transgender persons in preventive HIV vaccine clinical trials. AB - Observed seroincidence and prevalence rates in male-to-female (MTF) transgender individuals highlight the need for effective targeted HIV prevention strategies for this community. In order to develop an effective vaccine that can be used by transgender women, researchers must understand and address existing structural issues that present barriers to this group's participation in HIV vaccine clinical trials. Overcoming barriers to participation is important for ensuring HIV vaccine acceptability and efficacy for the MTF transgender community. To explore barriers and facilitators to MTF transgender participation in preventive HIV vaccine clinical trials, the HIV Vaccine Trials Network conducted focus groups among transgender women in four urban areas (Atlanta, Boston, Philadelphia, and San Francisco). Barriers and facilitators to engagement of transgender women in preventive HIV vaccine clinical trials led to the following recommendations: (a) transgender cultural competency training, (b) creating trans friendly environments, (c) true partnerships with local trans-friendly organizations and health care providers, (d) protocols that focus on transgender specific issues, and (e) data collection and tracking of transgender individuals. These results have implications for the conduct of HIV vaccine trials, as well as engagement of transgender women in research programs in general. PMID- 23446436 TI - A defined-multispecies microbial model for studying enamel caries development. AB - The aims of this study were to describe and validate an in vitro multispecies microbial biofilm model for caries development by evaluating the effects of varying medium concentration of sucrose (0.5 and 1.0%) and fluoride (0.4, 0.8 and 1.0 ppm F) in study 1, and calcium (1.0 and 2.0 mM Ca) in study 2. Defined multispecies biofilms, formed by Lactobacillus casei, Streptococcus mutans, S. salivarius and S. sanguinis, were grown on the surface of salivary-pellicle coated enamel slabs, with known baseline surface hardness; growth medium was changed daily. Counts of viable cells on biofilms and the percentage of surface microhardness change (%SMC), lesion depth (LD) and integrated mineral loss (IML) on enamel slabs were assessed after 4 days of biofilm formation under the tested conditions. Counts of viable cells on biofilms were significantly affected by sucrose, fluoride and calcium concentrations (p < 0.05). There was a decrease in %SMC in response to increased fluoride and calcium concentrations (p < 0.001). Lower IML (p < 0.001) and LD (p < 0.05) were found in the presence of 0.8 and 1.0 ppm F. A negative correlation was found between the response variables (%SMC, LD and IML) and fluoride and calcium concentrations. The results suggest that the microbial caries model developed was able to show distinct levels of caries inhibition in response to fluoride and calcium concentrations, corroborating clinical observations. An effect of sucrose concentration on caries development was found only in the presence of the lowest fluoride concentration. PMID- 23446437 TI - Cortical bone strains around straight and angulated immediate orthodontic microimplants: a pilot study. AB - PURPOSE: To measure strains around orthodontic implants upon torque tightening and loading and to assess correlations between factors influencing primary stability. MATERIALS AND METHODS: Self-drilling implants were placed into bovine iliac crest blocks after CT assessments. Upon bonding of strain gauges on bone adjacent to the implants, strain measurements were performed using a data acquisition system during torque tightening and 250 g orthodontic force application by elastic chains. RESULTS: The torque required to place straight implants (12.16 N.cm) was higher than 30- to 40-degree angulated implants (9.31 N.cm) (P < 0.05). Cortical bone strain amplitudes of both implant placements were comparable (P > 0.05). Strains during torque tightening of straight (196 MUepsilon) and tilted (114 MUepsilon) implants were higher than those obtained during orthodontic loading (20-30 MUepsilon). Despite the positive and direct relationship found between torque and torque strain output, strong correlations between other parameters could not be detected. CONCLUSION: Vertically aligned and 30- to 40-degree angulated immediate orthodontic microimplants are associated with low amplitude strains upon torque tightening and orthodontic loading. PMID- 23446438 TI - Electronic structures of bisnoradamantenyl and bisnoradamantanyl dications and related species. AB - The highly pyramidalized molecule bisnoradamantene is extremely reactive toward nucleophiles and dienes. In this work, we studied the electronic structure of bisnoaradamantene, as well as those of its cation and dication, which are previously unreported carbonium ions. According to QTAIM and MO analysis, there is a 3c-2e bonding system in the bisnoradamantenyl cation and a 4c-2e bonding system in the bisnoradamantenyl dication. A topological study indicated that, on going from bisnoradamantene to its dication, pi-bond interaction with the bridgehead carbon atom increases. Additional study of the bisnoradamantanyl dication also indicated that it has two multicenter bonding systems. Comparison of the D3BIA and NICS aromaticity indices of these molecules and other derivatives indicates that these indices are well correlated, and analysis of these indices shows that the cationic and dicationic bisnoradamantenyl species are homoaromatic. PMID- 23446439 TI - Investigation by MD simulation of the key residues related to substrate-binding and heme-release in human ferrochelatase. AB - Molecular dynamics (MD) simulations of three models based on the crystal structure of the E343K variant of human ferrochelatase were performed in this study. The "open" and "closed" conformations of the enzyme obtained by simulations are in agreement with the corresponding crystal structures. The snapshots and the structure analysis indicate that alterations of the hydrogen bonds and the positions of E347 and E351 lead to a conformational change in the pi-helix. The hydrogen bonded form of residue R164 could be regarded as a signal indicating alteration of the active site conformation. When R164 forms a hydrogen bond with D95, the active site is closed, and when a hydrogen bond is formed with E171, the active site is open. Interestingly, the protoporphyrin with Fe(2+) is observed to move noticeably out of the enzyme while the protoporphyrin lacking Fe(2+) remains almost fixed. Alterations of the hydrogen bonds between the propionate of the heme and R115, K118 and S303 trigger movement of the heme out of the active site. Residues E347 and E351, which are located on the pi-helix and form an acidic path leading to a salt bridge interaction with the propionate of the heme, accelerate the release process. PMID- 23446440 TI - A comparative theoretical investigation into the strength of the trigger-bond in the Na+, Mg2+ and HF complexes involving the nitro group of R-NO2 (R = -CH3, -NH2 and -OCH3) or the C = C bond of (E)-O2N-CH = CH-NO2. AB - A comparative theoretical investigation into the change in strength of the trigger-bond upon formation of the Na(+), Mg(2+) and HF complexes involving the nitro group of RNO2 (R = -CH3, -NH2, -OCH3) or the C = C bond of (E)-O2N-CH = CH NO2 was carried out using the B3LYP and MP2(full) methods with the 6-311++G**, 6 311++G(2df,2p) and aug-cc-pVTZ basis sets. Except for the Mg(2+)?pi system with (E)-O2N-CH = CH-NO2 (i.e., C2H2N2O4?Mg(2+)), the strength of the trigger-bond X NO2 (X = C, N or O) was enhanced upon complex formation. Furthermore, the increment of bond dissociation energy of the X-NO2 bond in the Na(+) complex was far greater than that in the corresponding HF system. Thus, the explosive sensitivity in the former might be lower than that in the latter. For C2H2N2O4?Mg(2+), the explosive sensitivity might also be reduced. Therefore, it is possible that introducing cations into the structure of explosives might be more efficacious at reducing explosive sensitivity than the formation of an intermolecular hydrogen-bonded complex. AIM, NBO and electron density shifts analyses showed that the electron density shifted toward the X-NO2 bond upon complex formation, leading to a strengthened X-NO2 bond and possibly reduced explosive sensitivity. PMID- 23446441 TI - Proteinuria in systemic sclerosis: reversal by ACE inhibition. AB - In systemic sclerosis (SSc), kidney damage is a major clinical problem which can lead to a deleterious outcome. Recently, in diabetes mellitus, early detection of proteinuria and treatment with angiotensin-converting enzyme (ACE) inhibitors has been shown to slow progression of kidney disease and to improve prognosis. In this study, we investigated the spontaneous course of proteinuria in SSc and the effects of ACE inhibitor therapy. Proteinuria was determined in SSc patients with urine protein electrophoresis. SSc patients with proteinuria (n = 31) were followed over a median of 12 months. Of all 31 patients with pathologic urine protein electrophoresis investigated in this study, 9 patients (29 %) had additional microalbuminuria and 4 patients (12.9 %) showed increased total urinary protein. ACE inhibitor treatment was subsequently given to 23 patients. A total of 8 patients remained untreated for various reasons. Proteinuria resolved in 74 % of patients treated with ACE inhibitors, whereas in the untreated group, remission was observed only in 25 % (p = 0.014). Improvement of proteinuria was predominantly achieved in patients with recently diagnosed proteinuria and short disease duration. In patients with SSc and proteinuria, initiation of ACE inhibitor therapy resulted in a significant decrease in proteinuria. PMID- 23446442 TI - Novel predictors of intravenous immunoglobulin resistance in Chinese children with Kawasaki disease. AB - BACKGROUND: The purpose of this study was to develop a predictive scoring system to identify intravenous immunoglobulin resistance in children with Kawasaki disease, to implement additional therapies early in the course of their illness and prevent coronary artery lesions. METHODS: We performed a retrospective review of children with Kawasaki disease treated within 10 days of fever onset. To identify independent predictors of intravenous immunoglobulin resistance, multivariable logistic regression models were constructed using variables selected by univariable analysis. The independent predictors were combined into a new scoring system and compared with 2 existing systems. The discriminatory capacity of the scoring system was assessed using the area under the receiver operating characteristic curves. RESULTS: By logistic regression analysis, polymorphous exanthema, changes around the anus, days of illness at initial treatment, percentage of neutrophils, C-reactive protein levels, albumin levels, and total bilirubin proved to be independent predictors of intravenous immunoglobulin resistance. The new scoring system gave an area under the receiver operating characteristic curve of 0.672. In this scoring system, 2 risk strata were identified: low risk, with scores of 0-3, and high risk, with scores of >=4. The sensitivity was 54.1% and the specificity was 71.2%. CONCLUSIONS: The new scoring system had a higher specificity and sensitivity for Chinese children, compared with the Kobayashi scoring system and the Egami scoring system, but, unfortunately, the new scoring system was not good enough to be widely used because of its low sensitivity. PMID- 23446443 TI - Skin findings of Staphylococcus aureus toxin-mediated infection in relation to toxin encoding genes. AB - BACKGROUND: Staphylococcal scalded skin syndrome and toxic shock syndrome are associated with exfoliatins and superantigens, respectively; and are easy to distinguish in their usual presentation. However, there is confusion about the mild forms of these 2 staphylococcal diseases. These mild forms are both designated as "staphylococcal scarlet fever" despite differences in their pathophysiology and clinical presentation. Our study aimed to distinguish between the clinical characteristics of the rash associated with exfoliatins and the rash associated with superantigens. METHODS: Patients were selected from the French National Reference Center for Staphylococci. We retrospectively compared the clinical characteristics of patients with a generalized rash during Staphylococcus aureus infection. Patients who met the criteria of staphylococcal scalded skin syndrome or toxic shock syndrome were excluded. The patients were classified into 2 groups depending on the presence of a gene coding for exfoliatin or for superantigenic toxin. RESULTS: We included 13 cases with exfoliatin and 9 with superantigens. The patients of the exfoliatin group were more likely to have facial involvement, fold involvement and a superficial focus of infection. In the second group, S. aureus was isolated from a deeper focus in 8 of 9 patients. CONCLUSION: Mild forms of S. aureus toxin-mediated infection affect the pediatric population. Examination made it possible to distinguish an exanthema associated with an exfoliatin from one associated with a superantigen. This early clinical distinction results in differences in management. PMID- 23446444 TI - Implementation of occult hepatitis screening in the Spanish cohort of HIV infected pediatric patients. AB - Regular screening methods may miss the diagnosis of occult hepatitis B infection and seronegative hepatitis C virus infection in immunocompromised patients. A cross-sectional study within a Spanish cohort of HIV-infected children yielded 6 of 254 (2.4%) possible occult hepatitis B infection cases and 2 of 254 (0.8%) seronegative hepatitis C virus-infected patients. Implementation of occult hepatitis screening in the routine care of these children may be warranted. PMID- 23446445 TI - Osteoarticular involvement in childhood brucellosis: experience with 133 cases in an endemic region. AB - AIM: To describe the main clinical and laboratory characteristics, frequency and distribution of osteoarticular involvement, therapeutic options and outcome in children with osteoarticular brucellosis. METHODS: This descriptive study includes 133 pediatric patients with osteoarticular brucellosis who were treated at the University Clinic for Infectious Diseases and Febrile Conditions in Skopje, Republic of Macedonia, during the period between 1989 and 2011. Brucellosis was presumptively diagnosed on the basis of clinical signs and confirmed by the detection of specific antibodies at significant titers. RESULTS: The median age of patients was 9 years (range, 2-14 years) and 63.9% were males. Family history of brucellosis was present in 54.1%. The dominant clinical symptoms were arthralgia and fever in 77.4% and 73.7%, respectively, and the dominant sign was hepatomegaly in 73.7% of patients. The main laboratory abnormalities were elevated C-reactive protein (81.0%) and circulating immunocomplexes (80.7%). In 71.4% of patients, the osteoarticular involvement was monoarticular. Hip arthritis was present in 49.6%, followed by the knee in 30.1%. Various therapeutic regimens with a duration of 6 weeks were used. In 87 patients during a follow-up of at least 6 months, relapse occurred in 13.8%. CONCLUSIONS: Osteoarticular involvement is frequent in children with brucellosis. It is most often manifested with monoarthritis of the large weight-bearing joints. Brucellosis should be included in the differential diagnosis of childhood arthritis in endemic countries, especially in the presence of family history, contact with infected animals or ingestion of unpasteurized food products, fever and hepatomegaly. PMID- 23446446 TI - Surgical outcomes of total knee replacement according to diabetes status and glycemic control, 2001 to 2009. AB - BACKGROUND: Poor glycemic control in patients with diabetes may be associated with adverse surgical outcomes. We sought to determine the association of diabetes status and preoperative glycemic control with several surgical outcomes, including revision arthroplasty and deep infection. METHODS: We conducted a retrospective cohort study in five regions of a large integrated health-care organization. Eligible subjects, identified from the Kaiser Permanente Total Joint Replacement Registry, underwent an elective first primary total knee arthroplasty during 2001 through 2009. Data on demographics, diabetes status, preoperative hemoglobin A1c (HbA1c) level, and comorbid conditions were obtained from electronic medical records. Subjects were classified as nondiabetic, diabetic with HbA1c < 7% (controlled diabetes), or diabetic with HbA1c >= 7% (uncontrolled diabetes). Outcomes were deep venous thrombosis or pulmonary embolism within ninety days after surgery and revision surgery, deep infection, incident myocardial infarction, and all-cause rehospitalization within one year after surgery. Patients without diabetes were the reference group in all analyses. All models were adjusted for age, sex, body mass index, and Charlson Comorbidity Index. RESULTS: Of 40,491 patients who underwent total knee arthroplasty, 7567 (18.7%) had diabetes, 464 (1.1%) underwent revision arthroplasty, and 287 (0.7%) developed a deep infection. Compared with the patients without diabetes, no association between controlled diabetes (HbA1c < 7%) and the risk of revision (odds ratio [OR], 1.32; 95% confidence interval [CI], 0.99 to 1.76), risk of deep infection (OR, 1.31; 95% CI, 0.92 to 1.86), or risk of deep venous thrombosis or pulmonary embolism (OR, 0.84; 95% CI, 0.60 to 1.17) was observed. Similarly, compared with patients without diabetes, no association between uncontrolled diabetes (HbA1c >= 7%) and the risk of revision (OR, 1.03; 95% CI, 0.68 to 1.54), risk of deep infection (OR, 0.55; 95% CI 0.29 to 1.06), or risk of deep venous thrombosis or pulmonary embolism (OR, 0.70; 95% CI, 0.43 to 1.13) was observed. CONCLUSIONS: No significantly increased risk of revision arthroplasty, deep infection, or deep venous thrombosis was found in patients with diabetes (as defined on the basis of preoperative HbA1c levels and other criteria) compared with patients without diabetes in the study population of patients who underwent elective total knee arthroplasty. PMID- 23446447 TI - Radiative recombination mechanisms in individual wurtzite ZnSe nanowires with a defect-free single-crystalline microstructure. AB - Photoluminescence (PL) spectroscopy performed on arrays of semiconductor nanowires (NWs) suffers from ensemble broadening of PL lines, and fails to separate the PL from NWs of different crystal structures in the ensemble. Even the results on PL from single NWs are not devoid of ambiguity. This is because the influence of structural defects in NWs, such as stacking faults, twin boundaries and dislocations, on their optical spectra cannot be accounted for since the structural characteristics of the same NW remain largely unknown. We performed low-temperature PL spectroscopy on individual wurtzite (WZ) ZnSe NWs, and confirmed a homogeneous single-crystalline microstructure without any extended defects in these NWs, thus excluding any role of structural imperfections in their optical spectra. The luminescence is shown to be dominated solely by native point defects, while no role of extrinsic impurities was found. The radiative recombination is shown to originate from excitons bound to vacancies of Zn (VZn), VZn-complexes, and their phonon replicas. The binding energies of the acceptor-bound excitons, ionization energies of the acceptors, and average number of phonons emitted for shallow donor-VZn acceptor pair related transition were determined. Distinct from previous studies on PL from arrays of ZnSe NWs, this work provides an unambiguous interpretation of the PL spectra and assignment of PL peaks to WZ ZnSe. Narrow excitonic emission of linewidths 2.9 meV indicate excellent optical quality of WZ ZnSe NWs. PMID- 23446448 TI - Nonsyndromic tooth agenesis patterns and associated developmental dental anomalies: a literature review with radiographic illustrations. AB - Tooth agenesis is one of the most intriguing phenomena, because it is frequently associated with other oral anomalies, structural variations and malformations of other teeth, late eruption, transposition and crowding. The diagnosis can be quite challenging as radiographic examination is critical for the diagnosis but not always possible and the late developing teeth may be sometimes scored developmentally missing. Accurate diagnosis therefore requires radiographic, clinical, and dental cast examinations. It is an important clinical and public health problem. Patients with missing permanent teeth may suffer from a reduced chewing ability, inarticulate pronunciation, and an unfavorable aesthetic appearance. Clinically, early diagnosis of a dental anomaly can alert the clinician to the possible development of other associated dental anomalies in the same patient or family, and avoid the possible sequelae. Understanding of tooth agenesis patterns and their impact on diagnosis, prevention, and eventually therapeutics are becoming integral parts of comprehensive dental care. Dental examination with radiographic screening of hypodontia in early childhood should be emphasized as part of public oral health policy to allow early diagnosis and timely intervention. PMID- 23446449 TI - Psychometric evaluation of the EORTC computerized adaptive test (CAT) fatigue item pool. AB - PURPOSE: Fatigue is one of the most common symptoms associated with cancer and its treatment. To obtain a more precise and flexible measure of fatigue, the EORTC Quality of Life Group has developed a computerized adaptive test (CAT) measure of fatigue. This is part of an ongoing project developing a CAT version of the widely used EORTC QLQ-C30 questionnaire. METHODS: Based on the literature search and evaluations by experts and patients, 41 new fatigue items were developed (in addition to the three QLQ-C30 fatigue items). Psychometric properties of the items, including evaluations of dimensionality, fit to item response theory (IRT) model, and differential item functioning (DIF), were assessed in an international sample of cancer patients. RESULTS: Responses were obtained from 1,321 cancer patients coming from eight countries. Factor analysis showed that 37 of the items could be included in a unidimensional model (RMSEA = 0.098, TLI = 0.995, CFI = 0.920). Of the 37 items, two were deleted because of poor fit to the IRT model forming the basis for the CAT, and one because of DIF between cancer sites. CONCLUSIONS: We have established a 34-item fatigue bank allowing for more precise and flexible measurement of fatigue, while still being backward compatible with the QLQ-C30 fatigue scale. PMID- 23446450 TI - Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic like effects and enhances cocaine-induced plasticity. AB - Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT) Cre), we developed constitutive KOR knockouts (KOR(-/-)) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR(lox/lox)). Autoradiography demonstrated complete ablation of KOR binding in the KOR(-/-) mutants, and reduced binding in the DAT-KOR(lox/lox) mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR(-/-) mice appeared normal in the open field and light/dark box tests, DAT-KOR(lox/lox) mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR(-/-) mutants, but was exaggerated in DAT-KOR(lox/lox) mutants. Increased sensitivity to cocaine in the DAT-KOR(lox/lox) mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR(-/-) mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function. PMID- 23446451 TI - Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice. AB - Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca(2+), which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressant related activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders. PMID- 23446452 TI - GDF9 modulates the reproductive and tumor phenotype of female inha-null mice. AB - Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha( /-)), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors characteristic of adult Inha-null mice. To ascertain the contribution of GDF9 to the Inha-null phenotype, we analyzed folliculogenesis in postnatal Inha Gdf9 double knockout mice. Deletion of Gdf9 from Inha(-/-) rescues the initial growth defects found at early follicle stages in Inha(-/-) ovaries, but surprisingly enhances the onset of pretumor lesions. The normalization of growth dynamics between granulosa cells and oocytes of Inha Gdf9 double knockout mice is also accompanied by a reduction in levels of the activin/inhibin beta B subunit, Inhbb, which is upregulated in Inha(-/-) ovaries. However, at later ages, Inha Gdf9 double knockout ovaries are similar to Inha(-/-) ovaries, and show upregulation of the activin/inhibin subunits and downregulation of the growth factor, kit ligand, thus resulting in a local environment that is growth promoting for granulosa cells but growth-inhibitory for oocytes. These data suggest a sequential mechanism of action initiated by GDF9 in the Inha knockout mouse that promotes defective folliculogenesis. These studies thus provide a novel role for GDF9 in causing reproductive defects and suppressing tumor initiation in the Inha(-/-) mouse model. PMID- 23446453 TI - Human implantation: a tale of mutual maternal and fetal attraction. PMID- 23446455 TI - L-carnitine supplementation during vitrification of mouse oocytes at the germinal vesicle stage improves preimplantation development following maturation and fertilization in vitro. AB - Oocyte cryopreservation is important for assisted reproductive technologies (ART). Although cryopreservation of metaphase II (MII) oocytes has been successfully used, MII oocytes are vulnerable to the damage inflicted by the freezing procedure. Cryopreservation of germinal vesicle stage oocytes (GV oocytes) is an alternative choice; however, blastocyst development from GV oocytes is limited largely due to the need for in vitro maturation (IVM). Herein, we evaluated the effects of l-carnitine (LC) supplementation during vitrification and thawing of mouse GV-oocytes, IVM, and embryo culture on preimplantation development after in vitro fertilization (IVF). We first compared the rate of embryonic development from the oocytes that had been collected at the GV stage from three mouse strains, (B6.DBA)F1, (B6.C3H)F1, and B6, and processed for IVM and IVF, as well as that from the oocytes matured in vivo, i.e. ovulated (IVO). Our results demonstrated that the rate of blastocyst development was the highest in the (B6.DBA)F1 strain and the lowest in the B6 strain. We then supplemented the IVM medium with 0.6 mg/ml LC. The rate of blastocyst development improved in the B6 but not in the (B6.DBA)F1 strain. Vitrification of GV-oocytes in the basic medium alone reduced the rate of blastocyst development in both of those mouse strains. LC supplementation to the IVM medium alone did not change the percentage of blastocyst development. However, LC supplementation to both vitrification and IVM media significantly improved blastocyst development to the levels comparable with those obtained from vitrified/thawed IVO oocytes in both of the (B6.DBA)F1 and B6 strains. We conclude that LC supplementation during vitrification is particularly efficient in improving the preimplantation development from the GV oocytes that otherwise have lower developmental competence in culture. PMID- 23446454 TI - Disruption of a spermatogenic cell-specific mouse enolase 4 (eno4) gene causes sperm structural defects and male infertility. AB - Sperm utilize glycolysis to generate ATP required for motility, and several spermatogenic cell-specific glycolytic isozymes are associated with the fibrous sheath (FS) in the principal piece of the sperm flagellum. We used proteomics and molecular biology approaches to confirm earlier reports that a novel enolase is present in mouse sperm. We then found that a pan-enolase antibody, but not antibodies to ENO2 and ENO3, recognized a protein in the principal piece of the mouse sperm flagellum. Database analyses identified two previously uncharacterized enolase family-like candidate genes, 64306537H0Rik and Gm5506. Northern analysis indicated that 64306537H0Rik (renamed Eno4) was transcribed in testes of mice by Postnatal Day 12. To determine the role of ENO4, we generated mice using embryonic stem cells in which an Eno4 allele was disrupted by a gene trap containing a beta galactosidase (beta-gal) reporter (Eno4(+/Gt)). Expression of beta-gal occurred in the testis, and male mice homozygous for the gene trap allele (Eno4(Gt/Gt)) were infertile. Epididymal sperm numbers were 2-fold lower and sperm motility was reduced substantially in Eno4(Gt/Gt) mice compared to wild type mice. Sperm from Eno4(Gt/Gt) mice had a coiled flagellum and a disorganized FS. The Gm5506 gene encodes a protein identical to ENO1 and also is transcribed at a low level in testis. We conclude that ENO4 is required for normal assembly of the FS and provides most of the enolase activity in sperm and that Eno1 and/or Gm5506 may encode a minor portion of the enolase activity in sperm. PMID- 23446456 TI - Semen parameters can be predicted from environmental factors and lifestyle using artificial intelligence methods. AB - Fertility rates have dramatically decreased in the last two decades, especially in men. It has been described that environmental factors as well as life habits may affect semen quality. In this paper we use artificial intelligence techniques in order to predict semen characteristics resulting from environmental factors, life habits, and health status, with these techniques constituting a possible decision support system that can help in the study of male fertility potential. A total of 123 young, healthy volunteers provided a semen sample that was analyzed according to the World Health Organization 2010 criteria. They also were asked to complete a validated questionnaire about life habits and health status. Sperm concentration and percentage of motile sperm were related to sociodemographic data, environmental factors, health status, and life habits in order to determine the predictive accuracy of a multilayer perceptron network, a type of artificial neural network. In conclusion, we have developed an artificial neural network that can predict the results of the semen analysis based on the data collected by the questionnaire. The semen parameter that is best predicted using this methodology is the sperm concentration. Although the accuracy for motility is slightly lower than that for concentration, it is possible to predict it with a significant degree of accuracy. This methodology can be a useful tool in early diagnosis of patients with seminal disorders or in the selection of candidates to become semen donors. PMID- 23446458 TI - Electron-transporting PAHs with dual perylenediimides: syntheses and semiconductive characterizations. AB - An effective method was developed to prepare triphenyleno[1,2,3,4 ghi]perylenediimide derivatives, via ICl-induced annulation, dehalogenation, followed by photocyclization. A perylenediimide (PDI) dimer featuring a terphenyl bisethynylene linker was thereby transformed into a benzo[k]tetraphene fused with two benzoperylenediimides. These PDI derivatives exhibited electron mobility up to 0.079 cm(2) V(-1) s(-1) in solution-processed thin film transistors. PMID- 23446457 TI - Multiple metastases in a novel LNCaP model of human prostate cancer. AB - Metastasis is a frequent and lethal consequence of prostate cancer. Current treatments for metastasis are palliative only. Thus, experimental animal models of metastatic prostate cancer are required for investigations of its pathogenesis and for the development of treatment strategies; however, few models exist at present. In the present study, the LNCaP prostate cancer cell line was co transfected with a PGK-luciferase-GFP lentivirual vector (LNCaP-luc). Repeated subcutaneous injections of LNCaP-luc cells with Matrigel in nude mice followed by isolation of the cells from tumors resulted in the generation of the LNCaP1-luc cell line. We used CCK-8 and Transwell migration assays, western blot analysis and polymerase chain reaction to detect differences in the characteristics between the LNCaP-luc and LNCaP1-luc cells, and used LNCaP cells to generate a mouse model of metastatic prostate cancer by intracardiac injection. Metastasis was evaluated by bioluminescence imaging, and histological and immunohistochemical staining. the characteristics of the LNCaP1-luc cells differed from those of LNCaP cells, and LNCaP1-luc cells showed increased cell proliferation, cell invasion, tumorigenicity and metastasis potential, and underwent epithelial-mesenchymal transition. In addition, the LNCaP1-luc cells induced multiple metastases in mice when injected into the left cardiac muscle. PMID- 23446459 TI - Ultrasensitive hydrogen sensor based on Pd(0)-loaded SnO2 electrospun nanofibers at room temperature. AB - Pd(0)-loaded SnO2 nanofibers have been successfully synthesized with different loaded levels via electrospinning process, sintering technology, and in situ reduction. This simple strategy could be expected to extend for the fabrication of similar metal-oxide loaded nanofibers using different precursors. The morphological and structural characteristics of the resultant product were investigated by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectra (XPS). To demonstrate the usage of such Pd(0)-loaded SnO2 nanomaterial, a chemical gas sensor has been fabricated and investigated for H2 detection. The sensing performances versus Pd(0)-loaded levels have been investigated in detail. An ultralow limit of detection (20 ppb), high response, fast response and recovery, and selectivity have been obtained on the basis of the sensors operating at room temperature. The combination of SnO2 crystal structure and catalytic activity of Pd(0)-loaded gives a very attractive sensing behavior for applications as real time monitoring gas sensors. PMID- 23446460 TI - [Magnetic resonance tomography and hybrid imaging in rheumatology]. AB - In rheumatologic diseases magnet resonance imaging (MRI) is capable of depicting early inflammatory changes which are frequently missed by other imaging modalities. New MRI protocols and hardware, primarily whole-body MRI and low field extremity MRI facilitate the use of MRI in rheumatology patients. The increasing number of functional MRI techniques provide additional molecular information on the tissue composition, e.g. cartilage quality. These molecular MRI techniques enable new ways for early disease detection and therapy monitoring. Hybrid imaging modalities, such as MRI-SPECT (single photon mmission tomography) and MRI-PET (positron emission tomography) provide a new level of molecular imaging in rheumatology by adding the advantages of the combined modalities. This article provides an up-to-date overview of new MRI techniques and innovative hybrid imaging modalities and summarizes the first available results of these procedures in rheumatologic applications. PMID- 23446462 TI - [Further improving the result of multi-modality treatment for gastric cancer by optimizing scheme and measures]. AB - The incidence of gastric cancer has declined worldwide in the past decades. However, due to the large number of population in mainland of China, the absolute number of newly-diagnosed patients in this developing country is still very high. Most of the major clinical centers have established multi-disciplinary team, but the strategy in treating this life-threatening disease still needs to be optimized, including the precise preoperative staging by various techniques, perioperative chemotherapy for locally advanced diseases, role of minimally invasive surgical approaches in treating patients with different stages, translational research to fill the gap between clinical trials and basic research, as well as the individualized treatment for gastric cancer. We believe that the biological behaviors and molecular events of gastric cancer in eastern countries are different from that of Western countries, so the clinical evidences derived from Eastern countries need to be strengthened to enrich the unmet demands in the clinical practice in China. PMID- 23446461 TI - [Revised consensus classification. Histopathological classification of diseases associated with joint endoprostheses]. AB - The revised classification of the periprosthetic membrane (synovial-like interface membrane SLIM) encompasses all pathological alterations which can occur as a result of endoprosthetic replacement of major joints and lead to a reduction in durability of prostheses. This also includes the established consensus classification of SLIM by which aseptic and septic prosthetic loosening can be subdivided into four histological types and histopathological criteria for additional pathologies: endoprosthesis-associated arthrofibrosis, immunological/allergic alterations and osseous pathologies. This revision represents the foundation for the histopathological diagnostics of the total spectrum of diseases associated with joint prostheses, is a suitable basis for a standardized diagnostic procedure and etiological clarification of endoprosthesis failure and also as a data standard for endprosthesis registers, in particular for registers based on routine data (e.g. German endoprosthesis register). PMID- 23446463 TI - [Pay attention to digestive tract reconstruction after curative resection of gastric cancer]. AB - Several reconstruction techniques are available after gastrectomy. Roux-en-Y reconstruction following distal gastrectomy is the reference in terms of long term functional and endoscopic outcomes. It is the preferred reconstruction for benign lesions and early gastric cancer. In patients with advanced gastric cancer, BillrothII (reconstruction is an acceptable alternative. After total gastrectomy, Roux-en-Y reconstruction is the simplest solution, with satisfactory functional outcome. Addition of a jejunal reservoir seems to improve long-term outcome after total gastrectomy and could be of benefit to patients with good prognosis. After distal or total gastrectomy, hand-sewn anastomoses should be preferred because of lower costs. Mechanical sutures can facilitate transhiatal esophagojejunostomy. After proximal gastrectomy, esophago-gastric anastomosis is the basic reconstruction method. Gastric remnant is made into gastric tube in the operation. The effect of pyloroplasty remains controversial, and further study is needed to improve the quality of life after operation. PMID- 23446464 TI - [The fifth metastasis route of gastric cancer and the third principle of radical operation]. AB - The local-regional recurrence is the most important failure reason of D2 radical operation for curative advanced gastric cancer. Another way of metastasis, which exists in the mesogastrium and separates apart from the primary tumor, blood vessels and lymph nodes, appears to be responsible for the local-regional recurrence partly. We call it as the fifth route of metastasis. The mesogastrium is surrounded by proper fascia completely and covered partly by serosa. We suggest that D2 radical operation should not only include the resection of primary tumor and lymphadenectomy, but also add the complete mesogastric excision (CME) as the third principle in gastric cancer radical operations to cut down the fifth metastasis route of gastric cancer, to prevent the fifth metastasis scattered on the field of operation which may induce the local-regional recurrence. PMID- 23446465 TI - [Clinical aspect of new international gastric cancer staging system]. AB - The 7th UICC/AJCC Gastric Cancer TNM Staging System includes major revisions of pT and pN classification. The Japanese Classification and UICC/AJCC TNM System have reached consistency in staging of gastric cancer. There are some new topics of lymphadenectomy in the new guidelines. The new TNM system accepts the database from Japan and Korea and it will be more accurate to predict the prognosis of gastric cancer patients. The rationality of splenectomy, total bursectomy, dissection of No.13 and No.14 lymph nodes is still not very clear and needs more evidences. D2 lymphadenectomy is the recommended surgical approach both in Eastern and Western countries. The benefit of paraaortic lymphadenectmoy for selected patients needs further evidences as well. The international gastric cancer staging project will collect the data from 23 countries and the new staging system will be applicable worldwide. PMID- 23446466 TI - [Application and value of preoperative staging in gastric cancer]. AB - A more differentiated therapy regimen for gastric carcinoma requires more precise preoperative staging. In patients with early gastric cancer (EGC), especially mucosa, endoscopic resection (ER) should be performed to avoid unnecessary surgical procedures. To achieve R0 resection for locally-advanced gastric cancer (AGC), neoadjuvant treatments have been investigated. Clinical staging of gastric cancer has been greatly improved by advance in imaging techniques such as endoscopic ultrasonography (EUS), transabdominal ultrasonography (TAUS), multi slice spiral CT (MSCT), magnetic resonance imaging (MRI), positron emission tomography (PET), combined PET-CT scans, and laparoscopic staging. This review is to summarize the clinical application and the value of preoperative staging in gastric cancer. PMID- 23446467 TI - [Never ignore the therapeutic principles during the procedure of laparoscopic gastrectomy for gastric cancer]. AB - In recent years, minimally invasive surgery has been adopted and widely used in Japan and Korea for early gastric cancer with low risk of lymph node metastasis, since laparoscopy-assisted distal gastrectomy (LADG) with lymph node dissection was first reported in 1994 by Kitano. The purposes of laparoscopic surgery for gastric cancer are to minimize surgical insults and to maximize patient's quality of life, while not compromising the oncologic clearance. As laparoscopic experience has accumulated, the indications for laparoscopic gastrectomy (LG) have been broadened to patients with advanced gastric cancer. However, the role of LG remains controversial, because studies of the long-term outcomes of LG are insufficient. Therefore, in order to make sure the same effectiveness of LG as conventional open operation, there are some basic principles should be strictly followed while performing LG, such as properly selected patients, sufficient surgical margins, standardized D2 lymphadenectomy, no-touch technique and so on. PMID- 23446468 TI - [Difficulty and settlement of digestive reconstruction after laparoscopic gastrectomy for gastric cancer]. AB - Digestive reconstruction after gastrectomy is one of the key steps to the success of surgery. The surgical difficulty is greater for digestive reconstruction after laparoscopic-assisted gastrectomy (LAG). In order to reduce the incidence of postoperative complication and ensure a good quality of life for patients after gastrectomy, surgeons should have experience in open surgery and proper reconstruction technique and surgical instruments should be selected. PMID- 23446469 TI - [To improve the cognition about the carcinoma of esophagogastric junction]. AB - Recently, the incidence of carcinoma at the esophagogastric junction (CEG), especially adenocarcinoma at esophagogastric junction (AEG) is increasing. AEG has obvious difference from other parts of stomach tumor in anatomy, physiology and pathology. The scholars have not made a consensus and standard about the treatment of AEG. It is necessary to improve the knowledge and cognition about AEG and find a feasible treatment strategy. PMID- 23446470 TI - [Emphasis on special types of stomach tumors]. AB - Some special types of stomach tumors are often encountered in clinical paractice, such as gastrointestinal stromal tumor (GIST), gastric neuroendocrine tumors (NETs), primary gastric lymphoma (PGL) and some special types of gastric cancer. Because of their special pathogenesis and pathological types with lower incidence, the choices of the treatment for these diseases are limited. This article analyzes these special types of stomach tumors in order to improve the understanding of doctors in these diseases. PMID- 23446471 TI - [Diagnosis and minimally invasive treatment of gastric remnant cancer]. AB - Gastric remnant cancer (GRC) is defined as cancer in the remnant stomach after partial gastrectomy. The incidence of GRC is rising in recent years. The carcinogenesis, development, and metastasis of GRC are different from primary gastric cancer. The early detection of GRC should be based on rational surveillance of patients following gastrectomy. For early stage GRC, endoscopic resection is one of the safe and effective methods. For advanced GRC, the primary treatment alternative is surgical resection. Minimally invasive procedures such as laparoscopic exploration, laparoscopic-assisted resection of GRC are still safe choices for experienced surgeons. PMID- 23446472 TI - [Meta-analysis on comparison of long-term complications and quality of life between two digestive tract reconstruction techniques following total gastrectomy]. AB - OBJECTIVE: To compare the incidence of postoperative long-term complications and quality of life between two digestive tract reconstruction techniques after total gastrectomy in order to provide evidence for clinical practice. METHODS: A systematic literature search was carried out to obtain studies of randomized controlled trials (RCTs) of reconstruction techniques including jejunal interposition and Roux-en-Y. Data extracted from RCTs for meta-analysis were independently assessed by two reviewers. A meta-analysis was performed by RevMan5.0 software. RESULTS: A total of 1628 gastric cancer cases undergoing total gastrectomy from 10 RCTs were eligible for inclusion, among whom 728 received jejunal interposition reconstruction and 954 Roux-en-Y anastomosis. As compared with Roux-en-Y anastomosis, jejunal interposition reconstruction significantly decreased the incidence of dumping syndrome (OR=0.19, 95%CI:0.11 0.34, P<0.01), increased the prognostic nutritional index (WMD=6.02, 95%CI:1.82 10.22, P<0.01), and improved the body weight postoperatively (WMD=-2.45, 95%CI: 3.81--1.71, P<0.01). Meanwhile, jejunal interposition reconstruction did not prolong operative time and hospital stay (both P>0.05). CONCLUSION: Jejunal interposition has better efficacy than Roux-en-Y in dumping syndrome and quality of life, and is a reasonable and effective digestive tract reconstruction for long-term survival of gastric cancer patients. PMID- 23446473 TI - [Application of delta-shaped anastomosis in totally laparoscopic distal gastrectomy]. AB - OBJECTIVE: To explore the technical feasibility, safety, and clinical efficacy of delta-shaped anastomosis in totally laparoscopic distal gastrectomy (TLDG). METHODS: Clinical data of 18 patients with gastric cancer who received TLDG with delta-shaped anastomosis from November 2012 to December 2012 were retrospectively analyzed. The delta-shaped anastomosis is a new method of intraabdominal Billroth I anastomosis using only linear stapler. The posterior wall of the stomach and that of the duodenum were put together using linear stapler, and the common stab incision was also closed with linear stapler. The anastomosis was finished with a delta-shaped. RESULTS: TLDG with delta-shaped anastomosis was successfully carried out in all the patients. The mean operation time and mean time for anastomosis were (156.3 +/- 38.5) minutes and (24.6 +/- 11.2) minutes. The lengths of upper and lower segment of resection form gastric cancer were (5.8 +/- 2.4) cm and (4.1 +/- 2.7) cm. Blood loss was (70.7 +/- 43.8) ml and number of dissected lymph nodes was 32.4 +/- 12.0 per patient. The average time to ground activities, time to flatus, time to fluid diet and length of hospital stay were (1.8 +/- 0.9) days, (3.1 +/- 1.2) days, (3.6 +/- 1.7) days, and (9.6 +/- 2.5) days, respectively. Only one patient developed chylus leak with intraabdominal infection. There was no mobility related to the anastomosis in all the patients. CONCLUSION: The delta-shaped anastomosis is a safe and feasible procedure for totally laparoscopic distal gastrectomy and provides satisfactory short-term efficacy. PMID- 23446474 TI - [Analysis of associated factors of lymph node metastasis in intramucosal early gastric cancer]. AB - OBJECTIVE: To analyze the associated predictive factors of lymph node metastasis in intramucosal early gastric cancer, and to provide reference for individualized treatment protocol. METHODS: Clinical data of 498 patients who were pathologically confirmed to be intramucosal early gastric cancer after radical resection of gastric cancer were retrospectively reviewed. Univariate and multivariate analyses were applied to evaluate the associated factors. RESULTS: Forty-three out of 498 patients (8.6%) had lymph node metastasis. Tumor size (HR=1.525, 95%CI:1.040-2.236), depth of invasion (HR=1.656, 95%CI:1.158-2.368) and histological type (HR=8.149, 95%CI:1.770-37.513) were the independent risk factors for lymph node metastasis in intramucosal early gastric cancer. CONCLUSIONS: Prediction and therapeutic guidance for lymph node metastasis in intramucosal early gastric cancer can be carried out according to clinicopathological risk factors. PMID- 23446475 TI - [Mode of lymph node metastasis in early gastric cancer and risk factors]. AB - OBJECTIVE: To investigate the status of lymph node metastasis (LNM) and to discuss reasonable lymphadenectomy in early gastric cancer (EGC). METHODS: Between January 1991 and December 2010, 242 EGC patients underwent surgery in the Tianjin Cancer Hospital. Their clinical characteristics, pathologic features, and lymph node metastasis were analyzed retrospectively. RESULTS: LNM was observed in 22 of 242 patients (9.1%), and 10 (5.5%) in 182 mucosal lesions and 12 (20.0%) in 60 submueosal lesions. There were 14 patients had LNM in the first tier alone, 4 patients had skipped metastasis, and 4 patients had LNM in the first, second, and third ties. The LNM was identified in 18 patients at the first tier with groups 7 and 3 being the most common (8 patients in each group), 7 patients at the second tier (4 patients in group 8a and 3 in group 9), and 2 patients at the third tier (one 16b, and one 4sa). Multivariable analysis showed that the depth of invasion (P=0.003, OR=4.386, 95%CI:1.656-11.617), and lymphatic vessel involvement(P=0.002, OR=13.621, 95%CI:2.711-68.447) were independent risk factors for LNM. CONCLUSIONS: LNM in EGC is mainly correlated with depth of invasion, and lymphatic vessel involvement. Precise evaluation of LNM pre- and intra operatively is very important for the reasonable surgery. PMID- 23446477 TI - [Impact of the extent of gastric resection on the prognosis of patients with middle one-third gastric cancer]. AB - OBJECTIVE: To investigate the impact of the extent of gastric resection on the prognosis of patients with middle one-third gastric cancer. METHODS: From January 1998 to December 2005, 222 patients with middle one-third gastric cancer underwent D2 radical resection in the Affiliated Union Hospital, Fujian Medical University. Among them, 66 underwent distal gastrectomy (DG group), while 156 underwent total gastrectomy (TG group). The 5-year survival rates were compared between two groups. The prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: The 5-year survival rates of DG group and TG group were 63.9% and 49.8% respectively, with significant difference (P<0.05). Nevertheless, compared to DG group, the tumors in TG group had bigger size, later TNM stage, and higher proportion of locating lesser curvature of stomach (all P<0.01). Multivariate analysis revealed that invasion depth, lymph node metastasis and TNM classification were independent prognostic factors (all P<0.05), but the extent of gastric resection was not (P>0.05). CONCLUSION: If curative resection can be performed, the long-term prognosis of patients with middle one-third gastric cancer is not affected by the extent of gastric resection, and distal gastrectomy is feasible. PMID- 23446476 TI - [Prognostic value of metastatic lymph node ratio for gastric cancer patients with less than 15 lymph nodes dissection]. AB - OBJECTIVE: To evaluate the prognostic value of metastatic lymph node ratio (MLR) for gastric cancer patients with less than 15 lymph nodes dissected. METHODS: Clinical data of 610 gastric cancer patients undergoing operation in Tianjin Cancer Hospictal from January 2003 to July 2007 were analyzed retrospectively. Patients were divided into two groups: <15 lymph nodes dissected group (n=320) and >= 15 lymph nodes dissected group (n=290). MLR was classified based on the following intervals: rN1 <= 10%, rN2 10%-30%, rN3 30%-60% and rN4 >60%. Survival was determined by Kaplan-Meier method and difference was assessed by Log-rank test. Multivariate analysis was performed using Cox proportional hazard regression model. Survival rates were compared between two groups in pN and rN stages respectively. RESULTS: In <15 nodes group, all the survival differences among various rN stages were not significant (all P>0.05), while in same rN stage, all the survival differences among various pN stages were not significant (all P>0.05). Significant differences of 5-year cumulative survival rates were found between the two groups in pN2 and pN3a stage patients (both P<0.05) while no significant differences were found among different rN stages (all P>0.05). Multivariate analysis demonstrated rN stage was an independent prognostic factor for gastric cancer patients with <15 lymph nodes dissected (P=0.012, RR=1.617, 95%CI:1.111-2.354). CONCLUSION: The rN staging system based on MLR can predict the prognosis of gastric cancer patients with less than 15 lymph nodes dissected. PMID- 23446478 TI - [Clinicopathological features and prognosis of young patients with gastric cancer]. AB - OBJECTIVE: To summarize the clinicopathological characteristics and analyze the prognostic factors of young patients with gastric cancer. METHODS: A total of 99 patients with the age less than or equal to 40 were admitted in The First Affiliated Hospital of Sun Yat-sen University from August 2001 to December 2009. Their clinicopathological and follow-up data were compared with middle-aged and elderly patients with the age more than 40. RESULTS: There were statistically significant differences in gender, tumor location, Borrmann type, histological type, differentiated histology, depth of invasion, peritoneal metastasis between young patients and elder ones. The 5-year survival rates of young and elder patients were 49.1% and 44.4% respectively, and the difference was not statistically significant (P>0.05). Univariate and multivariate analyses showed that TNM stage (P=0.014) and surgical methods (P=0.012) were independent predictive factors of survival for young patients. For the young patients, the 5 year survival rate was 56.7% after curative resection, 11.1% after palliative resection. Those who underwent palliative surgery or biopsy alone died within 1 year after surgery. The difference between difference surgical procedures in survival were statistically significant (P<0.05). CONCLUSIONS: As compared to elder patients, young patients with gastric cancer have special clinicopathological features. However, no significant difference of survival rate is found between the young and the elder patients. TNM stage and surgical methods are independent prognostic factors of young patients with gastric cancer. Radical resection appears to confer the only chance of prolonged survival. PMID- 23446479 TI - [Risk factors analysis of postsurgical gastroparesis syndrome and its impact on the survival of gastric cancer after subtotal gastrectomy]. AB - OBJECTIVE: To investigate the risk factors of postsurgical gastroparesis syndrome (PGS) after subtotal gastrectomy in gastric cancer and the impact of PGS on prognosis. METHODS: Clinical data of 422 patients who underwent subtotal gastrectomy for gastric cancer in the Central Hospital of Huzhou Sity from January 2004 to May 2010 were analyzed retrospectively. Risk factors of PGS were indentified and the recurrence-free survival was compared between the patients with and without PGS. RESULTS: PGS occurred in 42 patients (9.5%). Univariate analysis showed that: age over 65, combination of anxiety disorder, low albuminemia in perioperative period, pyloric obstruction in preoperative period, high serume glucose level (>= 11.2 mmol/L) in postoperative period, Billroth II (gastroenterostomy, operation time over 4 hours, using patient-controlled analgesia, or intravenous fluid over 3500 ml/d (all P<0.05) were prone to develop PGS. These might be potential clinical risk factors associated to PGS. Correlation analysis showed the number of clinical risk factors was positively correlated with the incidence of PGS (r=0.967, P<0.05). A total of 215 cases (50.9%) were followed up for 3-60 months. The mean recurrence-free survival time of patients with PGS was 26.1 months, which was shorter than that of those without PGS (33.4 months, P=0.029). CONCLUSIONS: Gastric cancer patients with the clinical risk factors mentioned above are prone to develop PGS after subtotal gastrectomy. PGS is associated with poor prognosis. PMID- 23446480 TI - [Efficacy of neoadjuvant chemotherpy in patients with locally advanced gastric cancer]. AB - OBJECTIVE: To evaluate the efficacy and safety of neoadjuvant chemotherapy in patients with locally advanced gastric cancer, and to analyze the relevant factors of recurrent death of gastric cancer after adjuvant chemotherapy. METHODS: Clinical data of 49 patients who underwent neoadjuvant chemotherapy for locally advanced gastric cancer between July 2007 and June 2011 were reviewed. Preoperative staging was determined by endoscopic ultrasonography and abdominal computer tomography (CT) or magnetic resonance imaging (MRI). Chemotherapy was administered for regimen of two or three drugs. Prognostic factors were analyzed by univariate and multivariate analysis with Cox proportional hazard model. RESULTS: The response rate was 33.3% (16/48) and disease control rate was 93.8% (45/48). Forty-four (89.8%, 44/49) patients received curative resection after neoadjuvant chemotherapy, among whom 90.9% (40/44) underwent D2 lymphadenctomy. Thirty-two cases had pathological response and 2 patients had pathological complete response. The average hospital stay was 11.6 days and 2 patients had longer hospitalization because of postoperative pancreatic complications. The toxicities were most in grade 1-2. All the patients were followed up postoperatively and the median follow-up was 21.6 months. Median progression-free survival was 29.6 (95%CI:24.0-35.2) months and median overall survival was 34.6 months (95%CI:29.8-39.4). Imaging response (P=0.038, RR=0.168, 95%CI:0.031-0.904) and pathological response (P=0.007, RR=0.203, 95%CI:0.064-0.642) were identified as independent prognostic factors with COX multivariate analysis. CONCLUSIONS: Neoadjuvant chemotherapy has quite high disease control rate and R0 resecting rate for patients with locally advanced gastric cancer. Imaging response and pathological response are most important prognostic factors in those patients. PMID- 23446481 TI - [Comparison of transabdominal-hiatal approach and standard thoracoabdominal approach in radical gastrectomy for advanced proximal gastric cancer]. AB - OBJECTIVE: To investigate the safety and efficacy of the transabdominal-hiatal approach of radical gastrectomy for the advanced proximal gastric cancer. METHODS: The clinical data of 40 advanced proximal gastric cancer patients with involvement of distal esophagus admitted in Tongcheng People's Hospital from June 2003 to September 2006 were analyzed retrospectively. Patients included 27 men and 13 women with a mean age of 56.1 years (range: 37 to 76 years). The data were compared with those of 40 proximal gastric cancer patients undergoing standard thoracoabdominal approach (control group) during the same period. RESULTS: As compared with the control group, the transabdominal-hiatal approach showed less blood loss [(181.3 +/- 63.7) ml vs.(248.8 +/- 79.7) ml], shorter operating time [(4.1 +/- 0.6) h vs. (5.3 +/- 0.7) h], shorter ICU stay [(6.5 +/- 5.7) d vs. (19.4 +/- 18.0) d] and shorter postoperative hospital stay [(14.0 +/- 2.3) d vs.(18.7 +/- 3.0) d] (all P<0.05). The complication rates of transabdominal hiatal approach group and thoracoabdominal approach group were 7.5% (3/40) and 10.0% (4/40), and the 5-year survival rates were 51.3% and 60.0%, respectively (both P>0.05). CONCLUSION: The transabdominal-hiatal approach of radical gastrectomy for proximal gastric cancer is safe and effective, which may substitute the standard thoracoabdominal technique. PMID- 23446482 TI - [Mechanism study on intestinal motility of reconstruction procedures after total gastrectomy]. AB - OBJECTIVE: To investigate the mechanism of reconstruction procedures affecting intestinal motility after total gastrectomy. METHODS: Beagle dogs were divided into 3 groups:3 dogs in sham operation group, 7 in functional jejunal interposition (FJI) group, and 3 in Roux-en Y(RY) group. These dogs were sacrificed 48 hours postoperatively. Dogs were gavaged with active carbon 1 h before sacrifice and the intestinal transit rate was evaluated. Intestinal tissues 5 cm away from the duodenojejunal anastomosis were collected for detecting inflammation, interstitial cells of Cajal (ICC), and apoptosis using HE staining, immunohistochemistry, and interference microscope respectively. RESULTS: The intestinal transit rate in sham and FJI group (0.14 +/- 0.03 and 0.32 +/- 0.11) was lower than that in RY group (0.52 +/- 0.21, P<0.05), which indicated FJI procedure had better food storage. More ICCs were found in submucosa of FJI group than those of RY group. Inflammation in serosal side of the intestine, including hemorrhage, fibrin deposition, and ulceration, neutrophil and macrophage infiltration, and intestinal epithelial cell apoptosis were significantly reduced in FJI group as compared to RY group, which indicated that amelioration of intestinal inflammation and damage might contribute to reducing ICC loss in FJI group. CONCLUSIONS: As a reconstruction procedure with less traumatic and intestinal continuity preserving, FJI has better reservoir function and quicker recovery of intestinal motility. PMID- 23446483 TI - [Expression of CCAAT/enhancer binding protein beta in human gastric carcinoma and its clinical significance]. AB - OBJECTIVE: To explore the expression of CCAAT/enhancer binding protein beta (CEBPB) in gastric carcinoma tissues and its association with clinicopathological features and prognosis. METHODS: CEBPB protein expression level was detected by immunohistochemistry method in resected gastric carcinomas and adjacent gastric mucosa tissues (n=81), and its association with clinicopathological features and prognosis was analyzed. RESULTS: The immunohistochemical staining of CEBPB was predominantly in the nucleus with some cytoplasmic staining. As a result, 16% (13/81) of the gastric carcinomas were stained positively, whereas there was hardly positive expression in adjacent gastric mucosa tissues. There was a significant association between the expression of CEBPB and distant metastasis on univariate analysis (P<0.05). The median survival time in patients with positive CEBPB expression was significantly lower than those with negative CEBPB expression (19.4 months vs. 45.2 months, P=0.024). Multivariable analysis showed that CEBPB was independently associated with prognosis (HR=2.544, 95%CI:1.154 5.610, P=0.021). CONCLUSION: Up-regulation of CEBPB suggests poor prognosis in patients with gastric cancer. PMID- 23446484 TI - [Expression of aldo-keto reductase family 1 member B10 in gastric cancer tissues and its clinical significance]. AB - OBJECTIVE: To investigate the association of AKR1B10 expression in gastric cancer tissues with clinicopathologic features and prognosis of gastric cancer patients. METHODS: Real-time polymerase chain reaction (RT-PCR) was conducted to detect AKR1B10 mRNA expression in gastric cancer and adjacent gastric mucosa tissues (n=36). AKR1B10 protein expression was measured by immunohistochemistry in primary gastric cancer tissues (n=100) and non-tumorous gastric mucosa tissues (n=70). RESULTS: RT-PCR results confirmed that AKR1B10 was significantly down regulated in gastric cancer tissues compared with that in paired adjacent mucosa [8.3% (3/36) vs. 91.7% (33/36), P=0.000]. Immunohistochemistry revealed that the percentage of AKR1B10 positive specimens in gastric carcinoma was lower than that in normal specimens [33.0% (33/100) vs. 92.9% (65/70), P=0.000]. The frequencies of positive AKR1B10 in patients was significantly correlated with tumor size (P=0.000), invasive depth (P=0.004), lymph node metastasis (P=0.028), distant metastasis (P=0.031) and TNM stages (P=0.000). The 5-year survival rate of positive AKR1B10 group was significantly higher as compared to negative group (60.6% vs. 32.8%, P<0.01). CONCLUSION: The down-regulation of AKR1B10 expression in gastric cancer may be associated with the progress of gastric cancer is suggestive of poor prognosis. PMID- 23446485 TI - [Prognostic biomarkers and targeted therapies for gastric cancer]. AB - Gastric cancer patients with the same clinical stage may vary greatly in prognosis, which makes the improvement of current staging-based treatment imperative. The systematic biology approaches are the solution for systematic identification of biomarkers for prognostic evaluation and targeted therapy. These markers will be applied to classify the patients by molecular traits and then to guide the individualized medication. Although HER-2 antibody is currently the only targeted drug in guideline, more drugs are now addressed in early phases of clinical trials and parts of them will be eventually approved. PMID- 23446486 TI - [Progression of preoperative regional arterial infusion chemotherapy in advanced gastric cancer]. AB - The outcome of surgery alone for advanced gastric cancer is unsatisfactory. Local recurrence rate and distant metastasis rate are still high in postoperative patients. In recent years, people have paid more attention to neo- adjuvant chemotherapy, because it can reduce tumor loading, degrade the staging, increase the surgery excision rate and improve the long-term survival. Preoperative regional arterial infusion chemotherapy can directly act on the tumor endothelial cells with higher local drug concentration, but with fewer systemic side effects. So it may offer an effective treatment for advanced gastric cancer. The indications, complications, therapeutic evaluation, timing of surgery, chemotherapy regimens and pathomorphological changes and so on of the preoperative regional arterial infusion chemotherapy are summarized in this review. PMID- 23446487 TI - Hairpin oligonucleotides anchored terbium ion: a fluorescent probe to specifically detect lead(II) at sub-nM levels. AB - A terbium based fluorescent probe was synthesized by coordinating terbium ions with a designed oligonucleotides (5'-ATATGGGGGATAT-3', termed GH5). GH5 improved the fluorescence of terbium ions by four orders of magnitude. The fluorescence enhancement of terbium ions by different oligonucleotides sequences indicated that the polyguanine loop of the hairpin GH5 is key to enhance terbium ion emission. The quantum yield of Tb-GH5 probe was 10.5% and the probe was photo stable. The result of conductivity titration indicated that the stoichiometry of the probe is 3.5 Tb: 1 GH5, which is confirmed by fluorescence titration. This probe had high sensitivity and specificity for the detection of lead ions. The fluorescence intensity of this probe was linear with respect to lead concentration over a range 0.3-2.1 nM (R(2) = 0.99). The limit of detection for lead ions was 0.1 nM at a signal-to-noise ratio of 3. PMID- 23446488 TI - The ability of rumen ciliates, Eudiplodinium maggii, Diploplastron affine, and Entodinium caudatum, to use the murein saccharides. AB - Murein polysaccharides may contribute to a considerable part of the dry matter of bacterial cells. Their utilization by protozoa inhabiting the rumen is, however, poorly recognized. The objective of this study was to examine the ability of three species of ciliates, i.e., Eudiplodinium maggii, Diploplastron affine, and Entodinium caudatum of digest, and ferment these saccharides. The cultivation experiments showed that the enrichment of growth medium with bacterial cell wall beta-glycans increased the ciliate number (p < 0.05). A statistically significant increase (p < 0.01) was followed by a continuous decrease (p < 0.01) in the percentage of individuals containing beta-glycans particles after 4- and 24-h incubation of ciliates with this substrate, respectively. The enzymatic experiments confirmed the ability of the examined protozoa to digest murein. E. caudatum exhibited the highest activity (8.2 unit (U)/mg protein per min), and E. maggii, the lowest (3.0 U/mg protein per min). The production rates of volatile fatty acids by starved and fed ciliate species were 0.7 and 1.6 (E. caudatum) pmol/ciliate cell per h, 30.5 and 42.5 (E. maggii) pmol/ciliate cell per h, and 8.3 and 19.2 (D. affine) pmol/ciliate cell per h (p < 0.05). PMID- 23446489 TI - The persistence of biofilm-associated antibiotic resistance of Staphylococcus aureus isolated from clinical bovine mastitis cases in Australia. AB - The aim of this investigation was to determine the persistence of biofilm associated antibiotic resistance developed by methicillin-sensitive Staphylococcus aureus (MSSA), of different capsular types, during biofilm formation. Because of superiority of the tissue culture plate (TCP) over the Congo Red Agar (CRA) method for measuring biofilm formation, it was used to determine the persistence of the antibiotic resistance developed by the isolates in biofilms. The antibiotic resistance was found to persist for 3-4 wk post propagation as planktonic subcultures. Interestingly, some strains even developed resistance to vancomycin and/or teicoplanin. However, no association of either biofilm formation or persistent antibiotic resistance with the major capsular phenotype was observed. These observations highlight the potential significance of (a) determining the antibiograms of S. aureus subcultured from biofilms developed in vitro using the TCP method as well as from planktonic cultures for formulation of an optimal therapeutic strategy, and (b) continuing to identify predominant non-capsular antigens contributing to biofilm formation, regardless of the capsular phenotype for the development of an effective potentially broad spectrum vaccine for prevention of bovine mastitis caused by S. aureus. PMID- 23446491 TI - A spoonful of sugar: commentary on an article by Annette L. Adams, PhD, MPH, et al.: "surgical outcomes of total knee replacement according to diabetes status and glycemic control, 2001 to 2009". PMID- 23446490 TI - In vitro synergistic activity of diketopiperazines alone and in combination with amphotericin B or clotrimazole against Candida albicans. AB - The synergistic anticandidal activity of three diketopiperazines [cyclo-(L-Pro-L Leu) (1), cyclo-(D-Pro-L-Leu) (2), and cyclo-(D-Pro-L-Tyr) (3)] purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) in combination with amphotericin B and clotrimazole was investigated using the macrodilution method. The minimum inhibitory concentration and minimum fungicidal concentration of the diketopiperazines was compared with that of the standard antibiotics. The synergistic anticandidal activities of diketopiperazines with amphotericin B or clotrimazole were assessed using the checkerboard and time-kill methods. The results of the present study showed that the combined effects of diketopiperazines with amphotericin B or clotrimazole predominantly recorded synergistic (<0.5). Time-kill study showed that the growth of the Candida was completely attenuated after 12-24 h of treatment with 50:50 ratios of diketopiperazines and antibiotics. These results suggest that diketopiperazines combined with antibiotics may be microbiologically beneficial and not antagonistic. These findings have potential implications in delaying the development of resistance as the anticandidal effect is achieved with lower concentrations of both drugs (diketopiperazines and antibiotics). The cytotoxicity of diketopiperazines was also tested against two normal human cell lines (L231 lung epithelial and FS normal fibroblast) and no cytotoxicity was recorded for diketopiperazines up to 200 MUg/mL. The in vitro synergistic activity of diketopiperazines with antibiotics against Candida albicans is reported here for the first time. PMID- 23446492 TI - Two Unusual Methylidenecyclopropane Glucosides from Metaxya rostrata C.Presl. AB - Two new natural compounds, (1R,2E)-2-(6-hydroxyhexylidene)cyclopropyl-beta-D glucopyranoside (1) and (6E)-6-[(2R)-2-(beta-D glucopyranosyloxy)cyclopropylidene]hexanoic acid (2), glucosides of a very rare methylidenecyclopropane alcohol, as well as two known glycosides of phenolic acids, namely 4-O-beta-D-glucopyranosylcaffeic acid (3) and (E)-4-O-beta-D glucopyranosylcoumaric acid (4), and methyl alpha-fructofuranoside (5) were isolated for the first time from the rhizomes of the tree fern Metaxya rostrata C.Presl. The structures were elucidated on the basis of detailed spectroscopic data analysis, and the structure of 1 was additionally confirmed by X-ray crystal structure analysis. PMID- 23446493 TI - From mice to men--mouse models in obesity research: what can we learn? AB - Obesity has become a world-wide epidemic and is associated with diseases such as diabetes, dyslipidaemia, cardiovascular disease and certain types of cancers. Understanding the adipose tissue developmental process, involving adipogenesis, angiogenesis and extracellular matrix remodelling, is therefore crucial to reveal the pathobiology of obesity. Experimental mouse models are extensively used to gain new insights into these processes and to evaluate the role of new key players, in particular proteolytic system components, in adipose tissue development and obesity. In this paper, we will review available in vitro and in vivo murine models of obesity and discuss their value in understanding the mechanisms contributing to obesity. PMID- 23446494 TI - Spirituality, religiosity, depression, anxiety, and drug-use consequences during methadone maintenance therapy. AB - Substance addiction is damaging to the health of persons, families, and society. Often the person with addiction has decreased spirituality and religiosity and suffers from anxiety, depression, or both, increasing the risk for continued substance use and its concomitant negative consequences. The study purpose was to describe spirituality and religiosity, among persons enrolled in methadone maintenance therapy and to examine associations between spirituality, religiosity, anxiety, depression, and drug-use consequences. Using a descriptive and cross-sectional correlational design, 108 participants completed questionnaires assessing the study variables. Spiritual well-being was similar to other addiction samples and lower than healthy person samples. Most participants described themselves as spiritual or religious though religious participation was lower than in their past. The analysis indicated that spirituality, religiosity, depression, anxiety, and negative drug-use consequences are interrelated in the person with addiction. Higher anxiety was predictive of negative drug-use consequences. PMID- 23446495 TI - Hematologic, hepatic, renal, and lipid laboratory monitoring after initiation of combination antiretroviral therapy in the United States, 2000-2010. AB - We assessed laboratory monitoring after combination antiretroviral therapy initiation among 3678 patients in a large US multisite clinical cohort, censoring participants at last clinic visit, combination antiretroviral therapy change, or 3 years. Median days (interquartile range) to first hematologic, hepatic, renal, and lipid tests were 30 (18-53), 31 (19-56), 33 (20-59), and 350 (96-1106), respectively. At 1 year, approximately 80% received more than 2 hematologic, hepatic, and renal tests consistent with guidelines. However, only 40% received 1 or more lipid tests. Monitoring was more frequent in specific subgroups, likely reflecting better clinic attendance or clinician perception of higher susceptibility to toxicities. PMID- 23446496 TI - Effect of the levonorgestrel intrauterine device on genital HIV-1 RNA shedding among HIV-1-infected women not taking antiretroviral therapy in Nairobi, Kenya. AB - The effect of the levonorgestrel-releasing intrauterine device (LNG-IUD) on genital HIV-1 RNA shedding and inflammation among 25 HIV-infected women was evaluated. Blood, endocervical, and cervicovaginal lavage samples were collected from HIV-infected women not taking antiretrovirals before LNG-IUD insertion and 1 month, 3 month, and 6 months thereafter. HIV-1 RNA was quantitated by real-time reverse transcriptase-polymerase chain reaction. Inflammatory markers were measured by enzyme immunoassay. Genital HIV-1 RNA shedding and inflammatory markers did not differ between LNG-IUD placement and month 6, with the exception of interleukin 1beta that increased (0.42 log10; 95% confidence interval: 0.10 to 0.75). The LNG-IUD did not increase genital HIV-1 RNA shedding after 6 months of use. PMID- 23446498 TI - A year in review. PMID- 23446499 TI - Plastic surgery nursing: a profession and a passion. PMID- 23446497 TI - Feasibility of identifying a cohort of US women at high risk for HIV infection for HIV vaccine efficacy trials: longitudinal results of HVTN 906. AB - BACKGROUND: Identifying cohorts of US women with HIV infection rates sufficient for inclusion in vaccine efficacy trials has been challenging. Using geography and sexual network characteristics to inform recruitment strategies, HVTN 906 determined the feasibility of recruiting a cohort of women at high risk for HIV acquisition. METHODS: HIV uninfected women who reported unprotected sex in the prior 6 months, resided or engaged in risk behavior in local geographical high risk pockets and/or had a male partner who had been incarcerated, injected drugs, or had concurrent partners were eligible. Behavioral risk assessment, HIV counseling and testing, and pregnancy testing were done at baseline, 6, 12, and 18 months. RESULTS: Among 799 women, 71% were from local high-risk pockets and had high-risk male partners. Median age was 37 years; 79% were Black; and 15% Latina. Over half (55%) reported a new partner in the prior 6 months, 57% reported a male partner who had concurrent female sexual partners, and 37% reported a male partner who had been incarcerated. Retention at 18 months was 79.5%. Annual pregnancy incidence was 12%. Annual HIV incidence was 0.31% (95% confidence interval: 0.06% to 0.91%). Risk behaviors decreased between screening and 6 months with smaller changes thereafter. DISCUSSION: This cohort of women recruited using new strategies based on geography and sexual network characteristics did not have an HIV incidence high enough for HIV vaccine efficacy trials, despite high baseline levels of risk and a high pregnancy rate. New strategies to identify cohorts of US women for efficacy trials are needed. PMID- 23446500 TI - Letter from the President of PSNCB. PMID- 23446501 TI - The use of Targeted MicroCurrent Therapy in postoperative pain management. AB - Effective postoperative analgesia is a prerequisite to enhance the recovery process and reduce morbidity. The use of local anesthetic techniques is well documented to be effective, but single-dose techniques (infiltration, peripheral blocks, neuraxial blocks) have been of limited value in major operations because of their short duration of analgesia. Recent advances in technology have led to the development of a noninvasive device, targeted MicroCurrent Therapy, which enhances postsurgical recovery by stimulating the body's natural healing process. This therapy transmits gentle, short bursts of electrical current targeted to the tissue cells at the surgical site. This article reviews recent clinical experience and evidence of this device in plastic and reconstructive surgery. PMID- 23446503 TI - The contralateral prophylactic mastectomy decision-making process. AB - Women facing an early-stage breast cancer diagnosis may elect to have a contralateral prophylactic mastectomy (CPM) to reduce the risk of developing a contralateral breast cancer. In the United States, CPM rates for all surgically treated women with stages I through III unilateral breast cancer increased dramatically from 1998 to 2003. In 1991, the National Institutes of Health Consensus Panel concluded that breast-conserving surgery is an appropriate and preferred treatment for the majority of women with stage I and II breast cancer because it provides survival rates equivalent to those of total mastectomy while preserving the breast. Owing to the near equivalence of the 2 surgical treatment options in terms of survival benefit and recurrence risk, surgical treatment for early-stage breast cancer qualifies as a "preference-sensitive decision" for which no one treatment is best (S. T. ; ). We performed a literature review to identify studies that examined CPM decision making in women facing an early-stage breast cancer diagnosis with the aim of determining the most influential factors affecting her surgical choice. Study outcome measures were largely based on demographic information retrospectively extracted from large databases representing trends rather than revealing influences reflecting preference sensitive decision making. While we may know demographically, which women choose CPM, we do not know why. To better understand this increasing trend, which greatly impacts patient counseling, prospective research is needed using decision quality methods developed to illuminate factors influencing a woman's decision. PMID- 23446505 TI - Compounding pharmacies: friend or foe. PMID- 23446506 TI - Guidelines for staff administering laser therapy in an office setting. AB - Advances in laser technology provide not only new opportunities, but an increase in laser applications. Many independent clinics now offer laser treatments. Use of laser treatment and related services should only be provided to patients by appropriately trained and qualified personnel. This article outlines the roles and responsibilities of the healthcare team working in independent laser healthcare facilities. The article is meant to assist clinics in developing their own quality management programs and is intended only to act as a guide to ensure that treatment is provided by qualified professionals in the safest, most effective manner. Staff working in laser clinics are responsible for the operation of lasers during treatment. They are also responsible for patient and staff safety, implementation of standards of care, and providing only procedures that meet and follow strict safety parameters. Accidents will occur with lasers when providers do not have the proper skills, training, and education on laser treatments. Regardless of many safety regulations involving laser use, little is written on the qualifications, selection, and ongoing education of the professional and technical staff working in independent healthcare facilities offering laser services. This article provides a detailed outline of the necessary skills and knowledge the nurses and the support staff need to possess to use lasers for patient treatment in laser treatment centers. Staff educated in laser science and safety can recognize potential hazards and ensure that safety standards are actively integrated into the daily practice of patient care. PMID- 23446507 TI - Developing a policy manual. AB - Do you really need to have a policy and procedure in the office? Frequently they are seen sitting on the shelf, collecting dust. The answer is yes for a number of very important reasons. A policy and procedure manual is a tool to set guidelines and expectations on the basis of the mission and vision of the office. A well written manual is a powerful training tool for new staff so they can get a feel for the office culture. Furthermore, it is a provincial or state legislative requirement that can reduce management's concern about potential legal issues or problems. If an office does not have a manual to set guidelines, the employees may be forced to make their own decisions to solve problems, which can often result in confusion, inconsistencies, and mistakes. PMID- 23446508 TI - Optimizing the closed suction surgical drainage system. AB - BACKGROUND: Closed suction drains are indicated in a wide array of postoperative settings, with many distinct drainage systems available to the surgeon. The purpose of this study was to compare the suction gradients achieved using 2 different sizes of suction reservoirs and 2 different techniques for generating negative pressure. MATERIALS AND METHODS: Drainage reservoirs of 100 and 400 ml were chosen to evaluate their ability to achieve suction. Suction was established in both sizes of drains by pressing the sides of the reservoir together or by pushing the bottom of the reservoir toward the top. Negative pressures were recorded with the reservoir empty, and after every 10-ml addition of saline. Averages were graphed to illustrate the applied suction over a range of drain volumes. RESULTS: The 100-ml drainage system reached a peak suction of -117.6 mmHg, while the 400-ml drainage system reached only a peak suction of -71.4 mmHg. Both of the maximum suction readings were achieved using the full-squeeze technique. The bottom-pushed-in technique did not result in any sustained measurable levels of suction using either of the reservoir volumes. CONCLUSIONS: Smaller drain reservoirs are more successful in generating a high initial suction than larger reservoirs, especially when the volume of fluid in the drain is relatively low. In all sizes of drains, compressing the sides of the reservoir is a far better technique for establishing negative pressure than pressing the bottom of the drain up toward the top. PMID- 23446510 TI - Skin care glossary. PMID- 23446511 TI - Vacuum-assisted ladder closure: an innovative prospect. AB - Negative pressure wound therapy (NPWT) has gained great recognition for its positive effects on enhancing the complex wound healing process. The aim of this limited presentation was to introduce the vacuum-assisted ladder closure (VALC) method as a novel wound care modality used in conjunction with NPWT that reduces wound closure time in complex wounds. Two patients with complex abdominal wounds were identified for this prospective study from August 2011 through October 2011. As this presentation shows, the use of the VALC method appears to reduce complex wound closure times significantly, as compared with the use of NPWT alone. As a result, there may be decreased risk for potential complications such as infection, disfiguration, scar tissue formation, and needless pain and suffering. Through the positive results represented in this limited presentation, the VALC method of wound care used in complex wounds validates the need for further research. PMID- 23446512 TI - Respiratory syncytial virus activity--United States, July 2011-January 2013. AB - Respiratory syncytial virus (RSV) causes lower respiratory infections among infants and young children worldwide. During 1997-2006, an estimated 132,000 172,000 children aged <5 years were hospitalized for RSV infection annually in the United States. In temperate climate zones, RSV generally circulates during the fall, winter, and spring, but the exact timing and duration of RSV seasons vary by region and year. To determine seasonal trends in the circulation of RSV at national and regional levels, data collected by the National Respiratory and Enteric Virus Surveillance System (NREVSS) were analyzed. For 2011-12, the RSV season onset ranged from late October to mid-January and season offset ranged from early March to early May in all 10 U.S. Department of Health and Human Services (HHS) regions, excluding Florida. Florida is reported separately because it has an earlier season onset and longer duration than the rest of the country. For data reported as of January 7, 2013, RSV onset for the 2012-13 season occurred in all but one of the HHS regions by December 15, 2012. Seasonal patterns remained consistent with previous years and demonstrated the usual differences in RSV circulation among HHS regions. Health-care providers and public health officials can use information on RSV circulation to guide diagnostic testing and timing of RSV immunoprophylaxis for children at high risk for severe respiratory infection. PMID- 23446513 TI - Secondary and tertiary transmission of vaccinia virus after sexual contact with a smallpox vaccinee--San Diego, California, 2012. AB - On June 24, 2012, CDC notified Public Health Services, County of San Diego Health and Human Services Agency, of a suspected case of vaccinia virus infection transmitted by sexual contact. The case had been reported to CDC by an infectious disease specialist who had requested vaccinia immune globulin intravenous (VIGIV) (Cangene Corporation, Berwyn, Pennsylvania) for a patient with lesions suspicious for vaccinia. The patient reported two recent sexual contacts: one with a partner who recently had been vaccinated against smallpox and a later encounter with an unvaccinated partner. Infections resulting from secondary transmission of vaccinia virus from the smallpox vaccinee to the patient and subsequent tertiary transmission of the virus from the patient to the unvaccinated partner were confirmed by the County of San Diego Public Health Laboratory. The smallpox vaccine had been administered under the U.S. Department of Defense smallpox vaccination program. The vaccinee did not experience vaccine-associated complications; however, the secondary and tertiary patients were hospitalized and treated with VIGIV. No further transmission was known to have occurred. This report describes the epidemiology and clinical course of the secondary and tertiary cases and efforts to prevent further transmission to contacts. PMID- 23446514 TI - Impact of an innovative approach to prevent mother-to-child transmission of HIV- Malawi, July 2011-September 2012. AB - Antiretroviral medications can reduce rates of mother-to-child transmission of human immunodeficiency virus (HIV) to less than 5%. However, in 2011, only 57% of HIV-infected pregnant women in low- and middle-income countries received a World Health Organization (WHO)-recommended regimen for prevention of mother-to-child transmission (PMTCT), and an estimated 300,000 infants acquired HIV infection from their mothers in sub-Saharan Africa; 15,700 (5.2%) of these infants were born in Malawi. An important barrier to PMTCT in Malawi is the limited laboratory capacity for CD4 cell count, which is recommended by WHO to determine which antiretroviral medications to start. In the third quarter of 2011, the Malawi Ministry of Health (MOH) implemented an innovative approach (called "Option B+"), in which all HIV-infected pregnant and breastfeeding women are eligible for lifelong antiretroviral therapy (ART) regardless of CD4 count. Since that time, several countries (including Rwanda, Uganda, and Haiti) have adopted the Option B+ policy, and WHO was prompted to release a technical update in April 2012 describing the advantages and challenges of this approach as well as the need to evaluate country experiences with Option B+. Using data collected through routine program supervision, this report is the first to summarize Malawi's experience implementing Option B+ under the direction of the MOH and supported by the Office of the Global AIDS Coordinator (OGAC) through the President's Emergency Plan for AIDS Relief (PEPFAR). In Malawi, the number of pregnant and breastfeeding women started on ART per quarter increased by 748%, from 1,257 in the second quarter of 2011 (before Option B+ implementation) to 10,663 in the third quarter of 2012 (1 year after implementation). Of the 2,949 women who started ART under Option B+ in the third quarter of 2011 and did not transfer care, 2,267 (77%) continue to receive ART at 12 months; this retention rate is similar to the rate for all adults in the national program. Option B+ is an important innovation that could accelerate progress in Malawi and other countries toward the goal of eliminating mother-to-child transmission of HIV worldwide. PMID- 23446516 TI - Clothing polymer fibers with well-aligned and high-aspect ratio carbon nanotubes. AB - It is believed that the crucial step towards preparation of electrical conductive polymer-carbon nanotube (CNT) composites is dispersing CNTs with a high length-to diameter aspect ratio in a well-aligned manner. However, this process is extremely challenging when dealing with long and entangled CNTs. Here in this study, a new approach is demonstrated to fabricate conductive polymer-CNT composite fibers without involving any dispersion process. Well-aligned CNT films were firstly drawn from CNT arrays, and then directly coated on polycaprolactone fibers to form polymer-CNT composite fibers. The conductivity of these composite fibers can be as high as 285 S m(-1) with only 2.5 wt% CNT loading, and reach 1549 S m(-1) when CNT loading is 13.4 wt%. As-prepared composite fibers also exhibit 82% retention of conductivity at a strain of 7%, and have improved mechanical properties. PMID- 23446515 TI - Impediments to replication fork movement: stabilisation, reactivation and genome instability. AB - Maintaining genome stability is essential for the accurate transmission of genetic material. Genetic instability is associated with human genome disorders and is a near-universal hallmark of cancer cells. Genetic variation is also the driving force of evolution, and a genome must therefore display adequate plasticity to evolve while remaining sufficiently stable to prevent mutations and chromosome rearrangements leading to a fitness disadvantage. A primary source of genome instability are errors that occur during chromosome replication. More specifically, obstacles to the movement of replication forks are known to underlie many of the gross chromosomal rearrangements seen both in human cells and in model organisms. Obstacles to replication fork progression destabilize the replisome (replication protein complex) and impact on the integrity of forked DNA structures. Therefore, to ensure the successful progression of a replication fork along with its associated replisome, several distinct strategies have evolved. First, there are well-orchestrated mechanisms that promote continued movement of forks through potential obstacles. Second, dedicated replisome and fork DNA stabilization pathways prevent the dysfunction of the replisome if its progress is halted. Third, should stabilisation fail, there are mechanisms to ensure damaged forks are accurately fused with a converging fork or, when necessary, re associated with the replication proteins to continue replication. Here, we review what is known about potential barriers to replication fork progression, how these are tolerated and their impact on genome instability. PMID- 23446517 TI - Synergistic cytotoxic effects of inorganic phosphate and chemotherapeutic drugs on human osteosarcoma cells. AB - Novel therapeutic approaches are required for the treatment of osteosarcoma. Combination chemotherapy is receiving increased attention in order to identify compounds that may increase the therapeutic index of clinical anticancer drugs. In this regard, naturally occurring molecules with antitumor activity and with limited toxicity to normal tissues have been suggested as possible candidates for investigation of their synergistic efficacy in combination with antineoplastic drugs. Inorganic phosphate (Pi) is an essential nutrient for living organisms. Relevantly, Pi has emerged as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. Previously, we showed that Pi inhibits proliferation and aggressiveness of U2OS human osteosarcoma cells and that Pi is capable of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner. In this study, we extended the role of Pi in the chemosensitivity of osteosarcoma cells to other anticancer drugs. Specifically, we report and compare the antiproliferative effects of a combination between Pi and doxorubicin, Taxol and 5-fluorouracil (5-FU) treatments. We found that Pi increases the antiproliferative response to both Taxol and doxorubicin to a similar extent. On the other hand, Pi did not potentiate the anticancer effects induced by 5-FU. These effects were paralleled by apoptosis induction and were cell cycle-dependent. The clinical significance of our data and their potential therapeutic applications for improving osteosarcoma treatment are discussed. PMID- 23446518 TI - Japan Diabetic Nephropathy Cohort Study: study design, methods, and implementation. AB - BACKGROUND: Diabetic nephropathy, leading to end-stage renal disease, has a considerable impact on public health and the social economy. However, there are few national registries of diabetic nephropathy in Japan. The aims of this prospective cohort study are to obtain clinical data and urine samples for revising the clinical staging of diabetic nephropathy, and developing new diagnostic markers for early diabetic nephropathy. METHODS: The Japanese Society of Nephrology established a nationwide, web-based, and prospective registry system. On the system, there are two basic registries; the Japan Renal Biopsy Registry (JRBR), and the Japan Kidney Disease Registry (JKDR). In addition to the two basic registries, we established a new prospective registry to the system; the Japan Diabetic Nephropathy Cohort Study (JDNCS), which collected physical and laboratory data. RESULTS: We analyzed the data of 321 participants (106 female, 215 male; average age 65 years) in the JDNCS. Systolic and diastolic blood pressure was 130.1 and 72.3 mmHg, respectively. Median estimated glomerular filtration rate (eGFR) was 33.3 ml/min/1.73 m(2). Proteinuria was 1.8 g/gCr, and serum levels of albumin were 3.6 g/dl. The majority of the JDNCS patients presented with preserved eGFR and low albuminuria or low eGFR and advanced proteinuria. In the JRBR and JKDR registries, 484 and 125 participants, respectively, were enrolled as having diabetes mellitus. In comparison with the JRBR and JKDR registries, the JDNCS was characterized by diabetic patients presenting with low proteinuria with moderately preserved eGFR. CONCLUSIONS: There are few national registries of diabetic nephropathy to evaluate prognosis in Japan. Future analysis of the JDNCS will provide clinical insights into the epidemiology and renal and cardiovascular outcomes of type 2 diabetic patients in Japan. PMID- 23446519 TI - Reference ranges for serum cystatin C measurements in Japanese children by using 4 automated assays. AB - OBJECTIVE: The data available on reference ranges for cystatin C in children are limited, and there are discrepancies among the available data. The aim of this study was to describe the reference ranges for cystatin C in Japanese children by using 4 automated assays. METHODS: Serum cystatin C levels were measured in 1128 Japanese children aged 3 month to 16 years without kidney disease. We calculated age-, gender-, race- and assay-specific cystatin C ranges. RESULTS: For all 4 assays, the median serum cystatin C levels were raised in term infants compared with older children and decreased by the first 2 years. The median serum cystatin C levels remained constant throughout up to the age of 14 years and decreased in children aged 15-16 years. The median serum cystatin C levels in children aged 12 16 years were slightly higher in males than in females. Assay-specific differences were also observed in the levels of serum cystatin C measured. CONCLUSION: Age-, gender-, race- and assay-specific ranges for serum cystatin C should be used as another tool to assess kidney function in children. PMID- 23446521 TI - Phenotypic engineering of sperm-production rate confirms evolutionary predictions of sperm competition theory. AB - Sperm production is a key male reproductive trait and an important parameter in sperm competition theory. Under sperm competition, paternity success is predicted to depend strongly on male allocation to sperm production. Furthermore, because sperm production is inherently costly, individuals should economize in sperm expenditure, and conditional adjustment of the copulation frequency according to their sperm availability may be expected. However, experimental studies showing effects of sperm production on mating behaviour and paternity success have so far been scarce, mainly because sperm production is difficult to manipulate directly in animals. Here, we used phenotypic engineering to manipulate sperm-production rate, by employing dose-dependent RNA interference (RNAi) of a spermatogenesis specific gene, macbol1, in the free-living flatworm Macrostomum lignano. We demonstrate (i) that our novel dose-dependent RNAi approach allows us to induce high variability in sperm-production rate; (ii) that a reduced sperm-production rate is associated with a decreased copulation frequency, suggesting conditional adjustment of mating behaviour; and (iii) that both sperm production and copulation frequency are important determinants of paternity success in a competitive situation, as predicted by sperm competition theory. Our study clearly documents the potential of phenotypic engineering via dose-dependent RNAi to test quantitative predictions of evolutionary theory. PMID- 23446522 TI - The strategy of psychopathy: primary psychopathic traits predict defection on low value relationships. AB - Recent evidence suggests that psychopathy is a trait continuum. This has unappreciated implications for understanding the selective advantage of psychopathic traits. Although clinical psychopathy is typically construed as a strategy of unconditional defection, subclinical psychopathy may promote strategic conditional defection, broadening the adaptive niche of psychopathy within human societies. To test this, we focus on a ubiquitous real-life source of conditional behaviour: the expected relational value of social partners, both in terms of their quality and the likely quantity of future interactions with them. We allow for conversational interaction among participants prior to their playing an unannounced, one-shot prisoner's dilemma game, which fosters naturalistic interpersonal evaluation and conditional behaviour, while controlling punishment and reputation effects. Individuals scoring higher on factor 1 (callous affect, interpersonal manipulation) of the Levenson self-report psychopathy scale defected conditionally on two kinds of low-value partners: those who interrupted them more during the conversation, and those with whom they failed to discover cues to future interaction. Both interaction effects support the hypothesis that subclinical primary psychopathy potentiates defection on those with low expected relational value. These data clarify the function and form of psychopathic traits, while highlighting adaptive variation in human social strategies. PMID- 23446523 TI - Rapid preflexes in smooth adhesive pads of insects prevent sudden detachment. AB - Many insects possess adhesive organs that can produce extreme attachment forces of more than 100 times body weight but they can rapidly release adhesion to allow locomotion. During walking, weaver ants (Oecophylla smaragdina) use only a fraction of their maximally available contact area, even upside-down on a smooth surface. To test whether the reduced contact area makes the ants more susceptible to sudden and unexpected detachment forces, for example, by rain or wind gusts, we investigated the reaction of untethered ants to rapid horizontal displacements of the substrate. High-speed video recordings revealed that the pad's contact area could more than double within the first millisecond after the perturbation. This contact area expansion is much faster than any neuromuscular reflex and therefore represents a passive 'preflex', resulting from the mechanical properties and geometrical arrangement of the (pre-)tarsus. This preflex reaction protects ants effectively against unexpected detachment, and allows them to use less contact area during locomotion. Contact area expanded most strongly when the substrate displacement generated a pull along the axis of the tarsus, showing that the ants' preflex is direction-dependent. The preflex may be based on the ability of Hymenopteran adhesive pads to unfold when pulled towards the body. We tested Indian stick insects (Carausius morosus), which have smooth pads that lack this motility. Similar to the ants, they showed a rapid and direction-dependent expansion of the contact area mainly in the lateral direction. We propose that the preflex reaction in stick insects is based on the reorientation of internal cuticle fibrils in a constant-volume system, whereas the ants' pad cuticle is probably not a hydrostat, and pad extension is achieved by the arcus, an endoscelerite of the arolium. PMID- 23446524 TI - Marine incursion into East Asia: a forgotten driving force of biodiversity. AB - Episodic marine incursion has been a major driving force in the formation of present-day diversity. Marine incursion is considered to be one of the most productive 'species pumps' particularly because of its division and coalescence effects. Marine incursion events and their impacts on diversity are well documented from South America, North America and Africa; however, their history and impacts in continental East Asia largely remain unknown. Here, we propose a marine incursion scenario occurring in East Asia during the Miocene epoch, 10-17 Ma. Our molecular phylogenetic analysis of Platorchestia talitrids revealed that continental terrestrial populations (Platorchestia japonica) form a monophyletic group that is the sister group to the Northwest Pacific coastal species Platorchestia pacifica. The divergence time between the two species coincides with Middle Miocene high global sea levels. We suggest that the inland form arose as a consequence of a marine incursion event. This is the first solid case documenting the impact of marine incursion on extant biodiversity in continental East Asia. We believe that such incursion event has had major impacts on other organisms and has played an important role in the formation of biodiversity patterns in the region. PMID- 23446526 TI - Meandering worms: mechanics of undulatory burrowing in muds. AB - Recent work has shown that muddy sediments are elastic solids through which animals extend burrows by fracture, whereas non-cohesive granular sands fluidize around some burrowers. These different mechanical responses are reflected in the morphologies and behaviours of their respective inhabitants. However, Armandia brevis, a mud-burrowing opheliid polychaete, lacks an expansible anterior consistent with fracturing mud, and instead uses undulatory movements similar to those of sandfish lizards that fluidize desert sands. Here, we show that A. brevis neither fractures nor fluidizes sediments, but instead uses a third mechanism, plastically rearranging sediment grains to create a burrow. The curvature of the undulating body fits meander geometry used to describe rivers, and changes in curvature driven by muscle contraction are similar for swimming and burrowing worms, indicating that the same gait is used in both sediments and water. Large calculated friction forces for undulatory burrowers suggest that sediment mechanics affect undulatory and peristaltic burrowers differently; undulatory burrowing may be more effective for small worms that live in sediments not compacted or cohesive enough to extend burrows by fracture. PMID- 23446525 TI - A biogenic amine and a neuropeptide act identically: tyramine signals through calcium in Drosophila tubule stellate cells. AB - Insect osmoregulation is subject to highly sophisticated endocrine control. In Drosophila, both Drosophila kinin and tyramine act on the Malpighian (renal) tubule stellate cell to activate chloride shunt conductance, and so increase the fluid production rate. Drosophila kinin is known to act through intracellular calcium, but the mode of action of tyramine is not known. Here, we used a transgenically encoded GFP::apoaequorin translational fusion, targeted to either principal or stellate cells under GAL4/UAS control, to demonstrate that tyramine indeed acts to raise calcium in stellate, but not principal cells. Furthermore, the EC(50) tyramine concentration for half-maximal activation of the intracellular calcium signal is the same as that calculated from previously published data on tyramine-induced increase in chloride flux. In addition, tyramine signalling to calcium is markedly reduced in mutants of NorpA (a phospholipase C) and itpr, the inositol trisphosphate receptor gene, which we have previously shown to be necessary for Drosophila kinin signalling. Therefore, tyramine and Drosophila kinin signals converge on phospholipase C, and thence on intracellular calcium; and both act to increase chloride shunt conductance by signalling through itpr. To test this model, we co-applied tyramine and Drosophila kinin, and showed that the calcium signals were neither additive nor synergistic. The two signalling pathways thus represent parallel, independent mechanisms for distinct tissues (nervous and epithelial) to control the same aspect of renal function. PMID- 23446528 TI - Personal experience and reputation interact in human decisions to help reciprocally. AB - There is ample evidence that human cooperative behaviour towards other individuals is often conditioned on information about previous interactions. This information derives both from personal experience (direct reciprocity) and from experience of others (i.e. reputation; indirect reciprocity). Direct and indirect reciprocity have been studied separately, but humans often have access to both types of information. Here, we experimentally investigate information use in a repeated helping game. When acting as donor, subjects can condition their decisions to help recipients with both types of information at a small cost to access such information. We find that information from direct interactions weighs more heavily in decisions to help, and participants tend to react less forgivingly to negative personal experience than to negative reputation. Moreover, effects of personal experience and reputation interact in decisions to help. If a recipient's reputation is positive, the personal experience of the donor has a weak effect on the decision to help, and vice versa. Yet if the two types of information indicate conflicting signatures of helpfulness, most decisions to help follow personal experience. To understand the roles of direct and indirect reciprocity in human cooperation, they should be studied in concert, not in isolation. PMID- 23446527 TI - A dynamic history of gene duplications and losses characterizes the evolution of the SPARC family in eumetazoans. AB - The vertebrates share the ability to produce a skeleton made of mineralized extracellular matrix. However, our understanding of the molecular changes that accompanied their emergence remains scarce. Here, we describe the evolutionary history of the SPARC (secreted protein acidic and rich in cysteine) family, because its vertebrate orthologues are expressed in cartilage, bones and teeth where they have been proposed to bind calcium and act as extracellular collagen chaperones, and because further duplications of specific SPARC members produced the small calcium-binding phosphoproteins (SCPP) family that is crucial for skeletal mineralization to occur. Both phylogeny and synteny conservation analyses reveal that, in the eumetazoan ancestor, a unique ancestral gene duplicated to give rise to SPARC and SPARCB described here for the first time. Independent losses have eliminated one of the two paralogues in cnidarians, protostomes and tetrapods. Hence, only non-tetrapod deuterostomes have conserved both genes. Remarkably, SPARC and SPARCB paralogues are still linked in the amphioxus genome. To shed light on the evolution of the SPARC family members in chordates, we performed a comprehensive analysis of their embryonic expression patterns in amphioxus, tunicates, teleosts, amphibians and mammals. Our results show that in the chordate lineage SPARC and SPARCB family members were recurrently recruited in a variety of unrelated tissues expressing collagen genes. We propose that one of the earliest steps of skeletal evolution involved the co-expression of SPARC paralogues with collagenous proteins. PMID- 23446529 TI - Learning and signal copying facilitate communication among bird species. AB - Signals relevant to different sets of receivers in different contexts create a conflict for signal design. A classic example is vocal alarm signals, often used both during intraspecific and interspecific interactions. How can signals alert individuals from a variety of other species in some contexts, while also maintaining efficient communication among conspecifics? We studied heterospecific responses to avian alarm signals that drive the formation of anti-predator groups but are also used during intraspecific interactions. In three species-rich communities in the western Himalayas, alarm signals vary drastically across species. We show that, independently of differences in their calls, birds respond strongly to the alarm signals of other species with which they co-occur and much more weakly to those of species with which they do not co-occur. These results suggest that previous exposure and learning maintain heterospecific responses in the face of widespread signal divergence. At an area where only two species regularly interact, one species' calls incorporate the call of the other. We demonstrate experimentally that signal copying allows strong responses even without previous exposure and suggest that such hybrid calls may be especially favoured when pairwise interactions between species are strong. PMID- 23446530 TI - A trade-off between oxidative stress resistance and DNA repair plays a role in the evolution of elevated mutation rates in bacteria. AB - The dominant paradigm for the evolution of mutator alleles in bacterial populations is that they spread by indirect selection for linked beneficial mutations when bacteria are poorly adapted. In this paper, we challenge the ubiquity of this paradigm by demonstrating that a clinically important stressor, hydrogen peroxide, generates direct selection for an elevated mutation rate in the pathogenic bacterium Pseudomonas aeruginosa as a consequence of a trade-off between the fidelity of DNA repair and hydrogen peroxide resistance. We demonstrate that the biochemical mechanism underlying this trade-off in the case of mutS is the elevated secretion of catalase by the mutator strain. Our results provide, to our knowledge, the first experimental evidence that direct selection can favour mutator alleles in bacterial populations, and pave the way for future studies to understand how mutation and DNA repair are linked to stress responses and how this affects the evolution of bacterial mutation rates. PMID- 23446531 TI - Inbreeding in horsenettle (Solanum carolinense) alters night-time volatile emissions that guide oviposition by Manduca sexta moths. AB - Plant volatiles serve as key foraging and oviposition cues for insect herbivores as well as their natural enemies, but little is known about how genetic variation within plant populations influences volatile-mediated interactions among plants and insects. Here, we explore how inbred and outbred plants from three maternal families of the native weed horsenettle (Solanum carolinense) vary in the emission of volatile organic compounds during the dark phase of the photoperiod, and the effects of this variation on the oviposition preferences of Manduca sexta moths, whose larvae are specialist herbivores of Solanaceae. Compared with inbred plants, outbred plants consistently released more total volatiles at night and more individual compounds-including some previously reported to repel moths and attract predators. Female moths overwhelmingly chose to lay eggs on inbred (versus outbred) plants, and this preference persisted when olfactory cues were presented in the absence of visual and contact cues. These results are consistent with our previous findings that inbred plants recruit more herbivores and suffer greater herbivory under field conditions. Furthermore, they suggest that constitutive volatiles released during the dark portion of the photoperiod can convey accurate information about plant defence status (and/or other aspects of host plant quality) to foraging herbivores. PMID- 23446532 TI - Embryos, polyps and medusae of the Early Cambrian scyphozoan Olivooides. AB - The Early Cambrian organism Olivooides is known from both embryonic and post embryonic stages and, consequently, it has the potential to yield vital insights into developmental evolution at the time that animal body plans were established. However, this potential can only be realized if the phylogenetic relationships of Olivooides can be constrained. The affinities of Olivooides have proved controversial because of the lack of knowledge of the internal anatomy and the limited range of developmental stages known. Here, we describe rare embryonic specimens in which internal anatomical features are preserved. We also present a fuller sequence of fossilized developmental stages of Olivooides, including associated specimens that we interpret as budding ephyrae (juvenile medusae), all of which display a clear pentaradial symmetry. Within the framework of a cnidarian interpretation, the new data serve to pinpoint the phylogenetic position of Olivooides to the scyphozoan stem group. Hypotheses about scalidophoran or echinoderm affinities of Olivooides can be rejected. PMID- 23446534 TI - [Association of suicide attempts with childhood traumatic experiences in patients with major depression]. AB - OBJECTIVE: Childhood traumatic experiences are widely known risk factors in the development of various psychiatric disorders and unfavorable behavior patterns, including suicide attempts. Moreover, in the course of some psychiatric disorders, suicide attempts are more frequent in patients with childhood traumatic experiences. This study explores the influence of childhood traumatic experiences on suicide attempts in patients with major depression. METHOD: Our study involved 30 patients with major depressive disorder in full remission who had attempted suicide, and 30 patients with major depressive disorder in full remission who had never attempted suicide, as well as 30 healthy controls matched with patients for age, gender, and education. All the subjects were interviewed with Structural Clinical Interview for DSM-IV (SCID-I). Subsequently, all subjects were administered Childhood Trauma Questionnaire (CTQ). RESULTS: Patients who had attempted suicide reported significantly higher CTQ scores for emotional abuse and emotional neglect, physical abuse, and sexual abuse than healthy controls. Moreover, patients who had attempted suicide reported significantly higher CTQ scores for each three subdomains than patients who had never attempted suicide. There were no significant difference between patients who had never attempted suicide and healthy controls in any of the CTQ subdomains. CONCLUSION: Childhood trauma may be a risk factor for suicide attempts in patients with depression. Inquiring childhood traumatic experiences could make an important contribution to predict suicide risk in patients with depression. PMID- 23446533 TI - Major urinary protein 5, a scent communication protein, is regulated by dietary restriction and subsequent re-feeding in mice. AB - Major urinary proteins (Mups) are important for rodent scent communication and sexual behaviour. Recent evidence suggests that Mup1 may be regulated by fasting and re-feeding (RF). However, other Mup isoforms are poorly investigated, and data on the impact of long-term dietary restriction (DR) and ad libitum RF on Mup expression are missing. We investigated the effects of long-term 25 per cent DR and subsequent RF on Mup expression in male C57BL6 mice. DR significantly decreased Mup gene expression, hepatic and urinary protein levels compared with ad libitum (AL) fed control mice, with the greatest downregulation found for Mup5 expression. The decline in Mup expression was inverted by six months of RF. Because of inhibitory glucocorticoid response elements in the genomic sequence of the Mup5 gene, the observed inverse correlation of nuclear glucocorticoid receptor levels with Mup expression in response to DR and subsequent RF is a possible regulatory mechanism. Additionally, gene-expression-inhibiting histone deacetylation (H3K9) occurred in the region of the Mup5 gene in response to DR. We assume that Mup may act as a molecular switch linking nutritional status to sexual behaviour of mice, and thereby regulating male fertility and reproduction in response to food supply. PMID- 23446535 TI - [Association of serum homocysteine and methionine levels with cognition and functioning in bipolar disorder]. AB - OBJECTIVE: The relationship between homocysteine (HCY) levels and cognitive impairments, particularly executive functions in bipolar disorder (BD), has recently been investigated. However, conflicting results were reported. The aim of the present study is to investigate changes in serum HCY, methionine, vitamine B12 and levels in BD patients are relative to controls and to investigate the relationship between HCY, methionine, vitamin B12, and folate levels and clinical features, cognitive functions and psychosocial functioning in euthymic BD patients and controls. METHODS: Sixty BD type I euthymic patients and twenty controls were assessed with Global Assessment of Functioning and a battery of neuropsychological tests including the Wisconsin card sorting test, the Rey's auditory verbal learning test, the Cancellation test, Trail making test A, Trail making test B, and the Stroop test. HCY, vitamin B12, methionine and folate levels were measured together after collecting blood samples from both patient and controls. RESULTS: Mean serum methionine concentration was different between groups. Low serum methionine was found to be a predictor of BD. However, a statistically significant difference was not detected between groups for mean serum values of HCY, folate, or vitamin B12. HCY levels showed a positive correlation with illness duration, the number of total episodes, and the number of manic episodes. A significant correlation was not found between HCY, methionine, folate, B12 levels with cognitive functions and functioning in the BD group. CONCLUSION: Low serum methionine was found to be a predictor of BD, a condition which can lead to a decrease in SAM synthesis and thus to a variety of complications in methylation reactions. Additional studies are needed to clarify the impact of single carbon metabolism on BD. PMID- 23446536 TI - [Violent behavior variables among patients with schizophrenia under forensic psychiatric process: a case-control study]. AB - OBJECTIVE: The aim of this study is to investigate the patterns of offense and treatment outcomes in patients with schizophrenia who have exhibited violent behavior and to provide data for mental health professionals to aid in the treatment and therapeutic support of schizophrenia patients. METHODS: The subjects included in this study include a total of 52 patients with schizophrenia who had committed violent crime and who were under observation or mandatory treatment, and a control group of 31 subjects who assumed full responsibility for the crime they were accused of. Patients with schizophrenia and control subjects were examined based on the assumption that prior exhibition of violent behavior may be a determining factor for socio-demographic characteristics and the early identification of violent crime. Life-long aggressive behavior was also examined using the Overt Aggression Scale (OAS). RESULTS: A total of 80.7% of the patients with schizophrenia were found to be paranoid subtype. The mean age of schizophrenia, the age for the first criminal behavior and the mean age at the time of crime were significantly higher in the schizophrenic group, compared to controls. Previous criminal history, self-injurious behavior before the violent crime, and alcohol and substance use at the time of crime were found to be significantly lower in the schizophrenia group. It was found that more crimes were committed during the daytime in the schizophrenia group, in comparison to the control group. It was also observed that patients with schizophrenia primarily targeted the people around them. CONCLUSION: Investigation into the behavior patterns of patients with schizophrenia exhibiting violent behavior and taking measures to manage the potential risks in these individuals may help to reduce the incidence of future violent behavior. Studies such as this one can aid in improving a patient's social measures and in protecting the people around these individuals. PMID- 23446537 TI - [Quality of life in children with neurofibromatosis type 1, based on their mothers' reports]. AB - OBJECTIVE: The aim of this study was to investigate health-related quality of life (HRQoL) in children with neurofibromatosis type 1 (NF1) and to determine the factors affecting HRQoL in these children, with particular emphasis on NF1 specific findings and complications. MATERIALS AND METHODS: The patient group included 60 NF1 patients aged 3-18 years that were evaluated at our pediatric neurology outpatient clinic between January 2001 and January 2011. The control group included 96 age-matched patients without chronic disease and whose mothers had similar levels of education as the mothers of those in the patient group. All the mothers completed the Pediatric Quality of Life Inventory PedsQoL-Parent Form and the PedsQoL scores in the 2 groups were statistically compared. In addition, the effects of sociodemographic variables, as well as NF1-specific findings and complications (skin findings, neurofibromas, Lisch nodules, arterial hypertension and/or cardiac pathology, short stature, macrocephaly, orthopedic problems, hyperintense lesions on cranial MRI, epileptic seizures, psychiatric disease, and cognitive involvement) were statistically analyzed. RESULTS: All PedsQoL domain scores were lower in the patient group than in the control group (P = 0.0001). HRQoL decreased, and the number of NF1-specific findings and complications increased as age increased in the patient group (P = 0.013). Short stature, neurofibromas and/or plexiform neurofibromas, bone lesions, and psychiatric problems were factors specifically related to low-level HRQoL in the NF1 patients. CONCLUSION: NF1 negatively affected HRQoL in the patient group. We think that multidisciplinary evaluation and, in particular, psychiatric management of NF1 patients are necessary to improve patient HRQoL. PMID- 23446538 TI - [Mental problems and impulsivity reported by adolescents: an epidemiological study]. AB - OBJECTIVE: To determine whether number of self-reported impulsivity symptoms was associated with conduct problems, substance use, academic problems, relational problems and exposure to physical violence in adolescents. METHOD: A survey was developed to be used in a nationally representative general community sample. A 2 staged, stratified and clustered sampling was used. For the first stage (school selection) an equal probability, systematic random sampling and for the second stage (class selection) a simple random selection was used. The statistical analysis included the full and usable surveys obtained from 26009 students (97.5% of the invited sample). RESULTS: After parental education, parental employment, economic status and age; presence of antisocial behaviors; substance abuse; and exposure to physical violence were controlled, presence of even one self-reported impulsivity symptom was associated with physical violence, frequent smoking, frequent alcohol use, substance use, self injurious behaviors, carrying weapons, gang membership, poor relations with others, academic failure and poor mental health. ORs increased with the number of self-reported impulsivity symptoms for several behaviors. Several other associations among conduct problems, substance use, academic failure and relational problems are also reported. CONCLUSION: Even one definite impulsivity symptom must be addressed since it is associated with serious behavioral and relational problems. There may be dose-response interaction between the number of definite impulsivity symptoms and behavioral and relational problems. PMID- 23446539 TI - [Googling suicide: evaluation of websites according to the content associated with suicide]. AB - OBJECTIVE: The Internet is increasingly being used to acquire information about personal experiences and health, but the credibility of this information is debatable. It has been reported that methods of suicide and access to suicidal means are explicitly discussed in some of the websites, with users being encouraged to attempt suicidal acts in some cases. Access to web content with pro suicidal features is monitored in many countries. In Turkey, the frequency of people visiting these websites is unknown. Moreover, a program has not been established that targets online users. This study aims to provide information about the information that a person may come across after searching online for suicide and suicide methods in Turkish language. METHOD: After searching for particular suicidal phrases (i.e., "suicide methods," "painless suicide," "guaranteed suicide," "killing yourself" and "how can I die") in the Google search engine, three psychiatrists evaluated the results independently, according to the content. RESULTS: 42 of the 100 websites (42%) were found to have properties that are pro-suicidal, whereas 13 of them (13%) were found to have content that may be considered protective against suicidal thoughts and actions. Among the websites that were reported to be protective, none had any kind of supervision or guidance from mental health professionals. CONCLUSION: Suicidal content, as well as the possibility of content generated on the Internet, should be taken into account while planning suicide prevention programs. Further studies are needed to determine which risk factors and protective features of the Internet affect suicidal behavior among individuals. PMID- 23446540 TI - [The validity and reliability of the Turkish version of the inventory of statements about self-injury]. AB - OBJECTIVE: Non-suicidal self-injury (NSSI) is defined as the repetitive deliberate destruction of one's body tissue without suicidal intent and is frequently repetitive. The aim of this study was to examine the psychometric properties of the Inventory of Statements About Self-injury (ISAS), a measure designed to comprehensively assess non-suicidal self-injury (NSSI). The ISAS assesses 13 functions of NSSI, as well as the frequency of 12 NSSI behaviors. METHOD: The ISAS was administered to 529 high school students who had performed at least one NSSI behavior. The internal consistency and test-retest reliability of the scale were examined; for construct validity, the relationship between the Turkish form of the ISAS and various criteria scales was examined, and confirmatory factor analysis (CFA) was conducted. RESULTS: Consistent with previous research, factor analysis of the functions scale confirmed the good-fit of the original's 2-dimension model (c2=243; s.d. = 59; NCI (c2/sd) = 4; RMSEA = 0.08 (.07-.09); CFI=0.97; NFI=0.97). In order to test the scale for construct validity, the Brief Symptom Inventory and Suicide Probability Scale were administered to participants, in addition to the ISAS, and the correlations with clinical constructs (e.g., suicidality, depression, anxiety) were in the expected direction. Also the reliability analysis revealed that the ISAS subscales demonstrated high internal consistency. CONCLUSION: In the light of the findings, it was concluded that the Turkish version of ISAS could be used as a reliable and valid tool in assessing non-suicidal self-injury in research and treatment contexts. PMID- 23446541 TI - [From crisis to adjustment disorder: a medicalization of a concept?]. AB - This review aimed to compare two concepts in the psychiatric literature: crisis and adjustment disorder. The two concepts stem from different theoretical perspectives, rely upon different (though relatively loose) bodies of data, and may serve different purposes. The concept of crisis originated from an approach that could be considered psychodynamic, humanistic, and community oriented. Treatment, according to this approach, is known as crisis intervention and is characterized as being principally psychological, social, humanistic, and systemic. The generic approach to crisis calls for immediate aid rather than for a diagnosis and regular appointments, as is customary in psychiatric practice. The concept of adjustment disorder, on the other hand, is a rather medical nosological approach, which strives to achieve a phenomenological and objective description of the patient, and which may lead to ordinary psychiatric treatment, such as pharmacotherapy. Herein we present a review of literature on both approaches, with an emphasis on theoretical and empirical data. The findings appear to provide rather weak empirical support for both concepts. Some theoretical resolutions are proposed in an attempt to link the two concepts, such as a continuum of severity. We conclude that practitioners should decide for themselves, according to one's own theoretical framework and purpose of usage. Nonetheless, as formal psychiatric diagnosis demands more extensive scientific support and bears further implications (such as stigma), the current use of the diagnosis of adjustment disorder may seems less justified. PMID- 23446542 TI - [Fragile X premutation in adult psychiatry: four cases and overview of clinical presentation]. AB - Fragile X carrier status, also named as Fragile X premutation (FraX-PM), is defined by trinucleotide repeat expansions of shorter length compared to those that cause the full syndrome. Its clinical significance has been limited to the risk of further expansion to a full mutation in the offspring of carriers, until it was recently recognized as a clinical syndrome on its own, manifested by unique symptom constellations, as well as a combination of neuropsychiatric signs and symptoms that may be indistinguishable from several commonly seen disorders. The complex heterogeneity of its neuropsychiatric manifestations may render the diagnosis challenging, unless the clinician is familiar with the clinical picture and transmission pattern. We present four cases of FraX-PM, diagnosed in an adult psychiatry setting and confirmed by genetic testing. The aim of this report is to increase familiarity among psychiatric practitioners, since this common condition is seldom included in the current diagnostic practice, which is based on atheoretical definitions. PMID- 23446543 TI - [Aphasia, prosopagnosia and mania: a case diagnosed with right temporal variant semantic dementia]. AB - Neurologic disorders can produce "secondary" mania, and clinicians must distinguish secondary mania from bipolar disorders (BD). Patients with new and late onset mania require an evaluation that includes a thorough history, a neurologic examination, neuroimaging, and other selected tests. Neurologic causes of mania include strokes in the right basotemporal or inferofrontal region, strokes or tumors in the perihypothalamic region, Huntington's disease and other movement disorders, multiple sclerosis and other white matter diseases, head trauma, infections such as neurosyphilis and Creutzfeldt-Jakob disease, and frontotemporal lobar degeneration. The term Frontotemporal Lobar Degeneration (FTLD) is suggested for neurodegenerative diseases characterized by focal degeneration such as Primer Progressive Aphasia (PPA), Frontal Lobe Dementia, PPA Amyotrophic Lateral Sclerosis (ALS), and Corticobasal Degeneration. In this article, we report a frontotemporal dementia (FTD) case that referred with manic symptoms. The female patient was 46 years old, married, graduated from primary school, and had been admitted with complaints of hyperactivity, excessive talking, and decreased sleep for one week. She presented first with complaints that began three years ago that included the inability to remember names, recognize faces, use household appliances, and follow rules. She had also been repeating the same words and behaviors. Prosopagnosia, aphasia, and a positive family history of ALS were discussed with related index in our case. PMID- 23446544 TI - [Letter to the Editor]. PMID- 23446546 TI - Non-coding RNAs: The cancer X factor. PMID- 23446545 TI - Translational control of cell growth and malignancy by the CPEBs. AB - The cytoplasmic polyadenylation element binding proteins (CPEBs) associate with specific sequences in mRNA 3' untranslated regions to promote translation. They do so by inducing cytoplasmic polyadenylation, which requires specialized poly(A) polymerases. Aberrant expression of these proteins correlates with certain types of cancer, indicating that cytoplasmic RNA 3' end processing is important in the control of growth. Several CPEB-regulated mRNAs govern cell cycle progression, regulate senescence, establish cell polarity, and promote tumorigenesis and metastasis. In this Opinion article, we discuss the emerging evidence that indicates a key role for the CPEBs in cancer biology. PMID- 23446548 TI - Melanoma: Horses for courses. PMID- 23446547 TI - Cancer metabolism: fatty acid oxidation in the limelight. AB - Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the 'metabolic switch' in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function. PMID- 23446549 TI - Photophysics and light-activated biocidal activity of visible-light-absorbing conjugated oligomers. AB - The photophysical properties of three cationic pi-conjugated oligomers were correlated with their visible light activated biocidal activity vs S. aureus. The oligomers contain three arylene units (terthiophene, 4a; thiophene-benzotriazole thiophene, 4b; thiophene-benzothiadiazole-thiophene, 4c) capped on each end by cationic -(CH2)3NMe3(+) groups. The oligomers absorb in the visible region due to their donor-acceptor-donor electronic structure. Oligomers 4a and 4b have high intersystem crossing and singlet oxygen sensitization efficiency, but 4c has a very low intersystem crossing efficiency and it does not sensitize singlet oxygen. The biocidal activity of the oligomers under visible light varies in the order 4a > 4b ~ 4c. PMID- 23446550 TI - Elemental mercury vapor interaction with individual gold nanorods. AB - We show that single gold nanorods can act as highly sensitive mercury vapor sensors with attogram resolution. We exposed assorted gold nanorods, with aspect ratios ranging from 2.8-4.1, to MUg m(-3) concentrations of mercury vapor in air for 1 hour. Pre- and post-exposure, the nanorods were examined with a combination of dark field spectroscopy and transmission electron microscopy. Because we isolated individual particles, we can describe the shape and size effects distinctly rather than statistically (a constraint of studying heterogeneous nanoparticle films). No measurable changes occurred to the shape and size of the nanorods due to their saturation with mercury vapor. The localized surface plasmon resonance (LSPR) of the mercury-saturated nanorods blue shifted 2.6-3.8 nm; the magnitude of the shift depended on the initial shape and size of the nanorod. Larger aspect ratios and surface-area-to-volume ratios both enhance the LSPR shift seen in saturated nanoparticles. The predictions of a core-shell model mirrors the shape and size effects observed experimentally. These results increase our understanding of mercury-adsorption by gold surfaces, and help to optimize nanoparticle-based plasmonic mercury sensing. PMID- 23446552 TI - Factor IX activity/antigen ratio and the risk of first unprovoked venous thromboembolism. PMID- 23446553 TI - Methodology of the Youth Risk Behavior Surveillance System--2013. AB - Priority health-risk behaviors (i.e., interrelated and preventable behaviors that contribute to the leading causes of morbidity and mortality among youths and adults) often are established during childhood and adolescence and extend into adulthood. The Youth Risk Behavior Surveillance System (YRBSS), established in 1991, monitors six categories of priority health-risk behaviors among youths and young adults: 1) behaviors that contribute to unintentional injuries and violence; 2) sexual behaviors that contribute to human immunodeficiency virus (HIV) infection, other sexually transmitted diseases, and unintended pregnancy; 3) tobacco use; 4) alcohol and other drug use; 5) unhealthy dietary behaviors; and 6) physical inactivity. In addition, YRBSS monitors the prevalence of obesity and asthma among this population. YRBSS data are obtained from multiple sources including a national school-based survey conducted by CDC as well as schoolbased state, territorial, tribal, and large urban school district surveys conducted by education and health agencies. These surveys have been conducted biennially since 1991 and include representative samples of students in grades 9-12. In 2004, a description of the YRBSS methodology was published (CDC. Methodology of the Youth Risk Behavior Surveillance System. MMWR 2004;53 [No RR-12]). Since 2004, improvements have been made to YRBSS, including increases in coverage and expanded technical assistance.This report describes these changes and updates earlier descriptions of the system, including questionnaire content; operational procedures; sampling, weighting, and response rates; data-collection protocols; data-processing procedures; reports and publications; and data quality. This report also includes results of methods studies that systematically examined how different survey procedures affect prevalence estimates. YRBSS continues to evolve to meet the needs of CDC and other data users through the ongoing revision of the questionnaire, the addition of new populations, and the development of innovative methods for data collection. PMID- 23446555 TI - Inhibition of the SK-N-MC human neuroblastoma cell line in vivo and in vitro by a novel nutrient mixture. AB - Neuroblastoma, a peripheral nervous system cancer that can be highly invasive and metastatic, accounts for 8-10% of all solid childhood tumors in children under the age of 15 years. Despite multiple clinical efforts, prognosis remains poor for this enigmatic disease. A nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has shown significant antitumor effects. Using the nude mouse xenograft model, we investigated the efficacy of NM. We also tested the effect of NM in vitro, evaluating cell viability, secretion of the matrix metalloproteinases (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 secretion, Matrigel invasion and cellular apoptosis and morphology. Athymic nude mice 5-6 weeks of age were inoculated with 3x106 SK N-MC neuroblastoma cells subcutaneously and randomly divided into two groups. Group A was fed a regular diet and group B a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. We also tested the effect of NM in vitro. NM inhibited the growth of xenograft tumors by 22% (P=0.04); and, in vitro, NM induced dose-dependent inhibition of cell proliferation with a decrease of 27% (P=0.001) and 36% (P=0.002) at 500 and 1000 ug/ml NM compared to the control, respectively. Zymography revealed MMP-2 secretion in normal cells and PMA (100 ng/ml)-induced MMP-9 secretion. NM inhibited the secretion of both MMPs with total blockage at a concentration of 100 ug/ml. Reverse zymography demonstrated a dose-dependent increase in TIMP-2 expression by NM. Notable, SK-N-MC human neuroblastoma cells were not invasive through Matrigel. NM induced dose-dependent apoptosis of SK-N-MC cells. The results suggest that NM may have therapeutic potential in treating neuroblastoma. PMID- 23446556 TI - Adalimumab for juvenile idiopathic arthritis-associated uveitis. AB - PURPOSE: To assess the long-term outcomes and complications of patients with uveitis from juvenile idiopathic arthritis (JIA) treated with adalimumab. METHODS: Prospective interventional case series. All patients who underwent treatment with adalimumab for JIA and anterior uveitis were prospectively included in the study. The anterior chamber inflammation was evaluated according to the Standardization of Uveitis Nomenclature criteria. RESULTS: Twenty-one patients (16 females, five males, 38 eyes) were included in the study. Mean age of patients at referral was 11.1 +/- 3.8 (5-17) years. Before initiation of treatment, mean duration of arthritis was 7.0 +/- 5.5 (median, 6) months, mean duration of uveitis was 7.0 +/- 4.4 (median, 7) months. Oligoarticular arthritis was present in 15 cases (71 %), polyarticular arthritis in six cases (28 %). After a mean follow-up of 18.2 +/- 7.7 (9-41) months, resolution of anterior chamber inflammation was obtained in 29/38 eyes (76 %). The anterior uveitis flare rate during the 12 months prior to enrollment was 1.6 +/- 0.4/year, and was reduced during adalimumab treatment to 0.7 +/- 0.3/year (p<0.001). A significant decrease of the number of relapses/month was present after onset of treatment with adalimumab (0.18 +/- 0.2 before versus 0.02 +/- 0.1 after treatment onset, p<0.001). No significant correlation was found between relapse number and age, sex, type of JIA and doses of previous steroid treatment (p>0.05). CONCLUSION: Adalimumab showed to be effective and relatively safe for treatment of JIA associated uveitis. PMID- 23446557 TI - Predisposing factors for primary acquired nasolacrimal duct obstruction. AB - BACKGROUND: Pathological origin of primary acquired nasolacrimal duct obstruction (PANDO) is considered as inflammation of unknown causes; however, specific predisposing factors have not been fully addressed to date. METHODS: In an institutional setting, background factors of 45 patients with PANDO were compared to those in 67 control subjects. The control subjects were persons with senile cataract, representing the non-pathological general population. The evaluated background factors were inflammatory medical histories (infectious conjunctivitis and allergic conjunctivitis and/or rhinitis), previously reported factors (POAG and topical timolol), and a novel factor proposed in the current study (exposure to swimming pool). Data were extracted from the patients through interview based on a standardized questionnaire as well as from their clinical records. RESULTS: After adjustment for age and gender, a history of infectious conjunctivitis was more common in the PANDO group than in the control group (55.6 % vs 32.8 %, P = 0.0027), and regular attendance to indoor swimming pools was also more common in the PANDO group (33.3 % vs 0 %, P < 0.0001). Furthermore, when age- and gender- matched subjects were selected, a history of conjunctivitis and swimming pool exposure were independently associated with the development of PANDO (P = 0.022 and P < 0.0001 respectively). On the other hand, the frequencies of histories of POAG, topical timolol, and allergic conjunctivitis and/or rhinitis were similar between the two groups. CONCLUSIONS: Histories of infectious conjunctivitis and swimming pool exposure could be associated with the development of PANDO, although the pathogenesis of this condition has been considered as inflammation of unknown causes. PMID- 23446558 TI - Relationship between gastric cancer tau protein expression and paclitaxel sensitivity. AB - The abnormal expression of Tau protein in breast cancer tissue affects paclitaxel sensitivity. The abnormal expression also exists in gastric carcinoma. Therefore, we speculate that the expression levels of Tau protein is closely related to paclitaxel sensitivity in gastric cancer, thus affecting the efficacy of paclitaxel. In this study, we used immunohistochemical methods to detect Tau protein expression levels in 47 cases of gastric cancer specimens. We also used Western blot to detect the level of Tau protein expression in gastric cancer cell lines and to check the efficacy of paclitaxel in vitro application. Findings indicate that Tau protein expression rate can reach as high as (+ +-+ + +) 63.83 % in gastric cancer. Paclitaxel induces inhibition and apoptosis with low expression of Tau protein in gastric cancer cell lines (P < 0.05). The level of Tau protein expression is significantly correlated with paclitaxel efficacy. If confirmed by further studies, the Tau protein can be another useful marker of gastric cancer, thereby leading to the application of paclitaxel in cancer treatment. PMID- 23446559 TI - Fat necrosis in autologous abdomen-based breast reconstruction: a systematic review. AB - BACKGROUND: Fat necrosis is a common and potentially exasperating complication of autologous breast reconstruction. The authors performed a systematic review of the English literature on autologous breast reconstruction to determine significant patient and surgical factors that are predictors of postoperative fat necrosis. METHODS: A PubMed search using the terms "fat necrosis" and "breast reconstruction" was conducted. Articles were screened using predetermined inclusion and exclusion criteria. Data collected included patient characteristics, reconstructive techniques used, and the specific postoperative morbidity of interest. Patient cohorts were pooled, and the incidence of fat necrosis was calculated in the presence and absence of each risk factor. Chi square analysis was applied, and p < 0.05 was considered statistically significant. RESULTS: Of 172 articles found, 70 met the inclusion criteria. The mean rate of fat necrosis was 11.3 percent. Deep inferior epigastric artery perforator flaps had the highest rate of fat necrosis (14.4 percent), followed by pedicled transverse rectus abdominis musculocutaneous (12.3 percent), superficial inferior epigastric artery (8.1 percent), and free transverse rectus abdominis musculocutaneous flaps (6.9 percent). Significant predictors of fat necrosis included obesity (p = 0.035), prereconstruction irradiation (p = 0.022), postreconstruction irradiation (p < 0.001), active smoking (p < 0.001), and abdominal scars (p = 0.05). Protective factors included supercharging (p < 0.001) and bilateral reconstruction (p = 0.01). CONCLUSIONS: Although there is little agreement in the literature regarding risk factors for fat necrosis, the authors were able to demonstrate several significant predictors by systematically analyzing 70 articles. Improved knowledge of the risk factors for fat necrosis can help surgeons provide improved preoperative counseling and take measures to minimize the risk of this complication. PMID- 23446560 TI - Postoperative antibiotic prophylaxis for implant-based breast reconstruction with acellular dermal matrix. AB - BACKGROUND: The use of acellular dermal matrix in implant-based breast reconstruction has been described for improving inferolateral prosthesis coverage and support and inframammary fold reconstruction. Recommended guidelines for infection prophylaxis are the same as for any clean procedure-antibiotic administration only before surgery. Previous studies have demonstrated increased postoperative rates of infection and seroma associated with the use of acellular dermal matrix. The authors evaluated the impact of postoperative antibiotic prophylaxis on infection rates in postmastectomy expander-based breast reconstruction with acellular dermal matrix. METHODS: : A retrospective study reviewed data of 96 patients who underwent either immediate or delayed expander based breast reconstruction using AlloDerm allogenic acellular dermal matrix. Infection rates were analyzed after patients received postoperative antibiotic prophylaxis for at least 48 hours compared with those who received only perioperative antibiotics. RESULTS: Infection rates for breast reconstructions with a postoperative antibiotic course were 7.9 and 3.2 percent. Patients with only perioperative antibiotics had an infection rate of 31.6 percent. Infections were defined by the endpoint of implant removal. Patient demographics, comorbidities, and intraoperative variables were recorded. Uncontrolled variables were time course between mastectomy and reconstruction, nodal dissection, operative history, and whether reconstruction was unilateral or bilateral. CONCLUSIONS: This study demonstrates significant differences in the rate of infection between the groups of patients undergoing the first stage of two-stage implant-based breast reconstruction who received postoperative antibiotic prophylaxis and the group that received only perioperative antibiotics. This study suggests that the optimal duration of postoperative antibiotic prophylaxis is at least 48 hours. PMID- 23446561 TI - The effect of subcutaneous mesenchymal stem cell injection on statis zone and apoptosis in an experimental burn model. AB - BACKGROUND: In an acute burn injury the zone of stasis is initially vital but may progress to coagulation necrosis with time. In this study, salvage of the zone of stasis was aimed at by subcutaneous mesenchymal stem cell injection. METHODS: Mesenchymal stem cells were obtained from the bone marrow of Sprague-Dawley rats (n = 10). Twenty Sprague-Dawley rats received thermal injury on the back according to the previously described "comb burn" model. Thirty minutes after the burn injury, mesenchymal stem cells were injected subcutaneously to the stasis zone of the experimental group (n = 10). Animals in the control group (n = 10) were given the same amount of saline without mesenchymal stem cells. Animals in the sham group (n = 6) did not receive any thermal trauma. Seventy-two hours after the burn injury, scintigraphic examination was applied to determine average vital tissue at the stasis zone. Thereafter, skin samples were assessed by immunohistochemistry assay for apoptosis count. The blood samples drawn before and 72 hours after the burn injury were analyzed to determine systemic cytokine levels. RESULTS: The apoptosis count of the control group was found to be significantly higher than that of the experimental group. Vital tissue percentage of the stasis zone was significantly higher for the experimental group than for the control group. The cytokine levels did not reveal any statistically significant difference between the groups. CONCLUSION: Apoptosis count and scintigraphic results of this study confirm that mesenchymal stem cell treatment has a statistically significant benefit for the survival of the stasis zone in acute burn. PMID- 23446562 TI - Pharmacologic prophylactic treatment for perioperative protection of skeletal muscle from ischemia-reperfusion injury in reconstructive surgery. AB - BACKGROUND: In autogenous muscle transplantation, unpredictable complications can cause prolonged ischemia, resulting in ischemia-reperfusion injury. The authors investigated the efficacy and mechanism of nicorandil, a nitrovasodilator and adenosine triphosphate-sensitive potassium channel opener, in inducing perioperative protection of muscle flaps from ischemia-reperfusion injury. METHODS: Pigs (18.2 +/- 2.4 kg) were assigned to one control and eight treatment groups. Bilateral latissimus dorsi muscle flaps were raised after saline administration (control) and 0, 4, 8, 12, 24, 48, 72, and 96 hours after nicorandil administration. Subsequently, flaps were subjected to 4 hours of ischemia and 48 hours of reperfusion. Viability was assessed, and biochemical probes were used to study nicorandil-induced infarct protection. RESULTS: Protection by nicorandil was biphasic. Infarction reduced from 40.2 +/- 1.9 percent (control) to 27.3 +/- 1.7 percent and 24.0 +/- 2.3 percent (p < 0.05) 0 and 4 hours after nicorandil administration, respectively (early phase protection). No difference was seen between control and treatment groups between 8 and 12 hours after nicorandil administration compared with the control. Infarct protection increased again (p < 0.05) at 24 (22.4 +/- 2.0 percent), 48 (25.1 +/- 2.1 percent), and 72 hours (28.5 +/- 2.1 percent) but not at 96 hours (43.9 +/- 4.6 percent) compared with control (late phase protection). The sarcolemmal and mitochondrial channels played a central role in the trigger and mediator mechanisms, respectively. Late protection was associated with lower myeloperoxidase activity and mitochondrial calcium overload and higher adenosine triphosphate content (p < 0.05). CONCLUSIONS: Nicorandil induced 48-hour uninterrupted muscle infarct protection, starting 24 hours after intravenous administration. This category of clinical drug is a potential prophylactic treatment against skeletal muscle ischemia-reperfusion injury in reconstructive surgery. PMID- 23446564 TI - Discussion: Autologous fat grafting and injectable dermal fillers for human immunodeficiency virus-associated facial lipodystrophy: a comparison of safety, efficacy, and long-term treatment outcomes. PMID- 23446565 TI - Discussion: New perspectives on the surgical anatomy and nomenclature of the temporal region: literature review and dissection study. PMID- 23446563 TI - Hydrogen sulfide reduces neutrophil recruitment in hind-limb ischemia-reperfusion injury in an L-selectin and ADAM-17-dependent manner. AB - BACKGROUND: Reperfusion following ischemia leads to neutrophil recruitment into injured tissue. Selectins and beta2-integrins regulate neutrophil interaction with the endothelium during neutrophil rolling and firm adhesion. Excessive neutrophil infiltration into tissue is thought to contribute to ischemia reperfusion injury damage. Hydrogen sulfide mitigates the damage caused by ischemia-reperfusion injury. This study's objective was to determine the effect of hydrogen sulfide on neutrophil adhesion receptor expression. METHODS: Human neutrophils were either left untreated or incubated in 20 MUM hydrogen sulfide and/or 50 MUg/ml pharmacologic ADAM-17 inhibitor TAPI-0; activated by interleukin 8, fMLP, or TNF-alpha; and labeled against P-selectin glycoprotein ligand-1, leukocyte function associated antigen-1, Mac-1 alpha, L-selectin, and beta2 integrin epitopes CBRM1/5 or KIM127 for flow cytometry. Cohorts of three C57BL/6 mice received an intravenous dose of saline vehicle or 20 MUM hydrogen sulfide with or without 50 MUg/ml TAPI-0 before unilateral tourniquet-induced hind-limb ischemia for 3 hours followed by 3 hours of reperfusion. Bilateral gastrocnemius muscles were processed for histology before neutrophil infiltration quantification. RESULTS: Hydrogen sulfide treatment significantly increased L selectin shedding from human neutrophils following activation by fMLP and interleukin-8 in an ADAM-17-dependent manner. Mice treated with hydrogen sulfide to raise bloodstream concentration by 20 MUM before ischemia or reperfusion showed a significant reduction in neutrophil recruitment into skeletal muscle tissue following tourniquet-induced hind-limb ischemia-reperfusion injury. CONCLUSIONS: Hydrogen sulfide administration results in the down-regulation of L selectin expression in activated human neutrophils. This leads to a reduction in neutrophil extravasation and tissue infiltration and may partially account for the protective effects of hydrogen sulfide seen in the setting of ischemia reperfusion injury. PMID- 23446566 TI - Evaluation of the facial artery on computed tomographic angiography using 64 slice multidetector computed tomography: implications for facial reconstruction in plastic surgery. AB - BACKGROUND: Preoperative knowledge of a patient's individual variations in facial artery anatomy would benefit plastic surgeons for reconstructive planning. The authors evaluated the feasibility of multislice computed tomographic angiography in vascular mapping of the facial artery. METHODS: In total, 187 facial arteries in 94 patients without facial tumor or vascular disease were studied. Anatomical variations of the facial artery were classified into four types: type 1, a short course that terminates proximal to the superior labial artery; type 2, an intermediate course that terminates distal to the superior labial artery near the nasolabial fold; type 3, a classic course that extends to the lateral nasal ala beyond the nasolabial fold with an angular branch; and type 4, duplex with dominant lateral angular branch. Facial artery patterns were compared with dominant patterns of the facial-submental artery bifurcation. The extent of the inferior and superior labial artery was evaluated separately. RESULTS: Sixty-four facial artery branches (34 percent) were classified as type 1, 74 (40 percent) as type 2, and 45 (24 percent) as type 3. Type 4 was seen in only four branches (2 percent). The facial artery was dominant in the facial-submental artery bifurcation in 84 percent of type 3 facial arteries. Three-dimensional volume rendered images allow detailed visualization of the facial artery and its branches and help preoperative mapping. CONCLUSION: Facial computed tomographic angiography allows detailed visualization of the facial artery and its branches and is a potential noninvasive imaging tool for preoperative vascular mapping for facial reconstructive operations. PMID- 23446567 TI - Design of a modified monobloc composite facial allograft technique in facial reconstruction. AB - BACKGROUND: Composite facial allografts have become increasingly popular in the reconstruction of complex facial defects. Good to excellent aesthetic results can be achieved, particularly when a foundation of donor skeleton has been transferred. The authors propose using a conventional craniofacial technique (monobloc osteotomy) to transfer a thin monocortical foundation of bone, even in lieu of a skeletal defect, to improve the recipient periorbital and malar aesthetics. METHODS: The monobloc osteotomy approach was used to obtain a full facial allograft and modified ex vivo to a thin monocortical layer and transferred to an anatomical facial skeleton. The authors have named this the "masque" flap because of the resemblance of the outline of the foundation of bone to a costume worn in masquerade balls. RESULTS: The masque flap was performed on two fresh-frozen cadavers. The total time to harvest and thin the osteomyocutaneous flap was 155 minutes (30 minutes to modify it ex vivo). The average total surface area was 1060 cm. Periorbital and malar ligaments were maintained, as was the integrity of the canthal tendons. CONCLUSION: The modified monobloc composite facial allograft technique allows transfer of a full facial allograft and maintains malar projection and excellent shape of the palpebral aperture. PMID- 23446568 TI - Delineating the vascular territory (perforasome) of a perforator in the lower extremity of the rabbit with four-dimensional computed tomographic angiography. AB - BACKGROUND: The anatomy of any particular vascular perforator relative to its vascular territory (perforasome) and flow characteristics is unique and complex. This arterial perforasome study with laboratory rabbits was conducted to assess four-dimensional computed tomographic angiography as an imaging tool for the design of individualized tissue transfers. This study offers clinically relevant information that should improve flap survival. METHODS: Six New Zealand White rabbits weighing 3.0 to 3.25 kg underwent contrast-enhanced four-dimensional computed tomographic angiography in a 128-slice scanner after intraarterial injection of iopromide iodinated contrast material. Based on the image data, the perforasome of the posterior thigh perforator was marked onto the posterior thigh skin. The perforasome size was confirmed by microangiography. Data from four dimensional computed tomographic angiography and microangiography were statistically compared. RESULTS: Four-dimensional computed tomographic angiography clearly and accurately delineated the perfusion and vascular territories of the perforators. The area of the perforator flap as measured with four-dimensional computed tomographic angiography compared favorably to that obtained by means of microangiography; there was no statistically significant difference in the results from the two methods. CONCLUSIONS: This study demonstrated that four-dimensional computed tomographic angiography was capable of accurately characterizing the vascular territory and flow characteristics of the arterial perforator in live rabbits. This technique for determining perforator location, axiality, and optimal perfusion territory will potentially benefit human patients. PMID- 23446569 TI - Program director opinions of core competencies in hand surgery training: analysis of differences between plastic and orthopedic surgery accredited programs. AB - BACKGROUND: The authors' aim was to conduct a national survey of hand surgery fellowship program directors to determine differences of opinions of essential components of hand surgery training between program directors from plastic and orthopedic surgery programs. METHODS: The authors performed a Web-based survey of 74 program directors from all Accreditation Council for Graduate Medical Education-accredited hand surgery fellowship programs to determine components that are essential for hand surgery training. The survey included assessment of nine general areas of practice, 97 knowledge topics, and 172 procedures. Twenty seven scales of related survey items were created to determine differences between specialty groups based on clinical themes. RESULTS: An 84 percent response rate was achieved, including 49 orthopedic and 12 plastic surgery program directors. There were significant differences in mean responses between the specialty groups in 11 of 27 scales. Only one scale, forearm fractures, contained items with a significantly stronger preference for essential rating among orthopedic surgeons. The other 10 scales contained items with a significantly higher preference for essential rating among plastic surgeons, most of which related to soft-tissue injury and reconstruction. The burn scale had the greatest discrepancy in opinion of essential ratings between the groups, followed by pedicled and free tissue transfer, and amputation and fingertip injuries. CONCLUSIONS: Despite being united under the subspecialty of hand surgery, program directors tend to emphasize clinical areas that are stressed in their respective primary disciplines. These differences promote the advantage of programs that provide exposure to both plastic surgery-trained and orthopedic surgery-trained hand surgeons. PMID- 23446570 TI - Discussion: Program director opinions of core competencies in hand surgery training: analysis of differences between plastic and orthopedic surgery accredited programs. PMID- 23446571 TI - Patients transferred for emergency upper extremity evaluation: does insurance status matter? AB - BACKGROUND: Academic institutions receive many patients transferred specifically for hand surgery evaluation. The purpose of this study was to evaluate the demographics and insurance status of patients transferred for this reason. METHODS: A retrospective review was performed of 155 transferred and 1017 nontransferred patients with a primary hand diagnosis during 3 summer months at two urban academic institutions. Patients were evaluated for insurance status/type, medical comorbidities, employment status, and reason for transfer. Insurance was defined as present/absent and favorable/unfavorable, with unfavorable defined as Medicaid or state-sponsored insurance. Reason for transfer or presenting diagnosis was separated by category. RESULTS: The mean age was similar between groups, but a higher percentage of transfer patients were men (69.9 percent versus 59.7 percent; p < 0.05). The percentage of insured patients was similar (92.9 percent versus 93.2 percent), but the number with no insurance or undesirable insurance was greater for transferred patients (30.1 percent versus 22.9 percent; p < 0.05). Patients with poor or no insurance were twice as likely to be inappropriately transferred (OR, 2.17; p = 0.03). Transferred patients were less likely to be employed (55.1 percent versus 64.8 percent; p < 0.05); however, the percentages of workers' compensation (13.5 percent versus 14.6 percent) and diabetes (6.41 percent versus 6.10 percent) cases were similar. Common reasons for transfer were closed fractures/dislocations (21.9 percent), infection (17.4 percent), and amputation/devascularization (17.4 percent). CONCLUSION: Patients transferred to tertiary care centers for emergency upper extremity evaluation have a higher rate of undesirable or no insurance and are more likely to be male or unemployed. PMID- 23446572 TI - The financial impact of multidisciplinary cleft care: an analysis of hospital revenue to advance program development. AB - BACKGROUND: The purpose of this study was to determine the financial impact of cleft care on the hospital and to evaluate trends in reimbursement over the past 6 years. METHODS: Medical and accounting records of 327 consecutive infants undergoing cleft repair between 2005 and 2011 were reviewed. Charges, payments, and direct cost data were analyzed to illustrate hospital revenue and margins. RESULTS: Hospital payments for all inpatient services (cleft and noncleft) during the first 24 months of life were $9,483,168. Mean hospital payment varied from $5525 (Medicaid) to $10,274 (managed care) for a cleft lip repair (p < 0.0001) and from $6573 (Medicaid) to $12,933 (managed care) for a cleft palate repair (p < 0.0001). Hospital charges for a definitive lip or palate repair to both Medicaid and managed care more than doubled between 2005 and 2011 (p < 0.0001). Overall, mean hospital margins were $3904 and $3520, respectively, for a cleft lip repair and cleft palate repair. Medicaid physician payments for cleft lip and palate were, respectively, $588 and $646. From 2005 to 2006, 2007 to 2008, and 2009 to 2010, 41 percent, 43 percent, and 63 percent of patients, respectively, were enrolled in Medicaid. CONCLUSIONS: Cleft care generates substantial revenue for the hospital. For their mutual benefit, hospitals should join with their cleft teams to provide administrative support. Bolstered reimbursement figures, based on the overall value of cleft care to the hospital system, would better attract and retain skilled clinicians dedicated to cleft care. This may become particularly important if Medicaid enrollment continues to increase. PMID- 23446573 TI - Striae distensae after breast augmentation: treatment using the nonablative fractionated 1550-nm erbium glass laser. AB - BACKGROUND: Stretch marks, or striae distensae, are dermal scars and result in considerable aesthetic concern. The responsible factors for their development are poorly understood. Development of striae distensae is a rare complication after breast augmentation. Successfully treating striae distensae has always been challenging. Lasers and light devices have recently become a good therapeutic option. The fractional laser has shown encouraging results with less risk of pigmentation in the treatment of recent stretch marks. METHODS: Forty-seven patients underwent breast augmentation over a period of 2 months; of these, 10 patients developed new striae distensae. They were submitted to nonablative fractionated 1550-nm erbium glass laser treatment. Response was assessed from photographs obtained before and 4 weeks after the end of treatment. Two plastic surgeons analyzed improvements clinically and photographically, and a patient satisfaction score was recorded as well. RESULTS: There was a significant relationship between age and development of striae, (p = 0.003), but there was no significant relationship between striae distensae and nulliparity (p = 0.147), volume of the silicone implant (p = 0.892), or use of oral contraceptive (p = 1.00). The scores achieved by both the evaluators and the patients were high, with 50 percent of them between 9 and 10 (maximum scores), and with a high index of satisfaction with the treatment. CONCLUSIONS: Age is statistically significant in the development of striae distensae after breast augmentation. This report demonstrates excellent patient and plastic surgeon satisfaction after treatment. The use of fractional photothermolysis is a good treatment modality for striae rubrae. PMID- 23446574 TI - Scarpa fascia preservation during abdominoplasty: randomized clinical study of efficacy and safety. AB - BACKGROUND: Scarpa fascia preservation has been suggested as a way of reducing complications associated with conventional abdominoplasty. A prospective randomized study was conducted to evaluate the effect on results and complications of preserving the Scarpa fascia during a full abdominoplasty. METHODS: This was a single-center study conducted from August of 2009 to February of 2011. Patients were assigned randomly to one of two procedures: classic full abdominoplasty (group A) or a similar type of abdominoplasty except for the preservation of the Scarpa fascia and the deep fat compartment in the infraumbilical area (group B). Four surgeons were involved in the study. Several variables were determined: general characteristics, time to suction drain removal, total volume of drain output, length of hospital stay, systemic complications, local complications, and aesthetic result. RESULTS: A total of 160 full abdominoplasties were performed in women (group A, 80 patients; group B, 80 patients) equally divided by the four involved surgeons. There were no statistically significant differences between groups with respect to general characteristics, complications (except for the seroma rate), and aesthetic result. The Scarpa fascia preservation group had a highly significant reduction of 65.5 percent on the total drain output, 3 days on the time to drain removal, and 86.7 percent on the seroma rate. CONCLUSION: Preservation of the Scarpa fascia during an abdominoplasty had a beneficial effect on patient recovery, as it reduced the total drain output, time to drain removal, and seroma rate without compromising the aesthetic result. PMID- 23446575 TI - Evidence on prognosis. AB - In the clinical decision-making process, prognostic information gives physicians guidance regarding disease and treatment that can be passed along to patients. Using the clinical scenario of a type IIIB open tibial fracture as an example, this article focuses on how to search prognostic literature effectively and how to critically appraise prognostic studies. A well-built clinical question using the Patients, Intervention, Comparison, and Outcomes methodology helps plastic surgeons derive information from the vast resources in an effective and time efficient manner. Subsequent critical appraisal of the collected studies is the essential step for identifying the most relevant high-quality evidence to provide the best prognostic information to guide patient decision-making. PMID- 23446580 TI - A paradigm shift in U.S. breast reconstruction: Part 2. The influence of changing mastectomy patterns on reconstructive rate and method. AB - BACKGROUND: The aims of the current study were to (1) measure trends in the type of mastectomy performed, (2) evaluate sociodemographic/hospital characteristics of patients undergoing contralateral prophylactic mastectomy versus unilateral mastectomies, and (3) analyze reconstruction rates and method used following different mastectomy types. METHODS: Mastectomies from 1998 to 2008 were analyzed using the Nationwide Inpatient Sample database. Mastectomies (n = 178,603) were classified as either unilateral, contralateral prophylactic, or bilateral prophylactic. Reconstructive procedures were categorized into either implant or autologous. Longitudinal trends were analyzed with Poisson regression and sociodemographic/hospital variables were analyzed with logistic regression. RESULTS: Unilateral mastectomies decreased 2 percent per year, whereas contralateral and bilateral prophylactic mastectomies increased significantly by 15 and 12 percent per year, respectively (p < 0.01). Independent predictors for contralateral prophylactic mastectomy (compared with unilateral mastectomy) were patients younger than 39 years, Caucasian and Hispanic race, private insurance carriers, treated in teaching hospitals, and from South and Midwest regions. Contralateral prophylactic mastectomy is the only group with increased reconstruction rates throughout the study period (p < 0.01). Although implant use increased for all mastectomy types, it remains greater in bilateral and contralateral prophylactic mastectomy. CONCLUSIONS: There is increasing use of bilateral mastectomies in the United States, particularly in patients with unilateral cancer. Although implant use has increased for all mastectomy types, they are used most commonly following bilateral and contralateral prophylactic mastectomies. Changing mastectomy patterns are one factor underlying the paradigm shift away from autologous tissue to implant-based reconstruction. PMID- 23446581 TI - Rib-sparing and internal mammary artery-preserving microsurgical breast reconstruction with the free DIEP flap. AB - BACKGROUND: Using an internal mammary artery as the recipient vessel in a free flap autologous breast reconstruction is common practice, but this vessel is often sacrificed for end-to-end anastomosis and is typically assessed by removing a costal cartilage segment. The authors studied the reliability of the end-to side arterial anastomosis using a rib-sparing approach by comparing it with end to-end anastomosis. METHODS: The authors analyzed 100 consecutive medical records of patients who underwent autologous breast reconstruction with a free deep inferior epigastric artery perforator flap in which the internal mammary vessels were assessed using a rib-sparing technique. The study compared the complications between the two groups of end-to-side arterial anastomosis (50 cases) and end-to end arterial anastomosis (50 cases). RESULTS: Exposure of the internal mammary artery using a rib-sparing technique was performed successfully in all 100 flaps. The second and third intercostal spaces were used in 46 and 54 cases, respectively. The mean width of the used intercostal space was 18.3 +/- 2.4 mm in the end-to-side group and 18.3 +/- 2.9 mm in the end-to-end group (p = 0.923). All flaps survived without partial or total necrosis. One case of venous insufficiency that required exploration occurred in the end-to-side group; the flap was totally saved with venous revision. There was no significant statistical difference between the end-to-side and end-to-end groups in all other variables, including mean flap ischemic time (p = 0.431) and fat necrosis (p = 0.339). CONCLUSION: The rib-sparing and internal mammary artery-preserving free deep inferior epigastric artery perforator flap transfer is an efficient and safe technique for microsurgical breast reconstruction. PMID- 23446582 TI - Usefulness of polyglycolic acid-polypropylene composite scaffolds for three dimensional cartilage regeneration in a large-animal autograft model. AB - BACKGROUND: Approaches to auricular reconstruction have shown improved outcome when a basic fibroblast growth factor (bFGF) slow-release system and fibrin spraying are combined with biodegradable polymers. More complex, three dimensional structures, such as those that replicate the human auricle, are often lost because of biodegradation of the synthetic scaffold. METHODS: To improve the mechanical strength of regenerated cartilage, the authors grafted canine autologous chondrocytes after seeding onto scaffolds made of a complex of polyglycolic acid and polypropylene, incorporating a slow-release bFGF system with a fibrin spray coating. RESULTS: Five weeks after grafting, thicker cartilage with increased bending stress was obtained with the slow-release bFGF. In a three-polyglycolic acid-layer construct sandwiched around polypropylene, simulating a three-dimensional auricular structure, greater cartilage regeneration and angiogenesis were found around the implant. Sox5-positive cells were identified, indicative of maturation of neocartilage with chondroblast proliferation. CONCLUSION: These results support the usefulness of combining absorbable and nonabsorbable materials (polyglycolic acid and polypropylene) in composite scaffolds for autologous cartilage regeneration in a large-animal autograft model. PMID- 23446583 TI - Immunosuppression with a combination of triptolide and cyclosporin A in rat vascularized groin flap allotransplantation. AB - BACKGROUND: Triptolide is an immunosuppressive fraction purified from a Chinese medicinal plant. In an effort to develop a new immunosuppressive strategy for vascularized composite allotransplantation, the authors investigated the effects of combined treatment with cyclosporin A and triptolide on the survival of rat groin flap allotransplants. METHODS: Groin flap transplantation was performed from Brown Norway rats to Fischer 344 recipients, which were then treated with triptolide, cyclosporin A, or both. Flap biopsy specimens were harvested, stained, and submitted to histopathologic evaluation. Levels of CCR5, CCR7, CCL19, CCL21, and Foxp3 in spleen were examined by real-time polymerase chain reaction, and the percentage of CD4+CD25+ regulatory T cells was detected by flow cytometry. RESULTS: The mean survival time for allografts in recipients receiving triptolide and cyclosporin A was 57 +/- 7.7 days compared with 20.5 +/- 2.3 days for cyclosporin A alone, 23.3 +/- 3.6 days for triptolide alone, and 7.8 +/- 0.8 days for no treatment. Histologic examination also showed that inflammatory cell infiltration was reduced in grafts with combination treatment. Down-regulation of CCR5, CCR7, and CCL19 in the combination treatment was accompanied by increased expression of Foxp3. Flow cytometric analysis also revealed that the percentage of CD4+CD25+ regulatory T cells in the combination treatment was higher than in the monotherapy groups. CONCLUSIONS: Combination therapy with triptolide and cyclosporin A substantially prolonged allograft survival, which means calcineurin inhibitor-related drug-toxicity may be alleviated and treatment cost reduced. This immunosuppressive effect is mediated by inhibition of dendritic cells maturation and the expansion of regulatory T cells. PMID- 23446584 TI - The role of occipital artery resection in the surgical treatment of occipital migraine headaches. AB - BACKGROUND: This study was designed to compare the success of occipital migraine headache surgery with and without occipital artery ligation. METHODS: The medical charts of 170 occipital migraine headache surgery recipients who fulfilled the study criteria were reviewed. Patients were divided into either the occipital artery resection group (one or both occipital arteries or its branches resected) or the control group (occipital arteries untouched). Preoperative and 12-month or more postoperative migraine frequency, duration, and intensity were analyzed. RESULTS: Fifty-five of the 170 patients met the inclusion criteria for the resection group; the remaining 115 were included in the control group. Of the 55 occipital artery resection patients, 44 (80.0 percent) had successful outcomes (>= 50 percent reduction in occipital migraine headaches), with 21 (38.2 percent) experiencing elimination of migraines. Of the 115 control patients, 105 (91.3 percent) experienced success, with 74 (64.3 percent) experiencing elimination of occipital migraine headache. The control group had significantly higher success (p = 0.047) and elimination rates (p = 0.002) compared with the resection group. The control group had significantly greater mean reduction in migraine duration compared with the resection group (p = 0.008). CONCLUSIONS: Occipital artery resection significantly lowered the success of occipital migraine headache surgery. Greater occipital nerve decompression alone, without ligation of the occipital artery, significantly improved or eliminated occipital migraine headache in most patients. This suggests that routine removal of the occipital artery or its branches may not be necessary. PMID- 23446585 TI - Medial femoral condyle flap donor-site morbidity: a radiographic assessment. AB - BACKGROUND: The medial femoral condyle has become a reliable source of vascularized bone with many advantages to the reconstructive microsurgeon. The authors examined the donor-site morbidity of medial femoral condyle flap harvest. METHODS: A retrospective review of all patients who underwent medial femoral condyle free flap procedures between April of 2009 and December of 2010 was conducted. Study participants underwent computed tomographic scans of their bilateral distal femurs and knee joints to evaluate the donor site and examine differences between the operated and nonoperated sides. RESULTS: Fifteen patients underwent medial femoral condyle free flap procedures. Ten of them agreed to participate in the study. The average time between surgery and computed tomographic scans was 18.0 months (range, 12.2 to 30.4 months). Average bone harvested per procedure was 16.1 cm3 (range, 2 to 34 cm3), representing an average condylar volume of 9 percent (range, 1 to 18 percent). Reparative bone formation was minimal, with an average thickness of 4.5 mm (range, 4 to 6 mm). There were no findings of new degenerative joint disease on computed tomographic scans resulting from medial femoral condyle harvest. The flap success rate was 100 percent (10 of 10) for patency and achieving osseous union. There were no major or flap-related complications. Two patients reported numbness of the donor site at long-term follow-up (average, 17.5 months; range, 12.2 to 30.4 months). CONCLUSIONS: Medial femoral condyle harvest creates minimal donor-site morbidity according to radiographic measures at more than 1-year follow-up. Surgeons can anticipate minimal unassisted bone regeneration at the donor site at this time interval. PMID- 23446586 TI - Anatomical variations of the saphenous and descending genicular artery perforators: cadaveric study and clinical implications for vascular flaps. AB - BACKGROUND: With increasing use of free vascular flaps of the saphenous artery and descending genicular artery, the authors investigated the anatomical variations in cadavers. METHODS: Thirty-one fresh cadaveric thighs were studied by anatomical dissection. The perforators and their source arteries were skeletonized along their courses to the superficial femoral artery and measured. The perforators' nomenclature and abbreviations were modified from the Gent consensus. The skin and bone perforators were evaluated for their role in skin, bone, and osteocutaneous flaps. RESULTS: The descending genicular artery was noted in 27 thighs (87 percent) and gave rise to at least one skin perforator that could be used to develop an osteocutaneous flap. The chimeric pedicle length increased and the chimeric arm length decreased, as the descending genicular artery skin perforators were more distally located. The saphenous artery was noted in all 31 thighs, and in 16 (52 percent) it originated from the superficial femoral artery. Most musculocutaneous perforators of the saphenous artery were associated with the sartorius, whereas those of the descending genicular artery were associated with the vastus medialis. Superficial femoral artery skin perforators were noted in 10 thighs (32 percent). Two clinical cases, illustrating the use of the descending genicular artery vastus medialis perforator flap and of the distal-direct perforator osteocutaneous flap, are reported. CONCLUSIONS: This study investigated the anatomical variations in the skin and bone perforators of the medial knee. Free skin or bone flaps were achieved in all specimens and osteocutaneous chimera flaps were achieved in 87 percent of the thighs. PMID- 23446587 TI - Complicated infantile hemangioma of the lip: outcomes of early versus late resection. AB - BACKGROUND: Lip hemangiomas have traditionally been approached with expectant management. However, intervention is warranted for associated complications, including facial disfigurement, feeding difficulties, speech impairment, and psychosocial manifestations. The authors evaluated outcomes of complicated lip hemangiomas resected during the proliferative as compared with the involutional phase. METHODS: A retrospective review of patients with complicated lip hemangiomas managed with resection in the proliferative or involutional phase from 2005 to 2011 was performed. A transverse elliptical vermilion-mucosal resection technique was used. Review parameters included demographics, lesion size and location, growth phase, hemangioma-related complications, and preoperative management (corticosteroid or pulsed dye laser). Evaluated outcomes included surgical complications, recurrence, and patient- and surgeon-reported aesthetics. RESULTS: Twenty-one patients underwent surgical resection of a lip hemangioma (10 proliferative and 11 involutional), with a mean follow-up of 21.4 and 23.3 months, respectively. The two groups were comparable with respect to lesion size and location. Patients in the involutional group experienced higher rates of hemangioma-related complications (bleeding, 45 percent versus 10 percent; speech impairment, 82 percent versus 0 percent; feeding difficulties, 82 percent versus 20 percent; and psychosocial issues, 100 percent versus 80 percent). There were no postoperative aesthetic concerns. One recurrence in the proliferative group was treated with reresection. Speech therapy was required for 82 percent of patients in the involutional group. CONCLUSIONS: Surgical resection is efficacious treatment for hemangiomas of the lip and yields acceptable aesthetic results during both the proliferative and involutional phases. Resection in the proliferative phase should be considered to prevent complications associated with delayed treatment. PMID- 23446588 TI - Repair of anterior cleft palate fistulae with cancellous bone graft: a simple technique that facilitates dental reconstruction. AB - BACKGROUND: Cleft palate fistulas of the anterior hard palate following previous repair are a challenging surgical problem. In addition to nasal regurgitation and potential adverse effects on speech, these fistulas may necessitate obturation with a removable dental prosthesis and can mitigate a fixed prosthodontic dental reconstruction. The authors present a method of repair using cancellous bone graft and only native palatal mucosa. METHODS: The authors carried out a retrospective review of 27 consecutive patients who underwent anterior palate fistula repair performed by a single surgeon over an 8-year period. RESULTS: The authors performed 29 fistula closure procedures using cancellous bone on 27 consecutive patients. Twenty-three (85 percent) of the initial 27 palatal fistula repairs in this study resulted in complete closure of the fistula. Two of the four patients who had incomplete closure went on to have a second operation using exactly the same technique, and complete closure was achieved. The remaining two patients in whom only partial closure was achieved were asymptomatic and no further treatment was necessary. All patients had an improvement in fistula symptoms after surgery. All patients who were using removable dentures/obturators were restored with fixed dental restorations supported by osseointegrated implants or fixed conventional bridges. CONCLUSIONS: This relatively simple method achieves reliable closure of most anterior hard palate fistulas and can be repeated if necessary. This technique removes the necessity of obturation of the defect with a removable prosthesis and in some cases facilitates the placement of dental implants. PMID- 23446589 TI - Endoscopic correction of frontal bossing. AB - BACKGROUND: Frontal bossing is a displeasing prominence of the supraorbital area. Aesthetic correction has been described as an open surgical technique. This report introduces an endoscopic approach to correction. METHODS: A retrospective review was performed on all patients who underwent endoscopic repair of frontal bossing from 2002 to 2009. Demographics, intraoperative and postoperative course, and outcome variables were collected. Standardized preoperative and postoperative photographs were used for analysis. Aesthetic improvement of the forehead was assessed with a four-point scale (1 = no improvement at all, 4 = significant improvement) by six randomly selected observers. Preoperative facial imaging (lateral skull radiography or computed tomography) was obtained on all patients to assess the thickness of the anterior wall of the frontal sinus. RESULTS: Ten patients met the study inclusion criteria. Overall, the observers assessed the degree of frontal bossing correction as moderate improvement (2.67 on a four point scale survey). All endoscopic frontal bossing corrections were performed on an outpatient basis by the senior author (B.G.). No patient was admitted to the hospital for postoperative complications. No complications (such as alopecia, hematoma, contour deformities, or penetration into the frontal sinus) were seen. The limiting factor in achieving optimal outcomes was inadequate thickness of the anterior wall of the frontal sinus. All patients had various concurrent facial rejuvenation procedures. CONCLUSIONS: Endoscopic correction of frontal bossing is an effective and safe surgical technique in forehead aesthetics. This technique is ideal for patients with a mild frontal bossing deformity who have an adequately thick anterior frontal sinus wall. PMID- 23446590 TI - The clinical and diagnostic consequences of Poly Implant Prothese silicone breast implants, recalled from the European market in 2010. AB - BACKGROUND: Recently, Poly Implant Prothese silicone breast implants were recalled from the European market. The authors studied 112 women and previously published data on rupture prevalence. Women are presenting with symptoms they feel may be a result of ruptured implants. The authors' aim was to study the clinical consequences of Poly Implant Prothese implants. METHODS: One hundred twelve women with 224 proven Poly Implant Prothese implants after 10 years of implantation were enrolled in this study. All women underwent physical examination and magnetic resonance imaging and were interviewed regarding symptoms. Details of the explantations of 35 women with at least one ruptured implant were documented. Tissue from 10 women was sent for pathologic investigation. RESULTS: Of 112 women, 34 (30.4 percent) had symptoms attributable to their implants. Physical examination showed that 12 of the 121 women (10.7 percent) had findings suggestive of rupture, most commonly pain. Three had lymphadenopathy that seemed to correlate with implant rupture or excessive "gel bleed." Pathologic findings showed no malignancies. Eight women who underwent explantation had no implant rupture. Excessive gel bleed was documented in half of them. CONCLUSIONS: Clinical consequences of women with Poly Implant Prothese implants are comparable to those reported in the literature of other manufacturers. Neither complaints nor findings at physical examination had a significant correlation with implant rupture at explantation. Magnetic resonance imaging is still the preferred method compared with physical examination for diagnosing rupture. The low specificity was probably caused by the difficulty in differentiating between rupture and excessive gel bleed in these implants. PMID- 23446592 TI - Scalp, skull, orbit, and maxilla reconstruction and hair transplantation. AB - Orbitomaxillary, skull, scalp, and hair restoration covers a broad segment of reconstructive surgery. The purpose of this article is to review considerations in available options for reconstruction, flap selection, relevant anatomy, and potential hazards. Although there are a variety of methods available to treat these complex defects, core principles are presented as a guide to obtaining a sound result specific to the priorities appropriate to an individual patient. PMID- 23446591 TI - Outcomes of traditional cosmetic abdominoplasty in a community setting: a retrospective analysis of 1008 patients. AB - BACKGROUND: Abdominoplasty is one of the most commonly performed cosmetic operative procedures. Few large studies have examined outcomes of cosmetic abdominoplasty in a community setting. The authors explored postoperative outcome and the preoperative and intraoperative factors that may contribute to these complications. METHODS: A retrospective review of consecutive patients undergoing abdominoplasty over an 11-year period was performed. Baseline patient demographics, intraoperative technique, and postoperative outcomes were recorded. Preoperative and intraoperative characteristics were analyzed to determine characteristics that predispose patients to complications and undesirable outcomes. RESULTS: The 1008 study patients underwent either a full or modified abdominoplasty with a total complication rate of 32.6 percent. The most common complication was seroma (15.4 percent). Liposuction of the abdominal flap was performed in 469 patients (46.5 percent) and liposuction of the flanks was performed in 555 patients (55.1 percent). Chi-square analysis followed by logistic regression revealed that liposuction of the flanks and abdomen was independently associated with seroma formation in addition to major and minor complications (p < 0.05). CONCLUSIONS: Seroma formation following abdominoplasty is the most common complication. Concomitant liposuction of the flanks and abdomen with the addition of aggressive undermining leads to higher seroma rates. This association is likely multifactorial and may be secondary to increased resorptive demands placed on the abdominal lymphatics in the setting of greater dead space and larger fluid shifts as a result of liposuction. To reduce seroma rates, surgeons should avoid aggressive liposuction and undermining, particularly in high-risk patients. PMID- 23446593 TI - A 9-year comparison of practice profiles of candidates for primary and recertification examinations of the American Board of Plastic Surgery relative to economic indicators. AB - BACKGROUND: This study compared the practice profiles of plastic surgeons applying for recertification/maintenance of certification with those applying for primary certification by the American Board of Plastic Surgery between 2003 and 2011. METHODS: American Board of Plastic Surgery case logs from both recertification and primary certification candidates from 2003 to 2011 were examined. Deidentified data included operative year, Current Procedural Terminology codes, and the candidate's designation of the case relative to (1) cosmetic or reconstructive and (2) the Maintenance of Certification in Plastic Surgery module (i.e., comprehensive, cosmetic, craniomaxillofacial, and hand). Department of Commerce unemployment data from 2003 to 2011 served as an economic indicator for the period studied. RESULTS: A negative trend in the median number of cases per candidate was observed for both groups for cosmetic, reconstructive, and total number of cases, corresponding to a rise in unemployment. With every 1 percent increase in the unemployment rate, recertification candidates demonstrated a greater loss of cosmetic cases relative to primary candidates and an accelerated decline in reconstructive cases starting in 2007. Distribution of the four Maintenance of Certification modules demonstrated a negative trend for cosmetic and comprehensive cases in both groups. Hand and craniofacial consistently constituted approximately 20 percent of cases for primary and 14 percent of cases for recertification candidates. There was a shift away from hand cases toward craniofacial cases in both groups. CONCLUSIONS: Both primary and recertification candidates reported a decline in overall caseload from 2003 to 2011. Negative economic trends have a greater impact on the practice profile of recertification candidates. PMID- 23446594 TI - A further strategy for managing intraoperative venous congestion in abdominally based autologous breast reconstruction. PMID- 23446595 TI - Reply: A further strategy for managing intraoperative venous congestion in abdominally based autologous breast reconstruction. PMID- 23446596 TI - Preoperative flap volume prediction in autologous abdominal breast reconstruction. PMID- 23446597 TI - Comparison of immediate implant-based versus staged tissue expander breast reconstruction technique. PMID- 23446598 TI - Reply: Comparison of immediate implant-based versus staged tissue expander breast reconstruction technique. PMID- 23446599 TI - Three dermoglandular flap support in reduction mammaplasty: the importance of photographic integrity. PMID- 23446600 TI - Donor-site lymphatic function after microvascular lymph node transfer should be followed using indocyanine green lymphography. PMID- 23446601 TI - Reply: Donor-site lymphatic function after microvascular lymph node transfer should be followed using indocyanine green lymphography. PMID- 23446602 TI - "Image-guided" perforator flaps versus "free-style" perforator flaps: where is the evidence? PMID- 23446603 TI - Reply: "Image-guided" perforator flaps versus "free-style" perforator flaps: where is the evidence? PMID- 23446604 TI - Harvesting the lateral femoral circumflex chimera free flap: guidelines for elevation. PMID- 23446605 TI - Reply: Harvesting the lateral femoral circumflex chimera free flap: guidelines for elevation. PMID- 23446606 TI - Soft-tissue reconstruction of open fractures of the lower limb: muscle versus fasciocutaneous flaps. PMID- 23446607 TI - Reply: Soft-tissue reconstruction of open fractures of the lower limb: muscle versus fasciocutaneous flaps. PMID- 23446608 TI - Reducing venous thromboembolism risk without chemoprophylaxis. PMID- 23446609 TI - Reply: Reducing venous thromboembolism risk without chemoprophylaxis. PMID- 23446611 TI - An intrasinus approach to the monobloc osteotomy. PMID- 23446610 TI - Targeted cranial bone transport distraction is enhanced using a novel device. PMID- 23446612 TI - A "French twist": practical hair control in plastic surgery. PMID- 23446613 TI - Dermis-fat grafts and enucleation in children in a West African population. PMID- 23446614 TI - Just another PICC line complication: cannulated vein thrombosis can result in total neck jejunal flap necrosis. PMID- 23446615 TI - Salvage operation using free vascularized tissue transfer to treat esophageal conduit necrosis. PMID- 23446616 TI - Nipple sensation losses in Hall-Findlay breast reduction technique. PMID- 23446617 TI - Breast implant complication: calcifications in the double capsule. PMID- 23446618 TI - Inframammary cardiac pacemaker insertion in women: an aesthetic alternative. PMID- 23446619 TI - Peri-implant gas following air travel to high altitude. PMID- 23446620 TI - Supraclavicular nerve graft interposition for reconstruction of pediatric brachial plexus injuries. PMID- 23446621 TI - Crossover replantation of carpometacarpal after traumatic amputation. PMID- 23446622 TI - Application of 320-row multidetector computed tomography angiography and three dimensional reconstruction for pudendal thigh perforator flap. PMID- 23446623 TI - Diagnostic efficacy of color Doppler ultrasonography in preoperative assessment of anterolateral thigh flap cutaneous perforators: an evidence-based review. PMID- 23446624 TI - The pinch test for perforator identification in the anterolateral thigh flap. PMID- 23446625 TI - Minimally invasive harvest of free fibula flap. PMID- 23446626 TI - Changes in the remuneration system for general practitioners: effects on contact type and consultation length. AB - In The Netherlands, the remuneration system for GPs changed in 2006. Before the change, GPs received a capitation fee for publicly insured patients and fee for service (FFS) for privately insured patients. In 2006, a combined system was introduced for all patients, with elements of capitation as well as FFS. This created a unique opportunity to investigate the effects of the change in the remuneration system on contact type and consultation length. Our hypothesis was that for former publicly insured patients the change would lead to an increase in the proportion of home visits, a decrease in the proportion of telephone consultations and an increase in consultation length relative to formerly privately insured patients. Data were used from electronic medical records from 36 to 58 Dutch GP practices and from 532,800 to 743,961 patient contacts between 2002 and 2008 for contact type data. For consultation length, 1,994 videotaped consultations were used from 85 GP practices in 2002 and 499 consultations from 16 GP practices in 2008. Multilevel multinomial regression analysis was used to analyse consultation type. Multilevel logistic and linear regression analyses were used to examine consultation length. Our study shows that contact type and consultation length were hardly affected by the change in remuneration system, though the proportion of home visits slightly decreased for privately insured patients compared with publicly insured patients. Declaration behaviour regarding telephone consultations did change; GP practices more consistently declared telephone consultations after 2006. PMID- 23446627 TI - A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection. AB - BACKGROUND: Staphylococcus aureus is among the leading causes of human infection. Widespread drug resistance, emergence of highly virulent strains, and the ability of S. aureus to colonize >30% of the human population contribute to this organism's pathogenic success. Human serologic responses to S. aureus and their relationship to protective immunity remain incompletely defined, challenging the strategic development of efficacious vaccines. METHODS: We measured humoral responses to 2 staphylococcal exotoxins, alpha-hemolysin (Hla) and Panton Valentine leukocidin (PVL; LukF-PV/LukS-PV subunits), both premier targets of current vaccine and immunotherapy development. We correlated acute and convalescent serum antibody levels with incidence of recurrent infection over 12 months follow-up in 235 children with S. aureus colonization, primary or recurrent skin and soft tissue infection, or invasive disease. RESULTS: Cutaneous infection elicited transient increases in anti-Hla and anti-PVL antibodies; however, subsequent infection risk was similar between primary and recurrent cutaneous infection cohorts. Patients with invasive infections had the lowest preexisting titers against Hla and LukF but displayed the highest convalescent titers. Across cohorts, convalescent anti-Hla titers correlated with protection against subsequent S. aureus infection. CONCLUSIONS: Cutaneous S. aureus infection does not reliably provoke durable, protective immune responses. This study provides the first link between protection from disease recurrence and the humoral response to Hla, a virulence factor already implicated in disease pathogenesis. These observations can be utilized to refine ongoing vaccine and immunotherapy efforts and inform the design of clinical trials. PMID- 23446629 TI - Neurobrucellosis: clinical and diagnostic features. AB - BACKGROUND: We describe the neurological involvement in brucellosis and revisited diagnostic criteria for neurobrucellosis. METHODS: Patients with laboratory confirmed brucellosis who were consequently hospitalized were observed prospectively in a brucellosis-endemic region. The neurobrucellosis was diagnosed by any one of the following criteria: (1) symptoms and signs consistent with neurobrucellosis; (2) isolation of Brucella species from cerebrospinal fluid (CSF) and/or presence of anti-Brucella antibodies in CSF; (3) the presence of lymphocytosis, increased protein, and decreased glucose levels in CSF; or (4) diagnostic findings in cranial magnetic resonance imaging or CT. RESULTS: Lumbar puncture was performed in 128 laboratory-confirmed brucellosis cases who had neurological symptoms and signs, and 48 (37.5%) were diagnosed as neurobrucellosis. The sensitivity of tube agglutination (TA) in CSF was 0.94, specificity 0.96, positive predictive value 0.94, and negative predictive value 0.96. Brucella bacteria were isolated from CSF in 7 of 48 patients (15%). The mean age of 48 neurobrucellosis patients was 42 years (SD, 19 years), and 16 (33%) were female. The most common neurological findings were agitation (25%), behavioral disorders (25%), muscle weakness (23%), disorientation (21%), and neck rigidity (17%). Cranial nerves were involved in 9 of 48 patients (19%). One patient was left with a sequela of peripheral facial paralysis and 2 patients with sensorineural hearing loss. CONCLUSIONS: Patients with severe and persistent headache and other neurologic symptoms and signs should be considered for neurobrucellosis in endemic regions and to possibly receive longer therapy than 6 weeks. Brucella TA with Coombs test in CSF is sensitive and specific by using a cutoff of >=1:8. PMID- 23446628 TI - Clinical implications of HIV-1 minority variants. AB - Technologic advances in human immunodeficiency virus type 1 (HIV-1) sequencing have revolutionized the study of antiretroviral drug resistance and are increasingly moving from the laboratory to clinical practice. These techniques are able to detect HIV-1 drug resistance mutations present at low frequencies not detectable by current HIV-1 genotyping assays. For a number of commonly used antiretroviral medications, such as nonnucleoside reverse transcriptase inhibitors, the detection of these drug-resistant minority variants significantly increases the risk of treatment failure. The level of evidence, however, is insufficient to determine the impact of HIV-1 minority variants for several other classes of antiretroviral medications. Clinicians should be aware of the novel technologies that are moving into routine clinical use and the clinical implications of HIV-1 minority variants. Additional studies are needed to determine the optimal platform for clinical application of these new technologies and to provide guidance to clinicians on the type and frequency of clinically important HIV-1 minority variants. PMID- 23446630 TI - Phosphomolybdic and phosphotungstic acids as efficient catalysts for the synthesis of bridged 1,2,4,5-tetraoxanes from beta-diketones and hydrogen peroxide. AB - Phosphomolybdic acid (PMA) and phosphotungstic acid (PTA) efficiently catalyze the addition of H2O2 to beta-diketones to form bridged 1,2,4,5-tetraoxanes. These reactions are not accompanied by the formation of monocyclic peroxides containing hydroxy and hydroperoxide groups or polymeric peroxides. The use of these catalysts made it possible to obtain bridged tetraoxanes from easily oxidizable benzoylacetone derivatives and alpha-unsubstituted beta-diketones. The syntheses are scaled up to ten grams. The resulting peroxides can be easily isolated from the reaction mixture by column chromatography. The yield of tetraoxanes depends on the structure of beta-diketone and varies from 12 to 83%. NMR monitoring of two bridged 1,2,4,5-tetraoxanes synthesis was carried out. PMID- 23446631 TI - Selective classification and quantification model of C&D waste from material resources consumed in residential building construction. AB - The unfortunate economic situation involving Spain and the European Union is, among other factors, the result of intensive construction activity over recent years. The excessive consumption of natural resources, together with the impact caused by the uncontrolled dumping of untreated C&D waste in illegal landfills have caused environmental pollution and a deterioration of the landscape. The objective of this research was to generate a selective classification and quantification model of C&D waste based on the material resources consumed in the construction of residential buildings, either new or renovated, namely the Conventional Constructive Model (CCM). A practical example carried out on ten residential buildings in Seville, Spain, enabled the identification and quantification of the C&D waste generated in their construction and the origin of the waste, in terms of the building material from which it originated and its impact for every m(2) constructed. This model enables other researchers to establish comparisons between the various improvements proposed for the minimization of the environmental impact produced by building a CCM, new corrective measures to be proposed in future policies that regulate the production and management of C&D waste generated in construction from the design stage to the completion of the construction process, and the establishment of sustainable management for C&D waste and for the selection of materials for the construction on projected or renovated buildings. PMID- 23446632 TI - [Technique of the urethral anastomosis in orthotopic neo-bladder following robot assisted radical cystectomy (RARC)]. AB - The urethral anastomosis in extracorporeally constructed orthotopic neo-bladder following robot-assisted radical cystectomy (RARC) remains a challenge. In principle either pre-posi-tioned single sutures or robotic continuous suture techniques can be applied. In the literature the different techniques are most often not described in detail. In the present work one example for each technique is given and the advantages and disadvantages of both methods are discussed. PMID- 23446633 TI - Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. AB - The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160Delta). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function. PMID- 23446635 TI - Subnormal levels of POLgammaA cause inefficient initiation of light-strand DNA synthesis and lead to mitochondrial DNA deletions and progressive external ophthalmoplegia [corrected]. AB - The POLG1 gene encodes the catalytic subunit of mitochondrial DNA (mtDNA) polymerase gamma (POLgamma). We here describe a sibling pair with adult-onset progressive external ophthalmoplegia, cognitive impairment and mitochondrial myopathy characterized by DNA depletion and multiple mtDNA deletions. The phenotype is due to compound heterozygous POLG1 mutations, T914P and the intron mutation c.3104 + 3A > T. The mutant genes produce POLgamma isoforms with heterozygous phenotypes that fail to synthesize longer DNA products in vitro. However, exon skipping in the c.3104 + 3A > T mutant is not complete, and the presence of low levels of wild-type POLgamma explains patient survival. To better understand the underlying pathogenic mechanisms, we characterized the effects of POLgamma depletion in vitro and found that leading-strand DNA synthesis is relatively undisturbed. In contrast, initiation of lagging-strand DNA synthesis is ineffective at lower POLgamma concentrations that uncouples leading strand from lagging-strand DNA synthesis. In vivo, this effect leads to prolonged exposure of the heavy strand in its single-stranded conformation that in turn can cause the mtDNA deletions observed in our patients. Our findings, thus, suggest a molecular mechanism explaining how POLgamma mutations can cause mtDNA deletions in vivo. PMID- 23446634 TI - Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network. AB - Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs. PMID- 23446636 TI - Tissue-specific effects of saposin A and saposin B on glycosphingolipid degradation in mutant mice. AB - Individual saposin A (A-/-) and saposin B (B-/-)-deficient mice show unique phenotypes caused by insufficient degradation of myelin-related glycosphingolipids (GSLs): galactosylceramide and galactosylsphingosine and sulfatide, respectively. To gain insight into the interrelated functions of saposins A and B, combined saposin AB-deficient mice (AB-/-) were created by knock-in point mutations into the saposins A and B domains on the prosaposin locus. Saposin A and B proteins were undetectable in AB-/- mice, whereas prosaposin, saposin C and saposin D were expressed near wild-type (WT) levels. AB /- mice developed neuromotor deterioration at >61 days and exhibited abnormal locomotor activity and enhanced tremor. AB-/- mice (~96 days) lived longer than A /- mice (~85 days), but shorter than B-/- mice (~644 days). Storage materials were observed in Schwann cells and neuronal processes by electron microscopy. Accumulation of p62 and increased levels of LC3-II were detected in the brainstem suggesting altered autophagy. GSL analyses by (liquid chromatography) LC/MS identified substantial increases in lactosylceramide in AB-/- mouse livers. Sulfatide accumulated, but galactosylceramide remained at WT levels, in the AB-/- mouse brains and kidneys. Brain galactosylsphingosine in AB-/- mice was ~68% of that in A-/- mice. These findings indicate that combined saposins A and B deficiencies attenuated GalCer-beta-galactosylceramidase and GM1-beta galactosidase functions in the degradation of lactosylceramide preferentially in the liver. Blocking sulfatide degradation from the saposin B deficiency diminished galactosylceramide accumulation in the brain and kidney and galctosylsphingosine in the brain. These analyses of AB-/- mice continue to delineate the tissue differential interactions of saposins in GSL metabolism. PMID- 23446637 TI - Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis. AB - Mutations in the human NPHP5 gene cause retinal and renal disease, but the precise mechanism by which NPHP5 functions is not understood. We report that NPHP5 is a centriolar protein whose depletion inhibits an early step of ciliogenesis, a phenotype reminiscent of Cep290 loss and contrary to IFT88 loss. Functional dissection of NPHP5 interactions with Cep290 and CaM reveals a requirement of the former for ciliogenesis, while the latter prevents NPHP5 self aggregation. Disease-causing mutations lead to truncated products unable to bind Cep290 and localize to centrosomes, thereby compromising cilia formation. In contrast, a modifier mutation cripples CaM binding but has no overt effect on ciliogenesis. Drugs that antagonize negative regulators of the ciliogenic pathway can rescue ciliogenesis in cells depleted of NPHP5, with response profiles similar to those of Cep290- but not IFT88-depleted cells. Our results uncover the underlying molecular basis of disease and provide novel insights into mitigating NPHP5 deficiency. PMID- 23446638 TI - Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest. AB - PTEN is a well-described predisposition gene for Cowden syndrome (CS), a familial cancer syndrome characterized by a high risk of breast and other cancers. KLLN, which shares a bidirectional promoter with PTEN, causes cell cycle arrest and apoptosis. We previously identified germline hypermethylation of the KLLN promoter in 37% of PTEN mutation-negative CS/CS-like (CSL) patients. Patients with germline KLLN hypermethylation have an increased prevalence of breast and renal cancers when compared with PTEN mutation carriers. We have consequently sought to identify and characterize germline KLLN variants/mutations in CS/CSL and in apparently sporadic breast cancer patients. KLLN variants in CS/CSL patients are rare (1 of 136, 0.007%). Interestingly, among 438 breast cancer patients, 13 (3%) have germline KLLN variants when compared with none in 128 controls (P = 0.049). Patients with KLLN variants have a family history of breast cancer when compared with those without (P = 0.02). We demonstrate that germline KLLN variants dysregulate the cell cycle at G2. Of 24 breast carcinomas analyzed, 3 (13%) have somatic KLLN hemizygous deletions, with somatic loss of the wild type allele in a patient with germline KLLN p.Leu119Leu. Of 452 breast carcinomas in The Cancer Genome Atlas project, 93 (21%) have KLLN hemizygous or homozygous deletions. This is the first study to associate germline KLLN variants with sporadic breast cancer and to recognize somatic KLLN deletions in breast carcinomas. Our observations suggest that KLLN may be a low penetrance susceptibility factor for apparently sporadic breast cancer. PMID- 23446639 TI - Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is a fatal neurodegenerative disease characterized by abnormal motor coordination, cognitive decline and psychiatric disorders. This disease is caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin. Reduced levels of brain-derived neurotrophic factor (BDNF) in the brain, which results from transcriptional inhibition and axonal transport deficits mediated by mutant huntingtin, have been suggested as critical factors underlying selective neurodegeneration in both HD patients and HD mouse models. BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest. In the present study, we evaluated the ability of a small-molecule TrkB agonist 7,8 dihydroxyflavone (7,8-DHF) and its synthetic derivative 4'-dimethylamino-7,8- dihydroxyflavone (4'-DMA-7,8-DHF) to protect neurons in the well-characterized N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 mg/kg) or 4'-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, ameliorated brain atrophy and extended survival in these N171-82Q HD mice. Moreover, 4'-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. These data highlight consideration of TrkB as a therapeutic target in HD and suggest that small-molecule TrkB agonists that penetrate the brain have high potential to be further tested in clinical trials of HD. PMID- 23446640 TI - Functional outcomes following a non-operative treatment algorithm for anterior cruciate ligament injuries in skeletally immature children 12 years and younger. A prospective cohort with 2 years follow-up. AB - BACKGROUND: The methodological quality of studies on treatment of anterior cruciate ligament (ACL) injuries in skeletally immature children after ACL injury is low, and no prospective studies have evaluated the functional outcomes following a non-operative treatment algorithm. PURPOSE: To report changes in knee function and activity level in skeletally immature children following a non operative treatment algorithm for a minimum of 2 years after ACL injury. STUDY DESIGN: Prospective cohort. METHODS: 46 skeletally immature children aged 12 years and younger were evaluated at baseline and subsequent yearly follow-ups using patient-reported outcome measurements, isokinetic muscle strength measurements, single-legged hop tests and clinical examinations over a minimum period of 2 years. Participation in physical activities was monitored using a monthly online activity survey, and the main leisure-time sport activity was registered at the yearly follow-ups. RESULTS: 36 (78%) of the children did not undergo an ACL reconstruction during the follow-up. Statistically significant changes with questionable clinical relevance were discovered with the patient reported outcome measurements or hop tests. Leg symmetry indexes were consistently above 90% for muscle strength and single legged hop tests throughout the study, and the isokinetic muscle strength improved significantly in the injured limb. Ninety-one per cent maintained participation in pivoting sports and/or physical education in school, although 38% of the ACL deficient children changed their main activity from a level 1 to a level 2 activity. CONCLUSIONS: A non-operative treatment algorithm may be appropriate for ACL injured skeletally immature children, although a reduced participation in level 1 activities may be necessary for some children. PMID- 23446641 TI - Brain stimulation modulates the autonomic nervous system, rating of perceived exertion and performance during maximal exercise. AB - BACKGROUND: The temporal and insular cortex (TC, IC) have been associated with autonomic nervous system (ANS) control and the awareness of emotional feelings from the body. Evidence shows that the ANS and rating of perceived exertion (RPE) regulate exercise performance. Non-invasive brain stimulation can modulate the cortical area directly beneath the electrode related to ANS and RPE, but it could also affect subcortical areas by connection within the cortico-cortical neural networks. This study evaluated the effects of transcranial direct current stimulation (tDCS) over the TC on the ANS, RPE and performance during a maximal dynamic exercise. METHODS: Ten trained cyclists participated in this study (33+/ 9 years; 171.5+/-5.8 cm; 72.8+/-9.5 kg; 10-11 training years). After 20-min of receiving either anodal tDCS applied over the left TC (T3) or sham stimulation, subjects completed a maximal incremental cycling exercise test. RPE, heart rate (HR) and R-R intervals (as a measure of ANS function) were recorded continuously throughout the tests. Peak power output (PPO) was recorded at the end of the tests. RESULTS: With anodal tDCS, PPO improved by ~4% (anodal tDCS: 313.2+/-29.9 vs 301.0+/-19.8 watts: sham tDCS; p=0.043), parasympathetic vagal withdrawal was delayed (anodal tDCS: 147.5+/-53.3 vs 125.0+/-35.4 watts: sham tDCS; p=0.041) and HR was reduced at submaximal workloads. RPE also increased more slowly during exercise following anodal tDCS application, but maximal RPE and HR values were not affected by cortical stimulation. CONCLUSIONS: The findings suggest that non invasive brain stimulation over the TC modulates the ANS activity and the sensory perception of effort and exercise performance, indicating that the brain plays a crucial role in the exercise performance regulation. PMID- 23446642 TI - Injury rates, types, mechanisms and risk factors in female youth ice hockey. AB - BACKGROUND: The objectives of this cohort study were to examine the rate, types, mechanisms and risk factors for injury in female youth (ages 9-17) ice hockey players in the Girls Hockey Calgary Association. METHODS: The main outcome was ice hockey injury, defined as any injury occurring during the 2008/2009 season that required medical attention, and/or removal from a session and/or missing a subsequent session. Potential risk factors included age group, level of play, previous injury, ice hockey experience, physical activity level, weight, height, position of play and menarche. Incidence rate ratios (IRR) were estimated with Poisson Regression adjusted for cluster (team). Exposure data were collected for every session for each participating player. RESULTS: Twenty-eight teams (n=324) from Atom (ages 9-10), PeeWee (11-12), Bantam (13-14) and Midget (15-17) participated with 53 reported injuries. The overall injury rate was 1.9 injuries/1000 player-hours (95% CI 1.4 to 2.7). Previous injury (IRR=2.7, 95% CI 1.7 to 4.3), games (IRR=2.1, 95% CI 1.1 to 4.2), menarche (PeeWee) (IRR=4.1, 95% CI 1.0 to 16.8) were significant risk factors. In Midget, the more elite divisions were associated with a lower injury risk (A-IRR=0.2, 95% CI 0.1 to 0.5) (AAA-IRR=0.5, 95% CI 0.2 to 0.9). CONCLUSIONS: Injury rates were lower in this study than previously found in male youth and women's ice hockey populations. Previous injury and game play as risk factors are consistent with the literature. Menarche as a risk factor is a new finding in this study. This research will inform future studies of the development of injury prevention strategies in this population. PMID- 23446643 TI - Big hits on the small screen: an evaluation of concussion-related videos on YouTube. AB - BACKGROUND: YouTube is one of the largest social networking websites, allowing users to upload and view video content that provides entertainment and conveys many messages, including those related to health conditions, such as concussion. However, little is known about the content of videos relating to concussion. OBJECTIVE: To identify and classify the content of concussion-related videos available on YouTube. STUDY DESIGN: An observational study using content analysis. METHODS: YouTube's video database was systematically searched using 10 search terms selected from MeSH and Google Adwords. The 100 videos with the largest view counts were chosen from the identified videos. These videos and their accompanying text were analysed for purpose, source and description of content by a panel of assessors who classified them into data-driven thematic categories. RESULTS: 434 videos met the inclusion criteria and the 100 videos with the largest view counts were chosen. The most common categories of the videos were the depiction of a sporting injury (37%) and news reports (25%). News and media organisations were the predominant source (51%) of concussion-related videos on YouTube, with very few being uploaded by professional or academic organisations. The median number of views per video was 26 191. CONCLUSIONS: Although a wide range of concussion-related videos were identified, there is a need for healthcare and educational organisations to explore YouTube as a medium for the dissemination of quality-controlled information on sports concussion. PMID- 23446644 TI - Full spectrum of psychiatric disorders related to foreign migration: a Danish population-based cohort study. AB - IMPORTANCE: Although increased risk for schizophrenia among immigrants is well established, knowledge of the broader spectrum of psychiatric disorders associated with a foreign migration background is lacking. OBJECTIVE: To examine the full range of psychiatric disorders associated with any type of foreign migration background among persons residing in Denmark, including foreign-born adoptees, first- and second-generation immigrants, native Danes with a history of foreign residence, and persons born abroad to Danish expatriates. DESIGN AND SETTING: Danish population-based cohort study. Persons were followed up from their 10th birthday for the development of mental disorders based on outpatient and inpatient data. PARTICIPANTS: All persons born between January 1, 1971, and December 31, 2000 (N = 1 859 419) residing in Denmark by their 10th birthday with follow-up data to December 31, 2010. MAIN OUTCOME MEASURES: Incidence rate ratios (IRRs) and cumulative incidences for psychiatric outcomes. RESULTS: All categories of foreign migration background, except persons born abroad to Danish expatriates, were associated with increased risk for at least 1 psychiatric disorder. Foreign-born adoptees had increased IRRs for all psychiatric disorders and had the highest IRRs for these disorders compared with other foreign migration categories. First- and second-generation immigrants having 2 foreign born parents had significantly increased IRRs for schizophrenia and schizophrenia spectrum disorders and had similar risk magnitudes. Second-generation immigrants having 1 foreign-born parent had significantly increased IRRs for all psychiatric disorders. Native Danes with a history of foreign residence had increased IRRs for bipolar affective disorder, affective disorders, personality disorders, and schizophrenia spectrum disorders. CONCLUSIONS AND RELEVANCE: The extent to which a background of foreign migration confers an increased risk for the broad spectrum of psychiatric disorders varies according to parental origin, with greatest risks for foreign-born adoptees. The spectrum of psychiatric disorders showed greater variation within the second-generation immigrant group than between first-generation vs second-generation immigrants, and the spectrum differed according to whether individuals had 1 or 2 foreign-born parents. PMID- 23446645 TI - Surgical management of the burn wound and use of skin substitutes: an expert panel white paper. PMID- 23446646 TI - Selective in situ protein expression profiles correlate with distinct phenotypes of basal cell carcinoma and squamous cell carcinoma of the skin. AB - Non-melanoma skin cancer is the most common malignancy that shows increasing incidence due to our cumulative exposure to ultraviolet irradiation. Its major subtypes, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) differ in pathobiology, phenotype and clinical behavior, which must be reflected at the molecular level. In this study, protein expression profiles of BCC and SCC were tested in tissue microarrays and correlated with that of actinic keratosis, Bowen's disease, seborrheic keratosis and normal epidermis by detecting 22 proteins involved in cell interactions, growth, cell cycle regulation or apoptosis. The significantly more reduced collagen XVII, CD44v6, pan-Desmoglein levels and more evident E-Cadherin delocalization in BCC compared to SCC correlated with the de novo dermal invasion of BCC against the progressive invasion from in situ lesions in SCC development. EGFR was also expressed at a significantly higher level in SCC than in BCC. The upregulated cell communication protein connexin43 in BCC could contribute to the protection of BCC from metastatic invasion. Elevated cell replication in BCC was underlined by the increased topoisomerase IIalpha and reduced p21(waf1) and p27(kip1) positive cells fractions compared to SCC. Compared to differentiated keratinocytes, caspase-8 and -9 were equally upregulated in skin carcinoma subtypes for either mediating apoptosis induction or immune escape of tumor cells. Hierarchical cluster analysis grouped SCC and actinic keratosis cases exclusively together in support of their common origin and malignant phenotype. BCC cases were also clustered fully together. Differentially expressed proteins reflect the distinct pathobiology of skin carcinoma subtypes and can serve as surrogate markers in doubtful cases. PMID- 23446647 TI - Aromatic amino acids in high selectivity bismuth(III) recognition. AB - The three aromatic amino acids, tyrosine, tryptophan and phenylalanine, play different physiological roles in life processes. Metal ions capable of binding these amino acids may aid in the reduction of effective concentration of these amino acids in any physiological system. Here we have studied the efficacy of some heavy metals for their complexation with these three amino acids. Bismuth has been found to bind selectively with these aromatic amino acids and this was confirmed using spectrofluorimetric, spectrophotometric and cyclic voltammetric studies. The series of heavy metals has been chosen because each of these metals remains associated with the others at very low concentration levels and Bi(III) is the least toxic amongst the other elements. So, selective recognition for Bi(III) would also mean no response for the other heavy elements if contaminants are present even at low concentration levels. The affinity towards these amino acids has been found to be in the order tryptophan < phenylalanine < tyrosine. The association constants of these amino acids have been calculated using Benesi Hildebrand equations and the corresponding free energy change has also been calculated. The values of the association constants obtained from BH equations using absorbance values corroborate with the Stern-Volmer constants obtained from fluorimetric studies. The evidence for complexation is also supported by the results of cyclic voltammetry. PMID- 23446648 TI - Impact of hemodynamics on lumen boundary displacements in abdominal aortic aneurysms by means of dynamic computed tomography and computational fluid dynamics. AB - The aim of the present work is to quantitatively assess the three-dimensional distributions of the displacements experienced during the cardiac cycle by the luminal boundary of abdominal aortic aneurysm (AAA) and to correlate them with the local bulk hemodynamics. Ten patients were acquired by means of time resolved computed tomography, and each patient-specific vascular morphology was reconstructed for all available time frames. The AAA lumen boundary motion was tracked, and the lumen boundary displacements (LBD) computed for each time frame. The intra-aneurysm hemodynamic quantities, specifically wall shear stress (WSS), were evaluated with computational fluid dynamics simulations. Co-localization of LBD and WSS distributions was evaluated by means of Pearson correlation coefficient. A clear anisotropic distribution of LBD was evidenced in both space and time; a combination of AAA lumen boundary inward- and outward-directed motions was assessed. A co-localization between largest outward LBD and high WSS was demonstrated supporting the hypothesis of a mechanistic relationship between anisotropic displacement and hemodynamic forces related to the impingement of the blood on the lumen boundary. The presence of anisotropic displacement of the AAA lumen boundary and their link to hemodynamic forces have been assessed, highlighting a new possible role for hemodynamics in the study of AAA progression. PMID- 23446649 TI - Domino synthesis of protochromic "ON-OFF-ON" luminescent 2-styryl quinolines. AB - The microwave-assisted coupling-isomerization reaction (MACIR) opens a straightforward domino access to 2-styryl quinolines in good to excellent yields. The push-pull character of these lumophores can be enhanced by placing a dimethyl amino group as an auxochrome in the para-position of the styryl moiety whereas anti-auxochromes are located in the 6-position of the quinoline part. The optical absorption and emission properties of the compounds were studied in solvents of different polarity and at various pH. The pronounced proto- and solvochromicity of the absorption and emission properties qualify them as luminescent pH sensors with "ON-OFF-ON" emission profiles triggered by pH variation over a broad pH range. The electronic structure of the chromophores is rationalized by DFT calculations. PMID- 23446650 TI - Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents. AB - Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5 one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2 thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA. PMID- 23446651 TI - Quality by design: screening of critical variables and formulation optimization of Eudragit E nanoparticles containing dutasteride. AB - The study was aimed at screening, understanding, and optimizing product variability of dutasteride-loaded Eudragit E nanoparticles prepared by solvent displacement using Plackett-Burman screening and a central composite design. The independent process and formulation factors selected included: drug loading (%), solute concentration (mg/mL), Soluplus concentration (mg/mL), injection rate (mL/min), organic solvent type (methanol or ethanol), stirring rate (rpm), and organic-to-aqueous phase volume ratio. Among these factors, solute concentration was associated with increased particle size, broad particle size distribution, and enhanced entrapment efficiency. On the other hand, Soluplus concentration played a role in decreasing particle size, narrowing particle size distribution, and reducing entrapment efficiency. Other formulation and process factors did not have a significant impact on nanoparticle properties, assuming they were within the limits used in this study. The optimized formulation was achieved with 20 mg/mL solute and 3.22 mg/mL Soluplus, and the observed responses were very close to the values predicted using the response surface methodology. The results clearly showed that quality by design concept could be effectively applied to optimize dutasteride-loaded Eudragit E nanoparticles. PMID- 23446652 TI - Comparison of urinary thallium levels in non-occupationally exposed people and workers. AB - PURPOSE: To determine a reference background urinary thallium level; to compare urinary thallium data from workers to this background level; to investigate factors affecting these levels and whether creatinine correction is appropriate. METHODS: Urine samples from non-occupationally exposed people (n = 273, from 113 individuals) and workers (n = 896, from 447 individuals) were analysed for thallium by ICP-MS. A reference background level was calculated, defined as the 95th percentile value of a non-occupationally exposed population. Worker data were divided into two subsets: thallium workers (those who work directly with thallium or its compounds) and general workers; and compared to the background level. Bayesian linear mixed effects modelling was used to investigate factors affecting urinary thallium concentration and the efficacy of creatinine correction for the determination of urinary thallium. RESULTS: The reference background urinary thallium level is 0.27 MUmol/mol creatinine (creatinine corrected) or 0.40 MUg/l (uncorrected). Median values were 0.11 MUmol/mol creatinine or 0.17 MUg/l for non-occupationally exposed people, 0.12 MUmol/mol creatinine or 0.20 MUg/l for general workers and 0.19 MUmol/mol creatinine or 0.41 MUg/l for thallium workers. Variation was lower in creatinine-corrected models. Nine per cent of samples from general workers and 39 % of samples from thallium workers exceeded the creatinine-corrected background level. By 2010, 90 % of all workers had urinary thallium levels below the 95th percentile reference background level. CONCLUSIONS: Urinary thallium concentrations were higher in thallium workers than non-occupationally exposed people and general workers. Creatinine correction is appropriate. PMID- 23446653 TI - Variable response of vascularized pigment epithelial detachments to ranibizumab based on lesion subtypes, including polypoidal choroidal vasculopathy. AB - PURPOSE: The purpose of this study was to evaluate the prognosis and response to intravitreal ranibizumab (IVR) of neovascular age-related macular degeneration, according to the type of pigment epithelial detachment (PED). METHODS: The authors prospectively studied 57 eyes of 57 consecutive patients with PED associated with exudative age-related macular degeneration, who were treated by IVR. All patients received 3 consecutive monthly injections of 0.5 mg/0.05 mL of ranibizumab as induction treatment. Retreatment was allowed if evidence of clinical deterioration was noted or spectral domain optical coherence tomography at the 1-month follow-up showed intraretinal edema, subretinal fluid, or recurrent PED. The best-corrected visual acuity (BCVA) values measured before and at 3, 6, and 12 months after the first injection were compared according to the type of PED. Changes in the height of PED to treatment with IVR were also investigated. RESULTS: Fifty-six eyes were assessed at the 12-month follow-up examination. There were 4 types of PED, including serous PED in 11 patients (19.6%), fibrovascular PED in 28 patients (50.0%), mixed PED with serous and fibrovascular component in 7 patients (12.5%), and hemorrhagic PED in 10 patients (17.9%). Eyes with serous PED showed significant improvement of the mean logarithm of the minimum angle of resolution (logMAR) BCVA as compared with the value at the baseline, which was sustained throughout the 12-month period (P < 0.05). Regarding the eyes with fibrovascular and mixed PED, significant improvement of the mean logMAR BCVA was observed compared with the value at the baseline at 3 months; however, a slight decrease was observed at 6 and 12 months. In the eyes with hemorrhagic PED, no significant difference in the mean BCVA values compared with the value at the baseline was observed at any follow-up time point. In relation to the height of the PED, all eyes in the serous and mixed PED group, 17 eyes in the fibrovascular PED group (60.7%), and 9 eyes in the hemorrhagic PED group (90.0%) showed reduction of the maximum PED height by 100 MUm or more. The PED response to IVR was not correlated with the final BCVA. CONCLUSION: Intravitreal ranibizumab for the treatment of exudative age-related macular degeneration is effective for stabilizing vision in patients with PED, but it may be better tolerated in patients with serous PED. Although it may be important to consider the type of PED to predict the visual acuity in patients treated by IVR, the anatomical response of the PED may not correlate directly with the visual outcome. PMID- 23446654 TI - Diagnostic and therapeutic challenges. PMID- 23446655 TI - Correlation of spectral domain optical coherence tomography characteristics with visual acuity in eyes with subfoveal scarring after treatment for wet age-related macular degeneration. AB - PURPOSE: Correlating spectral domain optical coherence tomography characteristics with final best-corrected visual acuity (BCVA) in eyes with subfoveal scarring after treatment for wet age-related macular degeneration. METHODS: Seventy-nine eyes from 64 subjects, who developed subfoveal scarring after treatment of wet age-related macular degeneration, were retrospectively studied. Spectral domain optical coherence tomography characteristics were analyzed, including percentage disruption of inner segment/outer segment junction and external limiting membrane, central macular thickness, subfoveal scar thickness, subretinal scar area, and proximity of retina with intact outer structures to the fovea. A multivariate stepwise regression analysis was performed with the final BCVA logarithm of minimum angle of resolution as a response and the above-identified spectral domain optical coherence tomography variables as predictors. RESULTS: There was no correlation between the final BCVA and any of the demographic data, treatment modality received, and central macular thickness. The final BCVA was significantly correlated with the percentage of inner segment/outer segment disruption (P = 0.011), external limiting membrane disruption (P = 0.005), and scar area on spectral domain optical coherence tomography (P = 0.018). Multivariate analysis showed that the baseline BCVA and distance between the fovea and nearest retina with intact outer structures are the most predictive of the final BCVA (R(2) = 0.52). CONCLUSION: Baseline BCVA and integrity of outer retinal structures are good predictors of the final BCVA of wet age-related macular degeneration patients developing scarring after treatment. PMID- 23446656 TI - Study on the potential benefit of adding topical bromfenac to intravitreal injections of ranibizumab for the therapy of exudative age-related macular degeneration. PMID- 23446658 TI - Sleep duration and weight loss among overweight/obese women enrolled in a behavioral weight loss program. AB - OBJECTIVE: The purpose of this study was to examine whether baseline sleep duration predicts weight loss outcomes in a randomized controlled trial examining a behavioral weight loss (BWL) intervention among overweight and obese (OW/OB) women with urinary incontinence; and whether participation in the BWL intervention is associated with changes in sleep duration. DESIGN: Longitudinal, clinical intervention study of a 6-month BWL program. SUBJECTS: Three hundred sixteen OW/OB women, with urinary incontinence (age: 30-81 years, body mass index (BMI; 25-50 kg m(-2)) enrolled from July 2004-April 2006. MEASUREMENTS: Measured height and weight, self-report measures of demographics, sleep and physical activity. RESULTS: Neither self-reported total sleep time (TST) nor time in bed (TIB) at baseline significantly predicted weight loss outcomes among OW/OB women in a BWL treatment. BWL treatment was successful regardless of how much subjects reported sleeping at baseline, with an average weight loss of 8.19 kg for OW/OB women receiving BWL treatment, versus a weight loss of 1.44 kg in the control condition. Similarly, changes in weight, BMI and incontinence episodes did not significantly predict changes in sleep duration or TIB across the treatment period. CONCLUSION: Although epidemiological and cross-sectional studies support a relationship between short sleep and increased BMI, the present study found no significant relationship between TST or TIB and weight loss for OW/OB women participating in a BWL treatment. PMID- 23446659 TI - Night eating syndrome: implications for severe obesity. AB - Night eating syndrome (NES) was first identified in 1955 by Stunkard, a psychiatrist specialising in eating disorders (ED). Over the last 20 years considerable progress has been made in defining NES as a significant clinical entity in its own right and it has now been accepted for inclusion in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) due for publication in 2013. NES is considered a dysfunction of circadian rhythm with a disassociation between eating and sleeping. Core criteria include a daily pattern of eating with a significantly increased intake in the evening and/or night time, as manifested by one or both of the following: at least 25% of food intake is consumed after the evening meal or at least two episodes of nocturnal eating per week. An important recent addition to core criteria includes the presence of significant distress and/or impairment in functioning. Stunkard's team recommend further investigation on the pathogenesis of NES, in particular its relationship with traumatic life events, psychiatric comorbidity, the age of onset of NES and course of NES over time. The relationship between NES and other ED also requires further clarification as night-eaters exhibit some features of other ED; previous guidance to separate NES from other ED may have hindered earlier characterisation of NES. Evidence from European and American studies suggests NES features strongly in populations with severe obesity. The complex interplay between depression, impaired sleep and obesity-related comorbidity in severely obese individuals makes understanding NES in this context even more difficult. This review examines evidence to date on the characterisation of NES and concludes by examining the applicability of current NES criteria to individuals with severe obesity. PMID- 23446660 TI - Adiponectin gene therapy ameliorates high-fat, high-sucrose diet-induced metabolic perturbations in mice. AB - BACKGROUND AND DESIGN: Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance. METHODS AND RESULTS: The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins. CONCLUSION: Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity. PMID- 23446661 TI - Vascular and metabolic effects of adrenaline in adipose tissue in type 2 diabetes. AB - OBJECTIVE: The aim was to investigate adipose tissue vascular and metabolic effects of an adrenaline infusion in vivo in subjects with and without type 2 diabetes mellitus (T2DM). DESIGN: Clinical intervention study with 1-h intravenous adrenaline infusion. SUBJECTS: Eight male overweight T2DM subjects and eight male weight-matched, non-T2DM subjects were studied before, during and after an 1-h intravenous adrenaline infusion. Adipose tissue blood flow (ATBF) was determined by (133)Xenon wash-out technique, and microvascular volume in the adipose tissue was studied by contrast-enhanced ultrasound imaging. Adipose tissue fluxes of glycerol, non-esterified fatty acids (NEFA), triacylglycerol and glucose were measured by Fick's principle after catherisation of a radial artery and a vein draining the abdominal, subcutaneous adipose tissue. RESULTS: ATBF increased similarly in both groups during the adrenaline infusion. One hour post adrenaline, ATBF was still increased in overweight T2DM subjects. Adrenaline increased microvascular volume in non-T2DM subjects while this response was impaired in overweight T2DM subjects. Adrenaline-induced increase in lipolysis was similar in both groups, but NEFA output from adipose tissue was delayed in overweight T2DM subjects. Glucose uptake in adipose tissue increased in non-T2DM subjects during adrenaline infusion but was unchanged in overweight T2DM subjects. This results in a delayed excess release of NEFA from the adipose tissue in overweight T2DM subjects after cessation of the adrenaline infusion. CONCLUSION: Capillaries in the adipose tissue are recruited by adrenaline in non T2DM subjects; however, this response is impaired in overweight T2DM subjects. NEFA, released in adipose tissue during adrenaline stimulation, is insufficiently re-esterified in situ in overweight T2DM subjects, probably owing to increased ATBF after adrenaline infusion and inability to increase adipose tissue glucose uptake. PMID- 23446662 TI - Zbtb16 has a role in brown adipocyte bioenergetics. AB - OBJECTIVE: A better understanding of the processes influencing energy expenditure could provide new therapeutic strategies for reducing obesity. As the metabolic activity of the brown adipose tissue (BAT) and skeletal muscle is an important determinant of overall energy expenditure and adiposity, we investigated the role of genes that could influence cellular bioenergetics in these two tissues. DESIGN: We screened for genes that are induced in both the BAT and skeletal muscle during acute adaptive thermogenesis in the mouse by microarray. We used C57BL/6J mice as well as the primary and immortalized brown adipocytes and C2C12 myocytes to validate the microarray data. Further characterization included gene expression, mitochondrial density, cellular respiration and substrate utilization. We also used a Hybrid Mouse Diversity Panel to assess in vivo effects on obesity and body fat content. RESULTS: We identified the transcription factor Zbtb16 (also known as Plzf and Zfp14) as being induced in both the BAT and skeletal muscle during acute adaptive thermogenesis. Zbtb16 overexpression in brown adipocytes led to the induction of components of the thermogenic program, including genes involved in fatty acid oxidation, glycolysis and mitochondrial function. Enhanced Zbtb16 expression also increased mitochondrial number, as well as the respiratory capacity and uncoupling. These effects were accompanied by decreased triglyceride content and increased carbohydrate utilization in brown adipocytes. Natural variation in Zbtb16 mRNA levels in multiple tissues across a panel of >100 mouse strains was inversely correlated with body weight and body fat content. CONCLUSION: Our results implicate Zbtb16 as a novel determinant of substrate utilization in brown adipocytes and of adiposity in vivo. PMID- 23446663 TI - Cyclooxygenase-2 is induced by p38 MAPK and promotes cell survival. AB - The Na+ ionophore monensin affects cellular pH and, depending on its concentration, causes the survival or death of tumor cells. In the present study, we elucidated the survival pathway activated in U937 cells, a human lymphoma derived cell line. These cells treated with monensin at a concentration of 5 uM were growth-arrested in G1, activated p38 mitogen-activated protein kinase (MAPK) and showed an increased expression of cyclooxygenase-2 (COX-2). The latter two molecular events were linked, as pharmacological inhibition of the MAPK did not allow COX-2 increased expression. Furthermore, we showed that p38 and COX-2 keep monensin-stressed U937 cells alive, as pharmacological inhibition of each enzyme caused cell death. PMID- 23446664 TI - A systematic review of stress-management programs for medical students. AB - OBJECTIVE: Because medical students experience a considerable amount of stress during training, academic leaders have recognized the importance of developing stress-management programs for medical students. The authors set out to identify all controlled trials of stress-management interventions and determine the efficacy of those interventions. METHOD: The authors searched the published English-language articles on PsycINFO and PubMed, using a combination of the following search terms: stress-management, distress, burnout, coping, medical student, wellness. Both randomized, controlled trials and controlled, non randomized trials of stress-management programs were selected and critically appraised. RESULTS: A total of 13 randomized, controlled trials or controlled, non-randomized trials were identified. Interventions included self-hypnosis, meditation, mindfulness-based stress-reduction, feedback on various health habits, educational discussion, changes in the length and type of curriculum, and changes in the grading system. Only one study was identified to be of very high quality, although several had described group differences at baseline, used blinding, had good follow-up, and used validated assessment tools. There was a wide heterogeneity of outcome measures used. Interventions that were supported by a reduction in stress and anxiety in medical students included mindfulness-based stress-reduction or meditation techniques, self-hypnosis, and pass/fail grading. CONCLUSIONS: Significant opportunities to advance educational research in this field exist by developing more high-quality studies with particular attention to randomization techniques and standardizing outcome measures. PMID- 23446666 TI - Computed tomography colonography vs. colonoscopy for colorectal cancer screening: close call, but not closed case. PMID- 23446665 TI - Five-year weight loss experience of outpatients receiving laparoscopic adjustable gastric band surgery. AB - BACKGROUND: This study evaluated the efficacy and safety of laparoscopic adjustable gastric banding (LAGB) in a large cohort of morbidly obese patients followed for up to 5 years. METHODS: Morbidly obese patients, >= 16 years of age, who underwent LAGB surgery at the Surgical Weight Loss Clinic in Ontario, Canada, between May 2005 and January 2011 were eligible for this retrospective chart review. Electronic files were searched to identify all patients who met the inclusion/exclusion criteria. Demographics, weights at baseline and follow-up visits (up to 60 months following surgery), and post-operative complications were documented. As follow-up visits occurred at unevenly spaced intervals within and across patients, modeling methods were used to more accurately assess mean % weight loss (WL) and % excess weight loss (EWL) over time. RESULTS: This study included 2,815 patients (82 % female, mean age 43 years, mean baseline BMI 44.6 kg/m(2)) followed for a mean of 21.8 +/- 15.4 months. Complications developed in 238 patients (8.5 %), the most frequent being prolapse/slippage (4.2 %), tubing/access port problems (1.2 %), and explantation (1.2 %). Mean %WL and %EWL progressed continuously over the first 2.5 years post-LAGB, plateauing at 20 and 49 %, respectively, for up to 5 years of follow up. Factors associated with increased weight loss were time since surgery, greater baseline weight (excess weight), older age at time of surgery, and male gender. CONCLUSIONS: Weight loss was maintained for up to 5 years in our population of patients who underwent LAGB for the treatment of morbid obesity. PMID- 23446667 TI - Time requirements and health effects of participation in colorectal cancer screening with colonoscopy or computed tomography colonography in a randomized controlled trial. AB - BACKGROUND AND STUDY AIMS: Time limitations and unwanted health effects may act as barriers to participation in colorectal cancer (CRC) screening. The aim of the study was to measure the time requirements and health effects of colonoscopy and computed tomography colonography (CTC) screening. PATIENTS AND METHODS: This was a prospective diary study in a consecutive sample within a randomized controlled CRC screening trial, comparing primary colonoscopy and CTC screening for average risk individuals aged 50 - 74 years. The diary ended when all screening-related complaints had passed. RESULTS: The diary was returned by 75 % (241/322) of colonoscopy and 75 % (127/170) of CTC screenees. The median interval between leaving home and returning from the examination was longer for colonoscopy (4 hours and 18 minutes [4:18], interquartile range [IQR] 3:30 - 5:00) than for CTC (2:30 hours, IQR 2:06 - 3:00; P < 0.001). Similarly, the time to return to routine activities was longer after colonoscopy (3:54 hours, IQR 1:48 - 15:00) than after CTC (1:36 hours, IQR 0:54 - 4:42). The duration of screening-related symptoms after the examination was shorter for colonoscopy (11:00 hours, IQR 2:54 - 20:00) than for CTC (22:00 hours; IQR 5:30 - 47:00; P < 0.001). Abdominal complaints were reported more frequently after CTC. Anxiety, pain, and quality of life worsened during the screening process, with no differences between the two examinations. CONCLUSIONS: Compared with colonoscopy, CTC screening required less time and allowed screenees to return to their daily activities more quickly. In contrast, CTC was associated with a twofold longer duration of screening-related symptoms. Feelings of anxiety, pain, and quality of life scores were similar during colonoscopy and CTC screening. These results should be incorporated into cost-effectiveness analyses of CRC screening techniques. PMID- 23446668 TI - NOTES in Europe: summary of the working group reports of the 2012 EURO-NOTES meeting. AB - The sixth EURO-NOTES workshop (4 - 6 October 2012, Prague, Czech Republic) focused on enabling intensive scientific dialogue and interaction between surgeons, gastroenterologists, and engineers/industry representatives and discussion of the state of the practice and development of natural orifice transluminal endoscopic surgery (NOTES) in Europe. In accordance with previous meetings, five working groups were formed. In 2012, emphasis was put on specific indications for NOTES and interventional endoscopy. Each group was assigned an important indication related to ongoing research in NOTES and interventional endoscopy: cholecystectomy and appendectomy, therapy of colorectal diseases, therapy of adenocarcinoma and neoplasia in the upper gastrointestinal tract, treating obesity, and new therapeutic approaches for achalasia. This review summarizes consensus statements of the working groups. PMID- 23446669 TI - The utility of duodenal endosonography examination in the diagnostic work-up of primary sclerosing cholangitis. PMID- 23446670 TI - Reply to Ustundag et al. PMID- 23446671 TI - Handcrafted two-channel colonoscope for grasping forceps-assisted resection of large pedunculated polyps in the sigmoid colon. PMID- 23446672 TI - Reply to Matsushita. PMID- 23446674 TI - Skeletonized versus pedicled internal thoracic artery and risk of sternal wound infection after coronary bypass surgery: meta-analysis and meta-regression of 4817 patients. AB - It is suggested that the internal thoracic artery (ITA) harvesting technique influences the incidence of sternal wound infection (SWI) after coronary artery bypass graft (CABG). To determine if there is any real difference between skeletonized vs pedicled ITA, we performed a meta-analysis to determine if there is any real difference between these two established techniques in terms of SWI. We performed a systematic review using MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles to search for studies that compared the incidence of SWI after CABG between skeletonized vs pedicled ITA until June 2012. The principal summary measures were odds ratio (OR) with 95% confidence interval (CI) and P values (statistically significant when <0.05). The ORs were combined across studies using the weighted DerSimonian-Laird random effects model and weighted Mantel-Haenszel fixed effects. Meta-analysis, sensitivity analysis and meta-regression were completed using the software Comprehensive Meta-Analysis version 2 (Biostat, Inc., Englewood, NJ, USA). Twenty two studies involving 4817 patients (2424 skeletonized; 2393 pedicled) met the eligibility criteria. There was no evidence for important heterogeneity of effects among the studies. The overall OR (95% CI) of SWI showed a statistically significant difference in favour of skeletonized ITA (fixed effect model: OR 0.443, 95% CI 0.323-0.608, P < 0.001; random effect model: OR 0.443, 95% CI 0.323 0.608, P < 0.001). In the sensitivity analysis, the difference in favour of skeletonized ITA was also observed in subgroups such as diabetic, bilateral ITA and diabetic with bilateral ITA; we also observed that there was a difference in the type of study, since non-randomized studies together demonstrated the benefit of skeletonized ITA in comparison with pedicled ITA, but the randomized studies together did not show this difference (although close to statistical significance and with the tendency to favour the skeletonized group). In meta-regression, we observed a statistically significant coefficient for SWI and proportion of diabetic patients (coefficient -0.02, 95% CI -0.03 to -0.01, P = 0.016). In conclusion, skeletonized ITA appears to reduce the incidence of postoperative SWI in comparison with pedicled ITA after CABG, with this effect being modulated by the presence of diabetes. PMID- 23446676 TI - Does HIV age your brain? PMID- 23446675 TI - Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity. AB - OBJECTIVE: Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging. METHODS: In this cross sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV uninfected (HIV-) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks. RESULTS: Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV- controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4(+) cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV- participants. No interaction was observed between HIV and aging. CONCLUSIONS: HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging. PMID- 23446677 TI - Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI. AB - OBJECTIVE: To compare the predictive accuracy of beta-amyloid (Abeta)1-42 and total tau in CSF, hippocampal volume (HCV), and APOE genotype for Alzheimer disease (AD)-type dementia in subjects with amnestic mild cognitive impairment (aMCI) and nonamnestic mild cognitive impairment (naMCI). METHODS: We selected 399 subjects with aMCI and 226 subjects with naMCI from a multicenter memory clinic-based cohort. We measured CSF Abeta1-42 and tau by ELISA (n = 231), HCV on MRI (n = 388), and APOE epsilon4 (n = 523). Follow-up was performed annually up to 5 years. Outcome measures were progression to AD-type dementia and cognitive decline. RESULTS: At least 1 follow-up was available for 538 subjects (86%). One hundred thirty-two subjects with aMCI (38%) and 39 subjects with naMCI (20%) progressed to AD-type dementia after an average follow-up of 2.5 years. CSF Abeta1-42, tau, Abeta1-42/tau ratio, HCV, and APOE epsilon4 predicted AD-type dementia in each MCI subgroup with the same overall diagnostic accuracy. However, CSF Abeta1-42 concentration was higher and hippocampal atrophy less severe in subjects with naMCI compared with aMCI. This reduced the sensitivity but increased the specificity of these markers for AD-type dementia in subjects with naMCI. CONCLUSIONS: AD biomarkers are useful to predict AD-type dementia in subjects with aMCI and naMCI. However, biomarkers might not be as sensitive for early diagnosis of AD in naMCI compared with aMCI. This may have implications for clinical implementation of the National Institute on Aging and Alzheimer's Association criteria. PMID- 23446678 TI - Hemi-seesaw nystagmus in lateral medullary syndrome. AB - Seesaw and hemi-seesaw nystagmus are rare in lateral medullary syndrome. We describe a patient with lateral medullary syndrome who, in addition to other more typical ocular manifestations, demonstrated hemi-seesaw nystagmus (HSSN). PMID- 23446679 TI - Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size. AB - OBJECTIVE: To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1). METHODS: We searched a North American FSHD registry and the University of Rochester (UR) FSHD research database, reviewed the literature, and sent surveys to 14 FSHD referral centers in the United States and overseas to identify patients with genetically confirmed FSHD1 with a diagnosis of Coats syndrome. RESULTS: Out of 357 genetically confirmed patients in a North American FSHD registry and 51 patients in the UR database, 3 patients had a self-reported history of Coats disease (0.8%; 95% confidence interval 0.2%-2.2%). In total, we identified 14 patients with FSHD with known genetic contraction size and Coats syndrome confirmed by ophthalmologic examination: 10 from our survey and 4 from the literature. The median age at diagnosis of Coats syndrome was 10 years (interquartile range 14 years). The median D4Z4 fragment size was 13 kilobases (kb) (interquartile range 1 kb). One patient was mosaic (55% 11 kb, and 45% 78 kb). CONCLUSIONS: Coats syndrome is a rare extramuscular complication of FSHD1 associated with large D4Z4 contractions. Closer surveillance for retinal complications is warranted in patients with D4Z4 fragments <=15 kb. PMID- 23446681 TI - Alice in Wonderland Syndrome: somesthetic vs visual perceptual disturbance. AB - In 1955, English psychiatrist John Todd (1914-1987) described Alice in Wonderland syndrome (AIWS) as self-experienced paroxysmal body image illusions involving distortions of the size, mass, or shape of the patient's own body or its position in space, often occurring with depersonalization and derealization.(1) Todd named AIWS for the perceptual disorder of altered body image experienced by the protagonist in the novel Alice's Adventures in Wonderland (1865), written by Lewis Carroll(2) (the pseudonym of Reverend Charles Lutwidge Dodgson [1832 1898]), possibly based in part on Dodgson's own migrainous experiences.(3) In the story, Alice followed a talking white rabbit down a rabbit hole and then experienced several dramatic changes in her own body size and shape (e.g., shrinking to 10 inches high, growing unnaturally large, and growing unnaturally tall but not any wider).(2) Although Todd's report was the most influential, Lippman(4) provided an earlier description in 1952. In Lippman's article, one of the patients reported feeling short and wide as she walked, and referenced Alice's Adventures in Wonderland in regard to her body image illusions, referring to them as a "Tweedledum" or "Tweedledee" feeling. PMID- 23446680 TI - Brain beta-amyloid load approaches a plateau. AB - OBJECTIVE: To model the temporal trajectory of beta-amyloid accumulation using serial amyloid PET imaging. METHODS: Participants, aged 70-92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association. RESULTS: Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined-reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5-2.5 is approximately 15 years. CONCLUSION: This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions. PMID- 23446682 TI - Backwaters and rapids on the amyloid river. PMID- 23446683 TI - Propagation of cortical spreading depolarization in the human cortex after malignant stroke. AB - OBJECTIVE: To investigate hemodynamic response pattern and spatiotemporal propagation of cortical spreading depolarization in the peri-infarct region of malignant hemispheric stroke. METHODS: In this prospective observational case study we used intraoperative laser speckle technology to measure cerebral blood flow in patients with malignant hemispheric stroke. Additionally, postoperative occurrence of cortical spreading depolarization was monitored using a subdural recording strip for electrocorticography and infarct progression was assessed by serial MRI. RESULTS: In 7 of 20 patients, 19 blood flow changes typical of cortical spreading depolarizations occurred during a 20-minute period. Thirteen events were characterized by increase, 2 by biphasic response, and 4 by decrease of blood flow. Propagation velocity ranged from 1.7 to 9.2 mm/min and propagation area from 0.1 to 4.8 cm(2). Intrinsic optical signal alterations preceded and low frequency vascular fluctuations were suppressed during the hemodynamic responses. A mean number of 56 +/- 82 cortical spreading depolarizations per patient was recorded and a mean infarct progression of 30 +/- 13 cm(3) was detected in 5 of 7 patients. CONCLUSIONS: We visualize the spatiotemporal propagation of spreading depolarizations in the human cerebral cortex intraoperatively. In patients with focal ischemia, multiple cortical spreading depolarizations with either hyperemic or hypoemic flow responses occurred. Our data suggest that, in patients with focal ischemia, cortical spreading depolarizations are associated with both unfavorable and protective hemodynamic responses. PMID- 23446684 TI - One-year safety and tolerability profile of pridopidine in patients with Huntington disease. AB - OBJECTIVE: To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease. METHODS: Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day). RESULTS: Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported >=1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and >=1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported >=1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified. CONCLUSION: Pridopidine (<=90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that pridopidine (<=90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year. PMID- 23446685 TI - Probiotics for the treatment of pediatric helicobacter pylori infection: a randomized double blind clinical trial. AB - OBJECTIVE: Helicobacter pylori is recognized as a major etiological factor in the pathogenesis of gastritis and peptic ulcer disease. H. Pylori eradication has a failure rate of more than 30% in pediatric patients, particularly because of poor compliance, antibiotic resistance and occurrence of side-effects. This study was aimed to determine whether adding the probiotics to a standard anti-H. pylori regimen could minimize the gastrointestinal side-effect prevalence and improve the eradication rate. METHODS: Double-blind randomized placebo controlled study conducted at Children's Medical Center in Tehran, Iran. Sixty six H. pylori positive children were treated with a triple drug treatment protocol (omeprazole+amoxycillin+furazolidon) and randomly allocated to receive either probiotic or placebo. All patients underwent esophagogastroduodendoscopy. H. pylori infection was diagnosed by either rapid urease test (RUT) or histology. H. pylori status was assessed after 4-8 weeks of the completion of treatment with stool H. pylori antigen test. The side effects of the treatment were determined in each group. FINDINGS: Mean age of patients was 9.09 (range 3-14) years, 44 (65.7%) patients were boys (sex ratio 2:1). All 66 patients completed the course of treatment and follow-up. The rate of H. pylori eradication was significantly higher in probiotic group (P=0.04). In probiotic supplemented children there was a lower rate of nausea/vomiting (P=0.02) and diarrhea (P=0.039) during treatment. CONCLUSION: This study showed that probiotics have positive effect on the eradication of H. pylori infection. Adjuvant therapy with probiotic is recommended in order to reduce the frequency of antibiotic induced side-effects during treatment with antibiotics. PMID- 23446686 TI - Corneal dry-responsive neurons in the spinal trigeminal nucleus respond to innocuous cooling in the rat. AB - Corneal primary afferent neurons that respond to drying of the ocular surface have been previously characterized and found to respond to innocuous cooling, menthol, and hyperosmotic stimuli. The purpose of the present study was to examine the receptive field properties of second-order neurons in the trigeminal nucleus that respond to drying of the ocular surface. Single-unit electrophysiological recordings were performed in anesthetized rats, and dry responsive corneal units were isolated in the brain stem at the transition zone between the spinal trigeminal subnucleus caudalis and subnucleus interpolaris. Corneal units were characterized according to their responses to changes in temperature (cooling and heating), hyperosmotic artificial tears, menthol, and low pH. All dry-responsive neurons (n = 18) responded to cooling of the ocular surface. In addition, these neurons responded to hyperosmotic stimuli and menthol application to the cornea. One-half of the neurons were activated by low pH, and these acid-sensitive neurons were also activated by noxious heat. Furthermore, neurons that were activated by low pH had a significantly lower response to cooling and menthol. These results indicate that dry-responsive neurons recorded in the trigeminal nucleus receive input from cold, sensitive primary afferent neurons, with a subset of these neurons receiving input from corneal primary afferent neurons sensitive to acid and noxious heat. It is proposed that acid insensitive corneal neurons represent a labeled line for lacrimation in response to evaporation of tears from the ocular surface, whereas acid-sensitive neurons are involved in tearing, elicited by damaging or potentially damaging stimuli. PMID- 23446687 TI - The zona incerta modulates spontaneous spike-wave discharges in the rat. AB - The contribution of the zona incerta (ZI) of the thalamus on spike-wave discharges (SWDs) was investigated. Chronic recordings of bilateral cortices, bilateral vibrissa muscle, and unilateral ZI were performed in Long-Evans rats to examine the functional role of SWDs. Rhythmic ZI activity appeared at the beginning of SWD and was accompanied by higher-oscillation frequencies and larger spike magnitudes. Bilateral lidocaine injections into the mystacial pads led to a decreased oscillation frequency of SWDs, but the phenomenon of ZI-related spike magnitude enhancement was preserved. Moreover, 800-Hz ZI microstimulation terminates most of the SWDs and whisker twitching (WT; >80%). In contrast, 200-Hz ZI microstimulation selectively stops WTs but not SWDs. Stimulation of the thalamic ventroposteriomedial nucleus showed no obvious effect on terminating SWDs. A unilateral ZI lesion resulted in a significant reduction of 7- to 12-Hz power of both the ipsilateral cortical and contralateral vibrissae muscle activities during SWDs. Intraincertal microinfusion of muscimol showed a significant inhibition on SWDs. Our present data suggest that the ZI actively modulates the SWD magnitude and WT behavior. PMID- 23446688 TI - Neural integrators for decision making: a favorable tradeoff between robustness and sensitivity. AB - A key step in many perceptual decision tasks is the integration of sensory inputs over time, but a fundamental questions remain about how this is accomplished in neural circuits. One possibility is to balance decay modes of membranes and synapses with recurrent excitation. To allow integration over long timescales, however, this balance must be exceedingly precise. The need for fine tuning can be overcome via a "robust integrator" mechanism in which momentary inputs must be above a preset limit to be registered by the circuit. The degree of this limiting embodies a tradeoff between sensitivity to the input stream and robustness against parameter mistuning. Here, we analyze the consequences of this tradeoff for decision-making performance. For concreteness, we focus on the well-studied random dot motion discrimination task and constrain stimulus parameters by experimental data. We show that mistuning feedback in an integrator circuit decreases decision performance but that the robust integrator mechanism can limit this loss. Intriguingly, even for perfectly tuned circuits with no immediate need for a robustness mechanism, including one often does not impose a substantial penalty for decision-making performance. The implication is that robust integrators may be well suited to subserve the basic function of evidence integration in many cognitive tasks. We develop these ideas using simulations of coupled neural units and the mathematics of sequential analysis. PMID- 23446691 TI - Changes in task parameters during walking prism adaptation influence the subsequent generalization pattern. AB - An understanding of the transfer (or generalization) of motor adaptations between legs and across tasks during walking has remained elusive due to limited research and mixed results. Here, we asked whether stepping sequences or task constraints introduced during walking prism-adaptation tasks influence generalization patterns. Forty subjects adapted to prism glasses in precision-walking or obstacle-avoidance tasks that required a specific stepping sequence to the center of two/three targets or laterally over an obstacle. We then tested for generalization, reflected by aftereffects in the nonadapted task. Our previous study using these tasks found that only one leg generalized. Here, we reversed the stepping sequence and found that only the opposite leg generalized in the subject group that adapted in a precision-walking task. The combination of stepping sequence and direction of prism shift caused subjects in two groups to collide with the obstacle early during adaptation, thus making the step prior to going over the obstacle more important. Both legs subsequently generalized. A fourth subject group experienced a three-target, precision-walking task, resulting in a balanced, right-left, left-right stepping sequence, meant to induce bilateral generalization. While only one leg generalized, foot placement aftereffects before stepping over the obstacle would have caused subjects to collide with it. Together with our previous study, the results suggest a contribution of stepping sequence during the adapted task on generalization patterns, likely driven by proprioceptive feedback. The results also support the idea that negative consequences during adaptation and/or perceived threat can influence generalization. PMID- 23446690 TI - Animal-to-animal variability in the phasing of the crustacean cardiac motor pattern: an experimental and computational analysis. AB - The cardiac ganglion (CG) of Homarus americanus is a central pattern generator that consists of two oscillatory groups of neurons: "small cells" (SCs) and "large cells" (LCs). We have shown that SCs and LCs begin their bursts nearly simultaneously but end their bursts at variable phases. This variability contrasts with many other central pattern generator systems in which phase is well maintained. To determine both the consequences of this variability and how CG phasing is controlled, we modeled the CG as a pair of Morris-Lecar oscillators coupled by electrical and excitatory synapses and constructed a database of 15,000 simulated networks using random parameter sets. These simulations, like our experimental results, displayed variable phase relationships, with the bursts beginning together but ending at variable phases. The model suggests that the variable phasing of the pattern has important implications for the functional role of the excitatory synapses. In networks in which the two oscillators had similar duty cycles, the excitatory coupling functioned to increase cycle frequency. In networks with disparate duty cycles, it functioned to decrease network frequency. Overall, we suggest that the phasing of the CG may vary without compromising appropriate motor output and that this variability may critically determine how the network behaves in response to manipulations. PMID- 23446689 TI - V1 mechanisms underlying chromatic contrast detection. AB - To elucidate the cortical mechanisms of color vision, we recorded from individual primary visual cortex (V1) neurons in macaque monkeys performing a chromatic detection task. Roughly 30% of the neurons that we encountered were unresponsive at the monkeys' psychophysical detection threshold (PT). The other 70% were responsive at threshold but on average, were slightly less sensitive than the monkey. For these neurons, the relationship between neurometric threshold (NT) and PT was consistent across the four isoluminant color directions tested. A corollary of this result is that NTs were roughly four times lower for stimuli that modulated the long- and middle-wavelength sensitive cones out of phase. Nearly one-half of the neurons that responded to chromatic stimuli at the monkeys' detection threshold also responded to high-contrast luminance modulations, suggesting a role for neurons that are jointly tuned to color and luminance in chromatic detection. Analysis of neuronal contrast-response functions and signal-to-noise ratios yielded no evidence for a special set of "cardinal color directions," for which V1 neurons are particularly sensitive. We conclude that at detection threshold--as shown previously with high-contrast stimuli-V1 neurons are tuned for a diverse set of color directions and do not segregate naturally into red-green and blue-yellow categories. PMID- 23446693 TI - Limits in motor control bandwidth during stick balancing. AB - Why can we balance a yardstick but not a pencil on the tip of our finger? As with other physical systems, human motor control has constraints, referred to as bandwidth, which restricts the range of frequency over which the system can operate within some tolerated level of error. To investigate control bandwidth, the natural frequency of a stick used during a stick-balancing task was modified by adjusting the height of a mass attached to the stick. The ability to successfully balance the stick with the mass positioned at four different heights was determined. In addition, electromyographic signals from forearm and trunk muscles were recorded during the trials. We hypothesized that 1) the probability of successfully balancing would decrease as mass height decreased; and 2) the level of muscle activation in both agonist and antagonist would increase as the natural frequency of the stick increased. Results showed that as the mass height decreased the probability of successfully balancing the stick decreased. Changes in the probability of success with respect to mass height showed a threshold effect, suggesting that limits in human control bandwidth were approached at the lowest mass height. Also, the level of muscle activation in both the agonist and antagonist of the forearm and trunk increased linearly as the natural frequency of the stick increased. These changes in muscle activation suggest that the central nervous system adapts muscle activation to task dynamics, possibly to improve control bandwidth. PMID- 23446692 TI - Intrinsic connections in the anterior part of the bed nucleus of the stria terminalis. AB - Intrinsic connections in the anterior portion of the bed nucleus of the stria terminalis (BNST-A) were studied using patch recordings and ultraviolet (UV) glutamate uncaging (GU) in vitro. UV light was delivered at small BNST-A sites in a grid-like pattern while evoked responses were monitored in different BNST-A regions. Three sectors were distinguished in the BNST-A using fiber bundles readily identifiable in transilluminated slices: the anterior commissure, dividing the BNST-A into dorsal and ventral (BNST-AV) regions, and the intra-BNST component of the stria terminalis, subdividing the dorsal portion into medial (BNST-AM) and lateral (BNST-AL) regions. Overall, GU elicited GABAergic inhibitory postsynaptic potentials (IPSPs) more frequently than excitatory postsynaptic potentials. The incidence of intraregional connections was higher than interregional links. With respect to the latter, asymmetric connections were seen between different parts of the BNST-A. Indeed, while reciprocal connections were found between the BNST-AL and BNST-AM, BNST-AL to BNST-AM connections were more frequent than in the opposite direction. Similarly, while GU in the BNST-AM or BNST-AL often elicited IPSPs in BNST-AV cells, the opposite was rarely seen. Within the BNST-AM, connections were polarized, with dorsal GU sites eliciting IPSPs in more ventrally located cells more frequently than the opposite. This trend was not seen in other regions of the BNST. Consistent with this, most BNST AM cells had dorsally directed dendrites and ventrally ramified axons, whereas this morphological polarization was not seen in other parts of the BNST-A. Overall, our results reveal a hitherto unsuspected level of asymmetry in the connections within and between different BNST-A regions, implying a degree of interdependence in their activity. PMID- 23446694 TI - Tests of linearity in the responses of eye-movement-sensitive vestibular neurons to sinusoidal yaw rotation. AB - The rotational vestibulo-ocular reflex in primates is linear and stabilizes gaze in space over a large range of head movements. Best evidence suggests that position-vestibular-pause (PVP) and eye-head velocity (EHV) neurons in the vestibular nuclei are the primary mediators of vestibulo-ocular reflexes for rotational head movements, yet the linearity of these neurons has not been extensively tested. The current study was undertaken to understand how varying magnitudes of yaw rotation are coded in these neurons. Sixty-six PVP and 41 EHV neurons in the rostral vestibular nuclei of 7 awake rhesus macaques were recorded over a range of frequencies (0.1 to 2 Hz) and peak velocities (7.5 to 210 degrees /s at 0.5 Hz). The sensitivity (gain) of the neurons decreased with increasing peak velocity of rotation for all PVP neurons and EHV neurons sensitive to ipsilateral rotation (type I). The sensitivity of contralateral rotation sensitive (type II) EHV neurons did not significantly decrease with increasing peak velocity. These data show that, like non-eye-movement-related vestibular nuclear neurons that are believed to mediate nonlinear vestibular functions, PVP neurons involved in the linear vestibulo-ocular reflex also behave in a nonlinear fashion. Similar to other sensory nuclei, the magnitude of the vestibular stimulus is not linearly coded by the responses of vestibular neurons; rather, amplitude compression extends the dynamic range of PVP and type I EHV vestibular neurons. PMID- 23446696 TI - The effect of contextual cues on the encoding of motor memories. AB - Several studies have shown that sensory contextual cues can reduce the interference observed during learning of opposing force fields. However, because each study examined a small set of cues, often in a unique paradigm, the relative efficacy of different sensory contextual cues is unclear. In the present study we quantify how seven contextual cues, some investigated previously and some novel, affect the formation and recall of motor memories. Subjects made movements in a velocity-dependent curl field, with direction varying randomly from trial to trial but always associated with a unique contextual cue. Linking field direction to the cursor or background color, or to peripheral visual motion cues, did not reduce interference. In contrast, the orientation of a visual object attached to the hand cursor significantly reduced interference, albeit by a small amount. When the fields were associated with movement in different locations in the workspace, a substantial reduction in interference was observed. We tested whether this reduction in interference was due to the different locations of the visual feedback (targets and cursor) or the movements (proprioceptive). When the fields were associated only with changes in visual display location (movements always made centrally) or only with changes in the movement location (visual feedback always displayed centrally), a substantial reduction in interference was observed. These results show that although some visual cues can lead to the formation and recall of distinct representations in motor memory, changes in spatial visual and proprioceptive states of the movement are far more effective than changes in simple visual contextual cues. PMID- 23446695 TI - Iberiotoxin-sensitive and -insensitive BK currents in Purkinje neuron somata. AB - Purkinje cells have specialized intrinsic ionic conductances that generate high frequency action potentials. Disruptions of their Ca or Ca-activated K (KCa) currents correlate with altered firing patterns in vitro and impaired motor behavior in vivo. To examine the properties of somatic KCa currents, we recorded voltage-clamped KCa currents in Purkinje cell bodies isolated from postnatal day 17-21 mouse cerebellum. Currents were evoked by endogenous Ca influx with approximately physiological Ca buffering. Purkinje somata expressed voltage activated, Cd-sensitive KCa currents with iberiotoxin (IBTX)-sensitive (>100 nS) and IBTX-insensitive (>75 nS) components. IBTX-sensitive currents activated and partially inactivated within milliseconds. Rapid, incomplete macroscopic inactivation was also evident during 50- or 100-Hz trains of 1-ms depolarizations. In contrast, IBTX-insensitive currents activated more slowly and did not inactivate. These currents were insensitive to the small- and intermediate-conductance KCa channel blockers apamin, scyllatoxin, UCL1684, bicuculline methiodide, and TRAM-34, but were largely blocked by 1 mM tetraethylammonium. The underlying channels had single-channel conductances of ~150 pS, suggesting that the currents are carried by IBTX-resistant (beta4 containing) large-conductance KCa (BK) channels. IBTX-insensitive currents were nevertheless increased by small-conductance KCa channel agonists EBIO, chlorzoxazone, and CyPPA. During trains of brief depolarizations, IBTX insensitive currents flowed during interstep intervals, and the accumulation of interstep outward current was enhanced by EBIO. In current clamp, EBIO slowed spiking, especially during depolarizing current injections. The two components of BK current in Purkinje somata likely contribute differently to spike repolarization and firing rate. Moreover, augmentation of BK current may partially underlie the action of EBIO and chlorzoxazone to alleviate disrupted Purkinje cell firing associated with genetic ataxias. PMID- 23446697 TI - Functional connectivity patterns of medial and lateral macaque frontal eye fields reveal distinct visuomotor networks. AB - It has been previously shown that small- and large-amplitude saccades have different functions during vision in natural environments. Large saccades are associated with reaching movements toward objects, whereas small saccades facilitate the identification of more detailed object features necessary for successful grasping and manual manipulation. To determine whether these represent dichotomous processing streams, we used resting-state functional MRI to examine the functional connectivity patterns of the medial and lateral frontal eye field (FEF) regions that encode large- and small-amplitude saccades, respectively. We found that the spontaneous blood oxygen level-dependent signals of the medial FEF were functionally correlated with areas known to be involved in reaching movements and executive control processes, whereas lateral FEF was functionally correlated with cortical areas involved in object processing and in grasping, fixation, and manipulation of objects. The results provide strong evidence for two distinct visuomotor network systems in the primate brain that likely reflect the alternating phases of vision for action in natural environments. PMID- 23446698 TI - A modulatory effect of the feedback from higher visual areas to V1 in the mouse. AB - Using a mouse brain slice preparation, we studied the modulatory effects of a feedback projection from higher visual cortical areas, mostly or exclusively area LM (or V2), on two inputs to layer 4 cells in the first visual area (V1). The two inputs to these cells were geniculocortical and an unspecified intracortical input, possibly involving layer 6 cells. We found that activation of metabotropic glutamate receptors (mGluRs) from stimulation of the feedback projection reduced the evoked excitatory postsynaptic currents of both of these inputs to layer 4 but that this modulation acts in an input-specific way. Reducing the strength of the geniculocortical input in adults involved both presynaptic and postsynaptic group I mGluRs (although in younger animals presynaptic group II mGluRs were also involved), whereas modulation of the intracortical input acted entirely via postsynaptic group II mGluRs. These results demonstrate that one of the effects of this feedback pathway is to control the gain of geniculocortical transmission. PMID- 23446700 TI - A method for measurement of drug sensitivity of myeloma cells co-cultured with bone marrow stromal cells. AB - The tumor microenvironment can profoundly affect tumor cell survival as well as alter antitumor drug activity. However, conventional anticancer drug screening typically is performed in the absence of stromal cells. Here, we analyzed survival of myeloma cells co-cultured with bone marrow stromal cells (BMSC) using an automated fluorescence microscope platform, ScanR. By staining the cell nuclei with DRAQ5, we could distinguish between BMSC and myeloma cells, based on their staining intensity and nuclear shape. Using the apoptotic marker YO-PRO-1, the effects of drug treatment on the viability of the myeloma cells in the presence of stromal cells could be measured. The method does not require cell staining before incubation with drugs, and less than 5000 cells are required per condition. The method can be used for large-scale screening of anticancer drugs on primary myeloma cells. This study shows the importance of stromal cell support for primary myeloma cell survival in vitro, as half of the cell samples had a marked increase in their viability when cultured in the presence of BMSC. Stromal cell-induced protection against common myeloma drugs is also observed with this method. PMID- 23446699 TI - High-throughput identification of promiscuous inhibitors from screening libraries with the use of a thiol-containing fluorescent probe. AB - Testing small molecules for their ability to modify cysteine residues of proteins in the early stages of drug discovery is expected to accelerate our ability to develop more selective drugs with lesser side effects. In addition, this approach also enables the rapid evaluation of the mode of binding of new drug candidates with respect to thiol reactivity and metabolism by glutathione. Herein, we describe the development of a fluorescence-based high-throughput assay that allows the identification of thiol-reactive compounds. A thiol-containing fluorescent probe, MSTI, was synthesized and used to evaluate small molecules from the Library of Pharmacologically Active Compounds (LOPAC) collection of bioactive molecules. LOPAC compounds that are known to react with sulfur nucleophiles were identified with this assay, for example, irreversible protease inhibitors, nitric oxide-releasing compounds, and proton-pump inhibitors. The results confirm that both electrophilic and redox reactive compounds can be quickly identified in a high-throughput manner, enabling the assessment of screening libraries with respect to thiol-reactive compounds. PMID- 23446701 TI - Repetitive transcranial magnetic stimulation not beneficial in severe choreiform movements of Huntington disease. AB - Repetitive transcranial magnetic stimulation (rTMS) has been used therapeutically for reducing choreiform movements in patients with Huntington disease. There have been case studies reporting improvement in choreiform movements with administration of low-frequency rTMS lasting for a brief period. We report a case series where application of 7 consecutive sessions of bilateral low-frequency rTMS over the scalp area corresponding to supplementary motor area in patients with severe Huntington chorea did not reduce the intensity of choreiform movements even transiently. Hence, the proposed role of rTMS in reducing intensity of choreiform movements by altering neuronal plasticity may not hold true in severe cases. PMID- 23446702 TI - A rational insurance coverage policy for repetitive transcranial magnetic stimulation for major depression. AB - Although most health insurance plans do not cover repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression, coverage is increasing, with approval often granted on a case-by-case basis. Accordingly, it is important for physicians who are advocating for coverage on behalf of their patients to provide cogent arguments based on published data. Most patients presenting for rTMS have medication resistance that is beyond the Food and Drug Administration-approved indication of one failed but adequate trial of an antidepressant medication. However, recent naturalistic studies lend support to the proposition that rTMS is efficacious for more medication-resistant patients. PMID- 23446703 TI - Devosia epidermidihirudinis sp. nov. isolated from the surface of a medical leech. AB - A Gram-negative, rod-shaped organism, isolated from the surface of the medical leech Hirudo verbana was characterized phenotypically and genotypically. The calculated 16S rRNA gene sequence similarities to those of the most closely related species grouped strain E84(T) into the genus Devosia showing the highest similarities to Devosia limi (98.1 %), followed by Devosia psychrophila (97.9 %), Devosia neptuniae (97.3 %), and Devosia glacialis (97.5 %). Chemotaxonomic analyses showed that the major quinone was ubiquinone Q-10. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol and three glycolipids. The major fatty acid profile consisted of C18:1 omega7c 11-methyl, C19:0 cyclo omega8c, and C16:0, C18:0 and C18:1 omega7c with C18:0 3OH as hydroxylated fatty acid. This profile is very similar to those of the patterns reported for the already described Devosia species. The results of DNA-DNA hybridization, physiological and biochemical tests allowed both genotypic and phenotypic differentiation of strain E84(T) from all other Devosia species suggesting a novel species for which the name Devosia epidermidihirudinis sp. nov. is proposed, with the type strain E84(T) (=CIP 110375(T) = LMG 26909(T) = CCM 8398(T)). PMID- 23446704 TI - Reflection-mode multifocal optical-resolution photoacoustic microscopy. AB - Compared with single-focus optical-resolution photoacoustic microscopy (OR-PAM), multifocal OR-PAM utilizes both multifocal optical illumination and an ultrasonic array transducer, significantly increasing the imaging speed. A reflection-mode multifocal OR-PAM system based on a microlens array that provides multiple foci as well as an ultrasonic array transducer that receives the excited photoacoustic waves from all foci simultaneously is presented. Using a customized microprism to reflect the incident laser beam to the microlens array, the multiple optical foci are aligned confocally with the focal zone of the ultrasonic array transducer. Experiments show the reflection-mode multifocal OR-PAM is capable of imaging microvessels in vivo, and it can image a 6*5*2.5 mm3 volume at 16 MUm lateral resolution in ~2.5 min, which was limited by the signal multiplexing ratio and laser pulse repetition rate. PMID- 23446711 TI - [Presentation]. PMID- 23446706 TI - Analysis of maternal risk factors associated with congenital vertebral malformations. AB - STUDY DESIGN: A retrospective medical record review of cases with congenital vertebral malformations (CVMs) and controls with normal spine morphology. OBJECTIVE: To determine the relative contribution of maternal environmental factors (MEFs) during pregnancy to CVM development. SUMMARY OF BACKGROUND DATA: CVMs represent defects in formation and segmentation of somites occurring with an estimated incidence of between 0.13 and 0.50 per 1000 live births. CVMs may be associated with various phenotypes and represent significant morbidity due to pain and cosmetic disfigurement. METHODS: A multicenter retrospective medical record review of 229 cases with CVM and 267 controls with normal spine morphology between the ages of 1 and 50 years was performed to obtain the odds ratio (OR) of MEF related to CVM among cases versus controls. An imputation-based analysis was performed in which subjects with no documentation of MEF history were treated as "no maternal exposure." Univariate and multivariate analyses were conducted to calculate the OR. RESULTS: Of the 229 total cases, 104 cases had single or multiple CVMs without additional congenital malformations (group 1) and 125 cases had single or multiple CVMs and additional congenital malformations (group 2). Nineteen percent of total cases had an identified MEF. The OR for MEF history for group 1 was 6.0 (95% confidence interval, 2.4-15.1; P < 0.001) in the univariate analysis. The OR for MEF history in group 2 was 9.1 (95% confidence interval, 3.8 21.6, P < 0.001) in the univariate analysis. The results were confirmed in the multivariate analysis after adjusting for age, sex, and institution. CONCLUSIONS: These results support a hypothesis for an association between these MEFs during pregnancy and CVM and have implications for development of prevention strategies. Further prospective studies are needed to quantify association between CVMs and specific MEF. LEVEL OF EVIDENCE: 4. PMID- 23446710 TI - Parenchyma-sparing anatomical liver resection based on Hjortsjo's concept: a venous-drainage-guided approach to identify the ventral segment fissure. AB - PURPOSE: Anatomical liver resection is usually based on Couinaud's anatomical concept. In contrast, Hjortsjo's concept, which divides the right anterior section of the liver into ventral and dorsal segments by the vertical plane named the ventral segment fissure (VSF), has been rarely utilized for liver resection. Identification of the VSF is the most difficult step in liver resection based on Hjortsjo's concept. This study aimed to detail liver resection based on Hjortsjo's concept and report surgical outcomes of this procedure. METHODS: We reviewed the records of 166 consecutive patients who underwent liver resection between September 2009 and June 2012 at Kyoto Medical Center and identified seven liver resections in which Hjortsjo's concept was utilized. These patients consisted of four men and three women aged 55-79 years. Four patients had hepatocellular carcinoma and cirrhosis and three patients had metachronous colorectal liver metastasis. RESULTS: Liver resection along the VSF consisted of two extended left medial sectionectomies, three extended right posterior sectionectomies, and one Sg 7+8-dorsal resection by a venous-drainage-guided approach and one Sg 8-dorsal resection by a Glissonian approach. In all patients, the VSF was successfully identified as a congested or ischemic border on the liver surface. Mortality and major morbidity were nil. No patients underwent blood transfusion. After a median follow-up of 15 months, there were no deaths or local recurrence. CONCLUSIONS: Anatomical liver resection based on Hjortsjo's concept is feasible and advantageous over conventional liver resection because it preserves more parenchyma. The venous-drainage-guided approach is an effective method for identifying the VSF. PMID- 23446712 TI - [Executive functioning and evoked potentials P300 pre- and post- treatment in attention deficit hyperactivity disorder]. AB - INTRODUCTION: Evoked potentials P300 and the analysis of executive functions have shown their utility in the monitoring of patients with symptoms of attention deficit hyperactivity disorder (ADHD). PATIENTS AND METHODS: Neuropsychological profiles and evoked potentials P300 have been analysed for two groups of children with an ADHD treatment with atomoxetine and methylphenidate respectively. Correlations between P300 and the selected neuropsychological parameters are studied, and the differences between basal values and 1 year follow-up are analysed. Two groups were performed: a group of 22 children ADHD in the atomoxetine condition, and a group of 24 children ADHD in the methylphenidate condition. RESULTS: The results show a global improvement of all the parameters, in terms of executive function and P300 values in both, the atomoxetine and the methylphenidate group. CONCLUSION: Executive functions and evoked potentials P300 reflect an underlying processing and they are very useful in the clinical practice. This exploratory study shows the importance of designing personalized objective variables-based treatments. PMID- 23446713 TI - [Bases for the selection of pharmacological treatment in attention deficit hyperactivity disorder]. AB - AIMS: To collect some factors that can help the clinician to design a plan of pharmacologic treatment for children and adolescents with attention deficit hyperactivity disorder (ADHD). DEVELOPMENT: We did a literature search of current available studies on the pharmacological treatment of ADHD. Treatment of ADHD requires the design of a comprehensive and individualized plan for each patient, family and environment, which includes three main parts: psychoeducation and behavioral management training, academic support, and medication. Stimulants (methylphenidate) and non-stimulants (atomoxetine) are the two drugs approved in Spain for children and adolescents and then treatment in adults with ADHD. The effect size of stimulants (1.0) is higher than for atomoxetine (0.7-0.8). The methodology of the study, especially the duration, may affect the effect size. The range of NNT is 1.9 to 5.3, higher than other drugs for other disorders (antidepressants or antipsychotics). Some factors that impact the choice of medication for ADHD are: comorbidity, potential adverse effects (especially low appetite, insomnia, tics and potential abuse of medication), parental preference and patient need for action along the day or at specific times of day, need rapid onset of action, and any visa price of medication. CONCLUSIONS: There are some factors related to the patient and the features of ADHD, drug, and the patient's situation or environment which should be considered when selecting a treatment for ADHD. PMID- 23446714 TI - [Empathy, social cognition and autism spectrum disorders]. AB - From their earliest reports, Kanner and Asperger included the hierarchy of difficulties in socialisation as one of the key axes in persons affected with autism spectrum disorders (ASD), associated to development delay or language disorders and restricted interests. This deficiency in social cognition has been related with a deficit in empathy. The theory of deficit in empathising and hypersystematisation provides a coherent, comprehensible explanation with which to partially understand the genesis of these disorders. Empathy is an essential component for emotional experiencing and social interaction, and denotes an affective response to mental states that are either perceived directly or imagined or are feelings inferred by another person. It enables us to understand, feel and respond appropriately to social stimuli, thereby giving rise to an adequate socialisation. Empathy has been considered a synonym of emotional contagion, mimicry, sympathy, compassion and empathic interest. Although these are concepts that are related and necessary for the development of adequate social cognition, they are not the same; nonetheless, they are all essential for the development of empathy or its consequences. Empathy allows individuals to 'feel with', whereas sympathy, compassion and empathic interest are related with 'feeling for' or feeling what is appropriate. Studies conducted in persons with ASD have shown them to have a low empathy quotient. In this work, different aspects of empathy, its components, its neurobiological foundations, the manifestations related with its deficit and its relation with the development of ASDs are all analysed. PMID- 23446715 TI - [Perception-production relations in substitution phonological processes in children with language disorders]. AB - It is generally agreed that the auditory perception skills of children with developmental language disorders are more limited than those of typically developing children. It is not easy to determine exactly how the capacity to discriminate and the capacity to pronounce phonemes influence each other in children with language disorders. For most authors, the inability to discriminate certain phonemes accurately causes a developmental delay in pronunciation, whereas others claim the influence is mutual. The aim of this study is to determine in which consonants perceptive difficulty is more likely to occur and in which cases there is a greater probability of difficulty when it comes to articulating them. The sample used in the study consisted of 86 children with a mean age of 4 years and 7 months. The phonological processes involved in simplifying speech were identified. Their errors were used as the basis on which to construct and apply a specific speech perception test. The relationship between the articulatory and perceptive skills of children with substitutive processes were analysed by means of two comparisons: first, in all the processes detected taken as a whole and, second, in the three most frequent substitutive processes. These analyses were carried out to determine whether the nature of the consonant implied a greater probability of perceptive difficulty. The findings provide information about a relation between the articulatory and perceptive skills, and about whether the nature of the consonant determines a higher probability of perceptive or articulatory difficulties. These results can be of value in the assessment, design and effectiveness of speech therapy programmes. PMID- 23446716 TI - [Inferences and verbal comprehension in children with developmental language disorders]. AB - We review the concept of inference in language comprehension -both oral and written- recalling the different proposals of classification. We analyze the type of difficulties that children might encounter in their application of the inferences, depending on the type of language or development pathology. Finally, we describe the proposals for intervention that have been made to enhance the ability to apply inferences in language comprehension. PMID- 23446717 TI - [Cognitive development in Dravet's syndrome as a model of epileptic encephalopathy]. AB - Cognitive development in Dravet's syndrome is accompanied by a slowing or stagnation of the cognitive abilities during childhood. The fact that the syndrome is classified within the group of epileptic encephalopathies suggests that the epileptiform activity plays an important role in the genesis of the cognitive disorders. In this review it is shown that the epileptic phenotype and the critical and intercritical activity do not, by themselves, explain the cognitive development in children with Dravet's syndrome. Substantial changes in the treatment, with impact on cognitive development, will probably come with therapies that act by directly modifying the pathophysiology of the syndrome rather than its consequences. PMID- 23446718 TI - [Autism, epilepsy and tuberous sclerosis complex: a functional model linked to mTOR pathway]. AB - INTRODUCTION: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. Brain disorders are the origin of more frequent and severe problems and include infantile spasms, intractable epilepsy, brain tumors, cognitive disabilities, and autism. TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. AIM. To review the etiopathogenic mechanisms and the natural course of the association of autism and epilepsy in TSC. DEVELOPMENT: Both the clinical and the neuroimaging findings of TSC, including early onset epilepsy and the localization of cortical tubers in the temporal lobes, and the molecular understanding of the mTOR signaling pathway, not only involved in cell growth, but also in synaptogenesis, synaptic plasticity and neuronal functioning, have suggested a multimodal origin of autism in these patients. CONCLUSIONS: A greater understanding of the pathogenetic mechanisms underlying autism in TSC could help in devising targeted and potentially more effective treatment strategies. Antagonism of the mTOR pathway with rapamycin and everolimus may provide new therapeutic options for these TSC patients. PMID- 23446719 TI - [Is the early brain organisation of spatial information conveyed by tactile stimuli performed in different ways in congenital and acquired blind children? A pilot study]. AB - Cortical reorganization after congenital blindness is not sufficiently known yet it does offer an optimum window of opportunity to study the effects of absolute sensorial deprivation. Cross-modality in people with blindness has been documented, but it may differ in congenital blindness and in early blindness. Vibrotactile passive stimulation of lines and letters generates different electroencephalographic patterns with different source localizations in two children with blindness, aged 9 and 10, respectively with congenital blindness and early blindness with some remnants of vision. Most of the brain electrical activity is centered in auditive areas in P50 and P100 in the case of the child with congenital blindness, while the other shows activity in multiple areas. Reaction times to letters are shorter than to lines of different orientation in both children. PMID- 23446721 TI - [The genetic bases of neurodevelopmental disorders]. AB - In the last decade, progress made in genetics is questioning the current implicit nosological model in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) and the International Classification of Diseases, tenth revision. Both the categorical nature and the comorbidity detected on applying diagnostic criteria become unsustainable in the light of the genetic architecture that is emerging from studies being conducted on the genetics of mental disorders. The classical paradigms -one gene for one disease- or even a specific distinctive genetic pattern for each condition, are concepts restricted to specific cases. In this review the objective is to describe the current scenario that has arisen following the latest advances in genetics. The lines of work being traced by research both in the present and in the near future include: the identification of variations in the number of copies (both frequent and rare), indiscriminately linked to different disorders; the concurrence of multiple variants for a single disorder; the double hit phenomenon; and epigenetic modulation. The new version of the DSM, fully aware of the deficiencies in the current model, will mark a turning point that, while somewhat timid, is decidedly oriented towards incorporating a dimensional conception of mental disorders. PMID- 23446722 TI - Deconstructing autism spectrum disorders: clinical perspective. AB - Autism spectrum disorder (ASD) is a term used to describe a heterogeneous group of children whose behaviorally defined characteristics overlap with the clinical manifestations of a variety of distinct behaviorally defined developmental disorders. ASD has many etiologies and strong but complex genetic and molecular underpinnings supporting genetic and phenotypic heterogeneity. Clinical and biological heterogeneity in ASD is consistent with the view of autism spectrum disorders as the expression of atypical brain development resulting in variable clinical manifestations that reflect differences in specific genetic and molecular pathways. It is likely that there are risk genes and early environmental risk factors for ASD that contribute to an altered trajectory of brain and behavioral development. These alterations are hypothesized to lead to altered social interaction and consequently to abnormal development of the neural networks critical for social and communicative interaction. This amplifies the abnormal socio-communicative developmental process leading to the full ASD syndrome. The hope is that interventions can alter these early developmental processes and put an infant back on a more typical developmental trajectory. In this discussion an overview of the limitations of the triad of behaviors used to diagnose ASD, specifically from the perspective of how these issues impact diagnosis and treatment of children with ASD will be presented and the clinical boundaries of the autism spectrum will be explored. PMID- 23446723 TI - [Interest of electroencephalogram in autism]. AB - Autism spectrum disorders (ASD) have been associated with physiopathology in cerebral organization and function. Electroencephalography is a noninvasive technique that provides information about brain electrocortical activity. Electroencephalographic (EEG) studies using power spectra have documented differences associated with ASD, particularly in frontal areas that have been functionally linked to cognitive functions that are disrupted in individuals with ASD. Furthermore, EEG studies confirm coherence changes in individuals with ASD. Many studies have also reported high rates of interictal epileptiform EEG abnormalities in children with ASD with or without history of seizures. Several polysomnography studies have confirmed the presence of disrupted sleep architecture in children with ASD. Polysomnographic abnormalities include reduction of REM sleep, longer sleep latency, increased arousals, lower sleep efficiency, increased stage 1 sleep and decreased slow wave sleep as well as decreased density of spindle activity. The objective of this review is to present research data on the EEG findings in patients with ASD, with emphasis on their power EEG, coherence EEG, epileptiform EEG abnormalities and sleep disorders. PMID- 23446724 TI - [Co-occurrence of anxiety and autism. The social error and allostatic load hypotheses]. AB - INTRODUCTION. The concept of comorbidity in neurodevelopmental disorders like autism is sometimes ambiguous. The co-occurrence of anxiety and autism is clinically significant, yet it is not always easy to determine whether it is a 'real' comorbidity, where the two comorbid conditions are phenotypically and aetiologically identical to what that anxiety would mean in persons with a neurotypical development, whether it is an anxiety that has been phenotypically modified by the pathological processes of the autism spectrum disorders, thus resulting in a specific variant of these latter, or whether we are dealing with a false comorbidity resulting from rather inaccurate differential diagnoses. DEVELOPMENT. The article puts forward two hypotheses to explain this co occurrence, which provide each other with feedback and are little more than our reflections on the scientific evidence we have available today, but expressed aloud. The first is the 'social error' hypothesis, which considers that the maladjustments in the social behaviour of persons with autism (which arises from alterations affecting the processes involved in social cognition) help to aggravate anxiety in autism. The second hypothesis, referring to allostatic load, holds that anxiety is a response to chronic stress, wear or exhaustion that is produced by the hyperactivation of certain structures in the limbic system. CONCLUSIONS. The prototypical manifestations of anxiety present in the person with autism are not always related with the same biopsychosocial variables as those observed in persons without autism. Evidence points to hyper-reactive flee or-fight responses (hypervigilance) when the person finds him or herself outside their comfort zone, and supports the hypotheses of 'social error' and of decompensation of the allostatic mechanism that makes it possible to cope with stress. PMID- 23446725 TI - [Development and follow-up of autism spectrum disorders]. AB - INTRODUCTION: Autism spectrum disorders are neurodevelopmental disorders with qualitative impairment in functioning domains and areas of human characteristically. It is important to know how is the outcome in the adolescent and adult age of these people to provide the services and support needed. DEVELOPMENT: We review the most important follow-up studies have been conducted in autism spectrum disorders, realizes the kind of designs that have been carried out and the results obtained in different areas of development and independent functioning. CONCLUSIONS: Improvements in outcome but these are generally poor in the population. A small proportion close or around 25% are experiencing better outcome. These cases generally correspond to what is known as high-functioning autism or Asperger syndrome. PMID- 23446726 TI - [High intellectual capacity, problem-solving and creativity]. AB - The aim of the study is focused on the characteristics and components of creativity as a multidimensional construct in the context of intelligence, divergent thinking and problem solving, and their incorporation into the definition and explanation of intellectual functioning of giftedness and talent. It shows the progress of the investigation from the initial postulates of Guilford about the nature and cognitive processes involved in the creative act, its features and components, development and differential expression in the high intellectual ability, and the neurological correlates neuropsychological research is beginning to show. We present the results obtained with 41 participants with high intellectual capacity profiles of giftedness or talent of 6 to 14 years. We measure their cognitive skills through BADyG or DAT tests, and creative skills by the Torrance Test of Creative Thinking (TTCT), in two measuring points. Analyses show comparatively among high ability profiles: 1) the creative measurement stability between the two time points, 2) statistically significant differences between the creative components of fluency, flexibility and originality, related to the profiles of giftedness or talent (convergent or divergent), 3) the statistically significant changes among the scores of the creative components, at all ages studied. PMID- 23446727 TI - [From inattentive-type attention deficit hyperactivity disorder to the restrictive type]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a very heterogeneous neurobiological condition. It is the most common neurodevelopmental disorder in the childhood population. Its prevalence is estimated to be 3-6% in school-age children. AIM. To review the characteristics of patients with inattentive subtype ADHD, including those who could be grouped in a more homogenous subtype which the DSM-5 proposes for classification as the restrictive subtype. DEVELOPMENT: The characteristic triad of symptoms consists of attention deficit, hyperactivity and impulsivity. The diagnostic criteria are defined in the DSM-IV-TR. For those with deterioration due to ADHD with no significant hyperactivity problems, this manual offers a confusing diagnostic label. Indeed, the neurobiological substrate underlying the diverse subtypes seems to be different in certain aspects, since the frontostriatal circuit appears to be more affected in combined ADHD, while the frontoparietal circuit is more compromised in the inattentive subtype. For these and other reasons, the DSM-5 will reformulate the different subtypes of ADHD and will probably include a new subgroup that will comprise those patients who satisfy at least six inattention criteria and fewer than two criteria for hyperactivity-impulsivity (restrictive ADHD). CONCLUSIONS: The definition of this subgroup could make it easier to detect some patients who have so far received little attention from the point of view of both research and clinical practice. PMID- 23446728 TI - [Moderators of psychosocial intervention in preschoolers with attention deficit hyperactivity disorder]. AB - INTRODUCTION. Although the diagnosis of attention deficit hyperactivity disorder in preschoolers is increasingly common, relatively little is known about the treatment in this developmental period. Some side effects of pharmacological intervention discourage its use as first-line intervention at this age. AIM. To analyze the effectiveness of psychosocial interventions designed to respond to the needs presented by these children, especially those based on cognitive behavioral and socio-constructivist models. DEVELOPMENT. The review highlights the effectiveness of parent training programs, alone or combined with interventions at school and with the children. Communication between parents and teachers has been shown to be a determinant of their success. Another aspect that seems to favor the efficacy of treatment in this stage of education is the inclusion in the school curriculum of mediated activities aimed at developing self-regulation. CONCLUSIONS. In preschoolers with attention deficit hyperactivity disorder, preventive action based on these models, increasing the intensity of the intervention depending on the student's response, can help to avoid future problems. PMID- 23446729 TI - [The neuroanatomy of attention deficit hyperactivity disorder in adults: structural and functional neuroimaging findings]. AB - The objective of this work is to review the existing literature on findings from structural and functional magnetic resonance and connectivity. For a long time it was thought that children 'grew out' of attention deficit hyperactivity disorder (ADHD) on reaching adolescence. Yet, it is now known that up to 70% of children who present ADHD in childhood go on to present symptoms in the behavioural and cognitive sphere in adulthood. Neuroimaging studies conducted in adults with ADHD have shown alterations in the brain at the structural and functional levels, and also in terms of connectivity. These findings have been observed mainly in the inferior frontal and dorsolateral prefrontal cortex, as well as in striatal, anterior cingulate, parietotemporal and cerebellar regions. However, certain inconsistencies have also been found, which may be related with the presence of comorbidity, a history of medication, gender-related differences and the small size of the sample used in some studies. Differences have also been noted in relation to studies carried out in children with ADHD. Hence the importance for future studies of avoiding the existence of variables that can affect the findings in ADHD in adults and, moreover, of being able to determine whether the anatomical and functional deficits continue into adulthood. PMID- 23446730 TI - Synthesis of imidazo and benzimidazo[2,1-a]isoquinolines by rhodium-catalyzed intramolecular double C-H bond activation. AB - The rhodium-catalyzed intramolecular direct arylation of imidazole and benzimidazole derivatives via double C-H bond activation is described. This approach provides new access to a wide range of imidazo and benzimidazo[2,1 a]isoquinoline derivatives in moderate to high yields. This reaction provides an alternative method to the known Pd-catalyzed intramolecular oxidative cross coupling reactions. PMID- 23446731 TI - Genome-wide analysis of DNA methylation in tongue squamous cell carcinoma. AB - Tongue squamous cell carcinoma (TSCC) is one of the most common types of oral cancer; however, its molecular mechanisms remain unclear. In this study, methylated DNA immunoprecipitation (MeDIP) coupled with methylation microarray analysis was performed to screen for aberrantly methylated genes in adjacent normal control and TSCC tissues from 9 patients. Roche NimbleGen Human DNA Methylation 385K Promoter Plus CpG Island Arrays were used to detect 28,226 CpG sites. A total of 1,269 hypermethylated CpG sites covering 330 genes and 1,385 hypomethylated CpG sites covering 321 genes were found in TSCC tissue, compared to the adjacent normal tissue. Furthermore, we chose three candidate genes (FBLN1, ITIH5 and RUNX3) and validated the DNA methylation status by methylation specific PCR (MS-PCR) and the mRNA expression levels by reverse transcription PCR (RT-PCR). In TSCC tissue, FBLN1 and ITIH5 were shown to be hypermethylated and their expression was found to be decreased, and RUNX3 was shown to be hypomethylated, however, its mRNA expression was found to be increased. In addition, another three genes (BCL2L14, CDCP1 and DIRAS3) were tested by RT-PCR. In TSCC tissue, BCL2L14 and CDCP1 expressions were markedly upregulated, and DIRAS3 expression was significantly downregulated. Our data demonstrated that aberrant DNA methylation is observed in TSCC tissue and plays an important role in the tumorigenesis, development and progression of TSCC. PMID- 23446732 TI - Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. AB - IMPORTANCE: Untreated depression during pregnancy has been associated with increased morbidity and mortality for both mother and child and, as such, optimal treatment strategies are required for this population. CONTEXT: There are conflicting data regarding potential risks of prenatal antidepressant treatment. OBJECTIVE: To determine whether prenatal antidepressant exposure is associated with risk for selected adverse pregnancy or delivery outcomes. DATA SOURCES MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and the Cochrane Library were searched from their start dates to June 30, 2010. STUDY SELECTION English-language studies reporting outcomes associated with pharmacologic treatment during pregnancy were included. We reviewed 3074 abstracts, retrieved 735 articles, and included 23 studies in this meta-analysis. DATA EXTRACTION: Study design, antidepressant exposure, adjustment for confounders, and study quality were extracted by 2 independent reviewers. RESULTS: There was no significant association between antidepressant medication exposure and spontaneous abortion (odds ratio [OR], 1.47; 95% CI, 0.99 to 2.17; P = .055). Gestational age and preterm delivery were statistically significantly associated with antidepressant exposure (mean difference [MD] [weeks], -0.45; 95% CI, -0.64 to -0.25; P < .001; and OR, 1.55; 95% CI, 1.38 to 1.74; P < .001, respectively), regardless of whether the comparison group consisted of all unexposed mothers or only depressed mothers without antidepressant exposure. Antidepressant exposure during pregnancy was significantly associated with lower birth weight (MD [grams], -74; 95% CI, -117 to -31; P = .001); when this comparison group was limited to depressed mothers without antidepressant exposure, there was no longer a significant association. Antidepressant exposure was significantly associated with lower Apgar scores at 1 and 5 minutes, regardless of whether the comparison group was all mothers or only those who were depressed during pregnancy but not exposed to antidepressants. CONCLUSIONS AND RELEVANCE: Although statistically significant associations between antidepressant exposure and pregnancy and delivery outcomes were identified, group differences were small and scores in the exposed group were typically within the normal ranges, indicating the importance of considering clinical significance. Treatment decisions must weigh the effect of untreated maternal depression against the potential adverse effects of antidepressant exposure. PMID- 23446733 TI - Release of ANP and fat oxidation in overweight persons during aerobic exercise in water. AB - Exercise in water compared to land-based exercise (LE) results in a higher release of natriuretic peptides, which are involved in the regulation of exercise induced adipose tissue lipolysis. The present study was performed to compare the release of atrial natriuretic peptide (ANP) and free fatty acids (FFA) during prolonged aerobic water-based exercise (WE) with the release after an identical LE. 14 untrained overweight subjects performed 2 steady state workload tests on the same ergometer in water and on land. Before and after exercise, venous blood samples were collected for measuring ANP, FFA, epinephrine, norepinephrine, insulin and glucose. The respiratory exchange ratio (RER) was determined for fat oxidation.The exercises resulted in a significant increase in ANP in LE (61%) and in WE (177%), and FFA increased about 3-fold in LE and WE with no significant difference between the groups. Epinephrine increased, while insulin decreased similarly in both groups. The RER values decreased during the exercises, but there was no significant difference between LE and WE. In conclusion, the higher ANP concentrations in WE had no additional effect on lipid mobilization, FFA release and fat oxidation. Moderate-intensity exercises in water offer no benefit regarding adipose tissue lipolysis in comparison to LE. PMID- 23446734 TI - The calcineurin-NFAT pathway negatively regulates megakaryopoiesis. AB - The calcium regulated calcineurin-nuclear factor of activated T cells (NFAT) pathway modulates the physiology of numerous cell types, including hematopoietic. Upon activation, calcineurin dephosphorylates NFAT family transcription factors, triggering their nuclear entry and activation or repression of target genes. NFATc1 and c2 isoforms are expressed in megakaryocytes. Moreover, human chromosome 21 (Hsa21) encodes several negative regulators of calcineurin-NFAT, candidates in the pathogenesis of Down syndrome (trisomy 21)-associated transient myeloproliferative disorder and acute megakaryoblastic leukemia. To investigate the role of calcineurin-NFAT in megakaryopoiesis, we examined wild-type mice treated with the calcineurin inhibitor cyclosporin A and transgenic mice expressing a targeted single extra copy of Dscr1, an Hsa21-encoded calcineurin inhibitor. Both murine models exhibited thrombocytosis with increased megakaryocytes and megakaryocyte progenitors. Pharmacological or genetic inhibition of calcineurin in mice caused accumulation of megakaryocytes exhibiting enhanced 5-bromo-2'-deoxyuridine uptake and increased expression of messenger RNAs encoding CDK4 and G1 cyclins, which promote cell division. Additionally, human megakaryocytes with trisomy 21 show increased proliferation and decreased NFAT activation compared with euploid controls. Our data indicate that inhibition of calcineurin-NFAT drives proliferation of megakaryocyte precursors by de-repressing genes that drive cell division, providing insights into mechanisms of normal megakaryopoiesis and megakaryocytic abnormalities that accompany Down syndrome. PMID- 23446735 TI - Novel diagnostic assays for heparin-induced thrombocytopenia. AB - Laboratory testing for heparin-induced thrombocytopenia (HIT) has important shortcomings. Immunoassays fail to discriminate platelet-activating from nonpathogenic antibodies. Specific functional assays are impracticable due to the need for platelets and radioisotope. We describe 2 assays that may overcome these limitations. The KKO-inhibition test (KKO-I) measures the effect of plasma on binding of the HIT-like monoclonal antibody KKO to platelet factor 4 (PF4)/heparin. DT40-luciferase (DT40-luc) is a functional test comprised of a B cell line expressing FcgammaRIIa coupled to a luciferase reporter. We compared these assays to polyspecific and immunoglobulin (Ig)G-specific PF4/heparin enzyme linked immunosorbent assays (ELISAs) in samples from 58 patients with suspected HIT and circulating anti-PF4/heparin antibodies. HIT was defined as a 4Ts score >= 4 and positive (14)C-serotonin release assay. HIT-positive plasma demonstrated greater mean inhibition of KKO binding than HIT-negative plasma (78.9% vs 26.0%; P < .0001) and induced greater luciferase activity (3.14-fold basal vs 0.96-fold basal; P < .0001). The area under the receiver-operating characteristic curve was greater for KKO-I (0.93) than for the polyspecific (0.82; P = .020) and IgG specific ELISA (0.76; P = .0044) and for DT40-luc (0.89) than for the IgG specific ELISA (P = .046). KKO-I and DT40-luc showed better discrimination than 2 commercially available immunoassays, are simple to perform, and hold promise for improving the specificity and feasibility of HIT laboratory testing. PMID- 23446736 TI - A new approach for eradication of residual lymphoma cells by host nonreactive anti-third-party central memory CD8 T cells. AB - Generation of T cells endowed with graft-versus-leukemia (GVL) and depleted of graft-versus-host (GVH) activity represents a highly desirable goal in bone marrow transplantation (BMT). Here, we demonstrate that donor anti-third-party CD8 T cells with central memory phenotype (Tcm) exhibit marked GVL reactivity through a unique T-cell receptor-independent mechanism. Thus, in a residual disease mouse model, Tcm therapy following autologous BMT led to significant survival prolongation, with 30% to 40% of the treated mice displaying long-term tumor-free survival. A more impressive finding was that infusion of donor Tcm in an allogeneic model rapidly eliminated residual lymphoma cells and led to long term survival of 100% in the absence of GVH disease. Collectively, the strong GVL reactivity of anti-third-party Tcm, coupled with their demonstrated enhancement of bone marrow allografting, suggests that the use of Tcm therapy in conjunction with allogeneic T-cell-depleted BMT could be of particular benefit in patients with B-cell malignancies who cannot tolerate intensive myeloablative conditioning. PMID- 23446737 TI - Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs). OBJECTIVE: We reasoned that chloroquine, based on its ability to inhibit autophagy and block lysosomal degradation of the bone morphogenetic protein type II receptor (BMPR-II), might exert beneficial effects in this disease. METHODS AND RESULTS: PAH was induced in male Sprague-Dawley rats by administering monocrotaline. The induction of PAH was associated with changes in lung expression of LC3B-II, ATG5, and p62, consistent with increased autophagy, and decreased BMPR-II protein expression. Administration of chloroquine prevented the development of PAH, right ventricular hypertrophy, and vascular remodelling after monocrotaline, and prevented progression of established PAH in this model. Similar results were obtained with hydroxychloroquine. Chloroquine treatment increased whole lung and PASMC p62 protein levels consistent with inhibition of autophagy, and increased levels of BMPR-II protein. Chloroquine inhibited proliferation and increased apoptosis of PASMCs in vivo. In cultured rat PASMCs we confirmed that chloroquine both inhibited autophagy pathways and increased expression of BMPR-II protein via lysosomal inhibition. Consistent with the in vivo findings, chloroquine inhibited the proliferation and stimulated apoptosis of rat PASMCs in vitro, with no effect on endothelial cell proliferation or survival. Moreover, direct inhibition of autophagy pathways by ATG5 small interfering RNA knockdown inhibited proliferation of rat PASMCs. CONCLUSIONS: Chloroquine and hydroxychloroquine exert beneficial effects in experimental PAH. The mechanism of action includes inhibition of autophagy pathways and inhibition of lysosomal degradation of BMPR-II. PMID- 23446738 TI - Discovery and characterization of alamandine: a novel component of the renin angiotensin system. AB - RATIONALE: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7). OBJECTIVE: To characterize a novel component of the RAS, alamandine. METHODS AND RESULTS: Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand beta-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/beta hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. CONCLUSIONS: The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders. PMID- 23446739 TI - Gastric antral polyps: a manifestation of portal hypertensive gastropathy. PMID- 23446740 TI - Association of Helicobacter pylori infection with inflammatory cytokine expression in patients with gallbladder cancer. AB - AIM: Gallbladder cancer (GBC) may be associated with Helicobacter pylori. The present study was designed to analyze the association of cytokine expression with H. pylori in patients with GBC. METHODS: GBC tissue sample and 5 mL blood were collected from each of 54 GBC patients. H. pylori was identified in tissue samples using biochemical tests, histology, culture, nested polymerase chain reaction (PCR), and partial genome sequencing. Tissue samples were categorized as H. pylori-positive (case) and H. pylori-negative groups (control) on the basis of nested PCR of tissue sample. Cytokines interleukin 1-beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin 5 (IL-5) were assayed in blood samples using ELISA. RESULTS: Presence of H. pylori was confirmed in 18 (33 %) of 54 GBC tissue samples. Levels of IL-1beta (p = 0.001) and TNF-alpha (p = 0.01) were significantly elevated in H. pylori positive GBC compared to the control group. IFN-gamma and IL-5 levels did not significantly differ between the two groups. CONCLUSIONS: H. pylori DNA was detected in the gallbladder of a third of GBC patients and was associated with higher circulating levels of some cytokines. PMID- 23446741 TI - Intrathoracic papillary thyroid carcinoma from occult primary disease. AB - A 42-year-old woman undertook a chest radiograph for a routine evaluation prior to surgery for pelvic endometrioma, which revealed a right paratracheal mass slightly displacing the trachea to the left. CT of the thorax disclosed a well demarcated, heterogeneous, lobular, right paratracheal mass, bearing punctate, coarse, and curvilinear calcifications. MRI further revealed two components within the lesion: a larger, cystic, exhibiting thin septations, and a solid component at the lower part exhibiting strong enhancement. No continuity of the mass with the thyroid gland was demonstrated, which had normal size and no focal lesion. Histological examination of the resected mass disclosed lymph node tissue infiltrated by papillary thyroid carcinoma; subsequent total thyroidectomy revealed small foci of papillary carcinoma within both lobes of the thyroid gland. Ablative dose I-131 was administered and the patient was put on daily thyroid supplements. PMID- 23446742 TI - The applied basic research of systemic lupus erythematosus based on the biological omics. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies directed against nuclear self-antigens and circulating immune complexes. This results in damages to various organs or systems, including skin, joints, kidneys and the central nervous system. Clinical manifestations of SLE could be diverse, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures and arthritis. The complicated pathogenesis and varied clinical symptoms of SLE pose great challenges in the diagnosis and monitoring of this disease. Unfortunately, the etiological factors and pathogenesis of SLE are still not completely understood. It is noteworthy that recent advances in our understanding of the biological omics and emerging technologies have been providing new tools in the analyses of SLE, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics and so on. In this article, we summarize our current knowledge in this field for a better understanding of the pathogenesis, diagnosis and treatment for SLE. PMID- 23446743 TI - An interleukin-33 gene polymorphism is a modifier for eosinophilia in rats. AB - In previous studies, we identified a loss-of-function mutation in the Cyba gene as the primary cause of hereditary eosinophilia in the Matsumoto Eosinophilia Shinshu (MES) rat strain. We also identified a modifier locus for eosinophilia named eos3 in rats. In this study, we examined the interleukin-33 (Il33) gene as a candidate for the eos3 and found a missense nucleotide substitution in the gene, which resulted in a G171S amino-acid substitution in the IL-33 protein. Recombinant IL-33 isoform with the G171S substitution had approximately 50% of activity of normal isoform in NF-kappaB-dependent reporter assay, and reduced bioactivity (~65% of normal) to provoke eosinophilia when injected into mice. In a genetic association study using (ACI * MES) * MES backcross rats, we found that the effects of polymorphic Il33 alleles on blood eosinophil level were manifested only in rats with loss of Cyba function. In these rats, the blood eosinophil level was significantly lower (~50%) in heterozygotes for the ACI allele of Il33 compared with homozygotes for the MES allele. Oddly, however, eosinophilic MES rats had blood IL-33 content below the detectable limits. These results suggest that the Il33 gene polymorphism could be a modifier of eosinophilia in rats. PMID- 23446744 TI - Total effects of contact and residual exposure of bifenthrin and lambda cyhalothrin on the predatory mite Galendromus occidentalis (Acari: Phytoseiidae). AB - Pyrethroid insecticides are generally regarded as acutely toxic to predatory phytoseiid mites; however, persistence of hull split spray pyrethroid residues on almond trees and their effects on phytoseiids have not been quantified over time. Hull split, the separation of the almond hull along the suture, exposes the new crop nuts to infestation by Amyelois transitella (Walker) larvae, and is the preferred timing for insecticides applied for their control. Galendromus occidentalis (Nesbitt) is the most important phytoseiid biocontrol agent for web spinning spider mites in California (USA) almond orchards, and the impact of bifenthrin and lambda-cyhalothrin pyrethroid residue on their survival, fertility, and fecundity was determined. The total effects of direct contact with esfenvalerate, permethrin, bifenthrin and lambda-cyhalothrin were also evaluated for comparison. The total effects (E) of direct contact treatments of the four pyrethroids ranged from 77.8 % for esfenvalerate to 98.8 % for bifenthrin. Both bifenthrin and lambda-cyhalothrin twig residue would be considered harmful (IOBC class 4) following field application at hull split timing. Bifenthrin twig residue would be considered slightly harmful (IOBC class 2) for up to 3.5 months and harmless (IOBC class 1) after 6 months. lambda-cyhalothrin residue would be considered moderately harmful (IOBC class 3) for up to 3.5 months following application and harmless (IOBC class 1) after 6 months. Bifenthrin and lambda cyhalothrin twig residue on treated trees significantly reduced G. occidentalis female survival for up to 6 months post-treatment, however total effects (E) classify these residues as harmless (IOBC class 1) after 6 months. Harmful effects of direct and residual exposure following application have implications for the use of these pyrethroids in an integrated mite management program for perennial crops. PMID- 23446745 TI - Percutaneous radiofrequency ablation of renal cell carcinomas in patients with von Hippel Lindau disease: indications, techniques, complications, and outcomes. AB - Renal cell carcinoma (RCC) in patients with von Hippel Lindau (VHL) disease tends to be multifocal, bilateral, and recur or develop new tumors after removal. These characteristics make treating hereditary RCCs difficult for urologists or radiologists compared to treating a sporadic RCC. Radiofrequency ablation (RFA) is a minimally-invasive treatment for small hereditary RCCs associated with a low complication rate and a minimal decrease in renal function. No RFA guidelines have been established about what to treat and when and how to ablate RCCs in patients with VHL disease. Besides, reports on complications and treatment outcomes in this patient group are rare. The purpose of this review is to discuss the indications, techniques, complications, and outcomes of RFA in treating RCC in patients with VHL disease. PMID- 23446746 TI - Damage to pig bile duct caused by intraluminal brachytherapy using a (125)I ribbon. AB - BACKGROUND: Stent occlusion by tumor ingrowth or overgrowth is the main cause of jaundice recurrence after metal stent insertion in patients with malignant obstructive jaundice (MOJ). The application of intraluminal brachytherapy (ILBT) in patients with MOJ results in local control of malignant tumors, which prolong stent patency. PURPOSE: To evaluate the safety of ILBT in pig bile ducts using ribbons of iodine-125 ((125)I) seeds. MATERIAL AND METHODS: Sixteen healthy pigs were randomly assigned to four groups of four pigs each. A (125)I seed ribbon was implanted into the common bile duct of each animal through an incision in the duct wall, and was fixed by suturing. The four groups of animals were sacrificed at 15, 30, 60, and 120 days after ribbon implantation, respectively. Serum bilirubin concentrations, alanine aminotransferase concentrations, and white blood cell counts before and after implantation were compared within each group. Pathological changes to the bile duct wall were observed using a light microscope. Morphological changes in biliary epithelial cells and organelles were observed with electron microscopy. RESULTS: (125)I ribbons were successfully implanted in all animals without surgery-related death. We found no significant difference in pre- and post-implant serum bilirubin, alanine aminotransferase, or white blood cell counts. Light and electron microscopy showed that the most severe bile duct damage occurred in the 15-day group, which exhibited necrosis and detachment of numerous epithelial cells, and infiltration of inflammatory cells. Repair and proliferation of the bile duct epithelium began 30 days after implantation and was nearly complete at 60 days. CONCLUSION: This study demonstrated the safety of ILBT using a (125)I ribbon in the pig bile duct. (125)I seed ribbons may be used in the treatment of MOJ in humans. PMID- 23446747 TI - Enhancement characteristics of retroperitoneal lymphomatous lymph nodes. AB - BACKGROUND: Previous studies of CT enhancement of lymphomatous lymph nodes (LLN) of the neck and the mediastinum showed that the LLN had lower enhancement values than normal lymph nodes. PURPOSE: To elucidate the contrast medium enhancement curves of LLN in the retroperitoneum by comparing the curves of LLN with those of normal lymph nodes, to test whether differences between these curves could be of diagnostic value, and to compare the present enhancement curves of LLN of the retroperitoneum with the curves of LLN of the neck and the mediastinum from previous similar investigations. MATERIAL AND METHODS: Twenty-eight consecutive patients with LLN of the retroperitoneum (three with Hodgkin's lymphoma [HL]) and 21 control patients with sarcomas and thus presumably normal retroperitoneal nodes underwent dynamic CT examinations. The previous, similar investigation of lymph nodes of the neck comprised 28 patients with LLN and the investigation of mediastinal lymph nodes comprised 24 patients with LLN. RESULTS: The enhancement curves of the retroperitoneal LLN had significantly lower attenuation than those of the retroperitoneal control nodes. A combination of peak contrast value and time to peak adjusted to total body weight yielded a diagnostic accuracy which at the best showed a sensitivity of 90.5% with a specificity of 82.6%. The LLN of the retroperitoneum had higher attenuation values than corresponding nodes of the mediastinum but no significant difference was found between LLN of the retroperitoneum and LLN of the neck in previous similar investigations. CONCLUSION: The comparison of enhancement curves of retroperitoneal LLN with retroperitoneal control nodes showed a marked similarity with and substantiates our previous findings in lymph nodes of the neck and of the mediastinum. The best diagnostic accuracy was achieved by combining the parameters peak contrast value and time to peak and adjusting these values to the body weight. Peak enhancement of the retroperitoneal LLN was higher and arrived earlier than that of the mediastinal nodes from the previous investigation. PMID- 23446748 TI - The multislice CT findings of renal carcinoma associated with XP11.2 translocation/TFE gene fusion and collecting duct carcinoma. AB - BACKGROUND: Renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusion (Xp11.2/TFE RCC), and collecting duct carcinoma (CDC) are uncommon subtypes of renal cell carcinomas. PURPOSE: To investigate the multislice CT (MSCT) characteristics of these two tumor types. MATERIAL AND METHODS: Nine patients with Xp11.2/TFE RCC and 10 patients with CDC were studied retrospectively. MSCT was undertaken to investigate differences in tumor characteristics and enhancement patterns. RESULTS: All patients had single tumors centered in the renal medulla. Two patients with each tumor type had lymph node involvement and there was a single case of hepatic metastasis (Xp11.2/TFE RCC). The mean tumor diameter of Xp11.2/TFE RCC tumors was significantly larger than for CDC tumors. Two patients with Xp11.2/TFE RCC had cystic components as did eight patients with CDC (P < 0.05). Calcifications were present in six patients, each with CDC. Clear tumor boundaries were visible in two patients with CDC and in nine with Xp11.2/TFE RCC (P < 0.05). The density of Xp11.2/TFE RCC tumors was greater than that of CDC tumors, normal renal cortex, or medulla on unenhanced CT. Enhancement was higher with Xp11.2/TFE RCC than with CDC tumors during all phases. Xp11.2/TFE RCC enhancement was higher than in the renal medulla during cortical and medullary phase but lower than in normal renal medulla during the delayed phase. CDC tumor enhancement was lower than that for normal renal medulla during all enhanced phases. CONCLUSION: Both tumor types originated from the renal medulla. Distinguishing features included density on unenhanced CT, enhancement patterns, and capsule signs. Identifying these differences may aid diagnosis. PMID- 23446749 TI - Changes in renal Doppler ultrasonographic parameters in patients managed with rigid ureteroscopy. AB - BACKGROUND: There has been no study evaluating the intrarenal hemodynamic changes after ureteroscopy in the published literature. PURPOSE: To determine preoperative and postoperative intrarenal vascular parameters such as resistive index (RI), pulsatility index (PI), peak systolic velocity (PSV), end-diastolic velocity (EDV), measure changes on these values (DeltaRI, DeltaPI, DeltaPSV, DeltaEDV) after ureteroscopy (URS) and compare the outcomes with the results of normal contralateral kidneys, and finally investigate possible parameters that would affect renal vascular resistance changes. MATERIAL AND METHODS: We prospectively studied 47 patients who underwent rigid URS. Preoperative gray scale and Doppler ultrasonography (CDUS) measurements were obtained 24 h before URS. Similarly, postoperative CDUS measurements were done 24 h after the operation. The degree of hydronephrosis and location of stones in the obstructed kidneys, diameters of both kidneys, and thickness of renal parenchyma were evaluated with gray-scale US followed by CDUS with calculation of the intrarenal RI, PI, PSV, and EDV values for each kidney. RESULTS: For the operated kidneys, statistically significant P values were noticed when RI and PI values were considered (P < 0.001). DeltaRI and DeltaPI of the operated kidneys were also significantly greater than the values for non-operated kidneys (P < 0.001). However, it was not the case for DeltaPSV and DeltaEDV values. In Spearman correlation coefficient analysis, DeltaRI was found to be correlated with the parameters: "operative time" and "irrigation fluid volume". No significant relation was documented between DeltaRI and the other parameters: age, gender, side of ureteroscopy, stone location, and degree of hydronephrosis. CONCLUSION: Significant changes in RI and PI values in patients treated with URS reveal that URS can cause a significant increase in renal vascular resistance. With the increase in operative time and irrigation fluid volume used during the operation, RI seems to be significantly increased. PMID- 23446750 TI - MDCT coronary angiography -- postprocessing, reading, and reporting: last but not least. AB - Significant literature on MDCT coronary angiography (MDCT-CA) has emerged in the last decade concerning patient's selection, technical aspects of different generations of CT equipment, ECG gating, contrast material and beta-blockade administration, acquisition parameters, and radiation dose. However, the literature regarding postprocessing, reading, and reporting is not so extensive. This review highlights the main elements of MDCT-CA data analysis, thereby allowing the radiologist to take full advantage of this technology and enable a structured report to be generated, promoting best practice with high-quality results. PMID- 23446751 TI - Histological characteristics of biliary intraepithelial neoplasia-3 and intraepithelial spread of cholangiocarcinoma. AB - The increasing grades of biliary intraepithelial neoplasia (BilIN) reflect multistep carcinogenesis of cholangiocarcinoma, BilIN-3 representing the carcinoma in situ stage. A different form of in situ growth form of cancer cells is the intraepithelial spreading of cholangiocarcinoma cells. We examined the histological characteristics of carcinoma in situ in the biliary tract on 64 partial hepatectomy specimens with a diagnosis of hepatolithiasis. We distinguished two forms of carcinoma in situ: BilIN-3 and intraepithelial spread of carcinoma (IES). BilIN-3 is defined by epithelial atypia gradually decreasing towards the transition to adjacent normal biliary epithelium. In IES, the lesion shows an abrupt transition to normal biliary epithelium, in which the intraepithelial carcinoma then tends to spread. BilIN-3 and IES were observed in 17 (94 %) and seven (39 %), respectively, in cases of invasive cholangiocarcinoma (n = 18), and neither of them was observed in cases without invasive cholangiocarcinoma (n = 46). Most lesions of BilIN-3 and IES microscopically showed a flat or pseudopapillary pattern. The less frequent micropapillary configuration was noted more often in BilIN-3. BilIN-3 was not observed in septal and small intrahepatic bile ducts, while IES was regularly observed in such bile ducts. Immunohistochemical analysis showed p53 to be expressed significantly more frequently in IES (29 %) than in BilIN-3 (8 %). In conclusion, carcinoma in situ in the biliary tract is morphologically heterogeneous, and it is important to distinguish BilIN-3 and intraepithelial carcinoma spreading as distinct lesions, to better understand their biology. PMID- 23446752 TI - The archives of internal medicine: 2011 recap and looking forward in 2012. PMID- 23446753 TI - Synergistic anticancer effects of curcumin and resveratrol in Hepa1-6 hepatocellular carcinoma cells. AB - Hepatocellular carcinoma remains one of the most prevalent malignancies worldwide. Curcuma aromatica and Polygonum cuspidatum are one of the commonly used paired-herbs for liver cancer treatment. Curcumin and resveratrol are the major anticancer constituents of Curcuma aromatica and Polygonum cuspidatum, respectively. Curcumin and resveratrol have been found to exhibit a synergistic anticancer effect in colon cancer. However, the combined effect of curcumin and resveratrol against hepatocellular carcinoma remains unknown. In the present study, we evaluated the combined effects of curcumin and resveratrol in hepatocellular carcinoma Hepa1-6 cells. The results showed that curcumin and resveratrol significantly inhibited the proliferation of Hepa1-6 cells in a dose- and time-dependent manner. The combination treatment of curcumin and resveratrol elicited a synergistic antiproliferative effect in Hepa1-6 cells. The apoptosis of Hepa1-6 cells induced by the combination treatment with curcumin and resveratrol was accompanied by caspase-3, -8 and -9 activation, which was completely abrogated by a pan caspase inhibitor, Z-VAD-FMK. Combination of curcumin and resveratrol upregulated intracellular reactive oxygen species (ROS) levels in Hepa1-6 cells. The ROS scavenger, NAC, partially attenuated the apoptosis and caspase activation induced by the combination treatment of curcumin and resveratrol. In addition, the combination of curcumin and resveratrol downregulated XIAP and survivin expression. These data suggest that the combination treatment of curcumin and resveratrol is a promising novel anticancer strategy for liver cancer. The present study also provides new insights into the effective mechanism of paired-herbs in traditional Chinese medicine. PMID- 23446754 TI - The value of bedside shift reporting enhancing nurse surveillance, accountability, and patient safety. AB - A study was undertaken to explore nurses' experiences and perceptions associated with implementation of bedside nurse-to-nurse shift handoff reporting. Interviews were conducted with nurses and analyzed using directed content analysis. Two themes emerged that illustrated the value of bedside shift reporting. These themes included clarifying information and intercepting errors and visualizing patients and prioritizing care. Nurse leaders can leverage study findings in their efforts to embed nurse-to-nurse bedside shift reporting in their respective organizations. PMID- 23446757 TI - [Immune reactions after DMEK, DSAEK and DALK]. AB - PURPOSE: The aim of this study is to describe incidence, diagnosis and therapy for endothelial immune reactions after modern lamellar corneal transplantat surgery (DMEK, DSAEK, DALK). METHODS: A PubMed-based literature review and our own clinical and experimental data are evaluated. RESULTS: There is no longer an endothelial immune reaction after DALK for keratoconus. DMEK significantly reduces the risk for endothelial immune reactions after surgery for Fuchs dystrophy. CONCLUSIONS: Modern lamellar corneal transplant techniques such as DALK and DMEK have nearly abolished the risk for endothelial immune reactions in the avascular recipient bed. PMID- 23446755 TI - Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex. AB - BACKGROUND: Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown. METHODS: The AHI-1-BCR-ABL-JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL (+) cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided. RESULTS: The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1-overexpressing and IM resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34(+) leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy. CONCLUSIONS: Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance. PMID- 23446756 TI - Overcoming chronic myeloid leukemia stem cell resistance to imatinib by also targeting JAK2. PMID- 23446758 TI - Assessment of the ferret as an in vivo model for mumps virus infection. AB - Humans are the sole reservoir for mumps virus (MuV), the causative agent of mumps. No animal model currently exists; therefore, in vivo knowledge of the virus is limited. Ferrets were assessed for their susceptibility to MuV based on their success as a model for influenza. We infected ferrets with clinical or attenuated vaccine MuVs by the nasal route and demonstrated evidence of immunogenicity in these animals with generation of a serum antibody response specific to MuV infection and cytokine production consistent with infection. However, no live virus or viral RNA was detected in nasal washes, oral swabs, urine, faeces or tissue homogenates, and no animals exhibited clinical signs. We suggest results to be obtained from ferrets are limited in fundamental in vivo MuV research and that they may not be a suitable animal model for this virus. PMID- 23446759 TI - Regioselective and stereoselective benzylidene installation and one-pot protection of D-mannose. AB - Oligosaccharide syntheses are an important source of well-defined sugar constructs particularly needed for the evaluation of structure-activity relationships. The chemical assembly of oligosaccharides requires several building blocks, that is, glycosyl donors and acceptors, which are prepared in multistep processes and in a generally tedious and time-consuming manner. Having developed one-pot procedures meant to minimise the effort in sugar building block preparation, we tackled herein the one-pot preparation of fully protected and 2-, 3-, 4-, and 6-alcohol derivatives of d-mannose, a widely distributed monosaccharide. As a consequence of the hydroxyl group pattern of D-mannose, regioselective and stereoselective benzylidenations were developed and later seamlessly utilised as the first transformation in the one-pot procedure. PMID- 23446760 TI - Cell-seeded extracellular matrices for bladder reconstruction: an ex vivo comparative study of their biomechanical properties. AB - PURPOSE: Autogenous ileal tissue remains the gold-standard biomaterial for bladder replacement purposes; however, cell-seeded extracellular matrix (ECM) scaffolds have shown promise. Although the biological advantages of cell-seeded ECMs in urological settings are well documented, there is a paucity of data available on their biomechanical properties. In this study, the biomechanical properties of cell-seeded ECMs are compared with autogenous ileal tissue. METHODS: Human urothelial cells (UCs) and smooth muscle cells (SMCs) were obtained by bladder biopsy and cultured onto porcine urinary bladder matrix (UBM) scaffolds under dynamic and static growth conditions for 14 days. The biomechanical properties of cell-seeded UBM (n = 12), and porcine ileum (n = 12) were determined with uni-axial tensile testing protocols and compared with stress strain curves. In addition, their biomechanical properties were compared with porcine bladder tissue (n = 12) and unseeded UBM (n = 12). RESULTS: There were significant differences in the biomechanical properties of each biomaterial assessed. Strain to failure occurred at 92 +/- 24% for dynamically cultured cell seeded UBM compared to 42.2 +/- 5.20% for ileal tissue (p<0.01). Values for linear stiffness at 30% strain were significantly lower in dynamically cultured cell-seeded UBM compared to ileal tissue (0.36 +/- 0.14 MPa versus 0.67 +/- 0.32 MPa respectively, p<0.01). Bladder tissue remained the most distensible biomaterial throughout, with linear stiffness measuring 0.066 +/- 0.034 MPa at 30% strain. CONCLUSIONS: Dynamically cultured cell-seeded ECMs are biomechanically superior to ileal tissue for bladder replacement purposes. Additional comparative in vivo studies will be necessary before their role as a reliable alternative is clearly established. PMID- 23446761 TI - Techniques of extracorporeal cytokine removal: a systematic review of the literature on animal experimental studies. AB - BACKGROUND AND AIMS: Extracorporeal cytokine removal may be desirable. We sought to assess extracorporeal blood purification (EBP) techniques for cytokine removal in experimental animal studies.? METHODS: We conducted a targeted, systematic search and identified 17 articles. We analyzed cytokine clearance, sieving coefficient (SC), ultrafiltrate (UF) concentration, and percentage removal. As this review concerns technical appraisal of EBP techniques, we made no attempts to appraise the methodology of the studies included. Results are in descriptive terms only.? RESULTS: Applying predicted clearance for 80 kg human, high volume hemofiltration (HVHF) techniques and plasmafiltration (PF) showed the highest rates of cytokine removal. High cutoff (HCO)/HF and PF techniques showed modest ability to clear cytokines using low to medium flows. Standard hemofiltration had little efficacy. At higher flows, HCO/HF achieved clearances between 30 and 70 ml/min for IL-6 and IL-10. There was essentially no removal of tumor necrosis factor (TNF)-alpha outside of PF.? CONCLUSIONS: Experimental animal studies indicate that HVHF (especially with HCO filters) and plasmafiltration have the potential to achieve appreciable IL-6 and IL-10 clearances. However, only PF can remove TNF-alpha reliably. PMID- 23446762 TI - Antiviral therapy of symptomatic HCV-mixed cryoglobulinemia after liver transplant: case report and literature review. AB - Hepatitis C virus (HCV) infection may be associated with extra-hepatic illness including mixed cryoglobulinemia (MC). Consistent evidence exists on HCV-MC in the non-transplantation setting but information on HCV-related cryoglobulinemia after solid organ transplantation is limited, particularly after liver transplantation (LT). We report on a 48-year-old man who developed HCV-associated cryoglobulinemic vasculitis with recurrent hepatitis after liver transplant. One year after transplant for HCV-positive ?cirrhosis, he presented severe cutaneous manifestations, and biopsy-proven cryoglobulinemic membrano-proliferative glomerulonephritis (MPGN). HCV RNA clearance occurred within a few weeks of antiviral therapy; sustained viral response (SVR) was obtained by one year of anti-HCV combination therapy (eight months of pegylated IFN/ribavirin and four months of standard IFN/ribavirin). SVR was linked to complete remission of skin, liver, and kidney abnormalities. Tolerance to the pegylated IFN/ribavirin regimen was not excellent due to the occurrence of lobar pneumonia with anemia; thus, peg IFN was replaced by recombinant IFN, with a favorable outcome. Clinical and viral remission persisted over a 48-month follow-up. HCV-associated mixed cryoglobulinemia flareups following LT were successfully managed with combined antiviral therapy. HCV-related MC is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed at evaluating the efficacy and safety of anti-HCV therapy after solid organ transplantation or in the non-transplantation setting. PMID- 23446763 TI - A new gyro-based method for quantifying eyelid motion. AB - PURPOSE: We present an innovative method to quantify the eyeblink by using a miniature gyroscopic sensor (gyro), which is applied on the upper eyelid. Electrical Stimulation (ES) of the facial nerve is a promising technology to treat dysfunctional eyelid closure following facial paralysis. We used the new gyro-based method to evaluate the biomechanics of both the spontaneous and the ES induced eyeblink, and to identify the best ES protocol.? METHODS: During blinking, eyelids rotate about the axis passing through the eye canthi, thus we propose to use a gyro for measuring the angular velocity of the upper eyelid (omegae ). The angular displacement of the eyelid (thetae ) was calculated by integrating the omegae signal. Two indices were derived from thetae: 1) the eyelid angular displacement during eye closure (C), calculated as the peak value of thetae ; 2) the eyelid closure duration (D), calculated as the time interval between zero signal and the peak value of thetae. In a healthy volunteer we used this method to quantify both the spontaneous eyeblink and the blinks elicited by different ES patterns.? RESULTS: For the spontaneous eyeblink, indices C = 14.0 +/- 1.8 degrees and D = 94.0 +/- 10.8 ms were computed. By comparing C and D indices for spontaneous and ES cases, trains of 10 pulses with a frequency ranging from 200 Hz to 400 Hz proved to induce the most effective and natural like eyeblinks.? CONCLUSIONS: The new gyro-based method proved to be a valuable tool to provide dynamic and real-time quantification of eyelid motions. It could be particularly useful for evaluating the effective and natural-like eyeblink restoration provided by ES. PMID- 23446764 TI - Review of the adenocarcinoma cell surface receptor for human alpha-fetoprotein; proposed identification of a widespread mucin as the tumor cell receptor. AB - The identification of a tumor cell receptor for alpha-fetoprotein (AFP) has long been sought in the field of medicine. The uptake and endocytosis of AFP by rat tumor cells in 1983 sparked a series of confirmatory reports which were extended to include multiple tumor types in rats, mice, and humans. The following year, French investigators characterized the binding properties of the AFP receptor but they did not purify and characterize the receptor. It was not until 1991-1992 that an AFP receptor was partially purified and characterized from both human monocytes and breast cancer cells. By 1993, monoclonal antibodies had been raised against the "AFP receptor" derived from breast cancer extracts with claims that the receptor was a widespread oncoprotein biomarker for cancer. To date, that receptor has yet to be identified due to its complex multimeric structure and carbohydrate composition. The present report will review the literature of the multiple AFP receptors previously including their cellular uptake, transmembrane passage, and partial biochemical characterization. . In addition, evidence derived from computer modeling, proteolytic/fragmentation cleavage patterns, domain structure analysis, and protein binding software analysis will be presented in a proposed identification of a widespread protein/gene family of transmembrane proteins which fits many, if not most, of the criteria attributed to the AFP receptor. The proposed receptor protein family is tentatively identified as an epithelial cell surface mucin constituting one (or more) of many classes of single-pass transmembrane proteins. Present data do not support the concept that the AFP receptor is a "universal" tumor receptor and/or biomarker, but rather a widespread mucin protein that functions primarily in protecting and lubricating epithelial mucosal layers, and engaging in signal transduction; the mucin only binds AFP as a molecule serving in a subordinate or ancillary function. PMID- 23446765 TI - Outcomes of cervical spine surgery in teaching and non-teaching hospitals. AB - STUDY DESIGN: Retrospective national database analysis. OBJECTIVE: A national population-based database was analyzed to characterize cervical spine procedures performed at teaching and nonteaching hospitals with regards to patient demographics, clinical outcomes/complications, resource use, and costs. SUMMARY OF BACKGROUND DATA: There are mixed reports in the literature regarding the quality and costs of health care provided by teaching hospitals in the United States. However, outcomes of cervical spine surgery based upon teaching status remains largely unknown. METHODS.: Data from the Nationwide Inpatient Sample were obtained from 2002-2009. Patients undergoing elective anterior or posterior cervical fusion, or posterior cervical decompression (i.e., laminoforaminotomy, laminectomy, laminoplasty) for a diagnosis of cervical myelopathy and/or radiculopathy were identified and separated into 2 cohorts (teaching and nonteaching hospitals). Patient demographics, comorbidities, complications, length of hospitalization, costs, and mortality were compared for both groups. Regression analysis was performed to assess independent predictors of mortality. RESULTS: A total of 212,385 cervical procedures were identified from 2002-2009 in the United States, with 54.6% performed at teaching hospitals. More multilevel fusions and posterior approaches were performed in teaching hospitals (P < 0.0005). Patients treated in teaching hospitals trended toward male sex, increased costs, and hospitalizations. Overall, procedure-related complications and inhospital mortality were increased in teaching hospitals. Regression analysis revealed that significant predictors of mortality were age 65 years or more (odds ratio = 3.0) and multiple comorbidities. Teaching status was not a significant predictor of mortality (P = 0.07). CONCLUSION: Patients treated in teaching hospitals for cervical spine surgery demonstrated longer hospitalizations, increased costs, and mortality compared with patients treated in nonteaching hospitals. Incidences of postoperative complications were identified to be higher in teaching hospitals. Possible explanations for these findings are an increased complexity of procedures performed at teaching hospitals. Older age and presence of comorbidities were more significant predictors of inhospital mortality than teaching status. Future studies should identify long-term complications and costs beyond an inpatient setting to assess if differences extend beyond the perioperative period. LEVEL OF EVIDENCE: 4. PMID- 23446766 TI - Transforming growth factor beta 1 is a novel susceptibility gene for adolescent idiopathic scoliosis. AB - STUDY DESIGN: A genetic association study of the transforming growth factor beta 1 (TGFB1) gene with adolescent idiopathic scoliosis (AIS) in Russian population. OBJECTIVE: To determine whether common genetic polymorphisms C-509T (rs1800469) and Arg25Pro (rs1800471) of the TGFB1 gene are associated with susceptibility to AIS. SUMMARY OF BACKGROUND DATA: An importance of growth factors for the pathogenesis of AIS has been demonstrated by the findings of abnormal expression of these proteins in the spine and surrounding tissues in patients with AIS. However, no studies have been performed to investigate the relationship between genetic polymorphisms of the TGFB1 gene and susceptibility to AIS. METHODS: A total of 600 unrelated adolescents from Central Russia (Moscow) were recruited in this study, including 300 patients with AIS and 300 age- and sex-matched healthy adolescents. The polymorphisms were genotyped by polymerase chain reaction restriction fragment length polymorphism. RESULTS: The allele -509T and genotype 509TT of the TGFB1 gene were significantly associated with the increased risk of idiopathic scoliosis in both females and males (P < 0.01). Logistic regression analysis has revealed a recessive model of the genetic association between polymorphism C-509T of the TGFB1 gene and AIS. Moreover, we found sexual dimorphisms in the relationships of SNP C-509T of the TGFB1 gene with both the age of disease onset and curve severity: the polymorphism was found to determine both an early onset of scoliosis and the severity of curvature in females but not in males (P < 0.05). CONCLUSION: This study, for the first time, highlights the importance of TGFB1 gene for the development and progress of AIS. We hypothesize several mechanisms by which the TGFB1 gene may contribute to spinal deformity in patients with AIS. PMID- 23446767 TI - Partial pedicle subtraction osteotomy as an alternative option for spinal sagittal deformity correction. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To describe the technique of a partial pedicle subtraction osteotomy (PPSO) and to report on the clinical and radiological outcomes. SUMMARY OF BACKGROUND DATA: Numerous corrective osteotomy techniques have been reported. Until now, there has been no reported method that can achieve a correction angle between those of the Smith-Petersen osteotomy and pedicle subtraction osteotomy as a posterior closing osteotomy that can be safely performed on the thoracic spine. METHODS: A total of 38 patients aged between 31 and 72 years, who underwent PPSO for spinal sagittal deformity correction were enrolled in this study. The mean postoperative follow-up period was 30.1 months (range, 24-36 mo). The assessments included the Oswestry Disability Index scores, immediate postoperative and 2-year postoperative correction angles, correction loss, pseudoarthrosis, and complications. RESULTS: There were 6 patients who underwent PPSO alone and 32 patients who underwent PPSO combined with at least one other surgical procedure (PSO in 16 patients, anterior lumbar interbody fusion in 12 patients, and Smith-Petersen osteotomy in 4 patients). The level of the osteotomy was T10 in 6 patients, T11 in 15 patients, T12 in 10 patients, 1 in 4 patients, L2 in 2 patients, and L3 in 1 patient. There were significant improvements in the overall Oswestry Disability Index scores (P = 0.001). The mean postoperative correction angle immediately after the PPSO was 18.8 degrees (range, 12.4 degrees -26.1 degrees ) and the mean postoperative correction angle at 2 years was 18.4 degrees (range, 11.9 degrees -25.7 degrees ). There was no significant loss of correction found during the 2-year follow-up. There was also no pseudoarthrosis or neurological complications. CONCLUSION: PPSO had resulted in intermediate correction rates between those of Smith-Petersen osteotomy and PSO. PPSO is considered to be a safe and reliable procedure for patients with spinal sagittal deformities even at the thoracic spine level. LEVEL OF EVIDENCE: 4. PMID- 23446768 TI - Current practice of methylprednisolone administration for acute spinal cord injury in Germany: a national survey. AB - STUDY DESIGN: Written mail-out survey. OBJECTIVE: To determine current practice in high-dose methylprednisolone succinate (MPSS) administration for treatment of acute spinal cord injury (SCI) in Germany. SUMMARY OF BACKGROUND DATA: Reanalysis of the National Acute Spinal Cord Injury Studies (NASCIS) resulted in criticism of the use of high-dose MPSS for treatment of acute SCI. Subsequently, SCI treatment guidelines were revised leading to a reduction in MPSS use across North America. The impact of these revisions on SCI treatment in Germany is not known. METHODS: A questionnaire was sent to all trauma, orthopedic and neurosurgical departments of German university centers, affiliated teaching hospitals, and specialized SCI care centers. Survey included 6 questions about the administration of MPSS after acute SCI. RESULTS: Three hundred seventy-two respondents completed the survey (response rate: 51% overall, 76% university hospitals, 85% specialized SCI care centers). Overall, 55% of departments that treat SCI prescribe MPSS. Among them, 73% are "frequent" users administering MPSS to more than 50% of their patients. Ten percent prescribe according to NASCIS I, 43% NASCIS II, 33% NASCIS III, and 13% "generic protocols." As justification for MPSS treatment, "effectiveness" ranked before "common practice" and "medicolegal reasons." "Specialized" SCI care centers differ in that (1) MPSS is administered less frequently, (2) NASCIS I doses are not used, and (3) during the past several years, practice patterns are more likely to have shifted away from the treatment of SCI with MPSS. CONCLUSION: About one-half of the institutions continue to prescribe MPSS in the setting of acute SCI. A need for further education in almost one-fourth of German departments treating acute SCI is demonstrated through responses indicating use of the outdated NASCIS I protocol, a "legal need" or "unchanged MPSS application during the last years." "Specialized" SCI centers are more likely to change their practice in accordance with evolving literature. LEVEL OF EVIDENCE: 3. PMID- 23446770 TI - Aberrant expression of circulating Th17, Th1 and Tc1 cells in patients with active and inactive ulcerative colitis. AB - Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease, yet its etiology and pathogenesis remain poorly understood. The aberrant expression of T lymphocytes plays an essential role in the progression of UC. This study aimed to evaluate the expression profile of circulating Th17, Th1 and Tc1 cells in patients with active and inactive UC. Our results revealed that the percentage of circulating Th17 cells (CD3+CD8-IL-17+) was significantly increased in patients with active UC when compared with the percentage in patients with inactive UC, Crohn's disease (CD) and healthy controls. The percentages of circulating Th1 (CD3+CD8-IFN-gamma+) and Tc1 (CD3+CD8+IFN-gamma+) cells were also higher in patients with active UC when compared with the percentages in patients with inactive UC and normal controls, although levels were lower than that in CD. Further analysis showed that Th17 cells were positively correlated with Th1 cells, but not with Tc1 cells. Notably, the three cells had a positive correlation with disease activity, extent of disease, detection of erythrocyte sedimentation rate and c-reactive protein in active UC. Moreover, plasma IL-17 was higher in patients with active UC, and a similar trend applied to the mRNA levels of RORgammat and T-bet in peripheral blood mononuclear cells (PBMCs). The levels of p-STAT3 and p-STAT5 in PBMCs, as well as the ratio of p-STAT3/p-STAT5, were also elevated in active UC patients. Taken together, our findings revealed that elevated circulating Th17, Th1 and Tc1 cells and the aberrant activation of the STAT pathway may be implicated in the progression of UC. These findings may provide preliminary experimental clues for the development of new therapies for UC. PMID- 23446771 TI - Evaluation of immobilized enzymes for industrial applications. AB - In contrast to the application of soluble enzymes in industry, immobilized enzymes often offer advantages in view of stability, volume specific biocatalyst loading, recyclability as well as simplified downstream processing. In this tutorial review the focus is set on the evaluation of immobilized enzymes in respect to mass transport limitations, immobilization yield and stability, to enable industrial applications. PMID- 23446769 TI - A randomized trial of balloon kyphoplasty and nonsurgical management for treating acute vertebral compression fractures: vertebral body kyphosis correction and surgical parameters. AB - STUDY DESIGN: Multicenter randomized controlled trial. OBJECTIVE: To compare the efficacy and safety of balloon kyphoplasty (BKP) with nonsurgical management (NSM) during 24 months in patients with painful vertebral compression fractures (VCFs). SUMMARY OF BACKGROUND DATA: Recently, several large randomized controlled trials have been conducted and reported how vertebral augmentation compares with NSM for patients with acute VCFs. Few of these trials report on the surgical aspects and radiographical vertebral deformity results. METHODS: Adults with 1 to 3 VCFs were randomized within 3 months of pain to undergo bilateral BKP (n = 149) or NSM (n = 151). Surgical parameters, subjective quality of life assessments and objective functional (timed up and go) and radiographical assessments were collected. RESULTS: Compared with NSM, the BKP group had greater improvements in SF-36 physical component summary (PCS) scores at 1 month (5.35 points; 95% CI, 3.41-7.30; P < 0.0001) and when averaged across the 24 months (overall treatment effect 2.71 points; 95% CI, 1.34-4.09; P = 0.0001). The kyphoplasty group also had greater functionality by assessing timed up and go (overall treatment effect 2.49 s; 95% CI, -0.82 to -4.15; P = 0.0036). At 24 months, the change in index fracture kyphotic angulation was statistically significantly improved in the kyphoplasty group (average 3.13 degrees of correction for kyphoplasty compared with 0.82 degrees in the control, P = 0.003). Number of baseline prevalent fractures (P = 0.0003) and treatment assignment (P = 0.004) are the most predictive variables for PCS improvement; however, in patients who underwent BKP, there may also be a link with kyphotic angulation. In BKP, the highest quart for kyphotic angulation correction had higher PCS improvement (13.4 points) than the quart having lowest correction of angulation (7.40 points, P = 0.0146 for difference). The most common adverse events temporally related to surgery (i.e., within 30 d) were back pain (20 BKP, 11 NSM) new VCF (11 BKP, 7 NSM), nausea/vomiting (12 BKP, 4 NSM), and urinary tract infection (10 BKP, 3 NSM). Several other adverse events were possibly related to patient positioning in the operating room. CONCLUSION: Compared with NSM, BKP improves patient quality of life and pain averaged during 24 months and results in better improvement of index vertebral body kyphotic angulation. Perioperative complications may be reduced with more care in patient positioning. LEVEL OF EVIDENCE: 2. PMID- 23446772 TI - HSD11B2 CA-repeat and sodium balance. AB - Type 2 11beta-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone and thus protects the mineralocorticoid receptor from cortisol exposure. Impaired activity of this enzyme leads to mineralocorticoid excess, suggesting HSD11B2 as a candidate locus for patients at risk of developing low renin or salt-sensitive essential hypertension. In the present study, we searched for frequent polymorphisms in 155 Japanese subjects but detected none in the proximal promoter or coding regions of HSD11B2. Following this result, we genotyped a highly polymorphic CA-repeat polymorphism within the first intron in 848 normotensive and 430 hypertensive Japanese patients, and we then analyzed its association with disease and clinical parameters. We confirmed 12 alleles (12, 15-25 CA repeats) in the population and found no significant difference in the distribution of the allele length between normotensive and hypertensive patients. In 174 normal subjects without medication, urinary cortisol excretion was higher in subjects with more CA repeats in the shorter allele, but the ratio of urinary cortisone to cortisol, a reliable marker of renal HSD11B2 activity, did not differ. However, longer CA repeat length was positively correlated with 24-h urinary sodium excretion, fractional sodium excretion and potassium clearance, and this observation was confirmed when the longer CA-repeat length was dichotomized. Thus, HSD11B2 CA repeat genotype is not associated with hypertension itself, but with renal sodium excretion, probably through salt intake/appetite. PMID- 23446773 TI - Therapeutic effect of eNOS-transfected endothelial progenitor cells on hemodynamic pulmonary arterial hypertension. AB - Hemodynamic pulmonary arterial hypertension (HPAH) is a common symptom in congenital heart disease (CHD) patients with a left-to-right shunt. Endothelial NO synthase (eNOS) and endothelial-like progenitor cells result in significant improvement of right ventricular systolic pressure in established pulmonary arterial hypertension (PAH) models. We hypothesized that bone marrow (BM)-derived endothelial progenitor cells (EPCs) and eNOS would prevent HPAH in a newly established rat model. The heNOS gene was cloned into a PSUCMV vector, and a high titer adenovirus was generated. Mononuclear cells (MNCs) from rat BM were differentiated into EPCs by treatment with various cytokines, and a high purity of EPCs (>70%) was confirmed using the markers DiI ac-LDL, UEA-1, vWF and Flk-1. An ideal rat HPAH model was successfully established based on right lung lobectomy, and was confirmed by pressure measurement and histological staining. heNOS was successfully transfected into EPCs, which were then transplanted into HPAH rats. Two weeks after transplantation, the systolic pulmonary arterial blood pressure (sPAP) was significantly reduced by heNOS-EPCs treatment and by transplantation of control EPCs. The high number of muscular pulmonary arteries and the thickness of the muscular coat characteristic of HPAH rats were clearly reversed or even restored to normal levels following transplantation of EPCs, particularly eNOS-EPCs. These findings indicate a critical role of eNOS in HPAH treatment and suggest that eNOS-transfected EPCs may provide an effective strategy for HPAH treatment in CHD patients. PMID- 23446774 TI - Association between hypertension status and the screening test for frailty in elderly community-dwelling Japanese. AB - To clarify the possible association of frailty with hypertension prevalence, treatment and blood pressure (BP) control in the elderly, we conducted a screening survey of 1091 elderly community-dwelling subjects aged >=65 years, using data from public health check-ups and frailty was determined by a 25-item questionnaire, the Basic Checklist for Frailty (BCF). The significance of differences in the association of BCF categories or BCF items with each hypertension status was analyzed using multiple logistic regression analysis after adjusting for age, sex and possible confounding underlying chronic conditions. A total of 63% of subjects were hypertensive (BP>=140/90 mm Hg), and of those, 85% were receiving antihypertensive treatment, and 56.0% of those receiving treatment had controlled BP (<140/90 mm Hg). BCF categories that showed an independent association with hypertension status were 'impaired walking status' and absence of 'impaired nutritional status' for prevalence of hypertension, 'impaired instrumental activity of daily living status' and 'impaired nutritional status' for untreated hypertension among hypertensives and 'impaired oral function' for BP-uncontrolled hypertension among treated hypertensives. In addition, BCF items that showed an independent association were 'inability to walk for more than 15 min without rest' and absence of 'Body mass index (BMI) <18.5 kg m(-2') for prevalence of hypertension, 'weight loss of more than 2-3 kg in the past 6 months' for untreated hypertension, and 'difficulty eating hard food' for BP-uncontrolled hypertension. These observations indicate that assessment of these specified frailty categories and/or items may be useful for evaluating hypertension status in elderly community-dwelling subjects. PMID- 23446775 TI - Synergistic influence of age and serum uric acid on blood pressure among community-dwelling Japanese women. AB - Serum uric acid (SUA) levels are strongly correlated with aging, gender, renal function, obesity, and metabolic abnormality; however, whether SUA has a causative role in elevated blood pressure (BP) is still a matter of debate. From a single community, we recruited 1177 eligible women (mean age, 61+/-13 years) during their annual health examination. All subjects were divided into two groups according to their age (participants aged >=55 years and those aged <55 years). We investigated whether age and SUA are synergistically associated with BP, independent of confounding factors. Of these subjects, SUA significantly correlated with both systolic BP (SBP; r=0.236, P<0.001) and diastolic BP (DBP; r=0.263, P<0.001) in female participants aged <55 years but not in those aged >=55 years. The interaction between age and SUA on BP as well as age and body mass index, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, prevalence of antidiabetic medication and SUA was a significant and independent determinant of both SBP (beta=-0.106, P=0.011) and DBP (beta=-0.070, P=0.003). In participants aged <55 years, the multivariate-adjusted odds ratio (95% confidence interval) for hypertension was 3.03 (1.13-8.11) for the highest tertile (4.8-10.8 mg dl(-1)) of SUA compared with the lowest tertile (0.7-3.8 mg dl(-1)) but was not significant in those aged >=55 years. These results suggested that age and SUA have a synergistic effect on BP status in community-dwelling women, independent of conventional cardiovascular risk factors. PMID- 23446776 TI - Green synthesis and characterization of selenium nanoparticles and its augmented cytotoxicity with doxorubicin on cancer cells. AB - Green synthesis of selenium nanoparticles (SeNPs) was achieved by a simple biological procedure using the reducing power of fenugreek seed extract. This method is capable of producing SeNPs in a size range of about 50-150 nm, under ambient conditions. The synthesized nanoparticles can be separated easily from the aqueous sols by a high-speed centrifuge. These selenium nanoparticles were characterized by UV-Vis spectroscopy, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and elemental analysis by X-ray fluorescence spectrometer (XRF). Nanocrystalline SeNPs were obtained without post-annealing treatment. FTIR spectrum confirms the presence of various functional groups in the plant extract, which may possibly influence the reduction process and stabilization of nanoparticles. The cytotoxicity of SeNPs was assayed against human breast-cancer cells (MCF-7). It was found that SeNPs are able to inhibit the cell growth by dose-dependent manner. In addition, combination of SeNPs and doxorubicin shows better anticancer effect than individual treatments. PMID- 23446777 TI - Repeats in transforming acidic coiled-coil (TACC) genes. AB - Transforming acidic coiled-coil proteins (TACC1, 2, and 3) are essential proteins associated with the assembly of spindle microtubules and maintenance of bipolarity. Dysregulation of TACCs is associated with tumorigenesis, but studies of microsatellite instability in TACC genes have not been extensive. Microsatellite or simple sequence repeat instability is known to cause many types of cancer. The present in silico analysis of SSRs in human TACC gene sequences shows the presence of mono- to hexa-nucleotide repeats, with the highest densities found for mono- and di-nucleotide repeats. Density of repeats is higher in introns than in exons. Some of the repeats are present in regulatory regions and retained introns. Human TACC genes show conservation of many repeat classes. Microsatellites in TACC genes could be valuable markers for monitoring numerical chromosomal aberrations and or cancer. PMID- 23446778 TI - Zinc-alpha2-glycoprotein: a proliferative factor for breast cancer? In vitro study and molecular mechanisms. AB - Zinc-alpha2-glycoprotein (ZAG) is a new adipokine whose gene expression is downregulated in obese patients. We recently reported ZAG expression in breast tumor or healthy breast tissue and detected this expression at high levels in ductal carcinoma and in normal epithelial adjacent tissue but not in normal tissue of healthy women. In the present study, we used two human breast tumor cell lines (MCF-7 and MDA-MB-231) and one fibrocystic breast cell line (MCF-10a) to examine whether recombinant ZAG has an effect on proliferative/apoptotic response in breast cancer cell lines. ZAG seemed to exert a proliferative effect on breast cancer cell proliferation [+11 to 27% in MCF-7 with (ZAG) = 5-20 ug/ml; +13% in MDA-MB-231 with (ZAG) = 5 ug/ml] and, on the contrary, an anti proliferative effect in the fibrocystic breast cell line [-5 to -8% in MCF-10a with (ZAG) = 5-10 ug/ml]. ZAG was able to modulate gene and protein expression involved in the apoptotic response. However, further studies are required to fully elucidate the effects of ZAG on the proliferation of mammary cells. PMID- 23446779 TI - Raising the bar for primary prevention: comment on "cardiovascular primary prevention". PMID- 23446781 TI - Adverse drug events in older geriatric patients: does safe prescribing exist? PMID- 23446780 TI - Diabetes and HIV: current understanding and future perspectives. AB - Diabetes mellitus is a chronic disease with a higher risk of associated infections. HIV infection severely affects diabetic patients and acts as a significant health concern. Highly active antiretroviral therapy (HAART) has changed HIV from an acute infection to a chronic infection with associated significant metabolic abnormalities such as insulin resistance, impaired glucose tolerance, metabolic syndrome, diabetes, dyslipidemia, obesity, and lipodystrophy. These metabolic disturbances add complexity to the standards of care in HIV infection and further increase the risk for cardiovascular disease and renal complications. The co-association of diabetes and HIV needs to be managed appropriately to prevent mortality and morbidity and improve patient outcome. The current understanding of diabetes and other metabolic abnormalities along with management strategies in HIV infected patients are summarized in this article. The review also focuses on recent challenges in the diagnosis and management of co-existent diabetes and HIV infection. PMID- 23446783 TI - Explicit criteria for potentially inappropriate medications to reduce the risk of adverse drug reactions in elderly people: from Beers to STOPP/START criteria. AB - Balanced and safe prescribing is difficult to achieve in frail older adults with multiple comorbid diseases. For this reason, great efforts have been made in the search for interventions to improve efficacy, safety and appropriateness of prescriptions in this vulnerable population. Among these interventions, the avoidance of medications that are considered to be inappropriate, i.e. potentially inappropriate medications (PIMs), has been considered a valuable treatment option. The aim of the present review was to summarize evidence about the use of explicit criteria for PIMs to reduce the risk of adverse drug reactions (ADRs) in older people. A PIM is a drug in which the risk of an adverse event outweighs its clinical benefit, particularly when there is evidence in favour of a safer or more effective alternative therapy for the same condition. Explicit criteria have been developed to identify PIMs, and among these, the Beers criteria have been the most frequently applied until recently. However, evidence suggests that such criteria can not easily be applied in European countries: several drugs listed in the 2003 Beers criteria were rarely prescribed or were not available in Europe and 2003 Beers-listed PIMs were not associated with ADRs in some studies. In the past few years, START/STOPP criteria have been developed and applied in several different studies and populations showing a greater ability to predict ADRs with respect to Beers criteria and to prevent potentially inappropriate prescribing. In 2012, Beers criteria have been updated using an evidence-based approach and future studies will investigate the impact of these and other criteria coming from ongoing studies on clinical outcomes relevant to geriatric populations. PMID- 23446782 TI - A review of pharmacogenetics of adverse drug reactions in elderly people. AB - Older adults are more susceptible to the prevalence of therapeutic failure and adverse drug reactions (ADRs). Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and genes responsible for a compound's mechanism of action, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. The interindividual variations of these genes may account for the differences observed in drug efficacy and the appearance of ADRs in elderly people. The advent of whole genome mapping techniques has allowed researchers to begin to characterize the genetic components underlying serious ADRs. The identification and validation of these genetic markers will enable the screening of patients at risk of serious ADRs and to establish personalized treatment regimens.The aim of this review was to provide an update on the recent developments in geriatric pharmacogenetics in clinical practice by reviewing the available evidence in the PubMed database to September 2012. A Pubmed search was performed (years 1999-2012) using the following two search strategies: ('pharmacogenomic' OR 'pharmacogenetic ') AND ('geriatric' or 'elderly ') AND 'adverse drug reactions'; [gene name] AND ('geriatric' or 'elderly ') AND 'adverse drug reactions', in which the gene names were those contained in the Table of Pharmacogenomic Biomarkers in Drug Labels published online by the US Food and Drug Administration ( http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378 htm ). Reference lists of included original articles and relevant review articles were also screened. The search was limited to studies published in the English language. PMID- 23446785 TI - Estimating renal function to reduce the risk of adverse drug reactions. AB - The aging process is characterized by relevant changes in pharmacokinetics. Renal function is known to decline with aging. However, as a result of reduced muscle mass, older individuals frequently have a depressed glomerular filtration rate (GFR) despite normal serum creatinine, and such a concealed renal insufficiency may impact significantly on the clearance of hydrosoluble drugs, as well as the risk of adverse drug reactions (ADRs) from hydrosoluble drugs. The assessment of renal function should thus be a mandatory item in the global examination of patient characteristics. Equations for estimating GFR have become very popular in recent years. However, different equations may yield significantly different estimated glomerular filtration rate (eGFR) values, which have important implications in dosing drugs cleared by the kidney. Current knowledge suggests that eGFR based on the Chronic Kidney Disease-Epidemiological Collaboration (CKD EPI) study equation outperformed eGFR based on the Modification of Diet in Renal Disease (MDRD) study equation and creatinine clearance estimate based on the Cockcroft-Gault formula as a predictor of ADRs from kidney cleared drugs. More recently, the combined creatinine-cystatin C equation was shown to perform better than equations based on either of these markers alone in diagnosing CKD, even in older patients. However, its accuracy in predicting ADRs and usefulness in drug dosing is still to be investigated. PMID- 23446786 TI - Geriatric conditions and the risk of adverse drug reactions in older adults: a review. AB - While polypathology and polypharmacy are well known risk factors for adverse drug reactions (ADRs), the association between geriatric conditions (GCs), i.e. a set of clinical and functional problems partly constitutive of and partly related to frailty, and ADRs is suspected but has not been fully elucidated. Several studies have assessed the relationship between single GCs and ADRs, but only a few studies have systematically evaluated the relationship between the whole spectrum of GCs and ADRs. The mechanism by which select GCs increase the risk of developing ADRs during a hospital stay might simply reflect a sort of general predictability of physical disability with respect to adverse outcomes. However, GCs pertaining to the physical dimension of frailty are generally associated with relevant changes in pharmacokinetics and pharmacodynamics of select drugs. While current evidence could not be considered either unequivocal or conclusive, select GCs, e.g. a history of falls and loss of independence in the activities of daily living, seem to define a condition of particular vulnerability of elderly patients to ADRs. PMID- 23446787 TI - Frailty and safety: the example of diabetes. AB - Frailty is considered a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia and disability. In addition, there is a close relationship between age-related metabolic changes and the occurrence of comorbidities that may in turn lead to frailty.Even though the downward spiral of frailty is activated more quickly in older persons with type 2 diabetes, it is reversible with appropriate interventions before reaching a high level of severity. The hazard for geriatric patients with type 2 diabetes is that frailty encompasses diverse complications already associated with or caused by diabetes. Frailty is also associated with cognitive impairment, reduced ability to perform activities of daily living and increased expression of inflammatory and coagulation markers that may contribute to the adverse microvascular effects of diabetes. Although glycaemic control remains the main targeting achievement in type 2 diabetes, especially in well-functioning older persons, this is not appropriate for those with frailty. Frail elderly people with type 2 diabetes are a specific group in need of treatment parameters for both initial and maintenance therapy with oral antidiabetic agents. Therefore, the prescription of an antidiabetic agent in such individuals must take into consideration not only the standard goal of lowering hyperglycaemic levels, but also improving the quality of life and life expectancy. The clinical management of this population is currently particularly demanding, requiring special considerations with good medical decision making. Clinical aspects complicating diabetes care in older people include cognitive decline, physical functional decline and frailty. Available oral antidiabetic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors, thiazolidinediones and inhibitors of glucagon-like peptide 1 (GLP-1) degrading enzyme dipeptidyl peptidase 4. In addition, we will discuss injection treatment with GLP-1 analogues. This review will underline the association between diabetes and some frailty components in old patients and how specific antidiabetic agents may play a specific role in improving outcomes. PMID- 23446789 TI - Adverse drug events in older geriatric patients: identifying the knowledge gaps to support research and clinical practice guidelines. PMID- 23446784 TI - Adverse drug events as a cause of hospitalization in older adults. AB - Older adults are about four to seven times more likely than younger persons to experience adverse drug events (ADEs) that cause hospitalization, especially if they are women and take multiple medications. The prevalence of drug-related hospitalizations has been reported to be as high as 31%, with large heterogeneity between different studies, depending on study setting (all hospital admissions or only acute hospital admissions), study population (entire hospital, specific wards, selected population and/or age groups), type of drug-related problem measured (adverse drug reaction or ADE), method of data collection (chart review, spontaneous reporting or database research) and method and definition used to detect ADEs. The higher risk of drug-related hospitalizations in older adults is mainly caused by age-related pharmacokinetic and pharmacodynamic changes, a higher number of chronic conditions and polypharmacy, which is often associated with the use of potentially inappropriate drugs. Other factors that have been involved are errors related to prescription or administration of drugs, medication non-adherence and inadequate monitoring of pharmacological therapies. A few commonly used drugs are responsible for the majority of emergency hospitalizations in older subjects, i.e. warfarin, oral antiplatelet agents, insulin and oral hypoglycaemic agents, central nervous system agents. The aims of the present review are to summarize recent evidence concerning drug-related hospitalization in older adults, to assess the contribution of specific medications, and to identify potential interventions able to reduce the occurrence of these drug-related events, as they are, at least partly, potentially preventable. PMID- 23446788 TI - The economic burden of inappropriate drug prescribing, lack of adherence and compliance, adverse drug events in older people: a systematic review. AB - Adverse drug events (ADEs) are an increasingly relevant issue for healthcare systems as they are associated with poorer health outcomes and avoidable misuse of resources. The rates of ADEs are higher in the elderly population, as many older patients have comorbidities, multiple drug prescriptions and deteriorated physical and cognitive functioning. The occurrence of ADEs can lead to a perceived lack of therapy efficacy and further underuse or suboptimal adherence in elderly people, with detrimental clinical outcomes. The present article systematically reviews the studies evaluating the economic impact of ADEs occurring as consequence of poor therapy adherence, inappropriate drug use, underuse of effective treatments and poor adherence, medication errors, drug-drug and drug-disease interactions.A Medline systematic literature review of studies evaluating the economic consequences of inappropriate drug prescribing, lack of adherence and compliance, ADEs in older people was performed. English-language articles were screened through a three-step approach (title review, abstract review, full article review) to select pertinent studies quantitatively evaluating costs. We systematically reviewed evidence from767 articles. After title, abstract and full text review, 21 articles were found to measure economic implications ofADEs, inappropriate drug prescribing and poor adherence in elderly patients. Studies suggested that the economic impact of these undesired effects is substantial: hospital costs were the main cost driver, with a relevant part of them being preventable (consequences of inappropriate prescribing). Healthcare costs for unused drug wastage and destruction were also surprisingly high.Although economic evidence in elderly patients is still limited, all studies seemed to confirm that the financial burden due to pharmacological treatment issues is relevant in elderly people. Including economic effects of adverse events in pharmacoeconomic analysis would be beneficial to improve the reliability of results. Preliminary evidence suggests that programmes aimed at comprehensively assessing geriatric conditions, detecting 'high-risk' prescriptions and training patients to comply with prescribed therapies could be costeffective measures to reduce the burden of ADEs. PMID- 23446790 TI - Conjugal giant cell arteritis. AB - While the pathogenesis of giant cell arteritis (GCA) remains unclear, a number of factors may be contributory, including genetic, environmental, and immune. There have been few reports of GCA occurring in a conjugal pair, all originating from Northern Europe or the Northern United States. We document GCA occurring in a husband and wife from the southern Gulf Coast of the United States and discuss the implications of this, as well as the current understanding of the pathogenesis of GCA. PMID- 23446791 TI - Daughter dearest: Sex-biased calcium in mother's milk among rhesus macaques. AB - Mother's milk provides building blocks necessary for infant development and growth postnatally. Minerals in milk are particularly important for infant skeletal development and may reflect maternal characteristics that are associated with the capacity to synthesize milk and sex-specific developmental priorities of the infant. Using a large sample of mother-infant dyads assigned to the outdoor breeding colony at the California National Primate Research Center (N=104), we investigated the relationship of milk calcium (Ca) and phosphorus (P) concentrations and the ratio of Ca/P to maternal and infant characteristics and to other milk variables. Ca and P are largely associated with casein micelles, and as expected, both Ca and P were positively correlated with protein concentrations in milk. Neither Ca nor P concentrations were associated with maternal parity. Mothers rearing daughters tended to produce higher mean Ca concentration in milk, and consequently a higher Ca/P ratio, than did mothers rearing sons, even though protein concentration was not elevated. These results suggest that the Ca/P ratio in rhesus milk may have been under separate selective pressure from protein content to facilitate the accelerated rate of skeletal calcification that has been observed in female Macaca mulatta infants. PMID- 23446792 TI - Peter-Emil-Becker-Price 2012. PMID- 23446800 TI - A quorum sensing-mediated switch contributes to natural transformation of Vibrio cholerae. AB - There is a fundamental gap in our understanding of how horizontal gene transfer contributes to the enormous range of genetic variations that are observed among bacteria. The objective of our study was to better understand how the acquisition of genetic material by natural transformation is regulated within a population of Vibrio cholerae cells. V. cholerae is an aquatic bacterium and a facultative human pathogen. It acquires natural competence for transformation in response to changing environmental signals, such as the presence of chitinous surfaces, the absence of monomeric sugars and quorum sensing-linked autoinducers. The latter play a distinctive role in V. cholerae as they fine-tune a switch from the degradation of extracellular DNA toward the uptake of intact DNA strands in competence-induced cells. The link between quorum sensing and natural competence for transformation will be discussed. Furthermore, we speculate on the overrepresentation of transformation-negative strains of V. cholerae in patient derived culture collections, which might be the result of a biased sampling strategy as virulence and natural transformation are contrarily regulated by the quorum sensing network. PMID- 23446801 TI - Metal hierarchical patterning by direct nanoimprint lithography. AB - Three-dimensional hierarchical patterning of metals is of paramount importance in diverse fields involving photonics, controlling surface wettability and wearable electronics. Conventionally, this type of structuring is tedious and usually involves layer-by-layer lithographic patterning. Here, we describe a simple process of direct nanoimprint lithography using palladium benzylthiolate, a versatile metal-organic ink, which not only leads to the formation of hierarchical patterns but also is amenable to layer-by-layer stacking of the metal over large areas. The key to achieving such multi-faceted patterning is hysteretic melting of ink, enabling its shaping. It undergoes transformation to metallic palladium under gentle thermal conditions without affecting the integrity of the hierarchical patterns on micro- as well as nanoscale. A metallic rice leaf structure showing anisotropic wetting behavior and woodpile-like structures were thus fabricated. Furthermore, this method is extendable for transferring imprinted structures to a flexible substrate to make them robust enough to sustain numerous bending cycles. PMID- 23446802 TI - Cerebellar mutism caused by primary varicella infection in an immunocompetent child. AB - Varicella (chickenpox) is a common childhood infection caused by the varicella zoster virus, which is often self-limiting and usually benign. Although uncommon, neurologic complications of varicella have been documented that include postinfectious cerebellar ataxia, meningoencephalitis, Reye syndrome, myelitis, optic neuritis, stroke, Guillain-Barre syndrome, seventh cranial nerve palsy, and Ramsay-Hunt syndrome. In this case study, the authors describe a 7-year-old girl who presented with varicella skin rash with unsteady gait and anarthria on day 2, and her condition was attributed to cerebellar mutism. To date, this complication has never been reported in a child with primary varicella infection. Therefore, this case study documents a rare but serious complication of childhood chickenpox. PMID- 23446803 TI - Lower back pain as a symptom of migrainous corpalgia. AB - The symptoms and prevalence of migraine headaches are widely recognized; however, less is known about migraine-related spontaneous body pain, or migrainous corpalgia. Only a few reports have described it. The case of a 13-year-old boy with onset of migrainous corpalgia at the age of 12 years is presented. He suffered from pulsatile headaches and bilateral lower back pain, which would appear either with the headache or as an isolated symptom. Various medical examinations showed no abnormalities. He was diagnosed as having migraine without aura and successfully treated with valproic acid. It is unique for this patient to have lower back pain as a symptom of migrainous corpalgia. It would be important for physicians to understand the variety of pain symptoms in migraine patients, as shown here, for better and comprehensive understanding of migraine and its related condition. PMID- 23446804 TI - Etiology and complications of central nervous system infections in children treated in a pediatric intensive care unit in Poland. AB - Central nervous system infections are significant causes of mortality and long term neurologic complications in children. Survivors often require an extended period of rehabilitation. The authors carried out a retrospective analysis of 1158 children (aged 1 month to 16 years; 31 boys) treated in one pediatric intensive care unit in Warsaw between 2002 and 2010. Forty-three of 1158 (3.7%) children presented with neuroinfections. Nearly two-thirds of the children were younger than age 5 years. The majority of cases (62.8%) were vaccine-preventable bacterial infections. The most frequent complications were brain edema (30.2%), brain hemorrhage (27.9%), and secondary nosocomial pneumonia (25.6%). One-fifth of children developed late, long-term neurologic complications. The mortality rate was 20.9%. The study showed that central nervous system infections are significant causes of hospitalization in the pediatric intensive care unit and often result in death or long-term complications. These infections mainly affect children younger than age 5 years. The majority could be prevented with immunizations. PMID- 23446805 TI - Benzo[a]pyrene induces oxidative stress and endothelial progenitor cell dysfunction via the activation of the NF-kappaB pathway. AB - Smoking is a major risk factor for atherosclerosis. In this study, we evaluated the effects of benzo[a]pyrene (BaP, a prominent component of tobacco smoke) on the function and pro-inflammatory response of human endothelial progenitor cells (EPCs). EPCs were isolated from umbilical cord blood and treated with different concentrations (10, 20 and 50 umol/l) of BaP. The proliferation, migration, adhesion and angiogenesis of BaP-treated EPCs were evaluated using the cell counting kit-8 (CCK-8), Transwell assay, adhesion assay and in vitro tube formation assay, respectively. The activation of nuclear factor-kappaB (NF kappaB) was evaluated by measuring the mRNA expression of NF-kappaB p65 and p50 by real-time RT-PCR and NF-kappaB translocation assay. Reactive oxygen species (ROS) production was determined by the reduction of fluorescent 2',7' dichlorofluorescein diacetate (DCFH-DA). The results demonstrated that BaP treatment significantly inhibited the proliferation, migration, adhesion and angiogenesis of EPCs in vitro. In addition, BaP induced the release of interleukin (IL)-1beta and tumor necrosis factor-alpha from these cells. Moreover, the exposure of EPCs to BaP induced ROS generation and the activation of NF-kappaB. Experiments with EPCs pre-treated with pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB, revealed that the BaP-mediated inhibition of proliferation, migration, adhesion and angiogenesis of EPCs is mainly regulated by NF-kappaB. Thus, tobacco smoke may induce oxidant-mediated stress responses in EPCs and impair their function via the activation of the NF-kappaB pathway. PMID- 23446806 TI - Proposal for a predictive model of erectile function after permanent (125)I prostate brachytherapy for localized prostate cancer. AB - To determine the risk factors for EDin men treated by prostate brachytherapy (PB) for localized prostate cancer and to propose a model to predict post-implant erectile function. Out of a series of 270 sexually active men treated by PB, 241 (89%) (mean age=66 years (range, 43-80)) accepted to participate in a mail-based study on erectile function. The risk factors for erectile dysfunction were determined by regression analysis and a predictive model was proposed. The performance of the model was determined in this population and subsequently verified in a population of 50 men treated by PB in another treatment center. The risk factors for ED after PB were age, the pre-implant IIEF score and prostate volume. In the studied population, the final model to predict a post-treatment IIEF-5 score, using these factors, had a sensitivity of 69% and a specificity of 68% associated to an area under the ROC curve (AUC) of 0.75. The same performance was obtained in another treatment center. Age, pre-implant IIEF-5 score and prostate volume may be used to predict post-implant erectile function in patients treated by PB. PMID- 23446807 TI - Surgical therapy of Peyronie's disease by partial plaque excision and grafting with collagen fleece: feasibility study of a new technique. AB - Surgery is gold-standard for correction of Peyronie's curvature. Grafting is preferred in advanced deviations. We present our novel surgical technique and early results of grafting with collagen fleece. Patients with stable Peyronie's disease (PD) were included. Grafting was performed by a ready-to-use collagen fleece coated with tissue sealant (TachoSil, Nycomed, Konstanz, Germany), following partial plaque excision/incision. Results of correction were documented by artificial erection. In all, n=70 consecutive patients underwent surgery. Mean patient age was 56.4 years (range: 33-72); 88.6% of patients had dorsal deviation, 11.4% lateral or ventral deviation. Grafting after partial plaque excision was performed in 61 patients (87.1%), after plaque incision in 2 (2.9%) patients. In the former patients, mean operative time was 94.2 min (range: 65 165). Totally straightness was achieved in 83.6%. Three patients required surgical drainage because of subcutaneous haematoma formation. After mean early follow-up of 5.2 days (range: 2-15), glans sensation was normal in 56 patients (91.8%). Seven patients (10.0%) underwent Nesbit procedure alone. Grafting by collagen fleece in PD is feasible and promising. Major advantages are decreased operative times and easy application. Moreover, an additional haemostatic effect is provided. However, long-term clinical outcomes are necessary to confirm these encouraging findings. PMID- 23446808 TI - A trend analysis of breast cancer incidence rates in the United States from 2000 to 2009 shows a recent increase. AB - Recent reports have shown that the breast cancer incidence rate in the US stabilized after a sharp reduction in 2002 and 2003. It is important to continue monitoring breast cancer incidence rates according to age group, race/ethnicity, estrogen receptor (ER) status, and tumor stage. Age-standardized breast cancer incidence rates were calculated using data from the surveillance, epidemiology, and end results 18 registries from 2000 to 2009, for 677,774 female breast cancer patients aged 20 and above. Jointpoint regression models were used to fit a series of joined straight lines on a log scale to annual age-standardized rates. The incidence rates of all breast cancer significantly increased for non-Hispanic blacks from 2005 to 2009 (annual percentage change, APC = 2.0 %, p = 0.01) and Asian/Pacific Islanders from 2000 to 2009 (APC = 1.2 %, p = 0.02). Since 2004, incidence rates in women aged 40-49 years significantly increased for most racial/ethnic groups (overall APC = 1.1 %, p = 0.001). The incidence rate of carcinoma in situ significantly increased in all racial/ethnic groups, with an APC range from 2.3 to 3.0 % (p < 0.005). The localized breast cancer incidence significantly increased in non-Hispanic blacks (APC = 1.3 %, p = 0.004) and Asians (APC = 1.2 %, p = 0.03). ER-positive breast cancer significantly increased in almost all age/race sub-groups after 2005 (APC by race: non-Hispanic whites 1.5 %, non-Hispanic blacks 4.3 %, Asian/Pacific Islanders 1.7 %, and Hispanics 1.8 %; all p values <0.05), while ER-negative breast cancer decreased in most sub groups (APC by race: non-Hispanic whites-3.9 %, non-Hispanic blacks-3.7 %, Asian/Pacific Islanders-1.5 %, and Hispanics-4.3 %; all p values <0.05). Recently the incidence of breast cancer appears to be increasing in certain subgroups, including ER-positive, early-stage breast cancers, in particular among non Hispanic blacks and Asian/Pacific Islanders. Further studies are warranted to examine possible reasons for these changes, such as changes in mammography screening methods and risk factors prevalence. PMID- 23446809 TI - Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer. AB - Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188-0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies. PMID- 23446810 TI - Postoperative complications and survival of elderly breast cancer patients: a FOCUS study analysis. AB - Old age is associated with comorbidity and decreased functioning which influences treatment decisions in elderly breast cancer patients. The purpose of this study was to identify risk factors for complications after breast cancer surgery in elderly patients, and to assess mortality in patients with postoperative complications. The FOCUS cohort is a detailed retrospective cohort of all breast cancer patients aged 65 years and older who were diagnosed between 1997 and 2004 in the South-West of the Netherlands. Risk factors for postoperative complications were assessed using univariable and multivariable logistic regression models. One-year survival and overall survival were calculated using univariable and multivariable Cox Regression models, and relative survival was calculated according to the Ederer II method. 3179 patients received surgery, of whom 19 % (n = 618) developed 1 or more postoperative complication(s). The odds ratio of having postoperative complications increased with age [OR 1.85 (95 % confidence interval (CI) 1.37-2.50, p = 0.001) in patients >85 years] and number of concomitant diseases [OR 1.71 (95 % CI 1.30-2.24, p <= 0.001) for 4 or more concomitant diseases]. One-year overall survival, overall survival, and relative survival were worse in patients with postoperative complications [multivariable HR 1.49 (95 % CI 1.05-2.11), p = 0.025. HR 1.21, (95 % CI 1.07-1.36), p = 0.002 and RER 1.19 (95 % CI 1.05-1.34), p = 0.006 respectively]. Stratified for comorbidity, relative survival was lower in patients without comorbidity only. Increasing number of concomitant disease increased the risk of postoperative complications. Although elderly patients with comorbidity did have a higher risk of postoperative complications, relative mortality was not higher in this group. This suggests that postoperative complications in itself did not lead to higher relative mortality, but that the high relative mortality was most likely due to geriatric parameters such as comorbidity or poor physical function. PMID- 23446811 TI - The protective effect of intermittent calorie restriction on mammary tumorigenesis is not compromised by consumption of a high fat diet during refeeding. AB - Previously we reported that intermittent calorie restriction (ICR) provided greater prevention of mammary tumors (MTs) than chronic calorie restriction (CCR). Here the impact of increased fat intake during refeeding in an ICR protocol was evaluated. MMTV-TGF-alpha female mice were assigned to one of three groups: ad libitum (AL) fed (n = 45) with free access to a moderately high fat diet (22 % fat calories); ICR (n = 45) 50 % calorie restricted for 3-week intervals followed by 3 weeks of 100 % of AL intake; and CCR (n = 45) fed 75 % of AL mice, matching each 6-week cycle of ICR mice. ICR mice were further designated as ICR-Restricted or ICR-Refed for data obtained during these intervals. All mice consumed the same absolute amount of dietary fat. Mice were followed to assess MT incidence, body weight and serum IGF-1, IGFBP3, leptin and adiponectin levels until 79 (end of final 3-week restriction) or 82 (end of final 3-weeks refeeding) weeks of age. Age of MT detection was significantly extended for CCR (74 weeks) and ICR (82 weeks) mice, compared to 57.5 weeks for AL mice. MT incidence for AL, ICR and CCR mice was 66.7, 4.4, and 52.3 %, respectively. Mammary and fat pad weights were reduced significantly following 50 % calorie restriction in ICR Restricted mice compared to AL, CCR and ICR-Refed mice. IGF-1 and leptin levels also tended to be reduced in ICR-Restricted mice over the course of the study while adiponectin was not compared to AL, CCR, and ICR-Refed mice. The adiponectin:leptin ratio was consistently higher following 50 % restriction in ICR-Restricted mice. There was no relationship of IGF-1, leptin, or adiponectin with the presence of MTs in any groups. Thus the manner in which calories are restricted impacts the protective effect of calorie restriction independently of high fat intake. PMID- 23446812 TI - Fluoroscopic evaluation of tongue and jaw movements during mastication in healthy humans. AB - When chewing solid food, part of the bolus is propelled into the oropharynx before swallowing; this is named stage II transport (St2Tr). However, the tongue movement patterns that comprise St2Tr remain unclear. We investigated coronal jaw and tongue movements using videofluorography. Fourteen healthy young adults ate 6 g each of banana, cookie, and meat (four trials per foodstuff). Small lead markers were glued to the teeth and tongue surface to track movements by videofluorography in the anteroposterior projection. Recordings were divided into jaw motion cycles of four types: stage I transport (St1Tr), chewing, St2Tr, and swallowing. The range of horizontal tongue motion was significantly larger during St1Tr and chewing than during St2Tr and swallowing, whereas vertical tongue movements were significantly larger during chewing and St2Tr than during swallowing. Tongue movements varied significantly with food consistency. We conclude that the small horizontal tongue marker movements during St2Tr and swallowing were consistent with a "squeeze-back" mechanism of bolus propulsion. The vertical dimension was large in chewing and St2Tr, perhaps because of food particle reduction and transport in chewing and St2Tr. PMID- 23446813 TI - Diagnosis and treatment of phagophobia: a review. AB - This narrative review summarizes published studies on diagnostic examinations and therapeutic interventions for phagophobia. The electronic databases Embase, PubMed, PsycINFO((r)), and The Cochrane Library were used. The literature search was limited to publications in the English, German, French, Spanish, or Dutch language. The original articles are summarized in the present narrative review. The body of literature on phagophobia and swallowing fear remains very limited; only 12 studies were found. The present narrative review discovered heterogeneity in the definitions of phagophobia or similar syndromes. A systematic review, including a qualitative analysis, was planned but not carried out as studies were not of sufficient quality to warrant doing so. All the studies had severe methodological shortcomings. In general, the conclusions could not be compared across the studies because of the different study designs, small populations, different ways of evaluating and treating phagophobia, and complex combinations of treatments. A general conclusion is provided. PMID- 23446814 TI - Influence of the multidrug transporter P-glycoprotein on the intracellular pharmacokinetics of vandetanib. AB - Efflux transporters play an important role in the resistance of tumor cells against anticancer agents. Interaction between these transporters, including P glycoprotein (P-gp), and drugs might influence their pharmacological properties and toxicities. The aim of this study was to investigate whether vandetanib (Caprelsa((r))), a small tyrosine kinase inhibitor, could interact with the multidrug transporter P-gp. Interaction of vandetanib with the P-gp was investigated using the parental cell line (IGROV1) and the P-gp doxorubicin resistant (IGROV1-DXR) cell line, derived from the parental drug-sensitive IGROV1 cells. Cytotoxicity tests were assessed in both cell lines to examine the impact of P-gp on the cell survival after a vandetanib treatment. The effects of P-gp on vandetanib intracellular pharmacokinetics were investigated. To this aim, we developed a quantitative liquid chromatography tandem mass spectrometry to quantify vandetanib in cell medium. Results showed that overexpression of P-gp confers resistance to vandetanib in the IGROV1-DXR cell line. Using a LC-MS/MS assay validated in cell medium, cellular pharmacokinetic studies revealed that in cells overexpressing the P-gp intracellular concentrations of vandetanib were decreased compared to parental cell line. For the first time, vandetanib is described as a substrate of P-gp. In tumor cells, P-gp could be responsible for cellular resistance to vandetanib. It may be relevant to the clinical efficacy of vandetanib. Moreover, interaction of vandetanib with P-gp could modify the pharmacodynamics of other conventional chemotherapeutics, substrates of P-gp. It could impact on the overall response to anticancer therapy. PMID- 23446815 TI - Genotype-phenotype correlation of cytochrome P450 2C9 polymorphism in Indian National Capital Region. AB - Identification of polymorphism of cytochrome P450 2C9 (CYP2C9) enzymes in different ethnic populations is important to understand the differences in clinical responses to drugs. This study determines the CYP2C9 genetic polymorphism in Indian National Capital Region and correlates the phenotype genotype. Losartan (25 mg) was administered to 107 volunteers to assess CYP2C9 activity, and, on the basis of results, volunteers were categorized as rapid and poor metabolizers. Molecular typing of CYP2C9*1 (wild type), CYP2C9*2, and CYP2C9*3 (the most common variant) was carried out by single-base primer extension technology for 37 subjects, of which 9 were poor metabolizers, and 28 were rapid metabolizers. 14.28 % of the studied population was identified as poor metabolizer for the category of drugs metabolized by CYP2C9. Significant difference was observed between the mean ratio (drug/metabolite) of poor (11.38 +/- 5.88) and rapid (1.18 +/- 1.11) drug metabolizers. The study suggests that phenotyping of CYP2C9 is desirable before enrollment of subjects for clinical trials or for deciding drug dose regimen as 14.28 % of study population was found to be poor metabolizer for the category of drugs metabolized by CYP2C9. This study establishes phenotype-genotype correlation, and proposes to use genotyping or phenotyping to evaluate the status of drug metabolizing capacity of CYP2C9 as a primary screening procedure before enrolling subjects in clinical trials or in clinical practice. PMID- 23446816 TI - Copper-catalyzed aromatic C-H bond halogenation with lithium halides under aerobic conditions. AB - A concise and practical Cu-catalyzed protocol for the preparation of chloro- and bromoarenes via C-H bond activation has been developed. The advantages of this strategy are the employment of cheap Cu(NO3)2.3H2O, LiX and O2, and its compatibility with both electron-donating and electron-withdrawing substituents on aryl rings. PMID- 23446817 TI - Dual-chamber implantable cardioverter-defibrillators for nonpacing indications: comment on "variation in use of dual-chamber implantable cardioverter defibrillators". PMID- 23446819 TI - Model studies of heterogeneous catalytic hydrogenation reactions with gold. AB - Supported gold nanoparticles have recently been shown to possess intriguing catalytic activity for hydrogenation reactions, particularly for selective hydrogenation reactions. However, fundamental studies that can provide insight into the reaction mechanisms responsible for this activity have been largely lacking. In this tutorial review, we highlight several recent model experiments and theoretical calculations on a well-structured gold surface that provide some insights. In addition to the behavior of hydrogen on a model gold surface, we review the reactivity of hydrogen on a model gold surface in regards to NO2 reduction, chemoselective C=O bond hydrogenation, ether formation, and O-H bond dissociation in water and alcohols. Those studies indicate that atomic hydrogen has a weak interaction with gold surfaces which likely plays a key role in the unique hydrogenative chemistry of classical gold catalysts. PMID- 23446818 TI - The BaeSR regulon is involved in defense against zinc toxicity in E. coli. AB - Intracellular zinc homeostasis is regulated by an extensive network of transporters, ligands and transcription factors. The zinc detoxification functions of three transporters and a periplasmic protein regulated by the BaeSR two-component system were explored in this work by evaluating the effect of single gene knockouts in the BaeSR regulon on the cell growth rate, free zinc, total zinc and total copper after zinc shock. Two exporters, MdtABC and MdtD, and the periplasmic protein, Spy, are involved in zinc detoxification based on the growth defects at high cell density and increases in free (>1000-fold) and total zinc/copper (>2-fold) that were observed in the single knockout strains upon exposure to zinc. These proteins complement the ATP-driven zinc export mediated by ZntA in E. coli to limit zinc toxicity. These results highlight the functions of the BaeSR regulon in metal homeostasis. PMID- 23446820 TI - Total synthesis of padanamides A and B. AB - The first total syntheses of padanamides A and B have been achieved, unambiguously confirming their structures. PMID- 23446821 TI - Vaccination and clinical severity: is the effectiveness of contact tracing and case isolation hampered by past vaccination? AB - While contact tracing and case isolation are considered as the first choice of interventions against a smallpox bioterrorist event, their effectiveness under vaccination is questioned, because not only susceptibility of host and infectiousness of case but also the risk of severe clinical manifestations among cases is known to be reduced by vaccine-induced immunity, thereby potentially delaying the diagnosis and increasing mobility among vaccinated cases. We employed a multi-type stochastic epidemic model, aiming to assess the feasibility of contact tracing and case isolation in a partially vaccinated population and identify data gaps. We computed four epidemiological outcome measures, i.e., (i) the threshold of a major epidemic under the interventions; (ii) the expected total number of cases; (iii) the probability of extinction, and (iv) the expected duration of an outbreak, demonstrating that all of these outcomes critically depend on the clinical impact of past vaccination on the diagnosis and movement of vaccinated cases. We discuss that, even in the absence of smallpox in the present day, one should consider the way to empirically quantify the delay in case detection and an increase in the frequency of contacts among previously vaccinated cases compared to unvaccinated during the early stage of an epidemic so that the feasibility of contact tracing and case isolation in a vaccinated population can be explicitly assessed. PMID- 23446822 TI - Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH-RH analogue with tamoxifen: results of the JMTO BC08-01 phase II trial. AB - The aim of the present study was to assess the efficacy and tolerability of a luteinizing hormone-releasing hormone (LH-RH) analogue plus an aromatase inhibitor following failure to respond to standard LH-RH analogue plus tamoxifen (TAM) in premenopausal patients. Premenopausal women with estrogen receptor (ER) positive and/or progesterone-receptor positive, advanced or recurrent breast cancer refractory to an LH-RH analogue plus TAM received goserelin (GOS) in conjunction with anastrozole (ANA). The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Between September 2008 and November 2010, 37 patients were enrolled. Thirty-five patients (94.6%) had ER-positive tumors, and 36 (97.3%) had human epidermal growth factor receptor (HER) 2-negative tumors. Thirty-six (97.3%) had measurable lesions and 1 (2.7%) had only bone metastasis. The ORR was 18.9% [95% confidence interval (CI), 8.0-35.2%], the CBR was 62.2% (95% CI, 44.8-77.5%) and the median PFS was 7.3 months. Eight patients had adverse drug reactions but none resulted in discontinuation of treatment. GOS plus ANA is a safe effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast cancer. The treatment may become viable treatment in the future, particularly when TAM is ineffective or contraindicated. Further studies and discussion are warranted. PMID- 23446823 TI - Prophylactic antibiotics in open fractures: a pilot randomized clinical safety study. AB - OBJECTIVE: To develop preliminary data on Staphylococcus aureus colonization and surgical site infections (SSIs) in patients with open fractures who received standard antibiotic prophylaxis compared with a regimen including targeted methicillin-resistant Staphylococcus aureus (MRSA) coverage. DESIGN: Randomized prospective clinical trial. PATIENTS: Adult patients who presented to the emergency department with an open fracture between April 2009 and July 2011. INTERVENTIONS: One hundred thirty patients were randomized to receive prophylaxis with either cefazolin alone (control arm) or vancomycin and cefazolin (experimental arm) from presentation to the emergency department until 24 hours after the surgical intervention. Screening for S. aureus carriage was performed with nares swabs and predebridement and postdebridement open fracture wound swabs. Patients underwent prospective assessment for the development of SSI for no less than 30 days and up to 12 months. RESULTS: Nasal colonization of methicillin-sensitive S. aureus and MRSA among the sample was 20% and 3%, respectively. No significant difference in the rates of SSI was observed between the study arms (15% vs 19%, respectively, P = 0.62). Staphylococcus aureus caused 55% of the deep incisional/organ space SSI, with 18% attributed to MRSA. A significantly higher rate of MRSA SSIs was observed among MRSA carriers compared with noncarriers (33% vs 1%, respectively, P = 0.003). CONCLUSIONS: Staphylococcus aureus nasal colonization in trauma patients with open fractures is similar to that of the general community. In this pilot study, the addition of vancomycin to standard antibiotic prophylaxis was found safe, but its efficacy should be evaluated in a larger multiinstitutional trial. PMID- 23446824 TI - [Quality control of printed patient information]. AB - Printed material is an important part in patient information and is called bibliotherapy. It is subject to quality control similar to any other types of treatment. This paper presents an outline of important quality criteria and methods of quality control. Important quality criteria are: (a) Correctness and validity of content evaluated by mentioning the expertise of the authors, appraisal through external experts, reference to scientific literature, and empirical tests of the content, (b) Readability in respect to text structure measured by the "Flesch-Reading-Ease-Formula" supported by fair graphical design including fond and structure of text, (c) Comprehensibility tested by feedback of patients or standardized by the Hamburg comprehensibility rating, (d) Utility including securing availability, acceptance, differential indication and use. Writing and publication of patient leaflets must be accompanied by quality control measures. PMID- 23446825 TI - [Associations of resources factors, chronic activated distress, and fatigue in the German general population]. AB - The study examined the relationships of resources, chronic activated distress, and fatigue. Data acquisition was carried out by a market research institute in a multitopic questionnaire in the general population (N=2 552). Administered were the TICS, the CFS-Scale, and the SWOP. The analyses focused on structural equation modelling. Hypotheses derived from a demands-resources model proved to be most worthwhile. Especially dispositional optimism, seemed to be most relevant. The prevalence rate for elevated chronic stress was 19.1%. Group differences were significant for age but not for gender. Part-time worker exhibited the highest rates of chronic stress. A lower social economic status also favoured an increased chronic stress experience. Theoretical implications, practical consequences for health promotion and prevention as well as limitations of the study are discussed. PMID- 23446826 TI - [Dimensions of parental rearing styles in alcohol dependent patients: first results of the questionnaire on parental attitudes and rearing practices (FEPS)]. AB - To date no instrument for the assessment of parenting styles is available in the German -language area that has been validated in patients with addictive disorders. Therefore the aim of this study was the confirmatory evaluation of the factor structure of the Questionnaire on Parental Attitudes and Rearing Practices (FEPS) in 186 alcohol dependent patients. The model as proposed by the test developers with the 4 factors Care, Autonomy, Low Punishment, and Low Material Reinforcement showed acceptable fit when residual correlations were allowed (mother: chi(2)/df=1,92, RMSEA=0,07, TLI=0,79; father: chi(2)/df=1,75, RMSEA=0,07, TLI=0,82). All factors showed sufficient factor reliabilities as well as good to very good internal consistencies. Factor loadings, discriminations and difficulties of the indicators could be regarded as good, with the exception of 2 items. These results indicate the factorial validity of the FEPS in patients with alcohol dependence. PMID- 23446827 TI - Addressing injecting drug use in Asia and Eastern Europe. AB - While the global HIV incidence dropped about 20% in the past 10 years, HIV incidences among people who inject drugs (PWID) in Asia and Europe continue to increase and to account for high proportions of new HIV infections among PWID globally. Great changes have been observed in this region, such as progressing from rejection to acceptance of harm reduction strategies in Asian countries, but no such change has occurred in Eastern European countries. China has quickly scaled up harm reduction activities nationwide, resulting in the decline of HIV incidence and HIV prevalence among PWID since 2006. However, insufficient scaling up of harm reduction programs in other countries has failed to slow down their HIV epidemics. In Eastern European countries where the spread of HIV among PWID is the most severe, only about 15% of funding for harm reduction programs are from domestic sources. Strong political and financial commitment from countries in this region is urgently needed to quickly scale up evidence-based harm reduction strategies in order to prevent the HIV epidemic from spreading rapidly from PWID to the heterosexual general population. PMID- 23446828 TI - Genetic determinant for amino acid metabolites and changes in body weight and insulin resistance in response to weight-loss diets: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial. AB - BACKGROUND: Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial. METHODS AND RESULTS: We genotyped the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all P for interaction <=0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P <= 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group (P=0.02 and P=0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss (P=0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain. CONCLUSIONS: Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00072995. PMID- 23446829 TI - Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases. AB - BACKGROUND: Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases. METHODS AND RESULTS: By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used beta-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters. CONCLUSIONS: Hemopexin treatment is a promising novel therapy to protect against heme-induced cardiovascular dysfunction in hemolytic disorders. PMID- 23446830 TI - Metabolic model for the filamentous 'Candidatus Microthrix parvicella' based on genomic and metagenomic analyses. AB - 'Candidatus Microthrix parvicella' is a lipid-accumulating, filamentous bacterium so far found only in activated sludge wastewater treatment plants, where it is a common causative agent of sludge separation problems. Despite attracting considerable interest, its detailed physiology is still unclear. In this study, the genome of the RN1 strain was sequenced and annotated, which facilitated the construction of a theoretical metabolic model based on available in situ and axenic experimental data. This model proposes that under anaerobic conditions, this organism accumulates preferentially long-chain fatty acids as triacylglycerols. Utilisation of trehalose and/or polyphosphate stores or partial oxidation of long-chain fatty acids may supply the energy required for anaerobic lipid uptake and storage. Comparing the genome sequence of this isolate with metagenomes from two full-scale wastewater treatment plants with enhanced biological phosphorus removal reveals high similarity, with few metabolic differences between the axenic and the dominant community 'Ca. M. parvicella' strains. Hence, the metabolic model presented in this paper could be considered generally applicable to strains in full-scale treatment systems. The genomic information obtained here will provide the basis for future research into in situ gene expression and regulation. Such information will give substantial insight into the ecophysiology of this unusual and biotechnologically important filamentous bacterium. PMID- 23446831 TI - Short-term observations of marine bacterial and viral communities: patterns, connections and resilience. AB - Observation of short-term temporal variation in bacterial and viral communities is important for understanding patterns of aquatic microbial diversity. We collected surface seawater once daily for 38 consecutive days with seven more samples interspersed over 40 more days at one location ~2 km from Santa Catalina Island, California. Bacterial communities were analyzed by automated ribosomal intergenic spacer analysis (ARISA) and viral communities were analyzed by terminal restriction fragment length polymorphism (TRFLP) of the conserved T4 like myoviral gene encoding the major capsid protein (g23). Common bacterial and viral taxa were consistently dominant, and relatively few displayed dramatic increases/decreases or 'boom/bust' patterns that might be expected from dynamic predator-prey interactions. Association network analysis showed most significant covariations (associations) occurred among bacterial taxa or among viral taxa and there were several modular (highly-interconnected) associations (P<=0.005). Associations observed between bacteria and viruses (P<=0.005) occurred with a median time lag of 2 days. Regression of all pairwise Bray-Curtis similarities between samples indicated a rate of bacterial community change that slows from 2.1%-0.18% per day over a week to 2 months; the rate stays around 0.4% per day for viruses. Our interpretation is that, over the scale of days, individual bacterial and viral OTUs can be dynamic and patterned; resulting in statistical associations regarded as potential ecological interactions. However, over the scale of weeks, average bacterial community variation is slower, suggesting that there is strong community-level ecological resilience, that is, a tendency to converge towards a 'mean' microbial community set by longer-term controlling factors. PMID- 23446832 TI - Enrichment of specific protozoan populations during in situ bioremediation of uranium-contaminated groundwater. AB - The importance of bacteria in the anaerobic bioremediation of groundwater polluted with organic and/or metal contaminants is well recognized and in some instances so well understood that modeling of the in situ metabolic activity of the relevant subsurface microorganisms in response to changes in subsurface geochemistry is feasible. However, a potentially significant factor influencing bacterial growth and activity in the subsurface that has not been adequately addressed is protozoan predation of the microorganisms responsible for bioremediation. In field experiments at a uranium-contaminated aquifer located in Rifle, CO, USA, acetate amendments initially promoted the growth of metal reducing Geobacter species, followed by the growth of sulfate reducers, as observed previously. Analysis of 18S rRNA gene sequences revealed a broad diversity of sequences closely related to known bacteriovorous protozoa in the groundwater before the addition of acetate. The bloom of Geobacter species was accompanied by a specific enrichment of sequences most closely related to the ameboid flagellate, Breviata anathema, which at their peak accounted for over 80% of the sequences recovered. The abundance of Geobacter species declined following the rapid emergence of B. anathema. The subsequent growth of sulfate-reducing Peptococcaceae was accompanied by another specific enrichment of protozoa, but with sequences most similar to diplomonadid flagellates from the family Hexamitidae, which accounted for up to 100% of the sequences recovered during this phase of the bioremediation. These results suggest a prey-predator response with specific protozoa responding to increased availability of preferred prey bacteria. Thus, quantifying the influence of protozoan predation on the growth, activity and composition of the subsurface bacterial community is essential for predictive modeling of in situ uranium bioremediation strategies. PMID- 23446833 TI - Active nitrogen-fixing heterotrophic bacteria at and below the chemocline of the central Baltic Sea. AB - The Baltic Sea receives large nitrogen inputs by diazotrophic (N2-fixing) heterocystous cyanobacteria but the significance of heterotrophic N2 fixation has not been studied. Here, the diversity, abundance and transcription of the nifH fragment of the nitrogenase enzyme in two basins of the Baltic Sea proper was examined. N2 fixation was measured at the surface (5 m) and in anoxic water (200 m). Vertical sampling profiles of >10 and <10 MUm size fractions were collected in 2007, 2008 and 2011 at the Gotland Deep and in 2011 in the Bornholm Basin. Both of these stations are characterized by permanently anoxic bottom water. The 454-pyrosequencing nifH analysis revealed a diverse assemblage of nifH genes related to alpha-, beta- and gammaproteobacteria (nifH cluster I) and anaerobic bacteria (nifH cluster III) at and below the chemocline. Abundances of genes and transcripts of seven diazotrophic phylotypes were investigated using quantitative polymerase chain reaction revealing abundances of heterotrophic nifH phylotypes of up to 2.1 * 10(7) nifH copies l(-1). Abundant nifH transcripts (up to 3.2 * 10(4) transcripts l(-1)) within nifH cluster III and co-occurring N2 fixation (0.44+/-0.26 nmol l(-1) day(-1)) in deep water suggests that heterotrophic diazotrophs are fixing N2 in anoxic ammonium-rich waters. Our results reveal that N2 fixation in the Baltic Sea is not limited to illuminated N-deplete surface waters and suggest that N2 fixation could also be of importance in other suboxic regions of the world's oceans. PMID- 23446834 TI - Diversification of endosymbiosis: replacements, co-speciation and promiscuity of bacteriocyte symbionts in weevils. AB - The processes and mechanisms underlying the diversification of host-microbe endosymbiotic associations are of evolutionary interest. Here we investigated the bacteriocyte-associated primary symbionts of weevils wherein the ancient symbiont Nardonella has experienced two independent replacement events: once by Curculioniphilus symbiont in the lineage of Curculio and allied weevils of the tribe Curculionini, and once by Sodalis-allied symbiont in the lineage of grain weevils of the genus Sitophilus. The Curculioniphilus symbiont was detected from 27 of 36 Curculionini species examined, the symbiont phylogeny was congruent with the host weevil phylogeny, and the symbiont gene sequences exhibited AT-biased nucleotide compositions and accelerated molecular evolution. These results suggest that the Curculioniphilus symbiont was acquired by an ancestor of the tribe Curculionini, replaced the original symbiont Nardonella, and has co speciated with the host weevils over evolutionary time, but has been occasionally lost in several host lineages. By contrast, the Sodalis-allied symbiont of Sitophilus weevils exhibited no host-symbiont co-speciation, no AT-biased nucleotide compositions and only moderately accelerated molecular evolution. These results suggest that the Sodalis-allied symbiont was certainly acquired by an ancestor of the Sitophilus weevils and replaced the original Nardonella symbiont, but the symbiotic association must have experienced occasional re associations such as new acquisitions, horizontal transfers, replacements and/or losses. We detected Sodalis-allied facultative symbionts in populations of the Curculionini weevils, which might represent potential evolutionary sources of the Sodalis-allied primary symbionts. Comparison of these newcomer bacteriocyte associated symbiont lineages highlights potential evolutionary trajectories and consequences of novel symbionts after independent replacements of the same ancient symbiont. PMID- 23446835 TI - The biogeography of fungal communities in wetland sediments along the Changjiang River and other sites in China. AB - Whether fungal community structure depends more on historical factors or on contemporary factors is controversial. This study used culture-dependent and independent (polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE)) methods to assess the influence of historical and contemporary factors on the distributions of fungi in the wetland sediments at 10 locations along the Changjiang River and at 10 other locations in China. The culture dependent approach detected greater species diversity (177 operational taxonomic units (OTUs)) than PCR-DGGE analysis (145 OTUs), and the species in the genera of Penicillium (relative frequency=16.8%), Fusarium (15.4%), Aspergillus (7.6%), Trichoderma (5.8%) and Talaromyces (4.2%) were dominant. On the basis of DGGE data, fungal diversity along the Changjiang River increased from upstream to downstream; altitude explained 44.8% of this variation in diversity. And based on the data from all 20 locations, the fungal communities were geographically clustered into three groups: Southern China, Northern China and the Qinghai Tibetan Plateau. Multivariate regression tree analysis for data from the 20 locations indicated that the fungal community was influenced primarily by location (which explained 61.8% of the variation at a large scale), followed by total potassium (9.4%) and total nitrogen (3.5%) at a local scale. These results are consistent with the concept that geographic distance is the dominant factor driving variation in fungal diversity at a regional scale (1000-4000 km), whereas environmental factors (total potassium and total nitrogen) explain variation in fungal diversity at a local scale (<1000 km). PMID- 23446836 TI - Archaeal and anaerobic methane oxidizer communities in the Sonora Margin cold seeps, Guaymas Basin (Gulf of California). AB - Cold seeps, located along the Sonora Margin transform fault in the Guaymas Basin, were extensively explored during the 'BIG' cruise in June 2010. They present a seafloor mosaic pattern consisting of different faunal assemblages and microbial mats. To investigate this mostly unknown cold and hydrocarbon-rich environment, geochemical and microbiological surveys of the sediments underlying two microbial mats and a surrounding macrofaunal habitat were analyzed in detail. The geochemical measurements suggest biogenic methane production and local advective sulfate-rich fluxes in the sediments. The distributions of archaeal communities, particularly those involved in the methane cycle, were investigated at different depths (surface to 18 cm below the sea floor (cmbsf)) using complementary molecular approaches, such as Automated method of Ribosomal Intergenic Spacer Analysis (ARISA), 16S rRNA libraries, fluorescence in situ hybridization and quantitative polymerase chain reaction with new specific primer sets targeting methanogenic and anaerobic methanotrophic lineages. Molecular results indicate that metabolically active archaeal communities were dominated by known clades of anaerobic methane oxidizers (archaeal anaerobic methanotroph (ANME)-1, -2 and 3), including a novel 'ANME-2c Sonora' lineage. ANME-2c were found to be dominant, metabolically active and physically associated with syntrophic Bacteria in sulfate-rich shallow sediment layers. In contrast, ANME-1 were more prevalent in the deepest sediment samples and presented a versatile behavior in terms of syntrophic association, depending on the sulfate concentration. ANME-3 were concentrated in small aggregates without bacterial partners in a restricted sediment horizon below the first centimetres. These niche specificities and syntrophic behaviors, depending on biological surface assemblages and environmental availability of electron donors, acceptors and carbon substrates, suggest that ANME could support alternative metabolic pathways than syntrophic anaerobic oxidation of methane. PMID- 23446837 TI - Phylogenetic beta diversity in bacterial assemblages across ecosystems: deterministic versus stochastic processes. AB - Increasing evidence has emerged for non-random spatial distributions of microbes, but knowledge of the processes that cause variation in microbial assemblage among ecosystems is lacking. For instance, some studies showed that deterministic processes such as habitat specialization are important, while other studies hold that bacterial communities are assembled by stochastic forces. Here we examine the relative influence of deterministic and stochastic processes for bacterial communities from subsurface environments, stream biofilm, lake water, lake sediment and soil using pyrosequencing of the 16S ribosomal RNA gene. We show that there is a general pattern in phylogenetic signal in species ecological niches across recent evolutionary time for all studied habitats, enabling us to infer the influences of community assembly processes from patterns of phylogenetic turnover in community composition. The phylogenetic dissimilarities among-habitat types were significantly higher than within them, and the communities were clustered according to their original habitat types. For communities within-habitat types, the highest phylogenetic turnover rate through space was observed in subsurface environments, followed by stream biofilm on mountainsides, whereas the sediment assemblages across regional scales showed the lowest turnover rate. Quantifying phylogenetic turnover as the deviation from a null expectation suggested that measured environmental variables imposed strong selection on bacterial communities for nearly all sample groups. For three sample groups, spatial distance reflected unmeasured environmental variables that impose selection, as opposed to spatial isolation. Such characterization of spatial and environmental variables proved essential for proper interpretation of partial Mantel results based on observed beta diversity metrics. In summary, our results clearly indicate a dominant role of deterministic processes on bacterial assemblages and highlight that bacteria show strong habitat associations that have likely emerged through evolutionary adaptation. PMID- 23446838 TI - Emergence of network features from multiplexity. AB - Many biological and man-made networked systems are characterized by the simultaneous presence of different sub-networks organized in separate layers, with links and nodes of qualitatively different types. While during the past few years theoretical studies have examined a variety of structural features of complex networks, the outstanding question is whether such features are characterizing all single layers, or rather emerge as a result of coarse graining, i.e. when going from the multilayered to the aggregate network representation. Here we address this issue with the help of real data. We analyze the structural properties of an intrinsically multilayered real network, the European Air Transportation Multiplex Network in which each commercial airline defines a network layer. We examine how several structural measures evolve as layers are progressively merged together. In particular, we discuss how the topology of each layer affects the emergence of structural properties in the aggregate network. PMID- 23446839 TI - Sex differences in structural brain asymmetry predict overt aggression in early adolescents. AB - The devastating social, emotional and economic consequences of human aggression are laid bare nightly on newscasts around the world. Aggression is principally mediated by neural circuitry comprising multiple areas of the prefrontal cortex and limbic system, including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), amygdala and hippocampus. A striking characteristic of these regions is their structural asymmetry about the midline (i.e. left vs right hemisphere). Variations in these asymmetries have been linked to clinical disorders characterized by aggression and the rate of aggressive behavior in psychiatric patients. Here, we show for the first time that structural asymmetries in prefrontal cortical areas are also linked to aggression in a normal population of early adolescents. Our findings indicate a relationship between parent reports of aggressive behavior in adolescents and structural asymmetries in the limbic and paralimbic ACC and OFC, and moreover, that this relationship varies by sex. Furthermore, while there was no relationship between aggression and structural asymmetries in the amygdala or hippocampus, hippocampal volumes did predict aggression in females. Taken together, the results suggest that structural asymmetries in the prefrontal cortex may influence human aggression, and that the anatomical basis of aggression varies substantially by sex. PMID- 23446840 TI - Neural mechanisms underlying the integration of situational information into attribution outcomes. AB - When forming impressions and trying to figure out why other people behave the way they do, we should take into account not only dispositional factors (i.e., personality traits) but also situational constraints as potential causes for a behavior. However, in their attributions, people often ignore the importance of situational factors. To investigate the neural mechanisms underlying the integration of situational information into attributions, we decomposed the attribution process by separately presenting information about behaviors and about the situational circumstances in which they occur. After reading the information, participants judged whether dispositional or situational causes explained the behavior (attribution), and how much they liked the person described in the scenario (affective evaluation). The dorsolateral prefrontal cortex showed increased blood oxygenation-level-dependent activation during the encoding of situational information when the resulting attribution was situational, relative to when the attribution was dispositional, potentially reflecting a controlled process that integrates situational information into attributions. Interestingly, attributions were strongly linked to subsequent affective evaluations, with the dorsomedial prefrontal cortex emerging as potential substrate of the integration of attributions and affective evaluations. Our findings demonstrate how top-down control processes regulate impression formation when situational information is taken into account to understand others. PMID- 23446842 TI - p73 participates in WWOX-mediated apoptosis in leukemia cells. AB - The WWOX gene is considered to be a tumor-suppressor gene which encodes a protein (Wwox) implicated in various types of solid human cancers. It has been shown that overexpression of WWOX in human tumors promotes apoptosis in vitro and suppresses tumor growth in vivo. Recently, we investigated the effects of WWOX overexpression in vitro and observed marked growth arrest in human leukemia cells; however, the underlying mechanism(s) for this effect is unknown. The present study aimed to elucidate the primary mechanism(s) underlying WWOX mediated apoptosis in human leukemia. We traced the interactions between WWOX and its associated factors p73 and p53 after WWOX overexpression was induced in Jurkat and K562 cells. Our data revealed that p73 participates in WWOX-mediated apoptosis in Jurkat and K562 cells through binding with Wwox in the cytoplasm without a nuclear-cytoplasmic translocation. PMID- 23446843 TI - Do diagnostic and treatment delays for colorectal cancer increase risk of death? AB - BACKGROUND: Using 1998-2005 SEER-Medicare data, we examined the effect of diagnostic and treatment delays on all-cause and colorectal cancer (CRC)-specific death among US adults aged >= 66 years with invasive colon or rectal cancer. We hypothesized that longer delays would be associated with a greater risk of death. METHODS: We defined diagnostic and treatment delays, respectively, as days between (1) initial medical consult for CRC symptoms and pathologically confirmed diagnosis (maximum: 365 days) and (2) pathologically confirmed diagnosis and treatment (maximum: 120 days). Cases (CRC deaths) and controls (deaths due to other causes or censored) were matched on survival time. Logistic regression analyses adjusted for sociodemographic, tumor, and treatment factors. RESULTS: Median diagnostic delays were 60 (colon) and 40 (rectal) days and treatment delays were 13 (colon) and 16 (rectal) days in 10,663 patients. Colon cancer patients with the longest diagnostic delays (8-12 months vs. 14-59 days) had higher odds of all-cause (aOR: 1.31 CI: 1.08-1.58), but not CRC-specific death. Colon cancer patients with the shortest treatment delays (<1 vs. 1-2 weeks) had higher odds of all-cause (aOR: 1.23 CI: 1.01-1.49), but not CRC-specific death. Among rectal cancer patients, delays were not associated with risk of all-cause or CRC-specific death. CONCLUSIONS: Longer delays of up to 1 year after symptom onset and 120 days for treatment did not increase odds of CRC-specific death. There may be little clinical benefit in detecting and treating existing symptomatic disease earlier. Screening prior to symptom onset must remain the primary goal to reduce CRC incidence, morbidity, and mortality. PMID- 23446845 TI - From association to mechanism: comment on "antipsychotic use and myocardial infarction in older patients with treated dementia". PMID- 23446844 TI - Gene expression as a biomarker for human radiation exposure. AB - Accidental exposure to ionizing radiation can be unforeseen, rapid, and devastating. The detonation of a radiological device leading to such an exposure can be detrimental to the exposed population. The radiation-induced damage may manifest as acute effects that can be detected clinically or may be more subtle effects that can lead to long-term radiation-induced abnormalities. Accurate identification of the individuals exposed to radiation is challenging. The availability of a rapid and effective screening test that could be used as a biomarker of radiation exposure detection is mandatory. We tested the suitability of alterations in gene expression to serve as a biomarker of human radiation exposure. To develop a useful gene expression biomonitor, however, gene expression changes occurring in response to irradiation in vivo must be measured directly. Patients undergoing radiation therapy provide a suitable test population for this purpose. We examined the expression of CC3, MADH7, and SEC PRO in blood samples of these patients before and after radiotherapy to measure the in vivo response. The gene expression after ionizing radiation treatment varied among different patients, suggesting the complexity of the response. The expression of the SEC PRO gene was repressed in most of the patients. The MADH7 gene was found to be upregulated in most of the subjects and could serve as a molecular marker of radiation exposure. PMID- 23446846 TI - The -308 G>A SNP of TNFA is a factor predisposing to chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarian individuals: conclusions of a genetic study with multiple stratifications. AB - Single nucleotide polymorphisms (SNPs) of the tumour necrosis factor alpha (TNFalpha) gene (TNFA) have been extensively studied and shown to be associated with an increased risk of the development of various chronic inflammatory diseases. Inflammation has been demonstrated to play a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFalpha is a key pro inflammatory cytokine with important functions in these processes. In order to determine whether the well-known TNFA -308 G>A SNP has a role in a genetic predisposition to CRS in the Hungarian population, we analyzed our genomic collection containing control and CRS patient samples in a case-control study, and compared the genotype and allele frequencies. There was no significant difference in the observed genotype or allele frequencies between the controls and the total CRS group. However, after careful stratification of the patient group on the basis of the observed clinical symptoms, we found a significantly higher carriage rate of the rare A allele-containing genotypes among the CRS patients with nasal polyposis (NP) who also exhibited sensitivity to aspirin (acetylsalicylic acid, ASA(+)). It is concluded that genetic variants of the TNFA gene may affect the risk of CRS in a clinically well-defined group of CRSNP(+)ASA(+) patients in the Hungarian population. Our results also emphasize that the group of CRS patients is not homogenous in that patients exhibiting different clinical symptoms exist. Their carried genetic predisposing factors, and as a result, the exact molecular events leading to the development of various forms of CRS, may also differ. PMID- 23446847 TI - Modulation of the phenotype and function of Mycobacterium tuberculosis-stimulated dendritic cells by adrenal steroids. AB - Cell-mediated immunity, cytokines induced during the specific immune response and T-cell populations are crucial factors for containing Mycobacterium tuberculosis infection. Recent reports suggest a cross-regulation between adrenal steroids (glucocorticoids and dehydroepiandrosterone, DHEA) and the function of antigen presenting cells (APCs). Therefore, we investigated the role of adrenal hormones on the functional capacity of M. tuberculosis-induced dendritic cells (DCs). Cortisol significantly inhibited the functions of M. tuberculosis-induced DCs. Interestingly, the presence of DHEA enhanced the M. tuberculosis-induced expression of MHC I, MHC II and CD86 and also increased ERK1/2 phosphorylation. Moreover, DHEA improved the production of IL-12 in response to M. tuberculosis stimulation, diminished IL-10 secretion and could not modify TNF-alpha synthesis. Importantly, we observed that DHEA enhanced the antigen-specific T-cell proliferation and IFN-gamma production induced by M. tuberculosis-stimulated DC. These data show for the first time the relevance of the adrenal axis (especially of DHEA) in the modulation of DC function in the context of tuberculosis, a disease where the induction of a Th1 environment by APCs is crucial for the development of an effective immune response to the mycobacteria. PMID- 23446848 TI - Anti-transglutaminase immunoreactivity and histological lesions of the duodenum in coeliac patients. AB - Coeliac disease (CD) is characterized by several markers, including anti transglutaminase auto-antibodies (tTGAb) directed against multiple epitopes of the gliadin protein. We aimed to investigate the correlation among CD duodenal lesions, tTGAb titres and the immunoreactivity against tTG constructs. A total of 345 CD patients (209 females, 136 males, overall median age: 7.3 years) were tested for full-length (fl) tTGAb with a fluid-phase radioimmunoassay. Out of the total, 231 patients were also tested for immunoreactivity against tTG fragments (F1: a.a. 227-687 and F2: a.a. 473-687). Patients were classified according to diffuse (D), patchy (P) or bulb (B) histological lesions. All sera were found fltTGAb positive. Patients with D, P and B lesions had a mean Ab index of 0.84+/ 0.39, 0.57+/-0.39 and 0.45+/-0.24, respectively. Mean tTGAb titre varied between D and localized (P+B) patients (0.84+/-0.39 versus 0.52+/-0.34, P < 0.0001). Overall, 86.1% of patients were F1 auto-antibody (F1Ab) positive (D: 89%, P: 75%, B: 40%; D versus P+B: P = 0.004) and 49% of patients were F2 auto-antibody (F2Ab) positive (D: 53%, P: 19%, B: 10%; D versus P+B: P = 0.0006). Of the D patients 50.7% showed combined F1Ab-F2Ab (D versus P+B: P = 0.001), whereas 60% of B patients were negative for both F1Ab and F2Ab (B versus D: P < 0.0001). Coeliac specific tTGAb immunoreactivity correlates with the grading and extension of histological duodenal lesions in CD patients at diagnosis. The immunoreactivity against single and combined tTG fragments is significantly higher in patients with D lesions. This is the first evidence of a distinct coeliac-specific immunoreactivity in patients with different duodenal involvement. PMID- 23446849 TI - Essential role for Toll-like receptor 7 (TLR7)-unique cysteines in an intramolecular disulfide bond, proteolytic cleavage and RNA sensing. AB - Toll-like receptor 7 (TLR7) an innate immune sensor for microbial RNA, erroneously responds to self-derived RNA. To avoid autoimmune responses, TLR7 is suggested to be silenced until the N-terminal half of the TLR7 ectodomain (TLR7N) is cleaved off. Resultant truncated TLR7 (TLR7C) is thought to signal microbial RNA. We here show that TLR7N remains associated with TLR7C through a disulfide bond. By N-terminal amino acid sequencing, TLR7C was found to start at 461E or 462A. The newly established monoclonal anti-TLR7N showed that endogenous TLR7 in bone marrow-derived dendritic cells was almost all cleaved and cleaved TLR7N remained in endolysosomes. TLR7N in endolysosomes was linked with TLR7C by a disulfide bond. In contrast, TLR9 did not have a disulfide bond between TLR9N and TLR9C fragments. Among the cysteines unique to the ectodomain of TLR7 but not TLR9 (Cys98, Cys445, Cys475 and Cys722), Cys98 in TLR7N and Cys475 in TLR7C were required for an intramolecular disulfide bond. These cysteines were also needed for proteolytic cleavage of and RNA sensing by TLR7, but not for TLR7 trafficking from endoplasmic reticulum to endosomes. No response was seen in TLR7 mutants lacking the proteolytic cleavage site or TLR7C alone. These results demonstrate requirement for proteolytic cleavage and TLR7N in TLR7 responses and indicate RNA sensing by TLR7N + TLR7C. PMID- 23446850 TI - Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. AB - Pathogenic intracellular bacteria often hijack macrophages for their propagation. The infected macrophages release IL-1beta and IL-18 and simultaneously commit suicide, which is called pyroptosis; both responses require caspase-1. Here, we found that pyroptotic cells induced by microbial infection were efficiently engulfed by human monocytic THP-1-cell-derived macrophages or mouse peritoneal macrophages. This engulfment was inhibited by the D89E mutant of milk fat globule (MFG) epidermal growth factor (EGF) factor 8 (MFG-E8; a phosphatidylserine binding protein) that has been shown previously to inhibit phosphatidylserine dependent engulfment of apoptotic cells by macrophages, suggesting that the engulfment of pyroptotic cells by macrophages was also phosphatidylserine dependent. Using a pair of cell lines that respectively exhibited pyroptosis or apoptosis after muramyl dipeptide treatment, we showed that both pyroptotic and apoptotic cells bound to a T-cell immunoglobulin and mucin domain-containing 4 (Tim4; another phosphatidylserine-binding protein)-coated plate, whereas heat killed necrotic cells did not, indicating that phosphatidylserine was externalized in pyroptosis and apoptosis but not in accidental necrosis. Macrophages engulfed apoptotic cells most efficiently, followed by pyroptotic and then heat-killed necrotic cells. Pyroptotic cells also released a macrophage attractant(s), 'find-me' signal, whose activity was diminished by apyrase that degrades nucleoside triphosphate to nucleoside monophosphate. Heat-killed necrotic cells and pyroptotic cells released ATP much more efficiently than apoptotic cells. These results suggest that pyroptotic cells, like apoptotic cells, actively induce phagocytosis by macrophages using 'eat-me' and find-me signals. Based on these results, a possible role of coordinated induction of pyroptosis and inflammatory cytokine production is discussed. PMID- 23446851 TI - Anticoagulation therapy in haemophilia. Managing the unknown. AB - Patients with haemophilia (PWH) are relatively protected from cardiovascular death. Recent insights have shown that this is not due to less formation of atherosclerosis than in non-haemophilic men, therefore protection from the final occlusive thrombus will be the major determinant. Prevalence and incidence rates of cardiovascular disease (especially non-fatal events) are scarce, although ongoing studies are addressing this issue. Meanwhile, because the haemophilia population is aging, we are increasingly confronted with cardiovascular events. The main cardiovascular risk factors that should be part of regular screening programs are hypertension, overweight, lipometabolic disorders and smoking. Anticoagulation therapy in haemophilia is feasible, provided that individual tailored coagulation therapy and close monitoring is provided. Here, we present our view on anticoagulation management in PWH. There is an absolute need for risk assessment tools and prospective validation of suggested anticoagulation management strategies in PWH. Until then, we are managing the unknown. PMID- 23446852 TI - 3D porous nano/micro nickel sulfides with hierarchical structure: controlled synthesis, structure characterization and electrochemical properties. AB - A series of nickel sulfide nanocrystallines with hierarchical structures was successfully fabricated in situ on a nickel substrate. The nanocrystalline materials with three dimensional (3D) structures were synthesized via self assembly under moderate conditions, with ethylenediamine and ethylene glycol as the mixed solvents. The structure and morphology of each nickel sulfide could be controlled by adjusting the polarity of the mixed solvents. With the reduced solvent polarity, the 3D flower-like nickel sulfide spheres were transformed into two-dimensional (2D) nanoflakes, then into one-dimensional (1D) prism-like microrods, and finally into 1D pearl-like nanochains. When the nickel sulfides were used as electrode materials in lithium-ion batteries, the obtained samples with different morphologies had different initial discharge capacities. The initial discharge capacity of the as-prepared nickel sulfides with 1D nanostructures reached approximately 550 mA h g(-1), which was higher than that of the samples with 2D and 3D structures. This study explores a novel method to control the synthesis of metal chalcogenides with specific morphologies. PMID- 23446856 TI - Ramifications and adaptations to endometriosis-induced infertility. Preface. PMID- 23446857 TI - Adenomyosis and subfertility: evidence of association and causation. AB - Due to the confounding or unknown presence of endometriosis in both cases and controls, it is difficult to test the hypothesis that adenomyosis causes infertility. Based on the limited available evidence, there is evidence to support a causal association between adenomyosis and subfertility: Adenomyosis is associated with lifelong infertility in baboons, is associated with impaired reproductive outcome after assistive reproductive technique, and a dose-effect relationship between the degree of adenomyosis and the degree of abnormal uterotubal contractility has been demonstrated. More and better designed studies are needed to assess the impact of adenomyosis on infertility in women with the laparoscopic-proven presence or absence of endometriosis. PMID- 23446853 TI - Inhibition of Cdk2 activity decreases Aurora-A kinase centrosomal localization and prevents centrosome amplification in breast cancer cells. AB - Centrosome amplification plays a key role in the origin of chromosomal instability (CIN) during cancer development and progression. In this study, MCF-7 breast cancer cell lines harboring abrogated p53 function (vMCF-7DNp53) were employed to investigate the relationship between induction of genotoxic stress, activation of cyclin-A/Cdk2 and Aurora-A oncogenic signalings and development of centrosome amplification. Introduction of genotoxic stress in the vMCF-7DNp53 cell line by treatment with hydroxyurea (HU) induced centrosome amplification that was mechanistically linked to Aurora-A kinase activity. In cells carrying defective p53, the development of centrosome amplification also occurred following treatment with another DNA damaging agent, methotrexate. Importantly, we demonstrated that Aurora-A kinase-induced centrosome amplification was mediated by Cdk2 kinase since molecular inhibition of Cdk2 activity by SU9516 suppressed Aurora-A centrosomal localization and consequent centrosome amplification. In addition, we employed vMCF-7DRaf-1 cells that display high levels of endogenous cyclin-A and demonstrated that molecular targeting of Aurora A by Alisertib reduces cyclin-A expression. Taken together, these findings demonstrate a novel positive feed-back loop between cyclin-A/Cdk2 and Aurora-A pathways in the development of centrosome amplification in breast cancer cells. They also provide the translational rationale for targeting 'druggable cell cycle regulators' as an innovative therapeutic strategy to inhibit centrosome amplification and CIN in breast tumors resistant to conventional chemotherapeutic drugs. PMID- 23446858 TI - Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. AB - The endometrium is ground zero when it comes to understanding how implantation occurs and how it might also fail, resulting in infertility or pregnancy loss. Many of the causes of diminished uterine receptivity are acquired during a woman's lifetime. Endometriosis, a major inflammatory disease affecting women, is also a leading cause of infertility and miscarriage. Once established, the inflammatory changes can, in some women, lead to progesterone resistance and downstream changes in endometrial gene expression. Much is now known about how inflammation translates to progesterone resistance and infertility, but much remains to be learned. In this review we provide an overview for understanding how the endometrium becomes dysfunctional, what biomarkers may hold promise for the diagnosis of endometriosis, and how progesterone resistance leads to infertility. Understanding the pathophysiology of this disease will likely lead to better treatment options. PMID- 23446859 TI - Translational animal models to study endometriosis-associated infertility. AB - Although there is an apparent association between endometriosis and impaired fertility, the pathophysiology of the reduced fecundity in women with endometriosis still remains unclear. Reproduction is a complex and multifactorial process, and possible factors contributing to the reduced fertility of endometriosis patients include defective function of the ovary, gametes, and endometrium as well as developmental disorders of the embryo. Because controlled experiments in humans are limited due to ethical reasons, experimental animal models have been developed mainly in nonhuman primates and laboratory rodents by induction of endometriosis via autologous transplantation of endometrial tissue. Animals with induced endometriosis reveal an impairment of fecundity similar to the situation described for humans and have been used to identify effects of ectopic endometrial tissue on adhesion formation, peritoneal fluid composition, ovarian function, endometrial gene expression, and embryo implantation. These animal models of endometriosis yield a valuable tool to study the mechanisms of endometriosis-associated infertility especially during the onset of the disease that cannot be investigated in women. PMID- 23446860 TI - Role of surgery in endometriosis-associated subfertility. AB - Analysis of published series reveals that no more than a fourth of subfertile patients undergoing surgery for peritoneal endometriotic implants, rectovaginal endometriotic lesions, or recurrent endometriomas achieved conception spontaneously. First-line surgery for ovarian endometriotic cysts appears associated with a better reproductive performance, that is, a mean postoperative pregnancy rate of ~50%. At the same time, excision of endometriomas paradoxically seems to induce gonadal damage. With the exception of peritoneal disease, no randomized trials are available to assess the effect of surgery in subfertile women with endometriosis. Therefore, it is not possible to define the absolute benefit increase of the treatment of ovarian and rectovaginal lesions. The decision to undergo surgery for endometriosis-associated subfertility must be shared with the woman after detailed information and taking into account several additional conditions, such as presence of pain, large or complex adnexal masses, bowel or ureteral stenosis, and coexisting infertility factors. When considering surgery, a therapeutic equipoise should be reached that includes demonstrated benefits, potential morbidity, and costs of treatment alternatives. Particularly in case of recurrent endometriosis, in vitro fertilization should generally be preferred to surgery. The role of surgery in endometriosis-associated subfertility includes temporary pain relief in symptomatic women desiring a spontaneous conception. PMID- 23446861 TI - Diminished ovarian reserve and endometriosis: insult upon injury. AB - Endometriosis is a disease that affects a significant proportion of reproductive age women. The impact of the disease on ovarian reserve is an important consideration when planning treatment in women who want to maintain their potential for future childbearing. The existing literature supports an adverse effect of both superficial endometriosis and ovarian endometriomas on ovulation rates, markers of ovarian reserve, and response to ovarian stimulation, although data on clinical pregnancy and live-birth rates remain inconsistent. Surgical treatment of endometriomas may further worsen ovarian responsiveness by inadvertently removing healthy ovarian tissue or compromising vascular supply to the ovary. Although the evidence overall supports a role for surgery in improving spontaneous pregnancy rates, the question of whether identification of an endometrioma warrants its excision in the subgroup of women undergoing infertility treatment remains a subject of ongoing debate. Many practitioners recommend proceeding directly to in vitro fertilization to reduce time to pregnancy, reserving surgery for women who present with large endometriomas and concomitant symptoms of pain. Further study is required as to the mechanisms by which endometriosis damages ovarian damage as well as the most appropriate treatment in various subpopulations of women with the disease. PMID- 23446862 TI - Impact of superovulation for women with endometriosis. AB - Superovulation (SO)/Intrauterine insemination (IUI) has been used as a treatment approach for endometriosis-associated infertility. The existing medical literature regarding SO in endometriosis patients is composed of heterogeneous studies that differ in terms of study design, SO protocols, the addition of IUI, and comparison groups. There is a need for more well-designed studies to further investigate the efficacy of SO in women with endometriosis-associated infertility. Although in vitro fertilization (IVF) is most effective and is significantly superior to other treatments in endometriosis patients, most of the existing studies suggest some benefit of SO/IUI in infertility patients with early-stage disease. Therefore, SO/IUI is a reasonable early fertility treatment option for women with endometriosis who desire a short trial of potentially more cost-effective treatment options prior to pursuing an IVF cycle and those for whom IVF is not a feasible or desirable option. It appears that gonadotropins are most effective for SO in this patient population even though more head-to-head comparisons are needed. PMID- 23446863 TI - Endometriosis and assisted reproductive technologies: maximizing outcomes. AB - In vitro fertilization (IVF) represents the most efficient means of overcoming endometriosis-related infertility. Compromised pelvic anatomy and a hostile peritoneal environment are bypassed. Despite the results of early trials, more contemporary outcomes data would suggest that when controlled for age, IVF cycle outcome is not compromised by the presence of endometriosis. One exception to this concept is the finding that patients with ovarian endometriomas demonstrate poorer response to gonadotropin therapy, although it is not clear that this affects the likelihood of implantation. Surgical ablation of superficial endometriosis has no clear impact on IVF pregnancy rates, although a small number of recent trials suggest that pre-cycle resection of deeply infiltrative disease may be beneficial. With the exception of traditional gynecologic indications, there is no evidence to suggest that resection of ovarian endometriomas has any positive impact on cycle outcome. There are, in fact, data demonstrating that resection may exert a deleterious effect on ovarian reserve. A subset of patients will benefit from administration of a prolonged course of a gonadotropin releasing hormone agonist prior to an IVF cycle. However, the characteristics of that subset have not been identified. It would be logical to consider this approach in women with more advanced disease, severe symptoms, and a history of implantation failure. Data on the impact of other pre-cycle medical interventions such as aromatase inhibitors, danazol, or oral contraceptives are more limited. There is also no evidence to suggest that the ovarian stimulation associated with IVF induces progression of endometriosis. PMID- 23446864 TI - Endometriomas and assisted reproductive technology. AB - Endometriomas in the assisted reproductive technology patient present a challenging clinical scenario for the infertility specialist. Although surgical management is often pursued in cases of pain or large cyst diameter, patients without such factors must be counseled regarding surgical versus expectant management. Decisions to pursue surgery must be viewed in the context of potentially decreased ovarian reserve and more difficult stimulation for in vitro fertilization. In this article, three distinct cases are presented along with a summary of the most current literature available to guide clinicians in the optimal management of in vitro fertilization patients with endometriomas. PMID- 23446865 TI - Oocyte donation and endometriosis: What are the lessons? AB - Outcomes of in vitro fertilization cycles in women with endometriosis are significantly worse than in patients without this condition. The impact of endometriosis on ovarian reserve and the quality of retrieved oocytes seems evident. Lower implantation rates, however, raise the question whether this finding is purely the consequence of lower number and poorer quality of embryos, or whether it also reflects compromised endometrial receptivity. Oocyte donation provides an interesting model to investigate reproductive outcome because factors affecting the oocytes are excluded, especially if cycles using oocytes derived from the same donor are analyzed. These studies have shown lower implantation rates in nonendometriotic patients who received oocytes from women with endometriosis, whereas healthy donated oocytes have proven to contribute to a pregnancy with similar chances in women without the disease. The question still to be answered is whether this situation applies for natural cycles or whether it is the use of gonadotropin-releasing hormone analogs and hormonal replacement therapy used for endometrial priming in oocyte recipients that reestablishes an adequate uterine environment. Using a genomic tool based on microarray technology (endometrial receptivity array), the study of differential gene expression in the eutopic endometrium of endometriosis patients undergoing oocyte donation treatment is still underway. PMID- 23446866 TI - Pregnancy outcomes in women with endometriosis. AB - The association between endometriosis and subfertility is well known and has been the object of intense research in the last decades. However, the potential association between endometriosis and adverse pregnancy outcome has not been studied until recently. The results from epidemiological studies suggest that endometriosis is associated with preterm birth, preeclampsia, antepartal hemorrhage, and an increase in cesarean delivery. These findings suggest that women with endometriosis may need special care during pregnancy. The underlying mechanisms for the observed associations are unknown, and further studies, both experimental and epidemiological, are necessary. PMID- 23446867 TI - Exploration of the protection of riboflavin laurate on oral mucositis induced by chemotherapy or radiotherapy at the cellular level: what is the leading contributor? AB - Oral or gastrointestinal mucositis is a frequent phenomenon in cancer patients receiving chemotherapy or radiotherapy. In addition, several clinical investigations have demonstrated in recent years that riboflavin laurate has the potential to protect the patients from the disease induced by chemotherapy or radiotherapy. In our studies, it is observed that riboflavin laurate can ameliorate either chemotherapy- or radiotherapy-induced toxicities on Helf cells, and the effect is greater than that of riboflavin. In addition, riboflavin laurate is able to transport through the Caco-2 cell monolayer as the prototype, indicating the protective effects may be produced by the prototype of riboflavin laurate, rather than simply by the released riboflavin. PMID- 23446869 TI - Studying the evolution of transcription factor binding events using multi-species ChIP-Seq data. AB - Recent technology advances make it possible to collect whole-genome transcription factor binding (TFB) profiles from multiple species through the ChIP-Seq data. This provides rich information to understand TFB evolution. However, few rigorous statistical models are available to infer TFB evolution from these data. We have developed a phylogenetic tree based method to model the on/off rates of TFB events. There are two unique features of our method compared to existing models. First, we mask nucleotide substitutions and focus on INDEL disruption of TFB events, which are rarer evolution events and more appropriate for divergent species and non-coding regulatory regions. Second, we correct for ascertainment bias in ChIP-Seq data by maximizing likelihood conditional on the observed (incomplete) data. Simulations show that our method works well in model selection and parameter estimation when there are sufficient aligned TFB events. When this method is applied to a ChIP-Seq data set with five vertebrates, we find that the instantaneous transition rates to INDELs are higher in TFB regions than in homologous non-binding regions. This is driven by an excess of alignment columns showing binding in one species but gaps in all other species. When we compare the inferred transition rates between the conserved and non-conserved regions, as expected, the conserved regions are estimated to have lower transition rates. The R package TFBphylo that implements the described model can be downloaded from http://bioinformatics.med.yale.edu/. PMID- 23446870 TI - Approximate Bayesian computation with functional statistics. AB - Functional statistics are commonly used to characterize spatial patterns in general and spatial genetic structures in population genetics in particular. Such functional statistics also enable the estimation of parameters of spatially explicit (and genetic) models. Recently, Approximate Bayesian Computation (ABC) has been proposed to estimate model parameters from functional statistics. However, applying ABC with functional statistics may be cumbersome because of the high dimension of the set of statistics and the dependences among them. To tackle this difficulty, we propose an ABC procedure which relies on an optimized weighted distance between observed and simulated functional statistics. We applied this procedure to a simple step model, a spatial point process characterized by its pair correlation function and a pollen dispersal model characterized by genetic differentiation as a function of distance. These applications showed how the optimized weighted distance improved estimation accuracy. In the discussion, we consider the application of the proposed ABC procedure to functional statistics characterizing non-spatial processes. PMID- 23446868 TI - Low oxygen response mechanisms in green organisms. AB - Low oxygen stress often occurs during the life of green organisms, mostly due to the environmental conditions affecting oxygen availability. Both plants and algae respond to low oxygen by resetting their metabolism. The shift from mitochondrial respiration to fermentation is the hallmark of anaerobic metabolism in most organisms. This involves a modified carbohydrate metabolism coupled with glycolysis and fermentation. For a coordinated response to low oxygen, plants exploit various molecular mechanisms to sense when oxygen is either absent or in limited amounts. In Arabidopsis thaliana, a direct oxygen sensing system has recently been discovered, where a conserved N-terminal motif on some ethylene responsive factors (ERFs), targets the fate of the protein under normoxia/hypoxia. In Oryza sativa, this same group of ERFs drives physiological and anatomical modifications that vary in relation to the genotype studied. The microalga Chlamydomonas reinhardtii responses to low oxygen seem to have evolved independently of higher plants, posing questions on how the fermentative metabolism is modulated. In this review, we summarize the most recent findings related to these topics, highlighting promising developments for the future. PMID- 23446871 TI - In reply: response to Sammartino et al. PMID- 23446873 TI - Nurse retention in a correctional facility: a study of the relationship between the nurses' perceived barriers and benefits. AB - Retention of nursing staff is more complex in a correctional facility. After a period of 3 years, only 20% of the staff remained employed at this study facility. Without retention of qualified correctional nurses, there are decreases in access to care, gaps in continuity of care, and less time for mentorship. Trained correctional nurses improve patient and staff safety, provide more education, and are more team-oriented. The purpose of this study was to identify barriers and benefits to nursing staff satisfaction with their job and the likelihood that they will continue to work in correctional settings. Practice and patient care will be favorably impacted if correctional nurses are provided with services such as new hire orientation, clinical ladder programs to recruit and retain nursing staff, and teambuilding. PMID- 23446874 TI - Misconceptions about traumatic brain injury among correctional health care professionals. AB - This study explored the prevalence of misconceptions of traumatic brain injury (TBI) among a sample of correctional health care professionals. Prior research has identified a high prevalence of TBI among criminal offenders, and misconceptions about TBI exist among laypersons and nonexpert professionals. Participants (N = 155) completed a 25-item survey about the sequelae of TBI. Results were compared with previous studies. This sample performed significantly better than laypersons and commensurable to other nonexpert professionals. Misconceptions were higher on items related to loss of consciousness, memory, and recovery. Gender, prior familiarity to someone with a history of TBI, and prior training in TBI accounted for statistically fewer misconceptions. The findings support the need for continued training and increased awareness about TBI among inmates. PMID- 23446875 TI - Determinants of the core functions of local public health agencies: examining what matters in local public health practice. AB - CONTEXT: This study examines a model of performance measurement in public health on the basis of logic model constructs focusing upon explanatory variables (inputs) within the realm of control of the local public health agency (LPHA), and their subsequent effect on LPHA functions (outputs). METHODS: Study protocol was reviewed and approved by an institutional review board, and informed consent was obtained from all participants. The investigation included measuring the human, informational, organizational and fiscal resources of the LPHAs (inputs) to determine the effect upon LPHA performance of the assessment, policy development, and assurance functions of public health (outputs), commonly referred to as the 3 core functions of public health. RESULTS: Study participants included the lead health officials (termed "administrators") representing the LPHAs within the state of Illinois. Forty-three of the 46 LPHAs selected participated in the study for a response rate of 93%. Analysis to identify the presence of any relationship between the explanatory variables (LPHA inputs or resources) and the dependent variables (LPHA outputs or core functions) was undertaken utilizing multiple regression analysis. CONCLUSIONS: Results concluded that higher-level performance in areas noted as LPHA inputs or resources were associated with higher-level performance of the core functions of public health. PMID- 23446876 TI - Assessment of public health perspectives on responding to an emerging pathogen: carbapenem-resistant Enterobacteriaceae. AB - CONTEXT: Public health has an important and critical role in responding to emerging multidrug-resistant organisms, such as carbapenem-resistant Enterobacteriaceae. The Centers for Disease Control and Prevention developed a survey as a tool for state health departments to determine carbapenem-resistant Enterobacteriaceae prevalence within their region. OBJECTIVE: This report summarizes an assessment of the health department experience with the survey, their perceived roles and responsibilities in responding to an emerging health care-associated pathogen, and potential barriers to public health engagement of acute care facilities in response activities. DESIGN: Key informant interviews consisting of open-ended and 5-point Likert scale questions were conducted. PARTICIPANTS: Interviewees represented state health departments that administered the survey and select states that did not. RESULTS: Of 11 states interviewed, 7 (64%) had administered the survey to acute care facilities. Despite similar competing priorities and concerns about administering the survey, different perspectives emerged among the 11 states; those that administered the survey regarded it as a learning opportunity, whereas other states emphasized concerns about survey logistics and other public health demands. All 11 states perceived the prevention of an emerging pathogen to be a public health priority, but the degree of their action depended on availability of resources and existing relationships with infection preventionists. Health departments had less interaction with other hospital personnel (eg, facility leadership) and limited knowledge of the roles and associated responsibilities of other health care partners (eg, Quality Improvement Organizations). CONCLUSIONS: Although considered a public health priority, response efforts to emerging pathogens were reported to vary among state health departments. A better understanding is needed of the factors that motivate and facilitate state health departments to engage in a public health activity despite the challenges of competing priorities and limited resources. Efforts should also focus on improving the relationship between health departments and hospital leadership and other health care partners. PMID- 23446877 TI - Addressing rural health disparities through policy change in the stroke belt. AB - CONTEXT: Obesity-prevention policies are needed, particularly in low-income rural areas of the southern United States, where obesity and chronic disease prevalence are high. In 2009, the Centers for Disease Control and Prevention issued the "Common Community Measures for Obesity Prevention" (COCOMO), a set of 24 recommended community-level obesity-prevention strategies. OBJECTIVE: A variety of stakeholders in Lenoir County, North Carolina, were surveyed and interviewed, ranking the winnability, defined as feasibility and acceptability, of each of the 24 COCOMO-recommended strategies based on local culture, infrastructure, funding, and community support. DESIGN: Mixed-methods. SETTING: This study was part of the Heart Healthy Lenoir project, a community-based project to reduce cardiovascular disease risk and disparities in risk in Lenoir County, North Carolina. PARTICIPANTS: COCOMO assessments were conducted with 19 Community Advisory Council members and in-depth interviews were conducted with 11 community stakeholders. Heart Healthy Lenoir lifestyle intervention participants (n = 366) completed surveys wherein they ranked their support for 7 obesity-prevention strategies (based on the COCOMO strategies). MAIN OUTCOME MEASURES: Ranking of obesity-prevention strategies. RESULTS: Policies to improve physical activity opportunities were deemed the most winnable, whereas policies that would limit advertisement of unhealthy food and beverages were deemed the least winnable. The most winnable food-related strategy was improving mechanisms to procure food from local farms. Stakeholders perceived the public as unfavorably disposed toward government mandates, taxes, and incentives. Among Heart Healthy Lenoir participants, males indicated lower levels of support for COCOMO-related strategies than females, and African Americans indicated higher levels of support than white participants. CONCLUSION: The formative work presented here provides insight into the winnability of proposed obesity-prevention policy change strategies in Lenoir County, North Carolina. PMID- 23446878 TI - Health reform and the US Virgin Islands: high-need-limited impact. AB - OBJECTIVES: There are 4.1 million residents living in the US territories, which is more than the combined population of many US states, yet the territories and their citizens are often overlooked from a policy perspective, because most individual territories are relatively small, geographically isolated, and have been treated differently than the states historically. This tendency to fall beneath the radar is clear in the realm of health policy, especially in the area of insurance coverage. This article provides an initial assessment of the potential impact of health reform on the US Virgin Islands (USVI) and, in light of this assessment, considers how the results of a USVI household survey conducted in 2003 and 2009 might be used as a baseline for future monitoring of the impact of national reform. METHODS: A study by the Virgin Island's Bureau of Economic Research, Office of the Governor, and the University of Minnesota, was conducted in 2003 and 2009. The Virgin Islands Health Insurance telephone Surveys were random digit dial landline telephone surveys of households in the USVI. A stratified sample was drawn to produce precise estimates of insurance coverage for the USVI as a whole and for the 3 islands separately. RESULTS: Almost one third of the residents (28.7%) in the Virgin Islands were uninsured in 2009. This rate is twice the US average (15.4%) and significantly higher than the uninsured rate of 24.1% when a similar survey was last conducted the Virgin Islands in 2003. CONCLUSIONS: The Patient Protection and Affordable Care Act of 2010 provides special funding to the territories through a mix of increased Medicaid caps for each territory and the provision of premium subsidies through newly established health insurance exchanges to low-income populations. However, the Affordable Care Act's Medicaid expansions to newly eligible adults--primarily adults without children--are limited to current eligibility levels in the territories, which is $5,500 in annual income for adult coverage in the USVI. Within these abbreviated parameters, the Medicaid expansion can go so far only toward mitigating uninsurance among the lowest income groups in the territories. With certain low-income childless adults overlooked, the Affordable Care Act does not fully address the high need for affordable health insurance coverage in the territories. PMID- 23446879 TI - Development of a postexposure biologic treatment algorithm on a medical center campus. AB - OBJECTIVE: To describe the development of an easily accessible online biologic exposure algorithm to guide postexposure medical evaluation and treatment of medical research personnel and health care workers in a Midwest medical center campus. METHODS: We describe the steps involved in the creation of a biologic exposure algorithm from design through implementation. RESULTS: One point of contact allows phone evaluation and immediate triage, providing effective and timely medical care for exposed employees as well as important guidance for clinicians. The algorithm and exposure response system achieved the goal of integrating clinical and research laboratory exposure response. CONCLUSIONS: Development of an integrated clinical and research exposure protocol may be an efficient way to maximize biosafety for workers. PMID- 23446880 TI - Falls and functional impairments in cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study. AB - PURPOSE: This study was conducted in order to characterize the prevalence of falls and functional impairments (FIs) and their association with chemotherapy induced peripheral neuropathy (CIPN) in cancer survivors. METHODS: We analyzed baseline assessments from a phase III RCT in cancer survivors with self-reported CIPN scores of >4 out of 10. Patients completed the EORTC QLQ-CIPN-20 for neuropathy and reported falls in the previous 3 months. FIs were defined using the Activities of Daily Living subsection of the Vulnerable Elder's Scale. Associations of baseline characteristics and CIPN with falls and FIs were examined using logistic regression. RESULTS: Of 421 patients, 11.9 % experienced recent falls and 26.6 % reported FIs. Motor neuropathy was the only factor associated with falls (OR = 1.127, p = 0.01). Factors associated with FIs included non-white race (OR = 0.335 white relative to non-white, 0.781, p = 0.01) and greater motor neuropathy scores (OR = 1.262, p < 0.0001). CONCLUSION: CIPN, primarily motor, is associated with falls and FIs. Future prospective research should investigate the ability of motor neuropathy severity to predict falls. PMID- 23446882 TI - A new era in stroke prevention for atrial fibrillation: comment on "current trial associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation. PMID- 23446881 TI - Associations of interleukin-6 with vegetative but not affective depressive symptoms in terminally ill cancer patients. AB - PURPOSE: Previous studies have reported associations of depressive symptoms with pro-inflammatory cytokines, especially with interleukin-6 (IL-6) in noncancer subjects and cancer patients. Meanwhile, symptoms such as tiredness and appetite loss may be vegetative symptoms of depression when associated with other diagnostic criteria of depression. Such vegetative-type symptoms worsen during the last 6 months of life in cancer patients and may not be associated with affective depressive symptoms such as sadness and nervousness. This study explored associations between depressive symptoms and plasma IL-6 in terminally ill cancer patients whose survival period was confirmed to be less than 6 months by follow-up, with attention to differences in vegetative and affective depressive symptoms. METHODS: Data from 112 consecutively recruited terminally ill cancer patients who registered at a palliative care unit without any active anticancer treatment were used. Plasma IL-6 levels were measured using an electrochemiluminescence assay. Depressive symptoms included in the DSM-IV and Cavanaugh criteria were assessed by structured interviews and were categorized into affective symptoms and vegetative symptoms. Affective symptoms were also measured with the depression subscale of the Hospital Anxiety and Depression Scale, which does not include vegetative symptoms. RESULTS: Vegetative symptoms, such as appetite loss, insomnia, and fatigue, were significantly associated with IL-6 levels. However, neither of the affective symptoms nor their severity was associated with IL-6 levels. CONCLUSIONS: IL-6 was associated with vegetative depressive symptoms in terminally ill cancer patients but not with affective depressive symptoms, suggesting possible differences in the pathophysiological mechanisms between these sets of symptoms. PMID- 23446883 TI - The immune system of halophilic archaea. AB - Prokaryotes have developed several strategies to defend themselves against foreign genetic elements. One of those defense mechanisms is the recently identified CRISPR/Cas system, which is used by approximately half of all bacterial and almost all archaeal organisms. The CRISPR/Cas system differs from the other defense strategies because it is adaptive, hereditary and it recognizes the invader by a sequence specific mechanism. To identify the invading foreign nucleic acid, a crRNA that matches the invader DNA is required, as well as a short sequence motif called protospacer adjacent motif (PAM). We recently identified the PAM sequences for the halophilic archaeon Haloferax volcanii, and found that several motifs were active in triggering the defense reaction. In contrast, selection of protospacers from the invader seems to be based on fewer PAM sequences, as evidenced by comparative sequence data. This suggests that the selection of protospacers has stricter requirements than the defense reaction. Comparison of CRISPR-repeat sequences carried by sequenced haloarchaea revealed that in more than half of the species, the repeat sequence is conserved and that they have the same CRISPR/Cas type. PMID- 23446884 TI - Changes in serum IGF-1 level and tumor VEGF expression in mice with colorectal cancer under hyperglycemic conditions. AB - The present study aimed to observe the growth of transplanted tumors in mice with colorectal cancer (CRC) under hyperglycemic conditions and to detect the expression of vascular endothelial growth factor (VEGF) in these tumors. The study also aimed to observe the changes in serum insulin-like growth factor-1 (IGF-1) levels and to determine whether type 2 diabetes mellitus (T2DM) was a risk factor for the progression and development of CRC. A mouse model of a transplanted colorectal tumor with T2DM was established to observe the changes in volume and size of the transplanted tumor. Mice were sacrificed at the end of the 5th week to determine the serum IGF-1 level and VEGF expression in the tumor tissues. The tumor volume (1628.5 +/- 882 mm3) in the CRC-DM group was larger than that in the CRC group (1950.2 +/- 726 mm3; P<0.05). The serum IGF-1 level (105.33 +/- 32.32 ng/ml) was higher than that in the normal (69.83 +/- 25.57 ng/ml) and CRC groups (70.17 +/- 25.27 ng/ml; P<0.05). The VEGF expression in the tumor tissues of the CRC-DM group(70.0 +/- 11.5%) was higher than that in the CRC group (42.9 +/- 7.5%; P<0.05). T2DM may be one of the causes for the promotion of CRC growth and its mechanism may be correlated with the increased IGF-1 action observed in the blood that induces VEGF gene transcription, upregulates VEGF expression, causes tumor angiogenesis and thus leads to the occurrence and metastasis of tumors. PMID- 23446885 TI - Occurrence of disinfection by-products in tap water distribution systems and their associated health risk. AB - The concentrations of trihalomethanes (THMs), including chloroform, bromodichloromethane, dibromochloromethane, and bromoform, and haloacetic acids (HAAs; monochloroacetic acid, monobromoacetic acid, dibromoacetic acid, dichloroacetic acid, and trichloroacetic acid) were measured in tap waters passing through water distribution systems of six water treatment plants in Seoul, Korea, and their associated health risks from exposure to THMs through ingestion, dermal contact, and inhalation were estimated using a probabilistic approach. The concentration ranges for total THMs and HAA5 were 3.9-53.5 and T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure. PMID- 23446888 TI - A commentary on DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan. PMID- 23446889 TI - Cessation of neoangiogenesis in Alzheimer's disease follows amyloid-beta immunization. AB - Pathogenic neoangiogenesis in Alzheimer's disease (AD) is due to amyloid-beta (Abeta) and results in blood-brain barrier (BBB) leakiness in AD. It likely occurs as a compensatory response to impaired cerebral blood flow and provides a strong link between brain vascularity and AD. Abeta immunotherapy is an experimental treatment for AD; however, unexpected negative vascular side effects seen in early human clinical trials demonstrate that our knowledge of Abeta and AD pathogenesis is incomplete. We demonstrate that immunization with Abeta peptides neutralizes the amyloid trigger leading to neoangiogenesis and reverses hypervascularity in Tg2576 AD mice. This process resolves plaque burden suggesting that neoangiogenesis is a key mechanism underlying plaque formation. A meta-analysis demonstrated that hypervascular reversion in vaccinated Alzheimer's patients. This appears to be the first example of vascular reversion following any therapeutic intervention and supports the conclusion that modulation of neoangiogenesis may repair damage in the AD brain. PMID- 23446890 TI - Eating attentively: a systematic review and meta-analysis of the effect of food intake memory and awareness on eating. AB - BACKGROUND: Cognitive processes such as attention and memory may influence food intake, but the degree to which they do is unclear. OBJECTIVE: The objective was to examine whether such cognitive processes influence the amount of food eaten either immediately or in subsequent meals. DESIGN: We systematically reviewed studies that examined experimentally the effect that manipulating memory, distraction, awareness, or attention has on food intake. We combined studies by using inverse variance meta-analysis, calculating the standardized mean difference (SMD) in food intake between experimental and control groups and assessing heterogeneity with the I(2) statistic. RESULTS: Twenty-four studies were reviewed. Evidence indicated that eating when distracted produced a moderate increase in immediate intake (SMD: 0.39; 95% CI: 0.25, 0.53) but increased later intake to a greater extent (SMD: 0.76; 95% CI: 0.45, 1.07). The effect of distraction on immediate intake appeared to be independent of dietary restraint. Enhancing memory of food consumed reduced later intake (SMD: 0.40; 95% CI: 0.12, 0.68), but this effect may depend on the degree of the participants' tendencies toward disinhibited eating. Removing visual information about the amount of food eaten during a meal increased immediate intake (SMD: 0.48; 95% CI: 0.27, 0.68). Enhancing awareness of food being eaten may not affect immediate intake (SMD: 0.09; 95% CI: -0.42, 0.35). CONCLUSIONS: Evidence indicates that attentive eating is likely to influence food intake, and incorporation of attentive-eating principles into interventions provides a novel approach to aid weight loss and maintenance without the need for conscious calorie counting. PMID- 23446891 TI - Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood. AB - BACKGROUND: The Western diet increases risk of metabolic disease. OBJECTIVE: We determined whether lowering the ratio of saturated fatty acids to monounsaturated fatty acids in the Western diet would affect physical activity and energy expenditure. DESIGN: With the use of a balanced design, 2 cohorts of 18 and 14 young adults were enrolled in separate randomized, double-masked, crossover trials that compared a 3-wk high-palmitic acid diet (HPA; similar to the Western diet fat composition) to a low-palmitic acid and high-oleic acid diet (HOA; similar to the Mediterranean diet fat composition). All foods were provided by the investigators, and the palmitic acid (PA):oleic acid (OA) ratio was manipulated by adding different oil blends to the same foods. In both cohorts, we assessed physical activity (monitored continuously by using accelerometry) and resting energy expenditure (REE). To gain insight into a possible mood disturbance that might explain changes in physical activity, the Profile of Mood States (POMS) was administered in cohort 2. RESULTS: Physical activity was higher during the HOA than during the HPA in 15 of 17 subjects in cohort 1 (P = 0.008) (mean: 12% higher; P = 0.003) and in 12 of 12 subjects in the second, confirmatory cohort (P = 0.005) (mean: 15% higher; P = 0.003). When the HOA was compared with the HPA, REE measured during the fed state was 3% higher for cohort 1 (P < 0.01), and REE was 4.5% higher in the fasted state for cohort 2 (P = 0.04). POMS testing showed that the anger-hostility score was significantly higher during the HPA (P = 0.007). CONCLUSIONS: The replacement of dietary PA with OA was associated with increased physical activity and REE and less anger. Besides presumed effects on mitochondrial function (increased REE), the dietary PA:OA ratio appears to affect behavior. The second cohort was derived from a study that was registered at clinicaltrials.gov as R01DK082803. PMID- 23446892 TI - Plasma phospholipid trans fatty acids and risk of heart failure. AB - BACKGROUND: Although trans fatty acids (TFAs) may increase the risk of dyslipidemia and coronary artery disease (CAD), limited data are available on their association with heart failure (HF). OBJECTIVE: Our goal was to assess associations of plasma and dietary TFAs with HF and CAD. DESIGN: We used a prospective, nested case-control design to select 788 incident HF cases and 788 matched controls from the Physicians' Health Study for biomarker analyses and a prospective cohort for the dietary analyses. Plasma fatty acids were assessed by using gas chromatography, and dietary intake was estimated by using a food frequency questionnaire. Self-reported HF was ascertained by using annual follow up questionnaires with validation in a subsample. We used conditional logistic (or Cox) regression to estimate multivariable-adjusted ORs (or HRs) for HF and CAD. RESULTS: Multivariable-adjusted ORs (95% CIs) for HF across consecutive quintiles of plasma trans 18:2 (linoleic acid) fatty acids were 1.0 (reference), 1.10 (0.79, 1.54), 0.88 (0.62, 1.25), 0.71 (0.49, 1.02), and 0.67 (0.45, 0.98) (P trend = 0.01). Each SD of plasma trans 18:2 was associated with a 22% lower risk of HF (95% CI: 6%, 36%). Plasma trans 16:1 and 18:1 were not associated with risk of HF (P > 0.05). Dietary trans fats were not associated with incident HF or CAD. CONCLUSIONS: Our data are consistent with a lower risk of HF with higher concentrations of plasma trans 18:2 but not with trans 16:1 or trans 18:1 fatty acids in male physicians. Dietary TFAs were not related to incident HF or CAD. PMID- 23446893 TI - Indirect calorimetry in humans: a postcalorimetric evaluation procedure for correction of metabolic monitor variability. AB - BACKGROUND: Indirect calorimetry (IC) with metabolic monitors is widely used for noninvasive assessment of energy expenditure and macronutrient oxidation in health and disease. OBJECTIVE: To overcome deficiencies in validity and reliability of metabolic monitors, we established a procedure that allowed correction for monitor-specific deviations. DESIGN: Randomized comparative IC (canopy mode) with the Deltatrac MBM-100 (Datex) and Vmax Encore 29n (SensorMedix) was performed in postabsorptive (overnight fast >8 h) healthy subjects (n = 40). In vitro validation was performed by simulation of oxygen consumption (VO2) and carbon dioxide output (VCO2) rates by using mass-flow regulators and pure gases. A simulation-based postcalorimetric calibration of cart readouts [individual calibration control evaluation (ICcE)] was established in adults (n = 24). RESULTS: The comparison of carefully calibrated monitors showed marked differences in VCO2 and VO2 (P < 0.01) and derived metabolic variables [resting energy expenditure (REE), respiratory quotient (RQ), glucose/carbohydrate oxidation (Gox), and fat oxidation (Fox); P < 0.001]. Correlations appeared to be acceptable for breath gas rates and REE (R(2) ~ 0.9) but were unacceptable for RQ (R(2) = 0.3), Gox, and Fox (R(2) = 0.2). In vitro simulation experiments showed monitor-dependent interferences for VCO2 and VO2 as follows: 1) within series, nonlinear and variable deviations of monitor readouts at different exchange rates; 2) between series, differences and unsteady variability; and 3) differences in individual monitor characteristics (eg, rate dependence, stability, imprecision). The introduction of the postcalorimetric recalibration by ICcE resulted in an adjustment of gas exchange rates and the derived metabolic variables with reasonable correlations (R(2) > 0.9). CONCLUSIONS: Differential, metabolic, monitor-specific deviations are the primary determinants for lack of accuracy, comparability, and transferability of results. This problem can be overcome by the present postcalorimetric ICcE procedure. PMID- 23446894 TI - Impact of dairy products on biomarkers of inflammation: a systematic review of randomized controlled nutritional intervention studies in overweight and obese adults. AB - BACKGROUND: Recent data from cross-sectional studies suggest that consumption of dairy products is inversely associated with low-grade systemic inflammation, but a cause-and-effect relation can be confirmed only with results from randomized controlled trials. OBJECTIVE: We reviewed the results of randomized controlled nutritional intervention studies that have assessed the impact of dairy product consumption (ie, milk, yogurt, and/or cheese) on biomarkers of inflammation in adults (aged >=18 y). DESIGN: We performed a systematic literature search in PubMed in April 2012, which was limited to randomized controlled trials in humans published in English. Studies that included pregnant or lactating women or that did not include a low-dairy control intervention were excluded. RESULTS: Eight trials that were conducted in overweight or obese adults were included in the review. The only study that had identified change in the inflammatory profile as its primary outcome measure showed that dairy food consumption improved pro- and antiinflammatory biomarker concentrations compared with the low-dairy control diet. Three of the 7 studies in which inflammation was a secondary or undefined outcome showed improvement in key inflammatory biomarkers, ie, C-reactive protein, IL-6, or TNF-alpha after dairy product consumption, whereas the other 4 studies showed no effect. CONCLUSIONS: Dairy product consumption does not exert adverse effects on biomarkers of inflammation in overweight or obese adults. Several methodologic factors and limitations among existing studies do not allow differentiation between a beneficial or neutral impact of dairy products on inflammation. Further studies specifically designed to assess inflammation related outcomes are warranted. PMID- 23446896 TI - Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. AB - BACKGROUND: The achievement of adequate nutritional intakes in preterm infants is challenging and may explain the poor growth often seen in this group. The use of early parenteral nutrition (PN) is one potential strategy to address this problem, although the benefits and harms are unknown. OBJECTIVE: We determined whether earlier administration of PN benefits growth outcomes in preterm infants. DESIGN: We conducted a systematic review of randomized controlled trials (RCTs) and observational studies. RESULTS: Eight RCTs and 13 observational studies met the inclusion criteria (n = 553 and 1796 infants). The meta-analysis was limited by disparate growth-outcome measures. An assessment of bias was difficult because of inadequate reporting. Results are given as mean differences (95% CIs). Early PN reduced the time to regain birth weight by 2.2 d (1.1, 3.2 d) for RCTs and 3.2 d (2.0, 4.4 d) in observational studies. The maximum percentage weight loss with early PN was lower by 3.1 percentage points (1.7, 4.5 percentage points) for RCTs and by 3.5 percentage points (2.6, 4.3 percentage points) for observational studies. Early PN improved weight at discharge or 36 wk postmenstrual age by 14.9 g (5.3, 24.5 g) (observational studies only), but no benefit was shown for length or head circumference. There was no evidence that early PN significantly affects risk of mortality, necrotizing enterocolitis, sepsis, chronic lung disease, intraventricular hemorrhage, or cholestasis. CONCLUSIONS: The results of this review, although subject to some limitations, show that early PN provides a benefit for some short-term growth outcomes. No evidence that early PN increases morbidity or mortality was found. Neonatal research would benefit from the development of a set of core growth outcome measures. PMID- 23446895 TI - Plasma concentrations of trans fatty acids in persons with type 2 diabetes between September 2002 and April 2004. AB - BACKGROUND: transFatty acids (TFAs) increase cardiovascular disease risk. TFAs and polyunsaturated fatty acids (PUFAs) in the food supply may be declining with reciprocal increases in cis-monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs). OBJECTIVES: We sought to determine whether plasma 18-carbon TFA and PUFA concentrations might decrease over time and whether there might be reciprocal increases in plasma cis-MUFAs and SFAs. DESIGN: We studied 305 persons (171 women) taking part in Look AHEAD (Action for Health in Diabetes), a randomized trial of lifestyle intervention for weight loss to reduce major cardiovascular events in overweight and obese adults (aged 45-76 y) with type 2 diabetes who also participated in an ancillary study of oxidative stress. This study was a cross-sectional analysis of TFAs, cis-MUFAs, SFAs, and PUFAs measured in plasma before intervention (September 2002-April 2004). RESULTS: In a model that included demographic characteristics, plasma total fatty acid concentration, BMI, serum insulin, statin use, season, and longitudinal time trend (R(2) = 0.167, P < 0.0001), plasma TFAs decreased by 13.5%/y (95% CI: -22.7, -3.2%/y; absolute decrease 7.0 mg . L(-1) . y(-1); 95% CI: -12.5, -1.6 mg . L(-1) . y(-1); P = 0.012). This longitudinal trend was not significantly altered by further adjustment for dietary variables and physical activity. In contrast, longitudinal trends for PUFAs, cis-MUFAs, and SFAs were weak and not significant. CONCLUSIONS: This change in plasma concentrations of TFAs is consistent with changes in fatty acid composition that food manufacturers are likely to have made to avoid declaring TFAs on food labels. Further research will be needed to determine the overall effect of these changes on cardiovascular risk. The Look AHEAD trial is registered at clinicaltrials.govas NCT00017953. PMID- 23446897 TI - Choline intake influences phosphatidylcholine DHA enrichment in nonpregnant women but not in pregnant women in the third trimester. AB - BACKGROUND: Phosphatidylcholine (PC) produced via the S-adenosylmethionine dependent phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway is enriched with docosahexaenoic acid (DHA). DHA plays a critical role in fetal development and is linked to health endpoints in adulthood. It is unknown whether choline, which can serve as a source of S-adenosylmethionine methyl groups, influences PC-DHA or the PC:PE ratio in pregnant and nonpregnant women. OBJECTIVE: This study tested whether choline intake affects indicators of choline related lipid metabolism, including erythrocyte and plasma PC-DHA and PC:PE ratios, in pregnant women in the third trimester and nonpregnant women. DESIGN: Pregnant (n = 26) and nonpregnant (n = 21) women consumed 480 or 930 mg choline/d and a daily DHA supplement for 12 wk. Blood was collected at baseline and at the midpoint and end of the study. PC-DHA was analyzed as the proportion of total PC fatty acids. RESULTS: Pregnant women had greater (P = 0.002) PC-DHA concentrations than did nonpregnant women at baseline. The proportion of erythrocyte and plasma PC-DHA increased (P <= 0.002) in pregnant and nonpregnant women regardless of choline intake. However, in nonpregnant women, consumption of 930 mg choline/d led to greater (P < 0.001) erythrocyte PC-DHA and a more rapid increase (P < 0.001) in plasma PC-DHA. Lower (P = 0.001-0.024) erythrocyte and plasma PC:PE in pregnant women was not modified by choline intake. CONCLUSIONS: A higher choline intake may increase PEMT activity, resulting in greater PC-DHA enrichment of the PC molecule in nonpregnant women. Increased production of PC DHA during pregnancy indicates elevated PEMT activity and a higher demand for methyl donors. This trial was registered at clinicaltrials.gov as NCT01127022. PMID- 23446898 TI - Price discounts significantly enhance fruit and vegetable purchases when combined with nutrition education: a randomized controlled supermarket trial. AB - BACKGROUND: Reducing fruit and vegetable (F&V) prices is a frequently considered policy to improve dietary habits in the context of health promotion. However, evidence on the effectiveness of this intervention is limited. OBJECTIVE: The objective was to examine the effects of a 50% price discount on F&Vs or nutrition education or a combination of both on supermarket purchases. DESIGN: A 6-mo randomized controlled trial within Dutch supermarkets was conducted. Regular supermarket shoppers were randomly assigned to 1 of 4 conditions: 50% price discounts on F&Vs, nutrition education, 50% price discounts plus nutrition education, or no intervention. A total of 199 participants provided baseline data; 151 (76%) were included in the final analysis. F&V purchases were measured by using supermarket register receipts at baseline, at 1 mo after the start of the intervention, at 3 mo, at 6 mo (end of the intervention period), and 3 mo after the intervention ended (9 mo). RESULTS: Adjusted multilevel models showed significantly higher F&V purchases (per household/2 wk) as a result of the price discount (+3.9 kg; 95% CI: 1.5, 6.3 kg) and the discount plus education intervention (+5.6 kg; 95% CI: 3.2, 7.9 kg) at 6 mo compared with control. Moreover, the percentage of participants who consumed recommended amounts of F&Vs (>=400 g/d) increased from 42.5% at baseline to 61.3% at 6 mo in both discount groups (P = 0.03). Education alone had no significant effect. CONCLUSIONS: Discounting F&Vs is a promising intervention strategy because it resulted in substantially higher F&V purchases, and no adverse effects were observed. Therefore, pricing strategies form an important focus for future interventions or policy. However, the long-term effects and the ultimate health outcomes require further investigation. This trial was registered at the ISRCTN Trial Register as number ISRCTN56596945 and at the Dutch Trial Register (http://www.trialregister.nl/trialreg/index.asp) as number NL22568.029.08. PMID- 23446899 TI - Human skeletal muscle ascorbate is highly responsive to changes in vitamin C intake and plasma concentrations. AB - BACKGROUND: Vitamin C (ascorbate) is likely to be essential for skeletal muscle structure and function via its role as an enzyme cofactor for collagen and carnitine biosynthesis. Vitamin C may also protect these metabolically active cells from oxidative stress. OBJECTIVE: We investigated the bioavailability of vitamin C to human skeletal muscle in relation to dietary intake and plasma concentrations and compared this relation with ascorbate uptake by leukocytes. DESIGN: Thirty-six nonsmoking men were randomly assigned to receive 6 wk of 0.5 or 2 kiwifruit/d, an outstanding dietary source of vitamin C. Fasting blood samples were drawn weekly, and 24-h urine and leukocyte samples were collected before intervention, after intervention, and after washout. Needle biopsies of skeletal muscle (vastus lateralis) were carried out before and after intervention. RESULTS: Baseline vastus lateralis ascorbate concentrations were ~16 nmol/g tissue. After intervention with 0.5 or 2 kiwifruit/d, these concentrations increased ~3.5-fold to 53 and 61 nmol/g, respectively. There was no significant difference between the responses of the 2 groups. Mononuclear cell and neutrophil ascorbate concentrations increased only ~1.5- and ~2-fold, respectively. Muscle ascorbate concentrations were highly correlated (P < 0.001) with dietary intake (R = 0.61) and plasma concentrations (R = 0.75) in the range from 5 to 80 MUmol/L. CONCLUSIONS: Human skeletal muscle is highly responsive to vitamin C intake and plasma concentrations and exhibits a greater relative uptake of ascorbate than leukocytes. Thus, muscle appears to comprise a relatively labile pool of ascorbate and is likely to be prone to ascorbate depletion with inadequate dietary intake. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12611000162910. PMID- 23446900 TI - One-carbon metabolism factors and leukocyte telomere length. AB - BACKGROUND: Dietary and genetic factors involved in the one-carbon metabolism pathway may affect telomere length through DNA methylation and synthesis, but this has not been comprehensively investigated in epidemiologic studies. OBJECTIVE: We cross-sectionally examined associations between dietary and genetic factors in the one-carbon metabolism pathway and relative peripheral blood leukocyte telomere length. DESIGN: A total of 1715 participants from the Nurses' Health Study (NHS) had measurements of relative telomere length and plasma concentrations of folate, vitamin B-6, vitamin B-12, cysteine, and homocysteine. Food-frequency questionnaire (FFQ) measurements were also used for the assessment of folate, choline, methionine, riboflavin, vitamin B-6, vitamin B-12, and alcohol intakes. Genotyping was performed on 475 participants with telomere measurements on 29 mostly nonsynonymous single-nucleotide polymorphisms (SNPs) involved in one-carbon metabolism. Unconditional logistic and linear regression models were used. RESULTS: There were no significant dose-response relations between any plasma- or FFQ-measured dietary factors and relative telomere length in multivariate analyses. For folate, vitamin B-6, and vitamin B-12, results from the use of FFQ data were consistent with plasma-biomarker findings. We showed no significant associations that involved SNPs and relative telomere length after we accounted for the false discovery rate. CONCLUSION: Our analyses involving plasma and questionnaire measurements of one-carbon metabolism factors show that some key dietary and genetic factors in this metabolic network are not associated with relative peripheral blood leukocyte telomere length. PMID- 23446901 TI - Dietary patterns in Blacks and Hispanics with diagnosed diabetes in New York City's South Bronx. AB - BACKGROUND: An understanding of dietary patterns in diverse populations may guide the development of food-based, rather than nutrient-based, recommendations. OBJECTIVE: We identified and determined predictors of dietary patterns in low income black and Hispanic adults with diagnosed diabetes. DESIGN: A food frequency questionnaire was used to assess dietary intake in 235 adults living in the South Bronx, New York City, NY. We used principal factor analysis with promax rotation to identify dietary patterns. Multivariate linear regression models were used to test associations between demographic variables and dietary pattern scores. RESULTS: The following 5 dietary patterns were identified: pizza and sweets, meats, fried foods, fruit and vegetables, and Caribbean starch. The Caribbean starch and fruit and vegetables patterns were high in fruit and vegetables and low in trans fats. In multivariate analyses, sex, language spoken, years living in the United States, and region of birth were significant predictors of dietary patterns. Compared with English speakers, Spanish speakers were less likely to have high scores in pizza and sweets (P = 0.001), meat (P = 0.004), and fried food (P = 0.001) patterns. Participants who lived longer in the United States were less likely to have a meat (P = 0.024) or Caribbean starch pattern (P < 0.001). In Hispanics, the consumption of foods in the Caribbean starch pattern declined for each year that they lived in the United States. CONCLUSIONS: In adults with diagnosed diabetes who were living in the South Bronx, a Caribbean starch pattern, which included traditional Hispanic and Caribbean foods, was consistent with a healthier dietary pattern. In developing dietary interventions for this population, one goal may be to maintain healthy aspects of traditional diets. This trial was registered at clinicaltrials.gov as NCT00797888. PMID- 23446902 TI - Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. AB - BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentration has been linked to mortality in several studies, but appropriate cutoffs to define risk categories are under debate. OBJECTIVE: We aimed to conduct a repeated-measurements analysis on the association of serum 25(OH)D concentrations with all-cause and cause specific mortality, with particular attention given to the shape of dose-response relations. DESIGN: Concentrations of 25(OH)D were measured in n = 9578 baseline and n = 5469 5-y follow-up participants of the ESTHER study, which is a German population-based cohort aged 50-74 y at baseline. Deaths were recorded during 9.5 y of follow-up (median). Restricted cubic splines were used to assess dose response relations, and Cox regression with time-dependent variables was used to estimate hazard ratios. RESULTS: During follow-up, 1083 study participants died; of those, 350 individuals died of cardiovascular diseases, 433 individuals died of cancer, and 55 individuals died of respiratory diseases. The overall mortality [HR (95% CI)] of subjects with vitamin D deficiency [25(OH)D concentrations <30 nmol/L] or vitamin D insufficiency [25(OH)D concentrations from 30 to 50 nmol/L) was significantly increased [1.71 (1.43, 2.03) and 1.17 (1.02, 1.35), respectively] compared with that of subjects with sufficient 25(OH)D concentrations (>50 nmol/L)]. Vitamin D deficiency was also associated with increased cardiovascular mortality [1.39 (95% CI: 1.02, 1.89)], cancer mortality [1.42 (95% CI: 1.08, 1.88)] and respiratory disease mortality [2.50 (95% CI: 1.12, 5.56)]. The association of 25(OH)D concentrations with all-cause mortality proved to be a nonlinear inverse association with risk that started to increase at 25(OH)D concentrations <75 nmol/L. CONCLUSIONS: In this large cohort study, serum 25(OH)D concentrations were inversely associated with all-cause and cause specific mortality. In particular, vitamin D deficiency [25(OH)D concentration <30 nmol/L] was strongly associated with mortality from all causes, cardiovascular diseases, cancer, and respiratory diseases. PMID- 23446903 TI - Modeling dietary patterns to assess sodium recommendations for nutrient adequacy. AB - BACKGROUND: The 2010 Dietary Guidelines Advisory Committee report contained dietary patterns developed by using nutrient-dense foods. In most cases, low sodium forms of foods were incorporated into the patterns. OBJECTIVES: We wanted to determine whether choosing lower-sodium foods could lower the sodium content to 1500 mg without compromising nutrient adequacy. We also explored the effect of choosing typical foods (more calories with higher sodium) and the feasibility of implementing sodium recommendations on a density basis (mg Na/kcal). DESIGN: Food patterns developed during the 2010 Dietary Guidelines development process were used as the base for this analysis. Modeling was then used to analyze the effect of substituting lower-sodium foods on nutrient adequacy. RESULTS: Sodium amounts in the base model varied directly with energy level (1.0 mg Na/kcal) and ranged from 996 to 3176 mg/d. Amounts in the lowest-sodium model also varied with energy level (~0.5 mg/kcal) and ranged from 500 to 1250 mg/d. A comparison of sodium density for the base and the lowest sodium models showed that sodium in the lowest model is ~50% of the base. For typical food choices, sodium amounts were much higher (1.6-2.0 mg/kcal and 1715-5078 mg/d). Comparison of sodium density for the base and the typical food choice models showed that amounts were 1.6-2.0 times greater than the base. CONCLUSIONS: By choosing only low-sodium foods, it was possible to construct nutritionally adequate dietary patterns with 1500 mg Na/d. Sodium density (mg Na/kcal) is a practical approach for expressing sodium recommendations. PMID- 23446904 TI - Secular trends in trans fatty acids: decreased trans fatty acids in the food supply are reflected in decreased trans fatty acids in plasma. PMID- 23446905 TI - Management of obesity at worksites: less work for greater success? PMID- 23446907 TI - Dominance style of female white-faced capuchins. AB - Dominance style, the level of tolerance displayed by dominant individuals toward subordinate ones, is exhibited along a continuum from despotic to relaxed. It is a useful concept to describe the nature of dominance relationships in macaque species and it bridges among multiple features of dominance hierarchies, aggression, kinship and conflict resolution. Capuchins share many behavioral similarities with Old World monkeys and like macaques, may exhibit a suite of covarying characteristics related to dominance. Here, we provide an assessment of dominance style by examining measures of aggression and kin bias in 22 adult female white-faced capuchin monkeys (Cebus capucinus) in three social groups at Santa Rosa Sector, Costa Rica. We found that bidirectionality of aggression was low (mean = 6.9% +/- SE 1.6). However, there were few significant correlations between kin relatedness and social behavior (approaching, grooming, proximity, and co-feeding), even though the intensity of kin bias in grooming was moderate and higher in the larger group. We conclude that patterns of aggression and kin biased behavior in our study animals are dissimilar to the patterns of covariation observed in macaque species. While unidirectional aggression suggests a despotic dominance style, the moderate expression of kin bias suggests an intermediate to relaxed classification when compared with results from an analysis of 19 macaque species. Additional studies of capuchin species and behaviors associated with dominance style (i.e., conciliatory tendencies) would help to create a comparative framework for the genus Cebus, and allow for more detailed cross-species comparison of dominance relationships across all primates. PMID- 23446906 TI - Beneficial effects of a higher-protein breakfast on the appetitive, hormonal, and neural signals controlling energy intake regulation in overweight/obese, "breakfast-skipping," late-adolescent girls. AB - BACKGROUND: Breakfast skipping is a common dietary habit practiced among adolescents and is strongly associated with obesity. OBJECTIVE: The objective was to examine whether a high-protein (HP) compared with a normal-protein (NP) breakfast leads to daily improvements in appetite, satiety, food motivation and reward, and evening snacking in overweight or obese breakfast-skipping girls. DESIGN: A randomized crossover design was incorporated in which 20 girls [mean +/ SEM age: 19 +/- 1 y; body mass index (in kg/m(2)): 28.6 +/- 0.7] consumed 350 kcal NP (13 g protein) cereal-based breakfasts, consumed 350-kcal HP egg- and beef-rich (35 g protein) breakfasts, or continued breakfast skipping (BS) for 6 d. On day 7, a 10-h testing day was completed that included appetite and satiety questionnaires, blood sampling, predinner food cue-stimulated functional magnetic resonance imaging brain scans, ad libitum dinner, and evening snacking. RESULTS: The consumption of breakfast reduced daily hunger compared with BS with no differences between meals. Breakfast increased daily fullness compared with BS, with the HP breakfast eliciting greater increases than did the NP breakfast. HP, but not NP, reduced daily ghrelin and increased daily peptide YY concentrations compared with BS. Both meals reduced predinner amygdala, hippocampal, and midfrontal corticolimbic activation compared with BS. HP led to additional reductions in hippocampal and parahippocampal activation compared with NP. HP, but not NP, reduced evening snacking of high-fat foods compared with BS. CONCLUSIONS: Breakfast led to beneficial alterations in the appetitive, hormonal, and neural signals that control food intake regulation. Only the HP breakfast led to further alterations in these signals and reduced evening snacking compared with BS, although no differences in daily energy intake were observed. These data suggest that the addition of breakfast, particularly one rich in protein, might be a useful strategy to improve satiety, reduce food motivation and reward, and improve diet quality in overweight or obese teenage girls. This trial was registered at clinicaltrials.gov as NCT01192100. PMID- 23446908 TI - Receptor recognition of transferrin bound to lanthanides and actinides: a discriminating step in cellular acquisition of f-block metals. AB - Following an internal contamination event, the transport of actinide (An) and lanthanide (Ln) metal ions through the body is facilitated by endogenous ligands such as the human iron-transport protein transferrin (Tf). The recognition of resulting metallo-transferrin complexes (M2Tf) by the cognate transferrin receptor (TfR) is therefore a critical step for cellular uptake of these metal ions. A high performance liquid chromatography-based method has been used to probe the binding of M2Tf with TfR, yielding a direct measurement of the successive thermodynamic constants that correspond to the dissociation of TfR(M2Tf)2 and TfR(M2Tf) complexes for Fe(3+), Ga(3+), La(3+), Nd(3+), Gd(3+), Yb(3+), Lu(3+), (232)Th(4+), (238)UO2(2+), and (242)Pu(4+). Important features of this method are (i) its ability to distinguish both 1 : 1 and 1 : 2 complexes formed between the receptor and the metal-bound transferrin, and (ii) the requirement for very small amounts of each binding partner (<1 nmol of protein per assay). Consistent with previous reports, the strongest receptor affinity is found for Fe2Tf (Kd1 = 5 nM and Kd2 = 20 nM), while the lowest affinity was measured for Pu2Tf (Kd1 = 0.28 MUM and Kd2 = 1.8 MUM) binding to the TfR. Other toxic metal ions such as Th(IV) and U(VI), when bound to Tf, are well recognized by the TfR. Under the described experimental conditions, the relative stabilities of TfR:(MxTf)y adducts follow the order Fe(3+) >> Th(4+) ~ UO2(2+) ~ Cm(3+) > Ln(3+) ~ Ga(3+) >>> Yb(3+) ~ Pu(4+). This study substantiates a role for Tf in binding lanthanide fission products and actinides, and transporting them into cells by receptor-mediated endocytosis. PMID- 23446909 TI - A microporous luminescent europium metal-organic framework for nitro explosive sensing. AB - A microporous metal-organic framework (MOF) Eu3(MFDA)4(NO3)(DMF)3 (1, H2MFDA = 9,9-dimethylfluorene-2,7-dicarboxylic acid) has been solvothermally synthesized and structurally characterized by single-crystal X-ray diffraction. 1 is a three dimensional coordination polymer with pcu type rod-packing structure, through which 1D rhombic channels penetrate. The solvent-free form 1a could be obtained by direct heating of 1. Both 1 and 1a exhibit high intensity red light emissions with high quantum yields and long luminescence lifetimes when excited at 336 nm at ambient temperature. The potential of 1a for nitro explosive sensing is studied through luminescence quenching experiments, which show that 1a is a potential luminescent sensory material for nitro explosives. PMID- 23446910 TI - Prognostic value of post-procedural aPTT in patients with ST-elevation myocardial infarction treated with primary PCI. AB - Unfractionated heparin is the most commonly used anticoagulant in ST-elevation myocardial infarction (STEMI) and its effect can be monitored with activated partial thromboplastin time (aPTT). However, the optimal aPTT range during heparin therapy after primary percutaneous coronary intervention (PCI) is yet to be defined. A mean aPTT was calculated of all aPTT measurements in the first 24 hours after pPCI in a total of 1,876 STEMI patients. Mean aPTT measurements were stratified into four categories; < 1.5 times the upper limit of normal (ULN), 1.5 - 2.0 times ULN (the therapeutic group), 2.01 - 3.99 times ULN, and >= 4 times ULN. Compared to patients with a therapeutic aPTT, patients with aPTTs < 1.5 times ULN had no increase in recurrent ischaemic events and had similar rates of bleeding complications. Patients with a mean aPTT >= 4 times ULN had higher rates recurrent ischaemic and haemorrhagic complications. After multivariable analyses, aPTT ratios >= 4 times ULN were no longer associated with recurrent ischaemic events, but remained a strong predictor of severe and moderate bleeding (hazard ratio [HR] 4.64, p = 0.016 and HR 2.27, p = 0.052). In conclusion, in 1,876 STEMI patients treated with pPCI, low aPTTs in the first 24 hours after PCI were not associated with an increase in ischaemic events, whereas high aPTT values were associated with more frequent bleeding complications. These results indicate no clear benefit as well as a safety concern with heparin treatment after primary PCI. PMID- 23446911 TI - Development challenges in the preparation of solution-based phytochemical and vitamin certified reference materials. PMID- 23446912 TI - Recent advances in graphite powder-based electrodes. AB - Graphite powder-based electrodes have the electrochemical performance of quasi noble metal electrodes with intrinsic advantages related to the possibility of modification to enhance selectivity and their easily renewable surface, with no need for hazardous acids or bases for their cleaning. In contrast with commercial electrodes, for example screen-printed or sputtered-chip electrodes, graphite powder-based electrodes can also be fabricated in any laboratory with the form and characteristics desired. They are also readily modified with advanced materials, with relatively high reproducibility. All these characteristics make them a very interesting option for obtaining a large variety of electrodes to resolve different kinds of analytical problems. This review summarizes the state of-the-art, advantages, and disadvantages of graphite powder-based electrodes in electrochemical analysis in the 21st century. It includes recent trends in carbon paste electrodes, devoting special attention to the use of emergent materials as new binders and to the development of other composite electrodes. The most recent advances in the use of graphite powder-modified sol-gel electrodes are also described. The development of sonogel-carbon electrodes and their use in electrochemical sensors and biosensors is included. These materials extend the possibilities of applications, especially for industrial technology-transfer purposes, and their development could affect not only electroanalytical green chemistry but other interesting areas also, for example catalysis and energy conversion and storage. PMID- 23446914 TI - Role of fibrinolysis in sepsis. AB - Sepsis, defined as infection-induced systemic inflammatory response syndrome, invariably leads to hemostatic abnormalities ranging from insignificant coagulopathy to disseminated intravascular coagulation (DIC). The inflammation induced activation of coagulation, the downregulation of physiologic anticoagulant pathways, and impairment of fibrinolysis play a pivotal role in the pathogenesis of microvascular fibrin thrombosis and multiple organ dysfunction syndrome (MODS) in DIC associated with sepsis. The balance between tissue plasminogen activator and plasminogen activator inhibitor-1 mainly regulates fibrinolytic activity. Thrombin-activatable fibrinolysis inhibitor and neutrophil elastase also modulate fibrinolysis. Dynamic changes in these molecules are deeply involved in the pathomechanisms of the impairment of fibrinolysis, leading to MODS in DIC associated with sepsis. Evidence indicates that physical entrapment of bacteria by fibrin at the site of infection may limit their capacity to disseminate into nearby tissues, organs, and systemic circulation. Under this circumstance, impairment of fibrinolysis has protective role in the host defense. Given the protective and pathologic potential of fibrinolysis during sepsis, therapeutics that control DIC as a systemic syndrome, while maintaining the host defense at the infectious foci, are required for the protection against both the development of MODS and for the host defense mechanisms. PMID- 23446913 TI - LeMAPK4 participated in cold-induced ethylene production in tomato fruit. AB - BACKGROUND: Mitogen-activated protein kinase (MAPK, EC 2.7.11.24) cascade from several plant species has been shown to be activated during response to abiotic stress. Ethylene plays an important role in fruit tolerance to environmental stress. However, the mechanisms by which MAPK regulates defence systems in fruit and the relationship between MAPK and ethylene remain to be determined. RESULTS: MAPK inhibitor significantly decreased the chilling tolerance of tomato (Lycopersicon esculentum cv. Lichun) fruit during cold storage. Moreover, decreases in ethylene content, LeACS2 expression and activities of 1 aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS, EC 4.4.1.14) and ACC oxidase (ACO, EC 1.14.17.4) due to MAPK inhibitor occurred within 24 h after cold treatment. Upon treatment with cold and ethephon, the ethylene content, activities of ACS and ACO and expression of LeACS2, LeACO1 and LeMAPK4 increased. CONCLUSION: The results showed the regulation of MAPK in ethylene biosynthesis to protect tomato fruit from cold stress. In addition, the participation of LeMAPK4 in cold-induced ethylene biosynthesis in tomato fruit was indicated. PMID- 23446915 TI - Thrombolysis for intraventricular hemorrhage. AB - Intraventricular hemorrhage is a frequent complication of intracerebral hemorrhage and is independently associated with significant morbidity and mortality. Intraventricular fibrinolytic therapy is used with increasing frequency to accelerate clot clearance. We review the recent evidence and discuss the therapeutic benefits as well as the current concerns and limitations of fibrinolytic use in this setting. PMID- 23446916 TI - Using virtual human technology to capture dentists' decision policies about pain. AB - Healthcare professionals use race, gender, and age cues when making pain management decisions. Use of these demographic cues, therefore, is an important topic in the study of healthcare disparities. This study used virtual human (VH) technology to investigate the effects of VH patients' demographic cues on dentists' pain management decisions. Eighty-nine dentists viewed patients with different demographic cues. Analyses revealed that dentists rated pain intensity higher and were more willing to prescribe opioids to female, African-American, and younger patients than to their demographic counterparts. Results also found significant 2-way interactions between race and age for both pain assessment and treatment decisions. The interaction results suggest that the race difference (Caucasian < African American) was more pronounced for younger than for older patients. This is the first study to examine demographic cue use in dentists' decision-making for pain. The study found that dentists used demographic cues when making pain management decisions. Currently, there are no guidelines for decision- making practices for gender-, race-, or age-related pain. Since dentists see thousands of patients during their careers, the use of demographic cues could affect a substantial portion of the population. The findings could improve future training programs for dentists and dental students. PMID- 23446917 TI - Ulososides and urabosides--triterpenoid saponins from the Caribbean marine sponge Ectyoplasia ferox. AB - Three new triterpene glycosides, named ulososide F (1), urabosides A (2) and B (3), together with the previously reported ulososide A (4), were isolated from the Caribbean marine sponge Ectyoplasia ferox. Their structures were elucidated using extensive interpretation of 1D and 2D-NMR data, as well as HRESIMS. The aglycon of all compounds is a rare 30-norlonastane and the sugar residues were identified after acid hydrolysis and GC analyses. Cytotoxicities of the isolated compounds were evaluated against Jurkat and CHO cell lines by a MTT in vitro assay as well as a hemolysis assay. Unexpectedly, all these saponin derivatives showed very low activity in our bioassays. PMID- 23446918 TI - alpha(delta')-Michael addition of alkyl amines to dimethyl (E)-hex-2-en-4 ynedioate: synthesis of alpha,beta-dehydroamino acid derivatives. AB - The direct nucleophilic addition of alkyl amines to the alpha(delta')-carbon atom of dimethyl (E)-hex-2-en-4-ynedioate to generate alpha,beta-dehydroamino acid derivatives is reported. Herein, we have studied the reactivity of various primary and secondary alkyl amines in the alpha-selective nucleophilic conjugate addition to conjugated dimethyl (E)-hex-2-en-4-ynedioate. The reaction with primary alkyl amines gives only the (2E,4E)-stereoisomer, while that with secondary alkyl amines gives the (2E,4E) and (2Z,4E)-stereoisomers of dimethyl (2 alkylamino)-muconic ester. PMID- 23446919 TI - Main alkaloids of Peganum harmala L. and their different effects on dicot and monocot crops. AB - Alkaloids with allelopathic activity are not as well-known as other allelochemicals. Our study revealed that total alkaloids from seeds of the medicinal plant Peganum harmala L. possessed significant growth inhibitory effect on four treated plants, with dicot plants (lettuce and amaranth) being more sensitive than the tested monocot plants (wheat and ryegrass). Further investigation led to the isolation of harmaline and harmine as the main active ingredients in the total alkaloids of P. harmala seeds. Harmaline exerted potent inhibitory effects on seedling growth of treated plants, especially dicots, inhibiting root elongation of lettuce and amaranth by 31% and 47% at a very low concentration (5 ug/mL), whereas harmine exhibited much weaker non-selective inhibitory effect on the plants. Considering the high yield and poor utilization of P. harmala in China, we anticipate that this plant could be exploited as an alternative weed management tool in the future. PMID- 23446920 TI - Synthesis of pyrrolo[2,1-a]isoquinolines by multicomponent 1,3-dipolar cycloaddition. AB - Pyrrolo[2,1-a]isoquinoline derivatives were synthesized by one-pot three component reactions starting from isoquinoline, 2-bromoacetophenones and different non-symmetrical acetylenic dipolarophiles using 1,2-epoxypropane as solvent. The structure of the compounds was assigned by IR and NMR spectroscopy. PMID- 23446921 TI - Volatile compounds in dry dog foods and their influence on sensory aromatic profile. AB - The aim of this study was to determine volatile compounds in dry dog foods and their possible influence on sensory aromatic profile. Grain-free dry dog foods were compared to dry dog foods manufactured with grain, but also with different protein sources for their aromatic volatiles. Solid-phase microextraction/gas chromatography/mass spectrometry was used to determine the aromatic compounds present in the headspace of these samples. Partial Least Squares regression was performed to correlate the instrumental aromatic data with the descriptive aroma analysis data. A total of 54 aromatic compounds were tentatively identified in the dry dog food samples, with aldehydes and ketones being the most represented organic volatiles group. Grain-added products were on the average higher in total volatiles than grain-free products. Partial Least Squares regression analysis indicated possible connections with sensory aromatic profile and grain-added samples, such as rancid aroma and aldehydes, especially hexanal. The results of this study showed that dry dog foods are products with complex odor characteristics and that grain-free products are less aromatic. PMID- 23446922 TI - QRS complex duration enhancement as ventricular late potential indicator by signal-averaged ECG using time-amplitude alignments. AB - Ventricular late potentials (VLPs) are small-amplitude waves with a short duration that appear at the end part of the QRS complex, making a QRS complex duration larger. The signal-averaged electrocardiography (ECG) technique enhances VLPs and beats, assuming noise as the only random variable. However, ECG signals are not completely stationary and different elongations appear in both time and amplitude in each beat. This research proposes to use piecewise linear approximation to segment each beat and performs the alignment of the beats using the technique known as derivative dynamic time-warping to have beats better aligned and consequently enhance the presence of VLPs. We recorded high resolution ECGs (HRECGs) from 50 subjects in supine position with no heart-stroke antecedents. VLPs were created synthetically and added to the HRECGs. Two cases were evaluated: (i) duration of the QRS complexes with VLPs without beats alignment, and (ii) duration of QRS complexes with VLPs using beats alignment in time and amplitude. Considering QRS duration as an indicative of VLP presence, results show that when using beats alignment in time and amplitude it is possible to reach a sensitivity of 0.96 and a specificity of 0.52, as opposed to 0.72 and 0.40, respectively, when using only averaging without beats alignment in time and amplitude. PMID- 23446923 TI - Validity of subthalamic-cortical coherency observed in patients with Parkinson's disease. AB - Simultaneous magnetoencephalography (MEG) and local field potential (LFP) recordings in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS) treatment is a promising tool for both clinical application and basic research. Recordings can be accomplished during the time interval between electrode insertion and its connection to the pulse generator while electrodes are being externalized. In nine PD patients, coherence (COH) between LFP and MEG signals was calculated from the data of a 5-min simultaneous MEG-LFP rest recording. For the observed COH patterns, a validation procedure is introduced based on time-shift principal component analysis (TSPCA), which was originally developed to suppress background signals from MEG. Here TSPCA is used as a regression of the MEG signal with filtered versions of the LFP signal to intentionally remove COH. The channel mean of the original COH is compared with the residual channel mean COH after TSPCA application. COH peaks are suppressed in the 15- to 30-Hz range; at lower frequencies, the results are less obvious due to the presence of an artifact caused by a weak remanent magnetization of the externalization wires. The COH suppression is statistically significant for four out of nine subjects, and validation has been achieved, as the COH suppression yields the hypothesized outcome. PMID- 23446924 TI - Coupling analysis of transient cardiovascular dynamics. AB - The analysis of effects from coupling in and between systems is important in data driven investigations as practiced in many scientific fields. It allows deeper insights into the mechanisms of interaction emerging among individual smaller systems when forming complex systems as in the human circulatory system. For systems featuring various regimes, usually only the epochs before and after a transition between different regimes are analyzed, although relevant information might be hidden within these transitions. Transient behavior of cardiovascular variables may emerge, on the one hand, from the recovery of the system after a severe disturbance or, on the other hand, from adaptive behavior throughout changes of states. It contains important information about the processes involved and the relations between state variables such as heart rate, blood pressure, and respiration. Therefore, we apply an ensemble approach to extend the method of symbolic coupling traces to time-variant coupling analysis. These new ensemble symbolic coupling traces are capable of determining coupling direction, strength, and time offset tau from transient dynamics in multivariate cardiovascular data. We use this method to analyze data recorded during an orthostatic test to reveal a transient structure that cannot be detected by classic methods. PMID- 23446925 TI - Evaluation of the Project P.A.T.H.S. (extension phase) based on the perspective of the program participants. AB - Subjective outcome evaluation data were collected from 236 schools (n=87,943 students) after students had participated in the Tier 1 Program in the second year of the Extension Phase of the Project P.A.T.H.S. in Hong Kong. Using schools as the units of analysis, results showed that the program and implementers were perceived in a positive manner and approximately four-fifths of the participants regarded the program as helpful to them. There were some significant grade differences in the subjective outcome evaluation findings with small effect size. Multiple regression analyses showed that whereas perceived qualities of the program positively predicted perceived effectiveness of the program, perceived qualities of implementers negatively predicted program effectiveness. The present study suggests that irrespective of cohorts at different times, junior secondary school students perceived the program to be beneficial to them. The theoretical and practical implications of the present findings are discussed. PMID- 23446926 TI - Helping adolescents with greater psychosocial needs: the extension phase of the Project P.A.T.H.S. in Hong Kong. AB - Subjective outcome evaluation data were collected from 24,198 students of 236 schools after completion of the Tier 2 Program in the second year of the Extension Phase of the Project P.A.T.H.S. in Hong Kong. Using schools as units of analysis, results showed that the program, implementers, and effectiveness were perceived in a positive manner. Although subjective outcome evaluation findings differed across participant types, grades, and program types did not show significant differences on the outcome measures. Consistent with previous reports, perceived effectiveness of the program was significantly predicted by student perceptions about the program and program instructor. These findings provide support for the claim that the Tier 2 Program is effective in promoting positive development among adolescents with greater psychosocial needs in the extension phase of the Project P.A.T.H.S. in Hong Kong. PMID- 23446927 TI - Evaluation of Project P.A.T.H.S. by the program implementers: findings based on the extension phase. AB - A total of 236 schools participated in the Project P.A.T.H.S. in the 2010/2011 school year. After completion of the Tier 1 Program, subjective outcome evaluation data were collected from 3275 program implementers. Based on the consolidated findings based on schools as units, results showed that participants had positive perceptions of the program, implementers, and benefits of the program. More than four-fifths of the implementers regarded the program as helpful to the program participants. Multiple regression analysis revealed that perceived qualities of the program and the program implementers predicted perceived effectiveness of the program. Grade differences were not significant. The present study provides additional support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in Hong Kong. PMID- 23446928 TI - Transforming potential program implementers in professional development: the Project P.A.T.H.S. in Hong Kong. AB - High quality pre-implementation professional training is the cornerstone for successful implementation of positive youth development programs. A qualitative evaluation study was conducted to understand the experiences of the potential program implementers of the Project P.A.T.H.S. in Hong Kong. The findings showed that participants highly valued the learning experiences acquired from the training program, particularly in the areas of knowledge acquisition and personal growth. Participants who benefited from these dimensions developed attitudes and skills that are desirable for the implementation of the Project P.A.T.H.S. Implications about the conditions that are conducive to the P.A.T.H.S. training program in promoting knowledge, skills acquisition, retention, application, and generalization are discussed. PMID- 23446929 TI - Development of an e-learning package on Service-Learning for university teachers: experience from Hong Kong. AB - To help university teachers to understand Service-Learning and develop Service Learning subjects, a 3-h+ e-learning package was developed at The Hong Kong Polytechnic University (PolyU). There are seven units in this e-learning package: introduction session (Unit 1), what is Service-Learning? (Unit 2), impact and benefits of Service-Learning (Unit 3), myths and positive attitudes toward Service-Learning (Unit 4), developing a Service-Learning subject at PolyU (Unit 5), self-reflection about Service-Learning (Unit 6), and concluding session (Unit 7). To understand the views of the users on the e-learning package, the package was offered before formal launching. For the first offering, three focus group sessions were held. Results showed that the users were satisfied with the structural arrangement of the e-learning package and agreed that the e-learning package was useful for them to understand more about Service-Learning. For the second offering, colleagues were generally satisfied with the e-learning package and demonstrated gain in knowledge on Service-Learning. Suggestions for improvement were noted. PMID- 23446930 TI - Factors influencing the quality of implementation of a positive youth development program in Hong Kong. AB - This study examines how social workers collaborate with school teachers in implementing a school-based positive youth development program in Hong Kong. Individual and focus group interviews are conducted with social workers cooperating with school teachers in implementing the Project P.A.T.H.S. in a school context. Through the interviews, strategies for establishing inter disciplinary collaboration and factors that hinder or facilitate program implementation are identified. This case study highlights factors that facilitate the collaboration between social workers and school teachers, including the following: 1) sufficient training for instructors, 2) sharing of the practice wisdom and teaching experiences, 3) building up mutual support among different parties, 4) use of proactive communication, and 5) demonstration of self disclosure. PMID- 23446931 TI - Perception of collaborative learning in associate degree students in Hong Kong. AB - Although collaborative learning has been widely researched in Western contexts, no study has been carried out to understand how associate degree students look at collaborative learning in Hong Kong. In this study, perceptions of and attitudes to collaborative learning among associate degree students were studied. A total of 44 associate degree students completed an online questionnaire including measures of perceived benefits and attitudes to collaborative learning, and social-emotional competence. Results showed that there were no significant differences between male and female students on perceived benefits of and attitudes towards collaborative learning. Social-emotional competence was related to perceived benefits of and attitudes to collaborative learning. Attitudes were also related to perceived benefits of collaborative learning. This paper is the first known study looking at the relationships among perceived benefits and attitudes to collaborative learning and social-emotional competence in Chinese associate degree students in different Chinese contexts. PMID- 23446932 TI - Implementation of the extension phase of the Project P.A.T.H.S. in Hong Kong: observations based on the Co-Walker Scheme. AB - The implementation quality of the Tier 1 Program (Secondary 1 Program) of the Project P.A.T.H.S. in the second year of the Extension Phase was examined in this study, with classroom observations of 218 units in 172 schools. Results demonstrated that the overall level of program adherence was generally high with an average of over 90%. Different aspects regarding program delivery were significantly correlated, suggesting that different aspects of program implementation were intimately related. Regarding predictors of global implementation quality, analyses indicated that overall implementation quality was significantly predicted by interactive delivery method, achievement of objectives, time management, and lesson preparation; success of implementation was predicted by student participation and involvement, interactive delivery method, achievement of objectives, and time management. The present study replicated the findings in previous studies. PMID- 23446933 TI - Service-learning from the views of university teachers: a qualitative study based on focus groups. AB - Under the New Undergraduate Curriculum at The Hong Kong Polytechnic University (PolyU), students are required to take a 3-credit subject to fulfill service learning requirements. To understand the views of teachers regarding service learning, five focus group interviews (n=33) are conducted to examine the perceived characteristics and myths of service-learning as well as colleagues' views on the policy at PolyU. Results showed that most informants are aware of service-learning and have seen its benefits to both students and teachers. Most informants also possess positive views about service-learning. Nevertheless, in terms of service-learning at PolyU, three different groups of views on service learning are observed, namely, positive, negative, and mixed views. This paper also discusses teachers' views on the anticipated difficulties of service learning implementation and the ways, by which to promote the subject in the PolyU context. PMID- 23446934 TI - Implementation quality of the Tier 1 Program of the Project P.A.T.H.S. in Hong Kong: findings from the extension phase. AB - To evaluate the implementation quality of the Tier 1 Program of the Project P.A.T.H.S. (Secondary 1 to Secondary 3), a study based on classroom observations of 597 units in 207 schools was conducted under the Co-Walker Scheme. Results demonstrated that the implementation quality of the program was high in general, with a mean program adherence of 80.8%. The 13 aspects of program delivery under observation were significantly intercorrelated. Multiple regression analyses indicated that: (i) overall implementation quality was significantly predicted by classroom control, interactive delivery method, use of positive and supportive feedback, opportunity for reflection, degree of achievement of the objectives, time management, and lesson preparation; (ii) success of implementation was significantly predicted by student participation and involvement, opportunity for reflection, degree of achievement of the objectives, and time management. PMID- 23446935 TI - Promotion of the holistic development of high school and university students in Hong Kong. PMID- 23446937 TI - The young and suicide. PMID- 23446936 TI - Developmental outcomes of economically disadvantaged adolescents in Hong Kong: a replication. AB - The purpose of this study is to examine the relationships between economic disadvantage and adolescent and developmental outcomes as well as perceived family qualities in 3580 Secondary 2 students in Hong Kong. Developmental outcomes include positive youth development constructs, problem behavior and drug taking behavior, whereas perceived family qualities include perceived family interaction and parental parenting. Generally speaking, poor and non-poor adolescents differ in terms of overall positive youth development and family life quality. Although adolescents experiencing poverty do not display significant differences from non-poor adolescents in terms of risk behavior and psychosocial competencies, adolescents with economic disadvantage show lower levels of positive identity, family interaction, and perceived paternal parenting than do those without economic disadvantage. PMID- 23446938 TI - Health and educational performance among young migrants. AB - This study is a part replication of an earlier study by on health efficacy, educational attainment and well-being among 30 nations. It includes, however, data from these nations, as well as the latest Pisa results and update socioeconomic data and sociological variables which include divorce rate, number of persons/household, employment rates, and measures of physical and mental health (including new scales of well-being, e.g., mental health index, life satisfaction, suicide rates). More importantly, it includes measures of migrant rates among children and adults in each country, the focus of attention of this article. New material on health and educational expenditure are provided. PMID- 23446939 TI - The levels and patterns of resilience among male street children in Dhaka City. AB - Abstract This study was carried out to identify the factors affecting resilience among street children. The study used a convenience sample of 366 male street children aged 14-17 years in Dhaka City, Bangladesh. The levels of resilience among the street children were mostly moderately low-low (54.1%), followed by low (29.0%), and moderately high-high resilience (16.9%). Multinomial logistic regression analyses indicated that the pre-street factors of education, economic constraint in the family, as well as experiencing and witnessing domestic violence were associated with resilience, with associated street characteristics being drug abuse, experiencing and witnessing violence on street, access to prevention services, and political involvement. PMID- 23446940 TI - Screening physical examinations in 25,000 Israeli schoolchildren. AB - Physical examinations in childhood and adolescence have been recommended by various professional organizations. In order to assess the value of periodic physical examinations in identifying previously undetected conditions, we analyzed the results of school screening examinations of approximately 25,000 Israeli students. METHODS: Entire student populations in the 1st, 5th, 7th, and 10th grades in the Tel Aviv-Yafo public school system were offered physical examinations during the 1996-1997 and 1997-1998 school years. Nine physicians performed these examinations. Referrals to the primary care physician were made for abnormal findings. The frequencies of the leading referrals were determined, and comparisons were made according to gender and grade. RESULTS: A total of 24,846 students were examined. The overall referral rate was 7.8 per 100 examinations. Leading referrals included "overweight", "heart murmur", and "spinal structural abnormalities" at all grade levels, and "nevi" in grades 5, 7, and 10. Referral rates increased between various grade levels for "spinal structural abnormalities", "nevi", and "varicocele", and decreased for "short stature" and "overweight". Of the 196 diagnoses documented after referral, 182 (93%) fell into three categories, namely, spinal, hernia and scrotal, and short stature. CONCLUSIONS: A wide range of physical findings were detected or referred at each of the grade levels in this large population of schoolchildren. Many of these were triggers for preventive health counseling, while approximately 1% of the examinations yielded important findings requiring intervention. These results provide a measure of justification for the American Academy of Pediatrics' recommendations for periodic physical examinations in childhood and adolescence. PMID- 23446941 TI - Adolescent suicide: characterizing the need and identifying the predictive factors for preventive consultation or hospitalization in a rural community setting. AB - BACKGROUND: Studies from India consistently document the highest suicide rates in the world, and the majority of completed suicides had been within adolescents. OBJECTIVE: To characterize the need and identify the predictive factors for preventive consultation or hospitalization for adolescent suicide in a community setting. SUBJECTS: We prospectively collected data from 500 adolescents in a rural South Indian community with independent, trained raters. METHODS: The need for suicide prevention was measured with the SAD PERSONS scale, socio-economic status with the Modified Kuppusamy Scale, depression and anxiety disorders with the Beck Depression Inventory and the Screen for Child Anxiety Related Emotional Disorders, respectively. The relationship between predictors and the need for preventive action was analyzed with univariate and multivariate regression analyses and a predictive model was built. RESULTS: Of those investigated, 2% and 0.6% required emergency consultation and hospitalization, respectively. Males needed more preventive action (p=0.04). Age (OR=3.40, p=0.07), gender (OR=3.13, p=0.05), presence of anxiety (OR=16.35, p=0.001), or depressive (OR=42.59, p=0.001) disorder independently predicted a need for protective action and, together, contributed to a parsimonious predictive model. CONCLUSIONS: The majority of adolescents in the community do not require preventive steps to address suicide risk. These predictors could identify the high-risk adolescents for suicide prevention and reduce the burden of care in the community. PMID- 23446943 TI - Striated heron-Galapagos Islands. PMID- 23446942 TI - Tattoo, piercing, and adolescent tobacco consumption. AB - Abstract The objective of the study was to evaluate the link between tattoos and/or piercings and young people's tobacco consumption. METHODS: A total of 2587 students (1168 females and 1419 males) were asked about tattoos, piercings, and tobacco consumption. RESULTS: Young men and young girls who had tattoos and/or wore piercings were more likely to report smoking behavior, earlier smoking behavior, and higher cigarette consumption per day. It was also found that both with men and women, the combined effects of piercings and tattoos were associated with an increase in smoking behavior. CONCLUSION: Piercings and/or tattoos as well as combined piercings and tattoos appeared as markers of tobacco consumption. Such marks could serve as signs for educators, parents, and physicians. PMID- 23446944 TI - Nitric oxide reactivity of Cu(II) complexes of tetra- and pentadentate ligands: structural influence in deciding the reduction pathway. AB - Four Cu(II) complexes, 1, 2, 3 and 4, are synthesized with ligands, L1, L2, L3 and L4 [L1 = N1,N2-bis((pyridin-2-yl)methyl)ethane-1,2-diamine; L2 = N1,N3 bis((pyridin-2-yl)methyl)propane-1,3-diamine; L3 = N1,N1,N2-tris((pyridin-2 yl)methyl)ethane-1,2-diamine; L4 = N1-((1-methyl-1H-imidazol-2-yl)methyl)-N1,N2 bis((pyridin-2-yl)methyl)ethane-1,2-diamine], respectively, as their perchlorate salts. The complexes were characterized by various spectroscopic techniques as well as single crystal X-ray structure determination. Nitric oxide reactivities of the complexes were studied in acetonitrile as well as methanol solvent. It has been found that the ligand frameworks have a considerable effect in controlling the mechanism of the reduction of a Cu(II) center by nitric oxide. The flexibility of the ligand/s for a Cu(II) complex to attain a trigonal bipyramidal geometry after NO coordination is found to be the most important parameter in dictating the pathway for their interaction. In the present study, all the four compounds, because of structural constraints, were found to follow a deprotonation pathway for the reduction of a Cu(II) center by nitric oxide rather than [Cu(II)-NO] intermediate formation. All the ligands were found to yield an N nitrosoamine product along with the reduction of Cu(II) centers by nitric oxide. PMID- 23446945 TI - The dynamics of friendships and victimization in adolescence: a longitudinal social network perspective. AB - This study investigated the development of relational and physical victimization in adolescent friendship networks over time. Using longitudinal social network analysis (SIENA) it was simultaneously tested whether similarity in victimization contributed to friendship formation (selection effects) and whether victimization of friends contributed to changes in victimization (influence effects). This was done for peer-reported relational and physical victimization separately in two middle schools (total N = 480; N = 220, 47% girls, in School 1; N = 260, 52% girls, in School 2) across three time points (Grades 6 through 8; M ages 11.5 13.5). Gender, ethnicity, and baseline aggression were controlled as individual predictors of victimization. Similarity in physical victimization predicted friendship formation, whereas physical victimization was not influenced by friends' victimization but rather by adolescents' own physical aggression. Peer influence effects existed for relational victimization, in that adolescents with victimized friends were more likely to increase in victimization over time as well, over and above the effect of adolescents' own relational aggression. These selection and influence effects were not further qualified by gender. The results suggested that both selection and influence processes as well as individual characteristics play a role in the co-evolution of friendships and victimization, but that these processes are specific for different types of victimization. PMID- 23446946 TI - Enhancement of the finite-frequency superfluid response in the pseudogap regime of strongly disordered superconducting films. AB - The persistence of a soft gap in the density of states above the superconducting transition temperature Tc, the pseudogap, has long been thought to be a hallmark of unconventional high-temperature superconductors. However, in the last few years this paradigm has been strongly revised by increasing experimental evidence for the emergence of a pseudogap state in strongly-disordered conventional superconductors. Nonetheless, the nature of this state, probed primarily through scanning tunneling spectroscopy (STS) measurements, remains partly elusive. Here we show that the dynamic response above Tc, obtained from the complex ac conductivity, is highly modified in the pseudogap regime of strongly disordered NbN films. Below the pseudogap temperature, T*, the superfluid stiffness acquires a strong frequency dependence associated with a marked slowing down of critical fluctuations. When translated into the length-scale of fluctuations, our results suggest a scenario of thermal phase fluctuations between superconducting domains in a strongly disordered s-wave superconductor. PMID- 23446947 TI - Effects of the downregulation of SnoN expression on HepG2 cell proliferation and apoptosis. AB - Ski-novel protein (SnoN) is a proto-oncogene that belongs to the Ski protein family and is involved in regulating processes such as cell proliferation and apoptosis. To investigate the role of SnoN in the proliferation and apoptosis of HepG2 cells, we downregulated its expression by the use of small interfering RNA (siRNA). Three fragments predicted to have RNAi capacity were designed and synthesized as the target siRNAs (siRNA-A, -B and -C). Following transfection, inhibition efficiency was detected by reverse transcription PCR (RT-PCR) and western blot analysis. The siRNA with the optimal inhibition efficiency was used for the cell proliferation and apoptosis analysis. Cell proliferation was analyzed by the Cell Counting Kit-8 (CCK-8) and cell apoptosis was investigated by flow cytometry. In our study, all three siRNAs efficiently inhibited SnoN expression, and siRNA-C demonstrated the optimal inhibition efficiency. We found that following downregulation of SnoN expression, HepG2 cell proliferation was significantly inhibited (P<0.05), while HepG2 cell apoptosis was significantly increased (P<0.05). SnoN-specific siRNA is capable of effectively inhibiting the expression of SnoN in human HepG2 cells, and the downregulation of SnoN expression induces growth inhibition and apoptosis. PMID- 23446948 TI - Methylmalonic aciduria: newborn screening in mainland China? PMID- 23446949 TI - Prevalence of multiple forms of autoimmunity in Egyptian patients with Turner syndrome: relation to karyotype. AB - Our study aimed to investigate: the prevalence of autoantibodies related to organ specific disease; the prevalence of some autoimmune diseases (AID) in Egyptian Turner syndrome (TS) patients; and the association of autoimmunity with patients' karyotypes. Eighty TS patients were subjected to history, auxological assessment and measurement of antithyroid peroxidase antibody (ATPOAb), antithyroglobulin antibody (ATGAb), anti-tissue transglutaminase IgA antibodies (ATTIgAAb), anti glutamic acid decarboxylase-65 antibodies (GAD-65-Ab) and anti-adrenal cortex antibodies (AACAb). Of the 80 TS patients, 54 (67.5%) were seropositive for one or more autoantibodies. Thirty-five percent were positive for ATPOAb, 15% for ATGAb, 12.5% for ATTIgAAb, 3.75% for Anti-GAD-65Ab and 1.25% for AACAb. There was a non-significant association between the 45,X karyotype and overall prevalence of autoantibodies (p=0.20), while IsoXq was associated with increased prevalence of ATPOAb (p<0.01), ATGAb (p=0.01) and anti-GAD-65Ab (p=0.02). Thus, female TS patients face a high prevalence of autoimmunity and associated AID. PMID- 23446950 TI - Body fat distribution of children and adolescents in Abeokuta, Southwest Nigeria. AB - Excessive central fat in children and adolescents is a risk factor for cardiovascular and metabolic disorders. This study aimed to compare the body fat distribution patterns of children and adolescents in Abeokuta, Nigeria with international reference standards. Five hundred seventy children aged 5 to 19 years were selected from seven schools using multistage random sampling. Weight, height, triceps and subscapular skinfold thickness (TSF, SSF), and circumference at the waist and hips (WC, HC) were measured. Body mass index (BMI), subscapular:triceps skinfold ratio (STR), waist:hip circumference ratio (WHR), and waist: height ratio (WHtR) were derived. Females had higher mean BMI, TSF, SSF, WC, HC, WHR, and WHtR, while males had significantly higher STR. The mean BMI, WC, TSF, and SSF values were lower for our subjects than for African American subjects at all ages. On the other hand, in both sexes, STR was higher among Nigerian than African-American subjects up to 12 years old. Thereafter the values were similar. The mean WC was similar to those reported for African American males up to 8 years, and females up to 7 years of age; thereafter, African-American had higher values. The prevalence of central obesity using WC and WHtR measures was 4.4% and 5.8%, respectively. There is a need to validate each index against serum lipid profiles and other cardiovascular and metabolic risk factors. PMID- 23446951 TI - Serum levels of vitamin D are not associated with future risk of venous thromboembolism. The Tromso Study. AB - Previous studies have provided indirect evidence for a possible association between vitamin D status and risk of venous thromboembolism (VTE). However, no study has so far investigated the association between serum levels of 25 hydroxyvitamin D (25(OH)D), the biomarker of vitamin D status, and risk of VTE. The aim of our study was to investigate whether high levels of 25(OH)D were associated with decreased risk of VTE in a prospective population-based study. Serum levels of 25(OH)D were measured in 6,021 men and women, aged 25-84 years, who participated in the Tromso Study in 1994-1995. Incident VTE-events were registered from date of inclusion through the end of follow-up, September 1, 2007. Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) for VTE. There were 201 incident VTE-events during a median of 10.7 years of follow-up. The risk of VTE did not decrease per one standard deviation (SD) (19.8 nmol/l) increase in serum 25(OH)D (multivariable HR 1.02; 95% CI 0.91-1.22). Moreover, subjects with serum 25(OH)D >= 70 nmol/l (upper quartile) did not have decreased risk of VTE compared to those <= 44 nmol/l (lower quartile) in age- and sex-adjusted analysis (HR 0.91, 95% CI: 0.60 1.37, p for trend across quartiles 0.9) or multivariable analysis adjusted for age, sex, body mass index, smoking, and physical activity (HR 0.76, 95% CI: 0.45 1.28, p for trend across quartiles 0.9). Subgroup analyses showed no associations between serum levels of 25(OH)D and unprovoked or provoked VTE. In conclusion, in our study, normal serum levels of 25(OH)D were not associated with future risk of VTE, suggesting that vitamin D status does not play an important role in the pathogenesis of VTE. However, our findings did not apply to subjects with vitamin D deficiency (< 30 nmol/l) due to lack of statistical power among these subjects. PMID- 23446953 TI - [Injuries in male and female adolescent soccer players]. AB - This study addresses the epidemiology of injuries in adolescent male and female soccer players in Germany. Therefore, the purpose of the study was to analyse the injuries in male and female youth soccer players in Germany. This study was designed as a cross-sectional web-based survey. From March until December 2011 we investigated 1110 soccer players (male n = 841; female n = 269) aged 12 - 19 years (15.0 +/- 2.0 years) from 60 clubs in Southern Germany. A total of 664 (79 %) of the 841 boys and 67 (25 %) of the 269 girls reported being injured due to soccer. The total number of injuries was 2373. Respectively the frequency of injury was 2.85 in boys and 7.10 in girls. The lower extremities were affected in 70 % of all reported cases. Strains were the most common injuries in the lower and upper extremities (35 %). The boys reported in 51.5 % of all injuries that the injury was non-contact in nature. In contrast, 52.1 % of the injuries in girls were reported as contact injuries. Similar amounts of injuries were observed in training versus games for both genders. Prevention procedures, such as a thorough warm-up, should be implemented before every game and training to reduce the risk of injury. PMID- 23446952 TI - Antibacterial and immunomodulatory properties of azithromycin treatment implications for periodontitis. AB - Macrolide antibiotics have been found to possess not only antimicrobial properties, but also modulate inflammation. In this review the multi-faceted properties of azithromycin are discussed. Due to the unique anti-inflammatory and antimicrobial properties, macrolides, and especially azithromycin, are currently used for a number of conditions which have both an inflammatory and microbial component. For the same reason, azithromycin may be of value as an adjunct in the management of periodontitis which, although driven by an infectious component, is largely a result of uncontrolled chronic inflammation. PMID- 23446956 TI - Alterations in diastolic function in masked hypertension: findings from the masked hypertension study. AB - BACKGROUND: In a prior study of patients with diabetes, diastolic function was similarly impaired in masked hypertension (MHT) and sustained hypertension (SHT). We evaluated whether MHT is associated with impaired diastolic function compared with SHT and sustained normotension (NT) in the general population. METHODS: From February 2005 to December 2010, 798 participants without a history of cardiovascular disease or treated hypertension, were enrolled in the Masked Hypertension Study. Participants underwent clinic blood pressure (CBP) and 24 hour ambulatory blood pressure (ABP) measurements. A 2-dimensional Doppler echocardiogram was performed to evaluate diastolic function,s cardiac structure, volume, and systolic function. The 9 CBPs obtained across 3 clinic visits and awake ABP measurements were averaged. Clinic hypertension was defined as systolic/diastolic blood pressure (SBP/DBP) >= 140/90 mmHg. Ambulatory hypertension was defined as awake SBP/DBP >= 135/85mm Hg. MHT was defined as having ambulatory but not clinic hypertension. White-coat hypertensives (n = 8) were excluded from the analysis. RESULTS: Of the 790 participants, 116 (14.7%) participants had MHT, 37 (4.7%) participants had SHT, and 637 (80.6%) participants had NT. After age, sex, race/ethnicity, and body mass index adjustment, compared with NT, E'-velocities were significantly lower in MHT (P < 0.01) and SHT (P < 0.05), and E/E' ratios were significantly higher MHT (P < 0.05) and SHT (P < 0.05). These associations were independent of left ventricular mass. Diastolic function parameters did not significantly differ between MHT and SHT. CONCLUSIONS: Diastolic function was impaired in MHT compared with NT independent of changes in left ventricular mass. PMID- 23446958 TI - Idyll wild. PMID- 23446957 TI - Low-grade inflammation and ambulatory blood pressure response to antihypertensive treatment: the ALPHABET study. AB - BACKGROUND: We examined whether the level of highsensitivity C-reactive protein (hsCRP), a marker of low-grade inflammation, predicted the response of clinic and ambulatory blood pressure (BP) to antihypertensive treatment. METHODS: A randomized, open-label, multicenter trial was performed in 88 hypertensive patients (mean age = 63.4 years) allocated to receive losartan 50 mg or amlodipine 5 mg for 4 weeks, and each treatment was changed to losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg in combination or amlodipine 10 mg for a further 4 weeks. Clinic and ambulatory BP were measured before and after 8 weeks of treatment, and hsCRP was measured at baseline. RESULTS: The patients were divided into groups with hsCRP levels above and below the median (0.47 mg/L) for the study population. In the total population, 24-hour systolic BP (SBP) (P = 0.03) and daytime SBP (P = 0.01) were significantly higher in the above-median hsCRP group after 8 weeks of treatment. In multivariable regression analysis, baseline hsCRP was a significant determinant of the percentage change in daytime SBP (beta = 0.29; P = 0.02) in the total population. In the losartan/HCTZ treatment group, changes in 24-hour SBP, daytime SBP, and diastolic BP were significantly smaller in the above-median hsCRP group than the below-median hsCRP group, whereas the amlodipine group did not show these differences. CONCLUSIONS: Baseline low-grade inflammation in patients with hypertension was associated with a poor ambulatory BP response, especially with losartan/HCTZ treatment. Initial measurement of hsCRP could be useful for selection of an appropriate antihypertensive drug. PMID- 23446959 TI - Reduction in range of cervical motion on serial long-term follow-up in patients undergoing oblique corpectomy for cervical spondylotic myelopathy. AB - PURPOSE: To determine whether motion preservation following oblique cervical corpectomy (OCC) for cervical spondylotic myelopathy (CSM) persists with serial follow-up. METHODS: We included 28 patients with preoperative and at least two serial follow-up neutral and dynamic cervical spine radiographs who underwent OCC for CSM. Patients with an ossified posterior longitudinal ligament (OPLL) were excluded. Changes in sagittal curvature, segmental and whole spine range of motion (ROM) were measured. Nathan's system graded anterior osteophyte formation. Neurological function was measured by Nurick's grade and modified Japanese Orthopedic Association (JOA) scores. RESULTS: The majority (23 patients) had a single or 2-level corpectomy. The average duration of follow-up was 45 months. The Nurick's grade and the JOA scores showed statistically significant improvements after surgery (p < 0.001). 17% of patients with preoperative lordotic spines had a loss of lordosis at last follow-up, but with no clinical worsening. 77% of the whole spine ROM and 62% of segmental ROM was preserved at last follow-up. The whole spine and segmental ROM decreased by 11.2 degrees and 10.9 degrees , respectively (p <= 0.001). Patients with a greater range of segmental movement preoperatively had a statistically greater range of movement at follow-up. The analysis of serial radiographs indicated that the range of movement of the whole spine and the range of movement at the segmental spine levels significantly reduced during the follow-up period. Nathan's grade showed increase in osteophytosis in more than two-thirds of the patients (p <= 0.01). The whole spine range of movement at follow-up significantly correlated with Nathan's grade. CONCLUSIONS: Although the OCC preserves segmental and whole spine ROM, serial measurements show a progressive decrease in ROM albeit without clinical worsening. The reduction in this ROM is probably related to degenerative ossification of spinal ligaments. PMID- 23446961 TI - Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences. AB - Numerous studies have demonstrated that the early postnatal environment can influence body weight and energy homeostasis into adulthood. Rodents raised in small litters have been shown to be a useful experimental model to study the short- and long-term consequences of early overnutrition, which can lead to modifications not only in body weight but also of several metabolic features. Postnatal overfeeding (PNOF) induces early malprogramming of the hypothalamic system, inducing acquired persisting central leptin and insulin resistance and an increase in orexigenic signals. Visceral white adipose tissue, lipogenic activity, and inflammatory status are increased in PNOF rodents, while brown adipose tissue shows reduced thermogenic activity. Pancreatic and hepatic glucose responsiveness is persistently reduced in PNOF rodents, which also frequently present disturbances in plasma lipids. PNOF rodents present increased circulating concentrations of leptin, elevated corticosterone secretion, and significant changes in glucocorticoid sensitivity. PNOF also influences nephrogenesis and renal maturation. Increased oxidative stress is also described in circulating blood and in some tissues, such as the heart or liver. At the cardiovascular level, a moderate increase in arterial blood pressure is sometimes observed and rapid cardiac hypertrophy is observed at weaning; however, during maturation, impaired contractility and fibrosis are observed. Myocardial genome expression is rapidly modified in overfed mice. Moreover, hearts of PNOF rodents are more sensitive to ischemia-reperfusion injury. Together, these results suggest that the nutritional state in the immediate postnatal period should be taken into account, because it may have an impact on cardiometabolic risk in adulthood. PMID- 23446960 TI - Supplementing monosodium glutamate to partial enteral nutrition slows gastric emptying in preterm pigs(1-3). AB - Emerging evidence suggests that free glutamate may play a functional role in modulating gastroduodenal motor function. We hypothesized that supplementing monosodium glutamate (MSG) to partial enteral nutrition stimulates gastric emptying in preterm pigs. Ten-day-old preterm, parenterally fed pigs received partial enteral nutrition (25%) as milk-based formula supplemented with MSG at 0, 1.7, 3.0, and 4.3 times the basal protein-bound glutamate intake (468 mg.kg( 1).d(-1)) from d 4 to 8 of life (n = 5-8). Whole-body respiratory calorimetry and (13)C-octanoic acid breath tests were performed on d 4, 6, and 8. Body weight gain, stomach and intestinal weights, and arterial plasma glutamate and glutamine concentrations were not different among the MSG groups. Arterial plasma glutamate concentrations were significantly higher at birth than after 8 d of partial enteral nutrition. Also at d 8, the significant portal-arterial concentration difference in plasma glutamate was substantial (~500 MUmol/L) among all treatment groups, suggesting that there was substantial net intestinal glutamate absorption in preterm pigs. MSG supplementation dose-dependently increased gastric emptying time and decreased breath (13)CO2 enrichments, (13)CO2 production, percentage of (13)CO2 recovery/h, and cumulative percentage recovery of (13)C-octanoic acid. Circulating glucagon-like peptide-2 (GLP-2) concentration was significantly increased by MSG but was not associated with an increase in intestinal mucosal growth. In contrast to our hypothesis, our results suggest that adding MSG to partial enteral nutrition slows the gastric emptying rate, which may be associated with an inhibitory effect of increased circulating GLP-2. PMID- 23446962 TI - Normal protein intake is required for body weight loss and weight maintenance, and elevated protein intake for additional preservation of resting energy expenditure and fat free mass. AB - Energy-restricted high-protein diets (HPDs) have shown favorable results for body weight (BW) management, yet studies differ in their outcomes depending on the dietary protein content. Our objective was to determine the effects of dietary protein content on BW loss-related variables during a 6-mo energy restriction with the use of diets containing protein at the level of requirement [normal protein diet (NPD), 0.8 g . kg BW(-1) (.) d(-1)] and above (HPD, 1.2 g . kg BW( 1) (.) d(-1)). In overweight and obese participants (24 men and 48 women), BW, body composition, and metabolic responses were assessed before and after subsequent energy intakes of 100, 33, and 67% of the original individual daily energy requirements. Protein intake was consistent in the NPD (0.8 +/- 0.3 g . kg BW(-1) (.) d(-1)) and HPD (1.2 +/- 0.3 g . kg BW(-1) (.) d(-1)) groups throughout the study (P < 0.001). BMI and body fat mass similarly decreased in the NPD and HPD groups (P < 0.01). Fat free mass (FFM), resting energy expenditure (REE) compared with predicted REE, and diastolic blood pressure (DBP) changed favorably with the HPD compared with the NPD group after BW loss (P < 0.05). A NPD of 0.8 g . kg BW(-1) (.) d(-1) is sufficient for BW management, whereas a HPD of 1.2 g . kg BW(-1) (.) d(-1) is necessary for preservation of REE and a stronger initial sparing effect of FFM and lowering of DBP. PMID- 23446963 TI - The Oportunidades program's fortified food supplement, but not improvements in the home diet, increased the intake of key micronutrients in rural Mexican children aged 12-59 months. AB - Mexico's Oportunidades program provides conditional cash transfers, nutrition education, health services, and fortified food supplements for the young children of poor families. We have documented the effects of the program on growth and reduction of anemia. To better understand the impact pathways and disentangle the relative effects on dietary intake of the food supplements compared with other program components, we analyzed data from a randomized effectiveness evaluation of the Oportunidades program in rural children aged 12-59 mo. All Oportunidades beneficiaries received the cash transfers and the health and education components, but some children did not consume the supplements. The children's diet was evaluated using a single 24-h recall. The impact was estimated using multiple linear regression models with community-level random effects. Comparisons were made among children who received all the benefits of Oportunidades, including the fortified food supplement (SG), beneficiaries of the program who did not consume the food supplement (NSG), and the control group (CG). Relative to the NSG and CG, respectively, the SG consumed greater amounts of [mean (95% CI)]: energy, 94 (28, 160) and 111 (43, 180) kcal/d; iron, 7.6 (6.3, 8.9) and 7.7 (6.5, 9.0) mg/d; zinc, 7.5 (6.4, 8.6) and 7.6 (6.5, 8.7) mg/d; and vitamin A, 0.109 (0.071, 0.147) and 0.120 (0.080, 0.159) mg retinol equivalents/d. No differences were found between the NSG and CG (P > 0.05). To conclude, the Oportunidades program had a positive impact on the diet of children. The effects of the program on dietary intake resulted from the food supplement and not from improvements in the home diet. Our findings are useful for identifying which program components contributed to the effects on the nutritional status of children. PMID- 23446964 TI - Evaluation of the proliferation and differentiation behaviors of mesenchymal stem cells with partially converted borate glass containing different amounts of strontium in vitro. AB - The objective of this study was to examine the proliferation and differentiation behaviors of different compositions of strontium-containing (from 0-12 mol%) borate glasses with mesenchymal stem cells (MSCs). The Cell Counting Kit-8 (CCK 8) assay revealed that after three days of culturing, the 6Sr group had the highest cell growth rate. Analysis of cell morphology revealed that cells proliferated well near the particles of the samples in all the groups on day 3. On day 7, cells in the 6Sr group demonstrated a higher proliferation rate than other 4 groups under the microscope. When performing the Live-Dead staining experiment, the 6Sr group had the least number of dead cells. Total DNA qualification indicated that the 6Sr group had a statistically higher concentration compared with the remaining groups. It was found that on day 7, compared with the 0Sr group, the core binding factor alpha1 (Cbfa1) mRNA expression level was significantly higher in the 6Sr, 9Sr and 12Sr groups. On day 14, compared with the 0Sr group, the bone sialoprotein (BSP) mRNA level was significantly higher in the 6Sr group. Additionally, on day 21, the 6Sr and 9Sr groups demonstrated higher osteocalcin (OCN) mRNA expression levels compared with the 0Sr group. In the alkaline phosphatase (ALP) activity test, on day 21, the 6Sr group presented a higher activity than the 0Sr group. Further, the number of mineralized nodules per unit in MSCs was measured by Alizarin Red S staining. The results showed that the 6Sr and 9Sr groups had the greatest number of mineralized nodules. Therefore, it could be concluded that borate glasses containing strontium oxide of 0, 3, 6, 9 and 12 mol% demonstrate a significant level of proliferation when interacting with MSCs. The borate glass containing 6 mol% strontium oxide had the greatest level of proliferation when cultured with MSCs. The borate glass containing 6 and 9 mol% strontium oxide facilitated an improved bone formation ability compared with the remaining two compositions. PMID- 23446965 TI - Metal fluoride-based transparent nanocomposites with low refractive indices. AB - The utilisation of magnesium and aluminium fluoride nanoparticles in the preparation of transparent composites leading to materials with superior properties was investigated. Nanoscopic magnesium and aluminium fluoride has been prepared by the fluorolytic sol-gel route from the alkoxides and was surface modified by the reaction with trifluoroacetic acid or perfluorobutyric acid. IR spectroscopic experiments of the xerogels and crystal structure analysis of a trinuclear [Mg3(MU3F)(MU-TFA)6(OCH3)2(py)](3-) cluster unit indicate that the carboxylate group is bound to the particle surface in a monodentate or bidentate bridging fashion. These particles were successfully incorporated into acrylate polymers with up to 40 wt% content to give fully transparent material. Ellipsometry and m-line measurements of thin films show the reduction of the refractive index of composite films with increasing metal fluoride filler content. PMID- 23446966 TI - First survey for the amphibian chytrid fungus Batrachochytrium dendrobatidis in Connecticut (USA) finds widespread prevalence. AB - The amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) is an emerging infectious fungal pathogen of amphibians and is linked to global population declines. Until now, there has only been 1 survey for the fungus in the northeastern USA, which focused primarily on northern New England. We tested for Bd in a large number of samples (916 individuals from 116 sites) collected throughout the state of Connecticut, representing 18 native amphibian species. In addition, 239 preserved wood frog Lithobates sylvaticus tadpoles from throughout the state were screened for the fungus. Bd presence was assessed in both the fresh field swabs and the preserved samples using a sensitive quantitative PCR assay. Our contemporary survey found widespread Bd prevalence throughout Connecticut, occurring in 14 species and in 28% of all sampled animals. No preserved L. sylvaticus specimens tested positive for the fungus. Two common species, bullfrogs R. catesbeiana and green frogs R. clamitans had particularly high infection rates (0.21-0.39 and 0.33-0.42, respectively), and given their wide distribution throughout the state, we suggest they may serve as sentinels for Bd occurrence in this region. Further analyses found that several other factors increase the likelihood of infection, including life stage, host sex, and host family. Within sites, ponds with ranids, especially green frogs, increased the likelihood of Bd prevalence. By studying Bd in populations not facing mass declines, the results from this study are an important contribution to our understanding of how some amphibian species and populations remain infected yet exhibit no signs of chytridiomycosis even when Bd is widely distributed. PMID- 23446967 TI - Batrachochytrium dendrobatidis haplotypes on the hellbender Cryptobranchus alleganiensis are identical to global strains. AB - To determine whether the chytrid fungus Batrachochytrium dendrobatidis (Bd) found on the hellbender Cryptobranchus alleganiensis in the southern US is endemic or exotic, we identified the genetic type of this fungus using partial DNA sequences of the internal transcribed spacer (ITS) region. We identified 3 genetic types, which are found on Japanese amphibians other than the Japanese giant salamander Andrias japonicus, a species that belongs to the same family (Cryptobranchidae) as hellbenders. The fungus collected from hellbenders exhibited low genetic diversity and matched the common Bd genetic types which have been detected from around the world. These results support that the chytrid fungus on the hellbender is a novel pathogen, as proposed by previous studies. Although we have not observed disease symptoms directly linked to this fungus on this endangered salamander, further evaluation of the influence of this exotic fungus on this species is warranted. PMID- 23446968 TI - Batrachochytrium dendrobatidis in amphibians of Cameroon, including first records for caecilians. AB - Amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) has been hypothesised to be an indigenous parasite of African amphibians. In Cameroon, however, previous surveys in one region (in the northwest) failed to detect this pathogen, despite the earliest African Bd having been recorded from a frog in eastern Cameroon, plus one recent record in the far southeast. To reconcile these contrasting results, we present survey data from 12 localities across 6 regions of Cameroon from anurans (n = 1052) and caecilians (n = 85) of ca. 108 species. Bd was detected in 124 amphibian hosts at 7 localities, including Mt. Oku, Mt. Cameroon, Mt. Manengouba and lowland localities in the centre and west of the country. None of the hosts were observed dead or dying. Infected amphibian hosts were not detected in other localities in the south and eastern rainforest belt. Infection occurred in both anurans and caecilians, making this the first reported case of infection in the latter order (Gymnophiona) of amphibians. There was no significant difference between prevalence and infection intensity in frogs and caecilians. We highlight the importance of taking into account the inhibition of diagnostic qPCR in studies on Bd, based on all Bd-positive hosts being undetected when screened without bovine serum albumin in the qPCR mix. The status of Bd as an indigenous, cosmopolitan amphibian parasite in Africa, including Cameroon, is supported by this work. Isolating and sequencing strains of Bd from Cameroon should now be a priority. Longitudinal host population monitoring will be required to determine the effects, if any, of the infection on amphibians in Cameroon. PMID- 23446969 TI - A new species of nucleo-cytoplasmic large DNA virus (NCLDV) associated with mortalities in Manitoba lake sturgeon Acipenser fulvescens. AB - A newly discovered virus, Namao virus, associated with morbidity and mortality, was detected among juvenile lake sturgeon Acipenser fulvescens being propagated by a conservation stocking program for this endangered species in Manitoba, Canada. The outbreaks resulted in cumulative mortalities of 62 to 99.6% among progeny of wild Winnipeg River or Nelson River lake sturgeon and occurred at 2 geographically separate facilities. Namao virus was detected in almost 94% of the moribund or dead lake sturgeon according to a conventional polymerase chain reaction (cPCR) test that is based upon amplification of a 219 bp fragment of the virus major capsid protein (MCP). The virus itself was large (242 to 282 nm) and icosahedral-shaped with 2 capsids and a condensed bar-shaped core. It was found in virus factories within the host cell cytoplasm and displayed a tropism for the integument. Namao virus caused cellular changes characterized by enlarged eosinophilic epithelial cells in the gills and skin. Samples suspected of containing Namao virus did not have cytopathic effects on primary lake sturgeon or established white sturgeon cell lines. However, viral nucleic acid was detected in the former after prolonged incubation periods. Using primers designed from conserved regions of the MCP from NCLDVs, an estimated 95 to 96% of the Namao virus MCP open reading frame was captured. Phylogenetic analysis using the MCP of Namao virus and 27 other NCLDVs suggested that Namao virus and white sturgeon iridovirus share a common evolutionary past and might be members of the family Mimiviridae or a new, as yet unrecognized, virus family. PMID- 23446970 TI - Comparison of treatments to inactivate viral hemorrhagic septicemia virus (VHSV IVb) in frozen baitfish. AB - Current US state and federal fish health regulations target the spread of viral hemorrhagic septicemia virus-IVb (VHSV-IVb) through movement restrictions of live fish; however, they largely ignore the potential for the virus to be spread through commercial distribution and use of frozen baitfish from VHSV-IVb-positive regions. Some state laws do require treatment of frozen baitfish to inactivate VHSV, and additional methods have been proposed, but few scientific studies have examined the efficacy of these treatments. In this study, bluegills Lepomis macrochirus were challenged with VHSV-IVb and frozen to represent standard industry methods, disinfected by various treatments, and tested for infectious VHSV-IVb using virus isolation. The virus was isolated from 70% of fish subjected to 3 freeze/thaw cycles. All other treatment methods were effective in inactivating the virus, including treatment with isopropyl alcohol, mineral oil, salt and borax, and dehydration. Dehydration followed by rehydration is rapid and effective, and therefore, seems to be the best option for inactivating VHSV-IVb present in frozen baitfish while maintaining their usefulness as bait. PMID- 23446971 TI - Sealworm Pseudoterranova decipiens s.s. infection of European smelt Osmerus eperlanus in German coastal waters: ecological implications. AB - European smelt Osmerus eperlanus (n = 501) from the German Wadden Sea (North Sea) near the city of Cuxhaven were examined for their infestation with parasitic anisakid nematodes, especially with sealworms of the genus Pseudoterranova. The distribution of third-stage larvae (L3) in the musculature and viscera of the fish was analyzed. In total, we isolated 543 L3 from the hosts' body cavity and musculature. A subsample of 105 larvae were identified as the (sibling) species P. decipiens s.s. using direct sequencing of the highly variable ribosomal ITS1 5.8S-ITS2 genetic marker. The mean abundance was 1.1, the mean intensity was 2.3 P. decipiens s.s. and the prevalence was 47.3%. Total length and total weight, but not Fulton's condition factor (K), were significantly different in infected compared to uninfected smelt. No correlation was found between the total length of infected fish and the intensity of anisakid nematodes. The vast majority of P. decipiens s.s. was found in the musculature of the smelt. More than half (55.7%) of all nematodes were located in the 3 parts of the epaxial musculature, whereas 18.4 and 26.0% were found in the hypaxial musculature and the compartments of the tail muscles, respectively. PMID- 23446972 TI - Development of a sensitive and specific LAMP PCR assay for detection of fish pathogen Lactococcus garvieae. AB - Based on use of a loop-mediated isothermal amplification (LAMP) identification protocol, this study attempted to detect Lactococcus garvieae in fish by using primer sets designed from an L. garvieae alpha/beta fold family hydrolase gene. Reaction time and temperatures were optimized for 60 min at 60 degrees C with the resulting amplicons visualized by adding SYBR Green I to the reaction tube. The assay specificity was assessed using 45 different bacterial strains. Positive results were observed in all 30 L. garvieae isolates from various aquatic animals. No false-positive results were observed in 15 non-L. garvieae strains. The detection limit of the LAMP assay was 10-fold more sensitive than the conventional polymerase chain reaction (PCR) targeting 16S rDNA when using purified L. garvieae DNA. The detection limit of the LAMP assay was approximately 300 colony-forming units (CFU) using crude bacterial lysates, 100-fold more sensitive than PCR. Furthermore, L. garvieae in spleen, kidney and brain of experimentally challenged tilapia and grey mullet were detected using this optimized LAMP assay. Results of this study demonstrate the effectiveness of LAMP in providing a rapid yet simple test for detecting L. garvieae in fish. PMID- 23446973 TI - Pansteatitis associated with high levels of polychlorinated biphenyls in a wild loggerhead sea turtle Caretta caretta. AB - We describe the morphologic and toxicological findings in a case of pansteatitis in a stranded loggerhead sea turtle Caretta caretta. At necropsy, a large amount of adipose tissue in the celomic cavity showing very firm, yellow to orange irregular formations was observed. Histological lesions ranged from the infiltration of necrotic fat by scarce multinucleated giant cells and numerous macrophages containing xylene-insoluble lipopigment inclusions to the presence of several granulomas characterized by an irregular central necrotic area consisting of lipopigment surrounded by numerous multinucleated giant cells. Microbiological cultures were negative. Celomic fat was analyzed for PCBs and DDTs, resulting in very high levels of PCB 138, 153, 180 209 (3170, 2830, 980 and 1190 ng g-1, respectively). Although a nutritional cause cannot be ruled out, the high levels of PCBs detected in the celomic fat could have induced lipid peroxidation in adipocytes, resulting in cell damage, deposition of ceroid pigment and inflammatory response. This is the first report of pansteatitis in a wild sea turtle. PMID- 23446974 TI - Evidence of regression of fibropapillomas in juvenile green turtles Chelonia mydas caught in Niteroi, southeast Brazil. AB - Fibropapillomatosis is a disease characterized by cutaneous tumors affecting all marine turtle species, but mostly Chelonia mydas. The disease was first reported in 1938, and since then, the number of sightings has been increasing over the years. This disease can cause many complications in the affected animal and can lead to death, and is thus included in the many threats to marine turtle populations. It is still not known for certain what causes this disease, although many studies indicate a herpesvirus as the main etiologic agent. The incidence of fibropapillomatosis is rarely reported in adults, leading to speculations that there may be a cure for the disease or that the animals die before reaching adulthood. In this paper, 2 cases of fibropapillomatosis regression are reported from juvenile C. mydas caught between July 2008 and July 2010 in the coastal zone of Itaipu, Niteroi, Rio de Janeiro, Brazil. These individuals were identified photographically upon recapture. One individual had a total regression (disappearance) of external papilloma within 164 d between first capture and recapture, and the other individual had a partial regression (decrease in size) observed within 13 to 188 d of recapture. The mechanism that triggers the regression is still unknown but is likely to be an immune system response or removal of the tumor promoter. There are few reported cases of regression in the world, and constant monitoring through mark-recapture is necessary to assess whether the marine turtles affected by this disease have real chances of survival. PMID- 23446975 TI - Chytridiomycosis in endemic amphibians of the mountain tops of the Cordoba and San Luis ranges, Argentina. AB - Chytridiomycosis is a major threat to amphibian conservation. In Argentina, the pathogenic fungus Batrachochytrium dendrobatidis has been recorded in several localities, and recently, it was registered in amphibians inhabiting low elevation areas of mountain environments in Cordoba and San Luis provinces. In the present study, we searched for B. dendrobatidis in endemic and non-endemic amphibians on the mountain tops of Cordoba and San Luis provinces. We collected dead amphibians in the upper vegetation belt of the mountains of Cordoba and San Luis. Using standard histological techniques, the presence of fungal infection was confirmed in 5 species. Three of these species are endemic to the mountain tops of both provinces. Although there are no reported population declines in amphibians in these mountains, the presence of B. dendrobatidis in endemic species highlights the need for long-term monitoring plans in the area. PMID- 23446976 TI - Shuffling of mobile genetic elements (MGEs) in successful healthcare-associated MRSA (HA-MRSA). AB - Methicillin-resistant Staphylococcus aureus (MRSA) CC22 SCCmecIV is a successful hospital-associated (HA-) MRSA, widespread throughout the world, and now the dominant clone in UK hospitals. We have recently shown that MRSA CC22 is a particularly fit clone, and it rose to dominance in a UK hospital at the same time as it began acquiring an increased range of antibiotic resistances. These resistances were not accumulated by individual CC22 isolates, but appear to shuffle frequently between isolates of the MRSA CC22 population. Resistances are often encoded on mobile genetic elements (MGEs) that include plasmids, transposons, bacteriophage and S. aureus pathogenicity islands (SaPIs). Using multi-strain whole genome microarrays, we show that there is enormous diversity of MGE carried within a MRSA CC22 SCCmecIV population, even among isolates from the same hospital and time period. MGE profiles were so variable that they could be used to track the spread of variant isolates within the hospital. We exploited this to show that the majority of patients colonised with MRSA at hospital admission that subsequently became infected were infected with their own colonising isolate. Our studies reveal MGE spread, stability, selection and clonal adaptation to the healthcare setting may be key to the success of HA-MRSA clones, presumably by allowing rapid adaptation to antibiotic exposure and new hosts. PMID- 23446978 TI - Surface display of malolactic enzyme from Oenococcus oeni on Saccharomyces cerevisiae. AB - In order to display malolactic enzyme (MLE) on the cell surface of Saccharomyces cerevisiae, a yeast cell surface display plasmid pADH1-AGG was constructed by fusing the alpha-factor signal encoding sequence (267 bp) and the C-terminal half of alpha-agglutinin encoding sequence (1,645 bp) into the plasmid pADH1. The pADH1-AGG could successfully express and anchor the enhanced green fluorescent protein (EGFP) onto the yeast cell surface when the EGFP was used to verify its function. Then the pADH1-MLE was constructed by inserting the MLE encoding sequence (1,600 bp) into the pADH1-AGG and introduced into S. cerevisiae cells. The positive strain carrying pADH1-MLE was confirmed by use of the 6* His monoclonal antibody and fluorescein isothiocyanate-conjugated goat anti-mouse IgG. All results indicated that the MLE was displayed successfully on the cell surface of positive transformant. The MLE activity of genetically engineered yeast strain could turn 21.11 % L-malate into lactic acid after 12 h reaction with L-malate. The constructed yeast strain might be used to conduct malolactic fermentation (MLF) in wine to solve the important issues of sluggish MLF, microbial spoilage, and adverse metabolic substances produced by the lactic acid bacteria. PMID- 23446977 TI - Naringin improves diet-induced cardiovascular dysfunction and obesity in high carbohydrate, high fat diet-fed rats. AB - Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats. PMID- 23446979 TI - Adaptive evolution of Saccharomyces cerevisiae in a continuous and closed circulating fermentation (CCCF) system coupled with PDMS membrane pervaporation. AB - As an efficient means of strain improvement, adaptive evolution is a technique with great potential. Long-term cultivation of Saccharomyces cerevisiae was performed in a polydimethylsiloxane membrane bioreactor system which was constructed by coupling the fermentation with pervaporation. A parent strain was subjected to three rounds of fermentation-screening-transfer procedure lasting 1,500 h in a continuous and closed circulating fermentation (CCCF) system, and its 600-generation descendant S33 was screened. In shaking flask culture test, the selected strain S33 from the third round showed great superiority over the parent strain in the residual broth medium, with the ethanol yield and specific ethanol productivity increasing by 34.5 and 34.7 %, respectively. In the long term CCCF test, the fermentation performance of the descendant strain in the third round was higher than that of its parent strain in the second round. These results show the potential of this novel adaptive evolution approach in optimization of yeast strains. PMID- 23446980 TI - Effects of ELF magnetic field in combination with Iron(III) chloride (FeCl3) on cellular growth and surface morphology of Escherichia coli (E. coli). AB - This study investigated the effects of extremely low frequency (ELF) magnetic field with/without iron(III) chloride (FeCl3) on bacterial growth and morphology. The ELF exposures were carried out using a pair of Helmholtz coil-based ELF exposure system which was designed to generate 50 Hz sinusoidal magnetic field. The field was approximately uniform throughout the axis of the coil pair. The samples which were treated or non-treated with different concentrations FeCl3 were exposed to 50 Hz, 2 millitesla (mT) magnetic field for 24 h. ELF effect on viability was assessed in terms of viable colony counts (in colony-forming unit per milliliter) with the standard plate count technique. Scanning electron microscopy was used to investigate the magnetic field effect on surface morphology of Escherichia coli. No significant results were seen in terms of cell viability between ELF and sham-exposed bacterial strains. Similarly, FeCl3 treatment did not change cell viability of E. coli samples. However, we observed some morphological changes on E. coli cell surfaces. Pore formations and membrane destruction were seen on the surface of 24 h ELF field-exposed cells. We concluded that ELF magnetic field exposure at 2 mT does not affect cell viability; however, it may affect bacterial surface morphology. PMID- 23446981 TI - Candida biofilm disrupting ability of di-rhamnolipid (RL-2) produced from Pseudomonas aeruginosa DSVP20. AB - Biosurfactant produced from Pseudomonas aeruginosa DSVP20 was evaluated for its potential to disrupt Candida albicans biofilm formed on polystyrene (PS) surfaces in this investigation. P. aeruginosa DSVP20 exhibited optimum production of biosurfactant (5.8 g L(-1)) after 96 h of growth with an ability to reduce surface tension of the aqueous solution from 72 to 28 mN m(-1). Analysis of purified biosurfactant with FT-IR, (1)H and (13)C NMR and MALDI-TOF MS revealed it to be di-rhamnolipid (RL-2) in nature. Biofilm disrupting ability of RL-2 (0.16 mg mL(-1)) on Candida cells when checked using XTT reduction assay revealed that about 50 % of the cells remain adhered to 96-well plate after 2 h of treatment, while up to 90 % reduction in pre-formed C. albicans biofilm on PS surface was observed with RL-2 (5.0 mg mL(-1)) in a dose-dependent manner. Microscopic analyses (SEM and CLSM) further confirm the influence of RL-2 on disruption of Candida biofilm extracellular matrix on PS surface which can be exploited as a potential alternative to the available conventional therapies. PMID- 23446982 TI - Cloning, expression, and characterization of beta-mannanase from Bacillus subtilis MAFIC-S11 in Pichia pastoris. AB - The beta-mannanase gene (1,029 nucleotide) from Bacillus subtilis MAFIC-S11, encoding a polypeptide of 342 amino acids, was cloned and expressed in Pichia pastoris. To increase its expression, the beta-mannanase gene was optimized for codon usage (mannS) and fused downstream to a sequence-encoding modified alpha factor signal peptide. The expression level was improved by 2-fold. This recombinant enzyme (mannS) showed its highest activity of 24,600 U/mL after 144-h fermentation. The optimal temperature and pH of mannS were 50 degrees C and 6.0, respectively, and its specific activity was 3,706 U/mg. The kinetic parameters V max and K m were determined as 20,000 U/mg and 8 mg/mL, respectively, representing the highest ever expression level of beta-mannanase reported in P. pastoris. In addition, the enzyme exhibited much higher binding activity to chitin, chitosan, Avicel, and mannan. The superior catalytic properties of mannS suggested great potential as an effective additive in animal feed industry. PMID- 23446983 TI - High frequency shoots regeneration for mass multiplication of Phyllanthus fraternus Webster--an important antiviral and hepatoprotective plant. AB - An efficient, rapid, and highly reproducible regeneration protocol was successfully developed for Phyllanthus fraternus from the field-derived mature nodal segments. The explants induced multiple shoots on cytokinin containing medium. The highest frequency (99 %) and maximum number of shoots (19.75) were induced on Murashige and Skoog's (MS) medium supplemented with 2.22 MUM 6 benzylaminopurine after 3-4 weeks of culture initiation. The elongated shoots were rooted on MS medium supplemented with indol-3-butyric acid (IBA) or alpha naphthalene acetic acid. Pulse treatment of microshoots promoted significant increase in the percentage of rooting and number of root regeneration per shoot. The highest rooting (100 %) and maximum number of roots (8.75) per shoot was obtained when shoots were dipped in IBA solution (0.98 mM) for 5 min and further subcultured on MS basal medium. Plantlets were successfully acclimatized and established in soil. Regenerated plants were grown normally in the field without showing any morphological variations. This cost-effective protocol will help the mass multiplication of P. fraternus for commercial propagation and high biomass production of this valuable medicinal plant. PMID- 23446984 TI - Evidence for a molten globule state in Cicer alpha-galactosidase induced by pH, temperature, and guanidine hydrochloride. AB - Physiologically as well as industrially, alpha-galactosidases are very important enzymes, but very little is known about the stability and folding aspect of enzyme. In the present study, we have investigated the temperature, pH, and guanidine hydrochloride (GuHCl) induced unfolding of Cicer alpha-galactosidase using circular dichroism and fluorescence spectroscopy. Strong negative ellipticities at 208, 215, and 222 nm indicate the presence of both alpha and beta structures in Cicer alpha-galactosidase and showed that its secondary structure belongs to alpha + beta class of proteins with 31 % alpha-helicity. For Cicer alpha-galactosidase the emission maximum was found to be 345 nm which suggests that tryptophan residues are less exposed to solvent. However, at pH 2.0, protein showed blue-shift. This state of protein lacked activity but it retained significant secondary structure. Enhanced binding of ANS at pH 2.0 indicated significant unfolding and exposure of hydrophobic regions. The unfolded state of Cicer alpha-galactosidase showed a red-shift of 15 nm with a concomitant decrease in the fluorescence intensity. The enzyme maintained its native structure and full activity up to 40 degrees C; however, above this temperature, denaturation was observed. PMID- 23446985 TI - The Staphylococcus aureus extracellular adherence protein promotes bacterial internalization by keratinocytes independent of fibronectin-binding proteins. AB - Staphylococcus aureus, the leading causal pathogen of skin infections, is strongly associated with skin atopy, and a number of bacterial adhesins allow the microbe to adhere to and invade eukaryotic cells. One of these adhesive molecules is the multifunctional extracellular adherence protein (Eap), which is overexpressed in situ in authentic human wounds and was shown to delay wound healing in experimental models. Yet, its role during invasion of keratinocytes is not clearly defined. By using a gentamicin/lysostaphin protection assay we demonstrate here that preincubation of HaCaT cells or primary keratinocytes with Eap results in a concentration-dependent significant increase in staphylococcal adhesion, followed by an even more pronounced internalization of bacteria by eukaryotic cells. Flow cytometric analysis revealed that Eap increased both the number of infected eukaryotic cells and the bacterial load per infected cell. Moreover, treatment of keratinocytes with Eap strongly enhanced the internalization of coagulase-negative staphylococci, as well as of E. coli, and markedly promoted staphylococcal invasion into extended-culture keratinocytes, displaying expression of keratin 10 and involucrin as differentiation markers. Thus, wound-related staphylococcal Eap may provide a major cellular invasin function, thereby enhancing the pathogen's ability to hide from the host immune system during acute and chronic skin infection. PMID- 23446986 TI - Mesenchymal contribution to recruitment, infiltration, and positioning of leukocytes in human melanoma tissues. AB - To understand factors that regulate leukocyte entry and positioning within human melanoma tissues, we performed a multiparametric quantitative analysis of two separated regions: the intratumoral area and the peritumoral stroma. Using two mesenchymal markers, fibroblast activation protein (FAP) and CD90, we identified three subsets of mesenchymal cells (MCs): (i) intratumoral FAP(+)CD90(low/-) MC, (ii) peritumoral FAP(+)CD90(+) MC, and (iii) FAP(-)CD90(+) perivascular MC. We characterized CD90(+) MCs, which showed a stable CCL2-secretory phenotype when long-term expanded ex vivo, and heavily surrounded peritumoral Duffy antigen receptor for chemokine(+) (DARC) postcapillary venules, supporting a role for these vessels in peritumoral inflammatory leukocyte recruitment. Conversely, the intratumoral area was variably invaded by FAP(+)CD90(low/-) MCs that colocalized with a distinct extracellular matrix (ECM) network. A positive correlation was observed between intratumoral stromal cell/ECM networks and leukocyte infiltration among tumor cells (TCs), as well as in a stroma-dependent xenograft tumor model. Adoptively transferred T lymphocytes preferentially infiltrated tumors composed of TC+MC, compared with TCs only. Altogether, our results suggest that a variety of MCs contribute to regulate different steps of leukocyte tumor infiltration, that is, CD90(+) cells surrounding peritumoral vessels secrete CCL2 to recruit CCR2(+) leukocytes at the tumor periphery, whereas intratumoral FAP(+) cells organize a stromal scaffold that contact guide further invasion among densely packed tumor cells. PMID- 23446987 TI - Pharmacological inhibition of stearoyl CoA desaturase in the skin induces atrophy of the sebaceous glands. PMID- 23446988 TI - Dental wear among cercopithecid monkeys of the Tai forest, Cote d'Ivoire. AB - Studies of dental macrowear can be useful for understanding masticatory and ingestive behavior, life history, and for inferring dietary information from the skeletal material of extinct and extant primates. Such studies to date have tended to focus on one or two teeth, potentially missing information that can be garnered through examination of wear patterns across the tooth row. Our study measured macrowear in the postcanine teeth of three sympatric cercopithecid species from the Tai Forest, Cote d'Ivoire (Cercocebus atys, Procolobus badius, and Colobus polykomos), whose diets have been well-described. Inter-specific analyses suggest that different diets and ingestive behaviors are characterized by different patterns of wear across the molar row, with Cercocebus atys emphasizing tooth use near P4 -M1 , P. badius emphasizing a large amount of tooth use near M2 -M3 , and Colobus polykomos exhibiting wear more evenly across the postcanine teeth. Information regarding differential tooth use across the molar row may be more informative than macrowear analysis of isolated teeth for making inferences about primate feeding behavior. PMID- 23446989 TI - In vitro metabolism of obovatol and its effect on cytochrome P450 enzyme activities in human liver microsomes. AB - Obovatol, a major constituent of the leaves of Magnolia obovata Thunb, is known to inhibit nuclear factor-kappaB activity and arachidonic acid-induced platelet aggregation. This study was performed to identify the metabolites of obovatol in human liver microsomes. Human liver microsomes incubated with obovatol in the presence of NADPH and/or UDPGA resulted in the formation of six metabolites, M1 M6. M1 and M2 were identified as hydroxyobovatol, on the basis of liquid chromatography/tandem mass spectrometric (LC-MS/MS) analysis. M1, M2 and obovatol were further metabolized to their glucuronide conjugates, obovatol-glucuronide (M3), obovatol-diglucuronide (M4) and hydroxyobovatol-glucuronide (M5 and M6). The inhibitory potency of obovatol on eight major human P450s was also investigated in human liver microsomes. In these experiments, obovatol strongly inhibited CYP2C19-mediated S-mephenytoin hydroxylase activity with an IC(50) value of 0.8 uM, which could have implications for drug-drug interactions. PMID- 23446990 TI - Cholestasis in a patient with gallstones and a normal gamma-glutamyl transferase. AB - Cholestasis with normal gamma glutamyl transferase characterizes functional deficiencies in the gene ABCB11, which encodes the bile salt export pump (BSEP), a liver-specific adenosine triphosphate (ATP)-binding cassette transporter. Here we report the case of a patient presenting with features of benign recurrent intrahepatic cholestasis associated with a heterozygous mutation in the ABCB11 gene. Immunohistochemistry showed a gradual decrease of BSEP from zone 1 to zone 3 of the liver lobule, suggesting that the mutation identified here may predispose patients to cholestasis through a delocalization process of BSEP at the lobular level. (HEPATOLOGY 2013;57:2539-2541). PMID- 23446991 TI - Simultaneous measurement of deep tissue blood flow and oxygenation using noncontact diffuse correlation spectroscopy flow-oximeter. AB - We report a novel noncontact diffuse correlation spectroscopy flow-oximeter for simultaneous quantification of relative changes in tissue blood flow (rBF) and oxygenation (Delta[oxygenation]). The noncontact probe was compared against a contact probe in tissue-like phantoms and forearm muscles (n = 10), and the dynamic trends in both rBF and Delta[oxygenation] were found to be highly correlated. However, the magnitudes of Delta[oxygenation] measured by the two probes were significantly different. Monte Carlo simulations and phantom experiments revealed that the arm curvature resulted in a significant underestimation (~-20%) for the noncontact measurements in Delta[oxygenation], but not in rBF. Other factors that may cause the residual discrepancies between the contact and noncontact measurements were discussed, and further comparisons with other established technologies are needed to identify/quantify these factors. Our research paves the way for noncontact and simultaneous monitoring of blood flow and oxygenation in soft and vulnerable tissues without distorting tissue hemodynamics. PMID- 23446992 TI - Utility of the Psychoeducational Profile-3 for assessing cognitive and language skills of children with autism spectrum disorders. AB - The Psychoeducational Profile-3's (PEP-3) ability to estimate cognitive and language skills of 136 children (20-75 months) with autism spectrum disorders (ASDs) across a range of functioning, and the association between the PEP-3 and ASD symptomatology was examined using retrospective data. PEP-3 cognitive and language measures were positively correlated with similar measures on the Child Development Inventory, the Merrill-Palmer Revised, and the Vineland Adaptive Behaviour Scale-2. The PEP-3 sometimes provided higher or lower estimates than other measures. Significant differences were found between diagnostic groups on PEP-3 cognitive and language measures. PEP-3 cognitive scores correlated positively with scores on the Autism Diagnostic Observation Schedule. Findings support the use of the PEP-3 to measure cognition and language in children with ASDs. PMID- 23446993 TI - The phenomenology and clinical correlates of suicidal thoughts and behaviors in youth with autism spectrum disorders. AB - This study investigated the phenomenology and clinical correlates of suicidal thoughts and behaviors in youth with ASD (N = 102; range 7-16 years). The presence of suicidal thoughts and behavior was assessed through the Anxiety Disorders Interview Schedule-Child and Parent Versions. Children and parents completed measures of anxiety severity, functional impairment, and behavioral and emotional problems. Approximately 11 % of youth displayed suicidal thoughts and behaviors. Children with autism were more likely to have suicidal thoughts and behaviors whereas children with Asperger's disorder were less likely. Suicidal thoughts and behaviors were associated with the presence of depression and post traumatic stress disorder. Overall, results suggest that suicidal thoughts and behaviors are common in youth with ASD, and may be related to depression and trauma. PMID- 23446995 TI - Invited Commentary-Can We Begin With the End in Mind? End-of-Life Care Preferences Before Long-term Dialysis. PMID- 23446994 TI - Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases. AB - Atherothrombosis is the major determinant of acute ischaemic cardiovascular events, such as myocardial infarction and stroke. Inflammatory processes have been linked to all phases of atherogenesis In particular, the identification of autoimmunity mediators in the complex microenvironment of chronic inflammation has become the focus of attention in both early and advanced atherogenic processes. Auto-antibodies against self-molecules or new epitopes generated by oxidative processes infiltrate atherosclerotic plaques and were shown to modulate the activity of immune cells by binding various types of receptors. However, despite mounting evidence for a pathophysiological role of autoantibodies in atherothrombosis, the clinical relevance for circulating autoantibodies in cardiovascular outcomes is still debated. This review aims at illustrating the mechanisms by which different types of autoantibodies might either promote or repress atherothrombosis and to discuss the clinical studies assessing the role of auto-antibodies as prognostic biomarkers of plaque vulnerability. PMID- 23446996 TI - Bridging-hydride influence on the electronic structure of an [FeFe] hydrogenase active-site model complex revealed by XAES-DFT. AB - Two crystallized [FeFe] hydrogenase model complexes, 1 = (MU pdt)[Fe(CO)(2)(PMe(3))](2) (pdt = SC1H2C2H2C3H2S), and their bridging-hydride (Hy) derivative, [1Hy](+) = [(MU-H)(MU-pdt)[Fe(CO)(2) (PMe(3))](2)](+) (BF(4)( )), were studied by Fe K-edge X-ray absorption and emission spectroscopy, supported by density functional theory. Structural changes in [1Hy](+) compared to 1 involved small bond elongations (<0.03 A) and more octahedral Fe geometries; the Fe-H bond at Fe1 (closer to pdt-C2) was ~0.03 A longer than that at Fe2. Analyses of (1) pre-edge absorption spectra (core-to-valence transitions), (2) Kbeta(1,3), Kbeta', and Kbeta(2,5) emission spectra (valence-to-core transitions), and (3) resonant inelastic X-ray scattering data (valence-to valence transitions) for resonant and non-resonant excitation and respective spectral simulations indicated the following: (1) the mean Fe oxidation state was similar in both complexes, due to electron density transfer from the ligands to Hy in [1Hy](+). Fe 1s->3d transitions remained at similar energies whereas delocalization of carbonyl AOs onto Fe and significant Hy-contributions to MOs caused an ~0.7 eV up-shift of Fe1s->(CO)s,p transitions in [1Hy](+). Fed-levels were delocalized over Fe1 and Fe2 and degeneracies biased to O(h)-Fe1 and C(4v) Fe2 states for 1, but to O(h)-Fe1,2 states for [1Hy](+). (2) Electron-pairing of formal Fe(d(7)) ions in low-spin states in both complexes and a higher effective spin count for [1Hy](+) were suggested by comparison with iron reference compounds. Electronic decays from Fe d and ligand s,p MOs and spectral contributions from Hys,p->1s transitions even revealed limited site-selectivity for detection of Fe1 or Fe2 in [1Hy](+). The HOMO/LUMO energy gap for 1 was estimated as 3.0 +/- 0.5 eV. (3) For [1Hy](+) compared to 1, increased Fed (x(2) y(2)) - (z(2)) energy differences (~0.5 eV to ~0.9 eV) and Fed->d transition energies (~2.9 eV to ~3.7 eV) were assigned. These results reveal the specific impact of Hy-binding on the electronic structure of diiron compounds and provide guidelines for a directed search of hydride species in hydrogenases. PMID- 23446997 TI - Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer. AB - PURPOSE: Mucin expression is a common feature of most adenocarcinomas and features prominently in current attempts to improve diagnosis and therapy for pancreatic cancer and other adenocarcinomas. We investigated the expression of a number of mucin core proteins and associated O-linked glycans expressed in pancreatic adenocarcinoma-sialyl Tn (STn), Tn, T antigen, sialyl Lewis A (CA19 9), sialyl Lewis C (SLeC), Lewis X (LeX), and sialyl LeX (SLeX)-during the progression of pancreatic cancer from early stages to metastatic disease. EXPERIMENTAL DESIGN: Immunohistochemical analyses of mucin and associated glycan expression on primary tumor and liver metastatic tumor samples were conducted with matched sets of tissues from 40 autopsy patients diagnosed with pancreatic adenocarcinoma, 14 surgically resected tissue samples, and 8 normal pancreata. RESULTS: There were significant changes in mucin expression patterns throughout disease progression. MUC1 and MUC4 were differentially glycosylated as the disease progressed from early pancreatic intraepithelial neoplasias to metastatic disease. De novo expression of several mucins correlated with increased metastasis indicating a potentially more invasive phenotype, and we show the expression of MUC6 in acinar cells undergoing acinar to ductal metaplasia. A "cancer field-effect" that included changes in mucin protein expression and glycosylation in the adjacent normal pancreas was also seen. CONCLUSIONS: There are significant alterations in mucin expression and posttranslational processing during progression of pancreatic cancer from early lesions to metastasis. The results are presented in the context of how mucins influence the biology of tumor cells and their microenvironment during progression of pancreatic cancer. PMID- 23446998 TI - Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas. AB - PURPOSE: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment. EXPERIMENTAL DESIGN: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models. RESULTS: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth. CONCLUSION: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma. PMID- 23446999 TI - Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth. AB - PURPOSE: Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma. EXPERIMENTAL DESIGN: Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors. RESULTS: Either transient-enforced expression or lentivirus-based constitutive expression of miR 21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6-dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal-regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21 induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors. CONCLUSION: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease. PMID- 23447000 TI - New strategies in Hodgkin lymphoma: better risk profiling and novel treatments. AB - Recent advances in Hodgkin lymphoma research are expected to prelude a promising new treatment era for patients and their treating physicians. Scientific investigations over the last few years have provided new insights into risk stratification, and, simultaneously, a plethora of novel targeted therapies are emerging for patients with relapsed and refractory disease. These novel therapies will be tested primarily in high-risk patients because 75% of the patients are cured with conventional therapies. The challenges, as Hodgkin lymphoma therapy moves forward, will be using these biologic insights to identify the patients who may benefit earlier in treatment from these novel agents, and tailoring the therapy to the tumor biology of the patient. These dual aims are intertwined; as our therapeutic arsenal increases, these biologic determinants of risk may themselves inform the design of therapies and the choice of treatments for high risk patients. PMID- 23447002 TI - Inhibitory effect of ARHI on pancreatic cancer cells and NF-kappaB activity. AB - The aim of this study was to investigate the effect of aplasia ras homolog member I (ARHI) on proliferation, apoptosis and the cell cycle in the pancreatic cancer cell line PANC-1. The study also aimed to examine the effect of ARHI on the activity of the nuclear factor (NF)-kappaB and to determine whether ARHI acts as a tumor suppressor in the development of pancreatic cancer by inhibiting the activity of NF-kappaB. A pIRES2-EGFP-ARHI vector, constructed by reverse transcrition (RT)-PCR, was transiently transfected into the PANC-1 cells and analyzed for the expression of the ARHI protein by western blotting. A MTT assay was used to quantify cell proliferation, and apoptosis was analyzed by flow cytometry. The NF-kappaB signaling pathway, specifically the pathway using the nuclear phosphorylated p65 isoform, was analyzed by western blotting. Expression of the ARHI protein was detected by western blotting subsequent to the PANC-1 cells being transiently transfected with the pIRES2-EGFP-ARHI construct. Cell proliferation was strongly inhibited in the PANC-1 cells transfected with pIRES2 EGFP-ARHI. The cell cycle assays indicated an increase in the number of cells at the G0/G1 phase and a decrease in the cells at the S phase, but the difference was not significant (P>0.05). Time course studies also indicated a marked increase in the apoptotic index following transient transfection, as well as a gradual decrease in the expression of the nuclear phosphorylated p65 protein. ARHI acts as a tumor suppressor by downregulating the NF-kappaB signaling pathway, which results in the inhibition of cell proliferation, apoptosis and the cell cycle in the pancreatic tumor PANC-1 cell line. PMID- 23447001 TI - Phase Ib dose-escalation study (PX-171-006) of carfilzomib, lenalidomide, and low dose dexamethasone in relapsed or progressive multiple myeloma. AB - PURPOSE: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study. EXPERIMENTAL DESIGN: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m(2) on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly. RESULTS: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. CONCLUSION: The maximum planned CRd dose, carfilzomib 27 mg/m(2), lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy. PMID- 23447003 TI - Creation of a percutaneous mesocaval shunt to control variceal bleeding in a child. AB - Although transjugular intrahepatic portosystemic shunt (TIPS) placement is the standard procedure for the treatment of portal hypertension, it is often impossible to perform in patients with extrahepatic portal vein occlusion. In these patients, options for decompressing the liver are few. In this report, we present a novel solution for managing gastro-esophageal hemorrhage in a child with portal hypertension and extrahepatic portal vein occlusion, through the creation of a percutaneous mesocaval shunt. PMID- 23447004 TI - Very severely obese patients have a high prevalence of type 2 diabetes mellitus and cardiovascular disease. AB - The prevalence of very severe obesity has increased progressively and faster than other classes of obesity over the last years. It is unclear whether the prevalence of obesity-related complications and health risks increases progressively or reaches a plateau above a certain degree of obesity. The aim of our study was to investigate whether the severity of obesity was correlated with the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose, impaired glucose tolerance (IGT), metabolic syndrome (MS), and cardiovascular diseases (CVDs) in a large cohort of patients with different degrees of obesity. A cross-sectional study was conducted in 938 obese patients without a previous diagnosis of diabetes. Patients were assigned to different categories of obesity: mild-moderate obesity (BMI 30-39.9 kg/m(2)), morbid obesity (BMI 40-49.9 kg/m(2)), and super-obesity (SO, BMI >=50 kg/m(2)). The prevalence of IGF, IGT, screen-detected T2DM, MS, and CVD was higher in SO patients than in the other groups. Interestingly, the association between SO and either MS or CVD was independent of glucose tolerance status, indicating that factors other than glucose metabolism also favor cardio-metabolic complications in obese patients. In patients without screen-detected T2DM (n = 807), insulin sensitivity and secretion OGTT-derived indexes indicated that SO patients had the worst glucose homeostasis relative to the other categories of obesity, which was indicated by the most reduced disposition index in these patients, a predictor of future T2DM. In conclusion, SO patients have an extremely high prevalence of glucose metabolism deterioration, and cardio-metabolic complications are more prevalent in these patients compared to less obese patients. PMID- 23447005 TI - Software for storage and management of microclimatic data for preventive conservation of cultural heritage. AB - Cultural Heritage preventive conservation requires the monitoring of the parameters involved in the process of deterioration of artworks. Thus, both long term monitoring of the environmental parameters as well as further analysis of the recorded data are necessary. The long-term monitoring at frequencies higher than 1 data point/day generates large volumes of data that are difficult to store, manage and analyze. This paper presents software which uses a free open source database engine that allows managing and interacting with huge amounts of data from environmental monitoring of cultural heritage sites. It is of simple operation and offers multiple capabilities, such as detection of anomalous data, inquiries, graph plotting and mean trajectories. It is also possible to export the data to a spreadsheet for analyses with more advanced statistical methods (principal component analysis, ANOVA, linear regression, etc.). This paper also deals with a practical application developed for the Renaissance frescoes of the Cathedral of Valencia. The results suggest infiltration of rainwater in the vault and weekly relative humidity changes related with the religious service schedules. PMID- 23447006 TI - A harsh environment wireless pressure sensing solution utilizing high temperature electronics. AB - Pressure measurement under harsh environments, especially at high temperatures, is of great interest to many industries. The applicability of current pressure sensing technologies in extreme environments is limited by the embedded electronics which cannot survive beyond 300 degrees C ambient temperature as of today. In this paper, a pressure signal processing and wireless transmission module based on the cutting-edge Silicon Carbide (SiC) devices is designed and developed, for a commercial piezoresistive MEMS pressure sensor from Kulite Semiconductor Products, Inc. Equipped with this advanced high-temperature SiC electronics, not only the sensor head, but the entire pressure sensor suite is capable of operating at 450 degrees C. The addition of wireless functionality also makes the pressure sensor more flexible in harsh environments by eliminating the costly and fragile cable connections. The proposed approach was verified through prototype fabrication and high temperature bench testing from room temperature up to 450 degrees C. This novel high-temperature pressure sensing technology can be applied in real-time health monitoring of many systems involving harsh environments, such as military and commercial turbine engines. PMID- 23447007 TI - Virtual estimator for piecewise linear systems based on observability analysis. AB - This article proposes a virtual sensor for piecewise linear systems based on observability analysis that is in function of a commutation law related with the system's outpu. This virtual sensor is also known as a state estimator. Besides, it presents a detector of active mode when the commutation sequences of each linear subsystem are arbitrary and unknown. For the previous, this article proposes a set of virtual estimators that discern the commutation paths of the system and allow estimating their output. In this work a methodology in order to test the observability for piecewise linear systems with discrete time is proposed. An academic example is presented to show the obtained results. PMID- 23447008 TI - Systematic angle random walk estimation of the constant rate biased ring laser gyro. AB - An actual account of the angle random walk (ARW) coefficients of gyros in the constant rate biased rate ring laser gyro (RLG) inertial navigation system (INS) is very important in practical engineering applications. However, no reported experimental work has dealt with the issue of characterizing the ARW of the constant rate biased RLG in the INS. To avoid the need for high cost precise calibration tables and complex measuring set-ups, the objective of this study is to present a cost-effective experimental approach to characterize the ARW of the gyros in the constant rate biased RLG INS. In the system, turntable dynamics and other external noises would inevitably contaminate the measured RLG data, leading to the question of isolation of such disturbances. A practical observation model of the gyros in the constant rate biased RLG INS was discussed, and an experimental method based on the fast orthogonal search (FOS) for the practical observation model to separate ARW error from the RLG measured data was proposed. Validity of the FOS-based method was checked by estimating the ARW coefficients of the mechanically dithered RLG under stationary and turntable rotation conditions. By utilizing the FOS-based method, the average ARW coefficient of the constant rate biased RLG in the postulate system is estimated. The experimental results show that the FOS-based method can achieve high denoising ability. This method estimate the ARW coefficients of the constant rate biased RLG in the postulate system accurately. The FOS-based method does not need precise calibration table with high cost and complex measuring set-up, and Statistical results of the tests will provide us references in engineering application of the constant rate biased RLG INS. PMID- 23447009 TI - Characterization of microparticle separation utilizing electrokinesis within an electrodeless dielectrophoresis chip. AB - This study demonstrated the feasibility of utilizing electrokinesis in an electrodeless dielectrophoresis chip to separate and concentrate microparticles such as biosamples. Numerical simulations and experimental observations were facilitated to investigate the phenomena of electrokinetics, i.e., electroosmosis, dielectrophoresis, and electrothermosis. Moreover, the proposed operating mode can be used to simultaneously convey microparticles through a microfluidic device by using electroosmotic flow, eliminating the need for an additional micropump. These results not only revealed that the directions of fluids could be controlled with a forward/backward electroosmotic flow but also categorized the optimum separating parameters for various microparticle sizes (0.5, 1.0 and 2.0 MUm). Separation of microparticles can be achieved by tuning driving frequencies at a specific electric potential (90 Vpp.cm(-1)). Certainly, the device can be designed as a single automated device that carries out multiple functions such as transportation, separation, and detection for the realization of the envisioned Lab-on-a-Chip idea. PMID- 23447010 TI - Multi reflection of Lamb wave emission in an acoustic waveguide sensor. AB - Recently, an acoustic waveguide sensor based on multiple mode conversion of surface acoustic waves at the solid-liquid interfaces has been introduced for the concentration measurement of binary and ternary mixtures, liquid level sensing, investigation of spatial inhomogenities or bubble detection. In this contribution the sound wave propagation within this acoustic waveguide sensor is visualized by Schlieren imaging for continuous and burst operation the first time. In the acoustic waveguide the antisymmetrical zero order Lamb wave mode is excited by a single phase transducer of 1 MHz on thin glass plates of 1 mm thickness. By contact to the investigated liquid Lamb waves propagating on the first plate emit pressure waves into the adjacent liquid, which excites Lamb waves on the second plate, what again causes pressure waves traveling inside the liquid back to the first plate and so on. The Schlieren images prove this multi reflection within the acoustic waveguide, which confirms former considerations and calculations based on the receiver signal. With this knowledge the sensor concepts with the acoustic waveguide sensor can be interpreted in a better manner. PMID- 23447011 TI - Contactless impedance sensors and their application to flow measurements. AB - The paper provides a critical discussion of the present state of the theory of high-frequency impedance sensors (now mostly called contactless impedance or conductivity sensors), the principal approaches employed in designing impedance flow-through cells and their operational parameters. In addition to characterization of traditional types of impedance sensors, the article is concerned with the use of less common sensors, such as cells with wire electrodes or planar cells. There is a detailed discussion of the effect of the individual operational parameters (width and shape of the electrodes, detection gap, frequency and amplitude of the input signal) on the response of the detector. The most important problems to be resolved in coupling these devices with flow through measurements in the liquid phase are also discussed. Examples are given of cell designs for continuous flow and flow-injection analyses and of detection systems for miniaturized liquid chromatography and capillary electrophoresis. New directions for the use of these sensors in molecular biology and chemical reactors and some directions for future development are outlined. PMID- 23447012 TI - Anti-quorum sensing potential of crude Kigelia africana fruit extracts. AB - The increasing incidence of multidrug-resistant pathogens has stimulated the search for novel anti-virulence compounds. Although many phytochemicals show promising antimicrobial activity, their power lies in their anti-virulence properties. Thus the quorum sensing (QS) inhibitory activity of four crude Kigelia africana fruit extracts was assessed qualitatively and quantitatively using the Chromobacterium violaceum and Agrobacterium tumefaciens biosensor systems. Inhibition of QS-controlled violacein production in C. violaceum was assayed using the qualitative agar diffusion assay as well as by quantifying violacein inhibition using K. africana extracts ranging from 0.31-8.2 mg/mL. Qualitative modulation of QS activity was investigated using the agar diffusion double ring assay. All four extracts showed varying levels of anti-QS activity with zones of violacein inhibition ranging from 9-10 mm. The effect on violacein inhibition was significant in the following order: hexane > dichloromethane > ethyl acetate > methanol. Inhibition was concentration-dependent, with the >=90% inhibition being obtained with >=1.3 mg/mL of the hexane extract. Both LuxI and LuxR activity were affected by crude extracts suggesting that the phytochemicals target both QS signal and receptor. K. africana extracts with their anti-QS activity, have the potential to be novel therapeutic agents, which might be important in reducing virulence and pathogenicity of drug-resistant bacteria in vivo. PMID- 23447013 TI - Determination of odor release in hydrocolloid model systems containing original or carboxylated cellulose at different pH values using static headspace gas chromatographic (SHS-GC) analysis. AB - Static headspace gas chromatographic (SHS-GC) analysis was performed to determine the release of 13 odorants in hydrocolloid model systems containing original or regio-selectively carboxylated cellulose at different pH values. The release of most odor compounds was decreased in the hydrocolloid solutions compared to control, with the amounts of 2-propanol, 3-methyl-1-butanol, and 2,3-butanedione released into the headspace being less than those of any other odor compound in the hydrocolloid model systems. However, there was no considerable difference between original cellulose-containing and carboxylated-cellulose containing systems in the release of most compounds, except for relatively long-chain esters such as ethyl caprylate and ethyl nonanoate. The release from the original and carboxylated cellulose solutions controlled to pH 10 was significantly higher than that from solutions adjusted to pH 4 and 7 in the case of some esters (ethyl acetate, methyl propionate, ethyl propionate, ethyl butyrate, butyl propionate, ethyl caproate) and alcohols (2-propanol, 3-methyl-1-butanol), in particular, ethyl butyrate and 3-methyl-1-butanol. In contrast, the release of 2,3 butanedione from both the original and carboxylated cellulose solutions was increased at pH 4 and 7 compared to that at pH 10 by about 70% and 130%, respectively. Our study demonstrated that the release of some odorants could be changed significantly by addition of both original and carboxylated cellulose in hydrocolloid model systems, but only minor effect was observed in pH of the solution. PMID- 23447015 TI - No time to waste. PMID- 23447014 TI - BreedVision--a multi-sensor platform for non-destructive field-based phenotyping in plant breeding. AB - To achieve the food and energy security of an increasing World population likely to exceed nine billion by 2050 represents a major challenge for plant breeding. Our ability to measure traits under field conditions has improved little over the last decades and currently constitutes a major bottleneck in crop improvement. This work describes the development of a tractor-pulled multi-sensor phenotyping platform for small grain cereals with a focus on the technological development of the system. Various optical sensors like light curtain imaging, 3D Time-of-Flight cameras, laser distance sensors, hyperspectral imaging as well as color imaging are integrated into the system to collect spectral and morphological information of the plants. The study specifies: the mechanical design, the system architecture for data collection and data processing, the phenotyping procedure of the integrated system, results from field trials for data quality evaluation, as well as calibration results for plant height determination as a quantified example for a platform application. Repeated measurements were taken at three developmental stages of the plants in the years 2011 and 2012 employing triticale (*Triticosecale Wittmack L.) as a model species. The technical repeatability of measurement results was high for nearly all different types of sensors which confirmed the high suitability of the platform under field conditions. The developed platform constitutes a robust basis for the development and calibration of further sensor and multi-sensor fusion models to measure various agronomic traits like plant moisture content, lodging, tiller density or biomass yield, and thus, represents a major step towards widening the bottleneck of non-destructive phenotyping for crop improvement and plant genetic studies. PMID- 23447016 TI - A new horizon in asthma: inhibiting ILC function. AB - Innate lymphoid cells (ILCs) produce cytokines that drive allergic responses in asthma and can be inhibited by lipoxin A4 (Barnig et al., this issue). PMID- 23447017 TI - Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. AB - Asthma is a prevalent disease of chronic inflammation in which endogenous counterregulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 ILCs (ILC2s), can participate in the regulation of allergic airway responses, in particular airway mucosal inflammation. We have identified both NK cells and ILC2s in human lung and peripheral blood in healthy and asthmatic subjects. NK cells were highly activated in severe asthma, were linked to eosinophilia, and interacted with autologous eosinophils to promote their apoptosis. ILC2s generated antigen-independent interleukin-13 (IL-13) in response to the mast cell product prostaglandin D2 alone and in a synergistic manner with the airway epithelial cytokines IL-25 and IL-33. Both NK cells and ILC2s expressed the pro resolving ALX/FPR2 receptors. Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly increased NK cell-mediated eosinophil apoptosis and decreased IL-13 release by ILC2s. Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation. Because lipoxin A4 generation is decreased in severe asthma, these findings also implicate unrestrained ILC activation in asthma pathobiology. PMID- 23447018 TI - Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. AB - Relapse remains a leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk leukemias. The potentially beneficial donor T cell-mediated graft-versus-leukemia (GVL) effect is often mitigated by concurrent graft-versus-host disease (GVHD). Providing T cells that can selectively target Wilms tumor antigen 1 (WT1), a transcription factor overexpressed in leukemias that contributes to the malignant phenotype, represents an opportunity to promote antileukemic activity without inducing GVHD. HLA-A*0201-restricted WT1-specific donor-derived CD8 cytotoxic T cell (CTL) clones were administered after HCT to 11 relapsed or high-risk leukemia patients without evidence of on-target toxicity. The last four treated patients received CTL clones generated with exposure to interleukin-21 (IL-21) to prolong in vivo CTL survival, because IL-21 can limit terminal differentiation of antigen specific T cells generated in vitro. Transferred cells exhibited direct evidence of antileukemic activity in two patients: a transient response in one patient with advanced progressive disease and the induction of a prolonged remission in a patient with minimal residual disease (MRD). Additionally, three treated patients at high risk for relapse after HCT survive without leukemia relapse, GVHD, or additional antileukemic treatment. CTLs generated in the presence of IL-21, which were transferred in these latter three patients and the patient with MRD, all remained detectable long-term and maintained or acquired in vivo phenotypic and functional characteristics associated with long-lived memory CD8 T cells. This study supports expanding efforts to immunologically target WT1 and provides insights into the requirements necessary to establish potent persistent T cell responses. PMID- 23447020 TI - The alteration of miR-222 and its target genes in nickel-induced tumor. AB - Nickel is an important kind of metal and a necessary trace element in people's production and livelihood; it is also a well-confirmed human carcinogen. In the past few years, researchers did a large number of studies about the molecular mechanisms of nickel carcinogenesis, and they focused on activation of proto oncogenes and inactivation of anti-oncogenes caused by gene point mutation, gene deletion, gene amplification, DNA methylation, chromosome condensation, and so on that were induced by nickel. However, the researches on tumorigenic molecular mechanisms regulated by microRNAs (miRNAs) are rare. In this study, we established nickel-induced tumor by injecting Ni3S2 compounds to Wistar Rattus. By establishing a cDNA library of miRNA from rat muscle tumor tissue induced by Ni3S2, we found that the expression of miR-222 was significantly upregulated in tumor tissue compared with the normal tissue. As we expected, the expression levels of target genes of miR-222, CDKN1B and CDKN1C, were downregulated in the nickel-induced tumor. The same alteration of miR-222 and its target genes was also found in malignant 16HBE cells induced with Ni3S2 compounds. We conclude that miR-222 may promote cell proliferation infinitely during nickel-induced tumorigenesis in part by regulating the expression of its target genes CDKN1B and CDKN1C. Our study elucidated a novel molecular mechanism of nickel-induced tumorigenesis. PMID- 23447019 TI - Mutant HSP70 reverses autoimmune depigmentation in vitiligo. AB - Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell-mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substrate-binding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, and mutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A encoding DNA applied months before spontaneous depigmentation prevented vitiligo in mice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70iQ435A therapeutically in a different, rapidly depigmenting model after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift from quiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo. PMID- 23447021 TI - A metabolic prototype for eliminating tryptophan from the genetic code. AB - We set out to reduce the chemical constitution of a living organism to 19 amino acids. A strain was constructed for reassigning the tryptophan codon UGG to histidine and eliminating tryptophan from Escherichia coli. Histidine codons in the gene for an essential enzyme were replaced with tryptophan codons and the restoration of catalytic activity by missense suppressor His-tRNA bearing a CCA anticodon was selected. We used automated cultivation to assess the stability of this genetic construct during evolution. Histidine to tryptophan mutation at codon 30 in the transketolase gene from yeast and its cognate suppressor tRNA were stably propagated in a tktAB deletant of E. coli over 2500 generations. The ratio of histidine misincorporation at tryptophan sites in the proteome increased from 0.0007 to 0.03 over 300 days of continuous culture. This result demonstrated that the genetic code can be forced to evolve by permanent metabolic selection. PMID- 23447022 TI - Cooperative binding of 2,2'-bipyridine into polynucleotide poly(A)-poly(U-) in an alkaline aqueous solution. AB - UV absorption data analysis has been used to evaluate equilibrium constants of the pH-induced interaction of 2,2'-Bipy with polyadenylnic-polyuridylic acid in aqueous solution. The conditional probabilities hard model has been adopted in treatment of concentration diagrams calculated by the soft modelling-based Multivariate Curve Resolution-Alternating Least Squares approach. Intrinsic binding constant (lgKg = 1.93), and the cooperativity parameter (omega = 340), were calculated as the best fit. The plot of the experimental binding constant versus 2,2'-Bipy equilibrium concentration shows two modes of ligand with polymer interactions. The equilibrium hard model correctly reproduced the binding constant variations observed in the experiment. The results indicated that ligand binding in two steps is governed by a cooperative process, that is, the enhancement of deprotonated structure stability. It would appear that proposed calculation approach can be used in future combined hard modelling theoretical and soft modelling experimental works. PMID- 23447023 TI - Estimation of hemoglobin levels in the optic nerve head for glaucoma management. PMID- 23447024 TI - General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. AB - Contrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. "Classical" anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors. PMID- 23447025 TI - Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokine-related genes were up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC specific gene signature in the liver microenvironment significantly correlates with recurrence. CONCLUSION: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs. PMID- 23447026 TI - Restricting marketing to children: consensus on policy interventions to address obesity. AB - Obesity presents major challenges for public health and the evidence is strong. Lessons from tobacco control indicate a need for changing the policy and environments to make healthy choices easier and to create more opportunities for children to achieve healthy weights. In April 2011, the Alberta Policy Coalition for Chronic Disease Prevention convened a consensus conference on environmental determinants of obesity such as marketing of unhealthy foods and beverages to children. We examine the political environment, evidence, issues, and challenges of placing restrictions on marketing of unhealthy foods and beverages within Canada. We recommend a national regulatory system prohibiting commercial marketing of foods and beverages to children and suggest that effective regulations must set minimum standards, monitor compliance, and enact penalties for non-compliance. PMID- 23447027 TI - Distracted driving - it is time for public health to step in. PMID- 23447028 TI - Societal context and the production of immigrant status-based health inequalities: a comparative study of the United States and Canada. AB - BACKGROUND: We compare disparities in health status between first-generation immigrants and others in the United States (US) and Canada. METHODS: We used data from the Joint Canada-US Survey of Health. The regression models adjusted for demographics, socioeconomic status, and health insurance (the US). RESULTS: In both countries, the health advantage belonged to immigrants. Fewer disparities between immigrants and those native-born were seen in Canada versus the US. Canadians of every immigrant/race group fared better than US native-born Whites. DISCUSSION: Fewer disparities in Canada and better overall health of all Canadians suggest that societal context may create differences in access to the resources, environments, and experiences that shape health and health behaviors. PMID- 23447029 TI - Cellphone bans and fatal motor vehicle crash rates in the United States. AB - A number of states in the United States have laws restricting drivers from using cellphones. Using state-level panel data, we examined the effect of cellphone laws on fatal crashes in the United States between 2000 and 2010. Our results show that there is insufficient power to detect a reduction in overall fatal crash rates scaled by vehicle miles and population estimates. Cellphone bans, however, have significantly reduced the fatal crash rates of drivers in certain age cohorts. The effect was most pronounced among drivers between 18 and 34 years of age. We did not find any significant effect among drivers in the 55 and older age cohorts. PMID- 23447030 TI - Rubella in Israel after the MMR vaccine: elimination or containment? AB - Since 1996, after the full institution of the two-dose measles, mumps, and rubella vaccine (MMR) regimen in Israel, rubella incidence has declined dramatically and has remained extremely low. Cyclical outbreaks ended; the two brief outbreaks that did occur were quickly contained; and epidemiological data indicate that the disease is practically absent from the country. But similar steep declines in the incidence of measles and mumps, the two other MMR preventable diseases, were followed by major outbreaks in 2007 and 2010. Epidemiological analyses show that undervaccination of subgroups within the Jewish ultra-orthodox population, both in Israel and abroad, and virus importation into Israel, continue to be risk factors for all three MMR preventable diseases. Israel's public health system, therefore, should focus on a policy of containment: improve MMR coverage among undervaccinated subgroups and assure that virus importation is no longer a risk. Then the goal of rubella elimination will become feasible. We discuss how the Israeli experience may contribute to the World Health Organization Initiative to eliminate simultaneously measles and rubella. PMID- 23447031 TI - Does India need an indigenous HPV vaccine and why? AB - Cervical cancer is the most common form of cancer in Indian women, causing high morbidity and mortality. Two effective and safe vaccines exist, but these remain out of reach of most people due to their high cost. It is imperative that an Human Papillomavirus (HPV) vaccine be affordable and cheap so that the target population can be vaccinated, to make a real impact in reducing the disease burden. We argue that in the long run India needs to develop and manufacture its own HPV vaccine in order to bridge this price gap. We also explore other strategies that can be adopted to increase the accessibility and affordability of this life-saving vaccine during the interim period. PMID- 23447032 TI - Building national public health capacity for managing chemical events: a case study of the development of health protection services in the United Kingdom. AB - The revised International Health Regulations (2005) require that countries develop plans for chemical threats. In 2012, the World Health Assembly reported that most countries had not yet achieved 'adequate capacity'. We review the evolution of chemical hazards services in the United Kingdom, the result of 15 years of grass-roots pressure and an accumulating weight of chemical incidents that eventually convinced the UK Department of Health of the need for a new national public health function, culminating, in 2003, in the creation of the Chemical Hazards Division of the new Health Protection Agency. Ten years later, public health services are again being radically reorganized with the creation of Public Health England, potentially destabilizing health protection arrangements and creating confusion among roles in managing chemical emergencies. Incorporating health protection into a broader public health organization, however, offers a new opportunity to broaden the scope of health protection services to embrace prevention of non-infectious environmental diseases. PMID- 23447033 TI - Knowledge, attitudes and beliefs of health care workers towards influenza vaccination. AB - BACKGROUND: Influenza vaccination is routinely offered to health care workers in the U.K. to prevent nosocomial spread to patients and illness among health care workers. Despite its importance uptake has been low in the U.K. AIMS: To describe the knowledge, attitudes and behaviour of health care workers towards influenza vaccination offered as part of occupational health and to understand their relative importance in promoting uptake of influenza vaccine. We also sought to make comparisons with other vaccines more readily accepted as part of occupational health. METHODS: An online survey was distributed by e-mail to health care workers in the South Central Strategic Health Authority. The questionnaire included the following: demographic characteristics; vaccination status; and knowledge, attitudes and behaviour towards influenza, MMR and hepatitis B vaccination. We used logistic regression to identify the independent predictors of receipt of influenza vaccine. RESULTS: The survey was completed by 998 health care workers representing just over 1% of health care workers in the region. Of those, 69% thought that overall benefits of influenza vaccination were greater than the risks and inconvenience (versus 92% for hepatitis B and 86% for MMR). The following predicted receipt of influenza vaccine: belief that influenza poses a risk to one's own health (OR 3.74; 95% CI 2.45-5.71); belief that influenza vaccine is harmful (OR 0.25; 95% CI 0.16-0.37); and belief that influenza vaccine will protect patients (OR 2.96; 95% CI 1.89-4.62). CONCLUSIONS: Staff knowledge, attitudes and beliefs concerning influenza and its vaccine are an important predictor of uptake and should be a target for campaigns to promote uptake. PMID- 23447034 TI - Prospective evaluation of mental health training for occupational health practitioners. AB - BACKGROUND: Occupational health (OH) practitioners need to be confident in identifying and managing mental health problems in the workforce. AIMS: To evaluate the effectiveness of a one-day workshop in improving the knowledge, attitude and confidence of OH practitioners in detecting and managing depression, anxiety, suicide risk, alcohol misuse and drug abuse. METHODS: Interactive mental health workshops for 164 OH practitioners held in five regions in England were evaluated by self-administered questionnaire. Data were collected immediately prior to the workshop (T1), immediately after the workshop (T2) and 4 months following the workshop (T3). RESULTS: At T1, the response rate was 97% (159/164), 90% at T2 and 63% at T3. The mean improvement in participants' knowledge was 8% (95% CI 6-10) at T2 compared with T1. The biggest improvement was in participants with no previous training in the management of common mental health problems in the workplace, mean improvement 9% (95% CI 6-12). Participants' confidence improved in all areas assessed at T2, and the improvement in confidence compared with that at baseline was sustained at 4 months (T3). Participants reported using the knowledge gained in clinical practice in all topic areas covered. Use of knowledge gained at the workshop was significantly higher in those who had had previous training in managing common mental health disorders. CONCLUSIONS: This one-day interactive workshop was a feasible and effective method of improving OH professionals' confidence, knowledge and application of skills in practice in key areas of mental health. PMID- 23447035 TI - Bone morphogenetic protein 2 decreases TRPC expression, store-operated Ca(2+) entry, and basal [Ca(2+)]i in rat distal pulmonary arterial smooth muscle cells. AB - Recent studies indicate that multiple bone morphogenetic protein (BMP) family ligands and receptors are involved in the development of pulmonary arterial hypertension, yet the underlying mechanisms are incompletely understood. Although BMP2 and BMP4 share high homology in amino acid sequence, they appear to exert divergent effects on chronic hypoxic pulmonary hypertension (CHPH). While BMP4 promotes vascular remodeling, BMP2 prevents CHPH. We previously demonstrated that BMP4 upregulates the expression of canonical transient receptor potential channel (TRPC) proteins and, thereby, enhances store-operated Ca(2+) entry (SOCE) and elevates intracellular Ca(2+) concentration ([Ca(2+)]i) in pulmonary arterial smooth muscle cells (PASMCs). In this study, we investigated the effects of BMP2 on these variables in rat distal PASMCs. We found that treatment with BMP2 (50 ng/ml, 60 h) inhibited TRPC1, TRPC4, and TRPC6 mRNA and protein expression. Moreover, BMP2 treatment led to reduced SOCE and decreased basal [Ca(2+)]i in PASMCs. These alterations were associated with decreased PASMC proliferation and migration. Conversely, knockdown of BMP2 with specific small interference RNA resulted in increased cellular levels of TRPC1, TRPC4, and TRPC6 mRNA and protein, enhanced SOCE, elevated basal [Ca(2+)]i, and increased proliferation and migration of PASMCs. Together, these results indicate that BMP2 participates in regulating Ca(2+) signaling in PASMCs by inhibiting TRPC1, TRPC4, and TRPC6 expression, thus leading to reduced SOCE and basal [Ca(2+)]i and inhibition of cell proliferation and migration. PMID- 23447036 TI - ICAM-1-mediated leukocyte adhesion is critical for the activation of endothelial LSP1. AB - Leukocyte-endothelial interaction triggers signaling events in endothelial cells prior to transendothelial migration of leukocytes. Leukocyte-specific protein 1 (LSP1), expressed in endothelial cells, plays a pivotal role in regulating subsequent recruitment steps following leukocyte adhesion. In neutrophils, LSP1 is activated by phosphorylation of its serine residues by molecules downstream of p38 MAPK and PKC. Whether leukocyte adhesion to endothelial cells is required for endothelial LSP1 activation remains elusive. In addition, discrepancies in the functions of endothelial and leukocyte LSP1 in leukocyte adhesion prevail. We demonstrate that adhesion of wild-type (Lsp1(+/+)) neutrophils to LSP1-deficient (Lsp1(-/-)) endothelial cells was significantly reduced compared with adhesion to Lsp1(+/+) endothelial cells. Immunoblotting revealed increased phosphorylated endothelial LSP1 in the presence of adherent Lsp1(-/-) neutrophils [stimulated by macrophage inflammatory protein-2 (CXCL2), TNF-alpha, or thapsigargin], but not cytokine or chemokine alone. Pharmacological inhibition of p38 MAPK by SB-203580 (10 MUM) significantly blunted the phosphorylation of endothelial LSP1. Functionally blocking endothelial ICAM-1 or neutrophil beta2-integrins diminished neutrophil adhesion and phosphorylation of endothelial LSP1. The engagement of endothelial ICAM-1 cross-linking, which mimics leukocyte adhesion, resulted in phosphorylation of endothelial LSP1. In neutrophil-depleted Lsp1(+/+) mice, administration of ICAM-1 cross-linking antibody resulted in increased phosphorylation of LSP1 and p38 MAPK in TNF-alpha-stimulated cremaster muscle. In conclusion, endothelial LSP1 participates in leukocyte adhesion in vitro, and leukocyte adhesion through ICAM-1 fosters the activation of endothelial LSP1, an effect at least partially mediated by the activation of p38 MAPK. Endothelial LSP1, in contrast to neutrophil LSP1, is not phosphorylated by cytokine or chemokine stimulation alone. PMID- 23447039 TI - Editorial. PMID- 23447037 TI - The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. AB - Mutations in the human gene encoding connexin 26 (Cx26 or GJB2) cause either nonsyndromic deafness or syndromic deafness associated with skin diseases. That distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Here we use three different expression systems to examine the functional characteristics of two Cx26 mutations causing either mild (Cx26-D50A) or lethal (Cx26-A88V) keratitis-ichthyosis-deafness (KID) syndrome. In either cRNA-injected Xenopus oocytes, transfected HeLa cells, or transfected primary human keratinocytes, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26. This increased membrane current accelerated cell death in low extracellular calcium solutions and was not due to increased mutant protein expression. Elevated mutant hemichannel currents could be blocked by increased extracellular calcium concentration. These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome. PMID- 23447038 TI - Detection of multiple viral and bacterial infections in acute exacerbation of chronic obstructive pulmonary disease: a pilot prospective study. AB - Few studies have evaluated the contribution of multiple virus and bacterial infections in acute exacerbation of chronic obstructive pulmonary disease. This study estimated the burden of multiple viral and bacterial respiratory infections in moderate to very severe chronic obstructive pulmonary disease patients that were prospectively followed-up during a 12-month pilot study. Clinical data were collected monthly and sputum was collected at the time of each acute exacerbation event. Classical culture techniques for bacteria and multiplex polymerase chain reaction (PCR) and microarray detection assays were performed to identify viral and atypical bacterial pathogens in the sputum. Overall, 51 patients were included and 45 acute exacerbation events were investigated clinically and microbiologically. Among the 45 acute exacerbation events, 44% had evidence of viral infection involving human rhinovirus (HRV) and metapneumovirus (hMPV) in 20% and 18%, respectively. Intracellular bacteria were not found in sputum by PCR. Common bacterial pathogens were identified in 42% of acute exacerbation patients, most frequently Branhamella catarrhalis, Streptococcus pneumoniae and Haemophilus influenzae. Viral or virus and bacteria co-infections were detected in 27% of acute exacerbation events (n = 12) with HRV and hMPV involved in 92% of cases. Patients with co-infections did not present greater clinical severity scores at exacerbation and more recurrence of acute exacerbation events at 3 and 6 months than those with single infections (P > 0.4). These results suggest that HRV and hMPV may be contributors or cofactors of AECOPD. These findings indicate that viral or virus and bacterial co-infections do not impact significantly on the clinical severity of acute exacerbation of chronic obstructive pulmonary disease and recurrence at 3 and 6 months. PMID- 23447042 TI - Preparation and characterization of chitosan/beta-cyclodextrin nanoparticles containing plasmid DNA encoding interleukin-12. AB - Interleukin-12 (IL-12) as a cytokine has been proved to possess antitumor effects via stimulating the immune system. Non-viral gene delivery systems offer several advantages, including easiness in production, low cost, safety; low immunogenicity and can carry higher amounts of genetic material without limitation on their sizes.pUMVC3-hIL12 loaded Low Molecular Weight chitosan/beta cyclodextrin (LMW CS/CD) nanoparticles were prepared using ionotropic gelation method and characterized in terms of size, zeta potential, polydispersity index, morphology, loading efficiency and cytotoxicity against the CT-26 colon carcinoma cell line.All prepared particles were spherical in shape and nano-sized (171.3+/ 2.165 nm, PdI: 0.231+/-0.014) and exhibited a positive zeta potential (34.3+/ 1.55). The nanoparticles demonstrated good DNA encapsulation efficiencies (83.315%+/-2.067). Prepared pUMVC3-hIL12 loaded LMW CS/CD nanoparticles showed no cell toxicity in murine CT-26 colon carcinoma cells. At the concentration of 0.1 ug/ml of nanoparticles, the transfection ability was obviously higher than that of the naked DNA.LMW CS/CD-plasmid DNA nanoparticles encoding IL-12 prepared using ionotropic gelation method with no toxic effect on the tested cells can be considered as a basis for further gene delivery studies both in vitro and in vivo to enhance the expression of IL-12. PMID- 23447043 TI - Pharmacokinetics and bioequivalence study of two indapamide formulations after single-dose administration in healthy Chinese male volunteers. AB - The pharmacokinetics and relative bioavailability/bioequivalence of 2 formulations of indapamide were assessed in this paper. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single blind, 2-way crossover study design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 84 h post-dose, and indapamide concentrations in plasma were determined by a validated liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Based on the plasma concentration-time data of each individual in each period, pharmacokinetic parameters, Cmax, AUC0-tau, AUC0-infinity and t1/2, were calculated by non-compartmental analysis. Pharmacokinetic parameters for test and reference formulations were analyzed statistically to assess bioequivalence of the 2 formulations. The values of Cmax, Tmax, t1/2, AUC0-tau, AUC0-infinity for test and reference formulations were 49.53+/-5.53 and 47.79+/-4.68 ng/mL, 1.9+/ 0.6 and 2.0+/-0.5 h, 22.49+/-5.93 and 23.23+/-4.48 h, 859.51+/-160.92 and 840.90+/-170.62 ng . h/mL, 934.35+/-190.60 and 919.52+/-179.74 ng . h/mL, respectively. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were within the accepted range of 80-125%. It showed that the 2 formulations of indapamide were bioequivalent. Both preparations were well tolerated and no adverse reactions were found throughout the study. PMID- 23447044 TI - A multi-centre, randomised, double-blind, placebo-controlled clinical trial on the efficacy and tolerability of GeloMyrtol(r) forte in acute bronchitis. AB - GeloMyrtol(r) forte (Myrtol(r)) is a phytomedicine obtained by distillation from essential oils. The trial was conducted to confirm the efficacy of Myrtol(r) in the treatment of acute bronchitis. METHODS: Patients with acute bronchitis and without confounding co-morbidity or co-medication were randomly assigned to treatment with either Myrtol(r) 300 mg 4 times daily or matched placebo in double blind, parallel-group fashion. Signs and symptoms were evaluated by the investigator at baseline and after 7, 10 and 14 days of treatment; intake of medication, wellbeing and symptoms were recorded daily by the patient in the patients' diaries. FINDINGS: 413 patients were enrolled and randomised (Myrtol(r): 202; Placebo: 211); 398 had at least one on-treatment efficacy evaluation (Myrtol(r): 196; Placebo: 202). The mean change in coughing fits from D01 (baseline) to D07-D09 (after about one week treatment) was 62.1% (95% CI: 57.6-66.6%) and 49.8% (95% CI: 44.6-55.0%) for treatment with Myrtol(r) and placebo, respectively (p<0.0001). With Myrtol(r), the median time to 50% reduction in coughing fits was statistically significantly shorter and there were more patients without day-time coughing fits; there also were statistically significantly less day-time coughing fits, less difficulty coughing up, less sleep disturbance due to night-time coughing; with Myrtol(r) there was less symptomatic impairment (composite bronchitis severity score and subscores) and significant more patients had a clinically satisfying response to the investigational treatment.Both treatments were generally well tolerated. CONCLUSIONS: Myrtol(r) is statistically significantly superior to placebo in treating acute bronchitis. PMID- 23447045 TI - Synthesis and biological evaluation of a novel series of pyrazolylcoumarins as anti-inflammatory and antioxidant agents. AB - A new series of pyrazolylcoumarins (4a-k) was synthesized by reaction of appropriate dibromochalcones (3a-k) with phenyl hydrazine in ethanol. Structures of all new synthesized compounds were characterized on the basis of elemental analysis and spectral data (UV, IR and 1H NMR). The title compounds were screened for in vivo anti-inflammatory activities at a dose of 200 mg/kg b.w. Among the 11 prepared compounds, Compounds 4c, d, h and i exhibited significant anti inflammatory activity in model of acute inflammation such as carrageenan-induced rat edema paw while compound 4d showed considerable activity in model of chronic inflammation such as adjuvant-induced arthritis along with minimum ulcerogenic index and were compared with diclofenac (13.5 mg/kg b.w.) as a standard drug. Additionally, the synthesized compounds were evaluated for their in vitro antioxidant activity. Compound 4k was found to be the most active antioxidant in the series compared with standard vitamin C. PMID- 23447046 TI - Enantioselective disposition after single dose I.V administration of ketorolac in male Wistar rats. AB - Ketorolac, a commonly used anti-inflammatory and analgesic agent, was studied in male wistar rats. The plasma samples were analysed using chiral AGP column with UV detection. The experimental data was analysed for probable fit in the compartmental and non-compartmental models using WinNolin software. The data of (+)-R-Ketorolac and (-)-S-Ketorolac was found to fit into the compartmental as well as non compartmental model. There was a difference between the plasma concentrations of (+)-R-Ketorolac and (-)-S-Ketorolac; the plasma concentrations of (+)-R-Ketorolac were higher than those of (-)-S-Ketorolac throughout the time course of the study. The area under the curve (AUC) of time vs. concentration profile of (+)-R-Ketorolac was found to be higher than (-)-S-Ketorolac. Volume of distribution and clearance was found to be higher for (-)-S-Ketorolac. PMID- 23447047 TI - A more rapid, sensitive, and specific HPLC-MS/MS method for nifedipine analysis in human plasma and application to a pharmacokinetic study. AB - A more rapid, sensitive and specific high-performance liquid chromatography coupled to -tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the quantification of nifedipine in human plasma, and applied to the pharmacokinetic study of nifedipine in Chinese healthy volunteers. Nifedipine and internal standard (IS) acetaminophen in plasma were extracted with ethyl acetate, separated on a C18 (150 mm*4.6 mm, 5 um) reversed-phase column, eluted with acetonitrile mixed with 5 mM ammonium acetate solution (pH=6.62) (60:40, v/v), ionized by negative ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor->product ions of m/z 354.1->222.2 for nifedipine and 150.1->107.1 for the IS. A single oral dose of 20 mg nifedipine sustained release tablets and blood samples (4 mL) was collected before and 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, and 36 h after administration. The main pharmacokinetic parameters of nifedipine, as Tmax, t1/2alpha, t1/2beta, t1/2z, Cmax, AUC0~36, AUC0~infinity were 2.80+/-0.50 h, 6.78+/-2.52 h, 6.82+/-2.53 h, 6.69+/-2.22 h, 76.69+/-19.51 (ng/mL), 546.49+/ 162.28 (ng . h/mL) and 564.05+/-176.74 (ng . h/mL), respectively. The calibration curve was linear over the concentration range of 0.17-102 ng/mL (r2>0.99, n=5) with a lower limit of quantification (LLOQ) of 0.17 ng/mL. The intra- and inter day precision was less than 15% for all quality control samples at concentrations of 0.42, 6.53 and 81.60 ng/mL and the accuracy (relative error, RE) was - 3.92% to 7.31% at 3 quality control levels. The specificity, matrix effect, recovery, sensitivity, linearity, accuracy, precision and stabilities were validated, and can fulfill the requirement of pharmacokinetic study of nifedipine sustained release tablets in Chinese volunteers. PMID- 23447048 TI - Synthesis of 2,4-dihydroxychalcone derivatives as potential antidepressant effect. AB - In this study, twelve 2,4-dihydroxychalcone derivatives were synthesized and evaluated for antidepressant activities using the forced swimming test (FST). The pharmacological test showed that 6 compounds significantly reduced the immobility times in the FST at a dose of 10 mg/kg, indicative of antidepressant activity. Among the derivatives, compounds designated 3d and 3 h exhibited the best antidepressant activity, with reduced immobility time by 32.05% and 34.33%, respectively. In the 5-hydroxytryptophan-induced head-twitch test and yohimbine induced mortality test, compounds 3d and 3 h increased head-twitch and increased the mortality rate. The mechanisms of the antidepressant effects of compounds 3d and 3 h may be related with the 5-HTP and NE nervous system. PMID- 23447049 TI - Growth inhibition effect of peptide P110 plus cisplatin on various cancer cells and xenotransplanted tumors in mice. AB - The combined use of currently used anticancer genotoxins with other drugs is a therapeutic tool for potentially increasing the efficacy of the genotoxins. In the present study, the effects of a RasGAP-derived peptide, P110 (RasGAP301-316), designed to target Ras-GTPase activating protein SH3 domain-binding proteins (G3BPs), on the chemotherapeutic agent, cisplatin (DDP), were examined. P110 was demonstrated to enhance the effect of DPP in vitro and in vivo. The results indicate that P110 significantly increased the DDP-induced apoptosis in SGC-7901, HCT-116, HeLa and A-549 cells. Furthermore, P110 combined with DDP significantly suppressed the growth of C26 xenograft tumors in a dose-dependent manner. This synergistic effect may be associated with DDP-induced apoptosis, involving the downregulation of Bcl-2 and the upregulation of Bax, cytochrome c and caspase-3. The results of the present study indicate that P110, in combination with chemotherapeutics, is likely to represent a potential therapeutic strategy for cancer. PMID- 23447051 TI - The transurethral seminal vesiculoscopy in the diagnosis and treatment of the seminal vesicle disease. AB - To develop a transurethral endoscopy technique of the transurethral seminal vesiculoscopy to examine and treat seminal vesicle disease. A total of 61 patients with seminal vesicle disease were diagnosed and treated with the transurethral seminal vesiculoscopy through the distal seminal tracts and vesicles. 58 cases were successfully treated using transurethral seminal vesiculoscopy via the seminal vesicles. The operation took 25 ~ 85 min, with an average of (35.6) mins. In this group, seven cases were diagnosed as ejaculatory orifice cyst, 14 cases had blood clots in the seminal vesicles, and nine patients had stones in the seminal vesicles. All patients were treated properly. Follow-up occurred at 3 months, with two cases showing post-operative discomfort in perineal region. One patient had recurrence with seminal vesiculitis, which improved with treatment. Four infertile patients had a significant increase in sperm count and ejaculation volume and two of these patients were able to naturally inseminate within seven to 18 months post-surgery. This approach enables a new endoscopic technique with the transurethral seminal vesiculoscopy to diagnose and treat seminal vesicle disease through the normal anatomic pathway which can be easily performed with few post-operative complications. PMID- 23447052 TI - Recent advances and safety issues of transgenic plant-derived vaccines. AB - Transgenic plant-derived vaccines comprise a new type of bioreactor that combines plant genetic engineering technology with an organism's immunological response. This combination can be considered as a bioreactor that is produced by introducing foreign genes into plants that elicit special immunogenicity when introduced into animals or human beings. In comparison with traditional vaccines, plant vaccines have some significant advantages, such as low cost, greater safety, and greater effectiveness. In a number of recent studies, antigen specific proteins have been successfully expressed in various plant tissues and have even been tested in animals and human beings. Therefore, edible vaccines of transgenic plants have a bright future. This review begins with a discussion of the immune mechanism and expression systems for transgenic plant vaccines. Then, current advances in different transgenic plant vaccines will be analyzed, including vaccines against pathogenic viruses, bacteria, and eukaryotic parasites. In view of the low expression levels for antigens in plants, high level expression strategies of foreign protein in transgenic plants are recommended. Finally, the existing safety problems in transgenic plant vaccines were put forward will be discussed along with a number of appropriate solutions that will hopefully lead to future clinical application of edible plant vaccines. PMID- 23447050 TI - A global approach to analysis and interpretation of metabolic data for plant natural product discovery. AB - Discovering molecular components and their functionality is key to the development of hypotheses concerning the organization and regulation of metabolic networks. The iterative experimental testing of such hypotheses is the trajectory that can ultimately enable accurate computational modelling and prediction of metabolic outcomes. This information can be particularly important for understanding the biology of natural products, whose metabolism itself is often only poorly defined. Here, we describe factors that must be in place to optimize the use of metabolomics in predictive biology. A key to achieving this vision is a collection of accurate time-resolved and spatially defined metabolite abundance data and associated metadata. One formidable challenge associated with metabolite profiling is the complexity and analytical limits associated with comprehensively determining the metabolome of an organism. Further, for metabolomics data to be efficiently used by the research community, it must be curated in publicly available metabolomics databases. Such databases require clear, consistent formats, easy access to data and metadata, data download, and accessible computational tools to integrate genome system-scale datasets. Although transcriptomics and proteomics integrate the linear predictive power of the genome, the metabolome represents the nonlinear, final biochemical products of the genome, which results from the intricate system(s) that regulate genome expression. For example, the relationship of metabolomics data to the metabolic network is confounded by redundant connections between metabolites and gene products. However, connections among metabolites are predictable through the rules of chemistry. Therefore, enhancing the ability to integrate the metabolome with anchor-points in the transcriptome and proteome will enhance the predictive power of genomics data. We detail a public database repository for metabolomics, tools and approaches for statistical analysis of metabolomics data, and methods for integrating these datasets with transcriptomic data to create hypotheses concerning specialized metabolisms that generate the diversity in natural product chemistry. We discuss the importance of close collaborations among biologists, chemists, computer scientists and statisticians throughout the development of such integrated metabolism-centric databases and software. PMID- 23447053 TI - The "onco-functional balance" in surgery for diffuse low-grade glioma: integrating the extent of resection with quality of life. AB - Diffuse low-grade glioma (DLGG) is a growing pre-cancerous tumor, often diagnosed in patients with no or only mild deficit. Maximal and early surgical resection is currently the first therapeutic option, in order to delay the malignant transformation and thus increase the overall survival. Preserving the quality of life (QoL) is nonetheless another priority. Here, our purpose is to weight the value of the extent of resection versus the neurological worsening that could be voluntarily generated by a radical resection; that is, to study the "onco functional balance" at the individual level. To this end, we will examine DLGG involving the supplementary motor area and DLGG involving visual pathways. We will consider the benefit-risk ratio of different strategies of resection, according to the brain structures actually invaded and their plastic potential. The aim is to increase both the quantity of life and the time with a normal QoL, on the basis of strong interactions between the tumor course, brain reorganization and multistage surgical approach adapted to each patient over time. To this end, beyond the conceptual and technical issues, the most important point remains the honest and unique relationship between the surgical oncologist and the patient, based on clear and complete information about the behavior of DLGG versus the expected medical and social consequences of a resection over years. In other words, in the era of "evidence-based medicine", it is crucial to not forget "individual-based medicine" by offering tailored resections adapted to each patient. PMID- 23447054 TI - Development of a short measure of psychological recovery in serious mental illness: the STORI-30. AB - OBJECTIVE: To develop a brief measure of stage of psychological recovery from mental illness by identifying the best-performing items of the 50-item Stages of Recovery Instrument (STORI). METHOD: Item response modelling was used to identify a short form of the full-length STORI. The resulting items were subjected to factor analysis to further refine the subscales. A second data set was used to confirm the construct validity of the new measure. A correlational analysis was conducted to examine relationships among the five subscale scores. RESULTS: Analyses identified 30 items that represented the five stages of the full STORI. The five stage subscale scores of the shorter measure, the STORI-30, showed a pattern of correlations that demonstrated an ordinal relationship between the stages. CONCLUSIONS: There is a need for recovery-oriented measures to augment established clinical assessment tools. The shorter version of the STORI, the STORI-30, shows promise as a brief measure of stage of recovery, more feasible for routine clinical use. Further psychometric and longitudinal testing is recommended. Qualitative research would be valuable in establishing acceptability to consumers and the clinical usefulness of the STORI-30. PMID- 23447055 TI - In vivo investigation of restricted diffusion in the human brain with optimized oscillating diffusion gradient encoding. AB - PURPOSE: Previous studies in phantoms and animals using animal MR systems have shown promising results in using oscillating gradient spin echo (OGSE) diffusion acquisition to depict microstructure information. The OGSE approach has also been shown to be a sensitive biomarker of tumor treatment response and white matter related diseases. Translating these studies to a human MR scanner faces multiple challenges due to the much weaker gradient system. The goals of this study are to optimize the OGSE acquisition for a human MR system and investigate its applicability in the in vivo human brain. METHODS: An analytical analysis of the OGSE modulation spectrum was provided. Based on this analysis and thorough simulation experiments, the OGSE acquisition was optimized in terms of diffusion waveform shape, waveform timing, and sequence timing-to achieve higher diffusion sensitivity and better sampling of the diffusion spectrum. RESULTS: The trapezoid cosine waveform was found to be the optimal OGSE waveform. At the three employed peak encoding frequencies of 18 Hz, 44 Hz, and 63 Hz, the waveform polarity for the least blurry sampling of the diffusion spectrum was 90+/180-, 90+/180+, and 90+/180+, respectively. For the highest diffusion-to-noise ratio at 63 Hz, the b value was 200 s/mm(2) and the echo time was 116 ms. Using the optimized sequence, a frequency dependence of the measured apparent diffusion coefficients was observed in white matter-dominant regions such as the corpus callosum. CONCLUSION: The obtained results demonstrate, for the first time, the potential of using an OGSE acquisition for investigating microstructure information on a human MR system. PMID- 23447056 TI - Gene expression levels of cytokines in peripheral blood mononuclear cells from patients with pulmonary embolism. AB - The aim of this study was to investigate the differential gene expression of cytokines in peripheral blood mononuclear cells (PBMCs) from patients with pulmonary embolism (PE) and controls. Twenty patients with PE and twenty control patients matched for gender and age with the PE group were recruited into the study. Human cDNA microarray analysis was used to detect differences in the expression of cytokine-associated genes between the two groups. In PE patients, the expression levels of the genes encoding IFNalpha5, IFNalpha6, IFNalpha8, IFNalpha14, IFNkappa, IFNomega1, IFNepsilon1 and IFNgamma were significantly lower compared with controls (P<0.05). The expression levels of the genes encoding IL1alpha, IL2, IL3, IL9, IL13, IL17beta, IL19, IL22, IL23alpha, IL24, IL25 and IL31 were significantly lower (P<0.05), while IL10 and IL28A mRNA expression levels were higher in PE patients compared with controls (P<0.05). In PE patients, Cxcl1, Cxcl2, Cxcl6, Cxcl13 and Cxcl14 mRNAs were significantly upregulated (P<0.05), however, Cxcl10 mRNA was significantly downregulated (P<0.01). In PE patients, the mRNA expression levels of TNF superfamily members 1, 9 and 13, and TNF receptor superfamily members 1A, 1B, 9, 10B, 10C, 10D and 19L, were significantly upregulated (P<0.05), whereas TNF receptor superfamily members 11B, 19 and 25 were significantly downregulated compared with controls (P<0.05). The mRNA expression levels of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, thrombopoietin and mast cell growth factor were significantly lower in PE patients compared with controls (P<0.05). In PE patients, the mRNA expression levels of a variety of cytokines were imbalanced and cellular immune function was downregulated compared with controls. Thus, PE patients may be more susceptible to infections caused by viruses, intracellular bacteria and parasites. PMID- 23447057 TI - Mechanism of the DL-alpha-aminoadipic acid inhibitory effect on form-deprived myopia in guinea pig. AB - AIM: To investigate the effect of intravitreal injection of DL-alpha-aminoadipic acid (DL-alpha-AAA) on ocular refractive state and retinal dopamine, transforming growth factor-beta2 (TGFbeta2), vasoactive intestinal polypeptide (VIP) in guinea pig form-deprived myopia. METHODS: Four-week-old pigmented guinea pigs were randomly assigned to 4 groups: normal control, deprivation, deprivation plus DL alpha-AAA, deprivation plus saline. Form deprivation was induced with the self made translucent eye shields, and lasted for 14 days. 8ug DL-alpha-AAA was injected into the vitreous chamber of deprived eyes. The corneal radius of curvature, refraction and axial length were measured. Retinal dopamine content was evaluated by the high-performance liquid chromatography with electrochemical detection, and TGFbeta2 and VIP protein were detected by Western blotting. RESULTS: Fourteen days of eye occlusion caused the axial length to elongate and become myopic in the form-deprived eyes, with the decrease of retinal dopamine and the increase of TGFbeta2 and vasoactive intestinal polypeptide (VIP) protein. Intravitreal injection of DL-alpha-AAA could inhibit the myopic shift from ( 3.65+/-1.06)D to (-1.48+/-0.63)D, P<0.01 due to goggles occluding and cause the decrease of retinal TGFbeta2 protein in the deprived eyes. However, intravitreal injection of DL-alpha-AAA had no significant effect on retinal dopamine and VIP protein in deprived eyes. Retinal TGFbeta2 protein correlated highly with the ocular refraction (y=-3.34+0.31/x, F=74.75, P<0.001) and axial length (y=8.39 0.02/x, F=48.32, P<0.001) in different treatment groups. CONCLUSION: Intravitreal injection of DL-alpha-AAA is effectively able to suppress the development of form deprivation myopia, which may be associated with retinal TGFbeta2 protein in guinea pigs. PMID- 23447058 TI - Emergency department services use among immigrant and non-immigrant groups in the United States. AB - Immigrants have disproportionate lack of access to healthcare and insurance. Emergency departments could serve as a healthcare substitute and increased demand can negatively affect the US emergency services system. Medical Expenditures Panel Survey (2000-2008) data was modeled to compare emergency departments (ED) use between non-citizens, foreign-born (naturalized), and US-born citizens. Group differences were assessed using non-linear decomposition techniques. Non-citizens were less likely to use ED services (8.7 %) compared to naturalized immigrants (10.6 %) and US-born Americans (14.7 %). Differences in ED use persisted after adjusting for the Behavioral Model covariates. Healthcare need and insurance partially explained the differences in ED use between the groups. Between 2000 and 2008 non-citizen immigrants used markedly less ED services compared to US citizens, regardless of their nation of origin. We also found that demographic and healthcare need profiles contributed to the divergence in use patterns between groups. A less restrictive healthcare policy environment can potentially contribute to lower population disease burden and greater efficiencies in the US health care system. PMID- 23447059 TI - Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature. AB - In Western countries, thrombotic risk factors for Budd-Chiari syndrome (BCS) are very common, including factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, etc. However, the data regarding thrombotic risk factors in Chinese BCS patients are extremely limited. An observational study was conducted to examine this issue. A total of 246 BCS patients who were consecutively admitted to our department between July 1999 and December 2011 were invited to be examined for thrombotic risk factors. Of these, 169 patients were enrolled. Neither factor V Leiden mutation nor prothrombin G20210A mutation was found in any of 136 patients tested. JAK2 V617F mutation was positive in four of 169 patients tested. Neither MPL W515L/K mutation nor JAK2 exon 12 mutation was found in any of 135 patients tested. Overt myeloproliferative neoplasms were diagnosed in five patients (polycythemia vera, n=3; essential thrombocythemia, n=1; idiopathic myelofibrosis, n=1). Two of them had positive JAK2 V617F mutation. Both CD55 and CD59 deficiencies were found in one of 166 patients tested. This patient had a previous history of paroxysmal nocturnal haemo-globinuria before BCS. Anticardiolipin IgG antibodies were positive or weakly positive in six of 166 patients tested. Hyperhomocysteinaemia was found in 64 of 128 patients tested. 5,10-methylenetetrahydrofolate reductase C677T mutation was found in 96 of 135 patients tested. In conclusion, factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, and paroxysmal nocturnal haemoglobinuria are very rare in Chinese BCS patients, suggesting that the etiological distribution of BCS might be different between Western countries and China. PMID- 23447060 TI - Development of metabolic function biomarkers in the common marmoset, Callithrix jacchus. AB - Metabolic assessment of a non-human primate model of metabolic syndrome and obesity requires the necessary biomarkers specific to the species. While the rhesus monkey has a number of specific assays for assessing metabolic syndrome, the marmoset does not. Furthermore, the common marmoset (Callithrix jacchus) has a small blood volume that necessitates using a single blood volume for multiple analyses. The common marmoset holds a great potential as an alternative primate model for the study of human disease but assay methods need to be developed and validated for the biomarkers of metabolic syndrome. Here we report on the adaptation, development, and validation of commercially available immunoassays for common marmoset samples in small volumes. We have performed biological validations for insulin, adiponectin, leptin, and ghrelin to demonstrate the use of these biomarkers in examining metabolic syndrome and other related diseases in the common marmoset. PMID- 23447061 TI - Viable herpes simplex virus type 1 and varicella-zoster virus in the trigeminal ganglia of human cadavers. AB - Human herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) were isolated in the bilateral trigeminal ganglia of 12 human cadavers with no history of herpes-related symptoms within 1-5 days of death. Sixteen trigeminal ganglia were subjected to explant culture by using Vero cells, but no cytopathogenic effects (CPE) were observed. However, when another eight trigeminal ganglia were placed in a cell strainer and kept from direct contact with Vero cells during culture, CPE were clearly apparent in all cultures. The amount of DNA in the culture supernatants of 16 trigeminal ganglia decreased over time; 12 and 9 of these samples were PCR-positive for HSV-1 and VZV, respectively. In new Vero cells inoculated with supernatants collected 2 days after culture initiation, immunofluorescence staining revealed HSV-1 and VZV in 6 and 5 of 8 trigeminal ganglia, respectively. HSV-1 and VZV DNA was detected in supernatants collected 3 and 7 days after culture initiation and in Vero cells collected after culture completion, but real-time PCR revealed the DNA amounts decreased over time. There was less VZV DNA than HSV-1 DNA. These results demonstrate that infective HSV-1 and VZV can be isolated in culture, and confirm that viable HSV-1 and VZV persist in human trigeminal ganglia for some time after death. PMID- 23447062 TI - The GFR and GFR decline cannot be accurately estimated in type 2 diabetics. AB - There are no adequate studies that have formally tested the performance of different estimating formulas in patients with type 2 diabetes both with and without overt nephropathy. Here we evaluated the agreement between baseline GFRs, GFR changes at month 6, and long-term GFR decline measured by iohexol plasma clearance or estimated by 15 creatinine-based formulas in 600 type 2 diabetics followed for a median of 4.0 years. Ninety patients were hyperfiltering. The number of those identified by estimation formulas ranged from 0 to 24:58 were not identified by any formula. Baseline GFR was significantly underestimated and a 6 month GFR reduction was missed in hyperfiltering patients. Long-term GFR decline was also underestimated by all formulas in the whole study group and in hyper-, normo-, and hypofiltering patients considered separately. Five formulas generated positive slopes in hyperfiltering patients. Baseline concordance correlation coefficients and total deviation indexes ranged from 32.1% to 92.6% and from 0.21 to 0.53, respectively. Concordance correlation coefficients between estimated and measured long-term GFR decline ranged from -0.21 to 0.35. The agreement between estimated and measured values was also poor within each subgroup considered separately. Thus, our study questions the use of any estimation formula to identify hyperfiltering patients and monitor renal disease progression and response to treatment in type 2 diabetics without overt nephropathy. PMID- 23447063 TI - Albuminuria is associated with too few glomeruli and too much testosterone. AB - Normally, the glomerular filtration barrier almost completely excludes circulating albumin from entering the urine. Genetic variation and both pre- and postnatal environmental factors may affect albuminuria in humans. Here we determine whether glomerular gene expression in mouse strains with naturally occurring variations in albuminuria would allow identification of proteins deregulated in relatively 'leaky' glomeruli. Albuminuria increased in female B6 to male B6 to female FVB/N to male FVB/N mice, whereas the number of glomeruli/kidney was the exact opposite. Testosterone administration led to increased albuminuria in female B6 but not female FVB/N mice. A common set of 39 genes, many expressed in podocytes, were significantly differentially expressed in each of the four comparisons: male versus female B6 mice, male versus female FVB/N mice, male FVB/N versus male B6 mice, and female FVB/N versus female B6 mice. The transcripts encoded proteins involved in oxidation/reduction reactions, ion transport, and enzymes involved in detoxification. These proteins may represent novel biomarkers and even therapeutic targets for early kidney and cardiovascular disease. PMID- 23447064 TI - Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. AB - In this study, we measured soluble urokinase receptor levels, a possible permeability factor, in the plasma of patients with primary focal segmental glomerulosclerosis (FSGS) and determined their association with clinical and pathological data in 74 patients with primary FSGS. Healthy donors and patients with minimal change disease, membranous nephropathy, and secondary FSGS were used as controls. The plasma-soluble urokinase receptor levels, measured by commercial ELISA kits, of patients with primary FSGS (median: 2923, interquartile range 2205 4360 pg/ml) were significantly higher than those of patients with minimal change disease (median 2050 pg/ml), membranous nephropathy (median 2029 pg/ml), and normal individuals (median 1739 pg/ml). There was no significant difference in plasma-soluble urokinase receptor levels between the 74 patients with primary and 14 patients with secondary FSGS. The soluble urokinase receptor levels increased in the order of tip variant, to a not otherwise specified variant and a cellular variant. The soluble urokinase receptor levels were significantly but negatively correlated with creatinine clearance at presentation but positively correlated with crescent formation in patients with primary FSGS. During follow-up, receptor levels decreased significantly in patients with complete remission. Thus, plasma soluble urokinase receptor levels did not differentiate primary and secondary FSGS, and although significantly elevated in FSGS, they showed considerable overlap with other glomerular diseases. PMID- 23447065 TI - Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss. AB - Collapsing focal segmental glomerulosclerosis (cFSGS) is a progressive kidney disease characterized by glomerular collapse with epithelial hyperplasia. Here we used a transgenic mouse model of cFSGS with immunotoxin-induced podocyte-specific injury to determine the role for Notch signaling in its pathogenesis. The mice exhibited progressive loss of podocytes and severe proteinuria concomitant with histological features of cFSGS. Hyperplastic epithelium was negative for genetic podocyte tags, but positive for the parietal epithelial cell marker claudin-1, and expressed Notch1, Jagged1, and Hes1 mRNA and protein. Enhanced Notch mRNA expression induced by transforming growth factor-beta1 in cultured parietal epithelial cells was associated with mesenchymal markers (alpha-smooth muscle actin, vimentin, and Snail1). Notch inhibition in vitro suppressed these phenotypic transcripts and Notch-dependent cell migration. Moreover, Notch inhibition in vivo significantly decreased parietal epithelial cell lesions but worsened proteinuria and histopathology in our cFSGS model. Thus, aberrant Notch1 mediated parietal epithelial cell migration with phenotypic changes appears to underlie the pathogenesis of cFSGS. Parietal epithelial cell hyperplasia may also represent an adaptive response to compensate for a disrupted filtration barrier with progressive podocyte loss. PMID- 23447067 TI - Research needs in the area of device-related treatments for hypertension. AB - Hypertension is the primary risk factor for cardiovascular and renal-disease endpoints. Medications help many patients but not all. Recently, two device related treatments have been introduced, catheter-based renal denervation and electrical carotid sinus stimulation. Remuneration for these treatments is guaranteed in many countries even though basic information is missing. We draw attention to deficiencies in the database. For catheter-based renal denervation, few large-animal data are available to investigate the effect of the intervention on the histology of the arterial wall. No functional data are available regarding re-innervation. For carotid sinus stimulation, the situation is similar. Acute activation of either treatment seems to reduce sympathetic tone dramatically. However, whether or not the effects are sustained over time is unknown. No 'end point' data are available for either treatment. Devices should be subjected to evidence-based standards before widespread introduction. PMID- 23447066 TI - Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production. AB - Netrin-1 regulates inflammation but the mechanism by which this occurs is unknown. Here we explore the role of netrin-1 in regulating the production of the prostanoid metabolite PGE2 from neutrophils in in vitro and in vivo disease models. Ischemia reperfusion in wild-type and RAG-1 knockout mice induced severe kidney injury that was associated with a large increase in neutrophil infiltration and COX-2 expression in the infiltrating leukocytes. Administration of netrin-1 suppressed COX-2 expression, PGE2 and thromboxane production, and neutrophil infiltration into the kidney. This was associated with reduced apoptosis, inflammatory cytokine and chemokine expression, and improved kidney function. Treatment with the PGE2 receptor EP4 agonist enhanced neutrophil infiltration and renal injury, which was not inhibited by netrin-1. Consistent with in vivo data, both LPS- and IFNgamma-induced inflammatory cytokine production in macrophages and IL-17-induced IFNgamma production in neutrophils were suppressed by netrin-1 in vitro by suppression of COX-2 expression. Moreover, netrin-1 regulates COX-2 expression at the transcriptional level through the regulation of NFkappaB activation. Thus, netrin-1 regulates the inflammatory response of neutrophils and macrophages through suppression of COX-2 mediated PGE2 production. This could be a potential drug for treating many inflammatory immune disorders. PMID- 23447070 TI - Chief executive officer: the need to be healthy. PMID- 23447068 TI - Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients. AB - In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients. PMID- 23447069 TI - Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. AB - A dietary potassium load induces a rapid kaliuresis and natriuresis, which may occur even before plasma potassium and aldosterone (aldo) levels increase. Here we sought to gain insight into underlying molecular mechanisms contributing to this response. After gastric gavage of 2% potassium, the plasma potassium concentrations rose rapidly (0.25 h), followed by a significant rise of plasma aldo (0.5 h) in mice. Enhanced urinary potassium and sodium excretion was detectable as early as spot urines could be collected (about 0.5 h). The functional changes were accompanied by a rapid and sustained (0.25-6 h) dephosphorylation of the NaCl cotransporter (NCC) and a late (6 h) upregulation of proteolytically activated epithelial sodium channels. The rapid effects on NCC were independent from the coadministered anion. NCC dephosphorylation was also aldo-independent, as indicated by experiments in aldo-deficient mice. The observed urinary sodium loss relates to NCC, as it was markedly diminished in NCC deficient mice. Thus, downregulation of NCC likely explains the natriuretic effect of an acute oral potassium load in mice. This may improve renal potassium excretion by increasing the amount of intraluminal sodium that can be exchanged against potassium in the aldo-sensitive distal nephron. PMID- 23447071 TI - Harmful drinking and experiences of alcohol-related violence in Australian male construction industry apprentices. AB - This study sought to understand the prevalence of harmful alcohol use in a sample of Australian male construction industry apprentices and also examine alcohol related violence. Although previous Australian research indicated that 45% of construction industry apprentices had Alcohol Use Disorders Identification Test scores indicative of harmful drinking, the current study identified that 66% of construction industry apprentices were drinking at harmful levels. It also identified positive correlations between harmful drinking behavior and alcohol related violence (and precursors of violence such as verbal abuse). The article notes the role of masculine identity in alcohol consumption, particularly as it relates to the male-dominated construction industry. The article concludes by making recommendations for implementation of preventative education campaigns in apprentices' workplaces (or in training colleges), as it provides opportune settings to focus on high-risk groups, which are otherwise often difficult to access. PMID- 23447072 TI - Metabolic differences in microbial cell populations revealed by nanophotonic ionization. PMID- 23447073 TI - Occupational exposure to trichloroethylene and perchloroethylene and the risk of lymphoma, liver, and kidney cancer in four Nordic countries. AB - OBJECTIVES: Trichloroethylene (TCE) and Perchloroethylene (PER) are two chlorinated solvents that are applied widely as degreasers of metal parts, and in dry cleaning and other applications. In 2012, the International Agency for Research on Cancer classified TCE as carcinogenic to humans and PER as probably carcinogenic to humans. We explored exposure-response relations for TCE and PER and non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and cancers of the kidney and liver in the Nordic Occupational Cancer cohort. METHODS: The cohort was set up by linking occupational information from censuses to national cancer registry data using personal identity codes in use in all Nordic countries. Country, time period, and job-specific exposure estimates were generated for TCE, PER and potentially confounding occupational exposures with a job-exposure matrix. A conditional logistic regression was conducted for exposure groups as well as for continuous cumulative exposure. RESULTS: HRs for liver cancer, NHL and MM but not kidney cancer were slightly elevated in groups with high exposure to PER (compared to occupationally unexposed subjects). HRs for liver cancer and NHL also increased with increasing continuous exposure to PER. We did not observe evidence for an association between exposure to TCE and NHL, MM or liver and kidney cancer. CONCLUSIONS: Although this study was subject to limitations related to the low prevalence of exposure to PER and TCE in the Nordic population and a limited exposure assessment strategy, we observed some evidence indicative of an excess risk of cancer of the liver and NHL in subjects exposed to PER. PMID- 23447074 TI - Preparation and evaluation of sustained release calcium alginate beads and matrix tablets of acetazolamide. AB - The aim of this study was to develop sustained release dosage forms of acetazolamide (ACZ) preparing its calcium alginate beads and matrix tablets. ACZ was incorporated into calcium alginate beads using microencapsulation method. Two methods were applied to prolong ACZ release rate. In the first method, the drug was incorporated into calcium alginate beads either alone or with various polymers in internal phase. The second method involved the preparation of matrix tablet from the beads benefiting direct compression method with or without various polymers in external phase. The release rate of these prepared formulations and an innovator's sustained-release capsule (Diamox(r)) were assessed. In-vitro dissolution studies revealed that the matrix tablets prepared by the second method containing NaCMC could sustain ACZ release properly and the drug released until 9 h. It was also found that several parameters such as concentration of sodium alginate, calcium chloride and ACZ; type and concentration of polymers; syringe needle size as well as distance between needle tip and surface of the calcium chloride could affect the properties of beads, matrix tablets and subsequently release profile. Preparation of polymer free beads, incorporation of polymers in internal phase of the beads and direct compression of the beads did not give sustained release property. Whereas, incorporation of NaCMC in the external phase of the beads in matrix tablets or in combination with alginate powder in directly compressed conventional tablets could produce dosage form with sustained release property similar to reference formulation. PMID- 23447075 TI - Broad spectrum antibacterial activity of a mixture of isothiocyanates from nasturtium (Tropaeoli majoris herba) and horseradish (Armoraciae rusticanae radix). AB - Isothiocyanates have been reported to exert antimicrobial activity. These compounds are found in a licensed native preparation of nasturtium (Tropaeoli majoris herba) and horseradish (Armoraciae rusticanae radix) which is used for treatment of upper respiratory and urinary tract infections. The aim of our investigation was to assess the antimicrobial activity of a mixture of the contained benzyl-, allyl-, and phenylethyl- isothiocyanates against clinically important bacterial and fungal pathogens including antimicrobial resistant isolates. Susceptibility testing was performed by agar-dilution technique. Isothiocyanates were mixed in proportions identical to the licensed drug. Minimum inhibitory- and minimum bactericidal concentrations were assessed. The Minimum inhibitory concentration90 was defined as the concentration which inhibited 90% of the microbial species tested. H. influenzae, M. catarrhalis, S. marcescens, P. vulgaris, and Candida spp. were found to be highly susceptible, with minimum inhibitory concentration90 -values ranging between <=0.0005% and 0.004% (v/v) of total ITC. Intermediate susceptibilities were observed for S. aureus, S. pyogenes, S. pneumoniae, K. pneumoniae, E. coli and P. aeruginosa, with Minimum inhibitory concentration90 -values ranging between 0.004% and 0.125% (v/v), but with elevated Minimum bactericidal concentrations90-values (2-7 dilution steps above Minimum inhibitory concentration90). Low susceptibilities were determined for viridans streptococci and enterococci. Interestingly, both resistant and non resistant bacteria were similarly susceptible to the test preparation. PMID- 23447076 TI - A simple and sensitive LC-MS/MS method for quantitation of peimine and its pharmacokinetic in beagle dogs. AB - A simple LC-MS/MS method was developed for determination and pharmacokinetic study of peimine in beagle dogs. The chromatographic separation was carried out on a Agilent Zobax SB C18 column with a mobile phase consisting of acetonitrile 10 mmol/L ammonium formate (35:65, v/v) at a flow rate of 0.3 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by MRM via electro spray ionization source with positive mode. The standard curve for peimine was linear (r>0.999) over the concentration range of 1-200 ng/mL with a lower limit of quantification of 1 ng/mL. The intra- and inter-day precision (relative standard deviation) values were not higher than 15% and the accuracy (relative error) was <5% at 3 quality control levels. This simple, fast and highly sensitive method was fully validated and successfully applied to a preclinical pharmacokinetic study of peimine in dogs after oral and intravenous administration. PMID- 23447077 TI - Bioequivalence and pharmacokinetic evaluation of two tablet formulations of carvedilol 25-mg: a single-dose, randomized-sequence, open-label, two-way crossover study in healthy Chinese male volunteers. AB - BACKGROUND: Carvedilol is a nonselective-blocking agent and is used in the treatment of hypertension and angina pectoris. OBJECTIVE: The aim of this study was to evaluate bioequivalence of two 25-mg tablet formulations of carvedilol following single oral dose in adult male volunteers. METHODS: This was a randomized, single-dose, open-label, crossover bioequivalence study. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 h after dosing. Plasma concentrations of Carvedilol were determined by using a validated LC-MS/MS method. Statistical analysis of the pharmacokinetic parameters Cmax, AUC0-24, and AUC0-infinity was conducted to determine bioequivalence. METHODS: 23 healthy male Chinese volunteers were enrolled in the study. The mean (SD) Cmax, AUC0-24, and AUC0 infinity values after administration of the test and reference formulations, respectively, were as follows: 73.71 (34.04) vs. 78.93 (43.64) ng/mL, 285.1 (147.0) vs. 296.9 (176.1) ng/mL . h, and 296.5 (161.4) vs. 303.4 (177.9) ng/mL . h. The 90% CIs of the ratios (test vs. reference) for the ln-transformed Cmax, AUC0-24, and AUC0 - infinity were 85.3% to 114.3%, 90.4% to 107.6%, and 90.9% to 108.4%, respectively, meeting the criteria of SFDA, FDA and EMEA for bioequivalence. The relative bioavailability of the test formulation to reference formulation was 100.1%. Both formulations were generally well tolerated and no serious AEs were reported in the study. CONCLUSIONS: The 90% CIs for the ratios of mean Cmax, AUC0-24, and AUC0-infinity met the regulatory criteria for bioequivalence. PMID- 23447078 TI - Pharmacokinetics and bioequivalence evaluation of two acipimox tablets: a single dose, randomized-sequence, two-way crossover study in healthy Chinese male volunteers. AB - OBJECTIVE: The study was designed to compare the pharmacokinetic parameters and relative bioavailability of a newly generic acipimox 250-mg tablets (test formulation) with a branded 250-mg tablets (reference formulation). METHODS: A single-dose, randomized-sequence, 2-way crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Plasma samples were collected over 12 h after a single oral dose of 250-mg acipimox test or reference, followed by a 7-day washout period. Plasma concentrations of acipimox were analyzed by high-performance liquid chromatography. Drug And Statistical Version 2.0 was used to calculate the pharmacokinetic parameters and assess bioequivalence of the 2 formulations. It is considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-infinity are all within the range from 80% to 125%. RESULTS: No period, formulation, or sequence effects were observed on any pharmacokinetic parameters. The main pharmacokinetic parameters for the test and reference were as follows: t1/2 were 1.412+/-0.168 h and 1.390+/-0.162 h; Tmax were 1.850+/-0.462 h and 1.800+/-0.571 h; Cmax were 4.035+/-1.055 MUg . ml-1 and 3.858+/-0.986 MUg . ml-1; AUC0-12 were 14.006+/-2.564 MUg . ml-1 . h and 13.345+/-2.128 MUg . ml-1 . h, and the AUC0 infinity were 14.147+/-2.568 MUg . ml-1 . h and 13.486+/-2.117 MUg . ml-1 . h. The 90% CIs for the ratios (test/reference) of Cmax, AUC0-12, and AUC0 - infinity were 98.0-111.2%, 100.8-108.5%, and 100.8-108.3%, respectively. CONCLUSIONS: In this small study, a single 250-mg oral dose of an acipimox tablet (test formulation) is bioequivalent to the established reference formulation. PMID- 23447079 TI - Absorption, distribution and excretion of radioactivity by male rats after a single intravenous or subcutaneous dose of 14C-azacitidine. AB - The absorption, distribution and excretion of radioactivity were investigated in male Sprague-Dawley rats after a single intravenous or subcutaneous dose of 14C azacitidine. After subcutaneous administration, 14C-azacitidine was rapidly absorbed and the radioactivity was distributed to the tissues. The absorption of radioactivity after subcutaneous administration was 76.6% of that observed after intravenous administration. There were no marked differences in the tissue distribution of the radioactivity between administration routes. The concentrations of radioactivity in most tissues, including the spleen and bone marrow, which are sites of action of azacitidine, were higher than those in the plasma. Particularly high concentrations of radioactivity were detected in the spleen, kidney and liver. The accumulation of radioactivity in blood cells increased from 0.5 to 48 h. The binding of azacitidine to serum protein was low at <9%, and the cumulative urinary and fecal excretion of radioactivity for 168 h after intravenous or subcutaneous administration was >95% of the administered dose, indicating that radioactivity did not accumulate in the tissues. The radioactivity was mainly excreted in the urine. PMID- 23447080 TI - Effect of the treatment with alpha-macroglobulin on the development of experimental pancreatitis. AB - Alpha-macroglobulins are proteinase inhibitors. Monofluorophosphate increases alpha-macroglobulin levels in plasma, inducing a higher survival rate and lower pancreatic damage in rats with pancreatitis. The aim of this study was to evaluate the effect of alpha-macroglobulin on the development of pancreatitis. Pancreatitis was surgically induced in Sprague-Dawley rats divided into groups of 16 rats each and -subjected to the following intravenous treatments for 3 days: CONTROLS: pancreatitis without treatment, Enriched plasma: pancreatitis+-alpha macroglobulin-enriched plasma, Normal plasma: pancreatitis+plasma with normal levels of alpha-macroglobulin, Saline Solution: pancreatitis+saline solution, Purified alpha-macroglobulin: pancreatitis+purified alpha-macroglobulin. After 14 days pancreatic damage was assessed using a score that measures: edema, fibrin, neutrophils, mononuclear leukocytes, necrosis, vascular congestion, thrombosis, hemorrhage and fibrosis. Pancreatic damage decreased and the percentage of animals with pancreatitis was lower in enriched-plasma and purified alpha macroglobulin groups. We conclude that the intravenous administration of alpha macroglobulins causes a reduction in the histological damage produced by pancreatitis. PMID- 23447081 TI - Initial DNA interactions of the binuclear threading intercalator Lambda,Lambda [MU-bidppz(bipy)4Ru2]4+: an NMR study with [d(CGCGAATTCGCG)]2. AB - Binuclear polypyridine ruthenium compounds have been shown to slowly intercalate into DNA, following a fast initial binding on the DNA surface. For these compounds, intercalation requires threading of a bulky substituent, containing one Ru(II), through the DNA base-pair stack, and the accompanying DNA duplex distortions are much more severe than with intercalation of mononuclear compounds. Structural understanding of the process of intercalation may greatly gain from a characterisation of the initial interactions between binuclear Ru(II) compounds and DNA. We report a structural NMR study on the binuclear Ru(II) intercalator Lambda,Lambda-B (Lambda,Lambda-[MU-bidppz(bipy)4Ru2](4+); bidppz = 11,11'-bis(dipyrido[3,2-a:2',3'-c]phenazinyl, bipy = 2,2'-bipyridine) mixed with the palindromic DNA [d(CGCGAATTCGCG)]2. Threading of Lambda,Lambda-B depends on the presence and length of AT stretches in the DNA. Therefore, the latter was selected to promote initial binding, but due to the short stretch of AT base pairs, final intercalation is prevented. Structural calculations provide a model for the interaction: Lambda,Lambda-B is trapped in a well-defined surface-bound state consisting of an eccentric minor-groove binding. Most of the interaction enthalpy originates from electrostatic and van der Waals contacts, whereas intermolecular hydrogen bonds may help to define a unique position of Lambda,Lambda-B. Molecular dynamics simulations show that this minor-groove binding mode is stable on a nanosecond scale. To the best of our knowledge, this is the first structural study by NMR spectroscopy on a binuclear Ru compound bound to DNA. In the calculated structure, one of the positively charged Ru(2+) moieties is near the central AATT region; this is favourable in view of potential intercalation as observed by optical methods for DNA with longer AT stretches. Circular dichroism (CD) spectroscopy suggests that a similar binding geometry is formed in mixtures of Lambda,Lambda-B with natural calf thymus DNA. The present minor-groove binding mode is proposed to represent the initial surface interactions of binuclear Ru(II) compounds prior to intercalation into AT-rich DNA. PMID- 23447082 TI - In situ preparation of gold nanoparticle-loaded lysozyme-dextran nanogels and applications for cell imaging and drug delivery. AB - An effective, green, and facile approach to synthesize gold nanoparticle-loaded protein-polysaccharide nanogels was developed in this study. Biocompatible gold nanoparticle-loaded lysozyme-dextran (Au@Lys-Dex) nanogels were produced using lysozyme-dextran nanogels as reducing and stabilizing agents. Lysozyme-dextran nanogels have a size of about 200 nm and a structure of lysozyme core and dextran shell. At pH around 4, AuCl4(-) ions are attracted and locally enriched by lysozyme due to the electrostatic and coordination interactions. When the solution is under UV irradiation, the AuCl4(-) ions are reduced to gold nanoparticles in situ by solvated electrons and reactive radicals produced from aromatic amino acid residues in the lysozyme. The produced gold nanoparticles with a size of about 8 nm are trapped inside the nanogels and the Au@Lys-Dex nanogels are well dispersible by virtue of the dextran shell. Antitumor drug, doxorubicin, can be loaded effectively inside Au@Lys-Dex nanogels via diffusion. In vitro study demonstrates the doxorubicin loaded Au@Lys-Dex nanogels have the same antitumor activity as free doxorubicin. The nanogels can be used as a contrasting agent in optical cell imaging, in which direct visual images of the subcellular distributions of the gold nanoparticles and the released doxorubicin are presented synchronously. The dual functional drug loaded Au@Lys-Dex nanogels are a promising system for simultaneous drug delivery and biomedical imaging. PMID- 23447083 TI - Both chondroinduction and proliferation account for growth of cartilage nodules in mouse limb bud cultures. AB - High density micromass culture of limb bud mesenchymal stem cells isolated from mouse embryos represents a well-established model to study chondro- and osteogenesis. In spite of wide usage of the limb bud model, the mechanisms underlying cartilage nodule growth remain unclear. To determine whether cartilage nodules grow solely by induction of surrounding cells or proliferation of cells within the nodules, we performed BrdU/Collagen II (Col II) double-labelling and 3D reconstruction of growing cartilage nodules. We demonstrated that Col II positive replicating chondrocytes are present throughout the nodules with the majority of replicating cells localized on the top (cell-medium interface) and periphery/sides of nodules. Kinetic analysis of cellular proliferation within the nodules demonstrated the time-dependent reduction in number of Col II-positive replicating cells. The sequential expression of Col I, Col II, Col X, parathyroid hormone related peptide receptor 1 (Pthr1), bone sialoprotein (Bsp) and osteocalcin (Ocn) mRNAs was similar to that characterizing chondrocyte differentiation and maturation in vivo. We conclude that the limb bud model recapitulates events seen during endochondral bone formation: cellular aggregation, proliferation, differentiation and maturation to hypertrophy. We also conclude that not only induction of peri-nodular mesenchymal cells but also proliferation of chondrocytes within cartilage nodules contribute to cartilage nodule growth. PMID- 23447084 TI - Selective, sensitive, and rapid analysis with lateral-flow assays based on antibody-gated dye-delivery systems: the example of triacetone triperoxide. AB - Set them free: Brightly fluorescent indicators that are loaded into mesoporous silica nanoparticle carriers, capped with bulky antibodies, are released into the lateral flow of a test strip upon analyte arrival. Integration of the system into a rapid, simple flow test with fluorescence readout is applied for the selective and sensitive determination of the presence of triacetone triperoxide (TATP) as a prototype small-molecule analyte (see figure). PMID- 23447086 TI - Tailoring colloidal photonic crystals with wide viewing angles. AB - Photonic crystal materials are developed from colloidal crystal fibers or beads. As the fibers have cylindrical symmetry, the fiber-composed PhCs show anisotropic angle independence. By contrast, the bead-composed PhCs display angle-independent structural colors because of the spherical symmetry of their bead elements. PMID- 23447085 TI - Measuring stress before and during pregnancy: a review of population-based studies of obstetric outcomes. AB - Mounting evidence from clinic and convenience samples suggests that stress is an important predictor of adverse obstetric outcomes. Using a proposed theoretical framework, this review identified and synthesized the population-based literature on the measurement of stress prior to and during pregnancy in relation to obstetric outcomes. Population-based, peer-reviewed empirical articles that examined stress prior to or during pregnancy in relation to obstetric outcomes were identified in the PubMed and PsycInfo databases. Articles were evaluated to determine the domain(s) of stress (environmental, psychological, and/or biological), period(s) of stress (preconception and/or pregnancy), and strength of the association between stress and obstetric outcomes. Thirteen studies were evaluated. The identified studies were all conducted in developed countries. The majority of studies examined stress only during pregnancy (n = 10); three examined stress during both the preconception and pregnancy periods (n = 3). Most studies examined the environmental domain (e.g. life events) only (n = 9), two studies examined the psychological domain only, and two studies examined both. No study incorporated a biological measure of stress. Environmental stressors before and during pregnancy were associated with worse obstetric outcomes, although some conflicting findings exist. Few population-based studies have examined stress before or during pregnancy in relation to obstetric outcomes. Although considerable variation exists in the measurement of stress across studies, environmental stress increased the risk for poor obstetric outcomes. Additional work using a lifecourse approach is needed to fill the existing gaps in the literature and to develop a more comprehensive understanding of the mechanisms by which stress impacts obstetric outcomes. PMID- 23447087 TI - Does the molecular electrostatic potential reflect the effects of substituents in aromatic systems? AB - A detailed analysis of the molecular electrostatic potential (MEP) at selected positions in molecular space was performed for a series of substituted benzene derivatives. We show that appropriately selected MEP values can quantitatively reflect the regiospecific effects of substituents on the aromatic ring. Theoretically evaluated electrostatic potentials in close proximity to the ring carbon atoms reflect well both through-space and resonance effects and excellent correlation is established between the MEP values and substituent constants. The best descriptor of the local properties at different ring positions is the electrostatic potential at nuclei (EPN). PMID- 23447089 TI - Effect of food on the pharmacokinetics of rosuvastatin after administration of a single oral dose in dogs. AB - Rosuvastatin is a highly effective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used for the treatment of patients with hyperlipidemia. We examined the effect of food on the pharmacokinetics of rosuvastatin by administering it while fasting and after intake of low-fat and high-fat meals. We administered a single 10-mg oral dose of rosuvastatin while fasting and after intake of a low-fat and high-fat meal in a parallel design. The plasma concentrations of rosuvastatin were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), and the pharmacokinetics of rosuvastatin was analyzed using both noncompartmental and compartmental models. The values of area under the curve at 24 h (AUC 24 h ) and peak plasma concentration (C max) in fed conditions were significantly lower than the corresponding values in the fasting conditions. In addition, consumption of a high-fat meal significantly delayed the time required to achieve the maximum concentration (T max) of rosuvastatin. Both the models sufficiently explained the effect of food on the pharmacokinetics of rosuvastatin and showed that the volume of distribution (V c) was increased and absorption rate constant (K a) was decreased in fed dogs. These findings suggest that food intake affects both the rate and extent of absorption of rosuvastatin, and that rosuvastatin should be administered on an empty stomach to avoid food effect. PMID- 23447088 TI - Unique antimicrobial effects of platelet-rich plasma and its efficacy as a prophylaxis to prevent implant-associated spinal infection. AB - Platelet-rich-plasma (PRP) has attracted great attention and has been increasingly used for a variety of clinical applications including orthopedic surgeries, periodontal and oral surgeries, maxillofacial surgeries, plastic surgeries, and sports medicine. However, very little is known about the antimicrobial activities of PRP. PRP is found to have antimicrobial properties both in vitro and in vivo. In vitro, the antimicrobial properties of PRP are bacterial-strain-specific and time-specific: PRP significantly (80-100 fold reduction in colony-forming units) inhibits the growth of methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Group A streptococcus, and Neisseria gonorrhoeae within the first few hours but it has no significant antimicrobial properties against E. coli and Pseudomonas. The antimicrobial properties of PRP also depend on the concentration of thrombin. In vivo, an implant-associated spinal infection rabbit model is established and used to evaluate the antimicrobial and wound-healing properties of PRP. Compared to the infection controls, PRP treatment results in significant reduction in bacterial colonies in bone samples at all time points studied (i.e. 1, 2, and 3 weeks) and significant increase in mineralized tissues (thereby better bone healing) at postoperative weeks 2 and 3. PRP therefore may be a useful adjunct strategy against postoperative implant-associated infections. PMID- 23447090 TI - Cytotoxic activities of some novel benzhydrylpiperazine derivatives. AB - This study presents the synthesis of nineteen 1-(substitutedbenzoyl)-4 benzhydrylpiperazine and 1-[(substitutedphenyl)sulfonyl]-4-benzhydrylpiperazine derivatives. In vitro cytotoxic activities of the compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Among the test compounds, benzamide derivatives had high cytotoxic activity whereas sulfonamide derivatives showed variable 50% growth inhibition (GI50). PMID- 23447091 TI - CREB participates in the IGF-I-stimulation cyclin D1 transcription. AB - IGF-I stimulates proliferation and cell cycle progression in progenitor cells of a number of neural cell types, including neuronal and glial progenitors. The precise mechanisms of this regulation, however, have not been fully defined. To elucidate the mechanism of IGF-I actions on neural cell proliferation, we utilized a rat oligodendroglial cell line (OL-1) and primary oligodendrocyte precursors (OPC) and studied IGF-I regulation of cyclin D1 expression and its promoter activity, because cyclin D1 is critical to the promotion of cell proliferation and cell cycle progression. Transient transfection of a reporter driven by the rat cyclin D1 promoter showed that IGF-I stimulates cyclin D1 promoter activity. Furthermore, 5'-end deletions and mutation analysis of this promoter revealed that a cAMP response element (CRE) within -174 base pair (bp) upstream of the transcription start site is crucial to the IGF-induced increase in cyclin D1 transcription. Consistently, Western immunoblot analysis demonstrated that IGF-I induced CREB (CRE binding protein) phosphorylation, while ablation of CREB expression with small interfering RNAs (siRNA) blocked IGF-I actions on cyclin D1 mRNA expression and cell proliferation. Additionally, IGF-I stimulated CREB phosphorylation was blunted by the MAP kinase inhibitor, PD98059, but not by the PI3 kinase inhibitor, wortmannin. ChIP assays revealed that IGF-1 increased the association of CREB with the cyclin D1 promoter. Taken together, our data indicate that IGF-I upregulates cyclin D1 transcription partially by inducing CREB phosphorylation through the ERK-MAP kinase pathway, and thus increasing its recruitment to the cyclin D1 promoter. These results provide an important mechanism of IGF-I-induced glial cell growth and proliferation. (c) 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 559-570, 2013. PMID- 23447092 TI - Motor unit firing pattern of vastus lateralis muscle in type 2 diabetes mellitus patients. AB - INTRODUCTION: We investigated the motor unit (MU) firing pattern in type 2 diabetes mellitus (T2DM) patients by means of multichannel surface electromyography (SEMG). METHODS: Eight T2DM patients and 8 age-matched, healthy men performed a ramp-up contraction to 20% of maximal voluntary contraction (MVC). They also performed a sustained contraction at 10% of MVC during isometric knee extension. Multichannel SEMG signals recorded from the vastus lateralis muscle were decomposed with the convolution kernel compensation technique to extract individual MU firing patterns. RESULTS: During the ramp contraction, the extent of MU firing modulation was significantly attenuated in T2DM. Variability of MU firing rate was significantly higher in T2DM at later periods during the sustained contraction. CONCLUSIONS: Our findings suggest that T2DM patients manifest characteristic MU activity patterns due possibly to some degree of neuromuscular impairment affecting the integrity of MU firing modulation. PMID- 23447093 TI - Synthesis of perovskite-based porous La(0.75)Sr(0.25)MnO3 nanotubes as a highly efficient electrocatalyst for rechargeable lithium-oxygen batteries. PMID- 23447094 TI - Construction of an infectious cDNA clone of radish mosaic virus, a crucifer infecting comovirus. AB - Radish mosaic virus (RaMV) is a crucifer-infecting comovirus that has been detected worldwide. Here, we report the successful construction of a full-length infectious cDNA clone of RaMV. The full-length cDNA clones corresponding to RNA1 and RNA2 of a Japanese isolate of RaMV were cloned into the pBlueScript plasmid or the binary vector pCAMBIA1301 downstream of the cauliflower mosaic virus 35S promoter. Mechanical inoculation or agroinoculation of Nicotiana benthamiana with these vectors resulted in systemic RaMV infections causing symptoms similar to those caused by the wild-type parental virus. The presence of progeny virus was verified by western blot analysis and electron microscopy. PMID- 23447095 TI - Controlling the structural and electrical properties of diacid oligo(phenylene ethynylene) Langmuir-Blodgett films. AB - The preparation, characterization and electrical properties of Langmuir-Blodgett (LB) films composed of a symmetrically substituted oligomeric phenylene ethynylene derivative, namely, 4,4'-[1,4-phenylenebis(ethyne-2,1-diyl)]dibenzoic acid (OPE2A), are described. Analysis of the surface pressure versus area per molecule isotherms and Brewster angle microscopy reveal that good-quality Langmuir (L) films can be formed both on pure water and a basic subphase. Monolayer L films were transferred onto solid substrates with a transfer ratio of unity to obtain LB films. Both L and LB films prepared on or from a pure water subphase show a red shift in the UV/Vis spectrum of about 14 nm, in contrast to L and LB films prepared from a basic subphase, which show a hypsochromic shift of 15 nm. This result, together with X-ray photoelectron spectroscopic and quartz crystal microbalance experiments, conclusively demonstrate formation of one-layer LB films in which OPE2A molecules are chemisorbed onto gold substrates and consequently -COO-Au junctions are formed. In LB films prepared on a basic subphase the other terminal acid group is also deprotonated and associates with an Na(+) counterion. In contrast, LB films prepared from a pure water subphase preserve the protonated acid group, and lateral H-bonds with neighbouring molecules give rise to a supramolecular structure. STM-based conductance studies revealed that films prepared from a basic subphase are more conductive than the analogous films prepared from pure water, and the electrical conductance of the deprotonated films also coincides more closely with single-molecule conductance measurements. This result was interpreted not only in terms of better electron transmission in -COO-Au molecular junctions, but also in terms of the presence of lateral H-bonds in the films formed from pure water, which lead to reduced conductance of the molecular junctions. PMID- 23447096 TI - Subchondral insufficiency fracture of the femoral head: a report of two cases with a history of internal fixation of a femoral neck fracture. AB - We report our experience in two cases of subchondral insufficiency fracture of the femoral head with a history of internal fixation of the femoral neck fracture. Both cases were young females (26 and 43 years old, respectively). Their hip pain occurred more than 2 years and 1 year after the primary surgical treatment, respectively. MRI revealed bone marrow edema pattern, as well as a low intensity band on the T1-weighted images, which are commonly observed in osteonecrosis. However, the low-intensity bands were parallel to the subchondral bone end-plate, which are characteristic findings of subchondral insufficiency fracture. Both patients were administered anti-inflammatory drugs and/or bisphosphonate. One patient underwent a transtrochanteric curved varus osteotomy 1 year and 9 months after the onset, and the other healed without collapse of the femoral head. Our cases indicate that subchondral insufficiency fractures may need to be considered as one of the possible conditions after the internal fixation of a femoral neck fracture, in addition to posttraumatic osteonecrosis. PMID- 23447097 TI - Functional MRI in human subjects with gradient-echo and spin-echo EPI at 9.4 T. AB - PURPOSE: The increased signal-to-noise ratio and blood oxygen level dependent signal at ultra-high field can only help to boost the resolution in functional MRI studies if the spatial specificity of the activation signal is improved. At a field strength of 9.4 T, both gradient-echo and spin-echo based echo-planar imaging were implemented and applied to investigate the specificity of human functional MRI. A finger tapping paradigm was used to acquire functional MRI data with scan parameters similar to standard neuroscientific applications. METHODS: Spatial resolution, echo, and readout times were varied to determine their influence on the distribution of the blood oxygen level dependent signal. High resolution co-localized images were used to classify the signal according to its origin in veins or tissue. RESULTS: High-quality activation maps were obtained with both sequences. Signal contributions from tissue were found to be smaller or slightly larger than from veins. Gradient-echo echo-planar imaging yielded lower ratios of micro-/macro-vascular signals of around 0.6 than spin-echo based functional MRI, where this ratio varied between 0.75 and 1.02, with higher values for larger echo and shorter readout time. CONCLUSION: This study demonstrates the feasibility of human functional MRI at 9.4 T with high spatial specificity. Although venous contributions could not be entirely suppressed, venous effects in spin-echo echo-planar imaging are significantly reduced compared with gradient echo echo-planar imaging. PMID- 23447099 TI - Surgical assessment of significant steatosis in donor livers: the beginning of the end for frozen-section analysis? PMID- 23447098 TI - Imprinting of cerebral and hepatic cytochrome p450s in rat offsprings exposed prenatally to low doses of cypermethrin. AB - Oral administration of low doses (1.25 or 2.5 or 5 mg/kg) corresponding to 1/200th or 1/100th or 1/50th of LD50 of cypermethrin, a synthetic type II pyrethroid, to pregnant Wistar rats from gestation day 5 to 21 produced a dose dependent increase in the expression of xenobiotic metabolizing cytochrome P450 (CYP) 1A-, 2B- and 2E1 in the brain and liver of offsprings postnatally at 3 weeks that persisted up to 12 weeks. This persistent increase in CYPs was associated with alterations in circulating concentrations of testosterone, luteinizing hormone and follicle stimulating hormone, spontaneous locomotor activity and accumulation of cypermethrin in the brain of exposed offsprings. Rechallenge of exposed offsprings at adulthood (12 weeks old) with cypermethrin (p.o., 10 mg/kg * 6 days) led to a much higher increase in the expression of CYPs in the exposed offsprings when compared to the control offsprings treated with cypermethrin. Further, bioinformatic analysis demonstrating absence of specific short interspersed elements in CYPs suggests that persistence in the increase in CYPs in exposed offsprings could be attributed to the imprinting of the cerebral and hepatic CYPs following prenatal exposure to low doses of cypermethrin. This imprinting could be of toxicological relevance as it may modify the response of drugs or environmental exposures in exposed offsprings particularly for those chemicals which require CYP-mediated metabolism to produce their beneficial or toxic effects. PMID- 23447100 TI - Docking of a novel DNA methyltransferase inhibitor identified from high throughput screening: insights to unveil inhibitors in chemical databases. AB - Inhibitors of DNA methyltransferase (DNMT) are attractive compounds not only as potential therapeutic agents for the treatment of cancer and other diseases, but also as research tools to investigate the role of DNMTs in epigenetic events. Recent advances in high-throughput screening (HTS) for epigenetic targets and the availability of the first crystallographic structure of human DNMT1 encourage the integration of research strategies to uncover and optimize the activity of DNMT inhibitors. Herein, we present a binding model of a novel small-molecule DNMT1 inhibitor obtained by HTS, recently released in a public database. The docking model is in agreement with key interactions previously identified for established inhibitors using extensive computational studies including molecular dynamics and structure-based pharmacophore modeling. Based on the chemical structure of the novel inhibitor, a sequential computational screening of five chemical databases was performed to identify candidate compounds for testing. Similarity searching followed by molecular docking of chemical databases such as approved drugs, natural products, a DNMT-focused library, and a general screening collection, identified at least 108 molecules with promising DNMT inhibitory activity. The chemical structures of all hit compounds are disclosed to encourage the research community working on epigenetics to test experimentally the enzymatic and demethylating activity in vivo. Five candidate hits are drugs approved for other indications and represent potential starting points of a drug repurposing strategy. PMID- 23447101 TI - Diet, activity, habitat use, and ranging of two neighboring groups of food enhanced long-tailed macaques (Macaca fascicularis). AB - We conducted observations of two neighboring groups of food-enhanced long-tailed macaques (Macaca fascicularis) over a period of one year. We examined their diet, behavior, habitat use, and ranging and how within-population variability reflected differential utilization of anthropogenic food resources. The group that consumed more anthropogenic food spent less time feeding on wild fruits and flowers, less time resting, and more time locomoting. They used forest habitats less often, and had a larger total home range and mean monthly home range. Some of these results contrasted with previous studies of food-enhanced primates which reported that food-enhancement resulted in smaller home ranges, shorter daily ranges, less time traveling and feeding, and more time resting. These contrasting patterns may relate to the nature of anthropogenic foods. In most studies of food enhanced primates, anthropogenic food resources were abundant and concentrated but the macaques in this study used anthropogenic foods mainly from a few refuse sites where they had limited access, and from dispersed and irregular human provisioning. The group consuming more anthropogenic food therefore showed more spatially dispersed feeding activity and home range use, an effect that was likely further enhanced by lower natural food resource availability within their home range. The Singapore macaque population shows small-scale variability in feeding and ranging behavior, contributing to the complexity of their adaptive variability in a human-altered habitat. Our findings could have important implications for mitigating human-macaque conflict as measures applied at a higher spatial or population level may achieve highly inconsistent results, intensifying the challenges for wildlife managers. PMID- 23447102 TI - Dectin-1 expression at early period of Aspergillus fumigatus infection in rat's corneal epithelium. AB - AIM: To investigate the expression of dendritic cell-associated C-type lectin 1(dectin-1) at the early period of Aspergillus fumigatus infection in rat's corneal epithelium. METHODS: A total of 72 Wistar rats were randomly divided into three groups: A, B and C. The right eyes were chosen as experimental eyes. Group A was control group. Rats in group B were not inoculated with Aspergillus fumigatus. Group C was taken as Aspergillus fumigatus keratitis model. Rats in group B and C (six from each group) were executed randomly at 4, 8, 16 and 24 hours after experimental model being established to assess the expression of dectin-1 mRNA through real-time PCR. Another six rats in group B and C were executed randomly at 24 hours to assess the expression of dectin-1 protein through immunohistochemistry. RESULTS: The results of real-time PCR indicated that dectin-1 mRNA expression was low in corneal epithelium of normal rats'. There was no significantly difference of dectin-1 mRNA expression in group A and B (P>0.05). The expression of Aspergillus fumigatus infected corneal epithelium increased gradually after 8 hours in group C. The synchronous expression of group A and C had significant difference (P<0.01). Immunohistochemisty discovered that dectin-1 receptor existed in normal rat's corneal epithelium. Dectin-1 protein increased after 24 hours in group C. There was a significant difference of synchronous expression in group B and C (P<0.01). CONCLUSION: Dectin-1 exists in rat's corneal epithelium and its expression significantly increases at the early period of Aspergillus fumigatus infection. Dectin-1 is a pattern recognition receptor that expresses in corneal epithelium and involves in immune response to Aspergillus fungal keratitis. PMID- 23447103 TI - The Peaceful Mind manual: a protocol for treating anxiety in persons with dementia. AB - Anxiety disorders are highly prevalent among individuals with dementia and have a significant negative impact on their lives. Peaceful Mind is a form of cognitive behavioral therapy for anxiety in persons with dementia. The Peaceful Mind manual was developed, piloted, and modified over 2 years. In an open trial and a small randomized, controlled trial, it decreased anxiety and caregiver distress. The treatment meets the unique needs of individuals with dementia by emphasizing behavioral rather than cognitive interventions, slowing the pace, limiting the material to be learned, increasing repetition and practice, using cues to stimulate memory, including a friend or family member in treatment as a coach, and providing sessions in the home. The manual presented here includes modules that teach specific skills, including awareness, breathing, calming self statements, increasing activity, and sleep management, as well as general suggestions for treatment delivery. PMID- 23447104 TI - Genetic combination of angiotensin-converting enzyme with methylene tetrahydrofolate reductase polymorphisms and the risk of type 2 diabetes mellitus in Bahrain. AB - INTRODUCTION: Bahrain has a high prevalence of type 2 diabetes mellitus (T2DM). Previously, Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was found to be associated with T2DM in Bahrainis. The relationship between the disease progression in Bahraini T2DM population and the genetic polymorphism of methylene-tetrahydrofolate-reductase (MTHFR) C677T is still under investigation. AIM: The current study investigated the distribution of MTHFR C677T gene polymorphism among Bahraini T2DM patients and examined the interaction between ACE I/D and MTHFR C677T polymorphisms on the risk of developing T2DM and its long-term complications. MATERIALS AND METHODS: Polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) were used to test for the presence of ACE I/D and MTHFR C677T polymorphisms in 171 patients with T2DM compared to 188 healthy (non-diabetic) age-matched control subjects from Bahrain. RESULTS: The incidence of the DD genotype and D allele of the ACE gene was high among Bahraini T2DM patients. MTHFR allele and genotype frequencies did not differ between patients and controls. No significant relationship was identified between the combinations of ACE I/D and MTHFR C677T polymorphisms with T2DM. CONCLUSIONS: The results clearly showed an association of the ACE I/D polymorphism with the progression of T2DM, but when it interacts with MTHFR polymorphism no influence was detected on the increased risk of T2DM. PMID- 23447105 TI - A cotton gene encoding MYB-like transcription factor is specifically expressed in pollen and is involved in regulation of late anther/pollen development. AB - In flowering plants, pollen development is a highly programmed process, in which a lot of genes are involved. In this study, a gene, designated as GhMYB24, encoding R2R3-MYB-like protein was isolated from cotton. GhMYB24 protein is localized in the cell nucleus and acts as a transcriptional activator. Northern blot analysis revealed that GhMYB24 transcripts were predominantly detected in anthers. It was further found that strong expression of GhMYB24 was mainly detected in pollen and was regulated during anther development by in situ hybridization. Overexpression of GhMYB24 in Arabidopsis caused flower malformation, shorter filaments, non-dehiscent anthers and fewer viable pollen grains. Further analysis revealed that the septum and stomium cells of anthers were not broken, and fewer fibrous bands were found in the endothecium cells in transgenic plants. A complementation test demonstrated that GhMYB24 was able to recover partially the male fertility of the myb21 myb24 double mutant. Expression levels of the genes involved in the phenylpropanoid biosynthetic pathway and reactive oxygen species homeostasis were altered in GhMYB24-overexpressing transgenic plants. Furthermore, the genes involved in jasmonate biosynthesis and its signaling pathway were up-regulated in the transgenic plants. Yeast two hybrid assay indicated that GhMYB24 interacted with GhJAZ1/2 in cells. Taking the data together, our results suggest that GhMYB24 may play an important role in normal anther/pollen development. PMID- 23447106 TI - Calbindin-D28k and calretinin in chicken inner retina during postnatal development and neuroplasticity by dim red light. AB - Members of the family of calcium binding proteins (CBPs) are involved in the buffering of calcium (Ca2+) by regulating how Ca2+ can operate within synapses or more globally in the entire cytoplasm and they are present in a particular arrangement in all types of retinal neurons. Calbindin D28k and calretinin belong to the family of CBPs and they are mainly co-expressed with other CBPs. Calbindin D28k is expressed in doubles cones, bipolar cells and in a subpopulation of amacrine and ganglion neurons. Calretinin is present in horizontal cells as well as in a subpopulation of amacrine and ganglion neurons. Both proteins fill the soma at the inner nuclear layer and the neuronal projections at the inner plexiform layer. Moreover, calbindin D28k and calretinin have been associated with neuronal plasticity in the central nervous system. During pre and early postnatal visual development, the visual system shows high responsiveness to environmental influences. In this work we observed modifications in the pattern of stratification of calbindin immunoreactive neurons, as well as in the total amount of calbindin through the early postnatal development. In order to test whether or not calbindin is involved in retinal plasticity we analyzed phosphorylated p38 MAPK expression, which showed a decrease in p-p38 MAPK, concomitant to the observed decrease of calbindin D28k. Results showed in this study suggest that calbindin is a molecule related with neuroplasticity, and we suggest that calbindin D28k has significant roles in neuroplastic changes in the retina, when retinas are stimulated with different light conditions. PMID- 23447107 TI - Nucleation and growth of chrysotile nanotubes in H2SiO3/MgCl2/NaOH medium at 90 to 300 degrees C. AB - Herein, we report new insights into the nucleation and growth processes of chrysotile nanotubes by using batch and semi-continuous experiments. For the synthesis of this highly carcinogenic material, the influences of temperature (90, 200, and 300 degrees C), Si/Mg molar ratio, and reaction time were investigated. From the semi-continuous experiments (i.e., sampling of the reacting suspension over time) and solid-state characterization of the collected samples by XRPD, TGA, FTIR spectroscopy, and FESEM, three main reaction steps were identified for chrysotile nucleation and growth at 300 degrees C: 1) formation of the proto-serpentine precursor within the first 2 h of the reaction, accompanied by the formation of brucite and residual silica gel; 2) spontaneous nucleation and growth of chrysotile between about 3 and 8 h reaction time, through a progressive dissolution of the proto-serpentine, brucite, and residual silica gel; and 3) Ostwald ripening growth of chrysotile from 8 to 30 h reaction time, as attested to by BET and FESEM measurements. Complementary results from batch experiments confirmed a significant influence of the reaction temperature on the kinetics of chrysotile formation. However, FESEM observations revealed some formation of chrysotile nanotubes at low temperatures (90 degrees C) after 14 days of reaction. Finally, doubling the Si/Mg molar ratio promoted the precipitation of pure smectite (stevensite-type) under the same P (8.2 MPa)/T (300 degrees C)/pH (13.5) conditions. PMID- 23447108 TI - Antiplatelet activity of a novel formula composed of malic acid, succinic acid and citric acid from Cornus officinalis fruit. AB - The present study investigated the antiplatelet activity of a novel formula composed by malic acid, succinic acid and citric acid with a ratio of 3:2:2. The IC50 and inhibition of platelet aggregation induced by various agonists as well as platelet adhesion were evaluated in vitro. Of note, the IC50 for the formula inhibiting adenosine diphosphate (ADP)-induced platelet aggregation was 0.185 mg/mL. Meanwhile, the formula showed more potent inhibitory effect on platelet aggregation induced by ADP and thrombin than the single component at same concentration (0.37 mg/mL). Moreover, the formula could prevent platelet adhesion significantly without influence on platelet viability. PMID- 23447109 TI - Functional living biointerphases. AB - Lactococcus lactis is modified to express a fibronectin fragment (FNIII7-10) as a membrane protein. This interphase, based on a living system, can be further exploited to provide spatio-temporal factors to direct cell function at the material interface. This approach establishes a new paradigm in biomaterial surface functionalization for biomedical applications. PMID- 23447110 TI - Fe(III) distribution varies substantially within and between atherosclerotic plaques. AB - PURPOSE: Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture. METHODS: Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy. RESULTS: Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 +/- 0.21 vs. 0.06 +/- 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 +/- 11% vs. 2.3 +/- 2.3%, P < 0.01). CONCLUSION: Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity. PMID- 23447111 TI - Pressure-induced water insertion in synthetic clays. PMID- 23447112 TI - Surfactant-free sub-2 nm ultrathin triangular gold nanoframes. AB - Ultrathin triangular gold nanoframes are synthesized in high yield through selective gold deposition on the edges of triangular silver nanoprisms and subsequent silver etching with mild wet etchants. These ultrathin gold nanoframes are surfactant-free with tailorable ridge thickness from 1.8 to 6 nm and exhibit adjustable and distinct surface plasmon resonance bands in the visible and near IR region. In comparison, etching of the nanoprism template by galvanic replacement can only create frame structures with much thicker ridges, which have much lower catalytic activity for 4-nitrophenol reduction than the ultrathin gold nanoframes. PMID- 23447113 TI - Director of anesthesiology for liver transplantation: existing practices and recommendations by the United Network for Organ Sharing. AB - A new Organ Procurement and Transplantation Network/United Network for Organ Sharing bylaw recommends that all centers appoint a director of liver transplant anesthesia with a uniform set of criteria. We obtained survey data from the Liver Transplant Anesthesia Consortium so that we could compare existing criteria for a director in the United States with the current recommendations. The data set included responses from adult academic liver transplant programs before the new bylaw. The respondent rates were within statistical limits to exclude sampling bias. All centers had a director of liver transplant anesthesia. The criteria varied between institutions, and the data suggest that the availability of resources influenced the choice of criteria. The information suggests that the criteria used in the new bylaw reflect existing practices. The bylaw plays an important role in supporting emerging leadership roles in liver transplant anesthesia and brings greater uniformity to the directorship position. PMID- 23447115 TI - Isostructural metal-organic frameworks assembled from functionalized diisophthalate ligands through a ligand-truncation strategy. AB - Four isostructural metal-organic frameworks (MOFs) with various functionalized pore surfaces were synthesized from a series of diisophthalate ligands. These MOFs exhibit a new network topology of {4.6(4).8}2{4(2).6(4)}{6(4).8(2)}2{6(6)}. Hydrogen uptake as high as 2.67 wt % at 77 K/1 bar and CO2 uptake of 15.4 wt % at 297 K/1 bar have been observed for PCN-308, which contains -CF3 groups. The isostructural series of MOFs also showed reasonable adsorption selectivity of CO2 over CH4 and N2 . PMID- 23447114 TI - The role of chemokines in Guillain-Barre syndrome. AB - INTRODUCTION: Chemokines and their receptors are important mediators of inflammation. Guillain-Barre syndrome (GBS) is the most common cause of acute paralysis worldwide. Despite current treatments, outcomes are suboptimal. Specific chemokine receptor antagonists have the potential to be efficacious against pathogenic leukocyte trafficking in GBS. METHODS: A 36-year literature review was performed to summarize available data on chemokine expression in GBS and its representative animal model, experimental autoimmune neuritis (EAN). RESULTS: Although there were a few observational human and animal studies demonstrating chemokine ligand/receptor expression in GBS and EAN, in vitro and in vivo functional studies using gene knockouts, neutralizing antibodies, or small molecular antagonists were limited. CCL2-CCR2, CCL5-CCR5, and CXCL10-CXCR3 have been most strongly implicated in EAN and GBS pathogenesis, providing targets for molecular blockade. CONCLUSIONS: Preclinical human in vitro and in vivo EAN studies are needed to evaluate the potential efficacy of chemokine signaling inhibition in GBS. PMID- 23447116 TI - A previously undiscovered group of chimpanzees (Pan troglodytes verus) is observed living in the Tonkolili district of Sierra Leone. AB - A previously undocumented group of wild chimpanzees (Pan troglodytes verus) was recently discovered along the Pampana River in the Tonkolili District of Sierra Leone. Based on interviews from local residents (N = 6), we estimate the group size to be approximately 30 individuals. Though this population does not show up in the most recent census of chimpanzees in Sierra Leone, it concurs with findings that indicate most of the chimpanzees in Sierra Leone live scattered throughout the country alongside villages, rather than in protected areas. During a three-week observation in the area, two chimpanzees were hunted and killed. The reason for these deaths, along with other reported instances of hunting in the area, are primarily due to crop-raiding and competition for resources between chimpanzees and humans. We conclude that this is a heavily imperiled population. Based on the ecology of the area and composition of local villages, we propose a number of conservation strategies that will promote a symbiotic relationship between the chimpanzees and human populations residing in the area. PMID- 23447117 TI - Synthesis and biological activity of new donepezil-hydrazinonicotinamide hybrids. AB - Currently available treatment used in Alzheimer's disease is based on acetylcholinesterase inhibitors, e. g. donepezil, tacrine, galantamine, and rivastigmine. In the present study some derivatives of donepezil were synthesized, and their potential anticholinesterase properties were investigated using the colorimetric Ellman's method. These compounds were synthesized by condensation between indanone derivatives and the hydrazine nicotinated moiety (Hynic). For received derivatives, the selectivity and the IC50 values for acetylcholinesterase and butyrylcholinesterase were calculated. All the tested compounds exhibited lower affinity for AChE than donepezil and higher affinity for BChE than donepezil. Compound 33 showed the most selectivity for AChE among the obtained indanone derivatives. PMID- 23447118 TI - Intramedullary schwannomas: long-term outcomes of ten operated cases. AB - Intramedullary schwannomas are very rare. Most studies on intramedullary schwannomas have been case reports with literature reviews. This study presented a surgical series of ten patients with histologically proven intramedullary schwannomas. From 1995 to 2010, ten patients (2.7 %) presented with intramedullary schwannomas out of 365 patients with spinal schwannomas. Their clinical and radiological findings and operative records were reviewed. There were 6 female and 4 male patients with a mean age of 45.5 years. The mean follow up period was 75.7 months. Three tumors were located in the cervical spine and 7 were located in the thoracic spine. Intraoperatively, the tumor was connected with the dorsal rootlet in 4 cases and with the ventral rootlet in 1 case. Gross total resection (GTR) of the tumor with a well-demarcated dissection plane was achieved in 8 cases and subtotal resection (STR) was achieved in 2 cases. The current status of all the patients was improved compared to the preoperative presentation at last follow-up and the symptoms present before the surgery were improved in all the cases at last follow-up. The postoperative follow-up magnetic resonance imaging showed no recurrence in the 8 GTR cases during the follow-up period of 83.5 months on average. No interval change in residual tumors was observed in the 2 STR cases (45- and 55-month follow-up periods). Intramedullary schwannomas are amenable to surgery. It is possible to achieve GTR of intramedullary schwannomas that have a well-demarcated dissection plane. Additionally, a good clinical outcome after GTR can be expected. PMID- 23447119 TI - Erdheim-Chester disease with prominent pericardial effusion: cytologic findings and review of the literature. AB - Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin with distinct clinicopathologic and radiographic features. Reports detailing the cytology of ECD are rare. We describe a case of ECD with pericardial effusion. Cytologic examination revealed a hypercellular specimen composed of clusters and singly dispersed foamy macrophages with round nuclei and inconspicuous nucleoli, admixed with lymphocytes, eosinophils, and Touton-type multinucleated giant cells. Immunostains for CD68 were strongly positive in the foamy macrophages while S100 and CD1a were negative. The presence of foamy histiocytes, multinucleated giant cells, lymphocytes and eosinophils are also features of other systemic histiocytic disorders, including Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD) and sarcoidosis. To the best of out knowledge, this is the first report describing the cytological features of ECD in a pericardial effusion. PMID- 23447120 TI - Enantioselective total synthesis of (+)-ophiobolin A. AB - The enantioselective total synthesis of (+)-ophiobolin A is described. This total synthesis features the construction of the spiro CD ring of (+)-ophiobolin A through a stereoselective intramolecular Hosomi-Sakurai cyclization reaction, the joining of the A ring to the CD ring by using a reaction reported by Utimoto, and the construction of the ophiobolin eight-membered carbocyclic ring through ring closing metathesis (RCM), which was performed for the first time in this study. This successful RCM reaction required the use of a substrate that contained either a benzyloxy or a methoxymethoxy group at the C5 position and either an isopropenyl group or its hydroxylated form at the C6 position. PMID- 23447121 TI - A noninvasive tumor oxygenation imaging strategy using magnetic resonance imaging of endogenous blood and tissue water. AB - PURPOSE: To present a novel imaging strategy for noninvasive measurement of tumor oxygenation using MR imaging of endogenous blood and tissue water. THEORY AND METHODS: The proposed approach for oxygen partial pressure (pO2) estimation is based on intravoxel incoherent motion diffusion MRI and the dependence of the blood R2 relaxation rate on the inter-echo spacing measured using a multiple spin echo Carr-Purcell-Meiboom-Gill sequence and weak-field diffusion model. The accuracy of the approach was validated by comparison with (19)F MRI oximetry. RESULTS: The results in eight rats at 4.7 T showed that tumors have longer T1 (1980 +/- 186 ms) and T2 (59 +/- 9 ms) relaxation times, heterogeneous blood volume fraction (0.23 +/- 0.1), oxygen saturation level (Y) (0.53 +/- 0.12), and pO2 (36 +/- 15 mmHg) distributions compared with normal muscle (T1 1480 +/- 86 ms, T2 29 +/- 2 ms, blood volume fraction 0.22 +/- 0.03, Y 0.49 +/- 0.06, and pO2 39 +/- 5 mmHg). pO2 estimates based on the novel (1)H approach were essentially identical with (19)F observations. CONCLUSION: The study indicates that noninvasive measurement of tumor pO2 using (1)H MRI derived multiparametric maps is feasible and could become a valuable tool to evaluate tumor hypoxia. PMID- 23447122 TI - Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes. AB - Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell- and B cell-directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve therapeutic efficacy remains to be explored. We show that combined treatment with intravenous antihuman CD20 (hCD20) and oral anti-CD3 significantly delays diabetes development in prediabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reverses diabetes in >60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B-cell depletion therapy synergistically enhances the suppressive function of regulatory T cells. Of note, the oral anti CD3 treatment induced a fraction of interleukin (IL)-10-producing CD4 T cells in the small intestine through IL-10- and IL-27-producing dendritic cells. Thus, the findings demonstrate that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell-directed therapy for T1D. PMID- 23447124 TI - Expression of a dominant negative mutant innexin in identified neurons and glial cells reveals selective interactions among gap junctional proteins. AB - Neurons and glia of the medicinal leech CNS express different subsets of the 21 innexin genes encoded in its genome. We report here that the punctal distributions of fluorescently tagged innexin transgenes varies in a stereotypical pattern depending on the innexin expressed. Furthermore, whereas certain innexins colocalize extensively (INX1 and INX14), others do not (e.g., INX1 and INX2 or INX6). We then demonstrate that the mutation of a highly conserved proline residue in the second transmembrane domain of innexins creates a gap junction protein with dominant negative properties. Coexpressing the mutated INX1 gene with its wild type blocks the formation of fluorescent puncta and decouples the expressing neuron from its normal gap junction-coupled network of cells. Similarly, expression of an INX2 mutant transgene (a glial cell innexin), blocks endogenous INX2 puncta and wild-type transgene puncta, and decouples the glial cell from the other glial cells in the ganglion. We show in cell culture with dye-uptake and plasma membrane labeling experiments that the mutant innexin transgene is not expressed on the cell membrane but instead appears to accumulate in the cell's perinuclear region. Lastly, we use these mutant innexin transgenes to show that the INX1 mutant transgene blocks not only INX1 puncta formation, but also puncta of INX14, with which INX1 usually colocalizes. By contrast, the formation of INX6 puncta was unaffected by the INX1 mutant. Together, these experiments suggest that leech innexins can selectively interact with one another to form gap junction plaques, which are heterogeneously located in cellular arbors. (c) 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 571-586, 2013. PMID- 23447123 TI - Diurnal pattern of insulin action in type 1 diabetes: implications for a closed loop system. AB - We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide-negative diabetes (HbA1c 7.1 +/- 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P < 0.01) and endogenous glucose production less suppressed (P < 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized. PMID- 23447125 TI - A near-infrared fluorescent nanosensor (AuC@Urease) for the selective detection of blood urea. PMID- 23447126 TI - Sodium salicylate protects against rotenone-induced parkinsonism in rats. AB - Complex I deficiency culminating in oxidative stress is proposed as one of the upstream mechanisms of nigral neuronal death in Parkinson's disease. We investigated whether sodium salicylate, an active metabolite of aspirin, could afford protection against rotenone-induced oxidative stress, neuronal degeneration, and behavioral dysfunction in rats, because it has the potential to accept a molecule each of hydroxyl radical (*OH) at the third or fifth position of its benzyl ring. Rotenone caused dose-dependent increase in *OH in isolated mitochondria from the cerebral cortex and time- (24-48 h) and dose-dependent (0.1 100 uM) increase in the substantia nigra and the striatum, ipsilateral to the side of rotenone infusion. Administration of sodium salicylate at 12-h intervals for 4 days showed dose-dependent (50-100 mg/kg, i.p) reductions in the levels of *OH in the nigra on the fifth day. These animals showed significant attenuation in rotenone-induced loss in striatal dopamine levels, number of nigral dopaminergic neurons, reduced and oxidized glutathione levels, and complex I activity loss, but superoxide dismutase activity was increased further. Amphetamine- or apomorphine-induced ipsilateral rotations in rotenone-treated rats were significantly reduced in rats treated with sodium salicylate. Our results indicate a direct role of *OH in mediating nigral neuronal death by rotenone and confirm the neuroprotective potential of salicylate in a rodent model of parkinsonism. PMID- 23447127 TI - A novel p.R890C mutation in EPHA2 gene associated with progressive childhood posterior cataract in a Chinese family. AB - AIM: To identify the genetic defect in a Chinese family with bilateral progressive childhood posterior cataract. METHODS: A two-generation family was recruited in this study. Family history and clinical data were recorded. All reported candidate genes associated with congenital posterior cataract were screened by direct DNA sequencing. RESULTS: All affected individuals presented posterior opacities in the lens. Direct sequencing of the candidate genes showed a heterozygous c. 2668C>T variation in EPHA2 gene, which resulted in the replacement of arginine by cysteine at codon 890 (p. R890C). This mutation was found in two affected individuals, but was not observed in 200 normal controls. CONCLUSION: We report a novel mutation (p. R890C) in the EPHA2 receptor tyrosine kinase gene. The finding expands the mutation spectrum of EPHA2 in association with posterior cataract. PMID- 23447128 TI - Effect of graduated compression stockings on venous blood velocity in supine resting hospitalized patients. AB - The effects of graduated compression stockings (GCSs) on venous blood velocity were measured in 26 hospitalized medical patients while supine at rest. Peak blood velocity in the right femoral vein was 21.6 cm/s without GCS and 23.0 cm/s with GCS [not significant (NS)]. Peak blood velocity in the right popliteal vein was 12.5 cm/s without GCS and 15.0 cm/s with GCS (NS). Mean blood velocity in the right femoral vein did not increase significantly with GCS, but mean blood velocity in the right popliteal vein increased marginally from 5.0 cm/s to 5.8 cm/s (P = .05). Among 11 patients with venous insufficiency (refilling time <=19 s), neither peak nor mean blood velocity in the femoral or popliteal veins increased significantly with GCS. In conclusion, thigh-length GCS in hospitalized patients had little or no effect on popliteal or femoral vein blood velocity while supine at rest, irrespective of whether the patients had venous insufficiency. PMID- 23447129 TI - Linalool-rich rosewood oil induces vago-vagal bradycardic and depressor reflex in rats. AB - Cardiovascular effects of the linalool-rich essential oil of Aniba rosaeodora (here named as EOAR) in normotensive rats were investigated. In anesthetized rats, intravenous (i.v.) injection of EOAR induced dose-dependent biphasic hypotension and bradycardia. Emphasis was given to the first phase (phase 1) of the cardiovascular effects, which is rapid (onset time of 1-3 s) and not observed in animals submitted to bilateral vagotomy or selective blockade of neural conduction of vagal C-fibre afferents by perineural treatment with capsaicin. Phase 1 was also absent when EOAR was directly injected into the left ventricle injection, but it was unaltered by i.v. pretreatment with capsazepine, ondansetron or HC030031. In conscious rats, EOAR induced rapid and monophasic hypotensive and bradycardiac (phase 1) effects that were abolished by i.v. methylatropine. In endothelium-intact aortic rings, EOAR fully relaxed phenylephrine-induced contractions in a concentration-dependent manner. The present findings reveal that phase 1 of the bradycardiac and depressor responses induced by EOAR has a vago-vagal reflex origin resulting from the vagal pulmonary afferents stimulation. Such phenomenon appears not to involve the recruitment of C-fibre afferents expressing 5HT3 receptors or the two chemosensory ion channels TRPV1 and TRPA1 . Phase 2 hypotensive response appears resulting from a direct vasodilatory action. PMID- 23447130 TI - Sizing up the individual market for health insurance: a comparison of survey and administrative data sources. AB - Provisions within the Affordable Care Act, including the introduction of subsidized, Exchange-based coverage for lower income Americans lacking access to employer coverage, are expected to greatly expand the size and importance of the individual market. Using multiple federal surveys and administrative data from the National Association of Insurance Commissioners, we generate national-, regional-, and state-level estimates of the individual market. In 2009, the number of nonelderly persons with individual coverage ranged from 9.55 million in the Medical Expenditure Panel Survey to 25.3 million in the American Community Survey. Notable differences also exist between survey estimates and National Association of Insurance Commissioners administrative counts, an outcome likely driven by variation in the type and measurement of individual coverage considered by surveys relative to administrative data. Future research evaluating the impact of the Affordable Care Act coverage provisions must be mindful of differences across surveys and administrative sources as it relates to the measurement of individual market coverage. PMID- 23447131 TI - Nucleophilic ortho-propargylation of aryl sulfoxides: an interrupted Pummerer/allenyl thio-Claisen rearrangement sequence. PMID- 23447132 TI - Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions. AB - Since the discovery nearly 60 years ago, cAMP is envisioned as one of the most universal and versatile second messengers. The tremendous feature of cAMP to tightly control highly diverse physiologic processes, including calcium homeostasis, metabolism, secretion, muscle contraction, cell fate, and gene transcription, is reflected by the award of five Nobel prizes. The discovery of Epac (exchange protein directly activated by cAMP) has ignited a new surge of cAMP-related research and has depicted novel cAMP properties independent of protein kinase A and cyclic nucleotide-gated channels. The multidomain architecture of Epac determines its activity state and allows cell-type specific protein-protein and protein-lipid interactions that control fine-tuning of pivotal biologic responses through the "old" second messenger cAMP. Compartmentalization of cAMP in space and time, maintained by A-kinase anchoring proteins, phosphodiesterases, and beta-arrestins, contributes to the Epac signalosome of small GTPases, phospholipases, mitogen- and lipid-activated kinases, and transcription factors. These novel cAMP sensors seem to implement certain unexpected signaling properties of cAMP and thereby to permit delicate adaptations of biologic responses. Agonists and antagonists selective for Epac are developed and will support further studies on the biologic net outcome of the activation of Epac. This will increase our current knowledge on the pathophysiology of devastating diseases, such as diabetes, cognitive impairment, renal and heart failure, (pulmonary) hypertension, asthma, and chronic obstructive pulmonary disease. Further insights into the cAMP dynamics executed by the Epac signalosome will help to optimize the pharmacological treatment of these diseases. PMID- 23447133 TI - Dominant negative PPARgamma promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle. AB - Agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) have potent insulin-sensitizing effects and inhibit atherosclerosis progression in patients with Type II diabetes. Conversely, missense mutations in the ligand-binding domain of PPARgamma that render the transcription factor dominant negative (DN) cause early-onset hypertension and Type II diabetes. We tested the hypothesis that DN PPARgamma-mediated interference of endogenous wild-type PPARgamma in the endothelium and vascular smooth muscle exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE(-/ )) mice. Endothelium-specific expression of DN PPARgamma on the ApoE(-/-) background unmasked significant impairment of endothelium-dependent relaxation in aortic rings, increased systolic blood pressure, altered expression of atherogenic markers (e.g., Cd36, Mcp1, Catalase), and enhanced diet-induced atherosclerotic lesion formation in aorta. Smooth muscle-specific expression of DN PPARgamma, which induces aortic dysfunction and increased systolic blood pressure at baseline, also resulted in enhanced diet-induced atherosclerotic lesion formation in aorta on the ApoE(-/-) background that was associated with altered expression of a shared, yet distinct, set of atherogenic markers (e.g., Cd36, Mcp1, Osteopontin, Vcam1). In particular, induction of Osteopontin expression by smooth muscle-specific DN PPARgamma correlated with increased plaque calcification. These data demonstrate that inhibition of PPARgamma function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease. PMID- 23447134 TI - Prolonged high fat/alcohol exposure increases TRPV4 and its functional responses in pancreatic stellate cells. AB - The present study investigated transient receptor potential vanilloid type 4 (TRPV4) ion channels in pancreatic stellate cells (PSCs) isolated from rats with high-fat and alcohol diet (HFA)-induced chronic pancreatitis. TRPV4 is a calcium permeable nonselective ion channel responsive to osmotic changes, alcohol metabolites arachidonic acid, anandamide, their derivatives, and injury-related lipid mediators. Male Lewis rats were fed HFA for 6-8 wk before isolation and primary culture of PSCs. Control PSCs were harvested from rats fed standard chow. Immunoreactivity for cytoskeletal protein activation product alpha-smooth muscle actin (alpha-SMA) and platelet-derived growth factor receptor-beta subunit (PDGFR beta) characterized the cells as PSCs. TRPV4 expression increased in PSCs of HFA fed rats and control cultures after alcohol treatment (50 mM). Cell responses to activation of inducible TRPV4 were assessed with live cell calcium imaging. Threefold increased and sustained intracellular calcium mobilization responses occurred in 70% of pancreatic stellate cells from HFA-fed rats in response to TRPV4 activators arachidonic acid, lipid second messenger, phorbol ester 4 alpha phorbol 12,13-didecanoate (4alphaPDD), and 50% hypoosmotic media compared with relatively unresponsive PSCs from control rats. Activation responses were attenuated by nonselective TRPV channel blocker ruthenium red. Tumor necrosis factor-alpha (TNF-alpha, 1 ng/ml, 16 h) increased responses to 4alphaPDD in control PSCs. These findings implicate TRPV4-mediated calcium responses inducible after HFA exposure and inflammation in reactive responses of activated PSCs that impair pancreatic function, such as responsiveness to cytokines and the deposition of collagen fibrosis that precipitates ductal blockage and pain. PMID- 23447136 TI - Multifocal radiculoneuropathy during ipilimumab treatment of melanoma. AB - INTRODUCTION: Ipilimumab, a monoclonal anti-CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. METHODS: In this investigation we undertook a retrospective review of patient records. RESULTS: After 3 doses of ipilimumab, a 31-year-old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749 mg/dl. Nerve pathology showed inflammation around the endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. CONCLUSIONS: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood-nerve barrier due to a microvasculopathy. PMID- 23447135 TI - Hypoxic depression of PKG-mediated inhibition of serotonergic contraction in ovine carotid arteries. AB - Chronic hypoxia attenuates soluble guanylate cyclase-induced vasorelaxation in serotonin (5-HT)-contracted ovine carotid arteries. Because protein kinase G (PKG) mediates many effects of soluble guanylate cyclase activation through phosphorylation of multiple kinase targets in vascular smooth muscle, we tested the hypothesis that chronic hypoxia reduces the ability of PKG to phosphorylate its target proteins, which attenuates the ability of PKG to induce vasorelaxation. We also tested the hypothesis that hypoxia attenuates PKG expression and/or activity. Arteries from normoxic and chronically hypoxic (altitude of 3,820 m for 110 days) fetal and adult sheep were denuded of endothelium and equilibrated with 95% O2-5% CO2 in the presence of nitro-l arginine methyl ester (l-NAME) and N(G)-nitro-l-arginine (l-NNA) to inhibit residual endothelial nitric oxide synthase. Concentration-response relations for 5-HT were determined in the presence of prazosin to minimize activation of alpha adrenergic receptors. The PKG activator 8-(p-chlorophenylthio)-guanosine 3',5' cyclic monophosphate (8-pCTP-cGMP) reduced agonist binding affinity of the 5-HT receptor in a concentration-dependent manner that was attenuated by hypoxia. Expression and activity of PKG-I was not significantly affected by chronic hypoxia in either fetal or adult arteries, although PKG-I abundance was greater in fetal arteries. Pretreatment with the large conductance calcium-sensitive potassium channel (BK) inhibitor iberiotoxin attenuated the vasorelaxation induced by 8-pCPT-cGMP in normoxic but not chronically hypoxic arteries. These results support the hypothesis that hypoxia attenuates the vasorelaxant effects of PKG through suppression of the ability of PKG to activate large conductance calcium-sensitive potassium channels in arterial smooth muscle. The results also reveal that this hypoxic effect is greater in fetal than adult arteries and that chronic maternal hypoxia can profoundly affect fetal vascular function. PMID- 23447137 TI - Technical aspects and outcomes of living donor liver transplantation for pediatric patients with situs inversus. AB - The vascular anomalies encountered in patients with biliary atresia associated with polysplenia syndrome and situs inversus (SI) demand technical refinements when liver transplantation is being performed. The available data describing the technique used in living donor liver transplantation (LDLT) in this population are limited; the short vascular stumps of the donor's liver can impart additional technical difficulties during vascular reconstruction. Here we describe our experience with 9 children with biliary atresia and SI who underwent LDLT. In our series, the retrohepatic vena cava was absent for 7 patients, 7 had a preduodenal portal vein (PV), and 4 had a variant arterial anatomy. The donor's left hepatic vein was anastomosed to the confluence of the recipient's 3 hepatic veins in 7 patients. Vascular grafts were used for PV reconstruction in 3 cases. A left lateral segment graft was used in all but 1 patient who needed a graft reduction. All grafts were placed in the upper left abdomen. There were no vascular complications after transplantation. All patients were alive and well at a median follow-up of 55 months. In conclusion, LDLT can be successfully performed in pediatric patients with SI. Complex vascular anomalies associated with the use of partial liver grafts obtained from living donors are not associated with an increased occurrence of vascular complications. PMID- 23447138 TI - Plasma apolipoprotein A1 as a biomarker for Parkinson disease. AB - OBJECTIVE: To identify plasma-based biomarkers for Parkinson disease (PD) risk. METHODS: In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n = 134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging was performed, to evaluate the association of plasma protein levels with dopaminergic system integrity. RESULTS: One of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1; p = 0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards, p < 0.001, hazard ratio = 0.742). The association between plasma ApoA1 levels and age at PD onset was replicated in an independent cohort of PD patients (p < 0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p = 0.037). INTERPRETATION: Lower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk. PMID- 23447139 TI - Minimizing human infection from Escherichia coli O157:H7 using GUMBOS. AB - OBJECTIVES: Reduction in faecal shedding of Shiga toxin-producing enterohaemorrhagic Escherichia coli (EHEC) in food-producing animals is a viable strategy to minimize human disease initiated by exposure to these microorganisms. To this end, an intervention strategy involving the electrostatic hybridization of two commonly used anti-infective agents for veterinary practice (i.e. chlorhexidine and ampicillin) was evaluated to curtail EHEC-transmitted disease from ruminant sources. Chlorhexidine di-ampicillin is a novel group of uniform material based on organic salts (GUMBOS) with inherent in vitro antibacterial activity that comes from its parent antimicrobial ions, chlorhexidine and ampicillin. METHODS: Antibacterial activities for chlorhexidine diacetate, sodium ampicillin, chlorhexidine di-ampicillin and stoichiometrically equivalent 1 : 2 chlorhexidine diacetate : sodium ampicillin were assessed using the serial 2-fold dilution method and time-kill studies against seven isolates of E. coli O157:H7 and one non-pathogenic E. coli 25922. Further studies to investigate synergistic interactions of reacted and stoichiometrically equivalent unreacted antimicrobial agents at MICs and possible mechanisms were also investigated. RESULTS: Synergism and in vitro antibacterial activities against EHEC were observed in this study, which suggests chlorhexidine di-ampicillin could be a useful reagent in reducing EHEC transmission and minimizing EHEC-associated infections. Likewise, chlorhexidine di-ampicillin reduced HeLa cell toxicity as compared with chlorhexidine diacetate or the stoichiometric combination of antimicrobial agents. Further results suggest that the mechanisms of action of chlorhexidine di ampicillin and chlorhexidine diacetate against E. coli O157:H7 are similar. CONCLUSIONS: Reacting antimicrobial GUMBOS as indicated in this study may enhance the approach to current combination drug therapeutic strategies for EHEC disease control and prevention. PMID- 23447140 TI - Chromosome-mediated OXA-48 carbapenemase in highly virulent Escherichia coli. AB - OBJECTIVES: Bacteria multiresistant to antibiotics are widely supposed to be weakly virulent. However, the virulence traits of carbapenem-resistant Enterobacteriaceae have not been investigated. In this work, we investigated the virulence and resistance mechanism of an extraintestinal pathogenic Escherichia coli (ExPEC) strain (LEB15) that exhibited decreased susceptibility to carbapenems. METHODS: The MICs were determined by a microdilution method. The beta-lactamase-encoding gene was identified by PCR and sequencing, and the genetic environment was analysed by PFGE and PCR mapping. The genetic background was investigated by multilocus sequence typing (MLST). Virulence-factor-encoding genes and pathogenic islands (PAIs) were detected by multiplex PCR. Virulence was assessed in a mouse sepsis model. RESULTS: Strain LEB15 produced a chromosomal OXA-48 carbapenemase. The complete bla(OXA-48)-encoding Tn1999.2 transposon was inserted in the LEB15 chromosome. The strain belonged to an MLST cluster of emerging ExPEC strains (ST-127/ST-22). It had a high pathogenic score and eight PAIs (I536, II536, III536, IV536, VI536, I(CFT073), II(CFT073) and II(J96)) and induced an unusually high lethality in the mouse sepsis model. CONCLUSIONS: Strain LEB15 combines both an atypical broad accumulation of virulence factors, which confers a strong killer phenotype, and a decrease in susceptibility to carbapenems following the chromosomal acquisition of bla(OXA-48). This association of virulence and carbapenemase in E. coli strains might pose major problems in the future for E. coli infection management. PMID- 23447141 TI - Mycobacterium canettii is intrinsically resistant to both pyrazinamide and pyrazinoic acid. PMID- 23447142 TI - Fine-needle aspiration of metanephric adenoma of the kidney with clinical, radiographic and histopathologic correlation: a review. AB - Metanephric adenoma of the kidney is an uncommon benign epithelial neoplasm with only a small number of reports that describe its cytologic features. We describe two additional cases of metanephric adenoma diagnosed on fine-needle aspiration biopsy and review the available literature. Our cases showed similar cytology and were composed of cellular smears with numerous clusters of small, oval to round cells arranged in a microfollicular pattern and papillary configurations. The tumor cells had scant cytoplasm, fine chromatin and absent nucleoli. Psamomma bodies, nuclear atypia, cellular cpleomorphism, necrosis, and mitoses were absent. Because of the rarity of this tumor and the common cytologic features it shares with other lesions, including malignant tumors such as Wilms' tumor and papillary renal cell carcinoma, awareness of the cytologic features of metanephric adenoma may aid in avoiding a diagnosis of malignancy, especially preoperatively, and in guiding the proper management for the patients. PMID- 23447143 TI - The antioxidant activity of sulphurous thermal water protects against oxidative DNA damage: a comet assay investigation. AB - Various studies have recently shown that sulphurous waters acts against the oxidants released during respiratory bursts of human neutrophils, and free radicals such as HO*, O2-*, Tempol and Fremy's salt. However, there is still a lack of data concerning their direct protection of DNA. The aim of this study was to investigate the antigenotoxicity effects of sulphurous water, which has never been previously investigated for this purpose, using the alkaline single cell gel electrophoresis (SCGE) approach (comet assay). The comet assay is a sensitive method for assessing DNA fragmentation in individual cells in genotoxicity studies but can also be used to investigate the activity of agents that protect against DNA damage. The extent of migration was measured by means of SCGE, and DNA damage was expressed as tail moment. All of these assays were made using natural sulphurous water, degassed sulphurous water (no detectable HS), and reconstituted sulphurous water (degassed plus NaHS). DNA damages was significantly inhibited by natural water with HS concentrations of 5.0 and 2.5 MUg/mL. The use of degassed water did not lead to any significant differences from baseline values, whereas the reconstituted water led to significant results overlapping those obtained using natural water. These findings confirm the importance of the presence of an HS group (reductive activity) and indicate that, in addition to their known mucolytic activity and trophic effects on respiratory mucosa, HS groups in sulphurous water also protect against oxidative DNA damage and contribute to the water's therapeutic effects on upper and lower airway inflammatory diseases. PMID- 23447144 TI - CuO quantum-dot-sensitized mesoporous ZnO for visible-light photocatalysis. AB - How to extend ultraviolet photocatalysts to the visible-light region is a key challenge for solar-driven photocatalysis. Herein, we show that ultraviolet ZnO photocatalysts can present high visible-light photocatalytic activity when combined with CuO quantum dots (QDs; <3 nm). Theoretical analysis demonstrates that the quantum size effect plays a key role in the photoactivity of the CuO/ZnO composite. For CuO QDs smaller than 3 nm, the separated charges could transfer from CuO QDs to the conduction bands of ZnO due to quantum splitting of the CuO energy level and phonon compensation for the difference in the conduction band minimum of CuO and ZnO; however, this process would not occur with the disappearance of the quantum size effect. Further structural analysis demonstrates that interfacial charge separation and transfer between ZnO and CuO dominate the photocatalytic processes instead of a single CuO or ZnO surface. Compared with ZnO-noble metal structures (e.g., ZnO-Ag or ZnO-Au), these ZnO-CuO QD composites present wider absorption bands, higher visible photocatalytic efficiencies, and lower costs. PMID- 23447331 TI - Reactions of Group 4 metallocene complexes with mono- and diphenylacetonitrile: formation of unusual four- and six-membered metallacycles. AB - Reactions of Group 4 metallocene alkyne complexes [Cp'2M(eta(2)-Me3SiC2SiMe3)] (1: M = Zr, Cp' = Cp* = eta(5)-pentamethylcyclopentadienyl; 2 a: M = Ti, Cp' = Cp*, and 2 b: M = Ti, Cp'2 = rac-(ebthi) = rac-1,2-ethylene-1,1'-bis(eta(5) tetrahydroindenyl)) with diphenylacetonitrile (Ph2CHCN) and of the seven-membered zirconacyclocumulene 3 with phenylacetonitrile (PhCH2CN) were investigated. Different compounds were obtained depending on the metal, the cyclopentadienyl ligand and the reaction temperature. In the first step, Ph2CHCN coordinated to 1 to form [Cp*2Zr(eta(2)-Me3SiC2SiMe3)(NCCHPh2)] (4). Higher temperatures led to elimination of the alkyne, coordination of a second Ph2CHCN and transformation of the nitriles to a keteniminate and an imine ligand in [Cp*2Zr(NC2Ph2)(NCHCHPh2)] (5). The conversion of 4 to 5 was monitored by using (1)H NMR spectroscopy. The analogue titanocene complex 2 a eliminated the alkyne first, which led directly to [Cp*2Ti(NC2Ph2)2] (6) with two keteniminate ligands. In contrast, the reaction of 2 b with diphenylacetonitrile involved a formal coupling of the nitriles to obtain the unusual four-membered titanacycle 7. An unexpected six-membered fused zirconaheterocycle (8) resulted from the reaction of 3 with PhCH2CN. The molecular structures of complexes 4, 5, 6, 7 and 8 were determined by X-ray crystallography. PMID- 23447145 TI - Renal perfusion imaging with two-dimensional navigator gated arterial spin labeling. AB - PURPOSE: To develop a navigator technique enabling free-breathing acquisition to afford sufficient signal averaging for quantitative renal perfusion measurement using arterial spin labeling MRI. METHODS: A novel two-dimensional (2D) navigator technique was implemented in concert with flow-sensitive alternating inversion recovery (FAIR) preparation and true fast imaging with steady precession (True FISP) readout. The navigator images were obtained with a low-resolution fast low angle shot readout at end of each arterial spin labeling acquisition. A retrospective algorithm was developed to automatically detect respiratory motion for selective signal averaging. The 2D navigator-gated FAIR True-FISP sequence was performed in ten healthy volunteers and five patients with chronic kidney disease. RESULTS: Excellent image quality and comparable cortical perfusion rates (healthy: 276 +/- 28 mL/100 g/min, patients: 155 +/- 25 mL/100 g/min) to literature values were obtained. An average of 3-fold signal-to-noise ratio improvement was obtained in the 2D navigator-gated approach compared with the breath-hold acquisition in healthy volunteers. Good image quality was achieved in patients while the results from breath-hold acquisition were unusable. The quantitative perfusion rates were significantly lower in chronic kidney disease patients compared with the healthy volunteers. CONCLUSION: 2D navigator-gated free breathing arterial spin labeling is feasible and is a noninvasive method to evaluate renal perfusion both in healthy subjects and those with chronic kidney disease. PMID- 23447332 TI - Improved conformational stability of the visual G protein-coupled receptor rhodopsin by specific interaction with docosahexaenoic acid phospholipid. AB - Rhodopsin is the photoreceptor located in the rod cells of the retina. It has seven transmembrane helices and is a prototypic member of the G protein-coupled receptor superfamily. The structures and functions of these receptors are clearly affected by the lipid composition of the cell membrane, and their study in a purified recombinant form is usually performed in detergent solution. There is a need to study these receptors in a physiologically relevant environment because the lipid environment is known to have an important effect on their function. In this work, rhodopsin reconstituted in docosahexaenoic acid (DHA) liposomes is shown to have more thermal stability than when it is solubilised with the neutral detergent dodecyl maltoside. Moreover, the specific interaction between rhodopsin and DHA was followed by means of Langmuir experiments with insertion of rhodopsin into lipid monolayers; this showed high affinity for the lipid-receptor interaction. Furthermore, fluorescence spectroscopy measurements indicate that the conformation of opsin obtained after photobleaching is preserved in DHA containing liposomes, thereby allowing retinal to re-enter the binding pocket even long after bleaching. Overall, our results demonstrate that liposomes of this specific lipid provide a more stable environment for ground-state inactive rhodopsin in the dark, than dodecyl maltoside detergent, and that this lipid can also preserve the native correctly folded ligand-free opsin conformation obtained after illumination. This strategy will be used in further studies on mutations of rhodopsin associated with congenital retinopathies. PMID- 23447333 TI - Anatomy and age estimation of an early blue whale (Balaenoptera musculus) fetus. AB - The external anatomy of a 130-mm blue whale fetus (Balaenoptera musculus) is described, and its internal anatomy is reconstructed noninvasively from microCT scans. The specimen lies developmentally at the junction of the embryonic and fetal periods. Similarly to the embryos of many odontocetes, it lacks a caudal fluke and dorsal fin, but it also exhibits an elongated rostrum, resorbed umbilical hernia, partially exposed cornea, and spatial separation of the anus and genitalia seen in early odontocete fetuses. Dermal ossification of the cranial bones has begun, but the endochondral skeleton is completely cartilaginous. The shape and position of the maxilla suggest that the earliest stages of anterior skull telescoping have begun, but there is no indication of occipital overlap posteriorly. The nasopharynx, larynx, and heart already display the distinctive morphology characteristic of Balaenoptera. This study develops a model of body length changes during blue whale development by integrating the large International Whaling Statistics (IWS) database, historical observations of blue whale migration and reproduction, and descriptions of fetal growth trends in other mammals. The model predicts an age of 65 days postconception for the specimen. The early developmental milestones of Balaenoptera mirror those of the odontocete Stenella to a remarkable extent, but the first appearance of the caudal fluke and dorsal fin are delayed relative to other morphological transitions. The accelerated prenatal growth characteristic of Balaenoptera occurs during fetal, not embryonic, development. PMID- 23447334 TI - The epigenetic effect of nicotine on dopamine D1 receptor expression in rat prefrontal cortex. AB - Nicotine is a highly addictive drug and exerts its effect partially through causing dopamine release, thereby increasing intrasynaptic dopamine levels in the brain reward systems. Dopaine D1 receptor (DRD1) mRNAs and receptors are localized in reward-related brain regions, which receive cholinergic input. The aim of this study is to evaluate whether nicotine administration affects the expression of DRD1s, and if so, whether epigenetic mechanisms, such as histone acetylation, are involved. Twenty Male Sprague Dawley rats received nicotine (0.4 mg/kg/day, s.c.) or saline injections for 15 days. After nicotine/saline treatment, rats were perfused with saline; prefrontal cortex (PFC), corpus striatum (STR), and ventral tegmental area (VTA) were dissected. Homogenates were divided into two parts for total RNA isolation and histone H4 acetylation studies. DRD1 mRNA expression was significantly higher in the PFC of the nicotine treated group compared with controls; similar trends were observed in the VTA and STR. To study epigenetic regulation, the 2kb upstream region of the DRD1 gene promoter was investigated for histone H4 acetylation in PFC samples. After chromatin immunoprecipitation with anti-acetyl histone H4 antibody, we found an increase in histone acetylation by two different primer pairs which amplified the -1365 to -1202 (P < 0.005) and -170 to +12 (P < 0.05) upstream regions of the DRD1 promoter. Our results suggest that intermittent subcutaneous nicotine administration increases the expression of DRD1 mRNA in the PFC of rats, and this increase may be due to changes in histone H4 acetylation of the 2kb promoter of the DRD1 gene. PMID- 23447335 TI - Identification of kazinol Q, a natural product from Formosan plants, as an inhibitor of DNA methyltransferase. AB - DNA methylation plays a pivotal role in the epigenetic regulation of the transcription of a number of cancer-related genes, thereby representing an important target for cancer prevention and treatment. In our search for DNA methyltransferase (DNMT) inhibitors from Formosan plants, by screening against a library consisting of 12 structurally distinct natural products, we identified kazinol Q {4-[6-(1,1-dimethyl-allyl)-7-hydroxy-chroman-2-yl]-3,6-bis-(3-methyl but-2-enyl)-benzene-1,2-diol} as an inhibitor of recombinant DNMT1 with IC50 of 7 MUM. The effect of kazinol Q on DNMT inhibition was validated by its ability to reactivate the expression of a DNA methylation-silenced gene, E-cadherin, in MDA MB-231 breast cancer cells. Moreover, kazinol Q suppressed the proliferation of MCF-7 breast and LNCaP prostate cancer cells, in part, through apoptosis induction. The role of DNMT1 inhibition in mediating kazinol Q's antiproliferative effect was supported by the protective effect of ectopic expression of DNMT1 on kazinol Q-induced cell death. Molecular modeling analysis suggests that kazinol Q inhibited DNMT activity by competing with cytosine binding, a mechanism similar to that described for (-)-epigallocatechin-3-gallate (EGCG). Relative to EGCG, kazinol Q exhibits several desirable features for drug development, including chemical stability and increased hydrophobicity, and might have therapeutic relevance to cancer treatment. PMID- 23447336 TI - A fast process for imprinting micro and nano patterns on electrospun fiber meshes at physiological temperatures. AB - Electrospun fiber meshes are patterned at length scales comparable to or lower than their fiber diameter. Simple nano- and microgrooves and closed geometric shapes are imprinted in different tones using a fast imprint process at physiological temperatures. Human mesenchymal stromal cells cultured on patterned scaffolds show differences in cellular morphology and cytoskeleton organization. Microgrooved electrospun fibers support upregulation of alkaline phosphatase and bone morphogenetic protein-2 gene expression when cells are cultured in osteogenic medium. PMID- 23447337 TI - Hepatitis C pathogenesis and outcomes after liver transplantation: probing microRNA expression for new insights. PMID- 23447339 TI - Dabigatran "non-inferior" to warfarin, but only just. PMID- 23447338 TI - Cemented, cementless, and hybrid prostheses for total hip replacement: cost effectiveness analysis. AB - OBJECTIVE: To compare the cost effectiveness of the three most commonly chosen types of prosthesis for total hip replacement. DESIGN: Lifetime cost effectiveness model with parameters estimated from individual patient data obtained from three large national databases. SETTING: English National Health Service. PARTICIPANTS: Adults aged 55 to 84 undergoing primary total hip replacement for osteoarthritis. INTERVENTIONS: Total hip replacement using either cemented, cementless, or hybrid prostheses. MAIN OUTCOME MEASURES: Cost (L), quality of life (EQ-5D-3L, where 0 represents death and 1 perfect health), quality adjusted life years (QALYs), incremental cost effectiveness ratios, and the probability that each prosthesis type is the most cost effective at alternative thresholds of willingness to pay for a QALY gain. RESULTS: Lifetime costs were generally lowest with cemented prostheses, and postoperative quality of life and lifetime QALYs were highest with hybrid prostheses. For example, in women aged 70 mean costs were L6900 ($11 000; ?8200) for cemented prostheses, L7800 for cementless prostheses, and L7500 for hybrid prostheses; mean postoperative EQ-5D scores were 0.78, 0.80, and 0.81, and the corresponding lifetime QALYs were 9.0, 9.2, and 9.3 years. The incremental cost per QALY for hybrid compared with cemented prostheses was L2500. If the threshold willingness to pay for a QALY gain exceeded L10 000, the probability that hybrid prostheses were most cost effective was about 70%. Hybrid prostheses have the highest probability of being the most cost effective in all subgroups, except in women aged 80, where cemented prostheses were most cost effective. CONCLUSIONS: Cemented prostheses were the least costly type for total hip replacement, but for most patient groups hybrid prostheses were the most cost effective. Cementless prostheses did not provide sufficient improvement in health outcomes to justify their additional costs. PMID- 23447340 TI - Young adults with shorter telomeres have lower resistance to colds. PMID- 23447341 TI - Worse outcomes for adults given lactated Ringer's solution during resuscitation. PMID- 23447342 TI - Advanced breast cancers increasing in young women. PMID- 23447343 TI - Andy Burnham's "whole person" care: the labour shadow health secretary's proposal for merging health and social care gives grounds for hope. PMID- 23447344 TI - GLP-1 based agents and acute pancreatitis : drug safety falls victim to the three monkey paradigm. PMID- 23447345 TI - Physician groups each identify five of their own inappropriate practices. PMID- 23447346 TI - Inquiry launched into newspaper story about babies on "death pathway". PMID- 23447347 TI - Making the best use of administrative data : the difficulty of teasing out demand and supply. PMID- 23447348 TI - Mediterranean diets do work, confirms trial from Spain. PMID- 23447349 TI - CABG not PCI for most people with complex coronary artery disease. PMID- 23447350 TI - Spironolactone made no difference to patients with mild diastolic heart failure. PMID- 23447352 TI - Novel coronavirus: how much of a threat? We know the questions to ask; we don't yet have many answers. PMID- 23447353 TI - In and out of hospital. Retirement: the four year itch. PMID- 23447354 TI - Maximising opportunities for increased antiretroviral treatment in children in an existing HIV programme in rural South Africa. PMID- 23447355 TI - Suspected left sided diverticulitis. PMID- 23447356 TI - Surface topographic characterization for polyamide composite injection molds made of aluminum and copper alloys. AB - In order to ensure flexibility and rapid new product development, the mold industry made use of soft materials for cavity inserts in injection molds. However, materials of this kind are prone to wear. This article analyzes the topographic characterization of the surface and wear processes in injection molds cavities. Two materials have been used to produce the cavities: aluminum alloy EN AW-6082 T4 and copper alloy Cu Zn39 Pb3. The surface topography was measured with the use of optical interferometry profiling technology; roughness and surface parameters were determined according to ISO 4287, ISO 25178, and EUR 15178N. In order to complete this research, an experimental part with different thicknesses and shapes was designed, and cavity inserts of aluminum and copper were made. Polyamide PA6, with 30% fiberglass reinforcement, was employed in the experimental procedure. Measurements of cavity mold surfaces were performed after 9,200 cycles on each mold and at different locations on the mold. The surface measurement was made with a white light vertical scanning interferometry, also known as coherence scanning interferometry (ISO DIS 25178-604). The results are analyzed and differences between the two types of cavity inserts materials are discussed. PMID- 23447357 TI - Estrogen, progesterone, and HER-2 receptor immunostaining in cytology: the effect of varied fixation on human breast cancer cells. AB - The ASCO/CAP Expert Panel recommends that all invasive breast carcinomas and breast cancer recurrences be tested for ER, PR and HER-2 expression. The guidelines for testing of surgical specimens by immunohistochemistry (IHC) are well defined, whereas they are lacking for cytological samples. We evaluated various fixation protocols for optimal receptor testing by immunohistochemistry and immunocytochemistry (ICC) of human breast cancer cell lines MCF-7 (ER/PR positive) and SKBR-3 (overexpressing HER-2). The cells were fixed in 10% neutral buffered formalin or Saccomanno Fixative (SF) for various time points, and either embedded in paraffin as cell blocks or prepared as cytospins. ER and PR slides were assigned a proportion score (PS; 0-5), an intensity score (IS; 0-3) and a total score (TS = PS + IS). Standard DAKO scoring system ranging from 0 to 3+ was used for the evaluation of HER-2 staining. Human breast cancer cells stained successfully for ER, PR and HER-2 when fixed in formalin and prepared as cell blocks. The optimal fixation time for formalin-fixed cells ranged from 2 to 96 hours. Cells fixed in SF from 2 to 96 hours also stained well for ER and PR. However, SF produced variable results for HER-2 staining; particularly, SF fixation beyond 24 hours caused false negative results. The interpretation of HER 2 staining on cytospins was not feasible irrespective of the fixative and fixation time. In summary, formalin fixation from 2 to 96 hours and preparation of cells as cell blocks produces optimal results for ER, PR, and HER-2 testing in human breast cancer cells. PMID- 23447358 TI - 1H and 13C NMR assignments of two new isomeric bisbenzylisoquinoline alkaloids from Cissampelos sympodialis Eichl. (Menispermaceae). AB - des-7'-O-methylroraimine (compound 1) and epi-des-7'-O-methylroraimine (compound 2), two new isomeric bisbenzylisoquinoline alkaloids were isolated and characterized as a mixture from the rhizomes of Cissampelos sympodialis Eichl. The unambiguous structural elucidation of both isomers was performed with the aid of HR-ESI-MS, FT-IR, and NMR techniques including COSY, HMQC, HMBC, and NOESY. PMID- 23447361 TI - Resident-to-resident violence triggers in nursing homes. AB - Certified nurses' assistants (CNAs) employed by a rural nursing home in Northeast Arkansas described their perceptions of resident-to-resident violence in order to provide insight on factors, including unmet needs, that may trigger the phenomenon. Semistructured interviews were conducted with 11 CNAs. Data were analyzed using content analysis and constant comparison. Two categories of triggers emerged from the data-active and passive. Active triggers involved the actions of other residents that were intrusive in nature, such as wandering into a residents' personal space, taking a resident's belongings, and so forth. Passive triggers did not involve the actions of residents but related to the internal and external environment of the residents. Examples were factors such as boredom, competition for attention and communication difficulties. Results indicate that there are factors, including unmet needs within the nursing home environment that may be identified and altered to prevent violence between residents. PMID- 23447360 TI - Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. AB - OBJECTIVE: To examine changes in the response properties of meningeal nociceptors that might lead to migraine pain and examine endogenous processes that could play a role in mediating them using a clinically relevant model of migraine triggering, namely infusion of the nitric oxide (NO) donor nitroglycerin (NTG). METHODS: Single-unit recordings made in the trigeminal ganglion of rats were used to test changes in the activity and mechanosensitivity of meningeal nociceptors in response to administration of the migraine trigger NTG or another NO donor S nitroso-N-acetyl-DL-penicillamine (SNAP) at doses relevant to the human model of migraine headache. Immunohistochemistry and pharmacological manipulations were used to investigate the possible role of meningeal vascular signaling in mediating the responses of meningeal nociceptors to NO. RESULTS: Infusion of NTG promoted a delayed and robust increase in the mechanosensitivity of meningeal nociceptors, with a time course resembling the development of the delayed migraine headache. A similar sensitization was elicited by dural application of NTG and SNAP. NTG-evoked delayed meningeal nociceptor sensitization was associated with a robust extracellular signal-regulated kinase (ERK) phosphorylation in meningeal arteries. Pharmacological blockade of meningeal ERK phosphorylation inhibited the development of NTG-evoked delayed meningeal nociceptor sensitization. INTERPRETATION: The development of delayed mechanical sensitization evoked by the migraine trigger NTG is potentially of great importance as the first finding of a neurophysiological correlate of migraine headache in meningeal nociceptors. The arterial ERK phosphorylation and its involvement in mediating the NTG-evoked delayed sensitization points to an important, yet unappreciated, role of the meningeal vasculature in the genesis of migraine pain. PMID- 23447362 TI - Alanine scan of the peptide antibiotic feglymycin: assessment of amino acid side chains contributing to antimicrobial activity. AB - The antibiotic feglymycin is a linear 13-mer peptide synthesized by the bacterium Streptomyces sp. DSM 11171. It mainly consists of the nonproteinogenic amino acids 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine. An alanine scan of feglymycin was performed by solution-phase peptide synthesis in order to assess the significance of individual amino acid side chains for biological activity. Hence, 13 peptides were synthesized from di- and tripeptide building blocks, and subsequently tested for antibacterial activity against Staphylococcus aureus strains. Furthermore we tested the inhibition of peptidoglycan biosynthesis enzymes MurA and MurC, which are inhibited by feglymycin. Whereas the antibacterial activity is significantly based on the three amino acids D-Hpg1, L Hpg5, and L-Phe12, the inhibitory activity against MurA and MurC depends mainly on L-Asp13. The difference in the position dependence for antibacterial activity and enzyme inhibition suggests multiple molecular targets in the modes of action of feglymycin. PMID- 23447359 TI - Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. AB - OBJECTIVE: The purpose of this study was to determine the effects of oral teriflunomide on multiple sclerosis (MS) pathology inferred by magnetic resonance imaging (MRI). METHODS: Patients (n=1088) with relapsing MS were randomized to once-daily teriflunomide 7 mg or 14 mg, or placebo, for 108 weeks. MRI was recorded at baseline, 24, 48, 72 and 108 weeks. Annualized relapse rate and confirmed progression of disability (sustained >=12 weeks) were the primary and key secondary outcomes. The principal MRI outcome was change in total lesion volume. RESULTS: After 108 weeks, increase in total lesion volume was 67.4% (p=0.0003) and 39.4% (p=0.0317) lower in the 14 and 7 mg dose groups versus placebo. Other measures favoring teriflunomide were accumulated enhanced lesions, combined unique activity, T2-hyperintense and T1-hypointense component lesion volumes, white matter volume, and a composite MRI score; all were significant for teriflunomide 14 mg and most significant for 7 mg versus placebo. CONCLUSIONS: Teriflunomide provided benefits on brain MRI activity across multiple measures, with a dose effect evident on several markers. These effects were also consistent across selected subgroups of the study population. These findings complement clinical data showing significant teriflunomide-related reductions in relapse rate and disease progression, and demonstrate containment of MRI-defined disease progression. PMID- 23447363 TI - Viruses: are they really culprits for periodontal disease? A critical review. AB - Periodontal diseases are multifactorial, and many etiological agents are suggested to play a role in their etiopathogenesis. Various risk factors are also suggested to influence the progression of periodontal disease. Until recently, specific bacteria were considered the major pathogens for the disease. However, the occurrence of periodontal disease in some patient groups is still poorly understood, and the role of other initiating agents is being investigated. Evidence strongly suggests the presence of many strains of viruses in the periodontal environment, and possible mechanisms have also been suggested. Periodontal disease as a risk factor for other systemic diseases can also be better explained based on this viral etiology. In this review, we critically analyze the role of viruses in different periodontal diseases, and provide a categorical description of the underlying mechanisms. Clinical implications and future directions are also discussed. Evidence of a causal role of herpes viruses in periodontitis might revolutionize existing strategies to diagnose, prevent, and treat the disease. PMID- 23447364 TI - Stereodynamics of metal-ligand assembly: what lies beneath the "simple" spectral signatures of C2-symmetric chiral chelates. AB - A series of C2-symmetric chiral tetra-dentate ligands were prepared by using [4,5]- or [5,6]-pinene-fused 2,2'-bipyridyl units that are supported across a rigid arylene-ethynylene backbone. These conformationally pre-organised chelates support stable 1:1 metal complexes, which were fully characterised by UV/Vis, fluorescence, circular dichroism (CD), and (1)H NMR spectroscopy. A careful inspection of the exciton-coupled circular dichroism (ECCD) and (1)H NMR spectra of the reaction mixture in solution, however, revealed the evolution and decay of intermediate species en route to the final 1:1 metal-ligand adduct. Consistent with this model, mass spectrometric analysis revealed the presence of multiple metal complexes in solution at high ligand-to-metal ratios, which were essentially unobservable by UV/Vis or fluorescence spectroscopic techniques. Comparative studies with a bi-dentate model system have fully established the functional role of the pi-conjugated ligand skeleton that dramatically enhances the thermodynamic stability of the 1:1 complex. In addition to serving as a useful spectroscopic handle to understand the otherwise "invisible" solution dynamics of this metal-ligand assembly process, temperature-dependent changes in the proton resonances associated with the chiral ligands allowed us to determine the activation barrier (DeltaG(?)) for the chirality switching between the thermodynamically stable but kinetically labile (P)- and (M)-stereoisomers. PMID- 23447365 TI - Circulating tumor cells in pancreatic cancer patients: methods of detection and clinical implications. AB - The poor prognosis of pancreatic cancer patients is associated with the frequent and early dissemination of the disease, as well as late detection due to unspecific and late symptoms from the primary tumor. Pancreatic cancers frequently spread to the liver, lung and skeletal system, suggesting that pancreatic tumor cells must be able to intravasate and travel through the circulation to distant organs. Circulating tumor cells (CTCs) are tumor cells that have acquired the ability to enter the circulatory system; this cell population is ultimately responsible for the development of metastases in distant organs. Clinical studies have revealed that the presence of CTCs in blood is correlated with disease progression for other cancers, such as breast, colorectal and prostate cancer. However, as CTCs are extremely rare, both enrichment and sensitive methods of detection are required for their enumeration. This review highlights various enrichment procedures and methods for the detection of CTCs. Furthermore, we systematically review previously reported studies of the clinical relevance of CTC detection in pancreatic cancer patients. There is evidence that the presence of CTCs also correlates with an unfavorable outcome in pancreatic cancer patients. However, technical/methodological issues may explain why some studies only show a trend toward an association between CTC detection and disease progression. Larger studies, as well as characterization of the CTC population, are required to achieve further insight into the clinical implications of CTC detection in pancreatic cancer patients. PMID- 23447366 TI - Comparative pharmacokinetic study of chlorogenic acid after oral administration of Lonicerae Japonicae Flos and Shuang-Huang-Lian in normal and febrile rats. AB - Shuang-Huang-Lian (SHL), a famous traditional Chinese medicine recipe containing Lonicerae Japonicae Flos (LJF), Forsythiae Fructus, and Scutellariae Radix, is clinically used for the treatment of fever and acute upper respiratory tract infection. In this research, a comparative study was conducted to compare the pharmacokinetic difference of chlorogenic acid (ChA) after oral administration of LJF and SHL to normal and febrile rats with approximately the same dose of 60 mg/kg, and the antipyrexia effect of LJF and SHL on rectal temperature changes induced by Baker's yeast was investigated. The results indicated that AUC(0-t) and plasma concentrations of ChA in the febrile rats were significantly higher than normal rats whether in the extract of LJF or SHL. In addition, SHL increased the values of AUC of ChA in both febrile and normal rats compared with LJF alone (p < 0.05), and SHL showed better antipyrexia effect than LJF. These results indicate that fever could play an important role in pharmacokinetic process of ChA. Meanwhile, the combined formula SHL exhibits higher bioavailability of ChA and superior antipyrexia effect than the single herb. PMID- 23447367 TI - Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats. AB - Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-Fos, FosB/DeltaFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/DeltaFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. PMID- 23447368 TI - Self-organization of honeycomb-like porous TiO2 films by means of the breath figure method for surface modification of titanium implants. AB - This study describes a facile breath-figure method for the preparation of honeycomb-like porous TiO2 films with an organometallic small-molecule precursor. Multiple characterization techniques have been used to investigate the porous films and a mechanism for the formation process of porous TiO2 films through the breath-figure method is proposed. The pore size of the TiO2 films could be modulated by varying the experimental parameters, such as the concentration of titanium n-butoxide (TBT) solution, the content of cosolvent, and the air flow rate. In vitro cell-culture experiments indicate that NIH 3T3 fibroblast cells seeded on the honeycomb-like porous TiO2 films show good adhesion, spreading, and proliferation behaviors, which suggests that honeycomb-like porous TiO2 films are an attractive biomaterial for surface modification of titanium and its alloys implants in tissue engineering to enhance their biocompatibility and bioactivity. PMID- 23447369 TI - A quantitative approach for understanding small-scale human mesenchymal stem cell culture - implications for large-scale bioprocess development. AB - Human mesenchymal stem cell (hMSC) therapies have the potential to revolutionise the healthcare industry and replicate the success of the therapeutic protein industry; however, for this to be achieved there is a need to apply key bioprocessing engineering principles and adopt a quantitative approach for large scale reproducible hMSC bioprocess development. Here we provide a quantitative analysis of the changes in concentration of glucose, lactate and ammonium with time during hMSC monolayer culture over 4 passages, under 100% and 20% dissolved oxgen (dO2 ), where either a 100%, 50% or 0% growth medium exchange was performed after 72h in culture. Yield coefficients, specific growth rates (h(-1) ) and doubling times (h) were calculated for all cases. The 100% dO2 flasks outperformed the 20% dO2 flasks with respect to cumulative cell number, with the latter consuming more glucose and producing more lactate and ammonium. Furthermore, the 100% and 50% medium exchange conditions resulted in similar cumulative cell numbers, whilst the 0% conditions were significantly lower. Cell immunophenotype and multipotency were not affected by the experimental culture conditions. This study demonstrates the importance of determining optimal culture conditions for hMSC expansion and highlights a potential cost savings from only making a 50% medium exchange, which may prove significant for large-scale bioprocessing. PMID- 23447370 TI - Find it in your heart. PMID- 23447371 TI - Combination of COSMOmic and molecular dynamics simulations for the calculation of membrane-water partition coefficients. AB - The importance of membrane-water partition coefficients led to the recent extension of the conductor-like screening model for realistic solvation (COSMO RS) to micelles and biomembranes termed COSMOmic. Compared to COSMO-RS, this new approach needs structural information to account for the anisotropy of colloidal systems. This information can be obtained from molecular dynamics (MD) simulations. In this work, we show that this combination of molecular methods can efficiently be used to predict partition coefficients with good agreement to experimental data and enables screening studies. However, there is a discrepancy between the amount of data generated by MD simulations and the structural information needed for COSMOmic. Therefore, a new scheme is presented to extract data from MD trajectories for COSMOmic calculations. In particular, we show how to calculate the system structure from MD, the influence of lipid conformers, the relation to the COSMOmic layer size, and the water/lipid ratio impact. For a 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer, 66 partition coefficients for various solutes were calculated. Further, 52 partition coefficients for a 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer system were calculated. All these calculations were compared to experimental data. PMID- 23447372 TI - Psammoma bodies and abundant stromal amyloid in an endoscopic ultrasound guided fine needle aspirate (EUS-FNA) of a pancreatic neuroendocrine tumor: a potential pitfall. PMID- 23447374 TI - Candida tropicalis BPU1, a novel isolate from the rumen of the Malabari goat, is a dual producer of biosurfactant and polyhydroxybutyrate. AB - This unique study reports a new strain (BPU1) of Candida tropicalis isolated from the rumen of the Malabari goat, showing dual production of biosurfactant and polyhydroxybutyrate. C. tropicalis strain BPU1, a facultative anaerobe, was tuned to become an aerobe in specially designed flask, the Benjamin flask. The puffy circular colonies were smooth, white-to-cream in colour, with pseudo-filaments. The strain fermented glucose, sucrose, maltose and dextrose, but not lactose and cellulose. It assimilated (NH4 )2 SO4 , peptone, glycine and arginine, but not NaNO3 , as the nitrogen source. Interestingly, it utilized groundnut oil (up to 0.3%) in a specially designed basal mineral salt medium (BSM). Its capability for dual production of a biosurfactant and a polyhydroxybutyarate (PHB) was explored by various methods from the BSM-oil medium. Extracted biosurfactant from 6 day old culture was biochemically characterized as a complex of lipid and carbohydrate with an Rf value of 0.88 by thin layer chromatography. Its PHB production was confirmed by specific staining methods with Nile blue sulphate, Sudan black B and Sudan 3. Briefly, this first-ever report gives ample physical evidence for the dual production of a glycolipid (biosurfactant) and PHB by C. tropicalis strain BPU1 on a specially designed medium, which would open up elaborate research on this yeast. PMID- 23447373 TI - Cholinergic enhancement of functional networks in older adults with mild cognitive impairment. AB - OBJECTIVE: The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group. METHODS: We conducted a 3-month, double-blind, placebo-controlled study on the effects of donepezil in 27 older adults with mild memory deficits. Participants completed a delayed recognition memory task. Functional magnetic resonance imaging (fMRI) scans were collected at baseline prior to treatment and at 3-month follow-up while subjects were on a 10mg daily dose of donepezil or placebo. RESULTS: Donepezil treatment significantly enhanced the response time for face and scene memory probes when compared to the placebo group. A group-by visit interaction was identified for the functional network connectivity of the left fusiform face area (FFA) with the hippocampus and inferior frontal junction, such that the treatment group showed increased connectivity over time when compared to the placebo group. Additionally, the enhanced functional network connectivity of the FFA and hippocampus significantly predicted memory response time at 3-month follow-up in the treatment group. INTERPRETATION: These findings suggest that increased cholinergic transmission improves goal-directed neural processing and cognitive ability and may serve to facilitate communication across functionally-connected attention and memory networks. Longitudinal fMRI is a useful method for elucidating the neural changes associated with pharmacological modulation and is a potential tool for monitoring intervention efficacy in clinical trials. PMID- 23447375 TI - Genetic analysis of Porphyromonas gingivalis (fimA), Aggregatibacter actinomycetemcomitans, and red complex in coronary plaque. AB - AIM: The objective of the present study was to detect the presence of Porphyromonas gingivalis (fimA), Aggregatibacter actinomycetemcomitans, and red complex in the coronary plaque of patients with coronary artery disease. METHODS: The study population consisted of 51 patients with chronic periodontitis undergoing coronary artery bypass grafting. DNA was extracted from subgingival and coronary atherosclerotic plaque samples. Polymerase chain reaction was used to amplify the part of 16S rRNA gene to detect the presence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis (fimA), Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola. RESULTS: Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, Porphyromonas gingivalis (fimA), and Treponema denticola were detected in 0%, 31.4%, 45.1%, 39.2%, and 51% of the atherosclerotic plaque samples, respectively. In both subgingival and coronary atherosclerotic plaque samples, Tannerella forsythia was detected in 19.6%, Porphyromonas gingivalis in 39.2%, Porphyromonas gingivalis (fimA) in 33.3%, and Treponema denticola in 35.3% of the samples. CONCLUSION: The study confirmed the detection of red complex bacteria in coronary plaque samples. However Aggregatibacter actinomycetemcomitans could not be detected in these samples. PMID- 23447376 TI - Efficacy of Seprafilm((r)) graft with adhesiolysis in experimentally induced lid adhesion in rabbits. AB - AIM: To evaluate the efficacy of Seprafilm((r)) transplantation following adhesiolysis for preventing postoperative readhesion and improving surgical outcomes. METHODS: Primary blepharoplasty was carried out on both eyelids of 18 albino rabbits. After 2 weeks, a new skin incision was made, and adhesiolysis was performed on both eyelids. The rabbits were categorized into two groups, one with adhesiolysis alone in the left eyelid (control group), and the other with adhesiolysis with a Seprafilm((r)) graft in the right eyelid (Seprafilm((r)) group). The degrees of inflammation and fibrosis were examined with hematoxylin eosin (HE) and Masson's trichrome stains. Expression of alpha-smooth muscle actin (alpha-SMA) was also immunohistochemically examined. RESULTS: Eyelid examination immediately after the operation revealed mild swelling and hemorrhage in both groups, but these symptoms resolved after 1 week-2 weeks, and eyelid shape had recovered completely in both groups. Microscopic assessments demonstrated that the Seprafilm((r)) group showed less inflammation and fibrosis than the control group. The Seprafilm((r)) group also exhibited fewer alpha-SMA-positive cells than the control group. CONCLUSION: Based on these findings, we conclude that Seprafilm((r)) graft with adhesiolysis is an effective method for preventing postoperative readhesions after eyelid surgery. PMID- 23447377 TI - D-penicillamine capped cadmium telluride quantum dots as a novel fluorometric sensor of copper(II). AB - D-penicillamine-capped cadmium telluride quantum dots (DPA-capped CdTe QDs) were synthesized as the new fluorescent semiconductor nanocrystal in aqueous solution. Fourier transmission infrared spectroscopy, X-ray diffraction, transmission electron microscopy, ultraviolet-visible and photoluminescence spectroscopy were used for characterization of the QDs. Based on the quenching effect of Cu(2+) ions on the fluorescence intensity of DPA-capped CdTe QDs, a new fluorometric sensor for copper(II) detection was developed that showed good linearity over the concentration range 5 * 10(-9)-3 * 10(-6) M with the detection limit 0.4 * 10(-9) M. Owing to the strong affinity of the DPA to copper(II), the sensor showed appropriate selectivity for copper(II) compared with conventional QDs. The DPA capped CdTe QDs was successfully applied for determination of Cu(2+) concentration in river, well and tap waters with satisfactory results. PMID- 23447379 TI - Systematic investigation of silver-carbon bonding in coordination frameworks with aryl ligands that contain ethynyl and ethenyl substituents. AB - Single-crystal X-ray diffraction of a series of ten crystalline silver(I) trifluoroacetate complexes that contained designed ligands, each of which was composed of an aromatic system that was functionalized with terminal and internal ethynyl groups and a vinyl substituent, provided detailed information on the influence of ligand disposition and orientation, coordination preferences, and the co-existence of different types of silver(I)-carbon bonding interactions (silver-ethynide, silver-ethynyl, silver-ethenyl, and silver-aromatic) on the construction of coordination networks that were consolidated by argentophilic and weak inter/intramolecular interactions. The complex AgL10?6 AgCF3CO2?H2O? MeOH (HL10 = 1-{[4-(prop-2-ynyloxy)-3-vinylphenyl]ethynyl}naphthalene) is the first reported example that exhibits all four kinds of silver(I)-carbon bonding interactions in the solid state. PMID- 23447378 TI - Development of 3D hydrogel culture systems with on-demand cell separation. AB - Recently there has been an increased interest in the effects of paracrine signaling between groups of cells, particularly in the context of better understanding how stem cells contribute to tissue repair. Most current 3D co culture methods lack the ability to effectively separate two cell populations after the culture period, which is important for simultaneously analyzing the reciprocal effects of each cell type on the other. Here, we detail the development of a 3D hydrogel co-culture system that allows us to culture different cell types for up to 7 days and subsequently separate and isolate the different cell populations using enzyme-sensitive glues. Separable 3D co-culture laminates were prepared by laminating PEG-based hydrogels with enzyme-degradable hydrogel adhesives. Encapsulated cell populations exhibited good segregation with well-defined interfaces. Furthermore, constructs can be separated on-demand upon addition of the appropriate enzyme, while cell viability remains high throughout the culture period, even after laminate separation. This platform offers great potential for a variety of basic cell signaling studies as the incorporation of an enzyme-sensitive adhesive interface allows the on-demand separation of individual cell populations for immediate analysis or further culture to examine persistence of co-culture effects and paracrine signaling on cell populations. PMID- 23447380 TI - Synthesis of highly strained mesostructured SrTiO(3)/BaTiO(3) composite films with robust ferroelectricity. AB - A new class of highly stable ferroelectric material, that is, a mesostructured SrTiO(3)/BaTiO(3) composite film, obtained by a surfactant-templated sol-gel method is reported. Due to the concave surface geometry and abundant hetero interface between SrTiO(3) (ST) and BaTiO(3) (BT) phases, a large number of strains can be created in the composite film, thereby leading to dramatic enhancement of ferroelectric property (see scheme). PMID- 23447381 TI - Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis. AB - OBJECTIVE: The immunopathogenesis of multiple sclerosis (MS) has always been thought to be driven by chronically activated and autoreactive Th-1 and Th-17 cells. Recently, dendritic cells (DCs) have also been thought to significantly contribute to antigenic spread and to maturation of adaptive immunity, and have been linked with disease progression and exacerbation. However, the role of DCs in MS pathogenesis remains poorly understood. METHODS: We compared the level of cytokine production by myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in healthy subjects and MS patients, following in vitro stimulation of Toll-like receptors 7/8. We also evaluated the effect of the main endocannabinoid, anandamide (AEA), in these DC subsets and correlated cytokine levels with defects in the endocannabinoid system. RESULTS: mDCs obtained from MS patients produce higher levels of interleukin-12 and interleukin-6, whereas pDCs account for lower levels of interferon-alpha compared to healthy subjects. AEA significantly inhibited cytokine production from healthy mDCs and pDCs, as well as their ability to induce Th-1 and Th-17 lineages. Moreover, we found that in MS only pDCs lack responsiveness to cytokine inhibition induced by AEA. Consistently, this specific cell subset expresses higher levels of the anandamide hydrolase fatty acid amide hydrolase (FAAH). INTERPRETATION: Our data disclose a distinct immunomodulatory effect of AEA in mDCs and pDCs from MS patients, which may reflect an alteration of the expression of FAAH, thus forming the basis for the rational design of new endocannabinoid-based immunotherapeutic agents targeting a specific cell subset. PMID- 23447382 TI - White matter integrity affected by depressive symptoms in migraine without aura: a tract-based spatial statistics study. AB - Previous studies have proven that migraine and depression are bidirectionally linked. However, few studies have investigated white matter (WM) integrity affected by depressive symptoms in patients suffering from migraine without aura (MWoA). Forty patients with MWoA were divided into two groups according to their self-rating depression scale (SDS) score in the present study, including 20 in the SDS (+) (SDS > 49) group and 20 in the SDS (-) (SDS <= 49) group. Forty healthy participants were also recruited as the control group. Tract-based spatial statistics analyses with multiple diffusion tensor imaging-derived indices [fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)] were employed collectively to investigate WM integrity between all patients with MWoA and all healthy controls, between each subgroup (SDS (-) group and SDS (+) group) and healthy controls, and between the SDS (-) and SDS (+) groups. Compared with healthy controls, decreased AD was shown in several WM tracts of the whole MWoA group, SDS (-) group and SDS (+) group. In addition, compared with the SDS (-) group, the SDS (+) group showed decreased FA and increased MD and RD, with conserved AD, including the genu, body and splenium of the corpus callosum, bilateral superior longitudinal fasciculi, the right anterior corona radiata and some other WM tracts, similar to previous findings in depression disorder. Furthermore, mean FA and RD in some of the above mentioned WM tracts in the SDS (+) group were correlated significantly with SDS scores, including the genu and splenium of the corpus callosum, the right anterior corona radiata and the superior longitudinal fasciculi. Our results suggest that WM integrity may be affected by both depression symptoms (more sensitive as RD) and migraine (more sensitive as AD). The findings may serve as a sensitive biomarker of depression severity in MWoA. PMID- 23447383 TI - The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients. AB - Angiogenesis has been shown to substantially contribute to the progression of chronic lymphocytic leukemia (CLL). Neuropilin-1 (NRP1) represents a receptor for vascular endothelial growth factor (VEGF), which has been reported to be overexpressed in several malignancies. In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed. Earlier we described the specific Treg reduction during the therapy with thalidomide in vivo. Now we observe the reduction of the NRP1 expression on Tregs in vitro, thereby suggesting a possible target of thalidomide action. In conclusion, NRP1 might represent an interesting link between angiogenesis and tolerance mechanisms and represents interesting target for therapy. PMID- 23447384 TI - When there is not plenty for everyone: options for reconstructing a suprahepatic vena cava injured during organ procurement. PMID- 23447385 TI - Prenatal counseling for congenital anomaly tests: parental preferences and perceptions of midwife performance. AB - OBJECTIVE: Evidence-based instruments to evaluate the preferences and experiences of future parents regarding prenatal counseling for congenital anomaly tests are currently lacking. We developed the quality of care through clients' eyes prenatal questionnaire (QUOTE(prenatal) ), a client-centered instrument, and assessed its components. Furthermore, the QUOTE(prenatal) was used to provide insight into (1) clients' previsit preferences and (2) clients' postvisit experience, that is, perceived care provider performance regarding the counseling they received. METHOD: In the questionnaire survey, a principal component analysis was used to gain insight into the underlying components of the questionnaire. Regression analysis was performed to examine differences between groups. RESULTS: In 17 Dutch midwifery practices, 941 pregnant women and their partners (response rate 79%) completed the 59-item QUOTE(prenatal) previsit and postvisit, measuring preferences and perceived performances, respectively. A principal component analysis revealed three counseling components: client-midwife relation, health education and decision-making support. Reponses showed that, previsit, most clients consider the client-midwife relationship and health education to be (very) important. One third of the clients consider decision making support to be (very) important. Nulliparae had higher preferences for health education and decision-making support than multiparae. CONCLUSION: Clients perceive that their midwives perform well in building the client-midwife relationship and in giving health education. Improvement is needed in decision making support. PMID- 23447386 TI - Prevalence and associated factors of gingival recession in Greek adults. AB - AIM: The aim of the present cross-sectional study was to estimate gingival recession (GR) prevalence and associated risk factors in young Greek adults. METHODS: The study population consisted of 420 young adults (200 males and 220 females). All individuals were clinically examined and answered questions regarding their smoking status, educational level, and oral hygiene practices. In addition, the association between GR and the following aspects was assessed: sex, smoking status, educational level, plaque index, gingival index, calculus presence, and plaque control methods. Statistical analysis of data was accomplished using the multivariate linear regression analysis model. RESULTS: The average number of GR overall was 1.38 mm (standard deviation: 0.18 mm). Gingival index (P = 0.000) and smoking (P = 0.01) were the most important associated risk factors of GR, while sex, oral hygiene practices, presence of supragingival calculus, educational level, and plaque index were not significantly associated with it. CONCLUSION: Gingival inflammation, as determined by the gingival index, and smoking were the most important associated risk factors of GR. PMID- 23447387 TI - Relative sensitivity of thyroid fine-needle aspiration by tumor type and size. AB - BACKGROUND: Fine-needle aspiration (FNA) of papillary thyroid carcinoma (PTC) has high sensitivity. Previous studies demonstrated correlation between FNA sensitivity and PTC size, and lower sensitivity for follicular variant of PTC (FVPTC). Data are lacking for other types of thyroid carcinomas. METHODS: 996 resected thyroid carcinomas at two institutions (6- and 10-year periods) were correlated with FNA diagnoses and clinical and radiologic data to determine sensitivity for each malignancy type. RESULTS: There were 867 PTCs (371 FVPTC), 101 follicular carcinomas (FCs) (31 oncocytic), 16 medullary carcinomas, and 12 poorly differentiated carcinomas (PDCAR). Mean size of classical PTC (CPTC; 1.9 cm) was smaller than FVPTC (2.2 cm), FC (3.0 cm), oncocytic FC (3.0 cm), and PDCAR (2.8 cm) (P<0.003 each), but not medullary carcinoma (1.7 cm) (P=0.45). Sensitivity was higher for CPTC (88%), compared to FVPTC (78%; P<0.0001) and FC (71%; P=0.0006) and was lower for FC than PDCAR (100%; P<0.04). For tumors <=1.0 cm, FNA sensitivity for CPTC was higher than for FVPTC (P=0.02). For tumors 1.1 2.9 cm, sensitivity for CPTC was better than FVPTC (P=0.0001) and FC (P=0.0008). Between size groups, only CPTC showed a significant change with decreased sensitivity for tumors >=3.0 cm (P<0.003). CONCLUSION: FNA is more sensitive for CPTC, PDCAR, and medullary carcinoma. For CPTC, FNA sensitivity is highest for tumors 1.1-2.9 cm. FNA sensitivity is higher for CPTC than FVPTC for nodules <3.0 cm. FNA sensitivity is lower for FC than CPTC and PDCAR. PMID- 23447389 TI - Liver transplantation in a patient with Ehlers-Danlos syndrome. PMID- 23447388 TI - GABA shunt mediates thermotolerance in Saccharomyces cerevisiae by reducing reactive oxygen production. AB - The GABA shunt pathway involves three enzymes, glutamate decarboxylase (GAD), GABA aminotransferase (GAT) and succinate semialdehyde dehydrogenase (SSADH). These enzymes act in concert to convert glutamate (alpha-ketoglutarate) to succinate. Deletion mutations in each of these genes in Saccharomyces cerevisiae resulted in growth defects at 45 degrees C. Double and triple mutation constructs were compared for thermotolerance with the wild-type and single mutant strains. Although wild-type and all mutant strains were highly susceptible to brief heat stress at 50 degrees C, a non-lethal 30 min at 40 degrees C temperature pretreatment induced tolerance of the wild-type and all of the mutants to 50 degrees C. The mutant strains collectively exhibited similar susceptibility at 45 degrees C to the induced 50 degrees C treatments. Intracellular reactive oxygen intermediate (ROI) accumulation was measured in wild-type and each of the mutant strains. ROI accumulation in each of the mutants and in various stress conditions was correlated to heat susceptibility of the mutant strains. The addition of ROI scavenger N-tert-butyl-alpha-phenylnitrone (PBN) enhanced survival of the mutants and strongly inhibited the accumulation of ROI, but did not have significant effect on the wild-type. Measurement of intracellular GABA, glutamate and alpha ketoglutarate during lethal heat exposure at 45 degrees C showed higher levels of accumulation of GABA and alpha-ketoglutarate in the uga1 and uga2 mutants, while glutamate accumulated at higher level in the gad1 mutant. These results suggest that the GABA shunt pathway plays a crucial role in protecting yeast cells from heat damage by restricting ROI production involving the flux of carbon from alpha ketoglutarate to succinate during heat stress. PMID- 23447390 TI - Flow cytometric 96-well microplate-based in vitro micronucleus assay with human TK6 cells: protocol optimization and transferability assessment. AB - An automated approach for scoring in vitro micronuclei (MN) has been described in which flow cytometric analysis is combined with compound exposure, processing, and sampling in a single 96-well plate (Bryce SM et al. [2010]: Mutat Res 703:191 199). The current report describes protocol optimization and an interlaboratory assessment of the assay's transferability and reproducibility. In a training phase, the methodology was refined and collaborating laboratories were qualified by repeatedly testing three compounds. Second, a set of 32 chemicals comprised of reference genotoxicants and presumed non-genotoxicants was tested at each of four sites. TK6 cells were exposed to 10 closely spaced compound concentrations for 1.5- to 2-cell population doublings, and were then stained and lysed for flow cytometric analysis. MN frequencies were determined by evaluating >= 5,000 cells per replicate well, and several indices of cytotoxicity were acquired. The prevalence of positive results varied according to the MN-fold increase used to signify a genotoxic result, as well as the endpoint used to define a cytotoxicity limit. By varying these parameters, assay sensitivity and specificity values ranged from 82 to 98%, and 86 to 97%, respectively. In a third phase, one laboratory tested a further six genotoxicants and five non-genotoxic apoptosis inducers. In these experiments assay specificity was markedly improved when top concentration selection was based on two cytotoxicity endpoints-relative survival and quantification of ethidium monoazide-positive events. Collectively, the results indicate that the miniaturized assay is transferable across laboratories. The 96-well format consumes considerably less compound than conventional in vitro MN test methods, and the high information content provided by flow cytometry helps guard against irrelevant positive results arising from overt toxicity. PMID- 23447392 TI - Acneiform eruptions. PMID- 23447393 TI - Brown birthmarks. PMID- 23447395 TI - Two drugs for type 2 diabetes seem to raise risk of acute pancreatitis, study shows. PMID- 23447396 TI - NHS could learn from developing countries about efficiency, conference hears. PMID- 23447397 TI - Cognitive rest and school-based recommendations following pediatric concussion: the need for primary care support tools. AB - OBJECTIVES: (1) Assess pediatric primary care providers' understanding of cognitive rest for concussion and (2) describe their concussion management practices. METHODS: This study included (1) a survey of general pediatric providers and (2) an electronic medical record (EMR) review of children 5 to 18 years old treated for concussion from September 1, 2010, to May 31, 2011. The survey asked about treatment recommendations for concussion, and results were coded to identify cognitive rest recommendations. The EMR review included the following: injury details, medical evaluation, and recommendations for resuming school and sports/recreation. RESULTS: In all, 89 of 201 providers responded to the survey, and 52 of the 84 clinicians who included comments about concussion management mentioned cognitive rest (62%, 95% confidence interval [CI] = 51% 72%). Of the 91 EMRs reviewed for patients' first visits following the concussion, only 10 (11%, 95% CI = 6%-19%) included written cognitive rest recommendations. CONCLUSIONS: Although the majority of pediatric providers identified cognitive rest as important in pediatric concussion management, few provided written recommendations in the EMR. PMID- 23447398 TI - Hybrid molecular systems containing tetrathiafulvalene and iron-alkynyl electrophores: five-component functional molecules obtained from C-H bond activation. AB - Treatment of [Cp*(dppe)Fe-C=C-TTFMe3] (1) with Ag[PF6] (3 equiv) in DMF provides the binuclear complex [Cp*(dppe)Fe=C=C=TTFMe2 =CH-CH=TTFMe2 =C=C=Fe(dppe)Cp*][PF6]2 (2[PF6 ]2) isolated as a deep-blue powder in 69 % yield. EPR monitoring of the reaction and comparison of the experimental and calculated EPR spectra allowed the identification of the radical salt [Cp*(dppe)Fe=C=C=TTFMe2 =CH][PF6]2 ([1-CH][PF6]) an intermediate of the reaction, which results from the activation of the methyl group attached in vicinal position with respect to the alkynyl-iron on the TTF ligand by the triple oxidation of 1 leading to its deprotonation by the solvent. The dimerization of [1-CH][PF6] through carbon-carbon bond formation provides 2[PF6]2. The cyclic voltammetry (CV) experiments show that 2[PF6]2 is subject to two sequential well reversible one-electron reductions yielding the complexes 2[PF6] and 2. The CV also shows that further oxidation of 2[PF6]2 generates 2[PF6]n (n=3-6) at the electrode. Treatment of 2[PF6]2 with KOtBu provides 2[PF6] and 2 as stable powders. The salts 2[PF6] and 2[PF6]2 were characterized by XRD. The electronic structures of 2(n+) (n=0-2) were computed. The new complexes were also characterized by NMR, IR, Mossbauer, EPR, UV/Vis and NIR spectroscopies. The data show that the three complexes 2[PF6]n are iron(II) derivatives in the ground state. In the solid state, the dication 2(2+) is diamagnetic and has a bis(allenylidene-iron) structure with one positive charge on each iron building block. In solution, as a result of the thermal motion of the metal-carbon backbone, the triplet excited state becomes thermally accessible and equilibrium takes place between singlet and triplet states. In 2[PF6], the charge and the spin are both symmetrically distributed on the carbon bridge and only moderately on the iron and TTFMe2 electroactive centers. PMID- 23447399 TI - Characterization of xylazine metabolism in rat liver microsomes using liquid chromatography-hybrid triple quadrupole-linear ion trap-mass spectrometry. AB - Xylazine is an alpha2 -adrenoceptor agonist and it is widely used in veterinary anesthesia in combination with ketamine. There is limited information on the metabolism of xylazine. A quantitative method for the determination of xylazine by HPLC-ESI/MS/MS was developed. The method consisted of a protein precipitation extraction followed by analysis using liquid chromatography electrospray tandem mass spectrometry. The chromatographic separation was achieved using a Thermo Betasil Phenyl 100 * 2 mm column combined with an isocratic mobile phase composed of acetonitrile, methanol, water and formic acid (60:20:20:0.4) at a flow rate of 300 MUL/min. The mass spectrometer was operating in selected reaction monitoring mode and the analytical range was set at 0.05-50 MUm. The precision (%CV) and accuracy (%NOM) observed were 2.3-7.2 and 88.2-96.4%. In vitro metabolism studies were performed in rat liver microsomes and results showed moderate cytochrome P450 affinity (Km = 10.1 MUm) and a low metabolic stability of xylazine with a half-life of 4.1 min in rat liver microsomes. Five phase 1 metabolites were observed. The main metabolite observed was an oxidation of the thiazine moiety at m/z 235 and, to a lesser extent, we observed the formation of N-(2,6 dimethylphenyl)thiourea at m/z 181 and three distinctive hydroxylated metabolites at m/z 237. Further experiments with ketamine and ketoconazole strongly supported that the metabolism of xylazine to its main metabolite is mediated by CYP3A in rat liver microsomes. PMID- 23447400 TI - Probing the different life stages of a fluid catalytic cracking particle with integrated laser and electron microscopy. AB - While cycling through a fluid catalytic cracking (FCC) unit, the structure and performance of FCC catalyst particles are severely affected. In this study, we set out to characterize the damage to commercial equilibrium catalyst particles, further denoted as ECat samples, and map the different pathways involved in their deactivation in a practical unit. The degradation was studied on a structural and a functional level. Transmission electron microscopy (TEM) of ECat samples revealed several structural features; including zeolite crystals that were partly or fully severed, mesoporous, macroporous, and/or amorphous. These defects were then correlated to structural features observed in FCC particles that were treated with different levels of hydrothermal deactivation. This allowed us not only to identify which features observed in ECat samples were a result of hydrothermal deactivation, but also to determine the severity of treatments resulting in these defects. For functional characterization of the ECat sample, the Bronsted acidity within individual FCC particles was studied by a selective fluorescent probe reaction with 4-fluorostyrene. Integrated laser and electron microscopy (iLEM) allowed correlating this Bronsted acidity to structural features by combining a fluorescence and a transmission electron microscope in a single set-up. Together, these analyses allowed us to postulate a plausible model for the degradation of zeolite crystals in FCC particles in the ECat sample. Furthermore, the distribution of the various deactivation processes within particles of different ages was studied. A rim of completely deactivated zeolites surrounding each particle in the ECat sample was identified by using iLEM. These zeolites, which were never observed in fresh or steam-deactivated samples, contained clots of dense structures. The structures are proposed to be carbonaceous deposits formed during the cracking process, and seem resistant towards burning off during catalyst regeneration. PMID- 23447401 TI - Germline and somatic polymerase epsilon and delta mutations define a new class of hypermutated colorectal and endometrial cancers. AB - Polymerases epsilon and delta are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through Watson-Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations (EDMs) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma (CRC). POLD1 mutations also predispose to endometrial cancer (EC). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading-associated polyposis (PPAP). Somatic POLE EDMs have also been found in sporadic CRCs and ECs, although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an 'ultramutated', apparently microsatellite-stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field. PMID- 23447402 TI - Synthesis, cytotoxicity, and apoptosis induction study of antitumor dinuclear platinum(II) complexes. AB - Five novel dinuclear platinum(II) complexes with a new chiral ligand, 3-(2-amino cyclohexylamino)-propionic acid (HP), were designed, prepared and spectrally characterized. The in vitro cytotoxicities of these compounds were evaluated against the HepG-2, MCF-7, A549, and HCT-116 cell lines. The results indicated that all compounds showed cytotoxicity towards the HepG-2 cell line. Particularly, complex X5, which has SO 42- as a bridge, exhibited better cytotoxicity than carboplatin or oxaliplatin against all selected cell lines. Moreover, double dyeing flow cytometric resection indicated that the target compounds inhibited tumor cell growth by inducing apoptosis. PMID- 23447403 TI - Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates. AB - Without effective prophylaxis, liver transplantation for hepatitis B virus (HBV) related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. Combination prophylaxis with hepatitis B immune globulin (HBIG) and lamivudine (LAM) reduces long-term recurrence rates below 10%; however, HBIG is costly and inconvenient to administer. We, therefore, conducted a multicenter, prospective study of outcomes with an HBIG-sparing regimen of LAM plus adefovir dipivoxil (ADV) initiated at the time of listing for liver transplantation and continued after transplantation. Twenty-six patients were recruited into this study at the time of listing for transplantation, and 20 subsequently underwent transplantation. Twelve of the 26 patients had LAM exposure before the study baseline, but none had LAM resistance. The median HBV viral load before the institution of antiviral therapy was approximately 4.0 log(10) IU/mL (range=2.3 7.5 log(10) IU/mL). To the 20 patients who underwent transplantation, 800 IU of intramuscular HBIG was given immediately after transplantation and daily for 7 days only (total HBIG dose=6400 IU). All transplant patients remained alive without HBV recurrence (they were negative for hepatitis B surface antigen, and HBV DNA was undetectable) after a median follow-up of 57 months after transplantation (range=27-83 months). The median serum creatinine level in these patients rose from 81 to 119 MUmol/L over the course of the study. No patient required dose reduction or cessation. After the completion of this prospective study, the regimen was modified so that no perioperative HBIG was administered if the pretransplant serum HBV DNA level was suppressed below 3 log(10) IU/mL. Another 28 patients with HBV-related liver disease underwent transplantation (18 without HBIG). All remained alive and well without HBV recurrence after a median follow-up of 22 months after transplantation (range=10-58 months). In conclusion, a combination of LAM and ADV initiated at the time of wait listing provides safe and effective protection against recurrent HBV infection without the high costs and inconvenience associated with long-term HBIG therapy. PMID- 23447404 TI - Clinical grading system of orbitopathy secondary to sinus disease. PMID- 23447405 TI - Quantitative analysis of human ras localization and function in the fission yeast Schizosaccharomyces pombe. AB - Ras signalling is central to fundamental and diverse cellular processes. In higher eukaryotes ras signalling is highly complex, involving multiple isoforms, regulatory proteins and effectors. As a consequence, the study of ras activity in mammalian systems presents a number of technical challenges. The model organism Schizosaccharomyces pombe has previously proved a key system for the study of human signalling components and provides an ideal model for the study of ras, as it contains just one ras protein (Ras1p), which is non-essential and controls a number of downstream processes. Here we present data demonstrating the quantitative analysis of three distinct Ras1-related signalling outputs, utilizing the three most abundant human ras isoforms, H-Ras, N-Ras and K-Ras4B, in Sz. pombe. Further, we have characterized the localization of these three human ras isoforms in Sz. pombe, utilizing quantitative image analysis techniques. These data indicate that all three human ras isoforms are functional in fission yeast, displaying differing localization patterns which correlate strongly with function in the regulation of pheromone response and cell shape. These data demonstrate that such yeast strains could provide powerful tools for the investigation of ras biology, and potentially in the development of cancer therapies. PMID- 23447406 TI - Direct observation of hole accumulation in polymer solar cells during device operation using light-induced electron spin resonance. PMID- 23447407 TI - Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation. AB - Long-term prophylaxis with hepatitis B immunoglobulin (HBIG) for the prevention of hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) in patients with chronic HBV infection is inconvenient and costly. This randomized, prospective phase 2 study compared emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) after HBIG withdrawal to FTC/TDF plus HBIG for the prevention of HBV recurrence after OLT. Forty patients with a median time since liver transplantation of 3.4 years (interquartile range = 1.9-5.6 years) received 24 weeks of open-label FTC/TDF plus HBIG before randomization. Patients who maintained confirmed viral suppression were randomized to continue FTC/TDF plus HBIG (n = 19) or receive FTC/TDF alone (n = 18) for an additional 72 weeks. No patient experienced HBV recurrence through 72 weeks of the study while he or she was receiving the randomized treatment. Both treatment arms were safe and well tolerated; no serious or severe drug-related adverse events were observed. Renal function was consistent with that observed in a posttransplant population. The withdrawal of HBIG after 6 months' treatment with FTC/TDF should be considered in liver transplant recipients to prevent chronic HBV recurrence. PMID- 23447408 TI - Body composition in prepubertal, HIV-infected children: a comparison of bioelectrical impedance analysis and dual-energy X-ray absorptiometry. AB - BACKGROUND: The aim of this study was to compare bioelectrical impedance analysis (BIA) equations developed for healthy pediatric populations and for HIV-infected children using dual-energy X-ray absorptiometry (DXA) as the gold standard. MATERIALS AND METHODS: A cross-sectional study was carried out with 40 prepubertal, HIV-infected children who regularly attended the Pediatric Infectious Disease Clinic at the Universidade Federal de Sao Paulo, Sao Paulo, Brazil. The study was conducted from August to November 2008. Demographic data, clinical parameters, immunological status, and use of antiretroviral therapy were obtained from the patients' medical records. We performed anthropometric parameters and body composition analyses, analyzed body composition by BIA and DXA, and compared the results obtained from BIA through using equations for both healthy and HIV-infected populations. RESULTS: The mean +/- SD age of the study population was 9.8 +/- 1.2 years. Half of the population were females, and 82.5% of the children were clinically classified as B and C. Total body fat, by both absolute mass and by percentage, exhibited high homogeneity between the results obtained from BIA and DXA. However, there was no concordance in fat-free mass. The equation for healthy children showed good sensitivity and specificity when comparing the percentage of total body fat measured by DXA. CONCLUSION: BIA provides reliable data on total body fat but not fat-free mass when compared with DXA. The BIA equation developed for healthy pediatric populations can be used to determine total body fat in HIV-infected children. PMID- 23447409 TI - The role of the institutional review board in the oversight of the ethical aspects of human studies research. AB - Institutional review boards are charged with overseeing that human studies research is conducted in accordance with federal and state regulations and with their own policies and procedures, with the goal of minimizing risks to participants and maximizing the quality of the research data. Nutrition research often involves vulnerable populations, including children and the cognitively impaired, for whom there are specific regulations. Ethical issues are common in nutrition research, and both the investigative team and the institutional review board should seek input regarding ethical issues that arise. PMID- 23447410 TI - Parenteral nutrition prescribing pattern: a medical chart review of 191 preterm infants. AB - BACKGROUND: In 2005, the European Society for Clinical Nutrition and Metabolism released guidelines for the use of pediatric parenteral nutrition (PN). The purpose of this study was to compare PN prescribing patterns in preterm infants with current guideline recommendations. MATERIALS AND METHODS: Six neonatologists in Germany conducted observational, retrospective medical chart reviews on preterm infants <28 days postnatal, hospitalized from October 2009 to April 2011. Infants with a complete medical record who received PN for a minimum of 4 days were enrolled. Patient weight and the change in daily amino acids and intravenous fat emulsion (IVFE) doses administered for the first 7 days of life were abstracted. Median data were used to determine quartiles to compare study results with the current guidelines. RESULTS: Only 30% of patients met current guidelines that recommend all preterm infants receive amino acids on the first day of life. When amino acids were given, the dose was lower than recommended in the current guidelines. The start of IVFE by day 3 of life was given only to 34% of patients despite the guideline recommendation of 100%. CONCLUSION: This study identified several gaps between the current guidelines and patient care that should be explored further. PMID- 23447411 TI - STED Super-resolution Microscopy in Drosophila Tissue and in Mammalian Cells. AB - Far-field super-resolution microscopy is a rapidly emerging method that is opening up opportunities for biological imaging beyond the optical diffraction limit. We have implemented a Stimulated Emission Depletion (STED) microscope to image single dye, cell, and tissue samples with 50-80 nm resolution. First, we compare the STED performance imaging single molecules of several common dyes and report a novel STED dye. Then we apply STED to image planar cell polarity protein complexes in intact fixed Drosophila tissue for the first time. Finally, we present a preliminary study of the centrosomal protein Cep164 in mammalian cells. Our images suggest that Cep164 is arranged in a nine-fold symmetric pattern around the centriole, consistent with findings suggested by cryoelectron tomography. Our work demonstrates that STED microscopy can be used for superresolution imaging in intact tissue and provides ultrastructural information in biological samples as an alternative to immuno-electron microscopy. PMID- 23447412 TI - Synthesis and evaluation of 1,omega-bis(1,2,3,5-thiatriazol-5-yl)alkanes as in vitro and in vivo alpha-amylase and lipase inhibitors. AB - Thionyl chloride reacts with 1,omega-bis-(1-tosylamidrazone)alkanes 1 to give a series of 1,omega-bis-(4-alkyl-2-tosyl-1,2,3,5-thiatriazol-5-yl)alkanes 2. All the newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, elemental analysis, and ESI-MS spectral data. All the new compounds were screened for their inhibitory effect on key enzymes related to diabetes and obesity, such as alpha-amylase and lipase. In vitro and in vivo studies revealed that these thiatriazole derivatives exert an inhibitory action against these key enzymes. Moreover the administration of these compounds to surviving diabetic rats induced a significant decrease in plasma glucose level. Additively 2d significantly protected the liver-kidney functions and modulated lipid metabolism, which were evidenced by the decrease in aspartate transaminase (AST), alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) activities and creatinine, urea albumin, LDL-cholesterol and triglycerides levels as well as an increase in the HDL-cholesterol level in surviving diabetic rats. Overall, the findings of the current study indicate that 2d exhibits attractive properties and can, therefore, be considered for future application in the development of anti-diabetic and hypolipidemic drugs. PMID- 23447413 TI - Total syntheses of ainsliadimer B and gochnatiolides a and B. AB - Oh my goch: The total syntheses of ainsliadimer B and gochnatiolides A and B from alpha-santonin have been accomplished in 25 steps with approximately 1 % overall yield. A Diels-Alder reaction of natural dehydrozaluzanin C with a monomeric guaianolide derivative allows stereoselective assembly of a dimeric gochnatiolide type skeleton with the required stereochemistry and preinstalled functionalities for the synthesis of dimeric ainsliadimer B and gochnatiolides A and B (see scheme). PMID- 23447415 TI - Chiral M3L2 self-assembled capsules through metal coordination of enantiopure ligating benzocyclotrimers: NMR spectroscopic and ESI mass spectrometric investigation. AB - The synthesis of enantiopure (+)-benzotricamphor syn-5, an important chiral C3 symmetric rigid building block for supramolecular applications, was studied in detail to reduce the number of steps and to increase the diastereoselectivity and overall yield. The new synthetic procedure allowed larger amounts of syn-5 to be obtained and used for the preparation of new derivatives, such as the corresponding tris-trifluoromethanesulfonate syn-12, which was efficiently transformed into (+)-benzotribornenetrinitrile syn-1 and (+) benzotribornenetris(ethynyl-4-pyridine) syn-2. The previously reported (+) benzotricamphortrioxime syn-6 was transformed into tris-nitrile syn-3 by Beckman reaction. Compounds syn-1-3 were employed as multidentate ligands for silver(I) and platinum(II) centres in apolar solvents. The linear coordination geometry of Ag(I) and square-planar geometry of cis-chelated Pt(II) in combination with the chiral tripodal ligands syn-1-3 led to the formation of chiral enantiopure capsules with M3 L2 stoichiometry, as confirmed by 2D NMR NOESY and DOSY experiments as well as ESI mass spectrometry. PMID- 23447416 TI - Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. AB - TMPRSS2-ERG rearrangements occur in approximately 50% of prostate cancers and therefore represent one of the most frequently observed structural rearrangements in all cancers. However, little is known about the genomic architecture of such rearrangements. We therefore designed and optimized a pipeline involving target capture of TMPRSS2 and ERG genomic sequences coupled with paired-end next generation sequencing to resolve genomic rearrangement breakpoints in TMPRSS2 and ERG at nucleotide resolution in a large series of primary prostate cancer specimens (n = 83). This strategy showed > 90% sensitivity and specificity in identifying TMPRSS2-ERG rearrangements, and allowed identification of intra- and inter-chromosomal rearrangements involving TMPRSS2 and ERG with known and novel fusion partners. Our results indicate that rearrangement breakpoints show strong clustering in specific intronic regions of TMPRSS2 and ERG. The observed TMPRSS2 ERG rearrangements often exhibited complex chromosomal architecture associated with several intra- and inter-chromosomal rearrangements. Nucleotide resolution analysis of breakpoint junctions revealed that the majority of TMPRSS2 and ERG rearrangements (~88%) occurred at or near regions of microhomology or involved insertions of one or more base pairs. This architecture implicates non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) pathways in the generation of such rearrangements. These analyses have provided important insights into the molecular mechanisms involved in generating prostate cancer specific recurrent rearrangements. PMID- 23447417 TI - Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance. AB - Hepatitis B virus (HBV) persistence aggravates hepatic immunotolerance, leading to the failure of cell-intrinsic type I interferon and antiviral response, but whether and how HBV-induced hepatocyte-intrinsic tolerance influences systemic adaptive immunity has never been reported, which is becoming the major obstacle for chronic HBV therapy. In this study, an HBV-persistent mouse, established by hydrodynamic injection of an HBV-genome-containing plasmid, exhibited not only hepatocyte-intrinsic but also systemic immunotolerance to HBV rechallenge. HBV specific CD8(+) T-cell and anti-HBs antibody generation were systemically impaired by HBV persistence in hepatocytes. Interestingly, HBV-induced hepatocyte intrinsic immune tolerance was reversed when a dually functional vector containing both an immunostimulating single-stranded RNA (ssRNA) and an HBx silencing short hairpin RNA (shRNA) was administered, and the systemic anti-HBV adaptive immune responses, including CD8(+) T-cell and anti-HBs antibody responses, were efficiently recovered. During this process, CD8(+) T cells and interferon-gamma (IFN-gamma) secreted play a critical role in clearance of HBV. However, when IFN-alpha/beta receptor was blocked or the Toll-like receptor (TLR)7 signaling pathway was inhibited, the activation of CD8(+) T cells and clearance of HBV was significantly impaired. CONCLUSION: These results suggest that recovery of HBV-impaired hepatocyte-intrinsic innate immunity by the dually functional vector might overcome systemic adaptive immunotolerance in an IFN alpha- and TLR7-dependent manner. The strategy holds promise for therapeutic intervention of chronic persistent virus infection and associated cancers. PMID- 23447418 TI - Moving toward evidence-based liver allocation in patients with primary sclerosing cholangitis. PMID- 23447420 TI - Fast-tracking and fairness: getting organ offers quickly to candidates who will accept them. PMID- 23447419 TI - Influence of local objects on hippocampal representations: Landmark vectors and memory. AB - The hippocampus is thought to represent nonspatial information in the context of spatial information. An animal can derive both spatial information as well as nonspatial information from the objects (landmarks) it encounters as it moves around in an environment. In this article, correlates of both object-derived spatial as well as nonspatial information in the hippocampus of rats foraging in the presence of objects are demonstrated. A new form of CA1 place cells, called landmark-vector cells, that encode spatial locations as a vector relationship to local landmarks is described. Such landmark vector relationships can be dynamically encoded. Of the 26 CA1 neurons that developed new fields in the course of a day's recording sessions, in eight cases, the new fields were located at a similar distance and direction from a landmark as the initial field was located relative to a different landmark. In addition, object-location memory in the hippocampus is also described. When objects were removed from an environment or moved to new locations, a small number of neurons in CA1 and CA3 increased firing at the locations where the objects used to be. In some neurons, this increase occurred only in one location, indicating object + place conjunctive memory; in other neurons, the increase in firing was seen at multiple locations where an object used to be. Taken together, these results demonstrate that the spatially restricted firing of hippocampal neurons encode multiple types of information regarding the relationship between an animal's location and the location of objects in its environment. PMID- 23447421 TI - Global challenges and globalization of bioethics. AB - This article analyzes problems and implications for man and nature connected with the formation of a new architecture of science, based on the convergence of nanotechnology, biotechnology, information technology, and cognitive science (NBIC). It also describes evolution and genesis of bioethics, a scientific discipline and social practice with a special role of ethical management of potential risks of scientific research. The aim was to demonstrate the necessity of bioethical social control in the development of a global bioeconomy driven by NBIC technologies. PMID- 23447422 TI - A common variant in the FTO locus is associated with waist-hip ratio in Indian adolescents. AB - BACKGROUND: Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups. Associations with obesity traits among Indian adolescents have not been determined. OBJECTIVE: To study the association of rs9939609 (FTO) and rs17782313 (MC4R) to obesity related anthropometric traits in Indian adolescents. METHODS: Subjects for the current study were recruited from a cross sectional cohort of 1,230 adolescents (age mean +/- SD: 17.1 +/- 1.9 years) from South India. RESULTS: The variant at the FTO locus was found to be associated with waist-hip ratio (WHR) but not with overall obesity in this population. No significant association was observed for obesity-traits and Mc4R variant rs17782313. CONCLUSION: The common variant of FTO (rs9939609) is associated with body fat distribution during early growth in Indian adolescents and may predispose to obesity and metabolic consequences in adulthood. PMID- 23447423 TI - NHS should ban use of starch based intravenous fluids, say researchers. PMID- 23447424 TI - Facile synthesis of magnetite/perfluorocarbon co-loaded organic/inorganic hybrid vesicles for dual-modality ultrasound/magnetic resonance imaging and imaging guided high-intensity focused ultrasound ablation. AB - Multifunctional organic/inorganic hybrid nanovesicles, fabricated by a facile self-assembly/sol-gel approach, display a unique morphology (figure) and satisfactory stability under physiological conditions. By co-encapsulation of superparamagnetic magnetite nanoparticles and a liquid perfluorocarbon, the nanovesicles can be used not only as a dual-modality ultrasound/magnetic resonance contrast agent for accurate cancer diagnosis and monitoring, but also as a therapeutic enhancement agent for effective high-intensity focused ultrasound (HIFU) ablation. PMID- 23447425 TI - Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo controlled and active-comparator trials. AB - BACKGROUND: The extent to which individual statins vary in terms of clinical outcomes across all populations, in addition to secondary and primary prevention has not been studied extensively in meta-analyses. METHODS: We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials. Systematic review registration: PROSPERO 2011:CRD42011001470. RESULTS: There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. No trial directly compared all six statins to each other. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.82-0.92) and major coronary events (OR 0.69, 95% CI 0.64-0.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.48-0.94) and fluvastatin (OR 0.59, 95% CI 0.36-0.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75-0.90) and major coronary events (OR 0.69, 95% CI 0.62-0.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.43-0.99) and simvastatin (OR 0.68, 95% CI 0.38-0.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.83-0.99) and major coronary events (OR 0.69, 95% CI 0.61-0.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected. CONCLUSIONS: Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol reducing effects. The observed differences between statins should be investigated in future prospective studies. PMID- 23447426 TI - A cup of coffee a day keeps dyskinesia away? PMID- 23447427 TI - Ion-induced synthesis of uniform single-crystalline sulphide-based quaternary alloy hexagonal nanorings for highly efficient photocatalytic hydrogen evolution. AB - Uniform single-crystalline quaternary sulphide nanoring photocatalysts are synthesized via the copper-ion-induced Kirkendall effect and is followed by a cation exchange reaction. The obtained Cu(2+)-doped ZnIn(2)S(4) nanorings show highly preserved morphology, and demonstrate high visible-light-driven photocatalytic activity for H(2) evolution in water splitting. PMID- 23447428 TI - Adiponectin, bile acids, and burnt-out nonalcoholic steatohepatitis: new light on an old paradox. PMID- 23447429 TI - Synthesis of luminescent ethynyl-extended regioisomers of borate complexes based on 2-(2'-hydroxyphenyl)benzoxazole. AB - A series of thirteen luminescent tetrahedral borate complexes based on the 2-(2' hydroxyphenyl)benzoxazole (HBO) core is presented. Their synthesis includes the incorporation of an ethynyl fragment by Sonogashira cross-coupling reaction, with the goal of extending the conjugation and consequently redshifting their emission wavelength. Different regioisomers, substituted in the 3-, 4-, or 5-position of the phenolate side of the HBO core, were studied in order to compare their photophysical properties. The complexes were characterized by X-ray diffraction and NMR, UV/Vis, and emission spectroscopy in solution and in the solid state. In all cases, complexation to boron leads to a donor-acceptor character that impacts their photophysical properties. Complexes with a 3- or 5-substituted fragment display mild to pronounced internal charge transfer (ICT), a feature strengthened by the presence of p-dibutylaminophenylacetylene in the molecular structure, protonation of the nitrogen atom of which leads to a significant blueshift and an increase in quantum yield. On the contrary, when the ethynyl module is grafted on the 4-position, narrow, structured, symmetrical absorption/emission bands are observed. Moreover, the fact that protonation has little effect on the emission maximum wavelength reveals singlet excited-state decay. Solid-state emission properties reveal a redshift compared to solution, explained by tight packing of the pi-conjugated systems and the high planarity of the dyes. Subsequent connection of these complexes to other photoactive subunits (BODIPY, Boranil) provides dyads in which efficient cascade energy transfer is observed. PMID- 23447430 TI - Does antidepressant medication use affect persistence with diabetes medicines? AB - PURPOSE: This study aimed to examine the effect of antidepressant use on persistence with newly initiated oral antidiabetic medicines in older people. METHODS: A retrospective study of administrative claims data from the Australian Government Department of Veterans' Affairs, from 1 July 2000 to 30 June 2008 of new users of oral antidiabetic medicines (metformin or sulfonylurea). Antidepressant medicine use was determined in the 6 months preceding the index date of the first dispensing of an oral antidiabetic medicine. The outcome was time to discontinuation of diabetes therapy in those with antidepressant use compared with those without. Competing risks regression analyses were conducted with adjustment for covariates. RESULTS: A total of 29,710 new users of metformin or sulfonylurea were identified, with 7171 (24.2%) dispensed an antidepressant. Median duration of oral antidiabetic medicines was 1.81 years (95% CI 1.72-1.94) for those who received an antidepressant at the time of diabetes medicine initiation, by comparison to 3.23 years (95% CI 3.10-3.40) for those who did not receive an antidepressant. Competing risk analyses showed a 42% increased likelihood of discontinuation of diabetes medications in persons who received an antidepressant (subdistribution hazard ratio 1.42, 95% CI 1.37-1.47, p < 0.001). CONCLUSIONS: The results of this large population-based study demonstrate that depression may be contributing to non-compliance with medicines for diabetes and highlight the need to provide additional services to support appropriate medicine use in those initiating diabetes medicines with co-morbid depression. PMID- 23447431 TI - Body fat in children does not adversely influence bone development: a 7-year longitudinal study (EarlyBird 18). AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Both negative and positive associations have been reported between body fat and bone density. Extra mechanical loading from excess fat may lead to greater bone mass. Excess ectopic fat may lead to bone demineralisation through inflammatory pathways. WHAT THIS STUDY ADDS: Longitudinally collected data from narrow-angle beam densitometry gives a novel insight into bone growth through adolescence. There is no evidence of a deleterious effect of body fat on children's growing bones after adjustment for height and age. Body fat, mediated by puberty, is associated with larger bones in boys and bones that are both denser and larger in girls. OBJECTIVE: Bone growth is an important determinant of peak bone mass and fracture risk, but there is limited data on the impact of fat-on-bone development at a time when childhood obesity is reaching epidemic proportions. Accordingly, we explored the effect of body fat (BF) on bone growth over time in the context of age, pubertal tempo and gender. METHOD: A cohort of 307 children was measured biannually from 9-16 years for height and weight, and every 12 months for percent BF, bone area (BA), bone mineral content and areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry. Pubertal tempo was determined quantitatively by age at peak height velocity. RESULTS: Percent BF increased and then fell in the boys, but increased throughout in the girls. aBMD and BA increased in both genders (P < 0.001). Greater BF was associated with higher aBMD and BA in girls (P < 0.001), but only BA in boys (P < 0.001). The extra aBMD associated with increased BF was greater in older girls. The rise in aBMD and BA was associated with earlier puberty in both genders (P < 0.001). The impact of BF on aBMD was greater in later puberty in girls (0.0025 g cm(-2) per 10% BF at 10 years versus 0.016 g cm( 2) per 10% BF at 14 years, P < 0.001). CONCLUSION: Greater BF is associated with larger bones, but also denser bones in girls. The effects of fat and puberty are complex and gender specific, but BF of contemporary UK children does not appear to be deleterious to bone quality. PMID- 23447433 TI - Role of microdialysis catheters in clinical decision making: bench to bedside? PMID- 23447432 TI - The external validity of MRI-defined vascular depression. AB - OBJECTIVE: Multiple diagnostic criteria have been used to define vascular depression (VD). As a result, there are discrepancies in the clinical characteristics that have been established for the illness. The aim of this study was twofold. First, we used empirically established diagnostic criteria to determine the clinical characteristics of magnetic resonance imaging (MRI) defined VD. Second, we assessed the agreement between a quantitative and qualitative method for identifying the illness. METHOD: We examined the baseline clinical and neuropsychological profile of 38 patients from a larger, double blind, randomized, 12-week clinical trial comparing nortriptyline with sertraline in depressed older adults. Ten patients met quantitative criteria for MRI-defined VD based on the highest quartile of deep white matter hyperintensity (DWMH) volume. Fourteen patients met qualitative criteria for MRI-defined VD based on a DWMH score of 2 or higher on the Fazekas' modified Coffey rating scale. RESULTS: Age, gender, cumulative illness rating scale-geriatric (CIRS-G) score, two measures of psychomotor retardation [the psychomotor retardation item of the Hamilton Rating Scale for Depression (HRSD) as well as performance on the Purdue Pegboard], and performance on the Stroop Color/Word test (a measure of the response inhibition component of executive functioning) were significantly different between those with VD and non-VD. CONCLUSIONS: Patients with VD have a distinct clinical and neuropsychological profile that is mostly consistent across different methods for identifying the illness. These findings support the notion that MRI-defined VD represents a unique and valid subtype of late-life depression. PMID- 23447434 TI - Designing a fully automated multi-bioreactor plant for fast DoE optimization of pharmaceutical protein production. AB - The identification of optimal expression conditions for state-of-the-art production of pharmaceutical proteins is a very time-consuming and expensive process. In this report a method for rapid and reproducible optimization of protein expression in an in-house designed small-scale BIOSTAT(r) multi bioreactor plant is described. A newly developed BioPAT(r) MFCS/win Design of Experiments (DoE) module (Sartorius Stedim Systems, Germany) connects the process control system MFCS/win and the DoE software MODDE(r) (Umetrics AB, Sweden) and enables therefore the implementation of fully automated optimization procedures. As a proof of concept, a commercial Pichia pastoris strain KM71H has been transformed for the expression of potential malaria vaccines. This approach has allowed a doubling of intact protein secretion productivity due to the DoE optimization procedure compared to initial cultivation results. In a next step, robustness regarding the sensitivity to process parameter variability has been proven around the determined optimum. Thereby, a pharmaceutical production process that is significantly improved within seven 24-hour cultivation cycles was established. Specifically, regarding the regulatory demands pointed out in the process analytical technology (PAT) initiative of the United States Food and Drug Administration (FDA), the combination of a highly instrumented, fully automated multi-bioreactor platform with proper cultivation strategies and extended DoE software solutions opens up promising benefits and opportunities for pharmaceutical protein production. PMID- 23447435 TI - Excellent quality of life after liver transplantation for patients with perihilar cholangiocarcinoma who have undergone neoadjuvant chemoradiation. AB - Patients with perihilar cholangiocarcinoma (CCA) undergoing neoadjuvant chemoradiation followed by liver transplantation (LT) have excellent survival. However, little is known about their quality of life (QOL). We assessed the QOL of these patients and compared it to the QOL of patients who underwent transplantation for other liver diseases. From 1993 to 2010, 129 CCA patients underwent LT, and 93 (72%) were alive as of November 2010. All recipients were sent a previously validated QOL questionnaire composed of disease-specific QOL metrics (liver disease symptoms, Karnofsky score, health perception, and index of well-being) and generic QOL metrics [Short Form 36 (SF-36) and European Quality of Life (EuroQol)]. These recipients were compared to 110 transplant recipients with other liver diseases (excluding hepatitis C). Among the recipients with CCA, the response rate was 85% (n = 79). Patients with CCA did significantly better on liver disease symptoms (3.3 versus 3.2, P = 0.05), the Karnofsky score (90.8 versus 86.6, P = 0.03), the SF-36 Physical Functioning domain (52.0 versus 46.3, P < 0.001), and the EuroQol Mobility category (10% versus 33%, P = 0.001), and they rated their overall health better in comparison with non-CCA patients (85.9 versus 80.7, P = 0.02). CCA patients scored consistently higher on all other domains, albeit without significant differences. The observed differences in QOL remained unchanged when adjustments were made for demographic factors, including the level of education. In conclusion, patients who underwent neoadjuvant chemoradiation followed by LT for perihilar CCA reported excellent QOL that was equal to or better than that of recipients with other liver diseases. These results are important in light of the continued debate about the feasibility of this aggressive treatment in patients with perihilar CCA. PMID- 23447436 TI - Synthesis, structural characterisation and stereochemical investigation of chiral sulfur-functionalised N-heterocyclic carbene complexes of palladium and platinum. AB - Palladium and platinum complexes containing a sulfur-functionalised N heterocyclic carbene (S-NHC) chelate ligand have been synthesised. The absolute conformations of these novel organometallic S-NHC chelates were determined by X ray structural analyses and solution-phase 2D (1)H-(1)H ROESY NMR spectroscopy. The structural studies revealed that the phenyl substituents on the stereogenic carbon atoms invariably take up the axial positions on the Pd-C-S coordination plane to afford a skewed five-membered ring structure. All of the chiral complexes are structurally rigid and stereochemically locked in a chiral ring conformation that is either (Rs ,S,R)-lambda or (Ss ,R,R)-delta in both the solid state and solution. PMID- 23447437 TI - One-pot laccase-catalysed synthesis of 5,6-dihydroxylated benzo[b]furans and catechol derivatives, and their anticancer activity. AB - A commercial laccase, Suberase(r) from Novozymes, was used to catalyse the synthesis of 5,6-dihydroxylated benzo[b]furans and catechol derivatives. The yields were, in some cases, similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The synthesised derivatives were screened against renal (TK10), melanoma (UACC62), breast (MCF7) and cervical (HeLa) cancer cell lines. GI50, TGI and LC50 are reported for the first time. Anticancer screening showed that the cytostatic effects of the 5,6-dihydroxylated benzo[b]furans were most effective against the melanoma (UACC62) cancer cell line with several compounds exhibiting potent growth inhibitory activities (GI50=0.77 9.76 uM), of which two compounds had better activity than the anticancer agent etoposide (GI50 0.89 uM). One compound exhibited potent activity (GI50=9.73 uM) against the renal (TK10) cancer cell line and two exhibited potent activity (GI50=8.79 and 9.30 uM) against the breast (MCF7) cancer cell line. These results encourage further studies of the 5,6-dihydroxylated benzo[b]furans for their potential application in anticancer therapy. PMID- 23447438 TI - What does a mouse tell us about neuregulin 1-cannabis interactions? AB - The link between cannabis and psychosis has been debated although there is substantial epidemiological evidence showing that cannabis increases the risk of psychosis. It has been hypothesized that schizophrenia patients carrying particular risk genes might be more sensitive to the psychosis-inducing effects of cannabis than other patients and healthy test subjects. Here we review the effects of cannabinoids on a mutant mouse model for the schizophrenia candidate gene neuregulin 1 (Nrg1). The studies suggest a complex interaction between cannabis and Nrg1: the neuro-behavioral effects of cannabinoids were different in Nrg1 mutant and control mice and depended on exposure time, sex, and age of test animals. This research provides the first evidence of complex cannabis-Nrg1 interactions suggesting Nrg1 as a prime target for future clinical investigations. Furthermore, it highlights that animal model research can broaden our understanding of the complex multi-factorial etiology of schizophrenia. Finally, the findings are important to preventive psychiatry: if the genes that confer genetic vulnerability to cannabis-induced psychosis were identified patients at-high risk could be forewarned of the potential dangers of cannabis abuse. PMID- 23447440 TI - Connecting C=C bonds to tetrairidium chains. PMID- 23447439 TI - Slower processing speed after treatment for pediatric brain tumor and acute lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) and brain tumor (BT) survivors are at risk for post-treatment IQ declines. The extent to which lower scores represent global cognitive decline versus domain-specific impairment remains unclear. This study examined discrepancies between processing speed and estimated IQ (EIQ) scores and identified clinical characteristics associated with score discrepancies in a sample of pediatric cancer survivors. PROCEDURE: Survivors (50 ALL, 50 BT) ages 12-17 years completed cognitive testing. The Wechsler Abbreviated Scale of Intelligence provided an untimed measure of general reasoning ability (EIQ). The age-appropriate Wechsler Intelligence Scale provided a Processing Speed Index (PSI) score. Scores were examined and compared. RESULTS: Survivors' PSI scores were lower than their EIQ scores (BT t(45) =6.3, p<0.001; ALL t(49) =6.9, p<0.001). For BT survivors, lower PSI scores were associated with history of craniospinal irradiation, t(44) =3.3, p<0.01. For ALL survivors, lower PSI scores were associated with male gender, grade retention, and time since diagnosis, F(3, 46) =10.1, p<0.001. Clinically significant EIQ-PSI score discrepancies were identified in 41.3% of BT and 14.0% of ALL survivors. CONCLUSIONS: Many pediatric BT and ALL survivors exhibit slower processing speed than expected for age, whereas general reasoning ability remains largely intact. Risk factors associated with larger EIQ-PSI discrepancies include the following: BT diagnosis, craniospinal irradiation (BT only), male gender, and younger age at diagnosis (ALL only). Grade retention was frequent and associated with lower EIQ scores (both groups) and PSI scores (ALL only). Describing post-treatment cognitive declines using global measures of intellectual ability may underestimate dysfunction or fail to isolate specific underlying deficits contributing to impairment. PMID- 23447441 TI - Strengthening protections for human subjects: proposed restrictions on the publication of transplant research involving prisoners. AB - Publication is one of the primary rewards in the academic research community and is the first step in the dissemination of a new discovery that could lead to recognition and opportunity. Because of this, the publication of research can serve as a tacit endorsement of the methodology behind the science. This becomes a problem when vulnerable populations that are incapable of giving legitimate informed consent, such as prisoners, are used in research. The problem is especially critical in the field of transplant research, in which unverified consent can enable research that exploits the vulnerabilities of prisoners, especially those awaiting execution. Because the doctrine of informed consent is central to the protection of vulnerable populations, we have performed a historical analysis of the standards of informed consent in codes of international human subject protections to form the foundation for our limit and ban recommendations: (1) limit the publication of transplant research involving prisoners in general and (2) ban the publication of transplant research involving executed prisoners in particular. PMID- 23447442 TI - Acoustic detection of cell adhesion to a coated quartz crystal microbalance - implications for studying the biocompatibility of polymers. AB - Biocompatibility of polymers is an important parameter for the successful application of polymers in tissue engineering. In this work, quartz crystal microbalance (QCM) devices were used to follow the adhesion of NIH 3T3 fibroblasts to QCM surfaces modified with fibronectin (FN) and poly-D-lysine (PDL). The variations in sensor resonant frequency (Deltaf) and motional resistance (DeltaR), monitored as the sensor signal, revealed that cell adhesion was favored in the PDL-coated QCMs. Fluorescence microscopy images of seeded cells showed more highly spread cells on the PDL substrate, which is consistent with the results of the QCM signals. The sensor signal was shown to be sensitive to extracellular matrix (ECM)-binding motifs. Ethylenediaminetetraacetic acid (EDTA) and soluble Gly-Arg-Gly-Asp-Ser (GRGDS) peptides were used to interfere with cell-ECM binding motifs onto FN-coated QCMs. The acquired acoustic signals successfully showed that in the presence of 30 mM EDTA or 1 mM GRGDS, cell adhesion is almost completely abolished due to the inhibition/blocking of integrin function by these compounds. The results presented here demonstrate the potential of the QCM sensor to study cell adhesion, to monitor the biocompatibility of polymers and materials, and to assess the effect of adhesion modulators. QCM sensors have great potential in tissue engineering applications, as QCM sensors are able to analyze the biocompatibility of surfaces and it has the added advantage of being able to evaluate, in situ and in real time, the effect of specific drugs/treatments on cells. PMID- 23447443 TI - Portal hypertensive vaginal bleeding. PMID- 23447444 TI - Fifteen years of the Family Eating and Activity Habits Questionnaire (FEAHQ): an update and review. AB - BACKGROUND: The Family Eating and Activity Habits Questionnaire (FEAHQ) is a 32 item self-report instrument designed to assess the eating and activity habits of family members as well as obesogenic factors in the overall home environment (stimulus and behaviour patterns) related to weight. Originally, this questionnaire, which was developed in Israel, was designed for use in family based weight-management interventions that emphasized changes in the environment, and in parents' knowledge, behaviours and modelling. It was developed for use with children aged 6-11 years and designed for co-completion by parents or caretakers and their children. Over the years, it has been administered in research and clinical settings in Israel, England, Australia and other countries. Its 15-year anniversary calls for an update in the literature regarding adjustments made to improve its use in different settings and with different ethnic populations and the psychometric properties of the revised version. OBJECTIVE: The goal of this paper is threefold: (i) to describe the history and development of the FEAHQ; (ii) to present new data supporting the psychometric properties of the subscales of the Revised FEAHQ (FEAHQ-R) for ages 6-12 years and (iii) to review the clinical and research literature reporting on FEAHQ subscales. METHODS: The psychometric properties of the revised questionnaire were evaluated in a randomized control trial and in a naturalistic, community-based study to promote healthy lifestyle among families with children 6-12 years of age from different ethnic populations. RESULTS: The tool demonstrated good test retest reliability when completed by caretakers and very good internal consistency. The questionnaire scores discriminated between obese and normal weight children and predicted the weight classification of 66% of the participants. CONCLUSIONS: The FEAHQ-R is a useful clinical tool for identifying target behaviors for treatment and monitoring treatment progress that centers on overweight prevention and weight management. PMID- 23447445 TI - Survey of academic pediatric hospitalist programs in the US: organizational, administrative, and financial factors. AB - BACKGROUND: Many pediatric academic centers have hospital medicine programs. Anecdotal data suggest that variability exists in program structure. OBJECTIVE: To provide a description of the organizational, administrative, and financial structures of academic pediatric hospital medicine (PHM). METHODS: This online survey focused on the organizational, administrative, and financial aspects of academic PHM programs, which were defined as hospitalist programs at US institutions associated with accredited pediatric residency program (n = 246) and identified using the Accreditation Council for Graduate Medical Education (ACGME) Fellowship and Residency Electronic Interactive Database. PHM directors and/or residency directors were targeted by both mail and the American Academy of Pediatrics Section on Hospital Medicine LISTSERV. RESULTS: The overall response rate was 48.8% (120/246). 81.7% (98/120) of hospitals reported having an academic PHM program, and 9.1% (2/22) of hospitals without a program reported plans to start a program in the next 3 years. Over a quarter of programs provide coverage at multiple sites. Variability was identified in many program factors, including hospitalist workload and in-house coverage provided. Respondents reported planning increased in-house hospitalist coverage coinciding with the 2011 ACGME work-hour restrictions. Few programs reported having revenues greater than expenses (26% single site, 4% multiple site). CONCLUSIONS: PHM programs exist in the majority of academic centers, and there appears to be variability in many program factors. This study provides the most comprehensive data on academic PHM programs and can be used for benchmarking as well as program development. PMID- 23447446 TI - Large resistive switching in ferroelectric BiFeO3 nano-island based switchable diodes. PMID- 23447447 TI - One-pot synthesis of pyrazoles through a four-step cascade sequence. AB - A one-pot synthesis of 3,4,5- and 1,3,5-pyrazoles from tertiary propargylic alcohols and para-tolylsulfonohydrazide has been accomplished. The pyrazoles are formed through a four-step cascade sequence, including FeCl3 -catalyzed propargylic substitution, aza-Meyer-Schuster rearrangement, base-mediated 6pi electrocyclization, and thermal [1,5] sigmatropic shift. In this reaction, the 3,4,5- and 1,3,5-pyrazoles are produced selectively according to different substituents in the starting alcohols. PMID- 23447448 TI - Systems metabolic engineering of xylose-utilizing Corynebacterium glutamicum for production of 1,5-diaminopentane. AB - The sustainable production of industrial platform chemicals is one of the great challenges facing the biotechnology field. Ideally, fermentation feedstocks would rather rely on industrial waste streams than on food-based raw materials. Corynebacterium glutamicum was metabolically engineered to produce the bio-nylon precursor 1,5-diaminopentane from the hemicellulose sugar xylose. Comparison of a basic diaminopentane producer strain on xylose and glucose feedstocks revealed a 30% reduction in diaminopentane yield and productivity on the pentose sugar. The integration of in vivo and in silico metabolic flux analysis by (13) C and elementary modes identified bottlenecks in the pentose phosphate pathway and the tricarboxylic acid cycle that limited performance on xylose. By the integration of global transcriptome profiling, this could be specifically targeted to the tkt operon, genes that encode for fructose bisphosphatase (fbp) and isocitrate dehydrogenase (icd), and to genes involved in formation of lysine (lysE) and N acetyl diaminopentane (act). This was used to create the C. glutamicum strain DAP Xyl1 icd(GTG) Peftu fbp Psod tkt Deltaact DeltalysE. The novel producer, designated DAP-Xyl2, exhibited a 54% increase in product yield to 233 mmol mol( 1) and a 100% increase in productivity to 1 mmol g(-1) h(-1) on the xylose substrate. In a fed-batch process, the strain achieved 103 g L(-1) of diaminopentane from xylose with a product yield of 32%. Xylose utilization is currently one of the most relevant metabolic engineering subjects. In this regard, the current work is a milestone in industrial strain engineering of C. glutamicum. See accompanying commentary by Hiroshi Shimizu DOI: 10.1002/biot.201300097. PMID- 23447449 TI - Catalytic enantioselective decarboxylative cyanoalkylation of imines by using palladium pincer complexes with C2-symmetric chiral bis(imidazoline)s. AB - Manifold products: The enantioselective decarboxylative Mannich-type reaction of cyanoacetic acid with N-(2-pyridinesulfonyl)imines catalyzed by chiral 1,3 bis(imidazolin-2-yl)benzene (Phebim)-Pd(II) complexes afforded products with good enantioselectivity (see scheme). The reaction was applied to a wide range of imines with good yield and enantioselectivity. The obtained products can be converted into various compounds without the loss of enantiopurity. PMID- 23447450 TI - Offer patterns of nationally placed livers by donation service area. AB - We previously reported that national liver distribution is highly concentrated in 6 US centers, and this raises the possibility of expedited placement. Therefore, we evaluated all national offers of nationally placed livers (n=1625) to adult wait-list candidates from February 2005 to January 2010. We developed a model to predict national utilization pathways; pathways exceeding the best-fit linear unbiased predictions by >=3 standard errors were defined as preferred. All 51 donation service areas (DSAs) placed 1 or more livers nationally, but the percentage per DSA ranged from 1% to 36%. Of 2830 possible national DSA-center pathways, 87% were used. Five hundred eighty livers (36%) were accepted on the first national offer. Four DSAs accounted for 47% of first-national-offer livers, and 44% of these were accepted by a single center. In comparison with first-offer livers using nonpreferred pathways, first offers along a preferred pathway were offered to fewer status 1 candidates (19% versus 61%) and had lower median model for end-stage liver disease (MELD) scores (22 versus 36, P<0.001). In conclusion, DSA placement patterns of national livers vary widely, with 4 DSAs exporting a high proportion of national livers on the first national offer to non-status 1 candidates with MELD scores less than their local transplant MELD scores. Although this practice may facilitate liver placement, it raises the possibility of expedience trumping patient need. Here we propose changes to the national liver distribution system that will help to balance equity, efficiency, and transparency. PMID- 23447451 TI - Desmosterol in human nonalcoholic steatohepatitis. AB - Dysregulation of the cholesterol synthesis pathway and accumulation of cholesterol in the liver are linked to the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we investigated the association of serum and liver levels of cholesterol precursors with NASH. Liver histology was assessed in 110 obese patients (Kuopio Obesity Surgery Study [KOBS] study, age 43.7 +/- 8.1 years [mean +/- standard deviation, SD], body mass index [BMI] 45.0 +/- 6.1 kg/m(2) ). Serum and liver levels of cholesterol precursors were measured with gas-liquid chromatography. The association between cholesterol precursors and serum alanine aminotransferase (ALT), as a marker of liver disease, was also investigated in a population cohort of 717 men (Metabolic Syndrome in Men Study [METSIM] study, age 57.6 +/- 5.8 years, BMI 27.1 +/- 4.0 kg/m(2) ). Serum desmosterol levels and the desmosterol-to-cholesterol ratio were higher in individuals with NASH, but not in individuals with simple steatosis, compared to obese subjects with normal liver histology (P = 0.002 and P = 0.003, respectively). Levels of serum and liver desmosterol correlated strongly (r = 0.667, P = 1 * 10(-9) ), suggesting a shared regulation. Both serum and liver desmosterol levels correlated positively with steatosis and inflammation in the liver (P < 0.05). Serum desmosterol had a higher correlation with the accumulation of cholesterol in the liver than serum cholesterol. Serum desmosterol levels (P = 2 * 10(-6) ) and the serum desmosterol-to-cholesterol ratio (P = 5 * 10(-5) ) were associated with serum ALT in the population study. CONCLUSION: Levels of desmosterol in serum and the liver were associated with NASH. These results suggest that serum desmosterol is a marker of disturbed cholesterol metabolism in the liver. Whether desmosterol has a more specific role in the pathophysiology of NASH compared to other cholesterol precursors needs to be investigated. PMID- 23447453 TI - Does exercise intensity affect blood pressure and heart rate in obese adolescents? A 6-month multidisciplinary randomized intervention study. AB - BACKGROUND: Aerobic exercise improves cardiovascular health in general, but whether the impact varies with exercise intensity is not clear. OBJECTIVE: The aim of the current study was to compare the effects of a high-intensity aerobic exercise training (HIT) vs. a low-intensity aerobic exercise training (LIT) on blood pressure (BP), heart rate (HR) and heart rate variability (HRV) in obese adolescents. METHODS: Forty-three (13-18 years) Tanner stage (III-IV) matched obese adolescents were studied in a randomized trial of either HIT (corresponding to the ventilatory threshold I; n = 20) or LIT (corresponding to 20% below the ventilatory threshold I; n = 23) programme for a period of 6 months. All participants also received a multidisciplinary therapy that included nutritional, psychological and clinical counselling. Both HIT and LIT sessions were isocaloric, with energy expenditure set at 350 kcal. BP, HR and HRV were measured along with markers of body adiposity and insulin resistance before and after the respective interventions. RESULTS: The participants in both groups had similar physical and clinical characteristics. After the 6-month intervention, systolic, diastolic and mean BP decreased (P < 0.05, for all) similarly in both groups, whereas waist circumference, HR and HRV showed beneficial changes only in the HIT group (P < 0.05). CONCLUSION: Aerobic exercise training set at a high intensity compared with the low intensity appears to have additional benefits on abdominal obesity and cardiovascular health in that it enhances the parasympathetic and autonomic modulation of the heart in obese adolescents. PMID- 23447452 TI - Conveying genomic recurrence risk estimates to patients with early-stage breast cancer: oncologist perspectives. AB - OBJECTIVE: The development and increased use of genomic profiling has led to refinement of breast cancer treatment. This study sought to examine medical and surgical oncologists' perceptions of factors related to the translation and integration of Oncotype DX(r) (Genomic Health, Inc., Redwood City, CA, USA) into routine clinical care. METHODS: Twenty oncologists (10 medical and 10 surgical oncologists) participated in qualitative interviews. Questions centered on the following themes: oncologists' perceptions about the clinical utility of testing, the impact of patient preferences on the decision to test and use results to inform treatment decisions, methods of communicating risk associated with test results to patients, and benefits of and barriers to incorporating testing into multidisciplinary care settings. RESULTS: Oncologists found Oncotype DX test results useful in their practice but had concerns as well. These included that some oncologists either used testing inappropriately or placed undue emphasis on the results at the expense of other clinical information. The use of intermediate test results, which have less clear clinical implications, incorporating results with patient treatment preferences, and the use of testing in multidisciplinary teams were noted as specific challenges. CONCLUSION: Oncologists noted several benefits of testing and also many challenges, despite wide dissemination and common use. Education for health providers should include specific training in how to interpret and communicate the uncertainty inherent in genomic tests while integrating patient preferences to inform treatment decision making. PMID- 23447454 TI - Enzyme-free unlabeled DNA logic circuits based on toehold-mediated strand displacement and split G-quadruplex enhanced fluorescence. AB - Adopting fluorescence of PPIX enhanced by a split G-quadruplex and toehold mediated strand displacement reaction, a series of unlabeled fluorescent logic gates is set up and some of them are cascaded into circuits. Controlled release of PPIX, which is also a photosensitizer in photodynamic diagnosis and therapy, is realized by this circuit, making it a wise choice for DNA computing. PMID- 23447457 TI - Cu-catalyzed asymmetric allylic alkylation of phosphonates and phosphine oxides with Grignard reagents. AB - An efficient and highly enantioselective copper-catalyzed allylic alkylation of phosphonates and phosphine oxides with Grignard reagents and Taniaphos or phosphoramidites as chiral ligands is reported. Transformation of these products leads to a variety of new phosphorus-containing chiral intermediates. PMID- 23447456 TI - Acute on-chip HIV detection through label-free electrical sensing of viral nano lysate. AB - Development of portable biosensors has broad applications in environmental monitoring, clinical diagnosis, public health, and homeland security. There is an unmet need for pathogen detection at the point-of-care (POC) using a fast, sensitive, inexpensive, and easy-to-use method that does not require complex infrastructure and well-trained technicians. For instance, detection of Human Immunodeficiency Virus (HIV-1) at acute infection stage has been challenging, since current antibody-based POC technologies are not effective due to low concentration of antibodies. In this study, we demonstrated for the first time a label-free electrical sensing method that can detect lysed viruses, i.e. viral nano-lysate, through impedance analysis, offering an alternative technology to the antibody-based methods such as dipsticks and Enzyme-linked Immunosorbent Assay (ELISA). The presented method is a broadly applicable platform technology that can potentially be adapted to detect multiple pathogens utilizing impedance spectroscopy for other infectious diseases including herpes, influenza, hepatitis, pox, malaria, and tuberculosis. The presented method offers a rapid and portable tool that can be used as a detection technology at the POC in resource-constrained settings, as well as hospital and primary care settings. PMID- 23447455 TI - Six months of dance intervention enhances postural, sensorimotor, and cognitive performance in elderly without affecting cardio-respiratory functions. AB - During aging, sensorimotor, cognitive and physical performance decline, but can improve by training and exercise indicating that age-related changes are treatable. Dancing is increasingly used as an intervention because it combines many diverse features making it a promising neuroplasticity-inducing tool. We here investigated the effects of a 6-month dance class (1 h/week) on a group of healthy elderly individuals compared to a matched control group (CG). We performed a broad assessment covering cognition, intelligence, attention, reaction time, motor, tactile, and postural performance, as well as subjective well-being and cardio-respiratory performance. After 6 months, in the CG no changes, or further degradation of performance was found. In the dance group, beneficial effects were found for dance-related parameters such as posture and reaction times, but also for cognitive, tactile, motor performance, and subjective well-being. These effects developed without alterations in the cardio respiratory performance. Correlation of baseline performance with the improvement following intervention revealed that those individuals, who benefitted most from the intervention, were those who showed the lowest performance prior to the intervention. Our findings corroborate previous observations that dancing evokes widespread positive effects. The pre-post design used in the present study implies that the efficacy of dance is most likely not based on a selection bias of particularly gifted individuals. The lack of changes of cardio-respiratory fitness indicates that even moderate levels of physical activity can in combination with rich sensorimotor, cognitive, social, and emotional challenges act to ameliorate a wide spectrum of age-related decline. PMID- 23447458 TI - A facile phosphine-free method for synthesizing PbSe nanocrystals with strong optical limiting effects. AB - PbSe semiconductor nanocrystals (NCs) have attracted ever-growing interest owing to both their fundamental physics and potential applications in a diverse range of fields such as optoelectronic devices and nonlinear optics. The current fabrication strategy for colloidal PbSe NCs, however, frequently involves acutely toxic reagents and tedious reaction procedures, and is plagued by products with poorly controlled size and morphology. Herein, we report a facile, low-cost, and phosphine-free method for synthesizing PbSe NCs, which provides highly uniform NCs with tunable mid-IR absorption, and they are promising for bio-related applications. These high quality NCs were obtained by the reaction of elemental Se and PbCl2 in oleylamine as both the ligand and reaction medium. The high flexibility and reproducibility of the method reported in this study allows us to synthesize monodispersed PbSe NCs with well-controlled size and morphology. In addition, these products show strong optical limiting effects, and thus hold potential for developing nonlinear optical devices. PMID- 23447459 TI - Liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus at different stages of fibrotic evolution. AB - Transient elastography (TE) is increasingly employed in clinical practice for the noninvasive detection of tissue fibrosis in patients with chronic liver disease (CLD), and particularly chronic hepatitis C virus (HCV)-related hepatitis. The present study was designed to provide a definitive characterization of the "confounding" increase in liver stiffness (LS) following a standardized meal in a consecutive population of 125 patients with chronic HCV infection at different stages of fibrotic evolution. LS values were obtained after overnight fasting and 15, 30, 45, 60, and 120 minutes following the onset of a standardized liquid meal (400 mL, 600 Kcal, 16.7% protein, 53.8% carbohydrates, 29.5% fat). An evident increase in LS values was observed 15 to 45 minutes after the onset of the meal with return to baseline premeal levels within 120 minutes in all patients. The peak postmeal delta increase in LS was progressively more marked with increasing stages of fibrosis (P < 0.001), becoming maximal in patients with cirrhosis. However, the probability of identifying the Metavir stage of fibrosis, the Child Pugh class, or the presence/absence of esophageal varices with the postmeal delta increase in LS was inferior to that obtained with baseline LS values. CONCLUSION: The results of the present study provide definitive evidence of the confounding effect of a meal on the accuracy of LS measurements for the prediction of fibrosis stage in patients with chronic HCV hepatitis and suggest that a fasting period of 120 minutes should be observed before the performance of TE. PMID- 23447460 TI - Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency ablation? AB - The objective of this study was to evaluate the efficacy of salvage liver transplantation (SLT), repeated hepatic resection (RR), and repeated radiofrequency ablation (rRFA) for patients with postoperative tumor recurrence. The optimal treatment strategy for patients with recurrent hepatocellular carcinoma (HCC) remains unclear. From January 1993 to September 2009, 532 patients underwent either hepatic resection or radiofrequency ablation (RFA) for HCC within the Milan criteria. In all, 219 patients experienced intrahepatic recurrence, and 87 were selected for SLT (n=19), RR (n=24), or rRFA (n=44). Their clinicopathological data were reviewed, and their survival outcomes were assessed with Kaplan-Meier methods. Seventy-four of 220 patients (33.6%) developed recurrent HCC within the Milan criteria. The median Model for End-Stage Liver Disease (MELD) scores for SLT, RR, and rRFA were 10.7, 7.2, and 8.3, respectively (P<0.001). The 1-, 3-, and 5-year tumor-free survival rates were 68.4%, 57.9%, and 57.9%, respectively, for SLT; 69.7%, 49.3%, and 49.3%, respectively, for RR; and 40.0%, 19.8%, and 10.6%, respectively, for rRFA (P=0.001). For recurrent HCC within the Milan criteria, the 1-, 3-, and 5-year tumor-free survival rates for SLT were all 60%; the corresponding rates were 70.2%, 48.0%, and 48.0% for RR and 41.0%, 20.3%, and 10.9% for RFA (P=0.004). After adjustments of the MELD score, the 5-year survival rates for SLT, RR, and rRFA were 50.0%, 48.0%, and 11.4%, respectively (P=0.003). A subgroup analysis showed that SLT and RR led to comparable survival outcomes, but both treatments led to significantly better survival outcomes than rRFA (P<0.001). In conclusion, SLT is an efficacious treatment for patients with recurrent HCC and should be considered when RR is not feasible. PMID- 23447461 TI - Using reference databases of genetic variation to evaluate the potential pathogenicity of candidate disease variants. AB - The potential pathogenicity of genetic variants identified in disease-based resequencing studies is often overlooked where variants have previously been reported in dbSNP, the 1000 genomes project, or the National Heart, Lung and Blood Institute Exome Sequencing Project (ESP). In this work, we estimate that collectively, these databases capture ~52% of mutations (dbSNP 50.4%; 1000 genomes 4.8%; and ESP 10.2%) reported as disease causing within phenotype-based locus-specific databases (LSDBs). To investigate whether these mutations may simply represent benign population variants, we evaluated whether the carrier frequencies associated with mutations implicated in amyotrophic lateral sclerosis were higher than what could be accounted for by high-penetrance disease models. In doing so, we have questioned the veracity of 51 mutations, but also demonstrated that each of the three databases included credible disease variants. Our results demonstrate the benefits of using databases such as dbSNP, the 1000 genomes project, and the ESP to evaluate the pathogenicity of putative disease variants, and suggest that many disease mutations reported across LSDBs may not actually be pathogenic. However, they also demonstrate that even in the context of rare Mendelian disorders, the potential pathogenicity of variants reported by these databases should not be overlooked without proper evaluation. PMID- 23447462 TI - Reactions of copper(II) chloride in solution: facile formation of tetranuclear copper clusters and other complexes that are relevant in catalytic redox processes. AB - Mixing CuCl2?2 H2O with benzylamine in alcoholic solutions led to an extremely colorful chemistry caused by the formation of a large number of different complexes. Many of these different species could be structurally characterized. These include relatively simple compounds such as [Cu(L(1))4Cl2] (L(1) = benzylamine) and (HL(1))2[CuCl4]. Most interestingly is the easy formation of two cluster complexes, one based on two cluster units Cu4OCl6(L(1))4 connected through one [Cu(L(1))2Cl2] complex and one based on a cubane-type cluster ([Cu4O4](C11H14)4Cl4). Both clusters proved to be highly reactive in a series of oxidation reactions of organic substrates by using air or peroxides as oxidants. Furthermore, it was possible to isolate and structurally characterize ([Cu(L(1))Cl]3 and [Cu(benz2mpa)2]CuCl2 (benz2mpa = benzyl-(2-benzylimino-1 methyl-propylidene)-amine), two copper(I) complexes that formed in solution, demonstrating the high redox activity of the cluster systems. In addition, it was possible to solve the molecular structures of the compounds Cu4OCl6(MeOH)4, [Cu(MeOH)2Cl2], [Cu(aniline)2Cl2], and an organic side product (HC13 H19 NOCl). In fact all determined structures are of a known type but the chemical relation between these compounds could be explained for the first time. The paper describes these different compounds and their chemical equilibria. Some of these complexes seem to be relevant in catalytic oxidation reactions and their reactivity is discussed in more detail. PMID- 23447463 TI - School closures and influenza: systematic review of epidemiological studies. AB - OBJECTIVE: To review the effects of school closures on pandemic and seasonal influenza outbreaks. DESIGN: Systematic review. DATA SOURCES: MEDLINE and EMBASE, reference lists of identified articles, hand searches of key journals and additional papers from the authors' collections. STUDY SELECTION: Studies were included if they reported on a seasonal or pandemic influenza outbreak coinciding with a planned or unplanned school closure. RESULTS: Of 2579 papers identified through MEDLINE and EMBASE, 65 were eligible for inclusion in the review along with 14 identified from other sources. Influenza incidence frequently declined after school closure. The effect was sometimes reversed when schools reopened, supporting a causal role for school closure in reducing incidence. Any benefits associated with school closure appeared to be greatest among school-aged children. However, as schools often closed late in the outbreak or other interventions were used concurrently, it was sometimes unclear how much school closure contributed to the reductions in incidence. CONCLUSIONS: School closures appear to have the potential to reduce influenza transmission, but the heterogeneity in the data available means that the optimum strategy (eg, the ideal length and timing of closure) remains unclear. PMID- 23447464 TI - The incidence of rugby-related catastrophic injuries (including cardiac events) in South Africa from 2008 to 2011: a cohort study. AB - OBJECTIVES: To establish an accurate and comprehensive injury incidence registry of all rugby union-related catastrophic events in South Africa between 2008 and 2011. An additional aim was to investigate correlates associated with these injuries. DESIGN: Prospective. SETTING: The South African amateur and professional rugby-playing population. PARTICIPANTS: An estimated 529 483 Junior and 121 663 Senior rugby union ('rugby') players (population at risk). OUTCOME MEASURES: Annual average incidences of rugby-related catastrophic injuries by type (cardiac events, traumatic brain and acute spinal cord injuries (ASCIs)) and outcome (full recoveries-fatalities). Playing level (junior and senior levels), position and event (phase of play) were also assessed. RESULTS: The average annual incidence of ASCIs and Traumatic Brain Injuries combined was 2.00 per 100 000 players (95% CI 0.91 to 3.08) from 2008 to 2011. The incidence of ASCIs with permanent outcomes was significantly higher at the Senior level (4.52 per 100 000 players, 95% CI 0.74 to 8.30) than the Junior level (0.24 per 100 000 players, 95% CI 0 to 0.65) during this period. The hooker position was associated with 46% (n=12 of 26) of all permanent ASCI outcomes, the majority of which (83%) occurred during the scrum phase of play. CONCLUSIONS: The incidence of rugby-related catastrophic injuries in South Africa between 2008 and 2011 is comparable to that of other countries and to most other collision sports. The higher incidence rate of permanent ASCIs at the Senior level could be related to the different law variations or characteristics (eg, less regular training) compared with the Junior level. The hooker and scrum were associated with high proportions of permanent ASCIs. The BokSmart injury prevention programme should focus efforts on these areas (Senior level, hooker and scrum) and use this study as a reference point for the evaluation of the effectiveness of the programme. PMID- 23447465 TI - Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports. AB - OBJECTIVE: To explore the structure and content of a non-random sample of clinical study reports (CSRs) to guide clinicians and systematic reviewers. SEARCH STRATEGY: We searched public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators. SELECTION CRITERIA: CSRs reporting sufficient information for extraction ('adequate'). PRIMARY OUTCOME MEASURES: Presence and length of essential elements of trial design and reporting and compression factor (ratio of page length for CSRs compared to its published counterpart in a scientific journal). DATA EXTRACTION: Data were extracted on standard forms and crosschecked for accuracy. RESULTS: We assembled a population of 78 CSRs (covering 90 randomised controlled trials; 144 610 pages total) dated 1991-2011 of 14 pharmaceuticals. Report synopses had a median length of 5 pages, efficacy evaluation 13.5 pages, safety evaluation 17 pages, attached tables 337 pages, trial protocol 62 pages, statistical analysis plan 15 pages and individual efficacy and safety listings had a median length of 447 and 109.5 pages, respectively. While 16 (21%) of CSRs contained completed case report forms, these were accessible to us in only one case (765 pages representing 16 individuals). Compression factors ranged between 1 and 8805. CONCLUSIONS: Clinical study reports represent a hitherto mostly hidden and untapped source of detailed and exhaustive data on each trial. They should be consulted by independent parties interested in a detailed record of a clinical trial, and should form the basic unit for evidence synthesis as their use is likely to minimise the problem of reporting bias. We cannot say whether our sample is representative and whether our conclusions are generalisable to an undefined and undefinable population of CSRs. PMID- 23447466 TI - Use of a simple liquid meal test to evaluate insulin sensitivity and beta-cell function in children. AB - Insulin sensitivity and beta-cell function are useful indices of metabolic disease risk but are difficult to assess in young children because of the invasive nature of commonly used methodology. A meal-based method for assessing insulin sensitivity and beta-cell function may at least partially alleviate concerns. The objectives of this study were to: (i) determine the association of insulin sensitivity assessed by liquid meal test with that determined by an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT); (ii) examine the association of insulin sensitivity derived from each test with measures of body composition, fat distribution and metabolic health (lipids, fasting insulin and glucose, and surrogate indices of insulin sensitivity); and (iii) examine the associations of indices of beta-cell function derived from each test with total and regional adiposity. Forty-seven children (7-12 years) underwent both a liquid meal test and an FSIGT. The insulin sensitivity index derived from the meal test (SI-meal) was positively associated with that from the FSIGT (SI-FSIGT; r = 0.63; P < 0.001), and inversely with all measures of insulin secretion derived from the meal test. Both SI-meal and SI-FSIGT were associated with measures of total and regional adiposity. SI-meal, but not SI-FSIGT, was associated with triglycerides and fasting insulin, after adjusting for ethnicity, gender, pubertal stage and fat mass. Basal insulin secretion measured during the meal test was positively associated with all measures of adiposity, independent of insulin sensitivity. In conclusion, a liquid meal offers a valid and sensitive means of assessing insulin sensitivity and beta-cell responsivity in young children. PMID- 23447467 TI - A minimally invasive method for gender determination in the prehensile-tailed porcupine (Coendou prehensilis). AB - Prehensile-tailed porcupines (Coendou prehensilis), like other rodents, lack external sexual traits, making it difficult to non-invasively determine their gender. By exploiting genetic differences between the X and the Y chromosome, we developed a simple genetic test to determine the gender of Coendous from shed quills. We Sanger sequenced a short portion (195 bp) of the zinc finger protein gene of known male (XY) Coendous to identify positions that are polymorphic between the X and Y chromosomes at this locus. By directly sequencing this fragment, we were able to correctly determine (confirmed via anatomical sexing) the gender of male and female Coendous by the presences or absence of polymorphisms in the resulting chromatograms. This assay is simple, quick and is applicable to other porcupine species. PMID- 23447469 TI - N-heterocyclic carbene (NHC)-catalyzed/Lewis acid mediated conjugate umpolung of alkynyl aldehydes for the synthesis of butenolides: a formal [3+2] annulation. AB - Reverse to success! A new formal [3+2] annulation reaction combining alkynyl aldehydes and beta,gamma-unsaturated alpha-ketoesters has been disclosed by using a NHC-catalyzed/Lewis acid mediated strategy. This cooperative catalysis strategy first allows the "allenolate" intermediate as a nucleophilic synthon at the beta position to react with activated electrophilic reagents by an addition reaction as the key C-C bond-forming step. PMID- 23447470 TI - Right papillary muscle sling: proof of concept and pilot clinical experience. AB - OBJECTIVES: Left-sided intraventricular remodelling by papillary muscle approximation associated with annuloplasty of the mitral valve improved outcomes for severe functional mitral regurgitation compared with annuloplasty alone. We conceived of, and studied, a papillary muscle sling on the right side of the heart associated with annuloplasty, seeking to reduce tricuspid valve tethering and right ventricular volumes and to preserve ventricular function. METHODS: An experimental model on ex vivo porcine hearts established the anatomical feasibility of the procedure. A first-in-man clinical series of 5 patients (3 men) with a mean age of 63.3 years (51-73) had mean right ventricular volumes of 320 ml (280-350) and 200 ml (155-250) in diastole and systole, respectively, and an ejection fraction of 30% (25-40). The mean pulmonary artery pressure was 60 mmHg (55-70), and all had Grade IV/IV tricuspid regurgitation (TR). RESULTS: There was no operative mortality. Post-repair, magnetic resonance imaging and echocardiographic studies showed mean right ventricle volumes of 165 ml (155-180) and 124 ml (110-140) in diastole and systole, respectively, and an ejection fraction of 28% (25-35) (P = 0.03). TR was <2, gradient across tricuspid valve was <= 4 mmHg and there was no right ventricular outflow tract obstruction. All patients were in New York Heart Association Class <= 2. CONCLUSION: Intraventricular remodelling with a papillary muscle sling is safe and feasible on the right heart. Short-term follow-up shows that it ameliorates clinical functional status and improves valve competency through reduced tension and tethering of tricuspid leaflets. PMID- 23447471 TI - The developing pulmonary veins and left atrium: implications for ablation strategy for atrial fibrillation. AB - The majority of cases of atrial fibrillation (AF) are the result of triggers originating in the area of the pulmonary veins. The reason for the predilection for that area remains unclear. We sought to examine the different mechanisms responsible for this observation through an extensive search of the medical literature, examining the development of the pulmonary veins, genetics of AF and left to -right cardiac chamber differentiation. Results confirm that the LAA is anatomically and embryologically different from other areas of the atrial walls and develops under distinct genetic and transcriptional pathways. Findings support an ablation strategy whose primary focus should be the creation of a 'box' lesion set, plus additional lines to prevent propagation to the left atrial appendage, the isthmus of the left atrium and the right atrium are likely to be more effective than simple pulmonary vein isolation. PMID- 23447468 TI - Biodegradation of single-walled carbon nanotubes by eosinophil peroxidase. AB - Eosinophil peroxidase (EPO) is one of the major oxidant-producing enzymes during inflammatory states in the human lung. The degradation of single-walled carbon nanotubes (SWCNTs) upon incubation with human EPO and H2O2 is reported. Biodegradation of SWCNTs is higher in the presence of NaBr, but neither EPO alone nor H2O2 alone caused the degradation of nanotubes. Molecular modeling reveals two binding sites for SWCNTs on EPO, one located at the proximal side (same side as the catalytic site) and the other on the distal side of EPO. The oxidized groups on SWCNTs in both cases are stabilized by electrostatic interactions with positively charged residues. Biodegradation of SWCNTs can also be executed in an ex vivo culture system using primary murine eosinophils stimulated to undergo degranulation. Biodegradation is proven by a range of methods including transmission electron microscopy, UV-visible-NIR spectroscopy, Raman spectroscopy, and confocal Raman imaging. Thus, human EPO (in vitro) and ex vivo activated eosinophils mediate biodegradation of SWCNTs: an observation that is relevant to pulmonary responses to these materials. PMID- 23447472 TI - Surgical technique for heart transplantation: a strategy for congenital heart disease. AB - The standard techniques for orthotopic heart transplantation often require certain adjustments when the procedure is carried out for complex congenital heart disease. This is because of both the unusual anatomy and possible distortions caused by previous surgery. Such technical adjustments have been described in various published reports over the years. Those reports, when combined, do cover the full spectrum of the technical difficulties that may be encountered, whether the defects are in their original form or altered by surgery, such that no cardiac malformation or distortion would prohibit transplantation. However, those reports are comprehensive only when combined. None of the individual reports addresses all the possible technical challenges. Consequently, the available information is somewhat fragmented. In addition, the generic aspect of the described technical strategies is not always given the emphasis that it deserves. Indeed, occasionally a technique may be presented as a specific solution for a specific malformation, without necessarily pointing out that the same technique may be applied to other hearts with different overall pathologies but which share that specific malformation. The aim of this review article was to combine all the available published information in one article in a manner that constructs a simple but comprehensive and generic system of decision-making that may be applied to any heart in order to determine the exact technical adjustments needed for transplantation in each case. Such a strategy is possible for two reasons. First, only a few anatomical sites are technically significant, namely the points of anastomosis between the donor's organ and the recipient. The rest of the intracardiac morphology does not affect the operation and may be ignored. Second, each of those anatomical sites can present difficulties in only a few ways, and each of those few difficulties has a well described and published solution already. Therefore, the exact technical adjustments required in each case may be worked out by the sequential assessment of the anastomotic sites alone. PMID- 23447473 TI - Chest-wall reconstruction in case of infection of the operative site: is there any interest in titanium rib osteosynthesis? AB - OBJECTIVES: To describe the management of thoracic reconstructions in the presence of primary chest-wall infection (PCWI) or secondary deep chest-wall infection (SCWI), focussing on local tolerance of a titanium rib osteosynthesis system. METHODS: PCWI included infected chest wall tumours (CWT), infected T3 non small-cell lung carcinoma (NSCLC) and open flail chest. SCWI was defined by deep infection of previous thoracic-wall reconstructions. Infection was identified by preoperative bacterial analysis of the tumour or surgical site. In PCWI, a one step procedure combined extensive resection of infected tissues and rigid reconstruction of the defect; skeletal rigidity was achieved using titanium implants. In SCWI, we removed all synthetic material except titanium implants. In both groups, the surgical field was thoroughly cleaned and implants were wrapped or covered by flaps. RESULTS: From January 2005 to December 2011, 11 patients (54 +/- 10.2 years) with either PCWI (3 CWT, 3 T3 NSCLC, 1 open flail chest) or SCWI (3 CWT, 1 funnel chest) were treated. Infection was polymicrobial in all but 1 case. Bacteria observed in PCWI patients were multidrug resistant. In PCWI, we resected 4.2 +/- 0.6 ribs en bloc with the lung (n = 5), the skin and the pectoralis major and then used mesh and 2.1 +/- 1.2 titanium implants for reconstruction (n = 6). The mean defect was 1154.4 +/- 318 cm(3). Surgical SCWI management removed polytetrafluoroethylene-mesh and preserved the titanium implants. A Vicryl mesh (n = 3) and greater omentum flap (n = 3) were added. One of the 2 postoperative deaths in the PCWI group was related to infection recurrence. No other patient had infection at the 6-month follow-up with leucocyte-labelled scintigraphy. CONCLUSION: Titanium rib osteosynthesis is reliable in two complex and life-threatening situations: PCWIs and SCWIs. In combination with a flap, this allows rapid, reliable, rigid reconstruction of infected full-thickness chest-wall defects in a single-step procedure. PMID- 23447474 TI - Is rheumatic aetiology a predictor of poor outcome in the current era of mitral valve repair? Contemporary long-term results of mitral valve repair in rheumatic heart disease. AB - OBJECTIVES: Contemporary experience with mitral valve (MV) repair in the rheumatic population is limited. We aimed to examine the long-term outcomes of rheumatic MV repair, to identify the predictors of durability and to compare the repair for rheumatic and degenerative MVs. METHODS: MV repairs for both rheumatic and degenerative lesions were analysed prospectively from our valve-repair registry. The primary outcomes investigated were mortality, survival, freedom from reoperation and freedom from valve failure. Logistic and Cox regression analyses were performed to define the predictors of reoperation and valve failure. RESULTS: Between 1997 and 2010, 627 consecutive rheumatic MV repairs were performed (46.7% of all mitral repair procedures). The mean age of our study group was 32 +/- 19 (range 3-75 years). In-hospital mortality was 2.4% and late mortality was 0.3%. Freedoms from reoperation for rheumatics at 5 and 10 years were 91.8 +/- 4.8 and 87.3 +/- 3.9%, respectively, comparable with that for degenerative valves at 92.0 +/- 1.7 and 91.8 +/- 4.8%, respectively (P = 0.79). Freedoms from valve failure for rheumatics at 5 and 10 years were 85.6 +/- 2.3 and 72.8 +/- 4.6%, respectively, whereas those for degenerative repairs were 88.7 +/- 5.1 and 82.4 +/- 7.7%, respectively (P = 0.45). Independent predictors for reoperation and valve failure in rheumatic patients were residual mitral regurgitation >2+ and performance of commissurotomy. CONCLUSIONS: The durability of MV repair for rheumatic disease in the current era has improved and is comparable with the outstanding durability of repairs for degenerative disease. Modifications of standard repair techniques, adherence to the importance of good leaflet coaptation and strict quality control with stringent use of intraoperative transoesophageal echocardiography have all contributed to the improved long-term results. PMID- 23447475 TI - Anatomical and functional assessment of the intra-atrial lateral tunnel in the Fontan circulation. AB - OBJECTIVES: In patients after completion of the total cavopulmonary connection (TCPC) with an intra-atrial lateral tunnel, deviations of the tunnel from an ideal straight tubular shape were observed. However, little is known about frequency and adverse effects of such shape deviations. We sought to analyse tunnel anatomy, dimensions and blood flow using cardiac magnetic resonance imaging (CMR). METHODS: Fifty-four patients with hypoplastic left heart syndrome (HLHS; mean age 6.0 +/- 2.4 years) underwent CMR with gradient-echo cine sequences, 2D- and 3D-phase-contrast imaging. We analysed anatomy, diameters, cross-sectional areas, volumes and blood flow of the tunnel. RESULTS: Twenty-five patients had a tubular tunnel. In 29 patients, bulging and/or narrowing of the tunnel were present. Cross-sectional areas and volumes of the tunnel were not significantly different between the two groups. There were also no differences for the mean blood flow and the mean and maximal flow velocity (P = 0.05-0.6). In all the patients, the normalized tunnel volume was related to age (r = 0.44; P = 0.002) and body surface area (BSA; r = 0.42; P = 0.005). The mean tunnel blood flow correlated with age (r = 0.73; P = 0.001) and BSA (r = 0.83; P < 0.0001). CONCLUSIONS: A considerable percentage of patients with an intra-atrial lateral tunnel develop mild deviations of the tunnel from ideal tubular shape. The correlation between tunnel volume and mean blood flow with age and BSA suggests that the capacity of the tunnel adjusts to body growth, independent of tunnel shapes that deviate from a fluid-dynamically favourable shape. Follow-up CMRs are needed to detect long-term effects of irregular tunnel shapes on flow dynamics. PMID- 23447476 TI - Chlorination of reduced graphene oxide enhances the dielectric constant of reduced graphene oxide/polymer composites. PMID- 23447477 TI - Azithromycin for the treatment of gastroparesis. AB - OBJECTIVE: To evaluate the use of azithromycin for the treatment of gastroparesis. DATA SOURCES: Literature was accessed through PubMed/MEDLINE and Web of Science (both 1966-October 2012) using the terms gastroparesis, diabetic gastroparesis, and azithromycin. Literature was limited to English-language publications. In addition, references from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated. DATA SYNTHESIS: The treatment of gastroparesis depends on the severity of the symptoms, but generally includes dietary modifications, prokinetic medications, and antiemetics. The initial treatment for gastroparesis is a prokinetic agent, and because erythromycin has the greatest effect on gastric emptying, it is often used. Limitations to erythromycin include adverse reactions (nausea, vomiting, and abdominal pain), QTc interval prolongation, CYP3A-associated drug interactions, and tachyphylaxis. Azithromycin, another macrolide, has been shown to increase gastrointestinal motility and may have fewer limitations to its use. Azithromycin has fewer drug interactions, less incidence of QTc interval prolongation, a longer half-life, and fewer gastrointestinal adverse effects. Use of azithromycin may be beneficial in patients with gastric and small bowel dysmotility. Two observational studies have supported its use in gastroparesis, but there have been no controlled studies. All studies published have been performed during testing procedures for gastroparesis; thus, longer-term treatment effects and symptom control need to be studied. There is one ongoing prospective controlled trial with preliminary data available only in abstract form. CONCLUSIONS: Azithromycin may prove to be an alternative prokinetic agent in gastroparesis, but further study is needed before it can be recommended. PMID- 23447478 TI - Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study. AB - OBJECTIVE: To study the pharmacokinetics and pharmacogenetics of leflunomide and document its efficacy and safety in the treatment of inflammatory arthritis in a patient with end-stage renal disease (ESRD) who was on peritoneal dialysis. CASE SUMMARY: Therapy for a 78-year-old man with ESRD who required peritoneal dialysis was started with leflunomide 10 mg/day for psoriatic arthritis. The dosage was increased to 20 mg/day after 3 months. Monitoring was continued until the patient's unexpected death from myocardial infarction at 8 months. Total and unbound teriflunomide (the active metabolite of leflunomide) concentrations were measured by liquid-chromatography-tandem mass spectrometry. Genotyping for CYP2C19 and ABCG2 polymorphisms, both known to influence teriflunomide pharmacokinetics, was also performed. DISCUSSION: Total concentrations of teriflunomide varied between 5.2 and 23.2 mg/L, while unbound concentrations varied between 0.0306 and 0.1468 mg/L. The unbound fraction varied between 0.367% and 0.71%. Teriflunomide was found in the dialysate at a concentration of 0.0981 mg/L. A single CYP2C19 loss of function allele was present, as was wild-type ABCG2. Leflunomide appeared to be therapeutically effective, as evidenced by a reduction in daily prednisolone dosage from 20 mg to 6mg; the Disease Activity Score in 28 joints (DAS28) was 5.46 at enrollment and 4.03 after 7 months. Health Assessment Questionnaire-Disability Index improved from 0.5 to 0.125 at 7 months. Numerous significant adverse events that were considered unrelated to leflunomide occurred. CONCLUSIONS: Dose adjustment for leflunomide does not appear to be required in the context of ESRD requiring peritoneal dialysis. We present novel evidence that a small amount of teriflunomide is removed by peritoneal dialysis. This case suggests that leflunomide is safe to use as therapy for inflammatory arthritis despite the presence of ESRD requiring peritoneal dialysis. PMID- 23447479 TI - Review on the influence of protocol design on clinical outcomes in rheumatoid arthritis treated with rituximab. AB - OBJECTIVE: To critically analyze the influence of protocol design on clinical outcome in patients with rheumatoid arthritis (RA) treated with rituximab. DATA SOURCES: A PubMed and EMBASE search (January 2000-January 2012) using the key words rheumatoid arthritis and rituximab was performed. STUDY SELECTION AND DATA EXTRACTION: A search of English-language studies from the data sources was conducted for randomized, double-blind, placebo-controlled studies with 100 patients or more assessing the efficacy and safety of rituximab in the treatment of RA. From these studies, 2 authors independently extracted, compiled, and aggregated the data. DATA SYNTHESIS: Eight studies met the inclusion criteria. In these studies, some patients had not been treated with tumor necrosis factor-alfa (TNF-alpha) inhibitors, while most did not respond to it. The variables compared included dose (500 vs 1000 mg), duration of study (24 vs 48 weeks), and number of cycles (1 vs 2). They were statistically analyzed using the chi(2) test. There was a statistically significant difference in the response to rituximab compared to the control (methotrexate) (p < 0.001). In patients who were studied for only 24 weeks, given 500 or 1000 mg for 1 or 2 cycles, a 90% or greater response rate was reported in those who achieved an ACR 20, but no statistically significant differences were observed (p = 0.75). In patients studied for 48 weeks who received 2 cycles of either 500 mg or 1000 mg of rituximab and achieved an ACR 20, a statistically significant difference (p < 0.001) was observed in those who received a dose of 1000 mg for 2 cycles (42.77% vs 67.49%). CONCLUSIONS: In patients who are nonresponsive to disease-modifying antirheumatic drugs and TNF alpha inhibitors, rituximab may be a promising and well-tolerated biologic agent. The capacity of rituximab to produce long-term, sustained remissions could not be evaluated because the duration of the studies was limited to 24 weeks or 48 weeks. Studies with longer periods of observation are warranted. PMID- 23447480 TI - Tranexamic acid-induced toxic epidermal necrolysis. AB - OBJECTIVE: To report a case of toxic epidermal necrolysis (TEN) induced by orally administered tranexamic acid in a patient with liver cirrhosis and acute rectal bleeding. CASE SUMMARY: A 67-year-old male with a history of liver cirrhosis due to alcohol consumption with ascitic decompensation, esophageal varices, and multifactorial renal insufficiency presented with rectal bleeding. The patient was prescribed oral tranexamic acid (1000 mg every 8 hours), with partial resolution of symptoms. Ten days after treatment with tranexamic acid began, a purplish macular rash appeared over the patient's trunk. The dose of tranexamic acid was reduced to 1000 mg every 12 hours, adjusting for renal function. In the following days the lesions extended and became confluent with blisters and epidermal necrosis. Multiple mucosal surfaces were also affected. He denied allergies to any medications and had no history of tranexamic acid exposure. Treatment with tranexamic acid was suspended and fluid replacement therapy, oral prednisone therapy (0.4 mg/kg per day), and N-acetylcysteine 2 g every 6 hours was started, with the empiric diagnosis of TEN. Results of a skin biopsy were compatible with TEN. Resolution of the skin lesions was favorable, but after 2 weeks the patient died secondary to acute renal failure, respiratory infection, and multiorgan failure. DISCUSSION: TEN is a rare, severe mucocutaneous adverse reaction. Although infrequent, TEN has a significant impact on public health because of its high mortality. Its pathogenesis is unclear, but it seems to be a form of delayed hypersensitivity. To our knowledge, a well-documented case of TEN following tranexamic acid use has not been reported (MEDLINE search to June 2012). There have been recent reports of skin hypersensitivity reactions through different mechanisms (immunologic and nonimmunologic). The Naranjo probability scale indicates a probable relationship between the development of TEN and tranexamic acid use in our patient. CONCLUSIONS: This appears to be the first report of a case of TEN that occurred in a patient being treated with oral tranexamic acid. Clinicians should be made aware of this potential severe cutaneous adverse reaction that may be caused by tranexamic acid administration. PMID- 23447481 TI - A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock. AB - BACKGROUND: Early goal-directed therapy is a time-sensitive therapeutic algorithm with a tiered approach to target hypoperfusion and cardiovascular collapse within the first 6 hours of septic shock. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine as the initial vasoactive agent for resuscitation in septic shock, reserving the administration of vasopressin as adjunctive therapy. OBJECTIVE: To determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset. METHODS: This retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock. Patients were excluded if the treatment arm was not monotherapy, if they were admitted to a cardiology or cardiothoracic surgery service, or if they lacked a comparator-based 1:1 frequency matching. RESULTS: A total of 130 patients were included, 65 in each treatment arm. The proportion of patients who achieved a goal MAP in the vasopressin group was 63% (95% CI 51%-75%) and was 67.7% (95% CI 56%-79%) in the norepinephrine group. This observed difference between goal MAP attainment did not exceed the predefined noninferiority margin of -25% (CI for 4.7% difference -21.2% to 12%), suggesting noninferiority of vasopressin. No significant difference was identified between vasopressin and norepinephrine for final mean (SD) MAP achieved (75 [9.6] and 76.0 [8.2] mm Hg, respectively; p = 0.06) or the mean total change from baseline MAP to goal (14.1 [8.4] and 15.1 [9.1] mm Hg, respectively; p = 0.6). CONCLUSIONS: Vasopressin was noninferior to norepinephrine for the achievement of a MAP goal in the first 6 hours from onset of septic shock. Further prospective analysis is warranted; however, the results are useful for consideration of alternative vasopressors in the setting of drug shortages. PMID- 23447484 TI - Incompatibility of piritramide with cephalosporins. PMID- 23447485 TI - Comparison of cochlear implant performance after round window electrode insertion compared with traditional cochleostomy. AB - OBJECTIVE: To compare speech perception after undergoing round window (RW) electrode insertion with those who underwent traditional cochleostomy (C) cochlear implant (CI) surgery. STUDY DESIGN: Case series with chart review. SETTING: Academic cochlear implant center. SUBJECTS: Patients who met CI criteria with favorable intraoperative RW anatomy who underwent RW CI electrode insertion. Patients who underwent traditional C surgery were matched for age, duration of deafness, and preoperative hearing. METHODS: Postoperative speech performance using the consonant-nucleus-consonant (CNC) test, Northwestern University Children's Perception of Speech (NUCHIPS), and Hearing in Noise Test (HINT) between 3 and 48 months after CI. RESULTS: A total of 84 patients underwent RW insertion between 2004 and 2011. Of these, 55 had pre- and postoperative speech perception data for analysis. Average age of implantation ranged from 2.4 to 87.3 years (mean +/- SD, 42.1 +/- 24.2 years) for RW patients. Average age of implantation for matched traditional C patients ranged from 2.3 to 85.6 years (mean +/- SD, 43.3 +/- 25.0 years). No significant differences in postoperative CI speech perception scores were noted between the RW and C groups at 12 months post-CI (RW group, 55.28% +/- 23.26% vs C group, 53.19% +/- 24.14%; P = .70). CONCLUSION: Our study found that patients with favorable RW anatomy who underwent RW CI electrode insertion demonstrated comparable speech perception compared with the traditional cochleostomy insertion group. PMID- 23447486 TI - The expression of activin receptor-like kinase 1 among patients with head and neck cancer. AB - OBJECTIVES: We investigated the expression and clinical significance of activin receptor-like kinase 1 (ACVRL1) in patients with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Case series with chart review. SETTING: Academic Institute of Otolaryngology, Kaohsiung, Taiwan. SUBJECTS AND METHODS: Patients diagnosed with HNSCC (n = 169) underwent surgical resection followed by radiotherapy and/or chemotherapy for aggressive tumors between November 2000 and March 2004. ACVRL1 expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry approaches. RESULTS: High levels of ACVRL1 expression were significantly correlated with advanced T classification (P < .001), positive N classification (P = .002), advanced TNM stage (P < .001), lymphovascular invasion (P < .001), and extracapsular spread of lymph node metastasis (P = .021). A poor 5-year overall survival rate was correlated with high ACVRL1 expression (P = .0048), advanced T classification (P = .0075), positive N classification (P = .0024), advanced TNM stage (P = .0077), and extracapsular spread of lymph node (P = .0002), but a multivariate analysis using the Cox regression model revealed that the only independent prognostic factors for survival were ACVRL1 expression (P = .043; odds ratio [OR], 1.635; 95% confidence interval [CI], 1.017-2.629) and extracapsular spread of lymph node metastasis (P = .003; OR, 2.052; 95% CI, 1.270 3.315). CONCLUSION: A high level of ACVRL1 expression in tumor tissue is significantly correlated with advanced T classification, positive N classification, advanced TNM stage, and poorer prognosis. PMID- 23447487 TI - Use of pulsed dye laser in the treatment of sulcus vocalis. AB - OBJECTIVE: The pulsed dye laser (PDL) has been shown to be effective in the treatment of hypertrophic scars and keloids in dermatology. On the basis of histopathologic similarities between sulcus vocalis and scar tissue and numerous reports on the treatment of laryngeal lesions, especially scar tissue, with PDL, we evaluated the efficacy of treating sulcus vocalis with PDL. We named this surgical procedure PDL glottoplasty. STUDY DESIGN: Case series with planned data collection. SETTING: A university-based, tertiary care medical center. SUBJECTS AND METHODS: This study was conducted on 25 patients diagnosed with sulcus vocalis by videostroboscopy at the Gangnam Severance Hospital Otorhinolaryngology Department between August 2006 and February 2012. Energy delivery was fixed at 0.75 Joules (J) per pulse, and each vocal fold was administered 60 to 110 pulses (average 72.5 pulses) during each procedure. Aerodynamic, stroboscopic, and acoustic voice analyses were performed pre- and postoperatively. RESULTS: Although assessment was necessarily subjective, our study indicated that vocal folds showed decreased stiffness and improved mucosal wave properties after treatment, resulting in improved vibration and dysphonia. In the objective assessments, most patients who underwent PDL glottoplasty showed improvement in several postoperative voice analysis indices. The differences between preoperative and some postoperative voice parameter indices were statistically significant. CONCLUSION: We found PDL glottoplasty to be beneficial in the treatment of sulcus vocalis. Objective measurements of voice quality and normalization of vocal fold vibration improved after PDL treatment in most cases. Our results warrant further studies with larger numbers of participants and longer follow-up periods. PMID- 23447488 TI - An overview of administrative and national survey databases for use in otolaryngology research. AB - An emerging focus on measurement and reporting of health care quality indicators calls for a sound evidence base that otolaryngologists can use to support clinical care decisions. In addition to traditional clinical trials, practitioners are heeding results of high-quality comparative-effectiveness and health services research analyses to better understand the complexity of disease epidemiology, care variation, health care costs, and surgical utilization for common conditions. Many national publicly available data sources exist for use in clinical research that may be of benefit for the academic and clinical otolaryngologist. The strength and value of these sources vary depending on the intended use or research question. The purpose of this commentary is to introduce and provide an overview of some major national and administrative databases, highlight potential strengths and limitations of these data, and suggest applications for use in advancing the care of our patients in otolaryngology. PMID- 23447489 TI - Hydrogen-bonding-induced polymorphous phase transitions in 2D organic nanostructures. AB - The 2D self-assembly of various 2-hydroxy-7-alkoxy-9-fluorenone (HAF) molecules has been investigated by scanning tunneling microscopy (STM) at the liquid/solid interface. A systematic study revealed that HAF molecules with different numbers of carbon atoms in their alkoxy chains could form two or three different kinds of nanostructures, that is, less-ordered, flower-like, and zig-zag patterns, owing to the formation of different types of intermolecular hydrogen bonds. The observed structural transition was found to be driven by molecular thermodynamics, surface diffusion, and the voltage pulse that was applied to the STM tip. The zig-zag pattern was the most stable of these configurations. An odd even effect on the flower-like structure, as induced by the odd and even number of carbon atoms in the side chain, was observed by STM. The influence of the odd even effect on the melting point has a close relationship with the molecular self assembled pattern. Our results are significant for understanding the influence of hydrogen-bonding interactions on the dominant adsorption behavior on the surface and provide a new visual approach for observing the influence of the odd-even effect on the phase transition. PMID- 23447491 TI - Three new imidazole-functionalized hexanuclear oxidovanadium clusters with exceptional catalytic oxidation properties for alcohols. AB - Cluster cat: Three new imidazole-functionalized neutral hexanuclear vanadium clusters have been prepared, one of which shows exceptional catalytic activity in the selective aerobic oxidation of alcohols (see scheme). Furthermore, these new polyoxovanadium clusters can be readily recycled and reused with unchanged catalytic activity. A plausible catalytic cycle is also proposed. PMID- 23447490 TI - Erythrocytosis after liver transplantation: the experience of a university hospital. AB - The prevalence and causes of erythrocytosis after liver transplantation have never been studied, even though this condition is known to predispose patients to thrombosis leading to graft failure or death. Erythrocytosis after orthotopic liver transplantation (OLT) can be defined as an increase in the red cell mass >125% in patients without a pre-OLT history of this condition. The study population was composed of 96 patients: 33 had undergone transplantation for a hepatitis B virus (HBV) infection (18 had a hepatitis D virus coinfection), 43 had undergone transplantation for a hepatitis C virus infection, 9 had undergone transplantation for alcohol abuse, and 11 had undergone transplantation for other causes [autoimmune liver disease (6), Wilson's syndrome (1), or cryptogenetic liver cirrhosis (4)]. Idiopathic erythrocytosis was reported in 11 male patients with a history of HBV infection. Patients with the diagnosis of erythrocytosis underwent phlebotomy every 3 weeks until the hematocrit level reached 45%, and this was repeated if the level exceeded 49%, so no patient presented with cardiovascular accidents during the follow-up. In conclusion, a history of HBV infection, male sex, and hepatitis B immune globulin therapy are all possible cofactors for an increased risk of erythrocytosis in OLT patients. PMID- 23447492 TI - Partial replacement of an artificial nectar diet with native browse for feather tail gliders (Acrobates pygmaeus) in captivity. AB - Captive-bred feather-tail gliders (Acrobates pygmaeus) housed at Taronga Zoo have had a long history of eye cholesterol plaques that may be associated with a largely sugar-based diet such as artificial nectar. The gliders also have prolonged periods of reduced activity when they are not visible in exhibits. This may be due to the ad libitum supply of an energy rich feed and reduced need to forage. This study examined behavioral and physiological changes associated with supplementing the high sugar-based diet with two species of native browse. The experiment was conducted over two consecutive periods of 3 weeks and consisted of two treatment groups: one group was offered the artificial nectar only, while the other group was offered the artificial nectar supplemented with a variety of native flowers. Live weight was recorded weekly. There was no change (P > 0.10) in artificial nectar intake with the supplementation of native browse in the diet. Blood metabolites (cholesterol, triglycerides, glucose) tested for the two groups had no differences (P > 0.10) between treatments. Upon examination, there were no signs of tooth decay or cholesterol plaques in all animals throughout the experiment. Feed intake and behavior were recorded via sensor cameras. There was an increase (P < 0.05) in the daily foraging activity of gliders supplemented with native flowers compared to gliders fed the artificial nectar alone. In conclusion, supplementing to provide a more native diet to A. pygmaeus enhanced their natural foraging behavior, suggesting that it may result in long-term improvements in their health. PMID- 23447493 TI - Simultaneous microfabrication and tuning of the permselective properties in microporous polymers using X-ray lithography. AB - Microchannels are fabricated using a photosensitive polymer to which microporosity is tuned with different X-ray doses. Using hard X-ray irradiation, the micropattern is positioned with various geometries in a multi-level, three dimensional structure, while controlling the pore size and transport properties of small molecules. This highly reliable fabrication process has potential for use in microfluidic devices with enhanced transport properties through microchannels. PMID- 23447494 TI - Rapid and specific post-synthesis modification of DNA through a biocompatible condensation of 1,2-aminothiols with 2-cyanobenzothiazole. AB - Post-synthesis modification of DNA is an important way of functionalizing DNA molecules. Herein, we describe a method that first enzymatically incorporates a cyanobenzothiazole (CBT)-modified thymidine. The side-chain handle CBT can undergo a rapid and site-specific cyclization reaction with 1,2-aminothiols to afford DNA functionalization in aqueous solution. Another key advantage of this method is the formation of a single stereo/regioisomer in the process, which allows for precise control of DNA modification to yield a single component for aptamer selection work and other applications. PMID- 23447495 TI - Is there spontaneous energy expenditure compensation in response to intensive exercise in obese youth? AB - BACKGROUND: Physical activity is mainly used in weight control strategies to favour energy expenditure. Some evidence suggests that exercise might not have the expected impact on energy balance, and may actually cause a decrease in the subsequent physical activity energy expenditure. OBJECTIVE: To question the impact of an acute exercise session of varying intensities on daily energy expenditure in lean and obese adolescents. METHODS: Data from three separate studies conducted in lean and obese 12-15 years old adolescents (study 1: 12 obese; study 2: 10 obese and nine lean; study 3: 15 obese) have been used. Daily energy expenditure (DEE) was assessed in studies 1 and 2 during an exercise condition with an exercise bout at 70%VO(2max) (EX) and a rest day (REST) (using Actiheart and Armbands, respectively). In study 3, DEE was assessed in calorimetric chambers during (i) a high intensity exercise condition (HIE - 75%VO(2max)) and (ji) a condition with a low intensity exercise (LIE - 40%VO(2max)) and (iii) a rest condition (REST). RESULTS: Morning energy expenditure was significantly higher during the exercise conditions whatever the intensity compared with rest. Afternoon energy expenditure was significantly lower following HIE compared to the rest condition in studies 2 and 3. Afternoon energy expenditure was not significantly different between LIE and REST in study 2. Total DEE was not significantly different between conditions in the three studies. CONCLUSION: Obese adolescents seem to show a compensatory response to an acute session of HIE (>70%VO(2max)) by decreasing their following physical activity energy expenditure. Although HIE favours body composition, physical fitness and metabolic profile improvements, this induced compensatory energy expenditure response has to be considered to optimize its effect on weight loss. PMID- 23447496 TI - Total synthesis of the Escherichia coli O111 O-specific polysaccharide repeating unit. AB - The first total synthesis of the O-antigen pentasaccharide repeating unit from Gram-negative bacteria Escherichia coli O111 was achieved starting from four monosaccharide building blocks. Key to the synthetic approach was a bis glycosylation reaction to combine trisaccharide 10 and colitose 5. The colitose building block (5) was obtained de novo from non-carbohydrate precursors. The pentasaccharide was equipped at the reducing end with an amino spacer to provide a handle for subsequent conjugation to a carrier protein in anticipation of immunological studies. PMID- 23447497 TI - Synthesis and photophysical properties of doubly beta-to-beta bridged cyclic Zn(II) porphyrin arrays. AB - A series of doubly beta-to-beta bridged cyclic Zn(II) porphyrin arrays were prepared by a stepwise Suzuki-Miyaura coupling reaction of borylated Zn(II) porphyrin with different bridge groups. The coupling of the building block of beta,beta'-diboryl Zn(II) porphyrin 1 with different bridges provided the doubly beta-to-beta carbazole-bridged Zn(II) porphyrin array 3, the fluorene-bridged Zn(II) porphyrin array 5, the fluorenone-bridged Zn(II) porphyrin array 7, and the three-carbazole-bridged Zn(II) porphyrin ring 8. The structural assignment of 3 was confirmed by the X-ray diffraction analysis, which revealed a highly symmetrical and remarkably bent syn-form structure. The incorporation of bridge units with different electronic effects results in different photophysical properties of the cyclic Zn(II) porphyrin arrays. Comprehensive photophysical studies demonstrate that the electron-withdrawing bridge fluorenone has the largest electronic interaction with the Zn(II) porphyrin unit among the series, thus resulting in the highest two-photon absorption cross-section values (sigma((2))) of 6570+/-60 GM for 7. The present work provides a new strategy for developing porphyrin-based optical materials. PMID- 23447499 TI - Experimentally induced cam impingement in the sheep hip. AB - Sheep hips have a natural non-spherical femoral head similar to a cam-type deformity in human beings. By performing an intertrochanteric varus osteotomy, cam-type femoro-acetabular impingement (FAI) during flexion can be created. We tested the hypotheses that macroscopic lesions of the articular cartilage and an increased Mankin score (MS) can be reproduced by an experimentally induced cam type FAI in this ovine in vivo model. Furthermore, we hypothesized that the MS increases with longer ambulatory periods. Sixteen sheep underwent unilateral intertrochanteric varus osteotomy of the hip with the non-operated hip as a control. Four sheep were sacrificed after 14, 22, 30, and 38-weeks postoperatively. We evaluated macroscopic chondrolabral alterations, and recorded the MS, based on histochemical staining, for each ambulatory period. A significantly higher prevalence of macroscopic chondrolabral lesions was found in the impingement zone of the operated hips. The MS was significantly higher in the acetabular/femoral cartilage of the operated hips. Furthermore, these scores increased as the length of the ambulatory period increased. Cam-type FAI can be induced in an ovine in vivo model. Localized chondrolabral degeneration of the hip, similar to that seen in humans (Tannast et al., Clin Orthop Relat Res 2008; 466: 273-280; Beck et al., J Bone Joint Surg Br 2005; 87: 1012-1018), can be reproduced. This experimental sheep model can be used to study cam-type FAI. PMID- 23447498 TI - Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: a hippocampal proteomic study in mice. AB - Neuregulin 1 (NRG1) is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for Nrg1 (Nrg1 HET mice) display schizophrenia-relevant behavioral phenotypes and aberrant expression of serotonin and glutamate receptors. Nrg1 HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, Delta(9) tetrahydrocannabinol (THC). To gain traction on the molecular pathways disrupted by Nrg1 hypomorphism and Nrg1-cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT) and Nrg1 HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and Nrg1 HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with Nrg1. These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and proteins affecting growth factor expression. Nrg1 HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent Nrg1 HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover novel proteins altered in response to Nrg1 hypomorphism and Nrg1-cannabinoid interactions that improves our molecular understanding of Nrg1 signaling and Nrg1-mediated genetic vulnerability to the neurobehavioral effects of cannabinoids. PMID- 23447500 TI - Nickel(II)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine imines with alkylidene malonates. AB - We demonstrated an asymmetric 1,3-dipolar cycloaddition of azomethine betaines with alkylidene malonates by using a chiral N,N'-dioxide-Ni(II) complex as a catalyst. Both aromatic- and aliphatic-substituted alkylidene malonates were found to be suitable for the reaction. A range of trans-pyrazolone derivatives was exclusively obtained with excellent yields (up to 99% yield) and good enantioselectivities (up to 97% ee) under mild reaction conditions. The reaction could be carried out on a gram scale with the good results being maintained. Control experiments were performed to elucidate the specific diastereoselectivity of the reaction. The formation of single trans isomers was dominated by secondary orbital interactions between the ester groups of the dipolarophile and the azomethine imine. On the basis of the experimental results and previous reports, a possible catalytic model was assumed. PMID- 23447501 TI - Effect of substrate stiffness on the osteogenic differentiation of bone marrow stem cells and bone-derived cells. AB - There is a profound dependence of cell behaviour on the stiffness of its microenvironment. To gain a better understanding of the regulation of cellular differentiation by mechanical cues, we investigated the influence of matrix stiffness (E = 1.46 kPa and E = 26.12 kPa) on differentiated osteogenic cell lineage of bone marrow stem cells (BM-MSCs) and bone-derived cells (BDCs) using flexible collagen-coated polyacrylamide substrates. Differentiation potential was determined by measuring alkaline phosphatase activity, expression of osteoblast specific markers including alkaline phosphatase, osteocalcin, Runx2 and collagen type I, as well as assessment of mineralisation (Alizarin Red S staining). We found that osteogenic differentiation can be regulated by the rigidity of the substrate, which may depend on the commitment in multi- or uni-potent targeting cells. Osteogenic differentiation of BM-MSCs was enhanced on a stiff substrate compared to a soft one, whereas BDCs osteogenic differentiation did not vary depending on the substrate stiffness. The data help in understanding the role of the external mechanical determinants in stem cell differentiation, and can also be useful in translational approach in functional tissue engineering. PMID- 23447502 TI - Goal-directed therapy in cardiac surgery: a systematic review and meta-analysis. AB - BACKGROUND: Perioperative mortality after cardiac surgery has decreased in recent years although postoperative morbidity is still significant. Although there is evidence that perioperative goal-directed haemodynamic therapy (GDT) may reduce surgical mortality and morbidity in non-cardiac surgical patients, the data are less clear after cardiac surgery. The objective of this review is to perform a meta-analysis on the effects of perioperative GDT on mortality, morbidity, and length of hospital stay in cardiac surgical patients. METHODS: We conducted a systematic review using Medline, EMBASE, and the Cochrane Controlled Clinical Trials Register. Additional sources were sought from experts. The inclusion criteria were randomized controlled trials, mortality reported as an outcome, pre emptive haemodynamic intervention, and cardiac surgical population. Included studies were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. Data synthesis was obtained by using odds ratio (OR) and mean difference (MD) for continuous data with 95% confidence interval (CI) utilizing a random-effects model. RESULTS: From 4986 potential studies, 5 met all the inclusion criteria (699 patients). The quantitative analysis showed that the use of GDT reduced the postoperative complication rate (OR 0.33, 95% CI 0.15-0.73; P=0,006) and hospital length of stay (MD -2.44, 95% CI -4.03 to -0.84; P=0,003). There was no significant reduction in mortality. CONCLUSION: The use of pre-emptive GDT in cardiac surgery reduces morbidity and hospital length of stay. PMID- 23447503 TI - Pattern recognition analysis of proteins using DNA-decorated catalytic gold nanoparticles. AB - A label-free protein analysis strategy is based on patterns of gold nanoparticle (AuNP) growth. AuNPs pretreated with different oligonucleotides are challenged with various proteins. After Au reduction, the colorimetric patterns are processed with linear discriminant analysis. This method discriminates different proteins, or one protein of different concentrations, in mixed samples or even serum and urine. PMID- 23447504 TI - Liver transplantation for children with biliary atresia in the pediatric end stage liver disease era: the role of insurance status. AB - Socioeconomic status influences health outcomes, although its impact on liver transplantation (LT) in children with biliary atresia (BA) is unknown. We hypothesized that governmental insurance [public insurance (PU)], rather than private insurance (PR), would be associated with poorer outcomes for children with BA. Children with BA who underwent first isolated LT between January 2003 and June 2011 were identified from United Network for Organ Sharing Standard Transplant Analysis and Research files. We identified 757 patients with PR and 761 patients with PU. The race/ethnicity distribution was significantly different between the groups (65% white, 12% black, and 10% Hispanic in the PR group and 33% white, 26% black, and 29% Hispanic in the PU group, P < 0.01). Wait-list mortality was higher for the PU group versus the PR group [46/1654 (2.7%) versus 29/1895 (1.5%), P < 0.01]. PR patients were older than PU patients at transplant (2.4 +/- 4.5 versus 1.5 +/- 3.0 years, P < 0.01). The donor types differed between the groups: 165 children (21.8%) in the PR group received living donor grafts, whereas 79 children (10.4%) in the PU group did (P < 0.01). The 1- and 5 year posttransplant patient survival rates were greater for the PR group versus the PU group (98.0% versus 94.1% at 1 year, P < 0.01; 97.8% versus 92.2% at 5 years, P < 0.01). Cox proportional hazards models revealed that the insurance type (PU), the donor type (deceased), and life support were significant risk factors for death. A separate analysis of deceased donor LT revealed that the PU group still had significantly worse patient and graft survival. In conclusion, PU coverage is an independent risk factor for significantly increased wait-list and posttransplant mortality in children with BA. Further studies are needed to unearth the reasons for these important differences in outcomes. PMID- 23447505 TI - Tissue mineral concentrations are profoundly altered in neonatal piglets fed identical diets via gastric, central venous, or portal venous routes. AB - BACKGROUND: Because gut absorption and liver sequestration are major mechanisms of mineral homeostasis, intestinal and hepatic bypass with parenteral feeding can lead to mineral toxicities. We employed a piglet model with multiple feeding routes to identify target organs susceptible to abnormal accumulation of minerals and to determine the importance of intestinal or hepatic metabolism. METHODS: Fifteen 2- to 4-day-old piglets were fed identical complete elemental diets continuously for 8 days via central venous (intravenous [IV]), gastric (intragastric [IG]), or portal (intraportal [IP]) catheters. Concentrations of calcium, phosphorus, magnesium, zinc, copper, iron, manganese, sodium, potassium, and chloride were measured in small intestinal mucosa, liver, kidney, and femur. RESULTS: Compared with IG-fed piglets, mineral sequestration patterns in IV- and IP-fed piglets can be attributed to bypass of intestinal absorption inefficiencies, with moderate accumulations of minerals in tissues involved in mineral homeostasis. However, differences between IP and IV feeding were notable for iron, manganese, and copper, suggesting first-pass hepatic metabolism is key to homeostasis of these minerals. Moreover, manganese and copper sequestration patterns reflected that for zinc, suggesting induction of metallothionein by parenteral zinc could interfere with metabolism of other minerals. CONCLUSIONS: We conclude that parenteral delivery of minerals to neonates needs to consider not only absorption efficiency but also mineral interactions and potentially toxic accumulation in target tissues, with particular concern for iron, copper, and zinc. PMID- 23447506 TI - Anomalous peroneal tendon insertion masquerading as a retracted tendon tear: case report. PMID- 23447507 TI - Complications following treatment of supination external rotation ankle fractures through the posterolateral approach. AB - BACKGROUND: The posterolateral approach to the ankle is a valuable approach for the treatment of ankle fractures (SER) ankle fractures. The purpose of this study was to determine the complication rate for ankle fractures treated through the posterolateral approach. We hypothesized that this approach would be associated with a low incidence of complications and good clinical outcomes. METHODS: A total of 112 patients with SER ankle fractures treated through a posterolateral approach met inclusion criteria. Prospectively collected data were examined retrospectively from chart review, preoperative plain radiographs, and MRI as well as postoperative radiographs. The mean age was 51.5 (range, 18 to 86) years. The primary outcome of the study was major (surgical debridement, flap, or split thickness skin graft) and minor (epidermolysis requiring local wound care) wound complications. The secondary outcomes included infection, symptomatic hardware, reoperation, loss of reduction, malreduction, nonunion, Foot and Ankle Outcome Scores, range of motion, and other perioperative complications. RESULTS: There were 11 minor wound related complications (9.8%) and 3 major wound complications (2.7%), 1 of which required a split thickness skin graft. The overall postoperative wound infection rate was 4.4% (5 of 112); 2 patients required hardware removal due to deep infection. Of patients, 7% (8 of 112) reported symptomatic lateral sided hardware and thus underwent removal of implants. The overall reoperation rate was 12.5%. The complication rate was 23%. No patients experienced loss of reduction. CONCLUSIONS: The posterolateral approach to the ankle was a valuable approach for SER ankle fractures. This series demonstrated many key aspects of this approach including access to the apex of the fibula fracture for posterior antiglide plating, access to the posterior malleolus for fixation, access to the posterior inferior tibiofibular ligament for repair, minimal major wound complications, good functional outcomes, and minimal need for reoperation. PMID- 23447508 TI - Comparison of supination external rotation type IV ankle fractures in geriatric versus nongeriatric populations. AB - BACKGROUND: Geriatric patients' (defined as those older than 65 years old) inherent comorbidities, functional limitations, and bone quality present obstacles to successful clinical outcomes for operatively treated supination external rotation (SER) ankle fractures. We retrospectively reviewed a prospectively collected series of SER injuries between 2004 and 2010. This is a comparison of the radiographic and clinical outcomes of our geriatric (27 patients) and nongeriatric (81 patients) populations. We hypothesized that geriatric patients would have worse outcomes when compared to nongeriatric patients. METHODS: All SER ankle fractures (176) treated by a single surgeon were enrolled in a prospective database. All patients fulfilled inclusion criteria (108) consisting of 1 year of having clinical follow-up, postoperative radiographs, and Foot & Ankle Outcome Scores (FAOS). The primary outcome evaluated was functional outcome as exhibited by the FAOS. The secondary outcomes included adequacy of reduction, loss of reduction, postoperative complications (wound complications, infection, pain-driven hardware removal), and range of motion. RESULTS: Despite significantly higher rates of diabetes (P < .001) and peripheral vascular disease (P < .001), there were statistically significantly better FAOS outcomes in the symptoms subcategory among the geriatric population. There was no significant difference in the articular reduction, syndesmotic reduction, wound complications, postoperative infections, or range of motion between these groups. CONCLUSION: Geriatric patients exhibited equivalent complication rates, radiographic outcomes, and functional outcomes compared to nongeriatric patients in this series. Anatomic fixation and soft tissue management counter the inherent risks of operative intervention in geriatric populations that report higher rates of comorbidities. This study supports aggressive fracture- and ligament-specific operative intervention in geriatric patients presenting with unstable SER injuries. PMID- 23447509 TI - Treatment of type C pilon fractures by external fixator combined with limited open reduction and absorbable internal fixation. AB - INTRODUCTION: This study was conducted to evaluate the clinical outcome of the treatment of type C pilon fractures by using an external fixator combined with limited open reduction and absorbable internal fixation. PATIENTS AND METHODS: Twenty-five type C pilon fractures, including 4 open fractures, were included in this retrospective study. The procedure of first-stage manipulation and external fixation spanning the ankle joint was conducted as early as possible. For the second stage, the tibial and fibular fractures were reduced and fixed with absorbable screws or rods through a limited incision. Clinical and radiographic evaluations were performed. The American Orthopaedic Foot & Ankle Society score (AOFAS) was obtained for evaluation of function. Twenty-one patients were followed postoperatively for a minimum of 18 months. RESULTS: The mean time of union was 4.8 months. Delayed union of the distal tibia occurred in 1 patient. Minor infection occurred in 8 patients and deep infection in 1 patient. No skin necrosis, malunion, loss of reduction, nonunion, or fixation failure was observed during the follow-up period. No hardware removal was needed, nor was adverse tissue reaction to the implants observed. An excellent or good AOFAS outcome was obtained in 81% (17/21) of the patients. CONCLUSIONS: External fixator combined with limited open reduction and absorbable internal fixation was a reliable treatment for closed and open AO/OTA type C pilon fractures of the distal tibia. PMID- 23447510 TI - Fibular lengthening using distraction osteogenesis for the treatment of fibular malunion: a case report. PMID- 23447511 TI - Minimally invasive reconstruction of lateral ligaments of the ankle using semitendinosus autograft. AB - BACKGROUND: Multiple techniques have been described for reconstruction of the lateral ligaments of the ankle. Most require extensive exposure and dissection, which may lead to potential problems with wound healing, higher risk of nerve injury, fibrosis, and stiffness. This study reports on the results of a minimally invasive method to reconstruct the ligaments using a semitendinosus tendon autograft and achieve a stable ankle while avoiding these problems. MATERIALS AND METHODS: From September 2006 to May 2010, 25 patients (14 males, 11 females) with chronic ankle instability underwent lateral ligament reconstruction. The average age was 32.4 (range, 17 to 62) years old. A semitendinosus autograft was harvested through 2 small knee incisions. For the ankle reconstruction, 4 small incisions of 5 mm each were made at the medial and lateral side of the fibular tip, the talar neck, and the middle of the calcaneus. Anatomical reconstruction of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) was then performed through these small incisions. The mean final follow-up was 32.3 (range, 12 to 56) months. AOFAS questionnaires were used to measure clinical outcomes and donor site morbidity and patient satisfaction are also reported. Preoperative and postoperative stress tests were performed and radiographic parameters were measured. RESULTS: The mean AOFAS score increased on average from 71.1 to 95.1 (P < .001). Two patients reported residual instability on uneven ground. No patient reported weakness or disability from the donor site. The satisfaction level was excellent in 20 patients and good in 5 patients. Significant improvement in stress radiographic parameters was noted for the talar tilt angle, with reduction from a mean of 14.0 to 3.8 degrees (P < .001); anterior talar displacement reduced from a mean of 12.3 to 4.6 mm (P < .001). CONCLUSION: Reconstruction of the lateral ankle ligaments using a semitendinosus tendon autograft and a minimally invasive approach can achieve a stable ankle while avoiding extensive exposure and risk of nerve injury. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23447512 TI - Use of collagen conduits in management of painful neuromas of the foot and ankle. AB - BACKGROUND: Painful neuromas of the foot and ankle frequently pose a treatment dilemma due to persistent pain or recurrence after resection. The purpose of this survey was to evaluate the clinical and functional outcomes in patients in which collagen nerve conduits were used as an adjunct to the resection of a painful neuroma. Our prior experience with vein conduits for this purpose suggested that we might have similar success with the use of these devices. MATERIALS AND METHODS: Chart reviews and telephone surveys were performed on patients operated by the senior surgeon (JSG) at our medical center from June 2006 to June 2011. A total of 50 patients underwent excision of painful single or multiple neuromas with the end of the resected nerve sutured into the collagen conduit. Each patient preoperatively was asked to describe the amount of pain he or she was experiencing on a scale from 1 to 10, with 10 indicating the most severe pain. In the telephone interview conducted during this study, the same question was asked of each patient following revision. Patient ages ranged from 16 to 77 years, with a mean of 54 years. In all, 30 right and 20 left sides were operated, and 1 patient had bilateral involvement. Mean follow-up was 36 months (6-55 months). There were a total of 69 nerves that underwent conduit procedures. RESULTS: Of 69 nerve conduit constructs, 30 (43%) were painless at final outcome, 23 (33%) had pain scores of 1 to 4, 6 (9%) had pain scores of 5 to 7, and 10 (15%) had severe symptoms with pain scores of 8 to 10. Satisfactory outcomes in which patients stated that they were significantly improved with the procedure and now functional occurred in 59/69 (85%). In all, 24 (48%) patients were completely symptom free, 13 (26%) had a pain score of 1 to 4, 6 (12%) had scores of 5 to 7, and 10 (15%) had severe pain with scores of 8 to 10. Three patients had superficial infections (stitch abscesses): 2 resolved with oral antibiotics and 1 resolved spontaneously. Three patients developed complex regional pain syndrome. One patient responded to a dorsal column stimulator and 2 responded to sympathetic blocks. No other complications were reported. CONCLUSION: Collagen conduits were safe and generally successful adjuncts to simple excision in the management of painful neuromas of the foot and ankle. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23447513 TI - Visfatin and its genetic variants are associated with obesity-related morbidities and cardiometabolic risk in severely obese children. AB - BACKGROUND: Visfatin is an adipokine, associated with obesity and possibly glucose regulation. OBJECTIVE: The aim of this study was to examine the association of visfatin and its genetic variants with adiposity, cardiometabolic risk factors and obesity-related morbidities in obese children. METHODS: Anthropometric measurements, dual energy X-ray absorptiometry scan, fasting blood samples and oral glucose tolerance tests were performed for 243 obese children. We screened the visfatin gene of 24 obese subjects and then performed genotyping of identified genetic variants in other 219 obese children through direct DNA sequencing. RESULTS: Fasting serum visfatin correlated with measures of obesity and liver enzymes and was elevated in obese children with abnormal glucose tolerance and non-alcoholic fatty liver disease. The two upstream single nucleotide polymorphisms, -3187G>A (rs11977021) and -1537C>T (rs61330082), were at complete linkage disequilibrium. The AA genotype of -3187G>A was associated with higher serum visfatin (6.17 +/- 0.76 ng mL(-1) vs. 3.92 +/- 0.44 ng mL(-1)) and higher triglyceride (1.39 +/- 0.08 mmol L(-1) vs. 1.19 +/- 0.07 mmol L(-1)) as compared with the GG genotype. There was also a significant linear increase in serum visfatin across GG to GA to AA genotype of -3187G>A, indicating possible additive effect of A allele. The dominant GA + AA genotype model of +21426G>A (rs2302559) was associated with lower serum visfatin (3.83 +/- 0.56 ng mL(-1) vs. 5.13 +/- 0.34 ng mL(-1)) and lower plasma glucose (4.37 +/- 0.08 mmol L(-1) vs. 4.77 +/- 0.12 mmol L(-1)) as compared with the GG genotype. CONCLUSION: Visfatin and its genetic variants were associated with adiposity, obesity-related morbidities and adverse cardiometabolic parameters. This supported our hypothesis that visfatin plays a significant role in the development of obesity-related morbidities and cardiometabolic risk. PMID- 23447514 TI - Synthesis of 2-azulenyl-1,1,4,4-tetracyano-3-ferrocenyl-1,3-butadienes by [2+2] cycloaddition of (ferrocenylethynyl)azulenes with tetracyanoethylene. AB - 1-, 2-, and 6-(Ferrocenylethynyl)azulene derivatives 10-16 have been prepared by palladium-catalyzed alkynylation of ethynylferrocene with the corresponding haloazulenes under Sonogashira-Hagihara conditions. Compounds 10-16 reacted with tetracyanoethylene (TCNE) in a [2+2] cycloaddition-cycloreversion reaction to afford the corresponding 2-azulenyl-1,1,4,4,-tetracyano-3-ferrocenyl-1,3 butadiene chromophores 17-23 in excellent yields. The redox behavior of the novel azulene chromophores 17-23 was examined by using cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which revealed their multistep electrochemical reduction properties. Moreover, a significant color change was observed by visible spectroscopy under electrochemical reduction conditions. PMID- 23447515 TI - Multifunctional Co3S4/graphene composites for lithium ion batteries and oxygen reduction reaction. AB - Cobalt sulfide is a good candidate for both lithium ion batteries (LIBs) and cathodic oxygen reduction reaction (ORR), but low conductivity, poor cyclability, capacity fading, and structural changes hinder its applications. The incorporation of graphene into Co3S4 makes it a promising electrode by providing better electrochemical coupling, enhanced conductivity, fast mobility of ions and electrons, and a stabilized structure due to its elastic nature. With the objective of achieving high-performance composites, herein we report a facile hydrothermal process for growing Co3S4 nanotubes (NTs) on graphene (G) sheets. Electrochemical impedance spectroscopy (EIS) verified that graphene dramatically increases the conductivity of the composites to almost twice that of pristine Co3S4. Electrochemical measurements indicated that the as-synthesized Co3S4/G composites exhibit good cyclic stability and a high discharge capacity of 720 mA h g(-1) up to 100 cycles with 99.9% coulombic efficiency. Furthermore, the composites react with dissolved oxygen in the ORR by four- and two-electron mechanisms in both acidic and basic media with an onset potential close to that of commercial Pt/C. The stability of the composites is much higher than that of Pt/C, and exhibit high methanol tolerance. Thus, these properties endorse Co3 S4 /G composites as auspicious candidates for both LIBs and ORR. PMID- 23447516 TI - Sodium hydrazinidoborane: a chemical hydrogen-storage material. AB - Herein, we present the successful synthesis and full characterization (by (11) B magic-angle-spinning nuclear magnetic resonance spectroscopy, infrared spectroscopy, powder X-ray diffraction) of sodium hydrazinidoborane (NaN2 H3 BH3 , with a hydrogen content of 8.85 wt %), a new material for chemical hydrogen storage. Using lab-prepared pure hydrazine borane (N2 H4 BH3 ) and commercial sodium hydride as precursors, sodium hydrazinidoborane was synthesized by ball milling at low temperature (-30 degrees C) under an argon atmosphere. Its thermal stability was assessed by thermogravimetric analysis and differential scanning calorimetry. It was found that under heating sodium hydrazinidoborane starts to liberate hydrogen below 60 degrees C. Within the range of 60-150 degrees C, the overall mass loss is as high as 7.6 wt %. Relative to the parent N2 H4 BH3 , sodium hydrazinidoborane shows improved dehydrogenation properties, further confirmed by dehydrogenation experiments under prolonged heating at constant temperatures of 80, 90, 95, 100, and 110 degrees C. Hence, sodium hydrazinidoborane appears to be more suitable for chemical hydrogen storage than N2 H4 BH3 . PMID- 23447517 TI - Chronic autoimmune atrophic gastritis associated with primary hyperparathyroidism: a transversal prospective study. AB - DESIGN: The coexistence of chronic autoimmune atrophic gastritis (CAAG) and primary hyperparathyroidism (PHPT) has been described previously, even if its extent and underlying mechanisms remain poorly understood. We therefore prospectively evaluated this association in two series of patients, one with CAAG and the other with sporadic PHPT. METHODS: From January 2005 to March 2012, 107 histologically confirmed CAAG patients and 149 PHPT patients were consecutively enrolled. Routine laboratory assays included serum calcium, parathyroid hormone (PTH), plasma gastrin and chromogranin A (CgA). In CAAG patients with high PTH levels, ionized calcium and 25(OH)-vitamin D were evaluated. All CAAG and hypergastrinemic PHPT patients received an upper gastrointestinal endoscopy. Exclusion criteria were familial PHPT, MEN1 syndrome, treatment with proton pump inhibitor drugs, Helicobacter pylori infection and renal failure. RESULTS: Of the 107 CAAG patients, nine (8.4%) had PHPT and 13 (12.1%) had secondary hyperparathyroidism stemming from vitamin D deficiency. Among the 149 PHPT patients, 11 (7.4%) had CAAG. Gastrin and CgA levels were similar in the CAAG patients with vs those without hyperparathyroidism (either primary or secondary), and calcium and PTH levels were similar in the PHPT patients with vs those without CAAG. CONCLUSIONS: This study confirms a non-casual association between PHPT and CAAG. The prevalence of PHPT in CAAG patients is threefold that of the general population (8.4 vs 1-3%), and the prevalence of CAAG in PHPT patients is fourfold that of the general population (7.4 vs 2%). The mechanisms underlying this association remain unknown, but a potential role for autoimmunity is suggested. PMID- 23447518 TI - Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin. AB - OBJECTIVES: We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort. DESIGN: Single-blind, randomized, crossover design study. METHODS: Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22-74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo. RESULTS: Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479+/-11 vs 431+/-19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559+/-125 vs 794+/-219 MUV(2) respectively; P=0.048). CONCLUSIONS: Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH. PMID- 23447520 TI - Synergistic empirical and theoretical study on the stereoselective mechanism for the aluminum salalen complex mediated polymerization of rac-lactide. PMID- 23447519 TI - Cholic acid for hepatic steatosis in patients with lipodystrophy: a randomized, controlled trial. AB - OBJECTIVE: Hepatic steatosis is a common complication in patients with lipodystrophies and can lead to cirrhosis. There is no proven effective therapy for hepatic steatosis, but cholic acid (CA), a farnesoid X receptor agonist, has previously been shown to reduce hepatic triglyceride (TG) content in mice and serum TG in humans. Our objective was to assess clinical efficacy and tolerability of CA therapy in patients with lipodystrophy and hepatic steatosis. DESIGN: A randomized, double-blind, placebo-controlled, crossover study. METHODS: Eighteen patients with genetic or autoimmune lipodystrophies and elevated hepatic TG content participated in the study. The intervention was CA (15 mg/kg per day) compared with placebo for a period of 6 months each. Hepatic TG content, the primary outcome variable, was measured with (1)H magnetic resonance spectroscopy at baseline and at 3 and 6 months during each study period. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), and TG were secondary end points of the study. RESULTS: Compared with placebo, CA did not reduce (median (interquartile range) hepatic TG content (14.8% (9.4-19.0%) vs 15.9% (10.5-26.5%) respectively; P=0.42) or serum TG ((340 mg/dl (233-433 mg/dl) vs 390 mg/dl (233-595 mg/dl) respectively; P=0.45)). CA therapy also did not change AST, ALT, or GGT levels. Two patients developed diarrhea and excessive flatus while taking CA and these symptoms resolved after reducing the dose of CA. CONCLUSION: CA was well tolerated but did not reduce hepatic TG content in patients with lipodystrophy. PMID- 23447521 TI - Functional impact of cholesterol sequestration on actin cytoskeleton in normal and transformed fibroblasts. AB - Membrane cholesterol and lipid rafts are implicated in various signalling processes involving actin rearrangement in living cells. However, functional link between raft integrity and organisation of cytoskeleton remains unclear. We have compared the effect of cholesterol sequestration on F-actin structures in normal and transformed fibroblasts in which microfilament system is developed to a different extent. The depletion of membrane cholesterol by methyl-beta cyclodextrin (MbCD) resulted in a disruption of lipid rafts in plasma membrane as it was revealed by fluorescent labelling of GM1 ganglioside. In normal fibroblasts with highly developed microfilament system, the cholesterol depletion resulted in actin disassembly and reduction of stress fibres. However, in transformed cells containing low amount of fibrillar actin, MbCD treatment induced intensive formation of stress fibres and increased cell spreading. The results show that the effect of cholesterol depletion and lipid raft disruption on microfilament system is critically determined by the initial state of cytoskeleton, specifically, by the balance of polymerised and monomeric actin in the cell. We assume that uncapping of the microfilaments is the key step of cholesterol-regulated actin remodelling. PMID- 23447522 TI - Facile colloidal lithography on rough and non-planar surfaces for asymmetric patterning. AB - Free-standing colloidal arrays can be easily transferred to supported fibers. These films conform and provide the template to have consistent submicrometer and nanometer features transferred to the periphery of rough, 7 MUm diameter fibers. This technique is adjustable to a number of fiber surfaces and colloidal template sizes. PMID- 23447523 TI - Left hepatectomy versus right hepatectomy for living donor liver transplantation: shifting the risk from the donor to the recipient. AB - Living donor liver transplantation (LDLT), originally used in children with left lateral segment grafts, has been expanded to adults who require larger grafts to support liver function. Most adult LDLT procedures have been performed with right lobe grafts, and this means a significant risk of morbidity for the donors. To minimize the donor risk for adults, there is renewed interest in smaller left lobe grafts. The smaller graft size increases the recipient risk in the form of small-for-size syndrome (SFSS) and essentially transfers the risk from the donor to the recipient. We review the donor and recipient risks of LDLT and pay particular attention to the different types of liver grafts and the use of graft inflow modification to ameliorate the risk of SFSS. Finally, a new metric is proposed for quantifying the recipient benefit in exchange for a specific donor risk. PMID- 23447524 TI - Chloroplast DNA replication is regulated by the redox state independently of chloroplast division in Chlamydomonas reinhardtii. AB - Chloroplasts arose from a cyanobacterial endosymbiont and multiply by division. In algal cells, chloroplast division is regulated by the cell cycle so as to occur only once, in the S phase. Chloroplasts possess multiple copies of their own genome that must be replicated during chloroplast proliferation. In order to examine how chloroplast DNA replication is regulated in the green alga Chlamydomonas reinhardtii, we first asked whether it is regulated by the cell cycle, as is the case for chloroplast division. Chloroplast DNA is replicated in the light and not the dark phase, independent of the cell cycle or the timing of chloroplast division in photoautotrophic culture. Inhibition of photosynthetic electron transfer blocked chloroplast DNA replication. However, chloroplast DNA was replicated when the cells were grown heterotrophically in the dark, raising the possibility that chloroplast DNA replication is coupled with the reducing power supplied by photosynthesis or the uptake of acetate. When dimethylthiourea, a reactive oxygen species scavenger, was added to the photoautotrophic culture, chloroplast DNA was replicated even in the dark. In contrast, when methylviologen, a reactive oxygen species inducer, was added, chloroplast DNA was not replicated in the light. Moreover, the chloroplast DNA replication activity in both the isolated chloroplasts and nucleoids was increased by dithiothreitol, while it was repressed by diamide, a specific thiol-oxidizing reagent. These results suggest that chloroplast DNA replication is regulated by the redox state that is sensed by the nucleoids and that the disulfide bonds in nucleoid associated proteins are involved in this regulatory activity. PMID- 23447525 TI - Transcriptome responses to combinations of stresses in Arabidopsis. AB - Biotic and abiotic stresses limit agricultural yields, and plants are often simultaneously exposed to multiple stresses. Combinations of stresses such as heat and drought or cold and high light intensity have profound effects on crop performance and yields. Thus, delineation of the regulatory networks and metabolic pathways responding to single and multiple concurrent stresses is required for breeding and engineering crop stress tolerance. Many studies have described transcriptome changes in response to single stresses. However, exposure of plants to a combination of stress factors may require agonistic or antagonistic responses or responses potentially unrelated to responses to the corresponding single stresses. To analyze such responses, we initially compared transcriptome changes in 10 Arabidopsis (Arabidopsis thaliana) ecotypes using cold, heat, high-light, salt, and flagellin treatments as single stress factors as well as their double combinations. This revealed that some 61% of the transcriptome changes in response to double stresses were not predic from the responses to single stress treatments. It also showed that plants prioritized between potentially antagonistic responses for only 5% to 10% of the responding transcripts. This indicates that plants have evolved to cope with combinations of stresses and, therefore, may be bred to endure them. In addition, using a subset of this data from the Columbia and Landsberg erecta ecotypes, we have delineated coexpression network modules responding to single and combined stresses. PMID- 23447526 TI - Understanding the role of defective invertases in plants: tobacco Nin88 fails to degrade sucrose. AB - Cell wall invertases (cwINVs), with a high affinity for the cell wall, are fundamental enzymes in the control of plant growth, development, and carbon partitioning. Most interestingly, defective cwINVs have been described in several plant species. Their highly attenuated sucrose (Suc)-hydrolyzing capacity is due to the absence of aspartate-239 (Asp-239) and tryptophan-47 (Trp-47) homologs, crucial players for stable binding in the active site and subsequent hydrolysis. However, so far, the precise roles of such defective cwINVs remain unclear. In this paper, we report on the functional characterization of tobacco (Nicotiana tabacum) Nin88, a presumed fully active cwINV playing a crucial role during pollen development. It is demonstrated here that Nin88, lacking both Asp-239 and Trp-47 homologs, has no invertase activity. This was further supported by modeling studies and site-directed mutagenesis experiments, introducing both Asp 239 and Trp-47 homologs, leading to an enzyme with a distinct Suc-hydrolyzing capacity. In vitro experiments suggest that the addition of Nin88 counteracts the unproductive and rather aspecific binding of tobacco cwINV1 to the wall, leading to higher activities in the presence of Suc and a more efficient interaction with its cell wall inhibitor. A working model is presented based on these findings, allowing speculation on the putative role of Nin88 in muro. The results presented in this work are an important first step toward unraveling the specific roles of plant defective cwINVs. PMID- 23447527 TI - A diamond nanoneedle array for potential high-throughput intracellular delivery. AB - A dense diamond nanoneedle array is capable of rapidly and conveniently delivering fluorescent probe and drug molecules to a large number of cells. This simple approach paves the way for potential high-throughput delivery of genes, drugs, and fluorescent probes into cells without endocytosis. PMID- 23447528 TI - IMPACT is a developmentally regulated protein in neurons that opposes the eukaryotic initiation factor 2alpha kinase GCN2 in the modulation of neurite outgrowth. AB - The product of the mouse Imprinted and Ancient gene, IMPACT, is preferentially expressed in neurons. We have previously shown that IMPACT overexpression inhibits the activation of the protein kinase GCN2, which signals amino acid starvation. GCN2 phosphorylates the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha), resulting in inhibition of general protein synthesis but increased translation of specific messages, such as ATF4. GCN2 is also involved in the regulation of neuronal functions, controlling synaptic plasticity, memory, and feeding behavior. We show here that IMPACT abundance increases during differentiation of neurons and neuron-like N2a cells, whereas GCN2 displays lowered activation levels. Upon differentiation, IMPACT associates with translating ribosomes, enhances translation initiation, and down-regulates the expression of ATF4. We further show that endogenous IMPACT promotes neurite outgrowth whereas GCN2 is a strong inhibitor of spontaneous neuritogenesis. Together, these results uncover the participation of the GCN2-IMPACT module of translational regulation in a highly controlled step in the development of the nervous system. PMID- 23447529 TI - Real-time kinetics of high-mobility group box 1 (HMGB1) oxidation in extracellular fluids studied by in situ protein NMR spectroscopy. AB - Some extracellular proteins are initially secreted in reduced forms via a non canonical pathway bypassing the endoplasmic reticulum and become oxidized in the extracellular space. One such protein is HMGB1 (high-mobility group box 1). Extracellular HMGB1 has different redox states that play distinct roles in inflammation. Using a unique NMR-based approach, we have investigated the kinetics of HMGB1 oxidation and the half-lives of all-thiol and disulfide HMGB1 species in serum, saliva, and cell culture medium. In this approach, salt-free lyophilized (15)N-labeled all-thiol HMGB1 was dissolved in actual extracellular fluids, and the oxidation and clearance kinetics were monitored in situ by recording a series of heteronuclear (1)H-(15)N correlation spectra. We found that the half-life depends significantly on the extracellular environment. For example, the half-life of all-thiol HMGB1 ranged from ~17 min (in human serum and saliva) to 3 h (in prostate cancer cell culture medium). Furthermore, the binding of ligands (glycyrrhizin and heparin) to HMGB1 significantly modulated the oxidation kinetics. Thus, the balance between the roles of all-thiol and disulfide HMGB1 proteins depends significantly on the extracellular environment and can also be artificially modulated by ligands. This is important because extracellular HMGB1 has been suggested as a therapeutic target for inflammatory diseases and cancer. Our work demonstrates that the in situ protein NMR approach is powerful for investigating the behavior of proteins in actual extracellular fluids containing an enormous number of different molecules. PMID- 23447530 TI - Structural integrity of the B24 site in human insulin is important for hormone functionality. AB - Despite the recent first structural insight into the insulin-insulin receptor complex, the role of the C terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant Phe(B24), one of the key residues of the hormone, in this process remains unclear. For example, the B24 site functionally tolerates substitutions to D-amino acids but not to L-amino acids. Here, we prepared and characterized a series of B24-modified insulin analogues, also determining the structures of [D-HisB24]-insulin and [HisB24]-insulin. The inactive [HisB24] insulin molecule is remarkably rigid due to a tight accommodation of the L-His side chain in the B24 binding pocket that results in the stronger tethering of B25-B28 residues to the protein core. In contrast, the highly active [D-HisB24] insulin is more flexible, and the reverse chirality of the B24C(alpha) atom swayed the D-His(B24) side chain into the solvent. Furthermore, the pocket vacated by Phe(B24) is filled by Phe(B25), which mimics the Phe(B24) side and main chains. The B25->B24 downshift results in a subsequent downshift of Tyr(B26) into the B25 site and the departure of B26-B30 residues away from the insulin core. Our data indicate the importance of the aromatic L-amino acid at the B24 site and the structural invariance/integrity of this position for an effective binding of insulin to its receptor. Moreover, they also suggest limited, B25-B30 only, unfolding of the C terminus of the B-chain upon insulin activation. PMID- 23447531 TI - Signaling between transforming growth factor beta (TGF-beta) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial mesenchymal transition and tumor metastasis. AB - TGF-beta promotes tumor invasion and metastasis by inducing an epithelial mesenchymal transition (EMT). Understanding the molecular and epigenetic mechanisms by which TGF-beta induces EMT may facilitate the development of new therapeutic strategies for metastasis. Here, we report that TGF-beta induced SNAI2 to promote EMT by repressing miR-203. Although miR-203 targeted SNAI2, SNAI2 induced by TGF-beta could directly bind to the miR-203 promoter to inhibit its transcription. SNAI2 and miR-203 formed a double negative feedback loop to inhibit each other's expression, thereby controlling EMT. Moreover, we found that miR-203 was significantly down-regulated in highly metastatic breast cancer cells. The restoration of miR-203 in highly metastatic breast cancer cells inhibited tumor cell invasion in vitro and lung metastatic colonization in vivo by repressing SNAI2. Taken together, our results suggest that the SNAI2 and miR 203 regulatory loop plays important roles in EMT and tumor metastasis. PMID- 23447532 TI - A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling. AB - Understanding the regulation of cardiomyocyte growth is crucial for the management of adverse ventricular remodeling and heart failure. MicroRNA-378 (miR 378) is a newly described member of the cardiac-enriched miRNAs, which is expressed only in cardiac myocytes and not in cardiac fibroblasts. We have previously shown that miR-378 regulates cardiac growth during the postnatal period by direct targeting of IGF1R (Knezevic, I., Patel, A., Sundaresan, N. R., Gupta, M. P., Solaro, R. J., Nagalingam, R. S., and Gupta, M. (2012) J. Biol. Chem. 287, 12913-12926). Here, we report that miR-378 is an endogenous negative regulator of cardiac hypertrophy, and its levels are down-regulated during hypertrophic growth of the heart and during heart failure. In primary cultures of cardiomyocytes, overexpression of miR-378 blocked phenylephrine (PE)-stimulated Ras activity and also prevented activation of two major growth-promoting signaling pathways, PI3K-AKT and Raf1-MEK1-ERK1/2, acting downstream of Ras signaling. Overexpression of miR-378 suppressed PE-induced phosphorylation of S6 ribosomal kinase, pERK1/2, pAKT, pGSK-3beta, and nuclear accumulation of NFAT. There was also suppression of the fetal gene program that was induced by PE. Experiments carried out to delineate the mechanism behind the suppression of Ras, led us to identify Grb2, an upstream component of Ras signaling, as a bona fide direct target of miR-378-mediated regulation. Deficiency of miR-378 alone was sufficient to induce fetal gene expression, which was prevented by knocking down Grb2 expression and blocking Ras activation, thus suggesting that miR-378 interferes with Ras activation by targeting Grb2. Our study demonstrates that miR 378 is an endogenous negative regulator of Ras signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy. PMID- 23447533 TI - Polar residues and their positional context dictate the transmembrane domain interactions of influenza A neuraminidases. AB - Interactions that facilitate transmembrane domain (TMD) dimerization have been identified mainly using synthetic TMDs. Here, we investigated how inherent properties within natural TMDs modulate their interaction strength by exploiting the sequence variation in the nine neuraminidase subtypes (N1-N9) and the prior knowledge that a N1 TMD oligomerizes. Initially, consensus TMDs were created from the influenza A virus database, and their interaction strengths were measured in a biological membrane system. The TMD interactions increased with respect to decreasing hydrophobicity across the subtypes (N1-N9) and within the human N1 subtype where the N1 TMDs from the pandemic H1N1 strain of swine origin were found to be significantly less hydrophobic. The hydrophobicity correlation was attributed to the conserved amphipathicity within the TMDs as the interactions were abolished by mutating residues on the polar faces that are unfavorably positioned in the membrane. Similarly, local changes enhanced the interactions only when a larger polar residue existed on the appropriate face in an unfavorable membrane position. Together, the analysis of this unique natural TMD data set demonstrates how polar-mediated TMD interactions from bitopic proteins depend on which polar residues are involved and their positioning with respect to the helix and the membrane bilayer. PMID- 23447534 TI - Differential roles of the C and N termini of Orai1 protein in interacting with stromal interaction molecule 1 (STIM1) for Ca2+ release-activated Ca2+ (CRAC) channel activation. AB - The entry of extracellular Ca(2+), which is mediated by Ca(2+) release-activated Ca(2+) (CRAC) channels, is essential for T cell activation and the normal functioning of other immune cells. Although the molecular components of CRAC channels, the Orai1 pore-forming subunit and the STIM1-activating subunit have been recently identified, the gating mechanism by which Orai1 channels conduct Ca(2+) entry upon Orai1-STIM1 interaction following Ca(2+) store release remains elusive. Herein, we show that C-terminal truncations or point mutations prevented Orai1 from binding to STIM1 and subsequent channel opening. In contrast, an Orai1 mutant with an N-terminal truncation interacted with but failed to be activated by STIM1. Moreover, Orai1 channels with C-terminal disruption, but not N-terminal truncation, could be gated by fused functional domains of STIM1. Interestingly, the channel activities of Orai1 mutants carrying either an N-terminal or a C terminal truncation were restored by a methionine mutation at the putative gating hinge, the conserved Gly-98 site in the first transmembrane segment (TM1) of Orai1. Collectively, these results support a stepwise gating mechanism of STIM1 operated Orai1 channels; the initial binding between STIM1 and the C terminus of Orai1 docks STIM1 onto the N terminus of Orai1 to initiate conformational changes of the pore-lining TM1 helix of Orai1, leading to the opening of the channel. PMID- 23447535 TI - Syk inhibits the activity of protein kinase A by phosphorylating tyrosine 330 of the catalytic subunit. AB - The Syk protein-tyrosine kinase can have multiple effects on cancer cells, acting in some as a tumor suppressor by inhibiting motility and in others as a tumor promoter by enhancing survival. Phosphoproteomic analyses identified PKA as a Syk specific substrate. Syk catalyzes the phosphorylation of the catalytic subunit of PKA (PKAc) both in vitro and in cells on Tyr-330. Tyr-330 lies within the adenosine-binding motif in the C-terminal tail of PKAc within a cluster of acidic amino acids (DDYEEEE), which is a characteristic of Syk substrates. The phosphorylation of PKAc on Tyr-330 by Syk strongly inhibits its catalytic activity. Molecular dynamics simulations suggest that this additional negative charge prevents the C-terminal tail from interacting with the substrate and the nucleotide-binding site to stabilize the closed conformation of PKAc, thus preventing catalysis from occurring. Phosphoproteomic analyses and Western blotting studies indicate that Tyr-330 can be phosphorylated in a Syk-dependent manner in MCF7 breast cancer cells and DT40 B cells. The phosphorylation of a downstream substrate of PKAc, cAMP-responsive element-binding protein (CREB), is inhibited in cells expressing Syk but can be rescued by a selective inhibitor of Syk. Modulation of CREB activity alters the expression of the CREB-regulated gene BCL2 and modulates cellular responses to genotoxic agents. Thus, PKA is a novel substrate of Syk, and its phosphorylation on Tyr-330 inhibits its participation in downstream signaling pathways. PMID- 23447536 TI - Mediator recruitment to heat shock genes requires dual Hsf1 activation domains and mediator tail subunits Med15 and Med16. AB - The evolutionarily conserved Mediator complex is central to the regulation of gene transcription in eukaryotes because it serves as a physical and functional interface between upstream regulators and the Pol II transcriptional machinery. Nonetheless, its role appears to be context-dependent, and the detailed mechanism by which it governs the expression of most genes remains unknown. Here we investigate Mediator involvement in HSP (heat shock protein) gene regulation in the yeast Saccharomyces cerevisiae. We find that in response to thermal upshift, subunits representative of each of the four Mediator modules (Head, Middle, Tail, and Kinase) are rapidly, robustly, and selectively recruited to the promoter regions of HSP genes. Their residence is transient, returning to near-background levels within 90 min. Hsf1 (heat shock factor 1) plays a central role in recruiting Mediator, as indicated by the fact that truncation of either its N- or C-terminal activation domain significantly reduces Mediator occupancy, whereas removal of both activation domains abolishes it. Likewise, ablation of either of two Mediator Tail subunits, Med15 or Med16, reduces Mediator recruitment to HSP promoters, whereas deletion of both abolishes it. Accompanying the loss of Mediator, recruitment of RNA polymerase II is substantially diminished. Interestingly, Mediator antagonizes Hsf1 occupancy of non-induced promoters yet facilitates enhanced Hsf1 association with activated ones. Collectively, our observations indicate that Hsf1, via its dual activation domains, recruits holo Mediator to HSP promoters in response to acute heat stress through cooperative physical and/or functional interactions with the Tail module. PMID- 23447537 TI - Chaperonins fight aminoglycoside-induced protein misfolding and promote short term tolerance in Escherichia coli. AB - For almost half of a century, we have known that aminoglycoside antibiotics corrupt ribosomes, causing translational misreading, yet it remains unclear whether or not misreading triggers protein misfolding, and possible effects of chaperone action on drug susceptibilities are poorly understood. Here, we show that aminoglycosides cause cytosolic protein misfolding and that chaperonin GroEL/GroES overexpression counters this defect. During aminoglycoside exposure to exponential cultures, chaperonin overexpression protected the bacterial membrane potential, rescued cell growth, and facilitated survival, whereas inhibition of chaperonin expression sensitized bacteria. Overexpression of the DnaK/DnaJ/GrpE chaperone system similarly facilitated survival but did not promote growth of aminoglycoside-treated bacteria. Inhibition of chaperonin expression sensitized bacteria to aminoglycosides as measured by reduced minimum inhibitory concentrations, whereas GroEL/GroES overexpression did not increase minimum inhibitory concentrations. Our observations establish misfolding of cytosolic proteins as an effect of aminoglycoside action and reveal that chaperones, chaperonins in particular, help bacteria cope during early exposure to these drugs. PMID- 23447538 TI - Mutational tail loss is an evolutionary mechanism for liberating marapsins and other type I serine proteases from transmembrane anchors. AB - Human and mouse marapsins (Prss27) are serine proteases preferentially expressed by stratified squamous epithelia. However, mouse marapsin contains a transmembrane anchor absent from the human enzyme. To gain insights into physical forms, activities, inhibition, and roles in epithelial differentiation, we traced tail loss in human marapsin to a nonsense mutation in an ancestral ape, compared substrate preferences of mouse and human marapsins with those of the epithelial peptidase prostasin, designed a selective substrate and inhibitor, and generated Prss27-null mice. Phylogenetic analysis predicts that most marapsins are transmembrane proteins. However, nonsense mutations caused membrane anchor loss in three clades: human/bonobo/chimpanzee, guinea pig/degu/tuco-tuco/mole rat, and cattle/yak. Most marapsin-related proteases, including prostasins, are type I transmembrane proteins, but the closest relatives (prosemins) are not. Soluble mouse and human marapsins are tryptic with subsite preferences distinct from those of prostasin, lack general proteinase activity, and unlike prostasins resist antiproteases, including leupeptin, aprotinin, serpins, and alpha2 macroglobulin, suggesting the presence of non-canonical active sites. Prss27-null mice develop normally in barrier conditions and are fertile without overt epithelial defects, indicating that marapsin does not play critical, non redundant roles in development, reproduction, or epithelial differentiation. In conclusion, marapsins are conserved, inhibitor-resistant, tryptic peptidases. Although marapsins are type I transmembrane proteins in their typical form, they mutated independently into anchorless forms in several mammalian clades, including one involving humans. Similar pathways appear to have been traversed by prosemins and tryptases, suggesting that mutational tail loss is an important means of evolving new functions of tryptic serine proteases from transmembrane ancestors. PMID- 23447539 TI - Chitoporin from Vibrio harveyi, a channel with exceptional sugar specificity. AB - Chitoporin (VhChiP) is a sugar-specific channel responsible for the transport of chitooligosaccharides through the outer membrane of the marine bacterium Vibrio harveyi. Single channel reconstitution into black lipid membrane allowed single chitosugar binding events in the channel to be resolved. VhChiP has an exceptionally high substrate affinity, with a binding constant of K = 5.0 * 10(6) M(-1) for its best substrate (chitohexaose). The on-rates of chitosugars depend on applied voltages, as well as the side of the sugar addition, clearly indicating the inherent asymmetry of the VhChiP lumen. The binding affinity of VhChiP for chitohexaose is 1-5 orders of magnitude larger than that of other known sugar-specific porins for their preferred substrates. Thus, VhChiP is the most potent sugar-specific channel reported to date, with its high efficiency presumably reflecting the need for the bacterium to take up chitin-containing nutrients promptly under turbulent aquatic conditions to exploit them efficiently as its sole source of energy. PMID- 23447541 TI - A soluble phosphorus-centered Keggin polyoxoniobate with bicapping vanadyl groups. AB - A water-soluble tetramethylammonium (TMA) salt of a novel Keggin-type polyoxoniobate has been isolated as TMA9[PV2Nb12O42].19H2O (1). This species contains a central phosphorus site and two capping vanadyl sites. Previously only a single example of a phosphorus-containing polyoxoniobate, [(PO2)3PNb9O34](15-), was known, which is a lacunary Keggin ion decorated with three PO2 units. However, that cluster was isolated as an insoluble structure consisting of chains linked by sodium counterions. In contrast, the [PV2Nb12O42](9-) cluster in 1 is stable over a wide pH range, as evident by (31)P and (51)V NMR, UV/Vis spectroscopy, and ESI-MS spectrometry. The ease of substitution of phosphate into the central tetrahedral position suggests that other oxoanions can be similarly substituted, promising a richer set of structures in this class. PMID- 23447540 TI - The TP0796 lipoprotein of Treponema pallidum is a bimetal-dependent FAD pyrophosphatase with a potential role in flavin homeostasis. AB - Treponema pallidum, an obligate parasite of humans and the causative agent of syphilis, has evolved the capacity to exploit host-derived metabolites for its survival. Flavin-containing compounds are essential cofactors that are required for metabolic processes in all living organisms, and riboflavin is a direct precursor of the cofactors FMN and FAD. Unlike many pathogenic bacteria, Treponema pallidum cannot synthesize riboflavin; we recently described a flavin uptake mechanism composed of an ABC-type transporter. However, there is a paucity of information about flavin utilization in bacterial periplasms. Using a discovery-driven approach, we have identified the TP0796 lipoprotein as a previously uncharacterized Mg(2+)-dependent FAD pyrophosphatase within the ApbE superfamily. TP0796 probably plays a central role in flavin turnover by hydrolyzing exogenously acquired FAD, yielding AMP and FMN. Biochemical and structural investigations revealed that the enzyme has a unique bimetal Mg(2+) catalytic center. Furthermore, the pyrophosphatase activity is product-inhibited by AMP, indicating a possible role for this molecule in modulating FMN and FAD levels in the treponemal periplasm. The ApbE superfamily was previously thought to be involved in thiamine biosynthesis, but our characterization of TP0796 prompts a renaming of this superfamily as a periplasmic flavin-trafficking protein (Ftp). TP0796 is the first structurally and biochemically characterized FAD pyrophosphate enzyme in bacteria. This new paradigm for a bacterial flavin utilization pathway may prove to be useful for future inhibitor design. PMID- 23447542 TI - Synthesis and properties of oval-shaped iron oxide/ethylene glycol mesostructured nanosheets. AB - We have demonstrated a new and facile bottom-up protocol for the effective synthesis of oval-shaped iron oxide/ethylene glycol (FeOx /EG) mesostructured nanosheets. Deprotonated ethylene glycol molecules are intercalated into iron oxide layers to form an interlayer distance of 10.6 A. These materials display some peculiar magnetic properties, such as the low Morin temperature T(M) and ferromagnetism below this T(M) value. CdSe/ZnS nanoparticles can be loaded onto these mesostructured nanosheets to produce nanocomposites that combine both magnetic and fluorescence functions. In addition, iron oxide/propanediol (or butanediol) mesostructured materials with increased interlayer distances can also be synthesized. The developed synthetic strategy may be extended toward the creation of other ultrathin mesostructured nanosheets. PMID- 23447543 TI - Fluorinated carbohydrates as lectin ligands: dissecting glycan-cyanovirin interactions by using 19F NMR spectroscopy. AB - NMR spectroscopy and isothermal titration calorimetry (ITC) are powerful methods to investigate ligand-protein interactions. Here, we present a versatile and sensitive fluorine NMR spectroscopic approach that exploits the (19)F nucleus of (19)F-labeled carbohydrates as a sensor to study glycan binding to lectins. Our approach is illustrated with the 11 kDa Cyanovirin-N, a mannose binding anti-HIV lectin. Two fluoro-deoxy sugar derivatives, methyl 2-deoxy-2-fluoro-alpha-D mannopyranosyl-(1->2)-alpha-D-mannopyranoside and methyl 2-deoxy-2-fluoro-alpha-D mannopyranosyl-(1->2)-alpha-D-mannopyranosyl-(1->2)-alpha-D-mannopyranoside were utilized. Binding was studied by (19)F NMR spectroscopy of the ligand and (1)H (15)N HSQC NMR spectroscopy of the protein. The NMR data agree well with those obtained from the equivalent reciprocal and direct ITC titrations. Our study shows that the strategic design of fluorinated ligands and fluorine NMR spectroscopy for ligand screening holds great promise for easy and fast identification of glycan binding, as well as for their use in reporting structural and/or electronic perturbations that ensue upon interaction with a cognate lectin. PMID- 23447548 TI - Ambulance call-outs and response times in Birmingham and the impact of extreme weather and climate change. AB - Although there has been some research on the impact of extreme weather on the number of ambulance call-out incidents, especially heat waves, there has been very little research on the impact of cold weather on ambulance call-outs and response times. In the UK, there is a target response rate of 75% of life threatening incidents (Category A) that must be responded to within 8 min. This paper compares daily air temperature data with ambulance call-out data for Birmingham over a 5-year period (2007-2011). A significant relationship between extreme weather and increased ambulance call-out and response times can clearly be shown. Both hot and cold weather have a negative impact on response times. During the heat wave of August 2003, the number of ambulance call-outs increased by up to a third. In December 2010 (the coldest December for more than 100 years), the response rate fell below 50% for 3 days in a row (18 December-20 December 2010) with a mean response time of 15 min. For every reduction of air temperature by 1 degrees C there was a reduction of 1.3% in performance. Improved weather forecasting and the take up of adaptation measures, such as the use of winter tyres, are suggested for consideration as management tools to improve ambulance response resilience during extreme weather. Also it is suggested that ambulance response times could be used as part of the syndromic surveillance system at the Health Protection Agency. PMID- 23447544 TI - Gold nanoparticle-protein agglomerates as versatile nanocarriers for drug delivery. AB - The fabrication of a versatile nanocarrier based on agglomerated structures of gold nanoparticle (Au NP)-lysozyme (Lyz) in aqueous medium is reported. The carriers exhibit efficient loading capacities for both hydrophilic (doxorubicin) and hydrophobic (pyrene) molecules. The nanocarriers are finally coated with an albumin layer to render them stable and also facilitate their uptake by cancer cells. The interaction between agglomerated structures and the payloads is non covalent. Cell viability assay in vitro showed that the nanocarriers by themselves are non-cytotoxic, whereas the doxorubicin-loaded ones are cytotoxic, with efficiencies higher than that of the free drug. Transmission electron microscopy and fluorescence microscopy along with flow cytometry analysis confirm the uptake of the drug-loaded nanocarriers by a human cervical cancer HeLa cell line. Field-emission scanning electron microscopy reveals the formation of apoptotic bodies leading to cell death, confirming the release of the payloads from the nanocarriers into the cell. Overall, the findings suggest the fabrication of novel Au NP-protein agglomerate-based nanocarriers with efficient drug-loading and -releasing capabilities, enabling them to act as multimodal drug delivery vehicles. PMID- 23447549 TI - Targeted and pH-responsive delivery of doxorubicin to cancer cells using multifunctional dendrimer-modified multi-walled carbon nanotubes. AB - We report the use of multifunctional dendrimer-modified multi-walled carbon nanotubes (MWCNTs) for targeted and pH-responsive delivery of doxorubicin (DOX) into cancer cells. In this study, amine-terminated generation 5 poly(amidoamine) (PAMAM) dendrimers modified with fluorescein isothiocyanate (FI) and folic acid (FA) were covalently linked to acid-treated MWCNTs, followed by acetylation of the remaining dendrimer terminal amines to neutralize the positive surface potential. The formed multifunctional MWCNTs (MWCNT/G5.NHAc-FI-FA) were characterized via different techniques. Then, the MWCNT/G5.NHAc-FI-FA was used to load DOX for targeted and pH-responsive delivery to cancer cells overexpressing high-affinity folic acid receptors (FAR). We showed that the MWCNT/G5.NHAc-FI-FA enabled a high drug payload and encapsulation efficiency both up to 97.8% and the formed DOX/MWCNT/G5.NHAc-FI-FA complexes displayed a pH-responsive release property with fast DOX release under acidic environment and slow release at physiological pH conditions. Importantly, the DOX/MWCNT/G5.NHAc-FI-FA complexes displayed effective therapeutic efficacy, similar to that of free DOX, and were able to target to cancer cells overexpressing high-affinity FAR and effectively inhibit the growth of the cancer cells. The synthesized multifunctional dendrimer modified MWCNTs may be used as a targeted and pH-responsive delivery system for targeting therapy of different types of cancer cells. PMID- 23447550 TI - Rhenium-germanium triple bonds: syntheses and reactions of the germylidyne complexes mer-[X2(PMe3)3Re=Ge-R] (X=Cl, I, H; R=m-terphenyl). AB - A general approach to the first compounds that contain rhenium-germanium triple and double bonds is reported. Heating [ReCl(PMe3)5] (1) with the arylgermanium(II) chloride GeCl(C6H3-2,6-Trip2) (2; Trip=2,4,6 triisopropylphenyl) results in the germylidyne complex mer-[Cl2 (PMe3)3Re=Ge-C6H3 2,6-Trip2] (4) upon PMe3 elimination. An equilibrium that is dependent on the PMe3 concentration exists between complexes 1 and 4. Removal of the volatile PMe3 shifts the equilibrium towards complex 4, whereas treatment of 4 with an excess of PMe3 gives a 1:1 mixture of 1 and the PMe3 adduct of 2, GeCl(C6H3-2,6 Trip2)(PMe3) (2-PMe3). Adduct 2-PMe3 can be selectively obtained by addition of PMe3 to chlorogermylidene 2. The NMR spectroscopic data for 2-PMe3 indicate an equilibrium between 2-PMe3 and its dissociation products, 2 and PMe3 , which is shifted far towards the adduct site at ambient temperature. NMR spectroscopic monitoring of the reaction of complex 1 with 2 and the reaction of complex 4 with PMe3 revealed the formation of two key intermediates, which were identified to be the chlorogermylidene complexes cis/trans-[Cl(PMe3)4 Re=Ge(Cl)C6H3-2,6-Trip2] (cis/trans-3) by using NMR spectroscopy. Labile chlorogermylidene complexes cis/trans-3 can be also generated from trans-[Cl(PMe3)4 Re=Ge-C6H3-2,6-Trip2]BPh4 (9) and (nBu4N)Cl at low temperature, and decompose at ambient temperature to give a mixture of complexes 1 and 4. Complex 4 reacts with LiI to give the diiodido derivative mer-[I2(PMe3)3Re=Ge-C6H3-2,6-Trip2] (5), which undergoes a metathetical iodide/hydride exchange with Na(BEt3H) to give the dihydrido germylidyne complex mer-[H2(PMe3)3Re=Ge-C6H3-2,6-Trip2] (6). Carbonylation of 4 induces a chloride migration from rhenium to the germanium atom to afford the chlorogermylidene complex mer-[Cl(CO)(PMe3)3Re=Ge(Cl)C6H3-2,6-Trip2] (7). Similarly, MeNC converts complex 4 into the methylisocyanide analogue mer [Cl(MeNC)(PMe3)3Re=Ge(Cl)C6H3-2,6-Trip2] (8). Chloride abstraction from 4 by NaBPh4 in the presence of PMe3 gives the cationic germylidyne complex trans [Cl(PMe3)4 Re=Ge-C6H3-2,6-Trip2]BPh4 (9). Heating complex 4 with cis [Mo(PMe3)4(N2)2] induces a germylidyne ligand transfer from rhenium to molybdenum to afford the germylidyne complex trans-[Cl(PMe3)4Mo=Ge-C6H3-2,6-Trip2] (10). All new compounds were fully characterized and their molecular structures studied by X-ray crystallography, which led to the first experimentally determined Re-Ge triple- and double-bond lengths. PMID- 23447551 TI - Expression of sall4 in taste buds of zebrafish. AB - We characterized the expression of sall4, a gene encoding a zinc finger transcription factor involved in the maintenance of embryonic stem cells, in taste buds of zebrafish (Danio rerio). Using an enhancer trap line (ET5), we detected enhanced green fluorescent protein (EGFP) in developing and adult transgenic zebrafish in regions containing taste buds: the lips, branchial arches, and the nasal and maxillary barbels. Localization of EGFP to taste cells of the branchial arches and lips was confirmed by co-immunolabeling with antibodies against calretinin and serotonin, and a zebrafish-derived neuronal marker (zn-12). Transgenic insertion of the ET construct into the zebrafish genome was evaluated and mapped to chromosome 23 in proximity (i.e. 23 kb) to the sall4 gene. In situ hybridization and expression analysis between 24 and 96 h post-fertilization (hpf) demonstrated that transgenic egfp expression in ET5 zebrafish was correlated with the spatial and temporal pattern of expression of sall4 in the wild-type. Expression was first observed in the central nervous system and branchial arches at 24 hpf. At 48 hpf, sall4 and egfp expression was observed in taste bud primordia surrounding the mouth and branchial arches. At 72 and 96 hpf, expression was detected in the upper and lower lips and branchial arches. Double fluorescence in situ hybridization at 3 and 10 dpf confirmed colocalization of sall4 and egfp in the lips and branchial arches. These studies reveal sall4 expression in chemosensory cells and implicate this transcription factor in the development and renewal of taste epithelia in zebrafish. PMID- 23447552 TI - Two-phase synthesis of small thiolate-protected Au15 and Au18 nanoclusters. PMID- 23447553 TI - The formation of CuCl2-specific metallogels of pyridyloxalamide derivatives in alcohols. AB - Isomeric pyridyloxalamide derivatives 1-3, which differed in the position of the nitrogen atom on the pyridyl ring, showed remarkably different gel-forming aptitudes in the presence of CuCl2 salt in alcohols. Whilst derivatives 1 and 3 formed a soluble complex and a solid precipitate, respectively, ligand 2 generated a remarkably metal- and anion-specific metallogel. PMID- 23447554 TI - Industrial applications of the Diels-Alder reaction. AB - The Diels-Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large-scale applications (>1 kg) from a process research and development perspective. PMID- 23447555 TI - Expanding insight into asymmetric palladium-catalyzed allylic alkylation of N heterocyclic molecules and cyclic ketones. AB - Eeny, meeny, miny ... enaminones! Lactams and imides have been shown to consistently provide enantioselectivities substantially higher than other substrate classes previously investigated in the palladium-catalyzed asymmetric decarboxylative allylic alkylation. Several new substrates have been designed to probe the contributions of electronic, steric, and stereoelectronic factors that distinguish the lactam/imide series as superior alkylation substrates (see scheme). These studies culminated in marked improvements on carbocyclic allylic alkylation substrates. PMID- 23447556 TI - Rules or consequences? The role of ethical mind-sets in moral dynamics. AB - Recent research on the dynamics of moral behavior has documented two contrasting phenomena-moral consistency and moral balancing. Moral balancing refers to the phenomenon whereby behaving ethically or unethically decreases the likelihood of engaging in the same type of behavior again later. Moral consistency describes the opposite pattern-engaging in ethical or unethical behavior increases the likelihood of engaging in the same type of behavior later on. The three studies reported here supported the hypothesis that individuals' ethical mind-set (i.e., outcome-based vs. rule-based) moderates the impact of an initial ethical or unethical act on the likelihood of behaving ethically on a subsequent occasion. More specifically, an outcome-based mind-set facilitated moral balancing, and a rule-based mind-set facilitated moral consistency. PMID- 23447557 TI - Hurting you hurts me too: the psychological costs of complying with ostracism. AB - Much research has documented the harmful psychological effects of being ostracized, but research has yet to determine whether compliance with ostracizing other people is psychologically costly. We conducted two studies guided by self determination theory to explore this question, using a paradigm that borrows from both ostracism research and Milgram's classic study of obedience. Supporting our guiding hypothesis that compliance with ostracizing others carries psychological costs, the results of Experiment 1 showed that such compliance worsened mood compared with complying with instructions to include others and with receiving no instructions involving inclusion or exclusion, an effect explained by thwarted psychological needs resulting from ostracizing others. Experiment 2 revealed increases in negative affect both when individuals ostracized others and when individuals were ostracized themselves. Our findings point to the robust psychological costs associated with ostracizing other people, with implications for group behaviors. PMID- 23447558 TI - Dopamine-d2-receptor blockade reverses the association between trait approach motivation and frontal asymmetry in an approach-motivation context. AB - Individual differences in the behavioral approach system (BAS)-referred to as trait approach motivation or trait BAS)-have been linked to both frontal electroencephalogram (EEG) alpha asymmetry between left and right hemispheres (frontal alpha asymmetry) and brain dopamine. However, evidence directly linking frontal alpha asymmetry and dopamine is scarce. In the present study, female experimenters recorded EEG data in 181 male participants after double-blind administration of either a placebo or a dopamine D2 blocker. As expected, trait BAS was associated with greater left- than right-frontal cortical activity (i.e., greater right- than left-frontal EEG alpha) in the placebo group, but a reversed association emerged in the dopamine-blocker group. Furthermore, frontal alpha asymmetry was associated with a genetic variant known to modulate prefrontal dopamine levels (the catechol-O-methyltransferase Val158Met polymorphism). Finally, each of these effects was significant only in the subgroup of male participants interacting with female experimenters rated as most attractive; this finding suggests that associations between frontal alpha asymmetry and both dopamine and trait BAS are detectable only in approach-motivation contexts. PMID- 23447559 TI - Learning to see, but not discriminate, visual forms is impaired in aging. AB - Despite the central role of learning in visual recognition, it is largely unknown whether visual form learning is maintained in older age. We examined whether training improved performance in both young and older adults at two key stages of visual recognition: integration of local elements and global form discrimination. We used a shape-discrimination task (concentric vs. radial patterns) in which young and older adults showed similar performance before training. Using a parametric stimulus space that allowed us to manipulate global features and background noise, we were able to distinguish integration and discrimination processes. We found that training improves global form discrimination in both young and older adults. However, learning to integrate local elements is impaired in older age, possibly because of reduced tolerance to external noise. These findings suggest that visual selection processes, rather than global feature representations, provide a fundamental limit for learning-dependent plasticity in the aging brain. PMID- 23447560 TI - Allopurinol in subjects with colorectal adenoma--letter. PMID- 23447561 TI - Allopurinol in subjects with colorectal adenoma--response. PMID- 23447562 TI - The role of estrogen receptor beta in transplacental cancer prevention by indole 3-carbinol. AB - In the present study, the efficacy of indole-3-carbinol (I3C), a key bioactive component of cruciferous vegetables, for prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[def,p]chrysene (DBC) was evaluated using an estrogen receptor beta (ERbeta) knockout mouse model. I3C was provided either through the maternal diet coincident with carcinogen exposure during pregnancy or directly to offspring postinitiation with DBC. I3C was effective at reducing T-cell acute lymphoblastic lymphoma/leukemia (T-ALL) related mortality in offspring only if provided via the maternal diet, although a gender difference in the role of ERbeta in mediating this response was evident. In female offspring, chemoprevention of T-ALL by maternal dietary I3C required expression of ERbeta; survival in Esr2 wild-type and heterozygous female offspring was more than 90% compared with 66% in Esr2 null females. Alternatively, ERbeta status did not significantly impact the transplacental chemoprevention by I3C in males. The possible role of ERbeta in mediating lung carcinogenesis or chemoprevention by I3C was similarly complicated. Lung tumor incidence was unaltered by either dietary intervention, whereas lung tumor multiplicity was substantially reduced in Esr2 null females on the control diet and marginally lower in Esr2 null males exposed to I3C via the maternal diet compared with their wild-type and heterozygous counterparts. These findings suggest that I3C may act via ERbeta to prevent or suppress DBC-initiated transplacental carcinogenesis but that the involvement of this receptor seems to differ depending on the cancer type and gender of the offspring. PMID- 23447563 TI - Chemoprevention activity of dipyridamole in the MMTV-PyMT transgenic mouse model of breast cancer. AB - Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter-driven polyoma middle T oncoprotein metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics, and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and miRNA expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChip or miRNA 2.0 arrays. Real-time quantitative PCR was used to confirm changes in gene expression. Treatment with DPM beginning at the age of 4 weeks delayed the onset of palpable lesions, delayed tumor progression, and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPM's chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention. PMID- 23447564 TI - Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. AB - Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of NF-kappaB, activator protein-1, and STAT3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. PMID- 23447565 TI - BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. AB - Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ~30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy. PMID- 23447566 TI - Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. AB - Many vaccines include aluminum salts (alum) as adjuvants despite little knowledge of alum's functions. Host DNA rapidly coats injected alum. Here, we further investigated the mechanism of alum and DNA's adjuvant function. Our data show that DNase coinjection reduces CD4 T-cell priming by i.m. injected antigen + alum. This effect is partially replicated in mice lacking stimulator of IFN genes, a mediator of cellular responses to cytoplasmic DNA. Others have shown that DNase treatment impairs dendritic cell (DC) migration from the peritoneal cavity to the draining lymph node in mice immunized i.p. with alum. However, our data show that DNase does not affect accumulation of, or expression of costimulatory proteins on, antigen-loaded DCs in lymph nodes draining injected muscles, the site by which most human vaccines are administered. DNase does inhibit prolonged T-cell-DC conjugate formation and antigen presentation between antigen-positive DCs and antigen-specific CD4 T cells following i.m. injection. Thus, from the muscle, an immunization site that does not require host DNA to promote migration of inflammatory DCs, alum acts as an adjuvant by introducing host DNA into the cytoplasm of antigen-bearing DCs, where it engages receptors that promote MHC class II presentation and better DC-T-cell interactions. PMID- 23447567 TI - Tales of volcanoes and El-Nino southern oscillations with the oxygen isotope anomaly of sulfate aerosol. AB - The ability of sulfate aerosols to reflect solar radiation and simultaneously act as cloud condensation nuclei renders them central players in the global climate system. The oxidation of S(IV) compounds and their transport as stable S(VI) in the Earth's system are intricately linked to planetary scale processes, and precise characterization of the overall process requires a detailed understanding of the linkage between climate dynamics and the chemistry leading to the product sulfate. This paper reports a high-resolution, 22-y (1980-2002) record of the oxygen-triple isotopic composition of sulfate (SO4) aerosols retrieved from a snow pit at the South Pole. Observed variation in the O-isotopic anomaly of SO4 aerosol is linked to the ozone variation in the tropical upper troposphere/lower stratosphere via the Ozone El-Nino Southern Oscillations (ENSO) Index (OEI). Higher (17)O values (3.30/00, 4.50/00, and 4.20/00) were observed during the three largest ENSO events of the past 2 decades. Volcanic events inject significant quantities of SO4 aerosol into the stratosphere, which are known to affect ENSO strength by modulating stratospheric ozone levels (OEI = 6 and (17)O = 3.30/00, OEI = 11 and (17)O = 4.50/00) and normal oxidative pathways. Our high resolution data indicated that (17)O of sulfate aerosols can record extreme phases of naturally occurring climate cycles, such as ENSOs, which couple variations in the ozone levels in the atmosphere and the hydrosphere via temperature driven changes in relative humidity levels. A longer term, higher resolution oxygen-triple isotope analysis of sulfate aerosols from ice cores, encompassing more ENSO periods, is required to reconstruct paleo-ENSO events and paleotropical ozone variations. PMID- 23447568 TI - Rising incidence, no change in survival and decreasing mortality from thyroid cancer in The Netherlands since 1989. AB - The incidence of thyroid cancer (TC) is increasing worldwide, partly due to increased detection. We therefore assessed combined trends in incidence, survival and mortality of the various types of TC in The Netherlands between 1989 and 2009. We included all patients >=15 years with TC, diagnosed in the period 1989 2009 and recorded in The Netherlands Cancer Registry (n=8021). Information on age, gender, date of diagnosis, histological type of tumour and tumour-node metastasis classification was recorded. Mortality data (up to 1st January 2010) were derived from Statistics Netherlands. Annual percentages of change in incidence, mortality and relative survival were calculated. Since 1989 the incidence of TC increased significantly in The Netherlands (estimated annual percentage change (EAPC)=+1.7%). The incidence rates increased for all age groups (except for females >60 years), papillary tumours (EAPC=+3.5%), T1 and T3 TC (EAPC=+7.9 and +5.8% respectively). Incidence rates decreased for T4 TC (-2.3%) and remained stable for follicular, medullary anaplastic and T2 TC. Five-year relative survival rates remained stable for papillary (88%) and follicular (77%) TC, all age groups and T1-T3 TC (96, 94 and 80% respectively) and somewhat lower for T4 (53%), medullary (65%) and anaplastic TC (5%) in the 2004-2009 period compared with earlier periods. Mortality due to TC decreased (EAPC=-1.9%). TC detection and incidence has been rising in The Netherlands, while mortality rates are decreasing and survival rates remained stable or slightly decreasing. PMID- 23447569 TI - Androgen activates beta-catenin signaling in bladder cancer cells. AB - Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/beta-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and beta-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of beta-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and beta-catenin in bladder tumors (P=0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous beta-catenin expression (P=0.0276), nuclear beta-catenin expression (P=0.0802), and co-expression of nuclear AR and beta-catenin (P=0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on beta-catenin in AR-positive and AR negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of beta-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of beta-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of beta-catenin when co-localized with AR. Finally, co immunoprecipitation revealed androgen-induced associations of AR with beta catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate beta-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of beta-catenin signaling possibly via formation of AR/beta-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach. PMID- 23447570 TI - In vitro model systems to study androgen receptor signaling in prostate cancer. AB - Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen deprivation therapy, the current mainstay systemic treatment for advanced PCa. Thus, a better understanding of AR signaling and new strategies to abrogate AR activity are essential for improved therapeutic intervention. Consequently, a large number of experimental cell culture models have been established to facilitate in vitro investigations into the role of AR signaling in PCa development and progression. These different model systems mimic distinct stages of this heterogeneous disease and exhibit differences with respect to AR expression/status and androgen responsiveness. Technological advances have facilitated the development of in vitro systems that more closely reflect the physiological setting, for example via the use of three-dimensional coculture to study the interaction of prostate epithelial cells with the stroma, endothelium, immune system and tissue matrix environment. This review provides an overview of the most commonly used in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is hoped that the continued development of in vitro models will provide more biologically relevant platforms for mechanistic studies, drug discovery and design ensuring a more rapid transfer of knowledge from the laboratory to the clinic. PMID- 23447571 TI - Acute haemodynamic comparison of multisite and biventricular pacing with a quadripolar left ventricular lead. AB - AIMS: Pacing from multiple sites in the left ventricle (LV) may bring about further resynchronization of the diseased heart compared with biventricular (BiV) pacing. We compared acute haemodynamic response (LV dP/dtmax) of multisite and BiV pacing using a quadripolar LV lead. METHODS AND RESULTS: In 21 patients receiving cardiac resynchronization therapy, a quadripolar LV lead and conventional right atrial and ventricular leads were connected to an external pacing system. A guidewire pressure sensor was placed in the LV for continuous dP/dt measurement. Four multisite pacing configurations were tested three times each and compared with BiV pacing using the distal LV electrode. Nineteen patients had useable haemodynamic data. Median increase in LV dP/dtmax with BiV vs. atrial-only pacing was 8.2% (interquartile range 2.3%, 15.7%). With multisite pacing using distal and proximal LV electrodes, median increase in LV dP/dtmax was 10.2% compared with atrial-only pacing (interquartile range 6.1%, 25.6%). In 16 of 19 patients (84%), two or more of the four multisite pacing configurations increased LV dP/dtmax compared with BiV pacing. Overall, 72% of all tested configurations of multisite pacing produced greater LV dP/dtmax than obtained with BiV pacing. Pacing from most distal and proximal electrodes was the most common optimal configuration, superior to BiV pacing in 74% of patients. CONCLUSION: In the majority of patients, multisite pacing improved acute systolic function further compared with BiV pacing. Pacing with the most distal and proximal electrodes of the quadripolar LV lead most commonly yielded greatest LV dP/dtmax. PMID- 23447572 TI - Neighbourhood deprivation and hospitalization for atrial fibrillation in Sweden. AB - AIMS: Several cardiovascular disorders (CVDs) are strongly associated with socioeconomic disparities and neighbourhood deprivation. However, no study has determined whether neighbourhood deprivation is associated with atrial fibrillation (AF). We aimed to determine whether there is an association between neighbourhood deprivation and hospitalization for AF. METHODS AND RESULTS: The entire Swedish population aged 25-74 years was followed from 1 January 2000 until hospitalization for AF, death, emigration, or the end of the study period (31 December 2008). Data were analysed by multilevel logistic regression, with individual-level characteristics (age, marital status, family income, educational attainment, migration status, urban/rural status, mobility, and comorbidity) at the first level and level of neighbourhood deprivation at the second level. Neighbourhood deprivation was significantly associated with AF hospitalization rate in women [odds ratio (OR) = 1.40, 95% confidence interval (CI) 1.35-1.47], but not men (OR = 1.01, 95% CI 0.97-1.04). The odds of AF in women living in the most deprived neighbourhoods remained significant after adjustment for age and individual-level socioeconomic characteristics (OR = 1.12, 95% 1.08-1.16). However, in the full model, which took account of age, individual-level socioeconomic characteristics, and comorbidities (chronic lower respiratory diseases, OR = 1.30; type 2 diabetes, OR = 1.32; alcoholism and alcohol-related liver disease, OR = 1.57; hypertension, OR = 2.84; obesity, OR = 1.80; heart failure, OR = 7.40; coronary heart disease, OR = 1.81; and hyperthyroidism, OR = 6.79), the odds of AF did not remain significant in women in the most deprived neighbourhoods (OR = 1.03, 95% CI 0.99-1.07). CONCLUSION: Neighbourhood deprivation and socioeconomic disparities are not independently associated with hospitalized AF in contrast to many other CVDs. PMID- 23447573 TI - Deactivation of implantable cardioverter-defibrillators: results of patient surveys. AB - AIMS: The indications for implantable cardioverter-defibrillators (ICDs) have been expanding, especially for primary prevention of sudden cardiac death. Implantable cardioverter-defibrillator saves lives; however, in near end-of-life situations linked to incurable diseases, the question arises as to whether or not to turn off the ICD to avoid excessive numbers of shocks as the heart begins to fail. This study examined the wishes of a cohort of ICD recipients. METHODS AND RESULTS: Consecutive recipients of ICDs for primary or secondary prevention of sudden cardiac death were examined during a routine out-patient follow-up visit. Subjects completed a written survey about expected ICD benefits, feelings and circumstances under which they would want to deactivate the device. One hundred and nine patients fully completed the survey. Mean age was 67.6 +/- 8.7 years, 91 (83.5%) were male and the mean systolic ejection fraction was 31.5 +/- 10.9%. The severity of symptoms of heart failure according to the New York Heart Association classification was 2.1 +/- 0.59 at implantation. Ninety-nine (90.8%) patients felt more secure and safe following ICD implantation and 66 (60.6%) patients reported a sense of improved health status after implantation. Thirty-one (28.4%) patients had experienced an ICD shock. Fifty (45.9%) patients indicated that they had never considered ICD deactivation during near end-of-life situations. This topic had been discussed with only eight (7.3%) patients. Forty-four (40.1%) patients wanted more information about ICD deactivation. On the other hand, 10 (41.7%) patients from secondary prevention and 19 (22.4%) from primary prevention groups categorically refused more information or further discussion on this topic (P = 0.058). CONCLUSION: Most ICD recipients felt safer following ICD implantation and most wanted more information regarding ICD deactivation. However, a significant number of patients (especially, secondary prevention patients) had no interest in receiving additional information about this topic. PMID- 23447574 TI - A new methodology for atrial flutter ablation by direct visualization of cavotricuspid conduction with voltage gradient mapping: a comparison to standard techniques. AB - AIMS: To demonstrate that critical conduction within the cavotricuspid isthmus (CTI) can be directly visualized by voltage gradient mapping and facilitate efficient ablation compared to standard techniques. METHODS AND RESULTS: Group 1 (1 operator, n = 11) ablated based upon contact voltage measurements and voltage gradient mapping. Ablation targeted low-voltage bridges (LVBs) within the CTI. Repeat maps were obtained following ablation. Group 2 (operators 2, 3, and 4 n = 35) utilized electroanatomic navigation and ablated by the creation of linear lesions from the tricuspid valve to the inferior vena cava. Demonstration of bidirectional block (BDB) was required in both groups. LVB were associated with CTI conduction in all Group A patients. LVB ablation terminated flutter, or created BDB. Following ablation, CTI voltage connections were absent in all patients. Compared with Group B, Group A had less radiofrequency (RF) lesions to atrial flutter (AFL) termination (P = 0.001), less total RF lesions (P = 0.0001), and less total RF time (P = 0.001). Group 1 had no recurrent AFL whereas Group 2 had three recurrences. (follow-up median of 231 +/- 181 days). CONCLUSION: (i) Voltage gradient mapping visualized regions of critical CTI conduction, (ii) ablation of LVB terminated AFL and resulted in BDB, (iii) repeat mapping confirmed the absence of trans-isthmus voltage, and (iv) Compared with standard ablation, voltage gradient mapping decreases total RF lesions, lesions to AFL termination, and total RF time. Use of voltage gradient mapping can facilitate successful AFL ablation. PMID- 23447575 TI - Kinetic modeling-based detection of genetic signatures that provide chemoresistance via the E2F1-p73/DNp73-miR-205 network. AB - Drug resistance is a major cause of deaths from cancer. E2F1 is a transcription factor involved in cell proliferation, apoptosis. and metastasis through an intricate regulatory network, which includes other transcription factors like p73 and cancer-related microRNAs like miR-205. To investigate the emergence of drug resistance, we developed a methodology that integrates experimental data with a network biology and kinetic modeling. Using a regulatory map developed to summarize knowledge on E2F1 and its interplay with p73/DNp73 and miR-205 in cancer drug responses, we derived a kinetic model that represents the network response to certain genotoxic and cytostatic anticancer drugs. By perturbing the model parameters, we simulated heterogeneous cell configurations referred to as in silico cell lines. These were used to detect genetic signatures characteristic for single or double drug resistance. We identified a signature composed of high E2F1 and low miR-205 expression that promotes resistance to genotoxic drugs. In this signature, downregulation of miR-205, can be mediated by an imbalance in the p73/DNp73 ratio or by dysregulation of other cancer-related regulators of miR-205 expression such as TGFbeta-1 or TWIST1. In addition, we found that a genetic signature composed of high E2F1, low miR-205, and high ERBB3 can render tumor cells insensitive to both cytostatic and genotoxic drugs. Our model simulations also suggested that conventional genotoxic drug treatment favors selection of chemoresistant cells in genetically heterogeneous tumors, in a manner requiring dysregulation of incoherent feedforward loops that involve E2F1, p73/DNp73, and miR-205. PMID- 23447576 TI - Spreaders and sponges define metastasis in lung cancer: a Markov chain Monte Carlo mathematical model. AB - The classic view of metastatic cancer progression is that it is a unidirectional process initiated at the primary tumor site, progressing to variably distant metastatic sites in a fairly predictable, although not perfectly understood, fashion. A Markov chain Monte Carlo mathematical approach can determine a pathway diagram that classifies metastatic tumors as "spreaders" or "sponges" and orders the timescales of progression from site to site. In light of recent experimental evidence highlighting the potential significance of self-seeding of primary tumors, we use a Markov chain Monte Carlo (MCMC) approach, based on large autopsy data sets, to quantify the stochastic, systemic, and often multidirectional aspects of cancer progression. We quantify three types of multidirectional mechanisms of progression: (i) self-seeding of the primary tumor, (ii) reseeding of the primary tumor from a metastatic site (primary reseeding), and (iii) reseeding of metastatic tumors (metastasis reseeding). The model shows that the combined characteristics of the primary and the first metastatic site to which it spreads largely determine the future pathways and timescales of systemic disease. PMID- 23447577 TI - Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis. AB - Hepatocyte growth factor activator inhibitor type 1 (HAI-1/SPINT1) is a membrane bound serine protease inhibitor expressed on the surface of epithelial cells. Although HAI-1/SPINT1 is abundantly expressed in the intestinal epithelium, its role in intestinal tumorigenesis is not known. In this study, we investigated the role of Hai-1/Spint1 in intestinal tumorigenesis using mouse models. The membranous Hai-1/Spint1 immunoreactivity was decreased in murine Apc(Min/+) tumors and also in carcinogen (azoxymethane treatment followed by dextran sodium sulfate administration)-induced colon tumors compared with the adjacent non neoplastic epithelium. The decreased immunoreactivity appeared to be due to sheddase activity of membrane-type 1 matrix metalloprotease. Then, we examined the effect of intestine-specific deletion of Spint1 gene on Apc(Min/+) mice. The loss of Hai-1/Spint1 significantly accelerated tumor formation in Apc(Min/+) mice and shortened their survival periods. Activation of HGF was enhanced in Hai 1/Spint1-deficient Apc(Min/+) intestine. Gene expression profiling revealed upregulation of the Wnt/beta-catenin signaling circuit, claudin-2 expression, and angiogenesis not only in tumor tissue but also in the background mucosa without macroscopic tumors in Hai-1/Spint1-deficient Apc(Min/+) intestine. Intestinal deletion of Spint1 also enhanced the susceptibility to carcinogen-induced colon tumorigenicity of wild-type Apc mice. Our findings suggest that HAI-1/SPINT1 has a crucial role in suppressing intestinal tumorigenesis, which implies a novel link between epithelial cell surface serine protease inhibitors and protection from carcinogenic stimuli. PMID- 23447578 TI - Inherited variation in miR-290 expression suppresses breast cancer progression by targeting the metastasis susceptibility gene Arid4b. AB - The metastatic cascade is a complex and extremely inefficient process with many potential barriers. Understanding this process is of critical importance because the majority of cancer mortality is associated with metastatic disease. Recently, it has become increasingly clear that microRNAs (miRNA) play important roles in tumorigenesis and metastasis, yet few studies have examined how germline variations may dysregulate miRNAs, in turn affecting metastatic potential. To explore this possibility, the highly metastatic MMTV-PyMT mice were crossed with 25 AKXD (AKR/J * DBA/2J) recombinant inbred strains to produce F1 progeny with varying metastatic indices. When mammary tumors from the F1 progeny were analyzed by miRNA microarray, miR-290 (containing miR-290-3p and miR-290-5p) was identified as a top candidate progression-associated miRNA. The microarray results were validated in vivo when miR-290 upregulation in two independent breast cancer cell lines suppressed both primary tumor and metastatic growth. Computational analysis identified breast cancer progression gene Arid4b as a top target of miR-290-3p, which was confirmed by luciferase reporter assay. Surprisingly, pathway analysis identified estrogen receptor (ER) signaling as the top canonical pathway affected by miR-290 upregulation. Further analysis showed that ER levels were elevated in miR-290-expressing tumors and positively correlated with apoptosis. Taken together, our results suggest miR-290 targets Arid4b while simultaneously enhancing ER signaling and increasing apoptosis, thereby suppressing breast cancer progression. This, to the best of our knowledge, is the first example of inherited differences in miRNA expression playing a role in breast cancer progression. PMID- 23447579 TI - TNRC9 downregulates BRCA1 expression and promotes breast cancer aggressiveness. AB - Although the linkage between germline mutations of BRCA1 and hereditary breast/ovarian cancers is well established, recent evidence suggests that altered expression of wild-type BRCA1 might contribute to the sporadic forms of breast cancer. The breast cancer gene trinucleotide-repeat-containing 9 (TNRC9; TOX3) has been associated with disease susceptibility but its function is undetermined. Here, we report that TNRC9 is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. Gene amplification was associated with reduced disease-free and metastasis-free survival rates. Ectopic expression of TNRC9 increased breast cancer cell proliferation, migration, and survival after exposure to apoptotic stimuli. These phenotypes were associated with tumor progression in a mouse model of breast cancer. Gene expression profiling, protein analysis, and in silico assays of large datasets of breast and ovarian cancer samples suggested that TNRC9 and BRCA1 expression were inversely correlated. Notably, we found that TNRC9 bound to both the BRCA1 promoter and the cAMP responsive element-binding protein (CREB) complex, a regulator of BRCA1 transcription. In support of this connection, expression of TNRC9 downregulated expression of BRCA1 by altering the methylation status of its promoter. Our studies unveil a function for TNRC9 in breast cancer that highlights a new paradigm in BRCA1 regulation. PMID- 23447580 TI - Activation of HIF2alpha in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis. AB - Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1alpha (HIF1alpha) and HIF2alpha has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2alpha (P405A, P530A, and N851A, named as HIF2alphaM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1alphaM3 oncogenesis when coexpressed with constitutively active HIF1alphaM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), gammaH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2alpha is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2alpha activation is critical for ccRCC tumorigenesis. PMID- 23447582 TI - Increasing dietary protein acutely augments intestinal iron transporter expression and significantly increases iron absorption in rats. AB - Iron (Fe) deficiency is endemic worldwide. Little data are available regarding acute effects of dietary protein on intestinal Fe absorption. The current study evaluated the short-term effects of increasing dietary protein on Fe absorption and expression of genes involved in Fe homeostasis. Sprague Dawley rats (24, female) were randomly assigned to custom-formulated isocaloric diets containing 40, 20 (control), or 5% protein (as percentage of total kilocalories) for 7 d. Whole-body Fe balance studies demonstrated that Fe retention was greater in the 40% group than in the 5% group (30.8 vs. 7.3%; P<0.01). In a separate study utilizing stable iron isotopes, the 40% group absorbed 30% of ingested Fe, while the 20% group absorbed 18% (P=0.005). Whole-genome profiling revealed that increasing dietary protein from 5 to 40% increased duodenal transcript expression of divalent metal transporter 1 (DMT1) 3.2-fold, duodenal cytochrome b (Dcytb) 1.8-fold, and transferrin receptor (TfR) 1.8-fold. Consistent with these findings, DMT1 transcript expression was 4-fold higher in RNA prepared from duodenal mucosa in the 40% group compared to the 20% group (P<0.001). These data suggest that increasing dietary protein increases intestinal Fe absorption in part by up-regulating DMT1, Dcytb, and TfR. PMID- 23447583 TI - Maternal adiposity and newborn vascular health. PMID- 23447581 TI - Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. AB - The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1beta and a cell-free mPGES 1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3 fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1beta-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 MUM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1alpha, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis. PMID- 23447584 TI - A novel population of cholinergic neurons in the macaque spinal dorsal horn of potential clinical relevance for pain therapy. AB - Endogenous acetylcholine (ACh) is a well-known modulator of nociceptive transmission in the spinal cord of rodents. It arises mainly from a sparse population of cholinergic interneurons located in the dorsal horn of the spinal cord. This population was thought to be absent from the spinal cord of monkey, what might suggest that spinal ACh would not be a relevant clinical target for pain therapy. In humans, however, pain responses can be modulated by spinal ACh, as evidenced by the increasingly used analgesic procedure (for postoperative and labor patients) consisting of the epidural injection of the acetylcholinesterase inhibitor neostigmine. The source and target of this ACh remain yet to be elucidated. In this study, we used an immunolabeling for choline acetyltransferase to demonstrate, for the first time, the presence of a plexus of cholinergic fibers in laminae II-III of the dorsal horn of the macaque monkey. Moreover, we show the presence of numerous cholinergic cell bodies within the same laminae and compared their density and morphological properties with those previously described in rodents. An electron microscopy analysis demonstrates that cholinergic boutons are presynaptic to dorsal horn neurons as well as to the terminals of sensory primary afferents, suggesting that they are likely to modulate incoming somatosensory information. Our data suggest that this newly identified dorsal horn cholinergic system in monkeys is the source of the ACh involved in the analgesic effects of epidural neostigmine and could be more specifically targeted for novel therapeutic strategies for pain management in humans. PMID- 23447585 TI - Postsynaptic GABAB receptors enhance extrasynaptic GABAA receptor function in dentate gyrus granule cells. AB - Ambient GABA in the brain tonically activates extrasynaptic GABA(A) receptors, and activity-dependent changes in ambient GABA concentration can also activate GABA(B) receptors. To investigate an interaction between postsynaptic GABA(B) and GABA(A) receptors, we recorded GABA(A) currents elicited by exogenous GABA (10 MUm) from dentate gyrus granule cells (DGGCs) in adult rat hippocampal slices. The GABA(B) receptor agonist baclofen (20 MUm) enhanced GABA(A) currents. This enhancement was blocked by the GABA(B) receptor antagonist CGP 55845 and intracellular solutions containing the GTP analog GDP-beta-s, indicating that baclofen was acting on postsynaptic GABA(B) receptors. Modulation of GABA(A) currents by postsynaptic GABA(B) receptors was not observed in CA1 pyramidal cells or layer 2/3 cortical pyramidal neurons. Baclofen reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) but did not alter sIPSC amplitude or kinetics. Thus, GABA(A) receptors activated at synapses were not modulated by postsynaptic GABA(B) receptors. In contrast, tonic GABA currents and currents activated by the GABA(A) receptor delta subunit-selective agonist THIP (10 MUm) were potentiated by baclofen. Our data indicate that postsynaptic GABA(B) receptors enhance the function of extrasynaptic GABA(A) receptors, including delta subunit-containing receptors that mediate tonic inhibition in DGGCs. The modulation of GABA(A) receptor function by postsynaptic GABA(B) receptors is a newly identified mechanism that will influence the inhibitory tone of DGGCs when GABA(B) and GABA(A) receptors are both activated. PMID- 23447586 TI - Safety encoding in the basal amygdala. AB - Learning to fear and avoid life-threatening stimuli are critical survival skills but are maladaptive when they persist in the absence of a direct threat. Thus, it is important to detect when a situation is safe and to increase behaviors leading to naturally rewarding actions, such as feeding and mating. It is unclear how the brain distinguishes between dangerous and safe situations. Here, we present a novel protocol designed to investigate the processing of cues that predict danger, safety, or reward (sucrose). In vivo single unit recordings were obtained in the basal amygdala of freely behaving rats undergoing simultaneous reward, fear, and safety conditioning. We observed a population of neurons that did not respond to a Fear Cue but did change their firing rate during the combined presentation of a fear cue simultaneous with a second, safety, cue; this combination of Fear + Safety Cues signified "no shock." This neural population consisted of two subpopulations: neurons that responded to the Fear + Safety Cue but not the Fear or Reward Cue ("safety" neurons), and neurons that responded to the Fear + Safety and Reward Cue but not the Fear Cue ("safety + reward" neurons). These data demonstrate the presence of neurons in the basal amygdala that are selectively responsive to Safety Cues. Furthermore, these data suggest that safety and reward learning use overlapping mechanisms in the basal amygdala. PMID- 23447588 TI - Suppression of spontaneous activity before visual response in the primate V1 neurons during a visually guided saccade task. AB - Visually guided saccadic eye movements are thought to involve multiple stages of processing in diverse brain structures including the primary visual cortex (V1). The variability of neural activity in each of these structures may present ambiguities for downstream stages in identifying sensory and motor signals among spontaneous discharges. The response time of saccadic eye movements made toward a visual target is correlated with the time of the first spikes in V1 that are evoked by the target (Lee et al., 2010). This suggests that downstream neurons receiving the output of V1 are faced with a challenging task of discriminating first spikes of visual response against spontaneous discharge. Here we report a novel response property of the macaque V1 neurons. Immediately before neurons discharge a burst of activity to a visual saccade target, spontaneous discharges were transiently suppressed. This suppression was maximal ~18 ms after target onset. Based on simulations of artificial spike trains, we propose that the transient suppression enhances temporal contrast for identifying the onset of visual response by increasing the reliability of detection of response onset by downstream neurons, thereby facilitating visually guided behavioral responses. PMID- 23447587 TI - Cortical metabolic activity matches the pattern of visual suppression in strabismus. AB - When an eye becomes deviated in early childhood, a person does not experience double vision, although the globes are aimed at different targets. The extra image is prevented from reaching perception in subjects with alternating exotropia by suppression of each eye's peripheral temporal retina. To test the impact of visual suppression on neuronal activity in primary (striate) visual cortex, the pattern of cytochrome oxidase (CO) staining was examined in four macaques raised with exotropia by disinserting the medial rectus muscles shortly following birth. No ocular dominance columns were visible in opercular cortex, where the central visual field is represented, indicating that signals coming from the central retina in each eye were perceived. However, the border strips at the edges of ocular dominance columns appeared pale, reflecting a loss of activity in binocular cells from disruption of fusion. In calcarine cortex, where the peripheral visual field is represented, there were alternating pale and dark bands resembling ocular dominance columns. To interpret the CO staining pattern, [(3)H]proline was injected into the right eye in two monkeys. In the right calcarine cortex, the pale CO columns matched the labeled proline columns of the right eye. In the left calcarine cortex, the pale CO columns overlapped the unlabeled columns of the left eye in the autoradiograph. Therefore, metabolic activity was reduced in the ipsilateral eye's ocular dominance columns which serve peripheral temporal retina, in a fashion consistent with the topographic organization of suppression scotomas in humans with exotropia. PMID- 23447589 TI - Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer amyloidosis. AB - Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet Off vector systems provide an alternative model for assessing short- and long term effects of Abeta-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Abeta has been suppressed. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Abeta production produced highly significant improvements in performing short-term spatial memory tasks, which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Abeta production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Abeta42. Additionally, we observed persistent levels of Abeta immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Abeta assemblies and low, but detectable solubilizable Abeta42 peptides. These findings implicate complex relationships between accumulating Abeta and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis. PMID- 23447590 TI - GABAB Receptors Regulate Extrasynaptic GABAA Receptors. AB - Tonic inhibitory GABA(A) receptor-mediated currents are observed in numerous cell types in the CNS, including thalamocortical neurons of the ventrobasal thalamus, dentate gyrus granule cells, and cerebellar granule cells. Here we show that in rat brain slices, activation of postsynaptic GABA(B) receptors enhances the magnitude of the tonic GABA(A) current recorded in these cell types via a pathway involving G G proteins, adenylate cyclase, and cAMP-dependent protein kinase. Using a combination of pharmacology and knockout mice, we show that this pathway is independent of potassium channels or GABA transporters. Furthermore, the enhancement in tonic current is sufficient to significantly alter the excitability of thalamocortical neurons. These results demonstrate for the first time a postsynaptic crosstalk between GABA(B) and GABA(A) receptors. PMID- 23447591 TI - Latent modulation: a basis for non-disruptive promotion of two incompatible behaviors by a single network state. AB - Behavioral states often preferentially enhance specific classes of behavior and suppress incompatible behaviors. In the nervous system, this may involve upregulation of the efficacy of neural modules that mediate responses to one stimulus and suppression of modules that generate antagonistic or incompatible responses to another stimulus. In Aplysia, prestimulation of egestive inputs [esophageal nerve (EN)] facilitates subsequent EN-elicited egestive responses and weakens ingestive responses to ingestive inputs [Cerebral-Buccal Interneuron (CBI 2)]. However, a single state can also promote incompatible behaviors in response to different stimuli. This is the case in Aplysia, where prestimulation of CBI-2 inputs not only enhances subsequent CBI-2-elicited ingestive responses, but also strengthens EN-elicited egestive responses. We used the modularly organized feeding network of Aplysia to characterize the organizational principles that allow a single network state to promote two opposing behaviors, ingestion and egestion, without the two interfering with each other. We found that the CBI-2 prestimulation-induced state upregulates the excitability of neuron B65 which, as a member of the egestive module, increases the strength of egestive responses. Furthermore, we found that this upregulation is likely mediated by the actions of the neuropeptides FCAP (Feeding Circuit Activating Peptide) and CP2 (Cerebral Peptide 2). This increased excitability is mediated by a form of modulation that we refer to as "latent modulation" because it is established during stimulation of CBI-2, which does not activate B65. However, when B65 is recruited into EN elicited egestive responses, the effects of the latent modulation are expressed as a higher B65 firing rate and a resultant strengthening of the egestive response. PMID- 23447593 TI - Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions. AB - Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA)-mediated Pavlovian reactions. Pretraining lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC mediated diminution of pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat. PMID- 23447592 TI - The Angelman syndrome protein Ube3a/E6AP is required for Golgi acidification and surface protein sialylation. AB - Angelman syndrome (AS) is a severe disorder of postnatal brain development caused by neuron-specific loss of the HECT (homologous to E6AP carboxy terminus) domain E3 ubiquitin ligase Ube3a/E6AP. The cellular role of Ube3a remains enigmatic despite recent descriptions of synaptic and behavioral deficits in AS mouse models. Although neuron-specific imprinting is thought to limit the disease to the brain, Ube3a is expressed ubiquitously, suggesting a broader role in cellular function. In the current study, we demonstrate a profound structural disruption and cisternal swelling of the Golgi apparatus (GA) in the cortex of AS (UBE3A(m /p+)) mice. In Ube3a knockdown cell lines and UBE3A(m-/p+) cortical neurons, the GA is severely under-acidified, leading to osmotic swelling. Both in vitro and in vivo, the loss of Ube3a and corresponding elevated pH of the GA is associated with a marked reduction in protein sialylation, a process highly dependent on intralumenal Golgi pH. Altered ion homeostasis of the GA may provide a common cellular pathophysiology underlying the diverse plasticity and neurodevelopmental deficits associated with AS. PMID- 23447594 TI - Cytotoxicity of intracellular abeta42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. AB - Oligomeric forms of beta-amyloid (Abeta(42)) peptides associated with Alzheimer's disease (AD) disrupt cellular Ca(2+) regulation by liberating Ca(2+) into the cytosol from both extracellular and intracellular sources. We elucidated the actions of intracellular Abeta by imaging Ca(2+) responses to injections of Abeta oligomers into Xenopus oocytes. Two types of signal were observed: (1) local, "channel-like" transients dependent on extracellular Ca(2+) influx, which resembled signals from amlyoid pores formed by extracellular application of oligomers; and (2) local transients and global Ca(2+) waves, resembling Ca(2+) puffs and waves mediated by inositol trisphosphate (IP(3)). The latter responses were suppressed by antagonists of the IP(3) receptor (caffeine and heparin), pretreatment with the G(i)(o)-protein inhibitor pertussis toxin, and pretreatment with lithium to deplete membrane inositol lipids. We show that G-protein-mediated stimulation of IP(3) production and consequent liberation of Ca(2+) from the endoplasmic reticulum by intracellular Abeta oligomers is cytotoxic, potentially representing a novel pathological mechanism in AD which may be further exacerbated by AD-linked mutations in presenilins to promote opening of IP(3) receptor/channels. PMID- 23447596 TI - The sparseness of mixed selectivity neurons controls the generalization discrimination trade-off. AB - Intelligent behavior requires integrating several sources of information in a meaningful fashion-be it context with stimulus or shape with color and size. This requires the underlying neural mechanism to respond in a different manner to similar inputs (discrimination), while maintaining a consistent response for noisy variations of the same input (generalization). We show that neurons that mix information sources via random connectivity can form an easy to read representation of input combinations. Using analytical and numerical tools, we show that the coding level or sparseness of these neurons' activity controls a trade-off between generalization and discrimination, with the optimal level depending on the task at hand. In all realistic situations that we analyzed, the optimal fraction of inputs to which a neuron responds is close to 0.1. Finally, we predict a relation between a measurable property of the neural representation and task performance. PMID- 23447595 TI - Identification of nonvisual photomotor response cells in the vertebrate hindbrain. AB - Nonvisual photosensation enables animals to sense light without sight. However, the cellular and molecular mechanisms of nonvisual photobehaviors are poorly understood, especially in vertebrate animals. Here, we describe the photomotor response (PMR), a robust and reproducible series of motor behaviors in zebrafish that is elicited by visual wavelengths of light but does not require the eyes, pineal gland, or other canonical deep-brain photoreceptive organs. Unlike the relatively slow effects of canonical nonvisual pathways, motor circuits are strongly and quickly (seconds) recruited during the PMR behavior. We find that the hindbrain is both necessary and sufficient to drive these behaviors. Using in vivo calcium imaging, we identify a discrete set of neurons within the hindbrain whose responses to light mirror the PMR behavior. Pharmacological inhibition of the visual cycle blocks PMR behaviors, suggesting that opsin-based photoreceptors control this behavior. These data represent the first known light-sensing circuit in the vertebrate hindbrain. PMID- 23447597 TI - Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus. AB - In recent years, the glutamatergic system has been implicated in the development and treatment of psychiatric disorders. Glutamate signaling is processed by different receptors, including metabotropic glutamate receptors (mGluRs), which in turn interact with the scaffolding protein Homer1 to modulate downstream Ca(2+) signaling. Stress is a major risk factor for the incidence of psychiatric diseases, yet acute stress episodes may have diverging effects on individuals. Cognitive impairments have often been shown to occur after episodes of stress, however the specific role of mGluR5/Homer1 signaling in the interaction of stress and cognition has not yet been elucidated. In this study we show that a single episode of social defeat stress is sufficient to specifically induce cognitive impairments in mice 8 h after the stressor without affecting the animals' locomotion or anxiety levels. We also demonstrate that Homer1b/c levels as well as mGluR5/Homer1b/c interactions in the dorsal hippocampus are reduced up to 8 h after stress. Blockade of mGluR5 during the occurrence of social stress was able to rescue the cognitive impairments. In addition, a specific overexpression of Homer1b/c in the dorsal hippocampus also reversed the behavioral phenotype, indicating that both mGluR5 and Homer1b/c play a crucial role in the mediation of the stress effects. In summary, we could demonstrate that stress induces a cognitive deficit that is likely mediated by mGluR5/Homer1 signaling in the hippocampus. These findings help to reveal the underlying effects of cognitive impairments in patients suffering from stress-related psychiatric disorders. PMID- 23447599 TI - Progression of neurogenesis in the inner ear requires inhibition of Sox2 transcription by neurogenin1 and neurod1. AB - Sox2 is required for proper neuronal formation in the CNS, but the molecular mechanisms involved are not well characterized. Here, we addressed the role of Sox2 in neurogenesis of the developing chicken inner ear. Overexpressing Sox2 from a constitutive (beta-actin) promoter induces the expression of the proneural gene, Neurogenin1 (Ngn1); however, the expression of a downstream target of Ngn1, Neurod1, is unchanged. As a result, there is a reduction of neural precursors to delaminate and populate the developing cochleo-vestibular ganglion. In contrast, overexpression of either Ngn1 or Neurod1 is sufficient to promote the neural fate in this system. These results suggest that high levels of Sox2 inhibit progression of neurogenesis in the developing inner ear. Furthermore, we provide evidence that Ngn1 and Neurod1 inhibit Sox2 transcription through a phylogenetically conserved Sox2 enhancer to mediate neurogenesis. We propose that Sox2 confers neural competency by promoting Ngn1 expression, and that negative feedback inhibition of Sox2 by Ngn1 is an essential step in the progression from neural precursor to nascent neuron. PMID- 23447598 TI - Pro- and anti-mitogenic actions of pituitary adenylate cyclase-activating polypeptide in developing cerebral cortex: potential mediation by developmental switch of PAC1 receptor mRNA isoforms. AB - During corticogenesis, pituitary adenylate cyclase-activating polypeptide (PACAP; ADCYAP1) may contribute to proliferation control by activating PAC1 receptors of neural precursors in the embryonic ventricular zone. PAC1 receptors, specifically the hop and short isoforms, couple differentially to and activate distinct pathways that produce pro- or anti-mitogenic actions. Previously, we found that PACAP was an anti-mitogenic signal from embryonic day 13.5 (E13.5) onward both in culture and in vivo and activated cAMP signaling through the short isoform. However, we now find that mice deficient in PACAP exhibited a decrease in the BrdU labeling index (LI) in E9.5 cortex, suggesting that PACAP normally promotes proliferation at this stage. To further define mechanisms, we established a novel culture model in which the viability of very early cortical precursors (E9.5 mouse and E10.5 rat) could be maintained. At this stage, we found that PACAP evoked intracellular calcium fluxes and increased phospho-PKC levels, as well as stimulated G1 cyclin mRNAs and proteins, S-phase entry, and proliferation without affecting cell survival. Significantly, expression of hop receptor isoform was 24 fold greater than the short isoform at E10.5, a ratio that was reversed at E14.5 when short expression was 15-fold greater and PACAP inhibited mitogenesis. Enhanced hop isoform expression, elicited by in vitro treatment of E10.5 precursors with retinoic acid, correlated with sustained pro-mitogenic action of PACAP beyond the developmental switch. Conversely, depletion of hop receptor using short-hairpin RNA abolished PACAP mitogenic stimulation at E10.5. These observations suggest that PACAP elicits temporally specific effects on cortical proliferation via developmentally regulated expression of specific receptor isoforms. PMID- 23447600 TI - Linear processing of interaural level difference underlies spatial tuning in the nucleus of the brachium of the inferior colliculus. AB - The spatial location of sounds is an important aspect of auditory perception, but the ways in which space is represented are not fully understood. No space map has been found within the primary auditory pathway. However, a space map has been found in the nucleus of the brachium of the inferior colliculus (BIN), which provides a major auditory projection to the superior colliculus. We measured the spectral processing underlying auditory spatial tuning in the BIN of unanesthetized marmoset monkeys. Because neurons in the BIN respond poorly to tones and are broadly tuned, we used a broadband stimulus with random spectral shapes (RSSs) from which both spatial receptive fields and frequency sensitivity can be derived. Responses to virtual space (VS) stimuli, based on the animal's own ear acoustics, were compared with the predictions of a weight-function model of responses to the RSS stimuli. First-order (linear) weight functions had broad spectral tuning (approximately three octaves) and were excitatory in the contralateral ear, inhibitory in the ipsilateral ear, and biased toward high frequencies. Responses to interaural time differences and spectral cues were relatively weak. In cross-validation tests, the first-order RSS model accurately predicted the measured VS tuning curves in the majority of neurons, but was inaccurate in 25% of neurons. In some cases, second-order weighting functions led to significant improvements. Finally, we found a significant correlation between the degree of binaural weight asymmetry and the best azimuth. Overall, the results suggest that linear processing of interaural level difference underlies spatial tuning in the BIN. PMID- 23447601 TI - GABA-independent GABAA receptor openings maintain tonic currents. AB - Activation of GABA(A) receptors (GABA(A)Rs) produces two forms of inhibition: phasic inhibition generated by the rapid, transient activation of synaptic GABA(A)Rs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of perisynaptic or extrasynaptic GABA(A)Rs, which can detect extracellular GABA. Such tonic GABA(A)R-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex vivo hippocampal slices, tonic currents are predominantly generated by GABA independent GABA(A) receptor openings. This tonic GABA(A)R conductance is resistant to the competitive GABA(A)R antagonist SR95531 (gabazine), which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker, picrotoxin. When slices are perfused with 200 nm GABA, a concentration that is comparable to CSF concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABA(A)Rs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations. PMID- 23447603 TI - The cooperation of sustained and phasic inhibitions increases the contrast of ITD tuning in low-frequency neurons of the chick nucleus laminaris. AB - Neurons in the nucleus laminaris (NL) of birds detect the coincidence of binaural excitatory inputs from the nucleus magnocellularis (NM) on both sides and process the interaural time differences (ITDs) for sound localization. Sustained inhibition from the superior olivary nucleus is known to control the gain of coincidence detection, which allows the sensitivity of NL neurons to ITD tolerate strong-intensity sound. Here, we found a phasic inhibition in chicken brain slices that follows the ipsilateral NM inputs after a short time delay, sharpens coincidence detection, and may enhance ITD sensitivity in low-frequency NL neurons. GABA-positive small neurons are distributed in and near the NL. These neurons generate IPSCs in NL neurons when photoactivated by a caged glutamate compound, suggesting that these GABAergic neurons are interneurons that mediate phasic inhibition. These IPSCs have fast decay kinetics that is attributable to the alpha1-subunit of the GABAA receptor, the expression of which dominates in the low-frequency region of the NL. Model simulations demonstrate that phasic IPSCs narrow the time window of coincidence detection and increase the contrast of ITD-tuning during low-level, low-frequency excitatory input. Furthermore, cooperation of the phasic and sustained inhibitions effectively increases the contrast of ITD-tuning over a wide range of excitatory input levels. We propose that the complementary interaction between phasic and sustained inhibitions is the neural mechanism that regulates ITD sensitivity for low-frequency sound in the NL. PMID- 23447602 TI - Pathological activity in mediodorsal thalamus of rats with spinal cord injury pain. AB - Spinal cord injury (SCI) results not only in motor deficits, but produces, in many patients, excruciating chronic pain (SCI pain). We have previously shown, in a rodent model, that SCI causes suppression of activity in the GABAergic nucleus, the zona incerta (ZI), and concomitant increased activity in one of its main targets, the posterior nucleus of the thalamus (PO); the increased PO activity is correlated with the maintenance and expression of hyperalgesia after SCI. Here, we test the hypothesis that SCI causes a similar pathological increase in other thalamic nuclei regulated by the ZI, specifically the mediodorsal thalamus (MD), which is involved in the emotional-affective aspects of pain. We recorded single and multiunit activity from MD of either anesthetized or awake rats, and compared data from rats with SCI with data from sham-operated controls (anesthetized experiments) or with data from the same animals prelesion (awake experiments). Consistent with our hypothesis, MD neurons from rats with SCI show significant increases in spontaneous firing rates and in the magnitude and duration of responses to noxious stimuli. In a subset of anesthetized animals, similar changes in activity of MD neurons were produced by pharmacologically inactivating ZI in naive rats, suggesting that the changes in the MD after SCI are related to suppressed inhibition from the ZI. These data support our hypothesis that SCI pain results, at least in part, from a loss of inhibition to thalamic nuclei associated with both the sensory-discriminative and emotional-affective components of pain. PMID- 23447604 TI - Temporal characteristics of the influence of punishment on perceptual decision making in the human brain. AB - Perceptual decision making is the process by which information from sensory systems is combined and used to influence our behavior. In addition to the sensory input, this process can be affected by other factors, such as reward and punishment for correct and incorrect responses. To investigate the temporal dynamics of how monetary punishment influences perceptual decision making in humans, we collected electroencephalography (EEG) data during a perceptual categorization task whereby the punishment level for incorrect responses was parametrically manipulated across blocks of trials. Behaviorally, we observed improved accuracy for high relative to low punishment levels. Using multivariate linear discriminant analysis of the EEG, we identified multiple punishment induced discriminating components with spatially distinct scalp topographies. Compared with components related to sensory evidence, components discriminating punishment levels appeared later in the trial, suggesting that punishment affects primarily late postsensory, decision-related processing. Crucially, the amplitude of these punishment components across participants was predictive of the size of the behavioral improvements induced by punishment. Finally, trial-by-trial changes in prestimulus oscillatory activity in the alpha and gamma bands were good predictors of the amplitude of these components. We discuss these findings in the context of increased motivation/attention, resulting from increases in punishment, which in turn yields improved decision-related processing. PMID- 23447606 TI - Wnt signal specifies the intrathalamic limit and its organizer properties by regulating Shh induction in the alar plate. AB - The structural complexity of the brain depends on precise molecular and cellular regulatory mechanisms orchestrated by regional morphogenetic organizers. The thalamic organizer is the zona limitans intrathalamica (ZLI), a transverse linear neuroepithelial domain in the alar plate of the diencephalon. Because of its production of Sonic hedgehog, ZLI acts as a morphogenetic signaling center. Shh is expressed early on in the prosencephalic basal plate and is then gradually activated dorsally within the ZLI. The anteroposterior positioning and the mechanism inducing Shh expression in ZLI cells are still partly unknown, being a subject of controversial interpretations. For instance, separate experimental results have suggested that juxtaposition of prechordal (rostral) and epichordal (caudal) neuroepithelium, anteroposterior encroachment of alar lunatic fringe (L fng) expression, and/or basal Shh signaling is required for ZLI specification. Here we investigated a key role of Wnt signaling in the molecular regulation of ZLI positioning and Shh expression, using experimental embryology in ovo in the chick. Early Wnt expression in the ZLI regulates Gli3 and L-fng to generate a permissive territory in which Shh is progressively induced by planar signals of the basal plate. PMID- 23447605 TI - Reducing GABAA alpha5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome. AB - Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5 a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) alpha5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) alpha5 NAMs to treat cognitive dysfunction in DS. PMID- 23447607 TI - Punishment-induced behavioral and neurophysiological variability reveals dopamine dependent selection of kinematic movement parameters. AB - Action selection describes the high-level process that selects between competing movements. In animals, behavioral variability is critical for the motor exploration required to select the action that optimizes reward and minimizes cost/punishment and is guided by dopamine (DA). The aim of this study was to test in humans whether low-level movement parameters are affected by punishment and reward in ways similar to high-level action selection. Moreover, we addressed the proposed dependence of behavioral and neurophysiological variability on DA and whether this may underpin the exploration of kinematic parameters. Participants performed an out-and-back index finger movement and were instructed that monetary reward and punishment were based on its maximal acceleration (MA). In fact, the feedback was not contingent on the participant's behavior but predetermined. Blocks highly biased toward punishment were associated with increased MA variability relative to blocks either with reward or without feedback. This increase in behavioral variability was positively correlated with neurophysiological variability, as measured by changes in corticospinal excitability with transcranial magnetic stimulation over the primary motor cortex. Following the administration of a DA antagonist, the variability associated with punishment diminished and the correlation between behavioral and neurophysiological variability no longer existed. Similar changes in variability were not observed when participants executed a predetermined MA, nor did DA influence resting neurophysiological variability. Thus, under conditions of punishment, DA-dependent processes influence the selection of low-level movement parameters. We propose that the enhanced behavioral variability reflects the exploration of kinematic parameters for less punishing, or conversely more rewarding, outcomes. PMID- 23447608 TI - MicroRNA-195 protects against dementia induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats. AB - Previous studies have demonstrated that chronic brain hypoperfusion (CBH) causes Abeta aggregation by upregulating expression of amyloid precursor protein (APP) and beta-site APP cleaving enzyme 1 (BACE1) protein, which is accompanied by cognitive impairment, but the mechanisms are not fully understood. In this study, we evaluated the effect of microRNA on memory impairment in rats induced by CBH. We show here that CBH generated by bilateral common carotid artery occlusion (2VO) significantly decreased the learning and memory ability in rats, as assessed by Morris water maze, and upregulated expression of APP and BACE1 proteins in the hippocampus and cortex of rats, as evaluated by Western blot and immunofluorescence. In reciprocal, qRT-PCR analysis showed that microRNA-195 (miR 195) was downregulated in both the hippocampus and cortex of rats following CBH, and in the plasma of dementia patients. APP and BACE1 proteins were downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation or miR-masks, indicating that APP and BACE1 are two potential targets for miR-195. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) elicited dementia in rats, whereas overexpression of miR-195 using lenti-pre-miR 195 reduced dementia vulnerability triggered by 2VO. Additionally, chromatin immunoprecipitation analysis showed that NFkappaB was bound to the promoter region of miR-195 and inhibited its expression. We conclude that miR-195 may play a key role in determining dementia susceptibility in 2VO rats by regulating APP and BACE1 expression at the post-transcriptional level, and exogenous complement of miR-195 may be a potentially valuable anti-dementia approach. PMID- 23447609 TI - Temporal expectation enhances contrast sensitivity by phase entrainment of low frequency oscillations in visual cortex. AB - Although it is increasingly accepted that temporal expectation can modulate early perceptual processing, the underlying neural computations remain unknown. In the present study, we combined a psychophysical paradigm with electrophysiological recordings to investigate the putative contribution of low-frequency oscillatory activity in mediating the modulation of visual perception by temporal expectation. Human participants judged the orientation of brief targets (visual Gabor patterns tilted clockwise or counterclockwise) embedded within temporally regular or irregular streams of noise-patches used as temporal cues. Psychophysical results indicated that temporal expectation enhanced the contrast sensitivity of visual targets. A diffusion model indicated that rhythmic temporal expectation modulated the signal-to-noise gain of visual processing. The concurrent electrophysiological data revealed that the phase of delta oscillations overlying human visual cortex (1-4 Hz) was predictive of the quality of target processing only in regular streams of events. Moreover, in the regular condition, the optimum phase of these perception-predictive oscillations occurred in anticipation of the expected events. Together, these results show a strong correspondence between psychophysical and neurophysiological data, suggesting that the phase entrainment of low-frequency oscillations to external sensory cues can serve as an important and flexible mechanism for enhancing sensory processing. PMID- 23447610 TI - Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense. AB - This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway. PMID- 23447611 TI - The thalamus and brainstem act as key hubs in alterations of human brain network connectivity induced by mild propofol sedation. AB - Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices. PMID- 23447612 TI - Neutralization of inhibitory molecule NG2 improves synaptic transmission, retrograde transport, and locomotor function after spinal cord injury in adult rats. AB - NG2 belongs to the family of chondroitin sulfate proteoglycans that are upregulated after spinal cord injury (SCI) and are major inhibitory factors restricting the growth of fibers after SCI. Neutralization of NG2's inhibitory effect on axon growth by anti-NG2 monoclonal antibodies (NG2-Ab) has been reported. In addition, recent studies show that exogenous NG2 induces a block of axonal conduction. In this study, we demonstrate that acute intraspinal injections of NG2-Ab prevented an acute block of conduction by NG2. Chronic intrathecal infusion of NG2-Ab improved the following deficits induced by chronic midthoracic lateral hemisection (HX) injury: (1) synaptic transmission to lumbar motoneurons, (2) retrograde transport of fluororuby anatomical tracer from L5 to L1, and (3) locomotor function assessed by automated CatWalk gait analysis. We collected data in an attempt to understand the cellular and molecular mechanisms underlying the NG2-Ab-induced improvement of synaptic transmission in HX-injured spinal cord. These data showed the following: (1) that chronic NG2-Ab infusion improved conduction and axonal excitability in chronically HX-injured rats, (2) that antibody treatment increased the density of serotonergic axons with ventral regions of spinal segments L1-L5, (3) and that NG2-positive processes contact nodes of Ranvier within the nodal gap at the location of nodal Na(+) channels, which are known to be critical for propagation of action potentials along axons. Together, these results demonstrate that treatment with NG2-Ab partially improves both synaptic and anatomical plasticity in damaged spinal cord and promotes functional recovery after HX SCI. Neutralizing antibodies against NG2 may be an excellent way to promote axonal conduction after SCI. PMID- 23447613 TI - A small group of neurosecretory cells expressing the transcriptional regulator apontic and the neuropeptide corazonin mediate ethanol sedation in Drosophila. AB - In the fruit fly Drosophila melanogaster, as in mammals, acute exposure to a high dose of ethanol leads to stereotypical behavioral changes beginning with increased activity, followed by incoordination, loss of postural control, and eventually, sedation. The mechanism(s) by which ethanol impacts the CNS leading to ethanol-induced sedation and the genes required for normal sedation sensitivity remain largely unknown. Here we identify the gene apontic (apt), an Myb/SANT-containing transcription factor that is required in the nervous system for normal sensitivity to ethanol sedation. Using genetic and behavioral analyses, we show that apt mediates sensitivity to ethanol sedation by acting in a small set of neurons that express Corazonin (Crz), a neuropeptide likely involved in the physiological response to stress. The activity of Crz neurons regulates the behavioral response to ethanol, as silencing and activating these neurons affects sedation sensitivity in opposite ways. Furthermore, this effect is mediated by Crz, as flies with reduced crz expression show reduced sensitivity to ethanol sedation. Finally, we find that both apt and crz are rapidly upregulated by acute ethanol exposure. Thus, we have identified two genes and a small set of peptidergic neurons that regulate sensitivity to ethanol-induced sedation. We propose that Apt regulates the activity of Crz neurons and/or release of the neuropeptide during ethanol exposure. PMID- 23447614 TI - Vertebrate intersectin1 is repurposed to facilitate cortical midline connectivity and higher order cognition. AB - Invertebrate studies have highlighted a role for EH and SH3 domain Intersectin (Itsn) proteins in synaptic vesicle recycling and morphology. Mammals have two Itsn genes (Itsn1 and Itsn2), both of which can undergo alternative splicing to include DBL/PH and C2 domains not present in invertebrate Itsn proteins. To probe for specific and redundant functions of vertebrate Itsn genes, we generated Itsn1, Itsn2, and double mutant mice. While invertebrate mutants showed severe synaptic abnormalities, basal synaptic transmission and plasticity were unaffected at Schaffer CA1 synapses in mutant mice. Surprisingly, intercortical tracts-corpus callosum, ventral hippocampal, and anterior commissures-failed to cross the midline in mice lacking Itsn1, but not Itsn2. In contrast, tracts extending within hemispheres and those that decussate to more caudal brain segments appeared normal. Itsn1 mutant mice showed severe deficits in Morris water maze and contextual fear memory tasks, whereas mice lacking Itsn2 showed normal learning and memory. Thus, coincident with the acquisition of additional signaling domains, vertebrate Itsn1 has been functionally repurposed to also facilitate interhemispheric connectivity essential for high order cognitive functions. PMID- 23447615 TI - Paired related homeobox protein 1 is a regulator of stemness in adult neural stem/progenitor cells. AB - Newborn neurons are generated from neural stem cells (NSCs) in two major niches of the adult brain. Maintenance of self-renewal and multipotency of adult NSCs is controlled by multiple transcription factor networks. We show here that paired related homeobox protein Prx1 (MHox1/Prrx1) plays an important role in the maintenance of adult NSCs. Prx1 works with the transcription factor Sox2 as a coactivator, and depletion of Prx1 in cultured adult mouse NSCs reduces their self-renewal. In addition, we find that Prx1 protein is expressed in Sox2(+)/GFAP(+)/Nestin(+) astrocytes in the germinal regions of the adult mouse forebrain. The continuous expression of Prx1 in proliferating adult mouse hippocampal stem/progenitor cells in vivo leads to the generation of radial/horizontal-shaped astrocyte progenitor- and oligodendrocyte progenitor like cells with no newborn neurons in the neurogenic niche. These data suggest that Prx1 plays an important role as a key switch for neural cell lineage determination and the maintenance of the self-renewal of adult NSCs at several stages in the adult brain. PMID- 23447617 TI - Altered synaptic dynamics during normal brain aging. AB - What is the neuroanatomical basis for the decline in brain function that occurs during normal aging? Previous postmortem studies have blamed it on a reduction in spine density, though results remain controversial and spine dynamics were not assessed. We used chronic in vivo two-photon imaging of dendritic spines and axonal boutons in somatosensory cortex for up to 1 year in thy1 GFP mice to test the hypothesis that aging is associated with alterations in synaptic dynamics. We find that the density of spines and en passant boutons (EPBs) in pyramidal cells increases throughout adult life but is stable between mature (8-15 months) and old (>20 months) mice. However, new spines and EPBs are two to three times more likely to be stabilized over 30 d in old mice, although the long-term retention (over months) of stable spines is lower in old animals. In old mice, spines are smaller on average but are still able to make synaptic connections regardless of their size, as assessed by serial section electron microscopy reconstructions of previously imaged dendrites. Thus, our data suggest that age-related deficits in sensory perception are not associated with synapse loss in somatosensory cortex (as might be expected) but with alterations in the size and stability of spines and boutons observed in this brain area. The changes we describe here likely result in weaker synapses that are less capable of short-term plasticity in aged individuals, and therefore to less efficient circuits. PMID- 23447616 TI - Simultaneous top-down modulation of the primary somatosensory cortex and thalamic nuclei during active tactile discrimination. AB - The rat somatosensory system contains multiple thalamocortical loops (TCLs) that altogether process, in fundamentally different ways, tactile stimuli delivered passively or actively sampled. To elucidate potential top-down mechanisms that govern TCL processing in awake, behaving animals, we simultaneously recorded neuronal ensemble activity across multiple cortical and thalamic areas while rats performed an active aperture discrimination task. Single neurons located in the primary somatosensory cortex (S1), the ventroposterior medial, and the posterior medial thalamic nuclei of the trigeminal somatosensory pathways exhibited prominent anticipatory firing modulations before the whiskers touching the aperture edges. This cortical and thalamic anticipatory firing could not be explained by whisker movements or whisker stimulation, because neither trigeminal ganglion sensory-evoked responses nor EMG activity were detected during the same period. Both thalamic and S1 anticipatory activity were predictive of the animal's discrimination accuracy. Inactivation of the primary motor cortex (M1) with muscimol affected anticipatory patterns in S1 and the thalamus, and impaired the ability to predict the animal's performance accuracy based on thalamocortical anticipatory activity. These findings suggest that neural processing in TCLs is launched in anticipation of whisker contact with objects, depends on top-down effects generated in part by M1 activity, and cannot be explained by the classical feedforward model of the rat trigeminal system. PMID- 23447618 TI - Basolateral amygdala lesions facilitate reward choices after negative feedback in rats. AB - The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) constitute part of a neural circuit important for adaptive, goal-directed learning. One task measuring flexibility of response to changes in reward is discrimination reversal learning. Damage to OFC produces well documented impairments on various forms of reversal learning in rodents, monkeys, and humans. Recent reports show that BLA, though highly interconnected with OFC, may be differentially involved in reversal learning. In the present experiment, we compared the effects of bilateral, ibotenic acid lesions of OFC or BLA (or SHAM) on visual discrimination and reversal learning. Specifically, we used pairwise visual discrimination methods, as is commonly administered in non-human primate studies, and analyzed how animals use positive and negative trial-by-trial feedback, domains not previously explored in a rat study. As expected, OFC lesions displayed significantly slower reversal learning than SHAM and BLA rats across sessions. Rats with BLA lesions, conversely, showed facilitated reversal learning relative to SHAM and OFC groups. Furthermore, a trial-by-trial analysis of the errors committed showed the BLA group benefited more from incorrectly performed trials (or negative feedback) on future choices than either SHAM or OFC rats. This provides evidence that BLA and OFC are involved in updating responses to changes in reward contingency and that the roles are distinct. Our results are discussed in relation to a competitive framework model for OFC and BLA in reward processing. PMID- 23447619 TI - Visual salience improves spatial working memory via enhanced parieto-temporal functional connectivity. AB - In everyday life, the brain is bombarded with a multitude of concurrent and competing stimuli. Only some of these enter consciousness and memory. Attention selects relevant signals for in-depth processing depending on current goals, but also on the intrinsic properties of stimuli. We combined behavior, computational modeling, and functional imaging to investigate mechanisms supporting access to memory based on intrinsic sensory properties. During fMRI scanning, human subjects were presented with pictures of naturalistic scenes that entailed high levels of competition between possible target objects. Following a retention interval of 8 s, participants judged the location (same/different) of a target object extracted from the initial scene. We found that memory performance at retrieval increased with increasing object salience at encoding, indicating a "prior entry" for salient information. fMRI analyses revealed encoding-related activation in the posterior parietal cortex, selectively for salient objects that were later remembered. Moreover, parietal cortex showed increased functional coupling with the medial-temporal lobe, for remembered objects only. These findings reveal a parietotemporal circuit that integrates available sensory cues (based on attention-grabbing saliency signals) and current memory requirements (storing objects' locations) to encode object-related spatial information in working memory. PMID- 23447621 TI - Multimodal convergence within the intraparietal sulcus of the macaque monkey. AB - The parietal cortex is highly multimodal and plays a key role in the processing of objects and actions in space, both in human and nonhuman primates. Despite the accumulated knowledge in both species, we lack the following: (1) a general description of the multisensory convergence in this cortical region to situate sparser lesion and electrophysiological recording studies; and (2) a way to compare and extrapolate monkey data to human results. Here, we use functional magnetic resonance imaging (fMRI) in the monkey to provide a bridge between human and monkey studies. We focus on the intraparietal sulcus (IPS) and specifically probe its involvement in the processing of visual, tactile, and auditory moving stimuli around and toward the face. We describe three major findings: (1) the visual and tactile modalities are strongly represented and activate mostly nonoverlapping sectors within the IPS. The visual domain occupies its posterior two-thirds and the tactile modality its anterior one-third. The auditory modality is much less represented, mostly on the medial IPS bank. (2) Processing of the movement component of sensory stimuli is specific to the fundus of the IPS and coincides with the anatomical definition of monkey ventral intraparietal area (VIP). (3) A cortical sector within VIP processes movement around and toward the face independently of the sensory modality. This amodal representation of movement may be a key component in the construction of peripersonal space. Overall, our observations highlight strong homologies between macaque and human VIP organization. PMID- 23447620 TI - Increased agonist affinity at the MU-opioid receptor induced by prolonged agonist exposure. AB - Prolonged exposure to high-efficacy agonists results in desensitization of the MU opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling; however, the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased after prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa594, was unaffected by similar agonist pretreatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise, the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knock-out animals increased after treatment of the cells with the desensitization protocol. Thus, opioid receptors were "imprinted" with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long-lasting but reversible conformational change in the receptor. PMID- 23447622 TI - Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock. AB - NMDA receptor (NMDAR)-mediated currents depend on membrane depolarization to relieve powerful voltage-dependent NMDAR channel block by external magnesium (Mg(o)(2+)). Mg(o)(2+) unblock from native NMDARs exhibits a fast component that is consistent with rapid Mg(o)(2+) -unbinding kinetics and also a slower, millisecond time scale component (slow Mg(o)(2+) unblock). In recombinant NMDARs, slow Mg(o)(2+) unblock is prominent in GluN1/2A (an NMDAR subtype composed of GluN1 and GluN2A subunits) and GluN1/2B receptors, with slower kinetics observed for GluN1/2B receptors, but absent from GluN1/2C and GluN1/2D receptors. Slow Mg(o)(2+) unblock from GluN1/2B receptors results from inherent voltage-dependent gating, which increases channel open probability with depolarization. Here we examine the mechanisms responsible for NMDAR subtype dependence of slow Mg(o)(2+) unblock. We demonstrate that slow Mg(o)(2+) unblock from GluN1/2A receptors, like GluN1/2B receptors, results from inherent voltage-dependent gating. Surprisingly, GluN1/2A and GluN1/2B receptors exhibited equal inherent voltage dependence; faster Mg(o)(2+) unblock from GluN1/2A receptors can be explained by voltage independent differences in gating kinetics. To investigate the absence of slow Mg(o)(2+) unblock in GluN1/2C and GluN1/2D receptors, we examined the GluN2 S/L site, a site responsible for several NMDAR subtype-dependent channel properties. Mutating the GluN2 S/L site of GluN2A subunits from serine (found in GluN2A and GluN2B subunits) to leucine (found in GluN2C and GluN2D) greatly diminished both voltage-dependent gating and slow Mg(o)(2+) unblock. Therefore, the residue at the GluN2 S/L site governs the expression of both slow Mg(o)(2+) unblock and inherent voltage dependence. PMID- 23447623 TI - Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors. AB - Selective control of receptor trafficking provides a mechanism for remodeling the receptor composition of excitatory synapses, and thus supports synaptic transmission, plasticity, and development. GluN3A (formerly NR3A) is a nonconventional member of the NMDA receptor (NMDAR) subunit family, which endows NMDAR channels with low calcium permeability and reduced magnesium sensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits. Because of these special properties, GluN3A subunits act as a molecular brake to limit the plasticity and maturation of excitatory synapses, pointing toward GluN3A removal as a critical step in the development of neuronal circuitry. However, the molecular signals mediating GluN3A endocytic removal remain unclear. Here we define a novel endocytic motif (YWL), which is located within the cytoplasmic C terminal tail of GluN3A and mediates its binding to the clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motif inhibited clathrin-dependent internalization and led to accumulation of GluN3A-containing NMDARs at the cell surface, whereas mimicking phosphorylation of the tyrosine residue promoted internalization and reduced cell-surface expression as shown by immunocytochemical and electrophysiological approaches in recombinant systems and rat neurons in primary culture. We further demonstrate that the tyrosine residue is phosphorylated by Src family kinases, and that Src-activation limits surface GluN3A expression in neurons. Together, our results identify a new molecular signal for GluN3A internalization that couples the functional surface expression of GluN3A-containing receptors to the phosphorylation state of GluN3A subunits, and provides a molecular framework for the regulation of NMDAR subunit composition with implications for synaptic plasticity and neurodevelopment. PMID- 23447624 TI - Tbr2 expression in Cajal-Retzius cells and intermediate neuronal progenitors is required for morphogenesis of the dentate gyrus. AB - The dentate gyrus (DG) is a unique cortical region whose protracted development spans the embryonic and early postnatal periods. DG development involves large scale reorganization of progenitor cell populations, ultimately leading to the establishment of the subgranular zone neurogenic niche. In the developing DG, the T-box transcription factor Tbr2 is expressed in both Cajal-Retzius cells derived from the cortical hem that guide migration of progenitors and neurons to the DG, and intermediate neuronal progenitors born in the dentate neuroepithelium that give rise to granule neurons. Here we show that in mice Tbr2 is required for proper migration of Cajal-Retzius cells to the DG; and, in the absence of Tbr2, formation of the hippocampal fissure is abnormal, leading to aberrant development of the transhilar radial glial scaffold and impaired migration of progenitors and neuroblasts to the developing DG. Furthermore, loss of Tbr2 results in decreased expression of Cxcr4 in migrating cells, leading to a premature burst of granule neurogenesis during early embryonic development accompanied by increased cell death in mutant animals. Formation of the transient subpial neurogenic zone was abnormal in Tbr2 conditional knock-outs, and the stem cell population in the DG was depleted before proper establishment of the subgranular zone. These studies indicate that Tbr2 is explicitly required for morphogenesis of the DG and participates in multiple aspects of the intricate developmental process of this structure. PMID- 23447625 TI - Layer-specific experience-dependent rewiring of thalamocortical circuits. AB - Thalamocortical circuits are central to sensory and cognitive processing. Recent work suggests that the thalamocortical inputs onto L4 and L6, the main input layers of neocortex, are activated differently by visual stimulation. Whether these differences depend on layer-specific organization of thalamocortical circuits; or on specific properties of synapses onto receiving neurons is unknown. Here we combined optogenetic stimulation of afferents from the visual thalamus and paired recording electrophysiology in L4 and L6 of rat primary visual cortex to determine the organization and plasticity of thalamocortical synapses. We show that thalamocortical inputs onto L4 and L6 differ in synaptic dynamics and sensitivity to visual drive. We also demonstrate that the two layers differ in the organization of thalamocortical and recurrent intracortical connectivity. In L4, a significantly larger proportion of excitatory neurons responded to light activation of thalamocortical terminal fields than in L6. The local microcircuit in L4 showed a higher degree of recurrent connectivity between excitatory neurons than the microcircuit in L6. In addition, L4 recurrently connected neurons were driven by thalamocortical inputs of similar magnitude indicating the presence of local subnetworks that may be activated by the same axonal projection. Finally, brief manipulation of visual drive reduced the amplitude of light-evoked thalamocortical synaptic currents selectively onto L4. These data are the first direct indication that thalamocortical circuits onto L4 and L6 support different aspects of cortical function through layer-specific synaptic organization and plasticity. PMID- 23447626 TI - The perirhinal cortex and recognition memory interference. AB - There has recently been an increase in interest in the effects of visual interference on memory processing, with the aim of elucidating the role of the perirhinal cortex (PRC) in recognition memory. One view argues that the PRC processes highly complex conjunctions of object features, and recent evidence from rodents suggests that these representations may be vital for buffering against the effects of pre-retrieval interference on object recognition memory. To investigate whether PRC-dependent object representations play a similar role in humans, we used functional magnetic resonance imaging to scan neurologically healthy participants while they performed a novel interference-match-to-sample task. This paradigm was specifically designed to concurrently assess the impact of object versus spatial interference, on recognition memory for objects or scenes, while keeping constant the amount of object and scene information presented across all trials. Activity at retrieval was examined, within an anatomically defined PRC region of interest, according to the demand for object or scene memory, following a period of object compared with spatial interference. Critically, we found greater PRC activity for object memory following object interference, compared with object memory following scene interference, and no difference between object and scene interference for scene recognition. These data demonstrate a role for the human PRC during object recognition memory, following a period of object, but not scene interference, and emphasize the importance of representational content to mnemonic processing. PMID- 23447627 TI - Understanding others' feelings: the role of the right primary somatosensory cortex in encoding the affective valence of others' touch. AB - Brain imaging studies in humans have shown the existence of a shared somatosensory representation in the primary somatosensory cortex (S1), putatively involved in understanding others' sensations (Keysers et al., 2010); however, the role of S1 in such a high-level process is still unknown. To ascertain the causal involvement of S1, and its possible hemispheric lateralization, in encoding the affective valence of emotional scenes, depicting, or not, a tactile event, we gave to healthy participants a picture-based affective go/no-go task and low frequency repetitive transcranial magnetic stimulation (rTMS). The dorsolateral prefrontal cortex (DLPFC) was chosen as control site. rTMS over the right, but not the left, S1 selectively increased the participants' latencies in the affective go/no-go task, but only when the affective state was conveyed by touch; intriguingly, this interfering effect was associated with the empathic ability to adopt the subjective perspective of others. The left, not the right, DLPFC is also involved in affective go/no-go performance, but regardless of the sight of touch, and independently of empathic abilities. This novel evidence demonstrates the crossmodal role of right S1 in encoding the pleasant and aversive consequences of others' sensations evoked by touch. PMID- 23447628 TI - Rhes deletion is neuroprotective in the 3-nitropropionic acid model of Huntington's disease. AB - Although the mutated protein causing Huntington's disease (HD) is expressed throughout the body, the major pathology of HD is localized to the striatum of the brain. We previously reported that the striatal-enriched protein Rhes binds the mutated huntingtin protein and enhances its cytotoxicity. We now demonstrate that Rhes-deleted mice are dramatically protected from neurotoxicity and motor dysfunction in a striatal-specific model of HD elicited by 3-nitropropionic acid. This finding suggests that Rhes may, in part, determine the striatal selectivity of HD. PMID- 23447629 TI - Baseline epidemiology and genetic structure of Streptococcus pneumoniae serotype 6D in southern Israel prior to introduction of pneumococcal conjugate vaccines. AB - We characterized Streptococcus pneumoniae serotype 6D from among previously identified S. pneumoniae serotype 6B strains from Jewish and Bedouin children in southern Israel during a decade before vaccination. S. pneumoniae serotype 6D isolates constituted 6.7% of the presumed S. pneumoniae serotype 6B isolates. S. pneumoniae serotype 6D strains belonged to 20 sequence types that were differentially distributed between the two ethnic groups. PMID- 23447630 TI - Mistaken identity of Brucella infection. PMID- 23447631 TI - Optimized method for Acinetobacter species carbapenemase detection and identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - The use of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for rapid detection and identification of the enzymes responsible for carbapenem resistance in Acinetobacter spp. appears as a promising option, but it will be necessary to have a standardized protocol that facilitates routine use. Based on the results reported herein and comparisons of several previously published reports, we identified the significant peaks for imipenem detection. Optimal bacterial inoculum and incubation time were established, and results obtained with and without dipicolinic acid (DPA) and Zn(2+) allowed us to distinguish between metallo-beta-lactamases and oxacillinases. PMID- 23447632 TI - Multiple human papillomavirus infections with high viral loads are associated with cervical lesions but do not differentiate grades of cervical abnormalities. AB - Multiple human papillomavirus (HPV) genotypes often coexist within cervical epithelia and are frequently detected together in smears of different grades of cervical neoplasia. Describing the association between multiple infections and cervical disease is important in generating hypotheses regarding its pathogenesis. We analyzed the prevalence of multiple HPV infections and their attribution to cervical disease in a screening population of 999 consecutive BD SurePath liquid-based cervical cytology samples enriched with atypical squamous cells of undetermined significance (ASCUS) (n = 100), low-grade squamous intraepithelial lesions (LSIL) (n = 100), and high-grade squamous intraepithelial lesions (HSIL) (n = 97). HPV genotyping was performed only on cytology specimens using a broad-spectrum GP5(+)/6(+)-PCR/multiplex HPV genotyping (BSGP5(+)/6(+) PCR/MPG) assay that detects and quantifies 51 HPV genotypes and 3 subtypes. Using a recently defined high viral load cutoff, the quantitative data were scored as high or low viral load. In the 36-month follow-up, 79 histologically confirmed cervical intraepithelial neoplasia grade 2 or greater (CIN2+) cases were identified. In the screening population, there was a trend of having more multiple infections at a younger age. Multiple HPV infections were common. Multiple HPV types were most prevalent in LSIL (75.9% of HPV positives), followed by HSIL (65.5%), ASCUS (64.6%), and negative for intraepithelial lesion or malignancy (NILM) (36.8%). On average, 3.2 and 2.5 HPV types were detected per LSIL and HSIL sample, respectively. Multiple HPV types with high viral loads were most prevalent in LSIL (62.6% of high viral load positives), followed by HSIL (51.9%), ASCUS (40.7%), and NILM (19.3%). Patients with multiple high viral loads showed a 4- to 6-fold-higher risk of having cervical precancerous cytological lesions than did patients with single high viral loads. Compared to NILM, multiple infections, especially with multiple high viral loads, were significantly associated with cytological precancerous lesions. However, the presence of multiple infections did not distinguish low-grade from high-grade cytological lesions. PMID- 23447633 TI - Suspected goat-to-human transmission of methicillin-resistant Staphylococcus aureus sequence type 398. AB - Transmission of methicillin-resistant Staphylococcus aureus (MRSA) between animals and humans is widely recognized. In this study, we describe the first case of infection of a goat and suspected transmission of MRSA ST398 to a human, which resulted in colonization of animal owners by MRSA sequence type 398. PMID- 23447634 TI - Comparative evaluation of conventional and real-time PCR assays for detecting Bacteroides fragilis in clinical samples. AB - A conventional PCR and a real-time PCR for detecting Bacteroides fragilis were evaluated against clinical specimens. Analytical sensitivities were 100 and 40 fg of DNA, respectively. Detection limits were 100 and 10 CFU/ml, respectively. A total of six culture-negative specimens were positive by PCR. Altering the gold standard from "positive culture" to "positive culture or both PCR assays positive" resulted in sensitivities of 91.7% and 100%, respectively, and in specificities of 100% and 98.6%, respectively. PMID- 23447635 TI - Importance of using Bruker's security-relevant library for Biotyper identification of Burkholderia pseudomallei, Brucella species, and Francisella tularensis. PMID- 23447636 TI - Kingella kingae keratitis. AB - We present the first two cases of Kingella kingae keratitis in adults. This species is a rare isolate from ophthalmic samples for which final identification was obtained with matrix-assisted laser desorption ionization-time of flight mass spectrometry. One of the patients recovered uneventfully with topical therapy. Results from the second patient cannot be confirmed as he was lost to follow-up. PMID- 23447637 TI - PCR-reverse blot hybridization assay for screening and identification of pathogens in sepsis. AB - Rapid and accurate identification of the pathogens involved in bloodstream infections is crucial for the prompt initiation of appropriate therapy, as this can decrease morbidity and mortality rates. A PCR-reverse blot hybridization assay for sepsis, the reverse blot hybridization assay (REBA) Sepsis-ID test, was developed; it uses pan-probes to distinguish Gram-positive and -negative bacteria and fungi. In addition, the assay was designed to identify bacteria and fungi using six genus-specific and 13 species-specific probes; it uses additional probes for antibiotic resistance genes, i.e., the mecA gene of methicillin resistant Staphylococcus aureus (MRSA) and the vanA and vanB genes of vancomycin resistant enterococci (VRE). The REBA Sepsis-ID test successfully identified clinical isolates and blood culture samples as containing Gram-positive bacteria, Gram-negative bacteria, or fungi. The results matched those obtained with conventional microbiological methods. For the REBA Sepsis-ID test, of the 115 blood culture samples tested, 47 (40.8%) and 49 (42.6%) samples were identified to the species and genus levels, respectively, and the remaining 19 samples (16.5%), which included five Gram-positive rods, were identified as Gram-positive bacteria, Gram-negative bacteria, or fungi. The antibiotic resistances of the MRSA and VRE strains were identified using both conventional microbiological methods and the REBA Sepsis-ID test. In conclusion, the REBA Sepsis-ID test developed for this study is a fast and reliable test for the identification of Gram-positive bacteria, Gram-negative bacteria, fungi, and antibiotic resistance genes (including mecA for MRSA and the vanA and vanB genes for VRE) in bloodstream infections. PMID- 23447639 TI - Multicenter clinical evaluation of the illumigene group A Streptococcus DNA amplification assay for detection of group A Streptococcus from pharyngeal swabs. AB - Acute pharyngitis is a nonspecific symptom that can result from a number of viral or bacterial infections. For most etiologies, symptoms are self-limited and resolve without lasting effects; however, pharyngitis resulting from infection with Streptococcus pyogenes (a group A Streptococcus [GAS]) can be associated with serious sequelae, including acute rheumatic fever and acute glomerulonephritis. Rapid accurate detection of GAS in pharyngeal specimens from individuals suffering from pharyngitis aids in the management and selection of antibiotic therapy for these patients. A total of 796 pharyngeal swabs were collected at three separate clinical centers. Each specimen was analyzed using the illumigene group A strep DNA amplification assay (Meridian Bioscience Inc., Cincinnati, OH). To confirm GAS identification, the results were compared to those from direct and extracted culture methods using Gram staining and a GAS specific latex agglutination test. Discrepant results were resolved using an alternative nucleic acid amplification test. The prevalence of culture-detected GAS in this study was 12.8% (102/796 specimens). The illumigene assay detected GAS in 74/74 direct culture-positive specimens (100% sensitivity) and 100/102 extracted culture-positive specimens (98.0% sensitivity). GAS was detected by the illumigene assay in an additional 42 specimens that were direct culture negative (94.2% specificity) and 16 specimens that were extracted culture negative (97.7% specificity). Discrepant analysis using an alternative molecular assay detected GAS nucleic acid in 13/16 (81.3%) false-positive specimens and 1/2 false-negative specimens, resulting in a final sensitivity of 99.0% and a specificity of 99.6% for the detection of GAS in pharyngeal swabs using the illumigene assay. PMID- 23447638 TI - Epidemiology of Clostridium difficile infection and risk factors for unfavorable clinical outcomes: results of a hospital-based study in Barcelona, Spain. AB - Prospective hospital-based surveillance for Clostridium difficile-associated disease (CDAD) was conducted in Barcelona (Spain) to describe the epidemiology of this condition and investigate the risk factors for an unfavorable outcome. All patients diagnosed with CDAD during 2009 were included. Using logistic regression modeling, we analyzed the potential risk factors associated with recurrent and complicated CDAD, defined as a need for colectomy or death within 30 days. There were 365 episodes of CDAD, yielding an incidence of 22.5 cases/10(5) person years, 1.22 cases/10(3) hospital discharges, and 1.93 cases/10(4) patient-days. The main PCR ribotypes identified were 241 (26%), 126 (18%), 078 (7%), and 020 (5%). PCR ribotype 027 was not detected. Among the 348 cases analyzed, 232 (67%) patients were cured, 63 (18%) had a recurrence of CDAD, and 53 (15%) developed complicated CDAD. Predictors of complicated CDAD were continued use of antibiotics following CDAD diagnosis (odds ratio [OR], 2.009; 95% confidence interval [CI], 1.012 to 3.988; P = 0.046), Charlson comorbidity index score (OR, 1.265; 95% CI, 1.105 to 1.449; P = 0.001), and age (OR, 1.028; 95% CI, 1.005 to 1.053; P = 0.019). A leukocyte count of >15 * 10(3) cells/ml (OR, 2.277; 95% CI, 1.189 to 4.362; P = 0.013), continuation of proton pump inhibitor (PPI) use after CDAD diagnosis (OR, 2.168; 95% CI, 1.081 to 4.347; P = 0.029), and age (OR, 1.021; 95% CI, 1.001 to 1.041; P = 0.036) were independently associated with higher odds of recurrence. The incidence of CDAD in Barcelona during 2009 was on the lower end of the previously described range for all of Europe. Our analysis suggests that the continuation of non-C. difficile antibiotics and use of PPIs in patients diagnosed with CDAD are associated with unfavorable clinical outcomes. PMID- 23447640 TI - Development and characterization of the cobas human papillomavirus test. AB - The cobas human papillomavirus (HPV) test, approved by the FDA in April 2011, is a fully automated assay for the detection of 14 high-risk (hr) HPV genotypes from cervical specimens collected in liquid-based cytology medium using real-time PCR amplification of the L1 gene and TaqMan probes. Results are simultaneously reported as positive or negative for the pooled 12 oncogenic HPV types (HPV31, 33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68) from channel 1, with HPV16 and HPV18 genotypes read individually from channels 2 and 3. A fourth channel detects the human beta-globin gene as a control for sample adequacy and assay inhibition. To optimize clinical sensitivity and specificity, cutoff values (cycle thresholds [C(T)]) were established for each channel based on the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or greater (>=CIN2). For women aged >=21 years with cytology results indicating atypical squamous cells of undetermined significance (ASC-US), CT values provided a sensitivity of 90% (95% confidence interval [CI], 81.5% to 94.8%) for the detection of >=CIN2 and a specificity of 70.5% (95% CI, 68.1% to 72.7%). The analytic sensitivity (limit of detection) ranged from 150 to 2,400 copies/ml, depending on genotype. The analytic specificity, evaluated by comparing the HPV result with a combined comparator of Sanger sequencing and the Qiagen digene HC2 high-risk HPV DNA test (hc2), demonstrated overall positive agreement of 96.3% for 14 hrHPV types in women with ASC-US cytology results who were aged >=21 years and 86.1% in women with NLIM (negative for intraepithelial neoplasia or malignancy) cytology who were aged >=30 years. These and other performance validation studies demonstrate that the cobas HPV test is a fully automated and clinically validated robust test. PMID- 23447641 TI - Can molecular methods detect 1% isoniazid resistance in Mycobacterium tuberculosis? AB - Patients may harbor both drug-susceptible and -resistant bacteria, representing heteroresistance. We studied mixtures of isoniazid-resistant and -susceptible Mycobacterium tuberculosis strains. Conventional drug susceptibility testing was the most sensitive method of detection, whereas the line probe assay and sequencing were not able to detect the clinically relevant 1% proportion of resistant bacteria. PMID- 23447643 TI - Anti-KCNQ1 K+ channel autoantibodies increase IKs current and are associated with QT interval shortening in dilated cardiomyopathy. AB - AIMS: Autoimmune-associated proarrhythmia in dilated cardiomyopathy (DCM) is poorly understood. Given the significance of KCNQ1 potassium channels in heart rhythm disorders, we hypothesized that circulating anti-KCNQ1 autoantibodies directly modulate cardiac electrophysiology in DCM patients. The purpose of this pilot study was to characterize ion channel autoantibodies in DCM targeting the cardiac repolarizing K(+) current, IKs, and the underlying KCNQ1 potassium channel. METHODS AND RESULTS: One hundred and fifty DCM patients were screened for anti-KCNQ1 autoantibodies using an enzyme-linked immunosorbent assay. Autoantibodies targeting the extracellular pore domain of the KCNQ1 channel were detected in 6% of study patients. Seropositive individuals exhibited significantly shorter corrected QT intervals when compared with seronegative patients (371 +/- 39.9 ms vs. 408 +/- 47.9 ms; P = 0.036). There was no difference in clinical severity of heart failure between groups. The functional significance of anti-KCNQ1 antibodies was determined in human embryonic kidney 293 cells expressing KCNQ1/KCNE1 using the whole-cell patch clamp technique. IKs recordings demonstrated a 2.7-fold increase in mean current density on exposure to patients' sera containing anti-KCNQ1 antibodies in contrast to seronegative controls (8.74 +/- 1.44 pA/pF vs. 3.26 +/- 0.36 pA/pF; P = 0.003). IKs enhancement was not associated with increased KCNQ1 protein levels or altered cell surface expression of the channel. CONCLUSION: Anti-KCNQ1 autoantibodies found in a subgroup of DCM patients are associated with QT interval shortening and increased IKs current. PMID- 23447642 TI - miR-424/322 regulates vascular smooth muscle cell phenotype and neointimal formation in the rat. AB - AIMS: Our aim was to identify new microRNAs (miRNAs) implicated in pathological vascular smooth muscle cells (VSMCs) proliferation and characterize their mechanism of action. METHODS AND RESULTS: MicroRNAs microarray and qRT-PCR results lead us to focus on miR-424 or its rat ortholog miR-322 (miR-424/322). In vitro mir-424/322 level was decreased shortly after the induction of proliferation and increased in a time-dependent manner later on. In vivo its expression increased in the rat carotid artery from Day 4 up to Day 30 after injury. miR-424/322 overexpression in vitro inhibited proliferation and migration without affecting apoptosis and prevented VSMC dedifferentiation. Furthermore, miR-424/322 overexpression resulted in decreased expression of its predicted targets: cyclin D1 and Ca(2+)-regulating proteins calumenin and stromal interacting molecule 1 (STIM1). Using reporter luciferase assays, we confirmed that cyclin D1 and calumenin mRNAs were direct targets of miR-322, whereas miR 322 effect on STIM1 was indirect. Nevertheless, consistent with the decreased STIM1 level, the store-operated Ca(2+) entry was reduced. We hypothesized that miR-424/322 could be a negative regulator of proliferation overridden in pathological situations. Thus, we overexpressed miR-424/322 in injured rat carotid arteries using an adenovirus, and demonstrated a protective effect against restenosis. CONCLUSION: Our results demonstrate that miR-424/322 is up regulated after vascular injury. This is likely an adaptive response to counteract proliferation, although this mechanism is overwhelmed in pathological situations such as injury-induced restenosis. PMID- 23447644 TI - Extracellular HSP60 induces inflammation through activating and up-regulating TLRs in cardiomyocytes. AB - AIMS: The molecular events leading from cardiomyocyte ischaemia to inflammatory cytokine production are not well understood. We previously found that heat shock protein 60 (HSP60) appeared in extracellular space after cardiomyocyte ischaemia. This study examined the activation and regulation of toll-like receptors (TLRs) by HSP60 in cardiomyocytes. METHODS AND RESULTS: Cytokine production and TLRs regulation mediated by TLRs signalling were examined in response to exogenous HSP60 (exHSP60) and endogenous HSP60 (enHSP60) released extracellularly under ischaemia. The results showed that exHSP60 induced inflammatory cytokine production in adult rat cardiomyocytes and H9c2 cells (a standard cardiac cell line derived from embryonic cells), through a pathway dependent on TLR4, myeloid differentiation factor 88 (MyD88), p38, and nuclear factor-kappaB (NF-kappaB). Further study revealed up-regulated expression of both TLR2 and TLR4 by exHSP60, which was dependent on the activation of TLR4, MyD88, c-Jun NH2-terminal kinase (JNK), and NF-kappaB, but not on p38. In myocytes exposed to ischaemia, enHSP60 was released into the media, and triggered cytokine production and TLR2/4 overexpression, through the same pathways as exHSP60. In rats subjected to LAD ligation, the released enHSP60 contributed to cytokine production and TLR2/4 overexpression in the ischaemic myocardium. CONCLUSION: Extracellular HSP60 induces cytokine production via TLR4-MyD88-p38/NF-kappaB pathway, and up regulates TLR2/4 expression via TLR4-MyD88-JNK/NF-kappaB pathway. Both pathways contribute to myocardial inflammation induced by ischaemia. PMID- 23447645 TI - Impacts of alcohol duty reductions on cardiovascular mortality among elderly Chinese: a 10-year time series analysis. AB - BACKGROUND: In March 2007, the Hong Kong Government halved its heavy excise taxes on beer and wine, and 1 year later, it eliminated all duties on these beverages. This study examines the impact of such duty reductions on cardiovascular disease (CVD)-related mortality among the elderly in Hong Kong. METHODS: Box-Jenkins autoregressive integrated moving average intervention time series analyses were applied to monthly morality data from 2001 to 2010 to quantify the impacts of duty reduction and exemption on CVD death rates among those aged 65 years or older. RESULTS: The alcohol duty reduction in March 2007 was associated with an estimated 13% increase (95% CI 2% to 24%) in CVD death rates among elderly men, after controlling for the other intervention, outlier, trends and seasonal variations. This was equivalent to an extra 11 CVD deaths per 100 000 elderly men each month. Much of the observed impacts on CVD death rates were found to have contributed only by that on ischaemic heart disease mortality (18% increase in rate for men (95% CI 4% to 34%); 15% increase for women (95% CI 0.4% to 31%)), not by mortality due to stroke or hypertension. The alcohol duty exemption on March 2008 was not found to have impacted the CVD death rates. CONCLUSIONS: The increase in CVD death rates among the Chinese elderly after alcohol duty reduction suggest that the purported beneficial effect of moderate alcohol use may not apply to certain Chinese populations, adding fuel to the ongoing debate on the risks and benefits of moderate alcohol consumption on mortality. PMID- 23447646 TI - Regulating and inspecting working conditions could be good for both workers and business. PMID- 23447647 TI - Influence of room heating on ambulatory blood pressure in winter: a randomised controlled study. AB - BACKGROUND: Previous studies have proposed that higher blood pressure (BP) in winter is an important cause of increased mortality from cardiovascular disease during the winter. Some observational and physiological studies have shown that cold exposure increases BP, but evidence from a randomised controlled study assessing the effectiveness of intensive room heating for lowering BP was lacking. OBJECTIVES: The present study aimed to determine whether intensive room heating in winter decreases ambulatory BP as compared with weak room heating resulting in a 10 degrees C lower target room temperature when sufficient clothing and bedclothes are available. METHODS: We conducted a parallel group, assessor blinded, simple randomised controlled study with 1:1 allocation among 146 healthy participants in Japan from November 2009 to March 2010. Ambulatory BP was measured while the participants stayed in single experimental rooms from 21:00 to 8:00. During the session, participants could adjust the amount of clothing and bedclothes as required. Compared with the weak room heating group (mean temperature +/- SD: 13.9 +/- 3.3 degrees C), systolic morning BP (mean BP 2 h after getting out of bed) of the intensive room heating group (24.2 +/- 1.7 degrees C) was significantly lower by 5.8 mm Hg (95% CI 2.4 to 9.3). Sleep-trough morning BP surges (morning BP minus lowest night-time BP) in the intensive room heating group were significantly suppressed to about two thirds of the values in the weak room heating group (14.3 vs 21.9 mm Hg; p<0.01). CONCLUSIONS: Intensive room heating decreased morning BP and the morning BP surge in winter. PMID- 23447648 TI - Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson's disease. AB - BACKGROUND: Behavioural disorders associated with compulsive use of dopaminergic drugs for Parkinson's disease (PD) such as dopamine dysregulation syndrome (DDS) and impulse control disorders (ICDs) may have devastating consequences and are challenging to manage. Whether or not such patients should undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is controversial. A few case reports and small series have reported contrasting effects of STN DBS on dopamine misuse and ICDs, while a recent prospective study found clear beneficial effects of STN DBS on these disorders. METHODS: We conducted an observational study on 110 consecutive parkinsonian patients scheduled for STN DBS surgery. Patients were assessed preoperatively through extensive behavioural and psychiatric evaluations and divided into two groups: with or without compulsive dopaminergic medication use. Evaluations were repeated 1 year after surgery in both groups. RESULTS: Before surgery 18 patients (16.3%) were compulsive dopamine users of whom 12 (10.9%) fulfilled all criteria for DDS. 90% of these patients also had at least one ICD compared to 20% in the group without compulsive dopamine use. One year after surgery, one patient had persistent compulsive dopamine use, while no new occurrences were reported in the group without the condition before surgery. STN DBS did not provoke any major psychiatric complications and ICDs were reduced in all patients. CONCLUSIONS: Our results suggest that STN DBS may reduce compulsive use of dopaminergic medication and its behavioural consequences. Whether this improvement is the result of STN DBS or the consequence of better treatment management remains to be established. PMID- 23447649 TI - Increased premorbid physical activity and amyotrophic lateral sclerosis: born to run rather than run to death, or a seductive myth? PMID- 23447650 TI - Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1. AB - BACKGROUND: A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement. METHODS: We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations. RESULTS: Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present. CONCLUSIONS: These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype. PMID- 23447651 TI - Neurological pictures. Trigeminalepsy. PMID- 23447652 TI - Design and properties of efficient tRNA:EF-Tu FRET system for studies of ribosomal translation. AB - Formation of the ternary complex between GTP-bound form of elongation factor Tu (EF-Tu) and aminoacylated transfer RNA (aa-tRNA) is a key event in protein biosynthesis. Here we show that fluorescently modified Escherichia coli EF-Tu carrying three mutations, C137A, C255V and E348C, and fluorescently modified Phe tRNA(Phe) form functionally active ternary complex that has properties similar to those of the naturally occurring (unmodified) complex. Similarities include the binding and binding rate constants, behavior in gel retardation assay, as well as activities in tRNA protection and in vitro translation assays. Proper labeling of EF-Tu was demonstrated in MALDI mass spectroscopy experiments. To generate the mutant EF-Tu, a series of genetic constructions were performed. Two native cysteine residues in the wild-type EF-Tu at positions 137 and 255 were replaced by Ala and Val, respectively, and an additional cysteine was introduced either in position 324 or 348. The assembly FRET assay showed a 5- to 7-fold increase of Cy5-labeled EF-Tu E348C mutant fluorescence upon formation of ternary complex with charged tRNA(Phe)(Cy3-labeled) when the complex was excited at 532 nm and monitored at 665 nm. In a control experiment, we did not observe FRET using uncharged tRNA(Phe)(Cy3), nor with wild-type EF-Tu preparation that was allowed to react with Cy5 maleimide, nor in the absence of GTP. The results obtained demonstrate that the EF-Tu:tRNA FRET system described can be used for investigations of ribosomal translation in many types of experiments. PMID- 23447653 TI - Predictive value of intratumoral 99mTc-macroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y microspheres. AB - (90)Y radioembolization is a promising therapy for patients with primary and secondary liver malignancies. Pretherapeutic assessment consists of hepatic angiography and (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) perfusion scintigraphy to estimate the liver-to-lung shunt and exclude extrahepatic (99m)Tc MAA deposition. However, the predictive value of intratumoral (99m)Tc-MAA uptake remains unclear. METHODS: One hundred four patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer were treated with (90)Y radioembolization between December 2006 and December 2010. All of the patients underwent angiographic assessment and perfusion scintigraphy with (99m)Tc-MAA before lobar (90)Y radioembolization. For inclusion, patients must have undergone pretherapeutic and follow-up MR imaging (6 wk and 3 mo after radioembolization, respectively). The degree of intratumoral (99m)Tc-MAA uptake was rated, and liver metastases were classified according to changes in tumor diameter on both an individual and a patient basis using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response at both time points, MAA uptake, and catheter position were then statistically analyzed in a linear and generalized linear mixed model at a significance level of 0.05 (P value). RESULTS: Sixty-six patients with a total of 435 colorectal liver metastases (mean number of lesions +/- SD, 6.6 +/- 2.8; mean lesion size +/- SD, 33.8 +/- 21.2 mm; lesion size range, 10-154 mm) were included in this analysis. According to the patient-based analysis, 3 patients had partial response, 49 stable disease, and 6 progressive disease after 6 wk. After 3 mo, 5 patients showed partial response, 26 stable disease, and 17 progressive disease. There was no association of patient-based tumor response with overall (99m)Tc-MAA uptake (P = 0.172) or with catheter position (P = 0.6456). Furthermore, an interaction effect of (99m)Tc-MAA uptake and catheter position in relation to tumor response was not found (P = 0.512). Moreover, in lesion-based analysis according to RECIST 1.1 there was no association of tumor response with degree of (99m)Tc-MAA uptake, catheter position, or interaction of (99m)Tc-MAA uptake and catheter position (P = 0.339, 0.593, and 0.658, respectively). CONCLUSION: Response to (90)Y radioembolization was found to be independent of the degree of (99m)Tc-MAA uptake. Therefore, therapy should not be withheld from patients with colorectal liver metastases lacking intratumoral (99m)Tc-MAA accumulation. PMID- 23447654 TI - SPECT imaging of joint inflammation with Nanobodies targeting the macrophage mannose receptor in a mouse model for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease occurring in approximately 1% of the worldwide population. The disease primarily affects the joints, where inflammatory cells, such as macrophages, invade the synovium and cause cartilage and bone destruction. Currently, it is difficult to efficiently diagnose and monitor early-stage RA. In this study, we investigated whether SPECT/micro-CT imaging with (99m)Tc-labeled Nanobodies directed against the macrophage mannose receptor (MMR) is a useful tool for monitoring and quantifying joint inflammation in collagen-induced arthritis (CIA), a mouse model for RA. The expression of MMR was analyzed on macrophages and osteoclasts generated in vitro and in cells obtained from various organs from mice with CIA. METHODS: CIA was induced in DBA/1 mice by injection of collagen type II in complete Freund adjuvant, and cell suspensions from the inflamed joints and other organs were obtained. Macrophages and osteoclasts were generated in vitro from bone marrow cells. Expression of MMR was quantified by quantitative polymerase chain reaction and flow cytometry with specific Nanobodies and conventional antibodies. SPECT/micro-CT imaging was performed with (99m)Tc-labeled MMR and control Nanobodies. RESULTS: MMR was highly expressed on macrophages and to a lesser extent on osteoclasts generated in vitro. In mice with CIA, MMR expression was detected on cells from the bone marrow, lymph nodes, and spleen. In synovial fluid of arthritic joints, MMR was expressed on CD11b(+)F4/80(+) macrophages. On in vivo SPECT/micro-CT imaging with consecutive injections of MMR and control Nanobodies, a strong MMR signal was seen in the knees, ankles, and toes of arthritic mice. Quantification of the SPECT imaging confirmed the specificity of the MMR signal in inflamed joints as compared with the control Nanobody. Dissection of the paws revealed an additional significant MMR signal in nonarthritic paws of affected mice (i.e., mice displaying symptoms of arthritis in other paws). CONCLUSION: Our data show that MMR is expressed on macrophages in vitro and in vivo in synovial fluid of inflamed paws, whereas expression is relatively low in other tissues. The use of Nanobodies against MMR in SPECT/micro CT imaging generates the possibility to track inflammatory cells in vivo in arthritic joints. PMID- 23447655 TI - Multimodal fluorescence-mediated tomography and SPECT/CT for small-animal imaging. AB - Spatial and temporal coregistration of nuclear and optical images can enable the fusion of the information from these complementary molecular imaging modalities. A critical challenge is in integrating the optical and nuclear imaging hardware. Flexible fiber-based fluorescence-mediated tomography (FMT) systems provide a viable solution. The various bore sizes of small-animal nuclear imaging systems can potentially accommodate the FMT fiber imaging arrays. In addition, FMT imaging facilitates coregistration of the nuclear and optical contrasts in time. Herein, we combine a fiber-based FMT system with a preclinical SPECT/CT platform. Feasibility of in vivo imaging is demonstrated by tracking a monomolecular multimodal imaging agent (MOMIA) during transport from the forepaw to the axillary lymph node region of a rat. METHODS: The fiber-based, video-rate FMT imaging system is composed of 12 sources (785- and 830-nm laser diodes) and 13 detectors. To maintain high temporal sampling, the system simultaneously acquires ratio-metric data at each detector. A 3-dimensional finite element model derived from CT projections provides anatomically based light propagation modeling. Injection of a MOMIA intradermally into the forepaw of rats provided spatially and temporally coregistered nuclear and optical contrasts. FMT data were acquired concurrently with SPECT and CT data. The incorporation of SPECT data as a priori information in the reconstruction of FMT data integrated both optical and nuclear contrasts. RESULTS: Accurate depth localization of phantoms with different thicknesses was accomplished with an average center-of-mass error of 4.1 +/- 2.1 mm between FMT and SPECT measurements. During in vivo tests, fluorescence and radioactivity from the MOMIA were colocalized in spatially coincident regions with an average center-of-mass error of 2.68 +/- 1.0 mm between FMT and SPECT for axillary lymph node localization. Intravital imaging with surgical exposure of the lymph node validated the localization of the optical contrast. CONCLUSION: The feasibility of integrating a fiber-based, video-rate FMT system with a commercial preclinical SPECT/CT platform was established. These coregistered FMT and SPECT/CT results with MOMIAs may facilitate the development of the next generation of preclinical and clinical multimodal optical-nuclear platforms for a broad array of imaging applications and help elucidate the underlying biologic processes relevant to cancer diagnosis and therapy monitoring. PMID- 23447656 TI - Multisoftware reproducibility study of stress and rest myocardial blood flow assessed with 3D dynamic PET/CT and a 1-tissue-compartment model of 82Rb kinetics. AB - Routine quantification of myocardial blood flow (MBF) requires robust and reproducible processing of dynamic image series. The goal of this study was to evaluate the reproducibility of 3 highly automated software programs commonly used for absolute MBF and flow reserve (stress/rest MBF) assessment with (82)Rb PET imaging. METHODS: Dynamic rest and stress (82)Rb PET scans were selected in 30 sequential patient studies performed at 3 separate institutions using 3 different 3-dimensional PET/CT scanners. All 90 scans were processed with 3 different MBF quantification programs, using the same 1-tissue-compartment model. Global (left ventricle) and regional (left anterior descending, left circumflex, and right coronary arteries) MBF and flow reserve were compared among programs using correlation and Bland-Altman analyses. RESULTS: All scans were processed successfully by the 3 programs, with minimal operator interactions. Global and regional correlations of MBF and flow reserve all had an R(2) of at least 0.92. There was no significant difference in flow values at rest (P = 0.68), stress (P = 0.14), or reserve (P = 0.35) among the 3 programs. Bland-Altman coefficients of reproducibility (1.96 * SD) averaged 0.26 for MBF and 0.29 for flow reserve differences among programs. Average pairwise differences were all less than 10%, indicating good reproducibility for MBF quantification. Global and regional SD from the line of perfect agreement averaged 0.15 and 0.17 mL/min/g, respectively, for MBF, compared with 0.22 and 0.26, respectively, for flow reserve. CONCLUSION: The 1-tissue-compartment model of (82)Rb tracer kinetics is a reproducible method for quantification of MBF and flow reserve with 3-dimensional PET/CT imaging. PMID- 23447657 TI - Assessment of the global trigger tool to measure, monitor and evaluate patient safety in cancer patients: reliability concerns are raised. AB - BACKGROUND: Countries around the world are currently aiming to improve patient safety by means of the Institute for Healthcare Improvement global trigger tool (GTT), which is considered a valid tool for evaluating and measuring patient safety within organisations. So far, only few data on the measurement properties and utility of the GTT have been published. AIMS: To determine and evaluate the effect of interrater variation between review teams on the standard outcome measures of the GTT and to assess and quantify measurement error of the GTT. METHODS: Retrospective chart reviews were conducted on identical charts by two independent review teams in 2010 at a department of oncology in a university hospital. Standard GTT outcome measurements were obtained and compared between teams using statistical process control (SPC) charts. A Bland-Altman plot assessed measurement error and limits of agreement. RESULTS: Only 31% of adverse events (AE) were identified by both teams, and further differences in categorisation of identical events was found. Moderate interrater agreement (kappa=0.45) between teams gave rise to different conclusions on the patient safety process when monitoring using SPC charts. The Bland-Altman plot suggests little systematic error but large random error. CONCLUSIONS: Review teams may identify different AE and reach different conclusions on the safety process when using the GTT on identical charts. Tracking true change in the safety level is difficult due to measurement error of the GTT. The results do not encourage further use of the GTT until additional evaluation studies on the measurement properties of the GTT have been conducted. PMID- 23447658 TI - Developing a patient measure of safety (PMOS). AB - BACKGROUND: Tools that proactively identify factors that contribute to accidents have been developed within high-risk industries. Although patients provide feedback on their experience of care in hospitals, there is no existing measure which asks patients to comment on the factors that contribute to patient safety incidents. The aim of the current study was to determine those contributory factors from the Yorkshire Contributory Factors Framework (YCFF) that patients are able to identify in a hospital setting and to use this information to develop a patient measure of safety (PMOS). METHODS: Thirty-three qualitative interviews with a representative sample of patients from six units in a teaching hospital in the north of England were carried out. Patients were asked either to describe their most recent/current hospital experience (unstructured) or were asked to describe their experience in relation to specific contributory factors (structured). Responses were coded using the YCFF. Face validity of the PMOS was tested with 12 patients and 12 health professionals, using a 'think aloud' approach, and appropriate revisions made. The research was supported by two patient representatives. RESULTS: Patients were able to comment on/identify 13 of the 20 contributory factors contained within the YCFF domains. They identified contributory factors relating to communication and individual factors more frequently, and contributory factors relating to team factors, and support from central functions less frequently. In addition, they identified one theme not included in the YCFF: dignity and respect. The draft PMOS showed acceptable face validity. DISCUSSION: Patients are able to identify factors which contribute to the safety of their care. The PMOS provides a way of systematically assessing these and has the potential to help health professionals and healthcare organisations understand and identify, safety concerns from the patients' perspective, and, in doing so, make appropriate service improvements. PMID- 23447659 TI - To what extent are inpatient deaths preventable? PMID- 23447660 TI - The pathophysiology of elevated vitamin B12 in clinical practice. AB - Hypercobalaminemia (high serum vitamin B12 levels) is a frequent and underestimated anomaly. Clinically, it can be paradoxically accompanied by signs of deficiency, reflecting a functional deficiency linked to qualitative abnormalities, which are related to defects in tissue uptake and action of vitamin B12. The aetiological profile of high serum cobalamin predominantly encompasses severe disease entities for which early diagnosis is critical for prognosis. These entities are essentially comprised of solid neoplasms, haematological malignancies and liver and kidney diseases. This review reflects the potential importance of the vitamin B12 assay as an early diagnostic marker of these diseases. A codified approach is needed to determine the potential indications of a search for high serum cobalamin and the practical clinical strategy to adopt upon discovery of elevated cobalamin levels. While low serum cobalamin levels do not necessarily imply deficiency, an abnormally high serum cobalamin level forms a warning sign requiring exclusion of a number of serious underlying pathologies. Functional cobalamin deficiency can thus occur at any serum level. PMID- 23447661 TI - Raising the 'dead' - reperfusion from Torpor. PMID- 23447662 TI - Neglected losses and key costs: tracking the energetics of walking and running. AB - As one of the most energetically demanding daily activities, locomotion has attracted substantial investigative attention. Although legged locomotion has been well described, it is currently not well understood. Looking at energy accounting might be a good pathway with which to solve this problem. One relatively simple way of analyzing energy management is to look directly at the flow of mechanical energy into and out of the system, in terms of costs and losses (with some attention to the mechanisms responsible for this flow). In this commentary we argue that a key source of energetic loss has largely been neglected: the redirection of body motion from downward to upward at each step. We discuss the role of this loss and the compensating energetic costs, identifying some of the general features of the trade-offs that determine gait optimization strategies. We find that even at a conceptual level, a focus on the main mechanism of loss and the strategies available to the organism to effectively compensate for losses can yield substantial insight into observations as diverse as the functional limits of a playground swing through to the strikingly different effect of reduced gravity on human walking and running. Such insight changes the interpretation of fundamental features of leg function, such as push-off timing and the role of elastic deflection during stance. PMID- 23447663 TI - Maggot learning and Synapsin function. AB - Drosophila larvae are focused on feeding and have few neurons. Within these bounds, however, there still are behavioural degrees of freedom. This review is devoted to what these elements of flexibility are, and how they come about. Regarding odour-food associative learning, the emerging working hypothesis is that when a mushroom body neuron is activated as a part of an odour-specific set of mushroom body neurons, and coincidently receives a reinforcement signal carried by aminergic neurons, the AC-cAMP-PKA cascade is triggered. One substrate of this cascade is Synapsin, and therefore this review features a general and comparative discussion of Synapsin function. Phosphorylation of Synapsin ensures an alteration of synaptic strength between this mushroom body neuron and its target neuron(s). If the trained odour is encountered again, the pattern of mushroom body neurons coding this odour is activated, such that their modified output now allows conditioned behaviour. However, such an activated memory trace does not automatically cause conditioned behaviour. Rather, in a process that remains off-line from behaviour, the larvae compare the value of the testing situation (based on gustatory input) with the value of the odour-activated memory trace (based on mushroom body output). The circuit towards appetitive conditioned behaviour is closed only if the memory trace suggests that tracking down the learned odour will lead to a place better than the current one. It is this expectation of a positive outcome that is the immediate cause of appetitive conditioned behaviour. Such conditioned search for reward corresponds to a view of aversive conditioned behaviour as conditioned escape from punishment, which is enabled only if there is something to escape from - much in the same way as we only search for things that are not there, and run for the emergency exit only when there is an emergency. One may now ask whether beyond 'value' additional information about reinforcement is contained in the memory trace, such as information about the kind and intensity of the reinforcer used. The Drosophila larva may allow us to develop satisfyingly detailed accounts of such mnemonic richness - if it exists. PMID- 23447664 TI - Anemonefish oxygenate their anemone hosts at night. AB - Many stony coral-dwelling fishes exhibit adaptations to deal with hypoxia among the branches of their hosts; however, no information exists on the respiratory ecophysiology of obligate fish associates of non-coral organisms such as sea anemones and sponges. This study investigated metabolic and behavioral interactions between two-band anemonefish (Amphiprion bicinctus) and bulb tentacle sea anemones (Entacmaea quadricolor) at night. We measured the net dark oxygen uptake ( , MUmol O2 h(-1)) of fish-anemone pairs when partners were separate from each other, together as a unit, and together as a unit but separated by a mesh screen that prevented physical contact. We also measured the effects of water current on sea anemone and quantified the nocturnal behaviors of fish in the absence and presence of host anemones in order to discern the impacts of anemone presence on fish behavior. Net of united pairs was significantly higher than that of both separated pairs and united pairs that were separated by a mesh screen. Anemone increased with flow rate from 0.5 to 2.0 cm s(-1), after which remained constant up to a water flow rate of 8.0 cm s(-1). Furthermore, the percentage time and bout frequency of flow-modulating behaviors by fish increased significantly when anemones were present. We conclude that physical contact between anemonefish and sea anemones elevates the of at least one of the partners at night, and anemonefish behavior at night appears to oxygenate sea anemone hosts and to augment the metabolism of both partners. PMID- 23447665 TI - Sensorimotor responsiveness and resolution in the giraffe. AB - The ability of an animal to detect and respond to changes in the environment is crucial to its survival. However, two elements of sensorimotor control - the time required to respond to a stimulus (responsiveness) and the precision of stimulus detection and response production (resolution) - are inherently limited by a competition for space in peripheral nerves and muscles. These limitations only become more acute as animal size increases. In this paper, we investigated whether the physiology of giraffes has found unique solutions for maintaining sensorimotor performance in order to compensate for their extreme size. To examine responsiveness, we quantified three major sources of delay: nerve conduction delay, muscle electromechanical delay and force generation delay. To examine resolution, we quantified the number and size distribution of nerve fibers in the sciatic nerve. Rather than possessing a particularly unique sensorimotor system, we found that our measurements in giraffes were broadly comparable to size-dependent trends seen across other terrestrial mammals. Consequently, both giraffes and other large animals must contend with greater sensorimotor delays and lower innervation density in comparison to smaller animals. Because of their unconventional leg length, giraffes may experience even longer delays compared with other animals of the same mass when sensing distal stimuli. While there are certainly advantages to being tall, there appear to be challenges as well - our results suggest that giraffes are less able to precisely and accurately sense and respond to stimuli using feedback alone, particularly when moving quickly. PMID- 23447667 TI - Spatial memory and stereotypy of flight paths by big brown bats in cluttered surroundings. AB - The big brown bat, Eptesicus fuscus, uses echolocation for foraging and orientation. The limited operating range of biosonar implies that bats must rely upon spatial memory in familiar spaces with dimensions larger than a few meters. Prior experiments with bats flying in obstacle arrays have revealed differences in flight and acoustic emission patterns depending on the density and spatial extent of the obstacles. Using the same method, combined with acoustic microphone array tracking, we flew big brown bats in an obstacle array that varied in density and distribution in different locations in the flight room. In the initial experiment, six bats learned individually stereotyped flight patterns as they became familiar with the space. After the first day, the repetition rate of sonar broadcasts dropped to a stable level, consistent with low-density clutter. In a second experiment, after acquiring their stable paths, each bat was released from each of two unfamiliar locations in the room. Each bat still followed the same flight path it learned originally. In a third experiment, performed 1 month after the first two experiments, three of the bats were re-flown in the same configuration of obstacles; these three resumed flying in their accustomed path. The other three bats were flown in a mirror-image reconfiguration of the obstacles; these bats quickly found stable flight paths that differed from their originally learned paths. Overall, the flight patterns indicate that the bats perceive the cluttered space as a single scene through which they develop globally organized flight paths. PMID- 23447666 TI - Ectopic eyes outside the head in Xenopus tadpoles provide sensory data for light mediated learning. AB - A major roadblock in the biomedical treatment of human sensory disorders, including blindness, has been an incomplete understanding of the nervous system and its ability to adapt to changes in sensory modality. Likewise, fundamental insight into the evolvability of complex functional anatomies requires understanding brain plasticity and the interaction between the nervous system and body architecture. While advances have been made in the generation of artificial and biological replacement components, the brain's ability to interpret sensory information arising from ectopic locations is not well understood. We report the use of eye primordia grafts to create ectopic eyes along the body axis of Xenopus tadpoles. These eyes are morphologically identical to native eyes and can be induced at caudal locations. Cell labeling studies reveal that eyes created in the tail send projections to the stomach and trunk. To assess function we performed light-mediated learning assays using an automated machine vision and environmental control system. The results demonstrate that ectopic eyes in the tail of Xenopus tadpoles could confer vision to the host. Thus ectopic visual organs were functional even when present at posterior locations. These data and protocols demonstrate the ability of vertebrate brains to interpret sensory input from ectopic structures and incorporate them into adaptive behavioral programs. This tractable new model for understanding the robust plasticity of the central nervous system has significant implications for regenerative medicine and sensory augmentation technology. PMID- 23447668 TI - Bumblebee calligraphy: the design and control of flight motifs in the learning and return flights of Bombus terrestris. AB - Many wasps and bees learn the position of their nest relative to nearby visual features during elaborate 'learning' flights that they perform on leaving the nest. Return flights to the nest are thought to be patterned so that insects can reach their nest by matching their current view to views of their surroundings stored during learning flights. To understand how ground-nesting bumblebees might implement such a matching process, we have video-recorded the bees' learning and return flights and analysed the similarities and differences between the principal motifs of their flights. Loops that take bees away from and bring them back towards the nest are common during learning flights and less so in return flights. Zigzags are more prominent on return flights. Both motifs tend to be nest based. Bees often both fly towards and face the nest in the middle of loops and at the turns of zigzags. Before and after flight direction and body orientation are aligned, the two diverge from each other so that the nest is held within the bees' fronto-lateral visual field while flight direction relative to the nest can fluctuate more widely. These and other parallels between loops and zigzags suggest that they are stable variations of an underlying pattern, which enable bees to store and reacquire similar nest-focused views during learning and return flights. PMID- 23447669 TI - Coordinating compass-based and nest-based flight directions during bumblebee learning and return flights. AB - Bumblebees tend to face their nest over a limited range of compass directions when learning the nest's location on departure and finding it on their approach after foraging. They thus obtain similar views of the nest and its surroundings on their learning and return flights. How do bees coordinate their flights relative to nest-based and compass-based reference frames to get such similar views? We show, first, that learning and return flights contain straight segments that are directed along particular compass bearings, which are independent of the orientation of a bee's body. Bees are thus free within limits to adjust their viewing direction relative to the nest, without disturbing flight direction. Second, we examine the coordination of nest-based and compass-based control during likely information gathering segments of these flights: loops during learning flights and zigzags on return flights. We find that bees tend to start a loop or zigzag when flying within a restricted range of compass directions and to fly towards the nest and face it after a fixed change in compass direction, without continuous interactions between their nest-based and compass-based directions of flight. A preferred trajectory of compass-based flight over the course of a motif, combined with the tendency of the bees to keep their body oriented towards the nest automatically narrows the range of compass directions over which bees view the nest. Additionally, the absence of interactions between the two reference frames allows loops and zigzags to have a stereotyped form that can generate informative visual feedback. PMID- 23447670 TI - Caspase-2 at a glance. PMID- 23447671 TI - Membrane and actin reorganization in electropulse-induced cell fusion. AB - When cells of Dictyostelium discoideum are exposed to electric pulses they are induced to fuse, yielding motile polykaryotic cells. By combining electron microscopy and direct recording of fluorescent cells, we have studied the emergence of fusion pores in the membranes and the localization of actin to the cell cortex. In response to electric pulsing, the plasma membranes of two contiguous cells are turned into tangles of highly bent and interdigitated membranes. Live-imaging of cells double-labeled for membranes and filamentous actin revealed that actin is induced to polymerize in the fusion zone to temporarily bridge the gaps in the vesiculating membrane. The diffusion of green fluorescent protein (GFP) from one fusion partner to the other was scored using spinning disc confocal microscopy. Fusion pores that allowed intercellular exchange of GFP were formed after a delay, which lasted up to 24 seconds after exposure of the cells to the electric field. These data indicate that the membranes persist in a fusogenic state before pores of about 3 nm diameter are formed. PMID- 23447672 TI - A complex containing LPP and alpha-actinin mediates TGFbeta-induced migration and invasion of ErbB2-expressing breast cancer cells. AB - Transforming growth factor beta (TGFbeta) is a potent modifier of the malignant phenotype in ErbB2-expressing breast cancers. We demonstrate that epithelial derived breast cancer cells, which undergo a TGFbeta-induced epithelial-to mesenchymal transition (EMT), engage signaling molecules that normally facilitate cellular migration and invasion of mesenchymal cells. We identify lipoma preferred partner (LPP) as an indispensable regulator of TGFbeta-induced migration and invasion of ErbB2-expressing breast cancer cells. We show that LPP re-localizes to focal adhesion complexes upon TGFbeta stimulation and is a critical determinant in TGFbeta-mediated focal adhesion turnover. Finally, we have determined that the interaction between LPP and alpha-actinin, an actin cross-linking protein, is necessary for TGFbeta-induced migration and invasion of ErbB2-expressing breast cancer cells. Thus, our data reveal that LPP, which is normally operative in cells of mesenchymal origin, can be co-opted by breast cancer cells during an EMT to promote their migration and invasion. PMID- 23447673 TI - Stable incorporation versus dynamic exchange of beta subunits in a native Ca2+ channel complex. AB - Voltage-gated Ca(2+) channels are multi-subunit membrane proteins that transduce depolarization into cellular functions such as excitation-contraction coupling in muscle or neurotransmitter release in neurons. The auxiliary beta subunits function in membrane targeting of the channel and modulation of its gating properties. However, whether beta subunits can reversibly interact with, and thus differentially modulate, channels in the membrane is still unresolved. In the present study we applied fluorescence recovery after photobleaching (FRAP) of GFP tagged alpha1 and beta subunits expressed in dysgenic myotubes to study the relative dynamics of these Ca(2+) channel subunits for the first time in a native functional signaling complex. Identical fluorescence recovery rates of both subunits indicate stable interactions, distinct recovery rates indicate dynamic interactions. Whereas the skeletal muscle beta1a isoform formed stable complexes with CaV1.1 and CaV1.2, the non-skeletal muscle beta2a and beta4b isoforms dynamically interacted with both alpha1 subunits. Neither replacing the I-II loop of CaV1.1 with that of CaV2.1, nor deletions in the proximal I-II loop, known to change the orientation of beta relative to the alpha1 subunit, altered the specific dynamic properties of the beta subunits. In contrast, a single residue substitution in the alpha interaction pocket of beta1aM293A increased the FRAP rate threefold. Taken together, these findings indicate that in skeletal muscle triads the homologous beta1a subunit forms a stable complex, whereas the heterologous beta2a and beta4b subunits form dynamic complexes with the Ca(2+) channel. The distinct binding properties are not determined by differences in the I-II loop sequences of the alpha1 subunits, but are intrinsic properties of the beta subunit isoforms. PMID- 23447674 TI - UV-induced G2 checkpoint depends on p38 MAPK and minimal activation of ATR-Chk1 pathway. AB - In response to UV light, single-stranded DNA intermediates coated with replication protein A (RPA) are generated, which trigger the ATR-Chk1 checkpoint pathway. Recruitment and/or activation of several checkpoint proteins at the damaged sites is important for the subsequent cell cycle arrest. Surprisingly, upon UV irradiation, Rad9 and RPA only minimally accumulate at DNA lesions in G2 phase, suggesting that only a few single-stranded DNA intermediates are generated. Also, little phosphorylated Chk1 is observed in G2 phase after UV irradiation, and UV light fails to elicit efficient accumulation of typical DNA damage response proteins at sites of damage in this phase. By contrast, p38 MAPK is phosphorylated in G2 phase cells after UV damage. Interestingly, despite the lack of an obvious activation of the ATR-Chk1 pathway, only the combined inhibition of the ATR- and p38-dependent pathways results in a complete abrogation of the UV-induced G2/M arrest. This suggests that UV light induces less hazardous lesions in G2 phase or that lesions created in this phase are less efficiently processed, resulting in a low activation of the ATR-Chk1 pathway. UV induced G2 checkpoint activation in this situation therefore relies on signalling via the p38 MAPK and ATR-Chk1 signalling cascades. PMID- 23447675 TI - Mitochondrial aldehyde dehydrogenase-2 activation prevents beta-amyloid-induced endothelial cell dysfunction and restores angiogenesis. AB - Amyloid beta peptides (Abeta1-40 and Abeta1-42) cause cerebral degeneration by impairing the activity of angiogenic factors and inducing apoptosis and senescence in the endothelium. Amyloid peptides are known to induce oxidative stress. Impairment of mitochondrial aldehyde dehydrogenase 2 (ALDH2) following oxidative stress, results in accumulation of toxic aldehydes, particularly 4 hydroxynoneal (4-HNE). We sought to determine the role of mitochondrial ALDH2 in Abeta-related impairment of angiogenesis. We hypothesized that by increasing the detoxification activity of ALDH2 we would reduce Abeta-driven endothelial injuries and restore angiogenesis. We used a selective ALDH2 activator, Alda-1, assessing its ability to repair mitochondrial dysfunction in the endothelium. Treatment of human endothelial cells with Abeta1-40 (5-50 uM) induced loss of mitochondrial membrane potential, increased cytochrome c release and ROS accumulation. These events were associated with 4-HNE accumulation and decrease in ALDH2 activity (40%), and resulted in disassembly of endothelial junctions, as evidenced by beta-catenin phosphorylation, disorganization of adherens and tight junctions, and by disruption of pseudocapillary formation. Alda-1 (10-40 uM) abolished Abeta-induced 4-HNE accumulation, apoptosis and vascular leakiness, fully restoring the pro-angiogenic endothelial phenotype and responses to FGF-2. Our data document that mitochondrial ALDH2 in the endothelium is a target for the vascular effect of Abeta, including loss of barrier function and angiogenesis. ALDH2 activation, by restoring mitochondrial functions in the endothelium, prevents Abeta-induced dysfunction and anti-angiogenic effects. Thus, agents activating ALDH2 may reduce endothelial injuries including those occurring in cerebral amyloid angiopathy, preserving the angiogenic potential of the endothelium. PMID- 23447676 TI - ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1. AB - Parkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stress induced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin- and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a parkin-dependent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1. PMID- 23447677 TI - The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes. AB - Cellular directional migration in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC), in addition to its function of regulating sodium transport in kidney, has recently been found to modulate cell locomotory speed. Here we tested whether ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely blocks only galvanotaxis and does not decrease migration speed. Overexpression of ENaC is sufficient to drive galvanotaxis in otherwise unresponsive cells. Pharmacologic blockade or maintenance of the open state of ENaC also decreases or increases, respectively, galvanotaxis, suggesting that the channel open state is responsible for the response. Stable lamellipodial extensions formed at the cathodal sides of wild-type cells at the start of galvanotaxis; these were absent in the ENaC knockout keratinocytes, suggesting that ENaC mediates galvanotaxis by generating stable lamellipodia that steer cell migration. We provide evidence that ENaC is required for directional migration of keratinocytes in an electric field, supporting a role for ENaC in skin wound healing. PMID- 23447679 TI - Contour adaptation. AB - It is known that adaptation to a disk that flickers between black and white at 3 8 Hz on a gray surround renders invisible a congruent gray test disk viewed afterwards. This is contrast adaptation. We now report that adapting simply to the flickering circular outline of the disk can have the same effect. We call this "contour adaptation." This adaptation does not transfer interocularly, and apparently applies only to luminance, not color. One can adapt selectively to only some of the contours in a display, making only these contours temporarily invisible. For instance, a plaid comprises a vertical grating superimposed on a horizontal grating. If one first adapts to appropriate flickering vertical lines, the vertical components of the plaid disappears and it looks like a horizontal grating. Also, we simulated a Cornsweet (1970) edge, and we selectively adapted out the subjective and objective contours of a Kanisza (1976) subjective square. By temporarily removing edges, contour adaptation offers a new technique to study the role of visual edges, and it demonstrates how brightness information is concentrated in edges and propagates from them as it fills in surfaces. PMID- 23447678 TI - Deregulated G1-S control and energy stress contribute to the synthetic-lethal interactions between inactivation of RB and TSC1 or TSC2. AB - Synthetic lethality is a potential strategy for cancer treatment by specifically promoting the death of cancer cells with particular defects such as the loss of the RB (RB1) tumor suppressor. We previously showed that inactivation of both RB and TSC2 induces synergistic apoptosis during the development of Drosophila melanogaster and in cancer cells. However, the in vivo mechanism of this synthetic-lethal interaction is not clear. Here, we show that synergistic cell death in tissues that have lost the RB and TSC orthologs rbf and dtsc1/gig, respectively, or overexpress Rheb and dE2F1, are correlated with synergistic defects in G1-S control, which causes cells to accumulate DNA damage. Coexpression of the G1-S inhibitor Dap, but not the G2-M inhibitor dWee1, decreases DNA damage and reduces cell death. In addition, we show that rbf and dtsc1 mutant cells are under energy stress, are sensitive to decreased energy levels and depend on the cellular energy stress-response pathway for survival. Decreasing mitochondrial ATP synthesis by inactivating cova or abrogating the energy-stress response by removing the metabolic regulator LKB1 both enhance the elimination of cells lacking either rbf or dtsc1. These observations, in conjunction with the finding that deregulation of TORC1 induces activation of JNK, indicate that multiple cellular stresses are induced and contribute to the synthetic-lethal interactions between RB and TSC1/TSC2 inactivation. The insights gained from this study suggest new approaches for targeting RB-deficient cancers. PMID- 23447680 TI - Switching between visuomotor mappings: learning absolute mappings or relative shifts. AB - Adaptation to specific visuomotor mappings becomes faster when switching back and forth between them. What is learned when repeatedly switching between the visuomotor mappings: the absolute mappings or the relative shift between the mappings? To test this, we trained participants in a rapid pointing task using a unique color cue as context for each mapping between pointing location and visual feedback. After extensive training, participants adapted to a new mapping using a neutral contextual cue. For catch trials (a change in cue and no visual feedback) different adaptation performances are predicted depending on how the mappings are encoded. When encoding an absolute mapping for each cue, participants would fall back to the mapping associated with the cue irrespective of the state they are currently in. In contrast, when a shift in mapping is encoded for the cue, pointing performance will shift relative to the current mapping by an amount equal to the difference between the previously learned mappings. Results indicate that the contextual cues signal absolute visuomotor mappings rather than relative shifts between mappings. PMID- 23447681 TI - Pioneers in pediatric psychology: personal reflections for the young professional. PMID- 23447682 TI - Cutting edge: Leptin-induced RORgammat expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. AB - Th17 CD4(+) cells promote inflammation and autoimmunity. In this study, we report that Th17 cell frequency is reduced in ob/ob mice (that are genetically deficient in the adipokine leptin) and that the administration of leptin to ob/ob mice restored Th17 cell numbers to values comparable to those found in wild-type animals. Leptin promoted Th17 responses in normal human CD4(+) T cells and in mice, both in vitro and in vivo, by inducing RORgammat transcription. Leptin also increased Th17 responses in (NZB * NZW)F1 lupus-prone mice, whereas its neutralization in those autoimmune-prone mice inhibited Th17 responses. Because Th17 cells play an important role in the development and maintenance of inflammation and autoimmunity, these findings envision the possibility to modulate abnormal Th17 responses via leptin manipulation, and they reiterate the link between metabolism/nutrition and susceptibility to autoimmunity. PMID- 23447683 TI - Fast dendritic cells stimulated with alternative maturation mixtures induce polyfunctional and long-lasting activation of innate and adaptive effector cells with tumor-killing capabilities. AB - The clinical usage of dendritic cells (DC) for tumor immunotherapy still requires improvements. In this study, three alternative maturation mixtures were compared with the cytokine-based gold standard, and the overall interaction of the resulting DC with effector cells from the innate as well as the adaptive immunity was evaluated in healthy donors. Stimulation with the TLR-4 ligand monophosphoryl lipid A together with IFN-gamma (alt-2 DC) resulted in DC with the highest levels of costimulatory molecule expression and IL-12p70/IL-10 ratio. Whereas all alternative DC were able to induce NK and gammadelta T cells to acquire cytotoxic properties and secrete type 1 and proinflammatory cytokines, after both short (20 h)- and long (5-8 d)-time coculture, secretion of IFN-gamma by the innate populations was induced in response to alt-2 and alt-1 DC (TNF-alpha, IFN-alpha, IFN-gamma, IL-1beta, poly IC), but not to alt-3 DC (TNF-alpha, IFN-gamma, IL 1beta, CL097). Regarding CD8(+) T cell-mediated Ag-specific immune responses, a heterogeneous pattern of responses was obtained among the healthy donors, suggesting rather a competition than a synergy among the different effector cells. Our data promote further evaluation of alt-2 fast DC for translatability into clinical immunotherapy trials, while also fostering the need to identify biomarkers for immune cell responsiveness and tumor susceptibility to be able to select for each patient the best possible DC-based therapy. PMID- 23447684 TI - Impaired TLR5 functionality is associated with survival in melioidosis. AB - Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR5(1174C)>T, to elucidate the role of TLR5 in melioidosis. We measured NF kappaB activation induced by B. pseudomallei in human embryonic kidney-293 cells transfected with TLR5 and found that B. pseudomallei induced TLR5(1174C)- but not TLR5(1174T)-dependent activation of NF-kappaB. We tested the association of TLR5(1174C)>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR5(1174C)>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08-0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR5(1174C)>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-alpha, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1beta in carriers of TLR5(1174T) compared with carriers of TLR5(1174C). B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR5(1174T). We conclude that the hypofunctional genetic variant TLR5(1174C)>T is associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis. PMID- 23447686 TI - CXCL9 causes heterologous desensitization of CXCL12-mediated memory T lymphocyte activation. AB - The chemokine receptors CXCR3 and CXCR4 are primarily involved in memory Th1 cell driven autoimmune diseases. Although recent studies in chronic inflammatory disease showed therapeutic success using combined blockade, details of CXCR3 and CXCR4 synergism are not understood. In this investigation, we intended to unravel the interaction of these chemokine receptors in static and dynamic cell-migration assays at both the cellular and molecular levels. Effects of combined stimulation by murine CXCL9 and CXCL12, ligands of CXCR3 and CXCR4, respectively, were analyzed using a murine central memory Th1 cell clone. Costimulation with CXCL9 desensitized the chemotaxis of Th1 cells toward CXCL12 by up to 54%. This effect was found in murine EL-4 cells, as well as in primary human T cells. Furthermore, under dynamic flow conditions CXCL12-induced crawling and endothelial transmigration of Th1 cells was desensitized by CXCL9. Subsequent experiments uncovered several molecular mechanisms underlying the heterologous cross regulation of CXCR4 signaling by the CXCR3 ligand. CXCR4 surface expression was reduced, whereas CXCL12-induced Akt phosphorylation and intracellular Ca(2+) signals were modulated. Moreover, blockade of Rac by NSC23766 revealed differential effects on CXCL12 and CXCL9 chemotaxis and abolished the desensitizing effect of CXCL9. The desensitization of CXCR4 via CXCR3 in memory Th1 cells suggests that their in vivo homeostasis, widely regulated by CXCL12, seemed to be significantly altered by CXCR3 ligands. Our data provide a more detailed understanding for the continuing extravasation and recruitment of Th1 lymphocytes into sites of persistent inflammation. PMID- 23447685 TI - Macrophage scavenger receptor a promotes tumor progression in murine models of ovarian and pancreatic cancer. AB - Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that coculture of macrophages with tumor cells upregulates macrophage SR-A expression. We show in this study that macrophage SR-A deficiency inhibits tumor cell migration in a coculture assay. We further demonstrate that coculture of tumor-associated macrophages and tumor cells induces secretion of factors that are recognized by SR-A on tumor-associated macrophages. We tentatively identified several potential ligands for the SR-A receptor in tumor cell-macrophage cocultures by mass spectrometry. Competing with the coculture-induced ligand in our invasion assay recapitulates SR-A deficiency and leads to similar inhibition of tumor cell invasion. In line with our in vitro findings, tumor progression and metastasis are inhibited in SR-A(-/-) mice in two in vivo models of ovarian and pancreatic cancer. Finally, treatment of tumor-bearing mice with 4F, a small peptide SR-A ligand able to compete with physiological SR-A ligands in vitro, recapitulates the inhibition of tumor progression and metastasis observed in SR-A(-/-) mice. Our observations suggest that SR-A may be a potential drug target in the prevention of metastatic cancer progression. PMID- 23447687 TI - Class I phosphoinositide-3-kinases and SRC kinases play a nonredundant role in regulation of adhesion-independent and -dependent neutrophil reactive oxygen species generation. AB - Chemoattractant-induced reactive oxygen species (ROS) generation by adherent neutrophils occurs in two phases: the first is very rapid and transient, and the second one is delayed and lasts up to 30-40 min. We examined the role of phosphoinositide 3-kinases (PI3Ks) and Src-family kinases (SFKs) in these responses using human neutrophils treated with inhibitory compounds or murine neutrophils deficient of PI3Kgamma or Hck, Fgr, and Lyn. Our studies show that PI3Kgamma is indispensable for the early, fMLF-induced ROS generation and AKT and ERK phosphorylation, but is dispensable for the late response to fMLF. Additionally, the response to TNF, an agonist triggering only the delayed phase of ROS generation, was also unaffected in PI3Kgamma-deficient neutrophils. In contrast, inhibition of SFKs by a selective inhibitor in human, or SFK deficiency in murine, neutrophils resulted in the inhibition of both the early and late phase of ROS generation, without affecting the early phase of AKT phosphorylation, but inhibiting the late one. Selective inhibitors of PI3Kalpha and PI3Kdelta markedly reduced both the early and late response to fMLF and TNF in human neutrophils. These findings suggest that class IA PI3Ks may be activated by PI3Kgamma via Ras in the early phase of the response and by SFKs in the late phase. The evidence that inhibition of SFKs in human, or SFK deficiency in murine, neutrophils results in suppression of Vav phosphorylation at all time points of the response to fMLF or TNF suggests that SFKs are indispensable for Vav phosphorylation. PMID- 23447688 TI - Shear stress-dependent downregulation of the adhesion-G protein-coupled receptor CD97 on circulating leukocytes upon contact with its ligand CD55. AB - Adhesion G protein-coupled receptors (aGPCRs) are two-subunit molecules, consisting of an adhesive extracellular alpha subunit that couples noncovalently to a seven-transmembrane beta subunit. The cooperation between the two subunits and the effect of endogenous ligands on the functioning of aGPCRs is poorly understood. In this study, we investigated the interaction between the pan leukocyte aGPCR CD97 and its ligand CD55. We found that leukocytes from CD55 deficient mice express significantly increased levels of cell surface CD97 that normalized after transfer into wild-type mice because of contact with CD55 on both leukocytes and stromal cells. Downregulation of both CD97 subunits occurred within minutes after first contact with CD55 in vivo, which correlated with an increase in plasma levels of soluble CD97. In vitro, downregulation of CD97 on CD55-deficient leukocytes cocultured with wild-type blood cells was strictly dependent on shear stress. In vivo, CD55-mediated downregulation of CD97 required an intact circulation and was not observed on cells that lack contact with the blood stream, such as microglia. Notably, de novo ligation of CD97 did not activate signaling molecules constitutively engaged by CD97 in cancer cells, such as ERK and protein kinase B/Akt. We conclude that CD55 downregulates CD97 surface expression on circulating leukocytes by a process that requires physical forces, but based on current evidence does not induce receptor signaling. This regulation can restrict CD97-CD55-mediated cell adhesion to tissue sites. PMID- 23447689 TI - IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. AB - Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A(+) T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver. PMID- 23447690 TI - Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. AB - Bcl6 is required for CD4 T cell differentiation into T follicular helper cells (Tfh). In this study, we examined the role of IL-6 in early processes of in vivo Tfh differentiation, because the timing and mechanism of action of IL-6 in Tfh differentiation have been controversial in vivo. We found that early Bcl6(+)CXCR5(+) Tfh differentiation was severely impaired in the absence of IL-6; however, STAT3 deficiency failed to recapitulate that defect. IL-6R signaling activates the transcription factor STAT1 specifically in CD4 T cells. Strikingly, we found that STAT1 activity was required for Bcl6 induction and early Tfh differentiation in vivo. IL-6 mediated STAT3 activation is important for downregulation of IL-2Ralpha to limit Th1 cell differentiation in an acute viral infection. Thus, IL-6 signaling is a major early inducer of the Tfh differentiation program unexpectedly mediated by both STAT3 and STAT1 transcription factors. PMID- 23447691 TI - Functional macrophage heterogeneity in a mouse model of autoimmune central nervous system pathology. AB - Functional macrophage heterogeneity is well appreciated outside the CNS in wound healing and cancer, and was recently also demonstrated in several CNS compartments after "sterile" insults. Yet, such heterogeneity was largely overlooked in the context of inflammatory autoimmune pathology, in which macrophages were mainly associated with disease induction and propagation. In this article, we show the diversity of monocyte-derived macrophages along the course of experimental autoimmune uveitis, an inflammatory condition affecting the ocular system, serving as a model for CNS autoimmune pathology. Disease induction resulted in the appearance of a distinct myeloid population in the retina, and in the infiltration of monocyte-derived macrophages that were absent from control eyes. During the disease course, the frequency of CX3CR1(high) infiltrating macrophages that express markers associated with inflammation resolving activity was increased, along with a decrease in the frequency of inflammation-associated Ly6C(+) macrophages. Inhibition of monocyte infiltration at the induction phase of experimental autoimmune uveitis prevented disease onset, whereas monocyte depletion at the resolution phase resulted in a decrease in Foxp3(+) regulatory T cells and in exacerbated disease. Thus, monocyte-derived macrophages display distinct phenotypes throughout the disease course, even in an immune-induced pathology, reflecting their differential roles in disease induction and resolution. PMID- 23447692 TI - CaMKIalpha regulates AMP kinase-dependent, TORC-1-independent autophagy during lipopolysaccharide-induced acute lung neutrophilic inflammation. AB - Autophagy is an evolutionarily conserved cytoplasmic process regulated by the energy rheostats mammalian target of rapamycin and AMP kinase (AMPK) that recycles damaged or unused proteins and organelles. It has been described as an important effector arm of immune cells. We have shown that the cytoplasmically oriented calcium/calmodulin-dependent protein kinase (CaMK)Ialpha regulates the inflammatory phenotype of the macrophage (M). In this study, we hypothesize that CaMKIalpha mediates M autophagy. LPS induced autophagy in RAW 264.7 cells and murine peritoneal M that was attenuated with biochemical CaMK inhibition or CaMKIalpha small interfering RNA (siRNA). Inhibition of CaMKIalpha reduced LPS induced p-Thr(172)AMPK and target of rapamycin complex-1 activity, and expression of a constitutively active CaMKIalpha but not a kinase-deficient mutant induced p Thr(172)AMPK and autophagy that was attenuated by the AMPK inhibitor compound C. Coimmunoprecipitation and in vitro kinase assays demonstrated that CaMKIalpha activates AMPK, thereby inducing ATG7, which also localizes to this CaMKIalpha/AMPK complex. During LPS-induced lung inflammation, C57BL/6 mice receiving CaMKIalpha(siRNA) displayed reduced lung and bronchoalveolar immune cell autophagy that correlated with reduced neutrophil recruitment, myeloperoxidase activity, and air space cytokine concentration. Independently inhibiting autophagy, using siRNA targeting the PI3K VPS34, yielded similar reductions in lung autophagy and neutrophil recruitment. Thus, a novel CaMKIalpha/AMPK pathway is rapidly activated in M exposed to LPS and regulates an early autophagic response, independent of target of rapamycin complex-1 inhibition. These mechanisms appear to be operant in vivo in orchestrating LPS induced lung neutrophil recruitment and inflammation. PMID- 23447693 TI - Invasive pneumococcal disease and socioeconomic deprivation: a population study from the North East of England. AB - BACKGROUND: Some communicable diseases disproportionately affect poor and vulnerable groups. Invasive pneumococcal disease (IPD) is an important cause of morbidity and mortality; however, the relationship between IPD and deprivation has not been well described. METHODS: Population based study assessing the relationship between incidence of IPD and deprivation in the North East of England using data from an enhanced IPD surveillance system and the 2010 Indices of Multiple Deprivation and the Rural and Urban Area Classification. RESULTS: The incidence of IPD increased linearly with increasing deprivation from 7.0 per 100 000 population to 13.6 per 100 000 population. This association was demonstrated for the 16-64 and >=65 year age groups, but not the <16 year age group. IPD incidence was strongly associated with all individual domains of deprivation except for the 'barriers to housing and services' domain. IPD incidence was higher in urban than rural areas. CONCLUSIONS: The risk of IPD is strongly associated with deprivation in adults, but not children. The mechanisms producing the associations observed remain unclear and require further investigation. Findings from this study reinforce the need to address social inequalities to reduce the burden of disease. Targeting vaccination at adults living in deprived areas could reduce the burden of IPD. PMID- 23447694 TI - Quantitative proteomic analysis for radiation-induced cell cycle suspension in 92 1 melanoma cell line. AB - Melanoma is a malignant tumor with high invasive and metastatic properties. Though radiation is the major therapy for melanoma, its radio-resistance has been shown to severely influence the clinical outcome. So it is imperative to enhance the sensitivity of uveal melanoma cells to radiotherapy. Previously, we found that the cell cycle of 92-1 uveal melanoma cells was suspended and remained unchanged for up to 5 days after exposure to 10 Gy of X-rays, which might be relevant to the high radio-sensitivity of 92-1 cells. To further investigate the cell cycle suspension-associated proteins, we employed two analyses with stable isotope labeling with amino acids in cell culture technology and two-dimensional liquid chromatography tandem mass spectrometry. Cells were incubated for 15 h or 48 h after irradiation with 10 Gy of X-rays. We identified a total of 737 proteins at 15 h (Group A) and 530 proteins at 48 h post-irradiation (Group B). The gene ontology biological pathway was used to obtain a systems level view of proteome changes in 92-1cells under cell cycle suspension. We further selected the significantly changed proteins for investigation of their potential contribution to cell cycle suspension, growth arrest and cell senescence. These proteins are involved in the cell cycle, stress response, glycolysis and the tricarboxylic acid cycle, etc. Our study expected to reveal potential marker proteins associated with cell suspension induced by irradiation, which might contribute to understanding the mechanism beyond the cell cycle suspension. PMID- 23447695 TI - Identification of radiation-induced microRNA transcriptome by next-generation massively parallel sequencing. AB - Gene regulation in cells exposed to ionizing radiation (IR) occurs at the transcriptional and post-transcriptional levels. Recent studies have suggested that micro-RNA (miRNA) play a significant role in post-transcriptional gene regulation in irradiated cells. miRNA are RNA molecules 18-24 nucleotides in length that are involved in negatively regulating the stability or translation of target messenger RNA. Previous studies from our laboratory have shown that the expression of various miRNA is altered in IR-treated cells. In the present study we monitored genome-wide expression changes of miRNA transcriptome by massively parallel sequencing of human cells irradiated with X-rays. The baseline expression of 402 miRNA indicated a wide range of modulation without exposure to IR. Differences in the expression of many miRNA were observed in a time-dependent fashion following radiation treatment. The Short Time-series Expression Miner (STEM) clustering tool was used to characterize 190 miRNA to six statistically significant temporal expression profiles. miR-19b and miR-93 were induced and miR 222, miR-92a, and miR-941 were repressed after radiation treatment. miR-142-3p, miR-142-5p, miR-107, miR-106b, miR-191, miR-21, miR-26a, miR-182, miR-16, miR 146a, miR-22 and miR-30e exhibited two peaks of induction: one at 8 h and the other at 24 h post-irradiation. miR-378, miR-let-7a, miR-let-7g, miR-let-7f, miR 103b, miR-486-3p, miR-423-5p, miR-4448, miR-3607-5p, miR-20b, miR-130b, miR-155, miR-181, miR-30d and miR-378c were induced only at the 8-h time-point. This catalogue of the inventory of miRNA that are modulated as a response to radiation exposure will be useful for explaining the mechanisms of gene regulation under conditions of stress. PMID- 23447697 TI - Could a phosphotransferase system provide the means to control outbreaks of Enterococcus faecium infection? PMID- 23447696 TI - Pharmacokinetic predictors for recurrent malaria after dihydroartemisinin piperaquine treatment of uncomplicated malaria in Ugandan infants. AB - BACKGROUND: Although dihydroartemisinin-piperaquine (DP) is used primarily in children, pharmacokinetic/pharmacodynamic (PK/PD) data on DP use in young children are lacking. METHODS: We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63. RESULTS: The median capillary piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of <= 27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria. CONCLUSIONS: These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMP SMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of piperaquine. PMID- 23447698 TI - Identification of a genetic determinant in clinical Enterococcus faecium strains that contributes to intestinal colonization during antibiotic treatment. AB - Intestinal colonization by antibiotic-resistant Enterococcus faecium is the first step in a process that can lead to infections in hospitalized patients. By comparative genome analysis and subsequent polymerase chain reaction screening, we identified a locus that encodes a putative phosphotransferase system (PTS). The PTS locus was widespread in isolates from hospital outbreaks of infection (84.2%) and nonoutbreak clinical infections (66.0%) but absent from human commensal isolates. Deletion of pstD, which is predicted to encode the enzyme IID subunit of this PTS, significantly impaired the ability of E. faecium to colonize the murine intestinal tract during antibiotic treatment. This is the first description of a determinant that contributes to intestinal colonization in clinical E. faecium strains. PMID- 23447699 TI - ATF6alpha/beta-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish. AB - ATF6alpha and ATF6beta are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6alpha- and ATF6beta single-knockout mice develop normally, but ATF6alpha/beta double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6alpha is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6alpha/beta double knockout, but not ATF6alpha or ATF6beta single knockout, causes embryonic lethality, as in mice. Analyses of ER stress reporters reveal that ER stress occurs physiologically during medaka early embryonic development, particularly in the brain, otic vesicle, and notochord, resulting in ATF6alpha- and ATF6beta-mediated induction of BiP, and that knockdown of the alpha1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6alpha/beta double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6alpha/beta-mediated adjustment of chaperone levels to increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra. PMID- 23447700 TI - Dual function of the NDR-kinase Dbf2 in the regulation of the F-BAR protein Hof1 during cytokinesis. AB - The conserved NDR-kinase Dbf2 plays a critical role in cytokinesis in budding yeast. Among its cytokinesis-related substrates is the F-BAR protein Hof1. Hof1 colocalizes at the cell division site with the septin complex and, as mitotic exit progresses, moves to the actomyosin ring (AMR). Neither the function of Hof1 at the septin complex nor the mechanism by which Hof1 supports AMR constriction is understood. Here we establish that Dbf2 has a dual function in Hof1 regulation. First, we show that the coiled-coil region, which is adjacent to the conserved F-BAR domain, is required for the binding of Hof1 to septins. The Dbf2 dependent phosphorylation of Hof1 at a single serine residue (serine 313) in this region diminishes the recruitment of Hof1 to septins both in vitro and in vivo. Genetic and functional analysis indicates that the binding of Hof1 to septins is important for septin rearrangement and integrity during cytokinesis. Furthermore, Dbf2 phosphorylation of Hof1 at serines 533 and 563 promotes AMR constriction most likely by inhibiting the SH3-domain-dependent interactions of Hof1. Thus our data show that Dbf2 coordinates septin and AMR functions during cytokinesis through the regulation/control of Hof1. PMID- 23447701 TI - Rts1-protein phosphatase 2A antagonizes Ptr3-mediated activation of the signaling protease Ssy5 by casein kinase I. AB - Ligand-induced conformational changes of plasma membrane receptors initiate signals that enable cells to respond to discrete extracellular cues. In response to extracellular amino acids, the yeast Ssy1-Ptr3-Ssy5 sensor triggers the endoproteolytic processing of transcription factors Stp1 and Stp2 to induce amino acid uptake. Activation of the processing protease Ssy5 depends on the signal induced phosphorylation of its prodomain by casein kinase I (Yck1/2). Phosphorylation is required for subsequent Skp1/Cullin/Grr1 E3 ubiquitin ligase dependent polyubiquitylation and proteasomal degradation of the inhibitory prodomain. Here we show that Rts1, a regulatory subunit of the general protein phosphatase 2A, and Ptr3 have opposing roles in controlling Ssy5 prodomain phosphorylation. Rts1 constitutively directs protein phosphatase 2A activity toward the prodomain, effectively setting a signaling threshold required to mute Ssy5 activation in the absence of amino acid induction. Ptr3 functions as an adaptor that transduces conformational signals initiated by the Ssy1 receptor to dynamically induce prodomain phosphorylation by mediating the proximity of the Ssy5 prodomain and Yck1/2. Our results demonstrate how pathway-specific and general signaling components function synergistically to convert an extracellular stimulus into a highly specific, tuned, and switch-like transcriptional response that is critical for cells to adapt to changes in nutrient availability. PMID- 23447702 TI - The nucleolus stress response is coupled to an ATR-Chk1-mediated G2 arrest. AB - We report experiments on the connection between nucleolar stress and cell cycle progression, using HeLa cells engineered with the fluorescent ubiquitinylation based cell cycle indicator. Nucleolar stress elicited by brief exposure of cells to a low concentration of actinomycin D that selectively inhibits rRNA synthesis had no effect on traverse of G1 or S, but stalled cells in very late interphase. Additional experiments revealed that a switch occurs during a specific temporal window during nucleolar stress and that the subsequent cell cycle arrest is not triggered simply by the stress-induced decline in the synthesis of rRNA or by a ribosome starvation phenomenon. Further experiments revealed that this nucleolus stress-induced cell cycle arrest involves the action of a G2 checkpoint mediated by the ataxia telangiectasia and Rad3-related protein (ATR)-checkpoint kinase 1 (Chk1) pathway. Based on analysis of the cell cycle stages at which this nucleolar stress effect is put into action, to become manifest later, our results demonstrate a feedforward mechanism that leads to G2 arrest and identify ATR and Chk1 as molecular agents of the requisite checkpoint. PMID- 23447703 TI - An auxiliary, membrane-based mechanism for nuclear migration in budding yeast. AB - How nuclear shape correlates with nuclear movements during the cell cycle is poorly understood. We investigated changes in nuclear morphology during nuclear migration in budding yeast. In preanaphase cells, nuclear protrusions (nucleopodia [NP]) extend into the bud, preceding insertion of chromosomes into the bud neck. Surprisingly, formation of nucleopodia did not depend on the established nuclear migration pathways. We show that generation and maintenance of NP requires nuclear membrane expansion, actin, and the exocyst complex. Exocyst mutations cause nuclear positioning defects and display genetic interactions with mutations that deactivate astral microtubule-dependent nuclear migration. Cells that cannot perform DNA replication also fail to form nucleopodia. We propose that nuclear membrane expansion, DNA replication, and exocyst-dependent anchoring of the nuclear envelope to the bud affect nuclear morphology and facilitate correct positioning of nucleus and chromosomes relative to the cleavage apparatus. PMID- 23447704 TI - An analogue-sensitive approach identifies basal body rotation and flagellum attachment zone elongation as key functions of PLK in Trypanosoma brucei. AB - Polo-like kinases are important regulators of cell division, playing diverse roles in mitosis and cytoskeletal inheritance. In the parasite Trypanosoma brucei, the single PLK homologue TbPLK is necessary for the assembly of a series of essential organelles that position and adhere the flagellum to the cell surface. Previous work relied on RNA interference or inhibitors of undefined specificity to inhibit TbPLK, both of which have significant experimental limitations. Here we use an analogue-sensitive approach to selectively and acutely inhibit TbPLK. T. brucei cells expressing only analogue-sensitive TbPLK (TbPLK(as)) grow normally, but upon treatment with inhibitor develop defects in flagellar attachment and cytokinesis. TbPLK cannot migrate effectively when inhibited and remains trapped in the posterior of the cell throughout the cell cycle. Using synchronized cells, we show that active TbPLK is a direct requirement for the assembly and extension of the flagellum attachment zone, which adheres the flagellum to the cell surface, and for the rotation of the duplicated basal bodies, which positions the new flagellum so that it can extend without impinging on the old flagellum. This approach should be applicable to the many kinases found in the T. brucei genome that lack an ascribed function. PMID- 23447705 TI - The BAR domain of amphiphysin is required for cleavage furrow tip-tubule formation during cellularization in Drosophila embryos. AB - De novo formation of cells in the Drosophila embryo is achieved when each nucleus is surrounded by a furrow of plasma membrane. Remodeling of the plasma membrane during cleavage furrow ingression involves the exocytic and endocytic pathways, including endocytic tubules that form at cleavage furrow tips (CFT-tubules). The tubules are marked by amphiphysin but are otherwise poorly understood. Here we identify the septin family of GTPases as new tubule markers. Septins do not decorate CFT-tubules homogeneously: instead, novel septin complexes decorate different CFT-tubules or different domains of the same CFT-tubule. Using these new tubule markers, we determine that all CFT-tubule formation requires the BAR domain of amphiphysin. In contrast, dynamin activity is preferentially required for the formation of the subset of CFT-tubules containing the septin Peanut. The absence of tubules in amphiphysin-null embryos correlates with faster cleavage furrow ingression rates. In contrast, upon inhibition of dynamin, longer tubules formed, which correlated with slower cleavage furrow ingression rates. These data suggest that regulating the recycling of membrane within the embryo is important in supporting timely furrow ingression. PMID- 23447706 TI - Visualization of actin filaments and monomers in somatic cell nuclei. AB - In addition to its long-studied presence in the cytoplasm, actin is also found in the nuclei of eukaryotic cells. The function and form (monomer, filament, or noncanonical oligomer) of nuclear actin are hotly debated, and its localization and dynamics are largely unknown. To determine the distribution of nuclear actin in live somatic cells and evaluate its potential functions, we constructed and validated fluorescent nuclear actin probes. Monomeric actin probes concentrate in nuclear speckles, suggesting an interaction of monomers with RNA-processing factors. Filamentous actin probes recognize discrete structures with submicron lengths that are excluded from chromatin-rich regions. In time-lapse movies, these actin filament structures exhibit one of two types of mobility: 1) diffusive, with an average diffusion coefficient of 0.06-0.08 MUm(2)/s, or (2) subdiffusive, with a mobility coefficient of 0.015 MUm(2)/s. Individual filament trajectories exhibit features of particles moving within a viscoelastic mesh. The small size of nuclear actin filaments is inconsistent with a role in micron-scale intranuclear transport, and their localization suggests that they do not participate directly in chromatin-based processes. Our results instead suggest that actin filaments form part of a large, viscoelastic structure in the nucleoplasm and may act as scaffolds that help organize nuclear contents. PMID- 23447707 TI - A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization. AB - Short, repetitive, G-rich telomeric sequences are synthesized by telomerase, a ribonucleoprotein consisting of telomerase reverse transcriptase (TERT) and an integrally associated RNA. Human TERT (hTERT) can repetitively reverse transcribe its RNA template, acting processively to add multiple telomeric repeats onto the same substrate. We investigated whether certain threshold levels of telomerase activity and processivity are required to maintain telomere function and immortalize human cells with limited lifespan. We assessed hTERT variants with mutations in motifs implicated in processivity and interaction with DNA, namely the insertion in fingers domain (V791Y), and the E primer grip motif (W930F). hTERT-W930F and hTERT-V791Y reconstitute reduced levels of DNA synthesis and processivity compared with wild-type telomerase. Of interest, hTERT-W930F is more defective in translocation than hTERT-V791Y. Nonetheless, hTERT-W930F, but not hTERT-V791Y, immortalizes limited-lifespan human cells. Both hTERT-W930F- and hTERT-V791Y-expressing cells harbor short telomeres, measured as signal free ends (SFEs), yet SFEs persist only in hTERT-V791Y cells, which undergo apoptosis, likely as a consequence of a defect in recruitment of hTERT-V791Y to telomeres. Our study is the first to demonstrate that low levels of DNA synthesis--on the order of 20% of wild-type telomerase levels--and extension of as few as three telomeric repeats are sufficient to maintain functional telomeres and immortalize limited-lifespan human cells. PMID- 23447709 TI - MEDIAL TEMPORAL LOBE CONTRIBUTIONS TO FUTURE THINKING: EVIDENCE FROM NEUROIMAGING AND AMNESIA. AB - Following early amnesic case reports, there is now considerable evidence suggesting a link between remembering the past and envisioning the future. This link is evident in the overlap in neural substrates as well as cognitive processes involved in both kinds of tasks. While constructing a future narrative requires multiple processes, neuroimaging and lesion data converge on a critical role for the medial temporal lobes (MTL) in retrieving and recombining details from memory in the service of novel simulations. Deficient detail retrieval and recombination may lead to impairments not only in episodic, but also in semantic prospection. MTL contributions to scene construction and mental time travel may further compound impairments in amnesia on tasks that pose additional demands on these processes, but are unlikely to form the core deficit underlying amnesics' cross-domain future thinking impairment. Future studies exploring the role of episodic memory in other forms of self-projection or future-oriented behaviour may elucidate further the adaptive role of memory. PMID- 23447708 TI - Mapping and analysis of phosphorylation sites: a quick guide for cell biologists. AB - A mechanistic understanding of signaling networks requires identification and analysis of phosphorylation sites. Mass spectrometry offers a rapid and highly sensitive approach to mapping phosphorylation sites. However, mass spectrometry has significant limitations that must be considered when planning to carry out phosphorylation-site mapping. Here we provide an overview of key information that should be taken into consideration before beginning phosphorylation-site analysis, as well as a step-by-step guide for carrying out successful experiments. PMID- 23447711 TI - Survival rates in a small hibernator, the edible dormouse: a comparison across Europe. AB - Understanding how local environmental factors lead to temporal variability of vital rates and to plasticity of life history tactics is one of the central questions in population ecology. We used long-term capture-recapture data from five populations of a small hibernating rodent, the edible dormouse Glis glis, collected over a large geographical range across Europe, to determine and analyze both seasonal patterns of local survival and their relation to reproductive activity. In all populations studied, survival was lowest in early summer, higher in late summer and highest during hibernation in winter. In reproductive years survival was always lower than in non-reproductive years, and females had higher survival rates than males. Very high survival rates during winter indicate that edible dormice rarely die from starvation due to insufficient energy reserves during the hibernation period. Increased mortality in early summer was most likely caused by high predation risk and unmet energy demands. Those effects have probably an even stronger impact in reproductive years, in which dormice were more active. Although these patterns could be found in all areas, there were also considerable differences in average survival rates, with resulting differences in mean lifetime reproductive success between populations. Our results suggest that edible dormice have adapted their life history strategies to maximize lifetime reproductive success depending on the area specific frequency of seeding events of trees producing energy-rich seeds. PMID- 23447710 TI - Prevalence of multinucleotide replacements in evolution of primates and Drosophila. AB - Evolution of sequences mostly involves independent changes at different sites. However, substitutions at neighboring sites may co-occur as multinucleotide replacement events (MNRs). Here, we compare noncoding sequences of several species of primates, and of three species of Drosophila fruit flies, in a phylogenetic analysis of the replacements that occurred between species at nearby nucleotide sites. Both in primates and in Drosophila, the frequency of single nucleotide replacements is substantially elevated within 10 nucleotides from other replacements that occurred on the same lineage but not on another lineage. The data imply that dinucleotide replacements (DNRs) affecting sites at distances of up to 10 nucleotides from each other are responsible for 2.3% of single nucleotide replacements in primate genomes and for 5.6% in Drosophila genomes. Among these DNRs, 26% and 69%, respectively, are in fact parts of replacements of three or more trinucleotide replacements (TNRs). The plurality of MNRs affect nearby nucleotides, so that at least six times as many DNRs affect two adjacent nucleotide sites than sites 10 nucleotides apart. Still, approximately 60% of DNRs, and approximately 90% of TNRs, span distances more than two (or three) nucleotides. MNRs make a major contribution to the observed clustering of substitutions: In the human-chimpanzee comparison, DNRs are responsible for 50% of cases when two nearby replacements are observed on the human lineage, and TNRs are responsible for 83% of cases when three replacements at three immediately adjacent sites are observed on the human lineage. The prevalence of MNRs matches that is observed in data on de novo mutations and is also observed in the regions with the lowest sequence conservation, suggesting that MNRs mainly have mutational origin; however, epistatic selection and/or gene conversion may also play a role. PMID- 23447712 TI - Strength, Hardening, and Failure Observed by In Situ TEM Tensile Testing. AB - We present in situ transmission electron microscope tensile tests on focused ion beam fabricated single and multiple slip oriented Cu tensile samples with thicknesses in the range of 100-200 nm. Both crystal orientations fail by localized shear. While failure occurs after a few percent plastic strain and limited hardening in the single slip case, the multiple slip samples exhibit extended homogenous deformation and necking due to the activation of multiple dislocation sources in conjunction with significant hardening. The hardening behavior at 1% plastic strain is even more pronounced compared to compression samples of the same orientation due to the absence of sample taper and the interface to the compression platen. Moreover, we show for the first time that the strain rate sensitivity of such FIB prepared samples is an order of magnitude higher than that of bulk Cu. PMID- 23447713 TI - The devil is in the details: stem cells for the treatment of epilepsy. PMID- 23447714 TI - SAVAs: Molecular Snipers for Silencing GABAergic Interneurons. PMID- 23447715 TI - Sweets Are BAD for Seizures. PMID- 23447716 TI - Hot spots light up the recurrent excitation hypothesis of temporal lobe epilepsy. PMID- 23447717 TI - Runaway dendrites: blame the older siblings. PMID- 23447718 TI - Seven questions about stroke and epilepsy. AB - Seizures and stroke are both common neurologic conditions, but when they occur in close temporal proximity they produce much more concern than either does alone. The stroke specialist (and the family) fear that convulsions will worsen the stroke because of acute hypertension and airway compromise, and the epileptologist is concerned that these acute seizures are the harbingers of later epilepsy. Other less commonly recognized but important aspects of this relationship are that subclinical seizures worsen some forms of stroke, and some anticonvulsants may have more adverse effects on stroke patients than they do in other groups. In surveying the connections between these two conditions, I have attempted to address seven questions. For some questions, there are data to help provide an answer; for others, there is only opinion; and for a maddening few, newer research is making older suggestions less certain. PMID- 23447719 TI - Plaques on the wall: inducing anticonvulsant use and atherogenesis. PMID- 23447720 TI - Are we too pessimistic about drug-resistant epilepsy? PMID- 23447721 TI - Deep white matter track record of functional integrity in childhood absence epilepsy. PMID- 23447722 TI - Baseline psychiatric evaluations are needed to treat seizures. PMID- 23447723 TI - Functional connectivity in mesial temporal lobe epilepsy: a dynamic concept. PMID- 23447724 TI - Perampanel: Getting AMPed for AMPA Targets. PMID- 23447725 TI - Introduction to institute of medicine report: epilepsy across the spectrum: promoting health and understanding. PMID- 23447726 TI - Summary: a reprint from epilepsy across the spectrum: promoting health and understanding. PMID- 23447727 TI - Obliterating the Seizure Focus in AVMs is Effective: More Clinical Data Confirming Common Sense. PMID- 23447728 TI - Turning up the heat on the impact of febrile status epilepticus. PMID- 23447729 TI - Antiepileptic medications after extratemporal epilepsy surgery: when do we stop? PMID- 23447730 TI - Are newer antiepileptic drugs associated with improved safety in pregnancy compared to older antiepileptic drugs? PMID- 23447731 TI - A Lesson from "The Brodie Ultimatum": The Locus of Control for Epilepsy is Outside the Therapeutic Alliance. PMID- 23447732 TI - A mutation hot-spot for benign infantile epilepsy. PMID- 23447733 TI - Zonisamide should be considered a first-line antiepileptic drug for patients with newly diagnosed partial epilepsy. PMID- 23447734 TI - Autoimmune epilepsy: are we seeing the tip of the iceberg . . . Or the whole thing? PMID- 23447735 TI - Spatial Learning and Memory-What's TLE Got To Do With It? AB - Cognitive impairment is a significant comorbidity of epilepsy. At present, the molecular/cellular mechanisms that underlie these cognitive impairments remain unknown. It seems likely that a complete understanding at the molecular/cellular level will require the use of rodent models. A number of rodent models of epilepsy are used to study cognition in a variety of behavioral tasks. This review presents a brief overview of two commonly used tasks (the Morris water maze and the radial arm maze) that have been used to assess spatial learning/memory in two chemoconvulsant models of temporal lobe epilepsy. PMID- 23447736 TI - Voltage-gated ion channel accessory subunits: sodium, potassium, or both? PMID- 23447737 TI - O brother, wherefore are thou? Calcium-permeable AMPA receptors make an appearance in adult status epilepticus. PMID- 23447738 TI - Adenosine and seizure termination: endogenous mechanisms. PMID- 23447739 TI - How deactivating an inhibitor causes absence epilepsy: validation of a noble lie. PMID- 23447740 TI - Sleep and epilepsy: a summary of the 2011 merritt-putnam symposium. PMID- 23447742 TI - Local, regional and national responses for medical management of a radiological/nuclear incident. AB - Radiological and nuclear devices may be used by terrorists or may be the source of accidental exposure. A tiered approach has been recommended for response to a terrorist event wherein local, regional, state and federal assets become involved sequentially, as the magnitude in severity of the incident increases. State-wide hospital plans have been developed and published for Connecticut, New York and California. These plans address delineation of responsibilities of various categories of health professionals, protection of healthcare providers, identification and classification of individuals who might have been exposed to and/or contaminated by radiation and, in the case of Connecticut response plan, early management of victims. Regional response programs such as the New England Regional Health Compact (consisting of 6 member states) have been developed to manage consequences of radiation injury. The Department of Homeland Security is ultimately responsible for managing both health consequences and the crisis. Multiple US national response assets may be called upon for use in radiological incidents. These include agencies and programs that have been developed by the Department of Energy, the Environmental Protection Agency and the Department of Defense. Coordination of national, regional and state assets with local response efforts is necessary to provide a timely and efficient response. PMID- 23447743 TI - Resource list for cognitive motor and sensory supports in persons with autism. PMID- 23447744 TI - How does dancing promote brain reconditioning in the elderly? PMID- 23447745 TI - 'Tis in our nature: taking the human-cannabis relationship seriously in health science and public policy. PMID- 23447747 TI - Inherited Real Risk of Type 2 Diabetes Mellitus: bedside diagnosis, pathophysiology and primary prevention. PMID- 23447748 TI - Are cultured mesenchymal stromal cells an option for immunomodulation in transplantation? PMID- 23447750 TI - Understanding Structure and Bonding of Multilayered Metal-Organic Nanostructures. AB - For organic and hybrid electronic devices, the physicochemical properties of the contained interfaces play a dominant role. To disentangle the various interactions occurring at such heterointerfaces, we here model a complex, yet prototypical, three-component system consisting of a Cu-phthalocyanine (CuPc) film on a 3,4,9,10-perylene-tetracarboxylic-dianhydride (PTCDA) monolayer adsorbed on Ag(111). The two encountered interfaces are similar, as in both cases there would be no bonding without van der Waals interactions. Still, they are also distinctly different, as only at the Ag(111)-PTCDA interface do massive charge-rearrangements occur. Using recently developed theoretical tools, we show that it has become possible to provide atomistic insight into the physical and chemical processes in this comparatively complex nanostructure distinguishing between interactions involving local rearrangements of the charge density and long-range van der Waals attraction. PMID- 23447751 TI - Emergency Department Crowding is Associated with Reduced Satisfaction Scores in Patients Discharged from the Emergency Department. AB - INTRODUCTION: Emergency department (ED) crowding has been shown to negatively impact patient outcomes. Few studies have addressed the effect of ED crowding on patient satisfaction. Our objective was to evaluate the impact of ED crowding on patient satisfaction in patients discharged from the ED. METHODS: We measured patient satisfaction using Press-Ganey surveys returned by patients that visited our ED between August 1, 2007 and March 31, 2008. We recorded all mean satisfaction scores and obtained mean ED occupancy rate, mean emergency department work index (EDWIN) score and hospital diversion status over each 8 hour shift from data archived in our electronic tracking board. Univariate and multivariate logistic regression analysis was calculated to determine the effect of ED crowding and hospital diversion status on the odds of achieving a mean satisfaction score >= 85, which was the patient satisfaction goal set forth by our ED administration. RESULTS: A total of 1591 surveys were returned over the study period. Mean satisfaction score was 77.6 (standard deviation [SD] +/-16) and mean occupancy rate was 1.23 (SD +/- 0.31). The likelihood of failure to meet patient satisfaction goals was associated with an increase in average ED occupancy rate (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.17 to 0.59, P < 0.001) and an increase in EDWIN score (OR 0.05, 95% CI 0.004 to 0.55, P = 0.015). Hospital diversion resulted in lower mean satisfaction scores, but this was not statistically significant (OR 0.62, 95% CI 0.36 to 1.05). In multivariable analysis controlling for hospital diversion status and time of shift, ED occupancy rate remained a significant predictor of failure to meet patient satisfaction goals (OR 0.34, 95% CI 0.18 to 0.66, P = 0.001). CONCLUSION: Increased crowding, as measured by ED occupancy rate and EDWIN score, was significantly associated with reduced patient satisfaction. Although causative attribution was limited, our study suggested yet another negative impact resulting from ED crowding. PMID- 23447752 TI - The impact of emergency physician turnover on planning for prospective clinical trials. AB - INTRODUCTION: Emergency physician (EP) turnover is a significant issue that can have strong economic impact on hospital systems, as well as implications on research efforts to test and improve clinical practice. This work is particularly important to researchers planning randomized trials directed toward EPs because a large degree of turnover within a physician group would attenuate the effectiveness of the desired intervention. We sought to determine the incidence and factors associated with EP workforce changes. METHODS: In an attempt to determine EP turnover and workforce change, data from the INSTINCT (INcreasing Stroke Treatment through INterventional behavior Change Tactics) trial were used. The INSTINCT trial is a prospective, cluster-randomized, controlled trial evaluating a targeted behavioral intervention to increase appropriate use of tissue plasminogen activator in acute ischemic stroke. Individual EPs staffing each of the study hospitals were identified at baseline and 18 months. Surveys were sent to EPs at both intervals. Models were constructed to investigate relationships between physician/hospital characteristics and workforce change. RESULTS: A total of 278 EPs were identified at baseline. Surveys were sent to all EPs at baseline and 18 months with a response rate of 72% and 74%, respectively. At 18 months, 37 (15.8%) had left their baseline hospital and 66 (26.3%) new EPs were working. Seven EPs switched hospitals within the sample. The total number of EPs at 18 months was 307, a 10.8% overall increase. Among the 24 hospitals, 6 had no EP departures and 5 had no new arrivals. The median proportion of EP workforce departing by hospital was 16% (interquartile range [IQR] = 4%-25%; range = 0% 73%), and the median proportion added was 21% (IQR = 7%-41%; range = 0%-120%). None of the evaluated covariates investigating relationships between physician/hospital characteristics and workforce change were significant. CONCLUSION: EP workforce changes over an 18-month period were common. This has implications for emergency department directors, researchers, and individual EPs. Those planning research involving interventions upon EPs should account for turnover as it may have an impact when designing clinical trials to improve performance on healthcare delivery metrics for time-sensitive medical conditions such as stroke, acute myocardial infarction, or trauma. PMID- 23447753 TI - The treatment of cutaneous abscesses: comparison of emergency medicine providers' practice patterns. AB - INTRODUCTION: Cutaneous abscesses are commonly treated in the emergency department (ED). Although incision and drainage (I&D) remains the standard treatment, there is little high-quality evidence to support additional interventions such as pain control, type of incision, and use of irrigation, wound cultures, and packing. Although guidelines exist to support clinician management of abscesses, they do not clearly specify these additional interventions. This study sought to describe the ED treatments administered to adults with uncomplicated superficial cutaneous abscesses, defined as purulent lesions requiring incision and drainage that could be managed in an ED or outpatient setting. METHODS: Four hundred and seventy-four surveys were distributed to 15 EDs across the United States. Participants were queried about their level of training and practice environment as well as specific questions regarding their management of cutaneous abscesses in the ED. RESULTS: In total, 350 providers responded to the survey (74%). One hundred eighty-nine respondents (54%) were attending physicians, 135 (39%) were residents, and 26 (7%) were midlevel providers. Most providers (76%) used narcotics for pain management, 71% used local anesthetic over the roof of the abscess, and 60% used local anesthetic in a field block for pain control. More than 48% of responders routinely used irrigation after (I&D). Eighty-five percent of responders used a linear incision to drain the abscess and 91% used packing in the wound cavity. Thirty-two percent routinely sent wound cultures and 17% of providers routinely prescribed antibiotics. Most providers (73%) only prescribed antibiotics if certain historical factors or physical findings were present on examination. Antibiotic treatment, if used, favored a combination of 2 or more drugs to cover both Streptococcus and methicillin-resistant Staphylococcus aureus (47%). Follow-up visits were most frequently recommended at 48 hours unless wound was concerning and required closer evaluation. CONCLUSION: Variability exists in the treatment strategies for abscess care. Most providers used narcotic analgesics in addition to local anesthetic, linear incisions, and packing. Most providers did not irrigate, order wound cultures, or routinely prescribe oral antibiotics unless specific risk factors or physical signs were present. Limited evidence is available at this time to guide these treatment strategies. PMID- 23447754 TI - Variation in specialists' reported hospitalization practices of children sustaining blunt head trauma. AB - INTRODUCTION: Questions surround the appropriate emergency department (ED) disposition of children who have sustained blunt head trauma (BHT). Our objective was to identify physician disposition preferences of children with blunt head trauma (BHT) and varying computed tomography (CT) findings. METHODS: WE SURVEYED PEDIATRIC AND GENERAL EMERGENCY PHYSICIANS (EP), PEDIATRIC NEUROSURGEONS (PNSURG), GENERAL NEUROSURGEONS (GNSURG), PEDIATRIC SURGEONS (PSURG) AND TRAUMA SURGEONS REGARDING CARE OF TWO HYPOTHETICAL PATIENTS: Case 1: a 9-year-old who fell 10 feet and Case 2: an 11-month-old who fell 5 feet. We presented various CT findings and asked physicians about disposition preferences. We evaluated predictors of patient discharge using multivariable regression analysis adjusting for hospital and ED characteristics and clinician experience. Pediatric EPs served as the reference group. RESULTS: Of 2,341 eligible surveyed, 715 (31%) responded. Most would discharge children with linear skull fractures (Case 1, 71%; Case 2, 62%). Neurosurgeons were more likely to discharge children with small subarachnoid hemorrhages (Case 1 PNSurg OR 6.87, 95% CI 3.60, 13.10; GNSurg OR 6.54, 95% CI 2.38, 17.98; Case 2 PNSurg OR 5.38, 95% CI 2.64, 10.99; GNSurg OR 6.07, 95% CI 2.08, 17.76). PSurg were least likely to discharge children with any CT finding, even linear skull fractures (Case 1 OR 0.14, 95% CI 0.08, 0.23; Case 2 OR 0.18, 95% CI 0.11, 0.30). Few respondents (<6%) would discharge children with small intraventricular, subdural, or epidural bleeds. CONCLUSION: Substantial variation exists between specialties in reported hospitalization practices of neurologically-normal children with BHT and traumatic CT findings. PMID- 23447755 TI - Variation in specialists' reported hospitalization practices of children sustaining blunt abdominal trauma. AB - INTRODUCTION: Children with blunt abdominal trauma (BAT) are often hospitalized despite no intervention. We identified factors associated with emergency department (ED) disposition of children with BAT and differing computed tomography (CT) findings. METHODS: We surveyed pediatric and general emergency physicians (EPs), pediatric and trauma surgeons regarding care of 2 hypothetical asymptomatic patients: a 9-year-old struck by a slow-moving car (Case 1) and an 11-month-old who fell 10 feet (Case 2). We presented various abdominal CT findings and asked physicians about disposition preferences. We evaluated predictors of patient discharge using multivariable regression analysis, adjusting for hospital and ED characteristics, and clinician experience. Pediatric EPs served as the reference group. RESULTS: Of 2,003 eligible surveyed, 636 (32%) responded. For normal CTs, 99% would discharge in Case 1 and 88% in Case 2. Prominent specialty differences included: for trace intraperitoneal fluid (TIF), 68% would discharge in Case 1 and 57% in Case 2. Patients with TIF were less likely to be discharged by pediatric surgeons (Case 1: OR 0.52, 95% CI 0.32, 0.82; Case 2: OR 0.49, 95% CI 0.30, 0.79). Patients with renal contusions were less likely to be discharged by pediatric surgeons (Case 1: OR 0.55, 95% CI 0.32, 0.95) and more likely by general EPs (Case 1: OR 1.83, 95% CI 1.25, 2.69; Case 2: OR 2.37, 95% CI 1.14, 4.89). CONCLUSION: Substantial variation exists between specialties in reported hospitalization practices of asymptomatic children after abdominal trauma with minor CT findings. Better evidence is needed to guide disposition decisions. PMID- 23447756 TI - Sedation-assisted Orthopedic Reduction in Emergency Medicine: The Safety and Success of a One Physician/One Nurse Model. AB - INTRODUCTION: Much of the emergency medical research on sedation-assisted orthopedic reductions has been undertaken with two physicians--one dedicated to the sedation and one to the procedure. Clinical practice in community emergency departments (EDs), however, often involves only one physician, who both performs the procedure and simultaneously oversees the crendentialed registered nurse who administers the sedation medication and monitors the patient. Although the dual physician model is advocated by some, evidence in support of its superiority is lacking. METHODS: In this electronic health records review we describe sedation assisted closed reductions of major joints and forearm fractures in three suburban community EDs. The type of procedure and sedation medication, need for specialty assistance, success rates, and intervention-requiring adverse events are reported. RESULTS: During the 18-month study period, procedural sedation was performed 457 times on 442 patients undergoing closed reduction for shoulder dislocations (n = 111), elbow dislocations (n = 29), hip dislocations (n = 101), and forearm fractures (n = 201). In the vast majority of this cohort (98.4% [435/442]), a single emergency physician simultaneously managed both the procedural sedation and the initial orthopedic reduction without the assistance of a second physician. The reduction was successful or satisfactory in 96.6% (425/435; 95% confidence interval [CI], 95.8-98.8%) of these cases, with a low incidence of intervention-requiring adverse events (2.8% [12/435]; 95% CI, 1.5 4.8%). CONCLUSION: Sedation-assisted closed reduction of major joint dislocations and forearm fractures can be performed effectively and safely in the ED using a one physician/one nurse model. A policy that requires a separate physician (or nurse anesthetist) to administer medications for all sedation-assisted ED procedures appears unwarranted. Further research is needed to determine which specific clinical scenarios might benefit from a dual-physician approach. PMID- 23447757 TI - Impact of emergency department management of atrial fibrillation on hospital charges. AB - INTRODUCTION: Emergency department (ED) cardioversion (EDCV) and discharge of patients with recent onset atrial fibrillation or atrial flutter (AF) has been shown to be a safe and effective management strategy. This study examines the impact of such aggressive ED management on hospital charges. METHODS: A random sample of 300 AF patients were identified from an ED electronic data base and screened for timing of onset of their symptoms. Patients were considered eligible for EDCV if either nursing or physician notes documented an onset of symptoms less than 48 hours prior to ED presentation and the patient was less than 85 years of age. An explicit chart review was then performed to determine patient management and disposition. Cardioversion attempts were defined as ED administration of procainamide, flecainide, propafenone, ibutilide, amiodarone or direct current cardioversion (DCCV). Total hospital charges for each patient were obtained from the hospital billing office. Differences across medians were analyzed utilizing through Wilcoxon rank sum tests and chi square. RESULTS: A total of 51 patients were included in the study. EDCV was attempted on 24 (47%) patients, 22 (92%) were successfully cardioverted to normal sinus rhythm (NSR). An additional 12 (23%) spontaneously converted to NSR. Twenty (91%) of those successfully cardioverted were discharged from the ED along with 4 (33%) of those spontaneously converting. Pharmacologic cardioverson was attempted in six patients and was successful in three (50%), one after failed DCCV attempt. Direct current cardioversion was attempted in 21 (88%) and was successful in 19 (90%), two after failed pharmacologic attempts. Median charges for patients cardioverted and discharged from the ED were $5,460 (IQR $4,677-$6,190). Median charges for admitted patients with no attempt at cardioversion were $23,202 (IQR $19,663 $46,877). Median charges for patients whose final ED rhythm was NSR were $5,641 (IQR $4,638-$12,339) while for those remaining inAF median charges were $30,299 (IQR $20,655 - $69,759). CONCLUSION: ED cardioversion of recent onset AF patients results in significant hospital savings. PMID- 23447758 TI - Guidelines for Field Triage of Injured Patients: In conjunction with the Morbidity and Mortality Weekly Report published by the Center for Disease Control and Prevention. AB - The Centers for Disease Control and Prevention (CDC) has published significant data and trends related to the national public health burden associated with trauma and injury. In the United States (U.S.), injury is the leading cause of death for persons aged 1-44 years. In 2008, approximately 30 million injuries resulted in an emergency department (ED) evaluation; 5.4 million (18%) of these patients were transported by Emergency Medical Services (EMS).1 EMS providers determine the severity of injury and begin initial management at the scene. The decisions to transport injured patients to the appropriate hospital are made through a process known as "field triage." Since 1986, the American College of Surgeons Committee on Trauma (ACS-COT) has provided guidance for the field triage process though its "Field Triage Decision Scheme." In 2005, the CDC, with financial support from the National Highway Traffic Safety Administration (NHTSA), collaborated with ASC-COT to convene the initial meeting of the National Expert Panel on Field Triage (the Panel) to revise the decision scheme. This revised version was published in 2006 by ASC-COT, and in 2009 the CDC published a detailed description of the scientific rational for revising the field triage criteria entitled, "Guidelines for Field Triage of Injured Patients."2-3 In 2011, the CDC reconvened the Panel to review the 2006 Guidelines and recommend any needed changes. We present the methodology, findings and updated guidelines from the Morbidity & Mortality Weekly Report (MMWR) from the 2011 Panel along with commentary on the burden of injury in the U.S., and the role emergency physicians have in impacting morbidity and mortality at the population level. PMID- 23447759 TI - Commentary on "uncovering awareness: medical and ethical challenges in diagnosing and treating the minimally conscious state". PMID- 23447760 TI - Enhancing brains: what are we afraid of? PMID- 23447761 TI - Promoting brain-science literacy in the k-12 classroom. AB - There are many simple ways to incorporate neuroscience into the K-12 classroom, even when the subject is not explicitly part of the curriculum. Here, Michaela Labriole, a science instructor at the New York Hall of Science, provides tangible examples of how teachers can encourage brain-science literacy in students at a time when growing knowledge of the brain is shaping our understanding of how to best foster learning. PMID- 23447762 TI - The brain in science education: what should everyone learn? AB - Dr. Jo Ellen Roseman and Mary Koppal, from the American Academy for the Advancement of Science (AAAS), discuss how brain science fits into national classroom curricula. While recommendations published by AAAS, the National Research Council, the Society for Neuroscience, and the College Board all include standards relating to the brain, what students actually learn in the classroom varies greatly from state to state. PMID- 23447763 TI - Fear in love: attachment, abuse, and the developing brain. AB - Why do abused children attach and remain attached to abusive parents? In this article, Dr. Regina Sullivan explains how her research with rat pups has led to greater understanding of the infant brain, and how negative early experiences can cause long-term genetic, brain, behavioral, and hormonal changes that can affect not only the abuse victim but also the victim's descendants. PMID- 23447764 TI - Seizing an opportunity: broader definitions of epilepsy may lead to better treatments. AB - There is not just one type of epilepsy. While some forms of the disease are characterized by convulsive seizures, others involve seizures that are barely noticeable. Seizures can occur for many reasons: they can be caused by genetic mutations, injury, or infection early in life. In addition, events in daily life, such as stress, or normal variations in hormones, such as estrogen and testosterone, can influence brain activity and therefore influence seizures. By considering the powerful interactions between the brain and the endocrine system, this influence of hormones on seizures can be understood and new treatment options can be considered. PMID- 23447765 TI - The default network: your mind, on its own time. AB - Studies about the brain usually focus on neural activity during the completion of a specific task-remembering a series of words, for example. But over the last 20 years, researchers have been interested in what the brain does during periods of supposed inactivity. They discovered that when someone appears to be doing nothing at all, a network of brain regions-named the default network-is hard at work, allowing for the rich inner lives inside our heads. Applying what is known about the default network to diseases like Alzheimer's allows for new possibilities for diagnosis and evaluation of treatments. PMID- 23447766 TI - Long-term Memories: The Good, the Bad, and the Ugly. AB - Traumatic memories haunt the lives of people suffering from post-traumatic stress disorder, or PTSD, and other illnesses. Fortunately, recent research into the changeability of long-term memories may someday develop into treatments for such individuals. But before this can happen, writes Cristina Alberini, Ph.D., of Mount Sinai School of Medicine, researchers must determine just how effectively the fear associated with older memories-especially those involved in PTSD-can be reduced and for how long. Researchers must also address the ethical issues that go hand in hand with modifying memory. PMID- 23447767 TI - The great brain books, revisited. PMID- 23447768 TI - The diagnostic dilemma: why we need to change how we diagnose bipolar disorder in children. AB - Bipolar disorder diagnosis has been rising dramatically in children for the past decade. In response to this increase, writes Daniel Dickstein, M.D., of Bradley Hospital and Brown University, researchers at the National Institute of Mental Health and elsewhere are reviewing the diagnostic criteria. In coming years, Dickstein argues, recognizing and diagnosing bipolar disorder in children should be based more on biological markers, such as brain structure and the use of neural circuits, than on the inconsistent diagnostic categories laid out in the Diagnostic and Statistical Manual of Mental Disorders. PMID- 23447769 TI - The promise and the reality of stem-cell therapies for neurodegenerative diseases. AB - Jonathan D. Glass, M.D., is leading a clinical trial testing the safety of using adult stem cells to treat patients with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that remains untreatable. This trial, along with others like it, is just the beginning of a time-intensive process necessary to determine whether stem-cell treatments are safe and effective, meaning that the benefits-if there prove to be any-outweigh the risks. But even as FDA-approved trials are underway, some people with neurodegenerative disorders are turning to dangerous, unapproved stem-cell treatments out of desperation. Dr. Glass warns that researchers must strictly adhere to the scientific process in order to convert the hope of stem-cell treatments into reality. PMID- 23447770 TI - Commentary on "the promise and the reality of stem-cell therapies for neurodegenerative diseases". PMID- 23447771 TI - The crossroads of magic and science: sleights of mind: what the neuroscience of magic reveals about our everyday deceptions. PMID- 23447772 TI - Forecasting aggression: toward a new interdisciplinary understanding of what makes some troubled youth turn violent. AB - It takes a series of unfortunate circumstances for an adolescent to turn violent. While early exposure to familial violence can play a role, so too can biological influences such as hormone levels and genetic predispositions. The combination of these factors can be deadly. Although genes and other biological causes are difficult to identify and may be impossible to overcome through known therapeutic methods, medical professionals' intervention techniques can help minimize aggressive behavior related to environmental factors. PMID- 23447773 TI - The Mind's Eye. PMID- 23447774 TI - Cross-cultural barriers to mental health services in the United States. AB - Getting treatment for a mental illness can be difficult for any American-and more than half of all adults in the country will experience a mental illness during their lives. But for members of ethnic and racial minority groups, the road to treatment is often blocked by cultural views of mental illness and therapy, lack of insurance and access to appropriate care, and a critical deficiency of studies pertaining to nonwhite populations. Significant, national changes to the mental health field must be made in order for proper care to be widely available and accepted. PMID- 23447775 TI - Diagnosing the DSM: Diagnostic Classification Needs Fundamental Reform. AB - If all goes as planned, the American Psychiatric Association will release a new Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in May 2013. Since 1980, the DSM has provided a shared diagnostic language to clinicians, patients, scientists, school systems, courts, and pharmaceutical and insurance companies; any changes to the influential manual will have serious ramifications. But, argues Dr. Steven Hyman, the DSM is a poor mirror of clinical and biological realities; a fundamentally new approach to diagnostic classification is needed as researchers uncover novel ways to study and understand mental illness. PMID- 23447776 TI - Oversimplifying sex differences in the brain: man and woman: an inside story. PMID- 23447777 TI - Epigenetics and the human brain: where nurture meets nature. AB - While our genetic code determines a great deal of who and what we are, it does not act alone. It depends heavily on the epigenome, an elaborate marking of the DNA that controls the genome's functions. Because it is sensitive to the environment, the epigenome is a powerful link and relay between our genes and our surroundings. Epigenetic marks drive biological functions and features as diverse as memory, development, and disease susceptibility; thus, the nurture aspect of the nature/nurture interaction makes essential contributions to our body and behaviors. As scientists have learned more about how the epigenome works, they have begun to develop therapies that may lead to new approaches to treating common human conditions. PMID- 23447778 TI - Aging with Meaning: How We Age: A Doctor's Journey into the Heart of Growing Old. PMID- 23447779 TI - Promoting healthy, meaningful aging through social involvement: building an experience corps. AB - Pathways responsible for higher-order thinking in the prefrontal cortex (PFC), or executive center of the brain, remain vulnerable throughout life-during critical early-life developmental windows, when the PFC fully matures in the early 20s, and finally from declines associated with old age. At all ages, physical activity and PFC-navigated social connections are essential components to maintaining brain health. The Experience Corps, a community-based social-engagement program, partners seniors with local schools to promote purpose-driven involvement. Participating seniors have exhibited immediate short-term gains in brain regions vulnerable to aging, such as the PFC, indicating that people with the most to lose have the most to gain from environmental enrichment. PMID- 23447780 TI - Designing a plan for drug discovery in rare pediatric neurodegenerative disease. AB - There are currently no cures for neurodegenerative diseases, including Batten disease, a rare and fatal disorder affecting young children. While researchers have made headway in preventing genetic disorders through preconception carrier screenings and have found potential drug targets, the gap between basic research and clinical treatment development remains. To overcome this gap, write authors Dr. Danielle Kerkovich and Amy Drew, researchers in academia and the pharmaceutical industry, supported by government agencies and nonprofit institutions, must come together to share expertise and promote translational research. PMID- 23447782 TI - From lab bench to court bench: using science to inform decisions in juvenile court. AB - Juvenile court judges are asked to determine what is in the best interest of the child in every case they hear. As Judge Cindy S. Lederman writes, making these decisions without an awareness of the science of child development can be detrimental to the mental and physical well-being of the child. Yet until about a decade ago, court decisions were routinely made without taking into consideration the needs of toddlers and infants. The Miami Child Well-Being CourtTM (MCWBC) program, a partnership of clinicians and judges, has brought science into the courtroom, making it integral to the decision-making process and working to ensure that the needs of the child are met. PMID- 23447781 TI - Using brain imaging to unravel the mysteries of stuttering. AB - After many decades of attributing stuttering to causes ranging from childhood trauma to overly anxious personalities, scientists have used neuroimaging techniques to uncover measurable differences in the brain activity of people who stutter versus fluent speakers. But while researchers have made great strides in understanding stuttering in adults, the neural basis of stuttering in children largely remains a mystery. We do not yet know why up to 80 percent of children who stutter recover without intervention, nor do we know how to distinguish those who will recover without intervention from those who will not. However, recent findings support the idea that early intervention can alter or normalize brain function before stuttering-induced changes become hardwired. PMID- 23447783 TI - Effects of stress on the developing brain. AB - In a complementary article, Judge Cindy Lederman explains the importance of using science to inform family court decisions. Here, Dr. Bruce S. McEwen looks at that science in depth, discussing how early-life stress can lead to long-lasting behavioral, mental, and physical consequences. Fortunately, preventive measures can improve health outcomes, and while interventions for those who have already experienced debilitating early-life stress require considerable effort, they remain possible, thanks to the brain's plasticity. PMID- 23447784 TI - More mysterious than we suppose: making sense of people: decoding the mysteries of personality. PMID- 23447785 TI - Optogenetics: using light to control the brain. PMID- 23447786 TI - Social neuroscience: how a multidisciplinary field is uncovering the biology of human interactions. PMID- 23447787 TI - Suicide and the United States army: perspectives from the former psychiatry consultant to the army surgeon general. AB - The suicide rate of active-duty soldiers doubled between 2003 and 2010. In response, the Department of Defense and the United States Army improved their data collection methods to better understand the causes of military suicides. As retired colonel Dr. Elspeth Cameron Ritchie writes, unit history and the accumulation of stressors-from relationship problems to chronic pain-are significant suicide risk factors among soldiers. But, she argues, Army officials must use this knowledge to design more-effective strategies for suicide reduction, including limiting access to weapons, especially post-deployment, and better connecting soldiers with their communities. PMID- 23447788 TI - Musical creativity and the brain. AB - On the spot, as great jazz performers expertly improvise solo passages, they make immediate decisions about which musical phrases to invent and to play. Researchers, like authors Monica Lopez-Gonzalez and Dana Foundation grantee Charles J. Limb, are now using brain imaging to study the neural underpinnings of spontaneous artistic creativity, from jazz riffs to freestyle rap. So far, they have found that brain areas deactivated during improvisation are also at rest during dreaming and meditation, while activated areas include those controlling language and sensorimotor skills. Even with relatively few completed studies, researchers have concluded that musical creativity clearly cannot be tied to just one brain area or process. PMID- 23447789 TI - A new approach to rheumatoid arthritis: treating inflammation with computerized nerve stimulation. AB - Doctors currently treat rheumatoid arthritis, a crippling autoimmune disease, with an arsenal of drugs that, while often effective, can have serious side effects. Authors Ulf Andersson and Kevin J. Tracey describe a circuit between the immune system and the nervous system that enabled development of an implanted nerve stimulator to treat the disorder, now being tested by a patient in Bosnia. If further clinical trials show as much promise as this initial case, similar devices may be developed for a broad range of inflammation-related diseases, from diabetes to congestive heart failure. PMID- 23447791 TI - A family tree filled with mental illness: review: a lethal inheritance: a mother uncovers the science behind three generations of mental illness by victoria costello. PMID- 23447790 TI - The Role of Stress in Brain Development: The Gestational Environment's Long-Term Effects on the Brain. AB - During gestation, the fetal brain develops dramatically as structures and connections form, providing the foundation for all future development. The fetal environment plays a critical role in these early neural processes, for better or for worse. Scientists now know that exposure to maternal stress can sometimes have deleterious effects on the fetus, depending on the cause, timing, duration, and intensity of stress. Fortunately, postnatal interventions, such as a secure parent-infant bond and an enriched environment, can buffer the potential negative consequences. PMID- 23447792 TI - Biomarkers and the future of treatment for depression. AB - Doctors have a variety of drug options for treatment of depression. But there is currently no way to determine which antidepressant will work best for a given patient, which means that many people continue to suffer while their doctors try a series of medications. As Marisa Toups and Madhukar H. Trivedi write, however, many researchers have focused their efforts on developing biomarkers for depression-tests for aspects of a patient's physiology that can predict a clinical outcome. In the future, doctors may be able to screen patients to determine which treatment options will work for them, reducing the time a patient must continue to live with the effects of depression. PMID- 23447793 TI - A future without chronic pain: neuroscience and clinical research. AB - Chronic pain affects 1.5 billion people worldwide, an estimated 100 million of whom live in the United States. Yet we currently have no effective treatment options. Fortunately, writes David Borsook, director of the Pain and Imaging Neuroscience Group at Children's Hospital Boston, Massachusetts General Hospital, and McLean Hospital, research advances have determined some of the ways in which chronic pain changes the brain, and several promising research areas could lead to better treatment approaches. Dr. Borsook recommends steps to facilitate these new treatments, including the establishment of integrated clinical neuroscience centers bridging the gap between bench and bedside. PMID- 23447794 TI - Repairing the injured brain: why proper rehabilitation is essential to recovering function. AB - Recovery from a brain injury is a slow process with no obvious end point-a practical dilemma for patients, caregivers, and medical professionals. While research continues to advance the field to determine optimal interventions (see this complementary article on the neurobiology of injury), front-line providers, like author Mark J. Ashley, founder and CEO of the Centre for Neuro Skills, have found that certain rehabilitation environments and procedures encourage a stronger recovery than others. But even as specialized facilities make strides, many people face barriers to adequate care. PMID- 23447795 TI - The neurobiology of brain injury. AB - In a complementary article, Dr. Mark J. Ashley discusses frontline rehabilitation methods that can improve brain injury recovery outcomes. Here, Marcela Pekna and Milos Pekny explain what happens within the brain after injury and how scientists' growing awareness of the brain's capacity for repair could lead to better treatment options. PMID- 23447796 TI - Are you responsible for your hormones?: review: the moral molecule: the source of love and prosperity by paul j. Zak, ph.d. PMID- 23447797 TI - Re-opening Windows: Manipulating Critical Periods for Brain Development. AB - The brain acquires certain skills-from visual perception to language-during critical windows, specific times in early life when the brain is actively shaped by environmental input. Scientists like Takao K. Hensch are now discovering pathways in animal models through which these windows might be re-opened in adults, thus re-awakening a brain's youth-like plasticity. Such research has implications for brain injury repair, sensory recovery, and neurodevelopmental disorder treatment. In addition, what we know today about these critical windows of development already has enormous implications for social and educational policy. PMID- 23447798 TI - Play, stress, and the learning brain. AB - An extraordinary number of species-from squid to lizards to humans-engage in play. But why? In this article, adapted from Dr. Sam Wang and Dr. Sandra Aamodt's book Welcome to Your Child's Brain: How the Mind Grows from Conception to College (Bloomsbury USA, 2011; OneWorld Publications, 2011), the authors explore how play enhances brain development in children. As Wang and Aamodt describe, play activates the brain's reward circuitry but not negative stress responses, which can facilitate attention and action. Through play, children practice social interaction and build skills and interests to draw upon in the years to come. PMID- 23447799 TI - The cognitive benefits of being bilingual. AB - Today, more of the world's population is bilingual or multilingual than monolingual. In addition to facilitating cross-cultural communication, this trend also positively affects cognitive abilities. Researchers have shown that the bilingual brain can have better attention and task-switching capacities than the monolingual brain, thanks to its developed ability to inhibit one language while using another. In addition, bilingualism has positive effects at both ends of the age spectrum: Bilingual children as young as seven months can better adjust to environmental changes, while bilingual seniors can experience less cognitive decline. PMID- 23447802 TI - In this issue of Mobile Genetic Elements. PMID- 23447800 TI - Cognitive impairment in multiple sclerosis: a forgotten disability remembered. AB - Physicians first noted the presence of cognitive impairment in patients with multiple sclerosis (MS) more than 160 years ago, yet it took clinicians until 2001 to codify a standard test to measure cognitive function. We now know that cognitive impairment occurs in up to 65 percent of people with MS and usually lessens their ability to remember previously learned information. So far, trials of drugs formulated to treat cognitive impairment have failed, but the authors remain optimistic that new approaches to diagnosis and drug development could lead to effective therapies in the future. PMID- 23447803 TI - Treatment of traumatic globe dislocated completely into the maxillary sinus. PMID- 23447804 TI - Surgical treatment for neovascularized retinal pigment epithelial detachment in age-related macular degeneration. PMID- 23447805 TI - Anti-idiotype antibodies in cancer treatment. PMID- 23447812 TI - A Phase I/II trial of radiotherapy concurrent with TS-1 plus cisplatin in patients with clinically resectable type 4 or large type 3 gastric cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group OGSG1205. AB - A Phase I/II trial of radiotherapy administered concurrently with TS-1 plus cisplatin has been initiated in Japanese patients with clinical resectable type 4 or large type 3 gastric cancer. The aim of this trial is to determine the recommended dose of TS-1 and cisplatin combined with radiotherapy at a fixed dose in the Phase I study, and to evaluate the efficacy and safety in the Phase II study. The primary endpoint for Phase II is the pathological complete response rate, assessed using surgically resected specimens. Secondary endpoints are the response rate, progression-free survival, overall survival, operation transitional rate, R0 resection rate, rate of treatment completion, rate of down staging and rates of postoperative complications and adverse events. In Phase II, a total of 30 patients will be enrolled in the Osaka Gastrointestinal Cancer Chemotherapy Study Group trial over a period of 6 years. PMID- 23447813 TI - Current Medicinal Chemistry endeavors to provide its readership with extensive coverage. Foreword. PMID- 23447814 TI - Response to 'Remarks on the article of Packard: Julian Huxley, Uca pugnax and the allometric method'. PMID- 23447815 TI - The largest unmet market: chronic diseases of aging. PMID- 23447816 TI - Giant parallel tubular arrays in T lymphocytes. PMID- 23447817 TI - From dye-dilution to digital angiography. PMID- 23447818 TI - The futuristic nature of endoscopic approaches. Author's response. PMID- 23447819 TI - Retraction. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. PMID- 23447820 TI - UC-Davis veterinarians identify new raccoon polyomavirus: discovery could help explain how viruses cause cancer in animals and humans. PMID- 23447821 TI - [Reply]. PMID- 23447822 TI - [Mass vaccination against cholera]. PMID- 23447823 TI - Mutation screening for KRAS and BRAF in metastatic colorectal cancer proves costly in relation to benefits. PMID- 23447824 TI - Discovery of drug resistance biomarker could improve cancer treatment. PMID- 23447825 TI - Biochemical targets of tamoxifen and lithium in an animal model of mania. PMID- 23447827 TI - Evaluation of the role of HTR1A C-1019G polymorphism in antidepressant efficacy: a meta-analysis. PMID- 23447826 TI - CYP450 genotypes: metabolism and efficacy of the antidepressant mirtazapine. PMID- 23447828 TI - Reply to L Bennedsen et al. PMID- 23447829 TI - Reply to A Tremblay. PMID- 23447830 TI - [Culicidae of medical-veterinary importance in natural breeding sites located in three areas of Camaguey province in Cuba]. AB - INTRODUCTION: Malaria is a serious public health problem at present; it affects almost half of the population from over 100 countries and poses a high risk of reintroduction in Cuba. OBJECTIVE: To identify the Culicidae species present in natural breeding sites located in three areas of Camaguey municipality, particularly anopheles. METHODS: Larval inspections were carried out in 66 natural breeding sites of Anopheles almimanus located in three areas of Camaguey municipality from May to June 2010, according the World Health Organization methodology. The preferential breeding sites of Anopheles albimanus and the association of this species with other Culicidae were ascertained. RESULTS: Presence of Culicidae in 28.78% of inspected breeding sites, being Anopheles albimanus the prevailing one with 63.51%. This species was captured together with Culex quinquefasciatus, Culex nigripalpus, Culex erraticus, Culex corniger, Psorophora confinnis, Psorophora howardii and Ochlerottatus scapularis, in low polluted water bodies such as lagoons (58.34%) and streams (25%), and in others more polluted such as ditches (8.33%) and narrow trails (8.33%). CONCLUSIONS: The existence of species of medical and veterinary importance, particularly Anopheles albimanus, in the studied areas calls for constant monitoring of these species in order to draw up integrated strategies focused on the biological fight, and the involvement of the community in this process to help in preventing the emergence of cases or epidemic outbreaks of imported malaria. PMID- 23447836 TI - [A tool to share information about outpatient chemotherapy between hospital and pharmacy]. PMID- 23447837 TI - [Breast and endocrine tumor]. PMID- 23447838 TI - [Front line of sentinel lymph node biopsy]. PMID- 23447839 TI - [Current status and problems on preoperative hormone therapy]. PMID- 23447840 TI - [Front line for treatment of bone metastasis]. PMID- 23447841 TI - Diabetic foot infection. PMID- 23447842 TI - [Investigation on mental health state of 37 patients of femoral head]. PMID- 23447843 TI - The potency testing of botulinum neurotoxin products. PMID- 23447844 TI - Re: Pickett, the botulinum toxin LD50 potency assay - another chapter, another mystery. PMID- 23447845 TI - Pathophysiology, prevention, and treatment of ebullism. AB - INTRODUCTION: Ebullism is the spontaneous evolution of liquid water in tissues to water vapor at body temperature when the ambient pressure is 47 mmHg or less. While injuries secondary to ebullism are generally considered fatal, some reports have described recovery after exposure to near vacuum for several minutes. The objectives of this article are to review the current literature on ebullism and to present prevention and treatment recommendations that can be used to enhance the safety of high altitude activities and space operations. METHODS: A systematic review was conducted on currently available information and published literature of human and animal studies involving rapid decompression to vacuum and ebullism, with subsequent development of an applicable treatment protocol. RESULTS: Available research on ebullism in human and animal subjects is extremely limited. Literature available identified key pathophysiologic processes and mitigation strategies that were used for treatment protocol design and outlining appropriate interventions using current best medical practices and technologies. DISCUSSION: Available literature suggests that the pathophysiology of ebullism leads to predictable and often treatable injuries, and that many exposures may be survivable. With the growing number of high altitude and space-related activities, more individuals will be at risk for ebullism. An integrated medical protocol can provide guidance for the prevention and treatment of ebullism and help to mitigate this risk in the future. PMID- 23447846 TI - Ad libitum vs. restricted fluid replacement on hydration and performance of military tasks. AB - INTRODUCTION: The primary objective was to evaluate the effect of ad libitum vs. restricted fluid replacement protocol on hydration markers and performance in selected military tasks. The secondary objective was to determine if 300 ml x h( 1) could be considered a safe minimum fluid intake under the experimental conditions. METHODS: Data were collected simulating a route march over 16 km. There were 57 subjects who participated in the study. RESULTS: The mean pre exercise body mass of the ad libitum group was 70.4 +/- 13.3 (SD) kg compared to 69.3 +/- 8.9 kg in the restricted group. The mean total fluid intake of the ad libitum group was 2.1 +/- 0.9 L compared to 1.2 +/- 0.0 L in the restricted group. The ad libitum and restricted intake groups, respectively, lost a mean of 1.05 kg +/- 0.77 (1.5%) and 1.34 kg +/- 0.37 (1.9%). Calculated sweat rate was 608 +/- 93 ml x h(-1) compared to 762 +/- 162 ml x h(-1) in the ad libitum group. DISCUSSION: There were no significant differences for either urine specific gravity (USG) or urine osmolality (UOsm) before or after the exercise. It is not clear whether fluid intake and calculated sweat rates are causally related or explained by their codependence on a third variable; for example, the exercising metabolic rate. Thus, 300 ml x h(-1) intake could be considered a current safe minimum water intake for soldiers of similar mass under similar experimental conditions, namely similar exercise durations at equivalent exercise intensities in a moderate, dry climate. PMID- 23447847 TI - Motion sickness adaptation to Coriolis-inducing head movements in a sustained G flight simulator. AB - BACKGROUND: Technological advances have allowed centrifuges to become more than physiological testing and training devices; sustained G, fully interactive flight simulation is now possible. However, head movements under G can result in vestibular stimulation that can lead to motion sickness (MS) symptoms that are potentially distracting, nauseogenic, and unpleasant. In the current study an MS adaptation protocol was tested for head movements under +Gz. METHODS: Experienced pilots made 14 predetermined head movements in a sustained G flight simulator (at 3 +Gz) on 5 consecutive days and 17 d after training. Symptoms were measured after each head turn using a subjective 0-10 MS scale. The Simulator Sickness Questionnaire (SSQ) was also administered before and after each daily training session. RESULTS: After five daily training sessions, normalized mean MS scores were 58% lower than on Day 1. Mean total, nausea, and disorientation SSQ scores were 55%, 52%, and 78% lower, respectively. During retesting 17 d after training, nearly all scores indicated 90-100% retention of training benefits. DISCUSSION: The reduction of unpleasant effects associated with sustained G flight simulation using an adaptation training protocol may enhance the effectiveness of simulation. Practical use of sustained G simulators is also likely to be interspersed with other types of ground and in-flight training. Hence, it would be undesirable and unpleasant for trainees to lose adaptation benefits after a short gap in centrifuge use. However, current results suggest that training gaps in excess of 2 wk may be permissible with almost no loss of adaptation training benefits. PMID- 23447848 TI - Changed joint position sense and muscle activity in simulated weightlessness by water immersion. AB - BACKGROUND: Previous studies suggested that proprioceptive feedback for passive arm positioning and isometric forces deteriorates under water. Here we investigate whether a similar deficit exists for active arm positioning. Since deficits were attributed to a reduced muscle tone but findings about muscle tone in water are ambiguous, we re-evaluated this issue. METHODS: With their right forearm, 24 subjects reproduced visual templates which showed a forearm at 45 degrees, 90 degrees, and 135 degrees orientations in the sagittal plane on land (Dry) and during water immersion (Wet). Mean reproduction error and its standard deviation were calculated in allocentric (space-referenced) and egocentric (body referenced) coordinates. Additionally, 12 of the 24 subjects also participated in an experiment where relaxed left arm EMG was registered in Wet and Dry. RESULTS: Mean error was comparable in Wet (7.72 degrees) and Dry (6.79 degrees), but error variability was significantly smaller in Wet (7.52 degrees) than in Dry (9.58 degrees). Errors in allocentric (3.42 degrees) differed from egocentric coordinates (11.08 degrees), independent of Wet and Dry. Resting EMG was significantly lower in Wet (3.02 microV) than in Dry (3.73 microV). DISCUSSION: Proprioceptive feedback for active arm movements is enhanced under water, probably due to high water viscosity, which increases spindle afferents during active but not passive arm movements or isometric responses. We found no evidence that the reference frame for orientation judgments differ between Wet and Dry. Muscle tone of the relaxed arm was reduced under water, corroborating that water immersion degrades proprioception during isometric tasks and passive arm positioning. This is probably not relevant for active arm movements, which seem to increase rather than decrease muscle force to overcome water's viscosity. PMID- 23447849 TI - Pilot performance: assessing how scan patterns & navigational assessments vary by flight expertise. AB - INTRODUCTION: Helicopter overland navigation is a cognitively complex task that requires continuous monitoring of system and environmental parameters and many hours of training to master. This study investigated the effect of expertise on pilots' gaze measurements, navigation accuracy, and subjective assessment of their navigation accuracy in overland navigation on easy and difficult routes. METHODS: A simulated overland task was completed by 12 military officers who ranged in flight experience as measured by total flight hours (TFH). They first studied a map of a route that included both easy and difficult route sections, and then had to 'fly' this simulated route in a fixed-base helicopter simulator. They also completed pre-task estimations and post-task assessments of the navigational difficulty of the transit to each waypoint in the route. Their scan pattern was tracked via eye tracking systems, which captured both the subject's out-the-window (OTW) and topographical map scan data. RESULTS: TFH was not associated with navigation accuracy or root mean square (RMS) error for any route section. For the easy routes, experts spent less time scanning out the window (p = 0.61) and had shorter OTW dwell (p = -0.66). For the difficult routes, experts appeared to slow down their scan by spending as much time scanning out the window as the novices while also having fewer Map fixations (p = -0.65) and shorter OTW dwell (p = -0.69). However, TFH was not significantly correlated with more accurate estimates of route difficulty. DISCUSSION: This study found that TFH did not predict navigation accuracy or subjective assessment, but was correlated with some gaze parameters. PMID- 23447850 TI - Neck muscle activity in fighter pilots wearing night-vision equipment during simulated flight. AB - INTRODUCTION: Night-vision goggles (NVG) in jet fighter aircraft appear to increase the risk of neck strain due to increased neck loading. The present aim was, therefore, to evaluate the effect on neck-muscle activity and subjective ratings of head-worn night-vision (NV) equipment in controlled simulated flights. METHODS: Five experienced fighter pilots twice flew a standardized 2.5-h program in a dynamic flight simulator; one session with NVG and one with standard helmet mockup (control session). Each session commenced with a 1-h simulation at 1 Gz followed by a 1.5-h dynamic flight with repeated Gz profiles varying between 3 and 7 Gz and including aerial combat maneuvers (ACM) at 3-5 Gz. Large head-and neck movements under high G conditions were avoided. Surface electromyographic (EMG) data was simultaneously measured bilaterally from anterior neck, upper and lower posterior neck, and upper shoulder muscles. EMG activity was normalized as the percentage of pretest maximal voluntary contraction (%MVC). Head-worn equipment (helmet comfort, balance, neck mobility, and discomfort) was rated subjectively immediately after flight. RESULTS: A trend emerged toward greater overall neck muscle activity in NV flight during sustained ACM episodes (10% vs. 8% MVC for the control session), but with no such effects for temporary 3-7 Gz profiles. Postflight ratings for NV sessions emerged as "unsatisfactory" for helmet comfort/neck discomfort. However, this was not significant compared to the control session. CONCLUSIONS: Helmet mounted NV equipment caused greater neck muscle activity during sustained combat maneuvers, indicating increased muscle strain due to increased neck loading. In addition, postflight ratings indicated neck discomfort after NV sessions, although not clearly increased compared to flying with standard helmet mockup. PMID- 23447851 TI - Toxicological findings in fatally injured pilots of 979 amateur-built aircraft accidents. AB - BACKGROUND: Specimens from aviation accident pilot fatalities are submitted to the Civil Aerospace Medical Institute (CAMI) for toxicological analyses. Trends of fatal amateur-built aircraft accidents and toxicological findings in the associated pilot fatalities have not been examined. METHODS: Fatal amateur-built aircraft accidents that occurred during 1990-2009 were evaluated by retrieving information from the CAMI toxicology database. Probable cause/factor in the amateur-built aircraft mishaps were obtained from the National Transportation Safety Board's (NTSB's) aviation accident database. RESULTS: Of 6309 fatal aviation accidents from which CAMI received postmortem samples, 979 (16%) were related to amateur-built aircraft. There was a decreasing trend in non-amateur built aircraft accidents, but an increasing trend in amateur-built aircraft accidents. In the 979 accidents, 392 pilots (40%) were positive for ethanol and/or drugs. In these 392 accidents also, the review showed a decreasing trend with non-amateur-built aircraft and an increasing trend with amateur-built aircraft. Percentages of pilots with prescription drugs were 26% for amateur built aircraft, 16% for non-amateur-built aircraft, and 18% for all aircraft. Ethanol/drug use and medical condition were determined to be a cause/factor in 42 (11%) of the 385 ethanol/ drug-positive amateur-built aircraft accidents investigated by the NTSB. DISCUSSION: Drugs found in the pilots were consistent with commonly used medications in the general population. The contributory role of mechanical malfunction of home-built aircraft cannot be ruled out in the observed increasing trends in their accidents, with or without ethanol and/or drugs. Regardless, the increasing trends of such accidents are of significant concern. PMID- 23447852 TI - Coronary artery disease in aircrew fatalities: morphology, risk factors, and possible predictors. AB - BACKGROUND: Coronary artery disease (CAD) is a common diagnosis at autopsies of military and civil aircrews. Identifying aviators with a high risk of an acute coronary syndrome is of aeromedical interest as it allows flight surgeons to employ prevention and intervention strategies to avoid death or a lifelong duties not including flying (DNIF) status of aircrew members. The aim of this study was to identify possible predictors of high-risk CAD. METHODS: In this aeropathological and aeromedical study the coronary artery systems of 21 German aircrew members killed in aircraft accidents was comprehensively examined. Then laboratory findings and bicycle ergometry results from their medical records were correlated to evaluate their predictive potential for CAD in our cohort. RESULTS: Of those killed, 1/3 had no CAD whatsoever; the rest had mild, moderate, or severe CAD, depending on the classification system used. There were 48% who had findings considered disqualifying according to JAR FCL-3. Three cases (14%) showed thin cap fibroatheromas (TCFA). There were 15 ergometry tests recorded prior to the accident that could be reviewed. Minor findings were more frequent in the groups of more severe CAD, but not statistically significant. Laboratory findings did not correlate with CAD severity. Only serum cholesterol levels in the "disqualifying" group of the JAR-FCL classification were slightly higher compared to the remaining cases. DISCUSSION: Our results suggest that ergometry findings may help to identify individuals with asymptomatic CAD. Further verification, e.g., by noninvasive coronary imaging, would then be the basis for strict cardiovascular risk management. For future aeropathological studies on the prevalence of CAD, we suggest that a classification system be established regarding higher degree luminal narrowing as well as plaque morphology, and especially the occurrence of TCFA. PMID- 23447853 TI - Effects of 30-day head-down bed rest on ocular structures and visual function in a healthy subject. AB - INTRODUCTION: We report ocular changes occurring in a healthy human subject enrolled in a bed rest (BR) study designed to replicate the effects of a low gravity environment. CASE REPORT: A 25-yr-old Caucasian man spent 30 consecutive days in a 6 degrees head-down tilt (HDT) position at the NASA Flight Analogs Research Unit. Comprehensive ophthalmologic exams, optic disc stereo-photography, standard automated perimetry (SAP), and optic disc Spectralis OCT scans were performed at baseline, immediately post-BR (BR+0), and 6 mo post-BR. MAIN OUTCOME MEASURES: changes in best-corrected visual acuity, intraocular pressure (IOP), cycloplegic refraction, SAP, and Spectralis OCT measures. At BR+0 KIOP was 11 and 10 mmHg in the right (OD) and left eye (OS), respectively (a bilateral 4-mmHg decrease compared to baseline); SAP documented a possible bilateral symmetrical inferior scotoma; Spectralis OCT showed an average 19.4 microm (+5.2%) increase in peripapillary retinal thickness, and an average 0.03 mm3 (+5.0%) increase in peripapillary retinal volume bilaterally. However, there were no clinically detectable signs of optic disc edema. At 6 mo post-BR, IOP was 13 and 14 mmHg in OD and OS, respectively, and the scotoma had resolved. Spectralis OCT measurements matched the ones recorded at baseline. DISCUSSION: In this subject, a reduction in IOP associated with subtle structural and functional changes compared to baseline were documented after prolonged head-down BR. These changes may be related to cephalad fluid shifts in response to tilt. Further studies should clarify whether decreased translaminar pressure (i.e., the difference between IOP and intracranial pressure) may be responsible for these findings. PMID- 23447854 TI - Quantifying fatigue risk in model-based fatigue risk management. AB - The question of what is a maximally acceptable level of fatigue risk is hotly debated in model-based fatigue risk management in commercial aviation and other transportation modes. A quantitative approach to addressing this issue, referred to by the Federal Aviation Administration with regard to its final rule for commercial aviation "Flightcrew Member Duty and Rest Requirements," is to compare predictions from a mathematical fatigue model against a fatigue threshold. While this accounts for duty time spent at elevated fatigue risk, it does not account for the degree of fatigue risk and may, therefore, result in misleading schedule assessments. We propose an alternative approach based on the first-order approximation that fatigue risk is proportional to both the duty time spent below the fatigue threshold and the distance of the fatigue predictions to the threshold--that is, the area under the curve (AUC). The AUC approach is straightforward to implement for schedule assessments in commercial aviation and also provides a useful fatigue metric for evaluating thousands of scheduling options in industrial schedule optimization tools. PMID- 23447855 TI - Physician training in aerospace medicine--an historical review in the United States. AB - The training of U.S. physicians in aviation medicine closely followed the development of reliable airplanes. This training has matured as aviation and space travel have become more routine over the past several decades. In the U.S., this training began in support of military pilots who were flying increasingly complex aircraft in the early part of the 20th century. As individuals reached into the stratosphere, low Earth orbit, and eventually to the Moon, physicians were trained not only through military efforts but in academic settings as well. This paper provides an historical summary of how physician training in aerospace medicine developed in the U.S., citing both the development of the military activities and, more importantly, the perspectives of the academic programs. This history is important as we move forward in the development of commercial space travel and the needs that such a business model will be required to meet. PMID- 23447856 TI - Strength through science: using virtual technology to advance the warfighter. PMID- 23447857 TI - You're the flight surgeon: lymphatic filariasis. PMID- 23447858 TI - You're the flight surgeon: cervical degenerative joint disease and total disc arthroplasty. PMID- 23447859 TI - Lead recovery from cathode ray tube funnel glass with mechanical activation. AB - In the disposal of electronic waste, cathode ray tube (CRT) funnel glass remains an urgent environmental problem because of its high lead content. This research developed mechanical activation as a pretreatment process, and it proved to be an effective method for extracting lead from CRT funnel glass. The effects of mechanical activation on the structural changes of CRT funnel glass were investigated using X-ray diffraction (XRD), particle size analysis, specific surface area (SSA), and a scanning electron microscope (SEM). Nitric acid leaching behaviors of the activated CRT funnel glass were studied by varying several parameters: leaching time, liquid-to-solid ratio, acid concentration, and heating temperature, as well as various conditions of activation. The lead recovery rate was observed to increase rapidly, particularly with increases in activation time and leaching temperature, but to vary relatively less under other experimental parameters. Under the optimal leaching conditions, the lead recovery rate for funnel glass activated for 2 hr at the rotational speed of 500 rpm (by ball mill) reached 92.5%, compared with 1.2% from the unactivated sample. IMPLICATIONS: CRT funnel glass containing lead has become a serious environmental problem facing the whole world. In order to dispose of CRT funnel glass, some technologies have been developed. However, these technologies are associated with higher operation and maintenance costs. In this study, mechanical activation was introduced to change the physicochemical properties of CRT funnel glass, which can transform the glass into an easily dissolved one. Under atmospheric pressure leaching conditions, good recovery rate for lead can be achieved and the residue has wide uses. The process can be applied to treat other leaded glass or lead containing wastes. PMID- 23447860 TI - Impacts of temporary traffic control measures on vehicular emissions during the Asian games in Guangzhou, China. AB - To guarantee good traffic and air quality during the 16th Asian Games in Guangzhou, China, the government carried out two traffic control Drills before the Games and adopted traffic control measures during the Games. Vehicle activities before and during the first and second Drills, and during the Games, were surveyed. Based on the data under investigation, the impacts of control measures on traffic volumes and driving characteristics were analyzed during the first and second Drills, and the Games. The emission reduction of traffic control measures was also evaluated during the three stages using the MOBILE-China model. The results show that there were significant effects of implementing temporary traffic control measures on transportation activity and vehicular emissions. During the first and second Drills, and the Games, the average traffic volumes in monitored roads decreased, and the average speed of vehicles increased significantly The co-effects of traffic flow reduction, traffic congestion improvement, and the banning of high-emitting vehicles helped to greatly reduce the estimated emissions from motor vehicles in Guangzhou during the first and second Drills, and the Games. Estimated vehicular emissions were reduced by 38 52% during the first Drill and 28-36% for the second Drill. During the Asian Games, vehicular emissions of carbon monoxide (CO), hydrocarbon (HC), oxides of nitrogen (NO), and particulate matter with an aerodynamic diameter < 10 microm (PM10) reduced by an estimated 42%, 46%, 26%, and 30%, respectively, compared with those before the Games. Both the banning of high-emitting vehicles and the travel restrictions imposed by use of odd-even licenses had significant effects on the reduction of vehicular emissions of CO, HC, NOx, and PM10. IMPLICATIONS: Motor vehicles have become the most prevalent source of emissions and subsequently air pollution within Chinese cities. Understanding the impacts that different control measures have on vehicular emissions is very important in order to be able to control vehicle emissions. The results of this study will be very helpful for the further control of vehicle emissions in Guangzhou in the future. In addition, the effects of temporary transportation control measures will provide important awareness to other cities that will be hosting large-scale activities similar to the Asian Games. PMID- 23447861 TI - Characterization of aerosol emissions from wastewater aeration basins. AB - The emission of particulate matter (PM10 and PM2.5) and ammonia (NH3) by aeration processes at wastewater treatment plants (WWTPs) with and without odor control units was examined. Local concentrations of PM2.5, PM10, and NH3 at the aeration basins were within urban ranges. Emission fluxes of NH3 and PM2.5 for a medium sized WWTP were determined to be 136 g day(-1) and 43 g day(-1), respectively, which are not substantial emission fluxes for urban environments. Odor control treatment using a granulated activated carbon bed reduced aerosol and NH3 emissions substantially. Detection of sterols, in particular the fecal sterol campesterol, in the PM clearly demonstrates aerosolization of wastewater components in the aeration process. The presence of campesterol in PM2.5 at a remote fenceline location in a WWTP facility illustrates that wastewater components are aerosolized in the fine PM fraction and transported beyond the facilities. IMPLICATIONS: Wastewater treatment plants are potential emission sources of particulate matter and gases. This study characterized particulate matter emissions from aeration basins and quantified emissions fluxes of particulate matter and NH3. While fine and coarse particles as well as NH3 are being emitted, the overall emissions are small compared to other urban sources. However, fecal steroid presence in particles at the fence of a treatment plant demonstrates that wastewater material is getting aerosolized and transported beyond the facilities. PMID- 23447862 TI - Characteristics of particulate constituents and gas precursors during the episode and non-episode periods. AB - Size-segregated distribution of ambient particulate matter (PM) was determined using a micro-orifice uniform deposition impactor (MOUDI) and a nano-MOUDI in southern Taiwan. Eleven water-soluble ionic species including six anions (NO3-, SO4(2-), Cl-, F-, NO2-, Br-) and five cations (NH4+, Na+, K+, Ca2+, Mg2+) for particulate inorganic ions and five gaseous pollutants (i.e., HNO2, HNO3, HCl, SO2, NH3) were analyzed during episode and non-episode periods. The particulate mass concentration was about 30 microg/ m3 higher at night than during the day, and it reached 162 microg/m3 during the episode periods. The difference was mainly attributable to the particle size of 0.1-2.5 microm. Nitrate, sulfate, ammonium, and chloride ions were the dominant inorganic ions in PM. HONO and NH3 concentrations were high at night; in contrast, HNO3, HCl, and SO2 were high during the day. The equivalent ratio of {[NO3-] + 2 [SO4(2-)}/[NH4+] was about 0.98 and revealed a high correlation between {[NO3-] + 2[SO4(2-)]} and [NH4+] that clearly pointed to ammonium neutralization or condensation of ammonium nitrate and ammonium sulfate in PM0.32. The precursor gases and ionic species in different particle sizes did not reveal a strong correlation, which could be attributed to the complex of source emissions, atmospheric reactions and meteorological parameters in the area. IMPLICATIONS: Size-segregated distribution and chemical compositions of atmospheric aerosols play important roles in their visibility reduction, health effects, and toxicity in urban areas. Inorganic ionic species are major constituents in particulate matter, except carbonaceous chemicals. In this work, the compositions of water-soluble ions in particulate matter and acid/base gaseous pollutants (such as HNO2, HNO3, HCl, SO2, NH3) were determined during the day and at night during episode and non-episode periods from 2006 to 2007 in southern Taiwan. PMID- 23447863 TI - A multisensor evaluation of the asymmetric convective model, version 2, in southeast Texas. AB - There currently exist a number of planetary boundary layer (PBL) schemes that can represent the effects of turbulence in daytime convective conditions, although these schemes remain a large source of uncertainty in meteorology and air quality model simulations. This study evaluates a recently developed combined local and nonlocal closure PBL scheme, the Asymmetric Convective Model, version 2 (ACM2), against PBL observations taken from radar wind profilers, a ground-based lidar, and multiple daytime radiosonde balloon launches. These observations were compared against predictions of PBLs from the Weather Research and Forecasting (WRF) model version 3.1 with the ACM2 PBL scheme option, and the Fifth-Generation Meteorological Model (MM5) version 3.7.3 with the Eta PBL scheme option that is currently being used to develop ozone control strategies in southeast Texas. MM5 and WRF predictions during the regulatory modeling episode were evaluated on their ability to predict the rise and fall of the PBL during daytime convective conditions across southeastern Texas. The MM5 predicted PBLs consistently underpredicted observations, and were also less than the WRF PBL predictions. The analysis reveals that the MM5 predicted a slower rising and shallower PBL not representative of the daytime urban boundary layer. Alternatively, the WRF model predicted a more accurate PBL evolution improving the root mean square error (RMSE), both temporally and spatially. The WRF model also more accurately predicted vertical profiles of temperature and moisture in the lowest 3 km of the atmosphere. Inspection of median surface temperature and moisture time-series plots revealed higher predicted surface temperatures in WRF and more surface moisture in MM5. These could not be attributed to surface heat fluxes, and thus the differences in performance of the WRF and MM5 models are likely due to the PBL schemes. IMPLICATIONS: An accurate depiction of the diurnal evolution of the planetary boundary layer (PBL) is necessary for realistic air quality simulations, and for formulating effective policy. The meteorological model used to support the southeast Texas 03 attainment demonstration made predictions of the PBL that were consistently less than those found in observations. The use of the Asymmetric Convective Model, version 2 (ACM2), predicted taller PBL heights and improved model predictions. A lower predicted PBL height in an air quality model would increase precursor concentrations and change the chemical production of O3 and possibly the response to control strategies. PMID- 23447864 TI - Past and future ozone trends in California's South Coast Air Basin: reconciliation of ambient measurements with past and projected emission inventories. AB - This paper updates the historic trends (1980-2010) in ambient ozone and ozone precursor concentrations in the South Coast Air Basin (SoCAB) and examines the evolution of the ozone-precursor relationship in the Basin. Whereas reductions in NOx (oxide of nitrogen) emissions have decreased nitrate and PM2.5 (particulate matter with an aerodynamic diameter < or = 2.5 microm) concentrations in the Basin during the past decade, ozone levels have increased at the central basin locations since about 2005 following a reversal in the decline of volatile organic compound (VOC)/NOx ratios during the previous two decades. A chemical box model was used to simulate the effects of changes in precursor concentrations on ozone formation using day-of-week-specific initial precursor concentrations that were derived from measurements and'projected to 2020 based on expected emission reductions from 2005 (-10% VOC and -50% NOx). Results show that peak ozone formation rates in 2020 will increase on weekdays by a factor of 3 relative to 2005 and will be comparable to 1995 weekday and 2005 Sunday rates. Ozone production will become precursor limited on Sundays in 2020, but with higher initial rates than 2005. Although a greater NOx reduction scenario in 2020 of 75% will result in even higher initial ozone formation rates, precursor limitation is reached quickly, leading to a further shift westward in the location of peak ozone levels. However ozone levels will likely be lower in downwind areas where transport is more important than local production of ozone. The ambient versus emission inventory reconciliation indicates a factor of 2 underestimation of VOC emissions in 2009 relative to NOx. Other analyses suggest that there is an overall increase in VOC emissions on hot days that is not fully accounted for by emission inventory estimates. Air quality models using emission inventories that underestimate VOC emissions relative to NOx may lead to inaccurate forecasting of the consequence of emission reductions. IMPLICATIONS: The rate and efficiency of ozone formation and accumulation in the SoCAB is more rapid than would be indicated by air quality model simulations based on the current inventory. Projected reductions in NOx emissions without concurrent reductions in VOC emissions will likely cause ozone to increase during the next decade within central regions of the SoCAB compared with a flat or slightly declining trend in far downwind locations. Air quality statistics that are commonly used to track progress toward attainment, such as basin-wide ozone design value and standard exceedances mask these varying trends within the Basin. PMID- 23447865 TI - Harvesting equipment to reduce particulate matter emissions from almond harvest. AB - Almond harvest accounts for an estimated 12 Gg of PM10 emissions in California each harvest season. Emissions from three new, "low-dust" almond harvesters (Exact Harvest Systems E4000; Flory Industries 8550; Weiss-McNair 9800 California Special) and one exhaust abatement device (Joe DiAnna, Clean Air Concept) were compared to those from a conventional harvester operating in the same orchard. Emissions of TSP and PM10 trended lower for all new harvesters and were significantly lower for most harvesters (alpha < 0.10). Significant reductions in PM2.5 emissions were observed from two harvesters as well. Fractionation analysis was not conducted on nut samples collected in the second year of the project, but differences observed in the composition of material that would be delivered to the huller between the Exact E4000 and conventional harvesters were functionally insignificant. The results of these tests imply that new harvest technologies are able to reduce PM10 emissions from one of the largest sources in the San Joaquin Valley (SJV) of California without affecting product quality. As such, use of these new harvesters should be considered a conservation measure that would help the SJV Air Pollution Control District (SJVAPCD) meet the requirements of their PM10 maintenance plan. IMPLICATIONS: The results of this research indicate that new harvesting technologies have the potential to substantially reduce PM emissions from almond harvest operations over traditional harvester designs without negatively affecting product quality. As such, use of these new harvesters could aid the SJVAPCD in maintaining its attainment status for PM10 and should be considered as candidate conservation management practices for producers. PMID- 23447866 TI - The influence of defoamer on removal of PAHs in soil washing. AB - The use of surfactants during soil washing process can create massive foam, which has a negative impact on the effective use of equipment. A series of tests was conducted to evaluate the defoaming performance of three defoamers and to investigate the influence on removal of polycyclic aromatic hydrocarbons (PAHs) during enhanced soil washing by the addition of the defoamer. Results showed that polydimethylsiloxane oil, which is the most common biomaterial used in commercial antifoaming and defoaming agents, has the best defoaming performance. With the addition of 0.1% polydimethylsiloxane oil, the removal ratios of total 16 PAHs (SigmaPAHs) increased up to 53.48% and 75.92% when washing time was 5 min and 30 min, respectively, compared with the removal ratios of 44.12% and 67.28% with Triton X-100 solution only. This indicated that the proper selection of defoamer not only solves massive foaming problem but also brings out a positive influence on PAH removal during the soil washing process. IMPLICATIONS: Three kinds of defoamers (kieselguhr, dodecanol, and polydimethylsiloxane oil) were collected to destroy the foam produced by Triton X-100. Among those defoamers, the polydimethylsiloxane (PDMS) oil has the best defoaming performances. The surface tension of the Triton X-100 solution with the addition of PDMS was lower. The addition of PDMS could improve the removal ratio of SigmaPAHs during soil washing. That may be attributed to the addition of the nonionic surfactant Tergitol NP-10 as the emulsifier in the defoamer. After all, the results do not provide any indication of the influence on the solubilization micelles. It is thus questionable whether other components of PDMS oil could improve the PAH solubilization. PMID- 23447867 TI - Evaluation of an annular denuder system for carbonaceous aerosol sampling of diesel engine emissions. AB - Sampling of particle-phase organic carbon (OC) from diesel engines is complicated by adsorption and evaporation of semivolatile organic carbon (SVOC), defined as positive and negative artifacts, respectively. In order to explore these artifacts, an integrated organic gas and particle sampler (IOGAPS) was applied, in which an XAD-coated multichannel annular denuder was placed upstream to remove the gas-phase SVOC and two downstream sorbent-impregnated filters (SIFs) were employed to capture the evaporated SVOC. Positive artifacts can be reduced by using a denuder but particle loss also occurs. This paper investigates the IOGAPS with respect to particle loss, denuder efficiency, and particle-phase OC artifacts by comparing OC, elemental carbon (EC), SVOC, and selected organic species, as well as particle size distributions. Compared to the filterpack methods typically used, the IOGAPS approach results in estimation of both positive and negative artifacts, especially the negative artifact. The positive and negative artifacts were 190 microg/m3 and 67 microg/m3, representing 122% and 43% of the total particle OC measured by the IOGAPS, respectively. However particle loss and denuder break-through were also found to exist. Monitoring particle mass loss by particle number or EC concentration yielded similar results ranging from 10% to 24% depending upon flow rate. Using the measurements of selected particle-phase organic species to infer particle loss resulted in larger estimates, on the order of 32%. The denuder collection efficiencyfor SVOCs at 74 L/min was found to be less than 100%, with an average of 84%. In addition to these uncertainties the IOGAPS method requires a considerable amount of extra effort to apply. These disadvantages must be weighed against the benefits of being able to estimate positive artifacts and correct, with some uncertainty, for the negative artifacts when selecting a method for sampling diesel emissions. IMPLICATIONS: Measurements of diesel emissions are necessary to understand their adverse impacts. Much of the emissions is organic carbon covering a range ofvolatilities, complicating determination of the particle fraction because of sampling artifacts. In this paper an approach to quantify artifacts is evaluated for a diesel engine. This showed that 63% of the particle organic carbon typically measured could be the positive artifact while the negative artifact is about one-third of this value. However, this approach adds time and expense and leads to other uncertainties, implying that effort is needed to develop methods to accurately measure diesel emissions. PMID- 23447868 TI - Application of watershed deposition tool to estimate from CMAQ simulations the atmospheric deposition of nitrogen to Tampa Bay and its watershed. AB - The US. Environmental Protection Agency (EPA) has developed the Watershed Deposition Tool (WDT) to calculate from the Community Multiscale Air Quality (CMAQ) model output the nitrogen, sulfur and mercury deposition rates to watersheds and their sub-basins. The CMAQ model simulates from first principles the transport, transformation, and removal of atmospheric pollutants. We applied WDT to estimate the atmospheric deposition of reactive nitrogen (N) to Tampa Bay and its watershed. For 2002 and within the boundaries of Tampa Bay's watershed, modeled atmospheric deposition rates averaged 13.3 kg N ha(-1) yr(-1) and ranged from 6.24 kg N ha(-1) yr(-1) at the bay's boundary with Gulf of Mexico to 21.4 kg N ha(-1) yr(-1) near Tampa's urban core, based on a 12-km x 12-km grid cell size. CMAQ-predicted loading rates were 1,080 metric tons N yr(-1) to Tampa Bay and 8,280 metric tons N yr(-1) to the land portion of its watershed. If we assume a watershed-to-bay transfer rate of 18% for indirect loading, our estimates of the 2002 direct and indirect loading rates to Tampa Bay were 1,080 metric tons N and 1,490 metric tons N, respectively, for an atmospheric loading of 2,570 metric tons N or 71% of the total N loading to Tampa Bay. To evaluate the potential impact of the US. EPA Clean Air Interstate Rule (CAIR, replaced with Cross-State Air Pollution Rule), Tier 2 Vehicle and Gasoline Sulfur Rules, Heavy Duty Highway Rule, and Non-Road Diesel Rule, we compared CMAQ outputs between 2020 and 2002 simulations, with only the emissions inventories changed. The CMAQ-projected change in atmospheric loading rates between these emissions inventories was 857 metric tons N to Tampa Bay, or about 24% of the 2002 loading of 3,640 metric tons N to Tampa Bay from all sources. IMPLICATIONS: Air quality modeling reveals that atmospheric deposition of reactive nitrogen (N) contributes a significant fraction to Tampa Bay's total N loading from external sources. Regulatory drivers that lower nitrogen oxide emissions from power plants and motor vehicles are important to bay management strategies, which seek to improve water quality through N load reduction. PMID- 23447869 TI - Magnetic resonance and radiographic diagnosis of osseous resorption of the flexor surface of the distal phalanx in the horse. AB - REASONS FOR PERFORMING STUDY: Osseous resorption of the flexor surface of the distal phalanx of the horse has been identified previously using magnetic resonance (MR) imaging; however, little is known about the prevalence and characteristics of this lesion. OBJECTIVES: To establish the MR prevalence of resorptive lesions in the flexor surface of the distal phalanx and identify concurrent lesions associated with this finding and associations between the MR and radiographic findings. METHODS: Horses with distal extremity MR and radiographs performed within 2 weeks of each other were included in the study. The flexor surface of the distal phalanx was graded independently on both modalities for the presence of osseous resorption. The sensitivity and specificity of radiography for identifying osseous resorption was calculated using MR as the gold standard. RESULTS: Eighty-two MR studies met the inclusion criteria, 8 of which included osseous resorption of the flexor surface of the distal phalanx. Concurrent injury to the deep digital flexor tendon and the navicular bone was a common finding. An association between MR and radiographic grades was identified. Radiography had a high specificity (0.96) but lower sensitivity (0.45-0.55) for detecting osseous resorption. CONCLUSIONS: Osseous resorption of the flexor surface of the distal phalanx can be observed both on MR and radiographic examinations of horses with lameness localised to the foot. This lesion is most often associated with other pathological changes in the podotrochlear apparatus. POTENTIAL RELEVANCE: Focal radiolucency of the flexor surface of the distal phalanx is a newly recognised radiographic sign associated with pathological changes of the podotrochlear apparatus. PMID- 23447870 TI - Use of a wireless, inertial sensor-based system to objectively evaluate flexion tests in the horse. AB - OBJECTIVES: A wireless, inertial sensor-based system has previously been validated for evaluation of equine lameness. However, threshold values have not been determined for the assessment of responses to flexion tests. The aim of this investigation was to evaluate a sensor-based system for objective assessment of the response to flexion. METHODS: Healthy adult horses (n = 17) in work were recruited prospectively. Horses were instrumented with sensors on the head (accelerometer), pelvis (accelerometer) and right forelimb (gyroscope), before trotting in a straight line (minimum 25 strides) for 2 consecutive trials. Sensors measured 1) vertical pelvic movement asymmetry (PMA) for both right and left hindlimb strides and 2) average difference in maximum and minimum pelvic height (PDMax and PDMin) between right and left hindlimb strides in millimetres. A hindlimb was randomly selected for proximal flexion (60 s), after which the horse trotted a minimum of 10 strides. Response to flexion was blindly assessed as negative or positive by an experienced observer. Changes in PMA, PDMax and PDMin between baseline and flexion examinations were calculated for each test. Statistical analysis consisted of a Pearson's product moment test and linear regression on baseline trials, Mann-Whitney rank sum test for effect of flexion and receiver operator curve (ROC) analysis of test parameters. RESULTS: There was a strong correlation between trials for PMA, PDMin and PDMax measurements (P < 0.001). A positive flexion test resulted in a significant increase in PMA (P = 0.021) and PDMax (P = 0.05) only. Receiver-operator curve analysis established cut-off values for change in PMA and PDMax of 0.068 and 4.47 mm, respectively (sensitivity = 0.71, specificity = 0.65) to indicate a positive response to flexion. CONCLUSIONS: A positive response to flexion resulted in significant changes to objective measurements of pelvic symmetry. POTENTIAL RELEVANCE: Findings support the use of inertial sensor systems to objectively assess response to flexion tests. Further investigation is warranted to establish cut off values for objective assessment of other diagnostic procedures. PMID- 23447871 TI - Effects of repeated intra-articular administration of amikacin on serum amyloid A, total protein and nucleated cell count in synovial fluid from healthy horses. AB - REASONS FOR PERFORMING STUDY: Serum amyloid A (SAA) in synovial fluid has recently been used as a marker for septic arthritis in horses but the effects of repeated intra-articular (IA) administration of amikacin on synovial SAA concentrations are unknown. OBJECTIVES: To report the effect of repeated IA administration of amikacin on SAA, total protein (TP), nucleated cell count (NCC) and differential NCC in synovial fluid of healthy equine joints. METHODS: A controlled, 2 period crossover study was performed on 5 clinically healthy horses. Each intercarpal joint received one of 2 treatments every 48 h for 5 consecutive times: arthrocentesis alone (control group) or arthrocentesis combined with IA administration of 500 mg of amikacin (treatment group). Clinical and lameness examinations were performed daily. Serum SAA and synovial SAA, TP, NCC and differential NCC were measured and statistically compared. Significance level was set at P < 0.05. RESULTS: Horses remained healthy and nonlame throughout the study. Baseline values for all variables were not significantly different between groups. Values for TP in the treatment group were significantly higher than in the control group after the first sample (P < 0.05). In both groups NCC increased significantly (P < 0.05) after the first sample. No significant changes were identified in differential NCC. In both groups, all synovial and most serum SAA concentrations remained below the lower limit of quantification. CONCLUSIONS: Repeated IA administration of amikacin caused increased values of TP and NCC in synovial fluid, with some TP concentrations falling within the range reported for septic arthritis. In contrast, synovial SAA concentrations did not increase in either group. POTENTIAL RELEVANCE: Synovial SAA could serve as a more reliable marker than TP and NCC when evaluating a joint previously sampled or treated with amikacin. PMID- 23447872 TI - Dose titration of the clinical efficacy of intravenously administered flunixin meglumine in a reversible model of equine foot lameness. AB - REASONS FOR PERFORMING STUDY: There are no refereed controlled documentations of the skeletal analgesic efficacy of different dosages of flunixin meglumine (FM). OBJECTIVES: The objective of this experiment was to compare the efficacy of various dosages of FM with a negative control. The hypothesis was that higher doses would result in improved efficacy in a dose-dependent manner when tested in a reversible model of foot lameness. METHODS: Ten horses shod with adjustable heart bar shoes had weekly modified AAEP grade 4.0/5.0 lameness induced by tightening a set screw against the heart bar. Heart rate (HR) and lameness score (LS) were monitored by one double-blinded investigator at rest; every 20 min after lameness induction for 5 h and hourly for another 8 h. One hour after lameness induction, treatments were administered i.v. in a randomised order: negative control (isotonic saline: SAL) or FM at 0.55 (half-dose), 1.1 (single dose) or 2.2 (double-dose) mg/kg bwt. Results were compared using RM ANOVA and Student-Newman-Keul's test with the level of significance set at P < 0.05. RESULTS: Compared to SAL, half-dose FM reduced HR at 2.33, 2.67, 4.0-8.0, and 10.0 h and LS at 1.33-12.0 h (P < 0.05). Single- and double-dose FM reduced HR from 0.67 to 12.0 h and LS from 1.0 to 12.0 h post administration (P < 0.05). Compared with half-dose FM, single- and double-dose LS were further decreased from 1.67 to 12.0 h post administration (P < 0.05). Mean peak and decaying plasma FM concentrations were different between dosages in a dose-dependent manner through 6 h post administration (P < 0.05). CONCLUSIONS: Flunixin meglumine administration affected dependent variables in a dose-dependent manner with half dose FM clinically effective for a shorter period. Higher dosages did not perform differently from one another. POTENTIAL RELEVANCE: Practitioners must be aware that half-doses of FM are less efficacious than single doses but double doses are not more efficacious and yet are potentially more toxic. PMID- 23447873 TI - Influence of head and neck position on radiographic measurement of intervertebral distances between thoracic dorsal spinous processes in clinically sound horses. AB - REASONS FOR PERFORMING STUDY: Reductions in distances between dorsal spinous processes on radiographs are used as criteria for the diagnosis of impingement of the thoracic dorsal spinous processes in horses but are potentially altered by spine motion and different head and neck positions. OBJECTIVES: To determine the influence of head and neck positions on intervertebral distances between dorsal spinous processes on radiographs of thoracic spines of clinically sound horses. METHODS: Lateral-lateral radiographs were obtained from 23 horses in 3 head and neck positions. The width of the thoracic dorsal spinous processes and intervertebral distances between adjacent thoracic dorsal spinous processes were measured at points perpendicular to a tangent between the dorsal spinous processes and the caudal extremity of the thoracic vertebrae. RESULTS: A low head and neck position increased intervertebral distances between adjacent thoracic dorsal spinous processes from the 8th to 15th dorsal spinous processes whereas a high head and neck position had the opposite effect (P < 0.05). Overall, intervertebral distances between adjacent thoracic dorsal spinous processes decreased from cranial to caudal in intermediate head and neck positions (P < 0.01). The 12th thoracic dorsal spinous process was readily identifiable due to its significant difference to the narrower cranial and broader caudal dorsal spinous process (P < 0.05). CONCLUSIONS: The head and neck position influences the distances between the dorsal spinous processes of the vertebrae of equine thoracic spine on radiography. POTENTIAL RELEVANCE: The measuring system reported here offers potential to improve and standardise radiographic evaluation of thoracic dorsal spinous processes. PMID- 23447874 TI - Retrospective study investigating causes of abnormal respiratory noise in horses following prosthetic laryngoplasty. AB - REASONS FOR PERFORMING THE STUDY: To investigate causes of respiratory noises in horses following prosthetic laryngoplasty (with or without a ventriculocordectomy) and to examine potential associations between degree of arytenoid abduction and the presence of other upper respiratory tract (URT) abnormalities, including right-sided collapse. METHODS: Clinical records and dynamic videoendoscopic recordings were examined from horses presented between 1995 and 2010 for investigation of respiratory noise during exercise, following a prosthetic laryngoplasty (+/- a ventriculocordectomy). Relationships between the degree of left arytenoid cartilage abduction and the presence of other URT disorders were investigated. RESULTS: Thirty horses matched the inclusion criteria. All horses had previously undergone a prosthetic laryngoplasty in different hospitals and in 63% (19/30) of these horses a left-sided ventriculocordectomy had also been performed. The majority of cases (87%) had multiple respiratory abnormalities and only 13% had a single URT disorder. Palatal dysfunction was the most common diagnosis (83%), followed by axial deviation of the aryepiglottic folds (60%) and vocal cord collapse (43%). The right arytenoid cartilage was fully abducted in all cases and no statistically significant correlation between the degree of left arytenoid abduction and any other URT disorders was detected. CONCLUSIONS: Multiple forms of dynamic URT disorders were diagnosed in horses that presented with abnormal respiratory noise following laryngoplasty. There was no association between degree of left arytenoid abduction and other URT abnormalities. Furthermore, horses with suboptimal left arytenoid cartilage abduction were not predisposed to right-sided laryngeal collapse. CLINICAL RELEVANCE: Our results demonstrate the fundamental role of dynamic endoscopy in correctly diagnosing dynamic airway collapse in horses that have undergone surgical treatment of the upper respiratory tract. PMID- 23447875 TI - Selenium deficiency associations with gender, breed, serum vitamin E and creatine kinase, clinical signs and diagnoses in horses of different age groups: a retrospective examination 1996-2011. AB - REASONS FOR PERFORMING STUDY: Selenium and vitamin E deficiency have been associated with nutritional myopathy, more commonly known as white muscle disease (WMD) in horses. However, correlations between selenium concentrations and presenting clinical signs, age, breed, gender, serum vitamin E, creatine kinase (CK) and final diagnosis, have not previously been evaluated. OBJECTIVES: To determine the number of hospitalised horses in 3 age groups that were selenium tested and the proportions of horses with categorised presenting clinical signs; the association/odds risk of final diagnosis with selenium deficiency and to examine the association between selenium status, vitamin E status and serum CK in adult horses. METHODS: Two hundred and seventy-one hospitalised horses with a selenium concentration evaluated between 1996 and 2011 were examined retrospectively. Records were examined in order to ascertain selenium and vitamin E concentrations, age, breed, gender, CK values, presenting clinical signs and final diagnosis. Data were analysed with proportions, Fisher's exact t test, odds ratios and multivariate linear regressions. RESULTS: Within the < 30 day old age group, 13/20 animals had low selenium concentrations. There were 18/42 horses in the 30 days to 2 years old age group with low selenium and 77/209 horses more than 2 years of age with low selenium. There was an association between low selenium and myopathy in the < 30-day-old animals (P = 0.017), all of which were classified as having WMD. No associations were identified between nutritional myopathy and selenium status in horses between 30 days and 2 years of age or in horses more than 2 years of age. CONCLUSIONS AND POTENTIAL RELEVANCE: This study indicates that WMD occurs most commonly in foals < 30 days old and is associated with low selenium concentrations (7 out of 8 affected foals had blood Selenium levels < 1.26 microm/l). Low serum selenium concentrations are common in hospitalised adult horses while nutritional myopathy is rare in these animals. PMID- 23447876 TI - Acquired equine polyneuropathy in Norway and Sweden: a clinical and epidemiological study. AB - REASONS FOR PERFORMING STUDY: Acquired equine polyneuropathy (AEP, also known as 'Scandinavian knuckling syndrome'), is a serious disease of unknown aetiology, which emerged clustering in horse farms in Sweden, Norway and Finland in the 1990s. Clinical and epidemiological data regarding the syndrome are scarce. OBJECTIVES: To describe the clinical and epidemiological findings and outcome in outbreaks of AEP and compare risk factors in affected and unaffected horses on affected farms in Norway and Sweden during 2007-2009. METHODS: Neurological examinations were performed and data collected regarding demography, usage, turning-out, feeding, prophylactic strategies and long-term outcome. RESULTS: Thirteen affected farms with 157 horses of various breeds, of which 42 were AEP cases, were studied. Typical digital extensor dysfunction and knuckling of pelvic limbs were noted in 34 definitive cases. Eight additional plausible cases had a severe, acute course of neurological disease. There were no signs of brain orcranial nerve dysfunction. Cases occurred from December to April, with new cases emerging within 100 days of the index case. Affected and unaffected horses were fed wrapped forage. Prevalence for AEP was 27% and case fatality 29%. The median duration of AEP in survivors was 4.4 months (1-17 months). Survivors returned to full work within 19 months (median 6.6 months). Acquired equine polyneuropathy was less prevalent in horses aged > 12 years and young horses had a higher chance of survival than older horses. Management factors did not differ between affected and unaffected horses. CONCLUSIONS: Acquired equine polyneuropathy is a potentially fatal neurological disease characterised by pelvic limb knuckling. Surviving horses returned to normal function after a long period of rest. Cases were clustered in farms during the winter/spring season. Wrapped forage was used in all farms. POTENTIAL RELEVANCE: The results provide valuable insights into the dinical examination, handling and prognosis of cases of AEP, an emerging neurological disease of unknown aetiology in horses. PMID- 23447877 TI - Pathological evidence of pancreatitis in 43 horses (1986-2011). AB - REASONS FOR PERFORMING STUDY: Definitive ante mortem diagnosis of pancreatitis in horses is difficult. Reports summarising the most common clinical signs, clinicopathological features and concurrent disorders in horses with a definitive diagnosis of pancreatitis that may aid in the recognition of disease are lacking. OBJECTIVES: To describe case details, clinical signs, clinicopathological data and necropsy findings in horses with a definitive diagnosis of pancreatitis. METHODS: This was a retrospective study (1986-2011) and inclusion criteria consisted of horses with a definitive diagnosis of pancreatitis. A medical records database search was performed and data extracted included case details, clinical signs, clinical laboratory data and post mortem findings. Pancreatitis was defined as acute, active chronic or chronic and presumed primary or secondary, based on postmortem findings. RESULTS: Pancreatitis was diagnosed in 43 horses (acute pancreatitis in 34, active chronic in 4 and chronic in 5). A presumed diagnosis of primary pancreatitis was made in 6 horses. Pancreatitis was associated with gastrointestinal disorders in 28 horses (14 large colon, 10 small intestine and 4 gastric ruptures) and primary hepatic disease in 3 horses. Six horses had pancreatitis associated with other disorders: multiple endocrine neoplasia syndrome (one horse), strychnine toxicosis (one horse) and compromised immune system (4 horses). CONCLUSION: Pancreatitis is an uncommon disorder that can occur as a primary problem or secondary to gastrointestinal, hepatic or immunocompromising disorders, and when it occurs it affects adult horses more commonly. POTENTIAL RELEVANCE: Unexplained abdominal pain, gastric dilation or rupture, peritonitis and/or the presence of white fibrinous plaques and fat necrosis in the peritoneum and mesentery or mass-like structures in the root of the mesentery during an exploratory celiotomy should raise a suspicious of pancreatitis. PMID- 23447878 TI - Variability in particulate concentrations in a horse training barn over time. AB - REASONS FOR PERFORMING STUDY: Exposure of horses to airborne particulates during stable confinement has been linked with airway inflammation in these animals. Understanding that link requires accurate measures of exposures and greater understanding of the sources of variability in these exposures. OBJECTIVES: Area and breathing zone particulate concentrations were measured over time in order to determine the relative variability introduced by daily, monthly or between horse variations. Additionally, the relationship between area and breathing zone respirable particulate concentrations was examined. METHODS: The study was conducted in a Thoroughbred training stable. Breathing zone and area respirable particulate concentrations were measured over a 30-month period. Mixed-model analysis of variance was used to determine effect of month and year at the time of sampling and the daily variance upon area particulate concentrations. The effects of hay feeding method and horse variance on breathing zone measures were included in the model. Real-time concentrations of particulate matter with an aerodynamic diameter of 10 microm or smaller (PM10) were measured to determine the effect of barn door position. Significance was set at P < 0.05. RESULTS: Average area particulate concentration varied with month and year of sampling but daily variation was not significant. Maximum area respirable particulate concentrations were significantly affected by daily variation. Opening barn doors resulted in lower PM10 levels. Horses fed from hay nets were exposed to significantly higher concentrations of respirable particulates in their breathing zone than when fed hay on the ground. Horse-to-horse variability was significant. Breathing zone concentrations were significantly greater than area concentrations and the 2 measurements were not correlated. CONCLUSIONS: While area respirable particulate concentrations reflected seasonal changes, these measures are poor predictors of individual horse exposure. Instead, methods of feeding and individual horse behaviour are important determinants of exposure. POTENTIAL RELEVANCE: Studies investigating the effect of natural exposures on lung health in horses should consider the effects of individual behaviour and management practices on breathing zone exposure. PMID- 23447879 TI - Effect of sample handling and storage time on the stability of total CO2 in equine plasma. AB - REASONS FOR PERFORMING STUDY: The stability of total CO2 concentration (ctCO2) in plasma is influenced by storage temperature and handling during sample processing. Conflicting information exists regarding the stability of ctCO2 in equine plasma over time, and the effect of centrifugation on the measured value for plasma ctCO2 is unclear. OBJECTIVES: To determine plasma ctCO2 stability over 5 days when equine blood is collected into Vacutainer tubes, centrifuged within 30 min of collection, and stored at 4 degrees C; and to determine whether a delay in centrifugation increases the rate at which plasma ctCO2 decreases over time. METHODS: Blood was collected from 6 adult horses into 3 ml plastic Vacutainer tubes and randomly assigned to be centrifuged immediately, or after, storage. Plasma ctCO2 was measured in triplicate at 0, 24, 48, 72 and 96 h after collection using a NOVA-4 analyser Data were analysed using multivariable linear regression, with P < 0.05 being defined as significant. RESULTS: Plasma ctCO2 decreased linearly over time during storage at 4 degrees C. The measured value for ctCO2 decreased at a faster rate (-0.28 mmol/l/day; P < 0.0001) when centrifugation was delayed, compared with immediate centrifugation (-0.10 mmol/l/day). There was a significant effect of sequence of sample analysis on the ctCO2 value when measured in triplicate: the second and third measurements were 0.31 and 0.41 mmol/l lower than the first measurement, respectively. CONCLUSIONS: Blood samples collected from horses into Vacutainer tubes should be centrifuged immediately after collection and analysed as soon as possible to ensure accurate values for plasma ctCO2. POTENTIAL RELEVANCE: Failure to centrifuge, or excessive delay in measuring ctCO2 after centrifugation, produces values significantly lower than the true value. PMID- 23447880 TI - Equine piroplasmosis treatment protocols: specific effect on orocaecal transit time as measured by the lactose 13C-ureide breath test. AB - REASONS FOR PERFORMING STUDY: Imidocarb dipropionate is the drug of choice for equine piroplasmosis but its administration causes severe colic and diarrhoea. An imidocarb protocol that reduces these effects is needed. OBJECTIVES: 1) Quantification of the effects of imidocarb dipropionate on equine orocaecal transit time (OCTT), with and without atropine or glycopyrrolate premedication and 2) investigation of an improved pretreatment regimen for imidocarb administration. HYPOTHESIS: Treatment with imidocarb dipropionate will result in colic and reduced OCTT as demonstrated by the lactose 13C-ureide breath test which will be ameliorated by premedication with either atropine or glycopyrrolate. METHODS: The effects of 3 drug therapies on OCTT were compared in 6 healthy horses in a randomised double-blind study vs. a saline control: 1) imidocarb dipropionate 2.4 mg/kg bwt administered intramuscularly (i.m.) with saline administered intravenously (i.v.; imidocarb/saline); 2) imidocarb dipropionate 2.4 mg/kg bwt administered i.m. with atropine 0.035 mg/kg bwt administered i.v. (imidocarb/atropine) and 3) imidocarb dipropionate 2.4 mg/kg bwt administered i.m. with glycopyrrolate 0.0025 mg/kg bwt administered i.v. (imidocarb/glycopyrrolate). The lactose 13C-ureide breath test was used to measure OCTT in each case and significance of treatment effect determined by a linear model analysis of variance. RESULTS: Imidocarb/atropine treatment caused an increase in OCTT (P < 0.05) whereas imidocarb/saline produced a nonsignificant decrease in OCTT. Imidocarb/saline caused colic and diarrhoea in 4 of 6 horses, which were not seen in any of the horses treated with imidocarb/atropine or imidocarb/glycopyrrolate or administered the saline control. Intestinal borborygmi were increased in imidocarb/saline and decreased in imidocarb/atropine treated horses, respectively. CONCLUSIONS: Imidocarb/saline treatment induced colic signs and a potential reduction in OCTT while imidocarb/atropine treatment increased OCTT significantly when compared with imidocarb/saline. Both atropine and glycopyrrolate premedication ameliorated the clinical gastrointestinal effects of imidocarb but atropine produced significant inhibition of gastric and/or small intestinal motility not detected with glycopyrrolate. Premedication with glycopyrrolate is recommended when using imidocarb for treatment of equine piroplasmosis. PMID- 23447881 TI - Equine colostral carbohydrates reduce lipopolysaccharide-induced inflammatory responses in equine peripheral blood mononuclear cells. AB - REASONS FOR PERFORMING STUDY: Increasing evidence suggests that reactions to lipopolysaccharide (LPS), particularly in the gut, can be partly or completely mitigated by colostrum- and milk-derived oligosaccharides. Confirmation of this hypothesis could lead to the development of new therapeutic concepts. OBJECTIVES: To demonstrate the influence of equine colostral carbohydrates on the inflammatory response in an in vitro model with equine peripheral blood mononuclear cells (PBMCs). METHODS: Carbohydrates were extracted from mare colostrum, and then evaluated for their influence on LPS-induced inflammatory responses in PBMCs isolated from the same mares, mRNA expression of tumour necrosis factor-alpha, interleukin-6 and interleukin-10 was measured as well as the protein levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10). RESULTS: Equine colostral carbohydrates significantly reduced LPS induced TNF-alpha protein at both times measured and significantly reduced LPS induced TNF-alpha, IL-6 and IL-10 mRNA expression by PBMCs. Moreover, cell viability significantly increased in the presence of high concentrations of colostral carbohydrates. CONCLUSIONS: Carbohydrates derived from equine colostrum reduce LPS-induced inflammatory responses of equine PBMCs. POTENTIAL RELEVANCE: Colostrum and milk-derived carbohydrates are promising candidates for new concepts in preventive and regenerative medicine. PMID- 23447882 TI - Identification of periparturient mare and foal associated predictors of post parturient immunoglobulin A concentrations in Thoroughbred foals. AB - REASONS FOR PERFORMING THE STUDY: Prior to the start of endogenous production of immunoglobulins (Igs), absorption of maternal Igs is important to protect against pathogens in the early neonatal period. It is possible that mare- or foal associated factors may influence neonatal IgA concentrations. OBJECTIVES: The temporal relationships among serum and milk IgA concentrations in Thoroughbred mare-foal pairs were explored to determine if periparturient mare- and foal associated factors contribute to the prediction of foal serum IgA concentrations. METHODS: Blood and milk samples as well as complete veterinary records, were collected for 84 Thoroughbred mare-foal pairs from one month before to 2 months after parturition. Samples were tested using enzyme-linked immunosorbent assay (ELISA) for concentrations of IgA. Pairwise correlation coefficients were estimated (P < 0.01) and simple linear regression used to investigate unconditional associations between mare IgA levels, mare and foal risk factors and foal serum IgA concentration at 12 h. Backwards, stepwise elimination of nonsignificant factors was used to create a final model. RESULTS: There were significant temporal relationships among mare serum IgA and among colostrum and milk IgA concentrations within mares (P < 0.01). Mare serum IgA concentrations up to one month before parturition were associated with foal serum IgA concentrations at all time points and with colostrum and milk IgA concentrations. Mare serum IgA at -28 days and parity were associated with foal serum IgA concentration at 12 h (P < 0.001). CONCLUSIONS: Mare serum IgA concentrations up to 28 days before parturition, together with mare parity, are indicative of neonatal foal serum IgA concentrations. POTENTIAL RELEVANCE: Mare serum and colostrum IgA concentrations may be useful peripartum predictors of neonatal mucosal immune status, enabling earlier intervention to prevent the consequences of mucosal infections. PMID- 23447883 TI - Effects of repeated transvaginal aspiration of immature follicles on mare health and ovarian status. AB - REASONS FOR PERFORMING STUDY: Transvaginal ultrasound-guided follicle aspiration (TVA) is performed clinically but there is little information available on complications associated with this procedure. OBJECTIVES: It is possible that TVA is associated with damage to the ovary and may induce peritonitis or peritoneal adhesions. This study was conducted to determine the effect of repeated TVA on mare health and ovarian status. METHODS: Thirty-two mares were used for oocyte recovery via repeated TVA over a 3 year period; different mares were used each year. In Year 1, ovarian status was monitored in 11 mares by transrectal palpation and ultrasonography. In Year 2, 6 of 11 mares underwent abdominocentesis and were examined by laparoscopy after one TVA and again after multiple TVAs. In Year 3, 10 mares underwent multiple TVAs with either a 15 or a 12 gauge needle and the ovaries were removed for examination. RESULTS: Four hundred and twenty-seven aspiration sessions (390 via TVA and 37 via needle placement through the flank) and 3202 follicle punctures (3161 TVA and 41 flank) were performed. One mare developed an ovarian abscess. Transient rectal bleeding was evident after 16% of TVA sessions. No adhesions were found on laparoscopic or gross examination of ovaries and there were minimal changes on histological evaluation. CONCLUSIONS: Follicle aspiration carries a small possibility (< 0.5%) of ovarian abscess formation. There is a possibility of rectal abrasion or puncture but little gross or histological damage to the ovary. POTENTIAL RELEVANCE: These results provide a basis for using prophylactic administration of antibiotics after TVA and for advising mare owners of the rare but potential complications associated with the procedure. PMID- 23447884 TI - Retrospective study on equine uterine fungal isolates and antifungal susceptibility patterns (1999-2011). AB - REASONS FOR PERFORMING STUDY: Knowledge of commonly encountered fungi infecting the mare's reproductive tract and their respective drug susceptibilities should improve treatment efficacy in mares with fungal endometritis. This is particularly important when practitioners need to start empiric treatment before culture results are complete. OBJECTIVE: To report the spectrum of fungal isolates from uterine samples from mares with reproductive problems and their respective antifungal susceptibilities. METHODS: Equine uterine samples submitted to the Cornell University Animal Health Diagnostic Centre for fungal culture between July 1999 and June 2011 were reviewed. Each mare's reproductive history, fungal culture results, antifungal susceptibilities and concurrent aerobic culture results were evaluated. Patterns of antifungal susceptibility and resistance were assessed over time. RESULTS: One hundred and two fungal isolates were cultured from 92 uterine samples from mares with reproductive problems. Yeast (69%) and mould with septated hyphae (26%) were the most common isolates. Ninety-five to 100% of all fungal isolates were susceptible to the polyenes, while response to the azoles varied with 47-81% of fungal isolates displaying susceptibility. Yeast isolates were 100% susceptible to the polyenes and least susceptible to miconazole (48%) while isolates of mould with septated hyphae were most susceptible to natamycin (100%) and least susceptible to fluconazole (0%). From July 1999 to June 2005 and July 2005 to June 2011, yeast demonstrated increasing resistance to miconazole, while mould with septated hyphae demonstrated increasing resistance to ketoconazole. CONCLUSIONS AND CLINICAL RELEVANCE: Results from this study suggest that polyenes are effective against uterine fungal isolates in vitro and may be the empiric treatment of choice for fungal endometritis. Isolate resistance to specific azoles increased over time. PMID- 23447885 TI - B-mode and Doppler ultrasonography in pony mares with experimentally induced ascending placentitis. AB - REASONS FOR PERFORMING STUDY: Early, accurate diagnosis of ascending placentitis in mares remains a key challenge for successful treatment of the disease. Doppler ultrasonography has shown promise as a tool to diagnose pregnancy abnormalities and is becoming more available to equine clinicians. However, to date, no studies have prospectively compared this technique to standard B-mode measurement of the combined thickness of the uterus and placenta (CTUP). OBJECTIVES: The objective of the current study was to compare Doppler and B-mode ultrasonography for the detection of experimentally-induced ascending placentitis in mares. METHODS: Eleven healthy pony mares in late gestation were used in this study. Placentitis was induced in 6 mares between Days 280 and 295, while 5 mares served as negative controls. All mares were intensively monitored until delivery. Fetal heart rate, CTUP, uterine artery blood flow (resistance index, pulsatility index, arterial diameter and total arterial blood flow) and physical examination findings were recorded at each examination. Mares with an increased CTUP above published values were treated in accordance with published recommendations. Foals and fetal membranes were examined at birth. Ultrasonographic parameters were compared between groups using ANOVA. Foal viability and histological presence of placentitis were compared using a Fisher's exact test. RESULTS: The CTUP was increased above normal in 5 of 6 inoculated mares within 3 days after inoculation (P = 0.05). The sixth inoculated mare was excluded from subsequent data analysis. Uterine artery blood flow, physical examination findings and fetal heart rate were not different between groups. Gradual increases in CTUP, arterial diameter and total arterial blood flow were detected with increasing gestational age in the control mares (P = 0.02, P = 0.00001 and P = 0.00001, respectively). CONCLUSION: The CTUP, but not uterine blood flow, was different between groups (P = 0.00001). Recorded CTUP values for control pony mares were similar to previously published values for light breed horses. PMID- 23447886 TI - The addition of ticarcillin-clavulanic acid to INRA 96 extender for stallion semen cooling. AB - REASONS FOR PERFORMING STUDY: A commonly used commercial extender (i.e. INRA 96) contains antimicrobials that may have limited effectiveness. Therefore, addition of ticarcillin-clavulanic acid to this extender is a widespread procedure in the equine breeding industry in the United States. However, such practice has not been critically evaluated. OBJECTIVES: To evaluate the addition of ticarcillin clavulanic acid to INRA 96 and different extender and antimicrobial storage conditions on sperm function and antimicrobial effectiveness. METHODS: Gel-free semen (42 ejaculates from 14 mature Quarter Horse stallions) was extended with INRA 96 and stored for 24 h in an Equitainer II. The effects of added ticarcillin clavulanic acid and different extender storage procedures on sperm motion characteristics (by computer-assisted analysis), sperm membrane integrity (by fluorescence-based measurement) and suppression of bacterial growth (by aerobic and anaerobic culture methods) were evaluated using analysis-of-variance and Chi square statistical methods. The P value for significance was set at < 0.05. RESULTS: Freezing and thawing of modified or unmodified extender prior to use for stallion semen resulted in reduced sperm quality post cooling for 24 h, as evidenced by a significant reduction in sperm motility (i.e. total and progressive) and sperm membrane integrity. Addition of ticarcillin-clavulanic acid to extender resulted in higher sperm velocity when the reconstituted antimicrobial was subjected to cooled storage, as compared with frozen storage, prior to use. Only 28 of 42 ejaculates (67%) yielded presence of bacteria in neat semen but addition of ticarcillin-clavulanic acid to INRA 96 was not different than INRA 96 alone for inhibiting growth of bacteria (98 vs. 94%, respectively). CONCLUSIONS: Addition of ticarcillin-clavulanic acid (1 mg/ml) to INRA 96 did not adversely affect sperm quality in extended semen after cooled storage. Extender freezing and thawing prior to use had detrimental effects on sperm quality. POTENTIAL RELEVANCE: These data suggest that INRA 96 should not be frozen and thawed prior to use. Addition of ticarcillin-clavulanic acid to INRA 96 did not impair sperm quality. All extender treatments effectively controlled the bacterial growth compared with neat semen. PMID- 23447887 TI - Effect of surgical technique for unilateral orchiectomy on subsequent testicular function in Miniature Horse stallions. AB - REASONS FOR PERFORMING STUDY: Management decisions on unilateral orchiectomy are often influenced by the potential for post operative return to successful breeding. The effects of 2 surgical methods (first intention [FI] vs. second intention [SI] incision healing) for unilateral orchiectomy on resulting semen quality and scrotal temperature were evaluated. OBJECTIVE: To evaluate the effects of 2 surgical unilateral orchiectomy techniques on scrotal healing, size of the remaining testis and post operative sperm quality. MATERIALS AND METHODS: Unilateral orchiectomy was performed on mature Miniature Horse stallions. Semen was collected prior to and up to 60 days after, unilateral orchiectomy. Semen parameters, scrotal and body temperatures, testis volume and days to incision healing were evaluated. RESULTS: There was no effect of treatment or time on percent total sperm motility. Total sperm numbers were higher (P < 0.05) 60 days after unilateral orchiectomy compared with 14 and 30 days. Percent viable sperm were higher (P < 0.05) 30 and 60 days compared with pre- and 14 day post unilateral orchiectomy. Scrotal temperatures were lower after unilateral orchiectomy compared with preoperative values ( < or = 0.003). Higher scrotal temperatures were recorded in Group IF, as compared with Group IS, during recoveryfrom anaesthesia and at 1 and 2 h after surgery (P = 0.02). Mean time to incision healing was less in Group II (10.0 days) than in Group II (21.5 days; P = 0.05). CONCLUSION: In this study, total sperm motility was maintained and size of the remaining testis, total sperm numbers and percent viable sperm increased after unilateral orchiectomy. Incision healing time was shorter in Group II; however, surgical technique did not have an effect on semen quality at 30 and 60 days post unilateral orchiectomy. POTENTIAL RELEVANCE: These data suggest that surgical technique for unilateral orchiectomy may not dramatically influence function of the remaining testis. PMID- 23447888 TI - The clinical and pathological features of gastric impaction in twelve horses. AB - REASONS FOR PERFORMING STUDY: Gastric impaction in the horse is poorly described in the veterinary literature. OBJECTIVES: To review the clinical and pathological features of gastric impaction. METHODS: The clinical details of horses presenting with colic over a 7-year period and cases in which gastric impaction was considered to determine the outcome were reviewed. Clinical and clinicopathological data were recorded. RESULTS: Twelve cases of gastric impaction were recorded (1.4% of 857 horses hospitalised for colic). Diagnosis was achieved by ultrasonographic examination, gastroscopy, exploratory celiotomy and/or post mortem examination. Five out of 12 horses were successfully treated, 5/12 were subjected to euthanasia (3 at celiotomy and 2 due to recurrence of impaction) and 2/12 died. Three out of 12 horses had spontaneous gastric rupture despite attempted treatment (one was subjected to euthanasia at celiotomy and 2 died). Post mortem examination (7 horses) revealed gross muscular thickening of the stomach wall in 6/7 horses. Histological examination revealed focal fibrosis of the stomach wall in 4/6 and focal myositis in 1/6 horses. CONCLUSIONS AND PRACTICAL SIGNIFICANCE: Gastric impaction is a rare cause of colic and affected horses can present with acute, chronic or recurrent colic in the presence or absence of other gastrointestinal disease. Spontaneous gastric rupture may occur. A proportion of affected horses have gross thickening of the muscular layers of the stomach wall. PMID- 23447889 TI - Surgical treatment for acute small intestinal obstruction caused by Parascaris equorum infection in 15 horses (2002-2011). AB - REASONS FOR PERFORMING STUDY: There is a consensus in the veterinary literature that Parascaris equorum (ascarid) impaction carries a poor prognosis. Hence surgery is often delayed and foals are often subjected to euthanasia after diagnosis of ascarid impaction is established. Our clinical impression was that ascarid impaction carries a better prognosis than previously reported. OBJECTIVES: Our expectation was that manually evacuating the impaction into the caecum, thus refraining from opening the small intestine, would improve the prognosis for survival of horses with ascarid impaction. The aim of this study was to examine medical records of horses treated surgically for ascarid impaction, record their clinical findings and evaluate the association of outcome with the method of relieving the impaction. METHODS: The medical records of all horses presented to our hospital between October 2002 and December 2011 that underwent exploratory celiotomy for ascarid impaction were reviewed. Information retrieved from the medical record included surgical findings, surgical technique, complications, short- and long-term survival. The association between categorical variables was assessed using the Fisher's exact test. A P value < 0.05 was considered statistically significant. RESULTS: Fifteen horses fulfilled the inclusion criteria. Eighty percent of horses (12/15) survived to discharge and 60% (6/10) survived for at least one year. Five horses are doing well but are still in convalescence. Horses that underwent small intestinal enterotomy or resection and anastomosis (n = 5) were less likely to survive to discharge (P = 0.022). CONCLUSIONS: In our study, manual evacuation of ascarid impaction into the caecum, while refraining from opening the small intestine resulted in significantly improved survival in horses with ascarid impaction. POTENTIAL RELEVANCE: Refraining from opening the small intestine may be the key to improving surgical outcome in horses with ascarid impaction. PMID- 23447890 TI - Visual outcome after corneal transplantation for corneal perforation and iris prolapse in 37 horses: 1998-2010. AB - REASONS FOR PERFORMING STUDY: We wanted to investigate the visual outcome of horses presented with iris prolapse and treated with corneal transplantation. OBJECTIVE: To evaluate the visual outcome of horses with iris prolapse treated with penetrating keratoplasty alone and penetrating keratoplasty in combination with overlying conjunctival or amniotic membrane grafting. METHODS: A retrospective medical records study of horses presented to the University of Florida Veterinary Medical Center for iris prolapse and treated with penetrating keratoplasty in the period of 1998-2010. Data collected from the medical records included signalment, clinical descriptions of ocular lesions, treatments, and therapeutic outcome. RESULTS: Iris prolapses in this study were caused by corneal ulcers with keratomalacia (n = 37). All horses were treated medically for infection, hyperproteinase activity and iridocyclitis, and then surgically treated with either penetrating keratoplasty alone (n = 9) or penetrating keratoplasty with either a conjunctival pedicle flap (n = 22), amniotic membrane transplant (n = 5) or amnion membrane and conjunctival pedicle flap (n = 1). The eyes were visual postoperatively in a majority of the cases (n = 24; 64.9%). Limited vision was noted in 6 eyes (16.2%), 3 eyes became phthisical (8.1%) and 4 globes were enucleated (10.8%). Graft rejection manifested as some degree of donor corneal graft opacification in all cases. Anterior synechiae were present in 48.6% of the eyes. Wound dehiscence and aqueous humour leakage were also common as post operative problems. CONCLUSION: Penetrating keratoplasty alone or in combination with an overlying graft of conjunctiva or amniotic membrane can achieve a successful visual outcome in a high percentage of horses with iris prolapse. PMID- 23447891 TI - The use of maggot debridement therapy in 41 equids. AB - REASONS FOR PERFORMING STUDY: Maggot debridement therapy is a long-established tool to promote wound healing. OBJECTIVES: To describe and assess the results of this technique in equids with various lesions. METHODS: Retrospective analysis performed on cases in which, depending on clinical case, type, size and location of the wound, maggots were applied either in direct or indirect contact with the wound. RESULTS: Treated cases (n = 41) included horses with foot pathology (n = 9), laceration of the limbs (n = 15), other soft tissue abscesses or wounds (n = 6), fistulous withers (n = 5), other musculoskeletal infection (n = 2) and dehiscence of the linea alba (n = 4). In 5 cases, a second maggot application was necessary to reach the desired level of wound healing. In 38 cases a favourable outcome was reached in less than one week. In one individual with a sequestrum, healing was uneventful after its removal. In 2 other horses, squamous cell carcinoma and melanoma were involved in chronic infected wounds and complete healing was not achieved because of recurrence of underlying tumours. Some discomfort was recorded in 7 individuals between 24 and 72 h of treatment. CONCLUSIONS: Maggot debridement therapy can be recommended in equids for debridement and enhanced healing and its potent antibacterial action. Maggot debridement therapy is not recommended on wounds invaded with a tumour and if bone sequestration is suspected. POTENTIAL RELEVANCE: Maggot debridement therapy can be an integral part of modern wound care in equids. PMID- 23447892 TI - Hindlimb kinematics before and after laser fibrotomy in horses with fibrotic myopathy. AB - REASONS FOR PERFORMING STUDY: Fibrotic myopathy can cause incapacitating gait abnormalities. Transection of the fibrotic mass followed by early post operative exercise is the best treatment for fibrotic myopathy. A laser may be used to transect the fibrotic mass. Assessment of the effectiveness of therapies for fibrotic myopathy has been limited to subjective evaluation. OBJECTIVES: To objectively assess gait abnormalities associated with fibrotic myopathy before and after laser fibrotomy followed by early post operative exercise. METHODS: Kinematic evaluation of horses with fibrotic myopathy walking and trotting on a treadmill was used to investigate hindfeet trajectories (n = 8) and lameness (n = 5) before and after laser fibrotomy Hoof flight trajectory length (HFTL), relative protraction length (% PL), maximum hoof height during swing (MXHH), hoof height at end of protraction (HH(pro)) and retraction (HH(ret)) were measured and differences between fibrotic myopathy affected and nonaffected limbs were calculated. Lameness was quantified by measuring maximum and minimum pelvic height differences between right and left halves of the stride. RESULTS: Before surgery the foot of the fibrotic myopathy affected limb had abnormal trajectories characterised as increased HFTL, MXHH and HH(pro) and decreased % PL and HH(ret) and the 5 horses objectively evaluated for lameness were lame in the fibrotic myopathy affected limb. Immediately after surgery the difference between affected and nonaffected limbs decreased for HFTL, % PL and HH(pro). Six to 11 weeks after surgery, the HFTL difference increased but was still smaller than before surgery, which was interpreted as partial recurrence of the gait abnormality; all horses objectively evaluated for lameness were either improved (n = 1) or not lame (n = 4) in the previously affected, operated limb. CONCLUSIONS: Fibrotic myopathy affects the foot flight and leads to asymmetric vertical excursion of the pelvis. Laser fibrotomy followed by early post operative exercise can minimise these abnormalities. POTENTIAL RELEVANCE: Laser fibrotomy combined with early post operative exercise is a viable therapy for fibrotic myopathy. PMID- 23447893 TI - Introduction to commercially approved customized ablation: tenth year in review. PMID- 23447894 TI - WaveLight FS200 vs Hansatome LASIK: intraoperative determination of flap characteristics and predictability by hand-held bioptigen spectral domain ophthalmic imaging system. AB - PURPOSE: To intraoperatively determine and compare the characteristics and predictability of LASIK flaps made by the WaveLight FS200 femtosecond laser (Alcon Laboratories Inc) and Hansatome (Bausch & Lomb) microkeratome using a hand held spectral domain ophthalmic imaging system (Bioptigen Inc). METHODS: Sixty eyes from 30 patients undergoing bilateral LASIK were prospectively evaluated. Patients were divided into two equal groups to undergo flap creation with either 100-microm femtosecond laser flaps (FS flap group) or 120-microm microkeratome flaps (MK flap group). Flap thickness was measured intraoperatively after creation of the flap but prior to lifting using the hand-held probe of the spectral domain imaging system. Geometry of the flap edge and smoothness of the stromal bed after lifting the flap was also evaluated in all cases. RESULTS: Mean difference between planned and achieved flap thickness in the paracentral region was 2.84 +/- 3.16 mm for the FS flap group and 11.33 +/- 10.27 mm for the MK flap group, whereas in the periphery, it was 5.72 +/- 3.26 mm in the FS flap group and 24.67 +/- 10.35 mm in the MK flap group. The differences between groups were statistically significant (P < 0.001, Kruskal-Wallis test). The edges of the flaps were vertical in the FS flap group and the stromal bed was smoother, whereas in the MK flap group, the edges were more sloping and the stromal bed more irregular. CONCLUSIONS: The WaveLight FS200 femtosecond laser is able to produce planar flaps with a high degree of predictability between the desired and achieved flap thickness. The ability to study the flap characteristics intraoperatively (when flap edema and stromal bed hydration changes have not yet occurred) with the hand-held probe of the Bioptigen imaging system ensures greater accuracy than measurements done postoperatively using other anterior segment optical coherence tomography prototypes. PMID- 23447895 TI - Optimized femto-LASIK maintains preexisting spherical aberration independent of refractive error. AB - PURPOSE: To report the visual outcomes and change in spherical aberration in the first cohort of eyes treated at the Cole Eye Institute using the FS200 laser (Alcon Laboratories Inc). METHODS: A chart review was performed on 100 eyes targeted for emmetropia with wavefront-optimized femto-LASIK using the WaveLight Allegretto Wave Eye-Q (Alcon Laboratories Inc) and FS200 lasers. Patients were subdivided into low (< -3.00 D, n = 23), moderate (-3.00 to -6.00 D, n = 45), and high myopia (> -6.00 D, n = 2). Pre- and 3- to 9-month postoperative wavefront aberrometry and uncorrected distance visual acuity (UDVA) were compared. RESULTS: An increase was found in spherical aberration of 0.03 +/- 0.02 microm (P = .14) for low myopia, but decreases were found of 0.01 +/- 0.01 microm (P = .45) for moderate myopia and 0.02 +/- 0.04 microm (P = .48) for high myopia. An increase in coma was noted of 0.02 +/- 0.02 microm (P = .37), 0.04 +/- 0.02 microm (P = .02), and 0.11 +/- 0.04 microm (P = .01) for low, moderate, and high myopes, respectively. An increase was found in total higher order aberrations of 0.05 +/- 0.04 microm (P = .17), 0.04 +/- 0.01 microm (P = .01), and 0.11-0.03 microm (P = .01) for low, moderate, and high myopes, respectively. Uncorrected distance visual acuity of 20/15 and 20/20 was achieved in 70% and 91% of low myopes, 58% and 93% of moderate myopes, and 34% and 78% of high myopes, respectively. CONCLUSIONS: Wavefront-optimized femto-LASIK with the WaveLight Allegretto Wave Eye-Q and FS200 lasers achieved excellent postoperative UDVA outcomes, with no significant induction of spherical aberration at all refractive errors. PMID- 23447896 TI - Femtosecond laser (WaveLight FS200) customized keratoplasty for keratoconus: case report. AB - PURPOSE: To describe a case of a 52-year-old man with severe keratoconus who underwent femtosecond laser-assisted keratoplasty with the WaveLight FS200 femtosecond laser (Alcon Laboratories Inc). METHODS: The donor and recipient corneas were cut in a mushroom-shaped pattern. The laser parameters used on this platform for the donor and recipient corneas are described. RESULTS: Corrected distance visual acuity improved by 3 weeks postoperatively. Mean keratometry decreased from 60.00 to 46.00 diopters. CONCLUSIONS: This patient underwent a mushroom-shaped keratoplasty with the femtosecond laser to maximize preservation of his own endothelium. Increased energy and/or decreased spot line separation may be required depending on the degree of corneal edema or scarring involved. PMID- 23447897 TI - Clinical results of topography-based customized ablations for myopia and myopic astigmatism. AB - PURPOSE: To evaluate clinical outcomes after primary treatments for myopia and myopic astigmatism with topography-based ablation profiles on the Allegretto Wave Eye-Q platform (Alcon Laboratories Inc). METHODS: Records of patients who underwent topography-guided, Q-adjusted LASIK were retrieved and analyzed. Patients with mean refractive spherical equivalent up to -16.00 diopters (D) and cylindrical errors up to 6.00 D were included (2051 eyes). Refractive outcomes and visual acuities were analyzed preoperatively and 3 months postoperatively. RESULTS: Manifest spherical refractive error decreased from -5.05 +/- 2.33 to +0.04 +/- 0.35 D. Manifest cylindrical refractive error decreased from 0.83 +/- 0.75 to 0.23 +/- 0.22 D. At 3 months postoperatively, 86.1% (1766 eyes) had a spherical equivalent refraction within +/- 0.50 D of targeted refraction. The number of eyes with uncorrected distance visual acuity of 20/16 and 20/20 was 851 (41.5%) and 1495 (72.9%), respectively. At 3 months, 0.10% (2 eyes) lost more than 2 lines of corrected distance visual acuity and a loss of 2 lines occurred in 0.24% (5 eyes). All patients who lost lines of visual acuity were found to have corneal erosions related to dryness and recovered vision on further follow up. CONCLUSIONS: The results of this retrospective study demonstrate refractive predictability, efficacy, and safety comparable to other treatment modalities such as wavefront-optimized and wavefront-guided treatments. Results are also similar to those reported with other topography-guided systems. PMID- 23447898 TI - Topography-guided hyperopic LASIK with and without high irradiance collagen cross linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. AB - PURPOSE: To evaluate the safety and efficacy of intrastromally applied collagen cross-linking (CXL) in a comparative contralateral eye study of topography-guided femtosecond laser-assisted hyperopic LASIK. METHODS: Thirty-four consecutive patients with hyperopia and hyperopic astigmatism elected to have bilateral topography-guided LASIK and were randomized to receive a single drop of 0.1% sodium phosphate riboflavin solution under the flap followed by 3-minute exposure of 10 mW/cm2 ultraviolet A (UVA) light with the flap realigned in one eye (CXL group) and no intrastromal CXL in the contralateral eye (no CXL group). All eyes were treated with the WaveLight FS200 femtosecond laser and WaveLight EX500 excimer laser (Alcon Laboratories Inc). Refractive error and keratometric, topographic, and tomographic measurements were evaluated over mean follow-up of 23 months. RESULTS: Preoperatively, mean spherical equivalent refraction was +3.15 +/- 1.46 diopters (D) and +3.40 +/- 1.78 D with a mean cylinder of 1.20 +/- 1.18 D and 1.40 +/- 1.80 D and mean uncorrected distance visual acuity (UDVA) (decimal) of 0.1 +/- 0.26 and 0.1 +/-0.25 in the CXL and no CXL groups, respectively. At 2 years postoperatively, mean spherical equivalent refraction was -0.20 +/- 0.56 D and +0.20 +/- 0.40 D with mean cylinder of 0.65 +/- 0.56 D and 0.76 +/- 0.72 D and mean UDVA of 0.95 +/- 0.15 and 0.85 +/- 0.23 in the CXL and no CXL groups, respectively. Eyes with CXL demonstrated a mean regression from treatment of +0.22 +/- 0.31 D, whereas eyes without CXL showed a statistically significant greater regression of +0.72 +/- 0.19 D (P = .0001). CONCLUSIONS: Topography-guided hyperopic LASIK with or without intrastromal CXL is safe and effective, with greater long-term efficacy (less regression) in eyes with CXL. Our data suggest that the regression seen with hyperopic LASIK may be related to biomechanical changes in corneal shape over time. PMID- 23447899 TI - Clinical results of topography-based customized ablations in highly aberrated eyes and keratoconus/ectasia with cross-linking. AB - PURPOSE: To report results of a series of highly aberrated corneas treated with a topography-guided excimer laser ablation. METHODS: Retrospective, nonrandomized, consecutive series of eyes treated with topography-guided photorefractive keratectomy (TG-PRK) with the customized topographical neutralization technique (TNT). Cases included postoperative refractive surgery decentered ablations, optical zone enlargement, asymmetrical astigmatism, postoperative radial keratotomy (RK), postoperative keratoplasty, keratoconus combined with collagen cross-linking (CXL), and postoperative LASIK ectasia combined with CXL. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and manifest refraction were analyzed preoperatively and 6 months postoperatively. RESULTS: In decentered ablation cases, 94% of 37 eyes were within 1.00 diopter (D) of the attempted refractive outcome, with 76% within 0.50 D. Mean topographic, central, optical zone of uniform (monodioptric) power increased from 3.5 to 5.2 mm in 25 eyes. Thirty-one eyes treated for asymmetrical astigmatism showed improvement in cylinder from mean 1.31 to 0.52 D. Ten of 11 eyes treated for previous RK astigmatism achieved postoperative UDVA 20/40 or better. Twenty-seven eyes with postoperative keratoplasty astigmatism were treated, with 7 (25.9%) eyes gaining > or = 2 lines and 12 (44.4%) eyes gaining > or = 1 line of CDVA. Of eyes with keratoconus that were treated using TG-PRK with CXL, 42 (58%) eyes had UDVA 20/40 or better, and 66 (92%) eyes had CDVA 20/40 or better. Twelve (71%) of 17 eyes treated for postoperative LASIK ectasia using TG PRK with CXL had UDVA 20/40 or better. Nine (53%) eyes gained > or = 2 lines of CDVA. CONCLUSIONS: Topography-guided laser treatment with custom TNT, combined with CXL in keratoconus and ectasia, is an effective, safe, and increasingly predictable option for highly aberrated corneas. PMID- 23447900 TI - Experimental course of bioethics upon the bioethics core curriculum of UNESCO: methodoloy and result of investigation. AB - In October 2005 the General Conference of UNESCO adopted the Universal Declaration on Bioethics and Human Rights. The aim of this Declaration was to assist in the realization ofprinciples and support the thorough understanding of the consequences of the ethics of scientific and technical progress, especially for youth. In 2008, the Division of Ethics of Science and Technology Sector for Social and Human Sciences of UNESCO worked out an Educational Program (Bioethics Core Curriculum). On November 23, 2010 a Memorandum was signed between UNESCO and the Yerevan State Medical University after M. Heratsi. The Memorandum was aimed to test the Bioethics Core Curriculum of UNESCO. In this article we will analyze the aims and goals of studying the course, as well as disputable shortcomings of the Program, make recommendations for the improvement of the course of bioethics, and highlight the positive aspects of this Educational Program. PMID- 23447901 TI - Healthy by law: heading towards a brave new world? AB - The law is a tool used by Government to protect public health. Health is an omnipresent preoccupation, inviting each one of us to protect ourselves against potential risks at all times and in all places. The right to health protection is a source of benefit entitlements and rights-obligations that render it effective. However, believing that the law can and should regulate all sectors of human life, still a utopian belief. International law suffers from intrinsic weaknesses that limit its effectiveness. The current economic context has lead to stricter controls over healthcare expenditure faced with the ever-growing demand for treatment, limiting the right to healthcare protection. Through health law, the State has developed controls over individuals. Individual liberties tend to be limited to the cause of the public health policy. Healthy by law, raises a question: are we heading towards a brave new world as described by Aldous Huxley? PMID- 23447902 TI - Plain packaging and indirect expropriation of trademark rights under BITs: does FCTC help to establish a right to regulate tobacco products? AB - Recently the giant tobacco company Philip Morris served its notice to launch an investor-to-state dispute settlement proceeding against the Australian Government for its introduction of plain packaging requirements on tobacco products. It is an important event in the field of intellectual property, investment and international health law. The fundamental questions involved are whether the restriction of trademark rights as a result of the plain packaging requirement is a compensable indirect expropriation under BITs or whether it falls within the scope of government's right to regulate and thus become not compensable. This paper is of the view that the requirement of plain packaging will deprive the essential value or core function of trademark rights and thus constitutes an indirect expropriation under BITs. However, such indirect expropriation meets the public interest requirement and the necessity requirement. The paper further argues that sovereign States have an inherent right to regulate domestic economic activities. Since the pain packaging requirements provided in the FCTC Guidelines are expected to protect the value of human lives and health, the protected values clearly outweigh the affected commercial interests of tobacco companies. Also the justification for host States to adopt a plain packaging policy is strong. Thus, the interpreters of BITs need to pay higher respect to the host State's sovereign power concerning its right to regulate tobacco products for a legitimate purpose. The conclusion of the paper is that the host States should enjoy a defense of the right to regulate to refuse compensation. The author believes that this is the only reasonable conclusion to avoid possible conflicts between different treaty systems (BITs and the FCTC) and between different legal systems and fields (trademark law, investment law and international health law). PMID- 23447903 TI - Content of medical information and unpredictable results in Spanish law. AB - In this study we consider the problem of content of medical information the patient must receive before a medical treatment. Specifically, Spanish law doesn't clarify if doctors must inform patients about every known risk or consequence inherent to an operation, or only about the most probable ones. There have been several contradictory judicial decisions of the Supreme Court about this, and in some cases it's been affirmed that the duty of information is not absolute, while in other decisions it's been affirmed just the opposite. PMID- 23447904 TI - The role of criminal law within the healthcare sector. AB - Health is for most of us the most precious thing one can have. However, in practice situations occur where the patient is harmed within the healthcare institution. Traditionally, there are several ways to protect individuals in society: with civil, criminal and administrative procedures. Over the years in the Netherlands complaints procedures were established in which the complaints about healthcare providers' performance can be handled. Recently, there are some developments within the criminal law that concern the healthcare sector. Examples are: the establishment of the Public Prosecution Service's Expertise Center on Medical Matters, appointments of medical prosecutors. In addition, in legal literature suggestions are made that criminal law is nowadays applied in order to provide redress to the patients (relatives) and as a 'safety tool' that is to ensure security and to counter the risks within the healthcare sector. The article discusses the role of criminal law within the healthcare sector, and in particular, whether criminal procedure is suitable for handling complaints about healthcare. PMID- 23447905 TI - When autonomy kills: the case of Sami Mbarka Ben Garci. AB - Foucault suggested that foreigners and criminals are treated in a particularly unfavourable way by the law. We find arguable support for that proposition in the case of Sami Mbarka Ben Garci. He was a Tunisian Muslim prisoner, charged with rape, held in an Italian prison. He went on a hunger strike, protesting his innocence. He was not force-fed, and was allowed to die. Hunger strikers are commonly force fed. We ask why he was not, and although the reasons in his case are not clear, we suggest that many prisoners perceived as being 'undesirable' (in the sense of being foreigners, or facing particularly serious allegations) are allowed to die (the rhetoric being that their autonomy is being respected), while other prisoners' autonomy would be violated in order to ensure survival. We explore the European and some domestic jurisprudence surrounding force-feeding, and conclude that the law is applied in a worryingly inconsistent way. PMID- 23447906 TI - Nurses' intention to apply clinical practice guidelines. AB - Using Ajzen and Madden's Theory of Planned Behavior, this study investigates factors which influence nurses' intention to apply clinical practice guidelines in their daily ward work. A convenience sample of 91 nurses in internal medicine wards in three Israeli hospitals answered four questionnaires. Data were processed by Pearson correlation coefficients and multivariate regression. The main findings were that burnout was negatively correlated with the intention to work according to guidelines and that professionalism (in the sense of a tendency to follow taught procedure rather than personal judgment) was positively correlated with it. Furthermore, nurses who perceive their behavioral control and subjective norms to be positive will be the most determined to work according to guidelines, provided they personally command the necessary resources to do so. PMID- 23447907 TI - This is my kidney, I should be able to do with it what I want: towards a legal framework for organ transplants in South Africa. AB - In 2010 illegal kidney transplants performed in South African hospitals were exposed. Living donors (actually sellers) from Brazil and Romania were flown into South Africa where a kidney was harvested from each and transplanted into Israeli patients. The media reports that followed indicated an outcry against the sale of human kidneys. But by analysing the whole transplantation process from the point of view of each person involved in the transplantation, namely the recipient, the donor, the doctor and the black market in the background the feeling is created that a process of payment for a kidney seems fairer than the current way of procuring organs either legally or illegally. PMID- 23447908 TI - In search of donor relations and identity: the missing voices of Israel's children. AB - The voices of donor offspring and their families are missing from the debate regarding gamete donor anonymity v. openness in Israel, their unique predicament unheeded. Despite a context of worldwide change, various fears and myths impede the outlawing of donor anonymity, with Israel's medical establishment and legal representatives invested in maintaining a status quo characterized by regulations that discriminate between families whose members know their biological parents/siblings and those who do not. The most prominent of these is that abolishing anonymity leads to long-term shortage of donors, despite well documented evidence to the contrary. A review of key research findings regarding the particular needs and experiences of offspring, recipients and donors clearly supports the need for a well thought-out re-evaluation of persistent fears and myths via the prism of grassroots reality. This evidence-based approach can lead to the formulation of recommendations that should facilitate, reflect and constitute such policy change. PMID- 23447909 TI - 10 years of controversy, twists and turns in the Perruche wrongful life claim: compensation for children born with a disability in France. AB - Since March 1st, 2010, French citizens have been able to call on a new legal procedure for defending their rights: the priority preliminary ruling on issues of constitutionality (question prioritaire de constitutionnalite, QPC). If, during a trial, a citizen considers that a provision of the applicable law is inconsistent with the Constitution of the French Republic, he/she may request that the matter be referred to the Constitutional Council. One ofthe first QPCs concerned legislation related to the Perruche jurisprudence. In a ruling on November 17th, 2000, the French Supreme Court of Appeal had granted the child Nicolas Perruche the right to financial compensation for the material costs related to his physical disability (caused by congenital rubella). In response, Article 1 of the Patients' Rights and Quality of Care Act (passed on March 4th, 2002) prohibited the award of compensation to a child "just because he/she has been born [with a disability]", i.e. in "wrongful life" claims. Since the enactment of the Act, compensation in a case like Perruche may only be awarded to cover the parents' psychological suffering, rather than the child's status at birth. The application of this "anti-wrongful life claim" legislation has since been subject of heated debate. In a QPC ruling on June 11th, 2010, the Constitutional Council found that Article 1 of the Patients' Rights and Quality of Care Act was (with the exception of its transitional provisions) indeed consistent with the Constitution of the French Republic. PMID- 23447910 TI - Medication regimes in the context of end-of-life decisions in neonatology: legal considerations with regard to Dutch NICU-practice. AB - Developments in legal and medical research concerning end-of-life decisions regarding severely suffering neonates in the Netherlands provide good cause for reflection on specific items of this issue. This article deals with the outcomes of the first national survey on end-of-life practice in Dutch Neonatal Intensive Care Units (NICUs) and examines the legal aspects of the use of medication as a part of this practice. The authors particularly reflect on the application of analgesics and sedatives on the one hand and neuromuscular blockers (NMBs) on the other hand. Furthermore, they focus on different elements of medicinal use such as indication, the moment of administering, dosage, effects of combinations of drugs, the relationship to the causation of death and (failures in) documentation. PMID- 23447911 TI - Impact of health care reform on reproductive service providers. AB - The Affordable Care Act affects access to reproductive services in many ways. Beginning in 2014 many individuals will purchase health insurance through the State Insurance Exchanges being drawn to this market by the affordable coverage made even more so by premium subsidies available to lower income individuals. The plans being offered through these exchanges must provide coverage that meets the benefits as defined under the Essential Health Benefits. However, it still remains unclear how Essential Health Benefits will be described and specifically what, if any, reproductive services will be included. Beyond the exchanges low income individuals will have access to the expansion in Medicaid occurring in many states starting also in 2014. Each state Medicaid program is responsible for describing their extent of coverage for reproductive services. Already in place affecting many younger individuals in need of reproductive services is the Dependent 26 provision, which provides coverage to dependents up to the age of 26 under a guardian's insurance. These provisions of the Affordable Care Act may increase access to reproductive services for many individuals previously uninsured or underinsured. PMID- 23447913 TI - Effect of mode of delivery on neonatal outcome of monochorionic diamniotic twin pregnancies: a retrospective cohort study. AB - OBJECTIVE: To assess whether vaginal delivery increases the risk of adverse neonatal outcome among uneventful monochorionic diamniotic twin pregnancies. STUDY DESIGN: We conducted a retrospective controlled cohort study on 112 uneventful monochorionic diamniotic twin pregnancies at > or = 34 weeks' gestation. The outcomes of 52 monochorionic diamniotic twins delivered vaginally were compared with those of 172 monochorionic diamniotic twins delivered by cesarean section. RESULTS: Five babies (2.9%) in the cesarean section group had a 5-minute Apgar score < 7 and needed orotracheal intubation, whereas in the vaginal delivery group no 5-minute Apgar score < 7 or orotracheal intubation occurred (p = 0.002). Delivery by cesarean section presented higher rates of admission to neonatal intensive care unit (62 out of 172 babies delivered by cesarean section compared to 3 out of 52 babies delivered vaginally, p < 0.001). There were no cases of intrapartum twin-to-twin transfusion syndrome or neonatal death at time of hospital discharge in either group. CONCLUSION: Vaginal delivery appears to be a good management option in uneventful monochorionic diamniotic twin pregnancies after 34 weeks' gestation. PMID- 23447914 TI - Comparison of the efficacy and safety of surgical procedures utilizing autologous fascial and transobturator slings in patients with stress urinary incontinence. AB - OBJECTIVE: To evaluate whether the conventional autologous fascial (AF) sling is superior or equal to the readjustable transobturator (TOT) sling in efficacy and safety in women with stress urinary incontinence (SUI). STUDY DESIGN: This was a retrospective study comprised of a sample of 463 patients from 2003 to 2009. A total of 203 women received TOT slings for urodynamically confirmed SUI, and 260 patients received AF slings. We analyzed the subjective success rate (cure and/or improvement) after 12 and 24 months of surgery as well as any immediate and late surgical complications. RESULTS: Both groups were statistically similar with regard to age, parity, body mass index, number of previous gynecological surgeries, and antiincontinence therapies. After 12 months patients with the TOT sling had a higher subjective percentage efficacy rate when compared to those with the AF sling (94% vs. 88%, p < 0.05); however, after 24 months this percentage was no longer statistically significant (88.7% vs. 84.6%, p = 0.20). The TOT sling presented fewer postoperative complication rates (14.1% vs. 25.6%, p < 0.05), similar intraoperative complication rates (1.15% vs. 2.3%, p = 0.22) and a shorter mean operative time (23 vs. 112 minutes, p < 0.05) than the AF sling. CONCLUSION: Both techniques had similar subjective efficacy rates, but the TOT sling demonstrated fewer postoperative surgical complications than the AF sling. PMID- 23447912 TI - Patterns of preconception, prenatal and postnatal care for diabetic women by obstetrician-gynecologists. AB - OBJECTIVE: To assess barriers to and quality of care received by diabetic pregnant women from obstetrician-gynecologists. STUDY DESIGN: A questionnaire was mailed to 1,000 representative practicing Fellows of the American College of Obstetricians and Gynecologists; 74 did not treat pregnant patients and 510 (55.1%) returned completed surveys. Respondents were divided into 3 groups: maternal-fetal medicine specialists, physicians with high minority/low insurance patient populations, and physicians with low minority/ high insurance patient populations. RESULTS: Reported preconception and prenatal care was generally consistent with guidelines. Regarding gestational diabetes mellitus patients the 3 physician groups differed in assessing postpartum glycemic status, counseling about lifestyle changes, and counseling patients to consult a doctor before their next pregnancy. Patient demographics and perceived barriers to care were similar between maternal-fetal medicine specialists and physicians with high minority/low insurance patient populations. These two physician groups were more likely to agree that lack of educational materials, arranging specialist referrals, patient compliance with recommendations, and patients' ability to afford healthful food were barriers to quality care. CONCLUSION: According to physician self-report, pregnant diabetic patients with access to an obstetrician receive quality care regardless of insurance status. Postpartum care is more variable. Physicians with high minority/low insurance patient populations may lack access to resources. PMID- 23447915 TI - Risk of spontaneous preterm birth in relation to maternal depressive, anxiety, and stress symptoms. AB - OBJECTIVE: To examine the risk of preterm birth (PTB) in relation to maternal psychiatric symptoms during pregnancy in Peruvian women. STUDY DESIGN: This case control study included 479 PTB cases and 480 term controls. In-person interviews were conducted to assess women's depressive, anxiety, and stress symptoms using the Patient Health Questionnaire (PHQ-9) and the Depression Anxiety Stress Scales (DASS-21). Multivariable logistic regression procedures were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Compared with women reporting no or minimal depressive symptoms, the aOR (95% CI) for PTB associated with consecutive severity of depressive symptoms based on the PHQ-9 assessment method were as follows: mild, 2.22 (95% CI 1.64-3.00) and moderate severe, 3.67 (95% CI 2.09-6.46). The corresponding aORs for normal, mild, and moderate-severe depressive symptoms based on the DASS-21 assessment were 1.00 (reference), 3.82 (95% CI 1.90-7.66), and 2.90 (95% CI 1.66-5.04), respectively. A positive gradient was observed for the odds of PTB with severity of anxiety (Ptrend < 0.001) and stress symptoms (Ptrend < 0.001). CONCLUSION: The odds of PTB increased in pregnant Peruvian women with psychiatric symptoms. Efforts to screen and treat affected women may modify risks of PTB and possibly other associated disorders. PMID- 23447916 TI - Evaluation of the effect of vitamin E on pelvic pain reduction in women suffering from primary dysmenorrhea. AB - OBJECTIVE: To evaluate the effect of vitamin E on the reduction of pelvic pain in women with primary dysmenorrhea and to compare its effect with placebo. STUDY DESIGN: A double-blind randomized clinical trial was performed on 120 women suffering from primary dysmenorrhea. They were randomly assigned into 2 groups, and 94 women finished the study. In the study group (n = 42) 400 IU/day of vitamin E was prescribed starting 2 days before the beginning of menstruation and continuing for a total of 5 days, for 2 consecutive cycles. In the control group (n = 52) a placebo was prescribed. Pain severity was evaluated using the Visual Analogue Scale for 1 month before the study and during the 2 months of study. RESULTS: Pain severity during the first month of the study was 5.41 +/- 2.4 in the study group and 5.76 +/- 2.08 in the control group and 4.73 +/- 1.89 and 5.35 +/- 2.05 in the study and control groups, respectively, during the second month of the study. Pain severity during the first and second months of treatment with vitamin E and placebo was lower than the pain severity before treatment. The mean reduction of pain in the study group (-2.7 +/- 2.1) was greater than that in the control group (-1.8 +/- 2.4) during the second month of the study. CONCLUSION: Both vitamin E and placebo may reduce the pelvic pain of dysmenorrhea, but vitamin E seems to cause a more significant reduction in pain. With regard to its safety, the study indicates it can be a simple and safe option for the treatment of dysmenorrhea. PMID- 23447917 TI - Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To evaluate the efficacy of a relatively low daily dosage of Pycnogenol French maritime pine bark extract for improvement of climacteric symptoms. STUDY DESIGN: In a double-blind, placebo-controlled study 170 perimenopausal women were enrolled and treated with 30 mg Pycnogenol or placebo twice daily over a period of 3 months. Climacteric symptoms were evaluated by the Women's Health Questionnaire (WHQ) and by the Kupperman index, accompanied by an investigation of sex hormones and routine blood chemistry. RESULTS: Seven women dropped out of each group due to noncompliance or personal reasons, but not as a result of treatment. A significant placebo effect was apparent in this study, suggesting an improvement of a majority of the WHQ categories. Compared to baseline, Pycnogenol significantly (p < 0.05) improved all symptoms with the exception of formication sensation and abnormal perceptions. Pycnogenol was found to be especially effective for improving vasomotor and insomnia/sleep problem symptoms, which were significantly better after 4 and 12 weeks than with placebo (p < 0.05). Total Kupperman's index for perimenopausal symptom severity score decreased significantly by 56% as compared to placebo (-39%) after 12 weeks of treatment (p < 0.05). Symptom score was also significantly better already after 4 weeks of treatment with Pycnogenol as compared to placebo. CONCLUSION: This study, applying a relatively low daily dose, allows identification of those climacteric symptoms which respond particularly well to supplementation with Pycnogenol. PMID- 23447919 TI - Effects of human cumulus cells on in vitro fertilization outcomes and its significance in short-term insemination. AB - OBJECTIVE: To observe the effects of cumulus cells on in vitro fertilization. STUDY DESIGN: Oocytes were retrieved from 47 patients (> 10/patient) who underwent short-term insemination from August 2009 to June 2010. The oocytes from each patient were divided into a cumulus cell-free group (cumulus cells were removed from the incubation medium 4 hours after coincubation of male and female gametes) with 389 oocytes and a cumulus cell group (cumulus cells were retained with the gametes until fertilization was evaluated 16-18 hours after co incubation) with 402 oocytes. RESULTS: Polyspermic fertilization was 0.96 +/- 1.14 in the cumulus cell-free group and 0.47 +/- 0.72 in the cumulus cell group with p < 0.05. There were no significant differences in normal fertilization (5.96 g 1.73 vs. 6.55 +/- 3.72), 1PN fertilization (0.06 +/- 0.25 vs. 0.09 +/- 0.28), fertilization failure (1.34 +/- 1.17 vs. 1.45 +/- 1.84), cleavage (6.06 +/ 2.04 vs. 6.51 +/- 3.94), high-quality embryo (3.94 +/- 1.79 vs. 4.74 +/- 3.45) and usable embryo (5.06 +/- 1.86 vs. 5.68 +/- 3.98) between cumulus cell-free group and cumulus cell group, all with p > 0.05. CONCLUSION: In our study short term insemination (4 hours) causes a statistical increase in polyspermic fertilization. In order to ensure correct oocyte fertilization and reduction of polyspermic fertilization, it is better to retain the cumulus cells for 16-18 hours. PMID- 23447920 TI - Awareness and attitudes toward voluntary counseling and testing for HIV/AIDS among law undergraduates in tertiary institutions in southeast Nigeria. AB - OBJECTIVE: To determine the knowledge of and attitudes toward voluntary counseling and testing (VCT) for human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) among undergraduates of a law faculty in tertiary institutions in Anambra State in southeast Nigeria. STUDY DESIGN: This was a cross-sectional, questionnaire-based survey conducted among law undergraduates in Anambra State using a multistage, random sampling method. The respondents were all full-time law students and were aged from 15-42 years with a mean of 21.06 +/- 3.0 years and a modal age of 20-24 years. In all, 210 (71.4%) of the students were aware of VCT for HIV/AIDS, while 84 (28.6%) of the respondents had no knowledge of it. The most common sources of information about VCT for HIV/AIDS were electronic media (114 [38.8%]) followed by churches (67 [22.8%]) and print media (44 [15.0%1). Although a majority of respondents had a positive attitude toward VCT for HIV/AIDS, 20% of them disapproved of VCT, and this is quite high considering their educational status. CONCLUSION: Public health education, awareness programs and VCT centers dedicated to young people should be established. PMID- 23447918 TI - Imperforate hymen with elevated serum CA 125 and CA 19-9 levels. AB - OBJECTIVE: To report the clinical characteristics of 14 patients with imperforate hymen and their levels of tumor markers (CA 19-9 and CA 125). STUDY DESIGN: Fourteen patients with imperforate hymen who followed-up between September 2006 and September 2010 in the Department of Obstetrics and Gynecology, Dicle University School of Medicine, Diyarbakir, Turkey, were evaluated retrospectively. The clinical features and the management of the patients are discussed. RESULTS: The mean age of the patients was 13.8 years. All patients had primary amenorrhea and pelvic pain. The most common clinical symptoms were cryptomenorrhea in 14 patients, pelvic pain in 11, palpable abdominal mass in 6, voiding difficulties in 7, and defecation problems in 2. In 6 patients with palpable pelvic mass, the mean + standard deviation values of tumor markers were as follows: CA 125, 84.0 +/- 23.7 and CA 19-9, 162 +/- 189. One week after surgery we measured CA 125 and CA 19-9 levels once again. The postoperative mean CA 125 level was 13.8 +/- 3.6, and the mean postoperative CA 19-9 level was 17.5 +/- 3.5. Preoperative levels of CA 125 and CA 19-9 were significantly higher than those of the postoperative period (p < 0.001 for both comparisons). Six patients were treated by T-shaped incision and 8 patients by a central surgical incision through the hymenal membrane. CONCLUSION: Diagnosis of imperforate hymen is very important before undergoing surgery in a different clinic. Many patients have seen several doctors before receiving a clear diagnosis and have had tumor markers evaluated because the presence of pelvic mass in patients suggests the possibility of a gynecologic malignancy. Imperforate hymen is one of the benign conditions that increase serum CA 125 and CA 19-9 levels and which is not listed in the classical medical textbooks. These markers are not needed for the diagnosis. PMID- 23447921 TI - Undiagnosed celiac disease in women with infertility. AB - OBJECTIVE: To determine the prevalence of celiac disease in a group of Brazilian women with infertility. STUDY DESIGN: This was a cross-sectional study of 170 infertile Brazilian women tested for immunoglobulin A anti-tissue transglutaminase (IgA anti-tTG), endomysial antibody and total IgA. Women with positive serologies were recommended for intestinal biopsy. Patients with positive serology and villous atrophy on biopsy had the diagnosis of celiac disease, while those with positive serology but no villous atrophy were identified as having latent celiac disease. All of these women were typed for HLA DQ2 and HLA-DQ8. RESULTS: The prevalence of celiac disease confirmed by biopsy in the study group was 1.2% (2 out of 170) (95% confidence interval [CI], 0.1-4.2). Considering also those with latent celiac disease, the prevalence was estimated at 2.9% (5 out of 170) (95% CI, 1.0-6.7) and in the subgroup of unexplained infertility the prevalence was 10.3% (3 out of 29) (95% CI, 2.2-27.4). All seropositive patients were also HLA-DQ2 positive. CONCLUSION: Further studies are required to define the role of routine serological screening for celiac disease in infertile women as well as to elucidate the underlying mechanism for infertility in active celiac disease. PMID- 23447922 TI - Gestational trophoblastic diseases in Turkey. AB - OBJECTIVE: To evaluate epidemiological data, staging, prognostic scoring system and immunohistochemical reports as well as the management and outcome of hydatidiform mole (HM) in Turkey. STUDY DESIGN: All published data in the Turkish literature from 1932-2011 were evaluated retrospectively. RESULTS: The incidence of HM was 0.3-16 per 1,000 pregnancies and 1.0-24.5 per 1,000 deliveries. Of a total number of 929,323 pregnancies during a 68-year period, 2,227 HM cases were encountered, to give an average incidence of 2.39 per 1,000 pregnancies and 1.87 per 1,000 deliveries. Although there were big differences in reported incidences, the overall incidence is also very high, and the main reason for the differences was thought to be related to the origin of the studies: all were hospital based. An epidemiological field study of HM in the rural part of Turkey identified 4 HM cases and 6,274 pregnancies in 2,032 women aged 15-49. The frequency of HM per 1,000 live births and per 1,000 pregnancies was 0.8 and 0.6, respectively. CONCLUSION: Multicenter, community-based studies are needed to present the real incidence, and it is vital that women with gestational trophoblastic disease be followed by a multidisciplinary team, and ideally in trophoblastic disease centers and national case registry systems for gestational trophoblastic disease. PMID- 23447923 TI - Rupture of a degenerated uterine fibroid as a cause of acute abdomen: a case report. AB - BACKGROUND: Uterine fibroid is one of the most common pelvic neoplasms. It is rare for this condition to manifest as acute symptoms necessitating emergency surgical intervention. CASE: A 46-year-old, Japanese woman was referred to our emergency room for sudden epigastric discomfort. A pelvic mass was felt, and computed tomography demonstrated a 13-cm hypodense multilocular cystic mass adjacent to the uterus. The anterior wall of the cyst was thinned and discontinued, suggesting rupture of the cyst. There was also massive ascites. Peritoneal irritation caused by rupture of an ovarian cyst was suspected, and an emergency exploratory laparotomy was performed. The patient was found to have a distended cystic mass protruding from the posterior surface of the uterus with 3,200 mL of blood-stained ascites. Closer examination revealed a 1-cm tear on the tumor surface, and both solid and cystic parts to the mass. Microscopically the tumor showed a proliferation of myometrial cells without atypia and hyaline degeneration. These findings were interpreted as a rupture of uterine fibroid after cystic degeneration. CONCLUSION: Rupture of degenerated cystic fibroid is rare, but it should be included in the differential diagnosis when encountering patients with a cystic tumor and massive ascites. PMID- 23447924 TI - Ectopic pregnancy after hysterectomy: a case report. AB - BACKGROUND: Ectopic pregnancy after hysterectomy is an unusual diagnosis that may lead to significant morbidity, especially when diagnosis is not timely. CASE: A 41-year-old woman presenting with abdominal pain and vaginal bleeding 5 years after a vaginal hysterectomy was found to have a tubal ectopic pregnancy, which required emergent surgical intervention. CONCLUSION: Ectopic pregnancy after hysterectomy represents a challenging diagnosis because it is counter-intuitive and very uncommon. The diagnosis of posthys-terectomy ectopic pregnancy, though exceptionally rare, should be considered for women presenting with abdominal pain after hysterectomy. PMID- 23447925 TI - Naturally occurring heterotopic pregnancy with a monoamniotic monochorionic twin gestational pregnancy: a case report. AB - BACKGROUND: We describe a case of a heterotopic pregnancy that included a rare spontaneous twin gestational monoamniotic monochorionic pregnancy in a patient with a history of questionable contraceptive practices and a previous left salpingectomy secondary to a ruptured ectopic pregnancy. CASE: A 34-year-old woman, gravida 2, para 1001, at 9 weeks + 2 days' gestational age by her last menstrual period on etonogestrel vaginal ring contraception presented with progressively increasing right lower quadrant abdominal pain, increasing abdominal girth, and vaginal bleeding. Transvaginal ultrasound revealed an intrauterine pregnancy along with a ruptured right tubal pregnancy. The patient was taken to the operating room where a right salpingectomy was performed. Her main risk factor was a previous ectopic pregnancy that led to a left-sided salpingectomy 2 years prior to this incident. CONCLUSION: Cesarean delivery was performed at 30 weeks + 2 days' gestation because of preterm premature ruptured membranes followed by preterm labor and a nonreassuring fetal heart tracing in the presenting fetus. Twin female infants were delivered. There was entanglement of the umbilical cords as well as 2 true knots. PMID- 23447926 TI - Conservative management of cesarean scar pregnancy with uterine arteriovenous malformation: a case report. AB - BACKGROUND: Cesarean scar pregnancy is a rare type of ectopic pregnancy in which implantation occurs in a previous lower segment cesarean scar. It may be associated with uncontrolled hemorrhage ending in hysterectomy. It can become potentially life threatening for the patient when it further gets complicated by uterine arteriovenous malformation (AVM). To the best of our knowledge there are only a few previous reports of AVM complicating a scar pregnancy. It is still unclear which treatment is most optimal. CASE: We describe a case of a scar pregnancy complicated by uterine AVM. The diagnosis was made using 3D color Doppler ultrasound, showing a highly vascular tumor in the isthmic region of the uterus. Computed tomography angiography supported the diagnosis. The patient underwent selective embolization of the uterine artery followed by weekly intramuscular injections of methotrexate. Recovery was uneventful. CONCLUSION: The decision regarding mode of treatment should be made by the patient and the clinician based on the local expertise and experience. Judicious use of medical management (methotrexate) and uterine artery embolization may prevent hysterectomy and allow preservation of fertility. PMID- 23447927 TI - A rare case of primary retroperitoneal mucinous adenocarcinoma: a case report. AB - BACKGROUND: Primary retroperitoneal mucinous adenocarcinomas are very rare tumors that resemble ovarian mucinous cystadenocarcinomas. CASE: A 39-year-old woman presented with a 20-cm cystic lesion. Following surgery final pathology revealed mucinous adenocarcinoma consistent with a primary retroperitoneal process. The patient responded favorably to 6 cycles of paclitaxel and carboplatin chemotherapy and currently has no evidence of disease. CONCLUSION: During surgical resection of a primary retroperitoneal mucinous adenocarcinoma, ensuring that the lesion remains intact has clinically significant implications. PMID- 23447929 TI - Electrocatalytic oxidation of formic acid by poly(diallyldimethylammonium chloride) and Pt/Pd-functionalized carbon nanotubes mixtures. AB - Improving the catalytic activity of the anode catalyst is an important task in the direct formic acid fuel cell (DFAFC). In this study, the catalysts were prepared by dispersing either platinum or palladium metal on the surface of thiolated multi-walled carbon nanotubes (t-MWCNTs), denoted as t-MWCNT-Pt and t MWCNT-Pd, respectively. These modified t-MWCNT and poly(diallyldimethylammonium chloride) (PDDA) were ultrasonically mixed and loading on a glassy carbon electrode (GCE) for formic acid (FA) oxidation and the catalytic activities were then investigated by using cyclic voltammetry (CV) and chronoamperometry (CA) methods. The as-formed catalysts were characterized by several methods. To optimize the catalytic performance, we investigated the catalysts separately and together (in different ratios) for FA oxidation. The PDDA mixed catalyst demonstrated a slightly better performance. These results indicated that the PDDA/(t-MWCNT-Pt + t-MWCNT-Pd) catalyst exhibited better activity than that of the corresponding other catalysts. PMID- 23447928 TI - Omental implantation secondary to ruptured tubal pregnancy with a negative urine pregnancy test: a case report. AB - BACKGROUND: The first steps in the diagnosis of an ectopic pregnancy are to use a sensitive qualitative urine test to detect the beta-subunit of human chorionic gonadotropin (beta-hCG) and to perform a transvaginal ultrasonograph. y negative urine pregnancy test result is generally used to exclude an ectopic pregnancy; however, a few studies have reported the presence of a ruptured ectopic pregnancy in a patient with a negative urine pregnancy test result. Furthermore, because secondary omental implantation (SOI) is rare and probably underestimated or misdiagnosed, a case of an SOI with a negative urine hCG test has never been reported. CASE: This was a very rare case of an SOI from a ruptured tubal pregnancy in a patient with an initial series of negative urine pregnancy tests and decreased levels of serum beta-hCG. The SOI was managed with laparoscopy. CONCLUSION: For patients diagnosed with tubal or ovarian pregnancy who have negative urine pregnancy test results and decreased levels of serum beta-hCG, late-onset omental implantation should be considered as a possibility. PMID- 23447930 TI - Linear low-density polyethylene and zirconium phosphate nanocomposites: evidence from thermal, thermo-mechanical, morphological and low-field nuclear magnetic resonance techniques. AB - Lamellar alpha-zirconium phosphate was synthesized by direct precipitation and also directly expanded with octadecylamine, through alcoholic solution. To produce a nanocomposite, it was incorporated in linear low-density polyethylene in the molten state, using a counterrotating twin-screw extruder set at 170-190 degrees C and 100 rpm. The differential scanning calorimetry analysis revealed a decrease in the polyolefin melting temperature and crystallinity degree. The higher onset temperature of the zirconium phosphate modified with octadecylamine and linear low density polyethylene composite indicated an increasing of thermal stability and it suggests that some polyethylene chains entered into the filler's spacing. Dynamic-mechanical analysis evidenced an increase in both moduli (storage and loss). Wide-angle X-ray diffraction showed additional peaks- diffraction angles appeared in the region beneath 12 degrees--which were attributed to partial intercalation of polyethylene chains between filler interlamellar spacing. By hydrogen low-field nuclear magnetic resonance, the two low intensity relaxation time peaks shifted to higher values, strongly suggesting interaction between the octadecylamine and polymer matrix into the filler galleries. From these results, it may be postulated that a partially intercalated and/or exfoliated nanostructure in the zirconium phosphate modified with octadecylamine and linear low density polyethylene composite was achieved. PMID- 23447931 TI - Self-assembly of L-cysteine for chiral recognition of mandelic acid in gas phase. AB - This study demonstrates a new approach for the selective recognition of chiral mandelic acid by quartz crystal microbalance (QCM) using L-cysteine as the selector. The modification of L-cysteine on the QCM sensor was identified using resonant frequency detection, the contact angle, cyclic voltammetry, and X-ray photoelectron spectroscopy measurements. The chiral recognizability of L- and D MA on the L-cysteine-modified surface was examined using QCM detection integrated with a vapor diffused molecular assembly reaction technique. The present chiral recognition results suggest that the L-cysteine is a good resolving agent for detecting chiral mandelic acid. PMID- 23447932 TI - Fine-tuning the fluorescence emission wavelength of gold nanoclusters in the protein-directed synthesis: the effect of silver ions. AB - Highly fluorescent gold nanoclusters have attracted much attention recently. Here, we reported a "green", facile method for fine-tuning the fluorescence emission wavelength of gold nanoclusters synthesized with bovine serum albumin (BSA). The principle of the experimental work involved the utilization of BSA as the reductant for the synthesis of gold nanoclusters and the addition of small amounts of silver ions in the synthesis process for tuning the fluorescence properties of the synthesized gold nanoclusters. Our results showed that fluorescence emission wavelength of the synthesized gold nanoclusters could be fine-tuned in a fairly wide range (- 90 nm) by addition of different quantities of silver nitrate in the synthesis process. In addition, with increasing silver ions quantity the emission wavelength of the gold nanoclusters varied in a non monotonic manner. In this way, gold nanoclusters emitting yellow, orange or red fluorescence with decent quantum yields were readily obtained in a single batch. PMID- 23447933 TI - Electrocatalytic oxidation of hydrazine and hydroxylamine by graphene oxide-Pd nanoparticle-modified glassy carbon electrode. AB - Pd nanoparticle catalysts supported by thiolated graphene oxide (tGO) on a glassy carbon electrode (GCE), and denoted as tGO-Pd/GCE, are used in this study for the electrochemical determination of hydroxylamine and hydrazine. The physicochemical properties of tGO-Pd were characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). They showed strong catalytic activity toward the oxidation of hydroxylamine and hydrazine. Cyclic voltammetry (CV) and amperometry were used to characterize the sensors' performances. The detection limits of hydroxylamine and hydrazine by tGO-Pd/GCE were 0.31 and 0.25 microM (s/n = 3), respectively. The sensors' sensitivity, selectivity, and stability were also investigated. PMID- 23447934 TI - Effects of Eu3+ concentration on structural, optical and vibrational properties of multifunctional Ce(1-x)Eu(x)O2-delta) nanoparticles synthesized by thermolysis of 2,4-pentanedione complexes. AB - The 5-10 nm Ce(1-x)Eu(x)O(2-delta) (0 < or = x < or = 0.30) nanoparticles with fluorite structure were synthesized by thermal decomposition of Eu- and Ce-2,4 pentanedione complexes mixtures. X-ray line broadening analysis of mixed samples Ce(1-x)Eu(x)O(2-delta) (0.05 < or = x < or = 0.30) showed that the crystallite size was lower and root mean square strain higher than in pure ceria. However, within mixed samples Ce(1-x)Eu(x)O(2-delta) (0.05 < or = x < or = 0.30) crystallite size and root mean square strain were independent of Eu3+ concentration. Raman spectroscopy results indicated that europium ions yield disorder by breaking the phonon propagation and therefore making the non-centre Brillouin zone modes Raman active. The absorption bands in the spectra of mixed oxides were blue-shifted in comparison to pure CeO(2-delta) nanopowder. The samples show red emission typical for Eu ions. The biggest photoluminescent intensity was observed for the highest Eu3+ concentration (x = 0.30) and further enhanced with the increase in crystallinity. PMID- 23447935 TI - Production of size controlled aluminum and alumina nanoparticles via pulsed laser ablation in water. AB - An Al metal plate was ablated by a pulsed Nd-YAG laser to produce nano-structured Al and gamma-Al2O3 in deionized water in the absence of any surfactants or catalysts. In this study, the mean diameter and the width of size distribution of the nanoparticles was influenced by the laser power, resulting in the production of smaller and larger sizes of nanoparticles with higher and lower laser power, respectively. The influence of laser power on the mean diameter and the width of size distribution of as-prepared nanoparticles generated by the laser ablation process was explained by the space homogeneity of the plasma plume, where the nucleation of nanoparticles has occurred. Further explanations of the influence of laser power on the size distribution are proposed. Furthermore, structural and morphological characterization of aluminum and gamma-Al2O3 nanoparticles was conducted by X-ray diffraction (XRD) and field emission scanning electron microscope (FE-SEM). PMID- 23447936 TI - Superior field emissions from boron-doped nanocrystalline diamond compared to boron-doped microcrystalline diamond. AB - Boron-doped microcrystalline diamond (BMD) and nanocrystalline diamond (BND) thin films were grown on Si substrates by microwave-assisted chemical vapor deposition, and their field emission properties were evaluated. BND exhibited a lower turn-on field and higher field enhancement factor than BMD. Furthermore, in a long-term emission stability test, BND showed only a 4% increase in the current density after 12 h of emission, whereas the current density of BMD decreased by - 59%. These results indicate that BND is a more stable and viable current emitter than BMD. PMID- 23447938 TI - X-ray emission spectra of graphene nanosheets. AB - Investigations of the electronic structure of graphene nanosheets synthesized by the reduction of oxidized graphene nanosheets were carried out using ultra-soft X ray emission spectroscopy (USXES). Oxidized graphene nanosheets were produced from carbon nanofiber starting material using a modified Hummers method. X-ray diffraction, and scanning and transmission electron microscopy investigations were used in addition to USXES to study the electronic structure evolution from carbon nanofibers to graphene nanosheets. The effect of the degree of corrugation of the graphene nanosheets on the fine structure of the CK(alpha)-emission bands was revealed by USXES. It was found that corrugation of the graphene nanosheets is caused by overlapping of the pi-orbitals and formation of mixed (sigma + pi) states. PMID- 23447937 TI - Effect of annealing environments on self-organized TiO2 nanotubes for efficient photocatalytic applications. AB - In the present study, amorphous titanium dioxide (TiO2) nanotubes were synthesized by one-step anodization technique and subsequently annealed in different environments to investigate the effect of annealing atmospheres on the formation of different crystalline phases. X-ray Diffraction (XRD) patterns clearly showed the presence of anatase TiO2 phase with various crystallite sizes. The samples annealed in oxygen and air atmospheres at 500 degrees C showed a dominant anatase phase and a small amount of rutile phase, on the other hand, the samples annealed in nitrogen and argon atmospheres and in a vacuum at 500 degrees C contained the anatase phase only. XPS analysis of the samples showed a broadening in the binding energy curves with respect to variation in annealing atmosphere, confirming the variation in surface defects, which in turn affect photocatalytic degradation. The vacuum-annealed sample showed superior photocatalytic degradation efficiency as it had relatively higher pseudo-first order rate constants (k) of 0.009/min. PMID- 23447939 TI - Viscosity of suspensions of yttrium oxide (Y2O3) nanopowder in ethyl alcohol. AB - This paper presents results from measurements of viscosity of suspensions of Yttrium Oxide Y2O3 ceramic nanopowder in ethyl alcohol. The study was conducted at the request of and in cooperation with the ICMB. This research will add important information about the formation and viscosity characteristics of suspensions of nanopowders. The behavior of nanopowder suspensions has been examined in a wide range of shear rates from 0.01 s(-1) to 2000 s(-1). Additionally, the behavior of the suspension has been studied in the temperature range from -15 degrees C to 20 degrees C. Complementary experiments have been performed by application of a Rheo-NMR at Bruker Biospin and by the use of RheoScope at ThermoFisher companies. PMID- 23447940 TI - Preferential adhesion of silver nanoparticles onto crystal faces of alpha cyclodextrin/carboxylic acids inclusion compounds. AB - Alpha-Cyclodextrin (alpha-CD) inclusion compounds containing the carboxylic acids (octanoic, decanoic, lauric or dodecanoic, myristic or tetradecanoic, palmitic or hexadecanoic and stearic or octadecanoic) as guests were synthesized and applied for preferential adhesion of silver nanoparticles (AgNPs). The binding affinity depends of the chain length of the respective guest and is most efficient for octanoic and decanoic acids. The immobilization of nanoparticles is caused by the spatial replacing of the stabilized shell of the nanoparticles by COOH groups of the guests molecules, located at the entrance of cavity of alpha-CD, corresponding to the {001} crystal plane. Crystalline coating with nanoparticles provides a means of storing of AgNPs on solids state without aggregation. The stabilization of the particles on the surface is valid for a given length and ordering of the guest in the cavities of the alpha-CD being the octanoic and decanoic acid the most appropriated. PMID- 23447941 TI - Selective effect of procaine, tetracaine and dibucaine on gold nanoparticles. AB - An aqueous colloid dispersion of gold nanoparticles (AuNPs) was prepared by reduction of gold(III) chloride and its interaction with three local anesthetics (procaine, dibucaine or tetracaine) was investigated. Optical spectra reveal the modifications in the absorption band of nanoparticles related to their self assembly mediated by anesthetic molecules and depending on the progress in time of the aggregation process. TEM images show the features of the self assemblies formed by the association of gold nanoparticles in presence of anesthetics, and reveal marked differences in the behavior of the AuNPs against the three anesthetics. The main effect of various anesthetics can be described in terms of electrostatic forces between the negatively charged metal nanoparticles and anesthetic molecules, existing in their cationic form at the working pH. Then, the anesthetics functionalized nanoparticles trigger specific interactions to form different self assemblies through a selective combination of hydrophobic and hydrogen bonding interactions between the coated nanoparticles and anesthetics molecular species. PMID- 23447942 TI - Rational shape-controlled synthesis of rhombic copper-based mesostructures. AB - Solution synthesis of optoelectronic components has the advantages of processability, bandgap tuning, and large-scale manufacturing potential. The synthesis of monodispersed rhombs in solution, however, has rarely been reported, even though rhombs are promising for realizing unique optical functions in integrated optoelectronics. We present in this article our success in developing a facile chemical method that used two polyols to generate nearly monodispersed metal-organic rhombic platelets. The success lies on the careful selection of precursors of proper oxidation states and the optimization of both the thermodynamic and the kinetic conditions for synthesis. Cuprous acetate, which acted as a heterogeneous nucleation agent, was dispersed in ethylene glycol, which acted as a stabilizer, a ligand, and a monomer for the formation of polymeric glycolates. By adjusting the volume ratio of polyethylene glycol (PEG) to ethylene glycol and the polymer size of PEG, rhombic platelets of 200-580 nm in side length and 170-240 nm in thickness were synthesized with aid of suitable structure-directing and dispersing agents. Energy-dispersive X-ray spectroscopy and FT-IR analyses revealed that the rhombic platelets were mainly composed of copper glycolate polymer chains. Knowledge obtained from this study can be expected to be applied to and to shed light on broad research topics concerning novel metal-organic nanostructure syntheses. PMID- 23447943 TI - Chlorine effect on the formation of carbon nanofibers. AB - Platelet graphite nanofibers (GNFs) and turbostratic carbon nanofibers (CNFs) are synthesized by the thermal evaporation and decomposition of a polymer-based mixture at 700 degrees C using Ni as a catalyst. The mixture consists of poly(ethylene glycol) (PEG), serving as the carbon source, and hydrochloric acid solution (HCl(aq)), serving as the promoter/additive for the growth of CNFs. High purity zigzag-shaped platelet GNFs form with 10 wt% HCl(aq) as an additive in the PEG. The diameters of the platelet GNFs are in the range of 40-60 nm, with lengths of a few micrometers. High-resolution transmission electron microscopy images indicate a high degree of graphitization and well ordered graphene layers along the fiber axis. In contrast, high-purity turbostratic CNFs form with 20 wt% HCl(aq) in the PEG. The diameter and length of the turbostratic CNFs are 20-40 nm and a few micrometers, respectively. The participation of HCl in the thermal process leads to the formation of Ni-Cl compounds. The amount of chlorine affects the shape of the Ni catalyst, which determines the type of CNF formed. PMID- 23447944 TI - Preparation of cross-linked bimodal mesoporous SBA-15 with numerous pore openings. AB - Using poly (ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer (P123) as template and tetraethyl orthosilicate as silica source, well ordered cross-linked bimodal mesoporous SBA-15 was easily prepared via an one-pot synthetic strategy, where a pre-self-assembly of P123 with TEOS in strong acidic media was introduced followed by pH-adjusting. The pH-adjusting can effectively change the copolymer micelle size, which directly lead to the formation of the bimodal mesoporous structure at pH range of 6-7.5, with most typical value at pH = 7.5. Meanwhile, these bimodal mesopores are interconnected, which generates a 3D intra-particle porosity with many pore-openings on the surfaces of particles. After modified with tetraethylenepentamine, the as-synthesized bimodal mesoporous SBA-15 exhibited the CO2 adsorption capacities much higher than as-synthesized conventional SBA-15. These bimodal mesoporous SBA-15 materials have great potential application in CO2 capture. PMID- 23447945 TI - A single-source route for the synthesis of metal oxide nanoparticles using vegetable oil solvents. AB - We report a general method for the synthesis of metal oxide colloidal nanocrystals in sunflower oil using single-source precursors. In this research, iron oxide nanocrystals have been synthesized and characterized though this method can be extended to the synthesis of other common metal oxides such as ZnO and also to other types of vegetable oils as solvents. Using this method, nanoparticles with average diameters of 7 nm and 3 nm were obtained respectively for iron oxide and zinc oxide. The magnetic iron oxide phase was identified using powder XRD, surface enhanced Raman spectroscopy and magnetic measurements as maghemite as the main component. The magnetic measurements demonstrate the superparamagnetic behavior of the iron oxide nanoparticles. This synthetic approach is an interesting way to synthesize metal oxide nanocrystals in eco friendly solvents of natural origin. PMID- 23447946 TI - Quantitative analysis of nanometer anatase-rutile mixtures via experimentation and theoretical calculation. AB - In this paper, we developed a method based on X-ray diffractometry for determining the weight ratio of nanometer anatase to rutile or their relative amounts in TiO2 polymorphs, and corresponding formulas for such determination were put forward. The very key constant K in these formulas has been specially evaluated by experimentalizing nanometer polymorphs of titanium dioxide. Furthermore, a theoretical value of K was obtained through detailed theoretical calculation based on X-ray powder diffraction theory. The K value concluded from experimentation coincides well with that yielded from theoretical calculation, thus the validity and reliability of the experimental K value has been further confirmed. This coincidence may also suggest the applicability of X-ray powder diffraction theory to nanometer crystals. With this method, the relative amounts of nanometer anatase and rutile in their mixtures or the weight ratio of nanometer anatase to rutile in any a mixture can be easily determined only upon a XRD test. PMID- 23447947 TI - Mechanical and thermal properties of silane grafted organomodified montmorillonite reinforced silicone rubber nanocomposites. AB - The present work deals with the preparation and characterization of silane grafted MMT (S-MMT), organomodified MMT (O-MMT) and silane grafted organomodified montmorillonite (OS-MMT) reinforced silicone rubber (SR) nanocomposites. XRD of SR filled with O-MMT (1-8 wt%), OS-MMT (1-8 wt%) and S-MMT (1-5 wt%) suggested the formation exfoliated morphology, which has also been supported by the corresponding TEM images of 3 wt% filled SR nanocomposites. TGA and DSC studies of SR/OS-MMT (3 wt%) nanocomposites have shown that the thermal stability, glass transition temperature and crystallization temperature are maximum improved with respect to neat SR by 50, 14 and 10 degrees C respectively. This is attributed to the synergistic effect of organo-modification followed by amino silane grafting of MMT on thermal properties of SR. The tensile strength of SR/S-MMT (5 wt%), SR/O-MMT (3 wt%) and SR/OS-MMT (3 wt%) relatively improved by 134, 312, and 259% respectively suggesting that the synergistic effect of OS-MMT is not effective in reinforcing the mechanical properties of SR. In all probability, the curing of SR through hydrosilylation is inhibited by the lone pair on nitrogen in NH2 group of OS-MMT. PMID- 23447948 TI - Effective electron mass in quantum wires of III-V, ternary and quaternary materials. AB - In this paper, an attempt is made to study the effective electron mass (EEM) in Quantum wires (QWs) of III-V, ternary and quaternary materials on the basis of three and two band models of Kane within the framework of k x p formalism. It has been found, taking QWs of InAs, InSb, GaAs, Hg(1-x)Cd(x)Te and In(1-x)Ga(x)As(1 y)P(t) that the 1D EEM increases with electron concentration per unit length and decreases with increasing film thickness respectively. For ternary and quaternary materials the EEM increases with increase in alloy composition. Under certain special conditions all the results for all the 1-D materials get simplified into the well known parabolic energy bands and thus confirming the compatibility test. The results of this paper find two applications in the fields of nanoscience and technology. PMID- 23447949 TI - Significant enhancement of formic acid oxidation using rhodium nanostructures. AB - The electrocatalytic activity of as-synthesized shape selective Rh nanostructures has been demonstrated using cyclic voltammetry, revealing unique shape-dependant performance towards HCOOH oxidation. Interestingly, the enhancement factor (R) for different shapes of Rh with respect to that of commercial Rh towards formic acid oxidation ranges up to 20,000% for cubes as compared to 17,500% for pyramids and 11,000% for hexagons respectively. Mechanistic pathway for comparatively better sensitivity of cubes as compared to other shapes has been correlated with the results of X-ray diffraction. PMID- 23447950 TI - Sol-gel SiO2 film contained Au/SiO2/quantum dot core/shell/shell nanostructures with plasmonic enhanced photoluminescence. AB - A sol-gel method has been developed to fabricate functional silica film with Au/SiO2/quantum dot (QD) core/shell/shell nanostructures which exhibited plasmonic enhanced photoluminescence (PL). Au nanoparticles (NPs) were homogeneously coated with a SiO2 shell by an optimal Stober synthesis. Hydrophobic CdSe/ZnS QDs was transferred into water phase via a ligand exchange by a thin functional SiO2 layer consisted of partially hydrolyzed 3 aminopropyltrimethoxysilane (APS) sol. The Au/SiO2/QD core/shell/shell nanostructure was created by assembling the functional SiO2-coated QDs to the SiO2-coated Au NPs while QDs transferred into water phase. Those partially hydrolyzed APS molecules play an important role for the connection between the QDs and SiO2-coated Au NPs. The Au/SiO2/QD core/shell/shell nanostructures were embedded in functional sol-gel SiO2 films fabricated via spinning and dipping coating, in which the film revealed strong surface plasmon scattering and enhanced PL. Because of the dual functionality, the film is utilizable for various applications including biological and medical sensors, optical devices, and solar cells. This technique can serve as a general route for encapsulating a variety of nanomaterials in sol-gel films. PMID- 23447951 TI - Preparation of manganese doped cadmium sulfide nanoparticles in zincblende phase and their magnetic properties. AB - In this study, the random dope of Mn into CdS nanoparticles in zincblende phase has been carried out under the mild reaction condition. The resulting nanoparticles were characterized by energy dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), X-ray diffractometer (XRD), UV-Vis spectrometer, PL spectrometer, and SQUID. EDX showed that the compositions of Mn doped CdS nanoparticles were readily controlled. TEM showed the particle sizes were not significantly affected by the compositions, retaining to be ca. 3 nm with a narrow size distribution. UV-Vis and PL spectra of the resulting nanoparticles showed the intra-Mn level may be affected by the quantum size effect. SQUID measurement showed that the resulting nanoparticles showed diamagnetism, paramagnetism and superparamagnetism dependent on Mn content. PMID- 23447952 TI - Comparative in vitro cytotoxicity study on uncoated magnetic nanoparticles: effects on cell viability, cell morphology, and cellular uptake. AB - Magnetic iron oxide nanoparticles (MIONPs) must be biocompatible, and a thorough knowledge on their potential cytotoxicity is crucial for their biomedical applications. However, the detailed study about the effects of iron oxide nanoparticles on cell viability, cell morphology, and cellular uptake of different mammalian cells is still insufficient. In this paper, comparative cytotoxicity study of uncoated magnetite nanoparticles at different concentrations was performed on human cervical cancer cell line (HeLa) and immortalized normal human retinal pigment epithelial cell line (RPE). The size, structure, and magnetic behavior of the MIONPs were characterized using transmission electron microscopy (TEM), X-ray diffractometry (XRD), and vibrating sample magnetometry (VSM) respectively. After 24-hour incubation with the MIONPs, the cell viability was determined by live/dead assay, the cell morphology at high magnification was observed under scanning electron microscopy (SEM), and the cellular uptake of MIONPs was measured under TEM and verified by energy dispersive X-ray spectroscopy (EDX) analysis. Our results indicate that the uncoated MIONPs at a high concentration (0.40 mg/ml) were toxic to both HeLa and RPE cells. However, the cytotoxicity of uncoated MIONPs at low concentrations was cell-type specific, and RPE cells were more susceptible to these MIONPs than HeLa cells. The effects of the MIONPs on cell morphology and the nanoparticles uptake also showed different features between these two cell lines. Hence cell type should be taken into consideration in the in vitro cytotoxicity study of uncoated MIONPs. Additionally, it should be noticed that the cell morphological changes and the uptake of nanoparticles can take place even though no toxic effect of these MIONPs at low concentrations was reflected in the traditional cell viability assay. PMID- 23447953 TI - Application of OctaAmmonium-POSS functionalized single walled carbon nanotubes for thermal treatment of cancer. AB - INTRODUCTION: Single walled carbon nanotubes (SWCNTs) have distinctive physical and chemical properties. Additionally, innovative properties can be established to match the clinical need by attachment of functional groups to the SWCNT. In this experiment SWCNT was functionalized with OctaAmmonium-POSS. Evidence suggests that functionalization of SWCNT with OctaAmmonium-POSS would augment the dispersion of SWCNT. We further postulate that functionalization of SWCNT with OctaAmmonium-POSS would enhance the temperature increase of SWCNT upon exposure to NIR laser irradiation. METHODS: Functionalization of SWCNT was conferred by refluxing with acid and OctaAmmonium-POSS. Fourier Transform Infrared (FTIR) test UV-visible spectroscopy and morphology analysis using Transmission Electron Microscopy (TEM) confirmed successful functionalization of SWCNT. NIR irradiation of samples was conducted using an 808 nm laser at 1 watt. Temperature changes were documented using a thermal camera. A HT-29 colorectal cancer cell line was used as a model for photothermal ablation. Cell viability test was performed using trypan blue and fluorescence activated cell sorting (FACS) technique. Graph plotting and statistical analysis was conducted using Graph Pad Prism. RESULTS: Following the functionalization process, TEM images showed a layer on the surface of the SWCNT. In the FTIR experiment, results illustrated the presence of the COOH group on the functionalized SWCNTs. Upon further functionalization of SWCNT with OctaAmmonium-POSS, various peaks determined the formation of amide bond between the POSS molecule and functionalized SWCNT. The UV-visible spectra also determine the successful functionalization of the SWCNT following its treatment with acid and OctaAmmonium-POSS. Upon exposure to NIR, OctaAmmonium-POSS-SWCNT was the only treatment group that illustrated significantly higher temperature increase than the other treatment groups. Additionally cell death of NIR irradiated OctaAmmonium-POSS-SWCNT was statistically significant compared to other treatment groups. CONCLUSION: OctaAmmonium-POSS was used to render SWCNT biocompatible and water dispersible. Observation from this study determines that functionalization with OctaAmmonium-POSS show greater temperature increase compared to pristine SWCNTs upon its exposure NIR. This significant temperature increase is due to increasing the solubility of SWCNT following its functionalization with OctaAmmonium-POSS. PMID- 23447954 TI - Facile preparation of calcium phosphate nanoparticles for siRNA delivery: effect of synthesis conditions on physicochemical and biological properties. AB - Over the past few years, efforts in developing efficient non-viral carriers for the intracellular delivery of siRNA have become increasingly intensive, due to the great potentials exhibited by siRNA-mediated gene silencing. Major challenges existing in the research field of non-viral siRNA delivery are to develop safe and cost effective delivery systems. Calcium phosphate (CaP) is known to be biocompatible and non-cytotoxic. Hence, it could be a promising candidate material for the fabrication of siRNA delivery systems. Here we report a facile method to prepare PEGylated CaP/siRNA nanoparticles (NPs) by taking advantage of electrostatic interactions between the anionic charges of siRNA and the cationic charges on the CaP crystal surface. Physicochemical characterization of the resulting NPs reveals that the NPs exhibit a particle size between 90-200 nm, depending on preparation conditions. Detailed investigations were carried out regarding the effect of preparation parameters (i.e., pH value of precursor buffer, phosphate salt, poly(ethylene glycol) molecular weight) on the physicochemical and biological properties. The results show that under optimized preparation conditions, significant gene silencing efficiency was achieved on cultured cells. PMID- 23447955 TI - Biological properties of carbon powders synthesized using chemical vapour deposition and detonation methods. AB - Carbon powders can be synthesized using variety of CVD and detonation methods. Several interesting properties of carbon powder particles make them a very attractive material examined in many laboratories all over the world. However there is a lack of information discussing investigation of carbon powders directed to its application in pharmaceutical-cosmetic industry and medicine. Earlier investigation results proved that diamond powders present properties fighting free radicals. Presented work discusses the influence of carbon powder particles manufactured using MW/RF PACVD, RF PACVD and detonation methods onto hydro-lipid skin coat. Before the biological examinations physicochemical properties of carbon powders were determined. Grain size, shape and chemical composition of carbon powders were determined using the scanning electron microscopy. Surface functional groups were characterized by IR Fourier-transform spectroscopy and X-ray photoelectron spectroscopy. Structure and phase composition were investigated by means of the Raman spectroscopy. Results of allergy tests performed on laboratory mice proved that carbon powder particles synthesized using different methods do not cause allergy. In the following stage, the group of 20 patients applied the formula including carbon powder on their face skin. The influence of carbon powder onto hydro-lipid skin coat was determined by measurement of such parameters as: pH reaction, skin temperature, lipid fotometry and level of hydration. Additionally, macro pictures of places where the cream had been applied were registered. As the result of the investigation it was found that powders synthesized using various methods present different physicochemical properties which may individually affect the face skin parameters. The noticeable improvement of hydro-lipid skin coat kilter was observed. PMID- 23447957 TI - Spin Hall and spin Nernst effects due to intrinsic spin-orbit coupling in monolayer and bilayer graphene. AB - We consider intrinsic contributions to the spin Hall and spin Nernst effects in monolayer and bilayer graphene. The spin Hall (Nernst) effect consists in the generation of transverse spin current by longitudinal electric field (temperature gradient). The relevant electronic spectrum for monolayer and bilayer graphene has been obtained from the corresponding effective Hamiltonians. Both spin Hall and spin Nernst conductivities have been determined within the linear response theory and Green function formalism. The influence of an external vertical voltage between the two atomic sheets in the case of a bilayer graphene is also analyzed and discussed. This voltage can generally lead to a phase transition between the topological insulator phase and conventional insulator. In the case of bilayer graphene, the main focuss is on an asymmetrical case, with different spin-orbit parameters in the two atomic sheets. Such a difference may be generated by different atomic planes adjacent to bilayer graphene on its both sides. PMID- 23447956 TI - Replicable and shape-controllable fabrication of electrospun fibrous scaffolds for tissue engineering. AB - Controlling the architecture of electrospun fibers is one of the key issues in tissue engineering. This report describes a rapid and reproducible patterning method for the fabrication of an electrospun fibrous scaffold. The electrospun fibers were deposited on a patterned electrode. The patterned scaffold was fabricated using a thin insulating film between layers of this electrode. For a tissue engineering application, poly(lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable material, was electrospun. Fibroblast cells were cultured on the fibrous PLGA scaffold and the viability, morphology, and distribution of the cells were studied. PMID- 23447958 TI - Production of Sn/SnO2/MWCNT composites by plasma oxidation after thermal evaporation from pure Sn targets onto buckypapers. AB - In this study, tin/tinoxide/multi oxide/multi walled carbon nano tube (Sn/SnO2/MWCNT) composites were produced by thermal evaporation and then subsequent plasma oxidation. Buckypapers having controlled porosity were prepared by vacuum filtration from functionalized MWCNTs. Pure metallic tin was thermally evaporated on the buckypapers in argon atmosphere with different thicknesses. It was determined that the evaporated pure tin nano crystals were mechanically penetrated into pores of buckypaper to form a nanocomposite. The tin/MWCNT composites were subjected to plasma oxidation process at oxygen/argon gas mixture. Three different plasma oxidation times (30, 45 and 60 minutes) were used to investigate oxidation and physical and microstructural properties. The effect of coating thickness and oxidation time was investigated to understand the effect of process parameters on the Sn and SnO2 phases after plasma oxidation. Quantitative phase analysis was performed in order to determine the relative phase amounts. The structural properties were studied by field-emission gun scanning electron microscopy (FEG-SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD). PMID- 23447959 TI - Synthesis and characterization of TiFe(0.7-x)Mn(0.3)V(x) (x = 0.05, and 0.1) and Ti(1-y)Ta(y)Fe(0.7)Mn(0.3) (y = 0.2, and 0.4) nanostructured metal hydrides for low temperature applications. AB - Metal hydrides (MH) are often preferred to absorb and desorb hydrogen at ambient temperature and pressure with a high volumetric density. These hydrogen storage alloys create promising prospects for hydrogen storage and can solve the energetic and environmental issues. In the present research work, the goal of our studies is to find the influence of partial substitution of small amounts of vanadium and tantalum on the hydrogenation properties of TiFe(0.7-x)Mn(0.3)V(x) (x = 0.05, and 0.1) and Ti(1-y)Ta(y)Fe(0.7)Mn(0.3) (y = 0.2, and 0.4) alloys, respectively. The nominal compositions of these materials are TiFe(0.6)Mn(0.3)V(0.05), TiFe(0.6)Mn(0.3)V(0.1), Ti(0.8)Ta(0.2)Fe(0.7)Mn(0.3), and Ti(0.6)Ta(0.4)Fe(0.7)Mn(0.3). All samples were synthesized by arc-melting high purity elements under argon atmosphere. The structural and microstructural properties of the samples were studied by using XRD and SEM, respectively, while the corresponding microchemistry was determined by obtaining EDS measurements at specific regions of the samples. Mapping was obtained in order to investigate atomic distribution in microstructure. Moreover, to ensure the associations between the properties and structure, all samples were examined by an optical microscope for accessional characterization. From all these microscopic examinations a variety of photomicrographs were taken with different magnifications. The hydrogenation properties were obtained by using a Magnetic Suspension Balance (Rubotherm). In this equipment, the hydrogen desorption and re absorption, can be investigated at constant hydrogen pressures in the range of 1 to 20 MPa (flow-through mode). At least 3.43 wt.% of absorbed hydrogen amount was measured while the effect of substitutions was investigated at the same temperature. PMID- 23447960 TI - Effect of reciprocating sliding speed on the tribological performance of nano SiC(p) reinforced Ni-metal matrix composites produced by electrocodeposition. AB - In the present work, Ni/SiC metal matrix composite (MMC) coatings were prepared from a modified Watt's type electrolyte containing nano-SiC particles by direct current (DC) plating method to increase wear resistance of the electro co deposited Ni. SiC nano particles with average particle size of 0, 1-1 microm were co-deposited with nickel matrix on the steel substrates. For this purpose, several studies were carried out to optimize deposition parameters for specific applications. The depositions were controlled to obtain the specific thickness (between 175-200 microm) and particle volume fraction in the matrix (between 0.03 and 0.10). The hardness of the resultant coatings was measured and found to be 280-571 HV depending on the particle concentration in the electrolyte and therefore, particle volume in the Ni matrix. The tribological tests were performed by a reciprocating ball-on disk apparatus sliding against M50 steel ball (O10 mm). All the friction and wear tests were performed under the unlubricated conditions at room temperature and in the ambient air (relative humidity 55-65%). The wear tests were carried out at different sliding velocities of 50 mm/s, 100 mm/s and 150 mm/s by using a constant dead load of 1.0 N. It was detected that increasing sliding speed resulted to increase wear rate but decreasing friction coefficient due to change in wear mechanism. Increasing sliding speed showed formation of tribo induced oxides up to 20 g/l SiC(p) in the electrolyte and wear mechanism was controlled by temperature induced fatigue wear. Further increase in the SiC(p) in the electrolyte caused an abrasive type of the wear. PMID- 23447961 TI - Carboxylate and amino group coated silver nanoparticles as joining materials for copper-to-copper silver joints. AB - Organic silver complexes are introduced where silver is linked either with a carboxyl group or with an amino group. Upon heating, nanoparticles are generated if the respective ligands are long enough to act as stabilizing agents in the nanoparticulate regime. With decomposition and volatilization of the organic material, the sintering of silver occurs. The thermal characteristics of the carboxylates silver-n-octanoate, silver-n-decanoate, and AgOOC(CH2OCH2)2CH2OCH3 are compared with silver-n-alkylamines (n = 8, 9, and 12), and their thermal behavior is discussed based on thermogravimetry (TG) measurements. The consecutive stages of a metallization process are addressed based on the properties of AgOOC(CH2OCH2)2CH2OCH3, and the usable effects of the individual phases of this metal organic compound are analyzed by cross-sectional scanning electron microscope (SEM) images of silver joints. Selection criteria are addressed based on the thermal behavior. A mechanism for the joining process is proposed, considering formation and sintering of the nanoparticles. It was found that the bulk material can be used for low-temperature joining processes. Strong adherence to copper as a basic material can be achieved. PMID- 23447962 TI - Wear resistance of TiAlSiN thin coatings. AB - In the last decades TiAIN coatings deposited by PVD techniques have been extensively investigated but, nowadays, their potential development for tribological applications is relatively low. However, new coatings are emerging based on them, trying to improve wear behavior. TiAlSiN thin coatings are now investigated, analyzing if Si introduction increases the wear resistance of PVD films. Attending to the application, several wear test configurations has been recently used by some researchers. In this work, TiAISiN thin coatings were produced by PVD Unbalanced Magnetron Sputtering technique and they were conveniently characterized using Scanning Electron Microscopy (SEM) provided with Energy Dispersive Spectroscopy (EDS), Atomic Force Microscopy (AFM), Electron Probe Micro-Analyzer (EPMA), Micro Hardness (MH) and Scratch Test Analysis. Properties as morphology, thickness, roughness, chemical composition and structure, hardness and film adhesion to the substrate were investigated. Concerning to wear characterization, two very different ways were chosen: micro abrasion with ball-on-flat configuration and industrial non-standardized tests based on samples inserted in a feed channel of a selected plastic injection mould working with 30% (wt.) glass fiber reinforced polypropylene. TiAISiN coatings with a small amount of about 5% (wt.) Si showed a similar wear behavior when compared with TiAIN reported performances, denoting that Si addition does not improve the wear performance of the TiAIN coatings in these wear test conditions. PMID- 23447963 TI - Dispersion and precipitation strengthened nanocrystalline and ultra fine grained copper. AB - Dispersion and precipitation strengthened copper alloys is a group of functional and structural materials used where combination of high electrical conductivity with high strength is required. A growing trend to use new copper-based functional materials is observed recently world-wide. Within this group of materials particular attention is drawn to those with ultra fine grain size of a copper matrix. This study was aimed to investigate mechanical properties, electrical conductivity and microstructure in Cu-yttria microcomposite produced by powder metallurgy methods and in CuCr0.6 alloy strips processed by continuous repetitive corrugation and straightening (CRCS). The changes of mechanical properties (HV, ultimate tensile strength, 0.2 yield strength) electrical conductivity as well as microstructure evolution versus true strain were investigated. The microstructure was investigated using optical and electron microscopy (HRTEM and SEM). Possibility of quenching elimination during processing has been also analysed. The Cu-yttria microcomposite produced by powder metallurgy methods and CRCS process of a CuCr0.6 alloys strips effectively reduced the grain size, demonstrating the powder metallurgy and CRCS as a promising new methods for producing nano and ultra fine grained copper matrix. PMID- 23447964 TI - Influence of the rest pulse duration in pulsed electrodeposition of Fe nanowires. AB - Highly uniform iron nanowires were synthesized in porous anodic alumina, through a pulsed electrodeposition method. The effect of the rest pulse duration in the deposition quality was systematically investigated, being the best duration found at 0.6 s with 91.9% of pores filled. A methodology of surface response design of experiment was conducted to find the optimum predicted value for the rest pulse duration, by controlling the following experimental parameters/variables: current density, electrolyte concentration and temperature. The influence of the rest pulse in the grain size of the iron nanowires was also studied trough X-ray diffraction patterns. A numerical simulation of the concentration evolution along a nanopore was performed, allowing to achieve a deeper understanding of the importance of the rest pulse in the NW electrodeposition. PMID- 23447965 TI - Porous ZnO thin films as anode electrodes for lithium ion batteries. AB - Zinc oxide (ZnO) nano structured thin films were prepared on Cr coated stainless substrates via a simple thermal chemical reactions vapor transport deposition method in air with a mixture of Zinc acetate anhydrate as reactants. The growth process was carried out at 200 degrees C, 300 degrees C and 400 degrees C in a stainless steel reactor with one side opened to the air. High purity oxygen gas was used as the carrier gas and kept at 1 L/min flow rate during the deposition process. There is no other metal catalyst and carrier gas in the process. The materials are characterized by means of X-ray diffraction (XRD), scanning electron microscopy (SEM). Their electrochemical properties as anodes of lithium ion batteries are examined by galvanostatic discharge-charge tests. The results show that porous ZnO nano structured thin films exhibit higher reversible capacities and better cyclabilities than those of commercial ZnO powders. When cycled at 0.958 mA (1 C = 1 hour charge + 1 hour discharge) for the films deposited at 200 degrees C, these nano structured pyramid-like structures deliver initial discharge and charge capacities of 954, in addition, good rate capabilities have also obtained after 20 cycles. It is believed that the porous sheet nano structure plays an important role in the electrochemical performance. PMID- 23447966 TI - Optical properties of WO3 thin films modeled by finite-difference time-domain and fabricated by glancing angle deposition. AB - Optical transmittance spectra between 1.55 eV (800 nm) and 3.10 eV (400 nm) of tungsten oxide (WO3) thin films nanostructured thanks to the Glancing Angle Deposition technique are investigated both experimentally and theoretically, as a function of geometrical parameters. A Finite-Difference Time-Domain code was used to numerically model the films structure and to calculate their optical properties. The corresponding optical index and porosity are considered. It is found that the optical index of columnar structures always follows Cauchy's law as a function of energy and is reduced as the incident angle increases (alpha = 0 to 80 degrees) from n633 = 2.2 to 1.98 for experimental data against 2.1 to 1.75 for those computed with the Finite-Difference Time-Domain code. For zigzag architectures, an increase of the zigzag number from 0.5 to 8, amplifies interference fringes and improves the measured refractive indices. It agrees with modeled optical characteristics since n633 increases from 2.18 to 2.30. PMID- 23447967 TI - Determination of connectivity in porous materials. AB - A method of practical use was set up to determine the connectivity in a porous material, modelling the physical system as a lattice, whose coordination number is assumed to be an index of connectivity itself. This task was approached through the theory of percolation and input data were provided by two different experimental techniques, that is, adsorption/desorption of nitrogen and mercury porosimetry. The overall procedure is based on the calculation of probability f(P) of occupation of the porous channels and of probability F(P) of percolation. In the framework of the above--mentioned lattice model, the average coordination number Z is calculated through the best fitting of a universal curve to the values found for F(P) and f(P), adopting as fitting parameter the ratio L between the characteristic linear dimension of the whole lattice and the characteristic linear dimension of each of its cells. The procedure described was implemented through a numerical code and applied to three commercial alumina. A simple empirical relationship was found between Z and the percolation threshold, showing an excellent coefficient of statistical correlation. The three products proved different in connectivity, allowing subtle distinctions from each other, despite their hysteresis cycles in the adsorption/desorption process appeared quite similar from a qualitative standpoint. PMID- 23447968 TI - Functionalization of silicon crystal surface by energetic cluster ion bombardment. AB - We report the creation of a functional nanostructure on a Si crystal surface by 200 keV C60(++) cluster ion bombardment (CIB). We found that the modified layer produced by CIB includes two sublayers with different nanostructures. The top 24 nm-thick sublayer is an agglomeration of 5-nm-sized amorphous Si nanodots (a-Si NDs). The deeper 10-nm-thick sublayer is a transient layer of disordered Si as an interface between the a-Si top sublayer and the bulk Si(100). The top a-Si sublayer and the nc-Si transient layer are formed by the local heating effect and shock wave effect, respectively, induced by the cluster ion impacts. The photoluminescence (PL) spectra of the CIB-modified Si samples revealed an emission line centered at a photon energy of 1.92 eV. The absorption spectra of the modified samples exhibit enhanced light absorption at this photon energy. The parameters of the PL line require ascribing the emission origin to the quantum confinement-induced optical transitions in the a-Si nanodots. The core-shell structure of a-Si NDs is confirmed by detection of an additional PL line centered at 2.5 eV. Analysis of the Rutherford backscattering (RBS) and the PL spectra implies the existence of -Si--O- bonds in the nanodot outer shells, which are responsible for the additional PL line. The obtained results demonstrate the valuable potential of CIB for the controllable fabrication of Si surface nanostructures, which is attractive for optoelectronics and nanoelectronics. The obtained results elucidate the evolution of structure modification occurring in silicon due to the injection of energetic C60 cluster ions with an energy of hundreds of keV. PMID- 23447969 TI - Nickel metal with various morphologies: synthesis and performances for catalytic carbon dioxide reforming with methane. AB - In this research, nickel metal of three different morphologies including nanostar, icosahedra, and microsphere structures were synthesized. It was found nanostar nickel revealed the Ni(111) crystallographic plane with particle size in the range of 150-200 nm and BET surface area of 13 m2/g. The icosahedra nickel also showed the Ni(111) crystallographic plane with larger particle size (300-400 nm) and BET surface area of 20 m2/g, whereas microsphere nickel exhibited the relatively large cluster size (approximately 3 microm) and BET surface area (114 m2/g) as a result of an aggregation of Ni(101) nanoplates. The obtained nickel catalysts were tested for the activity in carbon dioxide reforming with methane. Based on the similar specific surface area of catalysts, nanostar nickel showed the highest carbon dioxide and methane conversions due to its crystallographic structure. At 700 degrees C, nanostar nickel catalyst exhibited the highest carbon dioxide and methane conversions of 17.6 and 10.5 times higher than those of microsphere nickel catalyst, respectively. PMID- 23447970 TI - Continuous and nanostructured TiO2 films grown by dc sputtering magnetron. AB - The growth of Anatase nanostructured films using dc reactive magnetron sputtering and post-annealing treatment is reported. TiO2 has been deposited on Porous Anodic Alumina Films used as templates which were previously grown in phosphoric acid solution and etched to modify their pore diameters. This synthesis via results in the formation of vertically aligned and spatially ordered TiO2 nanostructures replicating the underlying template. Previously, the growth optimization of TiO2 thin films deposited by dc magnetron sputtering on flat silicon substrates was done. The crystalline structure and Ti in-depth concentration profile were determined by grazing incidence X-ray diffraction and Rutherford backscattering spectrometry, respectively. The surface morphology of the samples was explored by mean of a Field Emission Gun scanning electron microscope. Optical properties of the nanostructured samples were studied by using the reflectance spectra received in the UV-visible range. In these spectra different band gap values and complex light absorption features were observed. PMID- 23447971 TI - Irreversible magnetic properties of nanocarbon. AB - Magnetization M(T, B) of powder and glassy samples containing carbon nanoparticles, not intentionally doped and doped with Ag, Au and Co, is investigated at temperatures T between - 3-300 K in magnetic fields B up to 5T. According to atomic force microscopy data, a system of carbon particles has a broad size distribution, given by the average and the maximum radii of -60 nm and - 110 nm, respectively. In low fields of B << B(K), where B(K) - 1T is the mean anisotropy field, M(T) exhibits large irreversibility or deviation of zero-field cooled and field-cooled magnetizations, which is suppressed completely at B > B(K). The dependence of M(B) saturates above B - 2T at T - 150-300 K and contains a large paramagnetic-like response below - 50-150 K. Hysteresis is observed already at 300 K and is characterized by a power-law temperature decay of the coercive field, B(c)(T). This is described by the exponent n approximately 0.8 and by the low-temperature values of B(c) (0) increasing from -36-53 mT in the undoped sample and those doped with Ag and Au, up to 80 mT in the Co-doped material, yielding the blocking temperatures T(b) approximately 400-580 K. Analysis of the experimental magnetization data above suggests distribution of the magnetization close to the surface of the particles, yielding a thickness of the near-surface layer, h, filled with localized magnetic moments, micro1 - microB, to be close to the average distance, a, between the moments, h approximately a - 1 nm. This is consistent with the origin of magnetism in nanocarbon being presumably due to intrinsic near-surface defects. PMID- 23447972 TI - Development of nanocomposite membranes with photocatalytic surfaces. AB - In 2030, 47% of the world population will be living in areas of high water stress (UN World Water Development Report 3, 2009). The global water shortage results in an emerging need for novel, more efficient and cost saving water purification methods. Membrane technology with its very low use of chemical substances and secure retention of contaminants represents a promising water cleaning method. The approach presented focuses on the application of nanocoating procedures to membrane processes which aims at reducing the fouling potential of membranes and destroying water contaminants. Photocatalytic titanium dioxide nanoparticles are applied. Novel suitable microsieves including a homogeneous pore size distribution and high robustness were developed from metallic material. An appropriate multilayer coating system was developed and applied on a new nanocomposite filter resulting in high photocatalytic activities with maximum photon efficiencies of 0.0733. The coating layer do not have a negative influence on the permeate flux. The effectiveness of the nanocomposite filter was proven in a 12 days biofouling experiment with activated sludge suspensions. PMID- 23447973 TI - The effect of oxidants on the formation of multi-walled carbon nanotube buckypaper. AB - In the present study, we report the systematic investigation of the effect of chemical oxidation on the structure of multi-walled carbon nanotubes (MWCNTs) and multi-walled carbon nanotubes buckypaper. The chemical oxidation of multi-walled carbon nanotubes was performed via using three types of chemical solutions: nitric acid, sulfuric acid/nitric acid (3/1) and ammonium hydroxide/hydrogen peroxide (1/1). The surfaces of the multi-walled carbon nanotubes were modified by forming Carboxyl and other functional groups. Flexible multi-walled carbon nanotubes buckypapers were then produced by vacuum filtration techniques from functionalized multi-walled carbon nanotubes. The characteristic properties of multi-walled carbon nanotubes specimens were investigated via Raman, and Fourier Transform Infrared Spectroscopies. The thermal properties and morphology of multi walled carbon nanotubes were also studied byThermogravimetric Analysis and Field Emission Scanning Electron Microscopy techniques. PMID- 23447974 TI - Synthesis of ZnO, SnO2 nanoparticles and preparation of ZnO-SnO2 nanocomposites. AB - This article reports the preparation of ZnO-SnO2 nanocomposites from ZnO and SnO2 nanoparticles produced by homogenous precipitation route. Zinc acetate dihydrate (Zn(CH3COO)2 x 2H2O) and tin(II) chloride dehydrates (SnCl2. 2H2O) have been used as precursors. Distilled water was used as a solvent, monoethanolamine (MEA) is used as sol stabilizer. Precursors individually dissolved and stirred at 60 degrees C for 1 h. Certain amount of MEA were added to solution and stirred for 2 h. Then solution was cooled to room temperature and gets precipitated. The collected nanosized precipitates were mixed together and deposited on glass substrates by drain coating and post-heated at different temperatures. X-ray diffractometer was used to determine preferred crystal orientation and particle size of the thin films. Morphologies of nanopowders were examined by scanning electron microscope (SEM). PMID- 23447975 TI - Annealing effects on electrical properties of pure and tin-doped indium oxide thin films. AB - The annealing effects on the properties of ITO and pure In2O3 thin films have been investigated. The thin films were deposited with various O2 flow ratios to total gas flow by pulsed dc magnetron sputtering. The post-deposition annealing of the thin films was carried out for 30 minutes at various temperatures ranging up to 500 degrees C in air. It was found through the comparison of the carrier density of ITO and In2O3 thin films that the carrier electrons of the ITO thin films came from both of the dopant Sn and oxygen vacancies under the annealing less than 400 degrees C. Therefore, the ITO thin films deposited with lower O2 flow ratio exhibited higher carrier density due to many oxygen vacancies; in consequence, they exhibited lower resistivity at the annealing up to 400 degrees C. On the other hand, the carrier density of ITO thin films was almost identical regardless of O2 flow ratio when they were annealed at 500 degrees C. This fact indicates that most carrier electrons of the ITO thin films were brought by the dopant Sn at the annealing temperature of 500 degrees C. However, the ITO thin films deposited with lower O2 flow ratio exhibited higher Hall mobility; as a result, they showed lower resistivity at the annealing of 500 degrees C. Atomic force microscope, X-ray diffraction and X-ray reflectivity measurements revealed that the ITO thin films deposited with lowe O2 flow ratio exhibited dense structure even after they were annealed at 500 degrees C. Hence, the carrier electrons of the dense ITO thin films deposited with low O2 flow ratio can conduct better, as a result, the ITO thin films exhibited high Hall mobility and low resistivity. PMID- 23447976 TI - Mechanical and tribological characterization of TiB2 thin films. AB - Titanium Diboride (TiB2) presents high mechanical and physical properties. Some wear studies were also carried out in order to evaluate its tribological properties. One of the most popular wear tests for thin films is the ball cratering configuration. This work was focused on the study of the tribological properties of TiB2 thin films using micro-abrasion tests and following the BS EN 1071-6: 2007 standard. Due to high hardness usually patented by these films, diamond was selected as abrasive on micro-abrasion tests. Micro-abrasion wear tests were performed under five different durations, using the same normal load, speed rotation and ball. Films were deposited by unbalanced magnetron sputtering Physical Vapour Deposition (PVD) technique using TiB2 targets. TiB2 films were characterized using different methods as Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS), Atomic Force Microscopy (AFM), X-ray Diffraction (XRD), Electron Probe Micro-Analyser (EPMA), Ultra Micro Hardness and Scratch-test Analysis, allowing to confirm that TiB2 presents adequate mechanical and physical properties. Ratio between hardness (coating and abrasive particles), wear resistance and wear coefficient were studied, showing that TiB2 films shows excellent properties for tribological applications. PMID- 23447977 TI - Stages of xylene transforming during carbon particle synthesis. AB - Xylene is one of the materials that could be used for synthesis of different carbon nanoparticles including perfect carbon spheres with diameters of 1 to 8 microm and ellipsoids. Its changes in the course of the pyrolytic process in a hermetically sealed stainless steal container have been examined by stopping the process at different stage of temperature treatment from 100 degrees C to 600 degrees C. The prepared material is in a liquid phase up to 400 degrees C and its relative weight and optical transmittance changes have been measured. The origins of these changes are traced to solid micro and nanoparticles and their morphology, which was studied by Scanning (SEM) and Transmission Electron Microscopy (TEM), X-ray diffraction (XRD), Electron Probe X-ray Micro Analysis and Energy Dispersive X-ray Spectrometry (EDS), and Fourier Transform Infrared Spectroscopy (FTIR). PMID- 23447978 TI - Experimental investigation on thermo-magnetic convection inside cavities. AB - This paper presents experimental results on thermo-magnetic convection inside cavities. We examine the flow induced by convective currents inside a cavity with aspect ratio near the unity and the heat transfer rates measurements inside a thin cavity with aspect ratio equal to twelve. The convective unstable currents are formed when a magnetic suspension is subjected to a temperature gradient combined with a gradient of an externally imposed magnetic field. Under these conditions, stratifications in the suspension density and susceptibility are both important effects to the convective motion. We show a comparison between flow patterns of magnetic and gravitational convections. The impact of the presence of a magnetic field on the amount of heat extracted from the system when magnetic and gravitational effects are combined inside the test cell is evaluated. The convection state is largely affected by new instability modes produced by stratification in susceptibility. The experiments reveal that magnetic field enhances the instability in the convective flow leading to a more effective mixing and consequently to a more statistically homogenous temperature distribution inside the test cell. The experimental results allow the validation of the scaling law proposed in a previous theoretical work that has predicted that the Nusselt number scales with the magnetic Rayleigh number to the power of 1/3, in the limit in which magnetic force balances viscous force in the convective flow. PMID- 23447979 TI - The effects of substrates on the geometry and optical properties of aluminum nitride nanowires. AB - Based on a Chemical Vapor Deposition (CVD) process, an alumina tube electric furnace was assembled to synthesize different one dimensional aluminum nitride (AIN) nanostructures via aluminum powder and nitrogen gas flow. The products obtained where nanowires, nanorods, a unique chain-linked nanocage structure made from an entanglement of AIN nanowires and an interesting micro-sized spherical architecture. The different growth parameters dictated to the system result the product variety, making structure tuning possible. The incorporation of different substrates (silicon and alumina) not only leads to the formation of different shaped structures, but also results different optical emissions ranging from 450 nm (blue) to 650 nm (red), indicating the high potential of AIN nanostructures in LED fabrication. Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Selective Area Electron Diffraction (SAED), X-ray Diffraction (XRD), Photoluminescence (PL) and Energy Dispersive X-ray (EDX) analysis results are discussed and a Vapor-Liquid-Solid (VLS)/Vapor-Solid (VS) based growth mechanism is proposed for the mentioned structures. PMID- 23447980 TI - Effect of thermal annealing in vacuum and in air on nanograin sizes in hard and superhard coatings Zr-Ti-Si-N. AB - Zr-Ti-Si-N coating had high thermal stability of phase composition and remained structure state under thermal annealing temperatures reached 1180 degrees C in vacuum and 830 degrees C in air. Effect of isochronous annealing on phase composition, structure, and stress state of Zr-Ti-Si-N-ion-plasma deposited coatings (nanocomposite coatings) was reported. Below 1000 degrees C annealing temperature in vacuum, changing of phase composition is determined by appearing of siliconitride crystallites (beta-Si3N4) with hexagonal crystalline lattice and by formation of ZrO2 oxide crystallites. Formation of the latter did not result in decay of solid solution (Zr, Ti)N but increased in it a specific content of Ti component. Vacuum annealing increased sizes of solid solution nanocrystallites from (12 to 15) in as-deposited coatings to 25 nm after annealing temperature reached 1180 degrees C. One could also find macro- and microrelaxations, which were accompanied by formation of deformation defects, which values reached 15.5 vol.%. Under 530 degrees C annealing in vacuum or in air, nanocomposite coating hardness increased. When Ti and Si concentration increased and three phases nc ZrN, (Zr, Ti)N-nc, and alpha-Si3N4 were formed, average hardness increased to 40.8 +/- 4 GPa. Annealing to 500 degrees C increased hardness and demonstrated lower spread in values H = 48 +/- 6 GPa and E = (456 +/- 78) GPa. Zr-Ti-Si-N coatings has high wear resistance and low friction coefficient in comparison at a temperature of 500 degrees C possess with coatings TiN, Ti-Si-N. PMID- 23447981 TI - New one-pot approach towards gold nanorods and nanowires: a parametric study of gold halide/lithium tert-butoxide systems. AB - Various gold nanomaterials are successful obtained using a mild and simple chemical approach, involving the use of gold halide and lithium tert-butoxide in organic solvents. It was found that the presence of bromide ions in a polar solvent is required to produce faceted gold nanoparticles such as nanorods/nanowires. The parametric study of the system AuBr3 in presence of lithium tert-butoxide in THF points out that the ratio [gold salt]/[alkoxide] has a strong influence on the formation of nanorods/nanowires. Moreover, the effect of additives such as AuCI, Aul and LiBr was also explored. Finally, nanoparticles morphology and formation are discussed in regard to the composition of reaction media. PMID- 23447982 TI - Bench scale production of pure nanocrystalline molybdenum nitride through solid gas phase reduction. AB - Solid-Gas phase reduction is an attractive method to produce high surface area, mesoporous powders, as well as pure product. Disadvantage of this method is low amount of product. Increasing the amount of precursor in quartz reactor causes the accumulation of reaction products and results in hydrothermal sintering. Therefore, the diameter of reactor was increased, and it allowed to increase the precursor and also to prevent the hydrothermal sintering. The products were investigated by XRD, BET, SEM and TEM. The surface area of mesoporous powder, from 7 g loaded precursor, was 112 m2/g and crystallite size was about 10 nm. Increasing the precursor up to 30 g, under controlled program, resulted in lower surface area, but still above 105 m2/g. The pore volume was 72.36 cm3/g, quite suitable for catalytic applications. PMID- 23447983 TI - Study of the properties of ZnO:Zn thin films obtained from ZnO/Zn/ZnO structure deposited by DC sputtering. AB - A method to manage the resistivity of n-type ZnO films is presented. It involves the controlled diffusion of Zn at low temperature in N2 atmosphere into the ZnO/Zn/ZnO structure. The structures were made by DC sputtering technique. The diffusion periods were varied from 5 to 30 min. This process allow us to obtain ZnO films with excess of Zn (ZnO:Zn). The electrical characterization showed that the resistivity of the films can be varied from 0.01 to 100 omega-cm, the electron concentration from 10(19) to 10(17) cm(-3) and the carrier mobility from 10 to 40 cm2N-s. The films are nanocrystalline with preferred (002) orientation and crystal size that varies from 13 to 20 nm depending on the diffusion period. The films have a band gap of 3.18 eV and 70% of transmittance in the visible region, these properties were obtained from the transmittance measurements of low resistivity films. Films have good structural, optical and electrical properties, and could be used in the manufacture of light emitting diodes. PMID- 23447984 TI - Zinc oxide based nanocomposite thin film electrodes and the effect of D.C. plasma oxidation power on discharge capacity for lithium ion batteries. AB - Zinc oxide based thin films have been grown on glass and stainless steel substrates in two steps; thermal evaporation from high purity metallic zinc and D.C. plasma oxidation. X-ray diffraction has shown that the films were polycrystalline nature and small predominant orientation at some specific planes. Analysis showed that plasma oxidation starts from the thermally evaporated leaf like surfaces and produces a core-shell structure of ZnO on the metallic Zn. Increasing plasma oxidation power causes increased amount of ZnO volume and resistivity. Coin-type (CR2016) test cells were assembled in an argon-filled glove box and cyclically tested. The electrochemical performance of the films has been studied by cyclic voltammetry. The dependence of converted Li-ions on voltage profile of the films has been determined. It was found that the Zn/ZnO films exhibited highest the number of converted Li-ions at 175 W plasma oxidation conditions. Discharge capacity measurements revealed the double phase structures of Zn/ZnO exhibited significantly high reversible capacities. The high capacity and low capacity fade values were attributed to the high electrical conductivity and buffering ability of metallic Zn in the anodes. PMID- 23447985 TI - Nano crystalline TiO2 thin films as negative electrodes for lithium ion batteries. AB - In this study, rutile (tetragonal, P42/mnm), anatase (tetragonal, I41/amd) polymorphs of titanium dioxide films were synthesized successfully magnetron sputtering of titanium films on stainless steel substrates followed by in situ direct current plasma oxidation. The as-prepared titanium dioxide thin films were oxidized at 75 W, 100 W and 125 W plasma powers in order to optimize the system with best electrochemical performance. The mean grain sizes of the deposited films were found to be in the range of 14.2-12.9 nm as revealed by the scanning electron microscopy and X-ray diffractometer studies. The electrochemical studies were performed with pure metallic lithium foil cathode with the best performing nano structured titanium dioxide as anode. The specific capacity of the nanocrystalline titanium dioxide films oxidized at 125 W direct current was 207 mA h g(-1) even after 20 cycles in the 0.02-2 V region, indicating excellent cycling stability and reversibility. PMID- 23447986 TI - Polymer encapsulated inorganic black pigment nanoparticles and their electrophoretic characteristics. AB - Black inorganic pigment modified with poly(styrene-co-acrylonitrile) was fabricated via dispersion polymerization, and then the synthesized hybrid nanoparticles were examined by SEM to confirm their morphology, while their density and size were studied using a gas pycnometer and electrophoretic light scattering apparatus, respectively. We also confirmed their chemical structure and coated state via FT-IR and TGA. Electrophoretic characteristics including the zeta potential were examined via an electrophoretic light scattering apparatus, while the movement of particles was directly observed by an optical microscopy under an electric field applied. The hybrid nanoparticles were confirmed to possess an electrophoretic property as a potential candidate for the microcapsule type electrophoretic display. PMID- 23447987 TI - Graphite nanoplatelets produced by oxidation and thermal exfoliation of graphite and electrical conductivities of their epoxy composites. AB - Graphite nanoplatelets were produced by sonication of thermally reduced graphite oxide produced from three precursor graphites. The thicknesses of the resulting graphite nanoplatlets were measured by X-ray diffraction and transmission electron microscopy. The type and size of the precursor graphite plays an important role in the final graphite nanoplatelet quality. The thinnest graphite nanoplatelets (average thickness of 4-7 nm) were obtained from Sri Lankan powdered graphite (average particle size of 0.1-0.2 mm). Thicker graphite nanoplatelets (average thickness of 30-60 nm), were obtained from a Canadian graphite (with an average flake size of 0.5-2 mm). Graphite nanoplatelets obtained by acid intercalation of Sri Lankan graphite were much thicker (an average thickness of 150 nm). Graphite nanoplatelet/epoxy composites containing 4 wt.% graphite nanoplatelets derived from Canadian or Sri Lankan natural graphite have electrical conductivities significantly above the percolation conductivity threshold. In contrast, corresponding composites, produced with (4 wt.%) commercial graphite nanoplatelets, either as-received or re-exfoliated, were electrically insulating. This behaviour is attributed to the highly wrinkled morphology, folded edges and abundant surface functional groups of the commercial graphite nanoplatelets. Thermal reduction of graphite oxide produced from natural flake graphite is therefore a promising route for producing graphite nanoplatelets fillers for electrically-conducting polymer composites. PMID- 23447988 TI - Surface plasmon excitations in cylindrical nanorods by electron-hole pair creation. AB - In this work we study the effect of the excitation of surface plasmons in a metallic cylindrical nanorod by a suddenly created electron-hole pair, using a classical model for the emerging electron and a quantum-mechanical model for the plasmon field in the cylinder. The electron and the hole interact independently with the plasmon field, generating electron density oscillations. Two different trajectories for the emerging electron (parallel to the axis and radial) are studied in an aluminum nanorod. The average number of excited plasmons indicates how important is the role of the hole in the excitation process. We found that the results can be very different according to the trajectory of the emerging electron. We also found that the distinction between intrinsic and extrinsic process is sometimes not applicable. PMID- 23447990 TI - Magnetic-induced migration in a sedimenting suspension of magnetic spherical particles. AB - We study the relative trajectories of two magnetic spheres interacting in a dilute suspension in the presence of particle inertia and Brownian motion effect. The particles settle relative to one another under the action of gravity and when in close contact they exert on each other a magnetic force and torque due to a permanent magnetization. The balance equations of forces and torques for the two particles are considered in the present formulation. The numerical simulations are based on direct computations of the hydrodynamic and the magnetic interactions among the rigid spheres in the regime of no-null Stokes number. The behavior of these suspensions is examined based on the relative trajectories calculated for several initial configurations. The calculations show that fluctuations in particle orientation produced by the continuous magnetic interactions and by the Brownian motion exerts a significant effect on the understanding of particle aggregation and particle migration in magnetic suspensions. PMID- 23447989 TI - Gamma-Fe2O3 nanopowders synthesized in microwave plasma and extraordinarily strong temperature influence on their Mossbauer spectra. AB - The article reports on two nanopowders synthesized in microwave plasma: the first sample was synthesized in a torch discharge at 1 bar and the second sample was synthesized in low-pressure plasma at 40 mbar. Morphology, composition and properties of the powders were studied by TEM, XRD, Raman and Mossbauer spectroscopies, and magnetic measurements. In the XRD patterns of the samples only gamma-Fe2O3 was identified (mean crystallite size d(XRD) was 24 nm for the first sample and 13 nm for the second sample). Based on the Mossbauer spectra measured at 5 K, the presence of other iron oxide phases was excluded in both samples. Unusually strong temperature dependence of the Lamb-Mossbauer factor was observed: I(SA)(5 K)/I(SA)(293 K) = 6 in the case of the first sample and I(SA)(5 K)/I(SA)(293 K) = 22 for the second sample (I(SA) denotes integral spectrum area). This effect is explained as the consequence of the reduced agglomeration of electrically charged nanoparticles in the plasma, i.e., particles can either move at 293 K (when they are free) or tilt (if they are a part of a chain). Superparamagnetic phase was not observed in the room-temperature Mossbauer spectra of both samples. PMID- 23447991 TI - Transport properties of alkali-doped multi walled carbon nanotubes. AB - In this work we propose a study on electrical properties of multiwalled carbon nanotubes (MWCNT) doped with the most commonly used alkali metals. We report resistivity measurements of MWCNT exposed to doping with Li, Na, K and Cs. Our results show that, increasing the alkali exposure, the resistance of the doped sample decreases denoting a progressive sample metallization. The changes in resistivity, contrary to that observed for single walled carbon nanotubes (SWCNT) in our previous work, are independent upon the alkali properties but appear related to alkali intercalation effects in the MWCNT random network. The doping effects have been also controlled by X-ray photo electron spectroscopy (XPS). The spectra confirm the absence of chemical bonds between carbon nanotubes and alkali, validating the hypothesis of intercalation of alkali in the interstitial channels between the tubes. Our results are also confirmed by comparison between SEM images of single walled and multiwalled carbon nanotubes. PMID- 23447992 TI - On the synthesis and physical properties of iron doped SnO2 nanoparticles. AB - The synthesis of iron doped tin oxide by pulsed laser pyrolysis is reported. The as obtained nanoparticles have a dominant SnO2 phase (as revealed by Wide Angle X ray Scattering), with particles of the order of 10 nm. The doping with iron or iron oxide triggers magnetic properties as confirmed by SQUID experiments. EDX measurements supported the presence of Fe while Wide Angle X-ray Scattering failed to sense any iron or iron-oxide phase. It is concluded that Fe is well dispersed within the tin-oxide nanoparticles. The coercitive field has a complex dependence on the Fe/Sn content suggesting that the magnetization is not controlled solely by the amount of Fe dispersed within the nanoparticles. PMID- 23447993 TI - Physicochemical and biological properties of hydrogel/gelatin/hydroxyapatite PAA/G/HAp/AgNPs composites modified with silver nanoparticles. AB - Composites comprising biodegradable polymer matrix, bioactive ceramic fillers and metallic nanoparticles can be applied in the substitution of bone tissue and many others medical and dental applications. Recently, fully resorbable composite materials applicable as bone substitutes are the subject of intensive studies in surgical reconstruction and bone tissue engineering. Biological composites, such as bone and teeth, contain hydroxyapatite (HAp), a mineral component with composition Ca10(PO4)6(OH)2. Silver nanoparticles or silver ions have long been known to have strong inhibitory and bactericidal effects as well as a broad spectrum of antimicrobial activities. In this study we applied natural origin hydroxyapatite obtained from pork bone sludge. As polymer matrix gelatin and poly(acrylic acid) were used. Composite materials were obtained with the use of microwave irradiation. The influence of metallic nanoparticles presence on the degradation process of composite materials was investigated by pH and conductivity analyses of water filtrates. In vitro tests in simulated body fluid (SBF) and artificial saliva confirmed that it is possible to produce hydroxyapatite/polymer composites doped with silver nanoparticles for medical applications. Tests proved that content of silver nanoparticles in composites had influence on degradation behaviour of HA/Polymer/AgNPs in artificial media such as simulated body fluid and saliva. PMID- 23447994 TI - Stabilization of ceramics particles with anionic polymeric dispersants. AB - The dispersion of colloidal ceramic particles in an aqueous media using a charged polymer has been investigated extensively. Most often, such a dispersion is obtained by an electrosteric mechanism. The stabilizing forces that result from electrical double layer repulsion and/or steric interaction must be sufficiently large in magnitude to provide an energy barrier against aggregation. Several factors, such as pH, temperature and ionic strength, nature, structure and molecular weight of the polyelectrolyte and its degree of dissociation can affect the respective contribution of electrostatic and steric interactions. In this study we applied silver nanoparticles prepared by reduction method with modifications. The hydroxyapatite was obtained from pork bone sludge. Polymer system contained poly(acrylic acid) and poly(ethylene glycol). The effects of dispersant structure on particle stabilization were investigated through properties of the suspensions. Viscosity and sedimentation height measurements indicated that addition of the dispersants improve particle stabilization. A dispersants were characterized using Scanning electron microscopy (SEM) with BSE detector (Back Scaterred Electrons), X-ray diffraction (XRD) and pH determination. PMID- 23447995 TI - Investigation of colloidal stability and insulation characteristics of magnetic oils. AB - Superparamagnetic iron-oxide (SPIO) particles were synthesized by the co precipitation method and the oleic acid-coated SPIO (OA-SPIO) was then obtained by a surface grafting procedure. A stock sample of magnetic oil (MO) with 1.6% particle volume fraction (VF) was obtained by dispersing the OA-SPIO in insulating naphthenic oil. The MO stock sample was diluted in the same naphthenic oil to yield MO with 0.1, 0.04, 0.02, and 0.01% VF. Moreover, the 0.04% VF MO sample was manipulated to yield MO samples with water content of 26, 37, and 63 mg L(-1). The spinel structure of OA-SPIO was assessed by XRD and the average diameter of 8.3 nm was provided by TEM analysis. The saturation magnetization at room temperature (RT) was 70 emu/g and no remanence or coercivity was observed. The average hydrodynamic diameter (D(H)) of the colloidal particles suspended within the 0.04% VF MO sample was 58 nm. After aging for 30 days at RT no change was observed for the lowest water content MO sample (26 mg L(-1)). However, D(H) equals to 270 nm was observed for the highest water content MO sample (63 mg L( 1)). The MO samples with 26 mg L(-1) water content were found stable under heating at 90 degrees C for all VF investigated. We found the insulation resistance dropping significantly as VF and temperature increases. The lowest value found was 11 GOhms for the 0.1% VF at 60 degrees C, which is an acceptable value for MO. PMID- 23447996 TI - Effect of core-shell structure and chitosan addition on catalytic activities of copper-containing silica-aluminosilicate composites in deNO(x) reaction by H2. AB - Mesoporous silica-aluminosilicate composites were used as supports for selective catalytic reduction of NO by H2 using copper catalyst. Effect of loading techniques and structures of the supports on the catalytic performance were investigated. The nature, the oxidation state of copper, the structural properties and the morphology of the catalysts were characterized by means of UV vis spectra, Fourier Transform Infrared Spectroscopy (FTIR), nitrogen sorption, and transmission electron microscopy, respectively. By using substitution technique, the copper(II) species were introduced into the silica-aluminosilicate framework by replacing aluminum atoms that located in the tetrahedral coordination. On the other hand, by using incipient wetness impregnation method, the copper species were deposited on the surface of composite materials. Upon testing their performances in deNO(x) reaction, the catalysts prepared by incipient wetness impregnation method showed higher catalytic activity than those prepared by substitution technique in any copper content. The core-shell structure was able to enhance the catalytic performance. It was found that, among the tested catalysts, the 1.5% Cu loaded core-shell mesoporous silica aluminosilicate composites prepared by an incipient wetness impregnation yielded the highest NO conversion of approximately 59%. However, the addition of chitosan creating macroporosity and controlling the uniform small clusters did not improve the catalytic performance. PMID- 23447997 TI - Internal denial reporting: informing payer communications. PMID- 23447998 TI - Case study: Building exception-based workflow and extracting management information in billing. PMID- 23447999 TI - Payment portals can improve self-pay collections and support meaningful use. PMID- 23448000 TI - View point: Episodes of mass hysteria in African schools: a study of literature. PMID- 23448001 TI - Implementing a dynamic street-children's program: successes and challenges. AB - The article has discusses the successes and challenges of implementing a dynamic street children's program in Mzuzu Malawi--using a developmental life-course framework blending psychodynamic approaches, risk-factor approaches, and strain and control theories of crime and delinquency. The framework has helped the programme implementation team consider not only the phase and stage of the child's development in their provision of care, but also the influence that early childhood dynamics of parent-child, parent-parent and child-parent-environment; life-events; peers and neighbourhoods have at each of the developmental stages of child and adolescent development, and how they can influence the child's behaviour in both positive and negative ways. The article also discusses successes and suggests ways of addressing the identified challenges. PMID- 23448002 TI - Increasing the capacity of health surveillance assistants in community mental health care in a developing country, Malawi. AB - Mental health services in Malawi are centralized in the three tertiary units which are located one in each of the three regions of Malawi and this means that most people with mental health problems do not get help. With severe shortages of mental health professionals in the country, integration of mental health into existing primary and community health services is the most feasible way of increasing access to services for people with mental health problems. This paper discusses a pilot program of integrating mental health in the activities of Health Surveillance Assistants (HSAs) who are community health workers in Malawi. PMID- 23448003 TI - Domiciliary mental health care program in community settings: is it is feasible in Malawi? PMID- 23448004 TI - Case report: Treatment of metastatic germ cell tumor in a newly diagnosed HIV infected man: use of BEP chemotherapy. PMID- 23448005 TI - Case report: A young man with progressive weakness, double vision and breathlessness. PMID- 23448006 TI - Thengo Kavinya talks to Dr Felix Kauye on his career in mental health. Interview by Thengo Kavinya. PMID- 23448007 TI - Opinions on mental health care in Malawi: Is Malawi getting mental health care right? PMID- 23448008 TI - Demographic analysis, a comparison of the jackknife and bootstrap methods, and predation projection: a case study of Chrysopa pallens (Neuroptera: Chrysopidae). AB - The life table of the green lacewing, Chrysopa pallens (Rambur), was studied at 22 degrees C, a photoperiod of 15:9 (L:D) h, and 80% relative humidity in the laboratory. The raw data were analyzed using the age-stage, two-sex life table. The intrinsic rate of increase (r), the finite rate of increase (lambda), the net reproduction rate (R0), and the mean generation time (T) of Ch. pallens were 0.1258 d(-1), 1.1340 d(-1), 241.4 offspring and 43.6 d, respectively. For the estimation of the means, variances, and SEs of the population parameters, we compared the jackknife and bootstrap techniques. Although similar values of the means and SEs were obtained with both techniques, significant differences were observed in the frequency distribution and variances of all parameters. The jackknife technique will result in a zero net reproductive rate upon the omission of a male, an immature death, or a nonreproductive female. This result represents, however, a contradiction because an intrinsic rate of increase exists in this situation. Therefore, we suggest that the jackknife technique should not be used for the estimation of population parameters. In predator-prey interactions, the nonpredatory egg and pupal stages of the predator are time refuges for the prey, and the pest population can grow during these times. In this study, a population projection based on the age-stage, two-sex life table is used to determine the optimal interval between releases to fill the predation gaps and maintain the predatory capacity of the control agent. PMID- 23448009 TI - Sublethal effects of paichongding on Nilaparvata lugens (Homoptera: Delphacidae). AB - Nilaparvata lugens (Stal) is a major rice pest in Asia Paichongding is a novel neonicotinoid insecticide developed in 2008. The effects of this insecticide on life-table parameters and wing formation of N. lugens were examined in the laboratory. The results showed that paichongding could significantly reduce the fecundity of N. lugens, demonstrating further activity against this pest in addition to direct toxicity. The fecundity of N. lugens treated with LC20, LC30, LC40, and LC50 of paichongding were 87.44, 79.63, 63.31, and 52.66% of the control, respectively. The relative fitness values were 0.55, 0.41, 0.21, and 0.09, respectively, for LC20, LC30, LC40, and LC50 paichongding treatments. Sublethal concentrations of paichongding showed significant induction of macropterous offspring, which would be one kind of coping mechanism of N. lugens response to insecticide stress. PMID- 23448010 TI - Dissecting the mode of maize chlorotic mottle virus transmission (Tombusviridae: Machlomovirus) by Frankliniella williamsi (Thysanoptera: Thripidae). AB - Maize chlorotic mottle virus (MCMV) (Tombusviridae: Machlomovirus) has been recorded in Hawaii (Kauai Island) since the early 1990s and has since become one of the most widespread corn viruses in the Hawaiian Islands. In the United States Mainland, MCMV has been reported to be transmitted by six different species of chrysomelid beetles, including the western corn rootworm, Diabrotica virgifera virgifera LeConte. However, none of these beetle species have been reported in Hawaii where the corn thrips, Frankliniella williamsi Hood (Thysanoptera: Thripidae) has been identified to be the main vector. In this study, we developed leaf disk transmission assays and real time reverse transcription-polymerase chain reaction to examine the mode of MCMV transmission by the corn thrips. We showed that thrips transmitted the virus with no evidence for latent periods. Both larvae and adults transmitted the virus for up to 6 d after acquisition, with decreasing rates of transmission as time progressed. There was no evidence that adult thrips that acquired the virus as larvae were competent vectors. Real time reverse-transcription polomerase chain reaction assays showed that viral load was depleted from the vector's body after thrips had access to healthy plant tissue. Depletion of viral load was also observed when thrips matured from larvae to adults. Thrips were able to transmit MCMV after acquisition and inoculation access periods of 3 h. However, transmission efficiency increased with longer acquisition and inoculation access periods. Taken altogether our data suggests that corn thrips transmit MCMV in a semipersistent manner. To our knowledge, this is the first work reporting evidence of a plant virus transmitted semipersistently by thrips. PMID- 23448011 TI - New excised-leaf assay method to test inoculativity of Asian citrus psyllid (Hemiptera: Psyllidae) with Candidatus Liberibacter asiaticus associated with citrus huanglongbing disease. AB - The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae), is the primary vector of Candidatus Liberibacter asiaticus (Las) associated with huanglongbing, or citrus greening, the most devastating citrus (Citrus spp.) disease worldwide. Here, we developed a new "excised-leaf assay" that can speed up Las-inoculativity tests on Asian citrus psyllid from the current 3-12 mo (when using whole citrus seedlings for inoculation) to only 2-3 wk. Young adults of Asian citrus psyllid that had been reared on Las-infected plants were caged on excised healthy sweet orange [Citrus sinensis (L.) Osbeck] leaves for a 1-2-wk inoculation access periods (IAP), and then both psyllids and leaves were tested later by quantitative polymerase chain reaction (PCR). When single adults were tested per leaf, percentages of Las-positive leaves averaged 2-6% by using HLBaspr primers and 10-20% by using the more sensitive LJ900 primers. Higher proportions of Las-positive leaves were obtained with 1) higher densities of inoculating psyllids (5-10 adults per leaf), 2) longer IAPs, and 3) incubation of leaves for 1 wk postinoculation before PCR. Logistic regression analysis indicated a positive correlation between Las titer in Asian citrus psyllid adults tested singly and the probability of detecting Las in the inoculated leaves, correlations that can be very useful in epidemiological studies. Comparison between excised leaves and whole seedlings, inoculated consecutively for 1 wk each by one or a group of psyllids, indicated no significant difference between Las detection in excised leaves or whole plants. This new excised-leaf assay method saves considerable time, materials, and greenhouse space, and it may enhance vector relation and epidemiological studies on Las and potentially other Liberibacter spp. associated with huanglongbing disease. PMID- 23448012 TI - The effect of gamma sterilization on the insecticidal toxicity of engineered and conventional Bacillus thuringiensis strains. AB - This study evaluates the effect of gamma radiation on the spore activity, toxicity, and crystal structures of two engineered Bacillus thuringiensis (Bt) strains, TnX and TnY, and the reference Bt strain HD-1. We attempted to identify dosages of cobalt-60 gamma radiation that would inactivate Bt spores but not affect its toxicity. In the radiation dosage range of 10-15 kilogray, no viable spore formation and no significant reduction of the efficiency of Bt against lepidopteran larvae were observed. However, further sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results show that the components of the protoxin are affected by gamma radiation and that some bands are absent after treatment compared with the controls; the change in the protoxin band pattern depends on the type of Bt strain. Furthermore, the spore crystal structure of three Bt strains was studied with scanning electron microscopy and transmission electron microscopy. The results show that there are no changes in the size or shape of the treated Bt spores and crystals compared with the controls. The use of gamma radiation is effective to inactivate the spores of engineered Bt strains while preserving stable Bt toxicity against the target insect larvae. PMID- 23448013 TI - The identification of a bacterial strain BGI-1 isolated from the intestinal flora of Blattella germanica, and its anti-entomopathogenic fungi activity. AB - A bacterial strain BGI-1 was isolated from the gut of German cockroaches (Blattella germanica L.) and was identified as Bacillus subtilis based on 16S rDNA sequence and morphological, physiological, and biochemical characters. The strain BGI-1 inhibited the growth of Beauveria bassiana; the diameter of the inhibition zone exceeded 30 mm. Vesicles were observed in B. bassiana hyphae on the edge of the inhibition zone. Fermentation of BGI-1 reduced the conidial germination rate by 12%. Further studies demonstrated that B. bassiana infections in German cockroaches orally treated with the extracts of BGI-1 fermentation were significantly weakened. Cumulative mortality rate was 49.5% in the treatment group at the 20 d, while that of the control group was 62.3%. The study intends to understand the relationship between the intestinal flora and the cockroach. Those microbes with anti-entomopathogenic fungi activity might contribute to resisting the infection of pathogenic fungi. PMID- 23448014 TI - Insecticidal characteristics of two commercial Spodoptera exigua nucleopolyhedrovirus strains produced on different host colonies. AB - The insecticidal characteristics of two Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) strains produced on two different S. exigua colonies were measured using the same two host colonies. These strains constitute the active ingredients of the biological insecticides Vir-ex and Spexit and were produced on insect colonies from Spain and Switzerland. Demographic characteristics of insects from each colony were examined before infection. Larval developmental time, larval survival, and adult sex ratio did not differ between the colonies, whereas mean pupal weight was significantly higher in the Spanish colony insects. After infection, susceptibility to virus occlusion bodies (OBs), time to death, larval weight at death, and total production of OBs/larva varied significantly depending on virus strain and the colony used. Vir-ex OBs produced in Spanish colony larvae had improved insecticidal characteristics in terms in lethal dose and speed of kill metrics than other strain-colony combinations. OB production was significantly higher in Spanish colony insects infected with Spexit compared with Vir-ex infected insects from the Swiss colony, with intermediate values for the other two strain-colony combinations. Virus strain and host colony origin were highly influential in determining the insecticidal characteristics of OBs and should be considered as key parameters that require optimization during the production of SeMNPV-based insecticides. PMID- 23448015 TI - Efficacy of a granular formulation containing Metarhizium brunneum F52 (Hypocreales: Clavicipitaceae) microsclerotia against nymphs of Ixodes scapularis (Acari: Ixoididae). AB - Technical improvements in the production and formulation of microbial agents will increase the potential for development of biological pesticides that are able to compete with chemical insecticides in the marketplace. Here we report the efficacy of a simple granule formulation containing microsclerotia of Metarhizium brunneum (Petch) (Hypocreales: Clavicipitaceae) for control of unfed and fed nymphs of Ixodes scpaularis Say (Acari: Ixoididae). Microsclerotial granules of M. brunneum applied to moist potting mix produce infective conidia within 2 wk and conidia remained viable for up to 8 wk after application. Microsclerotial granules produced from 3.05 x 10(9) to 1.24 x 10(10) conidia g(-1) granules in potting mix. Both unfed and fed nymphs were susceptible to infection when exposed to treated potting soil with up to 56 and 74% mortality, respectively. M. brunneum demonstrated a transtadial infection for fed nymphs exposed to treated potting mix with signs of a fungal infection becoming apparent only after molting into adults. High conidial production rates from microsclerotial granules of M. brunneum combined with significant tick mortality support the need for additional research to evaluate the efficacy of this treatment technology as a biopesticide option for control of ticks. PMID- 23448016 TI - Investigating alternatives to traditional insecticides: effectiveness of entomopathogenic fungi and Bacillus thuringiensis against citrus thrips and avocado thrips (Thysanoptera: Thripidae). AB - Citrus thrips, Scirtothrips citri (Moulton) (Thysanoptera: Thripidae), is a plant feeding pest most widely recognized for causing damage to citrus (Citrus spp. L. [Rutaceae]) and mango (Mangifera indica L. [Anacardiaceae]) fruits. This insect has recently broadened its known host range to become a significant pest of California grown blueberries. Avocado thrips, Scirtothrips. perseae Nakahara (Thysanoptera: Thripidae), is a recent, invasive pest of California avocados, Persea americana Mill. (Laurales: Lauraceae). Effective alternatives to traditional pesticides are desirable for both pests to reduce impacts on natural enemies and broaden control options in an effort to minimize pesticide resistance via rotation of control materials. We evaluated Bacillus thuringiensis (Bt) subsp. israelensis proteins (Cyt 1A and Cry 11A, activated and inactivated) and multiple strains (GHA, 1741ss, SFBb1, S44ss, NI1ss, and 3769ss) of Beauveria bassiana (Balsamo) Vuillemin against both species. Avocado thrips and citrus thrips were not susceptible to either Bt protein tested, regardless of activation status. All strains of B. bassiana were able to infect both avocado thrips and citrus thrips. However, the commercially available GHA strain was the most effective strain against both species and had a faster rate of infection then the other strains tested. Citrus thrips were more susceptible than avocado thrips to all B. bassiana strains (LC50 and LC95 of 8.6 x 10(4) and 4.8 x 10(6) conidia per ml for citrus thrips, respectively). Investigation of citrus thrips field control using the GHA strain of B. bassiana is therefore justified. PMID- 23448017 TI - Biology and efficacy of Aprostocetus (Eulophidae: Hymenoptera) as a parasitoid of the blueberry gall midge complex: Dasineura oxycoccana and Prodiplosis vaccinii (Diptera: Cecidomyiidae). AB - In the southeastern United States, bud-infesting larvae of two gall midge species, Dasineura oxycoccana (Johnson) and Prodiplosis vaccinii (Felt), destroy from 20 to 80% of the rabbiteye blueberry crop, Vaccinium virgatum Aiton (syn. V. ashei Reade). These midge larvae are attacked by five species of parasitoid wasps. The most effective of these is the bivoltine eulophid Aprostocetus sp. nr. marylandensis (Eulophidae), whose adults constitute one-third of the gall midge parasitoids, active in both conventional and organic blueberry fields. Broods of Aprostocetus use several reproductive strategies to keep sole possession of their larval hosts. As solitary endoparasitoids as well as facultative hyperparasitoids, precocial larvae of Aprostocetus devour hosts organs along with any younger siblings and rival parasitoid broods. Although larger hosts are preferred, any sized larvae can be parasitized, which reduces brood congestion and infanticide. An Aprostocetus female spends an hour or more in a systematic hunt for hosts, during which time 40 to 100% of midge larvae encountered are parasitized. Aprostocetus females could have located hosts more quickly had they recognized host-feeding scars as cues. Even so, high rates of larval parasitism achieved by Aprostocetus may kill as many midges as insecticides do. PMID- 23448018 TI - Biological control of Eotetranychus lewisi and Tetranychus urticae (Acari: Tetranychidae) on strawberry by four phytoseiids (Acari: Phytoseiidae). AB - The spider mite, Eotetranychus lewisi (McGregor) (Acari: Tetranychidae), is a new emerging pest in California commercial strawberries. The predatory mite Phytoseiulus persimilis (Athias-Henriot) (Acari: Phytoseiidae), typically used for biocontrol of Tetranychus urticae (Koch) (Acari: Tetranychidae), provided growers little to no control of E. lewisi. Four commonly used phytoseiid predatory mites: P. persimilis, Neoseiulus californicus (McGregor), N. fallacis (Garman), and Amblyseius andersoni (Chant), were used in lab studies to investigate which is best at managing E. lewisi populations. We als o investigated t he interactions between T. urticae and E. lewisi and in relation to phytoseiid efficiency given the potential for indirect effects of biocontrol. When E. lewisi and T. urticae are present on the same leaf, T. urticae populations increase and begin displacing E. lewisi. P. persimilis did not feed on E. lewisi, but the other three predatory mites consumed the spider mites and lowered their populations. When both E. lewisi and T. urticae are present on the same leaf, N. fallacis and A. andersoni fed on both types of mites equally and were capable of decreasing both populations. N. californicus fed on E. lewisi first and decreased its population, but allowed T. urticae populations to increase. P. persimilis may be insufficient at controlling E. lewisi and its use may instead enhance E. lewisi populations. PMID- 23448019 TI - Reproductive dormancy in boll-weevil from populations of the midwest of Brazil. AB - The boll weevil (Anthonomus grandis Boheman) (Coleoptera: Curculionidae) is an introduced pest in Brazil, which in 30 yr has successfully expanded to various eco-regions and became the most important pest of cotton (Gossypium hirsutum, Malvaceae). Given the limited knowledge about the adaptive mechanisms that allowed successful establishment of the pest population in a tropical region, in this work we studied the potential of the Midwest population of boll weevils to enter a reproductive dormancy and identified the importance of the feeding source for induction of dormancy. We investigated morphological and physiological characters as indicators of the dormancy. We also investigated the occurrence of reproductive dormancy in boll weevils populations from cotton farms of the Midwestern region of Brazil during the cotton and noncotton seasons of 2009 and 2010. The studies revealed that boll weevils entered facultative reproductive dormancy; however, unlike what has been observed for boll weevils from temperate and subtropical regions, the hypertrophy of fat body and hexamerin levels did not straightly correlated to reproductive dormancy. The food source and field conditions during early adult development were decisive factor for the induction of reproductive dormancy. The incidence of reproductive dormancy increased progressively as the phenology of cotton plant advanced, reaching approximately 90% at the end of the crop season. During the noncotton season, the boll weevil was predominantly found in reproductive dormancy, especially females; however, there is evidence of use of multiple adaptive strategies to colonize the next harvest. PMID- 23448020 TI - Wild bees visiting cucumber on midwestern U.S. organic farms benefit from near farm semi-natural areas. AB - Wild bees that provide pollination services to vegetable crops depend on forage resources, nesting sites, and overwintering sites in the agricultural landscape. The scale at which crop-visiting bees use resources in the landscape can vary regionally, and has not been characterized in the Midwestern United States. We investigated the effects of seminatural land cover on wild bee visitation frequency to cucumber (Cucumis sativus L.) and on wild bee species richness on 10 organic farms in Indiana. We estimated the spatial scale at which the effects of land cover were strongest, and also examined the effects of nonlandscape factors on wild bees. The visitation frequency of wild bees to cucumber was positively related to the proportion of seminatural land in the surrounding landscape, and this relationship was strongest within 250 m of the cucumber patch. The species richness of wild cucumber visitors was not affected by land cover at any spatial scale, nor by any of the nonlandscape factors we considered. Our results indicate that wild, crop visiting bees benefit from seminatural areas in the agricultural landscape, and benefit most strongly from seminatural areas within 250 m of the crop field. This suggests that setting aside natural areas in the near vicinity of vegetable fields may be an effective way to support wild, crop-visiting bees and secure their pollination services. PMID- 23448021 TI - Effect of temperature on the development of Laodelphax striatellus (Homoptera: Delphacidae). AB - Temperature has a significant influence on the development of Laodelphax striatellus (Fallen), an important rice pest insect in east Asia. We set eight constant temperatures from 18 to 32 degrees C in 2 degrees C-increments to check the effect of temperature on the developmental rate of this insect species. The developmental durations of eggs and nymphs were observed daily. To ensure the accuracy of developmental durations, 500 initial samples were taken for the nymphal stage at each temperature. Performance-2 model was used to fit these data because this model can provide the lower and upper developmental thresholds simultaneously. The estimate of lower developmental thresholds of eggs (10.0 degrees C) was different from that of nymphs (7.5 degrees C). And the estimate of upper developmental thresholds of eggs (35.5 degrees C) was also different from that of nymphs (30.2 degrees C). However, for male and female nymphs, the difference in the lower developmental threshold is nonsignificant, and the difference in the upper developmental thresholds is very small (95% confidence interval of the difference: [0.007 degrees C, 0.043 degrees C]). The rate isomorphy hypothesis considers that the lower developmental thresholds of different stages for the same insect might be constant. However, the current study provides a counterexample of this hypothesis that the lower developmental threshold of eggs is different from that of nymphs. Thus, we demonstrate that the rate isomorphy hypothesis does not apply all insects. In addition, we used a popular nonlinear model, Lactin model, to fit the developmental rate data of our experiment. And we found that the estimates of lower and upper developmental thresholds by using Performance-2 model were very approximate to those by using Lactin model. The current study provides reliable estimates of thermal parameters for L. striatellus by using large experimental samples at different temperatures. It would be useful for exploring the relationship of climate change and the outbreak of this insect on rice. PMID- 23448022 TI - Effect of temperature and button mushroom varieties on life history of Lycoriella auripila (Diptera: Sciaridae). AB - Temperature-dependent development and population growth parameters of the fungus gnat, Lycoriella auripila (Winnertz), on button (737 and A15) mushroom were evaluated at nine constant temperatures, ranging from 8, 10, 12.5, 15, 20, 22.5, 25, 27, and 30 degrees C and developmental rates were modeled as a function of temperature. At 25 and 27 degrees C, an average of 20.89 and 22.43 d was needed for L. auripila to complete its development from oviposition to adult eclosion on 737 and A15, respectively. The population failed to survive at 8 and 30 degrees C. The developmental times of males or females on each variety at various constant temperatures differed significantly. The regression and Ikemoto and Takai linear models, in the absence of 10, 12.5, and 27 degrees C, described the relationship of developmental rate to temperature for male and female of L. auripila very well. Data were fitted to various nonlinear temperature-dependent models. The Logan 6 and Briere 1 nonlinear models provided the best estimation for Topt and Tmax and are highly recommended for the description of temperature dependent development of L. auripila on 737 and A15, respectively. On 737 variety, significant differences were observed among all growth parameters at various temperatures. The intrinsic rate of natural increase (r(m)) for L. auripila was 0.134 on 737 variety at 25 degrees C, which was significantly >0.052 on A15 variety at the same temperature. No other data are available in using linear and nonlinear models to describe the relationship between temperature and L. auripila development. Understanding the influence of temperature on development of L. auripila is discussed with respect to pest management in mushroom production. PMID- 23448023 TI - Temperature-dependent egg development of Lygus hesperus (Hemiptera: Miridae). AB - Lygus hesperus Knight (Hemiptera: Miridae) is a key agricultural pest in the western United States, but certain aspects of its temperature-dependent development are poorly defined. Accurate models describing the relationships between temperature and development of L. hesperus would facilitate the study of Lygus seasonal population dynamics and overwintering ecology. We used nonlinear biophysical models to describe the development of L. hesperus eggs oviposited in green bean pods and semitransparent agarose and held under constant temperatures from 10 to 37.8 degrees C. The agarose substrate was used because it is less susceptible than green beans to deterioration at low and high temperature extremes, and because it allowed the observation of phases of embryonic development that are hidden from view from eggs developing in plant material. The models indicated that both low and high temperature inhibited development of each observed embryonic phase regardless of oviposition substrate. Developmental rates asymptotically approached zero with decreasing temperature in the lower thermal range, and decreased with increasing temperatures above 32.2 degrees C. Eggs oviposited in agarose developed slower than eggs oviposited in green bean pods suggesting that egg developmental rates were influenced by the type of host substrate. Our temperature-dependent developmental rate models for L. hesperus eggs supplement nonlinear models recently reported for L. hesperus nymphal and adult reproductive development and should be useful in planning and interpreting field studies of L. hesperus population dynamics and overwintering ecology. PMID- 23448024 TI - Toxicity and repellency of compounds from clove (Syzygium aromaticum) to red imported fire ants Solenopsis invicta (Hymenoptera: Formicidae). AB - The toxicity and repellency of the bioactive chemicals of clove (Syzygium aromaticum) powder, eugenol, eugenol acetate, and beta-caryophyllene were evaluated against workers of the red imported fire ant, Solenopsis invicta Buren. Clove powder applied at 3 and 12 mg/cm2 provided 100% ant mortality within 6 h, and repelled 99% within 3 h. Eugenol was the fastest acting compound against red imported fire ant compared with eugenol acetate, beta-caryophyllene, and clove oil. The LT50 values inclined exponentially with the increase in the application rate of the chemical compounds tested. However, repellency did not increase with the increase in the application rate of the chemical compounds tested, but did with the increase in exposure time. Eugenol, eugenol acetate, as well as beta caryophyllene and clove oil may provide another tool for red imported fire ant integrated pest management, particularly in situations where conventional insecticides are inappropriate. PMID- 23448025 TI - Safety evaluation of eleven insecticides to Trichogramma nubilale (Hymenoptera: Trichogrammatidae). AB - The safety of 11 pesticides (indoxacarb, chlorfluazuron, azadirachtin, methoxyfenozide, rotenone, spinosad, acetamiprid, imidacloprid, chlorfenapyr, chlorpyrifos, and triazophos) to Trichogramma nubilale (Hymenoptera: Trichogrammatidae) was evaluated in this study. The acute toxicity to the adults was investigated using dry-film method. The influences of the pesticides on both parasitic ability and different developmental stages were studied using corn leaves residual method, rice moth egg card dipping method, and T. nubilale parasitized rice moth egg dipping method. Results showed that methoxyfenozide, azadirachtin, and indoxacarb were safe for the whole life cycle of T. nubilale. Chlorfluazuron, rotenone, and acetamiprid had different levels of impacts on different developmental stages, and they should be chosen to be used according to their safety time with reduced exposure levels. Rotenone was safe for the adults but it was harmful to the other stages, whose dosage should be reduced when it was used. Acetamiprid could be applied during the pupae stage. Finally, to avoid large kill, spinosad, chlorfenapyr, chlorpyrifos, triazophos, and imidacloprid should not be used as they were not safe for any development stage of T. nubilale. PMID- 23448026 TI - Susceptibility to selected insecticides and risk assessment in the insect egg parasitoid Trichogramma confusum (Hymenoptera: Trichogrammatidae). AB - The parasitoid Trichogramma confusum Viggiani (Hymenoptera: Trichogrammatidae) is an important natural enemy of many lepidopterans throughout the world. Extensive toxicological tests have clarified the toxic effects of insecticides on trichogrammatids, but only few studies have examined these effects on T. confusum. Among the seven classes of tested chemicals, organophosphates and carbamates exhibited the highest intrinsic toxicity to the parasitoid with LC50 values ranging from 0.037 (0.030-0.046) to 0.29 (0.23-0.38) and from 0.17 (0.15 0.19) to 1.61 (1.45-1.79) mg AI L(-1), respectively. They were followed by phenylpyrazoles, avermectins, pyrethroids, and neonicotinoids, which induced variable toxicity responses with LC50 values ranging from 0.63 to 45.26, 1.06 21.73, 3.89-19.36, and 0.24-754.2 mg AI L(-1), respectively. In contrast, insect growth regulators (IGRs) showed the least toxicity to the parasitoid with LC50 values ranging from 3,907 (3,432-4,531) to 10,154 (8,857-12,143) mg AI L(-1). A risk quotient analysis indicated that neonicotinoids (except thiamethoxam), avermectins, pyrethroids, IGRs, and phenylpyrazoles are safe, but organophosphates and carbamates are slightly to moderately or dangerously toxic to T. confusum. This study provides informative data for implementing both biological and chemical control strategies in integrated pest management of lepidopterans. PMID- 23448027 TI - Impact of insecticide residue exposure on the invasive pest, Halyomorpha halys (Hemiptera: Pentatomidae): analysis of adult mobility. AB - Twenty eight insecticides were evaluated in the laboratory to characterize the impact of specific compounds on locomotory behavior and mobility of adult Halyomorpha halys (Stal) (Hemiptera: Pentatomidae). Horizontal distance and angular velocity were measured for individuals exposed to dry insecticide residue for 4.5 h to evaluate how quickly and intensely a given insecticide induced changes in motor activities in no-choice glass arenas. Eight out of nine pyrethroid insecticides induced uncoordinated and irregular movement within 10 min after exposure to insecticides. After 1.5 h, most adults were incapacitated. By contrast, there was no immediate stimulation when H. halys were exposed to organophosphate residues. After 1.5 h, four out of seven organophosphates resulted in increased horizontal distance moved and angular velocity indicating irregular walking paths by exposed adults. Carbamate and neonicotinoid insecticides produced fairly similar patterns with virtually no stimulation in horizontal distance moved or angular velocity, except for imidacloprid and thiacloprid. Neither endosulfan (organochlorine) nor indoxacarb (oxadiazine) affected the horizontal movement of H. halys. Vertical distance climbed by adult H. halys was measured immediately after the 4.5-h insecticide exposure period and at 7 d. In general, adults that survived until day 7 were able to climb vertical distances similar to those in the control. In particular, this result was observed for seven out of nine pyrethroid materials that incapacitated all adults after the 4.5-h exposure period. Mobility changes of adult H. halys are discussed in the context of enhancing integrated pest management programs. PMID- 23448028 TI - Acute toxicity of plant essential oils to scarab larvae (Coleoptera: Scarabaeidae) and their analysis by gas chromatography-mass spectrometry. AB - Larvae of scarab beetles (Coleoptera: Scarabaeidae) are important contaminant and root-herbivore pests of ornamental crops. To develop alternatives to conventional insecticides, 24 plant-based essential oils were tested for their acute toxicity against third instars of the Japanese beetle Popillia japonica Newman, European chafer Rhizotrogus majalis (Razoumowsky), oriental beetle Anomala orientalis (Waterhouse), and northern masked chafer Cyclocephala borealis Arrow. Diluted solutions were topically applied to the thorax, which allowed for calculating LD50 and LD90 values associated with 1 d after treatment. A wide range in acute toxicity was observed across all four scarab species. Of the 24 oils tested, allyl isothiocyanate, cinnamon leaf, clove, garlic, and red thyme oils exhibited toxicity to all four species. Allyl isothiocyanate was the most toxic oil tested against the European chafer, and among the most toxic against the Japanese beetle, oriental beetle, and northern masked chafer. Red thyme was also comparatively toxic to the Japanese beetle, oriental beetle, European chafer, and northern masked chafer. Interspecific variability in susceptibility to the essential oils was documented, with 12, 11, 8, and 6 of the 24 essential oils being toxic to the oriental beetle, Japanese beetle, European chafer, and northern masked chafer, respectively. Analysis of the active oils by gas chromatography-mass spectrometry revealed a diverse array of compounds, mostly consisting of mono- and sesquiterpenes. These results will aid in identifying active oils and their constituents for optimizing the development of plant essential oil mixtures for use against scarab larvae. PMID- 23448029 TI - Abundance and distribution of western and northern corn rootworm (Diabrotica spp.) and prevalence of rotation resistance in eastern Iowa. AB - The western corn rootworm Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae) and the northern corn rootworm Diabrotica barberi Smith & Lawrence (Coleoptera: Chrysomelidae) are major pests of corn (Zea mays L.). Historically, crop rotation has been an effective management strategy, but both species have adapted to crop rotation in the Midwest. For both species in eastern Iowa, we measured abundance and prevalence of rotation resistance using sticky traps and emergence cages in fields of corn and soybean (Glycine max L.). Based on currently available data, we calculated the economic thresholds for these pests at two Diabrotica spp. per trap per day in cornfields and 1.5 D. v. virgifera per trap per day in soybean fields. The economic injury level of rotation-resistant D. barberi was determined to be 3.5 adult insects per emergence cage per year. Peak abundance of rootworm adults in cornfields was below economic thresholds in the majority of fields sampled, suggesting that management of rootworm larvae in continuous cornfields may not always be necessary. Rotation-resistant D. barberi was found throughout eastern Iowa using emergence cages in first-year cornfields, however, the abundance was below levels expected to impose economic injury in 14 of 17 fields evaluated. The presence of rotation-resistant D. v. virgifera, as measured by the occurrence of this insect in soybean fields, occurred only in northeastern Iowa and was also below the economic threshold. These data suggests that crop rotation remains a viable pest management strategy in eastern Iowa. PMID- 23448030 TI - Effects of chlorantraniliprole and thiamethoxam rice seed treatments on egg numbers and first instar survival of Lissorhoptrus oryzophilus (Coleoptera: Curculionidae). AB - Effects of treatment of rice seeds with an anthranilic diamide, chlorantraniliprole, and a neonicotinoid, thiamethoxam, on egg laying and first instar survival in rice water weevil, Lissorhoptrus oryzophilus Kuschel, were examined under greenhouse conditions. Exposure of adult weevils to rice (6-7 leaf stage) grown from seeds treated with chlorantraniliprole and thiamethoxam resulted in reduction in numbers of eggs and first instars. The low egg numbers by adults exposed to chlorantraniliprole-treated plants was confirmed as a sublethal effect on adults: adult survival was not impacted after 4 d of feeding on foliage from chlorantraniliprole-treated plants but the number of eggs laid by these weevils was reduced when released on untreated plants. Furthermore, a comparison of first instar emergence from chlorantraniliprole-treated plants and from untreated plants infested with weevils previously exposed to this chemical suggested that chlorantraniliprole was also reducing egg or first instar survival. In contrast, adults that fed on foliage from thiamethoxam-treated plants showed increased mortality. Possible sublethal effects of thiamethoxam on the number of eggs laid by adults were investigated by infesting untreated plants with weevils that survived exposure to thiamethoxam via foliar feeding (7 microg active ingredient/seed). Prior exposure to thiamethoxam through adult feeding reduced egg numbers. However, potential larvicidal or ovicidal effects of thiamethoxam seed treatments could not be detected in this study because of low first instar emergence from both thiamethoxam-treated plants and from untreated plants infested with weevils previously exposed to this chemical. These experiments revealed that the two seed treatments accomplish weevil control in different ways. PMID- 23448031 TI - Verde plant bug (Hemiptera: Miridae) feeding injury to cotton bolls characterized by boll age, size, and damage ratings. AB - The verde plant bug, Creontiades signatus (Distant), has been present in south Texas for several years but has more recently been documented as an economic threat to cultivated cotton, (Gossypium hirsutum L. Our studies over 2 yr (2009 and 2010) and two locations (Weslaco and Corpus Christi, TX) investigated feeding injury of the verde plant bug to a range of cotton boll age classes defined by boll diameter and accumulated degree-days (anthesis to the time of infesting) for first-position cotton bolls infested with the plant bugs. The most detrimental damage to younger cotton holls from verde plant bug feeding was boll abscission. Cotton bolls <04 accumulating daily degree-days (ACDD), or a boll diameter of 1.3 cm were subject to 60-70% higher boll abscission when compared with the noninfested controls. Significantly higher boll abscission occurred from verde plant bug injured bolls compared with the controls up to 162 ACDD or a mean boll diameter 2.0 cm. Cotton seed weights were significantly reduced up to 179 ACDD or a boll diameter of 2.0 cm at Weslaco in 2009, and up to 317 ACDD or boll diameter 2.6 cm for Weslaco in 2010 when compared with the noninfested controls. Lint weight per cotton boll for infested and noninfested bolls was significantly reduced up to 262 ACDD or boll diameter 2.5 for Corpus Christi in 2010 and up to 288 ACCD or boll diameter 2.6 cm for Weslaco, TX, in 2010. Damage ratings (dependant variable) regressed against infested and noninfested seed-cotton weights showed that in every instance, the infested cotton bolls had a strong and significant relationship with damage ratings for all age classes of bolls. Damage ratings for the infested cotton bolls that did not abscise by harvest showed visual signs of verde plant bug feeding injury and the subsequent development ofboll rot; however, these two forms of injury causing lint and seed mass loss are hard to differentiate from open or boll-locked cotton bolls. Based on the results of both lint and seed loss over 2 yr and four studies cotton bolls should be protected up to approximately 300 ACDD or a boll diameter of 2.5 cm. This equilibrates to bolls that are 12-14 d of age dependent upon daily maximum and minimum temperatures. PMID- 23448032 TI - Effects of nitrogen fertilizer and magnesium manipulation on the Cnaphalocrocis medinalis (Lepidoptera: Pyralidae). AB - The rice leaffolder, Cnaphalocrocis medinalis Guenee (Lepidoptera: Pyralidae), is a rice pest that is prone to outbreaks when high levels of nitrogen (N) fertilizer are applied to rice. The larvae feed by scraping the mesophyll cells of leaves, which are mainly composed of chloroplasts containing significant levels of elemental magnesium (Mg). To determine the cause of N fertilizer induced rice leaffolder outbreaks and the effects of Mg and Mg uptake on the rice leaffolder, the changes in the life history traits and biochemistry of C. medinalis larvae feeding on rice leaves treated with different Mg and N concentrations were investigated in this study. The results showed that foliar treatment using different Mg concentrations under hydroponic culture conditions significantly decreased the developmental duration (days) (DD) of the larvae and pupae but did not influence the pupation rate or adult emergence rate. The number of eggs laid by adult females and the protein content and total sugar content in the larvae and pupae significantly increased with increasing Mg concentrations. Under soil culture conditions, the DD for the larvae and number of eggs laid by adult females significantly increased with increasing nitrogen fertilizer levels, but the applied fertilizer did not influence the DD in the pupae, pupation rate, or adult emergence rate. In contrast, the DD for adults decreased with increased fertilizer levels. In hydroponic culture, Mg in the culture solution and Mg foliar sprays significantly increased the Mg content in rice leaves. In soil cultures, the use of N fertilizer and Mg foliar spray did not significantly increase the leaf Mg content, except at a concentration of 12.5 g/L, indicating that the leaf Mg content may be related to the root uptake of Mg. PMID- 23448033 TI - Attaching lures to multiple-funnel traps targeting saproxylic beetles (Coleoptera) in pine stands: inside or outside funnels? AB - We conducted two field trapping experiments with multiple-funnel traps in 2008 and one experiment in 2010 to determine the effects of lure placement (inside or outside funnels) on catches of saproxylic species of beetles (Coleoptera). The experiments were conducted in southern pine (Pinus spp.) stands in central Georgia using combinations of ethanol, alpha-pinene, ipsenol, and ipsdienol lures. We report on a modification to the multiple-funnel trap that allows placement of large lures inside the confines of the funnels with minimal blockage. In general, catches of five species of common longhorn beetles (Cerambycidae), two species of regeneration weevils (Curculionidae), four species of bark beetles (Curculionidae: Scolytinae), and seven species of beetle predators and ectoparasites (Cleridae, Histeridae, Tenebrionidae, Trogossitidae, and Zopheridae) were higher in funnel traps with lures attached inside the funnels than in those with lures attached outside of the funnels. Catches of the remaining species were unaffected by lure placement. In no instance were catches of any species lower in funnel traps with lures attached inside the funnels than in those with lures attached outside of the funnels. For most species, catches in modified funnel traps with ethanol, alpha-pinene, ipsenol, and ipsdienol lures attached inside funnels were comparable with those in cross-vane panel traps. PMID- 23448034 TI - Reproductive traits of Glenea cantor (Coleoptera: Cerambycidae: Lamiinae). AB - Glenea cantor (F.) is a cerambycid species that attacks living trees of at least seven plant families in Asia, and has the potential to become an invasive pest. Here we investigated its reproductive biology in the laboratory to provide vital information for the development of pest control measures and preparation of pest risk analysis. Both sexes required a period of maturation feeding before mating, with the mean premating period of males (5.87 +/- 1.68 d) being significantly longer than that of females (4.59 +/- 2.34 d). This was a synovigenic species with the mean preoviposition and oviposition period being 13.50 +/- 3.15 d and 49.46 +/- 16.16 d, respectively. If no food was available after emergence, adult males died before reaching sexual maturation and females vanished before oviposition. Paired couples mated an average of 15.12 +/- 7.02 times; 28- to 53-d old beetles mated significantly more frequently than younger and older ones. The mean fecundity was 133.24 +/- 9.67 eggs. The oviposition rate significantly increased in the first 5 wk of the oviposition period, peaking when females were 40- to 54-d-old, and then significantly decreased in the following weeks. Reproductive activities occurred almost exclusively during the day, with most ovipositions taking place in the morning and matings in the afternoon with some overlaps. PMID- 23448035 TI - Population densities and tree diameter effects associated with verbenone treatments to reduce mountain pine beetle-caused mortality of lodgepole pine. AB - Mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae: Scolytinae), is among the primary causes of mature lodgepole pine, Pinus contorta variety latifolia mortality. Verbenone is the only antiaggregant semiochemical commercially available for reducing mountain pine beetle infestation of lodgepole pine. The success of verbenone treatments has varied greatly in previous studies because of differences in study duration, beetle population size, tree size, or other factors. To determine the ability of verbenone to protect lodgepole pine over long-term mountain pine beetle outbreaks, we applied verbenone treatments annually for 3 to 7 yr at five western United States sites. At one site, an outbreak did not develop; at two sites, verbenone reduced lodgepole pine mortality in medium and large diameter at breast height trees, and at the remaining two sites verbenone was ineffective at reducing beetle infestation. Verbenone reduced mountain pine beetle infestation of lodgepole pine trees in treated areas when populations built gradually or when outbreaks in surrounding untreated forests were of moderate severity. Verbenone did not protect trees when mountain pine beetle populations rapidly increase. PMID- 23448036 TI - Cone and seed pests of Pinus pinea: assessment and characterization of damage. AB - Cone and seed insects have played a key role in the decline of stone pine nut production in Italy. To evaluate the impact caused by native Palearctic and exotic insects, a greater knowledge of pest symptoms is required. During 2008 2009, first and second-year stone pine cones, as well as the seeds produced, were examined in Tuscany (Italy) to assess viability. Insect damage was characterized based on external signs on the cones and seed endosperms, and the impact of recorded insect species on nut production was evaluated. In the current study, cones attacked by anobiid beetles and Dioryctria spp. were observed, as well as asymptomatic dead cones and cones with resin drops and patches, that could not easily be related to a damaging agent. As regards the anobiid beetles, adults of Ernobius parens (Mulsant and Rey) and E. impressithorax Pic emerged from cones in laboratory rearing. A low number of cones damaged by Dioryctria spp. was recorded whereas high percentages of cones showed resin exudates. The presence of resin cannot be definitely related to a damaging agent, although the feeding activity of Leptoglossus occidentalis Heidemann could be one of the reasons. Damage by L. occidentalis was assessed by seed observation. Most of the seeds displayed tissues that had been damaged by this pest. PMID- 23448037 TI - Sanitation options for managing oak wood infested with the invasive goldspotted oak borer (Coleoptera: Buprestidae) in southern California. AB - Movement of invasive wood-boring insects in wood products presents a threat to forest health and a management challenge for public and private land managers. The goldspotted oak borer, Agrilus auroguttatus Schaeffer (Coleoptera: Buprestidae), is a new pest in San Diego and Riverside Cos., CA, believed to have been introduced on firewood. This beetle has caused elevated levels of oak mortality since 2002. From 2009-2011, we tested several sanitation methods, applicable to large and small land parcels, to reduce or prevent goldspotted oak borer emergence from infested oak wood. In most experiments, emergence of goldspotted oak borer adults from the positive controls demonstrated that the beetle could complete development in firewood-sized pieces of cut oak wood. In 2009, adult emergence from sun-exposed oak wood began and peaked 2- to 4-wks earlier at a low elevation site than at a high elevation site (late May to late June). However, there were no significant effects of elevation or host species on the emergence response of goldspotted oak borer by solarization treatment in this study. Solarization of infested wood with thick (6 mil) and thin (1 mil) plastic tarpaulins (tarps) did not significantly reduce emergence of adults despite recordings of greater mean and maximum daily temperatures in both tarped treatments and greater relative humidity in the thick-tarped treatment (all compared with nontarped controls). Grinding wood with a 3"-minus screen (< or = 7.6 cm) significantly reduced goldspotted oak borer emergence compared with control treatments, and this was the best method for reducing adult emergence among those tested. In a separate grinding study, no adults emerged when wood was ground to 9"-minus (22.9 cm), 2"-minus (5.1 cm), or 1"-minus (2.5 cm) screen sizes, but a low level of adult emergence from the positive controls limited any inferences from this experiment. Debarking cut wood pieces eliminated goldspotted oak borer emergence from the wood fraction, but adults emerged from the shaved bark and phloem. PMID- 23448038 TI - Efficacy of pesticide mixtures against the western flower thrips (Thysanoptera: Thripidae) under laboratory and greenhouse conditions. AB - Western flower thrips, Frankliniella occidentalis Pergande is a commonly encountered and economically important insect pest of greenhouses. Greenhouse producers typically apply pesticides as mixtures to mitigate western flower thrips populations; however, there is limited information available on the compatibility and efficacy of commonly used pesticide mixtures. This study assessed nine binary and three tertiary pesticide mixtures used in greenhouses which included pesticides containing abamectin, acephate, azadirachtin, bifenazate, bifenthrin, fenpropathrin, imidacloprid, novaluron, pymetrozine, and spinosad. Compatibility was determined for the binary pesticide mixtures using jar tests. In addition, the binary mixtures were applied to nine horticultural plant species to determine phytotoxicity based on visual appearance assessed 7 d after treatment. Bean-dip bioassays were performed in a laboratory using green bean (Phaseolus vulgaris L.) to determine LC50 values for each individual pesticide and the mixtures to establish whether the mixtures were synergistic, antagonistic, or there was no effect. The mortality of western flower thrips was assessed after 24 h, and LC50 values were calculated. Furthermore, semifield bioassays were performed in greenhouses for binary and tertiary mixtures to evaluate the efficacy (based on percent mortality) of the pesticide mixtures against western flower thrips. Results indicated that all binary mixtures were visibly compatible, and not phytotoxic to any of the plant species evaluated. Combination index calculations based on laboratory results indicated most of the binary mixtures were synergistic; however, the mixture containing spinosad + bifenazate appeared to be antagonistic against western flower thrips. The semifield bioassays demonstrated significantly reduced efficacy associated with mixtures containing azadirachtin, however, all binary mixtures provided approximately 80% western flower thrips mortality. PMID- 23448039 TI - Control of key pecan insect pests using biorational pesticides. AB - Key pecan insect pests include the black pecan aphid, Melanocallis caryaefoliae (Davis), pecan weevil, Curculio caryae (Horn), and stink bugs (Hemiptera: Pentatomidae). Alternative control tactics are needed for management of these pests in organic and conventional systems. Our objective was to evaluate the potential utility of several alternative insecticides including three plant extract formulations, eucalyptus extract, citrus extract-8.92%, and citrus extract-19.4%, and two microbial insecticides, Chromobacterium subtsugae (Martin et al.) and Isaria fumosorosea (Wize). In the laboratory, eucalyptus extract, citrus extract-8.92%, citrus extract-19.4%, and C. subtsugae caused M. caryaefoliae mortality (mortality was reached approximately 78, 83, and 96%, respectively). In field tests, combined applications of I. fumosorosea with eucalyptus extract were synergistic and caused up to 82% mortality in M. caryaefoliae. In laboratory assays focusing on C. caryae suppression, C. subtsugae reduced feeding and oviposition damage, eucalyptus extract and citrus extract-19.4% were ineffective, and antagonism was observed when citrus extract 19.4% was combined with the entomopathogenic nematode, Steinernema carpocapsae (Weiser). In field tests, C. subtsugae reduced C. caryae damage by 55% within the first 3d, and caused 74.5% corrected mortality within 7 d posttreatment. In the laboratory, C. subtsugae and eucalyptus extract did not cause mortality in the brown stink bug, Euschistus servus (Say). Applications of C. subtsugae for suppression of C. caryae, and eucalyptus extract plus I. fumosorosea for control of M. caryaefoliae show promise as alternative insecticides and should be evaluated further. PMID- 23448040 TI - Pheromone-based action thresholds for control of the swede midge, Contarinia nasturtii (Diptera: Cecidomyiidae), and residual insecticide efficacy in cole crops. AB - The swede midge, Contarinia nasturtii (Kieffer), is an invasive gall midge causing economic damage to cole crops (Brassica oleracea L.) and other crucifers in eastern Canada and United States. An effective decision-making tool for timing insecticide applications is a critical part of an integrated pest management program against C. nasturtii. Experiments were undertaken over 2 yr and at three locations in southern Ontario to develop pheromone-based action thresholds for C. nasturtii in cabbage and broccoli. An economic comparison between action threshold and calendar insecticide regimes was undertaken. The threshold approach was both economically viable and successful at minimizing swede midge damage for cabbage, and an action threshold of five males per trap per day with a minimum 7 d retreatment interval successfully reduced damage to acceptable levels. However, this approach was not successful with broccoli, which, unlike cabbage, is susceptible to damage by C. nasturtii through all plant stages, including heading. Acetamiprid and lambda-cyhalothrin both demonstrated approximately 7 d residual activity against C. nasturtii. Registration labels for both insecticides specify a minimum 7 d retreatment interval, which is supported by residual efficacy results. More effective insecticidal products may have longer residual efficacy and improve efficacy of the action threshold approach for broccoli and cabbage. PMID- 23448041 TI - Safety and acquisition potential of Metarhizium anisopliae in entomovectoring with bumble bees, Bombus terrestris. AB - In the context of integrated pest management with biological control and reduced pesticide use, dissemination of entomopathogenic fungi with insects has the potency to protect crops and specifically their flowers against pests and diseases. But before implementation of such entomovectoring system, a measurement of risks of the microbial biocontrol agent toward the vectoring insect is crucial. The essential contributions of this project are that 1) exposure of bumble bees, Bombus terrestris (L.) to powder containing 10(7) spores of the commercial biocontrol agent Metarhizium anisopliae strain F52 (Biol020) per gram, was safe; and 2) that when bumble bees had walked through this spore concentration (10(7) spores per gram) in a dispenser, their body carried 9.3 +/- 1 x 10(6) spores/bumble bee, and this was still 2.6 10(6) spores after a flight of 60 s, representing the average time to fly from the dispenser to the crop flowers. 3) In contrast, a 100-fold higher spore concentration (10(9) spores per gram powder) was highly toxic and the acquisition on the bumble bee body was only 2.5 times higher. Based on these data, future studies can start investigating the protection efficacy of this entomovector system with M. anisopliae and bumble bees without harming the vector and with a loading of the vector considered enough to obtain a good inoculation into and protection of the flowers. PMID- 23448042 TI - Host plant preference of harlequin bug (Hemiptera: Pentatomidae), and evaluation of a trap cropping strategy for its control in collard. AB - Harlequin bug, Murgantia histrionica (Hahn) (Hemiptera: Pentatomidae), is a piercing-sucking pest of cole crops, causing cosmetic damage in low populations, while heavy pest pressure can kill plants or entire fields. Field studies were conducted to evaluate a trap crop for control of harlequin bug in collard. Field cage choice tests found that potential trap crop plant species, mustard (Brassica juncea 'Southern Giant Curled'), rapeseed (B. napus 'Athena'), rapini (B. rapa), and arugula (Eruca satica) attracted more harlequin bugs than collard (B. oleracea 'Champion') and a nonbrassica control, bean (Phaseolus vulgaris'Bronco'). Mustard was the most consistently selected by harlequin bug over collard in choice tests, and was found to be an effective trap crop for reducing feeding injury on collard at two experimental sites. Augmentation of the mustard trap crop with a systemic, neonicotinoid insecticide provided no added control of harlequin bug for the 10 wk duration in the spring season. PMID- 23448043 TI - Ethanol injection of ornamental trees facilitates testing insecticide efficacy against ambrosia beetles (Coleoptera: Curculionidae: Scolytinae). AB - Exotic ambrosia beetles are damaging pests in ornamental tree nurseries in North America. The species Xylosandrus crassiusculus (Motshulsky) and Xylosandrus germanus (Blandford) are especially problematic. Management of these pests relies on preventive treatments of insecticides. However, field tests of recommended materials on nursery trees have been limited because of unreliable attacks by ambrosia beetles on experimental trees. Ethanol-injection of trees was used to induce colonization by ambrosia beetles to evaluate insecticides and botanical formulations for preventing attacks by ambrosia beetles. Experiments were conducted in Ohio, Tennessee, and Virginia. Experimental trees injected with ethanol had more attacks by ambrosia beetles than uninjected control trees in all but one experiment. Xylosandrus crassiusculus and X. germanus colonized trees injected with ethanol. In most experiments, attack rates declined 8 d after ethanol-injection. Ethanol-injection induced sufficient pressure from ambrosia beetles to evaluate the efficacy of insecticides for preventing attacks. Trunk sprays of permethrin suppressed cumulative total attacks by ambrosia beetles in most tests. Trunk sprays of the botanical formulations Armorex and Veggie Pharm suppressed cumulative total attacks in Ohio. Armorex, Armorex + Permethrin, and Veggie Pharm + Permethrin suppressed attacks in Tennessee. The bifenthrin product Onyx suppressed establishment of X. germanus in one Ohio experiment, and cumulative total ambrosia beetle attacks in Virginia. Substrate drenches and trunk sprays of neonicotinoids, or trunk sprays of anthranilic diamides or tolfenpyrad were not effective. Ethanol-injection is effective for inducing attacks and ensuring pressure by ambrosia beetles for testing insecticide efficacy on ornamental trees. PMID- 23448044 TI - Do weaver ant (Hymenoptera: Formicidae) marks affect mango internal quality and storage life? AB - In implementing the integrated pest management mango (Mangifera indica L.) program using weaver ants (Oecophylla smaragdina F.) as a major component in the Northern Territory of Australia, we received a number of questions from farmers and extension officers asking whether weaver ant marks reduce internal fruit quality and induce fruit rot, which is economically important. However, this issue has not been investigated. Soluble sugar content in fruits with and without weaver ant marks and observations on the storage of fruits with the ant marks were recorded in 2002 and 2003. The sugar contents were, in general, higher on the side of the fruit with a relatively large area of ant marks than on the side with a smaller area of ant marks, irrespective of whether fruits were exposed to the sun or not. The field experiment showed that sugar content was generally higher in the treatment with weaver ants plus soft chemicals than in the insecticide treatment. For the storage of fruits bearing weaver ant marks, no signs of diffuse rot from any ant marks were observed, but fruit skin without the ant marks developed a considerable number of dark open lenticels, most of which developed to rot marks and patches. These results suggest that weaver ant marks are positively correlated with internal fruit quality, do not induce fruit rot and can be used as an indicator of better fruit quality and safety. PMID- 23448045 TI - Attraction of pollinators to atemoya (Magnoliales: Annonaceae) in Puerto Rico: a synergistic approach using multiple nitidulid lures. AB - Atemoya, a hybrid between Annona squamosa (L.) and A. cherimola Miller (Annonaceae), has potential to be a major fruit crop in tropical and subtropical areas. A major setback to fruit production throughout the world is low fruit-set because of inadequate pollinator visits, typically Nitidulidae beetles. We identified beetle visitors to atemoya flowers in an orchard in Puerto Rico and used Universal moth traps to monitor the attractiveness of two commercially available Nitidulidae lures. The most common visitors to atemoya flowers were an unidentified Europs species (Coleoptera: Monotomidae), followed by Loberus testaceus (Coleoptera: Erotylidae), neither of which have been previously reported as visitors to Annona flowers. The commercial lures attracted few or no beetles when used separately, but attracted a large number of beetles, especially Carpophilus dimidiatus (Coleoptera: Nitidulidae) and Europs, when used in combination. This attraction is synergistic and increases with dose at the doses assayed (0-4 lures), and decreases over time with >50% of trap captures occurring in the first week and no beetles collected after 5 wk. This is the first report of aggregation pheromone lures in nitidulids acting synergistically to attract other species, including beetles not in the Nitidulidae. The results are discussed as they pertain to increasing fruit set, as well as the potential for altering fruit size and shape in atemoya. PMID- 23448046 TI - Predicting habitat suitability of Coptotermes gestroi (Isoptera: Rhinotermitidae) with species distribution models. AB - Coptotermes gestroi (Wasmann) is an important structural pest reported from Asia, Pacific islands, North America, Caribbean islands, South America, and Indian Ocean islands. This study summarized previous records of C. gestroi and its synonyms, presenting 184 infested counties from 24 countries. Based on the geo references occurrence locations and global raster data of climate, geography, and human population, C. gestroi were found most commonly in warm, high precipitation, low altitude, and human populated areas. By using species distribution models, we predicted its current infested area (model 1), habitat suitability (model 2), and probability of introduction (model 3) on a global scale. The results showed its recorded locations and the predicted distribution of the present day are similar, but the suitable habitat is larger than its current distribution. The patterns of the introduction frequency (model 3) and habitat suitability (model 2) are inconsistent. Temperate cities with high introduction risk are located in Europe, United Sates, northeastern China, and Japan where habitat suitability is low and hence successful colonization is unlikely. In tropics and subtropics, habitat suitability of C. gestroi is high. We speculate that continuous urbanization and increasing human population will increase its introduction frequency and cause further extension in fast developing tropical and subtropical countries. PMID- 23448047 TI - Mulch preferences of the Asian cockroach (Dictyoptera: Blattellidae). AB - Mulch preferences of the Asian cockroach, Blattella asahinai Mizukubo, were determined in a series of laboratory experiments. Because this species is a peridomestic pest, mulch preferences may be a key part of an integrated pest management program for homeowners. Five mulches were used: cypress, oak leaf litter, pine straw, rubber, and topsoil. Large arena experiments showed that adult male Asian cockroaches preferred oak leaf litter and pine straw, while adult females preferred oak leaf litter and rubber mulches. Nymphal stages preferred rubber (48.3-62.5% for small and medium instars, respectively) to all other mulches. All stages of the Asian cockroach showed very little preference to topsoil (0%) and cypress mulch (6.3%). Ebeling choice box tests confirmed lack of preference or repellency of adult males to topsoil (17.8 +/- 3.6%) and rubber mulch (15.7 +/- 3.6%). Continuous exposure experiments indicated that pine straw was significantly more toxic to adult males than other mulches (66.7 +/- 18.4% mortality at 7 d). Mulch preferences of the Asian cockroach may be mediated by characteristics of the interstitial spaces in the different mulches. Rubber mulch afforded smaller, more humid spaces that were inaccessible to adults. Because cypress mulch was least preferred by nymphs and adults, use of cypress mulch in an integrated pest management program around homes may help to reduce Asian cockroach populations and limit insecticide exposure to humans, animals, and the environment. PMID- 23448048 TI - International field trials of pyrethroid-treated wood exposed to Coptotermes acinaciformis in Australia and Coptotermes formosanus (Isoptera: Rhinotermitidae) in China and the United States. AB - Coptotermes Wasmann is one of the most important genera of wood-destroying insect pests, both in its native and introduced countries. Pyrethroids are among the most widely used insecticides in wood preservation around the world. Consequently, they have often been evaluated against different species of Coptotermes. However, because various test methods have been used between countries, comparing results is problematic. These field trials, using a single aboveground method of exposure, assessed a range of retentions of two pyrethroids (bifenthrin and permethrin) in Pinus radiata D. Don sapwood against two species of Coptotermes in three countries to provide directly comparable results. Coptotermes acinaciformis (Froggatt) in Australia consumed the most nontreated wood, followed by Coptotermes formosanus Shiraki in China, then C. formosanus in the United States, although these data were not significantly different. Both termite species demonstrated a dose-response to wood treated with the two pyrethroids; less wood was consumed as retention increased. Overall, C. acinaciformis consumed relatively little of the treated wood. In comparison, C. formosanus consumed 20-90% of the wood treated at the lowest retentions of the pyrethroids evaluated. Results indicated that C. acinaciformis was more sensitive to pyrethroid toxicity/repellency compared with C. formosanus. Factors that may have influenced the results are discussed. However, using a single aboveground method of exposure across three countries, that suited both species of Coptotermes, made it possible to determine unambiguously the actual differences between the species in their tolerances to the two pyrethroid insecticides. PMID- 23448049 TI - Influence of environmental factors on activity patterns of Incisitermes minor (Isoptera: Kalotermitidae) in naturally infested logs. AB - Acoustic emission (AE) activity patterns were measured from seven loquat [Eriobotrya japonica (Thunb.) Lindl.] logs, five containing live western drywood termite [Incisitermes minor (Hagen)] infestations, and two without an active drywood termite infestation. AE activity, as well as temperature, were monitored every 3 min under unrestricted ambient conditions in a small wooden building, under unrestricted ambient conditions but in constant darkness, or in a temperature-controlled cabined under constant darkness. Logs with active drywood termite infestations displayed similar diurnal cycles of AE activity that closely followed temperature with a peak of AE activity late in the afternoon (1700-1800 hours). When light was excluded from the building, a circadian pattern continued and apparently was driven by temperature. When the seven logs were kept at a relatively constant temperature (approximately 23 +/- 0.9 degrees C) and constant darkness, the pattern of activity was closely correlated with temperature, even with minimal changes in temperature. Temperature is the primary driver of activity of these drywood termites, but the effects are different when temperature is increasing or decreasing. At constant temperature, AE activity was highly correlated with the number of termites in the logs. The possible implications of these findings on our understanding of drywood termite biology and how this information may affect inspections and posttreatment evaluations are discussed. PMID- 23448050 TI - Evaluation of an insecticide dust band treatment method for controlling bed bugs. AB - Current bed bug, Cimex lectularius L., control usually involves insecticide applications that pose a high risk of insecticide exposure to residents and applicators. To minimize these risks and the amount of insecticides used, we designed and evaluated a dust band treatment technique. The laboratory assay showed that 1% cyfluthrin dust treated bands are highly effective in killing bed bugs. We further evaluated this technique in bed bug infested apartments. The "dust band" treatment consisted of installing a 3.8-cm-wide fabric band on furniture legs and brushing Tempo dust (1% cyfluthrin) (Bayer Environmental Science, Research Triangle Park, NC) onto the bands. In addition, interceptors were installed under furniture legs. Alpine (0.5% dinotefuran) aerosol spray was applied directly to live bed bugs found on furniture during biweekly inspections. This treatment was compared with two other treatments: "integrated pest management" (IPM) and "control." The IPM treatment included dust bands plus the following: applying hot steam to infested furniture and surrounding areas, installing mattress encasements, applying 1% cyfluthrin dust around room perimeters, and installing interceptors under furniture legs. Alpine aerosol was applied to live bed bugs found during biweekly inspections. In the control group, the apartments received cursory treatment with insecticide sprays by the existing pest control contractor hired by the property management office. Bed bug numbers before and after treatments were determined based on biweekly interceptor counts or a combination of interceptor counts and visual inspections. From 0 to 12 wk, mean bed bug counts of the dust band, IPM, and the control treatment decreased by 95, 92, and 85%, respectively. Both dust band and IPM resulted in higher bed bug reduction than the control. There was no significant difference in the final counts between dust band and IPM treatments. An additional field experiment showed installing 1% cyfluthrin dust band and interceptors in lightly infested apartments prevented bed bug population rebound. Results indicate applying insecticide dust bands to furniture legs is an effective bed bug control technique. PMID- 23448051 TI - Insecticide toxicity to oriental fruit fly Bactrocera dorsalis (Diptera: Tephritidae) is influenced by environmental factors. AB - In this study, we investigated the effects of environmental factors (temperature, dose, dietary source, and feeding density) on the insecticide tolerance of Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). The results indicated that the toxicities of trichlorphon and abamectin to B. dorsalis increased with an increase in temperature. At 15-35 degrees C, the toxicity of beta-cypermethrin decreased with an increase in temperature at low doses (0.82 and 1.86 mg/L), but was similar at a high dose (4.18 mg/L). These results demonstrated that the temperature coefficient of beta-cypermethrin was related to both temperature and dosage. The insecticide sensitivity of B. dorsalis reared on different dietary sources was significantly different. Trichlorphon sensitivity of B. dorsalis fed on banana was the highest with an LC50 of 1.61 mg/L, followed by on apple, carambola, semiartificial diet, pear, mango, guava, orange, and papaya. With an increasing feeding density, the sensitivity of B. dorsalis adults to trichlorphon increased, while the sensitivities of B. dorsalis adults to abamectin and beta cypermethrin decreased. The differences between LC50 values of insects reared at densities of 10 and 13 eggs/g of semiartificial diet to trichlorphon, abamectin and beta-cypermethrin were not significant. This result suggested that representative toxicity could be obtained by using adults developed at a feeding density between 10-13 eggs/g of semiartificial diet. Adult body weight was positively correlated with the LC50 value of trichlorphon, but was negatively correlated with the toxicities of abamectin and beta-cypermethrin. These results suggested that the effects of adult body weight on the toxicity of insecticides were different among different chemicals. PMID- 23448052 TI - Comparison of pyrethroid resistance in adults and larvae of Culex pipiens pallens (Diptera: Culicidae) from four field populations in China. AB - The susceptibility of adults and larvae from four field populations of Culex pipiens pallens (Coguillett) (Diptera: Culicidae) in China to deltamethrin, beta cypermethrin, and permethrin was investigated using the World Health Organization standard susceptibility test methods. One to 2 d old nonblood fed female mosquitoes emerged from pupae resulting from wild-caught larvae (F1 laboratory reared adults) were exposed to various doses of the pyrethroids. The larval bioassay was conducted using a range of concentrations to determine the LC50 values. Using allele-specific polymerase chain reaction, the frequency of the kdr resistance gene was determined in each population. The bioassay data indicated that deltamethrin was the most active larvicide in all four populations with resistance ratios (RR) of 1.6-3.9-fold. This was followed by beta-cypermethrin with RR of 1.1-3.3-fold, while larvae from three mosquito populations from Beijing, Jinan, and Kaifeng had developed resistance to permethrin with RR of 12.6-, 24.0-, and 18.8-fold, respectively. The overall RR of larvae for all insecticides in ascending order was Changchun < Beijing < Kaifeng < Jinan; and ranking of the adult mortality was Changchun < Jinan = Kaifeng < Beijing. For the three pyrethroids tested, the correlation coefficient among the three test methods on the four populations and one lab strain was quite weak. The R value was 0.113-0.320 when we compared kdr detection for kdr% with LC50, -0.565 to 0.793 when kdr% versus adult mortality test, and -0.750 to 0.505 for LC50 versus adult mortality. Permethrin showed the best correlation (R = -0.793) between kdr frequency and adult mortality. This indicates that levels of susceptibility changes to an insecticide should not be based on a single method of assessment. PMID- 23448053 TI - Insecticide resistance and malaria vector control: the importance of fitness cost mechanisms in determining economically optimal control trajectories. AB - The evolutionary dynamics of insecticide resistance in harmful arthropods has economic implications, not only for the control of agricultural pests (as has been well studied), but also for the control of disease vectors, such as malaria transmitting Anopheles mosquitoes. Previous economic work on insecticide resistance illustrates the policy relevance of knowing whether insecticide resistance mutations involve fitness costs. Using a theoretical model, this article investigates economically optimal strategies for controlling malaria transmitting mosquitoes when there is the potential for mosquitoes to evolve resistance to insecticides. Consistent with previous literature, we find that fitness costs are a key element in the computation of economically optimal resistance management strategies. Additionally, our models indicate that different biological mechanisms underlying these fitness costs (e.g., increased adult mortality and/or decreased fecundity) can significantly alter economically optimal resistance management strategies. PMID- 23448054 TI - Current status of insecticide resistance in Helicoverpa armigera after 15 years of Bt cotton planting in China. AB - Insecticide resistance was an important factor responsible for outbreaks of Helicoverpa armigera (Hubner) in China in the early 1990s. Bt cotton has been adopted in China since 1997, and has resulted in a reduction of insecticide use for H. armigera control. After 15 yr of Bt cotton planting, in 2011 we surveyed resistance to fenvalerate, phoxim, and emamectin benzoate in 16 field populations of H. armigera collected from major cotton production areas of China. Fourteen populations from northern China showed very strong resistance to fenvalerate (from 43- to 830-fold) and low levels of resistance to phoxim (3.0- to 8.9-fold) when compared with the susceptible SCD strain of H. armigera, whereas two populations from northwestern China showed low levels of resistance to fenvalerate (3.0- and 10-fold) and no resistance to phoxim (0.7- and 0.9-fold). Synergist bioassays demonstrated that oxidase-based detoxification was involved in fenvalerate resistance and esterase-based detoxification in phoxim resistance in the resistant field populations. In comparison with the resistance in field populations before Bt cotton adoption, we observed a maintenance of high levels of fenvalerate resistance, but a reversion of phoxim resistance from high levels to low levels in the field populations of H. armigera from northern China. All 16 field populations from both northern China and northwestern China were susceptible to emamectin benzoate (with about two-fold variations in LD50s among populations), but the SCD strain has an inherent tolerance of 11-fold compared with the most susceptible field population (Xiajin-1). Emamectin benzoate is not cross resistant to fenvalerate and may provide an alternative option for H. armigera control in China, if the efficacy of Bt cotton is compromised by Bt resistance in the field. PMID- 23448055 TI - Risk assessment for Helicoverpa zea (Lepidoptera: Noctuidae) resistance on dual gene versus single-gene corn. AB - Recent Environmental Protection Agency (EPA) decisions regarding resistance management in Bt-cropping systems have prompted concern in some experts that dual gene Bt-corn (CrylA.105 and Cry2Ab2 toxins) may result in more rapid selection for resistance in Helicoverpa zea (Boddie) than single-gene Bacillus thuringiensis (Bt)-corn (CrylAb toxin). The concern is that Bt-toxin longevity could be significantly reduced with recent adoption of a natural refuge for dual gene Bt-cotton (CrylAc and Cry2Ab2 toxins) and concurrent reduction in dual-gene corn refuge from 50 to 20%. A population genetics framework that simulates complex landscapes was applied to risk assessment. Expert opinions on effectiveness of several transgenic corn and cotton varieties were captured and used to assign probabilities to different scenarios in the assessment. At least 350 replicate simulations with randomly drawn parameters were completed for each of four risk assessments. Resistance evolved within 30 yr in 22.5% of simulations with single-gene corn and cotton with no volunteer corn. When volunteer corn was added to this assessment, risk of resistance evolving within 30 yr declined to 13.8%. When dual-gene Bt-cotton planted with a natural refuge and single-gene corn planted with a 50% structured refuge was simulated, simultaneous resistance to both toxins never occurred within 30 yr, but in 38.5% of simulations, resistance evolved to toxin present in single-gene Bt-corn (CrylAb). When both corn and cotton were simulated as dual-gene products, cotton with a natural refuge and corn with a 20% refuge, 3% of simulations evolved resistance to both toxins simultaneously within 30 yr, while 10.4% of simulations evolved resistance to CrylAb/c toxin. PMID- 23448056 TI - Dynamic insecticide susceptibility changes in Florida populations of Diaphorina citri (Hemiptera: Psyllidae). AB - Five field populations of Diaphorina citri Kuwayama from various regions of Florida were evaluated in 2011 for resistance to commonly used insecticides. Three diagnostic doses (LD50, LD75, and LD95), developed in 2009 using a laboratory susceptible population, were used to measure changes in susceptibility levels of field-collected populations as compared with a susceptible laboratory population. Further reductions in the susceptibility levels of D. citri to chlorpyriphos and fenpropathrin were determined, compared with results obtained in 2010. Mean percent mortality obtained from all five locations was significantly lower than observed with the laboratory susceptible population for all insecticides tested. Previously, expression of five CYP4 genes was implicated in contributing to insecticide metabolism in D. citri. In the current study, we compared the relative expression of these five CYP4 genes and their associated levels of protein expression among field-collected and laboratory susceptible populations. Expression of all CYP4 genes investigated was higher in field collected populations when normalized against the laboratory susceptible population. There was an increased signal of a band corresponding to a 45 kDa protein in four of the five field populations as measured by the Western blot assay, which suggests increased production of cytochrome P450 enzymes. The current results indicate that insecticide resistance continues to increase in Florida populations ofD. citri, particularly to chlorpyriphos and fenpropathrin. However, there was no further decrease in susceptibility of Florida populations of D. citri to neonicotinoid insecticides in 2011 as compared with previous years. PMID- 23448057 TI - Survey of resistance to four insecticides and their associated mechanisms in different genotypes of the green peach aphid (Hemiptera: Aphididae) from Chile. AB - The green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae) is amajor pest of agriculture worldwide that has proved to be particularly adept at evolving insecticide resistance. Several mechanisms that confer resistance to many insecticide types have been described in M. persicae. We measured the resistance status of nine multilocus genotypes (MLGs) of this aphid species collected in Chile. MLGs were identified using microsatellite markers, and these MLG clonal populations were measured for the presence of modified acetylcholinesterase (MACE), kdr and super kdr mutations, and enhanced carboxyl esterase activity. Toxicological bioassays were used to estimate aphid LC50 when treated with metamidophos (organophosphate), pirimicarb (dimethyl carbamate), cyfluthrin (pyrethroid), and imidacloprid (neonicotinoid). Two MLGs presented >20 fold resistance to pirimicarb, which was associated with the MACE mutation in the heterozygous condition. The kdr mutation was found in only four MLGs in the heterozygous condition and they showed resistance ratios (RR) to cyfluthrin of less than sevenfold. The super kdr mutation was not detected. Enhanced carboxyl esterase activity was predominantly found in the susceptible (S) to first level of resistance (R1) with RR to metamidophos less than eight-fold. Finally, RR to imidacloprid was also less than eight-fold in all MLGs tested. A few MLGs with resistance to pirimicarb were found, while susceptibility to cyfluthrin, metamidophos and imidacloprid was still predominant. A significant positive correlation between imidacloprid tolerance with pirimicarb resistance was detected, as well as between imidacloprid and metamidophos tolerance. With the increase in the use of neonicotinoid insecticides, better rotation of insecticides with different modes of action will be necessary to prevent further development of M. persicae insecticide resistance in Chile. PMID- 23448058 TI - Application of cytochrome oxidase I sequences for phylogenetic analysis and identification of thrips species occurring on vegetable crops. AB - Thrips are direct pests as well as vectors of important viruses infecting crop plants. One of the major constraints in studying the relationship between thrips vectors and tospoviruses is the difficulty of identifying the vector species because of high intraspecific variation among thrips populations. Molecular approaches have been used to identify species differences. In this study, partial cytochrome oxidase I (COI) sequences were used to understand the phylogenetic relationship among thrips populations, and assess their usefulness to identify and classify unknown thrips species collected from different crops. In total, 29 COI variants were obtained while examining the sequence polymorphisms in COI of 182 insects analyzed in this study, which were collected from six countries on tomato, chilli, onion, cabbage, cucumber, watermelon, Ethiopian mustard, French bean, and peanut. The phylogenetic analysis showed that the insects used in this study clustered with five distinct species-groups designated as Thrips palmi group, T. tabaci group, Frankliniella occidentalis group, Scirtothrips dorsalis group and an unclassified group. Higher intraspecific genetic variation was observed in S. dorsalis and T. palmi followed by T. tabaci and F. occidentalis. Thus, it was confirmed that the COI gene could be useful in grouping different thrips species and genera that coexist in a particular cropping system. PMID- 23448059 TI - Validation of the 16S rDNA and COI DNA barcoding technique for rapid molecular identification of stored product psocids (Insecta: Psocodea: Liposcelididae). AB - Psocids are serious storage pests, and their control is hampered by the fact that different species respond differently to insecticides used for the control of stored-product insect pests. Additionally, psocids of genus Liposcelis that are commonly associated with stored-products are difficult to identify using morphological characteristics. The goal of this study was to validate molecular identification of stored-product psocids of genus Liposcelis based on 16S rDNA and cytochrome oxidase I (COI) DNA barcoding. Unidentified liposcelids (Liposcelis DK) imported from Denmark to China were compared with 14 population samples of seven common species (L. bostrychophila, L. brunnea, L. corrodens, L. decolor, L. entomophila, L. mendax, and L. paeta). The explored species (DK) liposcelids shared >98% sequence similarity for both the 16S rDNA and COI genes with the reference L. corrodens samples (98.32 and 98.94% for 16S rDNA and COI, respectively). A neighbor-joining tree revealed that the explored DK sample and the reference L. corrodens samples belong to the same clade. These molecular results were verified by morphological identification of DK specimens, facilitated by SEM microphotography. The DNA barcoding method and the neighbor joining phylogenetic analyses indicated that both the 16S rDNA and COI genes were suitable for Liposcelis species identification. DNA barcoding has great potential for use in fast and accurate liposcelid identification. PMID- 23448060 TI - Phylogenetic analysis of the alfalfa weevil complex (Coleoptera: Curculionidae) in North America. AB - The Eastern, Western, and Egyptian strains of alfalfa weevil are pests introduced to North America on three separate occasions, now they share partially overlapping geographic ranges, covering most of the continental United States. Behavior, susceptibility to parasites, and subtle morphological differences separate the strains. The difficulty in differentiating among these strains morphologically has led to the application of molecular phylogeny approaches including restriction fragment-length polymorphism characterization and sequencing of mitochondrial genes. While valuable for strain identification, this approach cannot identify interstrain hybrids because mitochondrial markers are maternally inherited. The work reported here extends previous findings by comparing over 7 Kb of sequence from two mitochondrial and four nuclear loci to increase the resolution of molecular phylogeny for these weevils. The related clover leaf weevil, also an occasional pest of alfalfa, was included in the analysis because the molecular phylogeny of this weevil has not been examined to date. Analysis of nuclear loci indicate that the clover weevil is a distinct species. Furthermore, while the three alfalfa weevil strains are separable based on mitochondrial sequence data they cannot be separated using nuclearloci suggesting that they are all recently diverged members of the same species. These data refine the relationships among these strains and may find application in design of better control strategies. PMID- 23448061 TI - Molecular diagnosis of populational variants of Anthonomus grandis (Coleoptera: Curculionidae) in North America. AB - The utility of the cytochrome oxidase I (COI) DNA sequence used for DNA barcoding and a Sequence Characterized Amplified Region for diagnosing boll weevil, Anthonomus grandis Boheman, variants was evaluated. Maximum likelihood analysis of COI DNA sequences from 154 weevils collected from the United States and Mexico supports previous evidence for limited gene flow between weevil populations on wild cotton and commercial cotton in northern Mexico and southern United States. The wild cotton populations represent a variant of the species called the thurberia weevil, which is not regarded as a significant pest. The 31 boll weevil COI haplotypes observed in the study form two distinct haplogroups (A and B) that are supported by five fixed nucleotide differences and a phylogenetic analysis. Although wild and commercial cotton populations are closely associated with specific haplogroups, there is not a fixed difference between the thurberia weevil variant and other populations. The Sequence Characterized Amplified Region marker generated a larger number of inconclusive results than the COI gene but also supported evidence of shared genotypes between wild and commercial cotton weevil populations. These methods provide additional markers that can assist in the identification of pest weevil populations but not definitively diagnose samples. PMID- 23448062 TI - Molecular cloning, characterization, and mRNA expression of two Cryptochrome genes in Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Light is a major environmental signal for insect circadian. In this study, we isolated two cryptochrome (cry) genes from Helicoverpa armigera (Hubner) by reverse transcription polymerase chain reaction and RACE-PCR strategies, designated as Ha-cryl (GenBank accession GQ896502) and Ha-cry2 (GenBank accession GQ896503). Ha-CRY1 encoded a fly-like protein of 548 amino acids, while Ha-CRY2 encoded a mammal-like protein of 657 amino acids. Both of these proteins had two conserved domains: a DNA photolyase domain and a flavin adenine dinucleotide (FAD) binding seven domain, and alignment of the amino acid sequence indicated that there was a high degree of homology between the CRYs of H. armigera and other insects. Real-time polymerase chain reaction revealed that: 1) Ha-cry1 and Ha-cry2 mRNA expressions were neither organ-specific nor developmental-stage specific. 2) Under the light-dark cycle (16:8 L:D), Ha-cry1 abundance tended to increase during the day, then decrease in the night, whereas the expression pattern of Ha-cry2 was opposite. 3) The cyclings of Ha-cry1 and Ha-cry2 expression were disturbed by constant light and darkness. Our study has significant importance for the further study of the functions of the Ha-cry genes and potential control of the cotton bollworm. PMID- 23448063 TI - DNA-based identification of spider mites: molecular evidence for cryptic species of the genus Tetranychus (Acari: Tetranychidae). AB - Spider mites are difficult to identify because they are very small and have a limited number of diagnostic characters. Most species of the spider mite genus Tetranychus in Japan are morphologically similar, differing only in the diameter of the aedeagal knob in males. Because this genus contains many important pests, the unambiguous identification of species is crucial for effective pest management and quarantine procedures. DNA-based methods could complement the morphological methods. We examined whether Tetranychus species in Japan could be identified by DNA sequences using the internal transcribed spacer region of nuclear ribosomal DNA and the cytochrome c oxidase subunit I gene of mitochondrial DNA. We determined sequences of the 13 known Tetranychus species in Japan. We could identify 10 of the 13 species in the internal transcribed spacer tree. In the cytochrome c oxidase subunit I tree, we could identify all 13 known Tetranychus species in Japan. Although Tetranychus kanzawai Kishida and T. parakanzawai Ehara were identified by DNA sequences, they were clearly separated into two monophyletic clades each, indicating that a cryptic species existed in each species. PMID- 23448064 TI - Characterization of antibiosis and antixenosis to the woolly poplar aphid (Hemiptera: Aphididae) in the bark of different poplar genotypes. AB - The woolly poplar aphid, Phloeomyzus passerinii (Signoret) (Hemiptera: Aphididae), is a major pest of poplar plantations in the Mediterranean basin and the Near East. Aphids colonize poplar trunks and feed upon the cortical parenchyma. Despite the economic importance of poplar, little is known about the mechanisms involved in poplar resistance to this pest. However, Populus x canadensis Moench genotypes show various levels of resistance to P. passerinii. This study has investigated the type of poplar resistance (antibiosis or antixenosis) by assessing aphid settlement, physiology (survival, development, and reproduction), and stylet penetration behavior (electrical penetration graph) on three P. x canadensis genotypes; '1214' (susceptible), 'Brenta' (resistant), and '145/51' (intermediate). Because settlement was reduced, the highly resistant genotype Brenta exhibited surface antixenosis. In addition, nymphal survival was null on Brenta, and twice less adult aphid initiated a sustained intracellular phase in the cortical parenchyma of that genotype compared with the other two genotypes. Thus, Brenta also showed parenchyma-located antixenosis coupled with antibiosis characteristic. In contrast, P. passerinii had no difficulty to initiate a sustained ingestion in the cortical parenchyma of the intermediate genotype 145/51, but decreased fecundity and lower intrinsic rate of natural increase were clear expressions of antibiosis. PMID- 23448065 TI - Pheromone-based monitoring of Pseudococcus maritimus (Hemiptera: Pseudococcidae) populations in concord grape vineyards. AB - The grape mealybug, Pseudococcus maritimus (Ehrhorn), is the dominant mealybug in Washington's Concord grape vineyards (Vitis labrusca L.). It is a direct pest of fruit clusters and a vector of grapevine leafroll-associated viruses. Using traps baited with the sex pheromone of Ps. maritimus, we determined the optimal trap density for monitoring Ps. maritimus, with the goal of providing a more rapid monitoring method for Ps. maritimus than visual surveys. Varying densities of pheromone-baited traps (one, four, and eight traps per 12.14 ha) were deployed in Concord vineyards to monitor Ps. maritimus seasonal phenology in 2010 and 2011. In both years, flights of adult males were detected in early May and captures peaked twice per season in mid-June and mid-August, indicating two generations each year. Trap data were analyzed using Taylor's Power Law, Iwao's patchiness regression, and the K parameter of the negative binomial model to determine optimal sample size. The formula using the K parameter provided the lowest required sample size, showing that four to eight traps per 12.14 ha were needed to provide 30% sampling precision efficiency throughout the entire season. Fewer traps were needed during flight peaks when trap capture numbers were great. Only one pheromone-baited trap per 12.14 ha was sufficient to provide Ps. maritimus flight phenology data to make informed management decisions. Species-specific pheromone-baited traps deployed for Planococcus ficus (Signoret), Pseudococcus longispinus (Targioni Tozzetti), and Pseudococcus viburni (Signoret) did not detect any of these species in the vineyards sampled. PMID- 23448066 TI - Weight loss and germination failure caused by psocids in different wheat varieties. AB - We investigated weight loss caused by Liposcelis entomophila (Enderlein) feeding in damaged (cracked) and intact kernels of 'Jagger' variety of hard red winter wheat over a 90-d period at 30 +/- 1 degrees C and 75 +/- 5% relative humidity. L. entomophila caused 8.5% weight loss in damaged wheat kernels, which was significantly greater than the weight loss found in intact wheat kernels (0.2%). We also evaluated the suitability of six wheat varieties commonly grown in Oklahoma, namely, Jagger, 'Endurance,' 'Overley,' 'Jagalene,' 'OK Bullet,' and 'Deliver' to support populations of four psocid species, namely, Liposcelis bostrychophila Badonnel, L. decolor (Pearman), L. entomophila, and L. paeta Pearman over a 30-d period. The greatest population increase was observed in L. bostrychophila followed by L. paeta. Subsequently, weight loss of damaged and intact wheat kernels and germination of intact kernels infested by L. paeta over a 45-d period were assessed in OK Bullet variety. L. paeta caused weight loss of 3.3% in damaged kernels, which was significantly greater than the weight loss found in intact kernels (0.4%). Based on our data, 40% of infested intact kernels failed to germinate after 45 d of infestation by L. paeta, but this decreased to 32% when adjusted using germination failure of uninfested kernels. Our data show that psocid infestations do not only cause considerable loss in weight of wheat, but also result in significant germination failure. These data call for the formulation of effective integrated psocid management strategies for stored wheat to mitigate the negative impacts of psocid pests. PMID- 23448067 TI - Tribolium castaneum (Coleoptera: Tenebrionidae) associated with rice mills: fumigation efficacy and population rebound. AB - The red flourbeetle, Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae), is the most important stored-product insect pest infesting rice (Oryza sativa L.) mills in the United States. Due to the phasing out of methyl bromide in accordance with the 1987 Montreal Protocol, the efficacy of alternative fumigants in controlling flour beetles in mill structures must be evaluated. Long-term trapping data sets (2-6 yr) of T. castaneum in and around seven rice mills were analyzed to assess the efficacy of sulfuryl fluoride fumigation (n = 25). Fumigation efficacy was evaluated as the percentage reduction in mean trap captures of adults and proportion of traps capturing at least one adult beetle. Beetle trap captures fluctuated seasonally, with increased captures during the warmer months, June-September, that dropped off during the cooler months, October March. Fumigations resulted in a 66 +/- 6% (mean +/- SE) reduction in mean trap captures within mills and a 52 +/- 6% reduction in the proportion of traps capturing at least one adult beetle. Lengths of time for captures to reach prefumigation levels, or rebound rates, were variable, and adult capture levels inside were most influenced by seasonal temperature changes. Temperatures inside mills followed those outside the mill closely, and a significant positive relationship between outside temperatures and trap captures was observed. Inside and outside trap captures exhibited a significant, positive relationship, but fumigations consistently led to reductions in beetle captures outside of mills, highlighting the interconnectedness of populations located inside and outside mill structures. PMID- 23448068 TI - Evaluation of repellency of some Chinese medicinal herbs essential oils against Liposcelis bostrychophila (Psocoptera: Liposcelidae) and Tribolium castaneum (Coleoptera: Tenebrionidae). AB - The screening for repellency against the booklouse, Liposcelis bostrychophila (Badonnel), and the red flour beetle, Tribolium castaneum (Herbst), from 14 Chinese medicinal herbs showed that the essential oils of Curcuma longa L., Epimedium pubescens Maximouwicz, Lindera aggregate (Sims) Kostermans, Nardostachys chinensis Battandier, Schizonepeta tenuifolia Briquet, Zanthoxylum schinifolium Sieber et Zuccarini, and Z. officinale Roscoe exhibited strong repellency against L. bostrychophila and T. castaneum. A total of 35 components of the essential oil of E. pubescens were identified by gas chromatography and gas chromatography-mass spectrometry. Beta-Eudesmol (14.89%), alpha-pinene (13.38%), borneol (9.56%), (R)-carvone (7.89%), and menthol (7.45%) were the main components of the essential oil of E. pubescens. From the essential oil of E. pubescens, four monoterpenoids and one sesquiterpenoid were isolated by bioassay guided fractionation. The compounds were identified alpha-pinene, borneol, menthol, carvone, and beta-eudesmol. (R) -carvone, menthol, borneol, and beta eudesmol were strongly repellent against L. bostrychophila at concentration of 8.5 nl/cm2 after 2 h exposure whereas alpha-pinene exhibited moderate repellency. (R)-carvone exhibited stronger repellency against the booklouse than the positive control, N, N-diethyl-3-methylbenzamide (DEET). Moreover, (R)-carvone also possessed stronger repellency against T. castaneum than DEET. The other four constituents, menthol, borneol, and beta-eudesmol also showed repellency against the red flour beetles but weaker than DEET at lower concentrations. PMID- 23448069 TI - Effects of short photoperiod on codling moth diapause and survival. AB - The potential presence of codling moth, Cydia pomonella L., in apples shipped to countries within the 30th latitudes has raised concerns that this pest could establish and spread in these countries. Previous research demonstrated that codling moth in apples handled under simulated commercial cold storage conditions and held under short day lengths could not break diapause and emerge in sufficient numbers to establish a minimum viable population. This study expands the in-fruit work by examining the ability of codling moth to establish a laboratory population under a short photoperiod of 12:12 (L:D) h, as compared with a long photoperiod of 16:8 (L:D) h. Codling moth larvae were collected from field infested fruits in 2010 and 2011. Moths were collected from the infested fruits and separated into two groups representing the two daylength conditions. In total, 1,004 larvae were monitored for adult emergence and ability to generate a subsequent population. Larvae held under the photoperiod of 12:12 (L:D) h generated only one moth in the 2 yr period, whereas larvae held under the photoperiod of 16:8 (L:D) h generated 186 females and 179 males, that sustained subsequent generations on artificial diet under laboratory conditions. These results indicate that under controlled environmental conditions, codling moth cannot complete diapause and emerge in sufficient numbers to sustain a viable population when held under a short photoperiod. PMID- 23448070 TI - Nursing research and publishing challenges as the mantle passes to a new CJNR editor: Sean Clarke. PMID- 23448071 TI - Nursing scholarship in global health. PMID- 23448072 TI - Global health research as seen through a health-system lens. PMID- 23448073 TI - Global health for nursing...and nursing for global health. AB - This article draws on the literature to present a conceptualization of global health (GH) that corresponds with the discipline of nursing and defines the contributions of nursing to GH. The author's perspective is that "health" should be defined and considered holistically to reflect the fact that GH involves more than the eradication of disease and that health as a fundamental right of every human being must be made explicit. "Global" refers to the supraterritorial links among the social determinants of health located at points anywhere on earth within a whole-world context. The focus of GH is the supraterritorial determinants and its ultimate objective is health equity for all nations and all people. The contributions of nurses are advocacy, healing and alleviating suffering through caring, and increasing nursing capacity globally. To truly advance the GH agenda, a new world order is needed, one in which political decision-making is guided by our shared humanity. PMID- 23448074 TI - Intimate partner violence: a global health perspective. AB - Intimate partner violence is a serious violation of human rights and a significant global health problem. As the largest health workforce worldwide, nurses are well positioned to address this health issue. Based on literature from various countries, this article presents a summary of the literature on health consequences, costs, prevalence, risk factors, perceptions, and manifestations of intimate partner violence, and women's responses to it. Next, building on the author's program of research on intimate partner violence, the article highlights a number of implications for nursing: intersectionality; micro, meso, and macro levels; social violence; violence throughout a woman's lifespan; and the migration context and process. Finally, the article presents research and practice recommendations for nurses and proposes North-South collaborations and capacity-building to address the complex nature of this global health problem. PMID- 23448075 TI - Tuberculosis and common mental disorders: international lessons for Canadian immigrant health. AB - Tuberculosis is a pressing global health issue. Its association with other infections, illnesses, and social factors, including immigration, is well known, yet comparatively little research has examined the connections between tuberculosis and mental disorder, particularly among immigrants in Canada. The authors report on a scoping review conducted to better understand the synergies of tuberculosis, mental disorders, and underlying social conditions as they affect immigrants' health. They highlight the articles that focused on the co occurrence of tuberculosis and depression/anxiety. After describing their approach and strategy, the authors present key thematic categories: prevalence, clinical presentation, and effects of stigma and poverty. Examining the research within the global context, they argue that migration contributes to these synergistic conditions. The review shows that Canadians stand to gain much by learning from low- and middle-income countries about what constitutes best evidence in approaching complex global health issues. PMID- 23448076 TI - Tensions in anti-colonial research: lessons learned by collaborating with a mining-affected indigenous community. AB - Community-based nurse researchers strive to develop collaborative partnerships that are meaningful to the health priorities of participants and relevant to their sociopolitical realities. Within the context of global inequity, intersecting forces of privilege and oppression inevitably shape the research process, resulting in tensions, contradictions, and challenges that must be addressed. This article has 3 purposes: to examine the political context of mining corporations, to describe common health threats and challenges faced by mining-affected communities, and to reflect on research with a mining-affected Indigenous community in Guatemala whose health and capacity for self-advocacy are impacted by a legacy of colonialism. Using an anti-colonial lens, the authors discuss 3 central tensions: community agency and community victimhood, common ground and distinct identities, and commitment to outcomes and awareness of limitations. They conclude by offering methodological suggestions for nurse researchers whose work is grounded in anti-colonial perspectives. PMID- 23448077 TI - Leaving the Philippines: oral histories of nurses' transition to Canadian nursing practice. AB - Filipino nurses are the leading group of immigrant nurses in Canada, making up a substantial portion of the nursing workforce, yet little is known about the contexts surrounding their immigration and transition experiences at the individual level. This study examines the transition experiences of Filipino nurses who immigrated to Canada between 1970 and 2000. Using oral history as the framework and method, it establishes a body of work in examining the history of this group of nurses in a Canadian context. Individual interviews were conducted with 9 Filipino nurses working in 2 Canadian provinces. Findings suggest that nurses may have delayed the process of becoming a Registered Nurse because the family was considered a priority, they found that adjusting to the role and scope of Canadian nursing practice required time, and they felt "foreign" and sensed a need to prove their competence to Canadian nurses. PMID- 23448078 TI - New research initiatives: addressing global homelessness. PMID- 23448080 TI - Tobacco intervention practices of postsecondary campus nurses in Ontario. AB - Cessation interventions offered by nurses to postsecondary students could represent an important strategy for reducing smoking among young adults. This study examines how nurses working in campus health clinics identify smokers and provide cessation support. Of 108 nurses working at 16 universities in the Canadian province of Ontario, 83 completed a researcher-designed questionnaire. Of these, 8.2% asked almost all patients about their tobacco use and 27.4% asked almost none; 83.1% advised identified smokers to quit, 63.9% offered them assistance, and 59.0% arranged follow-up visits. Smoking was most often assessed during patient visits for respiratory or cardiovascular concerns. Assistance most often involved referral of smokers to other professionals or services. A government-funded tobacco control initiative implemented on 10 of the 16 campuses had limited influence on whether nurses assessed tobacco use and advised cessation. Education and support may be needed to improve the frequency and quality of tobacco interventions provided by nurses working on postsecondary campuses. PMID- 23448079 TI - A culturally targeted self-management program for African Americans with type 2 diabetes mellitus. AB - Inadequate knowledge of the influence of lifestyle on clinical outcomes contributes to the difficulties many African Americans experience with type 2 diabetes mellitus (T2DM). This pilot study examined a 12-week church-based culturally targeted diabetes self-management education (DSME) intervention for middle-aged and older African Americans with T2DM. Quantitative data were collected at baseline and at 12 weeks and included questionnaires and anthropometric measures. There were significant increases in medication adherence (p = .006), healthy eating (p = .009), and foot care adherence (p = .003). The intervention had a clinically significant effect on systolic blood pressure, blood lipids, physical activity, and waist circumference. Church-based culturally targeted DSME interventions may result in improved outcomes for African-American adults with T2DM. The authors discuss the value of community-based interventions that target behavioural changes in populations of chronically ill patients, particularly those who historically have been disenfranchised and/or underserved. PMID- 23448081 TI - Intelligent technology for superior cleaning of teeth and gums. PMID- 23448082 TI - Comparative efficacy of a specially engineered sonic powered toothbrush with unique sensing and control technologies to two commercially available power toothbrushes on established plaque and gingivitis. AB - OBJECTIVE: To evaluate the efficacy on plaque and established gingivitis of a new specially engineered sonic powered toothbrush with unique sensing and control technologies as compared to two commercially available power toothbrushes. METHODS: This examiner-blind, three-treatment, parallel clinical study assessed plaque reduction via the comparison of pre- to postbrushing after a single use, and following four weeks' use measured by the Rustogi Modification of the Modified Navy Plaque Index. This study also assessed gingivitis using the Loe and Silness Gingival Index after four weeks' use. Qualifying adult male and female subjects from the northern New Jersey area reported to the study site after refraining from all oral hygiene procedures for 24 hours, and from eating, drinking, or smoking for four hours. Following an examination for gingivitis and plaque (pre-brushing), they were randomized into three balanced groups, each group using one of the three study toothbrushes in the order specified by a predetermined randomization plan. Subjects were instructed to brush their teeth for two minutes under supervision with their assigned toothbrush according to the manufacturers' instructions and a commercially available toothpaste (Colgate Cavity Protection), after which they were once again evaluated for plaque (post brushing). Subjects were then dismissed from the study site with the toothpaste and their assigned toothbrush to use at home twice daily for the next four weeks. They again reported to the study site at which time they were evaluated for plaque and gingivitis. RESULTS: One-hundred eighty-four subjects complied with the protocol and completed the clinical study. Relative to the two commercially available toothbrushes, the new specially engineered sonic powered toothbrush with unique sensing and control technologies provided statistically significantly (p < 0.05) greater reductions in whole mouth plaque index scores (21.9 and 25.8%, respectively), gingival margin plaque index scores (14.5% and 18.9%, respectively), interproximal plaque index scores (160.0% and 136.4%, respectively), facial plaque index scores (17.9% for both), lingual plaque index scores (29.2% for both), and interproximal lingual plaque index scores (200.0% and 350.0%, respectively) after a single tooth brushing. Relative to the two commercially available toothbrushes, the new sonic powered toothbrush also provided statistically significantly (p < 0.05) greater reductions in whole mouth plaque index scores (47.4% and 40.0%, respectively), gingival margin plaque index scores (46.2% and 40.7%, respectively), interproximal plaque index scores (650% and 1400%, respectively), facial plaque index scores (47.6% and 40.9%, respectively), lingual plaque index scores (47.1% and 31.6%, respectively), and interproximal lingual plaque index scores (350.0% and 500.0%, respectively) after four weeks. There was no statistically significant (p > 0.05) difference between the two commercially available toothbrushes for any plaque index score comparison. Relative to one of the commercially available toothbrushes, the new sonic powered toothbrush provided statistically significant reductions (p < 0.05) in gingival index scores (25.0%) and gingivitis severity scores (33.3%) after four weeks of product use. There were no statistically significant (p > 0.05) differences in gingivitis or gingivitis severity index scores between the new sonic powered toothbrush and the other commercially available toothbrush. CONCLUSION: A new specially engineered sonic powered toothbrush with unique sensing and control technologies provides significantly greater levels of efficacy on the removal of dental plaque after a single tooth brushing and after four weeks' use when compared to two commercially available power toothbrushes. The new sonic powered toothbrush also provides significantly greater levels of efficacy on the reduction of gingivitis and gingival bleeding when compared to one of the commercially available power toothbrushes. PMID- 23448083 TI - A clinical study comparing the supragingival plaque and gingivitis efficacy of a specially engineered sonic powered toothbrush with unique sensing and control technologies to a commercially available manual flat-trim toothbrush. AB - OBJECTIVE: This study was designed to evaluate the efficacy of a new specially engineered sonic powered toothbrush with unique sensing and control technologies, as compared to a manual flat-trim toothbrush on supragingival plaque and established gingivitis. METHODS: This examiner-blind, two-treatment, parallel clinical research study assessed plaque removal via the comparison of pre- to post-brushing after a single use, and again after four- and 12-weeks' use using the Rustogi Modification of the Modified Navy Plaque Index. This study also assessed gingivitis at four and 12 weeks using the Loe and Silness Gingival Index. Qualifying adult male and female subjects from the southern Florida area reported to the study site after refraining from any oral hygiene procedures for 24 hours, and from eating, drinking, and smoking for four hours. Following an examination for plaque (pre-brushing) and gingivitis, they were randomized (for both plaque and gingivitis) into two balanced groups, each group using one of the two study toothbrushes. Subjects were instructed to brush their teeth for two minutes under supervision with their assigned toothbrush according to the manufacturer's instructions, and commercially available toothpaste (Colgate Cavity Protection Toothpaste), after which they were again evaluated for plaque (post-brushing). Subjects were then dismissed from the study site with the toothpaste and their assigned toothbrush to use at home twice daily for the next 12 weeks. They again reported to the study site after four and 12 weeks of product use, at which time they were evaluated for plaque and gingivitis. RESULTS: Seventy-six out of 82 enrolled subjects complied with the protocol and completed the clinical study. The new specially engineered sonic powered toothbrush with unique sensing and control technologies provided statistically significant reductions in gingival and gingivitis severity index scores after four and 12 weeks of product use. The manual toothbrush provided a statistically significant reduction in gingival index score only at the 12-week time point. Relative to the manual toothbrush group, after a single tooth brushing and after four and 12 weeks, the new sonic powered toothbrush provided statistically significantly greater reductions in whole mouth plaque index scores (1.6, 2.05, and 1.9 times, respectively), gingival margin plaque index scores (12.0, 90.0, and 8.2 times, respectively), and interproximal plaque index scores (2.0, 3.2, and 2.1 times, respectively). Relative to the manual toothbrush group after four and 12 weeks, the new sonic powered toothbrush provided statistically significant reductions in gingival index scores of 11.0 and 7.0 times, respectively, and in gingivitis severity index scores of 3.0 and 3.5 times, respectively. All statistically significant reductions were at the p < or = 0.05 level. CONCLUSION: The new specially engineered sonic powered toothbrush unique sensing and control technologies provides statistically significant and clinically relevant levels of efficacy in the removal of supragingival dental plaque after a single tooth brushing, and after four and 12 weeks' use. The new sonic powered toothbrush also provides statistically significantly greater levels of efficacy in the reduction of supragingival plaque, gingivitis, and gingival bleeding when compared to a manual flat-trim toothbrush. PMID- 23448084 TI - Laboratory evaluation of plaque removal at interproximal sites by a specially engineered powered toothbrush with unique sensing and control technologies. AB - OBJECTIVE: This laboratory study compared a specially engineered sonic powered toothbrush with unique sensing and control technologies and having two different brush heads to a manual flat-trim toothbrush for their ability to remove plaque at interproximal sites. METHODS: Interproximal access efficacy (IAE) was measured as the maximum width of plaque removed from the artificial plaque substrate around the teeth. Six brushes of each product were tested four times for a total of 24 tests. Results from these tests were statistically analyzed using an analysis of variance (ANOVA). A post hoc Tukey test for pair-wise comparisons, with a minimum significance level of 0.05, was used to identify significant mean differences between the test products. RESULTS: Relative to the manual flat-trim toothbrush, the sonic powered toothbrush, equipped with either the Triple Clean or Sensitive refill brush head, had statistically significantly higher IAE means (p < 0.001). In addition, when equipped with the Sensitive refill brush head, the new sonic powered toothbrush showed increased efficiencies compared to when it was equipped with the Triple Clean brush head with respect to IAE means. CONCLUSION: The specially engineered sonic powered toothbrush with unique sensing and control technologies had higher interproximal access efficacy compared to a manual flat-trim toothbrush, particularly with the Sensitive brush head. PMID- 23448085 TI - Laboratory evaluation of extrinsic stain removal by a specially engineered sonic powered toothbrush with unique sensing and control technologies. AB - OBJECTIVE: The purpose of this laboratory study was to evaluate extrinsic stain removal from teeth by a specially engineered sonic powered toothbrush with unique sensing and control technologies, using the Triple Clean and the Sensitive refill brush heads, in comparison to a manual flat-trim toothbrush. METHODS: Twelve (12) artificially stained bovine teeth were tested with each product. The percentage of stain removed by each product was calculated by taking the ratio of the amount of stain removed by brushing for 800 strokes to the total amount of stain removed by subsequent application of a dental prophylaxis. The stain was quantified by measuring the light reflected by the stained teeth with a spectrophotometer. Data were reported as L*, lightness of the stain, and as W*, a whiteness index comprising the lightness, hue, and chroma of reflected light. Statistical analyses were performed separately for the AL* and AW* scores. Comparisons of the toothbrushes with respect to baseline-adjusted deltaL* and deltaW* scores were performed using an analysis of covariance (ANCOVA). Post-ANCOVA pair-wise comparisons of the study toothbrushes were performed using Tukey's test for multiple comparisons. All statistical tests of hypotheses were two-sided, and employed a minimum level of significance of 0.05. RESULTS: The percentage of stain removed by the sonic powered toothbrush, using either the Triple Clean brush head or the Sensitive brush head under laboratory test conditions, is superior (p < 0.05) to the percentage of stain removed by the manual flat-trim toothbrush when analyzed for both the deltaL* and deltaW* scores. The mean percentage of stain removed was 62.10 for the power toothbrush with the Triple Clean brush head, 49.01 for the power toothbrush with the Sensitive brush head, and 30.56 for the manual flat-trim toothbrush when calculated using deltaL* scores. The mean percentage of stain removed was 59.89 for the power toothbrush with the Triple Clean brush head, 46.83 for the power toothbrush with the Sensitive brush head, and 29.25 for the manual flat-trim toothbrush when calculated using deltaW* scores. CONCLUSIONS: This new specially engineered sonic powered toothbrush with unique sensing and control technologies effectively removes extrinsic stains from the surface of teeth under laboratory test conditions with both the Triple Clean and the Sensitive brush heads. The effectiveness of stain removal with either brush head is significantly greater than the effectiveness of stain removal of a manual flat-trim toothbrush under these conditions. PMID- 23448086 TI - Ergonomic audit of a specially engineered sonic powered toothbrush with unique sensing and control technologies, the Sonicare Flexcare, and the Oral-B Smart Series 5000. AB - OBJECTIVE: The presence of ergonomic features can impact the marketplace success of a new product. Metaphase Design Group, Inc., in partnership with the Colgate Palmolive Company, conducted an ergonomic audit on three electric toothbrushes: a specially engineered sonic powered toothbrush with unique sensing and control technologies, the Sonicare FlexCare, and the Oral-B Smart Series 5000. METHODS: The ergonomic audit was conducted by Metaphase Design Groups's ergonomic and usability experts. Two experts used the toothbrushes over a one-week period and assessed the performance of each brush against a set of ergonomic principles. RESULTS: The three toothbrushes have some solid ergonomic features. They each have adequate grip zones, provide grip security with elastomeric materials, and provide easy access to the on/off button. The most distinctive feature is the longitudinal shape of the handle of the specially engineered sonic powered toothbrush with unique sensing and control technologies. This handle angles downward at the top end and provides additional advantages through improved grip security and visibility. Yet all three toothbrushes have different opportunities for improvement. The Sonicare Flex Care toothbrush has a cluttered and complicated user interface that is difficult to read. The disadvantages of the Oral-B Smart Series 5000 toothbrush are related to its physical dimensions and audible feedback. CONCLUSION: The specially engineered sonic powered toothbrush with unique sensing afid control technologies is surprising to use with its changes in speeds, brush movements, and resulting changes in audible feedback. PMID- 23448087 TI - Usability research study of a specially engineered sonic powered toothbrush with unique sensing and control technologies. AB - OBJECTIVE: This paper summarizes the results of a longitudinal usability research study of a specially engineered sonic powered toothbrush with unique sensing and control technologies. METHODS: The usability test was conducted with fourteen (14) consumers from the St. Louis, MO, USA area who use manual toothbrushes. The study consisted of consumers using the specially engineered sonic powered toothbrush with unique sensing and control technologies for three weeks. During the study, users participated in four toothbrush trials during weekly visits to the research facility. These trials were videotaped and were analyzed regarding brushing time, behavior, and technique. In addition, the users were required to use the toothbrush twice a day for their at-home brushing. RESULTS: The toothbrush had a positive impact on consumers' tooth brushing behavior. Users spent more time brushing their teeth with this toothbrush as compared to their manual toothbrush. In addition, users spent more time keeping the sonic toothbrush in the recommended angle during use. Finally, users perceived their teeth to be cleaner when using the specially engineered sonic powered toothbrush with unique sensing and control technologies. CONCLUSION: The specially engineered sonic powered toothbrush with unique sensing and control technologies left a positive impression on the users. The users perceived the toothbrush to clean their teeth better than a manual toothbrush. PMID- 23448088 TI - [RuCl2(p-cymene)]2-catalyzed conjugate addition of arylboronic acids to alpha,beta-unsaturated ketones under ligand-free and neutral conditions. AB - A simple and efficient Ru-catalyzed conjugate addition reaction of arylboronic acids to alpha,beta-unsaturated ketones under neutral conditions without any additional ligands has been developed. This Ru(II)-catalytic system both fulfilled the inhibition of the beta-hydride elimination in the catalytic cycle and minimized the protonolysis of arylboronic acids. PMID- 23448089 TI - Graphene-P(VDF-TrFE) multilayer film for flexible applications. AB - A flexible, transparent acoustic actuator and nanogenerator based on graphene/P(VDF-TrFE)/graphene multilayer film is demonstrated. P(VDF-TrFE) is used as an effective doping layer for graphene and contributes significantly to decreasing the sheet resistance of graphene to 188 ohm/sq. The potentiality of graphene/P(VDF-TrFE)/graphene multilayer film is realized in fabricating transparent, flexible acoustic devices and nanogenerators to represent its functionality. The acoustic actuator shows good performance and sensitivity over a broad range of frequency. The output voltage and the current density of the nanogenerator are estimated to be ~3 V and ~0.37 MUAcm(-2), respectively, upon the application of pressure. These values are comparable to those reported earlier for ZnO- and PZT-based nanogenerators. Finally, the possibility of rollable devices based on graphene/P(VDF-TrFE)/graphene structure is also demonstrated under a dynamic mechanical loading condition. PMID- 23448090 TI - Fabrication and properties of ZnO/GaN heterostructure nanocolumnar thin film on Si (111) substrate. AB - Zinc oxide thin films have been obtained on bare and GaN buffer layer decorated Si (111) substrates by pulsed laser deposition (PLD), respectively. GaN buffer layer was achieved by a two-step method. The structure, surface morphology, composition, and optical properties of these thin films were investigated by X ray diffraction, field emission scanning electron microscopy, infrared absorption spectra, and photoluminiscence (PL) spectra, respectively. Scanning electron microscopy images indicate that the flower-like grains were presented on the surface of ZnO thin films grown on GaN/Si (111) substrate, while the ZnO thin films grown on Si (111) substrate show the morphology of inclination column. PL spectrum reveals that the ultraviolet emission efficiency of ZnO thin film on GaN buffer layer is high, and the defect emission of ZnO thin film derived from Zni and Vo is low. The results demonstrate that the existence of GaN buffer layer can greatly improve the ZnO thin film on the Si (111) substrate by PLD techniques. PMID- 23448091 TI - Mechanical testing of hydrogels in cartilage tissue engineering: beyond the compressive modulus. AB - Injuries to articular cartilage result in significant pain to patients and high medical costs. Unfortunately, cartilage repair strategies have been notoriously unreliable and/or complex. Biomaterial-based tissue-engineering strategies offer great promise, including the use of hydrogels to regenerate articular cartilage. Mechanical integrity is arguably the most important functional outcome of engineered cartilage, although mechanical testing of hydrogel-based constructs to date has focused primarily on deformation rather than failure properties. In addition to deformation testing, as the field of cartilage tissue engineering matures, this community will benefit from the addition of mechanical failure testing to outcome analyses, given the crucial clinical importance of the success of engineered constructs. However, there is a tremendous disparity in the methods used to evaluate mechanical failure of hydrogels and articular cartilage. In an effort to bridge the gap in mechanical testing methods of articular cartilage and hydrogels in cartilage regeneration, this review classifies the different toughness measurements for each. The urgency for identifying the common ground between these two disparate fields is high, as mechanical failure is ready to stand alongside stiffness as a functional design requirement. In comparing toughness measurement methods between hydrogels and cartilage, we recommend that the best option for evaluating mechanical failure of hydrogel-based constructs for cartilage tissue engineering may be tensile testing based on the single edge notch test, in part because specimen preparation is more straightforward and a related American Society for Testing and Materials (ASTM) standard can be adopted in a fracture mechanics context. PMID- 23448092 TI - Effect of proteases on biofilm formation of the plastic-degrading actinomycete Rhodococcus ruber C208. AB - In most habitats, the vast majority of microbial populations form biofilms on solid surfaces, whether natural or artificial. These biofilms provide either increased physical support and/or a source of nutrients. Further modifications and development of biofilms are regulated by signal molecules secreted by the cells. Because synthetic polymers are not soluble in aqueous solutions, biofilm producing bacteria may biodegrade such materials more efficiently than planktonic strains. Bacterial biofilms comprise bacterial cells embedded in self-secreted extracellular polymeric substances (EPS). Revealing the roles of each component of the EPS will enable further insight into biofilm development and the EPS structure-function relationship. A strain of Rhodococcus ruber (C208) displayed high hydrophobicity and formed a dense biofilm on the surface of polyethylene films while utilizing the polyolefin as carbon and energy sources. This study investigated the effects of several proteases on C208 biofilm formation and stability. The proteolysis of C208 biofilm gave conflicting results. Trypsin significantly reduced biofilm formation, and the resultant biofilm appeared monolayered. In contrast, proteinase K enhanced biofilm formation, which was robust and multilayered. Presumably, proteinase K degraded self-secreted proteases or quorum-sensing peptides, which may be involved in biofilm detachment processes, leading to a multilayered, nondispersed biofilm. PMID- 23448093 TI - Unmet need in the treatment of postherpetic neuralgia. AB - The efficacy of first-line therapeutic agents for postherpetic neuralgia (PHN) has been established in randomized, controlled clinical trials. However, pain in PHN is often refractory to treatment. Many of the patients with PHN are elderly, with additional issues of polypharmacy and comorbidity. They experience various types of pain, suggesting that more than 1 pathophysiologic pain mechanism is involved. PHN adversely affects health-related quality of life. Up to this point, no single best treatment has been identified for PHN. Pharmacological treatments for PHN are inadequate, and many patients are undertreated. Suboptimal treatment can be related to intolerable side effects of medications, long titration periods to reach the effective dosage, inadequate dosing, poor compliance with dosing schedules, and low treatment satisfaction. Inadequate therapeutic response leads more than half the patients with PHN treated with either gabapentin or pregabalin to switch to another class of medication, and more than 30% of patients to add on another class of medication. Safety and tolerability are important considerations in therapy, especially in the elderly. Few patients with PHN and physicians are satisfied with the currently available treatments. Thus, the effective management of postherpetic neuralgia remains an ongoing challenge. New and improved treatment options are therefore needed for the effective management of PHN. PMID- 23448095 TI - Laboratory detection of strongyloidiasis: IgG-, IgG4 - and IgE-ELISAs and cross reactivity with lymphatic filariasis. AB - Enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of IgG, IgG4 and IgE antibodies against Strongyloides stercoralis. A commercial ELISA (IVD Research, USA) was also used, and the sensitivities and specificities of the four assays were determined. Serum samples from 26 patients with S. stercoralis infection and 55 patients with other infections or no infection were analysed. Sensitivities of the IgG4 , IgG, IgE and IgG (IVD) assays were 76.9%, 84.6%, 7.7% and 84.6%, respectively, while the specificities were 92.7%, 81.8%, 100% and 83.6%, respectively. If filariasis samples were excluded, the specificities of the IgG4 -ELISA and both IgG-ELISAs increased to 100% and 98%, respectively. A significant positive correlation was observed between IgG- and IgG4 -ELISAs (r = 0.4828; P = 0.0125). IgG- and IgG- (IVD) ELISAs (r = 0.309) were positively correlated, but was not significant (P = 0.124). Meanwhile there was no correlation between IgG4 - and IgG- (IVD) ELISAs (r = 0.0042; P = 0.8294). Sera from brugian filariasis patients showed weak, positive correlation between the titres of antifilarial IgG4 and the optical densities of anti-Strongyloides IgG4 -ELISA (r = 0.4544, P = 0.0294). In conclusion, the detection of both anti Strongyloides IgG4 and IgG antibodies could improve the serodiagnosis of human strongyloidiasis. Furthermore, patients from lymphatic filariasis endemic areas who are serologically diagnosed with strongyloidiasis should also be tested for filariasis. PMID- 23448094 TI - Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990. AB - BACKGROUND AND PURPOSE: Heat shock Protein 90 (Hsp90) is a molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins involved in oncogenic signaling and in the regulation of radiosensitivity. It is upregulated in response to stress such a heat. Hyperthermia is a potent radiosensitizer, but induction of Hsp90 may potentially limit its efficacy. Our aim was to investigate whether the new Hsp90 inhibitor NVP-HSP990 increases radiosensitivity, thermosensitivity and radiothermosensitivity of human tumor cell lines. MATERIAL AND METHODS: U251 glioblastoma and MIA PaCa-2 pancreatic carcinoma cells were used. To determine clonogenic survival, colony forming assays were performed. Cell viability and proliferation were assesed by Trypan blue staining. Cell cycle and apoptosis analyses were performed by flow cytometry. DAPI staining was used to detect mitotic catastrophe. RESULTS: NVP HSP990 increased the thermosensitivity, radiosensitivity and radio thermosensitivity of both cell lines in clonogenic assays. 72 hours after irradiation with 4 Gy, a significant reduction in cell number associated with considerable G2/M acumulation and mitotic catastrophe as well as cell death by apoptosis/necrosis was observed. CONCLUSIONS: Treatment with NVP-HSP990 strongly sensitized U251 and MIA PaCa-2 cells to hyperthermia and ionizing radiation or combination thereof through augmentation of G2/M arrest, mitotic catastrophe and associated apoptosis. PMID- 23448096 TI - Turnover of plant lineages shapes herbivore phylogenetic beta diversity along ecological gradients. AB - Understanding drivers of biodiversity patterns is of prime importance in this era of severe environmental crisis. More diverse plant communities have been postulated to represent a larger functional trait-space, more likely to sustain a diverse assembly of herbivore species. Here, we expand this hypothesis to integrate environmental, functional and phylogenetic variation of plant communities as factors explaining the diversity of lepidopteran assemblages along elevation gradients in the Swiss Western Alps. According to expectations, we found that the association between butterflies and their host plants is highly phylogenetically structured. Multiple regression analyses showed the combined effect of climate, functional traits and phylogenetic diversity in structuring butterfly communities. Furthermore, we provide the first evidence that plant phylogenetic beta diversity is the major driver explaining butterfly phylogenetic beta diversity. Along ecological gradients, the bottom up control of herbivore diversity is thus driven by phylogenetically structured turnover of plant traits as well as environmental variables. PMID- 23448097 TI - Halogenated organic molecules of Rhodomelaceae origin: chemistry and biology. PMID- 23448098 TI - Periodontal inflammation in renal transplant recipients receiving everolimus or tacrolimus - preliminary results. AB - OBJECTIVE: To compare oral health status between renal transplant recipients (RTRs) receiving tacrolimus (Tac) or everolimus (ERL) as immunosuppressive therapy. DESIGN: This study is a cross-sectional study. METHODS: Thirty-six RTRs receiving Tac and 22 RTRs receiving ERL were included in the study. Age, gender, time since transplant and pharmacological data were recorded for both groups. Oral health status was assessed through the evaluation of teeth, periodontal parameters as well as saliva flow rate and pH. RESULTS: RTRs receiving ERL were older than those receiving Tac. No differences were found between groups concerning oral hygiene habits, oral symptoms, smoking habits, unstimulated and stimulated saliva flow rate and pH, clinical attachment level or the number of decayed, missing and filled teeth. However, RTRs receiving ERL presented lower visible plaque index and lower values for bleeding on probing when compared to RTRs receiving Tac. In addition, RTRs receiving ERL presented a gingival index varying from normal to moderate inflammation whereas RTRs receiving Tac presented a gingival index varying from mild to severe inflammation. CONCLUSIONS: RTRs receiving ERL have lower periodontal inflammation when compared to RTRs receiving Tac. PMID- 23448099 TI - Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features. AB - PURPOSE: To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. METHODS: Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon-intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records. KEY FINDINGS: We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged. SIGNIFICANCE: Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2 -weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive. PMID- 23448101 TI - Does PPARgamma2 gene Pro12Ala polymorphism affect nonalcoholic fatty liver disease risk? Evidence from a meta-analysis. AB - Genetic factors can substantially contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A missense Pro12Ala substitution in the PPARgamma2 gene (rs1801282) has been studied in relation with NAFLD risk in different ethnic groups, but findings have been inconclusive. The aim of this was to evaluate the association between rs1801282 and NAFLD through meta-analysis of all relevant published evidence. A systematic search to find eligible studies was performed in Medline, HuGE Navigator, and SCOPUS databases. The strength of association was evaluated using odds ratios with 95% confidence intervals obtained from a random effect approach and under additive, dominant, co-dominant, recessive, and allelic contrast models. Seven studies comprising 1474 cases and 2259 controls met the eligibility criteria and included in the meta-analysis. Combined results did not indicate any predisposing or protective effect for rs1801282 under any of the assessed modes of inheritance. The rate of heterogeneity was generally high due to the inter-study variations in terms of age, gender, and ethnicity. Evidence from the current meta-analysis indicated that rs1801282 variants are not associated with NAFLD risk. Future large-scale studies are required to substantiate the present findings. PMID- 23448100 TI - Using a state cancer registry to recruit young breast cancer survivors and high risk relatives: protocol of a randomized trial testing the efficacy of a targeted versus a tailored intervention to increase breast cancer screening. AB - BACKGROUND: The Michigan Prevention Research Center, the University of Michigan Schools of Nursing, Public Health, and Medicine, and the Michigan Department of Community Health propose a multidisciplinary academic-clinical practice three year project to increase breast cancer screening among young breast cancer survivors and their cancer-free female relatives at greatest risk for breast cancer. METHODS/DESIGN: The study has three specific aims: 1) Identify and survey 3,000 young breast cancer survivors (diagnosed at 20-45 years old) regarding their breast cancer screening utilization. 2) Identify and survey survivors' high risk relatives regarding their breast cancer screening utilization. 3) Test two versions (Targeted vs. Enhanced Tailored) of an intervention to increase breast cancer screening among survivors and relatives. Following approval by human subjects review boards, 3,000 young breast cancer survivors will be identified through the Michigan Cancer Registry and mailed an invitation letter and a baseline survey. The baseline survey will obtain information on the survivors': a) current breast cancer screening status and use of genetic counseling; b) perceived barriers and facilitators to screening; c) family health history. Based on the family history information provided by survivors, we will identify up to two high-risk relatives per survivor. Young breast cancer survivors will be mailed consent forms and baseline surveys to distribute to their selected high risk relatives. Relatives' baseline survey will obtain information on their: a) current breast cancer screening status and use of genetic counseling; and b) perceived barriers and facilitators to screening. Young breast cancer survivors and high-risk relatives will be randomized as a family unit to receive two versions of an intervention aiming to increase breast cancer screening and use of cancer genetic services. A follow-up survey will be mailed 9 months after the intervention to survivors and high-risk relatives to evaluate the efficacy of each intervention version on: a) use of breast cancer screening and genetic counseling; b) perceived barriers and facilitators to screening; c) self-efficacy in utilizing cancer genetic and screening services; d) family support related to screening; e) knowledge of breast cancer genetics; and f) satisfaction with the intervention. DISCUSSION: The study will enhance efforts of the state of Michigan surrounding cancer prevention, control, and public health genomics. PMID- 23448102 TI - Insights into secondary organic aerosol formation mechanisms from measured gas/particle partitioning of specific organic tracer compounds. AB - In situ measurements of organic compounds in both gas and particle phases were made with a thermal desorption aerosol gas chromatography (TAG) instrument. The gas/particle partitioning of phthalic acid, pinonaldehyde, and 6,10,14-trimethyl 2-pentadecanone is discussed in detail to explore secondary organic aerosol (SOA) formation mechanisms. Measured fractions in the particle phase (f(part)) of 6,10,14-trimethyl-2-pentadecanone were similar to those expected from the absorptive gas/particle partitioning theory, suggesting that its partitioning is dominated by absorption processes. However, f(part) of phthalic acid and pinonaldehyde were substantially higher than predicted. The formation of low volatility products from reactions of phthalic acid with ammonia is proposed as one possible mechanism to explain the high f(part) of phthalic acid. The observations of particle-phase pinonaldehyde when inorganic acids were fully neutralized indicate that inorganic acids are not required for the occurrence of reactive uptake of pinonaldehyde on particles. The observed relationship between f(part) of pinonaldehyde and relative humidity suggests that the aerosol water plays a significant role in the formation of particle-phase pinonaldehyde. Our results clearly show it is necessary to include multiple gas/particle partitioning pathways in models to predict SOA and multiple SOA tracers in source apportionment models to reconstruct SOA. PMID- 23448103 TI - Comparison of ABR response amplitude, test time, and estimation of hearing threshold using frequency specific chirp and tone pip stimuli in newborns. AB - OBJECTIVE: To evaluate the auditory brainstem response (ABR) amplitudes evoked by tone pip and narrowband chirp (NB CE-Chirp) stimuli when testing post-screening newborns and to determine the difference in estimated hearing level correction values. DESIGN: Tests were performed with tone pips and NB CE-Chirps at 4 kHz or 1 kHz. The response amplitude, response quality (Fmp), and residual noise were compared for both stimuli. STUDY SAMPLE: Thirty babies (42 ears) who passed our ABR discharge criterion at 4 kHz following referral from their newborn hearing screen. RESULTS: Overall, NB CE-Chirp responses were 64% larger than the tone pip responses, closer to those evoked by clicks. Fmp was significantly higher for NB CE-Chirps. CONCLUSION: It is anticipated that there could be significant reductions in test time for the same signal to noise ratio by using NB CE-Chirps when testing newborns. This effect may vary in practice and is likely to be most beneficial for babies with low amplitude ABR responses. We propose that the ABR nHL threshold to eHL correction for NB CE-Chirps should be approximately 5 dB less than the corrections for tone pips at 4 and 1 kHz. PMID- 23448104 TI - Current understanding on micro RNAs and its regulation in response to Mycobacterial infections. AB - MicroRNAs (miRNAs) are evolutionarily conserved, naturally abundant, small, regulatory non-coding RNAs that inhibit gene expression at the post transcriptional level in a sequence-specific manner. Due to involvement in a broad range of biological processes and diseases, miRNAs are now commanding considerable attention. Although much of the focus has been on the role of miRNAs in different types of cancer, recent evidence also points to a critical role of miRNAs in infectious disease, including those of bacterial origin. Now, miRNAs research is exploring rapidly as a new thrust area of biomedical research with relevance to deadly bacterial diseases like Tuberculosis (caused by Mycobacterium tuberculosis). The purpose of this review is to highlight the current developments in area of miRNAs regulation in Mycobacterial diseases; and how this might influence the diagnosis, understanding of disease biology, control and management in the future. PMID- 23448105 TI - How do delivery mode and parity affect pelvic organ prolapse? AB - OBJECTIVE: To determine the association between mode of delivery, parity, and pelvic organ prolapse, as assessed by the pelvic organ prolapse quantification system. DESIGN: Cross-sectional study. SETTING: Tertiary referral center, Turkey. POPULATION: A total of 1964 women with benign gynecological disorders who presented between October 2009 and July 2011. METHODS: Evaluation using the pelvic organ prolapse quantification system and questionnaire assessing previous obstetrics and medical history. MAIN OUTCOME MEASURES: Difference in pelvic organ prolapse stages between nulliparous and multiparous women, impact of parity and mode of delivery. RESULTS: In the study population, 86.4, 7.2 and 6.4% had pelvic organ prolapse of stages 0-I, II, and III-IV, respectively, and 7.9% had significant prolapse beyond the hymen. The mean age, parity, and number of vaginal deliveries were significantly higher in the prolapse than in the non prolapse group. Vaginal delivery was associated with an odds ratio of 2.92 (95% confidence interval 1.19-7.17) for prolapse when compared with nulliparity. Each vaginal delivery increased the risk of prolapse (odds ratio 1.23; 95% confidence interval 1.12-1.35) after controlling for all confounding factors. Cesarean delivery had no impact on the odds for prolapse. CONCLUSIONS: Vaginal delivery was an independent risk factor for prolapse, and additional vaginal deliveries significantly increased the risk. However, cesarean delivery had no effect on the development of prolapse in this material. PMID- 23448106 TI - Comparative effectiveness research and formulary placement: the case of diabetes. PMID- 23448107 TI - Are benefits from diabetes self-management education sustained? AB - OBJECTIVES: To evaluate whether outcomes from diabetes self-management education for patients with suboptimal control were sustained. STUDY DESIGN: A randomized controlled trial of 623 adults with type 2 diabetes and glycated hemoglobin (A1C) > 7% assigned to receive conventional individual education (IE), group education (GE) using US Diabetes Conversation Maps, or usual care (UC) with no education. METHODS: A1C tests, Problem Areas in Diabetes (PAID), Diabetes Self-Efficacy (DES), Recommended Food Score (RFS), physical activity, and medication use were quantified at baseline and 1 year of follow-up through electronic health records and quarterly mailed surveys. Short-term (mean 6.8 months) and long-term (12.8 months) outcomes were evaluated using linear mixed models. In addition, follow-up trajectories were plotted in a random effects generalized additive model with smooth splines. RESULTS: Compared with UC, IE resulted in long-term improved DES and PAID scores (DES, +.11, P = .03 and PAID, -2.94, P = .04), but not significantly improved long-term RFS or physical activity change. The A1C trajectory declined more steeply in IE than GE and UC for the first 150 days post randomization. However, by 250 days, there was no treatment group A1C difference. The model fit likelihood ratio test for A1C intervention trends was significant for 3 distinct non-linear trajectories (P = .02). CONCLUSIONS: Conventional IE (but not GE) resulted in significant and sustained improvements in self-efficacy and reduced diabetes distress compared with UC, but short-term improvements in A1C, nutrition, and physical activity were not sustained. Patients may need ongoing reinforcement to achieve lasting behavioral change and glucose control. PMID- 23448108 TI - Oral nutritional supplementation. PMID- 23448109 TI - Impact of oral nutritional supplementation on hospital outcomes. AB - OBJECTIVES: To assess the effect of inpatient oral nutritional supplement (ONS) use on length of stay, episode cost, and 30-day readmission probability. STUDY DESIGN: Eleven-year retrospective study (2000 to 2010). METHODS: Analyses were conducted using the Premier Perspectives Database, which contained information on 44.0 million adult inpatient episodes. Using a matched sample of ONS and non-ONS episodes for any inpatient diagnosis, instrumental variables regression analysis was performed to quantify the effect of ONS use on length of stay, episode cost, and probability of approximate 30-day readmission. For the readmission outcome, the matched sample was restricted to episodes where the patient was known to be at risk of readmission. The fraction of a hospital's episodes in a given quarter involving ONS was used as an instrumental variable. RESULTS: Within the database, 1.6% of 44.0 million adult inpatient episodes involved ONS use. Based on a matched sample of 1.2 million episodes, ONS patients had a shorter length of stay by 2.3 days (95% confidence interval [CI] - 2.42 to -2.16), from 10.9 to 8.6 days (21.0% decline), and decreased episode cost of $4734 (95% CI - $4754 to - $4714), from $21,950 to $17,216 (21.6% decline). Restricting the matched sample to the 862,960 episodes where patients were readmitted at some point, ONS patients had a reduced probability of early readmission (within 30 days) of 2.3 percentage points (95% CI - 0.027 to - 0.019), from 34.3% to 32.0% (6.7% decline). CONCLUSIONS: Use of ONS decreases length of stay, episode cost, and 30-day readmission risk in the inpatient population. PMID- 23448110 TI - Medical homes require more than an EMR and aligned incentives. AB - BACKGROUND: The Veterans Health Administration (VHA) is changing its primary care delivery by implementing the patient-centered medical home (PCMH). OBJECTIVES: To evaluate PCMH implementation among 22 newly formed teams working in the VHA. STUDY DESIGN: Longitudinal formative evaluation of team members' role transformation during the first 18 months of implementation. METHODS: We used 3 sequential, semistructured focus groups to gather data from 4 different groups representing the principal team member roles: primary care providers, registered nurse care managers, licensed practical nurses, and clerical associates. RESULTS: Team members identified within-team role and interpersonal conflict, as well as discordant administrative leadership styles, as key implementation challenges. CONCLUSIONS: Our results suggest that, in addition to technological and fiscal infrastructure, healthcare leaders implementing the PCMH model must take into account interprofessional issues associated with changes in leadership and the adoption of team-based structures. PMID- 23448111 TI - Do electronic medical records improve diabetes quality in physician practices? AB - OBJECTIVES: To measure the effect of electronic medical records (EMRs) on a publicly reported composite measure indicating optimal diabetes care (ODC) rates in ambulatory settings. STUDY DESIGN: Data from Minnesota Community Measurement on 557 clinics were used, including information on ODC, EMR adoption, and clinic characteristics. METHODS: A difference-in-differences strategy was used to estimate the impact of EMR adoption on patient outcomes while controlling for observed and unobserved clinic characteristics. Results were compared with a cross-sectional analysis of the same data. RESULTS: EMRs had no observable effect on ODC for the average clinic during the first 2 years postadoption. EMRs may, however, generate modest (+4 percentage point) ODC increases for clinics in large, multisite practices. Cross-sectional analysis likely overestimates the effect of EMRs on quality. CONCLUSIONS: There is little evidence that EMR adoption improves diabetes care during the first 2 years postadoption. This is notable as diabetes is a condition for which information technology has the potential to improve care management. The results suggest that policy makers should not expect public sector EMR investments to yield significant short-term improvements in publicly reported measures. PMID- 23448112 TI - Short-term costs associated with primary prophylactic G-CSF use during chemotherapy. AB - BACKGROUND: Chemotherapy is vital for breast cancer treatment, but early-onset toxicities like neutropenia hinder its administration. Neutropenia also increases costs due to hospitalizations and aggressive systemic antibiotic administration. Primary prophylactic (PP) use of granulocyte colony-stimulating factor (G-CSF) helps prevent neutropenia. However, evidence supporting the cost-effectiveness of PPG-CSF is inconclusive, and American Society of Clinical Oncology guidelines state the need for performing cost analyses in high-risk groups like the elderly. OBJECTIVES: To examine the effect of PPG-CSF administration on neutropenia hospitalization costs and overall Medicare costs during the year following chemotherapy initiation. METHODS: A retrospective observational study of patients newly diagnosed with breast cancer between 1994 and 2002 was performed using the linked SEER-Medicare database. To account for the nonrandom nature of observational data, a covariate matching technique was used to preprocess the data before performing parametric analysis estimating the effect of PPG-CSF on costs. RESULTS: Administration of PPG-CSF during the first course of chemotherapy was associated with a 57% increase in overall Medicare costs during the study period, despite a drop in neutropenia hospitalization costs. Forty-two percent of the increase in costs was due to increase in chemotherapy costs during the year after chemotherapy initiation. CONCLUSIONS: A significant part of the increase in immediate medical costs in breast cancer patients receiving PPG-CSF is due to improved chemotherapy administration. It is important to determine whether these short-term cost increases lead to long-term health benefits and savings. Cost analyses with longer follow-ups are crucial for chronic diseases like breast cancer. PMID- 23448113 TI - The cost of implementing inpatient bar code medication administration. AB - OBJECTIVES: To calculate the costs associated with implementing and operating an inpatient bar-code medication administration (BCMA) system in the community hospital setting and to estimate the cost per harmful error prevented. STUDY DESIGN: This is a retrospective, observational study. Costs were calculated from the hospital perspective and a cost-consequence analysis was performed to estimate the cost per preventable adverse drug event averted. METHODS: Costs were collected from financial records and key informant interviews at 4 not-for profit community hospitals. Costs included direct expenditures on capital, infrastructure, additional personnel, and the opportunity costs of time for existing personnel working on the project. The number of adverse drug events prevented using BCMA was estimated by multiplying the number of doses administered using BCMA by the rate of harmful errors prevented by interventions in response to system warnings. Our previous work found that BCMA identified and intercepted medication errors in 1.1% of doses administered, 9% of which potentially could have resulted in lasting harm. RESULTS: The cost of implementing and operating BCMA including electronic pharmacy management and drug repackaging over 5 years is $40,000 (range: $35,600 to $54,600) per BCMA-enabled bed and $2000 (range: $1800 to $2600) per harmful error prevented. CONCLUSIONS: BCMA can be an effective and potentially cost-saving tool for preventing the harm and costs associated with medication errors. PMID- 23448114 TI - Spending and mortality in US acute care hospitals. AB - BACKGROUND: Despite evidence that greater US Medicare spending is not associated with better quality of care at a regional level, recent studies suggest that greater hospital spending is associated with lower risk-adjusted mortality. Studies have been limited to older data, specific US states and conditions, and the Medicare population. OBJECTIVES: To analyze the association between hospital spending and risk-adjusted inpatient mortality for 6 major medical conditions in US acute care hospitals. STUDY DESIGN: Retrospective cohort study of risk adjusted inpatient mortality, with hospital spending taken from the Dartmouth Atlas of Health Care. The study population included 2,635,510 patients admitted to 1201 US hospitals between 2003 and 2007. METHODS: Patient-level logistic regression models were used to estimate the effect of hospital spending on inpatient mortality, controlling for mortality risk, comorbidities, community characteristics (eg, median household income in a patient's zip code), hospital volume and ownership, and admission year. RESULTS: Patients treated at hospitals in the highest spending quintile (relative to the lowest) had lower risk-adjusted inpatient mortality for acute myocardial infarction (odds ratio [OR] 0.751, 95% confidence interval [CI] 0.656-0.859), congestive heart failure (OR 0.652, 95% CI 0.560-0.759), stroke (OR 0.852, 95% CI, 0.739-0.983), and hip fracture (OR 0.691, 95% CI 0.545-0.876). Greater spending was associated with lower mortality primarily in nonteaching hospitals, hospitals with fewer than the median number of beds, and nonprofit/public hospitals. CONCLUSIONS: Greater hospital spending is associated with lower risk-adjusted inpatient mortality for major medical conditions in the United States. PMID- 23448115 TI - Cost-effectiveness of Medicare drug plans in schizophrenia and bipolar disorder. AB - BACKGROUND: Medicare Part D has a drug coverage gap, which imposes risks for discontinuing medications, particularly in mental health disorders where drug costs are high. However, some beneficiaries have generic drug coverage in the gap. OBJECTIVES: To examine the health outcomes and cost-effectiveness of generic drug coverage compared with no gap coverage in patients with bipolar disorder and schizophrenia. STUDY DESIGN: Markov model-based cost-effectiveness analysis using identical hypothetical cohorts to examine drug coverage strategies. METHODS: The incremental cost-effectiveness of Part D coverage strategies was estimated, using differences in medical costs and quality-adjusted life years between plans. Coverage strategy-specific costs and hospitalization rates were obtained from 2007 Medicare data, adjusted for age, sex, race, and health status. RESULTS: When comparing generic-only coverage with no gap coverage, generic-only coverage cost less and was more effective than no gap coverage, due mainly to lower hospitalization rates. In sensitivity analyses, generic-only coverage continued to be favored over no gap coverage unless generic coverage costs increased > 3% in bipolar disorder and > 5% in schizophrenia; generic coverage in the gap was also favored in probabilistic sensitivity analyses. CONCLUSIONS: In Medicare Part D, generic drug coverage was cost saving compared with no coverage in bipolar disorder and schizophrenia while improving health outcomes. Policy makers and insurers might consider generic-only coverage, rather than no gap coverage, to both conserve healthcare resources and improve health. PMID- 23448116 TI - Guidance for structuring team-based incentives in healthcare. AB - New payment methods designed to incentivize more efficient care delivery are accelerating the movement of healthcare providers into organized provider groups. More efficient healthcare delivery requires explicit structuring of care delivery processes around teams of clinicians working toward common patient care goals. Provider organizations accepting new payment methods will need to design and implement compensation systems that provide incentives for team-based care. While lessons from studies performed both outside and inside healthcare provide some guidance on designing and implementing team-based incentives, organized delivery systems face several significant barriers to accomplishing this. PMID- 23448117 TI - Introducing forensic health services research. AB - Financial fraud and abuse are rampant within our healthcare system. Recent estimates suggest that $68 to $234 billion is lost to fraud annually. Despite numerous efforts, current strategies have met with limited success in preventing and remediating this practice. Why have we not been better able to tackle this problem? Current strategies aimed at preventing healthcare fraud and abuse fail to appreciate the spectrum that lies between clinically appropriate care and fraudulent practice. This oversight is critical, as what may be fitting treatment in one setting may just as easily be fraudulent in another. Therefore, in order to untangle the web of fraud and abuse, novel techniques and engagement of physicians who best understand these nuances are necessary. In this commentary, we introduce "forensic health services research," an extension of this scientific discipline that can best identify wasteful and fraudulent expenditure. The use of health services research in this fashion is not only synergistic with ongoing efforts, but greatly enhances current approaches. Despite the promise of this endeavor, important policy changes are needed to nurture this novel niche. We review these challenges and outline a path to move forward using this platform. PMID- 23448118 TI - The unique pseudanthium of Actinodium (Myrtaceae) - morphological reinvestigation and possible regulation by CYCLOIDEA-like genes. AB - BACKGROUND: Genes encoding TCP transcription factors, such as CYCLOIDEA-like (CYC like) genes, are well known actors in the control of plant morphological development, particularly regarding the control of floral symmetry. Despite recent understanding that these genes play a role in establishing the architecture of inflorescences in the sunflower family (Asteraceae), where hundreds of finely organized flowers are arranged to mimic an individual flower, little is known about their function in the development of flower-like inflorescences across diverse phylogenetic groups. Here, we studied the head-like pseudanthium of the Australian swamp daisy Actinodium cunninghamii Schau. (Myrtaceae, the myrtle family), which consists of a cluster of fertile flowers surrounded by showy ray-shaped structures, to fully characterize its inflorescence development and to test whether CYC-like genes may participate in the control of its daisy-like flowering structures. RESULTS: We used standard morphological and anatomical methods to analyze Actinodium inflorescence development. Furthermore, we isolated Actinodium CYC-like genes using degenerate PCR primers, and studied the expression patterns of these genes using quantitative RT-PCR. We found that the ray-shaped elements of Actinodium are not single flowers but instead branched short-shoots occasionally bearing flowers. We found differential expression of CYC-like genes across the pseudanthium of Actinodium, correlating with the showiness and branching pattern of the ray structures. CONCLUSIONS: The Actinodium inflorescence represents a novel type of pseudanthium with proximal branches mimicking ray flowers. Expression patterns of CYC-like genes are suggestive of participation in the control of pseudanthium development, in a manner analogous to the distantly related Asteraceae. As such, flowering plants appear to have recruited CYC-like genes for heteromorphic inflorescence development at least twice during their evolutionary history. PMID- 23448119 TI - Type 2 diabetes and the evolving paradigm in glucose regulation. AB - Type 2 diabetes mellitus (T2DM) is a multisystem disease comprising numerous metabolic defects that contribute to the development of hyperglycemia. Although insulin resistance in the skeletal muscle and liver together with progressive beta cell failure are traditionally thought of as the core defects responsible for the development and progression of hyperglycemia, research over the past 2 decades has revealed a far more complex interaction of organs and tissues, with consequences for the fundamental understanding of the mechanisms of glucose disequilibrium and the nature of T2DM itself. Dysfunctions in the gastrointestinal tract, adipose tissue, pancreatic alpha cells, brain, and kidneys have all been described, and together with insights into the involvement of liver, muscle, and beta cells produce a more robust picture of T2DM. The function of the kidneys in abnormal glucose homeostasis is a striking example of this evolution in T2DM knowledge, as the role of glucose transporters in regulating plasma glucose levels and producing hyperglycemia has enhanced current understanding of T2DM. As pathophysiologic mechanisms and defects continue to be discovered, they offer an expansion of potential targets for treatment of T2DM. PMID- 23448120 TI - Integrative care for pediatric patients with pain. AB - OBJECTIVES: Although pediatric patients with chronic pain often turn to complementary therapies, little is known about patients who seek academic integrative pediatric care. DESIGN: The study design comprised abstraction of intake forms and physician records from new patients whose primary concern was pain. SETTING/LOCATION: The study setting was an academic pediatric clinic between January 2010 and December 2011. SUBJECTS: Of the 110 new patients, 49 (45%) had a primary concern about headache (20), abdominal pain (18), or musculoskeletal pain (11). RESULTS: The average age was 13+/-4 years, and 37% were male. Patients reported an average pain level of 6+/-3 on a 10-point scale, and most reported more than one kind of pain; parents had an average of 7+/-3 health concerns per child, including fatigue (47%), mood or anxiety (45%), constipation/diarrhea (41%), and/or sleep problems (35%). Most patients (57%) were referred by specialists; 71% were taking prescription medications; and 53% were taking one or more dietary supplements at intake. Of those tested, most (61%) had suboptimal vitamin D levels. All families wanted additional counseling about diet (76%), exercise (66%), sleep (58%), and/or stress management (81%). In addition to encouraging continued medical care (100%) and referral to other medical specialists (16%), frequent advice included continuing or initiating dietary supplements such as vitamins/minerals (80%), omega-3 fatty acids (67%), and probiotics (31%). Stress-reducing recommendations included biofeedback (33%), gratitude journals (16%), and yoga/t'ai chi (8%). Other referrals included acupuncture (24%) and massage (20%). DISCUSSION: Patients who have chronic pain and who present to an integrative clinic frequently have complex conditions and care. They are interested in promoting a healthy lifestyle, reducing stress, and using selected complementary therapies. CONCLUSION: Patients with chronic pain who seek integrative care may benefit from the kind of coordinated, integrated, comprehensive care provided in a medical home. PMID- 23448122 TI - Effects of varying intraperitoneal pressure on liver function tests during laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy at standard-pressure pneumoperitoneum uses a pressure of 12-14 mm Hg, which may cause a variety of adverse physiological changes involving the respiratory, cardiovascular, and hepatorenal systems reflected as subclinical abnormalities in biochemical parameters. The use of low-pressure pneumoperitoneum in the range of 8-10 mm Hg has been shown to reduce the adverse physiological changes without affecting the outcome of surgery. SUBJECTS AND METHODS: This study was done in a randomized controlled manner. Patients with gallstone disease (n=101) underwent laparoscopic cholecystectomy. Patients were randomly assigned to high-pressure laparoscopic cholecystectomy (HPLC) (n=51) and low-pressure laparoscopic cholecystectomy (LPLC) (n=50) and underwent surgery at pressures of 14 mm Hg and 8 mm Hg, respectively. Liver function tests, including total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase, were obtained preoperatively and on postoperative Days 1 and 7. RESULTS: The two study groups had similar demographic profiles, and there were no significant differences in the operative time (HPLC, 47.25 +/- 6.73 minutes; LPLC, 48.00 +/- 7.76 minutes; P=.6071) and pneumoperitoneum time (HPLC, 34.02 +/- 5.29 minutes; LPLC, 34.60 +/- 6.13 minutes; P=.6115). On postoperative Day 1, the total bilirubin levels were 1.0684 +/- 0.4108 mg/dL and 0.8926 +/- 0.3162 mg/dL for HPLC and LPLC (P=.0179), respectively, AST levels were 66.0810 +/- 25.5868 IU/L and 42.2420 +/- 14.7301 IU/L (P=.0001), respectively, and ALT levels were 68.1410 +/- 31.4572 IU/L and 42.7460 +/- 17.9405 IU/L (P=.0001), respectively. Thus, liver enzyme activities were significantly elevated in the HPLC group compared with the LPLC group. CONCLUSIONS: LPLC causes less abnormality in liver function tests in the postoperative period compared with HPLC. LPLC should be considered in all patients undergoing laparoscopic cholecystectomy, especially those patients with compromised liver functions. PMID- 23448123 TI - Laparoscopic anatrophic nephrolithotomy for management of staghorn renal calculi. AB - BACKGROUND: Management of staghorn renal stones is still challenging. We present our experience with laparoscopic anatrophic nephrolithotomy as an alternative option for management of staghorn renal calculi. PATIENTS AND METHODS: Twenty four patients with staghorn renal calculi underwent 25 laparoscopic anatrophic nephrolithtomy procedures. Characteristics of patients and stones along with perioperative features such as operation time, transfusion, ischemic time, hospitalization, stone-free rate, and biochemical data were recorded prospectively. We applied the one-layer knotless technique for renorrhaphy repair. RESULTS: The mean age of the patients was 55.1 +/- 10.9 years (range, 28 74 years). Eleven (44%) operations were done on the right side, and 14 (56%) were done on the left side. Complete and partial staghorn stones existed in 17 (68%) and 8 (32%) renal units, respectively. The mean stone size was 61.5 +/- 11.5 mm. Ischemic time was 30.4 +/- 7.55 minutes. The stone-free rate was 88% on discharge and 92% after one session of extracorporeal shockwave lithotripsy. CONCLUSIONS: Although percutaneous nephrolithotomy is the standard of care for treatment of staghorn stone, laparoscopic anatrophic nephrolithotomy seems to be a safe and feasible option in select patients. PMID- 23448124 TI - Influence of implantation age on school-age language performance in pediatric cochlear implant users. AB - OBJECTIVE: This study examined specific spoken language abilities of 160 children with severe-to-profound sensorineural hearing loss followed prospectively 4, 5, or 6 years after cochlear implantation. STUDY SAMPLE: Ninety-eight children received implants before 2.5 years, and 62 children received implants between 2.5 and 5 years of age. DESIGN: Language was assessed using four subtests of the Comprehensive Assessment of Spoken Language (CASL). Standard scores were evaluated by contrasting age of implantation and follow-up test time. RESULTS: Children implanted under 2.5 years of age achieved higher standard scores than children with older ages of implantation for expressive vocabulary, expressive syntax, and pragmatic judgments. However, in both groups, some children performed more than two standard deviations below the standardization group mean, while some scored at or well above the mean. CONCLUSIONS: Younger ages of implantation are associated with higher levels of performance, while later ages of implantation are associated with higher probabilities of continued language delays, particularly within subdomains of grammar and pragmatics. Longitudinal data from this cohort study demonstrate that after 6 years of implant experience, there is large variability in language outcomes associated with modifiers of rates of language learning that differ as children with implants age. PMID- 23448125 TI - Fluorine-18 labeled fluorodeoxyglucose PET useful for therapy monitoring in localized AL amyloidosis? PMID- 23448121 TI - Ultrasound-mediated drug delivery for cardiovascular disease. AB - INTRODUCTION: Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery. AREAS COVERED: The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies. EXPERT OPINION: These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments. PMID- 23448126 TI - Identification of mouse colony-forming endothelial progenitor cells for postnatal neovascularization: a novel insight highlighted by new mouse colony-forming assay. AB - INTRODUCTION: Endothelial progenitor cells (EPCs) play a critical role in restoration of ischemic diseases. However, the actual status of EPC development and the mechanisms of EPC dysfunctions in patients with various ischemic diseases remain unknown. METHODS: To investigate the detailed function of EPCs in experimental murine models, we have established an EPC colony forming assay (EPC CFA) in murine EPCs. The abilities of murine EPCs in differentiation, adhesive capacity, proliferative potency, and transplantation in vitro and in vivo were then examined. RESULTS: Peripheral blood mononuclear cells (PB-MNCs), bone marrow mononuclear cells (BM-MNCs) or bone marrow c-Kit+/Sca-1+ lineage negative (BM KSL) cells differentiated into two types of EPC colony forming units (EPC-CFUs), large sized EPC (large-EPC)-CFUs and small sized EPC (small-EPC)-CFUs. Gene expression analysis demonstrated that both EPC-CFU-derived cells expressed eNOS, Flk-1 and VE-cadherin, markers of endothelial cells (ECs), although the small EPCs derived from small-EPC-CFU were higher in number and showed more immature features (higher population of KSL cells). Functionally, the large-EPCs derived from large-EPC-CFU had higher adhesive capacity but lower proliferative potency than small-EPCs, showing improved tubular forming capacity and incorporation potency into primary EC-derived tube formation. Importantly, hindlimb ischemia increased the frequencies of large-EPC-CFUs differentiated from PB-MNCs and bone marrow. Actually, transplantation of large-EPCs into ischemic hindlimb enhanced neovascularization in hindlimb ischemia model, although small-EPCs or murine ECs did not, suggesting that large-EPC-CFUs might play an important role in restoration of ischemic diseases. CONCLUSIONS: We demonstrated, using a murine ischemia model, that the EPC-CFA could be a useful way to investigate the differentiation levels of murine EPCs, further providing a crucial clue that large-EPC-CFU status may be more functional or effective EPCs to promote neovascularization. PMID- 23448127 TI - In vitro activity-guided identification of antioxidants in aged garlic extract. AB - Activity-guided fractionation was applied on an aged garlic extract (AGE), reported to show strong antioxidant activity, in order to locate the key in vitro antioxidant ingredients by means of the hydrogen peroxide scavenging (HPS) assay as well as the ORAC assay. Besides the previously reported four tetrahydro-beta carbolines, (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3 carboxylic acid and (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta carboline-1,3-dicarboxylic acid, LC-MS/MS, LC-TOF-MS, and 1D/2D-NMR experiments led to the identification of coniferyl alcohol and its dilignols (-)-(2R,3S) dihydrodehydrodiconiferyl alcohol, (+)-(2S,3R)-dehydrodiconiferyl alcohol, erythro-guaiacylglycerol-beta-O-4'-coniferyl ether, and threo-guaiacylglycerol beta-O-4'-coniferyl ether as the major antioxidants in AGE. The purified individual compounds showed high antioxidant activity, with EC50 values of 9.7 11.8 MUM (HPS assay) and 2.60-3.65 MUmol TE/MUmol (ORAC assay), respectively. PMID- 23448128 TI - Howard Elliott Zimmerman. PMID- 23448129 TI - Glutathione dimerization-based plasmonic nanoswitch for biodetection of reactive oxygen and nitrogen species. AB - Reactive oxygen and nitrogen species (ROS and RNS) are continuously produced in the cellular systems and are controlled by several antioxidant mechanisms. Here, we developed a straightforward, sensitive, and quantitative assay for the colorimetric and spectroscopic detection of various ROS and RNS such as H2O2, .OH, (-)OCl, NO., and O2(-) using glutathione-modified gold nanoparticles (GSH AuNPs). A basic principle here is that the GSHs on the AuNP surface can be readily detached via the formation of glutathione disulfides upon the addition of ROS and RNS, and destabilized particles can aggregate to generate the plasmonic couplings between plasmonic AuNPs that trigger the red shift in UV-vis spectrum and solution color change. For nonradical species such as H2O2, this process can be more efficiently achieved by converting them into radical species via the Fenton reaction. Using this strategy, we were able to rapidly and quantitatively distinguish among cancerous and normal cells based on ROS and RNS production. PMID- 23448130 TI - C-C bond formation and related reactions at the CNC backbone in (smif)FeX (smif = 1,3-di-(2-pyridyl)-2-azaallyl): dimerizations, 3 + 2 cyclization, and nucleophilic attack; transfer hydrogenations and alkyne trimerization (X = N(TMS)2, dpma = (di-(2-pyridyl-methyl)-amide)). AB - Molecular orbital analysis depicts the CNC(nb) backbone of the smif (1,3-di-(2 pyridyl)-2-azaallyl) ligand as having singlet diradical and/or ionic character where electrophilic or nucleophilic attack is plausible. Reversible dimerization of (smif)Fe{N(SiMe3)2} (1) to [{(Me3Si)2N}Fe]2(MU-kappa(3),kappa(3)-N,py2 smif,smif) (2) may be construed as diradical coupling. A proton transfer within the backbone-methylated, and o-pyridine-methylated smif of putative ((b)Me2(o)Me2smif)FeN(SiMe3)2 (8) provides a route to [{(Me3Si)2N}Fe]2(MU kappa(4),kappa(4)-N,py2,C-((b)Me,(b)CH2,(o)Me2(smif)H))2 (9). A 3 + 2 cyclization of ditolyl-acetylene occurs with 1, leading to the dimer [{2,5-di(pyridin-2-yl) 3,4-di-(p-tolyl-2,5-dihydropyrrol-1-ide)}FeN(SiMe3)2]2 (11), and the collateral discovery of alkyne cyclotrimerization led to a brief study that identified Fe(N(SiMe3)2(THF) as an effective catalyst. Nucleophilic attack by (smif)2Fe (13) on (t)BuNCO and (2,6-(i)Pr2C6H3)NCO afforded (RNHCO-smif)2Fe (14a, R = (t)Bu; 14b, 2,6-(i)PrC6H3). Calculations suggested that (dpma)2Fe (15) would favorably lose dihydrogen to afford (smif)2Fe (13). H2-transfer to alkynes, olefins, imines, PhN?NPh, and ketones was explored, but only stoichiometric reactions were affected. Some physical properties of the compounds were examined, and X-ray structural studies on several dinuclear species were conducted. PMID- 23448131 TI - Sofosbuvir, a nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus infection. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection is ubiquitous, affecting approximately 180 million individuals worldwide and around 3.2 million in the United States. While peginterferon and ribavirin alone continue to be used, the treatment landscape for patients with genotype 1 has recently changed to include one of two protease inhibitors: boceprevir and telaprevir. Despite this, effective therapies for chronic HCV for all genotypes represent a largely unmet need. AREAS COVERED: Sofosbuvir , formally labeled GS-7977, is an HCV NS5B nucleotide polymerase inhibitor that has entered multiple Phase III trials. Phase II trials demonstrated that treatments including sofosbuvir have higher sustained virologic response rates for genotypes 1, 2, 3, 4 and 6 in comparison with treatments that include only peginterferon and ribavirin. In addition, the side effect profile of sofosbuvir and ribavirin dual treatment has an improved tolerability in comparison with treatment regimes that include interferon-based options. EXPERT OPINION: The hope and expectation is that interferon is eliminated from the armamentarium of HCV therapy and that all-oral therapies prove effective although interferon in combination with multiple drugs may still be required to treat select patients. In addition, there is a need to develop effective therapies for all HCV genotypes with simple and well-tolerated regimes. PMID- 23448132 TI - Reproducibility of physical activity recall over fifteen years: longitudinal evidence from the CARDIA study. AB - BACKGROUND: To examine the benefits of physical activity (PA) on diseases with a long developmental period, it is important to determine reliability of long-term PA recall. METHODS: We investigated 15-year reproducibility of PA recall. Participants were 3605 White and African-American adults in the Coronary Artery Risk Development in Young Adults study, aged 33-45 at the time of recall assessment. Categorical questions assessed PA before and during high school (HS) and overall PA level at Baseline, with the same timeframes recalled 15 years later. Moderate- and vigorous-intensity scores were calculated from reported months of participation in specific activities. RESULTS: HS PA recall had higher reproducibility than overall PA recall (weighted kappa = 0.43 vs. 0.21). Correlations between 15-year recall and Baseline reports of PA were r = 0.29 for moderate-intensity scores, and r = 0.50 for vigorous-intensity. Recall of vigorous activities had higher reproducibility than moderate-intensity activities. Regardless of number of months originally reported for specific activities, most participants recalled either no activity or activity during all 12 months. CONCLUSION: PA recall from the distant past is moderately reproducible, but poor at the individual level, among young and middle aged adults. PMID- 23448133 TI - Biology of Chiloloba orientalis. AB - This study, related to emergence of the cetoniid beetle, Chiloloba orientalis D and R (Coleoptera: Scarabaeidae: Cetoniinae), was conducted annually from August to the middle of October from 2007 to 2010 in maize (Zea mays L. (Poales: Poaceae)), sorghum (Sorghum bicolor (L.) Moench), and grass (Hetropogon contortus (L.) P. Beauv. ex Roem. and Schult., Apluda mutica L.) cultivated fields in a selected plot of grassland in Kolhapur, Maharashtra, India. Adults of C. orientalis feed on the inflorescence of S. bicolor, Z. mays, H. contortus and A. mutica. The occurrence of adults in this study indicates that the emergence of beetles coincides with the flowering period of its host plants. The immature stages of this beetle feed on the decaying organic matter of crop residues in composting heaps, indicating these immature stages play a key role in the recycling of organic waste of plant and animal origin and help in the enrichment of soil nutrients, especially in the red brown soil where primary decomposers are scarce. This study provides detailed information on the morphological peculiarities of immature stages with the duration required for the completion of the life cycle. The average incubation period of eggs was 15.2 days. The first, second, and third instar lasted for 22.7, 54.3, and 46.6 days respectively. The mean pupal period was 14.7 days. The average adult longevity was 9.4 days. PMID- 23448135 TI - In memoriam: Kuan-Teh Jeang, MD PhD (1958-2013). PMID- 23448134 TI - Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia. AB - BACKGROUND: The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung. METHODS: We studied newborn wild type (WT), MIF knockout (MIFKO), and lung MIF transgenic (MIFTG) mice in room air and a BPD model, and examined the effects of administering a small molecule MIF agonist and antagonist. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed. RESULTS: The pulmonary phenotype of MIFKO and MIFTG mice lungs in room air (RA) and BPD model were comparable to the WT-BPD mice at postnatal (PN) day 14. Vascular endothelial growth factor (VEGF)-A, -R1 and Angiopoietin (Ang)1 mRNA were decreased, and Ang2 increased in the WT-BPD, MIFKO-RA, MIFKO-BPD, MIFTG-RA and MIFTG-BPD mice lungs, compared to appropriate controls. The protein expression of Ang1 in the MIFKO-RA was similar to WT-RA, but decreased in MIFTG-RA, and decreased in all the BPD groups. Ang2 was increased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. Tie2 was increased in WT-BPD compared to WT-RA, but decreased in MIFKO- and MIFTG- RA and BPD groups. VEGFR1 was uniformly decreased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. VEGF-A had a similar expression across all RA and BPD groups. There was partial recovery of the pulmonary phenotype in the WT-BPD model treated with the MIF agonist, and in the MIFTG mice treated with the MIF antagonist. CONCLUSIONS: These data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD. PMID- 23448136 TI - A functional genomics screen for microRNA regulators of NF-kappaB signaling. AB - BACKGROUND: The nuclear factor-KappaB (NF-kappaB) pathway is conserved from fruit flies to humans and is a key mediator of inflammatory signaling. Aberrant regulation of NF-kappaB is associated with several disorders including autoimmune disease, chronic inflammation, and cancer, making the NF-kappaB pathway an attractive therapeutic target. Many regulatory components of the NF-kappaB pathway have been identified, including microRNAs (miRNAs). miRNAs are small non coding RNAs and are common components of signal transduction pathways. Here we present a cell-based functional genomics screen to systematically identify miRNAs that regulate NF-kappaB signaling. RESULTS: We screened a library of miRNA mimics using a NF-kappaB reporter cell line in the presence and absence of tumor necrosis factor (+/- TNF). There were 9 and 15 hits in the -TNF and +TNF screens, respectively. We identified putative functional targets of these hits by integrating computational predictions with NF-kappaB modulators identified in a previous genome-wide cDNA screen. miR-517a and miR-517c were the top hits, activating the reporter 86- and 126-fold, respectively. Consistent with these results, miR-517a/c induced the expression of endogenous NF-kappaB targets and promoted the nuclear localization of p65 and the degradation of IkappaB. We identified TNFAIP3 interacting protein1 (TNIP1) as a target and characterized a functional SNP in the miR-517a/c binding site. Lastly, miR-517a/c induced apoptosis in vitro, which was phenocopied by knockdown of TNIP1. CONCLUSIONS: Our study suggests that miRNAs are common components of NF-kappaB signaling and miR 517a/c may play an important role in linking NF-kappaB signaling with cell survival through TNIP1. PMID- 23448137 TI - An improved cryosection method for polyethylene glycol hydrogels used in tissue engineering. AB - The high water content of hydrogels allows these materials to closely mimic the native biological extracellular conditions, but it also makes difficult the histological preparation of hydrogel-based bioengineered tissue. Paraffin embedding techniques require dehydration of hydrogels, resulting in substantial collapse and deformation, whereas cryosectioning is hampered by the formation of ice crystals within the hydrogel material. Here, we sought to develop a method to obtain good-quality cryosections for the microscopic evaluation of hydrogel-based tissue-engineered constructs, using polyethylene glycol (PEG) as a test hydrogel. Conventional sucrose solutions, which dehydrate cells while leaving extracellular water in place, produce a hydrogel block that is brittle and difficult to section. We therefore replaced sucrose with multiple protein-based and nonprotein based solutions as cryoprotectants. Our analysis demonstrated that overnight incubation in bovine serum albumin (BSA), fetal bovine serum (FBS), polyvinyl alcohol (PVA), optimum cutting temperature (OCT) compound, and Fisher HistoPrep frozen tissue-embedding media work well to improve the cryosectioning of hydrogels. The protein-based solutions give background staining with routine hematoxylin and eosin, but the use of nonprotein-based solutions PVA and OCT reduces this background by 50%. These methods preserve the tissue architecture and cellular details with both in vitro PEG constructs and in constructs that have been implanted in vivo. This simple hydrogel cryosectioning technique improves the methodology for creation of good-quality histological sections from hydrogels in multiple applications. PMID- 23448138 TI - Cardiac iron measurement and iron chelation therapy in patients with beta thalassaemia major: experience from Taiwan. AB - BACKGROUND: The aims of our study were to evaluate (i) the relationship between cardiac T2* values and cardiac complications in Asian beta-thalassaemia major (TM) patients, and (ii) the association between cardiac T2* values and other parameters currently used to predict cardiac complications as a result of transfusion iron overload. METHODS: We examined the myocardial iron loads of 88 TM patients from Taiwan with cardiac T2* magnetic resonance imaging (MRI) and assessed the correlation between cardiac T2* values and serum ferritin levels, liver iron concentration and left ventricular ejection fraction (LVEF). We also determined the predictive value of these measurements for the development of arrhythmia. RESULTS AND CONCLUSION: In our group of Taiwanese patients, the relative risk for arrhythmia was 10.36 when cardiac T2* values were less than 10 ms (compared with >=10 ms) and 1.98 when serum ferritin levels increased >2500 ng mL(-1) (compared with <=2500 ng mL(-1) ). Serum ferritin levels correlated with cardiac T2* values in patients with abnormal myocardial iron loads (T2* < 20 ms, r = -0.48, P = 0.004, n = 34), but LVEF (measured by echocardiography) gave no indication of excess myocardial iron deposition (r = -0.07, P = 0.52) or of the risk of developing arrhythmia. PMID- 23448139 TI - Does habitat disturbance increase infectious disease risk for primates? AB - Many studies have suggested that ecosystem conservation protects human and wildlife populations against infectious disease. We tested this hypothesis using data on primates and their parasites. First, we tested for relationships between species' resilience to human disturbance and their parasite richness, prevalence and immune defences, but found no associations. We then conducted a meta-analysis of the effects of disturbance on parasite prevalence, which revealed no overall effect, but a positive effect for one of four types of parasites (indirectly transmitted parasites). Finally, we conducted intraspecific analyses of malaria prevalence as a function of mammalian species richness in chimpanzees and gorillas, and an interspecific analysis of geographic overlap and parasite species richness, finding that higher levels of host richness favoured greater parasite risk. These results suggest that anthropogenic effects on disease transmission are complex, and highlight the need to define the conditions under which environmental change will increase or decrease disease transmission. PMID- 23448140 TI - Platelet activation: a link between psoriasis per se and subclinical atherosclerosis--a case-control study. AB - BACKGROUND: Pathomechanisms of both psoriasis and atherosclerosis may involve platelet activation. Activated platelets show increased P-selectin; CD62 expression, and mean platelet volume (MPV). Impaired brachial artery flow mediated dilatation (FMD) is related to atherosclerosis. OBJECTIVES: To determine the presence of subclinical atherosclerosis in patients with psoriasis (without overt cardiovascular complications or traditional cardiovascular disease risk factors), compared with controls. METHODS: In this case-control study, 25 patients with psoriasis and 25 age- and gender-matched healthy individuals were subjected to assessment of MPV, CD62 expression using flow cytometry, and brachial artery FMD and transthoracic echocardiography by cardiac ultrasound scanner. RESULTS: A statistically highly significant increased CD62 expression, but not MPV, was found in cases compared with controls, and in patients with moderate/severe psoriasis compared with either mild cases or controls (P < 0.001). CD62 expression was statistically significantly positively correlated with the Psoriasis Area and Severity Index (PASI) score (P < 0.001), baseline brachial artery diameter (P = 0.03) but not FMD and aortic root diameter (ARD; P = 0.03). ARD was statistically significantly higher in patients with moderate/severe psoriasis compared with controls (P = 0.017). Stepwise simple linear regression analysis revealed that PASI score was the most important factor affecting CD62 expression (P < 0.001). CONCLUSIONS: Our study showed increased atherosclerosis risk in patients with psoriasis, particularly those with moderate/severe disease, as evidenced by increased expression of platelet CD62 compared with healthy controls. Moreover, we found a positive correlation between CD62 expression and ARD (another possible marker of atherosclerosis), with positive correlation to the PASI score; the most important factor influencing CD62 expression. However, our data on MPV and FMD do not support the use of either value for diagnosing subclinical atherosclerosis in patients with psoriasis in further studies. PMID- 23448141 TI - Development of a nucleic acid lateral flow strip for detection of hepatitis C virus (HCV) core antigen. AB - The object of this study was to develop a simple, rapid, specific, and highly sensitive method to detect HCV core antigen. A nucleic acid aptamer was designed with the high specificity and sensitivity in a nucleic acid lateral flow strip to compete with HCV core antigen and DNA probes. The lower detection limit of the test strip was calculated to be 10 pg/mL with the scanner and 100 pg/mL with naked eyes. Results showed that there were no cross-interactions with other proteins such as HCV NS3, E1/E2 antigens, HIV p24 antigens, or BSA proteins (HCV unrelated protein). When the viral load exceeded 10(4) copies/mL, the positive coincidence rates of ELISA and strip detection, when compared with the HCV RNA assay, were 98.44% and 97.28%, respectively. The results indicated that the ELISA detection and strip assay were in good agreement with the measured value. The results indicated that a nucleic acid lateral flow strip was a simple, rapid, specific, highly sensitive, and cost-effective field-based method for detecting HCV core antigen. The strip assay is an acceptable alternative to diagnose HCV core antigen and to investigate its epidemiology in clinical laboratories lacking specialized equipment and skills. PMID- 23448142 TI - Synthesis and biological evaluation of nitrogen mustard derivatives of purine bases. AB - This paper deals with the synthesis of nitrogen mustard analogs, derivatives of purine bases. Alkylation in position N-9 and diethanolamine fixation on position 6 were managed by microwave irradiations. Chlorination of these dihydroxylated intermediates led to a cyclization, giving tricyclic purine base analogs bearing a chloroethyl chain. Finally, MTT assays on obtained compounds do not show cytotoxicity on four different cancer cell lines. PMID- 23448143 TI - Synthesis and biological activity of substituted 4H-1,4-benzothiazines, their sulfones, and ribofuranosides. AB - The present article describes the synthesis of new 4H-1,4-benzothiazines via condensation and oxidative cyclization of substituted 2-aminobenzenethiols with beta-diketones/beta-ketoesters in dimethyl sulfoxide. The oxidation of these synthesized 4H-1,4-benzothiazines with 30% hydrogen peroxide in glacial acetic acid yielded 4H-1,4-benzothiazine sulfones and the reaction of these synthesized benzothiazines with sugar (beta-D-ribofuranose-1-acetate-2,3,5-tribenzoate) afforded the new ribofuranosides. These compounds were evaluated for their antioxidant and antimicrobial activities (using broth microdilution method). The structural assignments of the synthesized compounds were made on the basis of elemental analyses and spectroscopic data. PMID- 23448144 TI - Synthesis of a new intercalating nucleic acid 6H-INDOLO[2,3-b] quinoxaline oligonucleotides to improve thermal stability of Hoogsteen-type triplexes. AB - A new intercalating nucleic acid monomer X was obtained in high yield starting from alkylation of 4-iodophenol with (S)-(+)-2-(2,2-dimethyl-1,3-dioxolan-4 yl)ethanol under Mitsunobu conditions followed by hydrolysis with 80% aqueous acetic acid to give a diol which was coupled under Sonogashira conditions with trimethylsilylacetylene (TMSA) to achieve the TMS protected (S)-4-(4 ((trimethylsilyl)ethynyl)phenoxy)butane-1,2-diol. Tetrabutylammonium flouride was used to remove the silyl protecting group to obtain (S)-4-(4 ethynylphenoxy)butane-1,2-diol which was coupled under Sonogashira conditions with 2-(9-bromo-6H-indolo[2,3-b]quinoxalin-6-yl)-N,N-dimethylethanamine to achieve (S)-4-(4-((6-(2-(dimethylamino)ethyl)-6H-indolo[2,3-b]quinoxalin-9 yl)ethynyl)phenoxy)butane-1,2-diol. This compound was tritylated with 4,4' dimethoxytrityl chloride followed by treatment with 2 cyanoethyltetraisopropylphosphordiamidite in the presence of N,N'-diisopropyl ammonium tetrazolide to afford the corresponding phosphoramidite. This phosphoramidite was used to insert the monomer X into an oligonucleotide which was used for thermal denaturation studies of a corresponding parallel triplex. PMID- 23448145 TI - MeCP2 regulates ethanol sensitivity and intake. AB - We have investigated the expression of chromatin-regulating genes in the prefrontal cortex and in the shell subdivision of the nucleus accumbens during protracted withdrawal in mice with increased ethanol drinking after chronic intermittent ethanol (CIE) vapor exposure and in mice with a history of non dependent drinking. We observed that the methyl-CpG binding protein 2 (MeCP2) was one of the few chromatin-regulating genes to be differentially regulated by a history of dependence. As MeCP2 has the potential of acting as a broad gene regulator, we investigated sensitivity to ethanol and ethanol drinking in MeCP2(308/) (Y) mice, which harbor a truncated MeCP2 allele but have a milder phenotype than MeCP2 null mice. We observed that MeCP2(308/) (Y) mice were more sensitive to ethanol's stimulatory and sedative effects than wild-type (WT) mice, drank less ethanol in a limited access 2 bottle choice paradigm and did not show increased drinking after induction of dependence with exposure to CIE vapors. Alcohol metabolism did not differ in MeCP2(308/) (Y) and WT mice. Additionally, MeCP2(308/) (Y) mice did not differ from WT mice in ethanol preference in a 24 hour paradigm nor in their intake of graded solutions of saccharin or quinine, suggesting that the MeCP2(308/) (Y) mutation did not alter taste function. Lastly, using the Gene Set Enrichment Analysis algorithm, we found a significant overlap in the genes regulated by alcohol and by MeCP2. Together, these results suggest that MeCP2 contributes to the regulation of ethanol sensitivity and drinking. PMID- 23448146 TI - Adherence to antiepileptic medicines in children: a multiple-methods assessment involving dried blood spot sampling. AB - PURPOSE: To evaluate adherence to prescribed antiepileptic drugs (AEDs) in children with epilepsy using a combination of adherence-assessment methods. METHODS: A total of 100 children with epilepsy (<=17 years old) were recruited. Medication adherence was determined via parental and child self-reporting (>=9 years old), medication refill data from general practitioner (GP) prescribing records, and via AED concentrations in dried blood spot (DBS) samples obtained from children at the clinic and via self- or parental-led sampling in children's own homes. The latter were assessed using population pharmacokinetic modeling. Patients were deemed nonadherent if any of these measures were indicative of nonadherence with the prescribed treatment. In addition, beliefs about medicines, parental confidence in seizure management, and the presence of depressed mood in parents were evaluated to examine their association with nonadherence in the participating children. KEY FINDINGS: The overall rate of nonadherence in children with epilepsy was 33%. Logistic regression analysis indicated that children with generalized epilepsy (vs. focal epilepsy) were more likely (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.37-15.81) to be classified as nonadherent as were children whose parents have depressed mood (OR 3.6, 95% CI 1.16-11.41). SIGNIFICANCE: This is the first study to apply the novel methodology of determining adherence via AED concentrations in clinic and home DBS samples. The present findings show that the latter, with further development, could be a useful approach to adherence assessment when combined with other measures including parent and child self-reporting. Seizure type and parental depressed mood were strongly predictive of nonadherence. PMID- 23448147 TI - Assessment of the oxidant tolerance of Methanosarcina acetivorans. AB - All methane-producing Archaea (methanogens) are strict anaerobes, but the majority of species are tolerant to oxidants. Methanosarcina species are important environmental and industrial methanogens as they are one of only two genera capable of producing methane with acetate. Importantly, Methanosarcina species appear to be the most oxidant-tolerant; however, the mechanisms underlying this tolerance are poorly understood. We report herein two similar methods (spot-plating and microtiter plate) developed to examine the oxidant tolerance of Methanosarcina acetivorans by viability assessment. Both methods revealed that M. acetivorans can tolerate exposure to millimolar levels of hydrogen peroxide (H2O2 ) without a complete loss of viability. The exogenous addition of catalase was also shown to protect M. acetivorans from H2O2 toxicity, indicating catalase can serve as an antioxidant enzyme in methanogens even though oxygen is a byproduct. Of the two methods, the microtiter plate method provided a simple, reliable, and inexpensive method to assess viability of M. acetivorans. Combined with recent advances in the genetic manipulation of methanogens, methods in assessment of methanogen oxidant tolerance will aid in the identification of components of the antioxidant defense systems. PMID- 23448149 TI - A1-3 chromosomal translocations in Italian populations of the peach potato aphid Myzus persicae (Sulzer) not linked to esterase-based insecticide resistance. AB - Esterase-based resistance in the peach-potato aphid, Myzus persicae (Sulzer), is generally due to one of two alternative amplified carboxylesterase genes, E4 or FE4 (fast E4). The E4 amplified form is distributed worldwide and it is correlated with a particular translocation between autosomes 1 and 3, whereas the FE4 form, which has hitherto not been found to be associated with chromosomal rearrangements, is typical of the Mediterranean regions. In this study, we present for the first time cytogenetic and molecular data on some M. persicae parthenogenetic lineages, which clearly show a chromosomal A1-3 translocation associated with esterase FE4 genes and unrelated to high levels of esterase-based resistance. PMID- 23448148 TI - Ratio of preoperative atrial natriuretic peptide to brain natriuretic peptide predicts the outcome of the maze procedure in mitral valve disease. AB - BACKGROUND: Although the maze procedure is an established surgical treatment for eliminating atrial fibrillation (AF), its efficacy in patients with mitral valve disease has remained unsatisfactory. A useful predictive marker for the outcome of the maze procedure is needed. The aim of this study was to investigate whether the preoperative ratio of atrial natriuretic peptide (ANP) to brain natriuretic peptide (BNP) reflects atrial fibrosis and can be used to predict the maze procedure outcome in patients with mitral valve disease. METHODS: A total of 23 consecutive patients who underwent the radial approach to the maze procedure combined with mitral valve surgery were included in this study and were divided into a sinus rhythm (SR) group (n=16) and an AF group (n=7) based on postoperative cardiac rhythm. Plasma samples were obtained at rest before the operation and were analysed for ANP and BNP levels. Atrial tissue samples taken during surgery were used to quantify interstitial fibrosis. RESULTS: The preoperative ANP-to-BNP ratio in the SR group was significantly higher than that in the AF group (0.74 +/- 0.29 vs. 0.42 +/- 0.28, respectively; p=0.025). Receiver operating characteristic (ROC) curve analysis was used to identify factors that predict outcomes after the maze procedure. The area under the ROC curve for the ANP-to-BNP ratio (0.81) was greater than for any other preoperative factors. Moreover, the preoperative ANP-to-BNP ratio demonstrated a negative correlation with left atrial fibrosis (r=-0.69; p=0.003). CONCLUSIONS: The preoperative ANP-to-BNP ratio can predict maze procedure outcome in patients with mitral valve disease, and it represents a potential biomarker for left atrial fibrosis. PMID- 23448150 TI - P27/Kip1 is responsible for magnolol-induced U373 apoptosis in vitro and in vivo. AB - Previously, we demonstrated that magnolol, a hydroxylated biphenyl compound isolated from the bark of Magnolia officinalis, at low concentrations (3-10 MUM) exerted an antiproliferation effect in colon cancer, hepatoma, and glioblastoma (U373) cell lines through upregulation of the p21/Cip1 protein. Magnolol at a higher concentration of 100 MUM, however, induced apoptosis and upregulated p27/Kip1 expression in U373. In the present study, we further studied whether the increased p27/Kip1 expression contributes to the magnolol-induced apoptosis in U373. Our data show that knock-down of p27/Kip1 expression significantly suppressed the magnolol-induced apoptosis, suggesting that p27/Kip1 might play an important role in the regulation of magnolol-induced apoptosis. This notion was further supported by demonstrating that magnolol induced an increase of the caspase activity in U373 in vitro and in vivo, and these effects were abolished by pretransfection of the cell with p27/Kip1 siRNA. To delineate the possible signaling pathways involved in the magnolol-induced increases of p27/Kip1 expression and apoptosis, we found that magnolol (100 MUM) increased the levels of phosphorylated cSrc (p-cSrc), p-ERK, p-p38 MAP kinase (p-p38 MAPK), and p-AKT but not p-JNK in U373. Moreover, pretreatment of U373 with a cSrc inhibitor (PP2), a PI3K inhibitor (LY294002), an ERK inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) but not a JNK inhibitor (SP600125) significantly reduced the magnolol-induced increases of p27/Kip1 protein levels and apoptosis. Taken together, our data suggest that magnolol at a higher concentration of 100 MUM induced apopotosis in U373 cells through cSrc-mediated upregulation of p27/Kip1. PMID- 23448152 TI - Mercury bismuth chalcohalides, Hg3Q2Bi2Cl8 (Q = S, Se, Te): syntheses, crystal structures, band structures, and optical properties. AB - Three quaternary mercury bismuth chalcohalides, Hg3Q2Bi2Cl8 (Q = S, Se, Te), are reported along with their syntheses, crystal structures, electronic band structures, and optical properties. The compounds are structurally similar with a layer comprised of a hole perforated sheet network of [Hg3Q2](2+) (Q = S and Te) that forms by fused cyclohexane, chairlike Hg6Q6 rings. The cationic charge in the network is balanced by edge-sharing monocapped trigonal-prismatic anions of [Bi2Cl8](2-) that form a two-dimensional network located between layers. Compound 1, Hg3S2Bi2Cl8, crystallizes in the monoclinic space group C12/m1 with a = 12.9381(9) A, b = 7.3828(6) A, c = 9.2606(6) A, and beta = 116.641(5) degrees . Compound 2, Hg3Te2Bi2Cl8, crystallizes in the monoclinic space group C12/c1 with a = 17.483(4) A, b = 7.684(2) A, c = 13.415(3) A, and beta = 104.72(3) degrees . The crystals of the Hg3Se2Bi2Cl8 analogue exhibit complex modulations and structural disorder, which complicated its structural refinement. Compounds 1 and 2 melt incongruently and show band gaps of 3.26 and 2.80 eV, respectively, which are in a good agreement with those from band-structure density functional theory calculations. PMID- 23448151 TI - The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone. METHODS: A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by 0.44 nmol/l (95% CI -0.75 to -0.13). CONCLUSIONS: Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58. PMID- 23448153 TI - A cross-sectional study of knowledge of sex partner serostatus among high-risk Peruvian men who have sex with men and transgender women: implications for HIV prevention. AB - BACKGROUND: Knowledge of a sex partner's HIV serostatus can influence sexual behavior and inform harm-reduction strategies. We sought to determine how often Peruvian men who have sex with men (MSM) and transgender women (TW) knew the HIV serostatus of their sex partners, if this knowledge was associated with any predictive factors or unprotected anal intercourse (UAI), and if UAI was associated with partner serostatus. METHODS: We analyzed data from the 2008 Peruvian MSM Sentinel Surveillance Survey. Data were collected by CASI about each participant's three most recent male sex partners. Primary outcome was knowledge of a partner's HIV test result. Multivariate analysis assessed the effect of age, education, sexual identity, number of male partners, alcohol use during intercourse, type of partnership and length of partnership using logistic regression. RESULTS: 735 participants provided data on 1,643 of their most recent sex partners from the last 3 months. 179/735 (24.4%) of all participants knew HIV test results for at least one of their 3 most recent partners, corresponding to 230/1643 (14.0%) of all sexual partnerships in the last 3 months. In multivariate analysis, casual (OR: 0.27, 95% CI: 0.17-0.42) and exchange sex (OR: 0.31, 95% CI: 0.11-0.88) partners, compared to stable partners, were negatively associated with knowledge of partner serostatus, whereas relationships lasting longer than one night (<3 months OR: 2.20, 95% CI: 1.39-3.51; 3 months to 1 year OR: 3.00, 95% CI: 1.80-5.01; >= 1 year OR: 4.13, 95% CI: 2.40-7.10) were positively associated with knowledge of partner serostatus. Knowledge of partner serostatus was not associated with unprotected anal intercourse with that partner. CONCLUSIONS: Few MSM and TW in Peru know their partners' HIV serostatus. Our findings suggest that the type and length of partnership influence the likelihood of knowing a partner's serostatus. Further research should explore the contexts and practices of partner communication, their effect on sexual behavior, and interventions to promote discussion of HIV testing and serostatus as an HIV prevention strategy in this population. PMID- 23448154 TI - Linear immunoglobulin-A bullous dermatosis complicating multi-organ tuberculosis at early-stage treatment. PMID- 23448155 TI - Direct anticoagulant drugs to overcome limitations of vitamin K antagonists. A critical appraisal of data in atrial fibrillation patients. AB - INTRODUCTION: The usefulness of anticoagulation in patients with atrial fibrillation (AF) is well known. However, the inherent limitations of vitamin K antagonists (VKAs) have made the development of new oral anticoagulants necessary. Drugs directed against thrombin or the factor Xa are currently available. AREAS COVERED: These molecules, being administered at fixed doses and not requiring laboratory monitoring, overcome one crucial problem associated with the use of VKAs. However, data about the bleeding risk related to the use of these molecules should be further analyzed. EXPERT OPINION: The efficacy of direct anticoagulants (DACs) in AF-related stroke prevention has been considered the primary outcome in all Phase III published trials. On the other hand, the reduction of the bleeding risk is an important goal achieved by the DACs as compared with VKAs. Besides data deriving from randomized trials, when talking about new drugs, the need of evidences from the 'everyday clinical practice' are often requested. The aim of this literature revision is to report and analyze data from specific subgroups about which little is known. In particular, information about the use of DACs in oncologic patients, in patients receiving concomitant antiplatelet drugs and in the perioperative period is currently lacking. The parallel evaluation of all these data may lead to the identification of clinical and demographical criteria to choose when to switch to DACs. PMID- 23448156 TI - Emerging mitotic inhibitors for non-small cell carcinoma. AB - INTRODUCTION: Mitosis is the key event of the cell cycle, and microtubules play an important part in an array of cellular functions besides mitosis, including maintenance of cell shape, cell locomotion, and the movement of intracellular organelles. Various anti-microtubule agents interfere with normal progression of mitosis, such as taxanes and vinca alkaloids. These compounds are widely used in the treatment of advanced non-small cell lung cancer (NSCLC), but their use has been limited by toxicity profile (hematologic and not), acquired resistance, and hypersensitivity reactions. AREAS COVERED: Recently innovative drug carrier such as nanoparticle showed to reduce toxicity and improve drugs' efficacy. Nanoparticle albumin-bound (nab)-paclitaxel has been recently approved for the use in breast and NSCLC with very promising results in pancreatic adenocarcinoma. Furthermore, the identification of novel mitotic drug targets other than microtubules has gained recently much attention, such as aurora kinases, Polo like kinase1 (PLK1), kinesin spindle protein (KSP), and centromeric protein E (CENPE). EXPERT OPINION: Despite recent advances in treatment, NSCLC continues to be the leading cause of cancer death worldwide. Novel agents that target the spindle microtubule elements of mitosis, as well as those that target the non microtubule effectors of mitosis, are under investigation. PMID- 23448158 TI - Assessment of nickel titanium and beta titanium corrosion resistance behavior in fluoride and chloride environments. AB - OBJECTIVE: To assess the influence of fluoride concentration on the corrosion behavior of nickel titanium (NiTi) superelastic wire and to compare the corrosion resistance of NiTi with that of beta titanium alloy in physiological solution with and without addition of fluoride. MATERIALS AND METHODS: NiTi corrosion resistance was investigated through electrochemical impedance spectroscopy and anodic polarization in sodium chloride (NaCl 0.15 M) with and without addition of 0.02 M sodium fluoride (NaF), and the results were compared with those associated with beta titanium. The influence of fluoride concentration on NiTi corrosion behavior was assessed in NaCl (0.15 M) with and without 0.02, 0.04, 0.05, 0.07, and 0.12 M NaF solution. Galvanic corrosion between NiTi and beta titanium were investigated. All samples were characterized by scanning electron microscopy. RESULTS: Polarization resistance decreased when NaF concentration was increased, and, depending on NaF concentration, NiTi can suffer localized or generalized corrosion. In NaCl solution with 0.02 M NaF, NiTi suffer localized corrosion, while beta titanium alloys remained passive. Current values near zero were observed by galvanic coupling of NiTi and beta titanium. CONCLUSIONS: There is a decrease in NiTi corrosion resistance in the presence of fluoride. The corrosion behavior of NiTi alloy depends on fluoride concentration. When 0.02 and 0.04 M of NaF were added to the NaCl solution, NiTi presented localized corrosion. When NaF concentration increased to 0.05, 0.07, and 0.12 M, the alloy presented general corrosion. NiTi corrosion resistance behavior is lower than that of beta titanium. Galvanic coupling of these alloys does not increase corrosion rates. PMID- 23448159 TI - Dr. Kuan-Teh Jeang (1958-2013): an outstanding scientist, a caring mentor, a role model and leader of the Asian American scientist community -- an eulogy delivered by Paul Liu at NIH on February 8, 2013, with additional modifications. PMID- 23448160 TI - Interactions between phoretic mites and the Arabian rhinoceros beetle, Oryctes agamemnon arabicus. AB - Oryctes agamemnon arabicus (Coleoptera: Scarabaeidae) is one of the main pests on date palm trees in the United Arab Emirates (UAE). Two mite species were found associated with this beetle: Sancassania sp. (Acari: Astigmata: Acaridae) and Hypoaspis rhinocerotis Oudemans (Acari: Mesostigmata: Laelapidae). Sancassania deutonymphs (hypopi) were phoretic on O. a. arabicus adults and larvae. However, they were also necromenic, because once the host dies they feed on its carcass. The highest deutonymph load was found in the subelytral space of O. a. arabicus adult. The phoretic and necromenic interactions between Sancassania sp. and O. a. arabicus need to be investigated in more detail. H. rhinocerotis was recorded for the first time in UAE. Its role has not yet been studied in the date palm agricultural ecosystem. PMID- 23448161 TI - Usefulness of maternal anti-HPA-1a antibody quantitation in predicting severity of foetomaternal alloimmune thrombocytopenia. AB - OBJECTIVE: To study the clinical usefulness of maternal anti-HPA-1a antibody levels in predicting severe foetomaternal alloimmune thrombocytopenia (FMAIT). BACKGROUND: Recent studies using an international anti-HPA-1a standard have shown a correlation between maternal antibody levels and neonatal thrombocytopenia. Cut off values for identifying high-risk pregnancies have also been suggested. MATERIALS: In 1986-2010, HPA-1a alloimmunisation was confirmed in 84 women with 129 pregnancies. Maternal samples were obtained at delivery and during subsequent pregnancies. Anti-HPA-1a was quantified using a MAIPA assay with a detection limit of 0.8 IU mL(-1) (WHO reference serum 03/152). Antibody levels were compared with the severity of neonatal disease in the index and in the subsequent pregnancies. RESULTS: In the index cases, the correlation between an anti-HPA-1a level and neonatal platelet count did not reach statistical significance (n = 77, P = 0.074). However, the platelet counts and antibody levels in cases with cutaneous (n = 45) or intracranial haemorrhage (n = 7) were significantly different from cases with no evidence of bleeding (n = 20). In the subsequent pregnancies, there was a stronger association between the second trimester anti HPA-1a level and the foetal platelet count (n = 16, P = 0.046). The positive predictive value of the maternal antibody level for a foetal platelet count <20 * 10(9) L(-1) was 90%, but the negative predictive value only 31%. CONCLUSION: Although a higher anti-HPA-1a level correlated with a more severe neonatal disease, barely detectable antibody levels were also observed in severely affected pregnancies. Cut-off values with sufficient sensitivity and specificity to identify these foetuses could not be found. A previous obstetric history still remains the most useful predictive parameter for severe FMAIT in clinical practice. PMID- 23448162 TI - Systematic review of the quality of clinical guidelines for aphasia in stroke management. AB - RATIONALE, AIMS AND OBJECTIVES: Aphasia affects up to 38% of stroke survivors. Clinical guidelines can improve patient care and outcomes. Given the importance of aphasia management in stroke care, the purpose of this study was to systematically search for, retrieve and assess the quality of currently published clinical guidelines for aphasia in stroke management. METHOD: Systematic search of bibliographic resources, publications, association websites, databases, Internet and pearling revealed multidisciplinary stroke and speech pathology specific clinical guidelines, which were evaluated using the Appraisal of Guidelines and Research and Evaluation (AGREE) II tool. Guidelines obtaining a rigour of development score above 66.67% in AGREE II evaluations underwent further ADAPTE Collaboration tool analysis. RESULTS: There was significant variability in methodological rigour, reporting of guideline development processes and scope of coverage of recommendations pertaining to aphasia management provided within the guidelines. The Australian Clinical Guidelines for Stroke Management (2010) and New Zealand Clinical Guidelines for Stroke Management (2010) achieved the highest scores (74% and 81%, respectively) in AGREE II analysis and both obtained a 'yes' in all seven ADAPTE domains. The Scottish Intercollegiate Guideline Network 108 (2008) guideline achieved 73% in AGREE II and six out of seven 'yes' in ADAPTE, however, contained no aphasia specific recommendations. The Royal College of Speech and Language Therapists (2005) guideline provided the most comprehensive aphasia coverage, however, demonstrated lower methodological rigour in AGREE II (64%) and ADAPTE evaluations (three 'yes' out of seven). CONCLUSION: Improvement is needed in the quality of methodological rigour in development and reporting within clinical guidelines, and in aphasia-specific recommendations within stroke multidisciplinary clinical guidelines. PMID- 23448163 TI - The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site. AB - BACKGROUND: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. METHODS: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor binding sites identified with this procedure were modified by site-directed mutagenesis. Active compounds were measured in a mammalian cell water permeability assay of mutated AQP9 isoforms and tested for changes in inhibitory effects. CONTROLS: Three independent cell lines were established for each mutated AQP9 isoform and functionality of mutant isoforms was established. PRINCIPAL FINDINGS: We have identified putative binding sites of recently established AQP9 inhibitors. This information facilitated successful identification of novel AQP9 inhibitors with low micromolar IC50 values in a cell based assay by in silico screening of a compound library targeting specifically this binding site. SIGNIFICANCE: We have established a successful strategy for AQP small molecule inhibitor identification. AQP inhibitors may be relevant as experimental tools, to enhance our understanding of AQP function, and in the treatment of various diseases. PMID- 23448164 TI - Nanomechanics of lipid encapsulated microbubbles with functional coatings. AB - Microbubbles (MBs) are increasingly being proposed as delivery vehicles for targeted therapeutics, as well as being contrast agents for ultrasound imaging. MBs formed with a lipid shell are promising candidates due to their biocompatibility and the opportunity for surface functionalization, both for specific targeting of tissues and as a means to tune their mechanical response for localized ultrasound induced destruction in vivo. Herein, we acquired force deformation data on coated lipid MBs using tip-less microcantilevers in an atomic force microscope. Model lipid MBs were designed to test the effects of adding a functional coating on the outside of the lipid leaflet, including a protein coat (streptavidin) or the addition of quantum dots (Q-dots) as optical reporters. MBs (~3 MUm diameter) were repeatedly compressed for deformations up to ~50% to obtain a full bubble response. Addition of a coating increased the initial deformation stiffness related to shell bending ~2-fold for streptavidin and ~3 fold for Q-dots. The presence of a polyethylene glycol (PEG) linker in between the lipid and functional coating, led to enhanced stiffening at high deformations. The plasticity index has been determined and only those MBs that included the PEG linker showed a force dependent short time-scale (<~1s) plasticity. This study demonstrates modulation of the mechanical response of biocompatible MBs through the addition of functional coatings necessary for rationale design of therapeutic lipid MBs for targeted drug delivery. PMID- 23448165 TI - Twisting bilayer graphene superlattices. AB - Bilayer graphene is an intriguing material in that its electronic structure can be altered by changing the stacking order or the relative twist angle, yielding a new class of low-dimensional carbon system. Twisted bilayer graphene can be obtained by (i) thermal decomposition of SiC; (ii) chemical vapor deposition (CVD) on metal catalysts; (iii) folding graphene; or (iv) stacking graphene layers one atop the other, the latter of which suffers from interlayer contamination. Existing synthesis protocols, however, usually result in graphene with polycrystalline structures. The present study investigates bilayer graphene grown by ambient pressure CVD on polycrystalline Cu. Controlling the nucleation in early stage growth allows the constituent layers to form single hexagonal crystals. New Raman active modes are shown to result from the twist, with the angle determined by transmission electron microscopy. The successful growth of single-crystal bilayer graphene provides an attractive jumping-off point for systematic studies of interlayer coupling in misoriented few-layer graphene systems with well-defined geometry. PMID- 23448166 TI - Modeling the evolution dynamics of exon-intron structure with a general random fragmentation process. AB - BACKGROUND: Most eukaryotic genes are interrupted by spliceosomal introns. The evolution of exon-intron structure remains mysterious despite rapid advance in genome sequencing technique. In this work, a novel approach is taken based on the assumptions that the evolution of exon-intron structure is a stochastic process, and that the characteristics of this process can be understood by examining its historical outcome, the present-day size distribution of internal translated exons (exon). Through the combination of simulation and modeling the size distribution of exons in different species, we propose a general random fragmentation process (GRFP) to characterize the evolution dynamics of exon intron structure. This model accurately predicts the probability that an exon will be split by a new intron and the distribution of novel insertions along the length of the exon. RESULTS: As the first observation from this model, we show that the chance for an exon to obtain an intron is proportional to its size to the 3rd power. We also show that such size dependence is nearly constant across gene, with the exception of the exons adjacent to the 5' UTR. As the second conclusion from the model, we show that intron insertion loci follow a normal distribution with a mean of 0.5 (center of the exon) and a standard deviation of 0.11. Finally, we show that intron insertions within a gene are independent of each other for vertebrates, but are more negatively correlated for non vertebrate. We use simulation to demonstrate that the negative correlation might result from significant intron loss during evolution, which could be explained by selection against multi-intron genes in these organisms. CONCLUSIONS: The GRFP model suggests that intron gain is dynamic with a higher chance for longer exons; introns are inserted into exons randomly with the highest probability at the center of the exon. GRFP estimates that there are 78 introns in every 10 kb coding sequences for vertebrate genomes, agreeing with empirical observations. GRFP also estimates that there are significant intron losses in the evolution of non-vertebrate genomes, with extreme cases of around 57% intron loss in Drosophila melanogaster, 28% in Caenorhabditis elegans, and 24% in Oryza sativa. PMID- 23448167 TI - Techniques for the isolation of high-quality RNA from cells encapsulated in chitosan hydrogels. AB - Extracting high-quality RNA from hydrogels containing polysaccharide components is challenging, as traditional RNA isolation techniques designed for cells and tissues can have limited yields and purity due to physiochemical interactions between the nucleic acids and the biomaterials. In this study, a comparative analysis of several different RNA isolation methods was performed on human adipose-derived stem cells photo-encapsulated within methacrylated glycol chitosan hydrogels. The results demonstrated that RNA isolation methods with cetyl trimethylammonium bromide (CTAB) buffer followed by purification with an RNeasy(r) mini kit resulted in low yields of RNA, except when the samples were preminced directly within the buffer. In addition, genomic DNA contamination during reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was observed in the hydrogels processed with the CTAB-based methods. Isolation methods using TRIzol(r) in combination with one of a Qiaex(r) gel extraction kit, an RNeasy(r) mini kit, or an extended solvent purification method extracted RNA suitable for gene amplification, with no evidence of genomic contamination. The latter two methods yielded the best results in terms of yield and amplification efficiency. Predigestion of the scaffolds with lysozyme was investigated as a possible means of enhancing RNA extraction from the polysaccharide gels, with no improvements observed in terms of the purity, yield, or amplification efficiency. Overall, this work highlights the application of a TRIzol(r)+extended solvent purification method for optimizing RNA extraction that can be applied to obtain reliable and accurate gene expression data in studies investigating cells seeded in chitosan-based scaffolds. PMID- 23448168 TI - Centrifugation-induced water-tunable photonic colloidal crystals with narrow diffraction bandwidth and highly sensitive detection of SCN-. AB - Novel opal hydrogels with water-tunable photonic bandgap (PBG) exhibiting responses to external stimuli were self-assembled from polystyrene-co-poly(N,N dimethylacrylamide) (PS-co-PDMAA) microspheres. The polymeric microspheres with narrow size distribution were successfully prepared in water, consisting of two regions. The inner region is rich in PS which is hard and hydrophobic; the outer region is rich in PDMAA which is soft and hydrophilic. The self-assembly of the PS-co-PDMAA hydrogel microspheres is ready induced by centrifugation and resulted in highly ordered three-dimensional (3D) photonic colloidal crystals (PCCs). With an increase of the amount of water, the PBG of the opal hydrogels shifted from the visible to near-infrared region of the electromagnetic spectrum. The maximum shift of diffraction peak positions could be larger than 500 nm with narrow full width at half maximum (FWHM) in the range of 20 to 40 nm only. The change in color was visible to the naked eye. The remarkable sensitivity to water of the lattice spacing of the opal hydrogels was repeatable after centrifugation. These observations are attributed to a reproducible degree of hydration of the hydrophilic outer region of the polymeric microspheres. Furthermore, the diffraction of the opal hydrogels was particularly sensitive to the presence of thiocyanate (SCN(-)) ions. The interaction between SCN(-) ions and DMAA repeat units is argued to block hydrogen bonds between DMAA and water molecules. Our PS co-PDMAA opal hydrogels could be a practical system for diffraction-based detections. PMID- 23448169 TI - Suicidal ideation and behavior screening in intractable focal epilepsy eligible for drug trials. AB - PURPOSE: Three suicidal ideation and suicidal behavior instruments were used to assess the prevalence of lifetime and recent suicidal ideation and suicidal behavior in patients with frequent treatment-resistant focal seizures who would be eligible for randomized clinical trials. This was done to determine which instrument was optimal for use in epilepsy. METHODS: In a cross-sectional study, we compared lifetime and recent suicidal ideation and suicide attempt on the MINI International Neuropsychiatric Interview (MINI), Columbia Suicide Severity Rating Scale (C-SSRS), and Interactive Voice Response System CSSRS (E-CSSRS). A safety algorithm determined treatment referral. Coordinators and participants evaluated experiences with the C-SSRS. The proportion of participants that baseline assessment would exclude from clinical trial enrollment was determined. KEY FINDINGS: Among 208 participants, 1.6-3.9% had recent high risk suicidal ideation and 1.0-4.7% had a recent suicide attempt across all instruments. Lifetime high risk suicidal ideation occurred in 12.1-14.1%. Lifetime suicide attempt occurred in 10.2-13.1% of participants. Of those with recent suicide attempt, 31.1% required referral to a health professional, and 3.9% needed urgent referral. Lifetime suicidal behavior (including aborted suicide attempt, interrupted suicide attempt, suicide attempt, preparatory acts or behavior, and nonsuicidal self-injurious behavior) was found in 21.1% on the E-CSSRS and 15.5% on the C SSRS. Agreement (Kappa) was good to excellent for comparisons of all instruments. Fifty-two percent of subjects preferred either the CSSRS or E-CSSRS, whereas the rest had no preference; of those having a preference, 87.5% favored the CSSRS. Of the 18.9% of participants who might have been excluded from trials based on suicidal ideation and suicide attempt, the CSSRS identified high-risk suicidal ideation or suicide attempt in the preceding 2 years in only 4.4%. SIGNIFICANCE: Suicidality screening is feasible in people with epilepsy. Slightly more suicidal behavior is reported with the E-CSSRS than C-SSRS, suggesting the E-CSSRS may be optimal. The proportion of patients who may be excluded from clinical trials based on worrisome suicidal ideation or suicide attempt is small, suggesting that it is possible to enroll most eligible individuals. PMID- 23448170 TI - Impact of Friedreich's Ataxia on health-care resource utilization in the United Kingdom and Germany. AB - BACKGROUND: Friedreich's Ataxia (FRDA) is a neurodegenerative disorder that causes progressive damage to the central and peripheral nervous systems having a significant impact upon quality of life. With little information in the literature, cross-sectional observational studies were conducted in the UK and Germany to collect data on resource use and the burden of the disease on individuals and their caregivers. METHODS: Cross-sectional observational studies were conducted in the UK and Germany to estimate the burden of FRDA on individuals and on the respective healthcare systems. A total of 75 individuals in the UK and 28 in Germany were recruited to the study. Participants in both countries were asked to complete a Patient and Caregiver Information Form (PCIF), regarding access to, and use of, healthcare resources, and the impact FRDA has on their lifestyle. In Germany, doctors were asked to complete a Patient Record Form (PRF). Analyses of annual direct and indirect resource utilization were conducted for both countries while costs were calculated for the UK only. These figures were compared to the costs associated with Parkinson's disease; one of the most common neurodegenerative conditions and the one most similar in terms of disease progression. RESULTS: The results showed that the annual burden of FRDA is significant and falls on the health and social care sectors, on society, on caregivers and on the individuals themselves. In the UK FRDA had a total annual cost per person of between L11,818 and L18,774 depending on whether the cost of long-term unemployment was included.Typically the largest component of direct costs is associated with professional care. Given the high proportion of children and young adults recruited and the long disease duration, (typically 40-50 years for FRDA, compared with 20 years for Parkinson's disease), these figures may underestimate the true burden of the disease. CONCLUSION: It is hoped that these estimates of resource utilization, can help in understanding the previously unquantified burden of FRDA. Given the long disease duration, management strategies should seek to minimise the impact of the condition on individuals and their caregivers, while maximising quality of life. PMID- 23448172 TI - Further characterisation of an experimental model of tendinopathy in the horse. AB - REASONS FOR PERFORMING STUDY: Injuries in energy-storing tendons are common in both horses and man. The high prevalence of reinjury and the relatively poor prognosis for returning to preinjury performance levels warrant further research, for which well characterised models would be very helpful. OBJECTIVES: Given the clinical similarities in tendinopathy of energy-storing tendons, we hypothesised that a recently developed experimental model of equine tendon injury would display many of the characteristics of clinical tendinopathy and could therefore be of use for both species, thus providing comparative insight to the human condition and offering direct potential impact to equine medicine. STUDY DESIGN: In vivo experimental study. METHODS: Surgical lesions were created in the superficial digital flexor tendon (SDFT) of 6 horses. Clinical examination, as well as biochemistry, histology and immunohistochemistry were performed on the harvested samples at 6 weeks post surgery. RESULTS: Disrupted collagen fibres, increased glycosaminoglycan content, increased presence of tenocytes with plump nuclei, the scarcity of inflammatory cells, increased matrix metalloproteinase (MMP) activity and neovascularisation were observed and found to be consistent with clinical tendinopathy. CONCLUSION AND RELEVANCE: This model displays the key features of the most common human and equine degenerative tendon disorders and is therefore an appropriate, if still imperfect, model of tendinopathy. PMID- 23448173 TI - Modeling temperature-dependent survival with small datasets: insights from tropical mountain agricultural pests. AB - Many regions are increasingly threatened by agricultural pests but suffer from a lack of data that hampers the development of adequate population dynamics models that could contribute to pest management strategies. Here, we present a new model relating pest survival to temperature and compare its performance with two published models. We were particularly interested in their ability to simulate the deleterious effect of extreme temperatures even when adjusted to datasets that did not include extreme temperature conditions. We adjusted the models to survival data of three species of potato tuber moth (PTM), some major pests in the Tropical Andes. To evaluate model performance, we considered both goodness-of fit and robustness. The latter consisted in evaluating their ability to predict the actual altitudinal limits of the species in the Ecuadorian Andes. We found that even though our model did not always provide the best fit to data, it predicted extreme temperature mortality and altitudinal limits accurately and better than the other two models. Our study shows that the ability to accurately represent the physiological limits of species is important to provide robust predictions of invasive pests' potential distribution, particularly in places where temperatures approach lethal extremes. The value of our model lies in its ability to simulate accurate thermal tolerance curves even with small datasets, which is useful in places where adequate pest management is urgent but data are scarce. PMID- 23448171 TI - Lifetime drinking trajectories among veterans in treatment for HIV. AB - BACKGROUND: Previous work on the course of drinking across the life course identified 4 distinct patterns of problem drinking: severe chronic (SC), severe nonchronic (SNC), late onset (LO), and young adult (YA). The purpose of the current study was to determine the generalizability of these findings to a sample of midlife veterans with quite different characteristics from those previously assessed; specifically, veterans in treatment for HIV and veterans in treatment for non-HIV medical issues. METHODS: Participants were drawn from the Veterans Aging Cohort Study that included HIV-positive and matched non-HIV participants. As in our earlier studies, the lifetime drinking history was used to assess drinking phases, and latent growth mixture models were used for analyses. RESULTS: Similar to previous findings, both the HIV+ and non-HIV groups exhibited 4 patterns of drinking (SC, SNC, LO, and YA). SC drinkers had younger ages of onset for drinking and longer duration of smoking. SC drinkers also had the highest rates of cocaine use. Within the HIV+ subsample, SC and LO drinkers increased their drinking after their HIV diagnosis. CONCLUSIONS: This study is the first to examine lifetime drinking patterns among those treated for HIV and provides an excellent starting point for examining finer-grained relationships involving drinking, onset of HIV, and treatment outcomes. Absent from the current study and of particular importance to future work in this area is the need for precise information regarding the temporal relationship between date of HIV diagnosis, onset of treatment, and changes in drinking behavior over the life course. PMID- 23448174 TI - Synthesis, structure, and reactivity of an anionic Zr-oxo relevant to CO2 reduction by a Zr/Co heterobimetallic complex. AB - Oxidative addition of CO2 to the reduced Zr/Co complex (THF)Zr(MesNP(i)Pr2)3Co (1) followed by one-electron reduction leads to formation of an unusual terminal Zr-oxo anion [2][Na(THF)3] in low yield. To facilitate further study of this compound, an alternative high-yielding synthetic route has been devised. First, 1 is treated with CO to form (THF)Zr(MesNP(i)Pr2)3Co(CO) (3); then, addition of H2O to 3 leads to the Zr-hydroxide complex (HO)Zr(MesNP(i)Pr2)3Co(CO) (4). Deprotonation of 4 with Li(N(SiMe3)2) leads to the anionic Zr-oxo species [2][Li(THF)3] or [2][Li(12-c-4)] in the absence or presence of 12-crown-4, respectively. The coordination sphere of the Li(+) countercation is shown to lead to interesting structural differences between these two species. The anionic oxo fragment in complex [2][Li(12-c-4)] reacts with electrophiles such as MeOTf and Me3SiOTf to generate (MeO)Zr(MesNP(i)Pr2)3Co(CO) (5) and (Me3SiO)Zr(MesNP(i)Pr2)3Co(CO) (6), respectively, and addition of acetic anhydride generates (AcO)Zr(MesNP(i)Pr2)3Co(CO) (7). Complex [2][Li(12-c-4)] is also shown to bind CO2 to form a monoanionic Zr-carbonate, [(12-crown 4)Li][(kappa(2)-CO3)Zr(MesNP(i)Pr2)3Co(CO)] ([8][Li(12-c-4)]). A more stable version of this compound [8][K(18-c-6)] is formed when a K(+) counteranion and 18 crown-6 are used. Binding of CO2 to [2][Li(12-c-4)] is shown to be reversible using isotopic labeling studies. In an effort to address methods by which these CO2-derived products could be turned over in a catalytic cycle, it is shown that the Zr-OMe bond in 5 can be cleaved using H(+) and the CO ligand can be released from Co under photolytic conditions in the presence of I2. PMID- 23448175 TI - Screening of patients with diabetes mellitus for tuberculosis in India. AB - OBJECTIVE: To assess the feasibility, results and challenges of screening patients with diabetes mellitus (DM) for tuberculosis (TB) within the healthcare setting of six DM clinics in tertiary hospitals across India. METHOD: Agreement on how to screen, monitor and record the screening was reached in October 2011 at a national stakeholders' meeting, and training was carried out for staff in the six tertiary care facilities in December 2011. Implementation started in the first quarter of 2012, and we report on activities up to 30th September 2012. Patients with DM were screened for TB on each clinic attendance using a symptom based enquiry, and those with positive symptoms were referred for TB investigations. RESULTS: In the three quarters, 26% of 7218, 52% of 12237 and 48% of 11691 patients with DM were screened for TB. A total of 254 patients were identified with TB, of whom 46% had smear-positive pulmonary disease. There were 18 patients newly diagnosed with TB as a result of screening and referral, with the remainder being patients already diagnosed from elsewhere. TB case rates per 100,000 patients attending the DM clinic each quarter were 859, 956 and 642. Almost 90% of patients with TB were recorded as starting or being on anti-TB treatment. Major implementation challenges related to human resources and recording systems. CONCLUSION: In India, it is feasible to screen patients with DM for TB resulting in high rates of TB detection. More attention to detail, human resource requirements and electronic medical records are needed to improve performance. PMID- 23448176 TI - Git can facilitate greater reproducibility and increased transparency in science. AB - BACKGROUND: Reproducibility is the hallmark of good science. Maintaining a high degree of transparency in scientific reporting is essential not just for gaining trust and credibility within the scientific community but also for facilitating the development of new ideas. Sharing data and computer code associated with publications is becoming increasingly common, motivated partly in response to data deposition requirements from journals and mandates from funders. Despite this increase in transparency, it is still difficult to reproduce or build upon the findings of most scientific publications without access to a more complete workflow. FINDINGS: Version control systems (VCS), which have long been used to maintain code repositories in the software industry, are now finding new applications in science. One such open source VCS, Git, provides a lightweight yet robust framework that is ideal for managing the full suite of research outputs such as datasets, statistical code, figures, lab notes, and manuscripts. For individual researchers, Git provides a powerful way to track and compare versions, retrace errors, explore new approaches in a structured manner, while maintaining a full audit trail. For larger collaborative efforts, Git and Git hosting services make it possible for everyone to work asynchronously and merge their contributions at any time, all the while maintaining a complete authorship trail. In this paper I provide an overview of Git along with use-cases that highlight how this tool can be leveraged to make science more reproducible and transparent, foster new collaborations, and support novel uses. PMID- 23448177 TI - Probing the binding of insecticide permethrin to calf thymus DNA by spectroscopic techniques merging with chemometrics method. AB - The binding of permethrin (PE) with calf thymus DNA (ctDNA) in physiological buffer (pH 7.4) was investigated by ultraviolet-visible (UV-vis) absorption, fluorescence, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy merging with multivariate curve resolution-alternating least-squares (MCR-ALS) chemometrics approach. The MCR-ALS was applied to resolve the combined spectroscopic data matrix, which was obtained by UV-vis and fluorescence methods. The concentration profiles of PE, ctDNA, and PE-ctDNA complex and their pure spectra were then successfully obtained. The PE molecular was found to be able to intercalate into the base pairs of ctDNA as evidenced by decreases in resonance light-scattering signal and iodide-quenching effect and increase in ctDNA viscosity. The results of FT-IR spectra indicated that PE was prone to bind to G C base pairs of ctDNA, and the molecular docking studies were used to validate and clarify the specific binding. The observed changes in CD signals revealed that the DNA turned into a more highly wound form of B-conformation. The calculated thermodynamic parameters, enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ), suggested that hydrogen bonds and van der Waals forces played a predominant role in the binding of PE to ctDNA. PMID- 23448178 TI - Introduction: Behind the iron curtain. PMID- 23448179 TI - Epilogue: Following in the footsteps. PMID- 23448180 TI - Biography of Dr. Nikolay Volodos. PMID- 23448181 TI - Historical perspective: The first steps in endovascular aortic repair: how it all began. PMID- 23448182 TI - A "drug cocktail" delivered by microspheres for the local treatment of rat glioblastoma. AB - For the treatment of glioblastoma multiforme, an "anticancer drug cocktail" delivered by biodegradable poly-lactide-co-glycolide (PLGA)-microspheres is proposed. Celecoxib, etoposide, and elacridar were encapsulated by an oil/water emulsification solvent evaporation method. Drug-loaded microspheres were analyzed for their physicochemical properties and evaluated in a rat glioblastoma model. Microspheres had a mean diameter 10-20 um, and encapsulation rates varied upon lipophilicity of the drug (celecoxib: 97.4 +/- 0.4%; elacridar: 98.1 +/- 0.3%; and etoposide: 38.7 +/- 8.3%). Drug release of celecoxib and elacridar resulted in a burst (t50: 3.1 h and 1.0 h, respectively) while etoposide release was slower (t50: 45.3 h). The comparison of celecoxib (p = 0.021) and etoposide microspheres (p = 0.002) as well as their combination (p = 0.011) led to a significant increase in the probability of survival compared to blank microspheres. Local delivery of celecoxib and etoposide microspheres was found to be suitable for the treatment of glioblastoma in rats although simultaneous drug administration did not improve the therapeutic outcome. PMID- 23448183 TI - Discoid lupus alopecia complicated by frontal fibrosing alopecia on a background of androgenetic alopecia. PMID- 23448184 TI - Core-shell nanoparticles as building blocks for the bottom-up production of functional nanocomposites: PbTe-PbS thermoelectric properties. AB - The bottom-up assembly of nanocrystals provides access to a three-dimensional composition control at the nanoscale not attainable by any other technology. In particular, colloidal nanoheterostructures, with intrinsic multiphase organization, are especially appealing building blocks for the bottom-up production of nanocomposites. In the present work, we use PbTe-PbS as the model material system and thermoelectricity as the paradigmatic application to investigate the potential of the bottom-up assembly of core-shell nanoparticles to produce functional nanocomposites. With this goal in mind, a rapid, high-yield and scalable colloidal synthetic route to prepare grams of PbTe@PbS core-shell nanoparticles with unprecedented narrow size distributions and exceptional composition control is detailed. PbTe@PbS nanoparticles were used as building blocks for the bottom-up production of PbTe-PbS nanocomposites with tuned composition. In such PbTe-PbS nanocomposites, synergistic nanocrystal doping effects result in up to 10-fold higher electrical conductivities than in pure PbTe and PbS nanomaterials. At the same time, the acoustic impedance mismatch between PbTe and PbS phases and a partial phase alloying provide PbTe-PbS nanocomposites with strongly reduced thermal conductivities. As a result, record thermoelectric figures of merit (ZT) of ~1.1 were obtained from undoped PbTe and PbS phases at 710 K. These high ZT values prove the potential of the proposed processes to produce efficient functional nanomaterials with programmable properties. PMID- 23448185 TI - Poly(ethylene oxide) star polymer adsorption at the silica/aqueous interface and displacement by linear poly(ethylene oxide). AB - Multiarm star copolymers with approximately 460 poly(ethylene oxide) (PEO) arms that have a degree of polymerization N = 45 were synthesized via atom transfer radical polymerization (ATRP) of PEO-methacrylate macromonomers in the presence of divinyl benzene cross-linkers. These are an example of molecular or nanoparticulate brushes that are of interest as steric stabilizers or boundary lubrication agents when adsorbed from solution to a solid/aqueous interface. We use ellipsometry to measure adsorption isotherms at the silica/aqueous interface for PEO star polymers and linear PEO chains having molecular weights comparable either to the star polymer or to the individual arms. The compactness of the PEO star polymers (molecular weight 1.2 * 10(6)) yields a saturation surface excess concentration that is approximately 3.5 times greater than that of the high molecular weight (1 * 10(6)) linear PEO. Adsorption of low molecular weight (6000) linear PEO was below the detection limit. Competitive adsorption experiments were conducted with ellipsometry, complemented by independent quartz crystal microbalance with dissipation (QCM-D) measurements. Linear PEO (high molecular weight) displaced preadsorbed PEO star polymers over the course of approximately 1.5 h, to form a mixed adsorbed layer having not only a significantly lower overall polymer surface excess concentration, but also a significantly greater amount of hydrodynamically entrapped water. Challenging a preadsorbed linear PEO (high molecular weight) layer with PEO star polymers produced no measurable change in the overall polymer surface excess concentration, but changes in the QCM-D energy dissipation and resonance frequency suggested that the introduction of PEO star polymers caused a slight swelling of the layer with a correspondingly small increase in entrapped water content. PMID- 23448186 TI - A general semi-parametric approach to the analysis of genetic association studies in population-based designs. AB - BACKGROUND: For genetic association studies in designs of unrelated individuals, current statistical methodology typically models the phenotype of interest as a function of the genotype and assumes a known statistical model for the phenotype. In the analysis of complex phenotypes, especially in the presence of ascertainment conditions, the specification of such model assumptions is not straight-forward and is error-prone, potentially causing misleading results. RESULTS: In this paper, we propose an alternative approach that treats the genotype as the random variable and conditions upon the phenotype. Thereby, the validity of the approach does not depend on the correctness of assumptions about the phenotypic model. Misspecification of the phenotypic model may lead to reduced statistical power. Theoretical derivations and simulation studies demonstrate both the validity and the advantages of the approach over existing methodology. In the COPDGene study (a GWAS for Chronic Obstructive Pulmonary Disease (COPD)), we apply the approach to a secondary, quantitative phenotype, the Fagerstrom nicotine dependence score, that is correlated with COPD affection status. The software package that implements this method is available. CONCLUSIONS: The flexibility of this approach enables the straight-forward application to quantitative phenotypes and binary traits in ascertained and unascertained samples. In addition to its robustness features, our method provides the platform for the construction of complex statistical models for longitudinal data, multivariate data, multi-marker tests, rare-variant analysis, and others. PMID- 23448187 TI - An implantable left atrial pressure sensor lead designed for percutaneous extraction using standard techniques. AB - BACKGROUND: An implantable left atrial pressure (LAP) monitoring system for guiding the management of patients with advanced heart failure has the potential to require extraction, particularly in the setting of infection. The LAP sensor lead was designed to be suitable for ease of percutaneous extraction using standard techniques for extracting pacemaker and defibrillator leads. The clinical experience, to date, with percutaneous extraction of the LAP sensor lead is presented. METHODS: A total of 82 patients underwent successful implantation of the LAP sensor lead using transseptal catheterization. Five patients of the 82 patients during a cumulative follow-up period of 267 patient-years (median of 2.9 years/patient) underwent percutaneous extraction using manual traction with a locking stylet and/or an excimer laser sheath to bore through adhesions. The distal fixation anchors of the LAP sensor lead are designed to fold forward during extraction so that the sensor module can easily separate from the interatrial septum. RESULTS: Percutaneous extraction of the LAP sensor lead was accomplished successfully in all five patients with no embolic events, vascular tears, perforations, or other complications requiring surgical intervention. Manual traction alone was sufficient to detach the LAP sensor lead from the interatrial septum in all cases. Use of the excimer laser sheath was needed in selected cases to bore through scar tissue within the venous insertion site, but not within the heart. CONCLUSIONS: The extraction of the LAP sensor lead was accomplished safely using standard techniques and equipment for percutaneously extracting pacemaker and defibrillator leads. PMID- 23448188 TI - Do statins lower testosterone and does it matter? AB - Drugs are two-sided swords and statins are no exception. Schooling et al. demonstrate that, on average, statins produce small, but statistically significant, decreases in testosterone. They appropriately emphasize that the clinical significance of their observations is unclear but suggest that changes in testosterone might be related to the benefits of therapy as well as the risks, such as the increased chance of diabetes mellitus. Their findings and hypotheses are noteworthy. However, we believe this represents another example of the limitations in the published summaries of drug effects. How do we know all changes induced by drugs are normally distributed? Some may be affected much more than others. Moreover, the confidence intervals of a meta-analysis describe the variance of the mean effect, not the range of effects, and while the mean change characterizes the impact of a drug on a group of patients, the range more fully characterizes its effects on individuals. We treat individuals not groups. Averages do not disclose enough about the risks and benefits of drugs. See related research article here http://www.biomedcentral.com/1741-7015/11/57. PMID- 23448189 TI - The effects of therapeutic concentrations of gentamicin, amikacin and hyaluronic acid on cultured bone marrow-derived equine mesenchymal stem cells. AB - REASONS FOR PERFORMING STUDY: Joint inflammation and septic arthritis are both potential complications of intra-articular injections of bone marrow-derived mesenchymal stem cells (BM-MSCs). Clinicians may prophylactically co-inject BM MSCs admixed with either antimicrobials or hyaluronic acid; however, the effect of these agents on cultured BM-MSCs is unknown. OBJECTIVE: To determine the effects of therapeutic levels of gentamicin, amikacin and hyaluronic acid on cultured equine BM-MSCs in vitro. STUDY DESIGN: In vitro experimental study. METHODS: Equine BM-MSCs from 4 healthy mature horses were isolated. Cultured BM MSCs from each donor were incubated with gentamicin (150 mg), amikacin (250 mg), hyaluronic acid (22 mg) or 1% penicillin/streptomycin (control) under sterile conditions. Mesenchymal stem cells viability, proliferation, mediator secretion and culture media pH were measured. RESULTS: Incubation of BM-MSCs with gentamicin resulted in >95% MSC death after 45 min, and incubation of BM-MSCs with amikacin resulted in >95% MSC death after 2 h. Incubation of BM-MSCs with hyaluronic acid or penicillin/streptomycin (control) for up to 6 h resulted in sustained BM-MSC viability of 80% and >93%, respectively. All additives resulted in decreased media pH in the first minute; however, the pH then remained constant over the 6 h incubation period. No significant differences in BM-MSC proliferation or mediator secretion between the penicillin/streptomycin (control) and cells treated with hyaluronic acid were observed. CONCLUSION: Therapeutic concentrations of aminoglycoside antimicrobials are toxic to cultured equine BM MSCs. The effects of hyaluronic acid on cultured MSC viability, proliferation and mediator secretion are minimal. POTENTIAL RELEVANCE: Based on these findings, the mixing of aminoglycoside antimicrobials and cultured equine BM-MSCs prior to therapeutic use is not recommended. PMID- 23448190 TI - The conceptualization and communication of risk among rural appalachian adolescents. AB - This study uses a meta-theoretical perspective for examining risk perceptions and behavior in the rural Appalachian cultural context, an area that remains largely unexplored. The authors conducted in-depth interviews with 113 rural adolescents to describe how youth conceptualize risk and how risk is communicated in the rural environment. Analyses revealed adolescents viewed behavior as risky when they had personal or vicarious experiences resulting in a loss of control or physical harm. Elements of the rural Appalachian culture including activities, familism, and community ties can prevent and promote adolescent risk taking in various forms. This study demonstrates the conceptualization of risk and messages about risk are culturally situated and communicatively devised and enacted. The implications of these findings for adolescent risk prevention programs are discussed. PMID- 23448191 TI - Gait speed correlates in a multiracial population of community-dwelling older adults living in Brazil: a cross-sectional population-based study. AB - BACKGROUND: Gait speed is a strong predictor of a wide range of adverse health outcomes in older adults. Mean values for gait speed in community-dwelling older adults vary substantially depending on population characteristics, suggesting that social, biological, or health factors might explain why certain groups tend to self-select their gait speed in different patterns. The vast majority of studies reported in the literature present data from North American and European populations. There are few population-based studies from other regions with a different ethnicity and/or social and health conditions. To address this, the present study identified the mean usual and fast gait speeds in a representative multiracial population of community-dwelling older adults living in a developing country, and explored their association with sociodemographic, mental and physical health characteristics. METHODS: This was a cross-sectional population based study of a sample of 137 men and 248 women, aged 65 years and over. Usual gait speed and fast gait speed were measured on a 4.6 m path. Participants were classified into slow, intermediate, and faster groups by cluster analysis. Logistic regression analysis was used to estimate the independent effect of each factor on the odds of presenting with a slower usual and slower fast gait speeds. RESULTS: Participants had a mean (SD) usual gait speed of 1.11 (0.27) m/s and a mean fast gait speed of 1.39 (0.34) m/s. We did not observe an independent association between gait speed and race/ethnicity, educational level, or income. The main contributors to present a slower usual gait speed were low physical activity level, stroke, diabetes, urinary incontinence, high concern about falling, and old age. A slower fast gait speed was associated with old age, low physical activity, urinary incontinence and high concern about falling. CONCLUSION: A multiracial population of older adults living in a developing country showed a similar mean gait speed to that observed in previously studied populations. The results suggest that low physical activity, urinary incontinence and high concern about falling should not be neglected and may help identify those who might benefit from early intervention. PMID- 23448193 TI - Spectroscopic identification of isomeric jet-cooled benzyl-type radicals generated from 4-fluoro-o-xylene. AB - Vibronically excited but jet-cooled benzyl-type radicals were generated by the corona discharge of precursor 4-fluoro-o-xylene seeded in a large amount of inert carrier gas helium using a pinhole-type glass nozzle, from which the vibronic emission spectra were observed with a long-path monochromator in the visible region. From an analysis of the spectra observed, we identified the existence of two isomeric benzyl-type radicals, 2-methyl-4-fluorobenzyl and 2-methyl-5 fluorobenzyl radicals in corona discharge, and determined the electronic energy of the D1 -> D0 transition and several vibrational mode frequencies in the D0 state of both isomers for the first time. PMID- 23448192 TI - Is there less to social anxiety than meets the eye? Behavioral and neural responses to three socio-emotional tasks. AB - BACKGROUND: Social anxiety disorder (SAD) is widely thought to be characterized by heightened behavioral and limbic reactivity to socio-emotional stimuli. However, although behavioral findings are clear, neural findings are surprisingly mixed. METHODS: Using functional magnetic resonance imaging (fMRI), we examined behavioral and brain responses in a priori emotion generative regions of interest (amygdala and insula) in 67 patients with generalized SAD and in 28 healthy controls (HC) during three distinct socio-emotional tasks. We administered these socio-emotional tasks during one fMRI scanning session: 1) looming harsh faces (Faces); 2) videotaped actors delivering social criticism (Criticism); and 3) written negative self-beliefs (Beliefs). RESULTS: In each task, SAD patients reported heightened negative emotion, compared to HC. There were, however, no SAD versus HC differential brain responses in the amygdala and insula. Between-group whole-brain analyses confirmed no group differences in the responses of the amygdala and insula, and indicated different brain networks activated during each of the tasks. In SAD participants, social anxiety symptom severity was associated with increased BOLD signal in the left insula during the Faces task. CONCLUSIONS: The similar responses in amygdala and insula in SAD and HC participants suggest that heightened negative emotion responses reported by patients with SAD may be related to dysfunction in higher cognitive processes (e.g., distorted appraisal, attention biases, or ineffective cognitive reappraisal). In addition, the findings of this study emphasize the differential effects of socio-emotional experimental tasks. PMID- 23448194 TI - Detection of haemophilia A during quality assurance of fresh frozen plasma. PMID- 23448195 TI - New data on the geographical distribution and host utilization of the entomopathogenic fungus Myrmicinosporidium durum. AB - Entomopathogenic Myrmicinosporidium durum Holldobler, 1933, a fungus known to exploit several ant species, is reported for the first time in five countries: Bulgaria, the Czech Republic, Romania, Slovakia, and Turkey. The discovery of the fungus in Anatolia significantly widens its known distribution. In addition, this fungal parasite was found to utilize two hitherto unknown host species: Tetramorium sp. D (sensu Schlick-Steiner et al. 2006 ) and Tetramorium sp. E (sensu Schlick- Steiner et al. 2006 ). According to the new data, M. durum seems to be more common in Europe than previously thought, while its host range is considerably larger. In the present paper, data on its currently known distribution and host preference are discussed. PMID- 23448196 TI - The need for better insulin therapy. AB - Insulin replacement therapy corrects a core defect of diabetes pathophysiology. Since its introduction as a therapeutic modality almost 100 years ago, insulin therapy has undergone remarkable changes in purity and ability to provide more physiologic control of blood glucose levels. With glucose-lowering potential limited only by risks of hypoglycaemia, which remains the major limitation in our ability to achieve glycaemic goals, insulin replacement therapy remains a cornerstone of therapy. Major progress in reducing the risks of hypoglycemia has occurred with the development of insulin analogs. This review article briefly chronicles the evolution of insulin replacement strategies, highlighting both challenges in pharmaceutical development and patient acceptance, underscoring achievements, as well as denoting what improvements are still needed. PMID- 23448197 TI - Newer insulin analogs: advances in basal insulin replacement. AB - Basal insulin analog therapy is the most common method of introducing insulin replacement therapy for the majority of patients with type 2 diabetes mellitus. Long-acting insulin analogs provide relatively peakless and more physiologic insulin replacement therapy than neutral protaminated Hagedorn insulin. Recently 2 new basal insulin analogs have been developed with superior pharmacokinetic and pharmacodynamics properties; insulin degludec and a pegylated insulin lispro. These agents are generally well tolerated and have been evaluated in both type 1 and type 2 diabetes. In this article we review the results of clinical trials assessing the efficacy, safety and tolerability of these newer longer-acting insulin analogs. In general rates of hypoglycaemia in these trials were low, glucose control was comparable to currently available basal insulin analogs, and rates of nocturnal hypoglycaemia were significantly and substantially lower. While further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies. PMID- 23448198 TI - Methods to enhance delivery of prandial insulin and basal-prandial insulin. AB - Most physicians are comfortable with initiating basal insulin replacement therapy in their patients with type 2 diabetes who are no longer meeting treatment goals with oral antidiabetic agents. What is more challenging is what to do when treatment goals are no longer being met despite adequate titration of basal insulin. Both fasting plasma glucose and postprandial glucose contribute to hemoglobin A1C levels. Addressing postprandial glucose levels can be accomplished by several approaches. Traditionally this has meant moving to basal bolus insulin, which is considered the gold standard. Premixed insulin may also be used. Data is also emerging for basal "plus" strategies, that is, incremental addition of prandial insulin injections. Newer approaches also reviewed in this article included premixed formulations containing ultra-long acting basal insulin with rapid-acting insulin analogs, inhaled insulin and insulin jet injectors, as well as the use of incretin-based therapies. PMID- 23448199 TI - Surface-based laminar analysis of diffusion abnormalities in cortical and white matter layers in neocortical epilepsy. AB - PURPOSE: Microstructural alterations seen in the epileptic cortex have been implicated as a cause and also result of multiple seizure activity. In the present study, we evaluated water diffusion changes at different cortical thickness fractions and in the underlying white matter of the epileptic cortex and compared them with electrographically normal cortex and also with corresponding cortical regions of healthy controls. METHODS: We selected 18 children with normal magnetic resonance imaging (MRI) who underwent two-stage epilepsy surgery to control seizures of neocortical origin, and compared their MR images with those of 18 age-matched healthy controls. First, delineation of the gray-white and gray-pial intersection surfaces was performed on high-resolution volumetric T1 MR images. Using the delineated surfaces as reference, diffusion values were measured at different cortical thickness fractions and in the underlying white matter at various depths, using diffusion tensor imaging (DTI). Cortical regions representing seizure onset and electrographically normal cortex were differentiated by electrocorticography in the epilepsy patients. KEY FINDINGS: We observed different patterns of diffusion abnormalities in both the seizure onset and electrographically normal cortical regions when compared to healthy controls. In the seizure-onset regions, a marked increase in diffusivity was noted in the cortical gray matter, and this increase was most pronounced in the outer fraction of the gray matter. Similarly, increased diffusivity was noted in the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to the controls. The white matter underlying the electrographically normal cortex did not show any difference in diffusivity between the children with epilepsy and controls. Finally, both the cortical gray matter and the underlying white matter regions showed decreased anisotropy in epileptic as well as electrographically normal regions when compared to controls. SIGNIFICANCE: Our results suggest specific patterns of diffusion changes in the cortical fractions and the underlying white matter of the epileptic region compared to electrographically normal and normal control regions. The abnormal increase in diffusivity of the superficial cortex might be associated with microstructural abnormalities commonly seen in layers II through IV of epileptic cortex. Such combined use of a high-resolution structural image to extract the laminar diffusion values, which are highly sensitive to microstructural alterations, could be of clinical value in localizing epileptogenic cortex. PMID- 23448200 TI - alpha-Fe2O3 nanocolumns and nanorods fabricated by electron beam evaporation for visible light photocatalytic and antimicrobial applications. AB - Both Fe2O3 thin films and nanorod arrays are deposited using electron beam evaporation through normal thin film deposition and oblique angle deposition (OAD) and are characterized structurally, optically, and photocatalytically. The morphologies of the thin films are found to be arrays of very thin and closely packed columnar structures, while the OAD films are well-aligned nanorod arrays. All films were determined to be in the hematite phase (alpha-Fe2O3), as confirmed by both structural and optical characterization. Texture measurements indicate that films have similar growth modes where the [110] direction aligns with the direction of material growth. Under visible light illumination, the thin film samples were more efficient at photocatalytically degrading methylene blue, while the nanorod arrays were more efficient at inactivating E. coli O157:H7. The size of the targeted agent and the different film morphologies result in different reactant/surface interactions, which is the main factor that determines photoactivity. Furthermore, an analytic mathematical model of bacterial inactivation based on chemotactic bacterial diffusion and surface deactivation is developed to quantify and compare the inactivation rate of the samples. These results indicate that alpha-Fe2O3 nanorods are promising candidates for antimicrobial applications and are expected to provide insight into the development of better visible-light antimicrobial materials for food products and processing environments, as well as other related applications. PMID- 23448201 TI - Molecular identification of Epitrix potato flea beetles (Coleoptera: Chrysomelidae) in Europe and North America. AB - Epitrix species (Coleoptera: Chrysomelidae) feed mostly on plants from the family Solanaceae and some of them are major pests of potato crops. All Epitrix species are morphologically highly similar, which makes them difficult to identify and limits their study and management. Identification of species is mostly based on the observation of the genitalia and requires a high level of expertise. Here, we propose a tool to reliably identify all developmental stages of the most economically important Epitrix species feeding on potato in Europe and North America (Epitrix cucumeris, Epitrix similaris, Epitrix tuberis, Epitrix subcrinita and Epitrix hirtipennis). We first sequenced two DNA markers (mitochondrial cytochrome c oxidase I (COI) and nuclear internal transcribed spacer 2 (ITS2)) to test their effectiveness in differentiating among six Epitrix species (126 specimens). Morphospecies of Epitrix were well-differentiated by both DNA barcodes and no mitochondrial introgression was detected. Then, we developed an RFLP-based diagnostic method and showed that unambiguous species discrimination can be achieved by using the sole restriction enzyme TaqI on COI polymerase chain reaction products. The tool proposed here should improve our knowledge about Epitrix species biology, distribution and host range, three capacities that are particularly important in the detection and management of these pest species. Specifically, this tool should help prevent the introduction of E. tuberis and E. subcrinita in Europe and limit the spread of the recently introduced E. cucumeris and E. similaris, with minimal disruption to Solanaceae trade. PMID- 23448202 TI - Large enhancement of nonlinear optical response in a hybrid nanobiomaterial consisting of bacteriorhodopsin and cadmium telluride quantum dots. AB - We report wavelength-dependent enormous enhancement of the nonlinear refractive index of wild-type bacteriorhodopsin in the presence of semiconductor quantum dots. The effect is strongest in the region just below the absorption edge of both constituents of this hybrid material and in samples that show strong Forster resonance energy transfer. We show that enhancements of up to 4000% can be achieved by controlled engineering of the hybrid structure involving variations of the molar ratio of the constituents. This new hybrid material with exceptional nonlinear properties will have numerous photonic and optoelectronic applications employing its photochromic, energy transfer, and conversion properties. PMID- 23448203 TI - Digital necrosis from dandelion tea. PMID- 23448204 TI - Detection of drug bioactivation in vivo: mechanism of nevirapine-albumin conjugate formation in patients. AB - The non-nucleoside reverse transcriptase inhibitor nevirapine (NVP) is widely used for the treatment of human immunodeficiency virus type 1 (HIV-1), particularly in developing countries. Despite its therapeutic benefits, NVP has been associated with skin and liver injury in exposed patients. Although the mechanism of the tissue injury is not yet clear, it has been suggested that reactive metabolites of NVP may be involved. The detection of NVP mercapturate in the urine of patients undergoing standard antiretroviral chemotherapy indicates that NVP undergoes bioactivation in vivo. However, covalent binding of drug to protein in patients remains to be determined. In this study, we investigate the chemical basis of NVP protein adduct formation by using human serum albumin (HSA) and glutathione S-transferase pi (GSTP) as model proteins in vitro. In addition, HSA was isolated from serum samples of HIV-1 patients undergoing NVP therapy to measure NVP haptenation. Mass spectrometric analysis of 12-sulfoxyl-NVP-treated HSA revealed that the drug bound selectively to histidine (His146, His242, and His338) and a cysteine residue (Cys34). The reaction proceeds most likely by a concerted elimination-addition mechanism. This pathway was further confirmed by the observation of NVP-modified Cys47 in GSTP. Importantly, the same adduct (His146) was detected in HSA isolated from the blood of patients receiving NVP, providing direct evidence that NVP modifies protein in vivo, via the formation of a reactive metabolite. PMID- 23448205 TI - A classical trajectory study of the dissociation and isomerization of C2H5. AB - Motivated by photodissociation experiments in which non-RRKM nanosecond lifetimes of the ethyl radical were reported, we have performed a classical trajectory study of the dissociation and isomerization of C2H5 over the energy range 100-150 kcal/mol. We used a customized version of the AIREBO semiempirical potential (Stuart, S. J.; et al. J. Chem. Phys. 2000, 112, 6472-6486) to more accurately describe the gas-phase decomposition of C2H5. This study constitutes one of the first gas-phase applications of this potential form. At each energy, 10,000 trajectories were run and all underwent dissociation in less than 100 ps. The calculated dissociation rate constants are consistent with RRKM models; no evidence was found for nanosecond lifetimes. An analytic kinetics model of isomerization/dissociation competition was developed that incorporated incomplete mode mixing through a postulated divided phase space. The fits of the model to the trajectory data are good and represent the trajectory results in detail through repeated isomerizations at all energies. The model correctly displays single exponential decay at lower energies, but at higher energies, multiexponential decay due to incomplete mode mixing becomes more apparent. At both ends of the energy range, we carried out similar trajectory studies on CD2CH3 to examine isotopic scrambling. The results largely support the assumption that a H or a D atom is equally likely to dissociate from the mixed-isotope methyl end of the molecule. The calculated fraction of products that have the D atom dissociation is ~20%, twice the experimental value available at one energy within our range. The calculated degree of isotopic scrambling is non-monotonic with respect to energy due to a non-monotonic ratio of the isomerization to dissociation rate constants. PMID- 23448206 TI - Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells. AB - BACKGROUND: There is accumulating evidence that obesity is closely associated with an impaired free fatty acid metabolism as well as with insulin resistance and inflammation. Excessive fatty acid uptake mediated by fatty acid translocase CD36 plays an important role in hepatic steatosis. Molecular hydrogen has been shown to attenuate oxidative stress and improve lipid, glucose and energy metabolism in patients and animal models of hepatic steatosis and atherosclerosis, but the underlying molecular mechanisms remain largely unknown. METHODS: Human hepatoma HepG2 cells were exposed to palmitate-BSA complex after treatment with or without hydrogen for 24 h. The fatty acid uptake was measured by using spectrofluorometry and the lipid content was detected by Oil Red O staining. JNK phosphorylation and CD36 expression were analyzed by Western blot and real-time PCR analyses. RESULTS: Pretreatment with hydrogen reduced fatty acid uptake and lipid accumulation after palmitate overload in HepG2 cells, which was associated with inhibition of JNK activation. Hydrogen treatment did not alter CD36 mRNA expression but reduced CD36 protein expression. CONCLUSION: Hydrogen inhibits fatty acid uptake and lipid accumulation through the downregulation of CD36 at the protein level in hepatic cultured cells, providing insights into the molecular mechanism underlying the hydrogen effects in vivo on lipid metabolism disorders. PMID- 23448207 TI - By design: a macrocyclic 3d-4f single-molecule magnet with quantifiable zero field slow relaxation of magnetization. AB - Rational modification of the equatorially bound tetranucleating macrocycle in the previously reported SMM complex of the propylene linked macrocycle [Cu(II)3Tb(III)(L(Pr))](NO3)2, to a new butylene linked analogue, is shown to tune the ligand field imposed on the encapsulated Cu(II)3Tb(III) cluster. This results in apical binding of two, rather than one, nitrate ions to the oblate Tb(III) ion, giving enhanced uniaxial anisotropy and SMM properties despite the low symmetry of the Tb(III) site. The resulting complex, [Cu(II)3Tb(III)(L(Bu))(NO3)2(MeOH)(H2O)](NO3).3H2O, is the first example of a macrocyclic 3d-4f single-molecule magnet that exhibits quantifiable relaxation of magnetization in zero dc field (Delta(eff)/k(B) = 19.5(5) K; tau0 = 3.4 * 10(-7) s). This SMM complex of this new, larger, tetranucleating macrocycle was prepared by the template method from the 3:3:3:1 reaction of 1,4-diformyl-2,3 dihydroxybenzene/diaminobutane/copper(II) acetate/terbium(III) nitrate. Similarly, the analogues, Zn3Tb(L(Bu))(NO3)3.MeOH.H2O.DMF and [Cu3La(L(Bu))(NO3)2(MeOH)(H2O)2](NO3).H2O.DMF, were prepared in order to facilitate the detailed magnetic analysis. Both copper(II) complexes were also structurally characterized, confirming the expected binding mode: lanthanide(III) ion in the central O6 pocket, and the three copper(II) ions in the outer N2O2 pockets. PMID- 23448208 TI - A pilot prospective study of the vascular repair response following red cell transfusion in critically ill patients. AB - BACKGROUND: Red blood cell transfusion has been associated with adverse outcomes including infection, delayed recovery and increased mortality in some patient populations. Circulating cells that yield endothelial-like vascular progenitor cell (VPC) clusters are correlated with vascular repair and recovery after ischaemic injury. The impact of red cell transfusion on VPC clusters and vascular repair remains uncertain. STUDY DESIGN: We prospectively enrolled patients admitted to intensive care requiring red cell transfusion and subjects at low likelihood of requiring red cell transfusion. Levels of VPC clusters and plasma levels of angiogenic cytokines were compared. A total of 17 patients were recruited and had blood samples collected at time of enrolment and at 24-48 h, 48 72 h and 1 week following transfusion. RESULTS: We could not discern differences in the number of VPC clusters between transfused patients (n = 6) and non transfused subjects (n = 11) at baseline or throughout the study period. VPC cluster levels demonstrated wide variance and were highest at 24-h post-enrolment in the entire cohort. Furthermore, levels of all 16 cytokines analysed were not significantly different between transfused and non-transfused patients and we did not observe a correlation between cytokine concentrations and levels of circulating VPC-cluster forming cells in the overall study population. CONCLUSIONS: Our data suggest that assessment of vascular repair responses after red blood cell transfusion in critically ill patients is challenging. Although our study did not allow us to discern an influence of red cell transfusion on VPC cluster levels or angiogenic cytokines, new methods evaluating vascular repair mechanisms may be required. PMID- 23448209 TI - A new species, Athous (Orthathous) cagatayae, from Turkey. AB - A new Elateridae species, Athous (Orthathous) cagatayae n. sp., is presented from Ankara, Turkey. The morphology of the new species is described. Photographs of imago and aedeagus, aedeagi drawings of the new species, and identification key are given. The new species is discussed with species of acutangulus group, with a differential diagnosis. PMID- 23448210 TI - The crossover between headache and epilepsy. PMID- 23448211 TI - Genome-wide association studies: will we ever predict susceptibility to multiple sclerosis through genetics? PMID- 23448212 TI - CNTF, STAT3 and new therapies for axonal degeneration: what are they and what can they do? PMID- 23448214 TI - Iron accumulation in multiple sclerosis: an early pathogenic event. AB - Iron has been shown to accumulate in deep gray matter structures in many forms of multiple sclerosis (MS), but detecting its presence early in the disease course (e.g., clinically isolated syndrome [CIS]) has been less clear. Here, we review a recent study where MRI scanning at 7 T together with susceptibility mapping was performed to assess iron deposition in CIS and control subjects. Susceptibility indicative of iron deposition was found to be increased in the globus pallidus, caudate, putamen and pulvinar of CIS patients compared with controls. The findings suggest that iron deposition is a pathological change that occurs early in the development of MS. Identifying the mechanisms of iron accumulation and determining whether iron promotes pathogenesis in MS are important areas of future research. PMID- 23448215 TI - Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. AB - When contemplating a pregnancy, women treated for multiple sclerosis (MS) with a disease-modifying drug must decide to discontinue their medication before conception or risk exposing their unborn child to potential drug toxicity. Few studies exist as reference for patients and physicians, and of those available, the majority are less than ideal due to real-world constraints, ethical issues and methodological shortcomings. The authors provide a brief summary of existing animal and human data with current recommendations regarding the safety of IFN beta, glatiramer acetate, natalizumab, mitoxantrone, fingolimod and teriflunomide during pregnancy and lactation in women with MS. We also assess the quality, strengths and limitations of the existing studies including challenges with study design. The investigation of outcomes such as spontaneous abortion and congenital anomalies are highlighted with potential methodological improvements for future studies on drug safety in pregnancy suggested. The authors explore the pharmacokinetics and pharmacodynamics of the MS disease-modifying drugs for their possible mechanistic role in fetal harm and discuss the potential role of clinical trials. Future pharmacovigilance studies should continue to pursue multicenter collaboration with an emphasis on appropriate study design. PMID- 23448216 TI - MRI in headache. AB - Headaches are described as primary, where no contributing cause is found, or secondary, where a discrete lesion or other condition has triggered the phenotype. Primary headache is a common condition; migraine causes much of the morbidity in this population, at great personal and economic cost. The decision to use MRI is a common dilemma facing clinicians, particularly as primary headache phenotypes can be triggered by secondary causes. Studies demonstrate that there is no appreciable difference in the frequency of pathological and incidental findings in common headache populations compared with the general community. Imaging is therefore not routinely required where a primary headache diagnosis can be made. Clinicians must be aware of the risk of manufacturing morbidity in uncovering incidental and nonsignificant imaging changes. However, patients demonstrating 'red flags' on medical history and examination do require imaging to help exclude a secondary cause of symptoms. Other headache phenotypes, such as the trigeminal autonomic cephalalgias, also generally require MRI. PMID- 23448217 TI - Relevance of functional neuroimaging studies for understanding migraine mechanisms. AB - Advances in imaging have provided further insights into the complex migraine pathophysiology. Functional neuroimaging by means of PET and functional MRI studies have addressed crucial migraine-related issues, improving our understanding of the circuitry that may be involved in the generation, maintenance and recurrence of pain symptoms in migraine. In the last few years, a growing body of imaging literature has also explored pathophysiology of associated migraine symptoms. Of great interest will be the use of advanced imaging techniques to elucidate neural correlates of migraine prodromal, in order to identify clinical subgroups of migrainous subjects. However, the interpretation of the biological significance of these various functional changes could remain incomplete without a combination of expanding genomic information about neurochemical pathways and genetic polymorphisms linked to specific migraine subtypes. Hopefully, a more detailed picture of the migraine neurobiology will emerge from future neuroimaging studies, which may eventually lead to better and more rational treatments. PMID- 23448218 TI - Epstein-Barr virus and multiple sclerosis: association or causation? AB - Multiple sclerosis (MS) is a multifactorial disease in which both genetic and environmental factors and their interactions underlie causation. The current evidence base supports a strong association between Epstein-Barr virus (EBV) and MS, but potential causality remains strongly debated. It is not possible to exclude the possibility that an abnormal response to EBV infection is a consequence, rather than a cause, of the underlying pathophysiology of MS, or indeed that the association may be a reflection of a similar underlying disease mechanism. Substantial experimental progress is necessary to achieve consistency of molecular findings to complement the strong epidemiological association between EBV and MS, which cannot alone show causation. Collectively, the strength of the association between EBV and MS warrants careful development and trial of anti-EBV drugs to observe any effect on MS disease course. PMID- 23448219 TI - Evaluation of brainstem involvement in multiple sclerosis. AB - Evidence suggests that brainstem involvement in multiple sclerosis (MS) is one of the major predictive factors for future disability. Recent work demonstrates that brainstem pathology is more frequent than can be depicted either clinically or with the use of MRI. Evoked potentials have been shown to reliably predict disability in MS patients. This review will consider the main clinical and neuroradiological aspects together with the role of different neurophysiological tests, as ancillary tools to conventional studies, in evaluation of brainstem pathology in MS patients. Specifically, the role of vestibular evoked myogenic potentials, trigeminal somatosensory evoked potentials, autonomic nervous system testing and sleep testing in MS, as correlates of brainstem damage, will be explored. PMID- 23448220 TI - Treating multiple sclerosis with monoclonal antibodies: a 2013 update. AB - The third part of this in-depth review series on the treatment of multiple sclerosis (MS) with monoclonal antibodies covers the years 2010-2012. The natalizumab section gives a progressive multifocal leukoencephalopathy update, focusing on clinically relevant aspects. Furthermore, it outlines problems around natalizumab cessation and current evidence on therapeutic strategies thereafter. Finally, it reviews evidence on Janus-faced modes of natalizumab action besides anti-inflammatory effects, including proinflammatory effects. The section on alemtuzumab critically analyzes recent Phase III results and discusses which patients might be best suited for alemtuzumab treatment, and reviews the long term immunological impact of this anti-CD52 antibody. The daclizumab section critically summarizes results from the Phase IIb SELECT/SELECTION trial and introduces the Phase III program. The section on anti-CD20 antibodies reviews Phase II results on ocrelizumab and ofatumumab, and discusses current perspectives of these antibodies for MS therapy. Promising recent Phase II results on the anti-IL-17A antibody secukinumab (AIN457) are outlined and a short update on tabalumab (LY2127399) is given. Other highlighted antibodies currently being tested in MS patients include GNbAC1, BIIB033, MOR103 and MEDI-551. Finally, the authors give an update on the role monoclonal antibodies could play in the therapeutic armamentarium for MS in the medium term. PMID- 23448223 TI - Different electroclinical picture of generalized epilepsy in two families with 15q13.3 microdeletion. AB - 15q.13.3 microdeletion has been described in a variety of neurodevelopmental disorders. Epilepsy appears to be a common feature and, specifically, the 15q13.3 microdeletion is found in about 1% of patients with idiopathic generalized epilepsy. Recently, absence seizures with intellectual disability (ID) have been reported in patients carrying this mutation. We describe two families in which several affected members carry a 15q13.3 microdeletion in a pattern suggestive of autosomal dominant inheritance. Their phenotype includes mainly absence epilepsy and mild ID, suggesting only similarities with genetic/idiopathic generalized epilepsies but not typical features. The importance of studying such families is crucial to broaden the phenotype and understand the long-term outcome of patients with this condition. PMID- 23448224 TI - Transmigration of polymorphnuclear neutrophils and monocytes through the human blood-cerebrospinal fluid barrier after bacterial infection in vitro. AB - BACKGROUND: Bacterial invasion through the blood-cerebrospinal fluid barrier (BCSFB) during bacterial meningitis causes secretion of proinflammatory cytokines/chemokines followed by the recruitment of leukocytes into the CNS. In this study, we analyzed the cellular and molecular mechanisms of polymorphonuclear neutrophil (PMN) and monocyte transepithelial transmigration (TM) across the BCSFB after bacterial infection. METHODS: Using an inverted transwell filter system of human choroid plexus papilloma cells (HIBCPP), we studied leukocyte TM rates, the migration route by immunofluorescence, transmission electron microscopy and focused ion beam/scanning electron microscopy, the secretion of cytokines/chemokines by cytokine bead array and posttranslational modification of the signal regulatory protein (SIRP) alpha via western blot. RESULTS: PMNs showed a significantly increased TM across HIBCPP after infection with wild-type Neisseria meningitidis (MC58). In contrast, a significantly decreased monocyte transmigration rate after bacterial infection of HIBCPP could be observed. Interestingly, in co-culture experiments with PMNs and monocytes, TM of monocytes was significantly enhanced. Analysis of paracellular permeability and transepithelial electrical resistance confirmed an intact barrier function during leukocyte TM. With the help of the different imaging techniques we could provide evidence for para- as well as for transcellular migrating leukocytes. Further analysis of secreted cytokines/chemokines showed a distinct pattern after stimulation and transmigration of PMNs and monocytes. Moreover, the transmembrane glycoprotein SIRPalpha was deglycosylated in monocytes, but not in PMNs, after bacterial infection. CONCLUSIONS: Our findings demonstrate that PMNs and monoctyes differentially migrate in a human BCSFB model after bacterial infection. Cytokines and chemokines as well as transmembrane proteins such as SIRPalpha may be involved in this process. PMID- 23448226 TI - Statement of Retraction: "Kishali NF, Imamoglu O, Kaldirimci M, Akyol P, Yildirim K. Comparison of lipid and lipoprotein values in men and women differing in training status.". AB - The editors and publisher would like to inform the readers that the following article has been retracted from publication in The International Journal of Neuroscience: Kishali NF, Imamoglu O, Kaldirimci M, Akyol P, Yildirim K. Comparison of lipid and lipoprotein values in men and women differing in training status. Int J Neurosci 2005 Sep;115(9):1247-57. The corresponding author, Dr. Kishali, notified the editors and the publisher that this article was previously published by The Biology of Sport: Imamoglu, O, Atan, T, Kishali, NF, Burmaoglu, G, Akyol, P, Yildirim, K. Comparison of lipid and lipoprotein values in men and women differing in training status. Biol Sport 2005 Sep;22(3):261-70. Dr. Kishali requested the retraction and we agreed. Our policy in this respect is clear: The International Journal of Neuroscience considers all manuscripts on the strict condition that they have been submitted only to The International Journal of Neuroscience, that they have not been published already, nor are they under consideration for publication or in press elsewhere. The International Journal of Neuroscience published this article in good faith, and on the basis of signed statements made by the corresponding author regarding the originality of their work. The article is withdrawn from all print and electronic editions. PMID- 23448225 TI - A comparison of tests for Hardy-Weinberg Equilibrium in national genetic household surveys. AB - BACKGROUND: This study is motivated by National Household Surveys that collect genetic data, in which complex samples (e.g. stratified multistage cluster sample), partially from the same family, are selected. In addition to the differential selection probabilities of selecting households and persons within the sampled households, there are two levels of correlations of the collected genetic data in National Genetic Household Surveys (NGHS). The first level of correlation is induced by the hierarchical geographic clustered sampling of households and the second level of correlation is induced by biological inheritances from individuals sampled in the same household. RESULTS: To test for Hardy-Weinberg Equilibrium (HWE) in NGHS, two test statistics, the CCS method [1] and the QS method [2], appear to be the only existing methods that take account of both correlations. In this paper, I evaluate both methods in terms of the test size and power under a variety of complex designs with different weighting schemes and varying magnitudes of the two correlation effects. Both methods are applied to a real data example from the Hispanic Health and Nutrition Examination Survey with simulated genotype data. CONCLUSIONS: The QS method maintains the nominal size well and consistently achieves higher power than the CCS method in testing HWE under a variety of sample designs, and therefore is recommended for testing HWE of genetic survey data with complex designs. PMID- 23448227 TI - Heritability estimates of tarsocrural osteochondrosis and palmar/plantar first phalanx osteochondral fragments in Standardbred trotters. AB - REASONS FOR PERFORMING STUDY: The pathogenesis of osteochondrosis (OC) and palmar/plantar first phalanx osteochondral fragments (POFs) is multifactorial, but specific knowledge of heritability is limited. OBJECTIVES: To improve the precision of heritability estimates and to estimate the genetic correlation between tarsocrural OC and POFs in Standardbred trotters. Further aims were to examine whether the prevalence of OC/POFs was different in the American and French lineages that have contributed to the Norwegian population, and if the prevalence was affected by heterozygosity. STUDY DESIGN: Retrospective cohort study. METHODS: Categorical data on tarsocrural OC and POFs from 2 radiographic studies performed in 1989 and 2007/2008 (n = 1217) were analysed with sire threshold models that included 230 sires. RESULTS: Heritability of OC at the distal intermediate ridge of the tibia and/or the lateral trochlear ridge of the talus was estimated at 0.29 +/- 0.15. For OC at the distal intermediate ridge of the tibia only, the estimate was 0.40 +/- 0.17. Heritability of POFs in all 4 limbs was estimated at 0.23 +/- 0.13; for metatarsophalangeal POFs this was 0.26 +/- 0.13 and for medial metatarsophalangeal POFs 0.32 +/- 0.14. Estimates of genetic correlation between OC and POFs ranged from 0.68 +/- 0.27 to 0.73 +/- 0.28 but were not significantly different from a zero-genetic correlation. Effects of lineages or heterozygosity were not observed. CONCLUSIONS AND POTENTIAL RELEVANCE: This study confirmed a moderate to high heritability of tarsocrural OC and POF, providing further evidence of the heritable nature of these diseases. Examination of specific lesions yielded the highest heritability; therefore, breeding programmes and future genome-analysis studies should focus on predilection sites rather than the entire disease complex. PMID- 23448229 TI - Hydrothermal synthesis of phosphate-functionalized carbon nanotube-containing carbon composites for supercapacitors with highly stable performance. AB - Phosphate-functionalized carbon nanotube (CNT)-containing carbon composites with hierarchical porous structure have been synthesized by a simple soft-template hydrothermal method followed by heat treatment. The resulting carbon composites are characterized by FE-SEM, TEM, TGA, FTIR microspectroscopy, and nitrogen sorption techniques. The electrochemical performance of the carbon composites as electrode materials for supercapacitors is also investigated. The results show that CNTs can be uniformly embedded in the carbon matrix, and the phosphate groups are introduced into the carbon composites successfully. The addition of CNTs with suitable content significantly improves the rate capability of carbon composites in 6 M KOH aqueous solution. Cell voltage window can be extended to 1.2 V when increasing the heat treatment temperature of carbon composites to 800 degrees C, and the resulting composites exhibit highly stable performance in supercapacitors at high current load of 5 A g(-1) and wide cell voltage of 1.2 V. PMID- 23448228 TI - Glucose-methanol co-utilization in Pichia pastoris studied by metabolomics and instationary 13C flux analysis. AB - BACKGROUND: Several studies have shown that the utilization of mixed carbon feeds instead of methanol as sole carbon source is beneficial for protein production with the methylotrophic yeast Pichia pastoris. In particular, growth under mixed feed conditions appears to alleviate the metabolic burden related to stress responses triggered by protein overproduction and secretion. Yet, detailed analysis of the metabolome and fluxome under mixed carbon source metabolizing conditions are missing. To obtain a detailed flux distribution of central carbon metabolism, including the pentose phosphate pathway under methanol-glucose conditions, we have applied metabolomics and instationary 13C flux analysis in chemostat cultivations. RESULTS: Instationary 13C-based metabolic flux analysis using GC-MS and LC-MS measurements in time allowed for an accurate mapping of metabolic fluxes of glycolysis, pentose phosphate and methanol assimilation pathways. Compared to previous results from NMR-derived stationary state labelling data (proteinogenic amino acids, METAFoR) more fluxes could be determined with higher accuracy. Furthermore, using a thermodynamic metabolic network analysis the metabolite measurements and metabolic flux directions were validated. Notably, the concentration of several metabolites of the upper glycolysis and pentose phosphate pathway increased under glucose-methanol feeding compared to the reference glucose conditions, indicating a shift in the thermodynamic driving forces. Conversely, the extracellular concentrations of all measured metabolites were lower compared with the corresponding exometabolome of glucose-grown P. pastoris cells.The instationary 13C flux analysis resulted in fluxes comparable to previously obtained from NMR datasets of proteinogenic amino acids, but allowed several additional insights. Specifically, i) in vivo metabolic flux estimations were expanded to a larger metabolic network e.g. by including trehalose recycling, which accounted for about 1.5% of the glucose uptake rate; ii) the reversibility of glycolytic/gluconeogenesis, TCA cycle and pentose phosphate pathways reactions was estimated, revealing a significant gluconeogenic flux from the dihydroxyacetone phosphate/glyceraldehydes phosphate pool to glucose-6P. The origin of this finding could be carbon recycling from the methanol assimilatory pathway to the pentose phosphate pool. Additionally, high exchange fluxes of oxaloacetate with aspartate as well as malate indicated amino acid pool buffering and the activity of the malate/Asp shuttle; iii) the ratio of methanol oxidation vs utilization appeared to be lower (54 vs 79% assimilated methanol directly oxidized to CO2). CONCLUSIONS: In summary, the application of instationary 13C-based metabolic flux analysis to P. pastoris provides an experimental framework with improved capabilities to explore the regulation of the carbon and energy metabolism of this yeast, particularly for the case of methanol and multicarbon source metabolism. PMID- 23448230 TI - 2D-fluoroscopic based navigation for Gamma 3 nail insertion versus conventional procedure- a feasibility study. AB - BACKGROUND: Intramedullary nailing is a standard surgical procedure for fixation of proximal femoral fractures, but is associated with considerable radiation exposure for controlling the implant placement, due to the percutaneous insertion technique.The aim of this study was the evaluation of potential benefits of 2D fluoroscopic based navigation focused on the reduction of radiation exposure, a decrease of procedure time, as well as an increase of accuracy for Gamma3 nail insertions. METHODS: Twenty randomized Gamma3 nail insertions were performed in non-fractured synthetic femora according to the manufactures operation guidelines (group I) or with use of a 2D-fluoroscopic based navigation system (group II). Time of different steps of the procedure and the radiation exposure were measured, as well as the accuracy evaluated in postoperative CT scans. RESULTS AND DISCUSSION: All Gamma3 nails were placed without any technical problems. Independent of the used procedure, the overall operating time (group I: 584 +/- 99.2 sec; group II: 662 +/- 64.9 sec; p=0.06) and accuracy of the final nail positions were equivalent, but the radiation exposure was significantly reduced (92% reduction in fluoroscopic images and 91% reduction in fluoroscopic time, p< 0.01), using the 2D fluoroscopic based navigation procedure. CONCLUSIONS: 2D fluoroscopic based navigation for Gamma3 nail insertion facilitates a relevant reduction of radiation exposure with equivalent accuracy of the final implant position and no prolonged operating time. This promising procedure modification is independent of different cephalomedullary implant manufacturers and specific implant designs, but needs to be evaluated in further clinical settings. PMID- 23448231 TI - Cardiac ablation catheter guidance by means of a single equivalent moving dipole inverse algorithm. AB - BACKGROUND: We developed and evaluated a novel system for guiding radiofrequency catheter ablation therapy of ventricular tachycardia. This guidance system employs an inverse solution guidance algorithm (ISGA) using a single equivalent moving dipole (SEMD) localization method. The method and system were evaluated in both a saline tank phantom model and in vivo animal (swine) experiments. METHODS: A catheter with two platinum electrodes spaced 3 mm apart was used as the dipole source in the phantom study. A 40-Hz sinusoidal signal was applied to the electrode pair. In the animal study, four to eight electrodes were sutured onto the right ventricle. These electrodes were connected to a stimulus generator delivering 1-ms duration pacing pulses. Signals were recorded from 64 electrodes, located either on the inner surface of the saline tank or on the body surface of the pig, and then processed by the ISGA to localize the physical or bioelectrical SEMD. RESULTS: In the phantom studies, the guidance algorithm was used to advance a catheter tip to the location of the source dipole. The distance from the final position of the catheter tip to the position of the target dipole was 2.22 +/- 0.78 mm in real space and 1.38 +/- 0.78 mm in image space (computational space). The ISGA successfully tracked the locations of electrodes sutured on the ventricular myocardium and the movement of an endocardial catheter placed in the animal's right ventricle. CONCLUSION: In conclusion, we successfully demonstrated the feasibility of using an SEMD inverse algorithm to guide a cardiac ablation catheter. PMID- 23448233 TI - Effect of warming with temperature oscillations on a low-latitude aphid, Aphis craccivora. AB - To estimate the net effect of climate change on natural populations, we must take into account the positive and negative effects of temperature oscillations and climate variability. Warming because of climate change will likely exceed the physiological optima of tropical insects, which currently live very close to their thermal optima. Tropical insects will be negatively affected if their optima are exceeded otherwise warming may affect them positively. We evaluate the demographic responses of the cowpea aphid, Aphis craccivora, to summer warming in subtropical and tropical Taiwan, and examine the effects of diel temperature oscillation on these responses. Aphids were reared at four temperatures (current summer mean, +1.4, +3.9 and +6.4 degrees C), the latter three simulating different levels of warming. At each average temperature, aphids experienced constant or oscillating (from -2.9 to +3.6 degrees C of each mean temperature) regimes. As the simulated summer temperatures increased, so did the negative effects on life-history traits and demographic parameters. Compared with aphids reared in constant temperatures, aphids reared in oscillating temperatures developed more slowly and had a longer mean generation time, but their net reproductive rate was higher. These findings demonstrate that climate warming will affect demographic parameters and life-history traits differentially. Studies that use constant temperatures are unlikely to accurately predict biotic responses to climate change. PMID- 23448232 TI - Cancer patient and survivor research from the cancer information service research consortium: a preview of three large randomized trials and initial lessons learned. AB - The authors describe 3 large randomized trials from the Cancer Information Service Research Consortium. Three web-based multimedia programs are being tested to help newly diagnosed prostate (Project 1) and breast cancer patients (Project 2) make informed treatment decisions and breast cancer patients prepare for life after treatment (Project 3). Project 3 also tests a telephone callback intervention delivered by a cancer information specialist. All participants receive standard print material specific to each project. Preliminary results from the 2-month follow-up interviews are reported for the initial wave of enrolled participants, most of whom were recruited from the Cancer Information Service (1-800-4-CANCER) telephone information program (Project 1: n =208; Project 2: n =340; Project 3: n =792). Self-reported use of the multimedia program was 51%, 52%, and 67% for Projects 1, 2, and 3, respectively. Self reported use of the print materials (read all, most, or some) was 90%, 85%, and 83% for Projects 1, 2, and 3, respectively. The callback intervention was completed by 92% of Project 3 participants. Among those using the Cancer Information Service Research Consortium interventions, perceived usefulness and benefit was high, and more than 90% reported that they would recommend them to other cancer patients. The authors present 5 initial lessons learned that may help inform future cancer communications research. PMID- 23448234 TI - Identification of drug candidate for osteoporosis by computational bioinformatics analysis of gene expression profile. AB - BACKGROUND: Osteoporosis is a condition of bones that leads to an increased susceptibility to fracture and consequent painful morbidity. It has become a major issue of life quality worldwide. However, until now, the molecular mechanism of this disease is far from being clear. METHODS: In this study, we obtained the gene expression profile of osteoporosis and controls from Gene Expression Omnibus and identified differentially expressed genes (DEGs) using classical t-test method. Then, functional enrichment analyses were performed to identify the dysregulated Gene Ontology categories and dysfunctional pathways in osteoporosis patients compared to controls. Besides, the connectivity map was used to identify compounds that induced inverse gene changes to osteoporosis. RESULTS: A total of 5581 DEGs were identified. We found these DEGs were enriched in 9 pathways by pathway enrichment analysis, including focal adhesion and MAPK signaling pathway. Besides, sanguinarine was identified as a potential therapeutic drug candidate capable of targeting osteoporosis. CONCLUSION: Although candidate agents identified by our approach may be premature for clinical trials, it is clearly a direction that warrants additional consideration. PMID- 23448235 TI - Imaging inward and outward trafficking of gold nanoparticles in whole animals. AB - Gold nanoparticles have emerged as novel safe and biocompatible tools for manifold applications, including biological imaging, clinical diagnostics, and therapeutics. The understanding of the mechanisms governing their interaction with living systems may help the design and development of new platforms for nanomedicine. Here we characterized the dynamics and kinetics of the events underlying the interaction of gold nanoparticles with a living organism, from the first interaction nanoparticle/cell membrane, to the intracellular trafficking and final extracellular clearance. By treating a simple water invertebrate (the cnidarian Hydra polyp) with functionalized gold nanoparticles, multiple inward and outward routes were imaged by ultrastructural analyses, including exosomes as novel undescribed carriers to shuttle the nanoparticles in and out the cells. From the time course imaging a highly dynamic picture emerged in which nanoparticles are rapidly internalized (from 30 min onward), recruited into vacuoles/endosome (24 h onward), which then fuse, compact and sort out the internalized material either to storage vacuoles or to late-endosome/lysosomes, determining almost complete clearance within 48 h from challenging. Beside classical routes, new portals of entry/exit were captured, including exosome-like structures as novel undescribed nanoparticle shuttles. The conservation of the endocytic/secretory machinery through evolution extends the value of our finding to mammalian systems providing dynamics and kinetics clues to take into account when designing nanomaterials to interface with biological entities. PMID- 23448236 TI - 1-Methyl-2-pyrrolidone: from exfoliating solvent to a paramagnetic ligand. AB - When 1-methyl-2-pyrrolidone molecule (1m2p) interacts with the T[Ni(CN)4] layer, its carbonyl pi bond homolytically disrupts and forms a coordination bond at the axial positions for the metal T, and hybrid inorganic-organic solids of formula unit T(L)2[Ni(CN)4], with T = Mn, Co, Ni, are obtained. The formed solids crystallize with a monoclinic unit cell in the C2/m space group where the metal T is found with octahedral coordination to four N ends of CN groups from a given layer and to two oxygen atoms from the organic ligands, while the inner metal (Ni) preserves its square planar coordination. In the interlayer region, the organic molecules achieve unusual planarity and are stacked through dipole-dipole interactions in a head-to-tail configuration to form a chain of molecular pillars. From such interactions, 3D pillared hybrid solids result. Upon the charge donation to the metal by oxygen atom from 1m2p, the latter becomes an organic radical whose SOMO frontier orbital has a strong pi character, associated with an essentially planar structure. The unpaired electron is delocalized between neighboring C and N atoms at the ligand ring plane, and it is featured by an outstanding broad absorption band in the near-IR region. For Ni, the metal of highest polarizing power within the considered series, the existence of pi overlapping interaction between organic ligand molecules leads to ferromagnetic ordering at low temperature, with TC = 10.07 K. For Mn and Co, related to the lower metal electron-withdrawing ability, the materials maintain the weak antiferromagnetic character resulting from the interaction between T metals in the layer -T-N=C-Ni-C=N-T- chains. PMID- 23448237 TI - Arabidopsis acyl-CoA-binding protein ACBP1 participates in the regulation of seed germination and seedling development. AB - A family of six genes encoding acyl-CoA-binding proteins (ACBPs), ACBP1-ACBP6, has been characterized in Arabidopsis thaliana. In this study, we demonstrate that ACBP1 promotes abscisic acid (ABA) signaling during germination and seedling development. ACBP1 was induced by ABA, and transgenic Arabidopsis ACBP1-over expressors showed increased sensitivity to ABA during germination and seedling development, whereas the acbp1 mutant showed decreased ABA sensitivity during these processes. Subsequent RNA assays showed that ACBP1 over-production in 12 day-old seedlings up-regulated the expression of PHOSPHOLIPASE Dalpha1 (PLDalpha1) and three ABA/stress-responsive genes: ABA-RESPONSIVE ELEMENT BINDING PROTEIN1 (AREB1), RESPONSE TO DESICCATION29A (RD29A) and bHLH-TRANSCRIPTION FACTOR MYC2 (MYC2). The expression of AREB1 and PLDalpha1 was suppressed in the acbp1 mutant in comparison with the wild type following ABA treatment. PLDalpha1 has been reported to promote ABA signal transduction by producing phosphatidic acid, an important lipid messenger in ABA signaling. Using lipid profiling, seeds and 12-day-old seedlings of ACBP1-over-expressing lines were shown to accumulate more phosphatidic acid after ABA treatment, in contrast to lower phosphatidic acid in the acbp1 mutant. Bimolecular fluorescence complementation assays indicated that ACBP1 interacts with PLDalpha1 at the plasma membrane. Their interaction was further confirmed by yeast two-hybrid analysis. As recombinant ACBP1 binds phosphatidic acid and phosphatidylcholine, ACBP1 probably promotes PLDalpha1 action. Taken together, these results suggest that ACBP1 participates in ABA-mediated seed germination and seedling development. PMID- 23448238 TI - Importance of protected areas for biodiversity conservation in central Cote D'ivoire: comparison of termite assemblages between two neighboring areas under differing levels of disturbance. AB - To highlight human impact on biodiversity in the Lamto region, termites were studied with regard to their use as bio-indicators of habitat change in the tropics. Using a standardized method, termites were sampled in the three most common habitat types, i.e., in semi-deciduous forest, savanna woodland, and annually burned savanna, all inside Lamto Reserve and its surrounding rural domain. Termite species richness fell from 25 species in the Lamto forest to 13 species in the rural area, involving strong modification in the species composition (species turnover = 59 %). In contrast, no significant change in diversity was found between the Lamto savannas and the rural ones. In addition, the relative abundance of termites showed a significantly greater decline in the rural domain, even in the species Ancistrotermes cavithorax (Sjostedt) (Isoptera: Termitidae), which is known to be ecologically especially versatile. Overall, the findings of this study suggest further investigation around Lamto Reserve on the impact of human activities on biodiversity, focusing on forest conversion to land uses (e.g. agricultural and silvicultural systems). PMID- 23448239 TI - Association between prosthetic factors and temporomandibular disorders in complete denture wearers. AB - OBJECTIVE: The purpose of this study was to investigate the prevalence of temporomandibular disorders (TMD) in denture wearers and the association between prosthetic factors and this condition. BACKGROUND: There is no consensus about the relationship between prosthetic factors and TMD among denture wearers. MATERIALS AND METHODS: The sample was composed of 92 patients wearing both maxillary and mandibular complete dentures. The Research Diagnostic Criteria for TMD (RDC/TMD) were adopted for patient examination. Objective evaluation of denture quality was determined by analysis of retention and stability of mandibular denture, interocclusal distance, articulation and occlusion. Association between denture quality and TMD diagnosis was analysed using chi square and Fisher's exact tests. RESULTS: 37.4% of the patients presented TMD. Denture quality was not significantly associated with the presence of TMD: mandibular retention (p = 0.466); mandibular stability (p = 0.466); interocclusal distance (p = 0.328); centric relation (p = 0.175); and balanced occlusion (p = 0.56). CONCLUSION: Within the scope of this case-controlled cross-sectional study, no robust association between prosthetic factors and TMD was found. PMID- 23448241 TI - Substituted purine and 7-deazapurine compounds as modulators of epigenetic enzymes: a patent evaluation (WO2012075381). AB - The patent presents 140 purine and 7-azapurine derivatives as potent inhibitors of DOT1L histone methyltransferase that might be useful in the treatment of leukemia with MLL rearrangements. It is becoming more and more evident that the deregulation of chromatin modifiers such as DOT1L plays a critical role in tumorigenesis. As yet, the number of pharmaceutical agents targeting chromatin modifiers is still limited. The market for such compounds has been estimated to be potentially as large as one third of all cancer patients. Overall, the prospective of a targeted product (i.e., a drug targeting a commonly affected chromatin modifier) is very promising, and exponentially growing investments into this market are anticipated. PMID- 23448240 TI - In vivo temporal and spatial profile of leukocyte adhesion and migration after experimental traumatic brain injury in mice. AB - BACKGROUND: Leukocytes are believed to be involved in delayed cell death following traumatic brain injury (TBI). However, data demonstrating that blood borne inflammatory cells are present in the injured brain prior to the onset of secondary brain damage have been inconclusive. We therefore investigated both the interaction between leukocytes and the cerebrovascular endothelium using in vivo imaging and the accumulation of leukocytes in the penumbra following experimentally induced TBI. METHODS: Experimental TBI was induced in C57/Bl6 mice (n = 42) using the controlled cortical impact (CCI) injury model, and leukocyte endothelium interactions (LEI) were quantified using both intravital fluorescence microscopy (IVM) of superficial vessels and 2-photon microscopy of cortical vessels for up to 14 h post-CCI. In a separate experimental group, leukocyte accumulation and secondary lesion expansion were analyzed in mice that were sacrificed 15 min, 2, 6, 12, 24, or 48 h after CCI (n = 48). Finally, leukocyte adhesion was blocked with anti-CD18 antibodies, and the effects on LEI and secondary lesion expansion were determined 16 (n = 12) and 24 h (n = 21), respectively, following TBI. RESULTS: One hour after TBI leukocytes and leukocyte platelet aggregates started to roll on the endothelium of pial venules, whereas no significant LEI were observed in pial arterioles or in sham-operated mice. With a delay of >4 h, leukocytes and aggregates did also firmly adhere to the venular endothelium. In deep cortical vessels (250 MUm) LEIs were much less pronounced. Transmigration of leukocytes into the brain parenchyma only became significant after the tissue became necrotic. Treatment with anti-CD18 antibodies reduced adhesion by 65%; however, this treatment had no effect on secondary lesion expansion. CONCLUSIONS: LEI occurred primarily in pial venules, whereas little or no LEI occurred in arterioles or deep cortical vessels. Inhibiting LEI did not affect secondary lesion expansion. Importantly, the majority of migrating leukocytes entered the injured brain parenchyma only after the tissue became necrotic. Our results therefore suggest that neither intravascular leukocyte adhesion nor the migration of leukocytes into cerebral tissue play a significant role in the development of secondary lesion expansion following TBI. PMID- 23448242 TI - Natural attenuation of perchlorate in denitrified groundwater. AB - Monitoring of a well-defined septic system groundwater plume and groundwater discharging to two urban streams located in southern Ontario, Canada, provided evidence of natural attenuation of background low level (ng/L) perchlorate (ClO4 ) under denitrifying conditions in the field. The septic system site at Long Point contains ClO4- from a mix of waste water, atmospheric deposition, and periodic use of fireworks, while the nitrate plume indicates active denitrification. Plume nitrate (NO3- -N) concentrations of up to 103 mg/L declined with depth and downgradient of the tile bed due to denitrification and anammox activity, and the plume was almost completely denitrified beyond 35 m from the tile bed. The ClO4- natural attenuation occurs at the site only when NO3 -N concentrations are <0.3 mg/L, after which ClO4- concentrations decline abruptly from 187 +/- 202 to 11 +/- 15 ng/L. A similar pattern between NO3- -N and ClO4- was found in groundwater discharging to the two urban streams. These findings suggest that natural attenuation (i.e., biodegradation) of ClO4- may be commonplace in denitrified aquifers with appropriate electron donors present, and thus, should be considered as a remediation option for ClO4- contaminated groundwater. PMID- 23448244 TI - Loss-of-function mutation in AAGAB in Chinese families with punctuate palmoplantar keratoderma. AB - BACKGROUND: Punctate palmoplantar keratoderma (PPPK, OMIM 148600) is a rare hereditary disorder characterized by multiple punctate keratoses on the palms and soles. Recently, mutations in the genes alpha- and gamma-adaptin-binding protein p34 (AAGAB) and collagen, type XIV, alpha1 (COL14A1) have been reported to cause PPPK. OBJECTIVES: To identify mutations in the genes AAGAB and COL14A1 in three Chinese families with PPPK. METHODS: Genomic DNA of the family members and 100 healthy individuals was isolated. Direct sequencing of all polymerase chain reaction products of the whole coding regions of AAGAB and COL14A1 was performed to identify the mutation. RESULTS: A heterozygous nonsense mutation c.61C>T (p.Q21X) was identified in AAGAB in two Chinese families with PPPK. We failed to detect any mutations in AAGAB or COL14A1 in family 3. CONCLUSIONS: A novel loss of-function mutation within AAGAB associated with PPPK was identified from two Chinese pedigrees. PMID- 23448243 TI - MicroRNAs and their putative targets in Brassica napus seed maturation. AB - BACKGROUND: MicroRNAs (miRNAs) are 20-21 nucleotide RNA molecules that suppress the transcription of target genes and may also inhibit translation. Despite the thousands of miRNAs identified and validated in numerous plant species, only small numbers have been identified from the oilseed crop plant Brassica napus (canola) - especially in seeds. RESULTS: Using next-generation sequencing technologies, we performed a comprehensive analysis of miRNAs during seed maturation at 9 time points from 10 days after flowering (DAF) to 50 DAF using whole seeds and included separate analyses of radicle, hypocotyl, cotyledon, embryo, endosperm and seed coat tissues at 4 selected time points. We identified more than 500 conserved miRNA or variant unique sequences with >300 sequence reads and also found 10 novel miRNAs. Only 27 of the conserved miRNA sequences had been previously identified in B. napus (miRBase Release 18). More than 180 MIRNA loci were identified/annotated using the B. rapa genome as a surrogate for the B.napus A genome. Numerous miRNAs were expressed in a stage- or tissue specific manner suggesting that they have specific functions related to the fine tuning of transcript abundance during seed development. miRNA targets in B. napus were predicted and their expression patterns profiled using microarray analyses. Global correlation analysis of the expression patterns of miRNAs and their targets revealed complex miRNA-target gene regulatory networks during seed development. The miR156 family was the most abundant and the majority of the family members were primarily expressed in the embryo. CONCLUSIONS: Large numbers of miRNAs with diverse expression patterns, multiple-targeting and co-targeting of many miRNAs, and complex relationships between expression of miRNAs and targets were identified in this study. Several key miRNA-target expression patterns were identified and new roles of miRNAs in regulating seed development are suggested. miR156, miR159, miR172, miR167, miR158 and miR166 are the major contributors to the network controlling seed development and maturation through their pivotal roles in plant development. miR156 may regulate the developmental transition to germination. PMID- 23448246 TI - Lumbar puncture and the diagnosis of CT negative subarachnoid haemorrhage: time for a new approach? AB - OBJECTIVE: Because of potential risks of poor outcome, lumbar puncture (LP) is recommended to exclude the presence of blood breakdown products in patients with suspected subarachnoid haemorrhage (SAH) and a normal CT scan. The aim of this study was to document how often this test proved useful. METHOD: A retrospective analysis of prospectively recorded data was conducted. Patients with suspected SAH and a normal CT scan in whom LP was recommended between May 2008 and May 2010 were identified using the neurosurgical referral database. CT scan results, LP results, inpatient stay, investigations and interventions were recorded. RESULTS: One hundred and sixty-three patients were identified in whom LP was recommended after a reported negative CT scan. Thirty-six of these 163 patients had a positive LP of which seven had evidence of SAH on the initial CT scan. In 66 patients, the LP was not diagnostic and 59/66 (90%) patients underwent secondary imaging in whom five with aneurysms were identified and treated. CONCLUSION: LP driven decision making in patients with a normal scan and suspected SAH is suboptimal in over a third of cases. Patients with a non-diagnostic LP harboured five aneurysms that merited treatment. These results support the need for secondary investigations following suspected SAH, but suggest that these could take the form of secondary imaging rather than a lumbar puncture. PMID- 23448245 TI - Tetraiodothyroacetic acid-conjugated PLGA nanoparticles: a nanomedicine approach to treat drug-resistant breast cancer. AB - AIM: The aim was to evaluate tetraiodothyroacetic acid (tetrac), a thyroid hormone analog of L-thyroxin, conjugated to poly(lactic-co-glycolic acid) nanoparticles (T-PLGA-NPs) both in vitro and in vivo for the treatment of drug resistant breast cancer. MATERIALS & METHODS: The uptake of tetrac and T-PLGA-NPs in doxorubicin-resistant MCF7 (MCF7-Dx) cells was evaluated using confocal microscopy. Cell proliferation assays and a chick chorioallantoic membrane model of FGF2-induced angiogenesis were used to evaluate the anticancer effects of T PLGA-NPs. In vivo efficacy was examined in a MCF7-Dx orthotopic tumor BALBc nude mouse model. RESULTS: T-PLGA-NPs were restricted from entering into the cell nucleus, and T-PLGA-NPs inhibited angiogenesis by 100% compared with 60% by free tetrac. T-PLGA-NPs enhanced inhibition of tumor-cell proliferation at a low-dose equivalent of free tetrac. In vivo treatment with either tetrac or T-PLGA-NPs resulted in a three- to five-fold inhibition of tumor weight. CONCLUSION: T-PLGA NPs have high potential as anticancer agents, with possible applications in the treatment of drug-resistant cancer. PMID- 23448247 TI - Direct observation of a bent carbonyl ligand in a 19-electron transition metal complex. AB - The photochemistry of [CpRu(CO)2]2 in P(OMe)3/CH2Cl2 solution has been studied using picosecond time-resolved infrared (TRIR) spectroscopy. Photolysis at 400 nm leads to the formation of 17-electron CpRu(CO)2(*) radicals, which react on the picosecond time scale to form 19-electron CpRu(CO)2P(OMe)3(*) adducts. The TRIR spectra of this adduct display an unusually low CO stretching frequency for the antisymmetric CO stretching mode, suggesting that one carbonyl ligand adopts a bent configuration to avoid a 19-electron count at the metal center. This spectral assignment is supported by analogous experiments on [CpFe(CO)2]2 in the same solvent, combined with DFT studies on the structures of the 19-electron adducts. The DFT results predict a bent CO ligand in CpRu(CO)2P(OMe)3(*), whereas approximately linear Fe-C-O bond angles are predicted for CpFe(CO)2P(OMe)3(*). The observation of a bent CO ligand in the 19-electron ruthenium adduct is a surprising result, and it provides new insight into the solution-phase behavior of 19-electron complexes. TRIR spectra were also collected for [CpRu(CO)2]2 in neat CH2Cl2, and it is interesting to note that no singly bridged [CpRu(CO)]2(MU CO) photoproduct was observed to form following 400- or 267-nm excitation, despite previous observations of this species on longer time scales. PMID- 23448248 TI - Graphene quantum-dot-doped polypyrrole counter electrode for high-performance dye sensitized solar cells. AB - Herein graphene quantum dot (GQD), a graphene material with lateral dimension less than 100 nm, is explored to dope PPy on F-doped tin oxide glass as an efficient counter electrode for high-performance dye-sensitized solar cells (DSSCs). The GQDs-doped PPy film has a porous structure in comparison to the densely structured plain PPy, and displays higher catalytic current density and lower charge transfer resistance than the latter toward I3(-)/I(-) redox reaction. The highest power conversion efficiency (5.27%) for DSSCs is achieved with PPy doped with10% GQDs, which is comparable to that of Pt counter electrode based DSSCs. This work provides an inexpensive alternative to replace platinum for DSSCs. PMID- 23448250 TI - Geographic distance and ecosystem size determine the distribution of smallest protists in lacustrine ecosystems. AB - Understanding the spatial distribution of aquatic microbial diversity and the underlying mechanisms causing differences in community composition is a challenging and central goal for ecologists. Recent insights into protistan diversity and ecology are increasing the debate over their spatial distribution. In this study, we investigate the importance of spatial and environmental factors in shaping the small protists community structure in lakes. We analyzed small protists community composition (beta-diversity) and richness (alpha-diversity) at regional scale by different molecular methods targeting the gene coding for 18S rRNA gene (T-RFLP and 454 pyrosequencing). Our results show a distance-decay pattern for rare and dominant taxa and the spatial distribution of the latter followed the prediction of the island biogeography theory. Furthermore, geographic distances between lakes seem to be the main force shaping the protists community composition in the lakes studied here. Finally, the spatial distribution of protists was discussed at the global scale (11 worldwide distributed lakes) by comparing these results with those present in the public database. UniFrac analysis showed 18S rRNA gene OTUs compositions significantly different among most of lakes, and this difference does not seem to be related to the trophic status. PMID- 23448249 TI - Barriers and facilitators of adherence to medical advice on skin self-examination during melanoma follow-up care. AB - BACKGROUND: Melanoma is the fastest growing tumor of the skin, which disproportionately affects younger and middle-aged adults. As melanomas are visible, recognizable, and highly curable while in early stages, early diagnosis is one of the most effective measures to decrease melanoma-related mortality. Skin self-examination results in earlier detection and removal of the melanoma. Due to the elevated risk of survivors for developing subsequent melanomas, monthly self-exams are strongly recommended as part of follow-up care. Yet, only a minority of high-risk individuals practices systematic and regular self-exams. This can be improved through patient education. However, dermatological education is effective only in about 50% of the cases and little is known about those who do not respond. In the current literature, psychosocial variables like distress, coping with cancer, as well as partner and physician support are widely neglected in relation to the practice of skin self-examination, despite the fact that they have been shown to be essential for other health behaviors and for adherence to medical advice. Moreover, the current body of knowledge is compromised by the inconsistent conceptualization of SSE. The main objective of the current project is to examine psychosocial predictors of skin self-examination using on a rigorous and clinically sound methodology. METHODS/DESIGN: The longitudinal, mixed-method study examines key psychosocial variables related to the acquisition and to the long-term maintenance of skin self-examination in 200 patients with melanoma. Practice of self-exam behaviors is assessed at 3 and 12 months after receiving an educational intervention designed based on best-practice standards. Examined predictors of skin self-exam behaviors include biological sex, perceived self-exam efficacy, distress, partner and physician support, and coping strategies. Qualitative analyses of semi-structured interviews will complement and enlighten the quantitative findings. DISCUSSION: The identification of short and long-term predictors of skin self-examination and an increased understanding of barriers will allow health care professionals to better address patient difficulties in adhering to this life-saving health behavior. Furthermore, the findings will enable the development and evaluation of evidence-based, comprehensive intervention strategies. Ultimately, these findings could impact a wide range of outreach programs and secondary prevention initiatives for other populations with increased melanoma risk. PMID- 23448251 TI - Interferon-gamma directly mediates developmental biliary defects. AB - Biliary atresia (BA) is the most common identifiable hepatobiliary disease affecting infants, in which there are defects in intra- and extrahepatic bile ducts and progressive fibrosis. Activation of interferon-gamma (IFNgamma) appears to be critical in both patients with BA and in rodent models of BA. We have recently reported a zebrafish model of biliary disease that shares features with BA, in which inhibition of DNA methylation leads to intrahepatic biliary defects and activation of IFNgamma target genes. Here we report that ifng genes are hypomethylated and upregulated in zebrafish larvae treated with azacytidine (azaC), an inhibitor of DNA methylation. Injection of IFNgamma protein into developing zebrafish larvae leads to biliary defects, suggesting that activation of the IFNgamma pathway is sufficient to cause developmental biliary defects. These defects are associated with decreased cholangiocyte proliferation and with a decrease in the expression of vhnf1 (hnf1b, tcf2), which encodes a homeodomain protein with previously reported roles in biliary development in multiple models. These results support an importance of IFNgamma in mediating biliary defects, and also demonstrate the feasibility of direct injection of intact protein into developing zebrafish larvae. PMID- 23448252 TI - Chemically induced intestinal damage models in zebrafish larvae. AB - Several intestinal damage models have been developed using zebrafish, with the aim of recapitulating aspects of human inflammatory bowel disease (IBD). These experimentally induced inflammation models have utilized immersion exposure to an array of colitogenic agents (including live bacteria, bacterial products, and chemicals) to induce varying severity of inflammation. This technical report describes methods used to generate two chemically induced intestinal damage models using either dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS). Methods to monitor intestinal damage and inflammatory processes, and chemical-genetic methods to manipulate the host response to injury are also described. PMID- 23448254 TI - Perceptions of an older patient on the role of the family doctor in health promotion: a qualitative case study. AB - INTRODUCTION: Health promotion and disease prevention are important aspects of primary health care. However, limited data are available concerning the opinions of older patients towards the respective services offered by family doctors. The aim of the present study was to evaluate an older patient's perception of the role of the family doctor in promoting his health, and identify those components that are difficult to examine in quantitative research. METHODS: A qualitative case study of an 80-year-old man using an in-depth interview was carried out. The interview transcript was analyzed thematically. Our patient was an 80-year-old university-educated man, with stable social and financial circumstances, living with his wife. He had retired early on grounds of ill health (tuberculosis) and had received a disability pension prior to formal retirement. At the time of the interview, his medical problems included mild prostatic hypertrophy, scoliosis and hypertension. He considered his health status to be satisfactory. He had changed family doctor five years prior to the interview, as he had been dissatisfied with the care provided. RESULTS: We found that our patient expected the family doctor to be aware of, and to discuss, the following issues: physical activity, diet, management of stress and mental health, use of alcohol and tobacco, personal hygiene, health screening, use of medication, and social activity. At the same time, our patient perceived the doctor's role as supplementary to his own in terms of the appraisal and maintenance of his health. CONCLUSIONS: Our findings provide evidence of what is important in the promotion of health among older people. PMID- 23448253 TI - Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis. AB - Decorin, a secreted small leucine-rich proteoglycan, acts as a tumor repressor in a variety of cancers, mainly by blocking the action of several receptor tyrosine kinases such as the receptors for hepatocyte, epidermal and insulin-like growth factors. In the present study we investigated the effects of decorin in an experimental model of thioacetamide-induced hepatocarcinogenesis and its potential role in modulating the signaling of platelet-derived growth factor receptor-alpha (PDGFRalpha). Genetic ablation of decorin in mice led to enhanced tumor prevalence and a higher tumor count compared with wild-type mice. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and concurrent activation (phosphorylation) of PDGFRalpha in the hepatocellular carcinomas generated in the decorin-null vis-a vis wild-type mice. Notably, in normal liver PDGFRalpha localized primarily to the membrane of nonparenchymal cells, whereas in the malignant counterpart PDGFRalpha was expressed by the malignant cells at their cell surfaces. This process was facilitated by a genetic background lacking endogenous decorin. Double immunostaining of the proteoglycan and the receptor revealed only minor colocalization, leading to the hypothesis that decorin would bind to the natural ligand PDGF rather than to the receptor itself. Indeed, we found, using purified proteins and immune-blot assays, that decorin binds to PDGF. Collectively, our findings support the idea that decorin acts as a secreted tumor repressor during hepatocarcinogenesis by hindering the action of another receptor tyrosine kinase, such as the PDGFRalpha, and could be a novel therapeutic agent in the battle against liver cancer. PMID- 23448255 TI - Sensitization to timothy grass pollen allergenic molecules in children. AB - BACKGROUND: Grass pollens are significant elicitors of IgE-mediated allergic disease in the world and timothy (Phleum pratense) is one of the most important pollens of the family. Molecular and biochemical characterization of Phleum pratense has revealed several allergen components: rPhl p 1 and rPhl p 5 have been shown to be "Species Specific Allergens", while the profilin rPhl p 12 and the calcium-binding protein rPhl p 7 are the principal Cross-Reactive components. METHODS: In this study the pattern of sensitization to rPhl p 1, rPhl p 5, rPhl p 7 and rPhl p 12 was analyzed in children with asthma and/or rhinoconjunctivitis and grass pollen allergy, in order to evaluate the frequency of sensitization to allergenic molecules of Phleum pratense among pediatric subjects allergic to grass pollen in a Mediterranean population. The correlation of sensitization to these Phleum allergenic molecules with IgE against grass pollen extract and its variation according to age and level of IgE against grass pollen extract were evaluated. RESULTS: IgE against to rPhl p 1 were found in 99% (205/207) of patients, to rPhl p 5 in 67% (139/207), to rPhl p 12 in 32% (66/207) and to rPhl p 7 only in 5% (10/207).Sensitization only to "Species Specific" (rPhl p1, rPhl p5) allergenic molecules of Phleum pratense was detected in 65% (135/207) of children. Our data show the predominant role of rPhl p 1 in pediatric populations as the most relevant sensitizing allergen detectable at all ages and at all levels of timothy grass pollen-specific IgE antibodies, while the importance of rPhl p 5 rises with the increase of patients' age and with grass pollen IgE levels. CONCLUSIONS: The assessment of sensitization to grass pollen allergenic molecules could help develop a better characterization of allergic sensitization in grass pollen allergy in children, which may be different in every patient. It could also enable clinicians to give more specific and effective immunotherapy, based on allergenic molecule sensitization. PMID- 23448256 TI - Saproxylic community, guild and species responses to varying pheromone components of a pine bark beetle. AB - Some bark beetle species (Coleoptera: Scolytinae) produce aggregation pheromones that allow coordinated attack on their conifer hosts. As a new saproxylic habitat is founded, an assemblage of associated beetles kairomonally respond to bark beetle infochemicals. Ips sexdentatus is one of the major damaging insects of Pinus spp. in Southern Europe. Its response to varying ipsenol (Ie) percentages in relation to ipsdienol (Id) was studied in northwestern Spain, along with the entire saproxylic beetle assemblage captured at multiple-funnel traps. Response profile modeling was undertaken for I. sexdentatus sexes and sex-ratios, associated species and for selected trophic groups using a reference Gaussian model. In addition, the effects on the saproxylic assemblages were analyzed. I. sexdentatus response curve peaked at 22.7% Ie content, while remaining taxa that could be modeled, peaked above ca. 40% Ie. Predator guilds showed a linear relationship with Ie proportion, while competitors showed a delayed response peak. Consequently, species assemblages differed markedly between varying pheromone component mixtures. Given that the evaluated pheromonal proportions mimicked that of logs being colonized by I. sexdentatus, results suggested that the registered differential responses at different levels might provide I. sexdentatus with a temporal window that maximizes conspecific attraction while reducing interference with competitor and predatory guilds. Described responses might help improve the monitoring of the population status of target bark beetles and their associates, but also point toward the by-catch of many natural enemies, as well as rare saproxylic beetle species, interfering with the aims of sustainable forest management. PMID- 23448260 TI - Regional flow and deformation analysis of Basin-fill aquifer systems using stress dependent parameters. AB - Changes in effective stress due to water pressure variations modify the intrinsic hydrodynamic properties of aquifers and aquitards. Overexploited groundwater systems, such as basins with heavy pumping, are subject to nonrecoverable modifications. This results in loss of permeability, porosity, and specific storage due to system consolidation. This paper presents (1) the analytical development of model functions relating effective stress to hydrodynamic parameters for aquifers and aquitards constituted of unconsolidated granular sediments, and (2) a modeling approach for the analysis of aquifer systems affected by effective stress variations, taking into account the aforementioned dependency. The stress-dependent functions were fit to laboratory data, and used in the suggested modeling approach. Based on only few unknowns, this approach is computationally simple, efficiently captures the hydromechanical processes that are active in regional aquifer systems under stress, and readily provides an estimate of their consolidation. PMID- 23448259 TI - Whole human genome proteogenomic mapping for ENCODE cell line data: identifying protein-coding regions. AB - BACKGROUND: Proteogenomic mapping is an approach that uses mass spectrometry data from proteins to directly map protein-coding genes and could aid in locating translational regions in the human genome. In concert with the ENcyclopedia of DNA Elements (ENCODE) project, we applied proteogenomic mapping to produce proteogenomic tracks for the UCSC Genome Browser, to explore which putative translational regions may be missing from the human genome. RESULTS: We generated ~1 million high-resolution tandem mass (MS/MS) spectra for Tier 1 ENCODE cell lines K562 and GM12878 and mapped them against the UCSC hg19 human genome, and the GENCODE V7 annotated protein and transcript sets. We then compared the results from the three searches to identify the best-matching peptide for each MS/MS spectrum, thereby increasing the confidence of the putative new protein coding regions found via the whole genome search. At a 1% false discovery rate, we identified 26,472, 24,406, and 13,128 peptides from the protein, transcript, and whole genome searches, respectively; of these, 481 were found solely via the whole genome search. The proteogenomic mapping data are available on the UCSC Genome Browser at http://genome.ucsc.edu/cgi bin/hgTrackUi?db=hg19&g=wgEncodeUncBsuProt. CONCLUSIONS: The whole genome search revealed that ~4% of the uniquely mapping identified peptides were located outside GENCODE V7 annotated exons. The comparison of the results from the disparate searches also identified 15% more spectra than would have been found solely from a protein database search. Therefore, whole genome proteogenomic mapping is a complementary method for genome annotation when performed in conjunction with other searches. PMID- 23448258 TI - TNF-alpha promotes cerebral pericyte remodeling in vitro, via a switch from alpha1 to alpha2 integrins. AB - BACKGROUND: There is increasing evidence to suggest that pericytes play a crucial role in regulating the remodeling state of blood vessels. As cerebral pericytes are embedded within the extracellular matrix (ECM) of the vascular basal lamina, it is important to understand how individual ECM components influence pericyte remodeling behavior, and how cytokines regulate these events. METHODS: The influence of different vascular ECM substrates on cerebral pericyte behavior was examined in assays of cell adhesion, migration, and proliferation. Pericyte expression of integrin receptors was examined by flow cytometry. The influence of cytokines on pericyte functions and integrin expression was also examined, and the role of specific integrins in mediating these effects was defined by function blocking antibodies. Expression of pericyte integrins within remodeling cerebral blood vessels was analyzed using dual immunofluorescence (IF) of brain sections derived from the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). RESULTS: Fibronectin and collagen I promoted pericyte proliferation and migration, but heparan sulfate proteoglycan (HSPG) had an inhibitory influence on pericyte behavior. Flow cytometry showed that cerebral pericytes express high levels of alpha5 integrin, and lower levels of alpha1, alpha2, and alpha6 integrins. The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha strongly promoted pericyte proliferation and migration, and concomitantly induced a switch in pericyte integrins, from alpha1 to alpha2 integrin, the opposite to the switch seen when pericytes differentiated. Inhibition studies showed that alpha2 integrin mediates pericyte adhesion to collagens, and significantly, function blockade of alpha2 integrin abrogated the pro-modeling influence of TNF-alpha. Dual-IF on brain tissue with the pericyte marker NG2 showed that while alpha1 integrin was expressed by pericytes in both stable and remodeling vessels, pericyte expression of alpha2 integrin was strongly induced in remodeling vessels in EAE brain. CONCLUSIONS: Our results suggest a model in which ECM constituents exert an important influence on pericyte remodeling status. In this model, HSPG restricts pericyte remodeling in stable vessels, but during inflammation, TNF-alpha triggers a switch in pericyte integrins from alpha1 to alpha2, thereby stimulating pericyte proliferation and migration on collagen. These results thus define a fundamental molecular mechanism in which TNF-alpha stimulates pericyte remodeling in an alpha2 integrin dependent manner. PMID- 23448261 TI - Combining primary and piggyback intraocular lenses to treat extreme myopic astigmatism in stable keratoconus following cataract surgery. AB - The majority of those with keratoconus can maximise visual acuity with spectacle or contact lens correction as they age; however, as subjects enter their sixties, cataracts may supervene and contact lens tolerance diminishes with consequent reduction in visual acuity. Following cataract extraction, the complex refractive error associated with keratoconus may not be readily corrected by an intraocular lens alone. This report highlights the planned implantation of a primary posterior chamber toric intraocular lens with a secondary piggyback, sulcus based, intraocular lens in advanced but stable keratoconus with extreme myopic astigmatism and cataract. PMID- 23448262 TI - Composition of the sand fly fauna in Khash County, Southeast Iran. AB - Sand flies (Diptera: Psychodidae: Phlebotominae) are the biological vectors of leishmaniasis all around the world. In 1997, sand flies were collected in 14 cities and villages of Khash County in southeastern Iran, using 848 sticky traps (castor oil-coated white papers 20 * 30 cm). In this study, a total of 4673 sand flies, with 25.23% females and 74.77% males, were collected and identified to species mainly from mountainous areas. The 21 species of sand flies belonged to the genus Phlebotomus (nine species) and the genus Sergentomyia (12 species). The following 14 species were reported for the first time in Khash County: P. papatasi, P. bergeroti, P. eleanorae, P. halepensis, P. major, P. mesghali, S. hodgsoni, S. mervynae, S. dreyfussi, S. iranica, S. theodori, S. africana, S. clydei, and S. christophersi. The composition of species in Khash County is similar to other parts of Iran. However, the dominance of P. kazeruni in Khash County may suggest that this species should be considered as a potential vector in the region of Khash. PMID- 23448263 TI - The role of the beta2 adrenergic receptor on endothelial progenitor cells dysfunction of proliferation and migration in chronic obstructive pulmonary disease patients. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), with > 44% of these patients presenting with generalized atherosclerosis at autopsy. It is accepted that endothelial progenitor cells (EPCs) participate in the repair of dysfunctional endothelium, thereby, protecting against atherosclerosis. The beta2 adrenergic receptor (beta2AR) expressed on mononuclear cells in peripheral blood and CD34(+) cells in bone has been shown to regulate T-cell traffic and proliferation. At present, there have been few systematic studies evaluating beta2AR expression on EPCs in the peripheral blood of COPD patients and its role in EPCs migration and proliferation. Therefore, the objective of this study was to determine the role of beta2ARs in EPCs function and, if this role is altered, in the COPD population. METHODS: EPCs from 25 COPD and 16 control patients were isolated by Ficoll density-gradient centrifugation and identified using fluorescence activated cell sorting. beta2AR expression on EPCs was determined by western blotting and real-time PCR. The transwell migration assay was performed to determine the migration capacity of EPCs treated with a beta2AR agonist, antagonist and beta2AR monoclonal antibody. EPCs proliferation was assayed throughout the cell cycle. Following arterial damage in NOD/SCID mice, the number of EPCs treated with siRNA-beta2AR incorporated at the injured vascular site was determined by fluorescence microscopy. RESULTS: Data showed a significant increase in the total number of beta2ARs in addition to an increased expression on early EPCs in COPD patients. COPD EPCs treated with beta2AR antagonist (ICI 118551) increased migration to SDF-1alpha when compared to treatment with the beta2AR agonist, norepinephrine. These changes were directly correlated to increase CXCR4 on EPCs. The proliferation of early EPCs treated with beta2AR antagonist was improved and was correlated to an intercellular decrease in reactive oxygen species. CONCLUSION: Changes in beta2AR in COPD patients alter EPCs migration and proliferation, contributing to altered EPC repair capacity in this patient population. PMID- 23448264 TI - Selective cancer therapy by extracellular activation of a highly potent glycosidic duocarmycin analogue. AB - Conventional cancer chemotherapy is limited by systemic toxicity and poor selectivity. Tumor-selective activation of glucuronide prodrugs by beta glucuronidase in the tumor microenvironment in a monotherapeutic approach is one promising way to increase cancer selectivity. Here we examined the cellular requirement for enzymatic activation as well as the in vivo toxicity and antitumor activity of a glucuronide prodrug of a potent duocarmycin analogue that is active at low picomolar concentrations. Prodrug activation by intracellular and extracellular beta-glucuronidase was investigated by measuring prodrug 2 cytotoxicity against human cancer cell lines that displayed different endogenous levels of beta-glucuronidase, as well as against beta-glucuronidase-deficient fibroblasts and newly established beta-glucuronidase knockdown cancer lines. In all cases, glucuronide prodrug 2 was 1000-5000 times less cytotoxic than the parent duocarmycin analogue regardless of intracellular levels of beta glucuronidase. By contrast, cancer cells that displayed tethered beta glucuronidase on their plasma membrane were 80-fold more sensitive to glucuronide prodrug 2, demonstrating that prodrug activation depended primarily on extracellular rather than intracellular beta-glucuronidase activity. Glucuronide prodrug 2 (2.5 mg/kg) displayed greater antitumor activity and less systemic toxicity in vivo than the clinically used drug carboplatin (50 mg/kg) to mice bearing human lung cancer xenografts. Intratumoral injection of an adenoviral vector expressing membrane-tethered beta-glucuronidase dramatically enhanced the in vivo antitumor activity of prodrug 2. Our data provide evidence that increasing extracellular beta-glucuronidase activity in the tumor microenvironment can boost the therapeutic index of a highly potent glucuronide prodrug. PMID- 23448265 TI - Indole-3-acetic acid biosynthetic pathway and aromatic amino acid aminotransferase activities in Pantoea dispersa strain GPK. AB - This investigation deals with the production of IAA by a bacterial isolate Pantoea dispersa strain GPK (PDG) identified by 16S rRNA gene sequence analysis. HPLC and Mass spectral analysis of metabolites from bacterial spent medium revealed that, IAA production by PDG is Trp-dependent and follows indole-3 pyruvic acid (IPyA) pathway. Substrate specificity study of aromatic amino acid aminotransferase (AAT) showed high activities, only when tryptophan (Trp) and alpha-ketoglutarate (alpha-kg) were used as substrates. AAT is highly specific for Trp and alpha-kg as amino group donor and acceptor, respectively. The effect of exogenous IAA on bacterial growth was established. Low concentration of exogenous IAA induced the growth, whereas high concentration decreased the growth of bacterium. PDG treatment significantly increased the root length, shoot length and dry mass of the chickpea and pigeon pea plants. PMID- 23448257 TI - Microbial communities in low permeability, high pH uranium mine tailings: characterization and potential effects. AB - AIMS: To describe the diversity and metabolic potential of microbial communities in uranium mine tailings characterized by high pH, high metal concentration and low permeability. METHODS AND RESULTS: To assess microbial diversity and their potential to influence the geochemistry of uranium mine tailings using aerobic and anaerobic culture-based methods, in conjunction with next generation sequencing and clone library sequencing targeting two universal bacterial markers (the 16S rRNA and cpn60 genes). Growth assays revealed that 69% of the 59 distinct culturable isolates evaluated were multiple-metal resistant, with 15% exhibiting dual-metal hypertolerance. There was a moderately positive correlation coefficient (R = 0.43, P < 0.05) between multiple-metal resistance of the isolates and their enzyme expression profile. Of the isolates tested, 17 reduced amorphous iron, 22 reduced molybdate and seven oxidized arsenite. Based on next generation sequencing, tailings depth was shown to influence bacterial community composition, with the difference in the microbial diversity of the upper (0-20 m) and middle (20-40 m) tailings zones being highly significant (P < 0.01) from the lower zone (40-60 m) and the difference in diversity of the upper and middle tailings zone being significant (P < 0.05). Phylotypes closely related to well known sulfate-reducing and iron-reducing bacteria were identified with low abundance, yet relatively high diversity. CONCLUSIONS: The presence of a population of metabolically-diverse, metal-resistant micro-organisms within the tailings environment, along with their demonstrated capacity for transforming metal elements, suggests that these organisms have the potential to influence the long-term geochemistry of the tailings. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first investigation of the diversity and functional potential of micro-organisms present in low permeability, high pH uranium mine tailings. PMID- 23448266 TI - Cobalt(II/III) redox electrolyte in ZnO nanowire-based dye-sensitized solar cells. AB - In this work, we explore the use of cobalt complex redox shuttles in dye sensitized solar cells (DSCs) based on ZnO nanowires (NWs). Arrays of vertically aligned ZnO NWs produced by a low-cost hydrothermal method are used to fabricate DSCs with [Co(bpy)3](2+/3+) as electrolyte. A direct comparison of the performance of [Co(bpy)3](2+/3+)-based ZnO DSC with I(-)/I3(-)-based ones demonstrates the higher suitability of the cobalt complex, both in terms of a larger open circuit voltage (VOC) and a higher photocurrent. The [Co(bpy)3](2+/3+) electrolyte results in VOC enhancements above 200 mV. This VOC increase is associated to the better match between the cobalt complex redox potential and the oxidation potential of the dye. The incident photon-to-current efficiency (IPCE) enhancement is attributed to a less competitive visible light absorption of the cobalt redox couple. Thus the present study opens new opportunities to improve energy conversion efficiency in ZnO-based DSCs. PMID- 23448267 TI - Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1. AB - 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a protein target that has generated considerable interest in both academia and the pharmaceutical industry. PDK1 is responsible for regulating the activity of related kinases in the AGC kinase family, including AKT, by phosphorylating a specific threonine or serine residue within the activation loop which is critical for kinase activation. Many of the kinases activated by PDK1 regulate cellular process such as cell survival, differentiation, growth, and protein expression. Although significant work has been done to understand the role of PDK1 function in cells, recently discovered potent and selective small molecule PDK1 inhibitors are providing a unique opportunity to further dissect PDK1 function and predict the pharmacological consequences of PDK1 inhibition. This Miniperspective reviews the discovery of these selective PDK1 inhibitors and highlights their value in cellular studies, the understanding of PDK1 biology, and the impact on the therapeutic potential of PDK1 inhibition in cancer. PMID- 23448268 TI - Enzymatic activity of a subtilisin homolog, Tk-SP, from Thermococcus kodakarensis in detergents and its ability to degrade the abnormal prion protein. AB - BACKGROUND: Tk-SP is a member of subtilisin-like serine proteases from a hyperthermophilic archaeon Thermococcus kodakarensis. It has been known that the hyper-stable protease, Tk-SP, could exhibit enzymatic activity even at high temperature and in the presence of chemical denaturants. In this work, the enzymatic activity of Tk-SP was measured in the presence of detergents and EDTA. In addition, we focused to demonstrate that Tk-SP could degrade the abnormal prion protein (PrPSc), a protease-resistant isoform of normal prion protein (PrPC). RESULTS: Tk-SP was observed to maintain its proteolytic activity with nonionic surfactants and EDTA at 80 degrees C. We optimized the condition in which Tk-SP functions efficiently, and demonstrated that the enzyme is highly stable in the presence of 0.05% (w/v) nonionic surfactants and 0.01% (w/v) EDTA, retaining up to 80% of its activity. Additionally, we also found that Tk-SP can degrade PrPSc to a level undetectable by western-blot analysis. CONCLUSIONS: Our results indicate that Tk-SP has a great potential for technological applications, such as thermo-stable detergent additives. In addition, it is also suggested that Tk-SP-containing detergents can be developed to decrease the secondary infection risks of transmissible spongiform encephalopathies (TSE). PMID- 23448269 TI - Successive C-C coupling of dienes to vicinally dioxygenated hydrocarbons: ruthenium catalyzed [4 + 2] cycloaddition across the diol, hydroxycarbonyl, or dione oxidation levels. AB - The ruthenium(0) catalyst generated from Ru3(CO)12 and tricyclohexylphosphine or BIPHEP promotes successive C-C coupling of dienes to vicinally dioxygenated hydrocarbons across the diol, hydroxyketone, and dione oxidation levels to form products of [4 + 2] cycloaddition. A mechanism involving diene-carbonyl oxidative coupling followed by intramolecular carbonyl addition from the resulting allylruthenium intermediate is postulated. PMID- 23448270 TI - Can one blood draw replace transrectal ultrasonography-estimated prostate volume to predict prostate cancer risk? AB - OBJECTIVE: To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting. SUBJECTS AND METHODS: The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (>=3 ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam (n = 2914) and Goteborg (n = 740). A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome. RESULTS: The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Goteborg. Adding digital rectal examination (DRE) or DRE plus transrectal ultrasonography (TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high-grade cancer. There was a strong correlation between the blood measurements and TRUS estimated prostate volume (Spearman's correlation 0.60 in Rotterdam and 0.57 in Goteborg). CONCLUSIONS: In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to day clinical practice. Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches. PMID- 23448271 TI - The surface area of the hand and the palm for estimating percentage of total body surface area: results of a meta-analysis. AB - BACKGROUND: The estimation of body surface area involvement is an important tool. Hand surface area (HSA) or palm surface area (PSA) is commonly used for the estimate, with an assumption that HSA represents 1% of the total body surface area (TBSA). OBJECTIVES: To establish (i) the most accurate values for mean HSA% and PSA% of TBSA, and (ii) the variability of these with patient variables. METHODS: The PubMed, Embase and Cochrane databases were searched and 14 eligible studies were identified. Weighted means of HSA% and PSA% were produced. The meta analysis examined systematic variation associated with sex, age (for children), body mass index (BMI) and ethnic group using random-effects models. RESULTS: HSA% is 13% lower than the accepted 1% value for all adults (P = 0.004). PSA% is not significantly different from the accepted 0.5% value (P = 0.82). Men have a significantly higher HSA% than women (P < 0.0001). Children have a significantly higher HSA% than adults (P < 0.0001). HSA% falls with increasing BMI in adults (P < 0.0001). A comparison of European, Chinese and Indian subcontinent ethnic groups showed that each group was different from the others (P < 0.05). CONCLUSIONS: The use of HSA equating to 1% TBSA results in an overestimate for adults (particularly women) and an underestimate for children. PSA equating to 0.5% TBSA appears to be suitable for adults. Patient variables including sex and BMI result in variation of HSA as a percentage of TBSA. The heterogeneity of the included studies and the lack of data for children are the major limitations of this study. PMID- 23448272 TI - Biosurveillance in outbreak investigations. AB - Following the terrorist attacks of September 11 and the anthrax attacks in 2001, public health entities implemented automated surveillance systems based on disease syndromes for early detection of bioterror events and to increase timeliness of responses. Despite widespread adoption, syndromic surveillance systems' ability to provide early notification of outbreaks is unproven, and there is little documentation on their role in outbreak response. We hypothesized that biosurveillance is used in practice to augment classical outbreak investigations, and we used case studies conducted in 2007-08 to determine (1) which steps in outbreak investigations were best served by biosurveillance, and (2) which steps presented the greatest opportunities for improvement. The systems used in the case studies varied in how they functioned, and there were examples in which syndromic systems had identified outbreaks before other methods. Biosurveillance was used successfully for all steps of outbreak investigations. Key advantages of syndromic systems were sensitivity, timeliness, and flexibility and as a source of data for situational awareness. Limitations of biosurveillance were a lack of specificity, reliance on chief complaint data, and a lack of formal training for users. Linking syndromic data to triage notes and medical chart data would substantially increase the value of biosurveillance in the conduct of outbreak investigations and reduce the burden on health department staff. PMID- 23448273 TI - Age-dependent modification of proteins: N-terminal racemization. AB - Age-dependent deterioration of long-lived proteins in humans may have wide ranging effects on health, fitness and diseases of the elderly. To a large extent, denaturation of old proteins appears to result from the intrinsic instability of certain amino acids; however, these reactions are incompletely understood. One method to investigate these reactions involves exposing peptides to elevated temperatures at physiological pH. Incubation of PFHSPSY, which corresponds to a region of human alphaB-crystallin that is susceptible to age related modification, resulted in the appearance of a major product. NMR spectroscopy confirmed that this novel peptide formed via racemization of the N terminal Pro. This phenomenon was not confined to Pro, because peptides with N terminal Ser and Ala residues also underwent racemization. As N-terminal racemization occurred at 37 degrees C, a long-lived protein was examined. LC MS/MS analysis revealed that approximately one third of aquaporin 0 polypeptides in the centre of aged human lenses were racemized at the N-terminal methionine. PMID- 23448274 TI - PASmiR: a literature-curated database for miRNA molecular regulation in plant response to abiotic stress. AB - BACKGROUND: Over 200 published studies of more than 30 plant species have reported a role for miRNAs in regulating responses to abiotic stresses. However, data from these individual reports has not been collected into a single database. The lack of a curated database of stress-related miRNAs limits research in this field, and thus a cohesive database system should necessarily be constructed for data deposit and further application. DESCRIPTION: PASmiR, a literature-curated and web-accessible database, was developed to provide detailed, searchable descriptions of miRNA molecular regulation in different plant abiotic stresses. PASmiR currently includes data from ~200 published studies, representing 1038 regulatory relationships between 682 miRNAs and 35 abiotic stresses in 33 plant species. PASmiR's interface allows users to retrieve miRNA-stress regulatory entries by keyword search using plant species, abiotic stress, and miRNA identifier. Each entry upon keyword query contains detailed regulation information for a specific miRNA, including species name, miRNA identifier, stress name, miRNA expression pattern, detection method for miRNA expression, a reference literature, and target gene(s) of the miRNA extracted from the corresponding reference or miRBase. Users can also contribute novel regulatory entries by using a web-based submission page. The PASmiR database is freely accessible from the two URLs of http://hi.ustc.edu.cn:8080/PASmiR, and http://pcsb.ahau.edu.cn:8080/PASmiR. CONCLUSION: The PASmiR database provides a solid platform for collection, standardization, and searching of miRNA-abiotic stress regulation data in plants. As such this database will be a comprehensive repository for miRNA regulatory mechanisms involved in plant response to abiotic stresses for the plant stress physiology community. PMID- 23448275 TI - Direct renin inhibitor, aliskiren, attenuates the progression of non-alcoholic steatohepatitis in the rat model. AB - AIM: Renin is a rate-limiting enzyme of the renin-angiotensin system (RAS), and several reports have shown that renin plays an important role in several pathological processes. Although RAS is known to play a pivotal role in the progression of non-alcoholic steatohepatitis (NASH), the role of renin is still obscure. The aim of the current study was to examine the effect of the clinically used direct renin inhibitor (DRI), aliskiren, on the progression of NASH in a rat model. METHODS: The effects of DRI on the choline-deficient L-amino acid-defined (CDAA) diet-induced rat NASH model was examined in conjunction with the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which are known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. RESULTS: DRI exerted a marked inhibitory effect against liver fibrosis development and glutathione-S-transferase placental form (GST-P) positive preneoplastic lesions along with suppression of the Ac-HSC and neovascularization in a dose-dependent manner. DRI also inhibited the hepatic expressions of transforming growth factor-beta 1 (TGF-beta 1), angiotensin-II (AT II) and vascular endothelial growth factor (VEGF). These results indicated that renin played a pivotal role in the liver fibrosis development and hepatocarcinogenesis of NASH. CONCLUSION: Because DRI is already widely used in the clinical practice with safety, this drug may represent a potential new strategy against the progression of NASH in the future. PMID- 23448276 TI - Differential regulation of gamma-glutamyltransferase and glutamate cysteine ligase expression after mitochondrial uncoupling: gamma-glutamyltransferase is regulated in an Nrf2- and NFkappaB-independent manner. AB - The enzymes gamma-glutamyltransferase (GGT) and glutamate cysteine ligase (GCL) have important roles in glutathione (GSH) homeostasis, and both are frequently upregulated after acute oxidative stress. Mitochondria are major producers of ROS, and incubating the colorectal adenocarcinoma cell line HT-29 cells with mitochondrial uncouplers significantly increased endogenous ROS as well as mRNA for both GGT and GCLC (the catalytic subunit of GCL). However, no elevation in GGT protein or activity was detected, in contrast to the increased levels of GCLC protein found. The uncouplers initiated endoplasmic reticulum (ER) stress, as demonstrated by highly increased levels of CHOP and GRP78 mRNA. Using inhibitors of proteasomes and ER-associated degradation (ERAD) together with a mitochondrial uncoupler, increased GGT protein and activity levels were obtained indicating that GGT may be a substrate for ERAD. Uncoupling increased the mRNA levels of the two redox-regulated transcription factors Nrf2 and NFkappaB. Using siRNA to suppress Nrf2 and NFkappaB expression, downregulation of GCLC expression both at the basal level and after mitochondrial uncoupling was achieved. In contrast, the expression level of GGT was not affected by this treatment. These data strongly indicate a discrepancy between the regulation of GCLC and of GGT following the oxidative stress situation due to mitochondrial uncoupling. Both the enzymes are considered to be part of the cellular antioxidant system; however, the role of GGT as a consistent oxidative response parameter needs to be reevaluated. PMID- 23448277 TI - The V86M mutation in HIV-1 capsid confers resistance to TRIM5alpha by abrogation of cyclophilin A-dependent restriction and enhancement of viral nuclear import. AB - BACKGROUND: HIV-1 is inhibited early after entry into cells expressing some simian orthologues of the tripartite motif protein family member TRIM5alpha. Mutants of the human orthologue (TRIM5alphahu) can also provide protection against HIV-1. The host protein cyclophilin A (CypA) binds incoming HIV-1 capsid (CA) proteins and enhances early stages of HIV-1 replication by unknown mechanisms. On the other hand, the CA-CypA interaction is known to increase HIV-1 susceptibility to restriction by TRIM5alpha. Previously, the mutation V86M in the CypA-binding loop of HIV-1 CA was found to be selected upon serial passaging of HIV-1 in cells expressing Rhesus macaque TRIM5alpha (TRIM5alpharh). The objectives of this study were (i) to analyze whether V86M CA allows HIV-1 to escape mutants of TRIM5alphahu, and (ii) to characterize the role of CypA in the resistance to TRIM5alpha conferred by V86M. RESULTS: We find that in single-cycle HIV-1 vector transduction experiments, V86M confers partial resistance against R332G-R335G TRIM5alphahu and other TRIM5alphahu variable 1 region mutants previously isolated in mutagenic screens. However, V86M HIV-1 does not seem to be resistant to R332G-R335G TRIM5alphahu in a spreading infection context. Strikingly, restriction of V86M HIV-1 vectors by TRIM5alphahu mutants is mostly insensitive to the presence of CypA in infected cells. NMR experiments reveal that V86M alters CypA interactions with, and isomerisation of CA. On the other hand, V86M does not affect the CypA-mediated enhancement of HIV-1 replication in permissive human cells. Finally, qPCR experiments show that V86M increases HIV-1 transport to the nucleus of cells expressing restrictive TRIM5alpha. CONCLUSIONS: Our study shows that V86M de-couples the two functions associated with CA-CypA binding, i.e. the enhancement of restriction by TRIM5alpha and the enhancement of HIV-1 replication in permissive human cells. V86M enhances the early stages of HIV-1 replication in restrictive cells by improving nuclear import. In summary, our data suggest that HIV-1 escapes restriction by TRIM5alpha through the selective disruption of CypA-dependent, TRIM5alpha-mediated inhibition of nuclear import. However, V86M does not seem to relieve restriction of a spreading HIV-1 infection by TRIM5alphahu mutants, underscoring context-specific restriction mechanisms. PMID- 23448279 TI - Successful management of unsuspected retroperitoneal paraganglioma via the use of combined epidural and general anesthesia: a case report. AB - INTRODUCTION: Similar to pheochromocytomas, paragangliomas can secrete catecholamines, although they are usually non-functional and clinical presentation is non-specific. We present a case of accidental, intra-operatively diagnosed neuroendocrine-active sympathetic paraganglioma, which was suspected and confirmed during elective retroperitoneal tumor removal. CASE PRESENTATION: A 25-year-old Caucasian Croatian man, American Society of Anesthesiologists status 1, underwent elective surgery for retroperitoneal tumor removal. The tumor had been discovered by chance during a routine examination and was suspected to be a sarcoma. Our patient had no history of previous medical conditions nor did he have symptoms characteristic of a neuroendocrine secreting tumor. The results of ultrasound and magnetic resonance imaging studies showed a large, well demarcated retroperitoneal tumor mass in his upper abdomen localized between the aorta and vena cava, measuring approximately 9*6*4.5cm. In the operating room an epidural catheter was inserted at the T7 to T8 level prior to induction of general anesthesia. Epidural analgesia was maintained by an infusion pump with local anesthetic and opiate mixture. During the surgical excision of the tumor, hemodynamic changes occurred, with hypertension (205/110mmHg) and tachycardia (up to 120 beats/minute). In spite of the fact that the surgical field of work did not include adrenal glands whose direct manipulation could explain this occurrence, there was a high degree of suspicion for the presence of a neurosecreting tumor. His clinical symptoms were relieved after administration of urapidil, esmolol and magnesium sulfate. After tumor excision, our patient developed severe hypotension. Hemodynamic stability was reinstated with aggressive volume replacement, with crystalloids and colloids, vasopressors and hydrocortisone. His post-operative course was unremarkable and on the eighth post operative day our patient was discharged from hospital, with no consequences or symptoms on follow-up two years after surgery. CONCLUSIONS: Our patient's case emphasizes the need to consider the presence of extra-adrenal paragangliomas in the differential diagnosis of retroperitoneal tumors, despite their rare occurrence. In our patient's case, invasive hemodynamic monitoring during combined general anesthesia and epidural analgesia and early recognition of catechol-induced symptoms raised suspicion of the existence of a paraganglioma, and this led to an adequate therapeutic approach and favorable outcome of the surgery. Pre-operative recognition of paragangliomas could lead to better pre operative preparation, but even high clinical suspicion in undiagnosed forms during surgery and the availability of rapid and short-acting vasodilatators, alpha-blockers and beta-blockers might favor good outcome. PMID- 23448278 TI - Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC chemokine receptor 4 antagonist, in healthy male subjects: results from an open label and from a randomised study. AB - BACKGROUND: The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy. METHODS: The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3 (5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2 hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 MUg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150-1500 mg (NCT01371812). RESULTS: Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t1/2: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%. CONCLUSION: In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor. PMID- 23448280 TI - Preparation of microporous silicone rubber membrane with tunable pore size via solvent evaporation-induced phase separation. AB - Silicone rubber membrane with ordered micropores in the surface was prepared by means of the solvent evaporation-induced phase separation. A ternary solution including liquid silicone rubber precursor, liquid paraffin, and hexane was cast to form a film with a two-phase structure after the hexane was evaporated. The micropores were generated by removing liquid paraffin phase in the cured silicone rubber film. The effects of the liquid paraffin concentration, casting temperature, initial casting solution thickness, air circulation, and addition of surfactant Span-80 on the pore structure in the membrane surface were investigated. The average pore size increases with increasing liquid paraffin concentration or the initial casting solution thickness. The formation of pore structure in the membrane surface is related to the phase separation and thus the phase separation process of the casting solution surface was in situ observed using the digital microscope. The formation mechanism of pore is attributed to a nucleation, growth, and coalescence process of liquid paraffin phase in the membrane surface. PMID- 23448281 TI - Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity. AB - Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6 oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 MUM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds. PMID- 23448282 TI - Impact of post-kidney transplant parathyroidectomy on allograft function. AB - BACKGROUND: The impact of parathyroidectomy on allograft function in kidney transplant patients is unclear. METHODS: We conducted a retrospective, observational study of all kidney transplant recipients from 1988 to 2008 who underwent parathyroidectomy for uncontrolled hyperparathyroidism (n = 32). Post parathyroidectomy, changes in estimated glomerular filtration rate (eGFR) and graft loss were recorded. Cross-sectional associations at baseline between eGFR and serum calcium, phosphate, and parathyroid hormone (PTH), and associations between their changes within subjects during the first two months post parathyroidectomy were assessed. RESULTS: Post-parathyroidectomy, the mean eGFR declined from 51.19 mL/min/1.73 m(2) at parathyroidectomy to 44.78 mL/min/1.73 m(2) at two months (p < 0.0001). Subsequently, graft function improved, and by 12 months, mean eGFR recovered to 49.76 mL/min/1.73 m(2) (p = 0.035). Decrease in serum PTH was accompanied by a decrease in eGFR (p = 0.0127) in the first two months post-parathyroidectomy. Patients whose eGFR declined by >=20% (group 1) in the first two months post-parathyroidectomy were distinguished from the patients whose eGFR declined by <20% (group 2). The two groups were similar except that group 1 had a higher baseline mean serum PTH compared with group 2, although not significant (1046.7 +/- 1034.2 vs. 476.6 +/- 444.9, p = 0.14). In group 1, eGFR declined at an average rate of 32% (p < 0.0001) during the first month post parathyroidectomy compared with 7% (p = 0.1399) in group 2, and the difference between these two groups was significant (p = 0.0003). The graft function recovered in both groups by one yr. During median follow-up of 66.00 +/- 49.45 months, 6 (18%) patients lost their graft with a mean time to graft loss from parathyroidectomy of 37.2 +/- 21.6 months. The causes of graft loss were rejection (n = 2), pyelonephritis (n = 1) and chronic allograft nephropathy (n = 3). No graft loss occurred during the first-year post-surgery. CONCLUSION: Parathyroidectomy may lead to transient kidney allograft dysfunction with eventual recovery of graft function by 12 months post-parathyroidectomy. Higher level of serum PTH pre-parathyoidectomy is associated with a more profound decrease in eGFR post-parathyroidectomy. PMID- 23448283 TI - Women's perceptions and reasons for choosing the pill, patch, or ring in the CHOICE study: a cross-sectional survey of contraceptive method selection after counseling. AB - BACKGROUND: The European CHOICE study was a cross-sectional survey that evaluated women's combined hormonal contraceptive choices before and after contraceptive counseling in Austria, Belgium, Czech Republic and Slovakia, the Netherlands, Poland, Sweden, Switzerland, Israel, Russia, and Ukraine. The changes in method selection before and after counseling were reported previously. In this paper we present the reasons given by the 18,787 participating women for selecting their contraceptive method of choice, as well as their perceptions about the contraceptive pill, patch, and ring after counseling. METHODS: Women with an interest in a combined hormonal contraceptive method (pill, patch, or ring) were counseled using a standardized counseling leaflet. The women completed questionnaires, which included questions on why they had selected a particular method of contraception, and the extent to which they agreed with statements about the attributes of the pill, patch, and ring. The results for each country were compared with the percentages for all countries combined by using a binomial regression model. Multiple logistic regression models were used to investigate the extent to which the probability of choosing a method was related to prespecified aspects (i.e. perceptions) of each contraceptive method. RESULTS: 'Easy to use', 'convenience', and 'regular menstrual bleeding' were important selection criteria. 'Nondaily administration' was one of the main reasons women selected the patch or ring. 'Daily use' and 'will forget to take it' were the primary reasons for not selecting the pill, while the main reasons for not choosing the patch included 'not discrete, visible' and 'can fall off'. In a small number of instances, the ring was rejected because some women don't like to use a 'foreign body'. Women's perceptions influenced their contraceptive decisions: positive perceptions about a method increased the likelihood that a woman would select it. After counseling, many women associated the pill with forgetfulness, and many still did not know about the patch or ring's key attributes. Women's knowledge about a particular method was generally greater if they had chosen it. CONCLUSIONS: To support informed contraceptive decision making, healthcare professionals should realize that a woman's view of a method's ease of use is more important than perceived efficacy, tolerability, health benefits, or risks. PMID- 23448285 TI - Efficacy of adding behavioural treatment or antimuscarinic drug therapy to alpha blocker therapy in men with nocturia. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Nocturia is a common and bothersome lower urinary tract symptom, particularly in men. Many single drug therapies have limited benefit. For men who have persistent nocturia despite alpha-blocker therapy, the addition of behavioural and exercise therapy is statistically superior to anticholinergic therapy. OBJECTIVE: To compare reductions in nocturia resulting from adding either behavioural treatment or antimuscarinic drug therapy to alpha-adrenergic antagonist (alpha-blocker) therapy in men. PATIENTS AND METHODS: Participants were men who had continuing urinary frequency >8 voids/day) and urgency after 4 weeks of alpha-blocker therapy run-in and who had >=1 nightly episode of nocturia. Participants received individually titrated drug therapy (extended-release oxybutynin) or multicomponent behavioural treatment (pelvic floor muscle training, delayed voiding and urge suppression techniques). Seven-day bladder diaries were used to calculate reductions in mean nocturia. RESULTS: A total of 127 men aged 42-88 years with >=1 nocturia episode per night were included in the study. There were 76 men who had a mean of >=2 nocturia episodes. Among those with >=1 nocturia episode, behavioural treatment reduced nightly nocturia by a mean of 0.97 episodes and was significantly more effective than drug therapy (mean reduction = 0.56 episodes; P = 0.01). Participants with >=2 episodes nocturia at baseline also showed larger changes with behavioural treatment compared with antimuscarinic therapy (mean reduction = 1.26 vs 0.61; P = 0.008). CONCLUSIONS: Both behavioural treatment and drug therapy reduced nocturia in men with >=1 episode of nocturia/night when added to alpha-blocker therapy. These results were similar even when only those with >=2 episodes of nocturia were considered. The addition of behavioural treatment was statistically better than bladder-relaxant therapy for nocturia. PMID- 23448284 TI - A new scenario of the evolutionary derivation of the mammalian diaphragm from shoulder muscles. AB - The evolutionary origin of the diaphragm remains unclear, due to the lack of a comparable structure in other extant taxa. However, recent researches into the developmental mechanism of this structure have yielded new insights into its origin. Here we summarize current understanding regarding the development of the diaphragm, and present a possible scenario for the evolutionary acquisition of this uniquely mammalian structure. Recent developmental analyses indicate that the diaphragm and forelimb muscles are derived from a shared cell population during embryonic development. Therefore, the embryonic positions of forelimb muscle progenitors, which correspond to the position of the brachial plexus, likely played an important role in the evolution of the diaphragm. We surveyed the literature to reexamine the position of the brachial plexus among living amniotes and confirmed that the cervico-thoracic transition in ribs reflects the brachial plexus position. Using this osteological correlate, we concluded that the anterior borders of the brachial plexuses in the stem synapsids were positioned at the level of the fourth spinal nerve, suggesting that the forelimb buds were laid in close proximity of the infrahyoid muscles. The topology of the phrenic and suprascapular nerves of mammals is similar to that of subscapular and supracoracoid nerves, respectively, of the other amniotes, suggesting that the diaphragm evolved from a muscle positioned medial to the pectoral girdle (cf. subscapular muscle). We hypothesize that the diaphragm was acquired in two steps: first, forelimb muscle cells were incorporated into tissues to form a primitive diaphragm in the stem synapsid grade, and second, the diaphragm in cynodonts became entrapped in the region controlled by pulmonary development. PMID- 23448286 TI - Lysiphlebus orientalis (Hymenoptera, Braconidae), a new invasive aphid parasitoid in Europe - evidence from molecular markers. AB - We report the occurrence of Lysiphlebus orientalis in Serbia, an aphid parasitoid from the Far East that is new to Europe and has the potential to become invasive. Our finding based on morphological characters is confirmed by analyses of mitochondrial cytochrome oxidase subunit I sequences. An increase in number and an expansion of the host range were observed during field studies over the past two years, and it is determined that the current host range encompasses nine aphid hosts on 12 different host plants, forming 13 tri-trophic associations. A host range determined for European populations of L. orientalis appears wider compared with that in its Far Eastern native habitats where Aphis glycines Mats. is the sole known host. Moreover, it overlaps considerably with the host ranges of European parasitoids that play an important role in the natural control of pest aphids. PMID- 23448287 TI - Origins of 1,6-stereoinduction in torquoselective 6pi electrocyclizations. AB - A novel stereoselective electrocyclization developed for the total synthesis of reserpine has been explored by both experiment and theory. A stereocenter six atoms away from the newly forming chiral center is responsible for the diastereoselectivity of the ring closure. This stereogenic center, lying at the junction of two six-membered rings, defines the conformation of the substrates' fused ring skeleton that ultimately distinguishes between the two allowed, disrotatory triene geometries at the transition state. The presence of allylic strain in the disfavored transition state results in a torquoselective ring closure (dr up to 15.7:1). PMID- 23448288 TI - Emotional distress -- a neglected topic among surgically treated oesophageal cancer patients. PMID- 23448289 TI - Defensive abdominal rotation patterns of tenebrionid beetle, Zophobas atratus, pupae. AB - Exarate pupae of the beetle Zophobas atratus Fab. (Coleoptera: Tenebrionidae) have free appendages (antenna, palp, leg, and elytron) that are highly sensitive to mechanical stimulation. A weak tactile stimulus applied to any appendage initiated a rapid rotation of abdominal segments. High-speed photography revealed that one cycle of defensive abdominal rotation was induced in an all-or-none fashion by bending single or multiple mechanosensory hairs on a leg or prodding the cuticular surface of appendages containing campaniform sensilla. The direction of the abdominal rotation completely depended on the side of stimulation; stimulation of a right appendage induced a right-handed rotation about the anterior-posterior axis of the pupal body and vice versa. The trajectories of the abdominal rotations had an ellipsoidal or pear-shaped pattern. Among the trajectory patterns of the rotations induced by stimulating different appendages, there were occasional significant differences in the horizontal (right-left) component of abdominal rotational movements. Simultaneous stimulation of right and left appendages often induced variable and complex patterns of abdominal movements, suggesting an interaction between sensory signals from different sides. When an abdominal rotation was induced in a freely lying pupa, the rotation usually made the pupa move away from or turn its dorsum toward the source of stimulation with the aid of the caudal processes (urogomphi), which served as a fulcrum for transmitting the power of the abdominal rotation to the movement or turning of the whole body. Pattern generation mechanisms for the abdominal rotation were discussed. PMID- 23448290 TI - Involvement of TRPA1 activation in acute pain induced by cadmium in mice. AB - BACKGROUND: Cadmium (Cd) is an environmental pollutant and acute exposure to it causes symptoms related to pain and inflammation in the airway and gastrointestinal tract, but the underlying mechanisms are still unclear. TRPA1 is a nonselective cation channel expressed in sensory neurons and acts as a nociceptive receptor. Some metal ions such as Ca, Mg, Ba and Zn are reported to modulate TRPA1 channel activity. In the present study, we investigated the effect of Cd on cultured mouse dorsal root ganglion neurons and a heterologous expression system to analyze the effect of Cd at the molecular level. In addition, we examined whether Cd caused acute pain in vivo. RESULTS: In wild-type mouse sensory neurons, Cd evoked an elevation of the intracellular Ca concentration ([Ca2+]i) that was inhibited by external Ca removal and TRPA1 blockers. Most of the Cd-sensitive neurons were also sensitive to cinnamaldehyde (a TRPA1 agonist) and [Ca2+]i responses to Cd were absent in TRPA1(-/-) mouse neurons. Heterologous expression of TRPA1 mutant channels that were less sensitive to Zn showed attenuation of Cd sensitivity. Intracellular Cd imaging revealed that Cd entered sensory neurons through TRPA1. The stimulatory effects of Cd were confirmed in TRPA1-expressing rat pancreatic cancer cells (RIN-14B). Intraplantar injection of Cd induced pain-related behaviors that were largely attenuated in TRPA1(-/-) mice. CONCLUSIONS: Cd excites sensory neurons via activation of TRPA1 and causes acute pain, the mechanism of which may be similar to that of Zn. The present results indicate that TRPA1 is involved in the nociceptive or inflammatory effects of Cd. PMID- 23448291 TI - Bioenergetic study of murine hepatic tissue treated in vitro with atorvastatin. AB - Atorvastatin (a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor) is a widely used cholesterol-lowering drug, which is recognized for its potential hepatotoxicity. This study investigated in vitro effects of this agent on hepatic tissue respiration, ATP content, caspase activity, urea synthesis and histology. Liver fragments from Taylor Outbred and C57Bl/6 mice were incubated at 37 degrees C in Krebs-Henseleit buffer continuously gassed with 95% O2: 5% CO2 in the presence and absence of atorvastatin. Phosphorescence O2 analyzer that measured dissolved [O2] as a function of time was used to monitor cellular mitochondrial O2 consumption. The caspase-3 substrate N-acetyl-asp-glu-val-asp-7-amino-4 methylcoumarin was used to monitor caspase activity. The rates of hepatocyte respiration (MUM O2 min(-1) mg(-1)) in untreated samples were 0.15+/-0.07 (n=31). The corresponding rates for samples treated with 50 nM (therapeutic concentration), 150 nM or 1.0 MUM atorvastatin for <=13 h were 0.13+/-0.05 (n=19), p=0.521. The contents of hepatocyte ATP (pmol(-1) mg(-1)) in untreated samples were 40.3+/-14.0 and in samples treated with 1.0 MUM atorvastatin for <=4.5 h were 48.7+/-23.9 (p=0.7754). The concentrations of urea (mg/dL mg(-1), produced over 50 min) for untreated samples were 0.061+/-0.020 (n=6) and for samples treated with 1.0 MUM atorvastatin for <=6 h were 0.072+/-0.022 (n=6), p=0.3866. Steadily, hepatocyte caspase activity and histology were unaffected by treatments with up to 1.0 MUM atorvastatin for <=6 h. Thus, the studied murine model showed preserved hepatocyte function and structure in the presence of high concentrations of atorvastatin. PMID- 23448292 TI - Prevalence of renal dysfunction in tacrolimus-treated pediatric transplant recipients: a systematic review. AB - Renal dysfunction after non-renal transplantation in adult tacrolimus-treated transplant patients is well documented. Little is known about its prevalence in children. Age-related changes in both disposition and effect of tacrolimus as well as renal function may preclude extrapolation of adult data to children. To systematically review the literature on renal dysfunction in non-renal pediatric transplant recipients treated with tacrolimus. PubMed/Medline, Embase, and Google were searched from their inception until April 19, 2012, with the search terms "tacrolimus," "renal function," "transplantation," and "children." Eighteen of 385 retrieved papers were considered relevant. Twelve dealt with liver, four with heart transplant, one with heart and lung transplant, and one with intestinal recipients. Reported prevalences of mild and severe chronic kidney disease ranged from 0% to 39% and 0% to 71.4%, respectively, for liver, and from 22.7% to 40% and 6.8% to 46%, respectively, for heart and/or lung transplant recipients. Ranges remained wide after adjusting for follow-up time and disease severity. Possible explanations are inclusion bias and definitions used for renal dysfunction. A considerable proportion of pediatric non-renal transplant patients who receive tacrolimus-based immunosuppression, appear to suffer from chronic kidney disease. This conclusion warrants further research into the real risk, its risk factors, and individualization of immunosuppressant therapy. PMID- 23448293 TI - A novel high throughput 1536-well Notch1 gamma -secretase AlphaLISA assay. AB - The Notch pathway plays a crucial role in cell fate decisions through controlling various cellular processes. Overactive Notch signal contributes to cancer development from leukemias to solid tumors. gamma-Secretase is an intramembrane protease responsible for the final proteolytic step of Notch that releases the membrane-tethered Notch fragment for signaling. Therefore, gamma-secretase is an attractive drug target in treating Notch-mediated cancers. However, the absence of high throughput gamma-secretase assay using Notch substrate has limited the identification and development of gamma- secretase inhibitors that specifically target the Notch signaling pathway. Here, we report on the development of a 1536- well gamma-secretase assay using a biotinylated recombinant Notch1 substrate. We effectively assimilated and miniaturized this newly developed Notch1 substrate with the AlphaLISA detection technology and demonstrated its robustness with a calculated Z' score of 0.66. We further validated this optimized assay by performing a pilot screening against a chemical library consisting of ~5,600 chemicals and identified known gamma-secretase inhibitors e.g. DAPT, and Calpeptin; as well as a novel gamma-secretase inhibitor referred to as KD-I-085. This assay is the first reported 1536-well AlphaLISA format and represents a novel high throughput Notch1-gamma-secretase assay, which provides an unprecedented opportunity to discover Notch-selective gamma-secretase inhibitors that can be potentially used for the treatment of cancer and other human disorders. PMID- 23448294 TI - Evaluation of fecal calprotectin in Campylobacter concisus and Campylobacter jejuni/coli gastroenteritis. AB - Calprotectin (CP) is a calcium-binding cytosolic neutrophil protein and the concentration in feces reflects the migration of neutrophils into the gut lumen. Testing for fecal CP (f-CP) in patients with negative cultures for enteric pathogens is widely accepted as a useful screening tool for identifying patients who are most likely to benefit from endoscopy for suspected inflammatory bowel disease (IBD) with the assumption that a negative f-CP is compatible with a functional disorder. Campylobacter concisus has recently been reported to have a high incidence in the Danish population almost equal to Campylobacter jejuni and Campylobacter coli and has been reported to cause prolonged watery diarrhea. However, isolation of C. concisus from feces requires the filter method in a hydrogen-enriched microaerobic atmosphere, which is not commonly used in the laboratory, and the diagnosis may consequently be missed. The aim of this study was to evaluate the f-CP levels, as a marker for the intestinal inflammation in C. jejuni/coli- and C. concisus-infected patients. The authors found a high concentration of f-CP (median 631: IQR 221-1274) among 140 patients with C. jejuni/coli infection, whereas the f-CP level among 99 C. concisus-infected patients was significantly lower (median 53: IQR 20-169). The data correlate to the severe inflammatory gastroenteritis seen in patients infected with C. jejuni/coli, whereas C. concisus-infected patients have a much lower intestinal inflammation which could be compared with viral gastroenteritis. Nevertheless, clinicians should be aware of C. concisus infection, especially in patients with prolonged mild diarrhea, in the differential diagnosis to IBD. PMID- 23448295 TI - Cellular differentiation and individuality in the 'minor' multicellular taxa. AB - Biology needs a concept of individuality in order to distinguish organisms from parts of organisms and from groups of organisms, to count individuals and compare traits across taxa, and to distinguish growth from reproduction. Most of the proposed criteria for individuality were designed for 'unitary' or 'paradigm' organisms: contiguous, functionally and physiologically integrated, obligately sexually reproducing multicellular organisms with a germ line sequestered early in development. However, the vast majority of the diversity of life on Earth does not conform to all of these criteria. We consider the issue of individuality in the 'minor' multicellular taxa, which collectively span a large portion of the eukaryotic tree of life, reviewing their general features and focusing on a model species for each group. When the criteria designed for unitary organisms are applied to other groups, they often give conflicting answers or no answer at all to the question of whether or not a given unit is an individual. Complex life cycles, intimate bacterial symbioses, aggregative development, and strange genetic features complicate the picture. The great age of some of the groups considered shows that 'intermediate' forms, those with some but not all of the traits traditionally associated with individuality, cannot reasonably be considered ephemeral or assumed transitional. We discuss a handful of recent attempts to reconcile the many proposed criteria for individuality and to provide criteria that can be applied across all the domains of life. Finally, we argue that individuality should be defined without reference to any particular taxon and that understanding the emergence of new kinds of individuals requires recognizing individuality as a matter of degree. PMID- 23448296 TI - No genetic support for a contribution of prostaglandins to the aetiology of androgenetic alopecia. PMID- 23448297 TI - Interactions of sexual activity, gender, and depression with immunity. AB - INTRODUCTION: Depression can suppress immune function, leading to lower resistance against infection and longer healing times in depressed individuals. Sexuality may also influence immune function, with evidence that sexual activity is associated with lowered immune function in women and mixed results in men. Immune mediators like immunoglobulin A (IgA) are immediately relevant to sexual health, since they are the first line of defense against pathogens at mucous membranes like the vagina. AIM: This study aims to determine if and how depression, sexual activity, and their interaction impact salivary IgA (SIgA) in men and women. METHODS: In Study 1, a community-based sample of 84 women and 88 men provided saliva samples and completed questionnaires on their demographic background, level of depression, and frequency of partnered and solitary sexual activity. Study 2, conducted separately in an undergraduate student sample of 54 women and 52 men, had similar methods. MAIN OUTCOME MEASURES: The main outcome measures were scores on the General Well-Being Schedule depression subscale, reported frequency of sexual activity, and SIgA levels as measured by enzyme immunoassay. RESULTS: Across studies, higher levels of partnered sexual activity were associated with lower SIgA for women with high depression scores, but not for women with low depression scores. In contrast, higher levels of partnered sexual activity were associated with higher SIgA for men with high depression scores, but not for men with low depression scores. CONCLUSION: Our results show that partnered sexual activity is a risk factor for lowered immunity in women with depressive symptoms but a possible resilience factor for men with depressive symptoms. This suggests a role for sexual activity in determining the impact of depression on physical health parameters. PMID- 23448298 TI - A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. AB - Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K(i) values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl 2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date. PMID- 23448299 TI - Morphological distribution of MU chains and cd15 receptors in colorectal polyp and adenocarcinoma specimens. AB - BACKGROUND: We have recently investigated the localisation of immunoglobulin producing cells (IPCs) in inflamed intestinal tissue samples from patients with inflammatory bowel disease (IBD), and identified two main patterns of B lymphocyte infiltration: one characterised by the moderate strong stromal localisation of small B1 cell-like IgM+/CD79+/CD20-/CD21-/CD23-/CD5 +/- IPCs, and the other by the peri-glandular localisation of IPCs with irregular nuclei that had surface markers specific for a B cell subset (IgM and CD79), but quantitative differences in their lambda and kappa chains. The same patients were also tested for CD15+ receptors, which were localised on inflammatory cell surfaces or in the crypts of the intestinal epithelium. CD15+ receptor distribution in inflamed tissues was limited to the cell structures. The aim of the study was to analyse variations in IPCs and CD15+ cell morphology or distribution in bowel biopsy specimens taken from patients with pre-malignant polyps or adenocarcinomas. METHODS: IPCs were analysed by means of immunofluorescence using polyclonal goat anti-human MU chains. The pre-malignant polyp specimens were tested for B cell surface phenotype lambda and kappa chains, CD79, CD20, CD21 and CD23 using an immunoperoxidase method. CD15+ cells were evaluated using the immunoperoxidase method and monoclonal anti-CD15 IgM. RESULTS: The study involved 14 patients (four with pre-malignant polyps and 10 with colorectal adenocarcinomas). The distribution of MU chains and CD15 markers varied in all of the biopsies, but delineated normal cell structures in the pre-malignant polyp specimens. B cell surface phenotype analysis of MU chain-positive cells identified a subset of CD79+/CD20-/CD21-/CD23- IPCs. The IPCs in certain areas showed the sporadic disintegration of inflammatory cell membranes or the accumulation of fluorescence in individual cells. IPC membrane disintegration was particularly marked in all of the adenocarcinoma samples, in which the CD15 markers also showed epithelial cell involvement. Furthermore, six of the ten adenocarcinoma samples had atypical and reorganised membranes that expressed an excess of both receptors and isolated small portions of tissue within the tumour. CONCLUSION: The findings of this preliminary morphological study suggest the presence of membrane disintegration and remodelling mechanisms in the tumours. The newly-formed membranes expressed high concentrations of inflammatory cell receptors that can confer adhesive properties. PMID- 23448300 TI - Corneal thickness and volume measurements by swept source anterior segment optical coherence tomography in normal subjects. AB - PURPOSE: To evaluate central corneal thickness (CCT) and corneal volume (CV) in healthy eyes using swept source anterior segment optical coherence tomography (SS AS-OCT) and other devices. METHODS: Thirty-three healthy right eyes of 33 subjects were investigated. CCT was measured with SS-AS-OCT, rotating Scheimpflug camera, ultrasonic pachymetry and specular microscopy. CV was determined within a diameter of 10 mm at the center using SS-AS-OCT and Scheimpflug camera. RESULTS: Mean CCT was 523.5 +/- 25.2 MUm by SS-AS-OCT, 523.9 +/- 26.1 MUm by Scheimpflug camera, 532.1 +/- 26.6 MUm by ultrasonic pachymetry, and 525.5 +/- 33.5 MUm by specular microscopy. The CCTs measured with SS-AS-OCT, Scheimpflug camera and specular microscopy were significantly thinner than those measured with ultrasonic pachymeter (p < 0.001). The mean CV within a diameter of 10 mm at the center was 57.2 +/- 3.0 mm(3) by SS-AS-OCT and 59.4 +/- 2.9 mm(3) by Scheimpflug camera. Scheimpflug measurements of CV were statistically larger than SS-AS-OCT measurements (p = 0.0008). Statistically significant correlation was found between the CCT and CV measurements of each imaging devices (p < 0.0001, r = 0.527, and p < 0.0001, r = 0.749, respectively). CONCLUSION: SS-AS-OCT enables the measurements of CCT and CV, demonstrating agreement with other devices. CV in addition to CCT measurement may serve as a practical parameter of the corneal endothelial pump function. PMID- 23448301 TI - Synthesis and electronic structure of bis(imino)pyridine iron metallacyclic intermediates in iron-catalyzed cyclization reactions. AB - The bis(imino)pyridine iron dinitrogen compound, ((iPr(TB))PDI)Fe(N2)2 ((iPr(TB))PDI = 2,6-(2,6-(i)Pr2-C6H3-N?C-(CH2)3)2(C5H1N)) is an effective precatalyst for the [2pi + 2pi] cycloaddition of diallyl amines as well as the hydrogenative cyclization of N-tosylated enynes and diynes. Addition of stoichiometric quantities of amino-substituted enyne and diyne substrates to ((iPr(TB))PDI)Fe(N2)2 resulted in isolation of catalytically competent bis(imino)pyridine iron metallacycle intermediates. A combination of magnetochemistry, X-ray diffraction, and Mossbauer spectroscopic and computational studies established S = 1 iron compounds that are best described as intermediate-spin iron(III) (SFe = 3/2) antiferromagnetically coupled to a chelate radical anion (SPDI = 1/2). Catalytically competent bis(imino)pyridine iron diene and metallacycles relevant to the [2pi + 2pi] cycloaddition were also isolated and structurally characterized. The combined magnetic, structural, spectroscopic, and computational data support an Fe(I)-Fe(III) catalytic cycle where the bis(imino)pyridine chelate remains in its one-electron reduced radical anion form. These studies revise a previous mechanistic proposal involving exclusively ferrous intermediates and highlight the importance of the redox active bis(imino)pyridine chelate for enabling catalytic cyclization chemistry with iron. PMID- 23448302 TI - Impact of pest control strategies on the arthropodofauna living in bird nests built in nestboxes in pear and apple orchards. AB - Pesticide applications have a strong impact on biodiversity in agroecosystems. The present study aimed to assess the impact of pest control strategies on the arthropodofauna of Parus major nests built within nestboxes installed in orchards. Unlike many studied groups, these arthropod communities are not in direct contact with pesticide sprays (on account of their being sheltered by nestboxes) and are also unable to move away from the treated area. In this pilot study, we estimated the prevalence and the taxonomic and ecological diversities of arthropodofauna sampled in the nests and assessed the extent to which the whole and nest-specific arthropodofauna were affected by pest control strategies. Sixteen different insect and arachnid Primary Taxonomic Groups (PTGs, order level or below) were found in nests. The best represented PTGs (>=10% occurrence in years 2007 and 2008) were Psocoptera (Insecta, detritivorous/saprophagous), detritivorous/saprophagous Astigmata (Acari) and hematophagous Mesostigmata (Acari). Pest control strategies had a large impact on the prevalence of arthropods in nests, with higher proportions of nests hosting arthropods in organic orchards than in conventional orchards and with intermediate proportions in nests in Integrated Pest Management orchards. In contrast, pest control strategies had no significant effect on the composition of the arthropod communities when only nests hosting nidicolous arthropods were considered. PMID- 23448303 TI - Mind the gut: secretion of alpha-synuclein by enteric neurons. PMID- 23448304 TI - Single-step ethanol production from lignocellulose using novel extremely thermophilic bacteria. AB - BACKGROUND: Consolidated bioprocessing (CBP) of lignocellulosic biomass to ethanol using thermophilic bacteria provides a promising solution for efficient lignocellulose conversion without the need for additional cellulolytic enzymes. Most studies on the thermophilic CBP concentrate on co-cultivation of the thermophilic cellulolytic bacterium Clostridium thermocellum with non cellulolytic thermophilic anaerobes at temperatures of 55 degrees C-60 degrees C. RESULTS: We have specifically screened for cellulolytic bacteria growing at temperatures >70 degrees C to enable direct conversion of lignocellulosic materials into ethanol. Seven new strains of extremely thermophilic anaerobic cellulolytic bacteria of the genus Caldicellulosiruptor and eight new strains of extremely thermophilic xylanolytic/saccharolytic bacteria of the genus Thermoanaerobacter isolated from environmental samples exhibited fast growth at 72 degrees C, extensive lignocellulose degradation and high yield ethanol production on cellulose and pretreated lignocellulosic biomass. Monocultures of Caldicellulosiruptor strains degraded up to 89-97% of the cellulose and hemicellulose polymers in pretreated biomass and produced up to 72 mM ethanol on cellulose without addition of exogenous enzymes. In dual co-cultures of Caldicellulosiruptor strains with Thermoanaerobacter strains the ethanol concentrations rose 2- to 8.2-fold compared to cellulolytic monocultures. A co culture of Caldicellulosiruptor DIB 087C and Thermoanaerobacter DIB 097X was particularly effective in the conversion of cellulose to ethanol, ethanol comprising 34.8 mol% of the total organic products. In contrast, a co-culture of Caldicellulosiruptor saccharolyticus DSM 8903 and Thermoanaerobacter mathranii subsp. mathranii DSM 11426 produced only low amounts of ethanol. CONCLUSIONS: The newly discovered Caldicellulosiruptor sp. strain DIB 004C was capable of producing unexpectedly large amounts of ethanol from lignocellulose in fermentors. The established co-cultures of new Caldicellulosiruptor strains with new Thermoanaerobacter strains underline the importance of using specific strain combinations for high ethanol yields. These co-cultures provide an efficient CBP pathway for ethanol production and represent an ideal starting point for development of a highly integrated commercial ethanol production process. PMID- 23448305 TI - Primary dermatofibrosarcoma protuberans of orbit--a rare entity. AB - Primary Dermatofibrosarcoma Protuberance (DFSP) is a rare neoplasm of dermal origin. Though it is a locally aggressive tumor with high recurrence rate, however distant metastasis can also occur. Orbital DFSP is an uncommon phenomenon. It has been reported due to distant metastasis or invasion from adjacent structures but Primary Orbital DFSP is a unique entity in itself. Herein we report a rare case of primary DFSP of the orbit in a 70-year- old lady who underwent orbital exenteration. Histopathology examination (HPE) revealed spindle cells arranged in storiform pattern and immunohistochemistry (IHC) revealed CD34 positive and S100 negative. PMID- 23448306 TI - Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction. AB - BACKGROUND: Increased levels of cardio-enriched microRNAs (miRNAs) have been described in patients with myocardial infarction (MI). We wanted to evaluate the diagnostic and prognostic potential of cardio-enriched miRNAs in patients presenting with a suspected acute coronary syndrome (ACS). METHODS: Cardio enriched miRNAs (miR-1, miR-208b and miR-499-5p) were measured using real time PCR in plasma samples from 424 patients with suspected ACS treated in a coronary care unit. miRNAs were assessed for discrimination of a clinical diagnosis of myocardial infarction and for association with 30-day mortality and diagnosis of heart failure. Correlation with left ventricular systolic dysfunction as measured by the ejection fraction (LVEF) was also assessed. To confirm myocardial origin miRNA was measured during coronary artery bypass surgery. RESULTS: miRNAs were higher in MI patients and correlated with LVEF (p < 0.001). Discrimination of MI was accurate for miR-208b (AUC = 0.82) and miR-499-5p (AUC = 0.79) but considerable lower than for Troponin T (AUC = 0.95). Increased miRNA levels were strongly associated with increased risk of mortality or heart failure within 30 days for miR-208b (OR 1.79, 95% CI = 1.38-2.23, p = 1 * 10(-5)) and miR-499-5p (OR 1.70, 95% CI = 1.31-2.20, p = 5 * 10(-5)) but the association was lost when adjusting for Troponin T. During surgery miR-208b and miR-499-5p was released in the coronary sinus after cardioplegia-reperfusion to markedly higher levels than in a peripheral vein. CONCLUSIONS: Our findings confirm increased levels of cardio-enriched miRNAs in the blood of MI patients and establish association of increased miRNA levels with reduced systolic function after MI and risk of death or heart failure. PMID- 23448307 TI - Poly[tri(ethylene glycol) ethyl ether methacrylate]-coated surfaces for controlled fibroblasts culturing. AB - Well-defined thermosensitive poly[tri(ethylene glycol) monoethyl ether methacrylate] (P(TEGMA-EE)) brushes were synthesized on a solid substrate by the surface-initiated atom transfer radical polymerization of TEGMA-EE. The polymerization reaction was initiated by 2-bromo-2-methylpropionate groups immobilized on the surface of the wafers. The changes in the surface composition, morphology, philicity, and thickness that occurred at each step of wafer functionalization confirmed that all surface modification procedures were successful. Both the successful modification of the surface and bonding of the P(TEGMA-EE) layer were confirmed by X-ray photoelectron spectroscopy (XPS) measurements. The thickness of the obtained P(TEGMA-EE) layers increased with increasing polymerization time. The increase of environmental temperature above the cloud point temperature of P(TEGMA-EE) caused the changes of surface philicity. A simultaneous decrease in the polymer layer thickness confirmed the thermosensitive properties of these P(TEGMA-EE) layers. The thermosensitive polymer surfaces obtained were evaluated for the growth and harvesting of human fibroblasts (basic skin cells). At 37 degrees C, seeded cells adhered to and spread well onto the P(TEGMA-EE)-coated surfaces. A confluent cell sheet was formed within 24 h of cell culture. Lowering the temperature to an optimal value of 17.5 degrees C (below the cloud point temperature of the polymer, TCP, in cell culture medium) led to the separation of the fibroblast sheet from the polymer layer. These promising results indicate that the surfaces produced may successfully be used as substrate for engineering of skin tissue, especially for delivering cell sheets in the treatment of burns and slow-healing wounds. PMID- 23448309 TI - Defensive gin-trap closure response of tenebrionid beetle, Zophobas atratus, pupae. AB - Pupae of the beetle Zophobas atratus Fab. (Coleoptera: Tenebrionidae) have jaws called gin traps on the lateral margin of their jointed abdominal segments. When a weak tactile stimulation was applied to the intersegmental region between the two jaws of a gin trap in a resting pupa, the pupa rapidly closed and reopened single or multiple gin traps adjacent to the stimulated trap for 100200 ms. In response to a strong stimulation, a small or large rotation of the abdominal segments occurred after the rapid closure of the traps. Analyses of trajectory patterns of the last abdominal segment during the rotations revealed that the rotational responses were graded and highly variable with respect to the amplitudes of their horizontal and vertical components. The high variability of these rotational responses is in contrast with the low variability (or constancy) of abdominal rotations induced by the tactile stimulation of cephalic and thoracic appendages. Since the closed state of the gin traps lasts only for a fraction of a second, the response may mainly function to deliver a "painful" stimulus to an attacker rather than to cause serious damage. PMID- 23448308 TI - HI-bone: a scoring system for identifying phenylisothiocyanate-derivatized peptides based on precursor mass and high intensity fragment ions. AB - Peptide sequence matching algorithms used for peptide identification by tandem mass spectrometry (MS/MS) enumerate theoretical peptides from the database, predict their fragment ions, and match them to the experimental MS/MS spectra. Here, we present an approach for scoring MS/MS identifications based on the high mass accuracy matching of precursor ions, the identification of a high intensity b1 fragment ion, and partial sequence tags from phenylthiocarbamoyl-derivatized peptides. This derivatization process boosts the b1 fragment ion signal, which turns it into a powerful feature for peptide identification. We demonstrate the effectiveness of our scoring system by implementing it on a computational tool called "HI-bone" and by identifying mass spectra of an Escherichia coli sample acquired on an Orbitrap Velos instrument using Higher-energy C-trap dissociation. Following this strategy, we identified 1614 peptide spectrum matches with a peptide false discovery rate (FDR) below 1%. These results were significantly higher than those from Mascot and SEQUEST using a similar FDR. PMID- 23448310 TI - Multicenter collaboration in pediatric lung transplantation--the importance of consensus. PMID- 23448311 TI - Enhancing the reporting and transparency of rheumatology research: a guide to reporting guidelines. AB - Manuscripts and abstracts from biomedical journals frequently do not contain proper information for meeting required standards and serving the multiple needs of their end users. Reporting guidelines and checklists help researchers to meet those standards by providing rules or principles for specific research areas. Rheumatology research includes a broad range of heterogeneous research areas, each with its own requirements, producing several distinct categories of articles. Our objectives with this article are to raise awareness of the existence and importance of reporting guidelines, to present a structured overview of reporting guidelines that rheumatology journals could apply, and to encourage their use by journal authors, editors, and reviewers, including those of Arthritis Research & Therapy. Internationally recognized reporting guidelines exist for a diversity of research areas. We encourage colleagues to consult the 'Enhancing the QUAlity and Transparency Of health Research' (EQUATOR) network when writing scientific papers. EQUATOR is an international initiative that seeks to improve the reliability and value of biomedical research literature by promoting transparent and accurate reporting of studies. We propose specific reporting guidelines for a number of study designs: animal research, randomized trials, reliability and agreement studies, systematic reviews with and without meta-analyses, diagnostic test accuracy studies, and also observational research including cross-sectional, cohort, and case-control studies. We encourage authors, editors, and reviewers to adhere to and enforce the use of the appropriate guidelines when writing, reading, and reviewing scientific papers. PMID- 23448312 TI - Diagnostic difficulties, therapeutic strategies, and performance of scoring systems in patients with autoimmune hepatitis and concurrent hepatitis B/C. AB - BACKGROUND: The diagnosis of autoimmune hepatitis (AIH) is already difficult, and that of AIH with chronic viral hepatitis including hepatitis B (HBV) or hepatitis C (HCV) is even more challenging. To date, only a few case-based studies have described this association. AIM: The aim was to retrospectively assess diagnostic difficulties, therapeutic approaches, and performance of the scoring systems in AIH patients with concurrent HBV and HCV. METHODS: A total of 25 patients from United States, Sweden, Italy, and Turkey were retrospectively evaluated. Both revised and simplified criteria suggested by the International Autoimmune Hepatitis Group were applied for each patient. All study data were obtained from medical records. RESULTS: Of the 25 patients, 20 (80%) had concomitant HCV and 5 (20%) had HBV. Based on the revised scoring system and simplified criteria, 18 (72%) and 12 (48%) patients were diagnosed as "probable" AIH. None of the patients were diagnosed as "definite" AIH according to both scoring systems. Patients with HCV initially were treated with immunosuppressive agents, and antiviral therapy was commenced when biochemical remission occurred. AIH patients with HBV were first treated with antiviral and thereafter, immunosuppressive therapy was started. CONCLUSIONS: This large case series describes concurrent AIH and chronic viral hepatitis. The revised scoring system for AIH had a better performance than the simplified scoring system. However, neither scoring system is optimal for diagnosing AIH alone. In these patients, a definitive diagnosis of AIH should be based on a combination of serological profiles, histological findings, scoring systems, treatment response, and outcomes. PMID- 23448313 TI - Exploring effective core drug patterns in primary insomnia treatment with Chinese herbal medicine: study protocol for a randomized controlled trial. AB - BACKGROUND: Chinese herbal medicine is one of the most popular Chinese medicine (CM) therapies for primary insomnia. One of the important characteristics of CM is that different Chinese clinicians give different prescriptions even for the same patient. However, there must be some fixed drug patterns in every clinician's prescriptions. This study aims to screen the effective core drug patterns in primary insomnia treatment of three prestigious Chinese clinicians. METHODS/DESIGN: A triple-blind, randomized, placebo-controlled, parallel-group clinical trial will be performed. Three clinicians will diagnose and treat every eligible patient individually and independently, producing three prescriptions from three clinicians for every patient. Patients will equally be randomized to one of four groups - medical group A, medical group B, medical group C, or placebo group - and observed for efficacy of treatment. The sample will include primary insomnia patients meeting DSM IV-TR criteria, Spiegel scale score >18, and age 18 to 65 years. A sequential design is employed. Interim analysis will be conducted when between 80 and 160 patients complete the study. The interim study could be stopped and treated as final if a statistically significant difference between treatment and placebo groups can be obtained and core effective drug patterns can be determined. Otherwise, the study continues until the maximum sample size reaches 300. Treatment of the CM group is one of three Chinese clinicians' prescriptions, who provide independently prescriptions based on their own CM theory and the patient's disease condition. Assessment will be by sleep diary and Pittsburgh sleep quality index, and CM symptoms and signs will be measured. Primary outcome is total sleep time. Assessment will be carried out at the washout period, weeks 1, 2, 3, and 4 and 4th week after the end of treatment. Effectiveness analysis will be per intent to treat. A multi-dimension association rule and scale-free networks method will be used to explore the effective core drug patterns. DISCUSSION: The effective core drug patterns will be found through analyzing several prestigious CM clinicians' treatment information. Screening the effective core drug patterns from prestigious clinicians can accelerate the development of new CM drugs. TRIAL REGISTRATION: NCT01613183. PMID- 23448314 TI - Bioactive proteins in breast milk. AB - Human milk contains many proteins that have been shown to be bioactive, but it is still not known whether these activities are exerted in breast-fed infants. These bioactivities include enzyme activities, enhancement of nutrient absorption, growth stimulation, modulation of the immune system and defence against pathogens. The antimicrobial activities are very diverse, ranging from stimulation of beneficial microorganisms (i.e. prebiotic effects), killing or inhibition of growth of pathogens, to mechanisms preventing attachment or invasion of harmful microorganisms. Among the bioactive proteins are lactoferrin, lysozyme, secretory immunoglobulin A, haptocorrin, lactoperoxidase, alpha lactalbumin, bile salt stimulated lipase, beta- and kappa-casein, and tumour growth factor beta. Human milk proteins may be largely resistant against digestion in the gastrointestinal tract, be partially digested into bioactive peptides, or be more or less completely digested and utilised as a source of amino acids. These events can be studied using an in vitro digestion model, which is useful for predicting results in human infants. Some bovine milk proteins, for example, lactoferrin and tumour growth factor beta, may also resist proteolysis and be capable of exerting bioactivities similar to those of human milk proteins. PMID- 23448315 TI - Charge recombination in S(n)Tyr(Z)(*)Q(A)(-*) radical pairs in D1 protein variants of Photosystem II: long range electron transfer in the Marcus inverted region. AB - Charge recombination in the light-induced radical pair SnTyrZ(*)QA(-*) in Photosystem II (PSII) from Thermosynechococcus elongatus has been studied at cryogenic temperatures by time-resolved EPR for different configurations of PSII that are expected to affect the driving force of the reaction (oxidation states S0, S1, or S2 of the Mn4CaO5 cluster; PsbA1, PsbA2, or PsbA3 as D1 protein). The kinetics were independent of temperature in the studied range from 4.2 to 50 K and were not affected by exchange of H2O for D2O, consistent with single-step electron tunneling over the distance of ~32 A without any repopulation through Boltzmann equilibration of intermediates lying higher in energy. In PsbA1-PSII, the charge recombinations in the radical pairs SnTyrZ(*)QA(-*) (ket = 3.4 * 10( 3) s(-1) for S1) were slower than in PsbA3-PSII despite an expected lower driving force owing to a downshifted Em(QA/QA(-*)) in PsbA1-PSII. Conversely, the reaction was slower in the presence of S2 than in the presence of S1, despite an expected larger driving force due to an upshifted Em(TyrZ(*)/TyrZ) in S2. These observations indicate that the charge recombination occurs in the Marcus inverted region. Assuming that the driving force of the reaction (-DeltaG(0) ~ 1.2 eV at room temperature for S1) does not vary strongly with temperature, the data indicate an optimal electron transfer rate (for a hypothetical -DeltaG(0) = lambda) substantially faster than would be predicted from extrapolation of room temperature intraprotein ET rates over shorter distances. Possible origins of this deviation are discussed, including a possible enhancement of the electronic coupling of TyrZ(*) and QA(-*) by aromatic cofactors located in between. Observed similar S1TyrZ(*)QA(-*) charge recombinations in PsbA2-PSII and PsbA3-PSII predict that Em(QA/QA(-*)) in PsbA2-PSII is similar to that in PsbA3-PSII. PMID- 23448316 TI - Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. AB - Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi , and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization. PMID- 23448317 TI - Apheresis in three dogs weighing <14 kg. AB - HISTORY: CaridianBCT apheresis machines require a ~285 mL priming volume (extracorporeal blood) that is withdrawn from the patient in ~10 minutes. Therefore, apheresis in dogs has generally been limited to dogs > ~20 kg to assure <20% of the blood volume is removed in the priming phase. ANIMALS/PHYSICAL EXAMINATION: Three dogs weighing <14 kg (13.6, 10.5, and 9.9 kg) with lymphoma that underwent apheresis. MANAGEMENT: The dogs were premedicated for placement of apheresis catheters with hydromorphone (0.1 mg kg(-1) ) IM. Anesthesia was induced with propofol, to effect, intravenously and general anesthesia was maintained with isoflurane in oxygen. Following catheter placement, dogs were allowed to recover from isoflurane but were kept sedated with either a dexmedetomidine constant rate infusion (CRI) or a propofol CRI. Real time autologous blood priming was not performed in any of the dogs. Instead, priming solutions were composed of a combination of hetastarch, lactated Ringer's solution, and/or autologous blood that was harvested 4 days before the procedure. During apheresis, dogs received anticoagulant citrate-dextrose, solution-A (ACD A) to prevent clotting and 10% calcium gluconate as needed to maintain normal ionized calcium concentrations. Dogs were monitored for cardiovascular and cardiopulmonary stability, anemia and lactic acidosis. FOLLOW-UP: All of the dogs had cardiovascular and cardiopulmonary values within clinically acceptable ranges. Immediately following apheresis all of the dogs were mildly to moderately anemic (PCV; 17-35%) although none of the dogs required a transfusion or had an increased lactate concentration. CONCLUSIONS: Dogs as small as 9.9 kg can successfully undergo apheresis with a variety of priming solutions. Dexmedetomidine or propofol given as a CRI provides sufficient sedation for this procedure. PMID- 23448318 TI - New stable anchor protein and peptide linker suitable for successful spore surface display in B. subtilis. AB - BACKGROUND: In last decade spores have been successfully used as a surface display platform. Various peptides or proteins were displayed this way as functional enzymes or antigens. Nearly all attempts involved use of three coat proteins: CotB, CotC or CotG. Increasing knowledge of the structure of the spore coat allowed us to propose the use of other proteins whose localization in the spore envelope has been determined. We also propose the application of a new linker suitable for building fusion proteins. RESULTS: We show that a member of the outer coat, CotZ, is a good candidate as a new anchor protein useful in spore surface display. This protein allows use of relatively large passenger proteins and their efficient display on the spore surface. Analysis by Western- and dot blotting, combined with immunofluorescence microscopy, allowed us to estimate the number of displayed fusion proteins molecules as 1.4 * 10(2) per spore. In addition, we present data indicating that the use of a peptide linker, which forms a stable alpha-helix, may greatly improve the display of anchored proteins on the spore surface. CONCLUSION: CotZ can be used as an efficient anchor protein in the outer spore coat. Its localisation in the coat crust layer should guarantee surface display of passenger proteins. Moreover, a CotZ based fusion can tolerate relatively large passenger proteins for efficient spore surface display. In addition, to the properties of both the anchor and passenger proteins, an important issue is the nature of the linker. Here we present evidence that the linker, which forms a stable alpha-helix, may be crucial for successful display. PMID- 23448319 TI - Functional heterologous expression of an engineered full length CipA from Clostridium thermocellum in Thermoanaerobacterium saccharolyticum. AB - BACKGROUND: Cellulose is highly recalcitrant and thus requires a specialized suite of enzymes to solubilize it into fermentable sugars. In C. thermocellum, these extracellular enzymes are present as a highly active multi-component system known as the cellulosome. This study explores the expression of a critical C. thermocellum cellulosomal component in T. saccharolyticum as a step toward creating a thermophilic bacterium capable of consolidated bioprocessing by employing heterologously expressed cellulosomes. RESULTS: We developed an inducible promoter system based on the native T. saccharolyticum xynA promoter, which was shown to be induced by xylan and xylose. The promoter was used to express the cellulosomal component cipA*, an engineered form of the wild-type cipA from C. thermocellum. Expression and localization to the supernatant were both verified for CipA*. When a DeltacipA mutant C. thermocellum strain was cultured with a CipA*-expressing T. saccharolyticum strain, hydrolysis and fermentation of 10 grams per liter SigmaCell 101, a highly crystalline cellulose, were observed. This trans-species complementation of a cipA deletion demonstrated the ability for CipA* to assemble a functional cellulosome. CONCLUSION: This study is the first example of an engineered thermophile heterologously expressing a structural component of a cellulosome. To achieve this goal we developed and tested an inducible promoter for controlled expression in T. saccharolyticum as well as a synthetic cipA. In addition, we demonstrate a high degree of hydrolysis (up to 93%) on microcrystalline cellulose. PMID- 23448320 TI - Colchicine toxicity precipitated by interaction with sunitinib. AB - WHAT IS KNOWN AND OBJECTIVE: Colchicine is an anti-inflammatory agent used primarily in treatment of gout and familial Mediterranean fever. Toxicity is uncommon, and depends on dose, hepatic or renal impairment, co-administration with P-glycoprotein or CYP3A4 inhibitors and route of administration. In patients taking p-glycoprotein inhibitors, maximum recommended dose is 0.3 mg per day. In renal or hepatic impairment, recommendation is to avoid concomitant administration of p-glycoprotein inhibitors and colchicine. CASE SUMMARY: We present an 82 year old patient, with a history of gout, chronic kidney disease and recurrent renal cell carcinoma who was admitted with features of colchicine toxicity after taking a cumulative dose of 41.4 mg over ten days, and taking sunitinib 50 mg daily from day seven of his high dose colchicine regimen. Symptoms started after commencing his cycle of sunitinib, which he had taken in 14 day cycles for many years. He developed severe diarrhea, normal anion gap metabolic acidosis, fever, pneumonia, white cell abnormalities including 30% bands and toxic granulation with Dohle bodies. Red cell abnormalities included anemia, burr cells and acanthocytosis. He also developed acute cardiovascular collapse with hypotension and acute systolic heart failure. Cardiac catheterization showed previously known coronary artery disease, with no significant progression to explain degree of cardiovascular collapse. WHAT IS NEW AND CONCLUSION: P-glycoprotein inhibition by sunitinib has been demonstrated. Interaction with colchicine metabolism precipitated colchicine toxicity in this case. Knowledge of p-glycoprotein and its role in drug interactions and potential drug toxicity may not be widespread among clinicians. We report the first case of colchicine toxicity precipitated by interaction with a tyrosine kinase inhibitor. PMID- 23448321 TI - Inferring the population structure of Myzus persicae in diverse agroecosystems using microsatellite markers. AB - Diverse agroecosystems offer phytophagous insects a wide choice of host plants. Myzus persicae is a polyphagous aphid common in moderate climates. During its life cycle it alternates between primary and secondary hosts. A spatial genetic population structure may arise due to environmental factors and reproduction modes. The aim of this work was to determine the spatial and temporal genetic population structure of M. persicae in relation to host plants and climatic conditions. For this, 923 individuals of M. persicae collected from six plant families between 2005 and 2008 in south-eastern Spain were genotyped for eight microsatellite loci. The population structure was inferred by neighbour-joining, analysis of molecular variance (AMOVA) and Bayesian analyses. Moderate polymorphism was observed for the eight loci in almost all the samples. No differences in the number of alleles were observed between primary and secondary hosts or between geographical areas. The proportion of unique genotypes found in the primary host was similar in the north (0.961 +/- 0.036) and the south (0.987 +/- 0.013), while in the secondary host it was higher in the north (0.801 +/- 0.159) than in the south (0.318 +/- 0.063). Heterozygosity excess and linkage disequilibrium suggest a high representation of obligate parthenogens in areas with warmer climate and in the secondary hosts. The F ST-values pointed to no genetic differentiation of M. persicae on the different plant families. F ST values, AMOVA and Bayesian model-based cluster analyses pointed to a significant population structure that was related to primary and secondary hosts. Differences between primary and secondary hosts could be due to the overrepresentation of parthenogens on herbaceous plants. PMID- 23448322 TI - A threshold method for immunological correlates of protection. AB - BACKGROUND: Immunological correlates of protection are biological markers such as disease-specific antibodies which correlate with protection against disease and which are measurable with immunological assays. It is common in vaccine research and in setting immunization policy to rely on threshold values for the correlate where the accepted threshold differentiates between individuals who are considered to be protected against disease and those who are susceptible. Examples where thresholds are used include development of a new generation 13 valent pneumococcal conjugate vaccine which was required in clinical trials to meet accepted thresholds for the older 7-valent vaccine, and public health decision making on vaccination policy based on long-term maintenance of protective thresholds for Hepatitis A, rubella, measles, Japanese encephalitis and others. Despite widespread use of such thresholds in vaccine policy and research, few statistical approaches have been formally developed which specifically incorporate a threshold parameter in order to estimate the value of the protective threshold from data. METHODS: We propose a 3-parameter statistical model called the a:b model which incorporates parameters for a threshold and constant but different infection probabilities below and above the threshold estimated using profile likelihood or least squares methods. Evaluation of the estimated threshold can be performed by a significance test for the existence of a threshold using a modified likelihood ratio test which follows a chi-squared distribution with 3 degrees of freedom, and confidence intervals for the threshold can be obtained by bootstrapping. The model also permits assessment of relative risk of infection in patients achieving the threshold or not. Goodness of-fit of the a:b model may be assessed using the Hosmer-Lemeshow approach. The model is applied to 15 datasets from published clinical trials on pertussis, respiratory syncytial virus and varicella. RESULTS: Highly significant thresholds with p-values less than 0.01 were found for 13 of the 15 datasets. Considerable variability was seen in the widths of confidence intervals. Relative risks indicated around 70% or better protection in 11 datasets and relevance of the estimated threshold to imply strong protection. Goodness-of-fit was generally acceptable. CONCLUSIONS: The a:b model offers a formal statistical method of estimation of thresholds differentiating susceptible from protected individuals which has previously depended on putative statements based on visual inspection of data. PMID- 23448323 TI - Combined rTMS to the auditory cortex and prefrontal cortex for tinnitus control in patients with depression: a pilot study. AB - CONCLUSION: The study showed that combined repetitive transcranial magnetic stimulation (rTMS) on the auditory cortex and prefrontal cortex has more benefit than rTMS on the auditory cortex alone for tinnitus control in patients with depression. Further studies for the most optimal combination of stimulation on both areas are needed. OBJECTIVE: Recent studies suggest that the neuronal network changes of chronic tinnitus are beyond the auditory pathway. There is increasing evidences for the application of rTMS on multiple brain cortices in addition to the auditory cortex for the treatment of tinnitus. Sequential rTMS was performed on the auditory cortex alone as well as the auditory cortex combined with prefrontal cortex in patients with both chronic tinnitus and depression. METHODS: Patients who presented with chronic tinnitus of more than 1 year were enrolled in the present study (seven males, four females; mean age 54 years). To select the site for the rTMS, PET CT was performed. Patients received the first rTMS on the primary auditory cortex for 5 days and on the primary auditory cortex and prefrontal cortex in the second application after tinnitus relapse. The Tinnitus Handicap Inventory (THI), visual analog scale (VAS), and Beck Depression Inventory (BDI) were evaluated before and after rTMS. RESULTS: The mean THI score of the eight patients with depression changed from 77.5 +/- 15 to 61.8 +/- 20.1 after the second rTMS. There was statistical significance only for the second rTMS. The VAS score changed from 8.6 +/- 1.6 to 6.3 +/- 1.8 after the first rTMS and from 7.6 +/- 2.4 to 4.6 +/- 2.7 after the second rTMS, showing statistically significant changes both times. The THI changes after the second rTMS were greater than after the first rTMS, and the changes in VAS score showed a similar pattern. The changes in BDI score, which indicates the severity of depression, showed a variable pattern after rTMS. Patients with mild depression (10<= BDI score <16, n = 4) showed significant improvement of THI with the second combined rTMS (DeltaTHI = 24.5) as compared with the first rTMS on the auditory area (DeltaTHI = 6). In contrast, combined rTMS did not show any better improvement on THI (DeltaTHI = 6.5) than the first rTMS on the auditory cortex (DeltaTHI = 7) in patients without depression (BDI <10, n = 3) and patients with moderate to severe depression (BDI >=16, n = 4). PMID- 23448324 TI - Evidence on the shelf? Continuous improvement. PMID- 23448325 TI - Recognition of the health assistant as a delegated clinical role and their inclusion in models of care: a systematic review and meta-synthesis of qualitative evidence. AB - AIM: Assistants have been utilised worldwide in healthcare as a means to ensure the provision of adequate and efficient healthcare in the midst of increased pressures on health services for many years. This review aimed to synthesise available qualitative evidence regarding the appropriateness of strategies used to establish the health assistant role as a recognised delegated clinical role and to promote their inclusion in models of care. This review focused on how to make strategies appropriate for health assistants and professionals. Health assistants were defined as those who provide assistance and support to health professionals by whom they are directly or indirectly supervised in all healthcare and health education sectors. METHODS: A systematic review with meta synthesis of qualitative studies using meta-aggregation was conducted. Types of participants considered included assistants in healthcare, including nursing and allied health assistants. The phenomena of interest was the appropriateness of strategies used to establish the assistant role as a recognised delegated clinical role and/or to promote their inclusion in models of care. Qualitative research studies including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research were considered for inclusion. Electronic searches of multiple databases including MEDLINE, AMED, CINAHL and EMBASE, limited to the English language were conducted during the period of 14 April to 13 May 2011. In addition, grey literature was also searched for, as well as a hand search of relevant journals. Assessment of methodological quality of papers prior to inclusion in the review was performed using a standardised critical appraisal instrument from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI QARI). Data were extracted using the standardised data extraction tool from JBI QARI. Data synthesis using the JBI QARI approach of meta-synthesis by meta-aggregation was performed. RESULTS: Ten studies met the inclusion criteria. From the 10 included studies, 66 findings were identified that were organised into 11 categories by similarity of meaning. Categories were then aggregated into four synthesised findings: assistants and professionals may have good or difficult inter professional relationships, which is dependent on a variety of factors, and can thus inform appropriate strategies to include assistants in models of care; professionals and assistants perceive the assistant role and the need for practice change in different ways, whereas the role itself and tasks performed may be influenced by a number of different factors; despite assistants feeling different levels of preparedness for training or the need for training, there are effective training programmes with certain characteristics that can result in positive training outcomes; there are concerns amongst health staff regarding responsibility in models of care using assistants, highlighting the need for appropriate supervision and mentoring of assistants. CONCLUSIONS: Qualitative meta-synthesis was performed providing a unique perspective on the role of health assistants and strategies used to include them in models of care. These synthesised findings can be used to guide practice in healthcare organisations considering strategies for implementing the assistant role, or where assistants are currently utilised. PMID- 23448326 TI - Maintenance of patency of central venous access devices by registered nurses in an acute ambulatory setting: an evidence utilisation project. AB - AIM: The aim of the project was to implement the best practice for the maintenance of patency for central venous access devices by registered nurses in an acute ambulatory setting. METHOD: This project utilised the Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research into Practice programs to facilitate a process of change using an audit, feedback and re-audit cycle as a strategy to improve clinical practice. The team conducted the project in three phases over a 5-month period (July to November 2011). It involved a sample size of 29 registered nurses. RESULTS: The compliance rate for both criteria increased post-implementation, demonstrating a positive improvement in compliance to the best practice. The pulsated flushing technique improved from 25% (baseline) to 93% (post-implementation) compliance rate. This showed a statistically significant improvement of 68% (chi(2) = 29.375, P = 0.000). The second criterion, the use of sterile normal saline to flush and lock the catheter, improved from 68% compliance in the baseline audit to 100% compliance rate in the post-implementation audit (chi(2) = 14.215, P = 0.005). CONCLUSION: This project utilised the process of audit, feedback and re-audit cycle as a strategy to improve clinical practice. It demonstrated the feasibility of translating evidence-based practice into the clinical setting, with remarkable improvement in maintaining patency of central venous access devices for patient with cancer. Finally, it is evidenced that the commitment and enthusiasm of team members and all the registered nurses in maintaining the patency of central venous access devices were the crucial factors for the success of this project. The support and assistance provided by the stakeholders also played an important role in the sustainment of the project. PMID- 23448327 TI - Nursing inter-shift handover process in mental health settings: a best practice implementation project. AB - AIMS: Nursing inter-shift handover remains an important traditional ritual in nursing. Timely and effective handover of critical information ensure continuity of patient care and safe delivery. This project took place in a tertiary mental health institution in Singapore. The project aims to (i) examine existing handover practices/process in the tertiary mental health institution; (ii) determine the strengths and limitations of the existing handover practice/process; and (iii) identify, implement and evaluate an evidence-based nursing inter-shift handover process to enhance patient safety and service delivery. METHODS: This project was conducted in three phases using the Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research Into Practice programmes. It was implemented over a period of 4 months from end of August 2011 to beginning of December 2011. Evidence-based strategies such as town hall meetings and education sessions that reinforce proper handover techniques and its importance were implemented to enhance the handover processes and practices in four acute admitting wards. Pre- and post-audit data were observed and recorded for each case handover during each inter-shift handover session in four acute admitting wards. RESULTS: The handover processes for 212 cases for four acute admitting wards were observed using the seven audit criteria. Post-implementation audit findings show that compliance rate had improved significantly for the four criteria: an improvement of 49% compliance rate in the use of standardised documentation during shift handover session; an increase of 74% compliance rate in proper identification of patient at the start of each case report; a 31% increase in proper handing over of significant patient's history; and 18% increased compliance in providing detailed observation of patients. CONCLUSION: This project had shown that handover sessions can be made effective by translating evidence into practice through ongoing evidence based audit. Continuous evidence-based evaluation, identification and implementation of nursing inter-shift handover process are imperative to enhance patient safety and service delivery. PMID- 23448328 TI - Fall prevention among children in the presence of caregivers in a paediatric ward: a best practice implementation. AB - AIM: This study aims to reduce the incidence of falls in paediatric inpatients aged 3 and below by implementing fall prevention strategies. METHODS: The Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research into Practice programmes were used for this project. The project was carried out in three phases over a 4-month period from March to June 2011. A fall prevention poster was introduced during the implementation phase, and pre- and post-implementation audits were carried out in a 43-bed acute care paediatric ward in Singapore, with a sample size of 30. RESULTS: The audit result of Criterion 1, evaluating the effectiveness of the fall prevention measures, improved by 13%, to 93%. Criterion 2, measuring nurses' compliance in the regular reinforcement of safety, improved significantly by 27%, to 40%. However, Criterion 3, which measured nurses' compliance in identifying patients at high risk of falls by placing a green identification wrist tag on such patients, decreased by 23%, to 50%. DISCUSSION: A multi-language poster on fall prevention was strategically positioned at the foot of all the cots. The poster served as an effective reminder and communication method between nurses and caregivers and also among caregivers of the child. Caregivers' increased awareness and knowledge of fall prevention contributed to a 50% decrease in fall incidence of patients aged 3 and below in the presence of a caregiver from January to June 2011, as compared with the incidence rate in 2010. CONCLUSION: This project has shown that fall incidents can be reduced when caregivers' awareness of fall prevention measures in the hospital setting were to be improved. The poster on fall prevention has increased caregivers' awareness and reduced inpatient falls in the acute care setting. The pre- and post-implementation audits showed that the presence of a poster on fall prevention to remind parents/caregivers to raise and securely lock the cot rails at all times was effective in reducing the number of falls for children aged 3 years and below. The experience gained from this project was that communication to every staff member and caregivers is essential in implementing practice change. As a result of the study, the hospital plans to implement constant monitoring and reminders to nurses and caregivers to improve compliance to the recommended measures on fall prevention in the near future. PMID- 23448329 TI - Implementing the best available evidence in early delirium identification in elderly hip surgery patients. AB - AIMS: Delirium is a frequent complication in the surgical experience of elderly hip surgery patients. Its impact can be severe and may even include death. Implementation of a delirium predictor tool might focus attention on early recognition of delirium, thereby potentially decreasing its impact. A related aim is to evaluate best practices in implementation strategies in this project. METHODS: After an exhaustive search of the literature, no consensus was found regarding delirium predictors for the elderly hip surgery patient. A local research study was implemented to determine factors that may predict delirium in this population. With evidence secured, a multidisciplinary implementation project augmented by ongoing audit was instituted. A variety of social diffusion and education tools were used. Implementation was guided by the use of the Promoting Action on Research Implementation in Health Services framework assessment tool and the Alberta Context Tool, as well as traditional performance improvement tools, such as fishbone charting. Audit identified the rate of use of the predictor tool and pre- and post-rates of delirium. This project was part of the Joanna Briggs Institute Signature Project, an implementation project consisting of six teams, each representing a different organisation. This overall project was supported by experts in the field of translation and implementation science internationally. RESULTS: Initial compliance to the use of the predictor tool was assessed at 54% within 3 months of implementation and increased to 56% in the ensuing months. Before the study use of the predictor tool, the delirium rate was 10.4% (12 of 115 patients). An interim analysis 4 months after implementation identified a 20% delirium rate (18 of 70 patients) and an updated analysis 8 months into the project showed a 16.3% delirium rate. Delirium predictor tool use was associated with a lower delirium rate (9/76, 11.84%) than no delirium predictor tool (13/60, 21.67%), but the difference was not statistically significant with a sample size of 133 (P = 0.122). CONCLUSIONS: The delirium predictor tool shows promise as a prompt for best practices in prevention of delirium. This study showed a change in delirium rates as a result of its use. Although the results were not statistically significant, they may be clinically meaningful. Comprehensive assessment and implementation planning by a multidisciplinary team contributed to only 56% compliance in use. Despite this low rate, delirium identification rates were higher. PMID- 23448330 TI - Implementing evidence in an onco-haematology nursing unit: a process of change using participatory action research. AB - AIM: To implement evidence in a nursing unit and to gain a better understanding of the experience of change within a participatory action research. METHODS: Study design of a participatory action research type was use from the constructivist paradigm. The analytical-methodological decisions were inspired by Checkland Flexible Systems for evidence implementation in the nursing unit. The study was carried out between March and November 2007 in the isolation unit section for onco-haematological patients in a tertiary level general university hospital in Spain. Accidental sampling was carried out with the participation of six nurses. Data were collected using five group meetings and individual reflections in participants' dairies. The participant observation technique was also carried out by researchers. Data analysis was carried out by content analysis. The rigorous criteria were used: credibility, confirmability, dependence, transferability and reflexivity. RESULTS: A lack of use of evidence in clinical practice is the main problem. The factors involved were identified (training, values, beliefs, resources and professional autonomy). Their daily practice (complexity in taking decisions, variability, lack of professional autonomy and safety) was compared with an ideal situation (using evidence it will be possible to normalise practice and to work more effectively in teams by increasing safety and professional recognition). It was decided to create five working areas about several clinical topics (mucositis, pain, anxiety, satisfaction, nutritional assessment, nauseas and vomiting, pressure ulcers and catheter-related problems) and seven changes in clinical practice were agreed upon together with 11 implementation strategies. Some reflections were made about the features of the study: the changes produced; the strategies used and how to improve them; the nursing 'subculture'; attitudes towards innovation; and the commitment as participants in the study and as healthcare professionals. CONCLUSIONS: The findings throw light on the process of change in the healthcare sector. The results are useful to modify nursing practice based on evidence. PMID- 23448331 TI - Chest pain in patients with 'normal angiography': could it be cardiac? AB - Approximately 20% of patients undergoing diagnostic angiography for the evaluation of chest pain are found to have a normal coronary angiogram. Although this finding is generally associated with a low risk of cardiac events, approximately half will continue to experience chest pain over the next 12 months. Therefore, the finding of normal angiography warrants further evaluation of the potential causes for the presenting chest pain if we are to improve the disability suffered by these patients. In this review, the potential non-cardiac and cardiac causes for the chest pain in patients with normal angiography are briefly discussed with an in-depth focus on coronary vasomotor disorders including coronary artery spasm (variant angina) and microvascular disorders such as syndrome X, microvascular angina, the coronary slow flow phenomenon and microvascular spasm. PMID- 23448332 TI - Working with interpreters: practical advice for use of an interpreter in healthcare. AB - The aim of this descriptive commentary is to improve communication in healthcare when an interpreter is used by providing practical advice to healthcare staff when they consider using interpreters. This descriptive commentary considered the issues of preparation and implementation of interpretation sessions to reveal the complexities and dilemmas of an effective healthcare encounter with interpreters. Using the design of a discursive paper, this article seeks to explore and position of what is published in the literature on the topic studied and on the basis of previous studies to provide practical advice on the use of interpreters. The descriptive commentary showed that the interpreter should be used not only as a communication aid but also as a practical and informative guide in the healthcare system. In preparing the interpretation session, it is important to consider the type (trained professional interpreter, family member or bilingual healthcare staff as interpreters) and mode (face to face and telephone) of interpreting. Furthermore, it is important to consider the interpreter's ethnic origin, religious background, gender, language or dialect, social group, clothes, appearance and attitude. During the healthcare encounter, the interpreter should follow the recommendations given in guidelines for interpreters. Healthcare staff should choose an appropriate room and be aware of their own behaviour, appearance and attitude during the healthcare encounter. Good planning is needed, with carefully considered choices concerning the right kind of interpreter, mode of interpretation and individual preferences for the interpretation in order to deliver high-quality and cost-effective healthcare. Depending on the nature of the healthcare encounter, healthcare staff need to plan interpreting carefully and in accordance with the individuals' desires and choose the type of interpreter and mode of interpreting that best suits the need in the actual healthcare situation in order to deliver high-quality healthcare. PMID- 23448333 TI - Painful diabetic neuropathy management. AB - Diabetic neuropathy is the most common complication of diabetes as it affects a significant number of patients. The management of patients with diabetic neuropathy is complicated by several factors including the varied symptoms and response to the various treatments available. Strict blood glucose control remains the key to the management thus far nonetheless; it is associated with complications such as hypoglycaemia. In order to provide the most up-to-date evidence-based clinical recommendations pertinent to the management of diabetic neuropathy, several databases and clinical practice guidelines were searched for this evidence-based report. The main outcome measures are reduction in pain associated with diabetic neuropathy and the number of withdrawal rates due to adverse effects of the medications both of which are discussed in this report. Various pharmacological and non-pharmacological treatments are available with varying degrees of success in pain relief. The current evidence suggests that use of tricyclics antidepressants and conventional anticonvulsants for the short term of pain relief is beneficial. Combination therapy of opioids and anticonvulsants has also been found to be superior to monotherapy. Other treatment modalities such as the use of alpha-lipoic acid as an antioxidant and evening primrose oil through increased PGE1 synthesis have also been trialled with evidence of improvement in neuropathic pain. Evidence also supports non-pharmacological treatment such as the use of percutaneous electrical nerve stimulation. There is a scope for further improvement of the reporting of rating pain scales and including various outcomes measures such as quality of life and physical function when trialling new therapies for better evaluation of future treatments. PMID- 23448338 TI - Guest packing motifs within a supramolecular nanocapsule and a covalent analogue. AB - Two hosts that utilize the hydrophobic effect to assemble and/or encapsulate guest molecules were studied. The hosts, octa-acid (OA) and hexalene diamine linked octa-acid (HOA), were shown to complex a broad range of n-alkanes up to n hexacosane (C26H54). A combination of (1)H NMR, NMR diffusion, COSY, and NOESY experiments revealed four different guest packing motifs, depending on the size of the guest and the nature of the host. As a function of guest size, smooth transitions from one motif to the next were observed and allowed qualification of their relative stabilities. Furthermore, although the two hosts engender ostensibly identical encapsulation environments, their different assembly properties lead to quite distinct packing-motif profiles, i.e., how the motifs change as a function of guest size. PMID- 23448339 TI - Data-dependent middle-down nano-liquid chromatography-electron capture dissociation-tandem mass spectrometry: an application for the analysis of unfractionated histones. AB - Middle-down mass spectrometry (MS) combined with electron capture dissociation (ECD) represents an attractive method for characterization of proteins and their post-translational modifications (PTMs). Coupling online chromatographic separation with tandem mass spectrometry enables a high-throughput analysis, while improving sensitivity of the electrosprayed peptides and reducing sample amount requirements. However, middle-down ECD has not been thus far coupled with online chromatographic separation. In this work, we examine the feasibility of coupling middle-down ECD with online nanoflow-liqiud chromatography (nano-LC) for the analysis of large, >3 kDa, and highly modified polypeptides in a data dependent acquisition mode. We evaluate the effectiveness of the method by analyzing peptides derived from Asp-N and Glu-C digestions of unfractionated histones from calf thymus and acid-extracted histones from HeLa, MCF-7, and Jurkat cells. Our results demonstrate that middle-down ECD is compatible with online chromatographic separation, providing high peptide and protein sequence coverage while allowing precise mapping of PTM sites. The high mass accuracy, obtained by the ICR mass analyzer, for both the precursor and product ions greatly increases confidence in peptide identification, particularly for modified peptides. Overall, for all samples examined, several histone variants were identified and modification sites were successfully localized, including single, multiple, and positional isomeric PTM sites. The vast majority of the identified peptides were in the mass range from 3 to 9 kDa. The data presented here highlight the feasibility and utility of nano-LC-ECD-MS/MS for high-throughput middle-down analysis. PMID- 23448340 TI - Autosomal recessive isolated familial acanthosis nigricans in a Pakistani family due to a homozygous mutation in the insulin receptor gene. PMID- 23448341 TI - Early inflammatory processes in the skin. AB - Skin is considered as the border defining the limits of the body from the external world and functions as a barrier between the two. In this capacity, it has evolved to be an integral part of the innate and adaptive immune system. Although many reviews have described skin inflammation and processes that lead to its clinical manifestations, we are not aware of any reviews that have focused on immunologic activity occurring in the absence of any visual inflammatory cues. In this review, we discuss the importance of subclinical inflammation in human skin and its relevance to innate immune surveillance under physiologic conditions. Reactive oxygen species generated by metabolic processes, ultraviolet radiation or oxidizers may damage cells, initiating proinflammatory cascades. In addition to serving as structural skin components, keratinocytes have significant immunologic activity: they secrete proinflammatory cytokines and mediators, including interleukin (IL)-1alpha, IL-6, IL-10, tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor. Infant skin is particularly susceptible to irritation, inflammation and infection, since skin barrier function is not fully developed after birth and continues to mature throughout the first few years of life. Non-invasive methods such as fluorescence spectroscopy, spectral imaging and diffuse reflectance spectroscopy, as well as minimally invasive tape stripping, can be used to assess subclinical inflammatory markers in vivo, including erythema, epidermal cell proliferation rate and cytokine concentrations. Appropriately formulated skin care products may help maintain skin barrier integrity and enhance its capacity. In the future, assessment of subclinical inflammation may help clinicians prevent acute or chronic inflammatory conditions of the skin. PMID- 23448342 TI - Kidney disease in lupus is not always 'lupus nephritis'. AB - In lupus erythematosus, elevated serum creatinine levels and urinary abnormalities implicate a kidney disorder, which may not always be lupus nephritis as defined by the current classification of the International Society of Nephrology/Renal Pathology Society. The signs of renal dysfunction may be caused by lupusunrelated renal injury such as drug toxicity or infection or by lupus-associated mechanisms that are not part of the classification, such as minimal change nephrotic syndrome or thrombotic microangiopathy. The latter seems to complicate lupus nephritis more frequently than previously thought. An unbiased assessment of kidney disease in lupus requires a kidney (re-)biopsy to define the appropriate management. PMID- 23448343 TI - Behavioral strategies of phorid parasitoids and responses of their hosts, the leaf-cutting ants. AB - Host-searching and oviposition behaviors of parasitoids, and defensive responses of the hosts, are fundamental in shaping the ecology of host-parasitoid interactions. In order to uncover key behavioral features for the little known interactions between phorid parasitoids (Diptera: Phoridae) and their leaf cutting ant hosts (Formicidae: Attini), host-related behavioral strategies (i.e., host searching and oviposition) for 13 phorid species, and host defensive responses (i.e., hitchhikers and particular body postures) for 11 ant species, were studied. Data was collected at 14 localities, one of them characterized by its high species richness for this host-parasitoid system. Phorid species showed both great variation and specificity in attacking behaviors. Some chose their hosts using either an ambush or an actively searching strategy, while some species attacked ants on different body parts, and specialized on ants performing different tasks, such as when ants were foraging, removing wastes to refuse piles, or repairing the nest. Combining all the behaviors recorded, most phorid species differed in performance in at least one, making it possible to recognize species in the field through their behavior. Phorid species that attacked hosts with greater activity levels showed overall higher attack rates, although there was no significant correlation between attack rates by most phorid species and ant activity outside the nest while parasitoids were attacking. The presence of phorids was a significant determinant for the presence of defensive behaviors by the ants. Although ant species varied in the incidence levels of these defensive behaviors, most ant species reacted against different phorids by utilizing similar behaviors, in contrast to what parasitoids do. General features of the observed phorid-ant interactions were parasitoid specialization and corresponding high interspecific variation in their behaviors, while their hosts showed generalized responses to attacks with high intraspecific variation. Behavioral patterns as well as specific features of these ant-parasitoid interactions are described, and their ecological importance discussed. PMID- 23448344 TI - Comparison of prasugrel and clopidogrel reloading on high platelet reactivity in clopidogrel-loaded patients undergoing percutaneous coronary intervention (PRAISE HPR): a study protocol for a prospective randomized controlled clinical trial. AB - BACKGROUND: Patients with reduced responsiveness to clopidogrel often have diminished platelet inhibition, a factor associated with increased rates of major adverse cardiovascular events. Clinical trials that have focused on reducing high on-treatment platelet reactivity (HPR) with an additional loading dose of clopidogrel have reported varying effects. Prasugrel, a newer thienopyridine, exhibits a more consistent antiplatelet effect and more rapid onset time when compared to clopidogrel. We hypothesize that prasugrel reloading would be more effective than clopidogrel reloading in patients with HPR after an initial loading dose of clopidogrel. METHOD/DESIGN: Comparison of Prasugrel and Clopidogrel Reloading on High Platelet Reactivity in Clopidogrel-loaded Patients Undergoing Percutaneous Coronary Intervention (PRAISE-HPR) is a prospective, randomized, open-label, active controlled study. A total of 76 patients undergoing percutaneous coronary intervention (PCI), with HPR after administration of a loading dose of clopidogrel will be randomly assigned to either prasugrel or clopidogrel groups, and patients in each group will be reloaded with 20 mg of prasugrel or 300 mg of clopidogrel. The primary endpoint will be HPR at 24 hours after PCI, as determined by the VerifyNow assay during the study period. The rate of sustained high platelet reactivity and 30-day clinical outcomes will also be measured. DISCUSSION: PRAISE-HPR is a randomized controlled clinical trial to investigate the efficacy and safety of reloading prasugrel and clopidogrel in suppressing residual high platelet reactivity. The results will be made publicly available in the year 2013. TRIAL REGISTRATION: NCT01609647. PMID- 23448346 TI - Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity. AB - Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17beta-estradiol (E2) with a bulky side chain attached to its C 7alpha position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERalpha transactivation activity in a luciferase reporter assay and blocked ERalpha interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERalpha-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERalpha and showed that they could tightly bind to the ERalpha in a manner similar to that of ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7alpha position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780. PMID- 23448347 TI - The risk of placenta accreta following primary elective caesarean delivery: a case-control study. AB - OBJECTIVE: To evaluate the risk of placenta praevia accreta following primary (first) elective or primary emergency caesarean section in a pregnancy complicated by placenta praevia. DESIGN: Retrospective matched case-control study, employing variable matching. SETTING: Tertiary referral centre between 1993 and 2008. POPULATION: Sixty-five cases and 102 controls were used for the analysis from a total of 82 667 births during the study period. METHODS: Relevant data were abstracted from clinical records. Matching of cases with controls was based on co-existing placenta praevia, number of previous caesarean sections, and age, with one or two controls per case. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). MAIN OUTCOME MEASURES: Placenta accreta in a pregnancy complicated by placenta praevia following a primary elective or emergency caesarean section, and morbidity associated with pregnancies complicated by placenta accreta. RESULTS: Significantly more cases than controls had an elective caesarean section for their primary caesarean delivery (46.2 versus 18.6%; P < 0.001). There were no differences between groups for previous pregnancy loss, uterine surgery, and vaginal delivery, before or after the primary caesarean section. Compared with primary emergency caesarean section, primary elective caesarean section significantly increased the risk of placenta accreta in a subsequent pregnancy in the presence of placenta praevia (OR 3.00; 95% CI 1.47-6.12; P = 0.025). CONCLUSIONS: Our results suggest that women with a primary elective caesarean section without labour are more likely, compared with those undergoing primary emergency caesarean section with labour, to develop an accreta in a subsequent pregnancy with placenta praevia. PMID- 23448348 TI - Age-related changes in accommodation measured with a double-pass system. AB - PURPOSE: To measure the accommodative response in a wide age range population using the retinal image quality assessments provided by a double-pass system. METHODS: The accommodative response was measured using a custom-built double-pass setup in 84 patients from 15 to 55 years of age. Patients were classified in four groups (A: 15-25 year old; B: 26-35; C: 36-45; D: 46-55). Accommodation was stimulated from 0 to 5 dioptres (D) with the push up method using an open field fixation test. The total accommodative response in the stimulated range, the accommodative stimulus-response curve, the slope and the progression of optical quality with accommodation were measured. RESULTS: The total accommodation obtained in groups A and B was high, with a mean value of 4 D or higher, whereas values in older individuals were significantly lower. The accommodative stimulus response curve and the slope were also high with a sudden decrease in patients over 35 years of age. The optical quality of the eye during accommodation did not change significantly. CONCLUSIONS: Participants aged 15-35 years showed a good accommodative response. Thereafter, a significant decrease of the response in the total accommodation, stimulus response curve and slope was observed. The younger groups showed a larger accommodative response than previously published. PMID- 23448350 TI - Exclusion of eleven candidate genes for ocular melanosis in Cairn terriers. AB - BACKGROUND: Ocular melanosis of Cairn terrier dogs is an inherited defect characterized by progressive pigmentation of both eyes which can result in glaucoma and blindness. Pedigree analysis suggests the trait has an autosomal dominant mode of inheritance. We selected 11 potential candidate genes and used an exclusion analysis approach to investigate the likelihood that one of the candidate gene loci contained the Cairn terrier-ocular melanosis locus. RESULTS: Two polymorphic loci were identified within or close to each candidate gene. Genotyping of at least 10 ocular melanosis Cairn terriers for each marker showed that there was no single shared allele for either of the two polymorphic markers identified in ASIP, COMT, GPNMB, GSK3B, LYST, MC1R, MITF, SILV, TYR, TYRP1,and TYRP2. This is strong evidence to exclude each locus as the site of the ocular melanosis mutation (probability of a false exclusion calculated for each gene ranged from 1.59 * 10-4 to 1 * 10-9). CONCLUSIONS: None of the 11 potential candidate genes selected are likely to be the gene locus for ocular melanosis in Cairn terriers. PMID- 23448345 TI - Demystifying animal models of adverse pregnancy outcomes: touching bench and bedside. AB - This represents an overview of the use of animal models to study the adverse pregnancy outcomes seen in humans. The purpose is to entice clinicians to utilize some of this information to seek out the literature and have more meaningful and profitable discussions with their academic colleagues and enhance transdisciplinary research in reproductive health. PMID- 23448351 TI - Vibrant Soundbridge in congenital osseous atresia: multicenter study of 12 patients with osseous atresia. AB - CONCLUSION: The study suggests that the Vibrant Soundbridge (VSB) middle ear implant could be a valid alternative for patients with congenital aural atresia to compensate for their hearing loss. OBJECTIVE: To determine the audiologic benefit the VSB provides in patients with congenital aural atresia. METHODS: Twelve patients with congenital aural atresia were implanted with VSB: eight patients were unilaterally atretic (67%) and 4 (33%) were bilaterally atretic. In five cases the implant was placed onto the round window, in another five cases the implant was placed on the stapes, in only one case a prosthesis (coupler) was used to fix the implant into the oval window, and in one case a fenestration on the cochlear endostium was performed. RESULTS: The mean functional gain obtained for all patients evaluated was 62 dB at 0.5 kHz, 60 dB at 1 kHz, 48.3 dB at 2 kHz, and 50.8 dB at 4 kHz. The mean functional gain for all frequencies evaluated was 55.1 dB. PMID- 23448349 TI - pH-Independence of trialanine and the effects of termini blocking in short peptides: a combined vibrational, NMR, UVCD, and molecular dynamics study. AB - Several lines of evidence now well establish that unfolded peptides in general, and alanine in specific, have an intrinsic preference for the polyproline II (pPII) conformation. Investigation of local order in the unfolded state is, however, complicated by experimental limitations and the inherent dynamics of the system, which has in some cases yielded inconsistent results from different types of experiments. One method of studying these systems is the use of short model peptides, and specifically short alanine peptides, known for predominantly sampling pPII structure in aqueous solution. Recently, He et al. ( J. Am. Chem. Soc. 2012 , 134 , 1571 - 1576 ) proposed that unblocked tripeptides may not be suitable models for studying conformational propensities in unfolded peptides due to the presence of end effect, that is, electrostatic interactions between investigated amino acid residues and terminal charges. To determine whether changing the protonation states of the N- and C-termini influence the conformational manifold of the central amino acid residue in tripeptides, we have examined the pH-dependence of unblocked trialanine and the conformational preferences of alanine in the alanine dipeptide. To this end, we measured and globally analyzed amide I' band profiles and NMR J-coupling constants. We described conformational distributions as the superposition of two-dimensional Gaussian distributions assignable to specific subspaces of the Ramachandran plot. Results show that the conformational ensemble of trialanine as a whole, and the pPII content (chipPII = 0.84) in particular, remains practically unaffected by changing the protonation state. We found that compared to trialanine, the alanine dipeptide has slightly lower pPII content (chipPII = 0.74) and an ensemble more reminiscent of the unblocked Gly-Ala-Gly model peptide. In addition, a two-state thermodynamic analysis of the conformational sensitive Deltaepsilon(T) and (3)J(H(N)H(alpha))(T) data obtained from electronic circular dichroism and H NMR spectra indicate that the free energy landscape of trialanine is similar in all protonation states. MD simulations for the investigated peptides corroborate this notion and show further that the hydration shell around unblocked trialanine is unaffected by the protonation/deprotonation of the C-terminal group. In contrast, the alanine dipeptide shows a reduced water density around the central residue as well as a less ordered hydration shell, which decreases the pPII propensity and reduces the lifetime of sampled conformations. PMID- 23448352 TI - Comparison study of transoral robotic surgery and radical open surgery for hypopharyngeal cancer. AB - CONCLUSIONS: The oncologic outcome of transoral robotic surgery (TORS) was comparable to radical open surgery. The TORS group showed a better functional recovery and quality of life (QOL) than the radical surgery group. Therefore, TORS was a valid treatment option as a minimally invasive surgery for selected patients with hypopharyngeal cancer. OBJECTIVES: To affirm rapid functional recovery and improved QOL of patients who underwent TORS, which is a minimally invasive surgical technique. METHODS: Between April 2008 and November 2011, 56 patients were enrolled in the study. During the study period, 30 patients underwent TORS and 26 patients underwent radical open surgery. RESULTS: In the TORS and radical surgery groups, the 3-year overall survival rate was 85% and 78%, respectively, and disease-free survival was 81% and 76%, respectively. Significant differences were not observed in the overall survival and disease free survival rates. As regards postoperative functional recovery, the TORS group showed statistically better results for decannulation, swallowing, and hospitalization compared with the radical surgery group. On the University of Washington (UW)-QOL, the TORS group showed better results than the radical open surgery group in the domains of pain, activity, recreation, swallowing, speech, anxiety, and health-related QOL. PMID- 23448353 TI - Supramaximal stimulation during intraoperative facial nerve monitoring as a simple parameter to predict early functional outcome after parotidectomy. AB - CONCLUSION: A supramaximal stimulation at 2 mA during intraoperative electromyographic (EMG) facial nerve monitoring appears to be a simple and effective parameter to predict immediate postoperative injury. OBJECTIVES: To assess the role of systematic intraoperative facial nerve monitoring in predicting the early functional outcomes obtained after parotidectomy. METHODS: Data were collected from patients who underwent parotidectomy. Intraoperative EMG monitoring of the facial nerve was performed by registering two parameters, event intensity (>100 MUV) and amplitude of response after a supramaximal stimulation at 2 mA, at the beginning and end of gland removal. Early postoperative clinical functional facial nerve disorder was assessed at day 2. RESULTS: Overall, 50 patients were included and an early facial dysfunction was detected in 27 cases (54%). The maximal response amplitude after supramaximal stimulation at the trunk of the facial nerve was higher in patients with normal facial function compared with those with poor outcomes at the end of surgery (p < 0.01). The postdissection to predissection ratios of maximal response amplitude, but not the stimulation thresholds, were indicative of a nerve conduction block and were significantly lower in the patient group with a poor outcome compared with the group with a normal facial outcome (p < 0.02). PMID- 23448354 TI - Separation and cultivation of laryngeal carcinoma-associated fibroblasts and biological influence on a laryngeal carcinoma cell line. AB - CONCLUSIONS: Carcinoma-associated fibroblasts (CAFs) can influence the biological characteristics of a laryngeal carcinoma cell line. These results could lay the foundation for further studies on the role of CAFs in the laryngeal tumor-host microenvironment. OBJECTIVE: CAFs are important contributors to the microenvironment in determining the fate of tumors. The aim of this study was to separate, culture, and identify laryngeal CAFs and investigate their biological influence on the laryngeal carcinoma cell line. METHODS: The primary CAFs and normal fibroblasts (NFs) of the larynx were obtained by tissue culture. The cells were verified according to immunohistochemical and immunofluorescence staining of certain proteins. Conditioned medium (CM) from CAFs and NFs was obtained. Functional assays were performed to test the influence of each CM on laryngeal carcinoma cell lines. RESULTS: Third-passage purified laryngeal CAFs and NFs were successfully attained. The CAFs showed positive staining for vimentin, alpha smooth muscle actin (alpha-SMA), and fibroblast activation protein (FAP). The migration ability of the CAFs increased significantly compared with that of NFs (p < 0.05). CM from CAFs (compared with CM from NFs) stimulated proliferation, migration, and invasion to a greater extent. PMID- 23448355 TI - Lingual artery CTA-guided midline partial glossectomy for treatment of obstructive sleep apnea hypopnea syndrome. AB - CONCLUSION: Midline partial glossectomy guided by lingual artery computed tomographic angiography (CTA) demonstrated a satisfactory safety profile and therapeutic effect for patients with obstructive sleep apnea hypopnea syndrome (OSAHS) due to tongue hypertrophy. OBJECTIVE: To evaluate the efficacy and safety profile of midline partial glossectomy guided by lingual artery CTA for the treatment of OSAHS due to tongue hypertrophy. METHODS: Sixty-seven OSAHS patients with a narrowed airway at the hypopharyngeal region due to tongue hypertrophy underwent uvulopalatopharyngoplasty (UPPP) in combination with midline partial glossectomy. The operation zone was determined according to the anatomic measurement obtained from lingual artery CTA and the resected region was much larger than with conventional midline partial glossectomy. Postoperative complications were closely monitored and sleep condition was followed up for more than 6 months and re-evaluated by polysomnography (PSG). RESULTS: All the operations proceeded uneventfully without any complications, demonstrating a satisfactory safety profile. After a follow-up period of more than 6 months, of the 67 patients undergoing the procedure, 24 were cured and 34 exhibited markedly improved sleep, whereas 9 showed little or no improvement, giving an effectiveness rate of 86.6% for the operation. PMID- 23448356 TI - Diagnostic accuracy of computed tomography findings for patients undergoing salvage total laryngectomy. AB - CONCLUSIONS: Computed tomography (CT) imaging has clear limitations for the diagnosis of cartilage invasion or tumor spread in recurrent laryngeal cancer. Alternative methods of pretreatment assessment are needed for recurrent laryngeal cancer. OBJECTIVES: The diagnosis and staging of recurrent laryngeal cancer, previously treated by radiation therapy (RT), remains challenging. Practically, surgeons need to depend on imaging to predict which patients will have a chance for conservation salvage laryngectomy. The purpose of the present study was to determine the accuracy of preoperative CT performed for recurrent laryngeal carcinoma evaluation following RT. METHODS: This retrospective review identified 32 patients who underwent salvage total laryngectomy after RT from 1998 to 2010. For our radiologic classification of the thyroid cartilage, we analyzed the conditions as normal, sclerosis, invasion, penetration, and extralaryngeal spread and categorized the state of the arytenoids and cricoid into three possible conditions: normal, sclerosis, and destruction. Radiographic findings were correlated with pathology findings. RESULTS: Sensitivity and specificity for the detection of the thyroid cartilage infiltration were 57% and 94%, 50% and 89% for the cricoid cartilage, and 33% and 76% for arytenoid cartilage, respectively. The accuracy of recurrent tumor classification was 59.4%. Three carcinomas were over staged and 10 were under-staged. PMID- 23448357 TI - Celiac disease and juvenile idiopathic arthritis: a still enigmatic crossover. PMID- 23448359 TI - Background-free in vivo time domain optical molecular imaging using colloidal quantum dots. AB - The interest in optical molecular imaging of small animals in vivo has been steadily increased in the last two decades as it is being adopted by not only academic laboratories but also the biotechnical and pharmaceutical industries. In this Spotlight paper, the elements for in vivo optical molecular imaging are briefly reviewed, including contrast agents, i.e., various fluorescent reporters, and the most commonly used technologies to detect the reporters. The challenges particularly for in vivo fluorescence imaging are discussed and solutions to overcome the said-challenges are presented. An advanced imaging technique, in vivo fluorescence lifetime imaging, is introduced together with a few application examples. Taking advantage of the long fluorescence lifetime of quantum dots, a method to achieve background-free in vivo fluorescence small animal imaging is demonstrated. PMID- 23448358 TI - Function and fate of myofibroblasts after myocardial infarction. AB - The importance of cardiac fibroblasts in the regulation of myocardial remodelling following myocardial infarction (MI) is becoming increasingly recognised. Studies over the last few decades have reinforced the concept that cardiac fibroblasts are much more than simple homeostatic regulators of extracellular matrix turnover, but are integrally involved in all aspects of the repair and remodelling of the heart that occurs following MI. The plasticity of fibroblasts is due in part to their ability to undergo differentiation into myofibroblasts. Myofibroblasts are specialised cells that possess a more contractile and synthetic phenotype than fibroblasts, enabling them to effectively repair and remodel the cardiac interstitium to manage the local devastation caused by MI. However, in addition to their key role in cardiac restoration and healing, persistence of myofibroblast activation can drive pathological fibrosis, resulting in arrhythmias, myocardial stiffness and progression to heart failure. The aim of this review is to give an appreciation of both the beneficial and detrimental roles of the myofibroblast in the remodelling heart, to describe some of the major regulatory mechanisms controlling myofibroblast differentiation including recent advances in the microRNA field, and to consider how this cell type could be exploited therapeutically. PMID- 23448360 TI - Repair and follow-up of Tetralogy of Fallot with pulmonary stenosis. AB - Tetralogy of Fallot is the most common cyanotic congenital heart defect. Advances in surgical technique and postoperative care have improved survival which is now very good. Patients now face long-term morbidities such as reduced exercise tolerance and arrthymias. Cardiologists caring for these patients are confronted with decisions regarding best care practices. This article will review the evidence available on repair and postoperative follow-up for patients with Tetralogy of Fallot with pulmonary stenosis. PMID- 23448361 TI - Scaling properties of charge transport in polycrystalline graphene. AB - Polycrystalline graphene is a patchwork of coalescing graphene grains of varying lattice orientations and size, resulting from the chemical vapor deposition (CVD) growth at random nucleation sites on metallic substrates. The morphology of grain boundaries has become an important topic given its fundamental role in limiting the mobility of charge carriers in polycrystalline graphene, as compared to mechanically exfoliated samples. Here we report new insights to the current understanding of charge transport in polycrystalline geometries. We created realistic models of large CVD-grown graphene samples and then computed the corresponding charge carrier mobilities as a function of the average grain size and the coalescence quality between the grains. Our results reveal a remarkably simple scaling law for the mean free path and conductivity, correlated to atomic scale charge density fluctuations along grain boundaries. PMID- 23448362 TI - Contralateral breast cancer risk in BRCA1/2-positive families needs to be adjusted for phenocopy rates particularly in second-degree untested relatives. AB - In the previous issue of Breast Cancer Research, Rhiem and colleagues report contralateral breast cancer risks in relatives of BRCA1/2 mutation carriers as well as those testing negative. The authors quote 25-year risks of 44.1% for BRCA1 and 33.5% for BRCA2. The risks quoted are somewhat lower than might be inferred from previous estimates in BRCA1/2 carriers, which have been as high as 40% at 10 years . This discrepancy may be explained in part by the decision to exclude index cases in which there may have been testing bias to bilateral disease. However, the authors dismiss a second bias of including many non carriers in their analysis as 'putative' carriers. PMID- 23448363 TI - Do the digestive tract symptoms in eating disorder patients represent functional gastrointestinal disorders? AB - BACKGROUND: Gastrointestinal (GI) symptoms are common in patients with eating disorders. The aim of this study was to determine, using factor analysis, whether these GI symptom factors (clusters) in eating disorder patients hold true to the Rome II classification of functional gastrointestinal disorders (FGIDs). METHODS: Inpatients in a specialised eating disorder unit completed the Rome II questionnaire. Data from 185 patients were analysed using factor analysis of 17 questions cited as present in 30% to 70% of the patients. RESULTS: Five factors emerged accounting for 68% of the variance and these were termed: 'oesophageal discomfort', 'bowel dysfunction', 'abdominal discomfort', 'pelvic floor dysfunction', and 'self-induced vomiting'. These factors are significantly related to the Rome II FGID categories of functional oesophageal, bowel and anorectal disorders, and to the specific FGIDs of IBS, functional abdominal bloating, functional constipation and pelvic floor dyssynergia. Both heartburn and chest pain were included in the oesophageal discomfort factor. The 'pelvic floor dysfunction' factor was distinct from functional constipation. CONCLUSIONS: The GI symptoms common in eating disorder patients very likely represent the same FGIDs that occur in non-ED patients. Symptoms of pelvic floor dysfunction in the absence of functional constipation, however, are prominent in eating disorder patients. Further investigation of the items comprising the 'pelvic floor dysfunction' factor in other patient populations may yield useful results. PMID- 23448364 TI - Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging. AB - Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down-regulated in cultured fibroblasts after oxidative stress, and, in vivo, in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging. PMID- 23448365 TI - Serum selenium is low in newly diagnosed Graves' disease: a population-based study. AB - CONTEXT: Selenium deficiency may play an important role in the initiation and progression of autoimmune thyroid disease. OBJECTIVE: To compare serum selenium (s-Se) values in patients with newly diagnosed autoimmune thyroid disease and controls from the Danish population. DESIGN AND SETTINGS: S-Se was measured in triplicate by a fluorimetric method. PARTICIPANTS: Patients with newly diagnosed Graves' disease (GD) (n = 97) or autoimmune overt hypothyroidism (AIH) (n = 96), euthyroid subjects with high serum levels of thyroid peroxidase antibody (TPO-Ab) (TPO-Ab > 1500 U/ml, n = 92) and random controls (n = 830). MAIN OUTCOME MEASURE: Differences in s-Se values. RESULTS: S-Se was lower in patients with GD than in controls (mean (SD), GD: 89.9 MUg/l (18.4); controls: 98.8 MUg/l (19.7), P < 0.01). This was confirmed in a multivariate logistic regression model adjusting for age, sex, mineral supplements, smoking, geographical region and time of sampling (P < 0.01). In a linear model, s-Se was similar in patients with AIH (mean (SD): 98.4 MUg/l (24.9)) and in controls (P = 0.86). In the multivariate model however, s-Se was marginally lower in patients with AIH compared to controls (P = 0.04). There was no significant difference in s-Se between euthyroid participants with high TPO-Ab and random controls (linear: P = 0.97; multivariate: P = 0.27). CONCLUSION: Patients with newly diagnosed GD and AIH had significantly lower s-Se compared with random controls. Our observation supports the postulated link between inadequate selenium supply and overt autoimmune thyroid disease, especially GD. PMID- 23448367 TI - Characterization of two unrelated satellite DNA families in the Colorado potato beetle Leptinotarsa decemlineata (Coleoptera, Chrysomelidae). AB - The Colorado potato beetle (Leptinotarsa decemlineata, family Chrysomelidae),a phytophagous insect, which feeds preferably on potatoes, constitutes a serious pest of this crop and causes extensive damage to tomatoes and egg plants. It has a remarkable ability to develop resistance quickly against insecticides and shows a diversified and flexible life history. Consequently, the control of this pest has become difficult, requiring the development of new alternative biotechnology based strategies. Such strategies require a thorough knowledge of the beetle's genome,including the repetitive DNA. Satellite DNA (stDNA), composed of long arrays of tandemly arranged repeat units, constitutes the major component of heterochromatin and is located mainly in centromeric and telomeric chromosomal regions. We have studied two different unrelated satellite-DNA families of which the consensus sequences were 295 and 109bp in length, named LEDE-I and LEDE-II, respectively.Both were AT-rich (70.8% and 71.6%, respectively). Predictive models of sequence-dependent DNA bending and the study of electrophoretic mobility on non-denaturing polyacrylamide gels have shown that the DNA was curved in both satellite-DNA families. Among other features, the chromosome localization of both stDNAs has been studied. In situ hybridization performed on meiotic and mitoticnuclei showed chromosomes, including the X chromosome, with zero, one, or two stDNAs. In recent years, it has been proposed that the repetitive DNA may play a key role in biological diversification processes. This is the first molecular and cytogenetic study conducted on L. decemlineata repetitive DNA and specifically on stDNA, which is one of the important constituents of eukaryotic genomes. PMID- 23448366 TI - Capsaicin sensitivity in patients with chronic cough- results from a cross sectional study. AB - BACKGROUND: A subgroup of patients with chronic cough is recognised as having airway symptoms resulting exposure to chemicals and scents related to enhanced cough sensitivity to inhaled capsaicin. Sensory hyperreactivity, which has an estimated prevalence of more than 6%, is one possible explanation for the symptoms experienced by these patients. We hypothesized that a number of patients diagnosed with chronic unexplained cough also have coughing provoked by chemical irritants associated with augmented capsaicin cough reaction, but the extent of such a relation is not known. One aim of the present study was to analyse cough sensitivity to inhaled capsaicin in patients with chronic unexplained cough. Another aim was to compare capsaicin sensitivity in individuals with chemically induced coughing (the chemical-sensitive group) to capsaicin sensitivity in those without such chemical sensitivity (non-sensitive group). METHODS: Fifty-six participants from an earlier cross-sectional study of 62 patients with chronic unexplained cough were asked to participate in this study: 33 were chemical sensitive and 23 were non-sensitive. Each participant visited the clinic once and performed a capsaicin inhalation test with one of two inhalation devices. The number of coughs, induced airway symptoms, and spirometry results were recorded. RESULTS: Thirty-nine of the invited patients participated in the study, with 32 in the chemical-sensitive group (21 women, 11 men), and 7 in the non-sensitive group (4 women, 3 men). The chemical-sensitive patients coughed significantly more on inhaling capsaicin, and had significantly more other airway symptoms compared to those in the non-sensitive group. Women coughed significantly more than men after receiving the higher concentration of capsaicin. CONCLUSIONS: Environmental irritants often trigger chronic unexplained cough. The current findings confirm that this sensitivity is related to enhanced capsaicin cough sensitivity and indicates more involvement of airway sensory nerves in the pathophysiology of the disease than in cough without evident trigger factors. PMID- 23448368 TI - Suppression of tumor growth by designed dimeric epidithiodiketopiperazine targeting hypoxia-inducible transcription factor complex. AB - Hypoxia is a hallmark of solid tumors, is associated with local invasion, metastatic spread, resistance to chemo- and radiotherapy, and is an independent, negative prognostic factor for a diverse range of malignant neoplasms. The cellular response to hypoxia is primarily mediated by a family of transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. Under normoxia, the oxygen-sensitive alpha subunit of HIF1 is rapidly and constitutively degraded but is stabilized and accumulates under hypoxia. Upon nuclear translocation, HIF1 controls the expression of over 100 genes involved in angiogenesis, altered energy metabolism, antiapoptotic, and pro-proliferative mechanisms that promote tumor growth. A designed transcriptional antagonist, dimeric epidithiodiketopiperazine (ETP 2), selectively disrupts the interaction of HIF1alpha with p300/CBP coactivators and downregulates the expression of hypoxia-inducible genes. ETP 2 was synthesized via a novel homo-oxidative coupling of the aliphatic primary carbons of the dithioacetal precursor. It effectively inhibits HIF1-induced activation of VEGFA, LOX, Glut1, and c-Met genes in a panel of cell lines representing breast and lung cancers. We observed an outstanding antitumor efficacy of both (+/-)-ETP 2 and meso-ETP 2 in a fully established breast carcinoma model by intravital microscopy. Treatment with either form of ETP 2 (1 mg/kg) resulted in a rapid regression of tumor growth that lasted for up to 14 days. These results suggest that inhibition of HIF1 transcriptional activity by designed dimeric ETPs could offer an innovative approach to cancer therapy with the potential to overcome hypoxia-induced tumor growth and resistance. PMID- 23448370 TI - A new record and description of a new species of the genus Thrips, with an updated key to species from Iran. AB - An illustrated key is provided to distinguish the 26 species of the genus Thrips L. (Thripidae: Thripinae) recorded from Iran. Thrips alavii Mirab-balou, Tong & Chen, sp. n. is described and illustrated. Thrips alliorum (Priesner) is newly recorded for the fauna of Iran. A checklist is provided for all recorded species in this genus from Iran, with information on the geographical distribution for each species. PMID- 23448369 TI - A multicenter observational safety study in Swedish children and adolescents using insulin detemir for the treatment of type 1 diabetes. AB - This 26-wk observational study in children and adolescents with type 1 diabetes (T1D) in Sweden investigated the safety and efficacy of insulin detemir (IDet) in newly diagnosed (ND) patients and those with established diabetes (ED) switching to IDet. A total of 159 patients initiated IDet as part of basal-bolus therapy, 59 in the ND stratum (mean age 9.7 yr) and 97 in the ED stratum (mean age 12.5 yr). The primary outcome measure was the incidence of severe adverse drug reactions; just one major hypoglycemic event occurred in a patient in the ND stratum during the study and one patient was withdrawn due to injection-site reactions. All other events were classified as mild. In the ED stratum, there was a reduction in hypoglycemic events in the 4 wk prior to study end from baseline (mean reduction of 2.46 events, not significant) and a significant reduction in nocturnal hypoglycemia (mean reduction of 2.24 events, p = 0.0078). Glycemic control improved in the ND stratum as expected and, in the ED stratum, there was no significant change in HbA1c from baseline (mean reduction of -0.45%). At study end, mean daily IDet doses were 0.39 U/kg (ND) and 0.54 U/kg (ED). Weight increased by 5.7 and 2.0 kg in the ND and ED strata, respectively, and was within the normal limits for growing children. IDet provided good glycemic control and was well tolerated, with a reduced risk of nocturnal hypoglycemia in a heterogeneous cohort of children and adolescents with T1D. PMID- 23448371 TI - Partial ear canal ablation and lateral bulla osteotomy in rabbits. AB - Six lop rabbits were presented with clinical signs of otitis media or externa. The presence of disease was confirmed by computerized tomography examination, with two rabbits suffering from bilateral disease. The rabbits were anaesthetized and underwent surgery of the affected bulla. Rabbits with bilateral disease had a minimum of 2 weeks between procedures. A single vertical incision was made over the base of the vertical canal, which was bluntly dissected free from surrounding tissue. The ventral portion of the vertical canal was removed and a lateral bulla osteotomy was performed. The mucosa at the base of the dorsal vertical canal was apposed and the aural cartilage sutured to form a blind-ending pouch open at the pretragic incisure. Histopathological samples taken from the dorsal margin of the vertical canal yielded subtle and non-specific changes in the six samples submitted. All rabbits were discharged within 48 hours of surgery. The cosmetic outcome was excellent with animals retaining visually normal aural anatomy. The partial ear canal ablation/lateral bulla osteotomy procedure is quick and has a good cosmetic result when performed in rabbits. PMID- 23448372 TI - Inhibition of cardiac inward rectifier currents by cationic amphiphilic drugs. AB - Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships. PMID- 23448373 TI - Mid-term outcomes of the Helex septal occluder for percutaneous closure of secundum atrial septal defects. AB - BACKGROUND: The HELEX Septal Occluder (HSO) was approved by the Food and Drug Administration for closure of secundum atrial septal defects (ASD) in 2006. However, little mid-term follow-up information is available. The object of this study was to examine mid-term outcomes after HSO implantation METHODS: A retrospective chart review was performed on the first 74 patients who underwent ASD closure with the HSO between 4/00-10/04. Only patients who left the catheterization laboratory after successful implantation and had a minimum follow up of 5 years were selected for analysis. RESULTS: Thirty-three patients met entry criteria. At implantation the mean age was 10.9 years and the median ASD size was 15.1 mm. At a median follow-up of 88 months, 26 patients had complete ASD closure, 6 had trivial left-right shunts, and 1 had a significant residual shunt having a reintervention. Fluoroscopy, performed in 27 patients revealed a frame fracture in 3 patients (9%), all of whom were asymptomatic and had effective ASD closure. All 3 devices were 30 mm or 35 mm HSO and were left in place. One patient developed first-degree heart block and remained asymptomatic with no progression. There were no instances of late device embolization, cardiac perforation, erosion, or death. CONCLUSIONS: Following successful implantation, HSO results in effective closure of secundum ASD in mid-term follow-up. Late complications appear to be rare with the exception of frame fracture, which in this series did not result in clinical sequelae. PMID- 23448374 TI - Eyebrow alopecia: centrofacial trichoblastomatosis. PMID- 23448376 TI - Chondroblastoma associated with aneurysmal cyst of the navicular bone: a case report. AB - Chondroblastoma is a rare tumor. It is usually benign; however, it can have an aggressive course before or after operative treatment, even resulting in pulmonary metastases. The foot is a rare location for chondroblastoma, and to our knowledge, chondroblastoma occurring in the navicular bone has not been reported previously in the English literature. We describe a case of navicular chondroblastoma case associated with an aneurysmal bone cyst. Treatment consisted of aggressive curettage, phenolization, and bone allograft. The patient was able to resume normal activities after treatment, and there was no recurrence of the chondroblastoma during a follow-up of 3 years. PMID- 23448375 TI - The utility of copy number variation (CNV) in studies of hypertension-related left ventricular hypertrophy (LVH): rationale, potential and challenges. AB - The ultimate goal of human genetics is to understand the role of genome variation in elucidating human traits and diseases. Besides single nucleotide polymorphism (SNP), copy number variation (CNV), defined as gains or losses of a DNA segment larger than 1 kb, has recently emerged as an important tool in understanding heritable source of human genomic differences. It has been shown to contribute to genetic susceptibility of various common and complex diseases. Despite a handful of publications, its role in cardiovascular diseases remains largely unknown. Here, we deliberate on the currently available technologies for CNV detection. The possible utility and the potential roles of CNV in exploring the mechanisms of cardiac remodeling in hypertension will also be addressed. Finally, we discuss the challenges for investigations of CNV in cardiovascular diseases and its possible implications in diagnosis of hypertension-related left ventricular hypertrophy (LVH). PMID- 23448377 TI - Solute and solvent dynamics in confined equal-sized aqueous environments of charged and neutral reverse micelles: a combined dynamic fluorescence and all atom molecular dynamics simulation study. AB - Here a combined dynamic fluorescence and all-atom molecular dynamics simulation study of aqueous pool-size dependent solvation energy and rotational relaxations of a neutral dipolar solute, C153, trapped in AOT (charged) and IGPAL (neutral) reverse micelles (RMs) at 298 K, is described. RMs in simulations have been represented by a reduced model where SPC/E water molecules interact with a trapped C153 that possesses realistic charge distributions for both ground and excited states. In large aqueous pools, measured average solvation and rotation rates are smaller for the neutral RMs than those in charged ones. Interestingly, while the measured average solvation and rotation rates increase with pool size for the charged RMs, the average rotation rates for the neutral RMs exhibit a reverse dependence. Simulations have qualitatively reproduced this experimental trend and suggested interfacial location for the solute for all cases. The origin for the subnanosecond Stokes shift dynamics has been investigated and solute interface interaction contribution quantified. Simulated layer-wise translational and rotational diffusions of water molecules re-examine the validity of the core shell model and provide a resolution to a debate regarding the origin of the subnanosecond solvation component in dynamic Stokes shift measurements with aqueous RMs but not detected in ultrafast IR measurements. PMID- 23448378 TI - Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage? AB - AIM: Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. RESULTS: CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P < 0.001 in all cases). Circulating levels of pro-inflammatory cytokine TNF-alpha were significantly increased in rats with liver fibrosis as compared with normal rats, while symbiotic treatment normalized the plasma levels of TNF alpha and significantly enhanced anti-inflammatory cytokine IL 10. TNF-alpha, TGF beta, TLR4, TLR2, iNOS and alpha-SMA mRNA expression in the liver were up regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. CONCLUSIONS: Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis. PMID- 23448379 TI - Transoral robotic surgery for large mixed laryngocoele. AB - BACKGROUND: A laryngocoele is an abnormal dilatation of Morgagni's ventricle in direct communication with the laryngeal lumen. Surgical excision through a cervical approach is traditionally considered the treatment of choice for large (external and mixed) laryngocoeles. This paper describes the first reported case of a large mixed laryngocoele treated with transoral robotic surgery without cervical incisions. METHOD: A 69-year-old female underwent transoral robotic surgery for the excision of a large mixed left laryngocoele. The surgery was performed using the da Vinci S surgical robotic system (Intuitive Surgical, Sunnyvale, California, USA). RESULTS: No complications were observed and the patient was discharged 2 days post-operation. CONCLUSION: Transoral robotic surgery enabled accurate dissection with complete removal of the large mixed laryngocoele via a minimally invasive approach. The advantages of transoral robotic surgery over other techniques for laryngocoele excision are discussed. PMID- 23448380 TI - The multiple faces of the decidual natural killer cell. AB - The decidual NK (dNK) cell is called on to support placental growth by providing an array of growth factors that directly transform the spiral artery and direct trophoblast invasion. Successful transformation is dependent upon adequate stimulation paradoxically stimulating the cell for placental support rather than cytotoxicity. With the identification of its supportive role, the presence of an intact cytotoxic mechanism has been confusing. Investigators have found that the cell remains fully capable of cytotoxic responses particularly in response to pathogen-specific signals. We postulate a dual threshold model where moderate stimulation results in release of stimulatory factors supporting placentation while intense stimulation, particularly triggered through pathogen-specific receptors, restores the cell to its protective, cytotoxic, role. Individual dNK cells mature attaining the capacity to respond to the delivery of cognate signals. The process, known as 'licensing' tunes responsiveness to the degree to which stochastically selected inhibitory receptors block cytotoxic response to self. A changing licensing milieu within the decidua may result in altered and unsuitable receptor expression. We postulate that a heterogeneous population of dNK cells where cells inappropriately licensed for the milieu contributes to pathology. PMID- 23448381 TI - Unraveling the 'TGF-beta paradox' one metastamir at a time. AB - Transforming growth factor beta (TGF-beta) has received noteworthy attention in the recent past due to its unique characteristic of functionally switching roles from tumor suppressor to metastasis promoter. To uncover the black box surrounding the mechanisms of TGF-beta, Taylor and colleagues performed global miRNA expression analyses using a murine mammary carcinoma progression model. They discovered multiple miRNA regulated by TGF-beta and matrix stiffness. Focusing on miR-181a, they uncovered an intricate pathway regulating breast cancer metastasis that sheds new insight into metastasis regulation that may prove useful in clinical settings. PMID- 23448382 TI - Cost and burden of gastroesophageal reflux disease among patients with persistent symptoms despite proton pump inhibitor therapy: an observational study in France. AB - BACKGROUND: Gastrointestinal reflux disease (GERD) is a common disorder that negatively impacts health-related quality of life (HRQL) and work productivity. Many patients have only a partial response to proton pump inhibitor (PPI) therapy and continue to experience GERD symptoms despite optimized treatment. This observational study aimed to provide information on symptoms, HRQL, resource usage, costs and treatment pathways associated with partial response to PPI therapy in French patients with GERD. METHODS: Patients with partial response to PPI therapy, defined as persistent GERD symptoms >=3 days/week despite optimized treatment with a PPI, were recruited for this 12-month observational study. GERD symptoms, HRQL, work productivity and resource use were assessed by patient surveys. Costs were calculated based on lost work productivity and resource use. RESULTS: The patient population (n=262; mean age, 54 years; 40% men) carried a significant symptom burden, with 98% of patients having moderate-to-severe GERD symptoms and 65% of patients experiencing daily symptoms at baseline. HRQL and work productivity were significantly impaired, with a greater degree of impairment in patients with higher symptom burden. The mean total cost per patient over the 12-month follow-up period was ?5237, of which ?4674 (89%) was due to lost work productivity. CONCLUSIONS: Partial response to PPI therapy for GERD is associated with a high symptom burden, significant impairment of HRQL and work productivity, and substantial GERD-related costs. PMID- 23448383 TI - Visible light-induced antibacterial activity of metaloxide nanoparticles. AB - OBJECTIVE: The purpose of this article was to review studies that use visible light instead of dangerous ultraviolet (UV) radiation, for inducing antibacterial properties in metal oxide nanoparticles (NPs). BACKGROUND DATA: Metal oxide NPs such as ZnO, CuO, and TiO2 are frequently studied for their antibacterial effects, based on their capability to generate reactive oxygen species (ROS) in their water suspensions, following UV light absorption. METHODS: Research articles on shifting metal oxide NPs absorption into the visible light region, published up to 2011, were retrieved from library sources, as well as PubMed and MEDLINE((r)) databases. RESULTS: The studies indicated that doping metaloxide NPs with transition metals ions, or attaching the metal oxide nanoparticles to an organic molecule, enhanced their activity in the visible and near infrared (NIR) range. Moreover, ZnO and TiO2 nanoparticles were found to have an absorption peak in UV-A, with a marked absorption in the blue region. CONCLUSIONS: It is possible to extend the absorption region of metal oxide NPs to the red/NIR, increasing their antibacterial activity without inducing damage to tissues and cells. PMID- 23448384 TI - High-temperature and pressure-induced ferroelectricity in hydrogen-bonded supramolecular crystals of anilic acids and 2,3-di(2-pyridinyl)pyrazine. AB - Cocrystallization of anilic acids (H2xa) and 2,3-di(2-pyridinyl)pyrazine (dppz) affords a variety of molecular geometries, including hydrogen-bonding and supramolecular structures. Proton-transferred 1:1 salts of [H-dppz][Hca] and [H dppz][Hba] (H2ca = chloranilic acid, H2ba = bromanilic acid) were found to host room-temperature ferroelectricity with a spontaneous polarization of 3-4 MUC/cm(2) along the hydrogen-bonded chains. Compared with the Curie points of other supramolecular ferroelectrics, those of the salts are relatively high (402 K and >420 K, respectively) because of the elongated hydrogen bonds, which stabilize the proton-ordered state against thermal agitation. In addition to the ferroelectric black (alpha) form, dppz and H2ba gave two different crystal forms with a 2:3 ratio: the brown beta form of [H(1.5)-dppz]2[Hba]3 and the brownish red gamma form of [H-dppz]2[Hba]2[H2ba]. Mixed solutions of dppz with the less acidic fluoranilic acid (H2fa) exhibit valence instability; the H2fa molecules remain mostly neutral in absolute ethanol, whereas methanol (MeOH) solution apparently increases the deprotonated Hfa(-) content. Crystallizations of these solutions gave a neutral [dppz][H2fa] cocrystal and ionic [H-dppz(+)][Hfa( )].MeOH salt, respectively. The ferroelectricity induced by a modest hydrostatic pressure corroborates the conclusion that the ionic state with a dipolar [H dppz(+)][Hfa(-)] chain is energetically close to the nonpolar neutral ground state of the [dppz][H2fa] crystal. PMID- 23448385 TI - Overexpression and secretion of the soluble CTLA-4 splice variant in various autoimmune diseases and in cases with overlapping autoimmunity. AB - AIM: To explore the potential genetic association of CTLA-4 Exon1 +49A/G and 3'UTR (AT)(n) to susceptibility to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and overlapping (OP) autoimmunity; affected with more than one autoimmune disease. Expression of two major CTLA-4 isoforms; full length (mCTLA 4) and soluble (sCTLA-4) were explored in all subjects. A total of 680 age/gender/ethnically matched Kuwaitis were recruited and polymerase chain reaction (PCR)-fragment analysis was employed for genotyping both markers. mCTLA 4 and sCTLA-4 mRNA expression were analyzed using quantitative real time-PCR. The enzyme-linked immunosorbent assay (ELISA) was used to screen sCTLA-4 in all subjects' sera. RESULTS: Only two CTLA-4 3'UTR (AT)(n) allelotypes; (AT)(15) and (AT)(6) were detected. The heterozygous (AT)(15/6) genotype confers protectivity rather than susceptibility to SLE (p=0.01, odds ratio=0.43, and confidence interval=0.21-0.86). No significant association was observed between Exon 1 +49A/G and any of the tested diseases. A consistently high serum sCTLA-4 level was observed in RA (6.8 ng/mL, p=0.005), SLE (6.34 ng/mL, p=0.007), and OP (8.75 ng/mL, p=0.012) compared to healthy control. A significant increase in the expression of sCTLA-4 mRNA was observed in OP (p=0.05) and SLE (p=0.047), while a significant increase in the expression of mCTLA-4 (p=0.01) was observed only in OP. CONCLUSION: The present study is the first to report a statistically significant association between OP and serum sCTLA-4. The novelty of our study is the significance of CTLA-4 in the pathogenesis of OP besides SLE and RA. PMID- 23448386 TI - A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer. AB - PURPOSE: This study describes practitioner knowledge and practices related to BRCA testing and management and explores how training may contribute to practice patterns. METHODS: A survey was mailed to all BRCA testing providers in Florida listed in a publicly available directory. Descriptive statistics characterized participants and their responses. RESULTS: Of the 87 respondents, most were community-based physicians or nurse practitioners. Regarding BRCA mutations, the majority (96%) recognized paternal inheritance and 61% accurately estimated mutation prevalence. For a 35-year-old unaffected BRCA mutation carrier, the majority followed national management guidelines. However, 65% also recommended breast ultrasonography. Fewer than 40% recognized the need for comprehensive rearrangement testing when BRACAnalysis((r)) was negative in a woman at 30% risk. Finally, fewer than 15% recognized appropriate testing for a BRCA variant of uncertain significance. Responses appeared to be positively impacted by presence and type of cancer genetics training. CONCLUSIONS: In our sample of providers who order BRCA testing, knowledge gaps in BRCA prevalence estimates and appropriate screening, testing, and results interpretation were identified. Our data suggest the need to increase regulation and oversight of genetic testing services at a policy level, and are consistent with case reports that reveal liability risks when genetic testing is conducted without adequate knowledge and training. PMID- 23448387 TI - Molecular prenatal diagnosis of autosomal recessive spinal muscular atrophies using quantification polymerase chain reaction. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. SMA is the second most common neuromuscular disorder and a common cause of infant disability and mortality. About 95% of patients have a homozygous deletion of exon7 in the survival motor neuron 1 gene. About 50 fetuses from 47 Chinese couples at risk of having an affected child were recruited in this study. The homozygous absence of exon7 of the survival motor neuron 1 gene was detected by both polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the quantitative PCR method. Short tandem repeat microsatellite markers linked to the survival motor neuron 1 gene were used to do linkage analysis. In conclusion, the quantitative PCR method results were as reliable as the results using the PCR RFLP method in prenatal diagnosis. The quantitative PCR method can give more information on SMA carrier status that coincides with the result of linkage analysis. PMID- 23448388 TI - ALOX5 is associated with tuberculosis in a subset of the pediatric population of North China. AB - BACKGROUND: Genetic factors are involved in the etiology of Mycobacterium tuberculosis infection. Recently, ALOX5 has been identified as a candidate gene for tuberculosis (TB) susceptibility. We investigated whether an association between ALOX5 and TB exists in a Chinese pediatric population from northern China. METHODS: We conducted a case-control study comprising 488 individuals aged 2 months to 17 years by genotyping 18 tag-single-nucleotide polymorphisms (SNPs) from the ALOX5 gene. The tag-SNPs were selected from the international HapMap project. An Illumina BeadXpress Scanner was utilized for genotyping, supported by the high-density BeadArray technology in combination with an allele-specific extension, adapter ligation, and amplification assay. Statistical analyses were performed to determine correlations between genetic variation and disease. RESULTS: Our study is the first to show that ALOX5 is associated with susceptibility to pediatric TB in a subset of children in northern China. The rs2115819 T allele of ALOX5 presents a risk factor for childhood TB disease. PMID- 23448389 TI - Surgical technique of a vertical sleeve gastrectomy in mice. AB - BACKGROUND/AIMS: The prevalence of morbid obesity is increasing. In failing of conservative methods to weight reduction, one effective surgical option is the sleeve gastrectomy. Aim of this study was to show the feasibility of simplified surgical techniques of sleeve gastrectomy in normal weight mice as base model for surgery in super-obese mice. METHODS: In an animal study, 15 male C57/Bl6 mice were randomized into two groups of 5 (1) and 10 animals (2) to undergo sleeve gastrectomy with antidromic suture course. The sutures of the tubular stomach were performed from aborally to orally in group 1 and from orally to aborally in group 2. Mean body weight was 20.8 +/- 0.6 g. Body weight was recorded daily for 14 days after surgery and weekly for further 10 weeks. RESULTS: In our study, 12 of 15 animals survived the procedure and follow-up period. Out of group 1, two mice died because of leakage of the gastric sleeve with diffuse peritonitis. Out of group 2, one animal died seven weeks after surgery due to an abscess in the abdominal wall. Regarding the weight charts, there was a decrease until the third postoperative day with continuous increase thereafter. CONCLUSION: The presented model of sleeve gastrectomy is feasible in mice with low mortality and tolerable morbidity. The simplified model enables short operation times, which is decisive especially in obese mice. PMID- 23448390 TI - Short- and medium-chain chlorinated paraffins in air and soil of subtropical terrestrial environment in the pearl river delta, South China: distribution, composition, atmospheric deposition fluxes, and environmental fate. AB - Research on the environmental fate of short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) in highly industrialized subtropical areas is still scarce. Air, soil, and atmospheric deposition process in the Pearl River Delta of South China were investigated, and the average SCCP and MCCP concentrations were 5.2 MUg/sampler (17.69 ng/m(3)) and 4.1 MUg/sampler for passive air samples, 18.3 and 59.3 ng/g for soil samples, and 5.0 and 5.3 MUg/(m(2)d) for deposition samples, respectively. Influenced by primary sources and the properties of chlorinated paraffins (CPs), a gradient trend of concentrations and a fractionation of composition from more to less industrialized areas were discovered. Intense seasonal variations with high levels in summer air and winter deposition samples indicated that the air and deposition CP levels were controlled mainly by the vapor and particle phase, respectively. Complex environmental processes like volatilization and fractionation resulted in different CP profiles in different environment matrixes and sampling locations, with C(10-11) C(l6-7) and C(14) C(l6-7), C(10-12) C(l6-7) and C(14) C(l6-8), and C(11-12) C(l6-8) and C(14) C(l7-8) dominating in air, soil, and atmospheric deposition, respectively. Shorter-chain and less chlorinated congeners were enriched in air in the less industrialized areas, while longer-chain and higher chlorinated congeners were concentrated in soil in the more industrialized areas. This is suggesting that the gaseous transport of CPs is the dominant mechanism responsible for the higher concentrations of lighter and likely more mobile CPs in the rural areas. PMID- 23448391 TI - Fragmentation of an aflatoxin-like gene cluster in a forest pathogen. AB - Plant pathogens use a complex arsenal of weapons, such as toxic secondary metabolites, to invade and destroy their hosts. Knowledge of how secondary metabolite pathways evolved is central to understanding the evolution of host specificity. The secondary metabolite dothistromin is structurally similar to aflatoxins and is produced by the fungal pine pathogen Dothistroma septosporum. Our study focused on dothistromin genes, which are widely dispersed across one chromosome, to determine whether this unusual distributed arrangement evolved from an ancestral cluster. We combined comparative genomics and population genetics approaches to elucidate the origins of the dispersed arrangement of dothistromin genes over a broad evolutionary time-scale at the phylum, class and species levels. Orthologs of dothistromin genes were found in two major classes of fungi. Their organization is consistent with clustering of core pathway genes in a common ancestor, but with intermediate cluster fragmentation states in the Dothideomycetes fungi. Recombination hotspots in a D. septosporum population matched sites of gene acquisition and cluster fragmentation at higher evolutionary levels. The results suggest that fragmentation of a larger ancestral cluster gave rise to the arrangement seen in D. septosporum. We propose that cluster fragmentation may facilitate metabolic retooling and subsequent host adaptation of plant pathogens. PMID- 23448392 TI - Detecting gene expression in buccal mucosa in subjects with asthma versus subjects without asthma. AB - BACKGROUND: Differences in mRNA expression for inflammatory markers have been observed between subjects with asthma vs. controls and in relation to corticosteroid response. However, these studies utilized methods (e.g., bronchoscopy) that are too invasive to be used routinely in children and in the clinic. The primary purpose of this study was to determine the feasibility of obtaining RNA of adequate quantity and quality from buccal mucosa of children and adults for gene expression studies. Secondly, this study aimed to determine whether gene expression patterns in buccal mucosa are similar to those that have been observed in respiratory epithelium. METHODS: We enrolled 94 subjects with and without asthma between 5 and 54 years of age. Relative gene expression in buccal mucosa was determined with quantitative RT-PCR for the following genes: CCL2, EDN1, FKBP5, IL8, IFNAR2, NFKB1, RELA, SERPINB2, DENND1B, HRH1, ICAM1, ORMDL3, NR3C1, CLCA1, CRHR1, MUC5B, FCER2, POSTN, GAPDH, PPIA. RESULTS: mRNA Expression of the following genes was detected in buccal mucosa: CCL2, EDN1, FKBP5, IL8, IFNAR2, NFKB1, RELA, SERPINB2, DENND1B, HRH1, ICAM1, ORMDL3, NR3C1, GAPDH, PPIA. HRH1 was differentially expressed in adults with asthma vs. controls (p = 0.04), and EDN1 was differentially expressed in children with asthma vs. controls 12-18 years old (p = 0.03). A similar trend for HRH1 was observed in children 12-18 years old. CONCLUSIONS: Buccal mucosa sampling is a reliable method for detecting changes in gene expression in patients with asthma. This non invasive technique may serve as a valuable tool for diagnosing asthma and evaluating therapeutic response. PMID- 23448393 TI - The "Glucositter" overnight automated closed loop system for type 1 diabetes: a randomized crossover trial. AB - BACKGROUND: Tight glucose control is needed to prevent long-term diabetes complications; this is hindered by the risk of hypoglycemia, especially at night. OBJECTIVE: To assess the safety and efficacy of the closed-loop MD-Logic Artificial Pancreas (MDLAP), controlling nocturnal glucose levels in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: This was a randomized, multicenter, multinational, crossover trial conducted in Slovenia, Germany, and Israel. Twelve patients with T1DM (age 23.8 +/- 15.6 yr; duration of diabetes 13.5 +/- 11.9 yr; A1c 8.1 +/- 0.8%, mean +/- SD) were randomly assigned to participate in two sequential overnight sessions: one using continuous subcutaneous insulin infusion (CSII) and the other, closed-loop insulin delivery by MDLAP. The primary outcome was the number of hypoglycemic events below 63 mg/dL. Endpoints analyses were based on sensor glucose readings. RESULTS: Three events of nocturnal hypoglycemia occurred during CSII and none during the closed loop control (p = 0.18). The percentage of time spent in the near normal range of 63-140 mg/dL was significantly higher in the overnight closed-loop sessions [76% (54-85)] than during CSII therapy [29% (11-44)] [p = 0.02, median (interquartile range)]. The mean overnight glucose level was reduced by 36 mg/dL with closed loop insulin delivery (p = 0.02) with a significantly less glucose variability when compared with the CSII nights (p < 0.001). CONCLUSION: The results of this study demonstrate the ability of the MDLAP to safely improve overnight glucose control without increased risk of hypoglycemia in patients with T1DM at three different national, geographic, and clinical centers (ClinicalTrials.gov number, NCT 01238406). PMID- 23448394 TI - Expression of interleukin-17 associated with disease progression and liver fibrosis with hepatitis B virus infection: IL-17 in HBV infection. AB - BACKGROUND/OBJECTIVES: As a proinflammatory cytokine, interleukin-17 (IL-17) contributes to the inflammation of many autoimmune diseases. We examined IL-17 levels in serum and tissues from patients with chronic hepatitis B virus infection (HBV), and especially evaluated the role of IL-17 in the pathogenesis and progression of liver fibrosis. MATERIALS AND METHODS: Whole venous blood was obtained from four patient groups: chronic hepatitis B (CHB, n = 47), liver cirrhosis (LC, n = 49), primary hepatocellular carcinoma (PHC, n = 44), chronic liver failure (CLF, n = 33), and a normal control group (n = 20). HBsAg was positive in all patients. Liver biopsy samples were acquired from asymptomatic HBsAg carriers (ASC, n = 35), CHB (n = 57), and LC (n = 31) patients. We performed ELISA to measure IL-17 levels in serum samples, and used reverse RT-PCR to measure IL-17 mRNA levels in peripheral blood mononuclear cells (PBMC). IL-17 protein expression was detected in liver biopsy tissues by immunohistochemistry. RESULTS: Compared to normal controls, serum IL-17 protein and mRNA levels were significantly higher in the four infection groups. LC patients exhibited the highest serum IL-17 and PBMC mRNA levels. No significant differences were found between the other three groups. High levels of IL-17 were also observed in tissues from CHB and LC patients, compared to ASC. IL-17 expression was mainly located in the portal area and was positively correlated with inflammation grade and fibrosis stage. CONCLUSIONS: IL-17 expression was found to be increased with increasing degrees of liver fibrosis. This suggests that IL-17 may not only induce the inflammation, but also contribute to disease progression and chronicity. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5306959258322482. PMID- 23448395 TI - Does the z-score value of the abdominal aorta predict recoarctation in an infant? AB - OBJECTIVE: We evaluated left ventricular dimensions and aortic arch z-scores in infants who underwent balloon angioplasty (BAP) or surgery for coarctation of aorta (CoA). We searched for risk factors predicting recoarctation. PATIENTS: Between 2007-2011, 27 male and 17 female infants (mean age 2.93 +/- 4.78 months, range 2 days-24 months) with CoA were evaluated. Left ventricular dimensions, systolic functions, mitral and aortic annuli, transverse aortic arch, isthmus, coarctation site, and diaphragmatic aorta measurements were done and z-scores were determined before intervention. RESULTS: Six patients underwent primary operation, 38 patients had BAP (86.4%). Associated cardiac pathologies in operated patients were double outlet right ventricle (n = 2), atrioventricular septal defect (n = 1), Ebstein's anomaly (n = 1), arch hypoplasia (n = 2). Twelve patients (27.2%) had simple coarctation. Ventricular septal defect was the most frequent associated cardiac pathology (n = 20, 45.4%). The patients were followed for 10.22 +/- 8.21 months. Among 33 primary successful BAP's, 14 had recoarctation (42%). Eleven patients were primarily operated (including 5 with unsuccessful BAP), two had recoarctation (18%). Abdominal and transverse aorta values and z-scores were significantly lower in the recoarctation group (7.15 +/- 2.12 mm and 6.07 +/- 1.86 mm respectively in the "no-recoarctation group"; vs. 5.53 +/- 0.75 mm and 4.94 +/- 1.53 mm in the "recoarctation group" P <.05). Abdominal aorta z-score of 0.42 was 88.9% sensitive and 53.8% specific to predict recoarctation (area under ROC curve: 0.618-0.902, P <.05). CONCLUSION: Although BAP for native coarctation is still a controversial treatment option due to frequent restenosis rates, abdominal aorta z-score of 0.42 could correctly eliminate recoarctation in 89% of these cases. This cutoff value might help us choose patients for primary BAP and decrease the recoarctation rate after BAP. PMID- 23448396 TI - Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose-response study. AB - OBJECTIVE: To analyse the endocrine response in relation to the Delta-4 and Delta 5 pathways of ovarian steroidogenesis after different doses of human chorionic gonadotrophin (hCG) supplementation to recombinant FSH from Day 1 of controlled ovarian stimulation for IVF. DESIGN: A randomized dose-response pilot study. PATIENTS: A total of 62 IVF patients aged 25-37 years with regular cycles and FSH <12 IU/l were treated with a fixed dose of rFSH 150 IU/day and randomized to four hCG dose groups: Dose 0: 0 IU/day, Dose 50: 50 IU/day, Dose 100: 100 IU/day and Dose 150: 150 IU/day. RESULTS: A significant hCG dose-dependent incremental increase was found for progesterone (49-160%), 17-OH-progesterone (223-614%), androstenedione (91-340%) and testosterone (95-338%) from Dose 0 to Dose 150, respectively. Dehydroepiandrosterone (DHEA) showed minor changes during stimulation and no differences between the groups. The highest oestradiol concentrations were observed in Dose 100 and Dose 150. Sex hormone-binding globulin (SHBG) increased similarly in all groups at the end of stimulation. No difference was observed for anti-mullerian hormone (AMH) concentration between the groups, but a 50% decline from the start to the end of the stimulation was found. CONCLUSION: Supplementation with hCG resulted in a clear dose-related response for androgens, progesterone and 17-OH-progesterone. Oestradiol concentration reached maximum levels with an hCG dose of 100 IU/day, suggesting saturation of aromatase function. No difference between the groups was observed for DHEA, supporting that the stimulatory effects of hCG doses on androgens and oestrogen production were mainly induced via the Delta-5 pathway. SHBG, being a biomarker of oestrogen/androgen balance, was not changed by increasing hCG. PMID- 23448397 TI - Screening for hepatitis B and C in first-generation Egyptian migrants living in the Netherlands. AB - BACKGROUND: Egypt has high prevalence of hepatitis C virus (HCV) infection and intermediate prevalence of hepatitis B virus (HBV) infection; however, infection prevalence among Egyptian migrants is unknown. Considering the asymptomatic onset and development of disease in chronically-infected patients, many may remain undiagnosed. AIMS: To evaluate an HCV- and HBV-screening programme designed to identify undetected infections among first-generation Egyptian migrants in Amsterdam, the Netherlands. METHODS: In 2009 and 2010, viral hepatitis educational and screening sessions were established at Egyptian meeting places. Data regarding demographics and HCV risk factors were collected. Chronically infected participants were referred and followed up. Phylogenetic analyses were used to ascertain the geographic origin of infections. RESULTS: Eleven of 465 (2.4%; 95% CI = 1.3-4.2%) migrants had HCV antibodies; 10/11 were HCV RNA positive. All had genotype 4a, and strains were typical of those of Egypt and the Middle East. Older age and exposure to parenteral antischistosomal therapy (PAT) were significantly associated with HCV. Anti-HBc prevalence was 16.8% (95% CI = 13.7-20.4%); HBsAg prevalence was 1.1% (95% CI = 0.5-2.5%). All had genotype D, typical of those of the Middle East. Most (9/10 HCV; 3/5 HBV) chronic infections were newly diagnosed; four of the HCV-infected individuals started treatment. CONCLUSIONS: Anti-HCV and HBsAg prevalence among Egyptian migrants was lower compared with the general Egyptian population, but higher than the general population of Western countries. Phylogenetic analyses suggest that all infections were from the region of origin. HCV-screening programmes should target first-generation Egyptian migrants, especially those of older age and those who received PAT. PMID- 23448399 TI - Blood MUC-18/MCAM expression in patients with melanoma: a suitable marker of poor outcome. PMID- 23448398 TI - Genetic variants and their interactions in disease risk prediction - machine learning and network perspectives. AB - A central challenge in systems biology and medical genetics is to understand how interactions among genetic loci contribute to complex phenotypic traits and human diseases. While most studies have so far relied on statistical modeling and association testing procedures, machine learning and predictive modeling approaches are increasingly being applied to mining genotype-phenotype relationships, also among those associations that do not necessarily meet statistical significance at the level of individual variants, yet still contributing to the combined predictive power at the level of variant panels. Network-based analysis of genetic variants and their interaction partners is another emerging trend by which to explore how sub-network level features contribute to complex disease processes and related phenotypes. In this review, we describe the basic concepts and algorithms behind machine learning-based genetic feature selection approaches, their potential benefits and limitations in genome-wide setting, and how physical or genetic interaction networks could be used as a priori information for providing improved predictive power and mechanistic insights into the disease networks. These developments are geared toward explaining a part of the missing heritability, and when combined with individual genomic profiling, such systems medicine approaches may also provide a principled means for tailoring personalized treatment strategies in the future. PMID- 23448400 TI - Stereochemistry of 1,2-elimination and proton-transfer reactions: toward a unified understanding. AB - Many mechanistic and stereochemical studies have focused on the breaking of the C H bond through base-catalyzed elimination reactions. When we began our research, however, chemists knew almost nothing about the stereospecificity of addition elimination reactions involving conjugated acyclic carbonyl compounds, even though the carbonyl group is a pivotal functional group in organic chemistry. Over the last 25 years, we have studied the addition-elimination reactions of beta-substituted acyclic esters, thioesters, and ketones in order to reach a comprehensive understanding of how electronic effects influence their stereochemistry. This Account brings together our understanding of the stereochemistry of 1,2-elimination and proton-transfer reactions, describing how each study has built upon previous work and contributed to our understanding of this field. When we began, chemists thought that anti stereospecificity in base catalyzed 1,2-elimination reactions occurred via concerted E2 mechanisms, which provide a smooth path for anti elimination. Unexpectedly, we discovered that some E1cBirrev reactions produce the same anti stereospecificity as E2 reactions even though they proceed through diffusionally equilibrated, "free" enolate-anion intermediates. This result calls into question the conventional wisdom that anti stereochemistry must result from a concerted mechanism. While carrying out our research, we developed insights ranging from the role of historical contingency in the evolution of hydratase-dehydratase enzymes to the influence of buffers on the stereochemistry of H/D exchange in D2O. Negative hyperconjugation is the most important concept for understanding our results. This idea provides a unifying view for the largely anti stereochemistry in E1cBirrev elimination reactions and a basis for understanding the stereoelectronic influence of electron-withdrawing beta-substituents on proton-transfer reactions. PMID- 23448401 TI - Significance of CD133 expression in esophageal squamous cell carcinoma. AB - BACKGROUND: CD133 was recently reported to be a cancer stem cell marker and a prognostic marker for several tumors. However, few studies have investigated CD133 expression in esophageal squamous cell carcinoma (ESCC). Therefore, we examined whether CD133 could serve as a prognostic marker of ESCC and investigated the correlation between CD133 expression and the clinicopathological findings of ESCC patients and several markers. METHODS: We studied 86 ESCC patients who underwent curative surgery without neoadjuvant treatment at Tohoku University Hospital (Sendai, Japan) between January 2000 and December 2005. We analyzed tissue specimens by immunohistochemical staining for CD133, p53, p16, p27, murine double minute 2 (MDM2), Ki-67, and epidermal growth factor receptor (EGFR). RESULTS: Pathological tumor depth and tumor stage were significantly more advanced among CD133-negative patients than among CD133-positive patients. A log rank test showed that CD133 immunoreactivity was significantly correlated with the overall survival of the patients (P = 0.049). However, multivariate analysis showed that it was not significantly correlated (P = 0.078). Moreover, CD133 was significantly positively correlated with p27 immunoreactivity (P = 0.0013) and tended to be positively correlated with p16 immunoreactivity (P = 0.057). In addition, p16 immunoreactivity was correlated with smoking history (P = 0.018), pathological lymph node status (P = 0.033), and lymphatic invasion (P = 0.018). CONCLUSIONS: This study indicated that CD133 immunoreactivity is a good predictor of prognosis in ESCC patients. In addition, CD133 may play a role in the regulation of tumor cell cycle through p27 and p16 in ESCC. At present, it thus remains controversial whether CD133 expression is a valid prognostic marker for ESCC. To elucidate this relationship, further investigations are required. PMID- 23448402 TI - Concise total synthesis of spirocurcasone. AB - A concise total synthesis of spirocurcasone was accomplished. Key features of the synthesis involved a vinylogous Mukaiyama aldol reaction, a Carroll rearrangement of beta-keto allyl ester derivative, an intramolecular aldol condensation, and a spiro ring formation by ring-closing metathesis of the pentaene compound. This synthetic work was complete in nine steps from (S)- or (R)-perillaldehyde without the use of protecting groups. Interestingly, the optical rotation of the synthetic spirocurcasone was different from the reported value of the natural product. PMID- 23448403 TI - Device physics and operation of lateral bulk heterojunction devices. AB - Measurements of lateral bulk heterojunction (BHJ) devices have recently been reported as a means to characterize charge transport and recombination properties within organic photovoltaic (OPV) materials. These structures allow for the direct measurement of the lateral extents of the space charge regions, potential and electric field profiles, current versus voltage characteristics, and other physical and chemical properties. This article describes numerical simulations that show three different transport regimes present within lateral BHJ devices and two different experimental methods, which verify those findings. These measurement techniques utilize typical confocal microscopy tools as well as steady-state current versus voltage measurements on high aspect ratio nanofabricated structures in order to probe the material properties between the electrodes. Experimental results show that the lateral extents of space charge regions within these devices are approximately 1-5 MUm, which are related to the drift lengths of the charge carriers, and that the mechanism of bimolecular recombination is shown to be a bulk material property. The results within this article describe a series of methods to evaluate charge transport and recombination along the in-plane direction in BHJ films and provide complementary insights to those obtained from vertical-device-based measurements. PMID- 23448405 TI - Ordered mesoporous cobalt oxide as highly efficient oxygen evolution catalyst. AB - Oxygen evolution from water by use of earth-abundant element-based catalysts is crucial for mass solar fuel production. In this report, a mesoporous cobalt oxide with an ultrahigh surface area (up to 250 m(2).g(-1)) has been fabricated through Mg substitution in the mesoporous Co3O4 spinel, followed by a Mg-selective leaching process. Approximately a third of Mg cations were removed in the leaching process, resulting in a highly porous cobalt oxide with a significant amount of defects in the spinel structure. The activated mesoporous cobalt oxide exhibited high oxygen evolution activities in both the visible-light-driven [Ru(bpy)3](2+)-persulfate system and the Ce(4+)/Ce(3+) chemical water oxidation system. Under a strong acidic environment, a high turnover frequency (TOF) of ~2.2 * 10(-3) s(-1) per Co atom was achieved, which is more than twice the TOF of traditional hard-templated, mesoporous Co3O4. PMID- 23448404 TI - Left femoral vein is a better choice for cannulation in children: a computed tomography study. AB - BACKGROUND: Central venous catheters are often required in emergency rooms and intensive care and/or those undergoing major surgical procedures. In this study, we aimed to gain a better understanding of the anatomy of the femoral vessel in relation to central venous cannulation. METHODS: The right and left (total of 180) femoral veins (FVs) of 90 consecutive pediatric patients were retrospectively evaluated using computed tomography images. Patients were divided into two groups according to their age: group 1, patients up to 9 years of age; and group 2, patients between 9 and 16 years of age. RESULTS: The position and overlap of femoral artery (FA) to FV are significantly different between the left and right sides in both groups (P = 0.001). The left FV was most commonly located medial to the FA. However, the right FV was most commonly located posterior medial to the FA. The incidence of overlap of the FA over the FV was significantly lower at the left side in both groups. CONCLUSION: The incidence of overlap of the FA over the FV was significantly lower at the left side in pediatric patients. This finding was similar between the patients aged 2-8 years and those aged 9-16 years and may have significant clinical implications. Guiding clinicians to select the left FV of children for cannulation may result in lower arterial puncture rates while accessing the central vein. PMID- 23448406 TI - Dry night cough as a marker of allergy in preschool children: the PARIS birth cohort. AB - BACKGROUND: Early detection of children at risk for developing allergy is an important challenge. Our first analyses in infants from the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort suggested that dry night cough was associated with parental-reported allergic disorders. The aim of the present study was to refine this finding by investigating the time course of dry night cough from birth to age 4 yr in relation to blood markers of atopy and allergic morbidity. METHODS: Health outcomes were regularly assessed by parental self administered questionnaires. Blood markers of atopy were measured at age 18 months. Children with similar patterns of dry night cough over the first 4 yr of life were grouped together using k-means clustering. Associations with atopy/allergy were studied using multinomial logistic regression. RESULTS: Three trajectories of dry night cough were identified in 1869 children. Besides the never/infrequent pattern (72.4%), the transient pattern (8.8%) was composed of children who coughed in the first year and recovered by age 4 yr, while the rising pattern (18.8%) included all symptomatic children at age 4 yr, whether they were persistent or late coughers. Compared with the never/infrequent pattern, the rising pattern was significantly associated with elevated total immunoglobulin E (IgE) level (odds ratio [OR] = 1.70, 95% confidence interval [CI] = 1.21-2.39) and inhalant allergens sensitization (OR = 2.66, 95% CI = 1.26 5.61) at age 18 months, and with doctor-diagnosed allergic diseases over the first 4 yr such as hay fever (OR = 2.52, 95% CI = 1.49-4.26) and eczema (OR = 1.29, 95% CI = 1.00-1.66). CONCLUSIONS: This study provides evidence that persistent/late dry night cough may indicate allergy in preschool children. PMID- 23448407 TI - Sudden death in a young female with an under-recognised coronary anomaly. AB - Anomalies of coronary number and course represent an opinion-dividing topic in cardiopathology, particularly for their relationship with sudden cardiac death.To the best of our knowledge, we herein report the first fatal case of a young female whose coronary anatomy was characterised by the absence of any septal perforator branch in the proximal segment of the LAD.This case could be useful for pathologists, coronary angiographers, and interventional cardiologists in detecting this infrequent anomaly, thus providing a more accurate estimation of its incidence. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3570015858473043. PMID- 23448408 TI - Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. AB - BACKGROUND: Patients with persistent symptoms and/or villous atrophy despite strict adherence to a gluten-free diet (GFD) have non-responsive celiac disease (NRCD). A subset of these patients has refractory celiac disease (RCD), yet some NRCD patients may simply be reacting to gluten cross-contamination. Here we describe the effects of a 3-6 month diet of whole, unprocessed foods, termed the Gluten Contamination Elimination Diet (GCED), on NRCD. We aim to demonstrate that this diet reclassifies the majority of patients thought to have RCD type 1 (RCD1). METHODS: We reviewed the records of all GFD-adherent NRCD patients cared for in our celiac center from 2005-2011 who were documented to have started the GCED. Response to the GCED was defined as being asymptomatic after the diet, with normal villous architecture on repeat biopsy, if performed. RESULTS: Prior to the GCED, all patients were interviewed by an experienced dietitian and no sources of hidden gluten ingestion were identified. 17 patients completed the GCED; 15 were female (88%). Median age at start of the GCED was 42 years (range 6-73). Fourteen patients (82%) responded to the GCED. Six patients met criteria for RCD prior to the GCED; 5 (83%) were asymptomatic after the GCED and no longer meet RCD criteria. Of the 14 patients who responded to the GCED, 11 (79%) successfully returned to a traditional GFD without resurgence of symptoms. CONCLUSIONS: The GCED may be an effective therapeutic option for GFD-adherent NRCD patients. Response to this diet identifies a subgroup of patients, previously classified as RCD1, that is not truly refractory to dietary treatment. Preventing an inaccurate diagnosis of RCD1 avoids immunotherapy. Most patients are able to return to a traditional GFD without return of symptoms. PMID- 23448409 TI - Posaconazole vs fluconazole/itraconazole in the prophylaxis of invasive fungal infections in immunocompromised patients: a cost-effectiveness analysis in Greece. AB - BACKGROUND: Invasive fungal infections (IFIs) present a major issue in clinical practice, due to their high morbidity and mortality rates. In a pivotal multi centre, randomized clinical trial, posaconazole prophylaxis prevented IFIs more effectively than did either fluconazole or itraconazole, and improved overall survival. OBJECTIVE: The aim of this study was to perform an economic evaluation of the aforementioned therapeutic strategies for IFI prophylaxis in neutropenic patients, in the Greek healthcare setting. METHOD: A decision analytic model was developed, which described the course of neutropenic patients under posaconazole or standard azole (fluconazole or itraconazole) treatment. Effectiveness data for each treatment regimen were derived from published results of a pivotal, multi centre, randomized clinical trial. Cost and healthcare resources utilization data depict Greek clinical practice and are derived from official Greek sources, from a third party payer perspective. RESULTS: Prophylaxis with posaconazole resulted in fewer IFIs (0.05 vs 0.11 per patient) compared to treatment with fluconazole or itraconazole, during the first 100 days from initiation of prophylaxis treatment. The cost per avoided IFI with posaconazole was ?6455, while the incremental cost per life year gained (LYG) was estimated at ?24,196. Extensive sensitivity analyses corroborated the base-case results. Possible limitations of the study are the exclusion of indirect and outpatient costs from the analysis and the inherent uncertainty with regards to the transferability of the clinical efficacy results of the clinical trial to the Greek healthcare setting. CONCLUSIONS: The utilization of posaconazole for prophylaxis of IFIs neutropenic patients is a therapeutic strategy that provides superior clinical efficacy, while being cost-effective compared to alternative therapies. PMID- 23448410 TI - Health behavior and behavioral economics: economic preferences and physical activity stages of change in a low-income African-American community. AB - PURPOSE: To examine the relationship between physical activity stages of change and preferences for financial risk and time. DESIGN: A cross-sectional, community based study. SETTING: A low-income, urban, African-American neighborhood. SUBJECTS: One hundred sixty-nine adults. MEASURES: Self-reported physical activity stages of change-precontemplation to maintenance, objectively measured body mass index and waist circumference, and economic preferences for time and risk measured via incentivized economic experiments. ANALYSIS: Multivariable ordered logistic regression models were used to examine the association between physical activity stages of change and economic preferences while controlling for demographic characteristics of the individuals. RESULTS: Individuals who are more tolerant of financial risks (odds ratio [OR] = 1.31, p < .05) and whose time preferences indicate more patience (OR = 1.68, p < .01) are more likely to be in a more advanced physical activity stage (e.g., from preparation to action). The likelihood of being in the maintenance stage increases by 5.6 and 10.9 percentage points for each one-unit increase in financial risk tolerance or one-unit increase in the time preference measure, respectively. CONCLUSION: Greater tolerance of financial risk and more patient time preferences among this low income ethnic minority population are associated with a more advanced physical activity stage. Further exploration is clearly warranted in larger and more representative samples. PMID- 23448411 TI - Effects of social injustice on breast health-seeking behaviors of low-income women. AB - PURPOSE: The study uses qualitative research to gain a better understanding of what occurs after low-income women receive an abnormal breast screening and the factors that influence their decisions and behavior. A heuristic model is presented for understanding this complexity. DESIGN: Qualitative research methods used to elicited social and cultural themes related to breast cancer screening follow-up. SETTING: Individual telephone interviews were conducted with 16 women with confirmed breast anomaly. PARTICIPANTS: Low-income women screened through a national breast cancer early detection program. METHOD: Grounded theory using selective coding was employed to elicit factors that influenced the understanding and follow-up of an abnormal breast screening result. Interviews were digitally recorded, transcribed, and uploaded into NVivo 8, a qualitative management and analysis software package. RESULTS: For women (16, or 72% of case management referrals) below 250% of the poverty level, the impact of social and economic inequities creates a psychosocial context underlined by structural and cultural barriers to treatment that forecasts the mechanism that generates differences in health outcomes. The absence of insurance due to underemployment and unemployment and inadequate public infrastructure intensified emotional stress impacting participants' health decisions. CONCLUSION: The findings that emerged offer explanations of how consistent patterns of social injustice impact treatment decisions in a high-risk vulnerable population that have implications for health promotion research and systems-level program improvement and development. PMID- 23448412 TI - An empirical analysis of the association between social interaction and self rated health. AB - PURPOSE: To empirically investigate the relationship of social interactions with self-rated health status. DESIGN: Cross-sectional study. SETTING: The United States, 1972-2008. SUBJECTS: 53,043 respondents interviewed. MEASURES: In-person interviews were conducted by the National Opinion Research Center. Health is measured via self-assessment, and a binary indicator defines whether the respondent reports excellent or good health. Impersonal social interaction is binary, reflecting membership in at least one organization; personal interaction is binary, reflecting whether the respondent visits relatives, neighbors, friends, or bars at least once a month. Demographic, region, and time variables are standard controls. ANALYSIS: Probit models were estimated at aggregated and disaggregated (race, gender, age, and education) levels. RESULTS: Impersonal interaction fell 5% between 1974 and 1994, with deeper declines (12%) in personal interaction. Neighbor visits fell most (24%), but friends gained (5%). Marginal estimates indicate both personal and impersonal interactions are associated with better health. However, friends show the strongest effect. A 1-SD increase in the probability of meeting friends versus joining a club or association is associated with a higher (.019 vs. .014) probability of being in very good or excellent health. CONCLUSION: Social interaction, impersonal or personal, is significantly associated with health. Public policy facilitating greater interactions of the type that benefits different demographic groups may be health promoting. Results are suggestive of potential network effects at the individual and community levels, which have implications for designing and targeting more effective health interventions. PMID- 23448413 TI - Feasibility of a parenting program to prevent substance use among Latino youth: a community-based participatory research study. AB - PURPOSE: Family-skills training programs prevent adolescent substance use, but few exist for immigrant Latino families. This study assesses the feasibility of a family-skills training intervention developed using a community-based participatory research framework, and explores parental traditional values as a modifier of preliminary effects. DESIGN: One-group pretest-posttest. SETTING: Four Latino youth-serving sites (school, clinic, church, social-service agency). SUBJECTS: Immigrant Latino parents of adolescents aged 10 to 14 years (N = 83). INTERVENTION: Eight-session program in Spanish to improve parenting practices and parent-youth interpersonal relations designed with Latino parents and staff from collaborating organizations. MEASURES: Feasibility was assessed through retention, program appropriateness, and group interaction quality. Preliminary outcomes evaluated were (1) parenting self-efficacy, discipline, harsh parenting, monitoring, conflict, attachment, acceptance, and involvement, and (2) parent perception of adolescent internalizing, externalizing, and substance use behaviors. Covariates included sociodemographics and parental endorsement of traditional values. ANALYSIS: Feasibility outcomes were assessed with descriptive statistics. Paired t-tests measured changes in parenting outcomes. Adjusted multiple regression models were conducted for change in each outcome, and t-tests compared mean changes in outcomes between parents with high and low traditional values scores. RESULTS: Program appropriateness and group interaction scores were positive. Improvement was noted for eight parenting outcomes. Parents perceived that adolescent internalizing behaviors decreased. Parents with lower endorsement of traditional values showed greater pretest-posttest change in attachment, acceptance, and involvement. CONCLUSION: This intervention is feasible and may influence parenting contributors to adolescent substance use. PMID- 23448414 TI - A descriptive evaluation of CDC's LEAN Works! Leading employees to activity and nutrition--a Web-based employer tool for workplace obesity management. AB - PURPOSE: The study aim was to determine the utility of and satisfaction with a Centers for Disease Control and Prevention (CDC) Web-based employer tool, CDC's LEAN Works!, which provides evidence-based recommendations and promising practices for obesity prevention and control at worksites. DESIGN: This study examined employers' natural usage (i.e., without any study parameters on how, when, or how much to use the Web site and its resources) and impressions of the Web site. SETTING: Employers of varying sizes, industry types, and levels of maturity in offering obesity management programs and from both private and public sectors were recruited to participate in the study. PARTICIPANTS: A convenience sample of 29 employers enrolled to participate. METHOD: Participants were followed over a 12-month period. First impressions, bimonthly use of the Web site, and final assessments were collected using self-report surveys and individual interviews. Descriptive analyses were conducted. RESULTS: Almost all (96%) of participants reported a positive experience with the Web site, noting it provided a wealth of information. Most reported they planned to continue to use the Web site to develop (77%), implement (92%), and evaluate (85%) their obesity management programs. Aspects of the Web site that employers found valuable included a step-by-step implementation process, templates and toolkits, specific recommendations, and promising practices. CONCLUSION: CDC's LEAN Works! is a useful resource for employers wishing to develop and implement evidence-based workplace obesity prevention programs. PMID- 23448415 TI - Community mobilization, participation, and blood pressure status in a Cardiovascular Health Awareness Program in Ontario. AB - PURPOSE: To determine the feasibility of a community-wide approach integrated with primary care (Cardiovascular Health Awareness Program [CHAP]) to promote monitoring of blood pressure (BP) and awareness of cardiovascular disease risk. DESIGN: Demonstration project. SETTING: Two midsized Ontario communities. PARTICIPANTS: Community-dwelling seniors. INTERVENTION: CHAP sessions were offered in pharmacies and promoted to seniors using advertising and personalized letters from physicians. Trained volunteers measured BP, completed risk profiles, and provided risk-specific education materials. METHOD: We examined the distribution of risk factors among participants and predictors of multiple visits and elevated BP. RESULTS: Opinion leaders aided recruitment of family physicians (n = 56/63) and pharmacists (n = 18/19). Over 90 volunteers were recruited. Invitations were mailed to 4394 seniors. Over 10 weeks, there were 4165 assessments of 2350 unique participants (approximately 30% of senior residents). 37.5% of attendees had untreated (16%; 360/2247) or uncontrolled (21.5%; 482/2247) high BP. Participants who received a letter (odds ratio [OR] 2.5, 95% confidence interval [CI] 2.1-3.0), had an initial elevated BP (OR 1.2, 95% CI 1.0 1.5), or reported current antihypertensive medication (OR 1.4, 95% CI 1.1-1.6) were more likely to attend multiple sessions (p <= .05 for all). Older age (>= 70 years; OR 1.5, 95% CI 1.3-1.8), BMI >= 30 (OR 1.7, 95% CI 1.4-2.2), current antihypertensive medication (OR 1.6, 95% CI 1.3-1.9), and diabetes (OR 2.4, 95% CI 1.9-3.2) predicted elevated BP (p < .001 for all). CONCLUSION: The program yielded learning about community mobilization and identified a substantial number of seniors with undiagnosed/uncontrolled high BP. PMID- 23448416 TI - Associations between body mass index and park proximity, size, cleanliness, and recreational facilities. AB - PURPOSE: To determine whether body mass index (BMI) is associated with proximity to neighborhood parks, the size of the parks, their cleanliness, and the availability of recreational facilities in the parks. DESIGN: Cross-sectional. SETTING: New York City. SUBJECTS: Adults (13,102) were recruited from 2000 to 2002 (median age 45 years, 36% male). MEASURES: Anthropometric and sociodemographic data from study subjects were linked to Department of Parks & Recreation data on park space, cleanliness, and facilities. Neighborhood-level sociodemographic and park proximity metrics were created for half-mile-radius circular buffers around each subject's residence. Proximity to park space was measured as the proportion of the subject's neighborhood buffer area that was total park space, large park space (a park > 6 acres) and small park space (a park <= 6 acres). Analysis. Hierarchical linear models were used to determine whether neighborhood park metrics were associated with BMI. RESULTS: Higher proximity to large park space was significantly associated with lower BMI (beta = -1.69, 95% confidence interval = -2.76, -.63). Across the population distribution of proximity to large park space, compared to subjects living in neighborhoods at the 10th percentile of the distribution, the covariate-adjusted average BMI was estimated to be .35 kg/m lower for those living in neighborhoods at the 90th percentile. The proportion of neighborhood area that was small park space was not associated with BMI, nor was park cleanliness or the availability of recreational facilities. CONCLUSION: Neighborhood proximity to large park spaces is modestly associated with lower BMI in a diverse urban population. PMID- 23448417 TI - Ethnic differences in the home environment and physical activity behaviors among low-income, minority preschoolers in Texas. AB - PURPOSE: To evaluate the ethnic differences in the home physical activity and screen time environment of preschoolers enrolled in Head Start. DESIGN: Cross sectional. SETTING: Sixteen Harris County Department of Education (HCDE) Head Start centers, Texas. SUBJECTS: Seven hundred and six preschoolers enrolled in HCDE Head Start centers and their parents. MEASURES. Items from the parent reported Healthy Home Survey evaluating the home physical activity environment and the Nutrition Screening form evaluating screen time. ANALYSIS: Mixed model linear and logistic regression analysis. RESULTS: Of the parents, 75.06% were overweight or obese. Hispanic parents were more likely to have a yard or open space (p = .014) and usable play equipment in the yard (p = .019) for their children to play in compared to African-Americans. Conversely, more African American parents reported having a television (TV) in their preschooler's bedroom (p = .032) and were less likely to cut down their child's TV viewing time (p = .036). African-American preschoolers were reportedly more likely to eat while watching TV (p = .009), play video games for >= 2 hours on weekdays (p = .018) and have computer time for >= 2 hours on weekends (p = .007), compared to Hispanics. CONCLUSION: The Hispanic participants of this study had a healthier home environment for physical activity and screen time as compared with their African-American counterparts. Future interventions targeting lifestyle change need to address these factors in an ethnic-specific manner. PMID- 23448419 TI - Evaluation of the food store environment on and near the campus of 15 postsecondary institutions. AB - PURPOSE: This study evaluated the food stores on and near postsecondary campuses varying in institutional size. DESIGN: The design of the study is an environmental audit survey. SETTING: Fifteen U.S. postsecondary education institutions participated in this study between 2009-2011. SUBJECTS: Eighty-one stores (44% grocery, 17% campus, and 39% convenience/drug) were evaluated. MEASURES: The Nutrition Environment Measures Survey for Stores was modified to evaluate food stores. Analysis. Analysis of variance with post hoc Tukey B and t tests assessed differences between store types and by institutional size. RESULTS: Grocery stores had significantly higher scores than campus/convenience stores for healthy foods (19.5 +/- 3.8 vs. 2.4 +/- 1.7), and for the availability (19.5 +/- 3.8 vs. 2.4 +/- 1.7) and quality (5.9 +/- 0.5 vs. 1.8 +/- 2.2) of fruits/vegetables (p < .001). Healthy foods and beverages were significantly more expensive (-0.6 +/- 3.4 vs. 0.9 +/- 2.0; p < .031) than their less healthful alternatives in grocery stores, but not in convenience stores. There were no differences by institutional size for grocery stores; however, smaller institutions' convenience stores had significantly lower availability and quality of fruits/vegetables and total food store environment scores. CONCLUSION: A college campus provides a food environment with an array of shopping venues, most of which are not consistent with dietary recommendations for obesity prevention. The limited quality of healthy food in on-campus and convenience stores and the exacerbated deficiencies for small postsecondary institutions provide evidence to support environmental and policy initiatives to improve the quality of campus food store environments. PMID- 23448422 TI - Do we have the evidence we need and are we communicating it well? AB - Despite the growth of evidence on the health and financial impact of workplace health promotion, experts in health policy and management are not aware of this evidence. To change this, we need to publish in their journals, speak at their conferences, and collaborate with them on evaluation and research. These collaborations have the additional advantage of our learning how to conduct population level analysis and express findings in the terms policy makers understand. PMID- 23448420 TI - Comparison of enrollment rates of African-American families into a school-based tobacco prevention trial using two recruitment strategies in urban and rural settings. AB - PURPOSE: This study evaluated similarities and differences of enrollment rates using two different recruitment strategies for a tobacco control trial in rural and urban African-American (AA) elementary school families. DESIGN: A comparative study, nested within a larger randomized controlled trial, was used to test the effectiveness of two recruitment approaches on enrollment rates in rural and urban AA families. SETTING: The study was conducted in 14 Title 1 elementary schools in the southeastern United States: 7 rural and 7 urban. SUBJECTS: There were 736 eligible AA families, and 332 (45%) completed informed consent and were enrolled into the study. INTERVENTION: The Facilitate, Open and transparent communication, Shared benefits, Team and tailored, Educate bilaterally, and Relationships, realistic and rewards (FOSTER) approach guided the two recruitment strategies: (1) written informational packets provided to fourth graders to take home to parents; and (2) proactive, face-to-face family information sessions held at schools. MEASURES: Enrollment rates were based on responsiveness to the two recruitment strategies and completion of the informed consent process. ANALYSIS: Chi-square, Cochran-Mantel-Haenszel, and Breslow-Day tests were performed. RESULTS: Higher enrollment rates occurred during the family session for both rural and urban families (100% rural, 93.6% urban; p = .0475) than informational packets alone (28.7% rural, 22% urban; p < .0001). Rural family enrollment rates were overall higher than urban rates regardless of recruitment strategy (52.0% rural vs. 39.6% urban; p = .0008). CONCLUSION: The findings suggest the FOSTER approach, although effective in both rural and urban settings, was more successful in recruiting rural families. PMID- 23448423 TI - The motivation issue. PMID- 23448425 TI - Manchester iStent study: early results from a prospective UK case series. AB - BACKGROUND: To evaluate the 6-month efficacy and safety of the iStent microtrabecular bypass stent in patients with open-angle glaucoma. DESIGN: A prospective, uncontrolled, interventional case series. PARTICIPANTS: Forty-four eyes with open-angle glaucoma were reported. METHODS: All subjects underwent ab interno implantation of a single iStent together with (n = 40) or without (n = 4) cataract surgery. MAIN OUTCOME MEASURES: Patients were assessed at postoperative week 1, months 1 and 3, and quarterly, thereafter. Data collected included visual acuity, intraocular pressure measurement using Goldmann tonometry, number of glaucoma medications, and number and type of complications. RESULTS: The mean age of the sample was 76.8 years. The mean duration since glaucoma diagnosis was 5.3 years (standard deviation 2.9 years). The mean visual acuity was 0.53 logMAR at baseline that improved to 0.23 at 6 months postoperatively. The mean baseline intraocular pressure was 21.1 mmHg, and this decreased significantly to 16.7 mmHg at 6 months (P < 0.01). The mean number of drops prescribed preoperatively was 2.3, which decreased to 0.6 at 6 months (P < 0.01). Sixty-six per cent of patients were drop-free at 6 months. One patient developed an hyphaema following surgery; no other adverse events were recorded. CONCLUSIONS: The iStent proved to be a safe and effective treatment for patients with open-angle glaucoma over our 6-month follow up period. Insertion resulted in a significant decrease in intraocular pressure as well as the number of topical antiglaucoma medications required for adequate intraocular pressure control. PMID- 23448424 TI - Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer. AB - INTRODUCTION: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response. METHODS: Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high resolution magic angle spinning magnetic resonance spectroscopy. RESULTS: Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level. CONCLUSION: The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAktser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAktser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC. PMID- 23448426 TI - AaORA, a trichome-specific AP2/ERF transcription factor of Artemisia annua, is a positive regulator in the artemisinin biosynthetic pathway and in disease resistance to Botrytis cinerea. AB - . Six transcription factors of APETALA2/ethylene-response factor (AP2/ERF) family were cloned and analyzed in Artemisia annua. Real-time quantitative polymerase chain reaction (RT-Q-PCR) showed that AaORA exhibited similar expression patterns to those of amorpha-4,11-diene synthase gene (ADS), cytochrome P450-dependent hydroxylase gene (CYP71AV1) and double bond reductase 2 gene (DBR2) in different tissues of A. annua. . AaORA is a trichome-specific transcription factor, which is expressed in both glandular secretory trichomes (GSTs) and nonglandular T shaped trichomes (TSTs) of A. annua. The result of subcellular localization shows that AaORA is targeted to the nuclei and the cytoplasm. . Overexpression and RNA interference (RNAi) of AaORA in A. annua regulated, positively and significantly, the expression levels of ADS, CYP71AV1, DBR2 and AaERF1. The up-regulated or down regulated expression levels of these genes resulted in a significant increase or decrease in artemisinin and dihydroartemisinic acid. The results demonstrate that AaORA is a positive regulator in the biosynthesis of artemisinin. . Overexpression of AaORA in Arabidopsis thaliana increased greatly the transcript levels of the defense marker genes PLANT DEFENSIN1.2 (PDF1.2), HEVEIN-LIKE PROTEIN (HEL) and BASIC CHITINASE (B-CHI). After inoculation with Botrytis cinerea, the phenotypes of AaORA overexpression in A. thaliana and AaORA RNAi in A. annua demonstrate that AaORA is a positive regulator of disease resistance to B. cinerea. PMID- 23448427 TI - Assessing the contribution of 38 genetic loci to the risk of type 2 diabetes in the Saudi Arabian Population. AB - BACKGROUND: Previous genome-wide association studies have identified multiple type 2 diabetes (T2D) genetic risk loci in many populations. However, the contribution of these loci to T2D in the Middle Eastern populations with high T2D prevalence is unknown. METHODS: Here, we investigated the association of 38 T2D risk loci in the Saudi Arabian population (1166 patients with T2D and 1235 healthy controls), which has one of the world's highest prevalence of T2D. RESULTS: Eight common genetic variants showed a significant association with T2D in our study population. The effect sizes of these loci were comparable to those previously identified in other populations with the exception of HNF4A, which showed a trend for larger effect size in our study population (OR = 1.27) compared to that reported in South Asian populations (OR = 1.09; I(2) = 65.9). Analysis of risk allele scores (RASs) defined by the 8 loci showed that subjects in the top RAS quintile (n = 480) had 2.5-fold increase in disease risk compared to those in the bottom quintile (n = 480; P = 9.5 * 10(-12)). RASs were also associated with fasting glucose level (beta = 0.12; P = 2.2 * 10(-9)), but not with BMI (P = 0.19). Analysis of a subgroup of subjects with BMI<=30 resulted in two additional loci (SLC30A8; P = 0.03, HMG20A; P = 0.02) showing significant association with T2D. CONCLUSIONS: We have shown for the first time that variants at WFS1, JAZF1, SLC30A8, CDKN2A/B, TCF7L2, KCNQ1, HMG20A, HNF4A and DUSP9 are associated with T2D in the Saudi population. Our findings also suggest substantial overlap of T2D risk loci across many ethnic groups regardless of disease prevalence. PMID- 23448429 TI - Health workforce remuneration: comparing wage levels, ranking, and dispersion of 16 occupational groups in 20 countries. PMID- 23448428 TI - Physiological fluctuations in brain temperature as a factor affecting electrochemical evaluations of extracellular glutamate and glucose in behavioral experiments. AB - The rate of any chemical reaction or process occurring in the brain depends on temperature. While it is commonly believed that brain temperature is a stable, tightly regulated homeostatic parameter, it fluctuates within 1-4 degrees C following exposure to salient arousing stimuli and neuroactive drugs, and during different behaviors. These temperature fluctuations should affect neural activity and neural functions, but the extent of this influence on neurochemical measurements in brain tissue of freely moving animals remains unclear. In this Review, we present the results of amperometric evaluations of extracellular glutamate and glucose in awake, behaving rats and discuss how naturally occurring fluctuations in brain temperature affect these measurements. While this temperature contribution appears to be insignificant for glucose because its extracellular concentrations are large, it is a serious factor for electrochemical evaluations of glutamate, which is present in brain tissue at much lower levels, showing smaller phasic fluctuations. We further discuss experimental strategies for controlling the nonspecific chemical and physical contributions to electrochemical currents detected by enzyme-based biosensors to provide greater selectivity and reliability of neurochemical measurements in behaving animals. PMID- 23448431 TI - Incidence of post-intubation subglottic stenosis in children: prospective study. AB - OBJECTIVE: To evaluate the incidence of subglottic stenosis in children undergoing endotracheal intubation. METHODS: Children in the paediatric intensive care unit of a tertiary care hospital were considered eligible for inclusion if they received endotracheal intubation for more than 24 hours. After extubation, children underwent flexible fibre-optic nasolaryngoscopy. Based on this first evaluation, they were divided into two groups: 'acute normal', with mild laryngeal alterations or normal findings; and 'acute alterations', with moderate to severe laryngeal alterations. Further laryngoscopic follow up (7-10 days later) was undertaken for those children in the acute normal group who developed symptoms during follow up (after discharge from the intensive care unit), and for all children in the acute alterations group. Children were then classified into two final groups: 'normal final examination', with no chronic changes; and 'subglottic stenosis'. RESULTS: We included 123 children. The incidence of subglottic stenosis was 11.38 per cent (95 per cent confidence interval, 6.63 17.94 per cent). All the children who developed subglottic stenosis had had moderate to severe alterations immediately after extubation. CONCLUSION: This incidence of subglottic stenosis is quite high and needs further investigation to identify risk factors. PMID- 23448430 TI - Transactions between child social wariness and observed structured parenting: evidence from a prospective adoption study. AB - This investigation examined the mutual influences between structured parenting and child social wariness during toddlerhood using a longitudinal adoption design. The sample consisted of 361 adoption-linked families, each including an adopted child, adoptive parents, and a birth mother. Heightened social wariness in children at age 18 months predicted reduced levels of observed structured parenting (i.e., less directive parenting with fewer commands and requests) in adoptive mothers at age 27 months. Adoptive fathers' lower structured parenting at age 18 months predicted subsequent elevation in child social wariness. Birth mothers' history of fear-related anxiety disorders was not associated with child social wariness. Findings highlight the role of dynamic family transactions in the development of social wariness during toddlerhood. PMID- 23448432 TI - Selective access to trisubstituted macrocyclic E- and Z-alkenes from the ring closing metathesis of vinylsiloxanes. AB - Macrocyclic (E)-alkenylsiloxanes, obtained from E-selective ring-closing metathesis reactions, can be converted to the corresponding (Z)-alkenyl bromides and (E)-alkenyl iodides allowing access to both E- and Z-trisubstituted macrocyclic alkenes. The reaction conditions and substrate scope of these stereoselective transformations are explored. PMID- 23448433 TI - The flow field near a venous needle in hemodialysis: a computational study. AB - The vascular access used in hemodialysis can suffer from numerous complications, which may lead to failure of the access, patient morbidity, and significant costs. The flow field in the region of the venous needle may be a source of damaging hemodynamics and hence adverse effects on the fistula. In this study, the venous needle flow has been considered, using three-dimensional computational methods. Four scenarios where the venous needle flow could potentially influence dialysis treatment outcome were identified and examined: Variation of the needle placement angle (10 degrees , 20 degrees , 30 degrees ), variation of the blood flow rate settings (200, 300, 400 mL/min), variation of the needle depth (top, middle, bottom), and the inclusion of a back eye in the needle design. The presence of the needle has significant effect on the flow field, with different scenarios having varying influence. In general, wall shear stresses were elevated above normal physiological values, and increased presence of areas of low velocity and recirculation-indicating increased likelihood of intimal hyperplasia development-were found. Computational results showed that the presence of the venous needle in a hemodialysis fistula leads to abnormal and potentially damaging flow conditions and that optimization of needle parameters could aid in the reduction of vascular access complications. Results indicate shallow needle angles and lower blood flow rates may minimize vessel damage. PMID- 23448435 TI - A preliminary study of individual cognitive behavior therapy for social anxiety disorder in Japanese clinical settings: a single-arm, uncontrolled trial. AB - BACKGROUND: Cognitive behavior therapy (CBT) is regarded as an effective treatment for social anxiety disorder (SAD) in Europe and North America. Individual CBT might be acceptable and effective for patients with SAD even in non-Western cultures; therefore, we conducted a feasibility study of individual CBT for SAD in Japanese clinical settings. We also examined the baseline predictors of outcomes associated with receiving CBT. METHODS: This single-arm trial employed a 14-week individual CBT intervention. The primary outcome was the self-rated Liebowitz Social Anxiety Scale, with secondary measurements of other social anxiety and depressive severity. Assessments were conducted at baseline, after a waiting period before CBT, during CBT, and after CBT. RESULTS: Of the 19 subjects screened, 15 were eligible for the study and completed the outcome measures at all assessment points. Receiving CBT led to significant improvements in primary and secondary SAD severity (ps < .001). The mean total score on the Liebowitz Social Anxiety Scale improved from 91.8 to 51.7 (before CBT to after CBT), and the within-group effect size at the end-point assessment was large (Cohen's d = 1.71). After CBT, 73% of participants were judged to be treatment responders, and 40% met the criteria for remission. We found no significant baseline predictors of those outcomes. CONCLUSION: Despite several limitations, our treatment-which comprises a 14-week, individual CBT program-seems feasible and may achieve favorable treatment outcomes for SAD in Japanese clinical settings. Further controlled trials are required in order to address the limitations of this study. TRIAL REGISTRATION: UMIN-CTR UMIN000005897. PMID- 23448434 TI - Pain, fentanyl consumption, and delirium in adolescents after scoliosis surgery: dexmedetomidine vs midazolam. AB - BACKGROUND: The study aim was to compare the efficacy of dexmedetomidine vs midazolam for sedation during the early postoperative period in adolescents who underwent scoliosis surgery. METHODS: We performed a prospective, randomized trial in an intensive care unit (ICU) in a tertiary care center. In this study, 42 patients (American Society of Anesthesiology physical status I and II) who underwent scoliosis surgery were divided into two groups according to sedation protocols: group dexmedetomidine (DEX) (n = 22) and group midazolam (MDZ) (n = 20). Adolescents (12-18 years) requiring mechanical ventilation underwent a continuous infusion of either dexmedetomidine (group DEX; starting dose, 0.4 MUg.kg(-1) .h(-1)) or midazolam (group MDZ; starting dose, 0.1 mg.kg(-1) .h(-1)) with intermittent fentanyl, as needed. The efficacy of sedation was assessed using the Richmond Agitation Sedation Scale (RASS). Quality of pain relief was measured using the Numeric Visual Analog Scale (NVAS). Delirium was determined in patients in the RASS range of -2 to +1 using the Confusion Assessment Method for the ICU (CAM-ICU). Fentanyl consumption, incidence of delirium, NVAS scores, and hemodynamics were recorded postoperatively at 2, 4, 6, and 24 h in the ICU. RESULTS: The NVAS pain scores and fentanyl consumption at all the evaluation time points were significantly higher in group MDZ than those in group DEX (P < 0.05). Further, total fentanyl consumption in group MDZ was significantly higher than that in group DEX (P < 0.05). Delirium was significantly higher in the group MDZ than that in group DEX (31.3% vs 12.5%) when analyzed as the endpoint of CAM-ICU (P < 0.05). The heart rate was significantly lower in group DEX compared with that in group MDZ at all the evaluation time points (P < 0.05). CONCLUSION: Dexmedetomidine was associated with the decreased postoperative fentanyl consumption, NVAS scores, and a decreased incidence of delirium. These findings may be beneficial for managing sedation protocols in adolescents who have undergone scoliosis surgery. PMID- 23448436 TI - Comparison of disc analysis algorithms provided by cirrus OCT and stereo optic disc photography in normal and open angle glaucoma patients. AB - PURPOSE: To compare optic nerve head (ONH) parameters obtained by semi-automated disc analysis of stereo optic-disc photography (ODP) with those by spectral domain optical coherence tomography (SD-OCT) regarding their reproducibility, agreement and relationship with the retinal nerve fiber layer (RNFL) thickness. PATIENTS AND METHODS: In this cross-sectional retrospective study, 91 eyes (50 normal and 41 with open angle glaucoma) from 47 patients were examined. ONH parameters were obtained by ODP and SD-OCT. Agreement and reproducibility were assessed by intra-class correlation coefficients (ICCs). Inter-device agreement and precision were also evaluated. The structural factors related to the ONH measurements by both instruments and the disparity between the measurements were evaluated by the generalized estimating equation model. RESULTS: ODP showed good intra-reader and inter-reader reproducibility, comparable to that of SD-OCT (ICC: >0.970). Disc area (DA) (ICC: 0.950) showed better inter-device agreement than rim area (RA) (ICC: 0.859). RNFL thickness was correlated with RA, but not with DA, for both devices. SD-OCT RA showed significant correlation with RNFL thickness in both the normal and glaucoma groups, whereas ODP RA correlated with RNFL only in the glaucoma group. The measurement disparity between the devices was influenced by the DA in both groups. The inter-device difference in RA was not correlated with RA, but instead with the RNFL thickness in the glaucoma group. CONCLUSION: ONH parameters obtained by semi-automated algorithms of ODP showed excellent reproducibility and good agreement with those measured by SD OCT. SD-OCT RA was a better indicator of RNFL thickness, compared with ODP RA for both normal patients and glaucoma patients; however, the inter-device disparity of the RA was less in glaucoma patients who had a thinner RNFL. PMID- 23448437 TI - Monitoring the folding of Trp-cage peptide by two-dimensional infrared (2DIR) spectroscopy. AB - Protein folding is one of the most fundamental problems in modern molecular biology. Uncovering the detailed folding mechanism requires methods that can monitor the structures at high temporal and spatial resolution. Two-dimensional infrared (2DIR) spectroscopy is a new tool for studying protein structures and dynamics with high time resolution. Using atomistic molecular dynamics simulations, we illustrate the folding process of Trp-cage along the dominant pathway on the free energy landscape by analyzing nonchiral and chiral coherent 2DIR spectra along the pathway. Isotope labeling is used to reveal residue specific information. We show that the high resolution structural sensitivity of 2DIR can differentiate the ensemble evolution of protein and thus provides a microscopic picture of the folding process. PMID- 23448438 TI - Manipulation and engineering of metabolic and biosynthetic pathway of plant polyphenols. AB - Polyphenols are bioactive natural molecules biogenerated through secondary metabolic pathways. They are involved in different functions in the ecology, physiology, and biochemistry of plants such as chemical defense against predators and in plant-plant interferences. These compounds are known to have important biological activities related to human health such as antioxidant action, antiinflammatory and antimicrobial effects. The immense health benefits as well as use of many polyphenolic compounds as anti-infective agents against human pathogens have heightened the need for continuous supply of rare and expensive secondary metabolites. It has been demonstrated that the chemical structure of dietary polyphenols, such as the number and position of hydroxyl groups, can change their biological properties and bioavailability. This review focuses on prospects for, and success in metabolic engineering, including manipulation of structural regulatory genes to develop plants with tailor-made, optimized levels and composition of polyphenols. PMID- 23448439 TI - Chemical synthesis of tea polyphenols and related compounds. AB - Tea polyphenol "catechin", which is a major constituent of green tea extract, has received special attention for its important bioactivities. In this article, we review the recent various syntheses of catechins by classifying the mode of of flavan ring-construction. Additionally, we also take notice of the application of the modified catechins that were created to uncover the mechanism of bioactivities and discover new activities. PMID- 23448441 TI - Total polyphenols and bioactivity of seeds and sprouts in several legumes. AB - Seeds and sprouts from legume crop plants have received attention as functional foods, because of their nutritive values including amino acid, fiber, trace elements, vitamins, flavonoids, and phenolic acids. Consumption of seeds and sprouts has become increasingly popular among people interested in improving and maintaining their health status by changing dietary habits. The seeds and sprouts are excellent examples of functional food defined as lowering the risk of various diseases and/or exerting health promoting effects in addition to its nutritive value. Phenolic compounds are considered as secondary metabolites that are synthesized by plants during normal development and in response to stress conditions, and the compounds occur ubiquitously in plants as the diversified group of phytochemicals derived from phenylalanine and tyrosine. Plant phenolics include simple phenols, phenolic acids, coumarins, flavonoids, stilbenes, hydrolyzable and condensed tannins, lignans, and lignins. In plant, phenolics may act as phytoalexins, antifeedants, attractants for pollinators, contributors to the plant pigmentation, antioxidants, and protective agents against UV light, among others. In food, phenolics may contribute to the bitterness, astringency, color, flavor, odor, and oxidative stability of products. In addition, health protecting capacity of some and antinutritional properties of other plant phenolics are of great importance to producers, processors and consumers. Several researches were conducted to compare the content of phenolics and flavonoids, antioxidant activity and antioxidant enzyme activity from seeds and sprouts of legume plants. Total phenolics (TP) content and total flavonoids (TF) level were highest in soybean sprout extracts, followed by cowpea and mungbean sprout extracts (p < 0.05). DPPH (1, 1-diphenyl-2-picryl hydrazyl radical) free radical scavenging activity was higher in cowpea or mungbean sprouts than in soybean sprouts. Among antioxidant enzymes, ascorbate peroxidase (APX) and peroxidase (POX) activities were highest in cowpea sprouts and catalase (CAT) and superoxide dismutase (SOD) activities in soybean sprouts. During sprouting in mungbean, TP and TF levels significantly increased and improved free radical scavenging, tyrosinase inhibition, anticancer, and ADH (alcohol dehydrogenase) activities, showing higher contents and activities in sprouts than in seeds. Sprouting of seeds is known to increase the nutritive value such as phenolics and flavonoids and the health qualities of foods in a natural way. Phasic bioactive responses from dry seeds to 7-day-old seedlings of cowpea showed differential growth, contents of TP and TF, antioxidant activity and antioxidant enzyme activity. Plant length and weight of cowpea sprouts were significantly increased until 7 days after seeding. TP content, however, was highest in dry seed (DS) extracts of cowpea (63.9 mg kg(1)), followed by imbibed seed (IS) (56.8 mg kg(1)) and 1-day old sprout (1DOS) (46.4 mg kg(1)) extracts, and significantly reduced with increase of sprout age (p < 0.05). DPPH free radical scavenging activity was higher in DS or IS than in cowpea sprouts. APX, POX, and POX activities were highest in 7DOS and lowest in DS. SOD activity was lowest in DS and much higher in additional sprouting days. PMID- 23448442 TI - Avocado (Persea americana) seed as a source of bioactive phytochemicals. AB - The pulp of avocado (Persea americana, Lauraceae) has been reported to have beneficial cardiovascular health effects. Avocado oil is used for dermatological applications and its unsaponifiable portion is reported to have beneficial effects against osteoarthritis. Although the seed represents a considerable percentage of the total fruit, scientific research on the phytochemistry and biological effects of avocado seeds is in the nascent stages,. Currently, the seed represents an under-utilized resource and a waste issue for avocado processors. There is ethno-pharmacological information on the use of seeds for the treatment of health-related conditions, especially in South American countries where avocados are endemic and currently grown on a large scale. Current research has shown that avocado seeds may improve hypercholesterolemia, and be useful in the treatment of hypertension, inflammatory conditions and diabetes. Seeds have also been found to possess insecticidal, fungicidal, and anti-microbial activities. The avocado seeds and rich in phenolic compounds, and these may play a role in the putative health effects. Historically, extracts of avocado seeds were also used as ink for writing and research in our laboratory has explored the potential colorant properties of a polyphenol oxidase-produced colored avocado seed extract. Here, we review the currently-available data on the bioactivity and other functional properties of avocado seeds. We discuss the strength of the available data, the putative active compounds, and potential directions for future studies. PMID- 23448444 TI - Bioactive polyphenols from grapes and wine emphasized with resveratrol. AB - Grape polyphenols are abundant. They play essential roles in the plant's life, particularly in defence mechanisms. Moreover, the grape, fresh or dried, is a widely consumed fruit by humans, as are its by-products, grape juice and wine. They also contain vast and highly varied quantities of polyphenols. Like other phytophenols, grape and wine resveratrol is considered a protective micronutrient. Resveratrol is a well known antioxidant, for example, a protector of low-density lipoproteins against oxidation. Its applications are therefore highly varied. Research supports the idea that wine consumed regularly, without excess, is a natural biological product possesses preventive properties, and not only well-known properties against vascular diseases (illustrated by the so called French paradox). At least in experimental models so far, resveratrol prevents infections, inflammation, neurodegenerative diseases, and cancer. This review addresses whether the pro-longevity properties of resveratrol are preserved in the human species. If such is the case, it will be possible to imagine new ways of eating based on natural foods, with or without supplements, based on resveratrol. On the other hand, studies such as ours are investigating the synergies between resveratrol and some of the many polyphenols found in wine. These studies should fill in the gaps between the study of a molecule tested in isolation or in a binary system (e.g., with alcohol) and this same molecule in its biological context. PMID- 23448443 TI - Tea and health: studies in humans. AB - Tea, next to water is the cheapest beverage humans consume. Drinking the beverage tea has been considered a healthpromoting habit since ancient times. The modern medicinal research is providing a scientific basis for this belief. The evidence supporting the health benefits of tea drinking grows stronger with each new study that is published in the scientific literature. Tea plant Camellia sinensis has been cultivated for thousands of years and its leaves have been used for medicinal purposes. Tea is used as a popular beverage worldwide and its ingredients are now finding medicinal benefits. Encouraging data showing cancer preventive effects of green tea from cell-culture, animal and human studies have emerged. Evidence is accumulating that black tea may have similar beneficial effects. Tea consumption has also been shown to be useful for prevention of many debilitating human diseases that include maintenance of cardiovascular and metabolic health. Various studies suggest that polyphenolic compounds present in green and black tea are associated with beneficial effects in prevention of cardiovascular diseases, particularly of atherosclerosis and coronary heart disease. In addition, anti-aging, antidiabetic and many other health beneficial effects associated with tea consumption are described. Evidence is accumulating that catechins and theaflavins, which are the main polyphenolic compounds of green and black tea, respectively, are responsible for most of the physiological effects of tea. This article describes the evidences from clinical and epidemiological studies in the prevention of chronic diseases like cancer and cardiovascular diseases and general health promotion associated with tea consumption. PMID- 23448445 TI - Consumption of polyphenol plants may slow aging and associated diseases. AB - Slowing aging is a widely shared goal. Plant-derived polyphenols, which are found in commonly consumed food plants such as tea, cocoa, blueberry and grape, have been proposed to have many health benefits, including slowing aging. In-vivo studies have demonstrated the lifespan-extending ability of six polyphenol containing plants. These include five widely consumed foods (tea, blueberry, cocoa, apple, pomegranate) and a flower commonly used as a folk medicine (betony). These and multiple other plant polyphenols have been shown to have beneficial effects on aging-associated changes across a variety of organisms from worm and fly to rodent and human. PMID- 23448446 TI - Epigenetic and disease targets by polyphenols. AB - An epigenetic change is defined as an alteration in gene expression that does not involve a change in the DNA sequence. Epigenetic modifications, including DNA methylation, histone modification (acetylation, methylation and phosphorylation) and miRNA, are critical for regulating developmental events. However, aberrant epigenetic mechanisms may lead to pathological consequences such as cardiovascular disease (CAD), neurodegenerative disease, obesity, metabolic disorder, bone and skeletal diseases and various cancers. Given that epigenetic modifications are heritable and reversible, in contrast to genetic changes, they have been identified as promising targets for disease prevention strategies. Over the past few decades, polyphenols, which are widely present in foods such as fruits and vegetables, have been shown to exhibit a broad spectrum of biological activities for human health. Polyphenols reverse adverse epigenetic regulation by altering DNA methylation and histone modification, and they modulate microRNA expression or directly interact with enzymes that result in the reactivation of silenced tumor suppressor genes or the inactivation of oncogenes. Therefore, dietary polyphenol- targeted epigenetics becomes an attractive approach for disease prevention and intervention. In this review, we summarize the current knowledge and underlying mechanisms of the most common dietary polyphenols and their influence on major epigenetic mechanisms associated with disease intervention. PMID- 23448440 TI - Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of foodstuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol- based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of 'potential' benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called 'Resveratrol Paradox', i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol's effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug. PMID- 23448447 TI - Breast cancer and flavonoids - a role in prevention. AB - Endogenous estrogens, such as 17beta-estradiol (E2), are implicated in the development of breast cancer. The putative mechanisms by which estrogens exert the carcinogenic effects have been recognized to involve the redox cycling of estrogen metabolites and subsequent estrogen-DNA adduct formation as well as the estrogen receptor-dependent pathway of estrogen-induced cell growth. The former pathway is regulated by phase I enzymes, mainly cytochrome P450 (CYP) 1A1, 1A2, and 1B1. Among them, CYP1B1 predominantly catalyzes the C4-position of E2 and forms carcinogenic 4-hydroxy-E2 (4-OHE2), whereas CYP1A1 and CYP1A2 convert E2 to noncarcinogenic 2-hydroxy-E2. Formed 4-OHE2 is further oxidized to semiquinones and quinones, which form DNA adducts, leading to mutagenic lesions. Consequently, CYP1B1 is highly expressed, and 4-OHE2 is predominantly detected in estrogen target neoplastic tissues. Moreover, invasion and metastasis are also involved in the development of breast cancer. Epidemiological studies suggest an inverse association between a higher intake of flavonoids and breast cancer risk. Flavonoids, which are widely distributed in the plant kingdom, have been recently reported as candidate compounds that can exert chemopreventive effects in estrogen-dependent or independent breast cancer. In this review, we provide a comprehensive overview of breast cancer and chemoprevention by flavonoids, mainly focusing on ER-mediated hormonal regulation, redox cycling of estrogen metabolites, and selective inhibition of CYP1B1. PMID- 23448449 TI - Human clinical studies of tea polyphenols in allergy or life style-related diseases. AB - Many previous epidemiological studies have revealed that green tea or green tea catechins contributed to the preveintion of lifestyle-related diseases. Several cohort studies on the relationship between green tea consumption and cardiovascular disease (CVD) risk/type 2 diabetes mellitus risk have been conducted. The results showed that green tea consumption (5 or more cups/day) was inversely associated with mortality from CVD and all causes. Within CVD mortality, the strongest inverse association was observed for stroke mortality. Furthermore, consumption of green tea, coffee, and total caffeine was associated with a reduced risk for type 2 diabetes. On the other hand, the analysis of randomized clinical trial (RCT) studies showed that the administration of green tea beverages or extracts resulted in significant reductions in serum total cholesterol and LDL-cholesterol concentrations, but had no apparent effect on HDL cholesterol. Green tea reduced fasting blood glucose levels in a small intervention trial, although no improvements in HbA1c levels were seen. Continuous intake of green tea containing catechins and caffeine (5 or more cups per day) may be beneficial for body weight management, vascular disease risk reduction via LDL-cholesterol improvement, and type 2 diabetes risk reduction through the lowering of fasting blood glucose levels. Epigallocatechin-3-O-(3-O methyl) gallate (EGCG3"Me) isolated from cv. "Benifuuki" green tea has been shown to strongly inhibit mast cell activation and histamine release after FcepsilonRI cross-linking through the suppression of tyrosine phosphorylation (Lyn) of cellular protein kinase, and the suppression of myosin light chain phosphorylation and high-affinity IgE receptor expression via the binding to 67 kDa laminin receptors. A double-blind clinical study on subjects with Japanese cedar pollinosis was carried out. At the eleventh week after starting intake, which was coincident with the most severe period of cedar pollen-scattering, symptoms such as nose blowing and eye itching were significantly relieved in the Benifuuki group compared with the placebo group. Six weeks of intake of Benifuuki green tea containing O-methylated catechins was useful for reducing some of the symptoms derived from Japanese cedar pollinosis, and did not affect any of the normal immune responses in the subjects with Japanese cedar pollinosis. Based on an investigation into the effects of the cultivars, tea seasons of crops and manufacturing methods, it was concluded that green or semi-fermented tea made from fully-matured Benifuuki in the second crop season should be consumed. PMID- 23448448 TI - Bioactivity of turmeric-derived curcuminoids and related metabolites in breast cancer. AB - While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurallyrelated metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10-16ug/mL) and secretion of osteolytic PTHrP (IC50=2-3ug/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58uM), demethoxycurcumin did not have any effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22-31uM) to the same degree as the curcuminoid mixture (IC50=16uM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations >=10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti cancer effects. PMID- 23448450 TI - Plant polyphenols and health benefitts. PMID- 23448451 TI - Anderson-Fabry disease: a multiorgan disease. AB - Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A. FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations (Table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional control of the vessels, secondary to endothelial dysfunction as a consequence of alpha galactosidase A deficiency. The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas (Fig. 19 A, B), irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, intestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index (MSSI) (Table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. PMID- 23448452 TI - Neurological complications of Anderson-Fabry disease. AB - Characteristic clinical manifestations of AFD such as acroparesthesias, angiokeratoma, corneal opacity, hypo/ and anhidrosis, gastrointestinal symptoms, renal and cardiac dysfunctions can occur in male and female patients, although heterozygous females with AFD usually seem to be less severely affected. The most prominent CNS manifestations consist of cerebrovascular events such as transient ischaemic attacks (TIAs) and (recurrent) strokes. For the most part, CNS complications in AFD have been attributed to cerebral vasculopathy, including anatomical abnormalities. The natural history of Fabry patients includes transitory cerebral ischaemia and strokes, even in very young persons of both genders. The mechanism is partly due to vascular endothelial accumulation of Gb 3. White matter lesions (WML) on occur MRI. Both males and females can be safely treated with enzyme replacement; and thus screening for Fabry disease of young stroke populations should be considered. There are, however, no hard data of treatment effect on mortality and morbidity. Stroke in Anderson-Fabry disease study of 721 patients with cryptogenic stroke, aged 18-55 years, showed a high prevalence of Fabry disease in this group: 5% (21/432) of men and 3% (7/289) of women. Combining results of both sexes showed that 4% of young patients with stroke of previously unknown cause had Fabry disease, corresponding to about 1-2% of the general population of young stroke patients. Cerebral micro- and macro vasculopathy have been described in Fabry disease. Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. Another Neurologic hallmark of Fabry disease (FD) includes small fiber neuropathy as well as cerebral micro- and macroangiopathy with premature stroke. Cranial MRI shows progressive white matter lesions (WML) at an early age, increased signal intensity in the pulvinar, and tortuosity and dilatation of the larger vessels. Conventional MRI shows a progressive load of white matter lesions (WMLs) due to cerebral vasculopathy in the course of FD. Another study has been conducted to quantify brain structural changes in clinically affected male and female patients with FD. The peripheral neuropathy in Fabry disease manifests as neuropathic pain, reduced cold and warm sensation and possibly gastrointestinal disturbances. Patients with Fabry disease begin having pain towards the end of the first decade of life or during puberty. Children as young as 6 years of age have complained of pain often associated with febrile illnesses with reduced heat and exercise tolerance. The patients describe the pain as burning that is often associated with deep ache or paresthesiae. Some patients also have joint pain. A high proportion of patients with Fabry disease is at increased risk of developing neuropsychiatric symptoms, such as depression and neuropsychological deficits. Due to both somatic and psychological impairment, health-related quality of life (QoL) is considerably reduced in patients with Fabry disease. Targeted screening for Fabry disease among young individuals with stroke seems to disclose unrecognized cases and may therefore very well be recommended as routine in the future. Furthermore, ischemic stroke is related to inflammation and arterial stiffness and no study had addressed this relationship in patients with AF disease and cerebrovascular disease, so this topic could represent a possible future research line. PMID- 23448453 TI - Fabry disease and cardiovascular involvement. AB - Fabry disease (FD, OMIM 301500) is a rare X-linked lysosomal storage disorder of the glycosphigolipid metabolism caused by total or partial deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Progressive intralysosomal accumulation of neutral glycosphingolipids in a variety of cell types triggers a cascade of pathophysiological events including cellular death, compromised energy metabolism, small vessel injury, K(Ca)3.1 channel dysfunction in endothelial cells, oxidative stress, impaired autophagosome maturation, tissue ischemia and, importantly, development of irreversible cardiac and renal tissue fibrosis, leading to major multisystemic manifestations. Cardiovascular complications of the disease are very frequent and contribute substantially to disease-related morbidity and mortality in men. Cardiovascular involvement is the leading cause of premature death in heterozygous female patients with FD. Left ventricular hypertrophy is the most prominent cardiac manifestation followed by conduction system disease, valve dysfunction, arrhythmias, vessel disease and coronary microvascular dysfunction. The diagnosis of subclinical forms of the disease, before the development of cardiac hypertrophy, using newer techniques (tissue doppler imaging, strain rate and cardiac magnetic resonance) is crucial to the early initation of the treatment. Greatest benefit of the enzyme replacement treatment is achieved when started at an early stage of the disease before extensive fibrosis or other irreversible tissue damage takes place. Fabry disease should be included in the differential diagnosis algorithm of idiopathic hypertrophy. Determination of Alpha-Gal A activity on plasma and peripheral leukocytes in males and genetic testing in females are the diagnostic gold standards. PMID- 23448454 TI - Cutaneous complications of Anderson-Fabry disease. AB - Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by a defect in the alpha-galactosidase A gene, which leads to the deficiency of the hydrolytic enzyme alpha-galactosidase A. The consequent inability to catabolize glycosphingolipids causes progressive accumulation of globotriaosylceramide in the vascular endothelium throughout the body. Fatalities in the classical phenotype may usually occur as a consequence of cerebral, cardiac or renal disease. Dermatological manifestations are a relevant feature of Fabry disease and include angiokeratomas, telangiectasiae, lymphedema, anhidrosis or hypohidrosis and pseudo-acromegalic facial appearance. The actual causal treatment for Fabry disease is the enzyme replacement therapy. Dermatologists have a key role, since cutaneous manifestations may lead to the diagnosis. This may help an early therapeutic intervention, reducing both morbidity and mortality. PMID- 23448455 TI - Anderson-Fabry disease in children. AB - Although clinical evidence of major organ damage is typical of adulthood, many of the signs and symptoms of Anderson Fabry Disease (AFD) occur frequently in childhood. The clinical phenotype of AFD in pediatric patients has been described in several studies which show a higher incidence and an earlier onset of symptoms in male patients than in females. These include neurological manifestations (acroparaesthesias, chronic neuropathic pain, hypo-anhidrosis, tinnitus, hearing, loss), gastrointestinal (GI) symptoms (abdominal pain and diarrhea), angiokeratomas, ocular abnormalities (cornea verticillata, tortuous retinal vessels and subcapsular cataracts). Such manifestations may impair quality of life and, because of their unspecific nature, rarely lead to an early diagnosis. In addition, signs of major organ damage (microalbuminuria or proteinuria, urinary hyperfiltration, impaired heart rate variability, left ventricular hypertrophy, stroke) are encountered in children with AFD. Clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa and agalsidase beta have been conducted in children, with clinical and pharmacodinamc effects proved by both enzyme formulations, whereas differences in safety profile and administration were found. Although several studies suggest that ERT should be started before irreversible damage in critical organs have occurred, the issue of when to initiate it has not yet been resolved. More controlled trials must be done in order to demonstrate that an early start of ERT could prevent adult complications and to assess the optimal timing of treatment in children with AFD. This review aims to provide an update of the current understanding for a better approach of pediatric AFD. PMID- 23448456 TI - Renal complications of Fabry disease. AB - Fabry disease is a progressive devastating disease caused by absent or deficient activity of lysosomal enzyme alpha-galactosidase A, with progressive accumulation of globotriaosylceramide (GL-3) within lysosomes in a different cell types. Accumulation of GL-3 and related glycosphingolipids in different cell types may create diverse clinical picture depending on the organ which is dominantly affected. Renal pathology progresses in severity with aging. Globotryaosil ceramide deposits may be found in different cell types within the kidney. Deposition within the glomeruli may be found in endothelial cells, mesangial cells, interstitial cells, with the highest level found within the podocytes. Although Fabry disease is not curable at the moment, availability of enzyme replacement therapy made it possible to treat this group of patients. Two formulations of recombinant human alpha-galactosidase A are present on the market: agalsidase alfa and agalsidase beta. Longer follow-up period is necessary to estimate the impact of ERT on mortality. Patients with end-stage renal disease caused by Fabry disease could be safely treated with enzyme replacement therapy regardless of the method of renal replacement therapy. PMID- 23448457 TI - Gastroenterological complications of Anderson-Fabry disease. AB - Fabry disease is a multisystemic X-linked lysosomal storage disorder, caused by the partial or complete deficiency of alpha-galactosidase A activity. The storage of glycosphingolipids in the vascular endothelium and in various tissues can lead to a broad spectrum of clinical manifestations. Renal failure, cardiovascular disease, and strokes are the main causes of morbidity and mortality. Gastrointestinal symptoms, although common, are often under-reported in the literature. This review covers the gastroenterological aspects of Fabry disease. PMID- 23448458 TI - Anderson Fabry disease: a multiorgan metabolic disease susceptible of treatment. PMID- 23448459 TI - Histone acetylation: from code to web and router via intrinsically disordered regions. AB - Structural changes of chromatin, which consists of nucleosomes and nucleosome associated factors, lead to functional changes that are important determinants of eukaryotic gene regulation. These structural changes are regulated by modifications of histones and DNA, both of which are components of nucleosomes, as well as by replacement of histone variants and the actions of noncoding RNAs. In studies of chromatin modifications, a great deal of attention has been paid to histone acetylation. Progress in understanding this subject has been extensive, including i) elucidation of the relationship of histone acetylation and gene activity; ii) the first isolation of a histonemodifying enzyme; iii) the first identification of a factor that recognizes a modified site; iv) elucidation of the mechanism by which histone modification leads to structural changes in nucleosomes; and v) elucidation of the mechanism of border formation between euchromatin and heterochromatin. Histone acetylation is considered to be fundamental in several fields, including studies of a) the role of chromatin and epigenetics in higher-order biochemical systems such as transcription, DNA replication, and repair; b) biological phenomena such as cell proliferation and differentiation; and c) cancer and aging, potentially leading to clinical applications. In this review, I will discuss the histone code hypothesis, at one time believed to represent a unified theory regarding the functions of histone modification. In addition, I will describe the "modification web theory, " by which the problems in the histone code hypothesis can be overcome, as well as the "signal router theory, " which explains the mechanisms of formation, development, and evolution of the modification web from a structural viewpoint. Lastly, I will illustrate how these novel theories partially explain the robustness of biological systems against various perturbations, and elucidate the strategy that a cell employs to avoid fatal fragility. PMID- 23448460 TI - Histone acetylation in neurodevelopment. AB - Post-translational modification of histones is a primary mechanism through which epigenetic regulation of DNA transcription does occur. Among these modifications, regulation of histone acetylation state is an important tool to influence gene expression. Epigenetic regulation of neurodevelopment contributes to the structural and functional shaping of the brain during neurogenesis and continues to impact on neural plasticity lifelong. Alterations of these mechanisms during neurodevelopment may result in later occurrence of neuropsychatric disorders. The present paper reviews and discusses available data on histone modifications, in particular histone acetylation, in neurogenesis considering results obtained in culture systems of neural progenitors as well as in in vivo studies. Possible teratogenic effects of altered histone acetylation state during development are also considered. The use during pregnancy of drugs such as valproic acid, which acts as a histone deacetylase inhibitor, may result during postnatal development in autistic-like symptoms. The effect of gestational administration of the drug has been, therefore, tested on adult hippocampal neurogenesis in animals showing behavioral impairment as a consequence of the drug administration at a specific stage of pregnancy. These experimental results show that adult neurogenesis in the hippocampal dentate gyrus is not quantitatively altered by gestational valproic acid administration. Future steps and goals of research on the role and mechanisms of histone acetylation in neurodevelopment are briefly discussed. PMID- 23448462 TI - Histone post-translational modifications to target memory-related diseases. AB - Epigenetic mechanisms, i.e. the control gene of expression without changing DNA sequence, include DNA methylation, histone post-translational modifications (PTMs) and microRNAs (miRNAs). Aberrant epigenetic modifications are associated with several pathological conditions, including brain diseases, resulting from environmental causes, ageing or genetic factors. The role of histone PTMs, including acetylation, phosphorylation, methylation and ubiquitylation, has been demonstrated in learning and memory, both in physiological conditions and in neuropathologies. Abnormalities in these modifications or in the machinery that control them are associated with several neurodegenerative, neuro-developmental and psychiatric diseases. Therefore, these epigenetic marks are promising targets to address memory-related diseases and strong efforts are presently focused on pharmacological and genetic approaches to this field. PMID- 23448463 TI - Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer's disease-like phenotype of a commonly used mouse model. AB - 4-Phenylbutyrate (PBA) is a histone deacetylase (HDAC) inhibitor whose efficacy in the Tg2576 mouse model of Alzheimer's disease (AD) is correlated with decreased tau phosphorylation, clearance of intraneuronal Abeta and restoration of dendritic spine density in hippocampal CA1 pyramidal neurons. PBA is also a chemical chaperone that facilitates cell proteostasis. To determine the relative contributions of HDAC inhibition and chaperone-like activity in the anti-AD effects of PBA, we compared the effect of PBA with that of sodium butyrate (NaBu), an HDAC inhibitor with no chaperone activity. In neuronal cultures from Tg2576 mice, we observed a correlation between histone 3 acetylation and decreased p-tau levels. Moreover, we observed a decrease in the processing of the amyloid precursor protein (APP) in Tg2576 neurons treated with PBA, but not with NaBu. In Tg2576 mice administered PBA or NaBu for 3 weeks, only PBA normalized the pathological AD markers, implicating, at least in part, other mechanism as the chaperone-like activity in the reversal of the AD-like phenotype of Tg2576 mice. Furthermore, treatment with PBA but not NaBu prevented the neuronal loss in the hippocampus of hAPPWT-overexpressing mice, as was particularly evident in the CA1 layer. In addition to its activity as a HDAC inhibitor, the chaperone activity of PBA appears to at least partially, mediate its reversal of the AD phenotype in Tg2576 mice and its neuroprotective effect in a model of hippocampal neuronal loss. PMID- 23448464 TI - Histone post-translational modifications in Huntington's and Parkinson's diseases. AB - Gene expression is controlled by several epigenetic mechanisms involving post translational modification of histones (acetylation, phosphorylation and others). These mechanisms in the brain are not only important for normal function but also for the development of pathologies when their derangement does occur. The present review deals with post-translational modifications of histones in two neurodegenerative diseases characterized by different etiology and pathological progression, Huntington's disease and Parkinson's disease. A relatively large body of evidence supports an important role of these mechanisms in Huntington's disease while knowledge of similar mechanisms in Parkinson's disease is at a lower degree of understanding. Starting from available information on pathologies, the present state of possible therapeutic targets is considered and future developments are discussed. PMID- 23448465 TI - Histone acetylation as a potential therapeutic target in motor neuron degenerative diseases. AB - Among hereditary diseases, the group of motor neuron diseases (MNDs) includes some of the most devastating and rapidly progressive lethal conditions. Although degeneration of motor neurons is common to all of them, the phenotypic spectrum of MNDs is relatively broad and ranges from perinatal conditions like spinal muscular atrophy (SMA) to adult-onset diseases such as amyotrophic lateral sclerosis (ALS). While the understanding of the pathology of the diseases is constantly growing, the development of therapeutic approaches lags behind. In fact, there is no approved therapy for MNDs available at the moment. Recent findings demonstrated the existence of some patterns that are shared by several MNDs such as transcriptional dysregulation. In addition, conditions like SMA or certain types of Charcot-Marie-Tooth disease provide some defined targets which may be amenable to therapeutic approaches. Consequently, counteracting this dysregulation may be a valuable therapeutic option and ameliorate disease progression in MND patients. The feasibility of such an approach has been proven during the past years by the epigenetic treatment of various neoplastic entities with histone deacetylase inhibitors (HDACi). On these grounds, also epigenetic therapy of MNDs has become a promising option. So far, several HDACi have been tested in vitro and in animal models and some proceeded further and were evaluated in clinical trials. This review will summarize the advances of HDACi in MNDs and will give a perspective where the road will lead us. PMID- 23448461 TI - Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders. AB - Neuropsychiatric pathologies, including neurodegenerative diseases and neurodevelopmental syndromes, are frequently associated with dysregulation of various essential cellular mechanisms, such as transcription, mitochondrial respiration and protein degradation. In these complex scenarios, it is difficult to pinpoint the specific molecular dysfunction that initiated the pathology or that led to the fatal cascade of events that ends with the death of the neuron. Among the possible original factors, epigenetic dysregulation has attracted special attention. This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300). We first comment on the role of chromatin acetylation and the enzymes that control it, particularly CBP and p300, in neuronal plasticity and cognition. Next, we describe the involvement of these proteins in intellectual disability and in different neurodegenerative diseases. Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders. PMID- 23448467 TI - Targeting histone acetylation for neuroprotection. PMID- 23448466 TI - Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. AB - Ischemic stroke is a leading cause of death and disability worldwide, with few available treatment options. The pathophysiology of cerebral ischemia involves both early phase tissue damage, characterized by neuronal death, inflammation, and blood-brain barrier breakdown, followed by late phase neurovascular recovery. It is becoming clear that any promising treatment strategy must target multiple points in the evolution of ischemic injury to provide substantial therapeutic benefit. Histone deacetylase (HDAC) inhibitors are a class of drugs that increase the acetylation of histone and non-histone proteins to activate transcription, enhance gene expression, and modify the function of target proteins. Acetylation homeostasis is often disrupted in neurological conditions, and accumulating evidence suggests that HDAC inhibitors have robust protective properties in many preclinical models of these disorders, including ischemic stroke. Specifically, HDAC inhibitors such as trichostatin A, valproic acid, sodium butyrate, sodium 4 phenylbutyrate, and suberoylanilide hydroxamic acid have been shown to provide robust protection against excitotoxicity, oxidative stress, ER stress, apoptosis, inflammation, and bloodbrain barrier breakdown. Concurrently, these agents can also promote angiogenesis, neurogenesis and stem cell migration to dramatically reduce infarct volume and improve functional recovery after experimental cerebral ischemia. In the following review, we discuss the mechanisms by which HDAC inhibitors exert these protective effects and provide evidence for their strong potential to ultimately improve stroke outcome in patients. PMID- 23448468 TI - ULK1 plays a critical role in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge. AB - This study was designed to evaluate the role of ULK1 in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge. Wild type and AMPK knockout mice were challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial function was evaluated using echocardiography and edge detection. Western blot analysis was employed to evaluate the levels of AMPK, Raptor, mTOR, the AMPK downstream signal ULK1 and autophagy markers Beclin-1 and LC3-II. siRNA was used to knockdown ULK1 in H9C2 myoblasts. GFP-LC3 puncta was used to evaluate autophagosome formation. Alcohol challenge compromised cardiac function as evidenced by decreased fractional shortening, peak shortening and intracellular Ca2+ rise, prolonged relengthening and intracellular Ca2+ decay in WT mice, the effects of which were mitigated by AMPK knockout. Ethanol exposure facilitated myocardial autophagy as evidenced by enhanced LC3-II level, as well as phosphorylation of AMPK, Raptor, and dephosphorylation of mTOR and ULKI in WT hearts, which were alleviated by AMPK knockout. Pharmacological inhibition of AMPK using compound C attenuated ethanol-induced autophagosome formation, AMPK phosphorylation, ULK1 dephosphorylation and apoptosis. Ethanol exposure-induced cardiomyocyte contractile defects and autophagosome accumulation were reversed by the autophagy inhibitor 3-MA. Similarly, knockdown of ULK1 using siRNA in H9C2 cells ablated ethanol-induced autophagosome accumulation, LC3-II expression and cell death. Lysosomal inhibition using bafilomycin, E64-D and pepstatin A potentiated ethanol-induced increase in autophagosome formation. Taken together, our results suggest that ULK1 may play a critical role in AMPK-mediated myocardial autophagy, apoptosis and contractile dysfunction following acute alcohol challenge. PMID- 23448469 TI - Targeted radiosensitization in prostate cancer. AB - Radiotherapy is one of the treatment options for locally or regionally advanced prostate cancer, but radioresistance of prostate cancer cells is a practical limitation of radiotherapy. The identification of molecular targets of radioresistance in prostate cancer is important to improve therapeutic intervention. The aim of this review is to give more biological insight into some well known processes involved in radioresistance of prostate cancer especially Apoptotic pathway; DNA damage response; and NF- kappaB(nuclear factor kappalight- chain-enhancer of activated B cells) signaling pathway. This review integrates salient, published, research findings with underlying molecular mechanisms, preclinical efficacy, and potential clinical applications of combining radiotherapy with these molecular targeted agents for the treatment of prostate cancer. PMID- 23448470 TI - Opiate-induced analgesia: contributions from mu, delta and kappa opioid receptors mouse mutants. AB - The three opioid receptors, mu, delta and kappa all mediate analgesia, and knockout mice with opioid receptor deletion have proven unique tools to investigate in vivo opioid pharmacology. Since a few years, a number of new mouse lines have been engineered, with several distinct mutations of the mu receptor, to assess the role of specific amino acid residues or peptidic sequences of this receptor in analgesia and tolerance. The analysis of analgesia in mice deleted in kappa receptor and triple mu/delta/kappa receptor knockout mice have provided advances in opioid-induced analgesia. Also, the global and conditional deletion of the delta receptor in peripheral nociceptive neurons has revealed the participation of the targeted receptors in opioid-induced analgesia. Another approach for the study of opioid receptors is the visualization of these receptors in vivo, by engineering of knock-in mice with fluorescently tagged receptors. A mouse line with a fluorescent delta receptor has allowed live imaging of this receptor in behavioral paradigms and first studies on ligand biased agonism at this receptor in vivo. The studies with mutant mouse lines for opioid receptors, combined with novel molecular and pharmacological approaches, will allow to develop novel strategies for opioid-based analgesia. This review summarizes the different genetically modified mouse lines for opioid receptors as well as the data and concepts inferred from analgesia results on these mutant mouse lines. PMID- 23448471 TI - Tritiated opioid receptor ligands as radiotracers. AB - Tritiated opioid ligands are essential tools for the identification of opioid receptors. This review deals with the syntheses of tritiated opioid peptide derivatives, including enkephalins, dynorphins, dermorphins, deltorphins and endomorphins, and also discusses tritium-labeled nonpeptide opioids. It additionally focuses on the relevance of tritium-labeled opioid compounds as research tools for investigating opioid receptor pharmacology. Agonists and antagonists are used for the characterization of new opioid ligands by means of radioreceptor binding assays. Further topics covered in this review are the distribution of the endogenous peptides in the central nervous system and peripheral tissues, and degradation studies of opioids in brain membrane preparations and the blood. PMID- 23448472 TI - Current kappa opioid receptor ligands and discovery of a new molecular scaffold as a kappa opioid receptor antagonist using pharmacophore-based virtual screening. AB - The kappa opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral nervous systems, and are specifically activated by endogenous opioids derived from prodynorphin. They are members of the G protein-coupled receptor superfamily, and the crystal structure of the human KOR was recently elucidated. KORs were initially studied for their involvement in mediation of pain as stimulation of KOR produces analgesia and minimizes abuse liability and other side effects. Nowadays, the KOR is rapidly emerging as an important target for the treatment of a variety of other human disorders. Specifically, the KOR system has become increasingly implicated as a modulator of stress-related and addictive behaviors. Several selective KOR partial agonists and antagonists have been developed as potential antidepressants, anxiolytic and anti-addiction medications. Although many KOR ligands have not demonstrated desirable pharmacological properties, some have been shown to be viable drug candidates. Herein, we describe chemical and pharmacological developments on KOR ligands, advantages and challenges, and potential therapeutic applications of ligands for KORs. In the second part, recent advances in the KOR drug design utilizing computational approaches are presented, with focus on the discovery of a new naturally derived scaffold, sewarine, as a novel class of selective KOR ligands with antagonist properties, using a pharmacophore-based virtual screening strategy. PMID- 23448473 TI - Functionalization of the carbonyl group in position 6 of morphinan-6-ones. Development of novel 6-amino and 6-guanidino substituted 14-alkoxymorphinans. AB - The well-known opioid agonists, oxycodone and oxymorphone, and the opioid antagonists, naloxone and naltrexone, are commonly used clinical agents and research tools in the opioid field. They belong to the class of morphinan-6-ones, and produce their pharmacological effects by interacting with opioid receptors, i.e. mu (MOR), delta (DOR) and kappa (KOR). The search for potent agonists and antagonists has continuously engaged the interest of pharmaceutical research, aiming for the identification of safer therapeutic agents or discovery of opioids with novel therapeutic properties and with lesser unwanted side effects. The chemically highly versatile carbonyl group in position 6 of mophinan-6-ones permits functionalization and modification leading to numerous opioid ligands. We have focused on representative examples of various derivatives and interesting approaches for the development of structurally distinct molecules with substitution at C6 (e.g. 6-methylene, 6-hydroxy, 6-amido, bifunctional ligands), as preclinically and clinically valuable opioids. In this work, the development of 6-amino and 6-guanidino substituted 14-alkoxymorphinans, including the synthesis and pharmacological investigations is presented. The new approach represented by the introduction of amino and guanidino groups into position 6 of the morphinan skeleton of 14-O-methyloxymorphone, led to compounds with high efficacy, MOR affinity and selectivity, which act as potent antinociceptive agents. Altogether, as a consequence of target drug design and synthetic efforts in the field of morphinan-6-ones, we achieve a better understanding of the function of the opioid system, and such efforts may open new avenues for further investigations. PMID- 23448474 TI - Essential structure of the kappa opioid receptor agonist nalfurafine for binding to the kappa receptor. AB - The selective kappa opioid receptor agonist nalfurafine was launched in 2009 as an antipruritic drug for patients undergoing hemodialysis. It is the first clinically used compound with high selectivity for the kappa opioid receptor. Nalfurafine had a different pharmacological feature from other kappa opioid agonists. Nalfurafine induced neither addictive nor aversive effects, whereas other kappa agonists such as U- 50,488H or salvinorin A produced psychotomimetic effects like dysphoria. Therefore, identification of the essential structural moieties of nalfurafine for binding to the kappa opioid receptor was important for elucidation of the pharmacological discrepancies observed with these kappa opioid agonists. Based on the investigations of various nalfurafine derivatives, the essential structural moieties of nalfurafine were unveiled. Both the nitrogen substituted by a cyclopropylmethyl group and the 6-amide side chain were indispensable. The phenol ring was important for obtaining strong binding affinities for the opioid receptors, but not indispensable for exerting selectivity for the kappa receptor. This structure-activity information is expected to lead to the development of novel kappa opioid receptor selective agonists. PMID- 23448475 TI - Microglia activation precedes the anti-opioid BDNF and NMDA receptor mechanisms underlying morphine analgesic tolerance. AB - Herein, we investigated the role of periaqueductal gray (PAG)-resident microglia in the development of morphine tolerance and its underlying mechanisms. We showed that clodronate and minocycline known as microglia inhibitors reversed morphine tolerance, providing proof that microglia activation has key role in the development of morphine tolerance. The microglia-mediated anti-opioid mechanism occurs via sequential BDNF release and NMDA expression. Experimental evidence is provided here as conditional bdnf knockout mice (bdnf-/-) failed to develop tolerance following Cre-recombinase adenovirus treatment. Increased BDNF expression followed microglia activation in acute minocycline treatment reversible manner. Following BDNF release, NR2A subunit of NMDA receptor was upregulated in anti-BDNF reversible manner showing the contribution of BDNF signaling in the control of NMDA receptor expression following chronic morphine treatment. Our data provide compelling evidence that microglia activation and BDNF release are key regulators in opioid tolerance mechanism via glutaminergic synapse plasticity. PMID- 23448476 TI - Opioid receptor interacting proteins and the control of opioid signaling. AB - Opioid receptors are seven-transmembrane domain receptors that couple to intracellular signaling molecules by activating heterotrimeric G proteins. However, the receptor and G protein do not function in isolation but their activities are modulated by several accessory and scaffolding proteins. Examples include arrestins, kinases, and regulators of G protein signaling proteins. Accessory proteins contribute to the observed potency and efficacy of agonists, but also to the direction of signaling and the phenomenon of biased agonism. This review will present current knowledge of such proteins and how they may provide targets for future drug design. PMID- 23448477 TI - The use of bifunctional NOP/mu and NOP receptor selective compounds for the treatment of pain, drug abuse, and psychiatric disorders. AB - The NOP receptor, the fourth receptor in the opioid receptor family, is found throughout the brain and is involved in a variety of CNS systems and pathways. The endogenous ligand for NOP receptors, nociceptin/orphanin FQ (now called N/OFQ), was originally thought to increase a painful stimulus since intracerebroventricular (i.c.v.) administration of this heptadecapeptide led to a decrease in tail-flick and hot-plate latency in mice. Further studies suggested that N/OFQ blocks opiate analgesia when administered i.c.v. but potentiates opiate analgesia and has antinociceptive activity when administered intrathecally. I.c.v. administration of N/OFQ has other beneficial actions including inhibition of reward induced by several different abused drugs, as well as anti-anxiety activity. Recent work has demonstrated that individual small molecules that activate both NOP and mu receptors possess mu-mediated antinociceptive activity with reduced reward, as determined by conditioned place preference tests. Furthermore, selective NOP receptor agonists appear to be active in certain chronic pain models and reduce both drug craving and anxiety. NOP receptor antagonists may also have therapeutic benefits since both peptide and small molecule antagonists have anti-depressant activity in two different animal models. Therefore, both selective NOP receptor compounds and non-selective compounds, with both NOP receptor and mu opioid receptor activity, appear to have potential for clinical use for several neurological and psychiatric disorders including acute and chronic pain, drug abuse, anxiety and depression. PMID- 23448478 TI - Lack of regulatory changes of u-opioid receptors by 14-methoxymetopon treatment in rat brain. Further evidence for functional selectivity. AB - Here we have studied regulatory changes of u-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting u-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of u-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down regulated the endogenous u-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of u-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that u-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist- directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence. PMID- 23448479 TI - The u opioid receptor and ligands acting at the u opioid receptor, as therapeutics and potential therapeutics. AB - Although the u opioid receptor (MOR) was pharmacologically and biochemically identified in binding studies forty years ago, its structure, function, and true complexity only have emerged after its cloning in 1993. Continuous efforts from many laboratories have greatly advanced our understanding of MORs, ranging from their anatomic distribution to cellular and molecular mechanisms, and from cell lines to in vivo systems. The MOR is recognized as the main target for effective pain relief, but its involvement in many other physiological functions has also been recognized. This review provides a synopsis on the history of research on MORs and ligands acting at the MOR with the focus on their clinical and potential use as therapeutic drugs, or as valuable research tools. Since the elucidation of the chemical structure of morphine and the characterization of endogenous opioid peptides, research has stimulated the development of new generations of MOR ligands with distinct pharmacological profiles (agonist, antagonist, mixed agonist/antagonist and partial agonist) or site of action (central/peripheral). Discovery of therapeutically useful morphine-like drugs and innovative drugs with new scaffolds, with several outstanding representatives, is discussed. Extensive efforts on modifications of endogenous peptides to attain stable and MOR selective analogs are overviewed with stimulating results for the development of peptide-based pharmaceuticals. With pharmacophore modeling as an important tool in drug discovery, application of modern computational methodologies for the development of morphinans as new MOR ligands is described. Moreover, the crystal structure of the MOR available today will enable the application of structure based approaches to design better drugs for the management of pain, addiction and other human diseases, where MORs play a key role. PMID- 23448480 TI - Opioid receptors and their ligands in the musculoskeletal system and relevance for pain control. AB - Interest in opioid drugs like morphine, as the oldest and most potent pain killing agents known, has been maintained through the years. One of the most frequent chronic pain sensations people experience is associated with pathological conditions of the musculoskeletal system. Chronic musculoskeletal pain is a major health problem, and an adequate management requires understanding of both peripheral and central components, with more attention drawn to the former. Intense experimental and clinical research activities resulted in important knowledge on the mechanisms and functions of the endogenous opioid system located in the periphery. This review describes the occurrence and distribution of endogenous opioids and their receptors in the musculoskeletal system, and their role in pain control in musculoskeletal disorders, such as rheumatoid arthritis and osteoarthritis. Using different techniques, including immunohistochemistry, electron microscopy or radioimmunoassay, expression of enkephalins, dynorphin, beta-endorphin, and endomorphins was demonstrated in musculoskeletal tissues of animals and humans. Localization of opioid peptides was found in synovial membrane, periosteum, bone and bone marrow, loose connective tissue, the paratenon and musculotendinous junction of the achilles tendon. Animal and human studies have also demonstrated expression of u, delta and kappa opioid receptor proteins in musculoskeletal tissues using radioligand binding assays, autoradiography, electrophysiology, immunohistochemistry and Western blotting. Opioid receptor gene expression was reported based on polymerase chain reaction and in situ hybridization techniques. Combining morphological and quantitative approaches, important evidence that the musculoskeletal apparatus is equipped with a peripheral opioid system is provided. Demonstration of the occurrence of an endogenous opioid system in bone and joint tissues represents an essential step for defining novel pharmacological strategies to attain peripheral control of pain in musculoskeletal disorders. PMID- 23448481 TI - Hybrid opioid/non-opioid ligands in pain research. AB - To address the different types of pain (e.g. acute, chronic, neuropathic) different classes of medications, mainly non-steroidal anti-inflammatory drugs and narcotics (opioids), are used. More specifically, the alleviation or treatment of moderate to severe pain states commonly invokes the use of opioids. Unfortunately, their chronic administration induces various undesirable side effects, such as for example physical dependence and tolerance. One strategy to overcome these major side effects and to prolong the antinociceptive efficiency of the applied drugs involves the creation of multifunctional compounds which contain hybridized structures. Combination of opioid agonist and antagonist pharmacophores in a single chemical entity has been considered and extensively investigated, but opioids have also been combined with other bioactive neurotransmitters and peptide hormones that are involved in pain perception (e.g. substance P, neurotensin, cholecystokinin, cannabinoids, melanocortin ligands, etc.). Such novel chimeras (also called designed multiple ligands or twin/triplet drugs), may interact independently with their respective receptors and potentially result in more effective antinociceptive properties. The designed multiple ligands presented in this work include opioid-non-opioid peptide dimer analogs, mixed peptidic- non-peptidic bifunctional ligands and dual non-peptidic dimers. The main focus herein is placed on the design and biological evaluation of these multiple opioid compounds, rather than the synthetic approach and preparation. PMID- 23448483 TI - Structural, biochemical and non-traditional cardiovascular risk markers in PCOS. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome of reproductive and metabolic derangements. The combination of anovulation and hyperandrogenism signifies the classic form of PCOS which displays the adverse metabolic phenotype of the syndrome. This phenotype includes visceral obesity and insulin resistance as well as a constellation of other traditional cardiovascular risk factors, mainly low grade inflammation, disturbances of glucose metabolism and dyslipidemia. The resultant increased risk for cardiovascular disease may affect not only obese but also lean women with classic PCOS. The mechanisms underlying the increased cardiovascular risk in the context of PCOS may include not only metabolic aberrations, but also hormonal factors, in particular hyperandrogenemia. However, the consequences in terms of CV morbidity remain questionable due to the difficulties in conducting long-term, prospective studies aimed at identifying potential late-arriving clinical outcomes. PMID- 23448484 TI - Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. AB - Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus. PMID- 23448485 TI - Why does obesity increase the risk for cardiovascular disease? AB - Insulin resistance and inflammation are recognized as important links between obesity and cardiovascular disease (CVD). Plasma free fatty acids (FFA), either released from the abnormally enlarged adipose tissue or as part of the excessive nutrient intake, produce insulin resistance and inflammation. Both insulin resistance and inflammation are tightly linked to several independent CVD risk factors such as type 2 diabetes (T2DM), hypertension, dyslipidemia and disorders of blood coagulation. Several hypotheses have been proposed to explain how increased plasma FFA levels can cause insulin resistance including a) the lipid metabolite hypothesis, b) the inflammation hypothesis, c) the hyperinsulinemia hypothesis and d) the endoplasmic reticulum (ER) stress hypothesis. The latter does not require presence of elevated plasma FFA levels and thus provides a mechanism to explain the development of insulin resistance and inflammation in all obese individuals, i.e., those with and without elevated plasma FFA levels. Hyperinsulinemia per se has been suspected to cause CVD based on epidemiologic studies which have associated chronic hyperinsulinemia with CVD without, however, establishing a cause and effect relationship. There are, however, newer results which support the hypothesis that chronic hyperinsulinemia per se can promote the development of CVD. For instance, hyperinsulinemia can activate triglyceride formation, several matrix metalloproteinases (MMP), and the tissue factor pathway of blood coagulation, all of which are known to be associated with CVD, even in the presence of "metabolic insulin resistance". PMID- 23448486 TI - Role of adiponectin in the metabolic syndrome: current perspectives on its modulation as a treatment strategy. AB - Adiponectin, a secretory protein specifically expressed by adipose tissue, has been shown to play a critical role in the maintenance of metabolic homeostasis. A deficiency of adiponectin has been linked to a wide variety of metabolic abnormalities, including obesity and associated disorders such as insulin resistance, hyperglycemia, dyslipidemia, hypertension and nonalcoholic fatty liver disease, collectively referred to as the "metabolic syndrome". Conversely, increased expression of adiponectin corrects these abnormalities, as revealed by the positive metabolic effects observed in genetic over expression studies or by administration of recombinant adiponectin. This has led to widespread interest in its role as a therapeutic target for treatment of a range of metabolic disorders such as diabetes mellitus, obesity, inflammatory and cardiovascular diseases. Various therapeutic approaches targeted at increasing adiponectin levels, or its activity, are being explored. These consist of increasing expression of adiponectin or its receptors by inducers, increasing circulating levels of adiponectin by administering recombinant protein, peptide mimetic approaches, or increasing expression/activity of its downstream effectors such as AMPK or PPAR alpha. Many of these approaches have achieved therapeutic benefits in animal models of metabolic diseases. Despite the profusion of research on adiponectin and ways to modulate it, there are limited number of studies focused on smallmolecule based-therapeutic approaches. In this review, we summarize what is currently known with respect to the therapeutic potential of adiponectin and discuss the challenges in designing small molecule-based therapies. PMID- 23448487 TI - Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). AB - Chronic low-grade subclinical inflammation has been increasingly recognized as an interposer in the endocrine, metabolic and reproductive disturbances that characterize the polycystic ovary syndrome (PCOS). Abdominal adiposity and obesity are often present in PCOS. Mounting evidence indicates that adipose tissue is involved in innate and adaptive immune responses. Continuous release of inflammatory mediators such as cytokines, acute phase proteins, and adipokines perpetuates the inflammatory condition associated with obesity in women with PCOS, possibly contributing to insulin resistance and other long-term cardiometabolic risk factors. Genetic variants in the genes encoding inflammation related mediators underlie the development of PCOS and their interaction with environmental factors may contribute to the heterogeneous clinical phenotype of this syndrome. In the future, strategies ameliorating inflammation may prove useful for the management of PCOS and associated conditions. PMID- 23448488 TI - Roles of p38-MAPK in insulin resistant heart: evidence from bench to future bedside application. AB - Insulin resistance is associated with the impairment of the response of insulin receptor to insulin, resulting in the reduction of glucose uptake, leading to the alteration of myocardial glucose metabolism, impairment of cardiac electrophysiology, and increased susceptibility to ischemia-induced myocardial injury. Insulin resistance is associated with the impairment of the intracellular insulin signal transduction pathway. Among the MAPK family, p38-MAPK is a serine/threonine protein kinase, which has been shown to play an important role in cellular responses to various kinds of stress, including insulin resistance. Since growing evidence indicates the involvement of p38-MAPK in cardiovascular dysfunction, it is possible that the activation of p38-MAPK is responsible in part as a causative mechanism for cardiovascular complications in the insulin resistant heart. In addition, several anti-diabetic drugs have been shown to affect the myocardial p38-MAPK pathway. The effect of these drugs on p38-MAPK could be associated with their cardiovascular results in patients with insulin resistance. In this article, the signal transduction pathways of myocardial p38 MAPK activation in the insulin resistant heart, as well as the effects of anti diabetic drugs on the myocardial p38-MAPK pathway, are comprehensively reviewed. Furthermore, the possible therapeutic approach regarding the utilization of a p38 MAPK inhibitor in diabetes patients to prevent cardiovascular complications is also addressed. PMID- 23448489 TI - MicroRNAs as early biomarkers in obesity and related metabolic and cardiovascular diseases. AB - The increasing prevalence of obesity has significant implications for healthcare, more particularly since it is a major risk factor for type 2 diabetes and cardiovascular diseases. However, not every obese patient is at the same risk of developing future metabolic and cardiovascular complications. Therefore, there is an urgent need for novel biomarkers for early identification of obese patients at high risk. Possible candidate biomarkers are microRNAs, which are highly conserved non-coding RNA molecules of approximately 22 nucleotides that exert post-transcriptional effects on gene expression. They are expressed in a tissue- and cell-type specific manner, play essential roles in many biological and pathological processes and are released in human peripheral blood in a disease specific manner where they remain stable due to association with lipoprotein and phospholipids. All these characteristics suggest that they are putative diagnostic biomarkers. This review summarizes microRNAs with a functional role in the pathogenesis of atherosclerosis, myocardial infarction, ischemia/reperfusion injury and cardiac remodeling. It emphasizes those which have already been deregulated in association with obesity-related risk factors clustered in the metabolic syndrome. It demonstrates that several microRNAs which have been claimed to be biomarkers for cardiovascular diseases have already been deregulated in association with metabolic disorders prior to cardiovascular diseases. Finally, it summarizes which of these functionally validated microRNAs are deregulated in the circulation making them easily accessible for detection and thus into candidate biomarkers for early diagnosis of obesity-induced cardiovascular events. PMID- 23448490 TI - Insulin resistance, oxidative stress and cardiovascular complications: role of sirtuins. AB - Cardiovascular disease (CVD) is one of the major lifestyle associated disorders and leading causes of death worldwide. The incidence of CVD in diabetic patients has increased up to 3 folds and it became the major risk for diabetes associated morbidity and mortality. Insulin resistance and oxidative stress both play a central role in the pathogenesis and progression of diabetes. The high prevalence of CVD among diabetic patients suggests the role of insulin resistance and oxidative stress in developing cardiovascular complications. Finding molecular mechanisms which could control both insulin resistance and oxidative stress would be more efficacious in improving the cardiovascular complications. Recent literatures show that an epigenetic mechanism could control or regulate the cardiovascular complications in diabetes. Sirtuins, a group of enzymes, modulate epigenetic changes by deacetylating histone and non-histone proteins. These enzymes are distributed in different cell organelles and are found to regulate different biological processes. Recent findings showed that sirtuins modulate different important proteins related to insulin signaling pathway and oxidative stress. This review summarizes how sirtuins could affect the insulin resistance and oxidative stress pathways in cardiovascular system and thus attenuate the cardiovascular complications. Understanding the role of sirtuins in insulin resistance and oxidative stress will increase the prospects for controlling or preventing cardiovascular complications in the future. PMID- 23448492 TI - Mitochondrial dysfunction and oxidative stress in insulin resistance. AB - Evidence is mounting of the involvement of mitochondrial dysfunction in insulin resistance, diabetes and associated complications. This review aims to provide an overview of the effects of insulin resistance on mitochondrial function in several tissues. We consider the pathogenesis of insulin resistance from a mitochondrial perspective and contemplate potential beneficial effects of strategies aimed at modulating mitochondrial function in insulin resistance, including insulin and insulin-sensitizing drugs, antioxidants, and selectively targeting antioxidants to mitochondria. PMID- 23448493 TI - Endothelial dysfunction in morbid obesity. AB - Morbid obesity is a chronic multifunctional disease characterized by an accumulation of fat. Epidemiological studies have shown that obesity is associated with cardiovascular and metabolic disorders. Endothelial dysfunction, as defined by an imbalance between relaxing and contractile endothelial factors, plays a central role in the pathogenesis of these cardiometabolic diseases. Diminished bioavailability of nitric oxide (NO) contributes to endothelial dysfunction and impairs endothelium- dependent vasodilatation. But this is not the only mechanism that drives to endothelial dysfunction. Obesity has been associated with a chronic inflammatory process, atherosclerosis, and oxidative stress. Moreover levels of asymmetrical dimethyl-L-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are elevated in obesity. On the other hand, increasing prostanoid-dependent vasoconstriction and decreasing vasodilator prostanoids also lead to endothelial dysfunction in obesity. Other mechanisms related to endothelin-1 (ET-1) or endothelium derived hyperpolarizing factor (EDHF) have been proposed. Bariatric surgery (BS) is a safe and effective means to achieve significant weight loss, but its use is limited only to patients with severe obesity including morbid obesity. BS also proved efficient in endothelial dysfunction reduction improving cardiovascular and metabolic comorbidities associated with morbid obesity such as diabetes, coronary artery disease, nonalcoholic fatty liver disease and cancer. This review will provide a brief overview of the mechanisms that link obesity with endothelial dysfunction, and how weight loss is a cornerstone treatment for cardiovascular comorbidities obesity-related. A better understanding of the mechanisms of obesity-induced endothelial dysfunction may help develop new therapeutic strategies to reduce cardiovascular morbidity and mortality. PMID- 23448494 TI - New insights into insulin resistance, cardiovascular diseases and oxidative stress: pathophysiological and clinical consequences. PMID- 23448495 TI - Anomalous origin of the left coronary artery from the proper sinus with acute angulation and an intramural segment. AB - This is the first report of a coronary artery with an anomalous origin from the proper sinus resulting in ischemic events in a child. Transthoracic echocardiogram, computed tomogram, and coronary angiogram revealed that, although the left main coronary trunk originated from the left sinus, its ostium was displaced horizontally and was located near the commissure between the left and noncoronary valve cusps. Moreover, it was associated with an acute take off angle and an intramural segment, which are known contributing features for ischemia in cases of anomalous origin of a coronary artery from the wrong sinus. Surgical intervention, involving the unroofing procedure, was employed successfully to eliminate the ischemic events. At the latest follow up, no chest pain was reported and the transthoracic echocardiogram showed no stenosis of the neo ostium. Even in a coronary artery that originates from the proper sinus, an abnormal ostial location could be associated with an acute takeoff angle and an intramural segment. This finding is extremely rare but entails the risk of ischemia and sudden death. PMID- 23448491 TI - Cardiac aging and insulin resistance: could insulin/insulin-like growth factor (IGF) signaling be used as a therapeutic target? AB - Intrinsic cardiac aging is an independent risk factor for cardiovascular disease and is associated with structural and functional changes that impede cardiac responses to stress and to cardio-protective mechanisms. Although systemic insulin resistance and the associated risk factors exacerbate cardiac aging, cardiac-specific insulin resistance without confounding systemic alterations, could prevent cardiac aging. Thus, strategies aimed to reduce insulin/insulin like growth factor (IGF) signaling in the heart prevent cardiac aging in lower organisms and in mammals but the mechanisms underlying this protection are not fully understood. In this review, we describe the impact of aging on the cardiovascular system and discuss the mounting evidence that reduced insulin/IGF signaling in the heart could alleviate age-associated alterations and preserve cardiac performance. PMID- 23448496 TI - The chicken hypersensitivity site 4 core insulator blocks promoter interference in lentiviral vectors. AB - Lentiviral vectors, including double internal promoters, can be used to express two transgenes in a single vector construct; however, transcriptional activities from double internal promoters are often inhibited by promoter interference. To determine whether the chicken hypersensitivity site 4 insulator (cHS4) could block promoter interference, lentiviral vectors including an MSCV-U3 promoter (Mp) and an EF1alpha promoter (Ep) were generated, and transgene expression was evaluated among transduced cells. In the Ep-Mp configuration, transcriptional activity from Mp was much lower, while Mp-Ep had similar transcription levels from both promoters. The cHS4 core insulator increased expression levels from Mp in HeLa cells, hematopoietic cell lines, and mouse peripheral blood cells following hematopoietic stem cell transplantation transduced with the Mp-Ep configured vector. This blocking function was mainly mediated by barrier activity regions in the insulator but not by CCCTC-binding factor (CTCF) binding sites. Cytosine-phosphate-guanine (CpG) methylation did not contribute to this barrier activity. In summary, combining the cHS4 insulator in double promoter vectors can improve transgene expression levels in various cell lines and mouse hematopoietic repopulating cells. These findings are useful for developing hematopoietic stem cell gene therapy. PMID- 23448498 TI - Ultrasound-based multimodal molecular imaging and functional ultrasound contrast agents. AB - Ultrasound-based multimodal molecular imaging and functional ultrasound contrast agents (UCAs) have garnered great interest in biomedical imaging over the past few years. With the rapid development of molecular imaging technique, UCAs with single-function and single imaging modality can no longer satisfy increasingly growing medical diversification and hominization demand. The device of functional UCAs including multimodality and multifunction is of great value for disease diagnosis, treatment and research, and greatly accelerate the development of ultrasound-based multimodal molecular imaging. Functional UCAs can not only be applied for multimodality imaging to compensate for the disadvantages of each imaging modality whilst taking advantage of their individual strengths to acquire more biological information, but also can act as a vector carrying drugs or therapeutic genes to accomplish the combination of diagnosis and treatment, which is an existing study hotspot and has achieved initiatory success. In this paper, we reviewed the advances of ultrasound-based multimodal imaging, multimodal and multifunctional UCAs. PMID- 23448497 TI - Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families. AB - INTRODUCTION: Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. METHODS: The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high-resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. RESULTS: The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), 10 missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense-mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods applied. The majority of breast cancers arising in carriers that were available for review were high-grade invasive ductal carcinomas. CONCLUSIONS: About 1.5% (95% CI 0.6to 2.4) of Australasian multiple-case breast cancer families attending clinics are segregating protein-truncating mutations in PALB2, most being PALB2 c.3113G>A, p.Trp1038*. Given the prevalence, breast cancer risk, and tumour grade associated with this mutation, consideration of clinical PALB2 testing is warranted. PMID- 23448499 TI - Response inhibition in preschoolers at familial risk for attention deficit hyperactivity disorder: a behavioral and electrophysiological stop-signal study. AB - Children participating in the Ben-Gurion Infant Development Study were assessed with a dynamic-tracking version of the stop-signal task at the age of 5 years. The sample consisted of 60 males. Stop-signal reaction time (SSRT) was correlated with concurrent ratings of the child's attention deficit hyperactivity disorder (ADHD) symptoms. Paternal symptoms measured in the child's early infancy predicted the child's performance in the stop-signal task: Paternal inattentiveness predicted SSRT, whereas hyperactivity predicted error proportion. Maternal symptoms were not correlated with the performance of the child in the task. A subsample of children, who were tested while electrophysiological brain activity was measured, showed that having higher ADHD symptomatology, especially hyperactivity, correlated with less activity in the brain areas that are usually recruited by children for successful inhibition. PMID- 23448500 TI - Relationship between diabetic retinopathy, diabetic macular oedema and erectile dysfunction in type 2 diabetics. AB - BACKGROUND: To investigate the relationship of diabetic retinopathy and diabetic macular oedema with erectile dysfunction in patients with type 2 diabetes. DESIGN: Hospital-based, cross-sectional study. PARTICIPANTS: Three hundred twenty four men with diabetes from the Diabetic Management Project were recruited. METHODS: Participants underwent a comprehensive interview, a complete eye examination, fasting blood tests, and had retinal and macula assessments using fundus images and optical coherence tomography, respectively. Diabetic retinopathy was categorized as none, mild, moderate, severe non-proliferative and proliferative, and diabetic macular oedema as none, mild, moderate and severe. Erectile dysfunction was defined as problems achieving or maintaining an erection and was assessed using a self-reported questionnaire. MAIN OUTCOME MEASURES: Erectile dysfunction. RESULTS: The mean +/- standard deviation age of 324 men with type 2 diabetes was 65.2 +/- 11.1 years. Compared with patients without diabetic retinopathy, those with any retinopathy (odds ratio 2.06, 95% confidence interval 1.22-3.48, P = 0.007) had a twofold increased odds of having erectile dysfunction. Patients with severe non-proliferative diabetic retinopathy (odds ratio 4.39, 95% confidence interval 1.48-13.0, P = 0.008) and proliferative diabetic retinopathy (odds ratio 2.74, 95% confidence interval 1.44-5.19, P = 0.002) had fourfold and threefold increased odds of having erectile dysfunction, respectively, compared with those without diabetic retinopathy. Diabetic macular oedema, irrespective of presence or severity, was not independently associated with erectile dysfunction. CONCLUSION: The presence and severity of diabetic retinopathy but not diabetic macular oedema are independently associated with self-reported erectile dysfunction. PMID- 23448501 TI - In vivo and in vitro studies of epithelial cell behavior around titanium implants with machined and rough surfaces. AB - BACKGROUND: The surface roughness of a dental implant affects the epithelial wound healing process and may significantly enhance implant prognosis. PURPOSE: We explored the influence of surface roughness on peri-implant epithelium (PIE) sealing and down-growth by comparing machine-surfaced (Ms) and rough-surfaced (Rs) implants. MATERIALS AND METHODS: (1) Maxillary first molars were extracted from rats and replaced with Ms or Rs implants. (2) We also compared changes in the morphology of cultured rat oral epithelial cells (OECs) grown on Ms or Rs titanium (Ti) plates. RESULTS: (1) After 4 weeks, the PIE around Ms and Rs implants showed a similar structure to junctional epithelium (JE). At 16 weeks, Rs implants appeared to form a weak epithelial seal at the tissue-implant interface and exhibited markedly less PIE down-growth than Ms implants but was deeper than that observed in natural teeth. (2) We observed less expression of adhesion proteins in OECs cultured on Rs plates than in cells grown on Ms plates. Additionally, cell adherence, migration, and proliferation on Rs plates were lower, whereas apoptosis was reduced on Ms plates. CONCLUSION: Ms implants are a better choice for integration with an epithelial wound healing process. PMID- 23448502 TI - Isolation and characterization of nine polymorphic microsatellite markers for the deep-sea shrimp Nematocarcinus lanceopes (Crustacea: Decapoda: Caridea). AB - BACKGROUND: The shrimp Nematocarcinus lanceopes Bate, 1888 is found in the deep sea around Antarctica and sub-Antarctic islands. Previous studies on mitochondrial data and species distribution models provided evidence for a homogenous circum-Antarctic population of N. lanceopes. However, to analyze the fine-scale population genetic structure and to examine influences of abiotic environmental conditions on population composition and genetic diversity, a set of fast evolving nuclear microsatellite markers is required. FINDINGS: We report the isolation and characterization of nine polymorphic microsatellite markers from the Antarctic deep-sea shrimp species Nematocarcinus lanceopes (Crustacea: Decapoda: Caridea). Microsatellite markers were screened in 55 individuals from different locations around the Antarctic continent. All markers were polymorphic with 9 to 25 alleles per locus. The observed heterozygosity ranged from 0.545 to 0.927 and the expected heterozygosity from 0.549 to 0.934. CONCLUSIONS: The reported markers provide a novel tool to study genetic structure and diversity in Nematocarcinus lanceopes populations in the Southern Ocean and monitor effects of ongoing climate change in the region on the populations inhabiting these. PMID- 23448503 TI - Attitudes and local ecological knowledge of experts fishermen in relation to conservation and bycatch of sea turtles (reptilia: testudines), Southern Bahia, Brazil. AB - BACKGROUND: The use of ethnoecological tools to evaluate possible damage and loss of biodiversity related to the populations of species under some degree of threat may represent a first step towards integrating the political management of natural resources and conservation strategies. From this perspective, this study investigates fishermen's ecological knowledge about sea turtles and attitudes towards the conservation and bycatch in Ilheus, Southern Bahia, Brazil. METHODS: Fishermen experts semi-structured interviews were performed using snowball sampling method. The interviews consisted of a series of questions relating to the fishermen's profile, structure and work equipment, the local ecological knowledge of fishermen about sea turtles and bycatch, a projective test, attitudes towards turtle conservation and beliefs and taboos regarding turtles. Indicators for quantitative comparisons of respondents in terms of their broad knowledge and attitudes towards turtle conservation were created. Correlation analyses were made between indicators of knowledge and attitude as well as the relationship between education level and knowledge and attitudes. RESULTS: Thirty experts were interviewed for the study. The local ecological knowledge and attitudes of fishermen towards the conservation of sea turtles were respectively medium (0.43) and moderate (0.69) according to experts (based on Likert scale and Cronbach's Alpha). Potential areas of spawning were reported from Barra Grande to Una covering the entire coast of Ilheus. Methods for identifying the animal, behavior, and popular names were described by fishermen. The most recent captures of turtles were attributed to fishing line, but according to the respondents, lobster nets and shrimp traps are more likely to capture turtles. Knowledge and attitudes were weakly inversely correlated (r = -0.38, p = 0.04), and the education level of the respondent showed a positive correlation with positive attitudes towards turtle conservation (H = 8.33; p = 0.04). Life history, habitat, specific and exogenous taboos, beliefs and the use of hawksbill turtle to make glasses and other handcrafts are also reported in the study. CONCLUSIONS: Monitoring of spawning areas, preservation of traditional practices, strategies to moderate the use of fishery resources and the local ecological knowledge/attitudes can provide data to improve the conservation practices and management of sea turtles. PMID- 23448505 TI - Does tonsillectomy improve quality of life in adults? A systematic literature review. AB - AIM: To determine whether tonsillectomy improves quality of life in adults suffering from chronic or recurrent tonsillitis. METHOD: A systematic literature search of the Medline and Pubmed databases was conducted in order to identify all relevant studies measuring quality of life directly. RESULTS AND CONCLUSION: Eight studies were identified. The Glasgow Benefit Inventory and the Short Form questionnaire were the main tools used to assess quality of life changes. Tonsillectomy is likely to improve the overall quality of life as it particularly improves patients' physical and general health. The social benefits of tonsillectomy appear to be non-significant. The effects are likely to be long lasting and have a greater impact on younger patients. The presence of coexisting chronic conditions and the severity of infective symptoms due to tonsillitis are also influencing factors. PMID- 23448506 TI - Emergent biological properties of arrestin pathway-selective biased agonism. AB - Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) signaling, combined with the phenomenon of orthosteric ligand "bias", has created the possibility of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. When viewed from the short-term perspective, e.g. changes in receptor conformation, effector coupling or second messenger generation, biased ligands appear to activate a subset of the response profile produced by a conventional agonist. Yet when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. What is currently missing, at least with respect to G protein and arrestin pathway-selective ligands, is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will enable drug screening programs to identify ligands with the desired biological effects. PMID- 23448504 TI - The brain-in-motion study: effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults. AB - BACKGROUND: Aging and physical inactivity are associated with declines in some cognitive domains and cerebrovascular function, as well as an elevated risk of cerebrovascular disease and other morbidities. With the increase in the number of sedentary older Canadians, promoting healthy brain aging is becoming an increasingly important population health issue. Emerging research suggests that higher levels of physical fitness at any age are associated with better cognitive functioning and this may be mediated, at least in part, by improvements in cerebrovascular reserve. We are currently conducting a study to determine: if a structured 6-month aerobic exercise program is associated with improvements or maintenance of both cerebrovascular function and cognitive abilities in older individuals; and, the extent to which any changes seen persist 6 months after the completion of the structured exercise program. METHODS/DESIGN: Two hundred and fifty men and women aged 55-80 years are being enrolled into an 18-month combined quasi-experimental and prospective cohort study. Participants are eligible for enrollment into the study if they are inactive (i.e., not participating in regular physical activity), non-smokers, have a body mass index <35.0 kg/m(2), are free of significant cognitive impairment (defined as a Montreal Cognitive Assessment score of 24 or more), and do not have clinically significant cardiovascular, cerebrovascular disease, or chronic obstructive pulmonary airway disease. Repeated measurements are done during three sequential six-month phases: 1) pre-intervention; 2) aerobic exercise intervention; and 3) post-intervention. These outcomes include: cardiorespiratory fitness, resting cerebral blood flow, cerebrovascular reserve, and cognitive function. DISCUSSION: This is the first study to our knowledge that will examine contemporaneously the effect of an exercise intervention on both cerebrovascular reserve and cognition in an older population. This study will further our understanding of whether cerebrovascular mechanisms might explain how exercise promotes healthy brain aging. In addition our study will address the potential of increasing physical activity to prevent age-associated cognitive decline. PMID- 23448507 TI - Detoxification of alpha-tomatine by Cladosporium fulvum is required for full virulence on tomato. AB - . alpha-Tomatine is an antifungal glycoalkaloid that provides basal defense to tomato (Solanum lycopersicum). However, tomato pathogens overcome this basal defense barrier by the secretion of tomatinases that degrade alpha-tomatine into the less fungitoxic compounds beta-tomatine and tomatidine. Although pathogenic on tomato, it has been reported that the biotrophic fungus Cladosporium fulvum is unable to detoxify alpha-tomatine. . Here, we present a functional analysis of the glycosyl hydrolase (GH10), CfTom1, which is orthologous to fungal tomatinases. . We show that C. fulvum hydrolyzes alpha-tomatine into tomatidine in vitro and during the infection of tomato, which is fully attributed to the activity of CfTom1, as shown by the heterologous expression of this enzyme in tomato. Accordingly, ?cftom1 mutants of C. fulvum are more sensitive to alpha tomatine and are less virulent than the wild-type fungus on tomato. . Although alpha-tomatine is thought to be localized in the vacuole, we show that it is also present in the apoplast, where it is hydrolyzed by CfTom1 on infection. The accumulation of tomatidine during infection appears to be toxic to tomato cells and does not suppress defense responses, as suggested previously. Altogether, our results show that CfTom1 is responsible for the detoxification of alpha-tomatine by C. fulvum, and is required for full virulence of this fungus on tomato. PMID- 23448508 TI - Dendrite-free lithium deposition via self-healing electrostatic shield mechanism. AB - Rechargeable lithium metal batteries are considered the "Holy Grail" of energy storage systems. Unfortunately, uncontrollable dendritic lithium growth inherent in these batteries (upon repeated charge/discharge cycling) has prevented their practical application over the past 40 years. We show a novel mechanism that can fundamentally alter dendrite formation. At low concentrations, selected cations (such as cesium or rubidium ions) exhibit an effective reduction potential below the standard reduction potential of lithium ions. During lithium deposition, these additive cations form a positively charged electrostatic shield around the initial growth tip of the protuberances without reduction and deposition of the additives. This forces further deposition of lithium to adjacent regions of the anode and eliminates dendrite formation in lithium metal batteries. This strategy may also prevent dendrite growth in lithium-ion batteries as well as other metal batteries and transform the surface uniformity of coatings deposited in many general electrodeposition processes. PMID- 23448509 TI - Role of interstitial inflammation in the pathogenesis of polycystic kidney disease. AB - Interstitial infiltrates, consisting of macrophages and other inflammatory cells, have been consistently reported in human and animal models of polycystic kidney diseases (PKD). However, the mechanisms underlying this inflammation are not well defined. Evidence suggests that interstitial inflammation in PKD is driven by pro inflammatory chemoattractants such as monocyte chemoattractant protein-1 (MCP-1), and cytokines such as tumour necrosis factor (TNF)-alpha. Putative upregulated inflammatory pathways include JAK-STAT and nuclear factor (NF)-kappaB signalling. In addition, the genetic mutations of PKD may further complicate the relationship between inflammation and cystic disease, by increasing the susceptibility to inflammatory injury, and facilitating interactions between the genetically determined cystoproteins and biological mediators of inflammation. Moreover, the roles of interstitial inflammation in promoting cyst growth and progression to kidney failure in PKD are not clearly understood. Although anti-inflammatory therapies have attenuated cystogenesis in animal models, inflammatory cells may also have reparative actions. Thus, in developing therapies for PKD, it is prudent to consider the potential negative outcomes of ablating inflammation, and whether it is more viable to target certain inflammatory pathways over others. PMID- 23448510 TI - Mortality and excess risk in US adults with pre-diabetes and diabetes: a comparison of two nationally representative cohorts, 1988-2006. AB - BACKGROUND: There is strong evidence on the efficacy of behavioral modification and treatment for reducing diabetes incidence and diabetes-related morbidity and mortality in persons with pre-diabetes and diabetes. But the extent to which the evidence has translated into gains in health in these population sub-groups in the US is unclear. Monitoring national diabetes-related mortality levels over time is important for evaluating the effectiveness of the US health system response to diabetes. METHODS: We identified individuals with pre-diabetes and diabetes using Hemoglobin A1c. Two consecutive periods for investigating differences in mortality according to categories of glycemia were derived using nationally representative survey data on US adults ages 35-74 from subsequent rounds of the National Health and Nutrition Examination Survey (1988-1994 and 1999-2002). Age-standardized mortality rates were calculated for individuals with pre-diabetes and diabetes and proportional hazards models were used to assess change in the relative risks of dysglycemia (pre-diabetes and diabetes) adjusting for multiple confounding factors. RESULTS: Age-standardized mortality rates in individuals with pre-diabetes and diabetes showed no statistically significant change between 1988-2001 and 1999-2006. In individuals with pre-diabetes, mortality rates were 11.19 and 14.02 deaths per 1,000 person-years in the early and later period, respectively. The corresponding values for individuals with diabetes were 20.34 and 20.82 deaths per 1,000 person-years. In contrast, the absolute level of mortality in the normo-glycemic population declined significantly between 1988-2001 and 1999-2006 (7.81 to 6.04; p for difference < 0.05). Adjusting for social and demographic variables, smoking and body mass index in a multivariate analysis, the hazard ratio of dysglycemia increased from 1.62 (95% CI: 1.36-1.93) in 1988-2001 to 2.36 (95% CI: 1.70-3.27) in 1999-2006 (p for difference < 0.05). CONCLUSIONS: We find no evidence of declines in excess mortality in persons with dysglycemia between 1988-2001 and 1999-2006, a result that was robust to adjustment for social and demographic variables, smoking and body mass index. In the context of long-term secular declines in mortality in the US population, our findings suggest that individuals with pre-diabetes and diabetes should be an important focus of future interventions aimed at improving population health in the US. PMID- 23448511 TI - Which exercise test to use for chest pain from an anomalous coronary artery. AB - Chest pain in children and young people is a frequent cause of contact to general practitioners and outpatient clinics. However, in children, chest pain is typically benign and self-limiting; it is not usually a manifestation of organic disease, and it is very rarely of cardiac origin. The cause of chest pain often remains undiagnosed. There are a number of chronic conditions known to be associated with recurrent chest pain. Symptoms and signs include crushing left sided precordial pain, pain radiating to the left arm or the jaw, pain onset with exercise and subsiding at rest (with asthma excluded), and an abnormal cardiovascular examination suggests referral for cardiac evaluation. We here report a case of stable angina pectoris in the young. PMID- 23448512 TI - Femtosecond laser-induced macular hole followed by spectral domain optical coherence tomography. PMID- 23448513 TI - A randomized maternal evaluation of epinephrine autoinjection devices. AB - BACKGROUND: Intramuscular epinephrine (adrenaline) is the first-line therapy for anaphylaxis and prompt administration improves outcome. In 2011, two epinephrine autoinjectors existed in the United Kingdom, differing in their users' administration method: EpiPen((r)) and Anapen((r)) . We routinely train all families who receive these devices. AIM: To evaluate: Maternal competence in using epinephrine autoinjectors following our standard anaphylaxis training package. Which device mothers found easier to use. METHODS: Mothers with no previous epinephrine autoinjector experience were approached to participate. One clinician provided a standardized demonstration on using a randomly assigned autoinjector device. She immediately evaluated the mothers' performance using ten predetermined criteria. Four criteria were device specific and six were common criteria to both devices. RESULTS: One hundred mothers participated: 50 EpiPen((r)) and 50 Anapen((r)) . A substantial proportion of mothers (15% overall) were not able to successfully 'fire' these training devices: Anapen((r)) 4% and EpiPen((r)) 26% (OR 8.43, p = 0.005). Only 22% of mothers overall were able to perform all ten procedures completely successfully: Anapen((r)) 32% and EpiPen((r)) 12%. Chi-squared analysis showed a significantly higher proportion of mothers correctly performing all Anapen((r)) specific procedures than EpiPen((r)) (OR 14.24, p < 0.0001). CONCLUSION: It is concerning that 15% of mothers overall could not 'fire' these devices correctly despite a one-to-one demonstration, identifying a need for more user friendly devices and training. Mothers found the Anapen((r)) device significantly easier to use, which may have implications for future prescribing. Evaluation of the next generation of autoinjectors and their training packages needs to be performed as important practical differences may be found. PMID- 23448514 TI - Comparative evaluation of uniplex, nested, semi-nested, multiplex and nested multiplex PCR methods in the identification of microbial etiology of clinically suspected infectious endophthalmitis. AB - PURPOSE: This study is aimed to determine the utility of various polymerase chain reaction (PCR) methods in vitreous fluids (VFs) for detecting the infectious genomes in the diagnosis of infectious endophthalmitis in terms of sensitivity and specificity. METHODS: This prospective and consecutive analysis included a total of 66 VFs that were submitted for the microbiological evaluation, which were obtained from 66 clinically diagnosed endophthalmitis patients presented between November 2010 and October 2011 at the tertiary eye care referral centre in South India. Part of the collected VFs were subjected to cultures and smears, and the remaining parts were utilized for five PCR methods: uniplex, nested, semi nested, multiplex and nested multiplex after extracting DNA, using universal eubacterial and Propionibacterium acnes species-specific primer sets targeting 16S rRNA gene in all bacteria and P. acnes, and panfungal primers, targeting 28S rRNA gene in all fungi. RESULTS: Of the 66 VFs, five (7.5%) showed positive results in smears, 16 (24%) in cultures and 43 (65%) showed positive results in PCRs. Among the 43 positively amplified VFs, 10 (15%) were positive for P. acnes genome, one for panfungal genome and 42 (62%) for eubacterial genome (including 10 P. acnes positives). Among 42 eubacterial-positive VFs, 36 were positive by both uniplex (first round) and multiplex (first round) PCRs, while nested (second round) and nested multiplex (second round) PCRs produced positive results in 42 and 41 VFs, respectively. Of the 43 PCR-positive specimens, 16 (37%) had positive growth (15 bacterial and one fungal) in culture. Of 50 culture-negative specimens, 27 (54%) were showed positive amplification, of which 10 were amplified for both P. acnes and eubacterial genomes and the remaining 17 were for eubacterial genome alone. CONCLUSIONS: Nested PCRs are superior than uniplex and multiplex PCR. PCRs proved to be a powerful tool in the diagnosis of endophthalmitis, especially for detecting uncultured microbes. PMID- 23448515 TI - Protease-activated receptor-1: key player in the sepsis coagulation-inflammation crosstalk. AB - Protease-activated receptors (PARs) belong to the family of G protein-coupled receptors. Among the four members, PAR1 plays a major role in orchestrating the interactions between coagulation and inflammation. PAR1 has opposing functions during sepsis, and PAR1 blockade or activation may be alternatively beneficial at early or late stages of different sepsis models. Studying molecular mechanisms of the crosstalk between inflammation and coagulation may lead to the identification of new targets for therapies in sepsis. However, the time-dependent switch of PAR1 from an exacerbating proinflammatory receptor to a protective anti inflammatory receptor needs to be investigated before clinical trials can be recommended. Finally, as PAR1 seems to play a singular role in Streptococcus pneumoniae-induced sepsis through a crosstalk between PAR1 and platelet activating factor receptor, the exact role of PAR1 needs to be investigated in other models of sepsis. PMID- 23448516 TI - Synthesis and properties of naphthobisbenzothiophene diimides. AB - Laterally extended naphthalene diimides composed of naphthobisbenzothiophene skeleton and two imide groups were synthesized, which exhibit interesting packing arrangements and optoelectrical properties. PMID- 23448517 TI - The L444P GBA mutation is associated with early-onset Parkinson's disease in Mexican Mestizos. PMID- 23448519 TI - Providing social support in a persuasive context: forms of social support reported by organ procurement coordinators. AB - Eighty-five organ procurement coordinators (OPCs) completed face-to-face interviews designed to elicit the emotional and instrumental social support strategies communicated to potential donor families throughout the request for deceased organ donation. OPCs identified six forms of emotional support and eight forms of instrumental support, with greater reported use of instrumental support strategies. In terms of instrumental support, OPCs most frequently ensured in hospital comfort (61.2%) or met the nutritional needs of family members (51.8%). With respect to emotional support, OPCs most often expressed sympathy (31.8%) to families and provided support in the form of physical contact (27.1%) with family members. Identifying the forms of social support used by OPCs is a first step toward understanding the strategies that are more (or less) effective in achieving persuasive and support goals. PMID- 23448518 TI - Functional characterization of EZH2beta reveals the increased complexity of EZH2 isoforms involved in the regulation of mammalian gene expression. AB - BACKGROUND: Histone methyltransferase enhancer of zeste homologue 2 (EZH2) forms an obligate repressive complex with suppressor of zeste 12 and embryonic ectoderm development, which is thought, along with EZH1, to be primarily responsible for mediating Polycomb-dependent gene silencing. Polycomb-mediated repression influences gene expression across the entire gamut of biological processes, including development, differentiation and cellular proliferation. Deregulation of EZH2 expression is implicated in numerous complex human diseases. To date, most EZH2-mediated function has been primarily ascribed to a single protein product of the EZH2 locus. RESULTS: We report that the EZH2 locus undergoes alternative splicing to yield at least two structurally and functionally distinct EZH2 methyltransferases. The longest protein encoded by this locus is the conventional enzyme, which we refer to as EZH2alpha, whereas EZH2beta, characterized here, represents a novel isoform. We find that EZH2beta localizes to the cell nucleus, complexes with embryonic ectoderm development and suppressor of zeste 12, trimethylates histone 3 at lysine 27, and mediates silencing of target promoters. At the cell biological level, we find that increased EZH2beta induces cell proliferation, demonstrating that this protein is functional in the regulation of processes previously attributed to EZH2alpha. Biochemically, through the use of genome-wide expression profiling, we demonstrate that EZH2beta governs a pattern of gene repression that is often ontologically redundant from that of EZH2alpha, but also divergent for a wide variety of specific target genes. CONCLUSIONS: Combined, these results demonstrate that an expanded repertoire of EZH2 writers can modulate histone code instruction during histone 3 lysine 27-mediated gene silencing. These data support the notion that the regulation of EZH2-mediated gene silencing is more complex than previously anticipated and should guide the design and interpretation of future studies aimed at understanding the biochemical and biological roles of this important family of epigenomic regulators. PMID- 23448520 TI - Short- and long-range neural synchrony in grapheme-color synesthesia. AB - Grapheme-color synesthesia is a perceptual phenomenon where single graphemes (e.g., the letter "E") induce simultaneous sensations of colors (e.g., the color green) that were not objectively shown. Current models disagree as to whether the color sensations arise from increased short-range connectivity between anatomically adjacent grapheme- and color-processing brain structures or from decreased effectiveness of inhibitory long-range connections feeding back into visual cortex. We addressed this issue by examining neural synchrony obtained from EEG activity, in a sample of grapheme-color synesthetes that were presented with color-inducing versus non-color-inducing graphemes. For color-inducing graphemes, the results showed a decrease in the number of long-range couplings in the theta frequency band (4-7 Hz, 280-540 msec) and a concurrent increase of short-range phase-locking within lower beta band (13-20 Hz, 380-420 msec at occipital electrodes). Because the effects were both found in long-range synchrony and later within the visual processing stream, the results support the idea that reduced inhibition is an important factor for the emergence of synesthetic colors. PMID- 23448522 TI - Individual sequence representations in the medial temporal lobe. AB - Much of what we need to remember consists of sequences of stimuli, experiences, or events. Repeated presentation of a specific sequence establishes a more stable long-term memory, as shown by increased recall accuracy over successive trials of an STM task. Here we used fMRI to study the neural mechanisms that underlie sequence learning in the auditory-verbal domain. Specifically, we track the emergence of neural representations of sequences over the course of learning using multivariate pattern analysis. For this purpose, we use a serial recall task, in which participants have to recall overlapping sequences of letter names, with some of those sequences being repeated and hence learned over the course of the experiment. We show that voxels in the hippocampus come to encode the identity of specific repeated sequences although the letter names were common to all sequences in the experiment. These changes could have not been caused by changes in overall level of activity or to fMRI signal-to-noise ratios. Hence, the present results go beyond conventional univariate fMRI methods in showing a critical contribution of medial-temporal lobe memory systems to establishing long term representations of verbal sequences. PMID- 23448521 TI - The neurobiology of rhyme judgment by deaf and hearing adults: an ERP study. AB - We used electrophysiology to determine the time course and distribution of neural activation during an English word rhyme task in hearing and congenitally deaf adults. Behavioral performance by hearing participants was at ceiling and their ERP data replicated two robust effects repeatedly observed in the literature. First, a sustained negativity, termed the contingent negative variation, was elicited following the first stimulus word. This negativity was asymmetric, being more negative over the left than right sites. The second effect we replicated in hearing participants was an enhanced negativity (N450) to nonrhyming second stimulus words. This was largest over medial, parietal regions of the right hemisphere. Accuracy on the rhyme task by the deaf group as a whole was above chance level, yet significantly poorer than hearing participants. We examined only ERP data from deaf participants who performed the task above chance level (n = 9). We observed indications of subtle differences in ERP responses between deaf and hearing groups. However, overall the patterns in the deaf group were very similar to that in the hearing group. Deaf participants, just as hearing participants, showed greater negativity to nonrhyming than rhyming words. Furthermore the onset latency of this effect was the same as that observed in hearing participants. Overall, the neural processes supporting explicit phonological judgments are very similar in deaf and hearing people, despite differences in the modality of spoken language experience. This supports the suggestion that phonological processing is to a large degree amodal or supramodal. PMID- 23448523 TI - Hemispheric asymmetry in perception: a differential encoding account. AB - Hemispheric asymmetry in the processing of local and global features has been argued to originate from differences in frequency filtering in the two hemispheres, with little neurophysiological support. Here we test the hypothesis that this asymmetry takes place at an encoding stage beyond the sensory level, due to asymmetries in anatomical connections within each hemisphere. We use two simple encoding networks with differential connection structures as models of differential encoding in the two hemispheres based on a hypothesized generalization of neuroanatomical evidence from the auditory modality to the visual modality: The connection structure between columns is more distal in the language areas of the left hemisphere and more local in the homotopic regions in the right hemisphere. We show that both processing differences and differential frequency filtering can arise naturally in this neurocomputational model with neuroanatomically inspired differences in connection structures within the two model hemispheres, suggesting that hemispheric asymmetry in the processing of local and global features may be due to hemispheric asymmetry in connection structure rather than in frequency tuning. PMID- 23448524 TI - Rapid feature-driven changes in the attentional window. AB - Spatial attention must adjust around an object of interest in a manner that reflects the object's size on the retina as well as the proximity of distracting objects, a process often guided by nonspatial features. This study used ERPs to investigate how quickly the size of this type of "attentional window" can adjust around a fixated target object defined by its color and whether this variety of attention influences the feedforward flow of subsequent information through the visual system. The task involved attending either to a circular region at fixation or to a surrounding annulus region, depending on which region contained an attended color. The region containing the attended color varied randomly from trial to trial, so the spatial distribution of attention had to be adjusted on each trial. We measured the initial sensory ERP response elicited by an irrelevant probe stimulus that appeared in one of the two regions at different times after task display onset. This allowed us to measure the amount of time required to adjust spatial attention on the basis of the location of the task relevant feature. We found that the probe-elicited sensory response was larger when the probe occurred within the region of the attended dots, and this effect required a delay of approximately 175 msec between the onset of the task display and the onset of the probe. Thus, the window of attention is rapidly adjusted around the point of fixation in a manner that reflects the spatial extent of a task-relevant stimulus, leading to changes in the feedforward flow of subsequent information through the visual system. PMID- 23448525 TI - Mind wandering and the adaptive control of attentional resources. AB - Mind wandering is a natural, transient state wherein our neurocognitive systems become temporarily decoupled from the external sensory environment as our thoughts drift away from the current task at hand. Yet despite the ubiquity of mind wandering in everyday human life, we rarely seem impaired in our ability to adaptively respond to the external environment when mind wandering. This suggests that despite widespread neurocognitive decoupling during mind wandering states, we may nevertheless retain some capacity to attentionally monitor external events. But what specific capacities? In Experiment 1, using traditional performance measures, we found that both volitional and automatic forms of visual spatial attentional orienting were significantly attenuated when mind wandering. In Experiment 2, however, ERPs revealed that, during mind wandering states, there was a relative preservation of sensitivity to deviant or unexpected sensory events, as measured via the auditory N1 component. Taken together, our findings suggest that, although some selective attentional processes may be subject to down-regulation during mind wandering, we may adaptively compensate for these neurocognitively decoupled states by maintaining automatic deviance-detection functions. PMID- 23448526 TI - Diagnostic accuracy of a short-duration 3 Tesla magnetic resonance protocol for diagnosing stifle joint lesions in dogs with non-traumatic cranial cruciate ligament rupture. AB - BACKGROUND: Magnetic resonance (MR) imaging is the preferred diagnostic tool to evaluate internal disorders of many joints in humans; however, the usefulness of MR imaging in the context of osteoarthritis, and joint disease in general, has yet to be characterized in veterinary medicine. The objective of this study was to assess the diagnostic accuracy of short-duration 3 Tesla MR imaging for the evaluation of cranial and caudal cruciate ligament, meniscal and cartilage damage, as well as the degree of osteoarthritis, in dogs affected by non traumatic, naturally-occurring cranial cruciate ligament rupture (CCLR). Diagnoses made from MR images were compared to those made during surgical exploration. Twenty-one client-owned dogs were included in this study, and one experienced evaluator assessed all images. RESULTS: All cranial cruciate ligaments were correctly identified as ruptured. With one exception, all caudal cruciate ligaments were correctly identified as intact. High sensitivities and specificities were obtained when diagnosing meniscal rupture. MR images revealed additional subclinical lesions in both the cranial and caudal cruciate ligaments and in the menisci. There was a "clear" statistical (kappa) agreement between the MR and the surgical findings for both cartilage damage and degree of osteoarthritis. However, the large 95% confidence intervals indicated that evaluation of cartilage damage and of degree of osteoarthritis is not clinically satisfactory. CONCLUSIONS: The presence of cruciate ligament damage and meniscal tears could be accurately assessed using the MR images obtained with our protocol. However, in the case of meniscal evaluation, occasional misdiagnosis did occur. The presence of cartilage damage and the degree of osteoarthritis could not be properly evaluated. PMID- 23448528 TI - The Parental Dental Concerns Scale (PDCS): its development and initial psychometric properties. AB - OBJECTIVES: To assess the validity and reliability of a Parental Dental Concerns Scale (PDCS) to identify parents unable to access preventive dental care for their children. METHODS: Two studies were conducted. In Study One, a purposive convenience sample of 399 Scottish parents answered questions on going to the dentist, family life and demographics. Parents were retested eight weeks later. In Study Two, 574 Scottish parents participating in a preventive oral health programme were posted the same questionnaire. Information on child dental attendance was gained from dental records. Data were analysed using exploratory (EFA) and confirmatory (CFA) factor analysis. Internal consistency and test retest correlations provided reliability estimates. Validity was assessed with confirmatory factor analysis, correlations and independent t-tests. RESULTS: EFA indicated that the PDCS had a four factor structure, supported by a subsequent CFA. The PDCS and its four subscales had good internal consistency, concurrent validity and test-retest reliability. Further work is required to confirm the scale's predictive validity in discriminating between children and parents who did and did not attend the dental practice. CONCLUSIONS: The PDCS is a reliable scale, which demonstrates good construct validity. Further testing is required to confirm its predictive validity. PMID- 23448527 TI - Structural studies of the interaction of Crataeva tapia bark protein with heparin and other glycosaminoglycans. AB - CrataBL, a protein isolated from Crataeva tapia bark, which is both a serine protease inhibitor and a lectin, has been previously shown to exhibit a number of interesting biological properties, including anti-inflammatory, analgesic, antitumor, and insecticidal activities. Using a glycan array, we have now shown that only sulfated carbohydrates are effectively bound by CrataBL. Because this protein was recently shown to delay clot formation by impairing the intrinsic pathway of the coagulation cascade, we considered that its natural ligand might be heparin. Heparin is a glycosaminoglycan (GAG) that interacts with a number of proteins, including thrombin and antithrombin III, which have a critical, essential pharmacological role in regulating blood coagulation. We have thus employed surface plasmon resonance to improve our understanding of the binding interaction between the heparin polysaccharide and CrataBL. Kinetic analysis shows that CrataBL displays strong heparin binding affinity (KD = 49 nM). Competition studies using different size heparin-derived oligosaccharides showed that the binding of CrataBL to heparin is chain length-dependent. Full chain heparin with 40 saccharides or large oligosaccharides, having 16-18 saccharide residues, show strong binding affinity for CrataBL. Heparin-derived disaccharides through tetradecasaccharides show considerably lower binding affinity. Other highly sulfated GAGs, including chondroitin sulfate E and dermatan 4,6-disulfate, showed CrataBL binding affinity comparable to that of heparin. Less highly sulfated GAGs, heparan sulfate, chondroitin sulfate A and C, and dermatan sulfate displayed modest binding affinity as did chondroitin sulfate D. Studies using chemically modified heparin show that N-sulfo and 6-O-sulfo groups on heparin are essential for CrataBL-heparin interaction. PMID- 23448530 TI - Unusual coexistence of sinonasal myeloid sarcoma and acute fulminant invasive fungal sinusitis: a diagnostic dilemma. AB - OBJECTIVE: We report a rare case of concurrent myeloid sarcoma and acute fulminant invasive fungal sinusitis in a patient with relapsed acute myeloid leukaemia. CASE REPORT: A 73-year-old man was diagnosed with acute myeloid leukaemia and developed relapse one year later. After two courses of azacytidine, he began suffering from a dull pain in the left temporal and orbital regions. Sinus computed tomography showed a localised lesion in the left ethmoid sinus, which rapidly progressed to an extensive intracranial mass within one month. Surgical debridement was performed, and histopathological analysis revealed the coexistence of myeloid sarcoma and acute fulminant invasive fungal sinusitis. The patient responded well to prompt surgical debridement, antifungal medication and radiotherapy. CONCLUSION: Coexistence of sinonasal myeloid sarcoma and acute fulminant invasive fungal sinusitis poses an urgent diagnostic and management challenge to clinicians. Timely recognition of this rare comorbid condition is warranted as application of appropriate treatment can save lives. PMID- 23448529 TI - Prevalence dependent calibration of a predictive model for nasal carriage of methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Published models predicting nasal colonization with Methicillin resistant Staphylococcus aureus among hospital admissions predominantly focus on separation of carriers from non-carriers and are frequently evaluated using measures of discrimination. In contrast, accurate estimation of carriage probability, which may inform decisions regarding treatment and infection control, is rarely assessed. Furthermore, no published models adjust for MRSA prevalence. METHODS: Using logistic regression, a scoring system (values from 0 to 200) predicting nasal carriage of MRSA was created using a derivation cohort of 3091 individuals admitted to a European tertiary referral center between July 2007 and March 2008. The expected positive predictive value of a rapid diagnostic test (GeneOhm, Becton & Dickinson Co.) was modeled using non-linear regression according to score. Models were validated on a second cohort from the same hospital consisting of 2043 patients admitted between August 2008 and January 2012. Our suggested correction score for prevalence was proportional to the log transformed odds ratio between cohorts. Calibration before and after correction, i.e. accurate classification into arbitrary strata, was assessed with the Hosmer Lemeshow-Test. RESULTS: Treating culture as reference, the rapid diagnostic test had positive predictive values of 64.8% and 54.0% in derivation and internal validation corhorts with prevalences of 2.3% and 1.7%, respectively. In addition to low prevalence, low positive predictive values were due to high proportion (> 66%) of mecA-negative Staphylococcus aureus among false positive results. Age, nursing home residence, admission through the medical emergency department, and ICD-10-GM admission diagnoses starting with "A" or "J" were associated with MRSA carriage and were thus included in the scoring system, which showed good calibration in predicting probability of carriage and the rapid diagnostic test's expected positive predictive value. Calibration for both probability of carriage and expected positive predictive value in the internal validation cohort was improved by applying the correction score. CONCLUSIONS: Given a set of patient parameters, the presented models accurately predict a) probability of nasal carriage of MRSA and b) a rapid diagnostic test's expected positive predictive value. While the former can inform decisions regarding empiric antibiotic treatment and infection control, the latter can influence choice of screening method. PMID- 23448531 TI - Effects of chronic stress and alendronate therapy on the osseointegration of titanium implants. AB - PURPOSES: The purposes of this study were to evaluate the influence of chronic stress (CS) on implant osseointegration and also to analyze whether alendronate (ALN) therapy could prevent these eventual stress-negative effects. MATERIALS AND METHODS: Adult male Holtzmann rats were assigned to one of the four experimental groups: AL (ALN; 1 mg/kg/week; n = 12), ALS (ALN + CS; 1 mg/kg/week; n = 12), CTL (sterile physiological saline; n = 12), or CTLS (sterile physiological saline + CS; n = 12). After 58 days of drug therapy, the ALS and CTLS groups were exposed to CS, and 2 days later all animals underwent tibial implant installation. The animals were euthanized 28 days following the operative surgical procedure. RESULTS: It was observed that the CTLS group presented an impairment of bone metabolism represented by lowest levels of bone-specific alkaline phosphatase and bone area fraction occupancy values. Furthermore, these animals presented a higher proportion of empty osteocytic lacunae. In contrast, the ALN therapy showed increased osseointegration and torque value parameters, regardless of stress exposition. CONCLUSIONS: Analysis of the data presented suggests that CS partially impairs the osseointegration of tibial implants and that ALN therapy is able to prevent these negative effects. PMID- 23448532 TI - Abstracts of the Thoracic Society of Australia & New Zealand and the Australian & New Zealand Society of Respiratory Science 2013 Annual Scientific Meetings. March 22-27, 2013. Darwin, Northern Territory, Australia. PMID- 23448533 TI - Population-based pediatric reference intervals for hematology, iron and transferrin. AB - Reference intervals are crucial decision-making tools aiding clinicians in differentiating between healthy and diseased populations. However, for children such values often are lacking or incomplete. Blood samples were obtained from 689 healthy children, aged 6 months to 18 years, recruited in day care centers and schools. Hematology and anemia analytes were measured on the Siemens Advia 2120 and Abbott Architect ci8200 platforms (hemoglobin, erythrocyte volume fraction [EVF], erythrocytes, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], reticulocytes, leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, platelets, iron, transferrin, transferrin saturation). Age- and gender-specific pediatric reference intervals were defined by calculating 2.5th and 97.5th percentiles. The data generated is primarily applicable to a Caucasian population, but could be used by any laboratory if verified for the local patient population. PMID- 23448534 TI - Lipid peroxidation in multidrug-resistant Gram-negative sepsis: translating science to the septic patient? AB - Multidrug-resistant Gram-negative induced sepsis poses an increasing threat to the vulnerable intensive care patient. The study by Toufekoula and colleagues reports the serum and tissue concentration of malondialdehyde (MDA), the toxic end product of lipid peroxidation, during the course of experimental and human Gram-negative sepsis. The complementary results from this dual experimental and clinical approach argue for highly compartmentalized lipid peroxidation during sepsis. Establishing a correlation between MDA concentration and survival provides valuable insights into the pathophysiology of Gram-negative sepsis. Yet, further studies are needed to understand and establish MDA as a biomarker during sepsis aggravated by organ failure. PMID- 23448535 TI - Functional relevance of genetic variations of endothelial nitric oxide synthase and vascular endothelial growth factor in diabetic coronary microvessel dysfunction. AB - The prevalence of type 1 diabetes (T1D) is increasing worldwide and is associated with significant microvessel complications, of which nephropathy, retinopathy and neuropathy are the most commonly studied. Although clinically evident microvascular complications of diabetes are rarely seen in childhood, early vascular abnormalities develop during childhood and accelerate during puberty. Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis, which is regulated by endothelial nitric oxide synthase (NOS3) at several levels. Together, VEGF and NOS3 play an important role in the pathogenesis of the microvascular complications of diabetes. Genetic variations in NOS3 and VEGF critically regulate endothelial survival and function and increase the susceptibility of patients to develop severe microvessel complications. Identification of the risk factors for and improved understanding of the subclinical signs of these diabetic microvascular complications will enable implementation of therapeutic strategies, potentially changing the course of vascular complications and improving the prognosis of children, adolescents and young adults with diabetes. Moreover, early detection of these variations may have a prognostic value or may suggest interventional approaches to regulate these proteins in patients with diabetes. PMID- 23448536 TI - Effects of eight weeks of resistance training on the risk factors of metabolic syndrome in overweight /obese women - "A Pilot Study". AB - BACKGROUND: The purpose of the present study was to examine the effects of eight weeks of resistance training (RT) on anthropometric, cardiovascular and biochemical risk factors of metabolic syndrome (MetS), and neuromuscular variables on overweight/obese women. METHODS: Fourteen middle-aged (33.9 +/- 8.6 years) overweight/obese women (body mass index - BMI 29.6 +/- 4.1 kg/m2) underwent 24 sessions (3 times/week) of a whole body RT program with 3 sets of 8 12 repetitions maximum (RM). The following variables were evaluated: maximum strength on chest press and frontal lat pull-down; isometric hand-grip strength; biceps brachii (BB) and rectus femoris (RF) muscle thickness, body mass; BMI; body adiposity index (BAI); waist, hip and neck circumferences; visceral fat volume; blood glucose; glycated hemoglobin (HbA1c); insulin; HDL-C and triglycerides. RESULTS: There was an increase of chest press (from 52.9 +/- 9.7 to 59.8 +/- 7.7 kg; P = 0.02) and front lat pull-down (from 51.5 +/- 7.5 to 57.6 +/- 9.2 kg; P = 0.01) muscle strength, isometric handgrip (P = 0.02) and RF muscle thickness (from 42.2 +/- 8.5 to 45.1 +/- 7.3 mm; P = 0.02) after the 8 week RT program. There were no statistically significant alterations on plasma glucose, HbA1c, insulin, triglycerides, HDL-C, anthropometric indexes and BB muscle thickness (p > 0.05). CONCLUSIONS: A RT program without caloric restriction promotes an increase on muscle thickness and strength, with no effects on risk factors of MetS in overweight/obese women. PMID- 23448537 TI - A case of lipoprotein glomerulopathy with thrombotic microangiopathy due to malignant hypertension. AB - BACKGROUND: Lipoprotein glomerulopathy (LPG) is a rare inherited renal disease characterized by intraglomerular lipoprotein within the lumina of severely dilated glomerular capillaries. The common clinical presentation of LPG includes proteinuria or nephrotic syndrome. Hypertension and anemia were thought to be mild in LPG. Thrombotic microangiopathy (TMA) in LPG has not been previously reported. In this report, we present a patient with LPG that developed TMA. To the best of our knowledge, this is the first report of TMA in LPG. CASE PRESENTATION: Four years ago (2005), a 19-year-old Chinese woman was diagnosed with nephrotic syndrome and provided prednisone treatment. A combination of prednisone and cyclophosphamide did not have any effect and was discontinued after six months. Although she was steroid-resistant, over the next subsequent three years, she maintained normal renal function without anemia and thrombocytopenia. In February 2009, she had a severe headache and blurry vision and presented at a local hospital with severe hypertension. Blood pressure was 220/160 mmHg. Laboratory data showed hemoglobin 3.8 g/dL; platelet counts 29 * 10(9)/L; urinary protein 7.90 g/d; total bilirubin 29.9 umol/L; indirect bilirubin 28.2 umol/L; LDH 1172 U/L; ALB 2.66 g/dL; urea nitrogen 52 mg/dL; serum creatinine 3.2 mg/dL; triglyceride 25 mg/dL; total cholesterol 273 mg/dL. ANA, ds-DNA, ANCA, anti-GBM antibody and anticardiolipin were all negative. A renal biopsy revealed LPG with TMA. Genetic evaluation showed the patient carried the APOE Kyoto mutation. Adequate control of blood pressure improved microangiopathic anemia and thrombocytopenia, however, renal function did not improve and she eventually developed uremia and became hemodialysis dependent. CONCLUSION: We report on a rare case of TMA probably due to malignant hypertension in LPG. Early lipid-lowering and antihypertensive treatment may improve outcome. The pathophysiologic relationship between LPG and TMA should be investigated further. PMID- 23448538 TI - The role of hematopoietic stem cell transplantation in SP110 associated veno occlusive disease with immunodeficiency syndrome. AB - BACKGROUND: Veno-occlusive disease with immunodeficiency (VODI) is an autosomal recessive disorder of combined immunodeficiency (CID) and hepatic injury. Hematopoietic stem cell transplantation (HSCT) - the only definitive treatment for CID - appeared to have a high rate of complications in a previous report. In this study, we describe a new group of patients with VODI highlighting further clinical and immunologic aspects of this disease and re-evaluating the effectiveness of HSCT for the treatment of this disorder. PATIENTS AND METHODS: Review of clinical data, immunologic features, molecular studies, treatment, and final outcome of eight kindred members with VODI. RESULTS: The patients described had clinical and immunologic findings consistent with VODI. The molecular studies revealed a new mutation in the SP110 gene. HSCT was carried out in five patients and was successful in three. CONCLUSIONS: The diagnosis of VODI should be considered in all patients regardless of ethnicity with a severe combined immunodeficiency (SCID)-like presentation, especially with a normal mitogen response, or with signs of hepatic injury. VODI is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of disease using appropriate conditioning. PMID- 23448539 TI - Designing a deep-ultraviolet nonlinear optical material with a large second harmonic generation response. AB - The generation of intense coherent deep-UV light from nonlinear optical materials is crucial to applications ranging from semiconductor photolithography and laser micromachining to photochemical synthesis. However, few materials with large second harmonic generation (SHG) and a short UV-cutoff edge are effective down to 200 nm. A notable exception is KBe2BO3F2, which is obtained from a solid-state reaction of highly toxic beryllium oxide powders. We designed and synthesized a benign polar material, Ba4B11O20F, that satisfies these requirements and exhibits the largest SHG response in known borates containing neither lone-pair-active anions nor second-order Jahn-Teller-active transition metals. We developed a microscopic model to explain the enhancement, which is unexpected on the basis of conventional anionic group theory arguments. Crystal engineering of atomic displacements along the polar axis, which are difficult to attribute to or identify within unique anionic moieties, and greater cation polarizabilities are critical to the design of next-generation SHG materials. PMID- 23448540 TI - Size does matter: women mentally rotate large objects faster than men. AB - Performance in a computerized "mental rotation" task was measured in groups of males and females while they rotated Shepard-Metzler-like cube assemblies on either a standard laptop screen (size = 36 cm) or on a large display wall (584 cm) where the stimuli appeared at considerably larger sizes and within a much wider field of view than that typically used in most spatial tasks. Males and females did not differ significantly in performance in the standard size condition with regards to response time but females performed faster than males in the large display condition. Males were also found to be significantly more accurate than females, regardless of display. We found no sign of trading accuracy for speed for either of the sexes or screen size conditions. We surmise that such an effect may be due to differences in task-solving strategies between the sexes, where a holistic strategy--which may be preferred by males--is negatively affected by large object sizes, whereas a piecemeal approach, that may be preferred by females, is virtually unaffected by display size. PMID- 23448541 TI - Hospitalization rates of children who are blind. AB - BACKGROUND: To evaluate the impact of blindness on hospitalization rates of children. DESIGN: Matched cohort study. PARTICIPANTS: Children confirmed as legally blind (2003-2009), age- and gender-matched to control cohort of normally sighted children from the state register of births. METHODS: The rates and reasons for admission to hospital were compared using hospital morbidity records. The association of blindness with rates of admission and length of stay in hospital, 2003-2010, were estimated using multivariate negative binomial regression models. MAIN OUTCOME MEASURES: Descriptive statistics, incident rate ratios, and predicted means for hospital separations and length of stay. RESULTS: Fifty-nine blind and 59 control children had a combined total of 107 separations accounting for 237 bed days in hospital after the index date of legal blindness. The median age at the index date was 8 years. Over 90% of separations and 92% of bed days were incurred by 22 blind children. Blind children had four (95% confidence interval 1.9-9.3) times more hospital separations and stayed in hospital six (95% confidence interval 1.9-17.5) times longer than the control cohort children. There were more than 40 times as many comorbidities recorded by the blind children (n = 201) compared with the control children (n = 5). A third of the blind children were hospitalized for respiratory conditions. CONCLUSIONS: Children who are born or become blind in childhood have more and longer periods in hospital than sighted children likely because of complex comorbid health problems. There was a disproportionate incidence of comorbid respiratory diseases in the blind children. PMID- 23448542 TI - Percutaneous pulmonary valve implantation using Edwards SAPIEN transcatheter heart valve in different types of conduits: initial results of a single center experience. AB - BACKGROUND: Percutaneous pulmonary valve implantation is frequently used as a less invasive method in patients with conduit dysfunction. The common valve type cannot be used in conduits with a diameter larger than 22 mm. There has been limited experience concerning the used of the SAPIEN Transcatheter Heart Valve, produced for use in conduits with a large diameter. This study presents hemodynamic and early follow-up results from a single center in Turkey concerning the use of the SAPIEN Transcatheter Heart Valve in different types of conduits and different lesions. PATIENTS AND METHOD: Between October 2010 and July 2012, seven SAPIEN Transcatheter Heart Valve implantations were performed. There was mixed type 2 pure insufficiency with stenosis and insufficiency in five patients. Three different conduits were used, and one native pulmonary artery process was performed. Patients were followed for hemodynamic findings, functional capacities, valve competence, reshrinking, and breakage in the stent, and the results were evaluated. RESULTS: Implantations were successfully performed in all patients. Right ventricular pressures and gradients were significantly reduced, and there was no pulmonary regurgitation in any patient. Functional capacities evidently improved in all patients except for one with pulmonary hypertension. No major complication was observed. During the mean time of follow-up (7.2 +/- 4.7 months), no valve insufficiency or stent breakage was observed. CONCLUSION: Procedural results and short-term outcomes of the SAPIEN Transcatheter Heart Valve were very promising in the patients included in the study. The SAPIEN Transcatheter Heart Valve can be a good alternative to surgical conduit replacement, particularly in patients with larger and different types of conduits. PMID- 23448543 TI - Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high-cholesterol diet: a metabolomic approach. AB - Oxidative stress is a determinant of liver steatosis and the progression to more severe forms of disease. The present study investigated the effect of paraoxonase 1 (PON1) deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. We performed nontargeted metabolomics on liver tissues from 8 male PON1-deficient mice and 8 wild-type animals fed a high fat, high-cholesterol diet for 22 weeks. We also measured 8-oxo-20 deoxyguanosine, reduced and oxidized glutathione, malondialdehyde, 8-isoprostanes and protein carbonyl concentrations. Results indicated lipid droplets in 14.5% of the hepatocytes of wild-type mice and in 83.3% of the PON1-deficient animals (P < 0.001). The metabolomic assay included 322 biochemical compounds, 169 of which were significantly decreased and 16 increased in PON1-deficient mice. There were significant increases in lipid peroxide concentrations and oxidative stress markers. We also found decreased glycolysis and the Krebs cycle. The urea cycle was decreased, and the pyrimidine cycle had a significant increase in orotate. The pathways of triglyceride and phospholipid synthesis were significantly increased. We conclude that PON1 deficiency is associated with oxidative stress and metabolic alterations leading to steatosis in the livers of mice receiving a high-fat high-cholesterol diet. PMID- 23448544 TI - Questionnaire-based survey on distribution and clinical incidence of canine babesiosis in France. AB - BACKGROUND: The causative agent of canine babesiosis is the protozoan Babesia canis, transmitted by the tick Dermacentor reticulatus within France. While the parasite can be found everywhere in France however cases of infection are associated with distinct geographical foci. The aim of the study was to evaluate the clinical occurrence of canine babesiosis diagnosed in veterinary clinics in order to propose an updated map of the disease distribution in France. RESULTS: Questionnaires were sent via email to all canine veterinary clinics in continental France. Information collected included the number of babesiosis cases diagnosed in 2010, the number of veterinary practitioners and the location of the clinic. The total number of dogs and practitioners per administrative department were used to define the reference population. The annual incidence rate of canine babesiosis per department was calculated as the ratio between the number of babesiosis cases reported by the clinics and the total number of dogs in the clinics of the same department. Data were geo-referenced for map construction (Quantum GIS version 1.7.4). The overall annual incidence rate of clinical babesiosis among the surveyed population was 1.07% (CI95 1.05-1.09) with geographical variations between departments, ranging from 0.01% to 16.05%. Four enzootic areas were identified: South-West, Center, East and Paris area. The South-West region should be considered as a hyper-enzootic area with the higher incidence rates. CONCLUSION: Our results confirmed the burden of canine babesiosis in France. In the context of tick-borne disease emergence in Europe, the risk for canine babesiosis may become more significant in other European countries in the coming years. PMID- 23448545 TI - Exposure of the yeast Saccharomyces cerevisiae to functionalized polystyrene latex nanoparticles: influence of surface charge on toxicity. AB - Novel nanoparticles with unique physicochemical characteristics are being developed with increasing frequency, leading to higher probability of nanoparticle release and environmental accumulation. Therefore, it is important to assess the potential environmental and biological adverse effects of nanoparticles. In this study, we investigated the toxicity and behavior of surface-functionalized nanoparticles toward yeast (Saccharomyces cerevisiae). The colony count method and confocal microscopy were used to examine the cytotoxicity of manufactured polystyrene latex (PSL) nanoparticles with various functional groups (amine, carboxyl, sulfate, and nonmodified). S. cerevisiae were exposed to PSL nanoparticles (40 mg/L) dispersed in 5-154 mM NaCl solutions for 1 h. Negatively charged nanoparticles had little or no toxic effect. Interestingly, nanoparticles with positively charged amine groups (p-Amine) were not toxic in 154 mM NaCl, but highly toxic in 5 mM NaCl. Confocal microscopy indicated that in 154 mM NaCl, the p-Amine nanoparticles were internalized by endocytosis, whereas in 5 mM NaCl they covered the dead cell surfaces. This demonstrates that nanoparticle-induced cell death might to be related to their adhesion to cells rather than their internalization. Together, these findings identify important factors in determining nanoparticle toxicity that might affect their impact on the environment and human health. PMID- 23448547 TI - Predicting attitude toward methamphetamine use: the role of antidrug campaign exposure and conversations about meth in Montana. AB - This investigation utilized the integrative model of behavioral prediction to assess the Montana Meth Project (MMP) campaign by testing theoretical antecedents of attitude toward methamphetamine (meth) use. College students in Montana (N = 403) were surveyed about their exposure to MMP ads and communication about meth in conversation. Structural equation modeling showed that the data fit the specified model well. Significant parameters indicated that only beliefs about the negative relational outcomes of meth use, and not about personal well-being or physical appearance, were related to attitude. Attention, rather than encoded exposure, to MMP ads related to each belief about meth use. Conversation frequency related to engagement with MMP ads, and a conversational partner's conveyed attitude toward meth use related to personal and physical beliefs as well as attitudes. Theoretical and practical implications of the findings are discussed. PMID- 23448548 TI - Association of blood lipids, creatinine, albumin, and CRP with socioeconomic status in Malawi. AB - BACKGROUND: The objective of these analyses is to document the relationship between biomarker-based indicators of health and socioeconomic status (SES) in a low-income African population where the cumulative effects of exposure to multiple stressors on physiological functions and health in general are expected to be highly detrimental for the well-being of individuals. METHODS: Biomarkers were collected subsequent to the 2008 round of the Malawi Longitudinal Study of Families and Health (MLSFH), a population-based study in rural Malawi, including blood lipids (total cholesterol, LDL, HDL, ratio of total cholesterol to HDL), biomarkers of renal and liver organ function (albumin and creatinine) and wide range C-reactive protein (CRP) as a non-specific biomarker for inflammation. These biomarkers represent widely used indicators of health that are individually or cumulatively recognized as risk factors for age-related diseases among prime aged and elderly individuals. Quantile regressions are used to estimate the age gradient and the within-day variation of each biomarker distribution. Differences in biomarker levels by socioeconomic status are investigated using descriptive and multivariate statistics. RESULTS: Overall, the number of significant associations between the biomarkers and socioeconomic measures is very modest. None of the biomarkers significantly varies with schooling. Except for CRP where being married is weakly associated with lower risk of having an elevated CRP level, marriage is not associated with the biomarkers measured in the MLSFH. Similarly, being Muslim is associated with a lower risk of having elevated CRP but otherwise religion does not predict being in the high-risk quartiles of any of the MLSFH biomarkers. Wealth does not predict being in the high-risk quartile of any of the MLSFH biomarkers, with the exception of a weak effect on creatinine. Being overweight or obese is associated with increased likelihood of being in the high-risk quartile for cholesterol, Chol/HDL ratio, and LDL. CONCLUSIONS: The results provide only weak evidence for variation of the biomarkers by socioeconomic indicators in a poor Malawian context. Our findings underscore the need for further research to understand the determinants of health outcomes in a poor low-income context such as rural Malawi. PMID- 23448549 TI - Precise sequence control in linear and cyclic copolymers of 2,5-bis(2 thienyl)pyrrole and aniline by DNA-programmed assembly. AB - A series of linear and cyclic, sequence controlled, DNA-conjoined copolymers of aniline (ANi) and 2,5-bis(2-thienyl)pyrrole (SNS) were synthesized. In one approach, linear copolymers were prepared from complementary DNA oligomers containing covalently attached SNS and ANi monomers. Hybridization of the oligomers aligns the monomers in the major groove of the DNA. Treatment of the SNS- and ANi-containing duplexes with horseradish peroxidase (HRP) and H2O2 causes rapid and efficient polymerization. In this way, linear copolymers (SNS)4(ANi)6 and (ANi)2(SNS)2(ANi)2(SNS)2(ANi)2 were prepared and analyzed. A second approach to the preparation of linear and cyclic copolymers of ANi and SNS employed a DNA encoded module strategy. In this approach, single-stranded DNA oligomers composed of a central region containing (SNS)6 or (ANi)5 covalently attached monomer blocks and flanking 5'- and 3'-single-strand DNA recognition sequences were combined in buffer solution. Self-assembly of these oligomers by Watson-Crick base pairing of the recognition sequences creates linear or cyclic arrays of SNS and ANi monomer blocks. Treatment of these arrays with HRP/H2O2 causes rapid and efficient polymerization to form copolymers having patterns such as cyclic BBA and linear ABA, where B stands for an (SNS)6 block and A stands for an (ANi)5 block. These DNA-conjoined copolymers were characterized by melting temperature analysis, circular dichroism spectroscopy, native and denaturing polyacrylamide gel electrophoresis, and UV-visible-near-IR optical spectroscopy. The optical spectra of these copolymers are typical of those of conducting polymers and are uniquely dependent on the specific order of monomers in the copolymer. PMID- 23448550 TI - Reference values for glomerular filtration rate in healthy Brazilian adults. AB - BACKGROUND: Glomerular filtration rate (GFR) is the best index of renal function, but age, gender and ethnicity can putatively affect its values. The aim of this study was to establish reference values for GFR in healthy Brazilian subjects while taking these factors into account. METHODS: In this cross-sectional study, GFR was measured by the 51Cr-EDTA single-injection method. GFR reference values were developed according to CLSI Guidelines for Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory (CLSI C28 protocol). RESULTS: The age range of the 285 healthy individuals was 19 to 70 years, 57% were females, and GFR was 106 +/- 18 mL/min/1.73 m(2). There was no difference between male and female GFRs (108 +/- 18 vs. 104 +/- 18 mL/min/1.73 m(2) respectively, P = 0.134), and reference values were therefore developed from the pooled sample. GFR values were lower in subjects aged >=45 years as compared with those younger than 45 years (98 +/- 15 vs.112 +/- 18 mL/min/1.73 m(2), P < 0.001). Based on mean +/- 2 SD, GFR reference values were 76 to 148 mL/min/1.73 m(2) for subjects younger than 45 years and 68 to 128 mL/min/1.73 m(2) for individuals older than 45 years, irrespective of gender. CONCLUSION: The age adjusted reference intervals reported may be reliably adopted to evaluate kidney function, since they are based on recommended standards. PMID- 23448551 TI - Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. AB - AIM: The aim of this study was to characterize patients diagnosed with glucose transporter protein-1 deficiency syndrome (GLUT-1 DS) clinically and genetically, and to evaluate the effect of treatment with the classic ketogenic or modified Atkins diet. METHOD: We retrospectively studied medical records of 10 patients diagnosed with GLUT-1 DS. Four females and six males with a median age of 15 years were included. RESULTS: The study illustrates the genetic and clinical heterogeneity of GLUT-1 DS. Analysis of the SLC2A1 gene disclosed a variety of mutation types. The time between onset of symptoms and diagnosis was more than 11 years on average. The outcome in those with early diagnosis and intervention was surprisingly good. All but one patient with the classic phenotype became seizure free after treatment with the classic ketogenic or modified Atkins diet. Acetazolamide was effective in one patient with paroxysmal exercise-induced dyskinesia. A point prevalence of GLUT-1 DS in Norway was estimated as 2.6 per 1,000,000 inhabitants. INTERPRETATION: Although the long-term prognosis in patients with GLUT-1 DS partly depends on the underlying genetics, our study supports the assumption that early initiation of treatment with a ketogenic diet may positively affect the outcome. PMID- 23448552 TI - Mitochondrial signaling in Saccharomyces cerevisiae pseudohyphae formation induced by butanol. AB - Yeasts growing limited for nitrogen source or treated with fusel alcohols form elongated cells--pseudohyphae. Absence of mitochondrial DNA or anaerobic conditions inhibits this process, but the precise role of mitochondria is not clear. We found that a significant percentage of pseudohyphal cells contained mitochondria with different levels of membrane potential within one cell. An uncoupler carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), but not the ATP-synthase inhibitor oligomycin D, prevented pseudohyphal growth. Interestingly, repression of the MIH1 gene encoding phosphatase activator of the G2/M transition partially restores the ability of yeast to form pseudohyphal cells in the presence of FCCP or in the absence of mitochondrial DNA. At the same time, retrograde signaling (the one triggered by dysfunctional mitochondria) appeared to be a positive regulator of butanol-induced pseudohyphae formation: the deletion of any of the retrograde signaling genes (RTG1, RTG2, or RTG3) partially suppressed pseudohyphal growth. Together, our data suggest that two subpopulations of mitochondria are required for filamentous growth: one with high and another with low transmembrane potential. These mitochondria-activated signaling pathways appear to converge at Mih1p level. PMID- 23448553 TI - Association between water consumption from polycarbonate containers and bisphenol A intake during harsh environmental conditions in summer. AB - With the exception of polycarbonate (PC) baby bottles, little attention has been paid to bisphenol A (BPA) intake from packaged water consumption (PC water dispensers), especially during summer weather conditions. We determined the magnitude and variability of urinary BPA concentrations during summer in 35 healthy individuals largely relying upon PC packaged water to satisfy their potable needs. We used liquid chromatography-tandem mass spectrometry to measure urinary BPA concentrations. A questionnaire was administered in July/August and a spot urine sample was collected on the same day and 7 days after the completion of the interview (without intervention). Linear regression was performed to assess the association of variables, such as water consumption from different sources, on urinary BPA levels for the average of the two urine samples. A significant positive association (p = 0.017) was observed between PC water consumption and urinary BPA levels in females, even after adjusting for covariates in a multivariate regression model. The geometric mean of daily BPA intake back-calculated from urinary BPA data was 118 ng . (kg bw)(-1) . day(-1), nearly double the average intake levels observed in biomonitoring studies worldwide. High urinary BPA levels were partially ascribed to summer's high PC water consumption and weather characteristics (high temperatures, >40 degrees C; very high UV index values, >8), which could be causing BPA leaching from PC. It is suggested that PC-based water consumption could serve as a proxy for urinary BPA, although the magnitude of its relative contribution to overall daily intake requires further investigation. PMID- 23448554 TI - Prospective and concurrent correlates of emotion perception in psychotic disorders: a naturalistic, longitudinal study of neurocognition, affective blunting and avolition. AB - This naturalistic study investigated longitudinal and cross-sectional symptomatic and neurocognitive correlates of social cognition indexed by emotion perception. Participants were 31 persons admitted to a psychiatric emergency ward due to acute psychosis. Positive and negative (i.e., affective blunting and avolition) symptoms were assessed at baseline and 12-month follow-up using the Positive and Negative Syndrome Scale. Participants completed neuropsychological assessments with alternative versions of the Repeatable Battery for the Assessment of Neuropsychological Status at baseline and at 12-month follow-up. Emotion perception was measured using the Face/Voice Emotion Test at 12-month follow-up. Correlational analyses (Spearman's rho) revealed strong and statistically significant associations between neurocognition and emotion perception (baseline r = 0.58, follow-up r = 0.43). Associations between positive symptoms and emotion perception were weak or non-existent (baseline r = 0.13, follow-up r = -0.01). Emotion perception was moderately, but not significantly, associated with affective blunting at follow-up (r = 0.33), but not at baseline (r = 0.21). The association with avolition was non-existent (baseline r = -0.05, follow-up r = 0.01). This study supports the notion that emotion perception has neurocognitive correlates. The cross-sectional trend level association with affective blunting suggests that the ability to perceive emotions might be related to, but dissociable from the ability to express emotions. PMID- 23448555 TI - Management of cataracts and oculo-cutaneous malignancy in xeroderma pigmentosum. AB - This case report describes the management of a 17-year-old woman with xeroderma pigmentosum (XP) with bilateral mature cataract, conjunctival squamous cell carcinoma in the left eye (OS) and a cutaneous squamous cell carcinoma on her nose. To our knowledge, this is the first reported XP case with a cataract developing in the last couple of years without any ocular trauma, any history of inadequate diet or of previous corticosteroid use. We believe that cataracts can be related to improper working of the DNA repair mechanism of the lens epithelial cells in XP patients. PMID- 23448556 TI - Superior ophthalmic vein thrombosis developed after orbital cellulitis. AB - A 65-year-old female patient presented with eye pain, swelling and blurred vision in the left eye. Routine biochemistry and microbiological analyzes were conducted. Orbital tomography (CT), magnetic resonance imaging (MRI) findings, and cerebral angiography were performed. Orbital cellulitis due to a complication of ethmoidal sinusitis was diagnosed with thrombosis of the SOV in the patient. Systemic broad-spectrum antibiotic and anticoagulant therapy was started on the patient. The patient's symptoms were recorded at the end of two weeks of the treatment. PMID- 23448557 TI - Effect of Dorzolamide/Timolol or Brinzolamide/Timolol prophylaxis on intravitreal anti-VEGF injection-induced intraocular hypertension. AB - PURPOSE: To evaluate prospectively whether anti-glaucomatic drugs administered prior to intravitreal anti-vascular endothelial growth factor (VEGF) injection bevacizumab (Avastin,(r) Roche) or ranibizumab (Lucentis,(r) Novartis) prevents intraocular hypertension after the injection. SUBJECTS AND METHODS: In total, 166 patients (175 eyes) scheduled for intravitreal anti-VEGF injection treatment were prophylactically treated 1 hour before the procedure with Dorzolamide/Timolol (Cosopt,(r) MSD) (Group 1, 53 eyes) or Brinzolamide/Timolol (Elazop,(r) Alcon) (Group 2, 84 eyes) or left untreated (Group 3, 29 eyes). Intraocular pressure was analyzed 5 minutes prior to the injection, every 5 minutes for 30 minutes after the procedure, and 1 hour, 1 day, 7 days, and 1 month after the procedure. RESULTS: The intraocular pressures 5 minutes before the procedure (baseline) for Groups 1, 2, and 3 were 12.06 +/- 1.85, 13.98 +/- 2.68, and 13.81 +/- 2.24 mmHg, respectively. Five and 30 minutes after the procedure, the intraocular pressures of the three groups were 14.12 +/- 4.18, 14.87 +/- 3.35, and 28.21 +/- 3.16 mmHg, respectively, and 10.87 +/- 1.58, 14.25 +/- 2.43, and 17.48 +/- 2.34 mmHg, respectively. For all three groups, the changes relative to baseline 5 and 30 minutes after injection were significant. When the three groups were divided according to whether they received bevacizumab or ranibizumab and the changes in intraocular pressure relative to baseline were analyzed, all six subgroups exhibited significant changes in intraocular pressure 5 and 30 minutes after the procedure. CONCLUSION: The prophylactic administration of anti-glaucomatic drugs prior to intravitreal anti-VEGF injection effectively reduced the early intraocular pressure elevation. This approach was also safe and could be performed accurately. PMID- 23448558 TI - Anterior capsular phimosis occluding the capsulorhexis opening after cataract surgery in a diabetic patient with high hemoglobin A1C. AB - PURPOSE: To report a case of complete occlusion of the capsulorhexis opening in a DM patient with high hemoglobin A1C level. METHODS: A 77-year-old woman with non insulin-dependent diabetes underwent uncomplicated phacoemulsification in both eyes. One year later, she presented again because of reduced vision (best corrected visual acuity of 16/20 in the right eye, 6/20 in the left eye). Dilated examination revealed marked anterior capsular contraction in the right eye and anterior capsular phimosis totally occluding the capsulorhexis opening in the left eye. RESULTS: The severity of diabetic retinopathy and her fasting blood sugar (225 mg/dl) and hemoglobin A1C level (8.5%) increased during the previous year. Uncorrected visual acuity of 18/20 (OS) was achieved after a neodymium:YAG (Nd:YAG) radial anterior capsulotomy was performed. CONCLUSION: Microvascular complications such as diabetic retinopathy or diabetic iritis can occur in patient with uncontrolled diabetes mellitus. The pathophysiology of anterior capsular phimosis in this patient is probably increased vascular permeability chronically associated with diabetes. PMID- 23448559 TI - Intraocular pressure following combined routes of bevacizumab-augmented trabeculectomy for refractory neovascular glaucoma. AB - PURPOSE: To evaluate the intraocular pressure (IOP) control following combined routes of adjuvant bevacizumab with trabeculectomy in refractory neovascular glaucoma. METHODS: From June 2011 to December 2011, 5 consecutive cases of neovascular glaucoma with persistent raised IOP on maximal medical treatment underwent adjuvant bevacizumab by combined routes (subconjunctival (SC) and/or intracameral (IC), intravitreal (IV) injections) before pan-retinal photocoagulation (PRP). Needs for repeat procedures or medications for IOP control over the postoperative period were assessed. RESULTS: The mean IOP (1 SC, 1 IC + IV, 3 SC + IC routes) reduced from 40 +/- 5.5 mm Hg to 17 +/- 3.7 mm Hg at a mean final follow-up of 4 +/- 3.7 months (range 1-9 months), respectively (p < 0.001 for each). All eyes had transient IOP spikes 1-3 months after surgery, which normalized spontaneously after PRP, while one eye required topical medications for IOP control. CONCLUSIONS: Combined routes of adjuvant bevacizumab augmented trabeculectomy may help in better IOP control (IC + IV > IC + SC > SC) in refractory neovascular glaucoma but require additional procedures for sustained effect. PMID- 23448560 TI - Fungal corneal ulcer and bacterial orbital cellulitis occur as complications of bacterial endophthalmitis after cataract surgery in an immunocompetent patient. AB - PURPOSE: To report a case of fungal corneal ulcer and bacterial orbital cellulitis as complications of bacterial endophthalmitis following cataract surgery. METHODS: A 51-year-old man underwent anterior chamber irrigation and aspiration in the left eye one day after cataract surgery because of bacterial endophthalmitis. Marked lid swelling with purulent discharge was developed after 5 days. Slit lamp examination showed generalized corneal ulcer and pus in the total anterior chamber. A computerized tomography scan showed left retrobulbar fat stranding with thickened optic disc. Streptococcus pneumonia was cultured from corneal scraping, vireous, and subconjunctival pus. RESULTS: The patient improved gradually with antibiotics treatments, but the corneal ulcer did not fully recover 2 months after cataract surgery. Candida albicans was detected in repetitive corneal culture. After antifungal and antibacterial therapy, the corneal epithelium had healed, but phthisis bulbi had developed. CONCLUSION: Fungal corneal ulcer and bacterial orbital cellulitis can occur as complications of endophthalmitis in an immunocompetent patient. PMID- 23448562 TI - Phakic cystoid macular edema secondary to idiopathic macular telangiectasia type 1 responsive to topical anti-inflammatory agents. AB - PURPOSE: To report a 65-year-old male patient with bilateral phakic cystoid macular edema secondary to idiopathic macular telangiectasia type 1, with robust response to topical steroidal and non-steroidal agents. METHODS: Retrospective interventional case report. Chart review. RESULTS: Snellen visual acuity was 20/40 bilaterally. Color fundus photographs showing golden crystalline deposits temporal to the fovea; fluorescein angiography demonstrating telangiectasias with late leakage; and spectral-domain optical coherence tomography revealing intraretinal and subretinal fluid demonstrated findings consistent with idiopathic macular telangiectasia type 1 with bilateral cystoid macular edema. The patient was treated with steroidal and non-steroidal anti-inflammatory drops with complete resolution of edema within two months and improved visual acuity. Over the next two years, edema recurred whenever the drops were stopped and disappeared with reinstitution of topical therapy. CONCLUSION: Topical steroidal and non-steroidal anti-inflammatory agents may lead to long-term resolution of cystoid macular edema secondary to idiopathic macular telangiectasia type 1. PMID- 23448561 TI - Cystoid macular edema in retinitis pigmentosa patients without associated macular thickening. AB - PURPOSE: To describe the occurrence of cystoid macular edema (CME) in the setting of central foveal thickness (CFT) under 250 MUm as measured by optical coherence tomography (OCT) in patients with retinitis pigmentosa (RP). METHODS: Stratus OCT was used to measure CFT in a total of 90 eyes from 46 patients with RP. Cross sectional OCT images were also evaluated for CME, which was defined as cystoid changes in the macula seen on at least two linear scans. RESULTS: CME was identified in 13 of the 46 patients or in 22 of 90 eyes by OCT. In eyes with macular edema, CFT ranged from 224 to 718 MUm (mean = 339 +/- 137 MUm). In eyes without macular edema, CFT ranged from 99 to 273 MUm (mean = 184 +/- 40 MUm). Bilateral CME occurred in 9 of 13 patients (69%). CFT was considered "normal" in 7 of the 22 eyes (32%) with CME. Two patients had bilateral CME with normal CFTs, under 250 MUm. CONCLUSION: We demonstrate the occurrence of CME in RP patients without associated thickening, which has not been described. This concept likely is applicable to other diseases with retinal thinning. PMID- 23448563 TI - Branch retinal vein occlusion associated with tamoxifen use. AB - Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of hormone-responsive breast cancer. Tamoxifen-induced ocular complications are very rare. A post-menopausal woman with carcinoma of the left breast had presented with sudden loss of vision. The patient had been on tamoxifen therapy 20 mg daily for the last three years. Fundus examination showed left branch retinal vein occlusion. Fluorescein angiography and optical coherence tomography confirmed the diagnosis. Tamoxifen therapy was discontinued. Although branch retinal vein occlusion is rare, careful evaluation of patients on tamoxifen therapy with visual symptoms is required. PMID- 23448564 TI - Unilateral acute dacryocystitis associated with oculoglandular tularemia: a case report. AB - PURPOSE: To describe an unusual case of oculoglandular tularemia associated with unilateral acute dacryocystitis and purulent conjunctivitis with 18 weeks pregnancy. METHODS: It is difficult to culture francisella tularensis on media so serological tests such as micro-agglutination methods are used to diagnose the infection. PCR test results were weak positive. The serum sample was analyzed for the presence of f. tularensis antibody, which was determined positive with a titer of 1/160. RESULTS: Oral amoksicilin-clavulonic acid treatment was applied to the patient because of the side-effects of other antibiotics on the fetus. Dacryocystitis was surgically drained but relapsed a few weeks later, so it was drained again and a ciprofloksasin-impregnated sponge was placed into the tissue defect that occured after drainage. No relapses were seen after recovery of dacryocystitis. CONCLUSIONS: Oculoglandular tularemia is not only suspected in cases who complain of fever, cervical lymphadenopathy and purulent conjunctivitis, it should also be suspected in cases who are admitted to the hospital with acute dacryocystitis, which is a rare component of oculoglandular syndrome. PMID- 23448565 TI - Intraconal orbital dermoid cyst in an adult patient: a rare location. AB - Orbital dermoid cyst is a rare cause of orbital tumor in the adult population. Most of the orbital dermoids are extraconal, arising adjacent to bone suture and occurring in the pediatric patients. Deep orbital dermoid cyst located entirely intraconally is extremely rare. We report a case of intraconal orbital dermoid in an adult patient with CT and MRI evaluation. PMID- 23448567 TI - Total macular volume and foveal retinal thickness alterations in healthy pregnant women. AB - ABSTRACT Purpose: To evaluate whether there are alterations in total macular volume (TMV) and foveal retinal thickness (FT) values during pregnancy. METHODS: This study included 60 healthy pregnant women in their first, second, and third trimester (groups 1, 2, and 3) and 20 nonpregnant women (group 4). TMV and FT values were measured by optical coherence tomography (OCT) in each group. RESULTS: Mean TMV was 1.43 +/- 0.56 mm(3), 1.88 +/- 0.54 mm(3), 2.04 +/- 0.66 mm(3) and 1.35 +/- 0.41 mm(3) in groups 1, 2, 3, and 4, respectively. Mean FT was 199.20 +/- 64.35 u, 274.35 +/- 67.45 u, 287.95 +/- 95.50 u and 192.100 +/- 58.61 u in groups 1, 2, 3, and 4, respectively. There was statistical significance among group 1-2 (p1 = 0.014, p2 = 0.001), group 1-3 (p1 = 0.003, p2 = 0.002), group 2-4 (p1 = 0.001, p2 = 0.001), and group 3-4 (p1 = 0.001, p2 = 0.001) for both TMV and FT, respectively. CONCLUSION: The increase of fluid in the body, in particular in the second and last trimester, may cause an increase of TMV and FT. PMID- 23448566 TI - Retinal nerve fiber layer thickness in children <18 years by spectral-domain optical coherence tomography. AB - OBJECTIVES: To establish a normative database for retinal nerve fiber layer (RNFL) thickness in children<18 years by spectral-domain optical coherence tomography (SD-OCT). METHODS: Children <18 years, who were consecutively enrolled from July-August 2011 in this cross-sectional hospital study, underwent Cirrus SD OCT. Recorded demographics and clinical characteristics included age, sex, axial length, spherical equivalent, intraocular pressure (by Perkins tonometry) and cup disc ratio. The RNFL thickness full circle (RNFL-FC), superior, (RNFL-S), inferior (RNFL-I), temporal (RNFL-T), and nasal (RNFL-N) and the influence of clinical and demographic factors on the RNFL thickness were assessed using linear regression analysis. RESULTS: 148 eyes of 74 children were analyzed (females: males = 37: 37) with a mean age of 10 +/- 3.4 years (range 4-17 years) and a mean spherical equivalent of -0.6 +/- 1.2 dioptres. The mean RNFL-FC was 94 +/- 10.9 and 93 +/- 10.6 um in the right and left eyes, respectively, with maximum thickness found in the superior quadrant. The RNFL-FC and RNFL-S decreased by 1.9 um for every 1 dioptre increase in myopic shift, p < 0.001, and by 1.9 um for every mm increase in axial length, p < 0.001. There was no effect of age on RNFL thickness in females or males. CONCLUSIONS: The RNFL thickness in children was influenced most by axial length and refractive error while it was independent of age. The normative data from this study could serve as reference for further studies on pediatric glaucoma using newer imaging devices. PMID- 23448568 TI - Seeing is believing: the direct and contingent influence of pictures in health promotion advertising. AB - Because pictures, compared with words, are more effective in triggering vivid imagery, their effects should increase in situations in which they play a crucial role in facilitating imagery. This study accordingly explored the relative effects of information presented in pictorial formats and verbal formats in health promotion advertising. Symptoms presented in pictorial formats increased perceptions of the severity of a disease, whereas prevention options presented in pictorial formats enhanced efficacy in preventing the disease. This study also examined two contingent situations: when people were oriented toward visual processing, and when imagery could not be easily triggered without the help of pictures, such as when symptoms or prevention options were difficult or unpleasant to imagine. The findings of three studies supported the offered predictions. PMID- 23448569 TI - Aspergillus petrous apicitis associated with cerebral and peritubular abscesses in an immunocompetent man. AB - BACKGROUND: Petrous apex aspergillosis is an uncommon and dangerous condition, with only four previously reported cases. As with other forms of petrous apicitis, the clinical symptoms are often non-specific and this contributes to diagnostic delay. This paper presents the first reported case of Aspergillus petrous apicitis associated with an intracranial or nasopharyngeal abscess. CASE REPORT: A 72-year-old man with chronic otorrhoea developed neuralgic headaches and progressive lower cranial nerve palsies despite antibiotic therapy. Imaging revealed petrous apicitis, a temporal lobe abscess and nasopharyngeal abscess. Analysis of biopsy tissue indicated invasive aspergillosis. The patient recovered on a protracted course of voriconazole in addition to medium-term antibiotic therapy. CONCLUSION: Invasive fungal disease should be considered early in the course of skull base osteomyelitis that is clinically unresponsive to empirical broad spectrum antibiotics. This paper highlights the role of tissue biopsy in diagnosis, and the efficacy of voriconazole therapy without the need for radical surgery. PMID- 23448571 TI - FGF-2 prevents cancer cells from ER stress-mediated apoptosis via enhancing proteasome-mediated Nck degradation. AB - Induction of ER (endoplasmic reticulum) stress-mediated apoptosis in cancer cells represents an alternative approach for cancer therapy. Whether FGF-2 (fibroblast growth factor 2)-induced survival signals may interact with ER stress signalling in cancer cells remains elusive. In the present study, we showed that pretreatment with FGF-2 decreased the inhibition of DNA synthesis and induction of apoptosis by two different ER stress inducers, TM (tunicamycin) and TG (thapsigargin), in both human hepatoblastoma HepG2 cells and breast cancer MCF-7 cells. Pretreatment with FGF-2 prevented ER stress-mediated apoptosis by decreasing ER stress-induced CHOP [C/EBP (CCAAT/enhancer-binding protein) homologous protein] expression. We further demonstrated that pretreatment with FGF-2 mediated the decrease in TM-induced CHOP expression and apoptosis through ERK1/2 (extracellular-signal-regulated kinases 1 and 2) pathway. Finally, we demonstrated that FGF-2 promoted proteasome-mediated degradation of Nck (non catalytic region of tyrosine kinase adaptor protein), an SH (Src homology) 2/SH3 containing adaptor protein. Whereas overexpression of Nck1 decreased FGF-2 induced ERK1/2 phosphorylation to inhibit the effect of FGF-2 on TM-induced CHOP expression and apoptosis, a decrease in Nck expression prevented TM-induced CHOP expression and apoptosis. Taken together, the findings of the present study provide the first evidence that Nck plays a pivotal role in integrating FGF-2 and ER stress signals to counteract the ER stress deleterious effect on cancer cell survival. PMID- 23448570 TI - Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. AB - INTRODUCTION: Improved methods to optimize drug dosing in the critically ill are urgently needed. Traditional prescribing culture involves recognition of factors that mandate dose reduction (such as renal impairment), although optimizing drug exposure, through more frequent or augmented dosing, represents an evolving strategy. Elevated creatinine clearance (CLCR) has been associated with sub therapeutic antibacterial concentrations in the critically ill, a concept termed augmented renal clearance (ARC). We aimed to determine the prevalence of ARC in a cohort of septic and traumatized critically ill patients, while also examining demographic, physiological and illness severity characteristics that may help identify this phenomenon. METHODS: This prospective observational study was performed in a 30-bed tertiary level, university affiliated, adult intensive care unit. Consecutive traumatized and septic critically ill patients, receiving antibacterial therapy, with a plasma creatinine concentration <=110 MUmol/L, were eligible for enrolment. Pulse contour analysis (Vigileo / Flo Trac system, Edwards Lifesciences, Irvine, CA, USA), was used to provide continuous cardiac index (CI) assessment over a single six-hour dosing interval. Urinary CLCR measures were obtained concurrently. RESULTS: Seventy-one patients contributed data (sepsis n = 43, multi-trauma n = 28). Overall, 57.7% of the cohort manifested ARC, although there was a greater prevalence in trauma (85.7% versus 39.5%, P <0.001). In all patients, a weak correlation was noted between CI and CLCR (r = 0.346, P = 0.003). This was mostly driven by septic patients (r = 0.508, P = 0.001), as no correlation (r = -0.012, P = 0.951) was identified in trauma. Those manifesting ARC were younger (P <0.001), male (P = 0.012), with lower acute physiology and chronic health evaluation (APACHE) II (P= 0.008) and modified sequential organ failure assessment (SOFA) scores (P = 0.013), and higher cardiac indices (P = 0.013). In multivariate analysis, age <=50 years, trauma, and a modified SOFA score <=4, were identified as significant risk factors. These had greater utility in predicting ARC, compared with CI assessment alone. CONCLUSIONS: Diagnosis, illness severity and age, are likely to significantly influence renal drug elimination in the critically ill, and must be regularly considered in future study design and daily prescribing practice. PMID- 23448572 TI - The application of Kingdon's Multiple Streams Theory for human papillomavirus related anal intraepithelial neoplasia. AB - AIMS: This paper presents a discussion of the advantages and disadvantages of redefining human papillomavirus-related anal intraepithelial neoplasia as a problem of sexually active people by using Kingdon's Multiple Streams Theory to examine possible policy solutions for increasing anal cancer screening. BACKGROUND: Human papillomavirus is the most common sexually transmitted infection worldwide. Anal cancer associated with human papillomavirus infections is increasing in incidence in both men and women. The prevalence of anal cancer does not decrease with age. DATA SOURCE: Pubmed was searched for articles and internet references from 1995-2012. DISCUSSION: Although a large body of literature suggests that human papillomavirus-related anal intraepithelial neoplasia is a problem, no effective policy solutions have emerged. However, as almost the entire sexually active population is exposed to human papillomavirus, it should be thought of as every person's problem. This suggests that human papillomavirus-related anal intraepithelial neoplasia calls for different types of problem definitions and policy solutions to address the disease. The issue of anal cancer is typically defined as a problem of HIV-positive individuals. IMPLICATIONS FOR NURSING: Nurses are focused on improving patient outcomes. We play a key role in helping to identify problems, moving problems onto policymaker's agendas, and influencing the creation of new healthcare policies. CONCLUSION: Human papillomavirus-related anal intraepithelial neoplasia demands attention and the development of national level policies to ensure public health and safety. Kingdon's Multiple Streams Theory has provided a pragmatic framework to evaluate the problem. PMID- 23448573 TI - Improving the therapeutic ratio in stereotactic radiosurgery: optimizing treatment protocols based on kinetics of repair of sublethal radiation damage. AB - Sublethal damage after radiation exposure may become lethal or be repaired according to repair kinetics. This is a well-established concept in conventional radiotherapy. It also plays an important role in single-dose stereotactic radiotherapy treatments, often called stereotactic radiosurgery, when duration of treatment is extended due to source decay or treatment planning protocol. The purpose of this study is to look into the radiobiological characteristics of normal brain tissue and treatment protocols and find a way to optimize the time course of these protocols. The general problem is nonlinear and can be solved numerically. For numerical optimization of the time course of radiation protocol, a biexponential repair model with slow and fast components was considered. With the clinically imposed constraints of a fixed total dose and total treatment time, three parameters for each fraction (dose-rate, fraction duration, time of each fraction) were simultaneously optimized. A biological optimization can be performed by maximizing the therapeutic difference between tumor control probability and normal tissue complication probability. Specifically, for gamma knife radiosurgery, this approach can be implemented for normal brain tissue or tumor voxels separately in a treatment plan. Differences in repair kinetics of normal tissue and tumors can be used to find clinically optimized protocols. Thus, in addition to considering the physical dose in tumor and normal tissue, we also account for repair of sublethal damage in both these tissues. PMID- 23448574 TI - Resonance Raman and Raman spectroscopy for breast cancer detection. AB - Raman spectroscopy is a sensitive method to detect early changes of molecular _composition and structure that occur in lesions during carcinogenesis. The Raman spectra of normal, benign and cancerous breast tissues were investigated in vitro using a near-infrared (NIR) Raman system of 785 nm excitation and confocal micro resonance Raman system of 532 nm excitation. A total number of 491 Raman spectra were acquired from normal, benign and cancerous breast tissues taken from 15 patients. When the 785 nm excitation was used, the dominant peaks in the spectra were characteristic of the vibrations of proteins and lipids. The differences between the normal and cancerous breast tissues were observed in both the peak positions and the intensity ratios of the characteristic Raman peaks in the spectral region of 700-1800 cm(21). With 532 nm excitation, the resonance Raman (RR) spectra exhibited a robust pattern of peaks within the region of 500-4000 cm(21). The intensities of four distinct peaks at 1156, 1521, 2854 and 3013 cm(21) detected in the spectra collected from normal breast tissue were found to be stronger in comparison with those collected from cancerous breast tissue. The twelve dramatically enhanced characteristic peaks, including the enhanced amide II peak at 1548 cm(21) in the spectra collected from cancerous breast tissue, distinguished the cancerous tissue from the normal tissue. Principal component analysis (PCA) combined with support vector machine (SVM) analysis of the Raman and RR spectral data yielded a high performance in the classification of cancerous and benign lesions from normal breast tissue. PMID- 23448575 TI - Isolation and identification of renal cell carcinoma-derived peptides associated with GP96. AB - We determined the possible associated determinants and analyzed whether gp96 _associated antigenic peptides can be found in renal cell carcinoma (RCC). The gp96-peptide complexes were chromatographically purified from resected tumor tissue of RCC patients. SDS-PAGE and Western blot analysis confirmed gp96 using the gp96 monoclonal antibody, and its concentration was measured using BCA. Approximately 20 to 50 MUg gp96-peptide complexes was obtained from 1 g RCC tissue. The mass spectrometry (MS) analysis of the eluted peptides included the initial profiling using matrix-assisted laser desorption/ionization time-of flight MS. Quadrupole time-of-flight MS combined with the Mascot search engine was used to identify the peptides and find proteins from primary sequence databases. MS analysis results demonstrated that the mass range of peptide associated with gp96 was from 1046.48 to 3501.56 Da. Further research confirmed the sequences of two gp96-associated peptides, namely, LVPLEGWGGNVM and PPVYYVPYVVL. However, the original protein of the two peptides could not be found. The results demonstrated that the gp96-associated peptides are small molecular peptides, and the two peptides are deduced to be RCC-associated peptides. The identified peptides were confirmed to be associated with gp96 using the protocols described above. However, the specificity and relevance of the association to the immunogenicity of gp96 remains to be examined. Further analysis must be accomplished before the findings can be applied in peptide vaccine. PMID- 23448576 TI - The role of regularization in deformable image registration for head and neck adaptive radiotherapy. AB - Deformable image registration provides a robust mathematical framework to quantify morphological changes that occur along the course of external beam radiotherapy treatments. As clinical reliability of deformable image registration is not always guaranteed, algorithm regularization is commonly introduced to prevent sharp discontinuities in the quantified deformation and achieve anatomically consistent results. In this work we analyzed the influence of regularization on two different registration methods, i.e. B-Splines and Log Domain Diffeomorphic Demons, implemented in an open-source platform. We retrospectively analyzed the simulation computed tomography (CTsim) and the corresponding re-planning computed tomography (CTrepl) scans in 30 head and neck cancer patients. First, we investigated the influence of regularization levels on hounsfield units (HU) information in 10 test patients for each considered method. Then, we compared the registration results of the open-source implementation at selected best performing regularization levels with a clinical commercial software on the remaining 20 patients in terms of mean volume overlap, surface and center of mass distances between manual outlines and propagated structures. The regularized B-Splines method was not statistically different from the commercial software. The tuning of the regularization parameters allowed open source algorithms to achieve better results in deformable image registration for head and neck patients, with the additional benefit of a framework where regularization can be tuned on a patient specific basis. PMID- 23448577 TI - Recent advances and prospects in the isolation by size of epithelial tumor cells (ISET) methodology. AB - Current technologies to identify and characterize circulating tumor cells (CTCs) and _ circulating tumor microemboli (CTMs) among hundreds of millions of leukocytes in the bloodstream can be classified into tumor-marker-dependent and independent technology. Isolation by size of epithelial tumor cells (ISET) is a tumor-marker-independent technology, in which CTCs are isolated by filtration without use of tumor-associated markers, as a result of their large size relative to circulating blood leukocytes. ISET allows cytomorphological, immunocytological, and genetic characterization of CTCs and CTMs. It offers a number of advantages, including retention of cell morphology; non-antigen dependence; amenability of cells to further interrogation by immunolabeling, fluorescence in situ hybridization, and RNA/DNA analysis; ability to isolate CTMs; reliability. Therefore, morphological-analysis-based and antigen independent ISET methodology can yield more accurate and objective characterization of epithelial-mesenchymal transition. We can evaluate efficacy of _chemotherapy and radiotherapy and other cancer-targeting therapies by using xenografts that are suitable models for mechanistic studies of ISET-isolated CTC/CTM biology. In addition, a new _ISET-based device could be designed to increase sensitivity to CTCs/CTMs greatly and reduce the number of CTCs/CTMs directly during the blood flow, thus decreasing the _possibility of tumor recurrence and metastasis while retaining normal blood cells. This article reviews recent advances and prospects in ISET methodology and provides new insights into ISET methodology, with important implications for the clinical management of cancer patients. PMID- 23448578 TI - Stereotactic body radiotherapy with helical tomotherapy for pain palliation in spine metastasis. AB - To evaluate the pain response, local tumor control and toxicity of stereotactic body radiotherapy (SBRT) with helical tomotherapy (HT) in the patients with spine metastasis. From May 2009 to June 2010, 22 patients with 31 lesions were treated by SBRT. Dose scheme were 24 Gy in 3 fractions (87.1%), 30 Gy in 5 fractions (9.7%), and 16 Gy in a single fraction (3.2%). Pain was assessed using a numerical rating scale. Analgesic consumption was recalculated into the daily oral morphine-equivalent dose (OMED). The response criteria of International Bone Metastases Consensus Group (IBMCG) was used. The median follow-up duration was 10 months (range 3-23 months). After SBRT the mean pain score decreased significantly (4.32 before SBRT, 0.71 at 3 months). However, median OMED didn't decrease until 3 months after SBRT (Median OMED; 34.5 mg before SBRT, 45 mg at 3 months). Pain response rate and pain progression-free survival rate at 3 month was 96.8 and 93.5%, respectively. Local progression-free survival rate at 3 month was 93.5%. There was no severe acute toxicity. SBRT with HT is a safe and effective treatment modality for local tumor control and pain palliation associated with spine metastasis. PMID- 23448579 TI - Impact of system-level changes and training on alcohol screening and brief intervention in a family medicine residency clinic: a pilot study. AB - BACKGROUND: Although screening and brief intervention (SBI) are effective in reducing unhealthy alcohol use, major challenges exist in implementing clinician delivered SBI in primary care settings. This 2006-2007 pilot study describes the impact of systems changes and booster trainings designed to increase SBI rates in a family medicine residency clinic which annually screened adults with a self administered AUDIT-C questionnaire and used paper prompts to encourage physician interventions for patients with positive screens. METHODS: Investigators added the Single Alcohol Screening Question (SASQ) to nursing vital signs forms, added a checkbox for documenting brief interventions to the clinicians' outpatient encounter form, and conducted one-hour nurse and clinician booster trainings. Impact was measured using chart reviews conducted before implementing systems changes, then six weeks and six months post-implementation. RESULTS: At all three time points screening rates using AUDIT-C plus SASQ exceeded 90%, however AUDIT-C screening decreased to 85% after 6 months (p=.025). Identification of unhealthy alcohol users increased from 4% to 22.9% at six weeks and 18.8% at six months (p=.002) using both screens. Nursing vital signs screening using the SASQ reached 71.4% six weeks after implementation but decreased to 45.5% at six months. Changes in clinician brief intervention rates did not achieve statistical significance. CONCLUSIONS: This is the second study reporting sustained primary care alcohol screening rates of more than 90%. Screening patients with SASQ and/or AUDIT-C identified a higher percentage of patients with unhealthy alcohol use. Dissemination of effective strategies for identifying unhealthy alcohol users should continue, while future research should focus on identifying more effective strategies for increasing intervention rates. PMID- 23448580 TI - Enzyme responsive hyaluronic acid nanocapsules containing polyhexanide and their exposure to bacteria to prevent infection. AB - Antibacterial nanodevices could bring coatings of plastic materials and wound dressings a big step forward if the release of the antibacterial agents could be triggered by the presence of the bacteria themselves. Here, we show that novel hyaluronic acid (HA)-based nanocapsules containing the antimicrobial agent polyhexanide are specifically cleaved in the presence of hyaluronidase, a factor of pathogenicity and invasion for bacteria like Staphylococcus aureus and Escherichia coli. This resulted in an efficient killing of the pathogenic bacteria by the antimicrobial agent. The formation of different polymeric nanocapsules was achieved through a polyaddition reaction in inverse miniemulsion. After the synthesis, the nanocapsules were transferred to an aqueous medium and investigated in terms of size, size distribution, functionality, and morphology using dynamic light scattering, zeta potential measurements and scanning electron microscopy. The enzyme triggered release of a model dye and the antimicrobial polyhexanide was monitored using fluorescence and UV spectroscopy. The stability of the nanocapsules in several biological media was tested and the interaction of nanocapsules with human serum protein was studied using isothermal titration calorimetry. The antibacterial effectiveness is demonstrated by determination of the antibacterial activity and determination of the minimal bactericidal concentration (MBC). PMID- 23448581 TI - Reduction in cardiovascular risk using proactive multifactorial intervention versus usual care in younger (< 65 years) and older (>= 65 years) patients in the CRUCIAL trial. AB - OBJECTIVE: To compare the reduction in calculated Framingham 10 year coronary heart disease (CHD) risk after 52 weeks' intervention with a proactive multifactorial intervention (PMI) strategy (based on single-pill amlodipine/atorvastatin [SPAA]) versus continuing usual care (UC) (based on investigators' best clinical judgment) among younger (<65 years) and older (>= 65 years) patients. RESEARCH DESIGN AND METHODS: Sub-analysis of the Cluster Randomized Usual Care versus Caduet Investigation Assessing Long-term risk (CRUCIAL) trial. Eligible patients had hypertension and >= 3 cardiovascular risk factors. MAIN OUTCOME MEASURE: Treatment-related reduction in calculated Framingham 10 year CHD risk between baseline and Week 52 in younger and older patients. RESULTS: Nine hundred patients (63.5%) were <65 years (mean age 54.2 years, 57.4% men) and 517 patients (36.5%) were >= 65 years (mean age 70.5 years, 42.7% men). Younger patients had lower mean baseline CHD risk versus older patients (17.1% vs. 22.6%). A greater reduction in calculated CHD risk at Week 52 was observed in the PMI versus the UC arm in both younger (-33.2% vs. -2.9%, p < 0.001) and older (-32.7% vs. -5.7%, p < 0.001) patients. Least-squares mean treatment differences (PMI vs. UC) in percentage change from baseline in calculated CHD risk were similar in younger and older patients (-26.3% vs. 25.7%, age interaction p = 0.887). CHD risk reduction was slightly greater among younger men than younger women (-29.3 vs. -23.9, gender interaction p = 0.062). A low proportion of patients discontinued the PMI strategy due to adverse events in both age groups (5.8% vs. 6.1%, respectively). Study limitations included ad-hoc (not pre-specified) sub-group analysis and short duration of follow-up. CONCLUSIONS: The PMI strategy based on the inclusion of SPAA in the treatment regimen is more effective than UC in reducing calculated CHD risk. This strategy may be considered as the treatment of choice in younger and older hypertensive patients with additional cardiovascular risk factors. PMID- 23448582 TI - Curcumin improves expression of SCF/c-kit through attenuating oxidative stress and NF-kappaB activation in gastric tissues of diabetic gastroparesis rats. AB - BACKGROUND: Diabetes mellitus is associated with many kinds of complications. Recent studies have shown that oxidative stress and inflammatory reactions have critical roles in the pathogenesis of diabetic gastroparesis. Curcumin is known to have antioxidant and anti-inflammatory properties. In the present study, we investigated the effect of curcumin on diabetic gastric motility in a Sprague Dawley rat model of type 1 diabetes mellitus. METHODS: Male SD rats were divided into a control group, a control group receiving curcumin, a diabetic group, and a diabetic group receiving curcumin. Diabetes was induced by intraperitoneal injection of streptozotocin. Curcumin (150 mg/kg) was given intragastrically for 6 weeks, and blood glucose levels and body weights were measured. Stomachs were excised for analysis of gastric emptying rates, and levels of oxidative stress. NF-kappaB, I-kappaB, and stem cell factor (SCF)/c-kit protein levels were assessed by western blot analysis, while the apoptosis of interstitial cells of Cajal (ICCs) was assessed by TUNEL staining. RESULTS: Curcumin-treated diabetic rats showed significantly improved gastric emptying rates [(59.4 +/- 7.5)%] compared with diabetic rats [(44.3 +/- 5.7)%], as well as decreased levels of MDA [21.4 +/- 1.8 (nmol/mg) vs 27.9 +/- 2.1 (nmol/mg)], and increased SOD activity [126.2 +/- 8.8 (units/mg) vs 107.9 +/- 7.5 (units/mg)]. On the other hand, the gastric emptying level in the control group was not significantly different from that in the control group receiving curcumin treatment. In addition, curcumin treated diabetic rats showed significantly increased levels of SCF/c-kit protein in stomach tissues, inhibited I-kappaB degradation and NF-kappaB activation, and reduced ICC apoptosis index [(26.2 +/- 4.1)% vs (47.5 +/- 6.2)%], compared with the diabetic group. CONCLUSION: Curcumin treatment improved gastric emptying by blocking the production of oxidative stress, abolishing NF-kappaB signal transduction and enhancing expression of SCF/c-kit in rats with diabetic gastroparesis. PMID- 23448583 TI - Delivering at home or in a health facility? health-seeking behaviour of women and the role of traditional birth attendants in Tanzania. AB - BACKGROUND: Traditional birth attendants retain an important role in reproductive and maternal health in Tanzania. The Tanzanian Government promotes TBAs in order to provide maternal and neonatal health counselling and initiating timely referral, however, their role officially does not include delivery attendance. Yet, experience illustrates that most TBAs still often handle complicated deliveries. Therefore, the objectives of this research were to describe (1) women's health-seeking behaviour and experiences regarding their use of antenatal (ANC) and postnatal care (PNC); (2) their rationale behind the choice of place and delivery; and to learn (3) about the use of traditional practices and resources applied by traditional birth attendants (TBAs) and how they can be linked to the bio-medical health system. METHODS: Qualitative and quantitative interviews were conducted with over 270 individuals in Masasi District, Mtwara Region and Ilala Municipality, Dar es Salaam, Tanzania. RESULTS: The results from the urban site show that significant achievements have been made in terms of promoting pregnancy- and delivery-related services through skilled health workers. Pregnant women have a high level of awareness and clearly prefer to deliver at a health facility. The scenario is different in the rural site (Masasi District), where an adequately trained health workforce and well-equipped health facilities are not yet a reality, resulting in home deliveries with the assistance of either a TBA or a relative. CONCLUSIONS: Instead of focusing on the traditional sector, it is argued that more attention should be paid towards (1) improving access to as well as strengthening the health system to guarantee delivery by skilled health personnel; and (2) bridging the gaps between communities and the formal health sector through community-based counselling and health education, which is provided by well-trained and supervised village health workers who inform villagers about promotive and preventive health services, including maternal and neonatal health. PMID- 23448585 TI - Carbon tetrachloride degradation by alkaline ascorbic acid solution. AB - Ascorbic acid (AA) mediated electron transfer may induce reductive dechlorination of carbon tetrachloride (CCl(4)). This study investigated the role of AA in conjunction with the presence of iron minerals over a wide pH range for the reduction of CCl(4) in aqueous systems. The results indicate that CCl(4) was reduced by AA at a pH of 13 (>pKa(2, AA) of 11.79) and chloroform (CHCl3) was a transformation byproduct of CCl(4). When CCl(4) levels were reduced to near complete disappearance, the decrease of CHCl(3) was then observed. The degradation rate of CCl(4) and also the formation rate of CHCl(3) increased with increased AA concentrations. Analysis of reaction kinetics between CCl(4) and AA revealed an overall second-order reaction with a rate constant of 0.253 +/- 0.018 M(-1) s(-1). Furthermore, the reduction rate of CCl(4) by AA at pH of 13 could be enhanced with the presence of iron minerals (Fe(3)O(4), Fe(2)O(3), FeOOH, and FeS2). In the absence or presence of iron minerals, the fraction of CCl(4) transformed to CHCl(3) was less than 1, indicating simultaneous one- and two electron transfer processes. The end-products of AA at a pH of 13 included threonic acid and oxalic acid. This study highlights the potential of an alkaline AA solution for remediating chlorinated solvents. PMID- 23448584 TI - Tuning the moenomycin pharmacophore to enable discovery of bacterial cell wall synthesis inhibitors. AB - New antibiotic drugs need to be identified to address rapidly developing resistance of bacterial pathogens to common antibiotics. The natural antibiotic moenomycin A is the prototype for compounds that bind to bacterial peptidoglycan glycosyltransferases (PGTs) and inhibit cell wall biosynthesis, but it cannot be used as a drug. Here we report the chemoenzymatic synthesis of a fluorescently labeled, truncated analogue of moenomycin based on the minimal pharmacophore. This probe, which has optimized enzyme binding properties compared to moenomycin, was designed to identify low-micromolar inhibitors that bind to conserved features in PGT active sites. We demonstrate its use in displacement assays using PGTs from S. aureus, E. faecalis, and E. coli. 110,000 compounds were screened against S. aureus SgtB, and we identified a non-carbohydrate based compound that binds to all PGTs tested. We also show that the compound inhibits in vitro formation of peptidoglycan chains by several different PGTs. Thus, this assay enables the identification of small molecules that target PGT active sites, and may provide lead compounds for development of new antibiotics. PMID- 23448586 TI - A 2013 updated systematic review & meta-analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti-inflammatory agents on the risk of bleeding after tonsillectomy. AB - BACKGROUND: Although the literature suggests that non-steroidal anti-inflammatory drugs (NSAIDs) are effective in controlling post-operative pain in the paediatric population, physicians have been reluctant to utilise these medications after tonsillectomy due to concerns of increased bleeding rates. While many surgeons prescribe opioid analgesics postoperatively, these are associated with a number of potential adverse side-effects including nausea, vomiting, constipation, excessive sedation and respiratory compromise. OBJECTIVE OF REVIEW: To compare bleeding rates and severity between recipients of NSAIDs versus placebo or opioid analgesics for tonsillectomy. SEARCH STRATEGY: Two authors independently searched electronic databases including PubMed, OVID, EMBASE and Cochrane Review from inception to July 2012. The keywords used included: Adenotonsillectomy, Tonsillectomy, Analgesia, Bleeding, Perioperative and Postoperative. These were then combined in various combinations with specific NSAIDs. EVALUATION METHOD: A systematic review and meta-analysis of all randomised control trials comparing bleeding rates and severity between NSAIDs versus placebo or opioids post tonsillectomy. RESULTS: A total of 36 studies met our inclusion criteria including 1747 children and 1446 adults. When all of the studies were combined in a meta-analysis using the most severe outcome, there was no increased risk of bleeding in those using NSAIDs after tonsillectomy. Use of NSAIDs in general [1.30 (0.90-1.88)] or in children [1.06 (0.65-1.74)] was not associated with increased risk of bleeding in general, most severe bleeding, secondary haemorrhage, readmission or need of reoperation due to bleeding. Similarly, there was no increased bleeding risk for specific NSAIDs in adults. In the studies looking at paediatric subjects, the overall odds ratio of bleeding was even lower than in the general population and not significant. This result is based on 18 studies, six of which had zero outcomes in either treatment arm. Similar to the general population analysis, there was no significant difference in any of the subanalyses: bleeds treated with reoperation, readmission or bleeds in children that could be managed conservatively. There were also no significant differences in the subanalyses of individual NSAIDs. Similarly, there was no significant difference in rates of bleeding in the subanalysis of studies that gave NSAIDs multiple times, for instance, both before and after surgery. CONCLUSIONS: These results suggest that NSAIDs can be considered as a safe method of analgesia among children undergoing tonsillectomy. PMID- 23448587 TI - Iris floculli: elevated intraocular pressure or threat to life? PMID- 23448589 TI - Deep thigh abscess after coil embolization of a pseudoaneurysm of the profunda femoris artery. PMID- 23448588 TI - Whither the etiopathogenesis (and scoliogeny) of adolescent idiopathic scoliosis? Incorporating presentations on scoliogeny at the 2012 IRSSD and SRS meetings. AB - This paper aims to integrate into current understanding of AIS causation, etiopathogenetic information presented at two Meetings during 2012 namely, the International Research Society of Spinal Deformities (IRSSD) and the Scoliosis Research Society (SRS). The ultimate hope is to prevent the occurrence or progression of the spinal deformity of AIS with non-invasive treatment, possibly medical. This might be attained by personalised polymechanistic preventive therapy targeting the appropriate etiology and/or etiopathogenetic pathways, to avoid fusion and maintain spinal mobility. Although considerable progress had been made in the past two decades in understanding the etiopathogenesis of adolescent idiopathic scoliosis (AIS), it still lacks an agreed theory of etiopathogenesis. One problem may be that AIS results not from one cause, but several that interact with various genetic predisposing factors. There is a view there are two other pathogenic processes for idiopathic scoliosis namely, initiating (or inducing), and those that cause curve progression. Twin studies and observations of family aggregation have revealed significant genetic contributions to idiopathic scoliosis, that place AIS among other common disease or complex traits with a high heritability interpreted by the genetic variant hypothesis of disease. We summarize etiopathogenetic knowledge of AIS as theories of pathogenesis including recent multiple concepts, and blood tests for AIS based on predictive biomarkers and genetic variants that signify disease risk. There is increasing evidence for the possibility of an underlying neurological disorder for AIS, research which holds promise. Like brain research, most AIS workers focus on their own corner and there is a need for greater integration of research effort. Epigenetics, a relatively recent field, evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Research on the role of environmental factors, epigenetics and chronic non communicable diseases (NCDs) including adiposity, after a slow start, has exploded in the last decade. Not so for AIS research and the environment where, except for monozygotic twin studies, there are only sporadic reports to suggest that environmental factors are at work in etiology. Here, we examine epigenetic concepts as they may relate to human development, normal life history phases and AIS pathogenesis. Although AIS is not regarded as an NCD, like them, it is associated with whole organism metabolic phenomena, including lower body mass index, lower circulating leptin levels and other systemic disorders. Some epigenetic research applied to Silver-Russell syndrome and adiposity is examined, from which suggestions are made for consideration of AIS epigenetic research, cross-sectional and longitudinal. The word scoliogeny is suggested to include etiology, pathogenesis and pathomechanism. PMID- 23448591 TI - Obturator internus abscess: spontaneous perforation into the vagina. PMID- 23448592 TI - Dose-ranging study to assess the application of intranasal 2% mupirocin calcium ointment to eradicate Staphylococcus aureus nasal colonization. AB - BACKGROUND: Mupirocin nasal ointment may be prescribed for decolonization prior to surgical procedures, especially for carriers of methicillin-resistant Staphylococcus aureus (MRSA). The approved regimen for decolonization of S. aureus from the anterior nares is twice daily for 5 d (10 doses). We performed a two-center, randomized, open-label study to compare the utility of six and 10 doses for decolonization of S. aureus. METHODS: Patients expecting to undergo surgery were screened for S. aureus nasal carriage approximately three weeks prior to the procedure. Those found to be positive were offered enrollment in the study. In the first arm (n=41), patients were randomized to receive 2, 3, or 5 d (six or 10 doses) of treatment prior to their operation. Their anterior nares were swabbed for culture and S. aureus polymerase chain reaction (PCR) during the decolonization therapy period as well as for four weeks after surgery. In the second arm (n=60), all patients were given 5 d (10 doses) of nasal mupirocin treatment, and the patient's anterior nares were swabbed for culture and S. aureus PCR for four weeks after surgery. Data from six of the patients were excluded from analysis because of failure to submit swabs after operation. All S. aureus isolates were tested for susceptibility to mupirocin and the presence of the mecA gene to detect MRSA. RESULTS: In Arm 1, 16 patients received 10 doses of mupirocin, 18 received six doses (twice daily for 3 d), and 7 received six doses (thrice daily for 2 d). In the second arm, all patients received 10 doses of mupirocin (twice a day for 5 d). Overall, 89.5% patients who received 10 doses of mupirocin remained decolonized for at least four weeks after surgery versus 68.0% of patients who received six doses (p=0.016). There was no difference between arms 1 and 2 for those given mupirocin twice daily for 5 d. CONCLUSION: The ten dose regimen is superior to any six-dose regimen for de-colonizing S. aureus from the anterior nares of patients and for maintaining the decolonized state for at least four weeks after therapy. PMID- 23448593 TI - Trauma after transplant: hold the antibiotics please. AB - OBJECTIVE: Despite the increase in transplantation and the prevalence of trauma as a major disease entity, few data exist about transplant patients who suffer trauma. We conducted a study to determine whether transplant patients (TP) have worse outcomes, particularly of infections, than do their non-transplant (NTP) counterparts after trauma. METHODS: We performed a retrospective review of trauma patients from 2006 to 2010. All patients who had undergone organ transplantation were included and compared through 1:3 propensity matching with their NTP counterparts. Data for the groups were compared to determine differences in outcomes. RESULTS: The review included 17 TP (13 kidney, 2 liver, 1 kidney/liver, and 1 kidney/pancreas) as compared with 51 NTP. The patients were matched for injury severity score (ISS), age, and gender, with most suffering blunt trauma (82.4% [14/17] TP vs. 90% [46/51] NTP, p = 0.5). The groups had similar initial Glasgow Coma Scale (GCS) scores (13.2 +/- 4.5 TP vs. 13.9 +/- 2.5 NTP, p=0.6), serum lactate concentrations (2.0 +/- 1.8 mmol/L TP vs. 2.3 +/- 1.5 mmol/L NTP, p=0.39), and base deficits (-1.5 +/- 4.0 TP vs. 0.6 +/- 3.0 NTP, p=0.21). Comorbidities were more common in the TP than in the NTP group. The groups had similar lengths of stay (days on ventilator: 0.1 +/- 0.3 TP vs. 0.4 +/- 1.6 NTP, p=0.9; days in ICU: 0.2 +/- 0.6 TP vs. 2.4 +/- 5.9 NTP, p=0.16; days in hospital: 5.2 +/- 6.8 TP vs. 7.5 +/- 10.2 NTP, p=0.86), and two deaths occurred in each of the two groups (p=0.26). Overall complications were similar (52.94% [9/17] TP vs. 62.75% [32/51] NTP, p=0.57), and there were only two infections, both in the NTP group (p=1.0). Antibiotics were given to 59% of the TP vs. 39% of the NTP, with an average duration of 8.4 days for the TP vs. 3.9 days for the NTP. CONCLUSION: When matched equally for degree of injury, the TP and NTP had similar outcomes. There also appeared to be no differences in infectious complications in the two groups, yet more of the TP had exposure to more days of antibiotics. Similar protocols of antimicrobial therapy should apply to both TP and NTP to avoid the overuse of antimicrobial agents and ensure maintenance of the susceptibility patterns of pathogens. PMID- 23448594 TI - Endolymphatic sac tumour: case report and literature review. AB - OBJECTIVE: To increase awareness of the presentation, diagnostic difficulties and management of endolymphatic sac tumours. CASE REPORTS: A 79-year-old man with a 6 month history of unilateral hearing loss, tinnitus and vertigo, who was suspected to have an endolymphatic sac tumour on imaging, underwent successful transmastoid translabyrinthine resection. A 53-year-old man with unilateral hearing loss and pulsatile tinnitus underwent subtotal resection of a suspected paraganglioma, which was identified histologically. Due to interval growth, gamma knife radiosurgery was performed followed by subtotal petrosectomy, at which juncture an endolymphatic sac tumour was reported. METHODS: A review of the world literature was carried out using Medline, which identified less than 150 reported cases of endolymphatic sac tumour. CONCLUSION: Endolymphatic sac tumours are rare lesions of the petrous temporal bone. Although benign, they can be locally destructive. At present, there is no consensus regarding the management and long term follow up of these tumours. Surgical resection is usually favoured, although treatment with radiotherapy and gamma knife surgery has also been reported. PMID- 23448590 TI - Use of silver in the prevention and treatment of infections: silver review. AB - BACKGROUND: The use of silver for the treatment of various maladies or to prevent the transmission of infection dates back to at least 4000 b.c.e. Medical applications are documented in the literature throughout the 17th and 18th centuries. The bactericidal activity of silver is well established. Silver nitrate was used topically throughout the 1800 s for the treatment of burns, ulcerations, and infected wounds, and although its use declined after World War II and the advent of antibiotics, Fox revitalized its use in the form of silver sulfadiazine in 1968. METHOD: Review of the pertinent English-language literature. RESULTS: Since Fox's work, the use of topical silver to reduce bacterial burden and promote healing has been investigated in the setting of chronic wounds and ulcers, post-operative incision dressings, blood and urinary catheter designs, endotracheal tubes, orthopedic devices, vascular prostheses, and the sewing ring of prosthetic heart valves. The beneficial effects of silver in reducing or preventing infection have been seen in the topical treatment of burns and chronic wounds and in its use as a coating for many medical devices. However, silver has been unsuccessful in certain applications, such as the Silzone heart valve. In other settings, such as orthopedic hardware coatings, its benefit remains unproved. CONCLUSION: Silver remains a reasonable addition to the armamentarium against infection and has relatively few side effects. However, one should weigh the benefits of silver-containing products against the known side effects and the other options available for the intended purpose when selecting the most appropriate therapy. PMID- 23448596 TI - Experimental test of escape theory: accessibility to implicit suicidal mind. AB - This study tested the Escape Theory prediction that individuals blaming themselves for failure experience increased accessibility to implicit suicidal mind. One hundred and thirty-eight undergraduate medical students were randomly assigned to three groups: failure-related priming, success-related priming, and control. Following experimental conditions, participants completed a death/suicide Implicit Association Test. Results revealed significant differences between groups in accessibility to implicit suicidal mind. Furthermore, priming manipulation interacted with individual differences in locus of control (LOC). Significant differences in accessibility to implicit suicidal mind were observed in individuals with internal LOC, while effects of priming manipulation were eliminated in individuals with external LOC. PMID- 23448595 TI - Hydrosilylated porous silicon particles function as an intravitreal drug delivery system for daunorubicin. AB - PURPOSE: To evaluate in vivo ocular safety of an intravitreal hydrosilylated porous silicon (pSi) drug delivery system along with the payload of daunorubicin (DNR). METHODS: pSi microparticles were prepared from the electrochemical etching of highly doped, p-type Si wafers and an organic linker was attached to the Si-H terminated inner surface of the particles by thermal hydrosilylation of undecylenic acid. DNR was bound to the carboxy terminus of the linker as a drug loading strategy. DNR release from hydrosilylated pSi particles was confirmed in the excised rabbit vitreous using liquid chromatography-electrospray ionization multistage mass spectrometry. Both empty and DNR-loaded hydrosilylated pSi particles were injected into the rabbit vitreous and the degradation and safety were studied for 6 months. RESULTS: The mean pSi particle size was 30*46*15 MUm with an average pore size of 15 nm. Drug loading was determined as 22 MUg per 1 mg of pSi particles. An ex vivo drug release study showed that intact DNR was detected in the rabbit vitreous. An in vivo ocular toxicity study did not reveal clinical or pathological evidence of any toxicity during a 6-month observation. Hydrosilylated pSi particles, either empty or loaded with DNR, demonstrated a slow elimination kinetics from the rabbit vitreous without ocular toxicity. CONCLUSIONS: Hydrosilylated pSi particles can host a large quantity of DNR by a covalent loading strategy and DNR can be slowly released into the vitreous without ocular toxicity, which would appear if an equivalent quantity of free drug was injected. PMID- 23448598 TI - GLUT-1 deficiency syndrome in Norway--yet another piece of the puzzle. PMID- 23448597 TI - Expression level of methanol-inducible peroxisomal proteins and peroxisome morphology are affected by oxygen conditions and mitochondrial respiratory pathway function in the methylotrophic yeast Candida boidinii. AB - In the methylotrophic yeast, Candida boidinii, methanol-inducible peroxisomal proteins, for example alcohol oxidase (AOD), dihydroxyacetone synthase (DAS), and peroxisomal glutathione peroxidase (Pmp20), were induced only under aerobic conditions, while expression of PMP47 encoding peroxisomal integral membrane protein Pmp47 was independent of oxygen conditions. Expression of the methanol inducible peroxisomal enzymes was repressed by inhibition of the mitochondrial respiratory chain. In the respiratory-deficient (rho0) mutant strain, their induction was at very low levels despite the presence of oxygen, whereas the expression of PMP47 was unaffected. Taken together, these facts indicate that C. boidinii can sense oxygen conditions, and that mitochondrial respiratory function may have a profound effect on induction of methanol-inducible gene expression of peroxisomal proteins. Peroxisome morphology was also affected by oxygen conditions and respiratory function. Under hypoxic conditions or respiration inhibited conditions, cells induced by methanol contained small peroxisomes, indicating that peroxisome biogenesis and the protein import machinery were not affected by oxygen conditions but that peroxisome morphology was dependent on induction of peroxisomal matrix proteins. PMID- 23448599 TI - Aspergillus terreus complex: an emergent opportunistic agent of Onychomycosis. AB - The incidence of onychomycosis due to non-dermatophyte moulds (NDM) is increasing. Aspergillus terreus is relatively undocumented as an agent of this fungal infection. The aim of this work is to show the prevalence of onychomycosis caused by A. terreus and to describe its clinical features. Nail samples were collected for microscopic examination and culturing in selective media. All cases of onychomycosis due to NDM were confirmed by a second sample. Aspergillus terreus isolates were identified through their morphological characteristics and using molecular methods. A total of 2485 samples were obtained. Positive cultures were obtained in 1639 samples. From 124 NDM confirmed cultures, 23 were identified as A. terreus (18.5%). Superficial white onychomycosis was the most frequent clinical pattern. A high percentage was found in fingernails. The prevalence of A. terreus in this study considerably exceeded the percentages reported by other authors. Onychomycosis due to A. terreus presents similar clinical patterns to those caused by dermatophytes, but is difficult to eradicate and is associated with less predictable treatment outcomes. Better knowledge of the aetiology of A. terreus may be important for accomplishing more accurate and effective treatment. PMID- 23448600 TI - Highly diverse chromoviruses of Beta vulgaris are classified by chromodomains and chromosomal integration. AB - BACKGROUND: Chromoviruses are one of the three genera of Ty3-gypsy long terminal repeat (LTR) retrotransposons, and are present in high copy numbers in plant genomes. They are widely distributed within the plant kingdom, with representatives even in lower plants such as green and red algae. Their hallmark is the presence of a chromodomain at the C-terminus of the integrase. The chromodomain exhibits structural characteristics similar to proteins of the heterochromatin protein 1 (HP1) family, which mediate the binding of each chromovirus type to specific histone variants. A specific integration via the chromodomain has been shown for only a few chromoviruses. However, a detailed study of different chromoviral clades populating a single plant genome has not yet been carried out. RESULTS: We conducted a comprehensive survey of chromoviruses within the Beta vulgaris (sugar beet) genome, and found a highly diverse chromovirus population, with significant differences in element size, primarily caused by their flanking LTRs. In total, we identified and annotated full-length members of 16 families belonging to the four plant chromoviral clades: CRM, Tekay, Reina, and Galadriel. The families within each clade are structurally highly conserved; in particular, the position of the chromodomain coding region relative to the polypurine tract is clade-specific. Two distinct groups of chromodomains were identified. The group II chromodomain was present in three chromoviral clades, whereas families of the CRM clade contained a more divergent motif. Physical mapping using representatives of all four clades identified a clade-specific integration pattern. For some chromoviral families, we detected the presence of expressed sequence tags, indicating transcriptional activity. CONCLUSIONS: We present a detailed study of chromoviruses, belonging to the four major clades, which populate a single plant genome. Our results illustrate the diversity and family structure of B. vulgaris chromoviruses, and emphasize the role of chromodomains in the targeted integration of these viruses. We suggest that the diverse sets of plant chromoviruses with their different localization patterns might help to facilitate plant-genome organization in a structural and functional manner. PMID- 23448602 TI - Increased risk of ischemic stroke in cervical cancer patients: a nationwide population-based study. AB - BACKGROUND: Increased risk of ischemic stroke has been validated for several cancers, but limited study evaluated this risk in cervical cancer patients. Our study aimed to evaluate the risk of ischemic stroke in cervical cancer patients. METHODS: The study analyzed data from the 2003 to 2008 National Health Insurance Research Database (NHIRD) provided by the National Health Research Institutes in Taiwan. Totally, 893 cervical cancer patients after radiotherapy and 1786 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the risk of ischemic stroke. RESULTS: The 5-year cumulative risk of ischemic stroke was significantly higher for the cervical cancer group than for the control group (7.8% vs 5.1%; p <0.005). The risk of stroke was higher in younger (age <51 years) than in older (age >=51 years) cervical cancer patients (HR = 2.73, p = 0.04; HR = 1.37, p = 0.07) and in patients with more than two comorbid risk factors (5 years cumulative stroke rate of two comorbidities: 15% compared to no comorbidities: 4%). CONCLUSIONS: These study demonstrated cervical cancer patients had a higher risk of ischemic stroke than the general population, especially in younger patients. Strategies to reduce this risk should be assessed. PMID- 23448601 TI - Molecular immunologic correlates of spontaneous latency in a rabbit model of pulmonary tuberculosis. AB - BACKGROUND: Infection of humans with Mycobacterium tuberculosis (Mtb) results in latent tuberculosis infection (LTBI) in 90-95% of immune competent individuals, with no symptoms of active disease. The World Health Organization estimates that 1.5 billion people have LTBI, which can reactivate in the setting of waning host immunity, posing a threat to global TB control. Various animal models have been used to study the pathogenesis of TB. However, besides nonhuman primates, rabbits are the only animal model that fully recapitulates the pathological features of human TB, including progressive disease with necrosis and cavitation or establishment of spontaneous latency. RESULTS: We defined the molecular immunological correlates of LTBI establishment in a rabbit model of pulmonary infection with Mtb CDC1551. After aerosol infection, exponential bacterial growth was noted in the lungs for 4 weeks, followed by a significant decline by 12 weeks, resulting in the absence of cultivable bacilli by 24 weeks. We used rabbit whole genome microarrays to profile the lung transcriptome during the course of infection. At 2 weeks post-infection, gene networks involved in natural killer (NK) and dendritic cell (DC) activation and macrophage antimicrobial activities were highly upregulated. This was followed by upregulation of gene networks involved in macrophage and T cell activation and autophagy, peaking at 4 to 8 weeks. Concomitantly, host Th1, but not Th2 or inflammatory, immune response genes were significantly upregulated. Thus, the expression kinetics of genes involved in cross-talk between innate and adaptive immunity over the first 8 weeks post-infection were consistent with early efficient control of infection in the lungs. Interestingly, expression of many genes of the host innate and adaptive immune response pathways was downregulated at 12 weeks, suggesting that immune activation did not persist once bacilli began to clear from the infected lungs. CONCLUSIONS: Our results suggest that early activation of host innate immunity prior to efficient activation of T cell-mediated adaptive immunity but not inflammation is essential for establishment of LTBI in Mtb CDC1551-infected rabbits. We also show that T cell activation and the host adaptive immune response networks are dampened once bacterial growth is controlled, ultimately resulting in spontaneous LTBI. PMID- 23448603 TI - Nitric oxide as a potential biomarker in inflammatory bowel disease. AB - The aim of this study was to investigate changes in serum nitric oxide (NO) concentration in inflammatory bowel diseases (IBD) patients and its use as potential biomarker in differential diagnosis of ulcerative colitis (UC) and Crohn's disease (CD) and in disease activity assessment. In 60 patients of both genders - 30 with ulcerative colitis and 30 with Crohn's disease - and 30 controls serum nitric oxide concentration was determined by measuring nitrite concentration, a stable metabolic product of NO with oxygen. Conversion of nitrates (NO3-) to nitrites (NO2-) was done with elementary zinc. The nitrite concentration was determined by classic colorimetrical Griess reaction. Median serum NO concentration was statistically different (p=0,0005) between UC patients (15.25 umol/L; 13.47 - 19.88 umol/L), CD patients (14.54 umol/L; 13.03 -16.32 umol/L) and healthy controls (13.29 umol/L; 12.40 - 13.92 umol/L). When active UC and CD patients were compared with inactive UC and CD patients respectively a significant difference in serum NO level was found (p=0.0005). With a cut-off level of 17.39 umol/L NO had a sensitivity of 100% and a specificity of 100% in discriminating between active and inactive UC patients. With cut-off value of 14.01 umol/L serum NO level had a sensitivity of 88% and a specificity of 69% in distinguishing between patients with active CD and inactive CD. Serum NO concentration is a minimally invasive and rapid tool for discriminating between active and inactive IBD patients and could be used as useful biomarker in monitoring of disease activity in IBD patients. PMID- 23448604 TI - Molecular-genetic variance of RH blood group system within human population of Bosnia and Herzegovina. AB - There are two major theories for inheritance of Rh blood group system: Fisher - Race theory and Wiener theory. Aim of this study was identifying frequency of RHDCE alleles in Bosnian - Herzegovinian population and introduction of this method in screening for Rh phenotype in B&H since this type of analysis was not used for blood typing in B&H before. Rh blood group was typed by Polymerase Chain Reaction, using the protocols and primers previously established by other authors, then carrying out electrophoresis in 2-3% agarose gel. Percentage of Rh positive individuals in our sample is 84.48%, while the percentage of Rh negative individuals is 15.52%. Inter-rater agreement statistic showed perfect agreement (K=1) between the results of Rh blood system detection based on serological and molecular-genetics methods. In conclusion, molecular - genetic methods are suitable for prenatal genotyping and specific cases while standard serological method is suitable for high-throughput of samples. PMID- 23448605 TI - The role of inflammation and apoptosis in cyclosporine A-induced gingival overgrowth. AB - Cyclosporin A(CsA) - induced gingival overgrowth(GO) is a current problem of tissue-specific mechanism which is still incompletely explained. The apoptotic process has been of particular interest like a new concept in the etiology of this unwanted effect. The aim of our study was to detect the level of apoptosis, expression bcl-2 and p53, associated with the different doses of CsA. in gingival stroma. A cohort of 84 kidney transplant recipients was divided into four subgroups based on average daily dose of therapeutically applied CsA (Neoral(r)), (100 mg, 125 mg, 150 mg and 175 mg). The control group consisted of 21 patients, clinically diagnosed with periodontitis, who were not subjected to any medicamentous treatment causing gingival overgrowth. The following indexes were analyzed: plaque index (PI), index of gingival inflammation (GI) according to Loe Silnes, and gingival overgrowth index (GOI) according to MacGaw et al. The tissue samples were subjected to a semiquantitative analysis to detect apoptotical cells and immunohistochemically stained to detect the expression of the bcl-2 and p53 proteins. The difference in percentage of apoptotic cells between the group taking 175 mg and other subgroups, as well as the control group was statistically significant (p<0.05). There was a significant difference in percentage of expression bcl-2 between the 175 mg group compared to the other three subgroups and the control (p=0.001). However, a statistically significant positive correlation between the medicament dose, p53, apoptosis, and bcl-2 was registered (p<0.05). Inflammation plays the most important role in the induction of apoptosis and proliferation in gingival tissues. PMID- 23448606 TI - Some acute phase reactants and cholesterol levels in serum of patient with Crimean-Congo haemorrhagic fever. AB - The purpose of this study is to determine erythrocyte sedimentation rate (ESR), C - reactive protein (CRP), serum amyloid-A (SAA) and cholesterol levels in patients with Crimean-Congo Hemorrhagic Fever (CCHF) and determine the relationship of these parameters with the severity of disease. By polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) method 40 patients were diagnosed as CCHF and 39 volunteer without any systemic disease whose blood were taken and their serum separated. SAA, CRP and ESR were measured with ELISA, nephelometry and Mix-Rate x100 vital diagnostic device, respectively, in serum samples. High density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol levels were determined by using autoanalyzer HDL, LDL and total cholesterol kit (Syncron LX20). Statistically significant difference was determined between patients and controls in terms of the levels of SAA, CRP, HDL, LDL and total cholesterol (p<0.05). However, there was no significant difference between the groups in terms of the levels of ESR. In addition, neither SAA, CRP, ESR nor HDL, LDL and total cholesterol levels varied with the severity of disease in the cases assessed (p>0.05). Using of CRP and SAA together might increase the sensitivity of diagnosis of CCHF infection. However, none of the parameters investigated in this study were found to be a proper marker of the prognosis in CCHF. Cholesterol levels were significantly decreased in patients with CCHF, which was suggested to be associated with the increased serum levels of SAA in the patient group. PMID- 23448607 TI - Rat bone marrow stem cells isolation and culture as a bone formative experimental system. AB - Bone marrow mesenchymal cells have been identified as a source of pluripotent stem cells with multipotential potential and differentiation in to the different cells types such as are osteoblast, chondroblast, adipoblast. In this research we describe pioneering experiment of tissue engineering in Bosnia and Herzegovina, of the isolation and differentiation rat bone marrow stromal cells in to the osteoblast cells lineages. Rat bone marrow stromal cells were isolated by method described by Maniatopulos using their plastic adherence capatibility. The cells obtained by plastic adherence were cultured and serially passaged in the osteoinductive medium to differentiate into the osteocytes. Bone marrow samples from rats long bones used for isolation of stromal cells (BMSCs). Under determinate culture conditions BMSCs were differentiated in osteogenic cell lines detected by Alizarin red staining three weeks after isolation. BMSCs as autologue cells model showed high osteogenetic potential and calcification capatibility in vitro. In future should be used as alternative method for bone transplantation in Regenerative Medicine. PMID- 23448608 TI - Prevalence of 1691G>A FV mutation in females from Bosnia and Herzegovina--a preliminary report. AB - Factor V is the liver-synthesized multidomain glycoprotein encoded by a gene localised on chromosome 1q23. The point mutation 1691G>A in this gene results in formation of an altered protein of V Factor resistant to activated protein C (APC) cleavage. This mutation alone is the most frequent cause of inborn thrombophilia and the most widely acknowledged genetic risk factor for venous thrombosis in a Caucasian population. This study was designed to provide the first estimate of the frequency of the allele 1691A FV in the Bosnian female population. The 1691G>A FV mutation was examined by polymerase chain reaction restriction fragment length polymorphism, in a group of 67 women, mean age of 58.6 years with no history of cardiovascular incident. Our findings revealed an absence of the mutated allele 1691A FV in the studied group. This is the first report on the 1691G>A FV mutation in a population from Bosnia and Herzegovina. Further research is needed to establish prevalence of the mutated allele in the population from Bosnia and Herzegovina. PMID- 23448609 TI - Determination of surface roughness and topography of dental resin-based nanocomposites using AFM analysis. AB - The aim of this study was to determine surface roughness and topography of polished dental resin-based nanocomposites. Four representative dental resin based nanocomposites were tested in the study: two nanohybrids (Filtek Z550 and Tetric EvoCeram) and two nanofilled (Filtek Ultimate Body and Filtek Ultimate Translucent); and two reference materials: one microfilled (Gradia Direct) and one microhybrid (Filtek Z250). Polymerized cylindrical specimens (4 mm x 2 mm) were polished with multi-step polishing system- Super Snap. Immediately after the polishing, topography of each specimen was examined by Veeco di CP-II Atomic Force Microscope. Specimen's surface has been scanned in 6 points in contact mode with CONT20A-CP tips. 1 Hz scan rate and 256 * 256 resolution were used to obtain topography on a 90 um * 90 um scanning area. Measured topography data were processed by Image Processing and Data Analysis v2.1.15 software. Following parameters were compared among specimens: average roughness and maximum peak-to valley distance. All of the tested materials had similar average surface roughness after finishing and polishing procedure. The lowest values occurred in the material Filtek Ultimate Body, and the highest in the Filtek Z550. When interpreting maximum peak-to-valley distance the larger differences in values (up to 100%) occurred in Filtek Z550, Filtek Z250 and Filtek Ultimate Body, which is a result of the deep polishing channels and tracks. Type, size, distribution of fillers and filler loading in tested materials, didn't influence average roughness values, but had an impact on maximum peak-to-valley distance values. PMID- 23448610 TI - Signaling prodromes of sudden cardiac death. AB - The new criteria in detection of ARVC/D produced more subtle noninvasive parameters that raised sensitivity in diagnosis. Since heart rate dynamics have prognostic significance for the progression of a disease and for mortality, the main objective was to explore its value in disclosing risk for serious arrhythmias. Out of 100 ARVC/D patients, 35 with normal ECG Holter recordings (PVC<100) and no medical treatment (either antiarrhythmic or proarrhythmic drugs) were analyzed according to severity of ARVC/D (Group 1/mild, n=23 and Group 2/overt, n=12) and regarding positive late potentials (noise interval between 0.1 0.3 MUV). Severity of ARVC/D is defined: group 1 with no clinical recognizable signs and group 2 with clinical readily recognizable signs. Group 3 (control) consisted of 35 randomly assigned healthy subjects. The differences between the 3 groups were assessed by ANOVA followed by Bonferroni's post hoc multiple-range tests. NLD methods, as opposed to linear time and frequency, show very significant differences between investigated groups vs. control. NLD methods by mean of the standard deviations of all NN intervals of sinus beats for all 5 minute segments (SDNN index) showed prevalence of parasympathetic activity as opposed to control. This was even more obvious through interpolation of data as % of deviation of Mean NN interval in function % frequency (p<0.005). NLD methods describe complex rhythm fluctuations in ARVC/D patients that put insight at proarrhythmic potential of affected subjects. Furthermore, in combination with late potentials they improve recognizing hidden risks for serious arrhythmias. PMID- 23448611 TI - Low molecular weight heparin prevents CLP-induced acute lung injury in rats by anti-inflammatory coagulation. AB - The aim of our study was to observe the influence of low molecular Weight heparin (LMWH) on systemic inflammation, including high mobility group box 1 protein (HMGB1) and protective effect on acute lung injury induced by cecal ligation and puncture(CLP). Discuss the mechanism of this effect. 144 male SD rats were randomly divided into sham operation group (A), normal treatment group (B), the LMWH treatment group (C), n=48.Group A received a sham operation and the other groups were underwent CLP operation. Groups A and B accepted intraperitoneal injection (i.p.) of normal saline (NS) at a dose of 2.0 ml/kg and ceftriaxone (30 mg/kg), Group C were intraperitoneal injection additional LMWH (150 U/kg) except saline and ceftriaxone. Observe points were made at 3, 6, 12, 18, 24, 48 h, the rats were anesthetized and killed, mortality, lungs wet/dry ratio and Pathology change were determined. HMGB-1 mRNA, protein of lung tissues was calculated by RT PCR and Western blot. TNF-alpha and IL-6 of blood plasma calculated by ELSIA. There was significantly different in each index between A and B group (p<0.05).Compared with CLP group, there was a significant decrease in the lung injury, the mortality, HMGB1 mRNA and protein expression on lung tissues (p<0.05). LMWH can decreases cytokine, HMGB1 levels of lung tissue during CLP induced inflammation. As a result, LMWH ameliorated lung pathology and reduces mortality in CLP-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of axis of inflammation and coagulation. PMID- 23448612 TI - Distribution of human leukocyte antigen alleles in systemic lupus erythematosus patients with angiotensin converting enzyme insertion/deletion polymorphism. AB - Systemic Lupus Erythematosus is one of the classic examples of autoimmune diseases among human beings and is a rare disease in Pakistani population. Clinically it is a quite diverse and complicated autoimmune disease in a sense that it involves multiple organs of the body and mimics with other diseases as well. This study focused on the distribution of HLA alleles in SLE patients with ACE I/D Polymorphism. A total of 122 individuals were enrolled in this study, 61 were the SLE patients who fulfilled revised ACR criteria and 61 were the healthy controls. Mean age of SLE patients at diagnosis was 30.35 +/- 1.687 years (Range: 12-68 years). ACE gene I/D polymorphism was performed by nested PCR and DNA based HLA typing technique was used. ACE gene I/D polymorphism of Intron16 was studied and found to be involved in the activity of SLE. There is high frequency of HLA A*01, HLA-B*40, HLA-DRB1*01 alleles in SLE patients with ACE DD genotype. The distribution of HLA-A, -B, -DRB1 alleles was analyzed in SLE patients with various disease phenotypes. HLA-A*01 and HLA-B*40 was the most common allele found in SLE patients with the involvement of skin. HLA-A*01, -A*03, HLA-B*13 and -B*46 were common in SLE patients with arthritis while HLA-A*26 and -A*69 were commonly found in Lupus nephritis cases. SLE patients involving both skin and kidney had an allele HLA-DRB1*01 common in them. PMID- 23448613 TI - Anaesthesia in Naxos disease: first case report. AB - Naxos disease is a recessively inherited arrhythmogenic right ventricular cardiomyopathy in which the cardiac phenotype is associated with palmoplantar keratoderma and woolly hair. The hair phenotype is unique, characterized by congenital woolly, curly, rough, and light-colored scalp hair and sparse eyebrows. However, arrhythmias and severe cardiomyopathies are causes of severe life threatened intracardiac thrombus. Thrombus therapy needs private care and sedative, operative processes need to give close attention to these patients. In this case report, sedation given a patient who having severe congestive heart failure with huge mural thrombus in left ventriculus has been presented. PMID- 23448614 TI - Atmospheric chemistry of benzyl alcohol: kinetics and mechanism of reaction with OH radicals. AB - The atmospheric oxidation of benzyl alcohol has been investigated using smog chambers at ICARE, FORD, and EUPHORE. The rate coefficient for reaction with OH radicals was measured and an upper limit for the reaction with ozone was established; kOH = (2.8 +/- 0.4) * 10(-11) at 297 +/- 3 K (averaged value including results from Harrison and Wells) and kO(3) < 2 * 10(-19) cm(3) molecule(-1) s(-1) at 299 K. The products of the OH radical initiated oxidation of benzyl alcohol in the presence of NOX were studied. Benzaldehyde, originating from H-abstraction from the -CH(2)OH group, was identified using in situ FTIR spectroscopy, HPLC-UV/FID, and GC-PID and quantified in a yield of (24 +/- 5) %. Ring retaining products originating from OH-addition to the aromatic ring such as o-hydroxybenzylalcohol and o-dihydroxybenzene as well as ring-cleavage products such as glyoxal were also identified and quantified with molar yields of (22 +/- 2)%, (10 +/- 3)%, and (2.7 +/- 0.7)%, respectively. Formaldehyde was observed with a molar yield of (27 +/- 10)%. The results are discussed with respect to previous studies and the atmospheric oxidation mechanism of benzyl alcohol. PMID- 23448615 TI - Factors associated with obstetric fistulae occurrence among patients attending selected hospitals in Kenya, 2010: a case control study. AB - BACKGROUND: In Kenya, about 3000 fistula cases are estimated to occur every year with an incidence of 1/1000 women. This study sought to identify risk factors associated with developing obstetrics fistula in order to guide implementation of appropriate interventions. METHODS: An unmatched case control study was conducted in three major hospitals in Kenya between October and December 2010. Cases were patients who had fistula following delivery within the previous five years. Controls were systematically selected from women who attended obstetrics and gynecology clinics at these hospitals, and did not have present or past history of fistula. Odds ratio was used as measure of association with their corresponding 95% confidence interval. Factors with p value of <0.1 were included into forward additive logistic regression model to generate adjusted odds ratios. RESULTS: Seventy cases and 140 controls were included in the study. Independent risk factors associated with obstetrics fistula included duration of labour of >24 hours (OR = 4.7, 95% CI = 2.4 -9.2), seeking delivery services after 6 hours of labour onset (OR = 6.9, 95% CI = 2.2-21.3), taking more than 2 hours to reach a health facility (OR = 5.7, 95% CI = 2.9 -11.5), having none or primary education (OR = 9.6, 95% CI = 3.3 -27.9) and being referred to another facility for emergency obstetrics services (OR = 8.6, 95% CI = 2.7 -27). CONCLUSIONS: Risk factors for developing obstetrics fistula were delays in care seeking including delay in making decision to seek delivery servers after six hours of labour onset, taking more than two hours to reach a health facility, labour duration of more than 24 hours and having no formal or primary education. Efforts geared at strengthening all levels of the health system to reduce delays in access to emergency obstetric care are needed. PMID- 23448616 TI - Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients. AB - BACKGROUND: Ticagrelor is a direct-acting, reversibly binding, oral P2Y12 platelet inhibitor that reduces thrombotic cardiovascular events in patients with acute coronary syndrome. Dyspnea is one of the most commonly reported adverse events associated with ticagrelor. OBJECTIVE: To determine the effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease (COPD) patients. METHODS: Two randomized, double-blind, placebo-controlled, two-way crossover, single-center studies were conducted: 1) healthy elderly volunteers (55-75 years; n = 12); 2) patients with mild asthma (n = 11) or mild-to-moderate COPD (n = 7). Subjects were randomized to receive ticagrelor (a single 450 mg dose, 180 mg 12 hours later, twice daily for 2 days, and once on day 4) or placebo, with a 7 day washout. Pulmonary function at rest and during exercise was monitored using similar schedules and assessments across the two studies. RESULTS: Resting pulmonary function parameters, including respiratory rate, minute ventilation, or tidal volume, were similar between ticagrelor and placebo in any cohort. Furthermore, bronchospasm (as determined by spirometry and pulse oximetry), was not observed with either ticagrelor or placebo in any cohort. Perception of breathing was generally similar following ticagrelor or placebo. Exercise performance was not affected, and no clinically relevant differences were seen in pulmonary parameters during exercise for ticagrelor or placebo. There was no apparent relationship between plasma concentrations of ticagrelor and its main metabolite and pulmonary function. Ticagrelor was well tolerated in all cohorts. Study limitations include the use of relatively few subjects without documented coronary artery disease. CONCLUSIONS: Short-term administration of high doses of ticagrelor did not appear to alter pulmonary function at rest and during exercise in subjects at risk of (healthy elderly) or with respiratory impairment (mild asthma or mild-to-moderate COPD). PMID- 23448617 TI - A comparison of the quality of life of vulnerable young males with severe emotional and behaviour difficulties in a residential setting and young males in mainstream schooling. AB - One hundred and seventy-four males completed a quality of life (QoL) assessment utilizing, a generic paediatric quality of life inventory (PedsQL) and the short form (36) health survey (SF36). The adolescents aged 13-16 years were in a Scottish Centre for young males with social, emotional, behavioural and educational problems. To identify similarities and differences, a comparison group (n = 110) of males in the third and fourth year in a mainstream secondary school were also administered the PedsQL and the SF36 self-rating scales. The effectiveness of the PedsQL and the SF36 for assessing QoL for adolescent males was investigated. There were significant differences between the groups in the Centre and between the Centre groups and the comparison group in terms of their QoL. The results between the groups were found in the PedsQL subscales 'physical functioning' where secure > comparison (P = 0.04); secure > residential (P = 0.008); and PedsQL subscale 'social functioning' day > comparison (P = 0.026); secure > comparison (P = 0.037). SF36 subscales 'role physical functioning' secure > residential (P < 0.001); day > residential (P < 0.001). SF36 'role mental functioning' day > residential (P = 0.001). This study provides a unique insight into the complex dimensions influencing the QoL of this specific group of young people. PMID- 23448618 TI - Solvent detergent vs. fresh frozen plasma in cirrhotic patients undergoing liver transplant surgery: a prospective randomized control study. AB - BACKGROUND: Although orthotopic liver transplantation (OLT) is nowadays considered standard practice at experienced centres, it can still be affected by a significant risk of massive bleeding and its related complications. Solvent/detergent plasma (S/D Plasma) has been proposed as an alternative to fresh frozen plasma (FFP) to curtail such complications. This study aimed at evaluating the efficacy of S/D Plasma in OLT patients by comparing it to FFP. MATERIALS AND METHODS: Sixty-three OLT patients were randomized into two groups depending on whether they were transfused with FFP or S/D plasma. A thromboelastography-based protocol aimed at achieving and maintaining predetermined coagulation goals was used to guide plasma transfusions. At the beginning and the end of surgery, standard laboratory coagulation tests were performed together with the assessment of the VII, VIII, V, XII factors and S protein blood levels. RESULTS: The two study groups equally achieved the thromboelastography goals but with a reduced amount of transfusions in the S/D plasma group (P < 0.0001). At the end of surgery, factors V and XII and S protein blood levels were lower in the S/D plasma patients who also showed lower INR, aPTT and antithrombin III levels. CONCLUSION: In cirrhotic patients undergoing OLT, the use of S?D plasma associated with thromboelastography allows the same clinical results but with a significant reduction in the amount of plasma transfusions. PMID- 23448619 TI - Latent autoimmune diabetes in adults in Asians: similarities and differences between East and West. AB - Latent autoimmune diabetes in adults (LADA) is a form of autoimmune diabetes with features of both type 1 and type 2 diabetes and in the middle of the diabetes spectrum. Scientists clash on the question of whether this type of diabetes is a unique diabetes subtype. Multicenter studies have been performed in different countries, including the Korea National Diabetes Program (KNDP) collaboratory group, the Ehime study in Japan, the Not Insulin-Requiring Autoimmune Diabetes (NIRAD) study in Italy, the Nord-Trondelag Health (HUNT) study in Norway, the UK Prospective Diabetes Study (UKPDS) in the UK, the Action LADA study in Europe and the LADA China study in China. These studies found universal immunogenetic effects associated with LADA, but with some ethnic differences. Herein we summarize those multicenter studies and compare the ethnic similarities and differences between East and West from epidemiological, clinical, immune, and genetic viewpoints. PMID- 23448620 TI - Multiple targeted drugs carrying biodegradable membrane barrier: anti-adhesion, hemostasis, and anti-infection. AB - A multiple targeted drug carrying bilayer membrane for preventing an abdominal adhesion is prepared by electrospinning. Two bioactive drugs were successfully incorporated into this bilayer membrane and can be independently released from nanofibrous scaffolds without losing structural integrity and functionality of the anti-adhesion membrane. Besides, the drug release profile could be easily adjusted by optimizing the swelling behavior of the fibrous scaffold. The inner layer of the bilayered fibrous membranes loaded with carbazochrome sodium sulfonate (CA) showed an excellent vascular hemostatic efficacy and formed little clot during in vivo experiment. The outer layer loaded with tinidazole (TI) had outstanding antibacterial effect against the anaerobe. We believe this approach could serve as a model technique to guide the design of implants with drug delivery functions. PMID- 23448621 TI - Defining genes using "blueprint" versus "instruction" metaphors: effects for genetic determinism, response efficacy, and perceived control. AB - Evidence supports mixed attributions aligned with personal and/or clinical control and gene expression for health in this era of genomic science and health care. We consider variance in these attributions and possible relationships to individual mind sets associated with essentialist beliefs that genes determine health versus threat beliefs that genes increase susceptibility for disease and severity linked to gene-environment interactions. Further, we contribute to theory and empirical research to evaluate the use of metaphors to define genes. Participants (N = 324) read a message that varied the introduction by providing a definition of genes that used either an "instruction" metaphor or a "blueprint" metaphor. The "instruction" metaphor compared to the "blueprint" metaphor promoted stronger threat perceptions, which aligned with both belief in the response efficacy of genetic research for health and perceived behavioral control linked to genes and health. The "blueprint" metaphor compared to the "instruction" metaphor promoted stronger essentialist beliefs, which aligned with more intense positive regard for the efficacy of genetic research and human health. Implications for health communicators include societal effects aligned with stigma and discrimination that such findings portend. PMID- 23448622 TI - Prospects for routine childhood vaccination against rotavirus in India. PMID- 23448623 TI - Quality of life among people with epilepsy: a cross-sectional study from rural southern India. AB - BACKGROUND: Epilepsy can be associated with profound physical, social and psychological consequences and it has an impact on a person's quality of life. We assessed the quality of life and factors associated with a poor quality of life, among adults with epilepsy in a rural block of Tamil Nadu. METHODS: We interviewed 91 epilepsy patients from 20 randomly selected villages using a structured questionnaire including World Health Organization Quality of Life BREF (WHOQOL-BREF), Patient Health Questionnaire 2 (PHQ-2) and Generalized Anxiety Disorder 7 (GAD-7) questionnaires. RESULTS: The mean (SD) total score of the quality of life scale was 61.49 (12.56). Those who were single, separated or widowed (t statistic= -2.71, p<0.01), had not completed primary education (t statistic=-2.308, p<0.05), not currently going for work (t statistic=-2.748, p<0.01), had seizure in the past one year (t statistic=-4.068, p<0.01),had depressive symptoms (t statistic=-3.207, p<0.01),had higher anxiety scores (t statistic=-2.727, p<0.01), had low scores in the quality of life questionnaire. Multivariate analysis showed increasing age, education less than grade V, being unmarried, widowed or separated, lower per capita income, a high anxiety score and experiencing a seizure episode in the past one year to be significantly associated with a low score in the WHOQOL-BREF questionnaire (adjusted R2=0.378, SE 9.90). CONCLUSION: The presence of anxiety, lack of primary education, being single, separated or widowed, increasing age, low per capita income and having a seizure episode in the past year are associated with lower quality of life among people with epilepsy. PMID- 23448624 TI - Association of hypertriglyceridaemia with pre-eclampsia, preterm birth, gestational diabetes and uterine artery pulsatility index. AB - BACKGROUND: We aimed to determine whether high plasma triglyceride levels in the second trimester of pregnancy are associated with adverse pregnancy outcomes including preterm birth, gestational diabetes mellitus, pre-eclampsia and high uterine artery pulsatility index. METHODS: This prospective cohort study was done between 2008 and 2010. Plasma levels of low-density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride were measured after 8 hours of overnight fasting. We compared the outcomes of 45 pregnant women who had high triglyceride levels (>195 mg/dl) with 135 pregnant women with triglyceride levels <195 mg/dl. The main outcome measures were the incidence of preterm birth, gestational diabetes, pre-eclampsia and uterine artery pulsatility index. RESULTS: Eight women with high triglyceride levels had preeclampsia (17.8% v. 3.7% in the control group, p<0.004), preterm birth occurred in 24.4% and 5.9% in the high triglyceride group and the control group, respectively (OR 5.1,95% CI 1.9-13.8, p<0.0001). The incidence of gestational diabetes in the high triglyceride group was significantly higher than that in the control group. There was no difference in uterine artery Doppler ultrasound between the two groups. CONCLUSION: There is a positive relation between hypertriglyceridaemia and pre eclampsia, preterm birth and gestational diabetes. PMID- 23448625 TI - Post-exposure prophylaxis against rabies at two newly designated intradermal rabies vaccination clinics in Kerala, India. AB - BACKGROUND: The two-site intradermal rabies vaccination (IDRV) regimen was recently introduced in Kerala. We aimed to determine factors associated with exposure of category III severity among patients seeking prophylaxis against rabies at IDRV clinics. METHODS: This hospital-based, cross-sectional study was done at two clinics in Thiruvananthapuram district, Kerala. Data were collected using a semi-structured questionnaire by direct interview and 320 patients were included. Bivariate analysis of quantitative variables was done using t-test and that of qualitative variables using chi-square test. RESULTS: The mean (standard deviation) age of patients was 32.4 (19.6) years. Among the 320 cases, 202 (63.1%) had category III exposure. Lower extremities were the most frequent site of exposure (146, 45.6%). The most frequent mode of exposure was being bitten by an animal (214, 66.9%), often a dog. Residence in rural areas, exposure to dogs and wounds on the extremities had a significant association with severity of exposure. CONCLUSION: Animal exposures were more among people from rural areas. About two-thirds of exposures which necessitated post-exposure prophylaxis were category III. PMID- 23448626 TI - Epstein-Barr virus-induced haemophagocytic syndrome. AB - Haemophagocytic syndrome or haemophagocytic lymphohistiocytosis is a disorder of histiocytes that has sepsis-like features, combined with haemophagocytosis, cytopenias, hyperferritinaemia, hypercytokinaemia and splenomegaly. Diagnostic, therapeutic and prognostic guidelines are available for childhood (familial) haemophagocytic syndrome. The disorder is diagnosed less frequently among adults than children. We report a case of Epstein-Barr virus-induced haemophagocytic syndrome in a 23-year-old man, who responded to treatment with steroids and chemotherapy. PMID- 23448627 TI - Integrating mental health into cardiovascular disease research in India. AB - Mental health refers to a diverse field where individuals can cope with daily stress, realize their potential and maintain a state of well-being. In recent years, there has been increasing recognition of the influence of mental health on general health, and in particular on cardiovascular diseases and their risk factors. Epidemiological research has focused on several psychosocial components including social determinants, comorbid psychiatric disorders, psychological stress, coping styles, social support, burden on the family, well-being, life satisfaction, personality and cognitive factors in connection with cardiovascular diseases. There is epidemiological research in India that integrates mental health with common cardiovascular diseases such as coronary health disease and stroke. Data from mental health research is sufficiently compelling to highlight the role of chronic stress, socioeconomic status and psychiatric disorders such as depression, substance use, social networks and support in relation to vulnerability to cardiovascular diseases. There are psychosocial consequences of cardiovascular diseases including deficits in the domains of life skills, coping skills and neurocognition, in addition to caregiver burden. The implications of bio-psychosocial models of assessments and interventions that target complex individual and contextual variables simultaneously on cardiovascular treatment outcomes have highlighted the importance of studying mental health in Indian settings. Integration of mental health into mainstream research is the need of the hour. A multidimensional approach to accomplish this is required including at the level of research conceptualization, discussions with key stakeholders, at the policy level, at the institutional level, and at the clinical and community level. PMID- 23448628 TI - The surgical cure for diabetes? PMID- 23448629 TI - Can daily aspirin help to reduce the incidence and mortality due to cancer? PMID- 23448630 TI - Student assessment: issues and dilemmas regarding objectivity. AB - I recently purchased a laptop. The manufacturer claimed that its battery time was over 8 hours. However, when I started using the laptop, the battery never lasted that long. I called the customer care helpline. They told me that the figure of 8 hours was arrived at by using a very advanced and standardized software, which estimates the battery time under 'standard' conditions (for the uninitiated, this means putting the machine on at its lowest brightness and then not using it, except for low-end applications such as word processing). Now that was a problem. I hate carrying the chargers in my handbag. How do I know how long the battery will last under actual work conditions? So I started using the laptop as I would normally do, i.e. for word processing, making slides, connecting to the Internet, listening to music and occasionally watching movies. After about a week, I thought 5 hours was a fair estimate. Just to be sure, I also requested my son to use it for a week (you guessed it, for gaming), and he also thought 4-5 hours was a good estimate. Now when I travel, I do not carry my charger along if I estimate my computer use to be less than 4 hours. This incident got me thinking about the assessment of medical students. We are fond of objective and standardized tests, which are administered under standard test-taking conditions and in which the students are awarded certain grades. However, what happens when these doctors face a real-life situation? Are we incorrectly estimating the competences of our students in a controlled environment? Whether it is estimating the time of a laptop battery, the mileage of a new car or the competence of students, the issue seems to be the same-one-shot observation using standardized tools in artificial settings or long-term observation in real-life situations. PMID- 23448632 TI - Religion from a science perspective. PMID- 23448631 TI - Need for mentorship to improve learning in low-performers. AB - BACKGROUND: About 15% of medical students perform poorly in examinations. This study was done to ascertain the causes for low performance and the effectiveness of counselling and advice regarding study skills in improving performance in a subsequent assessment. METHODS: Of the 353 students who appeared for the first internal assessment examination in pathology, 83 (23.5%) scored less than 30% marks. These 83 low-performers were given a questionnaire listing stress-inducing factors and academic problems; 81 filled the questionnaire. Of these, 73 attended sessions on study skills and counselling where they interacted on a one-to-one basis regarding their personal problems. Their performance was evaluated in an internal assessment 6 months later. RESULTS: The low-performers included 52 boys and 29 girls, 19-20 years of age. Non-academic problems contributing to low performance included language problems, problems in adjustment to life outside home, lack of self-confidence, fear of failure and worrying about the future. Academic problems included difficulty in managing study time, lack of concentration while studying, inability to retain what is studied, anxiety before examinations and inability to write an examination. Paired t-test revealed a statistically significant improvement in the post-programme performance of the 73 students who participated in the counselling sessions (p<0.001), while that of the 10 who did not participate in the project, showed no statistically significant difference (p=0.54, Wilcoxon signed rank test). A majority of students felt that the sessions helped to improve their performance (average score 3.83/6.00), change their study behaviour (3.74/6.00) and change their attitude (3.46/6.00). The programme also improved their confidence and self esteem. CONCLUSION: Low-performers can benefit from tailored remedial programmes which include counselling and training in stress-coping strategies. PMID- 23448633 TI - From Modinos' cure to lecithin treatment: detoxification and withdrawal management in the state-sponsored mass treatment scheme for opium addicts in Assam, 1938-39. PMID- 23448634 TI - Balu Sankaran. PMID- 23448635 TI - Horror in hospital. PMID- 23448636 TI - Two things and seven habits. PMID- 23448640 TI - Boundary violations: our response to the commentaries on the Bangalore Declaration. PMID- 23448641 TI - Reference data for height, weight and body mass index. PMID- 23448642 TI - A more representative sample is required. PMID- 23448643 TI - Investigator-initiated research in India: Nipped in the bud? PMID- 23448644 TI - New AIIMS at all state capitals: boon for urban and bane for rural healthcare. PMID- 23448645 TI - Eye and body donation: a proposal for a single window. PMID- 23448646 TI - MCI and NEET-PG: understanding the point of view of medical graduates. PMID- 23448647 TI - Enterovirus 71 causes hand, foot and mouth disease outbreak in Cambodia. PMID- 23448650 TI - Researchers show gender disparities among Indo-Canadian live-births. PMID- 23448651 TI - Twin Ebola outbreaks in Africa: Uganda and Democratic Republic of Congo affected. PMID- 23448653 TI - Feasibility of absolute cerebral tissue oxygen saturation during cardiopulmonary resuscitation. AB - INTRODUCTION: Current monitoring during cardiopulmonary resuscitation (CPR) is limited to clinical observation of consciousness, breathing pattern and presence of a pulse. At the same time, the adequacy of cerebral oxygenation during CPR is critical for neurological outcome and thus survival. Cerebral oximetry, based on near-infrared spectroscopy (NIRS), provides a measure of brain oxygen saturation. Therefore, we examined the feasibility of using NIRS during CPR. METHODS: Recent technologies (FORE-SIGHTTM and EQUANOXTM) enable the monitoring of absolute cerebral tissue oxygen saturation (SctO2) values without the need for pre calibration. We tested both FORE-SIGHTTM (five patients) and EQUANOX AdvanceTM (nine patients) technologies in the in-hospital as well as the out-of-hospital CPR setting. In this observational study, values were not utilized in any treatment protocol or therapeutic decision. An independent t-test was used for statistical analysis. RESULTS: Our data demonstrate the feasibility of both technologies to measure cerebral oxygen saturation during CPR. With the continuous, pulseless near-infrared wave analysis of both FORE-SIGHTTM and EQUANOXTM technology, we obtained SctO2 values in the absence of spontaneous circulation. Both technologies were able to assess the efficacy of CPR efforts: improved resuscitation efforts (improved quality of chest compressions with switch of caregivers) resulted in higher SctO2 values. Until now, the ability of CPR to provide adequate tissue oxygenation was difficult to quantify or to assess clinically due to a lack of specific technology. With both technologies, any change in hemodynamics (for example, ventricular fibrillation) results in a reciprocal change in SctO2. In some patients, a sudden drop in SctO2 was the first warning sign of reoccurring ventricular fibrillation. CONCLUSIONS: Both the FORE-SIGHTTM and EQUANOXTM technology allow non-invasive monitoring of the cerebral oxygen saturation during CPR. Moreover, changes in SctO2 values might be used to monitor the efficacy of CPR efforts. PMID- 23448655 TI - The hidden effects of environmental noise. PMID- 23448654 TI - Cord lining-mesenchymal stem cells graft supplemented with an omental flap induces myocardial revascularization and ameliorates cardiac dysfunction in a rat model of chronic ischemic heart failure. AB - Myocardial restoration using tissue-engineered grafts to regenerate the ischemic myocardium offers improved donor cell retention, yet a limited cell survival resulting from poor vascularization needs to be addressed. A cell type derived from the subamnion, namely, cord-lining mesenchymal stem cells (CL-MSC), has recently been identified. Here we present a restorative strategy that combines a fibrin graft containing human CL-MSC and omental flap providing, thereby, cell-, structural-, and angiogenic support to the injured myocardium. The graft consisted of a mixture of 2*10(6) CL-MSC-GFP-Fluc and fibrin. Myocardial infarction (MI) was induced in nude rats and following confirmation of ensued heart failure with echocardiography 2 weeks after injury, therapeutic intervention was performed as follows: untreated (MI, n=7), CL-MSC graft (CL MSCG, n=8), CL-MSCG and omental flap (CL-MSCG+OM, n=11), and omental flap (OM, n=8). In vivo bioluminescence imaging at 1, 3, 7, and 14 days post-treatment indicated comparable early donor cell viability between the CL-MSCG and CL MSCG+OM. Treatment with CL-MSCG+OM improved the myocardial function as assessed by the measurement of end-diastolic left ventricular (LV) pressure (3.53+/-0.34 vs. 5.21+/-0.54 mmHg, p<0.05), contractility (+dP/dt, 3383.8+/-250.78 mmHg vs. 2464.9+/-191.8 mmHg, p<0.05), and the relaxation rate (-dP/dt, -2707.2+/-250.7 mmHg vs. 1948.7+/-207.8 mmHg, p<0.05), compared to MI control 6 weeks after ischemic injury. Furthermore, evidence of a 20.32% increase in the ejection fraction was observed in CL-MSCG+OM rats from week 2 to 6 after injury. Both CL MSCG and CL-MSCG+OM led to an enhanced cardiac output (p<0.05), and attenuated the infarct size (35.7%+/-4.2% and 34.7%+/-4.8%), as compared to MI (60.7%+/ 3.1%; p<0.01 and p<0.001, respectively). All treated groups had a higher arteriole density than controls. Yet, a higher amount of functional blood vessels, and a 20-fold increase in arteriole numbers were found in CL-MSCG+OM. Altogether, CL-MSCGs supplemented with vascular supply have the potential to repair the failing, chronically ischemic heart by improving myocardial revascularization, attenuating remodeling, and ameliorating cardiac dysfunction. PMID- 23448656 TI - Impact and control of protozoan parasites in maricultured fishes. AB - Aquaculture, including both freshwater and marine production, has on a world scale exhibited one of the highest growth rates within animal protein production during recent decades and is expected to expand further at the same rate within the next 10 years. Control of diseases is one of the most prominent challenges if this production goal is to be reached. Apart from viral, bacterial, fungal and metazoan infections it has been documented that protozoan parasites affect health and welfare and thereby production of fish in marine aquaculture. Representatives within the main protozoan groups such as amoebae, dinoflagellates, kinetoplastid flagellates, diplomonadid flagellates, apicomplexans, microsporidians and ciliates have been shown to cause severe morbidity and mortality among farmed fish. Well studied examples are Neoparamoeba perurans, Amyloodinium ocellatum, Spironucleus salmonicida, Ichthyobodo necator, Cryptobia salmositica, Loma salmonae, Cryptocaryon irritans, Miamiensis avidus and Trichodina jadranica. The present report provides details on the parasites' biology and impact on productivity and evaluates tools for diagnosis, control and management. Special emphasis is placed on antiprotozoan immune responses in fish and a strategy for development of vaccines is presented. PMID- 23448657 TI - Ocular involvement in generalized fixed drug eruption from nimesulide. PMID- 23448658 TI - Coproporphyrin III excretion identifies the anaerobic coproporphyrinogen III oxidase HemN as a copper target in the Cu+-ATPase mutant copA- of Rubrivivax gelatinosus. AB - Two genes encoding structurally similar Copper P1B -type ATPases can be identified in several genomes. Notwithstanding the high sequence and structural similarities these ATPases held, it has been suggested that they fulfil distinct physiological roles. In deed, we have shown that the Cu(+) -ATPase CtpA is required only for the activity of cuproproteins in the purple bacterium Rubrivivax gelatinosus; herein, we show that CopA is not directly required for cytochrome c oxidase but is vital for copper tolerance. Interestingly, excess copper in the copA(-) mutant resulted in a substantial decrease of the cytochrome c oxidase and the photosystem under microaerobic and anaerobic conditions together with the extrusion of coproporphyrin III. The data indicated that copper targeted the tetrapyrrole biosynthesis pathway at the level of the coproporphyrinogen III oxidase HemN and thereby affects the oxidase and the photosystem. This is the first in vivo demonstration that copper, like oxygen, affects tetrapyrrole biosynthesis presumably at the level of the SAM and [4Fe-4S] containing HemN enzyme. In light of these results and similar findings in Escherichia coli, the potential role of copper ions in the evolution of [4Fe-4S] enzymes and the Cu(+) -ATPases is discussed. PMID- 23448659 TI - Letters to the editor: re: "real-time quantitative polymerase chain reaction analysis of patients with refractory chronic periodontitis". PMID- 23448660 TI - Letter to the editor: authors' response. PMID- 23448663 TI - Dystonia Severity Action Plan: a simple grading system for medical severity of status dystonicus and life-threatening dystonia. PMID- 23448662 TI - Association between peripheral T-Lymphocyte activation and impaired bone mineral density in HIV-infected patients. AB - BACKGROUND: HIV-infected patients display an increased and early incidence of osteopenia/osteoporosis. We investigated whether bone metabolism disorders in HIV infected patients are related to immune hyperactivation and premature immune senescence. METHODS: Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA): low BMD (LBMD) was defined as T-score or z-score < -1. CD4+/CD8+ phenotype (CD38/HLA-DR, CD127, CD28/CD57), and circulating IL-7, TNF alpha, RANKL, OPG were measured. The variables with p < .05 were evaluated by multivariate logistic regression. RESULTS: 78 patients were enrolled: 55 were LBMD. LBMD patients showed increased activated HDLADR + CD4+ and CD8+ (p = .03 and p = .002, respectively). Interestingly, no differences in senescent CD28-CD57 + CD4+/CD8+ T-cells were observed between groups. However, LBMD patients displayed a decreased CD4 + CD28- phenotype (p = .04) at the advantage of the CD28+ pool (p = .03), possibly reflecting heightened apoptosis of highly differentiated CD28-negative cells.Activated HLADR + CD4+/CD8+ and CD28 + CD4+ cells were independently associated with impaired BMD (AOR = 1.08 for each additional HLADR + CD4+ percentage higher; CI 95%,1.01-1.15; p = .02; AOR = 1.07 for each additional HLADR + CD8+ percentage higher; CI 95%,1.01-1.11; p = .01; AOR = 1.06 for each additional CD28 + CD4+ percentage higher; CI 95%,1.0-1.13; p = .05). CONCLUSIONS: Heightened T-cell activation in HIV-infected patients independently predicts BMD disorders, suggesting a critical role of immune activation in the pathogenesis of osteopenia/osteoporosis, even in patients achieving full viral suppression with HAART. PMID- 23448664 TI - Flogging a dead horse. PMID- 23448665 TI - Abundant FUS-immunoreactive pathology in the skin of sporadic amyotrophic lateral sclerosis. AB - OBJECTIVES: The fused in sarcoma (FUS) protein is a 526 amino acid and its expression is ubiquitous. Recently, mutations in a gene coding FUS have been identified in familial amyotrophic lateral sclerosis (ALS). Also, FUS has been found in neuronal cytoplasmic inclusions in sporadic forms of ALS, suggesting that FUS has an important role in the neurodegeneration occurring in sporadic disease. However, there has been no study of FUS in ALS skin. MATERIAL AND METHODS: We made a quantitative immunohistochemical study of the expression of FUS in the skin from patients with sporadic ALS and controls. RESULTS: The proportion of FUS-immunoreactive (ir) cells in the epidermis in ALS patients was significantly higher (P < 0.001) than in controls. There was a significant positive relationship (r = 0.78, P < 0.001) between the proportion and duration of illness in ALS patients. The optical density of FUS-ir cells in the epidermis in ALS patients is markedly stronger (P < 0.001) than in controls. There was a significant positive relation (r = 0.49, P < 0.05) between the immunoreactivity and duration of illness in ALS patients. CONCLUSIONS: These data suggest that changes of FUS in ALS skin are related to the disease process, and that metabolic alterations of FUS may take place in the skin of patients with ALS. PMID- 23448666 TI - Use of standardised assessment forms in referrals to hepatology outpatient services: implications for accurate triaging of patients with chronic hepatitis C. AB - OBJECTIVES: To determine the spectrum of disease among non-urgent referrals to a tertiary hospital hepatology outpatient clinic, assess the adequacy of referral information in terms of risk stratification and determine whether a specifically designed referral template altered urgency for specialist assessment. METHODS: A snapshot of the waiting list of a hepatology clinic at a tertiary hospital was taken from the scheduling database. Information was retrieved from referrals and attached investigations. Updated information was requested from subjects and their current general practitioner. RESULTS: Hepatitis C virus accounted for 68.7% of the 1223 reviewed referrals. Clinical information provided by referring clinicians was often incomplete. Provision of updated information identified the presence of comorbidities (obesity, 'heavy' alcohol consumption, mental health issues) and altered the need or urgency for specialist assessment in 22% of cases. CONCLUSIONS: Hepatitis C virus accounts for the majority of non-urgent referrals waiting to access hepatology outpatient consultations. Using a standardised assessment form as part of the referral process provides more information on comorbidities and risk factors and facilitates more accurate triaging of clinical urgency. Wider adoption of this strategy may increase appropriate access to hepatology services and reduce the future burden of cirrhosis and hepatocellular cancer. WHAT IS KNOWN ABOUT THE TOPIC? Little published data are available that describe the content and standard of hepatology referrals, or the urgency with which these patients need to be reviewed. Inadequate clinical information impairs the ability to accurately triage referrals and may lead to delays in access. WHAT DOES THE PAPER ADD? Almost 70% of reviewed referrals were for management of patients with hepatitis C virus infection, confirming this condition remains a major priority area in liver disease. Clinical information provided by referring clinicians was often incomplete, impairing the ability to accurately triage referrals. Only a minority of referrals provided information about relevant comorbidities (alcohol intake, injecting drug use, mental health issues and obesity) that negatively impact on the progression of liver disease or the response to antiviral treatment. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Hepatitis C virus remains a major health priority area in liver disease, increasing the future burden of cirrhosis and hepatocellular cancer. Many referred patients have comorbidities that increase their risk of progressive liver disease and related complications. Strategies to increase recognition and management of liver disease and its comorbidities in the community are required. The use of a standardised assessment form in referrals to hepatology outpatient services may assist with triaging of patients and improve access to appropriate care. PMID- 23448668 TI - A CRISPR way to engineer the human genome. AB - RNA-guided genome engineering based on the type II prokaryotic CRISPR/Cas system provides an efficient and versatile method for targeted manipulation of mammalian genomes. PMID- 23448667 TI - Bcl-2 associated athanogene 5 (Bag5) is overexpressed in prostate cancer and inhibits ER-stress induced apoptosis. AB - BACKGROUND: The Bag (Bcl-2 associated athanogene) family of proteins consists of 6 members sharing a common, single-copied Bag domain through which they interact with the molecular chaperone Hsp70. Bag5 represents an exception in the Bag family since it consists of 5 Bag domains covering the whole protein. Bag proteins like Bag1 and Bag3 have been implicated in tumor growth and survival but it is not known whether Bag5 also exhibits this function. METHODS: Bag5 mRNA and protein expression levels were investigated in prostate cancer patient samples using real-time PCR and immunoblot analyses. In addition immunohistological studies were carried out to determine the expression of Bag5 in tissue arrays. Analysis of Bag5 gene expression was carried out using one-way ANOVA and Bonferroni's Multiple Comparison test. The mean values of the Bag5 stained cells in the tissue array was analyzed by Mann-Whitney test. Functional studies of the role of Bag5 in prostate cancer cell lines was performed using overexpression and RNA interference analyses. RESULTS: Our results show that Bag5 is overexpressed in malignant prostate tissue compared to benign samples. In addition we could show that Bag5 levels are increased following endoplasmic reticulum (ER)-stress induction, and Bag5 relocates from the cytoplasm to the ER during this process. We also demonstrate that Bag5 interacts with the ER-resident chaperone GRP78/BiP and enhances its ATPase activity. Bag5 overexpression in 22Rv.1 prostate cancer cells inhibited ER-stress induced apoptosis in the unfolded protein response by suppressing PERK-eIF2-ATF4 activity while enhancing the IRE1-Xbp1 axis of this pathway. Cells expressing high levels of Bag5 showed reduced sensitivity to apoptosis induced by different agents while Bag5 downregulation resulted in increased stress-induced cell death. CONCLUSIONS: We have therefore shown that Bag5 is overexpressed in prostate cancer and plays a role in ER-stress induced apoptosis. Furthermore we have identified GRP78/BiP as a novel interaction partner of Bag5. PMID- 23448669 TI - PPE2 protein of Mycobacterium tuberculosis may inhibit nitric oxide in activated macrophages. AB - Although the pathophysiological role of PE/PPE proteins of Mycobacterium tuberculosis is yet to be fully understood, recent evidence shows that these proteins play important roles in antigenic diversity, as well as in host-pathogen interactions and mycobacterial pathogenesis. Most of the PE/PPE proteins are highly expressed in pathogenic bacteria, pointing to their role in the pathogenesis of mycobacteria. Here, we provide an overview of our work in progress on a specific PPE protein, PPE2 (Rv0256c), which may inhibit nitric oxide (NO) production in activated macrophages. As NO and its by-products are considered to be toxic to bacilli, it is possible that the bacilli recruit Rv0256c in order to inhibit higher production of NO during infection. PMID- 23448670 TI - [Management of giant inguinal hernias: five cases]. AB - In Africa, difficulties in health care access and illiteracy promote the development of giant inguinal hernias. Management of these hernias can be very challenging, according to the risk of replacing the intestines into the abdominal cavity. We report five cases in Senegal. PMID- 23448671 TI - [Differential diagnosis of the ileum diseases]. AB - Inflammation of the ileum - ileitis - is classically connected with Crohn's disease. But a wide variety of diseases is associated with inflammation of the ileum. These include inflammatory bowel disease, infections, spondyloarthropathies, vascular diseases, drug-related enteritis, infiltration (e.g. sarcoidosis, amyloidosis), postirradiation enteritis, tumors, endometriosis, celiac disease and collagenosis. PMID- 23448672 TI - [Significance of human papillomavirus infections]. AB - Human papillomavirus is one of the most frequent sexually transmitted diseases; more than three quarters of sexually active population are infected during their lifetime. Most of papillomavirus infections clear spontaneously, however persistent high-risk human papillomavirus 16 and 18 are responsible for over 70% of all cases of cervical cancer and related to a major part of cancers in the vulva, vagina, penis, anal region, and oropharynx. It is estimated that approximately 5.2% of all cancers are associated with oncogenic human papillomavirus infection. PMID- 23448673 TI - [Vitamin D: Its physiology, pathophysiology and significance in etiopathogenesis of malignant diseases]. AB - Vitamin D is an endogenous product of mammalian organisms from which an active agent of a steroid hormone nature is synthesized. These hormones participate in a variety of key metabolic processes in every nuclear cell, whether on endocrine, paracrine and autocrine or subcellular level. Vitamin D represents a very interesting molecule which participates in a great deal of body processes. This review summarizes the findings about the metabolism of vitamin D focusing on pathophysiology of malignant diseases. PMID- 23448674 TI - [The role of smoking in the epigenetic modification of phenotype: the latest knowledge about smoking-induced pathways]. AB - Many environmental factors, including chemicals in cigarette smoke, have deleterious effects on human health. Epidemiological studies have repeatedly confirmed that prenatal exposure to maternal smoking is associated not only with complications of pregnancy, foetal growth retardation and disturbed development, but also with an increased risk of serious diseases manifested during childhood and adulthood. The possible pathways of aberrant foetal programming are the interactions of genes and environmental factors through epigenetic mechanisms. Although these scientific problems are just beginning to be understood, some models of altered epigenetic regulations were described: DNA methylation, non coding RNA(ncRNA)-mediated gene regulation and histone modification. Our contemporaneous knowledge has confirmed that both active smoking and in utero exposure to cigarette smoke can induce changes in all studied epigenetic pathways, and even can be transmitted to future generations through the male germ line. PMID- 23448675 TI - Revealing all: misleading self-disclosure rates in laboratory-based online research. AB - Laboratory-based experiments in online self-disclosure research may be inadvertently compromising the accuracy of research findings by influencing some of the factors known to affect self-disclosure behavior. Disclosure-orientated interviews conducted with 42 participants in the laboratory and in nonlaboratory settings revealed significantly greater breadth of self-disclosure in laboratory interviews, with message length and intimacy of content also strongly related. These findings suggest that a contrived online setting with a researcher presence may stimulate motivation for greater self-disclosure than would occur naturally in an online environment of an individual's choice. The implications of these findings are that researchers should consider the importance of experimental context and motivation in self-disclosure research. PMID- 23448676 TI - Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide case-control study in Denmark. AB - BACKGROUND AND PURPOSE: To evaluate the association between the use of azathioprine and risk of cancer in patients with non-thymoma myasthenia gravis (MG) in a nationwide setting. METHODS: Case-control study based on population based registries. Cases were patients with MG with a first time diagnosis of cancer (except non-melanoma skin cancer) registered during 2000-2009, and controls were patients with MG with no history of cancer. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for cancer associated with a high cumulative dose [>= 1000 defined daily doses (DDD)] or long-term use (>= 5 years) of azathioprine, compared with never use of the drug and adjusted for potential confounders. RESULTS: We identified 89 cases and 873 controls. The prevalence of ever use of azathioprine was similar among cases (39.3%) and controls (39.4%). We observed a slightly elevated OR for cancer overall associated with long-term use of azathioprine (1.22; 95% CI: 0.62-2.40, P = 0.56). The highest ORs were observed for use of 2000 DDD or more of azathioprine; however, these risk estimates were based on small numbers. CONCLUSIONS: Use of azathioprine in patients with non-thymoma MG may be associated with a slightly increased risk of cancer overall. Larger studies are necessary to address the risk of site-specific cancers. PMID- 23448677 TI - Decision making about frozen supernumerary human embryos. AB - Frozen storage of supernumerary in vitro fertilisation (IVF) embryos benefits patients, but when a decision is required for their disposal this may be experienced as a difficult, emotionally loaded process for many patients. There is the potential at several points for patients to become "stuck" in their decision making and a need for clinics to consider information provision, and implications and decision support counselling to patients in the aftermath of infertility treatment. This paper presents a review of studies about decision making for supernumerary embryos and the implications for counselling within clinics. PMID- 23448678 TI - Identifying permethrin resistance loci in malaria vectors by genetic mapping. AB - Identification of the major loci responsible for insecticide resistance in malaria vectors would aid the development and implementation of effective resistance management strategies, which are urgently needed to tackle the growing threat posed by resistance to the limited insecticides available for malaria control. Genome-wide association studies in the major malaria vector, Anopheles gambiae, have been hindered by the high degree of within-population structuring and very low levels of linkage disequilibrium hence we revisited the use of quantitative trait loci (QTL) mapping to study resistance phenotypes in this vector species. Earlier work, identified two major QTL associated with pyrethroid resistance in A. gambiae s.s. from East Africa using genetic crossing of laboratory-colonized resistant and susceptible strains. In this study, we report the results from genetic mapping of pyrethroid resistance in three isofemale pedigrees established from wild-caught female A. gambiae s.s. mosquitoes from Benin. We identified two QTL on chromosomes 2L and 3R in these field populations, in similar genomic locations to the QTL identified in laboratory strains. The relative merits of two alternative study designs are discussed and suggestions made for future genetic mapping studies of insecticide resistance in mosquitoes. PMID- 23448679 TI - Inflow-weighted pulmonary perfusion: comparison between dynamic contrast-enhanced MRI versus perfusion scintigraphy in complex pulmonary circulation. AB - BACKGROUND: Due to the different properties of the contrast agents, the lung perfusion maps as measured by 99mTc-labeled macroaggregated albumin perfusion scintigraphy (PS) are not uncommonly discrepant from those measured by dynamic contrast-enhanced MRI (DCE-MRI) using indicator-dilution analysis in complex pulmonary circulation. Since PS offers the pre-capillary perfusion of the first pass transit, we hypothesized that an inflow-weighted perfusion model of DCE-MRI could simulate the result by PS. METHODS: 22 patients underwent DCE-MRI at 1.5T and also PS. Relative perfusion contributed by the left lung was calculated by PS (PS(L%)), by DCE-MRI using conventional indicator dilution theory for pulmonary blood volume (PBV(L%)) and pulmonary blood flow (PBFL%) and using our proposed inflow-weighted pulmonary blood volume (PBV(iw)(L%)). For PBViw(L%), the optimal upper bound of the inflow-weighted integration range was determined by correlation coefficient analysis. RESULTS: The time-to-peak of the normal lung parenchyma was the optimal upper bound in the inflow-weighted perfusion model. Using PSL% as a reference, PBV(L%) showed error of 49.24% to -40.37% (intraclass correlation coefficient R(I) = 0.55) and PBF(L%) had error of 34.87% to -27.76% (R(I) = 0.80). With the inflow-weighted model, PBV(iw)(L%) had much less error of 12.28% to -11.20% (R(I) = 0.98) from PS(L%). CONCLUSIONS: The inflow-weighted DCE MRI provides relative perfusion maps similar to that by PS. The discrepancy between conventional indicator-dilution and inflow-weighted analysis represents a mixed-flow component in which pathological flow such as shunting or collaterals might have participated. PMID- 23448680 TI - Assembly of substituted 3-aminoindazoles from 2-bromobenzonitrile via a CuBr catalyzed coupling/condensation cascade process. AB - CuBr-catalyzed coupling reaction of 2-halobenzonitriles with hydrazine carboxylic esters and CuBr/4-hydroxy-l-proline-catalyzed coupling reaction of 2 bromobenzonitriles with N'-arylbenzohydrazides proceed smoothly at 60-90 degrees C to provide substituted 3-aminoindazoles through a cascade coupling/condensation (or coupling/deacylation/condensation) process. A wide range of 3-aminoindazoles with substituents at both the 1-position and the phenyl ring part can be prepared from the corresponding coupling partners. PMID- 23448681 TI - Plant-derived recombinant human collagen: a strategic approach for generating safe human ECM-based scaffold. PMID- 23448682 TI - Synthetically tractable click hydrogels for three-dimensional cell culture formed using tetrazine-norbornene chemistry. AB - The implementation of bio-orthogonal click chemistries is a topic of growing importance in the field of biomaterials, as it is enabling the development of increasingly complex hydrogel materials capable of providing dynamic, cell instructive microenvironments. Here, we introduce the tetrazine-norbornene inverse electron demand Diels-Alder reaction as a new cross-linking chemistry for the formation of cell laden hydrogels. The fast reaction rate and irreversible nature of this click reaction allowed for hydrogel formation within minutes when a multifunctional PEG-tetrazine macromer was reacted with a dinorbornene peptide. In addition, the cytocompatibility of the polymerization led to high postencapsulation viability of human mesenchymal stem cells, and the specificity of the tetrazine-norbornene reaction was exploited for sequential modification of the network via thiol-ene photochemistry. These advantages, combined with the synthetic accessibility of the tetrazine molecule compared to other bio orthogonal click reagents, make this cross-linking chemistry an interesting and powerful new tool for the development of cell-instructive hydrogels for tissue engineering applications. PMID- 23448683 TI - Acanthamoeba lenticulata keratitis in a hard contact lens wearer. PMID- 23448684 TI - Prevalence of BRAF and NRAS mutations in fast-growing melanomas. PMID- 23448685 TI - Co-option of a coordinate system defined by the EGFr and Dpp pathways in the evolution of a morphological novelty. AB - BACKGROUND: Morphological innovation is an elusive and fascinating concept in evolutionary biology. A novel structure may open up an array of possibilities for adaptation, and thus is fundamental to the evolution of complex multicellular life. We use the respiratory appendages on the dorsal-anterior side of the Drosophila eggshell as a model system for morphological novelty. To study the co option of genetic pathways in the evolution of this novelty we have compared oogenesis and eggshell patterning in Drosophila melanogaster with Ceratitis capitata, a dipteran whose eggs do not bear dorsal appendages. RESULTS: During the final stages of oogenesis, the appendages are formed by specific groups of cells in the follicular epithelium of the egg chamber. These cells are defined via signaling activity of the Dpp and EGFr pathways, and we find that both pathways are active in C. capitata oogenesis. The transcription factor gene mirror is expressed downstream of EGFr activation in a dorsolateral domain in the D. melanogaster egg chamber, but could not be detected during C. capitata oogenesis. In D. melanogaster, mirror regulates the expression of two important genes: broad, which defines the appendage primordia, and pipe, involved in embryonic dorsoventral polarity. In C. capitata, broad remains expressed ubiquitously throughout the follicular epithelium, and is not restricted to the appendage primordia. Interestingly pipe expression did not differ between the two species. CONCLUSIONS: Our analysis identifies both broad and mirror as important nodes that have been redeployed in the Drosophila egg chamber patterning network in the evolution of a morphologically novel feature. Further, our results show how pre-existing signals can provide an epithelium with a spatial coordinate system, which can be co-opted for novel patterns. PMID- 23448686 TI - Glycemia control using A1C level in terminal cancer patients with preexisting type 2 diabetes. AB - BACKGROUND: No method is available for evidence-based glycemic-control management in the context of advanced cancer. OBJECTIVE: This study aimed to analyze, by investigating A1C levels, the necessity of glycemic control in terminal cancer patients with preexisting type 2 diabetes. DESIGN: This was a retrospective study. SUBJECTS: We analyzed 53 terminal cancer patients who had preexisting type 2 diabetes. All patients first visited Kondo Hospital between April 2002 and December 2006. MEASUREMENTS: We assessed the necessity of glycemic control based on the length of hospitalization and the length of the end-of-life period by using the Kaplan-Meier method and Cox hazard model. Length of the end-of-life period was calculated from the completion of palliative chemotherapy until death. Length of hospitalization was calculated from last admission until death. RESULTS: The median length of hospitalization was significantly longer in relatively well controlled patients--with A1C levels <7.5% (49 days; 95% confidence interval [CI] 34.9-63.1)--than in poorly controlled patients, with A1C levels >=7.5% (23 days; 95% CI 14.6-31.4, P=0.05). The median length of end of life was significantly longer in the relatively well controlled patients (144 days; 95% CI 115.9-172.1) than in poorly controlled patients (45 days; 95% CI 13.8-76.2, P=0.02). Cox multivariate analysis indicated that performance status (PS) at the initial visit to the hospice (hazard ratio [HR] 2.79; 95% CI 1.46 5.32, P=0.002) and glycemic control (HR 2.10; 95% CI 1.18-3.75, P=0.01) were independent, positive prognostic factors. CONCLUSION: Good glycemic control, that is, maintenance of A1C levels at <7.5% during the terminal phase of cancer, conferred a significant survival benefit in cancer patients who had preexisting type 2 diabetes. PMID- 23448687 TI - Symptom screening in palliative care patients. PMID- 23448688 TI - Comparison of international medical graduates with US medical students and residents after a four-week course in palliative medicine: a pilot study. AB - BACKGROUND: The need for doctors who have skills in pain management and palliative medicine is greatest in low and moderate resource countries where patients most frequently present to their health care system with advanced illness and greater than 80% of the global deaths occur. While medical students trained in the United States are required to have training in palliative medicine, international medical graduates (IMGs), who have completed medical school outside North America, may not have the same exposure to palliative medicine training as U.S. physicians. The goal of this study was to evaluate whether a four-week course in palliative medicine could bring IMG attitudes, concerns, competence, and knowledge to the level of U.S. trainees. METHODS: As part of a prospective cohort study, 21 IMGs from 14 countries participated in a four-week course in palliative medicine. Attitudes, concerns, self-reported competence, and knowledge were assessed pre-course and post-course. The course was evaluated weekly and at the end of the four-week program. The data from the IMGs was compared to data from U.S. medical students and residents using the same assessment tools. RESULTS: After the course, IMGs had significantly decreased concern about ethical and legal issues in palliative medicine to the level of U.S.-trained residents and a significant increase in knowledge and self-rated competence equivalent to the level of U.S. trainees. CONCLUSIONS: A four-week course in palliative medicine can improve the levels of concern, knowledge and self-assessed competence in IMGs to the level of US trainees. PMID- 23448689 TI - The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation. AB - During disseminated infection by the opportunistic pathogen Candida glabrata, uptake of sterols such as serum cholesterol may play a significant role during pathogenesis. The ATP-binding cassette transporter Aus1p is thought to function as a sterol importer and in this study, we show that uptake of exogenous sterols occurred under anaerobic conditions in wild-type cells of C. glabrata but not in AUS1-deleted mutant (aus1Delta) cells. In aerobic cultures, growth inhibition by fluconazole was prevented in the presence of serum, and AUS1 expression was upregulated. Uptake of sterol by azole treated cells required the presence of serum, and sterol alone did not reverse FLC inhibition of growth. However, if iron availability in the growth medium was limited by addition of the iron chelators ferrozine or apo-transferrin, growth of wild-type cells, but not aus1Delta cells, was rescued. In a mouse model of disseminated infection, the C. glabrata aus1Delta strain caused a significantly decreased kidney fungal burden than the wild-type strain or a strain in which AUS1 was restored. We conclude that sterol uptake in C. glabrata can occur in iron poor environment of host tissues and thus may contribute to C. glabrata pathogenesis. PMID- 23448690 TI - Engineering of a functional thermostable kanamycin resistance marker for use in Moorella thermoacetica ATCC39073. AB - A transformation system for Moorella thermoacetica ATCC39073 was developed using thermostable kanamycin resistant gene (kanR) derived from the plasmid pJH1 that Streptococcus faecalis harbored. When kanR with its native promoter was introduced into uracil auxotrophic mutant of M. thermoacetica ATCC39073 together with a gene to complement the uracil auxotrophy as a selection marker, it did not give kanamycin resistance due to poor transcription level of kanR. However, the use of glyceraldehyde-3-phosphate dehydrogenase promoter cloned from M. thermoacetica ATCC39073 significantly improved transcription level of kanR and resulted in the cell growth in the presence of more than 150 MUg mL(-1) kanamycin. It was also demonstrated that kanR with G3PD promoter can be used as a selection marker for transformation of wild-type strain of M. thermoacetica ATCC39073. PMID- 23448692 TI - Fine structure of Metchnikovella incurvata Caullery and Mesnil 1914 (microsporidia), a hyperparasite of gregarines Polyrhabdina sp. from the polychaete Pygospio elegans. AB - Class Rudimicrosporea Sprague 1977, with its single family Metchnikovellidae, comprises hyperparasites of gregarines from the guts of marine invertebrates. Metchnikovellids remain poorly studied in spite of their significance to the evolutionary history of microsporidia; their ultrastructure and life cycles require further investigation. Here we present results of the light- and electron microscopy study of Metchnikovella incurvata Caulleri and Mesnil 1914, isolated from lecudinid gregarines, parasitizing polychaetes Pygospio elegans in the White Sea littoral zone, and yet described only on the light-microscopic level. The life cycle of this microsporidium includes 2 sporogonies: free (FS) and sac-bound (SBS). In FS, sporonts develop into multinuclear cells (sporogonial plasmodia), which generate sporoblasts and free spores residing in direct contact with the host cytoplasm. Electron microscopy revealed their metchnikovellidean structure: a horseshoe-shaped nucleus, short manubrium perpendicular to the long axis of the spore, and a polar cap in a separate membrane container. Merogony was not observed. The earliest stages of SBS were chains of binucleate cells. They underwent a series of nuclear and cell divisions, produced extracellular envelopes, and split into boomerang-shaped spore sacs, containing up to 16 spores each. Ultrastructure and sizes of sac-bounded spores were similar to those of free-living ones. An amended diagnosis of M. incurvata is provided. PMID- 23448691 TI - Class III peroxidases are activated in proanthocyanidin-deficient Arabidopsis thaliana seeds. AB - BACKGROUND AND AIMS: It has previously been shown that proanthocyanidins (PAs) in the seed coat of Arabidopsis thaliana have the ability to scavenge superoxide radicals (O2(-)). However, the physiological processess in PA-deficit seeds are not clear. It is hypothesized that there exist alternative ways in PA-deficient seeds to cope with oxidative stress. METHODS: The content of hydrogen peroxide (H2O2) and its relevance to the activities of superoxide dismutase (SOD), catalase (CAT) and peroxidases was investigated in both wild-type and PA-deficit mutant seeds. A biochemical staining approach was used to detect tissue localizations of peroxidase activities in PA-deficit mutant seeds. KEY RESULTS: PA-deficient mutants possess significantly lower levels of H2O2 than the wild type, despite their higher accumulation of superoxide radicals. Screening of the key antioxidant enzymes revealed that peroxidase activity was significantly over activated in mutant seeds. This high peroxidase activity was mainly confined to the seed coat zone. Interestingly, neither ascorbate peroxidase nor glutathione peroxidase, just the guaiacol peroxidases (class III peroxidases), was specifically activated in the seed coat. However, no significant difference in peroxidase activity was observed in embryos of either mutants or the wild-type, although gene expressions of several candidate peroxidases were down-regulated in the embryos of PA-deficient seeds. CONCLUSIONS: The results suggest that enhanced class III peroxidase activity in the seed coat of PA-deficient mutants is an adaptive strategy for seed development and survival. PMID- 23448693 TI - Criterion validity of the GMFM-66 item set and the GMFM-66 basal and ceiling approaches for estimating GMFM-66 scores. AB - AIM: The aim of this study was to compare the accuracy of two abbreviated approaches for estimating Gross Motor Function Measure 66 (GMFM-66) scores against the full GMFM-66 and to explore their strengths and limitations. METHOD: An existing dataset (n=224) comprising children aged 1 to 13 years (mean age 6y 11mo, SD 4y 6mo; 132 males, 92 females) with cerebral palsy (CP) of all Gross Motor Function Classification System (GMFCS) levels was used to compare the validity of the item set version (GMFM-66-IS) and the basal and ceiling version (GMFM-66-B&C) with the full GMFM-66 scores. Follow-up assessment at 1 year (n=109) allowed evaluation of change scores and accuracy at a single point in time. RESULTS: The cross-sectional agreement was excellent for both abbreviated measures (all intraclass correlation coefficients [ICCs] >0.98). When measuring change over time, both the GMFM-66-IS and the GMFM-66-B&C showed good agreement for children with bilateral CP (ICCs >0.9). However, the GMFM-66-IS assessed change over 1 year more accurately than the GMFM-66-B&C in children with unilateral CP (ICC=0.89 vs ICC=0.58; 95% confidence intervals do not overlap). INTERPRETATION: Both approaches for estimating GMFM-66 scores are accurate at a single point in time. If the primary goal of assessment is to measure change, the full GMFM-66 should still be regarded as the criterion standard. The GMFM-66-IS should be the preferred shortened measure for children with unilateral CP. PMID- 23448694 TI - Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP). AB - Abstract Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardization of analysis and presentation of glucose monitoring data, with the initial focus on data derived from CGM systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile (AGP), and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This paper provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients. PMID- 23448696 TI - Differential characterization of emerging skin diseases of rainbow trout--a standardized approach to capturing disease characteristics and development of case definitions. AB - Farmed and wild salmonids are affected by a variety of skin conditions, some of which have significant economic and welfare implications. In many cases, the causes are not well understood, and one example is cold water strawberry disease of rainbow trout, also called red mark syndrome, which has been recorded in the UK since 2003. To date, there are no internationally agreed methods for describing these conditions, which has caused confusion for farmers and health professionals, who are often unclear as to whether they are dealing with a new or a previously described condition. This has resulted, inevitably, in delays to both accurate diagnosis and effective treatment regimes. Here, we provide a standardized methodology for the description of skin conditions of rainbow trout of uncertain aetiology. We demonstrate how the approach can be used to develop case definitions, using coldwater strawberry disease as an example. PMID- 23448697 TI - Cognitive biases and auditory verbal hallucinations in healthy and clinical individuals. AB - BACKGROUND: Several cognitive biases are related to psychotic symptoms, including auditory verbal hallucinations (AVH). It remains unclear whether these biases differ in voice-hearers with and without a 'need-for-care'. METHOD: A total of 72 healthy controls, 72 healthy voice-hearers and 72 clinical voice-hearers were compared on the Cognitive Biases Questionnaire for psychosis (CBQp), which assesses 'intentionalizing', 'jumping to conclusions', 'catastrophizing', 'dichotomous thinking' and 'emotional reasoning' in vignettes characterized by two themes, 'threatening events' and 'anomalous perceptions'. RESULTS: Healthy voice-hearers scored intermediately on total CBQp between the control and clinical groups, differing significantly from both. However, on four out of five biases the scores of the healthy voice-hearers were comparable with those of the healthy controls. The only exception was 'emotional reasoning', on which their scores were comparable with the clinical group. Healthy voice-hearers demonstrated fewer biases than the psychotic patients on the 'threatening events', but not the 'anomalous perceptions', vignettes. CBQp scores were related to both cognitive and emotional, but not physical, characteristics of voices. CONCLUSIONS: Most cognitive biases prevalent in clinical voice-hearers, particularly with threatening events themes, are absent in healthy voice-hearers, apart from emotional reasoning which may be specifically related to the vulnerability to develop AVH. The association between biases and both beliefs about voices and distress/emotional valence is consistent with the close links between emotions and psychotic phenomena identified by cognitive models of psychosis. The absence of reasoning biases might prevent the formation of threatening appraisals about anomalous experiences, thereby reducing the likelihood of distress and 'need for care'. PMID- 23448698 TI - 'It still leaves me sixty dollars out of pocket': experiences of diabetes medical care among low-income earners in Perth. AB - Diabetes prevalence is increasing in Australia, and there are stark inequities in prevalence and clinical outcomes experienced by Indigenous people and low socioeconomic groups compared with non-Indigenous and socioeconomically advantaged groups. This paper explores the impact of Indigenous status and socioeconomic disadvantage on the experience of diabetes care in the primary health setting. Data were collected through focus groups and interviews. The sample, comprising 38 participants (Indigenous and non-Indigenous), was recruited from disadvantaged areas in Perth, Australia. Data analysis was mainly deductive and based on a conceptual framework for the relationship between socioeconomic position and diabetes health outcomes. Most participants reported accessing general practitioners regularly; however, evidence of access to dietitians and podiatrists was very limited. Perceived need, cost, lack of information on available services and previous negative experiences influenced health care seeking behaviour. Complexity and lack of coordination characterised the model of care reported by most participants. In contrast, Indigenous participants accessing an Aboriginal community-controlled health organisation reported a more accessible and coordinated experience of care. Our analysis suggests that Indigenous and socioeconomically disadvantaged people tailor their health care seeking behaviour to the limitations imposed by their income and disadvantaged circumstances. To reduce inequities in care experiences, diabetes services in primary care need to be accessible and responsive to the needs of such groups in the community. PMID- 23448699 TI - Doxapram and hypokalaemia in very preterm infants. AB - BACKGROUND: We observed two preterm infants who developed severe hypokalaemia following doxapram. We therefore wished to review the possible association between doxapram and severe hypokalaemia. STUDY DESIGN: A retrospective study of preterm infants born before 32 weeks of gestation and hospitalised in our intensive care unit in 2004. For each infant, treatment with doxapram or with any drug known to interfere with potassium metabolism, potassium intakes and episodes of hypokalaemia have been recorded. RESULTS: Out of 105 infants, 54 received doxapram. Doxapram-treated infants were significantly younger and had a lower birth weight. Doxapram treated infants were more likely to receive caffeine, furosemide, insulin and mechanical ventilation. There was no difference between the two groups for the other parameters. Hypokalaemia was frequently encountered in our population since it occurred in 76% of enrolled patients and severe hypokalaemia (potassium plasma level below 3 mmol/l) was found in 41%. Bivariate analysis underlined several risk factors for severe hypokalaemia: use of doxapram, gestational age below 28 weeks, use of mechanical ventilation, furosemide, ibuprofen, insulin and postnatal corticosteroids. Cox model's multivariate analysis showed that administration of furosemide and doxapram significantly increased the occurrence of severe hypokalaemia with relative risks of 4.9 (95% CI 1.9 to 12.5) and 8.2 (95% CI 3.1 to 21.7), respectively. CONCLUSIONS: This retrospective study underlines the high incidence of severe hypokalaemia in very preterm infants and an increased risk of severe hypokalaemia during doxapram treatment. We recommend potassium monitoring during any use of doxapram. PMID- 23448700 TI - Primary penile lymphoma: the use of PET-CT for accurate staging and response monitoring. AB - Primary penile lymphoma is an extremely rare neoplasm. We present a case of 63 year-old man with painless diffuse pe- nile swelling and retention of urine. Biopsy from the penile swelling demonstrated CD20+ diffuse large B-cell lymphoma. Staging was performed using fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) and revealed a FDG avid penile mass with enlarged and FDG avid multiple inguinal and aortocaval lymph nodes. A follow-up FDG PET-CT scan after eight cycles of combination chemotherapy showed complete remission of the dis- ease. Thus, FDG PET-CT should be integrated in management protocols of rare primary penile lymphoma. PMID- 23448701 TI - Synthesis of 3-cyanoindole derivatives mediated by copper(I) iodide using benzyl cyanide. AB - Copper-mediated direct and regioselective C3-cyanation of indoles using benzyl cyanide as the cyanide anion source is presented. A wide range of indoles undergo cyanation smoothly by employing a reaction system of copper(I) iodide under open to-air vessels. PMID- 23448702 TI - [STARR surgery in the treatment of rectocele and rectal intussusception]. AB - INTRODUCTION: Rectocele and intussusceptions are amongst the most frequent causes of Obstructed Defecation Syndrome (ODS). ODS diagnostics has been constantly improving which results in more precise indication criteria for individual surgical approaches. The work discusses indications for Stapled TransAnal Rectal Resection (STARR) as well as the results of the seven-year follow-up. MATERIAL AND METHODS: Female patients with ODS score over 7 were indicated for STARR procedure after all conservative treatment possibilities failed. The proper indication requires that other causes of ODS be excluded. The retrospective analysis of prospectively collected data was employed. RESULTS: Between January 2005 and October 2012 29 STARR procedures for rectocele were performed. Morbidity rate of the set of our patients was 6.9%. None of the patients died. We recorded bleeding from the staple line in seven patients (without surgical revision), and urinary infection in two patients. Bleeding from staple line was present in seven causes and urinary infection was present twice. CONCLUSION: The STARR procedure seems to be an effective and safe treatment for ODS associated with rectocele and intussusception. The overall morbidity rate is low. Further investigation is required to optimize patient's selection and to reduce the potential complications and failure during postoperative period. PMID- 23448703 TI - [Wound microbial sampling methods in surgical practice, imprint techniques]. AB - The wound is a damage of tissue. The process of healing is influenced by many systemic and local factors. The most crucial and the most discussed local factor of wound healing is infection. Surgical site infection in the wound is caused by micro-organisms. This information is known for many years, however the conditions leading to an infection occurrence have not been sufficiently described yet. Correct sampling technique, correct storage, transportation, evaluation, and valid interpretation of these data are very important in clinical practice. There are many methods for microbiological sampling, but the best one has not been yet identified and validated. We aim to discuss the problem with the focus on the imprint technique. PMID- 23448704 TI - [Central venous cannulation under ultrasonographic and fluoroscopic navigation - 2 year experience]. AB - INTRODUCTION: The aim of our study was to evaluate the influence of ultrasonographic and fluoroscopic navigation on the rate of procedural and early complications during central venous cannulation. MATERIAL AND METHODS: We retrospectively evaluated procedural and early complications in patients who had undergone central venous cannulation under sonographic and fluoroscopic control within a two year period (from January 2010 to December 2011). We studied procedural and early complications (within 24 hours after the procedure). We summarized all cases of pneumothorax, haemothorax and haematoma of soft tissue larger than 5 cm in long axis, and other severe complications e.g. ardiac arrhythmias or hypotension. The set of patients indicated for central venous cannulation included mainly oncological patients who were implanted central venous port systems, and a small group of patients who were cannulated either at the intensive care unit (ICU) or at the department of anesthesiology after unsuccessful blind cannulation. There were three patients cannulated because of transjugular liver biopsy. RESULTS: We cannulated 165 patients under sonographic control within two years. There were 66 men, the mean age of 58.6 years (20-82) and 99 women, the mean age of 58.3 years (36- 94). We cannulated internal jugular vein 148 times and subclavian vein 17 times. The primary technical success was 100% in our study group. Totally, we had 6 complications (3.6%). Immediatelly after the procedure we observed two pneumothoraxes (1.2%) which did not require chest drainage. We punctured artery wall three times, but without haematoma developement, and after a ten-minute commpression, all procedures were successfully finished. We had serious vagal reaction during the cannulation in one patient. We had no fatal procedural complication in our group. There are significantly fewer complications using jugular approach compared to subclavian one. CONCLUSION: We conclude that the ultrasonographic central venous cannulation is a very safe method with a low risk of procedural and early complications. There were significantly fewer complications in case of jugular cannulation compared to subclavian approach in our group of patients. Ultrasonographically navigated central venous cannulation should be used more fequently in emergency medicine as well as in case of non-acute central venous cannulation performed a tan intensive care unit or by anesthesiologists. PMID- 23448705 TI - [Classification of surgical complications: analysis of the group of consecutive patients]. AB - INTRODUCTION: The aim of the work was to evaluate the implementation of Clavien - Dindo classification of surgical complications into a routine clinical praxis and to evaluate the results achieved at the university department of surgery. MATERIAL AND METHODS: Prospectively collected data of patients hospitalized at the Clinic of Surgery of the University Hospital in Hradec Kralove between January 2010 and September 2012 were retrospectively evaluated. Incidence, spectrum and severity of postoperative complications were evaluated according to individual surgical specializations. RESULTS: 9039 patients were operated and enrolled into the database during the time period from January 2010 to October 2012. A surgical complication was recorded in 1248 (12.9%) patiens, grade I. in 284 (3.4%) cases, grade II. in 384 (4.3%) cases, grade III in 370 (4.1%) cases, grade IV. in 67 (0.7%) patients. Death,i.e. grade V., occurred in 143 (1.43%) patients. CONCLUSION: Clavien - Dindo classification of surgical complications was successfully implemented into a routine clinical praxis at the department of surgery, University Hospital Hradec Kralove. Wider use of this classification system would improve conditions for evaluation and comparison of results between different surgical approaches, surgeons or departments. PMID- 23448706 TI - [Upside down stomach]. AB - The recent view on the treatment strategy with a rare diagnosis of gastric volvulus with the help of a literature review inspired by the case of the elderly patient with "upside down stomach". PMID- 23448707 TI - [Lung pneumatocele in adult patient - case report]. AB - Lung pneumatoceles are characterized by a thin-walled air-filled cavity present in lung parenchyma. Mostly they are the result of acute bronchopneumonia after spontaneous drainage of altered lung parenchyma with subsequent development and progression of cavities due to ventile mechanism. This disease is more prevalent in infants and young children, it is rather rare in adults. In the present case report, videothoracoscopy resection of lung pneumatocele of the right lower lobe was performed a 43-years old man. The operation was indicated for the presence of chronic persisting and progressing pneumatocele as a preventive measure of pneumatocele complications. PMID- 23448708 TI - [Chronic pancreatitis--classification, diagnosis and therapy]. PMID- 23448709 TI - [Acute pancreatitis--a complex problem]. PMID- 23448710 TI - [Surgical treatment of chronic pancreatitis]. PMID- 23448711 TI - [Surgical treatment of pancreatic carcinoma]. PMID- 23448712 TI - Towards the engineering of molecular nanostructures: local anchoring and functionalization of porphyrins on model-templates. AB - We demonstrate that Cu(111) surfaces pre-covered with a submonolayer of copper oxide or metallic nickel are suitable model-templates for the selective adsorption and/or localized functionalization of functional molecules such as different free base porphyrins and metalloporphyrins. The oxide/Cu(111) model template is able to steer the adsorption of tetraphenylporphyrins (TPP): 2HTPP selectively adsorbs on the bare Cu areas, and for CoTPP anchoring at the rim of the copper oxide islands is found. On the Ni/Cu(111) model-template TPP molecules are pinned on the Ni areas while they are mobile on the bare Cu surface. Interestingly, adsorption of free base octaethylporphyrin on Ni/Cu(111) leads to a local functionalization, namely the metalation to NiOEP on the Ni areas. Model template preparation and characterization by scanning tunneling microscopy is performed at room temperature. PMID- 23448713 TI - Synergy of low-energy {101} and high-energy {001} TiO2 crystal facets for enhanced photocatalysis. AB - Controlled crystal growth determines the shape, size, and exposed facets of a crystal, which usually has different surface physicochemical properties. Herein we report the size and facet control synthesis of anatase TiO2 nanocrystals (NCs). The exposed facets are found to play a crucial role in the photocatalytic activity of TiO2 NCs. This is due to the known preferential flow of photogenerated carriers to the specific facets. Although, in recent years, the main focus has been on increasing the surface area of high-energy exposed facets such as {001} and {100} to improve the photocatalytic activity, here we demonstrate that the presence of both the high-energy {001} oxidative and low energy {101} reductive facets in an optimum ratio is necessary to reduce the charge recombination and thereby enhance photocatalytic activity of TiO2 NCs. PMID- 23448714 TI - Bulk, surface and point defect properties in UO2 from a tight-binding variable charge model. AB - A tight-binding variable-charge model (SMTB-Q) has been used to calculate bulk, surface and point defect properties in uranium dioxide. It provides us with a better description of the iono-covalent oxides than classical, purely ionic models. A good agreement is found in the structural properties and cohesive energy between the model and experimental data; the charges calculated on the uranium and oxygen ions are Q(U) = 2.804 and Q(O) =- 1.402 respectively. The stability and relaxation of low index surfaces were evaluated: the (111) surface consistently has the lowest surface energy and the smallest surface relaxation, followed by the (110) surface and the (100) surface, in agreement with previous predictions from semi-empirical potentials and from ab initio calculations. The energy ranking of intrinsic defects is oxygen Frenkel pair < Schottky trio < uranium Frenkel pair, which is consistent with literature. The clustering energy of small vacancy clusters has been also calculated. Additionally, the atomic relaxations and the charge transfer at surfaces and around defects have been investigated. All the results obtained in the present work prove the ability of the SMTB-Q model to describe the bulk properties as well as the surface and defect properties in uranium dioxide. Finally, this model provides us with a new fundamental insight into the role played by the charge transfer in UO2 properties. PMID- 23448715 TI - Discovery, molecular and pharmacological characterization of GSA-10, a novel small-molecule positive modulator of Smoothened. AB - Activation of the Smoothened (Smo) receptor mediates Hedgehog (Hh) signaling. Hh inhibitors are in clinical trials for cancer, and small-molecule Smo agonists may have therapeutic interests in regenerative medicine. Here, we have generated and validated a pharmacophoric model for Smo agonists and used this model for the virtual screening of a library of commercially available compounds. Among the 20 top-scoring ligands, we have identified and characterized a novel quinolinecarboxamide derivative, propyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2 dihydroquinoline-3-carboxamido) benzoate, (GSA-10), as a Smo agonist. GSA-10 fits to the agonist pharmacophoric model with two hydrogen bond acceptor groups and four hydrophobic regions. Using pharmacological, biochemical, and molecular approaches, we provide compelling evidence that GSA-10 acts at Smo to promote the differentiation of multipotent mesenchymal progenitor cells into osteoblasts. However, this molecule does not display the hallmarks of reference Smo agonists. Remarkably, GSA-10 does not recognize the classic bodipy-cyclopamine binding site. Its effect on cell differentiation is inhibited by Smo antagonists, such as MRT-83, SANT-1, LDE225, and M25 in the nanomolar range, by GDC-0449 in the micromolar range, but not by cyclopamine and CUR61414. Thus, GSA-10 allows the pharmacological characterization of a novel Smo active site, which is notably not targeted to the primary cilium and strongly potentiated by forskolin and cholera toxin. GSA-10 belongs to a new class of Smo agonists and will be helpful for dissecting Hh mechanism of action, with important implications in physiology and in therapy. PMID- 23448716 TI - GK4, a G-protein-coupled receptor with a phosphatidylinositol phosphate kinase domain in Phytophthora infestans, is involved in sporangia development and virulence. AB - For dispersal and host infection plant pathogens largely depend on asexual spores. Pathogenesis and sporulation are complex processes that are governed by cellular signalling networks including G-protein and phospholipid signalling. Oomycetes possess a family of novel proteins called GPCR-PIPKs (GKs) that are composed of a seven-transmembrane spanning (7-TM) domain fused to a phosphatidylinositol phosphate kinase (PIPK) domain. Based on this domain structure GKs are anticipated to link G-protein and phospholipid signal pathways; however, their functions are currently unknown. Expression analyses of the 12 GK genes in Phytophthora infestans and their orthologues in Phytophthora sojae, revealed differential expression during asexual development. PiGK1 and PiGK4 were fused to monomeric red fluorescent protein (mRFP) and ectopically expressed in P. infestans. In growing hyphae different subcellular distribution patterns were observed indicating that these two GKs act independently during development. We focused on the functional analyses of PiGK4. Its localization suggested involvement in cell differentiation and elongation and its 7-TM domain showed a canonical GPCR membrane topology. Silencing of GK4 and overexpression of full length and truncated constructs in P. infestans revealed that PiGK4 is not only involved in spore germination and hyphal elongation but also in sporangia cleavage and infection. PMID- 23448718 TI - Overweight in singletons compared to children with siblings: the IDEFICS study. AB - The aim of this study was to compare the prevalence of overweight in only children to those with siblings and to explore potential behavioral mediating factors. This study relies upon cross-sectional data collected at survey centers in eight European countries participating in Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS). The present analysis is based on measured anthropometry and parent or guardian reported socio-demographic characteristics. Subjects include 12 720 children aged 2-9 years for whom number of siblings was known. Singletons were more likely (odds ratio 1.52, 95% confidence interval (CI):1.34-1.72) to be overweight than their peers with siblings when controlling for factors related to childhood overweight, including survey country, parental education, parental weight, maternal age, child's age, birth weight and gender. The three southernmost countries have over threefold risk of overweight, dominated by Italy, compared with the north-central countries, which is not explained by the prevalence of singleton children. The excess risk of overweight among children without siblings was robustly observed even when considering behavioral mediating factors (playtime, screen time per day, dietary propensities for sugar or fat, parental attitudes towards food rewards and television in the child's bedroom). Among singletons aged 6-9 years, the excess risk of overweight was 1.70 (95% CI: 1.44 2.01) compared with 1.32 (95% CI: 1.10-1.60) in younger singletons. PMID- 23448717 TI - [How are leisure activity and shiftwork schedule associated with recovery from fatigue in shiftwork nurses?]. AB - OBJECTIVES: The period of leisure is an appropriate time to recover from work induced fatigue, though some recovery takes place during rest breaks at work. Recently, much attention has been paid to the critical role of leisure activity in recovery. However, the findings relevant to shiftwork nurses who cannot take a day-off regularly are limited. This study explored how leisure activity during days off and shift work schedule are associated with recovery from fatigue in nurses working rotating shifts. METHODS: A total of 426 nurses working rotating shifts at a university hospital returned a questionnaire regarding leisure activity and fatigue (response rate: 81.5%). Nurses were eligible for this study if they were female, worked 2 or 3 shifts, and had no missing data. A total of 390 respondents satisfied the inclusion criteria. A factor analysis classified their responses on how to spend an assumed period of two consecutive days off into three activity types: outdoor-, sleep-, and indoor-oriented. Fatigue (recovery from fatigue, accumulated fatigue, burnout), work conditions (working time, overtime, nightshift napping), sleep (sleep duration before day shift or day off, sleepiness) were measured. These data were analyzed using a two-way mixed model analysis of covariance (type [outdoor, sleep, indoor], shift schedule [two or three-shift system]). Covariates included age, length of career, partner, children, and hospital ward. Multiple regression analyses were performed to examine the factors determining the level of fatigue. RESULTS: Outdoor-oriented nurses showed significantly faster fatigue recovery, lower accumulated fatigue and less burnout symptoms than others, regardless of the shiftwork schedule. In contrast, sleep-oriented nurses showed significantly slower recovery from fatigue. Besides, their level of fatigue deteriorated more when they worked under a 3-shift system (counter-clockwise) compared with under 2-shift system (with mainly 16-hour nightshift). Multiple regression analysis indicated that sleep oriented type of leisure activity, workload perception of working time, work induced insomnia and length of nightshift naps were significantly related to fatigue-related outcomes. CONCLUSIONS: The primary finding of this study suggests that the level of fatigue is associated with the type of leisure activity, especially sleep-oriented activity, during shiftwork nurses' days off. Also, ensuring sufficient nightshift nap time may be one of the most important nightshift-related factors for recovery from fatigue. The present findings may have implications for appropriate activities during days off as factors facilitating recovery from work, though further investigations are needed to examine the causal links. PMID- 23448720 TI - Modeling uncertain outcomes of genetic testing: factor V Leiden mutation and pregnant women. PMID- 23448719 TI - Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice. AB - OBJECTIVE: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of omega-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). DESIGN: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks-26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either omega-3 or omega-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. RESULTS: The omega-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a omega-6PUFA-rich diet. There was also an enhanced ability of omega-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of omega-3PUFAs. CONCLUSION: This study identifies beneficial effects of dietary omega-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As omega-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing omega-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM. PMID- 23448721 TI - The responses of research participants and their next of kin to receiving feedback of genetic test results following participation in the Australian Ovarian Cancer Study. AB - PURPOSE: The generation of clinically significant genetic data during research studies raises a number of ethical issues about the feedback of this information to research participants. Little is known about research participants' experiences of this practice. METHODS: This qualitative interview study investigated research participants' (n = 10) or their nominated next of kin's (relatives) (n = 15) experiences of receiving BRCA1 and BRCA2 genetic test information following participation in the Australian Ovarian Cancer Study. RESULTS: Interviewees had mixed responses to receiving feedback. The participants of the Australian Ovarian Cancer Study were more positive about receiving feedback, acknowledging that the genetic information may be useful for their kin. Relatives frequently described themselves as initially distressed at receiving feedback, particularly those who were unaware of the participation of their mothers in the Australian Ovarian Cancer Study. The participants of the Australian Ovarian Cancer Study and their relatives expressed an intention to disseminate the information to relatives following confirmation of the result. CONCLUSION: We suggest that research participants be encouraged to discuss their participation with family members from the outset. We also outline a number of different strategies for providing feedback to research participants and their next of kin that may lessen the immediate negative impact of receiving feedback of research results. PMID- 23448722 TI - What does it mean to be genomically literate?: National Human Genome Research Institute Meeting Report. AB - Genomic discoveries will increasingly advance the science of medicine. Limited genomic literacy may adversely impact the public's understanding and use of the power of genetics and genomics in health care and public health. In November 2011, a meeting was held by the National Human Genome Research Institute to examine the challenge of achieving genomic literacy for the general public, from kindergarten to grade 12 to adult education. The role of the media in disseminating scientific messages and in perpetuating or reducing misconceptions was also discussed. Workshop participants agreed that genomic literacy will be achieved only through active engagement between genomics experts and the varied constituencies that comprise the public. This report summarizes the background, content, and outcomes from this meeting, including recommendations for a research agenda to inform decisions about how to advance genomic literacy in our society. PMID- 23448723 TI - Managing incidental genomic findings: legal obligations of clinicians. AB - PURPOSE: Clinical whole-exome and whole-genome sequencing will result in a broad range of incidental findings, but clinicians' obligations to identify and disclose such findings are a matter of debate. We sought legal cases that could offer insights into clinicians' legal liability. METHODS: We searched for cases in which incidental findings were related to the cause of action, using the search engines WestLaw, WestLaw Next, Lexis, and Lexis Advance. RESULTS: We found no case law related to incidental findings from genetic testing but identified eight cases involving incidental findings in medical imaging. These cases suggest that clinicians may face liability for failing to disclose incidental findings that would have offered an opportunity for interventions to improve health outcome, if under the applicable standard of care, they fail to identify or appreciate the significance of the incidental finding or they negligently fail to notify other clinicians and/or the patient of the identified incidental finding. Other cases support liability for failure to refer appropriately to a clinician with greater expertise. CONCLUSIONS: Clinicians may face liability if they fail to disclose incidental information that could inform interventions to improve health outcome; information lacking clinical actionability is likely to have less import. PMID- 23448724 TI - "It was the missing piece": adolescent experiences of predictive genetic testing for adult-onset conditions. AB - PURPOSE: Predictive genetic testing for adult-onset conditions, such as Huntington disease, is available to at-risk adults. Guidelines consistently recommend against such testing before adulthood unless there is associated medical benefit. Guidelines, and related commentary, cite a range of potential harms that might be associated with young people undergoing testing, yet evidence is limited. Clinical practice has forged ahead, with research demonstrating that some clinicians are making their own determinations about the best interests of individual young people and are providing testing in specific cases. For the first time, this study reports empirical evidence concerning the process and impacts of predictive testing in mature minors for adult-onset conditions where no medical benefit exists. METHODS: First-hand accounts from nine young people have been documented. All were aged 16 or 17 years of age when tested. Six tested gene positive. RESULTS: Contrary to existing assumptions, the results convey a range of benefits and absence of harms flowing from testing. Some individuals reported considerable distress associated with institutional processes before testing. CONCLUSION: The results highlight that young people from families affected by genetic conditions might possess task-specific competence relating to decision making about predictive testing. Further research and longer-term follow up is required to study the outcomes of testing in young people. PMID- 23448725 TI - Utilization of epidermal growth factor receptor (EGFR) testing in the United States: a case study of T3 translational research. AB - PURPOSE: We examined hospital use of the epidermal growth factor receptor assay in patients with lung cancer in the United States. Our goal was to inform the development of a model to predict phase 3 translation of guideline-directed molecular diagnostic tests. METHODS: This was a retrospective observational study. Using logistic regression, we analyzed the association between hospitals' institutional and regional characteristics and the likelihood that an epidermal growth factor receptor assay would be ordered. RESULTS: Significant institutional predictors included affiliation with an academic medical center (odds ratio, 1.48; 95% confidence interval, 1.20-1.83), participation in a National Cancer Institute clinical research cooperative group (odds ratio, 2.06, 1.66-2.55), and availability of positron emission tomography scan (odds ratio, 1.44, 1.07-1.94) and cardiothoracic surgery (odds ratio, 1.90, 1.52-2.37) services. Significant regional predictors included metropolitan county (odds ratio, 2.08, 1.48-2.91), population with above-average education (odds ratio, 1.46, 1.09-1.96), and population with above-average income (odds ratio, 1.46, 1.04-2.05). Distance from a National Cancer Institute cancer center was a negative predictor (odds ratio, 0.996, 0.995-0.998), with a 34% decrease in likelihood for every 100 miles. CONCLUSION: In 2010, only 12% of US acute-care hospitals ordered the epidermal growth factor receptor assay, suggesting that most patients with lung cancer did not have access to this test. This case study illustrated the need for: (i) increased dissemination and implementation research, and (ii) interventions to improve adoption of guideline-directed molecular diagnostic tests by community hospitals. PMID- 23448726 TI - Improved pregnancy outcomes in women exposed to malaria with high antibody levels against Plasmodium falciparum. AB - BACKGROUND: Antibodies against VAR2CSA, the Plasmodium falciparum variant surface antigen that binds placental chondroitin sulfate A, have been suggested to mediate protection against malaria in pregnancy but also to be markers of infection. Here, we aimed to identify clinically relevant antibody responses, taking into consideration variations in parasite exposure and human immunodeficiency virus type 1 (HIV) infection status. METHODS: Levels of immunoglobulin G (IgG) against placental and pediatric isolates, VAR2CSA (DBL2X, DBL3X, DBL5epsilon, and DBL6epsilon domains), and other blood-stage antigens (DBLgamma, DBLalpha, MSP119, AMA1, and EBA175) were measured in plasma specimens from 293 pregnant Mozambican women at delivery. Associations between antibody responses, factors influencing malaria exposure, HIV infection status, and pregnancy outcomes were assessed. RESULTS: Maternal antibodies were affected by placental infection, parity, season, and neighborhood of residence. HIV infection modified these associations and attenuated the parity-dependent increase in IgG level. High levels of antibody against AMA1, DBL3X, DBL6epsilon, placental isolates, and pediatric isolates were associated with increased weight and gestational age of newborns (P <= .036) among women with malaria episodes during pregnancy. CONCLUSIONS: Antiparasite IgGs in women at delivery are affected by HIV infection, as well as by variations in the exposure to P. falciparum. Heterogeneity of malaria transmission needs to be considered to identify IgGs against VAR2CSA and other parasite antigens associated with improved pregnancy outcomes. PMID- 23448728 TI - Mannose-binding lectin and susceptibility to schistosomiasis. AB - BACKGROUND: Human ficolin 2 (encoded by FCN2) and mannose-binding lectin (encoded by MBL2) bind to specific pathogen-associated molecular patterns, activate the complement lectin cascade in a similar manner, and are associated with several infectious diseases. Our recently published study established certain FCN2 promoter variants and ficolin-2 serum levels as protective factors against schistosomiasis. METHODS: We used the Nigerian cohort from our recently published study, which included 163 Schistosoma haematobium-infected individuals and 183 matched healthy subjects, and investigated whether MBL deficiency and MBL2 polymorphisms are associated with schistosomiasis. RESULTS: MBL serum levels were significantly higher in controls and were associated with protection (P < .0001). The -550H minor allele was significantly associated with protection (P = .03), and the heterozygous genotypes -550HL were observed to confer protection (P = .03). The MBL2*HYPA haplotype was significantly associated with protection (P = .03), with significantly higher serum MBL levels in controls (P = .00073). The heterozygous 6-bp deletion in the promoter was observed to be a susceptibility factor in schistosomiasis (P = .03). CONCLUSIONS: In agreement with findings from our recently published study, the findings reported here support the observation that MBL is also associated with protection in schistosomiasis. PMID- 23448727 TI - Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity. AB - BACKGROUND: Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced. METHODS: We treated P. falciparum malaria in 215 Malian children aged 0.5-15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring parasite density every 6 hours until undetectable and evaluated the effects of age, sex, ethnicity, and red blood cell (RBC) polymorphisms on half life. We quantified the proportion of parasitized RBCs recognized by autologous immunoglobulin G (IgG). RESULTS: The geometric mean half-life was 1.9 hours (95% confidence interval, 1.8-2.0) and did not correlate with parasite ex vivo susceptibility to artemisinins. In a linear model accounting for host factors, half-life decreased by 4.1 minutes for every 1-year increase in age. The proportion of parasitized RBCs recognized by IgG correlated inversely with half life (r = -0.475; P = .0006). CONCLUSIONS: Parasite clearance in response to artesunate is faster in Mali than in southeast Asia. IgG responses to parasitized RBCs shorten half-life and may influence this parameter in areas where age is not an adequate surrogate of immunity and correlates of parasite-clearing immunity have not been identified. CLINICAL TRIALS REGISTRATION: NCT00669084. PMID- 23448730 TI - Low-dose recombinant activated factor VII temporally stopped bleeding from small artery in severe postpartum hemorrhage: a case report. AB - Recombinant activated factor VII has been used to effectively treat uncontrolled massive hemorrhage at parturition in an off-label manner. Interventional radiology, including vessel embolization of the internal iliac artery or uterine artery for postpartum hemorrhage, is now familiar to obstetricians. However, this therapeutic technique is applicable only in patients who are hemodynamically stable. We encountered a case with severe and uncontrolled postpartum bleeding from the vaginal fornix. The patient received a low dose (<20 MUg/kg) of factor VIIa and subsequently underwent vessel embolization. We herein report that this stepwise treatment was very effective for uncontrolled bleeding. PMID- 23448731 TI - Subsets of preterm and term infants: call for consistency in terminology. PMID- 23448732 TI - Sudden sensorineural hearing loss: an otologic emergency. AB - The study purpose was to determine the efficacy of steroids, volume expanders and antivirals in the management of idiopathic sudden sensory neural hearing loss and to establish importance of early medical intervention. In this prospective study, thirty-four patients presenting with idiopathic sudden hearing loss of 30 db or more were enrolled in study group between 2005 and 2009. Patient variables as they related to recovery were studied and include patient age, time to onset of therapy, status of contralateral ear, presence of diabetes, severity of hearing loss, pattern of hearing loss in audiogram and presence of associated symptoms, (tinnitus, vertigo). Treatment protocol with intravenous hydrocortisone, intravenous dextran and oral anti-viral agent was followed. Pre-treatment and post-treatment pure tone average was analyzed. With combination therapy the overall improvement in pure tone threshold was seen in 27 patients (79.4%). A statistically significant association was found between the time at which medical intervention was started and hearing improvement. Early intervention in patients presenting before 3 days has given 77.8% complete type 1 recovery Idiopathic sudden sensory neural hearing loss is a medical emergency. It should not be misdiagnosed. Early detection and management with volume expanders, steroids and antivirals will improve the chances of complete recovery. PMID- 23448733 TI - Couples and cancer. PMID- 23448734 TI - We've come a long way: a review of cancer pain management. PMID- 23448735 TI - Succession planning in oncology nursing: a professional must-have. PMID- 23448736 TI - Management of pancreatic exocrine insufficiency. PMID- 23448737 TI - The relationships among coping strategies, religious coping, and spirituality in African American women with breast cancer receiving chemotherapy. AB - PURPOSE/OBJECTIVES: To (a) examine coping capacity, psychological distress, spiritual well-being, positive and negative religious coping, and coping strategies among African American (AA) women with breast cancer, and (b) explore relationships among these variables to enhance an already tested comprehensive coping strategy program (CCSP) intervention for AA women with breast cancer (CCSP AA). DESIGN: Descriptive-correlational. SETTING: Comprehensive cancer center in Maryland. SAMPLE: 17 AA women with breast cancer. METHODS: Women completed the Hospital Anxiety and Depression Scale, Sense of Coherence scale, Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, Brief Religious Coping Inventory, and Coping Strategies Questionnaire. MAIN RESEARCH VARIABLES: Psychological distress, coping capacity, coping strategies, religious coping, and spiritual well-being. FINDINGS: A higher coping capacity was beneficial, as it was related to less psychological distress, negative religious coping, and catastrophizing. Women using less negative religious coping had greater spiritual well-being and less distress. Using more coping self-statements was associated with higher spiritual well-being and less negative religious coping. Catastrophizing had a negative effect on psychological distress and spiritual well-being. CONCLUSIONS: The development of a CCSP-AA that incorporates aspects of spirituality and components in a coping intervention needs to be tested in a clinical trial. The intervention will teach patients to recognize and restructure their thinking to avoid catastrophizing and negative religious coping. IMPLICATIONS FOR NURSING: Nurses need to work collaboratively with AA women to reinforce beneficial coping patterns and approaches. A tailored CCSP-AA for women with breast cancer administered by a nurse can be taught to assist AA patients in coping more effectively. KNOWLEDGE TRANSLATION: AA women with breast cancer use more positive religious coping and experience less distress and greater spiritual well-being, but catastrophizing has a negative effect on spiritual well-being. Nurses need to reinforce positive coping patterns for AA women with cancer. PMID- 23448738 TI - The relationship between learned resourcefulness and cancer-related fatigue in patients with non-Hodgkin lymphoma. AB - PURPOSE/OBJECTIVES: To investigate the effect of learned resourcefulness on fatigue symptoms in patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy. DESIGN: Quasi-experimental with repeated measures. SETTING: Two large hospitals in Israel. SAMPLE: 46 patients with NHL. METHODS: On the first day of a cycle of chemotherapy treatment, participants completed questionnaires assessing fatigue and learned resourcefulness. Fatigue was assessed again after 10 and 21 days. MAIN RESEARCH VARIABLES: Cancer-related fatigue, learned resourcefulness. FINDINGS: Fatigue increased 10 days following chemotherapy treatment and returned to pretreatment levels at day 21. Learned resourcefulness correlated negatively with each of the three measurements of fatigue. In addition, a calculated partial correlation showed the specific effect of learned resourcefulness on chemotherapy-related fatigue. CONCLUSIONS: The findings showed a negative correlation between a physiologic variable (fatigue) and a psychological variable (learned resourcefulness), which is related to individual coping ability. IMPLICATIONS FOR NURSING: Nurses should receive education about learned resourcefulness to potentially help patients with cancer cope with chemotherapy-related fatigue. KNOWLEDGE TRANSLATION: As learned resourcefulness was negatively correlated with chemotherapy-related fatigue in patients with NHL, having this personality trait may help those patients manage fatigue. PMID- 23448739 TI - Stress reactivity, health behaviors, and compliance to medical care in breast cancer survivors. AB - PURPOSE/OBJECTIVES: To explore relationships among quality of life (QOL), stress reactivity, health behaviors, and compliance to medical care in breast cancer survivors. DESIGN: One-time descriptive laboratory study. SETTING: A visual motor laboratory at a rural university in the southeastern United States. SAMPLE: 25 breast cancer survivors. METHODS: Participants were subjected to the Trier Social Stress Test (TSST) in a laboratory setting and completed questionnaires at home prior to and after the laboratory session. main research variables: Changes in heart rate variability (HRV), salivary cortisol, and state anxiety from the State Trait Anxiety Inventory (STAI) estimated stress reactivity. Health behaviors, QOL, and trait anxiety were determined by questionnaires. Compliance to medical care was determined from medical records. FINDINGS: Analyses of variance (ANOVAs) indicated that QOL scores were higher for participants with lower compared to higher stress reactivity (p < 0.05). In addition, ANOVAs revealed that participants high in compliance to medical care indicated a lower stress response as determined by HRV (p < 0.01) and the STAI (p < 0.05) compared to those low in compliance. No significant differences were noted in any of the health behaviors based on stress reactivity. CONCLUSIONS: The data suggest that breast cancer survivors who indicate the greatest stress reactivity tend to have the poorest compliance to medical care and lowest QOL. IMPLICATIONS FOR NURSING: Nurses may wish to provide additional support to breast cancer survivors who indicate high stress reactivity in the hopes of improving compliance to medical care and QOL. KNOWLEDGE TRANSLATION: The data suggest that supportive care strategies that reduce stress could potentially improve compliance to medical care in breast cancer survivors. In addition, strategies for managing stress may result in improvements in QOL. Health behaviors, according to the data, do not seem to be influenced by stress reactivity. PMID- 23448740 TI - Demographic and disease characteristics associated with non-hodgkin lymphoma survivors' quality of life: does age matter? AB - PURPOSE/OBJECTIVES: To examine demographic and disease characteristics by age and the moderating effect of age on quality of life (QOL) among non-Hodgkin lymphoma (NHL) survivors. DESIGN: A cross-sectional, secondary analysis study of NHL survivors. SETTING: Two North Carolina cancer registries. SAMPLE: 741 NHL survivors with a mean age of 62 years and a mean time since diagnosis of 10 years. METHODS: Mailed surveys were sent to individuals treated for NHL. All analyses were conducted using SPSS(r), version 18.0. Multiple regression was used to analyze relationships among demographic and disease characteristics, age, and QOL. MAIN RESEARCH VARIABLES: Demographic, disease, and clinical characteristics on QOL. FINDINGS: In relation to QOL, income and gender were moderated by age; for example, younger survivors who earned less than $30,000 annually had a poorer QOL. Women reported a higher QOL than men. CONCLUSIONS: Age was a moderator for income and an indicator for how income could affect care of younger survivors. Men reported a lower QOL than women and gender-specific resources may be helpful to them. IMPLICATIONS FOR NURSING: Nursing research should focus on age-sensitive resources targeted for younger NHL survivors. KNOWLEDGE TRANSLATION: Age is an important characteristic that impacts overall health-related QOL. Oncology nurses are instrumental in identifying patients at all ages who could benefit from age specific resources. PMID- 23448741 TI - Ginger as an antiemetic modality for chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis. AB - PURPOSE/OBJECTIVES: To evaluate the effect of ginger as an antiemetic modality for the control of chemotherapy-induced nausea and vomiting (CINV). DATA SOURCES: Databases searched included MEDLINE(r) (PubMed), Embase, CINAHL(r), Cochrane Central Register of Controlled Trials, Korean Studies Information Service System, Research Information Sharing Service by the Korean Education and Research Information Service, and Dissertation Central. DATA SYNTHESIS: A systematic review was conducted of five randomized, controlled trials involving 872 patients with cancer. Ginger was compared with placebo or metoclopramide. The participant characteristics, chemotherapy regimen and antiemetic control, ginger preparation and protocol, measurements, results of the studies, adherence to the treatment protocol, and side effects were reviewed systematically. The incidence and severity of acute and delayed CINV were subject to meta-analysis. The incidence of acute nausea (p = 0.67), incidence of acute vomiting (p = 0.37), and severity of acute nausea (p = 0.12) did not differ significantly between the ginger and control groups. CONCLUSIONS: Current evidence does not support the use of ginger for the control of CINV. Ginger did not contribute to control of the incidence of acute nausea and vomiting or of the severity of acute nausea. IMPLICATIONS FOR NURSING: Ginger has long been regarded as a traditional antiemetic modality, but its effectiveness remains to be established. The findings of this study could be incorporated into clinical guidelines, such as the Oncology Nursing Society's Putting Evidence Into Practice resources. Current evidence supports the need for more methodologically rigorous studies in this area. KNOWLEDGE TRANSLATION: Although ginger is known as a traditional antiemetic, current evidence does not support the effect of ginger in CINV control. The findings of this study inform healthcare providers that its effectiveness remains to be established from methodologically rigorous future trials. PMID- 23448742 TI - Sleep characteristics of family caregivers of individuals with a primary malignant brain tumor. AB - PURPOSE/OBJECTIVES: To describe the sleep characteristics of family caregivers of individuals with a primary malignant brain tumor (PMBT). DESIGN: Cross-sectional, correlational design using baseline data from a longitudinal study. SETTING: Neuro-oncology and neurosurgery clinics at an urban tertiary medical center in the United States. SAMPLE: 133 family caregivers recruited one to two months following diagnosis of family member's PMBT. METHODS: Subjective and objective measures of sleep were obtained via self-report and the use of accelerometers (three nights). MAIN RESEARCH VARIABLES: Sleep characteristics including sleep latency, total sleep time, wake after sleep onset, number of naps, number of arousals, sleep-wake cycle, and sleep quality. FINDINGS: Sleep latency in caregivers was, on average, 35 minutes (SD = 34.5)-more than twice as long as the norm of 15 minutes (t[113]) = 6.18, p < 0.01). Caregivers averaged a total sleep time of 5 hours and 57 minutes (SD = 84.6), significantly less than the recommended 7 hours (t[113] = -8, p < 0.01), and were awake in the night 15% of the time, significantly more than the norm of 10% (t[111] = 5.84, p < 0.01). Caregivers aroused an average of 8.3 times during nocturnal sleep (SD = 3.5, range = 2-21), with about 32% reporting poor or very poor sleep quality. CONCLUSIONS: Caregivers experienced sleep impairments that placed them at risk for poor mental and physical health, and may compromise their ability to continue in the caregiving role. IMPLICATIONS FOR NURSING: Nurses need to assess sleep in caregivers of individuals with PMBT and implement interventions to improve sleep. KNOWLEDGE TRANSLATION: Sleep deprivation is common in family caregivers during the early stages of care for individuals with a PMBT. A single-item sleep quality question could be an easy but valuable tool in assessing sleep disturbances in family caregivers of individuals with a PMBT. The health trajectory of family caregivers warrants further longitudinal study, in addition to the examination of the bidirectional relationship of health status of care recipients and their family caregiver. PMID- 23448743 TI - Evaluation of a compassion fatigue resiliency program for oncology nurses. AB - PURPOSE/OBJECTIVES: To evaluate a resiliency program designed to educate oncology nurses about compassion fatigue. DESIGN: Descriptive pilot study. SETTING: A National Cancer Institute-designated comprehensive cancer center in the midwestern United States. SAMPLE: 13 oncology nurses employed in an outpatient infusion center. METHODS: Nurses attended a five-week program involving five 90 minute sessions on compassion fatigue resiliency. A pre- and post-test design, using repeated measures, was conducted over six months. MAIN RESEARCH VARIABLES: Scores on the Professional Quality of Life (ProQOL) IV, Maslach Burnout Inventory Human Services Survey, Impact of Event Scale-Revised (IES-R), and the Nursing Job Satisfaction Scale. FINDINGS: Long-term benefits were realized from the program. Secondary traumatization scores on the ProQOL IV declined immediately after the program, remained down at three months, and then dropped again at six months, with a statistically significant mean difference compared with baseline. The average IES-R total scores improved significantly overall and for each of the three postintervention time points. Participants evaluated the program positively with respect to their ability to apply and benefit from resiliency techniques. CONCLUSIONS: This is the first reported study to show benefits gained from a compassion fatigue intervention program. Participants received useful strategies for managing stress at work and home. IMPLICATIONS FOR NURSING: Compassion fatigue is a prevalent condition among healthcare providers. Development of resiliency to compassion fatigue may improve decision making, clarity of communication, and patient and nurse satisfaction. KNOWLEDGE TRANSLATION: Self regulation offers an approach to reduce stress during a perceived threat. Working by intention reduces reactivity in the workplace and makes communication more intentional and, therefore, effective. PMID- 23448745 TI - Cannabinoids may be therapeutic in breast cancer. PMID- 23448746 TI - The beneficial effect of ST-36 (Zusanli) acupressure on postoperative gastrointestinal function in patients with colorectal cancer. AB - PURPOSE/OBJECTIVES: To evaluate the effectiveness of ST-36 (Zusanli) acupressure on recovery of postoperative gastrointestinal function in patients with colorectal cancer. DESIGN: A longitudinal, randomized, controlled trial design. SETTING: An urban medical center in Taiwan. SAMPLE: 60 patients with colorectal cancer who had undergone abdominal surgery. METHODS: Patients were randomly assigned to two groups, the ST-36 acupressure group (n = 30) and a sham acupressure group (n = 30). Patients in the ST-36 group received an acupressure procedure in a three-minute cycle performed three times per day during the five days after surgery. Patients in the control group received routine postoperative care and sham acupressure. Generalized estimating equations (GEEs) were used to gauge longitudinal effects of the two groups of patients. MAIN RESEARCH VARIABLES: Frequency of bowel sounds, the time to first flatus passage, first liquid intake, solid intake, and defecation. FINDINGS: Patients who received acupressure had significantly earlier flatus passage and time to liquid intake as compared to patients in the control group. Other main variables, including the first time to solid intake and defecation, did not show significant difference between the two groups. The GEE method revealed that all patients had increasing bowel sounds over time, and the experimental group had greater improvement of bowel motility than the control group within the period of 2-3 days postoperatively. CONCLUSIONS: ST-36 acupressure was able to shorten the time to first flatus passage, oral liquid intake, and improve gastrointestinal function in patients after abdominal surgery. IMPLICATIONS FOR NURSING: ST-36 acupressure can be integrated into postoperative adjunct nursing care to assist patients' postoperative gastrointestinal function. KNOWLEDGE TRANSLATION: Few studies have explored the effectiveness of acupressure techniques on promoting bowel sounds. Evidence from this study suggests stimulation of the ST-36 acupressure point can increase bowel sound frequency for patients with colorectal cancer in the first three days after surgery. Application of this technique may improve a patient's comfort after surgery. PMID- 23448747 TI - Do older adults with cancer fall more often? A comparative analysis of falls in those with and without cancer. AB - PURPOSE/OBJECTIVES: To examine whether a history of cancer increased the likelihood of a fall in community-dwelling older adults, and if cancer type, stage, or time since diagnosis increased falls. DESIGN: A longitudinal, retrospective, cohort study. SETTING: A home- and community-based waiver program in Michigan. SAMPLE: 862 older adults aged 65 years or older with cancer compared to 8,617 older adults without cancer using data from the Minimum Data Set-Home Care and Michigan cancer registry. METHODS: Reports of falls were examined for 90 180 days. Generalized estimating equations were used to compare differences between the groups. MAIN RESEARCH VARIABLES: Cancer, falls, patient characteristics, comorbidities, medications, pain, weight loss, vision, memory recall, and activities, as well as cancer type, stage, and time since diagnosis. FINDINGS: A fall occurred at a rate of 33% in older adults with cancer compared to 29% without cancer (p < 0.00). Those with a history of cancer were more likely to fall than those without cancer (adjusted odds ratio 1.16; 95% confidence interval [1.02, 1.33]; p = 0.03). No differences in fall rates were determined by cancer type or stage, and the odds of a fall did not increase when adding time since cancer diagnosis. CONCLUSIONS: The fall rate was higher in older adults with cancer than in older adults without cancer. IMPLICATIONS FOR NURSING: Nurses need to assess fall risk and initiate fall prevention measures for older adults at the time of cancer diagnosis. KNOWLEDGE TRANSLATION: When caring for older adults with cancer, nurses should be aware of an increased risk for falls. Healthcare staff also should be aware of an increased risk for falls in that population during cancer treatment. Evidence-based fall prevention measures should be included in care plans for older adult cancer survivors. PMID- 23448748 TI - Development and validation of a chemotherapy-induced taste alteration scale. AB - PURPOSE/OBJECTIVES: To develop an instrument to assess the specific symptoms of chemotherapy-induced taste alterations. DESIGN: Cross-sectional study. SETTING: Two outpatient chemotherapy centers in Kanto, Japan. SAMPLE: Convenience sample of 214 adult patients with chemotherapy-induced taste alterations. METHODS: Items on the chemotherapy-induced taste alteration scale (CiTAS) were developed by a qualitative study of patients with taste alterations, and the content validity of each item was assessed by a panel of specialized oncology nurses. Data were analyzed for item consistency using Cronbach alpha and construct validity using factor analysis. MAIN RESEARCH VARIABLES: Taste alterations, symptoms of discomfort, and impact of taste alterations on daily life. FINDINGS: An 18-item scale was developed with four dimensions identified through factor analysis: decline in basic taste, discomfort, phantogeusia and parageusia, and general taste alterations. The scale demonstrated excellent reliability (Cronbach alpha = 0.9) and test-retest reliability (r = 0.94, p < 0.001, n = 28), as well as good validity, which was indicated by its strong correlation with a visual analog scale of the impact of taste alterations on daily life (r = 0.62, p < 0.001) and by negative correlations with Short Form-8 quality-of-life measures (physical component summary, r = -0.33; mental component summary, r = -0.47). CONCLUSIONS: The CiTAS enabled valid, reliable measurement of specific symptoms of chemotherapy-induced taste alterations. The CiTAS has potential as a clinical tool and also could be used as a measure of chemotherapy-induced taste alterations in future studies. KNOWLEDGE TRANSLATION: The CiTAS may help evaluate the effectiveness of interventions to reduce the symptoms of taste alterations, such as administering zinc and self-care strategies. PMID- 23448749 TI - Mentorship in surgical training: a systematic review. AB - OBJECTIVE: This review systematically examines the literature regarding mentor mentee relationships in surgery. BACKGROUND: The usefulness of mentorship in surgical training has been expressed in many articles. However, to date, there has been no systematic review on mentoring surgical trainees. This surgical environment is different from other areas of medicine and requires young surgeons to learn skills not readily available from textbooks. Instead, mentors are a valuable mode of transferring this knowledge to the next generation of surgeons. Thus, mentorship is a worthy area of research and attention. METHODS: We identified all articles discussing mentorship in surgery between January 1985 and August 2010 using PubMed and ISI Web of Knowledge. Predetermined exclusion and inclusion criteria were used to screen articles by title, abstract, and full text in sequence. We extracted the relevant data, and then analyzed the prevalence of major surgical mentoring themes in the literature. RESULTS: Of the 1,091 unique articles found during our original literature search, 38 were selected for review. The majority (68%) were commentary/editorial articles. The most discussed themes include the desirable qualities of a surgical mentor, the structure of mentor-mentee relationships, and advice for overcoming barriers to mentoring. Much less discussed themes include the desirable traits in a mentee and the appreciation of generational and cultural differences in mentorship. CONCLUSIONS: Several barriers to effective surgical mentoring were identified, such as time constraints and a lack of female mentors. By focusing on the positive traits found in this review, for example, developing formal programs to alleviate time constraints, these barriers can be overcome and effective mentor-mentee relationships can be built. Many articles draw attention to the dying art of mentorship in surgical training programs, and currently, the literature on mentorship in surgery is somewhat scarce. These concerns should serve as motivation to revive mentorship in surgery education and to expand the literature regarding underexplored themes and overcoming the current barriers. Although mentorship may not always take on a structured form, it should not be treated casually because proper mentorship is the foundation for training quality surgeons. PMID- 23448750 TI - What proportion of sexually transmissible infections and HIV are diagnosed in New South Wales' public sexual health services compared with other services? AB - BACKGROUND: In New South Wales (NSW), publicly funded sexual health services (PFSHSs) target the populations at greatest risk for important sexually transmissible infections (STIs) and so may make a large contribution to the diagnosis of notifiable STIs. We aimed to determine the proportions of STIs diagnosed in PFSHSs and notified to the NSW Ministry of Health in 2009, and describe geographical variations. METHODS: The number of notifiable STIs (infectious syphilis, gonorrhoea, HIV and chlamydia) diagnosed in 2009 was obtained for each Area Health Service (AHS) and each PFSHS. The proportion of diagnoses made by PFSHSs was calculated at the state and AHS level according to five geographical regions: inner and outer metropolitan, regional, rural and remote. RESULTS: The overall proportions of diagnoses made by NSW PFSHSs were syphilis, 25%; gonorrhoea, 25%; HIV, 21%; and chlamydia, 14%. Within each zone, the proportions of these STIs were (respectively): (i) inner metropolitan: 32%, 26%, 21% and 13%; (ii) outer metropolitan: 41%, 24%, 43% and 9%; (iii) regional: 62%, 15%, 23% and 10%; (iv) rural: 8%, 29%, <5% and 20%; and (v) remote: <5%, 43%, <5% and 29%. There was considerable variation in proportions of STIs between and within AHSs (<5-100%). CONCLUSIONS: NSW PFSHSs contribute a large proportion of diagnoses for syphilis, gonorrhoea and HIV, but less so for chlamydia. Across AHSs and zones, there was considerable variation in the proportions. These data support the role of PFSHS in identifying and managing important STIs in high-risk populations. PMID- 23448751 TI - Performance of a new dynamic model for predicting diurnal time courses of stomatal conductance at the leaf level. AB - Under natural conditions, plants are subjected to continuous changes of irradiance that drive variations of stomatal conductance to water vapour (g(s)). We propose a dynamic model to predict the temporal response of g(s) at the leaf level using an asymmetric sigmoid function with a unique parameter describing time constants for increasing and decreasing g(s). The model parameters were adjusted to observed data using Approximate Bayesian Computation. We tested the model performance for (1) instant changes of irradiance; or (2) continuous and controlled variations of irradiance simulating diurnal time courses. Compared with the two mostly used steady-state models, our dynamic model described daily time courses of g(s) with a higher accuracy. In particular, it was able to describe the hysteresis of g(s) responses to increasing/decreasing irradiance and the resulting rapid variations of intrinsic water-use efficiency. Compared to the mechanistic model of temporal responses of g(s) by Kirschbaum, Gross & Pearcy, for which time constants were estimated with a large variance, our model estimated time constants with a higher precision. It is expected to improve predictions of water loss and water-use efficiency in higher scale models by using a small number of parameters. PMID- 23448752 TI - Socio-economic, clinical and biological risk factors for mother - to - child transmission of HIV-1 in Muhima health centre (Rwanda): a prospective cohort study. AB - BACKGROUND: Three decades since the first HIV-1 infected patients in Rwanda were identified in 1983; the Acquired Immunodeficiency Syndrome epidemic has had a devastating history and is still a major public health challenge in the country. This study was aimed at assessing socioeconomic, clinical and biological risk factors for mother - to - child transmission of HIV- in Muhima health centre (Kigali/Rwanda). METHODS: The prospective cohort study was conducted at Muhima Health centre (Kigali/Rwanda).During the study period (May 2007 - April 2010), of 8,669 pregnant women who attended antenatal visits and screened for HIV-1, 736 tested HIV-1 positive and among them 700 were eligible study participants. Hemoglobin, CD4 count and viral load tests were performed for participant mothers and HIV-1 testing using DNA PCR technique for infants.Follow up data for eligible mother-infant pairs were obtained from women themselves and log books in Muhima health centre and maternity, using a structured questionnaire.Predictors of mother-to-child transmission of HIV-1 were assessed by multivariable logistic regression analysis. RESULTS: Among the 679 exposed and followed-up infants, HIV 1 status was significantly associated with disclosure of HIV status to partner both at 6 weeks of age (non-disclosure of HIV status, adjusted odds ratio [AOR] 4.68, CI 1.39 to 15.77, p < 0.05; compared to disclosure) and at 6 months of age (non-disclosure of HIV status, AOR, 3.41, CI 1.09 to 10.65, p < 0.05, compared to disclosure).A significant association between mother's viral load (HIV-1 RNA) and infant HIV-1 status was found both at 6 weeks of age (> = 1000 copies/ml, AOR 7.30, CI 2.65 to 20.08, p < 0.01, compared to <1000 copies/ml) and at 6 months of age (> = 1000 copies/ml, AOR 4.60, CI 1.84 to 11.49, p < 0.01, compared to <1000 copies/ml). CONCLUSION: In this study, the most relevant factors independently associated with increased risk of mother - to - child transmission of HIV-1 included non-disclosure of HIV status to partner and high HIV-1 RNA. Members of this cohort also showed socioeconomic inequalities, with unmarried status carrying higher risk of undisclosed HIV status. The monitoring of maternal HIV-1 RNA level might be considered as a routinely used test to assess the risk of transmission with the goal of achieving viral suppression as critical for elimination of pediatric HIV, particularly in breastfeeding populations. PMID- 23448753 TI - Proximal tibial derotation osteotomy for torsion of the tibia: a review of 43 cases. AB - PURPOSE: Persistent tibial torsion in the older child can be treated with a derotation osteotomy. Distal tibial osteotomy has been recommended due to concerns of peroneal nerve palsy, vascular injury, and compartment syndrome with a proximal tibial osteotomy. However, an osteotomy in the proximal tibia may achieve union more rapidly and skin issues, as described for distal tibial osteotomies, are less likely. This study investigates the safety and efficacy of proximal tibial derotation osteotomies. METHODS: We retrospectively reviewed 43 tibiae in 25 consecutive children with persistent tibial torsion treated with a proximal tibial derotation osteotomy between 1991 and 2006. Patients with concomitant varus or valgus osteotomies were excluded. Diaphyseal fibular osteotomies were performed in five patients, while all patients had a prophylactic anterior compartment fasciotomy. RESULTS: The mean age at surgery was 10.4 +/- 4.0 years and the mean follow-up was 3.2 +/- 3.5 years. Patients with internal tibial torsion had a mean preoperative thigh-foot angle (TFA) of 14 degrees +/- 6 degrees and a mean postoperative TFA of 8 degrees +/- 4 degrees . Patients with external tibial torsion had a mean preoperative TFA of 38 degrees +/- 9 degrees and a mean postoperative TFA of 7 degrees +/- 5 degrees . The overall mean correction was 26 degrees +/- 9 degrees . Major postoperative complications occurred in 4 patients (9%), including one peroneal nerve palsy which resolved, one delayed union requiring revision surgery, and two patients with mild postoperative valgus deformities. CONCLUSIONS: Proximal tibial derotation osteotomy with an anterior compartment fasciotomy is a reliable method for treating tibial torsion with an acceptable complication rate. Given the larger bony surface area and improved soft tissue envelope, proximal tibial derotation osteotomy can be considered as an alternative to a distal tibial derotation osteotomy. PMID- 23448754 TI - Identification of thermophilic bacterial strains producing thermotolerant hydrolytic enzymes from manure compost. AB - Ten thermophilic bacterial strains were isolated from manure compost. Phylogenetic analysis based on 16S rRNA genes and biochemical characterization allowed identification of four different species belonging to four genera: Geobacillus thermodenitrificans, Bacillus smithii, Ureibacillus suwonensis and Aneurinibacillus thermoaerophilus. PCR-RFLP profiles of the 16S-ITS-23S rRNA region allowed us to distinguish two subgroups among the G. thermodenitrificans isolates. Isolates were screened for thermotolerant hydrolytic activities (60-65 degrees C). Thermotolerant lipolytic activities were detected for G. thermodenitrificans, A. thermoaerophilus and B. smithii. Thermotolerant protease, alpha-amylase and xylanase activities were also observed in the G. thermodenitrificans group. These species represent a source of potential novel thermostable enzymes for industrial applications. PMID- 23448755 TI - Post-lithography pattern modification and its application to a tunable wire grid polarizer. AB - This study reports a simple and cost-effective post-lithography solution for reducing the characteristic dimensions of structures on the nanometer scale using an external mechanical force without any modification of the existing exposure system. In particular, this study presents a tunable aluminum wire grid polarizer (WGP) made by a laser interference lithography and i-line (365 nm) exposure setup on polyethylene naphthalate. The WGP achieves a 58% maximum linewidth shrinkage of the metal nanowire on the polymer substrate, and further improved the polarization extinction ratio by 83% with a defined operation window and optimized strain. The simulations in this study prove the rise of the extinction ratio with the modulation of the WGP pattern. Physical evidence explains the fall of the extinction ratio for both the increase of the metal crack volume and the delaminated randomly oriented fall-on fragments under extensive operation. PMID- 23448756 TI - Lattice dynamics and pressure-induced phase transitions in alpha-BaTeMo2O9. AB - Orthorhombic alpha-BaTeMo2O9 nonlinear optical single crystals were investigated at ambient pressure by micro-Raman and infrared spectroscopy with a focus on the polarization properties of the vibrational modes. These results were analyzed based on classical lattice dynamics calculations, allowing us to propose the normal-mode symmetries and assignments. In addition to the ambient-pressure studies, high-pressure Raman scattering studies were performed. These studies showed the onset of a reversible first-order phase transition near 3.5 GPa. The pressure dependence of Raman bands provides strong evidence that the phase transition involves significant distortion of the TeOx (x = 3,4) polyhedra, whereas the MoO6 octahedra are less affected. A large increase in the number of observed bands points to lower symmetry of the high-pressure phase. PMID- 23448757 TI - Chemotaxis and oospore formation in Phytophthora sojae are controlled by G protein-coupled receptors with a phosphatidylinositol phosphate kinase domain. AB - G-protein-coupled receptors (GPCRs) are key cellular components that mediate extracellular signals into intracellular responses. Genome mining revealed that Phytophthora spp. have over 60 GPCR genes among which a prominent class of 12 encoding novel proteins with an N-terminal GPCR domain fused to a C-terminal phosphatidylinositol phosphate kinase (PIPK) domain. This study focuses on two GPCR-PIPKs (GKs) in Phytophthora sojae. PsGK4 and PsGK5 are differentially expressed during the life cycle with the highest expression in cysts and during cyst germination, and at late infection stages. In P. sojae transformants that constitutively express RFP-tagged PsGK4 and PsGK5, the fusion proteins in hyphae reside in small, rapidly moving vesicular-like structures. Functional analysis using gene silencing showed that PsGK4-silenced transformants displayed higher levels of encystment and a reduced cyst germination rate when compared with the recipient strain. Moreover, GK4 deficiency (or reduction) resulted in severe defects in zoospore chemotaxis towards isoflavones and soybean roots. In contrast, PsGK5-silenced transformants exhibited no obvious defects in asexual development but oospore production was severely impaired. Both, PsGK4- and PsGK5 silenced transformants showed reduced pathogenicity. These results point to involvement of GKs in zoospore behaviour, chemotaxis and oospore development, and suggest that PsGK4 and PsGK5 each head independent signalling pathways. PMID- 23448758 TI - The pathophysiology and clinical relevance of rapid eye movement sleep behavior disorder. PMID- 23448759 TI - Significance of the presence of metabolic syndrome in patients with asymptomatic arteriosclerosis affecting the aorta and the cerebral, extra-cranial carotid and coronary arteries. AB - OBJECTIVE: The presence of metabolic syndrome (MetS) is strongly associated with stroke and cardiovascular diseases. However, the relationship between MetS and the localization of atherosclerosis at various sites remains uncertain. In this study, in order to reveal the relevance of MetS to atherosclerosis at several sites, we investigated the relationships among vascular risk factors, asymptomatic cerebral infarction and atherosclerosis in the aorta and carotid and coronary arteries in adults without overtly symptomatic cerebrovascular or cardiovascular disease. METHODS: The subjects in this study included 2,759 Japanese participants (1,845 men and 914 women, mean age: 52 years) with no history of stroke or cardiovascular events. The diagnosis of MetS was made based on modifications to criteria obtained from the National Cholesterol Education Program Adult Treatment Panel. In all subjects, the presence of cerebral infarction in the extra-cranial carotid, coronary and aortic arteries was investigated using MRI, B-mode ultrasonography and CT. RESULTS: Of the 2,759 subjects, 796 (28.9%) fulfilled the criteria for MetS. The presence of MetS increased the odds ratio (OR) to 1.89 (95% confidence interval (CI): 1.35-2.65, p value <0.0001) for asymptomatic cerebral infarction, 1.70 (95% CI: 1.37-2.10, p value <0.0001) for carotid arteriosclerosis, 2.07 (95% CI: 1.62-2.27, p-value <0.0001) for coronary calcification and 1.67 (95% CI: 1.33-2.09, p-value<0.0001) for aortic calcification. CONCLUSION: The presence of MetS was found to be significantly correlated with arteriosclerosis in all regions, including the cerebral small-vessels, extra-cranial carotid arteries, coronary arteries and abdominal aorta. MetS might be a predictor for small and large vessel disease throughout the body. PMID- 23448760 TI - Stroke knowledge: a nationwide, internet-based survey of 11,121 inhabitants in Japan. AB - OBJECTIVE: Stroke awareness among the general public is considered beneficial for improving stroke prevention and rapid responses to stroke onset. METHODS: An internet-based questionnaire survey designed to assess the degree of understanding of strokes was administered to over 10,000 people >=20 years of age from across Japan between November 8 to 11, 2010. RESULTS: Valid responses were obtained from 11,121 persons aged 44.8+/-13.1 years. Only 10.3% of the respondents answered that they had a good understanding of what sort of disease stroke is, and only 33.8% responded that they had access to information on strokes; these proportions increased with age. The information sources included television (85.2%) and newspapers (34.1%), with newspaper use increasing with age. Among the respondents, 95.5% recognized speech disturbance and 89.5% recognized hemiplegia as symptoms of stroke; however, only 2.3% stated that they could confidently identify stroke occurrence. For responses to stroke onset, 67.0% of the responders stated that they would call an ambulance, compared to only 22.4% for transient ischemic attacks. In both cases, the proportions were higher among older respondents. A logistic regression analysis showed that the factors contributing to recommending early transportation by ambulance were knowledge of stroke symptoms (odds ratio (OR): 1.579; p=0.00), knowledge of stroke risk factors (OR: 1.294; p=0.00) and experience of living with stroke patients (OR: 1.374; p=0.00). CONCLUSION: Although the survey was conducted over the internet and the respondents may have tended to be relatively young, knowledge of strokes and understanding of the correct actions to take were higher among the older respondents. Overall, the knowledge of strokes was considered to be insufficient. PMID- 23448761 TI - Anxiety and depression in patients with Parkinson's disease. AB - OBJECTIVE: To investigate the prevalence and clinical correlates of anxiety and depression in patients with Parkinson's disease (PD) and to examine the relationship between anxiety and depression and the quality of life (QOL). METHODS: One hundred and seventeen patients with PD completed the state-trait anxiety inventory (STAI), the beck depression inventory second edition (BDI-II), Starkstein's apathy scale (AS) and QOL battery. Hoehn and Yahr (HY) staging, the unified Parkinson's disease rating scale (UPDRS) and the mini-mental state examination (MMSE) were administered on the same day. RESULTS: Anxiety (STAI score >=41 for men or >=42 for women) was diagnosed in 55% of the patients and depression (BDI-II score >=14) was diagnosed in 56% of the patients. Anxiety coexisted with depression in 41% of the patients, while depression without anxiety was observed in 15% of the patients and anxiety without depression was observed in 14% of the patients. The STAI score was found to be significantly correlated with the UPDRS (I, IV) and AS scores, whereas the BDI-II score was found to correlate with the HY stage and the UPDRS (I, III, IV) and AS scores. Both the STAI and BDI-II scores were found to negatively correlate with QOL. A multivariate analysis revealed that depression and anxiety are similarly associated with the PD specific QOL (PDQ-39), while motor severity, as judged by the HY stage and UPDRS III score, is not. CONCLUSION: These findings indicate that recognizing anxiety and depression in patients with PD is important, since both conditions are commonly observed in patients with PD and are similarly associated with the QOL, independent of motor severity. PMID- 23448762 TI - Ulcerative colitis accompanied by idiopathic thrombocytopenic purpura and Helicobacter pylori infection. AB - The coexistence of idiopathic thrombocytopenic purpura (ITP) and active ulcerative colitis (UC) has been reported. We herein report a rare case of UC accompanied by ITP and Helicobacter pylori (H. pylori) infection. A female UC patient was diagnosed with ITP. At that time, the UC was almost in remission and we suspected that the ITP was caused by some factor other than UC. Accordingly, we found H. pylori infection and administered H. pylori eradication therapy. Consequently, the patient's serum platelet count recovered dramatically. Our report demonstrates the importance of conducting examinations for H. pylori infection in ITP patients, even those with UC. PMID- 23448763 TI - Necrotic hepatocellular carcinoma occurring within an inflammatory pseudotumor like nodule. AB - Hepatocellular carcinoma (HCC) and inflammatory pseudotumor of the liver (IPL) are often difficult to differentiate before surgery. To date, colocalization of IPL and HCC has not been reported. We experienced a case of necrotic HCC surrounded by IPL-like tissue. The raised levels of alpha-fetoprotein and PIVKA II declined to within the normal ranges after resection of the tumor. The IPL like nodule most likely developed as a process of an inflammatory reaction such as abscess formation after the spontaneous destruction of the HCC. Our case is a warning that the presence of a 'pseudotumor' does not rule out the possible simultaneous presence of carcinoma. PMID- 23448764 TI - Successful treatment using coil embolization of a symptomatic intrahepatic portosystemic venous shunt developing through a patent ductus venosus in a noncirrhotic adult. AB - The patient was a 60-year-old man with encephalopathy without liver cirrhosis. CT angiography revealed a patent ductus venosus between the anterior segmental branch of the portal vein and the middle hepatic vein. Coils were framed in the patent ductus venosus and then used to fill in the frame. After treatment, transarterial portography showed that the shunt flow of the ductus venosus had decreased significantly. After one day, the patient's disturbance of consciousness disappeared. Our case involved the adult-onset of a patent ductus venosus, which is extremely rare. This case is the first in which coil embolization was successfully achieved in a noncirrhotic elderly patient with a patent ductus venosus. PMID- 23448765 TI - Multiple metastatic leiomyosarcoma of the pancreas: a first case report and review of the literature. AB - A 60-year-old woman was referred to our hospital with swelling of the right leg. After surgery, leiomyosarcoma of the right leg was diagnosed. Computed tomography showed two hypovascular masses in the pancreatic body and tail that were heterogeneously enhanced compared with the pancreatic parenchyma. On endoscopic ultrasonography, the tumors in the pancreatic body and tail both exhibited regular margins and were visualized as well-circumscribed masses with uneven interiors. Distal pancreatectomy was performed under a presumptive diagnosis of metastatic pancreatic leiomyosarcoma diagnosed based on the findings of EUS-FNA. On laparotomy, peritoneal washing cytology yielded negative results, and no dissemination was observed. Ultimately, metastatic pancreatic leiomyosarcoma was histologically diagnosed. PMID- 23448766 TI - Japanese features of native valve endocarditis caused by coagulase-negative staphylococci: case reports and a literature review. AB - Although coagulase-negative staphylococci (CoNS) is a frequent cause of prosthetic valve endocarditis, native valve endocarditis (NVE) caused by CoNS is not commonly seen. Its high mortality is well known; however, there are no systematic reports published in Japan. We herein report the cases of two Japanese patients with CoNS NVE who were admitted to our hospital located in Tokyo and conduct literature searches on CoNS NVE in Japan from 1983 to March 2012 using PubMed and ICHUSHI WEB (Japan Medical Abstract Society). We also summarize the features of 22 Japanese patients with CoNS NVE, including our patients. PMID- 23448767 TI - Recovery from exocrine pancreatic insufficiency in a patient with fulminant type 1 diabetes. AB - A 34-year-old man was admitted to our hospital with diabetic ketoacidosis due to fulminant type 1 diabetes. The patient's pancreatic exocrine and endocrine functions were as follows: the bentiromide (PABA) test value on day 14 was 33.9%, thus indicating exocrine dysfunction. One year and a half later, the PABA test value had improved to 71.0%. On the other hand, the serum C-peptide level after meal ingestion was under the detection limit. The mechanisms underlying pancreatic exocrine abnormalities seem to be different from those underlying accelerated pancreatic beta-cell failure in patients with fulminant type 1 diabetes. PMID- 23448768 TI - Familial hypercholesterolemia with multiple large tendinous xanthomas and advanced coronary artery atherosclerosis. AB - We herein report the case of a 53-year-old man with severe coronary ischemia who underwent successful coronary artery bypass surgery. Of note, he had hypercholesterolemia and presented with multiple large tendinous xanthomas and thickened Achilles tendons that had been present for more than two decades. Together with a family history of dyslipidemia, the patient was diagnosed as having familial hypercholesterolemia. Irrespective of an extensive search for possible mutations in the genes presumably involved in the patient's pathophysiology, including low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), autosomal recessive hypercholesterolemia (ARH) and apolipoprotein B (APOB), we were not able to identify the gene mutations responsible for the phenotype observed in the present case. PMID- 23448769 TI - Regression of calcinosis following treatment with radiofrequency thermoablation for severe secondary hyperparathyroidism in a hemodialysis patient. AB - We herein present the case of a 41-year-old man who was misdiagnosed with a recurrent right shoulder tumor and underwent surgery twice. The pathological diagnosis was calcinosis. Secondary hyperparathyroidism was confirmed on further examination and the patient was therefore treated with two sessions of percutaneous ultrasonographically-guided radiofrequency tissue ablation. During the 20-month follow-up, the patient underwent four-hour hemodialysis three times a week. The calcinosis nearly completely resolved, and the PTH level was mildly elevated without the administration of any further medical therapy. Percutaneous ultrasonographically-guided radiofrequency tissue ablation is a feasible, safe and effective nonsurgical alternative treatment for secondary hyperparathyroidism. PMID- 23448770 TI - Periaortitis associated with anti-neutrophil cytoplasmic antibodies induced by bevacizumab combination therapy. AB - Drug-induced vessel vasculitis is a rare complication of chemotherapy. In particular, few reports have investigated drug-induced large vessel vasculitis. We herein report the case of a 57-year-old woman with advanced lung adenocarcinoma who developed perinuclear anti-neutrophil cytoplastic antibodies (p-ANCA)-positive periaortitis induced by bevacizumab combination chemotherapy. With the increasing use of combination therapy with bevacizumab, the incidence of vascular complications will potentially increase. A noninfectious fever occurring during chemotherapy might be a sign of vasculitis; therefore, we must ensure that possible periaortitis is not overlooked. PMID- 23448771 TI - Cytomegalovirus pneumonia in a patient with interstitial pneumonia and Nocardia asiatica presenting as cavitary lung lesions. AB - A 66-year-old man who suffered from an acute exacerbation of interstitial pneumonia developed a cavitary lesion after taking immunosuppressive drugs. He was diagnosed with cytomegalovirus (CMV) pneumonia. CMV was not thought to be the underlying cause of the cavitary lung lesions, as only six cases have been described thus far. However, this case clearly demonstrates that the development of cavitary lung lesions can be caused by CMV. Following CMV pneumonia, cavitary lesions again occurred in the patient's lungs that were thought to be the first case of cavitary lesions caused by Nocardia asiatica infection. PMID- 23448772 TI - Dose reduction or intermittent administration of erlotinib: which is better for patients suffering from intolerable toxicities? AB - Erlotinib is an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor that is widely used in the treatment of non-small cell lung cancer. Skin rashes and diarrhea are frequent side effects of erlotinib therapy. When these toxicities become intolerable, dose reduction is commonly performed. However, dose reduction may not maintain the effective dose levels in some specific situations, such as in cases of wild-type EGFR tumors or central nervous system metastases. We speculate that intermittent administration is better than dose reduction to simultaneously maintain the effective dose levels and reduce toxicities in such situations. We herein present four cases of patients who successfully received intermittent administration of erlotinib. PMID- 23448773 TI - Successful treatment with tacrolimus in a case of lung-dominant connective tissue disease. AB - A 49-year-old man with dyspnea was found to have reticular opacities and ground glass attenuation with traction bronchiectasis or bronchiolectasis on computed tomography. The patient met the criteria for lung-dominant connective tissue disease (LD-CTD) and histopathologically exhibited a chronic fibrotic interstitial pneumonia illustrating framework of a usual interstitial pneumonia like pattern. Due to worsening of the disease, therapy was initiated with corticosteroids in combination with cyclosporine A. However, treatment with these drugs was ineffective. Pirfenidone and intravenous cyclophosphamide therapy also proved ineffective. The cyclosporine A was therefore switched to tacrolimus, and the patient's disease improved, allowing for a reduction in the dose of the corticosteroids. Our experience in this case suggests that treatment with tacrolimus might be useful for treating refractory LD-CTD even when histopathologically chronic fibrotic interstitial pneumonia is evident. PMID- 23448774 TI - Oxaliplatin-induced acute thrombocytopenia: a case report and review of the literature. AB - We herein report the case of a 77-year-old woman who developed acute thrombocytopenia during the 23rd cycle of modified FOLFOX therapy. She developed a hypersensitivity reaction with nasal bleeding. The chemotherapy infusion was immediately discontinued. The patient's symptoms resolved with discontinuation of chemotherapy and the administration of supportive therapy. A complete blood count showed severe thrombocytopenia, and oxaliplatin-induced thrombocytopenia was diagnosed. The patient was admitted to the hospital, and the thrombocytopenia was corrected with a platelet transfusion followed by prednisolone. She was discharged after one week without requiring additional platelet transfusions. With the widespread use of oxaliplatin, the risk of oxaliplatin-induced acute thrombocytopenia should be considered an acute onset hematological emergency. PMID- 23448775 TI - Rapid eye movement sleep behavior disorder in a patient with brainstem lymphoma. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is common in patients with neurodegenerative diseases. RBD occurring in a patient with brainstem lymphoma has not yet been reported. A 30-year-old man had an eleven-month history of violent motor and vocal behavior during sleep. Brain magnetic resonance imaging disclosed hypointensity T1 and hyperintensity T2 signals in the pontomesencephalic junction and at the upper/mid pons level. A stereotactic biopsy demonstrated the presence of diffuse large B-cell lymphoma. On polysomnography, there was enhanced submental and limb electromyographic tone and increased muscular activity during REM sleep. Chemotherapy diminished the dream enacting behaviors. This case provides evidence that treatment aimed at the primary disease can partially improve the frequency of RBD. PMID- 23448776 TI - Successful treatment of an unresectable inflammatory myofibroblastic tumor of the frontal bone using a cyclooxygenase-2 inhibitor and methotrexate. AB - Inflammatory myofibroblastic tumor (IMT) is a disease characterized by tumorous lesions consisting of myofibroblastic spindle cells and inflammatory cells that occur primarily in the soft tissues and viscera of children and young adults. Total excision is the most effective therapy. Steroids have been used to treat unresectable lesions with some success. We herein report a case of IMT involving the frontal bone accompanied by pachymeningitis. The tumor was characterized by an aggressive clinical course that was refractory to prednisolone. Performing total excision seemed difficult. Celecoxib and methotrexate were effective treatments. Our experience suggests the efficacy of celecoxib and methotrexate as alternatives for treating unresectable IMT. PMID- 23448777 TI - Hemophagocytic syndrome in an acute human immunodeficiency virus infection. AB - Hemophagocytic syndrome (HPS) is an unrecognized complication occurring in the acute stage of human immunodeficiency virus (HIV) infection that is seldom reported in the literature. We herein present a case of HPS that occurred during the seroconversion stage of HIV infection. In this case, pancytopenia and liver dysfunction related to HPS recovered after the initiation of antiretroviral therapy (ART). This report indicates the importance of early recognition of HPS and suggests that prompt initiation of ART has the potential to control HPS in the acute stage of HIV infection. PMID- 23448778 TI - Small intestinal lipoma causing obscure gastrointestinal bleeding. PMID- 23448779 TI - Right ventricular fatty infiltration associated with cardiac sudden death. PMID- 23448780 TI - Epicarditis with late postoperative period pectus excavatum. PMID- 23448781 TI - Buerger's disease. PMID- 23448782 TI - Supraglottitis: a rare complication of betel quid chewing. PMID- 23448783 TI - Decompression illness with extensive gas bubble formation. PMID- 23448784 TI - Chicken or egg? Which one is first? Myocardial infarction or low thyroid hormones? PMID- 23448785 TI - Reply to the letter by Cakar M. Regarding "chicken or egg". Which one is first? Myocardial infarction or low thyroid hormones?". PMID- 23448786 TI - About the Bacillus cereus group. PMID- 23448787 TI - The significance of genome-based diagnosis for the Bacillus cereus species. PMID- 23448788 TI - Advances in novel diagnostic endoscopic imaging techniques in inflammatory bowel disease. AB - The description and grading of inflammation seen at endoscopic evaluation in inflammatory bowel disease (IBD) are based on conventional white light endoscopy in an era using normal definition endoscopes. The new generation of high definition endoscopes with electronic filter technology provides an opportunity to visualize mucosal inflammation in more details. The application of these new technologies in IBD is in its infancy, but the added value is beginning to be appreciated. Both the assessment of dysplasia and the assessment of inflammation may gain from use of high-definition endoscopy with filter technology. In addition, the advent of confocal laser endomicroscopy provides an opportunity to explore real-time histology, thus (perhaps) redefining our understanding of pathogenesis and nature of inflammation in IBD. We review the potential of these techniques to transform diagnostic endoscopic assessment of inflammation and dysplasia. PMID- 23448789 TI - The incidence and prevalence of inflammatory bowel disease among U.S. veterans: a national cohort study. AB - BACKGROUND: Temporal trends in incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in the United States have been reported only in regional populations. The Veterans Affairs (VA) health care system encompasses a national network of clinical care facilities. The aim of this study was to identify temporal trends in the incidence and prevalence of CD and UC among VA users using national VA data sets. METHODS: Veterans with CD and UC were identified during fiscal years 1998 to 2009 in the national VA outpatient and inpatient files. Incident and prevalent cases were identified by diagnosis code, and age-standardized and gender-standardized annual prevalence and incidence rates were estimated using the VA 1998 population as the standard population. RESULTS: The total of unique incident cases were 16,842 and 26,272 for CD and UC, respectively; 94% were men. The average annual age-standardized and gender standardized incidence rate of CD was 33 per 100,000 VA users (range, 27-40), whereas the average for UC was 50 per 100,000 VA users (range, 36-65). In 2009, the age-standardized and gender-standardized point prevalence rate of CD was 287 per 100,000 VA users, whereas the point prevalence of UC was 413 per 100,000 VA users. CONCLUSIONS: Prevalence of CD and UC increased 2-fold to 3-fold among VA users between 1998 and 2009. The incidence of UC decreased among VA users from 1998 to 2004 but has remained stable from 2005 to 2009. The incidence of CD has remained stable during the observed time period. PMID- 23448790 TI - Infliximab in steroid-dependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission. AB - BACKGROUND: Up to 20% of patients with ulcerative colitis (UC) become steroid dependent during their course. Thiopurines are recommended in steroid-dependent UC, but their efficacy is debated. Data exploring the use of infliximab in these patients are scarce. Aims of this study were to evaluate the effectiveness of infliximab in steroid-dependent UC and identify predictors of steroid-free remission, mucosal healing (MH), and colectomy. METHODS: Steroid-dependent UC patients were enrolled and intentionally treated with infliximab. The prospectively designed analyses evaluated (1) steroid-free clinical remission at 6 and 12 months, (2) steroid-free clinical remission and MH at 12 months, and (3) colectomy within 12 months. RESULTS: One hundred and twenty-six active steroid dependent UC patients were studied. Of the 126 patients, 36 patients were retrospectively included and 90 patients prospectively enrolled. Steroid-free remission was 53% and 47% at 6 and 12 months, respectively. Predictors of steroid free remission at 6 and 12 months were thiopurine-naive status (hazard ratio [HR], 2.5 and HR, 2.8, respectively) and combination therapy (HR, 2.1 and HR, 2.2, respectively). At 12 months, 32% were in steroid-free remission and MH. Thiopurine-naive status predicted steroid-free remission and MH (odds ratio, 3.6). C-reactive protein drop to normal after infliximab induction was predictive of steroid-free remission at 6 (HR, 5.9) and 12 months (HR, 4.6) and steroid-free remission and MH at 12 months (odds ratio, 6.0). Twelve patients underwent colectomy after a median of 4.7 months. Steroid sparing significantly reduced the risk of colectomy within 12 months (HR, 0.14). CONCLUSIONS: Infliximab seems effective in steroid-dependent UC. Thiopurine-naive status and combination therapy significantly increase the rate of steroid-free remission up to 12 months. PMID- 23448791 TI - Reduction of CD68+ macrophages and decreased IL-17 expression in intestinal mucosa of patients with inflammatory bowel disease strongly correlate with endoscopic response and mucosal healing following infliximab therapy. AB - BACKGROUND: Antibodies against tumor necrosis factor represent an effective therapy for patients with inflammatory bowel disease. Despite their successful results, the exact mechanism by which infliximab suppresses intestinal inflammation is still a matter of debate. In this study, we used a translational approach to identify the key mechanisms associated with resolution of mucosal inflammation induced by infliximab. METHODS: A total of 16 patients with active inflammatory bowel disease (9 with Crohn's disease and 7 with ulcerative colitis) and 16 controls were enrolled in the study. Patients received infliximab infusions at 0, 2, and 6 weeks. At enrollment and at week 6, patients underwent flexible sigmoidoscopy, and biopsies were taken from the sigmoid colon. RNA was extracted, and mucosal expression of 96 immune-related genes was evaluated by qRT PCR and confirmed by immunofluorescence microscopy on tissue. Correlation between infliximab-induced gene expression modulation and endoscopic response to therapy was calculated. Lamina propria mononuclear cell apoptosis induced by infliximab was evaluated on tissue sections by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: We found that infliximab-induced downregulation of macrophage and Th17 pathway genes was significantly associated with both endoscopic response to the therapy and achievement of mucosal healing. Importantly, the observed reduction of lamina propria CD68 macrophages was associated with an increased rate of macrophage apoptosis. CONCLUSIONS: The 2 mechanisms associated with infliximab-induced resolution of intestinal inflammation are the reduction of lamina propria infiltrating CD68 macrophages and the downregulation of interleukin 17A. Moreover, the data suggest that infliximab-induced macrophage apoptosis may represent a key mechanism for the therapeutic success of anti-tumor necrosis factor antibodies. PMID- 23448792 TI - Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. AB - BACKGROUND: Recently reported risks of colorectal cancer (CRC) in inflammatory bowel disease (IBD) have been lower than those reported before 2000. The aim of this meta-analysis was to update the CRC risk of ulcerative and Crohn's colitis, investigate time trends, and identify high-risk modifiers. METHODS: The MEDLINE search engine was used to identify all published cohort studies on CRC risk in IBD. Publications were critically appraised for study population, Crohn's disease localization, censoring for colectomy, and patient inclusion methods. The following data were extracted: total and stratified person-years at risk, number of observed CRC, number of expected CRC in background population, time period of inclusion, and geographical location. Pooled standardized incidence ratios and cumulative risks for 10-year disease intervals were calculated. Results were corrected for colectomy and isolated small bowel Crohn's disease. RESULTS: The pooled standardized incidence ratio of CRC in all patients with IBD in population based studies was 1.7 (95% confidence interval [CI], 1.2-2.2 ). High-risk groups were patients with extensive colitis and an IBD diagnosis before age 30 with standardized incidence ratios of 6.4 (95% confidence interval, 2.4-17.5) and 7.2 (95% confidence interval, 2.9-17.8), respectively. Cumulative risks of CRC were 1%, 2%, and 5% after 10, 20, and >20 years of disease duration, respectively. CONCLUSIONS: The risk of CRC is increased in patients with IBD but not as high as previously reported and not in all patients. This decline could be the result of aged cohorts. The risk of CRC is significantly higher in patients with longer disease duration, extensive disease, and IBD diagnosis at young age. PMID- 23448793 TI - Variation in management of intra-abdominal abscesses in children with Crohn's disease. AB - BACKGROUND: Complications of Crohn's disease may include intra-abdominal abscesses, which often result in hospitalization, surgery, and increased cost. There is a paucity of primary research and practice guidelines regarding optimal management in children. The study objective was to assess the current standard of care in an effort to define best practices and identify priority areas for additional research. METHODS: The web-based survey was approved by the Institutional Review Board and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. We examined preferences in imaging, drainage, anti-tumor necrosis factor-alpha therapy, and antibiotic use. We assessed for associations between provider level of experience and management strategies. RESULTS: A total of 248 of 1608 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition members responded. Of them, 64% were male, 87% practiced in the United States, and 74% practiced in an academic setting. Approximately 26% cared for >50 patients with Crohn's disease and 25% were in practice for >20 years. For initial imaging, computed tomography was chosen by 52%, followed by magnetic resonance imaging (26%) and ultrasound (21%), and upon reassessment computed tomography was chosen by 13%, magnetic resonance imaging by 33%, and ultrasound by 47%. About 77% recommended percutaneous drainage, whereas 21% would only do so if antibiotics were unsuccessful, and 2% proceed to immediate surgery. If a fistula was demonstrated, 70% planned medical therapy followed by surgical resection; only 30% planned surgical resection if no fistula was present. Approximately 55% would consider infliximab before surgery. There were no clinically significant associations between treatment strategies and practitioner experience. CONCLUSIONS: There is considerable variation in diagnostic and therapeutic interventions in the management of intra-abdominal abscesses, which was not explained by practitioner experience. PMID- 23448794 TI - Three-dimensional geometry of the Heineke-Mikulicz strictureplasty. AB - BACKGROUND: The objective of this study was to assess the regional geometry of the Heineke-Mikulicz (HM) strictureplasty. The HM intestinal strictureplasty is commonly performed for the treatment of stricturing Crohn's disease of the small intestine. This procedure shifts relatively normal proximal and distal tissue to the point of narrowing and thus increases the luminal diameter. The overall effect on the regional geometry of the HM strictureplasty, however, has not been previously described in detail. METHODS: HM strictureplasties were created in latex tubing and cast with an epoxy resin. The resultant casts of the lumens were then imaged using computed tomography. Using 3-dimensional vascular reconstruction software, the cross-sectional areas were determined and the surface geometry was examined. RESULTS: The HM strictureplasty, while increasing the lumen at the point of the stricture, also results in a counterproductive luminal narrowing proximal and distal to the strictureplasty. Within the model used, cross-sectional area was diminished 25% to 50% below baseline. This effect is enhanced when 2 strictureplasties are placed in close proximity to each other. CONCLUSIONS: The HM strictureplasty results in alterations in the regional geometry that may result in a compromise of the lumen proximal and distal to the location of the strictureplasty. When 2 HM strictureplasties are created in close proximity to each other, care should be undertaken to assure that the lumen of the intervening segment is adequate. PMID- 23448795 TI - Toward quantifying the thymic dysfunctional state in mouse models of inflammatory bowel disease. AB - Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in Galphai2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the Galphai2-deficient mice and in other mouse models of colitis. PMID- 23448796 TI - Challenges in IBD research: update on progress and prioritization of the CCFA's research agenda. PMID- 23448798 TI - Pure red cell aplasia in systemic onset juvenile idiopathic arthritis. AB - Common causes of anemia in juvenile idiopathic arthritis are anemia of chronic disease and iron deficiency. We report a 4 year old boy with biopsy proven systemic onset juvenile idiopathic arthritis and severe anemia. Bone marrow aspiration revealed pure red cell aplasia without evidence of hemophagocytosis. This rare, unexplained but well known entity responded to corticosteroids. PMID- 23448799 TI - Symptoms of delirium predict incident delirium in older long-term care residents. AB - BACKGROUND: Detection of long-term care (LTC) residents at risk of delirium may lead to prevention of this disorder. The primary objective of this study was to determine if the presence of one or more Confusion Assessment Method (CAM) core symptoms of delirium at baseline assessment predicts incident delirium. Secondary objectives were to determine if the number or the type of symptoms predict incident delirium. METHODS: The study was a secondary analysis of data collected for a prospective study of delirium among older residents of seven LTC facilities in Montreal and Quebec City, Canada. The Mini-Mental State Exam (MMSE), CAM, Delirium Index (DI), Hierarchic Dementia Scale, Barthel Index, and Cornell Scale for Depression were completed at baseline. The MMSE, CAM, and DI were repeated weekly for six months. Multivariate Cox regression models were used to determine if baseline symptoms predict incident delirium. RESULTS: Of 273 residents, 40 (14.7%) developed incident delirium. Mean (SD) time to onset of delirium was 10.8 (7.4) weeks. When one or more CAM core symptoms were present at baseline, the Hazard Ratio (HR) for incident delirium was 3.5 (95% CI = 1.4, 8.9). The HRs for number of symptoms present ranged from 2.9 (95% CI = 1.0, 8.3) for one symptom to 3.8 (95% CI = 1.3, 11.0) for three symptoms. The HR for one type of symptom, fluctuation, was 2.2 (95% CI = 1.2, 4.2). CONCLUSION: The presence of CAM core symptoms at baseline assessment predicts incident delirium in older LTC residents. These findings have potentially important implications for clinical practice and research in LTC settings. PMID- 23448800 TI - The national database of hospital-based cancer registries: a nationwide infrastructure to support evidence-based cancer care and cancer control policy in Japan. AB - Monitoring the current status of cancer care is essential for effective cancer control and high-quality cancer care. To address the information needs of patients and physicians in Japan, hospital-based cancer registries are operated in 397 hospitals designated as cancer care hospitals by the national government. These hospitals collect information on all cancer cases encountered in each hospital according to precisely defined coding rules. The Center for Cancer Control and Information Services at the National Cancer Center supports the management of the hospital-based cancer registry by providing training for tumor registrars and by developing and maintaining the standard software and continuing communication, which includes mailing lists, a customizable web site and site visits. Data from the cancer care hospitals are submitted annually to the Center, compiled, and distributed as the National Cancer Statistics Report. The report reveals the national profiles of patient characteristics, route to discovery, stage distribution, and first-course treatments of the five major cancers in Japan. A system designed to follow up on patient survival will soon be established. Findings from the analyses will reveal characteristics of designated cancer care hospitals nationwide and will show how characteristics of patients with cancer in Japan differ from those of patients with cancer in other countries. The database will provide an infrastructure for future clinical and health services research and will support quality measurement and improvement of cancer care. Researchers and policy-makers in Japan are encouraged to take advantage of this powerful tool to enhance cancer control and their clinical practice. PMID- 23448801 TI - Electrochemical current-sensing atomic force microscopy in conductive solutions. AB - Insulated atomic force microscopy probes carrying gold conductive tips were fabricated and employed as bifunctional force and current sensors in electrolyte solutions under electrochemical potential control. The application of the probes for current-sensing imaging, force and current-distance spectroscopy as well as scanning electrochemical microscopy experiments was demonstrated. PMID- 23448802 TI - Visceral adipose tissue, but not waist circumference is a better measure of metabolic risk in Singaporean Chinese and Indian men. AB - OBJECTIVES: Visceral adipose tissue (VAT) is an independent risk factor in cardiometabolic diseases and is commonly measured by computed tomography (CT). It is measured clinically by waist circumference (WC). The L4/5 intervertebral space VAT (L4/5 VAT) is traditionally used to represent total VAT volume. We set out to determine (1) the level of intervertebral space on CT that best approximates the total VAT volume; (2) compare the association between WC and VAT in Singaporean Chinese and Indian; and (3) examine the correlation between VAT and cardiometabolic risk factors. SUBJECTS: A total of 60 Chinese and 60 Asian Indian men older than 60 years were recruited. Their medical history was taken and anthropometry was measured. Fasting glucose, insulin, lipids, adipokines and inflammatory markers were measured. Insulin resistance was evaluated by homeostasis model assessment-insulin resistance. VAT was determined by CT. Total VAT volume was calculated in 22 patients from VAT areas at seven intervertebral levels. The optimal VAT area most representative of total VAT volume was determined and used for all patients to approximate total VAT volume. RESULTS: The VAT area at L2/3 intervertebral space (L2/3 VAT) correlated almost perfectly with VAT volume (R(2)=0.974 and 0.946 for Chinese and Indians, respectively). SUBJECTS from the two races had similar height, weight, body mass index (BMI), WC and L2/3 VAT but more Indian men had hypertension, hyperlipidemia and type 2 diabetes mellitus. WC was correlated with the L2/3 VAT area in both Chinese (r=0.484, P<0.001) and Indian subjects (r=0.366, P=0.004) without racial difference (P=0.2 for interaction term). L2/3 VAT also correlated better with cardiometabolic risk factors, adipokines and C-reactive protein than WC, BMI or L4/5 VAT. CONCLUSION: The L2-L3 intervertebral space was the best anatomic level for a single-slice CT cross-sectional area measurement of VAT to approximate total body visceral adipose volume in this population of Chinese and Asian Indian men older than 60 years. L2/3 VAT was better correlated with multiple cardiovascular risk factors, adipokines and inflammatory marker than either L4/5 VAT, WC or BMI. PMID- 23448803 TI - Impact of body mass index on diastolic function in patients with normal left ventricular ejection fraction. AB - BACKGROUND: Obesity is a major public health epidemic and is associated with increased risk of heart failure and mortality. We evaluated the impact of body mass index (BMI) on the prevalence of diastolic dysfunction (DD). METHODS: We reviewed clinical records and echocardiogram of patients with baseline echocardiogram between 1996 and 2005 that showed normal left ventricular ejection fraction (LVEF). Diastolic function was labeled as normal, stage 1, stage 2 or stage 3/4 dysfunction. Patients were categorized as normal weight (BMI <25 kg m( 2)), overweight (25-29.9 kg m(-2)), obese (30-39.9 kg m(-2)) and morbidly obese (?40 kg m(-2)). Multivariable ordinal and ordinary logistic regression were performed to identify factors associated with DD, and evaluate the independent relationship of BMI with DD. RESULTS: The cohort included 21 666 patients (mean (s.d.) age, 57.1 (15.1); 55.5% female). There were 7352 (33.9%) overweight, 5995 (27.6%) obese and 1616 (7.4%) morbidly obese patients. Abnormal diastolic function was present in 13 414 (61.9%) patients, with stage 1 being the most common. As BMI increased, the prevalence of normal diastolic function decreased (P<0.0001). Furthermore, there were 1733 patients with age <35 years; 460 (26.5%) and 407 (23.5%) were overweight and obese, respectively, and had higher prevalence of DD (P<0.001). Using multivariable logistic regression, BMI remained significant in both ordinal (all stages of diastolic function) and binary (normal versus abnormal). Also, obesity was associated with increased odds of DD in all patients and those aged <35 years. CONCLUSIONS: In patients with normal LVEF, higher BMI was independently associated with worsening DD. PMID- 23448804 TI - Comparison of the effects of 52 weeks weight loss with either a high-protein or high-carbohydrate diet on body composition and cardiometabolic risk factors in overweight and obese males. AB - BACKGROUND: A high-protein (HP), low-fat weight-loss diet may be advantageous for improving cardiometabolic health outcomes and body composition. To date, only limited research has been conducted in male participants. OBJECTIVE: To evaluate the medium to long-term effects of two, low-fat, hypocaloric diets differing in carbohydrate:protein ratio on body composition and cardiometabolic health outcomes in overweight and obese males. DESIGN: One hundred and twenty males (age 50.8+/-9.3 (s.d.) years, body mass index 33.0+/-3.9 kg m(-2)) were randomly assigned and consumed a low-fat, isocaloric, energy-restricted diet (7 MJ per day) with either HP (protein:carbohydrate:fat %energy, 35:40:25) or high carbohydrate (HC; 17:58:25). Body weight, body composition and cardiometabolic risk factors were assessed at baseline and after 12 and 52 weeks. RESULTS: Sixty eight participants completed the study (HP, n=33; HC, n=35). At 1 year both the groups experienced similar reductions in body weight (HP, -12.3+/-8.0 kg (-12%); HC, -10.9+/-8.6 kg (-11%); P=0.83 time * group interaction) and fat mass (-9.9+/ 6.0 kg (-27%) vs -7.3+/-5.8 kg (-22%); P=0.11). Participants who consumed the HP diet lost less fat-free mass (-2.6+/-3.7 kg (-4%) vs -3.8+/-4.7 kg (-6%); P<0.01). Both groups experienced similar increases in high-density lipoprotein cholesterol (8%) and reductions in total cholesterol (-7%), low-density lipoprotein cholesterol (-9%), triglycerides (-24%), glucose (-3%), insulin ( 38%), blood pressure (-7/-12%) and C-reactive protein (-29%), (P?0.14). CONCLUSION: In overweight and obese men, both a HP and HC diet reduced body weight and improved cardiometabolic risk factors. Consumption of a HP diet was more effective for improving body composition compared with an HC diet. PMID- 23448805 TI - Acylation stimulating protein reduction precedes insulin sensitization after BPD DS bariatric surgery in severely obese women. AB - OBJECTIVE: The mechanisms involved in early resolution of insulin resistance and type 2 diabetes mellitus after biliopancreatic diversion with duodenal switch (BPD-DS) surgery are still unknown. We evaluated early effects of BPD-DS on plasma acylation stimulating protein (ASP), an adipokine involved in lipid and glucose metabolism. SUBJECTS: 32 non-diabetic and 22 diabetic severely obese women (BMI?40 kg m(-2)) were evaluated for body composition and plasma parameters before, 24 h, 5 days, 6 and 12 months after surgery. RESULTS: Within the early postoperative period (24 h), ASP decreased 25 and 30% in non-diabetic and diabetic women, respectively (P<0.001). Twenty-four hours after surgery, triglyceride, cholesterol, HDL-Chol, LDL-Chol and C3 also decreased, while glucose, insulin and high-sensitivity C-reactive protein (hsCRP) increased (all P<0.001). By 5 days, without significant weight loss, the decreases in ASP, cholesterol, HDL-Chol and LDL-Chol levels were all maintained. At this time, glucose, insulin and HOMA-IR also decreased 11 to 52% (all P<0.001). At 6 and 12 months, with pronounced weight loss and decreased per cent fat mass, there were further decreases in ASP (maximal -56% non-diabetic, -61% diabetic, P<0.001), as well as in glucose, insulin, HOMA-IR, triglyceride, cholesterol, LDL-Chol, HDL Chol and hsCRP levels. Improved insulin resistance/diabetes at 5 days was predicted by 24 h changes as follows: per cent change ASP, HDL-Chol, hsCRP and total cholesterol predicted HOMA-IR (5 days) (r(2)=0.454, P<0.001), and per cent change ASP, HDL-Chol and hsCRP predicted change (5 days vs baseline) in HOMA-IR (r(2)=0.351, P<0.001). CONCLUSION: Acute postoperative decreases in ASP are associated with early improvement of insulin resistance/diabetes after BPD-DS surgery. PMID- 23448806 TI - Breast cancer survivors of different sexual orientations: which factors explain survivors' quality of life and adjustment? AB - BACKGROUND: Little is known about differences by sexual orientation in explanatory factors of breast cancer survivors' quality of life, anxiety, and depression. PATIENTS AND METHODS: Survivors were recruited from a cancer registry and additional survivors recruited through convenience methods. Data were collected via telephone survey from all 438 survivors, who were disease free and diagnosed with non-metastatic breast cancer an average of 5 years earlier. To explain quality of life, anxiety, and depression, we focused on sexual orientation as the primary independent factors, in addition, considering demographic, psychosocial, clinical, and functional factors as correlates. RESULTS: Sexual orientation had indirect associations with each of the outcomes, through disease-related and demographic factors as well as psychosocial and coping resources. The various explanatory models explain between 36% and 50% of the variance in outcomes and identified areas of strengths and vulnerabilities in sexual minority compared with heterosexual survivors. CONCLUSIONS: This study's findings of strengths among specific subgroups of sexual minority compared with heterosexual survivors require further explorations to identify the reasons for this finding. Most of the identified vulnerabilities among sexual minority compared with heterosexual survivors of breast cancer are amenable to change by interventions. PMID- 23448808 TI - Targeting glycogen metabolism: a novel strategy to inhibit cancer cell growth? PMID- 23448807 TI - Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer. AB - BACKGROUND: We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m(2) weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. RESULTS: Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. CONCLUSIONS: This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291. PMID- 23448809 TI - Facts and fiction: premalignant lesions of lung tissues. AB - Lung cancer is now the leading cause of death from cancer in Australia. Most patients are diagnosed with late-stage disease. Although diagnosis at pre invasive stages could theoretically improve outcomes, mooted precursor lesions are often asymptomatic and often undetectable by non-invasive investigations. Nonetheless, they merit study to identify early and essential molecular steps involved in lung carcinoma pathogenesis, with the aim of developing therapies targeted against one or more such steps. Some lung cancers appear to develop via a series of progressive morphological changes with correlating molecular alterations, but others seem to arise in histologically normal epithelium, and these differences may reflect anatomically and functionally distinct epithelial compartments of the respiratory tract. Pre-invasive precursor lesions recognised by the World Health Organization (WHO) include squamous metaplasia with dysplasia and carcinoma in situ, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Other lesions that likely represent pre-invasive lesions, but which are not currently WHO-listed, include human papillomavirus (HPV)-related respiratory papillomatosis and mesothelioma in situ. No single cancer stem cell marker has been identified. Field cancerisation plays an important role in lung cancer development, and includes the spread of pre invasive clones along the respiratory epithelium or the occurrence of multiple separate foci of pre-invasive abnormalities such as squamous dysplasia and carcinoma in situ.In addition to well-characterised step-wise progression in squamous cell carcinomas and some adenocarcinomas, alternative pathways exist, and are currently being investigated. In addition, molecular techniques, including miRNA screening on blood samples or cytology samples--such as sputum samples--may become clinically relevant and more accurate in predicting lung cancer progression. PMID- 23448810 TI - Premalignant lesions of the urinary bladder. AB - Although most carcinomas of the bladder occur de novo, some vesical lesions progress to malignancy over time. These lesions appear morphologically benign, but often harbour genetic changes that signify their malignant potential. Despite their benign appearance, accurate identification is important given that these patients will require close follow-up. In addition to this some lesions may mimic carcinoma, and as a consequence, misdiagnosis could result in serious over treatment. In this review, we discuss the clinical and histological features as well as the differential diagnosis of lesions of the bladder that have the potential to progress to cancer. Specifically, we present the features of flat, papillary and atypical urothelial hyperplasia, urothelial papilloma, urothelial dysplasia, intestinal metaplasia, keratinising squamous metaplasia, verrucous squamous hyperplasia and condyloma acuminatum and examine the molecular and clinical evidence relating to their malignant potential. PMID- 23448811 TI - Management of exorbitism using midface distraction osteogenesis. AB - INTRODUCTION: Management of patients with syndromal craniosynostosis is probably one of the greatest challenges. They usually present with variable deformities yet share common characteristics. Patients with Crouzon and Aperts syndrome present with exorbitism and midface hypoplasia. Exorbitism is a protrusion of the eyeball due to a decrease in the capacity of the orbital container, and it may lead to drastic consequences if left untreated. MATERIAL AND METHODS: Four cases with exorbitism and midface hypoplasia. Three presented with Aperts syndrome and one with Crouzon syndrome. They all underwent an intraoral modified Le Fort III osteotomy followed by midface distraction osteogenesis. CONCLUSION: Distraction osteogenesis of the midface is a safe and highly effective method in managing exorbitism associated with midface deficiency. PMID- 23448812 TI - Is it really crystal clear that using methamphetamine (or other recreational drugs) causes people to engage in unsafe sex? AB - Many studies have found associations between unsafe sexual behaviour and use of crystal methamphetamine (and many other recreational drugs). Researchers and authors of relevant articles in popular media have often interpreted these associations as meaning that using 'crystal' directly causes people to engage in unsafe sex, and that interventions should aim to reduce crystal use in order to reduce the prevalence of sexually transmissible infections such as HIV. There is consistent evidence that crystal users are a high-risk group in terms of sexual behaviour. However, most relevant studies have provided only circumstantial evidence regarding a causal relationship. Promoting the idea that a particular recreational drug is a major direct cause of unsafe sex may have the unintended adverse effect of creating an excuse for engaging in unsafe sex, thereby increasing its use, and may incur opportunity costs by preventing limited available health promotion resources from being directed more usefully. This paper examines the limitations, in terms of demonstrating causality, of various types of study that have been published on this topic in relation to crystal use in particular. Researchers who investigate relationships between recreational drug use and behaviour, including sexual behaviour, should be careful about the wording of their conclusions and recommendations, and should consider the possibly counterproductive ways in which their findings might be represented in the media. PMID- 23448813 TI - Toxic phytoplankton-induced spatiotemporal patterns. AB - Here we consider a reaction diffusion system of three plankton populations, a zooplankton feeding on two phytoplankton populations, in two different settings. Firstly, the two phytoplanktons are both non-toxic and both enhance the growth of the grazing zooplankton. Secondly, we assume that one of the phytoplankton releases toxin and thereby inhibits the growth of the zooplankton. Our analytic and numerical study shows that the spatiotemporal distribution of the plankton species is uniform when both phytoplankton populations are non-toxic. However, in the presence of toxin-producing phytoplankton, the biomass distribution of all the plankton populations becomes inhomogeneous. PMID- 23448814 TI - Pacesetters and pathfinders: an interview with Joyce K. Johnston, RN. PMID- 23448815 TI - Completeness and satisfaction with the education and information received by patients immediately after kidney transplant: a mixed-models study. AB - CONTEXT: Self-management is important in ensuring good clinical results in kidney transplant recipients. It was unclear whether the current education program at a single kidney transplant center sufficiently prepares recent transplant recipients for the many complex self-management tasks required. OBJECTIVE: To evaluate the completeness of and the satisfaction with the current inpatient kidney transplant education program and to determine recipients' needs for information in the first months after discharge. METHODS: We used a concurrent mixed-methods design, including 31 kidney transplant recipients who were assessed via a semistructured interview (qualitative part) and a questionnaire specifically designed for this study, consisting of 30 Likert-type and open-ended questions (quantitative part). RESULTS: Kidney transplant patients reported having received extensive information about medication use after transplant surgery (antirejection medication, 93.5%). Information about healthy lifestyle (physical activity and rehabilitation, 54.8%), return to work (54.8%), and emotional coping (25.8%) was considered suboptimal, although most patients expressed a need for such information. Patients indicated a need for more concrete and practical information, not only during their hospital stay, but also in the long term after transplant. CONCLUSIONS: This is the first mixed-models approach showing that our education program immediately after transplant focuses on the transfer of factual knowledge, which seems to insufficiently train patients in developing self-management skills. Updates of our program are warranted to overcome the gaps in the information provided, to provide more practical tips, and to repeat education in the long-term after the transplant surgery, tailored to the patients' needs. PMID- 23448816 TI - Survey of transplant-related pharmacy services at large comprehensive transplant centers in the United States. AB - CONTEXT: United Network for Organ Sharing (UNOS) 2011 bylaws and Centers for Medicare and Medicaid Services (CMS) regulations require a transplant pharmacist to be an active participant in the care of transplant patients. Transplant centers must be members in good standing with UNOS in order to perform transplants and must be certified by CMS to participate with Medicare. OBJECTIVE: To identify characteristics of transplant-related pharmacy services at comprehensive transplant centers. DESIGN: Survey regarding number of full-time equivalent (FTE) transplant pharmacists relative to number of annual transplants, transplant pharmacy model, roles in inpatient and clinic environments, training and specialization, funding sources, and expansion plans.Participants-Surveys were received from 14 (74%) of 19 identified centers that performed 200 to 400 kidney, liver, pancreas, simultaneous kidney/pancreas, heart, and lung transplants in 2010, representing 55 transplant pharmacists. RESULTS: A mean of 325 transplants were performed in 2010 at the surveyed centers. The mean number of pharmacist FTEs was 4.25, which yielded a transplant-to-pharmacist ratio of 76.5. Nine centers (64%) practiced in a pharmacy specialist-only model, 12 (86%) practiced in a service-based fashion, and 10 (71%) saw patients in clinic. Fifty four pharmacists (98%) had obtained a PharmD degree, 45 (82%) had completed 1 postgraduate year, and 28 (51%) had completed 2 postgraduate years of training. Nine centers (64%) funded FTEs solely through the pharmacy department. Ten centers (71%) plan to expand transplant pharmacist staff by a mean of 1.4 FTEs. CONCLUSIONS: Large comprehensive transplant centers use multiple transplant pharmacists to perform patient care in the inpatient and outpatient environments. Most centers plan to expand FTEs. Further characterization of transplant pharmacists appears warranted. PMID- 23448817 TI - Bariatric surgery for a patient with a HeartMate II ventricular assist device for destination therapy. AB - A patient with a HeartMate II left ventricular assist device who had a body mass index of 52 needed gastric bypass surgery in order to qualify for a heart transplant. Unlike previous experience in which the surgery was performed at the implant hospital, the gastric bypass surgery in this case was performed at a bariatric center of excellence that was a separate facility from the implant hospital. The artificial heart program of the University of Pittsburgh Medical Center worked with the bariatric center of excellence in scheduling the gastric bypass surgery using a multidisciplinary team approach at 2 hospitals to coordinate safe, high-quality patient care in a unique situation. PMID- 23448818 TI - Clinical and economic analysis of delayed administration of antithymocyte globulin for induction therapy in kidney transplantation. AB - CONTEXT: The increasing number of marginal deceased kidney donors and an aging recipient population, prolonged hospitalization, and increased costs have destabilized the economic viability of kidney transplants. OBJECTIVE: To determine if a delay in the administration of the day-of-discharge dose of rabbit antithymocyte globulin would result in equivalent clinical outcomes with cost savings. DESIGN: Single-center, prospective, observational before-and-after study of adult kidney transplant recipients who received induction with rabbit antithymocyte globulin.Intervention-Patients who received a transplant between June 2006 and February 2009 and received rabbit antithymocyte globulin served as the control group. Patients who received a transplant between March 2009 and August 2010 and received rabbit antithymocyte globulin had the day-of-discharge dose delayed to the following day and administered in the clinic. A total of 231 patients (146 in the control group, 85 in the study group) were included. Baseline demographic and clinical characteristics were similar in the 2 groups. RESULTS: Patients who had delayed administration of rabbit antithymocyte globulin had shorter stays (3.9 vs 3.1 days, P< .001) and reduced inpatient costs for rabbit antithymocyte globulin (mean $860/patient); these changes were achieved without affecting acute rejection rates (5% vs 5%, P> .99) or readmission rates. In conclusion, delayed inpatient administration of rabbit antithymocyte globulin provided identical clinical outcomes while helping to reduce inpatient costs and increase timely discharges. PMID- 23448819 TI - Monitoring patients with continuous-flow ventricular assist devices outside of the intensive care unit: novel challenges to bedside nursing. AB - Ventricular assist devices provide therapeutic options for patients with severe heart failure who have exhausted available medical therapies. With restoration of organ perfusion with ventricular assist devices, the heart failure resolves and quality of life and functional status improve. The current generation of continuous-flow devices present novel challenges to the clinical assessment of patients by substantially reducing or nearly eliminating any palpable pulse. Patients therefore generally have inadequate arterial pulsatility for most noninvasive monitoring devices such as pulse oximeters or automated blood pressure cuffs to work accurately. This article describes the function of continuous-flow devices and how this function affects common monitoring options, as well as how to clinically assess recipients of continuous-flow devices to promptly identify those whose condition may be deteriorating or who may be receiving inadequate perfusion. PMID- 23448820 TI - Assessing health literacy in renal failure and kidney transplant patients. AB - CONTEXT: A report released in 2004 by the Institute of Medicine estimated that as many as 90 million Americans do not have the necessary skills required to manage complex treatment regimens or navigate through current health care systems successfully. OBJECTIVES: To identify the level of health literacy in patients seen at a suburban transplant center by using the Newest Vital Sign tool to assess health literacy. DESIGN AND SETTING: This descriptive study used survey methods. The convenience sample included 44 adult patients, both English and Spanish speaking, who attended a routine clinic visit at a suburban transplant center. METHODS: The Newest Vital Sign tool was administered during routine outpatient medical visits. Demographic information collected included age, sex, highest level of education, and whether or not the participant was on dialysis or received a kidney transplant. Descriptive statistics were completed for each answer on the tool. Chisquare analyses were done to determine whether demographic factors or the presence of dialysis affected health literacy in this sample. A 1 way analysis of variance between-subjects test was run to compare the effect of primary language and educational level on scores. RESULTS: Of the 44 participants, 18 (41%) had scores indicating a possible likelihood to a high likelihood of limited health literacy. Twenty-nine percent of the English speaking participants and 89% of the Spanish-speaking participants scored in this range. An association was also found between performance on the survey and level of education. However, assessment of educational level alone is not predictive of health literacy; 8 participants (18%) had a high school or college education yet scored as having limited health literacy. PMID- 23448821 TI - Risk evaluation and mitigation strategies: a focus on the mammalian target of rapamycin inhibitors. AB - OBJECTIVE: To review the history of risk evaluation and mitigation strategies (REMS) with the mammalian target of rapamycin (mToR) inhibitors, evaluate their required REMS elements, and delineate the reasons for them being released from their REMS requirements. DATA SOURCES AND EXTRACTION: Articles were identified through a literature search of MEDLINE and EMBASE (January 2007-July 2012) using the search terms: risk evaluation and mitigation strategies, REMS, everolimus, sirolimus and organ transplant (individual organs also were searched). Information from the Federal Register, the Food and Drug Administration, and the manufacturers of the mToR inhibitors was also evaluated. DATA SYNTHESIS: REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. The mToR inhibitors have been associated with several potential risks, including proteinuria, graft thrombosis, and wound-healing complications. The Food and Drug Administration approved REMS programs for both sirolimus and everolimus. The manufacturers of both medications complied with the components of their approved REMS, but after less than 2 years, both medications have been relieved of their REMS obligations. CONCLUSION: The only element of the sirolimus REMS was a medication guide, whereas the everolimus REMS consisted of a medication guide and a communication plan. The sirolimus REMS was implemented more than 10 years after its initial approval by the Food and Drug Administration, but was released from its REMS requirement within 7 months of its implementation. The everolimus REMS was instituted upon initial approval and was removed approximately 2 years later. Both medications' REMS were always intended to educate health care providers and patients about the potential risks associated with this transplant immunosuppressant. Transplant practitioners should be familiar with the mToR inhibitors' associated risks and properly educate patients regarding the inhibitors' risk-benefit profiles. PMID- 23448822 TI - A guide to understanding and implementing risk evaluation and mitigation strategies in organ transplantation. AB - OBJECTIVE: To review the components of the Congressional mandate for risk evaluation and mitigation strategies (REMS) managed by the Food and Drug Administration and assess their impact on health care providers practicing within the organ transplant arena. DATA SOURCES AND EXTRACTION: A non-date-limited search of MEDLINE and EMBASE (January 2007-June 2012) was conducted by using the following search terms: risk evaluation and mitigation strategies, REMS, and organ transplant, including a query of the individual organs. Information from the Federal Register and the Food and Drug Administration was also evaluated. DATA SYNTHESIS: REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. Elements of REMS programs may consist of 3 levels: a medication guide, communication plan, and elements to assure safe use. A medication guide is used to help prevent serious adverse events, aid in patients' decision making, and enhance medication adherence. Communication plans help educate health care providers and encourage adherence with REMS. The elements to assure safe use is a restrictive process implemented when it is deemed necessary to ensure safe access for patients to products with known serious risks. In transplant medicine, REMS currently exist for belatacept (medication guide and communication plan) and the mycophenolic acid derivatives (medication guide and elements to assure safe use). CONCLUSION: REMS are another step in the evolution of the development and marketing of pharmaceutical agents. Use of REMS in solid-organ transplant is becoming common. Transplant clinicians must provide required patient education and become involved with other aspects of REMS implementation to reduce the serious risks of pharmaceuticals and to improve patients' outcomes. PMID- 23448823 TI - Risk evaluation and mitigation strategies: a focus on belatacept. AB - OBJECTIVE: To review the elements and components of the risk evaluation and mitigation strategies (REMS) for the costimulation blocker belatacept and associated implications for health care providers working with transplant recipients. DATA SOURCES AND EXTRACTION: The MEDLINE and EMBASE databases (January 1990 to March 2012) were searched by using risk evaluation and mitigation strategies, REMS, belatacept, and organ transplant as search terms (individual organs were also searched). Retrieved articles were supplemented with analysis of information obtained from the Federal Register, the Food and Drug Administration, and the manufacturer of belatacept. DATA SYNTHESIS: REMS are risk management strategies implemented to ensure that a product's benefits outweigh its known safety risks. Although belatacept offers a novel strategy in maintenance immunosuppression and was associated with superior renal function compared with cyclosporine in phase 2 and 3 trials, belatacept is also associated with increased risk of posttransplant lymphoproliferative disorder and central nervous system infections. The Food and Drug Administration required development of a REMS program as part of belatacept's approval process to ensure safe and appropriate use of the medication and optimization of its risk-benefit profile. CONCLUSION: Elements of the belatacept REMS include a medication guide that must be dispensed with each infusion and a communication plan. In the management of a complex population of patients, it is essential that those who care for transplant recipients, and patients, recognize the implications of potential and known risks of belatacept. The REMS program aims to facilitate careful selection and education of patients and vigilant monitoring. PMID- 23448824 TI - Aspergillus galactomannan antigen for diagnosis and treatment monitoring in cerebral aspergillosis. AB - Invasive aspergillosis, especially neuroaspergillosis, predominantly affects immunocompromised patients such as transplant recipients. Early diagnosis and subsequent early initiation of therapy may improve final outcome. In cerebral aspergillosis, samples for culture or histopathology, the diagnostic reference standard, are often impossible to obtain without risk. Because of these limitations, serological, nucleic acid amplification tests such as polymerase chain reaction or enzyme immunoassay from cerebrospinal fluid appear advantageous for early diagnosis and probably also for therapy monitoring. We report on the successful detection and treatment monitoring by serial testing of galactomannan in cerebrospinal fluid in a patient with neuroaspergillosis after heart transplant. PMID- 23448825 TI - Implantation of a left ventricular assist device with mini-pericardiotomy technique. AB - The left ventricular assist device may be a lifesaving therapy for a patient awaiting a heart transplant. The most common complications of this device are mediastinal bleeding, infections, embolic events, right-sided heart failure, and mediastinal adhesions. We are reporting a patient who had a Levitronix left ventricular assist device implanted with mini-pericardiotomy technique for bridging to heart transplant. PMID- 23448826 TI - Kidney transplantation in the United States: economic burden and recent trends analysis. AB - OBJECTIVE: As kidney transplant is the preferred mode of management of advanced kidney disease and economic trends for kidney transplant procedures are not well known, data were analyzed to assess these trends. DATA SOURCE: Annual data for 1998 to 2008 from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality were used to analyze characteristics of patients discharged from hospitals in the United States with kidney transplant as the primary procedure. DATA SYNTHESIS/RESULTS: The population more than 65 years old had the most significant increase in hospitalizations for kidney transplant procedures (P< .01). The mean length of stay decreased by 2.8 days over the period studied (P= .02). Mean hospital charge increased despite a decrease in length of stay resulting in a 225% increase in charge per day of hospitalization, from $6907 in 1998 to $22 484 in 2008. The national aggregate hospital charges for kidney transplant procedures rose from $0.9 billion in 1998 to $3.1 billion in 2008. Kidney transplant was overall ranked sixth by mean cost per hospitalization and ranked seventh by mean charge per hospitalization among the Clinical Classification Software's Services and Procedures in this database in 2008. CONCLUSION: Despite shorter hospital stays, the economic burden of kidney transplants increased from 1998 to 2008. PMID- 23448827 TI - Hemoglobin A1c testing is associated with improved pancreas utilization for transplant. AB - CONTEXT: Aging, higher prevalence of diabetes, worsening obesity, and hyperglycemia among potential donors increase the likelihood that pancreata will be declined by transplant centers. Hemoglobin A1c testing, also known as glycated hemoglobin testing, identifies a donor's average blood glucose concentration for the preceding 2 to 3 months and is the standard test for identifying prolonged periods of hyperglycemia. OBJECTIVE: To compare pancreas utilization rates before and after implementation of hemoglobin A1c testing. DESIGN: A retrospective study of data from the New York Organ Donor Network was conducted. Potential donors were defined as standard criteria donors who had no history of diabetes and were not seropositive for hepatitis B or C. Criteria for "ideal" potential pancreas donors were based on age, body mass index, lipase level, and terminal creatinine level. Potential donors who did not meet the criteria for ideal donors were considered "expanded" potential pancreas donors. Pancreas utilization rate was defined as the number of pancreata transplanted divided by the number of potential pancreas donors. RESULTS: Of 779 standard criteria donors, 691 (89%) were potential pancreas donors: 251 ideal (36%) and 440 expanded (64%) donors. In 2005 and 2006, before hemoglobin A1c testing, pancreas utilization rates were 21% and 18%, respectively. In 2008, 2009, and 2010, after hemoglobin A1c testing was incorporated, utilization rates were 27%, 28%, and 32%, respectively. Utilization of ideal donors increased from 33% to 51% (P= .003), and utilization of expanded donors increased from 11% to 17% (P= .05). Pancreas utilization increased 51.0%, and pancreas discards decreased 50.8% with the implementation of hemoglobin A1c testing. CONCLUSION: Hemoglobin A1c testing may increase utilization of ideal and expanded criteria pancreata. PMID- 23448828 TI - Telephone requests for donation: concerns expressed by families and the impact of the donor registry. AB - CONTEXT: The request process for eye and tissue donation is different from the process that families of organ donors experience, but the research into eye/tissue-only decision making has been sparse. OBJECTIVE: To determine the concerns of families approached over the phone for eye/tissue donations and to study the impact of the donor registry on those decisions. DESIGN, SETTING AND PARTICIPANTS: Written instrument filled out by family services coordinators while speaking with families about donation via phone in the San Diego, California, area during 2011.Main Outcome Measures-Responses marked on a 21-item instrument, contextual notes, donor registrations, and decisions made. RESULTS: With a 60% refusal rate, the most common reasons reported for declining donation are that the potential donor said during life he/she did not want to donate (26%) or that the family, not knowing the potential donor's wishes, opted not to donate (13%). Other specific reasons for not donating were as follows: wanting the body buried whole (8%), concerns about age and prior health (7%), and incompatibility with religion or culture (7%). Consenting families had different concerns: worries about delays (36%), the potential donors' age and health (25%), how the body might look for viewing (14%), the amount of paperwork (10%), for-profit status of beneficiaries (9%), international distribution (8%), and family disunity (8%). Registry-related refusals weighted against donations of tissues from registered donors amounted to a deficit of 92 potential donations. When donations lost to faulty assumptions based on public education are added, the deficit increases to 122 lost donations. PMID- 23448829 TI - Consent to organ donation: a review. AB - Successful transplant medicine hinges on consent to deceased organ donation. Yet rates of consent remain suboptimal. To increase the availability of transplantable organs, several policy strategies along with a rich body of evidence aimed at identifying best practices for obtaining consent have accumulated. This review describes past and current policies and practices, presents evidence illustrating the impact of these policies and practices on consent, and summarizes future directions and recommendations for the field. Key findings include evidence that although past policies such as required request have been unsuccessful, the recent policy, first-person authorization, shows promise. Additionally, practices such as decoupling and detailed discussions of brain death are unwarranted. On the other hand, the Organ Donation Breakthrough Collaboration was successful. We also underscore the impact of alternative procedures such as donation after cardiac death. Last, effective communication that is delivered by trained, caring requesters at the appropriate time, in a supportive environment, and allows sufficient time for families to make an informed decision, optimizes the request process. Organ procurement organizations' adoption of such request practices, implementation of evidence based policies regarding donation after cardiac death, and further investigations of the medical basis for dual brain death examinations are recommended. PMID- 23448830 TI - Evaluation of the applicability of the Clinical Care Classification System to the care of elderly nursing home residents. AB - The purpose of this study was to translate the Clinical Care Classification System into Turkish and evaluate its applicability to the care of elderly nursing home residents. This study uses a quasi-experimental design in which interventions and evaluations are repeated at specified time intervals in a single group and in which the Clinical Care Classification System is evaluated in a descriptive manner through the use of documents obtained from the system to test the applicability of the system for the care of elderly nursing home residents. Twenty-eight elderly people participated in the study. The health conditions of elderly people were evaluated using an elderly assessment form based on data obtained after nursing diagnoses and nursing interventions were determined using the Clinical Care Classification System. The change in nursing diagnoses as a result of the applied nursing interventions was evaluated. A total of 297 diagnoses were specified in 18 care components directed to the elderly, and 310 interventions were performed. Upon evaluation of the consequences of the interventions, changes in 208 nursing diagnoses were observed. The findings indicate that the Clinical Care Classification System is useful for determining the requirements of the elderly, providing suitable nursing care and enabling the evaluation of the process. PMID- 23448831 TI - Ab initio study of the effect of Si on the phase stability and electronic structure of gamma- and alpha-Al2O3. AB - Using density functional theory, the effect of Si on the stability and electronic structure of gamma- and alpha-Al2O3 has been investigated. The concentration range from 0 to 5 at.% is probed and the additive is positioned at different substitutional sites in the gamma-phase. The calculations for (Al,Si)2O3 predict a trend towards spontaneous decomposition into alpha-/gamma-Al2O3 and SiO2. Therefore, the formation of the metastable gamma-(Al,Si)2O3 phase can only be expected during non-equilibrium processing where the decomposition is kinetically hindered. The Si-induced changes in stability of this metastable solid solution may be understood based on the electronic structure. As the Si concentration is increased, stiff silicon-oxygen bonds are formed giving rise to the observed stabilization of the gamma-phase. PMID- 23448833 TI - On research. PMID- 23448834 TI - [Development of a tissue-equivalent magnetic resonance imaging phantom using indigestible dextrin and soluble calcium]. AB - In magnetic resonance imaging (MRI), the ideal phantom should have similar T1 and T2 values to those of organs of interest for measuring the change in signal intensity, contrast ratio and contrast noise ratio. There have been several reports to develop such a phantom using materials with limited availability or complex methods. In this study, we have developed a simple phantom using indigestible dextrin and soluble calcium at 1.5-tesla MRI. The T1 and T2 values have been reduced by dissolving indigestible dextrin and soluble calcium in distilled water. The similar T1 and T2 values to those of organs (i.e., kidney cortex, kidney medulla, liver, spleen, pancreas, bone marrow, uterus myometrium, uterus endometrium, uterus cervix, prostate, brain white matter, and brain gray matter) have been obtained by varying the concentration of indigestible dextrin and soluble calcium. This phantom is easy to develop and has a potential to increase the accuracy of MRI phantom experiments. PMID- 23448832 TI - Patient satisfaction in prosthodontic treatment: multidimensional paradigm. AB - A number of different factors contribute to an efficient clinical outcome in prosthetic dentistry. Differences between patient's and prosthodontist's perception of treatment display great variability. Patient satisfaction in prosthetic dentistry is a multidimensional concept as is patient's perception of dental care. Patient satisfaction can be assessed if it is carefully defined. In the prosthodontic treatment context patient satisfaction can be expected to interact with the patient's entire life situation. This article highlights the issues that reflect the different dimensions of patient satisfaction in prosthodontic care. PMID- 23448835 TI - [Development of in-house software for calculating and searching the restricted mass collision stopping powers for electrons]. AB - In external radiotherapy, the absorbed doses are measured using an ionization process in a gas-filled ionization chamber and estimated by the extended cavity theory. The calculation requires both the W-value of cavity gas and the restricted mass collision stopping powers (L/rho) for the gas and medium. ICRU Report 37 gives us the data regarding the mass collision stopping powers (S/rho) for several elements and chemical compounds or mixtures. However, there are no detailed data for L/rho. In this study, we developed an in-house program to calculate the L/rho for arbitrary substances by the use of the equation described in ICRU Report 37. With this program, we can search the calculated L/rho easily. When we calculated L/rho for chemical compounds and mixtures with implementation of Bragg's additivity rule, a large error of density effect corrections was observed. Therefore, our program adopted both the mean excitation energy and density effect correction obtained by ESTAR, which was developed by Berger et al. With adoption of these values, the calculation accuracy of our program was improved. Our program is useful to search L/rho for radiation dosimetry in radiotherapy. PMID- 23448836 TI - [Impact of the standardized uptake value on the body trunk with truncation error of MU-map in the positron emission tomography/computed tomography: phantom studies]. AB - PURPOSE: The aim of this study was evaluate to impact of standardized uptake value (SUV) on the body trunk with truncation error of MU-map for CT attenuation correction (CTAC) in whole-body 2-deoxy-2-[(18)F] fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/CT with use of anthropomorphic phantom. METHODS: We used body phantom (2.5 MBq/l) including simulated tumor targets (11.25 MBq/l) and arm phantom. The CT scan was used with a field of view (FOV) of 50 cm. The MU-maps were created by assuming a state of the arm protruding from the FOV (Pmap). A 3D-PET scan with an emission time of 20 min was performed. The PET images were then reconstructed with CTAC, and with and without scatter correction. We evaluated the relationship to Pmap size and the count of simulated tumors and background (B.G.) in PET images which reconstructed the use of each Pmap, respectively. RESULTS: The count of simulated tumor (large) with scatter correction was decreased to 1.3% (Pmap: 15 mm) and 8.8% (Pmap: 35 mm). Then, the count severe reduction was 86.9% in Pmap of 65 mm. The same trend was shown by simulated tumor (middle, small) and B.G. The count of the simulated tumor (large) without scatter correction decreased to 1.3% (Pmap: 15 mm), 6.4% (Pmap: 35 mm) and 13.1% (Pmap: 65 mm). CONCLUSION: Truncation error by MU-map for CTAC in whole body (18)F-PET/CT caused a decrease of the SUV on the body trunk used for attenuation and scatter correction in the PET images. PMID- 23448839 TI - [5. Comparing two groups for continuous data (2)]. PMID- 23448841 TI - [My experience of receiving the American Association of Physicists in Medicine Best Paper Award 2011]. PMID- 23448842 TI - [Report on investigation of radiation dose units for medical exposure doses]. PMID- 23448843 TI - [Presentation for safety management and preventive maintenance: maintenance before start working and after finish working for radiology equipment]. PMID- 23448844 TI - Influence of blood pressure and body mass index on retinal vascular caliber in preschool-aged children. AB - We assessed the associations between body mass index (BMI) and blood pressure (BP) with the retinal microvasculature among preschool-aged children. Three hundred and seventy-nine children aged 3-<6 years old had gradable retinal photographs, and quantifiable retinal vascular caliber using validated computer based methods. Weight, height, BMI, waist circumference and BP were obtained using standardized protocols. Mean (+/-s.d.) BMI and systolic BP in preschool aged children were 16.0 (+/-1.8) kg m(-2) and 93.2 (+/-9.9) mm Hg, respectively. After multivariable adjustment, each kg m(-2) increase in BMI was associated with a 1.06 MUm narrowing of retinal arteriolar caliber (P=0.01) and 1.12 MUm widening of retinal venular caliber (P=0.02). Children in the ?95th percentile (obese) compared with those in the <85th percentile (healthy weight) had narrower retinal arteriolar caliber (~6.1 MUm, Ptrend=0.01) and wider retinal venular caliber (~6.4 MUm, Ptrend=0.01). Each 10 mm Hg increase in systolic BP was associated with a 1.70 MUm narrower retinal arteriolar caliber (multivariable-adjusted P=0.02). We show that BMI and systolic BP have inverse linear associations with retinal arteriolar caliber, and BMI has a positive linear association with retinal venular caliber during early childhood. These findings suggests that the influence of BP and BMI on small vessels are continuous and commence early in life. PMID- 23448845 TI - A comparison of the association between glomerular filtration and L-arginine status in HIV-infected and uninfected African men: the SAfrEIC study. AB - Hypertension, a major risk factor for cardiovascular disease worldwide, is increasing significantly in urbanised South Africans. Impaired glomerular filtration is a potential contributor to hypertension. Although HIV infection is widespread, little is known regarding its contribution to diminished estimated glomerular filtration rate (eGFR) and, in turn, hypertension in Africans. We compared eGFRs and cardiovascular profiles of newly identified HIV infected African men (N=53) not yet undergoing anti-retroviral therapy, and uninfected African men of similar age and anthropometry. The aim of the study was to determine whether eGFR is diminished in treatment naive HIV infected individuals and whether eGFR is associated with a potential modulator of hypertension, namely serum L-arginine. Cardiovascular risk factor profiles of HIV infected and uninfected men were similar. In men with healthy eGFRs >90 ml min(-1) per 1.73 m(2), eGFR was significantly lower with HIV infection (114 (90; 147)) compared with that in uninfected men: (120 (91; 168)), P=0.043. Despite the absence of clinically-diagnosed renal dysfunction, eGFR associated significantly with serum L-arginine only in HIV infected men (R(2)=0.277, beta=-0.299, P=0.034), whereas L arginine did not stay in the model for uninfected men. This difference suggests that the fate of L-arginine as a substrate for nitric oxide generation may be altered in HIV infected individuals. Subsequently this is likely to escalate endothelial dysfunction, contributing to later hypertension and cardiovascular disease. Our findings show that while glomerular filtration rate is not associated with L-arginine in uninfected men, it is diminished and significantly negatively associated with serum L-arginine in HIV infected men. PMID- 23448847 TI - Oral antipsychotic update: a brief review of new and investigational agents for the treatment of schizophrenia. AB - Antipsychotics are the mainstay of treatment for patients with schizophrenia. However, these medications only work if they are taken and perhaps work best if they are taken for longer periods of time than seen in typical research trials. Here we explore the idea of "time as drug" by reviewing the data showing the potential benefits of long-term antipsychotic use. We also discuss the utility of depot antipsychotic formulations for improving the chances of attaining long-term therapeutic results. PMID- 23448846 TI - Barriers to achieving blood pressure treatment targets in elderly hypertensive individuals. AB - High blood pressure (BP) is highly prevalent among the elderly, and even with pharmacological therapy BP is difficult to control to guideline recommended levels. Although poor compliance to therapy is associated with less BP control, little is known regarding other barriers to attaining on-treatment target BP. This study examined factors associated with achieving on-treatment target BP in 6010 hypertensive participants aged 65-84 years from the Second Australian National Blood Pressure study. Participants were followed for a median of 4.1 years, with BP monitored every 6 months. 'Target BP' was defined as a reduction of systolic/diastolic BP of at least 20/10 mm Hg and BP <160/90 mm Hg from randomization in two consecutive follow-up visits. Cox regression was used to identify factors associated with achieving target BP from a number of baseline and in-study factors. Mean BP at randomization was 168/91 mm Hg and patients had a median of 9 (range: 2-20) study visits. Target BP was achieved in 50% of patients. Demographic factors associated with achieving target BP were male gender, living in a regional area; and clinical factors included history of antihypertensive therapy, increased plasma creatinine, lower pretreatment pulse pressure and in-study use of multiple BP-lowering drugs. Those aged >80 years and seeking care from multiple doctors (hazard ratio 0.40, 95% confidence interval 0.36-0.45, P<0.001) were less likely to achieve target BP. These findings identify clinical markers that can be targeted for intervention, but also demographic factors related to service delivery, which may provide further opportunity for achieving better BP control in hypertensive elderly. PMID- 23448848 TI - Comprehensive management of subclavian vein effort thrombosis. AB - Subclavian vein (SCV) effort thrombosis, also known as the Paget-Schroetter syndrome, is a relatively uncommon condition that affects young, active, otherwise healthy individuals. It is considered a form of thoracic outlet syndrome, arising as a consequence of compression and repetitive injury of the SCV between the first rib and the overlying clavicle, as well as the anterior scalene muscle, subclavius muscle, and costoclavicular ligament. Effort thrombosis is distinct from other forms of deep vein thrombosis with respect to pathophysiology, clinical presentation, and functional consequences, and it requires treatment considerations unique to effective management of thoracic outlet compression as well as the obstructed SCV. In this review the comprehensive management of SCV effort thrombosis is addressed, with an emphasis on current interventional radiology techniques used in conjunction with definitive surgical treatment, based on early catheter-based venography, thrombolytic therapy, and prompt paraclavicular thoracic outlet decompression with direct SCV reconstruction. PMID- 23448849 TI - Clinical presentation of patients with aseptic meningitis, factors influencing treatment and hospitalization, and consequences of enterovirus cerebrospinal fluid polymerase chain reaction testing. AB - INTRODUCTION: Clinical and laboratory features of enteroviral meningitis may overlap with those of bacterial meningitis. In the present retrospective review, we compared features of enteroviral (EV)-positive and -negative patients to determine those that were most influential in admission, discharge and in anti infective administration. METHODS: Data were analyzed from the records of 117 pediatric and adult patients who underwent cerebrospinal fluid (CSF) EV testing over a three-year period. RESULTS: The oldest EV-positive patient was 34 years of age and the occurrence of the disease was highly seasonal. EV-positive patients were more likely to report fever, rash, photophobia, short onset and exposure to an ill contact. A positive polymerase chain reaction (PCR) result was associated with relatively short hospitalization. Seizure and neurological symptoms were more strongly associated with a negative PCR test result. CSF characteristics did not discriminate well between patients with positive and negative PCR tests. Patients with imperfect Glasgow Coma Scores or with neurological symptoms were more likely to be admitted to hospital than those without. Fever and recent onset predicted determinants of anti-infective use. CONCLUSION: The present retrospective study confirms previous reports regarding seasonality and the young age of positive patients. Factors that indicate nonenteroviral etiology were appropriately also those that influenced hospitalization. Patients with EV meningitis were likely to be treated with empirical anti-infectives, and a substantial proportion continued to take antibiotics for more than 24 h after receiving the positive EV PCR test result. INTRODUCTION: Clinical and laboratory features of enteroviral meningitis may overlap with those of bacterial meningitis. In the present retrospective review, we compared features of enteroviral (EV)-positive and -negative patients to determine those that were most influential in admission, discharge and in anti-infective administration. METHODS: Data were analyzed from the records of 117 pediatric and adult patients who underwent cerebrospinal fluid (CSF) EV testing over a three-year period. RESULTS: The oldest EV-positive patient was 34 years of age and the occurrence of the disease was highly seasonal. EV-positive patients were more likely to report fever, rash, photophobia, short onset and exposure to an ill contact. A positive polymerase chain reaction (PCR) result was associated with relatively short hospitalization. Seizure and neurological symptoms were more strongly associated with a negative PCR test result. CSF characteristics did not discriminate well between patients with positive and negative PCR tests. Patients with imperfect Glasgow Coma Scores or with neurological symptoms were more likely to be admitted to hospital than those without. Fever and recent onset predicted determinants of anti-infective use. CONCLUSION: The present retrospective study confirms previous reports regarding seasonality and the young age of positive patients. Factors that indicate nonenteroviral etiology were appropriately also those that influenced hospitalization. Patients with EV meningitis were likely to be treated with empirical anti-infectives, and a substantial proportion continued to take antibiotics for more than 24 h after receiving the positive EV PCR test result. PMID- 23448850 TI - The limited contribution of DNA methylation to PML-RARalpha induced leukemia. PMID- 23448852 TI - Graphene oxide-modified electrodes for sensitive determination of diethylstilbestrol. AB - This paper reports an electrochemical sensor fabricated with graphene oxide (GO) modified on a chitosan-coated glassy carbon electrode (GO-CS/GCE) and its application for the detection of diethylstilbestrol (DES). It was observed that the effective electrochemical surface area of the GO modified electrode was nearly 10 times that of the bare GCE. This could be used to explain the results that the oxidation peak current of DES on the GO-CS/GCE was much larger than on the bare GCE. Under optimized conditions, the prepared electrode could be used to electrochemically detect DES according to the oxidation of the DES. Based on the technique of differential pulse voltammetry and the accumulation of DES on GO modified electrodes, the calibration curve for DES determination could be obtained with a linear range of 1.5 * 10(-8)-3.0 * 10(-5) M and an estimated detection limit of 3.0 * 10(-9) M (S/N = 3). The feasibility of the developed electrode for tablet sample analysis was investigated. Our investigation revealed that GO could significantly improve the analytical performance of electrochemical sensors. PMID- 23448851 TI - Preimplantation genetic diagnosis for aneuploidy and translocations using array comparative genomic hybridization. AB - At least 50% of human embryos are abnormal, and that increases to 80% in women 40 years or older. These abnormalities result in low implantation rates in embryos transferred during in vitro fertilization procedures, from 30% in women <35 years to 6% in women 40 years or older. Thus selecting normal embryos for transfer should improve pregnancy results. The genetic analysis of embryos is called Preimplantation Genetic Diagnosis (PGD) and for chromosome analysis it was first performed using FISH with up to 12 probes analyzed simultaneously on single cells. However, suboptimal utilization of the technique and the complexity of fixing single cells produced conflicting results. PGD has been invigorated by the introduction of microarray testing which allows for the analysis of all 24 chromosome types in one test, without the need of cell fixation, and with staggering redundancy, making the test much more robust and reliable. Recent data published and presented at scientific meetings has been suggestive of increased implantation rates and pregnancy rates following microarray testing, improvements in outcome that have been predicted for quite some time. By using markers that cover most of the genome, not only aneuploidy can be detected in single cells but also translocations. Our validation results indicate that array CGH has a 6Mb resolution in single cells, and thus the majority of translocations can be analyzed since this is also the limit of karyotyping. Even for translocations with smaller exchanged fragments, provided that three out of the four fragments are above 6Mb, the translocation can be detected. PMID- 23448853 TI - Postanesthesia care unit simulation: acute upper airway obstruction secondary to laryngospasm. PMID- 23448854 TI - Comparison of success rates using video laryngoscopy versus direct laryngoscopy by residents during a simulated pediatric emergency. AB - OBJECTIVE: Emergency airway situations are relatively rare events in pediatrics with most graduating residents having little exposure to intubate. Newer video technology offers the promise of reducing complications associated with intubation. This study proposes that video laryngoscopy (VL) should aid less skilled residents to intubate an infant mannequin with greater success and speed as compared with traditional direct laryngoscopy (DL). METHODS: Pediatric (PED) and emergency medicine (EM) residents were randomized in a prospective controlled study. A standard respiratory failure scenario was conducted using SimBaby with an uncomplicated airway. Residents who inadvertently performed esophageal intubation were made aware as part of the scenario and allowed to reattempt until successful. RESULTS: Sixty-nine residents voluntarily participated, 49% EM and 51% PED. Seven subjects in the DL group required multiple attempts (21%), compared with 6 subjects in the VL group (17%) (P = 0.718). Median time to intubation was 30 seconds (95% confidence interval [CI], 19-41 seconds) for DL and 39 seconds (95% CI, 36-42 seconds) for VL (P = 0.111). Comparison of programs revealed a 77% PED success rate versus 85% EM success rate (P = 0.578) and median time to intubation of 38 seconds (95% CI, 31-45 seconds) for PED compared with 32 seconds (95% CI, 23-41 seconds) for EM residents (P = 0.316). In a subanalysis, subjects successful at first attempt revealed a 13-second median difference (DL, 23 seconds [95% CI, 18-28 seconds] vs. VL, 36 seconds [95% CI, 29-43 seconds; P = 0.01). CONCLUSIONS: In a simulated respiratory failure scenario involving residents, VL provided no additional success over DL with slightly longer time to intubation. PMID- 23448855 TI - Elearning: the next step in ISCOS's worldwide education on comprehensive spinal cord management. PMID- 23448856 TI - Improving the quality of systematic reviews in Spinal Cord. PMID- 23448857 TI - www.elearnSCI.org: a global educational initiative of ISCoS. AB - OBJECTIVE: To develop a web-based educational resource for health professionals responsible for the management of spinal cord injury (SCI). The resource:www.elearnSCI.org is comprised of seven learning modules, each subdivided into various submodules. Six of the seven modules address the educational needs of all disciplines involved in comprehensive SCI management. The seventh module addresses prevention of SCI. Each submodule includes an overview, activities, self-assessment questions and references. DEVELOPMENT OF THE RESOURCE: Three hundred and thirty-two experts from The International Spinal Cord Society (ISCoS) and various affiliated societies from 36 countries were involved in developing the resource through 28 subcommittees. The content of each submodule was reviewed and approved by the Education and Scientific Committees of ISCoS and finally by an Editorial Committee of 23 experts. KEY FEATURES: The content of the learning modules is relevant to students and to new as well as experienced SCI healthcare professionals. The content is applicable globally, has received consumer input and is available at no cost. The material is presented on a website underpinned by a sophisticated content-management system, which allows easy maintenance and ready update of all the content. The resource conforms to key principles of e-learning, including appropriateness of curriculum, engagement of learners, innovative approaches, effective learning, ease of use, inclusion, assessment, coherence, consistency, transparency, cost effectiveness and feedback. CONCLUSION: www.elearnSCI.org provides a cost effective way of training healthcare professionals that goes beyond the textbook and traditional face-to face teaching. PMID- 23448858 TI - Two-Year Follow-up of Sirolimus-Eluting Stents versus Paclitaxel-Eluting Stents in Acute Myocardial Infarction. AB - It has been shown that drug-eluting stents (DESs) significantly reduce restenosis rate when compared with bare-metal stents in a broad range of patients with coronary artery disease. However, current data are limited about the efficacy of different DESs in treatment of ST segment elevation myocardial infarction (STEMI). The aim of this study was to compare the effectiveness and safety of sirolimus-eluting stents (SESs) with paclitaxel-eluting stents (PESs) in primary percutaneous coronary intervention. We retrospectively examined 127 STEMI patients who underwent primary percutaneous coronary intervention. PES group consisted of 79 patients and SES group consisted of 48 patients. Patients were analyzed for major adverse cardiac events (MACE) and stent thrombosis (ST). The mean follow-up period was 2 years. The mean age was 53 +/- 11 years in the SES group and 59 +/- 11 years in the PES group (p = 0.03). Baseline and procedural characteristics were similar in the two groups except stent lengths, which was longer in the SES group. Two-year MACE rates were 8.3% in the SES group and 16.4% in the PES group (p = 0.28). Rates for ST for SES and PES groups were as follows: early ST was 2.08 versus 2.53%; late ST was 2.08 versus 2.53%; and very late ST was 2.08 versus 2.53% (p > 0.05). There were no statistically significant differences in MACE and ST rates between the SES and PES groups in the 2-year follow-up period. High ST rates detected in our study need to be clarified with future prospective and randomized clinical trials. PMID- 23448859 TI - Assessment of genotoxicity of inorganic mercury in rats in vivo using both chromosomal aberration and comet assays. AB - The major objective of the present investigation was to assess the genotoxic effects of mercuric chloride (HgCl2), an inorganic mercury (Hg), in rats (Rattus norvegicus) using two different genetic endpoints, namely, chromosomal aberration (CA) and comet assays following both short-term (acute) and long-term (chronic) exposures. The study showed that the acute exposures to HgCl2 at 2 and 5 mg/kg body weight (b.w.) induced nonsignificant effects. HgCl2 at 10 and 12 mg/kg b.w. was significantly toxic and is exhibited by the induction of different types of CAs like chromatid breaks, chromosomal breaks, clumps and damaged cells and types of comets. HgCl2 at 15 mg/kg b.w. was found to be highly toxic, as mitostatic condition of cells were observed in CA assay. Chronic exposure to the lowest dose (2 mg/kg b.w.) of HgCl2 for 15 consecutive days produced a significant genotoxicity. Although Hg was found to induce both DNA strand breakage and chromosomal breaks in a dose-dependent manner, the results of the present investigation showed that the combination of comet and CA assays provided a better choice for assessing the genotoxicity of inorganicHg. PMID- 23448860 TI - Extremely low-frequency magnetic field induces manganese accumulation in brain, kidney and liver of rats. AB - The aim of the present study was to determine the effects of extremely low frequency magnetic field (ELF-MF) on accumulation of manganese (Mn) in the kidney, liver and brain of rats. A total of 40 rats were randomly divided into eight groups. Four control groups received 0, 3.75, 15 and 60 mg Mn per kg body weight orally every 2 days for 45 days, respectively. The remaining four groups received same concentrations of Mn and were also exposed to ELF-MF (1.5 mT; 50 Hz) for 4 h for 5 days a week during 45 days. Following the last exposure, kidney, liver and brain were taken from all rats and they were analyzed for Mn accumulation levels using an inductively coupled plasma-optical emission spectrometer. In result of the current study, we observed that Mn levels in brain, kidney and liver were higher in Mn groups than in control groups. Mn levels in brain, kidney and liver were also higher in Mn plus ELF-MF groups than in Mn groups. In conclusion, result of the current study showed that the ELF-MF induced manganese accumulation in kidney, liver and brain of rats. PMID- 23448861 TI - Acute respiratory distress syndrome due to exposure to high-concentration mixture of ethenone and crotonaldehyde. AB - INTRODUCTION: Acute inhalational exposure leads to rapidly progressive acute respiratory distress syndrome (ARDS). This report is the first one to present a patient with ARDS in relation to long-standing exposure to a high-concentration mixture of ethenone and crotonaldehyde. CASE REPORT: A male worker in a chemical plant was accidentally exposed to the mixture of high-concentrated ethenone and crotonaldehyde for 5 min in an open space and worked continuously in the polluted area for approximately 12 h. On admission, he was conscious with the following vital parameters: blood pressure, 151/91 mmHg; pulse rate, 107 beats/min; respiratory rate, 30 breaths/min; temperature, 37.6 degrees C; oxygen saturation, 92% supported by mask saturation 10 L/min; arterial blood gases showed P/F oxygen ratio of less than 200. Physical examination disclosed decreased bilateral vesicular sounds. A chest computed tomography revealed bilateral nonsegmental ground-glass opacities. The patient was mechanically ventilated and treated with corticosteroid. The patient was discharged without any symptoms. CONCLUSION: Exposure to mixtures of ethenone and crotonaldehyde can cause severe pulmonary injury leading to delayed ARDS. PMID- 23448862 TI - Density functional theory study of the electronic structure of fluorite Cu2Se. AB - We have investigated the electronic structure of fluorite Cu2Se using density functional theory calculations within the LDA, PBE and AM05 approximations as well as the non-local hybrid PBE0 and HSE approximations. We find that Cu2Se is a zero gap semiconductor when using either a local or semi-local density functional approximation while the PBE0 functional opens up a gap. For the HSE approximation, we find that the presence of a gap depends on the range separation for the non-local exchange. For the occupied part in the density of states we find that LDA, PBE, AM05, PBE0 and HSE agree with regard to the overall electronic structure. However, the hybrid functionals result in peaks shifted towards lower energy compared to LDA, PBE and AM05. The valence bands obtained using the hybrid functionals are in good agreement with experimental valence band spectra. We also find that the PBE, PBE0 and HSE approximations give similar results regarding bulk properties, such as lattice constants and bulk modulus. In addition, we have investigated the localization of the Cu d-states and its effect on the band gap in the material using the LDA + U approach. We find that a sufficiently high U indeed opens up a gap; however, this U leads to valence bands that disagree with experimental observations. PMID- 23448863 TI - Accessing electronic administrative health data for research takes time. PMID- 23448864 TI - Impact of internet use on loneliness and contact with others among older adults: cross-sectional analysis. AB - BACKGROUND: Older adults are at increased risk of experiencing loneliness and depression, particularly as they move into different types of care communities. Information and communication technology (ICT) usage may help older adults to maintain contact with social ties. However, prior research is not consistent about whether ICT use increases or decreases isolation and loneliness among older adults. OBJECTIVE: The purpose of this study was to examine how Internet use affects perceived social isolation and loneliness of older adults in assisted and independent living communities. We also examined the perceptions of how Internet use affects communication and social interaction. METHODS: One wave of data from an ongoing study of ICT usage among older adults in assisted and independent living communities in Alabama was used. Regression analysis was used to determine the relationship between frequency of going online and isolation and loneliness (n=205) and perceptions of the effects of Internet use on communication and social interaction (n=60). RESULTS: After controlling for the number of friends and family, physical/emotional social limitations, age, and study arm, a 1-point increase in the frequency of going online was associated with a 0.147-point decrease in loneliness scores (P=.005). Going online was not associated with perceived social isolation (P=.14). Among the measures of perception of the social effects of the Internet, each 1-point increase in the frequency of going online was associated with an increase in agreement that using the Internet had: (1) made it easier to reach people (b=0.508, P<.001), (2) contributed to the ability to stay in touch (b=0.516, P<.001), (3) made it easier to meet new people (b=0.297, P=.01, (4) increased the quantity of communication with others (b=0.306, P=.01), (5) made the respondent feel less isolated (b=0.491, P<.001), (6) helped the respondent feel more connected to friends and family (b=0.392, P=.001), and (7) increased the quality of communication with others (b=0.289, P=.01). CONCLUSIONS: Using the Internet may be beneficial for decreasing loneliness and increasing social contact among older adults in assisted and independent living communities. PMID- 23448865 TI - The geographic relationship between sexual health deprivation and the Index of Multiple Deprivation 2010: a comparison of two indices. AB - OBJECTIVES: To construct an Index of Sexual Health Deprivation (ISHD), examine its sensitivity, investigate the association between the ISHD and the Index of Multiple Deprivation 2010 (IMD2010), and interpret the observed geographic variation. METHODS: The modified IMD method was informed by the IMD2010. Thirteen profiles relating to sexual health were selected and grouped into four domains. The observed profile values for each primary care trust (PCT) were smoothed and converted to a normal distribution before principal component analysis. Loadings were used to calculate profile weights. Domain scores were calculated by combining weighted profiles, which were combined to create the ISHD. A Bayesian approach acted as a comparator for the ISHD. RESULTS: Substantial variation in sexual health deprivation was seen across strategic health authorities (SHA). The London SHA had the highest proportion of PCTs (61%) among the most deprived quartile, followed by North-West SHA (29%). More than half of PCTs in East of England (71%), South Central (56%) and South-West (50%) SHAs fell into the least deprived quartile. No PCTs within the East of England, South Central and South West SHAs were in the most deprived quartile. Only 57% of PCTs were attributed to the same quartile of the ISHD as the IMD2010. The modified IMD method and the Bayesian approach produced consistent results. CONCLUSIONS: The ISHD provides a robust picture of the geography of sexual health and shows a weak association with the IMD2010. It can be used to guide public health action to reduce the geographical gradient in sexual health inequality. PMID- 23448866 TI - Determinants of patient satisfaction 1 year after presenting to primary care with acute low back pain. AB - OBJECTIVES: To determine predictors of satisfaction with care and symptoms in patients with acute low back pain 1 year after presentation to primary care. METHODS: The study is a secondary analysis of an existing cohort study of 1343 patients with acute low back pain presenting to primary care. Participants presenting to general practitioners, physiotherapists, or chiropractors were assessed at the initial consultation and followed up over 12 months. Putative predictors of patient satisfaction were extracted from baseline questionnaires. Multivariate logistic regression models were developed to predict satisfaction with care and satisfaction with symptoms at the 12-month follow-up. RESULTS: Most patients were highly satisfied with the care received (76%) and a smaller proportion with their symptoms (55%) at 12 months. Pain intensity at 12 months had a strong association with both measures of satisfaction. After controlling for the level of pain intensity, those born outside Australia, older people, and those reporting more symptoms of depression were less likely to be satisfied with the care received. Patients reporting poor general health at the initial visit and more symptoms of depression were less likely to be satisfied with their symptoms at the 12-month follow-up. DISCUSSION: Pain intensity at the 12-month follow-up has a strong association with patient satisfaction. Primary care practitioners should remain aware of the influence of cultural, demographic, and psychological factors on satisfaction with care and symptoms. PMID- 23448867 TI - Does brain reserve protect older women from vascular depression? AB - OBJECTIVES: Brain reserve theory, typically discussed in relation to dementia, was examined with regard to late-life depression symptomatology and cerebrovascular burden (CVB) in older-old women. METHOD: It was predicted that in a 6-year longitudinal sample (Health and Retirement Study) of 1,355 stroke-free women aged 80 years and older, higher levels of depressive symptomatology (8-item Center for Epidemiologic Studies-Depression score) would be predicted by high CVB, less educational attainment, and the education * CVB interaction after controlling for age and cognitive functioning (Telephone Interview for Cognitive Status). A latent growth curve model was used to identify differences in depression symptomatology at baseline and over time. Logistic regression analyses were used to predict clinically significant depressive symptomatology at each wave based on CVB, education, and the education * CVB interaction. RESULTS: Results indicate that among older women, greater educational attainment predicted fewer depression symptoms at baseline, but this advantage was partially eroded over time. The education * CVB interaction predicted clinically significant depressive symptoms at baseline when the benefits of education were most robust. DISCUSSION: Brain reserve, characterized by educational attainment, may counterbalance the effect of high CVB with respect to depressive symptoms, thereby preserving mood in late life. These findings support the application of brain reserve theory to late-life depression. PMID- 23448868 TI - Contributions of medial temporal lobe and striatal memory systems to learning and retrieving overlapping spatial memories. AB - Many life experiences share information with other memories. In order to make decisions based on overlapping memories, we need to distinguish between experiences to determine the appropriate behavior for the current situation. Previous work suggests that the medial temporal lobe (MTL) and medial caudate interact to support the retrieval of overlapping navigational memories in different contexts. The present study used functional magnetic resonance imaging (fMRI) in humans to test the prediction that the MTL and medial caudate play complementary roles in learning novel mazes that cross paths with, and must be distinguished from, previously learned routes. During fMRI scanning, participants navigated virtual routes that were well learned from prior training while also learning new mazes. Critically, some routes learned during scanning shared hallways with those learned during pre-scan training. Overlap between mazes required participants to use contextual cues to select between alternative behaviors. Results demonstrated parahippocampal cortex activity specific for novel spatial cues that distinguish between overlapping routes. The hippocampus and medial caudate were active for learning overlapping spatial memories, and increased their activity for previously learned routes when they became context dependent. Our findings provide novel evidence that the MTL and medial caudate play complementary roles in the learning, updating, and execution of context dependent navigational behaviors. PMID- 23448869 TI - Age-related changes in tissue signal properties within cortical areas important for word understanding in 12- to 19-month-old infants. AB - Recently, our laboratory has shown that the neural mechanisms for encoding lexico semantic information in adults operate functionally by 12-18 months of age within left frontotemporal cortices (Travis et al., 2011. Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants. Cereb Cortex. 8:1832-1839). However, there is minimal knowledge of the structural changes that occur within these and other cortical regions important for language development. To identify regional structural changes taking place during this important period in infant development, we examined age-related changes in tissue signal properties of gray matter (GM) and white matter (WM) intensity and contrast. T1-weighted surface based measures were acquired from 12- to 19-month-old infants and analyzed using a general linear model. Significant age effects were observed for GM and WM intensity and contrast within bilateral inferior lateral and anterovental temporal regions, dorsomedial frontal, and superior parietal cortices. Region of interest (ROI) analyses revealed that GM and WM intensity and contrast significantly increased with age within the same left lateral temporal regions shown to generate lexico-semantic activity in infants and adults. These findings suggest that neurophysiological processes supporting linguistic and cognitive behaviors may develop before cellular and structural maturation is complete within associative cortices. These results have important implications for understanding the neurobiological mechanisms relating structural to functional brain development. PMID- 23448871 TI - Postsynaptic NO/cGMP increases NMDA receptor currents via hyperpolarization activated cyclic nucleotide-gated channels in the hippocampus. AB - The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiological analysis of hippocampal CA1 neurons in whole-cell recordings revealed a reduction of HCN currents and a hyperpolarizing shift of the activation curve in the NO-GC2 KOs associated with reduced resting membrane potentials. These features were mimicked in wild-type (WT) neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in the NO GC2 KO mice, which was mimicked in WT by HCN channel inhibition. Lowering extracellular Mg(2+) increased NMDA receptor currents in the NO-GC2 KO and allowed the induction of LTP that was absent at physiological Mg(2+). In sum, our data indicate that postsynaptic cGMP increases the N-methyl-D-aspartate (NMDA) receptor current by gating HCN channels and thereby is required for LTP. PMID- 23448870 TI - Neural correlates of covert face processing: fMRI evidence from a prosopagnosic patient. AB - Brains can perceive or recognize a face even though we are subjectively unaware of the existence of that face. However, the exact neural correlates of such covert face processing remain unknown. Here, we compared the fMRI activities between a prosopagnosic patient and normal controls when they saw famous and unfamiliar faces. When compared with objects, the patient showed greater activation to famous faces in the fusiform face area (FFA) though he could not overtly recognize those faces. In contrast, the controls showed greater activation to both famous and unfamiliar faces in the FFA. Compared with unfamiliar faces, famous faces activated the controls', but not the patient's lateral prefrontal cortex (LPFC) known to be involved in familiar face recognition. In contrast, the patient showed greater activation in the bilateral medial frontal gyrus (MeFG). Functional connectivity analyses revealed that the patient's right middle fusiform gyrus (FG) showed enhanced connectivity to the MeFG, whereas the controls' middle FG showed enhanced connectivity to the LPFC. These findings suggest that the FFA may be involved in both covert and overt face recognition. The patient's impairment in overt face recognition may be due to the absence of the coupling between the right FG and the LPFC. PMID- 23448873 TI - Essential role of the perirhinal cortex in complex tactual discrimination tasks in rats. AB - We designed a battery of tactual discrimination tasks to study whether rats with perirhinal cortex (Prh) lesions had any deficit in resolving complex/ambiguous tactual tasks in the dark. Animals had to discriminate among 3 stimuli simultaneously exposed in 3 arms of a 4-arm plus-shaped maze. Rats with Prh lesions showed a profound impairment in a texture discrimination learning task when the stimuli had a high or intermediate degree of feature ambiguity (experiments 1a and 1b), but not when they had a low degree of feature ambiguity (experiment. 1c). Hippocampal lesions, however, did not cause any impairment in task acquisition even when the stimuli had a high degree of feature ambiguity (experiment 2). Experiments 3a, 3b, and 4 showed that perirhinal and control rats performed the task similarly when the animals had to discriminate on the basis of simple/individual, nonoverlapping features of the stimuli (size) with different levels of difficulty. Finally, to isolate the task's memory functions from its perceptual functions, a reversal learning task revealed a profound deficit in the initial learning phase, but unimpaired learning in the reversal phase with identical stimuli (experiment 5). The findings suggest that the Prh plays an essential role in somatosensory perceptual functions. PMID- 23448872 TI - A long-range fronto-parietal 5- to 10-Hz network predicts "top-down" controlled guidance in a task-switch paradigm. AB - The capacity to rapidly adjust behavioral strategies according to changing task demands is closely associated with coordinated activity in lateral and medial prefrontal cortices. Subdivisions within prefrontal cortex are implicated to encode attentional task sets and to update changing task rules, particularly when changing task demands require top-down control. Here, we tested whether these top down processes precede stimulus processing and constitute a preparatory attentional state that functionally couples with parietal cortex. We examined this functional coupling by recording from intracranial EEG electrodes in macaques during performance of a task-switching paradigm that separates task performance that is based on controlled top-down guidance from automatic, stimulus-triggered processing modes. We identify a prefrontal-parietal network that phase synchronizes at 5-10 Hz, particularly during preparatory states that indicate top-down controlled task-processing modes. Phase relations in the network suggest that medial and lateral prefrontal cortices synchronize bidirectionally, with medial prefrontal cortex showing a phase-lead relative to left parietal recorded 5- to 10-Hz preparatory signals. These findings reveal a 5 to 10-Hz coordinated, long-range fronto-parietal network prior to actual task relevant stimulus processing, particularly when subjects engage in controlled task processing modes. PMID- 23448874 TI - Impaired development and competitive refinement of the cortical frequency map in tumor necrosis factor-alpha-deficient mice. AB - Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor alpha (TNF-alpha) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-alpha KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-alpha KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development. PMID- 23448875 TI - Functional networks in parallel with cortical development associate with executive functions in children. AB - Children begin performing similarly to adults on tasks requiring executive functions in late childhood, a transition that is probably due to neuroanatomical fine-tuning processes, including myelination and synaptic pruning. In parallel to such structural changes in neuroanatomical organization, development of functional organization may also be associated with cognitive behaviors in children. We examined 6- to 10-year-old children's cortical thickness, functional organization, and cognitive performance. We used structural magnetic resonance imaging (MRI) to identify areas with cortical thinning, resting-state fMRI to identify functional organization in parallel to cortical development, and working memory/response inhibition tasks to assess executive functioning. We found that neuroanatomical changes in the form of cortical thinning spread over bilateral frontal, parietal, and occipital regions. These regions were engaged in 3 functional networks: sensorimotor and auditory, executive control, and default mode network. Furthermore, we found that working memory and response inhibition only associated with regional functional connectivity, but not topological organization (i.e., local and global efficiency of information transfer) of these functional networks. Interestingly, functional connections associated with "bottom-up" as opposed to "top-down" processing were more clearly related to children's performance on working memory and response inhibition, implying an important role for brain systems involved in late childhood. PMID- 23448876 TI - High stakes trigger the use of multiple memories to enhance the control of attention. AB - We can more precisely tune attention to highly rewarding objects than other objects in our environment, but how our brains do this is unknown. After a few trials of searching for the same object, subjects' electrical brain activity indicated that they handed off the memory representations used to control attention from working memory to long-term memory. However, when a large reward was possible, the neural signature of working memory returned as subjects recruited working memory to supplement the cognitive control afforded by the representations accumulated in long-term memory. The amplitude of this neural signature of working memory predicted the magnitude of the subsequent behavioral reward-based attention effects across tasks and individuals, showing the ubiquity of this cognitive reaction to high-stakes situations. PMID- 23448877 TI - Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. AB - Malassezia yeasts are commensal microorganisms, which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia-associated diseases demonstrated 10- to 1,000-fold higher AhR activating capacity than control skin extracts. Liquid chromatography-tandem mass spectrometry analysis of the patients' extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9 out of 12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture extracts and pure metabolites in HaCaT cells by reverse transcriptase real-time PCR revealed significant alterations in mRNA levels of the endogenous AhR responsive genes Cyp1A1, Cyp1B1, and AhRR. Indirubin- and FICZ-activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared with the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development. PMID- 23448878 TI - Methylprednisolone blocks autoantibody-induced tissue damage in experimental models of bullous pemphigoid and epidermolysis bullosa acquisita through inhibition of neutrophil activation. AB - Corticosteroids are regularly used to treat autoimmune diseases, such as bullous pemphigoid (BP). In BP, autoantibodies bind to type XVII collagen (COL17), located at the dermal-epidermal junction. A crucial role of neutrophils in experimental BP has been established. Specifically, reactive oxygen species and proteolytic granule enzymes mediate tissue injury. Therefore, we investigated the effects of methylprednisolone (MP) on neutrophils, which are likely to be affected by topical treatment. First, MP inhibited dermal-epidermal separation ex vivo in cryosections of the human skin induced by co-incubation of BP autoantibodies with neutrophils from healthy volunteers. Next, MP inhibited neutrophil activation in vitro induced by immune complexes (ICs) of COL17 and autoantibodies. This neutrophil activation was associated with phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and Akt. In turn, inhibition of ERK1/2, p38 MAPK, or Akt phosphorylation inhibited neutrophil activation by IC in vitro and dermal epidermal separation ex vivo. In addition, we observed an increase of p38 MAPK phosphorylation in dermal infiltrates of BP patients. Treatment of mice with either MP or inhibitors of p38-MAPK or ERK1/2 phosphorylation impaired induction of autoantibody- or irritant-induced neutrophil-dependent inflammation. We here identify the inhibition of Akt, ERK1/2, and p38 MAPK phosphorylation as molecular mechanisms to promote MP's therapeutic effects. PMID- 23448879 TI - Neurocognition in psychometrically defined college Schizotypy samples: we are not measuring the "right stuff". AB - Although neurocognitive deficits are an integral characteristic of schizophrenia, there is inconclusive evidence as to whether they manifest across the schizophrenia-spectrum. We conducted two studies and a meta-analysis comparing neurocognitive functioning between psychometrically defined schizotypy and control groups recruited from a college population. Study One compared groups on measures of specific and global neurocognition, and subjective and objective quality of life. Study Two examined working memory and subjective cognitive complaints. Across both studies, the schizotypy group showed notably decreased subjective (d51.52) and objective (d51.02) quality of life and greater subjective cognitive complaints (d51.88); however, neurocognition was normal across all measures (d's,.35). Our meta-analysis of 33 studies examining neurocognition in at-risk college students revealed between-group differences in the negligible effect size range for most domains. The schizotypy group demonstrated deficits of a small effect size for working memory and set-shifting abilities. Although at risk individuals report relatively profound neurocognitive deficits and impoverished quality of life, neurocognitive functioning assessed behaviorally is largely intact. Our data suggest that traditionally defined neurocognitive deficits do not approximate the magnitude of subjective complaints associated with psychometrically defined schizotypy. PMID- 23448880 TI - Selection gradients, the opportunity for selection, and the coefficient of determination. AB - Abstract We derive the relationship between R(2) (the coefficient of determination), selection gradients, and the opportunity for selection for univariate and multivariate cases. Our main result is to show that the portion of the opportunity for selection that is caused by variation for any trait is equal to the product of its selection gradient and its selection differential. This relationship is a corollary of the first and second fundamental theorems of natural selection, and it permits one to investigate the portions of the total opportunity for selection that are involved in directional selection, stabilizing (and diversifying) selection, and correlational selection, which is important to morphological integration. It also allows one to determine the fraction of fitness variation not explained by variation in measured phenotypes and therefore attributable to random (or, at least, unknown) influences. We apply our methods to a human data set to show how sex-specific mating success as a component of fitness variance can be decoupled from that owing to prereproductive mortality. By quantifying linear sources of sexual selection and quadratic sources of sexual selection, we illustrate that the former is stronger in males, while the latter is stronger in females. PMID- 23448881 TI - Unexpected consequences of culling on the eradication of wildlife diseases: the role of virulence evolution. AB - The removal of individuals from an infected population (culling) is a common strategy used to eradicate wildlife diseases. The manipulation of host density can impose strong selective pressures on pathogen virulence by changing the ecological conditions, thus affecting the effectiveness of eradication programs. We present an analysis of the effect of virulence evolution on culling by extending a susceptible-infected model to the case of competing strains with superinfection. To assess both short- and long-term effects, we first carried out the analysis on an ecological timescale, with a two-strain competition model; then we explore the dynamics of a continuum of pathogenic strains on evolutionary timescales using a quantitative genetics approach (when infection and evolutionary processes occur on comparable timescales) and a game-theoretic approach (when evolutionary processes occur on a slower scale). We demonstrate that the competition among pathogenic variants in the presence of superinfection affects outcome of culling campaigns, since increased host mortality may select for less virulent strains able to establish in sparser populations. This can lead to the counterintuitive result that disease abundance and prevalence may even increase with culling, thus making the eradication of infections considerably less likely. This is particularly relevant in the case of zoonoses where higher prevalence and abundance of pathogens in wild reservoirs may increase the risk of spillover in livestock and humans. PMID- 23448882 TI - Competition for water and light in closed-canopy forests: a tractable model of carbon allocation with implications for carbon sinks. AB - Abstract The dependence of forest productivity and community composition on rainfall is the result of complex interactions at multiple scales, from the physiology of carbon gain and water loss to competition among individuals and species. In an effort to understand the role of these multiscale interactions in the dependence of forest structure on rainfall, we build a tractable model of individual plant competition for water and light. With game-theoretic analyses, we predict the dominant plant allocation strategy, forest productivity, and carbon storage. We find that the amount and timing of rainfall are critical to forest structure. Comparing two forests that differ only in the total time plants spend in water saturation, the model predicts that the wetter forest has fewer fine roots, more leaves, and more woody biomass than the drier forest. In contrast, if two forests differ only in the amount of water available during water limitation, the model predicts that the wetter forest has more fine roots than the drier forest and equivalent leaves and woody biomass. The difference in these responses to increases in water availability has significant implications for potential carbon sinks with rising atmospheric CO2. We predict that enhanced productivity from increased leaf-level water-use efficiency during water limitation will be allocated to fine roots if plants respond competitively, producing only a small and short-lived carbon sink. PMID- 23448883 TI - Density-dependent energy use contributes to the self-thinning relationship of cohorts. AB - In resource-limited populations, an increase in average body size can occur only with a decline in abundance. This is known as self-thinning, and the decline in abundance in food-limited populations is considered proportional to the scaling of metabolism with body mass. This popular hypothesis may be inaccurate, because self-thinning populations can also experience density-dependent competition, which could alter their energy use beyond the predictions of metabolic scaling. This study tested whether density-dependent competition has an energetic role in self-thinning, by manipulating the abundance of the fish Macquaria novemaculeata and tank size to partition the effects of competition from metabolic scaling. We found that self-thinning can be density dependent and that changes in intraspecific competition may be more influential than metabolic scaling on self thinning relationships. The energetic mechanism we propose is that density dependent competition causes variation in the allocation of energy to growth, which alters the energetic efficiency of self-thinning cohorts. The implication is that food-limited cohorts and populations with competitive strategies that encourage fast-growing individuals will have less body mass at equilibrium and higher mortality rates. This finding sheds light on the processes structuring populations and can be used to explain inconsistencies in the mass-abundance scaling of assemblages and communities (the energetic-equivalence rule). PMID- 23448884 TI - Explaining the effects of floral density on flower visitor species composition. AB - Floral density often influences the species composition of flower visitors. This variation in visitor species composition could have significant effects on pollination success and plant fitness but is poorly understood, especially in the many pollination guilds dominated by nonterritorial species. This article presents a foraging model that explores how flower visitors with diverse traits should distribute themselves across resource patches differing in floral density. The model predicts that species with low flower search speeds and low flower handling costs compared to those of competitors will usually dominate dense flower patches. In addition, among flower visitors that have lower energy expenditure rates while handling flowers than while traveling, species maximizing energetic efficiency are typically associated with dense flower patches, whereas those maximizing net rate of energy intake are associated with sparse patches. The model is able to predict some key aspects of a previously observed effect of floral density on species composition of flower visitors to the yellowflower tarweed (Holocarpha virgata). By providing insights into how flower visitors' traits shape the effects of floral density on the species composition of flower visitors, this study makes an important step towards understanding how pollinator diversity influences relationships between plant density and plant fitness. PMID- 23448885 TI - Does the risk of sperm competition help explain cooperation between reproductive competitors? A study in the ocellated wrasse (Symphodus ocellatus). AB - Although cooperating individuals may gain benefits, they risk being cheated by their allies. Therefore, to understand the persistence of cooperation by mutual benefits, it is important to document both the potential benefits of cooperation and the risks of cheating. We experimentally examined evidence of cooperation in the ocellated wrasse (Symphodus ocellatus), a fish species with males that exercise three reproductive strategies: satellite and sneaker males attempt to parasitically spawn in the nests of nesting males. Nesting males have been hypothesized to tolerate satellites as a result of satellite aid in defense against sneaker males and help in courting females. Here, we provide evidence that cooperation between reproductive competitors may arise in response to sperm competition from other males. After we experimentally removed satellites, nesting males had more sneakers at their nest and experienced a higher rate of sneaking when they spawned (increased sperm competition risk). When we experimentally distracted nesting males to prevent their acting aggressively toward satellites, satellites spawned with females and ate eggs in the nest. Our results suggest that nesting males and satellites gain fitness benefits of reduced direct reproductive and sperm competition through cooperation. However, nesting males risk losing paternity, while satellites experience increased aggression and must invest in aggression themselves (i.e., they act aggressively toward sneakers). PMID- 23448886 TI - A general allometric and life-history model for cellular differentiation in the transition to multicellularity. AB - The transition from unicellular, to colonial, to larger multicellular organisms has benefits, costs, and requirements. Here we present a model inspired by the volvocine green algae that explains the dynamics involved in the unicellular multicellular transition using life-history theory and allometry. We model the two fitness components (fecundity and viability) and compare the fitness of hypothetical colonies of different sizes with varying degrees of cellular differentiation to understand the general principles that underlie the evolution of multicellularity. We argue that germ-soma separation may have evolved to counteract the increasing costs and requirements of larger multicellular colonies. The model shows that the cost of investing in soma decreases with size. For lineages such as the Volvocales, as reproduction costs increase with size for undifferentiated colonies, soma specialization benefits the colony indirectly by decreasing such costs and directly by helping reproductive cells acquire resources for their metabolic needs. Germ specialization is favored once soma evolves and takes care of vegetative functions. To illustrate the model, we use some allometric relationships measured in Volvocales. Our analysis shows that the cost of reproducing an increasingly larger group has likely played an important role in the transition to multicellularity and cellular differentiation. PMID- 23448887 TI - Optimal foraging of little egrets and their prey in a foraging game in a patchy environment. AB - We explored the behavioral game between a predator, the little egret (Egretta garzetta), and a prey, the common goldfish (Carassius auratus), in a laboratory theater containing three fish pools. We tested the hypotheses that the egrets maximize their total capture success by responding to the fish's antipredatory behavior and that the behaviors of both players respond adaptively to the density distribution of fish among the pools. One experiment presented egrets with 15 fish per pool. The second experiment used a heterogeneous environment: pools 1, 2, and 3 had 10, 15, and 20 fish, respectively. Within each pool, fish could move between a safe, covered microhabitat and a risky, open microhabitat. Only the risky habitat had food, so fish were trading off food and safety by allocating the time spent in the two habitats. Egrets spent more total time in pools with more fish and returned to them sooner. Egrets maximized the number of fish they captured by following the matching rule of the ideal free distribution. The fish used the risky but productive habitat 65% of the time during experiments without egrets, but only 9% during experiments with 15 fish and egrets present somewhere in the theater. In addition, with egrets present, fish fine-tuned their behavior by reducing their use of the risky habitat as the egrets increased the frequency of their visits. PMID- 23448888 TI - Iridophores and not carotenoids account for chromatic variation of carotenoid based coloration in common lizards (Lacerta vivipara). AB - Abstract Carotenoids typically need reflective background components to shine. Such components, iridophores, leucophores, and keratin- and collagen-derived structures, are generally assumed to show no or little environmental variability. Here, we investigate the origin of environmentally induced variation in the carotenoid-based ventral coloration of male common lizards (Lacerta vivipara) by investigating the effects of dietary carotenoids and corticosterone on both carotenoid- and background-related reflectance. We observed a general negative chromatic change that was prevented by beta-carotene supplementation. However, chromatic changes did not result from changes in carotenoid-related reflectance or skin carotenoid content but from changes in background-related reflectance that may have been mediated by vitamin A1. An in vitro experiment showed that the encountered chromatic changes most likely resulted from changes in iridophore reflectance. Our findings demonstrate that chromatic variation in carotenoid based ornaments may not exclusively reflect differences in integumentary carotenoid content and, hence, in qualities linked to carotenoid deposition (e.g., foraging ability, immune response, or antioxidant capacity). Moreover, skin carotenoid content and carotenoid-related reflectance were related to male color polymorphism, suggesting that carotenoid-based coloration of male common lizards is a multicomponent signal, with iridophores reflecting environmental conditions and carotenoids reflecting genetically based color morphs. PMID- 23448889 TI - Contributions of covariance: decomposing the components of stochastic population growth in Cypripedium calceolus. AB - Although correlations between vital rates can have important effects on evolution and demography, few studies have investigated their effects on population dynamics. Here, we extend life-table response experiments (LTREs) to variable environments, showing how to quantify contributions made by (1) mean vital rates, (2) variability driven by environmental fluctuations, (3) correlations implying demographic trade-offs and reflecting stage transition synchrony, and (4) elasticities reflecting local selection pressures. Applying our methods to the lady's slipper orchid Cypripedium calceolus, we found that mean rates accounted for 77.1% of all effects on the stochastic growth rate, variability accounted for 12.6%, elasticities accounted for 6.6%, and correlations accounted for 3.7%. Stochastic effects accounted for 17.6%, 15.3%, and 35.9% of the total in our three populations. Larger elasticities to transitions between dormancy states and stronger correlations between emergence and survival suggest that one population was under greater pressure to remain active while the other two showed survival payoffs for dormancy in poor years. Strong negative correlations between dormancy, emergence, and stasis balanced opposing contributions, resulting in near stationarity in two populations. These new methods provide an additional tool for researchers investigating stochastic population dynamics and should be useful for a broad range of applications in basic ecology and conservation biology. PMID- 23448890 TI - General models for the spectra of surface area scaling strategies of cells and organisms: fractality, geometric dissimilitude, and internalization. AB - Surface areas and volumes of biological systems-from molecules to organelles, cells, and organisms-affect their biological rates and kinetics. Therefore, surface area-to-volume ratios and the scaling of surface area with volume profoundly influence ecology, physiology, and evolution. The zeroth-order geometric expectation is that surface area scales with body mass or volume as a power law with an exponent of two-thirds, with consequences for surface area-to volume (SA : V) ratios and constraints on size; however, organisms have adaptations for altering the surface area scaling and SA : V ratios of their bodies and structures. The strategies fall into three groups: (1) fractal-like surface convolutions and crinkles; (2) classic geometric dissimilitude through elongating, flattening, fattening, and hollowing; and (3) internalization of surfaces. Here I develop general quantitative theory to model the spectra of effects of these strategies on SA : V ratios and surface area scaling, from exponents of less than two-thirds to superlinear scaling and mixed-power laws. Applying the theory to cells helps quantitatively evaluate the effects of membrane fractality, shape-shifting, vacuoles, vesicles, and mitochondria on surface area scaling, informing understanding of cell allometry, morphology, and evolution. Analysis of compiled data indicates that through hollowness and surface internalization, eukaryotic phytoplankton increase their effective surface area scaling, attaining near-linear scaling in larger cells. This unifying theory highlights the fundamental role of biological surfaces in metabolism and morphological evolution. PMID- 23448891 TI - Levy meets poisson: a statistical artifact may lead to erroneous recategorization of Levy walk as Brownian motion. AB - The flow of GPS data on animal space is challenging old paradigms, such as the issue of the scale-free Levy walk versus scale-specific Brownian motion. Since these movement classes often require different protocols with respect to ecological analyses, further theoretical development in this field is important. I describe central concepts such as scale-specific versus scale-free movement and the difference between mechanistic and statistical-mechanical levels of analysis. Next, I report how a specific sampling scheme may have produced much confusion: a Levy walk may be wrongly categorized as Brownian motion if the duration of a move, or bout, is used as a proxy for step length and a move is subjectively defined. Hence, the categorization and recategorization of movement class compliance surrounding the Levy walk controversy may have been based on a statistical artifact. This issue may be avoided by collecting relocations at a fixed rate at a temporal scale that minimizes over- and undersampling. PMID- 23448892 TI - Are mixed-species bird flocks stable through two decades? AB - The stability of tropical systems has been hypothesized to explain the evolution of complex behavioral interactions among species. We evaluate the degree to which one highly evolved social system, mixed-species flocks, are stable in space and time in French Guiana, where flocks were characterized 17 years apart. These flocks are led by alarm-calling "sentinels," which may benefit from food flushed by other "beater" species. Using null models, we found that flock roost sites, home range overlap, and composition were more similar than expected by chance; home ranges were nearly identical between the two time periods. Such extremely stable conditions may be essential for the evolution and maintenance of the sentinel-beater system that appears to characterize some flocks. These results may reflect an evolutionarily stable strategy among potentially interdependent species within mixed-species flocks, where home ranges contribute to stability by being far larger than the most common local disturbances in the forest. PMID- 23448893 TI - Haplodiploidy, sex-ratio adjustment, and eusociality. AB - Hamilton's "haplodiploidy hypothesis" holds that inflated sororal relatedness has promoted altruistic sib rearing in haplodiploids, potentially explaining their apparent predisposition to eusociality. Here, we suggest that haplodiploidy may instead promote eusociality simply by facilitating sex-ratio adjustment. Specifically, haplodiploidy may enable sex-ratio bias toward the more helpful sex, owing to "local resource enhancement," and such sex-ratio bias may promote the evolution of helping by individuals of that sex, owing to the "rarer-sex effect." This could explain why haplodiploidy appears to have been important for eusociality in taxa with only female helpers, such as ants, wasps, and bees, but not in taxa with both male and female helpers, such as termites. PMID- 23448894 TI - New concepts for CML clonality. PMID- 23448895 TI - Effects of interfacial charge and the particle size of titanate nanotube supported Pt nanoparticles on the hydrogenation of cinnamaldehyde. AB - The oxidation state and size of Pt nanoparticles attached to alkali metal titanate nanotubes (MTNTs=M2Ti3O7, M = Li(+), Na(+), K(+), Cs(+)) via ion exchange (indicated by the added label '-IE') and wet impregnation (indicated by the added label '-IMP') methods varied systematically with the cation of the MTNTs. X-ray photoelectron spectroscopy revealed that the binding energy of Pt was reduced to a low value when the support was changed from LiTNTs to CsTNTs, yielding a Pt(delta-) oxidation state. Thus, a space charge layer (SCL) was constructed at the interface between the Pt particle and MTNT support; the former carried the negative charge, and the alkali cation and proton in the hydroxyl group of the latter carried the positive charge. Due to a higher M/Ti atomic ratio in MTNTs, a higher electron density accumulated on Pt particles in Pt/MTNTs IMP than on those in Pt/MTNTs-IE. Sub-ambient temperature temperature-programmed reduction and transmission electron microscopy revealed that because of the difference in reducibility of PtOx/MTNTs, the mean Pt particle size followed the order Pt/CsTNTs > Pt/KTNTs > Pt/NaTNTs > Pt/LiTNTs and Pt/MTNTs-IMP > Pt/MTNTs IE. DRIFTS (diffuse reflectance infrared Fourier transform spectroscopy) showed that owing to its interaction with SCL, cinnamaldehyde adsorbed on Pt mainly through the C=C bond at the Pt-MTNT interfaces, and the small Pt particles in Pt/LiTNTs adsorbed three times more cinnamaldehyde than those in Pt/CsTNTs. Due to the competition between the adsorption of cinnamaldehyde and C=C activation, Pt/KTNT-IMP is the most active Pt/MTNT catalysts, achieving a conversion of 100% in the hydrogenation of cinnamaldehyde at 2 atm and 313 K. The carbonyl stretching of adsorbed cinnamaldehyde was almost unperturbed by adsorption (at 1705 cm(-1)), suggesting that Pt(delta-) and the pi electrons in the carbonyl group repel each other, so the CH=O group points upward and away from the Pt surface, preventing it from being hydrogenated and causing Pt/MTNTs to exhibit high 3-phenyl propionaldehyde selectivities of 75-80%. PMID- 23448896 TI - New boron nitride structures B4N4: a first-principles random searching application. AB - The present investigation searched for new boron nitride (BN) polymorphs by means of first-principles simulations. The ab initio random structure searching strategy was implemented. The electronic and mechanical properties and equation of states of three new metastable BN crystal forms with equilibrium energies close to the most stable B4N4 form, c-BN, are presented. Results show either dynamically stable semiconductors or insulators, one of which is even slightly harder than c-BN. The equation of states is also presented and a phase transition is predicted. PMID- 23448897 TI - The embalmed heart of Richard the Lionheart (1199 A.D.): a biological and anthropological analysis. AB - During the Middle Ages, the partition of the cadaver of the elite members was a current practice, with highly technical treatment given to symbolic organs such as the heart. Considered mostly from a theoretical point of view, this notion of dilaceratio corporis has never been biologically explored. To assess the exact kind of embalming reserved to the heart, we performed a full biomedical analysis of the mummified heart of the English King Richard I (1199 A.D.). Here we show among other aspects, that the organ has been embalmed using substances inspired by Biblical texts and practical necessities of desiccation. We found that the heart was deposed in linen, associated with myrtle, daisy, mint, frankincense, creosote, mercury and, possibly, lime. Furthermore, the goal of using such preservation materials was to allow long-term conservation of the tissues, and good-smelling similar to the one of the Christ (comparable to the odor of sanctity). PMID- 23448898 TI - Predictors of surgical outcome in cervical spondylotic myelopathy. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To determine whether magnetic resonance imaging and clinical and demographic findings in patients with cervical spondylotic myelopathy (CSM) were independently associated with baseline functional scores and whether these were also predictive of postoperative functional outcomes. SUMMARY OF BACKGROUND DATA: There are considerable limitations in current literature that prevent making formal recommendations regarding the use of clinical and radiological prognostic factors in patients with CSM. METHODS: This prospective study included 65 consecutive patients with CSM treated in a tertiary referral center. The modified Japanese Orthopaedic Association (mJOA) scale was used to quantify disability at admission and at 12 month follow-up. Age, sex, duration of symptoms, severity of myelopathy, spinal column alignment, surgical technique, levels of compression, anteroposterior diameter and transverse area at the site of maximal cord compression, and magnetic resonance imaging signal intensity changes were assessed. Data were analyzed using Spearman rank correlation test, analysis of variance, Mann-Whitney U test, and stepwise multivariate regression. RESULTS: Higher baseline mJOA scores were associated with younger age (P = 0.0002), shorter duration of symptoms (P = 0.03), and greater transverse area (P = 0.02). Better recovery ratio was associated with younger age (P = 0.005) and higher baseline mJOA score (P = 0.003). Greater changes in mJOA score were associated with higher baseline mJOA score (P < 0.0001). Using multivariate analysis, the functional outcomes after surgery were best predicted by baseline mJOA score and age of patient. CONCLUSION: Age and baseline mJOA scores were highly predictive of outcome for patients undergoing surgical treatment of CSM. The degree of spinal cord compression and patterns of signal intensity changes on T1/T2 weighted images were not independently predictive of outcome, but it was found to correlate with the functional status at the time of presentation and age of the patient. The duration of symptoms correlated well with preoperative functional status but did not seem to affect the postoperative outcome. PMID- 23448899 TI - Factors influencing on retro-odontoid soft-tissue thickness: analysis by magnetic resonance imaging. AB - STUDY DESIGN: A retrospective, consecutive case series. OBJECTIVE: To analyze the relationship between retro-odontoid soft-tissue thickness and patients' age, sex, and degenerative changes of cervical spine and to investigate the effect these factors have on retro-odontoid soft-tissue thickness. SUMMARY OF BACKGROUND DATA: Thickening of the soft tissue posterior to the odontoid process can form a retro odontoid pseudotumor causing symptoms of spinal cord compression. Rheumatoid arthritis and long-term dialysis have been reported as possible causes for this. However, there have been reports of retro-odontoid pseudotumors without coexisting diseases. METHODS: Findings from a total of 503 cases of cervical spine magnetic resonance images were reviewed, and retro-odontoid soft-tissue thickness was measured. The values were matched for age, sex, presence of degenerative changes, rheumatoid arthritis, and dialysis and were analyzed for significance. RESULTS: Retro-odontoid soft tissue thickened with age, and this was also seen in male patients and patients with degenerative changes. Significant increase in thickness was also observed in patients undergoing dialysis and further increased with prolonged dialysis. There was no significant association with presence of rheumatoid arthritis. CONCLUSION: There is association between age, sex, degenerative cervical spine changes, and dialysis with retro-odontoid soft-tissue thickness. With dialysis, retro-odontoid soft tissue thickness increases with increasing duration. Thus, reviewing magnetic resonance image from daily practice indicates that cervical spine degeneration is associated with the development of retro-odontoid pseudotumors. PMID- 23448900 TI - Auditory complaints in scuba divers: an overview. AB - Pre-1970s, diving was seen as a predominantly male working occupation. Since then it has become a popular hobby, with increasing access to SCUBA diving while on holiday. For a leisure activity, diving puts the auditory system at the risk of a wide variety of complaints. However, there is still insufficient consensus on the frequency of these conditions, which ultimately would require more attention from hearing-healthcare professionals. A literature search of epidemiology studies of eight auditory complaints was conducted, using both individual and large-scale diving studies, with some reference to large-scale non-diving populations . A higher incidence was found for middle ear barotrauma, eustachian tube dysfunction, and alternobaric vertigo with a high correlation among females. Comparing these findings with a non-diving population found no statistically significant difference for hearing loss or tinnitus. Increased awareness of health professionals is required, training, and implementation of the Frenzel technique would help resolve the ambiguities of the Valsalva technique underwater. PMID- 23448901 TI - Enhancing the sensitivity of the comet assay as a genotoxicity test, by combining it with bacterial repair enzyme FPG. AB - The alkaline comet assay, when employed as a genotoxicity test, has relatively low sensitivity because it fails to detect--at non-cytotoxic concentrations- known genotoxins that do not induce breaks or alkali-labile sites. We demonstrate that this limitation is overcome by incorporating in the assay the DNA repair enzyme formamidopyrimidine DNA glycosylase (FPG) to convert damaged bases to breaks. We tested 11 chemicals in human TK-6 cells: three non-cytotoxic--D mannitol, Tris and EDTA; two cytotoxic--Triton X-100 and fluometuron; and six genotoxic--methylmethanesulphonate (MMS), methylnitrosourea (MNU), cyclophosphamide, benzo(a)pyrene, 4-nitroquinoline-1-oxide (4NQO) and etoposide. At concentrations of MMS, MNU, benzo(a)pyrene or 4NQO causing little or no cytotoxicity and few if any DNA breaks, FPG substantially enhanced the cellular response. Etoposide increased breaks but not FPG-sensitive sites. Cyclophosphamide, a DNA cross linker, gave a response without FPG at 1 MUM, but there was no increase with FPG. Triton X-100-induced breaks were secondary to cytotoxicity. The remaining compounds induced no damage. Thus, FPG enhances sensitivity of the comet assay without compromising selectivity. PMID- 23448902 TI - Artemis is required to improve the accuracy of repair of double-strand breaks with 5'-blocked termini generated from non-DSB-clustered lesions. AB - Clustered DNA lesions are defined as >=2 damage events within 20 bp. Oxidised bases, abasic (AP) sites, single-strand breaks and double-strand breaks (DSBs) exist in radiation-induced clusters, and these lesions are more difficult to repair and can be more mutagenic than single lesions. Understanding clustered lesion repair is therefore important for the design of complementary treatments to enhance radiotherapy. Non-DSB-clustered lesions consisting of opposing AP sites can be converted to DSBs by base excision repair, and non-homologous end joining (NHEJ) plays a role in repairing these DSBs. Artemis is an endonuclease that removes blocking groups from DSB termini during NHEJ. Hence, we hypothesised that Artemis plays a role in the processing of DSBs or complex DSBs generated from non-DSB-clustered lesions. We examined the repair of clusters containing two or three lesions in wild-type (WT) or Artemis-deficient (ART(-/-)) mouse fibroblasts using a reporter plasmid. Each cluster contained two opposing tetrahydrofurans (an AP site analogue), which AP endonuclease can convert to a DSB with blocked 5' termini. Loss of Artemis did not decrease plasmid survival, but did result in more mutagenic repair with plasmids containing larger deletions. This increase in deletions did not occur with ClaI-linearised plasmid. Since Mre11 has been implicated in deletional NHEJ, we used small interfering RNA to reduce Mre11 in WT and ART(-/-) cells, but decreasing Mre11 did not change the size of deletions in the repair products. This work implicates Artemis in limiting the deletions introduced during repair of 5'-blocked termini DSBs generated from non-DSB-clustered lesions. Decreasing repair accuracy without decreasing repair capacity could result in mutated cells surviving irradiation. Inhibiting Artemis in normal cells could promote carcinogenesis, while in tumour cells enhanced mutagenic repair following irradiation could promote tumour recurrence. PMID- 23448904 TI - Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. AB - Thalidomide is the best-known teratogen worldwide. It was first marketed as a sedative in the late 1950s, but the birth of ~10 000 children with birth defects resulted in the withdrawal of thalidomide from the market in 1962. Thalidomide embryopathy affects almost all organs but the main defects are concentrated in the limbs, eyes, ears, and heart. Shortly after the withdrawal of thalidomide from the market, its effectiveness in the treatment of erythema nodosum leprosum, an inflammatory condition resulting from leprosy, was reported and since the mid 1990s, the drug has been used widely in the treatment of cancers and autoimmune diseases, among other conditions. 40 000 new cases of leprosy are diagnosed every year in Brazil. Although there is a strict legislation for the prescription and use of thalidomide in Brazil, cases of thalidomide embryopathy have continued to be reported. Here, we present two new cases of thalidomide embryopathy identified in 2011 and review the major clinical findings in the literature that can aid the identification of the embryopathy. PMID- 23448903 TI - Clinical phenotype and the lack of mutations in the CHRNG, CHRND, and CHRNA1 genes in two Indian families with Escobar syndrome. AB - The objective of this study was to report the clinical phenotype and genetic analysis of two Indian families with Escobar syndrome (ES). The diagnosis of ES in both families was made on the basis of published clinical features. Blood samples were collected from members of both families and used in genomic DNA isolation. The entire coding regions and intron-exon junctions of the ES gene CHRNG (cholinergic receptor, nicotinic, gamma), and two other related genes, CHRND and CHRNA1, were amplified and sequenced to search for mutations in both families. Both families show a typical form of ES. Sequencing of the entire coding regions including the intron-exon junctions of the three genes did not yield any mutations in these families. In conclusion, it is possible that the mutations in these genes are located in the promoter or deep intronic regions that we failed to identify or the ES in these families is caused by mutations in a different gene. The lack of mutations in CHRNG has also been reported in several families, suggesting the possibility of at least one more gene for this syndrome. PMID- 23448905 TI - Clinical features associated with a 15.41 Mb deletion of chromosome 13q encompassing the MIR17HG locus. PMID- 23448906 TI - Subcortical white matter abnormalities because of previously undescribed de-novo 14q12-q13.1 triplication. PMID- 23448907 TI - Congenital metacarpal pseudoarthrosis, cleft palate, short stature, advanced bone age, and genu valgum: a new syndrome or a variant of Devriendt syndrome? PMID- 23448909 TI - Confirmation of the macroblepharon, ectropion, hypertelorism, and macrostomia syndrome. PMID- 23448908 TI - Early childhood presentation of Czech dysplasia. PMID- 23448910 TI - Froster syndrome: two further siblings with bilateral diaphragmatic hernia, asymmetric limb reduction defects, and exomphalos. PMID- 23448911 TI - Men's beliefs and attitudes toward intimate partner violence against women in Pakistan. AB - This article documents the beliefs and attitudes of men toward intimate partner violence in Pakistan. Men's beliefs and attitudes toward partner violence are shaped by the life-long process of gender socialization, where the role of wife is projected as submissive and docile. Drawing on eight in-depth interviews and four focus group discussions (FGDs) conducted in Lahore and Sialkot, this article presents how men perceive and justify partner violence within the context of Pakistani society. The data show that the construct of "ideal wife" inculcated among men fits into Foucault's notion of "docile bodies," which are subjected to control, discipline, and violent punishment. PMID- 23448913 TI - Brain-computer interfaces using capacitive measurement of visual or auditory steady-state responses. AB - OBJECTIVE: Brain-computer interface (BCI) technologies have been intensely studied to provide alternative communication tools entirely independent of neuromuscular activities. Current BCI technologies use electroencephalogram (EEG) acquisition methods that require unpleasant gel injections, impractical preparations and clean-up procedures. The next generation of BCI technologies requires practical, user-friendly, nonintrusive EEG platforms in order to facilitate the application of laboratory work in real-world settings. APPROACH: A capacitive electrode that does not require an electrolytic gel or direct electrode-scalp contact is a potential alternative to the conventional wet electrode in future BCI systems. We have proposed a new capacitive EEG electrode that contains a conductive polymer-sensing surface, which enhances electrode performance. This paper presents results from five subjects who exhibited visual or auditory steady-state responses according to BCI using these new capacitive electrodes. The steady-state visual evoked potential (SSVEP) spelling system and the auditory steady-state response (ASSR) binary decision system were employed. MAIN RESULTS: Offline tests demonstrated BCI performance high enough to be used in a BCI system (accuracy: 95.2%, ITR: 19.91 bpm for SSVEP BCI (6 s), accuracy: 82.6%, ITR: 1.48 bpm for ASSR BCI (14 s)) with the analysis time being slightly longer than that when wet electrodes were employed with the same BCI system (accuracy: 91.2%, ITR: 25.79 bpm for SSVEP BCI (4 s), accuracy: 81.3%, ITR: 1.57 bpm for ASSR BCI (12 s)). Subjects performed online BCI under the SSVEP paradigm in copy spelling mode and under the ASSR paradigm in selective attention mode with a mean information transfer rate (ITR) of 17.78 +/- 2.08 and 0.7 +/- 0.24 bpm, respectively. SIGNIFICANCE: The results of these experiments demonstrate the feasibility of using our capacitive EEG electrode in BCI systems. This capacitive electrode may become a flexible and non-intrusive tool fit for various applications in the next generation of BCI technologies. PMID- 23448912 TI - Medical male circumcision and HIV risk: perceptions of women in a higher learning institution in KwaZulu-Natal, South Africa. AB - BACKGROUND: Medical male circumcision (MMC) reduces the risk of HIV acquisition for men in heterosexual encounters by 50-60%. However, there is no evidence that a circumcised man with HIV poses any less risk of infecting his female partner than an uncircumcised man. There may be an additional risk of HIV transmission to female partners during the 6-week healing period and if condoms are used less often after circumcision. The aim was to explore young women's perspectives on MMC, with a view to developing clear messages about the limitations of MMC in reducing women's HIV risk. METHODS: We explored women's perspectives on MMC in KwaZulu-Natal, South Africa, with a sample of 30 female tertiary students via four focus groups (two for women only; two mixed gender). RESULTS: In all groups, women communicated a thorough understanding of the partial efficacy of MMC, but believed that others would not understand this concept. Participants noted that MMC affords no direct benefit to women. Most thought that MMC would increase females' risk of contracting HIV, that circumcised men may engage in risky behaviours and that men would increase their number of sexual partners after circumcision. Participants believed that condom use would decrease after MMC and speculated that men would have sex during the healing period, which could further compromise women's sexual health. CONCLUSION: The concerns expressed by women regarding MMC highlight the need for including women in the dialogue about MMC and for clarifying the impact of MMC on HIV risk for women. PMID- 23448914 TI - From the editor. Primary care physicians and health care reform. PMID- 23448915 TI - Open questions concerning influences on clinical decision making. AB - Efforts to influence utilization of services to bring down spending and to improve quality of care have largely failed. A critical reason is that most attention has focused on dysfunctional financial incentives without considering other factors that also influence physicians' utilization decisions. In this article, after providing a framework for ideal physician-patient interactions, questions are also raised about other influences, including physicians' impulse to help patients, professional codes of ethics, the threat of malpractice claims, and the leadership of health care organizations. An Appendix contains a summary of the literature on these factors. PMID- 23448916 TI - Improved cost, health, and satisfaction with a health home benefit plan for self insured employers and small physician practices. AB - We compared the impacts on total costs, health, and satisfaction among 615 adults enrolled 2 years in an employer's health home benefit plan to their baseline year in a standard preferred provider organization plan. The new plan combined strong continuity care incentives with nurse coaching support. After 24 months, total medical costs were 23% lower than the baseline year, biometric measures improved for more than 85% of members, and patient satisfaction exceeded 85%. Emergency department visits decreased by 16% and hospital days decreased by 48%. Health home benefit plans engaging small primary care physician practices and members in coordinated continuity care can deliver high value. PMID- 23448917 TI - Learning to fly: building de novo medical home practices to improve experience, outcomes, and affordability. AB - While most approaches to improving primary care delivery involve making incremental improvements to existing practices, for the past decade we have been engaged in a different approach-to build new practices from the ground up to demonstrate a vision of what is possible. Our Iora model of care combines a new payment model which does away with all fee for service billing, a new delivery model focused on robust team-based population management, and a new IT system to drive this very different care. We have demonstrated in several pilots improved experience, outcomes, and lower total cost of care. PMID- 23448918 TI - Primary care in England: between a rock and a hard place. AB - A well-established primary care sector has allowed England's National Health Service (NHS) to make efficient use of resources through the gatekeeping role that general practitioners have in controlling access to specialist services. Because of the poor economic situation in the United Kingdom, there is now considerable pressure on the NHS to use its resources more efficiently. These financial challenges are putting enormous pressure on general practices at a time when the NHS is also going through other major structural changes. Consequently, general practitioners in England increasingly find themselves having to make difficult decisions about the future of their practices. PMID- 23448919 TI - Modifying physician behavior to improve cost-efficiency in safety-net ambulatory settings. AB - Change interventions in one form or another are viewed as important tools to reduce variation in medical services, reduce costs, and improve quality of care. With the current focus on efficient resource use, the successful design and implementation of change strategies are of utmost importance for health care managers. We present a case study in which macro and micro level change strategies were used to modify primary care physicians' practice patterns of prescribing diagnostic services in a safety-net's ambulatory clinics. The findings suggest that health care managers using evidence-based strategies can create a practice environment that reduces barriers and facilitates change. PMID- 23448920 TI - A multilingual population health management program. AB - Many small- and medium-sized physician practices have developed specific programs and models toward becoming a successful patient-centered medical home. This article reports on a case-control quality improvement study of a multilingual population health management program for chronic disease management at International Community Health Services. In its first 2.5 years of operation, the International Community Health Services Population Health Management program for patients with hypertension and diabetes is associated with significant improvements in key health outcome measures for blood pressure and hemoglobin A1c control. This has significant implications for similar practices. PMID- 23448921 TI - Hospital readmission rates: the impacts of age, payer, and mental health diagnoses. AB - We examine impacts of age, payer, and mental health conditions upon hospital readmissions and the comparability of same-hospital and multiple-hospital readmission rates. Medicaid primary payment and extreme age are associated with significantly higher readmission rates. We find low correlation between same hospital and multiple-hospital readmission rates and identify urban hospitals with high proportions of Medicaid patients and mental health admissions as factors driving the use of multiple hospitals within readmission chains. Hospital payment incentives and performance measures using readmission rates will be distorted if factors leading to higher readmission rates are ignored, or if readmissions to different hospitals cannot be identified. PMID- 23448922 TI - Lessons in translation: insights from a collaboration integrating community health workers into diabetes care. AB - Beginning in 2007, a community health center and a community health worker organization collaborated on a community health worker initiative to improve diabetes outcomes among underserved communities. Despite a shared vision, the initiative ended prematurely because of a number of unexpected collaborative challenges. This article describes the results of a qualitative investigation into these challenges. Through examples, we show how our collaborative difficulties were due to 3 interacting influences: logistics, participation, and institutional culture. We argue for the importance of institutional cultural competency in health care collaborations and provide recommendations for future collaborations that takes into account these 3 overarching influences. PMID- 23448924 TI - [Research progress of Leber hereditary optic neuropathy]. AB - Leber hereditary optic neuropathy (LHON; MIM 535000) is one of the most common mitochondrial diseases, with a clinical manifestation of painless, acute or sub acute bilateral visual loss in young adults leading to blindness and central scotoma. Over 95% of LHON patients were caused by one of three primary mtDNA mutations (m.11778G>A, m.3460G>A and m.14484T>C). Incomplete penetrance and gender bias are two riddles of this disease. Here we summarized recent research progress of LHON, with a focus on the molecular pathogenic mechanisms, clinical features, in vitro experiments and animal models, and prevention and treatment of LHON. In particular, we presented the main findings and challenges in our recent efforts to decipher genetic susceptibility and mechanism of LHON in Chinese patients. PMID- 23448925 TI - [Application of DNA methyltransferase inhibitors for myelodysplastic syndrome]. AB - Epigenetic research plays an important role in the malignant tumor genotyping and tumor clinical treatment recently. Epigenetics is the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence, including DNA methylation and histone modifications. DNA methylation is one of the most important epigenetic modifications often occurring on the cytosine of CpG islands located in gene promoter regions, which is thought to be closely correlated with tumorigenesis. The inducibility and reversibility of DNA methylation provide us an insight into tumor development and treatment. Aberrant DNA hypermethylation is associated with the progress of myelodysplastic syndrome (MDS). The DNA methyltransferase inhibitors (azacytidine and decitabine) have achieved suc-cess in treating high-and intermediate-risk MDS. This will bring new ideas to understand the cause and develop the treat-ment of MDS. This review mainly introduces the latest progress of the action mechanism of those two medicines, the clini-cal effect and new problems during the clinical application on MDS. PMID- 23448926 TI - [Genetic susceptibility for acute high altitude disease]. AB - Acute high altitude disease(AHAD), which can be divided into acute mountain disease (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE), is one of the special illnesses occurred at high altitude, commonly encountered by travelers to high altitudes (>2 500 m), which affects people's work capacity and health and could be even a life-threatening disease. Despite extensive investigations over the last century, the pathophysiology of AHAD remains elusive. Nevertheless, numerous researches have confirmed the existence of AHAD susceptibility differences. The aim of this paper was to review the epidemiological evidence for a genetic component to the various forms of AHAD so far, as well as to supply helpful reference to its epidemiological studies. PMID- 23448927 TI - [Research progress on molecular genetic diversity of the yak (Bos grunniens)]. AB - Studies on genetic diversity, as the core of population genetics, reveal genetic variations of the yak (Bos grunniens). Since the 1970s, the morphological, chromosomal, physiological, and biochemical characteristics, as well as DNA sequence polymorphisms, in yak have been extensively investigated. Following the rapid development of molecular genetics and DNA sequencing technology, the molecular genetic diversity of yak has become a focus in recent studies. In this paper, the research progress on the molecular genetic diversity of yak was reviewed based on the information and knowledge on mtDNA sequences and nucleus molecular markers, as well as candidate genes, obtained over the last 15 years. The future perspectives of relevant research topics were discussed to shed more light on depth understanding of the population genomics of the yak. PMID- 23448928 TI - [Distribution of HLA-G 14 bp insertion/deletion polymorphism and their associations with HLA-A alleles in four Chinese ethnic groups]. AB - Recently, a 14 bp insertion/deletion polymorphism (+14 bp/-14 bp) in exon 8 of the human leucocyte antigen-G (HLA-G) gene has been widely recognized to associate with recurrent miscarriage, autoimmune diseases, hepatocellular carcinoma and other diseases. Our previous studies have shown the distribution characteristics of linguistic family for HLA-G 14 bp insertion/deletion in different ethnic groups. In the present study, we investigated the distribution of HLA-G 14 bp insertion/deletion polymorphism and their subsequent associations with HLA-A alleles in Tu, Yugu, Lisu and Nu ethnic populations based upon the HLA A genotyping data. Our results showed that the frequencies of the 14 bp insertion/deletion polymorphism were diverse in these four populations while that in the same linguistic subfamily was similar. The significant difference in different linguistic subfamily except for Han and Mongolian language subfamily was identified. In addition, the 14 bp insertion was found to associate with HLA A alleles in different ethnic populations. PMID- 23448930 TI - [Genetic diversity of DNA microsatellite for Tibetan Yak]. AB - To assess the genetic diversity and relationship of the Tibetan yak breeds. The genetic diversity and phylogenies of a total of 480 individual from 11 Tibetan yak groups were analyzed using PCR and multiplex gel electrophoresis of silver staining technology with eight pairs of microsatellite markers.The result showed that these markers were highly polymorphic loci with rich genetic diversity in the Tibetan yak populations.The average polymorphic information content (PIC) in 11 groups of yak were higher than 0.5. The highest HEL13 was 0.8496, and the lowest TGLA57 was 0.7349. Among them, the PICof Dingqing yak was minimum (0.7505), indicating that the group is relatively pure.Sangri Yak had the highest PIC value (0.7949) indicating greater genetic variationwithinthe groups. Among the 11 groups examined, the order of heterozygosity size wasSangri(0.8193)>Jiangda(0.8190)>Sangsang(0.8157)>Baqing(0.8150)>Kangbu(0.8123)> Jiali(0.8087)>Gongbujiangda(0.8054)>Sibu(0.8041)>Leiwuqi(0.8033)>Pali(0.8031)>Din qing(0.7831). The groups from eastern Tibet had grater genetic diversity than those from Western Tibet, which indicate that Tibet may be one of the cradles of the yak.According to the genetic distance, the cluster relationship constructed with UPGMA and NJ methods showed that 11 yak groups in Tibet could be divided into three forms. In summary,Tibet yak has abundant genetic diversity and the selected microsatellite markers can be used to evaluategenetic diversity of Tibetan yak. PMID- 23448929 TI - [Genetic analysis of Y chromosome and mitochondrial DNA poly-morphism of Mulam ethnic group in Guangxi, China]. AB - In order to study the molecular genetic structure of Mulam ethnic group in Guangxi, China, Y chromosome and mitochondrial DNA(mtDNA)polymorphisms were genotyped. High frequencies of the Y chromosome haplogroups O1a1-P203 and O2a1* M95 were found in Mulam, exhibiting a pattern similar to the neighboring indigenous populations, especially the Daic populations. MtDNA lineages F1a, M*, B4a, B5a, M7b, and N9a were found in Mulam, which always present at high frequencies among the populations of East Asia. Mulam exhibits genetic characteristics of southern Chinese in both paternal and maternal lineages. Multiplex detection of the 17 Y-STR loci and mtDNA HVS-I revealed the distribu tion of highly genetic diversity in Mulam, which would have potential application in population genetics and forensic practice. PMID- 23448931 TI - [Association of polymorphisms of exon 2 of GOLA-DQA2 gene with blood immune traits in goats]. AB - The polymorphisms of exon 2 of GOLA-DQA2 gene were analyzed by PCR-RFLP technique in Laiwu black goats, Lubo goats, and Boer goats; and the effects of genotypes of GOLA-DQA2 gene on blood immune traits were estimated. The results showed that four genotypes were detected in the three goats. Polymorphic sites were detected at base positions 77, 79, 80, and 169 in exon 2 of GOLA-DQA2 gene. The effects of breed were major effect. In Lubo goats, red blood count (RBC) with genotype AB was significantly higher than that with genotype BB (P<0.05), and white blood count (WBC) with genotype AB was significantly higher than that with genotype BC (P<0.05). Hematocrit (HCT) in Lubo goats with genotype AB was significantly higher than that with genotypes BB and BC (P<0.05). WBC-large cell ratio (W-LCR) in Lubo goats with genotype BC was significantly higher than that with genotype BB (P<0.05). In Laiwu black goats and Boer goats, there was certain degree of association between genotypes and blood immune traits, but it was not significant. Genotype AB and BC was an important factor affecting RBC, WBC, W LCR, and so on. It was concluded from these results that GOLA-DQA2 was the gene affecting the blood immune traits, which provides a basis for disease resistance breeding of goats. PMID- 23448932 TI - [Genetic variation analysis of wild populations of grass carp (Ctenopharyngodon idella) using microsatellite markers]. AB - Twelve microsatellites were used to analyze the genetic diversity and genetic structure of eight wild populations of grass carp, among which six populations from Yangtze River (Hanjiang, Wujian, Jiujiang, Shishou, Mudong, and Wanzhou), one population from Pearl River and Heilongjiang River for each, Zhaoqing, and Nenjiang, respectively. Twelve markers showed highly polymorphic and all the eight populations contained high genetic variations. The variations of six populations of Yangtze River and Zhaoqing population of Pearl River were higher than Nenjiang population of Heilongjiang River. Bottleneck analysis revealed that four populations (Zhaoqing, Nenjiang, Mudong, and Wangzhou) had experienced a recent genetic bottleneck, and the effective population size was reduced. Pairwise FST and AMOVA analysis detected significant genetic difference among populations. The pairwise population genetic distances and the UPGMA tree demonstrated that the genetic distances between six populations of Yangtze River and Zhaoqing population were closer and clustered together earlier, as compared to those populations with Nenjiang population. The genetic structure simulation analysis suggested that there were five logic populations of all individuals. The genetic structures of Zhaoqing and Nenjiang populations were shown with independent separation, but the genetic structures of populations from Yangtze River were shown with fuzzy distribution. The high diversity was found in the wild grass carp from three major watersheds in China, which would supply a basis for future genetic improvement. However, the bottleneck effect of some populations should be taken into account in the practical breeding programs. PMID- 23448933 TI - [Heritability of body weight and fork length for Oncorhynchus masou masou]. AB - Body weight and body length have been considered as the most important production traits for the fish genetic improvement. For cold-water fish, body length was usually substituted by fork length. In order to estimate the heritability of body weight and fork length of the sixth generation Oncorhynchus masou masou, which was introduced into China, the method of unbalanced nest design and an artificial insemination technigue were used. Twenty-nine full-sib families and fourteen half sib families were obtained. Body weight and fork length of O. masou masou were measured in 12 and 24 months after fertilization. Based on full-sib and half-sib families data, the causal components of phenotypic variance were calculated. The results showed that, (1) during the whole growth phase of O. masou masou, the coefficient variation (CV) of fork length was higher than body weight, and CV of 12-month old was higher than that of 24-month old; (2) body weight and fork length of O. masou masou among sires and dams among sires were significant difference (P<0.01) both at 12 months and at 24 months; (3) the maternal component estimates were significantly larger than those of paternal ones for body weight and fork length traits both at 12 months and at 24 months; (4) for 12 months of O. masou masou the heritabilities of body weight and fork length were 0.41~0.51 and 0.46~0.54, respectively. For 24 months the values were 0.55~0.60 and 0.53~0.59, respectively; and (5) it was concluded that the heritability of growth traits in O. masou masou was relatively high and this highlights the potential to improve its growth through selective breeding. This study shows important data supporting for further genetic improvement of O. masou masou. PMID- 23448934 TI - [Morphological characteristics and gene mapping of a novel bent pedicel branch (bpb1) mutant in rice]. AB - Rice pedicels are tightly associated with the yield of grain. In the present study, a novel and stable pedicel mutant bpb1 (bent pedicel branch 1) was obtained from the wild type "Zhenong 7" after 60Co gamma-ray treatment. The mutant had the typical phenotype of bent pedicel branches with multiple abnormal phenotypes, such as longer pedicels, short panicles, and dwarfism. Detail examination using scanning electron microscopy revealed that the pedicel epidermal hairs and stomas in the mutant were smaller than those in the wild type. The epidermal and sclerenchymatous cells were arranged irregularly, and the cells in the bend region of pedicels became smaller and arranged closely. The transverse observation of the mutant pedicel branches showed that the small vascular bundles arranged differently from those of the wild type. Genetic analysis indicated that the abnormal phenotypes were controlled by a single recessive gene. Using the F2 mapping population from the bpb1 mutant crossed with the japonica rice variety "Zhenongda 104", the bpb1 gene was mapped in a 343 kb region between two SSR markers, RM21537 and RM21552, at the long arm of chromosome 7. Because no homologous gene was found in this region until now, bpb1 might be a novel gene related to the pedicel development and growth. This study could be beneficial to future cloning and functional analysis of the bpb1 gene. PMID- 23448935 TI - [Integration and "Overview" analysis of QTLs related to plant height in soybean]. AB - Plant height, one of the most important factors for plant architectures, is closely related with some important traits such as plant density, lodging resistance and yields.. In the present study, 201 QTLs related to plant height of soybean from database and references were analyzed. The results revealed that 15 consensus QTLs located on chromosomes 6, 7, 11, 13, and 18 were identified after physical integrations and Meta analysis using the software BioMercator 2.1. Moreover, "Overview" method was used to optimize these QTLs based on statistic analysis. Some of the valid QTL regions were narrowed down to the 0.1 cM and mapped on certain chromosomes. Furthermore, the functions of all genes located in these confidence regions were predicted and 17 candidate genes that might be related to plant height were identified. These results would lay a foundation for fine mapping of QTLs related to plant height and marker-assisted breeding in soybean. PMID- 23448936 TI - [Development of EST-SSR marker and genetic diversity analysis in Sorghum bicolor*Sorghum sudanenes]. AB - A total of 57 498 non-redundant ESTs were identified from 210 878 ESTs of Sorghum in NCBI by sequence analysis. In all, 3 338 SSRs were distributed in 3 116 ESTs with an average frequency of one SSR per 11.28 kb, which included 215 SSR motifs. Analysis of SSR motifs revealed that the trinucleotides were major motifs, accounting for 68.33%.The dinucleotides motifs accounted for 17.97%. There were 1 694 sequences from 3 338 EST-SSR sequences could be designed into primers and the proportion was 50.75%. Fourteen primers were selected to amplify EST-SSR loci with 50 collections of Sorghum bicolor * S. sudanenes, 7 collections of S. bicolor and 3 collections of S. sudanenes. Seventy-two allele variations were detected and the frequency was 5.14 gene loci per primer. The polymorphism index of each primer was in the range of 0.54-0.93. The genetic distance ranged from 0.1646 to 0.6398. This showed abundant genetic diversity in the materials. The materials were divided into 5 groups with clustering analysis of EST-SSR data. Each group included the varieties with similar parents or similar regional distribution. Meanwhile, 4 specific molecular markers were found. Primer D1763 was specific in the registered variety GB-4-2 which was the progeny of S. bicolor 314A * S. sudanenes White Skull. The marker was specific in justification of the germ difference. These results showed that the EST-SSR was an effective marker for genetic diversity analysis and specificity studies on S. bicolor * S. sudanenes. PMID- 23448937 TI - [Effect of silencing lycB gene on the carotenoid synthesis in Haematococcus pluvialis]. AB - Haematococcus pluvialis is a freshwater planktonic single-cell microalgae. It will accumulate high amount of carotenoids under unfavorable environmental conditions. As one of carotenoids, lycopene is an important intermediate in the carotenoid biosynthesis pathway. Lycopene beta-cyclase (LycB) is the key enzyme that catalyzes the circularization of lycopene to form beta-carotene. In this study, we constructed a p1301-BS-RNAi vector using lycB from Dunaliella salina as the interference sequence with kanamycin and atrazine resistance marker, and then transformed it into H. pluvialis by electroporation. Sixteen independent transgenic lines were obtained after resistance selection, genome PCR, and RT-PCR analyses. Seven well-grown lines were selected to determine the contents of carotenoids by HPLC analysis after inducing by high light. The lycopene content in these lines was increased by 99.4% while the beta-carotene content was decreased by 48.4%, indicating that the interference by heterogenous lycB could inhibit the conversion of lycopene into beta-carotene. The amount of increase in lycopene was only 5% of the amount of decrease in beta-carotene, indicating that 95% of the decreased beta-carotene was converted into other metabolites. Therefore, in order to largely increase the lycopene content in H. pluvialis, it is necessary to coordinatively regulate other metabolic pathways. PMID- 23448939 TI - Randomized, placebo controlled, double blind trial evaluating early pregnancy phytonutrient supplementation in the prevention of preeclampsia. AB - OBJECTIVE: Daily provision of pregnant patients with dietary supplements containing antioxidants and phytonutrients, if initiated in the first trimester of pregnancy and continued throughout the gestation, may significantly decrease the incidence of preeclampsia. STUDY DESIGN: We conducted a single center, randomized, placebo-controlled investigation in which women were randomized by their risk status and assigned to daily ingestion of a supplement consisting primarily of a blended fruit and vegetable juice powder concentrate or placebo. RESULT: Of the 684 patients randomized to the trial, 267 (39.0%) completed it. The final analysis is based on those participants who completed the study. For the primary outcome of preeclampsia, there was no difference observed between the phytonutrient supplement group and the placebo group: 15.9% vs 16.3%, respectively, (R.R. 0.97 (0.56-1.69)). Non-significant trends toward lower placenta-related obstetrical complications were observed in the supplement group compared with the placebo cohort (8.3% vs 15.5%, respectively, (R.R. 0.57 (0.29 1.14). Those infants born to mothers taking the supplement in the high-risk stratified group demonstrated non-significant trends toward lower rates of respiratory distress syndrome (RDS); 5.3% in the supplement group vs 15.4% in the placebo group: R.R. 0.34 (0.12-1.01). CONCLUSION: Initiation of antioxidant/phytonutrient supplementation in the first trimester did not decrease rates of preeclampsia. Non-significant trends toward lower incidences of placental derived morbidity in those mothers taking the supplement in addition to decreased rates of RDS in infants born to supplemented mothers considered to be high-risk for preeclampsia, warrant further investigation. PMID- 23448938 TI - Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates. AB - OBJECTIVE: To determine the effects of low-dose dopamine on urine output (UOP) in very low birth weight premature neonates. STUDY DESIGN: Retrospective cohort study of all low-dose (3-5 MUg kg(-1) per min) dopamine infusions >24-h duration in neonates ?1500 g and ?32 weeks gestation from August 2009 through September 2011. Linear regression was used to estimate the impact of covariates on UOP. RESULT: We identified 91 episodes of low-dose dopamine use in 65 neonates. Increased UOP occurred in 64% of episodes. Low-dose dopamine use was associated with a 0.6 ml kg(-1) h(-1) increase in UOP (P<0.001) and a 1.3 ml kg(-1)h(-1) increase when baseline UOP was <1.5 ml kg(-1) h(-1) (P<0.001). The improvement remained statistically significant after controlling for medications (diuretics and hydrocortisone) and fluid intake. CONCLUSION: Low-dose dopamine use was associated with increased UOP in very low birth weight neonates. PMID- 23448940 TI - Neonatal Critical Care Communication (NC3): training NICU physicians and nurse practitioners. AB - OBJECTIVE: Communicating with families is a core skill for neonatal clinicians, yet formal communication training rarely occurs. This study examined the impact of an intensive interprofessional communication training for neonatology fellows and nurse practitioners. STUDY DESIGN: Evidence-based, interactive training for common communication challenges in neonatology incorporated didactic sessions, role-plays and reflective exercises. Participants completed surveys before, after, and one month following the training. RESULT: Five neonatology fellows and eight nurse practitioners participated (n=13). Before the training, participants overall felt somewhat prepared (2.6 on 5 point Likert-type scale) to engage in core communication challenges; afterwards, participants overall felt very well prepared (4.5 on Likert-type scale) (P<0.05). One month later, participants reported frequently practicing the taught skills and felt quite willing to engage in difficult conversations. CONCLUSION: An intensive communication training program increased neonatology clinicians' self-perceived competence to face communication challenges which commonly occur, but for which training is rarely provided. PMID- 23448941 TI - Low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis. AB - OBJECTIVE: In order to conclude on the megakaryopoietic activity during thrombocytopenia in sepsis or necrotizing enterocolitis (NEC), we analyzed the immature platelet fraction (IPF). STUDY DESIGN: Serial measurements of platelet counts and IPF in neonates with blood culture-proven late-onset sepsis (n=21) or surgical NEC (n=12) at T0: prior to the diagnosis of sepsis/NEC; T1: at diagnosis; T2: days 3 to 5 after onset; T3: days 8 to 12 after onset. RESULT: In parallel to declining platelet counts, the median absolute IPF significantly decreased between T0 and T2 in neonates with sepsis or NEC. We found a significant positive correlation between the platelet count and absolute IPF (r=0.71; P<0.001). In patients with low IPF (<2 per nl), the platelet count did not subsequently increase. Neonates with NEC who died exhibited significantly lower IPF compared with survivors (P<0.05). CONCLUSION: Low absolute IPF values during the course of neonatal sepsis/NEC suggest suppression of megakaryopoietic activity. PMID- 23448942 TI - Real-time bowel ultrasound to characterize intestinal motility in the preterm neonate. AB - OBJECTIVE: To characterize normal patterns of intestinal motility by ultrasound (US) in the preterm neonate during the first 5 days of life. STUDY DESIGN: Bowel US examinations were performed with an US machine (Vivid-i, General Electric) equipped with a 13-MHz linear and 7 MHz sector transducer. Still images and clips were taken from all abdominal quadrants along with Doppler of the superior mesenteric artery. Cumulative motility (CM) was quantified for each patient. Comparisons were made between CM for each day of life. Inter-observer correlations were made using the intra-class correlation coefficient. Notation was made of feeding status, bowel sounds and clinical demographics. RESULT: Twenty infants were enrolled in the study. Seventeen infants had 5 days of complete US results available. Mean CM visualized on day of life (DOL) 1 was 28+/ 12. By DOL 4 (38+/-17, P=0.006) and DOL 5 (41+/-20, P=0.008) mean CM increased. There was no difference in the resistance index on days imaged. Mean CM correlated with days to reach full feeds and gestational age, but gestational age was a stronger predictor of days to reach full feeds. Intra-observer correlation coefficient was 0.84. CONCLUSION: Real-time US provides a quantitative measure of intestinal motility in the preterm infant. Further studies are needed to establish the link between bowel US findings and feeding tolerance. PMID- 23448943 TI - Sociodemographic factors associated with healthy eating and food security in socio-economically disadvantaged groups in the UK and Victoria, Australia. AB - OBJECTIVE: To investigate the associations between sociodemographic factors and both diet indicators and food security among socio-economically disadvantaged populations in two different (national) contextual settings. DESIGN: Logistic regression was used to determine cross-sectional associations between nationality, marital status, presence of children in the household, education, employment status and household income (four low income categories) with daily fruit and vegetable consumption, low-fat milk consumption and food security. SETTING: Socio-economically disadvantaged neighbourhoods in the UK and Australia. SUBJECTS: Two samples of low-income women from disadvantaged neighbourhoods: (i) in the UK, the 2003-05 Low Income Diet and Nutrition Survey (LIDNS; n 643); and (ii) in Australia, the 2007-08 Resilience for Eating and Activity Despite Inequality (READI; n 1340). RESULTS: The influence of nationality, marital status and children in the household on the dietary outcomes varied between the two nations. Obtaining greater education qualifications was the most telling factor associated with healthier dietary behaviours. Being employed was positively associated with low-fat milk consumption in both nations and with fruit consumption in the UK, while income was not associated with dietary behaviours in either nation. In Australia, the likelihood of being food secure was higher among those who were born outside Australia, married, employed or had a greater income, while higher income was the only significant factor in the UK. CONCLUSIONS: The identification of factors that differently influence dietary behaviours and food security in socio-economically disadvantaged populations in the UK and Australia suggests continued efforts need to be made to ensure that interventions and policy responses are informed by the best available local evidence. PMID- 23448944 TI - Interleukin 22 polymorphisms and papillary thyroid cancer. AB - BACKGROUND: IL22RA1 (Interleukin 22 receptor-alpha 1), a member of the class II cytokine receptor family, mediates diverse biologic activities and appears to be important in pathogen defense, wound healing, and tissue reorganization. Polymorphisms in genes encoding inflammatory cytokines are associated with increased cancer risk. AIM: The aim of this study was to evaluate the association between the single nucleotide polymorphisms (SNP) in the IL22 and IL22RA1 and papillary thyroid cancer (PTC), and to assess the relationship between the SNP in the IL22 and IL22RA1 and the clinical parameters of PTC. MATERIAL AND METHODS: Study enrolled experimental group of 94 PTC patients and 213 controls. PTC patients were grouped and compared for clinical PTC parameters. One promoter SNP of IL22, -429C/T (rs2227485), and one SNP of IL22RA1, Arg518Gly (rs3795299) were analyzed using direct sequencing. Genetic data were analyzed using Helixtree, SNPAnalyzer Pro, SNPStats, and Haploview. RESULTS: A SNP in IL22 (rs2227485) was significantly associated with PTC (codominant2 model [C/C vs T/T], odds ratio (OR) 2.39, 95% confidence interval (CI) 1.21-4.71, p=0.012; dominant model, OR 1.89, 95% CI 1.08-3.31, p=0.022). The allele T frequency of rs2227485 in IL22 was also associated with PTC (OR 1.59, 95% CI 1.13-2.25, p=0.009). According to clinical parameters, rs2227485 of IL22 was associated with number of cancers (dominant model, OR 3.03, 95% CI 1.02-9.01, p=0.035). By haplotype analysis, TG was associated with PTC (codominant model, OR 1.52, 95% CI 1.07-2.16, p=0.019; dominant model, OR 1.91, 95% CI 1.13- 3.24, p=0.015). Genotype and allele analysis of rs3795299 in IL22RA1 showed no significant differences between PTC patients and controls. CONCLUSION: The rs2227485 SNP in IL22 might be associated with the risk and the multifocality of PTC. PMID- 23448945 TI - Structure and paramagnetism in weakly correlated Y8Co5. AB - We report the basic physical properties of monoclinic Y8Co5 determined by means of magnetic susceptibility, electrical resistivity, and specific heat measurements. The crystal structure of Y8Co5 is monoclinic (P2(1)/c) with lattice parameters a = 7.0582(6) A, b = 7.2894(6) A, c = 24.2234(19) A, and beta = 102.112(6) degrees as refined by using synchrotron powder x-ray diffraction data. The compound shows temperature independent paramagnetism with chi0 = 2.1 * 10(-3) emu mol(-1) and Sommerfeld parameter gamma = 63 mJ mol(-1) K(-2). The calculated Wilson ratio for Y8Co5, R(W) = 1.4, is close to that expected for a free electron gas R(W) = 1. Low temperature resistivity under high pressure does not reveal superconductivity in this compound down to 1.2 K, up to hydrostatic pressures of 5.56 GPa. Band structure calculations (full-potential linearized augmented plane wave, FP-LAPW) derive the Stoner exchange interaction parameter S = 0.24, excluding magnetic behavior for Y8Co5. PMID- 23448946 TI - A brain-to-brain interface for real-time sharing of sensorimotor information. AB - A brain-to-brain interface (BTBI) enabled a real-time transfer of behaviorally meaningful sensorimotor information between the brains of two rats. In this BTBI, an "encoder" rat performed sensorimotor tasks that required it to select from two choices of tactile or visual stimuli. While the encoder rat performed the task, samples of its cortical activity were transmitted to matching cortical areas of a "decoder" rat using intracortical microstimulation (ICMS). The decoder rat learned to make similar behavioral selections, guided solely by the information provided by the encoder rat's brain. These results demonstrated that a complex system was formed by coupling the animals' brains, suggesting that BTBIs can enable dyads or networks of animal's brains to exchange, process, and store information and, hence, serve as the basis for studies of novel types of social interaction and for biological computing devices. PMID- 23448948 TI - Metastatic breast cancer: the clinical nurse specialist. PMID- 23448947 TI - Luminescent behavior of cadmium sulfide quantum dots for gallic acid estimation. AB - Thioglycolic acid capped cadmium sulfide (CdS/T) quantum dots have been synthesized using wet chemistry and their optical behavior has been investigated using UV-visible absorption and fluorescence spectroscopy. The role of the capping agent, sulfide source concentration, pH and temperature has been studied and discussed. Studies showed that alkaline pH leads to a decrease in the size of quantum dots and reflux temperature above 70 degrees C resulted in red-shift of emission spectra which is due to narrowing of the bandgap. Further, to reduce the toxicity and photochemical instability of quantum dots, the quantum dots have been functionalized with polyethylene glycol (PEG), which resulted in a 20% enhancement of the fluorescence intensity. The application potential of CdS/T-PEG quantum dots was further studied using gallic acid as a model compound. The sensing is based on fluorescence quenching of quantum dots in the presence of gallic acid, and this study showed linearity in the range from 1.3 * 10(-8) to 46.5 * 10(-8) mM, with a detection limit of 3.6 * 10(-8) mM. PMID- 23448949 TI - Reducing patient distress: a model for dementia care. AB - More than 750000 people in the UK have some form of dementia; with a rise expected over the next 25 years. With early diagnosis of cancer, more patients with dementia will attend for cancer treatment. Immobilisation masks, used to ensure accurate head and neck radiotherapy, may trigger panic in patients, even without prior mental health problems. This single case study reports on the care provided to a patient with dementia and his carer, his wife Betty, during cancer treatment. Bert was diagnosed with dementia 10 years prior to his cancer diagnosis. The use of sedation appeared to trigger confusion rather than facilitate procedures. Bert's case illustrates how an individualised contract of care could be developed to help maximise interactions, ensure ongoing consent and maintain dignity during difficult and challenging medical procedures. PMID- 23448950 TI - Cancer-related oral considerations: implications and treatment. PMID- 23448951 TI - Spirituality as experienced by Muslim oncology nurses in Iran. AB - Spirituality, as an essential part of holistic care, is concerned with faith and meaning, and is usually conceptualised as a 'higher' experience or a transcendence of oneself. A resurgence of interest in this area is evident in post modern culture because of the effects that spirituality and religious beliefS may have on health. Up until the last two decades, spirituality and spiritual care, although vital, were invisible aspects of nursing. However, now that these concepts have made their way into the mainstream, literature in this area has burgeoned. In addition, modern nursing grew out of spiritual roots, and spiritual care is a component of holistic care. In the Islamic Republic of Iran,little information exists documenting the expressed spirituality of nurses in general and of oncology nurses in particular. This article presents spirituality as it is experienced by Muslim oncology nurses.The investigation involved a qualitative analysis of the spirituality of 24 participants, using semi-structured interviews. Participants were oncology nurses at 12 hospitals in two educational universities of medical sciences in Tehran. The main categories of spirituality as experienced by oncology nurses included religious and existential dimensions in an Iranian Muslim context. Findings are consistent with the holistic view of Islam, that considers all dimensions of personhood simultaneously. This study is important to transcultural nursing because of the benefits of increasing nursing knowledge through research that examines nurses' spirituality in diverse cultures. PMID- 23448952 TI - Despite change, the patient must always come first. PMID- 23448953 TI - Erectile dysfunction following retropubic prostatectomy. AB - Prostate cancer is the most common cancer to affect men in the UK. Treatment options depend on the grade of tumour, the patient's co-existing diseases and choice of treatment. One potentially curative option is surgery, specifically a radical retropubic prostatectomy or variation thereof. As a consequence of the surgery, men commonly experience two side-effects: urinary incontinence and erectile dysfunction (ED). This paper outlines the clinical management of ED following surgery and aims to provide an overview of how to assess a man who has developed ED and discuss the various treatment options available, along with the efficacy in terms of recovery of erections. PMID- 23448954 TI - No one sees the fear: becoming diseased before becoming ill--being diagnosed with breast cancer. AB - BACKGROUND: Breast cancer patients experience profound life changes that include feelings of fear years after concluding treatment. OBJECTIVE: The aim of this article was to understand the nature and origin of the persistent worry women experience after breast cancer treatment. METHODS: Materials from participant observation of an oncology ward and from interviews with 17 first-time breast cancer patients, 4 oncologists, and 10 nurses were analyzed. Interpretation of materials was guided by theoretical concepts such as embodiment and liminality to understand the phenomenological aspects and cultural shaping of the illness experience. RESULTS: Interviewees felt healthy at the time of diagnosis. It was the physician's word that initiated the illness process through the experience of shock. Nurses' work and therapeutic emplotment were instrumental in guiding the women to overcome the shock and engage in treatment. Study participants' lives were restructured under biomedical conditions. This included mistrust toward their bodies. Because of the mode of diagnosis and the initial shock, long-term fear can be seen as an integral part of the experience of having had breast cancer. CONCLUSIONS: The study participants' sense of being in the world had changed in that their bodies had become objects unto themselves, dangerous objects. Fear became part of women's lives. To control the fear, women relied on biomedical practices to interpret bodily sensations. IMPLICATIONS FOR PRACTICE: Therapeutic interventions and practices of care that facilitate a reconnection of trust with the (physical) body should be included in the care of posttreatment patients. PMID- 23448955 TI - Identification and evaluation of the salient physical activity beliefs of colorectal cancer survivors. AB - BACKGROUND: Physical activity (PA) has been associated with lower risk of disease recurrence and longer survival in colorectal cancer (CRC) survivors; however, less than one-third of CRC survivors are meeting PA guidelines. Interventions to promote PA in CRC survivors need to understand the most critical beliefs that influence PA behavior. OBJECTIVE: The objective of this study was to examine the strength of associations between the most common PA beliefs of CRC survivors and motivational constructs from the Theory of Planned Behavior (TPB) as well as PA behavior. INTERVENTION/METHODS: Colorectal cancer survivors (n = 600) residing in Alberta, Canada, completed self-report questionnaires assessing medical and demographic variables, PA beliefs, constructs from the TPB, and PA behavior. RESULTS: Colorectal cancer survivors identified improved fitness (69.5%), family members (67.3%), and medical/health problems (8.8%) as the most prevalent behavioral, normative, and control beliefs, respectively. All PA beliefs were significantly correlated with all TPB constructs and PA. CONCLUSIONS: Physical activity interventions for CRC survivors should target many salient beliefs including behavioral, normative, and control beliefs. IMPLICATIONS FOR PRACTICE: Insights into the salient beliefs for PA in CRC survivors can guide nurses in developing successful strategies to promote PA in this population and likely improve quality of life and possibly disease outcomes. PMID- 23448956 TI - The Cancer Worry Scale: detecting fear of recurrence in breast cancer survivors. AB - BACKGROUND: In 9% to 34% of cancer patients, the fear of cancer recurrence becomes so overwhelming that it affects quality of life. Clinicians need a brief questionnaire with a cutoff point that is able to differentiate between high- and low-fearful survivors. OBJECTIVE: This study investigated if the Cancer Worry Scale (CWS) could serve as an instrument to detect high levels of fear of recurrence in female breast cancer survivors. METHODS: One hundred ninety-four female breast cancer patients were assessed up to 11 years after their primary treatment for cancer. The women returned the questionnaires including the 8-item CWS, 2 items of the Cancer Acceptance Scale, the Checklist Individual Strength Fatigue subscale, and the Cancer Empowerment Questionnaire. RESULTS: A cutoff score of 13 versus 14 (low: <=13, high: >=14) on the CWS was optimal for detecting severe levels of fear of recurrence. A cutoff score of 11 versus 12 (low: <=11, high: >=12) was optimal for screening. The Cronbach alpha coefficient of the CWS was .87; evidence to support the convergent and divergent validity of the CWS was also obtained. The CWS is able to detect high levels of fear of recurrence. CONCLUSION: The CWS is a reliable and valid questionnaire to assess fear of recurrence in breast cancer survivors. IMPLICATIONS FOR PRACTICE: With the CWS, it is possible for nurses to screen breast cancer survivors for severe levels of fear of cancer recurrence. Thereby, nurses can screen and assist survivors in accessing appropriate and available support. PMID- 23448958 TI - Patient and clinician communication of self-reported insomnia during ambulatory cancer care clinic visits. AB - BACKGROUND: Insomnia, the most commonly reported sleep-wake disturbance in people with cancer, has an adverse effect on quality of life including emotional well being, distress associated with other symptoms, daily functioning, relationships, and ability to work. OBJECTIVE: The aim of this study was to describe the content of discussions between clinicians and 120 patients with self-reported insomnia and to examine the associations of sociodemographic, clinical, and environmental factors with insomnia. METHODS: A secondary analysis was conducted with self reported symptom data and sociodemographic, clinical, and environmental factors. Recordings of clinician and patient discussions during clinic visits were examined by conducting a content analysis. RESULTS: Severe insomnia was more likely to be reported by women, minority, and lower-income individuals. Seven major topics were identified in the discussions. The clinicians did not always discuss insomnia; discussion rates differed by diagnosis and clinical service. CONCLUSIONS: Reporting of insomnia by the patient and clinician communication about insomnia may have differed by demographic and clinical characteristics. Clinicians attended to insomnia about half the time with management strategies likely to be effective. Explanations may be that insomnia had a low clinician priority for the clinic visit or lack of clear evidence to support insomnia interventions. IMPLICATIONS FOR PRACTICE: A better understanding is needed about why insomnia is not addressed even when reported by patients; it is well known that structured assessments and early interventions can improve quality of life. Research is warranted to better understand potential disparities in cancer care. PMID- 23448957 TI - Comparison of groups with different patterns of symptom cluster intensity across the breast cancer treatment trajectory. AB - BACKGROUND: Comparing subgroups with different patterns of change in symptom intensity would assist in sorting out individuals at risk for more severe symptoms and worse functional outcomes. OBJECTIVES: The objectives of this study were to identify and compare subgroups of breast cancer patients with different patterns of change in a psychoneurological symptom cluster intensity across the treatment trajectory. METHODS: This secondary analysis used the data from 160 breast cancer patients undergoing chemotherapy or radiation treatment. Psychoneurological symptom cluster intensity was a composite score of 5 symptoms (depressed mood, cognitive disturbance, fatigue, insomnia, and pain) in a psychoneurological cluster at each of 3 time points (ie, at baseline and at 2 follow-ups after chemotherapy or radiation treatment). RESULTS: Five distinct subgroups representing different patterns of psychoneurological symptom cluster intensity during breast cancer treatment were identified: the gradually increasing pattern subgroup (group 1), the constantly low pattern subgroup (group 2), the start low with dramatic increase and decrease pattern subgroup (group 3), the constantly high pattern subgroup (group 4), and the start high with dramatic decrease and leveling pattern subgroup (group 5). Patients without previous cancer treatment experience, with higher level of education, treated with chemotherapy, and/or with more limitations at the baseline were more likely to follow the pattern group 4. Patients in group 4 had the most serious functional limitations measured at the second follow-up time point. CONCLUSION: The results suggest the need to evaluate interventions for specific subgroups and to examine the causal mechanisms underlying a psychoneurological symptom cluster. IMPLICATION: Clinicians should consider these diverse symptom experiences for assessment/management. PMID- 23448959 TI - Bilateral V-Y rotation advancement flap for fingertip amputations. AB - BACKGROUND: Fingertip amputation is the most common type of injury in the upper limb. Goals in fingertip amputation reconstruction are covering the defect, establishing maximum tactile gnosis, keeping the length of the finger, protecting the joint function, acquiring a well-padded pulp tissue, providing a bed for growing nail, obtaining a satisfactory cosmetic appearance and allowing the patient to return to work as soon as possible. Adjacent skin and soft tissue are the best covers for fingertip injuries. However, local homodigital flaps lack enough tissue to cover the defect. To solve this problem, we used V-Y rotation advancement flap bilaterally in fingertip amputations which meets all the reconstruction goals. Rotation besides advancement makes this flap more mobile and easier to cover larger defects in all amputation planes. METHODS: Between 2007 and 2009, we performed bilateral V-Y rotation advancement flap on seven male patients' pulpa (average age, 37.6 years) whose fingertips were not replantable. RESULTS: Fourteen flaps were made on 7 fingers. There was neither total nor partial flap loss. Patients had neither cold intolerance nor scar hypersensitivity. Stiffness of the PIP joint did not occur. No obvious hooked nail occurred in patients who have remaining nail matrix. Because flaps contain neurovascular bundle, there was no difference in sensation and perfusion between the finger's pre-operative and post-operative status. The result was satisfactory with painless pinching. CONCLUSION: In addition to the various and versatile fingertip reconstruction methods, we want to present V-Y rotation advancement flap as a quick, reliable and aesthetic method. PMID- 23448960 TI - Development of an instrument to measure staff-reported resident-to-resident elder mistreatment (R-REM) using item response theory and other latent variable models. AB - OBJECTIVES: Although numerous studies have measured behaviors among individuals in congregate settings, few have focused on resident-to-resident elder mistreatment (R-REM). To our knowledge, there is no psychometrically developed measure of R-REM extant. The quantitative development of a measure of staff reported R-REM is described. METHODS: The design was a prevalent cohort study of residents of 5 long-term care facilities. The primary certified nursing assistant was interviewed about R-REM. Advanced measurement methods were used to develop a measure of R-REM. RESULTS: The loadings on the general factor for the final 11 item scale were greater than those on the group factor except for the item "other physical behavior" (0.63 vs. 0.74), suggesting essential unidimensionality. Although the bifactor model fit was slightly better than that of the unidimensional model, the difference was trivial (bifactor comparative fit index [CFI] = 0.997, root mean square error of approximation [RMSEA] = 0.013, unidimensional CFI = 0.979, and RMSEA = 0.030). However, modest support was provided for use of verbal and physical subscales. The explained common variance statistics were 0.76 for the bifactor model compared with 0.63 for the unidimensional model. DISCUSSION: The development of this R-REM measure will help to advance the measurement and ultimately evaluation of interventions associated with this important and under recognized problem facing residents in long-term care settings. PMID- 23448961 TI - Recession and expected retirement age: another look at the evidence. AB - PURPOSE: This article expands on earlier analyses that assessed whether the recent recession influenced retirement expectations. DESIGN AND METHODS: Acknowledging that planning for retirement is a complex process influenced by personal preferences, resources, economic factors, institutional policies, and social norms, we test more comprehensive models than those used in previous studies, using data from the 2006 and 2008 waves (Waves 8 and 9) of the Health and Retirement Study. RESULTS: Our results confirm that economic changes impinge on retirement expectations, but they also show stronger influences of other factors such as debts and the work environment. IMPLICATIONS: As the baby boom cohorts approach retirement age, it will be important to better understand how workers consider macro factors such as the state of the economy and firm-level factors and personal finances when planning for retirement. PMID- 23448962 TI - Azithromycin: more lethal than chloramphenicol? AB - Azithromycin is commonly used in sexual health and respiratory medicine, often when the diagnosis is presumptive. A recent article by Ray et al. reported that 1 out of 20?000 courses of low-dose azithromycin was associated with (sudden) cardiovascular death (including 1 out of 4000 courses in high-risk cardiovascular patients), ascribing these deaths to azithromycin itself. Here, we critique the actual study and examine conflicting data from randomised control trials, animal studies and observational data. PMID- 23448963 TI - A study of the existing problems of estimating the information transfer rate in online brain-computer interfaces. AB - OBJECTIVE: Today, the brain-computer interface (BCI) community lacks a standard method to evaluate an online BCI's performance. Even the most commonly used metric, the information transfer rate (ITR), is often reported differently, even incorrectly, in many papers, which is not conducive to BCI research. This paper aims to point out many of the existing problems and give some suggestions and methods to overcome these problems. APPROACH: First, the preconditions inherent in ITR calculation based on Wolpaw's definition are summarized and several incorrect ITR calculations, which go against the preconditions, are indicated. Then, the issues affecting ITR estimation during the test of online BCI systems are discussed in detail. Finally, a task-oriented online BCI test platform was proposed, which may help BCI evaluations in real-world applications. MAIN RESULTS: The guidelines for ITR calculation in online BCIs testing are proposed. The platform executed in the Beijing BCI Competition 2010 shows that it can be used as a common way to compare the online performances (including the ITR) of existing BCI paradigms. SIGNIFICANCE: The proposed guidelines and task-oriented test platform may reduce the uncertainty and artifacts of online BCI performance evaluation; they provide a relatively objective way to compare different BCI's performances in real-world BCI applications, which is a forward step toward developing standards for BCI performance evaluation. PMID- 23448964 TI - Metal through metal: pacing lead across a mechanical tricuspid valve. PMID- 23448965 TI - A reliable witness: dual-chamber pacemaker prolonged intracardiac recordings of a resuscitated cardiac arrest episode. AB - We report the case of a patient with a previously implanted pacemaker, who suffered cardiac arrest due to ventricular fibrillation requiring cardiopulmonary resuscitation (CPR) manoeuvres and electrical cardioversion to restore sinus rhythm. Analysis of the pacemaker's stored electrograms showed the arrhythmia progression from monomorphic ventricular tachycardia to ventricular fibrillation and the electrophysiological effects of CPR manoeuvres and epinephrine administration before successful cardioversion. PMID- 23448966 TI - Call for case histories of BMT in patients with coincident schizophrenia. PMID- 23448967 TI - The Fulde-Ferrell-Larkin-Ovchinnikov state in layered d-wave superconductors: in plane anisotropy and resonance effects in the angular dependence of the upper critical field. AB - We study the anisotropy of the in-plane upper critical magnetic field coupled to the orbital motion and the spins of electrons in a layered d(x2-y2) organic superconductor in the spatially modulated Fulde-Ferrell-Larkin-Ovchinnikov phase. We show that the interplay between the nodal structure of the order parameter and its spatial modulation results in the very peculiar angular dependence of the onset of superconductivity in the high-field regime. The principal axis of the field-direction dependence of the onset of superconductivity is tilted by pi/4 in the temperature range 0.056 < or approximately equal T < 0.56. In some cases the resonance between the modulation wavevector and the vector potential of a parallel magnetic field may lead to anomalous cusps in the temperature and in plane angular dependences of the onset of superconductivity. The obtained results support the interpretation of the recent experiments as evidence of the FFLO state. PMID- 23448968 TI - Endocrine changes (beyond diabetes) after bariatric surgery in adult life. AB - Bariatric surgery is nowadays an effective therapeutic option for morbid obesity. Endocrinologists may thus have a growing opportunity to diagnose and treat obese patients eligible for surgery in pre- and post-operative phase. This requires a better understanding of endocrine changes caused by either obesity or weight loss surgery. Despite the large number of studies available in literature, only limited well-designed clinical trials have been performed so far to investigate changes of endocrine axes following bariatric procedures. There are still areas of unclear results such as female and male fertility, however, weight loss after bariatric surgery is considered to be associated with favorable effects on most endocrine axes. The aim of this clinical review is to overview the available literature on the effects of weight loss after bariatric surgery on the endocrine systems to suggest the most appropriate pre- and post-operative management of obese patients undergoing bariatric surgery in terms of "endocrine" health. PMID- 23448970 TI - Identification of a genetic locus on chromosome 11 that regulates leukocyte infiltration in mouse carotid artery. AB - OBJECTIVE: We demonstrated that inflammatory cells and intima-media thickening are increased in carotids exposed to low-blood flow in the SJL/J (SJL) strain compared with other mouse strains. We hypothesized that the extent of inflammation associated with intima-media thickening is a genetically regulated trait. APPROACH AND RESULTS: We performed a whole genome approach to measure leukocyte infiltration in the carotid intima as a quantitative trait in a genetic cross between C3HeB/FeJ (C3H/F) and SJL mice. Immunostaining for CD45(+) (a pan specific leukocyte marker) was performed on carotids from C3H/F, SJL, F1, and N2 progeny to measure leukocyte infiltration. We identified a nearly significant quantitative trait locus for CD45(+) on chromosome (chr) 11 (17 cM, LOD=2.3; significance was considered at threshold P=0.05). Interval mapping showed that the CD45(+) locus on chr 11 accounted for 8% of the variation in the logarithm of odds backcross. Importantly, the CD45(+) locus colocalized with the intima modifier 2 (Im2) locus, which controls 17% of intima variation. We created 2 Im2 congenic lines of mice (C3H/F.SJL.11.1 and C3H/F.SJL.11.2) to better understand the regulation of intima-media thickening by the chr 11 locus. The C3H/F.SJL.11.1 congenic mouse showed ~30% of the SJL trait, confirming that CD45(+) cell infiltration contributed to the intima trait. CONCLUSIONS: We discovered a novel locus on chr 11 that controls leukocyte infiltration in the carotid. Importantly, this locus overlaps with our previously published Im2 locus on chr 11. Our study reveals a potential mechanistic relationship between leukocyte infiltration and intima-media thickening in response to decreased blood flow. PMID- 23448969 TI - Total adiponectin and risk of symptomatic lower extremity peripheral artery disease in men. AB - OBJECTIVE: Lower concentrations of adiponectin have been linked to subsequent risk of coronary heart disease in healthy individuals. Whether similar relationships exist for the development of systemic atherosclerosis, such as peripheral artery disease (PAD), is uncertain. We investigated the association between total adiponectin and risk of lower extremity PAD. APPROACH AND RESULTS: We performed a prospective, nested case-control study among 18,225 male participants of the Health Professionals Follow-up Study who were free of diagnosed cardiovascular disease at the time of blood draw (1993-1995). During 14 years of follow-up, 143 men developed PAD. Using risk set sampling, controls were selected in a 3:1 ratio and matched on age, smoking status, fasting status, and date of blood draw (n=429). Median (interquartile range) adiponectin concentrations at baseline were lower among cases compared with controls (4.1 [3.2-5.5] versus 5.4 [3.8-7.5] ug/mL; P<0.001). A log-linear inverse association was evident over the full spectrum of adiponectin concentrations with PAD risk after controlling for baseline cardiovascular risk factors using restricted spline conditional logistic regression. Adiponectin was associated with a 42% lower risk of PAD per SD increase in natural log-transformed adiponectin (relative risk, 0.58; 95% confidence interval, 0.45-0.74) after adjustment for cardiovascular risk factors. The relative risk was attenuated (relative risk, 0.68; 95% confidence interval, 0.51-0.92) after further accounting for high density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein, and cystatin C. Additional adjustment for hemoglobin A(1c), triglycerides, and gamma-glutamyltransferase had little impact on this association (relative risk, 0.68; 95% confidence interval, 0.50-0.92). CONCLUSIONS: Total adiponectin is inversely associated with risk of symptomatic lower extremity PAD in men. PMID- 23448971 TI - Embryological-origin-dependent differences in homeobox expression in adult aorta: role in regional phenotypic variability and regulation of NF-kappaB activity. AB - OBJECTIVE: Different vascular beds show differing susceptibility to the development of atherosclerosis, but the molecular mechanisms underlying these differences are incompletely understood. This study aims to identify factors that contribute to the phenotypic heterogeneity of distinct regions of the adult vasculature. APPROACH AND RESULTS: High-throughput mRNA profiling in adult mice reveals higher expression of the homeobox paralogous genes 6 to 10 (Hox6-10) in the athero-resistant thoracic aorta (TA) than in the athero-susceptible aortic arch (AA). Higher homeobox gene expression also occurs in rat and porcine TA, and is maintained in primary smooth muscle cells isolated from TA (TA-SMCs) compared with cells from AA (AA-SMCs). This region-specific homeobox gene expression pattern is also observed in human embryonic stem cells differentiated into neuroectoderm-SMCs and paraxial mesoderm-SMCs, which give rise to AA-SMCs and TA SMCs, respectively. We also find that, compared with AA and AA-SMCs, TA and TA SMCs have lower activity of the proinflammatory and proatherogenic nuclear factor kappaB (NF-kappaB) and lower expression of NF-kappaB target genes, at least in part attributable to HOXA9-dependent inhibition. Conversely, NF-kappaB inhibits HOXA9 promoter activity and mRNA expression in SMCs. CONCLUSION: Our findings support a model of Hox6-10-specified positional identity in the adult vasculature that is established by embryonic cues independently of environmental factors and is conserved in different mammalian species. Differential homeobox gene expression contributes to maintaining phenotypic differences between SMCs from athero-resistant and athero-susceptible regions, at least in part through feedback regulatory mechanisms involving inflammatory mediators, for example, reciprocal inhibition between HOXA9 and NF-kappaB. PMID- 23448973 TI - Tri-track: free software for large-scale particle tracking. AB - The ability to correctly track objects in time-lapse sequences is important in many applications of microscopy. Individual object motions typically display a level of dynamic regularity reflecting the existence of an underlying physics or biology. Best results are obtained when this local information is exploited. Additionally, if the particle number is known to be approximately constant, a large number of tracking scenarios may be rejected on the basis that they are not compatible with a known maximum particle velocity. This represents information of a global nature, which should ideally be exploited too. Some time ago, we devised an efficient algorithm that exploited both types of information. The tracking task was reduced to a max-flow min-cost problem instance through a novel graph structure that comprised vertices representing objects from three consecutive image frames. The algorithm is explained here for the first time. A user-friendly implementation is provided, and the specific relaxation mechanism responsible for the method's effectiveness is uncovered. The software is particularly competitive for complex dynamics such as dense antiparallel flows, or in situations where object displacements are considerable. As an application, we characterize a remarkable vortex structure formed by bacteria engaged in interstitial motility. PMID- 23448972 TI - Combined in vivo depletion of glycoprotein VI and C-type lectin-like receptor 2 severely compromises hemostasis and abrogates arterial thrombosis in mice. AB - OBJECTIVE: Platelet inhibition is a major strategy to prevent acute ischemic cardiovascular and cerebrovascular events, which may, however, be associated with an increased bleeding risk. The (hem)immunoreceptor tyrosine activation motif bearing platelet receptors, glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2), might be promising antithrombotic targets because they can be depleted from circulating platelets by antibody treatment, leading to sustained antithrombotic protection, but only moderately increased bleeding times in mice. APPROACH AND RESULTS: We investigated whether both (hem)immunoreceptor tyrosine activation motif-bearing receptors can be targeted simultaneously and what the in vivo consequences of such a combined therapeutic GPVI/CLEC-2 deficiency are. We demonstrate that isolated targeting of either GPVI or CLEC-2 in vivo does not affect expression or function of the respective other receptor. Moreover, simultaneous treatment with both antibodies resulted in the sustained loss of both GPVI and CLEC-2, while leaving other activation pathways intact. However, GPVI/CLEC-2-depleted mice displayed a dramatic hemostatic defect and profound impairment of arterial thrombus formation. Furthermore, a strongly diminished hemostatic response could also be reproduced in mice genetically lacking GPVI and CLEC-2. CONCLUSIONS: These results demonstrate that GPVI and CLEC-2 can be simultaneously downregulated in platelets in vivo and reveal an unexpected functional redundancy of the 2 receptors in hemostasis and thrombosis. These findings may have important implications of the potential use of anti-GPVI and anti-CLEC-2-based agents in the prevention of thrombotic diseases. PMID- 23448974 TI - The liver in sepsis: patterns of response and injury. AB - PURPOSE OF REVIEW: Sepsis elicits profound changes in the concentrations of plasma proteins synthesized by liver parenchymal cells referred to as acute-phase proteins. Mechanisms controlling this orchestrated response include release of cytokines that induce acute-phase proteins, while other 'house-keeping' genes are downregulated. RECENT FINDINGS: Although some acute-phase proteins help to control damage, functions of many other acute-phase reactants remain obscure. Changes in acute-phase gene expression are primarily subject to transcriptional regulation and can be comprehensively monitored by array techniques. Emerging evidence from such strategies implies that in addition to a 'common host response' also highly specific pathways are induced in specific disease contexts. Applying a systems biology approach to the integrated response of the hepatocyte to infection would suggest that the reprogramming of metabolic functions occurs in parallel with a severity-dependent disruption of phase I and II biotransformation and canalicular transport, that is, excretory failure. Although traditionally bilirubin serves to monitor excretion, emerging evidence suggests that bile acids indicate liver dysfunction with higher sensitivity and specificity. SUMMARY: Sepsis induces reprogramming of the hepatic transcriptome. This includes induction of adaptive acute-phase proteins but also repression of phase I, II metabolism and transport with important implications for monitoring and pharmacotherapy. PMID- 23448975 TI - Repeat endovascular repair for multiple intimal tears after endovascular stent grafting of Stanford type B aortic dissection. AB - A 59-year-old man with hypertension was found to have a Stanford type B aortic dissection with a false lumen extending to the abdominal aorta. We placed a stent graft to the thoracic aorta covering the proximal entry and planned a second endovascular repair to cover the entries in the abdominal aorta. Five years later, computed tomography angiography revealed an extensive dissection to the right common iliac artery with multiple intimal tears. We placed stent grafts in the distal end of the primary stent graft and an abdominal stent graft to the aortic bifurcation to cover the entry tears. However, 3 months later it developed into a newly formed intimal tear in the right renal artery, leading to retrograde reperfusion into the false lumen. The patient was successfully treated with a third time endovascular repair and recovered smoothly during follow-up. PMID- 23448976 TI - Cool excimer laser-assisted angioplasty (CELA) and tibial balloon angioplasty (TBA) in management of infragenicular arterial occlusion in critical lower limb ischemia (CLI). AB - We aim to compare cool excimer laser-assisted angioplasty (CELA) versus tibial balloon angioplasty (TBA) in patients with critical limb ischemia (CLI) with tibial artery occlusive disease. The primary end point is sustained clinical improvement (SCI) and amputation-free survival (AFS). The secondary end points are binary restenosis, target extremity revascularization (TER), and cost effectiveness. From June 2005 to October 2010, 1506 patients were referred with peripheral vascular disease and 572 with CLI. A total of 80 patients underwent 89 endovascular revascularizations (EVRs) for tibial occlusions, 47 using TBA and 42 using CELA. All patients were Rutherford category 4 to 6. Three-year SCI was enhanced with CELA (81%) compared to TBA (63.8%; P = .013). Three-year AFS significantly improved with CELA (95.2%) versus TBA (89.4%; P = .0165). Three year freedom from TER was significantly improved with CELA (92.9%) versus 78.7% TBA (P = .026). Three-year freedom from MACE was comparable in both the groups (P = .455). Patients with CELA had significantly improved quality time without symptoms of disease or toxicity of treatment (Q-TWiST) at 3 years (10.5 months; P = .048) with incremental cost of ?2073.19 per quality-adjusted life year gained. Tibial EVR provides exceptional outcome in CLI. The CELA has superior SCI, AFS, and freedom from TER, with improved Q-TWiST and cost-effectiveness. PMID- 23448977 TI - Synthesis of reduced graphene oxide/CeO2 nanocomposites and their photocatalytic properties. AB - With a unique structure and extraordinary properties, graphene has attracted tremendous attention in the preparation of graphene-based composites for various applications. In this study, two different strategies, including in situ growth and a self-assembly approach, have been developed to load CeO2 nanoparticles onto reduced graphene oxide (RGO) nanosheets. The microstructure and morphology of the as-synthesized RGO/CeO2 nanocomposites were investigated by x-ray diffraction, Raman spectroscopy and transmission electron microscopy. The results reveal that CeO2 nanoparticles with well-controlled size and a uniform distribution on RGO sheets with tunable density can be achieved through the self-assembly approach. The significantly enhanced photocatalytic activity of the RGO/CeO2 nanocomposites in comparison with bare CeO2 nanoparticles was revealed by the degradation of methylene blue under simulated sunlight irradiation, which can be attributed to the improved separation of electron-hole pairs and enhanced adsorption performance due to the presence of RGO. A suitable loading content of CeO2 on RGO was found to be crucial for optimizing the photocatalytic activity of the nanocomposites. It is expected that this convenient assembly approach with high controllability can be extended to the attachment of other functional nanoparticles to RGO sheets, and the resultant RGO-supported highly dispersed nanoparticles are attractive for catalysis, sensing and power source applications. PMID- 23448978 TI - Extraction of mismatch negativity using a resampling-based spatial filtering method. AB - OBJECTIVE: It is currently a challenge to extract the mismatch negativity (MMN) waveform on the basis of a small number of EEG trials, which are typically unbalanced between conditions. APPROACH: In order to address this issue, a method combining the techniques of resampling and spatial filtering is proposed in this paper. Specifically, the first step of the method, termed 'resampling difference', randomly samples the standard and deviant sweeps, and then subtracts standard sweeps from deviant sweeps. The second step of the method employs the spatial filters designed by a signal-to-noise ratio maximizer (SIM) to extract the MMN component. The SIM algorithm can maximize the signal-to-noise ratio for event-related potentials (ERPs) to improve extraction. Simulation data were used to evaluate the influence of three parameters (i.e. trial number, repeated-SIM times and sampling times) on the performance of the proposed method. MAIN RESULTS: Results demonstrated that it was feasible and reliable to extract the MMN waveform using the method. Finally, an oddball paradigm with auditory stimuli of different frequencies was employed to record a few trials (50 trials of deviant sweeps and 250 trials of standard sweeps) of EEG data from 11 adult subjects. Results showed that the method could effectively extract the MMN using the EEG data of each individual subject. SIGNIFICANCE: The extracted MMN waveform has a significantly larger peak amplitude and shorter latencies in response to the more deviant stimuli than in response to the less deviant stimuli, which agreed with the MMN properties reported in previous literature using grand averaged EEG data of multi-subjects. PMID- 23448980 TI - Doctors' contracts: change will affect nurses too. PMID- 23448979 TI - Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction. AB - Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment. PMID- 23448981 TI - Cardiac rehabilitation outcomes: modifiable risk factors. AB - Cardiac rehabilitation (CR) plays a significant role in management of heart diseases resulting in an improvement in patients' physical activity and quality of life and a decrease of healthcare costs. The purpose of this article was to review studies that examine outcomes of CR regarding the modifiable risk factors. Literature published between 1995 and 2012 was researched using PubMed and MEDLINE and reference lists of articles. Five hundred and eight studies were identified, however, only 16 met the inclusion criteria. The majority of studies included patients with any coronary heart disease. The study concluded that CR improves patients' self-care; a reduction in cholesterol and body mass index was observed. In addition to this, patients tended to quit smoking and increase their exercise activity. This suggests that the establishment and development of CR services is essential for the most effective management of heart condition. PMID- 23448982 TI - Temperature measurement: the right thermometer and site. PMID- 23448983 TI - Science and intuition: do both have a place in clinical decision making? AB - Intuition is widely used in clinical decision making yet its use is underestimated compared to scientific decision-making methods. Information processing is used within scientific decision making and is methodical and analytical, whereas intuition relies more on a practitioner's perception. Intuition is an unconscious process and may be referred to as a 'sixth sense', 'hunch' or 'gut feeling'. It is not underpinned by valid and reliable measures. Expert health professionals use a rapid, automatic process to recognise familiar problems instantly. Intuition could therefore involve pattern recognition, where experts draw on experiences, so could be perceived as a cognitive skill rather than a perception or knowing without knowing how. The NHS places great importance on evidence-based practice but intuition is seemingly becoming an acceptable way of thinking and knowing in clinical decision making. Recognising nursing as an art allows intuition to be used and the environment or situation to be interpreted to help inform decision making. Intuition can be used in conjunction with evidence-based practice and to achieve good outcomes and deserves to be acknowledged within clinical practice. PMID- 23448984 TI - Lived experience of being a nurse from a male and female perspective. AB - The phenomenological psychology approach was used here to encourage reflection on the experience of nursing from both male and female perspectives, then to explore and analyse the experience and compare and contrast the findings with current literature. The research question being explored was 'Is the lived experience of being a nurse different depending on your gender?' Using individual semi structured interviews, questions were asked of two participants. These interviews were transcribed, analysed using an interpretative or 'hermeneutic' approach to identify main themes and, together with reflexive field notes written during the study, used to complete a qualitative analysis. The main themes identified in the analysis of the transcripts were intersubjectivity, career versus vocation and gender stereotyping. The experience expressed by the two research participants suggests that the gender of a nurse influences the lived experience when compared and contrasted. As no previous gender comparative research could be found during the background literature search, this study is novel. PMID- 23448985 TI - Role modelling and students' professional development. AB - Patients expect to be cared for by nurses who are not only competent but also behave professionally, so students must be educated to develop professional qualities. The Nursing and Midwifery Council stipulates that professional values must underpin education as well as practice (NMC, 2010a). Much has been written on the qualities of an effective role model and the potential barriers to becoming one. This article focuses on preregistration adult nursing education and role modelling, with a slant towards the development of professionalism, as opposed to skills competence. Attention is paid to the identity of students' role models and strategies for role modelling linked to teaching and the curriculum. Practice and academic staff have an equal stake in nurse education; for them to be seen equally as role models, there has to be a partnership approach to that education. Both practice and academic staff are able to exemplify behaviours and attitudes that directly influence the development of professionalism. This article is intended to stimulate discussion within and between nurse educators and practice-based staff about the impact their role modelling has on the development of adult nursing students' professional practice. PMID- 23448986 TI - Spiritual coping in rehabilitation - a comparative study: part 1. AB - Chronic illness is defined as a long-term disease that challenges a person's physical, psychological and spiritual wellbeing. However, individuals may adapt to their condition by adopting spiritual coping strategies that may or may not include religiosity. Part 1 of this article presents the methodology of this cross-sectional comparative study, which explored the spiritual coping of patients with chronic illness receiving rehabilitation services in Malta (n=44: lower limb amputation n=10; chronic heart disease n=9; osteoarthritis-in an institution n=10 and in the community n=15); and in Norway (n=16: post hip/shoulder surgery n=5; chronic heart disease n=5; chronic pain n=6). Data were collected from seven purposive samples during focus group sessions. Roy's Adaptation Model (1984) and Neuman's Systems Model (2010) guided the study. While acknowledging the limitations of this study, the findings presented in Part 2 identify commonalities in the spiritual coping of patients irrespective of cultural differences between Malta and Norway. A set of recommendations address clinical practice, education and further research. PMID- 23448987 TI - Child development and the scope of parental responsibility: part 1. AB - The scope of parental responsibility has once again come under scrutiny following the case of Neon Roberts (Walker, 2012) whose mother objected to treatment for his brain tumour. This first of two articles considering the scope of parental responsibility sets out the key provisions and discusses the right of the court to overrule a parent's decision to refuse medical treatment for their child. PMID- 23448988 TI - Care in local communities: a new vision for district nursing. PMID- 23448989 TI - Francis Report highlights issue of patient safety in hospital. PMID- 23448990 TI - Advancing Practice: from staff nurse to nurse consultant. Part 4: clinical supervision. PMID- 23448991 TI - Reflecting on the meaning of true nursing quality. PMID- 23448992 TI - The Francis Report: my priorities. PMID- 23448993 TI - Use of incentives to encourage sexually transmissible infection testing amongst sex-on-premises venue patrons. AB - BACKGROUND: Incentives have been explored as a strategy for increasing access to sexually transmissible infection (STI) testing. This project sought to trial the offer of free entry to sex-on-premises venues (SOPVs) for venue patrons as an incentive to access sexual health checks. METHOD: SOPV patrons were offered free entry into venues if they took advantage of sexual health testing at a range of clinics. Patrons were given testing cards from the SOPV that could be exchanged at the time of the clinical consultation for a free entry pass to the SOPV of their choice. Cards collected at clinics and SOPVs were collated. RESULTS: In total, 244 cards were distributed to patrons from four venues over a 6-month period. Ten persons accessed one of the six clinical sites, one person attending twice. Of these persons, five attended two general practices and the remaining five accessed public sexual health clinics. Of these 10 persons, three used their free entry passes to attend an SOPV. Two persons accessed these clinical sites for the first time, one of whom tested reactive for an STI. Another regular attendee also tested reactive. CONCLUSION: Despite the low uptake, the free entry promotion was inexpensive and could, given sufficient time, be considered an effective incentive. Nonetheless, this study may have contributed to at least two new persons undertaking testing, one of whom was diagnosed with an STI. PMID- 23448994 TI - Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia. PMID- 23448995 TI - Isolation and Characterization of a Bacteriocin-Like Substance Produced by Geobacillus toebii Strain HBB-247. AB - A total of 201 thermophilic bacteria isolated from various thermal spring, mud and soil were tested for their antibacterial activity. Among the mostly active isolates, Geobacillus toebii HBB-247 was further examined. Bacteriocin-like inhibitory substance (BLIS) produced by strain HBB-247 was found to be stable up to 60 degrees C, sensitive to proteolytic enzymes and effective against Enterococcus faecalis, Listeria sp., E. avium, Clostridium pasteurianum, Cellulomonas fimi and some thermophilic strains isolated and identified in this study. As a result of Tricine-SDS-PAGE molecular weight of BLIS was estimated about 38 kDa. Production studies showed that G. toebii HBB-247 starts to produce antibacterial substance at early logarithmic phase of growth and maximum production was detected at the end of the logarithmic phase. PMID- 23448996 TI - Symmetry-mode and spontaneous strain analysis of the structural transitions in Fe(1+y)Te and REFeAsO compounds. AB - Symmetry-mode and spontaneous strain analysis has been carried out for the structural transitions taking place in Fe(1+y)Te and REFeAsO compounds on cooling from room temperature. The P4/nmm -> P21/m structural transition occurring in Fe(1+y)Te is induced by a single irreducible representation E(g), indicating a pure ferroelastic transition. The increase of the interstitial Fe content hinders the displacement of the Te atoms according to the E(g) mode; as a result this mode is progressively suppressed in favour of the A(2g) mode. As a consequence the Pmmn polymorphic modification is stabilized, but in this case the P4/nmm -> Pmmn transition is not ferroelastic. The P4/nmm -> Cmme structural transition taking place in REFeAsO compounds is induced by a single irreducible representation B(2g), which is not active at the occupied sites. Hence, the transition is not driven by the condensation of a collective atomic displacement, but is likely characterized by a pseudo-proper ferroelastic behaviour. PMID- 23448998 TI - Endogenous sex hormones and their associations with cardiovascular risk factors in post-menopausal women. AB - AIMS: Our aim was to understand the relationship between endogenous sex hormones and cardiovascular disease (CVD) risk factors in post-menopausal women. MATERIALS AND METHODS: Eighty-three post-menopausal women from a previous prospectively designed study were included. We analyzed endogenous sex hormones and biochemical parameters. RESULTS: Levels of estradiol and free testosterone were higher in patients with metabolic syndrome. Estradiol correlated positively with interleukin-6 (IL-6), weight, body mass index (BMI), insulin, homocysteine, and homeostasis model assessment of insulin resistance (HOMA-IR). Free testosterone correlated positively with weight, waist circumference (WC), BMI, insulin, HOMA IR and negatively with HDL and SHBG. DHEAS correlated only with HDL. FSH correlated negatively with age, weight, WC, hip circumference, BMI, systolic blood pressure, diastolic blood pressure, duration of menopause, fasting glucose, HDL, C-reactive protein, and insulin. LH correlated negatively with IL-6, age, WC, duration of menopause and SHBG. CONCLUSIONS: We identified endogenous estradiol and free testosterone as the strongest links to CVD risk. They can be used as biomarkers for CVD risk estimation. PMID- 23448999 TI - Zinc-alpha2-glycoprotein as a marker of fat catabolism in humans. AB - PURPOSE OF REVIEW: Cachexia development is a feature of cancer as well as other chronic diseases. Fat mass loss appears of greatest importance in cachexia, as it is related to poorer survival. Zinc-alpha2-glycoprotein (ZAG), firstly isolated in human plasma 50 years ago, has emerged as a novel adipokine, which plays an important role in mobilization and utilization of lipids. This review will focus on recent evidences of ZAG as a fat catabolic marker in cancer and other diseases complicated by cachexia. RECENT FINDINGS: ZAG is a lipolytic factor produced by certain cachexia-inducing tumuors and by adipose tissue. It increases lipolysis in white adipose tissue through cyclic-AMP pathway and stimulates uncoupling protein-1 in brown adipose tissue leading to heat generation. In cancer cachexia, ZAG release from white adipocytes is elevated and closely related to body weight loss. In cardiac cachexia, ZAG and circulating free fatty acids are closely related, suggesting a causative role in fat catabolism. SUMMARY: ZAG may play an important role, probably as an autocrine/paracrine modulator of adipose mass in cachexia. A better comprehension of ZAG involvement in fat wasting mechanisms will be useful in the development of new therapeutic agents. PMID- 23449001 TI - Number of manic episodes is associated with elevated DNA oxidation in bipolar I disorder. AB - Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross sectional studies to confirm neuroprogression in BD are warranted. PMID- 23449000 TI - MicroRNA in myogenesis and muscle atrophy. AB - PURPOSE OF REVIEW: To understand the impact of microRNA on myogenesis and muscle wasting in order to provide valuable information for clinical investigation. RECENT FINDINGS: Muscle wasting increases the risk of morbidity/mortality in primary muscle diseases, secondary muscle disorders and elderly population. Muscle mass is controlled by several different signalling pathways. Insulin-like growth factor/PI3K/Akt is a positive signalling pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. This pathway is directly and/or indirectly downregulated by miR-1, miR-133, miR-206 or miR-125b, and upregulated by miR-23a or miR-486. Myostatin and the transforming growth factor-beta signalling pathway are negative regulators that cause muscle wasting. An increase of miR-27 reduces myostatin and increases muscle cell proliferation. Muscle regeneration capacity also plays a significant role in the regulation of muscle mass. This review comprehensively describes the effect of microRNA on myoblasts proliferation and differentiation, and summarizes the varied influences of microRNA on different muscle atrophy. SUMMARY: Growing evidence indicates that microRNAs significantly impact muscle growth, regeneration and metabolism. MicroRNAs have a great potential to become diagnostic and/or prognostic markers, therapeutic agents and therapeutic targets. PMID- 23449002 TI - Model-based rational feedback controller design for closed-loop deep brain stimulation of Parkinson's disease. AB - OBJECTIVE: To explore the use of classical feedback control methods to achieve an improved deep brain stimulation (DBS) algorithm for application to Parkinson's disease (PD). APPROACH: A computational model of PD dynamics was employed to develop model-based rational feedback controller design. The restoration of thalamocortical relay capabilities to patients suffering from PD is formulated as a feedback control problem with the DBS waveform serving as the control input. Two high-level control strategies are tested: one that is driven by an online estimate of thalamic reliability, and another that acts to eliminate substantial decreases in the inhibition from the globus pallidus interna (GPi) to the thalamus. Control laws inspired by traditional proportional-integral-derivative (PID) methodology are prescribed for each strategy and simulated on this computational model of the basal ganglia network. MAIN RESULTS: For control based upon thalamic reliability, a strategy of frequency proportional control with proportional bias delivered the optimal control achieved for a given energy expenditure. In comparison, control based upon synaptic inhibitory output from the GPi performed very well in comparison with those of reliability-based control, with considerable further reduction in energy expenditure relative to that of open-loop DBS. The best controller performance was amplitude proportional with derivative control and integral bias, which is full PID control. We demonstrated how optimizing the three components of PID control is feasible in this setting, although the complexity of these optimization functions argues for adaptive methods in implementation. SIGNIFICANCE: Our findings point to the potential value of model-based rational design of feedback controllers for Parkinson's disease. PMID- 23449004 TI - Prevalence and predictors of lymphogranuloma venereum among men who have sex with men at a Sydney metropolitan sexual health clinic. AB - During an 18-month period to June 2012, 1732 anal chlamydia (Chlamydia trachomatis) tests were performed among men who have sex with men (MSM) at RPA Sexual Health in Sydney's inner west. Positive anal chlamydia samples were subsequently tested for lymphogranuloma venereum (LGV). Seventy-five (4.3%) anal samples were positive for chlamydia among 67 men during the study period. Anal symptoms were reported for 16 out of 75 (21.3%) of anal chlamydia episodes overall. Three episodes of LGV (all serovar L2b) were identified, all three of whom reported anal symptoms (100%, 95% confidence interval (CI): 29.2-100%). In contrast, only 13/72 (18.1%, 95% CI: 10.0-28.9%) of those with non-LGV anal chlamydia reported anal symptoms. LGV was not identified in any of 59 episodes of asymptomatic anal chlamydia (0%, 95% CI: 0-6.1%). Of those with LGV, two were known to be HIV-positive and one subsequently seroconverted to HIV within a year of the LGV diagnosis. Our findings suggest that routine LGV testing among MSM is not warranted, except among those with anal symptoms. PMID- 23449003 TI - A first course in computing with applications to biology. AB - We believe that undergraduate biology students must acquire a foundational background in computing including how to formulate a computational problem; develop an algorithmic solution; implement their solution in software and then test, document and use their code to explore biological phenomena. Moreover, by learning these skills in the first year, students acquire a powerful tool set that they can use and build on throughout their studies. To address this need, we have developed a first-year undergraduate course that teaches students the foundations of computational thinking and programming in the context of problems in biology. This article describes the structure and content of the course and summarizes assessment data on both affective and learning outcomes. PMID- 23449005 TI - Potential changes in rat spermatogenesis and sperm parameters after inhalation of Boswellia papyrifera and Boswellia carterii incense. AB - In this study the effect of Boswellia papyrifera (B. papyrifera) and Boswellia carterii (B. carterii) smoke exposure on spermatogenesis and sperm parameters in male albino rats was investigated. Rats (n = 11) were exposed daily in smoking chambers to smoke emanated by burning 4 g each of either B. papyrifera or B. carterii for 48 days. At the end of exposure duration rats were killed, and the testes were excised and analysed for histopathological and ultrastructural changes. Sperm analysis including total sperm count, motility, velocity and relative percentage of abnormal sperms were recorded. Rats exposed to B. papyrifera and B. carterii showed significant disturbances in spermatogenetic patterns and changes in sperm kinetics compared to unexposed rats. Atrophied seminiferous tubules with dynamic changes were also noticed. The boundaries of intercellular and intracellular vacuoles were seen in the Sertoli cells. Furthermore, in spermatids acrosomal vesicles were not fully formed. Degenerating spermatids were devoid of their nuclear membrane with electron dense matrix and vacuolization. Structural changes in Leydig cells were observed. Sperm analysis in exposed rats exhibited significant decrease in the sperm count, motility, speed and an increase in sperm anomalies when compare to controls. These findings demonstrate that the B. papyrifera and B. carterii smoke affects the process of spermatogenesis and sperm parameters and indicate the detrimental effects of these incense materials on human reproductive system. PMID- 23449006 TI - Synthesis of silver nanoparticles in melts of amphiphilic polyesters. AB - The current work presents a one-step procedure for the synthesis of amphiphilic silver nanoparticles suitable for production of silver-filled polymeric materials. This solvent free synthesis via reduction of Tollens' reagent as silver precursor in melts of amphiphilic polyesters consisting of hydrophilic poly(ethylene glycol) blocks and hydrophobic alkyl chains allows the production of silver nanoparticles without any by-product formation. This makes them especially interesting for the production of medical devices with antimicrobial properties. In this article the influences of the chain length of the hydrophobic block in the amphiphilic polyesters and the process temperature on the particle size distribution (PSD) and the stability of the particles against agglomeration are discussed. According to the results of spectroscopic and viscosimetric investigations the silver precursor is reduced to elemental silver nanoparticles by a single electron transfer process from the poly(ethylene glycol) chain to the silver ion. PMID- 23449008 TI - Novel insights in the regulation and mechanism of androgen action on bone. AB - PURPOSE OF REVIEW: This review provides an update on the associations of testosterone, estrogens, sex hormone binding globulin, GH-IGF-I, osteocalcin and mechanical loading with relevance to skeletal health. RECENT FINDINGS: The simple concept of a dual model of action of androgens, i.e. either directly via the androgen receptor or indirectly by estrogens, is proving more complicated because of novel interactions of these hormones and their receptors with other hormonal as well as mechanical signals. SUMMARY: Testosterone - in contrast with estrogen is not uniformly associated with fracture risk in men. However, androgen receptor mediated action is clearly important for trabecular bone maintenance in male mice whereas both estrogens and androgens regulate cortical bone growth. The osteoblast and osteocyte appear to be involved in such androgen receptor mediated action on bone in male mice. Studies in mice also showed an unexpected interaction between osteocalcin and testosterone production in males and, vice versa, between ovarian production of follicle-stimulating hormone with testosterone and potentially bone formation. PMID- 23449007 TI - The effectiveness of physical therapist-administered group-based exercise on fall prevention: a systematic review of randomized controlled trials. AB - BACKGROUND: Falls are a verified cause of morbidity and mortality in adults older than 65 years. Exercise under the direction of a physical therapist has been shown to reduce the risk of falls in older adults; however, it is not clear whether physical therapist-directed group-based exercise could produce similar results. PURPOSE: The purpose of this systematic review was to summarize the evidence on the effectiveness of physical therapist-administered group-based exercise when compared with various controls for falls prevention and improvement of quality of life. METHODS: A computerized search of PubMed and CINAHL was performed. An exhaustive hand search was also performed of the references of all full-text articles. Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines were followed for this review. Studies were included if they met the following criteria: (1) comparison of group-based exercise led by a physical therapist to a control group; (2) ambulatory elderly men or women, aged 65 years or older; (3) subjects in the community or institutional setting; (4) the use of 1 or more outcome measures related to functional balance and/or quality of life; (5) randomized controlled or clinical trials; and (6) published in English, between December 1, 2001, and June 7, 2012. The PEDro scale was used to assess the quality of each study included in this review. RESULTS: The computerized search strategy and hand search revealed 213 potential articles, 10 of which met the inclusion criteria. After assessment with the PEDro scale, 8 of these were considered high-quality studies (score > 6/10). Seven studies compared group-based exercise to a nonexercise control group, while 3 studies compared group-based exercise with a physical therapist-prescribed home exercise program. Outcomes measured include fall rate, balance, physical performance, health related quality of life, and fear of falling. DISCUSSION: When group-based exercise was compared with no intervention, group-based exercise was found to be more effective in decreasing fall frequency, increase balance, and improve quality of life. When compared with a physical therapist-prescribed home exercise program, the group-based exercise results were not statistically different but showed improvements in some quality of life and physical functioning measures. There is also some evidence to suggest that group-based exercise promotes greater patient satisfaction and exercise adherence. CONCLUSION: There is preliminary evidence to suggest that the group-based exercise is effective for falls prevention, quality-of-life enhancement, and balance improvements in the older adults comparable with traditional home exercise programs. PMID- 23449009 TI - Defects in semipolar (1122) ZnO grown on (112) LaAlO3/(La,Sr)(Al,Ta)O3 substrate by pulsed laser deposition. AB - The microstructure of semipolar [Formula: see text] ZnO deposited on (112) LaAlO3/(La,Sr)(Al,Ta)O3 was investigated by transmission electron microscopy. The ZnO shows an in-plane epitaxial relationship of [Formula: see text] with oxygen face sense polarity. The misfit strain along [Formula: see text] and [Formula: see text] is relieved through the formation of misfit dislocations with the Burgers vectors [Formula: see text] and [Formula: see text], respectively. The line defects in the semipolar ZnO are predominantly perfect dislocations, and the dislocation density decreases with increasing ZnO thickness as a result of dislocation reactions. Planar defects were observed to lie in the M-plane and extend along <0001>, whereas basal stacking faults were rarely found. PMID- 23449011 TI - Black carbon aerosol size in snow. AB - The effect of anthropogenic black carbon (BC) aerosol on snow is of enduring interest due to its consequences for climate forcing. Until now, too little attention has been focused on BC's size in snow, an important parameter affecting BC light absorption in snow. Here we present first observations of this parameter, revealing that BC can be shifted to larger sizes in snow than are typically seen in the atmosphere, in part due to the processes associated with BC removal from the atmosphere. Mie theory analysis indicates a corresponding reduction in BC absorption in snow of 40%, making BC size in snow the dominant source of uncertainty in BC's absorption properties for calculations of BC's snow albedo climate forcing. The shift reduces estimated BC global mean snow forcing by 30%, and has scientific implications for our understanding of snow albedo and the processing of atmospheric BC aerosol in snowfall. PMID- 23449010 TI - Oral contraceptives and cardiovascular risk in women with polycystic ovary syndrome. AB - Because women affected by polycystic ovary syndrome (PCOS) present an increased cardiovascular risk, the safety of estroprogestin treatment is debated and contrasting data have been reported. However, cardiovascular risk is not the same in all PCOS women and individual cardiovascular risk should be assessed before staring any estroprogestin treatment. The available data show that products containing both 2nd-generation and 3rd-generation progestins (including drospirenone and cyproterone acetate) represent a safe treatment in PCOS patients with regular cardiovascular risk. In PCOS patients with increased cardiovascular risk, a careful choice of estroprogestin product is needed and cardiovascular risk should be monitored during treatment. In obese PCOS patients with normal glucose tolerance and lipid profile, products containing 2nd-generation progestins may be preferred because of lower venous thromboembolism risk. In PCOS patients with altered lipid profile or glucose intolerance, 3rd-generation progestins should be used but, during treatment, cardiovascular risk should be periodically re-assessed. In special situations, metformin or statins may be added to estroprogestin treatment. PMID- 23449012 TI - Expression of TNFRSF6B in kidneys is a novel predictor for progression of chronic kidney disease. AB - TNFRSF6B overexpression in tumors is a novel predictor for poor prognosis in various cancers; however, whether TNFRSF6B could be expressed in kidney tissues of patients with chronic kidney disease is unknown. Current established risk factors cannot fully predict the progression of chronic kidney disease, and, therefore, it is mandatory to develop a newer marker for predicting disease progression. We conducted a prospective cohort study comprised 167 patients with chronic kidney disease undergoing renal biopsy at a tertiary hospital with median follow-up of 30.5 months. Computer-assisted quantitative immunohistochemical staining analysis of TNFRSF6B in kidney tissues, the expression of alpha-smooth muscle actin and percentage of fibrosis in renal interstitium, estimated glomerular filtration rate, and urinary protein excretion rate were investigated. Study endpoint was a doubling of serum creatinine and/or end-stage renal failure requiring renal replacement therapy. We found that TNFRSF6B was predominantly expressed in the tubular epithelial cells of renal cortex. The higher the expression of TNFRSF6B, the more the expression of alpha-smooth muscle actin and fibrosis in interstitium (P<0.001). Forty patients reaching endpoint had lower baseline estimated glomerular filtration rate and higher expression of TNFRSF6B in renal tubular epithelial cells. Multivariate Cox regression analysis showed that high expression of TNFRSF6B independently predicted the risk toward the renal endpoint with a hazard ratio of 3.46 (95% confidence interval (CI) 1.76 6.80, P<0.001) by adjusting for clinical and pathologic variables. While added to a model of estimated glomerular filtration rate, proteinuria and other conventional risk factors, TNFRSF6B further significantly improved the model predictability for progression of chronic kidney disease (area under the curve, 0.82). In conclusion, TNFRSF6B is associated with renal fibrosis and high expression of TNFRSF6B is a novel biomarker for predicting the progression of chronic kidney disease. PMID- 23449013 TI - Role of melanin-concentrating hormone in the nucleus accumbens shell in rats behaviourally sensitized to methamphetamine. AB - Melanin-concentrating hormone (MCH) is a neuropeptide and its receptor is extensively expressed throughout the brain. MCH has been suggested to regulate the rewarding and reinforcing effects of psychostimulants by potentiating the dopaminergic system within the midbrain. Moreover, MCH and its receptor can regulate ERK activity. The present study investigated the role of MCH in the nucleus accumbens (NAc) in rats behaviourally sensitized to methamphetamine (Meth). We found that the development of Meth-induced locomotor sensitization was attenuated by MCH infused into the NAc shell but not core. Moreover, the elevation of ERK phosphorylation in the NAc shell induced by Meth was inhibited by locally infused MCH. Infusion of the MCH receptor 1 (MCHR1) antagonist SNAP 94847 into the NAc shell but not core augmented the initiation of locomotor sensitization and amplitude of elevated phosphorylated ERK levels induced by Meth. The expression of Meth-induced locomotor sensitization and ERK alterations after 1 wk withdrawal were not affected by either MCH or SNAP 94847 infused into the NAc shell or core. These results indicate that MCH in the NAc shell plays a critical role in the development but not expression of Meth-induced locomotor sensitization in rats, which might be mediated by the ERK signalling pathway. Our study suggests that MCH might be a potential target for the treatment of Meth addiction. PMID- 23449014 TI - A comprehensive outcome comparison of surgical and Ponseti clubfoot treatments with reference to pediatric norms. AB - PURPOSE: Isolated congenital clubfoot can be treated either operatively (posteromedial release) or conservatively (Ponseti method). This study retrospectively compared mid-term outcomes after surgical and Ponseti treatments to a normal sample and used multiple evaluation techniques, such as detailed gait analysis and foot kinematics. METHODS: Twenty-six children with clubfoot treated surgically and 22 children with clubfoot treated with the Ponseti technique were evaluated retrospectively and compared to 34 children with normal feet. Comprehensive evaluation included a full gait analysis with multi-segment and single-segment foot kinematics, pedobarograph, physical examination, validated outcome questionnaires, and radiographic measurements. RESULTS: The Ponseti group had significantly better plantarflexion and dorsiflexion range of motion during gait and had greater push-off power. Residual varus was present in both treatment groups, but more so in the operative group. Gait analysis also showed that the operative group had residual in-toeing, which appeared well corrected in the Ponseti group. Pedobarograph results showed that the operative group had significantly increased varus and significantly decreased medial foot pressure. The physical examination demonstrated significantly greater stiffness in the operative group in dorsiflexion, plantarflexion, ankle inversion, and midfoot abduction and adduction. Surveys showed that the Ponseti group had significantly more normal pediatric outcome data collection instrument results, disease specific indices, and Dimeglio scores. The radiographic results suggested greater equinus and cavus and increased foot internal rotation profile in the operative group compared with the Ponseti group. CONCLUSIONS: Ponseti treatment provides superior outcome to posteromedial release surgery, but residual deformity still persists. PMID- 23449015 TI - Right ventricular hypertrophy in systemic hypertension: an updated review of clinical studies. AB - AIM: Experimental and clinical evidence supports the view that right ventricular hypertrophy (RVH) may parallel left ventricular hypertrophy in systemic hypertension; a comprehensive analysis of this issue, however, is lacking. Thus, we analyzed the literature in order to provide an updated information on the right ventricular structural changes associated to systemic hypertension. DESIGN: A literature search using the key words 'right ventricle' 'right ventricular hypertrophy', 'biventricular hypertrophy' 'right and left ventricular hypertrophy'. 'hypertension', 'echocardiography' was performed in order to identify relevant articles. Full articles published in English language in the last three decades reporting studies in adult hypertensive individuals were considered. RESULTS: A total of 13 studies, including 1290 untreated (45%) and treated hypertensive patients and 259 normotensive controls, were considered. Overall, in hypertensive individuals right ventricular wall was thicker than in normotensive counterparts (standardized difference 1.3 mm, P < 0.001). RVH prevalence consistently varied among studies (17.0-80.0%) with an average of 28.6% in the pooled population. This was also the case for LVH prevalence rates (9.0-100%) with an average value of 30.6%. CONCLUSION: Clinical studies consistently indicate that RVH is a common cardiac phenotype in systemic hypertension. As this finding is based on a limited number of cross-sectional studies including small population samples, further investigations are needed to determine the clinical utility and prognostic value of this phenotype in clinical practice. PMID- 23449016 TI - Sex differences in salt-sensitivity risk approximated from ambulatory blood pressure monitoring and mortality. AB - BACKGROUND: Salt-sensitivity is difficult to assess with salt diet. METHODS: : Salt-sensitivity risk was estimated from ambulatory blood pressure monitoring indices, patient data, and 20-year all-cause mortality. Tracings of 2064 untreated patients from our clinical monitoring service were evaluated for the prevalence and associations of salt-sensitivity risk, which was considered low in patients with both mean arterial pressure dipping more than 10% and 24-h heart rate less than 70 bpm; high in patients with dipping 10% or less and 24-h heart rate at least 70 bpm; and intermediate in patients with the other combinations. RESULTS: Low, intermediate, and high salt-sensitivity categories were predicted for 33% (366/1099), 57% (624/1099), and 10% (109/1099) of men and 18% (177/965), 67% (630/965), and 16% (158/965) of women, respectively (chi(2) < 0.0001). Positive linear trends were noted between salt-sensitivity and BMI, clinic and 24 h ambulatory blood pressure, awake and sleep ambulatory heart rate and awake and sleep blood pressure variability, and negative trend with heart rate dipping (all P < 0.005). Kaplan-Meier analyses revealed increased mortality in association with salt-sensitivity in men but not in women (P < 0.02). With low and intermediate salt-sensitivity as reference, adjusted Cox proportional hazard ratios for all-cause mortality associated with high sensitivity were 1.96 (95% confidence interval 1.07-3.62) in men and 1.02 (0.51-2.07) in women. CONCLUSION: To the extent that ambulatory blood pressure-derived estimation of salt sensitivity is feasible, analysis of our database suggests increased mortality risk in men but not in women, in whom salt-sensitivity was more common. PMID- 23449017 TI - Treated and untreated hypertension, hospitalization, and medical expenditure: an epidemiological study in 314622 beneficiaries of the medical insurance system in Japan. AB - OBJECTIVE: This study investigated the effect of hypertension on hospitalization risk and medical expenditure according to treatment status in a Japanese population. METHODS: A total of 314 622 beneficiaries of the medical insurance system in Japan, aged 40-69 years, without a history of cardiovascular, cerebrovascular, or end-stage renal disease were classified into seven blood pressure categories. These categories were used to compare the risk of undergoing hospitalization in the 1 year after the baseline survey and to examine the percentage of inpatient medical expenditure attributable to overall hypertension relative to total medical expenditure in the study population. RESULTS: During the follow-up period, 6.6% of men and 5.1% of women were hospitalized. In men and women aged 40-54 years, cases of hypertension, especially grade 3 untreated hypertension, led to more frequent hospitalization, compared with optimal blood pressure. Individuals who were hospitalized, especially long-term, incurred considerably higher medical expenditure compared with those who were not hospitalized, regardless of their hypertension status. In women aged 55-69 years, there was little variation in hospitalization risk across blood pressure categories. The inpatient medical expenditure attributable to overall hypertension represented 7.2 and 6.9% of the total medical expenditure for men aged 40-54 and 55-69 years, whereas it represented 2.8 and 3.8% for women, respectively. CONCLUSION: Although cases of hypertension were an economic burden especially in men, grade 3 untreated hypertension was more likely to incur extremely high medical expenditure as a result of hospitalization, compared with other cases. PMID- 23449018 TI - Association of hypertension with depression in the community: results from the Gutenberg Health Study. AB - OBJECTIVE: The literature on the depression-hypertension (HTN) relationship came to conflicting results. Previous studies reported close positive as well as close negative associations between HTN and depression. Against this background, the present study sought to analyze this relationship in a large population-based study. METHODS: This cross-sectional population-based study (N = 5000) analyzed the association of depression and HTN in persons with different conditions of HTN (unaware of HTN, controlled HTN, uncontrolled HTN) as compared to persons without HTN. Furthermore, the relationships of depressive symptoms with antihypertensive drugs and blood pressure were examined. RESULTS: A total of 48.6% of participants were classified as 'no HTN', 13.5% had controlled HTN, 23.4% had uncontrolled HTN and 14.2% were unaware of their HTN. Unawareness of HTN was inversely associated with burden of depression. Controlled HTN was positively associated with depression. However, this association was due to generally increased disease burden (e.g. stroke, diabetes). Severity of cognitive symptoms of depression was negatively associated with SBP in persons free of antihypertensive drugs (beta = 0.64, P = 0.0005). Intake of beta-blockers and agents acting on the renin angiotensin system was associated with severity of somatic symptoms of depression (e.g. fatigue). CONCLUSION: The competing literature about the relationships between depression and HTN may be the result of the insufficient recognition of multiple pathways of opposite directions linking depressive symptoms with blood pressure, HTN and related medications. PMID- 23449019 TI - Elevated sensitivity to cardiac ischemia in proteinuric rats is independent of adverse cardiac remodeling. AB - OBJECTIVES: Chronic renal dysfunction severely increases cardiovascular risk. Adverse cardiac remodeling is suggested to play a major role as predisposition for increased cardiac ischemic vulnerability. The aim of the present study was to examine the role of adverse cardiac remodeling in cardiac sensitivity to acute ischemia/reperfusion damage in a rat model for renal dysfunction. METHODS: Munich Wistar Fromter (MWF) rats, developing spontaneous progressive renal dysfunction and mild hypertension, were compared to healthy Wistar rats, and to nonproteinuric spontaneously hypertensive rats (SHRs). In MWF rats, renal dysfunction and mild hypertension were confirmed. Hearts were analyzed for adverse cardiac remodeling, including myocyte hypertrophy, capillary density, and interstitial fibrosis, by histology. In parallel, sensitivity to cardiac ischemia/reperfusion damage was obtained from infarct size measured after 30-min coronary artery occlusion, followed by 24 h of reperfusion. RESULTS: Infarcts were larger in MWF rats [56 +/- 3% of risk area (P = 0.04)], but at a similar extent in SHRs [52 +/- 4% (P = 0.16)], when compared to Wistar rats (45 +/- 4%). However, whereas SHRs showed pronounced adverse cardiac remodeling, MWF rats did not: no left ventricular hypertrophy (myocyte size MWF rats +29%; SHRs +72%), no lower capillary density (MWF rats +34%; SHRs -13%), and no interstitial fibrosis (MWF rats -16%; SHRs +70%). CONCLUSION: Data indicate that chronic renal dysfunction in MWF rats is associated with elevated cardiac sensitivity to acute ischemia/reperfusion damage, as reflected by larger infarcts. Comparing results to SHRs suggests that this higher susceptibility could not be attributed to hypertension or adverse cardiac remodeling. PMID- 23449020 TI - Pulsatile hemodynamics and cardiovascular risk factors in very old patients: background, sex aspects and implications. AB - BACKGROUND: In the nineteenth century, prior to the introduction of the cuff sphygmomanometer, stiffening of arteries was recognized as an indicator of vascular ageing and cardiovascular risk. Through the twentieth century, views on vascular ageing came to focus on brachial blood pressures and on occlusive atherosclerotic disease. Such focus deflected attention from primary ageing changes, represented by stiffening and dilation of the proximal aorta. AIM: This review emphasizes the cushioning function of elastic arteries, principally the aorta, now when life expectancy largely exceeds 80 years providing new challenges for medical treatment in the very old. METHODS AND RESULTS: First, life expectancy has increased significantly for both sexes and is particularly prolonged after menopause. Second, phenotypic changes are noticed such as that the age-related increase of waist circumference and hyperlipidemia is markedly slowed, whereas the concomitant rise in C-reactive protein is enhanced and hyperglycaemia develops in many patients. Third, the systolic, diastolic and pulse pressures rise with age is attenuated or even stopped, as is the degree of arterial stiffness. Finally, in very old patients, the main causes of death are cardiovascular, including cardiac deaths, which differ markedly by causation in men (due to lowered ejection fraction) and women (due to arrhythmia disorders). Deaths associated with renal impairment are observed in both sexes. CONCLUSION: No simple linear relationships exist between all these phenotypic variables and the ageing process. Treatment goals of hypertension and diabetes mellitus remain difficult to predict from such data. Prevention of cardiovascular risk in the very old is thus influenced by limited evidence and important ethical considerations. PMID- 23449021 TI - Hypertensive retinopathy: comparing the Keith-Wagener-Barker to a simplified classification. AB - PURPOSE: This study assessed the interobserver and intraobserver grading reliability of the Keith-Wagener-Barker (KWB) system to the proposed Mitchell Wong 'simplified' three-grade classification for hypertensive retinopathy. METHODS: Digital retinal images of normal and hypertensive human fundii (n = 50 per group) were randomly graded by an optometrist and an ophthalmologist using the two systems. Interobserver agreement was compared to a 'gold standard' research grader. Intraobserver agreement was assessed through a repeat grading after 6 months. Cohen's kappa coefficients were used to assess the degree of agreement. RESULTS: Both clinicians demonstrated a good level of agreement with the KWB and simplified classification compared with a 'gold standard' grader; there was no significant difference in the level of agreement for either of the two classification methods for either observer. The simplified classification was found to be equally as efficacious as the KWB system with respect to interobserver and intraobserver agreement for both practitioners. CONCLUSION: These findings indicate that the simplified classification of hypertensive retinopathy is both reliable and repeatable. The advantage of the simplified method over the KWB system in correlating retinal microvascular signs to incident cardiovascular risk supports its adoption in clinical practice. PMID- 23449022 TI - Acute deep vein thrombosis cases in the real world. AB - Practicing interventional radiologists (IRs) are routinely faced with challenging decisions that pertain to the management of patients with acute deep vein thrombosis (DVT). In this article, we describe five questions that are commonly posed by interventionalists and discuss both the indirect published evidence as well as our own experience in dealing with these issues. Our aim is to address procedural and, perhaps more importantly, nonprocedural-related knowledge domains with which the IR physician is less familiar and are often not directly addressed by published data or evidence-based clinical practice guidelines. This discussion is meant to facilitate a stronger understanding of the published literature as it pertains to the justifiable indications for endovascular thrombolytic therapy, the optimal use of anticoagulant therapy, and the reasonable use of adjuncts such as inferior vena cava filters and elastic compression stockings. Our goal is to provide a framework for practicing IRs to help them make the best clinical decisions for their individual patients and, ultimately, achieve optimal DVT treatment outcomes. PMID- 23449023 TI - Performance of visually guided tasks using simulated prosthetic vision and saliency-based cues. AB - OBJECTIVE: The objective of this paper is to evaluate the benefits provided by a saliency-based cueing algorithm to normally sighted volunteers performing mobility and search tasks using simulated prosthetic vision. APPROACH: Human subjects performed mobility and search tasks using simulated prosthetic vision. A saliency algorithm based on primate vision was used to detect regions of interest (ROI) in an image. Subjects were cued to look toward the directions of these ROI using visual cues superimposed on the simulated prosthetic vision. Mobility tasks required the subjects to navigate through a corridor, avoid obstacles and locate a target at the end of the course. Two search task experiments involved finding objects on a tabletop under different conditions. Subjects were required to perform tasks with and without any help from cues. RESULTS: Head movements, time to task completion and number of errors were all significantly reduced in search tasks when subjects used the cueing algorithm. For the mobility task, head movements and number of contacts with objects were significantly reduced when subjects used cues, whereas time was significantly reduced when no cues were used. The most significant benefit from cues appears to be in search tasks and when navigating unfamiliar environments. SIGNIFICANCE: The results from the study show that visually impaired people and retinal prosthesis implantees may benefit from computer vision algorithms that detect important objects in their environment, particularly when they are in a new environment. PMID- 23449024 TI - African-American men's exposure to music videos and their sexual attitudes and risk behaviour. AB - BACKGROUND: Media is a social determinant of HIV and sexually transmissible infection (STI) risk. However, limited empirical data have examined men's media exposure and their sexual attitudes and behaviour towards women. METHODS: Eighty heterosexual African-American men were assessed on their exposure to music videos, sexual attitudes and behaviour. They also were tested for STIs. RESULTS: Findings indicated that men influenced by music videos reported more sexual adventurism, more condom barriers, more lifetime sexual partners, more condom request refusals, substance abuse and a history of incarceration. CONCLUSIONS: Further longitudinal research is needed to better understand this relationship and to address the role of media in HIV and STI prevention interventions. PMID- 23449025 TI - Genetics and treatment of bile duct stones: new approaches. AB - PURPOSE OF REVIEW: The global burden of gallstones is increasing. Although the gallbladder is the most common site for gallstone formation, 10-25% of patients display concurrent gallbladder and bile duct stones. Secondary stones are differentiated from primary stones that develop de novo in the biliary tree. Overall, the natural history of bile duct stones is less well defined and their diagnosis and treatment are more complex as compared to gallbladder stones. RECENT FINDINGS: Elevated liver function tests are not always reflective of bile duct stones, and noninvasive diagnosis by endoscopic ultrasound or MRI should be pursued in ambiguous cases. For treatment, recent studies report endoscopic dilation to result in similar clearance but lower complication and recurrence rates as with sphincterotomy. Pharmacological adjuvants such as ursodeoxycholic acid with sphincterotomy and stenting have been suggested for elderly patients. Indication and timing of cholecystectcomy after endoscopic treatment of bile duct stones is critical, and early cholecystectomy within 3-7 days prevents recurrent biliary events. SUMMARY: In this review we address the pathophysiology of bile duct stones and present the latest developments in the diagnosis and treatment of this challenging condition, with a consideration of stone recurrence. PMID- 23449026 TI - Endoscopic radiofrequency ablation for cholangiocarcinoma. AB - PURPOSE OF REVIEW: To describe the use of endobiliary radiofrequency ablation (RFA) in the treatment of malignant disease of the bile duct and offer a comprehensive review of the emerging evidence on the safety and effectiveness of this new technique. RECENT FINDINGS: Ex-vivo and in-vivo porcine studies have been reported, confirming the feasibility of the technique, gathering preliminary safety data and defining appropriate power settings for human studies. Moderate sized case series have now reported the use of RFA in mixed cohorts of human individuals with pancreatic cancer, cholangiocarcinoma and other malignant diseases of the bile duct. Endoscopic and percutaneous approaches have both been investigated. Small case series of blocked self-expanding metal stent clearance using RFA have been published. SUMMARY: Intraductal RFA, via both endoscopic and percutaneous approaches, is feasible. Complication rates appear to be comparable with the current standard endoscopic and percutaneous approaches to palliation of malignant strictures of the bile duct. The current body of literature is germinal, but warrants the further investigation of planned clinical trials. PMID- 23449028 TI - Gonadotropins activate oncogenic pathways to enhance proliferation in normal mouse ovarian surface epithelium. AB - Ovarian cancer is the most lethal gynecological malignancy affecting American women. The gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been implicated as growth factors in ovarian cancer. In the present study, pathways activated by FSH and LH in normal ovarian surface epithelium (OSE) grown in their microenvironment were investigated. Gonadotropins increased proliferation in both three-dimensional (3D) ovarian organ culture and in a two-dimensional (2D) normal mouse cell line. A mouse cancer pathway qPCR array using mRNA collected from 3D organ cultures identified Akt as a transcriptionally upregulated target following stimulation with FSH, LH and the combination of FSH and LH. Activation of additional pathways, such as Birc5, Cdk2, Cdk4, and Cdkn2a identified in the 3D organ cultures, were validated by western blot using the 2D cell line. Akt and epidermal growth factor receptor (EGFR) inhibitors blocked gonadotropin-induced cell proliferation in 3D organ and 2D cell culture. OSE isolated from 3D organ cultures stimulated with LH or hydrogen peroxide initiated growth in soft agar. Hydrogen peroxide stimulated colonies were further enhanced when supplemented with FSH. LH colony formation and FSH promotion were blocked by Akt and EGFR inhibitors. These data suggest that the gonadotropins stimulate some of the same proliferative pathways in normal OSE that are activated in ovarian cancers. PMID- 23449029 TI - Analysis of Epithelial Growth Factor-Receptor (EGFR) Phosphorylation in Uterine Smooth Muscle Tumors: Correlation to Mucin-1 and Galectin-3 Expression. AB - Uterine fibroids are the commonest uterine benign tumors. A potential mechanism of malignant transformation from leiomyomas to leiomyosarcomas has been described. Tyrosine phosphorylation is a key mechanism that controls biological functions, such as proliferation and cell differentiation. The aim of the current study was to evaluate the phosphorylation of epithelial growth factor-receptor (EGFR) in normal myometrium, uterine myomas and uterine leiomyosarcomas. Formalin fixed paraffin-embedded tissue samples from normal myometrium, leiomyomas and leiomyosarcomas were studied. Samples were immunohistochemically (IHC) assessed using the anti-EGFR phosphorylation of Y845 (pEGFR-Y845) and anti-pEGFR-Y1173 phosphorylation-specific antibodies. IHC staining was evaluated using a semiquantitative score. The expression of pEGFR-Y845 was significantly upregulated in leiomyosarcomas (p < 0.001) compared to leiomyomas and normal myometrium. In contrast, pEGFR-Y1173 did not differ significantly between the three groups of the study. Correlation analysis revealed an overall positive correlation between pEGFR Y845 and mucin 1 (MUC1). Further subgroup analysis within the tumoral group (myomas and leiomyosarcomas) revealed an additional negative correlation between pEGFR Y845 and galectin-3 (gal-3) staining. On the contrary no significant correlation was noted within the non-tumoral group. An upregulated EGFR phosphorylation of Y845 in leiomyosarcomas compared to leiomyomas implicates EGFR activation at this special receptor site. Due to these pEGFR-Y845 variations, it can be postulated that MUC1 interacts with it, whereas gal-3 seems to be cleaved from Y845 phosphorylated EGFR. Further research on this field could focus on differences in EGFR pathways as a potentially advantageous diagnostic tool for investigation of benign and malignant signal transduction processes. PMID- 23449027 TI - Proton pump inhibitors for eosinophilic oesophagitis. AB - PURPOSE OF REVIEW: To review the significance and plausible mechanisms underlying 'proton pump inhibitor (PPI) responsive oesophageal eosinophilia' in eosinophilic oesophagitis (EoE). RECENT FINDINGS: EoE is defined as an immune-mediated clinicopathologic condition characterized by oesophageal dysfunction and eosinophil-predominant inflammation. This new conceptual definition has been proposed partly due to a recently identified disease phenotype called 'PPI responsive oesophageal eosinophilia'. Emerging data support the possibility that this condition represents a clinical response to anti-inflammatory properties of PPIs that are independent of effects on gastric acid. SUMMARY: Currently, the diagnosis of EoE is reserved for patients with oesophageal eosinophilia and symptoms that do not respond to PPIs. This practice may not be appropriate, however, both because gastric acid suppression by PPIs might benefit EoE patients and because PPIs have anti-inflammatory properties that also might benefit EoE patients. More studies are sorely needed to understand the mechanisms underlying PPI-responsive oesophageal eosinophilia. Currently, a favourable response to PPI therapy should not be regarded as a proof of an underlying acid peptic disorder such as gastroesophageal reflux disease (GERD) nor should it preclude a diagnosis of EoE. Furthermore, it seems prudent to recommend a trial of PPI therapy for patients with oesophageal eosinophilia and symptoms, even when the diagnosis of EoE seems clear-cut. PMID- 23449030 TI - Rapid Microsatellite Marker Development Using Next Generation Pyrosequencing to Inform Invasive Burmese Python-Python molurus bivittatus-Management. AB - Invasive species represent an increasing threat to native ecosystems, harming indigenous taxa through predation, habitat modification, cross-species hybridization and alteration of ecosystem processes. Additionally, high economic costs are associated with environmental damage, restoration and control measures. The Burmese python, Python molurus bivittatus, is one of the most notable invasive species in the US, due to the threat it poses to imperiled species and the Greater Everglades ecosystem. To address population structure and relatedness, next generation sequencing was used to rapidly produce species specific microsatellite loci. The Roche 454 GS-FLX Titanium platform provided 6616 di-, tri- and tetra-nucleotide repeats in 117,516 sequences. Using stringent criteria, 24 of 26 selected tri- and tetra-nucleotide loci were polymerase chain reaction (PCR) amplified and 18 were polymorphic. An additional six cross-species loci were amplified, and the resulting 24 loci were incorporated into eight PCR multiplexes. Multi-locus genotypes yielded an average of 61% (39%-77%) heterozygosity and 3.7 (2-6) alleles per locus. Population-level studies using the developed microsatellites will track the invasion front and monitor population-suppression dynamics. Additionally, cross-species amplification was detected in the invasive Ball, P. regius, and Northern African python, P. sebae. These markers can be used to address the hybridization potential of Burmese pythons and the larger, more aggressive P. sebae. PMID- 23449031 TI - Granulocyte colony-stimulating factor promotes atherosclerosis in high-fat diet rabbits. AB - Granulocyte-colony stimulating factor (G-CSF) has been reported to improve the function of infarcted heart, but its effects on atherosclerosis are unclear. Here we examined the effects and the potential mechanisms in the high-fat diet rabbit model. Six-month-old male New Zealand white rabbits, fed a high-cholesterol diet or a normal diet for 10 weeks, were treated with vehicle or G-CSF. G-CSF increased lesion area in the thoracic aorta and the plasma levels of total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) at the early phase in the high-fat diet group. High-fat diet-induced arterial endothelium damage and apoptosis were greatly aggravated by G-CSF treatment. In vivo, G-CSF impaired apoptosis induced by oxidized low density lipoprotein (OX-LDL) but it had little effect on cultured endothelial cells (ECs) with vehicle treatment. Further research revealed that G-CSF promoted the upregulation of endothelin-1 (ET-1) and the downregulation of endothelial nitric oxide synthase (eNOS) of thoracic aortae induced by a high-fat diet. In vitro, the effects of G-CSF on expression of ET-1 and eNOS in cultured ECs were consistent with those in vivo. Our results suggested that G-CSF exacerbates lipid abnormity and endothelium damage in hyperlipidemia rabbits, thereby resulting in the deterioration of atherosclerosis and that the ET-1/eNOS system may regulate the progression. PMID- 23449032 TI - Ventral rectopexy for rectal prolapse and obstructed defecation. AB - Ventral rectopexy has gained popularity in Europe to treat full-thickness rectal external and internal prolapse. This procedure has been shown to achieve acceptable anatomic results with low recurrence rates, few complications, and improvements of both constipation and fecal incontinence. The authors review the principles, techniques, and outcomes of ventral rectopexy. PMID- 23449033 TI - Non-quantum electronic responses of zinc oxide nanomaterials. AB - The influence of the high surface-to-volume ratio of ZnO nanomaterials, whose sizes are large enough to exclude the quantum effect, on electronic properties was investigated by spatially resolved valence electron energy loss spectroscopy. ZnO nanowires, nanoplates, and nanotubes with different sizes were fabricated and characterized. Both the reduced volume and the increased surface area of the large ZnO nanomaterials were found to be able to modify electronic properties significantly. Hence, a nanoplate and a nanotube with very small volumes show unique energy loss functions and dielectric functions different from those of bulk ZnO at all the probe points. On the other hand, a nanowire with a relatively large diameter (70 nm) has electronic properties similar to those of bulk ZnO at the center. However, they are dissimilar at the edge of the nanowire due to the component of surface parallel to the electron path and the reduced interaction volume. Moreover, some interband transitions shift positions and bulk plasmons change oscillator strength depending upon the size of the volume and the geometry of the surface. These empirical results demonstrate that semiconducting nanomaterials larger than the exciton Bohr radius can still behave differently from bulk materials due to the high ratio between surface area and volume. PMID- 23449034 TI - Tubercular ulcer: mimicking squamous cell carcinoma of buccal mucosa. AB - Tuberculosis is a chronic granulomatous disease that rarely affects oral cavity. Tuberculous lesions of the oral cavity are frequently overlooked in the differential diagnosis of oral lesions. The oral clinical presentation of tuberculosis may take many forms as ulcers, nodules, tubercular fissure, tubercular papilloma and tuberculomas. Diagnosis is confirmed by histopathology. PMID- 23449035 TI - Spatial information analysis of chemotactic trajectories. AB - During bacterial chemotaxis, a cell acquires information about its environment by sampling changes in the local concentration of a chemoattractant, and then uses that information to bias its motion relative to the source of the chemoattractant. The trajectory of a chemotaxing bacteria is thus a spatial manifestation of the information gathered by the cell. Here we show that a recently developed approach for computing spatial information using Fourier coefficient probabilities, the k-space information (kSI), can be used to quantify the information in such trajectories. The kSI is shown to capture expected responses to gradients of a chemoattractant. We then extend the k-space approach by developing an experimental probability distribution (EPD) that is computed from chemotactic trajectories collected under a reference condition. The EPD accounts for connectivity and other constraints that the nature of the trajectories imposes on the k-space computation. The EPD is used to compute the spatial information from any trajectory of interest, relative to the reference condition. The EPD-based spatial information also captures the expected responses to gradients of a chemoattractant, although the results differ in significant ways from the original kSI computation. In addition, the entropy calculated from the EPD provides a useful measure of trajectory space. The methods developed are highly general, and can be applied to a wide range of other trajectory types as well as non-trajectory data. PMID- 23449037 TI - A magnetic polaron model for the enhanced Curie temperature of EuO(1-x). AB - The investigation of a series of oxygen-deficient EuO thin films provided strong evidence that the doped electrons form magnetic polarons with the nearby Eu2+ 4f spins; this is responsible for the enhanced Curie temperature observed near 140 K. Unlike in the previous magnetic polaron models proposed for the metal-to insulator transition in EuO, the exchange coupling J between the doped electron and its neighboring 4f spins is antiferromagnetic. The model explains satisfactorily the fact that the ordering temperature of the magnetic polarons occurs at ~140 K, independently of the oxygen vacancy concentration, and the contradiction that electron doping increases T(c) and yet reduces the red shift in the optical absorption. The magnetic polarons are coupled antiferromagnetically to the Eu2+ local moments that are ordered in the Heisenberg ferromagnet below 69 K. This coupling was observable in the vicinity of 69 K. We discuss how, with increasing concentration of the oxygen vacancies, their behaviors evolve from those of isolated superparamagnetic polarons to those of percolating magnetic polarons with a finite coercivity. PMID- 23449036 TI - Characteristics of sleep disturbance in patients with carpal tunnel syndrome. AB - BACKGROUND: Sleep disturbance is common in carpal tunnel syndrome (CTS), and we hypothesize that it has an important impact on the quality of life of CTS patients. The characteristic of sleep problems associated with CTS has not been evaluated. METHODS: We performed a case-control study to measure the association between a variety of sleep disturbances and CTS. Sixty-two cases with clinically diagnosed CTS and a probable or classic hand diagram were compared to 138 primary care patients without CTS. In addition to demographic features, we collected the nature of sleep disturbance experienced by the patients from a categorical list and the nature, impact, and severity of sleep disturbance using the Insomnia Severity Index. RESULTS: Patients with CTS complained of significantly more severe problems with sleep than the control population and had multiple sleep complaints compared to the control group. Sixty-three of the 138 control patients indicated that they had one cause of sleeping disturbance with no control patient choosing more than one. In contrast, in CTS patients, 44 of 63 patients indicated they had two or more causes of sleep disturbance. The Insomnia Severity Index was significantly higher in CTS patients and the impact of sleep disturbance on quality of life was higher in the cases. CONCLUSION: Sleep disturbance in CTS patients is characterized by a broad array of physical symptoms that have a significant impact on quality of life. PMID- 23449038 TI - Atropic tympanic membrane and hearing assessment. AB - The hearing threshold in atrophic tympanic membrane is assessed in 35 individuals. Assessment of hearing threshold in patients having atrophic tympanic membrane. Prospective clinical study. Tertiary referral centre. Thirty-five patients who had atrophic tympanic membrane in one ear and normal tympanic membrane of the other ear which was used as control, were selected Hearing threshold of patients having atrophic tympanic membrane. Twenty-nine patients with atrophic tympanic membrane had absolutely normal PTA of the ear and the opposite ear with normal tympanic membrane had similar normal PTA. Majority of the patients with atrophic tympanic membrane have normal hearing. PMID- 23449039 TI - Plasma cell leukemia: case series from a tertiary center with review of literature. AB - Plasma cell leukemia is an unusual manifestation of multiple myeloma, reported to occur in 2% of newly diagnosed patients. It may either present at the time of diagnosis (primary) or evolve as a late feature in the course of multiple myeloma (secondary). Most clinical signs of myeloma are observed in plasma cell leukemia, although osteolytic lesions and bone pain are less frequent and lymphadenopathy, organomegaly and renal failure are more often present. The immunophenotype of plasma cell leukemia differs typically from that of myeloma by lack of aberrant CD56 expression. An abnormal karyotype is more frequently found in plasma cell leukemia and there is higher incidence of unfavourable cytogenetics. Plasma cell leukemia is an aggressive disease, characterized by a fulminant course and a short survival. We are reporting cases of this rare condition which presented at our center over 3 years along with review of literature. PMID- 23449040 TI - Variations of serum levels of adiponectin and resistin in chronic viral hepatitis. AB - BACKGROUND AND AIMS: Several studies investigated the possible role of adipokines during chronic viral hepatitis, not producing defined results neither clearly establishing their behavior in course of anti-viral treatment. Our study evaluated blood concentrations of adiponectin and resistin in patients with chronic hepatitis C (CHC), B (CHB), and D (CHD) receiving anti-viral treatment, at baseline and after therapy. METHODS: We examined 122 subjects, divided into two groups: 64 patients with chronic hepatitis C virus (HCV) infection (38 males and 26 females, mean age 47.25 yr) and 58 patients including 39 ones with chronic hepatitis B virus (HBV) infection (26 males and 13 females, mean age 48.46 yr) and 19 ones with chronic HBV-hepatitis D virus (HDV) infection (15 males and 4 females, mean age 45.79 yr). Serum levels of adiponectin and resistin were assayed by enzyme-linked immunosorbent assay. RESULTS: In the group of CHC patients we observed a significant decrease in resistin after therapy (p=0.006), while not a significant increase in adiponectin after treatment (p=0.32). Evaluation of changes in adiponectin and resistin levels after anti-viral treatment, both in responders and non-responders, revealed no significant variations. In the group of HBV+ and HBV-HDV+ patients, we found a decrease in resistin after therapy (p=0.0016) and a not significant reduction in adiponectin after treatment (p=0.13). Furthermore, we noticed a significant reduction of resistin (p=0.006) in the sub-group of responders. CONCLUSIONS: Our data suggested the possible marker role of adiponectin and resistin in the inflammatory process in course of chronic viral hepatitis. PMID- 23449041 TI - On the Power of Additional and Complex Chromosomal Aberrations in CML. AB - Unregulated proliferation of mainly myeloid bone marrow cells and genetic changes in the hematopoietic stem cell system are important features in Chronic Myeloid Leukemia (CML). In clinical diagnosis of CML, classical banding techniques, fluorescence in situ hybridization (FISH) probing for the Philadelphia chromosome (Ph) or polymerase chain reaction amplifying the fusion products of the BCR-ABL fusion are state of the art techniques. Nevertheless, the genome of CML patients harbors many more cytogenetic changes. These might be hidden in subpopulations due to clonal events or involved in extremely complex aberrations. To identify these additional changes, several cytogenetic and molecular genetic techniques could be applied. Nevertheless, it has been proposed that identifying these aberrations is time consuming and costly and since they cannot be converted into a benefit for the patients, the necessity to perform these investigations has been questioned. In the times where highly specialized medicine is advancing into several areas of cancer, this attitude needs to be reassessed. Therefore, we looked at the usefulness of a combination of different techniques to unravel the genetic changes in CML patients and to identify new chromosomal aberrations, which potentially can be correlated to different stages of the disease and the strength of therapy resistance. We are convinced that the combination of these techniques could be extremely useful in unraveling even the most complex karyotypes and in dissecting different clones contributing to the disease. We propose that by doing so, this would improve CML diagnostic and prognostic findings, especially with regard to CML resistance mechanisms and new therapeutic strategies. PMID- 23449042 TI - Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment. AB - BACKGROUND: Electroconvulsive therapy (ECT) is a widely used, highly effective antidepressant treatment. Except for the most severely ill patients, right unilateral (RUL) electrode placement is the most frequent initial treatment choice. In current practice, RUL ECT is administered at several multiples of seizure threshold (ST) based on reports that lower stimulus intensity results in lower response/remission rates. Many patients, as part of an initial dose titration to determine ST, will receive a single treatment with low-dose RUL ECT and subsequent treatments with a stimulus at a multiple of ST. OBJECTIVE: To assess response to the first ECT. METHODS: A retrospective analysis of charts from clinical practice at Mount Sinai Medical Center was performed. RESULTS: A single treatment with low-dose (presumably near ST) RUL ECT had a significant and immediate antidepressant effect in our sample of patients with major depression. We determined that this response is similar to that of patients receiving a single initial treatment with high-dose RUL ECT (at a multiple of ST). CONCLUSIONS: These data suggest, contrary to commonly held belief, that RUL ECT may be effective at a low stimulus dose. This argues against restimulating at 6 times ST in the initial session, based on the belief that the near-threshold seizure has no antidepressant efficacy. Our findings suggest a need for further investigation of cases in which low-dose RUL ECT may be an effective antidepressant treatment. Further prospective studies, including larger numbers of patients who receive randomized treatment with low- or high-dose RUL with longer follow-up, are indicated. PMID- 23449043 TI - Quantifying the effects of social influence. AB - How do humans respond to indirect social influence when making decisions? We analysed an experiment where subjects had to guess the answer to factual questions, having only aggregated information about the answers of others. While the response of humans to aggregated information is a widely observed phenomenon, it has not been investigated quantitatively, in a controlled setting. We found that the adjustment of individual guesses depends linearly on the distance to the mean of all guesses. This is a remarkable, and yet surprisingly simple regularity. It holds across all questions analysed, even though the correct answers differ by several orders of magnitude. Our finding supports the assumption that individual diversity does not affect the response to indirect social influence. We argue that the nature of the response crucially changes with the level of information aggregation. This insight contributes to the empirical foundation of models for collective decisions under social influence. PMID- 23449044 TI - The neurobiology of bipolar disorder: identifying targets for specific agents and synergies for combination treatment. AB - Bipolar disorder (BD) is a chronic psychiatric illness described by severe changes in mood. Extensive research has been carried out to understand the aetiology and pathophysiology of BD. Several hypotheses have been postulated, including alteration in genetic factors, protein expression, calcium signalling, neuropathological alteration, mitochondrial dysfunction and oxidative stress in BD. In the following paper, we will attempt to integrate these data in a manner which is to understand targets of treatment and how they may be, in particular, relevant to combination treatment. In summary, the data suggested that BD might be associated with neuronal and glial cellular impairment in specific brain areas, including the prefrontal cortex. From molecular and genetics: (1) alterations in dopaminergic system, through catechol-O-aminotransferase; (2) decreased expression and polymorphism on brain-derived neurotrophic factor; (3) alterations cyclic-AMP responsive element binding; (4) dysregulation of calcium signalling, including genome-wide finding for voltage-dependent calcium channel alpha-1 subunit are relevant findings in BD. Future studies are now necessary to understand how these molecular pathways interact and their connection to the complex clinical manifestations observed in BD. PMID- 23449046 TI - Characterizing the HIV epidemic in the prairie provinces. AB - BACKGROUND: The numbers and demographics of HIV-positive patients in care between 2003 and 2007 in the prairie provinces were examined. METHODS: Estimates of HIV positive patients presenting to care between 2003 and 2007 were obtained from four clinic registries in Manitoba, Saskatchewan and southern Alberta. Detailed data were collected from clinical records of new patients in 2007. RESULTS: By the end of December 2007, 2263 HIV-positive persons were in care in Manitoba, Saskatchewan and southern Alberta. Males and females accounted for 1674 (74.0%) and 589 of the cases, respectively. Overall, there was a 12% increase per year in new HIV cases to care between 2003 and 2007 (P=0.026), with the rate of increase for males being 60% higher than for females over this time period (P=0.002). In 2007, there were 222 new HIV cases to care (37.4% female). Heterosexual contact was the most common HIV risk, but diversity was seen across sites with frequent injection drug use and men who have sex with men risk in Saskatchewan and southern Alberta, respectively. The Aboriginal population remains heavily over represented, with approximately 36.0% of new cases being Aboriginal. Late presentation was common across all care sites, with 35.1% of cases presenting with CD4 counts of less than 200 cells/mm(3). DISCUSSION: Heterosexual risk is the most common risk reported for HIV acquisition, but injection drug use risk remains significant in Saskatchewan. Aboriginals are over-represented at all sites, and in Saskatchewan accounted for the majority of new cases seen. In contrast to national trends, numbers of new and late diagnoses are increasing in the praire provinces, and this has significant treatment implications and potential public health consequences. Further efforts need to be made to facilitate earlier testing and linkage to care. BACKGROUND: The numbers and demographics of HIV-positive patients in care between 2003 and 2007 in the prairie provinces were examined. METHODS: Estimates of HIV-positive patients presenting to care between 2003 and 2007 were obtained from four clinic registries in Manitoba, Saskatchewan and southern Alberta. Detailed data were collected from clinical records of new patients in 2007. RESULTS: By the end of December 2007, 2263 HIV-positive persons were in care in Manitoba, Saskatchewan and southern Alberta. Males and females accounted for 1674 (74.0%) and 589 of the cases, respectively. Overall, there was a 12% increase per year in new HIV cases to care between 2003 and 2007 (P=0.026), with the rate of increase for males being 60% higher than for females over this time period (P=0.002). In 2007, there were 222 new HIV cases to care (37.4% female). Heterosexual contact was the most common HIV risk, but diversity was seen across sites with frequent injection drug use and men who have sex with men risk in Saskatchewan and southern Alberta, respectively. The Aboriginal population remains heavily over-represented, with approximately 36.0% of new cases being Aboriginal. Late presentation was common across all care sites, with 35.1% of cases presenting with CD4 counts of less than 200 cells/mm3. DISCUSSION: Heterosexual risk is the most common risk reported for HIV acquisition, but injection drug use risk remains significant in Saskatchewan. Aboriginals are over-represented at all sites, and in Saskatchewan accounted for the majority of new cases seen. In contrast to national trends, numbers of new and late diagnoses are increasing in the praire provinces, and this has significant treatment implications and potential public health consequences. Further efforts need to be made to facilitate earlier testing and linkage to care. PMID- 23449048 TI - Identification of optimal control compartments for serial near-infrared spectroscopy assessment of lower extremity compartmental perfusion. AB - Near-infrared spectroscopy (NIRS) has shown promise in detecting ischemic changes in acute compartment syndrome. The objectives of this study were to 1) assess the correlation in NIRS values between upper and lower extremity control sites for bilateral lower extremity trauma and 2) investigate the effect of skin pigmentation on NIRS values. Forty-four volunteers (14 male, 30 female) were monitored over separate 1-hour sessions. NIRS leads were placed over leg and upper extremity compartments. Colorimeters were used to document skin pigmentation. NIRS values between corresponding contralateral compartments were extremely well correlated (r = 0.76-0.90). Upper extremity NIRS values were correlated to leg values in the following order: volar (r = 0.65-0.71), dorsal (r = 0.36-0.60), and deltoid (r = 0.42-0.51). A negative correlation was observed between melanin and NIRS values. Analogous leg compartments are the optimal site of control for each other. The volar forearm may be the best upper extremity control. Skin pigmentation may affect absolute NIRS values. PMID- 23449049 TI - Outcomes following cervical disc arthroplasty in an active duty military population. AB - Symptomatic cervical radiculopathy is a common problem in the active duty military population and can cause significant disability leading to limited duty status and loss of operational readiness and strength. Based on their increasing experience with cervical disc arthroplasty (CDA) in this unique patient population, the authors set out to further evaluate the outcomes and complications of CDA in active duty military patients. A retrospective review of a single military tertiary medical center was performed between August 2008 and August 2012 and the clinical outcomes of patients who underwent cervical disc arthroplasty were evaluated. There were 37 active duty military patients, with a total of 41 CDA. The study found good relief of preoperative symptoms (92%) and the ability to maintain operational readiness with a high rate of return to full unrestricted duty (95%) with an average follow-up of 6 months. There was a low rate of complications related to the anterior cervical approach (5%-8%), with no device- or implant-related complications. PMID- 23449050 TI - Functional outcomes of hip arthroplasty in active duty military service members. AB - There are few reports on outcomes after hip arthroplasty in the military population despite increases among young, active patients. U.S. Army service members with coded hip arthroplasty between 2004 and 2010 were reviewed. Patient demographic variables were correlated with occupational outcomes. Of 183 patients, the occupational outcomes at a minimum 2 years postoperatively for service members undergoing primary hip arthroplasty were medically separated (n = 44, 24%), retired (n = 82, 45%), and returned to active duty (n = 57, 31%). Multivariate analysis identified that age less than 40 years [odds ratio (OR), 3.41; 95% confidence interval (CI), 1.14, 10.12] and enlisted rank (OR, 3.63; 95% CI, 1.29, 10.20) as major independent risk factors for medical separation. Univariate analysis revealed that officer rank had an increased likelihood of postoperative combat deployment than enlisted rank (OR, 3.39; 95% CI, 1.50, 7.94). Despite encouraging results in the civilian literature, this study documents modest retention rates on active duty at a minimum of 2 years after primary hip arthroplasty. PMID- 23449051 TI - Achillon mini-open Achilles tendon repair: early outcomes and return to duty results in U.S. military service members. AB - The purpose of this article is to report short-term outcomes and return to duty rates in a cohort of active duty U.S. military personnel who underwent repair of acute Achilles tendon ruptures using the Achillon mini-open technique. Between October 2009 and March 2012, 15 consecutive patients underwent mini-open repair of acute Achilles tendon ruptures using the Achillon device by a single surgeon. Minor and major complications were recorded, and American Orthopaedic Foot and Ankle Society (AOFAS) and pain visual analog scores were recorded at regular follow-up intervals. At mean latest follow-up of 16.7 months postoperatively, all 15 patients had returned to full active duty status without major complications. Specifically, no patient experienced major wound complication, infection, or rerupture. Mean AOFAS score in 9 of 15 patients was 94.1; mean pain visual analog score in 12 of 15 patients was 1.4. The Achillon mini-open technique can be used for treatment of acute Achilles tendon ruptures in appropriately selected high demand patient populations with the expectation of minimal adverse outcomes. PMID- 23449052 TI - Heterotopic ossification resection after open periarticular combat-related elbow fractures. AB - A retrospective review was performed to evaluate the outcomes and complications following heterotopic ossification (HO) resection and lysis of adhesion procedures for posttraumatic contracture, after combat-related open elbow fractures. From 2004 to 2011, HO resection was performed on 30 blast-injured elbows at a mean 10 months after injury. Injuries included 8 (27%) Gustilo Anderson type II fractures, 8 (27%) type III-A, 10 (33%) III-B, and 4 (13%) III C. Mean preoperative flexion-extension range of motion (ROM) was 36.4 degrees , compared with mean postoperative ROM of 83.6 degrees . Mean gain of motion was 47.2 degrees . Traumatic brain injury, need for flap, and nerve injury did not appear to have a significant effect on preoperative or postoperative ROM. Complications included one fracture, six recurrent contractures, and one nerve injury. The results and complications of HO resection for elbow contracture following high-energy, open injuries from blast trauma are generally comparable to those reported for HO resection following lower energy, closed injuries. PMID- 23449053 TI - Outcomes of manipulation under anesthesia versus surgical management of combat related arthrofibrosis of the knee. AB - The purpose of this study was to compare the outcomes of manipulation under anesthesia (MUA) to arthrolysis for combat-related arthrofibrosis. Sixty-one knees in 56 patients who underwent treatment for arthrofibrosis secondary to lower extremity trauma were reviewed. Knee range of motion preoperatively, postoperatively, and at follow-up was analyzed. The primary outcome measure was the difference in knee arc of motion between the two cohorts. Forty-one knees (67.2%) underwent MUA and 20 knees (32.8%) were managed operatively. There was no difference in the preoperative arc of motion. Knees that underwent MUA had significant improvements in arc of motion compared to knees that underwent arthrolysis (106.3 degrees vs. 82.3 degrees ) at a follow-up of 2 years (p = .008). The complication rate was greater in knees that underwent arthrolysis (40%) compared to knees that underwent MUA (12.2%; p = .04). In conclusion, knees that underwent MUA demonstrated significant improvements in arc of motion at 2 year follow-up with fewer complications. PMID- 23449054 TI - Acute compartment syndrome of the thigh in combat casualties. AB - Acute compartment syndrome of the thigh is a rare clinical entity often caused by high-energy trauma and presenting with a spectrum of associated injuries. Service members in combat are at risk for these causative mechanisms. This study presents a large cohort of thigh compartment syndrome combat casualties and investigates the injury mechanisms, associated mortality, and complications related to fasciotomies. Blasts were the most frequent injury mechanism, overall mortality was 23%, burns were associated with a higher mortality, and fasciotomy morbidity was reported by all respondents. The mortality was similar to civilian cohorts with thigh compartment syndrome and was isolated to patients with high Injury Severity Scores. While mortality associated with this injury is high, it is likely related to associated injury patterns rather than the compartment syndrome itself. Thigh compartment fasciotomies carried significant morbidity, consistent with civilian trauma publications. PMID- 23449055 TI - Tibial stress fractures in an active duty population: long-term outcomes. AB - Tibial stress fractures are a common overuse injury among military recruits. The purpose of this study was to determine what, if any, long-term effects that tibial stress fractures have on military personnel with respect to physical activity level, completion of military training, recurrence of symptoms, and active duty service. Twenty-six military recruits included in a previous tibial stress fracture study were contacted 10 years after initial injury and asked a series of questions related to any long-term consequences of their tibial stress fracture. Of the 13 patients available for contact, no patients reported any necessary limited duty while on active duty, and no patient reported being separated or discharged from the military as a result of stress fracture. Tibial stress fractures in military recruits are most often an isolated injury and do not affect ability to complete military training or reflect a long-term need for decreased physical activity. PMID- 23449056 TI - Prevalence of radiographic findings consistent with femoroacetabular impingement in military personnel with femoral neck stress fractures. AB - A femoral neck stress fracture is a serious condition that affects military personnel and endurance athletes. There is increasing evidence that femoroacetabular impingement contributes to significant hip pathology. This study investigates the prevalence of radiographic abnormalities associated with impingement in military personnel treated for femoral neck stress fractures. The radiographs of 69 consecutive soldiers being treated for a femoral neck stress fracture identified on magnetic resonance imaging were reviewed for radiographic signs of femoroacetabular impingement. In the cohort, the average incidence of a crossover sign was 51% (27/53). The incidence of a center edge angle greater than 40 degrees was 47% (25/53). The alpha angle was greater than 50 degrees in 55% (29/53). In conclusion, it appears that young patients with femoral neck stress fractures have a high prevalence of radiographic abnormalities suggestive of hip impingement. Hip impingement may lead to abnormal stress across the femoral neck, predisposing individuals to stress fractures. PMID- 23449057 TI - Anterior cruciate ligament augmentation for rotational instability following primary reconstruction with an accelerated physical therapy protocol. AB - The purpose of the present study is to present the results of anterior cruciate ligament (ACL) augmentation for patients having rotational instability despite an intact vertical graft in lieu of conventional revision ACL reconstruction. ACL augmentation surgery with a horizontal graft was performed to augment a healed vertical graft on five patients and an accelerated rehabilitation protocol was instituted. Functional outcomes were assessed by the Lower Extremity Functional Scale (LEFS) and the Modified Cincinnati Rating System (MCRS). All patients completed physical therapy within 5 months and were able to return to full military duty without limitation. LEFS and MCRS were significantly improved. ACL augmentation with a horizontal graft provides an excellent alternative to ACL revision reconstruction for patients with an intact vertical graft, allowing an earlier return to duty for military service members. PMID- 23449058 TI - Military movement training program improves jump-landing mechanics associated with anterior cruciate ligament injury risk. AB - As part of the physical education program at the United States Military Academy, all cadets complete a movement training course designed to develop skills and improve performance in military-related physical tasks as well as obstacle navigation. The purpose of this study was to determine if completion of this course would also result in changes in jump-landing technique that reduce the risk of anterior cruciate ligament (ACL) injury. Analysis of landing mechanics on a two-footed jump landing from a height of 30 cm with a three-dimensional motion capture system synchronized with two force plates revealed both positive and negative changes. Video assessment using the Landing Error Scoring System (LESS) revealed an overall improved landing technique (p=.001) when compared to baseline assessments. The studied military movement course appears to elicit mixed but overall improved lower extremity jump-landing mechanics associated with risk for ACL injury. PMID- 23449059 TI - Surgical technique affects outcomes in acromioclavicular reconstruction. AB - Optimal treatment for acromioclavicular (AC) dislocation is unknown. Numerous surgical procedures for AC injuries have been described with little comparison. This study sought to compare the clinical and radiographic results of various surgical techniques in order to identify the optimal surgical technique. Ninety patients met inclusion criteria of AC reconstruction at this institution. A retrospective review of outcomes was performed using the electronic records system. Radiographs were measured for pre- and postoperative grade and percent elevation versus the contralateral side. Overall revision rate was 9%. Suture button fixation had a revision rate of 0% compared to 14% (p = .01). Reconstruction procedures performed with distal clavicle excision showed a higher revision rate, 17% compared to 0% (p = .003). There were no statistically significant clinical differences. AC reconstructions performed with suture button construct were superior to other surgical techniques. Procedures performed with distal clavicle excision were inferior to those without. PMID- 23449060 TI - Comparison of complication rates of intramedullary pin fixation versus plating of midshaft clavicle fractures in an active duty military population. AB - Military service members have increased requirements of shoulder weight bearing to perform duties. Operative intervention has increased for treatment of displaced middle one-third clavicle fractures. Complications of operatively treated clavicle fixation have not been extensively studied. A retrospective, longitudinal cohort chart evaluation was conducted of all active duty members undergoing fixation of middle one-third clavicle fractures, for complications between intramedullary pin fixation and plate constructs. This review found 62 patients meeting inclusion criteria. Thirty-three patients underwent intramedullary pin fixation with Hagie pins and 31 patients underwent precontoured superior clavicle plate fixation of their middle one-third clavicle fractures. Complications included wound infection, skin and/or soft tissue irritation, and need for unplanned hardware removal. The overall complication rate was 31% in the plate fixation group versus 9% in the intramedullary pin group (p = .024). All patients achieved fracture union with return to duty; however, increased overall complications were seen in the plate fixation group. PMID- 23449061 TI - Completing records-based research within the military: a user's guide. AB - Many of the orthopaedic studies completed within the military come from records based research. This methodological article will assist researchers in completing such studies by highlighting the experiences and lessons learned from a recent retrospective study on amputees. Specifically, this article provides details on the various data sources available within the military, and how to access those systems, and offers general advice for the completion of retrospective studies using Department of Defense data systems. Although there are many obstacles that need to be overcome in order to successfully complete records-based research within the military, the authors hope this article will aid investigators in the completion of future projects. PMID- 23449062 TI - Allograft reconstruction of chronic pectoralis major tendon ruptures. AB - In chronic pectoralis tendon tears, primary repair may not be possible and allograft reconstruction may be required. The goal of this study was to report the authors' experience with chronic pectoralis major tendon reconstructions using an Achilles tendon allograft in three military patients. Three consecutive patients presenting with chronic, complete pectoralis major tendon tears underwent reconstruction by a single surgeon using the same described technique at a mean of 22.2 months after initial injury. Final outcomes were assessed at a mean of 24.5 months postoperatively, yielding one excellent and two good results. All patients were satisfied. All patients returned to full active duty military service and recreational weight lifting by 6 months. Achilles allograft reconstruction of chronic pectoralis major tendon ruptures is a viable treatment option. Good to excellent results can be achieved in active patients, even when reconstruction is performed nearly 2 years from the time of injury. PMID- 23449064 TI - Docking Studies of Adenosine Analogues with NS5 Methyltransferase of Yellow Fever Virus. AB - Yellow fever virus (YFV) is caused by single stranded positive RNA virus called Flavivirus. Till now no specific antiviral agents are available for the treatment of YFV, and despite a commercial YFV vaccine, there are still approximately 30,000 deaths worldwide each year and cases have been increasing in the last 20 years. Here, the effects of adenosine analogues and commercially available adenosine derivative drugs on NS5 methyltransferase of YFV have been performed by the comparative docking study. Based on the docking score, the glide energy and the number of interactions of the adenosine analogues with the Pubchem ID 13792 and 1077 showed the better scoring function than the best ranked commercially available adenosine analogue derived antiviral drug Cc3ado. From the docking result it reveals that these adenosine analogues can bind to the active site of NS5 methyltransferase protein and inhibit the viral replication. PMID- 23449065 TI - Recurrent left ventricular apical ballooning syndrome in a patient with pheochromocytoma. AB - Transient left ventricular apical ballooning syndrome is characterized by reversible left ventricular wall motion abnormalities, chest pain or dyspnea, ST segment elevation, and mild elevation of cardiac enzyme levels in the absence of obstructive coronary artery disease. The pathophysiology of the syndrome is still unknown. The probable mechanism is supposed to be a catecholamine discharge. We report the case of a 66-year-old woman with recently diagnosed pheochromocytoma who presented with chest pain and ST-segment elevation. Coronary angiography revealed normal coronaries and apical dyskinesia at ventriculography. A similar episode of chest pain occurred 4 years ago with same angiographic findings and reversible inferobasal akinesia. In-hospital course was uneventful and the patient was discharged from the hospital 4 days later with treatment of aspirin 1 * 100 mg, metoprolol 1 * 50 mg, lisinopril 1 * 10 mg, and atorvastatin 1 * 20 mg. At 2 years follow-up after the event, the patient remained asymptomatic. PMID- 23449066 TI - Grewia asiatica L., a food plant with multiple uses. AB - Grewia asiatica L., is a species native to south Asia from Pakistan, east to Cambodia, cultivated primarily for its edible fruit and well-reputed for its diverse medicinal uses. Fruits are a rich source of nutrients such as proteins, amino acids, vitamins, and minerals and contain various bioactive compounds, like anthocyanins, tannins, phenolics and flavonoids. Different parts of this plant possess different pharmacological properties. Leaves have antimicrobial, anticancer, antiplatelet and antiemetic activities; fruit possess anticancer, antioxidant, radioprotective and antihyperglycemic properties; while stem bark possesses analgesic and anti-inflammatory activities. This review focuses on the botanical description, phytochemistry, nutritional studies and pharmacological properties of this plant. PMID- 23449067 TI - Synthesis, antibacterial and antifungal activity of some new pyrazoline and pyrazole derivatives. AB - A series of 2-pyrazolines 5-9 have been synthesized from alpha,beta-unsaturated ketones 2-4. New 2-pyrazoline derivatives 13-15 bearing benzenesulfonamide moieties were then synthesized by condensing the appropriate chalcones 2-4 with 4 hydrazinyl benzenesulfonamide hydrochloride. Ethyl [1,2,4] triazolo[3,4 c][1,2,4]triazino[5,6-b]-5H-indole-5-ethanoate (26) and 1-(5H-[1,2,4]triazino[5,6 b] indol-3-yl)-3-methyl-1H-pyrazol-5(4H)-one (32) were synthesized from 3 hydrazinyl-5H-[1,2,4]triazino[5,6-b]indole (24). On the other hand ethyl[1,2,4]triazolo[3,4-c][1,2,4]triazino[5,6-b]-5,10-dihydroquinoxaline- 5 ethanoate (27) and 1-(5,10-dihydro-[1,2,4]triazino[5,6-b]quinoxalin-3-yl)-3 methyl-1H-pyrazol-5(4H)-one (33) were synthesized from 3-hydrazinyl-5,10-dihydro [1,2,4]triazino[5,6-b]quinoxaline (25) by reaction with diethyl malonate or ethyl acetoacetate, respectively. Condensation of 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro 1H-indole-2-carbaldehyde (1') with compound 24 or 25 afforded the corresponding Schiff's bases 36 and 37, respectively. Reaction of the Schiff's base 37 with benzoyl hydrazine or acetic anhydride afforded benzohydrazide derivative 39 and the cyclized compound 40, respectively. Furthermore, the pyrazole derivatives 42 44 were synthesized by cyclization of hydrazine derivative 25 with the prepared chalcones 2-4. All the newly synthesized compounds have been characterized on the basis of IR and 1H-NMR spectral data as well as physical data. Antimicrobial activity against the organisms E. coli ATCC8739 and P. aeruginosa ATCC 9027 as examples of Gram-negative bacteria, S. aureus ATCC 6583P as an example of Gram positive bacteria and C. albicans ATCC 2091 as an example of a yeast-like fungus have been studied using the Nutrient Agar (NA) and Sabouraud Dextrose Agar (SDA) diffusion methods. The best performance was found for the compounds 16, 17, 19 and 20. PMID- 23449068 TI - Singlet oxygen in antimicrobial photodynamic therapy: photosensitizer-dependent production and decay in E. coli. AB - Several families of photosensitizers are currently being scrutinized for antimicrobial photodynamic therapy applications. Differences in physical and photochemical properties can lead to different localization patterns as well as differences in singlet oxygen production and decay when the photosensitizers are taken up by bacterial cells. We have examined the production and fate of singlet oxygen in Escherichia coli upon photosensitization with three structurally different cationic photosensitizers, namely New Methylene Blue N (NMB), a member of the phenothiazine family, ACS268, a hydrophobic porphyrin with a single cationic alkyl chain, and zinc(II)-tetramethyltetrapyridinoporphyrazinium salt, a phthalocyanine-like photosensitizer with four positive charges on the macrocycle core. The kinetics of singlet oxygen production and decay indicate different localization for the three photosensitizers, whereby NMB appears to localize in an aqueous-like microenvironment, whereas ACS268 localizes in an oxygen-shielded site, highly reactive towards singlet oxygen. The tetracationic zinc(II) tetrapyridinoporphyrazine is extensively aggregated in the bacteria and fails to produce any detectable singlet oxygen. PMID- 23449069 TI - Red cell indices in classification and treatment of anemias: from M.M. Wintrobes's original 1934 classification to the third millennium. AB - PURPOSE OF REVIEW: Measurements of red cell volume, hemoglobin (Hb) concentration and Hb content continue to play a crucial role in the differential diagnosis of anemias 80 years after the publication of Wintrobe's seminal work. Modern hematology analyzers provide additional data on the heterogeneity of these parameters (distribution width) and quantify similar parameters of reticulocytes as well. Red cell and reticulocyte cellular indices are widely used in the diagnosis and monitoring of hematological diseases. RECENT FINDINGS: Quantification of hypochromic cells is valuable in the differential diagnosis of thalassemia trait and iron deficiency, and in monitoring therapeutic response to erythropoietic stimulating agents, while hyperchromic cells are an essential diagnostic component for hereditary spherocytosis and may correlate with hemolytic parameters in sickle cell disease. Values for these parameters however depend on the technology used. Red cell clearance is associated with a reduction in both Hb content and cell volume: normal cells are likely to be removed by the time they reach a volume of 72 fl. Reticulocyte parameters such as Hb content (CHr or ret-He) or maturity index (RMI) have shown value in a variety of hematological conditions. New findings from genetic association studies have identified several potential novel genes affecting red cell indices, which are not mediated by changes in iron availability. SUMMARY: Red cell indices continue to provide an essential support to the diagnosis and monitoring of hematological diseases. PMID- 23449070 TI - Aggressive management of pulmonary embolism. AB - Pulmonary embolism (PE) and deep vein thrombosis are two elements of the same pathophysiological process referred to as venous thromboembolism. PE occurs when a thrombus migrates from a deep vein to the pulmonary arteries. Although the true incidence of PE is not known, it is estimated that 530,000 cases of PE occur annually in the United States. Clinical presentation varies from asymptomatic (incidentally diagnosed) to fatal. Development of symptoms depends on the embolic burden and the severity of any underlying cardiopulmonary disease. Several treatment options are available for patients diagnosed with PE. The mainstay of treatment is anticoagulation, but given the high mortality associated with some presentations of symptomatic PE, some advocate more aggressive therapy. In this article we discuss such therapies and their potential and appropriate use. PMID- 23449071 TI - Alternative splice site recognition based on a new fuzzy support vector machine. PMID- 23449073 TI - Flanking sequence determination and event-specific detection of genetically modified wheat B73-6-1. AB - In order to establish a specific identification method for genetically modified (GM) wheat, exogenous insert DNA and flanking sequence between exogenous fragment and recombinant chromosome of GM wheat B73-6-1 were successfully acquired by means of conventional polymerase chain reaction (PCR) and thermal asymmetric interlaced (TAIL)-PCR strategies. Newly acquired exogenous fragment covered the full-length sequence of transformed genes such as transformed plasmid and corresponding functional genes including marker uidA, herbicide-resistant bar, ubiquitin promoter, and high-molecular-weight gluten subunit. The flanking sequence between insert DNA revealed high similarity with Triticum turgidum A gene (GenBank: AY494981.1). A specific PCR detection method for GM wheat B73-6-1 was established on the basis of primers designed according to the flanking sequence. This specific PCR method was validated by GM wheat, GM corn, GM soybean, GM rice, and non-GM wheat. The specifically amplified target band was observed only in GM wheat B73-6-1. This method is of high specificity, high reproducibility, rapid identification, and excellent accuracy for the identification of GM wheat B73-6-1. PMID- 23449072 TI - Interaction between misfolded PrP and the ubiquitin-proteasome system in prion mediated neurodegeneration. AB - Prion diseases are associated with the conformational conversion of cellular prion protein (PrP(C)) to pathological beta-sheet isoforms (PrP(Sc)), which is the infectious agent beyond comprehension. Increasing evidence indicated that an unknown toxic gain of function of PrP(sc) underlies neuronal death. Conversely, strong evidence indicated that cellular prion protein might be directly cytotoxic by mediating neurotoxic signaling of beta-sheet-rich conformers independent of prion replication. Furthermore, the common properties of beta-sheet-rich isoform such as PrP(Sc) and beta amyloid protein become the lynchpin that interprets the general pathological mechanism of protein misfolding diseases. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in various protein misfolding diseases. However, the mechanisms of this impairment remain unknown in many cases. In prion disease, prion-infected mouse brains have increased levels of ubiquitin conjugates, which correlate with decreased proteasome function. Both PrP(C) and PrP(Sc) accumulate in cells after proteasome inhibition, which leads to increased cell death. A direct interaction between 20S core particle and PrP isoforms was demonstrated. Here we review the ability of misfolded PrP and UPS to affect each other, which might contribute to the pathological features of prion mediated neurodegeneration. PMID- 23449074 TI - Changes of number of cells expressing proliferation and progenitor cell markers with age in rabbit intervertebral discs. AB - Basic knowledge about the normal regeneration process within the intervertebral disc (IVD) is important to the understanding of the underlying biology. The presence of progenitor and stem cells in IVD has been verified. However, changes of number of progenitor and stem cells with age are still unknown. In this study, changes of cell proliferation and progenitor cell markers with age in IVD cells from rabbits of two different ages were investigated using flow cytometry, immunohistochemistry, real-time polymerase chain reaction, and western blot analysis. Proliferating cell nuclear antigen (PCNA) was chosen as a marker for proliferation, and Notch1, Jagged1, C-KIT, CD166 were chosen as stem/progenitor cell markers. Cell cycle analysis showed that cell number in the G2/M phase of the young rabbits was significantly higher than that of mature rabbits. Immunohistochemical staining demonstrated the expression of PCNA, C-KIT, CD166, Notch1, and Jagged1 in both young and mature annulus fibrosus (AF). Protein expressions of these cell markers in the young rabbits were all significantly higher than those in the mature rabbits. The expression levels of PCNA, CD166, C KIT, Jagged1 were significantly higher in the AF, and PCNA, C-KIT in the nucleus pulposus from young rabbits than those from the mature rabbits. These findings demonstrated that both proliferation and progenitor cells exist in rabbit IVDs and the number of cells expressing proliferation and progenitor cell markers decreases with age in the rabbit IVD cells. Methods that are designed to maintain the endogenous progenitor cells and stimulate their proliferation could be successful in preventing or inhibiting degenerative disc disease. PMID- 23449075 TI - A new multilocus approach for a reliable DNA-based identification of Armillaria species. AB - In this paper we highlight and critically discuss limitations to molecular methods for identification of fungi via the example of the basidiomycete genus Armillaria. We analyzed a total of 144 sequences of three DNA regions commonly used for identifying fungi (ribosomal IGS-1 and ITS regions, translation elongation factor-1 alpha gene) from 48 specimens of six Armillaria species occurring in Europe (A. cepistipes, A. ostoyae, A. gallica, A. borealis, A. mellea, A. tabescens). Species were identified by comparing newly obtained sequences with those from the NCBI database, phylogenetic analyses and PCR-RFLP analyses of the three regions considered. When analyzed separately, no single gene region could unambiguously identify all six Armillaria species because of low interspecific and high intrasequence variability. We therefore developed a multilocus approach, which involves the stepwise use of the three regions. Following this scheme, all six species could be clearly discriminated. Our study suggests that, to improve the reliability of DNA-based techniques for species identification, multiple genes or intergenic regions should be analyzed. PMID- 23449076 TI - Morphological and molecular identification of four new resupinate species of Perenniporia (Polyporales) from southern China. AB - Four new resupinate species, Perenniporia hainaniana, P. macropora, P. russeimarginata and P. subtephropora, are described as new from southern China on the basis of morphological and molecular examination. Perenniporia hainaniana is characterized by a perennial growth habit, cream to buff pore surface, a dimitic to trimitic hyphal system with amyloid skeletal hyphae and presence of dendrohyphidia. Perenniporia macropora is distinguished by an annual growth habit, large pores (2-3 per mm), a dimitic hyphal system with branched skeletal hyphae and presence of dendrohyphidia. Perenniporia russeimarginata differs from other species in the genus by a perennial growth habit, white to cream pore surface and reddish to reddish brown sterile margin. Perenniporia subtephropora is characterized by a perennial growth habit, cream-buff to grayish buff pore surface, hymenophoral trama becoming black in KOH and a dimitic hyphal system with branched skeletal hyphae. Phylogenetic analysis inferred from the ITS and LSU-rDNA regions revealed eight clades for Perenniporia sensu lato with the four new species recognized in Perenniporia sensu stricto. The Perenniporia ochroleuca group, P. vicina group, P. martia group, P. subacida, Microporellus, Perenniporiella and Abundisporus, formed monophyletic entities respectively, and they are not related to P. medulla-panis (generic type), which belongs to Perenniporia sensu stricto. Abundisporus, Microporellus and Perenniporiella were widely applied as generic names. Other generic or clade names, Hornodermoporus, Truncospora, Vanderbylia and the P. subacida clade, have not been widely applied, but they are valid higher level taxa containing former species of Perenniporia. A key to genera and clades allied with Perennioporia sensu stricto and a key to species of Perennioporia are provided. PMID- 23449077 TI - Magnaporthiopsis, a new genus in Magnaporthaceae (Ascomycota). AB - The phylogenetic relationships among taxa in the Magnaporthaceae are investigated based on DNA sequences of multiple genes including SSU, ITS, LSU, MCM7, RPB1 and TEF1. The genera Magnaporthe and Gaeumannomyces are shown to be polyphyletic and their members are divided into four major groups based on the phylogenetic analyses. Considering morphological, biological and molecular data, we establish a new genus, Magnaporthiopsis. It is characterized by black and globose perithecia with a cylindrical neck, two-layered perithecial wall, clavate asci with a refractive apical ring, fusiform to fusoid and septate ascospores, simple hyphopodia, and Phialophora-like anamorph. Species in this genus are necrotrophic parasites infecting roots of grasses. Three new combinations, Magnaporthiopsis poae, M. rhizophila and M. incrustans, are proposed accordingly. Pyricularia is suggested as the generic name for the rice blast fungus over Magnaporthe, following Article 59.1 of the International Code of Nomenclature for algae, fungi and plants. A new combination, Nakataea oryzae, is proposed for the rice stem rot fungus. PMID- 23449078 TI - Development of sequence characterized amplified genomic regions (SCAR) for fungal systematics: proof of principle using Alternaria, Ascochyta and Tilletia. AB - SCARs were developed by cloning RAPD-PCR amplicons into commercially available vectors, sequencing them and designing specific primers for PCR, direct sequencing and phylogenetic analysis. Eighteen to seventy percent of cloned RAPD PCR amplicons were phylogenetically informative among closely related small spored Alternaria spp., Ascochyta spp. and Tilletia spp., taxa that have been resistant to phylogenetic analysis with universally primed, protein-coding sequence data. Selected SCARs were sequenced for larger, population-scale samples of each taxon and demonstrated to be useful for phylogenetic inference. Variation observed in the cloned SCARs generally was higher than variation in nuclear ribosomal internal transcribed spacer (ITS) and several protein-coding sequences commonly used in lower level fungal systematics. Sequence data derived from SCARs will provide sufficient resolution to address lower level phylogenetic hypotheses in Alternaria, Ascochyta, Tilletia and possibly many other fungal groups and organisms. PMID- 23449079 TI - Circumscription of the anthracnose pathogens Colletotrichum lindemuthianum and C. nigrum. AB - The anthracnose pathogen of common bean (Phaseolus vulgaris) is usually identified as Colletotrichum lindemuthianum, while anthracnose of potato (Solanum tuberosum), peppers (Capsicum annuum), tomato (S. lycopersicum) and several other crop plants is often attributed to C. coccodes. In order to study the phylogenetic relationships of these important pathogens, we conducted a multigene analysis (ITS, ACT, TUB2, CHS-1, GAPDH) of strains previously identified as C. lindemuthianum, C. coccodes and other related species, as well as representative species of the major Colletotrichum species complexes. Strains of C. lindemuthianum belonged to a single clade; we selected an authentic specimen as lectotype, and an appropriate specimen and culture from the CBS collection to serve as epitype. Two clades were resolved within C. coccodes s. lat. One clade included the ex-neotype strain of C. coccodes on Solanum, while an epitype was selected for C. nigrum, which represents the oldest name of the second clade, which occurs on Capsicum, Solanum, as well as several other host plants. Furthermore, we recognized C. lycopersici as a synonym of C. nigrum, and C. biologicum as a synonym of C. coccodes. PMID- 23449080 TI - Repeated traumatic experiences in eating disorders and their association with eating symptoms. AB - OBJECTIVE: This study aimed to analyze the association between traumatic experiences (TEs) and eating symptoms and their severity in a healthy group (HG) of students and an eating disorder group (EDG). METHOD: The HG (N=150) comprised first- and secondyear undergraduate psychology students, the EDG (N=150) day hospital patients. EDG patients were evaluated consecutively when they entered the Day Hospital Eating Disorder Unit. Information on TEs was collected via an ad hoc questionnaire, a semi-structured interview and the first part of The Dissociation Questionnaire (Part I). The Bulimic Investigatory Test Edinburgh was used to evaluate eating symptoms and their severity. RESULTS: Emotional abuse was the most frequent TE in both groups. In the EDG, TEs occurred more in patients with purging behavior (anorexia nervosa of the binge-eating/purging type, AN-P; and bulimia nervosa of the purging type, BN-P) than in those with AN-R (anorexia nervosa of the restricting type). In patients with purging behavior, TEs often begin in childhood and are repeated. When the severity of eating symptoms in patients with EDs who had suffered repeated TEs was compared with those who had suffered an isolated TE, a tendency towards greater severity of eating symptoms associated with TE repetition was observed. CONCLUSIONS: The results obtained with respect to the presence and type of TEs in EDs concurred with those of other studies. However, unlike other studies, we found high percentages of childhood TEs in ED subtypes with purging behavior. In these ED subtypes, TEs tended to be more repeated than in ED subtypes with restrictive behavior. Further studies are required to draw conclusions on the effect of the different TEs and their repetition on eating symptoms and their severity. PMID- 23449081 TI - Helplessness, mastery and the development of eating disorders: exploring the links between vulnerability and precipitating factors. AB - BACKGROUND: Helplessness and mastery in childhood and in response to the events that trigger onset are implicated in the development of eating disorders. However, no studies have yet explored how these are linked and whether the effects are additive or mediated. METHOD: Semi-structured interviews (Childhood Experience of Care and Abuse; Life Events and Difficulties Schedule; Coping Strategies Interview) were used to assess helplessness and mastery in childhood and in response to a provoking agent in 15 eating disordered and 19 non-eating disordered women. RESULTS: Helplessness and mastery in childhood were related to helplessness and mastery in response to the events and difficulties that triggered onset of the eating disorder. However, only the presence of helplessness and the lack of mastery in response to this provoking agent predicted onset. CONCLUSION: Helplessness and mastery are vulnerability and protective factors but only in those women who develop an eating disorder in the context of later life events. It is suggested that helplessness and mastery in childhood act via their influence on the adequacy of coping in response to later life events. PMID- 23449082 TI - Gender differences, personality and eating behaviors in non-clinical adolescents. AB - Few studies have focused on the relationship between personality trait and eating behaviors in a normal sample of adolescents. The purpose of this research was to examine differences between male and female non-clinical adolescents in eating behaviors, personality traits and state and trait anxiety and to verify the relationship between personality traits, anxiety and eating behaviors in males and females. 592 individuals (324 male and 267 females) were selected. Participants were asked to fill: Eating Disorder Inventory-2 (EDI-2), State Training Anxiety Inventory (STAI - Forma Y) and Eysenck Personality Questionnaire - Revised (EPQ-R). The results highlighted specific differences in eating behaviors and in personality traits between genders. No statistical differences in anxiety were found. Our results underline the importance of focussing on anxiety levels for girls, while, for boys, on personality traits such as neuroticism and psychoticism. It was confirmed the opinion that, to prevent eating disorders, not only is it necessary to carry out a campaign based on proper nutrition, but also to investigate thoroughly aspects of personality that may be predictive of these disorders. PMID- 23449083 TI - Predictors of dropout from in-patient treatment of eating disorders: an Italian experience. AB - INTRODUCTION: The aim of the study was to examine possible risk factors for dropout from in-patient treatment for eating disorders (ED). MATERIALS AND METHODS: The present study consisted of a retrospective analysis of clinical and non-clinical available information about 186 patients suffering from ED consecutively admitted into the Villa Maria Luigia Private Hospital (Parma, Italy) in a three-year period (01/01/2006 - 31/12/2009). Sociodemographics, clinical history and current features, and results to the following psychometric instruments were analysed: Eating Disorder Questionnaire (EDQ), Predisposing, On set and Maintaining risk factors list for Eating Disorders, Eating Disorders Inventory-II, Body Uneasiness Test and SCL-90. RESULTS: Of the 186 patients, 46 (24.7%) voluntarily left the treatment program prematurely. Predictive factors included poor educational and professional achievements, parents' divorcing, parents' history of substance abuse and difficulties in interpersonal relationships. DISCUSSION: Dropout is a multifactorial phenomenon with deep clinical consequences: the recognition of possible risk factors may support the choice of specific therapeutic strategies to improve the treatment of ED and its outcomes. PMID- 23449084 TI - Weight loss and clinical characteristics of young adults patients seeking treatment at medical centers: data from the QUOVADIS Study. AB - OBJECTIVE: To compare clinical characteristics, attrition, weight loss, and psychological changes of obese young adults and obese adults seeking treatment. MATERIALS AND METHODS: 1530 individuals seeking treatment in 18 Italian medical centers were evaluated. 382 cases (25%) were classified as young adults (age<=35 years), 1148 (75%) as adults (>35 years). Psychological distress, binge eating, body uneasiness, and attitude towards eating were evaluated, at baseline and after a 12-month weight-loss program, together with BMI changes. Weight-loss expectations and primary motivation for seeking treatment were also recorded. RESULTS: At baseline, young adults reported significantly higher BMI at age 20, weight loss expectations and body uneasiness scores than adults. A significantly higher percentage of young adults also reported improving appearance as primary reason for seeking treatment. The attrition rate was significantly larger in young adults. Among completers, the mean percent weight loss at 12 months and improvement of psychosocial variables were significantly higher in young adults than in adults. By intention to treat, BMI changes were no longer significant between groups. DISCUSSION: Obese young adults lose more weight and considerably improve psychological distress, but show a higher attrition rate after 12 months of continuous care in a real world medical setting. PMID- 23449085 TI - Surgical management of colonic inertia. AB - For the select small number of constipated patients that cannot be managed medically, surgical options should be considered. Increases in our knowledge of colorectal physiology and experience have fostered improvements in patient evaluation and surgical management. Currently, patients with refractory colonic inertia are offered total abdominal colectomy and ileorectal anastomosis, often with laparoscopic techniques. With proper patient selection, the results have been excellent for resolving the frequency and quality of bowel movements. However, symptoms such as bloating and abdominal pain, which may be related to irritable bowel syndrome rather than the colonic inertia, may persist. PMID- 23449086 TI - Metamagnetism in CePd5Ge3. AB - Metamagnetic transitions in CePd5Ge3 were investigated by means of low temperature magnetization, magnetic susceptibility, electrical resistivity and magnetoresistivity measurements. In transverse magnetic fields applied in a direction close to the b-axis the antiferromagnetic structure of the compound undergoes two successive transitions, first to a spin-flop phase and then to a paramagnetic phase with field-induced ferromagnetic-like alignment of the Ce magnetic moments. In contrast, a single anomaly occurs in the magnetic field dependences of the resistivity in a transverse magnetic field applied close to the c-axis, which reflects a direct transition from antiferromagnetic to paramagnetic state. Such behavior is in agreement with theoretical descriptions of metamagnetic transitions in uniaxial antiferromagnets. The experimental magnetic and electrical transport data indicate that the b-axis is the easy axis of magnetization in CePd5Ge3. PMID- 23449088 TI - Utility of magnetic resonance imaging (MRI) after closed reduction of developmental dysplasia of the hip. AB - PURPOSE: Magnetic resonance imaging (MRI) has been successfully used in the determination of the adequacy of the surgical reduction of congenitally dislocated hips in children. We present the results of a prospective series of patients treated conservatively. MRI was performed in all hips after positioning was deemed adequate on radiographs after spica cast application. The goal of this study was to evaluate the usefulness of MRI in this indication. METHODS: After the study was approved by our local ethics committee, 31 patients for a total of 36 dislocated hips were included. After the traction period, hip testing was performed and a hip spica cast was applied under general anaesthesia. All children had MRI within 1 week of reduction, without the need for contention or general anaesthesia. Hip reduction was assessed on axial and coronal MRI images. RESULTS: The concentric reduction of the hip was confirmed in 30 cases out of 36. In three cases, the dislocation was retrospectively suspected on radiographs and then confirmed. In the three remaining cases, hip dislocation was only diagnosed on MRI. CONCLUSIONS: MRI screening of congenitally dislocated hips after reduction procedures is a safe and reliable procedure to assess the concentric reduction of the hip. Even in doubtful cases, MRI detected persistent hip dislocations and was conducive to iterative reduction and satisfactory outcome and result. PMID- 23449089 TI - The management of aggressive cysts of the jaws. AB - There are essentially six types of aggressive cysts of the jaws that require special attention, so as to avoid recurrence, or even worse, widespread disease. They include, botryoid cysts, cysts in which carcinoma's arise, glandular odontogenic cysts, calcifying cystic odontogenic tumour, previously called calcifying odontogenic cyst and unicystic ameloblastoma and keratocystic odontogenic tumor, previously called odontogenic keratocysts. The estimated incidence of these cysts, based on some review studies has been discussed. The main issue, however, when treating a cyst of the jaws is; how sure can one be that the lesion is benign or potentially aggressive? In order to answer this question it is important to know how these cysts commonly present. The clinical presentation, frequency of occurrence and suggested modes of treatment has been addressed. PMID- 23449087 TI - Single cell genomics of the brain: focus on neuronal diversity and neuropsychiatric diseases. AB - Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer's disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and "omics". PMID- 23449090 TI - Veno-occlusive disease following high dose melphalan. AB - Hepatic veno-occlusive disease (VOD) is one of the complications following bone marrow transplantation. This complication is uncommon after HDT for autologous SCT (ASCT) in patients with multiple myeloma (MM). Here we report on a 54 years male with MM developed VOD on day 16 of transplant. The Patient was died due to multi-organ failure. The present case suggests that after HDT for ASCT in patients with MM can complicated with VOD. PMID- 23449091 TI - Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. AB - Monoamine oxidase A (MAOA) harbours a polymorphic upstream variable-number tandem repeat (u-VNTR). The MAOA-L allele of the u-VNTR leads to decreased gene expression levels in vitro and has been found to increase the risk of conduct disorder in males with childhood adversities. Early-life adversities have been associated with hypermethylation of the glucocorticoid receptor (NR3C1). In this study, we first performed a genetic association analysis of the MAOA u-VNTR using individuals with depression (n = 392) and controls (n = 1276). Next, DNA methylation analyses of MAOA and NR3C1 were performed using saliva samples of depressed and control subgroups. Adult MAOA-L females with childhood adversities were found to have a higher risk of developing depression (p = 0.006) and overall MAOA methylation levels were decreased in depressed females compared to controls (mean depressed, 42% vs. mean controls, 44%; p = 0.04). One specific childhood adversity [early parental death (EPD)] was associated with hypermethylation of NR3C1 close to an NGFI-A binding site (mean EPD, 19% vs. mean non-EPD, 14%; p = 0.005). Regression analysis indicated that this association may be mediated by the MAOA-L allele (adjusted R2 = 0.24, ANOVA: F = 23.48, p < 0.001). Conclusively: (1) depression in females may result from a gene * childhood adversity interaction and/or a dysregulated epigenetic programming of MAOA; (2) childhood-adversity subtypes may differentially impact DNA methylation at NR3C1; (3) baseline MAOA-genotypic variations may affect the extent of NR3C1 methylation. PMID- 23449092 TI - Mapping the local elastic properties of nanostructured germanium surfaces: from nanoporous sponges to self-organized nanodots. AB - Due to their reduced dimensions, the mechanical properties of nanostructures may differ substantially from those of bulk materials. Quantifying and understanding the nanomechanical properties of individual nanostructures is thus of tremendous importance both from a fundamental and a technological point of view. Here we employ a recently introduced atomic force microscopy mode, i.e., peak-force quantitative nanomechanical imaging, to map the local elastic properties of nanostructured germanium surfaces. This imaging mode allows the quantitative determination of the Young's modulus with nanometer resolution. Heavy-ion irradiation was used to fabricate different self-organized nanostructures on germanium surfaces. Depending on the sample temperature during irradiation, nanoporous sponge-like structures and hexagonally ordered nanodots are obtained. The sponge-like germanium surface is found to exhibit a surprisingly low Young's modulus well below 10 GPa, which furthermore depends on the ion energy. For the nanodot patterns, local variations in the Young's modulus are observed: at moderate sample temperatures, the dot crests have a lower modulus than the dot valley whereas this situation is reversed at high temperatures. These observations are explained by vacancy dynamics in the amorphous germanium matrix during irradiation. Our results furthermore offer the possibility to tune the local elastic properties of nanostructured germanium surfaces by adjusting the ion energy and sample temperature. PMID- 23449093 TI - SplicingCompass: differential splicing detection using RNA-seq data. AB - MOTIVATION: Alternative splicing is central for cellular processes and substantially increases transcriptome and proteome diversity. Aberrant splicing events often have pathological consequences and are associated with various diseases and cancer types. The emergence of next-generation RNA sequencing (RNA seq) provides an exciting new technology to analyse alternative splicing on a large scale. However, algorithms that enable the analysis of alternative splicing from short-read sequencing are not fully established yet and there are still no standard solutions available for a variety of data analysis tasks. RESULTS: We present a new method and software to predict genes that are differentially spliced between two different conditions using RNA-seq data. Our method uses geometric angles between the high dimensional vectors of exon read counts. With this, differential splicing can be detected even if the splicing events are composed of higher complexity and involve previously unknown splicing patterns. We applied our approach to two case studies including neuroblastoma tumour data with favourable and unfavourable clinical courses. We show the validity of our predictions as well as the applicability of our method in the context of patient clustering. We verified our predictions by several methods including simulated experiments and complementary in silico analyses. We found a significant number of exons with specific regulatory splicing factor motifs for predicted genes and a substantial number of publications linking those genes to alternative splicing. Furthermore, we could successfully exploit splicing information to cluster tissues and patients. Finally, we found additional evidence of splicing diversity for many predicted genes in normalized read coverage plots and in reads that span exon-exon junctions. AVAILABILITY: SplicingCompass is licensed under the GNU GPL and freely available as a package in the statistical language R at http://www.ichip.de/software/SplicingCompass.html PMID- 23449094 TI - Using tertiary structure for the computation of highly accurate multiple RNA alignments with the SARA-Coffee package. AB - MOTIVATION: Aligning RNAs is useful to search for homologous genes, study evolutionary relationships, detect conserved regions and identify any patterns that may be of biological relevance. Poor levels of conservation among homologs, however, make it difficult to compare RNA sequences, even when considering closely evolutionary related sequences. RESULTS: We describe SARA-Coffee, a tertiary structure-based multiple RNA aligner, which has been validated using BRAliDARTS, a new benchmark framework designed for evaluating tertiary structure based multiple RNA aligners. We provide two methods to measure the capacity of alignments to match corresponding secondary and tertiary structure features. On this benchmark, SARA-Coffee outperforms both regular aligners and those using secondary structure information. Furthermore, we show that on sequences in which <60% of the nucleotides form base pairs, primary sequence methods usually perform better than secondary-structure aware aligners. AVAILABILITY AND IMPLEMENTATION: The package and the datasets are available from http://www.tcoffee.org/Projects/saracoffee and http://structure.biofold.org/sara/. PMID- 23449095 TI - Self-regulation in a minimal model of chemical self-replication. AB - In biological systems, regulation plays an important role in keeping metabolite concentrations within physiological ranges. To study the dynamical implications of self-regulation, we consider a functional form used in genetic networks and couple it to a mechanism associated with chemical self-replication. For the two variable minimal model, we find that activation can yield chemical toggles similar to those reported for gene repression in E. coli as well as more complex dynamics. PMID- 23449096 TI - Past, present and future of otology. AB - Otology deals with hearing and balance and is an important aspect of the special senses of the human system. We are proud to be Otologists since we can restore the hearing of millions of people who have hard of hearing. In the past for several centuries, till the 1960s and 70s, Otology's development was like a flat curve. We have heard of several cases of brain abscess and neurological complications as a sequelae to CSOM. These events are declining. PMID- 23449097 TI - Endoscopic detection of compressing fascial bands around the ulnar nerve within the FCU. AB - BACKGROUND: The aim of this study is to endoscopically evaluate the ulnar nerve proximal and distal to the cubital tunnel after in situ decompression to identify and eventually release fascial bands capable of compressing the ulnar nerve. METHODS: We performed a retrospective review of 16 ulnar nerve compression cases in 12 patients. Eight men and four women with a mean age of 52 years (range, 23 77 years) were clinically diagnosed and confirmed with neurophysiologic studies. A 4-6-cm curvilinear incision was made at the medial elbow, and the ulnar nerve was identified and decompressed at the cubital tunnel. Then, a 2.7-mm endoscope was passed 8 to 10 cm proximal and distal to the medial epicondyle allowing for visualization of the ulnar nerve and its surrounding soft tissues. RESULTS: The endoscopic evaluation of the 16 ulnar nerves demonstrated no compressive bands outside of the cubital tunnel. All patients had satisfactory outcomes. CONCLUSIONS: The good results reported after in situ ulnar nerve decompression have questioned the need for endoscopically assisted decompression of the ulnar nerve proximal and distal to the cubital tunnel. Some authors suggest the existence of fascial bands within the flexor carpi ulnaris (FCU) capable of compressing the ulnar nerve. This study would suggest that fibrous bands deep in the FCU capable of compressing the ulnar nerve do not exist. Our satisfactory outcomes would support the perception that extensive decompression of the ulnar nerve beyond the cubital tunnel is not routinely needed. PMID- 23449098 TI - The reconstruction of tibial metaphyseal comminution using hybrid frames in severe tibial plafond fractures. AB - OBJECTIVES: To evaluate the treatment alternatives for the management of the metaphyseal tibial comminution in severe plafond fractures, and to investigate the role of the fibula fracture fixation. DESIGN: Retrospective clinical study. SETTING: Level-2 trauma hospital. PARTICIPANTS: Patients with highly comminuted tibial plafond fractures. INTERVENTION: All patients were treated with open reduction and internal fixation of the articular surface and external fixation of the metaphyseal fracture. If metaphyseal comminution was minimal, bone graft was applied and the fibular was plated (group 1); if comminution was between 1 and 3 cm, acute shortening and distraction osteogenesis was performed (group 2); and if comminution was >3 cm, distraction osteogenesis without acute shortening was performed (group 3). MAIN OUTCOME MEASUREMENTS: Radiographic union, AOFAS ankle score. RESULTS: Of 30 fractures, 15 fractures (50%) had an anatomic reduction of the joint. Union occurred in all but 2 fractures. Group 1 fractures healed at an average of 19 weeks (16-22). Four fractures had associated malalignment problems. The mean AOFAS score was 72.5 (range 45-100). Group 2 fractures healed at an average of 18.3 weeks (16-21). One fracture healed with 5-degrees of angulation. Group 3 fractures healed at an average of 17.5 weeks (14-24). Two fractures healed with malalignment. When groups 2 and 3 were combined to evaluate the AOFAS outcome for fractures treated with distraction osteogenesis, a score of 75.83 was obtained (45-90). There was no difference between the Group 1 versus combined Groups 2/3 with regard to this latter score (P = 0.372). Additionally, when fibula fixation (Group 1) was compared with those fractures where it was not performed (groups 2/3), no difference was seen (P = 0.276). CONCLUSIONS: The reconstruction of severe tibial plafond fractures treated with small wire hybrid fixation may be achieved by different techniques leading to a satisfactory result. The fixation of the fibula fracture is dependent mainly on the treatment chosen for the management of the metaphyseal lesion. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 23449099 TI - Loss of follow-up in orthopaedic trauma: is 80% follow-up still acceptable? AB - BACKGROUND: Loss of follow-up represents a potential source of bias. Suggested guidelines propose 20% loss of follow-up as acceptable. However, these guidelines have not been established through scientific investigations. The goal of this study was to evaluate how loss of follow-up influences the statistical significance in a trauma database. METHODS: A database of 637 polytrauma patients with an average follow-up of 17.5 years postinjury was used. The functional outcome of workers' compensation patients versus nonworkers' compensation patients was compared using a validated scoring system. A significant difference between the 2 groups was found (P < 0.05). We simulated a gradually increasing loss of follow-up by randomly deleting an increasing number of patients from 2%, 5%, and 10%, and then increasing in increments of 5% until the significance changed. This process was repeated 50 times, each time with a different electronic random generator. For each simulation series, we documented at which simulated loss of follow-up that the results turned from significant (P < 0.05) to nonsignificant (P > 0.05). RESULTS: Among 50 simulation series, the turning point from significant to nonsignificant varied between 15% and 75% loss of follow-up. A simulated loss of follow-up of 10% did not change the statistical significance in any of the simulation series; a simulated loss of follow-up of 20% changed the statistical significance in 28% of our simulation series. CONCLUSIONS: A loss of follow-up of 20% or less may frequently change the study results. Researchers should establish protocols to minimize loss of follow-up and clearly state the loss of follow-up in manuscript publications. PMID- 23449100 TI - Kohn singularity and Kohn anomaly in conventional superconductors--role of pairing mechanism. AB - We present a theoretical analysis of the Kohn singularity and Kohn anomaly in the superconducting phase of a three-dimensional metallic system. We show that a phonon mechanism-based Cooper pairing in a Fermi liquid metal can lead to these phenomena quite naturally. The results are discussed against the background of some recent experimental findings. PMID- 23449101 TI - Strong near field enhancement in THz nano-antenna arrays. AB - A key issue in modern photonics is the ability to concentrate light into very small volumes, thus enhancing its interaction with quantum objects of sizes much smaller than the wavelength. In the microwave domain, for many years this task has been successfully performed by antennas, built from metals that can be considered almost perfect at these frequencies. Antenna-like concepts have been recently extended into the THz and up to the visible, however metal losses increase and limit their performances. In this work we experimentally study the light coupling properties of dense arrays of subwavelength THz antenna microcavities. We demonstrate that the combination of array layout with subwavelength electromagnetic confinement allows for 10(4)-fold enhancement of the electromagnetic energy density inside the cavities, despite the low quality factor of a single element. This effect is quantitatively described by an analytical model that can be applied for the optimization of any nanoantenna array. PMID- 23449102 TI - miRNA overexpression induces cardiomyocyte proliferation in vivo. PMID- 23449105 TI - Transplantation of gene-corrected motor neurons as a therapeutic strategy for spinal muscular atrophy. PMID- 23449106 TI - Neural stem cells as a therapeutic approach for amyotrophic lateral sclerosis. PMID- 23449107 TI - Gene therapy for Canavan's disease takes a step forward. PMID- 23449108 TI - RNA-based vaccination: sending a strong message. PMID- 23449109 TI - Adipokines: novel players in rheumatic diseases. AB - A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis. PMID- 23449110 TI - Autoimmunity, end organ damage, and the origin of autoantibodies and autoreactive T cells in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmunity affecting many systems. Both antibodies and autoreactive T cells play significant roles in its pathogenesis. Experimental data and clinical observations indicate that autoimmunity and end organ damage are under separate genetic controls and that there are significant interactions between these two pathways. Experimental evidence has been obtained to support the hypothesis that autoantibodies and autoreactive T effector cells may be initiated by environmental factors through molecular mimicry and the inherent polyreactive nature of antigen receptors. A unified hypothesis has been postulated for the pathogenesis of SLE that has practical implications. PMID- 23449111 TI - Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. AB - Primary vitreoretinal lymphoma (PVRL), previously called primary intraocular lymphoma (PIOL), is a rare and fatal ocular malignancy. PVRL is a subset of primary central nervous system lymphoma (PCNSL), mostly a diffuse large B-cell lymphoma. The diagnosis of PVRL is often challenging as it often masquerades as chronic uveitis. PVRL requires invasive procedures for tissue diagnosis. Cytology/pathology, molecular pathology (immuno-globulin or T-cell receptor gene rearrangement), immunohistochemistry, biophysical technology (flow cytometry), and cytokine analysis (interleukine-10) are often required. The therapies that have been successful in systemic lymphomas have not been reliably effective in PVRL and PCNSL. Current management of PVRL involves aggressive chemotherapy (methotrexate and rituximab) and radiation therapy. PVRL normally responds well to initial treatment; however, relapse rate and CNS involvement are high, resulting in poor prognosis and limited survival. A professional team of medical experts in ophthalmology, oncology (particularly neuro-oncology), and pathology is essential for optimizing patient management. PMID- 23449112 TI - RNA interference and personalized cancer therapy. AB - Despite billions of dollars allocated to cancer research, cancer remains the number 2 cause of death in the United States with less than 50% of advanced cancer patients living one year following standard treatment. Cancer is a complex disease both intrinsically and in relation to its host environment. From a molecular standpoint no two cancers are the same despite histotypic similarity. As evidenced by the recent advances in molecular biology, treatment for advanced cancer is headed towards specific targeting of vulnerable signaling nodes within the reconfigured pathways created by "omic" rewiring. With advancements in proteo genomics and the capacity of bioinformatics, complex tumor biology can now be more effectively and rapidly analyzed to discover the vulnerable high information transfer nodes within individual tumors. RNA interference (RNAi) technology, with its capability to knock down the expression of targeted genes (the vulnerable nodes), is moving into the clinic to target these nodes, which are integral to tumor maintenance, with a low risk of side-effects and to block intrinsic immunosuppressors thereby priming the tumor for immune attack. An RNAi based sequential approach, a so called "one-two punch," is being advocated comprising tumor volume reduction (ideally to minimal residual disease status) effected by integrated multi-target knockdown followed by immune activation. Examples and recent developments are provided to illustrate this highly powerful approach heralding the future of personalized cancer therapy. PMID- 23449115 TI - Novel therapeutic approaches for cystic fibrosis. AB - Cystic fibrosis (CF) is the most common lethal monogenic disorder. Life expectancy of CF patients is rising towards a mean of 40 years with advances in all aspects of therapy apart from treating the basic molecular defect. In the twenty three years since the discovery of the gene that causes cystic fibrosis, our knowledge of how mutations in this gene cause the varied pathophysiological manifestations of this disease has increased substantially. This knowledge has led to the possibility of new therapeutic approaches aimed at the basic defect. Apart from gene therapy, several novel compounds have recently been discovered using high-throughput screening which appear promising enough to develop into effective drugs to cure the basic defect. This article will summarize our current knowledge of mutation specific therapy and will focus on orally bioavailable potentiators and correctors and suppressors of premature termination codons. Further development of these drugs will enable treatment of the basic defect in diseases like CF and open the door for treatment of disease according to gene sequencing -- true personalized medicine. PMID- 23449114 TI - Advances in cancer immunotherapy. AB - Our immune system is characterized by remarkable specificity, potency, and memory -- the ability of a single vaccine treatment to provide life-long protection. No pharmacologic treatment for any indication can provide the same level of safety, efficacy, and long-lasting effect that a vaccine can. Thus, researchers and clinicians alike have sought to apply these characteristics to the treatment of cancer. Yet, for the last 125 years, the field has failed to realize this potential. Here, we will review some of the most promising cancer immunotherapeutic approaches in development today, as recent clinical successes signal the beginning of cancer immuno-therapy's transition from experimental to established therapy. PMID- 23449113 TI - Recent gene therapy advancements for neurological diseases. AB - The past few years have seen rapid advancements in vector-mediated gene transfer to the nervous system and modest successes in human gene therapy trials. The purpose of this review is to describe commonly-used viral gene transfer vectors and recent advancements towards producing meaningful gene-based treatments for central nervous system (CNS) disorders. Gene therapy trials for Canavan disease, Batten disease, adrenoleukodystrophy, and Parkinson's disease are discussed to illustrate the current state of clinical gene transfer to the CNS. Preclinical studies are under way for a number of diseases, primarily lysosomal storage disorders, using a newer generation of vectors and delivery strategies. Relevant studies in animal models are highlighted for Mucopolysaccharidosis IIIB and Krabbe disease to provide a prelude for what can be expected in the coming years for human gene transfer trials, using recent advancements in gene transfer technology. In conclusion, recent improvements in CNS gene transfer technology are expected to significantly increase the degree of disease rescue in future CNS directed clinical trials, exceeding the modest clinical successes that have been observed so far. PMID- 23449116 TI - A novel low-cost sensor prototype for monitoring temperature during wine fermentation in tanks. AB - This paper presents a multipurpose and low cost sensor for temperature control over the wine fermentation process, in order to steadily communicate data through wireless modules in real time to a viticulturist's mobile or fixed device. The advantage of our prototype is due to the fact that it will be used by small winemakers in the "Ribera del Duero" area, and as it is a cheaper sensor and easy to use for the control and monitoring of the grape fermentation process, it will probably be used by other business men with the same necessities in the region. The microcontroller MSP430G2553 is among the components that make up the sensor, that are integrated onto a motherboard. It communicates with the RN-42 Bluetooth module through an UART interface. After verifying that all elements are working correctly, the parts are assembled to form the final prototype. This device has been tested in a winery in the region, fulfilling the initial project specifications. PMID- 23449117 TI - An automatic weighting system for wild animals based in an artificial neural network: how to weigh wild animals without causing stress. AB - This paper proposes a novel and autonomous weighing system for wild animals. It allows evaluating changes in the body weight of animals in their natural environment without causing stress. The proposed system comprises a smart scale designed to estimate individual body weights and their temporal evolution in a bird colony. The system is based on computational intelligence, and offers valuable large amount of data to evaluate the relationship between long-term changes in the behavior of individuals and global change. The real deployment of this system has been for monitoring a breeding colony of lesser kestrels (Falco naumanni) in southern Spain. The results show that it is possible to monitor individual weight changes during the breeding season and to compare the weight evolution in males and females. PMID- 23449118 TI - Trapping and propelling microparticles at long range by using an entirely stripped and slightly tapered no-core optical fiber. AB - A stripped no-core optical fiber with a 125 um diameter was transformed into a symmetric and unbroken optical fiber that tapers slightly to a 45-um-diameter waist. The laser light can be easily launched into the no-core optical fiber. The enhanced evanescent wave of the slightly tapered no-core optical fiber can attract nearby 5-um-diameter polystyrene microparticles onto the surface of the tapered multimode optical fiber within fast flowing fluid and propel the trapped particles in the direction of the light propagation to longer delivery range than is possible using a slightly tapered telecom single-mode optical fiber. PMID- 23449119 TI - Hand biometric recognition based on fused hand geometry and vascular patterns. AB - A hand biometric authentication method based on measurements of the user's hand geometry and vascular pattern is proposed. To acquire the hand geometry, the thickness of the side view of the hand, the K-curvature with a hand-shaped chain code, the lengths and angles of the finger valleys, and the lengths and profiles of the fingers were used, and for the vascular pattern, the direction-based vascular-pattern extraction method was used, and thus, a new multimodal biometric approach is proposed. The proposed multimodal biometric system uses only one image to extract the feature points. This system can be configured for low-cost devices. Our multimodal biometric-approach hand-geometry (the side view of the hand and the back of hand) and vascular-pattern recognition method performs at the score level. The results of our study showed that the equal error rate of the proposed system was 0.06%. PMID- 23449121 TI - Suppression of Ru (S = 1) spin dimerization in La2RuO5 by Ti substitution. AB - La2RuO5 shows a magneto-structural phase transition at 161 K with spin dimerization and concomitant formation of a non-magnetic singlet ground state. To gain a deeper insight into the origin of this transition systematic substitution of Ru by Ti has been carried out. Polycrystalline samples have been synthesized by thermal decomposition of citrate precursors leading to La2Ru(1-y)Ti(y)O5 (0 <= y <= 0.45). The crystal structure was investigated by x-ray powder diffraction at room temperature and at 100 K. The valences of Ti and Ru were obtained from x-ray absorption near edge structure spectroscopy at the Ti-K and the Ru-LIII absorption edges, respectively. The magnetic phase transition was investigated by magnetic susceptibility measurements as a function of Ti substitution, revealing a decreasing transition temperature on increasing the level of substitution. The step-like feature in the magnetic susceptibility reflecting the Ru-Ru spin dimerization transition becomes smeared out close to y = 0.3 and completely vanishes at y = 0.45, indicating complete suppression of spin-dimer formation. Additional specific-heat measurements show a continuous decrease of the magnetic entropy peak with increasing Ti substitution mirroring the reduced number of spin dimers due to the magnetic dilution. A magnetic anomaly of the dimerization transition can hardly be detected for y >= 0.3. Density functional theory calculations were carried out to study changes of the electronic band structure caused by the substitution. A possibly preferred distribution of Ti and Ru and the magnetic interactions as well as the change of the density of states close to the Fermi level are investigated. Based on these experimental results a detailed (y,T) phase diagram is proposed. PMID- 23449123 TI - An examination of the relationship of interpersonal influences with walking and biking to work. AB - Active commuting (AC) to the workplace is a successful strategy for incorporating more physical activity into daily life and is associated with health benefits. The purpose of this study was to understand the relationship between interpersonal influences and AC. METHODS: A cross-sectional online survey was delivered to workplaces in the mid-Atlantic region. A volunteer convenience sample of adults (N = 1234) completed questions about demographics, number of times per week actively commuting, spouse and coworker AC patterns, and spousal and coworker normative beliefs for AC. Basic descriptive and frequencies described the sample; bivariate correlations examined the relationship between AC and spouse and coworker variables. A multivariate regression analysis predicted the variance in AC with interpersonal independent variables. RESULTS: The sample was primarily middle-aged, white (92.7%), female (67.9%), and well-educated (83.3% college graduate or higher). Of those surveyed, 20.3% report AC to work at least once per week by means of walking or biking. The number of times per week of AC for spouse (P < .001) and coworkers (P = .006) and AC norms for spouse (P < .001) and coworker (P < .001) were positively related to AC. The multivariate regression model accounted for 37.9% of the variance in AC (F = 101.83, df = 4, P < .001). CONCLUSION: This study demonstrates that interpersonal influences are significantly related to actively commuting to work. Future interventions targeting AC should consider these interpersonal influences in addition to individual and environmental influences that have been previously documented. PMID- 23449122 TI - Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma. AB - DACT2 (Dapper, Dishevelled-associated antagonist of beta-catenin homolog 2) is a member of the DACT family involved in the regulation of embryonic development. Human DACT2 is localized on 6q27, a region of frequent loss of heterozygosity in human cancers. However, the regulation of DACT2 expression and function in hepatocellular carcinoma (HCC) remains unclear. In this study, genetic and epigenetic changes of DACT2 were analyzed in HCC cell lines and primary cancer. We found no single-nucleotide polymorphism (SNP) associated with HCC. Promoter region methylation was correlated with loss or reduction of DACT2 expression, and restoration of DACT2 expression was induced by 5-aza-2'-deoxycytidine (5-AZA) in HCC cell lines. Promoter region methylation was found in 54.84% of primary HCC. Reduction of DACT2 expression was associated with promoter hypermethylation, and expression of DACT2 was inversely related to beta-catenin expression in primary HCC. DACT2 suppressed cell proliferation, induced G 2-M arrest in cell lines and inhibited tumor growth in xenograft nude mice. The transcriptional activity of TCF-4 and the expression of Wnt signaling downstream genes were suppressed by DACT2 re-expression and reactivated by depletion of DACT2. In conclusion, DACT2 is frequently methylated in HCC and its expression is regulated by promoter hypermethylation. DACT2 suppresses HCC by inhibiting Wnt signaling in human HCC. PMID- 23449124 TI - Structures, roles, and procedures of state advisory committees on immunization. AB - CONTEXT: Advisory committees have the potential to play a critical role in decision making and implementation at the state level. Many states have advisory committees for their immunization programs to assist in decision making on topics such as implementing new vaccines in their states, school and childcare requirements and exemptions and addressing concerns about vaccine safety. OBJECTIVE: This article describes how immunization advisory committees work; their roles, formation, organization, and structure; membership; the issues they address; and their benefit to state immunization programs. DESIGN: In 2011, the Association of State and Territorial Health Officials, in collaboration with the Centers for Disease Control and Prevention, conducted an online survey of immunization program managers to determine which states have immunization advisory committees, how these committees function, and the perceived benefits of the committees to state immunization programs. Follow-up half-hour telephone interviews were conducted with 5 states to gain in-depth information on specific advisory committees. RESULTS: One hundred percent of states and 3 territories responded, giving an overall response rate of 91%. Thirty-four of the 53 respondents (64%) reported having an advisory committee for immunization issues. Membership is composed of physicians, public health representatives, and nurses as well as public advocates and members of the public. States reported a variety of issues their committee has worked on; the most frequently mentioned issue was school and childcare vaccination requirements. Others included immunization information systems and vaccination of health care personnel. CONCLUSIONS: Overall, states with immunization advisory committees reported that the committees were helpful on issues faced by the program and worth the time and monetary commitment. Given the reported benefits of state immunization advisory committees and the complex program and policy decisions that states face in the dynamic immunization environment, additional states may want to consider establishing immunization advisory committees. PMID- 23449125 TI - Evaluation of a pilot respiratory virus surveillance system linking electronic health record and diagnostic data. AB - CONTEXT: During the onset of 2009 pandemic influenza A (H1N1) (pH1N1), the New York City Department of Health and Mental Hygiene implemented a pilot respiratory virus surveillance system. OBJECTIVES: We evaluated the performance of this pilot system, which linked electronic health record (EHR) clinical, epidemiologic, and diagnostic data to monitor influenza-like illness (ILI) in the community. DESIGN: Surveillance was conducted at 9 community health centers with EHRs. Clinical decision support system alerts encouraged diagnostic testing of patients. Rapid influenza diagnostic testing (RIDT) and multiplex polymerase chain reaction assay (MassTag PCR) were performed sequentially. SETTING: Nine Institute for Family Health (IFH) clinics in Manhattan and the Bronx during May 26 to June 30, 2009, the pH1N1 outbreak peak. PARTICIPANTS: Adult and pediatric patients presenting to IFH clinics during May 26 to June 30, 2009. MAIN OUTCOME MEASURES: By using Centers for Disease Control and Prevention guidelines, we evaluated the system's completeness, sensitivity, timeliness, and epidemiologic usefulness. RESULTS: Of 537 ILI visits (5.7% of all visits), 17% underwent diagnostic testing. Of the 132 specimens with both a RIDT and MassTag PCR result, 90 (68%) had a MassTag PCR identified respiratory virus, most commonly pH1N1 (n = 69; 77%). Of the 81 specimens that met the ILI case definition, 58 (72%) were positive for a respiratory virus tested for by MassTag PCR; 48 (59%) were positive for pH1N1. Ninety-four percent of ILI patients positive for pH1N1 were 45 years or younger. Sensitivity and specificity of RIDT (29% and 94%) and ILI case definition (70% and 48%) for pH1N1 were calculated using MassTag PCR as the standard. Results of RIDT took a median of 6 days. CONCLUSIONS: Despite low RIDT sensitivity for pH1N1 and limited timeliness, integration of EHR and diagnostic data has potential to provide valuable epidemiologic information, guide public health response, and represents a new model for community surveillance for influenza and respiratory viruses. PMID- 23449126 TI - Enzymatically generated hydrogen peroxide reduces the number of acne lesions in acne vulgaris. AB - A major component to the etiology of acne is the growth and invasion by Propionibacterium acnes. Hydrogen peroxide is an excellent antimicrobial agent but is unstable in most formulations. We have developed a hydrogen peroxide generation system using the enzyme glucose oxidase and glucose. This system is stable in a simple formulation and nonirritating. In a short-term clinical study (4 days), this formulation was effective in reducing the individual lesion size and total number of inflammatory acne lesions. There was a 68% reduction in acne induced inflammation and 61% reduction in acne size within 4 days of treatment. A long-term clinical study (6 weeks in use) displayed 56% reduction in total number of inflamed lesions and a 45% reduction in noninflamed lesions after 6 weeks. This suggests that topical enzymatically generated hydrogen peroxide may help alleviate acne. PMID- 23449127 TI - Preparation and characterization of cosmeceutical liposomes loaded with avobenzone and arbutin. AB - The objective of this study was to develop and characterize a liposome delivery system coencapsulating two cosmeceutical ingredients, avobenzone (AVO) and arbutin (AR). Two different liposome preparation methods, that is, thin film hydration and reverse-phase evaporation, were evaluated. To obtain the optimal formulation, various ratios of lipid to AVO or AR were tested. The effects of liposome formulation and preparation method on particle size, entrapment efficiency (EE), and skin permeation rate were studied. The mean particle size of the liposome formulations obtained by the thin film hydration method was smaller than that obtained by the reverse-phase evaporation method. The EE of AR and AVO in liposomes prepared by the thin film method, however, was lower than that prepared by the reverse-phase evaporation method. No differences in membrane permeation were observed between the two preparation methods. A large portion of AR permeated through the membrane into the receptor chamber. On the other hand, AVO remained in the donor chamber or accumulated in the membrane. The results of this study revealed that liposomes are a promising delivery system for coencapsulated AR and AVO. Liposomes may aid in retaining the sunscreen (AVO) at the surface of the skin for sun protection meanwhile facilitating the penetration of the whitening agent (AR) into the deeper layers of the skin for whitening effect. PMID- 23449128 TI - Alignment control and softness creation in hair with glycylglycine. AB - Thick and coarse hair, as typically found among the Japanese population, frequently lacks softness that consumers are acutely aware of. Such poor feeling is accentuated by daily grooming, weathering, and chemical treatments, in particular, which can cause changes in the hair shape and the creation of frizzy or irregularly shaped hair. Existing technologies to improve the soft feel of hair, though effective, usually concentrate on the surface of the fiber and often leave the hair feeling either overconditioned or sometimes even sticky from product buildup. Hair softness is said to be governed by a number of factors, but primarily hair diameter and surface condition. In this study, we have also identified hair alignment as playing a critical role in hair softness. In addition, by studying how Japanese women perceive hair softness when touching their hair, we have identified that the strain on the hair fiber associated with these manipulations is far smaller than previously considered. With these factors in mind, we have studied the mechanisms behind a new softening technology containing glycylglycine (GG). It has been found that treatment with GG can give a tangible feeling of hair softness by dramatically improving alignment in unruly hair and by lowering the modulus of the fiber. Moreover, using the atomic force microscope, it has been revealed that the properties of the cell membrane complex of the hair cortex may be modified after GG treatment; the role of this additive in modifying the internal properties of the hair to create softness will thus be discussed. PMID- 23449129 TI - Effect and mechanism of epigallocatechin-3-gallate (EGCG). against the hydrogen peroxide-induced oxidative damage in human dermal fibroblasts. AB - This study was conducted to investigate the protective effects of epigallocatechin-3-gallate (EGCG) on hydrogen peroxide (H2O2)-induced oxidative stress injury in human dermal fibroblasts. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) colorimetric assay and the use of Hoechst staining and terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptosis detection indicated that the administration of H2O2 to human dermal fibroblasts caused cell damage and apoptosis. The incubation of human dermal fibroblasts with EGCG markedly inhibited the human dermal fibroblast injury induced by H2O2. The assay for 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity indicated that EGCG had a direct, concentration-dependent antioxidant activity. Treatment of human dermal fibroblasts with EGCG significantly reversed the H2O2-induced decrease of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), and the inhibition of malondialdehyde (MDA) levels. These results showed that EGCG possessed antioxidant activity and was effective against H2O2-induced human dermal fibroblast injury by enhancing the activity of SOD and GSH-px, and by decreasing the MDA level. Our results suggested that EGCG should have the potential to be used further in cosmetics and in the prevention of aging related skin injuries. PMID- 23449130 TI - A new strategy to modulate alopecia using a combination of two specific and unique ingredients. AB - Male pattern hair loss is a major cosmetic concern affecting both genders with a preference for men. Major causes of hair loss in genetically predisposed individuals include hormonal dysfunction, loss of extracellular matrix (ECM) proteins in the follicular bed, and localized microinflammation. Few options are yet available to correct the problem. For this purpose, a cosmetic active ingredient was developed by combining a Trifolium pratense flower extract and a biomimetic peptide and tested clinically for the prevention of hair loss. Thirty volunteers with recessing hair were recruited for this randomized, placebo controlled study. Clinical efficacy, following daily topical application of the mixture to the scalp, was checked using TrichoScanTM for the measurement of human hair. Within 4 months of application, anagen hair increased at an average by +13%, telogen hair density decreased by -29%, and the anagen/telogen (A/T) ratio increased by +46% over baseline in the treated group. Results strongly differed from those of the placebo group (anagen, -2%; telogen, +23%; A/T ratio, -33%). Investigation of the potential mechanisms involved in the positive effects of the test product on hair growth pointed at inhibition of 5-alpha-reductase activity, reduction of inflammatory reactions, and stimulation of ECM protein synthesis in the vicinity of the hair follicle. PMID- 23449131 TI - The importance and perspective of plant-based squalene in cosmetology. AB - Squalene is a highly unsaturated hydrocarbon from triterpenoid family, discovered as a major component of the liver oil of certain varieties of deep sea sharks. In the interest of protecting biodiversity, raw materials of animal origin must be replaced by alternative sources that respect our environment. Squalene is widely present as a component of the unsaponifiable fraction of vegetable oils (i.e., olive oil, amaranth oil). Amaranth oil seems to be the key source of squalene. Amaranth grains contains 7-7.7% lipids, and these lipids are extremely valuable because of the presence of ingredients like squalene, unsaturated fatty acids, vitamin E as tocopherols, tocotrienols, and phytosterols, which are not seen together in other common oils. In human skin physiology, squalene is not only used as an antioxidant, moisturizer, and material for topically applied vehicle, but is also used in treating skin disorders like seborrheic dermatitis, acne, psoriasis, or atopic dermatitis. Further studies on alternative sources are needed to explore the utility of squalene for treating skin. PMID- 23449132 TI - Investigation of parabens in commercial cosmetics for children in Beijing, China. AB - Parabens are one of the most common preservatives in cosmetics. Because allergenicity and cytotoxicity potential values are major aspects of preservative safety and parabens are xenoestrogens, safety levels of parabens have been restricted in "Hygienic Standard for Cosmetics" (2007 edition) by the Ministry of Public Health of China, and a high-performance liquid chromatography (HPLC) for the simultaneous determination of parabens is recommended. To investigate whether the commonly used parabens in children's cosmetics were at a safety level, 105 cosmetics for children were randomly purchased from the local market in Beijing and analyzed by the proposed HPLC method. The detection rate of methylparaben was the highest and the next was propylparaben. Among the 105 samples, two or more kinds of parabens were detected in 72 samples with concentrations ranging from 0.02% to 0.75%; 18 samples contained one kind of paraben with concentrations ranging from 0.002% to 0.06%. In this study, the contents of parabens in the 105 samples were all below the restricted levels. PMID- 23449133 TI - Characterization of the early CNS stress biomarkers and profiles associated with neuropsychiatric diseases. AB - Neuropsychiatric disorders (including dementia) have high personal, family, and social costs. Although many neuropsychiatric disorders share common patterns of symptoms and treatments, there are no validated biomarkers that define the underlying molecular mechanisms in the central nervous system (CNS). We hypothesize that there are early and common molecular changes in the CNS that will serve as sensitive indicators of CNS molecular stress and that will be predictive of neuropathological changes resulted in increasing the risk for neuropsychiatric diseases. Using the rodent model, we showed that systemic exposure to three diverse CNS stressors with different mechanisms of action (ketamine, low-dose and high-dose ionizing radiation, interferon-alpha) induced the expression of troponin T1 (Tnnt 1) within hours in adult mouse brain tissue. Tnnt 1 expression was induced in neuronal (not glial) cells, the hippocampal zone of neurogenesis, cerebral cortex, amygdale, and choroid plexus, which are important CNS locations in behavior and mental health. We also identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue for hours after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Our studies provide new molecular information on shared mechanisms and expression profiles of diverse neuropsychiatric disorders. This knowledge will be fundamental for developing molecular signatures of early CNS stress biomarker for early diagnosis and treatment of neuropsychiatric diseases. PMID- 23449134 TI - Recent immigrants show improved clinical outcomes at a tertiary care HIV clinic. AB - BACKGROUND: In recent years, the proportion of patients attending tertiary care HIV clinics who are recent immigrants to Canada has increased dramatically. METHODS: Among patients first seen at the Toronto Hospital Immunodeficiency Clinic (Toronto, Ontario) between January 1, 2000 and August 31, 2009, the time to death from the first positive HIV test was compared between individuals who had immigrated to Canada within 10 years of their first visit and individuals who were either Canadian-born or who had immigrated more than 10 years before their first clinic visit. In addition, for the antiretroviral-naive patients in these two groups who initiated combination antiretroviral therapy, the time to and the duration of virologic suppression were compared. RESULTS: In a multivariable proportional hazards (PH) model, recent immigrant status was associated with decreased mortality (HR 0.11, P=0.03) after adjusting for age, CD4 count and the risk factor for men having sex with men. In multivariable PH models, recent female immigrants achieved virologic suppression more quickly (HR 1.51, P=0.02), while male immigrants (HR 1.14, P=0.44) and female nonimmigrants (HR 0.90, P=0.61) had similar times to virologic suppression as male nonimmigrants, respectively, after adjusting for the year of and viral load at combination antiretroviral therapy initiation. When pregnant women were removed from the analysis, there were no significant differences in the rates of virologic rebound according to sex or immigration status. DISCUSSION: Despite the perceived barriers of newcomers to Canada, mortality was lower among recent immigrants and virologic suppression was achieved more quickly in recent female immigrants. BACKGROUND: In recent years, the proportion of patients attending tertiary care HIV clinics who are recent immigrants to Canada has increased dramatically. METHODS: Among patients first seen at the Toronto Hospital Immunodeficiency Clinic (Toronto, Ontario) between January 1, 2000 and August 31, 2009, the time to death from the first positive HIV test was compared between individuals who had immigrated to Canada within 10 years of their first visit and individuals who were either Canadian-born or who had immigrated more than 10 years before their first clinic visit. In addition, for the antiretroviral-naive patients in these two groups who initiated combination antiretroviral therapy, the time to and the duration of virologic suppression were compared. RESULTS: In a multivariable proportional hazards (PH) model, recent immigrant status was associated with decreased mortality (HR 0.11, P=0.03) after adjusting for age, CD4 count and the risk factor for men having sex with men. In multivariable PH models, recent female immigrants achieved virologic suppression more quickly (HR 1.51, P=0.02), while male immigrants (HR 1.14, P=0.44) and female nonimmigrants (HR 0.90, P=0.61) had similar times to virologic suppression as male nonimmigrants, respectively, after adjusting for the year of and viral load at combination antiretroviral therapy initiation. When pregnant women were removed from the analysis, there were no significant differences in the rates of virologic rebound according to sex or immigration status. DISCUSSION: Despite the perceived barriers of newcomers to Canada, mortality was lower among recent immigrants and virologic suppression was achieved more quickly in recent female immigrants. PMID- 23449135 TI - Spirituality and quality of life in limb amputees. AB - Limb amputation is a life-changing event that signifies long-term physical, social, psychological, and environmental change. Spiritual well-being in patients plays a significant role in coping and may affect outcomes of patients with limb loss. The objective of this study was to describe the role of spirituality in individuals with limb amputation and to determine whether spirituality is related to the quality of life (QOL) in this sample. Study participants were recruited through prosthetists, physicians, amputee support groups, the Amputee Coalition of America, and amputee listserv discussion groups in the United States and Canada. Participants completed questionnaires containing measures of satisfaction with life, general health, mobility, and social integration. A quantitative descriptive research design was used to examine the relationships between existential spirituality (belief that one's life is meaningful or has purpose) and religious spirituality and QOL among individuals with limb amputation. A prospective study of 108 patients with a history of limb amputation was performed. The study population consisted of 66.3% males and 33.7% females. Most patients were Caucasian (96.2%). Of the 108 participants, 86 (79.6%) were 41 years of age or older with a mean of 18 years since amputation. The most frequent cause of amputation was trauma (55.6%) and the most common location of amputation was below-the-knee (49.1%). Existential spirituality, female gender, and age above 50 years related to higher QOL in patients with a history of limb amputation. The findings of this research confirmed that amputees use spirituality to cope with limb amputation. Existential spirituality was a significant predictor of satisfaction with life, general health, and social integration. PMID- 23449136 TI - Magnetic phase diagram of clathrate compound Ce3Pd20Si6 with quadrupolar ordering. AB - We present results of specific heat measurements on a Ce3Pd20Si6 single crystal and construct the magnetic phase diagram for the three cubic principal directions [100], [110] and [111]. The highly anisotropic phase diagram is discussed and can be qualitatively explained by the Zeeman splitting at the 8c-site. For B || [100], the present study found two different quadrupolar ordered phases, which meet the paramagnetic phase at a tri-critical point and establish the new phase boundaries. PMID- 23449137 TI - Early life response to infection. AB - PURPOSE OF REVIEW: Sepsis is a serious complication in preterm and term infants, yet our understanding of how neonates respond to infection remains poorly defined. RECENT FINDINGS: We describe our current clinical, cellular and molecular understanding of the neonatal host systemic response to infection. We find that host resilience essentially relies on innate immune mechanisms despite there being a complete repertoire of cellular components of the adaptive immune arm. The functional interplay between metabolism, immunity and microbiome further suggests that neonatal vulnerability to infection is not simply due to immaturity of the immune system but how immune homeostasis is regulated. Further research is required for exploring regulatory homeostatic mechanisms between innate and adaptive responses and microbiome colonization at birth, but which can impart an adverse trajectory to infection. SUMMARY: The vulnerability and resilience against infection in neonates, including extreme preterm infants, still remains poorly understood. We advance the view that greater consideration should be given to understanding the set point in the regulation of homeostatic control of innate and adaptive immunity and its interplay with metabolism and the newly acquired microbiome. PMID- 23449138 TI - Genetic and epigenetic susceptibility to early life infection. AB - PURPOSE OF REVIEW: This review aims to interpret the current literature on the role of genetic and epigenetic factors in susceptibility to neonatal infection, a leading cause of early life mortality and morbidity. RECENT FINDINGS: Epidemiological data indicate that the differential susceptibility to infection is partly heritable. To date there have been relatively few studies on genetic determinants of susceptibility to neonatal infection and many of these have methodological shortcomings. Most studies predominantly focus on the innate immune system. There is growing interest in the potential role of epigenetic mechanisms in disease susceptibility and data are emerging on the role of epigenetics in the maturation of the immune system in early life. SUMMARY: Infection is a leading cause of morbidity and mortality, especially in preterm infants, but it remains unclear why neonates are so susceptible or what mediates differential risk. Genetic and epigenetic epidemiologic studies may assist in the identification of critical protective and pathogenic pathways. Despite the current relative lack of robust data, such studies may facilitate the development of interventions that ultimately decrease the significant morbidity and mortality of this highly vulnerable population. PMID- 23449139 TI - Pathogenesis of invasive fungal infections. AB - PURPOSE OF REVIEW: Invasive fungal infection (IFI) is increasingly being recognized as a significant cause of morbidity and mortality in immunosuppressed patients. This review focuses on the latest literature reports concerning the pathogenesis of IFI in this population. RECENT FINDINGS: New virulence factors of Candida and Aspergillus have recently been identified. The past few months have brought significant advances in our understanding of how the immune system acts against fungal infection, especially with regard to the role of mucosa in the innate immune system, the arsenal of innate immune recognition receptors and the pathways connecting innate and adaptive immunity. SUMMARY: Knowledge of fungal pathogenesis and host immune response can help to optimize the management of fungal infections. Greater understanding of these processes may aid physicians in developing better prophylactic measures and antifungal or immunomodulatory therapies. PMID- 23449140 TI - The pathogenesis of dengue. AB - PURPOSE OF REVIEW: Dengue is one of the most rapidly spreading vector-borne diseases in the world, with the incidence increasing 30-fold in the past 50 years. There are currently no licensed treatments or vaccines for dengue. This review covers the recent advances in our understanding of dengue pathogenesis, including host and viral determinants. RECENT FINDINGS: The pathogenesis of severe dengue is thought to be immune-mediated due to the timing of the clinical manifestations and higher incidence in secondary infections with a heterologous serotype. Recent evidence has provided further information of neutralizing versus enhancing monoclonal antibodies and their target epitopes on the dengue virion, which has major implications for vaccine design. The role of T-cell immunopathology has also been advanced with recent evidence of cross-reactive high pro-inflammatory cytokine producing T cells predominating in severe dengue. Recent large genome-wide association studies have identified specific susceptibility loci associated with severe disease. Epidemiological studies have served to define certain at-risk groups and specific viral virulence factors have recently been described. SUMMARY: The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors. Better understanding of the underlying mechanisms leading to severe dengue is crucial if we are to develop prognostic markers, novel diagnostics and therapeutics and ultimately a balanced and safe vaccine. PMID- 23449141 TI - A scoring system for the assessment of clinical severity in osteogenesis imperfecta. AB - INTRODUCTION: Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and fractures. Patients with OI have clinical features that may range from mild symptoms to severe bone deformities and neonatal lethality. Numerous approaches for the classification of OI have been published. The Sillence classification is the most commonly used. In this study, we aimed at developing a more refined sub-classification by applying a proposed scoring system for the quantitative assessment of clinical severity in different types of OI. SUBJECTS AND METHODS: This study included 43 patients with OI. Clinical examination and radiological studies were conducted for all patients. Cases were classified according to the Sillence classification into types I-IV. The proposed scoring system included five major criteria of high clinical value: number of fractures per year, motor milestones, long bone deformities, length/height standard deviation score (SDS), and bone mineral density (BMD). Each criterion was assigned a score from 1 to 4, and each patient was marked on a scale from 1 to 20 according to these five criteria. RESULTS: Applying the proposed clinical scoring system showed that all 11 patients with Sillence type I (100%) had a score between 6 and 10, denoting mild affection. The only patient with Sillence type II had a score of 19, denoting severe affection. In Sillence type III, 7 patients (31.8%) were moderately affected and 15 patients (68.2%) were severely affected. Almost all patients with Sillence type IV (88.9%) were moderately affected. CONCLUSIONS: Applying the proposed scoring system can quantitatively reflect the degree of clinical severity in OI patients and can be used in complement with the Sillence classification and molecular studies. PMID- 23449142 TI - Long-term outcomes of proximal row carpectomy: a minimum of 15-year follow-up. AB - INTRODUCTION: Proximal row carpectomy (PRC) is a popular procedure for the treatment of wrist arthritis; however, the long-term clinical outcomes of this procedure are not well-characterized. The purpose of this study was to evaluate long-term results with PRC and to identify factors that may improve clinical outcomes. METHODS: A retrospective study was performed on all patients who underwent proximal row carpectomy between January 1967 and January 1992. Medical records and available radiographs were reviewed. The Disabilities of the Arm, Shoulder and Hand, and Patient Rated Wrist Exam, as well as hand motion diagrams were sent to all surviving patients. The contralateral extremity was used as a control. Data was analyzed using multivariant analysis and a Student's t test. RESULTS: Eighty-one patients underwent PRC. Average age at the time of surgery was 41 years. Average follow-up was 19.8 years. Sixty-one patients responded to the questionnaires. On final follow-up, wrist motion and grip strength were not significantly different from preoperative values. Radiographic follow-up beyond 2 years revealed joint narrowing and arthritic changes within the radiocapitate joint. Forty-six patients (74%) were not satisfied with the results of their surgery due to persistent pain or inability to return to previous occupational activities. Fifty-two patients required daily pain medication for wrist pain. Twelve patients had undergone a wrist arthrodesis. CONCLUSIONS: Post-operative motion and grip strength values following PRC appear to remain stable over time. Surgical failure rates with conversion to wrist fusion occurred early within the post-operative follow-up. Many patients continued to complain of pain requiring daily medication and were unable to return to manual labor type jobs. The results of this study suggest that long-term patient satisfaction following PRC can be poor and the surgeon may wish to consider alternative treatment options for younger patients and those with high-demand jobs. PMID- 23449143 TI - A one-two punch of miR-126/126* against metastasis. AB - MicroRNAs regulate cancer metastasis by modulating both the intrinsic properties of tumour cells and their interactions with the tumour stroma. Both strands of the miR-126/miR-126* duplex are now shown to simultaneously target the Sdf-1alpha cytokine to reduce the recruitment of mesenchymal stem cells and inflammatory monocytes to primary tumours, thereby inhibiting lung metastasis. PMID- 23449144 TI - Endocytosis regulates VEGF signalling during angiogenesis. AB - Endocytosis has proved to be a versatile mechanism regulating diverse cellular processes, ranging from nutrient uptake to intracellular signal transduction. New work reinforces the importance of endocytosis for VEGF receptor signalling and angiogenesis in the developing eye, and describes a mechanism for its differential regulation in angiogenic versus quiescent endothelial cells. PMID- 23449145 TI - The dominant force of Centrobin in centrosome asymmetry. AB - Centrosomes play an important role in Drosophila melanogaster stem cells, where the different size and activity of the two centrosomes help these cells divide asymmetrically. The molecular basis of the centrosome asymmetry has remained unclear, but new work highlights the centrosomal protein Centrobin as a key player in this process. PMID- 23449146 TI - An alpha-catenin deja vu. AB - alpha-Catenin exists as part of the cadherin-catenin adhesion complex as well as in a cytoplasmic pool. However, which of these pools is responsible for its biological impact remains controversial. A structure-function analysis in Drosophila melanogaster illuminates how the molecular properties of alpha-catenin translate into functional outcomes in an intact organism. PMID- 23449153 TI - Transnasal Fixation of NOE Fracture: Minimally Invasive Approach. AB - PURPOSE: Nasal fractures may occur in association with other facial injuries like Le-forte II and III and also severe comminuted midface fractures or by themselves. Bony fractures of the nose may involve one or both nasal bones, the frontal process of the maxilla, the bony septum, and in severe trauma the nasal orbital-ethmoid complex. Treatment of these fractures range from closed reduction and support to open reduction and miniplate osteosynthesis. Purpose of this article is to describe a technique of managing nasal bone fractures associated with midface fractures. PATIENTS AND METHODS: Four consecutive patients who sustained nasal bone fracture associated with multiple midfacial fractures were included in the study. RESULTS: Postoperatively, results showed symmetry in the intercanthal to lateral canthal width. Nasofronal angle and nasal prominence was established to the expected position in most of the cases. CONCLUSION: This technique can be used for Le forte II and III cases where nasal bones to be addressed. This method has shown predictive results with minimal intervention. PMID- 23449154 TI - Genetic and environmental influences on longitudinal changes in leisure-time physical activity from adolescence to young adulthood. AB - The aim of this study was to estimate genetic and environmental influences on the longitudinal evolution of leisure-time physical activity habits from adolescence to young adulthood. Data were gathered at four time points, at mean ages 16.2, 17.1, 18.6, and 24.5 years. At baseline, the sample comprised 5,216 monozygotic and dizygotic twins, born 1975-1979, and, at the last follow-up point, of 4,531 monozygotic and dizygotic twins. Physical activity volume was assessed as frequency of leisure-time physical activity and participants were categorized into three groups: inactive, moderately active, and active. Genetic and environmental influences were estimated using a multivariate, longitudinal Cholesky decomposition with a 'multifactorial liability threshold' approach. The results suggest that, in both sexes the heritability of leisure-time physical activity remained moderate (~43-52%) during adolescence, declining to ~30% in young adulthood. Shared environmental influences increased from adolescence (~18 26%) to young adulthood (43% in men and 49% in women). Specific environmental influences remained relatively stable during the total follow-up (~20-30%). New genetic, shared, and specific environmental influences at every follow-up point were suggested by the low correlations across occasions. In conclusion, the study demonstrated gender differences in genetic influences in the evolution of leisure time physical activity habits from adolescence to young adulthood. However, shared environmental influences, especially in women, were crucial in explaining longitudinal changes in leisure-time physical activity. These outcomes emphasize the need of gender-specific measures to promote physical activity habits during young adulthood. PMID- 23449155 TI - Vascular endothelial growth factor levels in childhood acute lymphoblastic and myeloblastic leukemia. AB - Angiogenesis has been associated with the growth, dissemination and metastasis and has been shown to be a prognostic. Although there are some data suggesting that angiogenesis may have a role in the pathophysiology of leukemia, its role in patient prognosis is yet to be defined. We analyzed the expression level of vascular endothelial growth factor (VEGF), an angiogenesis promoter and its possible- prognostic value in bone marrow samples at the time of diagnosis and remission of acute childhood leukemia patients. Besides 46 patients diagnosed as ALL or AML, 16 children were also included as a control group in the study. Our data have demonstrated that VEGF levels of AML patients were found higher than the control group statistically (P = 0.022). However we could not find any significant difference between VEGF levels of diagnosis and remission in both AML and ALL groups by blastic VEGF expression (P > 0.05). In this study the higher levels of VEGF in AML patients is one of the main findings although we were not able to assess any role of VEGF in predicting prognosis in pediatric leukemia patients by evaluating blastic cell VEGF expression. These results have demonstrated that the relationship between angiogenesis or angiogenesis promoters and hematological malignancies is not clear and simple as different methods or different cells beside different angiogenesis promotors are involved to these studies. So that not only tumor cells and their cytokines but also surrounding cells and their cytokines must be taken into consideration with the standardized study methods in the further studies to obtain a promising treatment approach. PMID- 23449156 TI - Structural and magnetic phase transitions in triclinic Ca10(FeAs)10(Pt3As8). AB - We report the structural and magnetic phase transitions of triclinic Ca10(FeAs)10(Pt3As8), which is the parent compound of the 1038-type iron-arsenide superconductors. High-resolution x-ray diffraction reveals splitting of the in plane (a,b) lattice parameters at T(s) ~ 120 K. Platinum-doping weakens the distortion and shifts the transition temperature to 80 K in Ca10(Fe(1 x)Pt(x)As)10(Pt3As8) with x = 0.03. MUSR experiments show the onset of magnetic order near T and a broad magnetic phase transition. The structural transition involves no reduction of the space group symmetry in contrast to the other parent compounds of iron-arsenide superconductors; nevertheless the local fourfold symmetry of the FeAs-layers in Ca10(FeAs)10(Pt3As8) is broken. PMID- 23449157 TI - Tuning whispering gallery mode lasing from self-assembled polymer droplets. AB - Optical microcavities are important for both fundamental studies of light-matter interaction and applications such as microlasers, optical switches and filters etc... Tunable microresonators, in which resonant modes can be manipulated, are especially fascinating. Here we demonstrate a unique approach to mechanically tuning microresonators formed by polymer droplets with varying sizes. The droplets are self-assembly inside an elastic medium. By incorporating different dye molecules into the droplets, optically pumped lasing with selective wavelengths in a range of about 100 nm are achieved. Lasing action is ascribed to whispering gallery modes, verified by rigorous characterizations. Single longitudinal mode lasing is obtained when the droplet diameter is reduced to about 14 MUm. Tuning lasing modes are clearly demonstrated by mechanical deformation. Our finding provides an excellent platform for exploring flexible and tunable microlasers for plastic optoelectronic devices. PMID- 23449158 TI - Andropausal syndrome in men with systolic heart failure. AB - INTRODUCTION: Andropausal syndrome (AS) is an element of male aging, being associated with the age-related decline in circulating androgens. OBJECTIVES: We investigated the prevalence of AS, the severity of andropausal symptoms, and their clinical and hormonal determinants in men with heart failure (HF) and healthy peers. PATIENTS AND METHODS: We examined 232 men with systolic HF aged from 40 to 80 years (New York Heart Association [NYHA] class I/II/III-IV: 17%/54%/29%, left ventricular ejection fraction: 30% +/-8%) and 362 healthy peers. The severity of 17 andropausal symptoms were assessed using the Aging Males' Symptoms Rating Scale. RESULTS: In men with HF aged from 40 to 59 years, the prevalence of AS and the severity of andropausal symptoms were greater than in healthy peers (28% vs. 7%; 40 +/-14 vs. 35 +/-10 points; both P <0.001), while in the age group of 60 to 80 years, there were no differences in the prevalence of AS and the severity of andropausal symptoms between men with HF and healthy peers (31% vs. 40%; 44 +/-12 vs. 46 +/-10 points; respectively; both P >0.1). In men with HF aged from 40 to 59 years, advanced NYHA class, low hemoglobin, increased platelet number, and low serum dehydroepiandrosterone sulphate were independently associated with the greater prevalence of AS (all P <0.05). In men aged from 60 to 80 years, only reduced hemoglobin was borderline related to the higher prevalence of AS (P = 0.07). CONCLUSIONS: AS affects almost one-third of men with HF regardless of the age group. The clinical and hormonal determinants of the severity of andropausal symptoms differ between younger and older male patients. Endocrinological and sexual counseling is recommended in men with HF. PMID- 23449159 TI - Evaluation of constipation. AB - The evaluation of the chronically constipated patient is multifaceted and challenging. Many clinicians define constipation according to the latest Rome III diagnostic criteria for functional gastrointestinal disorders. Female sex, older age, low fiber diet, a sedentary life style, malnutrition, polypharmacy, and a lower socioeconomic status have all been identified as risk factors for functional constipation. In elderly patients, it is important to rule out a colonic malignancy as the cause of constipation. The initial evaluation of the constipated patient includes a detailed history to elicit symptoms distinguishing slow transit constipation from obstructive defecation. Slow transit and obstructive defecation are the two major subtypes of functional constipation. In addition, the clinician should identify any secondary causes of constipation. The office examination of the constipated patient includes an abdominal, perineal, and a rectal exam. Many patients improve with lifestyle modification. When dietary interventions and lifestyle modifications fail, many diagnostic studies are available to further evaluate the constipated patient. Sitzmark transit study, nuclear scintigraphic defecography, electromyography, anorectal manometry, balloon expulsion test, paradoxical puborectalis contraction, cinedefecography, and dynamic magnetic resonance imaging defecography have all been used to diagnose the underlying causes of functional constipation. PMID- 23449160 TI - Interaction of Azospirillum brasilense and Glomus intrarradix in Sugar Cane Roots. AB - Fifteen-day-old variety NA 56-79 sugar cane seedlings were inoculated with Azospirillum brasilense and Glomus intrarradix. This article aims at examining changes in sugar cane root seedlings inoculated with Glomus intrarradix and Azospirillum brasilense, the increase in microbial biomass and the acetylene reduction process as well. The internal root colonization was studied 20 days after inoculation using scanning and a transmission electron microscope. Both microorganisms entered the sugar cane root through the emergent lateral roots. The microorganisms were capable of coexisting both intra and intercellularly, producing changes in the cell wall, thus allowing colonization and interaction between the organisms. These changes increased the number of microorganisms inside the root as well as acetylene nitrogen reduction. Sugar cane plant biomass increased with joint-inoculation. The number of endophytic microorganisms and nitrogen fixing activity increased when they were colonized by Azospirillum and Glomus together. PMID- 23449161 TI - Deep vein thrombosis: thrombolysis in the pediatric population. AB - Improved medical treatment options have advanced pediatric care but often necessitate both invasive vascular procedures and venous access predisposing these patients to venous thrombotic events. Although pediatric deep vein thrombosis (DVT) is an increasingly recognized phenomenon, high-quality evidence for its antithrombotic treatment in general remains limited, and even more so with respect to thrombolytic therapy. Correspondingly, current American College of Chest Physicians guidelines discourage the routine use of thrombolytic therapy for pediatric DVT; by contrast, American Heart Association guidelines suggest consideration for such therapy in young patients in whom the balance of benefit to risk may be most favorable. The developing hemostatic system and relative rarity of thrombotic events have historically posed impediments to the design and conduction of prospective clinical trials of thrombolysis in children. This narrative review summarizes available information regarding thrombolytic therapy for pediatric DVT. PMID- 23449162 TI - Ear trauma in orlu, Nigeria: a five-year review. AB - To review the presentation, types and aetiology of ear trauma and various factors affecting ear trauma in our patients over a 5 year period. All patients treated for ear trauma over a 5 year period were studied using their clinical records. Data extracted were analysed using SPSS version 11 software. The results were presented in simple descriptive and tabular forms. Forty-one patients, 18(43.90%) males and 23(56.10%) females were studied, ages 12-43 years, average 26.3 + 5 years. Blows/Slaps (65.85%) from assault was the commonest aetiology while bleeding from the ear (73.17%), hearing loss (70.73%) and tympanic membrane perforation (68.29%) were the most frequent presentations. Ear trauma is common and mostly affects the tympanic membrane. Sudden increase in canal pressure from blows/slaps was the major mechanism of injury. Management outcome was good except for few late presenters with compilations. PMID- 23449163 TI - The nonlinear chemo-mechanic coupled dynamics of the F 1 -ATPase molecular motor. AB - The ATP synthase consists of two opposing rotary motors, F0 and F1, coupled to each other. When the F1 motor is not coupled to the F0 motor, it can work in the direction hydrolyzing ATP, as a nanomotor called F1-ATPase. It has been reported that the stiffness of the protein varies nonlinearly with increasing load. The nonlinearity has an important effect on the rotating rate of the F1-ATPase. Here, considering the nonlinearity of the gamma shaft stiffness for the F1-ATPase, a nonlinear chemo-mechanical coupled dynamic model of F1 motor is proposed. Nonlinear vibration frequencies of the gamma shaft and their changes along with the system parameters are investigated. The nonlinear stochastic response of the elastic gamma shaft to thermal excitation is analyzed. The results show that the stiffness nonlinearity of the gamma shaft causes an increase of the vibration frequency for the F1 motor, which increases the motor's rotation rate. When the concentration of ATP is relatively high and the load torque is small, the effects of the stiffness nonlinearity on the rotating rates of the F1 motor are obvious and should be considered. These results are useful for improving calculation of the rotating rate for the F1 motor and provide insight about the stochastic wave mechanics of F1-ATPase. PMID- 23449166 TI - The quality control in pancreatic surgery. AB - AIM: Over the past decade, several centralization programs for major pancreatic surgery have been implemented in hospitals with high procedural volumes. Although the impact of this process was altogether positive, also possible negative effects have been evidenced, above all the lack of comprehensive coverage and access to specialized centers. In order to solve these problems, it was proposed the utilization of an outcome-based and not volume-based center selection. For this purpose the choice of an appropriate outcome assessment system is crucial. MATERIAL OF STUDY: We retrospectively reviewed 74 patients undergoing pancreatoduodenectomy. The outcomes were evaluated utilizing the Accordion Severity Classification of Postoperative Complications. RESULTS: The morbidity of 58 % and the mortality of 4 % were comparable with the ones reported in large series utilizing the same classification system. CONCLUSIONS: The Accordion system is an effective method of quality control for pancreatic surgery both in high- and low-volume hospitals. PMID- 23449167 TI - Severe acute pancreatitis: clinical forms of different gravity. AB - INTRODUCTION AND AIMS: Severe Acute Pancreatitis (SAP) is characterized by some degree of severity. The aim of this study is to indentify within severe forms the critical, early severe acute pancreatitis (ESAP). METHODS AND PATIENTS: Since 1997 to 2011 we have treated 276 acute biliary pancreatitis. SAP was 21.7% (60); among SAP were defined 13 (21.6%) ESAP as presence of organ dysfunction within 72 hours after onset of symptoms. Clinical features, organ failure, therapeutic choices and results between SAP (47) and ESAP (13) were compared. RESULTS: The comparison has shown the following results: impairment degree of pancreas (Balthazar CT score): SAP 2.3 - ESAP 3.85; abdominal compartment syndrome (ACS): ESAP 7.6% (1/13); MODS: ESAP 46.1% (6/13); simgle organ dysfunction: SAP 51% (24/47) - ESAP 53.8% (7/13) ; hypoxemia: SAP 65.9 % (31/47) - ESAP 76.9% (10/13); pancreatic infections: SAP 6.3% (3/47) - ESAP 23% (3/13); mortality: SAP 4.2% (2/47) - ESAP 15.4% (2/13). DISCUSSION: ESAP is characterized early by major incidence of ACS, MODS, impairment degree of the pancreas. In a later phase the gravity of severe pancreatitis lies on the septic complications of fluid necrotic collections. In ESAP the mortality is higher: 15.4% because of multiorgan dysfunction (in first phase); in SAP is 4.3% because of septic complications (in later phase). CONCLUSIONS: Treatment of SAP and ESAP is now more conservative and less invasive than in the past: intensive care, prevention of intestinal failure and assure papillary patency in the first phase of the disease. In the later phase therapeutic procedure for fluid necrotic collections is US/CT percutaneous catheter drainage. PMID- 23449168 TI - Radiopaque markers equal gastrografin in the study of small bowel obstructions (SBO): a preliminary study. AB - AIM: To compare the diagnostic accuracy of a consolidated method (i.e.gastrografin) and a new one (i.e.radiopaque markers) in detecting complete intestinal obstruction. MATERIALS AND METHODS: Twenty-one patients with suspected small bowel obstruction were enrolled and received at admission orally 100 ml of Gastrografin and 10 radiopaque markers at the same time. A series of plain abdominal radiograms was taked and evaluated to decide whether the obstruction was complete or not. The results of radiological evaluations were not disclosed to the surgeons responsible for the patient's treatment, therefore clinical decisions were assumed on clinical grounds only. RESULTS: In 16 out of the 21 enrolled patients both methods demonstrated only a partial obstruction; clinically none of them required surgery. Five patients showed complete bowel obstruction by the radiopaque markers method; out of those the gastrografin study showed a complete obstruction in four of them. All of them were operated on. In the fifth case it was not clear if the gastrografin had passed through the ileum cecal valve or not. The unclear clinical picture induced to perform a TC that revealed that a small quantity of gastrografin had passed the ileo-cecal valve but there was a complete small bowel occlusion due to an internal hernia requiring a surgical treatment (thus implying a false negative picture). DISCUSSION: This preliminary study showed that both methods are effective in the early diagnosis of complete SBO. The use of radiopaque markers could avoid some false negatives of the gastrografin method and is significantly less expensive. PMID- 23449169 TI - Fast-track surgery concepts for congenital urogenital anomalies. AB - AIM: To investigate the possibility of fast-track surgery concepts in pediatric urology department as a single center study model of a developing country. MATERIAL OF STUDY: The study included 1620 patients surgically treated at the pediatric urology department, from 2009 to 2011. According to the congenital anomalies, all patients were classified in one of four groups: I - testicular anomalies (197 patients); II - external genital anomalies (453); III - upper urinary tract anomalies (801) and IV - associated anomalies (169). We analyzed the total duration of stay in the hospital of all patients among all treating doctors concerning the anomaly. RESULTS: Statistically significant difference in total length of hospitalization of all patients in Group I was noted in Doctors 1 and 5 (F=10.36** for F0.05;5;12=3.11 and F0.01;5;12=5.06), as well as in the Group II (F=17.01** for F0.05;5;12=3.11 and F0.01;5;12=5.06). Statistical analysis was not possible to be performed in groups III and IV because of lack of the patients. DISCUSSION: Analyzing the length of hospitalization of the patients treated at the urology department, all doctors showed the tendency to shorten the total length of hospitalization in patients of all groups. Majority of the studies carried out on pediatric urology departments in developed countries, showed that over 50% of children were successfully treated using fast-track surgery concept. CONCLUSIONS: Modern methods of surgical management and anesthesia allow decrease of hospitalization length, financial savings to the healthcare system and better comfort for patients. PMID- 23449171 TI - Update on the surgical treatment of epilepsy. AB - PURPOSE OF REVIEW: Using the most recent evidence, we provide an update about epilepsy surgery, focusing on the presurgical evaluation and surgical planning, epilepsy surgery outcomes, and utilization. RECENT FINDINGS: Great strides are being achieved in the presurgical evaluation and planning for epilepsy surgery, including fundamental advances in imaging and neurophysiology. A recent randomized controlled trial demonstrates that early surgery for patients with mesial temporal lobe epilepsy (TLE) is superior to medical therapy. The enduring benefits of surgery continue to be demonstrated, particularly after TLE surgery. However, studies examining the long-term outcomes after extratemporal lobe epilepsy surgery are scarce. Surgery is generally associated with an improvement in depression, but mostly in those with good surgical outcome. Complications from invasive monitoring or after epilepsy surgery are generally temporary, or limited in their symptomatology. One area in need of prospective studies is the topic of antiepileptic drug withdrawal after epilepsy surgery (Who? When? How?). Despite its proven effectiveness, epilepsy surgery continues to be underutilized, but new tools for health professionals are emerging to guide appropriate surgical referrals. SUMMARY: Important contributions to the field of epilepsy surgery are discussed, in particular emerging imaging (fMRI) and neurophysiological (high frequency oscillations) techniques. Epilepsy surgery is effective, well tolerated but still underutilized. PMID- 23449170 TI - Silver nanoparticle toxicity in the embryonic zebrafish is governed by particle dispersion and ionic environment. AB - The mechanism of action of silver nanoparticles (AgNPs) is unclear due to the particles' strong tendency to agglomerate. Preventing agglomeration could offer precise control of the physicochemical properties that drive biological response to AgNPs. In an attempt to control agglomeration, we exposed zebrafish embryos to AgNPs of 20 or 110 nm core size, and polypyrrolidone (PVP) or citrate surface coatings in media of varying ionic strength. AgNPs remained unagglomerated in 62.5 MUM CaCl2 (CaCl2) and ultrapure water (UP), but not in standard zebrafish embryo medium (EM). Zebrafish embryos developed normally in the low ionic strength environments of CaCl2 and UP. Exposure of embryos to AgNPs suspended in UP and CaCl2 resulted in higher toxicity than suspensions in EM. 20 nm AgNPs were more toxic than 110 nm AgNPs, and the PVP coating was more toxic than the citrate coating at the same particle core size. The silver tissue burden correlated well with observed toxicity but only for those exposures where the AgNPs remained unagglomerated. Our results demonstrate that size- and surface coating-dependent toxicity is a result of AgNPs remaining unagglomerated, and thus a critical design consideration for experiments to offer meaningful evaluations of AgNP toxicity. PMID- 23449172 TI - Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. AB - PURPOSE OF REVIEW: Combining human genomics and molecular biology, recent studies have made pivotal progress toward understanding the cause of hemimegalencephaly (HME) and other cerebral megalencephaly syndromes. The present article highlights recent advances of the genetic cause of these conditions, and considers the role of somatic postzygotic genetic lesions in brain maldevelopment. RECENT FINDINGS: Studies over the past 12 months have identified de-novo somatic mutations as one possible cause in HME. The gene mutations involve components of the phosphatidylinositol 3-kinase (PI3K)-AKT (also known as protein kinase B) mammalian target of rapamycin (mTOR) pathway and include PIK3CA, PIK3R2, AKT3, and MTOR. These mutations were identified by comparing genomic data obtained from surgically resected brain tissue with nondiseased tissue, and by single-neuron sequencing in combination with molecular biology techniques. The association between the somatic mutations and downstream activation of the PI3K-mTOR pathway suggests that HME is a neurodevelopmental disease caused by gain-of-function activation of the PI3K-AKT-mTOR pathway. SUMMARY: The studies reviewed suggest that somatic mutations of the PI3K-AKT-mTOR pathway limited to the brain may represent one cause of HME. Dysregulation of this pathway has possible therapeutic potential in the identification of HME. Somatic mutations may be an important yet underappreciated disease mechanism in developmental neurological diseases. PMID- 23449173 TI - Mechanisms and therapeutic challenges in autism spectrum disorders: insights from Rett syndrome. AB - PURPOSE OF REVIEW: A major challenge for understanding neurodevelopmental disorders, including autism spectrum disorders (ASDs), is to advance the findings from gene discovery to an exposition of neurobiological mechanisms that underlie these disorders and subsequently translate this knowledge into mechanism-based therapeutics. A promising way to proceed is revealed by the recent studies of rare subsets of ASDs. In this review, we summarize the latest advances in the mechanisms and emerging therapeutics for a rare single-gene ASD, Rett syndrome. RECENT FINDINGS: Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2). Although MeCP2 has diverse functions, examination of MeCP2 mutant mice suggests the hypothesis that MeCP2 deficiency leads to aberrant maturation and maintenance of synapses and circuits in multiple brain systems. Some of the deficits arise from alterations in specific intracellular pathways such as the PI3K/Akt signaling pathway. These abnormalities can be at least partially rescued in MeCP2 mutant mice by treatment with therapeutic agents. SUMMARY: Mechanism-based therapeutics are emerging for single-gene neurodevelopmental disorders such as Rett syndrome. Given the complexity of MeCP2 function, future directions include combination therapeutics that target multiple molecules and pathways. Such approaches will likely be applicable to other ASDs as well. PMID- 23449174 TI - Pediatric epilepsy genetics. AB - PURPOSE OF REVIEW: Genetic epilepsies in childhood are a complex group of disorders, with heterogeneous etiologies and clinicopathologic features. This review focuses on primary genetic epilepsies, which may have variable neuropsychiatric comorbidities, but usually have no underlying gross neuropathology or evident metabolic disturbance. Epilepsy due to inherited metabolic diseases, chromosomal abnormalities, phakomatoses, or malformations of cortical development is reviewed elsewhere. RECENT FINDINGS: The use of high throughput approaches to sequence DNA and to detect copy number variants is revealing a landscape of mutations in genetic epilepsies, affecting a variety of genes involved in neuronal excitability, synaptic transmission, neuronal metabolism, or network development. SUMMARY: A number of distinct clinical syndromes of pediatric genetic epilepsy have been described and linked to specific gene defects. Phenotypes may include, in addition to epilepsy, variable degrees of intellectual disability, elements of autism spectrum disorders, other psychiatric disorders, and motor impairment. In some cases, these comorbidities derive from uncontrolled seizure activity (epileptic encephalopathies), but in other cases they are direct, multifaceted consequences of global brain dysfunction. Mutations may be de novo, or, when inherited, show reduced penetrance and variable expressivity. Understanding the genetics of these conditions will improve diagnosis, reveal pathogenic mechanisms, and eventually lead to better treatment. PMID- 23449175 TI - ILAE/IBE/WHO Global Campaign Against Epilepsy: a partnership that works. AB - PURPOSE OF REVIEW: Epilepsy can hijack the lives of many persons of all ages. It is an unpredictable disease that can manifest itself in seizures, brain damage and cognitive and psychiatric disabilities, although some people with epilepsy can have a relatively normal life. People with epilepsy are among the most vulnerable in any society because the disease is misunderstood and often stigmatizing. Thus, many patients and their families are reluctant to admit that they suffer from epilepsy. This in turn affects public policy in terms of patient care, early diagnosis, medical research, advocacy, cure and their very lives. RECENT FINDINGS: A survey to evaluate the results of Global Campaign Against Epilepsy activities on a national level was performed in 2009. Data from the demonstration projects have already changed the public policies in several countries. SUMMARY: On the occasion of the launch of phase II of the Campaign, the WHO Director General stated: 'The collaboration between the IBE, ILAE and WHO has shown that when people with different backgrounds and roles come together with a shared purpose, creativity is released and expertise is used in innovative and constructive ways'. Indeed, this partnership led to many activities and all over the world to many people 'standing up for epilepsy'. PMID- 23449177 TI - A novel superhard BN allotrope under cold compression of h-BN. AB - Using first-principles calculations, we identify a new orthorhombic boron nitride (BN) phase (namely, P-BN; space group: Pmn2(1)), which has similar topological structure to Bct-BN and Z-BN, but without the six-membered ring. This P-BN allotrope is energetically more favorable than previously reported Pnma-BN, Bct BN and Z-BN phases. With only 0.06 eV/atom less stable than h-BN at ambient pressure, it can be formed from h-BN under cold compression at a low pressure of 4 GPa. The theoretical hardness and bulk modulus of the P-BN crystal are 403 GPa and 60.5 GPa, respectively, comparable to those of c-BN. Moreover, the P-BN phase along with Bct-BN and Z-BN are suggested as possible intermediate phases between h-BN and w-BN, which can be qualitatively explained by two empirical rules of Ostwald and Ostwald-Volmer. PMID- 23449176 TI - COMT val158met and 5-HTTLPR genetic polymorphisms moderate executive control in cannabis users. AB - The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Delta9 tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions. PMID- 23449178 TI - Use of acupuncture for pain management in an academic Korean medicine hospital: a retrospective review of electronic medical records. AB - OBJECTIVE: This study aimed to identify the descriptive characteristics of patients with pain conditions who visited an academic medical centre for traditional Korean medicine (TKM). METHODS: This work was a retrospective review of the electronic medical records of patients who received at least one session of acupuncture for pain management from March 2010 to February 2012 in the Korean medical hospital of Pusan National University. Demographic characteristics and data on patient conditions, treatment interventions received and costs associated with acupuncture treatments were analysed. RESULTS: We identified a total of 2167 patients, including 2105 outpatients and 237 inpatients. The mean age (SD) of the patients was 52.0 (15.3) years, and approximately two-thirds of the patients were women (64.0%). The average number of acupuncture treatment sessions was 8.0 (6.6 for outpatients and 14.5 for inpatients). The most treated conditions were low back pain (30.5%), neck pain (23.9%) and shoulder pain (17.5%). Interventions included needle acupuncture with manual (52.6%) or electrical (47.4%) stimulation, herbal medicine (44.2%), cupping (21.2%) and moxibustion (3.5%). Over one-third of outpatients (33.5%) received at least six sessions of acupuncture. The median total cost of each outpatient and inpatient care per person was 169 604 and 1 001 707 Korean Won (approximately L98 and L577), respectively. CONCLUSIONS: Acupuncture was primarily used for the treatment of low back, neck and shoulder pain with a wide range of related interventions at an academic medical centre for traditional Korean medicine. These data reflect real clinical practice and should inform the design of future prospective clinical research of acupuncture. PMID- 23449179 TI - Bilateral tension pneumothorax related to acupuncture. AB - We report on a patient with a rare case of bilateral tension pneumothorax that occurred after acupuncture. A 69-year-old large-bodied man, who otherwise had no risk factors for spontaneous pneumothorax, presented with chest pressure, cold sweats and shortness of breath. Immediately after bilateral pneumothorax had been identified on a chest radiograph in the emergency room, his blood pressure and percutaneous oxygen saturation suddenly decreased to 78 mm Hg and 86%, respectively. We confirmed deterioration in his cardiopulmonary status and diagnosed bilateral tension pneumothorax. We punctured his chest bilaterally and inserted chest tubes for drainage. His vital signs promptly recovered. After the bilateral puncture and drainage, we learnt that he had been treated with acupuncture on his upper back. We finally diagnosed a bilateral tension pneumothorax based on the symptoms that appeared 8 h after the acupuncture. Because the patient had no risk factors for spontaneous pneumothorax, no alternative diagnosis was proposed. We recommend that patients receiving acupuncture around the chest wall must be adequately informed of the possibility of complications and expected symptoms, as a definitive diagnosis can be difficult without complete information. PMID- 23449180 TI - Effect of acupuncture on target tissue distribution of Schisandra lignans. AB - BACKGROUND: Recently, the combination of acupuncture and Chinese medicine as a practical strategy to treat diseases is receiving considerable attention worldwide as they are usually found to exhibit intriguing therapeutic effectiveness. The current study aimed to study the adjunct effect of acupuncture on target tissue distribution of schisandra lignans when acupuncture is combined with Schisandra chinensis. METHODS: A simple and reliable high performance liquid chromatography-electrospray tandem-mass spectrometry (HPLC-ESI-MS) method for simultaneous analysis of three bioactive lignans (schisandrin, deoxyschisandrin and schisandrin B) in rat tissues was established. Using this analytical method we evaluated whether acupuncture had a synergistic effect on the tissue distribution of schisandra lignans. RESULTS: Tissue concentrations of the three lignans in the group receiving acupuncture were significantly higher than those in the schisandra only group, suggesting that acupuncture may potently increase tissue concentrations of schisandra lignans. The highest concentrations of the three lignans occurred in the liver compared with other tissues, and tissue concentrations in the heart, spleen, lungs and kidneys were increased by 315%, 203%, 250% and 224%, respectively. In addition, retention times of the lignans in tissues were prolonged for a relative long time. CONCLUSIONS: Our date indicate that the combined use of acupuncture and Schisandra chinensis could produce a synergistic effect which could play a beneficial role on promoting the tissue distribution of lignans. This has supported our initial hypothesis. The HPLC-MS method showed good sensitivity in quantifying the three schisandra lignans in different tissues. PMID- 23449181 TI - Complexities in assessing the effectiveness of inactivated influenza vaccines. PMID- 23449182 TI - Early estimates of influenza vaccine effectiveness in Navarre, Spain: 2012/13 mid season analysis. AB - We present estimates of influenza vaccine effectiveness (VE) in Navarre, Spain, in the early 2012/13 season, which was dominated by influenza B. In a population based cohort using electronic records from physicians, the adjusted VE in preventing influenzalike illness was 32% (95% confidence interval (CI): 15 to 46). In a nested test-negative case-control analysis the adjusted VE in preventing laboratory-confirmed influenza was 86% (95% CI: 45 to 96). These results suggest a high protective effect of the vaccine. PMID- 23449183 TI - Early estimates of seasonal influenza vaccine effectiveness in Europe: results from the I-MOVE multicentre case-control study, 2012/13. AB - We conducted a test-negative case-control study based in five European sentinel surveillance networks. The early 2012/13 adjusted influenza vaccine effectiveness was 78.2% (95% CI: 18.0 to 94.2) against influenza B, 62.1% (95% CI: -22.9 to 88.3%) against A(H1) pdm09, 41.9 (95% CI: -67.1 to 79.8) against A(H3N2) and 50.4% (95% CI: -20.7 to 79.6) against all influenza types in the target groups for vaccination. Efforts to improve influenza vaccines should continue to better protect those at risk of severe illness or complications. PMID- 23449184 TI - Real-time laboratory surveillance of sexually-transmissible infections in Marseille University hospitals reveals rise of gonorrhoea, syphilis and human immunodeficiency virus seroconversions in 2012. AB - Real-time systematic monitoring of the number of infections diagnosed in our clinical microbiology laboratory in Marseille recently drew attention to the fact that the incidence of gonorrhoea was 10-fold greater from September through December 2012 than during same months of previous years. We also found an increase in the annual incidence of syphilis and human immunodeficiency virus seroconversion. Our system allowed timely identification of an increase in sexually-transmitted infections in Marseille for the whole year of 2012. PMID- 23449185 TI - Letter to the editor: influenza vaccine effectiveness: heterogeneity in estimates for the 2012/13 season. PMID- 23449186 TI - Authors reply: influenza vaccine effectiveness: heterogeneity in estimates for the 2012/13 season. PMID- 23449187 TI - Welcome to the new year 2013 in the Polish Archives of Internal Medicine (Pol Arch Med Wewn). PMID- 23449188 TI - Management of familial heterozygous hypercholesterolemia. Position paper of the Polish Lipid Expert Forum. PMID- 23449189 TI - New treatment approaches for asthma. PMID- 23449190 TI - Rhabdomyolysis associated with Mycoplasma pneumoniae infection. PMID- 23449191 TI - Iron deficiency in patients with chronic kidney disease requiring hemodialysis: do inflammation and overexpressed hepcidin contribute significantly? PMID- 23449192 TI - Good bacteria for good mood: probiotics and the brain-gut axis interactions. PMID- 23449193 TI - Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats. AB - Acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final step in triacylglycerol (TAG) synthesis and is highly expressed in the small intestine. Because DGAT-1 knockout mice are resistant to diet-induced obesity, we investigated the acute effects of intragastric (IG) infusion of a small molecule diacylglycerol acyltransferase-1 inhibitor (DGAT-1i) on eating, circulating fat metabolites, indirect calorimetry, and hepatic and intestinal expression of key fat catabolism enzymes in male rats adapted to an 8 h feeding-16 h deprivation schedule. Also, the DGAT-1i effect on fatty acid oxidation (FAO) was investigated in enterocyte cell culture models. IG DGAT-1i infusions reduced energy intake compared with vehicle in high-fat diet (HFD)-fed rats, but scarcely in chow-fed rats. IG DGAT-1i also blunted the postprandial increase in serum TAG and increased beta-hydroxybutyrate levels only in HFD-fed rats, in which it lowered the respiratory quotient and increased intestinal, but not hepatic, protein levels of Complex III of the mitochondrial respiratory chain and of mitochondrial hydroxymethylglutaryl-CoA synthase. Finally, the DGAT-1i enhanced FAO in CaCo2 (EC50 = 0.3494) and HuTu80 (EC50 = 0.00762) cells. Thus, pharmacological DGAT-1 inhibition leads to an increase in intestinal FAO and ketogenesis when dietary fat is available. This may contribute to the observed eating-inhibitory effect. PMID- 23449194 TI - Synthesis of natural products with polycyclic systems. AB - Herein we present our unique strategies to synthesize natural products. To prepare mersicarpine, an atypical indole alkaloid, our procedure features an Eschenmoser-Tanabe fragmentation to synthesize an alkyne unit, a combination of a Sonogashira coupling and a gold(III) catalyzed cyclization to construct the indole skeleton, and a one-pot process to arrange the cyclic imine and the hemiaminal moieties. Additionally, we synthesized a frog poison, histrionicotoxin, via a chirality transfer from an allenylsilane to prepare a pseudosymmetrical dienyne, dienyne metathesis to produce an optically active bicyclo [5.4.0] system, and an asymmetric propargylation. To synthesize lyconadin A, a Lycopodium alkaloid, a combination of an aza-Prins reaction and electrocyclic ring opening constructed the highly fused tetracyclic compound. The synthesis of isoschizogamine features a facile construction of the carbon framework through a Wagner-Meerwein rearrangement, a tandem metathesis, a stereoselective rhodium-mediated 1,4-addition of an arylboronic acid, and a ring closing metathesis via a hemiaminal ether. PMID- 23449195 TI - Formulation, optimization, in vivo pharmacokinetic, behavioral and biochemical estimations of minocycline loaded chitosan nanoparticles for enhanced brain uptake. AB - The minocycline hydrochloride (MH), at higher doses, is useful in the treatment of neurodegenerative disorders and owing to its antioxidant potential, it may have nootropic effects. MH loaded nanoparticles (MHNP) were coated with tween 80 (cMHNP) to improve its brain uptake followed by their optimization employing two factor-three level (3(2)) central composite design (CCD) in order to minimize particle size and maximize drug entrapment efficiency (DEE) and validated. The optimized formulations were further subjected to in vitro drug release study; in vivo biodistribution studies in male wistar rats. The pharmacodynamic study was carried out using elevated plus maze (EPM) and Morris water maze (MWM) behavioral models for nootropic activity in swiss albino mice; and biochemical estimations (acetylcholine esterase, reduced glutathione, malondialdehyde and brain nitrite level). After intravenous (i.v.) administration, the concentration of MH in brain of cMHNP (6.21+/-0.64 ug/mL) treated rats was significantly higher with MH solution treated (0.70+/-0.06 ug/mL) as well as MHNP (1.03+/-0.12 ug/mL) treated animals. Pharmacodynamic studies revealed a significant improvement in memory of MH, MHNP and cMHNP treated swiss albino mice than saline treated control group. However, cMHNP revealed maximum decrease in transfer latency (TL) in EPM and maximum increase in time spent in target quadrant (TSTQ) in MWM. Although cMHNP did not produce significant change in brain acetylcholinesterase, but, significantly increased reduced glutathione, malondialdehyde and reduced brain nitrite level as compared to saline, MH solution and MHNP treated groups. The results suggest that cMHNP is a promising candidate for improved brain uptake of MH with better nootropic effect. PMID- 23449196 TI - Inhibitory effects of the constituents of Hippophae rhamnoides on 3T3-L1 cell differentiation and nitric oxide production in RAW264.7 cells. AB - Three new flavonol glycosides, hippophaeosides A-C (1-3), together with 27 known constituents, were isolated from Hippophae rhamnoides L. leaves. Their structures were determined by spectroscopic analyses. Their inhibitory activities on 3T3-L1 preadipocyte differentiation and triglyceride accumulation in maturing adipocytes, and nitric oxide production in RAW264.7 cells were examined. PMID- 23449197 TI - Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3 benzothiazole (TASP0382088): a potent and selective transforming growth factor beta type I receptor inhibitor as a topical drug for alopecia. AB - 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-beta (TGF-beta) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-beta-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). PMID- 23449198 TI - Self-organizing map analysis using multivariate data from theophylline tablets predicted by a thin-plate spline interpolation. AB - The "quality by design" concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space. We integrated thin-plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation. The tensile strength, disintegration time, and stability of these variables were measured as response variables. These responses were predicted quantitatively based on nonlinear TPS. A large amount of data on these tablets was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics. The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets. In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration. Increasing the proportion of magnesium stearate extended disintegration time. Increasing the compression force improved tensile strength, but degraded the stability of disintegration. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations. PMID- 23449199 TI - Discovery of aromatic components with excellent fragrance properties and biological activities: beta-ionols with antimelanogenetic effects and their asymmetric syntheses. AB - Both enantiomers of dihydro-beta-ionol and beta-ionol, contained in the aromatic components of Osmanthus flower and of Hakuto peach, were obtained with high optical purity by lipase-catalyzed kinetic resolution of the racemates. It was found that all these enantiomers had different characteristic favorable scents and high antimelanogenetic effects. The absolute configuration and the enantiomer ratios of dihydro-beta-ionol in the aromatic components of Osmanthus flower and of Hakuto peach were determined. The asymmetric synthesis of (R)-dihydro-beta ionol, one of the most valuable raw materials for fragrance and flavor, was performed from inexpensive beta-ionone via lipase-catalyzed dynamic kinetic resolution followed by reduction. PMID- 23449200 TI - Practical approach for measuring heat capacity of pharmaceutical crystals/glasses by modulated-temperature differential scanning calorimetry. AB - A practical protocol to obtain accurate heat capacity values of pharmaceutical compounds using modulated-temperature differential scanning calorimetry was established. Three pharmaceutical compounds, acetaminophen, indomethacin, and tri O-methyl-beta-cyclodextrin were used as model compounds. Powder samples did not produce reproducible results, presumably due to inclusion of gas in gap of powders that influenced the measured heat capacity and thermal homogeneity in the sample. Thus, the amorphous characteristics were evaluated using quench-cooled samples. Crystalline samples were obtained by partially melting the sample to allow recrystallization using the residual crystal as a template. Optimum sample mass was about 10 mg. Use of too small sample size resulted in poor reproducibility due to localization of the sample in the pan, while too large size resulted in low heat capacity values probably because of heterogeneity of the sample temperature. The optimum modulation period was in the range of 60 s and 90 s, to which the ramp rates of 2 degrees C/min and 1 degrees C/min, respectively, were applied. The ramp amplitude was less significant in the evaluation. This information should help in comprehending basic characteristics of pharmaceutical compounds. PMID- 23449201 TI - Influence of binder droplet dimension on granulation rate during fluidized bed granulation. AB - Here, we statistically identified the critical factor of the granulation rate during the fluidized bed granulation process. Lactose was selected as the excipient and was granulated with several binders, including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. The viscosity, density, and surface tension of the binder solution, contact angle, and the work done during adhesion and cohesion between the binder and lactose, mist diameter, Stokes number, and the dimension of the droplet were considered. The Stokes number was defined as the ratio of the inertial force to the viscous damping force of a particle. We confirmed that droplet diameter after adhesion had the highest correlation coefficient with the granulation rate constant in our investigated parameters. Partial least squares regression revealed two critical principal components of the granulation rate: one relating to the droplet dimension, which is composed of mist diameter and diameter and thickness of the droplet after adhesion of the binder to the lactose surface; and the other relating to wettability, which involves the work done during adhesion and cohesion, surface tension, and the thickness of the droplet after adhesion of the binder to the lactose surface. PMID- 23449202 TI - LC/MS/MS of steroids having vicinal diol as electrospray-active boronates. AB - A derivatization procedure with (3-dimethylaminophenyl)dihydroxyborane (DAPB) was introduced to enhance the detectability of steroids having a vicinal diol in LC/electrospray ionization (ESI)-MS/MS. DAPB reacted with the vicinal diol on the steroids [4beta-hydroxycholesterol (4-HCh), pregnanetriol (PT) and 20R,22R dihydroxycholesterol] in pyridine at 50 degrees C within 1 h. The resulting DAPB derivatives were highly responsive in ESI-MS operating in the positive-ion mode and gave characteristic product ions during MS/MS, which enabled sensitive detection using a selected reaction monitoring mode; the detection responses of the DAPB-derivatives were increased by 20-160-fold over those of the intact steroids and the limits of detection were in the low femtomole or attomole range. The derivatization procedure was successfully applied to biological sample analysis; the derivatization followed by LC/ESI-MS/MS enabled the specific detection of trace amounts of 4-HCh in human plasma and PT in human urine with a small sample volume, simple pretreatment and short chromatographic run time. PMID- 23449203 TI - Particle condition change in emulsion admixture evaluated by in situ flow particle imaging analysis. AB - We evaluated the particle state change in emulsion admixtures using in situ flow particle imaging analysis (FPIA). Ropion(r) intravenous (flurbiprofen axetil: Ropion(r)) served as the model emulsion formulation. A binary mixture of Ropion(r) and normal saline (NS), and a ternary admixture of Ropion(r), NS, and Gaster(r) injection (famotidine: Gaster(r)) or Primperan(r) injection (metoclopramide hydrochloride: Primperan(r)) were prepared and the change in emulsion particle state was analyzed using FPIA under in situ condition. The effect of storage on pH change and the chemical stability of flurbiprofen axetil were also investigated. In Ropion(r), various particle images (mean diameter: 2.4 um) were obtained. From our analysis of changes in scattergrams and particle images, changing behaviors of emulsion particles as a function of storage time depended on the systems of admixture samples. In Ropion(r)/NS and Ropion(r)/Gaster(r)/NS systems, mean particle size and particle number increased with lengthening storage time; however, these values were dramatically increased beyond 6 h in the Ropion(r)/Primperan(r)/NS system, corresponding to a decrease in measured pH. The decomposition of flurbiprofen axetil due to incompatibility was not observed in all systems. Detailed information on the change in emulsion particle state was obtained using FPIA, indicating that this method is useful to evaluate state changes in emulsion admixtures under in situ condition. PMID- 23449204 TI - Three new orcinol-conjugated hydrolysable tannins from the leaves of Cleyera japonica. AB - Three new orcinol (3-hydroxy-5-methylphenol)-conjugated hydrolysable tannins, together with two known compounds were isolated from the leaves of Cleyera japonica (CJ), and have been tentatively named cleyeratannin A (1), cleyeratannin B (2) and cleyeratannin C (3). The chemical structures of these compounds were elucidated using 1 dimensional (1D)/2D NMR and high resolution FAB-MS, and the absolute configuration was confirmed by circular dichroism (CD). To evaluate their anti-oxidative activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH)/free radical scavenging activity and nitroblue tetrazolium (NBT)/superoxide anion scavenging activity were determined. PMID- 23449205 TI - Lasiodiplodin analogues from the endophytic fungus Sarocladium kiliense. AB - A new 12-membered ring lactone, (3S),(6R)-6-hydroxylasiodiplodin (1), with two known analogues, (3R)-lasiodiplodin (2), and (3R),(5S)-5-hydroxylasiodiplodin (3) were isolated from the EtOH extracts of normal Apriona germari (Hope)-associated fungus Sarocladium kiliense grown in rice medium. The structures of compounds 1-3 were elucidated by a combination of spectroscopic data interpretation, single crystal X-ray diffraction analysis, and modified Mosher's method. PMID- 23449206 TI - New bisabolane sesquiterpene from the mycelia of Amanita virgineoides. AB - A bisabolane type of sesquiterpene was isolated from the culture medium of Amanita virgineoides BAS, together with two known compounds, including lignoren, and harziandion. The structure of the new compound "virgineol" was established using a combination of different NMR spectroscopy techniques, whereas the chemical structure of the known compound was identified as lignoren, and the structure of harziandion was confirmed by X-ray crystallographic analysis. PMID- 23449207 TI - Application of solution-processed metal oxide layers as charge transport layers for CdSe/ZnS quantum-dot LEDs. AB - We fabricated and characterized quantum-dot light emitting devices (QLEDs) that consisted of a CdSe/ZnS quantum-dot (QD) emitting layer, a hole-transporting nickel oxide (NiO) layer and/or an electron-transporting zinc oxide (ZnO) layer. Both the p-type NiO and n-type ZnO layers were formed by using sol-gel processes. All the fabricated CdSe/ZnS QLEDs showed similar electroluminescence spectra that originated from the green CdSe/ZnS QDs. However, different combinations of hole- and electron-transporting layers resulted in efficiency variations. In addition to the control of the respective concentrations of holes and electrons within a multilayer device structure, which determines the luminance and efficiency of QLEDs, the use of metal oxide layers is advantageous for long-term stability of QLEDs because they are air stable and can block the permeation of water vapor and oxygen in ambient air to a QD emitting layer. Moreover, the wet chemistry processing for their formation makes metal oxide layers attractive for low cost and/or large area manufacture of QLEDs. PMID- 23449208 TI - Sources of trans and saturated fatty acids in the diets of Vancouver children. AB - PURPOSE: Amounts and sources of trans fatty acids (TFA) and saturated fatty acids (SFA) were examined in the diets of children aged five to six years after changes in TFA in Canadian foods. METHODS: Dietary intake was assessed for 100 Vancouver children, using three 24-hour recalls during parental interviews. Trans fatty acid and SFA intakes and food sources were determined for each child. RESULTS: The TFA intake was 0.71 +/- 0.31% of energy, and 12% of children consumed over 1% of energy from TFA. Saturated fatty acids intakes were 12.5 +/- 3.39% of energy, and 81% of the children consumed more than 10% of energy from SFA. Monounsaturated and polyunsaturated fatty acid intakes were 12.0 +/- 3.0% and 5.79 +/- 2.16% of energy, respectively. Major sources of TFA were dairy products, fast foods, and bakery products. Major sources of SFA were dairy products, processed foods, fast food, and bakery products. CONCLUSIONS: The TFA intakes of children aged five to six years have decreased since 2004 to a 95th percentile intake of 1.28% of energy, but more than 80% of children consume over 10% of energy from SFA. Removing TFA from snacks and bakery products would decrease the highest TFA intakes to 1% of energy. This study suggests that increased efforts by industry or educational guidance for parents is required to enable selection of foods lower in TFA, and that greater emphasis is needed on SFA. PMID- 23449209 TI - Using Photovoice with at-risk youth in a community-based cooking program. AB - PURPOSE: We examined the facilitators of and barriers to participants' application of cooking skills beyond Cook It Up!, a pilot community-based cooking program targeting at-risk youth aged 13 to 18. METHODS: Photovoice is a qualitative research method using still-picture cameras to document participants' health and community realities. Four participants photographed items they perceived as facilitators of or barriers to the application of cooking skills. At a facilitated discussion group, youth discussed why they took certain pictures and how the photos best exemplified facilitators and barriers. Participants agreed upon the themes arising from the dialogue. Data trustworthiness tools were used to ensure that themes arising from the dialogue truly represented participants' perspectives. RESULTS: Four major themes emerged as facilitators: aptitude, food literacy, local and fresh ingredients, and connectedness. Access to unhealthy foods was the only barrier that participants identified. Participants and researchers decided to advocate for the sustainability of community-based cooking programs offered for high school credit. Participants' photos would enhance advocacy efforts with education stakeholders. CONCLUSIONS: Cook It Up! provided youth with cooking techniques for healthy, economical, homemade meals, but proof was needed of the transferability of skills outside the program environment. Youth in this study identified important facilitators that enabled the continued use of their cooking skills, and one barrier. Findings underscore the importance of community-based cooking programs tailored to at-risk youth. PMID- 23449210 TI - Fruit and vegetable preferences and intake among children in Alberta. AB - PURPOSE: The association between preference for and intake of fruits and vegetables was examined among Albertan children. METHODS: Data used were collected as part of a provincial population-based survey among grade 5 children in Alberta. Intake of two fruits and five vegetables was assessed using the Harvard food frequency questionnaire, and preference for individual fruit and vegetable items was rated using a three-point Likert-type scale. Random effects models with children nested within schools were used to test for associations between fruit and vegetable preference and intake. RESULTS: A total of 3398 children aged 10 to 11 years returned completed surveys. Children who reported a greater liking for fruits and vegetables also reported significantly (p<0.001) higher intake. On average, children who liked a food a lot ate 0.5 to 2.7 more weekly servings of the food than did children who did not like the food. CONCLUSIONS: These findings suggest that focusing on interventions designed to increase taste preference may lead to increased fruit and vegetable intake among children. Introducing children to unfamiliar fruits and vegetables through taste testing may be an effective and practical health promotion approach for improving dietary habits. PMID- 23449211 TI - Health-promoting vending machines: evaluation of a pediatric hospital intervention. AB - PURPOSE: Taking advantage of a natural experiment made possible by the placement of health-promoting vending machines (HPVMs), we evaluated the impact of the intervention on consumers' attitudes toward and practices with vending machines in a pediatric hospital. METHODS: Vending machines offering healthy snacks, meals, and beverages were developed to replace four vending machines offering the usual high-energy, low-nutrition fare. A pre- and post-intervention evaluation design was used; data were collected through exit surveys and six-week follow-up telephone surveys among potential vending machine users before (n=293) and after (n=226) placement of HPVMs. Chi-2 statistics were used to compare pre- and post intervention participants' responses. RESULTS: More than 90% of pre- and post intervention participants were satisfied with their purchase. Post-intervention participants were more likely to state that nutritional content and appropriateness of portion size were elements that influenced their purchase. Overall, post-intervention participants were more likely than pre-intervention participants to perceive as healthy the options offered by the hospital vending machines. Thirty-three percent of post-intervention participants recalled two or more sources of information integrated in the HPVM concept. No differences were found between pre- and post-intervention participants' readiness to adopt healthy diets. CONCLUSIONS: While the HPVM project had challenges as well as strengths, vending machines offering healthy snacks are feasible in hospital settings. PMID- 23449212 TI - Development of a resource to help consumers select nutrition supplements. AB - PURPOSE: In Canada, many people do not meet all the recommended nutrient intakes with food alone; the use of supplements may be one strategy to compensate for some of these inadequacies. Previous research has revealed several barriers to supplement use, including a lack of knowledge. In this qualitative study, we developed a resource to help inform and educate consumers on the selection of appropriate nutrition supplements. METHODS: Three focus groups with participants residing in low-income neighbourhoods in Saskatoon, Saskatchewan, and seven key informant interviews were conducted using a semi-structured interview guide and four resource examples. After transcription of the discussion and interviews, thematic analysis was used to identify emergent themes. RESULTS: Analysis yielded three overarching themes: barriers to use, interdisciplinary issues, and resource expectations. Each overarching theme had several subthemes. Subthemes of the overarching theme of resource expectations were subsequently used to create a new tool to help consumers select an appropriate multivitamin. CONCLUSIONS: A tool was developed after available resources were explored and stakeholders were interviewed. The new resource was based on community members' and health care professionals' expressed needs, ideas, and beliefs. PMID- 23449213 TI - Impact of a childcare centre nutrition program on nutrient intakes in Nunavik Inuit children. AB - PURPOSE: We assessed the impact of a nutrition program implemented in Nunavik childcare centres on Inuit children's food and dietary intakes. METHODS: Two hundred and forty-five Inuit children (aged 25.0 +/- 9.6 months) were recruited between 2006 and 2010 in Nunavik childcare centres. Dietary intakes were assessed using a single 24-hour dietary recall (n=217). We compared participants' energy and nutrient intakes, and the proportions who met iron requirements and Canada's Food Guide - First Nations, Inuit and Metis recommendations, depending on whether or not they attended a childcare centre during the 24-hour dietary reference period. RESULTS: Children who attended a childcare centre on the day of the recall had significantly higher intakes of omega-3 fatty acids, calcium, total iron, bioavailable iron, phosphorus, beta-carotene, folate, pantothenic acid, riboflavin, and vitamin K, while a higher proportion of them met the recommended intake for total and bioavailable iron. The proportion of children who met the recommended servings for vegetables and fruit, grain products, and milk and alternatives was also significantly higher among participants who attended a childcare centre. CONCLUSIONS: The nutrition program was effective at improving these Inuit preschoolers' diet. PMID- 23449214 TI - Promoting eHealth literacy in older adults: key informant perspectives. AB - Health literacy has the potential to improve an individual's capacity to access, understand, evaluate, and communicate basic health information and services in order to make appropriate health decisions. We developed a research agenda to help older adults become aware of health literacy and its function in promoting their nutritional health and well-being. A key activity is the development, implementation, and evaluation of an eHealth literacy tool, eSEARCH, targeted at older adults to help improve their eHealth literacy skills. Before consultations were held with this subpopulation to assess their eHealth literacy needs and abilities, key informant interviews were conducted with eight experts in the field of health literacy, the older adult population, and/or online communications. Some experts were identified from the relevant literature; others were identified by informants who had already been interviewed. Informants were asked nine questions about the perceived importance of health literacy in Canada, key considerations in developing an eHealth literacy tool, and supporting resources for advancement of the eHealth literacy tool. Informants agreed that health literacy is a key concept and stressed that key considerations for development of the eSEARCH tool are identifying the target population's needs, focusing on health promotion, and increasing confidence in information-seeking behaviours. Identified challenges are ensuring accessibility, applicability to older adults, and adoption of the tool by dietetic and other health care professionals. PMID- 23449215 TI - University students' reservations about dietetics as a career choice. AB - PURPOSE: Dietetics students' reservations about their career choice were investigated. METHODS: In several dietetics programs in various provinces, an in class or online survey was administered to students in the early or late stages of their education (n=397). Data were coded and analyzed, using descriptive statistics. Chi-square testing for independence was used to establish significant relationships. RESULTS: Forty-three percent (n=149) of those responding to the research question (n=344) indicated they had reservations about a dietetics career, primarily because of internship, salary, and employment concerns. Students enrolled in a coordinated internship/degree program experienced no reservations about internship. Students experienced fewer career reservations when they had made their career decision before grade 12, were influenced by a dietitian, or were in the later stages of their education. CONCLUSIONS: Findings have implications for dietetics recruitment, retention, research, and education. An understanding of sources of reservations about career choice will allow policy makers, researchers, and educators to address issues to ensure that potential professionals are well informed about career components and that educational programs meet students' needs. PMID- 23449217 TI - Elastic properties of monolayer graphene with different chiralities. AB - Using molecular mechanics simulations we investigate the in-plane elastic properties of monolayer graphene with different chirality angles under both uniaxial stretching and free-standing indentation. The effect of the loading range is also considered: the tensile strain ranges of 2% and 5% are selected. Under uniaxial stretching, all of the elastic properties including the second order elastic stiffness (E), the Poisson's ratio (nu) and the third-order elastic constant (c(m)) are essentially not sensitive to the graphene chirality angle. The values of E are essentially not sensitive to the tensile strain range (epsilon), while the values of c(m) slightly increase (numerically) with the decrease of epsilon. Under free-standing indentation, the values of E and c(m) determined are higher than those obtained from uniaxial stretching, and this difference significantly increases with the decrease of the tensile strain, especially for c(m). The difference between the in-plane stretching results and the indentation results arises mainly from the van der Waals (VDW) interaction between the indenter tip and the graphene, and the effect of the VDW interaction rapidly decreases with the tensile strain. The VDW effect is also not sensitive to the chirality angle. Therefore, a relatively large tensile strain is required (e.g. 5%) in order to obtain more accurate results from free-standing indentation. PMID- 23449216 TI - Mineral concentrations in bottled water products: implications for Canadians' mineral intakes. AB - PURPOSE: The popularity of bottled water products (BWPs) is growing in Canada. Concentrations of minerals with important implications for health were compared in different types of BWPs. METHODS: One sample of each brand and type of plain BWP (purified, remineralized, spring, mineral, and artesian), flavoured BWP, and nutrient-enriched BWP sold in major stores in Ottawa, Ontario, was purchased to allow determination of mineral concentrations by flame atomic absorption or emission spectroscopy. A total of 124 BWPs representing 37 brands were analyzed. RESULTS: In general, spring and mineral water contained higher amounts of magnesium and calcium than did purified, remineralized, artesian, flavoured, or nutrient-enriched water. Most plain BWPs contained little sodium and potassium, whereas 15% to 35% of flavoured and nutrient-enriched products had considerably higher concentrations. Only magnesium and calcium concentrations were highly correlated (r=0.76, p<0.001). Calculation of the percentage of Dietary Reference Intakes that could be supplied by each product revealed that, if they are consumed habitually, many products can contribute substantially to recommended intakes of these minerals. CONCLUSIONS: Mineral concentrations in most types of BWP varied, but distinct differences between types of products were identified. Consumers should be aware of the mineral content of BWPs because some could influence intakes of certain minerals significantly. PMID- 23449218 TI - Hematuria and risk for end-stage kidney disease. AB - PURPOSE OF REVIEW: Hematuria is a common clinical finding requiring medical attention and poses several clinical challenges. The main challenge is to predict the future risk for chronic kidney disease and therefore to design a long-term follow-up evaluation and treatment plan. This review focuses on the risk for subsequent end-stage kidney disease among young persons with persistent isolated microscopic hematuria. RECENT FINDINGS: It has been recently recognized that young persons with persistent isolated microscopic hematuria have an increased risk for end-stage kidney disease, mainly secondary to primary glomerular diseases. These predominantly include IgA nephropathy, thin basement membrane disease, and Alport syndrome. Among these causes, the association with progression to chronic kidney disease is best established for IgA nephropathy and Alport syndrome. Thin basement membrane disease had been considered 'benign' by most authors, although recent findings suggest otherwise. In addition, novel diagnostic markers and therapeutic interventions for these conditions have recently been studied. SUMMARY: Persistent isolated microscopic hematuria confers a risk for future chronic kidney disease, which is dependent on disease context, underlying genetics, environment interactions, and treatment. 'Benign (familial) hematuria' is a misnomer, which we recommend abandoning as it prompts loss to follow-up. Instead, we favor annual/biennial follow-up assessment that should include measurement of blood pressure, urinalysis, and kidney function tests. PMID- 23449219 TI - DNA bending-induced phase transition of encapsidated genome in phage lambda. AB - The DNA structure in phage capsids is determined by DNA-DNA interactions and bending energy. The effects of repulsive interactions on DNA interaxial distance were previously investigated, but not the effect of DNA bending on its structure in viral capsids. By varying packaged DNA length and through addition of spermine ions, we transform the interaction energy from net repulsive to net attractive. This allowed us to isolate the effect of bending on the resulting DNA structure. We used single particle cryo-electron microscopy reconstruction analysis to determine the interstrand spacing of double-stranded DNA encapsidated in phage lambda capsids. The data reveal that stress and packing defects, both resulting from DNA bending in the capsid, are able to induce a long-range phase transition in the encapsidated DNA genome from a hexagonal to a cholesteric packing structure. This structural observation suggests significant changes in genome fluidity as a result of a phase transition affecting the rates of viral DNA ejection and packaging. PMID- 23449220 TI - Development of modified siRNA molecules incorporating 5-fluoro-2'-deoxyuridine residues to enhance cytotoxicity. AB - Therapeutic small interfering RNAs (siRNAs) are composed of chemically modified nucleotides, which enhance RNA stability and increase affinity in Watson-Crick base pairing. However, the precise fate of such modified nucleotides once the siRNA is degraded within the cell is unknown. Previously, we demonstrated that deoxythymidine release from degraded siRNAs reversed the cytotoxicity of thymidylate synthase (TS)-targeted siRNAs and other TS inhibitor compounds. We hypothesized that siRNAs could be designed with specific nucleoside analogues that, once released, would enhance siRNA cytotoxicity. TS-targeted siRNAs were designed that contained 5-fluoro-2'-deoxyuridine (FdU) moieties at various locations within the siRNA. After transfection, these siRNAs suppressed TS protein and messenger RNA expression with different efficiencies depending on the location of the FdU modification. FdU was rapidly released from the siRNA as evidenced by formation of the covalent inhibitory ternary complex formed between TS protein and the FdU metabolite, FdUMP. These modified siRNAs exhibited 10-100 fold greater cytotoxicity and induced multiple DNA damage repair and apoptotic pathways when compared with control siRNAs. The strategy of designing siRNA molecules that incorporate cytotoxic nucleosides represents a potentially novel drug development approach for the treatment of cancer and other human diseases. PMID- 23449221 TI - The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double strand break repair. AB - APLF is a forkhead associated-containing protein with poly(ADP-ribose)-binding zinc finger (PBZ) domains, which undergoes ionizing radiation (IR)-induced and Ataxia-Telangiectasia Mutated (ATM)-dependent phosphorylation at serine-116 (Ser(116)). Here, we demonstrate that the phosphorylation of APLF at Ser(116) in human U2OS cells by ATM is dependent on poly(ADP-ribose) polymerase 3 (PARP3) levels and the APLF PBZ domains. The interaction of APLF at sites of DNA damage was diminished by the single substitution of APLF Ser(116) to alanine, and the cellular depletion or chemical inhibition of ATM or PARP3 also altered the level of accumulation of APLF at sites of laser-induced DNA damage and impaired the accumulation of Ser(116)-phosphorylated APLF at IR-induced gammaH2AX foci in human cells. The data further suggest that ATM and PARP3 participate in a common signalling pathway to facilitate APLF-Ser(116) phosphorylation, which, in turn, appears to be required for efficient DNA double-strand break repair kinetics and cell survival following IR. Collectively, these findings provide a more detailed understanding of the molecular pathway that leads to the phosphorylation of APLF following DNA damage and suggest that Ser(116)-APLF phosphorylation facilitates APLF-dependent double-strand break repair. PMID- 23449222 TI - Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation. AB - The eukaryotic DNA replication initiation factor Mcm10 is essential for both replisome assembly and function. Human Mcm10 has two DNA-binding domains, the conserved internal domain (ID) and the C-terminal domain (CTD), which is specific to metazoans. SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that belongs to the sirtuin family. It is conserved from yeast to human and participates in cellular controls of metabolism, longevity, gene expression and genomic stability. Here we report that human Mcm10 is an acetylated protein regulated by SIRT1, which binds and deacetylates Mcm10 both in vivo and in vitro, and modulates Mcm10 stability and ability to bind DNA. Mcm10 and SIRT1 appear to act synergistically for DNA replication fork initiation. Furthermore, we show that the two DNA-binding domains of Mcm10 are modulated in distinct fashion by acetylation/deacetylation, suggesting an integrated regulation mechanism. Overall, our study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis. PMID- 23449223 TI - A far-upstream (-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. AB - SOX9 encodes a transcription factor that presides over the specification and differentiation of numerous progenitor and differentiated cell types, and although SOX9 haploinsufficiency and overexpression cause severe diseases in humans, including campomelic dysplasia, sex reversal and cancer, the mechanisms underlying SOX9 transcription remain largely unsolved. We identify here an evolutionarily conserved enhancer located 70-kb upstream of mouse Sox9 and call it SOM because it specifically activates a Sox9 promoter reporter in most Sox9 expressing somatic tissues in transgenic mice. Moreover, SOM-null fetuses and pups reduce Sox9 expression by 18-37% in the pancreas, lung, kidney, salivary gland, gut and liver. Weanlings exhibit half-size pancreatic islets and underproduce insulin and glucagon, and adults slowly recover from acute pancreatitis due to a 2-fold impairment in Sox9 upregulation. Molecular and genetic experiments reveal that Sox9 protein dimers bind to multiple recognition sites in the SOM sequence and are thereby both necessary and sufficient for enhancer activity. These findings thus uncover that Sox9 directly enhances its functions in somatic tissue development and adult regeneration through SOM mediated positive auto-regulation. They provide thereby novel insights on molecular mechanisms controlling developmental and disease processes and suggest new strategies to improve disease treatments. PMID- 23449224 TI - Micro-RNA: new players in HIV-pathogenesis, diagnosis, prognosis and antiviral therapy. AB - The role of small RNA (microRNA) as key regulators of gene and protein expression has been well established. Currently there is greater interest in these small RNA molecules because of their involvement in the regulation of a variety of animal and plant diseases, animal development, and physiology in addition to their critical role in a variety of cellular activities such as cell proliferation, apoptosis, morphogenesis, and differentiation. Overall, microRNA regulate gene and protein expression to control and guide decisions on the fate of cells. Given their stability in vivo and their importance in human diseases, microRNA are gaining increasing importance as new generation biomarkers for diagnostics and prognostics, along with becoming excellent therapeutic targets for treating human diseases. This review is focused largely on the role of microRNA in HIV infection. The main purpose of this review is to provide a comprehensive perspective on host microRNA in the context of infection by HIV and other viruses, their effect on viral pathogenesis, along with providing insights into virally encoded microRNA that participate in the infectious process. PMID- 23449226 TI - The changing epidemiology of liver disease in HIV patients. AB - Liver disease continues to be one of the leading causes of hospitalization and death in HIV-infected individuals. Important etiologies include both alcoholic and non-alcoholic steatohepatitis, and coinfection with hepatitis viruses B and C. While non-alcoholic fatty liver disease is increasingly diagnosed in this population, most cases of chronic hepatitis B can be well controlled with tenofovir-based regimens, and hepatitis C has entered a revolutionary era in which most patients may be cured with direct-acting antivirals. However, important gaps remain unaddressed. Hepatitis delta is a neglected disease, despite 15 million people being infected worldwide, and represents the most severe form of viral hepatitis. Hepatitis E is largely unrecognized, despite being the major cause of acute viral hepatitis worldwide and occasionally leading to chronicity in immunosuppressed individuals. PMID- 23449225 TI - Effects of political conflict-induced treatment interruptions on HIV drug resistance. AB - Thirty-four million people worldwide were living with the HIV by the end of 2010. Despite significant advances in antiretroviral therapy, drug resistance remains a major deterrent to successful, enduring treatment. Unplanned interruptions in antiretroviral therapy have negative effects on HIV treatment outcomes, including increased morbidity and mortality, as well as development of drug resistance. Treatment interruptions due to political conflicts, not infrequent in resource limited settings, result in disruptions in health care, infrastructure, or treatment facilities and patient displacement. Such circumstances are ideal bases for antiretroviral therapy resistance development, but there is limited awareness of and data available on the association between political conflict and the development of HIV drug resistance. In this review we identify and discuss this association and review how varying antiretroviral therapy half-lives, genetic barriers, different HIV subtypes, and archived resistance can lead to lack of medication effectiveness upon post-conflict resumption of care. Optimized antiretroviral therapy stopping strategies as well as infrastructural concerns and stable HIV treatment systems to ensure continuity of care and rapid resumption of care must be addressed in order to mitigate risks of HIV drug resistance development during and after political conflicts. Increased awareness of such associations by clinicians as well as politicians and stakeholders is essential. PMID- 23449227 TI - How intestinal bacteria can promote HIV replication. AB - Since the 1950s, researchers have gradually realized that the body's bacteria help fight infection by crowding out potential pathogens. In the past decades, scientists have even begun to see our microbiota as thick-and-thin allies. However, the influence of gut bacteria on HIV is largely unknown. Our review likely sheds light on the previously indistinct role of commensal microbiota in retroviral pathogenesis. The delicate yet critical balance between this enormous bacterial population and the gastrointestinal tract is gradually destroyed along with HIV incursion. The leakage into the systemic circulation of bacterial and byproducts such as lipopolysaccharide directly stimulates the innate immune system through toll-like receptors. As a result, toll-like receptor-4 activation provokes production of interleukin-10, which mediates immunological tolerance. Therefore, a solid deduction is that intestinal microbes may be involved in triggering of replication and transmission of HIV, just like other retroviruses. PMID- 23449228 TI - Safety and efficacy of lopinavir/ritonavir during pregnancy: a systematic review. AB - The co-formulated, ritonavir-boosted protease inhibitor lopinavir is a frequently used component of HAART for treatment of HIV-infected women during pregnancy and prevention of mother-to-child transmission. We performed a systematic review to assess the effects of lopinavir/ritonavir on maternal and infant clinical and safety outcomes in HIV-infected pregnant women. PubMed, EMBASE, and select congresses were searched for studies published through May 31, 2012. Studies were selected that included HIV-infected pregnant mothers treated with a lopinavir/ritonavir-based regimen and described relevant maternal and infant outcomes. Ten articles or presentations describing nine studies were identified, comprising 2,675 lopinavir/ritonavir-treated women. In studies reporting HIV-1 RNA at delivery, HIV-1 RNA < 200 to < 1,000 copies/ml was achieved in 64-97% of subjects. Preterm delivery (< 37 weeks gestation) rates ranged from 8.3 to 25%; low birth weight (< 2,500 g) rates ranged from 11 to 20.3%. In one study, preterm delivery rates and low birth weight were similar between women who received standard or increased doses of lopinavir/ritonavir. In five studies reporting stillbirths and live births, 38 stillbirths occurred versus 2,058 live births (1.8%) among women receiving lopinavir/ritonavir. In eight studies reporting mother-to-child transmission at different time points, rates ranged from 0 to 3.3% and appeared to be similar in the one study comparing pregnant women who received standard or higher doses of lopinavir/ritonavir. The results from this systematic review suggest no unique safety or efficacy concerns with use of standard dose lopinavir/ritonavir as part of HAART in pregnant women. PMID- 23449229 TI - HIV-2 susceptibility to entry inhibitors. AB - Currently, there is a growing interest in using entry inhibitors to treat HIV-2 infected patients because, among the available drugs, few are fully active against HIV-2. Recent studies indicate that maraviroc and other experimental entry inhibitors, including new CCR5 and CXCR4 antagonists, inhibit primary isolates of HIV-2 as well as HIV-1 and may, therefore, expand the existing therapeutic armamentarium against HIV-2. There are, however, significant differences between the evolution of HIV-1 and HIV-2 envelope glycoproteins during infection that can lead to differences in the response to therapy with entry inhibitors over the course of the infection. Here, we review the available data on the susceptibility of HIV-2 to entry inhibitors in the context of the evolution of the sequence, structure, and function of envelope glycoproteins during infection. PMID- 23449230 TI - Imported dengue virus serotype 1 from Madeira to Finland 2012. AB - Imported dengue cases originating from the Madeiran outbreak are increasingly reported. In 2012 five Finnish travellers returning from Madeira were diagnosed with dengue fever. Viral sequence data was obtained from two patients. The partial C-preM sequences (399 and 396 bp respectively) were found similar to that of an autochthonous case from Madeira. The partial E-gene sequence (933 bp) which was identical among the two patients grouped phylogenetically with South American strains of dengue virus serotype 1. PMID- 23449231 TI - Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012. AB - On 24 October 2012, a patient with acute respiratory distress syndrome of unknown origin and symptom onset on 5 October was transferred from Qatar to a specialist lung clinic in Germany. Late diagnosis on 20 November of an infection with the novel Coronavirus (NCoV) resulted in potential exposure of a considerable number of healthcare workers. Using a questionnaire we asked 123 identified contacts (120 hospital and three out-of-hospital contacts) about exposure to the patient. Eighty-five contacts provided blood for a serological test using a two-stage approach with an initial immunofluorescence assay as screening test, followed by recombinant immunofluorescence assays and a NCoV-specific serum neutralisation test. Of 123 identified contacts nine had performed aerosol-generating procedures within the third or fourth week of illness, using personal protective equipment rarely or never, and two of these developed acute respiratory illness. Serology was negative for all nine. Further 76 hospital contacts also tested negative, including two sera initially reactive in the screening test. The contact investigation ruled out transmission to contacts after illness day 20. Our two stage approach for serological testing may be used as a template for similar situations. PMID- 23449232 TI - Q fever in humans and farm animals in four European countries, 1982 to 2010. AB - Q fever is a disease of humans, caused by Coxiella burnetii, and a large range of animals can be infected. This paper presents a review of the epidemiology of Q fever in humans and farm animals between 1982 and 2010, using case studies from four European countries (Bulgaria, France, Germany and the Netherlands). The Netherlands had a large outbreak between 2007 and 2010, and the other countries a history of Q fever and Q fever research. Within all four countries, the serological prevalence of C. burnetii infection and reported incidence of Q fever varies broadly in both farm animals and humans. Proximity to farm animals and contact with infected animals or their birth products have been identified as the most important risk factors for human disease. Intrinsic farm factors, such as production systems and management, influence the number of outbreaks in an area. A number of disease control options have been used in these four countries, including measures to increase diagnostic accuracy and general awareness, and actions to reduce spillover (of infection from farm animals to humans) and human exposure. This study highlights gaps in knowledge, and future research needs. PMID- 23449233 TI - Ultrasound as a treatment of mammary blocked duct among 25 postpartum lactating women: a retrospective case series. AB - OBJECTIVE: The purpose of this case series is to report the outcomes of 25 postpartum women who were experiencing difficulties with breastfeeding and were treated using therapeutic ultrasound. METHODS: Case files of postpartum women who presented to a chiropractic clinic between 2005 and 2011 with difficulties with breastfeeding due to blocked ducts were identified. RESULTS: Twenty-five cases were retrospectively identified of women who presented with a breast lump that was consistent with a blocked duct. Eight women experienced recurrent blocked ducts (5 had multiple episodes while nursing the same child; 3 women experienced episodes with more than 1 child). Patients had been treated with therapeutic ultrasound, receiving between 1 and 7 treatments (average, 3.3) to experience improvement in their presenting symptoms. A majority of the patients reported improvements in breastfeeding and symptoms after treatment. No adverse reactions were identified in the patient records. CONCLUSION: For women reported in this case series, chiropractic management including ultrasound therapy was a beneficial treatment for women presenting with blocked ducts and difficulties breastfeeding. PMID- 23449234 TI - Taking a bite out of pain: snake venom can be both a curse and a cure when targeting acid sensing ion channels (ASICs) in the pain pathway. PMID- 23449235 TI - What is an appropriate reference standard in the quantitation of plaque surface area by intravascular coronary ultrasound? AB - We reevaluate the predictive accuracy of intravascular ultrasound (IVUS)-derived per cent plaque area stenosis (PAS) in significant coronary lesions (CLs) with or without proximal and distal reference vessel area adjustment. IVUS is valuable in defining moderate CL severity (30 to 70%) in left main (LM) or non-left main (NLM) coronaries using minimum luminal area (MLA) of <=5.9 and <=4 mm(2), respectively. Despite a strong correlation with severe CLs, PAS (>= 70% for NLM and >=67% for LM) remains underutilized because of confusion about an appropriate reference standard. We studied 120 patients with symptomatic moderate CLs (74 NLM, 46 LM) who underwent IVUS. In-lesion and adjusted PAS were derived by subtracting MLA from in-lesion and proximal or distal reference's external elastic membrane (EEM) area, respectively, divided by corresponding EEM area multiplied by 100. In-lesion PAS was correlated with MLA cutoffs of <=5.9 and <=7.5 mm(2) for LM and <=4 mm(2) for NLM. Adjusted PAS strongly correlated with in-lesion PAS irrespective of reference segment (proximal reference, r = 0.879, p < 0.001; distal reference, r = 0.833, p < 0.001; mean proximal and distal reference, r = 0.896, p < 0.001). Considering MLA of <=4 mm(2) (for NLM) and <=5.9 mm(2) (for LM), in-lesion PAS of >=70 and >=67%, respectively, explained the majority of severe CLs but the sensitive LM MLA cutoff of <=7.5 mm(2) showed higher predictive accuracy. Based on results, both in-lesion PAS and adjusted PAS can be used interchangeably and correlate strongly with MLA. PMID- 23449236 TI - Pulmonary involvement in brucellosis. AB - BACKGROUND: Brucellosis is a zoonotic disease caused by a Gram-negative bacillus of the Brucella genus with multisystem involvement, primarily affecting the reticuloendothelial system, joints, heart and kidneys. Although the disease can be spread by inhalation, pulmonary involvement is rare. OBJECTIVE: To report a case of brucellosis with pulmonary involvement. CASE PRESENTAION: A previously healthy 36-year-old woman was admitted with complaints of fever, weakness, night sweats, dry cough and bilateral chest pain. She hed been diagnosed with pneumonia 20 days previously and was started on a course of ampicillin for 14 days, with no response. Her chest auscultation revealed diminished breath sounds and scattered crackles and rhonchi over the inferior zone of the right hemithorax. Wright and Coombs testing resulted in titres of 1:1280 and 1:640, respectively. Chest radiography revealed an area of confluent lobar consolidation in the right lower lobe. Treatment was started with a six-week course of oral doxycycline 200 mg/day and rifampicin 600 mg/day. This treatment regimen rapidly improved the patient's condition. Follow-up after one year showed no residual effects from the infection. CONCLUSION: Pulmonary involvement is a rare event in the course of brucellosis, but the rate could be higher than currently estimated. In endemic regions, brucellosis should be considered as a causative agent in patients with pulmonary symptoms. BACKGROUND: Brucellosis is a zoonotic disease caused by a Gram-negative bacillus of the Brucella genus with multisystem involvement, primarily affecting the reticuloendothelial system, joints, heart and kidneys. Although the disease can be spread by inhalation, pulmonary involvement is rare. OBJECTIVE: To report a case of brucellosis with pulmonary involvement. CASE PRESENTAION: A previously healthy 36-year-old woman was admitted with complaints of fever, weakness, night sweats, dry cough and bilateral chest pain. She hed been diagnosed with pneumonia 20 days previously and was started on a course of ampicillin for 14 days, with no response. Her chest auscultation revealed diminished breath sounds and scattered crackles and rhonchi over the inferior zone of the right hemithorax. Wright and Coombs testing resulted in titres of 1:1280 and 1:640, respectively. Chest radiography revealed an area of confluent lobar consolidation in the right lower lobe. Treatment was started with a six week course of oral doxycycline 200 mg/day and rifampicin 600 mg/day. This treatment regimen rapidly improved the patient's condition. Follow-up after one year showed no residual effects from the infection. CONCLUSION: Pulmonary involvement is a rare event in the course of brucellosis, but the rate could be higher than currently estimated. In endemic regions, brucellosis should be considered as a causative agent in patients with pulmonary symptoms. PMID- 23449237 TI - Metabolic responses at various intensities relative to critical swimming velocity. AB - To avoid any improper training load, the speed of endurance training needs to be regularly adjusted. Both the lactate threshold (LT) velocity and the velocity corresponding to the maximum lactate steady state (MLSS) are valid and reliable indices of swimming aerobic endurance and commonly used for evaluation and training pace adjustment. Alternatively, critical velocity (CV), defined as the velocity that can be maintained without exhaustion and assessed from swimming performance of various distances, is a valid, reliable, and practical index of swimming endurance, although the selection of the proper distances is a determinant factor. Critical velocity may be 3-6 and 8-11% faster compared with MLSS and LT, respectively. Interval swimming at CV will probably show steady lactate concentration when the CV has been calculated by distances of 3- to 15 minute duration, and this is more evident in adult swimmers, whereas increasing or decreasing lactate concentration may appear in young and children swimmers. Therefore, appropriate corrections should be made to use CV for training pace adjustment. Findings in young and national level adult swimmers suggest that repetitions of distances of 100-400 m, and velocities corresponding to a CV range of 98-102% may be used for pacing aerobic training, training at the MLSS, and possibly training for improvement of VO2max. Calculation of CV from distances of 200-400, 50-100-200-400, or 100-800 m is an easy and practical method to assess aerobic endurance. This review intends to study the physiological responses and the feasibility of using CV for aerobic endurance evaluation and training pace adjustment, to help coaches to prescribe training sets for different age-group swimmers. PMID- 23449238 TI - A systematic review of peer review for scientific manuscripts. AB - BACKGROUND: The usefulness of peer review has been expressed as a method to improve the quality of published work. However, there has been a lack of systematic reviews to date to highlight the essential themes of the peer-review process. METHODS: We performed a search of the English language literature published prior to October 2011 using PubMed to identify articles regarding peer review. Inclusion and exclusion criteria were developed a priori. Data were extracted and then analyzed for the prevalence of peer-review themes contained within the literature. RESULTS: Of the 941 articles found during our original literature search, 37 were selected for review. The majority were commentary/editorial articles. The themes in our search included the structure and process of the peer-review system, the criteria for papers, ethics, and the different forms of the peer-review process. CONCLUSIONS: The criteria for submission will vary, but our systematic review provides a comprehensive overview of what reviewers expect from authors. Our systematic review also highlighted ethical considerations for both authors and reviewers during the peer-review process. Although the topic of peer review is expansive and its process may vary from journal to journal, the understanding of the themes outlined in this paper will help authors recognize how to write a more successful paper. Also, more research must be carried out to establish the efficacy of the different styles of peer review, and it would be presumptuous to draw conclusions until further research is established. PMID- 23449239 TI - The immune response to one-lung-ventilation is not affected by repeated alveolar recruitment manoeuvres in pigs. AB - BACKGROUND: Acute lung injury after thoracic surgery relates to alveolar inflammation induced by one-lung ventilation (OLV) and surgical manipulation. However, alveolar recruitment manoeuvres (ARM), conventional ventilation, and airway manipulation may increase alveolar trauma. This study evaluates pulmonary immune effects of these co-factors in a porcine model. METHODS: Twenty-two piglets (27.3 kg) were randomised to spontaneous breathing (N.=4), two-lung ventilation (TLV, N.=6), OLV with propofol (6 mg/kg/h, N.=6) or desflurane anesthesia (1MAC, N.=6). Mechanical ventilation settings were constant throughout the experiment: VT=10 mL/kg, FIO2=0.4, PEEP=5 cmH2O. OLV was performed by left sided bronchial blockade. Thoracic surgery was simulated for 60 min. ARM (airway pressure of 40 mbar for 10 s) was applied before and after each airway manipulation. Cytokines and mRNA-expression were assessed by immunoassays and semi-quantitative RT-PCR in alveolar lavage fluids, serum and tissue samples prior to and after OLV (TLV in controls). RESULTS: Repetitive ARM and TLV induced no significant proinflammatory effects. OLV enhanced cytokine release but less with desflurane inhalation than propofol infusion (median (IQR) [pg/mL], dependent lung): Interleukin-8: TLV 44 (17) to 68 (35), propofol 82 (17) to 494 (231), desflurane 89 (30) to 282 (44). Likewise, serum cytokines were different: tumour necrosis factor-a: TLV 37 (13) to 62 (7), propofol 55 (39) to 94 (60), desflurane 43 (33) to 41 (25). Expression of interleukin-8-mRNA increased after OLV, but mRNA expression was not modulated by anesthetics. CONCLUSION: ARM, standard TLV and repetitive BAL do not additionally contribute to lung injury resulting from OLV for thoracic surgery in healthy porcine lungs. OLV induces expression of interleukin-8-mRNA in alveolar cells, which is not modulated by different anesthetic drugs. PMID- 23449241 TI - Donation after cardiac death: is a "paradigm shift" feasible in Italy? AB - Donation after cardiac death (DCD) is one of the growing strategies to overcome the problem of organ shortage. Cardiac death is defined as "irreversible cessation of circulatory and respiratory function"; the time interval to define irreversibility of cardiac death, the peculiarity of consent, and the framework of end-of-life decision making are the most compelling ethical issues which have been raised with DCD. National protocols that balance medical, ethical, and social issues are mandatory to guide transplant care professionals. In Italy, the 20 min cardiac arrest demonstrated by continuous electrocardiography recording is the time interval necessary for death diagnosis based on cardiopulmonary criteria. This time negatively affects donation after cardiac death because warm ischemic time (WIT) - the most important predictor of grafts' poor outcome - is prolonged. However, this time seems to be prudential to define the irreversibility of death and to respect the "dead donor rule", as established by the National Committee of Bioethics. National reference protocols regulating DCD practice are therefore a compelling issue. PMID- 23449240 TI - Absent SEP during therapeutic hypothermia did not reappear after re-warming in comatose patients following cardiac arrest. AB - BACKGROUND: Early prediction of neurological outcome for patients resuscitated from cardiac arrest (CA) is a challenging task. Therapeutic hypothermia (TH) has been shown to improve neurological outcome after CA. Two recent studies indicated that somatosensory evoked potentials (SEP) recorded during TH retains high prediction value for poor neurological outcome. It remains unclear whether TH can influence the recovery of bilaterally absent (BA) N20 after re-warming. The primary endpoint of the present study was to evaluate if patients with BA SEPs during TH can recover cortical responses after re-warming. The secondary endpoint was to evaluate whether BA SEPs recorded during TH retains its prediction value for poor neurological outcome as in normothermic patients. METHODS: A single centre prospective cohort study including comatose adults resuscitated from in/out-of-hospital CA treated with TH. SEPs were recorded during TH (6-24 hours after CA) and after re-warming in those patients who remained comatose. Neurological outcome was assessed 6 months after CA using the Glasgow Outcome Scale. RESULTS: Sixty patients were included. In patients with preserved SEP, no significant differences were found between N20 mean amplitude during TH and after re-warming. During TH, 24 patients showed bilaterally absent N20 but none of these recovered cortical responses after re-warming. All patients with absent SEPs during TH did not recover consciousness. CONCLUSIONS: In a single centre cohort of comatose CA patients, our results showed that all patients with absent SEPs during early recording (6-24 hours) during TH showed bilaterally absent SEPs after re-warming. As a secondary result we confirmed previous data that BA SEPs during TH retains its prognostic value for poor neurological outcome, as in normothermic patients. PMID- 23449242 TI - Effects of short sustained lung inflations on cerebral blood flow and cerebral tissue oxygenation in the juvenile rabbit. AB - BACKGROUND: Sustained lung inflations improve oxygenation but may impair hemodynamics. This study aimed to determine effects of short sustained inflations on cerebral blood flow and cerebral tissue oxygenation in experimental lung injury. METHODS: Experiments were performed in 6 juvenile ventilated New Zealand white rabbits. The effects of a series of sustained inflations at 20, 25 and 30 cmH2O pressure for 15 seconds duration each on hemodynamics, cerebral blood flow and cerebral tissue oxygenation were determined by laser Doppler flowmetry and cerebral tissue oxygen tension measurement in naive animals, after surfactant depletion and subsequent fluid filling of the lung. RESULTS: During the series of sustained inflations the mean arterial blood pressure decreased by 73%, 52% and 32% and the mean cerebral blood flow decreased by 73%, 39% and 30% in naive animals, after surfactant depletion and with fluid filling of the lung respectively. Arterial oxygen saturation was maintained or increased, while mean cerebral tissue oxygenation decreased by 48% (naive), 8% (surfactant depletion) or increased by 81% (surfactant depletion and fluid filling). Three minutes after the sustained inflations blood gases were similar to the blood gases prior to the sustained inflations. CONCLUSION: A series of short sustained lung inflations of 15 seconds duration can impair cerebral blood flow but increase arterial oxygen saturation in this juvenile animal model. The combination of these effects resulted in either a decrease or increase in regional cerebral tissue oxygenation. PMID- 23449243 TI - Sleep in the Intensive Care Unit measured by polysomnography. AB - BACKGROUND: Sleep deprivation has deleterious effects on most organ systems. Patients in the Intensive care unit (ICU) report sleep deprivation as the second worst experience during their stay only superseded by pain. The aim of the review is to provide the clinician with knowledge of the optimal sleep-friendly care and environment. METHODS: Pubmed was systematically searched. Studies regarding polysomnography in ICU populations or healthy volunteers exposed to ICU conditions were included. RESULTS: Thirty-eight studies were identified. The patients were qualitatively but not necessarily quantitatively sleep deprived with loss of circadian rhythm and extreme sleep fragmentation. Sedation, care interventions, noise, disease and mechanical ventilation are the most contributing factors to sleep deprivation. CONCLUSION: Sedation should be kept at a minimum and interrupted once daily. Care interventions should be clustered and noise reduced and/or masked with earplugs. NAVA, proportional assist+ or assist control ventilation should be preferred to pressure support ventilation and adjusted to allow smaller tidal volumes, thus avoiding central apnoeas. PMID- 23449244 TI - Routine screening and anticipation of difficult airways in the critical care setting. PMID- 23449245 TI - Percutaneous radiofrequency left cardiac sympathetic denervation for refractory ventricular arrhythmogenic storms: a report of three cases. PMID- 23449246 TI - Late respiratory failure after hematopoietic stem cells transplant: just "lung failure"? PMID- 23449247 TI - Paradoxical air embolism after cardiac computed tomography scan. PMID- 23449248 TI - Esophageal rupture due to a piece of meat in an epidermolysis bullosa patient. PMID- 23449249 TI - Effectiveness of helmet non-invasive ventilation with external PEEP valves: key remains inside the helmet. PMID- 23449250 TI - Reply to "Further studies should compare the different tidal volume with adjusted PEEP levels at the same time of anesthesia". PMID- 23449251 TI - Management of intensive care patients with open abdomen: evidence warranted. PMID- 23449252 TI - Prediction of compatibility between ozagrel sodium preparation for injection and calcium on the basis of the solubility product. AB - The purpose of the study was to evaluate the compatibility of ozagrel sodium solution and calcium-containing transfusions using solubility product constants. We calculated the solubility product constant of mixtures of ozagrel sodium and calcium chloride and evaluated the compatibility of ozagrel sodium solution (both the original and generic products) with calcium chloride solution using a light obscuration particle counter. Various volumes of ozagrel solution were added to the calcium solutions to make final ozagrel concentrations of 0, 0.8, 1.6, 2.0, 2.4, 3.2 and 4.0 mmol/L. The solutions were gently agitated and stored at 25 and 40 degrees C. The ozagrel concentration, calcium ion concentration and number of microparticles were measured. The solubility product constants obtained were 11.89*10(-9) mol(3)/L(3) (at 25 degrees C) and 7.82*10(-9) mol(3)/L(3) (40 degrees C). The number of insoluble microparticles was significantly increased when the ionic product was larger than the solubility product constant. In all ozagrel sodium products, the number of insoluble microparticles was within the allowable range according to the Japanese Pharmacopoeia. These results suggest that mixing ozagrel sodium with calcium-containing products is safe and without appreciable risk of incompatibility under clinical conditions. PMID- 23449253 TI - Using ProtMAX to create high-mass-accuracy precursor alignments from label-free quantitative mass spectrometry data generated in shotgun proteomics experiments. AB - Recently, new software tools have been developed for improved protein quantification using mass spectrometry (MS) data. However, there are still limitations especially in high-sample-throughput quantification methods, and most of these relate to extensive computational calculations. The mass accuracy precursor alignment (MAPA) strategy has been shown to be a robust method for relative protein quantification. Its major advantages are high resolution, sensitivity and sample throughput. Its accuracy is data dependent and thus best suited for precursor mass-to-charge precision of ~1 p.p.m. This protocol describes how to use a software tool (ProtMAX) that allows for the automated alignment of precursors from up to several hundred MS runs within minutes without computational restrictions. It comprises features for 'ion intensity count' and 'target search' of a distinct set of peptides. This procedure also includes the recommended MS settings for complex quantitative MAPA analysis using ProtMAX (http://www.univie.ac.at/mosys/software.html). PMID- 23449256 TI - Exact solution for square-wave grating covered with graphene: surface plasmon polaritons in the terahertz range. AB - We provide an analytical solution to the problem of scattering of electromagnetic radiation by a square-wave grating with a flat graphene sheet on top. We show that for deep groves there is a strong plasmonic response, with light absorption in the graphene sheet reaching more than 45% due to the excitation of surface plasmon-polaritons. The case of a grating with a graphene sheet presenting an induced periodic modulation of the conductivity is also discussed. PMID- 23449254 TI - Merging high-quality biochemical fractionation with a refined flow cytometry approach to monitor nucleocytoplasmic protein expression throughout the unperturbed mammalian cell cycle. AB - This protocol describes a method for nucleocytoplasmic protein tracking during normal cell cycle progression using unmanipulated, asynchronous cells. In contrast with prevalent traditional methods, our approach does not require time consuming, perturbing cell synchronization or separation. To this end, we chose a single-cell approach and developed a flow cytometry assay that is applied to whole cells and isolated nuclei. Our protocol involves a stepwise biochemical fractionation procedure to purify nuclei from whole cells, conventional DNA and indirect immunostaining techniques for the dual labeling of cells and nuclei for DNA and protein, and a refined concept of flow cytometric data processing and calculation: through the specific combination of DNA and cell size analyses, G1, S and G2/M phases of the cell cycle are further dissected to establish a high resolution map of cell cycle progression, to which protein expression in cells or nuclei is correlated. In a final data analysis step, cell cycle-related, cytoplasmic protein expression is calculated on the basis of results obtained for whole cells and isolated nuclei. A minimum of 8 h is required to complete the procedure. As the approach does not require cell type-restricting pretreatments, numerous cell types of different origin can be readily studied. Human amniotic fluid stem cells, primary human fibroblasts, immortalized mouse fibroblasts and transformed tumor cells are analyzed at comparable efficiencies, demonstrating low intercell assay variability. PMID- 23449255 TI - Mouse model of chronic and binge ethanol feeding (the NIAAA model). AB - Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption. PMID- 23449257 TI - Peripheral odontogenic myxoma: a review of the literature and report of two cases. AB - Two cases of peripheral odontogenic myxoma with a verifiable location in gingival soft tissue and without bone involvement were compared with those reported in the literature. This study showed that they form a distinct albeit rare clinical entity with a potential to grow into large disfiguring lesions. The probability that small peripheral odontogenic myxomas are interpreted as edematous irritation fibromas may contribute to the small number of peripheral odontogenic myxomas recorded in the literature. The differential diagnosis of soft tissue myxoid proliferations is discussed. PMID- 23449258 TI - Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. AB - BACKGROUND AND PURPOSE: A novel association between a single nucleotide polymorphism on chromosome 7p21.1 and large-vessel ischemic stroke was recently identified. The most likely underlying gene is histone deacetylase 9 (HDAC9). The mechanism by which HDAC9 increases stroke risk is not clear; both vascular and neuronal mechanisms have been proposed. METHODS: We determined whether the lead single nucleotide polymorphisms were associated with asymptomatic carotid plaque (N=25 179) and carotid intima-media thickness (N=31 210) detected by carotid ultrasound in a meta-analysis of population-based and community cohorts. Immunohistochemistry was used to determine whether HDAC9 was expressed in healthy human cerebral and systemic arteries. In the Tampere Vascular Study, we determined whether HDAC9 mRNA expression was altered in carotid (N=29), abdominal aortic (N=15), and femoral (N=24) atherosclerotic plaques compared with control (left internal thoracic, N=28) arteries. RESULTS: Both single nucleotide polymorphisms (rs11984041 and rs2107595) were associated with common carotid intima-media thickness (rs2107595; P=0.0018) and with presence of carotid plaque (rs2107595; P=0.0022). In both cerebral and systemic arteries, HDAC9 labeling was seen in nuclei and cytoplasm of vascular smooth muscle cells, and in endothelial cells. HDAC9 expression was upregulated in carotid plaques compared with left internal thoracic controls (P=0.00000103). It was also upregulated in aortic and femoral plaques compared with controls, with mRNA expression increased in carotid compared with femoral plaques (P=0.0038). CONCLUSIONS: Our results are consistent with the 7p21.1 association acting via promoting atherosclerosis, and consistent with alterations in HDAC9 expression mediating this increased risk. Further studies in experimental models are required to confirm this link. PMID- 23449259 TI - Accuracy of diffusion-weighted imaging in the diagnosis of stroke in patients with suspected cerebral infarct. AB - BACKGROUND AND PURPOSE: The accuracy of diffusion-weighted imaging (DWI) for the diagnosis of acute cerebral ischemia among patients with suspected ischemic stroke arriving to an emergency room has not been studied in depth. METHODS: DWI was performed in 712 patients with acute or subacute focal symptoms that suggested an acute ischemic stroke (AIS), 609 of them with AIS. RESULTS: DWI demonstrated a sensitivity of 90% and specificity of 97%, a positive likelihood ratio of 31 and a negative likelihood ratio of 0.1 for detecting AIS. The overall accuracy was 95%. Of those patients who demonstrated abnormal DWI studies, 99.5% were AIS patients, and of those patients with normal DWI studies 63% were stroke mimics. CONCLUSIONS: DWI is accurate in detecting AIS in unselected patients with suspected AIS; a negative study should alert for nonischemic conditions. PMID- 23449260 TI - Comparative effectiveness of unruptured cerebral aneurysm therapies: propensity score analysis of clipping versus coiling. AB - BACKGROUND AND PURPOSE: Endovascular therapy has increasingly become the most common treatment for unruptured cerebral aneurysms in the United States. We evaluated a national, multi-hospital database to examine recent utilization trends and compare periprocedural outcomes between clipping and coiling treatments of unruptured aneurysms. METHODS: The Premier Perspective database was used to identify patients hospitalized between 2006 to 2011 for unruptured cerebral aneurysm who underwent clipping or coiling therapy. A logistic propensity score was generated for each patient using relevant patient, procedure, and hospital variables, representing the probability of receiving clipping. Covariate balance was assessed using conditional logistic regression. Following propensity score adjustment using 1:1 matching methods, the risk of in hospital mortality and morbidity was compared between clipping and coiling cohorts. RESULTS: A total of 4899 unruptured aneurysm patients (1388 clipping, 3551 coiling) treated at 120 hospitals were identified. Following propensity score adjustment, clipping patients had a similar likelihood of in-hospital mortality (odds ratio [OR], 1.43; 95% confidence interval [CI], 0.49-4.44; P=0.47) but a significantly higher likelihood of unfavorable outcomes, including discharge to long-term care (OR, 4.78; 95% CI, 3.51-6.58; P<0.0001), ischemic complications (OR, 3.42; 95% CI, 2.39-4.99; P<0.0001), hemorrhagic complications (OR, 2.16; 95% CI, 1.33-3.57; P<0.0001), postoperative neurological complications (OR, 3.39; 95% CI, 2.25-5.22; P<0.0001), and ventriculostomy (OR, 2.10; 95% CI, 1.01-4.61; P=0.0320) compared with coiling patients. CONCLUSIONS: Among patients treated for unruptured intracranial aneurysms in a large sample of hospitals in the United States, clipping was associated with similar mortality risk but significantly higher periprocedural morbidity risk compared with coiling. PMID- 23449261 TI - Higher ambulatory blood pressure relates to new cerebral microbleeds: 2-year follow-up study in lacunar stroke patients. AB - BACKGROUND AND PURPOSE: Elevated blood pressure (BP) is associated with the presence of cerebral microbleeds (CMBs) in cross-sectional studies. However, longitudinal studies did not show a convincing relationship. We aimed to determine the association between elevated BP levels and the occurrence of new CMBs after a 2-year follow-up in first-ever lacunar stroke patients using ambulatory BP monitoring. METHODS: Ninety-six first-ever lacunar stroke patients underwent brain MRI and ambulatory BP monitoring at baseline and after 2-year follow-up. We used logistic regression analyses to assess the association of BP levels with new CMBs. RESULTS: We found new CMBs in 17 patients (18%). Higher 24 hour, day and night systolic BP (odds ratio, 2.69; 95% confidence interval, 1.40 5.21 per SD increase for 24-hour BP) and diastolic BP (odds ratio, 2.13; 95% confidence interval, 1.15-3.90 per SD increase for 24-hour BP) at baseline were associated with the development of new CMBs independent of age and sex. BP levels decreased during follow-up in both patients with and without new CMBs. Unlike BP levels at baseline, there was no difference in BP levels at follow-up between patients with and without new CMBs. CONCLUSIONS: Both higher systolic and diastolic BP levels were associated with the development of new CMBs in a population of lacunar stroke patients. Decrease of BP levels during follow-up did not halt progression of CMBs; however, it remains to be determined whether (early) intervention with antihypertensive drugs can slow down progression of CMBs. PMID- 23449262 TI - Reporting of aspiration pneumonia or choking as a cause of death in patients who died with stroke. AB - BACKGROUND AND PURPOSE: It is not known how many stroke patients die from fatal pulmonary complications such as aspiration pneumonia (AP) and choking each year in the United States. This study aimed to determine the frequency of reporting of AP or choking as a cause of death on death certificates with mention of stroke in the United States as a proxy measure of the incidence of dying from AP or choking among patients with stroke. METHODS: We used multiple-cause mortality data for the years 2001 to 2010 to identify death certificates with mention of stroke (International Classification of Diseases, Tenth Revision code I60-I69), AP (International Classification of Diseases, Tenth Revision code J69), and choking (International Classification of Diseases, Tenth Revision code W78-W80) for analysis. RESULTS: Of 2 424 379 death certificates with mention of stroke in the United States between 2001 and 2010, 5.1% (n=124 503) reported AP as a cause of death, and 1.5% (n=36 997) reported choking as a cause of death. However, if we confined the analysis to autopsy-confirmed cases, the frequency decreased to 1.3% (555/42 732) and 1.3% (541/42 732), respectively. The adjusted odds ratios of reporting AP or choking as a cause of death were higher among men, increased with age, and were higher among decedents who died in a nursing home/long-term care. CONCLUSIONS: The estimated incidence of dying from AP and choking among patients who died with stroke was 5% (~12 000 deaths per year) and 1% (~3700 deaths per year) according to information reported on death certificates. Efforts are needed to reduce the number of deaths from these 2 preventable complications. PMID- 23449263 TI - Coronary artery calcification is an independent stroke predictor in the general population. AB - BACKGROUND AND PURPOSE: Coronary artery calcification (CAC) is a noninvasive marker of plaque load that predicts myocardial infarcts in the general population. Herein, we investigated whether CAC predicts stroke events in addition to established risk factors that are part of the Framingham risk score. METHODS: A total of 4180 subjects from the population-based Heinz Nixdorf Recall study (45-75 years of age; 47.1% men) without previous stroke, coronary heart disease, or myocardial infarction were evaluated for stroke events over 94.9 +/- 19.4 months. Cox proportional hazards regressions were used to examine CAC as stroke predictor in addition to established vascular risk factors (age, sex, systolic blood pressure, low-density lipoprotein, high-density lipoprotein, diabetes mellitus, smoking, and atrial fibrillation). RESULTS: Ninety-two incident strokes occurred (82 ischemic, 10 hemorrhagic). Subjects suffering a stroke had significantly higher CAC values at baseline than the remaining subjects (median, 104.8[Q1;Q3, 14.0;482.2] vs 11.2[0;106.2]; P<0.001). In a multivariable Cox regression, log10(CAC+1) was an independent stroke predictor (hazards ratio, 1.52 [95% confidence interval, 1.19-1.92]; P=0.001) in addition to age (1.35 per 5 years [1.15-1.59]; P<0.001), systolic blood pressure (1.25 per 10 mm Hg [1.14-1.37]; P<0.001), and smoking (1.75 [1.07-2.87]; P=0.025). CAC predicted stroke in men and women, particularly in subjects <65 years of age and independent of atrial fibrillation. CAC discriminated stroke risk specifically in participants belonging to the low (<10%) and intermediate (10%-20%) Framingham risk score categories. CONCLUSIONS: CAC is an independent stroke predictor in addition to classical risk factors in subjects at low or intermediate vascular risk. PMID- 23449264 TI - Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. AB - BACKGROUND AND PURPOSE: A significant number of patients with cryptogenic stroke suffer from intermittent atrial fibrillation (iAF) which was not detected during the standard diagnostic procedures. We investigated whether implantation of an insertable cardiac monitor (ICM) is feasible in patients with cryptogenic stroke, and compared the iAF detection rate of the ICM with 7-day Holter monitoring. METHODS: Sixty patients (median age 63; interquartile range, 48.5-72 years) with acute cryptogenic stroke were included. ICM was implanted 13 days (interquartile range; 10-65 days) after the qualifying event. Seven-day Holter was performed after the ICM was implanted. RESULTS: The iAF was detected by the ICM in 10 patients (17%; 95% CI, 7% to 26%). Only 1 patient (1.7%; 95% CI, 0% to 5%) had iAF during 7-day Holter monitoring as well (P=0.0077). Episodes of iAF lasting 2 minutes or more were detected 64 (range, 1-556) days after implantation. There were no recurrent strokes during the observation period. The implantation procedure was well tolerated with no adverse events; the daily data transmission protocol was easy to handle by the patients. CONCLUSIONS: ICM implantation for the detection of iAF during outpatient follow-up is feasible in patients with cryptogenic stroke. ICMs offer a much higher diagnostic yield than 7-day Holter monitoring. PMID- 23449265 TI - Human umbilical vein endothelial cells protect against hypoxic-ischemic damage in neonatal brain via stromal cell-derived factor 1/C-X-C chemokine receptor type 4. AB - BACKGROUND AND PURPOSE: Agents that protect against neurovascular damage provide a powerful neuroprotective strategy. Human umbilical vein endothelial cells (HUVECs) may be used to treat neonates with hypoxic-ischemia (HI) because of its autologous capability. We hypothesized that peripherally injected HUVECs entered the brain after HI, protected against neurovascular damage, and provided protection via stromal cell-derived factor 1/C-X-C chemokine receptor type 4 pathway in neonatal brain. METHODS: Postpartum day 7 rat pups received intraperitoneal injections of low-passage HUVEC-P4, high-passage HUVEC-P8, or conditioned medium before and immediately after HI. HUVECs were transfected with adenovirus-green fluorescent protein for cell tracing. Oxygen-glucose deprivation was established by coculturing HUVEC-P4 with mouse neuroblastoma neuronal cells (Neuro-2a) and with mouse immortalized cerebral vascular endothelial cells (b.End3). RESULTS: HUVEC-P4-treated group had more blood levels of green fluorescent protein-positive cells than HUVEC-P8-treated group 3 hours postinjection. Intraperitoneally injected HUVEC-P4, but not HUVEC-P8, entered the cortex after HI and positioned closed to the neurons and microvessels. Compared with the condition medium-treated group, the HUVEC-P4-treated but not the HUVEC P8-treated group showed significantly less neuronal apoptosis and blood-brain barrier damage and more preservation of microvessels in the cortex 24 hours after HI. On postpartum day 14, the HUVEC-P4-treated group showed significant neuroprotection compared with the condition medium-treated group. Stromal cell derived factor 1 was upregulated in the ipsilateral cortex 3 hours after HI, and inhibiting the stromal cell-derived factor 1/C-X-C chemokine receptor type 4 reduced the protective effect of HUVEC-P4. In vitro transwell coculturing of HUVEC-P4 also significantly protected against oxygen-glucose deprivation cell death in neurons and endothelial cells. CONCLUSIONS: Cell therapy using HUVECs may provide a powerful therapeutic strategy in treating neonates with HI. PMID- 23449266 TI - Development of a point-based prediction model for the incidence of total stroke: Japan public health center study. AB - BACKGROUND AND PURPOSE: An individualized risk score for the development of stroke may be a useful tool to motivate patients to modify their risk behaviors. We developed and validated a point-based prediction model (risk score) for stroke incidence using a Japanese cohort of general men and women. METHODS: The Japan Public Health Center-based prospective study cohort II (age range, 40-69 years at baseline in 1993-1994; n=15 672) was used to derive the point-based model according to Cox regression results. The model was externally validated using the Japan Public Health Center study cohort I and also by bootstrap methods within cohort II. The model discrimination was evaluated by the area under the receiver operating characteristic curve, model calibration, by the Gronnesby-Borgan chi(2) statistic. Vascular age was also calculated. RESULTS: During 14 years of follow up, 790 incident stroke cases occurred. Variables selected for the model were age, sex, current smoking, body mass index, blood pressure, antihypertensive medication use, and diabetes mellitus. Interactions of sex with current smoking and of antihypertensive medication use with systolic blood pressure were statistically significant. The point-based model discriminated reasonably well (area under the receiver operating characteristic curve, 0.73). The area under the receiver operating characteristic curve of the point-based model applied externally to cohort I was reasonably good: 0.69. A 50-year-old man with diabetes mellitus and hypertension has an estimated vascular age of 69 years. High normal blood pressure and grade 1 hypertension accounted for one third of the stroke incidence. CONCLUSIONS: We developed score to predict 10-year stroke risk using variables that are easily available in the community setting. PMID- 23449267 TI - Complete early reversal of diffusion-weighted imaging hyperintensities after ischemic stroke is mainly limited to small embolic lesions. AB - BACKGROUND AND PURPOSE: Case reports have demonstrated complete early reversal of hyperintensities on diffusion-weighted imaging (DWI) after clinically diagnosed stroke. We aimed to investigate systematically the rate and characteristics of reversible diffusion hyperintensities (RDHs) in the first week after stroke. METHODS: Patients with clinical diagnosis of an acute cerebrovascular event and evidence of ischemia on DWI were included. MRI scans were performed on admission, on the following day, and 4 to 7 days after onset of symptoms with DWI and fluid attenuated inversion recovery. Baseline and follow-up DWIs were coregistered and examined for individual RDHs. Characteristics of patients and of hyperintensities associated with early reversal were identified. RESULTS: We included 153 patients with a median National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-8). In 3 patients (2%), MR images normalized completely. Thirty-seven patients (24%) displayed individual RDHs. Of 611 initial DWI hyperintensities, 97 (16%) reversed. Thirteen percent of the RDHs had corresponding abnormalities on fluid-attenuated inversion recovery images at the third measurement. Median size of the RDHs was 0.029 mL (interquartile range, 0.013-0.055). RDHs were associated with a multiple infarct pattern (odds ratio, 22.1; 95% confidence interval, 4.5-109.7) and symptomatic carotid stenosis (odds ratio, 5.5; 95% confidence interval, 1.4-21.5). Fifty-nine percent of the patients with RDHs had new additional lesions on follow-up DWI. RDHs were not associated with functional improvement on the National Institutes of Health Stroke Scale score. CONCLUSIONS: In this population of mainly minor to moderate stroke patients, complete normalization of MR images was rare. Complete reversal of individual DWI hyperintensities was limited to very small lesions and mostly occurred in embolic stroke patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715533. PMID- 23449268 TI - HLA-DP and IL28B polymorphisms: influence of host genome on hepatitis B surface antigen seroclearance in chronic hepatitis B. AB - BACKGROUND: The roles of single-nucleotide polymorphisms (SNPs) at HLA-DP and IL28B loci on hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B (CHB) infection are unknown. METHODS: We compared the HLA-DP (rs3077, rs9277378, rs3128917) and IL28B (rs12979860, rs8099917) polymorphisms of 203 CHB patients achieving spontaneous HBsAg seroclearance with 203 age- and sex-matched CHB patients without HBsAg seroclearance (controls). RESULTS: The distribution of all 5 polymorphisms was in Hardy-Weinberg equilibrium. HLA-DP rs3077 was associated with HBsAg seroclearance in terms of allelic frequency (minor allele A vs major allele G, P = .035; odds ratio [OR], 0.699; 95% confidence interval [CI], .501-.976) and genotypic frequency (AA vs GG/GA, P = .014; OR, 0.295; 95% CI, .106-.822). Haplotype analysis of HLA-DP polymorphisms showed haplotype block GAT (rs3077/rs9277378/rs3128917) to be associated with HBsAg seroclearance (OR, 2.17; 95% CI, 1.06-4.45, P = .034). Influence of HLA-DP polymorphisms on HBsAg seroclearance was more pronounced in younger patients, with the OR for rs3077 minor allele A and haplotype block GAT being 0.560 and 2.68, respectively, among patients aged <50 years (P = .027 and P = .047, respectively). IL28B haplotype block CG (rs12979860/rs8099917) was associated with HBsAg seroclearance (OR, 10.5, P = .026). None of the 5 polymorphisms influenced anti-HBs positivity among patients achieving HBsAg seroclearance, or serum HBV DNA and HBsAg titers among controls (P > .05). CONCLUSIONS: Specific SNPs in HLA-DP and IL28B locus, through individual and haplotype analysis, were associated with a higher chance of HBsAg seroclearance in CHB infection. The associations were more prominent in patients with HBsAg seroclearance at a younger age. PMID- 23449269 TI - Effectiveness of influenza vaccine for preventing laboratory-confirmed influenza hospitalizations in adults, 2011-2012 influenza season. AB - During the 2011-2012 influenza season, we enrolled hospitalized adults with acute respiratory illness and tested each for influenza using reverse transcription polymerase chain reaction. Influenza vaccination was verified in 35% (6/17) of adults with influenza-associated hospitalizations compared to 64% (97/152) of test-negative controls; adjusted vaccine effectiveness was 71.4% (95% confidence interval, 17.1%-94.9%). PMID- 23449270 TI - First-line antiretroviral therapy and changes in lipid levels over 3 years among HIV-infected adults in Tanzania. AB - BACKGROUND: With the rapid rollout of antiretroviral therapy (ART) in sub-Saharan Africa (SSA), there has been an increasing concern about cardiovascular risks related to ART. However, data from human immunodeficiency virus (HIV)-infected populations from this region are very limited. METHODS: Among 6385 HIV-infected adults in Dar es Salaam, Tanzania, we investigated the nonfasting lipid changes over 3 years following ART initiation and their associations with different first line ART agents that are commonly used in SSA. RESULTS: In the first 6 months of ART, the prevalence of dyslipidemia decreased from 69% to 54%, with triglyceride (TG) decreasing from 127 mg/dL to 113 mg/dL and high-density lipoprotein (HDL) cholesterol increasing from 39 mg/dL to 52 mg/dL. After 6 months, TG returned to its baseline level and increased to 139 mg/dL at 3 years; total cholesterol and low-density lipoprotein cholesterol continued to increase whereas HDL cholesterol leveled off. The prevalence of dyslipidemia increased to 73% after a 3-year follow-up. In multivariate analyses, patients on zidovudine-containing regimens had a greater reduction in TG levels at 6 months (-16.0 vs -6.3 mg/dL), and a lower increase at 3 years compared to patients on stavudine-containing regimens (2.1 vs 11.7 mg/dL, P < .001); patients on nevirapine-based regimens had a higher increase in HDL cholesterol levels at 3 years compared to those on efavirenz based regimens (13.6 vs 9.5 mg/dL, P = .01). CONCLUSIONS: Our findings support the latest World Health Organization guidelines on the substitution of stavudine in first-line ART in resource-limited settings, and provide further evidence for selection of lipid-friendly ART for patients in SSA. PMID- 23449271 TI - Early high-dose daptomycin for methicillin-resistant Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentrations: ready for prime time? PMID- 23449272 TI - Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study. AB - BACKGROUND: Recent reports have described decreased effectiveness with vancomycin treatment for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) when the vancomycin minimum inhibitory concentration (MIC) is >1 ug/mL. METHODS: This matched, retrospective cohort study compared the clinical effectiveness of daptomycin with that of vancomycin for the treatment of MRSAB with vancomycin MICs >1 ug/mL. The primary outcome was clinical failure, defined as a composite of 30-day mortality or bacteremia persisting for >=7 days. RESULTS: One hundred seventy patients were matched 1:1 with respect to the antimicrobial administered. In the daptomycin group, all patients received <72 hours of vancomycin (median, 1.7 days [interquartile range, 1.1-2.3 days]) prior to switching to daptomycin. The rate of clinical failure at 30 days was significantly lower in the daptomycin arm compared to the vancomycin arm (20.0% vs 48.2%; P < 0.001). Both 30-day mortality and persistent bacteremia were significantly lower in the daptomycin group compared to the vancomycin group (3.5% vs 12.9% [P = .047] and 18.8% vs 42.4% [P = .001], respectively). Logistic regression confirmed the association between vancomycin treatment and increased risk of clinical failure (adjusted odds ratio, 4.5; 95% confidence interval, 2.1-9.8). CONCLUSIONS: This is the first matched study comparing early daptomycin versus vancomycin for the treatment of MRSAB when the vancomycin MIC is >1 ug/mL. Treatment with daptomycin resulted in significantly improved outcomes, including decreased 30-day mortality and persistent bacteremia. These results support the practice of switching early from vancomycin to daptomycin for the treatment of MRSAB when the vancomycin MIC is >1 ug/mL. PMID- 23449273 TI - A first record of obligate halophilic aspergilli from the dead sea. AB - The isolation of obligate halophilic aspergilli from the Dead Sea and the range of salt tolerance of halophilic fungi isolated, are reported here for the first time. The mycobiota of the Dead Sea isolated in this study, was dominated by Aspergillus and Penicillium species; Cladosporium were found in lesser numbers. All three genera were obtained from the water sample; however, Aspergillus was the only genus obtained from the sediment. There was significant difference in growth of each isolate at different salt concentrations and intraspecies analysis revealed dissimilarity in response of strains to different salt concentrations in the growth medium The isolates were euryhaline, with halotolerance up to 20-25% solar salt, Aspergillus and Penicillium species showing a higher level of halotolerance, as compared to that of Cladosporium. Halophilic fungi were found in greater numbers in the sediment sample as compared to that in the water sample. Penicillium and Cladosporium species were exclusively facultative halophiles, while some species of Aspergillus were facultative halophiles. All the obligate halophiles isolated, belonged to the genus Aspergillus and were identified as A. penicillioides and A unguis, the latter being a first record of the species from the Dead Sea. PMID- 23449274 TI - Advances and challenges in the management of acute colonic pseudo-obstruction (ogilvie syndrome). AB - Although acute colonic pseudo-obstruction (ACPO), also known as Ogilvie syndrome, is a well-known clinical entity, in many respects it remains poorly understood and continues to challenge physicians and surgeons alike. Our understanding of ACPO continues to evolve and its epidemiology has changed as new conditions have been identified predisposing to ACPO with critical illness providing the common thread among them. A physician must keep ACPO high in the list of differential diagnoses when dealing with the patient experiencing abdominal distention, and one must be prepared to employ and interpret imaging studies to exclude mechanical obstruction. Rapid diagnosis is the key, and institution of conservative measures often will lead to resolution. Fortunately, when this fails pharmacologic intervention with neostigmine often proves effective. However, it is not a panacea: consensus on dosing does not exist, administration techniques vary and may impact efficacy, contraindications limit its use, and persistence and or recurrence of ACPO mandate continued search for additional medical therapies. When medical therapy fails or is contraindicated, endoscopy offers effective intervention with advanced techniques such as decompression tubes or percutaneous endoscopic cecostomy providing effective results. Operative intervention remains the treatment of last resort; surgical outcomes are associated with significant morbidity and mortality. Therefore, a surgeon should be aware of all options for decompression-conservative, pharmacologic, and endoscopic-and use them in best combination to the advantage of patients who often suffer from significant concurrent illnesses making them poor operative candidates. PMID- 23449275 TI - Peripheral blood mononuclear cell membrane fluidity and disease outcome in patients with multiple sclerosis. AB - Immune cell membrane lipids are important determinants of membrane fluidity, eicosanoid production and phagocytosis and fatty acid metabolic abnormalities have been reported in immune cells from patients with multiple sclerosis. The aim of this study was to investigate the relationship between peripheral blood mononuclear cell membrane fluidity, permeability status, and disease outcome as measured by the Kurtzke expanded disability status scale. Phospholipids, fatty acids and cholesterol composition in peripheral blood mononuclear cells from 26 patients diagnosed with multiple sclerosis and 25 healthy control subjects were determined by colorimetric assay, gas chromatography and enzymatic assays, respectively. Membrane fluidity was calculated according to previously established formulae and correlated with C-reactive protein and the Kurtzke expanded disability status scale. There were no significant differences in membrane lipids in peripheral blood mononuclear cells from patients and controls. However, correlation studies showed lipid metabolic abnormalities, which were reflected in significant correlations between membrane fluidity as measured by both its fatty acid and phospholipid compositions, and the functional system scores. C-reactive protein showed positive correlations with phosphatidylcholine, phosphatidylserine, phosphatidylinositol and total phospholipids in membranes from control subjects. Metabolic abnormalities, as well as correlations between membrane fluidity and the functional system scores, suggested the involvement of these immune cell membranes in the disease progression. Furthermore, the changed relationship between membrane phospholipids and C-reactive protein, which has been shown to correlate with infectious episodes and clinical relapse, could be an indication of immune cell dysfunction in patients with multiple sclerosis. PMID- 23449276 TI - Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma. AB - BACKGROUND: Malignant mesothelioma is a highly aggressive tumor arising from mesothelial-lined surfaces, most often in the pleura cavities. Antifolates belong to the most effective cytotoxic drugs for malignant pleural mesothelioma (MPM) treatment. Pemetrexed is an antifolate inhibiting different folate pathway genes (thymidylate synthase [TS], dihydrofolate reductase, glycinamide ribonucleotide formyltransferase [GARFT], and aminoimidazole carboxamide ribonucleotide formyltransferase, [AICARFT]). Increased activity of pemetrexed occurs by folylpolyglutamate synthetase (FPGS), intracellular transport by reduced folate carrier (RFC). The aim of the study was to explore potential correlations between TS, GARFT, AICARFT, RFC, and FPGS levels in MPM and associations with clinical benefit from pemetrexed treatment. METHODS: Samples from 63 patients were tested using immunohistochemistry (IHC) and quantitative polymerase chain reaction(qPCR) for expression levels of TS, GARFT, AICARFT, RFC, and FPGS. Clinical data were evaluated to determine associations between efficacy of pemetrexed and enzyme expression levels. Evaluation of expression levels was done through TaqMan-based qPCR, and IHC was evaluated semiquantitatively by using the H-score. RESULTS: qPCR analysis showed no difference in expression pattern of GARFT and AICARFT. IHC analysis revealed a heterogeneous staining pattern for all the enzymes. No significant association was found between TS expression and survival or objective response of the tumors after pemetrexed treatment. FPGS (p = 0.0111) and RFC (p = 0.0088) mRNA expression levels were strongly associated with overall survival in these patients. CONCLUSIONS: Our results reveal that in pemetrexed-treated MPMs TS expression levels have no influence on patient outcome. Furthermore, GARFT and AICARFT were homogeneously expressed in the patient samples. Folate uptake mechanisms by RFC and activation by FPGS were associated with clinical benefit from pemetrexed treatment. PMID- 23449277 TI - MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: molecular analysis of 25 ALK-positive cases. AB - INTRODUCTION: Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization. METHODS: Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets. RESULTS: Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested. CONCLUSIONS: In summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed. PMID- 23449278 TI - Quantum dynamical simulations of local field enhancement in metal nanoparticles. AB - Field enhancements (Gamma) around small Ag nanoparticles (NPs) are calculated using a quantum dynamical simulation formalism and the results are compared with electrodynamic simulations using the discrete dipole approximation (DDA) in order to address the important issue of the intrinsic atomistic structure of NPs. Quite remarkably, in both quantum and classical approaches the highest values of Gamma are located in the same regions around single NPs. However, by introducing a complete atomistic description of the metallic NPs in optical simulations, a different pattern of the Gamma distribution is obtained. Knowing the correct pattern of the Gamma distribution around NPs is crucial for understanding the spectroscopic features of molecules inside hot spots. The enhancement produced by surface plasmon coupling is studied by using both approaches in NP dimers for different inter-particle distances. The results show that the trend of the variation of Gamma versus inter-particle distance is different for classical and quantum simulations. This difference is explained in terms of a charge transfer mechanism that cannot be obtained with classical electrodynamics. Finally, time dependent distribution of the enhancement factor is simulated by introducing a time dependent field perturbation into the Hamiltonian, allowing an assessment of the localized surface plasmon resonance quantum dynamics. PMID- 23449280 TI - Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge. AB - BACKGROUND: Hospitalized carriers of carbapenem-resistant Enterobacteriaceae (CRE) are cohorted under contact precautions, including in the days between rehospitalization and surveillance culture results. This study investigates duration of CRE carriage to define populations requiring precautions upon readmission. METHODS: Patients with CRE-positive culture during 2009-2010 were followed up by rectal swab cultures taken retrospectively and prospectively for the study or as part of clinical follow-up. RESULTS: One hundred thirty-seven patients met the inclusion criteria, with follow-up cultures obtained from 97. Mean time to CRE negativity was 387 days (95% confidence interval: 312-463). Seventy-eight percent of patients (64/82) had positive culture at 3 months, 65% (38/58) at 6 months, and 39% (12/30) at 1 year. Duration of carriage was affected by repeat hospitalization (P = .001) and clinical, as opposed to surveillance, culture (P = .002). CONCLUSION: CRE carriers from a previous hospitalization have a lower probability of CRE carriage upon readmission if the index specimen was a surveillance culture and 1 year passed without further hospitalization. Multiple hospitalizations and CRE disease extend duration of carriage. This study better defines patients requiring cohorting and isolation, thus limiting spread of CRE and allowing for improved allocation of infection control measures. PMID- 23449281 TI - Healthy eating design guidelines for school architecture. AB - We developed a new tool, Healthy Eating Design Guidelines for School Architecture, to provide practitioners in architecture and public health with a practical set of spatially organized and theory-based strategies for making school environments more conducive to learning about and practicing healthy eating by optimizing physical resources and learning spaces. The design guidelines, developed through multidisciplinary collaboration, cover 10 domains of the school food environment (eg, cafeteria, kitchen, garden) and 5 core healthy eating design principles. A school redesign project in Dillwyn, Virginia, used the tool to improve the schools' ability to adopt a healthy nutrition curriculum and promote healthy eating. The new tool, now in a pilot version, is expected to evolve as its components are tested and evaluated through public health and design research. PMID- 23449282 TI - Implications of lessons learned from tobacco control for tanning bed reform. AB - Tanning beds used according to the manufacturer's instructions expose the user to health risks, including melanoma and other skin cancers. Applying the MPOWER model (monitor, protect, offer alternatives, warn, enforce, and raise taxes), which has been used in tobacco control, to tanning bed reform could reduce the number of people at risk of diseases associated with tanning bed use. Among the tactics available to government are restricting the use of tanning beds by people under age 18 and those with fair skin, increasing the price of tanning bed services through taxation, licensing tanning bed operators, and banning unsupervised tanning bed operations. PMID- 23449283 TI - An algorithm that identifies coronary and heart failure events in the electronic health record. AB - INTRODUCTION: The advent of universal health care coverage in the United States and the use of electronic health records can make the medical record a disease surveillance tool. The objective of our study was to identify criteria that accurately categorize acute coronary and heart failure events by using electronic health record data exclusively so that the medical record can be used for surveillance without manual record review. METHODS: We serially compared 3 computer algorithms to manual record review. The first 2 algorithms relied on ICD 9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) codes, troponin levels, electrocardiogram (ECG) data, and echocardiograph data. The third algorithm relied on a detailed coding system, Intelligent Medical Objects, Inc., (IMO) interface terminology, troponin levels, and echocardiograph data. RESULTS: Cohen's kappa for the initial algorithm was 0.47 (95% confidence interval [CI], 0.41-0.54). Cohen's kappa was 0.61 (95% CI, 0.55-0.68) for the second algorithm. Cohen's kappa for the third algorithm was 0.99 (95% CI, 0.98-1.00). CONCLUSION: Electronic medical record data are sufficient to categorize coronary heart disease and heart failure events without manual record review. However, only moderate agreement with medical record review can be achieved when the classification is based on 4-digit ICD-9-CM codes because ICD-9-CM 410.9 includes myocardial infarction with elevation of the ST segment on ECG (STEMI) and myocardial infarction without elevation of the ST segment on ECG (nSTEMI). Nearly perfect agreement can be achieved using IMO interface terminology, a more detailed coding system that tracks to ICD9, ICD10 (International Classification of Diseases, Tenth Revision, Clinical Modification), and SnoMED-CT (Systematized Nomenclature of Medicine - Clinical Terms). PMID- 23449284 TI - Bilateral simultaneous cochlear implantation in children: report of a case and review of literature. AB - The benefits of bilateral cochlear implant in adults are well established. Auditory ability in children is also substantially improved by binaural hearing. We report the first case of bilateral simultaneous paediatric cochlear implant in India and discuss the merits of bilateral implant. PMID- 23449285 TI - An evaluation of preoperative computed tomography on patients with chronic otitis media. AB - This study aimed to compare the veracity of computed tomography findings on patients undergoing surgery for chronic otitis media (COM) with the surgical findings, and to determine to what extent the preoperative computerized tomography (CT) findings are useful to the surgeon. A series of 56 patients with COM undergoing preoperative CT scanning followed by surgical exploration of the middle ear and mastoid. Operative notes were recorded and data collected on the nature of soft tissue masses, the status of the ossicles, presence or absence of facial canal dehiscence and semicircular canal (SCC) dehiscence and the presence or absence of dural plate erosion, and sigmoid sinus thrombosis. Fifty-six patients were recruited in the study, 30 males and 26 females. The age range was from 16 to 67 years with a mean of 26.51 +/- 1.4 years. The preoperative CT scan imaging in cases of cholesteatoma, ossicular chain erosion and SCC dehiscence have good correlation with the intraoperative findings. The specificity of preoperative CT scan in detecting facial canal dehiscence, dural plate erosion and sigmoid sinus thrombosis in patient of COM were weak. Preoperative computed tomography evaluation is fairly useful especially in cases of cholesteatoma. According to the results of this study, CT is of value particularly in the definition of cholesteatoma, and in determining ossicular chain erosion and semicircular canal fistula. PMID- 23449286 TI - Evolution of chylous fistula management after neck dissection. AB - PURPOSE OF REVIEW: The present review is focused on the management of lymphatic, chylous, and thoracic duct lesions following head and neck surgery, with particular attention to these complications after neck dissection. Postoperative scenarios may include chylous fistula, chylothorax, chylomediastinum, chylopericardium, lymphocele, persistent lymphorrhea, and secondary lymphedema. RECENT FINDINGS: There is a paucity of literature on the treatment of lymphatic, chylous, and thoracic duct injuries following head and neck surgery; however, this review suggests that the most appropriate treatment should include both conservative and surgical approaches. Nonsurgical options consist of low-fat diet with medium-chain triglycerides, total parenteral nutrition, careful monitoring of fluid and electrolytes, drainage of the leakage, somatostatin analogs such as octreotide, and negative-pressure wound therapy. On the other hand, surgical management includes therapeutic percutaneous lymphography-guided thoracic duct cannulation and embolization, thoracic duct ligation, excision and imbrication of leaking lymphatics, chylous fistula surgical/microsurgical repair, fistula closure by locoregional flaps, video-assisted thoracoscopic surgery, thoracotomy, pleurodesis and decortication, pericardial 'window', and pleura-venous/pleura peritoneal shunts. In addition, single or, preferably, multiple lymphovenous anastomoses may be taken into account. SUMMARY: The various possible clinical presentations of such challenging lymphatic, chylous, and thoracic duct injuries require an appropriate multidisciplinary approach by experienced teams. Primary prevention of these complications can be achieved through adequate surgical planning to minimize lesions, including structured and thorough patient assessment, and centralization of resources and teams. PMID- 23449287 TI - Nasal epithelial repair and remodeling in physical injury, infection, and inflammatory diseases. AB - PURPOSE OF REVIEW: To summarize the current knowledge of cellular and molecular mechanisms of nasal epithelial repair and remodeling during physical and pathophysiological conditions. RECENT FINDINGS: Nasal epithelial repair and remodeling is a highly organized and well coordinated process, involving inflammation, proliferation, differentiation, matrix deposition, and remodeling, and is regulated by a wide variety of growth factors and cytokines. From the in vivo and in-vitro studies conducted in both human and animal models, undifferentiated basal cells (progenitors) are able to migrate from adjacent epithelium, spread over the denuded basement membrane, and proliferate in injured regions (self-renewal) in necessary (homeostasis) or excessive (hyperplasia) degree. Progenitor cells reorient to an apical-basal polarity, and progressively differentiate into ciliated and nonciliated columnar cells and goblet cells, reconstituting a functional respiratory epithelium after several weeks. This recovery process can be observed during various types and severity of injury, and also in common nasal diseases, including acute viral, allergic, and nonallergic rhinitis, as well as chronic rhinosinusitis with and without nasal polyps. SUMMARY: Although nearly 10 000 articles about nasal epithelium have been published in the last decade, the mechanisms underlying the nasal epithelial repair are still understood at only a superficial descriptive level. In order to advance rhinology to the next level of a comprehensive knowledge of the orchestrated genetic and molecular processes acting during epithelial repair, combined clinical and experimental studies using sophisticated investigational plans to elucidate the functions of both the protein-coding and regulatory portions of the human genome are required. PMID- 23449288 TI - Sublingual immunotherapy and quality of life. AB - PURPOSE OF REVIEW: Sublingual immunotherapy (SLIT) has been shown to be a new and promising treatment for people with various allergic syndromes. Several studies have examined its efficacy. However, significantly fewer investigations have explored its specific impact on the patient's quality of life (QOL). RECENT FINDINGS: SLIT has an excellent safety profile, superior in many ways to subcutaneous immunotherapy (SCIT). Additionally, SLIT significantly decreases the use of allergy medications, as well as decreasing the money spent on allergy symptom control. Finally, SLIT has been shown to improve the patient's QOL when compared to placebo or even second-generation antihistamines. SUMMARY: Increasing data support the use of SLIT as a well tolerated, cost-effective, and time efficient modality for the treatment of multiple allergic syndromes. However, additional studies are needed, particularly QOL studies which compare SLIT to the FDA-approved SCIT. PMID- 23449289 TI - Ca/P concentration ratio at different sites of normal and osteoporotic rabbit bones evaluated by Auger and energy dispersive X-ray spectroscopy. AB - Osteoporosis is a systemic skeletal disorder associated with reduced bone mineral density and the consequent high risk of bone fractures. Current practice relates osteoporosis largely with absolute mass loss. The assessment of variations in chemical composition in terms of the main elements comprising the bone mineral and its effect on the bone's quality is usually neglected. In this study, we evaluate the ratio of the main elements of bone mineral, calcium (Ca), and phosphorus (P), as a suitable in vitro biomarker for induced osteoporosis. The Ca/P concentration ratio was measured at different sites of normal and osteoporotic rabbit bones using two spectroscopic techniques: Auger electron spectroscopy (AES) and energy-dispersive X-ray spectroscopy (EDX). Results showed that there is no significant difference between samples from different genders or among cortical bone sites. On the contrary, we found that the Ca/P ratio of trabecular bone sections is comparable to cortical sections with induced osteoporosis. Ca/P ratio values are positively related to induced bone loss; furthermore, a different degree of correlation between Ca and P in cortical and trabecular bone is evident. This study also discusses the applicability of AES and EDX to the semiquantitative measurements of bone mineral's main elements along with the critical experimental parameters. PMID- 23449290 TI - Management of the thrombosed filter-bearing inferior vena cava. AB - Inferior vena cava (IVC) filter thrombosis is a complex problem. Thrombus within an IVC filter may range from an asymptomatic small thrombus to critical IVC occlusion that affects both lower extremities. The published experience of IVC thrombosis management in relation to filters is either anecdotal or limited to a small group of patients; however, endovascular treatment methods appear to be safe and effective in patients with IVC thrombosis. This review focuses on filter related IVC thrombosis and its endovascular management. PMID- 23449291 TI - Nanomedicine: is the wave cresting? PMID- 23449292 TI - European lead factory opens for business. PMID- 23449293 TI - Tuberculosis success. PMID- 23449295 TI - Trial watch: pioneering RNAi therapy shows antitumour activity in humans. PMID- 23449299 TI - Stem cell therapy market. PMID- 23449300 TI - Cancer: double-pronged approach to combat mutant KRAS. PMID- 23449301 TI - Peptides: activating autophagy. PMID- 23449306 TI - The placebo response in medicine: minimize, maximize or personalize? AB - Our understanding of the mechanisms mediating or moderating the placebo response to medicines has grown substantially over the past decade and offers the opportunity to capitalize on its benefits in future drug development as well as in clinical practice. In this article, we discuss three strategies that could be used to modulate the placebo response, depending on which stage of the drug development process they are applied. In clinical trials the placebo effect should be minimized to optimize drug-placebo differences, thus ensuring that the efficacy of the investigational drug can be truly evaluated. Once the drug is approved and in clinical use, placebo effects should be maximized by harnessing patients' expectations and learning mechanisms to improve treatment outcomes. Finally, personalizing placebo responses - which involves considering an individual's genetic predisposition, personality, past medical history and treatment experience - could also maximize therapeutic outcomes. PMID- 23449309 TI - Er-doped light emitting slot waveguides monolithically integrated in a silicon photonic chip. AB - An integrated erbium-based light emitting diode has been realized in a waveguide configuration allowing 1.54 MUm light signal routing in silicon photonic circuits. This injection device is based on an asymmetric horizontal slot waveguide where the active slot material is Er(3+) in SiO2 or Er(3+) in Si-rich oxide. The active horizontal slot waveguide allows optical confinement, guiding and lateral extraction of the light for on-chip distribution. Light is then coupled through a taper section to a passive Si waveguide terminated by a grating which extracts (or inserts) the light signal for measuring purposes. We measured an optical power density in the range of tens of MUW/cm(2) which follows a super linear dependence on injected current density. When the device is biased at high current density, upon a voltage pulse (pump signal), free-carrier and space charge absorption losses become large, attenuating a probe signal by more than 60 dB/cm and thus behaving conceptually as an electro-optical modulator. The integrated device reported here is the first example, still to be optimized, of a fundamental block to realize an integrated silicon photonic circuit with monolithic integration of the light emitter. PMID- 23449307 TI - The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. AB - The role of stromal cells and the tumour microenvironment in general in modulating tumour sensitivity is increasingly becoming a key consideration for the development of active anticancer therapeutics. Here, we discuss how these tumour-stromal interactions affect tumour cell signalling, survival, proliferation and drug sensitivity. Particular emphasis is placed on the ability of stromal cells to confer - to tumour cells - resistance or sensitization to different classes of therapeutics, depending on the specific microenvironmental context. The mechanistic understanding of these microenvironmental interactions can influence the evaluation and selection of candidate agents for various cancers, in both the primary site as well as the metastatic setting. Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy. These recent advances can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents. PMID- 23449308 TI - Targeting pathological B cell receptor signalling in lymphoid malignancies. AB - Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma. PMID- 23449311 TI - Profile: transgene. PMID- 23449310 TI - Functional analysis of nocturnin, a circadian deadenylase, at maternal-to-zygotic transition in mice. AB - Degradation of maternally stored mRNAs after fertilization is an essential process for mammalian embryogenesis. Maternal mRNA degradation depending on deadenylases in mammalian early embryos has been mostly speculated, rather than directly demonstrated. Previously, we found that gene expression of nocturnin, which functions as a circadian clock-controlled deadenylase in mammalian cells, was clearly changed during the maternal-to-zygotic transition (MZT). Here, we investigated the possible role of nocturnin during mouse MZT. First, we examined the expression profile and localization of nocturnin in mouse oocytes and early embryos. The abundance of Nocturnin mRNA level was significantly decreased from the MII to 4-cell stages and slightly increased from the 8-cell to blastocyst stages, whereas the Nocturnin protein level was almost stable in all examined cells including GV and MII oocytes and early embryos. Nocturnin was localized in both the cytoplasm and the nucleus of all examined cells. We then examined the effect of loss or gain of Nocturnin function on early embryonic development. Knockdown of Nocturnin by injection of Nocturnin antisense expression vector into 1-cell embryos resulted in the delay of early embryonic development to the early blastocyst stage. Moreover, Nocturnin-overexpressed embryos by injection of Nocturnin expression vector impaired their development from the 1-cell to 2-cell or 4-cell stages. These results suggest that precise expression of nocturnin is critical to proper development of early mouse embryos. Functional analysis of nocturnin may contribute to the understanding of the possible role of the deadenylase at mouse MZT. PMID- 23449312 TI - GSK's four-strain seasonal influenza vaccine approved in the US. PMID- 23449313 TI - Letter from the editor. PMID- 23449315 TI - Botulinum toxin type A combined with neurodynamic mobilization for upper limb spasticity after stroke: a case report. AB - OBJECTIVE: The purpose of this study is to report a case in which combinatory therapy of botulinum toxin type A (BoNT-A) and neurodynamic mobilization (NM) was used as treatment for a patient with severe upper limb spasticity and pain after stroke. CLINICAL FEATURES: A 76-year-old male patient had spastic muscles in the upper limb 10 months after an ischemic stroke. INTERVENTION AND OUTCOME: The patient underwent combined treatment with BoNT-A and NM of the upper limb in 6 monthly applications. Evaluation was performed pretreatment, 3 months after the first injection, 3 months after the second injection, and at a follow-up session 9 months after starting the treatment. The following outcomes were measured: pain by using a numeric rating scale, spasticity by the Modified Ashworth Scale for Grading Spasticity, acceptance and emotional reaction to the treatment by the Hospital Anxiety and Depression Scale, and functionality by ranges of motion. The patient improved in all outcomes after treatment, and results were maintained during the follow-up sessions. CONCLUSION: The combined NM and BoNT-A treatment appeared to decrease pain and improve joint ranges of motion during treatment for this patient. The patient showed decreased anxiety and depression during and after the treatment. PMID- 23449316 TI - Estimation of C-reactive Protein Associated with Mandibular Fracture. AB - BACKGROUND: The aim of the present study is to evaluate the C-reactive protein (CRP) levels pre-operatively and post-operatively following a surgical intervention of mandibular fracture with osteosynthesis by rigid fixation using AO/ASIF principles and to try and correlate the prognosis of the convalescent period. METHODS: Twenty five patients with trauma were surgically treated. The blood samples are collected pre-operatively, immediate post-operatively, after 24 h and on the seventh post-operative day. RESULTS: The CRP levels were high pre operatively due to body's initial response to trauma. An increase was noticed immediately after the surgery (mean value 1.96 +/- 0.56 mg/dl). After 24 h of surgery, CRP levels were raised markedly (mean value of 2.3 +/- 0.58 mg/dl). On the seventh day after the surgery CRP levels were significantly decreased to attain normal level (mean value of 1.58 +/- 0.52 mg/dl), indicating normal healing at the surgical site. CONCLUSION: In cases of patients with mandibular fracture the CRP concentration increases directly after the trauma and the surgical procedure. Then it undergoes a gradual normalisation which ensures non complicated healing post operatively. PMID- 23449317 TI - Biotransformation of Acetamide to Acetohydroxamic Acid at Bench Scale Using Acyl Transferase Activity of Amidase of Geobacillus pallidus BTP-5x MTCC 9225. AB - The bioprocess employing acyl transferase activity of intracellular amidase of Geobacillus pallidus BTP-5x MTCC 9225 was harnessed for the synthesis of pharmaceutically important acetohydroxamic acid. G. pallidus BTP-5x exhibited highest acyl transferase activity with acetamide: hydroxylamine in ratio of 1:5 in 0.1 M NaH2PO4/Na2HPO4 buffer (pH 7.5) at 65 degrees C. In one liter fed-batch reaction containing 1:5 ratio of two substrates total of eight feedings of 0.05 M/20 min of acetamide were made and it was found that maximum acetohydroxamic production was achieved at 3:5 ratios of substrate and cosubstrate. In 1 l bench scale batch reaction containing 0.3 M acetamide, 0.5 M hydroxylamine in 0.1 M NaH2PO4/Na2HPO4 buffer (pH 7.5, 50 degrees C, 400 rpm) and 0.5 mg/ml (dry cell weight) of whole cells of G. pallidus BTP-5x (as biocatalyst) resulted in an yield of 0.28 M of acetohydroxamic acid after 20 min reaction time at 50 degrees C. The acetamide bioconversion rate was 90-95% (mol mol(-1)) and 51 g powder containing 40% (w/w) acetohydroxamic acid was recovered after lyophilization. PMID- 23449318 TI - Caulobacter species as a cause of postneurosurgical bacterial meningitis in a pediatric patient. AB - Caulobacter species have been rarely found to be a cause of human infection. A case of probable Caulobacter species meningitis occurring postneurosurgery in a pediatric patient is reported in the present article. Gram stain and colony morphology of the isolate were not consistent with the identification provided by commercial phenotypic identification systems. The present case illustrates the need to reconcile conflicting phenotypic test results using 16S ribosomal DNA sequencing. PMID- 23449319 TI - Cancellous bone graft and Kirschner wire fixation as a treatment for cavitary type scaphoid nonunions exhibiting DISI. AB - BACKGROUND: Cavitary-type scaphoid non-unions represent one of the most difficult treatment challenges amongst all scaphoid non-unions as they exhibit bone loss, scaphoid shortening, flexion ('humpback') deformity and dorsal intercalated segmental instability (DISI), creating altered carpal mechanics which may proceed to the degenerative changes of scapholunate advanced collapse of the wrist. Our technique and its rationale are presented in the largest-to-date series on cavitary scaphoid non-unions exhibiting DISI. METHODS: Our technique for treatment of these cavitary non-unions is presented through a series of 27 patients. RESULTS: Union was achieved in (26/27) 96% of cases, with no complications. Carpal mechanics was restored, with an average carpal height index of 1.52 +/- 0.06, and an average scapholunate angle was 46 +/- 9 degrees . Average follow-up was 2.2 years. CONCLUSION: In this subset of patients, we believe this technique is less technically demanding than the use of either cortico-cancellous grafts or various compression screws. Our success equals or betters that of other published techniques, with all patients enjoying a full return to work, even in occupations demanding heavy labour. We believe that scaphoid union, coupled with the often difficult restoration of carpal height and intra-carpal angles, has produced very good functional outcomes in the management of these challenging cases. PMID- 23449320 TI - Effect of using stencil masks made by focused ion beam milling on permalloy (Ni81Fe19) nanostructures. AB - Focused ion beam (FIB) milling is a common fabrication technique to make nanostencil masks which has the unintended consequence of gallium ion implantation surrounding milled features in silicon nitride membranes. We observe major changes in film structure, chemical composition, and magnetic behaviour of permalloy nanostructures deposited by electron beam evaporation using silicon nitride stencil masks made by a FIB as compared to stencil masks made by regular lithography techniques. We characterize the stenciled structures and both types of masks using transmission electron microscopy, electron energy loss spectroscopy, energy dispersive x-ray spectroscopy, magnetic force microscopy and kelvin probe force microscopy. All these techniques demonstrate distinct differences at a length scale of a 1-100 nm for the structures made using stencil mask fabricated using a FIB. The origin of these differences seems to be related to the presence of implanted ions, a detailed understanding of the mechanism however remains to be developed. PMID- 23449321 TI - A large retrospective multicenter study of vaginal melanomas: implications for new management. AB - The outcome of patients presenting with vaginal melanoma has been assessed in a large multicentric retrospective study. The databases of 12 French institutions were searched for primary vaginal melanomas managed between 1990 and 2007. Among the 54 patients recorded, 46 were managed with a curative intent and included in the study. The clinical characteristics, treatments, and detection of c-KIT protein expression have been studied. The median age of the patients was 63.5 years (42-88). Twenty-eight patients were classified as International Federation of Gynecology and Obstetrics (FIGO) stage I, five as stage II, six as stage III, and one as stage IVA. c-KIT protein was overexpressed in 80% of the patients. Forty-two patients underwent surgical resection of the tumor, nine patients received local adjuvant treatment, and 10 received systemic adjuvant therapy. The median relapse-free survival was 10.9 months. c-KIT-negative status (P=0.01) and stage I (P=0.02) were associated with locoregional recurrence. The rate of metastasis was increased for advanced FIGO stages (P<0.01). The median overall survival (OS) was 28.4 months. The finding of lymph node metastasis adversely affected OS (P<0.01). Conservative surgery and radiotherapy were associated with a decrease in metastasis-free and OS (P<0.01) compared with surgery alone, this group of patients presenting with advanced FIGO stages (P=0.02). Despite the use of limited data, conservative surgery combined with a sentinel lymph node procedure, followed by adjuvant radiotherapy could be proposed to patients with early FIGO stage in the absence of validated management. c-KIT negativity by immunochemistry appears to be a poor prognosis marker in terms of locoregional recurrences but not for metastatic spread nor survival. Further assessment of the role of c-KIT expression in this disease is thus mandatory to select patients for targeted therapy. PMID- 23449322 TI - Inhibitory effects of acorn extract on glutamate-induced calcium signaling in cultured rat hippocampal neurons. AB - Various effects of acorn extract have been reported including antioxidant activity, cytotoxicity against cancer cells, and the levels of acetylcholine and its related enzyme activities in the dementia mouse models. However, it is unclear whether acorn extract inhibits glutamate-induced calcium signaling in hippocampal neurons. This study was an investigation into the effect of acorn extract on intracellular free Ca concentrations ([Ca]) in cultured rat hippocampal neurons using fura-2-based digital calcium imaging and photometry. Hippocampal neurons were used between 10 and 14 d in culture from embryonic day 18 rats. Treatment with acorn extract (1 ug/mL to 1 mg/mL) for 30 min inhibited glutamate (100 uM)-induced [Ca] increases in a dose-dependent manner (IC=46.9 ug/mL). After depletion of intracellular Ca stores by treatment with the inhibitor endoplasmic reticulum Ca-ATPase, thapsigargin (1 uM), treatment with acorn extract (50 ug/mL) for 30 min decreased the subsequent glutamate-induced [Ca] increases. Acorn extract significantly inhibited (S)-alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) (30 uM)-induced [Ca] increases. In addition, acorn extract inhibited the AMPA-induced [Ca] responses in the presence of 1 uM nimodipine. Acorn extract also significantly inhibited N-methyl-D aspartate (100 uM)-induced [Ca] increases. Acorn extract significantly inhibited 50 mM KCl -induced [Ca] increases. Acorn extract significantly inhibited (S)-3,5 dihydroxyphenylglycine-induced [Ca] responses. Moreover, acorn extract almost completely blocked synaptically mediated [Ca] spikes induced by decreasing extracellular Mg concentration to 0.1 mM. These results suggest that acorn extract inhibits synaptically induced frequent [Ca] spikes through multiple pathways such as ionotropic glutamate receptors, voltage-gated Ca channels and metabotropic glutamate receptors in cultured rat hippocampal neurons. PMID- 23449323 TI - Mast cell stabilizing effect of (-)-Elema-1,3,11(13)-trien-12-ol and thujopsene from Thujopsis dolabrata is mediated by down-regulation of interleukin-4 secretion in antigen-induced RBL-2H3 cells. AB - Several isolated compounds from the wood part of Thujopsis dolabrata were evaluated for their inhibitory effects against antigen-induced mast cell degranulation and interleukin-4 (IL-4) secretion, as well as IL-4 mRNA and protein expression in immunoglobulin E (IgE)-sensitized RBL-2H3 cells. Among the five isolated compounds, (-)-elema-1,3,11(13)-trien-12-ol (1) and thujopsene (2) exhibited the potent inhibitory activity against mast cell degranulation measured by beta-hexosaminidase release with IC values of 27.4 uM and 25.1 uM, respectively. These compounds also inhibited the release of IL-4 (IC values of 7.0, 6.7 uM, respectively), IL-4 mRNA expression (IC values of 16.5, 7.2 uM, respectively) and IL-4 protein expression (IC values of 17.0, 9.6 uM, respectively) in antigen-induced IgE-sensitized RBL-2H3 cells. These results suggested that (-)-elema-1,3,11(13)-trien-12-ol (1) and thujopsene (2) effectively inhibits mast cell degranulation as well as IL-4 production, suggesting that these compounds from Thujopsis dolabrata can be used as candidates for IgE-mediated allergic disorders. PMID- 23449324 TI - Efficacy of disinfectants against naturally occurring and artificially cultivated bacteria. AB - Naturally occurring bacteria, is exist in nature, and is never cultivated on conventional culture medium. We evaluated the efficacy of disinfectants against naturally occurring bacteria in in-use cotton balls soaked in 0.02% benzalkonium chloride solution which had been used to disinfect the genital area by patients undergoing self-catheterization at home and the same bacteria subcultured on nutrient broth (artificially cultivated bacteria). The colony forming units (CFU) of naturally occurring bacteria such as Serratia marcescens, Alcaligenes xylosoxidans, and Burkholderia cepacia were not decreased after 48 h exposure to 0.025-0.1% benzalkonium chloride solution, but the same strains subcultured on nutrient broth were killed within only 10 min exposure to 0.025-0.1% benzalkonium chloride solution. In addition, the CFU of these three kinds of naturally occurring bacteria were not decreased after 48 h exposure to 0.02% chlorhexidine gluconate solution, but the same strains subcultured on nutrient broth were killed within 2 h exposure to chlorhexidine gluconate solution. The result showed that disinfectant efficacy differed markedly against naturally occurring and artificially cultivated bacteria. Therefore, it is preferable to use the naturally occurring bacteria not only artificially cultivated bacteria when examining disinfectant efficacy. PMID- 23449325 TI - The mechanism of action of bufalin in inhibition of lipid droplet accumulation in mouse macrophages. AB - A cardiotonic glycoside, bufalin, originally isolated from the dried white venom of Chinese toad Bufo gargarizans, was found to inhibit lipid droplet accumulation in mouse macrophages. Bufalin selectively inhibited synthesis of [C]cholesteryl ester (CE), a main component of lipid droplet, from [C]oleic acid and [C]cholesterol with IC values of 8.6 uM and 10 uM, respectively. The postlysosomal metabolism of cholesterol to CE in macrophages was also inhibited by the compound with a similar IC value of 13.2 uM. However, the compound exhibited almost no effect on acyl-CoA : cholesterol acyltransferase, a key enzyme in CE synthesis localized in the endoplasmic reticulum (ER). From the fluorescent microscopic observation of cellular lipids, bufalin-treated macrophages increased the accumulation of free cholesterol in lysosomes and caused to enlarge the shape and volume of lysosomes as well as pregnenolone treated macrophages. These findings suggest that bufalin inhibited the postlysosomal metabolism of cholesterol, leading to a reduction of lipid droplets in mouse macrophages without cytotoxicity. PMID- 23449326 TI - Percolation analysis in electrical conductivity of Madin-Darby canine kidney and Caco-2 cells by permeation-enhancing agents. AB - The control of permeability through the paracellular route has been paid great attention to for enhanced bioavailability of macromolecular and hydrophilic drugs. The paracellular permeability is controlled by tight junctions (TJ), and claudins are the major constituents of TJ. Despite numerous studies on TJ modulation, the dynamics is not well understood, although it could be crucial for clinical applications. Here, we studied the time (t) course of electrical conductivity (Sigma) in a monolayer of Madin-Darby canine kidney (MDCK) and Caco 2 cells upon treatment with modulators, the C-terminus fragments of Clostridium perfringens enterotoxin (C-CPE) and sodium caprate (C10). For C-CPE treatment, Sigma remains approximately constant, then starts increasing at t=tc (percolation threshold). For C10, on the other hand, Sigma increases to 1.6-2.0 fold of the initial value, stays constant, and then starts increasing again for both MDCK and Caco-2 cells at t=tc. We find that this behavior can be explained within a framework of percolation, where Sigma shows a logarithmic dependence on t-tc with the power of MU; MU denotes the critical exponent. We obtain MU=1.1-1.2 regardless of cell type or modulator. Notably, MU depends only on the dimensionality (d) of the system, and these values correspond to those for d=2. Percolation is thus the operative mechanism for the increase in Sigma through TJ modulation. The findings provide fundamental knowledge, not only on controlled drug delivery, but also on bio-nanotechnologies including the fabrication of biological devices. PMID- 23449327 TI - Pentamines as substrate for human spermine oxidase. AB - Substrate activities of various linear polyamines to human spermine oxidase (hSMO) were investigated. The activities were evaluated by monitoring the amount of H2O2 released from sample polyamines by hSMO. H2O2 was measured by a HPLC method that analyzed fluorescent dimers derived from the oxidation of homovanillic acid in the presence of horseradish peroxidase. Six triamines were tested and were found not to be hSMO substrates. Of sixteen tetramines tested, spermine (Spm) was the most active substrate, followed by homospermine and N butylated Spm. Pentamines showed a characteristic pattern of substrate activity. Of thirteen pentamines tested, 3343 showed higher substrate activity than Spm, and 4343 showed similar activity to Spm. The activities of the other pentamines were as follows: 3443, 4443, 4344, 3344, 4334, 4444, and 3334 (in decreasing order). Product amines released from these pentamines by hSMO were then analyzed by HPLC. Triamine was the only observed product, and the amount of triamine was nearly equivalent to that of released H2O2. A marked difference in the pH dependency curves between tetramines and pentamines suggested that hSMO favored reactions with a non-protonated secondary nitrogen at the cleavage site. The Km and Vmax values for Spm and 3343 at pH 7.0 and 9.0 were consistent with the higher substrate activity of 3343 compared to Spm, as well as with the concept of a non-protonated secondary nitrogen at the cleavage site being preferred, and 3343 was well degraded at a physiological pH by hSMO. PMID- 23449328 TI - Effect of rice cell-derived human granulocyte-macrophage colony-stimulating factor on 5-fluorouracil-induced mucositis in hamsters. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important regulator of the maturation and function of cells in the granulocyte and macrophage lineages, and also plays a significant role in wound healing. In a previous study, we expressed human GM-CSF in rice cells (rice cell-derived human GM-CSF; rhGM-CSF). The purpose of the present study was to evaluate its effect on wound healing in oral mucositis. Oral mucositis was induced in Syrian hamster cheek pouches by 5-fluorouracil treatment and mechanical scratching. Ulcerated areas were treated from days 3 to 14 with an application of 200 uL saline, or of the same volume of a solution containing 0.04, 0.2, or 1 ug/mL rhGM-CSF. Treatment of hamsters with rhGM-CSF reduced the ulcerated areas of the oral mucosa, compared with the control. Early in the healing process, the mucositis tissue layer of the rhGM-CSF-treated group showed significantly decreased myeloperoxidase activity and increased numbers of proliferating cell nuclear antigen (PCNA)-positive cells. Treatment with rhGM-CSF also affected expression of inflammatory cytokines in the ulcerative mucosal tissue. These results demonstrate the efficacy of plant-produced rhGM-CSF in wound healing and have significant implications for the development of rhGM-CSF as a therapeutic agent for ulcerative oral mucositis. PMID- 23449329 TI - Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479. AB - Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S 101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, beta catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues. PMID- 23449330 TI - cDNA cloning and functional analysis of minipig uridine diphosphate glucuronosyltransferase 1A1. AB - Uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) plays important roles in the glucuronidation of various drugs and endogenous substances. Minipigs have been used as experimental animals in pharmacological and toxicological studies, because many of their physiological characteristics are similar to those of humans. In this study, the similarities and differences in enzymatic properties of UGT1A1 between humans and minipigs were precisely identified. Minipig UGT1A1 (mpUGT1A1) cDNA was firstly cloned by the rapid amplification of cDNA ends (RACE) method, and the corresponding protein as well as human UGT1A1 (hUGT1A1) enzyme was expressed in insect cells. Then the kinetics of estradiol at 3-hydroxy position (E-3OH) and 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation by recombinant UGT1A1s as well as human and minipig liver microsomes were analyzed. The homology between mpUGT1A1 and hUGT1A1 at the amino acid level was 80.9%. E-3OH and SN-38 glucuronidation by recombinant hUGT1A1 and mpUGT1A1 showed allosteric sigmoidal kinetics. The CL value (29.1 uL/min/mg protein) for E-3OH glucuronidation of mpUGT1A1 was significantly higher (1.4 fold) than that of hUGT1A1, whereas the CL value (0.83 uL/min/mg protein) for SN 38 glucuronidation was significantly lower (27%) than that of hUGT1A1; however, the kinetic models and parameter levels for E-3OH and SN-38 glucuronidation by human and minipig liver microsomes did not parallel those in the respective species. These findings suggest that the enzymatic properties of UGT1A1 are considerably different between humans and minipigs. The information on species differences in UGT1A1 function gained in this study should help with in vivo extrapolation of xenobiotic metabolism and toxicity. PMID- 23449331 TI - Rapid degradation of poly(ADP-ribose) after injection into the mouse bloodstream. AB - Extensive DNA damage leads to the activation of poly(ADP-ribose) polymerase and subsequently to the formation of poly(ADP-ribose). When the damage is severe or leads to cell death, poly(ADP-ribose) may leak into the blood circulation. The metabolism of poly(ADP-ribose) in the bloodstream is not well understood. Thus, in the present study, the metabolism of P-labeled poly(ADP-ribose) was followed in mice after injection of this labeled compound into the tail vein. The results showed that 5 min after injection more than half of the radioactivity was concentrated in acid-soluble fractions, namely in low molecular weight compounds in the blood, liver, and kidneys. Most of this radioactivity was in the form of inorganic phosphate, detected 5 min post-injection in the blood, kidneys, and urine. By contrast, the metabolites ADP-ribose and phosphoribosyl-AMP were not detected in any of the tissues nor in blood or urine. Taken together, these findings suggest that once poly(ADP-ribose) enters the bloodstream it is rapidly degraded, thereby preventing its accumulation in the blood. PMID- 23449332 TI - Fimasartan, anti-hypertension drug, suppressed inducible nitric oxide synthase expressions via nuclear factor-kappa B and activator protein-1 inactivation. AB - Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-kappaB and AP-1. Taken together, our data suggest that fimasartan down regulates the expression of the iNOS in macrophages via NF-kappaB and AP-1 inactivation. PMID- 23449333 TI - Prevention of bone loss after ovariectomy in mice with preferential overexpression of the transcription factor paired box-5 in osteoblasts. AB - We have recently shown that the transcription factor Paired box-5 (Pax5) promotes bone formation in vivo and osteoblastogenesis in vitro. Here, we demonstrated the involvement of Pax5 in bone remodeling after ovariectomy (OVX). A significant increase was seen in vertebrae bone volume in transgenic mice preferentially overexpressing Pax5 in osteoblasts by using the mouse alpha1(I)Collagen promoter, whereas OVX significantly reduced vertebrae bone volume in wild-type (WT) mice without significantly affecting that in Pax5 transgenic mice. Preferential osteoblastic Pax5 overexpression invariably led to significant increases in osteoblastic and osteoclastic parameters in mice with sham operation. However, OVX significantly increased osteoclastic parameters in WT mice, without additionally increasing osteoblastic and osteoclastic parameters in Pax5 transgenic mice. These results suggest that osteoblastic Pax5 would play a role in OVX-induced bone loss through a mechanism relevant to the promotion of both osteoblastic bone formation and osteoclastic bone resorption in vivo. PMID- 23449334 TI - Paracellular barrier and tight junction protein expression in the immortalized brain endothelial cell lines bEND.3, bEND.5 and mouse brain endothelial cell 4. AB - The blood-brain barrier (BBB) is formed by brain endothelial cells. Many immortalized brain endothelial cell lines have been established; these have been used as in vitro BBB models. The aim of the present study was to assess the paracellular barrier properties of the immortalized mouse brain endothelial cell lines bEND.3, bEND.5 cells, and mouse brain endothelial cell 4 (MBEC4), and those of the primary mouse brain endothelial cells pMBECs. bEND.3 cells showed low permeability to sodium fluorescein and obvious staining of tight junction proteins (claudin-5, occludin and ZO-1) similar to pMBECs; these barrier properties of MBEC4 and bEND.5 cells were low. In addition, bEND.3 cells expressed the highest level of claudin-5 among all cells. These results suggest that bEND.3 cells are a convenient and useful model for evaluating BBB function, especially the paracellular barrier. PMID- 23449335 TI - Adjunctive colposcopy technologies for examination of the uterine cervix--DySIS, LuViva Advanced Cervical Scan and Niris Imaging System: a systematic review and economic evaluation. AB - BACKGROUND: Women in England (aged 25-64 years) are invited for cervical screening every 3-5 years to assess for cervical intraepithelial neoplasia (CIN) or cancer. CIN is a term describing abnormal changes in the cells of the cervix, ranging from CIN1 to CIN3, which is precancerous. Colposcopy is used to visualise the cervix. Three adjunctive colposcopy technologies for examination of the cervix have been included in this assessment: Dynamic Spectral Imaging System (DySIS), the LuViva Advanced Cervical Scan and the Niris Imaging System. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adjunctive colposcopy technologies for examination of the uterine cervix for patients referred for colposcopy through the NHS Cervical Screening Programme. DATA SOURCES: Sixteen electronic databases [Allied and Complementary Medicine Database (AMED), BIOSIS Previews, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Database of Abstracts of Reviews of Effects (DARE), EMBASE, Health Management Information Consortium (HMIC), Health Technology Assessment (HTA) database; Inspec, Inside Conferences, MEDLINE, NHS Economic Evaluation Database (NHS EED), PASCAL, Science Citation Index Expanded (SCIE) and Science Citation Index (SCI) - Conference Proceedings], and two clinical trial registries [ClinicalTrials.gov and Current Controlled Trials (CCT)] were searched to September-October 2011. REVIEW METHODS: Studies comparing DySIS, LuViva or Niris with conventional colposcopy were sought; a narrative synthesis was undertaken. A decision-analytic model was developed, which measured outcomes in terms of quality-adjusted life-years (QALYs) and costs were evaluated from the perspective of the NHS and Personal Social Services with a time horizon of 50 years. RESULTS: Six studies were included: two studies of DySIS, one study of LuViva and three studies of Niris. The DySIS studies were well reported and had a low risk of bias; they found higher sensitivity with DySIS (both the DySISmap alone and in combination with colposcopy) than colposcopy alone for identifying CIN2+ disease, although specificity was lower with DySIS. The studies of LuViva and Niris were poorly reported and had limitations, which indicated that their results were subject to a high risk of bias; the results of these studies cannot be considered reliable. The base-case cost-effectiveness analysis suggests that both DySIS treatment options are less costly and more effective than colposcopy alone in the overall weighted population; these results were robust to the ranges tested in the sensitivity analysis. DySISmap alone was more costly and more effective in several of the referral groups but the incremental cost-effectiveness ratio (ICER) was never higher than L1687 per QALY. DySIS plus colposcopy was less costly and more effective in all reasons for referral. Only indicative analyses were carried out on Niris and LuViva and no conclusions could be made on their cost-effectiveness. LIMITATIONS: The assessment is limited by the available evidence on the new technologies, natural history of the disease area and current treatment patterns. CONCLUSIONS: DySIS, particularly in combination with colposcopy, has higher sensitivity than colposcopy alone. There is no reliable evidence on the clinical effectiveness of LuViva and Niris. DySIS plus colposcopy appears to be less costly and more effective than both the DySISmap alone and colposcopy alone; these results were robust to the sensitivity analyses undertaken. Given the lack of reliable evidence on LuViva and Niris, no conclusions on their potential cost-effectiveness can be drawn. There is some uncertainty about how generalisable these findings will be to the population of women referred for colposcopy in the future, owing to the introduction of the human papillomavirus (HPV) triage test and uptake of the HPV vaccine. PMID- 23449336 TI - Prevalance of iron deficiency in thalassemia minor: a study from tertiary hospital. AB - Conflicting data are available about iron metabolism in thalassemia minors. As iron deficiency prevails largely in India, a study of 150 people was conducted to assess the iron level of beta thalassemia minor. The study population comprises of 59 males and 91 female who either attended outdoor services and with diagnosed thalassemia minor by hemoglobin high performance liquid chromatography or were the parents (diagnosed thalassemia minor) of beta Thalassemia patients visiting daycare services for transfusion. 29.67% females and 3.38% males are found to be iron deficient. Thus we can conclude that iron deficiency is one of the common co existing conditions in beta thalassemia minors. PMID- 23449338 TI - Cytokines: IRF7 lost in translation. PMID- 23449339 TI - Mucosal immunology: A wee immune response. PMID- 23449337 TI - Pharmacological risk factors for delirium after cardiac surgery: a review. AB - PURPOSE: The objective of this review is to evaluate the literature on medications associated with delirium after cardiac surgery and potential prophylactic agents for preventing it. SOURCE: Articles were searched in MEDLINE, Cumulative Index to Nursing and Allied Health, and EMBASE with the MeSH headings: delirium, cardiac surgical procedures, and risk factors, and the keywords: delirium, cardiac surgery, risk factors, and drugs. Principle inclusion criteria include having patient samples receiving cardiac procedures on cardiopulmonary bypass, and using DSM-IV-TR criteria or a standardized tool for the diagnosis of delirium. PRINCIPAL FINDINGS: Fifteen studies were reviewed. Two single drugs (intraoperative fentanyl and ketamine), and two classes of drugs (preoperative antipsychotics and postoperative inotropes) were identified in the literature as being independently associated with delirium after cardiac surgery. Another seven classes of drugs (preoperative antihypertensives, anticholinergics, antidepressants, benzodiazepines, opioids, and statins, and postoperative opioids) and three single drugs (intraoperative diazepam, and postoperative dexmedetomidine and rivastigmine) have mixed findings. One drug (risperidone) has been shown to prevent delirium when taken immediately upon awakening from cardiac surgery. None of these findings was replicated in the studies reviewed. CONCLUSION: These studies have shown that drugs taken perioperatively by cardiac surgery patients need to be considered in delirium risk management strategies. While medications with direct neurological actions are clearly important, this review has shown that specific cardiovascular drugs may also require attention. Future studies that are methodologically consistent are required to further validate these findings and improve their utility. PMID- 23449340 TI - T cells: Mitochondria and T cell activation. PMID- 23449342 TI - Chronic nicotine exposure and acute kidney injury: new concepts and experimental evidence. PMID- 23449343 TI - Unilateral renal agenesis: a systematic review on associated anomalies and renal injury. AB - BACKGROUND: Unilateral renal agenesis (URA) is associated with other congenital anomalies of the kidney and urinary tract (CAKUT) and extra-renal anomalies. However, the reported prevalences of these anomalies are highly variable. We estimated the prevalence of associated CAKUT and extra-renal anomalies in patients with URA. Furthermore, we determined the prevalence of renal injury in URA patients. METHODS: We conducted a systematic review of English and non English articles using PubMed and Embase.com. Included studies reported at least one of the following items: incidence of URA, gender, side of URA, prenatal diagnosis, performance of micturating cystourethrogram, associated CAKUT, urinary tract infection or extra-renal anomalies. Studies that described a mean/median glomerular filtration rate (GFR) and proportions of patients with hypertension, micro-albuminuria or a decreased GFR were also included. RESULTS: Analyses were based on 43 included studies (total number of patients: 2684, 63% male). The general incidence of URA was 1 in ~2000. Associated CAKUT were identified in 32% of patients, of which vesicoureteral reflux was most frequently identified (24% of patients). Extra-renal anomalies were found in 31% of patients. Hypertension could be identified in 16% of patients, whereas 21% of patients had micro albuminuria. Ten per cent of patients had a GFR<60 mL/min/1.73 m2;. CONCLUSIONS: These aggregate results provide insight in the prevalence of associated anomalies and renal injury in patients with URA. Our systematic review implicates that URA is not a harmless malformation by definition. Therefore, we emphasize the need for clinical follow-up in URA patients starting at birth. PMID- 23449341 TI - Treatment of obstructed defecation. AB - Obstructed defecation is a common problem that adversely affects the quality of life for many patients. Known causes of obstructed defecation include pelvic dyssynergy, rectocele, rectal intussusception, enterocele, pelvic organ prolapse, and overt rectal prolapse. Management of this condition requires an understanding of urinary, defecatory, and sexual function to achieve an optimal outcome. The goal of surgical treatment is to restore the various pelvic organs to their appropriate anatomic positions. However, there is a poor correlation between anatomic and functional results. As the pelvis contains many structures, a pelvic support or function defect frequently affects other pelvic organs. Optimal outcomes can only be achieved by selecting appropriate treatment modalities that address all of the components of a patient's problem. PMID- 23449344 TI - Serpiginous-like choroiditis as a marker for tuberculosis in a non-endemic area. AB - AIM: To describe the increasing incidence of multifocal outer retinal and inner choroidal inflammation as a marker for intraocular tuberculosis in the UK, a non endemic area. PATIENTS AND METHODS: Retrospective case series. RESULTS: 14 patients presented with serpiginous-like choroiditis over 10 years (seven within the last 2 years). Seven of 14 patients showed evidence of exposure to tuberculosis and received antituberculous treatment. 17 of 23 eyes showed stable or improved visual acuity. All with decreased acuity had direct macular involvement at presentation. CONCLUSIONS: Multifocal outer retinal and inner choroidal inflammation is a marker for intraocular tuberculosis of increasing importance, even in a non-endemic area. Originally described as 'serpiginous-like choroiditis', the lesions are multifocal, irregular in shape, very numerous, widespread, often asymmetrical and often demonstrating both active and resolved lesions simultaneously. Active lesions show contiguous extension. We recommend that every patient with SLC should undergo testing for previous exposure to tuberculosis, and undergo antituberculous treatment if lesions are progressive and sight-threatening. PMID- 23449345 TI - New insights in intestinal ischemia-reperfusion injury: implications for intestinal transplantation. AB - PURPOSE OF REVIEW: Ischemia-reperfusion injury is inevitable during intestinal transplantation and can negatively affect the transplant outcome. Here, an overview is provided of the recent advances in the pathophysiological mechanisms of intestinal ischemia-reperfusion injury and how this may impact graft survival. RECENT FINDINGS: The intestine hosts a wide range of microorganisms and its mucosa is heavily populated by immune cells. Intestinal ischemia-reperfusion results in the disruption of the epithelial lining, affecting also protective Paneth cells (antimicrobials) and goblet cells (mucus), and creates a more hostile intraluminal microenvironment. Consequently, both damage-associated molecular patterns as well as pathogen-associated molecular patterns are released from injured tissue and exogenous microorganisms, respectively. These 'danger' signals may synergistically activate the innate immune system. Exaggerated innate immune responses, involving neutrophils, mast cells, platelets, dendritic cells, as well as Toll-like receptors and complement proteins, may shape the adaptive T cell response, thereby triggering the destructive alloimmune response toward the graft and resulting in transplant rejection. SUMMARY: Innate immune activation as a consequence of ischemia-reperfusion injury may compromise engraftment of the intestine. More dedicated research is required to further establish this concept in man and to design more effective therapeutic strategies to better tolerize intestinal grafts. PMID- 23449346 TI - Economic and financial outcomes in transplantation: whose dime is it anyway? AB - PURPOSE OF REVIEW: Organ transplant is a resource-intensive service that has been subjected to increasing scrutiny in this era of cost containment. A detailed understanding of the economic (societal) and financial (transplant provider) implications of organ quality, recipient characteristics, and allocation policy is vital for the transplant professionals. RECENT FINDINGS: Prior studies of kidney transplant economics demonstrate significant cost savings achieved by eliminating the need for long-term dialysis. However, transplant providers are experiencing higher financial costs because of changes in recipient characteristics and broader use of marginal organs. Liver transplantation economics are also more challenging because of the severity of illness-based organ allocation. Furthermore, the use of more allografts recovered from donors after cardiac death has been demonstrated to increase costs with minimal benefits. Finally, successful long-term mechanical support devices have fundamentally changed the economic implications of advanced heart failure care. SUMMARY: Although care for end-stage organ failure through transplant is one of the landmark accomplishments of 20th century medicine, maintaining or expanding access to transplant care is threatened by the high cost of care. Novel strategies are vital to reduce the financial burden faced by the centers that transplant high-risk patients and utilize lower quality organs. PMID- 23449348 TI - Ab initio random structure search for 13-atom clusters of fcc elements. AB - The 13-atom metal clusters of fcc elements (Al, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au) were studied by density functional theory calculations. The global minima were searched for by the ab initio random structure searching method. In addition to some new lowest-energy structures for Pd13 and Au13, we found that the effective coordination numbers of the lowest-energy clusters would increase with the ratio of the dimer-to-bulk bond length. This correlation, together with the electronic structures of the lowest-energy clusters, divides the 13-atom clusters of these fcc elements into two groups (except for Au13, which prefers a two-dimensional structure due to the relativistic effect). Compact-like clusters that are composed exclusively of triangular motifs are preferred for elements without d electrons (Al) or with (nearly) filled d-band electrons (Ni, Pd, Cu, Ag). Non compact clusters composed mainly of square motifs connected by some triangular motifs (Rh, Ir, Pt) are favored for elements with unfilled d-band electrons. PMID- 23449347 TI - New and old technologies for organ replacement. AB - PURPOSE OF REVIEW: The demand for organ transplantation has increased over time, increasingly exceeding the supply of organs. Whether and how new or old technologies separately or together could be applied to replacing organs will thus remain a question of importance. RECENT FINDINGS: Estimating how the demand for organ transplantation will evolve over the decades and the need to bring forward and test new technologies will help establish the dimensions of the problem and the priorities for investigation. Pluripotent stem cells can in principle expand to sufficient numbers, differentiate, and assemble complex and functional organs. However, the devising of effective and reliable means to coax the stem cells to do so remains beyond the current grasp. SUMMARY: Given the time during which novel therapies are devised and applied, which organ transplantation reaches to 2-3 decades, one can anticipate the need for organ replacement will grow dramatically, but advances in science and technology will overcome the hurdles in generating new organs. Whether these advances will address the needs and priorities of society, however, is unclear. PMID- 23449349 TI - Insurability of HIV-positive people treated with antiretroviral therapy in Europe: collaborative analysis of HIV cohort studies. AB - OBJECTIVE: To increase equitable access to life insurance for HIV-positive individuals by identifying subgroups with lower relative mortality. DESIGN: Collaborative analysis of cohort studies. METHODS: We estimated relative mortality from 6 months after starting antiretroviral therapy (ART), compared with the insured population in each country, among adult patients from European cohorts participating in the ART Cohort Collaboration (ART-CC) who were not infected via injection drug use, had not tested positive for hepatitis C, and started triple ART between 1996-2008. We used Poisson models for mortality, with the expected number of deaths according to age, sex and country specified as offset. RESULTS: There were 1236 deaths recorded among 34,680 patients followed for 174,906 person-years. Relative mortality was lower in patients with higher CD4 cell count and lower HIV-1 RNA 6 months after starting ART, without prior AIDS, who were older, and who started ART after 2000. Compared with insured HIV negative lives, estimated relative mortality of patients aged 20-39 from France, Italy, United Kingdom, Spain and Switzerland, who started ART after 2000 had 6 month CD4 cell count at least 350 cells/MUl and HIV-1 RNA less than 104 copies/ml and without prior AIDS was 459%. The proportion of exposure time with relative mortality below 300, 400, 500 and 600% was 28, 43, 61 and 64%, respectively, suggesting that more than 50% of patients (those with lower relative mortality) could be insurable. CONCLUSION: The continuing long-term effectiveness of ART implies that life insurance with sufficiently long duration to cover a mortgage is feasible for many HIV-positive people successfully treated with ART for more than 6 months. PMID- 23449350 TI - miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. AB - BACKGROUND: Clear cell renal cancer frequently harbours von Hippel-Lindau (VHL) gene mutations, leading to stabilisation of the hypoxia-inducible factors (HIFs) and expression of their target genes. We investigated HIF-1 and HIF-2 in the regulation of microRNA-210 (miR-210), and its clinical relevance in renal tumours. METHODS: RCC4 and 786-O renal cancer cell lines transfected with either an empty vector or functional VHL and incubated in normoxia or hypoxia were examined for miR-210 expression. Hypoxia-inducible factor siRNAs were used to examine their regulation of miR-210. Seventy-one clear cell renal tumours were sequenced for VHL mutations. Expression of miR-210, VHL, CA9, ISCU and Ki-67 were determined by immunohistochemistry and qRT-PCR. RESULTS: In addition to HIF-1 regulating miR-210 in renal cancer, HIF-2 can regulate this microRNA in the absence of HIF-1. MicroRNA-210 is upregulated in renal cancer compared with normal renal cortex tissue. MicroRNA-210 correlates negatively with its gene target ISCU at the protein and mRNA level. MicroRNA-210 correlated with positive outcome variables and negatively with Ki-67. CONCLUSION: We provide further evidence of miR-210 activity in vivo, and show that high miR-210 expression is associated with better clinico-pathological prognostic factors. PMID- 23449351 TI - Prognostic and predictive value of VEGF, sVEGFR-2 and CEA in mCRC studies comparing cediranib, bevacizumab and chemotherapy. AB - BACKGROUND: The prognostic/predictive value of potential vascular endothelial growth factor (VEGF) signalling biomarkers was evaluated retrospectively using samples from two randomized Phase III studies (HORIZON II and III) investigating cediranib in metastatic colorectal cancer (mCRC). METHODS: Baseline levels of VEGF, soluble VEGF receptor-2 (sVEGFR-2) and carcinoembryonic antigen (CEA) were measured in plasma/serum samples collected from patients participating in HORIZON II (n=860; FOLFOX/XELOX plus cediranib 20 mg (n=502) or placebo (n=358)) and HORIZON III (n=1422; mFOLFOX6 plus cediranib 20 mg (n=709) or bevacizumab (n=713)). Median biomarker baseline levels determined cutoff values for the patient subgroups. RESULTS: Baseline data were available for 88-97% of patients/study (>2000 patients). In both the studies, high baseline VEGF and CEA were associated with worse outcomes for progression-free survival (PFS) and overall survival (OS) independent of treatment (HORIZON II OS: VEGF, hazard ratio (HR)=1.35 (95% confidence interval (CI): 1.12-1.63); CEA, HR=1.63 (1.36-1.96); HORIZON III OS: VEGF, HR=1.32 (1.12-1.54); CEA, HR=1.50 (1.29-1.76)). sVEGFR-2 was not prognostic for PFS/OS. Baseline VEGF and CEA were not predictive for PFS/OS outcome to cediranib treatment; low sVEGFR-2 was associated with a trend towards improved cediranib effect in HORIZON II. CONCLUSION: Baseline VEGF and CEA levels were treatment-independent prognostic biomarkers for PFS and OS in both the studies. PMID- 23449352 TI - A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma. AB - BACKGROUND: Transarterial chemoembolisation (TACE) has not been shown to be superior to bland embolisation (TAE) for treatment of hepatocellular carcinoma (HCC). METHODS: We conducted a randomised phase II/III trial in patients with untreated HCC. Patients were randomised to TAE with polyvinyl alcohol (PVA) particles alone or sequential TACE (sTACE) in which cisplatin 50 mg was administered intrarterially 4-6 h before PVA embolisation. Treatment was repeated 3-weekly for up to three treatments. The primary endpoint was overall survival and secondary endpoints were progression-free survival, toxicity and response. Target sample sizes for phase II and III were 80 and 322. RESULTS: The trial was terminated at phase II after 86 patients had been randomised. Patients were well matched for prognostic criteria. All three planned treatments were given to 57.1% (TAE) and 56.8% (TACE) patients. Grade 3/4 toxicity occurred in 63.5% and 83.7%, respectively (P=0.019). End-of-treatment RECIST response (CR+PR) was 13.2 and 32.6% (P=0.04) (mRECIST 47.3% and 67.4) and median overall survival and progression-free survival was 17.3 vs 16.3 (P=0.74) months and 7.2 vs 7.5 (P=0.59), respectively. CONCLUSION: Transarterial chemoembolisation according this novel schedule is feasible and associated with a higher response rate than TAE alone. The survival benefit of TACE over TAE remains unproven. PMID- 23449354 TI - Childhood cancer and factors related to prolonged diagnostic intervals: a Danish population-based study. AB - BACKGROUND: Early diagnosis of childhood cancer provides hope for better prognoses. Shorter diagnostic intervals (DI) in primary care require better knowledge of the association between presenting symptoms, interpretation of symptoms and the wording of the referral letter. METHODS: A Danish nationwide population-based study. Data on 550 children aged <15 years with an incident cancer diagnosis (January 2007-December 2010) were collected through questionnaires to parents (response rate=69%) and general practitioners (GPs) (response rate=87%). The DI from the first presentation in general practice until diagnosis was categorised as short or long based on quartiles. Associations between variables and long DIs were assessed using logistic regression. RESULTS: The GPs interpreted symptoms as 'vague' in 25.4%, 'serious' in 50.0% and 'alarm' in 19.0% of cases. Symptom interpretation varied by cancer type (P<0.001) and was associated with the DI (P<0.001). Vomiting was associated with a shorter DI for central nervous system (CNS) tumours, and pain with a longer DI for leukaemia. Referral letter wording was associated with DI (P<0.001); the shortest DIs were observed when cancer suspicion was raised in the letter. CONCLUSION: The GPs play an important role in recognising early signs of childhood cancer as their symptom interpretation and referral wording have a profound impact on the diagnostic process. PMID- 23449353 TI - Marked improvement of cytotoxic effects induced by docetaxel on highly metastatic and androgen-independent prostate cancer cells by downregulating macrophage inhibitory cytokine-1. AB - BACKGROUND: Overexpression of macrophage inhibitory cytokine-1 (MIC-1) frequently occurs during the progression of prostate cancer (PC) to androgen-independent (AI) and metastatic disease states and is associated with a poor outcome of patients. METHODS: The gain- and loss-of-function analyses of MIC-1 were performed to establish its implications for aggressive and chemoresistant phenotypes of metastatic and AI PC cells and the benefit of its downregulation for reversing docetaxel resistance. RESULTS: The results have indicated that an enhanced level of secreted MIC-1 protein in PC3 cells is associated with their acquisition of epithelial-mesenchymal transition features and higher invasive capacity and docetaxel resistance. Importantly, the downregulation of MIC-1 in LNCaP-LN3 and PC3M-LN4 cells significantly decreased their invasive capacity and promoted the antiproliferative, anti-invasive and mitochrondrial- and caspase dependent apoptotic effects induced by docetaxel. The downregulation of MIC-1 in PC3M-LN4 cells was also effective in promoting the cytotoxic effects induced by docetaxel on the side population (SP) endowed with stem cell-like properties and the non-SP cell fraction from PC3M-LN4 cells. CONCLUSION: These data suggest that the downregulation of MIC-1 may constitute a potential therapeutic strategy for improving the efficacy of current docetaxel-based chemotherapies, eradicating the total mass of PC cells and thereby preventing disease relapse and the death of PC patients. PMID- 23449356 TI - Reply: misunderstandings in the misconception on the use of pack-years in analysis of smoking. PMID- 23449355 TI - Use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs and risk of glioma: a case-control study. AB - BACKGROUND: Few studies have examined the association between use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and risk of glioma and the results have been equivocal. We therefore investigated the influence of NSAID use on glioma risk in a nationwide setting. METHODS: We used national registries in Denmark to identify all patients aged 20-85 years with a first diagnosis of histologically verified glioma during 2000-2009. Each case was matched on birth year and sex to eight population controls using risk-set sampling. We used prescription data to assess NSAID use and classified exposure to low-dose aspirin or non-aspirin (NA) NSAIDs into ever use or long-term use, defined as continuous use for 5 years. Conditional logistic regression was used to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with NSAID use, adjusted for potential confounders. RESULTS: A total of 2688 glioma cases and 18,848 population controls were included in the study. Ever use of low-dose aspirin (OR=0.90; 95% CI: 0.77-1.04) or NA-NSAIDs (OR=1.05; 95% CI: 0.96-1.14) was not associated with glioma risk. Compared with never use, long-term use of low-dose aspirin or of NA-NSAIDs was associated with ORs of 0.80 (95% CI: 0.53 1.21) and 1.11 (0.57-2.17), respectively. We observed no clear patterns of risk in stratified analysis according to estimated doses of low-dose aspirin (<= 100 mg, 150 mg). CONCLUSION: We did not find any apparent association between aspirin or NA-NSAID use and risk of glioma, although our results may be consistent with a slight reduction in glioma risk with long-term use of low-dose aspirin. PMID- 23449357 TI - Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201). AB - BACKGROUND: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. PATIENTS AND METHODS: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II-IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 3 months) or MFP (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 12 months with 6 monthly infusions of 60 mg m(-2) of cisplatin) chemotherapy. RESULTS: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89-1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89 1.39); P=0.33). CONCLUSION: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients. PMID- 23449358 TI - Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer. AB - BACKGROUND: Evidence for non-steroidal anti-inflammatory drugs (NSAIDs) preventing head and neck cancer (HNC) is inconclusive; however, there is some suggestion that aspirin may exert a protective effect. METHODS: Using data from the United States National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined the association between aspirin and ibuprofen use and HNC. RESULTS: Regular aspirin use was associated with a significant 22% reduction in HNC risk. No association was observed with regular ibuprofen use. CONCLUSION: Aspirin may have potential as a chemopreventive agent for HNC, but further investigation is warranted. PMID- 23449359 TI - Misunderstandings in the misconception on the use of pack-years in analysis of smoking. PMID- 23449360 TI - A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours. AB - BACKGROUND: This first-in-human, phase I clinical trial of p28 (NSC745104), a 28 amino-acid fragment of the cupredoxin azurin, investigated the safety, tolerability, pharmacokinetics and preliminary activity of p28 in patients with p53(+) metastatic solid tumours. METHODS: A total of 15 patients were administered p28 i.v. as a short infusion three times per week for 4 weeks followed by a 2-week rest under an accelerated titration 3+3 dose escalation design until either a grade 3-related adverse event occurred or the maximum tolerated dose (MTD) was reached. Single-dose and steady-state serum pharmacokinetics were characterised. Assessments included toxicity, best objective response by RECIST 1.1 Criteria, and overall survival. RESULTS: No patients exhibited any dose-limiting toxicities (DLTs), significant adverse events or exhibited an immune response (IgG) to the peptide. The No Observed Adverse Effect Level (NOAEL) and MTD were not reached. Seven patients demonstrated stable disease for 7-61 weeks, three a partial response for 44-125 weeks, and one a complete response for 139 weeks. Three patients are still alive at 158, 140, and 110 weeks post therapy completion. CONCLUSION: p28 was tolerated with no significant adverse events. An MTD was not reached. Evidence of anti tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non-HDM2-mediated peptide inhibitors of p53 ubiquitination. PMID- 23449361 TI - Does referral to specialist paediatric palliative care services reduce hospital admissions in oncology patients at the end of life? AB - BACKGROUND: Despite advances in the treatment of childhood cancer, some children continue to die from their disease. This study aimed to assess the impact of specialist paediatric palliative care services (SPPCSs) on the number of hospital admissions in children who subsequently died from cancer in Yorkshire, UK. METHODS: An extract of patients aged 0-19 years from the Yorkshire Specialist Register of Cancer in Children and Young People (YSRCCYP) diagnosed from 1990 to 2009 were linked to inpatient hospital episodes data and a SPPCS database. Deaths were included if they occurred before 31 August 2011. Differences in hospital admission patterns were assessed using negative binomial regression and presented as incidence rate ratios (IRRs). RESULTS: Of 2508 children on the YSRCCYP, 657 (26%) had died by the censoring date. A total of 211 children had been referred to the local SPPCS, of whom 182 (86%) had subsequently died. Referral to SPPCS was associated with a significant reduction in the rate of planned hospital admissions (IRR=0.60, 95% CI 0.43-0.85). Central nervous system tumours showed significant decreases for all planned and emergency admissions compared with all other diagnostic groups. CONCLUSION: Referral to SPPCS significantly reduced the number of planned hospital admissions for children and young people with cancer before their death, which are often integral to paediatric oncology treatment regimens. Overall, our findings show that SPPCS have a role in reducing hospital admissions during end of life care of paediatric cancer patients with potential personal, social and economic benefits. PMID- 23449363 TI - Taking drugs very seriously. AB - Neither anti-illegal drug proponents nor their detractors have wholly plausible arguments for their positions, because neither takes responsibility for drug use sufficiently seriously. Instead, only a policy that places users' responsibility at the forefront of the problem is acceptable, one that is sufficiently respectful of actual or potential nonusers' rights not to be wrongfully harmed, directly or indirectly, by drug use, or coerced to support it in any way. PMID- 23449364 TI - Justice and lung cancer. AB - Lung cancer is the leading cause of cancer deaths, yet research funding is by far the lowest for lung cancer than for any other cancer compared with respective death rates. Although this discrepancy should appear alarming, one could argue that lung cancer deserves less attention because it is more attributable to poor life choices than other common cancers. Accordingly, the general question that I ask in this article is whether victims of more avoidable diseases, such as lung cancer, deserve to have their needs taken into less consideration than those of less avoidable diseases, on the grounds of either retributive or distributive justice. Such unequal treatment may be the "penalty" one incurs for negligent or reckless behavior. However, I hope to show that such unequal treatment cannot be supported by any coherent accounts of retributive or distributive justice. PMID- 23449362 TI - Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study. AB - BACKGROUND: We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries. METHODS: We analysed the data on 257,362 women diagnosed with breast cancer during 2000-7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis. RESULTS: Age-standardised 3-year net survival was 87-89% in the UK and Denmark, and 91-94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42-45% elsewhere. Women in the UK had low survival for TNM stage III-IV disease compared with other countries. CONCLUSION: International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated. PMID- 23449365 TI - Continuous sedation until death as physician-assisted suicide/euthanasia: a conceptual analysis. AB - A distinction is commonly drawn between continuous sedation until death and physician-assisted suicide/euthanasia. Only the latter is found to involve killing, whereas the former eludes such characterization. I argue that continuous sedation until death is equivalent to physician-assisted suicide/euthanasia in that both involve killing. This is established by first defining and clarifying palliative sedation therapies in general and continuous sedation until death in particular. A case study analysis and a look at current practices are provided. This is followed by a defense of arguments in favor of definitions of death centering on higher brain (neocortical) functioning rather than on whole brain or cardiopulmonary functioning. It is then shown that continuous sedation until death simulates higher brain definitions of death by eliminating consciousness. Appeals to reversibility and double effect fail to establish any distinguishing characteristics between the simulation of death that occurs in continuous sedation until death and the death that occurs as a result of physician-assisted suicide/euthanasia. Concluding remarks clarify the moral ramifications of these findings. PMID- 23449366 TI - On the impacts of traditional Chinese culture on organ donation. AB - This article examines the impact of traditional Chinese culture on organ donation from the perspective of Confucianism, Buddhism, and Taoism. In each of these cultural systems, it appears that there are some particular sayings or remarks that are often taken in modern Chinese society to be contrary to organ donation, especially cadaveric organ donation. However, this article argues that the central concerns of Buddhism, Confucianism, and Taoism are "great love," "ren," and "dao," which can be reasonably interpreted to support organ donation. The author understands that each cultural system, in order to play its cultural function, must have its central concerns as well as relevant ritual practices (li) that incarnate its religious and ethical commitments. That is, each plays a general cultural role, which influences organ donation in particular not merely through abstract or general ethical principles and teachings, but through a combination of ethical teachings and the forming of particular ritual practices. This article contends that the primary reason Chinese individuals fail to donate sufficient cadaveric organs for transplantation is not because particular remarks or sayings from each of these systems appear to conflict with donation. Neither is it that the central concerns of these systems cannot support cadaveric donation. Rather, it is that modern Chinese individuals have failed to develop and secure relevant ritual practices that support the central concerns of organ transplantation. The article concludes that in order to promote more donations, there is a need to form relevant ritual practices supporting organ donation in conformity with the central concerns of these cultural systems. PMID- 23449367 TI - The durability of carotid endarterectomy: long-term results for restenosis and stroke. AB - BACKGROUND: Carotid endarterectomy is a low-risk treatment for carotid occlusive disease. Recent clinical trials have suggested that carotid angioplasty may be a viable alternative. One important issue that has not been evaluated is the long term recurrent stenosis rate after either intervention. OBJECTIVE: To examine the risk of recurrent stenosis after carotid endarterectomy and to provide long-term data on the durability of carotid endarterectomy. METHODS: A total of 1335 sequential patients were followed up prospectively with annual carotid ultrasonography. All patients were maintained on antiplatelet therapy, and arteriotomies were closed with a patch graft. Operations were performed under general anesthesia with electroencephalographic monitoring and selective shunting. There were no changes in surgical technique during this study. RESULTS: Two-thirds of the patients were men; the mean age was 70 years. Approximately 60% were symptomatic. The 90-day perioperative morbidity and mortality rate was 0.9% (0.4% stroke and 0.5% death). Five patients (0.4%) developed recurrent stenosis >70% over a mean follow-up of 15.8 years. Twelve patients (0.9%) had documentation of late stroke in the ipsilateral carotid distribution. The mean follow-up was 15.8 years. CONCLUSION: Carotid endarterectomy is an extremely safe treatment for carotid stenosis with very low perioperative complications and low rates of recurrent stenosis or late stroke. When endarterectomy is compared with angioplasty, in addition to periprocedural complications, the durability of both interventions needs to be considered, given the risks and costs of repeat interventions. PMID- 23449368 TI - A comparison of neon versus helium ion beam induced deposition via Monte Carlo simulations. AB - The ion beam induced nanoscale synthesis of PtCx (where x ~ 5) using the trimethyl (methylcyclopentadienyl)platinum(IV) (MeCpPt(IV)Me3) precursor is investigated by performing Monte Carlo simulations of helium and neon ions. The helium beam leads to more lateral growth relative to the neon beam because of its larger interaction volume. The lateral growth of the nanopillars is dominated by molecules deposited via secondary electrons in both the simulations. Notably, the helium pillars are dominated by SE-I electrons whereas the neon pillars are dominated by SE-II electrons. Using a low precursor residence time of 70 MUs, resulting in an equilibrium coverage of ~4%, the neon simulation has a lower deposition efficiency (3.5%) compared to that of the helium simulation (6.5%). At larger residence time (10 ms) and consequently larger equilibrium coverage (85%) the deposition efficiencies of helium and neon increased to 49% and 21%, respectively; which is dominated by increased lateral growth rates leading to broader pillars. The nanoscale growth is further studied by varying the ion beam diameter at 10 ms precursor residence time. The study shows that total SE yield decreases with increasing beam diameters for both the ion types. However, helium has the larger SE yield as compared to that of neon in both the low and high precursor residence time, and thus pillars are wider in all the simulations studied. PMID- 23449369 TI - Wooden foreign body embedded in the zygomatic region for 2 years. AB - We report a case of retained wooden foreign body in the zygomatic region which posed a considerable diagnostic difficulty and was the source of persistent draining sinus and other distressing symptoms. The patient was not aware of the foreign body in the maxillofacial region. In such cases a thorough history of the patient is of utmost importance. The case has been described to highlight the problems associated in managing unlikely foreign bodies at unusual facial sites when there is a possibility that radiolucent material is embedded in the wound. PMID- 23449370 TI - Adenomatous neoplasia presenting as aural polyp. AB - Adenomatous neoplasia or glandular tumours in the ear are very rare to occur. We are reporting two patients who presented with polypoid mass in external auditory canal of whom one patient was diagnosed to have ceruminous adenoma of external auditory canal and the other adenomatous carcinoma of middle ear based on histopathology findings of biopsied specimen. Review of available literature shows that both ceruminous adenoma of external auditory canal and adenocarcinoma of middle are very rare to occur and are even difficult to diagnose histopathologically. We would like to emphasize the importance of considering even such rare pathologies while evaluating aural polyps. PMID- 23449371 TI - Recent mortality and morbidity rates of Japanese atrial fibrillation patients: racial differences and risk stratification. AB - Atrial fibrillation (AF) is becoming an epidemiologically important syndrome among the developed countries. Although racial differences exist with regard to AF prevalence, it remains unclear whether the AF mortality and morbidity rates exhibit racial differences. Medical treatment and management of AF is aimed at improving the clinical course of AF patients who reside in a particular region; therefore, the AF mortality and morbidity rates should be assessed from both global and local viewpoints. AF is a progressive disease that might be first detected as paroxysmal, persistent, or permanent. The associations between AF progression and AF-related cardiovascular morbidities and those between the cardiovascular morbidity and mortality rates of AF are important matters of discussion, as they reflect the rationale of AF therapy. At present, AF patients have a wide variety of backgrounds, and these analyses would require stratification by risks, which would not be free from racial differences. In this review, the mortality and morbidity rates of Japanese AF patients are reviewed and discussed. PMID- 23449372 TI - Prevalence and clinical outcome of polyvascular atherosclerotic disease in patients undergoing coronary intervention. PMID- 23449373 TI - Prevalence and clinical outcome of polyvascular atherosclerotic disease in patients undergoing coronary intervention--reply. PMID- 23449374 TI - Is a novel SCN3B mutation commonly found in SCN5A-negative Brugada syndrome patients? PMID- 23449375 TI - Improved readout precision of the Bicoid morphogen gradient by early decoding. AB - Transcription factors (TFs) bind to specific DNA sequences to induce or repress gene expression. Expression levels can be tuned by changing TF concentrations, but the precision of such tuning is limited, since the fraction of time a TF occupies its binding site is subject to stochastic fluctuations. Bicoid (Bcd) is a TF that patterns the early Drosophila embryo by establishing an anterior-to posterior concentration gradient and activating specific gene targets ("gap genes") in a concentration-dependent manner. Recently, the Bcd gradient and its in-vivo diffusion were quantified in live embryos, raising a quandary: the precision by which the Bcd target genes are defined (one-cell resolution) appeared to exceed the physical limits set by the stochastic binding of Bcd to DNA. We hypothesize that early readout of Bcd could account for the observed precision. Specifically, we consider the possibility that gap genes begin to be expressed earlier than typically measured experimentally, at a time when the distance between the nuclei is large. At this time, the difference in Bcd concentration between adjacent nuclei is large, enabling better tolerance for measurement imprecision. We show that such early decoding can indeed increase the accuracy of gap-gene expression, and that the initial pattern can be stabilized during subsequent divisions. PMID- 23449376 TI - Fecal impaction: a cause for concern? AB - Fecal impaction (FI) is a common cause of lower gastrointestinal tract obstruction lagging behind stricture for diverticulitis and colon cancer. It is the result of chronic or severe constipation and most commonly found in the elderly population. Early recognition and diagnosis is accomplished by way of an adequate history and physical examination in conjunction with an acute abdominal series. Prompt identification and treatment minimizes the risks of complications such as bowel obstruction leading to aspiration, stercoral ulcers, perforation, and peritonitis. Treatment options include gentle proximal softening in the absence of complete bowel obstruction, distal washout, and manual extraction. Surgical resection of the involved colon or rectum is reserved for cases of FI complicated by ulceration and perforation leading to peritonitis. Recurrence is common, and can be managed by increasing dietary fiber content to 30 gm/day, increased water intake, and discontinuation of medications that can contribute to colonic hypomotility. PMID- 23449377 TI - Meningitis due to Bacillus cereus: A case report and review of the literature. AB - Bacillus cereus is infrequently associated with invasive central nervous system (CNS) disease. Infection is associated with conditions that lead to reduced host immunity and provide direct access to the CNS, such as spinal anesthesia and ventricular tubes and shunts. A case of ventriculitis secondary to B cereus in a patient receiving intrathecal chemotherapy is reported, along with a review of the current literature. B cereus can colonize medical devices, thus posing a risk for invasive disease. Despite aggressive treatment with broad-spectrum anti infectives, the mortality of CNS invasive B cereus is high. Clinicians should not dismiss Gram-positive rods resembling Bacillus species from normally sterile sites as contaminants in critically ill patients. Appropriate antibiotic therapy should be promptly initiated to limit morbidity and mortality. PMID- 23449378 TI - Sensorineural hearing loss in patients with chronic suppurative otitis media. AB - Even though there are other complications of chronic suppurative otitis media, the aspect of hearing loss is often studied. Nevertheless, the occurrence of sensorineural hearing loss in patients with this disease is still controversial. This study aim (1) to assess the association between sensorineural hearing loss and chronic suppurative otitis media, (2) to investigate some clinical factors that might affect the sensorineural component in patients with this disease. This was a retrospective analysis of the clinical records and pure tone audiograms of patients with chronic suppurative otitis media in a Nigerian Tertiary Health Institution from January 2003 to December 2008. Sixty-nine patients with a mean age of 28.93 years; standard deviation of 18.593 were studied. They had an age range of 4-73 years. The duration of otorrhea ranged from 2 months to 20 years; with a mean of 6.11 years (standard deviation of 6.393). The mean bone conduction threshold in the diseased ear was 39.07 dB (standard deviation of 12.028), and 10.26 dB (standard deviation of 2.620) in the control ear (P < 0.05). The mean bone conduction threshold differences between the diseased and control ears range from 21.69 to 34.52 dB across the frequencies 0.5, 1.0, 2.0, and 4.0 kHz. These differences tended to increase with increasing frequency and were all significant (P < 0.05). In the diseased ears, there were no significant correlation between the age, duration of otorrhea, and the degree of SNHL (r = 0.186, P > 0.05; r = 0.190, P > 0.05 respectively). Patients with chronic suppurative otitis media had a significant degree of sensorineural hearing loss in this study. The higher frequencies were more affected; however, the patient's age and duration of otorrhea seem not to have any correlation with the degree of sensorineural hearing loss. PMID- 23449379 TI - Medical management of venous thromboembolism: what the interventional radiologist needs to know. AB - Deep vein thrombosis and pulmonary embolism are considered manifestations of the same pathophysiological process and are together referred to as venous thromboembolism (VTE). VTE is a common disorder with an incidence of 1 to 3 in 1000 in the general population. It is estimated that the incidence of VTE is likely to increase as the average life expectancy of the U.S. population increases. Treatment of VTE consists of anticoagulation; the duration of anticoagulation is largely determined by the circumstances surrounding development of the thrombotic event. Vitamin K antagonists, the only oral anticoagulants approved for treatment of VTE in the United States, have several drawbacks and therefore new oral anticoagulants are currently in various stages of development. This review focuses on the risk factors for VTE and the approach to determining the duration of anticoagulation in patients with VTE. Results of clinical trials on the new oral anticoagulants that may soon be licensed for the treatment of VTE are also discussed. PMID- 23449380 TI - A New Secondary Model Developed for the Growth Rate of Escherichia coli O157:H7 in Broth. AB - This study was attempted to develop a new exponential sum model to describe the effect of temperature on growth rate (GR) of Escherichia coli O157:H7 in broth. The growth rates of E. coli O157:H7 at different storage temperatures (4, 10, 15, 20, 25, 30, and 35 degrees C) estimated by fitting with the modified Gompertz model were used to develop secondary models such as square root model, Ratkowsky model and exponential sum model. Measures of coefficient of determination (R(2)), root mean square error (RMSE) and the sum of squares due to error (SSE) were employed to compare the performances of these three secondary models. Based on these criteria, the developed exponential sum model showed the better goodness-of fit and performance. PMID- 23449381 TI - Asian women have greater abdominal and visceral adiposity than Caucasian women with similar body mass index. AB - BACKGROUND: In the Multiethnic Cohort Study, Japanese Americans (JA) have lower mean body mass index (BMI) compared with Caucasians, but show a higher waist-to hip ratio at similar BMI values and a greater risk of diabetes and obesity associated cancers. OBJECTIVE: We investigated the abdominal, visceral and hepatic fat distribution in these Asian and Caucasian Americans. DESIGN: A cross sectional sample of 60 female cohort participants (30 JA and 30 Caucasians), of ages 60-65 years and BMIs 18.5-40 kg m(-2), underwent anthropometric measurements and a whole-body dual energy X-ray absorptiometry (DXA) scan: a subset of 48 women also had abdominal magnetic resonance imaging (MRI). RESULTS: By design, JA women had similar BMIs (mean 26.5 kg m(-2)) to Caucasian women (27.1 kg m(-2)). JA women were found to have a significantly smaller hip circumference (96.9 vs 103.6 cm; P=0.007) but not a significantly lower DXA total fat mass (25.5 vs 28.8 kg; P=0.16). After adjusting for age and DXA total fat mass, JA women had a greater waist-to-hip ratio (0.97 vs 0.89; P<0.0001), DXA trunk fat (15.4 vs 13.9 kg; P=0.0004) and MRI % abdominal visceral fat (23.9 vs 18.5%; P=0.01) and a lower DXA leg fat mass (8.2 vs 10.0 kg; P=<.0001). Their MRI % subcutaneous fat (33.4 vs 30.2%; P=0.21) and % liver fat (5.8 vs 3.8%; P=0.06) did not significantly differ from that of Caucasian women. CONCLUSIONS: Our findings build on limited past evidence, suggesting that Asian women carry greater abdominal and visceral fat when compared with Caucasian women with similar overall adiposity. This may contribute to their elevated metabolic risk for obesity-related diseases. PMID- 23449382 TI - Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice. AB - BACKGROUND: Maternal obesity is linked with offspring obesity and type 2 diabetes. Skeletal muscle (SM) insulin resistance is central to the development of diabetes. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited in SM of fetuses born to obese mothers. OBJECTIVE: The aim of this study was to evaluate the effect of maternal metformin administration on AMPK activity and reversion of adverse changes in offspring SM of obese mice. DESIGN: Female weanling C57BL/6J mice received either control diet (CON, 6 mice) or high fat diet (HFD; OB, 12 mice) for 8 weeks before mating. After mating, mice continued receiving their respective CON or OB diets. In addition, 6 of those 12 mice fed with fat diet also received metformin administration (2 mg per ml in drinking water) throughout gestation and lactation (MET). After weaning at postnatal 21 days, offspring were fed a HFD to mimic a postnatal obesogenic environment until necropsy. RESULTS: Mothers receiving the fat diet developed obesity. OB offspring showed higher adiposity than CON and MET offspring. AMPK phosphorylation was lower in SM of OB offspring. beta-Catenin and myogenic regulatory factors, MyoD and myogenin, were downregulated in OB muscle, whereas the adipogenic marker, peroxisome proliferator-activated receptor-gamma, was upregulated compared with CON muscle. Metformin administration prevented these changes in OB offspring SM. OB but not MET offspring demonstrated glucose intolerance. Mitochondrial content decreased, and activities of citrate synthase and beta-hydroxyacyl-CoA dehydrogenase also decreased in OB offspring SM, whereas they were recovered in MET offspring SM. CONCLUSION: Maternal metformin administration improves SM development in OB offspring. PMID- 23449383 TI - Pulmonary embolism in a female collegiate cross-country runner presenting as nonspecific back pain. AB - OBJECTIVE: The purpose of this case report is to describe a female athlete with back and right scapular pain due to pulmonary embolism. CLINICAL FEATURES: A 20 year-old female collegiate cross-country runner presented to a chiropractic clinic with pain in the right scapular area that was severe, stabbing, and worsened with respiration. She had a cough and experienced difficulty lying on her right side. She had an elevated d-dimer. Chest radiograph demonstrated pleural effusion, prompting a thoracic computed tomographic angiogram that showed a large right lower lobe embolus and pulmonary infarct. INTERVENTION AND OUTCOME: The patient was hospitalized, prescribed anticoagulant therapy, and monitored for 6 months. She was able to return to competitive running 8 months later. CONCLUSION: This case raises awareness of the occurrence of birth control medication for the purpose of enhanced performance in female athletes and the associated risks of using this medication for enhanced performance. PMID- 23449384 TI - Respiratory bacterial infections in cystic fibrosis. AB - PURPOSE OF REVIEW: Bacterial respiratory infections are the main cause of morbidity and mortality in patients with cystic fibrosis (CF). Pseudomonas aeruginosa remains the main pathogen in adults, but other Gram-negative bacteria such as Achromobacter xylosoxidans and Stenotrophomonas maltophilia as well as nontuberculous mycobacteria have been shown to play an important role in the lung disease. The purpose of this review is to summarize the knowledge on disease and treatment of infection with CF-related pathogens. RECENT FINDINGS: The role of the paranasal sinuses as a source of infection and site of bacterial adaptation has been recognized. This review will focus on the different conditions encountered by the bacteria in sinuses and lung, as well as the principles of treatment in the different infection sites. SUMMARY: Chronic, pulmonary infections remain the single most prominent cause of the increased morbidity and mortality in CF. After the increasing efficiency of anti-P. aeruginosa treatment, newer pathogens have been identified, with individual clinical characteristics. Microbiological surveillance is very important in keeping the patients stable. Samples from both the lower and upper respiratory tract (nasal sampling) should be investigated and both infection sites should be treated. PMID- 23449385 TI - On alert for autism spectrum disorders. PMID- 23449387 TI - An asymptomatic subcutaneous nodule of the lower back: a sentinel lesion for a diagnosis not to be missed. PMID- 23449388 TI - BCR-ABL Translocation in Pediatric Acute Lymphoblastic Leukemia in Southern India. AB - Cytogenetics and polymerase chain reaction (PCR) based assays provide important information regarding biologically defined and prognostically relevant subgroups in acute leukemias. We utilized karyotyping and molecular analysis by reverse transcriptase PCR for the BCR-ABL translocation, in addition to morphological study, cytochemistry and immunophenotyping, to study 24 cases of pediatric acute lymphoblastic leukemia (ALL). Our objective was to determine the frequency of the BCRABL translocation in childhood ALL from southern India. Karyotyping showed one case of hyperdiploidy, one case of t (12; 21) translocation and one case of 46, XY-21+mar. The BCR-ABL translocation was found in 8.3% of these cases. One of these was a cryptic translocation, the karyotype being normal. BCR-ABL positivity in ALL is associated with aggressive disease and has been shown to be a poor prognostic factor, especially in children. PMID- 23449389 TI - The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover. AB - The serine threonine kinase checkpoint kinase 2 (CHK2) is a DNA damage checkpoint protein important for the ATM-p53 signaling pathway. In addition to its phosphorylation, CHK2 is also ubiquitylated, and both post-translational modifications are important for its function. However, although the mechanisms that regulate CHK2 phosphorylation are well established, those that control its ubiquitylation are not fully understood. In this study, we demonstrate that the ubiquitin E3 ligase PIRH2 (p53-induced protein with a RING (Really Interesting New Gene)-H2 domain) interacts with CHK2 and mediates its polyubiquitylation and proteasomal degradation. We show that the deubiquitylating enzyme USP28 forms a complex with PIRH2 and CHK2 and antagonizes PIRH2-mediated polyubiquitylation and proteasomal degradation of CHK2. We also provide evidence that CHK2 ubiquitylation by PIRH2 is dependent on its phosphorylation status. Cells deficient in Pirh2 displayed accumulation of Chk2 and enhanced hyperactivation of G1/S and G2/M cell-cycle checkpoints. This hyperactivation was, however, no longer observed in Pirh2-/-Chk2-/- cells, providing evidence for the importance of Chk2 regulation by Pirh2. These findings indicate that PIRH2 has central roles in the ubiquitylation of Chk2 and its turnover and in the regulation of its function. PMID- 23449392 TI - Retraction: Inhibition of RelA phosphorylation sensitizes chemotherapeutic agents mediated apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells. PMID- 23449390 TI - Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y? AB - The Y box is an important sequence motif found in promoters and enhancers containing a CCAAT box - one of the few elements enriched in promoters of large sets of genes overexpressed in cancer. The search for the transcription factor(s) acting on it led to the biochemical purification of the nuclear factor Y (NF-Y) heterotrimer, and to the cloning - through the screening of expression libraries of Y box-binding protein 1 (YB-1), an oncogene, overexpressed in aggressive tumors and associated with drug resistance. These two factors have been associated with Y/CCAAT-dependent activation of numerous growth-related genes, notably multidrug resistance protein 1. We review two decades of data indicating that NF-Y ultimately acts on Y/CCAAT in cancer cells, a notion recently confirmed by genome-wide data. Other features of YB-1, such as post-transcriptional control of mRNA biology, render it important in cancer biology. PMID- 23449391 TI - p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway. AB - There is growing evidence that the p53 tumour suppressor downregulates vascular endothelial growth factor (VEGF) expression, although the underlying mechanisms remain unclear and controversial. Here we provide insights from in vitro experiments and in vivo xenotransplantation assays that highlight a dual role for p53 in regulating VEGF during hypoxia. Unexpectedly, and for the first time, we demonstrate that p53 rapidly induces VEGF transcription upon hypoxia exposure by binding, in an HIF-1alpha-dependent manner, to a highly conserved and functional p53-binding site within the VEGF promoter. However, during sustained hypoxia, p53 indirectly downregulates VEGF expression via the retinoblastoma (Rb) pathway in a p21-dependent manner, which is distinct from its role in cell-cycle regulation. Our findings have important implications for cancer therapy, especially for tumours that harbour wild-type TP53 and a dysfunctional Rb pathway. PMID- 23449393 TI - Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage. AB - Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53 dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment. PMID- 23449394 TI - Shaping organisms with apoptosis. AB - Programmed cell death is an important process during development that serves to remove superfluous cells and tissues, such as larval organs during metamorphosis, supernumerary cells during nervous system development, muscle patterning and cardiac morphogenesis. Different kinds of cell death have been observed and were originally classified based on distinct morphological features: (1) type I programmed cell death (PCD) or apoptosis is recognized by cell rounding, DNA fragmentation, externalization of phosphatidyl serine, caspase activation and the absence of inflammatory reaction, (2) type II PCD or autophagy is characterized by the presence of large vacuoles and the fact that cells can recover until very late in the process and (3) necrosis is associated with an uncontrolled release of the intracellular content after cell swelling and rupture of the membrane, which commonly induces an inflammatory response. In this review, we will focus exclusively on developmental cell death by apoptosis and its role in tissue remodeling. PMID- 23449396 TI - Electronic structure, optical properties and the mechanism of the B3-B8 phase transition of BeSe: insights from hybrid functionals, lattice dynamics and NPH molecular dynamics. AB - We have investigated the electronic structure and the mechanism of the pressure induced phase transition of beryllium selenide (BeSe) by employing a first principles pseudopotential method within the framework of density functional theory. Our study demonstrates that use of the hybrid PBE0 functional (PBE stands for Perdew, Burke and Ernzerhof) leads to significant improvement in the band gap calculations, compared to those using either of the common density functionals (local density approximation (LDA) and generalized gradient approximation (GGA)), which severely underestimate the band gap of BeSe. The band gap obtained from the hybrid PBE0 functional shows excellent agreement with available experimental data. A constant-pressure (NPH) first-principles molecular dynamics (FPMD) approach has been adopted to characterize the first-order pressure induced phase transition from the zinc blende (ZB) to the nickel arsenide (NiAs) structure. We have shown that the FPMD simulation overestimates the transition pressure P(T) (compared to static enthalpy and experimental data) due to overpressure in the simulation box. The MD simulation reveals the structural pathway (cubic -> orthorhombic -> monoclinic -> hexagonal), leading from the ZB phase to the NiAs phase. To find an explanation for the phase transition we calculated the vibrational and elastic properties under pressure. Negative Gruneisen parameters were obtained for the transverse acoustic phonon modes at the X and L high symmetry points. However, no mechanical instability or imaginary frequencies were found at pressures near P(T). Thus the transition results from a thermodynamic instability rather than an elastic/dynamical one. We have also calculated the optical properties of both the B3 and B8 phases, such as the real and imaginary parts of the dielectric constant, reflectivity, loss function and refractive index, and compared them with the existing experimental and theoretical data. An abrupt decrease is obtained from the reflectivity spectrum of the NiAs phase at P(T), which is supported from the peaks in the loss function. PMID- 23449395 TI - IL-24 sensitizes tumor cells to TLR3-mediated apoptosis. AB - Interleukin-24 (IL-24), a member of the IL-10 cytokine family whose physiological function remains largely unknown, has been shown to induce apoptosis when expressed in an adenoviral background. It is yet little understood, why IL-24 alone induced apoptosis only in a limited number of tumor cell lines. Analyzing an influenza A virus vector expressing IL-24 for its oncolytic potential revealed enhanced pro-apoptotic activity of the chimeric virus compared with virus or IL 24 alone. Interestingly, IL-24-mediated enhancement of influenza-A-induced apoptosis did not require viral replication but critically depended on toll-like receptor 3 (TLR3) and caspase-8. Immunoprecipitation of TLR3 showed that infection by influenza A virus induced formation of a TLR3-associated signaling complex containing TRIF, RIP1, FADD, cFLIP and pro-caspase-8. Co-administration of IL-24 decreased the presence of cFLIP in the TLR3-associated complex, converting it into an atypical, TLR3-associated death-inducing signaling complex (TLR3 DISC) that induced apoptosis by enabling caspase-8 activation at this complex. The sensitizing effect of IL-24 on TLR3-induced apoptosis, mediated by influenza A virus or the TLR3-specific agonist poly(I:C), was also evident on tumor spheroids. In conclusion, rather than acting as an apoptosis inducer itself, IL-24 sensitizes cancer cells to TLR-mediated apoptosis by enabling the formation of an atypical DISC which, in the case of influenza A virus or poly(I:C), is associated with TLR3. PMID- 23449397 TI - Nanorings and nanocrescents formed via shaped nanosphere lithography: a route toward large areas of infrared metamaterials. AB - This paper presents a new approach to nanosphere lithography, which overcomes undesirable manufacturing issues such as complex tilted-rotary evaporation and ion beam milling. A key innovation in this process is the use of non-conductive edge strips placed on top of the samples prior to metal removal. Such elements help to direct the flow of reactive ions during plasma etching and produce well ordered arrays of metallic nanorings and nanocrescents over large areas of ~1 cm(2). The obtained highly uniform nanocrescent array exhibits an electric resonance of 1.7 MUm and a magnetic resonance of 3 MUm. The absorption resonances of the fabricated nanorings depend on their diameters and shift toward shorter wavelengths (lambda = 1.7 MUm for do = 308 nm) as compared to larger rings (lambda = 2.2 MUm do = 351 nm). FDTD-based simulations match well with the experimental results. This 'shaped nanosphere lithography' approach creates opportunities to generate nanorings and nanocrescents that promise potential applications in chemical and biological sensing, for surface enhanced spectroscopy and in the field of infrared metamaterials. PMID- 23449398 TI - Tobacco display and brand communication at the point of sale: implications for adolescent smoking behaviour. AB - BACKGROUND: In England, point-of-sale (PoS) displays in larger shops were prohibited in April 2012, with an exemption for smaller retailers until 2015. The aim of this study was to examine the association between tobacco displays and brand communication at the PoS and adolescent smoking behaviour, and to assess the potential benefits likely to accrue from this legislation. METHODS: Self completion questionnaire survey in students aged 11-15 years in March 2011. RESULTS: The odds of ever-smoking doubled for those visiting shops almost daily relative to less than once a week (OR 2.23, 95% CI 1.40 to 3.55), and susceptibility increased by around 60% (OR 1.62, 95% CI 1.25 to 2.10). Noticing tobacco on display every time during store visits increased the odds of susceptibility more than threefold compared with never noticing tobacco (OR 3.15, 95% CI 1.52 to 6.54). For each additional tobacco brand recognised at the PoS, the adjusted odds of being an ever-smoker increased by 5% (OR 1.05, 95% CI 1.03 to 1.06) and of susceptibility by 4% (OR 1.04, 95% CI 1.02 to 1.05). The association between frequency of visiting stores and susceptibility was predominantly due to exposure in small shops. CONCLUSIONS: Exposure to and awareness of PoS displays and brands in displays were associated with smoking susceptibility. The association between PoS display exposure and smoking susceptibility was predominantly due to exposure in small shops. These findings suggest that a one-off, comprehensive tobacco display ban is the recommended approach for countries considering a display ban. PMID- 23449400 TI - The epidemiology of upper extremity injuries presenting to the emergency department in the United States. AB - BACKGROUND: The epidemiology of upper extremity injuries presenting to emergency departments in the USA is not well studied. The purpose of this investigation was to estimate the incidence rates of upper extremity injuries presenting to emergency departments. METHODS: The National Electronic Injury Surveillance System (NEISS)-a database of emergency department visits based on a sample of hospitals selected and weighted to represent the entire US population in order to allow estimates of overall incidence-was queried for all upper extremity injuries presenting to US emergency departments in 2009. Injury types were analyzed for each region of the upper extremity, and incidence rates were calculated based on population estimates from the US Census. RESULTS: A query of the NEISS resulted in 92,601 records of upper extremity injury treated at an emergency department in the USA in 2009, which translates to an estimated total of 3,468,996 such injuries that year. This corresponds to an incidence of 1,130 upper extremity injuries per 100,000 persons per year. The most common region injured was the finger (38.4%). The most common upper extremity injury was a fracture (29.2%). Specific injuries with high incidence rates (all per 100,000 per year) included finger lacerations (221), wrist fractures (72), finger fractures (68), and lower arm fractures (64). Home is the most common setting for an upper extremity injury. CONCLUSIONS: The NEISS provides estimates of the incidences of upper extremity injuries that may be useful for public health initiatives. PMID- 23449399 TI - Technological Barriers in the Use of Electrochemical Microsensors and Microbiosensors for in vivo Analysis of Neurological Relevant Substances. AB - In this paper is presented an overview of the technological barriers faced by the in vivo brain analysis with microelectrodes. Numerous microsensors and enzymatic microbiosensors have been developed for the real time monitoring of neurotransmitters, neuromodulators, drugs and diverse other biological relevant substances. A clear understanding of the working principle, advantages and limitations is essential for the acquisition of valid data in neurological investigations. Some of the aspects presented here refer to: microelectrode insertion and positioning related to possibilities to minimize tissue damage, spatial and temporal resolution of the measurements, actual controversies in data interpretation and sensor calibration, simultaneous detection of multiple analytes, interferences and state of the art in the development of wireless devices. PMID- 23449401 TI - Two cases of congenital cholesteatoma of the tympanic membrane. AB - Congenital cholesteatoma of the tympanic membrane is rare, and lesions without a history of otitis media or any other adverse events involving the tympanic membrane are extremely rare. We report two cases of this lesion; one was a 3-year old girl who underwent removal of a cholesteatoma using retroauricular approach and a partial myringoplasty with an underlay technique, and the other was a 2 year-old girl in whom a cholesteatoma was enucleated without grafting. This disease is thought to be of embryonic origin. PMID- 23449403 TI - [New approaches to drug discovery research and medical treatment using viruses- viruses are valuable biomaterials]. PMID- 23449402 TI - Assessment of deformities of the lip and nose in cleft lip alveolus and palate patients by a rating scale. AB - INTRODUCTION: Labial and nasal deformities have always been a fundamental problem in the treatment of cleft lip, alveolus and palate patients. The primary surgical treatment of nasolabial area is of paramount importance in order to obtain both an esthetical correction of the deformity and a progressive and a balanced development of mid-face. In this study the nasal deformities in patients with cleft lip, alveolus and palate (CLAP) were analyzed and the relevant role of the perinasal, perioral muscular balance and the inborn dislocation of the alar cartilages are presented. PATIENTS AND METHODS: 50 CLAP patients were analyzed, 40 UCLP and 10BCLP. The lip repair was done by modification of Millard's technique. The severity of the cleft appearance was evaluated pre and post operatively, according to a pre-agreed visual rating scale. There are 4 degrees of severity of the deformity pre operatively (mild, moderate, severe and very severe) and post operatively 5 categories of outcome (excellent,very good, good, satisfactory and poor), depending on the scores obtained by summing up the points corresponding to different types of deformity. This scale is closely related to the American Cleft Palate classification of clefts. RESULTS: In the 40 UCLP patients, 8 excellent, 10 very good, 16 good and 6 satisfactory results were obtained following primary cheiloplasty. In 10 BCLP patients 1 very good, 7 good, 1 satisfactory and 1 poor result were obtained. CONCLUSIONS: During the primary repair, it is important to correct the abnormal position of ala nasi, the nasal floor and the base of the columella. Abnormalities in the insertion of the nasolabial muscles with their abnormal function contribute to the cleft nose deformities. Therefore the reconstruction not only the orbicularis muscle but also of the paranasal muscles is therefore important for a symmetrical growth of the nose. Separate suture of intrinsic orbicularis oris provide a better shape to the vermillion. The position of the alar cartilage plays an important role for the symmetry of the nose. It is necessary to place the alar base symmetrically in three dimensions. PMID- 23449404 TI - [Development of a detection system for circulating tumor cells in peripheral blood using a next generation conditionally-replicating adenovirus]. AB - An easy and sensitive detection method for circulating tumor cells (CTC) is expected to be developed because CTC are a promising biomarker for early diagnosis of tumors and prognosis prediction of tumor patients. Our group has already developed a CTC detection method using a conditionally replicating adenovirus (Ad) which efficiently replicates and expresses GFP in telomerase positive tumor cells. However, malignant tumor cells express much low levels of coxsackievirus and adenovirus receptor (CAR), leading to inefficient infection with a conventional conditionally replicating Ad. In addition, a tiny fraction of normal blood cells, including lymphocytes, express GFP following infection. To overcome these problems, we have developed a next-generation conditionally replicating Ad. The next-generation conditionally replicating Ad possesses the fiber protein derived from Ad serotype 35, leading to efficient infection in both CAR-positive and -negative tumor cells, because the fiber protein of Ad serotype 35 binds to CD46, which is expressed on almost all human cells. Furthermore, sequences complementary to blood cell-specific miRNA (miR-142-3p) were inserted into the 3' untranslated region of the E1 gene and GFP gene, leading to the suppression of GFP expression in normal blood cells. In this symposium, we will not only introduce the importance of CTC as a biomarker and conventional CTC detection methods but also show our data of the novel CTC detection using the next-generation conditionally replicating Ad. PMID- 23449405 TI - [Development of incurable cancer cell targeted agents using viral technology]. AB - The safety and anti-tumor effect of oncolytic virus have been reported in a clinical study conducted in Japan. We have engineered a novel multimutated tumor specific oncolytic herpes virus, harboring a smooth muscle-specific calponin promoter. Since tumor cells present in a hypoxic environment are known to be resistant to chemotherapy and radiotherapy, we also engineered a novel oncolytic herpes virus targeting a specific tumor microenvironment, which harbors a gene encoding a fusion protein of oxygen-dependent degradation (ODD) domain of HIF1alpha and ICP4, a master viral transcription factor required for replication. The recombinant virus selectively replicates in and disrupts the target tumor cells, including human sarcoma and malignant mesothelioma cells which are unresponsive to chemotherapy and molecular targeted therapy. We confirmed significant anti-tumor effects of the novel viruses in vivo in an allogeneic experimental model of an undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma; MFH) spontaneously generated in immunocompetent Fischer rats. Our viruses, manufactured in the Master Virus Seed Stock in the Good Manufacturing Practice facility will become novel agents that enable tumor cells unresponsive to conventional treatment to be disrupted. PMID- 23449406 TI - [Development of an adenovirus vector containing a hepatitis C virus expression cassette and its application]. AB - Hepatitis C virus (HCV) is a hepatotropic member of the Flaviviridae family and contains a 9.6 kb positive-sense RNA genome. Approximately 170-million people are infected with HCV worldwide. These people face increased risks of chronic hepatitis, cirrhosis and hepatocellular carcinoma compared with the general population. Transduction of the HCV genome into hepatocytes is essential for understanding the mode of action of HCV infection, and for preparing HCV, evaluating HCV replication, and screening anti-HCV drugs. Although electroporation of in vitro-synthesized HCV genome and transduction of plasmid vectors containing the HCV genome are widely used in HCV research, a more convenient system with higher transduction efficiency is needed. Among viral transduction systems, adenovirus (Ad) vector is one of the most efficient and convenient systems; Ad vector has been widely used in clinical gene therapies. Therefore, Ad vector is a promising system for the delivery of the HCV genome; however, an Ad vector expressing the HCV genome has never been developed. We here describe the preparation of an Ad vector expressing the HCV genome, and outline future directions of HCV research using this vector system. PMID- 23449407 TI - [Study of next generation influenza vaccine focused on "cross-protection by mucosal immunization" and "seed virus strains"]. AB - Endemic infection by seasonal influenza virus usually occurs every winter season. Inside the host, human influenza viruses frequently undergo various point mutations at antigenic regions, in response to antibody pressure. Furthermore, the influenza virus has undergone frequent antigenic shifts for at least 100 years, some of which have caused influenza pandemics. In Japan, intramuscular immunization with influenza split-virion vaccines has been used to prevent seasonal influenza virus infections. Unfortunately, the efficacy of the current influenza vaccine immunization method is limited, even against viruses belonging to the same clade. Furthermore, the current vaccines are not expected to be protective against antigenically shifted viruses. Therefore, new approaches to vaccine development are needed to protect human populations against a potential pandemic virus. We are studying novel influenza vaccine designs to resolve the above weaknesses of the current influenza vaccines. I will describe our vaccine studies, "Cross-protection by mucosal immunization," and, "Preparation of seed virus strains to produce vaccines for possible pandemic influenza," in this symposium. PMID- 23449408 TI - [Innate immune responses against viral infection and its suppression by viral proteins]. AB - Retinoic acid-inducible gene-I(RIG-I) is a cytoplasmic RNA helicase and a viral RNA sensor. RIG-I recognizes 5' triphosphate double-stranded RNA (dsRNA) and activates the IPS-1 adaptor molecule. The association of IPS-1 with RIG-I causes the formation of the prion-like structure of IPS-1. This structure is essential for activation of the signaling required for the induction of type I interferon (IFN), which possesses strong antiviral activity. Recent studies have revealed the novel factors involved in the RIG-I-dependent pathway. DDX3 and DDX60 RNA helicases associate with RIG-I and promote its binding to viral RNA. Riplet and TRIM25 ubiquitin ligase deliver Lys63-linked polyubiquitin moiety to RIG-I and result in signal activation. Several pathogenic viruses have evolved excellent systems to suppress type I IFN production. For example, NS3-4A of hepatitis C virus (HCV) cleaves IPS-1, which is the adaptor molecule of RIG-I, while the HCV core protein abrogates DDX3 function to suppress RIG-I-dependent IPS-1 activation, and the NS-1 of flu inhibits TRIM25 function to suppress RIG-I activation. PMID- 23449409 TI - [The future forms of medical services--seeking the ideal conditions of home medical care and pharmacists/pharmacies]. PMID- 23449410 TI - [The novel image of pharmacist of a super-aged society in Japan]. AB - The percentage of the population over age 65 in Japan was greater than 23% in 2010. Therefore, Japan is the world's first "super-aged society", and our country needs a new regional health care system. Our medical systems face many challenges, such as this increase in elderly population with chronic diseases, maintenance of universal health insurance and free access to hospitals, and expensive health care costs. It is not easy to change the current health care system without a sufficient number of doctors. On the other hand, Japan's curriculum in pharmaceutical education has been expanded to six years to establish a new profession of pharmacist. Rapid progress in the market of pharmacies in accepting prescriptions since 1974 has caused pharmacists to primarily act as "technicians". But this is not the best way to solve the serious problems of Japanese medical systems. I want to present the image of a next generation pharmacist (Pharmacist 3.0), to be involved in the idea of collaborative drug therapy management (CDTM) in this article. The total optimization of our medical supply system with all medical and pharmaceutical specialists is necessary in Japan. PMID- 23449411 TI - [Regional medical care coordination--what is the best way for pharmacists to work with the community?]. AB - In the future, home medical care will become increasingly significant. The Heisei 24 annual budget request included 2,000,000,000 yen for "the base pharmacy service which provides home medical care," more is anticipated, and greater expectations are attached to activity in the area of the pharmacist. However, as to the actual setting of this care, home medical care provided by pharmacists is still lacking. The community-based pharmacist is pursued and supported by the pharmaceutical business, and deals with issues of patient compatibility. Therefore, in the current pharmacy model, concern with home patients is not adequate. Also, as regards home medical care, the problem is not only with the community-based pharmacist. For medicine prescribed in a hospital to a patient for home medical care, it is a hospital-based pharmacist that serves as a bridge. However, hospital-based pharmacists are constantly tasked with multiple in hospital business functions, so in this present situation, the pharmacist's concern with home care is minimal. There should be cooperation between pharmacists concerned with treatment at home, discussion of how to introduce ideas based on cooperative medicine in the area, and so on, as regards the actual state of the conference. This would lead to the realization that "medical treatment without a break in care" would involve patients leaving the hospital, and assuring continued medical/pharmaceutical oversight, with a medical exchange as an example. PMID- 23449412 TI - [Community home healthcare in 6-year pharmacy education]. AB - As we enter more and more into a super-aging society, the requirement for home healthcare will increase. Pharmacists must work along with doctors and nurses in the field of home healthcare. Within the 6-year pharmacy curriculum, we must educate students as medicinal professionals who will join a medical team to serve the community. The Good Practice (GP) program, which has been supported by the Ministry of Education, Culture, Sports, Science & Technology, continues to be offered in our university. As a part of this program, students learn home healthcare in the community in cooperation with Yubari Medical Center. In addition, our students (pharmacy) can study community medicine together with students from Tenshi College (nursing and nutrition) in an optional class made available in Yubari during their summer vacation. According to the results of our survey after these programs, students have achieved a deep recognition of the importance of community medicine and cooperation with other medical staff in contributing to community home healthcare. We carry out these programs under agreements of collaboration with Yubari Medical Center and Tenshi College. We will talk today about training for pharmaceutical care in the community and the effect of training through this class on pharmacy education. PMID- 23449413 TI - [Nano-sized molecule: new approach for diagnosis and drug discovery]. PMID- 23449414 TI - [Development of functional 1H MRI probes based on nanoparticle design]. AB - Visualization of biomolecules in living bodies has attracted increasing attention in recent years. Magnetic resonance imaging (MRI) is a noninvasive technique that yields high-resolution structural information of deep anatomical regions; therefore, it has promising applications in the development of probes to visualize biological functions. By using stimuli-responsive polymers, we developed (1)H MRI probes to measure the pH of aqueous solutions. The longitudinal relaxivity of P-Gd, a conjugate of n-octylamine-modified poly(SM EVE) with Gd(3+) complexes, increased as the pH of the solution decreased from neutral to acidic. Fluorometric investigation confirmed that the side chains of P Gd were more rotationally restricted in acidic pH than in neutral pH conditions. In order to improve the magnitude of relaxivity, we developed novel probes C10-Gd and C30-Gd on the basis of cross-linked polymer nanoparticles. The relaxivities of these probes were measured, and the values showed that these nanoparticle based probes also possessed pH-responsive molecular switches. In addition, their relaxivities were much larger than those of non-cross-linked probes. These nanoparticle-based MRI probes would be useful for the diagnosis of various diseases such as cancer and inflammatory diseases. PMID- 23449415 TI - [Application of nanophosphors with near infrared excitation for biomedical imaging]. AB - Fluorescence bioimaging is an inevitable method for biological, medical and pharmaceutical sciences to visualize substances in biological objects in a highly sensitive, multicolor and dynamic way. Recently, elongation of the fluorescence wavelength is a trend used in this imaging to suppress scattering, which limits the imaging depth to within several millimeters. It has been known that the so called "biological window" with low loss for a biological tissue has been known to lie in the near-infrared (NIR) wavelength range between 1000 and 1700 nm. The use of fluorescence in the over-1000-nm (OTN) NIR can deepen the observation to several centimeters. The use of imaging devices based on semiconductor silicon has limited the wavelength of the fluorescence bioimaging to less than 1000 nm. However, the appearance of InGaAs CCD on the market, to allow for imaging of the OTN-NIR light, is now changing the situation. On the other hand, rare-earth doped ceramic nanophosphors (RED-CNP) can emit efficient fluorescence in the OTN-NIR wavelength range. The author's group has applied the RED-CNP to OTN-NIR fluorescence bioimaging by hybridizing the RED-CNP with various polymers or molecules. The present paper will review the development of the materials and systems for this OTN-NIR fluorescence bioimaging, together with some applications of the imaging method for biological research and a medical surgery. PMID- 23449416 TI - [Drug release system controlled by near infrared light]. AB - Gold nanorods have absorption bands in the near-infrared region; in this spectral range, light penetrates deeply into tissues. The absorbed light energy is converted into heat by gold nanorods. This is the so-called photothermal effect. Gold nanorods are therefore expected to act not only as thermal converters for photothermal therapy, but also as controllers for drug-release systems responding to irradiation with near-infrared light. To achieve a controlled-release system that could be triggered by light irradiation, the gold nanorods were modified with double-stranded DNA (dsDNA). When the dsDNA-modified gold nanorods were irradiated with near-infrared light, single-stranded DNA (ssDNA) was released from the gold nanorods because of the photothermal effect. The release of ssDNA was also observed in tumors grown on mice after near-infrared light irradiation. We also proposed a different controlled-release system responding to near infrared light. Gold nanorods were modified with polyethylene glycol (PEG) through Diels-Alder cycloadducts. When the gold nanorods were irradiated with near-infrared light, the PEG chains were released from the gold nanorods because of the retro Diels-Alder reaction induced by the photothermal effect. Such controlled-release systems triggered by near-infrared light irradiation will be expanded for gold nanorod drug delivery system applications. PMID- 23449417 TI - [Nanostructured RNA for RNA interference]. AB - RNA interference (RNAi) is a potent and highly specific gene-silencing phenomenon which is initiated or triggered by double-stranded RNAs (dsRNAs). Shortly after the development of RNAi, small interfering RNAs (siRNAs) that are 21 nucleotides in length with a 3' nucleotide overhang were shown to be very effective in mammalian cells. Much effort has been dedicated to the application of siRNAs, both as biological tools and as therapeutic agents. Currently, synthetic siRNA would be the method of choice for clinical purposes. However, natural RNA strands are quickly degraded in biological fluids. Chemically synthesized unnatural nucleotides have been developed and introduced into the siRNA strand. For example, modification of the ribose moiety with a 2'-deoxy, 2'-O-methyl, or 2' fluoro group, or modification of the phosphate backbone have been examined. Although these modifications improve the stability of siRNA in serum, they often cause a decrease in RNAi activity. There is also concern that unnatural RNA derivatives are toxic in the human body. A method to stabilize nontoxic natural RNA strands should be very useful for applications in RNAi technology. We came up with an idea that nano-structural design stabilizes natural RNA. We tested several new designs such as dumbbell RNA, double stranded circular RNA, or branched RNA in biological stability and RNA interference activity. Consequently, dumbbell or branched design offered prolonged RNAi effect due to high biological stability. PMID- 23449418 TI - [Development of siRNA delivery strategy by active control of tumor microenvironment]. AB - Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. We recently showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated liposome containing anticancer drug in solid tumor tissue and thereby increased therapeutic efficacy in tumor-bearing mouse model. To extend this work, we tried to investigate the effect of metronomic S-1 dosing on the intratumoral accumulation of PEG-coated siRNA-lipoplex and, thereby, their therapeutic efficacy in solid tumor-bearing mouse model. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siRNA lipoplexes into solid tumor tissue. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes showed potent tumor growth suppressive effect. Our proposed strategy may pose a promising therapeutic one to conquer cancer progression with siRNA. PMID- 23449419 TI - [Collagen-like triple helical peptides: applications in drug development and regenerative medicine]. AB - Collagen family proteins are the predominant components of extracellular matrices existing in all multicellular animals. They provide mechanical strength to tissues, and maintain structural integrity of organs. Also, collagens regulate various biological events, including cell attachment, migration, tissue regeneration and animal development. The specific functions of collagens are generally elicited by interactions of collagen-binding molecules (membrane receptors, soluble factors and other matrix components) with certain amino acid sequences displayed on the collagen triple helices. To date, numbers of functional sequences have been identified from the triple helical domains. Collagen is also acknowledged as one of useful biomaterials in regenerative medicine and tissue engineering. In this review, I summarize challenges made for the development of safer and highly-functional collagen surrogates by means of self-assembly of synthetic collagen-like peptides. I also describe other possible applications of collagen-like peptides in drug delivery focusing on the particular biophysical properties of the triple helical structure. PMID- 23449420 TI - [A screen for genes involved in adriamycin resistance in Saccharomyces cerevisiae]. AB - Adriamycin is an anthracycline antibiotic that is widely used in the treatment of various cancers. However, the efficacy of adriamycin-based chemotherapy is compromised by the development of adverse effects and the emergence of adriamycin resistant cancer cells. In a search for novel mechanisms of resistance to adriamycin, we searched for genes that are related to adriamycin resistance using the budding yeast Saccharomyces cerevisiae and identified several genes (Akl1, Bsd2, Ssl2 and Erg13, etc.). We investigated the role of Akl1, a member of Ark/Prk kinase family, in adriamycin resistance and found that Akl1 might reduce adriamycin toxicity by inhibition of the internalization step in endocytosis via phosphorylation of component of endocytic complex. Furthermore, defects in vesicle trafficking from endoplasmic reticulum (ER) to vacuole reduced the degree of the adriamycin resistance induced by Akl1-overexpression, suggesting that inhibition of internalization step in endocytosis facilitates transport of protein from ER to vacuole, and decreases adriamycin toxicity. PMID- 23449421 TI - Awareness and ever-use of electronic cigarettes among U.S. adults, 2010-2011. AB - INTRODUCTION: Electronic cigarettes, or e-cigarettes, were introduced into the U.S. market in recent years. However, little is known about the health impact of the product or the extent of its use. This study assessed the prevalence and correlates of awareness and ever-use of e-cigarettes among U.S. adults during 2010-2011. METHODS: Data were obtained from the HealthStyles survey, a national consumer-based survey of U.S. adults aged >=18 years old. In 2010, data collection for the HealthStyles survey was both mail-based (n = 4,184) and web based (n = 2,505), and in 2011, web-based (n = 4,050) only. Estimates of awareness and ever-use of e-cigarettes were calculated overall and by sex, age, race/ethnicity, educational attainment, household income, region, and smoking status. RESULTS: In 2010, overall awareness of e-cigarettes was 38.5% (mail survey) and 40.9% (web survey); in 2011, awareness was 57.9% (web survey). Ever use of e-cigarettes among all respondents was 2.1% in the 2010 mail survey, 3.3% in the 2010 web survey, and 6.2% in the 2011 web survey. Ever-use of e-cigarettes was significantly higher among current smokers compared with both former and never-smokers, irrespective of survey method or year. During 2010-2011, ever-use increased among both sexes, those aged 45-54 years, non-Hispanic Whites, those living in the South, and current and former smokers. CONCLUSIONS: Awareness and ever-use of e-cigarettes increased among U.S. adults from 2010 to 2011. In 2011, approximately 1 in 5 current smokers reported having ever-used e-cigarettes. Continued surveillance of e-cigarettes is needed for public health planning. PMID- 23449422 TI - Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague-Dawley rats. AB - OBJECTIVE: Initiation and intensification of insulin therapy commonly causes weight gain, a barrier to therapy. A contrasting body of evidence indicates that insulin functions as an adiposity negative feedback signal and reduces food intake, weight gain and adiposity via action in the central nervous system. Basal insulin analogs, detemir (Det) and glargine (Glar), have been associated with less hypoglycemia compared with neutral protamine hagedorn insulin, and Det with less weight gain, especially in patients with higher body mass index (BMI). We sought to determine whether insulin therapy per se causes body weight and fat mass gain when delivered via a clinically relevant subcutaneous (SC) route in the absence of hypoglycemia and glycosuria in non-diabetic lean and diet-induced obese rats. MATERIALS AND METHODS: Rats were exposed to either a low-fat diet (LFD; 13.5% fat) or high-fat diet (HFD; 60% fat), and received Det (0.5 U kg( 1)), Glar (0.2 U kg(-1)) or vehicle (Veh) SC once daily for 4 weeks. These dosages of insulin were equipotent in rats with respect to blood-glucose concentration and did not induce hypoglycemia. RESULTS: As predicted by current models of energy homeostasis, neither insulin Det nor Glar therapy affected food intake and weight gain in LFD rats. Det treatment significantly attenuated food intake, body weight gain and fat mass gain relative to the Glar and Veh in high fat fed animals, mirroring observations in humans. CONCLUSIONS: That neither insulin group gained excess weight, suggests weight gain with SC basal insulin therapy may not be inevitable. Our data further suggest that Det possesses a unique property to attenuate the development of obesity associated with a HFD. PMID- 23449423 TI - Differential effects of saturated versus unsaturated dietary fatty acids on weight gain and myocellular lipid profiles in mice. AB - OBJECTIVE: In conditions of continuous high-fat (HF) intake, the degree of saturation of the fatty acids (FAs) in the diet might have a crucial role in the onset of obesity and its metabolic complications. In particular, the FA composition of the diet might influence the storage form of lipids inside skeletal muscle. The aim of the present study was to examine whether the FA composition of HF diets differentially affects weight gain and accumulation of myocellular triacylglycerol (TAG) and diacylglycerol (DAG). Furthermore, we examined whether the FA composition of the diet was reflected in the composition of the myocellular lipid intermediates. DESIGN: C57Bl6 mice were fed HF diets (45% energy) mainly containing palm oil (PO), cocoa butter (CB), olive oil (OO) or safflower oil (SO; n=6 per group) for 8 weeks. A low-fat diet (10% energy, PO) was used as control. Body weight was monitored weekly. At the end of the dietary intervention, myocellular TAG and DAG content and profiles were measured. RESULTS: We here show that HF_CB prevented weight gain after 8 weeks of HF feeding. Furthermore, the HF diet rich in SO prevented the accumulation of both myocellular TAG and DAG. Interestingly, the FA composition of DAG and TAG in skeletal muscle was a reflection of the dietary FA composition. CONCLUSION: Already after a relatively short period, the dietary FA intake relates to the FA composition of the lipid metabolites in the muscle. A diet rich in polyunsaturated FAs seems to prevent myocellular lipid accumulation. PMID- 23449424 TI - The heart team of cardiovascular care. AB - The management of complex cardiovascular disease has changed markedly with the development of new strategies of care, an increasing amount of scientific evidence-based data and appropriate use criteria. Applying this plethora of information and synthesizing it for presentation and recommendations to the patient and family have assumed central importance. To facilitate this process of patient centric evidence-based care multidisciplinary Heart Teams have become identified as cornerstones. While specific strategies for implementation of these teams will vary, this broad approach will become the standard of cardiovascular care. PMID- 23449425 TI - Aortic annular sizing for transcatheter aortic valve replacement using cross sectional 3-dimensional transesophageal echocardiography. AB - OBJECTIVES: This study compared cross-sectional three-dimensional (3D) transesophageal echocardiography (TEE) to two-dimensional (2D) TEE as methods for predicting aortic regurgitation after transcatheter aortic valve replacement (TAVR). BACKGROUND: Data have shown that TAVR sizing using cross-sectional contrast computed tomography (CT) parameters is superior to 2D-TEE for the prediction of paravalvular aortic regurgitation (AR). Three-dimensional TEE can offer cross-sectional assessment of the aortic annulus but its role for TAVR sizing has been poorly elucidated. METHODS: All patients had severe symptomatic aortic stenosis and were treated with balloon-expandable TAVR in a single center. Patients studied had both 2D-TEE and 3D imaging (contrast CT and/or 3D-TEE) of the aortic annulus at baseline. Receiver-operating characteristic curves were generated for each measurement parameter using post-TAVR paravalvular AR moderate or greater as the state variable. RESULTS: For the 256 patients studied, paravalvular AR moderate or greater occurred in 26 of 256 (10.2%) of patients. Prospectively recorded 2D-TEE measurements had a low discriminatory value (area under the curve = 0.52, 95% confidence interval: 0.40 to 0.63, p = 0.75). Average cross-sectional diameter by CT offered a high degree of discrimination (area under the curve = 0.82, 95% confidence interval: 0.73 to 0.90, p < 0.0001) and mean cross-sectional diameter by 3D-TEE was of intermediate value (area under the curve = 0.68, 95% confidence interval: 0.54 to 0.81, p = 0.036). CONCLUSIONS: Cross-sectional 3D echocardiographic sizing of the aortic annulus dimension offers discrimination of post-TAVR paravalvular AR that is significantly superior to that of 2D-TEE. Cross-sectional data should be sought from 3D-TEE if good CT data are unavailable for TAVR sizing. PMID- 23449426 TI - High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. AB - OBJECTIVES: This study sought to ascertain if high-dose allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD). BACKGROUND: LV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH. METHODS: A randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry. RESULTS: Compared to placebo, allopurinol significantly reduced LVM (allopurinol -5.2 +/- 5.8 g vs. placebo -1.3 +/- 4.48 g; p = 0.007) and LVM index (LVMI) (allopurinol -2.2 +/- 2.78 g/m(2) vs. placebo -0.53 +/- 2.5 g/m(2); p = 0.023). The absolute mean difference between groups for change in LVM and LVMI was -3.89 g (95% confidence interval: -1.1 to -6.7) and -1.67 g/m(2) (95% confidence interval: -0.23 to 3.1), respectively. Allopurinol also reduced LV end-systolic volume (allopurinol 2.81 +/- 7.8 mls vs. placebo +1.3 +/- 7.22 mls; p = 0.047), improved FMD (allopurinol +0.82 +/- 1.8% vs. placebo -0.69 +/- 2.8%; p = 0.017) and augmentation index (allopurinol -2.8 +/- 5.1% vs. placebo +0.9 +/- 7%; p = 0.02). CONCLUSIONS: High-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina?; ISRCTN73579730). PMID- 23449427 TI - Nitroso-redox imbalance affects cardiac structure and function. PMID- 23449428 TI - The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). AB - OBJECTIVES: The aim of this study was to evaluate the relationship between left ventricular (LV) ejection fraction and clinical outcome to cardiac resynchronization therapy (CRT) in mild heart failure patients enrolled in MADIT CRT [corrected]. BACKGROUND: Left ventricular ejection fraction (LVEF) is a surrogate marker of heart failure (HF) status and associated risk. Data on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild HF and better LVEF are limited. METHODS: In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study, the echocardiography core laboratory assessed baseline LVEF independent of the enrolling centers and identified a range of LVEFs, including those >30% (i.e., beyond the eligibility criteria). Echocardiographic response with CRT, defined as percent change in left ventricular end-diastolic volume (LVEDV), was analyzed in 3 prespecified LVEF groups: >30%, 26% to 30%, and <=25%. The primary endpoint was HF or death. Secondary endpoint included all-cause mortality. RESULTS: LVEF was evaluated in 1,809 study patients. There were 696 (38%) patients with LVEF >30% (in the range of 30.1% to 45.3%); 914 patients (50.5%) with LVEF 26% to 30%; and 199 patients with LVEF <=25% (11%). The mean reduction in LVEDV with CRT-D therapy at the 1 year follow-up was directly related to increasing LVEF (LVEF >30%: 22.3%; LVEF 26% to 30%: 20.1%; and LVEF <=25%: 18.7% reduction, respectively [p = 0.001]). CRT-D treatment similarly reduced the risk of HF/death in patients with LVEF >30% (hazard ratio [HR]: = 0.56 [95% confidence interval (CI): 0.39 to 0.82], p = 0.003), LVEF 26% to 30% (HR: 0.67: [95% CI: 0.50 to 0.90], p = 0.007), and LVEF <=25% (HR: 0.57 [95% CI: 0.35 to 0.95], p = 0.03; all p values for LVEF-by treatment interactions >0.1). CONCLUSIONS: In MADIT-CRT, the clinical benefit of CRT was evident regardless of baseline LVEF, including those with LVEF >30%, whereas the echocardiographic response was increased with increasing LVEF, indicating that CRT might benefit patients with better LVEF. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). PMID- 23449429 TI - Device therapy in heart failure: has CRT changed "the sickest benefit the most" to "the healthiest benefit the most?". PMID- 23449431 TI - Eclipse of the right ventricular outflow tract: natural history of a sinus of valsalva aneurysm. PMID- 23449430 TI - Metformin impairs vascular endothelial recovery after stent placement in the setting of locally eluted mammalian target of rapamycin inhibitors via S6 kinase dependent inhibition of cell proliferation. AB - OBJECTIVES: This study sought to examine the effect of oral metformin (Mf) therapy on endothelialization in the setting of drug-eluting stents (DES). BACKGROUND: Mf is a commonly used therapy in diabetic patients receiving DES. Mf and locally eluted mammalian target of rapamycin (mTOR) inhibitors used in DES have convergent molecular signaling; however, the impact of this drug interaction on stent endothelialization is unknown. METHODS: We examined human endothelial aortic cells (HAECs) and a rabbit model of stenting to determine points on molecular convergence between these 2 agents and their impact on stent endothelialization. RESULTS: Western blotting of HAECs treated with Mf and the mTOR inhibitor sirolimus and 14-day rabbit iliacs treated with the combination of zotarolimus-eluting stents (ZES) and oral Mf demonstrated greater inhibition of S6 kinase (S6K), a downstream effector of mTOR complex 1, than either treatment alone. HAEC proliferation was significantly inhibited by Mf or sirolimus treatments alone and further reduced when they were combined. Knockdown of S6K via short interfering RNA in HAECs impaired cell proliferation via a cyclin D1 dependent mechanism, whereas its overexpression rescued the antiproliferative effects of both agents. Last, endothelialization and endothelial cell proliferation at 14 days were assessed in rabbits receiving ZES or bare-metal stents and Mf or placebo by scanning electron microscopy and bromodeoxyuridine/CD31 labeling, respectively. Both endpoints were inhibited by ZES treatment alone and were further reduced by the combination of Mf and ZES. CONCLUSIONS: Significant convergence of signaling occurs between Mf and locally delivered mTOR inhibitors at S6K. This further impairs endothelial recovery/proliferation via an S6K-dependent mechanism. Patients receiving Mf in combination with stents that elute mTOR inhibitors are potentially at increased risk of delayed endothelial healing and stent thrombosis. PMID- 23449432 TI - President's page: the year in retrospect: becoming CardioSmarter. PMID- 23449433 TI - Superior vena cava defibrillator coils make transvenous lead extraction more challenging and riskier. PMID- 23449434 TI - Is prolong use of statins associated with increase in the risk of diabetes? PMID- 23449435 TI - Reply: To PMID 22884288. PMID- 23449436 TI - Slimming the heart with bariatric surgery. PMID- 23449437 TI - Reply: To PMID 22939560. PMID- 23449438 TI - Cardiac allograft vasculopathy progression associated with intraplaque neovascularization. PMID- 23449439 TI - BIROpen: open access meets flexibility. PMID- 23449440 TI - The effects of residual hearing in traditional cochlear implant candidates after implantation with a conventional electrode. AB - OBJECTIVE: To analyze the effects of residual hearing on postoperative speech performance in traditional cochlear implant (CI) patients implanted with a conventional electrode. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary referral center. PATIENTS: A total of 129 adults implanted by a single surgeon at a tertiary care facility between June 2005 and November 2010 with measurable preoperative pure tone thresholds at any frequency were included. INTERVENTION: Cochlear implantation with a conventional electrode via an anterior inferior cochleostomy. MAIN OUTCOME MEASURE: Speech perception using monosyllabic word scores in quiet and sentences in quiet and noise in the electric (CI-only) condition of the implanted ear. Preservation of hearing was defined as complete for postoperative thresholds within 10 dB of preimplant values and partial if greater than 11 dB. Pure tone audiometry and speech perception testing were performed preoperatively and at regular intervals postoperatively, with the 1 year evaluation being the final outcome period. RESULTS: Preservation at any frequency or level was not a factor in speech perception outcome, although preservation was more common in low frequencies. Hearing preservation was correlated with younger age at implantation, but was not related to length of hearing loss, cause of deafness, device type, sex, preoperative speech performance, or low-frequency pure-tone average. CONCLUSION: Hearing can be preserved in traditional CI patients implanted with a conventional electrode. Although preservation of hearing may have implications for future technology, it is not currently correlated with speech performance in the CI-only condition. PMID- 23449441 TI - Cochlear nerve deficiency and associated clinical features in patients with bilateral and unilateral hearing loss. AB - OBJECTIVE: To clarify the prevalence and clinical characteristics of cochlear nerve deficiency (CND) in patients with congenital bilateral and unilateral hearing loss. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: One hundred fourteen children with bilateral and 56 children with congenital unilateral sensoneural hearing loss. MAIN OUTCOME MEASURES: Review of medical records, audiologic tests, and imaging studies. Imaging studies were evaluated for the presence or absence of abnormalities in the bony cochlear nerve canal (BCNC), internal auditory canal (IAC), and inner ear. RESULTS: The prevalence of CND, whether unilateral or bilateral, was much higher in the unilateral than in the bilateral hearing loss group: 50% (28/56) versus 5.3% (6/114). Among the 6 children with bilateral hearing loss and CND, 2 had bilateral BCNC stenosis alone, 2 had bilateral BCNC stenosis and unilateral IAC stenosis, 1 had unilateral BCNC stenosis alone, and 1 had unilateral IAC stenosis alone. All 28 children with unilateral hearing loss and CND had BCNC stenosis, whereas 9 (32.1%) also had concurrent IAC stenosis. Three of the 6 children with CND and bilateral hearing loss and 5 of the 28 children with CND and unilateral hearing loss also had other inner ear abnormalities. CONCLUSION: Our results suggest differences in the causes and mechanisms of CND in children with bilateral versus unilateral hearing loss. PMID- 23449442 TI - The role of electrophonics in electroacoustic stimulation of the guinea pig cochlea. AB - HYPOTHESIS: Interactions between cochlear responses to combined electrical and acoustic stimulation (EAS) depend on electrically evoked hair cell activity (i.e., electrophonics). BACKGROUND: Although relevant for EAS strategies in cochlear implant users with residual low-frequency hearing, cochlear responses to EAS are not well characterized. Previously, we have shown that acoustically evoked compound action potentials (CAPs) can be suppressed by electrical stimulation. In the present study, we characterized the role of electrophonics in CAP suppression in guinea pigs, under conditions representative of clinically applied EAS. METHODS: Electrophonics depend on the frequency spectrum of the electric pulse train, which is mainly determined by pulse width and, to a lesser extent, by pulse rate. We measured suppression of tone-evoked CAPs by electric pulse trains, while varying the pulse width (80 - 400 MUs, n = 5) and the pulse rate (500 - 4000 pps, n = 5). The role of outer hair cells (OHCs) in electrophonics was tested in animals with varying degrees of OHC loss (n = 24). RESULTS: Suppression of acoustically evoked CAPs varied with pulse width, indicating that electrophonics were involved. Short pulse widths resulted in minimal CAP suppression at low acoustic frequencies. Pulse rate did not significantly affect CAP suppression. OHC loss had no significant effect on electrophonic activity. CONCLUSION: Electrophonic activity was present in cochleae with extensive basal hair cell loss, indicating that electrophonics can occur in EAS users. Our results show that short pulse widths are optimal for use in EAS stimulation strategies, on the assumption that minimal suppression is best. PMID- 23449443 TI - Neuroglial heterotopia of the internal auditory canal. PMID- 23449444 TI - The peripheral processes of spiral ganglion cells after intracochlear application of brain-derived neurotrophic factor in deafened guinea pigs. AB - OBJECTIVE: To characterize the effects of deafening and subsequent treatment with brain-derived neurotrophic factor (BDNF) on the peripheral processes (PPs) of spiral ganglion cells (SGCs) in guinea pigs. BACKGROUND: BDNF may prevent degeneration of neural structures after loss of hair cells with possible relevance for cochlear implant candidates. METHODS: Guinea pigs were deafened with a combination of kanamycin and furosemide. Two weeks after deafening, intracochlear BDNF treatment was started with osmotic pumps for 4 weeks. Two weeks after cessation of BDNF treatment, the cochleae were analyzed. PPs were counted and morphologically characterized with respect to myelination, size, and shape. RESULTS: Deafening reduced the number of PPs. We found that BDNF treatment, started 2 weeks after deafening, significantly reduced this degenerative effect. The remaining processes showed an altered morphology; compared with normal, the size was reduced in deafened untreated animals and increased in BDNF-treated animals. The myelin sheath seemed thinner in BDNF treated animals. CONCLUSION: We conclude that BDNF has potential as an agent that can improve the interface between cochlear implants and the auditory periphery. PMID- 23449445 TI - Active smoking and breast cancer risk: original cohort data and meta-analysis. AB - BACKGROUND: The relationship between active cigarette smoking and breast cancer risk remains controversial because of unresolved issues of confounding and dose response. METHODS: To investigate these issues further, we analyzed data from 73 388 women in the American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort. Analyses were based on 3721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from multivariable-adjusted Cox proportional hazard regression models. P values were two-sided. We also conducted meta-analyses of our results with those published from 14 other cohort studies. RESULTS: In CPS-II, incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR =1.13, 95% CI = 1.06 to 1.21) than in never smokers. Women who initiated smoking before menarche (HR = 1.61, 95% CI = 1.10 to 2.34) or after menarche but 11 or more years before first birth (HR = 1.45, 95% CI = 1.21 to 1.74) had higher risk (P trend = .03). No relationships were observed with other smoking parameters. Alcohol consumption did not confound associations with smoking status, although neither current nor former smoking were associated with risk among never drinkers (P interaction = .11). In meta-analyses, current (HR = 1.12, 95% CI = 1.08 to 1.16) and former smoking (HR = 1.09, 95% CI = 1.04 to 1.15) were weakly associated with risk; a stronger association (HR = 1.21, 95% CI = 1.14 to 1.28) was observed in women who initiated smoking before first birth. CONCLUSIONS: These results support the hypothesis that active smoking is associated with increased breast cancer risk for women who initiate smoking before first birth and suggest that smoking might play a role in breast cancer initiation. PMID- 23449446 TI - Nuclear factor-kappaB modulates osteogenesis of periodontal ligament stem cells through competition with beta-catenin signaling in inflammatory microenvironments. AB - Inflammation can influence multipotency and self-renewal of mesenchymal stem cells (MSCs), resulting in their awakened bone-regeneration ability. Human periodontal ligament tissue-derived MSCs (PDLSCs) have been isolated, and their differentiation potential was found to be defective due to beta-catenin signaling indirectly regulated by inflammatory microenvironments. Nuclear factor-kappaB (NF kappaB) is well studied in inflammation by many different groups. The role of NF kappaB needs to be studied in PDLSCs, although genetic evidences have recently shown that NF-kappaB inhibits osteoblastic bone formation in mice. However, the mechanism as to how inflammation leads to the modulation of beta-catenin and NF kappaB signaling remains unclear. In this study, we investigated beta-catenin and NF-kappaB signaling through regulation of glycogen synthase kinase 3beta activity (GSK-3beta, which modulates beta-catenin and NF-kappaB signaling) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002. We identified that NF-kappaB signaling might be more important for the regulation of osteogenesis in PDLSCs from periodontitis compared with beta catenin. BAY 11-7082 (an inhibitor of NF-kappaB) could inhibit phosphorylation of p65 and partly rescue the differentiation potential of PDLSCs in inflammation. Our data indicate that NF-kappaB has a central role in regulating osteogenic differentiation of PDLSCs in inflammatory microenvironments. Given the molecular mechanisms of NF-kappaB in osteogenic differentiation governed by inflammation, it can be said that NF-kappaB helps in improving stem cell-mediated inflammatory bone disease therapy. PMID- 23449447 TI - B-Myb switches from Cyclin/Cdk-dependent to Jnk- and p38 kinase-dependent phosphorylation and associates with SC35 bodies after UV stress. AB - B-Myb is a highly conserved member of the Myb transcription factor family that has essential roles in cell-cycle progression. Recent work has suggested that B Myb is also involved in the cellular DNA-damage response. Here, we have investigated the fate of B-Myb in UV-irradiated cells. UV stress leads to the appearance of phosphorylated B-Myb in nuclear SC35 speckles during transcriptional shutdown. Furthermore, we show that UV irradiation leads to a change of the phosphorylation pattern of B-Myb, which is caused by a switch from Cyclin/Cdk-dependent to Jnk and p38 kinase-dependent phosphorylation. Taken together, we have identified Jnk and p38 kinase as novel regulators of B-Myb and established the localization of phosphorylated B-Myb in SC35 speckles as a potential novel regulatory mechanism for B-Myb in UV irradiated cells. PMID- 23449448 TI - Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells. AB - The potent and selective proteasome inhibitor bortezomib has shown remarkable antitumor activity and is now entering clinical trials for several cancers. However, the molecular mechanisms by which bortezomib induces cytotoxicity in ovarian cancer cells still remain unclear. In this study, we show that bortezomib induced apoptosis, which was demonstrated by the downregulation of antiapoptotic molecules (Bcl-2, Bcl-XL, p-Bad, and p-AKT) and the upregulation of proapoptotic proteins (p21, p27, and cleaved-Bid) in ovarian cancer cell lines. Moreover, bortezomib stimulates Janus kinase (JAK) phosphorylation and activates heat-shock transcription factor-1 (HSF-1) and heat-shock protein 70 (HSP70), ultimately leading to signal transducer and activator of transcription 1 (STAT1) phosphorylation. Phosphorylated STAT1 partially counteracted apoptosis induced by bortezomib in cancer cells. These findings suggest that the antitumor activity of bortezomib in ovarian cancer can be improved by inhibiting bortezomib-induced STAT1 phosphorylation. This effect can be achieved by STAT1 knockdown, HSP70 knockdown, JAK inhibition, or the addition of cisplatin, one of the most commonly used anticancer drugs. These results provide the first evidence that STAT1 phosphorylation can play a role in bortezomib resistance by exerting antiapoptotic effects. They also suggest the possibility to abolish or reduce bortezomib chemoresistance in ovarian cancer by the addition of cisplatin or JAK inhibitors. PMID- 23449449 TI - Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression. AB - VRK2 is a novel Ser-Thr kinase whose VRK2A isoform is located in the endoplasmic reticulum and mitochondrial membranes. We have studied the potential role that VRK2A has in the regulation of mitochondrial-mediated apoptosis. VRK2A can regulate the intrinsic apoptotic pathway in two different ways. The VRK2A protein directly interacts with Bcl-xL, but not with Bcl-2, Bax, Bad, PUMA or Binp-3L. VRK2A does not compete with Bax for interaction with Bcl-xL, and these proteins can form a complex that reduces apoptosis. Thus, high VRK2 levels confer protection against apoptosis. In addition, VRK2 knockdown results in an increased expression of BAX gene expression that is mediated by its proximal promoter, thus VRK2A behaves as a negative regulator of BAX. Low levels of VRK2A causes an increase in mitochondrial Bax protein level, leading to an increase in the release of cytochrome C and caspase activation, detected by PARP processing. VRK2A loss results in an increase in cell death that can be detected by an increase in annexinV+ cells. Low levels of VRK2A increase cell sensitivity to induction of apoptosis by chemotherapeutic drugs like camptothecin or doxorubicin. We conclude that VRK2A protein is a novel modulator of apoptosis. PMID- 23449450 TI - MiR203 mediates subversion of stem cell properties during mammary epithelial differentiation via repression of DeltaNP63alpha and promotes mesenchymal-to epithelial transition. AB - During reproductive life, the mammary epithelium undergoes consecutive cycles of proliferation, differentiation and apoptosis. Doing so relies on the retained proliferative capacity, prolonged lifespan and developmental potency of mammary stem cells (MaSCs). DeltaNp63alpha, the predominant TP63 isoform in mammary epithelia, is robustly expressed in MaSCs and is required for preservation of self-renewing capacity in diverse epithelial structures. However, the mechanism(s) underlying subversion of this activity during forfeiture of self renewing capacity are poorly understood. MicroRNAs (miRNAs) govern critical cellular functions including stem cell maintenance, development, cell cycle regulation and differentiation by disrupting translation of target mRNAs. Data presented here indicate that expression of miR203, a miRNA that targets DeltaNp63alpha and DeltaNp63beta is activated during luminal epithelial differentiation and that this pattern is observed in the murine mammary hierarchy. In addition, we present evidence that the transcription factor Zeb1 represses miR203 expression, thus enhancing DeltaNp63alpha protein levels. Furthermore, ectopic miR203 suppresses DeltaNp63alpha expression, proliferation and colony formation. The anti-clonogenic effects mediated by miR203 require suppression of DeltaNp63alpha. In addition, ectopic miR203 promotes mesenchymal to-epithelial transition and disrupts activities associated with epithelial stem cells. These studies support a model in which induction of miR203 mediates forfeiture of self-renewing capacity via suppression of DeltaNp63alpha and may also have anti-tumorigenic activity through its reduction of EMT and cancer stem cell populations. PMID- 23449451 TI - Downregulation of Mcl-1 through inhibition of translation contributes to benzyl isothiocyanate-induced cell cycle arrest and apoptosis in human leukemia cells. AB - Benzyl isothiocyanate (BITC) is one of the compounds of ITCs' family that has attracted a great deal of interest because of its ability to exhibit anticancer activity. In this study, we investigated the effects of BITC on cell cycle arrest and apoptosis in human leukemia cell lines, primary leukemia cells, and nude mice Jurkat xenograft. Exposure of Jurkat cells to BITC resulted in dose- and time dependent increase in apoptosis, caspase activation, cytochrome c release, nuclear apoptosis-inducing factor (AIF) accumulation, Bcl2-associated X protein (Bax) translocation, and myeloid cell leukemia-1 (Mcl-1) downregulation. Treatment with these cells also resulted in cell cycle arrest at the G2/M phase. The G2/M-arrested cells are more sensitive to undergoing Mcl-1 downregulation and apoptosis mediated by BITC. BITC downregulates Mcl-1 expression through inhibition of translation, rather than through a transcriptional, post translational, or caspase-dependent mechanism. Dephosphorylation of eukaryotic initiation factor 4G could contribute to the inhibition of Mcl-1 translation mediated by BITC. Furthermore, ectopic expression of Mcl-1 substantially attenuates BITC-mediated lethality in these cells, whereas knockdown of Mcl-1 through small interfering RNA significantly enhances BITC-mediated lethality. Finally, administration of BITC markedly inhibited tumor growth and induced apoptosis in Jurkat xenograft model in association with the downregulation of Mcl 1. Taken together, these findings represent a novel mechanism by which agents targeting Mcl-1 potentiate BITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of Jurkat xenograft model. PMID- 23449453 TI - Mutual regulation between DNA-PKcs and Snail1 leads to increased genomic instability and aggressive tumor characteristics. AB - Although the roles of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) in the non-homologous end joining (NHEJ) of DNA repair are well-recognized, the biological mechanisms and regulators by DNA-PKcs besides DNA repair, have not been clearly described. Here, we show that active DNA-PKcs caused by ionizing radiation, phosphorylated Snail1 at serine (Ser) 100, led to increased Snail1 stability. Furthermore, phosphorylated Snail1 at Ser100 reciprocally inhibited the kinase activity of DNA-PKcs, resulting in an inhibition of DNA repair activity. Moreover, Snail1 phosphorylation by DNA-PKcs was involved in genomic instability and aggressive tumor characteristics. Our results describe novel cellular mechanisms that affect genomic instability, sensitivity to DNA-damaging agents, and the migration of tumor cells by reciprocal regulation between DNA PKcs and Snail1. PMID- 23449452 TI - Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis. AB - We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2 deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients. PMID- 23449454 TI - HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway. AB - Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are widely used cholesterol-lowering drugs. Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. The objective here was to elucidate the molecular mechanism by which statins induce lymphoma cells death. Statins (atorvastatin, fluvastatin and simvastatin) treatment enhanced the DNA fragmentation and the activation of proapoptotic members such as caspase-3, PARP and Bax, but suppressed the activation of anti apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells, which was accompanied by inhibition of cell survival. Both increase in levels of reactive oxygen species (ROS) and activation of p38 MAPK and decrease in mitochondrial membrane potential and activation of Akt and Erk pathways were observed in statin treated lymphoma cells. Statin-induced cytotoxic effects, DNA fragmentation and changes of activation of caspase-3, Akt, Erk and p38 were blocked by antioxidant (N-acetylcysteine) and metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggests that HMG-CoA reductase inhibitors induce lymphoma cells apoptosis by increasing intracellular ROS generation and p38 activation and suppressing activation of Akt and Erk pathways, through inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP. PMID- 23449455 TI - HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses. AB - The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compounds that target the epigenome for the treatment of cancer. This notion is supported by biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through association with oncogenic fusion proteins such as PML-RARalpha and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biological and molecular responses of isogenic normal and transformed cells to the FDA approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific molecules and pathways in the tumor-selective cytotoxic activity of these compounds. PMID- 23449456 TI - Role of protein kinase C delta in ER stress and apoptosis induced by oxidized LDL in human vascular smooth muscle cells. AB - During atherogenesis, excess amounts of low-density lipoproteins (LDL) accumulate in the subendothelial space where they undergo oxidative modifications. Oxidized LDL (oxLDL) alter the fragile balance between survival and death of vascular smooth muscle cells (VSMC) thereby leading to plaque instability and finally to atherothrombotic events. As protein kinase C delta (PKCdelta) is pro-apoptotic in many cell types, we investigated its potential role in the regulation of VSMC apoptosis induced by oxLDL. We found that human VSMC silenced for PKCdelta exhibited a protection towards oxLDL-induced apoptosis. OxLDL triggered the activation of PKCdelta as shown by its phosphorylation and nuclear translocation. PKCdelta activation was dependent on the reactive oxygen species generated by oxLDL. Moreover, we demonstrated that PKCdelta participates in oxLDL-induced endoplasmic reticulum (ER) stress-dependent apoptotic signaling mainly through the IRE1alpha/JNK pathway. Finally, the role of PKCdelta in the development of atherosclerosis was supported by immunohistological analyses showing the colocalization of activated PKCdelta with ER stress and lipid peroxidation markers in human atherosclerotic lesions. These findings highlight a role for PKCdelta as a key regulator of oxLDL-induced ER stress-mediated apoptosis in VSMC, which may contribute to atherosclerotic plaque instability and rupture. PMID- 23449458 TI - GaAs nanowire growth on polycrystalline silicon thin films using selective-area MOVPE. AB - The growth mechanism of GaAs nanowires (NWs) grown on polycrystalline silicon (poly-Si) thin films using selective-area metalorganic vapor-phase epitaxy was investigated. Wire structures were selectively grown in the mask openings on a poly-Si substrate. The appearance ratio of wire structures strongly depended on the growth conditions and deposition temperature of the poly-Si substrate. Evaluation of the grown shapes and growth characteristics revealed that GaAs NWs grown on a poly-Si substrate have the same growth mechanism as conventional GaAs NWs grown on a single-crystalline GaAs or Si substrate. Experiments showed that the wire structure yield can be improved by increasing the Si grain size and/or increasing the Si deposition temperature. The growth model proposed for understanding NW growth on poly-Si is based on the mask opening size, the Si grain size, and the growth conditions. The ability to control the growth mode is promising for the formation of NWs with complex structures on poly-Si thin layers. PMID- 23449457 TI - TGF-beta1 and hypoxia-dependent expression of MKP-1 leads tumor resistance to death receptor-mediated cell death. AB - Sporadic occurrence of transformed tumor cells is under the surveillance of the host immune system and such cells are effectively eliminated by immune-mediated cell death. During tumor progression, the antitumor effects of the tumor microenvironment are suppressed by diverse immunosuppressive mechanisms. In this research, we suggest novel immune evasion strategy of tumor cells through a transforming growth factor (TGF)-beta1- and hypoxia-dependent mechanism. Experimental results showed that TGF-beta1 and hypoxia induced mitogen-activated protein kinase phosphatase (MKP)-1 expression within 1 h, resulting in attenuation of c-Jun N-terminal kinase (JNK) phosphorylation and subsequent death receptor-mediated cell death. In addition, analysis of microarray data and immunostaining of MKP-1 in hepatocellular carcinoma (HCC) patient samples revealed that expression of MKP-1 is notably higher in tumors than in normal tissues, implying that MKP-1-dependent suppression of immune-mediated cell death takes place only in the tumor. To prove that MKP-1 can act as a mediator of immune escape by tumors, we determined whether chemo-resistance against several anticancer drugs could be overcome by knockdown of MKP-1. Cytotoxic assays showed that chemotherapy with siRNA targeting MKP-1 was significantly more effective than chemotherapy in the presence of MKP-1. Thus, we conclude that TGF-beta1 and hypoxia ensure tumor cell survival and growth through expression of MKP-1. PMID- 23449459 TI - Dynamics of hydrocephalus: a physical approach. AB - As brain ventricles lose their ability to regulate the cerebrospinal fluid (CSF) pressure, serious brain conditions collectively named hydrocephalus can appear. By modelling ventricular dynamics with the laws of physics, dynamical instabilities are evidenced, caused by either CSF transport dysregulations or abnormal properties of the elasticity of the ependyma. We show that these instabilities would lead, in most cases, to dilation of the ventricles, establishing a close connection to hydrocephalus, or in some other cases to a ventricular contraction as observed in the slit ventricle syndrome. Signs seem to indicate the possibility of phase transitions occurring as a result of these instabilities, which might have important clinical consequences, such as the inability to recover a healthy state. Even so, our dynamical approach could allow the development of a unified view of these complex intracranial conditions along with a classification that might be clinically relevant. PMID- 23449460 TI - The nature of high-energy radiation damage in iron. AB - Understanding and predicting a material's performance in response to high-energy radiation damage, as well as designing future materials to be used in intense radiation environments, requires knowledge of the structure, morphology and amount of radiation-induced structural changes. We report the results of molecular dynamics simulations of high-energy radiation damage in iron in the range 0.2-0.5 MeV. We analyze and quantify the nature of collision cascades both at the global and the local scale. We observe three distinct types of damage production and relaxation, including reversible deformation around the cascade due to elastic expansion, irreversible structural damage due to ballistic displacements and smaller reversible deformation due to the shock wave. We find that the structure of high-energy collision cascades becomes increasingly continuous as opposed to showing sub-cascade branching as reported previously. At the local length scale, we find large defect clusters and novel small vacancy and interstitial clusters. These features form the basis for physical models aimed at understanding the effects of high-energy radiation damage in structural materials. PMID- 23449461 TI - Impact of commercially available diabetic prescription diets on short-term postprandial serum glucose, insulin, triglyceride and free fatty acid concentrations of obese cats. AB - Diet therapy is an important treatment component available for obese cats. In this study, the impact of four commercially available prescription diet regimens (1 for general use and 3 aimed at treating obesity and diabetes mellitus (DM)) on short-term postprandial serum glucose, insulin, triglyceride and nonesterified fatty acid (NEFA) concentrations was investigated with five obese cats. The diet regimens used were as follows: C/D dry (general use: moderate protein, moderate fat, high carbohydrate and low fiber), M/D dry (DM: high protein, high fat, low carbohydrate and high fiber), W/D dry (DM: high protein, low fat, high carbohydrate and high fiber) and Diabetic dry (DM: high protein, low fat, low carbohydrate and high fiber). A significant reduction (10-13%) in postprandial glucose (area under the curve; AUC) was observed with the M/D and Diabetic diets, which both contained lower concentrations of carbohydrates than the C/D diet. An accompanying significant reduction (30-36%) in postprandial insulin AUC was also observed with the three DM diets, which all had higher amounts of fiber, as compared with the C/D diet. Lastly, a significant increase (32-65%) in postprandial NEFA AUC was observed with the M/D and Diabetic diets as compared with the C/D diet. Therefore, dietary amounts of carbohydrates and fiber, as opposed to protein content or dietary fat, appear to have a very significant impact on postprandial glycemia and subsequent insulin requirement levels in obese cats. In addition, dietary amounts of carbohydrates may also impact lipid metabolism in obese cats. PMID- 23449462 TI - A 39-kDa capsular protein is a major cross-protection factor as demonstrated by protection of chickens with a live attenuated Pasteurella multocida strain of P 1059. AB - The aim of this study was to show that a 39-kDa protein or OmpH of Pasteurella multocida strain P-1059 is essential for cross protection. Strain PBA322, a thinly capsulated strain of P. multocida strain P-1059, was used as a live vaccine in chickens. Strain PBA322 is a thinly capsulated strain in comparison with the parental strain P-1059. Chickens were vaccinated by single injection and then challenge-exposed with strains P-1059 or X-73 at two weeks post vaccination. Moreover, immune responses were also evaluated for both humoral and cellular immune response by ELISA and lymphocyte proliferation assay, respectively. The results showed that the live vaccine induced efficient immunity to protect chickens from challenge-exposure to the parent strain, but that the heterologous protection was poor. We concluded that the 39-kDa protein is essential for cross protection. PMID- 23449463 TI - Echinostoma hortense infection with enteritis diagnosed by upper gastrointestinal endoscopy in a dog. AB - An 8-year-old male Shiba dog presented with chronic vomiting and diarrhea. Upper gastrointestinal endoscopy revealed severe enteritis and infection of the duodenal mucosa with Echinostoma hortense. We performed therapy for parasites and enteritis. The therapy was successful for deworming and temporarily improved the symptoms, but the dog died soon thereafter. To the authors' knowledge, this is the first case report of an antemortem diagnosis of E. hortense infection in a dog. PMID- 23449464 TI - Epidemiological survey of tick-borne protozoal infection in iriomote cats and tsushima leopard cats in Japan. AB - This epidemiological survey was conducted to determine the prevalence of Hepatozoon, Babesia and Theileria infection in the Iriomote cat (IC) and the Tsushima leopard cat (TLC). Blood samples from 43 ICs and 14 TLCs were collected between November 2002 and January 2012. Polymerase chain reaction and DNA sequencing analyses detected a Hepatozoon felis infection prevalence of 72.0% (31/43 cats) and 100% (14/14 cats) in ICs and TLCs, respectively. The degree of Hepatozoon parasitemia observed on blood smears ranged from 0.1 to 4.7%. However, no cases had obvious clinical signs of hepatozoonosis. Neither Babesia- nor Theileria-infected wildcats were detected in this study. PMID- 23449465 TI - Hepatic sonography in patients with hereditary hemorrhagic telangiectasia hospitalized for epistaxis. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the presence of telangiectasias and arteriovenous malformations in various organs and organ systems, including the liver. The most frequent clinical manifestation of HHT is epistaxis.In 2010 (January-December inclusive) 51 patients with HHT were admitted to the ENT ward of our hospital for epistaxis, and in accordance with routine protocols, all 51 underwent abdominal ultrasonography in our department to detect hepatovascular lesions. They included 27 males (53%) and 24 (47%) females ranging in age from 11 to 86 years (mean 48.5 years). The sample was selected in an arbitrary manner to take maximum advantage of the hospital stay and monitor patients from regions other than our own.Retrospective analysis of the findings from these sonographic examinations revealed hepatic HHT in 27 (53%) of the 51 patients. Nineteen (70%) of these (age range 40-86 years, mean 63) had vascular malformations of various dimensions but no portal hypertension; the other eight (30%) (age range 39-81 years, mean 60) had vascular malformations plus portal hypertension.Our retrospective analysis indicates that a significant number of patients can have unrecognized hepatic involvement; that the appearance of hepatic lesions can be fairly unpredictable, even when the HHT has been diagnosed for years and the patients are already symptomatic; and that the hepatic lesions are frequently progressive. Therefore, regular sonographic follow-up is advisable for patients with HHT.The limitations of this study are related to the small number of patients examined and to the fact that all of them were symptomatic. Further study is therefore needed (especially in asymptomatic patients) to define the indications for hepatic sonography and the optimum examination schedule. PMID- 23449466 TI - A bridge to understanding lipid droplet growth. AB - Lipid droplets, storage sites of fatty acids and sterols, expand when excess lipids are converted to triacylglycerols. In this issue of Developmental Cell, Wilfling et al. (2013) show that this expansion relies on relocalization, via membrane bridges, of triacylglycerol-synthesizing enzymes from the ER to a subset of lipid droplets. PMID- 23449467 TI - Dividing in epithelia: cells let loose during cytokinesis. AB - Epithelia must maintain barrier function-protecting interior tissues from a variable external environment-even while their cells divide. In the previous issue of Developmental Cell, Guillot and Lecuit (2013), Founounou et al. (2013), and Herszterg et al. (2013) present complementary findings on the regulation of adhesion and its impact on cell division. PMID- 23449468 TI - Dying to entrain: regulating ipRGC spacing. AB - In a recent issue of Neuron, Chen et al. (2013) show that apoptosis is required to ensure the even distribution of a class of retinal ganglion cells (ipRGCs), which sense luminance both intrinsically and through input from rods and cones. Disrupting apoptosis impairs photoentrainment mediated by rods/cones, but not that mediated by ipRGC-expressed melanopsin. PMID- 23449469 TI - Nerve control of blood vessel patterning. AB - Patterning of embryonic blood vessels occurs in association with nerves. In this issue of Developmental Cell, Li et al. (2013) report that nerve-derived chemokine Cxcl12 (also known as SDF-1), acting through its receptor Cxcr4, initiates blood vessel remodeling along cutaneous nerve trajectories to establish the proper pattern of cutaneous arteries. PMID- 23449470 TI - Pioneering barren land: mitotic bookmarking by transcription factors. AB - Genome condensation during mitosis presents a chromatin landscape largely inaccessible to RNA polymerase II and most transcription factors. Caravaca et al. (2013) now report in Genes and Development that the pioneer transcription factor FOXA1 is retained at mitotic chromosomes, bookmarking the genome to enable gene expression reestablishment upon mitotic exit. PMID- 23449471 TI - Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway. AB - The mechanisms that govern the maintenance and differentiation of tissue-specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by derepression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of Hdac1/2. In contrast to development, postnatal loss of Hdac1/2 in airway epithelium does not affect the expression of Sox2 or Bmp4. However, postnatal loss of Hdac1/2 leads to increased expression of the cell cycle regulators Rb1, p21/Cdkn1a, and p16/Ink4a, resulting in a loss of cell cycle progression and defective regeneration of Sox2+ lung epithelium. Thus, Hdac1/2 have both common and unique targets that differentially regulate tissue specific progenitor activity during development and regeneration. PMID- 23449472 TI - Three-dimensional epithelial morphogenesis in the developing Drosophila egg. AB - Morphogenesis of the respiratory appendages on eggshells of Drosophila species provides a powerful experimental system for studying how cell sheets give rise to complex three-dimensional structures. In Drosophila melanogaster, each of the two tubular eggshell appendages is derived from a primordium comprising two distinct cell types. Using live imaging and three-dimensional image reconstruction, we demonstrate that the transformation of this two-dimensional primordium into a tube involves out-of-plane bending followed by a sequence of spatially ordered cell intercalations. These morphological transformations correlate with the appearance of complementary distributions of myosin and Bazooka in the primordium. These distributions suggest that a two-dimensional pattern of line tensions along cell-cell edges on the apical side of the epithelium is sufficient to produce the observed changes in morphology. Computational modeling shows that this mechanism could explain the main features of tissue deformation and cell rearrangements observed during three-dimensional morphogenesis. PMID- 23449475 TI - The emerging antineoplastic effects of paeoniflorin. PMID- 23449474 TI - Regulation of leaf maturation by chromatin-mediated modulation of cytokinin responses. AB - Plant shoots display indeterminate growth, while their evolutionary decedents, the leaves, are determinate. Determinate leaf growth is conditioned by the CIN TCP transcription factors, which promote leaf maturation and are negatively regulated by miR319 in leaf primordia. Here we show that CIN-TCPs reduce leaf sensitivity to cytokinin (CK), a phytohormone implicated in inhibition of differentiation in the shoot. We identify the SWI/SNF chromatin remodeling ATPase BRAHMA (BRM) as a genetic mediator of CIN-TCP activities and CK responses. An interactome screen further revealed that SWI/SNF complex components including BRM preferentially interacted with basic-helix-loop-helix (bHLH) transcription factors and the bHLH-related CIN-TCPs. Indeed, TCP4 and BRM interacted in planta. Both TCP4 and BRM bound the promoter of an inhibitor of CK responses, ARR16, and induced its expression. Reconstituting ARR16 levels in leaves with reduced CIN TCP activity restored normal growth. Thus, CIN-TCP and BRM together promote determinate leaf growth by stage-specific modification of CK responses. PMID- 23449473 TI - Control of hematopoietic stem cell emergence by antagonistic functions of ribosomal protein paralogs. AB - It remains controversial whether the highly homologous ribosomal protein (RP) paralogs found in lower eukaryotes have distinct functions and this has not been explored in vertebrates. Here we demonstrate that despite ubiquitous expression, the RP paralogs, Rpl22 and Rpl22-like1 (Rpl22l1) play essential, distinct, and antagonistic roles in hematopoietic development. Knockdown of Rpl22 in zebrafish embryos selectively blocks the development of T lineage progenitors after they have seeded the thymus. In contrast, knockdown of the Rpl22 paralog, Rpl22l1, impairs the emergence of hematopoietic stem cells (HSC) in the aorta-gonad mesonephros by abrogating Smad1 expression and the consequent induction of essential transcriptional regulator, Runx1. Indeed, despite the ability of both paralogs to bind smad1 RNA, Rpl22 and Rpl22l1 have opposing effects on Smad1 expression. Accordingly, circumstances that tip the balance of these paralogs in favor of Rpl22 (e.g., Rpl22l1 knockdown or Rpl22 overexpression) result in repression of Smad1 and blockade of HSC emergence. PMID- 23449476 TI - Heterogeneity in liquid shaken cultures of Aspergillus niger inoculated with melanised conidia or conidia of pigmentation mutants. AB - Black pigmented conidia of Aspergillus niger give rise to micro-colonies when incubated in liquid shaken medium. These micro-colonies are heterogeneous with respect to gene expression and size. We here studied the biophysical properties of the conidia of a control strain and of strains in which the fwnA, olvA or brnA gene is inactivated. These strains form fawn-, olive-, and brown-coloured conidia, respectively. The DeltaolvA strain produced larger conidia (3.8 MUm) when compared to the other strains (3.2-3.3 MUm). Moreover, the conidia of the DeltaolvA strain were highly hydrophilic, whereas those of the other strains were hydrophobic. The zeta potential of the DeltaolvA conidia in medium was also more negative when compared to the control strain. This was accompanied by the near absence of a rodlet layer of hydrophobins. Using the Complex Object Parametric Analyzer and Sorter it was shown that the ratio of individual hyphae and micro colonies in liquid shaken cultures of the deletion strains was lower when compared to the control strain. The average size of the micro-colonies of the control strain was also smaller (628 MUm) than that of the deletion strains (790 858 MUm). The size distribution of the micro-colonies of the DeltafwnA strain was normally distributed, while that of the other strains could be explained by assuming a population of small and a population of large micro-colonies. In the last set of experiments it was shown that relative expression levels of gpdA, and AmyR and XlnR regulated genes correlate in individual hyphae at the periphery of micro-colonies. This indicates the existence of transcriptionally and translationally highly active and lowly active hyphae as was previously shown in macro-colonies. However, the existence of distinct populations of hyphae with high and low transcriptional and translational activity seems to be less robust when compared to macro-colonies grown on solid medium. PMID- 23449477 TI - Polymeric delivery of siRNA for dual silencing of Mcl-1 and P-glycoprotein and apoptosis induction in drug-resistant breast cancer cells. AB - Enhanced survival mechanisms of malignant cells in combination with elevated levels of drug transporters can sustain an undesirable resistance against drug therapy. Short interfering RNA (siRNA) delivery against targets involved in aberrant mechanisms is a promising approach and we hypothesize that simultaneous silencing of multiple targets could prove more advantageous than common approach to silence individual targets. To explore this approach, we targeted anti apoptotic proteins myeloid cell leukemia 1 (Mcl-1) and survivin along with the efflux pump P-glycoprotein (P-gp) in drug-resistant breast cancer cells. Polymeric siRNA delivery was employed for this purpose by using small polyethylenimine (PEI) substituted with lipids. While silencing Mcl-1 caused ~90% cell death in wild-type cells, this effect was less significant in P-gp over expressing cells. An additive effect for Mcl-1 and P-gp silencing was evident in the latter cells, where simultaneous silencing of these targets created a significantly higher effect compared with silencing each individual target. Prolonged exposure of wild-type cells to doxorubicin (DOX) resulted in upregulation of P-gp, breast cancer resistance protein, survivin and Mcl-1. Dual silencing of P-gp and Mcl-1 again resulted in an additive effect in resistance induced cells, which displayed an increased dependency on Mcl-1 for survival. Cytotoxic effect of DOX was also enhanced in resistance-induced cells after silencing Mcl-1. We conclude that polymer-mediated siRNA delivery can silence multiple targets simultaneously and reverse drug resistance. PMID- 23449478 TI - Matrix protein of vesicular stomatitis virus: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation. AB - Malignant ascites is common in various types of cancers and is difficult to manage. Vascular endothelial growth factor (VEGF) has a pivotal role in malignant ascites. The matrix protein of vesicular stomatitis virus (VSVMP) has been shown to inhibit host gene expression and induce the apoptosis of cancer cells. The present study was designed to determine whether VSVMP suppresses the formation of ascites in ascites-producing peritoneal carcinomatosis. BALB/c female mice, 6-8 weeks old, bearing peritoneal tumors of H22 or MethA cells received an intraperitoneal administration of 50 MUg VSVMP/250 MUg liposome complexes, 50 MUg empty plasmid/250 MUg liposome complexes or 0.9% NaCl solution, respectively, every 2 days for 3 weeks. Administration of VSVMP resulted in a significant inhibition in ascites formation, improvement in health condition and prolonged survival of the treated mice. Decreased peritoneum osmolarity and reduced tumor vascularity coincided with dramatic reductions in the VEGF level in ascites fluid and plasma. Examination of floating tumor cells collected from the peritoneal wash revealed an apparently increased number of apoptotic cells and profound downregulation of VEGF mRNA in the VSVMP-treated mice. Our data indicate for the first time that in BALB/c mice bearing H22 or MethA cell peritoneal tumors, VSVMP may inhibit VEGF production and suppress angiogenesis, consequently abolishing ascites formation. PMID- 23449479 TI - Intraocular lens power calculations in a patient with posterior keratoconus. AB - PURPOSE: We describe a patient with posterior keratoconus accompanied by hyperopia and a cataract, which were successfully treated by cataract surgery and secondary piggyback intraocular lens (IOL) implantation. METHODS: Case report. RESULTS: A 47-year-old woman presented to our clinic with low vision in her right eye. Uncorrected distant visual acuity was 20/400 in the right eye with a manifest refraction of +11.5 diopters. On the slit-lamp examination, localized posterior keratoconus and lens opacity were noted in the right eye. First, we performed phacoemulsification and posterior chamber IOL implantation. Postoperatively, hyperopic shift was noted because localized posterior elevation of the cornea is not considered in the conventional IOL power calculation. After secondary piggyback IOL implantation in the sulcus, her refractive error was finally properly corrected and uncorrected distant visual acuity improved to 20/50. CONCLUSIONS: In patients with posterior keratoconus, IOL power calculation from conventional keratometry may be inaccurate, and secondary piggyback IOL procedure may be needed after cataract surgery. PMID- 23449480 TI - Treatment of aniridia with Boston type I keratoprosthesis. AB - PURPOSE: To report the outcomes of Boston keratoprosthesis (K-pro) type I implantation for congenital aniridia. METHODS: A retrospective review of the medical records of every patient with congenital aniridia who underwent Boston K pro type I implantation at the University of Iowa Hospitals and Clinics from January 1, 2009, through December 31, 2011 was performed. The main outcome measures were visual acuity, graft retention, and postoperative complications. RESULTS: A total of 7 eyes (7 patients) met the inclusion criteria. The mean patient age was 52 years (range, 12-85 years). The preoperative visual acuity was 20/1600 in 6 eyes (85.7%) and hand motions in 1 eye (14.3%). After a median follow-up period of 18 months (range, 3-30 months), the median final best spectacle-corrected visual acuity was 20/200 (range, 20/100 to light perception). This included 2 eyes (28.6%) that were 20/100 and 5 eyes (71.4%) that were better than 20/300. Compared with the preoperative best spectacle-corrected visual acuity, the final vision was improved in 6 eyes (85.7%) and worse in 1 eye (14.3%). The K-pro graft was retained in all 7 eyes (100%). The most common complication was the formation of a retroprosthetic membrane in 3 eyes (42.9%), none of which required either a YAG capsulotomy or a vitrectomy. One eye (14.3%) developed a wound dehiscence that required surgical repair. CONCLUSIONS: The Boston K-pro type I is a good option for the visual rehabilitation of eyes with congenital aniridia. PMID- 23449481 TI - Hemorrhagic descemet detachment after combined canaloplasty and cataract surgery. AB - PURPOSES: To describe a case of hemorrhagic Descemet membrane detachment following canaloplasty and to discuss its management using neodymium:yttrium aluminum-garnet (Nd:YAG) laser Descemet membranotomy. METHODS: Interventional case report. RESULTS: A 71-year-old woman with chronic open-angle glaucoma developed a hemorrhagic Descemet detachment after combined phacoemulsification, intraocular lens insertion, and canaloplasty. The hematoma did not improve with initial expectant management. Two and a half weeks after surgery, the Nd:YAG laser was applied to create a break in the Descemet membrane in the region of the hematoma. The intracorneal blood quickly dissipated into the anterior chamber. Visual acuity improved to 20/20. The endothelial cell count was 2342 cells per square millimeter 4 years after the surgery. Pachymetry did not show any long term alterations as a result of the Nd:YAG treatment. CONCLUSIONS: Hemorrhagic Descemet detachment is an uncommon complication after canaloplasty. Nd:YAG Descemet membranotomy is a successful means of clearing the hematoma and thus can prevent further complications, such as corneal blood staining. PMID- 23449482 TI - Annular amniotic membrane transplantation as a host incorporated graft in the management of Brown-McLean syndrome. AB - PURPOSE: To report the use of annular amniotic membrane transplantation as a host incorporated graft in the management of Brown-McLean syndrome. METHODS: Case report. RESULTS: An 87-year-old man underwent annular amniotic membrane transplantation with ethylenediaminetetraacetic acid chelation resulting in resolution of pain, irritation, and foreign body sensation, and resolution of recurrent peripheral epithelial defects. CONCLUSIONS: Annular amniotic membrane transplantation is a safe and effective treatment strategy for the management of Brown-McLean syndrome. PMID- 23449484 TI - Increased expression of secreted frizzled-related protein-1 and microtubule associated protein light chain 3 in keratoconus. AB - PURPOSE: To study the expression of secreted frizzled-related protein-1 (SFRP-1) and microtubule-associated protein light chain 3 (LC3), an autophagy marker, in keratoconus. METHODS: Under an institutional review board-approved protocol, de identified and/or surgically discarded normal donor (n = 10) and keratoconus corneas (n = 10) were obtained. The corneal samples were fixed in formalin and embedded in paraffin. Immunohistochemical staining using SFRP-1 and LC3 antibodies was performed. RESULTS: The majority of expression of SFRP-1 was seen in the epithelium; however, in 3 tissues that showed high expression, staining was also present in the stroma and endothelium. Like SFRP-1, the LC3 expression in keratoconus tissues occurred at 3 different levels: low, medium, and high. Collectively these data suggest that there are differences in the expression levels of SFRP-1 and LC3 in keratoconus tissue compared with the normal tissue. Low expressivity of SFRP-1 seemed to correspond to low expressivity of LC3, whereas medium to high expressivity of SFRP-1 corresponded to medium to high expressivity of LC3. CONCLUSIONS: Increased expression of SFRP-1 and LC3 was observed in keratoconus corneas. Keratocyte autophagy seen with keratoconus may play a role in the pathogenesis of keratoconus. PMID- 23449483 TI - An association between the calpastatin (CAST) gene and keratoconus. AB - PURPOSE: Keratoconus (KC) is a genetically heterogeneous corneal dystrophy. Previously, we performed 2 genome-wide linkage scans in a 4-generation autosomal dominant pedigree and repeatedly mapped a KC locus to a genomic region located on chromosome 5q overlapping the gene encoding the inhibitor of calpains, calpastatin (CAST). To test whether variants in CAST gene are involved in genetic susceptibility to KC, we performed genetic testing of polymorphic markers in CAST gene in family and case-control panels of patients with KC. METHODS: We genotyped single-nucleotide polymorphisms (SNPs) located in CAST gene in 262 patients in 40 white KC families and in a white case-control panel with 304 cases and 518 controls. Generalized estimating equation models accounting for familial correlations implemented in GWAF program were used for association testing in families. Logistic regression models implemented in PLINK were performed to test the associations in case-control samples. RESULTS: Genetic testing of the first set of 7 SNPs in familial samples revealed 2 tentative nominally significant markers (rs4869307, P = 0.03; rs27654, P = 0.07). Additional genotyping of 12 tightly spaced SNPs identified CAST SNP rs4434401 to be associated with KC in both familial and case-control panels with P values of 0.005 and 0.05, respectively, and with combined meta P value of familial and case-control cohorts of 0.002 or after Bonferroni correction of 0.04. CONCLUSIONS: Linkage analysis and genetic association support involvement of CAST gene in the genetic susceptibility to KC. In silico analysis of CAST expression suggests differential regulation of calpain/calpastatin system in cornea as a potential mechanism of functional defect. PMID- 23449485 TI - Collagen cross-linking for advanced progressive keratoconus. AB - PURPOSE: Collagen cross-linking (CXL) is a safe and effective procedure to stop progression of keratoconus. However, corneas with a maxK of more than 55 to 58 diopters (D) have been suggested to have an increased failure rate. We report results of CXL for progressive keratoconus in corneas with a maxK of 55 D or more. METHODS: Retrospective follow-up. Twenty-eight eyes of 22 patients from 12 to 38 years were treated with CXL for progressive keratoconus. All patients had a preoperative maxK of at least 55 D. Patients were examined on 2 or more occasions after treatment, with a mean follow-up of 22 months. At all visits, patients received routine clinical examination with slit-lamp biomicroscopy, determination of corrected distance visual acuity (CDVA), and Pentacam tomography. RESULTS: The average preoperative maxK was 61.2 +/- 3.7 D. After CXL, maxK significantly decreased to 59.5 +/- 3.7 D at the last recorded visit. In 27 eyes, keratoconic progression seemed to have stopped, and in 14 eyes maxK improved with more than 2.0 D decrease, whereas 1 eye showed an increase in maxK of more than 2.0 D. The average CDVA remained unchanged after CXL treatment, although 11 eyes improved and 2 eyes had an unexplained loss of CDVA. CONCLUSIONS: CXL treatment in eyes with advanced progressive keratoconus prevented further progression in 27 of 28 eyes. Progression in cases with advanced keratoconus should not exclude CXL as a treatment to preserve visual acuity or as a supplement to other treatment modalities to delay or avoid keratoplasty. PMID- 23449486 TI - Descemet stripping automated endothelial keratoplasty in complex eyes: results with a donor insertion device. AB - PURPOSE: Descemet stripping automated endothelial keratoplasty (DSAEK) in eyes with complex anterior segment pathology or previous intraocular surgery is at risk of surgical complications and graft failure. We evaluated the use of the EndoGlide donor insertion device for DSAEK in these complex cases. METHODS: This was a retrospective interventional series of 45 consecutive eyes with endothelial dysfunction and higher risk ocular comorbidities that underwent DSAEK with the EndoGlide. We included eyes with aphakia, glaucoma surgery, prior vitrectomy, anterior chamber intraocular lenses, failed cornea grafts, and primary angle closure glaucoma. Demographic and clinical details, intraoperative and postoperative complications, and postoperative graft clarity, and endothelial cell density (ECD) loss were documented. RESULTS: The average age was 62 years (range, 16-88 years), and the majority were Chinese (n = 28). The commonest risk factors identified were previous trabeculectomy (n = 13) and failed penetrating keratoplasty (n = 12). Preoperative donor ECD averaged 2790 +/- 230 cells per square millimeter and modal graft diameter was 9.0 mm (range, 7.75-9.75 mm). One eye (2.2%) had primary graft failure, and 3 eyes (6.7%) had graft dislocation. Another 3 eyes suffered late graft failure within the first year and 2 were in eyes with an anterior chamber intraocular lenses. At 6 months, the mean ECD was 2363 + 242 cells/mm2 and the mean ECD loss was 17.9% (n = 16). By 12 months, the mean ECD was 2098 + 462 cells/mm2 and the mean ECD loss was 27.0% (n = 20). CONCLUSIONS: Donor insertion with this device can help address inherent intraoperative challenges and minimize endothelial cell damage during DSAEK in complex cases. PMID- 23449487 TI - One-year outcome of argon laser photocoagulation of pinguecula. AB - PURPOSE: To determine the efficacy and safety of argon laser photocoagulation of pinguecula by evaluating 1-year outcomes. METHODS: Twenty-one eyes of 15 patients treated with argon laser photocoagulation (photocoagulation group) and 23 eyes of 16 patients treated with surgical excision (excision group) were retrospectively reviewed. Cosmetic outcome was evaluated by patient's self-report on a 5-grade scale (excellent, good, acceptable, poor, and very poor), and evaluation of treatment outcome was based on objective findings of anterior segment photography and anterior segment optical coherence tomography. RESULTS: Overall cosmetic results were excellent or good in 90.5% of laser-treated cases and 78.6% of surgically treated cases. There was no significant difference in cosmetic outcome (P = 0.15). Nineteen (90.5%) and 17 (63.9%) cases demonstrated complete removal of pingueculae after laser photocoagulation and surgical excision, respectively. The anatomic outcome was not significantly different between the 2 groups (P = 0.25). Subconjunctival hemorrhage and conjunctival scarring with an irregular surface occurred less frequently in the photocoagulation group than in the excision group [34.8% vs. 0% (P = 0.003) and 30.4% vs. 4.8% (P = 0.048), respectively]. CONCLUSIONS: Argon laser photocoagulation is an effective and safe method for removing a pinguecula for cosmetic purposes. The method facilitates control of the extent and depth of removal and thus minimizes conjunctival defects and other complications. PMID- 23449488 TI - Studying physician knowledge, attitudes, and practices regarding the herpes zoster vaccine to address perceived barriers to vaccination. AB - PURPOSE: To increase usage of the herpes zoster (HZ) vaccine at an academic medical center by studying physicians' knowledge, attitudes, practices, and perceived barriers and analyze the findings by practice setting. METHODS: A cross sectional Internet-based survey administered to all 266 general internal medicine physicians in 4 clinical settings at an academic medical center between October 6 and December 12, 2011. Outcomes measures included knowledge questions regarding the disease and vaccine recommendations, Likert-type items about physician attitudes and practices, and questions about barriers and proposed interventions to improve utilization. RESULTS: Response rate was 33.5% (89 of 266). Responders did not answer all questions. Only 66% (42 of 64) responded that HZ vaccination was an important clinical priority, and 48% (38 of 79) reported that less than 10% of their patients received the HZ vaccine. 95% responded that the influenza (61 of 64) and 92% that the pneumococcal (59 of 64) vaccines were important. Approximately 53% (42 of 79) and 51% (40 of 78) reported that more than 75% of their patients received these vaccines, respectively. Top barrier to vaccination was cost to patients (51 of 66; 77%). Lack of awareness of national recommendations (46 of 65, 71%) varied by setting. Physicians' preferred interventions included nurse-initiated prompting about vaccination (36 of 75, 48%) and chart reminders (34 of 74, 46%). CONCLUSIONS: Not only increased knowledge but also a change in attitudes and practice are needed to enhance implementation of national recommendations. To improve use of this vaccine, physicians including ophthalmologists need to recommend it more strongly. PMID- 23449489 TI - Alterations in cyclic nucleotide phosphodiesterase activities in omental and subcutaneous adipose tissues in human obesity. AB - OBJECTIVE: To elucidate the activity and expression of cyclic nucleotide phosphodiesterase (PDE) families in omental (OM) and subcutaneous (SC) adipose tissue and adipocytes, and to study alterations in their activity in human obesity. DESIGN: Cross-sectional, translational research study. PATIENTS: In total, 25 obese and 9 non-obese subjects undergoing gastrointestinal surgery participated in the study. RESULTS: Inverse correlations between PDE activities and body mass index (BMI) were seen in both SC and OM adipose tissue. Inverse correlations between total PDE and PDE3 activity and BMI were seen in OM adipocytes but not in SC adipocytes. In both SC and OM adipose tissue of obese patients, total PDE and PDE3 activities were decreased compared with the controls. In SC adipose tissue of Type 2 diabetes (T2D) patients, the PDE activity not inhibitable by PDE3 or PDE4 inhibitors (PDEn) was increased compared with obese non-diabetic patients. In addition to PDE3 and 4 isoforms, PDE7B, PDE9A and PDE10A proteins were also detected in adipose tissue or adipocytes. CONCLUSIONS: Multiple PDE families are present in human adipose tissue and their activities are differentially affected by obesity and T2D. PMID- 23449490 TI - Novel cognitive enhancer ST101 enhances acetylcholine release in mouse dorsal hippocampus through T-type voltage-gated calcium channel stimulation. AB - We recently developed a novel cognitive enhancer, ST101 (spiro[imidazo[1,2 a]pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 MUM) but not with the L type VGCC inhibitor nifedipine (10 MUM). As expected, significantly reduced CaMKIIalpha, PKCalpha, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIalpha and PKCalpha but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) preadministration. Increased CaMKIIalpha and PKCalpha phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved cognitive function seen following ST101 administration. PMID- 23449491 TI - Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors. AB - Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia. PMID- 23449492 TI - Prevention of topical surfactant-induced itch-related responses by chlorogenic acid through the inhibition of increased histamine production in the epidermis. AB - Effects of chlorogenic acid on surfactant-induced itching were studied in mice. Topical application of sodium laurate increased hind-paw scratching, an itch related response, 2 h after application, which was inhibited by topical post treatment with chlorogenic acid. Sodium laurate increased the histamine content and 53-kDa L-histidine decarboxylase in the epidermis, which were also inhibited by post-treatment with chlorogenic acid. These results suggest that topical chlorogenic acid is effective in the prevention of itching induced by anionic surfactants. The inhibitory activity of chlorogenic acid may be due to the inhibition of an increase in histamine in the epidermis. PMID- 23449493 TI - Response to CPAP withdrawal in patients with mild versus severe obstructive sleep apnea/hypopnea syndrome. AB - BACKGROUND: Patients with obstructive sleep apnea/hypopnea syndrome (OSAHS), even those generally compliant with CPAP therapy, often intermittently discontinue CPAP. STUDY OBJECTIVE: Examine the impact of CPAP withdrawal on sleep, sleep disordered breathing (SDB), and daytime function in subjects with varying severity of OSAHS. PATIENTS AND INTERVENTIONS: Forty-two subjects (26M/16 F) with OSAHS (AHI4% = 45.2 +/- 35.5/h pretreatment) on CPAP for 4 months were evaluated on the second night of CPAP withdrawal. Sleep architecture, SDB indices, and subjective/objective daytime function were assessed pretreatment, on CPAP therapy, and after CPAP withdrawal. Comparisons were made between pretreatment and CPAP withdrawal for the entire group, and for subgroups of mild/moderate (AHI4% < 30/h, n = 22) and severe (AHI4% > 30/h, n = 20) SDB. RESULTS: Overall, and for mild/moderate subjects, SDB indices returned to pretreatment values on CPAP withdrawal but with fewer apneas and more hypopneas/RERAs. For severe SDB, the event frequency (AI, AHI4%, and RDI) was lower and O2 desaturation was improved on CPAP withdrawal. Across SDB severity, sleep architecture showed lower %REM (15.6% vs 12.9%, P = 0.009) on the CPAP withdrawal compared to pretreatment. Stanford Sleepiness Score, MSLT, and PVT measures were not significantly different between pretreatment and CPAP withdrawal. CONCLUSIONS: Over a wide range of SDB severity CPAP withdrawal results in recurrence of SDB, albeit with less severe O2 desaturation. Subjective/objective daytime function returned to pretreatment levels. Sleep architecture changes on CPAP withdrawal (acute SDB) may reflect reduced sleep pressure compared to pretreatment chronic SDB. Our data suggest detrimental effects of even brief withdrawal of CPAP in subjects with both mild and severe OSAHS. CITATION: Young LR; Taxin ZH; Norman RG; Walsleben JA; Rapoport DM; Ayappa I. Response to CPAP withdrawal in patients with mild versus severe obstructive sleep apnea/hypopnea syndrome. SLEEP 2013;36(3):405 412. PMID- 23449494 TI - Hypoxia-inducible factor and target gene expression are decreased in patients with sepsis: prospective observational clinical and cellular studies. AB - BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a molecular key player in response to hypoxemic/inflammatory conditions prevailing in sepsis. In a prospective observational study, we tested the hypotheses that sepsis affects HIF 1alpha messenger ribonucleic acid (mRNA) expression (primary hypothesis) and also (secondary hypotheses) the expression of the HIF-1alpha target genes adrenomedullin and beta2-integrins. Furthermore, we tested that lipopolysaccharide administration increases HIF-1alpha mRNA and protein in naive and endotoxin-tolerant monocytes. METHODS: In 99 patients with sepsis and 48 healthy volunteers, leukocyte HIF-1alpha mRNA expression (real-time polymerase chain reaction), cytokine concentrations (enzymelinked immunosorbent assay), and intracellular distribution of HIF-1alpha protein (immunofluorescence staining) were assessed. In vitro, HIF-1alpha mRNA expression and protein were measured in naive or endotoxin-tolerant (48 h; 0.05 ng/ml lipopolysaccharide) monocytes, with/without additional lipopolysaccharide (6h; 1 MUg/ml). RESULTS: In comparison to healthy volunteers, HIF-1alpha mRNA expression (-67%; P = 0.0001) and HIF 1alpha protein positive cells (-66.7%; P = 0.01) were decreased in sepsis. mRNA expression of adrenomedullin (-75%), CD11a (-85%), and CD11b (-86%; all P = 0.0001) was also decreased. In contrast, interleukin 6 (P = 0.0001), interleukin 10 (P = 0.0001), and tumor necrosis factor-alpha (P = 0.0002) concentrations were increased. Of note, HIF-1alpha mRNA expression was inversely associated with illness severity (Simplified Acute Physiology Score II; r = -0.29; P = 0.0001). In vitro, acute lipopolysaccharide administration of naive monocytic cells increased HIF-1alpha mRNA expression, whereas HIF-1alpha mRNA and protein (-60%; P = 0.001) were decreased in endotoxin-tolerant cells, which still up regulated cytokines. CONCLUSIONS: In sepsis, HIF-1alpha mRNA expression was suppressed and inversely associated with illness severity. While acute lipopolysaccharide administration increased HIF-1alpha mRNA expression, prolonged stimulation suppressed HIF-1alpha expression. The clinical implications of decreased HIF 1alpha may include maladaption to tissue hypoxia or depressed immune function. PMID- 23449495 TI - Irritable bowel syndrome: a review and update. AB - The understanding of irritable bowel syndrome (IBS) has undergone a rapid evolution with scientific advancement. IBS is a common functional bowel disorder that generates a significant health care burden and is the most commonly diagnosed gastrointestinal condition. There are well-established diagnostic criteria and algorithms for the initial evaluation of patients presenting with the symptoms of IBS. The symptoms can be targeted for therapy with a variety of pharmaceutical and nonpharmaceutical agents. Therapy should be individualized for the patient, and the cornerstone for any effective treatment strategy should be the solid patient-physician relationship. PMID- 23449496 TI - The economics of active surveillance for prostate cancer. AB - PURPOSE OF REVIEW: To review the economics of managing low-risk prostate cancer with active surveillance compared with other standard therapies. RECENT FINDINGS: The expenses of caring for men with prostate cancer vary depending on treatment modality chosen and appear to be escalating. Costs are generally lowest with traditional watchful waiting and highest with radiation therapy. Compared with immediate treatment, active surveillance can result in a net per-patient savings of $12194 at 5 years and $4329 at 10 years. Active surveillance demonstrates lower 5-year costs over other initial treatments as long as fewer than 70% exit active surveillance in any given year and at least 12% of men remain on active surveillance at year 5. Yearly surveillance biopsy reduces the average simulated cost savings at 10 years by $4951 per patient. SUMMARY: Active surveillance represents a cost-effective strategy for managing low-risk prostate cancer, as the majority of men remain without additional treatment over time. Prostate biopsy is the highest expenditure associated with active surveillance, and increasing the frequency of prostate biopsy will reduce the cost-effectiveness of this approach. PMID- 23449497 TI - Predicting high risk disease using serum and DNA biomarkers. AB - PURPOSE OF REVIEW: To explore several serum and genetic-based biomarkers that may prove useful in following men being managed with active surveillance for localized prostate cancer by predicting those that either have the potential to develop, or already harbor occult high grade disease. RECENT FINDINGS: There is increasing evidence that serum biomarkers human Kallikrein 2, early prostate cancer antigen, urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor, transforming growth factor-beta1 and interleukin 6/interleukin-6 receptor and genetic biomarkers BRCA1 and BRCA2, Phosphatase and tensin homolog, cellular myelocytomatosis oncogene and NKX3.1 may predict for aggressive high grade disease and are identifiable early in prostate carcinogenesis. SUMMARY: One of the barriers of widespread adoption of active surveillance for low risk, localized prostate cancer is the concern that some patients may harbor occult high-risk disease at diagnosis, or develop more aggressive/noncurable disease not detected by our current well established prognostic factors. This review examines several serum and genetic-based biomarkers that appear to be of value in localized prostate cancer, unlike the vast majority of more established prostate cancer biomarkers that have been validated in far more advanced disease. Although the biomarkers discussed show exciting promise, their clinical utility is unknown, and their role in the active surveillance scenario needs further study. PMID- 23449498 TI - [Epidemiology of the gynecological and mammary cancer to the HOMEL and in the CUGO Cotonou, Benin]. AB - INTRODUCTION: The gynecological and mammary cancers constitute a major preoccupation for the international community because they represent an important cause of mortality and morbidity among women. However, their systematic tracking is not always current in our countries of the south. This survey aims to evaluate the epidemiological features of these cancers in hospital-academic environment in Cotonou. METHOD: It is a retrospective survey with a structural descriptive and analytic aim during a period of 9 years, from January 1st, 2000 to December 31, 2008. RESULTS: On 210 cases of recorded gynecological and mammary cancers during this period, the cancer of the breast comes at the first rank with 44,3% of the cases. The cancer of the cervix represents 26,7% of the cases followed by the cancer of the ovaries (18,6%) and the cancer of the endometrium (9,5%). The cancers of the vulva and the vagina are weakly represented. The delay of consultation after the apparition of the first signs in our series is most often included between 1 and 6 months (32,2%) but goes also beyond 3 years (26,1%). The cancer of the cervix and the endometrium are found in most aged women, whereas the cancer of the breast covers all ages. Most cancers (65%) are diagnosed at an advanced stage (III stage or IV). The different anatomopathological types that are found more frequently are the ductal invasive carcinoma (33%) for the breast, the squamous cell carcinoma for cervix (62%) and the endometrioid adenocarcinoma for the endometrium (30%). The costly management of the cancers reduces the therapeutic possibilities, leading to 42% of survival at 5 years. CONCLUSION: In our survey, it comes out again that the screening of gynecological cancers is not well organized in our country as well as the health education of the woman and reproduction. It appears appropriate to set in motion a management program of the cancers in our country what would allow an early screening and appropriate management. PMID- 23449499 TI - Ring Finger Protein 14 is a new regulator of TCF/beta-catenin-mediated transcription and colon cancer cell survival. AB - T-cell factor/lymphoid enhancer factor (TCF/LEF) proteins regulate transcription by recruiting beta-catenin and its associated co-regulators. Whether TCF/LEFs also recruit more factors through independent, direct interactions is not well understood. Here we discover Ring Finger Protein 14 (RNF14) as a new binding partner for all TCF/LEF transcription factors. We show that RNF14 positively regulates Wnt signalling in human cancer cells and in an in vivo zebrafish model by binding to target promoters with TCF and stabilizing beta-catenin recruitment. RNF14 depletion experiments demonstrate that it is crucial for colon cancer cell survival. Therefore, we have identified a key interacting factor of TCF/beta catenin complexes to regulate Wnt gene transcription. PMID- 23449500 TI - Increased vegetable and fruit consumption during weight loss effort correlates with increased weight and fat loss. AB - BACKGROUND: Individuals who focused on calorie counting lost more weight than those who focused on increasing vegetable and fruit (V&F) intake in a weight loss program. We now present serum carotenoid data (biomarkers of V&F intake) from both groups and test whether these biomarkers correlate with changes in weight and body fat. DESIGN: Sixty obese volunteers were randomized to one of the following weight loss programs: 500 kcal per day reduction (Reduction) or a focus on consuming eight vegetables per day and 2-3 fruits per day (HiVeg). Volunteers in the Reduction group were 36.8+/-10.3 years with a body mass index of 33.5; 83% were white, 17% chose not to report race; 70% were not Hispanic or Latino, 13% were Hispanic or Latino and 17% chose not to report ethnicity. Volunteers in the HiVeg group were 30.4+/-6.6 years with a body mass index of 33.2: 74% white, 11% Asian, 5% black or African American, 5% multiracial and 5% chose not to report race; 89% were not Hispanic or Latino, 5% were Hispanic or Latino and 5% chose not to report ethnicity. Subjects were taught basic nutrition principles, received breakfast and lunch 5 days per week for 3 months, meals 2 days per week during month 4, then regular phone calls to month 12. RESULTS: Total serum carotenoid concentrations increased from baseline to 3 months and remained elevated at 12 months, but there was no difference between groups. Changes in weight, fat and % fat correlated negatively with serum carotenoid concentrations. CONCLUSION: Increased serum carotenoids (a biomarker for V&F intake) correlated with improved weight and fat loss indicating that increased V&F consumption is an appropriate strategy for weight loss. However, in light of the fact that the Reduction group lost more weight, the consumption of increased V&F for the purpose of weight loss should happen within the context of reducing total caloric intake. PMID- 23449502 TI - Reply: complexity in camalexin biosynthesis. PMID- 23449501 TI - Ca2+-dependent protein kinase11 and 24 modulate the activity of the inward rectifying K+ channels in Arabidopsis pollen tubes. AB - Potassium (K(+)) influx into pollen tubes via K(+) transporters is essential for pollen tube growth; however, the mechanism by which K(+) transporters are regulated in pollen tubes remains unknown. Here, we report that Arabidopsis thaliana Ca(2+)-dependent protein kinase11 (CPK11) and CPK24 are involved in Ca(2+)-dependent regulation of the inward K(+) (K(+)in) channels in pollen tubes. Using patch-clamp analysis, we demonstrated that K(+)in currents of pollen tube protoplasts were inhibited by elevated [Ca(2+)]cyt. However, disruption of CPK11 or CPK24 completely impaired the Ca(2+)-dependent inhibition of K(+)in currents and enhanced pollen tube growth. Moreover, the cpk11 cpk24 double mutant exhibited similar phenotypes as the corresponding single mutants, suggesting that these two CDPKs function in the same signaling pathway. Bimolecular fluorescence complementation and coimmunoprecipitation experiments showed that CPK11 could interact with CPK24 in vivo. Furthermore, CPK11 phosphorylated the N terminus of CPK24 in vitro, suggesting that these two CDPKs work together as part of a kinase cascade. Electrophysiological assays demonstrated that the Shaker pollen K(+)in channel is the main contributor to pollen tube K(+)in currents and acts as the downstream target of the CPK11-CPK24 pathway. We conclude that CPK11 and CPK24 together mediate the Ca(2+)-dependent inhibition of K(+)in channels and participate in the regulation of pollen tube growth in Arabidopsis. PMID- 23449504 TI - A radiological study on the trabecular pattern in the upper end of the femur in post-menopausal women. AB - OBJECTIVE: Anatomically, the upper end of the femur is a common site for osteoporosis. Therefore, The trabecular pattern in the upper end of femur is analyzed on the basis of the presence or absence, the relative number and density of the trabeculae, trabecular group and also by the grading of trabeculae. The present study was undertaken to identify the trabecular pattern in the upper end of the femur radiographically in postmenopausal women and to establish that the changes in the trabecular pattern can be used for the diagnosis and the grading of osteoporosis. While osteoporosis is observed in both elderly men and women, its prevalence is much higher in post-menopausal women. The validated data from this study will be of use to all the clinicians to recognize the trabecular patterns and it will possibly help them in detecting osteoporosis and in limiting its progress in its early stages. METHOD: Two hundred frontal projection pelvis radiographs of women who were between 18-100 years of age were studied during 2006-2007. In this study, an attempt was made to test the presence, pattern and the grading of the trabecular pattern in pre and post-menopausal females and to find out the influence of the post menopausal age on the trabecular patterns. All the readings were tabulated and subjected to analysis. RESULTS: The distribution of the grading of the trabecular pattern in the upper end of the femur on the left and right sides for the severity of osteoporosis showed that as the number of years increased after menopause, the grading progressed from Grade N (Normal) to Grade A to Grade B to Grade C. CONCLUSION: This study will be useful for anatomists, radiologists and clinicians for recognizing the trabecular pattern and it will possibly help them in detecting osteoporosis and in limiting its progress in its early stages. PMID- 23449503 TI - Assigning gene function in biosynthetic pathways: camalexin and beyond. PMID- 23449505 TI - Squamous Cell Carcinoma Arising in Warthin's Tumour: A Case Report. AB - Warthin's tumour (adenolymphoma) is a well defined salivary gland tumour which consists of epithelial and lymphoid components. However, the malignant transformation of adenolymphoma is extremely rare. We are reporting a case of squamous cell carcinoma which arose in a Warthin's tumour of the right parotid gland, to highlight its varied cytolomorphological features which can cause diagnostic problems on cytological examination. The review of the literature has been discussed. PMID- 23449506 TI - Progressive ocular inflammation following anti-tubercular therapy for presumed ocular tuberculosis in a high-endemic setting. AB - PURPOSE: To analyze the incidence and clinical course of patients developing progressive ocular inflammation following anti-tubercular therapy (ATT) for presumed ocular tuberculosis (TB). METHODS: Retrospective analysis of medical records of patients who received ATT for presumed ocular TB and completed at least 12 months follow-up after initiation of ATT. The diagnosis of presumed ocular TB was based on presence of ocular signs suggestive of TB, evidence of past tubercular infection, and exclusion of mimicking clinical entities. All patients received a combination of ATT and corticosteroid therapy. Primary outcome measure was progression (worsening) of ocular inflammation, defined as a two-step increase in level of inflammation (anterior chamber/ vitreous) or the appearance of new lesions following initiation of ATT. RESULTS: A total of 106 patients (64 male, 42 female) received ATT for presumed ocular TB. Twenty-six (24.5%) patients developed progressive intraocular inflammation following ATT. Primary diagnoses in these patients were: anterior uveitis (n=1), intermediate uveitis (n=9), retinal vasculitis (n=3), serpiginous-like choroiditis (n=7), multifocal choroiditis (n=2), and pan-uveitis (n=4). Following progressive inflammation, diagnosis was revised in two patients (7.7%)-both responded to alternative therapy. Of the rest, majority (n=16; 61.5%) resolved with escalation of corticosteroid therapy. Five patients (19.2%)-all having intermediate uveitis required therapeutic vitrectomy for resolution. Three patients (11.5%) had persistent inflammation at end of follow-up period. CONCLUSION: Progressive inflammation following ATT for presumed ocular TB is common. It generally resolves on escalation of corticosteroid therapy. Cases not responding to increased immunosuppression need to be re-investigated to rule out a nontubercular cause. PMID- 23449507 TI - Response to Banerjee et al. PMID- 23449508 TI - Ranibizumab for the treatment of choroidal neovascularisation secondary to pathological myopia: interim analysis of the REPAIR study. AB - AIMS: To evaluate the efficacy and safety of intravitreal ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia (myopic CNV). Data are from a pre-planned, 6-month interim analysis. METHODS: Phase II, open label, single arm, multicentre, 12-month study, recruiting patients (aged >=18 years) with active primary or recurrent subfoveal or juxtafoveal myopic CNV, with a best-corrected visual acuity (BCVA) score of 24-78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the study eye and a diagnosis of high myopia of at least -6 dioptres. Patients received 0.5 mg ranibizumab administered intravitreally to the study eye, followed by monthly injections given as needed (based on a predefined algorithm) for up to 11 months. RESULTS: At 6 months, mean BCVA improved from baseline by 12.2 letters, as did central macular thickness (in this interim analysis defined as a measure of either central subfield macular thickness or centre point macular thickness) from baseline by 108 MUm in the 48 study eyes of 48 patients. Fewer patients had centre-involving intraretinal oedema (13.0% vs 91.5%), intraretinal cysts (10.9% vs 57.4%), or subretinal fluid (13.0% vs 66.0%) at 6 months than at baseline. Patients received a mean of 1.9 retreatments, were satisfied with ranibizumab treatment, and well being was maintained. No new safety signals were identified. CONCLUSIONS: Results from the planned interim analysis support the role of ranibizumab in the treatment of myopic CNV, with excellent efficacy achieved with a low number of injections and few serious adverse events. PMID- 23449509 TI - United Kingdom National Ophthalmology Database Study of Vitreoretinal Surgery: report 1; case mix, complications, and cataract. AB - AIM: To report the vitreoretinal (VR) surgical case mix in the United Kingdom, the intraoperative complication rate of pars plana vitrectomy (PPV), and the incidence of post-vitrectomy cataract extraction. METHODS: Participating hospitals prospectively collected ophthalmic data using a single electronic medical record system, with automatic extraction of anonymised data to a national database. This study included the subset of 11618 VR operations undertaken on 9619 eyes, of 8741 patients, over 8 years, from 27 sites. Surgical data included the indication for surgery, all procedure elements, and whether or not an intraoperative complication occurred. Post-vitrectomy cataract data were also analysed. The main outcome measures were a description of the indications for surgery, intraoperative PPV complication rate, and percentage of eyes undergoing post-vitrectomy cataract surgery (PVCS). RESULTS: The most common indications for VR intervention were retinal breaks and rhegmatogenous retinal detachment (48.5%), macular hole (9.8%), epiretinal membrane (9.6%), and diabetic eye disease (7.3%). Overall, 7.8% of PPVs had at least one intraoperative complication-the most common were iatrogenic retinal breaks (3.2%), and lens touch (1.2-1.6% of phakic eyes). PVCS occurred in 50.2, 68.7, and 74.0% of eyes at 1, 2, and 3 years, respectively. CONCLUSION: VR surgery is undertaken for a wide range of conditions, but a small number of diagnoses encompass the majority of cases. Intraoperative PPV complications are not uncommon, and post-vitrectomy cataract is to be expected in most phakic eyes. PMID- 23449510 TI - Risk factors for iatrogenic retinal breaks induced by separation of posterior hyaloid face during 23-gauge pars plana vitrectomy. AB - PURPOSE: To describe the incidence and features of intraoperative retinal breaks caused by induction of posterior hyaloid face (PHF) separation during 23-gauge pars plana vitrectomy (PPV). METHODS: A prospective, consecutive, single surgeon, observational study of patients undergoing 23-gauge transconjunctival sutureless vitrectomy for macular pathology or floaters, was carried out between 2009 and 2011 at Calderdale Royal Hospital, UK. PHF separations were categorised as either suction induced or requiring membrane blue (DORC Limited) with suction (adherent). The outcome measure was dichotomised into retinal break or tear and no retinal break or tear. Forced entry and parsimonious multiple logistic regression analyses were conducted, using statistical software, to test for significance of association of the set of recorded factors and covariates with the dichotomised outcome measure. RESULTS: Data were collected and analysed from 137 patients. The incidence of iatrogenic retinal breaks associated with PHF separation during 23-gauge PPV was 18.2%. Under both forced entry and parsimonious multiple logistic regression models, the odds of a retinal break or tear reduce by about 3-4% for each increasing year of age. Findings also showed some substantive association in the forced entry model, with the odds of a retinal break or tear for adherent cases being around 3.8 times those for suction only cases. CONCLUSIONS: Mechanical detachment of the PHF represents an important risk factor in the formation of retinal breaks. Particular care should be taken to examine intraoperatively for iatrogenic breaks in order to prevent missed breaks and subsequent rhegmatogenous retinal detachments. PMID- 23449511 TI - Routine use of topical cyclopentolate as a predisposing factor to recurrent urinary tract infections in a susceptible adult. PMID- 23449512 TI - Macular thickness changes evaluated with spectral domain optical coherence tomography after uncomplicated phacoemulsification. AB - PURPOSE: To determine macular thickness changes after uncomplicated cataract surgery using spectral domain optical coherence tomography (OCT). METHODS: This was a prospective non-randomized, clinical study. Data were analysed for 40 healthy patients undergoing uneventful phacoemulsification. OCT measurements were performed before surgery and postoperatively at day 1, week 1 and 2, and month 1, 2, 3, and 6. The retinal map was divided into central point thickness (CPT), central 1-mm subfield (CSF), and two peripheral ring areas with diameters of 3 and 6 m. Fellow eyes were used as controls. Retinal thickness change between the operated and fellow eyes were compared using unpaired t-test. Correlations were analysed using the Spearman or the Pearson analysis. RESULTS: There was a progressive significant increase in retinal thickness of the operated eyes compared with the fellow eyes, with a peak at 1 month (P<0.0001) for the 3- and 6 mm areas and a peak at 2 months for CPT and CSF (P=0.01 and P<0.0001, respectively). At 6 months, retinal thickness was still significantly increased only in the peripheral areas (P<0.0001). There was no significant correlation between macular thickness changes and preoperative factors (age, axial length, anterior chamber depth, posterior vitreous detachment, best-corrected visual acuity), intraoperative factors (length of surgery, effective phaco time, phaco energy) or BCVA change. CONCLUSIONS: The present study demonstrated a significant increase in macular thickness up to 6 months after uncomplicated cataract surgery. The most important finding was the regional pattern of retinal thickening with an early involvement of the parafoveal area. PMID- 23449513 TI - Central corneal haze after wedge resection following penetrating keratoplasty and photorefractive keratectomy. PMID- 23449514 TI - John David Scott, 4th June 1936 in Godalming Surrey to 10th january 2013 in Llangattock Powes. PMID- 23449516 TI - Arcuate scotoma associated with traction at the optic disc. PMID- 23449515 TI - Efficacy of half-fluence photodynamic therapy depending on the degree of choroidal hyperpermeability in chronic central serous chorioretinopathy. AB - PURPOSE: The purpose of this study is to determine the efficacy of half-fluence photodynamic therapy (PDT) depending on the degree of hyperfluorescence based on indocyanine green angiography (ICGA) for treatment of chronic central serous chorioretinopathy (CSC). METHODS: We conducted a prospective study of 30 eyes of 30 patients with chronic CSC. Half-fluence PDT (25 J/cm(2) for 83 s) with ICGA guidance was applied to the area of choroidal hyperpermeability. The baseline middle-phase ICGA findings were classified as intense or weak hyperfluorescence depending on the degree of hyperpermeability from choriocapillaris. Changes in mean best-corrected visual acuity, resolution of subretinal fluid, recurrence rate, and complications were compared between the two groups. RESULTS: The baseline ICGA findings showed intense hyperfluorescence in 16 eyes (53.3%) and weak hyperfluorescence in 14 eyes (46.7%). Subretinal fluid showed complete resolution in both the groups 1 month after a single application of half-fluence PDT. Recurrence of subretinal fluid was observed in one of 14 eyes (7.1%) with weak hyperfluorescence and in no eyes (0%) with intense hyperfluorescence. No statistically significant difference in the rate of recurrence was observed between the two groups. CONCLUSION: Half-fluence PDT appears to be an effective and safe treatment option for patients with chronic CSC regardless of the degree of hyperfluorescence based on ICGA. According to these findings, choroidal hyperpermeability, rather than dysfunction of retinal pigment epithelium, might be more important as primary pathogenesis of chronic CSC. PMID- 23449517 TI - An unusual presentation of aqueous misdirection. PMID- 23449518 TI - Incidental gall bladder carcinoma in laparoscopic cholecystectomy: a report of 6 cases and a review of the literature. AB - BACKGROUND: Gall bladder carcinoma accounts for 98% of all the gall bladder malignancies and it is the sixth most common malignancy of the gastrointestinal tract worldwide. The incidence of incidental gall bladder carcinoma which is diagnosed during or after a laparoscopic cholecystectomy is reported to be around 0.19-3.3% in the literature. AIM: This study was aimed at detecting the incidence of gall bladder carcinomas which were diagnosed incidentally during or after laparoscopic cholecystectomies which were done for gall stone disease and cholecystitis. MATERIALS AND METHODS: We analyzed the medical records of patients with symptomatic gallstone disease and acute or chronic cholecystitis, who underwent laparoscopic cholecystectomies at the Hakeem Abdul Hameed Centenary Hospital during the period from January 2007 to June 2012. RESULTS: A total of 622 laparoscopic cholecystectomies were performed at our institute during the study period of five and a half years. In 6 (0.96%) cases, incidental carcinomas of the gallbladder were discovered. CONCLUSION: A laparoscopic cholecystectomy which is performed for benign gall bladder disease rarely results in a diagnosis of unexpected gallbladder cancer. The microscopic examination of the specimens, with special attention to the depth of invasion, range of the mucosal spread and the lymphovascular involvement, is critical in diagnosing the incidental malignancies as well as for the subsequent management of the cases. PMID- 23449519 TI - Are there any differences in various polyaxial locking systems? A mechanical study of different locking screws in multidirectional angular stable distal radius plates. AB - Numerous angular stable plates for the distal radius exist, and technically based comparisons of the polyaxial locking interfaces are lacking. The aim of this mechanical study was to investigate three different locking interfaces of angular stable volar plates by cantilever bending: VA-LCP Two-Column Distal Radius Plates 2.4 mm (Synthes(r) GmbH, Oberdorf, Switzerland), IXOS(r) P4 (Martin, Tuttlingen, Germany) and VariAXTM (Stryker(r), Duisburg, Germany). We assessed the strength of 0 degrees , 5 degrees , 10 degrees and 15 degrees screw locking angles and tested the bending strength from 10 degrees to 5 degrees angles by cyclic loading until breakage. The final setup repeated the above assessments by inclusion of four locking screws. The single screw-plate interfaces of the VA-LCP showed the highest bending moment at an angle of 0 degrees and 5 degrees , the IXOS(r) P4 at an angle of 10 degrees and 15 degrees and the VariAXTM when changing the insertion angle from 10 degrees into 5 degrees . The strength of polyaxial locking interfaces and mechanism of failure proved to be different among the examined plates. PMID- 23449520 TI - Clinical pharmacology of drug metabolism and drug interactions: clinical, interethnical and regulatory aspects. PMID- 23449521 TI - A critical appraisal of the role of respiratory supercomplexes in mitochondria. AB - Substantial evidence exists that the mitochondrial respiratory chain is organized in supramolecular units called supercomplexes or respirasomes. While the structural evidence of the supercomplexes is overwhelming, fewer studies have focused on their functional relevance. Although the presence of coenzyme Q channeling between complexes I and III has been ascertained, no such clear demonstration has been carried out for cytochrome c between complexes III and IV, at least in mammalian mitochondria. This review also discusses the implications concerning the number of respiratory complexes organized in supercomplexes and the possibility that they represent associations in dynamic equilibrium with the individual complexes. PMID- 23449522 TI - Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors. AB - The neuropeptide Y system is known to be involved in the regulation of many central physiological and pathophysiological processes, such as energy homeostasis, obesity, cancer, mood disorders and epilepsy. Four Y receptor subtypes have been cloned from human tissue (hY1, hY2, hY4 and hY5) that form a multiligand/multireceptor system together with their three peptidic agonists (NPY, PYY and PP). Addressing this system for medical application requires on the one hand detailed information about the receptor-ligand interaction to design subtype-selective compounds. On the other hand comprehensive knowledge about alternative receptor signaling, as well as desensitization, localization and downregulation is crucial to circumvent the development of undesired side-effects and drug resistance. By bringing such knowledge together, highly potent and long lasting drugs with minimized side-effects can be engineered. Here, current knowledge about Y receptor export, internalization, recycling, and degradation is summarized, with a focus on the human Y receptor subtypes, and is discussed in terms of its impact on therapeutic application. PMID- 23449523 TI - Special issue on advances and controversies in B vitamins and choline. PMID- 23449524 TI - Red cell or serum folate: what to do in clinical practice? AB - Folate deficiency has been linked to diverse clinical manifestations and despite the importance of accurate assessment of folate status, the best test for routine use is uncertain. Both serum and red cell folate assays are widely available in clinical laboratories; however, red cell folate is the more time-consuming and costly test. This review sought to evaluate whether the red cell assay demonstrated superior performance characteristics to justify these disadvantages. Red cell folate, but not serum folate, measurements demonstrated analytical variation due to sample pre-treatment parameters, oxygen saturation of haemoglobin and haematocrit. Neither marker was clearly superior in characterising deficiency but serum folate more frequently showed the higher correlation with homocysteine, a sensitive marker of deficiency. Similarly, both serum and red cell folate were shown to increase in response to folic acid supplementation. However, serum folate generally gave the greater response and was able to distinguish different supplementation doses. The C677T polymorphism of methylenetetrahydrofolate reductase alters the distribution of folate forms in red cells and may thereby cause further analytical variability in routine red cell folate assays. Overall, serum folate is cheaper and faster to perform than red cell folate, is influenced by fewer analytical variables and provides an assessment of folate status that may be superior to red cell folate. PMID- 23449526 TI - Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver. AB - Carcinogenesis is a multi-step and multifactorial process. It includes genetic, epigenetic, nutritional and environmental factors, which are closely interconnected. Human hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. Imbalance in the S-adenosylmethionine (SAM) concentration, the main methyl group donor, strongly influences the development of HCC. Key enzymes of carbon metabolism are greatly reduced in patients with cirrhosis and HCC. These alterations play a role in genetic instability and epigenetic modifications (DNA methylation, and histone modifications), however, the molecular underlying mechanisms are still poorly understood. We aimed to investigate betaine homocysteine methyltransferase (BHMT) expression in HepG2 cells and human hepatocarcinoma tissues. Tumor and surrounding healthy tissue were compared. HepG2 cells and tumor samples showed a strong decrease in BHMT transcripts resulting from the transcription of a splicing variant that contained a frameshift mutation generating a premature termination codon and gene loss of function. This splicing variant, not detected in normal adult and fetal liver, cannot be explained by any mechanism involving the known splicing consensus sequences. BHMT activity was abolished in HepG2 cells and protein expression was detected neither in HepG2 cells nor in five of the six tumor samples investigated. Further investigation is needed to elucidate whether this abnormal BHMT transcription is part of cause or consequence of liver carcinogenesis. PMID- 23449525 TI - The role of homocysteine in bone remodeling. AB - Bone remodeling is a very complex process. Homocysteine (Hcy) is known to modulate this process via several known mechanisms such as increase in osteoclast activity, decrease in osteoblast activity and direct action of Hcy on bone matrix. Evidence from previous studies further support a detrimental effect on bone via decrease in bone blood flow and an increase in matrix metalloproteinases (MMPs) that degrade extracellular bone matrix. Hcy binds directly to extracellular matrix and reduces bone strength. There are several bone markers that can be used as parameters to determine how high levels of plasma Hcy (hyperhomocysteinemia, HHcy) affect bone such as: hydroxyproline, N-terminal collagen 1 telopeptides. Mitochondrion serves an important role in generating reactive oxygen species (ROS). Mitochondrial abnormalities have been identified during HHcy. The mechanism of Hcy-induced bone remodeling via the mitochondrial pathway is largely unknown. Therefore, we propose a mitochondrial mechanism by which Hcy can contribute to alter bone properties. This may occur both through generations of ROS that activate MMPs and could be extruded into matrix to degrade bone matrix. However, there are contrasting reports on whether Hcy affects bone density, with some reports in favour and others not. Earlier studies also found an alteration in bone biomechanical properties with deficiencies of vitamin B12, folate and HHcy conditions. Moreover, existing data opens speculation that folate and vitamin therapy act not only via Hcy-dependent pathways but also via Hcy-independent pathways. However, more studies are needed to clarify the mechanistic role of Hcy during bone diseases. PMID- 23449527 TI - B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes. AB - Therapy to lower homocysteine with B vitamins does reduce the risk of stroke, if not myocardial infarction. The apparent lack of efficacy of vitamin therapy in most of the large clinical trials was probably determined by the failure to take account of the metabolic deficiency of vitamin B12, which is very common and often missed, and by the failure to take account of impaired renal function. Metabolic B12 deficiency is present in 20% of people over 65 years of age, and in 30% of vascular patients above 70 years, so higher doses of B12 are needed in elderly patients. However, high-dose cyanocobalamin leads to accumulation of cyanide in patients with renal failure. B vitamin therapy is beneficial in patients with good renal function, but harmful in patients with significantly impaired renal function (a glomerular filtration rate <50). It seems likely that in patients with renal impairment, methylcobalamin should be used instead cyanocobalamin. PMID- 23449529 TI - Relation of depot-specific adipose inflammation to insulin resistance in human obesity. AB - BACKGROUND: A low-grade state of adipose tissue inflammation associated with obesity has been linked to mechanisms of systemic metabolic dysfunction. However, the relation of clinical phenotypes to depot-specific inflammation has not been well examined in human obesity. OBJECTIVE: To characterize the inflammatory status of subcutaneous and visceral fat depots, as assessed by tissue presence of macrophage crown-like structures (CLS) as a hallmark of chronic inflammation, and determine the relation of systemic insulin resistance to inflammatory abnormalities in subcutaneous and visceral fat. METHODS: We collected adipose tissue simultaneously from subcutaneous and visceral (omental and mesenteric) depots in 92 obese participants (age 42+/-11 years; BMI?30 kg m(-2)) during planned bariatric surgery. Using immunohistochemistry, we categorized individuals as CLS(+) or CLS(-) based on the presence or absence, respectively, of macrophage CLS in subcutaneous (CLSs), omental (CLSo) and mesenteric (CLSm) adipose depots. RESULTS: The majority of participants exhibited adipose tissue inflammation manifest by the presence of CLS (CLS(+)) in both subcutaneous and intra-abdominal visceral depots. CLS status in subcutaneous fat was highly sensitive and modestly specific for inflammation of visceral fat. In multivariable models, plasma insulin and homeostatis model assessment levels were positively associated with CLS(+) status in all depots independent of age, waist circumference, BMI and type 2 diabetes, and worsened with the increasing number of adipose regions involved. CONCLUSIONS: In severely obese participants, systemic insulin resistance is linked to adipose inflammation in both subcutaneous and visceral depots. The findings suggest that examination of subcutaneous regions that are more easily accessible by transcutaneous biopsy may prove useful in clinical studies designed to investigate adipose phenotypes in relation to human disease. PMID- 23449528 TI - Getting 'Smad' about obesity and diabetes. AB - Recent findings on the role of transforming growth factor (TGF)-beta/Smad3 signaling in the pathogenesis of obesity and type 2 diabetes have underscored its importance in metabolism and adiposity. Indeed, elevated TGF-beta has been previously reported in human adipose tissue during morbid obesity and diabetic neuropathy. In this review, we discuss the pleiotropic effects of TGF-beta/Smad3 signaling on metabolism and energy homeostasis, all of which has an important part in the etiology and progression of obesity-linked diabetes; these include adipocyte differentiation, white to brown fat phenotypic transition, glucose and lipid metabolism, pancreatic function, insulin signaling, adipocytokine secretion, inflammation and reactive oxygen species production. We summarize the recent in vivo findings on the role of TGF-beta/Smad3 signaling in metabolism based on the studies using Smad3(-/-) mice. Based on the presence of a dual regulatory effect of Smad3 on peroxisome proliferator-activated receptor (PPAR)beta/delta and PPARgamma2 promoters, we propose a unifying mechanism by which this signaling pathway contributes to obesity and its associated diabetes. We also discuss how the inhibition of this signaling pathway has been implicated in the amelioration of many facets of metabolic syndromes, thereby offering novel therapeutic avenues for these metabolic conditions. PMID- 23449530 TI - A proposed potential role for increasing atmospheric CO2 as a promoter of weight gain and obesity. AB - Human obesity has evolved into a global epidemic. Interestingly, a similar trend has been observed in many animal species, although diet composition, food availability and physical activity have essentially remained unchanged. This suggests a common factor-potentially an environmental factor affecting all species. Coinciding with the increase in obesity, atmospheric CO2 concentration has increased more than 40%. Furthermore, in modern societies, we spend more time indoors, where CO2 often reaches even higher concentrations. Increased CO2 concentration in inhaled air decreases the pH of blood, which in turn spills over to cerebrospinal fluids. Nerve cells in the hypothalamus that regulate appetite and wakefulness have been shown to be extremely sensitive to pH, doubling their activity if pH decreases by 0.1 units. We hypothesize that an increased acidic load from atmospheric CO2 may potentially lead to increased appetite and energy intake, and decreased energy expenditure, and thereby contribute to the current obesity epidemic. PMID- 23449531 TI - Effect of moderate weight loss on hepatic, pancreatic and visceral lipids in obese subjects. AB - OBJECTIVE: To compare the effects of weight loss on visceral and subcutaneous abdominal fat, liver and pancreas lipid content and to test the effects of these changes on metabolic improvement observed after weight loss. DESIGN: Weight-loss program designed to achieve a loss of 7-10% of the initial weight. SUBJECTS: 24 obese subjects (13 males and 11 females) with age ranging from 26 to 69 years and body mass index (BMI) 30.2-50.5 kg m(-2). MEASUREMENTS: weight, BMI, waist circumference, body composition as assessed by dual-energy X-ray absorptiometry, metabolic variables, leptin, adiponectin, visceral and subcutaneous abdominal fat, liver and pancreas lipid content as assessed by magnetic resonance were evaluated before and after weight loss achieved by hypocaloric diet. RESULTS: After a mean body weight decrease of 8.9%, BMI, waist circumference, fat mass, all metabolic variables, homeostasis model assessment of insulin resistance (HOMA), alanine amino transferase, gamma glutamyl transpeptidase, high sensitivity C-reactive protein (hs-CRP) and leptin, but not adiponectin and high density lipoprotein-cholesterol, significantly decreased (all P<0.01). Visceral and subcutaneos abdominal fat, liver and pancreas lipid content significantly decreased (all P<0.01). Percent changes in liver lipid content were greater (84.1+/-3%) than those in lipid pancreas content (42.3+/-29%) and visceral abdominal fat (31.9+/-15.6%). After weight loss, percentage of subjects with liver steatosis decreased from 75 to 12.5%. Insulin resistance improvement was predicted by changes in liver lipid content independently of changes in visceral fat, pancreas lipid content, systemic inflammation, leptin and gender. CONCLUSION: Moderate weight loss determines significant decline in visceral abdominal fat, lipid content in liver and pancreas. Reduction of liver lipid content was greater than that of pancreas lipid content and visceral fat loss. Liver lipid content is the strongest predictor of insulin resistance improvement after weight loss. PMID- 23449532 TI - Transitions: the birth of flora Arden. AB - In this column, a young mother shares the story of her second home birth. Like the birth of her first baby, her daughter Flora's birth was supported by the presence of a midwife and doula, the peace and quiet of her own home, and the love of her husband and family. Birth is described as transforming and a powerful transition for women. She describes the births of both her children as being "forever emblazoned on my heart as the sweetest and strongest days of my small life." Paralleling this story of birth is the story of her mother-in-law as she faces brain cancer and seizes the power of that life transition. PMID- 23449533 TI - The clinical impact of humoral immunity in pediatric renal transplantation. AB - The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study. PMID- 23449534 TI - Cystathionine gamma-lyase protects against renal ischemia/reperfusion by modulating oxidative stress. AB - Hydrogen sulfide (H2S) is an endogenous gasotransmitter with physiologic functions similar to nitric oxide and carbon monoxide. Exogenous treatment with H2S can induce a reversible hypometabolic state, which can protect organs from ischemia/reperfusion injury, but whether cystathionine gamma-lyase (CSE), which produces endogenous H2S, has similar protective effects is unknown. Here, human renal tissue revealed abundant expression of CSE, localized to glomeruli and the tubulointerstitium. Compared with wild-type mice, CSE knockout mice had markedly reduced renal production of H2S, and CSE deficiency associated with increased damage and mortality after renal ischemia/reperfusion injury. Treatment with exogenous H2S rescued CSE knockout mice from the injury and mortality associated with renal ischemia. In addition, overexpression of CSE in vitro reduced the amount of reactive oxygen species produced during stress. Last, the level of renal CSE mRNA at the time of organ procurement positively associated with GFR 14 days after transplantation. In summary, these results suggest that CSE protects against renal ischemia/reperfusion injury, likely by modulating oxidative stress through the production of H2S. PMID- 23449535 TI - Brg1 determines urothelial cell fate during ureter development. AB - Developing and adult ureters express the epigenetic regulator Brg1, but the role of Brg1 in ureter development is not well understood. We conditionally ablated Brg1 in the developing ureter using Hoxb7-Cre and found that Brg1 expression is upstream of p63, Ppargamma, and sonic hedgehog (Shh) expression in the ureteral epithelium. In addition, epithelial stratification in the basal cells required Brg1-dependent p63 expression, whereas terminal differentiation of the umbrella cells required Brg1-dependent Ppargamma expression. Furthermore, the loss of ureteric Brg1 resulted in failure of Shh expression, which correlated with reduced smooth muscle cell development and hydroureter. Taken together, we conclude that Brg1 expression unifies three aspects of ureter development: maintenance of the basal cell population, guidance for terminal differentiation of urothelial cells, and proper investment of ureteral smooth muscle cells. PMID- 23449536 TI - Pulmonary congestion predicts cardiac events and mortality in ESRD. AB - Pulmonary congestion is highly prevalent and often asymptomatic among patients with ESRD treated with hemodialysis, but whether its presence predicts clinical outcomes is unknown. Here, we tested the prognostic value of extravascular lung water measured by a simple, well validated ultrasound B-lines score (BL-US) in a multicenter study that enrolled 392 hemodialysis patients. We detected moderate to-severe lung congestion in 45% and very severe congestion in 14% of the patients. Among those patients with moderate-to-severe lung congestion, 71% were asymptomatic or presented slight symptoms of heart failure. Compared with those patients having mild or no congestion, patients with very severe congestion had a 4.2-fold risk of death (HR=4.20, 95% CI=2.45-7.23) and a 3.2-fold risk of cardiac events (HR=3.20, 95% CI=1.75-5.88) adjusted for NYHA class and other risk factors. Including the degree of pulmonary congestion in the model significantly improved the risk reclassification for cardiac events by 10% (P<0.015). In summary, lung ultrasound can detect asymptomatic pulmonary congestion in hemodialysis patients, and the resulting BL-US score is a strong, independent predictor of death and cardiac events in this population. PMID- 23449537 TI - Does urinary metabolic assessment in idiopathic calcium nephrolithiasis matter? A matched case control study among Indian siblings. AB - OBJECTIVE: To identify the differences in urinary profile of a stone former and the matched member of the family. PATIENTS AND METHODS: This prospective case control study was conducted from April 2006 to January 2008. Forty-one matched pairs from one geographic region were recruited. Renal/ureteric idiopathic calcium nephrolithiasis in patients of 18 years and above were included as cases. Controls were of the same gender and first-degree relative with no urolithiasis or history. They were living together at least for the last 5 years and consuming minimum of two out of three major meals together per day. For cases and controls besides fluid intake, ambulatory serum analysis for calcium, phosphorus, uric acid, albumin-globulin ratio, sodium, potassium and bicarbonate was done. Ambulatory 24-hour urinalysis was done for urinary volume, calcium, phosphorus, oxalate, uric acid, citrate, magnesium, creatinine and urinary pH was measured. For controls X-ray and USG-Kidney-Ureter-Bladder was done to rule out stone disease. The statistical analysis was done using Mc-Nemar test. RESULTS: Of the 41, 31 cases (76%) were first-time stone formers. No statistical difference was found for 24-hour urinary calcium (P = 0.68), oxalate (P = 0.68), citrate (P = 0.45) and urinary volume (P = 0.14). All pairs had normal 24-hour urinary magnesium, uric acid and urinary pH. CONCLUSIONS: The urinary biochemical profile of idiopathic calcium nephrolithiasis was similar to the appropriately matched family member. It appears that an independent intrinsic factor may possibly be present and responsible for stone disease. The usefulness of urinary metabolic evaluation is seems to be of doubtful significance. PMID- 23449538 TI - Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. AB - There is shortage of extensive clinicopathologic studies of cellular senescence because the most reliable senescence biomarker, the detection of Senescence Associated-beta-galactosidase activity (SA-beta-gal), is inapplicable in archival material and requires snap-frozen tissues. We validated the histochemical Sudan Black-B (SBB) specific stain of lipofuscin, an aggregate of oxidized proteins, lipids and metals, known to accumulate in aged tissues, as an additional reliable approach to detect senescent cells independently of sample preparation. We analyzed cellular systems in which senescence was triggered by replicative exhaustion or stressful stimuli, conditional knock-in mice producing precancerous lesions exhibiting senescence, and human preneoplastic lesions known to contain senescent cells. In the above settings we demonstrated co-localization of lipofuscin and SA-beta-gal in senescent cells in vitro and in vivo (cryo preserved tissue), strongly supporting the candidacy of lipofuscin for a biomarker of cellular senescence. Furthermore, cryo-preserved tissues positive for SA-beta-gal were formalin-fixed, paraffin-embedded, and stained with SBB. The corresponding SA-beta-gal positive tissue areas stained specifically for lipofuscin by SBB, whereas tissues negative for SA-beta-gal were lipofuscin negative, validating the sensitivity and specificity of the SBB staining to visualize senescent cells in archival material. The latter unique property of SBB could be exploited in research on widely available retrospective tissue material. PMID- 23449539 TI - Multifaceted management of the postthrombotic syndrome. AB - The postthrombotic syndrome (PTS) is a frequent cause of chronic pain, swelling, ulceration, and disability in patients with lower extremity deep vein thrombosis (DVT). As interventional radiologists are consulted on more patients with chronic DVT and PTS, their management strategies must be informed by a balanced understanding of the different facets of chronic DVT care and the available treatment options. This article provides an overview of the important elements of a multifaceted approach to the management of patients with PTS that includes pharmacological, physiological, and endovascular aspects of care. PMID- 23449540 TI - Measurement of lumbar lordosis in static standing posture with and without high heeled shoes. AB - OBJECTIVE: Some doctors and therapists believe that wearing high-heeled shoes causes increased lumbar lordosis and that this may be a cause of low back pain. The purpose of this study was to evaluate whether high-heeled shoes increase lumbar lordosis and to do so with more reliable methods and a larger sample size than used in previous studies. METHODS: Fifty participants from a chiropractic university were included in a test group (32 female and 18 male) and 9 in a control group (3 female and 6 male). A Spinal Mouse was used to measure lumbar lordosis in test participants barefoot and then again with 3- or 4-in high-heeled shoes after a 10-minute adaptation period of walking and sitting and standing while wearing the shoes. Reliability of the testing conditions was evaluated with 9 barefoot control participants before and after an identical adaptation period, and intra- and interexaminer reliability of Spinal Mouse measurements was tested by use of a wooden model built to mimic the proportions of a human spine. RESULTS: Both groups showed non-significant decreases in lordosis between the first and second scans (high heels: 23.4 degrees to 22.8 degrees , P = .17; control: 18.8 degrees to 17.6 degrees , P = .16). Scans of the wooden spine model were highly reliable (intra- and interexaminer intraclass correlation coefficients > .999). CONCLUSIONS: Consistent with most previous studies, high heeled shoes did not affect lumbar lordosis in most people while standing. Future research could investigate the effect of shoes during dynamic conditions or identify affected subgroups. PMID- 23449541 TI - Evaluation of the use of gel card system for assessment of direct coombs test: weighing the pros and cons. AB - A positive direct Coombs test (DCT) is the hallmark of diagnosis of immune hemolytic anemias. The reagent used for the test is the Antihuman globulin (AHG), which may be either 'Polyspecific' or 'Monospecific'. The advent of the Gel card systems has made the procedure and interpretation of DCT simpler. Aim of this study is to evaluate three of the various techniques used for the performance and interpretation of DCT. A total of 96 EDTA samples were included in the study. DCT was performed by (i) polyspecific AHG manual tube method (ii) polyspecific AHG Gel card method and (iii) monospecific AHG (Anti IgG and Anti Complement) manual tube method. In our study we considered positivity by monospecific AHG as the standard for diagnosis. Of the total 96 samples evaluated, 44 cases positive by Gel card method, were also positive for either one or both the monospecific AHG reagents. 17 cases positive by Gel card were negative by all manual methods. These false positive cases were attributed to reasons such as increased ESR, macrocytosis and marked leucocytosis. Nine cases were negative by Gel card but were positive with the Monospecific AHG. The sensitivity of DCT done by the Gel card technique was 83.01% and the specificity was 60.46%. Use of Gel card technique to perform and interpret DCT is easier than manual tube methods, but positivity by Gel card needs to be correlated with clinical presentation of the patient and other laboratory findings. Monospecific antisera can be used to confirm cases that are positive by the Gel card systems. PMID- 23449542 TI - Neutrophils usher monocytes into sites of inflammation. PMID- 23449543 TI - Therapeutic transdifferentiation: a novel approach for vascular disease. PMID- 23449544 TI - Bruce Beutler: the persistent prospector. Interview by Ruth Williams. PMID- 23449545 TI - Introduction to the series on Computational Approaches to Cardiac Arrhythmias: Translation Into Diagnostics and Therapy. PMID- 23449546 TI - Three-dimensional impulse propagation in myocardium: arrhythmogenic mechanisms at the tissue level. AB - Impulse propagation in the heart depends on the excitability of individual cardiomyocytes, impulse transmission between adjacent myocytes, and the 3 dimensional arrangement of those cells. Here, we review the role of each of these factors in normal and aberrant cardiac electric activation, with particular emphasis on the effects of 3-dimensional myocyte architecture at the tissue scale. The analysis draws on findings from in vivo and in vitro experiments, as well as biophysically based computer models that have been used to integrate and interpret these experimental data. It indicates that discontinuous arrangement of myocytes and extracellular connective tissue at the tissue scale can give rise to current source-to-sink mismatch, spatiotemporal distribution of refractoriness, and rate-sensitive electric instability, which contribute to the initiation and maintenance of reentrant cardiac arrhythmia. This exacerbates the risk of rhythm disturbance associated with heart disease. We conclude that structure-based, multiscale computer models that incorporate accurate information about local cellular electric activity provide a powerful platform for investigating the basis of reentrant cardiac arrhythmia. However, it is important that these models capture key features of structure and related electric function at the tissue scale. PMID- 23449548 TI - Noninvasive electrocardiographic imaging of arrhythmogenic substrates in humans. AB - Cardiac excitation is determined by interactions between the source of electric activation (membrane depolarization) and the load that cardiac tissue presents. This relationship is altered in pathology by remodeling processes that often create a substrate favoring the development of cardiac arrhythmias. Most studies of arrhythmia mechanisms and arrhythmogenic substrates have been conducted in animal models, which may differ in important ways from the human pathologies they are designed to represent. Electrocardiographic imaging is a noninvasive method for mapping the electric activity of the heart in humans in real-world conditions. This review summarizes results from electrocardiographic imaging studies of arrhythmogenic substrates associated with human clinical arrhythmias. Examples include heart failure, myocardial infarction scar, atrial fibrillation, and abnormal ventricular repolarization. PMID- 23449549 TI - Effects of bezafibrate treatment in a patient and a carrier with mutations in the PNPLA2 gene, causing neutral lipid storage disease with myopathy. PMID- 23449547 TI - Rotors and the dynamics of cardiac fibrillation. AB - The objective of this article is to present a broad review of the role of cardiac electric rotors and their accompanying spiral waves in the mechanism of cardiac fibrillation. At the outset, we present a brief historical overview regarding reentry and then discuss the basic concepts and terminologies pertaining to rotors and their initiation. Thereafter, the intrinsic properties of rotors and spiral waves, including phase singularities, wavefront curvature, and dominant frequency maps, are discussed. The implications of rotor dynamics for the spatiotemporal organization of fibrillation, independent of the species being studied, are described next. The knowledge gained regarding the role of cardiac structure in the initiation or maintenance of rotors and the ionic bases of spiral waves in the past 2 decades, as well as the significance for drug therapy, is reviewed subsequently. We conclude by examining recent evidence suggesting that rotors are critical in sustaining both atrial and ventricular fibrillation in the human heart and its implications for treatment with radiofrequency ablation. PMID- 23449550 TI - Detection and Capturing of (14)C Radioactively-Labeled Small Subunit rRNA from Mixed Microbial Communities of a Microbial Mat Using Magnetic Beads. AB - Carbon cycling in the hypersaline microbial mats from Chiprana Lake, Spain is primarily dependent on phototrophic microorganisms with the ability to fix CO2 into organics that can be further utilized by aerobic as well as anaerobic heterotrophic bacteria. Here, mat pieces were incubated in seawater amended with (14)C sodium bicarbonate and the incorporation of the radiocarbon in the small subunit ribosomal RNA (SSU rRNA) of mat organisms was followed using scintillation counter and autoradiography. Different domains of SSU rRNA were separated from the total RNA by means of streptavidin-coated magnetic beads and biotin-labeled oligonucleotide probes. The (14)C label was detected in isolated RNA by both scintillation counter and autoradiography, however the latter technique was less sensitive. Using scintillation counter, the radiolabel incorporation increased with time with a maximum rate of 0.18 Bq ng(-1) detected after 25 days. The bacterial SSU rRNA could be captured using the magnetic beads, however the hybridization efficiency was around 20%. The captured RNA was radioactively labeled, which could be mainly due to the fixation of radiocarbon by phototrophic organisms. In conclusion, the incubation of microbial mats in the presence of radiolabeled bicarbonate leads to the incorporation of the (14)C label into RNA molecules through photosynthesis and this label can be detected using scintillation counter. The used approach could be useful in studying the fate of fixed carbon and its uptake by other microorganisms in complex microbial mats, particularly when species-specific probes are used and the hybridization efficiency and RNA yield are further optimized. PMID- 23449551 TI - Rimonabant, gastrointestinal motility and obesity. AB - BACKGROUND: Obesity and overweight affect more than half of the US population and are associated with a number of diseases. Rimonabant, a cannabinoid receptor 1 blocker in the endocannabinoid (EC) system, was indicated in Europe for the treatment of obesity and overweight patients with associated risk factors but withdrawn on Jan, 2009 because of side effects. Many studies have reported the effects of rimonabant on gastrointestinal (GI) motility and food intake. THE AIMS OF THIS REVIEW ARE: to review the relationship of EC system with GI motility and food intake;to review the studies of rimonabant on GI motility, food intake and obesity;and to report the tolerance and side effects of rimonabant. METHODS: THE LITERATURE (PUBMED DATABASE) WAS SEARCHED USING KEYWORDS: rimonabant, obesity and GI motility. RESULTS: GI motility is related with appetite, food intake and nutrients absorption. The EC system inhibits GI motility, reduces emesis and increases food intake; Rimonabant accelerates gastric emptying and intestinal transition but decreases energy metabolism and food intake. There is rapid onset of tolerance to the prokinetic effect of rimonabant. The main side effects of rimonabant are depression and GI symptoms. CONCLUSIONS: Rimonabant has significant effects on energy metabolism and food intake, probably mediated via its effects on GI motility. PMID- 23449552 TI - Medial pectoral nerve to axillary nerve neurotization following traumatic brachial plexus injuries: indications and clinical outcomes. AB - INTRODUCTION: The medial pectoral nerve (MPN) represents a viable donor nerve for neurotization procedures for restoration of shoulder function following upper trunk brachial plexus injuries. MATERIALS AND METHODS: We report an eight-case series, single-surgeon experience of patients with upper trunk brachial plexus injuries who underwent MPN to axillary nerve (AXN) transfer from 2001-2007 for shoulder stability and abduction. RESULTS: The mean patient age was 31.5 (range, 19-51 years). The mean follow-up for all patients was 22.25 +/- 7.4 months. Surgery was performed at a mean of 5.8 +/- 2.9 months post-injury. On initial evaluation, all eight patients had no deltoid function (M0). Of the eight patients examined postoperatively, we observed excellent recovery in four, good recovery in two, fair recovery in one, and poor functional recovery in the remaining patient. DISCUSSION: MPN to AXN neurotization is a valid surgical option in the restoration of shoulder stability and shoulder abduction following trauma-related upper trunk brachial plexus injury. PMID- 23449553 TI - Prevalence of Otitis Media with Effusion among Primary School Children in Eastern Black Sea, in Turkey and the Effect of Smoking in the Development of Otitis Media with Effusion. AB - The aim of this study was to determine the prevalence of otitis media with effusion (OME) in primary school children in Rize (Eastern Black Sea Region) and the impact of tobacco smoke exposure in the development of OME in primary school children. This study involved a total of 2960 children who appeal for ENT examination to our department at Rize Training and Research Hospital between November 2007 and April 2009. All children were evaluated with regard to OME and exposure to cigarette smoke. Pure tone audiometry and tympanometry tests and pneumatic otoscopy were performed on the children who were diagnosed with OME by otoscopic examination. The association between the children diagnosed as OME and exposure to cigarette smoke was evaluated. The prevalence of OME in this study was 9.86% (292/2960). Exposure to cigarette smoke was a statistically significant factor in development of OME (P < 0.0001). Environmental factors such as smoking are important in the development of OME. To prevent delayed diagnosis or development of this disease, parents must be informed about the preventable risk factors and symptoms for the development of OME. PMID- 23449554 TI - Walking motion of an overdamped active particle in a ratchet potential. AB - An active particle can convert its internal energy into mechanical work. We study a generalized energy-depot model of an overdamped active particle in a ratchet potential. Using well-known biological parameters for kinesin-1 and modeling ATP influx as a pulsed energy supply, we apply our model to the molecular motor system. We find that our simple model can capture the essential properties of the kinesin motor such as forward stepping, stalling, backward stepping, dependence on ATP concentration, and stall force. Our model might be quite universal in the sense that it is able to describe dynamics of various types of motors as long as realistic parameters for each motor species are adopted. PMID- 23449555 TI - Osteomyelitis of maxilla in poorly controlled diabetics in a rural Indian population. AB - OBJECTIVES: To retrospectively analyze all patients who were diagnosed with Osteomyelitis of jaws in our unit. STUDY DESIGN: 31 patients with Osteomyelitis of jaws were analyzed retrospectively from 2002 to 2008 at the Department of Oral & Maxillofacial Surgery, S.D.M College of dental sciences and hospital, Dharwad, India. Parameters considered were age, gender, jaws involved, clinical features, surgical management & complications. RESULTS: Of the 31 patients, maxilla was involved in 16 patients and mandible was involved in the remaining 15. 11 out of the 16 patients with maxillary osteomyelitis were immuno-compromised. The predominant etiology noted was odontogenic infection. With the treatment protocol we have adopted, all our patients showed satisfactory resolution of the condition by 6 weeks. CONCLUSION: Incidence of maxillary osteomyelitis & their association with diabetes mellitus was higher in our series compared to others. The cause for this high incidence was analyzed in our study. Based on our results we conclude that a conservative surgical method with an attempt to preserve vital bone and an appropriate antibiotic therapy with the correction of the underlying medical problems is adequate to treat Osteomyelitis of jaws. PMID- 23449556 TI - Analysis of longitudinal data of Nellore cattle from performance test at pasture using random regression model. AB - This study was carried out to estimate (co)variance components and genetic parameters for live weight of Nellore cattle from Performance Test of Young Bulls using random regression models. Data of weights and ages of 925 weaned males was used. The animal model included the fixed effect of contemporary group, age of the animal at weighing as a covariate and as random effects it was considered the effect of additive genetic and permanent environment of the animal. The residue was modeled considering four classes of variances. The models were compared based on the Bayesian information criteria of Akaike and Schwartz. The model polynomial of fourth and sixth order for the direct additive genetic effects and permanent environment of the animal, respectively was the most appropriate to describe the changes in the variances of the weights during the period in which the animals participating in the performance test young bulls. Heritability estimates showed moderate magnitudes and indicated that direct selection will promote improvement of selection criteria adopted. Furthermore, due to high positive correlation between the estimated weights, it was suggested selecting the best animals before at 365 days of age, because it is the period in which the animals have a higher growth rate and thus you can select animals heavier and less delayed. PMID- 23449557 TI - Iceman revisited. PMID- 23449558 TI - Managing cancer-related fatigue with acupuncture: is it all good news for patients? PMID- 23449559 TI - Responses to the Acupuncture Trialists' Collaboration individual patient data meta-analysis. AB - In September 2012 the Acupuncture Trialists' Collaboration published the results of an individual patient data meta-analysis of almost 18 000 patients in high quality randomised trials. The results favoured acupuncture. Although there was little argument about the findings in the scientific press, a controversy played out in blog posts and the lay press. This controversy was characterised by ad hominem remarks, anonymous criticism, phony expertise and the use of opinion to contradict data, predominantly by self-proclaimed sceptics. There was a near complete absence of substantive scientific critique. The lack of any reasoned debate about the main findings of the Acupuncture Trialists' Collaboration paper underlines the fact that mainstream science has moved on from the intellectual sterility and ad hominem attacks that characterise the sceptics' movement. PMID- 23449560 TI - Cover stories: Animal attraction. PMID- 23449561 TI - Why national science academies? PMID- 23449566 TI - U.S. science policy. What it means for agencies to be under the sequester. PMID- 23449567 TI - Scientific publishing. U.S. agencies directed to make research papers available. PMID- 23449568 TI - Neuroscience. Brain project draws presidential interest, but mixed reactions. PMID- 23449569 TI - Clinical Trials. Europe debates ethics reviews, data release. PMID- 23449571 TI - A call to cyber arms. PMID- 23449570 TI - Dual use research. New U.S. rules increase oversight of H5N1 studies, other risky science. PMID- 23449572 TI - Japan disaster. Cooling a hot zone. PMID- 23449573 TI - Japan disaster. Astronomers lend know-how to cleanup. PMID- 23449574 TI - Environmental science. Pollutants capture the high ground in the Himalayas. PMID- 23449575 TI - A call for integrative thinking. PMID- 23449576 TI - Data re-identification: prioritize privacy. PMID- 23449577 TI - Data re-identification: societal safeguards. PMID- 23449578 TI - Data re-identification: protect the children. PMID- 23449580 TI - Comment on "Lethally hot temperatures during the Early Triassic greenhouse". AB - Sun et al. (Reports, 19 October 2012, p. 366) reconstructed Permian to Middle Triassic equatorial seawater temperatures. After correct temporal positioning of their data points, their presumed trends of temperature changes, and hence their assumption of a one-to-one relationship between putative "lethally hot" seawater temperatures and a disputable equatorial "eclipse" of some organisms, are no longer supported by their data. PMID- 23449581 TI - Response to comment on "lethally hot temperatures during the Early Triassic greenhouse". AB - Goudemand et al. replot a subset of our well-constrained data using a new Early Triassic biostratigraphic scheme based on a lower-resolution ammonoid zonation scheme and hypothetical ammonoid-conodont correlation to produce a less distinct seawater temperature history. We dispute their unsubstantiated correlation and, consequently, their allegations. PMID- 23449582 TI - Conservation. Legal trade of Africa's rhino horns. PMID- 23449584 TI - Physics. Two indistinguishable electrons interfere in an electronic device. PMID- 23449583 TI - Biochemistry. Machinery to reverse irreversible aggregates. PMID- 23449585 TI - Atmosphere. Leads and lags at the end of the last ice age. PMID- 23449586 TI - Immunology. Welcome to the microgenderome. PMID- 23449587 TI - Plant science. One genome, two ontogenies. PMID- 23449588 TI - A black hole nova obscured by an inner disk torus. AB - Stellar-mass black holes (BHs) are mostly found in x-ray transients, a subclass of x-ray binaries that exhibit violent outbursts. None of the 50 galactic BHs known show eclipses, which is surprising for a random distribution of inclinations. Swift J1357.2-093313 is a very faint x-ray transient detected in 2011. On the basis of spectroscopic evidence, we show that it contains a BH in a 2.8-hour orbital period. Further, high-time-resolution optical light curves display profound dips without x-ray counterparts. The observed properties are best explained by the presence of an obscuring toroidal structure moving outward in the inner disk, seen at very high inclination. This observational feature should play a key role in models of inner accretion flows and jet collimation mechanisms in stellar-mass BHs. PMID- 23449589 TI - Synchronous change of atmospheric CO2 and Antarctic temperature during the last deglacial warming. AB - Understanding the role of atmospheric CO2 during past climate changes requires clear knowledge of how it varies in time relative to temperature. Antarctic ice cores preserve highly resolved records of atmospheric CO2 and Antarctic temperature for the past 800,000 years. Here we propose a revised relative age scale for the concentration of atmospheric CO2 and Antarctic temperature for the last deglacial warming, using data from five Antarctic ice cores. We infer the phasing between CO2 concentration and Antarctic temperature at four times when their trends change abruptly. We find no significant asynchrony between them, indicating that Antarctic temperature did not begin to rise hundreds of years before the concentration of atmospheric CO2, as has been suggested by earlier studies. PMID- 23449590 TI - KNOX2 genes regulate the haploid-to-diploid morphological transition in land plants. AB - Unlike animals, land plants undergo an alternation of generations, producing multicellular bodies in both haploid (1n: gametophyte) and diploid (2n: sporophyte) generations. Plant body plans in each generation are regulated by distinct developmental programs initiated at either meiosis or fertilization, respectively. In mosses, the haploid gametophyte generation is dominant, whereas in vascular plants-including ferns, gymnosperms, and angiosperms-the diploid sporophyte generation is dominant. Deletion of the class 2 KNOTTED1-LIKE HOMEOBOX (KNOX2) transcription factors in the moss Physcomitrella patens results in the development of gametophyte bodies from diploid embryos without meiosis. Thus, KNOX2 acts to prevent the haploid-specific body plan from developing in the diploid plant body, indicating a critical role for the evolution of KNOX2 in establishing an alternation of generations in land plants. PMID- 23449591 TI - Interferon-epsilon protects the female reproductive tract from viral and bacterial infection. AB - The innate immune system senses pathogens through pattern-recognition receptors (PRRs) that signal to induce effector cytokines, such as type I interferons (IFNs). We characterized IFN-epsilon as a type I IFN because it signaled via the Ifnar1 and Ifnar2 receptors to induce IFN-regulated genes. In contrast to other type I IFNs, IFN-epsilon was not induced by known PRR pathways; instead, IFN epsilon was constitutively expressed by epithelial cells of the female reproductive tract (FRT) and was hormonally regulated. Ifn-epsilon-deficient mice had increased susceptibility to infection of the FRT by the common sexually transmitted infections (STIs) herpes simplex virus 2 and Chlamydia muridarum. Thus, IFN-epsilon is a potent antipathogen and immunoregulatory cytokine that may be important in combating STIs that represent a major global health and socioeconomic burden. PMID- 23449592 TI - Spreading depression triggers headache by activating neuronal Panx1 channels. AB - The initial phase in the development of a migraine is still poorly understood. Here, we describe a previously unknown signaling pathway between stressed neurons and trigeminal afferents during cortical spreading depression (CSD), the putative cause of migraine aura and headache. CSD caused neuronal Pannexin1 (Panx1) megachannel opening and caspase-1 activation followed by high-mobility group box 1 (HMGB1) release from neurons and nuclear factor kappaB activation in astrocytes. Suppression of this cascade abolished CSD-induced trigeminovascular activation, dural mast cell degranulation, and headache. CSD-induced neuronal megachannel opening may promote sustained activation of trigeminal afferents via parenchymal inflammatory cascades reaching glia limitans. This pathway may function to alarm an organism with headache when neurons are stressed. PMID- 23449593 TI - Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. AB - Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits. PMID- 23449595 TI - When the best is the enemy of the good: the case of bone-marrow mononuclear cells to treat ischemic syndromes. PMID- 23449594 TI - The continuing challenge of understanding, preventing, and treating neural tube defects. AB - Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects. PMID- 23449596 TI - Efficacy of acute myeloid leukemia therapy without stem-cell transplantation in a child with blastic plasmacytoid dendritic cell neoplasm. PMID- 23449597 TI - Reply to "A combination treatment approach and cord blood stem cell transplant for blastic plasmacytoid dendritic cell neoplasm" and to "A low-grade B-cell lymphoma with prolymphocytic/paraimmunoblastic proliferation and IRF4 rearrangement" dendritic cell leukemia. PMID- 23449599 TI - Central and peripheral fat and subclinical vascular damage in older women. AB - OBJECTIVE: the aim of this study was to evaluate the relationship between fat distribution and arterial compliance in a group of elderly women, in particular to test a possible independent role of abdominal fat mass and peripheral fat mass on subclinical vascular damage, defined by a pulse wave velocity (PWV) >12 m/s. METHODS: in 96 women with age range 60-80 years (68.65 +/- 4.98 years) and BMI range from 18.8 to 41.2 kg/m(2) (27.07 +/- 4.61 kg/m(2)), we evaluated the body mass index, waist circumference, systolic and diastolic blood pressure, fasting glucose, cholesterol, LDL and HDL cholesterol, triglycerides and body composition by dual energy X-ray absorptiometry (DXA). Arterial stiffness was assessed by carotid-femoral (PWVcf) and carotid-radial pulse wave velocity (PWVcr). RESULTS: significant associations were found between PWVcf, age, waist circumference, BMI and trunk fat assessed by DXA, as well as TG and HDL cholesterol. After adjustment for the total fat mass a negative statistically significant association between PWVcf and leg fat mass was shown. In multiple regression analyses the mean arterial pressure, trunk fat mass and leg fat mass were significant predictors of vascular damage with OR, respectively, of 1.06 (CI: 1.01-1.11), 1.25 (CI: 1.06-1.48) and 0.73 (CI: 0.53-0.99). CONCLUSIONS: the results of this study show, in a sample of apparently healthy elderly women, that central and peripheral adiposity are independent predictors, with an opposite effect on subclinical vascular damage, confirming and strengthening the protective role of the gluteal-femoral fat on cardiovascular risk even in elderly. PMID- 23449600 TI - Trichomonas vaginalis infection among women receiving gynaecological care at an Alabama HIV Clinic. AB - OBJECTIVE: Trichomoniasis vaginalis is a risk factor for the acquisition and transmission of HIV. The objective of this study was to determine the prevalence of T vaginalis (using culture) among HIV-infected women receiving gynaecological care at an university HIV clinic in Alabama in addition to predictors of infection. METHODS: Electronic medical record review of women presenting to the clinic for gynaecological care during 2006-2012 was performed. Demographic and sexual history data was abstracted in addition to absolute CD4 cell count, HIV-1 viral load and sexually transmitted infection (STI) (including T vaginalis) testing results. Analysis was conducted using Stata V.12. RESULTS: T vaginalis was prevalent in 17.4% (83/478) of HIV-infected women; other STIs were less prevalent. Among these women, 384 presented for routine STI screening, of which 12% (46/384) were T vaginalis-infected. Younger age, African-American race, lifetime history of tobacco and drug abuse, lack of HIV therapy, HIV-1 viral load >400 copies/ml, and report of seeking gynaecological care for reasons other than routine STI screening (ie, having symptoms) were significant predictors of T vaginalis in univariate analysis. Age, African American race, and report of seeking gynaecological care for reasons other than routine STI screening remained associated with T vaginalis in multivariable analysis. CONCLUSIONS: T vaginalis remains highly prevalent among HIV-infected women, a proportion of which may be asymptomatic. If left undiagnosed and untreated, these women may be more likely to transmit HIV. Increased emphasis on screening for high risk sexual behaviours, testing for T vaginalis, and risk reduction counselling is necessary for all HIV infected women. PMID- 23449598 TI - Germination of conidia of Aspergillus niger is accompanied by major changes in RNA profiles. AB - The transcriptome of conidia of Aspergillus niger was analysed during the first 8 h of germination. Dormant conidia started to grow isotropically two h after inoculation in liquid medium. Isotropic growth changed to polarised growth after 6 h, which coincided with one round of mitosis. Dormant conidia contained transcripts from 4 626 genes. The number of genes with transcripts decreased to 3 557 after 2 h of germination, after which an increase was observed with 4 780 expressed genes 8 h after inoculation. The RNA composition of dormant conidia was substantially different than all the subsequent stages of germination. The correlation coefficient between the RNA profiles of 0 h and 8 h was 0.46. They were between 0.76-0.93 when profiles of 2, 4 and 6 h were compared with that of 8 h. Dormant conidia were characterised by high levels of transcripts of genes involved in the formation of protecting components such as trehalose, mannitol, protective proteins (e.g. heat shock proteins and catalase). Transcripts belonging to the Functional Gene Categories (FunCat) protein synthesis, cell cycle and DNA processing and respiration were over-represented in the up regulated genes at 2 h, whereas metabolism and cell cycle and DNA processing were over-represented in the up-regulated genes at 4 h. At 6 h and 8 h no functional gene classes were over- or under-represented in the differentially expressed genes. Taken together, it is concluded that the transcriptome of conidia changes dramatically during the first two h and that initiation of protein synthesis and respiration are important during early stages of germination. PMID- 23449601 TI - Health equity impact assessment. AB - The World Health Organization's Commission on Social Determinants of Health has called for 'health equity impact assessments' of all economic agreements, market regulation and public policies. We carried out an international study to clarify if existing health impact assessment (HIA) methods are adequate for the task of global health equity assessments. We triangulated data from a scoping review of the international literature, in-depth interviews with health equity and HIA experts and an international stakeholder workshop. We found that equity is not addressed adequately in HIAs for a variety of reasons, including inadequate guidance, absence of definitions, poor data and evidence, perceived lack of methods and tools and practitioner unwillingness or inability to address values like fairness and social justice. Current methods can address immediate, 'downstream' factors, but not the root causes of inequity. Extending HIAs to cover macro policy and global equity issues will require new tools to address macroeconomic policies, historical roots of inequities and upstream causes like power imbalances. More sensitive, participatory methods are also required. There is, however, no need for the development of a completely new methodology. PMID- 23449603 TI - The impact of dreams of the deceased on bereavement: a survey of hospice caregivers. AB - Many recently bereaved persons experience vivid and deeply meaningful dreams featuring the presence of the deceased that may reflect and impact the process of mourning. The present study surveyed 278 bereaved persons regarding their own perspective of the relationship between dreams and the mourning process. Fifty eight percent of respondents reported dreams of their deceased loved ones, with varying levels of frequency. Most participants reported that their dreams were either pleasant or both pleasant and disturbing, and few reported purely disturbing dreams. Prevalent dream themes included pleasant past memories or experiences, the deceased free of illness, memories of the deceased's illness or time of death, the deceased in the afterlife appearing comfortable and at peace, and the deceased communicating a message. These themes overlap significantly with previous models of bereavement dream content. Sixty percent of participants felt that their dreams impacted their bereavement process. Specific effects of the dreams on bereavement processes included increased acceptance of the loved one's death, comfort, spirituality, sadness, and quality of life, among others. These results support the theory that dreams of the deceased are highly prevalent among and often deeply meaningful for the bereaved. While many counselors are uncomfortable working with dreams in psychotherapy, the present study demonstrates their therapeutic relevance to the bereaved population and emphasizes the importance for grief counselors to increase their awareness, knowledge, and skills with regards to working with dreams. PMID- 23449602 TI - Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. AB - STUDY OBJECTIVES: Humans with narcolepsy and orexin/ataxin-3 transgenic (TG) mice exhibit extensive, but incomplete, degeneration of hypo-cretin (Hcrt) neurons. Partial Hcrt cell loss also occurs in Parkinson disease and other neurologic conditions. Whether Hcrt antagonists such as almorexant (ALM) can exert an effect on the Hcrt that remains after Hcrt neurodegeneration has not yet been determined. The current study was designed to evaluate the hypnotic and cataplexy inducing efficacy of a Hcrt antagonist in an animal model with low Hcrt tone and compare the ALM efficacy profile in the disease model to that produced in wild type (WT) control animals. DESIGN: Counterbalanced crossover study. SETTING: Home cage. PATIENTS OR PARTICIPANTS: Nine TG mice and 10 WT mice. INTERVENTIONS: ALM (30, 100, 300 mg/kg), vehicle and positive control injections, dark/active phase onset. MEASUREMENTS AND RESULTS: During the 12-h dark period after dosing, ALM exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/ kg) paradoxically induced a transient increase in active wakefulness. Core body temperature (Tb) decreased after acute Hcrt receptor blockade, but the reduction in Tb that normally accompanies the wake-to-sleep transition was blunted in TG mice. CONCLUSIONS: These complex dose- and genotype dependent interactions underscore the importance of effector mechanisms downstream from Hcrt receptors that regulate arousal state. Cataplexy promotion by ALM warrants cautious use of Hcrt antagonists in patient populations with Hcrt neurodegeneration, but may also facilitate the discovery of anticataplectic medications. CITATION: Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336. PMID- 23449604 TI - Earlobe crease may provide predictive information on asymptomatic peripheral arterial disease in patients clinically free of atherosclerotic vascular disease. AB - The diagonal earlobe crease (ELC) has been regarded as a simple marker of atherosclerosis. There is no knowledge concerning the relation of ELC to the presence, extent, and severity of peripheral arterial disease (PAD). Patients (n = 253) without known atherosclerotic vascular disease and symptoms were enrolled consecutively. Ankle brachial index (ABI) was measured. Patients with ELC had lower ABI compared to those with no ELC (1.02 +/- 0.12 vs 1.11 +/- 0.08, P < .001). Multivariate analysis demonstrated ELC (95% confidence interval [CI]: 3.3 21.9; P: .001) and age (95% CI: 0.87-0.99; P = .02) as independent determinants of abnormal ABI. There was incremental increased frequency of ELC from normal ABI to significant PAD. We have shown for the first time a significant and independent association between presence of ELC and increased prevalence, extent, and severity of PAD in patients without overt atherosclerotic vascular disease. PMID- 23449605 TI - Arterial stiffness and wave reflections in relation to plasma advanced glycation end products in a Chinese population. AB - BACKGROUND: Accumulation of advanced glycation end products (AGEs) in the human body might engender arterial stiffening. We investigated the relationship of plasma AGE concentration with arterial stiffness and wave reflections in a Chinese population. METHODS: The study subjects were recruited from a newly established residential area in the suburb of Shanghai in 2009. Using the SphygmoCor system, we measured carotid-femoral pulse wave velocity (cfPWV) and central augmentation indices (cAI) and peripheral augmentation indices (pAI). Plasma AGE concentration was measured by the enzyme-linked immunosorbent assay method and logarithmically transformed for statistical analysis. RESULTS: The 1,051 study participants (mean age = 55.1+/-13.1 years) included 663 (63.1%) women, 390 (37.1%) hypertensive patients, and 90 (8.6%) diabetic or prediabetic subjects. Plasma AGE concentration was higher in men than women (5.62 vs. 5.07 MUg/ml; P = 0.02) and with older age (r = 0.13 in both sexes; P <= 0.01) and higher serum total/high-density lipoprotein cholesterol ratio (r = 0.20 in men and r = 0.15 in women; P < 0.0001). In multiple regression analyses, plasma AGE concentration was significantly associated with cAI and pAI (1.9% and 4.0% increase per 10-time increase in plasma AGE concentration, respectively; P <= 0.02) but not with cfPWV (P = 0.62). However, there was significant (P = 0.001) interaction between plasma AGE concentration and age in relation to cfPWV. Only in subjects aged >=70 years, cfPWV increased with higher levels of plasma AGE concentration (bottom vs. top quintile distributions = 8.10 vs. 8.90 m/s; P = 0.02). CONCLUSIONS: AGEs accumulate with aging and high cholesterol and are associated with arterial wave reflections and, in an age-dependent manner, with arterial stiffness. PMID- 23449606 TI - Depressive symptoms contribute to increased wave reflection during cold pressor test in young adult men. AB - BACKGROUND: Major depressive disorder (MDD) is associated with increased cardiovascular risk. Although cardiovascular hyperactivity to stressors (e.g., cold pressor test (CPT)) is common in those with MDD, the aortic hemodynamic (AH) responses to sympatho-stimulation in healthy individuals with higher depressive scores (HDS) are not well understood. We hypothesized that individuals with HDS, compared with those with low depressive scores (LDS), would have greater changes in AH during the CPT. METHODS: Thirty-five male participants (mean age, 22.3+/ 0.7 years) completed a self-report measure of depressive symptoms and were classified as having an HDS or LDS. Radial waveforms were then obtained by means of applanation tonometry. The testing protocol consisted of a 10-minute seated rest, 5 minutes of baseline measurements, a 3-minute CPT, and a 3-minute recovery period. RESULTS: At baseline, no differences were found between the LDS (n=16) and HDS (n=19) groups on any variables studied. During CPT, there was a significant group-by-time interaction for aortic mean blood pressure (HDS vs. LDS = 107+/-3mm Hg vs. 96+/-3mm Hg; P = 0.008); augmentation index (HDS vs. LDS =19% +/- 3% vs. 11% +/- 2%; P = 0.02), a surrogate of wave reflection; and systolic time interval (HDS vs. LDS = 2295+/-78mm Hg/s.min(-1) vs. 1919+/-74mm Hg/s.min( 1); P = 0.001), a marker of myocardial work, such that the HDS group had significantly higher responses than the LDS group. CONCLUSIONS: HDS may be associated with cardiac hyperactivity during sympatho-stimulation, contributing to increased central blood pressure, wave reflection, and myocardial work. Prospective studies to unveil mechanisms explaining increased AH in healthy individuals with high depressive symptomatology are warranted. PMID- 23449607 TI - Effects of low-dose atorvastatin on arterial stiffness and central aortic pressure augmentation in patients with hypertension and hypercholesterolemia. AB - BACKGROUND: Experimental and clinical data suggest that statins exert anti inflammatory and antiproliferative actions on vasculature beyond their lipid lowering properties. Whether these pleiotropic effects of statins translate into a beneficial effect on arterial stiffness is not clear. This study aimed to evaluate the potential effects of low-dose atorvastatin treatment on arterial stiffness and central arterial pressure waveforms in patients with mild hypertension and hypercholesterolemia. METHODS: In a double-blind, randomized, placebo-controlled fashion, 50 hypertensive and hypercholesterolemic patients were allocated to receive 10 mg of atorvastatin or placebo for 26 weeks. Arterial stiffness was assessed by aortic pulse-wave velocity (PWV) using a Sphygmocor device. Central arterial pressure waveform parameters were estimated by radial artery applanation tonometry. Heart rate-adjusted augmentation index (AIx(75)) was used as measure of wave reflections. RESULTS: At study end, aortic PWV (9.0 +/- 1.5 vs. 10.9 +/- 2.6 m/sec; P < 0.001) and AIx(75) (24.9% +/- 9.7% vs 28.8% +/- 11.8%; P < 0.001) were significantly lower in the atorvastatin group than that placebo group. Furthermore, decreases in central aortic systolic blood pressure and pulse pressure were evident at study-end with atorvastatin but not with placebo (130 +/- 8 vs. 138 +/- 6 mm Hg, P < 0.001; 48 +/- 7 vs. 53 +/- 6 mm Hg, P < 0.05, respectively). Atorvastatin-induced reductions in aortic PWV during follow-up showed significant associations with changes in AIx(75) and central aortic systolic blood pressure and pulse pressure. CONCLUSIONS: This study shows that low-dose atorvastatin treatment improves arterial stiffness and exerts a reduction on central aortic pressures. These effects may represent a potential mechanism of cardiovascular risk reduction observed with statin use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Database Identifier Number: NCT01126684. PMID- 23449608 TI - Medical management of constipation. AB - Constipation is a common clinical problem. Initial management of chronic constipation should include lifestyle maneuvers, and increased fiber and fluids. Polyethylene glycol, sodium picosulfate, bisacodyl, prucalopride, lubiprostone, and linaclotide were all more effective than placebo for treating chronic idiopathic constipation. Many commonly used agents lack quality evidence supporting their use. PMID- 23449609 TI - The role of psychopathology in stalking by adult strangers and acquaintances. AB - OBJECTIVE: Individuals who stalk strangers and acquaintances are under-studied, although there is some evidence suggesting a greater prevalence of psychopathology than is present in those who stalk former partners. This study investigated the nature and prevalence of psychopathology in a sample of stranger and acquaintance stalkers and whether psychopathology was associated with increased duration or serial stalking in this group. It was hypothesised that mental illness, and specifically psychosis, would be more prevalent among strangers and acquaintances than among ex-intimate stalkers. METHOD: Two hundred and eleven stalkers (10% female; mean age = 35, SD = 10.8; 71 ex-intimates) were recruited between 2002 and 2007 from a specialist service in Melbourne, Australia. Each underwent psychiatric and psychological assessment and disorders were diagnosed according to DMS-IV-TR criteria. Non-parametric independent sample tests were used to examine associations between relationship type and psychopathology, and to identify individual and stalking-related characteristics associated with increased duration and serial stalking. RESULTS: Axis I disorders were significantly more prevalent among strangers and acquaintances than ex intimates (71% vs 48%, OR = 2.6, 95% CI = 1.4 to 4.7), as were psychotic disorders (29% vs 9%, OR = 4.4, 95% CI = 1.8 to 10.9). Psychosis was significantly associated with increased duration of stalking behaviour (U = 3043, p < 0.001). Those with a personality disorder were twice as likely to have stalked multiple times (OR = 2.4, 95% CI = 1.2 to 5.0). CONCLUSIONS: Those who stalk strangers and acquaintances are often mentally ill and psychopathology is associated with more persistent and recurrent stalking behaviour. Although limited by the use of clinical interview rather than structured assessment, these findings strongly support the argument for routine mental health assessment of stranger and acquaintance stalkers who become involved with the criminal justice system. PMID- 23449610 TI - HIV gene therapy research advances. AB - In this issue of Blood, Tebas et al report antiviral effects in a clinical trial of multiple infusions of lentiviral vector-modified autologous CD4T lymphocytes in 17 HIV-infected patients aviremic on antiretroviral therapy (ART). PMID- 23449611 TI - In Wiskott-Aldrich syndrome, platelet count matters. AB - In a retrospective analysis of the French Registry of patients with Wiskott Aldrich Syndrome (WAS), Mahlaoui et al have identified severe refractory thrombocytopenia (SRT) early in life as a major risk factor for poor outcome. PMID- 23449612 TI - Exhausting T cells in CLL. AB - In this issue of Blood, Riches and colleagues provide an in-depth characterization of T cells and particularly CD8+ T cells from patients with chronic lymphocytic leukemia (CLL). They demonstrate that CD8+ T cells exhibit defects in proliferation, cytotoxicity, and increased expression of inhibitory receptors and thus exhibit features of T-cell exhaustion. PMID- 23449613 TI - Saving orphans: BRAF targeting of histiocytosis. AB - In this issue of Blood, Haroche and colleagues report significant therapeutic activity of the BRAF inhibitor, vemurafenib, in 3 patients with rare histiocytic conditions, Erdheim-Chester disease and Langerhans cell histiocytosis. PMID- 23449614 TI - Demethylation demystification. AB - The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave? PMID- 23449615 TI - ECM: chemoattraction but not adhesion. AB - The mechanisms that regulate 3-dimensional (3D) neutrophil chemotaxis are poorly understood. In this issue of Blood, Afonso et al demonstrate that the collagen receptor Discoidin domain receptor 2 (DDR2) promotes neutrophil chemotaxis in 3D by triggering matrix metalloproteinase (MMP) activity and the generation of chemotactic collagen peptides. PMID- 23449616 TI - Red cell storage: does duration matter? AB - The report by Solomon et al in this issue of Blood is a welcome addition to understanding the clinical impact of prolonged red cell storage. PMID- 23449617 TI - Thyroid function and mental disorders: an insight into the complex interaction. AB - OBJECTIVE: To assess the serum levels of Thyroxine (T4), Triiodothyronine (T3) and the thyroid stimulating hormone (TSH) in patients with depression. METHODS: Sixty clinically diagnosed and drug naive depressed patients and an equal number of healthy, age and sex matched control subjects were included in this study. The Ham-D scale was used to classify the degree of depression into the mild, moderate and the severe grades. The biochemical parameters (T3, T4 and TSH) were estimated by using commercially available kits. The data were analyzed by using the SPSS-10 software, one way ANOVA and the chi2 test. RESULT: The female depressive (n = 48) cases outnumbered the male depressive cases. The distributions of the patients in the mild, moderate and the severe categories were similar. A significant decline in the T3 level and an elevation in the T4 level were found in the depressive cases as compared to those in the healthy controls. ANOVA with multiple comparisons testing among the patient group showed no significant difference in the TSH level when the depressive cases with various degrees of depression were compared. A total of twelve depressive patients were found to have thyroid abnormalities. CONCLUSION: This study therefore observed the presence of thyroid dysfunction among the depressive cases, which is most often characterized as the "Lower Thyroid Syndrome". Thus, the inclusion of the thyroid screening test among the depressive patients may be helpful in the proper management of the cases. PMID- 23449619 TI - Steatocystoma multiplex-a rare genetic disorder: a case report and review of the literature. AB - A 17 years old female presented with multiple asymptomatic cutaneous cysts all over body, sparing the head and neck region. The microscopic examination of the cysts showed the features of steatocystoma multiplex. This disorder, although it is asymptomatic, is a cosmetic threat to the patient. Only a few cases of the patients with an autosomal dominant mutation, who had keratin 17, have been reported. We are reporting here, a case of steatocystoma multiplex in a 17 years old female, along with its review of literature. PMID- 23449618 TI - MAP/microtubule affinity-regulating kinases, microtubule dynamics, and spermatogenesis. AB - During spermatogenesis, spermatids derived from meiosis simultaneously undergo extensive morphological transformation, to become highly specialized and metabolically quiescent cells, and transport across the seminiferous epithelium. Spermatids are also transported back-and-forth across the seminiferous epithelium during the epithelial cycle until they line up at the luminal edge of the tubule to prepare for spermiation at stage VIII of the cycle. Spermatid transport thus requires the intricate coordination of the cytoskeletons in Sertoli cells (SCs) as spermatids are nonmotile cells lacking the ultrastructures of lamellipodia and filopodia, as well as the organized components of the cytoskeletons. In the course of preparing this brief review, we were surprised to see that, except for some earlier eminent morphological studies, little is known about the regulation of the microtubule (MT) cytoskeleton and the coordination of MT with the actin based cytoskeleton to regulate spermatid transport during the epithelia cycle, illustrating that this is a largely neglected area of research in the field. Herein, we summarize recent findings in the field regarding the significance of actin- and tubulin-based cytoskeletons in SCs that support spermatid transport; we also highlight specific areas of research that deserve attention in future studies. PMID- 23449620 TI - The red cell distribution width as a sensitive biomarker for assessing the pulmonary function in automobile welders- a cross sectional study. AB - CONTEXT: Welding fumes are considered as a risk factor for pulmonary diseases and a periodic spirometry is essential to evaluate the lung function of the welders. The Red Cell Distribution Width (RDW) is a red cell measurement which is provided by automated haematology analyzers. It reflects the range of the red cell sizes which are measured within a sample. Few studies have shown a relationship between the RDW values and the changes in the spirometry. AIMS: This study was aimed at correlating the RDW% and the spirometry FEV1/FVC ratio (%) among automobile welders (cases). Further, we have analyzed the effect of smoking on the FEV1/FVC ratio% and the RDW% in the cases. SETTINGS AND DESIGN: A cross sectional study was done on 50 welders and 50 non-welding office workers (controls) who were working in an automobile industry on the outskirts of Chennai, india. All the cases were arc welders and the controls were from the same production unit, who had never worked as welders. This study was conducted during the period from March 2012 to May 2012. METHODS AND MATERIAL: The demographic data, smoking habits, work history and the respiratory symptoms were gathered by using a standard self -administered questionnaire. A complete haemogram study was done and pulmonary function tests were performed for both the cases and the controls. All the cases and the controls were examined in the hospital outpatients room and subsequently, their blood samples were collected. The pulmonary function tests were conducted in the spirometry room in the hospital. The statistical analysis was done using the SPSS, version 15.0. RESULTS: A statistically significant inverse correlation was found between the RDW% and the FEV1/FVC ratio% in the cases. CONCLUSIONS: RDW can be used as a biomarker to identify the pulmonary compromise in automobile welders. PMID- 23449621 TI - Relationship of PGC-1alpha gene polymorphism with insulin resistance syndrome in Korean children. AB - This study aimed to investigate the associations between peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) gene Gly482Ser polymorphism (rs8192678) and parameters of insulin resistance in a sample of Korean children. A total of 286 children aged 10 to 12 years old were recruited from local elementary schools. Measured variables included body fat, blood pressures, blood lipids, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and accelerometer-based physical activity (PA). Significant differences in percentage body fat (P = .016), insulin (P = .013), and HOMA-IR (P = .007) were found according to Gly482Ser genotype, with no significant genotype differences in the other measured variables. The genotype specific differences in insulin (P = .136) and HOMA-IR (P = .067) were significantly attenuated when adjusted for age, sex, Tanner stage, body fat, and PA. The findings of the study suggest that the genetic effects of the PGC-1alpha genotypes on parameters of insulin resistance might be modulated by lifestyle factors, including PA and body fatness. PMID- 23449622 TI - Factorial validity and reliability of the Malaysian simplified Chinese version of Multidimensional Scale of Perceived Social Support (MSPSS-SCV) among a group of university students. AB - This study was aimed at validating the simplified Chinese version of the Multidimensional Scale of Perceived Support (MSPSS-SCV) among a group of medical and dental students in University Malaya. Two hundred and two students who took part in this study were given the MSPSS-SCV, the Medical Outcome Study social support survey, the Malay version of the Beck Depression Inventory, the Malay version of the General Health Questionnaire, and the English version of the MSPSS. After 1 week, these students were again required to complete the MSPSS-SCV but with the item sequences shuffled. This scale displayed excellent internal consistency (Cronbach's alpha = .924), high test-retest reliability (.71), parallel form reliability (.92; Spearman's rho, P < .01), and validity. In conclusion, the MSPSS-SCV demonstrated sound psychometric properties in measuring social support among a group of medical and dental students. It could therefore be used as a simple screening tool among young educated Malaysian adolescents. PMID- 23449623 TI - Online resources for new mothers: opportunities and challenges for perinatal health professionals. AB - Studies have shown increasing Internet use for health information and service facilities. After consulting a convenience sample of new mothers, this study applied select terms and phrases to a widely accepted search engine and investigated its potential for providing resources for new mothers. Results of this quantitative content analysis showed that only four of the 13 phrases used in the search generated 50% or more websites containing content relevant to new mothers. Findings indicate that informational support by way of electronic fact sheets is available using the Google search engine. However, functional support (e.g., social networks, consultation phone details, and mother-infant activities) configured limited data resources using the Google search engine. In addition, because websites can be difficult to navigate, users' technical proficiency needs to be taken into consideration as well as the sites' up-to-date information. With Internet technology rapidly expanding, perinatal educators and other perinatal health-care professionals need to be informed about current online resources to help direct consumers to useful online resources and mitigate the often overwhelming and confusing information. PMID- 23449624 TI - Correlation between differential renal function estimation using CT-based functional renal parenchymal volume and (99m)Tc - DTPA renal scan. AB - INTRODUCTION AND OBJECTIVE: Nuclear renal scan is currently the gold standard imaging study to determine differential renal function. We propose helical CT as single modality for both the anatomical and functional evaluation of kidney with impaired function. In the present study renal parenchymal volume is measured and percent total renal volume is used as a surrogate marker for differential renal function. The objective of this study is to correlate between differential renal function estimation using CT-based renal parenchymal volume measurement with differential renal function estimation using (99m)TC - DTPA renal scan. MATERIALS AND METHODS: Twenty-one patients with unilateral obstructive uropathy were enrolled in this prospective comparative study. They were subjected to (99m)Tc - DTPA renal scan and 64 slice helical CT scan which estimates the renal volume depending on the reconstruction of arterial phase images followed by volume rendering and percent renal volume was calculated. Percent renal volume was correlated with percent renal function, as determined by nuclear renal scan using Pearson coefficient. RESULTS AND OBSERVATION: A strong correlation is observed between percent renal volume and percent renal function in obstructed units (r = 0.828, P < 0.001) as well as in nonobstructed units (r = 0.827, P < 0.001). CONCLUSION: There is a strong correlation between percent renal volume determined by CT scan and percent renal function determined by (99m)TC - DTPA renal scan both in obstructed and in normal units. CT-based percent renal volume can be used as a single radiological tests for both functional and anatomical assessment of impaired renal units. PMID- 23449626 TI - PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates. AB - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective dopaminergic cell loss in the substantia nigra, but its pathogenesis remains unclear. The recessively inherited familial PD genes PARK2 and PARK6 have been attributed to mutations in the Parkin and PTEN-induced kinase 1 (PINK1) genes, respectively. Recent reports suggest that PINK1 works upstream of Parkin in the same pathway to regulate mitochondrial dynamics and/or conduct autophagic clearance of damaged mitochondria. This phenomenon is preserved from Drosophila to human cell lines but has not been demonstrated in a vertebrate animal model in vivo. Here, we developed a medaka fish (Oryzias latipes) model that is deficient in Pink1 and Parkin. We found that despite the lack of a conspicuous phenotype in single mutants for Pink1 or Parkin, medaka that are deficient in both genes developed phenotypes similar to that of human PD: late-onset locomotor dysfunction, a decrease in dopamine levels and a selective degeneration of dopaminergic neurons. Further analysis also revealed defects in mitochondrial enzymatic activity as well as cell death. Consistently, PINK1 and Parkin double deficient MEF showed a further decrease in mitochondrial membrane potential and mitochondrial complex I activity as well as apoptosis compared with single deficient MEF. Interestingly, these mitochondrial abnormalities in Parkin deficient MEF were compensated by exogenous PINK1, but not by disease-related mutants. These results suggest that PINK1 and Parkin work in a complementary way to protect dopaminergic neurons by maintaining mitochondrial function in vertebrates. PMID- 23449625 TI - Role of Galpha(olf) in familial and sporadic adult-onset primary dystonia. AB - The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Galpha(olf)]. Galpha(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Galpha(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter. PMID- 23449628 TI - Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q. AB - Partial trisomy distal 4q (denoted 4q+) is a human chromosomal disorder caused by duplication of the distal end of the long arm of chromosome 4 (Chr4). This disorder manifests typical phenotypes, including craniofacial, renal, heart and thumb developmental defects. Although these clinical features are likely caused by a dosage imbalance in the gene network involving the trisomic region, the causative gene or genes and the molecular bases are largely unknown. Here, we report mouse Recombination-induced mutation 4 (Rim4) as a model animal of 4q+. The Rim4 genome contains an insertion of a 6.5 Mb fragment from mouse chromosome 8 into chromosome 6. This insertion fragment contains 17 genes, including Hand2, that encode the basic helix-loop-helix transcription factor and is syntenic to the distal end of human Chr4, 4q32.3 to 4q34.1, which is responsible for 4q+. A comparison of phenotypes between patients with Rim4 and 4q+ revealed that Rim4 shows direct parallels with many phenotypes of 4q+ such as craniofacial, heart, cervical vertebra and limb deformities. Rebalancing the gene dosage by a genetic cross with Hand2 knockout mice ameliorated symptoms of the heart and limb deformities of Rim4. Conversely, an increase in copy number of Hand2 in wild-type mice recaptures the heart and limb deformities of Rim4. Our results collectively demonstrate that overdosage of Hand2 is a major cause for at least the limb and heart phenotypes of 4q+ and that mouse Rim4 provides a unique animal model for understanding the molecular bases underlying the complex phenotypes of 4q+. PMID- 23449629 TI - Clinical effectiveness of comprehensive psychological intervention for nonadherence to medical treatment: a case series. AB - OBJECTIVE: To evaluate the effectiveness of an adherence promotion intervention provided to patients and families referred to a clinical service. METHODS: 6 patients and their caregivers representing 5 different chronic conditions were seen for comprehensive psychological intervention that was evaluated based on electronic monitoring of adherence to prescribed oral medication. RESULTS: Time series analysis (Auto-Regressive Integrated Moving Average) indicated that for each of the 6 cases, treatment adherence increased during the intervention phase relative to nonintervention periods, but for 5 of these 6 patients, adherence decreased during the follow-up period (p < .05). CONCLUSION: Comprehensive adherence promotion strategies delivered in standard clinical practice were effective, but the effects did not persist after treatment. Future adherence promotion interventions should focus on sustaining intervention effects. PMID- 23449630 TI - Growth patterns and their implications for preterm infants in a culture of rapid modernization. AB - This prospective longitudinal study explored the growth patterns of preterm infants and the implications of rearing them in an advancing culture. The study measured the weight, length, and head circumference of 343 Korean preterm infants over 12 months corrected age. Data were analyzed using a generalized estimation equation for growth patterns of preterm infants by the degree of prematurity (mild, moderate, or severe). Results showed that the early 'catch-up phenomenon', accelerated growth rate, occurred around 11 months corrected age, although the mild preterm group weighed less, was shorter, and had a smaller head circumference than the moderate and severe preterm groups. This may reflect the Asian culture's preference for big babies and draws special attention to the influence of cultural values and childrearing practices in the growth of preterm infants. Pediatric nurses should be alert to accelerated growth in preterm infants in societies in cultural transition. PMID- 23449631 TI - Triple negative breast cancer - our experience and review. AB - Triple negative breast cancer (TNBC) constitutes 10-25% of patients with breast cancer. TNBC is an aggressive phenotype affecting younger age groups and has poor prognosis. We retrospectively analysed 50 triple negative breast cancer patients attending our outpatient department among 270 breast cancer patients. The incidence of TNBC was 18.5%, and most of them were premenopausal 56% (28/50) with mean age was 46.66 +/- 13.87 (Range 28-72 years). Most of them had Invasive ductal cancer 94% (47/50) and were high grade (Grade 3-96%)(48/50). Five patients presented with metastatic disease (2 patients only Skeletal, 1 patient with Skeletal and Lung, 1 patient with Lung and 1 patient with Liver) and 7 patients developed recurrence (all 7 had chest wall recurrence, 3 had supraclavicular lymph node recurrence, 2 had skeletal metastases and 1 had developed brain metastases) during follow up. The mean disease free survival was 15 months (Range 3-58 months) and overall survival was 20.14 months (Range 5-70 months). Fifty six percent (28/50) of patients were premenopausal and mean age of presentation was 46.66 +/- 13.87 years (Range 28-72 years). Ten percent (5/50) presented with metastatic disease and 15% (7/45) developed metastases during follow up. Five patients (10%) died during follow up. Hence, Triple negative breast cancer is aggressive, with rapid progression leading to mortality in younger patients. PMID- 23449632 TI - Congenital Cholesteatoma of Temporal Bone with Bezold's Abscess: Case Report. AB - Congenital cholesteatoma is a rare entity. It may originate at various sites in the temporal bone, for example, in the petrous apex, the cerebellopontine angle, the middle ear cavity, the mastoid process or in the external auditory canal. The least common site being the mastoid process. Most common presentation is a retrotympanic pearly white mass with no previous history of ear discharge, perforation or any ear surgery. It can lead to various complications, both intracranial and extracranial, some of which may be life threatening. Bezold's abscess is an extracranial complication which is usually seen in children following acute otitis media with mastoiditis. Here we present a rare case of a 60 year old patient with congenital cholesteatoma complicating to Bezold's abscess. After necessary investigations patient underwent surgery for complete removal of cholesteatoma and the abscess drainage. PMID- 23449634 TI - Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. AB - Sulphonylureas (SUs) are widely used glucose-lowering agents in type 2 diabetes mellitus (T2DM) with apparent declining efficacy over time. Concerns have been raised from observational retrospective studies on the cardiovascular (CV) safety of SUs but there are few long-term data on CV outcomes from randomized controlled trials (RCTs) involving the use of this class of agents. Most of the observational studies and registry data are conflicting and vary with study population and methodology used for analyses. To address the SU controversy, we reviewed the recently published literature (until end of the year 2011) to evaluate the impact of SUs on CV outcomes in modern, longer-term (>=72 weeks) RCTs where they were compared in a head-to-head fashion versus an active comparator or were used as part of a treatment strategy. We identified 15 trials and found no report of an increase in the incidence of CV events with the use of SUs. However, the available data are limited, and, most importantly, there was no adequately powered formal head-to-head CV outcome trial designed to address CV safety. Since SUs are still being advocated as second-line therapy added-on to metformin, as one of several classes, and in certain circumstances first-line therapy in T2DM management, definitive data from a dedicated RCT addressing the CV safety question with SUs would be informative. Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is such a trial, ongoing since November 2010, and is currently the largest head-to head CV outcome trial that involves a comparison of a SU (glimepiride) with a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) and will provide a unique perspective with respect to CV outcomes with these two commonly used agents. PMID- 23449627 TI - Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity. AB - The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 * 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits. PMID- 23449635 TI - MYC/BCL2 protein coexpression contributes to the inferior survival of activated B cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. AB - Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP. PMID- 23449636 TI - A mechanistic role for DNA methylation in endothelial cell (EC)-enriched gene expression: relationship with DNA replication timing. AB - Proximal promoter DNA methylation has been shown to be important for regulating gene expression. However, its relative contribution to the cell-specific expression of endothelial cell (EC)-enriched genes has not been defined. We used methyl-DNA immunoprecipitation and bisulfite conversion to analyze the DNA methylation profile of EC-enriched genes in ECs vs nonexpressing cell types, both in vitro and in vivo. We show that prototypic EC-enriched genes exhibit functional differential patterns of DNA methylation in proximal promoter regions of most (eg, CD31, von Willebrand factor [vWF], VE-cadherin, and intercellular adhesion molecule-2), but not all (eg, VEGFR-1 and VEGFR-2), EC-enriched genes. Comparable findings were evident in cultured ECs, human blood origin ECs, and murine aortic ECs. Promoter-reporter episomal transfection assays for endothelial nitric oxide synthase, VE-cadherin, and vWF indicated functional promoter activity in cell types where the native gene was not active. Inhibition of DNA methyltransferase activity indicated important functional relevance. Importantly, profiling DNA replication timing patterns indicated that EC-enriched gene promoters with differentially methylated regions replicate early in S-phase in both expressing and nonexpressing cell types. Collectively, these studies highlight the functional importance of promoter DNA methylation in controlling vascular EC gene expression. PMID- 23449637 TI - KIR2DS1-dependent acquisition of CCR7 and migratory properties by human NK cells interacting with allogeneic HLA-C2+ DCs or T-cell blasts. AB - Natural killer (NK) cells may capture the CCR7 chemokine receptor from allogeneic CCR7(+) cells by trogocytosis and acquire migrating properties in response to lymph node chemokines. This event is negatively regulated by inhibitory killer Ig like receptors (KIRs) and NKG2A. In this study, we analyzed the role of the HLA C2-specific activating receptor KIR2DS1 in the process of CCR7 uptake by NK cells interacting with different allogeneic CCR7(+) cells. Co-incubation of KIR2DS1(+) fresh NK cells or NK-cell clones with HLA-C2(+) CCR7(+) lymphoblastoid cell lines resulted in increased CCR7 uptake. Remarkably, KIR2DS1 expression represented a major advantage for acquiring CCR7 from HLA-C2(+) allogeneic dendritic cells (DCs) and T-cell blasts. These findings have important implications in haploidentical hematopoietic stem cell transplantation in which donor-derived (alloreactive) KIR2DS1(+) NK cells, upon CCR7 acquisition, become capable of migrating toward lymph nodes, where they may kill patient DCs and T cells, preventing graft-versus-host and host-versus-graft reactions. PMID- 23449639 TI - Development of a porcine skin injury model and characterization of the dose dependent response to high-dose radiation. AB - A porcine skin model was developed to characterize the dose-dependent response to high-dose radiation. The dorsal skin of a mini pig was divided into four paraspinal sections, with 11 small irradiation fields (2 cm * 2 cm) in each section, and a single fraction of 15, 30, 50 or 75 Gy was delivered to each section using a 6 MeV electron beam. A spectrophotometer measured gross skin changes, and a biopsy for each radiation dose was performed in the 1st, 2nd, 4th, 6th and 9th weeks for histology, immunostaining with anti-CD31, and western blotting with IL-6 and TGF-beta1 to determine the degree of skin damage. After a 4-week latency period, erythema and dry desquamation, moist desquamation, and ulceration appeared at 4, 6 and 9 weeks, respectively. Gross skin toxicity was more pronounced, occurred early and continued to progress with irradiation >50 Gy, whereas complete healing was observed 12 weeks after 15 Gy. Spectrophotometry showed erythema indices rapidly increased during the first 4 weeks after irradiation. The number of eosinophils began rising sharply at 4 weeks and normalized after reaching peaks at 7-8 weeks. Microvessel density showed a biphasic pattern with a transient peak at 1 week, a nadir at 4-6 weeks, and maximum recovery at 9 weeks. Increase in the levels of IL-6 and TGF-beta1 was detected soon after irradiation. Most of these parameters indicated complete healing of the skin 12 weeks after 15 Gy. Our porcine skin model provides an effective platform for studying high-dose radiation-induced skin injury, in particular histologic and molecular changes, during the early latency period. PMID- 23449638 TI - Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in patients with acute myeloid leukemia. AB - Alterations of galectin-3 expression are often seen in cancers and may contribute to tumorigenesis, cancer progression, and metastasis. The studies concerning clinical implications of galectin-3 expression in patients with acute myeloid leukemia (AML) are scarce. We investigated the expression of LGALS3, the gene encoding galectin-3, in the bone marrow (BM) mononuclear cells from an original cohort comprising 280 adults with primary non-acute promyelocytic leukemia. Higher LGALS3 expression was closely associated with older age, French-American British M4/M5 subtypes, CD14 expression on leukemic cells, and PTPN11 mutation, but negatively correlated with CEBPA mutation and FLT3-ITD. Compared with patients with lower LGALS3 expression, those with higher expression had lower complete remission rates, higher primary refractory rates, and shorter overall survival. This result was validated in an independent validation cohort. A scoring system incorporating higher LGALS3 expression and 8 other risk factors, including age, white blood cell count, cytogenetics, and gene mutations, into survival analysis proved to be very useful to stratify patients with AML into different prognostic groups (P < .001). In conclusion, BM LGALS3 expression may serve as a new biomarker to predict clinical outcome in patients with AML, and galectin-3 may serve as a potential therapeutic target in those patients with higher expression of this protein. PMID- 23449640 TI - Modeling the biological response of normal human cells, including repair processes, to fractionated carbon beam irradiation. AB - To understand the biological response of normal cells to fractionated carbon beam irradiation, the effects of potentially lethal damage repair (PLDR) and sublethal damage repair (SLDR) were both taken into account in a linear-quadratic (LQ) model. The model was verified by the results of a fractionated cell survival experiment with normal human fibroblast cells. Cells were irradiated with 200-kV X-rays and monoenergetic carbon ion beams (290 MeV/u) at two irradiation depths, corresponding to linear energy transfers (LETs) of approximately 13 keV/MUm and 75 keV/MUm, respectively, at the Heavy Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences. When we only took into account the repair factor of PLDR, gamma, which was derived from the delayed assay, the cell survival response to fractionated carbon ion irradiation was not fully explained in some cases. When both the effects of SLDR and PLDR were taken into account in the LQ model, the cell survival response was well reproduced. The model analysis suggested that PLDR occurs in any type of radiation. The gamma factors ranged from 0.36-0.93. In addition, SLD was perfectly repaired during the fraction interval for the lower LET irradiations but remained at about 30% for the high LET irradiation. PMID- 23449641 TI - Assisted reproductive technology and birth defects: a systematic review and meta analysis. AB - BACKGROUND: It has been 10 years since we carried out a systematic search of the literature on birth defect risk in infants born following assisted reproductive technology (ART) compared with non-ART infants. Because of changes to ART practice since that review and the publication of more studies the objective of this review was to include these more recent studies to estimate birth defect risk after ART and to examine birth defect risk separately in ART singletons and multiples. METHODS: We searched Medline, Embase and Current Contents databases (1978-2012). We used the same data extraction sheet and questionnaire we had used previously with the addition of a quality score to the questionnaire. Pooled relative risk (RR) estimates were calculated using a random effects model. All data were analysed using Comprehensive Meta-Analysis V2. RESULTS: There were 45 cohort studies included in this review. ART infants (n = 92 671) had a higher risk of birth defects [RR 1.32, 95% confidence interval (CI) 1.24-1.42] compared with naturally conceived infants (n = 3 870 760). The risk further increased when data were restricted to major birth defects (RR 1.42, 95% CI 1.29-1.56) or singletons only (RR 1.36, 95% CI 1.30-1.43). The results for ART multiples were less clear. When all data for multiples were pooled the RR estimate was 1.11 (95% CI 0.98-1.26) but this increased to 1.26 (0.99-1.60) when the analysis was restricted to studies of ART twins where some adjustment was made for differences in zygosity distribution between ART and non-ART multiples. CONCLUSIONS: Birth defects remain more common in ART infants. Further research is required to examine risks for important subgroups of ART exposure. PMID- 23449642 TI - The longer-term health outcomes for children born as a result of IVF treatment: Part I--General health outcomes. AB - BACKGROUND Several million children have been born from in vitro fertilization (IVF) treatment, but limited data exist regarding their health and development beyond the first year of life. It has been alleged that IVF may lead to long-term adverse consequences, in addition to the documented worse perinatal outcome and increased risk of congenital abnormalities in children born resulting from IVF treatment. METHODS A search strategy restricted to studies relating to the medical condition of children of at least 1 year of age born as a result of IVF treatment was performed to include case series, data linkage and prospective studies published 1 January 2000-1 April 2012. RESULTS Limited long-term follow up data suggest that there is potentially an increase in the incidence of raised blood pressure, elevated fasting glucose, increase in total body fat composition, advancement of bone age and potentially subclinical thyroid disorder in the IVF offspring. Whether these potential associations are related to the IVF treatment per se, the adverse obstetric outcomes associated with IVF treatment or are related to the genetic origin of the children is yet to be determined. CONCLUSIONS This review provides evidence to suggest that the short-term health outcome for children born from IVF treatment is positive. However, it is expected that the cardiovascular and metabolic risk factors found in childhood and tracking into adulthood could be worse in later life, and may be responsible for chronic cardiometabolic disease. These observations need to be addressed by further studies. PMID- 23449643 TI - The longer-term health outcomes for children born as a result of IVF treatment. Part II--Mental health and development outcomes. AB - BACKGROUND Limited data exist with regard to longer-term mental health and psychological functioning of children born from IVF treatment. With the known adverse perinatal outcome for children born from IVF treatment, it would be expected that there is a negative impact upon their mental development. METHODS A search strategy restricted to studies relating to the medical condition of children of at least 1 year of age, born from IVF treatment was performed to include case series, data linkage and prospective studies published from 1 January 2000 to 1 April 2012. RESULTS Limited long-term follow-up data suggest that there is an increase in the incidence of cerebral palsy and neurodevelopmental delay related to the confounders of prematurity and low birthweight. Previous reports of associations with autism and attention-deficit disorder are believed to be related to maternal and obstetric factors. There exists a potential increase in the prevalence of early adulthood clinical depression and binge drinking in the offspring of IVF, with the reassuring data of no changes with respect to cognitive development, school performance, social functioning and behaviour. Whether these potential associations are related to the IVF treatment, the adverse obstetric outcomes associated with IVF treatment, the genetic or subsequent environmental influences on the children is yet to be determined. CONCLUSIONS In general, the longer-term mental and emotional health outcome for children born from IVF treatment is reassuring, and is very similar to that of naturally conceived children; however, further studies are required to explore any association with depression, and its causality in more detail. PMID- 23449644 TI - The Liverpool care pathway: what do specialists think? PMID- 23449645 TI - Rice LHS1/OsMADS1 controls floret meristem specification by coordinated regulation of transcription factors and hormone signaling pathways. AB - SEPALLATA (SEP) MADS box transcription factors mediate floral development in association with other regulators. Mutants in five rice (Oryza sativa) SEP genes suggest both redundant and unique functions in panicle branching and floret development. leafy hull sterile1/OsMADS1, from a grass-specific subgroup of LOFSEP genes, is required for specifying a single floret on the spikelet meristem and for floret organ development, but its downstream mechanisms are unknown. Here, key pathways and directly modulated targets of OsMADS1 were deduced from expression analysis after its knockdown and induction in developing florets and by studying its chromatin occupancy at downstream genes. The negative regulation of OsMADS34, another LOFSEP gene, and activation of OsMADS55, a SHORT VEGETATIVE PHASE-like floret meristem identity gene, show its role in facilitating the spikelet-to-floret meristem transition. Direct regulation of other transcription factor genes like OsHB4 (a class III homeodomain Leu zipper member), OsBLH1 (a BEL1-like homeodomain member), OsKANADI2, OsKANADI4, and OsETTIN2 show its role in meristem maintenance, determinacy, and lateral organ development. We found that the OsMADS1 targets OsETTIN1 and OsETTIN2 redundantly ensure carpel differentiation. The multiple effects of OsMADS1 in promoting auxin transport, signaling, and auxin-dependent expression and its direct repression of three cytokinin A-type response regulators show its role in balancing meristem growth, lateral organ differentiation, and determinacy. Overall, we show that OsMADS1 integrates transcriptional and signaling pathways to promote rice floret specification and development. PMID- 23449647 TI - Chiropractic management of a patient with symptoms of attention deficit/hyperactivity disorder. AB - OBJECTIVE: The purpose of this study is to report a case of a child with attention-deficit/hyperactivity disorder (ADHD) who was treated with chiropractic care. CLINICAL FEATURES: Parents of a 5-year-old boy with diagnosed ADHD brought him for chiropractic care to address his subjective signs (acting out, ability to follow instructions, and poor home and school performance), which also included waking at night due to asthmatic symptoms and low self-esteem. Palpation revealed hypertonicity and trigger points in the paraspinal muscles at the thoracolumbar region with local pain. A preliminary diagnosis included cervical and thoracolumbar facet joint irritation with concurrent muscle hypertonicity. INTERVENTION AND OUTCOMES: Treatment including spinal manipulative therapy, soft tissue therapy, and stretching was provided. Treatment began on a thrice-weekly basis and declined to twice weekly over the course of approximately 12 weeks. After 1 year of treatment, subjective improvements were noted in episodes of acting out, ability to follow instructions, and general home and school performance. CONCLUSIONS: The patient improved over 1 year in which he received chiropractic care, including manual treatments such as spinal manipulative therapy and soft tissue therapies. This suggests that there may be a role for doctors of chiropractic in the management of patients with ADHD. PMID- 23449648 TI - Observer variability of an angiographic grading scale used for the assessment of intracranial aneurysms treated with flow-diverting stents. AB - BACKGROUND AND PURPOSE: Novel angiographic grading scales for the assessment of intracranial aneurysms treated with flow-diverting stents have been recently developed because previous angiographic grading scales cannot be applied to these aneurysms. The purpose of this study was to evaluate the inter- and intraobserver variability of the novel O'Kelly Marotta grading scale, which was developed specifically for the angiographic assessment of aneurysms treated with flow diverting stents. MATERIALS AND METHODS: Multiple raters (n = 31) from the disciplines of neuroradiology and neurosurgery were presented with pre- and posttreatment angiographic images of 14 aneurysms treated with intraluminal flow diverters. Raters were asked to classify pre- and posttreatment angiograms by using the OKM grading scale. Statistical analyses were subsequently performed with calculation of a generalized multirater kappa statistic for assessment of inter- and intraobserver variability and by performing a Wilcoxon signed rank sum test for assessment of group differences. RESULTS: Variability analysis of the OKM grading scale yielded substantial (kappa = 0.74) and almost perfect (kappa = 0.99) inter- and intraobserver agreement, respectively, with no statistically significant differences between raters with a background of neuroradiology versus neurosurgery or attending physician versus trainee. CONCLUSIONS: The OKM grading scale for the assessment of intracranial aneurysms treated with flow-diverting stents is a reliable grading scale that can be used equally well by users of varying backgrounds and levels of training. Comparison with interobserver variability of pre-existing angiographic grading scales shows equal or better performance. PMID- 23449646 TI - Traffic of human alpha-mannosidase in plant cells suggests the presence of a new endoplasmic reticulum-to-vacuole pathway without involving the Golgi complex. AB - The transport of secretory proteins from the endoplasmic reticulum to the vacuole requires sorting signals as well as specific transport mechanisms. This work is focused on the transport in transgenic tobacco (Nicotiana tabacum) plants of a human alpha-mannosidase, MAN2B1, which is a lysosomal enzyme involved in the turnover of N-linked glycoproteins and can be used in enzyme replacement therapy. Although ubiquitously expressed, alpha-mannosidases are targeted to lysosomes or vacuoles through different mechanisms according to the organisms in which these proteins are produced. In tobacco cells, MAN2B1 reaches the vacuole even in the absence of mannose-6-phosphate receptors, which are responsible for its transport in animal cells. We report that MAN2B1 is targeted to the vacuole without passing through the Golgi complex. In addition, a vacuolar targeting signal that is recognized in plant cells is located in the MAN2B1 amino-terminal region. Indeed, when this amino-terminal domain is removed, the protein is retained in the endoplasmic reticulum. Moreover, when this domain is added to a plant-secreted protein, the resulting fusion protein is partially redirected to the vacuole. These results strongly suggest the existence in plants of a new type of vacuolar traffic that can be used by leaf cells to transport vacuolar proteins. PMID- 23449649 TI - Raise the bar and lower the dose: current and future strategies for radiation dose reduction in head and neck imaging. AB - SUMMARY: Technologic advances in CT have generated a dramatic increase in the number of CT studies, with a resultant increase in the radiation dose related to CT scanning. Such increase in radiation dose is becoming a concern for the radiology community, especially with increasing public awareness of the dose burden related to examinations. To cope with the increase in CT-related radiation exposure, it is becoming necessary to optimize CT imaging protocols and apply radiation dose reduction techniques to ensure the best imaging with the lowest radiation dose. PMID- 23449650 TI - Facet joint signal change on MRI at levels of acute/subacute lumbar compression fractures. AB - BACKGROUND AND PURPOSE: The prevalence of facet joint signal change in acute/subacute lumbar vertebral body compression fractures is unknown. We hypothesized that facet joint signal change on MR imaging is more common in facet joints associated with an acute/subacute lumbar compression fracture than those associated with normal vertebral bodies or ones that have a chronic compression fracture. MATERIALS AND METHODS: Three neuroradiologists and a neuroradiology fellow retrospectively graded facet joint inflammatory change on MR imaging in 900 facet joints in 75 patients with at least 1 painful osteoporotic lumbar compression fracture. Facet joint signal change was assessed on T2-weighted images with chemical fat-saturation, STIR images, and/or gadolinium-enhanced T1 weighted images with chemical fat-saturation. Each facet joint from the T12/L1 to L5/S1 level was assessed individually. An overall facet joint signal-change score, which is a composite measure of the grade of signal change for all 4 facet joints associated with a given lumbar vertebral level, was devised, and statistical significance was assessed via Wilcoxon rank sum tests. RESULTS: The overall facet joint signal-change scores were significantly higher at vertebral body levels affected by an acute/subacute compression fracture compared with control levels, which were associated with either normal bodies or chronic compression fractures. CONCLUSIONS: Our findings suggest an association between facet joint signal change on MR imaging and acute/subacute lumbar vertebral body compression fractures. PMID- 23449651 TI - Intracranial aneurysms in autosomal dominant polycystic kidney disease. AB - BACKGROUND AND PURPOSE: ADPKD correlates with an increased frequency of ICANs, but universal screening for ICANs in patients with ADPKD is not currently recommended. The aim of our study was to determine which groups might benefit from screening by determining the prevalence of ICANs in the Polish ADPKD population and identifying any subgroups with an increased risk for ICANs. MATERIALS AND METHODS: Eighty-three adult, predialysis-phase patients with ADPKD underwent screening for ICANs with MRA of the brain. RESULTS: The prevalence of ICANs in the studied population was 16.9%, with 6% of the screened group requiring neurosurgical intervention. We also found that the frequency of ICANs increases with age, reaching 22.4% in patients older than 45 years. All diagnosed ICANs were small (< 9 mm) and were localized in the anterior circulation. In addition, MR imaging revealed arachnoid cysts in 4.8% of patients with ADPKD. CONCLUSIONS: We suggest that patients older than 45 years with ADPKD be considered as candidates for screening for ICANs, and we propose a clinical algorithm for this subgroup. However, we could not find risk factors for ICANs in younger patients with ADPKD. PMID- 23449652 TI - iConsent. PMID- 23449653 TI - Advanced MRI morphologic study shows no atrophy in healthy individuals with hippocampal hyperintensity. AB - We have already shown that brain MR imaging of healthy individuals frequently reveals either unilateral or bilateral Hh, which is considered a hallmark of hippocampal sclerosis. We performed a follow-up (5-year interval) clinical and advanced imaging study of these individuals to address whether Hh may have masked occult brain atrophy or contributed to a later onset of epilepsy. Subjects with Hh (n = 13) underwent a detailed clinical-imaging protocol, with a 3T scan and were studied with automated hippocampal segmentation (FreeSurfer), whole brain voxel-based morphometry, and shape analysis. All 13 subjects with Hh had normal neurologic examination findings with no cognitive impairment. Multimodal structural neuroimaging methods did not show clear evidence of significant volumetric changes between subjects with or without Hh. We clearly showed that Hh is not associated with any occult brain atrophy; furthermore, none of the healthy subjects with MR imaging evidence of Hh developed epilepsy or trouble with cognition. PMID- 23449654 TI - Immediate pain response does not predict long-term outcome of CT-guided cervical transforaminal epidural steroid injections. AB - BACKGROUND AND PURPOSE: Imaging-guided cervical transforaminal epidural steroid injections have been shown to decrease verbal numerical pain scores and improve functionality (Roland Morris Disability Index). These injections are often administered in combination with local anesthetic. The purpose of this study was to determine if the immediate postprocedure VNPS predicts the long-term effectiveness of the injection. MATERIALS AND METHODS: A quality assurance data base review of 247 patient records was used to document the VNPS and RMDI of patients undergoing a single CT-guided CTESI. Pain scores were recorded before the procedure, immediately after the procedure, at 2 weeks, and at 2 months. The RMDI was recorded before the procedure, at 2 weeks, and at 2 months. Spearman rank correlation analysis and logistic regression models were used to determine if the immediate postprocedure or 2-week VNPS correlated with or predicted the longer-term VNPS and RMDI as measured at 2 weeks and 2 months. RESULTS: There was not a strong correlation between the pain score obtained immediately after the procedure and the 2-month outcome of the VNPS or RMDI. The pain scores at 2 weeks did correlate with the 2-month outcomes. The 2-week VNPS also was a significant predictor of patients who would achieve a >50% improvement in VNPS or RMDI at 2 months. CONCLUSIONS: Pain scores obtained immediately after completion of a single CT-guided CTESI do not predict the long-term effectiveness of this procedure. However, patient response at 2 weeks does correlate with the long-term effectiveness of these injections as measured by the VNPS and the RMDI. PMID- 23449655 TI - Contrast extravasation on CT angiography predicts hematoma expansion and mortality in acute traumatic subdural hemorrhage. AB - BACKGROUND AND PURPOSE: The presence of active contrast extravasation at CTA predicts hematoma expansion and in-hospital mortality in patients with nontraumatic intracerebral hemorrhage. This study aims to determine the frequency and predictive value of the contrast extravasation in patients with aSDH. MATERIALS AND METHODS: We retrospectively reviewed 157 consecutive patients who presented to our emergency department over a 9-year period with aSDH and underwent CTA at admission and a follow-up NCCT within 48 hours. Two experienced readers, blinded to clinical data, reviewed the CTAs to assess for the presence of contrast extravasation. Medical records were reviewed for baseline clinical characteristics and in-hospital mortality. aSDH maximum width in the axial plane was measured on both baseline and follow-up NCCTs, with hematoma expansion defined as >20% increase from baseline. RESULTS: Active contrast extravasation was identified in 30 of 199 discrete aSDHs (15.1%), with excellent interobserver agreement (kappa = 0.80; 95% CI, 0.7-0.9). The presence of contrast extravasation indicated a significantly increased risk of hematoma expansion (odds ratio, 4.5; 95% CI, 2.0-10.1; P = .0001) and in-hospital mortality (odds ratio, 7.6; 95% CI, 2.6-22.3; P = 0.0004). In a multivariate analysis controlled for standard risk factors, the presence of contrast extravasation was an independent predictor of aSDH expansion (P = .001) and in-hospital mortality (P = .0003). CONCLUSIONS: Contrast extravasation stratifies patients with aSDH into those at high risk and those at low risk of hematoma expansion and in-hospital mortality. This distinction could affect patient treatment, clinical trial selection, and possible surgical intervention. PMID- 23449656 TI - Stroke mismatch volume with the use of ABC/2 is equivalent to planimetric stroke mismatch volume. AB - BACKGROUND AND PURPOSE: In the clinical setting, there is a need to perform mismatch measurements quickly and easily on the MR imaging scanner to determine the specific amount of treatable penumbra. The objective of this study was to quantify the agreement of the ABC/2 method with the established planimetric method. MATERIALS AND METHODS: Patients (n = 193) were selected from the NINDS Natural History Stroke Registry if they 1) were treated with standard intravenous rtPA, 2) had a pretreatment MR imaging with evaluable DWI and PWI, and 3) had an acute ischemic stroke lesion. A rater placed the linear diameters to measure the largest DWI and MTT lesion areas in 3 perpendicular axes-A, B, and C-and then used the ABC/2 formula to calculate lesion volumes. A separate rater measured the planimetric volumes. Multiple mismatch thresholds were used, including MTT volume - DWI volume >=50 mL versus >=60 mL and (MTT volume - DWI volume)/MTT volume >=20% versus MTT/DWI = 1.8. RESULTS: Compared with the planimetric method, the ABC/2 method had high sensitivity (0.91), specificity (0.90), accuracy (0.91), PPV (0.90), and NPV (0.91) to quantify mismatch by use of the >=50 mL definition. The Spearman correlation coefficients were 0.846 and 0.876, respectively, for the DWI and MTT measurements. The inter-rater Bland-Altman plots demonstrated 95%, 95%, and 97% agreement for the DWI, MTT, and mismatch measurements. CONCLUSIONS: The ABC/2 method is highly reliable and accurate for quantifying the specific amount of MR imaging-determined mismatch and therefore is a potential tool to quickly calculate a treatable mismatch pattern. PMID- 23449657 TI - Lumbar facet joint synovial cysts: does T2 signal intensity predict outcomes after percutaneous rupture? AB - BACKGROUND AND PURPOSE: Lumbar facet synovial cysts are a cause of back pain and radiculopathy with facet joint degeneration, the most common cause for cyst formation. Typically, LFSCs are T2 hyperintense on MR imaging, but the signal intensity is variable. Treatment options include percutaneous rupture and surgical resection. This study evaluates the relationship between LFSC signal intensity on MR imaging and outcomes as it relates to percutaneous rupture success and need for subsequent surgery. MATERIALS AND METHODS: A retrospective review of 110 patients who underwent CT fluoroscopic-guided rupture of symptomatic LFSCs was performed. The LFSCs were characterized by their T2 signal intensity on MR imaging and divided into 3 groups: high, intermediate, and low T2 signal intensity. The rates of successful cyst rupture and need for subsequent surgery were recorded. RESULTS: Percutaneous LFSC rupture was technically successful in 87% of all cases. Cyst rupture was successful in 89% and 90% of high and intermediate signal intensity cysts, respectively, and in 65% of low signal intensity cysts (P = .017, .030). High signal intensity cysts had lower postprocedural surgical rates (29%) when compared with intermediate and low signal cyst as a group (P = .045). CONCLUSIONS: T2 hyperintense and intermediate signal intensity LFSCs are easier to rupture, perhaps because the cysts contain a higher proportion of fluid and are less gelatinous or calcified than T2 hypointense cysts. Patients with T2 hyperintense LFSCs are less likely to need surgery. PMID- 23449658 TI - Actual metal coverage at the neck is critical for flow-diverting stents in treating intracranial aneurysms. PMID- 23449659 TI - Alcohol marketing: grooming the next generation: children are more exposed than adults and need much stronger protection. PMID- 23449660 TI - Toe component excision in postaxial polydactyly of the foot. AB - BACKGROUND: Polydactyly of the fifth toe is the most common congenital malformation of the forefoot, and no consensus has been reached as to which toe component should be excised or by which surgical technique. The purpose of this study was to evaluate the results of the operative treatment of postaxial polydactyly and to offer treatment guidelines. METHOD: We retrospectively reviewed the details of 27 patients with postaxial polydactyly (36 feet) treated from September 2004 to March 2010. To select the dominant toe of postaxial polydactyly, we evaluated the morphological and radiological configurations. To excise the medial toe, we treated the polydactyly by dorsal rectangular flap and a full-thickness inguinal skin graft. To excise the lateral toe, we treated the polydactyly by racket-shape incision. Patient satisfaction indices were evaluated on the basis of responses to the PSQ-10 patient satisfaction questionnaire and clinical outcomes. RESULT: Overall surgical outcomes were satisfactory with the exception of 2 cases of skin graft problems. Eighteen of the 36 reconstructed toes were smaller than the normal toes, but valgus deformity was observed in only 3 cases. CONCLUSION: The described medial toe excision technique and the devised toe selection algorithm were able to satisfy functional and cosmetic requirements. PMID- 23449661 TI - Open ankle arthrodesis with a fibular-sparing technique. AB - BACKGROUND: Many ankle arthrodesis techniques excise the fibula or require a fibular osteotomy. Advantages of fibular preservation include increased surface area for bony union, preservation of the peroneal groove, prevention of valgus drift in cases of delayed union, and facilitation of future ankle arthroplasty. The goal of this study was to evaluate fusion rate and clinical outcomes of a novel open fibular-sparing ankle arthrodesis technique. METHODS: A total of 50 consecutive ankle arthrodeses using this technique were included in this study. These consisted of 46 patients with an average age of 52 (range, 30 to 71) years. Outcomes assessed postoperatively included radiographs, complications, patient satisfaction, and functional scoring. RESULTS: At an average of 28 (range, 19 to 56) months postoperatively, 38 patients (42 ankles) were available for review. Of the 42 cases, 39 (93%) achieved union at an average of 12 weeks postoperatively. Of patients, 86% reported being "completely satisfied" with the outcome. Average AOFAS Ankle-Hindfoot Scale was 84 +/- 12 and average Foot Function Index pain subscale was 1 +/- 0.9. Two ankles (5%) were fused in excessive varus; no patient required revision surgery for malalignment. CONCLUSION: This method of open ankle arthrodesis preserved the fibula and had a high fusion rate with good patient outcome scores. PMID- 23449662 TI - Foot center of pressure trajectory alteration by biomechanical manipulation of shoe design. AB - BACKGROUND: Footwear-generated biomechanical manipulations have been shown to alter lower limb kinetics. It has been suggested that this is due to altered trajectory of the foot's center of pressure (COP), conveying a shift in location of the ground reaction force and modifying moments and forces acting on proximal body segments. However, past studies have focused on qualitative association between footwear design and the COP locus. Moreover, this association was calculated via indirect analysis. The purpose of the present study was to directly examine and quantify the correlation between measured footwear biomechanical manipulation and the location of the COP trajectory during gait. METHODS: A novel biomechanical device allowing flexible positioning of 2 convex shaped elements attached to its sole was utilized. A total of 20 healthy male adults underwent direct in-shoe pressure measurements while walking with the device set at 7 mediolateral configurations. COP data were collected during gait and analyzed with respect to different stance subphases. RESULTS: COP location significantly correlated with a shift of the elements medially or laterally. The linear model describing this correlation was found to be statistically significant. CONCLUSION: There was significant correlation between the plantar orientation of the shoe device configuration and the COP. CLINICAL RELEVANCE: Changes in COP trajectory may be valuable in patients suffering from multiple foot disorders elevating pressure on the foot. Accurate COP control could aid in the manipulation of the forces acting on the proximal joints during gait. In addition, these findings may have implications in the field of biomechanical apparatus design and practice. PMID- 23449663 TI - Sternal closure after median sternotomy: a new technique using titanium hooks and wires applied parasternally. AB - OBJECTIVES: Osteosynthetic closure of the chest after median sternotomy is usually performed with steel wires. We describe, for the first time, a case series in which titanium hooks were implanted from the sternal surface in patients who required secondary or additional stabilization. In comparison to the classic wires, the diameters of the hooks are approximately three times bigger and therefore reduce the risk of cutting through the bones. Additionally, there is no need to dissect retrosternal adhesions, which may reduce the risk of injuring mediastinal tissues. METHODS: The hooks are shaped like fishing hooks and can be inserted parasternally into the intercostal spaces. They can be pulled to the contralateral side of the sternum by the attached wires and then intertwined with a second hook. RESULTS: In 13 patients, the system was used to provide additional stabilization, while in two patients the hooks were implanted for exclusive stabilization of sternal fractures. In all cases but one, the implantation was able to eliminate the sternal problems. No infections, necrosis or bleeding of neighbouring tissues occurred. One patient developed chronic sternal infection, which necessitated explantation of the hooks. CONCLUSIONS: This sternal closure system using titanium hooks inserted parasternally is an effective alternative to conventional techniques and may increase stability of the breastbone and reduce the risk of injury to retrosternal tissues. PMID- 23449664 TI - Does repair of pectus excavatum improve cardiopulmonary function? AB - A best evidence topic was written according to a structured protocol. The question addressed was 'Does repair of pectus excavatum (PE) improve cardiopulmonary function?' One hundred and sixty-eight papers were found using the reported search, 19 level III evidence papers and three meta-analyses were relevant. Studies were divided into four groups based on the surgical technique applied and pulmonary and cardiac functions in these groups were analysed. The meta-analyses show conflicting results for improvements in pulmonary and cardiac functions when comparing surgical techniques, while four more recent studies show improved long-term results using the Nuss technique. The best evidence of papers studying the PE repair using the minimally invasive Nuss technique demonstrates a decrease in pulmonary function during the early postoperative period, however, there is a small but significant improvement during the late postoperative period and after bar removal. The best evidence for cardiac function in this group suggests an early improvement that is sustained during further follow-up. The best evidence of papers studying the PE repair using the Ravitch technique shows that pulmonary function decreased during the early postoperative period, however, there is a small but significant improvement during the late postoperative period. The best evidence for cardiac function in this group suggests an early improvement that is sustained during further follow-up. The best evidence of papers studying the PE repair using other techniques (modified Daniel's technique, modified Baronofsky's technique, sterno-costal turn-over technique and sterno-costal elevation technique) or where surgical techniques used were not described (preceding year 1985) suggests that there is no improvement in pulmonary function after surgery. There is some evidence that certain aspects of cardiac function improved after surgery in this group. PMID- 23449665 TI - Is single-unit blood transfusion bad post-coronary artery bypass surgery? AB - OBJECTIVES: Publications in the surgical literature are very consistent in their conclusions that blood is dangerous with regard to in-hospital mortality, morbidity and long-term survival. Blood is frequently used as a volume expander while simultaneously increasing the haematocrit. We investigated the effects of a single-unit blood transfusion on long-term survival post-cardiac surgery in isolated coronary artery bypass grafting patients. METHODS: A prospective single institution cardiac surgery database was analysed involving 4615 patients. Univariate, multivariate stepwise Cox regression analysis and propensity matching were performed to identify whether a single-unit blood transfusion was detrimental to long-term survival. RESULTS: Univariate analysis revealed that blood was significantly associated with a reduced long-term survival even with a single-unit transfused, P = 0.0001. Cox multivariate regression analysis identified age, ejection fraction, preoperative dialysis, logistic EuroSCORE, postoperative CKMB, blood transfusion, urgent operative status and atrial fibrillation as significant factors determining long-term survival. When the Cox regression was repeated with patients who received no blood or only one unit of blood, transfusion was not a risk factor for long-term survival. An interaction analysis revealed that blood transfusion was significantly interacting with preoperative haemoglobin levels, P = 0.02. Propensity analysis demonstrated that a single-unit transfusion is not associated with a detrimental long-term survival, P = 0.3. CONCLUSIONS: Cox regression and propensity matching both indicate that a single-unit transfusion is not a significant cause of reduced long-term survival. Preoperative anaemia is a significant confounding factor. Despite demonstrating the negligible risks of a single-unit blood transfusion, we are not advocating liberal transfusion and would recommend changing from a double unit to a single-unit transfusion policy. We speculate that blood is not bad, but that the underlying reason that it is given might be. PMID- 23449666 TI - Newspaper coverage of implementation of the Michigan smoke-free law: lessons learned. AB - OBJECTIVE: To examine whether newspaper coverage of the Michigan smoke-free law was favorable or hostile, contained positive messages that had been disseminated by public health groups, contained negative messages, and differed across regions. METHOD: Articles about the smoke-free law in print or online editions of Michigan newspapers the month immediately before and after the law took effect were identified and were coded for tone, positive messages contained in media outreach materials, and negative messages commonly disseminated by smoke-free law opponents. RESULTS: A total of 303 print and online articles were identified; the majority were coded as "both positive and negative" (34%) or "mainly positive" in tone (32%). Of 303 articles, 75% contained at least one pro-law message and 56% contained at least one anti-law message. The most common pro-law messages were information about enforcement of the law (52%) and the benefits of smoke-free air (48%); the most common anti-law messages were about potential negative economic impact (36%), government intrusion/overreach (31%), and difficulties with enforcement (28%). CONCLUSIONS: Public health departments and partners play an important role in implementation of smoke-free laws by providing the public, businesses, and other stakeholders with clear and accurate rationale, provisions, and impacts of these policies. PMID- 23449668 TI - Persistently elevated laboratory markers of thrombosis and fibrinolysis after clinical recovery in malaria points to residual and smouldering cellular damage. AB - Screening coagulation tests and assays for thrombosis and fibrinolysis were performed in 80 cases of malaria at presentation and during the course of the disease. Close correlation between the degree of thrombocytopenia (observed in >97% cases) and the presence hemorrhagic manifestations at presentation, and improvement in the platelet count in parallel with clinical recovery emphasised the role of platelets in the pathogenesis of coagulopathy in malaria. A potential selection bias resulting from inclusion of only patients admitted at a tertiary care hospital could explain the higher incidence (27.5%) of clinical bleeding observed in this study compared to that reported in the literature. Although a significant correlation between overt bleeding and abnormal PT/INR and APTT (observed in 20-37% cases) could not be demonstrated, a good correlation existed between normal screening coagulation tests and the absence of bleeding complications. Elevated D-Dimer and FDP levels in almost all cases (90%) of both types of malaria confirmed the high prevalence of disseminated intravascular coagulation and fibrinolysis. A correlation between rising D-Dimer levels and the incidence of bleeding was observed. Follow up studies in six cases with complications showed normalization of platelet counts and of screening coagulation assays with clinical recovery. D-Dimer and FDP levels however, remained elevated in most of these cases indicating the continuation of a smouldering coagulopathy even after full clinical recovery possibly due to the persistence of residual damage to the cells caused by the parasitic infection. Knowledge of this fact is important for avoiding unnecessary investigations and longer hospital stay in patients admitted with malaria. PMID- 23449667 TI - Follicles in gut-associated lymphoid tissues create preferential survival niches for follicular Th cells escaping Thy-1-specific depletion in mice. AB - Although a substantial number of T cells may escape depletion following in vivo mAb treatment in patients undergoing immunosuppression, their specific tissue location and phenotypic characteristics in different peripheral lymphoid tissues have not been analyzed in detail. Here we investigated the survival of CD4(+) T cells immediately following anti-Thy-1 mAb treatment in mice. We found a preferential survival of CD4(+) T cells expressing Thy-1 antigen in the Peyer's patches (PP) and also in mesenteric lymph nodes (MLN), where the relative majority of the surviving CD4(+) T cells displayed CD44(high)/CD62L(-) phenotype corresponding to effector memory T-cell features. These CD4(+) T cells also expressed CXCR5 and PD-1 (programmed cell death-1) markers characteristic for follicular Th cells (TFH). We also demonstrate that the immediate survival of these cells does not involve proliferation and is independent of IL-7. Induction of germinal center formation in spleen enhanced while the dissolution of follicular architecture by lymphotoxin-beta receptor antagonist treatment slightly reduced TFH survival. Our results thus raise the possibility that the follicles within PP and MLN may create natural support niches for the preferential survival of TFH cells of the memory phenotype, thus allowing their escape during T-cell depletion. PMID- 23449669 TI - CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion. AB - Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion. PMID- 23449670 TI - Neonatal colonic inflammation sensitizes voltage-gated Na(+) channels via upregulation of cystathionine beta-synthetase expression in rat primary sensory neurons. AB - The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood, and treatment remains difficult. We have previously reported that colon-specific dorsal root ganglion (DRG) neurons were hyperactive in a rat model of IBS induced by neonatal colonic inflammation (NCI). This study was designed to examine plasticity of voltage-gated Na(+) channel activities and roles for the endogenous hydrogen sulfide-producing enzyme cystathionine beta-synthetase (CBS) in chronic visceral hyperalgesia. Abdominal withdrawal reflex (AWR) scores were recorded in response to graded colorectal distention in adult male rats as a measure of visceral hypersensitivity. Colon-specific DRG neurons were labeled with 1,1' dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate and acutely dissociated for measuring Na(+) channel currents. Western blot analysis was employed to detect changes in expressions of voltage-gated Na(+) (Na(V)) channel subtype 1.7, Na(V)1.8, and CBS. NCI significantly increased AWR scores when compared with age-matched controls. NCI also led to an ~2.5-fold increase in Na(+) current density in colon-specific DRG neurons. Furthermore, NCI dramatically enhanced expression of Na(V)1.7, Na(V)1.8, and CBS in colon-related DRGs. CBS was colocalized with Na(V)1.7 or -1.8 in colon-specific DRG neurons. Administration of O-(carboxymethyl)hydroxylamine hemihydrochloride (AOAA), an inhibitor for CBS, remarkably suppressed Na(+) current density and reduced expression of Na(V)1.7 and Na(V)1.8. More importantly, intraperitoneal or intrathecal application of AOAA attenuated AWR scores in NCI rats in a dose dependent manner. These data suggest that NCI enhances Na(+) channel activity of colon DRG neurons, which is most likely mediated by upregulation of CBS expression, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS. PMID- 23449671 TI - A PKG inhibitor increases Ca(2+)-regulated exocytosis in guinea pig antral mucous cells: cAMP accumulation via PDE2A inhibition. AB - In antral mucous cells, acetylcholine (ACh, 1 MUM) activates Ca(2+)-regulated exocytosis, consisting of an initial peak that declines rapidly (initial transient phase) followed by a second slower decline (late phase) lasting during ACh stimulation. The addition of 8-bromo-cGMP (8-BrcGMP) enhanced the initial phase, which was inhibited by the protein kinase G (PKG) inhibitor guanosine 3',5'-cyclic monophosphorothoiate, beta-phenyl-1,N(2)-etheno-8-bromo, Rp-isomer, sodium salt (Rp-8-BrPETcGMPS, 100 nM). However, Rp-8-BrPETcGMPS produced a delayed, but transient, increase in the exocytotic frequency during the late phase that was abolished by a protein kinase A (PKA) inhibitor (PKI-amide), suggesting that Rp-8-BrPETcGMPS accumulates cAMP. The cGMP-dependent phosphodiesterase 2 (PDE2), which degrades cAMP, may exist in antral mucous cells. The PDE2 inhibitor BAY-60-7550 (250 nM) mimicked the effect of Rp-8 BrPETcGMPS on ACh-stimulated exocytosis. Measurement of the cGMP and cAMP contents in antral mucosae revealed that ACh stimulates the accumulation of cGMP and that BAY-60-7550 accumulates cAMP similarly to Rp-8-BrPETcGMPS during ACh stimulation. Analyses of Western blot and immunohistochemistry demonstrated that PDE2A exists in antral mucous cells. In conclusion, Rp-8-BrPETcGMPS accumulates cAMP by inhibiting PDE2 in ACh-stimulated antral mucous cells, leading to the delayed, but transient, increase in the frequency of Ca(2+)-regulated exocytosis. PDE2 may prevent antral mucous cells from excessive mucin secretion caused by the cAMP accumulation. PMID- 23449672 TI - Osmotic regulation of hepatic betaine metabolism. AB - Betaine critically contributes to the control of hepatocellular hydration and provides protection of the liver from different kinds of stress. To investigate how the hepatocellular hydration state affects gene expression of enzymes involved in the metabolism of betaine and related organic osmolytes, we used quantitative RT-PCR gene expression studies in rat hepatoma cells as well as metabolic and gene expression profiling in primary hepatocytes of both wild-type and 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient mice. Anisotonic incubation caused coordinated adaptive changes in the expression of various genes involved in betaine metabolism, in particular of betaine homocysteine methyltransferase, dimethylglycine dehydrogenase, and sarcosine dehydrogenase. The expression of betaine-degrading enzymes was downregulated by cell shrinking and strongly induced by an increase in cell volume under hypotonic conditions. Metabolite concentrations in the culture system changed accordingly. Expression changes were mediated through tyrosine kinases, cyclic nucleotide-dependent protein kinases, and JNK-dependent signaling. Assessment of hepatic gene expression using a customized microarray chip showed that hepatic betaine depletion in MTHFR(-/-) mice was associated with alterations that were comparable to those induced by cell swelling in hepatocytes. In conclusion, the adaptation of hepatocytes to changes in cell volume involves the coordinated regulation of betaine synthesis and degradation and concomitant changes in intracellular osmolyte concentrations. The existence of such a well-orchestrated response underlines the importance of cell volume homeostasis for liver function and of methylamine osmolytes such as betaine as hepatic osmolytes. PMID- 23449673 TI - Publishing cardiac surgery mortality rates: lessons for other specialties. PMID- 23449675 TI - The appeal of large simple trials. PMID- 23449674 TI - Recurrent hypoglycaemia in a young man without diabetes. PMID- 23449676 TI - Obama widens access to government funded research. PMID- 23449677 TI - The relationships between posttraumatic stress disorder severity, depression severity and physical health. AB - This study examines the relationship among posttraumatic stress disorder severity, depression severity, and subjective and objective physical health in a sample of 200 adults with posttraumatic stress disorder. Posttraumatic stress disorder severity was correlated with subjective, but not objective, health. Similarly, depression symptoms had an indirect effect on the relationship between posttraumatic stress disorder symptom severity and three measures of subjective physical health. Finally, depression symptoms had an indirect effect on the relationship between both reexperiencing and hyperarousal symptoms and subjective physical health. This research underscores the important role that posttraumatic stress disorder, particularly reexperiencing and hyperarousal symptoms, and depression may have on perceptions of physical health. PMID- 23449678 TI - Patient-provider relationship predicts mental and physical health indicators for HIV-positive men who have sex with men. AB - We used secondary data analysis to examine associations among aspects of patient provider relationships and mental and physical health indicators. Positive patient perceptions of patient-provider relationships were associated with fewer mental health symptoms in this outpatient sample of HIV-positive men who have sex with men (N = 171). Regression analyses revealed the role of anxiety and depression in explaining associations between two aspects of patient-provider relationships (i.e. quality of information offered and provider interactional style) and health-related quality of life. The findings demonstrated the importance of patient-provider relationships to improving physical health and functioning and maintaining engagement in care, among HIV-positive men who have sex with men. PMID- 23449680 TI - Properties of single electrospun poly (diol citrate)-collagen-proteoglycan nanofibers for arterial repair and in applications requiring viscoelasticity. AB - Single nanofibers with chemical and functional properties consistent with artery extracellular matrix nanofibers were produced by electrospinning. Using weight ratios to mimic artery extracellular matrix, five materials were tested: (1) Collagen type I, (2) Collagen type I + Collagen type III, (3) Collagen type I + poly (diol citrate), (4) Collagen type I + Collagen type III + poly (diol citrate), and (5) Collagen type I + poly (diol citrate) + Decorin + Aggrecan. Fiber sizes for all materials ranged from 50 nm to 600 nm and random fiber mats had pore sizes from 21 to 40 = m(2) and porosities of 72-84%. Human embryonic palatal mesenchymal cells fibroblasts adhered to all fibers and proliferated over a 7-day study period. Mechanical properties of single fibers were investigated using a combined atomic force/optical microscope. Materials containing poly (diol citrate) showed elasticity increased 3.2 fold greater than composites without poly (diol citrate). Maximum stress was within functional range in comparison to decellularized artery extracellular matrix fibers. By incorporating poly (diol citrate) and proteoglycan along with collagen, a viscoelastic nanofibrous material was produced for use in tissues such as artery where viscoelasticity and tensile strength are required. PMID- 23449679 TI - Brain connectivity studies in schizophrenia: unravelling the effects of antipsychotics. AB - Impaired brain connectivity is a hallmark of schizophrenia brain dysfunction. However, the effect of drug treatment and challenges on the dysconnectivity of functional networks in schizophrenia is an understudied area. In this review, we provide an overview of functional magnetic resonance imaging studies examining dysconnectivity in schizophrenia and discuss the few studies which have also attempted to probe connectivity changes with antipsychotic drug treatment. We conclude with a discussion of possible avenues for further investigation. PMID- 23449682 TI - Tougher action is needed on alcohol pricing, labelling, and advertisements, say experts. PMID- 23449681 TI - Study of CTX-M Type of Extended Spectrum beta-Lactamase among Nosocomial Isolates of Escherichia coli and Klebsiella pneumoniae in South India. AB - Data on CTX-M type extended-spectrum beta-lactamase (ESBL) produced by Gram negative bacteria by molecular methods are limited from India. This study was conducted to investigate the prevalence of CTX-M type ESBL producing Escherichia coli and Klebsiella pneumoniae from nosocomial isolates in a tertiary care hospital in southern India. A total of 179 clinical isolates of K. pneumoniae (n = 72) and E. coli (n = 107) were obtained in a period of 3 months and assessed for ESBL production phenotypically. Associated resistance to a panel of antibiotics and Minimum Inhibitory Concentration for 3rd generation cephalosporins was determined. Phenotypically ESBL positive isolates were subjected to PCR for blaCTX-M gene using two sets of primers for the simultaneous detection of all the five major groups of CTX-M types. All the positive isolates were then subjected to a group specific PCR to detect the prevalent group. Out of 179 isolates, 156 (87.1%) were positive for ESBL phenotypically, which includes 39.2% of K. pneumoniae and 60.8% of E. coli. All of them were examined by PCR using two primers for the presence of blaCTX-M genes. Among the 156 phenotypic positive isolates, 124 (79.4%) were positive for blaCTX-M genes, of which 45 (36.2%) were K. pneumoniae, 79 (63.7%) were E. coli. When the 124 positive clinical isolates were further tested with CTX-M group-specific primers, all were positive for the CTX-M-1 group. Our findings document evidence of the high prevalence of multidrug resistant CTX-M group 1 type ESBL among nosocomial isolates in this region. High co-resistance to other non-beta-lactam antibiotics is a major challenge for management of ESBL infections. This is alarming and calls for the judicious use of carbapenems, especially in developing countries. This has significant implications for patient management, and indicates the need for increased surveillance and for further molecular characterization of these isolates. PMID- 23449683 TI - Nine out of 10 palliative care experts would choose Liverpool care pathway for themselves. PMID- 23449684 TI - Care commissioning process is too laborious, study concludes. PMID- 23449685 TI - New workhorse flaps in hand reconstruction. AB - With the passage of time, certain hand surgery procedures are anecdotally dubbed "workhorse" techniques. These are procedures that are extremely reliable and have repeatedly demonstrated good results. However, with time, paradigms undergo shifts, and this is as true for hand surgery as any other field. In this article, we will describe the use of three new "workhorse" flaps that we have found to have reliable results in complex hand reconstruction: the pedicled radial forearm fascia flap for dorsal hand reconstruction, the free anterolateral thigh flap for mangled hand reconstruction, and the medial femoral condyle vascularized bone graft for scaphoid fracture nonunion reconstruction. PMID- 23449686 TI - Disrupted response inhibition toward facial anger cues in children with attention deficit hyperactivity disorder (ADHD): an event-related potential study. AB - This event-related potential study focused on neural correlates of inhibitory affective control in attention-deficit hyperactivity disorder (ADHD). Sixteen boys with ADHD and 16 healthy boys underwent an emotional Go/NoGo task with pictures of facial expressions from the categories anger, sadness, happiness, and neutral. The participants were instructed to execute or withhold a motor response to specific emotions. Patients relative to controls displayed a severe impairment in response inhibition toward anger cues, which was accompanied by a reduced P300 amplitude (positive voltage deflection about 300 ms after picture onset). The control group showed a P300 differentiation of the affective categories that was absent in the ADHD group. The pronounced anger-processing deficit in ADHD patients might be linked to their interpersonal difficulties and should be addressed in psychotherapy. PMID- 23449687 TI - One novel and one recurrent mutation in IGHMBP2 gene, causing severe spinal muscular atrophy respiratory distress 1 with onset soon after birth. AB - A family with 2 siblings with severe spinal muscular atrophy with respiratory distress 1 (SMARD1) was genetically proved to be caused by mutations in IGHMBP2 gene. Both patients developed progressive muscular weakness and respiratory distress and died before 6 months of age. One novel deletion, c.780delG;p.(Gln260Hisfs*24), inherited from the father and a nonsense mutation, c.1488C>A;p.(Cys496*), inherited from the mother were detected. An attempt was made to correlate the genetic-clinical data available in the literature. The clinical case presented in this study might be considered as the most severe form of spinal muscular atrophy respiratory distress 1 reported so far, presumably because of the total absence of IGHMBP2 enzyme activity. PMID- 23449688 TI - Otitis media with effusion in relation to socio economic status: a community based study. AB - Otitis media with effusion (OME) is the presence of non purulent effusion within the middle ear cleft. The symptoms of this disease are not alarming as in suppurative otitis media. The disease is common in young children. The main symptom of this disease is decreased hearing, which may sometime go unnoticed more so if the parents are not attentive. We conducted a community based study among 1,020 school children of the age group 5-10 years from schools of sub-urban areas of Dakshina Kannada district, Karnataka, to explore the relationship of OME in relation to socioeconomic status. Diagnosis of OME was done by clinical examination and tympanometry. Prevalence of OME was 4.5%. Out of 46 cases, 4% belong to upper class, 26% to upper middle class, 26% to lower middle class, 43% to upper lower class. PMID- 23449690 TI - Macronutrients during pregnancy and life-threatening respiratory syncytial virus infections in children. AB - RATIONALE: Respiratory syncytial virus (RSV) is an important cause of hospitalization and death in infants worldwide. Most RSV deaths occur in developing countries, where burden and risk factors for life-threatening illness are unclear. OBJECTIVES: We defined the burden of life-threatening (O(2) saturation [O(2) sat] <= 87%) and fatal RSV infection, and characterized risk factors for life-threatening disease in hospitalized children. Special emphasis was placed on studying the impact of dietary habits during pregnancy. We hypothesized that dietary preferences, differing from those of our remote ancestors, would negatively impact children's pulmonary health. For instance, a diet rich in carbohydrates is a signature of recent millennia and typical of low income populations, heavily burdened by life-threatening RSV disease. METHODS: Prospective study in a catchment population of 56,560 children under 2 years of age during the RSV season in Argentina. All children with respiratory signs and O(2) sat less than 93% on admission were included. MEASUREMENTS AND MAIN RESULTS: Among 1,293 children with respiratory infections, 797(61.6%) were infected with RSV: 106 of these had life-threatening disease; 1.9 per 1,000 children (95% confidence interval [CI], 1.5-2.2/1,000) under 24 months. A total of 22 hospitalized children died (9 RSV(+)), 26 died at home due to acute respiratory infection (14 attributed to RSV); all were under 12 months old. The annual attributable mortality rate for RSV was 0.7 per 1,000 infants (95% CI, 0.4 1.1/1,000). Life-threatening disease was dose-dependently associated with carbohydrate ingestion during pregnancy (adjusted odds ratio from 3.29 [95% CI, 1.15-9.44] to 7.36 [95% CI, 2.41-22.5] versus the lowest quartile). CONCLUSIONS: Life-threatening and fatal RSV infections are a heavy burden on infants in the developing world. Diets rich in carbohydrates during pregnancy are associated with these severe outcomes. PMID- 23449689 TI - PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown. OBJECTIVES: We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH. METHODS: Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia+Sugen-5416 (CH+SU) PAH. The effects of adenoviral mitofusin-2 (Ad MFN2) overexpression were measured in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1alpha; conversely, siPGC1alpha reduced PGC1alpha and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1alpha were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381 +/- 35 vs. 245 +/- 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 +/- 0.02 vs. 0.38 +/- 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 +/- 0.8 vs. 19 +/- 1.7%; P < 0.05). Lung vascularity was increased by MFN2. CONCLUSIONS: Decreased expression of MFN2 and PGC1alpha contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH. PMID- 23449691 TI - Nonlinear exercise training in advanced chronic obstructive pulmonary disease is superior to traditional exercise training. A randomized trial. AB - RATIONALE: The optimal exercise training intensity and strategy for individualized exercise training in chronic obstructive pulmonary disease (COPD) is not clear. OBJECTIVES: This study compares the effects of nonlinear periodized exercise (NLPE) training used in athletes to traditional endurance and progressive resistance (EPR) training in patients with severe COPD. METHODS: A total of 110 patients with severe COPD (FEV1 32% predicted) were randomized to EPR or NLPE. Exercise training was performed three times per week for 10 weeks. The primary outcomes were cycling endurance time and health-related quality of life using the Chronic Respiratory Questionnaire. The difference in change between EPR and NLPE was assessed using linear mixed-effects modeling. MEASUREMENTS AND MAIN RESULTS: NLPE resulted in significantly greater improvements in cycling endurance time compared with EPR. The difference in change was +300.6 seconds (95% confidence interval [CI] = 197.2-404.2 s; P < 0.001). NLPE also resulted in significantly greater improvements in all domains of the Chronic Respiratory Questionnaire compared with EPR, ranging from +0.48 (95% CI = 0.19-0.78) for the domain, emotions, to +0.96 (95% CI = 0.57-1.35) for dyspnea. CONCLUSIONS: NLPE results in greater improvements in cycle endurance and health-related quality of life in patients with severe COPD than traditional training methods. Clinical trial registered with www.trialregister.nl (The Netherlands Trial Register; NTR 1045). PMID- 23449694 TI - The Paralympic effect on amputees' legal claims for prosthetics: demand for newer technology may be costly but offset by improved function in the future. PMID- 23449692 TI - Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB. AB - RATIONALE: Helper CD4(+) T cell subsets, including IL-9- and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation. OBJECTIVES: To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation. METHODS: COX-1(-/-), COX-2(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. MEASUREMENTS AND MAIN RESULTS: Experimental endpoints were not different between COX-1(-/-) and WT mice; however, the percentage of IL-9(+) CD4(+) T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2(-/-) mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD2 and PGE2, which also reduced Th9 cell differentiation of murine and human naive CD4(+) T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4(+) T cells isolated from WT mice in vitro. CONCLUSIONS: COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A dependent mechanism. PMID- 23449695 TI - Roche says it will not relinquish control over access to clinical trial data. PMID- 23449696 TI - Thousands of medical students in "unacceptable" situation after foundation school allocation error. PMID- 23449693 TI - IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. AB - RATIONALE: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. OBJECTIVES: To identify genetic risk variants for ARDS using large scale genotyping. METHODS: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 * 10(-4) for replication in stage II, a trauma case-control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS associated genotype and plasma protein levels. MEASUREMENTS AND MAIN RESULTS: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 * 10( 5)). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN. CONCLUSIONS: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk. PMID- 23449697 TI - Chemical mapping of DNA and counter-ion content inside phage by energy-filtered TEM. AB - Double-stranded DNA in many bacterial viruses (phage) is strongly confined, which results in internal genome pressures of tens of atmospheres. This pressure is strongly dependent on local ion concentration and distribution within the viral capsid. Here, we have used electron energy loss spectroscopy (EELS), energy filtered TEM (EFTEM) and X-ray energy dispersive spectroscopy to provide such chemical information from the capsid and the phage tail through which DNA is injected into the cell. To achieve this, we have developed a method to prepare thin monolayers of self-supporting virus/buffer films, suitable for EELS and EFTEM analysis. The method is based on entrapment of virus particles at air liquid interfaces; thus, the commonly used method of staining by heavy metal salts can be avoided, eliminating the risk for chemical artifacts. We found that Mg(2 + ) concentration was approximately 2-4 times higher in the DNA-filled capsid than in the surrounding TM buffer (containing 10 mM Mg(2 + )). Furthermore, we also analyzed the DNA content inside the phage tail by mapping phosphorus and magnesium. PMID- 23449698 TI - The Kidney Disease Improving Global Outcomes (KDIGO) guideline update for chronic kidney disease: evolution not revolution. PMID- 23449699 TI - Increased prolactin concentrations in a patient with bipolar disorder. PMID- 23449700 TI - Commentary. PMID- 23449701 TI - Commentary. PMID- 23449702 TI - Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers' blood on per se drugged driving laws. AB - BACKGROUND: Cannabis is the illicit drug most frequently reported with impaired driving and motor vehicle accidents. Some "per se" laws make it illegal to drive with any amount of drug in the body, while others establish blood, saliva, or urine concentrations above which it is illegal to drive. The persistence of Delta(9)-tetrahydrocannabinol (THC) in chronic daily cannabis smokers' blood is unknown. METHODS: Thirty male chronic daily cannabis smokers resided on a secure research unit for up to 33 days, with daily blood collection. Samples were processed in an ice bath during sample preparation to minimize cannabinoid adsorption onto precipitant material. We quantified THC by 2-dimensional GC-MS. RESULTS: Of the 30 participants, 27 were THC-positive on admission, with a median (range) concentration of 1.4 MUg/L (0.3-6.3). THC decreased gradually; only 1 of 11 participants was negative at 26 days, 2 of 5 remained THC-positive (0.3 MUg/L) for 30 days, and 5.0% of participants had THC >= 1.0 MUg/L for 12 days. Median 11 hydroxy-THC concentrations were 1.1 MUg/L on admission, with no results >= 1.0 MUg/L 24 h later. 11-Nor-9-carboxy-THC (THCCOOH) detection rates were 96.7% on admission, decreasing slowly to 95.7% and 85.7% on days 8 and 22, respectively; 4 of 5 participants remained THCCOOH positive (0.6-2.7 MUg/L) after 30 days, and 1 remained positive on discharge at 33 days. CONCLUSIONS: Cannabinoids can be detected in blood of chronic daily cannabis smokers during a month of sustained abstinence. This is consistent with the time course of persisting neurocognitive impairment reported in recent studies. PMID- 23449703 TI - Implications of adjustment of high-sensitivity cardiac troponin T assay. PMID- 23449704 TI - Implications of adjustment of high-sensitivity cardiac troponin T assay. PMID- 23449705 TI - Implications of adjustment of high-sensitivity cardiac troponin T assay. PMID- 23449706 TI - Disparate hemoglobin results. PMID- 23449708 TI - Will coffee rings find a place in the laboratory? PMID- 23449711 TI - The three worlds enabled by optics. PMID- 23449712 TI - Zoon vulvitis as a differential diagnosis in an HIV-infected patient: a short report. AB - Vulvitis circumscripta plasmacellularis or Zoon vulvitis is a rare benign condition that affects the vulva chronically. We herein report a case of Zoon vulvitis in a 52-year-old HIV-infected patient with an uncommon ulcerovegetating lesion diagnosed by histopathologic findings. The patient was treated with clobetasol propionate ointment and oral corticosteroid. Zoon vulvitisis is a rare vulvar disorder that offers a challenging diagnose and therapy. The patient was appropriately treated and remains disease free. PMID- 23449713 TI - Considerations on the new nevirapine: switching patients from twice-daily to once daily. AB - Nevirapine (NVP) was the first nonnucleoside reverse transcriptase inhibitor (NNRTI) approved for the treatment of HIV infection. NVP can provide safe and efficacious viral suppression for treatment-naive patients and for virologically controlled patients "switching" from other NNRTI or protease inhibitor-based regimens. Formulations allowing once-daily dosing of antiretrovirals can significantly improve regimen adherence, which is important for maintaining virologic control, especially for NNRTI-based regimens with low barriers for genetic resistance. Randomized and controlled clinical trials have established the clinical non inferiority of a new, extended-release formulation (XR) of NVP, in both treatment-naive (VERxVE) and treatment-experienced patients (TRANxITION), where patients already stable on the immediate-release formulation of NVP were safely transitioned directly to NVP XR. As a potentially more convenient once daily option, NVP XR may improve adherence and reduce the risk of mutant viruses, attendant virologic failure, and the spread of drug resistance. PMID- 23449714 TI - Oscillopsia and the influence of stress and motivation in fusion maldevelopment nystagmus syndrome. AB - PURPOSE: We examined factors influencing perceptual stability in observers with fusion maldevelopment nystagmus syndrome (FMNS). In addition, we also investigated the effect of visual demand, task-related physiologic stress, and motivation on the nystagmus waveform. METHODS: Perception of oscillopsia during daily activities was assessed via a questionnaire. Perception of oscillopsia in the laboratory was assessed using central and peripheral (10 degrees ) light emitting diodes (LEDs) in front of a background display of random, fixed-contrast shapes. Task-induced stress was achieved via a time restricted acuity task with or without concurrent mental arithmetic challenge, and motivation varied using a reward-penalty paradigm. The experiments have been previously described elsewhere. RESULTS: Six out of nine subjects reported experiencing oscillopsia in certain daily activities. in the laboratory, the percentages of trials with perceptions of motion of the led and background were as follows: neither, 60% to 70%; background only, 20% to 30%; both, 5% to 15%, and LED only, 5% to 15%. Over all trials, six of nine experienced oscillopsia for both the low- and high contrast image respectively (i.e., three subjects never experienced oscillopsia). The background was frequently seen moving for both images regardless of contrast and/or condition. Trials with and without oscillopsia did not differ when comparing foveation. In the second experiment, task-related physiologic stress and motivation were reflected in an increase in heart rate; nystagmus waveform intensity increased and foveation decreased. The magnitude of changes in heart rate was uncorrelated with changes in waveform parameters for all experiments, however. CONCLUSIONS: Preliminary results suggest that the FMNS group does perceive spatially inhomogeneous oscillopsia, similar to infantile nystagmus syndrome (INS), in certain visual environments. In investigating the effect of stress and motivation on FMNS, a new, if tentative, finding suggests that task induced stress and/or motivation may have a negative impact on the nystagmus. Taken together, our findings provide an insight into the particular environments and tasks that are likely to present particular challenges to persons with FMNS. PMID- 23449715 TI - Enrichment of retinal ganglion cells in rat retinal lysate by excimer laser ablation of the outer retina. AB - PURPOSE: Retinal ganglion cells (RGC) are a relatively small cell population in the retina. This leads to an unfavorable signal-to-noise ratio when analyzing RGC proteins in whole retina lysate. We present a novel technique to obtain RGC enriched rat retinal lysate by removing the outer retinal layers with an excimer laser before lysation. METHODS: Outer retinal layers were ablated with an excimer laser on flat mounted retinas from adult albino rats. 4'6-Diamidino-2 phenylindole dihydrochloride hydrate (DAPI) nuclear staining was used to assess the ablation efficacy (n = 6). Western blot for layer specific markers (rhodopsin, parvalbumin, beta-III-tubulin) was performed to quantify changes in protein composition (n = 7). Excimer-ablated (EX) and full-thickness (FT) retinas 48 hours after optic nerve crush (ONC) were compared regarding the effect on phospho-cAMP response element binding protein (pCREB) and Thy1 levels (n = 5). RESULTS: Area quantification of dapi-stained retinas showed that 73% 4.9% of the ablation area was free of photoreceptor and bipolar cell nuclei. In Western blot, laser ablation led to a significant reduction of the photoreceptor marker rhodopsin and increase of the ganglion cell layer (GCL) marker -iiitubulin (relative quantity: rhodopsin 0.47 +/- 0.05, P < 0.0001; beta-III-tubulin 2.35 +/ 0.37, P = 0.02). Changes of pCREB and Thy1 after ONC were significantly different between FT and EX retinas (relative quantity pCREB: FT 1.4 +/- 0.16, EX 0.78 +/- 0.07, P = 0.008; Thy1: FT 0.95 +/- 0.02, EX 0.63 +/- 0.07, P = 0.006). CONCLUSIONS: We demonstrated that excimer laser ablation of outer retinal layers is feasible, producing RGC-enriched retinal lysate. Laser ablation may allow a more specific detection of RGC responses to experimental stimuli. PMID- 23449716 TI - Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of retinopathy of prematurity. AB - PURPOSE: Inhibiting VEGF improves adult retino/choroido-vascular diseases, but can lead to recurrent intravitreous neovascularization (IVNV), avascular retina (AVA), and retinal detachment in preterm infants with retinopathy of prematurity (ROP). We sought to understand causes of late-onset IVNV and AVA following anti VEGF using an ROP model. METHODS: In the Penn model of ROP, postnatal day (p)12 pups received 1 MUL intravitreal VEGFA164 antibody (anti-VEGF; 25-100 ng) or IgG control in each eye. Analyses included lectin-stained percent IVNV and AVA; VEGF protein, erythropoietin, phosphorylated extracellular signal-related kinases and signal transducer and activator of transcription-3 (p-STAT3); and immunohistochemistry of retinal sections for p-VEGFR2. Western blots of human retinal microvascular endothelial cells (hRMVECs) stimulated with VEGF or erythropoietin were analyzed for p-STAT3. Statistical analysis was performed with one-way ANOVA or two-tailed t-tests. RESULTS: At p18, 50 ng anti-VEGF reduced IVNV, and at p25, caused increased IVNV and AVA compared with controls. VEGF and p-VEGFR2 labeling increased following 100 ng anti-VEGF. Following 50 ng anti VEGF, reduced p-STAT3 and increased erythropoietin occurred at p18. Erythropoietin or VEGF stimulated hRMVEC proliferation and STAT3 activation. In vivo, anti-VEGF reduced pup growth. CONCLUSIONS: Increases in erythropoietin and angiogenic signaling following anti-VEGF may account for recurrent IVNV. Anti VEGF reduced pup growth. Research is needed regarding safety, dose, and type of antiangiogenic treatment for ROP. PMID- 23449717 TI - Different intravitreal properties of three triamcinolone formulations and their possible impact on retina practice. AB - PURPOSE: We sought to better characterize the intravitreal profile of different triamcinolone formulations. METHODS: The study was performed in vitro and in vivo. Kenalog-40, Triesence, and Transton were characterized for ocular pharmacokinetics, particle size, crystallinity, and dissolving kinetics in vitreous following an intravitreal injection into 12 rabbit eyes. The relationship of free drug levels in the aqueous and vitreous was investigated through a dual-probe microdialysis and liquid chromatography tandem mass spectrometry. RESULTS: Triesence had the most uniform particle size distribution (mean 11.51 MUm) and Kenalog-40 had the largest particle sizes (mean 18.86 MUm). Triesence and Kenalog-40 had 100% crystallinity, while Transton had 89% crystallinity. Triesence had a slower dissolution in vitreous than that of Kenalog-40, and Transton had the fastest dissolution, though their solubility was very similar. Following a 1.2 mg intravitreal injection in the rabbit eye, Triesence had a significantly lower ocular free drug level than Kenolog-40 (P = 0.025) and Transton (P = 0.007). Quantitative dual-probe microdialysis revealed that the aqueous free triamcinolone (Kenolog-40) was less than 1% of the vitreous free triamcinolone during the first few hours, and this percentage increased to 26.8% at 2 weeks and was 11.7% at 3 weeks following an intravitreal injection. CONCLUSIONS: Triesence demonstrated a significantly slower dissolution profile and lower free drug level in the vitreous than the other preserved triamcinolone, which may translate into a longer therapeutic duration and lower rate of drug associated complications. PMID- 23449718 TI - Mutations in CRB1 are a relatively common cause of autosomal recessive early onset retinal degeneration in the Israeli and Palestinian populations. AB - PURPOSE: We evaluated the role of Crumbs homolog 1 (CRB1) in autosomal recessive (AR) retinal diseases in the Israeli and Palestinian populations using homozygosity mapping. METHODS: Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays and mutation analysis of CRB1. RESULTS: We recruited over 400 families with AR nonsyndromic retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). SNP array analysis was performed on 175 index cases, eight of whom carried a homozygous region on chromosome 1 harboring CRB1. A subsequent CRB1 mutation analysis of the eight families, followed by screening of candidate founder mutations in the whole cohort of patients, revealed a total of 13 mutations, six of which are novel, in 15 families. Nine mutations were family-specific, and four were founder mutations identified in patients of Arab-Muslim origin, and Jews originated from Iraq and Kurdistan. Interestingly, a null mutation on at least one of the two mutated CRB1 alleles results in the LCA diagnosis, whereas patients carrying missense mutations were diagnosed with either RP or LCA. The average age at which CRB1 patients were referred to ERG testing was young (11 years). Of the 30 identified CRB1 patients, five had Coats-like exudative vasculopathy. CONCLUSIONS: Our data show that CRB1 mutations are a relatively frequent cause of AR early-onset retinal degeneration in the Israeli and Palestinian populations (10% of LCA families), and causes severe retinal degeneration at an early age. PMID- 23449719 TI - Differential gene expression profiling after conditional Muller-cell ablation in a novel transgenic model. AB - PURPOSE: Muller cells, the principal glial cells in the mammalian retina, play an important role in the maintenance of retinal homeostasis. Recent reports suggest that Muller-cell dysfunction may contribute to the pathogenesis of retinal diseases such as idiopathic macular telangiectasia type 2. In the present study, we used microarray to compare retinae isolated from transgenic mice in which the Muller cells of adult mice retinae can be selectively ablated with control mice. METHODS: Retinae were isolated 1 week, 1 month, and 3 months after tamoxifen induced selective Muller-cell ablation and microarray were performed with Affymatrix microarrays. Differentially expressed (DE) genes, temporal trends of DE genes, and pathway analysis were conducted. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the results. RESULTS: Strong upregulation of mRNA of proteins involved in gliosis, apoptosis, and neurotrophism was found 1 week after ablation and their related pathways such as the apoptotic and Jak/Stat pathways were identified. Three months after induced Muller-cell ablation, Muller-cell metabolic pathways and vasculopathy-related pathways such as genes involved in glycolysis and tight junctions were downregulated. qRT-PCR analysis showed consistent expression trends of selected genes. CONCLUSIONS: The results were generally consistent with the previous morphologic findings in this model, in which photoreceptor degeneration soon after Muller-cell ablation, accompanied by blood-retinal barrier breakdown and subsequent retinal neovascularization were reported. These results are consistent with a significant contribution of Muller-cell dysfunction on retinal neuronal injury and vascular pathology at the mRNA level. PMID- 23449720 TI - The effects of macular ischemia on visual acuity in diabetic retinopathy. AB - PURPOSE: To investigate the impact of diabetic macular ischemia (DMI) on visual acuity (VA), through the analysis of novel fluorescein angiography (FA) parameters. METHODS: Data were retrospectively collected over a 6-month period. DMI severity was graded using Early Treatment Diabetic Retinopathy Study (ETDRS) protocols. Custom software was used to quantify areas of the foveal avascular zone (FAZ), and of capillary nonperfusion over the papillo-macular nerve fiber layer bundle, and temporal macula, and associations tested with VA. RESULTS: A total of 488 patients with type 2 diabetes mellitus and FAs of sufficient quality to allow detailed quantitative analyses were included. ETDRS-DMI SEVerity was graded as: none, 39.7%; questionable, 18.4%; mild, 25.2%; moderate, 11.0%; and severe, 5.6%. Median FAZ areas were 0.19 mm(2) (interquartile range [IQR], 0.13 0.25); 0.25 mm(2) (IQR, 0.18-0.32); 0.27 mm(2) (IQR, 0.19-0.38); 0.32 mm(2) (IQR, 0.25-0.54); and 0.78 mm(2) (IQR, 0.60-1.32), respectively, and were significantly different between all grades (P < 0.002), apart from "questionable" versus "mild" grades. Significant association of VA to FAZ area was observed only in the moderate (beta = 0.406, SE = 0.101, P = 0.001) and severe (beta = 0.299, SE = 0.108, P = 0.006) subgroups, but not in milder ETDRS-DMI grades. A strong association with VA was observed in cases with papillomacular ischemia (beta = 1.123, SE = 0.355, P = 0.005), independent of FAZ size or the presence of macular edema. CONCLUSIONS: Diabetic macular ischemia is associated with reduced VA in eyes with moderate to severe ETDRS-DMI grades of ischemia but preserved in milder grades. In addition, we describe the independent association of papillomacular nerve fiber bundle ischemia with reduced VA. PMID- 23449721 TI - Endothelial cell whole genome expression analysis in a mouse model of early-onset Fuchs' endothelial corneal dystrophy. AB - PURPOSE: To investigate the endothelial gene expression profile in a Col8a2 Q455K mutant knock-in mouse model of early-onset Fuchs' endothelial corneal dystrophy (FECD) and identify potential targets that can be correlated to human late-onset FECD. METHODS: Diseased or normal endothelial phenotypes were verified in 12 month-old homozygous Col8a2(Q455K/Q455K) mutant and wild-type mice by clinical confocal microscopy. An endothelial whole genome expression profile was generated by microarray-based analysis. Result validation was performed by real-time PCR. Endothelial COX2 and JUN expression was further studied in human late-onset FECD compared to normal samples. RESULTS: Microarray analysis demonstrated endothelial expression of 24,538 genes (162 up-regulated and 172 down-regulated targets) and identified affected gene ontology terms including Response to Stress, Protein Metabolic Process, Protein Folding, Regulation of Apoptosis, and Transporter Activity. Real-time PCR assessment confirmed increased Cox2 (P = 0.001) and Jun mRNA (P = 0.03) levels in Col8a2(Q455K/Q455K) mutant compared to wild-type mice. In human FECD samples, real-time PCR demonstrated a statistically significant increase in COX2 mRNA (P < 0.0001) and JUN mRNA (P = 0.002) and tissue microarray analysis showed increased endothelial COX2 (P = 0.02) and JUN protein (P = 0.04). CONCLUSIONS: The present study provides the first endothelial whole genome expression analysis in an animal model of FECD and represents a useful resource for future studies of the disease. In particular endothelial COX2 up-regulation warrants further investigation of its role in FECD. PMID- 23449723 TI - Enhancement of lamina cribrosa visibility in optical coherence tomography images using adaptive compensation. AB - PURPOSE: We improved the visibility of the lamina cribrosa (LC), including its posterior boundary, in optical coherence tomography (OCT) images of the human optic nerve head (ONH). METHODS: An adaptive compensation algorithm was developed to overcome a limitation of our standard compensation algorithm, that is the overamplification of noise at high depth. Such limitation currently hampers our ability to distinguish the posterior LC boundary. In adaptive compensation, standard compensation operations are performed until an energy threshold is reached, at which stage the compensation process is stopped to limit noise overamplification in the deeper portion of the OCT image. The performance of adaptive compensation was compared to that of standard compensation using OCT images of 5 human ONHs. RESULTS: Adaptive compensation significantly reduced the intralayer contrast (a measure of pixel intensity uniformity) in the deeper portion of the OCT images (from 0.62 +/- 0.11-0.30 +/- 0.03, P < 0.001), indicating successful removal of noise overamplification. Furthermore, adaptive compensation significantly increased the interlayer contrast (a measure of boundary visibility) across the posterior LC boundary (from 0.29 +/- 0.13-0.61 +/ 0.21, P < 0.001), indicating improved posterior LC boundary visibility. CONCLUSIONS: Adaptive compensation provided significant improvement compared to standard compensation by eliminating noise overamplification at high depth and improving the visibility of the posterior LC boundary. These improvements were performed while maintaining all other benefits of compensation, such as shadow removal and contrast enhancement. Adaptive compensation will help further our efforts to characterize in vivo ONH biomechanics for the diagnosis and monitoring of glaucoma. PMID- 23449722 TI - Photosensitized oxidative stress to ARPE-19 cells decreases protein receptors that mediate photoreceptor outer segment phagocytosis. AB - PURPOSE: To determine whether previously shown photodynamic (PD)-induced inhibition of specific photoreceptor outer segment (POS) phagocytosis by ARPE-19 cells is associated with reductions in receptor proteins mediating POS phagocytosis, and if PD treatment with merocyanine-540 (MC-540) produces additional effects leading to its inhibition of nonspecific phagocytosis. METHODS: ARPE-19 cells preloaded with MC-540 or rose bengal (RB) were sublethally irradiated with green light. Phagocytosis of POS was measured by flow cytometry and POS receptor proteins (Mer tyrosine kinase receptor [MerTK] and integrin subunits alphav and beta5) and beta-actin were quantified by Western blotting at 0.5 and 24 hours after irradiation, with comparison to samples from nonsensitized control cultures. The intact integrin heterodimer alphavbeta5 was quantified by immunoprecipitation followed by blotting. The distribution of N-cadherin, ZO-1, and F-actin was visualized by fluorescence microscopy. RESULTS: Mild PD stress mediated by both photosensitizers that elicits no significant morphologic changes produces transient and recoverable reductions in MerTK. The individual alphav and beta5 integrin subunits are also reduced but only partially recover. However, there is sufficient recovery to support full recovery of the functional heterodimer. Light stress mediated by MC-540 also reduced levels of actin, which is known to participate in the internalization of particles regardless of type. CONCLUSIONS: After PD treatment POS receptor protein abundance and phagocytosis show a coincident in time reduction then recovery suggesting that diminution in receptor proteins contributes to the phagocytic defect. The additional inhibition of nonspecific phagocytosis by MC-540-mediated stress may result from more widespread effects on cytosolic proteins. The data imply that phagocytosis receptors in RPE cells are sensitive to oxidative modification, raising the possibility that chronic oxidative stress in situ may reduce the efficiency of the RPE's role in photoreceptor turnover, thereby contributing to retinal degenerations. PMID- 23449724 TI - P2X7 receptor activation mediates retinal ganglion cell death in a human retina model of ischemic neurodegeneration. AB - PURPOSE: There is evidence implicating ischemia and excitotoxicity in the pathogenesis of glaucoma. ATP-mediated excitotoxicity via activation of the P2X7 receptor (P2X7R) has been proposed to play a role in retinal ganglion cell (RGC) degeneration in this disease. The aim of this research was to determine whether stimulation of the P2X7R mediated ischemia-induced RGC death in the human retina. METHODS: Human organotypic retinal cultures were exposed to the P2X7R agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) and simulated ischemia (oxygen/glucose deprivation) in the presence or absence of the P2X7R antagonist, Brilliant Blue G (BBG). Neuronal death in the RGC layer was quantified by neuronal nuclei (NeuN) positive cell counts and quantitative real-time PCR for THY-1 mRNA. The P2X7R was localized by immunohistochemistry and P2X7R mRNA profiling using a cryosectioning technique. RESULTS: P2X7R stimulation by BzATP (100 MUM) induced loss of RGC markers in human organotypic retinal cultures (HORCs), which was inhibited by BBG (1 MUM). Simulated ischemia led to loss of RGCs that was also inhibited by BBG, indicating that ischemia-induced RGC degeneration was mediated by the P2X7R. The P2X7R was immunolocalized to the outer and inner plexiform layers of the human retina, and P2X7R mRNA expression was confirmed in the inner retina and ganglion cell layer. CONCLUSIONS: These studies demonstrated that stimulation of the P2X7R can mediate RGC death and that this mechanism plays a role in ischemia-induced neurodegeneration in the human retina. PMID- 23449725 TI - Infantile osteomyelitis secondary to malignant osteopetrosis. AB - Osteopetrosis (OP) is a rare congenital disorder (present at birth) in which the bones become over dense. This results from an imbalance between the formation of bone and the resorption of the bone. Thickening of the bones which become abnormally dense due to an inherited defect in bone resorption, the process in which old bone is broken down and removed so that new bone can be added to the skeleton. Osteoclasts are the cells responsible for bone resorption. In osteopetrosis the osteoclasts do not perform normally. This flaw in bone resorption results in bones that are abnormally dense, yet are fragile and easily broken. Osteopetrosis is also known as Albers-Schonberg disease, generalized congenital osteosclerosis, ivory bones, marble bones, osteosclerosis fragilis generalisata. In this article, we have described about the diagnosis and medical and surgical management of osteopetrosis reported case to our hospital. PMID- 23449726 TI - Thyroglossal duct cysts: Two cases. AB - Thyroglossal duct cyst is the most common congenital neck mass in children and young adults. The authors present two cases affecting two patients aged 7 and 9 years, respectively, who had a palpable painless swelling in the submental region. In both patients ultrasound (US) examination showed an anechoic or hypoechoic rounded mass with well-defined margins thus confirming clinical suspicion of thyroglossal duct cyst. One patient also had a second, deep-lying, nonpalpaple cyst which communicated with the superficial cyst. These cases are typical and confirm that US is essential in suspected thyroglossal duct cyst to confirm clinical diagnosis, detect lesions which are not clinically appreciable due to their small size or deep location, to assess communication between the lesions and to detect possible complications. PMID- 23449727 TI - Comorbidity between reading disability and math disability: concurrent psychopathology, functional impairment, and neuropsychological functioning. AB - Reading disability (RD) and math disability (MD) frequently co-occur, but the etiology of this comorbidity is not well understood. Groups with RD only (N = 241), MD only (N = 183), and RD + MD (N = 188) and a control group with neither disorder (N = 411) completed a battery of measures of internalizing and externalizing psychopathology, social and academic functioning, and 10 neuropsychological processes. Groups with RD only, MD only, and RD + MD were significantly impaired versus the control group on nearly all measures, and the group with RD + MD was more impaired than the groups with MD and RD alone on measures of internalizing psychopathology, academic functioning, and 7 of 10 neuropsychological constructs. Multiple regression analyses of the neuropsychological measures indicated that deficits in reading and math were associated with shared weaknesses in working memory, processing speed, and verbal comprehension. In contrast, reading difficulties were uniquely associated with weaknesses in phoneme awareness and naming speed, and math deficits were uniquely associated with weaknesses in set shifting. These results support multiple deficit neuropsychological models of RD and MD and suggest that RD and MD are distinct but related disorders that co-occur because of shared neuropsychological weaknesses in working memory, processing speed, and verbal comprehension. PMID- 23449728 TI - Growth in rapid automatized naming from grades K to 8 in children with math or reading disabilities. AB - Rapid automatized naming (RAN) is widely used to identify reading disabilities (RD) and has recently been considered a potential predictor of risk for mathematics learning disabilities (MLD). Here we longitudinally examine RAN performance from Grades K to 8, to view how growth on RAN response time differs for children with RD versus MLD. Across all participants, there was significant stability of RAN performance for all three subtests. For all three subtests, there was significant between-child variability in response times (RTs) at kindergarten and Grade 8; for select combinations of subtests, there was also between-child variability in difference scores over time. Relative to typically achieving peers, children with MLD or RD were slower on all three subtests at kindergarten, but these deficits were most pronounced for children with MLD versus RD at kindergarten and more persistent through Grade 8 for children with RD. RAN numbers and letters performance was closely related in the RD group, more so than in the MLD group, despite deficits on both subtests across groups. Our findings indicate that empirically guided modifications of RAN are needed for extending its use for evaluating risk for MLD. PMID- 23449729 TI - PepT1 mRNA expression levels in sea bream (Sparus aurata) fed different plant protein sources. AB - The expression and regulation of intestinal oligopeptide transporter (PepT)-1 when vegetable sources are used as a substitute for fish meal in the diet of marine fish has not yet been explored. In the present study, as part of our ongoing work on elucidating PepT1 gene expression in relation to different dietary treatments, we have now isolated and deposited in Genbank database (accession no. GU733710) a cDNA sequence representing the PepT1 in the sea bream (Sparus aurata). The "de novo" prediction of the three-dimensional structure of PepT1 protein is presented.We also analyzed diet-induced changes in the expression of PepT1 mRNA via real-time RT-PCR using the standard curve method. Sea bream were fed for 140 days with one of the following four diet formulations (43% protein/21% lipid): a control fast growth-promoting diet (C), and three diets with the same formulation but in which 15% of the fish meal was substituted by protein concentrates either from lupine (LPC), chick pea (CPC), or green pea (PPC). Fish fed PPC had significantly (p < 0.05) lower levels of PepT1 transcripts in the proximal intestine than the controls, whereas PepT1 transcript levels in fish fed LPC or CPC were not significantly different from the controls. Although growth was similar between fish fed with different diets during the first 72 days of feeding, growth of the fish fed with PPC was reduced during the second part of the trial and was significantly (p < 0.05) lower than fish fed LPC and CPC diets by the end of the experiment. Correlation between these results and fish growth performances highlights that the intestinal PepT1 mRNA level may serve as a useful marker of the dietary protein quality and absorption efficiency. PMID- 23449730 TI - The effect of natamycin on the transcriptome of conidia of Aspergillus niger. AB - The impact of natamycin on Aspergillus niger was analysed during the first 8 h of germination of conidia. Polarisation, germ tube formation, and mitosis were inhibited in the presence of 3 and 10 MUM of the anti-fungal compound, while at 10 MUM also isotropic growth was affected. Natamycin did not have an effect on the decrease of microviscosity during germination and the concomitant reduction in mannitol and trehalose levels. However, it did abolish the increase of intracellular levels of glycerol and glucose during the 8 h period of germination.Natamycin hardly affected the changes that occur in the RNA profile during the first 2 h of germination. During this time period, genes related to transcription, protein synthesis, energy and cell cycle and DNA processing were particularly up-regulated. Differential expression of 280 and 2586 genes was observed when 8 h old germlings were compared with conidia that had been exposed to 3 MUM and 10 MUM natamycin, respectively. For instance, genes involved in ergosterol biosynthesis were down-regulated. On the other hand, genes involved in endocytosis and the metabolism of compatible solutes, and genes encoding protective proteins were up-regulated in natamycin treated conidia. PMID- 23449731 TI - Effects of stressor predictability on escape learning and sleep in mice. AB - STUDY OBJECTIVES: Controllable stress, modeled by escapable shock (ES), can produce significant alterations in post-stress sleep, including increased rapid eye movement (REM) sleep. Recent work has demonstrated that post-stress sleep may be influenced by stressor predictability, modeled by predictive auditory cues. In this study, we trained mice with ES, either signaled (SES) or unsignaled (UES) by auditory cues, and investigated the effects of predictability on escape learning and sleep associated with ES. DESIGN: Adult male BALB/cJ mice were implanted for recording electroencephalography and activity via telemetry. After the mice recovered from surgery, baseline sleep recordings were obtained. The mice were then randomly assigned to SES and UES conditions. Both groups had control over the duration of footshocks (0.5 mA; 5.0 sec maximum duration) by moving to the non-occupied chamber in a shuttlebox. SES mice were presented tones (90 dB, 2 kHz, 10 sec maximum duration) that started 5.0 sec prior to and co-terminated with footshocks. UES mice were presented identical tones that were not synchronized to shock presentation. ES training continued for 2 consecutive days (EST1 and EST2) with 20 footshock presentations (1 min inter-stimulus intervals). Seven days after EST2, the animals were re-exposed to the training chamber (context) alone for 30 min. MEASUREMENTS AND RESULTS: Escape latency was used to determine successful or unsuccessful escape learning. Sleep was scored for 20 h for baseline and on each treatment day. Freezing in the training context was scored as a behavioral index of fear. Nine of 14 SES mice successfully learned escape (SESl), and 5 failed to learn escape (SESf). Compared with baseline, SESl mice, but not SESf mice, showed significantly increased post-shock REM. All UES mice learned escape and showed enhanced post-shock REM. Freezing and sleep did not differ among groups on the context re-exposure day. CONCLUSIONS: The results indicate that information available in a stressful situation can affect an animal's ability to learn an appropriate response and post-stress sleep. CITATION: Machida M; Yang L; Wellman LL; Sanford LD. Effects of stressor predictability on escape learning and sleep in mice. SLEEP 2013;36(3):421-430. PMID- 23449732 TI - Personal technique for primary repair of alveolar clefts. AB - From 1969, the senior author (H.B.) has developed a technique for the repair of alveolar clefts during primary cheiloplasty at patient age of 3 months. The operation used palatally hinged mucoperiosteal flaps from the edges of the cleft to reconstruct the posterior and inferior walls of the alveolar box. The roof was reconstructed by repairing the nasal floor, and the anterior wall was reconstructed using a buccal mucosal flap from the undersurface of the lateral lip segment. Fourteen operated patients were selected to scientifically follow the long-term results of the technique. The results indicated restoration of the arch form, varying degrees of ossification in the repaired alveolar box, and eruption of canines through the repaired alveolus. One case of anterior cross bite was observed in these selected cases. However, a limited cross-bite was present at the site of the repaired cleft in many cases. PMID- 23449733 TI - Acute disseminated encephalomyelitis in two renal transplant patients: is there a role for Epstein-Barr virus reactivation? AB - Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory demyelinating disease of the central nervous system, usually occurring after a vaccination or infectious disease. It has been exceptionally described in transplanted patients. The pathophysiology remains incompletely understood. We report the clinical, biological and magnetic resonance imaging (MRI) presentation and evolution of two kidney-transplanted patients with ADEM associated with local Epstein-Barr virus (EBV) reactivation. ADEM may occur in transplanted patients with favorable evolution. Its pathophysiology is uncertain, and the implication of EBV is discussed. PMID- 23449734 TI - Cross-talk between transforming growth factor-beta1 and muscarinic M2 receptors augments airway smooth muscle proliferation. AB - Transforming growth factor-beta1 (TGF-beta1) is a central mediator in tissue remodeling processes, including fibrosis and airway smooth muscle (ASM) hyperplasia, as observed in asthma. The mechanisms underlying this response, however, remain unclear because TGF-beta1 exerts only weak mitogenic effects on ASM cells. In this study, we hypothesized that the mitogenic effect of TGF-beta1 on ASM is indirect and requires prolonged exposure to allow for extracellular matrix (ECM) deposition. To address this hypothesis, we investigated the effects of acute and prolonged treatment with TGF-beta1, alone and in combination with the muscarinic receptor agonist methacholine, on human ASM cell proliferation. Acutely, TGF-beta1 exerted no mitogenic effect. However, prolonged treatment (for 7 d) with TGF-beta1 increased ASM cell proliferation and potentiated the platelet derived growth factor-induced mitogenic response. Muscarinic receptor stimulation with methacholine synergistically enhanced the effect of TGF-beta1. Interestingly, the integrin-blocking peptide Arg-Gly-Asp-Ser, as well as integrin alpha5beta1 function-blocking antibodies, inhibited the effects of TGF-beta1 and its combination with methacholine on cell proliferation. Accordingly, prolonged treatment with TGF-beta1 increased fibronectin expression, which was also synergistically enhanced by methacholine. The synergistic effects of methacholine on TGF-beta1-induced proliferation were reduced by the long-acting muscarinic receptor antagonist tiotropium and the M2 receptor subtype-selective antagonist gallamine, but not the M3-selective antagonist DAU5884. In line with these findings, the irreversible Gi protein inhibitor pertussis toxin also prevented the potentiation of TGF-beta1-induced proliferation by methacholine. We conclude that prolonged exposure to TGF-beta1 enhances ASM cell proliferation, which is mediated by extracellular matrix-integrin interactions, and which can be enhanced by muscarinic M2 receptor stimulation. PMID- 23449735 TI - Human eosinophils express functional CCR7. AB - Human eosinophils display directed chemotactic activity toward an array of soluble chemokines. Eosinophils have been observed to migrate to draining lymph nodes in experimental models of allergic inflammation, yet it is unknown whether eosinophils express CCR7, a key chemokine receptor in coordinating leukocyte trafficking to lymph nodes. The purpose of this study is to demonstrate expression of CCR7 by human eosinophils and functional responses to CCL19 and CCL21, the known ligands of CCR7. Human eosinophils were purified by negative selection from healthy donors. CCR7 expression of freshly purified, unstimulated eosinophils and of IL-5-primed eosinophils was determined by flow cytometry and Western blot. Chemotaxis to CCL19 and CCL21 was measured in transwell assays. Shape changes to CCL19 and CCL21 were analyzed by flow cytometry and microscopy. Calcium fluxes of fluo-4 AM-loaded eosinophils were recorded by flow cytometry after chemokine stimulation. ERK phosphorylation of CCL19- and CCL21-stimulated eosinophils was measured by Western blot and Luminex assay. Human eosinophils expressed CCR7 as demonstrated by flow cytometry and Western blots. Eosinophils exhibited detectable cell surface expression of CCR7. IL-5-primed eosinophils exhibited chemotaxis toward CCL19 and CCL21 in a dose-dependent fashion. Upon stimulation with CCL19 or CCL21, IL-5-primed eosinophils demonstrated dose dependent shape changes with polarization of F-actin and exhibited calcium influxes. Finally, primed eosinophils stimulated with CCL19 or CCL21 exhibited increased phosphorylation of ERK in response to both CCR7 ligands. We demonstrate that human eosinophils express CCR7 and have multipotent responses to the known ligands of CCR7. PMID- 23449737 TI - Effect of asbestos exposure on differentiation of cytotoxic T lymphocytes in mixed lymphocyte reaction of human peripheral blood mononuclear cells. AB - Asbestos fibers are associated with tumorigenicity, and are thought to cause mesothelioma. However, their effect on immune response remains unclear. We examined the effect of asbestos exposure on differentiation of cytotoxic T lymphocytes (CTLs) in mixed lymphocyte reactions (MLR) of human peripheral blood mononuclear cells (PBMCs) upon exposure to chrysotile B (CB) or crocidolite (CR) asbestos at 5 MUg/ml for 7 days. Exposure to CB during MLR suppressed increases in the percentage and number of CD8+ T cells in response to allogenic cells. The cytotoxicity for allogenic targets decreased in PBMCs exposed to CB, but not CR, when compared with PBMCs without any exposure during MLR. Exposure to CB during MLR resulted in suppression of increases in granzyme B+ cells and IFN-gamma+ cells. CB exposure also resulted in suppression of increases in CD45RO+ effector/memory cells and CD25+-activated cells in CD8+ lymphocytes, and a decrease in CD45RA+ cells. CB exposure suppressed the proliferation of CD8+ lymphocytes without an increase in annexin V+ apoptotic cells in CD8+ lymphocytes. Moreover, the production of IL-10, IFN-gamma, and TNF-alpha, but not IL-2, decreased in the presence of CB. These results suggest that exposure to asbestos potentially suppresses the differentiation of cytotoxic T lymphocyte, accompanied by decreases in IFN-gamma and TNF-alpha. PMID- 23449736 TI - Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs. AB - Respiratory virus infections cause airway hyperreactivity (AHR). Preventative strategies for virus-induced AHR remain limited. Toll-like receptors (TLRs) have been suggested as a therapeutic target because of their central role in triggering antiviral immune responses. Previous studies showed that concurrent treatment with TLR2/6 and TLR9 agonists reduced lethality and the microbial burden in murine models of bacterial and viral pneumonia. This study investigated the effects of TLR2/6 and TLR9 agonist pretreatment on parainfluenza virus pneumonia and virus-induced AHR in guinea pigs in vivo. Synthetic TLR2/6 lipopeptide agonist Pam2CSK4 and Class C oligodeoxynucleotide TLR9 agonist ODN2395, administered in combination 24 hours before virus infection, significantly reduced viral replication in the lung. Despite a fivefold reduction in viral titers, concurrent TLR2/6 and TLR9 agonist pretreatment did not prevent virus-induced AHR or virus-induced inhibitory M2 muscarinic receptor dysfunction. Interestingly, the TLR agonists independently caused non-M2-dependent AHR. These data confirm the therapeutic antiviral potential of TLR agonists, while suggesting that virus inhibition may be insufficient to prevent virus-induced airway pathophysiology. Furthermore, TLR agonists independently cause AHR, albeit through a distinctly different mechanism from that of parainfluenza virus. PMID- 23449738 TI - An IL-4/IL-13 dual antagonist reduces lung inflammation, airway hyperresponsiveness, and IgE production in mice. AB - IL-4 and IL-13 comprise promising targets for therapeutic interventions in asthma and other Th2-associated diseases, but agents targeting either IL-4 or IL-13 alone have shown limited efficacy in human clinical studies. Because these cytokines may involve redundant function, dual targeting holds promise for achieving greater efficacy. We describe a bifunctional therapeutic targeting IL-4 and IL-13, developed by a combination of specific binding domains. IL-4-targeted and IL-13-targeted single chain variable fragments were joined in an optimal configuration, using appropriate linker regions on a novel protein scaffold. The bifunctional IL-4/IL-13 antagonist displayed high affinity for both cytokines. It was a potent and efficient neutralizer of both murine IL-4 and murine IL-13 bioactivity in cytokine-responsive Ba/F3 cells, and exhibited a half-life of approximately 4.7 days in mice. In a murine model of ovalbumin-induced ear swelling, the bifunctional molecule blocked both the IL-4/IL-13-dependent early phase response and the IL-4-dependent late-phase response. In the ovalbumin induced lung inflammation model, the bifunctional IL-4/IL-13 antagonist reduced the IL-4-dependent rise in serum IgE titers, and reduced IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression, and serum chitinase responses. Taken together, these findings demonstrate the effective dual blockade of IL-4 and IL-13 with a single agent, which resulted in the modulation of a more extensive range of endpoints than could be achieved by targeting either cytokine alone. PMID- 23449740 TI - Mucormycosis of the middle ear: a case report with review of literature. AB - Mucor is a saprophytic organism and commonly invades the nose and paranasal sinuses of immunocompromised and diabetic patients involvement of the middle ear and mastoid in a nondiabetic patients is very rare and this may be the first case report clinical presentation of ear pain with reference to the mastoid and upper neck may be the early symptoms unlike the foul smelling ear discharge as seen in atticoantral disease. Radical debridement in the form of M.R.M with or without the use of amphotericin B may suffice in non-diabetic patients this case is reported to highlight the point that mucormycosis can also involve middle ear and mastoid in nondiabetic patients. PMID- 23449741 TI - Effect of iron deficiency on glycation of haemoglobin in nondiabetics. AB - BACKGROUND: Protein glycation is a spontaneous reaction that is believed to play a key role in the pathogenesis of many clinical disorders. The glycation of proteins is enhanced by elevated glucose concentrations. The major form of protein glycation with a clinical consideration is glycated haemoglobin (HbA1c). The HbA1c fraction is abnormally elevated in chronic hyperglycaemic diabetic patients and it correlates positively with the glycaemic control. However, increased glycated haemoglobin levels have been documented in iron de.ciency anaemic patients without any history of diabetes. AIMS AND OBJECTIVE: The aim of this study was to determine the effect of IDA on the HbA1c levels in nondiabetic patients, so as to consider IDA as an important factor which influenced the HbA1c levels, while monitoring the glycaemic status of diabetics. METHODOLOGY: Fifty non-diabetic, anaemic patients and 50 age-matched healthy subjects were enrolled in this study. The patients who had glucose tolerance abnormalities (impaired glucose tolerance or diabetes mellitus), haemoglobinopathies, haemolytic anaemia, infestation, chronic alcohol ingestion and chronic renal failure were excluded from the study. Haematologic investigations were done and the fasting and postprandial glucose and HbA1c levels were measured in all the subjects. RESULTS: The mean HbA1c (7.6 +/- 0.5%) level in the patients with IDA was higher than that in the control group (5.5% +/- 0.8) (p < 0.001). There were no differences in the levels of fasting and postprandial glucose between the IDA and the control groups (p > 0.05). The haemoglobin, serum ferritin, fasting and postprandial glucose, and the HbA1c levels were normal in the control group (p > 0.05). CONCLUSION: HbA1c is not affected by the blood sugar levels alone, and there are various confounding factors when HbA1c is measured, especially that of iron de.ciency, which is the commonest of the de.ciency diseases worldwide. It is hence prudent to rule out IDA before making a therapeutic decision, based on the HbA1c levels. PMID- 23449739 TI - Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury. AB - Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI. PMID- 23449742 TI - Parathyroid incidentaloma. AB - Incidentalomas are lesions which are asymptomatic and detected incidently during imaging or surgery. Parathyroid incidentalomas are a rare entity. Enlargement of gland without hyperfunction may be an early stage of disease. Symptomatology is usually non-specific or related to renal and skeletal system. Total serum calcium estimation may be used as a screening modality. Sestamibi scan is a more accurate imaging technique than USG. FNAB - PTH measurement is the most reliable minimally invasive nonsurgical test for parathyroid tissue verification. Incidently discovered enlarged parathyroid gland may be removed to avoid a re-do surgery. PMID- 23449743 TI - A distance-based dynamical transition analysis of time series signals and application to biological systems. AB - This study demonstrates an application of distance-based numerical measures to the phase space of time series signals, in order to obtain a temporal analysis of complex dynamical systems. This method is capable of detecting alterations appearing in the characters of the deterministic dynamical systems and provides a simple tool for the real-time analysis of time series data obtained from a complex dynamical system even with black box functionality. The study presents a possible application of the method in the dynamical transition analysis of real EEG records from epilepsy patients. PMID- 23449744 TI - A cohort study on the rate of progression of diabetic chronic kidney disease in different ethnic groups. AB - OBJECTIVE: To compare the rate of progression of diabetic chronic kidney disease in different ethnic groups. DESIGN: Prospective longitudinal observational study. PARTICIPANTS: All new patients attending a tertiary renal unit in east London with diabetic chronic kidney disease between 2000 and 2007 and followed up till 2009 were included. Patients presenting with acute end-stage kidney failure were excluded. MAIN OUTCOME MEASURES: The primary outcome was annual decline in the estimated glomerular filtration rate (eGFR) in different ethnic groups. Secondary end points were the number of patients developing end-stage kidney failure and total mortality during the study period. RESULTS: 329 patients (age 60+/-11.9 years, 208 men) were studied comprising 149 south Asian, 105 White and 75 Black patients. Mean follow-up was 6.0+/-2.3, 5.0+/-2.7 and 5.6+/-2.4 years for White, Black and south Asian patients, respectively. South Asian patients were younger and had a higher baseline eGFR, but both systolic and diastolic blood pressures were higher in Black patients (p<0.05). Baseline proteinuria was highest for the south Asian group followed by the White and Black groups. Adjusted linear regression analysis showed that an annual decline in eGFR was not significantly different between the three groups. The numbers of patients developing end-stage kidney failure and total mortality were also not significantly different between the three groups. ACE or angiotensin receptor blockers use, and glycated haemoglobin were similar at baseline and throughout the study period. CONCLUSIONS: We conclude that ethnicity is not an independent factor in the rate of progression renal failure in patients with diabetic chronic kidney disease. PMID- 23449745 TI - A method-comparison study regarding the validity and reliability of the Lactate Plus analyzer. AB - OBJECTIVES: The aims of this study were to: (1) determine the validity and reliability of the Nova Biomedical Lactate Plus portable analyzer, and quantify any fixed or proportional bias; (2) determine the effect of any bias on the determination of the lactate threshold and (3) determine the effect that blood sampling methods have on validity and reliability. DESIGN: In this method comparison study we compared blood lactate concentration measured using the Lactate Plus portable analyzer to lactate concentration measured by a reference analyzer, the YSI 2300. SETTING: University campus in the USA. PARTICIPANTS: Fifteen active men and women performed a discontinuous graded exercise test to volitional exhaustion on a motorised treadmill. Blood samples were taken via finger prick and collected in microcapillary tubes for analysis by the reference instrument at the end of each stage. Duplicate samples for the portable analyzer were either taken directly from the finger or from the micro capillary tubes. PRIMARY OUTCOME MEASUREMENTS: Ordinary least products regressions were used to assess validity, reliability and bias in the portable analyzer. Lactate threshold was determined by visual inspection. RESULTS: Though measurements from both instruments were correlated (r=0.91), the differences between instruments had large variability (SD=1.45 mM/l) when blood was sampled directly from finger. This variability was reduced by ~95% when both instruments measured blood collected in the capillary tubes. As the proportional and fixed bias between instruments was small, there was no difference in estimates of the lactate threshold between instruments. Reliability for the portable instrument was strong (r=0.99, p<0.05) with no proportional bias (slope=1.02) and small fixed bias ( 0.19 mM/l). CONCLUSIONS: The Lactate Plus analyzer provides accurate and reproducible measurements of blood lactate concentration that can be used to estimate workloads corresponding to blood lactate transitions or any absolute lactate concentrations. PMID- 23449746 TI - Mortality (1950-1999) and cancer incidence (1969-1999) of workers in the Port Hope cohort study exposed to a unique combination of radium, uranium and gamma ray doses. AB - OBJECTIVES: Uranium processing workers are exposed to uranium and radium compounds from the ore dust and to gamma-ray radiation, but less to radon decay products (RDP), typical of the uranium miners. We examined the risks of these exposures in a cohort of workers from Port Hope radium and uranium refinery and processing plant. DESIGN: A retrospective cohort study with carefully documented exposures, which allowed separation of those with primary exposures to radium and uranium. SETTINGS: Port Hope, Ontario, Canada, uranium processors with no mining experience. PARTICIPANTS: 3000 male and female workers first employed (1932-1980) and followed for mortality (1950-1999) and cancer incidence (1969-1999). OUTCOME MEASURES: Cohort mortality and incidence were compared with the general Canadian population. Poisson regression was used to evaluate the association between cumulative RDP exposures and gamma-ray doses and causes of death and cancers potentially related to radium and uranium processing. RESULTS: Overall, workers had lower mortality and cancer incidence compared with the general Canadian population. In analyses restricted to men (n=2645), the person-year weighted mean cumulative RDP exposure was 15.9 working level months (WLM) and the mean cumulative whole-body gamma-ray dose was 134.4 millisieverts. We observed small, non-statistically significant increases in radiation risks of mortality and incidence of lung cancer due to RDP exposures (excess relative risks/100 WLM=0.21, 95% CI <-0.45 to 1.59 and 0.77, 95% CI <-0.19 to 3.39, respectively), with similar risks for those exposed to radium and uranium. All other causes of death and cancer incidence were not significantly associated with RDP exposures or gamma-ray doses or a combination of both. CONCLUSIONS: In one of the largest cohort studies of workers exposed to radium, uranium and gamma-ray doses, no significant radiation-associated risks were observed for any cancer site or cause of death. Continued follow-up and pooling with other cohorts of workers exposed to by-products of radium and uranium processing could provide valuable insight into occupational risks and suspected differences in risk with uranium miners. PMID- 23449747 TI - Hospitalisation rates for children with intellectual disability or autism born in Western Australia 1983-1999: a population-based cohort study. AB - OBJECTIVES: To describe the hospitalisation patterns in children with intellectual disability (ID) and/or autism spectrum disorder (ASD) after the first year of life and compare with those unaffected. DESIGN: Prospective cohort study using data linkage between health, ID and hospitalisation population-based datasets. SETTING: Western Australia. PARTICIPANTS: 416 611 individuals born between 1983 and 1999 involving 1 027 962 hospital admission records. Five case categories were defined (mild/moderate ID, severe ID, biomedically caused ID, ASD with ID and ASD without ID) and compared with the remainder of children and young people. PRIMARY AND SECONDARY OUTCOME MEASURES: Time to event analysis was used to compare time hospitalisation and rate of hospitalisation between the different case-groups by estimating HR, accounting for birth year and preterm birth status. RESULTS: ID and/or ASD were found to be associated with an increased risk of hospitalisation compared with the remainder of the population. The increase in risk was highest in those with severe ID and no ASD (HR=10.33, 95% CI 8.66 to 12.31). For those with ID of known biomedical cause or mild ID of unknown cause, the risk of hospitalisation was lower (HR=7.36, 95% CI 6.73 to 8.07 and HR=3.08, 95% CI 2.78 to 3.40, respectively). Those with ASDs had slightly increased risk (HR=2.82, 95% CI 2.26 to 3.50 for those with ID and HR=2.09, 95% CI 1.85 to 2.36 for those without ID). CONCLUSIONS: Children with an ID or ASD experience an increased risk of hospitalisation after the first year of life which varied from 2 to 10 times that of the rest of the population. Findings can inform service planning or resource allocation for these children with special needs. PMID- 23449748 TI - A blinded placebo-controlled randomized trial on the use of astaxanthin as an adjunct to splinting in the treatment of carpal tunnel syndrome. AB - BACKGROUND: Nutritional supplementation is a potential adjunct in the conservative management of carpal tunnel syndrome (CTS). This study investigated whether astaxanthin (a beta-carotenoid) increased the effectiveness of splinting in managing CTS. METHODS: This is a triple-blinded randomized controlled trial where 63 patients with electrodiagnostically confirmed CTS were randomly allocated into either the experimental group (n = 32) (astaxanthin-4-mg capsules + splinting) or the control group (n = 31) (placebo + splinting). Medications were taken for 9 weeks followed by a 3-week washout. The primary outcome measure was the Symptom Severity Scale (SSS). Secondary outcome measures in the study included physical impairments, disability, and health status measures. Electrodiagnostic testing was performed before entry into the study and again at 12 weeks. All other outcomes were measured at baseline, 6, and 12 weeks. RESULTS: There was a reduction in symptoms as measured by the SSS over the course of treatment in both groups (p = 0.002), but no differences between the groups (p = 0.18). The Disability of Arm, Shoulder and Hand questionnaire and the Short Form 36-item Health Survey showed no effects over time or between treatment groups. The baseline difference between the groups in the level of total cholesterol and low-density lipoproteins remained constant over the course of the study. Impairment measures demonstrated no significant changes in grip, dexterity, or sensation. CONCLUSION: At present, the role for astaxanthin as an adjunct in conservative management of CTS has not been established. PMID- 23449749 TI - Hematological malignancies in Al-amal oncology unit, aden. AB - The hematological malignancies (HM) are group of neoplasms that arise through malignant transformation of bone marrow derived cells. The great diversity seen in this group of disorders is a reflection of the complexity of normal hematopoiesis and the immune system. In the current study, the author retrospectively studied HM patients from 2008 to 2010, and compared with prevalence of solid tumor, and found HM represented one-fifth of all malignancies managed in the Oncology Unit, and lymphomas were the commonest HM. PMID- 23449750 TI - Development of an online education program for midwives in australia to improve perinatal oral health. AB - It is recommended that all pregnant women should receive a comprehensive oral health evaluation because poor maternal oral health may affect pregnancy outcomes and the general health of the woman and her baby. Midwives are well placed to provide dental health advice and referral. However, in Australia, little emphasis has been placed on the educational needs of midwives to undertake this role. This article outlines the development of an online education program designed to improve midwives' dental health knowledge, prepare them to assess the oral health of women, refer when required, and provide appropriate dental education to women and their families. The program consists of reading and visual material to assist with the oral health assessment process and includes competency testing. PMID- 23449751 TI - Virulence, bacterocin genes and antibacterial susceptibility in Enterococcus faecalis strains isolated from water wells for human consumption. AB - The objectives of this study were to detect genes for virulence and bacteriocins in addition to studying the antimicrobial susceptibility of 78 strains of E. faecalis isolated from water wells for human consumption. The virulence and bacteriocin genes of 78 E. faecalis were amplified by PCR and visualized in agarose gels. The antimicrobial susceptibility was determined through diffusion agar tests and the MIC through microdilution. It was observed that the major percentage of virulence genes in the E. faecalis strains corresponds to aggA (93.5%). The bacteriocin gene entA (64.1%) is the most frequently detected. The studied strains exhibited different virulence and bacteriocin genes, and an important antibacterial resistance. The most common resistant phenotype (n = 14) corresponds to tetracycline and chloramphenicol and the less frequent (n = 2) to ciprofloxacin and moxifloxacin. Eight different genetic profiles were observed for virulence y bacteriocin genes. It was determined a statistical association between the bacterial resistance and some of the genetic profiles detected. PMID- 23449752 TI - A novel technique for attaining maxillomandibular fixation in the edentulous mandible fracture. AB - Edentulous mandible fractures present a unique and challenging surgical problem, particularly because of lack of occlusive dental surfaces to capitalize upon maxillomandibular fixation (MMF). We present a novel technique to achieve MMF using rigid plates spanning the oral cavity to fixate the maxilla to the mandible. The process is rapid and allows stability using the established principles of rigidity, external fixation, and osteosynthesis. This technique allows for a faster MMF than with a Gunning splint and allows for easier oral hygiene. An illustrative case and pre- and postoperative imaging are provided. PMID- 23449753 TI - Disturbed dreaming and the instability of sleep: altered nonrapid eye movement sleep microstructure in individuals with frequent nightmares as revealed by the cyclic alternating pattern. AB - STUDY OBJECTIVES: Nightmares are disturbing mental experiences during sleep that usually result in abrupt awakenings. Frequent nightmares are associated with poor subjective sleep quality, and recent polysomnographic data suggest that nightmare sufferers exhibit impaired sleep continuity during nonrapid eye movement (NREM) sleep. Because disrupted sleep might be related to abnormal arousal processes, the goal of this study was to examine polysomnographic arousal-related activities in a group of nightmare sufferers and a healthy control group. DESIGN: Sleep microstructure analysis was carried out by scoring the cyclic alternating pattern (CAP) in NREM sleep and the arousal index in rapid eye movement (REM) sleep on the second night of the polysomnographic examination. SETTING: Hospital-based sleep research laboratory. PARTICIPANTS: There were 17 in the nightmare (NMs) group and 23 in the healthy control (CTLs) group. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The NMs group exhibited reduced amounts of CAP A1 subtype and increased CAP A2 and A3 subtypes, as well as longer duration of CAP A phases in comparison with CTLs. Moreover, these differences remained significant after controlling for the confounding factors of anxious and depressive symptoms. The absolute number and frequency of REM arousals did not differ significantly between the two groups. CONCLUSIONS: The results of our study indicate that NREM sleep microstructure is altered during nonsymptomatic nights of nightmares. Disrupted sleep in the NMs group seems to be related to abnormal arousal processes, specifically an imbalance in sleep-promoting and arousing mechanisms during sleep. CITATION: Simor P; Bodizs R; Horvath K; Ferri R. Disturbed dreaming and the instability of sleep: altered nonrapid eye movement sleep microstructure in individuals with frequent nightmares as revealed by the cyclic alternating pattern. SLEEP 2013;36(3):413-419. PMID- 23449754 TI - Intrapericardial hemangioma: a case report. AB - Hemangiomas of the pericardium are very rare primary pericardial tumours. Very few cases of pericardial hemangioma have been reported in the literature till date. We are reporting a case of a 40 years old male who presented with the complaints of chest discomfort and palpitation on exertion, of 3 months duration. ECHO and Colour Doppler ECHO which were done, revealed a large heterogeneous mass which measured 7.6 * 7.1cms, which was possibly attached to the roof and the anterior surface of the left atria, which was possibly a myxoma. Based on the radiological findings, a diagnosis of left atrial myxoma was considered. However, intra operatively, an encapsulated mass was seen within the pericardium, which was successfully excised and sent for histopathology. The histopathological examination revealed an intrapericardial hemangioma. This case has been reported on account of its extreme rarity. PMID- 23449755 TI - Influence of anabolic steroid on tibial fracture healing in rabbits - a study on experimental model. AB - INTRODUCTION: Anabolic steroid is an established drug for treating catabolic states. The said drug has been shown to restore the lean body mass, to prevent osteoporosis and to correct the impaired immune response, but only few studies have evaluated the effect of the same on fracture healing. METHODS: Fracture was produced by an impact device in 24 rabbits which were divided into experimental (I) and control (II) groups of 12 animals each. The experimental groups were further divided into the subgroups IA and IB of equal animals, which received Nandrolone Decanoate 10 mg/kg intramuscularly, biweekly for 2 weeks and 4 weeks respectively. RESULTS AND CONCLUSION: Radiographs taken on the post fracture day15 and 40 showed better healing in the Nandrolone Decanoate administrated groups as a dense periosteal bone formation and prevention of the local osteoporosis. Histochemical examination of the callus and high serum alkaline phosphatase levels on day 15 and 40 confirmed better mineralization in experimental animals. PMID- 23449756 TI - Antidepressant-like Effects of delta Opioid Receptor Agonists in Animal Models. AB - Recently, delta opioid receptor agonists have been proposed to be attractive targets for the development of novel antidepressants. Several studies revealed that single treatment of delta opioid receptor agonists produce antidepressant like effects in the forced swimming test, which is one of the most popular animal models for screening antidepressants. In addition, subchronic treatment with delta opioid receptor agonists has been shown to completely attenuate the hyperemotional responses found in olfactory bulbectomized rats. This animal model exhibits hyperemotional behavior that may mimic the anxiety, aggression, and irritability found in depressed patients, suggesting that delta opioid receptor agonists could be effective in the treatment of these symptoms in depression. On the other hand, prototype delta opioid receptor agonists produce convulsive effects, which limit their therapeutic potential and clinical development. In this review, we presented the current knowledge regarding the antidepressant-like effects of delta opioid receptor agonists, which include some recently developed drugs lacking convulsive effects. PMID- 23449758 TI - Interexaminer reliability of the Johnston and Friedman percussion scan of the thoracic spine: secondary data analysis using modified methods. AB - OBJECTIVE: The purpose of this study is to perform a secondary analysis using modified methods of previously reported data to analyze the amount of examiner concordance in the Johnston and Friedman percussion scan of the most fixated spinal level. METHOD: A 2001 study evaluated interexaminer reliability of the percussive method of Johnston and Friedman for detecting altered segmental mobility (somatic dysfunction, spinal/segmental dysfunction, or chiropractic subluxation) in the thoracic spine. The original reported level of agreement using the kappa statistic for discrete measures was only 0.07, judged "slight." The data were reformatted to permit recalculating the degree of interexaminer agreement using the intraclass correlation coefficient statistic, which uses continuous analysis, unlike kappa that performs discrete analysis. Following an initial calculation, the data were modified to reflect the caudally increasing vertebral height of the thoracic vertebrae. RESULTS: The reformatted and modified data, intraclass correlation coefficient (2,1) = 0.253 (0.100,0.482), showed the findings as "poor," which is better interexaminer agreement for percussion motion palpation than the original reported kappa value judged as "slight." CONCLUSIONS: Reanalyzing the data using an alternative statistical method showed greater interexaminer reliability than was originally reported. This secondary analysis demonstrates how study results may vary depending on the experimental design and statistical methods chosen for analysis. PMID- 23449757 TI - The Diagnostic Validity of Clinical Tests in Temporomandibular Internal Derangement: A Systematic Review and Meta-analysis. AB - PURPOSE: To assess the diagnostic validity of clinical tests for temporomandibular internal derangement relative to magnetic resonance imaging (MRI). METHODS: MEDLINE and Embase were searched from 1994 through 2009. Independent reviewers conducted study selection; risk of bias was assessed using Quality Assessment of studies of Diagnostic Accuracy included in Systematic reviews (QUADAS); >=9/14) and data abstraction. Overall quality of evidence was profiled using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Agreement was measured using quadratic weighted kappa (kappaw). Positive (+) or negative (-) likelihood ratios (LR) with 95% CIs were calculated and pooled using the DerSimonian-Laird method and a random-effects model when homogeneous (I(2)>=0.40, Q-test p<=0.10). RESULTS: We selected 8 of 36 studies identified. There is very low quality evidence that deflection (+LR: 6.37 [95% CI, 2.13-19.03]) and crepitation (LR:5.88 [95% CI, 1.95-17.76]) as single tests and crepitation, deflection, pain, and limited mouth opening as a cluster of tests are the most valuable for ruling in internal derangement without reduction (+LR:6.37 [95% CI, 2.13-19.03]), (-LR:0.27 [95% CI, 0.11-0.64]) while the test cluster click, deviation, and pain rules out internal derangement with reduction (-LR: 0.09 [95% CI, 0.01-0.72]). No single test or cluster of tests was conclusive and of significant value for ruling in internal derangement with reduction. CONCLUSIONS: Findings of this review will assist clinicians in deciding which diagnostic tests to use when internal derangement is suspected. The literature search revealed a lack of high-quality studies; further research with adequate description of patient populations, blinded assessments, and both sagittal and coronal MRI planes is therefore recommended. : Purpose: To assess the diagnostic validity of clinical tests for temporomandibular internal derangement relative to magnetic resonance imaging (MRI). Methods: MEDLINE and Embase were searched from 1994 through 2009. Independent reviewers conducted study selection; risk of bias was assessed using Quality Assessment of studies of Diagnostic Accuracy included in Systematic reviews (QUADAS); >=9/14) and data abstraction. Overall quality of evidence was profiled using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Agreement was measured using quadratic weighted kappa (kappaw). Positive (+) or negative (-) likelihood ratios (LR) with 95% CIs were calculated and pooled using the DerSimonian-Laird method and a random-effects model when homogeneous (I2>=0.40, Q test p<=0.10). Results: We selected 8 of 36 studies identified. There is very low quality evidence that deflection (+LR: 6.37 [95% CI, 2.13-19.03]) and crepitation (LR:5.88 [95% CI, 1.95-17.76]) as single tests and crepitation, deflection, pain, and limited mouth opening as a cluster of tests are the most valuable for ruling in internal derangement without reduction (+LR:6.37 [95% CI, 2.13-19.03]), ( LR:0.27 [95% CI, 0.11-0.64]) while the test cluster click, deviation, and pain rules out internal derangement with reduction (-LR: 0.09 [95% CI, 0.01-0.72]). No single test or cluster of tests was conclusive and of significant value for ruling in internal derangement with reduction. Conclusions: Findings of this review will assist clinicians in deciding which diagnostic tests to use when internal derangement is suspected. The literature search revealed a lack of high quality studies; further research with adequate description of patient populations, blinded assessments, and both sagittal and coronal MRI planes is therefore recommended. PMID- 23449759 TI - Recovery of hearing in Cisplatin-induced ototoxicity in the Guinea pig with intratympanic dexamethasone. AB - The purpose of this study was to investigate the effectiveness of intratympanic dexamethasone injection as a therapeutic agent against cisplatin-induced ototoxicity. Animals were randomly divided into three groups. Group one received intraperitoneal cisplatin alone, group two, received intratympanic dexamethasone after cisplatin ototoxicity had been demonstrated. Group three, which is control group, received intratympanic dexamethasone.Then we made three measurements. First we measured the baseline distortion product otoacustic emission (DPOAEs) of all the guine pigs. Second we injected cisplatin intraperitoneal group one and two the same day. Third we measured DPOAEs after 72 h of group one and two. Moreover DPOAEs were measured at the end of the first and second week only in group two. Cochleae were harvested and processed for electron microscopy after then. Values of The DPOAEs amplitudes and signal-to-noise ratio (SNR) at 1-6 kHz frequencies for group 1 after the injections significantly decreased over those before injections (P < 0.05). In group 3, there were no significant differences in DPOAE amplitude and SNR values When they are compare before and after their intratympanic dexamethasone injections (P > 0.05). In group 2, the DPOAEs measurements were close to significance at the end of the second week (P = 0.056). Intratympanic dexamethasone injection did not cause any ototoxic effect. Although intratympanic dexamethasone did not reach the statistically significant results, the measurements were close to significance. Intratympanic dexamethasone might have a significant therapeutic effect after cisplatin ototoxicity with different dose and application regimens. PMID- 23449760 TI - Case for resurgence of radical perineal prostatecomy in Indian subcontinent. AB - INTRODUCTION: Radical perineal prostatectomy was the first surgery described for prostatic carcinoma (Young, 1904) but it lost its eminent status after Walsh's description in 1982 of anatomic radical retropubic prostatectomy followed by the enthusiasm in laparoscopy and now robotics. It made resurgence after it was realized in early 1990s that the pelvic lymph node dissection is needed only in selected cases. Last decade witnessed over 80 publications addressing the results and advances in the perineal approach. Strangely, centres from the subcontinent have chosen to ignore this resurgence. We describe our early experience with the technique in 35 patients and present the case for its more widespread usage. PATIENTS AND METHODS: Thirty five patients of clinically localized carcinoma prostate were operated by perineal route in our institution from December 2006 onwards. All patients had serum prostate specific antigen levels less than 10 ng/ml. RESULTS: Operating time was 2 to 3.5 hours (mean 2.5 hours). Rectal injury occurred in three patients but was closed primarily in all and none required a colostomy. Mean duration of hospital stay was four days. The disease was organ confined in 25(71%). Positive margins were seen in 5(14%) patients. Biochemical recurrence occurred in 17% patients at one year. Seventy six percent patients had achieved continence at one year. CONCLUSIONS: As the world is taking note of radical perineal prostatectomy again, with a very small learning curve, minimal invasion and good oncological control urologists from Indian subcontinent should also embrace this procedure in view of the relative limited resources available. PMID- 23449761 TI - Efficacy of Colloidal Silver-Hydrogen Peroxide and 2-Bromo-2-nitroporopane-1,3 diol Compounds Against Different Serogroups of Legionella pneumophila Strains. AB - Cooling towers are considered as amplifier and disseminator sources for Legionella spp. despite preventive treatments. Information which was obtained from biocidal tests could improve the effectiveness of treatments. Therefore, the choice of appropriate biocides and the applying of biocides in correct dosages and contact times are important. Various oxidizing and non-oxidizing biocides have been investigated in vitro for their effectiveness against legionellae. Colloidal silver-hydrogen peroxide (CSHP) and 2-bromo-2-nitroporopane-1,3-diol (BNPD) biocides were selected as an example for oxidizing and non-oxidizing agents, respectively, in view of bactericidal action against different serogroups of L. pneumophila strains [serogroup 1 (S1) and serogroup 2-14 (S2)] which are isolated different cooling towers in the vicinity of Istanbul, Turkey and reference strain. In the current study, oxidizing biocide was found more effective than non-oxidizing biocide in terms of contact times, log reductions and recommended dosages. At the recommended concentrations for cooling towers (100 ppm), while CSHP compound killed all strains in 3 h contact time, BNPD compound killed S2 and reference strain in the same contact time, S1 strain after 6 h contact time. The results of the present study showed that effective biocide applications can be achieved by pre-determining minimum inhibitory concentration (MIC) and minimum contact time of different biocides to kill target bacteria. PMID- 23449762 TI - Creation and implementation of a historical controls database from randomized clinical trials. AB - BACKGROUND: Ethical concerns about randomly assigning patients to suboptimal or placebo arms and the paucity of willing participants for randomization into control and experimental groups have renewed focus on the use of historical controls in clinical trials. Although databases of historical controls have been advocated, no published reports have described the technical and informatics issues involved in their creation. OBJECTIVE: To create a historical controls database by leveraging internal clinical trial data at Pfizer, focusing on patients who received only placebo in randomized controlled trials. METHODS: We transformed disparate clinical data sources by indexing, developing, and integrating clinical data within internal databases and archives. We focused primarily on trials mapped into a consistent standard and trials in the pain therapeutic area as a pilot. RESULTS: Of the more than 20,000 internal Pfizer clinical trials, 2404 completed placebo controlled studies with a parallel design were identified. Due to challenges with informed consent and data standards used in older clinical trials, studies completed before 2000 were excluded, yielding 1134 studies from which placebo subjects and associated clinical data were extracted. CONCLUSIONS: It is technically feasible to pool portions of placebo populations through a stratification and segmentation approach for a historical placebo group database. A sufficiently large placebo controls database would enable previous distribution calculations on representative populations to supplement, not eliminate, the placebo arm of future clinical trials. Creation of an industry-wide placebo controls database, utilizing a universal standard, beyond the borders of Pfizer would add significant efficiencies to the clinical trial and drug development process. PMID- 23449763 TI - Hill's small systems nanothermodynamics: a simple macromolecular partition problem with a statistical perspective. AB - Using a simple example of biological macromolecules which are partitioned between bulk solution and membrane, we investigate T.L. Hill's phenomenological nanothermodynamics for small systems. By introducing a system size-dependent equilibrium constant for the bulk-membrane partition, we obtain Hill's results on differential and integral chemical potentials MU and [Formula: see text] from computations based on standard Gibbsian equilibrium statistical mechanics. It is shown that their difference can be understood from an equilibrium re-partitioning between bulk and membrane fractions upon a change in the system's size; it is closely related to the system's fluctuations and inhomogeneity. These results provide a better understanding of nanothermodynamics and clarify its logical relation with the theory of statistical mechanics. PMID- 23449764 TI - Gastric pull up reconstruction after pharyngo laryngo esophagectomy for advanced hypopharyngeal cancer. AB - Hypopharyngeal cancers are uncommon. The management of advanced hypopharyngeal carcinomas has been a difficult problem. Surgical resection has been more successful. While many surgical methods have been used and reported pharyngolaryngo esophagectomy with gastric pull up remains the best option. This study documents our experience with patients who underwent total pharyngolaryngoesophagectomy with immediate gastric pull-up for advanced carcinoma hypopharynx. The clinical data of 17 patients treated with pharyngo laryngo-esophagectomy for advanced carcinoma of the hypopharynx between 2001 and 2004 was analyzed. All patients had advanced disease and required a gastric pull up for reconstruction. Data obtained included age, sex, site, stage, post op complication, duration of follow up, recurrence & survival. Average age was 37.7 years and ranged from 27 to 56 years. There were 13 female patients and 4 male patients .13 patients presented with postcricoid tumours and 4 with posterior pharyngeal wall tumors, 13 patients presented with stage 3 tumors and 4 patients presented with stage 4 tumors. Wound infection was present in 2 patients (11.7%), anastomotic leak in 1(5.8%), hypocalcemia in 1(5.8%) and malignant pleural effusion in 1 patient (5.8%). Local recurrence occurred in 1(5.8%) while nodal recurrence occurred in 5(29.4%) patient. The average over all survival in our study was 19.5 months and ranged from 2 to 101 months. The gastric pull-up operation is a useful and effective method for the immediate reconstruction of the advanced hypopharyngeal malignancy. PMID- 23449765 TI - Altered fructosamine and lipid fractions in subclinical hypothyroidism. AB - BACKGROUND: Thyroid function disorders lead to changes in the lipoprotein metabolism. OBJECTIVES: To study the lipid and the glycaemic abnormalities in the subclinical hypothyroidism cases and to compare the same with the euthyroid, overt hypothyroid and the hyperthyroid subjects. METHODOLOGY: Four groups, euthyroid (Group-I), hypothyroid (Group-II), subclinical hypothyroid (Group-III) and hyperthyroid (Group-IV), which consisted of 30 subjects each, of either sex, who were aged 25-55 years, underwent Fasting Plasma Glucose (FPG), fructosamine, lipid profile and total T3, T4 and TSH estimations. The subjects who were on lipid lowering or thyroid disorder drugs and known diabetics were excluded from the study. RESULTS: In Group-III, all the lipid fractions were comparable to those of Group-II and they were significantly deranged, as compared to those of Group-I. The fructosamine levels were significantly higher in Group-II and Group III (p<0.05), but the subclinical hypothyroid pool had statistically lower levels than the hypothyroid pool (376.63+/-54.73, 587.80+/-65.10). In the Group-IV patients, the LDL-C levels were significantly higher as compared to those in the euthyroid pool. The fructosamine levels were significantly lower in comparison with both the euthyroid and the hypothyroid pools (both in Groups-II and III). The FPG levels were higher in all the classes of the thyroid abnormalities (subclinical hypothyroidnot significant) but within the reference range of 70 100mg/dl. CONCLUSION: Since the lipid derangement in subclinical hypothyroidism is on par with that in overt hypothyrodism, the subclinical hypothyroid cases also need to be treated similarly. The fructosamine values which are largely in excess of the FPG values, indicate a higher propensity to glycation and a decreased turnover of the proteins in the hypothyroid and the subclinical hypothyroid pools. Vice versa is true of the hyperthyroid pool. Fructosamine can be included in the thyroid work up of the patients to assess the metabolic function and the subsequent response after the initiation of the therapy. PMID- 23449766 TI - Quality of care for First Nations and non-First Nations People with diabetes. AB - BACKGROUND AND OBJECTIVES: Compared with non-First Nations, First Nations People with diabetes experience higher rates of kidney failure and death, which may be related to disparities in care. This study examined First Nations and non-First Nations People with diabetes for differences in quality indicators and their association with kidney failure and death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Adults with diabetes and an outpatient creatinine in Alberta from 2005 to 2008 were identified. Logistic regression was used to determine the likelihood of process of care indicators (measurement of urine albumin/creatinine ratio [ACR], LDL, and hemoglobin A1C [A1C]) and surrogate outcome indicators (achievement of LDL and A1C targets). Cox regression was used to determine the association between lack of achievement of indicator targets and each of kidney failure and death. RESULTS: This study identified 140,709 non-First Nations and 6574 First Nations People with diabetes. There was a significant interaction between First Nations status and CKD for the outcomes (P<0.01); therefore, results are stratified by CKD. Among participants without CKD, First Nations People were less likely to receive process of care indicators and achieve target A1C compared with non-First Nations People. For those with CKD, First Nations People were as likely to receive these indicators (other than LDL) and achieve LDL and A1C targets. Lack of LDL and A1C assessment and achievement of targets were associated with increased risk of kidney failure and death similarly for both groups. CONCLUSIONS: Compared with non-First Nations, First Nations People with diabetes but without CKD experience disparities in assessment of quality indicators and achievement of A1C target. PMID- 23449767 TI - Dietary and lifestyle factors and medical conditions associated with urinary citrate excretion. AB - BACKGROUND AND OBJECTIVES: Lower urinary citrate excretion is a risk factor for nephrolithiasis and associated with metabolic acidosis and higher prevalence of hypertension and insulin resistance. This study sought to quantify the independent predictors of urinary citrate excretion in population-based cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cross-sectional study of 2561 individuals from the Health Professionals Follow-Up Study and Nurses' Health Studies I and II who provided two 24-hour urine collections was conducted. Dietary data were ascertained from the semiquantitative food frequency questionnaire. Lifestyle and disease data were derived from responses to biennial questionnaires. Multivariable linear regression was used to quantify the predictors of urinary citrate excretion. RESULTS: After adjusting for age, urinary creatinine, dietary, and other factors, higher intake of nondairy animal protein (per 10 g/d; -20 mg/d; 95% confidence interval [-29 to -11]), higher body mass index (per 1 kg/m(2); -4 mg/d; [-6 to -2]), and history of nephrolithiasis ( 57 mg/d; [-79 to -36]), hypertension (-95 mg/d; [-119 to -71]), gout (-104 mg/d; [-155 to -54]), and thiazide use (-34 mg/d; [-68 to -1]) were independently associated with lower 24-hour urinary citrate excretion. Higher intake of potassium (per 1000 mg/d; 53 mg/d; [33 to 74]), higher urinary sodium (per 100 mEq/d; 56 mg/d; [31 to 80]), and history of diabetes (61 mg/d; [21 to 100]) were independently associated with higher citrate excretion. CONCLUSIONS: Several dietary and lifestyle factors and medical conditions are independently associated with urinary citrate excretion. PMID- 23449768 TI - Immunosuppression for membranous nephropathy: a systematic review and meta analysis of 36 clinical trials. AB - BACKGROUND AND OBJECTIVES: The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) with nephrotic syndrome are still controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cochrane Library, PUBMED, EMBASE, Chinese Database, and Clinical Trial Registries (June 2012) were searched to identify RCTs investigating the effect of immunosuppression on adults with IMN and nephrotic syndrome. RESULTS: This review was an update (36 RCTs, 1762 participants) of the 2004 version (18 RCTs, 1025 participants). Immunosuppression significantly reduced all-cause mortality or ESRD (15 RCTs, 791 participants; risk ratio, 0.58 [95% confidence interval, 0.36 0.95]; P=0.03). However, the result was not consistent when prespecified subgroup analyses were undertaken. Immunosuppression increased complete or partial remission (CR + PR) (16 RCTs, 864 participants; 1.31 [1.01-1.70]; P=0.04) but resulted in more withdrawals or hospitalizations (16 RCTs, 880 participants; 5.35 [2.19-13.02]; P=0.002). Corticosteroids combined with alkylating agents significantly reduced all-cause mortality or ESRD (8 RCTs, 448 participants; 0.44 [0.26-0.75]; P=0.002) and increased CR + PR (7 RCTs, 422 participants; 1.46 [1.13 1.89]; P=0.004) but led to more adverse events (4 RCTs, 303 participants; 4.20 [1.15-15.32]; P=0.03). Cyclophosphamide was safer than chlorambucil (3 RCTs, 147 participants; 0.48 [0.26-0.90]; P=0.02). Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria. CONCLUSIONS: Alkylating agents plus corticosteroids had long-term and short-term benefits for adult IMN, but resulted in more withdrawals or hospitalizations. PMID- 23449770 TI - Short-term pretransplant renal replacement therapy and renal nonrecovery after liver transplantation alone. AB - BACKGROUND AND OBJECTIVES: Candidates with AKI including hepatorenal syndrome often recover renal function after successful liver transplantation (LT). This study examined the incidence and risk factors associated with renal nonrecovery within 6 months of LT alone among those receiving acute renal replacement therapy (RRT) before LT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Scientific Registry of Transplant Recipients data were linked with Centers for Medicare and Medicaid Services ESRD data for 2112 adult deceased-donor LT-alone recipients who received acute RRT for <=90 days before LT (February 28, 2002 to August 31, 2010). Primary outcome was renal nonrecovery (post-LT ESRD), defined as transition to chronic dialysis or waitlisting or receipt of kidney transplant within 6 months of LT. Cumulative incidence of renal nonrecovery was calculated using competing risk analysis. Cox regression identified recipient and donor predictors of renal nonrecovery. RESULTS: The cumulative incidence of renal nonrecovery after LT alone among those receiving the pre-LT acute RRT was 8.9%. Adjusted renal nonrecovery risk increased by 3.6% per day of pre-LT RRT (P<0.001). Age at LT per 5 years (P=0.02), previous-LT (P=0.01), and pre-LT diabetes (P<0.001) were significant risk factors of renal nonrecovery. Twenty-one percent of recipients died within 6 months of LT. Duration of pretransplant RRT did not predict 6-month post-transplant mortality. CONCLUSIONS: Among recipients on acute RRT before LT who survived after LT alone, the majority recovered their renal function within 6 months of LT. Longer pre-LT RRT duration, advanced age, diabetes, and re-LT were significantly associated with increased risk of renal nonrecovery. PMID- 23449769 TI - Low 25-hydroxyvitamin D levels and cognitive impairment in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: 25-hydroxyvitamin D (25[OH]D) deficiency and cognitive impairment are both prevalent in hemodialysis patients in the United States. This study tested the hypothesis that 25(OH)D deficiency may be associated with cognitive impairment because of its vasculoprotective, neuroprotective, and immune-modulatory properties. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional analysis involved 255 patients enrolled in the Dialysis and Cognition Study between 2004 and 2012. In linear regression models, 25(OH)D was the exposure variable; it was used first as a continuous variable and then stratified as deficient (<12 ng/ml), insufficient (12 to <20 ng/ml), and sufficient (>=20 ng/ml). Principal component analysis was used to obtain the memory and the executive function domains from the individual neurocognitive tests. Scores on individual tests as well as on the memory and executive function domains were the outcome variables. Multivariable models were adjusted for age, sex, race, education, and other potential confounding variables. RESULTS: Mean serum 25(OH)D +/- SD was 17.2+/-7.4 ng/ml, with 14%, 55%, and 31% of patients in the deficient, insufficient, and sufficient groups, respectively. Patients in the deficient group were more likely to be women, African American, and diabetic and to have longer dialysis vintage. Higher 25(OH)D levels were independently associated with better performance on several tests of executive function (mean difference on component executive score, 0.16 [95% confidence interval, 0.04 0.28; P=0.01] for each SD higher 25[OH]D). No association was seen with tests assessing memory. CONCLUSIONS: 25(OH)D deficiency in hemodialysis patients is associated with worse cognitive function, particularly in domains that assess executive function. PMID- 23449772 TI - Basic statistical concepts in nutrition research. AB - Statistical principles are used in nutrition research to plan and conduct research studies and to answer research questions. This article describes general statistical concepts and provides some guidelines to assist in the interpretation of research literature. Prospective and retrospective study designs used in nutrition research are presented as well as the advantages and disadvantages of each of the study designs. Descriptive statistics used to summarize data and graphical tools used to display the shape of the distribution of a set of data guide nutrition support professionals to select appropriate statistical tests. Fundamental topics of statistics, including power analysis and sample size, confidence intervals and hypothesis testing, and analysis of variance and regression, are also reviewed. The article emphasizes the importance of effective collaboration with statisticians at an early stage of the research study to avoid potential pitfalls associated with improper utilization of statistical methods. PMID- 23449771 TI - Does primary surgical closure of the patent ductus arteriosus in infants <1500 g or <=32 weeks' gestation reduce the incidence of necrotizing enterocolitis? AB - BACKGROUND: The hemodynamic perturbation related to patent ductus arteriosus (PDA) is associated with a higher risk of necrotizing enterocolitis (NEC). OBJECTIVE: To determine whether primary surgical closure, as compared with treatment with indomethacin or exposure to prophylactic indomethacin, reduces the incidence of NEC in preterm infants <1500 g and/or <=32 weeks' gestation with clinically and echocardiogram-identified PDA. METHODS: The literature was reviewed using the methodology for systematic reviews for the Consensus of Science adapted from the American Heart Association's International Liaison Committee on Resuscitation. RESULTS: Ten studies were reviewed. The incidence of NEC was not lower in infants who underwent primary surgery for closure of the PDA compared with infants treated with indomethacin or infants exposed to prophylactic indomethacin (level of evidence 2). CONCLUSION: Primary surgical closure of the PDA cannot be recommended as an intervention to decrease the incidence of NEC in infants <1500 g and/or <=32 weeks' gestation. BACKGROUND: The hemodynamic perturbation related to patent ductus arteriosus (PDA) is associated with a higher risk of necrotizing enterocolitis (NEC). OBJECTIVE: To determine whether primary surgical closure, as compared with treatment with indomethacin or exposure to prophylactic indomethacin, reduces the incidence of NEC in preterm infants <1500 g and/or <=32 weeks' gestation with clinically and echocardiogram identified PDA. METHODS: The literature was reviewed using the methodology for systematic reviews for the Consensus of Science adapted from the American Heart Association's International Liaison Committee on Resuscitation. RESULTS: Ten studies were reviewed. The incidence of NEC was not lower in infants who underwent primary surgery for closure of the PDA compared with infants treated with indomethacin or infants exposed to prophylactic indomethacin (level of evidence 2). CONCLUSION: Primary surgical closure of the PDA cannot be recommended as an intervention to decrease the incidence of NEC in infants <1500 g and/or <=32 weeks' gestation. PMID- 23449773 TI - Standards for nutrition support: pediatric hospitalized patients. PMID- 23449774 TI - Comparative analysis of intralesional sclerotherapy with sodium tetradecyl sulfate versus bleomycin in the management of low flow craniofacial soft tissue vascular lesions. AB - OBJECTIVE: Comparison of the efficacy of bleomycin over sodium tetradecyl sulfate (STS) when given intralesionally in the treatment of oral and maxillofacial venous malformation. METHODS: 16 patients with venous malformation in craniofacial region were randomly divided into two groups of eight. Group 1 was given intralesional injection of bleomycin and group 2 was injected with STS. All the cases were evaluated for a minimum period of two and a maximum of 3 years. RESULTS: Efficacy of bleomycin was found to be superior to STS, when used as intralesional sclerotherapic agent. Most of the vascular lesions of group 1 resolved after first dose giving a cure rate of 87.5% and no recurrence was observed. Group 2 patients however, required 4-6, a mean of five repeated dosage of intralesional STS before their lesions started to resolve and three patients reported with recurrence within 2 years, giving an overall effective response rate of 62.5%. CONCLUSION: Bleomycin under selected conditions appears to be an excellent therapy for treating soft tissue vascular lesions of low flow nature in craniofacial region. Predictable results were obtained with a high success rate. No systemic or pulmonary complications occurred. PMID- 23449775 TI - 'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation. AB - We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies. PMID- 23449776 TI - Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease. AB - Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt-Jakob disease. Three cases of variant Creutzfeldt-Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt-Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt-Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt-Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt-Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt-Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt-Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen homogenates, providing initial evidence of similar transmission properties after propagation in PRNP codon 129 MV and MM individuals. These studies demonstrate that spleen tissue from a PRNP MV genotype individual can propagate the variant Creutzfeldt-Jakob disease agent and that the infectious agent can be present in the spleen without CNS involvement. PMID- 23449777 TI - Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. AB - Amyotrophic lateral sclerosis is a devastating, progressive neurodegenerative disease that affects upper and lower motor neurons. Although several genes are identified as the cause of familial cases, the pathogeneses of sporadic forms, which account for 90% of amyotrophic lateral sclerosis, have not been elucidated. Transactive response DNA-binding protein 43 a nuclear protein regulating RNA processing, redistributes to the cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons, suggesting that loss-of-function of transactive response DNA binding protein 43 is one of the causes of the neurodegeneration. To test this hypothesis, we assessed the effects of knockout of transactive response DNA binding protein 43 in mouse postnatal motor neurons using Cre/loxp system. These mice developed progressive weight loss and motor impairment around the age of 60 weeks, and exhibited degeneration of large motor axon, grouped atrophy of the skeletal muscle, and denervation in the neuromuscular junction. The spinal motor neurons lacking transactive response DNA-binding protein 43 were not affected for 1 year, but exhibited atrophy at the age of 100 weeks; whereas, extraocular motor neurons, that are essentially resistant in amyotrophic lateral sclerosis, remained preserved even at the age of 100 weeks. Additionally, ultra structural analysis revealed autolysosomes and autophagosomes in the cell bodies and axons of motor neurons of the 100-week-old knockout mice. In summary, the mice in which transactive response DNA-binding protein 43 was knocked-out specifically in postnatal motor neurons exhibited an age-dependent progressive motor dysfunction accompanied by neuropathological alterations, which are common to sporadic amyotrophic lateral sclerosis. These findings suggest that transactive response DNA-binding protein 43 plays an essential role in the long term maintenance of motor neurons and that loss-of-function of this protein seems to contribute to the pathogenesis of amyotrophic lateral sclerosis. PMID- 23449778 TI - The changing epidemiology of methicillin-resistant Staphylococcus aureus in the United States: a national observational study. AB - Methicillin-resistant Staphylococcus aureus (MRSA) can cause major illness and death and impose serious economic costs on patients and hospitals. Community associated MRSA (CA-MRSA) is a growing problem in US hospitals, which are already dealing with high levels of hospital-associated MRSA (HA-MRSA), but little is known about how patient age and seasonal differences in the incidence of these 2 forms of MRSA affect the epidemic. By using national data on hospitalizations and antibiotic resistance, we estimated the magnitude and trends in annual S. aureus and MRSA hospitalization rates from 2005-2009 by patient age, infection type, and resistance phenotype (CA-MRSA vs. HA-MRSA). Although no statistically significant increase in the hospitalization rate was seen over the study period, the total number of infections increased. In 2009, there were an estimated 463,017 (95% confidence interval: 441,595, 484,439) MRSA-related hospitalizations at a rate of 11.74 (95% confidence interval: 11.20, 12.28) per 1,000 hospitalizations. We observed significant differences in infection type by age, with HA-MRSA-related hospitalizations being more common in older individuals. We also noted significant seasonality in incidence, particularly in children, with CA-MRSA peaking in the late summer and HA-MRSA peaking in the winter, which may be caused by seasonal shifts in antibiotic prescribing patterns. PMID- 23449779 TI - Longevity in male and female joggers: the Copenhagen City Heart Study. AB - Since 1970, jogging has become an increasingly popular form of exercise, but concern about harmful effects has been raised following reports of deaths during jogging. The purpose of this study was to investigate if jogging, which can be very vigorous, is associated with increased all-cause mortality in men and women. Jogging habits were recorded in a random sample of 17,589 healthy men and women aged 20-98 years, invited between 1976 and 2003 to the Copenhagen City Heart Study. The expected lifetime was calculated by integrating the predicted survival curve estimated in the Cox model. In this study 1,878 persons (1,116 men and 762 women) were classified as joggers. During the 35-year maximum follow-up period, we registered 122 deaths among joggers and 10,158 deaths among nonjoggers. The age-adjusted hazard ratio of death among joggers was 0.56 (95% confidence interval: 0.46, 0.67) for men and 0.56 (95% confidence interval: 0.40, 0.80) for women. The age-adjusted increase in survival with jogging was 6.2 years in men and 5.6 years in women. This long-term study of joggers showed that jogging was associated with significantly lower all-cause mortality and a substantial increase in survival for both men and women. PMID- 23449780 TI - Choosing wisely: our list. AB - In February 2013, the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) released its list of 5 recommendations of diagnostic and therapeutic interventions that physicians and patients should question, as part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely campaign. This commentary outlines the impetus for the AAO-HNSF to join the campaign, our list of 5 recommendations, how they were developed, and our future involvement with the campaign. The AAO-HNSF's 5 recommendations are (1) don't order a computed tomography (CT) scan of the head/brain for sudden hearing loss, (2) don't prescribe oral antibiotics for uncomplicated acute tympanostomy tube otorrhea, (3) don't prescribe oral antibiotics for uncomplicated acute external otitis, (4) don't routinely obtain radiographic imaging for patients who meet diagnostic criteria for uncomplicated acute rhinosinusitis, and (5) don't obtain CT or magnetic resonance imaging in patients with a primary complaint of hoarseness prior to examining the larynx. PMID- 23449781 TI - Safety of outpatient surgery for obstructive sleep apnea. AB - OBJECTIVE: Determine the safety experience of adult obstructive sleep apnea patients undergoing airway surgery. STUDY DESIGN: A retrospective cohort study. SETTING: The experience of members of a large Medicaid managed care organization between January 10, 2009, and June 30, 2011. SUBJECTS AND METHODS: Four hundred fifty-two adult Medicaid obstructive sleep apnea (OSA) patients (404 ambulatory, 48 inpatient) receiving head and neck airway surgery form the basis of this report. Four safety indicators were reported from administrative data for 30 days: emergency room visit, inpatient admission, observation day, and 3 or more primary care physician visits. The occurrence of myocardial infarction, deep venous thrombosis, stroke, pulmonary embolism, tracheostomy, or transfusion was noted. RESULTS: Ninety-four percent of the nasal, 86% of the palatal, and 79% of the nasal/palatal surgeries (89% overall) were ambulatory. The observed catastrophic complication rate among ambulatory patients was zero (95% confidence interval, 0.0%-1.1%). Emergency room visits for pain-related diagnoses were the most common adverse outcome (51%). Administrative data sets can be used to provide insight into practice safety questions. CONCLUSION: Contrary to guidelines, most OSA patients underwent ambulatory head and neck airway surgery. The observed catastrophic complication rate was zero. Administrative data sets can be used to provide insight into practice safety questions. Further study is warranted of ambulatory surgery management of adult sleep apnea patients. PMID- 23449782 TI - SSRIs associated with increased risk of brain haemorrhage, but absolute risks low. PMID- 23449783 TI - Structural characterization of H-1 parvovirus: comparison of infectious virions to empty capsids. AB - The structure of single-stranded DNA (ssDNA) packaging H-1 parvovirus (H-1PV), which is being developed as an antitumor gene delivery vector, has been determined for wild-type (wt) virions and noninfectious (empty) capsids to 2.7- and 3.2-A resolution, respectively, using X-ray crystallography. The capsid viral protein (VP) structure consists of an alpha-helix and an eight-stranded anti parallel beta-barrel with large loop regions between the strands. The beta-barrel and loops form the capsid core and surface, respectively. In the wt structure, 600 nucleotides are ordered in an interior DNA binding pocket of the capsid. This accounts for ~12% of the H-1PV genome. The wt structure is identical to the empty capsid structure, except for side chain conformation variations at the nucleotide binding pocket. Comparison of the H-1PV nucleotides to those observed in canine parvovirus and minute virus of mice, two members of the genus Parvovirus, showed both similarity in structure and analogous interactions. This observation suggests a functional role, such as in capsid stability and/or ssDNA genome recognition for encapsulation. The VP structure differs from those of other parvoviruses in surface loop regions that control receptor binding, tissue tropism, pathogenicity, and antibody recognition, including VP sequences reported to determine tumor cell tropism for oncotropic rodent parvoviruses. These structures of H-1PV provide insight into structural features that dictate capsid stabilization following genome packaging and three-dimensional information applicable for rational design of tumor-targeted recombinant gene delivery vectors. PMID- 23449784 TI - The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus replication and pathogenesis in mice. AB - After receptor binding and internalization during influenza virus entry, the hemagglutinin (HA) protein is triggered by low pH to undergo irreversible conformational changes that mediate membrane fusion. To investigate how mutations that alter the activation pH of the HA protein influence the fitness of an avian H5N1 influenza virus in a mammalian model, we infected C57BL/6J or DBA/2J mice and compared the replication and virulence of recombinant A/chicken/Vietnam/C58/04 (H5N1) HA-Y231H mutant, wild-type, and HA-H241Q and HA K582I mutant viruses that have HA activation pH values of 6.3, 5.9, 5.6, and 5.4, respectively. The HA-Y231H mutant virus was highly susceptible to acid inactivation in vitro and was attenuated for growth and virulence in mice, suggesting that an H5N1 HA protein triggered at pH 6.3 is too unstable for the virus to remain fit. Wild-type and HA-H241Q viruses were similar in pathogenicity and grew to similar levels in mice, ducks, and cell cultures derived from both avian and mammalian tissues, suggesting that H5N1 HA proteins triggered at pH values in the range of 5.9 to 5.6 broadly support replication. The HA-K582I mutant virus had greater growth and virulence in DBA/2J mice than the wild type did, although the mutant virus was highly attenuated in ducks. The data suggest that adaptation of avian H5N1 influenza virus for infection in mammals is supported by a decrease in the HA activation pH to 5.4. Identification of the HA activation pH as a host-specific infectivity factor is expected to aid in the surveillance and risk assessment of currently circulating H5N1 influenza viruses. PMID- 23449785 TI - A systems biology examination of the human female genital tract shows compartmentalization of immune factor expression. AB - Many mucosal factors in the female genital tract (FGT) have been associated with HIV susceptibility, but little is known about their anatomical distribution in the FGT compartments. This study comprehensively characterized global immune factor expression in different tissue sites of the lower and upper FGT by using a systems biology approach. Tissue sections from the ectocervix, endocervix, and endometrium from seven women who underwent hysterectomy were analyzed by a combination of quantitative mass spectrometry and immunohistochemical staining. Of the >1,000 proteins identified, 281 were found to be differentially abundant in different tissue sites. Hierarchical clustering identified four major functional pathways distinguishing compartments, including innate immune pathways (acute-phase response, LXR/RXR) and development (RhoA signaling, gluconeogenesis), which were enriched in the ectocervix/endocervix and endometrium, respectively. Immune factors important for HIV susceptibility, including antiproteases, immunoglobulins, complement components, and antimicrobial factors, were most abundant in the ectocervix/endocervix, while the endometrium had a greater abundance of certain factors that promote HIV replication. Immune factor abundance is heterogeneous throughout the FGT and shows unique immune microenvironments for HIV based on the exposure site. This may have important implications for early events in HIV transmission and site specific susceptibility to HIV in the FGT. PMID- 23449786 TI - Functional analysis of the murine coronavirus genomic RNA packaging signal. AB - Coronaviruses selectively package genomic RNA into assembled virions, despite the great molar excess of subgenomic RNA species that is present in infected cells. The genomic packaging signal (PS) for the coronavirus mouse hepatitis virus (MHV) was originally identified as an element that conferred packaging capability to defective interfering RNAs. The MHV PS is an RNA structure that maps to the region of the replicase gene encoding the nonstructural protein 15 subunit of the viral replicase-transcriptase complex. To begin to understand the role and mechanism of action of the MHV PS in its native genomic locus, we constructed viral mutants in which this cis-acting element was altered, deleted, or transposed. Our results demonstrated that the PS is pivotal in the selection of viral genomic RNA for incorporation into virions. Mutants in which PS RNA secondary structure was disrupted or entirely ablated packaged large quantities of subgenomic RNAs, in addition to genomic RNA. Moreover, the PS retained its function when displaced to an ectopic site in the genome. Surprisingly, the PS was not essential for MHV viability, nor did its elimination have a severe effect on viral growth. However, the PS was found to provide a distinct selective advantage to MHV. Viruses containing the PS readily outcompeted their otherwise isogenic counterparts lacking the PS. PMID- 23449787 TI - Plasmin-mediated activation of pandemic H1N1 influenza virus hemagglutinin is independent of the viral neuraminidase. AB - Influenza virus is well recognized to modulate host tropism and pathogenesis based on mutations in the proteolytic cleavage site of the viral hemagglutinin (HA), which activates HA and exposes the fusion peptide for membrane fusion. Instead of the conventional trypsin-mediated cleavage event, modification of the cleavage site allows extended use of host cell proteases and enhanced spread in vivo. For H1N1 influenza viruses, the mouse-adapted A/WSN/33 strain is known to replicate in the brain based on recruitment of plasminogen by the viral neuraminidase (NA), as well as a Ser-Tyr substitution at the P2 position of the HA cleavage site. Here, we show that an equivalent Ser-Tyr substitution has occurred in the HA of naturally occurring human H1N1 influenza viruses. We characterize one of these viruses (A/Beijing/718/2009), as well as the prototype A/California/04/2009 with a Ser-Tyr substitution in the cleavage site, and show that these HAs are preferentially cleaved by plasmin. Importantly, cleavage activation by plasmin/plasminogen was independent of the viral NA, suggesting a novel mechanism for HA cleavage activation. We show that the viral HA itself can recruit plasminogen for HA cleavage. We further show that cellular factors, as well as streptokinase from bacteria commonly coinfecting the respiratory tract of influenza patients, can be a source of activated plasminogen for plasmin-mediated cleavage of influenza virus HAs that contain a Ser-Tyr substitution in the cleavage site. PMID- 23449788 TI - Variation of HIV-1 mutation spectra among cell types. AB - The high rates of mutation, recombination, and replication drive HIV-1 diversity. In this study, we investigated how cell type affects viral mutation rate and mutation spectra. In studying four different cell types, no differences in mutation rate were observed, but intriguingly cell type differences impacted HIV 1 mutation spectra. This is the first description of significant differences in HIV-1 mutation spectra observed in different cell types in the absence of changes in the viral mutation rate. PMID- 23449789 TI - APOBEC3 inhibition of mouse mammary tumor virus infection: the role of cytidine deamination versus inhibition of reverse transcription. AB - The apolipoprotein B editing complex 3 (APOBEC3) family of proteins is a group of intrinsic antiviral factors active against a number of retroviral pathogens, including HIV in humans and mouse mammary tumor virus (MMTV) in mice. APOBEC3 restricts its viral targets through cytidine deamination of viral DNA during reverse transcription or via deaminase-independent means. Here, we used virions from the mammary tissue of MMTV-infected inbred wild-type mice with different allelic APOBEC3 variants (APOBEC3(BALB) and APOBEC3(BL/6)) and knockout mice to determine whether cytidine deamination was important for APOBEC3's anti-MMTV activity. First, using anti-murine APOBEC3 antiserum, we showed that both APOBEC3 allelic variants are packaged into the cores of milk-borne virions produced in vivo. Next, using an in vitro deamination assay, we determined that virion packaged APOBEC3 retains its deamination activity and that allelic differences in APOBEC3 affect the sequence specificity. In spite of this in vitro activity, cytidine deamination by virion-packaged APOBEC3 of MMTV early reverse transcription DNA occurred only at low levels. Instead, the major means by which in vivo virion-packaged APOBEC3 restricted virus was through inhibition of early reverse transcription in both cell-free virions and in vitro infection assays. Moreover, the different wild-type alleles varied in their ability to inhibit this step. Our data suggest that while APOBEC3-mediated cytidine deamination of MMTV may occur, it is not the major means by which APOBEC3 restricts MMTV infection in vivo. This may reflect the long-term coexistence of MMTV and APOBEC3 in mice. PMID- 23449790 TI - Robust immunity to an auxotrophic Mycobacterium bovis BCG-VLP prime-boost HIV vaccine candidate in a nonhuman primate model. AB - We previously reported that a recombinant pantothenate auxotroph of Mycobacterium bovis BCG expressing human immunodeficiency virus type 1 (HIV-1) subtype C Gag (rBCGpan-Gag) efficiently primes the mouse immune system for a boost with a recombinant modified vaccinia virus Ankara (rMVA) vaccine. In this study, we further evaluated the immunogenicity of rBCGpan-Gag in a nonhuman primate model. Two groups of chacma baboons were primed or mock primed twice with either rBCGpan Gag or a control BCG. Both groups were boosted with HIV-1 Pr55(gag) virus-like particles (Gag VLPs). The magnitude and breadth of HIV-specific cellular responses were measured using a gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISPOT) assay, and the cytokine profiles and memory phenotypes of T cells were evaluated by polychromatic flow cytometry. Gag specific responses were detected in all animals after the second inoculation with rBCGpan-Gag. Boosting with Gag VLPs significantly increased the magnitude and breadth of the responses in the baboons that were primed with rBCGpan-Gag. These responses targeted an average of 12 Gag peptides per animal, compared to an average of 3 peptides per animal for the mock-primed controls. Robust responses of Gag-specific polyfunctional T cells capable of simultaneously producing IFN gamma, tumor necrosis alpha (TNF-alpha), and interleukin-2 (IL-2) were detected in the rBCGpan-Gag-primed animals. Gag-specific memory T cells were skewed toward a central memory phenotype in both CD4(+) and CD8(+) T cell populations. These data show that the rBCGpan-Gag prime and Gag VLP boost vaccine regimen is highly immunogenic, inducing a broad and polyfunctional central memory T cell response. This report further indicates the feasibility of developing a BCG-based HIV vaccine that is safe for childhood HIV immunization. PMID- 23449791 TI - HIV-specific CD8+ T cells from elite controllers are primed for survival. AB - HIV-specific cytotoxic T lymphocytes (CTL) are preferentially primed for apoptosis, and this may represent a viral escape mechanism. We hypothesized that HIV-infected individuals that control virus to undetectable levels without antiretroviral therapy (ART) (elite controllers [EC]) have the capacity to upregulate survival factors that allow them to resist apoptosis. To address this, we performed cross-sectional and longitudinal analysis of proapoptotic (cleaved caspase-3) and antiapoptotic (Bcl-2) markers of cytomegalovirus (CMV) and HIV specific CD8 T cells in a cohort of HIV-infected subjects with various degrees of viral control on and off ART. We demonstrated that HIV-specific CTL from EC are more resistant to apoptosis than those with pharmacologic control (successfully treated patients [ST]), despite similar in vivo conditions. Longitudinal analysis of chronically infected persons starting ART revealed that the frequency of HIV specific T cells prone to death decreased, suggesting that this phenotype is partially reversible even though it never achieves the levels present in EC. Elucidating the apoptotic factors contributing to the survival of CTL in EC is paramount to our development of effective HIV-1 vaccines. Furthermore, a better understanding of cellular markers that can be utilized to predict response durability in disease- or vaccine-elicited responses will advance the field. PMID- 23449792 TI - Maribavir inhibits Epstein-Barr virus transcription through the EBV protein kinase. AB - Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV transcripts during EBV lytic infection. Here we demonstrate, with the use of a BGLF4 knockout virus, that effects of MBV on transcription take place primarily through inhibition of BGLF4. MBV inhibits viral genome copy numbers and infectivity to levels similar to and exceeding levels produced by BGLF4 knockout virus. PMID- 23449793 TI - Human cell tropism and innate immune system interactions of human respiratory coronavirus EMC compared to those of severe acute respiratory syndrome coronavirus. AB - Infections with human coronavirus EMC (HCoV-EMC) are associated with severe pneumonia. We demonstrate that HCoV-EMC resembles severe acute respiratory syndrome coronavirus (SARS-CoV) in productively infecting primary and continuous cells of the human airways and in preventing the induction of interferon regulatory factor 3 (IRF-3)-mediated antiviral alpha/beta interferon (IFN alpha/beta) responses. However, HCoV-EMC was markedly more sensitive to the antiviral state established by ectopic IFN. Thus, HCoV-EMC can utilize a broad range of human cell substrates and suppress IFN induction, but it does not reach the IFN resistance of SARS-CoV. PMID- 23449794 TI - The nonstructural protein 2C of a Picorna-like virus displays nucleic acid helix destabilizing activity that can be functionally separated from its ATPase activity. AB - Picorna-like viruses in the Picornavirales order are a large group of positive strand RNA viruses that include numerous important pathogens for plants, insects, and humans. In these viruses, nonstructural protein 2C is one of the most conserved proteins and contains ATPase activity and putative RNA helicase activity. Here we expressed 2C protein of Ectropis obliqua picorna-like virus (EoV; genus Iflavirus, family Iflaviridae, order Picornavirales) in a eukaryotic expression system and determined that EoV 2C displays ATP-independent nucleic acid helix destabilizing and strand annealing acceleration activity in a concentration-dependent manner, indicating that this picornaviral 2C is more like an RNA chaperone than like the previously predicted RNA helicase. Our further characterization of EoV 2C revealed that divalent metal ions, such as Mg(2+) and Zn(2+), inhibit 2C-mediated helix destabilization to different extents. Moreover, we determined that EoV 2C also contains ATPase activity like that of other picornaviral 2C proteins and further assessed the functional relevance between its RNA chaperone-like and ATPase activities using mutational analysis as well as their responses to Mg(2+). Our data show that, when one of the two 2C activities was dramatically inhibited or almost abolished, the other activity could remain intact, showing that the RNA chaperone-like and ATPase activities of EoV 2C can be functionally separated. This report reveals that a picorna-like virus 2C protein displays RNA helix destabilizing and strand annealing acceleration activity, which may be critical for picornaviral replication and pathogenesis, and should foster our understanding of picorna-like viruses and viral RNA chaperones. PMID- 23449795 TI - KIR2DL4 copy number variation is associated with CD4+ T-cell depletion and function of cytokine-producing NK cell subsets in SIV-infected Mamu-A*01-negative rhesus macaques. AB - Here, we demonstrate that KIR2DL4 copy number variation (CNV) is associated with CD4(+) T-cell decline and functionality of cytokine-producing NK cells during primary simian immunodeficiency virus (SIV) infection in Mamu-A*01(-) Indian origin rhesus macaques, with higher KIR2DL4 copy numbers being associated with a better preservation of CD4(+) T cells and an increased gamma interferon (IFN gamma) production from stimulated cytokine-producing NK cell subsets during acute SIVmac251 infection. These findings underscore the crucial role of activating killer-cell immunoglobulin-like receptors (KIRs) in NK cell-mediated SIV responses during early SIV infection. PMID- 23449796 TI - Mother-offspring transmission and age-dependent accumulation of simian foamy virus in wild chimpanzees. AB - Simian foamy viruses (SFVs) are thought to infect virtually any adult nonhuman primate (NHP). While many data have accumulated about patterns of codivergence with their hosts and cross-species transmission events, little is known about the modalities of SFV transmission within NHP species, especially in the wild. Here we provide a detailed investigation of the dynamics of SFV circulation in a wild community of Western chimpanzees (Pan troglodytes verus). We demonstrate that mother-offspring (vertical) SFV transmission is common and hypothesize that it accounts for a number of primary infections. We also show that multiple infections with several chimpanzee-specific SFV strains (i.e., superinfection) commonly happen in adult chimpanzees, which might point to adult-specific aggressive behaviors as a lifelong source of SFV infection. Our data give evidence for complex SFV dynamics in wild chimpanzees, even at a single community scale, and show that linking wild NHP social interactions and their microorganisms' dynamics is feasible. PMID- 23449798 TI - A new determinant of H5N1 influenza virus pathogenesis in mammals. PMID- 23449797 TI - H2AX phosphorylation is important for LANA-mediated Kaposi's sarcoma-associated herpesvirus episome persistence. AB - The DNA damage response (DDR) of host cells is utilized by a number of viruses to establish and propagate their genomes in the infected cells. We examined the expression of the DDR genes during Kaposi's sarcoma-associated herpesvirus (KSHV) infection of human peripheral blood mononuclear cells (PBMCs). The genes were mostly downregulated, except H2AX, which was upregulated during infection. H2AX is important for gammaherpesvirus infectivity, and its phosphorylation at serine 139 is crucial for maintenance of latency during mouse gamma-herpesvirus 68 (MHV 68) infection. We now also observed phosphorylation of H2AX at serine 139 during KSHV infection. H2AX is a histone H2A isoform shown to interact with the latency associated nuclear antigen (LANA) encoded by KSHV. Here, we show that LANA directly interacted with H2AX through domains at both its N and C termini. The phosphorylated form of H2AX (gammaH2AX) was shown to colocalize with LANA. Chromatin immunoprecipitation (ChIP) assays showed that a reduction in H2AX levels resulted in reduced binding of LANA with KSHV terminal repeats (TRs). Binding preferences of H2AX and gammaH2AX along the KSHV episome were examined by whole-episome ChIP analysis. We showed that gammaH2AX had a higher relative binding activity along the TR regions than that of the long unique region (LUR), which highlighted the importance of H2AX phosphorylation during KSHV infection. Furthermore, knockdown of H2AX resulted in decreased KSHV episome copy number. Notably, the C terminus of LANA contributed to phosphorylation of H2AX. However, phosphorylation was not dependent on the ability of LANA to drive KSHV-infected cells into S-phase. Thus, H2AX contributes to association of LANA with the TRs, and phosphorylation of H2AX is likely important for its increased density at the TRs. PMID- 23449799 TI - Human cytomegalovirus pp71 stimulates major histocompatibility complex class i presentation of IE1-derived peptides at immediate early times of infection. AB - Suppression of major histocompatibility complex (MHC) class I-mediated presentation of human cytomegalovirus (HCMV) peptides is an important mechanism to avoid CD8 T lymphocyte recognition and killing of infected cells. Of particular interest is how MHC class I presentation of essential regulatory immediate early (IE) proteins of HCMV can be effectively compromised at times when known viral immunoevasins are not abundantly expressed. The tegument protein pp71 had been suggested to be involved in MHC class I downregulation. Intriguingly, this polypeptide is also critically engaged in the initial derepression of the major IE gene locus, leading to enhanced expression of IE proteins IE1-pp72 and IE2-pp86. Using a set of viral mutants, we addressed the role of pp71 in MHC class I presentation of IE1-pp72-derived peptides. We show that the amount of "incoming" pp71 positively correlates with IE1-pp72 protein levels and with the presentation of IE1-derived peptides. This indicates that the amount of the IE1 protein, induced by pp71, rather than a putative immunoevasive function of the tegument protein, determines MHC class I antigen presentation of IE1-derived peptides. This process proved to be independent of the presence of pp65, which had been reported to interfere with IE1 presentation. It may thus be beneficial for the success of HCMV replication to limit the level of pp71 delivered from infecting particles in order to avoid critical levels of MHC class I presentation of IE protein-derived peptides. PMID- 23449800 TI - Influenza viruses with rearranged genomes as live-attenuated vaccines. AB - H5N1 and H9N2 avian influenza virus subtypes top the World Health Organization's list for the greatest pandemic potential. Inactivated H5N1 vaccines induce limited immune responses and, in the case of live-attenuated influenza virus vaccines (LAIV), there are safety concerns regarding the possibility of reassortment between the H5 gene segment and circulating influenza viruses. In order to overcome these drawbacks, we rearranged the genome of an avian H9N2 influenza virus and expressed the entire H5 hemagglutinin open reading frame (ORF) from the segment 8 viral RNA. These vectors had reduced polymerase activities as well as viral replication in vitro and excellent safety profiles in vivo. Immunization with the dual H9-H5 influenza virus resulted in protection against lethal H5N1 challenge in mice and ferrets, and also against a potentially pandemic H9 virus. Our studies demonstrate that rearranging the influenza virus genome has great potential for the development of improved vaccines against influenza virus as well as other pathogens. PMID- 23449801 TI - Deep sequencing analysis of defective genomes of parainfluenza virus 5 and their role in interferon induction. AB - Preparations of parainfluenza virus 5 (PIV5) that are potent activators of the interferon (IFN) induction cascade were generated by high-multiplicity passage in order to accumulate defective interfering virus genomes (DIs). Nucleocapsid RNA from these virus preparations was extracted and subjected to deep sequencing. Sequencing data were analyzed using methods designed to detect internal deletion and "copyback" DIs in order to identify and characterize the different DIs present and to approximately quantify the ratio of defective to nondefective genomes. Trailer copybacks dominated the DI populations in IFN-inducing preparations of both the PIV5 wild type (wt) and PIV5-VDeltaC (a recombinant virus that does not encode a functional V protein). Although the PIV5 V protein is an efficient inhibitor of the IFN induction cascade, we show that nondefective PIV5 wt is unable to prevent activation of the IFN response by coinfecting copyback DIs due to the interfering effects of copyback DIs on nondefective virus protein expression. As a result, copyback DIs are able to very rapidly activate the IFN induction cascade prior to the expression of detectable levels of V protein by coinfecting nondefective virus. PMID- 23449802 TI - Porcine reproductive and respiratory syndrome virus Nsp1beta inhibits interferon activated JAK/STAT signal transduction by inducing karyopherin-alpha1 degradation. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) inhibits the interferon-mediated antiviral response. Type I interferons (IFNs) induce the expression of IFN-stimulated genes by activating phosphorylation of both signal transducer and activator of transcription 1 (STAT1) and STAT2, which form heterotrimers (interferon-stimulated gene factor 3 [ISGF3]) with interferon regulatory factor 9 (IRF9) and translocate to the nucleus. PRRSV Nsp1beta blocks the nuclear translocation of the ISGF3 complex by an unknown mechanism. In this study, we discovered that Nsp1beta induced the degradation of karyopherin-alpha1 (KPNA1, also called importin-alpha5), which is known to mediate the nuclear import of ISGF3. Overexpression of Nsp1beta resulted in a reduction of KPNA1 levels in a dose-dependent manner, and treatment of the cells with the proteasome inhibitor MG132 restored KPNA1 levels. Furthermore, the presence of Nsp1beta induced an elevation of KPNA1 ubiquitination and a shortening of its half-life. Our analysis of Nsp1beta deletion constructs showed that the N-terminal domain of Nsp1beta was involved in the ubiquitin-proteasomal degradation of KPNA1. A nucleotide substitution resulting in an amino acid change from valine to isoleucine at residue 19 of Nsp1beta diminished its ability to induce KPNA1 degradation and to inhibit IFN-mediated signaling. Interestingly, infection of MARC-145 cells by PRRSV strains VR-2332 and VR-2385 also resulted in KPNA1 reduction, whereas infection by an avirulent strain, Ingelvac PRRS modified live virus (MLV), did not. MLV Nsp1beta had no effect on KPNA1; however, a mutant with an amino acid change at residue 19 from isoleucine to valine induced KPNA1 degradation. These results indicate that Nsp1beta blocks ISGF3 nuclear translocation by inducing KPNA1 degradation and that valine-19 in Nsp1beta correlates with the inhibition. PMID- 23449803 TI - MicroRNA-27a regulates lipid metabolism and inhibits hepatitis C virus replication in human hepatoma cells. AB - The replication and infectivity of the lipotropic hepatitis C virus (HCV) are regulated by cellular lipid status. Among differentially expressed microRNAs (miRNAs), we found that miR-27a was preferentially expressed in HCV-infected liver over hepatitis B virus (HBV)-infected liver. Gene expression profiling of Huh-7.5 cells showed that miR-27a regulates lipid metabolism by targeting the lipid synthetic transcription factor RXRalpha and the lipid transporter ATP binding cassette subfamily A member 1. In addition, miR-27a repressed the expression of many lipid metabolism-related genes, including FASN, SREBP1, SREBP2, PPARalpha, and PPARgamma, as well as ApoA1, ApoB100, and ApoE3, which are essential for the production of infectious viral particles. miR-27a repression increased the cellular lipid content, decreased the buoyant density of HCV particles from 1.13 to 1.08 g/cm(3), and increased viral replication and infectivity. miR-27a overexpression substantially decreased viral infectivity. Furthermore, miR-27a enhanced in vitro interferon (IFN) signaling, and patients who expressed high levels of miR-27a in the liver showed a more favorable response to pegylated IFN and ribavirin combination therapy. Interestingly, the expression of miR-27a was upregulated by HCV infection and lipid overload through the adipocyte differentiation transcription factor C/EBPalpha. In turn, upregulated miR-27a repressed HCV infection and lipid storage in cells. Thus, this negative feedback mechanism might contribute to the maintenance of a low viral load and would be beneficial to the virus by allowing it to escape host immune surveillance and establish a persistent chronic HCV infection. PMID- 23449804 TI - 1918 Influenza virus hemagglutinin (HA) and the viral RNA polymerase complex enhance viral pathogenicity, but only HA induces aberrant host responses in mice. AB - The 1918 pandemic influenza virus was the most devastating infectious agent in human history, causing fatal pneumonia and an estimated 20 to 50 million deaths worldwide. Previous studies indicated a prominent role of the hemagglutinin (HA) gene in efficient replication and high virulence of the 1918 virus in mice. It is, however, still unclear whether the high replication ability or the 1918 influenza virus HA gene is required for 1918 virus to exhibit high virulence in mice. Here, we examined the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus (A/Kawasaki/173/2001 [K173]) in a mouse model. In addition to the 1918 influenza virus HA, we demonstrated the role of the viral RNA replication complex in efficient replication of viruses in mouse lungs, whereas only the HA gene is responsible for lethality in mice. Global gene expression profiling of infected mouse lungs revealed that the 1918 influenza virus HA was sufficient to induce transcriptional changes similar to those induced by the 1918 virus, despite difference in lymphocyte gene expression. Increased expression of genes associated with the acute-phase response and the protein ubiquitination pathway were enriched during infections with the 1918 and 1918HA/K173 viruses, whereas reassortant viruses bearing the 1918 viral RNA polymerase complex induced transcriptional changes similar to those seen with the K173 virus. Taken together, these data suggest that HA and the viral RNA polymerase complex are critical determinants of Spanish influenza pathogenesis, but only HA, and not the viral RNA polymerase complex and NP, is responsible for extreme host responses observed in mice infected with the 1918 influenza virus. PMID- 23449805 TI - Kaposi's sarcoma-associated herpesvirus-encoded viral IRF3 modulates major histocompatibility complex class II (MHC-II) antigen presentation through MHC-II transactivator-dependent and -independent mechanisms: implications for oncogenesis. AB - Evasion of immune T cell responses is crucial for persistent viruses to establish a normal carrier state. Most studies on active immune modulation mechanisms have focused on the stage of virus production in infected cells, when large numbers of viral antigens and potential immune modulators are expressed. For oncogenic viruses such as Kaposi's sarcoma-associated herpesvirus (KSHV), which is carried as a lifelong infection, usually with little harmful effect, but can cause various tumors, the immune evasion strategies can also be relevant in the context of tumorigenesis. Here we report that the virus-encoded interferon regulatory factor 3 (vIRF3) latent viral gene expressed in KSHV-related tumors functions as a potent immunevasin. Expression of vIRF3 downregulates surface major histocompatibility complex class II (MHC-II) DR expression with slow kinetics but, more importantly, can substantially inhibit recognition by KSHV-specific CD4 T cells prior to its effects on MHC-II DR downregulation in model cell systems. This property of vIRF3 is only partly due to its ability to inhibit the transcription of CIITA and, thus, MHC-II expression; CIITA-independent inhibition of MHC-II transcripts and another as yet unidentified posttranscriptional mechanism are also involved in qualitatively modulating the availability of specific peptide/MHC-II complexes at the cell surface. Consistent with these observations, the vIRF3-expressing KSHV-associated primary effusion lymphoma (PEL) lines are generally resistant to recognition by KSHV-specific CD4 T cells. Interestingly, some PEL lines exhibit small subpopulations with lower vIRF3 expression that can be recognized. These data implicate vIRF3 as a critical determinant of the MHC-II antigen presentation function in KSHV-associated PELs that is likely to be important in the pathogenesis of these tumors. PMID- 23449806 TI - A fully attenuated recombinant Salmonid alphavirus becomes pathogenic through a single amino acid change in the E2 glycoprotein. AB - A recombinant sleeping disease virus (rSDV) was previously shown to be totally attenuated and provide long-term protection in trout (C. Moriette, M. Leberre, A. Lamoureux, T. L. Lai, M. Bremont, J. Virol. 80:4088-4098, 2006). Sequence comparison of the rSDV to wild-type genomes exhibited a number of nucleotide changes. In the current study, we demonstrate that the virulent phenotype of SDV was essentially associated with two amino acid changes, V8A and M136T, in the E2 glycoprotein, with the V8A change mostly being involved in the acquisition of the virulent phenotype. PMID- 23449807 TI - A grandmothers' tea: evaluation of a breastfeeding support intervention. AB - This study's purpose was to evaluate an intervention to facilitate grandmothers' knowledge and support of breastfeeding. A pilot study with a quasi-experimental two-group posttest design was used to evaluate whether the intervention made a difference in grandmothers' knowledge, attitudes, and intent to recommend breastfeeding. The 26 grandmothers in the intervention group attended A Grandmothers' Tea program; the 23 grandmothers in the control group received written information. The intervention group had greater posttest knowledge scores than the control group but had no significant differences in attitudes or intent. However, a significant difference was evident between the attitude scores of grandmothers who breastfed their infants and of grandmothers who did not breastfeed their infants regardless of receiving the intervention. PMID- 23449808 TI - Complete genome sequence of Treponema pallidum strain DAL-1. AB - Treponema pallidum strain DAL-1 is a human uncultivable pathogen causing the sexually transmitted disease syphilis. Strain DAL-1 was isolated from the amniotic fluid of a pregnant woman in the secondary stage of syphilis. Here we describe the 1,139,971 bp long genome of T. pallidum strain DAL-1 which was sequenced using two independent sequencing methods (454 pyrosequencing and Illumina). In rabbits, strain DAL-1 replicated better than the T. pallidum strain Nichols. The comparison of the complete DAL-1 genome sequence with the Nichols sequence revealed a list of genetic differences that are potentially responsible for the increased rabbit virulence of the DAL-1 strain. PMID- 23449809 TI - Treatment protocol for high velocity/high energy gunshot injuries to the face. AB - Major causes of facial combat injuries include blasts, high-velocity/high-energy missiles, and low-velocity missiles. High-velocity bullets fired from assault rifles encompass special ballistic properties, creating a transient cavitation space with a small entrance wound and a much larger exit wound. There is no dispute regarding the fact that primary emergency treatment of ballistic injuries to the face commences in accordance with the current advanced trauma life support (ATLS) recommendations; the main areas in which disputes do exist concern the question of the timing, sequence, and modes of surgical treatment. The aim of the present study is to present the treatment outcome of high-velocity/high-energy gunshot injuries to the face, using a protocol based on the experience of a single level I trauma center. A group of 23 injured combat soldiers who sustained bullet and shrapnel injuries to the maxillofacial region during a 3-week regional military conflict were evaluated in this study. Nine patients met the inclusion criteria (high-velocity/high-energy injuries) and were included in the study. According to our protocol, upon arrival patients underwent endotracheal intubation and were hemodynamically stabilized in the shock-trauma unit and underwent total-body computed tomography with 3-D reconstruction of the head and neck and computed tomography angiography. All patients underwent maxillofacial surgery upon the day of arrival according to the protocol we present. In view of our treatment outcomes, results, and low complication rates, we conclude that strict adherence to a well-founded and structured treatment protocol based on clinical experience is mandatory in providing efficient, appropriate, and successful treatment to a relatively large group of patients who sustain various degrees of maxillofacial injuries during a short period of time. PMID- 23449810 TI - Using middle ear risk index and et function as parameters for predicting the outcome of tympanoplasty. AB - Otitis media is an important and a highly prevalent disease of the middle ear and poses serious health problem world wide especially in developing countries where large percentage of the population lack specialized medical care. With a large number of patients frequently undergoing tympanoplasty for tubotympanic type of CSOM, it's important to assess the severity of the disease and predict the outcome of the surgical management whenever done. A normally functioning eustachian tube is an equally essential physiologic requirement for a healthy middle ear and normal hearing. In this study we have used the middle ear risk index (MERI) developed by Kartush which generates a numeric indicator of the severity of the middle ear disease to stratify patient groups according to the severity of the disease and to evaluate the efficiency of MERI score in predicting the outcome of tympanoplasty. PMID- 23449811 TI - Multiple apocrine hidrocystomas: a case report. AB - Hidrocystomas are rare cystic lesions that form benign tumours of the sweat glands. In this report, a clinical case of multiple apocrine hidrocystomas on both the upper and lower eyelids, and on both the malar regions has been discussed. These lesions are less likely than the eccrine lesions to occur at the periorbital region. PMID- 23449812 TI - Mitigation of salt stress in wheat seedlings by halotolerant bacteria isolated from saline habitats. AB - Eighty four halotolerant bacterial strains were isolated from the saline habitats and screened for growth at different NaCl concentrations. All grew well at 5% NaCl, but only 25% isolates showed growth at 20% NaCl concentration. Five strains SL3, SL32, SL35, J8W and PU62 growing well in 20% NaCl concentrations were further characterized for multiple plant growth promoting traits such as indole 3- acetic acid (IAA) production, HCN and siderophore production, ACC deaminase activity and P-solubilization. None were positive for HCN production and PCR amplification of acdS, the structural gene for ACC deaminase enzyme was found negative. 16S rRNA gene sequencing analysis of the five strains showed them to belong to two genera Bacillus and Hallobacillus. In vitro experiments showed that salt concentrations had significant inhibitory effects on development of seedlings but not on the growth of the bacterial strains. Inoculation of the 5 halotolerant bacterial strains to ameliorate salt stress (80 mM, 160 mM and 320 mM) in wheat seedlings produced an increase in root length of 71.7% in comparison with uninoculated positive controls. In particular, Hallobacillus sp. SL3 and Bacillus halodenitrificans PU62 showed more than 90% increase in root elongation and 17.4% increase in dry weight when compared to uninoculated wheat seedlings at 320 mM NaCl stress indicating a significant reduction of the deleterious effects of NaCl. These results indicate that halotolerant bacteria isolated from saline environments have potential to enhance plant growth under saline stress through direct or indirect mechanisms and would be most appropriate as bioinoculants under such conditions. PMID- 23449813 TI - Rehabilitation in patients with dementia following hip fracture: a systematic review. AB - PURPOSE: Best rehabilitation practices after hip fracture for people with dementia have not been established. A systematic review was conducted to determine current evidence for rehabilitation in this population, including residents in continuing care. METHODS: Standardized review methodology was used to search eight databases for literature on hip-fracture rehabilitation for people with dementia. Eligible studies included participants with dementia who had a hip fracture; performed a rehabilitation intervention; and evaluated one or more of function, ambulation, discharge location, or falls. The Newcastle-Ottawa Scale was used to assess validity. RESULTS: A total of 13 studies were included: five randomized controlled trials (RCTs), seven prospective cohort series, and one retrospective cohort study. Average quality ratings for RCTs and cohort studies were good and fair respectively. Participants with mild to moderate dementia receiving rehabilitation showed similar relative gains in function to those without dementia. Only one study examined the effect of rehabilitation among residents in continuing care. CONCLUSIONS: People with mild or moderate dementia may show improved function and ambulation and decreased fall risk after rehabilitation post hip fracture, similar to gains achieved by those without dementia. More research is required to ascertain the effect of rehabilitation in people with moderate to severe dementia, including those residing in continuing care settings. : Purpose: Best rehabilitation practices after hip fracture for people with dementia have not been established. A systematic review was conducted to determine current evidence for rehabilitation in this population, including residents in continuing care. Methods: Standardized review methodology was used to search eight databases for literature on hip-fracture rehabilitation for people with dementia. Eligible studies included participants with dementia who had a hip fracture; performed a rehabilitation intervention; and evaluated one or more of function, ambulation, discharge location, or falls. The Newcastle-Ottawa Scale was used to assess validity. Results: A total of 13 studies were included: five randomized controlled trials (RCTs), seven prospective cohort series, and one retrospective cohort study. Average quality ratings for RCTs and cohort studies were good and fair respectively. Participants with mild to moderate dementia receiving rehabilitation showed similar relative gains in function to those without dementia. Only one study examined the effect of rehabilitation among residents in continuing care. Conclusions: People with mild or moderate dementia may show improved function and ambulation and decreased fall risk after rehabilitation post hip fracture, similar to gains achieved by those without dementia. More research is required to ascertain the effect of rehabilitation in people with moderate to severe dementia, including those residing in continuing care settings. PMID- 23449814 TI - Longitudinal course of depression scores with and without insomnia in non depressed individuals: a 6-year follow-up longitudinal study in a Korean cohort. AB - STUDY OBJECTIVE: This is a population-based longitudinal study that followed insomnia symptoms over a 6-year period in non-depressed individuals. The purpose of the study was to (1) investigate the longitudinal course of depression based on number of insomnia episodes; and (2) describe longitudinal associations between insomnia and depression, and insomnia and suicidal ideation. DESIGN: Population-based longitudinal study. SETTING: Community-based sample from the Korean Genome and Epidemiology Study (KoGES). PARTICIPANTS: 1,282 non-depressed individuals (44% male, mean age 52.3 +/- 7.14 years). MEASUREMENTS AND RESULTS: This study prospectively assessed insomnia, depression, and suicidal ideation with 4 time points. Individuals were classified into no insomnia (NI), single episode insomnia (SEI), and persistent insomnia (PI; >= insomnia at 2+ time points) groups based on number of times insomnia was indicated. Mixed effects modeling indicated that depression scores increased significantly faster in the PI group compared to the NI (P < 0.001) and SEI (P = 0.02) groups. Additionally, the PI group had significantly increased odds of depression as compared to NI or SEI (OR 2.44, P = 0.001) groups, with 18.7% meeting criteria for depression compared to the NI (5.3%) and SEI (11.6%) groups at end point. The PI group also had significantly increased odds of suicidal ideation as compared to NI or SEI (OR 1.86, P = 0.002) groups. CONCLUSIONS: Persistent insomnia significantly increases the rate in which depression occurs over time in non-depressed individuals, which ultimately leads to higher risk for depression. Additionally, having persistent insomnia also increased the risk of suicidal ideation. CITATION: Suh S; Kim H; Yang HC; Cho ER; Lee SK; Shin C. Longitudinal course of depression scores with and without insomnia in non-depressed individuals: a 6 year follow-up longitudinal study in a Korean cohort. SLEEP 2013;36(3):369-376. PMID- 23449815 TI - A comparitive clinical study between self tapping and drill free screws as a source of rigid orthodontic anchorage. AB - BACKGROUND AND OBJECTIVES: Self-tapping miniscrews are commonly being used as a temporary anchorage device for orthodontic purpose. A prerequisite for the insertion of these screws is the preparation of a pilot hole, which is time consuming and may result in damage to nerves, tooth root, drill bit breakage and thermal necrosis of bone. On the other hand the design of drill-free screws enables them to be inserted without drilling. The aim of this prospective study was to compare the stability and clinical response of the soft tissue around the self tapping and drill free screws when used for orthodontic anchorage for en mass retraction of maxillary anterior teeth. MATERIALS AND METHODS: The study sample consisted of 20 patients requiring retraction of maxillary anterior teeth. The screws were placed in the alveolar bone between maxillary 2nd premolar and 1st molar bilaterally at the junction of attached gingiva and moveable mucosa. Pilot hole was drilled on the side which was selected for insertion of the self tapping screw under copious irrigation, after which it was inserted. Drill free screw was inserted on the contralateral side without predrilling. All screws were immediately loaded with 150-200 gm of retraction force. Patients were recalled for regular follow up for a period of 6 months. If the screws became mobile or showed any signs of inflammation during the course of the study, they were considered to be a failure. RESULTS: After a period of 6 months an overall success rate of 77.5% was noted. Four self tapping and five drill-free screws failed during the study. There was no statistically significant difference between the two types of screws with respect to success/failure. Mobility was found to be the major cause for the failure. CONCLUSION: Both self-tapping and the drill-free screws are effective anchorage units. But the latter have an edge over the conventional self-tapping screws because of decrease in operative time, little bone debris, less thermal damage, lower morbidity, and minimal patient discomfort as predrilling is not required, thus they can be used as a viable alternative. But self-tapping screws are still recommended for areas with high bone density and thick cortical bone. PMID- 23449816 TI - Success with lifestyle monotherapy in youth with new-onset type 2 diabetes. AB - BACKGROUND: Evidence is lacking to support the efficacy of lifestyle modification as first-line therapy in the clinical management of type 2 diabetes mellitus (T2DM) in adolescents. METHODS: A retrospective chart review of youth diagnosed with T2DM between 1999 and 2008 was conducted. The authors describe the percentage of youth presenting with glycosylated hemoglobin (HbA1c) of <9% who achieved/maintained target glycemic control (HbA1c <=7.0%) with lifestyle monotherapy during the year following diagnosis. RESULTS: Among the 275 youth with T2DM, 38% (n=104) presented with an HbA1c <9% and were prescribed lifestyle monotherapy at diagnosis. Of the 80 youth who had sufficient follow-up data over 12 months, 54% successfully maintained target glycemic control solely with lifestyle management. The mean HbA1c score at diagnosis was lower in youth who where successful on lifestlye monotherapy compared with those who were not successful. CONCLUSIONS: A significant proportion of youth newly diagnosed with T2DM presenting with an HbA1c <9% effectively achieved/maintained target glycemic control with lifestyle recommendations alone for 12 months. BACKGROUND: Evidence is lacking to support the efficacy of lifestyle modification as first-line therapy in the clinical management of type 2 diabetes mellitus (T2DM) in adolescents. METHODS: A retrospective chart review of youth diagnosed with T2DM between 1999 and 2008 was conducted. The authors describe the percentage of youth presenting with glycosylated hemoglobin (HbA1c) of <9% who achieved/maintained target glycemic control (HbA1c <=7.0%) with lifestyle monotherapy during the year following diagnosis. RESULTS: Among the 275 youth with T2DM, 38% (n=104) presented with an HbA1c <9% and were prescribed lifestyle monotherapy at diagnosis. Of the 80 youth who had sufficient follow-up data over 12 months, 54% successfully maintained target glycemic control solely with lifestyle management. The mean HbA1c score at diagnosis was lower in youth who where successful on lifestlye monotherapy compared with those who were not successful. CONCLUSIONS: A significant proportion of youth newly diagnosed with T2DM presenting with an HbA1c <9% effectively achieved/maintained target glycemic control with lifestyle recommendations alone for 12 months. PMID- 23449818 TI - Neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer: The likelihood of initiation and completion. AB - INTRODUCTION: Chemotherapy was shown to improve survival in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). The initiation and completion rates for perioperative chemotherapy are variable. Our aim is to compare the likelihood of initiating and completing neoadjuvant (NAC) and adjuvant chemotherapy (AC) in patients who underwent of RC for MIBC. MATERIALS AND METHODS: We performed a retrospective analysis of patients who underwent RC between 1992 and 2011. NAC was advised for patients with clinical stage >=T2, hydronephrosis, extensive lymphovascular invasion (LVI), or prostatic stromal invasion. Patients with >=pT3 or lymph node metastases were considered for AC. RESULTS: A total of 363 patients were considered for perioperative chemotherapy. Among the 141 patients who were offered NAC, 125 (88.6%) initiated NAC. A total of 222 were considered for AC, and 151 (68.0%) initiated AC (P < 0.001). In the NAC group, 118 (83.5%) completed planned number of cycles of chemotherapy and 7 (5.6%) did not complete the planned chemotherapy. In the AC group, 79 (35.5%) completed at least four cycles and 72 (47.3%) could not complete the planned cycles (P < 0.001). CONCLUSIONS: Patients with MIBC are more likely to initiate and complete NAC than AC. PMID- 23449819 TI - Breast Screening in India: A UK Perspective on the Practicalities. AB - This paper is offered as an Editorial, providing a UK perspective on discussions about the merits of a Breast Screening programme in India, based upon the UK and European experience. PMID- 23449820 TI - Polymerase Chain Reaction (PCR) Versus Bacterial Culture in Detection of Organisms in Otitis Media with Effusion (OME) in Children. AB - The aim of this study was to compare between polymerase chain reaction (PCR) and bacterial culture in detection of Streptococcus Pneumonia and M. Catarrhalis in otitis media with effusion (OME) in children. Fifty patients having OME were included in this study between 2003 and 2008. Myringotomy and tympanostomy tube insertion were done in every patient and the middle ear effusion samples were aspirated. The samples were subjected to bacteriological study in the form of culture and molecular study in the form of PCR using JM201/202-204 primer probe set for both S. pneumonia and M. catarrhalis. The results of Bacterial cultures are as follows: five cases (10%) were culture positive for S. pneumonia. Six cases (12%) were culture positive for M. catarrhalis. Only one case (2%) showed positively for both S. pneumonia and M. catarrhalis. Polymerase chain reaction test shows that 18 cases (36%) were positive for S. pneumonia, 22 cases (44%) were positive for M. catarrhalis, 6 cases (12%) were positive for both organism and 4 cases (8%) were negative. The difference between the proportion of culture positive and PCR positive specimens for both organisms individually and collectively was significant (P < 0.001). From our study we can conclude that PCR is more accurate than bacterial culture in detection of organisms in middle ear fluid in OME and that M. catarrhalis plays a significant rule in OME as it is the sole organism identified more than the other one by PCR. PMID- 23449821 TI - PCR Based Molecular Detection of the Gyr-B-2 Gene from the Klebsiella Sp. Isolates from Patients who were Suffering with Pneumonia and Urinary Tract Infections (UTIs). AB - PURPOSE: Detection of the virulence gene is a key component in determining the pathogenicity of any isolates, because these genes act multi-functionally and multi-factorially. A gyrase specific gene primer, in combination with the PCR technology, allows the precise detection of the DNA gyrase subunit B2 gene (gyr-B 2) from different virulent microorganisms. In the present study, forward and reverse primers with lengths of 20bp and 21bp were used for the detection of the gyr-B-2 genes in the clinical isolates of the Klebsiella sp. which were collected from patients who were suffering from pneumonia and urinary tract infections (UTIs). MATERIALS AND METHODS: A total of 14 isolates viz., K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, K12, K13 and K14 were isolated from 3 different private medical colleges of Sylhet city. RESULTS: The gyr-B-2 gene which was amplified in 12 isolates viz., K1, K2, K3, K4, K5, K6, K7, K8, K10, K11, K12 and K14 gave the expected 411bp PCR product after its visualization under a gel documentation system in a 1.2% agarose gel. CONCLUSIONS: The present study was undertaken to detect the gyrB2 gene from Klebsiella sp, which will be helpful for further scientific studies. This PCR was outstanding in the detection of the gyb-B-2 gene in pneumonia and urinary tract infections in patients, which were caused by the Klebsiella species. PMID- 23449817 TI - The wnt pathway in mood disorders. AB - OBJECTIVES: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders. METHODS: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion. RESULTS: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders. CONCLUSIONS: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders. PMID- 23449822 TI - A clinical evaluation of the Maquet Quadrox-i Neonatal oxygenator with integrated arterial filter. AB - High-performance, low-prime-volume oxygenators for the pediatric patient population have become a growing market among manufacturers. In the summer of 2011, our institution clinically evaluated the performance of the newly released Maquet Quadrox-i Neonatal oxygenator with integrated arterial filter. The static priming volume, including the integrated arterial filter, is 40 ml and the maximum rated blood flow is 1.5 liters per minute (LPM). The device was used on seven pediatric patients, ranging from 3.2 to 14 kg, undergoing various congenital heart defect repairs. Data were collected to calculate gas transfer, trans-oxygenator pressure drop, and heat exchange performance. The mean cardiopulmonary bypass time was 85 minutes and the mean cross-clamp time was 56 minutes. The average oxygen transfer was 34.3 +/- 22.8 ml/O2/min and increased with both blood flow and FiO2. The average carbon dioxide transfer was 22.3 +/- 17.8 ml/min and increased with both blood flow and gas sweep to blood flow ratio. The average trans-oxygenator pressure drop per blood flow was 53.3 +/- 15.5 mmHg/L/min and increased with flow. The average heat exchanger performance factor was 47.6 +/- 11.6% and decreased with flow. The heat exchange performance factor at maximum observed clinical flow, 1.42 LPM, was 36.4%. During this evaluation, the Maquet Quadrox-i Neonatal oxygenator adequately performed within its operational flow in the clinical setting. PMID- 23449823 TI - Otitis media and spinal manipulative therapy: a literature review. AB - OBJECTIVE: Otitis media (OM) is one of the common conditions for doctor visits in the pediatric population. Spinal manipulation therapy (SMT) may be a potential conservative treatment of OM. The purpose of this study is to review the literature for OM in children, outlining the diagnosis of OM, SMT description, and adverse event notation. METHODS: Databases (PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health, Index to Chiropractic Literature, The Allied and Complementary Medicine, and Alt Health Watch) were queried and hand searches were performed to identify relevant articles. All potential studies were independently screened for inclusion by both authors. The inclusion criteria were as follows: written in the English language, addressed OM, involved human participants 6 years or younger, and addressed SMT. Studies were evaluated for overall quality using standardized checklists performed independently by both authors. RESULTS: Forty-nine articles were reviewed: 17 commentaries, 15 case reports, 5 case series, 8 reviews, and 4 clinical trials. Magnitude of effect was lower in higher-quality articles. No serious adverse events were found; minor transient adverse effects were noted in 1 case series article and 2 of the clinical trials. CONCLUSIONS: From the studies found in this report, there was limited quality evidence for the use of SMT for children with OM. There are currently no evidence to support or refute using SMT for OM and no evidence to suggest that SMT produces serious adverse effects for children with OM. It is possible that some children with OM may benefit from SMT or SMT combined with other therapies. More rigorous studies are needed to provide evidence and a clearer picture for both practitioner and patients. PMID- 23449824 TI - A survey on the knowledge, attitude and the practice of pharmacovigilance among the health care professionals in a teaching hospital in northern India. AB - OBJECTIVE: To assess the pharmacovigilance awareness among the healthcare professionals in a teaching hospital in Northern India. MATERIAL AND METHODS: A questionnaire which was suitable for assessing the basic Knowledge, Attitude and the Practice (KAP) of pharmacovigilance was designed and distributed among 100 doctors of the Punjab Institute of Medical Sciences (PIMS) Hospital, Jalandhar, Punjab, India. RESULTS: Among the 100 doctors, 61 responded. The data was analyzed by using the SPSS statistical software. Although 77% of the subjects knew the term 'pharmacovigilance', only 59% were aware of the existence of the National Pharmacovigilance Program. 23% volunteered to reports Adverse Drug Reactions (ADRs), but more than 60% doctors did not know how and where to report the ADRs. CONCLUSION: There is a need for a regular training and the reenforcement for the ADR reporting among the health care personnel. The perception of the reporting process being tedious, the lack of time, a poor knowledge on the reporting mechanism and inadequate expertise seemed to be the main reasons for not reporting the ADRs. A majority of the respondents suggested regular training sessions on a priority basis for the success of the pharmacovigilance program and for the better clinical management of the patients in general. PMID- 23449825 TI - Managing the edentulous dry mouth: the two part mandibular denture. AB - Treatment of patients suffering from xerostomia can be a challenge and more so in the completely edentulous. The difficulties encountered can be troublesome and at times may lead to complete failure of the prosthesis. Xerostomia may occur due to a number of reasons. Here is a report of an attempt at the fabrication of complete denture in one such case. The technique involves incorporation of a salivary reservoir in the denture in which a salivary substitute is added. A case report is hereby presented illustrating the technique. PMID- 23449827 TI - Complete sequence of the bla(NDM-1)-carrying plasmid pNDM-AB from Acinetobacter baumannii of food animal origin. PMID- 23449826 TI - Translational predictive biomarker analysis of the phase 1b sorafenib and bevacizumab study expansion cohort. AB - Predictive biomarkers are needed to triage patients to the best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm the mechanism and to identify potential predictive biomarkers in a phase Ib clinical trial expansion of patients with solid tumors receiving sorafenib/bevacizumab. The maximally tolerated doses of sorafenib at 200 mg twice daily with bevacizumab at 5 mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28-day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and fluorodeoxyglucose proton emission tomography were done pre-therapy and at 2 and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those that confirm the biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas a decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p endothelial nitric-oxide synthase, b-RAF, and cleaved poly(ADP-ribose) polymerase was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefits lasting longer than 4 months, and activity increased with progression of disease. Cleavage of caspase 3 and poly(ADP-ribose) polymerase was increased, and Ki67 expression decreased in patients with prolonged clinical benefits, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit. PMID- 23449828 TI - High cephalosporin resistance due to amino acid substitutions in PBP1A and PBP2X in a clinical isolate of group B Streptococcus. AB - OBJECTIVES: Group B Streptococcus (GBS; Streptococcus agalactiae) has been regarded as uniformly susceptible to penicillins. However, we recently reported the existence of GBS with reduced penicillin susceptibility (PRGBS), with amino acid substitutions in penicillin-binding protein (PBP) 2X. Although most PRGBS show high MICs of ceftizoxime (4-64 mg/L) and cefotaxime (0.12-1 mg/L), those for strain B1 are exceptionally high (ceftizoxime MIC >=256 mg/L and cefotaxime MIC 2 mg/L). We previously found an amino acid substitution (G539S) neighbouring the conserved K540TG motif in PBP1A in addition to the PRGBS-specific amino acid substitution Q557E in PBP2X of B1. The aim of this study was to reveal the effect of the amino acid substitutions in PBP1A and PBP2X of B1 on the high cephalosporin resistance. METHODS: A ceftizoxime competition assay was performed to reveal the PBPs that are the main targets of ceftizoxime. We generated two allelic exchange mutants from beta-lactam-susceptible GBS BAA-611. BAA-611 (B1PBP2X) contained the PBP2X gene derived from B1 and BAA-611 (B1PBP2X, B1PBP1A) contained both the PBP2X and the PBP1A gene derived from B1. These allelic exchange mutants and strain B1 were subjected to susceptibility testing. RESULTS: The ceftizoxime competition assay revealed that PBP1A and PBP2X were the main targets of ceftizoxime. Although the MICs of ceftizoxime and cefotaxime for BAA 611 (B1PBP2X) were 64 and 0.5 mg/L, respectively, BAA-611 (B1PBP2X, B1PBP1A) showed high cephalosporin resistance (ceftizoxime MIC >=256 mg/L and cefotaxime MIC 2 mg/L) comparable to B1. CONCLUSIONS: The high cephalosporin resistance of GBS was caused by amino acid substitutions in PBP1A and PBP2X. PMID- 23449829 TI - Activity of BAL30072 alone or combined with beta-lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters. AB - OBJECTIVES: We investigated the activity of BAL30072, a dihydroxypyridone monosulfactam, against carbapenem-resistant Enterobacteriaceae and non-fermenters (i) alone, (ii) combined with BAL29880 (to inhibit AmpC) and/or clavulanate [to inhibit extended-spectrum beta-lactamases (ESBLs)] and (iii) combined 1:1 with meropenem. METHODS: Isolates were from multiple UK hospitals. MICs were determined by CLSI agar dilution. Carbapenemases were identified by PCR and sequencing. RESULTS: BAL30072 inhibited 69% of the carbapenem-resistant Enterobacteriaceae at <=4 mg/L, including 60%-87% with OXA-48, IMP, NDM and VIM enzymes or combinations of impermeability with AmpC or ESBL, and 40% with KPC enzymes. The proportions susceptible exceeded 90% for BAL30072+BAL29880+clavulanate, except for isolates with KPC carbapenemases, where members of the international sequence type (ST) 258 Klebsiella pneumoniae clone remained resistant. At 4 mg/L, BAL30072 was active against all OprD-deficient Pseudomonas aeruginosa, against 8/12 with efflux-type beta-lactam resistance and 19/25 with metallo-carbapenemases; these proportions were little increased if inhibitors were added. Most Acinetobacter baumannii with OXA or NDM carbapenemases were susceptible to BAL30072 alone at <=4 mg/L, but those with OXA 58 were resistant, probably for reasons other than their beta-lactamase. Addition of meropenem to BAL30072 increased activity against some individual isolates, but with little clear relationship to the resistance mechanism, except for consistent potentiation against OprD-deficient P. aeruginosa. CONCLUSIONS: BAL30072 had good activity against many diverse carbapenem resistance types. Adding clavulanate and/or BAL29880 extended activity against carbapenem-resistant Enterobacteriaceae, but not non-fermenters. Adding meropenem resulted in small increases in activity against individual isolates. Resistance remained common in the K. pneumoniae ST258 KPC clone, even with both inhibitors or meropenem added. PMID- 23449830 TI - Granulated sugar to reduce an incarcerated prolapsed defunctioning ileostomy. AB - This case report discusses the successful application of granulated sugar to reduce a prolapsed ileostomy thereby eliminating the need for an emergency surgery. PMID- 23449831 TI - Dermoid cyst of the greater omentum: rare and innocent? PMID- 23449832 TI - Diversities in presentations of extrapulmonary tuberculosis. AB - The incidence of extrapulmonary tuberculosis (EPTB) has been increasing worldwide over the last few years. Tuberculous lymphadenitis is the most common form of the disease and is reported to occur in 25-60% of all EPTB cases. It is commonly seen in the cervical lymph nodes, but may also be in the larynx, pharynx, parotid and rarely, in the sinuses and petrous bone. The posterior triangle, supraclavicular and jugular nodes are most frequently affected. They are usually unilateral, although diffuse adenopathy may occur. TB involving cervical lymph nodes represents 50% of extrapulmonary TB. A series of six cases of tuberculous lymphadenitis with varying clinical features is documented here to alert one of its prevalence in developing countries. PMID- 23449833 TI - Variable ECG findings associated with pulmonary embolism. AB - An elderly man with a recent diagnosis of invasive rectal adenocarcinoma was admitted to the hospital because of a lower gastrointestinal bleeding and low haemoglobin. During the hospitalisation he complained of chest pain. ECG showed new onset ST-segment elevation in leads III, aVF and in the precordial leads V1 V4. Shortly thereafter, he became hypotensive and coded. Despite resuscitation he passed away. Autopsy revealed massive pulmonary emboli with near complete obstruction of the involved branches of the pulmonary arteries. Coronary arteries were free of significant coronary artery disease and multiple sections of the myocardium showed the absence of myocardial infarction. PMID- 23449834 TI - Continuing education module the courage to birth. AB - Childbirth educator Kathryn McGrath reflects on fear and courage and comes to see some levels of fear as a normal part of the process of pregnancy and birth and not something to be brushed aside. In this article, originally presented as a keynote address in 2005 at the Lamaze International Annual Conference, McGrath discusses fear during pregnancy and birth and presents ways in which the childbirth educator can acknowledge and accept women's fears, and help find the courage they need to give birth. PMID- 23449835 TI - Suprascapular neuropathy as a cause of swimmer's shoulder: results after arthroscopic treatment in 4 patients. PMID- 23449836 TI - Hip arthroscopic surgery: patient evaluation, current indications, and outcomes. AB - Arthroscopic surgery in the hip joint has historically lagged behind its counterparts in the shoulder and knee. However, the management of hip injuries in the athletic population has rapidly evolved over the past decade with our improved understanding of mechanical hip pathology as well as the marked improvement in imaging modalities and arthroscopic techniques. Current indications for hip arthroscopic surgery may include symptomatic labral tears, femoroacetabular impingement (FAI), hip capsular laxity/instability, chondral lesions, disorders of the peritrochanteric or deep gluteal space, septic joint, loose bodies, and ligamentum teres injuries. Furthermore, hip arthroscopic surgery is developing an increasingly important role as an adjunct diagnostic and therapeutic tool in conjunction with open femoral and/or periacetabular osteotomy for complex hip deformities. Arthroscopic techniques have evolved to allow for effective and comprehensive treatment of various hip deformities. Techniques for extensile arthroscopic capsulotomies have allowed for improved central and peripheral compartment exposure and access for labral takedown, refixation, treatment of chondral injury, and osteochondroplasty of the femoral head-neck junction and acetabular rim. While favorable short-term and midterm clinical outcomes have been reported after arthroscopic treatment of prearthritic hip lesions, greater long-term follow-up is necessary to assess the efficacy of hip arthroscopic surgery in altering the natural history and progressive degenerative changes associated with FAI. PMID- 23449837 TI - Kinematics of anterior cruciate ligament ruptures in World Cup alpine skiing: 2 case reports of the slip-catch mechanism. AB - BACKGROUND: Based on visual video analyses of 20 injury situations, the main mechanism of anterior cruciate ligament (ACL) injury in World Cup alpine skiing, termed the "slip-catch" mechanism, was identified. This situation is characterized by a common pattern in which the inside edge of the outer ski catches the snow surface while turning, forcing the knee into valgus and tibial internal rotation. To describe the exact joint kinematics at the time of injury, a more sophisticated approach is needed. PURPOSE: To describe the knee and hip kinematics in 2 slip-catch situations utilizing a model-based image-matching (MBIM) technique. STUDY DESIGN: Descriptive laboratory study. METHODS: Two typical slip-catch situations in World Cup alpine skiing reported through the International Ski Federation (FIS) Injury Surveillance System were captured on video with several camera views and high video quality. The injury situations were analyzed using the MBIM technique to produce continuous measurements of knee and hip joint kinematics. RESULTS: Within 60 milliseconds, the knee flexion angle increased rapidly from 26 degrees to 63 degrees in case 1 and from 39 degrees to 69 degrees in case 2. In the same period, we observed a rapid increase in internal rotation of the tibia with a peak of 12 degrees and 9 degrees , respectively. The knee valgus angle changed less markedly in both cases. We also observed a rapid increase of hip flexion as well as substantial hip internal rotation. CONCLUSION: Knee compression and knee internal rotation and abduction torque are important components of the injury mechanism in a slip-catch situation. CLINICAL RELEVANCE: Prevention efforts should focus on avoiding a forceful tibial internal rotation in combination with knee valgus. PMID- 23449838 TI - An epidemiological study of traumatic brachial plexus injury patients treated at an Indian centre. AB - BACKGROUND: Epidemiological studies on traumatic brachial plexus injuries are few and these studies help us to improve the treatment, rehabilitation of these patients and to allocate the resources required in their management. Epidemiological factors can vary in different countries. We wanted to know the situation in an Indian centre. MATERIALS AND METHODS: Data regarding age, sex, affected side, mode of injury, distribution of paralysis, associated injuries, pain at the time of presentation and the index procedure they underwent were collected from 304 patients. Additional data like the vehicle associated during the accident, speed of the vehicle during the accident, employment status and integration into the family were collected in 144 patients out of the 304 patients. RESULTS: Road traffic accidents accounted for 94% of patients and of the road traffic accidents 90% involved two wheelers. Brachial plexus injury formed a part of multitrauma in 54% of this study group and 46% had isolated brachial plexus injury. Associated injuries like fractures, vascular injuries and head injuries are much less probably due to the lower velocity of the vehicles compared to the western world. The average time interval from the date of injury to exploration of the brachial plexus was 127 days and 124 (40.78%) patients presented to us within this duration. Fifty-seven per cent had joined back to work by an average of 8.6 months. It took an average of 6.8 months for the global brachial plexus-injured patients to write in their non-dominant hand. PMID- 23449839 TI - Cochrane reviews allow firm conclusions to be made about the effectiveness of various local and systemic treatments for wounds and ulcers. PMID- 23449840 TI - Exposure to challenging behaviour from nursing home residents is associated with reduced general health and work ability, and increased burnout reported by nurses. PMID- 23449841 TI - Exercise improves fatigue during and after breast and prostate cancer treatment, with benefits seen for aerobic exercise. PMID- 23449842 TI - The majority of nurses first experience death in or before their first year of practice, and the experience can provoke feelings of helplessness, guilt and ongoing distress. PMID- 23449843 TI - When anger leads to rumination: induction of relative right frontal cortical activity with transcranial direct current stimulation increases anger-related rumination. AB - Anger is associated with various responses. Research on the neuroscience of anger has revealed that greater left than right frontal cortical activity is associated with angry approach-oriented responses, such as aggression, whereas greater right than left frontal cortical activity is associated with inhibited angry responses mixed with anxiety. In the current research, we extended these past studies by manipulating asymmetric frontal cortical activity using transcranial direct current stimulation and assessing its influence on ruminative responses to an interpersonal insult. Results revealed that self-reported rumination was greatest for participants who received a manipulated increase in relative right frontal cortical activity compared with those who received either a manipulated increase in relative left frontal cortical activity or sham stimulation. Taken together with past findings, the current results suggest that anger associated with greater relative left frontal cortical activity predicts approach-oriented aggressive action, whereas anger associated with greater relative right frontal cortical activity predicts inhibited rumination. PMID- 23449844 TI - The allure of the forbidden: breaking taboos, frustration, and attraction to violent video games. AB - Although people typically avoid engaging in antisocial or taboo behaviors, such as cheating and stealing, they may succumb in order to maximize their personal benefit. Moreover, they may be frustrated when the chance to commit a taboo behavior is withdrawn. The present study tested whether the desire to commit a taboo behavior, and the frustration from being denied such an opportunity, increases attraction to violent video games. Playing violent games allegedly offers an outlet for aggression prompted by frustration. In two experiments, some participants had no chance to commit a taboo behavior (cheating in Experiment 1, stealing in Experiment 2), others had a chance to commit a taboo behavior, and others had a withdrawn chance to commit a taboo behavior. Those in the latter group were most attracted to violent video games. Withdrawing the chance for participants to commit a taboo behavior increased their frustration, which in turn increased their attraction to violent video games. PMID- 23449845 TI - Complete genome sequence of Thermovibrio ammonificans HB-1(T), a thermophilic, chemolithoautotrophic bacterium isolated from a deep-sea hydrothermal vent. AB - Thermovibrio ammonificans type strain HB-1(T) is a thermophilic (Topt: 75 degrees C), strictly anaerobic, chemolithoautotrophic bacterium that was isolated from an active, high temperature deep-sea hydrothermal vent on the East Pacific Rise. This organism grows on mineral salts medium in the presence of CO2/H2, using NO3( ) or S(0) as electron acceptors, which are reduced to ammonium or hydrogen sulfide, respectively. T. ammonificans is one of only three species within the genus Thermovibrio, a member of the family Desulfurobacteriaceae, and it forms a deep branch within the phylum Aquificae. Here we report the main features of the genome of T. ammonificans strain HB-1(T) (DSM 15698(T)). PMID- 23449846 TI - Lost in translation. Homer in English; the patient's story in medicine. AB - In a series of previous articles, we have considered how we might reconceptualise central themes in medicine and medical education through 'thinking with Homer'. This has involved using textual approaches, scenes and characters from the Iliad and Odyssey for rethinking what is a 'communication skill', and what do we mean by 'empathy' in medical practice; in what sense is medical practice formulaic, like a Homeric 'song'; and what is lyrical about medical practice. Our approach is not to historicise medicine and medical education, but to use thinking with Homer as a medium and metaphor for questioning the habitual and the taken-for granted in contemporary practice. In this article, we tackle the complex theme of 'translation'. We use the lens of translation studies to examine the process of turning the patient's story into medical language. We address the questions: what makes a 'good' translation? What are the consequences of mistranslation and poor translation? And, while things are inevitably lost in translation, does this matter? PMID- 23449847 TI - Classifying unknowns: the idiopathic problem. AB - The term, idiopathic, emerged as a key concept in the classification of disease in the 18th century and has become ingrained in our terminology in defining diseases and their aetiologies throughout all fields of medicine. Despite, or perhaps because of this, little has been written about the meaning or meanings of the word itself. Although most medical professionals will be able to offer a definition of idiopathic, different definitions of the word are in use and are often confused or used without an appreciation of the range of meanings. This article aims to clarify these different meanings with reference to historic and current uses. The change from the earlier nosological definition of 'primary' to the most widely accepted current definition, 'of unknown cause', occurred in the late 19th century, reflecting changing perspectives of disease causation. Far from being an innocent translation of 'unknown', idiopathic creates problems for future terminology and adds little to medical understanding. In masking the unknown, the term idiopathic maintains a paternalistic patient-practitioner relationship, and so should be avoided in modern medical terminology. PMID- 23449848 TI - Effect of statin therapy on vaspin levels in type 2 diabetic patients. AB - BACKGROUND: Statins are commonly used antihyperlipidemic agents, with anti inflammatory and immunomodulatory properties that are thought to account for a significant portion of their ability to protect against atherosclerosis and cardiovascular disease. Vaspin, a visceral adipose tissue-derived serine protease inhibitor, is an emerging adipokine with important insulin-sensitizing, cardioprotective, and antiatherosclerotic properties in patients with diabetes. In this randomized controlled clinical trial, we evaluated the effect of statin therapy on vaspin levels in patients with type 2 diabetes mellitus. METHODS: Patients were divided into two groups, ie, those receiving simvastatin (study group, n = 33), and those who did not (control group, n = 29). Patient data, blood biochemistry, and vaspin levels were recorded at the beginning of the study (baseline) and after 8 weeks (end of the study). RESULTS: After 8 weeks of treatment, vaspin levels were increased in patients treated with simvastatin (504.58 +/- 203.07 pg/mL at baseline versus 629.15 +/- 68.39 pg/mL after 8 weeks, P < 0.01), but not in patients who were not treated with simvastatin (613.33 +/- 357.53 pg/mL at baseline versus 582.37 +/- 84.63 pg/mL after 8 weeks, P > 0.05). In addition, the lipid-lowering effect of simvastatin was reflected in a statistically significant reduction in total cholesterol in the study group (220.75 +/- 55.66 mg/dL at baseline versus 201.90 +/- 53.65 mg/dL after 8 weeks P < 0.01) but not in the control group (214.24 +/- 47.2 mg/dL at baseline versus 215.72 +/- 43.65 mg/dL after 8 weeks, P > 0.05) and in a statistically significant reduction in triglyceride levels in the study group (265.8 +/- 210.41 mg/dL at baseline versus 223.03 +/- 178.67 mg/dL after 8 weeks, P < 0.05) but not in the control group (225.44 +/- 115.13 mg/dL at baseline versus 215.58 +/- 110.2 mg/dL after 8 weeks, P > 0.05). Mean vaspin levels were significantly higher in the study group than in the control group. CONCLUSION: These results indicate that statin therapy increases plasma vaspin levels in addition to having a lipid lowering effect. This could be a mechanism underlying the pleiotropic effects seen with statins, including their cardioprotective and antiatherosclerotic effects. PMID- 23449849 TI - Breast elastography: A literature review. AB - Breast elastography is a new sonographic imaging technique which provides information on breast lesions in addition to conventional ultrasonography (US) and mammography. Elastography provides a noninvasive evaluation of the stiffness of a lesion. Today, two technical solutions are available for clinical use: strain elastography and shear wave elastography. Initial evaluations of these techniques in clinical trials suggest that they may substantially improve the possibility of differentiating benign from malignant breast lesions thereby limiting recourse to biopsy and considerably reducing the number of benign breast biopsy diagnoses. This article reviews the basics of this technique, how to perform the examination, image interpretation and the results of major clinical studies. Although elastography is easy to perform, training and technical knowledge are required in order to obtain images permitting a correct interpretation. This paper will highlight the technique and point out common pitfalls. PMID- 23449850 TI - Alopecias. PMID- 23449852 TI - Decision support for hemodynamic management: from graphical displays to closed loop systems. AB - The way hemodynamic therapies are delivered today in anesthesia and critical care is suboptimal. Hemodynamic variables are not always understood correctly and used properly. The adoption of hemodynamic goal-directed strategies, known to be clinically useful, is poor. Ensuring therapies are delivered effectively is the goal of decision support tools and closed loop systems. Graphical displays (metaphor screens) may help clinicians to better capture and integrate the multivariable hemodynamic information. This may result in faster and more accurate diagnosis and therapeutic decisions. Graphical displays (target screens) have the potential to increase adherence to goal-directed strategies and ultimately improve patients' outcomes, but this remains to be confirmed by prospective studies. Closed loop systems are the ultimate solution to ensure therapies are delivered. However, most therapeutic decisions cannot be based on a limited number of output variables. Therefore, one should focus on the development of systems designed to relieve clinicians from very simple and repetitive tasks. Whether intraoperative goal-directed fluid therapy may be one of these tasks remains to be evaluated. PMID- 23449854 TI - Respiration signals from photoplethysmography. AB - Pulse oximetry is based on the technique of photoplethysmography (PPG) wherein light transmitted through tissues is modulated by the pulse. In addition to variations in light modulation by the cardiac cycle, the PPG signal contains a respiratory modulation and variations associated with changing tissue blood volume of other origins. Cardiovascular, respiratory, and neural fluctuations in the PPG signal are of different frequencies and can all be characterized according to their sinusoidal components. PPG was described in 1937 to measure blood volume changes. The technique is today increasingly used, in part because of developments in semiconductor technology during recent decades that have resulted in considerable advances in PPG probe design. Artificial neural networks help to detect complex nonlinear relationships and are extensively used in electronic signal analysis, including PPG. Patient and/or probe-tissue movement artifacts are sources of signal interference. Physiologic variations such as vasoconstriction, a deep gasp, or yawn also affect the signal. Monitoring respiratory rates from PPG are often based on respiratory-induced intensity variations (RIIVs) contained in the baseline of the PPG signal. Qualitative RIIV signals may be used for monitoring purposes regardless of age, gender, anesthesia, and mode of ventilation. Detection of breaths in adult volunteers had a maximal error of 8%, and in infants the rates of overdetected and missed breaths using PPG were 1.5% and 2.7%, respectively. During central apnea, the rhythmic RIIV signals caused by variations in intrathoracic pressure disappear. PPG has been evaluated for detecting airway obstruction with a sensitivity of 75% and a specificity of 85%. The RIIV and the pulse synchronous PPG waveform are sensitive for detecting hypovolemia. The respiratory synchronous variation of the PPG pulse amplitude is an accurate predictor of fluid responsiveness. Pleth variability index is a continuous measure of the respiratory modulation of the pulse oximeter waveform and has been shown to predict fluid responsiveness in mechanically ventilated patients including infants. The pleth variability index value depends on the size of the tidal volume and on positive end-expiratory pressure. In conclusion, the respiration modulation of the PPG signal can be used to monitor respiratory rate. It is probable that improvements in neural network technology will increase sensitivity and specificity for detecting both central and obstructive apnea. The size of the PPG respiration variation can predict fluid responsiveness in mechanically ventilated patients. PMID- 23449853 TI - Decreased erythrocyte deformability after transfusion and the effects of erythrocyte storage duration. AB - BACKGROUND: Erythrocyte cell membranes undergo morphologic changes during storage, but it is unclear whether these changes are reversible. We assessed erythrocyte cell membrane deformability in patients before and after transfusion to determine the effects of storage duration and whether changes in deformability are reversible after transfusion. METHODS: Sixteen patients undergoing posterior spinal fusion surgery were studied. Erythrocyte deformability was compared between those who required moderate transfusion (>= 5 units erythrocytes) and those who received minimal transfusion (0-4 units erythrocytes). Deformability was measured in samples drawn directly from the blood storage bags before transfusion and in samples drawn from patients before and after transfusion (over 3 postoperative days). In samples taken from the blood storage bags, we compared deformability of erythrocytes stored for a long duration (>= 21 days), those stored for a shorter duration (<21 days), and cell-salvaged erythrocytes. Deformability was assessed quantitatively using the elongation index (EI) measured by ektacytometry, a method that determines the ability for the cell to elongate when exposed to shear stress. RESULTS: Erythrocyte deformability was significantly decreased from the preoperative baseline in patients after moderate transfusion (EI decreased by 12% +/- 4% to 20% +/- 6%; P = 0.03) but not after minimal transfusion (EI decreased by 3% +/- 1% to 4% +/- 1%; P = 0.68). These changes did not reverse over 3 postoperative days. Deformability was significantly less in erythrocytes stored for >= 21 days (EI = 0.28 +/- 0.02) than in those stored for <21 days (EI = 0.33 +/- 0.02; P = 0.001) or those drawn from patients preoperatively (EI = 0.33 +/- 0.02; P = 0.001). Cell-salvaged erythrocytes had intermediate deformability (EI = 0.30 +/- 0.03) that was greater than that of erythrocytes stored >= 21 days (P = 0.047), but less than that of erythrocytes stored <21 days (P = 0.03). CONCLUSIONS: The findings demonstrate that increased duration of erythrocyte storage is associated with decreased cell membrane deformability and that these changes are not readily reversible after transfusion. PMID- 23449855 TI - Ophthalmologic findings in patients with non-surgically treated blowout fractures. AB - We evaluated the ocular and visual status in a group of patients with a non surgically treated blowout fracture. Clinical examination with refraction, test of binocular function, and tear film evaluation was performed in 23 patients. These values were statistically correlated with the orbital volume measurements and ocular finding from the patient records at presentation. About 50% of the study group was symptomatic due to low visual acuity from refractive errors and decompensated phorias as a consequence of the blowout fracture. Several patients displayed changes in tear film production. There was no strong correlation between the measured parameters and orbital volume measurements. Patients with a non-surgically treated blowout fracture often display ocular and visual changes after discharge. A routine visual exam is advocated in all patients after the ocular status has stabilized after a blowout fracture. PMID- 23449856 TI - Low-fat yoghurt intake in pregnancy associated with increased child asthma and allergic rhinitis risk: a prospective cohort study. AB - Dairy products are important sources of micronutrients, fatty acids and probiotics which could modify the risk of child asthma and allergy development. To examine the association of dairy product intake during pregnancy with child asthma and allergic rhinitis at 18 months and 7 years in the Danish National Birth Cohort, data on milk and yoghurt consumption were collected in mid pregnancy (25th week of gestation) using a validated FFQ (n 61 909). At 18 months, we evaluated asthma and wheeze using interview data. We assessed asthma and allergic rhinitis using a questionnaire at the age of 7 years and through registry linkages. Current asthma was defined as self-reported ever asthma diagnosis and wheeze in the past 12 months. All associations were evaluated using multivariate logistic regression. At 18 months whole milk was inversely associated with child asthma (>=5.5 times/week v. none: 0.85, 95 % CI 0.75, 0.97); the reverse was true for semi-skimmed milk (>=5.5 times/week v. none: 1.08, 95 % CI 1.02, 1.15). For yoghurt, children of women who ate low-fat yoghurt >1 serving/d had 1.21 (95 % CI 1.02, 1.42) greater odds of a medication-related ever asthma diagnosis compared with children of women reporting no intake. They were also more likely to have a registry-based ever diagnosis and report allergic rhinitis. Low-fat yoghurt intake was directly related to increased risk of both child asthma and allergic rhinitis, while whole milk appeared protective for early-life outcomes only. Nutrient components or additives specific to low-fat yoghurt may be mediating the increase in risk. PMID- 23449857 TI - Clinical implications of JUPITER in a contemporary European population: the EPIC Norfolk prospective population study. AB - AIMS: Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) has raised several points of debate. We quantified the proportion of individuals meeting the JUPITER criteria, determined their risk profile, and their risk of coronary heart disease (CHD) events during a long-term follow-up in a contemporary European cohort. METHODS AND RESULTS: A total of 25 639 participants aged between 45 and 79 years were followed for 11.4 +/- 2.8 years in EPIC-Norfolk population cohort. A total of 8397 individuals with complete data available were considered potentially eligible for primary prevention. A total of 846 (10.1%) individuals fulfilled the JUPITER criteria [low-density lipoprotein cholesterol-C (LDL-C) <3.4 mmol/L/C-reactive protein >= 2 mg]. This group had a 10-person-year event rate of 14.6% compared with 7.0% for those with LDL-C <3.4 mmol/L/C-reactive protein <2 mg (P = 0.001); the corresponding adjusted hazard ratio for future CHD was 1.70 (95% CI: 1.31-2.21). The group fulfilling JUPITER criteria had significantly higher CHD risk compared with those with LDL-C >= 3.4 mmol/L and C-reactive protein <2 mg/L. Among individuals who did not qualify for statin therapy based on the Society of Cardiology Systematic COronary Risk Evaluation (SCORE) (n = 4652) or ATP III criteria (n = 4466), 18.1 and 18.9%, respectively, would have qualified using the JUPITER criteria. CONCLUSION: In this European cohort, JUPITER-eligible individuals had significantly higher event rates compared with those with LDL-C <3.4 mmol/L/C-reactive protein <2 mg and LDL-C >= 3.4 mmol/L/C-reactive protein <2 mg/L. Application of the JUPITER criteria qualified almost one-fifth of the population for statin therapy that otherwise would not have qualified based on SCORE or ATP III criteria. PMID- 23449858 TI - Preparation and characterization of an extract of german cockroach from a korean source. AB - PURPOSE: The cockroach (CR) is an important cause of respiratory allergic disorders. We prepared a German CR extract in a standardized way and analyzed its allergenic properties. METHODS: The extract was prepared from German CR (Blattella germanica) obtained from a Korean colony, and its allergenic activity was compared with that of the commercial Hollister-Stier (HS) extract. The concentrations of Bla g 1 and Bla g 2 were measured, and an in vitro specific IgE binding inhibition assay was performed to assess IgE reactivity. Proteolytic activity was examined by gelatin zymography. RESULTS: Bla g 1 and Bla g 2 were detected at 405 U/mg and 273 ng/mg, respectively, in the Korean extract, and at 187 U/mg and 56 ng/mg, respectively, in the HS extract. The Korean extract showed 94.2% inhibition of IgE reactivity, as compared with the HS extract. A similar pattern of IgE-reactive bands was detected for the two extracts, indicating that their allergenic components are similar. The proteolytic activities of the Korean and HS extracts were found to be similar in gelatin zymography. The endotoxin levels in the Korean and HS extracts were 3,440 EU/mL and 6,580 EU/mL, respectively. CONCLUSIONS: The German CR extract was prepared in a standardized way. The extract produced in this study will be useful for the development of allergy diagnostics and immunotherapeutic agents. PMID- 23449859 TI - Meat Science And Muscle Biology Symposium: in utero factors that influence postnatal muscle growth, carcass composition, and meat quality. PMID- 23449860 TI - Vasoconstriction in horses caused by endophyte-infected tall fescue seed is detected with Doppler ultrasonography. AB - The hypotheses that endophyte (Neotyphodium coenophialum)-infected tall fescue (TF) seed causes vasoconstriction in horses in vivo and that ground seed would cause more pronounced vasoconstriction than whole seed were tested. Ten horses each received 1 of 3 treatments: endophyte-free ground (E-G; n = 4 horses) seed, endophyte-positive whole (E+W; n = 3) seed, or endophyte-positive ground (E+G; n = 3) seed. There were two 14-d periods, P1 and P2. During P1, animals were adapted to a concentrate (0.2% BW, as fed, twice daily) and alfalfa cubes. During P2, the seed was mixed into the concentrate portion of the diet and alfalfa cubes were offered ad libitum. Fescue seed was fed in increasing amounts ranging from 0.02% BW on d 1 (averaging 76 ug/kg ergovaline + ergovalinine) to 0.22% BW on d 11 to 14 (averaging 713 ug/kg ergovaline + ergovalinine). The distal palmar artery of the left foreleg of each horse was scanned via Doppler ultrasonography for 4 d during each period, with 5 replicate scans performed on each scanning day. The measurements taken at each scan included artery luminal diameter, area, and circumference, peak systolic velocity, end diastolic velocity and blood flow variables. Animal temperature, heart rate, and respiration rate and ambient temperature and humidity were also recorded. Blood samples were taken on each scanning day to measure inflammatory cytokine mRNA abundances, and blood samples were collected on d 0, 4, 8, and 14 of P2 to measure prolactin concentrations. Consumption of E+G TF seed caused decreased artery lumen diameter (P = 0.0033), area (P = 0.0406), and circumference (P = 0.0480) compared with E-G seed, and E+W seed produced an intermediate response. Blood flow volume was reduced (P < 0.05) during P2 in horses receiving E+G seed compared with horses receiving E-G seed. Other ultrasound variables were not different (P > 0.05) among treatment groups, and neither were cytokine mRNA or prolactin concentrations. Treatment did not alter (P > 0.05) animal temperature, heart rate, or respiration rate, and neither ambient temperature nor relative humidity was consistently correlated with any response variable measured. Taken together, these data confirm that consumption of E+G fescue seed caused vasoconstriction in horses, which could be readily measured by Doppler ultrasonography. Use of Doppler ultrasound to monitor the diameter of the palmar artery of horses grazing endophyte-infected (E+) fescue pastures may provide a convenient and satisfactory biomarker to determine premonitory signs of fescue toxicosis. PMID- 23449861 TI - Genetic associations for gilt growth, compositional, and structural soundness traits with sow longevity and lifetime reproductive performance. AB - The objective of this study was to estimate genetic associations for gilt growth, compositional, and structural soundness with sow longevity and lifetime reproduction. Performance and pedigree information from 1,447 commercial females from 2 genetic lines were included in the data analyzed. Growth was expressed as days to 113.5 kg BW (DAYS) and compositional traits included loin muscle area (LMA), 10th rib backfat (BF10), and last rib backfat (LRF). Structural soundness traits included body structure traits [length (BL), depth (BD), width (BWD), rib shape (BRS), top line (BTL), and hip structure (BHS)], leg structure traits [front legs: legs turned (FLT), buck knees (FBK), pastern posture (FPP), foot size (FFS), and uneven toes (FUT); rear legs: legs turned (RLT), leg posture (RLP), pastern posture (RPP), foot size (RFS), and uneven toes (RUT)], and overall leg action (OLA). Lifetime (LT) and removal parity (RP) were considered as longevity traits whereas lifetime reproductive traits included lifetime total number born (LNB), lifetime number born alive (LBA), number born alive per lifetime day (LBA/LT), and percentage productive days from total herd days (PD%). Genetic parameters were estimated with linear animal models using the average information REML algorithm. Second, to account for censored longevity and lifetime reproduction records, genetic parameters were estimated using Markov Chain Monte Carlo and Gibbs sampling methods. Similar estimates were obtained across the analysis methods. Heritability estimates for growth and compositional traits ranged from 0.50 to 0.70 and for structural soundness traits from 0.07 to 0.31. Longevity and lifetime reproductive trait heritability estimates ranged from 0.14 to 0.17 when REML was used. Unfavorable genetic correlations were obtained for DAYS with LT, RP, LNB, LBA, and PD% and for LRF with PD%. However, LMA was favorably associated with LT, RP, and LNB. Moderate to high correlations were obtained for BL and BRS with all longevity and lifetime reproductive traits. Correlations of BWD with LT and RP were moderate. Associations for leg soundness traits with longevity and lifetime reproductive traits were mainly low and nonsignificant (P >= 0.10). However, RLP was moderately correlated with LBA/LT and PD%. Current results indicate that selection for fewer DAYS has an antagonistic effect on lifetime performance. Furthermore, great BL, flat BRS, narrow BWD, and upright RLP seem detrimental to sow longevity and lifetime reproduction. PMID- 23449862 TI - The effect of inhalation aromatherapy on anxiety level of the patients in preoperative period. AB - BACKGROUND: Anxiety is the one of the most common problems before the surgery. Its prevalence rate ranged from 11 to 80 percent in all the adult patients. Delay in wound healing and increasing use of narcotics and anesthetics are some of the other accompanying problems. Aromatherapy is one of the complementary medicine components. It is applied by special type of oil extracted from aromatic plants for medical objectives. This study aimed to investigate the effects of inhalation aromatherapy on anxiety level in preoperative patients. METHODS: This was a clinical study done on 72 patients candidate for heart and abdominal surgery admitted in Golestan and Imam Khomeini hospitals. The patients were selected according to our study objectives and inclusion criteria. Then, they were divided in two case and control groups. The Spielberger scale was used for evaluating the anxiety level. Twenty minute of inhalation with handkerchief containing lavandula was used in the case group and placebo also (water) in the control group. RESULTS: The average of anxiety level in inhalation aromatherapy group decreased from 51.00 to 38.61 from before to after the intervention. This average in the inhalation group with placebo was 50.67 before the intervention and decreased to 49.53 after the intervention. The results of independent t-test statistically showed a significant difference between the two groups after the intervention. CONCLUSIONS: The findings showed that inhalation aromatherapy was effective on reduction of anxiety level and this method can be applied as a complementary medicine on the clinic. PMID- 23449863 TI - Posterior ventricular anchoring neochordal repair of degenerative mitral regurgitation efficiently remodels and repositions posterior leaflet prolapse. AB - OBJECTIVES: Mitral valve repair techniques for degenerative disease typically entail leaflet resection or neochordal construction, which may require extensive resection, leaflet detachment/reattachment, reliance on diseased native chords or precise neochordal measuring. Occasionally, impaired leaflet mobility, reduced coaptation surface and systolic anterior motion (SAM) may result. We describe a novel technique for addressing posterior leaflet prolapse/flail, which both simplifies repair and addresses these issues. METHODS: Fifty-four patients (age 62 +/- 11 years) with degenerative MR underwent this new repair, 36 of whom minimally-invasively. A CV5 Gore-Tex suture was placed into the posterior left ventricular myocardium underneath the prolapsing segment as an anchor. This suture was then used to imbricate a portion of the prolapsed segment into the ventricle, creating a smooth, broad, non-prolapsed coapting surface on a leaflet with preserved mobility, additional neochordal support and posteriorly positioned enough to preclude SAM. RESULTS: Repair was successful in all patients. The mean MR grade was reduced from +3.8 to +0.1 with 50 of 54 patients having zero MR and 4 of the 54 having trace or mild MR. All patients had proper antero-posterior location of the coaptation line of a mean length of 10.2 mm, and preserved posterior leaflet mobility. No patients had SAM or mitral stenosis. All patients were discharged and are currently doing well. CONCLUSION: This new technique facilitated efficient single-suture repair of the prolapsed posterior leaflet mitral regurgitation without the need for resection or sliding annuloplasty. It precluded the need for precise neochordal measurement and preserved the leaflet coaptation surface. PMID- 23449864 TI - Effects of diaphragm plication on pulmonary function and cardiopulmonary exercise parameters. AB - OBJECTIVES: Paralysis of the diaphragm is an uncommon condition, which may result in dyspnoea on excertion and in orthopnea. In patients who have symptoms, the paralysed diaphragm is often plicated to prevent its paradoxical movement on inspiration. This procedure brings relief to many patients, but the mechanism for this improvement is not well understood. METHODS: Nine symptomatic patients who underwent plication of a unilateral paralysed hemidiaphragm were prospectively evaluated. All patients underwent pulmonary function tests and cardiopulmonary exercise tests before surgery and repeated them after surgery. RESULTS: Patients with hemidiaphragm paralysis before surgery were found to have lower tidal volumes at any given ventilation rate during exercise than normal subjects. A clear and consistent change was found in the manner in which patients increased their ventilation during exercise after surgery. All patients showed an increase in tidal volume for a given ventilation rate, which was significant. The plication procedure reduced the respiratory rate for any exercise level in all patients, and this effect was more pronounced during exercise. CONCLUSIONS: In patients with hemidiaphragm paralysis who underwent a diaphragm plication exercise, tidal volumes increased and the ventilatory frequency decreased. Despite this improvement, maximal exercise capacity remained unaltered. PMID- 23449865 TI - Effect of cannula position in the thoracic aorta with continuous left ventricular support: four-dimensional flow-sensitive magnetic resonance imaging in an in vitro model. AB - OBJECTIVES: Left ventricular assist devices (LVADs) have become an important treatment option for heart failure patients. However, altered blood flow patterns are suspected to affect perfusion in the aorta or cause structural changes to the aortic root, leading to regurgitation and valve dysfunction or thrombus formation. The purpose of this study was to evaluate flow patterns in a realistic in vitro model system using four-dimensional flow-sensitive magnetic resonance imaging. METHODS: A magnetic resonance compatible model system was developed consisting of an aorta connected to a VAD simulating the pulsatile flow of the native heart. An LVAD was connected to the aorta model via three different cannula positions. Flow patterns in the entire system as well as flow rates in predefined positions for reduced and zero cardiac output were evaluated. RESULTS: Cannula position influences flow patterns and flow rates in the entire thoracic aorta. For a residual cardiac output, a larger anastomosis and a decreased flow rate of the LAVD result in a higher flow rate and smaller retrograde flow in the ascending aorta when compared with a smaller anastomosis or a cannula position in the descending aorta. Pronounced flow turbulences in the aorta were observed for the cannula position in the descending aorta. CONCLUSIONS: In the setting of reduced cardiac output, as commonly observed in patients on LVAD therapy, a large anastomosis to the ascending aorta for the outflow cannula induces the least adverse flow patterns in the aortic root. Our approach may aid in a better understanding of LVAD-induced flow-pattern changes. Optimization of the cannula position and anastomosis may help to prevent the progression of aortic valve regurgitation and thrombus formation. PMID- 23449866 TI - A rare entity: sternal foramen. PMID- 23449867 TI - The behavior-analytic origins of constraint-induced movement therapy: an example of behavioral neurorehabilitation. AB - Constraint-induced (CI) therapy is a term given to a family of efficacious neurorehabilitation treatments including to date: upper extremity CI movement therapy, lower extremity CI movement therapy, pediatric CI therapy, and CI aphasia therapy. The purpose of this article is to outline the behavior analysis origins of CI therapy and the ways in which its procedures incorporate behavior analysis methods and principles. The intervention is founded on the concept of learned nonuse, a mechanism now empirically demonstrated to exist, which occurs after many different types of damage to the central nervous system (CNS). It results from the dramatic alteration of the contingencies of reinforcement that results from substantial CNS damage and leads to a greater deficit than is warranted by the actual damage sustained. CI therapy produces a countervailing alteration in the contingencies of reinforcement. The intervention has been used successfully to substantially improve motor deficits after stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, with cerebral palsy in a pediatric population, and for language impairment in poststroke aphasia. The protocol of CI therapy consists primarily of standard behavior-analytic methods. It produces a marked plastic brain change that is correlated with its therapeutic effect, and therefore provides an example of the way in which behavior change can contribute to a profound remodeling of the brain. CI therapy may be viewed as an example of behavioral neurorehabilitation. PMID- 23449868 TI - Intermittent respiration-dependent aortic valve regurgitation in a patient with a ruptured aneurysm of the non-coronary sinus of Valsalva. PMID- 23449869 TI - Small molecules inhibit growth, viability and ergosterol biosynthesis in Candida albicans. AB - The aim of this work was to evaluate the anti-Candida efficacy of twenty five molecules of plant origin. Based on their MICs, effective molecules were categorized into four categories. Susceptibility testing of test compounds was carried out by standard methodology (M27-A2) as per CLSI guidelines. Minimum Fungicidal Concentration (MFC) was determined as the lowest concentration of drug killing 99.9% cells. Effect on sterol profile was evaluated by sterol quantitation method. Among the screened molecules, cinnamaldehyde, piperidine, citral, furfuraldehyde and indole were potent inhibitors of growth and viability. Exposure of Candida cells to cinnamaldehyde, piperidine, citral, furfuraldehyde, indole, alpha- and beta- pinene at MIC's, altered ergosterol profile. Our results indicate that the molecules altering sterol profile may exert their antifungal effect through inhibition of ergosterol biosynthesis and could be good candidates for fungal specific drug development. PMID- 23449870 TI - Continuous culture of sessile human oropharyngeal microbiotas. AB - The microbiota of the human oropharynx plays an important role in health through involvement in the aetiology of infection and the carriage of adventitious pathogens. Despite this, there are few models available for the preclinical assessment of novel antimicrobials directed to the human throat. We have profiled bacterial consortia sampled from the palatine tonsil and posterior pharyngeal wall microbiotas of healthy adult volunteers (n = 10) using differential culture and 16S rRNA gene sequencing, together with PCR-denaturing gradient gel electrophoresis. The data generated were used to assess the validity of an oropharyngeal microcosm system based on replicated constant-depth film fermenters (CDFFs; n = 5), which were continuously fed using an artificial airway surface liquid. Developed microcosms exhibited significant homology to ex situ consortia according to principal components analysis, whilst compositional reproducibility was apparent in replicated models for tonsillar and pharyngeal inocula. Differential viable count data and Shannon-Weiner diversity indices indicated that representative tonsil and pharyngeal model systems achieved dynamic compositional stability about 6 days after inoculation which could be maintained for >=20 days. In conclusion, the CDFF facilitated the continuous maintenance of bacteriologically stable microcosms that were compositionally similar to ex situ inocula. PMID- 23449871 TI - Emergence of cfr-harbouring coagulase-negative staphylococci among patients receiving linezolid therapy in two hospitals in China. AB - This study reports on the emergence of cfr-harbouring coagulase-negative staphylococci (CoNS) among patients who received linezolid therapy in two hospitals in Hangzhou, China. The mechanisms of resistance and transmission were analysed for these resistant isolates. Eight Staphylococcus capitis isolates, one Staphylococcus epidermidis isolate and one Staphylococcus hominis isolate, obtained from patients who had received linezolid therapy in two hospitals in Hangzhou, China, were confirmed as linezolid resistant, with MICs ranging from 8 to >256 mg l(-1). The linezolid usage data of the ten patients before isolation of the linezolid-resistant CoNS were collected. PFGE analysis showed that the eight S. capitis isolates from the two hospitals belonged to the same clone. Nine of the linezolid-resistant CoNS isolates carried the cfr gene, which was located on plasmids of a similar size. A 5.3 kb fragment containing the cfr gene, revealing 99 % identity to the sequence of the cfr-harbouring plasmid pSS-01 reported previously, was determined by PCR mapping for all cfr-positive isolates, and the cfr gene was flanked by two copies of IS256-like elements. Thus, these results document the emergence of linezolid-resistant CoNS isolates carrying the cfr gene in Hangzhou, China. Effective nosocomial infection control strategies and the judicious use of antibiotics will be required to prevent further spread of this resistance mechanism. PMID- 23449872 TI - Fatal non-O1, non-O139 Vibrio cholerae septicaemia in a patient with chronic liver disease. AB - A 49-year-old male with underlying liver disease presented with fever and signs of sepsis. Non-O1/non-O139 Vibrio cholerae was isolated from his blood culture, which was positive for the hlyA and toxR genes. We report this fatal case of non O1/non-O139 V. cholera sepsis and review the literature on non-O1/non-O139 V. cholerae sepsis in patients with chronic liver disease. PMID- 23449873 TI - Subcutaneous phaeohyphomycosis caused by Exophiala equina, with susceptibility to eight antifungal drugs. AB - A case of subcutaneous phaeohyphomycosis caused by Exophiala equina is reported in a 75-year-old female, who showed subcutaneous abscesses on both forearms for 8 months. A lesion was initiated by inoculation with a spine from a tree. Histopathologically, suppurative granulomatous inflammation was present and short hyphal elements were observed. Upon culture greyish-black, velvety colonies of a black yeast were obtained after 3 weeks. The strain grew well at 25 degrees C, but poorly at 37 degrees C. After sequencing the internal transcribed spacer domain and the partial beta-tubulin gene, the fungus was identified as E. equina. The patient was successfully treated with fluconazole for 3 months. PMID- 23449875 TI - SubMICs of penicillin and erythromycin enhance biofilm formation and hydrophobicity of Corynebacterium diphtheriae strains. AB - Subinhibitory concentrations (subMICs) of antibiotics may alter bacterial surface properties and change microbial physiology. This study aimed to investigate the effect of a subMIC (⅛ MIC) of penicillin (PEN) and erythromycin (ERY) on bacterial morphology, haemagglutinating activity, cell-surface hydrophobicity (CSH) and biofilm formation on glass and polystyrene surfaces, as well as the distribution of cell-surface acidic anionic residues of Corynebacterium diphtheriae strains (HC01 tox(-) strain; CDC-E8392 and 241 tox(+) strains). All micro-organisms tested were susceptible to PEN and ERY. Growth in the presence of PEN induced bacterial filamentation, whereas subMIC of ERY caused cell-size reduction of strains 241 and CDC-E8392. Adherence to human erythrocytes was reduced after growth in the presence of ERY, while CSH was increased by a subMIC of both antibiotics in bacterial adherence to n-hexadecane assays. Conversely, antibiotic inhibition of biofilm formation was not observed. All strains enhanced biofilm formation on glass after treatment with ERY, while only strain 241 increased glass adherence after cultivation in the presence of PEN. Biofilm production on polystyrene surfaces was improved by ⅛ MIC of ERY. After growth in the presence of both antimicrobial agents, strains 241 and CDC-E8392 exhibited anionic surface charges with focal distribution. In conclusion, subMICs of PEN and ERY modified bacterial surface properties and enhanced not only biofilm formation but also cell-surface hydrophobicity. Antibiotic-induced biofilm formation may contribute to the inconsistent success of antimicrobial therapy for C. diphtheriae infections. PMID- 23449874 TI - Influence of the probiotic Streptococcus salivarius strain M18 on indices of dental health in children: a randomized double-blind, placebo-controlled trial. AB - The prevalence of dental caries continues to increase, and novel strategies to reverse this trend appear necessary. The probiotic Streptococcus salivarius strain M18 offers the potential to confer oral health benefits as it produces bacteriocins targeting the important cariogenic species Streptococcus mutans, as well as the enzymes dextranase and urease, which could help reduce dental plaque accumulation and acidification, respectively. In a randomized double-blind, placebo-controlled study of 100 dental caries-active children, treatment with M18 was administered for 3 months and the participants were assessed for changes to their plaque score and gingival and soft-tissue health and to their salivary levels of S. salivarius, S. mutans, lactobacilli, beta-haemolytic streptococci and Candida species. At treatment end, the plaque scores were significantly (P = 0.05) lower for children in the M18-treated group, especially in subjects having high initial plaque scores. The absence of any significant adverse events supported the safety of the probiotic treatment. Cell-culture analyses of sequential saliva samples showed no differences between the probiotic and placebo groups in counts of the specifically enumerated oral micro-organisms, with the exception of the subgroup of the M18-treated children who appeared to have been colonized most effectively with M18. This subgroup exhibited reduced S. mutans counts, indicating that the anti-caries activity of M18 probiotic treatments may be enhanced if the efficiency of colonization is increased. It was concluded that S. salivarius M18 can provide oral health benefits when taken regularly. PMID- 23449876 TI - Contamination of ready-to-eat raw vegetables with Clostridium difficile in France. AB - The presence of Clostridium difficile in food like shellfish, vegetables and meat has been reported in several publications during the past few years. The objective of this study was to assess the prevalence of ready-to-eat raw vegetables contaminated with C. difficile in France. One hundred and four ready to-eat salads and vegetables were studied. Toxigenic C. difficile strains were isolated in three samples (2.9 %): two ready-to-eat salads (one heart of lettuce and one lamb's lettuce salad) and one portion of pea sprouts. The strains belonged to three different PCR ribotypes: 001, 014/020/077 and 015. The detection thresholds for vegetative cells and spores cells varied between 1 and 3 c.f.u. in 20 g salad and between 6 and 15 c.f.u. in 20 g salad, respectively, for the method employed. PMID- 23449877 TI - Fatal sepsis caused by an unusual Klebsiella species that was misidentified by an automated identification system. AB - This is a description of fatal sepsis caused by infection with Klebsiella variicola, which is an isolate genetically related to Klebsiella pneumoniae. The patient's condition was incorrectly diagnosed as common sepsis caused by K. pneumoniae, which was identified using an automated identification system, but next-generation sequencing and the non-fermentation of adonitol finally identified the cause of sepsis as K. variicola. PMID- 23449878 TI - Characterization of the first isolate of Klebsiella pneumoniae carrying New Delhi metallo-beta-lactamase and other extended spectrum beta-lactamase genes from Malaysia. PMID- 23449879 TI - Hierarchical clustering as a rapid tool for surveillance of emerging antibiotic resistance phenotypes in Klebsiella pneumoniae strains. AB - Antimicrobial resistance is on the rise, and its early detection and surveillance are critical to implement effective control measures. The aim of this study was to develop a rapid hierarchical clustering bioinformatic tool for application on antibiotic susceptibility testing (AST) results (resistant, intermediate, sensitive) of a series of Klebsiella pneumoniae clinical isolates from Algeria and from France for surveillance of antibiotic-resistance phenotypes. A total of 1011 K. pneumoniae strains were collected from August 2008 to December 2012: 221 clinical isolates from western Algeria and 790 clinical isolates from Marseille, France. AST against a panel of 16 antibiotics was done for all isolates. Results of AST were introduced into MultiExperiment Viewer (MeV) software to perform hierarchical clustering, with resistant, intermediate and sensitive being translated to 1, 0 and -1 values, respectively. Hierarchical clustering results were compared to standard resistance phenotypes to evaluate the accuracy of the method. Based on the AST results, the 221 K. pneumoniae strains from Algeria could be separated into six phenotype groups as regards their resistance to beta lactam compounds: extended spectrum beta-lactamase (ESBL) (68.3 %), ESBL associated with cephalosporinase (13.1 %), cephalosporinase (0.9 %), penicillinase (3.6 %) and wild-type (14.0 %). Hierarchical clustering by the MeV software applied to the AST results for all 1011 isolates generated clusters that were significantly representative of phenotypic classification and geographical origin, in less than 1 min. Moreover, adding to the dataset the AST results of a K. pneumoniae NDM-1 positive strain, the only strain resistant to imipenem in the series, immediately generated a new branch in the dendrogram. We have developed a rapid and simple hierarchical clustering tool for application on AST results that was able to survey qualitatively and quantitatively the prevalence of known and unknown phenotypes. This tool could be easily implemented in routine clinical microbiology laboratories. PMID- 23449881 TI - Probiotics and their Effects on Metabolic Diseases: An Update. AB - Probiotics are lactic acid bacteria which are used extensively in therapeutic preparations and added to foods. There are many studies which have demonstrated the effects of probiotics on metabolic diseases. One study has shown the effect of fermented dairy products on the serum cholesterol, especially with selected strains of lactic acid bacteria. It has been found that a minute quantity of the dry culture of Lactobacillus fermentum KC4b, for example, can remove 14.8 mg of cholesterol from the culture medium. Lactobacilli also play an important role in deconjugating the bile salts in the intestine to form bile acids and thereby inhibiting the micelle formation. Probiotics reduce the lipid peroxidation and improve the lipid metabolism in vivo. The addition of probiotics to the diet for weeks improved the immune response without the release of inflammatory cytokines, thereby reducing the onset of systemic inflammatory induced diabetes. There are evidences that the differences in the composition of the gut microbiota may precede the development of obesity in children. This review has illustrated the potential of probiotics in mediating metabolic diseases via the positive modulation of several different physiological systems, apart from its conventional benefits for the gastrointestinal health. PMID- 23449880 TI - Task-related "cortical" bursting depends critically on basal ganglia input and is linked to vocal plasticity. AB - Basal ganglia-thalamocortical circuits are critical for motor control and motor learning. Classically, basal ganglia nuclei are thought to regulate motor behavior by increasing or decreasing cortical firing rates, and basal ganglia diseases are assumed to reflect abnormal overall activity levels. More recent studies suggest instead that motor disorders derive from abnormal firing patterns, and have led to the hypothesis that surgical treatments, such as pallidotomy, act primarily by eliminating pathological firing patterns. Surprisingly little is known, however, about how the basal ganglia normally influence task-related cortical activity to regulate motor behavior, and how lesions of the basal ganglia influence cortical firing properties. Here, we investigated these questions in a songbird circuit that has striking homologies to mammalian basal ganglia-thalamocortical circuits but is specialized for singing. The "cortical" outflow nucleus of this circuit is required for song plasticity and normally exhibits increased firing during singing and song-locked burst firing. We found that lesions of the striato-pallidal nucleus in this circuit prevented hearing-dependent song changes. These basal ganglia lesions also stripped the cortical outflow neurons of their patterned burst firing during singing, without changing their spontaneous or singing-related firing rates. Taken together, these results suggest that the basal ganglia are essential not for normal cortical firing rates but for driving task-specific cortical firing patterns, including bursts. Moreover, such patterned bursting appears critical for motor plasticity. Our findings thus provide support for therapies that aim to treat basal ganglia movement disorders by normalizing firing patterns. PMID- 23449882 TI - Weekend physiotherapy practice in community hospitals in Canada. AB - PURPOSE: To analyze weekend physiotherapy services in acute-care community hospitals across Canada. METHOD: Questionnaires were mailed to acute-care community hospitals (institutions with >100 inpatient beds, excluding psychiatric, mental health, paediatric, rehabilitation, tertiary, and long-term care facilities) across Canada from January to April 2010. The questionnaire collected information on patient referral criteria, staffing, workload, and compensation for weekend physiotherapy services and on the availability of other rehabilitation health professionals. RESULTS: Of 146 community hospitals deemed eligible, 104 (71%) responded. Weekend physiotherapy was offered at 69% of hospitals across Canada, but this rate varied: >=75% in all regions except Quebec (30%). Hospitals with a high proportion of acute-care beds were more likely to offer weekend physiotherapy services (logistic regression, p=0.021). Services differed among Saturdays, Sundays, and holidays in terms of the numbers of both physiotherapists and physiotherapy assistants working (Kruskal-Wallis, p<0.02 for each). Physiotherapists were predominantly compensated via time off in lieu. Of hospitals not offering weekend physiotherapy, 53% reported that it would benefit patients; most perceived staffing and financial barriers. Social-work services were offered on the weekend at 24% of hospitals and occupational therapy at 16%. CONCLUSIONS: Substantial regional variation exists in access to weekend physiotherapy services in acute-care community hospitals. To address the importance of this variation, research on the efficacy and cost-effectiveness of such services is required. : Purpose: To analyze weekend physiotherapy services in acute-care community hospitals across Canada. Method: Questionnaires were mailed to acute-care community hospitals (institutions with >100 inpatient beds, excluding psychiatric, mental health, paediatric, rehabilitation, tertiary, and long-term care facilities) across Canada from January to April 2010. The questionnaire collected information on patient referral criteria, staffing, workload, and compensation for weekend physiotherapy services and on the availability of other rehabilitation health professionals. Results: Of 146 community hospitals deemed eligible, 104 (71%) responded. Weekend physiotherapy was offered at 69% of hospitals across Canada, but this rate varied: >=75% in all regions except Quebec (30%). Hospitals with a high proportion of acute-care beds were more likely to offer weekend physiotherapy services (logistic regression, p=0.021). Services differed among Saturdays, Sundays, and holidays in terms of the numbers of both physiotherapists and physiotherapy assistants working (Kruskal-Wallis, p<0.02 for each). Physiotherapists were predominantly compensated via time off in lieu. Of hospitals not offering weekend physiotherapy, 53% reported that it would benefit patients; most perceived staffing and financial barriers. Social-work services were offered on the weekend at 24% of hospitals and occupational therapy at 16%. Conclusions: Substantial regional variation exists in access to weekend physiotherapy services in acute care community hospitals. To address the importance of this variation, research on the efficacy and cost-effectiveness of such services is required. PMID- 23449884 TI - Evaluation of morbidity associated with iliac crest harvest for alveolar cleft bone grafting. AB - PURPOSE: To evaluate the morbidity associated with iliac crest harvest for alveolar cleft grafting. PATIENTS AND METHODS: 18 patients treated for alveolar clefts in oral and maxillofacial surgery unit at SRM dental college and Hospital were included. Patients were interviewed to fill a questionnaire on postoperative recovery. The donor site was evaluated for the following factors: Pain, neuropraxia, abnormal gait and scar evaluation. RESULTS: The scars were evaluated, according to the satisfactory score-eleven patients (61.11%) had a score 2, Four patients (22.22%) had score 3 and three patients (16.66%) had score 1. The pain score after the first week-thirteen patients (72.22%) had score 2, five patients had score 3 (27.77%). After the first month-four patients (22.22%), had score 2, twelve patients (66.66%), had score 1 and Two patients (11.11%) had score 0. And when evaluated after 3 months, two patients (11.11%), had score 1 and sixteen patients (88.88%) had score 0. The gait was examined by asking the patient to walk and evaluated; in the first week, all eighteen patients had abnormality in gait; in the first month, five patients had abnormality in gait (27.77%), and in the third month, none of the patients had any abnormality in gait. CONCLUSIONS: Harvesting cancellous bone from anterior iliac crest in young patients is well tolerated, allows early resumption of normal activities, has no effect on growth, has minimal morbidity and a reasonable aesthetic outcome. PMID- 23449883 TI - Post-stroke Movement Disorders: Clinical Manifestations and Pharmacological Management. AB - Involuntary abnormal movements have been reported after ischaemic and haemorrhagic stroke. Post stroke movement disorders can appear as acute or delayed sequel. At the moment, for many of these disorders the knowledge of pharmacological treatment is still inadequate. Dopaminergic and GABAergic systems may be mainly involved in post-stroke movement disorders. This article provides a review on drugs commonly used in post-stroke movement disorders, given that some post-stroke movement disorders have shown a partial benefit with pharmacological approach. PMID- 23449885 TI - Kangaroo care for the preterm infant and family. AB - Kangaroo care (KC) is the practice of skin-to-skin contact between infant and parent. In developing countries, KC for low-birthweight infants has been shown to reduce mortality, severe illness, infection and length of hospital stay. KC is also beneficial for preterm infants in high-income countries. Cardiorespiratory and temperature stability, sleep organization and duration of quiet sleep, neurodevelopmental outcomes, breastfeeding and modulation of pain responses appear to be improved for preterm infants who have received KC during their hospital stay. No detrimental effects on physiological stability have been demonstrated for infants as young as 26 weeks' gestational age, including those on assisted ventilation. Mothers show enhanced attachment behaviours and describe an increased sense of their role as a mother. The practice of KC should be encouraged in nurseries that care for preterm infants. Information is available to assist in developing guidelines and protocols. PMID- 23449886 TI - Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. AB - STUDY OBJECTIVES: To determine the association between common genetic variation in the clock gene pathway and objectively measured acti-graphic sleep and activity rhythm traits. DESIGN: Genetic association study in two population-based cohorts of elderly participants: the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men (MrOS) study. SETTING: Population-based. PARTICIPANTS: SOF participants (n = 1,407, 100% female, mean age 84 years) and MrOS participants (n = 2,527, 100% male, mean age 77 years) with actigraphy and genotype data. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Common genetic variation in 30 candidate genes was captured using 529 single nucleotide polymorphisms (SNPs). Sleep and activity rhythm traits were objectively measured using wrist actigraphy. In a region of high linkage disequilibrium on chromosome 12p13 containing the candidate gene GNB3, the rs1047776 A allele and the rs2238114 C allele were significantly associated with higher wake after sleep onset (meta-analysis: rs1047776 PADD = 2 * 10(-5), rs2238114 PADD = 5 * 10(-5)) and lower LRRC23 gene expression (rs1047776: rho = -0.22, P = 0.02; rs2238114: rho = -0.50, P = 5 * 10(-8)). In MrOS participants, SNPs in ARNTL and NPAS2, genes coding for binding partners, were associated with later sleep and wake onset time (sleep onset time: ARNTL rs3816358 P2DF = 1 * 10(-4), NPAS2 rs3768984 P2DF = 5 * 10(-5); wake onset time: rs3816358 P2DF = 3 * 10(-3), rs3768984 P2DF = 2 * 10(-4)) and the SNP interaction was significant (sleep onset time PINT = 0.003, wake onset time PINT = 0.001). A SNP association in the CLOCK gene replicated in the MrOS cohort, and rs3768984 was associated with sleep duration in a previously reported study. Cluster analysis identified four clusters of genetic associations. CONCLUSIONS: These findings support a role for common genetic variation in clock genes in the regulation of inter-related sleep traits in the elderly. CITATION: Evans DS; Parimi N; Nievergelt CM; Blackwell T; Redline S; Ancoli-Israel S; Orwoll ES; Cummings SR; Stone KL; Tranah GJ. Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. SLEEP 2013;36(3):431-446. PMID- 23449887 TI - Identification of steroid-sensitive gene-1/Ccdc80 as a JAK2-binding protein. AB - The tyrosine kinase Janus kinase 2 (JAK2) is activated by many cytokine receptors, including receptors for GH, leptin, and erythropoietin. However, very few proteins have been identified as binding partners for JAK2. Using a yeast 2 hybrid screen, we identified steroid-sensitive gene-1 (SSG1)/coiled-coil domain containing protein 80 (Ccdc80) as a JAK2-binding partner. We demonstrate that Ccdc80 preferentially binds activated, tyrosyl-phosphorylated JAK2 but not kinase inactive JAK2 (K882E) in both yeast and mammalian systems. Ccdc80 is tyrosyl phosphorylated in the presence of JAK2. The binding of Ccdc80 to JAK2 occurs via 1 or more of the 3 DUDES/SRPX (DRO1-URB-DRS-Equarin-SRPUL/sushi repeat containing protein, x-linked) domain 5 domains of Ccdc80. Mutagenesis of the second DUDES domain suggests that the N-terminal third of the DUDES domain is sufficient for JAK2 binding. Ccdc80 does not alter the kinase activity of JAK2. However, Ccdc80 increases GH-dependent phosphorylation of Stat (signal transducer and activator of transcription) 5b on Tyr699 and substantially enhances both basal and GH dependent phosphorylation/activation of Stat3 on Tyr705. Furthermore, Ccdc80 belongs to the group of proteins that function both in the intracellular compartment and are secreted. Secreted Ccdc80 associates with the extracellular matrix and is also found in the medium. A substantial portion of the Ccdc80 detected in the medium is cleaved. Finally, consistent with the DUDES domain serving as a JAK2-binding domain, we also demonstrate that another protein that contains a DUDES domain, SRPX2, binds preferentially to the activated tyrosyl phosphorylated form of JAK2. PMID- 23449888 TI - ARF represses androgen receptor transactivation in prostate cancer. AB - Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of AR activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with AR and functions as an AR corespressor in both an androgen-dependent and androgen-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and AR colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2) probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3.1) expression. Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced AR transactivation activities in a dose dependent and p53-independent manner. Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of AR, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and AR proteins. p14ARF perturbs the androgen-induced interaction between the N terminus and C terminus of AR. Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues. Taken together, our results reveal a novel function of ARF in modulation of AR transactivation in PCa. PMID- 23449889 TI - Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database. AB - OBJECTIVE: To examine the magnitude of the adverse impact of high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury (SCI). METHODS: We examined the abstracted data from the Japanese Diagnosis Procedure Combination database, and included patients with ICD-10 code S141 who were admitted on an emergency basis between 1 July and 31 December in 2007-2009. The investigation evaluated the patients' sex, age, comorbidities, Japan Coma Scale, hospital volume and the amount of methylprednisolone administered. One-to one propensity-score matching between high-dose methylprednisolone group (>5000 mg) and control group was performed to compare the rates of in-hospital death and major complications (sepsis; pneumonia; urinary tract infection; gastrointestinal ulcer/bleeding; and pulmonary embolism). RESULTS: We identified 3508 cervical SCI patients (2652 men and 856 women; mean age, 60.8 +/- 18.7 years) including 824 (23.5%) patients who received high-dose methylprednisolone. A propensity-matched analysis with 824 pairs of patients showed a significant increase in the occurrence of gastrointestinal ulcer/bleeding (68/812 vs 31/812; p<0.001) in the high-dose methylprednisolone group. Overall, the high-dose methylprednisolone group demonstrated a significantly higher risk of complications (144/812 vs 96/812;OR, 1.66; 95% CI 1.23 to 2.24; p=0.001) than the control group. There was no significant difference in in-hospital mortality between the high-dose methylprednisolone group and the control group (p=0.884). CONCLUSIONS: Patients receiving high-dose methylprednisolone had a significantly increased risk of major complications, in particular, gastrointestinal ulcer/bleeding. However, high-dose methylprednisolone treatment was not associated with any increase in mortality. PMID- 23449890 TI - Predictive factors for longer length of stay in an emergency department: a prospective multicentre study evaluating the impact of age, patient's clinical acuity and complexity, and care pathways. AB - BACKGROUND: It has been reported that emergency department length of stay (ED LOS) for older patients is longer than average. Our objective was to determine the effect of age, patient's clinical acuity and complexity, and care pathways on ED-LOS and ED plus observation unit (EDOU) LOS (EDOU-LOS). METHODS: This was a prospective, multicentre, observational study including all patients attending in 2011. Age groups were: I, <50; II, >=50-64; III, >=65-74; IV, >=75-84; V, >=85 years. Univariate and multivariate analyses were performed. RESULTS: Of 125 478 attendances, 20 845(16.6%) were of patients aged >=65 years. Multivariate analysis found significant predictors for ED-LOS (C-statistics 0.79, p<0.0000001) to be: arrival mode (ambulance, OR 1.13 (95% CI 1.08 to 1.18)); acuity level (level 4, OR 1.24 (95% CI 1.21 to 1.28); level 1-3, OR 1.54 (95% CI 1.5 to 1.59)); haematological examinations (OR 3.34 (95% CI 3.15 to 3.56)); intravenous treatment (OR 1.58 (95% CI 1.47 to 1.69)); monitoring of vital signs (OR 1.89 (95% CI 1.69 to 2.10)); x-ray examinations (OR 1.53 (95% CI 1.45 to 1.61)); CT/MRI/ultrasound (OR 2.60 (95% CI 2.39 to 2.82)); and specialist advice (OR 1.39 (95% CI 1.30 to 1.48)). For EDOU-LOS (C-statistics 0.81, p<0.0000001) we found: age group (II, OR 1.19 (95% CI 1.16 to 1.22); III, OR 1.42 (95% CI 1.38 to 1.46); IV, OR 1.69 (95% CI 1.65 to 1.74); V, 2.01 (95% CI 1.96 to 2.07)); acuity level (level 4, OR 1.31 (95% CI 1.27 to 1.35); level 1-3, OR 1.71 (95% CI 1.66 to 1.77)); haematological examinations (OR 7.81 (95% CI 7.23 to 8.43)); intravenous treatment (OR 1.95 (95% CI 1.8 to 2.12)); x-ray examinations (OR 1.95 (95% CI 1.85 to 2.06)); CT/MRI/ultrasound (OR 6.74 (95% CI 5.98 to 7.6)); specialist advice (OR 2.24 (95% CI 2.07 to 2.42)); admission to a medical or surgical ward (OR 0.61 (95% CI 0.54 to 0.68)); and transfer (OR 1.79 (95% CI 1.54 to 2.07)). CONCLUSIONS: Whereas ED-LOS and EDOU-LOS seem to be directly related to patients' acuity and complexity, notably the need for diagnostic and therapeutic interventions, only EDOU-LOS was significantly associated with age and proposed care pathways. We propose that EDOU-LOS measurement should be made in EDs with an OU. PMID- 23449892 TI - Holmium laser fulguration of superficial urothelial carcinoma of the pendulous urethra. AB - Urothelial carcinoma may occur anywhere in the urinary tract including the pendulous urethra. To prevent urethral stricture after resection and monopolor fulguration we describe the use of the holmium laser to fulgurate recurrent pTa UC from the urethra. The surgical approach was staged and provided excellent long term results for management of superficial UC. PMID- 23449894 TI - The Internet-informed patient: opportunities for patient-centered care. AB - The JADA Editor urges dentists to engage in dialogue with patients regarding health information gathered from the Internet to promote a positive patient provider relationship. PMID- 23449893 TI - Functional plasticity of the human infant beta-cell exocytotic phenotype. AB - Our understanding of adult human beta-cells is advancing, but we know little about the function and plasticity of beta-cells from infants. We therefore characterized islets and single islet cells from human infants after isolation and culture. Although islet morphology in pancreas biopsies was similar to that in adults, infant islets after isolation and 24-48 hours of culture had less insulin staining, content, and secretion. The cultured infant islets expressed pancreatic and duodenal homeobox 1 and several (Glut1, Cav1.3, Kir6.2) but not all (syntaxin 1A and synaptosomal-associated protein 25) markers of functional islets, suggesting a loss of secretory phenotype in culture. The activity of key ion channels was maintained in isolated infant beta-cells, whereas exocytosis was much lower than in adults. We examined whether a functional exocytotic phenotype could be reestablished under conditions thought to promote beta-cell differentiation. After a 24- to 28-day expansion and maturation protocol, we found preservation of endocrine markers and hormone expression, an increased proportion of insulin-positive cells, elevated expression of syntaxin 1A and synaptosomal-associated protein 25, and restoration of exocytosis to levels comparable with that in adult beta-cells. Thus, human infant islets are prone to loss of their exocytotic phenotype in culture but amenable to experimental approaches aimed at promoting expansion and functional maturation. Control of exocytotic protein expression may be an important mechanism underlying the plasticity of the secretory machinery, an increased understanding of which may lead to improved regenerative approaches to treat diabetes. PMID- 23449895 TI - Key performance indicators. PMID- 23449891 TI - Predictive factors of severe multilobar pneumonia and shock in patients with influenza. AB - PURPOSE: To identify risk factors present at admission in adult patients hospitalised due to influenza virus infection during the 2009/10 and 2010/11 seasons--including whether infection was from pandemic or seasonal influenza A infections--that were associated with the likelihood of developing severe pneumonia with multilobar involvement and shock. METHODS: Prospective cohort study. Patients hospitalised due to influenza virus infection were recruited. We collected information on sociodemographic characteristics, pre-existing medical conditions, vaccinations, toxic habits, previous medications, exposure to social environments, and EuroQoL-5D (EQ-5D). Severe pneumonia with multilobar involvement and/or shock (SPAS) was the primary outcome of interest. We constructed two multivariate logistic regression models to explain the likelihood of developing SPAS and to create a clinical prediction rule for developing SPAS that includes clinically relevant variables. RESULTS: Laboratory-confirmed A(H1N1)pdm09, EQ-5D utility score 7 days before admission, more than one comorbidity, altered mental status, dyspnoea on arrival, days from onset of symptoms, and influenza season were associated with SPAS. In addition, not being vaccinated against seasonal influenza in the previous year, anaemia, altered mental status, fever and dyspnoea on arrival at hospital, difficulties in performing activities of daily living in the previous 7 days, and days from onset of symptoms to arrival at hospital were related to the likelihood of SPAS (area under the curve value of 0.75; Hosmer-Lemeshow p value of 0.84). CONCLUSIONS: These variables should be taken into account by physicians evaluating a patient affected by influenza as additional information to that provided by the usual risk scores. PMID- 23449896 TI - Bruxism and myofascial TMDs. PMID- 23449897 TI - Author's response. PMID- 23449898 TI - Bad breath. PMID- 23449899 TI - Response from the American Dental Association Division of Science. PMID- 23449900 TI - The contributions of Dr. Gies: promoting standards of dental education, research. AB - Dr. Ranney provides a commentary about two 1924 articles published in The Journal of the American Dental Association by Dr. William John Gies that highlight his many contributions to dental education. PMID- 23449902 TI - Craniofacial morphological characteristics in children with obstructive sleep apnea syndrome: a systematic review and meta-analysis. AB - BACKGROUND: The authors conducted a systematic review to consolidate the current knowledge regarding craniofacial morphological characteristics associated with obstructive sleep apnea syndrome (OSAS) in nonsyndromic pediatric patients. TYPES OF STUDIES REVIEWED: The authors included clinical studies in which participants were younger than 18 years, polysomnography was performed to determine the presence and severity of OSAS and the study group was compared with a control group or normative growth center data. The authors excluded studies with syndromic participants or participants who had received orthodontic treatment, orthognathic treatment or both previously. RESULTS: The authors identified nine articles. They conducted a meta-analyses of the data from all but one of the studies to evaluate the eight most common cephalometric variables in children with OSAS. The I(2) values were 79.53 percent for the angle from the basion point to the sella nasion (SN) line, 89.54 percent for the angle between the SN and palatal plane lines and 96.82 percent for the angle between the mandibular plane and SN lines (MP-SN). Therefore, for these three variables, the authors conducted a random-effect model meta-analysis. For the remaining five variables (MP-SN, the angle from SN to Apoint, the angle from SN to B point [SNB], the angle from A point to nasion point to B point [ANB] and the angle from articulare point to gonion point to gnathion point), I(2) values were all less than 40 percent, and therefore the authors conducted a fixed-effects model meta-analysis. Three of the evaluated cephalometric variables (MP-SN, SNB and ANB) had statistically significant differences in comparison with those in a control group. Although the values of these variables were increased in children with OSAS, results of the meta-analysis should be considered cautiously owing to the limited number of cephalometric variables included. PRACTICAL IMPLICATIONS: Dentists who identify patients with a craniofacial morphology consistent with pediatric OSAS (retrusive chin, steep mandibular plane, vertical direction of growth and a tendency toward Class II malocclusion) should inquire further into their patients' medical histories. When the craniofacial morphology is accompanied by a history of snoring, inability to breathe through the nose, significant allergies, asthma or obesity, the dentist should refer the patient to an otolaryngologist for assessment. PMID- 23449903 TI - Multiple papillary lesions of the gingival. PMID- 23449901 TI - Associations between smoking and tooth loss according to the reason for tooth loss: the Buffalo OsteoPerio Study. AB - BACKGROUND: Smoking is associated with tooth loss. However, smoking's relationship to the specific reason for tooth loss in postmenopausal women is unknown. METHODS: Postmenopausal women (n = 1,106) who joined a Women's Health Initiative ancillary study (The Buffalo OsteoPerio Study) underwent oral examinations for assessment of the number of missing teeth, and they reported the reasons for tooth loss. The authors obtained information about smoking status via a self-administered questionnaire. The authors calculated odds ratios (ORs) and 95 percent confidence intervals (CIs) by means of logistic regression to assess smoking's association with overall tooth loss, as well as with tooth loss due to periodontal disease (PD) and with tooth loss due to caries. RESULTS: After adjusting for age, education, income, body mass index, history of diabetes diagnosis, calcium supplement use and dental visit frequency, the authors found that heavy smokers (>= 26 pack-years) were significantly more likely to report having experienced tooth loss compared with never smokers (OR = 1.82; 95 percent CI, 1.10-3.00). Smoking status, packs smoked per day, years of smoking, pack years and years since quitting smoking were significantly associated with tooth loss due to PD. For pack-years, the association for heavy smokers compared with that for never smokers was OR = 6.83 (95 percent CI, 3.40 -13.72). The study results showed no significant associations between smoking and tooth loss due to caries. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Smoking may be a major factor in tooth loss due to PD. However, smoking appears to be a less important factor in tooth loss due to caries. Further study is needed to explore the etiologies by which smoking is associated with different types of tooth loss. Dentists should counsel their patients about the impact of smoking on oral health, including the risk of experiencing tooth loss due to PD. PMID- 23449904 TI - Application of current pain management concepts to the prevention and management of postoperative pain. PMID- 23449905 TI - The prevalence of dentin hypersensitivity in general dental practices in the northwest United States. AB - BACKGROUND: The prevalence of dentin hypersensitivity is uncertain, yet appropriate diagnosis and treatment of dentin hypersensitivity require accurate knowledge regarding its prevalence. The authors conducted a study to estimate the prevalence of dentin hypersensitivity in general dental practices and to investigate associated risk factors. METHODS: The authors conducted a cross sectional survey of 787 adult patients from 37 general dental practices within Northwest Practice-based Research Collaborative in Evidence-based DENTistry (PRECEDENT). Dentin hypersensitivity was diagnosed by means of participants' responses to a question regarding pain in their teeth and gingivae, and practitioner-investigators conducted a clinical examination to rule out alternative causes of pain. Participants recorded their pain level on a visual analog scale and the Seattle Scales in response to a one-second air blast. The authors used generalized estimating equation log-linear models to estimate the prevalence and the prevalence ratios. RESULTS: The prevalence of dentin hypersensitivity was 12.3 percent; patients with hypersensitivity had, on average, 3.5 hypersensitive teeth. The prevalence of dentin hypersensitivity was higher among 18- to 44-year olds than among participants 65 years or older; it also was higher in women than in men, in participants with gingival recession than in those without gingival recession and in participants who underwent at home tooth whitening than in those who did not. Hypersensitivity was not associated with obvious occlusal trauma, noncarious cervical lesions or aggressive toothbrushing habits. CONCLUSIONS: One in eight participants from general practices had dentin hypersensitivity, which was a chronic condition causing intermittent, low-level pain. Patients with hypersensitivity were more likely to be younger, to be female and to have a high prevalence of gingival recession and at-home tooth whitening. PRACTICAL IMPLICATIONS: Given dentin hypersensitivity's prevalence, clinicians should diagnose it only after investigating all other possible sources of pain. PMID- 23449906 TI - State Medicaid Early and Periodic Screening, Diagnosis, and Treatment guidelines: adherence to professionally recommended best oral health practices. AB - BACKGROUND: The authors evaluated the adherence of state Medicaid Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) guidelines to recommended best oral health practices for infants and toddlers. METHODS: The authors obtained state EPSDT guidelines via the Internet or from the Medicaid-CHIP State Dental Association, Washington. They identified best oral health practices through the American Academy of Pediatric Dentistry (AAPD), Chicago. They evaluated each EPSDT dental periodicity schedule with regard to the timing and content of seven key oral health domains. RESULTS: Thirty-two states and the District of Columbia (D.C.) had EPSDT dental periodicity schedules. With the exception of the dentist referral domain, 29 states (88 percent) adhered to the content and timing of best oral health practices, as established by the AAPD guideline. For the dentist referral domain, 31 of the 32 states and D.C. (94 percent) required referral of children to a dentist, but only 11 states (33 percent) adhered to best oral health practices by requiring referral by age 1 year. CONCLUSIONS: With the exception of the timing of the first dentist referral, there was high adherence to best oral health practices for infants and toddlers among states with separate EPSDT dental periodicity schedules. PRACTICAL IMPLICATIONS: States with low adherence to best oral health practices, especially regarding the dental visit by age 1 year, can strengthen the oral health content of their EPSDT schedules by complying with the AAPD recommendations. PMID- 23449907 TI - What are the ethical considerations in accepting lower reimbursement? PMID- 23449908 TI - A laboratory analysis of latex examination gloves. PMID- 23449909 TI - For the dental patient. Tackling tooth decay. PMID- 23449911 TI - Effects of gamma irradiation and silver nano particles on microbiological characteristics of saffron, using hurdle technology. AB - Saffron, a plant from the Iridaceae family, is the world's most expensive spice. Gamma irradiation and silver nano particles whose uses are gradually increasing worldwide, have positive effects on preventing decay by sterilizing the microorganisms and by improving the safety without compromising the nutritional properties and sensory quality of the foods. In the present study combination effects of gamma irradiation and silver nano particles packaging on the microbial contamination of saffron were considered during storage. A combination of hurdles can ensure stability and microbial safety of foods. For this purpose, saffron samples were packaged by Poly Ethylene films that posses up to 300 ppm nano silver particles as antimicrobial agents and then irradiated in cobalt-60 irradiator (gamma cell MODEL: PX30, dose rate 0.55 Gry/Sec) to 0, 1, 2,3 and 4 kGy at room temperature. The antimicrobial activities against Total Aerobic Mesophilic Bacteria, Entrobacteriace, Escherichia Coli and Clostridium Perfringines were higher in the irradiated samples, demonstrating the inhibition zone for their growth. Irradiation of the saffron samples packaged by Poly Ethylene films with nano silver particles showed the best results for decreasing microbial contamination at 2 kGy and for Poly Ethylene films without silver nano particles; it was 4 kGy. PMID- 23449910 TI - Unmet dental need in community-dwelling adults with mental illness: results from the 2007 Medical Expenditure Panel Survey. AB - BACKGROUND: Mental illness (MI) affects approximately one in five U.S. adults, and it is associated with oral disease and poor dental treatment outcomes. Little is known about dental care utilization or unmet dental need in this population. METHODS: The authors examined data regarding presence or absence of dental visits and unmet dental need in community-dwelling adults with MI from the 2007 Medical Expenditure Panel Survey. They tested differences between adults with and without MI by using multivariate logistic regression. RESULTS: Eighteen percent of adults (N = 19,368) had MI, and of these, 6.8 percent had unmet dental need. Although people with MI were not significantly more likely to have had a dental visit (46.3 percent) than were those without MI (42.2 percent; odds ratio [OR], 1.09; 95 percent confidence interval [CI], 0.97-1.23), they were significantly more likely to report unmet need (11.0 versus 5.3 percent; OR, 2.00; 95 percent CI, 1.67-2.41). Those with mood or anxiety disorders were most likely to report having an unmet dental need (P < .001 for all values). CONCLUSIONS: Although people with MI did not visit the dentist significantly more often than did adults without MI, their higher level of unmet need suggests that current use of dental services is not addressing their needs adequately. PRACTICAL IMPLICATIONS: Dentists should be familiar with MI conditions as patients with MI may have greater unmet dental need. PMID- 23449912 TI - Psychosocial predictors of affect in adult patients undergoing orthodontic treatment. AB - In this paper we propose to study the role of psychosocial variables in affect in adult patients undergoing orthodontic treatment, considering that affect is a key variable in treatment adherence. Seventy-four patients (average age 33,24 +/- 10,56) with metal multibracket-fixed orthodontic treatment were included. Patients were assessed twice. The first stage, at the beginning of treatment, included assessment of dental impact (Psychosocial Impact of Dental Aesthetics Questionnaire), trait anxiety (State-Trait Anxiety Inventory), self-esteem (Rosenberg's self-esteem scale), and self-efficacy (General Self-efficacy Scale). In the second stage, 6 months later, positive and negative affect towards treatment was assessed using the Positive and Negative Affect Scale. Dental social impact differentiates between patients with high and low negative affect, while self-efficacy differentiates between patients with high and low positive affect. Trait anxiety and self-esteem differentiate between both types of affect (positive and negative). Trait anxiety and self-esteem (when trait anxiety weight is controlled) are significant predictor variables of affective balance. These results have important practical implications, because it seems essential to adopt a bio-psychosocial model incorporating assessment methods focusing on day to-day changes in mood and well-being. PMID- 23449913 TI - Rehabilitation following lumbar diskectomy. PMID- 23449914 TI - Assessing the validity of the dynamic gait index in a balance disorders clinic: an application of Rasch analysis. AB - BACKGROUND: The Dynamic Gait Index (DGI) has emerged as a valid indicator of functional gait abilities for people with balance and vestibular disorders. Recent Rasch-based analyses have indicated possible concerns for multidimensionality and a ceiling effect within the DGI. OBJECTIVE: The aim of this study was to evaluate the DGI in a sample of patients from a dizziness and balance clinic to determine whether patient features such as dizziness or fall history influence the measurement characteristics of the DGI. DESIGN: This study used a retrospective design. METHODS: A sample of 117 patients' charts was reviewed, and patients were grouped according to a primary impairment of dizziness only or imbalance and were categorized based on a history of falls. A one-parameter Rasch-Andrich rating scale model was used with thorough analyses, including rating scale analysis, item-difficulty hierarchy, scale unidimensionality, and differential item functioning (DIF). RESULTS: The DGI demonstrated an effective rating scale design and was found to be a unidimensional measurement of dynamic gait. The DGI displayed a modest ceiling effect, primarily with patients with higher functional levels displaying symptoms of dizziness. Three items ("vertical head nods," "gait on level surface," and "stepping over obstacles") demonstrated DIF based on categories of patient characteristics, although the effects on measurement were negligible. LIMITATIONS: Functional categories were based on impairments and not underlying medical diagnoses derived from a retrospective chart review, whereas the limited sample size may have underestimated statistically significant DIF. CONCLUSIONS: Results from this study offer additional evidence supporting the validity of the DGI as a measure of gait ability. The present findings also are in agreement with prior research that has shown a ceiling effect for the DGI in people with balance or vestibular disorders. Effects of DIF were found to be negligible, yet the presence of DIF within the present sample helped to explain some differences in DGI item-difficulty hierarchies from prior studies. Continued research is needed to determine how population differences may affect performance on the DGI and to develop and test assessments capable of measuring a broader range of gait abilities. PMID- 23449915 TI - An overview of the surgical management of hepatic neuroendocrine metastases. AB - Neuroendocrine tumours (NET) frequently metastasise to the liver (NLM) and are associated with significant morbidity and mortality. Numerous treatment options have been implemented both for cure, and to implement disease control. Surgical treatment includes curative resection, palliative cytoreductive resection and transplantation. Complete surgical resection is only possible in a subset of people with NLMs due to excessive metastatic burden and anatomical location. Ablative therapies may be used either as an adjunct to surgery or as a primary treatment. The purpose of the following article is to summarise surgical treatment strategies in the management of patients with hepatic neuroendocrine metastases, based on the available literature. PMID- 23449916 TI - Biochemical analysis of three putative KaiC clock proteins from Synechocystis sp. PCC 6803 suggests their functional divergence. AB - Cyanobacteria have been shown to have a circadian clock system that consists mainly of three protein components: KaiA, KaiB and KaiC. This system is well understood in the cyanobacterium Synechococcus elongatus PCC 7942, for which robust circadian oscillations have been shown. Like many other cyanobacteria, the chromosome of the model cyanobacterium Synechocystis sp. PCC 6803 contains additional kaiC and kaiB gene copies besides the standard kaiABC gene cluster. The respective gene products differ significantly in their amino acid sequences, especially in their C-terminal regions, suggesting different functional characteristics. Here, phosphorylation assays of the three Synechocystis sp. PCC 6803 KaiC proteins revealed that KaiC1 phosphorylation depends on KaiA, as is well documented for the Synechococcus elongatus PCC 7942 KaiC protein, whereas KaiC2 and KaiC3 autophosphorylate independently of KaiA. This was confirmed by in vivo protein-protein interaction studies, which demonstrate that only KaiC1 interacts with KaiA. Furthermore, we demonstrate that the three different Kai proteins form only homomeric complexes in vivo. As only KaiC1 phosphorylation depends on KaiA, a prerequisite for robust oscillations, we suggest that the kaiAB1C1 gene cluster in Synechocystis sp. PCC 6803 controls circadian timing in a manner similar to the clock described in Synechococcus elongatus PCC 7942. PMID- 23449917 TI - Endemic malagasy Dalbergia species inhibit quorum sensing in Pseudomonas aeruginosa PAO1. AB - Various species of the plant genus Dalbergia are traditionally used as medicine for sundry ailments and some of them have been shown recently to quench the virulence of Gram-positive and Gram-negative bacteria. Cell-to-cell communication mechanisms, quorum sensing (QS) in particular, are key regulators of virulence in many pathogenic bacteria. Screening n-hexane extracts of leaves, roots and bark of endemic Malagasy Dalbergia species for their capacity to antagonize QS mechanisms in Pseudomonas aeruginosa PAO1 showed that many reduced the expression of the QS-regulated genes lasB and rhlA. However, only the extract of Dalbergia trichocarpa bark (DTB) showed a significant reduction of QS gene expression without any effect on the aceA gene encoding a QS-independent isocitrate lyase. Further characterization of DTB impact on QS revealed that the QS systems las and rhl are inhibited and that swarming, twitching, biofilm formation and the production of pyocyanin, elastase and proteases are also hampered in the presence of the DTB extract. Importantly, compared with the known QS inhibitor naringenin, the DTB extract showed a stronger negative effect on twitching, biofilm formation and tobramycin resistance. Preliminary structural characterization of these potent biofilm disrupters suggests that they belong to the phytosterols. The strong inhibition of motility and biofilm formation suggests that the DTB extract contains agents disrupting biofilm architecture, which is an important observation in the context of the design of new drugs targeting biofilm encapsulated pathogens. PMID- 23449918 TI - In vivo analysis of DNA binding and ligand interaction of BlcR, an IclR-type repressor from Agrobacterium tumefaciens. AB - Agrobacterium tumefaciens BlcR represses transcription of the blcABC operon, which is involved in metabolism of gamma-butyrolactone, and this repression is alleviated by succinate semialdehyde (SSA). BlcR exists as a homodimer, and the blcABC promoter DNA contains two BlcR-binding sites (IR1 and IR2) that correspond to two BlcR dimers. In this study, we established an in vivo system to examine the SSA-responsive control of BlcR transcriptional regulation. The endogenous blcR, encoded in the pAtC58 plasmid of A. tumefaciens C58, was not optimal for investigating the effect of SSA on BlcR repression, probably due to the SSA degradation mediated by the pAt-encoded blcABC. We therefore introduced blcR (and the blcABC promoter DNA, separately) exogenously into a strain of C58 cured of pAtC58 (and pTiC58). We applied this system to interrogate BlcR-DNA interactions and to test predictions from our prior structural and biochemical studies. This in vivo analysis confirmed the previously mapped SSA-binding site and supported a model by which DNA coordinates formation of a BlcR tetramer. In addition, we identified a specific lysine residue (K59) as an important determinant for DNA binding. Moreover, based on isothermal titration calorimetry analysis, we found IR1 to play the dominant role in binding to BlcR, relative to IR2. Together, these in vivo results expand the biochemical findings and provide new mechanistic insights into BlcR-DNA interactions. PMID- 23449919 TI - The role of two Pseudomonas aeruginosa anthranilate synthases in tryptophan and quorum signal production. AB - Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that causes infections in the lungs of individuals with the genetic disease cystic fibrosis. Density-dependent production of toxic factors regulated by the Pseudomonas quinolone signal (2-heptyl-3-hydroxy-4-quinolone; PQS) have been proposed to be involved in P. aeruginosa virulence. PQS biosynthesis requires conversion of the central metabolite chorismate to anthranilate by anthranilate synthase. This reaction is also the first step in tryptophan biosynthesis. P. aeruginosa possesses two functional anthranilate synthases, TrpEG and PhnAB, and these enzymes are not functionally redundant, as trpEG mutants are tryptophan auxotrophs but produce PQS while mutants in phnAB are tryptophan prototrophs but do not produce PQS in minimal media. The goal of the work described in this paper was to determine the mechanism for this lack of functional complementation of TrpEG and PhnAB. Our results reveal that overexpression of either enzyme compensates for tryptophan auxotrophy and PQS production in the trpEG and phnAB mutants respectively, leading to the hypothesis that differential regulation of these genes is responsible for the lack of functional complementation. In support of this hypothesis, trpEG was shown to be expressed primarily during low-density growth while phnAB was expressed primarily at high density. Furthermore, dysregulation of phnAB expression eliminated tryptophan auxotrophy in the P. aeruginosa trpEG mutant. Based on these data, we propose a model for anthranilate sequestration by differential transcriptional regulation of the two P. aeruginosa anthranilate synthase enzymes. PMID- 23449920 TI - Flow cytometry as a novel tool for structural and functional characterization of isolated yeast vacuoles. AB - The yeast vacuole is functionally analogous to the mammalian lysosome. Both play important roles in fundamental cellular processes such as protein degradation, detoxification, osmoregulation, autophagy and apoptosis which, when deregulated in humans, can lead to several diseases. Some of these vacuolar roles are difficult to study in a cellular context, and therefore the use of a cell-free system is an important approach to gain further insight into the different molecular mechanisms required for vacuolar function. In the present study, the potentialities of flow cytometry for the structural and functional characterization of isolated yeast vacuoles were explored. The isolation protocol resulted in a yeast vacuolar fraction with a degree of purity suitable for cytometric analysis. Moreover, isolated vacuoles were structurally and functionally intact and able to generate and maintain electrochemical gradients of ions across the vacuolar membrane, as assessed by flow cytometry. Proton and calcium gradients were dissipated by NH4Cl and calcimycin, respectively. These results established flow cytometry as a powerful technique for the characterization of isolated vacuoles. The protocols developed in this study can also be used to enhance our understanding of several molecular mechanisms underlying the development of lysosome-related diseases, as well as provide tools to screen for new drugs that can modulate these processes, which have promising clinical relevance. PMID- 23449921 TI - Prevention of aflatoxin contamination by a soil bacterium of Stenotrophomonas sp. that produces aflatoxin production inhibitors. AB - A soil bacterium, designated strain no. 27, was found to produce aflatoxin production inhibitors. The strain was identified as a species of the genus Stenotrophomonas, and was found to be closely related to Stenotrophomonas rhizophila. Two diketopiperazines, cyclo(L-Ala-L-Pro) and cyclo(L-Val-L-Pro), were isolated from the bacterial culture filtrate as main active components. These compounds inhibited aflatoxin production of Aspergillus parasiticus and Aspergillus flavus in liquid medium at concentrations of several hundred uM without affecting fungal growth. Both inhibitors inhibited production of norsorolinic acid, a biosynthetic intermediate involved in an early step of the aflatoxin biosynthetic pathway, and reduced the mRNA level of aflR, which is a gene encoding a key regulatory protein necessary for the expression of aflatoxin biosynthetic enzymes. These results indicated that the inhibitors targets are present in early regulatory steps leading to AflR expression. Co-culture of strain no. 27 with aflatoxigenic fungi in liquid medium effectively suppressed aflatoxin production of the fungus without affecting fungal growth. Furthermore, application of the bacterial cells to peanuts in laboratory experiments and at a farmer's warehouse in Thailand by dipping peanuts in the bacterial cell suspension strongly inhibited aflatoxin accumulation. The inhibitory effect was dependent on bacterial cell numbers. These results indicated that strain no. 27 may be a practically effective biocontrol agent for aflatoxin control. PMID- 23449922 TI - Patient experience in the accident and emergency department. PMID- 23449924 TI - United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. AB - AIMS: The aim of this study was to describe the early phase United Kingdom (UK) clinical experience with a novel entirely subcutaneous implantable cardioverter defibrillator (S-ICD). METHODS AND RESULTS: A questionnaire was sent to all UK hospitals implanting S-ICDs. Nineteen of 25 (76%) hospitals responded with the details of 111 implanted patients [median 5/hospital (range 1-18)]. Mean duration of follow-up was 12.7 +/- 7.1 months. Median patient age was 33 years (range 10 87 years). Underlying pathology was primary electrical disease in 43%, congenital heart disease 12%, hypertrophic cardiomyopathy 20%, ischaemic cardiomyopathy 14%, idiopathic dilated cardiomyopathy 5%, and other cardiomyopathies 7% patients. Nineteen (17%) patients required 20 re-operations, including permanent device explantation in 10 (9%). Twenty-four appropriate shocks were delivered in 13 (12%) patients, including 10 for ventricular fibrillation. One patient suffered arrhythmic death, but there were no failures to detect or terminate ventricular arrhythmias above the programmed detection rate. Fifty-one inappropriate shocks were delivered in 17 (15%) patients. Forty-one (80%) were for T-wave over-sensing and 1 (2%) for atrial flutter-wave over-sensing. The 11 patients who received inappropriate shocks due to T-wave over-sensing were significantly younger than patients who did not (24 +/- 10 vs. 37 +/- 19 years; P = 0.02). CONCLUSION: The S ICD is an important innovation in ICD technology. However, these data indicate that adverse event rates are significant during early clinical adoption. Important lessons in patient selection, implant technique, and device programming can be learnt from this experience. PMID- 23449923 TI - System upgrade and its complications in patients with a single lead atrial pacemaker: data from the DANPACE trial. AB - AIMS: To investigate the indications for system upgrade with single lead atrial pacing (AAIR), complications associated with these re-interventions, and possible predictors for system upgrade among patients included in the Danish Multicenter Randomized Trial on AAIR vs. dual-chamber pacing (DDDR) in sick sinus syndrome (DANPACE). METHODS AND RESULTS: A total of 707 of 1415 patients were randomized to AAIR pacing. Mean follow-up was 5.5 +/- 2.6 years. Information on indications for system upgrade and complications were collected by reviewing patient charts. Multiple logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (CI) for the association between predictors and system upgrade. Sixty-six patients (9.3%) in the AAIR group underwent system upgrade. Fifty-nine of these patients (89.3%) had a documented class I indication for system upgrade. Age (aOR 0.98 for each 1-year increase in age; 95% CI 0.6-1.0), and left atrial enlargement (aOR 1.9; 95% CI 1.0-3.8) were predictors for system upgrade. No single clinically applicable predictor for upgrade was identified. A total of 11 patients (16.7%) experienced at least one major complication after system upgrade. CONCLUSION: The majority of patients with AAIR pacing who underwent system upgrade had a class I indication. The incidence of major complications after system upgrade was high. The present data support the use of DDDR pacing rather than AAIR pacing in sick sinus syndrome. PMID- 23449925 TI - Non-invasive identification of stable rotors and focal sources for human atrial fibrillation: mechanistic classification of atrial fibrillation from the electrocardiogram. AB - AIMS: To develop electrocardiogram (ECG) tools to quantify the number of sources for atrial fibrillation (AF), i.e. spatially stable rotors and focal impulses, and whether they lie in right or left atrium. Intracardiac mapping has recently shown that paroxysmal and persistent AF is sustained by rotors or focal sources that are stable in location and thus targets for limited ablation [focal impulse and rotor modulation (FIRM)] to eliminate AF. Importantly, the numbers and locations of concurrent sources determine both the complexity of AF and the approach for ablation. METHODS AND RESULTS: In 36 AF patients (n = 29 persistent, 63 +/- 9 years) in the CONventional ablation with or without Focal Impulse and Rotor Modulation (CONFIRM) trial, we developed phase lock (PL) to quantify spatial repeatability of ECG 'F-waves' between leads over time. Phase lock spectrally quantifies the angle theta between F-wave voltages in planes formed by ECG leads I, aVF, and V1 at successive points in time. We compared PL with ECG spectral dominant frequency (DF) and organizational index (OI) to characterize stable rotors and focal sources validated by intracardiac FIRM mapping. Focal impulse and rotor modulation ablation alone at <=3 sources acutely terminated and rendered AF non-inducible or substantially slowed AF in 31 of 36 patients. Receiver operating characteristics of PL for this endpoint had area under the curve (AUC) = 0.72, and the optimum cut-point (PL = 0.09) had 74% sensitivity, 92% positive predictive value (PPV). Receiver operating characteristics areas for OI and DF were 0.50 and 0.58, respectively. Left (n = 28) or right (n = 3) atrial sources were localized by PL with AUC = 0.85, sensitivity 100%, PPV 30%, and negative predictive value 100%. Spectral DF provided AUC = 0.79. Notably, PL did not comigrate with diagnosis of paroxysmal or persistent AF (P = NS), unlike ECG DF. CONCLUSION: The novel metric of ECG PL identifies patients with fewer (<=3) or greater numbers of stable rotors/focal sources for AF, validated by intracardiac FIRM mapping, and localized them to right or left atria. These data open the possibility of using 12-lead ECG analyses to classify AF mechanistically and plan procedures for right- or left-sided FIRM ablation. PMID- 23449926 TI - Clinical Profile of Tubotympanic CSOM and Its Management With Special Reference to Site and Size of Tympanic Membrane Perforation, Eustachian Tube Function and Three Flap Tympanoplasty. AB - Otitis media is an important and a highly prevalent disease of the middle ear and poses serious health problem world wide especially in developing countries where large percentage of the population lack specialized medical care, suffer from malnutrition and live in poor hygienic environmental conditions. It has been a general view that the hearing loss increases with the size of the perforation, more so if it is in the posterio inferior quadrant. It was found that the maximum average loss occurred at 250 Hz. The hearing loss is less in small perforations (less than 2 mm diameter) then in larger ones; less in perforations touching the manubrium than in those away from it, and also less in perforations of the anterioinferior quadrant than in those on posterio-inferior quadrant. A normally functioning eustachian tube is also an essential physiologic requirement for a healthy middle ear and normal hearing. PMID- 23449927 TI - Evidence for diversifying selection in a set of Mycobacterium tuberculosis genes in response to antibiotic- and nonantibiotic-related pressure. AB - Tuberculosis (TB) is a global health problem estimated to kill 1.4 million people per year. Recent advances in the genomics of the causative agents of TB, bacteria known as the Mycobacterium tuberculosis complex (MTBC), have allowed a better comprehension of its population structure and provided the foundation for molecular evolution analyses. These studies are crucial for a better understanding of TB, including the variation of vaccine efficacy and disease outcome, together with the emergence of drug resistance. Starting from the analysis of 73 publicly available genomes from all the main MTBC lineages, we have screened for evidences of positive selection, a set of 576 genes previously associated with drug resistance or encoding membrane proteins. As expected, because antibiotics constitute strong selective pressure, some of the codons identified correspond to the position of confirmed drug-resistance-associated substitutions in the genes embB, rpoB, and katG. Furthermore, we identified diversifying selection in specific codons of the genes Rv0176 and Rv1872c coding for MCE1-associated transmembrane protein and a putative l-lactate dehydrogenase, respectively. Amino acid sequence analyses showed that in Rv0176, sites undergoing diversifying selection were in a predicted antigen region that varies between "modern" lineages and "ancient" MTBC/BCG strains. In Rv1872c, some of the sites under selection are predicted to impact protein function and thus might result from metabolic adaptation. These results illustrate that diversifying selection in MTBC is happening as a consequence of both antibiotic treatment and other evolutionary pressures. PMID- 23449928 TI - Giant thoracic schwannoma masquerading as transverse myelitis. PMID- 23449929 TI - Lessons from a patient with Turner syndrome. PMID- 23449930 TI - Genotoxicity of tobacco smoke-derived aromatic amines and bladder cancer: current state of knowledge and future research directions. AB - Bladder cancer is a significant public health problem, worldwide. In the United States, bladder cancer is the fourth most common cancer in men, and its recurrence rate is the highest among all malignancies. Tobacco smoking is the leading risk factor for bladder cancer. The risk of bladder cancer is directly related to the intensity and duration of smoking, while quitting smoking reduces this risk. The increased risk of smokers for developing bladder cancer is attributable to their exposure to aromatic amines, which constitute a family of known bladder carcinogens present in tobacco smoke. The underlying mechanism of action of aromatic amines in the genesis of bladder cancer is not, however, fully delineated. Research has identified a genotoxic mode of action, specifically DNA adduction and mutagenicity, for aromatic amines, which may account for their carcinogenicity. The present review summarizes our current knowledge on the DNA adduction and mutagenicity of aromatic amines in relation to smoking-associated bladder cancer. For illustrative purposes, representative results from published research on aromatic amine-induced DNA adduction and mutagenesis are discussed. The direction of future research on the underlying mechanisms of tobacco smoke associated bladder carcinogenesis is also outlined. Understanding the molecular mechanisms of bladder carcinogenesis is essential for improving future strategies for prevention, early detection, treatment, and prognosis of this malignancy. PMID- 23449931 TI - The neurobehavioural evaluation in schizophrenics: a comparative study. AB - BACKGROUND: The simple reaction time task assesses the ability of the subject to respond to an external cue and to retrieve a reward. The reaction time provides an indirect index of the processing capability of the central nervous system and a simple means to the determined sensory and the motor performances, which is a neurobehavioural evaluation. A general slowness in the latency in the reaction time tasks and a disengagement deficit in the visual and the hearing oriented tasks were seen in schizophrenics. AIMS: In order to clarify the feature of the attention disorders in schizophrenia, a simple reaction time task was given to schizophrenics. METHODS AND MATERIALS: Schizophrenics (34 males and 20 females, n=54) and healthy controls (40 males and 21 females, n=61) with a mean age of 35+/-7, who were individually matched for gender and age, were included in the study, by using a response analyser to evaluate the reaction time. STATISTICAL ANALYSIS: The performances were expressed in mean +/- standard deviation of the reaction time by using the unpaired 't' test. RESULTS AND CONCLUSIONS: The schizophrenic patients performed poorer than the healthy controls, which indicated a difficulty in sustaining attention and this was statistically very highly significant (p<0.000). The results suggested that the schizophrenics showed inattentiveness in the clinical settings and an emotional disturbance in interpersonal situations. The increased reaction time as compared to that in healthy controls, might be due to the impairment of the psychomotor poverty, disorganization and reality distortion which were associated with the deficits in the cortical neurological functions, such as planning, coordination and sequencing of the motor acts, which showed a greater involvement of the frontal lobe and temporal lobe dysfunction. PMID- 23449932 TI - Combination of acupuncture and spinal manipulative therapy: management of a 32 year-old patient with chronic tension-type headache and migraine. AB - OBJECTIVE: The purpose of this case study is to describe the treatment using acupuncture and spinal manipulation for a patient with a chronic tension-type headache and episodic migraines. CLINICAL FEATURES: A 32-year-old woman presented with headaches of 5 months' duration. She had a history of episodic migraine that began in her teens and had been controlled with medication. She had stopped taking the prescription medications because of gastrointestinal symptoms. A neurologist diagnosed her with mixed headaches, some migrainous and some tension type. Her headaches were chronic, were daily, and fit the International Classification of Headache Disorders criteria of a chronic tension-type headache superimposed with migraine. INTERVENTION AND OUTCOME: After 5 treatments over a 2 week period (the first using acupuncture only, the next 3 using acupuncture and chiropractic spinal manipulative therapy), her headaches resolved. The patient had no recurrences of headaches in her 1-year follow-up. CONCLUSION: The combination of acupuncture with chiropractic spinal manipulative therapy was a reasonable alternative in treating this patient's chronic tension-type headaches superimposed with migraine. PMID- 23449933 TI - Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. AB - We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBEC) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, and MYC) and followed the stepwise transformation of HBECs to full malignancy. This model showed that: (i) the combination of five genetic alterations (CDK4, hTERT, sh p53, KRAS(V12), and c-MYC) is sufficient for full tumorigenic conversion of HBECs; (ii) genetically identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; (iii) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; (iv) high levels of KRAS(V12) are required for full malignant transformation of HBECs, however, prior loss of p53 function is required to prevent oncogene-induced senescence; (v) overexpression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRAS(V12); (vi) growth of parental HBECs in serum-containing medium induces differentiation, whereas growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); (vii) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; (viii) an mRNA signature derived by comparing tumorigenic versus nontumorigenic clones was predictive of outcome in patients with lung cancer. Collectively, our findings show that this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes. PMID- 23449934 TI - The role of versican in modulating breast cancer cell self-renewal. AB - Versican is highly expressed during the early stages of tissue development and its expression is elevated during wound repair and tumor growth. There is little literature on the potential role of breast cancer stem cells on the cellular extracellular matrix interactions involving versican. An anti-versican short hairpin RNA (shRNA) was used to observe the effect of reduction of versican on breast cancer self-renewal. A versican G3 construct was exogenously expressed in breast cancer cell lines. Colony formation and mammosphere formation assays were conducted; flow cytometry was applied to analyze the prevalence of side population cells. The versican G3- and vector-transfected 66c14 cells were injected transdermally into BALB/c mice as a 10-fold dilution series from 1 * 10(5) to 1 * 10(2) cells per mouse. Versican G3 domain enhanced breast cancer self-renewal in both experimental in vitro and in vivo models. Versican G3 transfected cells contained high levels of side population cells, formed more mammospheres when cultured in the serum-free medium, and formed a greater number and larger colonies. Reduction of versican's functionality through anti-versican shRNA or knocking out the EGF-like motifs reduced the effect of versican on enhancing mammosphere and colony formation. Versican-enhanced self-renewal played a role in enhanced chemotherapeutic drug resistance, relating partly to the upregulated expression of EGF receptor (EGFR) signaling. Versican is highly expressed in breast cancer progenitor cells and was maintained at high levels before cell differentiation. Overexpression of versican enhanced breast cancer self-renewal through EGFR/AKT/GSK-3beta (S9P) signaling and conferred resistant to chemotherapeutic drugs tested. PMID- 23449935 TI - IL-6 is not essential for exercise-induced increases in glucose uptake. AB - Interleukin-6 (IL-6) increases glucose uptake in resting skeletal muscle. IL-6 is released from skeletal muscle during exercise; however; it is not known whether this IL-6 response is important for exercise-induced increases in skeletal muscle glucose uptake. We report that IL-6 knockout (KO) mice, 4 mo of age, have similar body weight to wild-type (WT), and, under resting conditions, oxygen consumption, food intake, substrate utilization, glucose tolerance, and insulin sensitivity are not different. Maximal exercise capacity is also similar to WT. We investigated substrate utilization and glucose clearance in vivo during steady state treadmill running at 70% of maximal running speed and found that WT and IL 6 KO mice had similar rates of substrate utilization, muscle glucose clearance, and phosphorylation of AMP-activated protein kinase T172. These data provide evidence that IL-6 does not play a major role in regulating substrate utilization or skeletal muscle glucose uptake during steady-state endurance exercise. PMID- 23449937 TI - Hyaluronan initiates chondrogenesis mainly via CD44 in human adipose-derived stem cells. AB - Cell-matrix adhesion is one of the important interactions that regulates stem cell survival, self-renewal, and differentiation. Our previous report (Wu SC, Chang JK, Wang CK, Wang GJ, Ho ML. Biomaterials 31: 631-640, 2010) indicated that a microenvironment enriched with hyaluronan (HA) initiated and enhanced chondrogenesis in human adipose-derived stem cells (hADSCs). We further hypothesize that HA-induced chondrogenesis in hADSCs is mainly due to the interaction of HA and CD44 (HA-CD44), a cell surface receptor of HA. The HA-CD44 interaction was tested by examining the mRNA expression of hyaluronidase-1 (Hyal 1) and chondrogenic marker genes (SOX-9, collagen type II, and aggrecan) in hADSCs cultured on HA-coated wells. Cartilaginous matrix formation, sulfated glycosaminoglycan, and collagen productions by hADSCs affected by HA-CD44 interaction were tested in a three-dimensional fibrin hydrogel. About 99.9% of hADSCs possess CD44. The mRNA expressions of Hyal-1 and chondrogenic marker genes were upregulated by HA in hADSCs on HA-coated wells. Blocking HA-CD44 interaction by anti-CD44 antibody completely inhibited Hyal-1 expression and reduced chondrogenic marker gene expression, which indicates that HA-induced chondrogenesis in hADSCs mainly acts through HA-CD44 interaction. A 2-h preincubation and coculture of cells with HA in hydrogel (HA/fibrin hydrogel) not only assisted in hADSC survival, but also enhanced expression of Hyal-1 and chondrogenic marker genes. Higher levels of sulfated glycosaminoglycan and total collagen were also found in HA/fibrin hydrogel group. Immunocytochemistry showed more collagen type II, but less collagen type X, in HA/fibrin than in fibrin hydrogels. Our results indicate that signaling triggered by HA-CD44 interaction significantly contributes to HA-induced chondrogenesis and may be applied to adipose-derived stem cell-based cartilage regeneration. PMID- 23449936 TI - Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation. AB - Pulmonary TNFalpha has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNFalpha impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFalpha construct, TNFalpha was overexpressed throughout life in mouse lungs (SP-C/TNFalpha+). TNFalpha levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFalpha+ mice, TNFalpha increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFalpha+ mice. While increases in lung volume and airspace size induced by TNFalpha were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/dt) was not altered by TNFalpha overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFalpha+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1alpha mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNFalpha+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFalpha are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen. PMID- 23449939 TI - Active, passive, and motor imagery paradigms: component analysis to assess neurovascular coupling. AB - The association between neural activity and cerebral blood flow (CBF) has been used to assess neurovascular coupling (NVC) in health and diseases states, but little attention has been given to the contribution of simultaneous changes in peripheral covariates. We used an innovative approach to assess the contributions of arterial blood pressure (BP), PaCO2, and the stimulus itself to changes in CBF velocities (CBFv) during active (MA), passive (MP), and motor imagery (MI) paradigms. Continuous recordings of CBFv, beat-to-beat BP, heart rate, and breath by-breath end-tidal CO2 (EtCO2) were performed in 17 right-handed subjects before, during, and after motor-cognitive paradigms performed with the right arm. A multivariate autoregressive-moving average model was used to calculate the separate contributions of BP, EtCO2, and the neural activation stimulus (represented by a metronome on-off signal) to the CBFv response during paradigms. Differences were found in the bilateral CBFv responses to MI compared with MA and MP, due to the contributions of stimulation (P < 0.05). BP was the dominant contributor to the initial peaked CBFv response in all paradigms with no significant differences between paradigms, while the contribution of the stimulus explained the plateau phase and extended duration of the CBFv responses. Separating the neural activation contribution from the influences of other covariates, it was possible to detect differences between three paradigms often used to assess disease-related NVC. Apparently similar CBFv responses to different motor-cognitive paradigms can be misleading due to the contributions from peripheral covariates and could lead to inaccurate assessment of NVC, particularly during MI. PMID- 23449938 TI - Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure. AB - Cardiovascular autonomic imbalance and breathing instability are major contributors to the progression of heart failure (CHF). Potentiation of the carotid body (CB) chemoreflex has been shown to contribute to these effects. Hydrogen sulfide (H2S) recently has been proposed to mediate CB hypoxic chemoreception. We hypothesized that H2S synthesis inhibition should decrease CB chemoreflex activation and improve breathing stability and autonomic function in CHF rats. Using the irreversible inhibitor of cystathione gamma-lyase dl propargylglycine (PAG), we tested the effects of H2S inhibition on resting breathing patterns, the hypoxic and hypercapnic ventilatory responses, and the hypoxic sensitivity of CB chemoreceptor afferents in rats with CHF. In addition, heart rate variability (HRV) and systolic blood pressure variability (SBPV) were calculated as an index of autonomic function. CHF rats, compared with sham rats, exhibited increased breath interval variability and number of apneas, enhanced CB afferent discharge and ventilatory responses to hypoxia, decreased HRV, and increased low-frequency SBPV. Remarkably, PAG treatment reduced the apnea index by 90%, reduced breath interval variability by 40-60%, and reversed the enhanced hypoxic CB afferent and chemoreflex responses observed in CHF rats. Furthermore, PAG treatment partially reversed the alterations in HRV and SBPV in CHF rats. Our results show that PAG treatment restores breathing stability and cardiac autonomic function and reduces the enhanced ventilatory and CB chemosensory responses to hypoxia in CHF rats. These results support the idea that PAG treatment could potentially represent a novel pathway to control sympathetic outflow and breathing instability in CHF. PMID- 23449940 TI - Effect of acute hyaluronidase treatment of the glycocalyx on tracer-based whole body vascular volume estimates in mice. AB - The endothelial glycocalyx forms a hyaluronan-containing interface between the flowing blood and the endothelium throughout the body. By comparing the systemic distribution of a small glycocalyx-accessible tracer vs. a large circulating plasma tracer, the size-selective barrier properties of the glycocalyx have recently been utilized to estimate whole body glycocalyx volumes in humans and animals, but a comprehensive validation of this approach has been lacking at the moment. In the present study, we compared, in anesthetized, ventilated C57Bl/6 mice, the whole body distribution of small (40 kDa) dextrans (Texas Red labeled; Dex40) vs. that of intermediate (70 kDa) and large (500 kDa) dextrans (both FITC labeled; Dex70 and Dex500, respectively) using tracer dilution and vs. that of circulating plasma, as derived from the dilution of fluorescein-labeled red blood cells and large-vessel hematocrit. The contribution of the glycocalyx was evaluated by intravenous infusion of a bolus of the enzyme hyaluronidase. In saline-treated control mice, distribution volume (in ml) differed between tracers (P < 0.05; ANOVA) in the following order: Dex40 (0.97 +/- 0.04) > Dex70 (0.90 +/- 0.04) > Dex500 (0.81 +/- 0.10) > plasma (0.71 +/- 0.02), resulting in an inaccessible vascular volume, i.e., compared with the distribution volume of Dex40, of 0.03 +/- 0.01, 0.15 +/- 0.04, and 0.31 +/- 0.05 ml for Dex70, Dex500, and plasma, respectively. In hyaluronidase-treated mice, Dex70 and Dex40 volumes were not different from each other, and inaccessible vascular volumes for Dex500 (0.03 +/- 0.03) and plasma (0.14 +/- 0.05) were smaller (P < 0.05) than those in control animals. Clearance of Dex70 and Dex500 from the circulation was enhanced (P < 0.05) in hyaluronidase-treated vs. control mice. These results indicate that the glycocalyx contributes to size-dependent differences in whole body vascular distribution of plasma solutes in mice. Whole body vascular volume measurements based on the differential distribution of glycocalyx-selective tracers appear appropriate for the detection of generalized glycocalyx degradation in experimental animals and humans. PMID- 23449941 TI - MDCT-based quantification of porcine pulmonary arterial morphometry and self similarity of arterial branching geometry. AB - The pig is frequently used as an experimental model for studies of the pulmonary circulation, yet the branching and dimensional geometry of the porcine pulmonary vasculature remains poorly defined. The purposes of this study are to improve the geometric definition of the porcine pulmonary arteries and to determine whether the arterial tree exhibits self-similarity in its branching geometry. Five animals were imaged using thin slice spiral computed tomography in the prone posture during airway inflation pressure at 25 cmH2O. The luminal diameter and distance from the inlet of the left and right pulmonary arteries were measured along the left and right main arterial pathway in each lung of each animal. A further six minor pathways were measured in a single animal. The similarity in the rate of reduction of diameter with distance of all minor pathways and the two main pathways, along with similarity in the number of branches arising along the pathways, supports self-similarity in the arterial tree. The rate of reduction in diameter with distance from the inlet was not significantly different among the five animals (P > 0.48) when normalized for main pulmonary artery diameter and total main artery pathlength, which supports intersubject similarity. Other metrics to quantify the tree geometry are strikingly similar to those from airways of other quadrupeds, with the exception of a significantly larger length to diameter ratio, which is more appropriate for the vascular tree. A simplifying self-similar model for the porcine pulmonary arteries is proposed to capture the important geometric features of the arterial tree. PMID- 23449942 TI - Examining the relationship between exercise tolerance and isoproterenol-based cardiac reserve in murine models of heart failure. AB - The loss of cardiac reserve is, in part, responsible for exercise intolerance in late-stage heart failure (HF). Exercise tolerance testing (ETT) has been performed in mouse models of HF; however, treadmill performance and at-rest cardiac indexes determined by magnetic resonance imaging (MRI) rarely correlate. The present study adopted a stress-MRI technique for comparison with ETT in HF models, using isoproterenol (ISO) to evoke cardiac reserve responses. Male C57BL/6J mice were randomly subjected to myocardial infarction (MI), transverse aortic constriction (TAC), or sham surgery under general anesthesia. Mice underwent serial ETT on a graded treadmill with follow-up ISO stress-MRI. TAC mice showed consistent exercise intolerance, with a 16.2% reduction in peak oxygen consumption vs. sham at 15-wk postsurgery (WPS). MI and sham mice had similar peak oxygen consumption from 7 WPS onward. Time to a respiratory exchange ratio of 1.0 correlated with ETT distance (r = 0.64; P < 0.001). The change in ejection fraction under ISO stress was reduced in HF mice at 4 WPS [10.1 +/- 3.9% change (Delta) and 8.9 +/- 3.5%Delta in MI and TAC, respectively, compared with 32.0 +/- 3.5%Delta in sham; P < 0.001]. However, cardiac reserve differences between surgery groups were not observed at 16 WPS in terms of ejection fraction or cardiac output. In addition, ETT did not correlate with cardiac indexes under ISO stress. In conclusion, ISO stress was unable to reflect consistent differences in ETT between HF and healthy mice, suggesting cardiac-specific indexes are not the sole factors in defining exercise intolerance in mouse HF models. PMID- 23449943 TI - Prior caloric restriction increases survival of prepubertal obese- and PCOS-prone rats exposed to a challenge of time-limited feeding and physical activity. AB - We hypothesized that a polycystic ovary syndrome (PCOS) background associated with obese-prone genotype, coupled with preconditioning by caloric restriction, would confer a survival benefit in genetically prepubertal obese/PCOS (O/PCOS) prone rats faced with an unpredictable challenge of food shortage. Female, juvenile JCR:LA-cp rats, O/PCOS- and lean-prone, were exposed to 1.5 h of daily meals and 22.5 h of voluntary wheel-running, a procedure that leads to activity anorexia (AA). One week before the AA challenge (AAC), O/PCOS-prone rats were freely fed (O/PCOS-FF) or pair fed (O/PCOS-FR) to lean-prone, free-feeding animals (Lean-FF). O/PCOS-FR and lean-prone, food-restricted (Lean-FR) groups were matched on relative average caloric intake. Animals were removed from protocol at 75% of initial body weight (starvation criterion) or after 14 days (survival criterion). The AAC induced weight loss in all rats, but there were significant effects of both genotype and feeding history on weight loss (lean prone rats exhibited a higher rate of weight loss than O/PCOS-prone; P < 0.001), and rats with prior caloric restriction retained more weight than those free fed previously (90.68 +/- 0.59% vs. 85.47 +/- 0.46%; P < 0.001). The daily rate of running was higher in lean-prone rats compared with O/PCOS-prone. This difference in running rate correlated with differences in mean days of survival. All O/PCOS FR rats survived at day 14. O/PCOS-FF rats survived longer (10.00 +/- 0.97 days) than Lean-FR (6.17 +/- 1.58 days) and Lean-FF (4.33 +/- 0.42 days) rats (P < 0.05). Thus preconditioning by caloric restriction induces a substantial survival advantage, beyond genotype alone, in prepubertal O/PCOS-prone rats. PMID- 23449945 TI - Isolated cleft of the ala nasi: A report of seven cases. AB - Craniofacial clefts other than cleft lip & palate are reported to be 1.4 to 4.9 per 100,000 live births. Of these, clefts of nose are usually associated with other clefts. Isolated cleft of Ala is rare, 0.7% of all clefts reported by Monasterio. In an analysis of photographic records of 3,500 consecutive patients with craniofacial clefts including cleft lip & palate registered with us between 1985- 2012 which were accessed through our data base, 13 patients with nasal clefts were identified, seven out of which had Isolated cleft of the Ala. All were treated by a rotation flap of the Ala with good results with the longest follow up of 14Yrs. The authors have emphasised the rarity of the condition and presented a simple surgical procedure for correction. In the opinion of the authors this very simple procedure which can be performed by the junior surgeon gives a good long term result in the management of cleft Ala. PMID- 23449944 TI - Imputation of unordered markers and the impact on genomic selection accuracy. AB - Genomic selection, a breeding method that promises to accelerate rates of genetic gain, requires dense, genome-wide marker data. Genotyping-by-sequencing can generate a large number of de novo markers. However, without a reference genome, these markers are unordered and typically have a large proportion of missing data. Because marker imputation algorithms were developed for species with a reference genome, algorithms suited for unordered markers have not been rigorously evaluated. Using four empirical datasets, we evaluate and characterize four such imputation methods, referred to as k-nearest neighbors, singular value decomposition, random forest regression, and expectation maximization imputation, in terms of their imputation accuracies and the factors affecting accuracy. The effect of imputation method on the genomic selection accuracy is assessed in comparison with mean imputation. The effect of excluding markers with a large proportion of missing data on the genomic selection accuracy is also examined. Our results show that imputation of unordered markers can be accurate, especially when linkage disequilibrium between markers is high and genotyped individuals are related. Of the methods evaluated, random forest regression imputation produced superior accuracy. In comparison with mean imputation, all four imputation methods we evaluated led to greater genomic selection accuracies when the level of missing data was high. Including rather than excluding markers with a large proportion of missing data nearly always led to greater GS accuracies. We conclude that high levels of missing data in dense marker sets is not a major obstacle for genomic selection, even when marker order is not known. PMID- 23449946 TI - Comparative evaluation of dimension and surface detail accuracy of models produced by three different rapid prototype techniques. AB - Rapid prototyping (RP) is a technology that produces physical models by selectively solidifying ultra violet (UV) sensitive liquid resin using a laser beam. These models can be formed using various techniques. A study was undertaken to compare the dimensional accuracy and surface details of three prototype models with a 3D STL (standard template library) image. In this study the STL file was used to produce three different rapid prototype models namely; model 1-fused deposition model (FDM) using ABS (acrylonitrile butadiene styrene), model 2 Polyjet using a clear resin and model 3-a 3 dimensional printing using a composite material. Measurements were made at various anatomical points. For surface detail reproductions the models were subjected to scanning electron microscopy analysis. The dimensions of the model created by Polyjet were closest to the 3D STL virtual image followed by the 3DP model and FDM. SEM analysis showed uniform smooth surface on Polyjet model with adequate surface details. PMID- 23449947 TI - The Lamaze Certified Childbirth Educator's Role in Teaching Survivors of Childhood Sexual Abuse. AB - There is a strong likelihood that at least one participant in any Lamaze childbirth education class has had personal experience with childhood sexual abuse. Using the wisdom of Lamaze Certified Childbirth Educators and respected authors in the field of childhood sexual abuse, this column enlightens the childbirth educator in three ways: understanding the incidence of female and male childhood sexual abuse; understanding the effects of sexual, emotional, physical, and verbal abuse on the pregnant and parenting family; and facilitating classes that are sensitive to the needs of survivors of childhood sexual abuse as well to all expectant parents. PMID- 23449948 TI - A comparative clinical evaluation of once daily versus alternate day application of topical clobetasol propionate cream in psoriasis. AB - BACKGROUND: Corticosteroids are extremely useful in the treatment of inflammatory skin disorders. Topical steroid applications are the most effective treatment for all types of psoriasis. AIMS: To compare the efficacy of once daily versus alternate day application of topical steroid clobetasol propionate 0.05% (Tenovate cream(r)) in patients who have mild to moderate plaque psoriasis. SETTINGS AND DESIGN: This study was conducted on 89 patients of plaque psoriasis, who attended the skin OPD in our hospital. METHODS AND MATERIAL: The patients who had a mild to moderate severity of plaque psoriasis were selected. Those patients who required systemic corticosteroids, those who were already undergoing any psoriasis treatment, those who had any other debilitating illness and pregnant and lactating women were excluded from the study. Eighty nine patients were enrolled for the study after taking written informed consent from them and they were randomly allocated into two groups. Two patients dropped out, one in each group and 1 of group 2 was prescribed systemic corticosteroids.Group 1- once daily application (n= 44)Group 2- alternate day application (n= 42)An objective scoring was done on the basis of the PSI (Psoriasis Severity Index) score, which was graded from 0-4. Follow ups were done in the 2nd, 4th and 6th weeks. STATISTICAL ANALYSIS: It was done by the Student's 't' test and ANOVA. RESULTS AND CONCLUSIONS: The results showed that there was equal improvement in both the groups in the 2nd week, since the p-value was not significant (P> 0.05), but in the 4th and 6th weeks, there was less improvement in the alternate day group (P< 0.05). An intra group comparison indicated that clobetasol was effective both in the once daily and the alternate day groups, but clinical and symptomatic improvement occurred more quickly in the once daily group after 6 weeks of assessment. Thus, it can be concluded that the alternate day application of the topical steroid clobetasol propionate cream is as effective as the once daily application in the initial 2 weeks, but by 6 weeks, its efficacy decreases. Therefore, initially, we can advocate a less frequent application of potent topical steroids but for the complete remission of the disease, the application frequency should be once daily. PMID- 23449949 TI - Non contiguous-finished genome sequence and description of Peptoniphilus timonensis sp. nov. AB - Peptoniphilus timonensis strain JC401(T) sp. nov. is the type strain of P. timonensis sp. nov., a new species within the Peptoniphilus genus. This strain, whose genome is described here, was isolated from the fecal flora of a healthy patient. P. timonensis is an obligate Gram-positive anaerobic coccus. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 1,758,598 bp long genome (1 chromosome, no plasmid) contains 1,922 protein-coding and 22 RNA genes, including 5 rRNA genes. PMID- 23449950 TI - Effectiveness of early and aggressive administration of fresh frozen plasma to reduce massive blood transfusion during cytoreductive surgery. AB - BACKGROUND: Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has been consistently associated with high volume blood loss and red blood cell (RBC) transfusion. This study evaluates the effectiveness of the introduction of a novel protocol to reduce blood loss and subsequent intra-operative transfusion in patients with high volume disease. METHODS: One hundred and thirty-one consecutive patients with high volume disease (peritoneal cancer index >=16) who underwent CRS and PIC were evaluated. Group I consisted of the sixty patients (46%) treated before June 2006. Group II consistent of the seventy-one (54%) patients treated after June 2006 under the new protocol. The clinical and treatment-related data of patients in the two groups were compared. RESULTS: Group II was associated with reduced intra operative red blood cell transfusion (P<0.001), reduced cryoprecipitate transfusion (P=0.020), reduced platelet transfusion (P<0.001), reduced fresh frozen plasma transfusion (P=0.024), reduced operation length (P<0.001), reduced crystalloid administration (P<0.001) and reduced colloid administration (P<0.001). Group II was also associated with increased transfusion of FFP in the first half of the surgical intervention relative to the second half [FFP1(st)(:)FFP2(nd) ratio >1 (P<0.001)] and increased transfusion of RBC in the first half of the surgical intervention relative to the second half [RBC1(st)(:)RBC2(nd) ratio >=1 (P=0.016)]. CONCLUSION: Early administration of fresh frozen plasma combined with restrictive fluid resuscitation may reduce overall intra-operative transfusion of RBC and other blood components. PMID- 23449951 TI - Swallowing disorders in nursing home residents: how can the problem be explained? AB - BACKGROUND: The swallowing mechanism changes significantly as people age, even in the absence of chronic diseases. Presbyphagia, a term that refers to aging related changes in the swallowing mechanism, may be linked to many health conditions and presents itself in distinct ways. Swallowing disorders are also identified as a major problem amongst the elderly population living in nursing homes. METHODS: The study sought to determine the prevalence of swallowing disorders in nursing home residents, to identify the relationship between self perceived swallowing disorders, cognitive functions, autonomy, and depression, and also to analyze which variables explain the score of the Dysphagia Self-Test (DST). For this purpose, the researchers chose to apply a survey conveying questions on demographic aspects, general health, eating and feeding, as well as instruments to assess functional performance and the 3 ounce Water Swallow Test. RESULTS: The sample consisted of 272 elderly people living in eight nursing homes in Portugal. Six did not sign the informed consent form. Of the total, 29% were totally dependent, 33% were depressed, 45% had cognitive impairment, and 38% needed help with feeding. About 43% of the individuals reported having problems related to eating. Regarding the DST, 40% showed signs of dysphagia. With respect to the 3 ounce Water Swallow Test, 38% revealed at least one of the symptoms, wet voice being the most prevalent. Correlation measures showed that age had no linear association with the DST score although correlation with the Barthel Index and Mini Mental State Examination was found to be significant. A linear regression model was estimated with the DST score as the dependent variable and the MMSE and BI scores, gender, age, education, the Geriatric Depression Scale score, 3 ounce Water Swallow Test, and diagnosed conditions (such as neurological disorder, dementia, and cardiorespiratory problems) as explaining variables. CONCLUSION: Results showed a high prevalence of dysphagia signs amongst a nursing home population. For the purpose of the present study, both a subjective and an objective assessment were applied. Results pointed to a significant statistical relation between objective and subjective measures, thus indicating that a self perception test should be included in the assessment of swallowing disorders in a nursing home population. Notwithstanding, it should not be used as a single or principal measure as it is influenced by the individuals' cognitive condition. PMID- 23449952 TI - Contrast-enhanced MR imaging of hand and finger joints in patients with early rheumatoid arthritis: do we really need a full dose of gadobenate dimeglumine for assessing synovial enhancement at 3 T? AB - PURPOSE: To investigate the diagnostic value of a half dose compared with a full dose of gadobenate dimeglumine in the assessment of synovitis or tenosynovitis in the wrist and finger joints in patients with early rheumatoid arthritis (RA) and a disease activity score greater than 3.2. MATERIALS AND METHODS: With institutional review board approval and informed consent, 57 patients with early RA underwent 3-T magnetic resonance (MR) imaging with two different doses of contrast media. The contrast enhancement was measured in inflamed synovial tissue at half dose (0.05 mmol per kilogram of body weight) and at full dose (0.1 mmol/kg) by using T1-weighted sequences with fat saturation. The differences and the correlation of signal intensities (SIs) at half- and full-dose sequences were compared by using the paired t test and Pearson correlations. Image quality, Rheumatoid Arthritis MRI Score (RAMRIS), and tenosynovitis score on half- and full-dose images were compared by two observers using the Wilcoxon test. Interrater agreement was assessed by using kappa statistics. RESULTS: A significant difference in SI was found between half-dose and full-dose gadobenate dimeglumine-enhanced synovial tissue (mean: 914.35 +/- 251.1 vs 1022 +/- 244.5, P < .001). Because the SI showed high correlation between the ratio at half dose and full dose (r = 0.875), the formula, ratio of synovial enhancement to saline syringe at full dose = 0.337 + 1.070 * ratio of synovial enhancement to saline syringe at half dose, can be used to convert the normalized value of half dose to full dose. However, no difference in RAMRIS (score 0 in 490 of 1026 joints; score 1 in 344; score 2 in 158; and score 3 in 34) or tenosynovitis scores in grading synovitis or tenosynovitis in image quality and in assessment of synovial enhancement was detected between half-dose and full-dose images (P = 1). CONCLUSION: Postcontrast synovial SIs showed high correlation between half dose and full dose, and image quality was rated identically. Therefore, half-dose gadobenate dimeglumine at 3-T MR imaging may be sufficient for assessing synovitis or tenosynovitis in early RA. PMID- 23449953 TI - Achilles tendon assessed with sonoelastography: histologic agreement. AB - PURPOSE: To compare and determine the level of agreement of findings at conventional B-mode ultrasonography (US) and sonoelastography of the Achilles tendon with findings at histologic assessment. MATERIALS AND METHODS: This study was conducted with the approval of the institutional review boards, and all cadavers were in legal custody of the study institution. Thirteen Achilles tendons in 10 cadavers (four male, six female; age range, 70-90 years) were examined with B-mode US and sonoelastography. B-mode US grading was as follows: Grade 1 indicated a normal-appearing tendon with homogeneous fibrillar echotexture; grade 2, a focal fusiform or diffuse enlarged tendon; and grade 3, a hypoechoic area with or without tendon enlargement. Sonoelastography grading was as follows: Grade 1 indicated blue (hardest) to green (hard); grade 2, yellow (soft); and grade 3, red (softest). Twenty-five biopsy specimens from representative lesions of the middle and distal thirds of the Achilles tendons were evaluated histologically. The concordance of B-mode US grading compared with sonoelastographic grading was assessed by using kappa analysis. RESULTS: With B mode US and sonoelastography, all 11 tendon thirds of histologically normal tendons were verified as normal (grade 1). Sonoelastography depicted 14 of 14 (100%) tendon thirds with histologic degeneration (grade 2 or 3), whereas B-mode US could depict only 12 of 14 (86%) lesions (grade 2 or 3). Only moderate agreement between B-mode US and sonoelastography was seen (kappa = 0.52, P < .001). CONCLUSION: Sonoelastography might help predict signs of histopathologic degeneration of Achilles tendinosis, potentially more sensitively than B-mode US. PMID- 23449954 TI - Variation in diagnostic performance among radiologists at screening CT colonography. AB - PURPOSE: To assess the variation in diagnostic performance among radiologists at screening computed tomographic (CT) colonography. MATERIALS AND METHODS: In this HIPAA-compliant, institutional review board-approved study, 6866 asymptomatic adults underwent first-time CT colonographic screening at a single center between January 2005 and November 2011. Results of examinations were interpreted by one of eight board-certified abdominal radiologists (mean number of CT colonographic studies per reader, 858; range, 131-2202). Findings at CT colonography and subsequent colonoscopy were recorded, and key measures of diagnostic performance, including adenoma and advanced neoplasia detection rate, were compared among the radiologists. RESULTS: The overall prevalence of histopathologically confirmed advanced neoplasia was 3.6% and did not differ significantly among radiologists (range, 2.4%-4.4%; P = .067; P = .395 when one outlier was excluded). Overall, 19.5% of polyps detected at CT colonography proved to be advanced neoplasia and did not differ significantly among radiologists (range, 14.4%-23.2%; P = .223). The overall per-polyp endoscopic confirmation rate was 93.5%, ranging from 80.0% to 97.6% among radiologists (P = .585). The overall percentage of nondiagnostic CT colonographic examinations was 0.7% and was consistent among radiologists (range, 0.3%-1.1%; P = .509). CONCLUSION: Consistent performance for adenoma and advanced neoplasia detection, as well as other clinically relevant end points, were observed among radiologists at CT colonographic screening. PMID- 23449955 TI - Optimizing trauma multidetector CT protocol for blunt splenic injury: need for arterial and portal venous phase scans. AB - PURPOSE: To retrospectively compare the diagnostic performance of arterial, portal venous, and dual-phase computed tomography (CT) for blunt traumatic splenic injury. MATERIALS AND METHODS: Informed consent was waived for this institutional review board-approved, HIPAA-compliant study. Retrospective record review identified 120 blunt trauma patients (87 male [72.5%] 33 female [27.5%]; age range, 18-94 years) who had undergone dual-phase abdominal CT within 5 years, including 30 without splenic injury, 30 with parenchymal injury only, 30 with splenic active bleeding, and 30 with intrasplenic pseudoaneurysm. Six radiologists each performed blinded review of 20 different cases, and scored the presence of pseudoaneurysm, active bleeding, parenchymal injury, and hematoma; 20 cases were interpreted by all radiologists. Data analysis included calculation of diagnostic performance measures with confidence intervals, areas under receiver operating characteristic curves, and interobserver agreement/variability. RESULTS: For intrasplenic pseudoaneurysm, arterial phase imaging was more sensitive (70% [21 of 30] vs 17% [five of 30]; P < .0002) and more accurate (87% [78 of 90] vs 72% [65 of 90]; P = .0165) than portal venous phase imaging. For active bleeding, arterial phase imaging was less sensitive (70% [21 of 30] vs 93% [28 of 30]; P = .0195) and less accurate (89% [80 of 90] vs 98% [88 of 90]; P = .0168) than portal venous phase imaging. For parenchymal injury, arterial phase CT was less sensitive (76% [68 of 90] vs 93% [84 of 90]; P = .001) and less accurate (81% [nine of 120] vs 95% [114 of 120]; P = .0008) than portal venous phase CT. For all injuries, dual-phase review was equivalent to or better than single-phase review. CONCLUSION: For CT evaluation of blunt splenic injury, arterial phase is superior to portal venous phase imaging for pseudoaneurysm but inferior for active bleeding and parenchymal disruption; dual-phase CT provides optimal overall performance. PMID- 23449956 TI - Unreported vertebral body compression fractures at abdominal multidetector CT. AB - PURPOSE: To retrospectively assess the prevalence and clinical outcomes of unreported vertebral compression fractures at abdominal computed tomography (CT). MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; the need for informed consent was waived for this retrospective analysis. A total of 2041 consecutive adult patients (1640 women, 401 men; age range, 19-94 years) underwent both abdominal multidetector CT and dual-energy x ray absorptiometry (DXA) within 6 months of each other between 2000 and 2007, before sagittal CT reconstructions were obtained routinely. Transverse (axial) and retrospective sagittal multidetector CT reconstructions were reviewed for the presence of moderate or severe vertebral body compression fractures of the lower thoracic and lumbar spine by using the Genant visual semiquantitative method. Twenty-six patients were excluded for evidence of pathologic fracture or for technical factors limiting compression fracture detection. Electronic medical records were reviewed for patients with moderate or severe compression fractures to determine whether the fracture was reported at prospective CT interpretation, was known previously, or was diagnosed subsequently. Correlation was made with central DXA T scores. Statistical analysis was performed with the Student t test and Fisher exact test. RESULTS: At least one moderate or severe vertebral body compression fracture was identified retrospectively at CT in 97 patients (mean age, 70.8 years). Fractures involved one level in 67 and multiple levels in 30 patients, for a total of 141 fractures. In 81 (84%) patients, prospective CT diagnosis was not made. Patients in whom fractures were reported prospectively were significantly older and were more likely to have a severe compression fracture (P < .05). In 52 (64%) patients with an unreported fracture, the vertebral compression fracture was not known clinically. In 18 patients, subsequent diagnosis of a compression fracture was determined by means of another imaging study (median interval, 7 months). At DXA, 39 (48%) of 81 patients with unreported vertebral body compression fractures had a nonosteoporotic T score (greater than -2.5). CONCLUSION: Most clinically important vertebral body compression fractures in nontrauma patients at risk for low bone mineral density may go unreported at abdominal multidetector CT if sagittal reconstructions are not routinely evaluated. PMID- 23449957 TI - Automated detection of sclerotic metastases in the thoracolumbar spine at CT. AB - PURPOSE: To design and validate a computer system for automated detection and quantitative characterization of sclerotic metastases of the thoracolumbar spine on computed tomography (CT) images. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and was HIPAA compliant; informed consent was waived. The data set consisted of CT examinations in 49 patients (14 female, 35 male patients; mean age, 57.0 years; range, 12-77 years), demonstrating a total of 532 sclerotic lesions of the spine of greater than 0.3 cm(3) in volume, and in 10 control case patients (four women, six men; mean age, 55.2 years; range, 19-70 years) without spinal lesions. CT examinations were divided into training and test sets, and images were analyzed according to prototypical fully-automated computer-aided detection (CAD) software. Free response receiver operating characteristic analysis was performed. RESULTS: Lesion detection sensitivity on images in the training set was 90%, relative to reference-standard marked lesions (95% confidence interval [CI]: 83%, 97%), at a false-positive rate (FPR) of 10.8 per patient (95% CI: 6.6, 15.0). For images in the testing set, sensitivity was 79% (95% CI: 74%, 84%), with an FPR of 10.9 per patient (95% CI: 8.5, 13.3). False-negative findings were most commonly (37 [40%] of 93) a result of endplate proximity, with 32 (34% of 93) caused by low CT attenuation. Marginal sclerosis caused by degenerative change (174 [28.1%] of 620 actual detections) was the most common cause of false-positive detections, followed by partial volume averaging with vertebral endplates (173 [27.9%] of 620) and pedicle cortex parallel to the axial imaging plane (121 [19.5%] 620). CONCLUSION: This CAD system successfully identified and segmented sclerotic lesions in the thoracolumbar spine. PMID- 23449958 TI - Dexmedetomidine offers an option for safe and effective sedation for nuclear medicine imaging in children. AB - PURPOSE: To determine the safety, efficacy, and outcomes of bradycardia, hypotension, and hypertension with dexmedetomidine (DEX), a recently approved sedative used for procedural sedation that has not been described previously for pediatric nuclear medicine imaging. MATERIALS AND METHODS: Between March 2005 and August 2011, 669 patients (mean age, 5.7 years +/- 4.5 [standard deviation]; median age, 4.5 years; age range, 0.1-22.5 years) received DEX in this HIPAA compliant study. Sedation was administered with DEX, an alpha-2 adrenergic agonist, as an intravenous bolus (2 MUg per kilogram of body weight) over a 10 minute period; this was followed by continuous infusion at a rate of 1 MUg/kg/h until imaging was complete. The bolus could be repeated up to two times, if needed, to achieve the targeted level of a Ramsay sedation score of 4. After institutional review board approval, collected quality assurance data were reviewed. RESULTS: Adequate sedation was achieved within 8.6 minutes +/- 4.6 (median, 8.0 minutes; range, 1.0-40.0 minutes) on average in studies that averaged 41.3 minutes +/- 25.5 (median, 31.5 minutes; range, 9.0-183.0 minutes). Of 669 studies, 667 (99.7%) were completed successfully. Six children (0.9%) had brief periods of oxygen desaturation below 95%, none of which required airway intervention. Hypotension, hypertension, and bradycardia (all defined as deviations of more than 20% from age-adjusted awake norms), occurred in 58.7% (n = 393), 2.1% (n = 14), and 4.3% (n = 29) of patients, respectively. Both hypotension and bradycardia were related to age (P = .033 and P = .002, respectively); older children tended to experience more of these events. None of these fluctuations required pharmacologic therapy. Discharge criteria (modified Aldrete score >= 9) were met, on average, within 41.4 minutes +/- 27.9 (median, 36.0 minutes; range, 1.0-220.0 minutes). CONCLUSION: DEX offers advantages for pediatric sedation for nuclear medicine imaging. DEX produces a condition similar to natural sleep, with no detrimental effect on respiration. The hemodynamic variability anticipated with DEX did not require pharmacologic treatment, and the drug was well tolerated. PMID- 23449960 TI - Non-response in telephone surveys of COPD patients does not introduce bias. AB - We examined the telephone response rates in a 2-year study of patients with COPD to identify factors associated with non-response. A total of 381 patients received monthly telephone calls to assess symptoms and treatment in 2007 and 2008. A total of 9019 calls were made over 24 months, of which 73% were answered. The highest response rate was obtained in February 2007 (81%), and the lowest in July 2008 (48%). The monthly response rate was lower in the second year of follow up. There were 39 patients (10%) who were less frequent responders, with 10 or fewer responses. Less frequent responders were more likely to be current smokers and have hypoxaemia. The median number of answered calls was 18 (interquartile range 16-20). In bivariate models the median number of responses was significantly lower in subjects with chronic cough. In multivariate models neither demographic nor disease characteristics were significantly associated with non-response. We found less frequent responders to monthly telephone calls to be similar in characteristics to frequent responders. This suggests that non response does not necessarily introduce bias in telephone surveys of patients with COPD. PMID- 23449959 TI - In vitro and in vivo investigations on the effects of low-density lipoprotein concentration polarization and haemodynamics on atherosclerotic localization in rabbit and zebrafish. AB - Atherosclerosis (AS) commonly occurs in the regions of the arterial tree with haemodynamic peculiarities, including local flow field disturbances, and formation of swirling flow and vortices. The aim of our study was to confirm low density lipoprotein (LDL) concentration polarization in the vascular system in vitro and in vivo, and investigate the effects of LDL concentration polarization and flow field alterations on atherosclerotic localization. Red fluorescent LDL was injected into optically transparent Flk1: GFP zebrafish embryos, and the LDL distribution in the vascular lumen was investigated in vivo using laser scanning confocal microscopy. LDL concentration at the vascular luminal surface was found to be higher than that in the bulk. The flow field conditions in blood vessel segments were simulated and measured, and obvious flow field disturbances were found in the regions of vascular geometry change. The LDL concentration at the luminal surface of bifurcation was significantly higher than that in the straight segment, possibly owing to the atherogenic effect of disturbed flow. Additionally, a stenosis model of rabbit carotid arteries was generated. Atherosclerotic plaques were found to have occurred in the stenosis group and were more severe in the stenosis group on a high-fat diet. Our findings provide the first ever definite proof that LDL concentration polarization occurs in the vascular system in vivo. Both lipoprotein concentration polarization and flow field changes are involved in the infiltration/accumulation of atherogenic lipids within the location of arterial luminal surface and promote the development of AS. PMID- 23449961 TI - Craniomaxillofacial trauma: synopsis of 14,654 cases with 35,129 injuries in 15 years. AB - Craniomaxillofacial (CMF) trauma occurs in isolation or in combination with other serious injuries, including intracranial, spinal, and upper- and lower-body injuries. It is a major cause of expensive treatment and rehabilitation requirements, temporary or lifelong morbidity, and loss of human productivity. The aim of this study was to evaluate patterns of CMF trauma in a large patient sample within a 15-year time frame. Between 1991 and 2005, CMF trauma data were collected from 14,654 patients with 35,129 injuries at the Department of Cranio Maxillofacial and Oral Surgery in Innsbruck, assessing a plethora of parameters such as injury type and mechanism as well as age and gender distribution over time. Three main groups of CMF trauma were evaluated: facial bone fractures, dentoalveolar trauma, and soft tissue injuries. Statistical comparisons were carried out using a chi-square test. This was followed by a logistic regression analysis to determine the impact of the five main causes for CMF injury. Older people were more prone to soft tissue lesions with a rising risk of 2.1% per year older, showing no significant difference between male and female patients. Younger patients were at higher risk of suffering from dentoalveolar trauma with an increase of 4.4% per year younger. This number was even higher (by 19.6%) for female patients. The risk of sustaining facial bone fractures increased each year by 4.6%. Male patients had a 66.4% times higher risk of suffering from this type of injury. In addition, 2550 patients (17.4%) suffered from 3834 concomitant injuries of other body parts. In summary, we observed changing patterns of CMF trauma over the last 15 years, paralleled by advances in refined treatment and management options for rehabilitation and reconstruction of patients suffering from CMF trauma. PMID- 23449962 TI - Patterns of Conflict Interaction in Mother-Toddler Dyads: Differences Between Depressed and Non-depressed Mothers. AB - We examined the differences in conflict interaction between depressed mothers and their toddler and non-depressed dyads and whether these differences mediated the association of maternal depression with compromised child socioemotional development. Mother/ child interaction was videotaped during a teaching task and during a free play task as part of a home visit when the target child was between 16 and 18 months old. Each turn of every conflict was coded for behavior and affect of each member of the dyad. Interaction data were summarized to calculate the number of conflict turns, the rate of conflict, and the proportion of mother initiated versus child-initiated conflicts per dyad. Sequential analysis was used to estimate the probability of specific maternal responses to specific child behaviors. Bivariate comparisons indicated that depressed dyads experienced higher rates of conflict, especially during the teaching task, and that depressed mothers were more likely to respond destructively to child oppositional behavior. Results of multivariate linear regression indicated that the higher probability of destructive response mediated the association of maternal depression with lower quality of mother-child attachment. These findings have implications for the development of interventions to support mothers in dealing with the conflicts that are so common during the second year of a child's life. PMID- 23449963 TI - IL-5 Promoter Polymorphism Enhances IgE Responses to Staphylococcal Superantigens in Adult Asthmatics. AB - Interleukin 5 (IL-5) is a key cytokine involved in the induction of T-helper type 2 (Th2) responses in the asthmatic airway. We investigated IL-5 genetic polymorphisms associated with asthma phenotypes, including IgE responses to staphylococcal enterotoxins A and B (SEA and SEB, respectively), in asthmatics. Adult asthmatics (n=310) and normal controls (n=160) were enrolled in the present study. Serum total and specific IgE to SEA and SEB were measured. Two IL-5 polymorphisms, -746A>G and +4499T>G, were genotyped using the primer-extension method. There were no significant differences in genotype or haplotype frequencies of these polymorphisms between the two groups. Asthmatics carrying the AG/GG genotype at -746A>G had a significantly higher prevalence of serum specific IgE to SEA (P=0.008), higher total IgE levels (P=0.014), and lower PC20 methacholine levels (P=0.002) compared to those with the AA genotype. These findings suggest that the IL-5 promoter polymorphism at -746A>G enhances serum total and specific IgE responses to SEA, which may augment airway hyperresponsiveness in adult asthmatics. PMID- 23449964 TI - Clinical violence in nursing students. AB - BACKGROUND: One of the significant issues in health studies is violence. Although violence against nurses has been recognized as a major occupational problem, its magnitude and extent is not clearly defined. The aim of this study was to determine the extent and types of violence during clinical training of nursing students. METHODS: In this descriptive and cross-sectional study, 180 sophomores, juniors and seniors of Shahid Beheshti, Tehran and Iran Medical Universities were selected by quota sampling method. A questionnaire was used for collecting data regarding violence over the past year. Content and test-retest methods were used for evaluating its validity and reliability, respectively. RESULTS: Findings showed that 6.7%, 8.3% and 39.4% of the students experienced physical assault, physical menace and insult, respectively, over the past year. Most cases of the assaults (66.7%) were done by patients, most menaces by staff as well as patients' attendants (18.1%) and most insults by staff (33.7%) and patients (31%). No significant relation was found between the sex as well as the educational year of the students and the experience of insult. 41.6% of the assaults were due to the effects of disease in assailants. However, no specific reason was found for physical menace and insult in most cases. 66.65%, 26.6% and 39.4% of the students reported physical assault, menace and insult to their tutors, respectively. CONCLUSIONS: Nursing students are subject to more violence because of young age and inadequate experience. Therefore, devising educational programs regarding occupational violence as well as its prevention and providing necessary support and consultation following violence are essential. PMID- 23449965 TI - Understanding preference shifts: a review and alternate explanation of within trial contrast and state-dependent valuation. AB - Stimuli that precede aversive events are typically less preferred than stimuli that precede nonaversive events. It has recently been demonstrated that stimuli that follow less preferred events may become favored more than stimuli that follow more preferred events. This phenomenon has been investigated under a variety of names, most commonly, within-trial contrast and state-dependent valuation. Although this effect has been replicated, there have been several failures to replicate and it is still little understood. This paper reviews and summarizes the literature on within-trial contrast and state-dependent valuation. Procedural variations across studies are identified and discussed. The two current models that explain the phenomenon are then outlined and the limitations of each model are described. A third explanation is offered that incorporates the concept of motivating operations. Last, the predictions of all three models are compared. PMID- 23449966 TI - Classification of four ovine breeds of southern peninsular zone of India: Morphometric study using classical discriminant function analysis. AB - Six morphometric traits (height at withers, body length, chest girth, ear length, tail length and body weight) were analyzed to characterize from a breed point of view 1981 sheep from four ovine breeds (Bellary, Kenguri, Hassan and Mandya) of southern peninsular zone of India. Discriminant Function Analysis was used to distinguish between four breeds by morphometric traits. The population variability showed Kenguri ewes were the largest and heaviest followed by Bellary, Hassan and Mandya whereas Kenguri rams were followed by Bellary, Mandya and Hassan. Overall sexual dimorphism (m/f) was 1.13, with Kenguri males being 47% heavier than females. The coefficient of variation of all traits in four breeds ranged from 4.06% to 30.28%. The flocks and age effects showed a high heterogeneity among females of different flocks. Height at withers was most discriminating trait in separating the four sheep breeds. The Mahalanobis distance of the morphological traits between Kenguri and Mandya sheep was most while the least differentiation was observed between Kenguri and Bellary sheep. Nearest neighbour discriminant analysis showed that most Kenguri sheep were classified into their source population followed by Mandya. However, varied percentages of misclassification between different breeds were observed showing the level of genetic exchange that has taken place between the breeds overtime. UPGMA based dendrogram showed formation of two separate groups; Mandya and Hassan clustered together while Bellary and Kenguri formed other group. PMID- 23449967 TI - Malnutrition and its oral outcome - a review. AB - Malnutrition affects the oral health and a poor oral health in turn, may lead to malnutrition. This interdependent relationship sees good nutritional health, thus promoting good oral health and vice versa. Malnutrition may alter the homeostasis, which can lead to disease progression of the oral cavity, reduce the resistance to the microbial biofilm and reduce the capacity of tissue healing. It may even affect the development of the oral cavity. Protein-energy malnutrition occurs when there is a deficiency of protein, energy foods or both, which are relative to a body's need. Studies have suggested that enamel hypoplasia, salivary gland hypofunction and saliva compositional changes may be the mechanisms through which the malnutrition is associated with caries, while an altered eruption timing may create a challenge in the analysis of the age specific caries rates. This paper gives an insight on the relationship of the malnutrition and the protein-energy malnutrition with the oral health status. PMID- 23449968 TI - The developing utility of zebrafish models for cognitive enhancers research. AB - Whereas cognitive impairment is a common symptom in multiple brain disorders, predictive and high-throughput animal models of cognition and behavior are becoming increasingly important in the field of translational neuroscience research. In particular, reliable models of the cognitive deficits characteristic of numerous neurobehavioral disorders such as Alzheimer's disease and schizophrenia have become a significant focus of investigation. While rodents have traditionally been used to study cognitive phenotypes, zebrafish (Danio rerio) are gaining popularity as an excellent model to complement current translational neuroscience research. Here we discuss recent advances in pharmacological and genetic approaches using zebrafish models to study cognitive impairments and to discover novel cognitive enhancers and neuroprotective mechanisms. PMID- 23449970 TI - Safety of colorado microdissection needle (stryker) for skin opening in craniomaxillofacial surgery. AB - PURPOSE: Diathermy is used widely in surgical procedures, mainly for subcutaneous and deeper layers dissection. The use on craniomaxillofacial skin has been precluded by the fear of scar formation, alopecia and wound dehiscence. The aim of this study was to clinically evaluate the safety of Colorado Microdissection needle (Stryker) for skin opening in craniomaxillofacial surgery. MATERIALS AND METHODS: 117 skin incisions for craniomaxillofacial procedures were performed using the Stryker Colorado microdissection needle (CMN). The incisions included Coronal, Hemicoronal, Preauricular, Subciliary, Lateral brow's, Submandibular, Retromandibular, Risdon's, Modified Blair's and Schoebinger's incision. The reason for the craniomaxillofacial operative intervention included: Craniofacial trauma, removal of benign and malignant pathology, craniofacial reconstruction and Temporomandibular joint surgeries. 115 incisions were performed in patients in the adult age group and 02 in the pediatric age group. RESULTS: All the patients tolerated the procedures well, with no increased risk from the use of the CMN. Only one incision had wound infection and dehiscence. All other patients had usual wound healing. At 6 months follow-up postoperative scar and alopecia was evaluated. Only on close up inspection minimal area of alopecia was noticed along the incision line. The postoperative scar was healthy in all the cases. CONCLUSION: The findings of this study recommend the use of the CMN in all craniomaxillofacial procedures. PMID- 23449969 TI - Imaging-Based Methods for Non-invasive Assessment of Bone Properties Influenced by Mechanical Loading. AB - PURPOSE: To describe the most common in vivo imaging-based research tools used to assess bone properties that are influenced by mechanical loading associated with exercise, habitual physical activity, or disease states. Bone is a complex metabolically active tissue that adapts to changes in mechanical loading by altering the amount and spatial organization of mineral. METHOD: Using a narrative review design, the authors provide an overview of bone biology and biomechanics to emphasize the importance of bone size scale, porosity, and degree of mineralization when interpreting measures acquired using quantitative ultrasound (QUS), dual-energy X-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), and finite element analysis (FEA). For each imaging modality, basic imaging principles, typical outcome measures associated with changes in mechanical loading, and salient features for physiotherapists are described. MAIN RESULTS: While each imaging modality has strengths and limitations, currently CT-based methods are best suited for determining the effects of mechanical loading on bone properties-particularly in the peripheral skeleton. CONCLUSIONS: Regardless of the imaging technology used, the physiotherapist must carefully consider the assumptions of the imaging-based method, the clinical context, the nature of the change in mechanical loading, and the expected time course for change in bone properties. : Purpose: To describe the most common in vivo imaging-based research tools used to assess bone properties that are influenced by mechanical loading associated with exercise, habitual physical activity, or disease states. Bone is a complex metabolically active tissue that adapts to changes in mechanical loading by altering the amount and spatial organization of mineral. Method: Using a narrative review design, the authors provide an overview of bone biology and biomechanics to emphasize the importance of bone size scale, porosity, and degree of mineralization when interpreting measures acquired using quantitative ultrasound (QUS), dual-energy X ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), and finite element analysis (FEA). For each imaging modality, basic imaging principles, typical outcome measures associated with changes in mechanical loading, and salient features for physiotherapists are described. Main Results: While each imaging modality has strengths and limitations, currently CT based methods are best suited for determining the effects of mechanical loading on bone properties-particularly in the peripheral skeleton. Conclusions: Regardless of the imaging technology used, the physiotherapist must carefully consider the assumptions of the imaging-based method, the clinical context, the nature of the change in mechanical loading, and the expected time course for change in bone properties. PMID- 23449972 TI - Biologic response modifiers to decrease inflammation: Focus on infection risks. AB - Biologic response modifiers are a novel class of drugs used by sub-specialists to treat immune-mediated conditions such as juvenile idiopathic arthritis and inflammatory bowel disease. Also known as 'cytokine inhibitors', they are proteins whose purpose is to block the action of cytokines involved in inflammation. The desired therapeutic effect is to reduce or control inflammation. Tumour necrosis factor-alpha (TNF-alpha) inhibitors are the prototypes, but newer agents in this class target other cytokines such as interleukin(IL)-6, IL-12, and IL-23, or the proteins that target cytokine receptors on lymphocytes. They typically act by inhibiting the normal inflammatory processes involved in the immune response, particularly for macrophages. These agents are often used in combination with other immunosuppressive drugs such as methotrexate or steroids. The immune-modulating effects can persist days to weeks after discontinuation. Evidence indicates that patients treated with biologic response modifiers are at higher risk of tuberculosis infection and may be at higher risk of fungal or other infections with intracellular pathogens. This practice point offers guidelines on the preventive strategies that should be used in patients who will be or who are taking these immune-modifying agents. PMID- 23449971 TI - The microarchitecture of C. elegans behavior during lethargus: homeostatic bout dynamics, a typical body posture, and regulation by a central neuron. AB - STUDY OBJECTIVES: The nematode C. elegans develops through four larval stages before it reaches adulthood. At the transition between stages and before it sheds its cuticle, it exhibits a sleep-like behavior during a stage termed lethargus. The objectives of this study were to characterize in detail behavioral patterns and physiological activity of a command interneuron during lethargus. MEASUREMENTS AND RESULTS: We found that lethargus behavior was composed of bouts of quiescence and motion. The duration of individual bouts ranged from 2 to 100 seconds, and their dynamics exhibited local homeostasis: the duration of bouts of quiescence positively correlated with the duration of bouts of motion that immediately preceded them in a cAMP-dependent manner. In addition, we identified a characteristic body posture during lethargus: the average curvature along the body of L4 lethargus larvae was lower than that of L4 larvae prior to lethargus, and the positions of body bends were distributed non-uniformly along the bodies of quiescent animals. Finally, we found that the AVA interneurons, a pair of backward command neurons, mediated locomotion patterns during L4 lethargus in similar fashion to their function in L4 larvae prior to lethargus. Interestingly, in both developmental stages backward locomotion was initiated and terminated asymmetrically with respect to AVA intraneuronal calcium concentration. CONCLUSIONS: The complex behavioral patterns during lethargus can be dissected to quantifiable elements, which exhibit rich temporal dynamics and are actively regulated by the nervous system. Our findings support the identification of lethargus as a sleep-like state. CITATION: Iwanir S; Tramm N; Nagy S; Wright C; Ish D; Biron D. The microarchitecture of C. elegans behavior during lethargus: homeostatic bout dynamics, a typical body posture, and regulation by a central neuron. SLEEP 2013;36(3):385-395. PMID- 23449973 TI - Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation. AB - Keratins 8 and 18 (K8/18) are simple epithelial cell-specific intermediate filament proteins. Keratins are essential for tissue integrity and are involved in intracellular signaling pathways that regulate cell response to injuries, cell growth, and death. K8/18 expression is maintained during tumorigenesis; hence, they are used as a diagnostic marker in tumor pathology. In recent years, studies have provided evidence that keratins should be considered not only as markers but also as regulators of cancer cell signaling. The loss of K8/18 expression during epithelial-mesenchymal transition (EMT) is associated with metastasis and chemoresistance. In the present study, we investigated whether K8/18 expression plays an active role in EMT. We show that K8/18 stable knockdown using shRNA increased collective migration and invasiveness of epithelial cancer cells without modulating EMT markers. K8/18-depleted cells showed PI3K/Akt/NF-kappaB hyperactivation and increased MMP2 and MMP9 expression. K8/18 deletion also increased cisplatin-induced apoptosis. Increased Fas receptor membrane targeting suggests that apoptosis is enhanced via the extrinsic pathway. Interestingly, we identified the tight junction protein claudin1 as a regulator of these processes. This is the first indication that modulation of K8/18 expression can influence the phenotype of epithelial cancer cells at a transcriptional level and supports the hypothesis that keratins play an active role in cancer progression. PMID- 23449974 TI - Up-regulation of survivin during immortalization of human myofibroblasts is linked to repression of tumor suppressor p16(INK4a) protein and confers resistance to oxidative stress. AB - Survivin is an essential component of the chromosomal passenger complex and a member of the inhibitor of apoptosis family. It is expressed at high levels in a large variety of malignancies, where it has been implicated in drug resistance. It was also shown previously that survivin is up-regulated during telomerase mediated immortalization, which occurs at a relatively early stage during carcinogenesis. This study shows that up-regulation of survivin during immortalization of human myofibroblasts is an indirect consequence of the repression of p16(INK4a). Survivin and p16(INK4a) were functionally linked by assays that showed that either the up-regulation of survivin or repression of p16(INK4a) rendered telomerase-transduced MRC-5 myofibroblasts resistant to oxidative stress. Conversely, siRNA-mediated down-regulation of survivin activated caspases and enhanced the sensitivity of immortal MRC-5 cells to oxidative stress. The E2F1 transcription factor, which is negatively regulated by the pRB/p16(INK4a) tumor suppressor pathway, was implicated in the up-regulation of survivin. Using the ChIP assay, it was shown that E2F1 directly interacted with the survivin gene (BIRC5) promoter in cells that spontaneously silenced p16(INK4a) during telomerase-mediated immortalization. E2F1 binding to the BIRC5 was also enhanced in telomerase-transduced cells subjected to shRNA-mediated repression of p16(INK4a). Together, these data show that repression of p16(INK4a) contributes to the up-regulation of survivin and thereby provides a survival advantage to cells exposed to oxidative stress during immortalization. The up regulation of survivin during immortalization likely contributes to the vulnerability of immortal cells to transformation by oncogenes that alter intracellular redox state. PMID- 23449975 TI - miR-155 regulates immune modulatory properties of mesenchymal stem cells by targeting TAK1-binding protein 2. AB - MSCs possess potent immunosuppressive capacity. We have reported that mouse MSCs inhibit T cell proliferation and function via nitric oxide. This immune regulatory capacity of MSCs is induced by the inflammatory cytokines IFNgamma together with either TNFalpha or IL-1beta. This effect of inflammatory cytokines on MSCs is extraordinary; logarithmic increases in the expression of iNOS and chemokines are often observed. To investigate the molecular mechanisms underlying this robust effect of cytokines, we examined the expression of microRNAs in MSCs before and after cytokine treatment. We found that miR-155 is most significantly up-regulated. Furthermore, our results showed that miR-155 inhibits the immunosuppressive capacity of MSCs by reducing iNOS expression. We further demonstrated that miR-155 targets TAK1-binding protein 2 (TAB2) to regulate iNOS expression. Additionally, knockdown of TAB2 reduced iNOS expression. In summary, our study demonstrated that miR-155 inhibits the immunosuppressive capacity of MSCs by reducing iNOS expression by targeting TAB2. Our data revealed a novel role of miR-155 in regulating the immune modulatory activities of MSCs. PMID- 23449976 TI - C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma derived regulator of adipogenesis. AB - C1q/TNF-related proteins (CTRPs) are a family of secreted regulators of glucose and lipid metabolism. Here, we describe CTRP11, a novel and phylogenetically conserved member of the C1q family. Our studies revealed that white and brown adipose are major tissues that express CTRP11, and its expression is acutely regulated by changes in metabolic state. Within white adipose tissue, CTRP11 is primarily expressed by stromal vascular cells. As a secreted multimeric protein, CTRP11 forms disulfide-linked oligomers. Although the conserved N-terminal Cys-28 and Cys-32 are dispensable for the assembly of higher-order oligomeric structures, they are unexpectedly involved in modulating protein secretion. When co-expressed, CTRP11 forms heteromeric complexes with closely related CTRP10, CTRP13, and CRF (CTRP14) via the C-terminal globular domains, combinatorial associations that potentially generate functionally distinct complexes. Functional studies revealed a role for CTRP11 in regulating adipogenesis. Ectopic expression of CTRP11 or exposure to recombinant protein inhibited differentiation of 3T3-L1 adipocytes. The expression of peroxisome proliferator-activated receptor-gamma and CAAT/enhancer binding protein-alpha, which drive the adipogenic gene program, was markedly suppressed by CTRP11. Impaired adipogenesis was caused by a CTRP11-mediated decrease in p42/44-MAPK signaling and inhibition of mitotic clonal expansion, a process essential for adipocyte differentiation in culture. These results implicate CTRP11 as a novel secreted regulator of adipogenesis and highlight the potential paracrine cross-talk between adipocytes and cells of the stromal vascular compartment in maintaining adipose tissue homeostasis. PMID- 23449977 TI - Substrate placement influences reactivity in non-heme Fe(II) halogenases and hydroxylases. AB - We employ error-corrected density functional theory methods to map out the dependence of reactivity on substrate position for SyrB2, a member of a family of non-heme iron halogenases and hydroxylases that are only reactive toward amino acid substrates delivered via prosthetic phosphopantetheine arms. For the initial hydrogen abstraction step, the inherent flexibility of the phosphopantetheine molecule weakens the position dependence for both the native substrate (threonine for SyrB2) and alternative substrates. Over a 5 A window of substrate positions, the tethered hydrogen abstraction step proceeds with nearly identical activation energies and donor-acceptor distances in the transition state. The propensity of a particular substrate toward halogenation or hydroxylation is found to depend strongly on the substrate placement following hydrogen abstraction, with deeper substrate delivery into the active (for native substrates) site favoring halogenation and shallower substrate delivery favoring hydroxylation. PMID- 23449978 TI - The transcription factor sterile alpha motif (SAM) pointed domain-containing ETS transcription factor (SPDEF) is required for E-cadherin expression in prostate cancer cells. AB - Loss of E-cadherin is one of the key steps in tumor progression. Our previous studies demonstrate that SAM pointed domain-containing ETS transcription factor (SPDEF) inhibited prostate cancer metastasis in vitro and in vivo. In the present study, we evaluated the relationship between SPDEF and E-cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor cell invasion and metastasis. The results presented here demonstrate a direct correlation between expression of E-cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that modulation of E-cadherin and SPDEF had similar effects on cell migration/invasion. In addition, siRNA-mediated knockdown of E cadherin was sufficient to block the effects of SPDEF on cell migration and invasion. We also show that stable forced expression of SPDEF results in increased expression of E-cadherin, whereas down-regulation of SPDEF decreased E cadherin expression. In addition, we demonstrate that SPDEF expression is not regulated by E-cadherin. Moreover, our chromatin immunoprecipitation and luciferase reporter assay revealed that SPDEF occupies E-cadherin promoter site and acts as a direct transcriptional inducer of E-cadherin in prostate cancer cells. Taken together, to the best of our knowledge, these studies are the first demonstrating requirement of SPDEF for expression of E-cadherin, an essential epithelial cell junction protein. Given that loss of E-cadherin is a central tenant in tumor metastasis, the results of our studies, by providing a new mechanism for regulation of E-cadherin expression, could have far reaching impact. PMID- 23449979 TI - The ubiquitin-fold modifier 1 (Ufm1) cascade of Caenorhabditis elegans. AB - Ufm1 (ubiquitin-fold modifier 1) is the most recently identified member of the ubiquitin-like protein family. We characterized the Ufm1 cascade of the model organism Caenorhabditis elegans in terms of function and analyzed interactions of the involved proteins in vitro and in vivo. Furthermore, we investigated the phenotypes of the deletion mutants uba5(ok3364) (activating enzyme of Ufm1) and ufc1(tm4888) (conjugating enzyme of Ufm1). The viable deletion mutants showed a decrease in reproduction, development, life span, and a reduced survival under heavy metal stress. However, an increased survival rate under pathogenic, oxidative, heat, and endoplasmic reticulum stress was observed. We propose that the Ufm1 cascade negatively regulates the IRE1-mediated unfolded protein response. PMID- 23449980 TI - Distinct roles of beta-arrestin 1 and beta-arrestin 2 in ORG27569-induced biased signaling and internalization of the cannabinoid receptor 1 (CB1). AB - The cannabinoid receptor 1 (CB1) is a G protein-coupled receptor primarily expressed in brain tissue that has been implicated in several disease states. CB1 allosteric compounds, such as ORG27569, offer enormous potential as drugs over orthosteric ligands, but their mechanistic, structural, and downstream effects upon receptor binding have not been established. Previously, we showed that ORG27569 enhances agonist binding affinity to CB1 but inhibits G protein dependent agonist signaling efficacy in HEK293 cells and rat brain expressing the CB1 receptor (Ahn, K. H., Mahmoud, M. M., and Kendall, D. A. (2012) J. Biol. Chem. 287, 12070-12082). Here, we identify the mediators of CB1 receptor internalization and ORG27569-induced G protein-independent signaling. Using siRNA technology, we elucidate an ORG27569-induced signaling mechanism for CB1 wherein beta-arrestin 1 mediates short term signaling to ERK1/2 with a peak at 5 min and other upstream kinase components including MEK1/2 and c-Src. Consistent with these findings, we demonstrate co-localization of CB1-GFP with red fluorescent protein-beta-arrestin 1 upon ORG27569 treatment using confocal microscopy. In contrast, we show the critical role of beta-arrestin 2 in CB1 receptor internalization upon treatment with CP55940 (agonist) or treatment with ORG27569. These results demonstrate for the first time the involvement of beta-arrestin in CB1-biased signaling by a CB1 allosteric modulator and also define the differential role of the two beta-arrestin isoforms in CB1 signaling and internalization. PMID- 23449981 TI - Ceramide phosphoethanolamine biosynthesis in Drosophila is mediated by a unique ethanolamine phosphotransferase in the Golgi lumen. AB - Sphingomyelin (SM) is a vital component of mammalian membranes, providing mechanical stability and a structural framework for plasma membrane organization. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase in the Golgi lumen. Drosophila lacks SM and instead synthesizes the SM analogue ceramide phosphoethanolamine (CPE) as the principal membrane sphingolipid. The corresponding CPE synthase shares mechanistic features with enzymes mediating phospholipid biosynthesis via the Kennedy pathway. Using a functional cloning strategy, we here identified a CDP-ethanolamine:ceramide ethanolamine phosphotransferase as the enzyme responsible for CPE production in Drosophila. CPE synthase constitutes a new branch within the CDP-alcohol phosphotransferase superfamily with homologues in Arthropoda (insects, spiders, mites, scorpions), Cnidaria (Hydra, sea anemones), and Mollusca (oysters) but not in most other animal phyla. The enzyme resides in the Golgi complex with its active site facing the lumen, contrary to the membrane topology of other CDP-alcohol phosphotransferases. Our findings open up an important new avenue to address the biological role of CPE, an enigmatic membrane constituent of a wide variety of invertebrate and marine organisms. PMID- 23449982 TI - Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. AB - G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84. These potential ligands and the surrogate agonist, 6-OAU, stimulated [(35)S]GTP binding and accumulated phosphoinositides in a GPR84-dependent manner. The surrogate agonist, 6-OAU, internalized GPR84-EGFP from the cell surface. Both the potential ligands and 6-OAU elicited chemotaxis of human polymorphonuclear leukocytes (PMNs) and macrophages and amplified LPS-stimulated production of the proinflammatory cytokine IL-8 from PMNs and TNFalpha from macrophages. Furthermore, the intravenous injection of 6-OAU raised the blood CXCL1 level in rats, and the inoculation of 6-OAU into the rat air pouch accumulated PMNs and macrophages in the site. Our results indicate a proinflammatory role of GPR84, suggesting that the receptor may be a novel target to treat chronic low grade inflammation associated-disease. PMID- 23449983 TI - An antedrug of the CXCL12 neutraligand blocks experimental allergic asthma without systemic effect in mice. AB - The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in normal tissue patterning but also in tumor cell growth and survival as well as in the recruitment of immune and inflammatory cells, as successfully demonstrated using agents that block either CXCL12 or CXCR4. In order to achieve selectivity in drug action on the CXCR4/CXCL12 pair, in particular in the airways, drugs should be delivered as selectively as possible in the treated tissue and should not diffuse in the systemic circulation, where it may reach undesired organs. To this end, we used a previously unexploited Knoevenagel reaction to create a short lived drug, or soft drug, based on the CXCL12-neutralizing small molecule, chalcone 4, which blocks binding of CXCL12 to CXCR4. We show that the compound, carbonitrile chalcone 4, blocks the recruitment of eosinophils to the airways in ovalbumin sensitized and challenged mice in vivo when administered directly to the airways by the intranasal route, but not when administered systemically by the intraperitoneal route. We show that the lack of effect at a distant site is due to the rapid degradation of the molecule to inactive fragments. This approach allows selective action of the CXCL12 neutraligands although the target protein is widely distributed in the organism. PMID- 23449985 TI - Rhabdomyosarcomatous differentiation in a spermatocytic seminoma with review of literature. AB - The sarcomatous differentiation occurring in spermatocytic seminoma (SS) renders an aggressive behavior with metastatic potential to this relatively indolent neoplasm. Correct identification of this sarcomatous component is essential as further management differs. Herein, we report a case of young male with SS with rapid increase in size of the tumor. Histopathology revealed a rhabdomyosarcomatous component infiltrating the rete-testis and epididymis along with a well-circumscribed SS. PMID- 23449984 TI - Human IL10 gene repression by Rev-erbalpha ameliorates Mycobacterium tuberculosis clearance. AB - Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erbalpha is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev erbalpha in monocytes and macrophages. The nuclear localization of Rev-erbalpha in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erbalpha elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erbalpha overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erbalpha binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erbalpha bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties. PMID- 23449986 TI - Potentials of exopolysaccharides from lactic Acid bacteria. AB - Recent research in the area of importance of microbes has revealed the immense industrial potential of exopolysaccharides and their derivative oligosaccharides from lactic acid bacteria. However, due to lack of adequate technological knowledge, the exopolysaccharides have remained largely under exploited. In the present review, the enormous potentials of different types of exopolysaccharides from lactic acid bacteria are described. This also summarizes the recent advances in the applications of exopolysaccharides, certain problems associated with their commercial production and the remedies. PMID- 23449987 TI - Anatomic variations of the marginal mandibular nerve. AB - Marginal Mandibular Nerve (MMN) is a branch of the facial nerve. Muscles supplied by this nerve are responsible for facial symmetry, facial expressions and phonation. Aim was to study the branching pattern and variations in the position of marginal mandibular nerve. 202 patients who underwent neck dissection from June 2005 to October 2006 at Regional Cancer Centre, Trivandrum, India were included in the study. During the course of neck dissection, the marginal mandibular nerve was first identified around the point where the facial artery crossed the lower border of the mandible. Once the nerve was identified, it was traced both backwards and forward till the whole nerve was exposed. Position of the nerve and its relation to lower border of mandible at the point where the facial artery crossed the lower border of the mandible was noted and number and position of each branches were recorded. In 161of the 202 patients (79.7%) the MMN had a single division. Two branches were noted in 26 patients (12.9%). Three branches for MMN are not uncommon, it was noted in 14 patients (6.9%) and in one patient there were four branches. Every effort should be made to preserve all the branches of MMN to ensure cosmesis and decrease morbidity. The mean distance from the lower border of the mandible to the point where the marginal mandibular nerve crossed the facial artery for all the branches taken together was 1.73 mm below the mandible. In 49 patients there was communication between MMN and the cervical branch of facial nerve. The point where the facial artery crosses the lower border of the mandible is a reliable landmark to locate the MMN. Variation in the branching pattern of marginal mandibular nerve is very common. PMID- 23449988 TI - Transient evoked and distortion product otoacoustic emission profile in patients of otosclerosis: a preliminary report. AB - The aim of this study was to investigate the profile of transient evoked and distortion product otoacoustic emissions in patients of otosclerosis and to assess any change in otoacoustic emission profile after surgical intervention. This prospective study under tertiary referral centre setting included 31 patients suffering from otosclerosis, who underwent surgical intervention in the form of stapedotomy. Air-bone gap on pure tone audiometry, pre-operative profile and postoperative profile of transient evoked and distortion product otoacoustic emissions at 1 month and 3 months were the main outcome measures of the subjects. The patients demonstrated subjective improvement in hearing and significant closure of air-bone gap on pure tone audiometry. There was statistically significant improvement in amplitudes of both transient-evoked and distortion product emissions in the low frequency range, after surgery. Cochran's Q test was applied to compare the statistical significances among preoperative values, 1 month values and 3 months values for the recorded otoacoustic emissions. It was observed that despite significant improvement in hearing, OAEs were not detected in all patients and correlation with behavioural thresholds was poor. As a result of these findings, the following conclusions can be drawn. The profile of otoacoustic emissions in patients of otosclerosis is variable and does not correlate with hearing thresholds. All patients showed improvement in amplitudes of OAEs after surgical intervention and there was further improvement between the followup profile at 1 month and 3 months, but this was not found to be statistically significant. However, further studies with larger number of patients of otosclerosis can perhaps establish baseline profile of the evoked OAEs and the effect of fixation of stapes on reverse transmission of OAEs. PMID- 23449989 TI - The effect of chronic tobacco smoking and chewing on the lipid profile. AB - BACKGROUND: A worldwide epidemic of cardio vascular diseases is evolving, out of which atherosclerosis appears to be the most frequent underlying cause. Cigarette smoking remains the most important cause of the preventable morbidity and the early mortality. Nicotine is highly addictive, it raises the brain levels of dopamine and it produces withdrawal symptoms on its discontinuation. AIM: To study the effect of tobacco smoking & chewing on serum lipid profile. METHODS: Although a genetic predis-position to atherosclerosis may be the cause, a vast majority of the atherosclerotic related diseases, which include coronary heart diseases, are acquired. Those which usually appear later in life are largely preventable. Tobacco is the major and the single most preventable risk factor for atherosclerotic related, clinical events like coronary heart disease. This study was conducted on three groups of male subjects, with each group containing 25 individuals of 25 to 35 years of age and who weighed 50-70 kgs.Group-I: non smokers and non chewers.Group-II: smokers and non chewersGroup-III: chewers and non smokers.To estimate the triglycerides, glycerol which is derived from the saponification of triglycerides is oxidized to formaldehyde, which in turn is made to react with ammonia and acetylacetone to give rise to a chromogen (3.5 diacetyle-1,4 dihydrolutidine). It is quantified spectro-photometrically (the HANTZSCH reaction). RESULTS: The mean serum total cholesterol level in the subjects of Group II was more by about 16.94 % (p< 0.001) and that in the subjects of Group -III was more by 23.21% (p< 0.001).The mean serum VLDL level in the subjects of Group II had an increase of about 27.54% (p< 0.01) and in Group III, it had increased by11.82% (p< 0.01).The mean serum LDL level in the subjects of Group II showed an increase of about 34.64% (p< 0.001) and in Group -III, it had increased by16.27% (p< 0.001).The mean serum HDL level in the subjects of Group II showed a decrease in the mean serum HDL level by about 9.78 % (p< 0.01) and in Group -III, it had decreased by 22.12% (p< 0.01).The mean serum Triglyceride level in the subjects of Group II showed an increase of about 25.40% (p< 0.001) and in Group -III, it was more by33.35% (p< 0.001). CONCLUSION: There was a significant increase in total cholesterol and LDL-C in tobacco users ,as compared to non tobacco users. PMID- 23449990 TI - Metastatic non-Hodgkin lymphoma presenting as low back pain and radiculopathy: a case report. AB - OBJECTIVE: The purpose of this case report is to describe a case of metastatic non-Hodgkin lymphoma in the lumbar spine presenting as lumbar radiculopathy. CLINICAL FEATURES: A 46-year-old man sought care from his doctor of chiropractic for low back pain and right leg radiculopathy. The patient was referred for a magnetic resonance imaging (MRI) scan to evaluate for a suspected disk herniation. The MRI scan revealed 2 lumbar pathologic compression fractures with cauda equina compression, and MRI short tau inversion recovery (STIR) sagittal image of the lumbar spine showed high signal in T12 and S2. INTERVENTION AND OUTCOME: The patient was referred for an immediate consultation with his medical physician with the preliminary diagnosis of metastatic bone lesions or primary bone lesions of unknown etiology. The patient underwent bone biopsy, computed tomography, and positron emission tomography scanning and was diagnosed with small cell non-Hodgkin lymphoma with osseous metastasis. The patient underwent chemo- and radiation therapy, and the lymphoma is now in remission 18 months later. CONCLUSION: This case describes the presentation of metastatic non-Hodgkin lymphoma as a possible contributing cause in a patient presenting with lumbar radiculopathy, a common musculoskeletal condition. As well, this case highlights the importance of STIR sequences as part of a routine lumbar spine MRI examination. Without the STIR sequences, the additional deposits in T12 and S1 would not have been readily appreciated. Although metastatic non-Hodgkin lymphoma of the spine is rare, it should be remembered in the differential diagnoses. PMID- 23449992 TI - The forked flap repair for hypospadias. AB - CONTEXT: Despite the abundance of techniques for the repair of Hypospadias, its problems still persist and a satisfactory design to correct the penile curvature with the formation of neourethra from the native urethral tissue or genital or extragenital tissues, with minimal postoperative complications has yet to evolve. AIM: Persisting with such an endeavor, a new technique for the repair of distal and midpenile hypospadias is described. MATERIALS AND METHODS: The study has been done in 70 cases over the past 11 years. The "Forked-Flap" repair is a single stage method for the repair of such Hypospadias with chordee. It takes advantage of the rich vascular communication at the corona and capitalizes on the established reliability of the meatal based flip-flap. The repair achieves straightening of the curvature of the penis by complete excision of chordee tissue from the ventral surface of the penis beneath the urethral plate. The urethra is reconstructed using the native plate with forked flap extensions and genital tissue relying on the concept of meatal based flaps. Water proofing by dartos tissue and reinforcement by Nesbit's prepucial tissue transfer completes the one stage procedure. STATISTICAL ANALYSIS: An analysis of 70 cases of this single stage technique of repair of penile hypospadias with chordee, operated at 3 to 5 years of age over the past 11 years is presented. RESULTS AND CONCLUSION: The Forked Flap gives comparable and replicable results; except for a urethrocutaneous fistula rate of 4% no other complications were observed. PMID- 23449993 TI - Rehabilitation of a patient with an intra oral prosthesis and an extra oral orbital prosthesis retained with magnets. AB - This clinical case report deals with a rehabilitation of a patient with an extensive maxillary and orbital defect using an intra oral prosthesis obturating the maxillary defect and extra oral orbital prosthesis retained with rare-earth magnets for secondary retention; primary retention was derived by snug fit of the prosthesis to underlying and adjacent tissues. The rehabilitation resulted in improved function, esthetics and comfort to the patient thus enabling him to lead a normal life. PMID- 23449991 TI - The genetic architecture of degenerin/epithelial sodium channels in Drosophila. AB - Degenerin/epithelial sodium channels (DEG/ENaC) represent a large family of animal-specific membrane proteins. Although the physiological functions of most family members are not known, some have been shown to act as nonvoltage gated, amiloride-sensitive sodium channels. The DEG/ENaC family is exceptionally large in genomes of Drosophila species relative to vertebrates and other insects. To elucidate the evolutionary history of the DEG/ENaC family in Drosophila, we took advantage of the genomic and genetic information available for 12 Drosophila species that represent all the major species groups in the Drosophila clade. We have identified 31 family members (termed pickpocket genes) in Drosophila melanogaster, which can be divided into six subfamilies, which are represented in all 12 species. Structure prediction analyses suggested that some subunits evolved unique structural features in the large extracellular domain, possibly supporting mechanosensory functions. This finding is further supported by experimental data that show that both ppk1 and ppk26 are expressed in multidendritic neurons, which can sense mechanical nociceptive stimuli in larvae. We also identified representative genes from five of the six DEG/ENaC subfamilies in a mosquito genome, suggesting that the core DEG/ENaC subfamilies were already present early in the dipteran radiation. Spatial and temporal analyses of expression patterns of the various pickpocket genes indicated that paralogous genes often show very different expression patterns, possibly indicating that gene duplication events have led to new physiological or cellular functions rather than redundancy. In summary, our analyses support a rapid early diversification of the DEG/ENaC family in Diptera followed by physiological and/or cellular specialization. Some members of the family may have diversified to support the physiological functions of a yet unknown class of ligands. PMID- 23449994 TI - In search of a common agenda for planned home birth in america. AB - Leading maternity provider organizations in North America have been in conflict about birth at home and birth centers, debating issues related to safety, access, the value of obstetric intervention, and patient autonomy. In today's environment, childbirth educators and doulas are often required to explain to parents why physiological birth and evidence-based, low-technology methods of labor and birth care are not available in every setting, and why maternity providers disagree about birth place. There are very few regions in the United States where home birth providers are integrated into interprofessional provider networks that allow for seamless care across birth settings. In October 2011, multidisciplinary leaders met at a Home Birth Consensus Summit in Warrenton, Virginia, to discuss the status of home birth within the greater context of maternity care in the United States. This article describes the intent and outcomes of the summit. Four of the nine consensus statements developed at the summit are of particular interest and importance to mothers and families and, hence, to childbirth educators and advocates. Consumers, educators, and birth advocates are encouraged to widen the circle, identify communications experts, lead individual projects, or serve as advisors. PMID- 23449995 TI - Ecology. The global plight of pollinators. PMID- 23449996 TI - Dust and biological aerosols from the Sahara and Asia influence precipitation in the western U.S. AB - Winter storms in California's Sierra Nevada increase seasonal snowpack and provide critical water resources and hydropower for the state. Thus, the mechanisms influencing precipitation in this region have been the subject of research for decades. Previous studies suggest Asian dust enhances cloud ice and precipitation, whereas few studies consider biological aerosols as an important global source of ice nuclei (IN). Here, we show that dust and biological aerosols transported from as far as the Sahara were present in glaciated high-altitude clouds coincident with elevated IN concentrations and ice-induced precipitation. This study presents the first direct cloud and precipitation measurements showing that Saharan and Asian dust and biological aerosols probably serve as IN and play an important role in orographic precipitation processes over the western United States. PMID- 23449997 TI - Wild pollinators enhance fruit set of crops regardless of honey bee abundance. AB - The diversity and abundance of wild insect pollinators have declined in many agricultural landscapes. Whether such declines reduce crop yields, or are mitigated by managed pollinators such as honey bees, is unclear. We found universally positive associations of fruit set with flower visitation by wild insects in 41 crop systems worldwide. In contrast, fruit set increased significantly with flower visitation by honey bees in only 14% of the systems surveyed. Overall, wild insects pollinated crops more effectively; an increase in wild insect visitation enhanced fruit set by twice as much as an equivalent increase in honey bee visitation. Visitation by wild insects and honey bees promoted fruit set independently, so pollination by managed honey bees supplemented, rather than substituted for, pollination by wild insects. Our results suggest that new practices for integrated management of both honey bees and diverse wild insect assemblages will enhance global crop yields. PMID- 23449999 TI - Plant-pollinator interactions over 120 years: loss of species, co-occurrence, and function. AB - Using historic data sets, we quantified the degree to which global change over 120 years disrupted plant-pollinator interactions in a temperate forest understory community in Illinois, USA. We found degradation of interaction network structure and function and extirpation of 50% of bee species. Network changes can be attributed to shifts in forb and bee phenologies resulting in temporal mismatches, nonrandom species extinctions, and loss of spatial co occurrences between extant species in modified landscapes. Quantity and quality of pollination services have declined through time. The historic network showed flexibility in response to disturbance; however, our data suggest that networks will be less resilient to future changes. PMID- 23450000 TI - A long-lived relativistic electron storage ring embedded in Earth's outer Van Allen belt. AB - Since their discovery more than 50 years ago, Earth's Van Allen radiation belts have been considered to consist of two distinct zones of trapped, highly energetic charged particles. The outer zone is composed predominantly of megaelectron volt (MeV) electrons that wax and wane in intensity on time scales ranging from hours to days, depending primarily on external forcing by the solar wind. The spatially separated inner zone is composed of commingled high-energy electrons and very energetic positive ions (mostly protons), the latter being stable in intensity levels over years to decades. In situ energy-specific and temporally resolved spacecraft observations reveal an isolated third ring, or torus, of high-energy (>2 MeV) electrons that formed on 2 September 2012 and persisted largely unchanged in the geocentric radial range of 3.0 to ~3.5 Earth radii for more than 4 weeks before being disrupted (and virtually annihilated) by a powerful interplanetary shock wave passage. PMID- 23449998 TI - Type I interferon suppresses type II interferon-triggered human anti mycobacterial responses. AB - Type I interferons (IFN-alpha and IFN-beta) are important for protection against many viral infections, whereas type II interferon (IFN-gamma) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-beta and IFN-gamma gene expression programs. IFN-gamma and its downstream vitamin D dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-beta and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-gamma-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-beta and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections. PMID- 23450001 TI - Complete genome sequence of the plant-associated Serratia plymuthica strain AS13. AB - Serratia plymuthica AS13 is a plant-associated Gammaproteobacteria, isolated from rapeseed roots. It is of special interest because of its ability to inhibit fungal pathogens of rapeseed and to promote plant growth. The complete genome of S. plymuthica AS13 consists of a 5,442,549 bp circular chromosome. The chromosome contains 4,951 protein-coding genes, 87 tRNA genes and 7 rRNA operons. This genome was sequenced as part of the project entitled "Genomics of four rapeseed plant growth promoting bacteria with antagonistic effect on plant pathogens" within the 2010 DOE-JGI Community Sequencing Program (CSP2010). PMID- 23450002 TI - Exploring modality switching effects in negated sentences: further evidence for grounded representations. AB - Theories of embodied cognition (e.g., Perceptual Symbol Systems Theory; Barsalou, 1999, 2009) suggest that modality specific simulations underlie the representation of concepts. Supporting evidence comes from modality switch costs: participants are slower to verify a property in one modality (e.g., auditory, BLENDER-loud) after verifying a property in a different modality (e.g., gustatory, CRANBERRIES-tart) compared to the same modality (e.g., LEAVES rustling, Pecher et al., 2003). Similarly, modality switching costs lead to a modulation of the N400 effect in event-related potentials (ERPs; Collins et al., 2011; Hald et al., 2011). This effect of modality switching has also been shown to interact with the veracity of the sentence (Hald et al., 2011). The current ERP study further explores the role of modality match/mismatch on the processing of veracity as well as negation (sentences containing "not"). Our results indicate a modulation in the ERP based on modality and veracity, plus an interaction. The evidence supports the idea that modality specific simulations occur during language processing, and furthermore suggest that these simulations alter the processing of negation. PMID- 23450003 TI - Comparison of fentanyl and clonidine for attenuation of the haemodynamic response to laryngocopy and endotracheal intubation. AB - INTRODUCTION: Laryngoscopy and tracheal intubation after the induction of anaesthesia, are nearly always associated with sympathetic hyperactivity. To 'blunt' this pressor response, various methods have been tried, but very few studies have been done to assess the effects of fentanyl orI.V. clonidine on the haemodynamic response during laryngoscopy and tracheal intubation. The purpose of this study was to compare these agents, to find the drug which was best suited for this purpose and the most favourable time for its administration. METHODS: This was a prospective study which involved 3 groups of patients. The patients in group-1 (control) were given normal saline and the groups 2 and 3 were given i.v. fentanyl and clonidine respectively. Each group had 50 patients who presented for elective, non-cardiovascular surgeries. All the patients were ASA-1 or ASA-II and were operated in PESIMSR, Kuppam. RESULTS: The heart rate rise was 48.07% in the control group, whereas it was significantly lower in the fentanyl (II) 27.75% and the clonidine groups (III) 12.57% (p<0.001). In the control group, the systolic blood pressure increased maximally after 5 minutes (42.62%) i.e., immediately after the laryngoscopy and the intubation. It decreased gradually over 10 minutes (17.39%). With the administration of fentanyl, the maximum increase as compared to the preinduction value was 9.91%, but it was only 7.38% in the clonidine group. Both, when they were compared with the control, showed a significant suppression (P<.001), with clonidine showing better results. The maximum increase in the diastolic blood pressure was 30.12% in the control group (P<.001) at 5 min and it was 18.22%, and 6.15% in the fentanyl and the clonidine groups respectively, with clonidine faring better again (P<.001). INTERPRETATION AND CONCLUSION: Clonidine showed better attenuation of the sympathetic response, which is statistically highly significant and it remained so till the end of 10 minutes. Intravenous clonidine 2;g/kg which is administered 5 minutes before the laryngoscopy can be recommended to attenuate the sympathetic response to the laryngoscopy and the intubation. PMID- 23450004 TI - The role of local excision in invasive adenocarcinoma of the ampulla of Vater. AB - BACKGROUND: Ampulla of Vater carcinomas are rare malignancies that have been traditionally treated with radical surgical resection. Given the mortality associated with pancreaticoduodenectomy, some patients may benefit from local resection. A single-institution outcomes analysis was performed to define the role of local resection. METHODS: Patients undergoing local resection (ampullectomy) for ampullary carcinomas at Duke University between 1976 and 2010 were analyzed retrospectively. Time-to-event analysis was conducted analyzing all patients undergoing surgery, with and without adjuvant chemoradiation therapy (CRT). Overall survival (OS), local control (LC), metastases-free survival (MFS), and disease-free survival (DFS) were studied using Kaplan-Meier analysis. RESULTS: A total of 17 patients with invasive carcinoma underwent ampullectomy. The 3-and 5-year LC, MFS, DFS and OS rates were 36% and 24%, 68% and 54%, 31% and 21%, and 35% and 21%, respectively. Patients receiving adjuvant CRT did not appear to have improved outcomes compared with surgery alone, although this group tended to have poorer histological grade, more advanced tumor staging and involved surgical margins. CONCLUSIONS: Ampullectomy for invasive ampullary adenocarcinomas is a safe procedure but does not offer satisfactory long-term results, mostly due to high local failure rates. Adjuvant CRT therapy does not appear to offer increased local control or survival benefit following ampullectomy, although these results may suffer from selection bias and small sample size. Local resection should be limited to benign ampullary lesions or patients with very small, early tumors with favorable histologic features where radical resection is not feasible. PMID- 23450005 TI - Foreign minds, fenceless imagination: the 2013 Vilcek Foundation Prizes. PMID- 23450006 TI - Characterization and rescue of telomeric abnormalities in ICF syndrome type I fibroblasts. AB - Mutations in the human DNA methyltransferase 3B (DNMT3B) gene lead to ICF (immunodeficiency, centromeric region instability, and facial anomalies) syndrome type I. We have previously described a telomere-related phenotype in cells from these patients, involving severe hypomethylation of subtelomeric regions, abnormally short telomeres and high levels of telomeric-repeat-containing RNA (TERRA). Here we demonstrate that ICF-patient fibroblasts carry abnormally short telomeres at a low population doubling (PD) and enter senescence prematurely. Accordingly, we attempted to rescue the senescence phenotype by ectopic expression of human telomerase, which led to elongated telomeres with hypomethylated subtelomeres. The senescence phenotype was overcome under these conditions, thus dissociating subtelomeric-DNA hypomethylation per se from the senescence phenotype. In addition, we examined whether the subtelomeric methylation could be restored by expression of a normal copy of full length DNMT3B1 in ICF fibroblasts. Ectopic expression of DNMT3B1 failed to rescue the abnormal hypomethylation at subtelomeres. However, partial rescue of subtelomeric hypomethylation was achieved by co-expression of DNMT3B1 together with DNA methyltransferase 3-like (DNMT3L), encoding a protein that functions as a stimulator of DNMT3A and DNMT3B. DNMT3B1 and DNMT3L are predominantly expressed during early embryonic development, suggesting that de novo subtelomeric DNA methylation during crucial stages of human embryonic development may be necessary for setting and maintaining normal telomere length. PMID- 23450008 TI - The skill of the primary rewriter. PMID- 23450007 TI - Maternal age and birth defects after the use of assisted reproductive technology in Japan, 2004-2010. AB - BACKGROUND: Older mothers are becoming more common in Japan. One reason for this is the widespread use of assisted reproductive technology (ART). This study assesses the relationship between maternal age and the risk of birth defects after ART. METHODS: Nationwide data on ART between 2004 and 2010 in Japan were analyzed. Diseases that were classified as code Q00-Q99 (ie, congenital malformations, deformations, and chromosomal abnormalities) in the International Classification of Diseases, tenth edition, were selected. There were 219,185 pregnancies and 153,791 live births in total ART. Of these, 1943 abortions, stillbirths, or live births with birth defects were recorded. Percentage of multiple birth defects in total birth defects, the prevalence, crude relative risk and 95% confidence interval per 10,000 pregnancies and per 10,000 live births were analyzed according to the maternal age class (ie, 25-29, 30-34 (reference), 35-39, and 40+ years). RESULTS: Multiple birth defects were observed among 14% of the 25-29 year old class, and 8% among other classes when chromosomal abnormalities were excluded. The prevalence of chromosomal abnormalities per pregnancy and per live birth became significantly and rapidly higher in mothers in the age classes of 30-35 and 40+ years. Nonchromosomal birth defects per pregnancy decreased linearly with advanced maternal age, while the number of nonchromosomal birth defects per live birth formed a gradual U-shaped distribution. The prevalence per pregnancy of congenital malformations of the nervous system was significantly lower with advanced maternal age. The relative risk per live birth was significant regarding congenital malformations of the circulatory system for a maternal age of 40+ years. Some other significant associations between maternal age and birth defects were observed. CONCLUSION: Maternal age is associated with several birth defects; however, older maternal age in itself does not produce noticeable extra risk for nonchromosomal birth defects overall. PMID- 23450009 TI - "When can I return to driving?": a review of the current literature on returning to driving after lower limb injury or arthroplasty. AB - Clinicians are often asked by patients, "When can I drive again?" after lower limb injury or surgery. This question is difficult to answer in the absence of any guidelines. This review aims to collate the currently available evidence and discuss the factors that influence the decision to allow a patient to return to driving. Medline, Web of Science, Scopus, and EMBASE were searched using the following terms: 'brake reaction time', 'brake response time', 'braking force', 'brake pedal force', 'resume driving', 'rate of application of force', 'driving after injury', 'joint replacement and driving', and 'fracture and driving'. Of the relevant literature identified, most studies used the brake reaction time and total brake time as the outcome measures. Varying recovery periods were proposed based on the type and severity of injury or surgery. Surveys of the Driver and Vehicle Licensing Agency, the Police, insurance companies in the United Kingdom and Orthopaedic Surgeons offered a variety of opinions. There is currently insufficient evidence for any authoritative body to determine fitness to drive. The lack of guidance could result in patients being withheld from driving for longer than is necessary, or returning to driving while still unsafe. PMID- 23450010 TI - Cementing techniques for the tibial component in primary total knee replacement. AB - The optimum cementing technique for the tibial component in cemented primary total knee replacement (TKR) remains controversial. The technique of cementing, the volume of cement and the penetration are largely dependent on the operator, and hence large variations can occur. Clinical, experimental and computational studies have been performed, with conflicting results. Early implant migration is an indication of loosening. Aseptic loosening is the most common cause of failure in primary TKR and is the product of several factors. Sufficient penetration of cement has been shown to increase implant stability. This review discusses the relevant literature regarding all aspects of the cementing of the tibial component at primary TKR. PMID- 23450011 TI - Focal femoral condyle resurfacing. AB - Focal femoral inlay resurfacing has been developed for the treatment of full thickness chondral defects of the knee. This technique involves implanting a defect-sized metallic or ceramic cap that is anchored to the subchondral bone through a screw or pin. The use of these experimental caps has been advocated in middle-aged patients who have failed non-operative methods or biological repair techniques and are deemed unsuitable for conventional arthroplasty because of their age. This paper outlines the implant design, surgical technique and biomechanical principles underlying their use. Outcomes following implantation in both animal and human studies are also reviewed. PMID- 23450012 TI - Pathology of the tendo Achillis: do our genes contribute? AB - The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals' tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases. This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry. PMID- 23450013 TI - The three-dimensional relationship between acetabular rim morphology and the severity of femoral cam lesions. AB - We examined the relationship between the size of the femoral cam in femoroacetabular impingement (FAI) and acetabular pathomorphology to establish if pincer impingement exists in patients with a femoral cam. CT scans of 37 symptomatic impinging hips with a femoral cam were analysed in a three dimensional study and were compared with 34 normal hips. The inclination and version of the acetabulum as well as the acetabular rim angle and the bony acetabular coverage were calculated. These measurements were correlated with the size and shape of the femoral cams. While the size of the femoral cam varied characteristically, the acetabular morphology of the two groups was similar in terms of version (normal mean 23 degrees (sd 7 degrees ); cam mean 22 degrees (sd 9 degrees )), inclination (normal mean 57 degrees (sd 5 degrees ); cam mean 56 degrees (sd 5 degrees )), acetabular coverage (normal mean 41% (sd 5%); cam mean 42% (sd 4%)) and the mean acetabular rim angle (normal mean 82 degrees (sd 5 degrees ); cam mean 83 degrees (sd 4 degrees )). We found no correlation between acetabular morphology and the severity of cam lesion and no evidence of either global or focal over-coverage to support the diagnosis of 'mixed' FAI. The femoral cam may provoke edge loading but removal of any acetabular bearing surface when treating cam FAI might induce accelerated wear. PMID- 23450014 TI - The effect of alcohol intake and the use of oral corticosteroids on the risk of idiopathic osteonecrosis of the femoral head: a case-control study in Japan. AB - The systemic use of steroids and habitual alcohol intake are two major causative factors in the development of idiopathic osteonecrosis of the femoral head (ONFH). To examine any interaction between oral corticosteroid use and alcohol intake on the risk of ONFH, we conducted a hospital-based case-control study of 71 cases with ONFH (mean age 45 years (20 to 79)) and 227 matched controls (mean age 47 years (18 to 79)). Alcohol intake was positively associated with ONFH among all subjects: the adjusted odds ratio (OR) of subjects with >= 3032 drink years was 3.93 (95% confidence interval (CI) 1.18 to 13.1) compared with never drinkers. When stratified by steroid use, the OR of such drinkers was 11.1 (95% CI 1.30 to 95.5) among those who had never used steroids, but 1.10 (95% CI 0.21 to 4.79) among those who had. When we assessed any interaction based on a two-by two table of alcohol and steroid use, the OR of those non-drinkers who did use steroids was markedly elevated (OR 31.5) compared with users of neither. However, no further increase in OR was noted for the effect of using both (OR 31.6). We detected neither a multiplicative nor an additive interaction (p for multiplicative interaction 0.19; synergy index 0.95), suggesting that the added effect of alcohol may be trivial compared with the overwhelming effect of steroids in the development of ONFH. PMID- 23450015 TI - New polyethylenes in total hip replacement: A ten- to 12-year follow-up study. AB - Between 1999 and 2001, 90 patients underwent total hip replacement using the same uncemented acetabular and femoral components with a 28 mm metallic femoral head but with prospective randomisation of the acetabular liner to either Durasul highly cross-linked polyethylene or nitrogen-sterilised Sulene polyethylene. We assessed 83 patients at a minimum follow-up of ten years. Linear penetration of the femoral head was estimated at six weeks, six and 12 months and annually thereafter, using the Dorr method, given the non-spherical shape of the acetabular component. There was no loosening of any component; only one hip in the Sulene group showed proximal femoral osteolysis. The mean penetration of the femoral head at six weeks was 0.08 mm (0.02 to 0.15) for the Durasul group and 0.16 mm (0.05 to 0.28) for the Sulene group (p = 0.001). The mean yearly linear penetration was 64.8% lower for the Durasul group at 0.05 mm/year (sd 0.035) for the Sulene group and 0.02 mm/year (sd 0.016) for the Durasul (p < 0.001). Mean linear femoral head penetration at ten years was 61% less in the Durasul than Sulene group. Highly cross-linked polyethylene gives excellent results at ten years. PMID- 23450016 TI - The use of ceramic-on-ceramic bearings in isolated revision of the acetabular component. AB - The practice of removing a well-fixed cementless femoral component is associated with high morbidity. Ceramic bearing couples are low wearing and their use minimises the risk of subsequent further revision due to the production of wear debris. A total of 165 revision hip replacements were performed, in which a polyethylene-lined acetabular component was revised to a new acetabular component with a ceramic liner, while retaining the well-fixed femoral component. A titanium sleeve was placed over the used femoral trunnion, to which a ceramic head was added. There were 100 alumina and 65 Delta bearing couples inserted. The mean Harris hip score improved significantly from 71.3 (9.0 to 100.0) pre operatively to 91.0 (41.0 to 100.0) at a mean follow up of 4.8 years (2.1 to 12.5) (p < 0.001). No patients reported squeaking of the hip. There were two fractures of the ceramic head, both in alumina bearings. No liners were seen to fracture. No fractures were observed in components made of Delta ceramic. At 8.3 years post-operatively the survival with any cause of failure as the endpoint was 96.6% (95% confidence interval (CI) 85.7 to 99.3) for the acetabular component and 94.0% (95% CI 82.1 to 98.4) for the femoral component. The technique of revising the acetabular component in the presence of a well-fixed femoral component with a ceramic head placed on a titanium sleeve over the used trunnion is a useful adjunct in revision hip practice. The use of Delta ceramic is recommended. PMID- 23450017 TI - The effects of age and gender on the diameter of the femoral canal in patients who undergo total hip replacement. AB - With greater numbers of younger patients undergoing total hip replacement (THR), the effect of patient age on the diameter of the femoral canal may become more relevant. This study aimed to investigate the relationship between the diameter of the diaphysis of the femoral canal with increasing age in a large number of patients who underwent THR. A total of 1685 patients scheduled for THR had their femoral dimensions recorded from calibrated radiographs. There were 736 males and 949 females with mean ages of 67.1 years (34 to 92) and 70.2 years (29 to 92), respectively. The mean diameter of the femoral canal was 13.3 mm (8.0 to 23.0) for males and 12.7 mm (6.0 to 26.0) for females. There was a poor correlation between age and the diameter of the canal in males (r = 0.071, p = 0.05) but a stronger correlation in females (r = 0.31, p < 0.001). The diameter of the femoral canal diameter of a female patient undergoing THR could be predicted to increase by 3.2 mm between the ages of 40 and 80 years, in contrast a male would be expected to experience only a 0.6 mm increase during the same period. This increase in the diameter of the canal with age might affect the long-term survival of the femoral component in female patients. PMID- 23450018 TI - Management of abductor mechanism deficiency following total hip replacement. AB - Deficiency of the abductor mechanism is a well-recognised cause of pain and limping after total hip replacement (THR). This can be found incidentally at the time of surgery, or it may arise as a result of damage to the superior gluteal nerve intra-operatively, or after surgery owing to mechanical failure of the abductor muscle repair or its detachment from the greater trochanter. The incidence of abductor failure has been reported as high as 20% in some studies. The management of this condition remains a dilemma for the treating surgeon. We review the current state of knowledge concerning post-THR abductor deficiency, including the aetiology, diagnosis and management, and the outcomes of surgery for this condition. PMID- 23450019 TI - The effect of osteoarthritis of the knee on the biomechanics of other joints in the lower limbs. AB - The aim of this study was to examine the loading of the other joints of the lower limb in patients with unilateral osteoarthritis (OA) of the knee. We recruited 20 patients with no other symptoms or deformity in the lower limbs from a consecutive cohort of patients awaiting knee replacement. Gait analysis and electromyographic recordings were performed to determine moments at both knees and hips, and contraction patterns in the medial and lateral quadriceps and hamstrings bilaterally. The speed of gait was reduced in the group with OA compared with the controls, but there were only minor differences in stance times between the limbs. Patients with OA of the knee had significant increases in adduction moment impulse at both knees and the contralateral hip (adjusted p values: affected knee: p < 0.01, unaffected knee p = 0.048, contralateral hip p = 0.03), and significantly increased muscular co-contraction bilaterally compared with controls (all comparisons for co-contraction, p < 0.01). The other major weight-bearing joints are at risk from abnormal biomechanics in patients with unilateral OA of the knee. PMID- 23450020 TI - A prospective randomised controlled study of patient-specific cutting guides compared with conventional instrumentation in total knee replacement. AB - Patient-specific cutting guides (PSCGs) are designed to improve the accuracy of alignment of total knee replacement (TKR). We compared the accuracy of limb alignment and component positioning after TKR performed using PSCGs or conventional instrumentation. A total of 80 patients were randomised to undergo TKR with either of the different forms of instrumentation, and radiological outcomes and peri-operative factors such as operating time were assessed. No significant difference was observed between the groups in terms of tibiofemoral angle or femoral component alignment. Although the tibial component in the PSCGs group was measurably closer to neutral alignment than in the conventional group, the size of the difference was very small (89.8 degrees (sd 1.2) vs 90.5 degrees (sd 1.6); p = 0.030). This new technology slightly shortened the bone-cutting time by a mean of 3.6 minutes (p < 0.001) and the operating time by a mean 5.1 minutes (p = 0.019), without tangible differences in post-operative blood loss (p = 0.528) or need for blood transfusion (p = 0.789). This study demonstrated that both PSCGs and conventional instrumentation restore limb alignment and place the components with the similar accuracy. The minimal advantages of PSCGs in terms of consistency of alignment or operative time are unlikely to be clinically relevant. PMID- 23450021 TI - Primary total knee replacement in patients with mental disability improves their mental health and knee function: a prospective study. AB - We assessed the effect of mental disability on the outcome of total knee replacement (TKR) and investigated whether mental health improves post operatively. Outcome data were prospectively recorded over a three-year period for 962 patients undergoing primary TKR for osteoarthritis. Pre-operative and one year Short-Form (SF)-12 scores and Oxford knee scores (OKS) were obtained. The mental component of the SF-12 was stratified into four groups according to level of mental disability (none >= 50, mild 40 to 49, moderate 30 to 39, severe < 30). Patients with any degree of mental disability had a significantly greater subjective physical disability according to the SF-12 (p = 0.06) and OKS (p < 0.001). The improvement in the disease-specific score (OKS) was not affected by a patient's mental health (p = 0.33). In contrast, patients with mental disability had less of an improvement in their global physical health (SF-12) (p < 0.001). However, patients with any degree of mental disability had a significant improvement in their mental health post-operatively (p < 0.001). Despite a similar improvement in their disease-specific scores and improvement in their mental health, patients with mental disability were significantly more likely to be dissatisfied with their TKR at one year (p = 0.001). Patients with poor mental health do benefit from improvements in their mental health and knee function after TKR, but also have a higher rate of dissatisfaction. PMID- 23450022 TI - Does pre-coating total knee tibial implants affect the risk of aseptic revision? AB - We evaluated the impact of pre-coating the tibial component with polymethylmethacrylate (PMMA) on implant survival in a cohort of 16 548 primary NexGen total knee replacements (TKRs) in 14 113 patients. In 13 835 TKRs a pre coated tray was used while in 2713 TKRs the non-pre-coated version of the same tray was used. All the TKRs were performed between 2001 and 2009 and were cemented. TKRs implanted with a pre-coated tibial component had a lower cumulative survival than those with a non-pre-coated tibial component (p = 0.01). After adjusting for diagnosis, age, gender, body mass index, American Society of Anesthesiologists grade, femoral coupling design, surgeon volume and hospital volume, pre-coating was an independent risk factor for all-cause aseptic revision (hazard ratio 2.75, p = 0.006). Revision for aseptic loosening was uncommon for both pre-coated and non-pre-coated trays (rates of 0.12% and 0%, respectively). Pre-coating with PMMA does not appear to be protective of revision for this tibial tray design at short-term follow-up. PMID- 23450023 TI - Outcome of arthrodesis of the hindfoot as a salvage procedure for complex ankle pathology using the Ilizarov technique. AB - Achieving arthrodesis of the ankle can be difficult in the presence of infection, deformity, poor soft tissues and bone loss. We present a series of 48 patients with complex ankle pathology, treated with the Ilizarov technique. Infection was present in 30 patients and 30 had significant deformity before surgery. Outcome was assessed clinically and with patient-reported outcome measures (Modified American Orthopaedic Foot and Ankle Society (MAOFAS) scale and the Short-Form (SF 36)). Arthrodesis was achieved in 40 patients with the Ilizarov technique alone and in six further patients with additional surgery. Infection was eradicated in all patients at a mean follow-up of 46.6 months (13 to 162). Successful arthrodesis was less likely in those with comorbidities and in tibiocalcaneal fusion compared with tibiotalar fusion. These patients had poor general health scores compared with the normal population before surgery. The mean MAOFAS score improved significantly from 24.3 (0 to 90) pre-operatively to 56.2 (30 to 90) post-operatively, but there was only a modest improvement in general health; the mean SF-36 improved from 44.8 (19 to 66) to 50.1 (21 to 76). There was a major benefit in terms of pain relief. Arthrodesis using the Ilizarov technique is an effective treatment for complex ankle pathology, with good clinical outcomes and eradication of infection. However, even after successful arthrodesis general health scores remain limited. PMID- 23450024 TI - Residual pain due to soft-tissue impingement after uncomplicated total ankle replacement. AB - We report the incidence and intensity of persistent pain in patients with an otherwise uncomplicated total ankle replacement (TAR). Arthroscopic debridement was performed in selected cases and the clinical outcome was analysed. Among 120 uncomplicated TARs, there was persistent pain with a mean visual analogue scale (VAS) of 2.7 (0 to 8). The intensity of pain decreased in 115 ankles (95.8%). Exercise or walking for more than 30 minutes was the most common aggravating factor (62 ankles, 68.1%). The character of the pain was most commonly described as dull (50 ankles, 54.9%) and located on the medial aspect of the joint (43 ankles, 47.3%). A total of seven ankles (5.8%) underwent subsequent arthroscopy. These patients had local symptoms and a VAS for pain >= 7 on exertion. Impingement with fibrosis and synovitis was confirmed. After debridement, the median VAS decreased from 7 to 3 and six patients were satisfied. The median VAS for pain and the American Orthopaedic Foot and Ankle Society score of the ankles after debridement was similar to that of the uncomplicated TARs (p = 0.496 and p = 0.066, respectively). Although TAR reduces the intensity of pain, residual pain is not infrequent even in otherwise uncomplicated TARs and soft-tissue impingement is the possible cause. PMID- 23450025 TI - Diffuse pigmented villonodular synovitis (diffuse-type giant cell tumour) of the foot and ankle. AB - Pigmented villonodular synovitis (PVNS) is a rare benign disease of the synovium of joints and tendon sheaths, which may be locally aggressive. We present 18 patients with diffuse-type PVNS of the foot and ankle followed for a mean of 5.1 years (2 to 11.8). There were seven men and 11 women, with a mean age of 42 years (18 to 73). A total of 13 patients underwent open or arthroscopic synovectomy, without post-operative radiotherapy. One had surgery at the referring unit before presentation with residual tibiotalar PVNS. The four patients who were managed non-operatively remain symptomatically controlled and under clinical and radiological surveillance. At final follow-up the mean Musculoskeletal Tumour Society score was 93.8% (95% confidence interval (CI) 85 to 100), the mean Toronto Extremity Salvage Score was 92 (95% CI 82 to 100) and the mean American Academy of Orthopaedic Surgeons foot and ankle score was 89 (95% CI 79 to 100). The lesion in the patient with residual PVNS resolved radiologically without further intervention six years after surgery. Targeted synovectomy without adjuvant radiotherapy can result in excellent outcomes, without recurrence. Asymptomatic patients can be successfully managed non-operatively. This is the first series to report clinical outcome scores for patients with diffuse-type PVNS of the foot and ankle. PMID- 23450026 TI - Single-stage revision for peri-prosthetic shoulder infection: outcomes and results. AB - There have been only a few small studies of patients with an infected shoulder replacement treated with a single-stage exchange procedure. We retrospectively reviewed 35 patients (19 men and 16 women) with a peri-prosthetic infection of the shoulder who were treated in this way. A total of 26 were available for clinical examination; three had died, two were lost to follow-up and four patients had undergone revision surgery. The mean follow-up time was 4.7 years (1.1 to 13.25), with an infection-free survival of 94%. The organisms most commonly isolated intra-operatively were Staphylococcus epidermidis and Propionibacterium acnes; two patients developed a recurrent infection. Three different types of prosthesis were used: a hemiarthroplasty, a hemiarthroplasty with a bipolar head and reverse prosthesis. The mean Constant-Murley score at final follow-up was 43.3 (14 to 90) for patients with a hemiarthroplasty, 56 (40 to 88) for those with a hemiarthroplasty with a bipolar head and 61 (7 to 90) for those with a reverse prosthesis. The mean hospital stay was 10.6 days (5 to 29). Single-stage exchange is a successful and practical treatment for patients with peri-prosthetic infection of the shoulder. PMID- 23450027 TI - Factors affecting late displacement following volar locking plate fixation for distal radial fractures in elderly female patients. AB - The purpose of this study was to evaluate the risk of late displacement after the treatment of distal radial fractures with a locking volar plate, and to investigate the clinical and radiological factors that might correlate with re displacement. From March 2007 to October 2009, 120 of an original cohort of 132 female patients with unstable fractures of the distal radius were treated with a volar locking plate, and were studied over a follow-up period of six months. In the immediate post-operative and final follow-up radiographs, late displacement was evaluated as judged by ulnar variance, radial inclination, and dorsal angulation. We also analysed the correlation of a variety of clinical and radiological factors with re-displacement. Ulnar variance was significantly overcorrected (p < 0.001) while radial inclination and dorsal angulation were undercorrected when compared statistically (p < 0.001) with the unaffected side in the immediate post-operative stage. During follow-up, radial shortening and dorsal angulation progressed statistically, but none had a value beyond the acceptable range. Bone mineral density measured at the proximal femur and the position of the screws in the subchondral region, correlated with slight progressive radial shortening, which was not clinically relevant. Volar locking plating of distal radial fractures is a reliable form of treatment without substantial late displacement. PMID- 23450028 TI - Comparison of unipedicular and bipedicular balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures: a prospective randomised study. AB - This is a prospective randomised study comparing the clinical and radiological outcomes of uni- and bipedicular balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures. A total of 44 patients were randomised to undergo either uni- or bipedicular balloon kyphoplasty. Self reported clinical assessment using the Oswestry Disability Index, the Roland Morris Disability questionnaire and a visual analogue score for pain was undertaken pre-operatively, and at three and twelve months post-operatively. The vertebral height and kyphotic angle were measured from pre- and post-operative radiographs. Total operating time and the incidence of cement leakage was recorded for each group. Both uni- and bipedicular kyphoplasty groups showed significant within-group improvements in all clinical outcomes at three months and twelve months after surgery. However, there were no significant differences between the groups in all clinical and radiological outcomes. Operating time was longer in the bipedicular group (p < 0.001). The incidence of cement leakage was not significantly different in the two groups (p = 0.09). A unipedicular technique yielded similar clinical and radiological outcomes as bipedicular balloon kyphoplasty, while reducing the length of the operation. We therefore encourage the use of a unipedicular approach as the preferred surgical technique for the treatment of osteoporotic vertebral compression fractures. PMID- 23450029 TI - Forced-air patient warming blankets disrupt unidirectional airflow. AB - We have recently shown that waste heat from forced-air warming blankets can increase the temperature and concentration of airborne particles over the surgical site. The mechanism for the increased concentration of particles and their site of origin remained unclear. We therefore attempted to visualise the airflow in theatre over a simulated total knee replacement using neutral-buoyancy helium bubbles. Particles were created using a Rocket PS23 smoke machine positioned below the operating table, a potential area of contamination. The same theatre set-up, warming devices and controls were used as in our previous study. This demonstrated that waste heat from the poorly insulated forced-air warming blanket increased the air temperature on the surgical side of the drape by > 5 degrees C. This created convection currents that rose against the downward unidirectional airflow, causing turbulence over the patient. The convection currents increased the particle concentration 1000-fold (2 174 000 particles/m(3) for forced-air warming vs 1000 particles/m(3) for radiant warming and 2000 particles/m(3) for the control) by drawing potentially contaminated particles from below the operating table into the surgical site. Cite this article: Bone Joint J 2013;95-B:407-10. PMID- 23450030 TI - The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone. AB - The aim of this study was to determine whether the level of circulating C reactive protein (CRP) before treatment predicted overall disease-specific survival and local tumour control in patients with a sarcoma of bone. We retrospectively reviewed 318 patients who presented with a primary sarcoma of bone between 2003 and 2010. Those who presented with metastases and/or local recurrence were excluded. Elevated CRP levels were seen in 84 patients before treatment; these patients had a poorer disease-specific survival (57% at five years) than patients with a normal CRP (79% at five years) (p < 0.0001). They were also less likely to be free of recurrence (71% at five years) than patients with a normal CRP (79% at five years) (p = 0.04). Multivariate analysis showed the pre-operative CRP level to be an independent predictor of survival and local control. Patients with a Ewing's sarcoma or chondrosarcoma who had an elevated CRP before their treatment started had a significantly poorer disease-specific survival than patients with a normal CRP (p = 0.02 and p < 0.0001, respectively). Patients with a conventional osteosarcoma and a raised CRP were at an increased risk of poorer local control. We recommend that CRP levels are measured routinely in patients with a suspected sarcoma of bone as a further prognostic indicator of survival. PMID- 23450031 TI - Prognostic factors for premature growth plate arrest as a complication of the surgical treatment of fractures of the medial malleolus in children. AB - McFarland fractures of the medial malleolus in children, also classified as Salter-Harris Type III and IV fractures, are associated with a high incidence of premature growth plate arrest. In order to identify prognostic factors for the development of complications we reviewed 20 children with a McFarland fracture that was treated surgically, at a mean follow-up of 8.9 years (3.5 to 17.4). Seven children (35%) developed premature growth arrest with angular deformity. The mean American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale for all patients was 98.3 (87 to 100) and the mean modified Weber protocol was 1.15 (0 to 5). There was a significant correlation between initial displacement (p = 0.004) and operative delay (p = 0.007) with premature growth arrest. Both risk factors act independently and additively, such that all children with both risk factors developed premature arrest whereas children with no risk factor did not. We recommend that fractures of the medial malleolus in children should be treated by anatomical reduction and screw fixation within one day of injury. PMID- 23450032 TI - The treatment of severe slipped capital femoral epiphysis via the Ganz surgical dislocation and anatomical reduction: a prospective study. AB - We present our experience of the modified Dunn procedure in combination with a Ganz surgical dislocation of the hip to treat patients with severe slipped capital femoral epiphysis (SCFE). The aim was to prospectively investigate whether this technique is safe and reproducible. We assessed the degree of reduction, functional outcome, rate of complications, radiological changes and range of movement in the hip. There were 28 patients with a mean follow-up of 38.6 months (24 to 84). The lateral slip angle was corrected by a mean of 50.9 degrees (95% confidence interval 44.3 to 57.5). The mean modified Harris hip score at the final follow-up was 89.1 (sd 9.0) and the mean Non-Arthritic Hip score was 91.3 (sd 9.0). Two patients had proven pre-existing avascular necrosis and two developed the condition post-operatively. There were no cases of nonunion, implant failure, infection, deep-vein thrombosis or heterotopic ossification. The range of movement at final follow-up was nearly normal. This study adds to the evidence that the technique of surgical dislocation and anatomical reduction is safe and reliable in patients with SCFE. PMID- 23450033 TI - Response to: Petheram TG, Bone M, Joyce TJ, et al. Surface finish of the Exeter Trauma Stem: a cause for concern? Bone Joint J 2013;95-B:173-6. PMID- 23450035 TI - New bone formation after ligation of the external carotid artery and resection of a large aneurysmal bone cyst of the mandible with reconstruction: a case report. AB - The aneurysmal bone cyst (ABC) is a benign cystic and expanding osteolytic lesion consisting of bone-filled spaces of variable size, separated by connective tissue containing trabeculae of bone or osteoid tissue and osteoclast giant cells. Radiographic findings may vary from unicystic or moth-eaten radiolucencies to extensive multilocular lesions with bilateral expansion and destruction of mandibular cortices. Treatment modalities include curettage (with reported recurrences) and resection with immediate reconstruction. The main arterial and feeder vessels may be embolized to prevent profuse intraoperative blood loss and achieve a bloodless surgical field. Failed embolization may necessitate ligation of the external carotid artery of the affected side. PMID- 23450036 TI - Stability of maternal discipline practices and the quality of mother-child interaction during toddlerhood. AB - This study examined the stability of maternal punitive/high-power discipline (PD) and inductive/authoritative discipline (ID) over the second and third years of life and the effect of maternal discipline on quality of mother-child interactions. Data from a longitudinal sample with 179 mother-toddler dyads were analyzed, and selected factors (i.e., child sex, temperament) that might moderate the association between maternal discipline and quality of mother-child interactions were also examined. Maternal discipline, quality of mother-child interactions, and temperamental moderators were measured at 16-18 months (Time 1) and 34-37 months (Time 2). Results showed that the stability of maternal use of discipline strategies over the toddler years was moderate. Lower maternal use of PD, higher maternal use of ID, and higher preference/reliance on ID (relative to PD) were associated with higher quality of mother-child interactions. Moderation effects of child temperament were also found. High ID and PD were associated with low quality of mother-child relationships in non-temperamentally difficult children but not in temperamentally difficult children. PMID- 23450037 TI - Hope in Iranian cancer patients. AB - BACKGROUND: Hope is an important factor in the recovery of cancer patients. Few Iranian studies investigated the level of hope in cancer patients. Therefore, the present study aimed to investigate the level of hope in Iranian cancer patients and the related factors. METHODS: In a descriptive correlational study, 150 cancer patients were selected by a consecutive sampling method. Hope in patients was measured by the Herth Hope Index. Data analysis was performed using descriptive and inferential statistics. RESULTS: Results indicated that 61.1% of the patients had high levels of hope, 35.4% had moderate levels of hope, and 3.5% had low levels of hope. Hope has a statistically significant relationship with family support, but it is not statistically associated with other patient characteristics. CONCLUSIONS: Many cancer patients had a high level of hope. However, further studies are recommended to investigate the relation between hope and patient characteristics. PMID- 23450038 TI - Anaphylaxis to topically applied sodium fusidate. AB - Fusidic acid is a bacteriostatic antibiotic that is effective primarily on gram positive bacteria, such as Staphylococcus and Corynebacterium species. It is often topically applied to the skin, but is also given systemically as a tablet or injection. Allergic contact dermatitis, or urticaria, has been reported as a side effect of fusidic acid treatment, whereas anaphylaxis to topically administered fusidic acid has not been reported previously. A 16-year-old boy visited an outpatient clinic for further evaluation of anaphylaxis. He suffered abrasions on his arms during exercise, which were treated with a topical ointment containing sodium fusidate. Within 30 minutes, he developed urticaria and eyelid swelling, followed by a cough and respiratory difficulty. His symptoms were relieved by emergency treatment in a nearby hospital. To investigate the etiology, oral provocation with fusidate was performed. After 125 mg (1/2 tablet) of sodium fusidate was administered, he developed a cough and itching of the throat within 30 minutes, which was followed by chest discomfort and urticaria. Forced expiratory volume in 1 second (FEV1) dropped from 4.09 L at baseline to 3.50 L after challenge, although wheezing was not heard in his chest. After management with an inhaled bronchodilator using a nebulizer, chest discomfort was relieved and FEV1 rose to 3.86 L. The patient was directed not to use fusidate, especially on abrasions. Here we report the first case of anaphylaxis resulting from topical fusidic acid application to abrasions. PMID- 23450039 TI - Detection of infectious bronchitis virus serotypes by reverse transcription polymerase chain reaction in broiler chickens. AB - Infectious bronchitis (IB) is a highly contagious disease of the respiratory and urogenital tract of chickens, caused by infectious bronchitis virus (IBV), a member of the family Coronaviridae. The disease is common throughout the world where chickens are produced commercially. PCR on reverse transcribed RNA is a potent technique for the detection of IBV. In comparison with classical detection methods, PCR-based techniques are both sensitive and fast. Dozens of serotypes and genotypes of IBV have been detected, and many more will surely be reported in future. This research was conducted to identify the infectious bronchitis virus with group specific primers of avian Coronaviruses in Zabol, southeast of Iran. Tracheal swabs were collected from eleven commercial broiler flocks and these swabs were used for RNA extraction. General primers included XCE2+ and XCE2- that amplify all IBV serotypes were used. Primers MCE1+, BCE1+ and DCE1+ was used to amplifying the specific nucleotide sequence of Massachusetts, 4/91 and D274 serotypes, respectively. The results of this study showed that 36.36% of the sampled flocks were positive to IBV by RT-PCR. Moreover, the Massachusetts was the identified serotype of infectious bronchitis virus. The results provide the first molecular evidence for the presence of infectious bronchitis virus and Massachusetts serotype in Zabol. PMID- 23450040 TI - Joseph v. Brady: synthesis reunites what analysis has divided. AB - Joseph V. Brady (1922-2011) created behavior-analytic neuroscience and the analytic framework for understanding how the external and internal neurobiological environments and mechanisms interact. Brady's approach offered synthesis as well as analysis. He embraced Findley's approach to constructing multioperant behavioral repertoires that found their way into designing environments for astronauts as well as studying drug effects on human social behavior in microenvironments. Brady created translational neurobehavioral science before such a concept existed. One of his most lasting contributions was developing a framework for ethical decision making to protect the rights of the people who participate in scientific research. PMID- 23450041 TI - How to help the oral pathologist in making an accurate diagnosis. AB - A biopsy is a valuable diagnostic tool in clinics. In this procedure, the sample tissue is obtained in order to study its structure both macro and microscopically, thus making it possible to establish a final diagnosis. Some clinicians are surprised and disappointed when the report from the oral pathologist comes as "not from the representative area and "inadequate specimen size", instead of a final diagnosis. To avoid such disappointments and to make the best utilization of the skills of the oral pathologist, certain ideas have been suggested. Right from the history taking to the clinical examination to the operative findings, the clinician can pave the way to a conclusive histopathological diagnosis. PMID- 23450043 TI - Clinical evaluation of early loaded and unloaded implants in edentulous mandible. AB - OBJECTIVES: The aim of this study is to compare and evaluate the clinical outcome of early loaded and unloaded implants in the interforaminal region of anterior mandible. MATERIALS AND METHODS: Five completely edentulous patients aged between 45 and 65 years were selected satisfying certain criteria. Four implants were placed in 33, 43, 35 and 45 regions; implants in 33 and 43 regions were loaded by a Dolder bar supported overdenture at 7th day. The implants at 35 and 45 regions were connected to 33 and 43 regions, respectively after 4 months. The implants were divided into two groups. Group I consisted of early loaded implants (implants in the region of 33 and 43) and Group II consisted of delayed loaded implants (implants in the region of 35 and 45). The implants were evaluated for various clinical parameters at 2, 4 and 6 month intervals after initial placement. RESULTS: There was significant increase in the bone to implant contact for unloaded implants as compared to early loaded at the end of 6 months of implant placement. There was increased marginal bone loss around early loaded implants as compared to unloaded implants at the end of 6 months. Clinical stability of early loaded implants was lower as compared to the unloaded implants at the end of 6 months. Survival rate for early loaded and unloaded implants was 100% at the end of 6 months with all implants in function. CONCLUSION: Early loading of interforaminal mandibular implants demonstrated a highly acceptable clinical success at the end of 6 months. However, the bone density, marginal bone level and clinical stability were significantly lower for the early loaded implants as compared to unloaded implants. PMID- 23450044 TI - The Impact of Structured Inter-professional Education on Health Care Professional Students' Perceptions of Collaboration in a Clinical Setting. AB - PURPOSE: To examine how a structured inter-professional education (IPE) clinical placement influences health care professional (HCP) students' perceptions of inter-professional collaboration (IPC) relative to that of students in a traditional clinical placement. METHODS: This study used a mixed-methods design. The Interdisciplinary Education Perception Scale (IEPS) was administered to HCP students (n=36) in two Toronto hospitals before and after a structured 5-week IPE clinical placement to examine changes in their perceptions of IPC. Students in a traditional clinical placement (n=28) were used as a control group. Focus groups were then conducted with seven students who took part in the structured IPE clinical placement. A coding framework was devised a priori, and the qualitative results were used to explain the quantitative findings. RESULTS: There were no statistically significant differences between groups after the structured IPE clinical placement, but the intervention group showed a greater positive trend in total IEPS scores from baseline to follow-up. Qualitative data suggest that students valued the knowledge and skills gained through the structured IPE clinical placement. CONCLUSIONS: Findings suggest that structured IPE clinical placements may provide students with valuable collaborative learning opportunities, enhanced respect for other professionals, and insight into the value of IPC in healthcare delivery. More research is needed to explore other factors that influence specific perceptions among physical therapy students. : Purpose: To examine how a structured inter-professional education (IPE) clinical placement influences health care professional (HCP) students' perceptions of inter-professional collaboration (IPC) relative to that of students in a traditional clinical placement. Methods: This study used a mixed-methods design. The Interdisciplinary Education Perception Scale (IEPS) was administered to HCP students (n=36) in two Toronto hospitals before and after a structured 5-week IPE clinical placement to examine changes in their perceptions of IPC. Students in a traditional clinical placement (n=28) were used as a control group. Focus groups were then conducted with seven students who took part in the structured IPE clinical placement. A coding framework was devised a priori, and the qualitative results were used to explain the quantitative findings. Results: There were no statistically significant differences between groups after the structured IPE clinical placement, but the intervention group showed a greater positive trend in total IEPS scores from baseline to follow-up. Qualitative data suggest that students valued the knowledge and skills gained through the structured IPE clinical placement. Conclusions: Findings suggest that structured IPE clinical placements may provide students with valuable collaborative learning opportunities, enhanced respect for other professionals, and insight into the value of IPC in healthcare delivery. More research is needed to explore other factors that influence specific perceptions among physical therapy students. PMID- 23450042 TI - NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer's Disease. AB - Dementia has become an all-important disease because the population is aging rapidly and the cost of health care associated with dementia is ever increasing. In addition to cognitive function impairment, associated behavioral and psychological symptoms of dementia (BPSD) worsen patient's quality of life and increase caregiver's burden. Alzheimer's disease is the most common type of dementia and both behavioral disturbance and cognitive impairment of Alzheimer's disease are thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dysfunctional glutamatergic neurotransmission had been reported in behavioral changes and cognitive decline in Alzheimer's disease. We review the literature regarding dementia (especially Alzheimer's disease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the effects of memantine, a NMDA receptor antagonist, and NMDA-enhancing agents, such as D-serine and D-cycloserine. Literatures suggest that behavioral disturbance and cognitive impairment of Alzheimer's disease may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in Alzheimer's disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms. We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of Alzheimer's disease. Prospective study using NMDA enhancers in patients with Alzheimer's disease and associated behavioral disturbance is needed to verify this hypothesis. PMID- 23450045 TI - Daily physical activity in young children and their parents: A descriptive study. AB - BACKGROUND: Little is known about physical activity (PA) in young children and about the relationship between their PA and that of their parents. OBJECTIVE: The main purpose of the present study (Y-Be-Active) was to examine the daily PA levels of young children and their parents, and to explore the relationship between children's and parents' PA. METHOD: Fifty-four children (mean age 4.3 years) and their parents (54 mothers, mean age 35.8 years; 50 fathers, mean age 38.2 years) wore accelerometers for three weekdays and two weekend days. Parents also completed questionnaires on family sociodemographics and PA habits. RESULTS: Children spent most of their time in light PA. Almost all children attained 30 min of daily moderate-to-vigorous PA (MVPA), and most boys and girls attained 60 min of daily MVPA on weekdays. Only 60% of fathers and approximately one-half of mothers attained 30 min of daily MVPA on weekdays and weekend days. Children's and fathers' PA were correlated on weekends. Few parents (20% to 30%) participated regularly in organised PA with their child. Fathers' involvement in PA with their children was associated with higher MVPA in children. CONCLUSIONS: Many young children and parents did not meet current Canadian recommendations for daily PA. Parental involvement in PA with their young children, particularly the involvement of fathers, appeared to promote higher levels of MVPA in young children. BACKGROUND: Little is known about physical activity (PA) in young children and about the relationship between their PA and that of their parents. OBJECTIVE: The main purpose of the present study (Y-Be-Active) was to examine the daily PA levels of young children and their parents, and to explore the relationship between children's and parents' PA. METHOD: Fifty-four children (mean age 4.3 years) and their parents (54 mothers, mean age 35.8 years; 50 fathers, mean age 38.2 years) wore accelerometers for three weekdays and two weekend days. Parents also completed questionnaires on family sociodemographics and PA habits. RESULTS: Children spent most of their time in light PA. Almost all children attained 30 min of daily moderate-to-vigorous PA (MVPA), and most boys and girls attained 60 min of daily MVPA on weekdays. Only 60% of fathers and approximately one-half of mothers attained 30 min of daily MVPA on weekdays and weekend days. Children's and fathers' PA were correlated on weekends. Few parents (20% to 30%) participated regularly in organised PA with their child. Fathers' involvement in PA with their children was associated with higher MVPA in children. CONCLUSIONS: Many young children and parents did not meet current Canadian recommendations for daily PA. Parental involvement in PA with their young children, particularly the involvement of fathers, appeared to promote higher levels of MVPA in young children. PMID- 23450046 TI - Oral treatment with etoposide in small cell lung cancer - dilemmas and solutions. AB - BACKGROUND: Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity. CONCLUSIONS: The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice. PMID- 23450047 TI - Whole-exome sequencing studies of nonfunctioning pituitary adenomas. AB - CONTEXT: The tumorigenic role of genetic abnormalities in sporadic pituitary nonfunctioning adenomas (NFAs), which usually originate from gonadotroph cells, is unknown. OBJECTIVE: The objective of the study was to identify somatic genetic abnormalities in sporadic pituitary NFAs. DESIGN: Whole-exome sequencing was performed using DNA from 7 pituitary NFAs and leukocyte samples obtained from the same patients. Somatic variants were confirmed by dideoxynucleotide sequencing, and candidate driver genes were assessed in an additional 24 pituitary NFAs. RESULTS: Whole-exome sequencing achieved a high degree of coverage such that approximately 97% of targeted bases were represented by more than 10 base reads; 24 somatic variants were identified and confirmed in the discovery set of 7 pituitary NFAs (mean 3.5 variants/tumor; range 1-7). Approximately 80% of variants occurred as missense single nucleotide variants and the remainder were synonymous changes or small frameshift deletions. Each of the 24 mutations occurred in independent genes with no recurrent mutations. Mutations were not observed in genes previously associated with pituitary tumorigenesis, although somatic variants in putative driver genes including platelet-derived growth factor D (PDGFD), N-myc down-regulated gene family member 4 (NDRG4), and Zipper sterile-alpha-motif kinase (ZAK) were identified; however, DNA sequence analysis of these in the validation set of 24 pituitary NFAs did not reveal any mutations indicating that these genes are unlikely to contribute significantly in the etiology of sporadic pituitary NFAs. CONCLUSIONS: Pituitary NFAs harbor few somatic mutations consistent with their low proliferation rates and benign nature, but mechanisms other than somatic mutation are likely involved in the etiology of sporadic pituitary NFAs. PMID- 23450048 TI - Impaired fasting glucose and impaired glucose tolerance have distinct lipoprotein and apolipoprotein changes: the insulin resistance atherosclerosis study. AB - CONTEXT: Cardiovascular risk is increased in individuals with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG); however, those with IGT appear to be at greater risk. Lipoprotein abnormalities occur also in the prediabetic state. OBJECTIVE: The authors examined lipoprotein composition in IGT and IFG. DESIGN AND SETTING: Cross-sectional analysis of a large epidemiological study was done. PARTICIPANTS: The Insulin Resistance Atherosclerosis Study had a total of 1107 participants. MAIN MEASURES: Lipoproteins and apolipoproteins were measured by conventional methods and lipoprotein composition by nuclear magnetic resonance spectroscopy. RESULTS: Compared with normal glucose tolerance, apolipoprotein B (105.2 vs 99.8 mg/dL, P < .05) was high in isolated IFG, triglyceride (1.48 vs 1.16 mmol/L, P < .001) was high in isolated IGT, and high density lipoprotein cholesterol was low in combined IFG/IGT (1.12 vs 1.26 mmol/L, P < .001). Nuclear magnetic resonance spectroscopy revealed additional changes: increased total low-density lipoprotein (LDL) particles (1190 vs 1096 nmol/L, P < .01) in isolated IFG; increased large very-low-density lipoprotein (3.61 vs 2.47 nmol/L, P < .01) and small LDL subclass particles (665 vs 541 nmol/L, P < .05) and decreased large LDL subclass particles (447 vs 513 nmol/L, P < .01) in isolated IGT; and decreased large high-density lipoprotein subclass particles in combined IFG/IGT (4.24 vs 5.39 MUmol/L, P < .001). CONCLUSIONS: Isolated IFG is characterized by increased apolipoprotein B and total LDL particles, whereas isolated IGT is associated with increased triglycerides, large very-low-density lipoprotein subclass particles, and structural remodeling of LDL particles. These results may help to explain differences in cardiovascular disease risk in the prediabetic state. PMID- 23450049 TI - MicroRNA23a and microRNA23b deregulation derepresses SF-1 and upregulates estrogen signaling in ovarian endometriosis. AB - CONTEXT: Steroidogenic factor (SF)-1 and its downstream target genes involved in estrogen signaling are aberrantly expressed in ovarian endometriosis. OBJECTIVE: Our objective was to explore the microRNA-mediated mechanism controlling aberrant SF-1 expression in ovarian endometriosis. DESIGN: Bioinformatics analysis predicted that microRNA23a and microRNA23b (miR23a/b) target the NR5A1 3' untranslated region. We investigated the relative expression and spatial distribution of miR23a/b and analyzed the relationship between miR23a/b and SF-1 expression in endometriotic tissues. SETTING: The study was conducted at the Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University. PATIENTS OR OTHER PARTICIPANTS: We enrolled 23 women with American Fertility Society stage III-IV ovarian endometriosis and 15 disease-free control subjects. INTERVENTIONS: Quantitative real-time RT-PCR, in situ hybridization, cell culture, transfections, and luciferase reporter assays were used in this study. MAIN OUTCOME MEASURES: The expression of miR23a/b and SF-1, CYP19A1, and StAR mRNAs; the relationships between miRNAs and SF-1 mRNA levels; and the effect of miR23a/b on SF-1 expression were measured in normal and eutopic endometrial stromal cells (ESCs) and 293T cells. RESULTS: Both miR23a and miR23b were downregulated in ectopic and eutopic endometrium, compared with normal endometrium, and their expression was inversely correlated with NR5A1 mRNA levels. SF-1 expression was inhibited by miR23a/b overexpression in eutopic ESCs and upregulated by miR23a/b inhibition in normal ESCs. CONCLUSIONS: MiR23a and miR23b are potential biomarkers of ovarian endometriosis. This study provides a novel approach for targeting the mechanisms controlling aberrant local estrogen biosynthesis in endometriosis. PMID- 23450050 TI - Interleukin-4 and prostaglandin E2 synergistically up-regulate 3beta hydroxysteroid dehydrogenase type 2 in endometrioma stromal cells. AB - CONTEXT: Endometriosis is a chronic inflammatory disease in which immune response and production of estrogen in endometriotic tissues are involved in the development of the disease. Prostaglandin E2 (PGE2) stimulates aromatase (P450arom) expression in endometrioma stromal cells (ESCs) and increases the production of estrogens. On the other hand, an accumulating amount of evidence suggests that IL-4, a typical Th2 cytokine, plays important roles in the disease. OBJECTIVE: The objective of the investigation was to study the effect of IL-4 on the expression of 3beta-hydroxysteroid dehydrogenase (HSD3B2), a pivotal enzyme for estrogen production, in ESCs. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: ESCs were isolated from ovarian endometrioma tissues and cultured with IL-4 and PGE2. CP-690550, a Janus protein tyrosine kinase 3 inhibitor, and HSD3B2 small interfering RNA were added to the culture. Gene expression of HSD3B2 and P450arom was examined by quantitative RT-PCR. Dehydroepiandrosterone (DHEA) was added to the culture, and then the combined enzyme activity of HSD3B2, which converts DHEA to androstenedione, and P450arom, which converts androstenedione to estrone, was examined by measuring estrone concentration in the supernatants with a specific enzyme immunoassay. RESULTS: IL-4 increased the expression of HSD3B2 mRNA in a dose-dependent manner. CP-650550 inhibited the IL-4-induced increase in HSD3B2 mRNA expression. PGE2 also increased the expression of HSD3B2 mRNA, and the combination of IL-4 and PGE2 synergistically increased the expression of HSD3B2 mRNA. IL-4 had no effect on the expression of P450arom mRNA, whereas PGE2 increased the expression of P450arom mRNA. Although PGE2 alone increased the production of estrone from DHEA, the combination of IL-4 and PGE2 significantly augmented the production of estrone from DHEA. The enhanced production of estrone by the combination of IL-4 and PGE2 was inhibited by CP-690550 and HSD3B2 small interfering RNA. CONCLUSIONS: IL-4 in combination with PGE2 may enhance estrogen production in endometriotic tissues, implying an elaborate mechanism that Th2 immune response augments inflammation-dependent progression of the disease. PMID- 23450051 TI - Plasma PCSK9 is a late biomarker of severity in patients with severe trauma injury. AB - CONTEXT: PCSK9 (proprotein convertase subtilisin kexin type 9) is a secreted protease that modulates cholesterol homeostasis by decreasing low-density lipoprotein receptor expression. Low levels of plasma lipoproteins are related to severity of illness and survival in patients of intensive care units (ICU). OBJECTIVE: The aim of the study was to investigate the regulation of plasma PCSK9 and its association with plasma lipid parameters and clinical markers of severity during critical illness. DESIGN AND PATIENTS: The plasma biobank from the previously published HYPOLYTE prospective study was used to measure PCSK9 concentrations by ELISA at days 0 and 8 in 111 patients admitted to surgical ICU for severe multiple trauma. Patients were randomly assigned to hydrocortisone therapy or placebo. RESULTS: Plasma PCSK9 levels were increased by 2-fold between days 0 and 8 (231 +/- 116 vs 481 +/- 227 ng/ml; P = .0001). Hydrocortisone therapy did not alter PCSK9 concentrations (451 +/- 216 vs 511 +/- 239 ng/ml in placebo group; P = .33). PCSK9 was positively associated with low-density lipoprotein-cholesterol (Pearson coefficient, 0.26; P = .007) at day 0, but not at day 8. At day 8, an inverse correlation was found between PCSK9 and high density lipoprotein-cholesterol (beta = -653; P = .004). Although baseline PCSK9 concentrations were not associated to severity scores, PCSK9 values at day 8 were related to injury severity score (beta = 6.17; P = .0007), length of stay in ICU (beta = 6.14; P = .0001), and duration of both mechanical ventilation (beta = 8.26; P = .0001) and norepinephrine infusion (beta = 18.57; P = .015). CONCLUSIONS: Plasma PCSK9 appears as a late biomarker of illness severity in patients with severe multiple trauma. PMID- 23450052 TI - Effects of endogenous androgens and abdominal fat distribution on the interrelationship between insulin and non-insulin-mediated glucose uptake in females. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance. Glucose disposal occurs via noninsulin-mediated glucose uptake (NIMGU) and insulin-mediated glucose uptake (IMGU). It is unknown whether in PCOS NIMGU increases to compensate for declining IMGU and whether androgens and fat distribution influence this relationship. OBJECTIVES: The objective of the study was to compare in women with PCOS and controls the interrelationship between NIMGU [ie, glucose effectiveness (Sg)] and IMGU [ie, the insulin sensitivity index (Si)] and the role of androgens and fat distribution. PARTICIPANTS: Twenty-eight PCOS (by National Institutes of Health 1990 criteria) and 28 control (age, race, and body mass index matched) women were prospectively studied. A subset of 16 PCOS subjects and 16 matched controls also underwent abdominal computed tomography. MAIN OUTCOME MEASURES: Glucose disposal (by a frequently sampled iv glucose tolerance test), circulating androgens, and abdominal fat distribution [by waist to hip ratio and visceral (VAT) and sc (SAT) adipose tissue content] were measured. RESULTS: PCOS women had lower mean Si and similar Sg and abdominal fat distribution compared with controls. PCOS women with Si below the PCOS median (more insulin resistant) had a lower mean Sg than controls with Si above the control median (more insulin sensitive). In PCOS only, body mass index, free T, modified Ferriman-Gallwey score, and waist to hip ratio independently predicted Sg, whereas Si did not. In PCOS, VAT and SAT independently and negatively predicted Si and Sg, respectively. CONCLUSION: The decreased IMGU in PCOS is not accompanied by a compensatory increase in NIMGU or associated with excessive VAT accumulation. Increased general obesity, SAT, and hyperandrogenism are primary predictors of the deterioration of NIMGU in PCOS. PMID- 23450054 TI - Recurrences of ACTH-secreting adenomas after pituitary adenomectomy can be accurately predicted by perioperative measurements of plasma ACTH levels. AB - BACKGROUND: Adenomectomy is the treatment of choice for ACTH-secreting adenomas. Although the development of ACTH deficiency immediately after adenomectomy suggests surgical success, disease recurrence was reported in patients who developed hypocortisolism postoperatively. In the current study, we examined the value of measuring perioperative plasma ACTH and cortisol levels in predicting disease recurrence of patients with ACTH-secreting adenomas. METHODS: Consecutive patients (n = 55; 41 females, 14 males) with clinical, biochemical, and histological documentation of ACTH-secreting adenomas were investigated after pituitary adenomectomy. All patients were followed with clinical monitoring and frequent measurements of plasma ACTH and serum cortisol levels, and none received glucocorticoids unless or until they developed symptoms of adrenal insufficiency or when their serum cortisol levels were <=3 MUg/dL. RESULTS: Postoperative serum cortisol levels reached <=3 MUg/dL in 46 of 55 and were >=4 MUg/dL in the remaining 9. Simultaneously measured plasma ACTH levels in the latter 9 patients were >40 ng/L when the serum cortisol reached its nadir. In contrast, among the 46 patients who had serum cortisol levels of <=3 MUg/dL, plasma ACTH levels measured simultaneously were <=20 ng/L in 38 of 46 and >20 ng/L in the remaining 8. During a mean follow-up period of nearly 7 years, patients who had a nadir plasma ACTH of >20 ng/L developed recurrences even though their postoperative serum cortisol levels were <=3 MUg/dL. CONCLUSIONS: Despite profound hypocortisolemia after adenomectomy, a simultaneously measured plasma ACTH level of >20 ng/L in the perioperative period is highly predictive of future recurrence of ACTH-secreting adenomas. PMID- 23450053 TI - Clinical review: kinase inhibitors: adverse effects related to the endocrine system. AB - CONTEXT: The use of kinase inhibitors (KIs) in the treatment of cancer has become increasingly common, and practitioners must be familiar with endocrine-related side effects associated with these agents. This review provides an update to the clinician regarding the management of potential endocrinological effects of KIs. EVIDENCE ACQUISITION: PubMed was employed to identify relevant manuscripts. A review of the literature was conducted, and data were summarized and incorporated. EVIDENCE SYNTHESIS: KIs, including small molecule KIs and monoclonal antibodies directed against kinases, have emerged over the past decade as an important class of anticancer agents. KIs specifically interfere with signaling pathways that are dysregulated in certain types of cancers and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. Currently, at least 20 KIs are approved as cancer therapeutics. However, KIs may affect a broad spectrum of targets and may have additional, unidentified mechanisms of action at the cellular level due to overlap between signaling pathways in the tumor cell and endocrine system. Recent reports in the literature have identified side effects associated with KIs, including alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, adrenal function, and glucose metabolism. CONCLUSIONS: Clinicians need to monitor the thyroid functions of patients on KIs. In addition, bone density and vitamin D status should be assessed. Special care should be taken to follow linear growth and development in children taking these agents. Clinicians should counsel patients appropriately on the potential adverse effects of KIs on fetal development. PMID- 23450055 TI - Sex-associated differences in free fatty acid flux of obese adolescents. AB - CONTEXT: In obesity, increases in free fatty acid (FFA) flux can predict development of insulin resistance. Adult women release more FFA relative to resting energy expenditure (REE) and have greater FFA clearance rates than men. In adolescents, it is unknown whether sex differences in FFA flux occur. OBJECTIVE: Our objective was to determine the associations of sex, REE, and body composition with FFA kinetics in obese adolescents. PARTICIPANTS: Participants were from a convenience sample of 112 non-Hispanic white and black adolescents (31% male; age range, 12-18 years; body mass index SD score range, 1.6-3.1) studied before initiating obesity treatment. MAIN OUTCOME MEASURES: Glucose, insulin, and FFA were measured during insulin-modified frequently sampled iv glucose tolerance tests. Minimal models for glucose and FFA calculated insulin sensitivity index (SI) and FFA kinetics, including maximum (l0 + l2) and insulin suppressed (l2) lipolysis rates, clearance rate constant (cf), and insulin concentration for 50% lipolysis suppression (ED50). Relationships of FFA measures to sex, REE, fat mass (FM), lean body mass (LBM) and visceral adipose tissue (VAT) were examined. RESULTS: In models accounting for age, race, pubertal status, height, FM, and LBM, we found sex, pubertal status, age, and REE independently contributed to the prediction of l2 and l0 + l2 (P < .05). Sex and REE independently predicted ED50 (P < .05). Sex, FM/VAT, and LBM were independent predictors of cf. Girls had greater l2, l0 + l2 and ED50 (P < .05, adjusted for REE) and greater cf (P < .05, adjusted for FM or VAT) than boys. CONCLUSION: Independent of the effects of REE and FM, FFA kinetics differ significantly in obese adolescent girls and boys, suggesting greater FFA flux among girls. PMID- 23450056 TI - Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. AB - CONTEXT: Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING: This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES: The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS: From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and 0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS: RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment. PMID- 23450058 TI - Aquaporin-1 plays a crucial role in estrogen-induced tubulogenesis of vascular endothelial cells. AB - CONTEXT: Aquaporin-1 (AQP1) has been proposed as a mediator of estrogen-induced angiogenesis in human breast cancer and endometrial cancer. Elucidation of the molecular mechanisms governing AQP1-mediated, estrogen-induced angiogenesis may contribute to an improved understanding of tumor development. OBJECTIVE: Our objective was to identify the estrogen-response element (ERE) in the promoter of the Aqp1 gene and investigate the effects and mechanisms of AQP1 on estrogen induced tubulogenesis of vascular endothelial cells. SETTING: The study was conducted in a university hospital in eastern China. MAIN OUTCOME MEASURES: Immunohistological, real-time PCR and Western blot analyses were used to determine the expression AQP1 mRNA and protein in vascular endothelial cells. Chromatin immunoprecipitation analyses and luciferase reporter assays identified ERE-like motif in the promoter of the Aqp1 gene. RESULTS: Expression of AQP1 in blood vessels of human breast and endometrial carcinoma tissues were significantly higher than controls. Estradiol (E2) dose-dependently increased the expression levels of AQP1 mRNA and protein in human umbilical vein endothelial cells (HUVECs). A functional ERE-like motif was identified in the promoter of the Aqp1 gene. AQP1 colocalized with ezrin, a component of the ezrin/radixin/moesin protein complex, and, ezrin colocalized with filamentous actin in HUVECs. Knockdown of AQP1 or ezrin with specific small interfering RNA significantly attenuated the formation of transcytoplasmic filamentous actin stress fibers induced by E2 and inhibited E2-enhanced cell proliferation, migration, invasion, and tubule formation of HUVECs. CONCLUSIONS: Estrogen induces AQP1 expression by activating ERE in the promoter of the Aqp1 gene, resulting in tubulogenesis of vascular endothelial cells. These results provide new insights into the molecular mechanisms underpinning the angiogenic effects of estrogen. PMID- 23450059 TI - Cancer protection elicited by a single nucleotide polymorphism close to the adrenomedullin gene. AB - CONTEXT: The risk of developing cancer is regulated by genetic variants, including polymorphisms. Characterizing such variants may help in developing protocols for personalized medicine. OBJECTIVE: Adrenomedullin is a regulatory peptide involved in cancer promotion and progression. Carriers of a single nucleotide polymorphism (SNP) in the proximity of the adrenomedullin gene have lower levels of circulating peptide. The aim of the present work was to investigate whether carriers of this SNP (rs4910118) are protected against cancer. DESIGN: This was a retrospective study. DNA samples were obtained from the Carlos III DNA National Bank (University of Salamanca, Salamanca, Spain). SETTING: Samples represent a variety of donors and patients from Spain. PATIENTS OR OTHER PARTICIPANTS: DNA from patients with breast cancer (n = 238), patients with lung cancer (n = 348), patients with cardiac insufficiency (n = 474), and healthy donors of advanced age (n = 500) was used. INTERVENTIONS: All samples were genotyped using double-mismatch PCR, and confirmation was achieved by direct sequencing. MAIN OUTCOME MEASURES: The minor allele frequency was calculated in all groups. The Pearson chi(2) was used to compare SNP frequencies. RESULTS: Of 1560 samples, 14 had the minor allele, with a minor allele frequency in healthy donors of 0.90%. Patients with cancer had a statistically significantly lower frequency than healthy donors (odds ratio = 0.216, 95% confidence interval = 0.048-0.967, P = .028). CONCLUSIONS: Carriers of the minor allele have a 4.6-fold lower risk of developing cancer than homozygotes for the major allele. Knowledge of the rs4910118 genotype may be useful for stratifying patients in clinical trials and for designing prevention strategies. PMID- 23450057 TI - Clinical review: improving the measurement of serum thyroglobulin with mass spectrometry. AB - CONTEXT: Serum thyroglobulin (Tg) measurements are central to the management of patients treated for differentiated thyroid carcinoma. For decades, Tg measurements have relied on methods that are subject to interference by commonly found substances in human serum and plasma, such as Tg autoantibodies. As a result, many patients need additional imaging studies to rule out cancer persistence or recurrence that could be avoided with more sensitive and specific testing methods. OBJECTIVES: The aims of this review are to: 1) briefly review the interferences common to Tg immunoassays; 2) introduce readers to liquid chromatography-tandem mass spectrometry as a method for quantifying proteins in human serum/plasma; and 3) discuss the potential benefits and limitations of the method in the quantification of serum Tg. RESULTS: Mass spectrometric methods have traditionally lacked the sensitivity, robustness, and throughput to be useful clinical assays. These methods failed to meet the necessary clinical benchmarks due to the nature of the mass spectrometry workflow and instrumentation. Over the past few years, there have been major advances in reagents, automation, and instrumentation for the quantification of proteins using mass spectrometry. More recently, methods using mass spectrometry to detect and quantify Tg have been developed and are of sufficient quality to be used in the management of patients. CONCLUSIONS: Novel serum Tg assays that use mass spectrometry may avoid the issue of autoantibody interference and other problems with currently available immunoassays for Tg. Prospective studies are needed to fully understand the potential benefits of novel Tg assays to patients and care providers. PMID- 23450060 TI - Robot-assisted laparoscopic bladder diverticulectomy in a seven-year-old child: Case report and points of technique. AB - Congenital bladder diverticulum is an uncommon anomaly of the bladder. Patients can present with urinary infection, heamaturia, and/or urinary obstruction. We report the case of a seven-year-old boy who presented with painful micturition and terminal haematuria due to a congenital bladder diverticulum. Robot-assisted laparoscopic diverticulectomy was performed. The patient had an uneventful recovery. We describe the points of technique pertinent to the procedure. PMID- 23450061 TI - Primary amelanotic melanoma of vulva in a young, lactating female. AB - Primary amelanotic melanoma of the vulva is extremely rare and it is a unique variant which is difficult to differentiate from other epithelial and nonepithelial malignancies due to absence of melanin pigmentation. It can be easily mistaken for other malignancies both clinically and pathologically. The difficulties in diagnosis and treatment aggravate the poor prognosis. This case highlights the rare case of vulval amelanotic melanoma occurring in a young lactating female. PMID- 23450062 TI - A study on outcome of underlay, overlay and combined techniques of myringoplasty. AB - Myringoplasty is a procedure which deals on repair of the tympanic membrane. This procedure can be done via postaural, endaural or endomeatal route. Various grafts such as temporalis fascia, vein graft, perichondrium are used. The technique can be categorized as underlay, overlay, interlay or its combination depending on the placement of the graft material. This study was done to compare underlay, overlay and combined technique in terms of the closure of the membrane defect, postoperative complications and over all success rates. Apart from few complications, this study revealed over all success rate was best with combined technique but the difference was not significant statistically when the methods are comparable among them. PMID- 23450063 TI - Hysterosalpingographic Tubal Abnormalities in Retroviral (HIV) Positive and Negative Infertile Females. AB - BACKGROUND: HIV and infertility are associated in several ways and the improved treatment options which are available for HIV patients have improved their health, increased their reproductive years and subsequently, their desire to procreate. OBJECTIVE: The objective was to compare the findings on hysterosalpingography in HIV positive and negative infertile females. STUDY DESIGN: All the 5250 patients who were referred to the radiodiagnosis unit of the centre in 2011, were counselled about the study, but only the two thousand and two hundred females who gave their consents had their retroviral status determined and were included in this study. Their sociodemographic histories were acquired with the aid of a structured questionnaire and their hysterosalpingography studies were reported by a radiologist. RESULTS: Most of the patients (54.5%) were within the age group of 31-40 years, they were mainly nullparous (76.8%) and a past history of induced abortions was statistically significant in the HIV positive patients compared to HIV negative patients. Also, the uterine synechiae were significantly higher in the HIV positive than the HIV negative patients (26.5% and 9.6% respectively). Tubal abnormalities were seen in 52% and 26% of the positive and negative individuals respectively, with hydrosalpinges being the commonest pathology in the HIV positive patients and distal occlusion being the commonest in the HIV negative patients. CONCLUSION: Tubal infertility is the commonest cause of the infertility in the HIV positive individuals and the commonest tubal pathology is hydrosalpinges as compared to distal tubal occlusion in the HIV negative patients .There is a need to not only research further into the treatment and other options for the patients with tubal infertility, but also to make them available and affordable to provide succour to this group of patients, no matter what their retroviral status is. PMID- 23450064 TI - Higher maternal education is associated with favourable growth of young children in different countries. AB - BACKGROUND: Childhood growth affects long-term health and could contribute to health inequalities that persist throughout life. METHODS: We compared growth data of 4-year-old to 6-year-old children born 1997-2002 in UK (n=15,168), Sweden (n=6749) and rural China (n=10,327). SD scores (SDS) were calculated against the WHO Growth Standard. Obesity and overweight were defined by the International Obesity Taskforce cut-offs, and stunting, underweight and thinness by height, weight or body mass index (BMI)<-2 SDS. Associations with maternal education were standardised by calculating the Slope Index of Inequality (SII). RESULTS: Mean SDS height, weight and BMI in the UK (-0.01, 0.42, 0.62, respectively) and Sweden (0.45, 0.59, 0.45) were higher than in China (-0.98, -0.82, -0.29). Higher maternal education was consistently associated with taller offspring height SDS (SII: UK 0.25; Sweden 0.17; China 1.06). Underweight and stunting were less common in the UK (prevalence: 0.6% and 2.2%, respectively) and Sweden (0.3% and 0.6%) than in China (9.5% and 16.4%), where these outcomes were inversely associated with maternal education (SII: -25.8% and -12.7%). Obesity prevalence in the UK, Sweden and China was 4.8%, 3.7% and 0.4%, respectively. Maternal education was inversely associated with offspring obesity in the UK (SII: -3.3%) and Sweden (-2.8%), but not in China (+0.3%). CONCLUSIONS: Higher maternal education was associated with more favourable growth in young children: lower obesity and overweight in the UK and Sweden, and lower stunting and underweight in rural China. Public health strategies to optimise growth in early childhood need to acknowledge socioeconomic factors, but possibly with a different emphasis in different settings. PMID- 23450066 TI - Stem cell mediated tooth regeneration: new vistas in dentistry. AB - The generation of dental structures and/or entire teeth in the laboratory depends upon the manipulation of stem cells and requires a synergy of all cellular and molecular events that finally lead to the formation of tooth-specific hard tissues, dentin and enamel. This review focuses on the different sources of stem cells that have been used for making teeth in vitro and their relative efficiency. Embryonic, post-natal and adult stem cells were assessed and proved to possess an enormous regenerative potential, but their application in dental practice is still limited due to various parameters that are not yet under control such as the high risk of rejection, cell behaviour, long tooth eruption period, appropriate crown morphology and suitable colour. Nevertheless, the development of biological approaches for dental reconstruction using stem cells is promising and remains one of the greatest challenges in the dental field. PMID- 23450065 TI - Mature microsatellites: mechanisms underlying dinucleotide microsatellite mutational biases in human cells. AB - Dinucleotide microsatellites are dynamic DNA sequences that affect genome stability. Here, we focused on mature microsatellites, defined as pure repeats of lengths above the threshold and unlikely to mutate below it in a single mutational event. We investigated the prevalence and mutational behavior of these sequences by using human genome sequence data, human cells in culture, and purified DNA polymerases. Mature dinucleotides (>=10 units) are present within exonic sequences of >350 genes, resulting in vulnerability to cellular genetic integrity. Mature dinucleotide mutagenesis was examined experimentally using ex vivo and in vitro approaches. We observe an expansion bias for dinucleotide microsatellites up to 20 units in length in somatic human cells, in agreement with previous computational analyses of germ-line biases. Using purified DNA polymerases and human cell lines deficient for mismatch repair (MMR), we show that the expansion bias is caused by functional MMR and is not due to DNA polymerase error biases. Specifically, we observe that the MutSalpha and MutLalpha complexes protect against expansion mutations. Our data support a model wherein different MMR complexes shift the balance of mutations toward deletion or expansion. Finally, we show that replication fork progression is stalled within long dinucleotides, suggesting that mutational mechanisms within long repeats may be distinct from shorter lengths, depending on the biochemistry of fork resolution. Our work combines computational and experimental approaches to explain the complex mutational behavior of dinucleotide microsatellites in humans. PMID- 23450067 TI - Chiropractic management of low back pain in a patient with a transfemoral amputation. AB - OBJECTIVE: The purpose of this case report is to describe the chiropractic management of a patient with a unilateral transfemoral amputation and low back pain (LBP). CLINICAL FEATURES: A 20-year-old woman with right transfemoral amputation and a right upper extremity amputation due to amniotic band syndrome had approximately 40 different prosthetic lower extremities in the prior 20 years. She presented for chiropractic care for LBP (5/10 numeric pain scale) that she experienced after receiving a new right prosthetic leg. The pain increased with walking, attempts to exercise, and lying supine. Physical evaluation revealed asymmetrical leg length (long right limb); restricted left ankle dorsiflexion; restricted lumbopelvic motion; and hypertonicity of the left triceps surae muscle complex as well as the gluteus maximus, quadratus lumborum, and erector spinae bilaterally. Gait examination revealed a right Trendelenberg gait as well as a pattern of left vaulting. The working diagnosis was sacroiliac joint dysfunction, with lumbar facet syndrome secondary to a leg length inequality causing alteration in gait. INTERVENTION AND OUTCOME: Chiropractic management included manipulative therapy to the lumbar spine and pelvis, trigger point therapy of hypertonic musculature, and strengthening of pelvic musculature. In addition, the patient's prosthetist shortened her new prosthetic device. After 18 treatments, LBP severity was resolved (0/10); and there was an overall improvement with gait biomechanics. CONCLUSION: This case illustrates the importance of considering leg length inequality in patients with amputations as a possible cause of lower back pain, and that proper management may include adjusting the length of the prosthetic device and strengthening of the hip flexors and abductors, in addition to trigger point therapy and chiropractic manipulation. PMID- 23450068 TI - Assessment of clinical benefit and quality of life in patients undergoing cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for management of peritoneal metastases. AB - Peritoneal metastasis is a significant clinical challenge; life expectancy following diagnosis is usually very short. Surgical cytoreduction with HIPEC is being used with increasing frequency in selected patients; most outcome data have shown that prolonged median survivals can be observed in selected patients. This review summarizes the published data related to outcome and quality of life after cytoreduction and HIPEC to provide insights into its use in patients with peritoneal carcinomatosis. PMID- 23450069 TI - Visual surround suppression in schizophrenia. AB - Compared to unaffected observers patients with schizophrenia (SZ) show characteristic differences in visual perception, including a reduced susceptibility to the influence of context on judgments of contrast - a manifestation of weaker surround suppression (SS). To examine the generality of this phenomenon we measured the ability of 24 individuals with SZ to judge the luminance, contrast, orientation, and size of targets embedded in contextual surrounds that would typically influence the target's appearance. Individuals with SZ demonstrated weaker SS compared to matched controls for stimuli defined by contrast or size, but not for those defined by luminance or orientation. As perceived luminance is thought to be regulated at the earliest stages of visual processing our findings are consistent with a suppression deficit that is predominantly cortical in origin. In addition, we propose that preserved orientation SS in SZ may reflect the sparing of broadly tuned mechanisms of suppression. We attempt to reconcile these data with findings from previous studies. PMID- 23450071 TI - The Socio-Demographic Characteristics of the Clients of Female Sex Workers and their Perspectives, Behaviours and Attitude on HIV and AIDS: A Questionnaire Based Survey from Pokhara, Nepal. AB - BACKGROUND: The clients of Female Sex Workers (FSWs) have been represented from different socio-demographic backgrounds and their risk behaviour depends upon their learning skills and attitudes and its impacts on practice. OBJECTIVE: The general objective of this study was to find the socio-demographic characteristics, background, knowledge, behaviour, and the attitude on STIs, HIV and AIDS of the clients of female sex workers. MATERIAL AND METHODS: This questionnaire based, cross sectional study was conducted on 109 clients of FSWs during the time period from January 2010 to July 2010 in Pokhara (submetropolitan city of the Kaski district), Nepal. The locations were the Baglung Bus Park, Lakeside and Mahendrapool. RESULT: Among the 109 respondents, the mininum and the maximum age were 18 and 50 years. According to the religion-wise distribution, 77.1% of the respondents were Hindus, 10.1% were Buddhists, 8.3% were Christians, 1% were Muslims and 3.7% were from other religions. 67.9% of the respondents were tested for HIV at least once, whereas nearly one third (32.1%) of the respondents were never tested for HIV. 49.5% of the respondents answered that there was no difference between HIV and AIDS. Among the respondents, 89.9% respondents knew how to be safe from STIs and the HIV infections and 99.1% knew about HIV and AIDS. CONCLUSION: HIV and AIDS is a cross cutting issue in the present situation rather than a health issue. One of the most at risk groups is the clients of female workers who frequently have risk behaviours like having sex with female sex workers. The sexual behaviour among these clients depends upon their attitude, knowledge and perception, which also influence several internal and external factors. In our study, the clients of the female sex workers had some extent of knowledge about the condom, sexually transmitted infections and HIV/AIDS. They were made aware on these by different organizations who were working in the field of HIV and AIDS, but still they intended to practise unsafe sex with the female sex workers. PMID- 23450070 TI - Complete genome sequence of Syntrophobacter fumaroxidans strain (MPOB(T)). AB - Syntrophobacter fumaroxidans strain MPOB(T) is the best-studied species of the genus Syntrophobacter. The species is of interest because of its anaerobic syntrophic lifestyle, its involvement in the conversion of propionate to acetate, H2 and CO2 during the overall degradation of organic matter, and its release of products that serve as substrates for other microorganisms. The strain is able to ferment fumarate in pure culture to CO2 and succinate, and is also able to grow as a sulfate reducer with propionate as an electron donor. This is the first complete genome sequence of a member of the genus Syntrophobacter and a member genus in the family Syntrophobacteraceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 4,990,251 bp long genome with its 4,098 protein-coding and 81 RNA genes is a part of the Microbial Genome Program (MGP) and the Genomes to Life (GTL) Program project. PMID- 23450072 TI - Biaxial serial excision: A technique to deal with benign skin lesions and scars. AB - BACKGROUND: In the best of hands, the ultimate surgical scar of an otherwise well performed surgery is unpredictable, and surgical techniques are constantly evolving to prevent or revise large scars. The present series uses the principles of serial excision to reduce the eventual scar length. MATERIALS AND METHODS: Between January 1991 and December 2010, 30 patients were operated upon. In the first stage, a lesion was reduced in two dimensions with the intent to create a smaller lesion with the long axis favourably placed. The residual lesion was then excised after 4 weeks or more. RESULTS: The resultant scars were smaller and better aligned, with an excellent skin match. CONCLUSION: A well-planned serial excision in a biaxial manner helps reduce the final scar. PMID- 23450073 TI - Sequence Analysis and Comparison of 16S rRNA, 23S rRNA and 16S/23S Intergenic Spacer Region of Greening Bacterium Associated with Yellowing Disease (Huanglongbing) of Kinnow Mandarin. AB - High incidence (up to 40%) of symptoms of yellowing and yellow mottling was observed in 5-8 years old orchards of kinnow mandarin {Citrus reticulate Balanco ('King' * 'Willow mandarin')} in the Punjab state of India during a survey in January 2007. These symptoms are often confused with nutrient deficiency and other stress related disorders. However, a greening bacterium has been attributed to cause the disease. The disease was graft transmissible and sequencing of 16S rRNA, 16S/23S intergenic spacer region and 23S rRNA of the greening bacterium associated with yellowing disease in kinnow mandarin confirmed it to be Candidatus Liberibacter asiaticus ('Ca L. asiaticus') showing maximum identity of 95.9% with 'Ca L. asiaticus' from USA and Brazil in 16S rRNA. The study indicates definite association of 'Ca L. asiaticus' with yellowing/chlorotic mottling symptoms of greening disease of kinnow mandarin in Punjab state of India. PMID- 23450074 TI - Giving birth: "we just don't talk about it". AB - In this column, Alyson Grauer, a young woman recently embarking on her postuniversity career, shares her experiences with friends who do not talk about childbirth. She contrasts their fear and their unwillingness to talk and learn about birth with her own experience being the daughter of a Lamaze Certified Childbirth Educator and doula. Grauer's experiences provide a backdrop for a deeper understanding of young adults' beliefs about childbirth. Judith Lothian provides insight related to when and why women and men stopped talking about birth and the implications for childbirth education. PMID- 23450075 TI - Poor Man's 1000 Genome Project: Recent Human Population Expansion Confounds the Detection of Disease Alleles in 7,098 Complete Mitochondrial Genomes. AB - Rapid growth of the human population has caused the accumulation of rare genetic variants that may play a role in the origin of genetic diseases. However, it is challenging to identify those rare variants responsible for specific diseases without genetic data from an extraordinarily large population sample. Here we focused on the accumulated data from the human mitochondrial (mt) genome sequences because this data provided 7,098 whole genomes for analysis. In this dataset we identified 6,110 single nucleotide variants (SNVs) and their frequency and determined that the best-fit demographic model for the 7,098 genomes included severe population bottlenecks and exponential expansions of the non-African population. Using this model, we simulated the evolution of mt genomes in order to ascertain the behavior of deleterious mutations. We found that such deleterious mutations barely survived during population expansion. We derived the threshold frequency of a deleterious mutation in separate African, Asian, and European populations and used it to identify pathogenic mutations in our dataset. Although threshold frequency was very low, the proportion of variants showing a lower frequency than that threshold was 82, 83, and 91% of the total variants for the African, Asian, and European populations, respectively. Within these variants, only 18 known pathogenic mutations were detected in the 7,098 genomes. This result showed the difficulty of detecting a pathogenic mutation within an abundance of rare variants in the human population, even with a large number of genomes available for study. PMID- 23450076 TI - Bilateral mandibular distraction osteogenesis in the neonate with pierre robin sequence and airway obstruction: a primary option. AB - Children with craniofacial abnormalities associated with retromicrognathia and glossoptosis often have compromised upper airway flow. In severe cases, emergency intubation is necessary immediately after birth, and tracheostomy is advocated to manage the airway in the neonatal period and to allow for feeding. Early intervention with bilateral mandibular osteogenesis avoids the need for tracheostomy, along with its complications, and it targets the primary etiologic factor of the problem-the anomalous anatomy of the mandible. We report two neonates with severe Pierre Robin sequence managed with bilateral mandibular distraction osteogenesis on day 9 and day 11 of life. The surgical techniques and distraction and consolidation periods were similar apart from the distraction devices used. The procedures were successful with early extubation (day 5 and day 7), oral feeding tolerance (day 11 and day 13) and hospital discharge (day 19 and day 18). Total mandibular distraction was 19 mm and 23.45 mm, respectively. No major complications were reported. Medium to long-term results were good. Bilateral mandibular distraction osteogenesis in the neonate is a safe and accurate procedure and is the primary option in cases of selected severe Pierre Robin sequence. PMID- 23450077 TI - Holding Tight: Cell Junctions and Cancer Spread. AB - Cell junctions are sites of intercellular adhesion that maintain the integrity of epithelial tissue and regulate signalling between cells. These adhesive junctions are comprised of protein complexes that serve to establish an intercellular cytoskeletal network for anchoring cells, in addition to regulating cell polarity, molecular transport and communication. The expression of cell adhesion molecules is tightly controlled and their downregulation is essential for epithelial-mesenchymal transition (EMT), a process that facilitates the generation of morphologically and functionally diverse cell types during embryogenesis. The characteristics of EMT are a loss of cell adhesion and increased cellular mobility. Hence, in addition to its normal role in development, dysregulated EMT has been linked to cancer progression and metastasis, the process whereby primary tumors migrate to invasive secondary sites in the body. This paper will review the current understanding of cell junctions and their role in cancer, with reference to the abnormal regulation of junction protein genes. The potential use of cell junction molecules as diagnostic and prognostic markers will also be discussed, as well as possible therapies for adhesive dysregulation. PMID- 23450078 TI - A case of levofloxacin-induced anaphylaxis with elevated serum tryptase levels. AB - Levofloxacin, a fluoroquinolone and L-isomer of the racemate ofloxacin, has been approved for the treatment of acute and chronic bacterial infections. Gastrointestinal complaints are the most frequently reported adverse drug reactions to fluoroquinolones. Other adverse events include headache, dizziness, increased liver enzyme levels, photosensitivity, tachycardia, QT prolongation, and eruptions. Anaphylaxis has been documented as a rare adverse drug reaction to levofloxacin; however, diagnostic tests are needed to evaluate whether these reactions are the result of levofloxacin treatment. While the results of skin tests are considered unreliable due to false-positive responses, the oral provocation test is currently considered to be the most reliable test. Tryptase, a neutral protease, is the dominant protein component of secretory granules in human mast cells, and an increased serum concentration of tryptase is a highly sensitive indicator of anaphylaxis. Herein, we report a case of levofloxacin induced anaphylaxis in which the patient exhibited elevated serum tryptase levels and a positive oral levofloxacin challenge test result. As anaphylaxis is potentially life-threatening, the administration of fluoroquinolones to patients who have experienced a prior reaction to this type of agent should be avoided. PMID- 23450079 TI - Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects. AB - Bile acids play an important role in post-prandial glucose metabolism by stimulating release of glucagon-like peptide-1 (GLP-1) via the G-protein-coupled receptor TGR5, which is expressed in intestinal L cells. Thus, bile acid sequestrants are expected to stimulate secretion of endogenous GLP-1 through TGR5. We investigated incretin and insulin secretion after a meal with and without ursodeoxycholic acid (UDCA), a widely used therapeutic agent in liver diseases, in 7 non-diabetic Japanese subjects. We found that UDCA intake resulted in higher GLP-1 secretion (area under the curve [AUC] of 0-60 min after meal without UDCA, 450 +/- 162 mmol.min/l; with UDCA, 649 +/- 232 mmol.min/l, P = 0.046) and lower blood glucose (AUC of 0-60 min without UDCA, 7191 +/- 250 mg.min/dl; with UDCA, 6716 +/- 189 mg.min/dl, P = 0.001) , although we did not find statistically significant insulin increase by UDCA intake (AUC of 0-60 min without UDCA, 1551 +/- 418 MUU.min/ml; with UDCA, 1941 +/- 246 MUU.min/ml, P = 0.065). These results suggest that UDCA increases bile-induced GLP-1 secretion. Ours is the first report showing increased GLP-1 secretion and decreased blood glucose in response to UDCA. PMID- 23450080 TI - The effect of family-centered empowerment model on quality of life of school-aged children with thalassemia major. AB - BACKGROUND: Chronic nature of thalassemia causes changes in different aspects of life in patients, including their quality of life. Because of the important role of family in caring for children with thalassemia, this study was done to evaluate the effect of family-centered empowerment model on quality of life of the children aged 6-12 years with thalassemia in Kerman Thalassemia Center. METHODS: The present experimental study was carried out on 86 thalassemic children aged 6-12 years who were randomly divided into case and control groups. Data collection tools consisted of demographic and general quality of life questionnaires in children that included physical, emotional and social aspects in addition to school functions. The questionnaires were used after determination of content validity and reliability by internal correlation method. This model was performed in test group according to four steps (threat perception, problem solving, educational participation and evaluation). Quality of life was measured 1.5 months after the intervention. RESULTS: The results showed that the average quality of life of thalassemic children before the intervention was 26.23 in test group and 27.62 in the control group and they were not significantly different (p > 0.05). However after performing the model, the average quality of life in the test group reached 35.19 while it was 28.02 in control group and the observed difference was statistically significant (p < 0.05). CONCLUSIONS: According to the impact of this model on quality of life in thalassemic children, it is recommended that evaluating the effectiveness of this model should be considered in further studies of other ages and other chronic diseases. PMID- 23450081 TI - Transition to a novel advanced integrated vitrectomy platform: comparison of the surgical impact of moving from the Accurus vitrectomy platform to the Constellation Vision System for microincisional vitrectomy surgery. AB - BACKGROUND: Microincisional vitrectomy surgery (MIVS) is the current standard surgical approach for pars plana vitrectomy. Historically, the most common surgical platform for vitrectomy surgery, since its introduction in 1997, has been the Accurus vitrectomy system. Recent introduction of the next generation of vitrectomy platforms has generated concerns associated with transitioning to new technology in the operating room environment. This study compared, in a matched fashion, surgical use of the Accurus vitrectomy system and the next generation Constellation Vision System to evaluate surgical efficiencies, complications, and user perceptions of this transition. METHODS: Electronic health records were abstracted as a hospital quality assurance activity and included all vitreoretinal surgical procedures at the Bascom Palmer Eye Institute, Anne Bates Leach Eye Hospital, during two discrete 12-month time periods. These two periods reflected dedicated usage of the Accurus (June 2008-May 2009) and Constellation Vision (July 2009-June 2010) systems. Data were limited to a single surgeon and evaluated for operating room (OR) total time usage/day, OR case time/case, and OR surgical time/case. Further analysis evaluated all patients undergoing combined MIVS and clear cornea phacoemulsification/intraocular lens (IOL) implantation during each individual time period to determine the impact of the instrumentation on these parameters. All records were evaluated for intraoperative complications. RESULTS: Five hundred and fourteen eligible patients underwent MIVS during the 2 year study windows, with 281 patients undergoing surgery with the Accurus system and 233 patients undergoing surgery with the Constellation system. Combined MIVS and phacoemulsification with IOL implantation was performed 141 times during this period with the Accurus and 158 times during the second study period with the Constellation. Total number of patients operated per day increased from 7.55 with Accurus to 8.53 with Constellation. Surgical room time decreased from 56 minutes with Accurus to 52 minutes with Constellation, and procedure time decreased from 35 minutes with Accurus to 31 minutes with Constellation (P < 0.004). Combined MIVS/phacoemulsification surgery saw similar declines in surgical room time and procedure time (P < 0.001). Subset analysis of procedures limited by case number per day (eg, four cases/day, five cases/day, six cases/day, and seven or more cases/day) showed similar outcomes with a decrease in surgical room time and procedure time. No increases in surgery-related complications were noted by quality assurance review during these time periods. DISCUSSION: Transitioning to advanced surgical technology is a complex issue for the surgeon, the hospital team, and the hospital administration. This study documents improvement in three significant measures of surgical efficiency: operative number of patients per day, operative room time, and surgical procedure time that reflect the positive impact of the novel, combined, integrated, posterior and anterior, ophthalmologic surgical platform of the Constellation Vision System. These data are imperative to evaluate the impact of transition from one surgical platform to another. During this transition, hospital quality assurance review and surgeon evaluation of operative complications showed no increased concerns for the shift from the Accurus to the Constellation Vision System surgical platform. Further, both operative staff and surgeons felt that the transition to the Constellation was not associated with increases in difficulty with setup, turnover, or use and that the Constellation decreased safety concerns for surgical usage. Ultimately, in this case, new technology benefited the surgeon, the patient, and the hospital. PMID- 23450082 TI - Operant variability: a conceptual analysis. AB - Some researchers claim that variability is an operant dimension of behavior. The present paper reviews the concept of operant behavior and emphasizes that differentiation is the behavioral process that demonstrates an operant relation. Differentiation is conceived as change in the overlap between two probability distributions: the distribution of reinforcement probability as a function of some response property (S distribution) and the probability distribution of the response property itself (R distribution). This concept implies that the differentiation process can be measured only if S distribution and R distribution are both established on the same response property. To determine whether the differentially reinforced behavioral variability fits the proposed concept of operant behavior, I examine the main procedures (lag n and threshold procedures) and the main dependent variable (U value) employed in the studies of operant variability. Because lag n and threshold procedures establish their S distributions on properties distinct from U value, differentiation cannot be measured over the change in U value. I conclude that studies of operant variability have failed to provide a direct demonstration that variability is an operant dimension of behavior. Hence, studies in which measures of variability provide a basis to measure differentiation can better support the claim that variability is an operant dimension of behavior. PMID- 23450083 TI - The application of vizilite in oral cancer. AB - This article depicts the various applications of Vizilite plus in oral cancer. The oral cavity demonstrates a variety of red and white, pigmented and vesiculo- bullous lesions. Oral cancer still happens to carry the highest mortality worldwide, especially in India. In India, the prime focus is on the downstreaming of oral cancer from an advanced stage to an early diseased state. The techniques that are promoted to facilitate an earlier detection and diagnosis of an oral malignancy include Toluidine blue, ViziLite Plus with TBlue, ViziLite, Microlux DL, Orascoptic DK, VEL scope, Oral CDx and brush biopsy. PMID- 23450084 TI - Patient Satisfaction with Hyaluronic Acid Fillers for Improvement of the Nasolabial Folds in Type IV & V Skin. AB - INTRODUCTION: Soft tissue augmentation by hyaluronic acid filler injections has become the most commonly done cosmetic procedure in the last 10 years. These are now being widely used for improvement of the nasolabial folds. The present study was done to evaluate the patient satisfaction after these injections. MATERIALS AND METHODS: The study was conducted on 10 consenting patients. Hyaluronic acid filler (22.5 ml cross linked), 1 ml on each groove was injected under an infraorbital block. Patient satisfaction was evaluated at 0, 14, 30, and 180 days. Photographic record was maintained. Any side effects experienced by the patients were recorded. RESULTS: All the patients were satisfied immediately after the procedure. More than 50% were not happy at 14 days. Majority of the patients were happy at 30 days and the satisfaction was maintained at 6 months. CONCLUSION: Fillers are a very safe and effective modality for improving the nasolabial fold. This could prove to be a very useful tool in dental practice. Setting the patient expectations before the procedure is performed can lead to satisfied and happy patients. PMID- 23450085 TI - Migrated embolization coil: A rare cause of urinary tract obstruction. AB - Refractory bleeding following percutaneous nephrolithotomy (PCNL) is mainly due to formation of pseudoaneurysm. Transarterial embolization is required to control the bleeding in such cases. We report a case of post-PCNL hematuria in whom angioembolization was done. An early erosion of the embolization coil from the renal vasculature into the urinary collecting system occurred, causing urinary tract obstruction and urinary tract infection (UTI). The coil was retrieved ureteroscopically after control of UTI with antibiotics. Migration of embolization coil into urinary collecting system is a rare but important cause of urinary tract obstruction. The treating physician as well as the patient should be aware of this complication. PMID- 23450086 TI - In Vitro Antibacterial Activity of 4-Phenyl-1-(2-phenyl-allyl)pyridinium bromide: A Novel Class of Pyridinium Based Antibacterial Compounds. AB - The continuing increase in the incidence of multi drug resistant pathogenic bacteria and shortage of new antimicrobial agents are the prime driver in efforts to identify the novel antimicrobial classes. In vitro antibacterial activity of 4 phenyl-1-(2-phenylallyl) pyridinium bromide was tested against Gram positive Staphylococcus aureus, Streptococcus species, Bacillus subtilis, and Gram negative Klebsiella aerogenes and Escherichia coli using disk diffusion method. Among them S. aureus showed strong antibacterial activity (21.99 +/- 0.03 mm) while E. coli showed very little activity (8.97 +/- 0.06 mm) towards the compound. The MIC of 4-phenyl-1-(2-phenyl-allyl)-pyridinium bromide for 90% S. aureus was <=20 MUg/ml and was compared with phenoxymethylpenicillin, cloxacillin, erythromycin and vancomycin. When 4-phenyl-1-(2-phenyl allyl)pyridinium bromide showed MIC at <=20 MUg/ml, all others showed MIC at <=100 MUg/ml. Strong antibacterial activity of 4-phenyl-1-(2-phenyl allyl)pyridinium bromide against S. aureus indicates that there is a possibility to use it as an effective antibacterial agent. PMID- 23450087 TI - A shortened version of the Western ontario rotator cuff disability index: development and measurement properties. AB - PURPOSE: The objective of this study was to develop and examine the measurement properties of a shortened version of the Western Ontario Rotator Cuff Index (WORC), the SHORTWORC, in individuals with rotator-cuff pathology. METHODS: The study occurred in two stages, both using secondary analysis of existing data sets. The first stage used cross-sectional data from candidates for rotator-cuff surgery to develop the SHORTWORC. The second stage examined various measurement properties of the SHORTWORC by analyzing scores from the WORC, the American Shoulder and Elbow Surgeons questionnaire, and the Constant-Murley score obtained from patients before and after rotator-cuff surgery. Approaches to validating the SHORTWORC included calculating the standard error of measurement (SEM) at an instant in time, performing a confirmatory factor analysis, correlating findings among the questionnaires, and examining differences between men and women. Sensitivity to change was investigated using standardized response mean and relative efficiency. RESULTS: Data for 712 patients were used to develop the SHORTWORC, the final version of which consisted of 7 questions. Data for 166 patients (86 men, 80 women; mean age 57+/-11 years) were used for validation. The SEM based on internal consistency (SEMIC) was calculated as 7.43 SHORTWORC points. The SHORTWORC had similar convergent validity (r=0.72-0.82) and sensitivity to change (SRM=1.20 vs. 1.25, p>0.05) to the longer version. The relative efficiency of the SHORTWORC was 3.19 times that of the WORC (95% CI, 1.50-71.51) in discriminating men's from women's level of disability. CONCLUSIONS: The SHORTWORC has indicators of validity, relative efficiency, and sensitivity to change comparable to those of the original version but has a smaller response burden. : Purpose: The objective of this study was to develop and examine the measurement properties of a shortened version of the Western Ontario Rotator Cuff Index (WORC), the SHORTWORC, in individuals with rotator cuff pathology. Methods: The study occurred in two stages, both using secondary analysis of existing data sets. The first stage used cross-sectional data from candidates for rotator-cuff surgery to develop the SHORTWORC. The second stage examined various measurement properties of the SHORTWORC by analyzing scores from the WORC, the American Shoulder and Elbow Surgeons questionnaire, and the Constant-Murley score obtained from patients before and after rotator-cuff surgery. Approaches to validating the SHORTWORC included calculating the standard error of measurement (SEM) at an instant in time, performing a confirmatory factor analysis, correlating findings among the questionnaires, and examining differences between men and women. Sensitivity to change was investigated using standardized response mean and relative efficiency. Results: Data for 712 patients were used to develop the SHORTWORC, the final version of which consisted of 7 questions. Data for 166 patients (86 men, 80 women; mean age 57+/-11 years) were used for validation. The SEM based on internal consistency (SEMIC) was calculated as 7.43 SHORTWORC points. The SHORTWORC had similar convergent validity (r=0.72-0.82) and sensitivity to change (SRM=1.20 vs. 1.25, p>0.05) to the longer version. The relative efficiency of the SHORTWORC was 3.19 times that of the WORC (95% CI, 1.50-71.51) in discriminating men's from women's level of disability. Conclusions: The SHORTWORC has indicators of validity, relative efficiency, and sensitivity to change comparable to those of the original version but has a smaller response burden. PMID- 23450088 TI - Iodine based radiopacity of experimental blood clots for testing of mechanical thrombectomy devices. AB - BACKGROUND: Barium sulfate powder used for radiopacity of experimental blood clots (EBCs) for testing mechanical thrombectomy devices (MTD) has negative effects on EBCs mechanical properties. In vitro and in vivo exploration was performed to determine if the iodine based contrast medium will have less negative effects on the EBCs than barium. MATERIALS AND METHODS: Fresh blood from 2 swine was used to create fibrinogen enhanced and thrombin initiated EBC in tubes. Iodine radiopacity was achieved by mixing the blood with 65% Iohexol or by soaking the EBCs for 2 or 24 hours in Iohexol. The EBCs opacified with barium served as controls. In vitro study: The EBCs were subjected to four tests, manual elongation, catheter injection, radiopacity and contrast wash out tests. In vivo study: The common carotid arteries of 2 swine were embolized by either barium EBC or EBC soaked for 24 hours in Iohexol. The duration of radiopacity of the different EBCs was compared. RESULTS: The EBCs opacified with Iohexol initially had higher radiopacity than the barium opacified EBCs. However, their opacity rapidly decreased with saline soaking and, particularly, after they were embolized in live animals. The mechanical properties of Iohexol opacified EBCs were inferior to barium opacified EBCs. The Iohexol mixed EBCs were less firm and elastic and half of them fragmented during catheter injection. The Iohexol soaked EBCs exhibited decreased tensile strength and elasticity compared to the barium EBCs. CONCLUSIONS: Compared to barium, iodine based contrast medium does not offer any advantage for opacifying EBCs. PMID- 23450089 TI - Dispersal at a snail's pace: historical processes affect contemporary genetic structure in the exploited wavy top snail (Megastraea undosa). AB - We used population genetics to assess historical and modern demography of the exploited wavy top snail, Megastraea undosa, which has a 5-10 day pelagic larval duration. Foot tissue was sampled from an average of 51 individuals at 17 sites across the range of M. undosa. Genetic structure at the mtDNA locus is strikingly high (PhiST of 0.19 across 1000 km), and a major cline occurs in northern Baja California (PhiCT of 0.29 between northern and southern populations). Genetic data indicate that the northern region is highly connected through larval dispersal, whereas the southern region exhibits low genetic structure. However, additional analyses based on patterns of haplotype diversity and relationships among haplotypes indicate that M. undosa has likely recently expanded into the Southern California Bight or expanded from a small refugial population, and analysis using isolation by distance to calculate dispersal distance indicates surprisingly short estimates of dispersal from 30 m to 3 km. This scenario of a northward expansion and limited larval dispersal is supported by coalescent-based simulations of genetic data. The different patterns of genetic variation between northern and southern populations are likely artifacts of evolutionary history rather than differences in larval dispersal and this may have applications to management of this species. Specifically, these data can help to inform the scale at which this species should be managed, and given the potentially very small dispersal distances, this species should be managed at local scales. Consideration of the evolutionary history of target species allows for a more accurate interpretation of genetic data for management. PMID- 23450090 TI - Microsatellite analysis of genetic diversity and population structure of Arabian horse populations. AB - The Arabian horse ignites imagination throughout the world. Populations of this breed exist in many countries, and recent genetic work has examined the diversity and ancestry of a few of these populations in isolation. Here, we explore 7 different populations of Arabians represented by 682 horses. Three of these are Middle Eastern populations from near the historical origin of the breed, including Syrian, Persian, and Saudi Arabian. The remaining Western populations are found in Europe (the Shagya Arabian and Polish Arabian) and in America (American Arabian). Analysis of genetic structure was carried out using 15 microsatellite loci. Genetic distances, analysis of molecular variance, factorial correspondence analysis, and a Bayesian method were applied. The results consistently show higher level of diversity within the Middle Eastern populations than the Western populations. The Western Arabian populations were the main source among population variation. Genetic differentiation was not strong among all Middle Eastern populations, but all American Arabians showed differentiation from Middle Eastern populations and were somewhat uniform among themselves. Here, we explore the diversities of many different populations of Arabian horses and find that populations not from the Middle East have noticeably lower levels of diversity, which may adversely affect the health of these populations. PMID- 23450091 TI - Chronic suppurative otitis media and its association with socio-econonic factors among rural primary school children of bangladesh. AB - Chronic Suppurative Otitis Media (CSOM) is a common community health disorder of children in all developing countries like Bangladesh which causes significant impact in speech, cognitive, educational and psychological development. The aim of the study was to determine the prevalence of CSOM and its association with certain socio-economic factors and health related practice and believes among rural primary school children of Bangladesh. The study was done among 1468 rural school going children (Boys:Girls, 1:1.23) aged between 4 and 12 years (mean 8.8 +/- 1.66) in five randomly selected rural primary school of Palash Upazilla of Narsingdi district, Bangladesh. They had underwent ENT check up by the doctors trained in ENT and their guardians were interviewed regarding their socioeconomic status, health related practices and beliefs and other related issues using a pre tested protocol. Total 77 (5.2%) cases of CSOM were detected with girl's predominance (5.7 vs. 4.7%). Our study revealed statistically significant association of CSOM with yearly income of guardian (P < 0.005), maternal education (P < 0.001), bathing habit (P < 0.001), ear cleaning habit (P < 0.05), pattern of primary medical consultation (P < 0.05). Disease prevalence was also found higher among the dwellers of kachha house. So, this preventable burning problem of CSOM can be resolved by collective effort by incorporating primary ear care program with primary health care system among the vulnerable children of rural area along with their socio-economic development. Thus, future citizens can be safeguarded from developing CSOM, hearing impairment and its resultant complications. PMID- 23450092 TI - Acoustic radiation force impulse imaging of the liver: measurement of the normal mean values of the shearing wave velocity in a healthy liver. AB - AIM: To find the normal mean values of the liver elasticity/stiffness by Acoustic Radiation Force Impulse (ARFI) Elastography in healthy subjects. MATERIAL AND METHOD: This study was conducted on 137 healthy subjects without any known liver pathology or a history of jaundice by using the Siemens Acuson S2000TM Ultrasound machine with a convex probe . A routine ultrasound was also performed in each case, and the subjects with fatty liver changes or any other signs of a chronic liver pathology were excluded. In each subject, 10 measurements were taken and the median value of the 10 measurements was calculated, which was expressed in metres/sec (m/s). The inter quartile range method was used for the interpretation of the data. Only the measurements with an IQR of < 30% and a Success Rate (SR) of >60% were considered. The measurements were taken at 1-2 cm depth from the liver capsule through an intercostal approach, with the subject lying in the decubitus position. The mean ARFI values and the mean values according to the age and gender of the subjects were evaluated. RESULT: Valid ARFI measurements were taken in 108/137 patients (78.83%). The mean value of the ARFI measurements in the normal individuals was 1.197+/-0.25 m/s. There were no significant differences between the mean ARFI values in men vs women (1.195+/-.25 vs. 1.199+/ 0.26m/s, p = 0.939), and also among the different age groups (p>0.05). CONCLUSION: In our study, the mean liver elasticity value (shearing wave velocity) which was obtained by ARFI in the healthy subjects was 1.197+/-0.25 m/s. PMID- 23450094 TI - Images: granular cell tumour of the breast mimics a malignancy. AB - Five percent of granular cell tumour occurs in the breast. They are benign in nature but mimick a carcinoma on imaging (mammography and breast ultrasound). We present radilogical and histopathological images of granular cell tumour in the breast. PMID- 23450093 TI - Unequal recombination and evolution of the mating-type (MAT) loci in the pathogenic fungus Grosmannia clavigera and relatives. AB - Sexual reproduction in fungi is regulated by the mating-type (MAT) locus where recombination is suppressed. We investigated the evolution of MAT loci in eight fungal species belonging to Grosmannia and Ophiostoma (Sordariomycetes, Ascomycota) that include conifer pathogens and beetle symbionts. The MAT1-2 idiomorph/allele was identified from the assembled and annotated Grosmannia clavigera genome, and the MAT locus is flanked by genes coding for cytoskeleton protein (SLA) and DNA lyase. The synteny of these genes is conserved and consistent with other members in Ascomycota. Using sequences from SLA and flanking regions, we characterized the MAT1-1 idiomorph from other isolates of G. clavigera and performed dotplot analysis between the two idiomorphs. Unexpectedly, the MAT1-2 idiomorph contains a truncated MAT1-1-1 gene upstream of the MAT1-2-1 gene that bears the high-mobility-group domain. The nucleotide and amino acid sequence of the truncated MAT1-1-1 gene is similar to its homologous copy in the MAT1-1 idiomorph in the opposite mating-type isolate, except that positive selection is acting on the truncated gene and the alpha(alpha)-box that encodes the transcription factor has been deleted. The MAT idiomorphs sharing identical gene organization were present in seven additional species in the Ophiostomatales, suggesting that the presence of truncated MAT1-1-1 gene is a general pattern in this order. We propose that an ancient unequal recombination event resulted in the ancestral MAT1-1-1 gene integrated into the MAT1-2 idiomorph and surviving as the truncated MAT1-1-1 genes. The alpha-box domain of MAT1-1-1 gene, located at the same MAT locus adjacent to the MAT1-2-1 gene, could have been removed by deletion after recombination due to mating signal interference. Our data confirmed a 1:1 MAT/sex ratio in two pathogen populations, and showed that all members of the Ophiostomatales studied here including those that were previously deemed asexual have the potential to reproduce sexually. This ability can potentially increase genetic variability and can enhance fitness in new, ecological niches. PMID- 23450095 TI - Evaluation of certain dentofacial characteristics as predisposing factors in patients with myofacial pain dysfunction syndrome. AB - Though a multifactorial etiology has been comprehensively documented in the literature over the years for temporomandibular joint (TMJ) disorder, none of the theories give a total explanation of all aspects of the syndrome. The aim of this study was to evaluate face form and certain occlusal parameters as relevant factors in the degree of dysfunction of the Temporomandibular joint. One hundred and three patients suffering from TMJ dysfunction attending the Out Patient Department of Dr R. Ahmed Dental College over a period of 2 years were clinically examined and subsequently tabulated and compared with the degree of dysfunction to analyze any correlation between them. The data were statistically analyzed by the student t test and chi(2) test to assess the significance of the dysfunction in relation to the various parameters examined. The study indicated a positive relationship between the degree of dysfunction of the TMJ to the face form and certain other attributes. PMID- 23450096 TI - Placenta previa and pre-eclampsia: analyses of 1645 cases at medani maternity hospital, Sudan. AB - A retrospective case-control study was conducted to investigate the risk factors for pre-eclampsia - including the protective effect of placenta previa - at Medani Maternity Hospital, Sudan. Medical files of the patients during the period 2003-2010 were reviewed for age, parity, education level, prenatal care, placenta previa, and hemoglobin level. Women with pre-eclampsia were the cases, and women with normal pregnancy were the controls. There were 54,339 singleton deliveries and 1765 women with pre-eclampsia in the hospital, giving the incidence of pre eclampsia of 3.2%. The risk factors for pre-eclampsia were; women with age >35 years (OR = 1.4, 95% CI: 1.1-1.8), primiparity (OR = 3.3, 95% CI: 2.7-4.0), para >5 (OR = 3.1, 95% CI: 2.4-4.0), and anemia (OR = 3.3, 95% CI: 2.8-3.9). The risk of pre-eclampsia was inversely increased with education level and prenatal care attendance. The prevalence of placenta previa was 0 (0%) and 55 (3.3%), P < 0.001 in pre-eclamptic and control women, respectively. Placenta previa was a significant protective factor of pre-eclampsia (OR = 0.3, 95% CI: 0.1-0.7). Although, the socio-demographic risk factors for pre-eclampsia observed among women at Medani hospital were similar to those found in other settings; placenta previa was associated with decreased incidence of pre-eclampsia. PMID- 23450097 TI - Palliative stenting of the digestive tract: a case series of a single centre. AB - BACKGROUND AND AIM: Obstruction of the gastrointestinal tract due to cancer can be treated with stenting. The aim was to review the local experience with endoscopic stenting. All patients treated with stenting in a ten years period from 2001-2010 were studied. RESULTS: Fifty one patients received 57 stents because of oesophageal cancer. Mean survival after stent placement was 141 days. No case of perforation occurred. In nine cases (17%) clogging with food occurred. Tumour overgrowth was noted in four cases. Twenty four patients received 28 stents in their colon or rectum. The stents were placed in the rectum (n=6), the sigmoid (n=14), the descending colon (n=1), and the transverse colon (n=3). Mean survival was 276 days. Perforation did not occur. Tumour ingrowth was seen in two patients. One patient received a second stent. Dislocation occurred in two cases. There were two cases of clogging (8%) by stool. Fourteen patients received a total of 18 stents because of obstructing stomach cancer. Mean survival after placement was 121 days. There was no perforation, one case of clogging, and four cases of tumour ingrowth. Eight patients had stent placement in their duodenum. Mean survival after stent placement was 84 days. No perforation or clogging occurred. But three cases of tumour ingrowth were seen. CONCLUSIONS: The present series shows that placement of expandable stents in the digestive tract in normal daily practice is feasible, safe, with a low number of complications, and provides good palliation for their remaining life. PMID- 23450098 TI - Occult osteoid osteoma presenting as shoulder pain: a case report. AB - OBJECTIVE: The purpose of this case study is to describe the clinical course and treatment of a patient with recalcitrant shoulder pain and osteoid osteoma. CLINICAL FEATURES: A 28-year-old man had a 2-year history of progressively worsening shoulder and midscapular pain. INTERVENTION AND OUTCOME: Before chiropractic consultation, he had been evaluated and treated by his family physician, an orthopedic surgeon, a neurologist, and a pain management specialist. The patient underwent arthroscopy with examination under anesthesia and debridement of a posterior labral tear and cervical spine epidural injections, but neither procedure relieved his symptoms. After seeking chiropractic care, presenting symptoms were reproducible during direct clinical examination; and an initial working diagnosis of secondary right glenohumeral impingement syndrome with coexisting scapulothoracic dyskinesis was made. After 2 weeks of chiropractic rehabilitation, therapy was stopped because of no change in symptoms. The patient was referred for orthopedic consultation. Another series of plain films were ordered, and follow-up magnetic resonance imaging revealed an osseous mass at the medial aspect of the proximal metadiaphyseal region of the right humerus, with a diagnosis of osteoid osteoma. The patient underwent radiofrequency thermoablation of the tumor nidus, which was unsuccessful and resulted in open surgical resection. Resolution of symptoms with minimal pain was reported 3 weeks after the surgery. Four years later, the patient's shoulder remains asymptomatic. CONCLUSION: This case demonstrates that osteoid osteoma may present with clinical features that mimic common functional musculoskeletal conditions of the shoulder. Information from the patient history and diagnostic imaging are important for diagnosis and appropriate management. PMID- 23450100 TI - NT-proBNP in Myocarditis after a Scorpion Sting Envenomation. AB - OBJECTIVE: This study was to evaluate the levels of NT-proBNP in patients with myocarditis which occurred after a scorpion sting envenomation. MATERIAL AND METHODS: A total of 30 patients with scorpion sting envenomation and 21 patients with heart failure which was caused by cardiomyopathy, were prospectively studied. The data included the patient demographics, clinical features, echocardiography and the NT-proBNP levels. RESULTS: An echocardiographic evidence of myocarditis with a left ventricular ejection fraction of less than 50%, was found in 22 patients. In all the 22 patients, NT-proBNP was significantly elevated. The NT-proBNP levels were very high in the patients with severe LV dysfunction. However, it was in the normal range in the patients without an evidence of myocarditis. The elevated NT-proBNP levels were correlated with the LV dysfunction and myocarditis. When they were compared with the patients with heart failure which was caused by cardiomyopathy, the NTproBNP levels were found to be significantly more elevated in scorpion sting myocarditis. CONCLUSIONS: The NT-proBNP levels were significantly elevated in myocarditis which occurred after a scorpion sting envenomation. PMID- 23450099 TI - Complete genome sequence of the facultatively chemolithoautotrophic and methylotrophic alpha Proteobacterium Starkeya novella type strain (ATCC 8093(T)). AB - Starkeya novella (Starkey 1934) Kelly et al. 2000 is a member of the family Xanthobacteraceae in the order 'Rhizobiales', which is thus far poorly characterized at the genome level. Cultures from this species are most interesting due to their facultatively chemolithoautotrophic lifestyle, which allows them to both consume carbon dioxide and to produce it. This feature makes S. novella an interesting model organism for studying the genomic basis of regulatory networks required for the switch between consumption and production of carbon dioxide, a key component of the global carbon cycle. In addition, S. novella is of interest for its ability to grow on various inorganic sulfur compounds and several C1-compounds such as methanol. Besides Azorhizobium caulinodans, S. novella is only the second species in the family Xanthobacteraceae with a completely sequenced genome of a type strain. The current taxonomic classification of this group is in significant conflict with the 16S rRNA data. The genomic data indicate that the physiological capabilities of the organism might have been underestimated. The 4,765,023 bp long chromosome with its 4,511 protein-coding and 52 RNA genes was sequenced as part of the DOE Joint Genome Institute Community Sequencing Program (CSP) 2008. PMID- 23450101 TI - Custom-made standardised over-dressings for torso burns; economical and efficient. AB - INTRODUCTION: Torso burns following debridement and skin grafting usually require fairly complex dressings. The dressing consists of an interface layer, an absorbent layer and a retaining layer. Although numerous inner dressings are now available from multiple manufacturers, Gamgee dressing (pad of cotton and gauze) is often used as an outer absorbent dressing. Dressing the torso is usually a challenge, and the purpose of this paper is to present a custom-made over dressing for torso burns, which reflects the current practice at our centre. MATERIALS AND METHODS: A U-shape cut is made at one end of the Gamgee to design the shoulder straps. This custom-made dressing is held in place by a custom designed netted vest. RESULTS: This custom-made over-dressing for the torso was found to be comfortable for patients, easily made from locally available materials, easy to apply, absorbent and not restrictive of movement. The shoulder straps prevent sliding of the Gamgee, and in a nonrestrictive way. The netted vest provides the required compression to keep the Gamgee in firm contact with the inner layers of the dressing without compromising respiration. CONCLUSION: In this report, we present our practice of a custom-made dressing that is very efficient and economical. We hope that this information will be of practical use to other centres managing burns. PMID- 23450102 TI - Make the stillborn baby and the loss real for the siblings: parents' advice on how the siblings of a stillborn baby can be supported. AB - This study aimed to investigate parents' advice to other parents on the basis of their own experiences of siblings' taking leave of a stillborn sister or brother. The study was a Web questionnaire study of 411 parents. The thematic content analysis resulted in two categories: "Make the stillborn baby and the loss real for the siblings" and "Take the siblings' resources and prerequisites into account." Parents' advised that siblings should see and hold the stillborn baby and, thus, be invited and included into the leave-taking process with respect to the siblings' feelings, resources, and prerequisites. Based on these findings, professional caregivers can usefully be proactive in their approach to facilitate and encourage the involvement of siblings. PMID- 23450104 TI - Low-Frequency Deep Brain Stimulation for Dystonia: Lower is Not Always Better. AB - BACKGROUND: It has been observed that low-frequency stimulation (LFS) may be effective for dystonia, and the use of LFS may alleviate the need for frequent battery changes in a subset of patients. The aim of this study was to analyze LFS as a strategy to treat deep brain stimulation (DBS) patients with various dystonias. METHODS: Subjects had to receive a minimum of 6 months of clinical follow-up at the University of Florida, and were required to have a minimum of 3 months on a LFS trial. Twenty-seven dystonia DBS patients were retrospectively analyzed from the UF-INFORM database. RESULTS: Thirteen subjects met inclusion criteria. Of the 13 subjects, all had bilateral internal pallidum (GPi) DBS, and five (38.5%) remained with at least one side on LFS settings at their last follow up (average follow up 24 months, range 6-46 months). Within the first 6 months, six (46%) subjects remained on LFS and seven (54%) were changed to high-frequency stimulation (HFS). Those who remained on LFS settings at 6 months were characterized by shorter disease durations than those on HFS settings. There were no significant differences in dystonia severity (Unified Dystonia Rating Scale and Burke-Fahn-Marsden Dystonia Rating Scale) at baseline between the two settings. The estimated battery life for LFS (79.9+/-30.5) was significantly longer than for HFS settings (32.2+/-13.1, p<0.001). DISCUSSION: LFS was ultimately chosen for 38.5% of all subjects. Although this study failed to yield solid predictive features, subjects on LFS tended to have shorter disease durations. PMID- 23450103 TI - Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates. AB - PURPOSE: Osteogenesis imperfecta (OI) has been treated with bisphosphonates for many years, with some clear clinical benefits. In adults, there are reports of a new pattern of atraumatic subtrochanteric fractures with bisphosphonate treatment. This study assesses if bisphosphonate treatment leads to an altered pattern of femoral fractures. METHODS: Retrospective review of imaging for a cohort of 176 bisphosphonate-treated OI patients to identify the locations of femoral fractures over a two-year period, as compared to a historical control group managed pre-bisphosphonates. RESULTS: Sixteen femoral fractures were identified in this time period in the bisphosphonate-treated group. All but two were within the subtrochanteric region. In comparison, the historical group composed of 26 femoral fractures-had a more widespread fracture pattern, with the most frequent location being the mid-diaphysis. Many of the subtrochanteric fractures in the treatment group occurred with minimal trauma. CONCLUSIONS: It appears that concerns over the treatment of the adult osteoporotic population with bisphosphonates are amplified and mirrored in OI. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs increase the risk of this type of injury, which warrants further modification of surgical management of the femur. PMID- 23450105 TI - Titanium mesh reconstruction of orbital roof fracture with traumatic encephalocele: a case report and review of literature. AB - Orbital roof fractures are rare. Traumatic encephaloceles in the orbital cavity are even rarer, with only 21 cases published to date. Orbital roof fractures are generally encountered in males between 20 and 40 years of age following automobile collision. We report a case of an orbital roof fracture with traumatic encephalocele into the left orbit. Early diagnosis and treatment are very important because the raised intraorbital pressure may irreversibly damage the optic nerve. Computed tomography with 3-D reconstruction, the imaging modality of choice, showed the displaced fracture fragment deep into the orbit. Reconstruction of the orbital roof should be performed in every case. We used an extracranial approach to elevate the fracture with titanium mesh to stabilize the fragment. The cosmetic results were excellent but delay in treatment was responsible for delayed recovery of vision. The case report is followed by a brief overview of orbital roof fractures including pertinent review of literature. PMID- 23450106 TI - Dorfman-chanarin syndrome: a case report. AB - An 8-year-old male child, diagnosed case of congenital ichthyosis presented with abdominal distension, hepatomegaly and pancytopenia. His peripheral blood and bone marrow showed clear punched out intracytoplasmic vacuolations in leucocytes (Jordans' anomaly). He had convergent strabismus, ectropion, blepharitis and genu valgum. He was diagnosed as a case of Dorfman-Chanarin syndrome. PMID- 23450107 TI - Voice handicap in essential tremor: a comparison with normal controls and Parkinson's disease. AB - BACKGROUND: Although voice tremor is one of the most commonly noted clinical features of essential tremor (ET), there are nearly no published data on the handicap associated with it. METHODS: The Voice Handicap Index (VHI) was self administered by participants enrolled in a research study at Columbia University Medical Center. The VHI quantifies patients' perceptions of handicap due to voice difficulties. Data from 98 ET cases were compared with data from 100 controls and 85 patients with another movement disorder (Parkinson's disease, PD). RESULTS: Voice tremor was present on examination in 25 (25.5%) ET cases; 12 had mild voice tremor (ETMild VT) and 13 had marked voice tremor (ETMarked VT). VHI scores were higher in ET cases than controls (p = 0.02). VHI scores among ETMarked VT were similar to those of PD cases; both were significantly higher than controls (p<0.001). The three VHI subscale scores (physical, functional, emotional) were highest in ETMarked VT, with values that were similar to those observed in PD. DISCUSSION: The voice handicap associated with ET had multiple (i.e., physical, functional, and emotional) dimensions. Moreover, ET cases with marked voice tremor on examination had a level of self-reported voice handicap that was similar to that observed in patients with PD. PMID- 23450108 TI - The innate immune response in house dust mite-induced allergic inflammation. AB - Hypersensitivity to house dust mite (HDM; Dermatophagoides sp.) allergens is one of the most common allergic responses, affecting up to 85% of asthmatics. Sensitization to indoor allergens is the strongest independent risk factor associated with asthma. Additionally, >50% of children and adolescents with asthma are sensitized to HDM. Although allergen-specific CD4(+) Th2 cells orchestrate the HDM allergic response through induction of IgE directed toward mite allergens, activation of innate immunity also plays a critical role in HDM induced allergic inflammation. This review highlights the HDM components that lead to activation of the innate immune response. Activation may due to HDM proteases. Proteases may be recognized by protease-activation receptors (PARs), Toll-like receptors (TLRs), or C-type lectin receptors (CTRs), or act as a molecular mimic for PAMP activation signaling pathways. Understanding the role of mite allergen-induced innate immunity will facilitate the development of therapeutic strategies that exploit innate immunity receptors and associated signaling pathways for the treatment of allergic asthma. PMID- 23450109 TI - Strategies for MCR image analysis of large hyperspectral data-sets. AB - Polymer microarrays are a key enabling technology for high throughput materials discovery. In this study, multivariate image analysis, specifically multivariate curve resolution (MCR), is applied to the hyperspectral time of flight secondary ion mass spectroscopy (ToF-SIMS) data from eight individual microarray spots. Rather than analysing the data individually, the data-sets are collated and analysed as a single large data-set. Desktop computing is not a practical method for undertaking MCR analysis of such large data-sets due to the constraints of memory and computational overhead. Here, a distributed memory High-Performance Computing facility (HPC) is used. Similar to what is achieved using MCR analysis of individual samples, the results from this consolidated data-set allow clear identification of the substrate material; furthermore, specific chemistries common to different spots are also identified. The application of the HPC facility to the MCR analysis of ToF-SIMS hyperspectral data-sets demonstrates a potential methodology for the analysis of macro-scale data without compromising spatial resolution (data 'binning'). Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 23450110 TI - Effects of walking on quality of life of mastectomy patients at selected hospitals of Tehran. AB - BACKGROUND: Breast cancer is the first-rank malignancy in women. Although surgery is the most common method of treatment, patients experience many threats both from the cancer and from the surgery itself. Exercises such as walking can improve body mass index, attitudes and life quality of patients. The aim of the present study was to determine the effect of walking on physical aspect of quality of life (QOL) in mastectomy patients in 2007. METHODS: Thirty four mastectomy patients took part in the study. Walking was performed in a flat surface 3 times a week, each lasting 30 minutes over 6 weeks. Data were collected by a questionnaire before and after the intervention and a self-report form. After identifying content and face validity of the questionnaire, its reliability was measured by Cronbach's alpha (alpha = 0.89) and test-retest (r = 0.91) methods. RESULTS: Mean scores (standard deviations) of physical, psychological, social, economic and religious aspects of QOL before the intervention were 64.55(8.10), 78.89 (5.81), 52.89 (10.74), 64.92 (8.64) and 64.76 (9.59), respectively. These aspects were 79.06 (25.62), 68.63 (16.29), 73.28 (15.32), 79.96 (12.57) and 82.54 (11.18) after the intervention, respectively. Total mean scores of QOL before the intervention was 66.16 (6.30) and increased to 75.74 (6.59) after the intervention with a significant difference in all aspects except the religious aspect. Therefore, this study showed the positive effects of walking on QOL of mastectomy patients. CONCLUSIONS: Patients with breast cancer experience physical as well as psychological malfunctions and fatigue during the condition and its treatment. Walking can solve many of their problems and, ultimately, improve their QOL. PMID- 23450111 TI - Short communication: Carboxylate functionalized superparamagnetic iron oxide nanoparticles (SPION) for the reduction of S. aureus growth post biofilm formation. AB - Biofilms formed by antibiotic resistant Staphylococcus aureus (S. aureus) continue to be a problem for medical devices. Antibiotic resistant bacteria (such as S. aureus) often complicate the treatment and healing of the patient, yet, medical devices are needed to heal such patients. Therefore, methods to treat these Biofilms once formed on medical devices are badly needed. Due to their small size and magnetic properties, superparamagnetic iron oxide nanoparticles (SPION) may be one possible material to penetrate Biofilms and kill or slow the growth of bacteria. In this study, SPION were functionalized with amine, carboxylate, and isocyanate functional groups to further improve their efficacy to disrupt the growth of S. aureus Biofilms. Without the use of antibiotics, results showed that SPION functionalized with carboxylate groups (followed by isocyanate then amine functional groups then unfunctionalized SPION) significantly disrupted Biofilms and retarded the growth of S. aureus compared to untreated Biofilms (by over 35% after 24 hours). PMID- 23450112 TI - Imaging techniques as predictive and prognostic biomarkers in renal cell carcinoma. AB - A number of imaging modalities are showing promise as predictive and prognostic biomarkers in advanced renal cell carcinoma. This review discusses progress to date in this exciting area and identifies areas of future promise. PMID- 23450113 TI - An assessment of air pollution and its attributable mortality in Ulaanbaatar, Mongolia. AB - Epidemiologic studies have consistently reported associations between outdoor fine particulate matter (PM2.5) air pollution and adverse health effects. Although Asia bears the majority of the public health burden from air pollution, few epidemiologic studies have been conducted outside of North America and Europe due in part to challenges in population exposure assessment. We assessed the feasibility of two current exposure assessment techniques, land use regression (LUR) modeling and mobile monitoring, and estimated the mortality attributable to air pollution in Ulaanbaatar, Mongolia. We developed LUR models for predicting wintertime spatial patterns of NO2 and SO2 based on 2-week passive Ogawa measurements at 37 locations and freely available geographic predictors. The models explained 74% and 78% of the variance in NO2 and SO2, respectively. Land cover characteristics derived from satellite images were useful predictors of both pollutants. Mobile PM2.5 monitoring with an integrating nephelometer also showed promise, capturing substantial spatial variation in PM2.5 concentrations. The spatial patterns in SO2 and PM, seasonal and diurnal patterns in PM2.5, and high wintertime PM2.5/PM10 ratios were consistent with a major impact from coal and wood combustion in the city's low-income traditional housing (ger) areas. The annual average concentration of PM2.5 measured at a centrally located government monitoring site was 75 MUg/m3 or more than seven times the World Health Organization's PM2.5 air quality guideline, driven by a wintertime average concentration of 148 MUg/m3. PM2.5 concentrations measured in a traditional housing area were higher, with a wintertime mean PM2.5 concentration of 250 MUg/m3. We conservatively estimated that 29% (95% CI, 12-43%) of cardiopulmonary deaths and 40% (95% CI, 17-56%) of lung cancer deaths in the city are attributable to outdoor air pollution. These deaths correspond to nearly 10% of the city's total mortality, with estimates ranging to more than 13% of mortality under less conservative model assumptions. LUR models and mobile monitoring can be successfully implemented in developing country cities, thus cost-effectively improving exposure assessment for epidemiology and risk assessment. Air pollution represents a major threat to public health in Ulaanbaatar, Mongolia, and reducing home heating emissions in traditional housing areas should be the primary focus of air pollution control efforts. PMID- 23450115 TI - Ureteroscopy-assisted retrograde nephrostomy for an obese patient. AB - Obesity is associated with increased surgical morbidity and mortality. We previously reported on the usefulness of ureteroscopy assisted retrograde nephrostomy (UARN) and here we report a case of renal calculi successfully treated with UARN during percutaneous nephrolithotomy (PCNL) in an obese patient. A 63-year-old female with left renal calculi was referred to Department of Urology, Ohguchi Higashi General Hospital. Her body mass index was 34.0 kg/m(2). Stone fragments were completely extracted. URS-assisted puncture from the renal collecting system to the skin under fluoroscopic guidance was a safe and easy procedure in our obese patient. PMID- 23450114 TI - Factors influencing the accuracy of cephalometric prediction of soft tissue profile changes following orthognathic surgery. AB - The cephalometric prediction of orthognathic treatment outcome is an important part of the surgical planning and the process of informed consent. The orthodontic and surgical changes must be described accurately prior to treatment in order to assess the treatment's feasibility, to optimize case management and to increase patient's understanding and acceptance of the recommended treatment. The aim of the present article was to investigate on the factors that could influence the accuracy of cephalometric prediction in planning orthognathic surgery. Review of the literature revealed that, besides factors directly related to the prediction method and its use, there exist a considerable number of factors which could affect significantly the accuracy of soft tissue response. These factors could be biological ones such as relapse, centre of mandibular rotation and individual variation in response to treatment and others such as gender, race, pre-operative soft tissue thickness and data bases for mean ratios of soft to hard tissue movement changes. Some of the factors affecting the accuracy of prediction of soft tissue response following orthognathic surgery are inevitable and there are others, difficult to control and predict. However, patients should be informed that predictions are only a guide, may not represent the actual result of the surgical outcome, and as such they should be implemented. PMID- 23450116 TI - Isolation of moderately halophilic pseudoalteromonas producing extracellular hydrolytic enzymes from persian gulf. AB - Extracellular hydrolytic enzymes such as amylases, proteases, lipases and DNases have quite diverse potential usages in different areas such as food industry, biomedical sciences and chemical industries, also it would be of great importance to have available enzymes showing optimal activities at different values of salt concentrations and temperature. Halophiles are the most likely source of such enzymes, because not only their enzymes are salt-tolerant, but many are also thermotolerant. The purpose of this study was isolation of hydrolytic extracellular enzyme producing halophilic bacteria from water and sediment of the Persian Gulf. Isolated bacteria from water and sediment were inoculated in media with concentration of 0-20% NaCl to determine the optimum salt concentration for growth, isolates were also inoculated in 4 types of solid medium containing substrates of 3 extracellular hydrolytic enzymes including amylase, Protease and Lipase, to determine the quantitative detection of enzyme production, selected strains after more accurate physiological and biochemical studies were identified regarding phylogeny and molecular characteristics using 16S rRNA technique. Isolated enzyme producing bacteria belong to Pseudoalteromonas genera. PMID- 23450117 TI - Draping education to promote patient dignity: canadian physiotherapy student and instructor perceptions. AB - PURPOSE: To determine the perceptions of educators and students in Canadian entry level professional physiotherapy programmes with respect to the current draping curriculum and the methods of delivery of that content and to determine if there is a need for additional draping education time and resources in these programmes. METHODS: Canadian university physiotherapy students (n=127) and educators (n=183) completed questionnaires designed by the authors. Data were collected via Survey Monkey, exported as Excel files, and analyzed using descriptive statistics and Pearson chi-square analysis. RESULTS: Students and educators agreed that dignity as a concept and draping as a skill to protect patient dignity are both important and should be included in Canadian physiotherapy curricula. Respondents also agreed that students often have difficulty with draping. Educators identified barriers to teaching draping while students identified components of an effective educational resource on draping. CONCLUSIONS: To enhance the development of effective draping skills among entry level physiotherapists, draping education should be included in Canadian physiotherapy curricula. An effective draping educational resource should be developed for educators and students. : Purpose: To determine the perceptions of educators and students in Canadian entry-level professional physiotherapy programmes with respect to the current draping curriculum and the methods of delivery of that content and to determine if there is a need for additional draping education time and resources in these programmes. Methods: Canadian university physiotherapy students (n=127) and educators (n=183) completed questionnaires designed by the authors. Data were collected via Survey Monkey, exported as Excel files, and analyzed using descriptive statistics and Pearson chi-square analysis. Results: Students and educators agreed that dignity as a concept and draping as a skill to protect patient dignity are both important and should be included in Canadian physiotherapy curricula. Respondents also agreed that students often have difficulty with draping. Educators identified barriers to teaching draping while students identified components of an effective educational resource on draping. Conclusions: To enhance the development of effective draping skills among entry-level physiotherapists, draping education should be included in Canadian physiotherapy curricula. An effective draping educational resource should be developed for educators and students. PMID- 23450118 TI - The value of the sagittal-oblique MRI technique for injuries of the anterior cruciate ligament in the knee. AB - BACKGROUND: Complete rupture of the anterior cruciate ligament (ACL) does not represent a diagnostic problem for the standard magnetic resonance (MR) protocol of the knee. Lower accuracy of the standard MR protocol for partial rupture of the ACL can be improved by using additional, dedicated MR techniques. The study goal was to draw a comparison between sagittal-oblique MR technique of ACL imaging versus flexion MR technique of ACL imaging and, versus ACL imaging obtained with standard MR protocol of the knee. PATIENTS AND METHODS: In this prospective study we included 149 patients who were referred to magnetic resonance imaging (MRI) examination due to knee soft tissues trauma during 12 months period. MRI signs of ACL trauma, especially detection of partial tears, number of slices per technique showing the whole ACL, duration of applied additional protocols, and reproducibility of examination were analysed. RESULTS: Accuracy of standard MRI protocol of the knee comparing to both additional techniques is identical in detection of a complete ACL rupture. Presentations of the partial ruptures of ACL using flexion technique and sagittal-oblique technique were more sensitive (p<0.001) than presentation using standard MR protocol. There was no statistically significant difference between MRI detection of the ruptured ACL between additional techniques (p> 0.65). Sagittal-oblique technique provides a higher number of MRI slices showing the whole course of the ACL and requires a shorter scan time compared to flexion technique (p<0.001). CONCLUSIONS: Both additional techniques (flexion and sagittal-oblique) are just as precise as the standard MR protocol for the evaluation of a complete rupture of the ACL, so they should be used in cases of suspicion of partial rupture of the ACL. Our study showed sagittal-oblique technique was superior, because it did not depend on patient's ability to exactly repeat the same external rotation if standard MR protocol was used or to repeat exactly the same flexion in flexion MR technique in further MR examinations. Sagittal-oblique technique does not require the patient's knee to be repositioned, which makes this technique faster. We propose this technique in addition to the standard MR protocol for detection of partial ACL tears. PMID- 23450119 TI - One-pot sequential C-N coupling and cross dehydrogenative couplings: synthesis of novel azole fused imidazo[1,2-a]pyridines. AB - An efficient one-pot protocol has been developed using sequential C-N coupling and intramolecular dehydrogenative cross-couplings for the synthesis of azole fused imidazo[1,2-a]pyridine derivatives in good yields (62-78%). PMID- 23450120 TI - Double lateral band transfer for treatment of traumatic hyperextension instability of the proximal interphalangeal joint: a report of two cases. AB - Post-traumatic hyperextension instability of the proximal interphalangeal joint may lead to pain, difficulty with initiating finger flexion, and a swan-neck deformity. Most techniques to correct a traumatic hyperextension deformity of the proximal interphalangeal joint require a window in the flexor retinaculum, retraction of the flexor tendons, and manipulation of the joint capsule with a conceivable potential for joint stiffness, tendon adhesions, and tendon bowstringing. We describe an extra-articular lateral band transfer technique that utilizes strips of both lateral bands and preserves the functional integrity of the flexor tendon sheath. PMID- 23450121 TI - Resonance-assisted hydrogen bonding induced nucleophilic addition to hamper ESIPT: ratiometric detection of cyanide in aqueous media. AB - For ratiometric "naked eye" detection of CN(-), an ESIPT exhibiting benzothiazole receptor (BHI) is designed having one aldehyde group ortho and the other aldehyde para to the OH group respectively. Due to RAHBs, the ortho aldehyde group is highly reactive undergoing nucleophilic cyanide addition selectively, which hampered ESIPT. This is also supported by DFT and TD-DFT calculations. PMID- 23450122 TI - Should the Functional Residual Capacity be Ignored? AB - AIM AND OBJECTIVES: The functional residual capacity was given the least importance than the other lung volume parameters. Studies have revealed the restrictive pattern of lung disease in patients with liver cirrhosis. We aimed to analyze the importance of the functional residual capacity and other lung volumes of cirrhotic patients. SUBJECTS AND METHODS: Forty (40) patients with cirrhosis (Child's-B) were enrolled in this study. The vital capacity was measured by an instrument called V02 Max 22. The other lung volumes which were measured were derived parameters. The functional residual capacity was measured by the nitrogen wash-out method. RESULTS: The measured value of the functional residual capacity was below normal as compared to the reference value. The total lung capacity and the vital capacity were positively correlated with the functional residual capacity. The residual volume was found to be increased in twelve out of forty cirrhotic patients. CONCLUSION: The functional residual capacity can be determined by the compliance of the lung and the chest wall. The patients with a reduced functional residual capacity may be suffering from dyspnoea, probably due to the restrictive pattern of the lung disease. Hence, the reduced lung volumes of the subjects may be due to the abnormalities in the mechanics of ventilation. PMID- 23450123 TI - Resource allocation for maximizing prediction accuracy and genetic gain of genomic selection in plant breeding: a simulation experiment. AB - Allocating resources between population size and replication affects both genetic gain through phenotypic selection and quantitative trait loci detection power and effect estimation accuracy for marker-assisted selection (MAS). It is well known that because alleles are replicated across individuals in quantitative trait loci mapping and MAS, more resources should be allocated to increasing population size compared with phenotypic selection. Genomic selection is a form of MAS using all marker information simultaneously to predict individual genetic values for complex traits and has widely been found superior to MAS. No studies have explicitly investigated how resource allocation decisions affect success of genomic selection. My objective was to study the effect of resource allocation on response to MAS and genomic selection in a single biparental population of doubled haploid lines by using computer simulation. Simulation results were compared with previously derived formulas for the calculation of prediction accuracy under different levels of heritability and population size. Response of prediction accuracy to resource allocation strategies differed between genomic selection models (ridge regression best linear unbiased prediction [RR-BLUP], BayesCpi) and multiple linear regression using ordinary least-squares estimation (OLS), leading to different optimal resource allocation choices between OLS and RR-BLUP. For OLS, it was always advantageous to maximize population size at the expense of replication, but a high degree of flexibility was observed for RR BLUP. Prediction accuracy of doubled haploid lines included in the training set was much greater than of those excluded from the training set, so there was little benefit to phenotyping only a subset of the lines genotyped. Finally, observed prediction accuracies in the simulation compared well to calculated prediction accuracies, indicating these theoretical formulas are useful for making resource allocation decisions. PMID- 23450124 TI - Optimizing hepatitis C therapy in HIV/hepatitis C virus (HCV) coinfected patients: Analysis of HCV viral kinetics on treatment. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is potentially curable, but the sustained virological response (SVR) has been shown to be lower in patients coinfected HIV. A single-centre experience treating individuals with HCV and HIV coinfection is reported. METHODS: Twenty-one patients who received standard doses of pegylated interferon with weight-based dosing of ribavirin (mean 14.3 mg/kg) were retrospectively reviewed. Qualitative HCV polymerase chain reaction (PCR) was performed prospectively every four weeks if the patient remained HCV PCR positive. All patients with HCV genotype 1 were treated for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks and 32 weeks to 36 weeks if their HCV RNA level was undetectable after four weeks (RVR4) or eight weeks (RVR8) of therapy, respectively. If RVR8 was not achieved, the treatment was continued for 48 weeks. RESULTS: There were no dropouts or dose reductions within the first 12 weeks of treatment. SVR status was available for 20 patients and adequate serum for viral kinetics analyses was available for 17 patients. Eighty per cent of the patients achieved SVR (50% genotype 1; 100% genotypes 2 and 3). The week 8 viral load remained elevated for all genotype 1 nonresponders. DISCUSSION: High effectiveness rates were seen, particularly in patients with HCV genotype 2 and 3 who were treated for shorter durations. HCV viral loads after eight weeks of therapy helped distinguish patients with HCV genotype 1 who would respond to therapy. INTRODUCTION: Hepatitis C virus (HCV) infection is potentially curable, but the sustained virological response (SVR) has been shown to be lower in patients coinfected HIV. A single-centre experience treating individuals with HCV and HIV coinfection is reported. METHODS: Twenty-one patients who received standard doses of pegylated interferon with weight-based dosing of ribavirin (mean 14.3 mg/kg) were retrospectively reviewed. Qualitative HCV polymerase chain reaction (PCR) was performed prospectively every four weeks if the patient remained HCV PCR positive. All patients with HCV genotype 1 were treated for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks and 32 weeks to 36 weeks if their HCV RNA level was undetectable after four weeks (RVR4) or eight weeks (RVR8) of therapy, respectively. If RVR8 was not achieved, the treatment was continued for 48 weeks. RESULTS: There were no dropouts or dose reductions within the first 12 weeks of treatment. SVR status was available for 20 patients and adequate serum for viral kinetics analyses was available for 17 patients. Eighty per cent of the patients achieved SVR (50% genotype 1; 100% genotypes 2 and 3). The week 8 viral load remained elevated for all genotype 1 nonresponders. DISCUSSION: High effectiveness rates were seen, particularly in patients with HCV genotype 2 and 3 who were treated for shorter durations. HCV viral loads after eight weeks of therapy helped distinguish patients with HCV genotype 1 who would respond to therapy. PMID- 23450125 TI - Functional impression technique for an ocular prosthesis. AB - The loss of an eye is the most devastating, psychologically damaging experience for a patient. All hope to bring such patients back to their accustomed and comfortable life-style rests on a cosmetically acceptable prosthesis. An intra orbital ocular prosthesis serves the purpose in those defects where the orbital margins are intact. Though the stock eye may match the natural eye's iris and sclera in color, the fit of the prosthesis to the tissue bed may not be as good as desired. Herein, a functional ocular impression technique is presented to achieve a better fit of the prosthesis to the defect area. This technique aims to combine cosmetic excellence with comfort for greater benefit to the patient. PMID- 23450126 TI - Scaled free-energy based reinforcement learning for robust and efficient learning in high-dimensional state spaces. AB - Free-energy based reinforcement learning (FERL) was proposed for learning in high dimensional state- and action spaces, which cannot be handled by standard function approximation methods. In this study, we propose a scaled version of free-energy based reinforcement learning to achieve more robust and more efficient learning performance. The action-value function is approximated by the negative free-energy of a restricted Boltzmann machine, divided by a constant scaling factor that is related to the size of the Boltzmann machine (the square root of the number of state nodes in this study). Our first task is a digit floor gridworld task, where the states are represented by images of handwritten digits from the MNIST data set. The purpose of the task is to investigate the proposed method's ability, through the extraction of task-relevant features in the hidden layer, to cluster images of the same digit and to cluster images of different digits that corresponds to states with the same optimal action. We also test the method's robustness with respect to different exploration schedules, i.e., different settings of the initial temperature and the temperature discount rate in softmax action selection. Our second task is a robot visual navigation task, where the robot can learn its position by the different colors of the lower part of four landmarks and it can infer the correct corner goal area by the color of the upper part of the landmarks. The state space consists of binarized camera images with, at most, nine different colors, which is equal to 6642 binary states. For both tasks, the learning performance is compared with standard FERL and with function approximation where the action-value function is approximated by a two-layered feedforward neural network. PMID- 23450127 TI - Synthesis of a cobalt(IV) ketimide with a squashed tetrahedral geometry. AB - Oxidation of [Li(THF)]2[Co(N=C(t)Bu2)4] with 1 equiv. of I2 generates Co(N=C(t)Bu2)4 in 85% yield. In the solid-state, this complex exhibits a squashed tetrahedral structure about the Co center. DFT calculations reveal this geometry arises, in part, to maximize ketimide-to-cobalt pi-donation. PMID- 23450128 TI - Evaluation of phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) and epidermal growth factor receptor (EGFR) gene mutations in pancreaticobiliary adenocarcinoma. AB - BACKGROUND: Phosphatidylinositol-3-kinase (PI3K) activation involves the epidermal growth factor receptor (EGFR) and plays an important role in cell survival signaling in pancreaticobiliary cancer. EGFR gene mutations have been correlated with clinical response to EGFR inhibitors in patients with advanced non-small cell lung cancer. This study examined the prevalence of PIK3CA and EGFR mutations in pancreaticobiliary cancer where erlotinib, an EGFR inhibitor, is approved for therapy. METHODS: Thirty patients who underwent pancreatectomy for pancreaticobiliary carcinoma were identified. Genomic DNA was extracted from formalin fixed paraffin embedded tumor and adjacent normal tissue, and exons 9 and 20 (for the PIK3CA gene) and exons 18-21 (for the EGFR gene) were amplified by PCR and sequenced. Literature review on EGFR and/or PIK3CA mutations in pancreaticobiliary adenocarcinomas was conducted. RESULTS: No mutations in either PIK3CA or EGFR genes were identified. The study identified one synonymous single nucleotide polymorphism (SNP) (rs1050171) in the coding region of EGFR. A previously unreported change, suspected to be a SNP, was observed in intron 18 of EGFR (IVS18+15, C>T). Review of the literature showed EGFR mutation rate of 2% and 10.5% in pancreatic and biliary tract carcinomas, respectively. PIK3CA mutations were found in 3.6% and 11.7% of pancreatic and biliary tract carcinomas, respectively. CONCLUSIONS: A low prevalence of EGFR or PIK3CA mutations exists in pancreatic cancer (<5%), indicating that mutation screening may not be as useful in determining prognosis or response to targeted inhibition. PMID- 23450129 TI - Copper-catalyzed aldol-type addition of ketones to aromatic nitriles: a simple approach to enaminone synthesis. AB - An efficient method for the synthesis of enaminones is described. The aldol-type addition of ketones to aromatic nitriles proceeded smoothly in the presence of a simple copper catalyst system (CuI-2,2'-bipyridine-NaO(t)Bu) in N,N dimethylformamide. Enaminones in satisfactory to excellent yields were produced using this technique. PMID- 23450130 TI - A broad-band capturing and emitting molecular triad: synthesis and photochemistry. AB - A novel broad-band capturing and emitting supramolecular triad useful for solar energy harvesting and building optoelectronic devices is reported. PMID- 23450131 TI - The Relationship of Serum Soluble Fas Ligand (sFasL) Level with the Extent of Coronary Artery Disease. AB - Fas/Fas ligand system contributes to the programmed cell death induced by myocardial ischemia. We investigated whether serum soluble Fas ligand (sFasL) level is independently related with the severity and extent of angiographically assessed coronary artery disease (CAD). We included 169 patients in this study. Two groups were formed based on the existence of a lesion on coronary angiography. First group included patients with normal coronary arteries (NCA; n = 53). Patients with atherosclerotic lesions were included in the second group (n = 116). We used the coronary vessel score (the number of the coronary arteries with a lesion leading to >= 50% luminal obstruction) and the Azar score to determine the extent and the severity of CAD. Standard enzyme-linked immunosorbent assay kits were used to measure serum sFasL levels. The serum sFasL level was higher in patients with CAD than in patients with NCA (0.52 +/- 0.23 mU/mL vs. 0.45 +/- 0.18 mU/mL, p = 0.023). The sFasL level correlated with Azar score (r = 0.231, p = 0.003) and with coronary vessel score (r = 0.269, p < 0.001). In the multivariate analysis, we found that age (beta: 0.188, p = 0.008), gender (beta: 0.317, p < 0.001), diabetes mellitus (DM; beta: 0.195, p = 0.008), and sFasL level (beta: 0.209, p = 0.003) were independently related with Azar score. When we used coronary vessel score as the dependent variable, we found that age (p = 0.020), gender (p < 0.001), DM (p = 0.006), and sFasL level (p = 0.001) were independent predictors. Serum sFasL level is associated with angiographically more severe CAD. Our findings suggest that sFasL level may be a biochemical surrogate of severe coronary atherosclerosis. PMID- 23450132 TI - Polymerization of a peptide-based enzyme substrate. AB - Polymers of norbornenyl-modified peptide-based enzyme substrates have been prepared via ring-opening metathesis polymerization (ROMP). Peptides displayed on water-soluble homopolymers retain the ability to be enzymatically processed by a disease-associated enzyme. In contrast, when the peptides are densely arrayed on a nanoparticle derived from a self-assembled amphiphilic block-copolymer, they function with reduced activity as enzymatic substrates. PMID- 23450133 TI - Complete genome sequence of Terriglobus saanensis type strain SP1PR4(T), an Acidobacteria from tundra soil. AB - Terriglobus saanensis SP1PR4(T) is a novel species of the genus Terriglobus. T. saanensis is of ecological interest because it is a representative of the phylum Acidobacteria, which are dominant members of bacterial soil microbiota in Arctic ecosystems. T. saanensis is a cold-adapted acidophile and a versatile heterotroph utilizing a suite of simple sugars and complex polysaccharides. The genome contained an abundance of genes assigned to metabolism and transport of carbohydrates including gene modules encoding for carbohydrate-active enzyme (CAZyme) family involved in breakdown, utilization and biosynthesis of diverse structural and storage polysaccharides. T. saanensis SP1PR4(T) represents the first member of genus Terriglobus with a completed genome sequence, consisting of a single replicon of 5,095,226 base pairs (bp), 54 RNA genes and 4,279 protein coding genes. We infer that the physiology and metabolic potential of T. saanensis is adapted to allow for resilience to the nutrient-deficient conditions and fluctuating temperatures of Arctic tundra soils. PMID- 23450134 TI - A chiral ionic polymer for direct visual enantioselective recognition of alpha amino acid anions. AB - A novel chiral ionic polymer exhibits high fluorescence enantioselectivity towards alpha-amino acid anions, and its solution appears bright green upon addition of (L)-alpha-amino acid anions, which can be clearly observed by the naked eye for direct visual enantioselective recognition. PMID- 23450135 TI - A study on the clinico-epidemiological profile and the outcome of snake bite victims in a tertiary care centre in southern India. AB - BACKGROUND: Snake bite is a common medical emergency and an occupational hazard, more so in tropical India, where farming is a major source of employment. The available data on the epidemiology of snake bite from the Indian subcontinent are sparse. Snake bite is a neglected disease that afflicts the most impoverished inhabitants of the rural areas in the tropical developing countries. AIMS: This study was carried out to describe the epidemiology, arrival delays, clinical features, complications, and the outcome of snakebites which were seen in a tertiary care hospital of southern India. SETTING: Sri Chamarajendra District Hospital which is attached to the Hassan Institute of Medical Sciences, Hassan, Karnataka, India. STUDY DESIGN: A record-based, retrospective, descriptive study. MATERIALS AND METHODS: One hundred eighty patients of snake bite were studied from January 2010 to December 2011. The data on the demographic factors, clinical features and complications, details of the treatment which was received and the outcome of the snake bite victims were recorded and analyzed. RESULTS: Among a total 180 cases of snake bite, there were 108 cases of viper bite which presented with haematotoxic manifestations and 74 elapid bites had neuroparalytic manifestations. The victims were predominantly males (60.5%) and they were aged 20-40 years. A majority of the victims are from the rural areas (81.1%) and most of the bites occurred during the day time (70.5%), mainly on the lower limbs (67.2%). The highest number of cases occurred during July- September. Most of the victims were farmers (54.4%) and plantation workers (30.5%), which suggested that snake bite was an occupational hazard. A reaction to the ASV was noted in 12.7% of the patients and the mortality rate in our study was 3.8%. CONCLUSION: In the tropics, snake bite is a rural and an occupational hazard among farmers, plantation workers, herders and hunters. Regular public health programmes regarding the prevention, pre -hospital management (first aid) and the importance of the early transfer to the hospital should be emphasized. PMID- 23450136 TI - An unprecedented 3-D SHG MOF material of silver(I) induced by chiral triple helices. AB - An unprecedented 3-D SHG-active metal-organic framework (MOF) of silver(I), Ag Amidn (1) (HAmidn: 2-amino-4,5-imidazoledicarbonitrile), has been successfully prepared by employing the new single ligand. The cooperative coordination of the imidazole and carbonitrile N atoms leads to the chiral triple helices accounting for the noncentrosymmetric space group, which are linked together to form a rare 10(3) topological structure. Ag-Amidn (1) with high thermal stability and insolubility may be considered as a potential second-order NLO material. PMID- 23450138 TI - Spreadsheet software to assess locomotor disability to quantify permanent physical impairment. AB - CONTEXT: Assessment of physical disability is an important duty of a plastic surgeon especially for those of us who are in an institutional practice. AIM: The Gazette of India notification gives a guideline regarding the assessment of the disability. However, the calculations as per the guidelines are time consuming. In this article, a spreadsheet program which is based on the notification is presented. The aim of this article is to design a spreadsheet program which is simple, reproducible, user friendly, less time consuming and accurate. MATERIALS AND METHODS: This spreadsheet program was designed using the Microsoft Excel. The spreadsheet program was designed on the basis of the guidelines in the Gazette of India Notification regarding the assessment of Locomotor Disability to Quantify Permanent Physical Impairment. Two representative examples are presented to help understand the application of this program. RESULTS: Two spreadsheet programs, one for upper limb and another for the lower limb are presented. The representative examples show the accuracy of the program to match the results of the traditional method of calculation. CONCLUSION: A simple spreadsheet program can be designed to assess disability as per the Gazette of India Notification. This program is easy to use and is accurate. PMID- 23450137 TI - Differences in Phosphorylated Histone H2AX Foci Formation and Removal of Cells Exposed to Low and High Linear Energy Transfer Radiation. AB - The use of particle ion beams in cancer radiotherapy has a long history. Today, beams of protons or heavy ions, predominantly carbon ions, can be accelerated to precisely calculated energies which can be accurately targeted to tumors. This particle therapy works by damaging the DNA of tissue cells, ultimately causing their death. Among the different types of DNA lesions, the formation of DNA double strand breaks is considered to be the most relevant of deleterious damages of ionizing radiation in cells. It is well-known that the extremely large localized energy deposition can lead to complex types of DNA double strand breaks. These effects can lead to cell death, mutations, genomic instability, or carcinogenesis. Complex double strand breaks can increase the probability of mis rejoining by NHEJ. As a consequence differences in the repair kinetics following high and low LET irradiation qualities are attributed mainly to quantitative differences in their contributions of the fast and slow repair component. In general, there is a higher contribution of the slow component of DNA double strand repair after exposure to high LET radiation, which is thought to reflect the increased amount of complex DNA double strand breaks. These can be accurately measured by the gamma-H2AX assay, because the number of phosphorylated H2AX foci correlates well with the number of double strand breaks induced by low or / and high LET radiation. PMID- 23450139 TI - Making bispirin: synthesis, structure and activity against Helicobacter pylori of bismuth(III) acetylsalicylate. AB - Reaction of Bi(O(t)Bu)3 with aspirin (acetylsalicylic acid = aspH) in dry toluene results in the bismuth(III) complex, [Bi(O2C(C6H4)OAc)3]infinity 1 (O2C(C6H4)OAc = asp), minimum inhibitory concentration (MIC) against Helicobacter pylori >= 6.25 MUg mL(-1), while the inclusion of a stoichiometric equivalent of KO(t)Bu leads to crystals of the bismuthate salt [KBi(O2C(C6H4)OAc)4]infinity 2. PMID- 23450140 TI - The utility of erythrocyte sedimentation rate values and white blood cell counts after spinal deformity surgery in the early (<=3 months) post-operative period. AB - PURPOSE: The erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count are frequently obtained in the work-up of post-operative fever. However, their diagnostic utility depends upon comparison with normative peri-operative trends which have not yet been described. The purpose of this study is to define a range of erythrocyte sedimentation rates and white blood cell counts following spinal instrumentation and fusion in non-infected patients. METHODS: Seventy-five patients underwent spinal instrumentation and fusion. The erythrocyte sedimentation rate and white blood cell count were recorded pre-operatively, at 3 and 7 days post-operatively, and at 1 and 3 months post-operatively. RESULTS: Both erythrocyte sedimentation rate and white blood cell count trends demonstrated an early peak, followed by a gradual return to normal. Peak erythrocyte sedimentation rates occurred within the first week post-operatively in 98% of patients. Peak white blood cell counts occurred with the first week in 85% of patients. In the absence of infection, the erythrocyte sedimentation rate was abnormally elevated in 78% of patients at 1 month and in 53% of patients at 3 months post-operatively. The white blood cell count was abnormally elevated in only 6% of patients at 1 month post-operatively. Longer surgical time was associated with elevated white cell count at 1 week post-operatively. The fusion of more vertebral levels had a negative relationship with elevated erythrocyte sedimentation rate at 1 week post-operatively. The anterior surgical approach was associated with significantly lower erythrocyte sedimentation rate at 1 month post-operatively and with lower white cell count at 1 week post-operatively. CONCLUSION: In non-infected spinal fusion surgeries, erythrocyte sedimentation rates are in the abnormal range in 78% of patients at 1 month and in 53% of patients at 3 months post-operatively, suggesting that the erythrocyte sedimentation rate is of limited diagnostic value in the early post-operative period. PMID- 23450141 TI - Reconstruction of periparotid defects using temporoparietal fascia flap with layered acellular human dermal allograft. AB - Excision of lesions in the periparotid area can leave a sizable concavity of the preauricular area with skeletonization of the mandible. To achieve the bulk necessary to fill this defect, we propose using a composite graft. Acellular human dermal allograft provides the thickness of the graft, and the temporoparietal fascia flap provides blood supply to the dermal graft. Our hypothesis is that vascularization of the graft will promote greater ingrowth of native tissue and prevent breakdown and absorption of the graft. Four representative patients are described. PMID- 23450142 TI - Palladium-catalyzed decarboxylative C2-acylation of indoles with alpha oxocarboxylic acids. AB - A palladium-catalyzed decarboxylative C2-acylation of indoles with alpha oxocarboxylic acids was achieved. This protocol represents a novel and complementary approach to 2-aroylindoles. PMID- 23450144 TI - Transient leukaemia: leukaemia or leukaemoid? A diagnostic dilemma. AB - We report a case of a newborn male who had mongoloid slant and was hypotonic at birth. Routine investigations revealed leucocytosis (WBC > 70,000/cmm) with 50% blasts in peripheral blood film. Marrow examination confirmed the excess of blasts. Karyotyping revealed 47, XY + 21 chromosomes. Due to absence of clinical symptoms, the baby was kept on follow-up without treatment. Within 7 weeks, PBF and bone marrow findings returned to normal, and the child was diagnosed as having Transient leukaemia with Down syndrome. PMID- 23450145 TI - Seasonal Specificity of Seasonal Allergens and Validation of the ARIA Classification in Korea. AB - PURPOSE: In Korea, tree pollens are known to be prevalent in spring, grass pollens in summer and weed pollens in autumn. However, few studies have revealed their seasonal specificity for allergic rhinitis symptoms. An ARIA (Allergic Rhinitis and its Impact on Asthma) classification of allergic rhinitis was recently introduced and its clinical validation has not been well proved. The aim of this study was to evaluate the seasonal specificity of seasonal allergens and to validate the ARIA classification with the conventional seasonal and perennial allergic rhinitis (SAR/PAR) classification. METHODS: Two hundred twenty six patients with allergic rhinitis were included in this study. The patients were classified according to the sensitized allergens and the ARIA classifications. A questionnaire survey was performed and the data on the seasonal symptom score, the severity of symptoms and the SNOT (sinonasal outcome test)-20 score was obtained and the data was analyzed and compared between the conventional SAR/PAR classification and the ARIA classification. RESULTS: Seasonal pollens (tree, grass, weed) were not specific to the pollen peak season and the patients' symptoms were severe during spring and autumn regardless of the offending pollens. More than 60% of the patients with SAR showed persistent symptoms and 33% of the patients with perennial allergic rhinitis (PAR) had intermittent symptoms, showing the lack of association between the SAR/PAR/PAR+SAR classification and the ARIA classification. The ARIA classification showed better association not only with the symptomatic score, but also with the SNOT-20 score, which showed better validity than the conventional SAR/PAR classifications. CONCLUSIONS: Seasonal pollens were not specific to their season of prevalence in terms of the severity of symptoms, and the ARIA classification showed better representation of allergic symptoms and quality of life (SNOT-20 score) than did the SAR/PAR classification. PMID- 23450146 TI - A comparative study on satisfaction from hormonal contraceptives: depot medroxyprogesterone acetate (DMPA), Cyclofem and LD. AB - BACKGROUND: Irregular population growth is considered as a serious threat to the international community and is also a major obstacle for nations' social and economic development. Thus, one of the ways to have a healthy community is to control the population and provide safe and effective contraceptive methods. Hormonal contraceptives are the most effective method of birth spacing. The present study aimed to determine and compare satisfaction from hormonal contraceptives including depot medroxyprogesterone acetate (DMPA), Cyclofem and LD in women referred to selected health care centers of Isfahan in 2010. METHODS: This was a descriptive-comparative study with cross-sectional data collection method from 26 April 2010 to 28 October 2010. Simple non-probability sampling was used to select 150 individuals (divided into three groups of 50) among the females who referred to 8 selected health care centers in Isfahan to receive DMPA, Cyclofem, or LD for the first time, and/or those who had used contraceptives for three months. To assess satisfaction rate and its related factors, the standard ORTHO Birth Control Satisfaction Assessment Tool (BC-SAT) was completed three months after medicine consumption through interviewing. Data was analyzed using descriptive and inferential statistics (Fisher's exact, chi square, ANOVA, and LSD tests). RESULTS: There were no significant differences in terms of mean score of satisfaction between the three groups. Cyclofem (192.2) and DMPA (188.1) gained the highest and lowest mean satisfaction scores, respectively. Although the mean satisfaction score in areas of ease of use/appropriateness, interference in menstruation pattern, acceptance and continuation of the method had significant differences in three groups, no statistically significant difference was observed in lifestyle, confidence to the method, side effects, concerns about future pregnancies and total satisfaction. CONCLUSIONS: Generally, there was no difference in satisfaction from the three studied hormonal contraceptives. PMID- 23450143 TI - Key issues in essential tremor genetics research: Where are we now and how can we move forward? AB - BACKGROUND: Genetics research is an avenue towards understanding essential tremor (ET). Advances have been made in genetic linkage and association: there are three reported ET susceptibility loci, and mixed but growing data on risk associations. However, causal mutations have not been forthcoming. This disappointing lack of progress has opened productive discussions on challenges in ET and specifically ET genetics research, including fundamental assumptions in the field. METHODS: This article reviews the ET genetics literature, results to date, the open questions in ET genetics and the current challenges in addressing them. RESULTS: SEVERAL INHERENT ET FEATURES COMPLICATE GENETIC LINKAGE AND ASSOCIATION STUDIES: high potential phenocopy rates, inaccurate tremor self-reporting, and ET misdiagnoses are examples. Increasing use of direct examination data for subjects, family members, and controls is one current response. Smaller moves towards expanding ET phenotype research concepts into non-tremor features, clinically disputed ET subsets, and testing phenotype features instead of clinical diagnosis against genetic data are gradually occurring. The field has already moved to considering complex trait mechanisms requiring detection of combinations of rare genetic variants. Hypotheses may move further to consider novel mechanisms of inheritance, such as epigenetics. DISCUSSION: It is an exciting time in ET genetics as investigators start moving past assumptions underlying both phenotype and genetics experimental contributions, overcoming challenges to collaboration, and engaging the ET community. Multicenter collaborative efforts comprising rich longitudinal prospective phenotype data and neuropathologic analysis combined with the latest in genetics experimental design and technology will be the next wave in the field. PMID- 23450147 TI - High throughput discovery of thermo-responsive materials using water contact angle measurements and time-of-flight secondary ion mass spectrometry. AB - Switchable materials that alter their chemical or physical properties in response to external stimuli allow for temporal control of material-biological interactions, thus, are of interest for many biomaterial applications. Our interest is the discovery of new materials suitable to the specific requirements of certain biological systems. A high throughput methodology has been developed to screen a library of polymers for thermo-responsiveness, which has resulted in the identification of novel switchable materials. To elucidate the mechanism by which the materials switch, time-of-flight secondary ion mass spectrometry has been employed to analyse the top 2 nm of the polymer samples at different temperatures. The surface enrichment of certain molecular fragments has been identified by time-of-flight secondary ion mass spectrometry analysis at different temperatures, suggesting an altered molecular conformation. In one example, a switch between an extended and collapsed conformation is inferred. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 23450148 TI - Molecular guided therapy for advanced pancreatic cancer patients with PI3K activated mutation: vision or illusion? AB - Despite a modern validated regimen of chemotherapy, advanced pancreatic adenocarcinoma remains the fourth most common cause of cancer-related death worldwide. The phosphoinositide 3-kinase pathway (PI3K)/Akt/mammalian target of rapamycin (mTOR) is a major signaling pathway that may be activated in advanced pancreatic cancer. To highlight the potential interest of this targetable pathway in selected advanced pancreatic cancer patients, we report herein a patient with an activated PI3K mutation who was treated in a phase I trial evaluating a treatment combination including an mTOR inhibitor. PMID- 23450149 TI - Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. AB - Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important. PMID- 23450151 TI - Highly luminescent water-soluble quaternary Zn-Ag-In-S quantum dots for tumor cell-targeted imaging. AB - Exploring the synthesis and biomedical applications of biocompatible quantum dots (QDs) is currently one of the fastest growing fields of nanotechnology. Hence, in this work, we present a facile approach to produce water-soluble (cadmium-free) quaternary Zn-Ag-In-S (ZAIS) QDs. Their efficient photoluminescence (PL) emissions can be tuned widely in the range of 525-625 nm by controlling the size and composition of the QDs with the PL quantum yields (QYs) of 15-30%. These highly luminescent ZAIS QDs are less toxic due to the absence of highly toxic cadmium, and can be versatilely modified by a DHLA-PEG-based ligand. Importantly, after being modified by tumor cell-specific targeting ligands (e.g., folate and RGD peptide), the PEGylated quaternary QDs show potential applications in tumor cell imaging as a promising alternative for Cd-based QDs. PMID- 23450152 TI - Halogen bonding and other sigma-hole interactions: a perspective. AB - A sigma-hole bond is a noncovalent interaction between a covalently-bonded atom of Groups IV-VII and a negative site, e.g. a lone pair of a Lewis base or an anion. It involves a region of positive electrostatic potential, labeled a sigma hole, on the extension of one of the covalent bonds to the atom. The sigma-hole is due to the anisotropy of the atom's charge distribution. Halogen bonding is a subset of sigma-hole interactions. Their features and properties can be fully explained in terms of electrostatics and polarization plus dispersion. The strengths of the interactions generally correlate well with the magnitudes of the positive and negative electrostatic potentials of the sigma-hole and the negative site. In certain instances, however, polarizabilities must be taken into account explicitly, as the polarization of the negative site reaches a level that can be viewed as a degree of dative sharing (coordinate covalence). In the gas phase, sigma-hole interactions with neutral bases are often thermodynamically unfavorable due to the relatively large entropy loss upon complex formation. PMID- 23450150 TI - Alzheimer's disease: which type of amyloid-preventing drug agents to employ? AB - The current paradigm in the amyloid hypothesis brands small beta-amyloid (Abeta) oligomers as the toxic species in Alzheimer's disease (AD). These oligomers are fibril-like; contain beta-sheet structure, and present exposed hydrophobic surface. Oligomers with this motif are capable of penetrating the cell membrane, gathering to form toxic ion channels. Current agents suppressing precursor Abeta cleavage have only met partial success; and to date, those targeting the peptides and their assemblies in the aqueous environment of the extracellular space largely fail in clinical trials. One possible reason is failure to reach membrane embedded targets of disease-'infected' cells. Here we provide an overview, point to the need to account for the lipid environment when aiming to prevent the formation of toxic channels, and propose a combination therapy to target the species spectrum. PMID- 23450153 TI - Management of a renal calculus larger than 4 cm in a patient with tuberous sclerosis complex-associated angiomyolipoma. AB - Renal calculi in patients with renal angiomyolipomas are difficult to treat because of the hemorrhagic potential of these tumors. We describe the case of a 65-year-old man having tuberous sclerosis complex-associated multifocal renal angiomyolipomas with a large renal calculus. The patient presented with left flank dullness and a previous history of spontaneous angiomyolipoma rupture. Intravenous pyelography revealed a 43 * 16 mm calculus in the pelvis and lower calyx of the left kidney. The calculus was successfully removed by retrograde flexible ureterorenoscopy and holmium-YAG lithotripsy. Flexible ureterorenoscopy is an effective, minimally invasive therapy for patients at high risk of renal hemorrhage. PMID- 23450154 TI - Arthrocentesis in TMJ Internal Derangement: A Prospective Study. AB - OBJECTIVES OF THE STUDY: To evaluate improvement in symptoms following arthrocentesis: Pain, Maximum Mouth Opening, Clicking/Crepitation. METHOD: Eleven patients who reported to the department of Oral and Maxillofacial Surgery, M S Ramaiah Dental College, Bangalore clinically diagnosed to have Internal Derangement of the TMJ underwent Arthrocentesis. Patients were evaluated at the end of 1 week, 1 and 3 months and results tabulated. RESULTS: 11 patients with clinically diagnosed Internal Derangement underwent Arthrocentesis and were followed up for 3 months. There was significant improvement in Pain, Maximum Mouth Opening and Clicking/Crepitation. All the results were statistically significant. There was no serious post operative complication. CONCLUSION: Arthrocentesis can be recommended as a simple chair-side procedure for the treatment of TMJ Internal Derangement refractory to conservative management. PMID- 23450155 TI - Infrared multiple photon dissociation (IRMPD) spectroscopy of oxazine dyes. AB - The structure and energetic properties of four common oxazine dyes, Nile red, Nile blue A, Cresyl violet, and Brilliant cresyl blue, have been probed using a combination of infrared multiple-photon dissociation (IRMPD) spectroscopy and quantum chemical calculations. IRMPD spectra of the protonated dyes, as generated from an electrospray ionization (ESI) source, were collected in the range of 900 1800 cm(-1). Vibrational band assignments related to carbonyl and substituted amine stretches were established from a comparison of the experimental spectra of these related systems as well as from a comparison with spectra generated by density functional theory (DFT) calculations. For Nile red, the thermochemical landscape for protonation at different basic sites was probed using DFT; comparison of IRMPD and calculated IR spectra reveals the site of protonation to be at the carbonyl oxygen. The structural information obtained here in the gas phase pertaining to these important fluorophores is anticipated to provide further insight into their associated intrinsic fluorescent properties in solution. PMID- 23450156 TI - Citrate milling of oxides: from poly-dispersed micron scale to nearly mono dispersed nanoscale. AB - Complex (multivalent/mixed valent) oxides involving two or more cations (e.g. ABO3, AB2O4 and A2B2O7) exhibit the most fascinating range of physical and chemical properties amongst the family of materials systems. There is growing interest in nanoscale forms of such oxides which emanates from the novel changes in their properties with size. To obtain nanomaterials with a high degree of crystallinity it is desirable to first make crystalline oxide powders by high temperature processing and then mill them down to nanometer size. In this paper we show that simple citric acid treatment of BiFeO3 and Bi2O3 powders leads to the desired micron-scale to nanoscale transformation, yielding nearly monodispersed nanoparticles. Importantly, these are highly dispersible and stable in water. By performing similar experiments on Fe3O4 and Fe2O3 we have elucidated the possible mechanism, which hinges on valence-controlled dissolution and ripening phenomena. PMID- 23450157 TI - Delftia acidovorans as an Unusual Causative Organism in Line-Related Sepsis. AB - The problem of line-related sepsis in patients undergoing chemotherapy for malignant disease remains a major problem in cancer-care even into the third millennium. We report a highly unusual pathogen which represented both a diagnostic and treatment challenge and highlights important issues around patient education as well as laboratory capability in the identification of causative organisms in line-related infections to facilitate clinical management. PMID- 23450158 TI - The effect of breast shielding during lumbar spine radiography. AB - BACKGROUND: The aim of the study was to determine the influence of lead shielding on the dose to female breasts in conventional x-ray lumbar spine imaging. The correlation between the body mass index and the dose received by the breast was also investigated. MATERIALS AND METHODS: Breast surface dose was measured by thermoluminescent dosimeters (TLD). In the first phase measurements of breast dose with and without shielding from lumbar spine imaging in two projections were conducted on an anthropomorphic phantom. In the second stage measurements were performed on 100 female patients, randomly divided into two groups of 50, with breast shielding only used in one group. RESULTS: On average, breast exposure dose in lumbar spine imaging in both projections (anteroposterior (AP) and lateral) was found reduced by approximately 80% (p < 0,001) when shielding with 0.5 mm lead equivalent was used (from 0.45+/-0.25 mGy to 0.09+/-0.07 mGy on the right and from 0.26+/-0.14 mGy to 0.06+/-0.04 mGy on the left breast). No correlation between the body mass index (BMI) and the breast surface radiation dose was observed. CONCLUSIONS: Although during the lumbar spine imaging breasts receive low-dose exposure even when shielding is not used, the dose can be reduced up to 80% by breast shielding with no influence on the image quality. PMID- 23450159 TI - Physiotherapists' perceptions of their role in the rehabilitation management of individuals with obesity. AB - PURPOSE: To examine physiotherapists' perceptions of their role in the rehabilitation management of individuals with obesity. METHODS: A Web-based survey was conducted in 2008. Participants were recruited through the Canadian Physiotherapy Association (CPA) via electronic communication and were eligible if they had entry level to practice qualifications and were residents of Canada. The online questionnaire consisted of 61 statements pertaining to potential PT roles, barriers, and learning needs, developed using the framework of CPA's position statement on obesity. Frequencies were computed for all Likert-scale response items on the questionnaire. RESULTS: A total of 851 physiotherapists, representative of CPA membership, participated in the study. There was strong agreement that physiotherapists have a role to play in the management of clients who are obese through exercise interventions (96%), mobility training (97%), and cardiorespiratory programmes for impairments associated with obesity (95%). Respondents were less clear about their role in the assessment of body fat or patients' weight loss. Lack of client motivation was identified as a barrier to treatment. CONCLUSION: Physiotherapists were clear that they see their role as largely focused on exercise and education to treat conditions associated with obesity. These are important components but do not by themselves constitute an overall management plan. : Purpose: To examine physiotherapists' perceptions of their role in the rehabilitation management of individuals with obesity. Methods: A Web-based survey was conducted in 2008. Participants were recruited through the Canadian Physiotherapy Association (CPA) via electronic communication and were eligible if they had entry level to practice qualifications and were residents of Canada. The online questionnaire consisted of 61 statements pertaining to potential PT roles, barriers, and learning needs, developed using the framework of CPA's position statement on obesity. Frequencies were computed for all Likert scale response items on the questionnaire. Results: A total of 851 physiotherapists, representative of CPA membership, participated in the study. There was strong agreement that physiotherapists have a role to play in the management of clients who are obese through exercise interventions (96%), mobility training (97%), and cardiorespiratory programmes for impairments associated with obesity (95%). Respondents were less clear about their role in the assessment of body fat or patients' weight loss. Lack of client motivation was identified as a barrier to treatment. Conclusion: Physiotherapists were clear that they see their role as largely focused on exercise and education to treat conditions associated with obesity. These are important components but do not by themselves constitute an overall management plan. PMID- 23450160 TI - Recent progress in biomedical applications of titanium dioxide. AB - As one of the most common chemical materials, titanium dioxide (TiO2) has been prepared and widely used for many years. Among all the applications, the biomedical applications of TiO2 have motivated strong interest and intensive experimental and theoretical studies, owing to its unique photocatalytic properties, excellent biocompatibility, high chemical stability, and low toxicity. Advances in nanoscale science suggest that some of the current problems of life science could be resolved or greatly improved through applying TiO2. This paper presents a critical review of recent advances in the biomedical applications of TiO2, which includes the photodynamic therapy for cancer treatment, drug delivery systems, cell imaging, biosensors for biological assay, and genetic engineering. The characterizations and applications of TiO2 nanoparticles, as well as nanocomposites and nanosystems of TiO2, which have been prepared by different modifications to improve the function of TiO2, are also offered in this review. Additionally, some perspectives on the challenges and new directions for future research in this emerging frontier are discussed. PMID- 23450161 TI - Tunable magnetoplasmons for efficient terahertz modulator and isolator by gated monolayer graphene. AB - Terahertz (THz) technology has been a promising tool for sensing, spectroscopy, imaging, and communication. However, only few devices have shown efficient performance for future THz technology. Herein, we propose a device based on tunable magnetoplasmons in gated monolayer graphene for THz wave modulation and isolation. The relative transmission and the Faraday rotation angle of the device have been calculated by combining the Fresnel method with the voltage-dependent Drude model. Our results suggest that a superior modulation depth and giant Faraday rotation due to the cyclotron effect in the classical regime by intraband transitions in graphene offer an effective, uniform, and flexible tunability for THz wave. And the modulating and isolating manipulations by graphene can range from 0 to 2 THz, with electron-hole asymmetry originating from variable scattering rate of magnetoplasmons. Moreover, the thickness effect of the thin substrate is also studied for better performance of the device, taking advantage of the unavoidable Fabry-Perot (F-P) effect. This work demonstrates a pathway for efficient THz modulator and isolator based on the magneto-optical polarization effect in graphene. PMID- 23450163 TI - Theoretical and experimental insights into applicability of solid-state 93Nb NMR in catalysis. AB - Ab initio DFT calculations of (93)Nb NMR parameters using the NMR-CASTEP code were performed for a series of over fifty individual niobates, and a good agreement has been found with experimental NMR parameters. New experimental and calculated (93)Nb NMR data were obtained for several compounds, AlNbO4, VNb9O25, K8Nb6O19 and Cs3NbO8, which are of particular interest for catalysis. Several interesting trends have been identified between (93)Nb NMR parameters and the specifics of niobium site environments in niobates. These trends may serve as useful guidelines in interpreting (93)Nb NMR spectra of complex niobium oxide systems, including amorphous samples and niobium-based multicomponent heterogeneous catalysts. Potential applications of (93)Nb NMR to study solid polyoxoniobates are discussed. PMID- 23450162 TI - Cold intolerance after brachial plexus nerve injury. AB - BACKGROUND: The purpose of this study was to evaluate cold intolerance symptoms in patients with brachial plexus nerve injury. We hypothesized that higher levels of cold intolerance would be associated with more pain, greater disability, and unemployment. METHODS: Following research ethics board approval and patient consent, we included English-speaking adults more than 6 months following brachial plexus nerve injury. Patient questionnaires included Cold Intolerance Severity Scale (CISS), McGill Pain Questionnaire, SF-36, DASH, pain catastrophizing scale, and Post-traumatic Stress Disorder Checklist. Statistical analyses evaluated the relationships among the questionnaires and the independent variables. Multivariable linear regression evaluated the factors associated with the CISS. RESULTS: There were 61 patients, 20 women and 41 men (mean age 40 +/- 17 years). The mean questionnaire scores indicated high scores in the CISS, DASH, and pain intensity. The CISS was significantly higher in women. The final regression model with CISS as the dependent variable included the following independent variables: McGill pain rating index, DASH score, and time since injury. Neither pain catastrophizing nor post-traumatic stress scores were retained in the final model. CONCLUSIONS: Patients with brachial plexus nerve injury reported substantial cold intolerance which was associated with the McGill pain rating index, upper extremity disability, and time since injury. PMID- 23450164 TI - The gas-phase reaction of methane sulfonic acid with the hydroxyl radical without and with water vapor. AB - The gas phase reaction between methane sulfonic acid (CH3SO3H; MSA) and the hydroxyl radical (HO), without and with a water molecule, was investigated with DFT-B3LYP and CCSD(T)-F12 methods. For the bare reaction we have found two reaction mechanisms, involving proton coupled electron transfer and hydrogen atom transfer processes that produce CH3SO3 and H2O. We also found a third reaction mechanism involving the double proton transfer process, where the products and reactants are identical. The computed rate constant for the oxidation process is 8.3 * 10(-15) cm(3) s(-1) molecule(-1). CH3SO3H forms two very stable complexes with water with computed binding energies of about 10 kcal mol(-1). The presence of a single water molecule makes the reaction between CH3SO3H and HO much more complex, introducing a new reaction that consists in the interchange of H2O between HO and CH3SO3H. Our kinetic calculations show that 99.5% of the reaction involves this interchange of the water molecule and, consequently, water vapor does not play any role in the oxidation reaction of methane sulfonic acid by the hydroxyl radical. PMID- 23450165 TI - A Study of Association of Ankle Brachial Index (ABI) and the Highly Sensitive C - Reactive Protein (hsCRP) in Type 2 Diabetic Patients and in Normal Subjects. AB - BACKGROUND: The Ankle-Brachial Index (ABI) objectively assesses the lower extremity arterial perfusion. A low ABI suggests atherosclerosis and Peripheral Arterial Disease (PAD). PAD is more common in individuals with type2 Diabetes mellitus (Type2 DM). Inflammatory markers are found to be associated with Type2 DM. But the association of the inflammatory markers with the atherosclerotic burden remains poorly defined. AIMS: To compare the ABI and the hsCRP in the Type 2 DM patients with those in the normal subjects and to study the association of serum hsCRP with ABI in the Type 2 DM patients and in normal subjects. METHODS: The subjects were 40 Type2 DM and 40 age, sex and BMI matched normal subjects who were aged between 45-60 yrs. The subjects were assigned to two different groups, Group1- the Type2 DM patients and Group2- the healthy controls. The serum hsCRP levels were determined by the turbidimetry method (BIOSYSTEMS) and the ABI values were determined by using the traditional continuous wave (CW) Doppler of NICOLET VERSALAB. STATISTICAL ANALYSIS: The data was analyzed by using the Student's t test (two tailed; independent) to find the significance of the study parameters between the two groups. Pearson's Correlation was used to find the correlation of serum hsCRP with the ABI in the two groups. RESULTS: The ABI showed a significantly low value (P=0.035*) and the serum hsCRP showed a trend towards a significant increase (p = 0.069+) in the type2diabetics as compared to those in the normals. There was a significant negative correlation between ABI and hsCRP in the Type 2 DM patients (r=-0.560, p<0.001**). However, such correlation was not observed in the normal subjects. CONCLUSION: As serum hsCRP is associated with ABI in the type2 DM patients, inflammation may play a role in the pathogenesis of atherosclerosis. PMID- 23450166 TI - Conductance steps in electromigrated Bi nanoconstrictions. AB - Bismuth nanostructures of initial lateral size of about 150 nm were successfully electromigrated at room temperature under high vacuum conditions through the application of voltage ramps and accurate control of their conductance. The imaging of the nanogap formation was followed by scanning electron microscopy. An appropriate design of the initial Bi nanostructures has made the electromigration process of semimetallic Bi feasible. Beyond the intrinsic interest in the generation of Bi structures with size tailored at the nanoscale, remarkable features have been observed in the time-dependent conductance curves of the Bi nanoconstrictions. In particular, sub-quantum conductance plateaus can be detected before the rupture of the constriction. An alternative procedure to study the transport through Bi nanoconstrictions has been explored using a focused-Ga-ion etching process with simultaneous control of the conductance. This second approach confirms the transport behavior observed in electromigrated Bi nanoconstrictions. PMID- 23450168 TI - Topology maps of bond descriptors based on the kinetic energy density and the essence of chemical bonding. AB - Analysis of the kinetic energy density within a molecule identifies patterns in its electronic structure that are intuitively linked to familiar concepts of chemical bonding. The function nu(r), termed localized-orbital locator and based on the positive-definite kinetic energy density tau+, is employed to characterize classes of covalent bonds in terms of its full topology of all critical points of rank three. Not only does nu(r) reveal patterns in chemical bonding, it also discloses features and the influence of extended electronic cores. Gradient paths define the extension of the valence space around an atomic centre; they separate various core level regions from bonding domains, and partition molecules in sensible bonded subunits. Location and nu(r)-values of critical points add a quantitative aspect to the bond characterization; profiles of unconventional chemical linkages such as charge-shift bonds emerge in a natural way. PMID- 23450169 TI - Ab initio simulations of scanning-tunneling-microscope images with embedding techniques and application to C58-dimers on Au(111). AB - We present a modification of the standard electron transport methodology based on the (non-equilibrium) Green's function formalism to efficiently simulate STM images. The novel feature of this method is that it employs an effective embedding technique that allows us to extrapolate properties of metal substrates with adsorbed molecules from quantum-chemical cluster calculations. To illustrate the potential of this approach, we present an application to STM-images of C58 dimers immobilized on Au(111)-surfaces that is motivated by recent experiments. PMID- 23450167 TI - Genetic interactions of Arabidopsis thaliana damaged DNA binding protein 1B (DDB1B) with DDB1A, DET1, and COP1. AB - Damaged DNA Binding protein 1 (DDB1)-CULLIN4 E3 ubiquitin ligase complexes have been implicated in diverse biological processes in a range of organisms. Arabidopsis thaliana encodes two homologs of DDB1, DDB1A, and DDB1B. In this study we use a viable partial loss of function allele of DDB1B, ddb1b-2, to examine genetic interactions with DDB1A, DET1 and COP1. Although the ddb1b-2 ddb1a double mutant is lethal, ddb1a ddb1b-2/+ and ddb1b-2 ddb1a/+ heterozygotes exhibit few developmental phenotypes but do exhibit decreased tolerance of ultraviolet light. In addition, germination in ddb1a and ddb1a ddb1b-2/+ was found to be sensitive to salt and mannitol, and both DDB1 single mutants as well as the heterozygotes exhibited heat sensitivity. DE-ETIOLATED1 (DET1) and CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) are negative regulators of light development which interact with DDB1-CUL4 complexes. Although ddb1a strongly enhances det1 phenotypes in both dark- and light-grown seedlings, ddb1b-2 weakly enhanced the det1 short hypocotyl phenotype in the dark, as well as enhancing anthocyanin levels and suppressing the det1 low chlorophyll phenotype in light grown seedlings. In adults, ddb1a suppresses det1 early flowering and enhances the det1 dwarf phenotype. A similar trend was observed in ddb1b-2 det1 double mutants, although the effects were smaller in magnitude. In cop1 mutants, ddb1b-2 enhanced the cop1-4 short hypocotyl phenotype in dark and light, enhanced anthocyanin levels in cop1-1 in the light, but had no effect in adults. Thus the requirement for DDB1B varies in the course of development, from COP1-specific effects in hypocotyls to DET1-specific in adults. PMID- 23450170 TI - Genital herpes in Canada: Deciphering the hidden epidemic. AB - INTRODUCTION: Genital herpes (GH) is the most common cause of genital ulceration, but is not reportable in Canada. Research in the United States has found that less than 10% of seropositive persons reported a diagnosis of GH. The present article investigates the rates of diagnosed cases of GH in Canada from 2002 to 2007. METHODS: Primary case diagnosis data on GH for the period between 2002 and 2007 were obtained from the Canadian Disease and Therapeutic Index, a proprietary database maintained by Intercontinental Medical Statistics (IMS) Health Canada. Of the 45,000 to 49,000 office-based physicians in Canada, IMS Health collected diagnosis-specific prescription diaries from a sample of 652, stratified according to geographic region and representing all major specialties, during this period. RESULTS: Between 2002 and 2007, there were approximately 84,398 to 122,456 medically attended GH cases annually in Canada. Approximately 74% to 93% of these diagnosed cases made one physician visit per year. The annual rate of medically attended GH cases ranged from 261.2 per 100,000 population to 386.6 per 100,000 population. DISCUSSION: The present report is the first time that administrative data have been used to estimate the annual rate of medically attended GH cases in Canada. The data include both incident and prevalent cases and are likely an underestimate of the actual number of cases because they only represent diagnosed cases presenting for medical care. Further seroepidemiological and clinical research studies would be helpful to assess the burden of infection and to plan appropriate diagnostic, treatment and preventive counselling services. INTRODUCTION: Genital herpes (GH) is the most common cause of genital ulceration, but is not reportable in Canada. Research in the United States has found that less than 10% of seropositive persons reported a diagnosis of GH. The present article investigates the rates of diagnosed cases of GH in Canada from 2002 to 2007. METHODS: Primary case diagnosis data on GH for the period between 2002 and 2007 were obtained from the Canadian Disease and Therapeutic Index, a proprietary database maintained by Intercontinental Medical Statistics (IMS) Health Canada. Of the 45,000 to 49,000 office-based physicians in Canada, IMS Health collected diagnosis-specific prescription diaries from a sample of 652, stratified according to geographic region and representing all major specialties, during this period. RESULTS: Between 2002 and 2007, there were approximately 84,398 to 122,456 medically attended GH cases annually in Canada. Approximately 74% to 93% of these diagnosed cases made one physician visit per year. The annual rate of medically attended GH cases ranged from 261.2 per 100,000 population to 386.6 per 100,000 population. DISCUSSION: The present report is the first time that administrative data have been used to estimate the annual rate of medically attended GH cases in Canada. The data include both incident and prevalent cases and are likely an underestimate of the actual number of cases because they only represent diagnosed cases presenting for medical care. Further seroepidemiological and clinical research studies would be helpful to assess the burden of infection and to plan appropriate diagnostic, treatment and preventive counselling services. PMID- 23450171 TI - On the method-dependence of transition state asynchronicity in Diels-Alder reactions. AB - This work discusses the dependence of transition state geometries on the choice of quantum chemical optimization method for the extensively studied Diels-Alder reaction. Rather significant differences are observed between post-Hartree-Fock methods and (hybrid) density functional theory, where the latter predicts larger asynchronicities. The results show that the low MP2 asynchronicity observed is likely artificial. Still, there are significant discrepancies between hybrid and pure density functionals. The role of the exchange functional seems to be most prominent in less activated reacting systems, while the importance of the correlation functional seems to increase as they become more activated by, e.g., an electron-donating group on the diene. To correct the dubious MP2 geometries, we employed the SCS-MP2 protocol for transition state optimization, which leads to significantly better results with respect to CCSD/6-31+G(d) level calculations. We conclude that in order for hybrid functionals to give descriptions consistent with the sample post-Hartree-Fock methods, a balanced combination of both Hartree-Fock exchange (with a couple of exceptions) and a well-behaved correlation functional is required. Given that the benchmark CCSD/6 31+G(d) geometries are sufficient representations, the best geometries were obtained using omegaB97X(D), B2PLYP(D) and M06-2X. PMID- 23450172 TI - In situ X-ray pair distribution function analysis of geopolymer gel nanostructure formation kinetics. AB - With the ever-increasing environmentally-driven demand for technologically advanced structural materials, geopolymer cement is fast becoming a viable alternative to traditional cements due to its proven engineering characteristics and the reduction in CO2 emitted during manufacturing (as much as 80% less CO2 emitted in manufacture, compared to ordinary Portland cement). Nevertheless, much remains unknown regarding the kinetics of reaction responsible for nanostructural evolution during the geopolymerisation process. Here, in situ X-ray total scattering measurements and pair distribution function (PDF) analysis are used to quantify the extent of reaction as a function of time for alkali-activated metakaolin/slag geopolymer binders, including the impact of various activators (alkali hydroxide/silicate) on the kinetics of the geopolymerisation reaction. Quantifying the reaction process in situ from X-ray PDF data collected during the initial ten hours can provide an estimate of the total reaction extent, but when combined with data obtained at longer times (128 days here) enables more accurate determination of the overall rate of reaction. To further assess the initial stages of the geopolymerisation reaction process, a pseudo-single step first order rate equation is fitted to the extent of reaction data, which reveals important mechanistic information regarding the role of free silica in the activators in the evolution of the binder systems. Hence, it is shown that in situ X-ray PDF analysis is an ideal experimental local structure tool to probe the reaction kinetics of complex reacting systems involving transitions between disordered/amorphous phases, of which geopolymerisation is an important example. PMID- 23450174 TI - Structures and ionization energies of small lithium doped germanium clusters. AB - We present a combined theoretical and experimental investigation of neutral and cationic lithium doped germanium clusters, GenLim (n = 5-10; m = 1-4). The vertical ionization energies and ionization thresholds are derived from threshold photoionization efficiency curves in the 4.68-6.24 eV range and are compared with calculated vertical and adiabatic ionization energies for the lowest energy isomers obtained using DFT computations. The agreement between experimental and computed values supports the identification of the ground state structures. Charge population analysis shows that lithium transfers its valence electron to the Gen hosts to form Gen(mdelta-)-mLi(delta+) and Gen((mdelta(-)+1))-mLi(delta+) complexes. This is also illustrated by the strong correlation between the size dependent lithium adsorption energies in GenLi and the Gen electron affinities. Neutral GenLim clusters are formed by adsorbing lithium atoms on either triangular or rhombic faces of the Gen framework with the lithium atoms tending to avoid each other. The chemical bonding phenomena of clusters are analyzed in detail using the densities of states and molecular orbitals. PMID- 23450175 TI - Masquerade without a mass: an unusual cause of severe acute pancreatitis. AB - After excluding the typical causes, the underlying etiology of severe acute pancreatitis is often elusive; tumors are on the differential but may be difficult to prove in the absence of a discrete mass on imaging. In this report, we describe the case of an elderly woman with diffuse large B-cell lymphoma masquerading as acute pancreatitis. To our knowledge, only twelve other cases of pancreatic B-cell lymphoma presenting as acute pancreatitis have been described. However, while other cases involved well-circumscribed tumors of the pancreas, this is the first known case of pancreatic lymphoma of a diffusely infiltrating pattern presenting as acute pancreatitis. PMID- 23450173 TI - MicroRNA regulation of natural killer cells. AB - Natural killer (NK) cells are innate immune lymphocytes critical for host defense against viral infection and surveillance against malignant transformation. MicroRNAs (miRNAs) are a family of small, non-coding RNAs that regulate a wide variety of cellular processes. Recent advances have highlighted the importance of miRNA-mediated post-transcriptional regulation in NK cell development, maturation, and function. This review focuses on several facets of this regulatory mechanism in NK cells: (1) the expressed NK cell miRNA transcriptome; (2) the impact of total miRNA deficiency on NK cells; (3) the role of specific miRNAs regulating NK cell development, survival, and maturation; (4) the intrinsic role of miRNAs regulating NK cell function, including cytokine production, proliferation, and cytotoxicity; and (5) the role of NK cell miRNAs in disease. Currently our knowledge of how miRNAs regulate NK cell biology is limited, and thus we also explore key open questions in the field, as well as approaches and techniques to ascertain the role of individual miRNAs as important molecular regulators. PMID- 23450176 TI - Characterization of titanium particles treated with N2 plasma using a barrel plasma-treatment system. AB - Metallic titanium (Ti) particles treated with N2 plasma via the barrel-plasma treatment system were thoroughly evaluated, to investigate changes in physical and chemical properties resulting from the treatment. The color of the Ti particles changed from gray to uniform brown upon plasma-treatment, indicating good surface uniformity. Depth profiling using X-ray photoelectron spectroscopy showed that the nitrogen implanted by plasma-treatment formed Ti-N bonds at or near the surface of the particles, resulting in the formation of a stoichiometric TiN layer. It was determined from cross-sectional transmission electron microscopy and nanobeam diffraction measurements that the resulting TiN layer had two different structures. Nanoindentation data showed that the surface of a treated sample was about five times harder than that of untreated particles. PMID- 23450177 TI - An analysis of the risk factors and the outcomes of cerebrovascular diseases in northern India. AB - INTRODUCTION: Stroke is a growing epidemic in the developing countries. The risk factors of stroke are the same as those of atherosclerosis, but the relative incidences of the various risk factors keep changing with time and cultural and environmental factors. So, a periodic analysis should be done. AIMS AND OBJECTIVE: The generation of the data which pertained to the clinical profile of stroke in our institution by using the WHO Steps Stroke Manual, version 2 and to make note of the risk factors and the correlation of the outcome with the Glasgow's Coma Scale (GCS) at admission and with the Modified Rankin Scale (MRS) on the 28th day. MATERIAL AND METHODS: A prospective study was conducted on 157 cases of stroke patients who were admitted to the Medicine Department of a tertiary care institute during June 2011 through June 2012. OBSERVATIONS: Amongst the 157 cases (92 males and 65 females), 86 % were above 40 years of age and this was the most prevalent age group in the age range of 51-60 years. The risk factor analysis showed hypertension as the most prevalent risk factor, followed by diabetes cum hypertension. Hemiplegia/hemi paresis was the most common presentation, followed by aphasia. Radiological studies showed that ischaemic strokes were the most frequent ones, followed by haemorrhagic strokes (71 vs. 29 %). Amongst the ischaemic infarcts, the anterior circulation infarct was the most frequent one. The outcome was poor with haemorrhagic strokes and in those who were presented with a GCS of less than 3. The overall mortality was 22.29 %. A significant residual deficit (MRS >3) was seen in 49.7 % of the patients. CONCLUSIONS: There is a need for prospective representative population based surveys viz. the WHO Stroke Steps 2 and 3.Public health measures are essential to enhance the awareness about the importance of knowing the risk factors. Hence, the message which has to be percolated to the masses is - stroke is a 'brain attack' that is preventable. PMID- 23450178 TI - Tunable doping and band gap of graphene on functionalized hexagonal boron nitride with hydrogen and fluorine. AB - First-principles calculations have been used to investigate the structural and electronic properties of graphene supported on functionalized hexagonal boron nitride (h-BN) with hydrogen and fluorine atoms. Our results show that the hydrogenation and fluorination of the h-BN substrate modify the electronic properties of graphene. Interactions of graphene with fully hydrogenated or fully fluorinated h-BN and half-hydrogenated and half-fluorinated h-BN with H at N sites and F at the B sites can lead to n- or p-type doping of graphene. The different doping effect may be attributed to the significant charge transfer from graphene to the substrate. Interestingly, when graphene is supported on the functionalized h-BN with H at B sites and F at N sites (G/HBNF), a finite band gap of 79 meV in graphene is opened due to the equivalence breaking of two sublattices of graphene, and can be effectively modulated by changing the interlayer spacing, increasing the number of functionalized BN layers, and applying an external electric field. More importantly, the modification of the band gap in G/HBNF with a functionalized BN bilayer by the electric field is more pronounced than that of the single-layer h-BN, which is increased to 408 meV with 0.8 V A(-1). Thus, graphene on chemically modified h-BN with a tunable and sizeable band gap may provide a novel way for fabricating high-performance graphene-based nanodevices. PMID- 23450180 TI - A novel technique in the use of fractional flow reserve in coronary artery bifurcation lesions. AB - The side branch (SB) in bifurcation lesions is a frequently encountered challenge that interventional cardiologists must face. There is great interest in determining fractional flow reserve (FFR) in the SB to help guide treatment decisions; however, difficulty with the pressure guidewire limits its widespread use. We propose a novel technique that will ease the incorporation of FFR in routine evaluation of bifurcation lesions, and allow better assessment of provisional stenting and need for SB intervention. Conventionally, to measure SB FFR, the jailed SB is re-crossed through the stent strut using a pressure wire. Our technique involves the use of a microcatheter and wire exchange within the SB, thereby alleviating some of the technical difficulties associated with the FFR wire. In light of the difficulties and clinical concerns associated with bifurcation lesions, we propose an innovative method to ease the incorporation of FFR to allow better assessment of provisional stenting and need for SB intervention. PMID- 23450179 TI - Contrast-enhanced MR imaging of atherosclerosis using citrate-coated superparamagnetic iron oxide nanoparticles: calcifying microvesicles as imaging target for plaque characterization. AB - OBJECTIVE: To evaluate the suitability of citrate-coated very small superparamagnetic iron oxide particles (VSOP) as a contrast agent for identifying inflammation in atherosclerotic lesions using magnetic resonance imaging (MRI). METHODS AND RESULTS: VSOP, which have already been evaluated as a blood pool contrast agent for MR angiography in human clinical trials, were investigated in Watanabe heritable hyper-lipidemic rabbits to determine to what extent their accumulation in atherosclerotic lesions is a function of macrophage density and other characteristics of progressive atherosclerotic plaques. In advanced atherosclerotic lesions, a significant MRI signal loss was found within 1 hour after intravenous administration of VSOP at the intended clinical dose of 0.05 mmol Fe/kg. Histological examinations confirmed correlations between the loss of MRI signal in the vessel wall and the presence of Prussian blue-stained iron colocalized with macrophages in the plaque cap, but surprisingly also with calcifying microvesicles at the intimomedial interface. Critical electrolyte magnesium chloride concentration in combination with Alcian blue stain indicates that highly sulfated glycosaminoglycans are a major constituent of these calcifying microvesicles, which may serve as the key molecules for binding VSOP due to their highly complexing properties. CONCLUSION: Calcifying microvesicles and macrophages are the targets for intravenously injected VSOP in atherosclerotic plaques, suggesting that VSOP-enhanced MRI may render clinically relevant information on the composition and inflammatory activity of progressive atherosclerotic lesions at risk of destabilization. PMID- 23450181 TI - Association of antioxidants with allergic rhinitis in children from seoul. AB - PURPOSE: The prevalence of allergic diseases has risen over the last few decades. Many factors, including environmental factors such as those related to diet, have been considered. Among dietary factors, intake of antioxidant-related nutrients has been associated with the risk of allergic disease. We investigated the association of antioxidant nutritional status with allergic rhinitis (AR) in Korean schoolchildren aged 6-12 years. METHODS: Subjects were 4,554 children in Seoul, Korea. The risk of allergic disease was measured using the Korean version of the International Study of Asthma and Allergies in Childhood, and dietary intake was measured by a semi-quantitative food frequency questionnaire. Intake of vitamins A (including retinol and beta-carotene), C, and E was used in the analysis. RESULTS: Vitamin C intake was negatively associated with an increased risk of current symptoms (adjusted odds ratio, 0.886; 95% confidence interval, 0.806-0.973). There was no association between AR and intake of vitamin A, retinol, beta-carotene, or vitamin E. Total serum IgE level and sensitization to allergen did not differ according to nutrient intake. CONCLUSIONS: The group of children with increased vitamin C consumption had fewer AR symptoms, despite the lack of a difference in total serum IgE level or allergen sensitization. These findings suggest that nutrient intake, especially that of vitamin C, influences AR symptoms. PMID- 23450182 TI - Ambient particulate air pollution and acute lower respiratory infections: a systematic review and implications for estimating the global burden of disease. AB - Acute lower respiratory infections (ALRI) account for nearly one fifth of mortality in young children worldwide and have been associated with exposures to indoor and outdoor sources of combustion-derived air pollution. A systematic review was conducted to identify relevant articles on air pollution and ALRI in children. Using a Bayesian approach to meta-analysis, a summary estimate of 1.12 (1.03, 1.30) increased risk in ALRI occurrence per 10 MUg/m3 increase in annual average PM2.5 concentration was derived from the longer-term (subchronic and chronic) effects studies. This analysis strengthens the evidence for a causal relationship between exposure to PM2.5 and the occurrence of ALRI and provides a basis for estimating the global attributable burden of mortality due to ALRI that is not influenced by the wide variation in regional case fatality rates. Most studies, however, have been conducted in settings with relatively low levels of PM2.5. Extrapolating their results to other, more polluted, regions will require a model that is informed by evidence from studies of the effects on ALRI of exposure to PM2.5 from other combustion sources, such as secondhand smoke and household solid fuel use. PMID- 23450184 TI - Inadvertent suprapubic gastrostomy: Report of a unique complication of blind percutaneous suprapubic trocar cystostomy. AB - Emergency percutaneous trocar suprapubic cystostomy is a common surgical procedure for acute urinary retention. Although uncommon it can be associated with a few complications. The most dangerous complication is iatrogenic bowel injury. Literature shows reported cases of small and large bowel injuries. We report a case of inadvertent placement of suprapubic catheter into a dilated and ptotic stomach. This is the first reported case of this complication of suprapubic cystostomy. PMID- 23450183 TI - Genome sequence of the Antarctic rhodopsins-containing flavobacterium Gillisia limnaea type strain (R-8282(T)). AB - Gillisia limnaea Van Trappen et al. 2004 is the type species of the genus Gillisia, which is a member of the well characterized family Flavobacteriaceae. The genome of G. limnea R-8282(T) is the first sequenced genome (permanent draft) from a type strain of the genus Gillisia. Here we describe the features of this organism, together with the permanent-draft genome sequence and annotation. The 3,966,857 bp long chromosome (two scaffolds) with its 3,569 protein-coding and 51 RNA genes is a part of the GenomicEncyclopedia of Bacteria and Archaea project. PMID- 23450185 TI - Surgical options for recalcitrant carpal tunnel syndrome with perineural fibrosis. AB - Surgical release of the transverse carpal ligament for the treatment of carpal tunnel syndrome (CTS) is, in general, a very successful procedure. Some patients, however, fail this standard release and have persistent or recurrent symptoms. Such recalcitrance may relate to incomplete release but more often relates to perineural or intraneural fibrosis of the median nerve. While there is no good treatment for intraneural fibrosis, numerous procedures have evolved in an attempt to treat perineural fibrosis which restricts nerve gliding. These include procedures to isolate the nerve from scar as well as procedures to bring neovascularization to the median nerve. This review describes the various surgical treatment options for recalcitrant CTS as well as their reported outcomes. PMID- 23450186 TI - The effect of acupressure at the Sanyinjiao point (SP6) on primary dysmenorrhea in students resident in dormitories of Tabriz. AB - BACKGROUND: There are two types of primary dysmenorrhea (spasmodic and congestive) which differ from each other in terms of the occurrence time in menstrual cycle, pain quality and other symptoms. The present study aimed to determine the effect of acupressure at the Sanyinjiao point (SP-6) on severity of menstrual symptoms (primary outcome) and the duration of resting time as well as the number of ibuprofen consumption (secondary outcome) in the two types of primary dysmenorrhea. METHODS: This was a clustered randomized controlled trial on 72 eligible students residing in dormitories of public universities of Tabriz, Iran. Determining the type of primary dysmenorrhea using a Menstrual symptoms questionnaire (MSQ), 36 participants which suffered from each type of dysmenorrhea were enrolled from the four dormitories. The dormitories were randomly divided into intervention and control groups. No intervention was carried out at the first cycle. During the two next cycles, Sanyinjiao point of the subjects in the intervention group was pressed for twenty minutes at the time of pain. The subjects in both groups were allowed to consume ibuprofen, if needed. During these three cycles, the participants recorded and reported menstrual symptoms severity, duration of resting time and the number of the used ibuprofen. RESULTS: The severity of menstrual symptoms and duration of resting time in the 2(nd) and 3(rd) cycles were significantly reduced more than control groups for both spasmodic and congestive types of primary dysmenorrhea. In addition, the aver-age numbers of ibuprofen pills taken by both intervention groups was significantly less than the control groups. There was no significant difference between the two intervention groups in terms of any of the outcomes. CONCLUSIONS: Acupressure is effective on lowering the symptoms of dysmenorrhea and duration of resting time almost equally in both spasmodic and congestive types. Therefore, using this method either alone or along with other methods is recommended to treat dysmenorrhea. PMID- 23450187 TI - Disentangling signaling gradients generated by equivalent sources. AB - Yeast cells approach a mating partner by polarizing along a gradient of mating pheromones that are secreted by cells of the opposite mating type. The Bar1 protease is secreted by a-cells and, paradoxically, degrades the alpha-factor pheromones which are produced by cells of the opposite mating type and trigger mating in a-cells. This degradation may assist in the recovery from pheromone signaling but has also been shown to play a positive role in mating. Previous studies suggested that widely diffusing protease can bias the pheromone gradient towards the closest secreting cell. Here, we show that restricting the Bar1 protease to the secreting cell itself, preventing its wide diffusion, facilitates discrimination between equivalent mating partners. This may be mostly relevant during spore germination, where most mating events occur in nature. PMID- 23450188 TI - Clinical, molecular- and cytogenetic analysis of a case of severe radio sensitivity. AB - In radiotherapy the normal tissue reaction is often a limiting factor for radiation treatment. Still there is no screening method, which predicts normal tissue reaction on radiotherapy, especially in comparison to tumor tissue, and therefore allows tailoring of the radiation dose to each patient. Here, we present a case of severe radiation-related side effects. We applied classical cytogenetic techniques (Giemsa-banding and staining of centromeric regions), the comet assay as well as multicolor fluorescence in situ hybridization on peripheral blood lymphocytes of this patient in order to determine the radio sensitivity on the DNA level and to correlate these findings with the clinical outcome. Our investigations revealed abnormalities on chromosome 9, deficiencies in the DNA-repair capacity after radiation exposure and a high number of radiation induced chromosomal aberrations. A detected high amount of residual damage two or three hours after radiation exposure and repair as well as the high number of chromosomal aberrations (ChAs) suggests a correlation between repair capacity and radiation induced ChAs. We concluded that the detected abnormalities might serve as a genetic basis for the radio-sensitive phenotype of this patient. Taken together this report strengthens the idea that intensive DNA genomic analysis of individual patients can serve as the basis for more favourable treatment of cancer patients. PMID- 23450189 TI - A Study on the Correlation Between the Body Mass Index (BMI), the Body Fat Percentage, the Handgrip Strength and the Handgrip Endurance in Underweight, Normal Weight and Overweight Adolescents. AB - INTRODUCTION: The handgrip strength and endurance have evolved as an important tool for the assessment of the nutritional status and as a marker of the muscle quality. In underweight as well as overweight individuals, there is the possibility of a change in the muscle quality. So, we undertook this study to find out the correlation between the BMI, the Body Fat percentage and the Hand grip strength and endurance. MATERIALS AND METHODS: One hundered eighty students in three BMI ranges-underweight (BMI<= 18.49), normal weight (BMI- 18.5- 24.99) and overweight (25-29.99) were included according to the WHO guidelines. The body fat percentage was measured by using a bioelectric impedance. The handgrip strength and the handgrip endurance were recorded by using an INCO handgrip dynamometer. The statistical correlation was done by using ANOVA. RESULTS: In males, the handgrip endurance was better in normal weight individuals, but among the females, the underweight females had a better handgrip endurance, but the difference was statistically insignificant (p>0.05). In both males and females, there was a statistically significant difference in the handgrip endurance, with the maximum grip endurance in the normal weight group and the minimum grip endurance in the overweight group (p< 0.05). The correlation between the BMI, the body fat percentage and the handgrip endurance was complex and different for males and females. CONCLUSION: The underweight and overweight groups had a lower grip strength and endurance than the normal weight group in males, but not in females. The correlation was weak and it suggested that on both sides of the normal BMI, the hand grip endurance tended to decrease in males as well as in females. The increase in the body fat percentage might decrease the handgrip endurance but not the handgrip strength. PMID- 23450190 TI - Precision attachment: retained overdenture. AB - Precision attachments are small interlocking devices to connect prosthesis and abutments that offer a variety of solutions to the challenge of balance between functional stability and cosmetic appeal. Precision attachments have wide applications, used in fixed removable bridge, removable partial dentures, overdentures, implant retained overdentures, and maxillofacial prosthesis. Attachment retained overdentures helps in distribution of masticatory forces, minimizes trauma to abutments and soft tissues, attenuate ridge resorption, improves the esthetics and retains proprioception. The following case report discusses the use of resilient stud attachments to retain maxillary and mandibular overlay complete dentures. PMID- 23450192 TI - Electrochemical reactivity of urea at Pt(100) surface in 0.5 M H2SO4 by AC impedance spectroscopy. AB - The present paper reports an alternate current impedance spectroscopic study on adsorption of urea (U) at Pt(100) single-crystal surface, examined in 0.5 M H2SO4 supporting electrolyte. The resulted information provided confirmation of the role of electrosorption of urea on the Pt(100) plane through evaluation of the associated charge transfer resistance and capacitance parameters. Obtained impedance results were compared to those previously recorded for guanidinium cation (G+) under analogous experimental conditions, especially with respect to the so-called ion pairing mechanism, as originally proposed for the G+ ion and bi(sulfate)/OH species, based on the voltammetric and in situ Fourier transform infrared spectroscopy results. PMID- 23450191 TI - Severe Thrombocytopenia in an Immune Thrombocytopenic Parturient Non-responder to Medical Line of Treatment: Anaesthetic Management for Splenectomy Combined with Caesarean Section. AB - We report anaesthesia management of a parturient with severe thrombocytopenia secondary to immune thrombocytopenic purpura (ITP). Her platelet count remained around 3 * 10(9)/l in spite of optimum medical therapy and hence was posted for splenectomy combined with caesarean section. Anaesthesia implications of severe thrombocytopenia comprises risk of central nervous system bleeding, perioperative haemorrhage causing placental hypoperfusion and foetal hypoxia, risk of trauma to compromised airway and risk of epidural haematoma. The purpose of this paper is to discuss the risk factors associated, different management strategies and also to review the literature in an attempt to ameliorate the anaesthesiologist in perioperative management of these cases. PMID- 23450193 TI - A genomic survey of Reb homologs suggests widespread occurrence of R-bodies in proteobacteria. AB - Bacteria and eukaryotes are involved in many types of interaction in nature, with important ecological consequences. However, the diversity, occurrence, and mechanisms of these interactions often are not fully known. The obligate bacterial endosymbionts of Paramecium provide their hosts with the ability to kill sensitive Paramecium strains through the production of R-bodies, highly insoluble coiled protein ribbons. R-bodies have been observed in a number of free living bacteria, where their function is unknown. We have performed an exhaustive survey of genes coding for homologs of Reb proteins (R-body components) in complete bacterial genomes. We found that reb genes are much more widespread than previously thought, being present in representatives of major Proteobacterial subdivisions, including many free-living taxa, as well as taxa known to be involved in various kinds of interactions with eukaryotes, from mutualistic associations to pathogenicity. Reb proteins display very good conservation at the sequence level, suggesting that they may produce functional R-bodies. Phylogenomic analysis indicates that reb genes underwent a complex evolutionary history and allowed the identification of candidates potentially involved in R body assembly, functioning, regulation, or toxicity. Our results strongly suggest that the ability to produce R-bodies is likely widespread in Proteobacteria. The potential involvement of R-bodies in as yet unexplored interactions with eukaryotes and the consequent ecological implications are discussed. PMID- 23450194 TI - Inferior vena cava filters for primary prophylaxis: when are they indicated? AB - Over the past several years there has been a rapid increase in the number of inferior vena cava (IVC) filters placed for primary thromboprophylaxis. Increased use has occurred in settings where other methods of thromboprophylaxis are viewed to be inadequate, technically challenging, or that place patients at an unacceptably high bleeding risk. These clinical services include trauma, bariatric surgery, neurosurgery, cancer, intensive care unit populations, and patients with a relative contraindication to anticoagulation. We review the studies to date addressing filter placement for these indications. Although preliminary data are promising, the patient populations most likely to benefit from prophylactic IVC filter placement have not been well defined, and randomized studies demonstrating efficacy have not been conducted. Moving forward, it will be critical to accomplish these two tasks if IVC filters are to continue to have a role in primary thromboprophylaxis. PMID- 23450195 TI - Tumor size and effectiveness of electrochemotherapy. AB - BACKGROUND: Electrochemotherapy (ECT) is an effective and safe method for local treatment of tumors. However, relatively large variability in effectiveness of ECT has been observed, which likely results from different treatment conditions and tumor characteristics. The aim of this study was to investigate the relationship between tumor size and effectiveness of a single-session ECT. MATERIALS AND METHODS: A systematic search of various bibliographic databases was performed and nine studies eligible for this study were extracted. Different statistical methods including meta-analysis were applied to analyze the data. RESULTS: The results of analysis based on data from 1466 tumors of any histotype show significantly lower effectiveness of ECT on tumors with maximal diameter equal to or larger than 3 cm (complete response (CR) of 33.3%, objective response (OR) of 68.2%) in comparison to smaller tumors (CR% of 59.5%, OR% of 85.7%). The results of meta-analysis indicated that ECT performed on tumors smaller than 3 cm statistically significantly increases the probability of CR by 31.0% and OR by 24.9% on average in comparison to larger tumors. The analysis of raw data about the size and response of tumors showed statistically significant decrease in effectiveness of ECT progressively with increasing tumor diameter. The biggest drop in CR% was detected at tumor diameters as small as 2 cm. CONCLUSIONS: The standard operating procedures for ECT should be reexamined and refined for the treatment of large tumors. We propose that future clinical trials should include accurate ECT treatment planning and/or multiple ECT cycles, besides a prolonged observation for tumor response evaluation. PMID- 23450196 TI - Bevacizumab and ovarian cancer. AB - Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor-A, and is indicated in the treatment of various tumors (colon, lung, renal, and glioblastoma). It has been recently approved for the treatment of ovarian cancer in various countries. This review summarizes the activity and toxicity of bevacizumab in the treatment of ovarian cancer, both as single-agent drug and in combination with cytotoxic chemotherapy. As a single-agent drug, it has shown response rates of 16-21% in the treatment of recurrent ovarian cancer. Two phase III randomized trials have been published evaluating the addition of bevacizumab to standard chemotherapy as front-line treatment of advanced ovarian cancer. In addition, trials evaluating the combination with chemotherapy in recurrent ovarian cancer (platinum-sensitive and platinum-resistant disease) have also been reported. All these trials showed a statistically significant improvement in progression-free survival although no improvement in overall survival has been reported. The main adverse event is hypertension. Other serious, but uncommon adverse events include gastrointestinal perforation as well as renal and central nervous system toxicity. PMID- 23450197 TI - Femoro-acetabular impingement: the diagnosis-a review. AB - BACKGROUND: The recognition of the importance of femoral acetabular impingement (FAI) as a potential cause of hip pain has been stimulated by major efforts to salvage hip joints by reconstruction in order to prevent or delay the need for replacement. The purpose of this review is to define the nature of FAI, the various types, and how to make the diagnosis. METHODS: The review describes the characteristics of the hip that cause FAI and emphasizes understanding that the femoral and acetabular components normally function as a unit, complementing each other. RESULTS/CONCLUSION: The methods of making the diagnosis of FAI and their limitations are described. If the acetabulum and femur are considered to be independent of each other, conflict may occur, hindering function, and not be apparent. The increasing frequency of making this diagnosis based on abnormal anatomy on one side of the joint, often in face of unclear physical findings, can bring the diagnosis into question. FAI seen in Perthes disease and acetabular dysplasia is explained. Knowing how to analyze the hip, being aware of the limitations of various available clinical and diagnostic studies, and recognizing the continued and ever-changing extensive body of literature is important and challenging. This primer is just the beginning. PMID- 23450198 TI - Plastic surgical trauma: A single-centre experience. AB - OBJECTIVES: To analyse the demographics, mechanism, nature, anatomical distribution, management and complications in trauma patients presenting to the plastic surgery unit. STUDY DESIGN: Descriptive cross-sectional study. SETTING: This study was conducted in the Plastic and Reconstructive Surgery Unit, Hayatabad Medical Complex, Peshawar, from 1(st) January 2009 to 30(th) April 2012. MATERIALS AND METHODS: All trauma patients referred from emergency department and other departments irrespective of age and gender were enrolled in the study, excluding acute burns and trauma sequelae patients. The details were obtained from the data sheets of the patients. All the data were analysed and projected in the form of tables and figures. RESULTS: A total of 1034 patients including 855 (82.7%) males and 179 (17.3%) females presented with plastic surgical trauma, with age ranging from 1 to 86 years, with a mean age of 20.84 +/ 15.469 SD. The upper limb was affected in 492 (47.6%) patients, followed by head and neck in 273 (26.4%) cases. Road traffic accidents (RTAs) were the main cause of trauma, affecting 340 (32.9%) patients. Wound excision and closure was performed in 473 (45.7%) patients, followed by skin grafting and flap coverage in 232 (22.4%) and 132 (13.2%) patients, respectively. Postoperative complications were observed in 45 (4.35%) patients. CONCLUSION: Males in their young age mainly presented with plastic surgical trauma with RTA as the main mechanism and laceration as the most common type of these injuries. The upper limb was the most commonly affected region. The frequency of different types of surgical procedures and postoperative complications observed are comparable with international literature except for the microvascular surgery which is not performed in our centre. Regular audit of the plastic surgical trauma should be conducted in all plastic surgical units to both improve trauma care and reaffirm the role of Plastic Surgery in the new age trauma. PMID- 23450199 TI - Early Controversies Over Athetosis: II. Treatment. AB - BACKGROUND: Athetosis has been controversial since it was first described by William Hammond in 1871; many aspects of Hammond's career were equally controversial. METHODS: Primary sources have been used to review treatment controversies in the 50-year period following the initial description of athetosis. RESULTS: The treatments used most commonly employed available pharmaceutical agents and modalities (e.g., galvanism). Initial anecdotal reports of success were seldom confirmed with subsequent experience. Several novel invasive therapies were also developed and promoted, all of which damaged or destroyed either upper or lower motor neuron pathways, and were also often associated with high mortality rates. In general, these therapies substituted paresis for abnormal spontaneous movements. These included peripheral nerve stretching, excision of a portion of the precentral gyrus, rhizotomy, nerve "transplantation" (i.e., neurotomy and nerve-to-nerve anastomoses), and "muscle group isolation" (i.e., alcohol neurolysis). There was no agreement on the appropriateness of such high-risk procedures, particularly given the intentional generation of further neurological morbidity. DISCUSSION: Pharmaceutical agents and modalities initially employed for athetosis had little a priori evidence based justification and no biologically plausible theoretical framework to guide empiric treatment selection. Subsequently, all the invasive procedures employed were directed at lessening or removing the manifestations, rather than the underlying cause, of the abnormal central nervous system "irritation," usually by imposing paresis or paralysis. Factors contributing to the disparity in outcomes between favorable initial reports and the often-disappointing results of later studies included reliance on anecdotal reports or small uncontrolled case series, placebo effects, biased observation, misdiagnosis, and biased reporting. PMID- 23450200 TI - Auricular reconstruction of congenital microtia using autogenous costal cartilage: report of 27 cases. AB - BACKGROUND: Total auricular reconstruction in congenital lobule type microtia is one of the most challenging problems faced by a reconstructive surgeon as it demands precise surgical technique combined with artistic creativity. Ear reconstruction requires carefully planned procedures. METHODS: We present a simple method for auricular reconstruction consisting of three stages. The first stage is carving the cartilage framework from the costal cartilages of 6th, 7th and 8th ribs, lobule transposition and insertion in a skin pocket. The second stage is performed 5 months later to elevate the ear framework using a full thickness skin graft and a cartilage spare part. The third stage is done after 3 4 months later to give finer detail to the reconstructed ear. This method was used in 27 patients with lobule type microtia. RESULTS: The results of the reconstructed auricles in 27 patients were satisfactory with good aesthetic balance. The complications ranged from small localized skin infection treated with topical and oral antibiotics to catastrophic loss of the skin pocket and the framework. CONCLUSION: Although various donor sites have been used for harvesting the cartilage, only costal cartilage provides a substantial source for fabricating total ear framework. The cosmetic outcome and least complication results in our series support this conclusion. PMID- 23450202 TI - Detection of Clostridium difficile in retail ground meat products in Manitoba. AB - The aim of the present study was to determine whether Clostridium difficile was present in uncooked retail ground beef and ground pork products sold in Winnipeg, Manitoba. Using an alcohol treatment protocol and inoculation of cultures on C difficile Moxalactam Norfloxacin (CDMN), toxigenic C difficile was found in 6.3% of 48 meat samples. The C difficile isolates belonged to different pulsotypes, all of which had been previously isolated from the stool of Manitoba patients with C difficile disease. Because cooking of meat will not eradicate C difficile spores, this raises a concern regarding potential foodborne transmissibility of this organism. PMID- 23450203 TI - Effect of pH and Temperature on Enzyme Activity of Chitosanase Produced Under Solid Stated Fermentation by Trichoderma spp. AB - Trichoderma strains were extensively studied as biocontrol agents due to their ability of producing hydrolytic enzymes, which are considered key enzymes because they attack the insect exoskeleton allowing the fungi infection. The present work aimed to evaluate the ability of chitosanase production by four Trichoderma strains (T. harzianum, T. koningii, T. viride and T. polysporum) under solid stated fermentation and to evaluate the effect of pH and temperature on enzyme activity. pH strongly affected the enzyme activity from all tested strains. Chitosanase from T. harzianum and T. viride presented optimum activity at pH 5.0 and chitosanase from T. koningii and T. polysporum presented optimum activity at pH 5.5. Temperature in the range of 40-50 degrees C did not affect enzyme activity. T. polysporum was found as the most promising strain to produce chitosanase with maximal enzyme activity of about 1.4 IU/gds, followed by T. viride (~1.2 IU/gds) and T. harzianum (1.06 IU/gds). PMID- 23450204 TI - Intrinsic electrochemical activity of single walled carbon nanotube-Nafion assemblies. AB - The intrinsic electrochemical properties and activity of single walled carbon nanotube (SWNT) network electrodes modified by a drop-cast Nafion film have been determined using the one electron oxidation of ferrocene trimethyl ammonium (FcTMA(+)) as a model redox probe in the Nafion film. Facilitated by the very low transport coefficient of FcTMA(+) in Nafion (apparent diffusion coefficient of 1.8 * 10(-10) cm(2) s(-1)), SWNTs in the 2-D network behave as individual elements, at short (practical) times, each with their own characteristic diffusion, independent of neighbouring sites, and the response is diagnostic of the proportion of SWNTs active in the composite. Data are analysed using candidate models for cases where: (i) electron transfer events only occur at discrete sites along the sidewall (with a defect density typical of chemical vapour deposition SWNTs); (ii) all of the SWNTs in a network are active. The first case predicts currents that are much smaller than seen experimentally, indicating that significant portions of SWNTs are active in the SWNT-Nafion composite. However, the predictions for a fully active SWNT result in higher currents than seen experimentally, indicating that a fraction of SWNTs are not connected and/or that not all SWNTs are wetted completely by the Nafion film to provide full access of the redox mediator to the SWNT surface. PMID- 23450205 TI - Cytopathologic diagnosis of liver mass lesions. AB - The liver is a common site for metastatic malignancies, particularly from the gastrointestinal tract. It also may be involved by primary neoplasms, both benign and malignant. Cytopathologic examination of mass lesions of the liver with pertinent use of ancillary studies is a useful method of establishing a correct diagnosis for patient management. The authors reviewed the literature for articles pertaining to cytologic characteristics of specific tumor types, utility of immunohistochemical markers and pertinent molecular studies, differential diagnoses and pitfalls. PMID- 23450201 TI - The nature of activatory and tolerogenic dendritic cell-derived signal II. AB - Dendritic cells (DCs) are central in maintaining the intricate balance between immunity and tolerance by orchestrating adaptive immune responses. Being the most potent antigen presenting cells, DCs are capable of educating naive T cells into a wide variety of effector cells ranging from immunogenic CD4(+) T helper cells and cytotoxic CD8(+) T cells to tolerogenic regulatory T cells. This education is based on three fundamental signals. Signal I, which is mediated by antigen/major histocompatibility complexes binding to antigen-specific T cell receptors, guarantees antigen specificity. The co-stimulatory signal II, mediated by B7 family molecules, is crucial for the expansion of the antigen-specific T cells. The final step is T cell polarization by signal III, which is conveyed by DC derived cytokines and determines the effector functions of the emerging T cell. Although co-stimulation is widely recognized to result from the engagement of T cell-derived CD28 with DC-expressed B7 molecules (CD80/CD86), other co stimulatory pathways have been identified. These pathways can be divided into two groups based on their impact on primed T cells. Whereas pathways delivering activatory signals to T cells are termed co-stimulatory pathways, pathways delivering tolerogenic signals to T cells are termed co-inhibitory pathways. In this review, we discuss how the nature of DC-derived signal II determines the quality of ensuing T cell responses and eventually promoting either immunity or tolerance. A thorough understanding of this process is instrumental in determining the underlying mechanism of disorders demonstrating distorted immunity/tolerance balance, and would help innovating new therapeutic approaches for such disorders. PMID- 23450207 TI - The role of sevista in the management of dysfunctional uterine bleeding. AB - OBJECTIVE: The complaints of excessive menstrual bleeding (menorrhagia) have a substantial impact on the gynaecological services and in most of the cases, no organic pathology is identified. Nonsteroidal anti-inflammatory drugs and tranexamic acid offer a simple therapy which has to be taken during menses, with reductions of 25-35% and 50% respectively in the Menstrual Blood Loss (MBL). Danazol and the gonadatrophin-releasing hormone analogues are highly effective, but their side-effects make them suitable only for a short-term use. In the present study, the role of ormeloxifene was studied in patients of DUB. MATERIALS & METHODS: The subjects were diagnosed cases of DUB. After ruling out the possible causes of the abnormal uterine bleeding, a diagnosis of DUB was made and the treatment with ormiloxifene was started. The number of cases were 35 cases. The treatment with ormeloxifene was evaluated by measuring the Hb g/dl and the endometrial thickness before and after 3 months of treatment with sevista. Ormeloxifene was given in the dosage of a 60 mg tablet twice a week for 3 months, followed by once a week for another 3 months. OBSERVATION & RESULTS: There was a statistically significant increase in the Hb g/dl (p < 0.001) and a statistically significant decrease in the endometrial thickness (p< 0.001) after the treatment with ormeloxifene. CONCLUSION: Ormeloxifene can be used asa effective drug in the treatment of Dysfunctional uterine bleeding. PMID- 23450208 TI - Uncovering intermittent entropion. AB - PURPOSE: Intermittent entropion may go unnoticed by both patient and physician, in some instances resulting in ocular surface disorders. Unfortunately, the current work-up used to diagnose entropion is not always sufficient to uncover the problem. We present an alternative diagnostic test. CASES: Two case reports are presented showing different situations where the current methods for detection of entropion failed and the diagnosis was only made with an alternative diagnostic test. RESULTS: The common denominator of both cases is an intermittent entropion which could not be detected by the conventional clinical work-up. Diagnosis was easy however using the "TIE test" described in the text. CONCLUSION: The important clues for suspicion of intermittent entropion are an intermittent foreign-body sensation in the eye accompanied with central punctate keratopathy. The TIE test is a simple and useful test for the diagnosis of intermittent entropion. PMID- 23450206 TI - Resveratrol, wine, and atherosclerosis. AB - This review emphasizes the effects of resveratrol on factors involved in the mechanism of atherosclerosis and risk factors for atherosclerosis. The effects of wine and resveratrol on atherosclerosis are also discussed. Resveratrol is a potent antioxidant and an anti-inflammatory agent. It reduces the expression of cell adhesion molecules, monocyte colony stimulating factors, matrix metalloproteinases, and growth factors; and inhibits platelet aggregation and vascular smooth muscle cell proliferation. It reduces the serum levels of total cholesterol, triglycerides (TG), and raises high-density lipoprotein cholesterol, inhibits expression of C-reactive protein and lowers the levels of advanced glycation end products and its receptor in the vascular tissue. It lowers the risk factors for plaque rupture. Epidemiological data show that moderate consumption of alcohol has an inverse association with carotid atherosclerosis while high consumption has a positive association with carotid atherosclerosis. Wine reduces the extent of atherosclerosis in animal model. The antiatherosclerotic effect of wine is mainly due to it resveratrol content. Resveratrol reduces the extent of atherosclerosis in animal model of atherosclerosis (apolipoprotein [Apo] E-deficient and Apo E(-/-)/low-density lipoprotein receptor-deficient mice and macrophage). In rabbit model of atherosclerosis, both reduction and acceleration of atherosclerosis have been reported with resveratrol. There are no data for regression and slowing of progression of atherosclerosis. Robust clinical trials for suppression of atherosclerosis are lacking. In conclusion, resveratrol has potential but experimental studies in depth and robust clinical trials are lacking for this agent to be of any value in the primary and secondary prevention of coronary and peripheral artery disease. PMID- 23450209 TI - Clinical predictors of primary immunodeficiency diseases in children. AB - PURPOSE: To promote awareness of primary immunodeficiency (PID), the "10 warning signs" of PID and an immunodeficiency-related (IDR) score were developed. However, their efficiency in identifying PID cases was not sufficiently evaluated in clinical practice. The objective of this study was to test the validity of the 10 warning signs and IDR score in identifying PID among children with recurrent infections at a tertiary pediatric hospital in Egypt. METHODS: A retrospective analysis of the medical records of 204 patients was performed. Of these patients, 92 had defined PID diseases and 112 were considered non-PID cases because investigations were inconclusive. RESULTS: Demonstrating two warning signs and an IDR score of 6 led to sensitivities of 94 and 66%, respectively, and specificities of 64 and 75%, respectively, in identifying PID cases. The strongest predictor of PID was family history that, if combined with the need for intravenous antibiotics, recurrent deep-seated infections, and failure to thrive, could identify 81% of PID patients. A family history of PID, sibling death, and/or parental consanguinity would predict 92% of combined immunodeficiencies, 92% of phagocyte defects, 87% of well-identified immunodeficiency syndromes, and 84% of antibody deficiency if the need for intravenous antibiotics is considered in the latter. CONCLUSIONS: The 10 warning signs and IDR score do not aid in an early diagnosis of severe PID. Educational campaigns should target pediatricians aiming to increase PID awareness and to address family history of PID, parental consanguinity, and previous sibling death as key predictors of PID in communities with a high prevalence of consanguineous marriages. PMID- 23450210 TI - Conjugate acene fused buckybowls: evaluating their suitability for p-type, ambipolar and n-type air stable organic semiconductors. AB - Elaborate and exhaustive first principles calculations were carried out to screen the novel properties of a series of acene fused buckybowls. The acene fused compounds exhibit hole transport property due to their higher electron injection and lower hole transport barrier relative to the work function potential of Au electrodes. The higher HOMO and lower LUMO energy levels suggest lower hole and electron injection barriers of F and CN substituted and boron doped bowls which indicates ambipolar property of these bowls. The dicyano substituted pentacene fused bowls show only electron transport property with lower LUMO (-4.26 eV to 4.27 eV) and higher HOMO (-5.56 eV to -5.90 eV) energy levels. High electron affinity (>2.80 eV) and low LUMO energy (< -4.00 eV) attributes air stability to these bowls. Curvature decreased frontier orbital energies and increased ionization energy and electron affinity of bowls. This study reveals substitution of electron withdrawing groups and boron doped acene fused bowls can be a prominent materials for ambipolar and electron transport organic semiconductors. PMID- 23450212 TI - Principles of electron capture and transfer dissociation mass spectrometry applied to peptide and protein structure analysis. AB - This tutorial review describes the principles and practices of electron capture and transfer dissociation (ECD/ETD or ExD) mass spectrometry (MS) employed for peptide and protein structure analysis. ExD MS relies on interactions between gas phase peptide or protein ions carrying multiple positive charges with either free low-energy (~1 eV) electrons (ECD), or with reagent radical anions possessing an electron available for transfer (ETD). As a result of recent implementation on sensitive, high resolution, high mass accuracy, and liquid chromatography timescale-compatible mass spectrometers, ExD, more specifically, ETD MS has received particular interest in life science research. In addition to describing the fundamental aspects of ExD radical ion chemistry, this tutorial provides practical guidelines for peptide de novo sequencing with ExD MS, as well as reviews some of the current capabilities and limitations of these techniques. The merits of ExD MS are discussed primarily within the context of life science research. PMID- 23450211 TI - Genome sequence of the orange-pigmented seawater bacterium Owenweeksia hongkongensis type strain (UST20020801(T)). AB - Owenweeksia hongkongensis Lau et al. 2005 is the sole member of the monospecific genus Owenweeksia in the family Cryomorphaceae, a poorly characterized family at the genome level thus far. This family comprises seven genera within the class Flavobacteria. Family members are known to be psychrotolerant, rod-shaped and orange pigmented (beta-carotene), typical for Flavobacteria. For growth, seawater and complex organic nutrients are necessary. The genome of O. hongkongensis UST20020801(T) is only the second genome of a member of the family Cryomorphaceae whose sequence has been deciphered. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 4,000,057 bp long chromosome with its 3,518 protein-coding and 45 RNA genes is a part of the GenomicEncyclopedia ofBacteriaandArchaea project. PMID- 23450213 TI - Static progressive orthoses for the upper extremity: a comprehensive literature review. AB - BACKGROUND: Static progressive orthoses are commonly used in the treatment of stiff joints or joint contractures of the upper extremity, but there are few high quality studies to support this intervention. In addition, there has not been a recently published review of the current literature describing this treatment technique and the outcomes achieved. The specific purpose of this comprehensive literature review is to investigate the current levels of evidence supporting the use of static progressive orthoses in the treatment of joint stiffness or contracture in clients with orthopedic conditions of the upper extremity. This review will also discuss common diagnoses of patients and outcomes achieved, as well as provide recommendations for future hand therapy practice. METHODS: A computerized database search of publications incorporating the use of static progressive orthoses for the upper extremity was conducted, dating from January 1979 through January of 2011. The search was limited to studies in English of adults with orthopedic conditions. RESULTS: A total of 65 publications were located. However, only 16 of these studies met this review's inclusion criteria of level 4 evidence or above. Each of the articles was critically appraised using the Structured Effectiveness for Quality Evaluation of Study (SEQES) and the Oxford Center for Evidence-Based Medicine 2011 Level of Evidence. Total SEQES scores ranged from 17 to 39. The majority of the studies are level 4 evidence. CONCLUSIONS: Although the overall level of evidence is low, the inclusion of static progressive orthoses as an intervention appears to result in positive outcomes, including increased active range of motion, increased grip strength, improved DASH scores, and improved patient satisfaction as well as reduced pain medications during orthotic intervention. The current evidence supports static progressive orthoses as an intervention for patients with upper extremity joint stiffness or contractures due to orthopedic conditions. PMID- 23450214 TI - Rare case of blastemal predominant adult Wilms' tumor with skeletal metastasis case report and brief review of literature. AB - Wilms' tumor (nephroblastoma) is extremely rare in adults, skeletal metastasis being still rarer. The clinical course of adult Wilms' tumor is very aggressive. The present case is a rare blastemal predominant adult Wilms' tumor presenting with skeletal metastasis. We report a case of 19-year-old female presented with severe low backache and colicky left loin pain of 3 months and progressive weakness of 15 days duration. Magnetic resonance image (MRI) of lumbosacral spine was reported as spinal metastasis with right renal mass. The patient underwent right radical nephrectomy and the tumor was histopathologically confirmed as adult Wilms' tumor. In case of adult Wilms' tumor, distant metastasis may be the first presentation and this possibility should be considered when an adult patient presents with flank pain and a renal mass. PMID- 23450215 TI - Studying the evolutionary relationships and phylogenetic trees of 21 groups of tRNA sequences based on complex networks. AB - To find out the evolutionary relationships among different tRNA sequences of 21 amino acids, 22 networks are constructed. One is constructed from whole tRNAs, and the other 21 networks are constructed from the tRNAs which carry the same amino acids. A new method is proposed such that the alignment scores of any two amino acids groups are determined by the average degree and the average clustering coefficient of their networks. The anticodon feature of isolated tRNA and the phylogenetic trees of 21 group networks are discussed. We find that some isolated tRNA sequences in 21 networks still connect with other tRNAs outside their group, which reflects the fact that those tRNAs might evolve by intercrossing among these 21 groups. We also find that most anticodons among the same cluster are only one base different in the same sites when S >= 70, and they stay in the same rank in the ladder of evolutionary relationships. Those observations seem to agree on that some tRNAs might mutate from the same ancestor sequences based on point mutation mechanisms. PMID- 23450216 TI - Secondary radiation-induced bone tumours demonstrate a high degree of genomic instability predictive of a poor prognosis. AB - Secondary bone tumours arising in the field of a preceding radiotherapy are a serious late effect, in particular considering the increasing survival times in patients treated for paediatric malignancies. In general, therapy associated tumours are known to show a more aggressive behaviour and a limited response to chemotherapy compared with their primary counterparts. It is not clear however whether this less favourable outcome is caused by inherent genetic factors of the tumour cells or by a general systemic condition of the patient. To elucidate this we analysed a series of bone sarcomas with a history of prior irradiation for the presence of genomic alterations and compared them with the alterations identified earlier in primary osteosarcomas. We analysed seven radiation induced bone sarcomas for genome-wide losses of heterozygosity (LOH) using Affymetrix 10K2 high-density single nucleotide polymorphism (SNP) arrays. Additionally, copy number changes were analysed at two distinct loci on 10q that were recently found to be of major prognostic significance in primary osteosarcomas. All the investigated tumours showed a LOH at 10q21.1 with 86% of cases (6/7) revealing a total genome-wide LOH score above 2400 and more than 24% of the genome being affected. Our results indicate similar genetic alterations in radiation induced sarcomas of bone and primary osteosarcomas with a poor prognosis. We speculate that the high degree of genomic instability found in these tumours causes the poor prognosis irrespective of the initiating event. PMID- 23450217 TI - A finite element analysis of stress distribution in the bone, around the implant supporting a mandibular overdenture with ball/o ring and magnetic attachment. AB - Today implant dentistry has made great inroads into the treatment modalities that are available in treating an edentulous patient. Popularity of a two implant retained overdenture has created a necessity to examine the various attachment systems being used and the stresses that are transmitted to the alveolar bone. Hence a Three dimensional Finite Element Analysis was done to analyze the stress distribution in the mandibular bone with implant-supported overdenture having Ball/O-ring and Magnet attachments of different diameters. A segment of the anterior region of the mandible was modeled with implant and the overdenture. Four different models were generated having Ball/O-Ring and Magnet Attachments. Forces of 10 N, 35 N and 70 N were applied from the horizontal, vertical and oblique directions respectively and the stress distribution studied. It was concluded that the greatest stress concentrations were seen at the crest of the cortical bone and could be reduced by using smaller sized attachments for implant supported-overdenture. PMID- 23450218 TI - Reviewing the nursing students' views toward OSCE test. AB - BACKGROUND: One of the essential components of learning and educational program is evaluation or examination. There are various methods for evaluating clinical skills among which objective structured clinical examination (OSCE) has been recognized as the most reliable method for evaluation of the clinical skills. METHODS: This was a one-step single-group descriptive study which was conducted through a researcher-made questionnaire. RESULTS: Results indicated that the view of most of the students in OSCE test has been good in terms of equipment and facilities with relative frequency of 59.2 percent, conditions of holding the examination with relative frequency of 50.9% and total test with relative frequency of 55.1%; in terms of physical environment, students' view was moderate with relative frequency of 469%. CONCLUSIONS: The results of the study showed that appropriateness of physical environment and equipment and facilities to hold OSCE can directly be involved in enhancing the quality of this test. PMID- 23450219 TI - The effect of yoga therapy on selected psychological variables among male patients with insomnia. AB - BACKGROUND: An estimated 30-50% of the general population is affected by insomnia and 10% have chronic insomnia. Yoga therapy is beneficial in such disorders and it has fewer side effects. AIM: The aim of this study was to find out the effect of yoga therapy on selected psychological variables among men with insomnia. METHODS: Forty males with insomnia were divided randomly into 2 groups (the experimental and the control groups). The experimental group received eight weeks of yoga therapy, while the control group did not receive any therapy. The pre and post treatment stress and the self confidence scores were taken. RESULTS: There was a significant improvement in the stress scores and the self confidence scores in the experimental group. There were neither any side effects nor any drop outs. CONCLUSION: We conclude that yoga is an effective treatment option for the patients with insomnia. There are no major side effects. PMID- 23450220 TI - New directions in thermoresponsive polymers. AB - Interest in thermoresponsive polymers has steadily grown over many decades, and a great deal of work has been dedicated to developing temperature sensitive macromolecules that can be crafted into new smart materials. However, the overwhelming majority of previously reported temperature-responsive polymers are based on poly(N-isopropylacrylamide) (PNIPAM), despite the fact that a wide range of other thermoresponsive polymers have demonstrated similar promise for the preparation of adaptive materials. Herein, we aim to highlight recent results that involve thermoresponsive systems that have not yet been as fully considered. Many of these (co)polymers represent clear opportunities for advancements in emerging biomedical and materials fields due to their increased biocompatibility and tuneable response. By highlighting recent examples of newly developed thermoresponsive polymer systems, we hope to promote the development of new generations of smart materials. PMID- 23450221 TI - Triplet photosensitizers: from molecular design to applications. AB - Triplet photosensitizers (PSs) are compounds that can be efficiently excited to the triplet excited state which subsequently act as catalysts in photochemical reactions. The name is originally derived from compounds that were used to transfer the triplet energy to other compounds that have only a small intrinsic triplet state yield. Triplet PSs are not only used for triplet energy transfer, but also for photocatalytic organic reactions, photodynamic therapy (PDT), photoinduced hydrogen production from water and triplet-triplet annihilation (TTA) upconversion. A good PS should exhibit strong absorption of the excitation light, a high yield of intersystem crossing (ISC) for efficient production of the triplet state, and a long triplet lifetime to allow for the reaction with a reactant molecule. Most transition metal complexes show efficient ISC, but small molar absorption coefficients in the visible spectral region and short-lived triplet excited states, which make them unsuitable as triplet PSs. One obstacle to the development of new triplet PSs is the difficulty in predicting the ISC of chromophores, especially of organic compounds without any heavy atoms. This review article summarizes some molecular design rationales for triplet PSs, based on the molecular structural factors that facilitate ISC. The design of transition metal complexes with large molar absorption coefficients in the visible spectral region and long-lived triplet excited states is presented. A new method of using a spin converter to construct heavy atom-free organic triplet PSs is discussed, with which ISC becomes predictable, C60 being an example. To enhance the performance of triplet PSs, energy funneling based triplet PSs are proposed, which show broadband absorption in the visible region. Applications of triplet PSs in photocatalytic organic reactions, hydrogen production, triplet-triplet annihilation upconversion and luminescent oxygen sensing are briefly introduced. PMID- 23450222 TI - Idiopathic Atypical Hemolytic Uremic Syndrome (aHUS) with Trilineage Myelodysplasia. AB - Atypical hemolytic uremic syndrome (HUS) is a heterogeneous group of disorders, with an unexplained pathogenesis. We report here with an interesting case of a 6 years old male child presenting with atypical feature of HUS and bone marrow trilineage myelodysplasia. PMID- 23450223 TI - Synthesis and X-ray characterization of novel palladium(II) complexes with tunable chiral anionic counterions. AB - Various novel palladium(II) complexes with tunable chiral and achiral anionic counterions have been prepared from dialkylpalladium(II) agents and characterized by NMR spectroscopy and X-ray diffraction. PMID- 23450224 TI - Development of microsatellite markers in Robinsonia (Asteraceae) an endemic genus of the Juan Fernandez Archipelago, Chile. AB - Ten microsatellite markers were developed for Robinsonia (Asteraceae), a genus endemic to the Juan Fernandez Archipelago, Chile. Polymorphisms of these markers were tested using one population each of R. evenia, R. gayana, and R. gracilis. The number of alleles for these markers ranged from 2 to 17 per locus, and expected heterozygosity ranged from 0 to 0.847 by population. A significant deviation from Hardy-Weinberg equilibrium was observed in zero to two markers in each population, and no significant linkage disequilibrium between markers was detected. The markers reported here would be useful for evolutionary studies and conservation strategies in Robinsonia. PMID- 23450225 TI - Argentivorous molecules with two kinds of aromatic side-arms: intramolecular competition between side-arms. AB - Three tetra-armed cyclens with two kinds of side-arms, 3',5'-difluorobenzyl/4' methylbenzyl, 3',5'-difluorobenzyl/1'-naphthylmethyl, and 3',5'-difluorobenzyl/9' anthrylmethyl groups, were prepared by reductive amination of 1,7-bis(3',5' difluorobenzyl)-1,4,7,10-tetraazacyclododecane and the corresponding aromatic aldehydes in the presence of NaBH(OAc)3. The X-ray structures of the Ag(+) complexes and Ag(+)-ion-induced (1)H NMR spectral changes suggest that (i) the chemical shift changes of the protons at the 2'- and 6'-positions in the 3',5' difluorobenzyl/4'-methylbenzyl side-arms are dependent on the electron density on the adjacent substituted benzenes, and (ii) in the tetra-armed cyclens with 3',5' difluorobenzyl/1'-naphthylmethyl and 3',5'-difluorobenzyl/9'-anthrylmethyl groups as side-arms, electron-rich aromatic rings preferentially cover the Ag(+) ions incorporated into the ligand cavities, and 3',5'-difluorobenzyl groups do not participate in the Ag(+) interactions. The log K values were estimated using Ag(+)-ion-induced UV-vis spectral changes. PMID- 23450227 TI - A joint experimental/theoretical investigation of the MMA polymerization initiated by yttrium phenoxyamine complexes. AB - A joint experimental/theoretical study has been carried out on the putative MMA polymerization catalyzed by an yttrium isopropyloxide complex. Despite its high activity in lactone polymerization, this catalyst is found to be unreactive on methyl methacrylate (MMA) polymerization. This surprising result is rationalized using a computational approach at the DFT level. Indeed, the endothermicity of the initiation step explains this lack of reactivity. The theoretical proposal of yttrium amido complexes as catalysts allows overcoming this initiation problem. PMID- 23450226 TI - PolyCat: a resource for genome categorization of sequencing reads from allopolyploid organisms. AB - Read mapping is a fundamental part of next-generation genomic research but is complicated by genome duplication in many plants. Categorizing DNA sequence reads into their respective genomes enables current methods to analyze polyploid genomes as if they were diploid. We present PolyCat-a pipeline for mapping and categorizing all types of next-generation sequence data produced from allopolyploid organisms. PolyCat uses GSNAP's single-nucleotide polymorphism (SNP)-tolerant mapping to minimize the mapping efficiency bias caused by SNPs between genomes. PolyCat then uses SNPs between genomes to categorize reads according to their respective genomes. Bisulfite-treated reads have a significant reduction in nucleotide complexity because nucleotide conversion events are confounded with transition substitutions. PolyCat includes special provisions to properly handle bisulfite-treated data. We demonstrate the functionality of PolyCat on allotetraploid cotton, Gossypium hirsutum, and create a functional SNP index for efficiently mapping sequence reads to the D-genome sequence of G. raimondii. PolyCat is appropriate for all allopolyploids and all types of next generation genome analysis, including differential expression (RNA sequencing), differential methylation (bisulfite sequencing), differential DNA-protein binding (chromatin immunoprecipitation sequencing), and population diversity. PMID- 23450228 TI - Aluminium coordination complexes in copolymerization reactions of carbon dioxide and epoxides. AB - Al complexes are widely used in a range of polymerization reactions (ROP of cyclic esters and cationic polymerization of alkenes). Since the discovery in 1978 that an Al porphyrin complex could copolymerize propylene oxide with carbon dioxide, Al coordination compounds have been studied extensively as catalysts for epoxide-carbon dioxide copolymerizations. The most widely studied catalysts are Al porphyrin and Al salen derivatives. This is partially due to their ability to act as mechanistic models for more reactive, paramagnetic Cr catalysts. However, this in depth mechanistic understanding could be employed to design more active Al catalysts themselves, which would be beneficial given the wide availability of this metal. Polymerization data (% CO3 linkages, M(n), M(w)/M(n) and TON) for these complexes are presented and mechanisms discussed. In most cases, especially those employing square-based pyramidal Al complexes, co-catalysts are required to obtain high levels of carbon dioxide incorporation. However, in some cases, the use of co-catalysts inhibits the copolymerization reaction. Lewis acidic Al phenolate complexes have been used as activators in CHO-carbon dioxide copolymerizations to increase TOF and this has recently led to the development of asymmetric copolymerization reactions. Given the ready availability of Al, the robustness of many complexes (e.g. use in immortal polymerizations) and opportunity to prepare block copolymers and other designer materials, Al complexes for copolymerization of carbon dioxide are surely worth a second look. PMID- 23450229 TI - The role of intravascular ultrasound in venous thromboembolism. AB - Venous thromboembolism (VTE) remains a serious problem, and treatments surrounding this potentially life-threatening disease continue to evolve. Evidence-based guidelines purport the need for minimally invasive catheter-based procedures as part of the armamentarium to prevent and treat VTE. When the appropriate clinical scenarios arise, intravascular ultrasound (IVUS) becomes a necessary part of those procedures to provide alternative imaging that complements traditional venography. IVUS of the major axial veins provides a 360 degree two-dimensional gray scale ultrasound image of lumen and vessel wall structures. IVUS remains the criterion standard for venous imaging when contemplating catheter-based procedures from the common femoral vein to the inferior vena cava. Not only can precise location and size of these veins be determined by the IVUS probe from key landmarks and venous branches, but other important abnormalities can be visualized. These include external compression, acute and chronic thrombus, fibrosis, mural wall thickening, spurs, and trabeculations. Specific procedures that use IVUS include the treatment of venous obstruction and the placement of vena cava filters at the bedside. IVUS remains a vital part of accurately imaging the major axial veins when contemplating catheter-based procedures to prevent or treat VTE-related disorders. PMID- 23450230 TI - An alternative picture of alkali-metal-mediated metallation: cleave and capture chemistry. AB - This perspective article takes an alternative look at alkali-metal-mediated chemistry (exchange of a relatively inert C-H bond for a more reactive C-metal bond by a multicomponent reagent usually containing an alkali metal and a less electropositive metal such as magnesium or zinc). It pictures that the cleavage of selected C-H bonds can be accompanied by the capturing of the generated anion by the multi (Lewis acid)-(Lewis base) character of the residue of the bimetallic base. In this way small atoms or molecules (hydrides, oxygen-based anions) as well as sensitive organic anions (of substituted aromatic compounds, ethers or alkenes) can be captured. Cleave and capture reactions which occur in special positions on the organic substrate are also included. PMID- 23450231 TI - p38 MAPK regulates the expression of ether a go-go potassium channel in human osteosarcoma cells. AB - BACKGROUND: The ether a go-go (Eag) channel has been shown to be overexpressed in a variety of cancers. However, the expression and function of Eag in osteosarcoma are poorly understood. In addition, the molecular mechanisms responsible for Eag overexpression in cancer cells remain unclear. METHODS: The expression of Eag in human osteosarcoma cell line MG-63 was detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The effect of Eag inhibition on MG-63 cell proliferation was assessed in vitro. The effect of short hairpin RNA (shRNA) mediated knockdown of Eag on osteosarcoma growth was evaluated in xenograft model in vivo. The activation of mitogen-activated protein kinase (MAPK) pathway and p53 in MG-63 cells was detected by Western blot analysis. RESULTS: Eag was overexpressed in MG-63 cells. Imipramine or Eag shRNA significantly suppressed the proliferation of MG-63 cells in vitro and in vivo. MG-63 cell proliferation was specifically inhibited by p38 MAPK inhibitor SB203580 or small interference RNA (siRNA). The inhibition of p38 MAPK activation by SB203580 or siRNA reduced Eag protein level but increased p53 protein level. Moreover, the activation of p53 by nutlin-3 induced cell growth arrest in MG-63 cells and reduced Eag protein level, while the inactivation of p53 by pifithrin alpha (PFT-alpha) promoted MG-63 cell growth and increased Eag protein expression. CONCLUSIONS: Eag channel functions as an oncogene to promote the proliferation of human osteosarocma cells. Furthermore, the high expression of Eag in osteosarcoma cells is regulated by p38 MAPK/p53 pathway. PMID- 23450232 TI - Synthesis and structures of calcium and strontium 2,4-di-tert-butylphenolates and their reactivity towards the amine co-initiated ring-opening polymerisation of rac-lactide. AB - Calcium and strontium metals react with Hg(C6F5)2 and 2,4-di-tert-butylphenol (H DBP) in tetrahydrofuran (THF) and 1,2-dimethoxyethane (DME) to give [Ca(DBP)2(THF)4] (1), [Ca2(DBP)4(DME)4(MU-DME)] (2), [Sr3(MU-DBP)6(THF)6] (3), and [Sr2(DBP)(MU-DBP)3(DME)3] (4). Compound 1 is a six coordinate trans octahedral monomer, whereas in binuclear 2 two seven-coordinate Ca centres are bridged by a DME ligand. In 3 a central Sr is connected by three bridging DBP groups to each of two terminal Sr(THF)3 moieties, all metal atoms being six coordinate. Compound 4 has one six- and one seven-coordinate Sr, bridged by three DBP ligands, the former Sr also having a terminal DBP and a bidentate DME ligand and the latter two DME ligands. Complexes 2 and 4 act as ring-opening polymerisation (ROP) catalysts for the benzyl alcohol or benzylamine co-initiated ROP rac-lactide forming atactic alcohol- or amine-terminated polylactide H-[PLA] XBn (X = O or NH) with reasonable control of molecular weight via an activated monomer propagation mechanism. Kinetic studies for BnNH2 found the unusual rate expression -d[LA]/dt = k(p(Ae))[2 or 4]0[rac-LA](2)[BnNH2]0(2.5) (k(p(Ca)) ~ 1.7 *k(p(Sr))). Preliminary studies suggest that [Y(DBP)3(THF)2] also catalyses amine or alcohol co-initiated ROP by an activated monomer mechanism without loss of a phenoxide ligand. PMID- 23450233 TI - Complications of pamidronate therapy in paediatric osteoporosis. AB - PURPOSE: Pamidronate, used for the treatment of paediatric osteoporosis, reduces the fracture rate and improves ambulatory status. Intravenous pamidronate therapy has known complications which have not been stratified based on its dose and distribution. This study aims to assess the early minor and major medical and late surgical complications and the effect of the dose and regimen of infusion on these events in paediatric osteoporosis. STUDY DESIGN: Retrospective cohort. MATERIALS AND METHODS: Three regimens for pamidronate infusion were followed in sequential periods in 10 years. Regimen A delivered 1.5 mg/kg/day as a single dose once in 3 months. Regimen B delivered 2 mg/kg/day for 3 days twice a year, while regimen C delivered 1 mg/kg/day for 3 days every 3-4 months. Adverse events were classified as early (major and minor) or late (surgical). RESULTS: Forty eight children received 158 infusions using one of the three regimens. Twenty nine complications occurred in 24 children. A significant difference in the complication rate was present among the three regimens (P = 0.005). Nineteen children had minor complications, mainly febrile reaction or asymptomatic hypocalcaemia. Four major complications consisting of one seizure, one respiratory distress and two hypocalcaemic tetany were encountered, all with regimen B. Intraoperative complication faced was loss of position due to splintering of the cortex while rush rodding. This was seen in 20% of the long bone segments operated in those who received pamidronate as compared to 4.4% of the segments which were operated prior to the initiation of pamidronate therapy; the odds of splintering were 5.4 times higher for those patients who were bone segment rodded after pamidronate therapy. DISCUSSION: Intravenous pamidronate is associated with complications in 50% of children with paediatric osteoporosis, with a dose-dependent significant difference. Major complications are not uncommon with higher doses and can be avoided by increasing the number of doses per year and decreasing the dose per cycle. Surgical difficulty, when possible, can be avoided by correcting any major deformities at presentation prior to the induction of pamidronate therapy. PMID- 23450234 TI - Gastric cancer and trastuzumab: first biologic therapy in gastric cancer. AB - Gastric cancer remains difficult to cure and has a poor overall prognosis. Chemotherapy and multimodality therapy has shown some benefit in the treatment of gastric cancer. Current therapies for gastric cancer have their limitations; thus, we are in need of newer treatment options including targeted therapies. Here, we review the biologic therapy with trastuzumab in human epidermal growth factor receptor 2 (HER2)+ gastric cancer. PMID- 23450235 TI - Ethical and legal issues in aesthetic surgery. AB - Rapid growth and expansion of plastic surgery in general and aesthetic surgery in particular in the past decade has brought in its wake some confusions particularly raising questions for the surgeons conduct towards his colleagues and the patients in the light of ethical requirements. Some thoughts from eminent thinkers form a backdrop to consideration of theories of medical ethics. In this article raging and continuous debates on these subjects have been avoided to maintain the momentum. Apart from the western thoughts, directions from our old scriptures on ethical conduct have been included to accommodate prevelant Indian practices. The confusion created by specialists advertising their abilities directly to the lay public following removal of ethical bars by the American Courts as also latitudes allowed by the General Medical Council of Great Britain have been discussed. The medical fraternity however has its reservations. Unnecessary skirmishes with the law arose in cosmetic surgery from the freedom exercised by the police to file criminal proceedings against attending doctors in the event of a patient's death with or without any evidence of wrong doing. This has now been curtailed in the judgement of the Supreme Court of India[1] where norms have been laid down for such prosecution. This has helped doctors to function without fear of harassment. An effort has been made to state a simple day-to-day routine for an ethical doctor-patient relationship. PMID- 23450236 TI - Tremor in patients with inflammatory bowel disease. PMID- 23450237 TI - The influence of valence and decision difficulty on self-referential processing. AB - Self-referential processing is defined as the process by which a person becomes aware that specific contents are related to his or her own self. Cortical midline structures (CMS), such as dorsal and medial prefrontal cortex, and regions such as inferior frontal cortex, insula, and temporal pole have been implicated in self-referential processing. However, the specific contribution of each of these areas is still largely unknown. More particularly, not many studies have examined the influence of valence and decision making difficulty on regions involved in self-referential processing. In this study, participants evaluated how well personality traits, differing in valence and decision difficulty, described themselves or the current US President. In line with predictions, ventral, rostral, and dorsal parts of medial prefrontal cortex showed greater activity when participants judged traits about themselves relative to judging traits about the current US President. However, none of these regions showed significant modulation by trait valence. Increasing trait decision difficulty was associated with increased activity within dorsal medial prefrontal cortex and bilateral anterior insula. However, there was very minimal overlap (6/119 voxels, i.e., 5%) of the regions of dorsal medial prefrontal cortex implicated in self-referential processing and those implicated in trait decision difficulty. The results are interpreted within current accounts of self-referential processing. PMID- 23450238 TI - Soft tissue reconstruction after hemimandibulectomy in oral malignancies: a retrospective study. AB - AIMS: The present study was under taken to evaluate the efficacy of various local and regional soft tissue flaps used for reconstruction after excision of various malignant lesions of the mouth and also to evaluate complications with length of hospital stay after the reconstruction. MATERIALS AND METHODS: The study was a record based retrospective analysis of 127 patients who were histologically proven squamous cell carcinoma of the oral cavity for which excision of the lesion along with segmental mandibulectomy and primary reconstruction with local or regional flaps was the treatment modality. RESULTS: The male:female mean age is 48.27:48.79. The Z-proportionality test for intra oral reconstruction showed 5% level of significance (P < 0.05) between pectoralis major myocutaneous flap (PMMC) and other flaps. Difference between deltopectoral (DP) and PMMC, PMMC and primary closure at 1% level of significance, i.e. P < 0.01 was found for extra oral defects. The mean stay was found to be 31.31 days. Recurrence rate of 11% was reported. CONCLUSION: A total of 127 patients formed the study group. In the absence of bone reconstruction PMMC still continues to be the "work horse" of reconstruction following wide excision and hemimandibulectomy. PMID- 23450239 TI - Homology modeling of dihydrofolate reductase from T. gondii bonded to antagonists: molecular docking and molecular dynamics simulations. AB - The aim of this work was to solve the structure of the enzyme dihydrofolate reductase from Toxoplasma gondii (TgondiiDHFR) as a target for drug discovery on account of recent reports of parasite's growing resistance to pyrimethamine (CP6), which is the reference pharmaceutical used to treat toxoplasmosis and malaria. The tertiary structure of the protein bonded to NADP(+) and CP6 was solved by homology modeling. The best output model was subjected to conjugate gradient minimization and the comparison with templates shows important replacements at the inhibitor's binding site allowing selective drug design. CP6 redocking in TgondiiDHFR shows a DeltaGbinding of -8.66 kcal mol(-1), higher than those found for templates Plasmodium vivax (-9.01) and P. falciparum (-8.99). Virtual screening of ligands similar to CP6 was performed using the ZINC database and docking procedures were carried out. The result indicates the substances ZINC14966516, ZINC13685962, ZINC13685929 and ZINC13686062 with a DeltaGbinding of -10.57, -10.09, -9.87, and -9.76 kcal mol(-1), respectively, as the best choices. NPT molecular dynamics with the complexes indicates that they remained stable along the 10 ns simulation and they dock to TgondiiDHFR by salt bridges to the Asp 30 and to nine other residues in the contact region, which makes it more difficult for single mutations to acquire resistance. The contact frequency of protein residues with ligands suggests plausible explanations for site-directed mutagenesis studies regarding CP6 resistance described previously in the literature. All results indicate that the new ligands could be tested as pyrimethamine substitutes in the treatment of toxoplasmosis, in addition to other protozoonosis diseases. PMID- 23450240 TI - Impact of cytolysis following transarterial chemoembolization for hepatocellular carcinoma. AB - BACKGROUND AIMS: Transarterial chemoembolization (TACE) is increasingly used as a treatment of hepatocellular carcinoma. Cytolysis, which may occur within days following the procedure is due to either necrosis of the tumour or of the non tumoral parenchyma. Therefore it may influence either tumour response or liver function or both. We evaluated the impact of cytolysis after TACE on tumour response, incidence of hepatobiliary complications and overall survival. METHODS: We conducted a retrospective analysis of 157 patients with liver disease who underwent 271 treatments for hepatocellular carcinoma. Cytolysis was defined as an increase of AST value above 100 IU/L with at least doubling of the baseline value. The associations between cytolysis and radiologic tumor response two months following each treatment and adverse hepatobiliary events were estimated using generalized estimating equations models. Comparison of 18 months survival after a first treatment of chemoembolization between the groups with and without cytolysis was performed using the proportional hazards model. RESULTS: Cytolysis occurred in 198 out of 271 cases and was associated with a favourable radiological response (OR 1.90, 1.03-3.54) at two months compared to non cytolysis with no difference in the occurrence of adverse hepatobiliary events. The adjusted hazard ratio for overall survival was 1.33 times greater in the group with cytolysis compared to non-cytolysis (0.45-3.90). CONCLUSIONS: The occurrence of cytolysis was associated with a favorable radiological response, but had no impact on short-term adverse events and on survival at 18 months. PMID- 23450241 TI - Parasitic disease screening among HIV patients from endemic countries in a Toronto clinic. AB - BACKGROUND: Many North American-based HIV patients originate from parasitic disease-endemic regions. Strongyloidiasis, schistosomiasis and filariasis are important due to their wide distribution and potential for severe morbidity. OBJECTIVES: To determine the prevalence, as determined by serological screening, of strongyloidiasis, schistosomiasis and filariasis among patients in an HIV focused, primary care practice in Toronto, Ontario. A secondary objective was to determine factors associated with positive serological screens. METHODS: A retrospective review of electronic patient records was conducted. Results of serological screens for parasites and relevant laboratory data were collected. RESULTS: Ninety-seven patients were identified. The patients' mean CD4(+) count was 0.45*10(9)/L, median viral load was undetectable and 68% were on highly active antiretroviral therapy (HAART). Most originated from Africa (37%) and South America (35%). Of the 97 patients, 10.4% and 8.3% had positive or equivocal screening results for strongyloidiasis, respectively, 7.4% and 4.2% had positive or equivocal screening results for schistosomiasis and 5.5% and 6.8% had positive or equivocal screens for filariasis. Persons with positive parasitic serologies were more often female (28% versus 9%, P=0.03), younger in age (36 versus 43 years of age, P<0.01), had been in Canada for a shorter duration (5 versus 12 years, P<0.0001) and had a higher viral load (10,990 copies/mL versus <50 copies/mL, P <0.001). All patients were asymptomatic. Eosinophilia was not associated with positive screening results. CONCLUSIONS: Using symptoms and eosinophilia to identify parasitic infection was not reliable. Screening for strongyloidiasis and schistosomiasis among patients with HIV from parasite endemic countries is simple and benign, and may prevent future complications. The clinical benefits of screening for filariasis require further elucidation, but this practice appears to be the least warranted. BACKGROUND: Many North American based HIV patients originate from parasitic disease-endemic regions. Strongyloidiasis, schistosomiasis and filariasis are important due to their wide distribution and potential for severe morbidity. OBJECTIVES: To determine the prevalence, as determined by serological screening, of strongyloidiasis, schistosomiasis and filariasis among patients in an HIV-focused, primary care practice in Toronto, Ontario. A secondary objective was to determine factors associated with positive serological screens. METHODS: A retrospective review of electronic patient records was conducted. Results of serological screens for parasites and relevant laboratory data were collected. RESULTS: Ninety-seven patients were identified. The patients' mean CD4+ count was 0.45*109/L, median viral load was undetectable and 68% were on highly active antiretroviral therapy (HAART). Most originated from Africa (37%) and South America (35%). Of the 97 patients, 10.4% and 8.3% had positive or equivocal screening results for strongyloidiasis, respectively, 7.4% and 4.2% had positive or equivocal screening results for schistosomiasis and 5.5% and 6.8% had positive or equivocal screens for filariasis. Persons with positive parasitic serologies were more often female (28% versus 9%, P=0.03), younger in age (36 versus 43 years of age, P<0.01), had been in Canada for a shorter duration (5 versus 12 years, P<0.0001) and had a higher viral load (10,990 copies/mL versus <50 copies/mL, P <0.001). All patients were asymptomatic. Eosinophilia was not associated with positive screening results. CONCLUSIONS: Using symptoms and eosinophilia to identify parasitic infection was not reliable. Screening for strongyloidiasis and schistosomiasis among patients with HIV from parasite-endemic countries is simple and benign, and may prevent future complications. The clinical benefits of screening for filariasis require further elucidation, but this practice appears to be the least warranted. PMID- 23450242 TI - Age, male gender, and atrial fibrillation predict lower extremity amputation or revascularization in patients with peripheral artery diseases: a population-based investigation. AB - By using the National Health Insurance (NHI) claim data of Taiwan, we sought to determine the predictors for nontraumatic lower extremity amputation (LEA) or peripheral revascularization procedures (PRP) in patients with peripheral artery disease (PAD). From the NHI claim data, we identified 12,206 patients with newly diagnosed PAD between 1998 and 2008, and followed them up to 2008. We explored the age, gender, and whether the patients had concomitant comorbid conditions, such as diabetes mellitus (DM), hypertension (HTN), atrial fibrillation (AF), stroke, hospitalization for coronary artery disease (CAD), myocardial infarction (MI), or heart failure (HF), and whether they were taking cilostazol at the time of recruitment. We searched for clinical parameters that might be important determinants for LEA or PRP in the study population. Of the 12,206 patients, 150 (1.2%) were found to undergo either LEA or PRP or both (LEA 81, PRP 53, both PRP and LEA 16). Old age, male gender, and history of hospitalization for CAD or MI and AF were found to be risk predictors for both procedures. Patients with DM were at lower risk for PRP (odds ratio 0.418, p = 0.001). Patients who were taking cilostazol had higher risk for LEA or PRP. HTN was not a risk predictor for LEA or PRP. From this nationwide study, we found that among PAD patients in Taiwan, age, male gender, AF, and hospitalization for CAD or MI are risk predictors for future LEA or PRP. DM is a negative predictor for PRP while both DM and HTN are not risk predictors for LEA. PMID- 23450243 TI - Outcome of 20-gauge transconjunctival cannulated sutureless vitrectomy using silicone oil or air tamponade. AB - BACKGROUND: The purpose of this study was to assess the outcome of pars plana vitrectomy using a 20-gauge transconjunctival cannulated sutureless system with air or silicone oil tamponade in cases of retinal detachment of different etiologies. METHODS: A prospective study was performed in 60 eyes from consecutive 60 patients who underwent 20-gauge transconjunctival cannulated sutureless vitrectomy (30 eyes with air tamponade and 30 eyes with silicone oil tamponade), with the inclusion of a further 30 patients who underwent conventional 20-gauge vitrectomy and served as a control group. The main outcome measures were intraocular pressure, wound leakage, and comfort score. RESULTS: Preoperative intraocular pressure increased from 17.67 +/- 5.6 mmHg preoperatively to 18.78 +/- 6.1 mmHg on the first postoperative day in group A and decreased from 16.97 +/- 4.9 mmHg to 15.88 +/- 5.3 mmHg in group B. These changes were not statistically significant (P > 0.05). The comfort score ranged from 1 to 5 (1 = very bad, 2 = bad, 3 = good, 4 = very good, and 5 = excellent), with a mean of 4.4 +/- 0.94 in group A and 4.35 +/- 0.99 in group B on the first postoperative day, and no significant difference in scores between the groups at any follow-up visit. There was intraoperative wound leakage in two cases (6.7%) in group A which required suturing and one case (3.3%) in group B, but the difference was not statistically significant (P > 0.05). There was no wound leakage at follow-up in either group. No cases of hypotony, endophthalmitis, or unsealed sclerotomies were noted. CONCLUSION: Pars plana vitrectomy using a 20 gauge transconjunctival cannulated sutureless system combines the advantages of smaller-gauge vitrectomy systems with the economic advantage of not needing to purchase any additional handheld instruments. It can be used with both air and silicone oil tamponade in most cases of retinal detachment. PMID- 23450244 TI - The quality of life during and after menopause among rural women. AB - INTRODUCTION: The overall health and well-being of middle-aged women has become a major public health concern around the world. More than 80% of the women experience physical or psychological symptoms in the years when they approach menopause, with various distresses and disturbances in their lives, leading to a decrease in the quality of life. The aim of our study was to assess the quality of life and the impact of hormonal changes in perimenopausal and postmenopausal women and to correlate the prevalence of the symptoms with their duration since menopause. MATERIAL AND METHODS: A cross- sectional study was done at Sri Manakula Vinayagar Medical College and Hospital, Puducherry, from January 2012 to April 2012. Five hundred women who were in the age group of 40-65 years, who came from rural areas to our hospital, were included in the study. The women who were receiving hormonal treatment and those who refused to participate in the study were excluded. The data such as the socio-demographic information and the menstruation status, which were based on the reported length of time since the last menstrual period and the experience of the symptoms, as were tested in the Menopause Specific Quality of Life (MENQOL) questionnaire, were collected from each patient. The women who were included in the study were divided into three groups as the menopause transition, early postmenopausal and the late postmenopausal groups. All the data which were gathered were analyzed by using SAS 9.2. The Chi square test and the relative risk and the confidence interval calculations were applied to compare the frequencies of the symptoms among the women with different menopausal statuses. A p-value of less than 0.05 was considered to be statistically significant. RESULTS: Mean menopausal age in the study group was 45 years. The most common symptom within study subjects were low back ache (79%) and muscle-joint pain (77.2%). The least frequent symptoms were increase in facial hair (15%) and feeling of dryness during intimacy (10.8%). Scores of vasomotor domain were significantly more in menopause transition group. Scores of physical domain were significantly more in late postmenopausal group. CONCLUSION: The menopause related symptoms had a negative effect on the quality of life of the perimenopausal and the postmenopausal women. Such regional studies can help in creating awareness and in educating women on the early identification of the common menopausal symptoms. PMID- 23450246 TI - Merging catalysis and supramolecular aggregation features of triptycene based Zn(salphen)s. AB - A series of trinuclear, triptycene-based metallosalphen complexes (M = Zn, Ni) have been prepared incorporating various peripheral substituents. The introduction of Zn metal centres into these triptycene based salphen ligands gives rise to cross-linking between different triptycene molecules through MU phenoxo bridges between the Zn metal centres, and variation in the peripheral groups allows the control of the self-assembling properties as shown by UV-Vis titration data. The strong association of these trinuclear Zn3 complexes under relatively apolar conditions has been exploited to recover the complex after its application as a catalyst in the cycloaddition of carbon dioxide to 1,2 epoxyhexane. The catalysis results and recycling studies show that the co catalyst structure is important for efficient recovery of the binary system, demonstrating that reversible supramolecular aggregation may become a useful tool for recycling homogeneous catalysts. PMID- 23450247 TI - The influence of the time and temperature of heat treatment on the allergenicity of egg white proteins. AB - PURPOSE: The present study was performed to determine the factor, either duration or the temperature of heat treatment, exerting maximal and significant influence on the composition and allergenicity of egg white (EW) proteins. METHODS: Raw EW and 4 kinds of heated EW (fried EW, boiled EW for 10 minutes, boiled EW for 30 minutes, and baked EW for 20 minutes at 170C) were prepared, and subsequently protein extraction was carried out. The proteins were separated by SDS-PAGE, and then immunoglobulin E (IgE) immunoblots were performed with the sera of 7 egg allergic patients. Furthermore, the antigenic activities of ovalbumin (OVA), ovomucoid (OM), and ovotransferrin (OT) in different EW samples were measured by inhibition enzyme-linked Immuno-sorbent assay (ELISA). RESULTS: In SDS-PAGE analysis, the intensity of the protein band at 45 kD (corresponding to OVA) decreased significantly in boiled EW (30 minutes) and baked EW, but no change was observed in the case of boiled EW for 10 minutes. In IgE immunoblots, the IgE response to 34-50 kD (OM and OVA) in boiled EW for 30 minutes decreased significantly, when compared with raw EW and other heated EWs. In inhibition ELISA, a significant decrease in the OVA antigenic activity was observed in boiled EW for 30 minutes amongst other heated EW samples. However, OM antigenic activity in all kinds of heated EW including boiled EW for 30 minutes did not reduce after heat treatment. The OT antigenic activity nearly disappeared in heated EWs except in the case of boiled EW for 10 minutes. CONCLUSIONS: Amongst 4 kinds of heated EWs, the boiled EW for 30 minutes showed the most significant changes both in composition and reduction in allergenicity. Our results revealed that the duration of heat treatment had more influence on the composition and allergenicity of EW proteins than the temperature. PMID- 23450245 TI - 21st century natural product research and drug development and traditional medicines. AB - Natural products and related structures are essential sources of new pharmaceuticals, because of the immense variety of functionally relevant secondary metabolites of microbial and plant species. Furthermore, the development of powerful analytical tools based upon genomics, proteomics, metabolomics, bioinformatics and other 21st century technologies are greatly expediting identification and characterization of these natural products. Here we discuss the synergistic and reciprocal benefits of linking these 'omics technologies with robust ethnobotanical and ethnomedical studies of traditional medicines, to provide critically needed improved medicines and treatments that are inexpensive, accessible, safe and reliable. However, careless application of modern technologies can challenge traditional knowledge and biodiversity that are the foundation of traditional medicines. To address such challenges while fulfilling the need for improved (and new) medicines, we encourage the development of Regional Centres of 'omics Technologies functionally linked with Regional Centres of Genetic Resources, especially in regions of the world where use of traditional medicines is prevalent and essential for health. PMID- 23450248 TI - Syntheses, structures, and magnetic properties of cyano- and phenoxide-bridged Fe(III)-Mn(III) tetrameric assemblies formed by blocked fac-Fe tricyanide with aliphatic rings. AB - Three tetranuclear clusters [(Tp(Me,mt3))Fe(CN)3Mn(L)]2 (1, L = 5-Clacphmen; 2, L = 5-Clsalen; 3, L = 5-MeOsalen; Tp(Me,mt3) = hydrotris(3-methyl-4,5-propylene-5 methylpyrazol-1-yl)borate) were prepared by assembling the fac-Fe tricyanide with the corresponding Mn Schiff bases. The assembled molecules are linked by cyanide and phenoxide bridges. Weak pi-pi contacts between molecules are evident in these clusters. Compounds 1-3 exhibit slow relaxation of the magnetization. The phenoxide linkers mediate ferromagnetic coupling between the Mn centers, which is ascribed to the long axial Mn-O* length. The overall magnetic exchange coupling nature of the Fe-C=N-Mn route is accounted for by the important structural parameters of bridging pathways such as Mn-N(cyano) length, Mn-N(cyano)-C(cyano) angle, and C(eq)-Fe...Mn-N(eq) (eq = equatorial) torsion angle. PMID- 23450249 TI - Hyperbranched polymer mediated fabrication of water soluble carbon nanotube-metal nanoparticle hybrids. AB - 1-Pyrenemethanol initiated hyperbranched polyglycerol (PiHP) has been synthesized and utilized to non-covalently functionalize pristine multi-walled carbon nanotubes (CNTs) through pi-pi stacking interactions. Mediated with the PiHP coating, a variety of metal nanoparticles (Au, Ag, Pd and Pt) were in situ generated and randomly tethered on the CNT sidewalls, producing various water soluble CNT/PiHP/metal hybrids. Particularly, the resulting CNT/PiHP/Pt hybrids possess improved metal coverage in comparison to the reported CNT/Pt nanohybrids obtained by the use of conventional non-covalent CNT surface-modifiers. Depending on the using concentration of Pt(2+) precursor, Pt coverage in CNT/PiHP/Pt hybrids can be effectively controlled. In the meanwhile, Pt component on the CNT sidewalls can be either well isolated nanoparticles or loose "nanoclusters". To test the promising catalytic application of these obtained CNT/PiHP/Pt hybrids, a systematic investigation on their catalytic performance towards the reduction of 4-nitrophenol to produce 4-aminophenol was performed. Surprisingly, these hybrids exhibited significantly enhanced catalytic activity compared with the conventionally utilized Au and Ag nanoparticles. Moreover, they can be easily recovered and reused without significant loss in catalytic activity after running 6 circles. PMID- 23450250 TI - Guest induced morphological transformation from nanospheres to nanowires by hydrogen bond self-assembly. AB - Phosphorescent nanospheres of a carboxyl-functionalized iridium complex ([Ir(ppy)2(Hdcbpy)], ppy: 2-phenylpyridine; Hdcbpy: 4-carboxy-2,2'-bipyridyl-4' carboxylate) were prepared by a conventional precipitation method. Driven by hydrogen bond interaction between carboxylic groups of the complex and the guest molecule tris(imidazoline), these nanospheres can be transformed into 1 dimensional nanowires in the presence of tris(imidazoline) at the concentration of the iridium complex higher than 4.8 mM, while nanowires change back to nanospheres with the diameter obviously smaller than that of the sole complex of [Ir(ppy)2(Hdcbpy)]. The interaction between carboxylic groups and tris(imidazoline) molecules was confirmed by FT-IR spectra. The structures of the nanowires and nanospheres were further studied by XRD diffraction analysis. With the morphological transformation from nanospheres to nanowires, the phosphorescence of nanostructures was blue shifted from 590 to 564 nm. PMID- 23450251 TI - Mixed sugar-core-phosphate chelation of D-fructose 1,6-bisphosphate with the Re(V)O(tmen) metal fragment. AB - Sugar phosphates provide metal-binding sites both at their sugar core and at their phosphate group(s). Mixed sugar-core-phosphate chelation has been considered as a typical bonding mode within the physiological pH range for the central metabolite D-fructose 1,6-bisphosphate. The Re(V)O(tmen) metal fragment was used to enrich this coordination type. The formation of the [ReO(tmen)(Fruf2,3H-21,6P2H2-kappa(3)O(2,3,P1))](-) monoanion was determined by NMR spectroscopy and mass spectrometry. The model compound rac-glycerol 1 phosphate yielded similar results in terms of NMR spectroscopy. Crystal-structure analyses of [ReO(tmen)(rac-Glyc2,3H-21PH-kappa(3)O(2,3,P))].2H2O and [ReO(phen)(rac-Glyc2,3H-21PH-kappa(3)O(2,3,P))].MeOH confirmed the coordination pattern. PMID- 23450253 TI - Copper(II) assembling with bis(2-pyridylcarbonyl)amidate and N,N'-2,2 phenylenebis(oxamate). AB - We herein present the synthesis and X-ray structures of five copper(II) complexes of formulae [Cu(bpca)(CF3SO3)(H2O)].H2O (1), [Cu(bpca)(Phpr)(H2O)].3/2H2O (2), {[Cu(bpca)]2[Cu(opba)(H2O)]}.H2O (3), {[Cu(bpca)]2(H2opba)}2.6H2O (4) and [Cu(bpca)(EtH2opba)]n (5), where bpca = bis(2-pyridylcarbonyl)amidate, Phpr = 3 phenylpropionate, CF3SO3(-) = triflate (anion of the trifluoromethanesulphonic acid), H4opba = N,N'-1,2-phenylenebis(oxamic acid), and EtH3opba = monoethyl ester derivative of the H4opba. 1 and 2 are mononuclear copper(II) complexes where the copper atom is five-coordinate in distorted square pyramidal surroundings with a tridentate bpca and a water molecule (1)/carboxylate oxygen (2) building the basal plane and a triflate oxygen (1)/water molecule (2) filling the apical position. 3 is a neutral tricopper(II) complex where the [Cu(opba)(H2O)]2- unit acts as a bis-bidentate ligand toward two peripheral [Cu(bpca)]+ fragments. The three crystallographically independent copper(II) ions in 3 are five-coordinate with two nitrogen and two oxygen atoms (inner copper atom)/three bpca-nitrogen and an oxamate oxygen (outer copper atom) building the basal plane plus a water molecule (inner copper)/an oxamate oxygen (outer copper) in the apical position (inner copper atom) of somewhat distorted square pyramidal surroundings. 4 is a centrosymmetric tetracopper(II) compound where four [Cu(bpca)]+ fragments are assembled by two H2opba2- groups adopting an unusual bidentate/bis-monodentate bridging mode. The two crystallographically independent copper(II) ions in 4 are also five-coordinate having the three bpca-nitrogens in basal positions, the other two sites of the distorted square pyramid being filled by two oxygens of either a bidentate oxamate (at one copper centre) or two bis monodentate oxamates (at the other copper atom). 5 is a zigzag chain of [Cu(bpca)(H2O)]+ units which are connected through the EtH2opba- ligand adopting a bidentate/monodentate bridging mode across the monodeprotonated oxamate group. Each copper(II) ion in 5 is six-coordinate in an elongated octahedral CuN3O3 chromophore. The magnetic properties of 3-5 were investigated in the temperature range 1.9-300 K. 3 exhibits an intermediate intramolecular antiferromagnetic interaction [J = -65.8(2) cm(-1) with the Hamiltonian H = -J(S(Cu1).S(Cu2) + S(Cu2).S(Cu3))] which leads to a low-lying spin doublet at low temperatures. A weak antiferromagnetic coupling between the inner copper(II) ions occurs in 4 [J = -2.36(2) cm(-1), H = -JS1.S2)] and a very small intrachain antiferromagnetic interaction is observed in 5 [J = -0.17(1) cm(-1) with H = -J?(i)S(i).S(i+1)]. These values are analyzed by means of simple orbital symmetry considerations and compared with those previously reported for parent systems. PMID- 23450254 TI - Theoretical mechanism studies on the electrocatalytic reduction of CO2 to formate by water-stable iridium dihydride pincer complex. AB - The reaction mechanism for electrocatalytic reduction of CO2 to formate by water stable iridium dihydride pincer complex is studied using density functional theory (DFT). The reaction pathways are investigated in detail. The results suggest that the reaction proceeds in three steps: insertion of carbon dioxide into the Ir(III) pincer dihydride, elimination of formate ligand from the hydridoformatoiridium complex, and catalyst regeneration. The reduction potential of the electrode reaction is calculated and accords well with the experimental value. The solvent effect of MeCN and water on the reaction is explored. The results indicate that water has an important effect on CO2 transforming to HCOO( ). In addition, it also plays a critical role for regeneration of the catalyst via non-classical intermolecular hydrogen bonding. PMID- 23450252 TI - Evaluation of a noninvasive algorithm for differentiation of obstructive and central hypopneas. AB - STUDY OBJECTIVES: The clear discrimination of central and obstructive hypopneas is highly relevant to avoid misinterpretation and inappropriate treatment of complicated breathing patterns. Esophageal manometry is the accepted standard for the differentiation of the phenotypes of sleep apnea. However, it is limited in its use due to poor acceptance by patients and therefore rarely performed in routine clinical practice. Flattening of the inspiratory airflow curve, paradoxical breathing, arousal position, sleep stages, and breathing pattern at the end of the hypopnea can each give hints for the classification of hypopnea. The aim of this study was to evaluate a standardized algorithm combining these polysomnographic parameters for the discrimination of hypopneas in everyday practice. METHODS: Polysomnography (PSG) and esophageal manometry were performed in 41 patients suspected of having sleep apnea (33 male, 52.3 +/- 15.9 yr, body mass index 28.6 +/- 4.5 kg/m(2)). Hypopneas were independently discriminated by blinded investigators based on esophageal pressure and the PSG-based algorithm. Only those hypopneas that could be differentiated with both methods were evaluated. RESULTS: There were 1,175 of 1,837 hypopneas (64%) that could be defined by esophageal pressure, 1,812 (98.6%) by the PSG-based algorithm. Using esophageal pressure as a reference, the new algorithm correctly defined 76.9% of central and 60.5% of obstructive hypopneas. The overall accuracy was 68%. The isolated analysis of single PSG parameters revealed a lower accuracy compared with the combined algorithm. CONCLUSIONS: The PSG-based algorithm allows for discrimination of most hypopneas. It is advantageous in comparison with esophageal pressure because it is noninvasive and less impaired by artefacts. Therefore, it is a potentially helpful tool for sleep specialists. CITATION: Randerath WJ; Treml M; Priegnitz C; Stieglitz S; Hagmeyer L; Morgenstern C. Evaluation of a noninvasive algorithm for differentiation of obstructive and central hypopneas. SLEEP 2013;36(3):363-368. PMID- 23450255 TI - An unprecedented polyoxometalate-based hybrid solid constructed from a neutral metal-organic macrocycle and Dawson polyoxotungstate anions. AB - The self-assembly procedure of a Dawson-type polyoxotungstate with pyridine-2,6 dicarboxylate (H2pdc) and copper(II) ions produces an exquisite supramolecular aggregation. In the structure, a neutral cucurbit[n]uril-like metal-organic macrocycle is formed of six copper centers and six pdc(2-) ligands, while a pair of Dawson-type polyoxotungstates are linked to the bottom and top portals of this macrocycle at the joint with the alkali metal ions. A control experiment was carried out to produce a different metalloligand-supported hybrid (instead of the metallomacrocycle) to verify the structure-directing role of Dawson polyanions in the title compound. In addition, the photoluminescent and magnetic properties of the hybrid solid have also been investigated. PMID- 23450256 TI - Selective C-F/C-H bond activation of fluoroarenes by cobalt complex supported with phosphine ligands. AB - The reactions of pentafluoropyridine C5NF5, hexafluorobenzene C6F6, and perfluoronaphthalene C10F8 with cobalt(0) complex, Co(PMe3)4, were investigated. The Co(I) complexes (4-C5NF4)Co(PMe3)3 (1), (C6F5)Co(PMe3)3 (2), (C10F7)Co(PMe3)3 (3), (4-C5NF4)Co(PMe3)4 (4) and (C10F7)Co(PMe3)4 (6) were obtained by selective activation of the C-F bonds. The reactions of 1 and 2 with CO afforded dicarbonyl cobalt(I) complexes (4-C5NF4)Co(CO)2(PMe3)2 (7), (C6F5)Co(CO)2(PMe3)2 (8). Under similar reaction conditions, 2 as a C-H bond activation product was obtained from the reaction of pentafluorobenzene, C6F5H, with Co(PMe3)4. The byproducts, hydrodefluorination product 1,2,4,5-C6F4H2 and F2PMe3 from the reaction of C6F5H and Co(PMe3)4 were also observed. The reaction mechanism of C6F5H with Co(PMe3)4 is proposed and partly-experimentally verified. The reaction of C6F5H with Co(PMe3)4 under 1 bar of CO at room temperature afforded hydrido dicarbonyl cobalt(II) complex (C6F5)Co(H)(CO)2(PMe3)2 (11). Treatment of the mixtures of C6F5H/Co(PMe3)4 with hexachlorobenzene, C6Cl6, resulted in (C6F5)CoCl(PMe3)3 (12) via C-H bond cleavage with the hydrodechlorination product pentachlorobenzene, C6Cl5H, and 1,2,4,5-tetrachlorobenzene, C6Cl4H2. The structures of complexes 1, 2, 6, 7, 8, 11 and 12 were determined by X-ray diffraction. PMID- 23450257 TI - Virtual education effect on cognitive learning and attitude of nursing students towards it. AB - BACKGROUND: Along with emersion of the Internet, virtual education increasingly has been growing. Many studies discussed this method and its impact on learning. Present study investigated students' attitude towards virtual education as well as its effect on learning. METHODS: This was a pretest-posttest quasi experimental study. The nursing students, who had selected fluids and electrolyte disorders course, were randomly divided into two virtual and conventional education groups. The knowledge of students was assessed through a written exam and students' attitude towards virtual education assessed by a researcher-made questionnaire. RESULTS: Mean scores of students in pretest were 0.8 (0.3) and 1.1 (0.59) in virtual and conventional group respectively [mean (SD)]. At the end of the semester their scores were 15.9 (0.58) and 16.51 (0.89) respectively. Mean attitude scores at baseline were 3.19 (0.48) and 3.21 (0.33) followed by 3.55 (0.45) and 3.21 (0.46) at the end of the semester in virtual and conventional groups respectively. CONCLUSIONS: Although the scores of conventional group at the end of the course were higher than virtual group, both methods acted similarly in terms of increasing the knowledge. Passing a virtual education course may improve the attitude of the nurses towards it. PMID- 23450258 TI - Hypofractionated stereotactic radiotherapy for large or involving critical organs cerebral arteriovenous malformations. AB - BACKGROUND: The treatment of large arteriovenous malformations (AVMs) or AVMs involving eloquent regions of the brain remains a challenge. For inoperable lesions, observation, volume-staged radiosurgery or hypofractionated stereotactic radiotherapy (HFSRT) are proposed. The aim of our study was to assess the safety and efficiency of HFSRT for large AVMs located in eloquent areas of the brain. MATERIALS AND METHODS: An analysis of records of 49 patients irradiated for cerebral AVMs with a mean dose of 19.9 Gy (12-28 Gy) delivered in 2-4 fractions with planned gap (at least one week) between fractions. Actuarial obliteration rates and annual bleeding hazard were calculated using Kaplan-Meier survival analysis and life tables. RESULTS: Annual bleeding hazard rates were 4.5% and 1.6% after one and two years of the follow-up, respectively. Actuarial total obliteration rates were 7%, 11%, and 21% and total response rate (total and partial obliterations) 22%, 41%, and 55% after one, two and three years of the follow-up, respectively. There was a trend towards larger total obliteration rate in patients irradiated with fraction dose >= 8 Gy and total dose > 21 Gy for lesions of volume <= 8.18 cm(3) which was not observed in case of partial obliterations. CONCLUSIONS: HFSRT results with relatively low obliteration rate but is not associated with a significant risk of permanent neurological deficits if both total and fraction doses are adjusted to size and location of the lesion. Predictive factors for total and partial obliterations can be different; this observation, however, is not firmly supported and requires further studies. PMID- 23450260 TI - To Study the Prevalence of Various Enteric Parasitic Infections Among HIV Infected Individuals in the P.D.U. Medical College and Hospital, Rajkot, Gujarat, India. AB - BACKGROUND AND OBJECTIVES: Enteric parasites are a major cause of diarrhoea in HIV infected individuals. The present study was undertaken to detect the enteric parasites in HIV infected patients with diarrhoea, who were at different levels of immunity. METHODS: This study was carried out in the P.D.U Medical College and Civil Hospital, Rajkot, India. during the period from June 2009 to June 2010. A total of 100 stool samples from HIV seropositive patients were examined for opportunistic, gastrointestinal parasitic infections. The samples were classified according to the age groups, sex, and occupation, a history of diarrhoea and different categories of the CD4 cell count. The stool samples were collected and examined for enteric parasites by microscopy and by special staining methods. The CD4 cell counts were estimated by using the FACS count system. RESULTS: The intestinal parasitic pathogens were detected in 28% patients. Among all, Isospora appeared to have the highest prevalence (18%), followed by Giardia lamblia (5%), Strongyloides stercoralies (3%) and Cryptosporidium parvum (2%). In the HIV infected patients with a CD4 count of < 200 cells/MUl, Isospora was the most commonly observed (56%) pathogen. The proportion of the opportunistic pathogens in the patients with CD4 counts of <200 cells/MUl was significantly higher as compared to those in the other two groups of patients with CD4 counts of >200 respectively. INTERPRETATION AND CONCLUSIONS: Parasitic infections were detected in 28% of the HIV infected patients and a low CD4 count was significantly associated with an opportunistic infection. The detection of the aetiologic pathogens might help the clinicians in deciding the appropriate management strategies. PMID- 23450259 TI - Bioinformatic Tools Identify Chromosome-Specific DNA Probes and Facilitate Risk Assessment by Detecting Aneusomies in Extra-embryonic Tissues. AB - Despite their non-diseased nature, healthy human tissues may show a surprisingly large fraction of aneusomic or aneuploid cells. We have shown previously that hybridization of three to six non-isotopically labeled, chromosome-specific DNA probes reveals different proportions of aneuploid cells in individual compartments of the human placenta and the uterine wall. Using fluorescence in situ hybridization, we found that human invasive cytotrophoblasts isolated from anchoring villi or the uterine wall had gained individual chromosomes. Chromosome losses in placental or uterine tissues, on the other hand, were detected infrequently. A more thorough numerical analysis of all possible aneusomies occurring in these tissues and the investigation of their spatial as well as temporal distribution would further our understanding of the underlying biology, but it is hampered by the high cost of and limited access to DNA probes. Furthermore, multiplexing assays are difficult to set up with commercially available probes due to limited choices of probe labels. Many laboratories therefore attempt to develop their own DNA probe sets, often duplicating cloning and screening efforts underway elsewhere. In this review, we discuss the conventional approaches to the preparation of chromosome-specific DNA probes followed by a description of our approach using state-of-the-art bioinformatics and molecular biology tools for probe identification and manufacture. Novel probes that target gonosomes as well as two autosomes are presented as examples of rapid and inexpensive preparation of highly specific DNA probes for applications in placenta research and perinatal diagnostics. PMID- 23450262 TI - Early Controversies over Athetosis: I. Clinical Features, Differentiation from other Movement Disorders, Associated Conditions, and Pathology. AB - BACKGROUND: Since the description of athetosis in 1871 by American neurologist William Alexander Hammond (1828-1900) the disorder has been a source of controversy, as were many aspects of Hammond's career. METHODS: Primary sources have been used to review controversies in the 50-year period since the initial description of athetosis, in particular those concerning clinical features, differentiation from other movement disorders, associated conditions, and pathology. Controversies concerning treatment will be addressed in a subsequent article. RESULTS: Hammond struggled to establish athetosis as a distinct clinical pathological entity, and had successfully predicted the striatal pathology in his initial case (albeit somewhat serendipitously). Athetosis was, nevertheless, considered by many neurologists to be a form of post-hemiplegic chorea or part of a continuum between chorea and dystonia. European neurologists, and particularly the French, initially ignored or discounted the concept. Additional controversies arose over whether the movements persisted during sleep, whether athetosis was, or could be, associated with imbecility or insanity, and how it should be treated. DISCUSSION: Some controversies concerning athetosis served to identify areas where knowledge was insufficient to make accurate statements, despite prior self-assured or even dogmatic statements to the contrary. Other controversies illustrated established prejudices, even if these biases were often only apparent with the greater detachment of hindsight. PMID- 23450261 TI - Calcineurin governs thermotolerance and virulence of Cryptococcus gattii. AB - The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In addition to a greater predilection for C. gattii to infect healthy hosts, the C. gattii genome sequence project revealed extensive chromosomal rearrangements compared with C. neoformans, showing genomic differences between the two Cryptococcus species. We investigated the roles of C. gattii calcineurin in three molecular types: VGIIa (R265), VGIIb (R272), and VGI (WM276). We found that calcineurin exhibits a differential requirement for growth on solid medium at 37 degrees , as calcineurin mutants generated from R265 were more thermotolerant than mutants from R272 and WM276. We demonstrated that tolerance to calcineurin inhibitors (FK506, CsA) at 37 degrees is linked with the VGIIa molecular type. The calcineurin mutants from the R272 background showed the most extensive growth and morphological defects (multivesicle and larger ring-like cells), as well as increased fluconazole susceptibility. Our cellular architecture examination showed that C. gattii and C. neoformans calcineurin mutants exhibit plasma membrane disruptions. Calcineurin in the C. gattii VGII molecular type plays a greater role in controlling cation homeostasis compared with that in C. gattii VGI and C. neoformans H99. Importantly, we demonstrate that C. gattii calcineurin is essential for virulence in a murine inhalation model, supporting C. gattii calcineurin as an attractive antifungal drug target. PMID- 23450263 TI - Soft tissue chondroma of hard palate associated with cleft palate. AB - Soft tissue chondroma of palate is very rare. It has never been reported in a cleft palate patient. We report a case of 22-year-old male who came with asymptomatic swelling on the palate since birth, along with complete cleft of secondary palate. He had symptoms related to cleft palate only, i.e., nasal regurgitation and speech abnormalities. Swelling was excised and the cleft palate was repaired. Histopathological examination revealed chondroma of the palate. The patient had no recurrence after 2 years of follow-up. PMID- 23450264 TI - Management of soft tissue wounds of the face. AB - Since time, immemorial soft-tissue injuries to the face have been documented in literature and even depicted in sculptures, reflecting the image of society. In a polytrauma the face may be involved or there may be isolated injury to the face. The face consists of several organs and aesthetic units. The final outcome depends on initial wound care and primary repair. So one should know the "do's and don'ts". Disfigurement following trauma, becomes a social stigma and has the gross detrimental effect on the personality and future of the victim. Therefore, such cases are most appropriately managed by Plastic Surgeons who have a thorough knowledge of applied anatomy, an aesthetic sense and meticulous atraumatic tissue handling expertise, coupled with surgical skill to repair all the composite structures simultaneously. PMID- 23450265 TI - The inter-relationship of clinical parameters in congenital talipes equinovarus: relevance to pathological anatomy and clinical classification. AB - BACKGROUND: The clinical features that define congenital talipes equinovarus (CTEV) are the presence of four principal components, equinus, varus, adductus and cavus. Classification systems in CTEV often include a form of assessment of these components and also other concurrent clinical parameters which feature in the condition. METHODS: Over a 14-year period from 1992 to 2006, 95 consecutive cases of CTEV were prospectively assessed and data recorded in order to investigate the relationships between the clinical parameters in CTEV and to compare these relationships with those that one would expect from our knowledge of the pathological anatomy and mechanics of the condition, relating these findings to the commonly used systems for classification. RESULTS: Ninety-five cases of CTEV had failed conservative treatment and had undergone surgical release. The mean age at surgical release and assessment was 9 months. Cluster analysis demonstrated that there were, broadly, two groups of patients. The first group was those patients with a greater equinus deformity (greater than 31 degrees ). This group had a greater adductus deformity and the presence of other parameters indicating increased severity (multiplanar stiffness with the presence of cavus and medial skin crease). The second group was those patients with a smaller equinus deformity (less than 31 degrees ) who were more heterogenous with regards to the other parameters. CONCLUSIONS: We analysed on a statistical basis the relevant aspects of the deformity in CTEV. We have demonstrated that there are certain parameters, namely, equinus and adductus, whose severity can reasonably predict the severity of other components of the deformity. With regards to hindfoot parameters, increased equinus is related to less sagittal plane reducibility and to stiff hindfoot varus (coronal plane stiffness). In terms of midfoot parameters, the degree of adductus is related to the presence of cavus deformity and the presence of a medial skin crease is associated with less reducibility of the adductus (axial plane stiffness). This is consistent with our current understanding of the pathological anatomy of CTEV and bears implications with regards to treatment and the design of proposed classification systems that are in use. PMID- 23450266 TI - The minimum transition hypothesis for intermittent hierarchical motor control. AB - In intermittent control, instead of continuously calculating the control signal, the controller occasionally changes this signal at certain sparse points in time. The control law may include feedback, adaptation, optimization, or any other control strategies. When, where, and how does the brain employ intermittency as it controls movement? These are open questions in motor neuroscience. Evidence for intermittency in human motor control has been repeatedly observed in the neural control of movement literature. Moreover, some researchers have provided theoretical models to address intermittency. Even so, the vast majority of current models, and I would dare to say the dogma in most of the current motor neuroscience literature involves continuous control. In this paper, I focus on an area in which intermittent control has not yet been thoroughly considered, the structure of muscle synergies. A synergy in the muscle space is a group of muscles activated together by a single neural command. Under the assumption that the motor control is intermittent, I present the minimum transition hypothesis (MTH) and its predictions with regards to the structure of muscle synergies. The MTH asserts that the purpose of synergies is to minimize the effort of the higher level in the hierarchy by minimizing the number of transitions in an intermittent control signal. The implications of the MTH are not only for the structure of the muscle synergies but also to the intermittent and hierarchical nature of the motor system, with various predictions as to the process of skill learning, and important implications to the design of brain machine interfaces and human robot interaction. PMID- 23450267 TI - Vitamin D receptor as a therapeutic target for benign prostatic hyperplasia. AB - The bioactive form of vitamin D, 1alpha, 25-dihydroxyvitamin D3 (1alpha, 25(OH)2D3), is a secosteroid hormone that binds to the vitamin D receptor (VDR), a member of the nuclear receptor super-family expressed in many cell types, and modulates a variety of biological functions. 1alpha, 25(OH)2D3 is essential for bone and mineral homeostasis, but also regulates growth and differentiation of multiple cell types, and displays immunoregulatory and anti-inflammatory activities. The antiproliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of chronic inflammatory and autoimmune diseases, including benign prostatic hyperplasia (BPH). It has been hypothesized that VDR may influence both the risk of a variety of diseases and their occurrence and prognosis. However, earlier studies investigating the associations between specific VDR polymorphisms and various diseases often show controversial results. We performed a systematic review of the current literature on vitamin D and BPH using the PubMed and Web of Knowledge databases. The aim of this review is to summarize the current knowledge on the utility of the VDR gene regarding prostate growth as well as the pathogenesis and treatment of BPH, a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic component responsible for urinary storage symptoms, and an inflammatory component. Despite the massive advances in recent decades, further research is needed to fully characterize the exact underlying mechanisms of VDR action on BPH and to comprehend how these cellular changes translate into clinical development in physical concert. PMID- 23450269 TI - Rapid and sensitive detection of bla KPC gene in clinical isolates of Klebsiella pneumoniae by a molecular real-time assay. AB - BACKGROUND: The aim of this study was the rapid identification of bla KPC gene in 38 Klebsiella pneumoniae clinical isolates with reduced susceptibility to carbapenems. The modified Hodge Test (MHT) was carried out to phenotypically determine whether resistance to carbapenems was mediated by a carbapenemase. The detection of the bla KPC gene was performed by real-time acid nucleic sequence based amplification (NASBATMTM), specifically designed for the detection of KPC RNA target. RESULTS: Thirty-two/38 isolates evaluated by MHT showed the production of carbapenemases, while all the strains exhibited the production of KPC by inhibition test with phenylboronic acid (the combined disk test with IPM/IPM plus phenylboronic acid). The detection of bla KPC gene by Nuclisens EasyQ KPC yielded positive results in 38/38 (100%) strains. The presence of bla KPC gene was confirmed in all K. pneumoniae isolates when tested by the gold standard PCR assay. CONCLUSIONS: In consideration of the serious challenge represented by infections due to K. pneumoniae it appears necessary the rapid identification of carbapenemases in clinical settings as it is made possible by the use of NASBATM assay. PMID- 23450268 TI - Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. AB - STUDY OBJECTIVES: Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis. DESIGN: EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18. SETTING: Mouse sleep laboratory. PARTICIPANTS: Male mice. INTERVENTIONS: Sleep deprivation. RESULTS: The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset. CONCLUSIONS: Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. CITATION: Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. SLEEP 2013;36(3):311-323. PMID- 23450270 TI - Evaluation of four risk-scoring methods to predict long-term outcomes in patients undergoing aorto-bifemoral bypass for aorto-iliac occlusive disease. AB - This study was done to determine the usefulness of the American Society of Anesthesiologists (ASA) classification, the comorbidity Charlson index unadjusted (CCIu),the comorbidity Charlson index adjusted by age (CCIa), and the Glasgow aneurysm score (GAS) for postoperative morbimortality and survival in patients treated with aorto-bifemoral bypass (AFB) for aorto-iliac occlusive disease (AIOD). A series of 278 patients who underwent AFB were restrospectively studied. For the CCIu, CCIa, ASA, and GAS, receiver operating characteristics curve analysis for prediction of morbidity showed area under the curves of 0.61 (p = 0.004), 0.59 (p = 0.026), 0.569 (p = 0.087), and 0.63 (p = 0.001), respectively. Additionally, univariate analysis showed that CCIa (p = 0.016) and GAS (p = 0.006) were associated significantly with an increased risk of developing complications. Furthermore, CCIa (p < 0.001) and GAS (p = 0.001) showed a significant association with survival. Finally, the variable age was related to morbidity (p = 0.004), mortality (p = 0.038), and survival (p < 0.001). The comorbididity and the age should be taken in account in clinical treatment decisions for patients with AIOD. The CCIa and GAS may play a role as predictive factors for postoperative morbidity and survival after AFB. PMID- 23450271 TI - Complete penoscrotal transposition: A three-stage procedure. AB - Complete penoscrotal transposition (CPST) with an intact scrotum is a rare anomaly in which the scrotum is located cephalic to the penis. It is the most severe degree of malformation of a spectrum of abnormalities in scrotal development. There are few cases reported in the literature, and there are few descriptions of the technique for correction and results. We describe a new case of CPST and its sequential correction. PMID- 23450272 TI - The transcervical foley catheter versus the vaginal prostaglandin e2 gel in the induction of labour in a previous one caesarean section - a clinical study. AB - OBJECTIVE: To compare the effectiveness and the safety of the transcervical Foley catheter and the prostaglandin E2 (PGE2) gel for the induction of labour in women with a previous one caesarean section with an unfavourable cervix at term. METHOD: This study was conducted in the Department of Obstetrics and Gynaecology, J.N. Medical College, Aligarh, (U.P),India. Seventy women with singleton pregnancies at term, with previous one lower segment caesarean sections with a cephalic presentation and a Bishop's score of <= 6, who required induction at term were included in the study. Group A had 35 women in whom the transcervical Foley catheter was inserted and Group B included 35 women in whom the PGE2 gel was inserted vaginally for the induction of labour.The Bishop's score after 12 hours of induction, the oxytocin requirement, the induction to delivery interval, the mode of delivery, the maternal complications and the neonatal outcome were compared. RESULTS: The Foley catheter and the PGE2 gel had a comparable effect on the Bishop's score after 12 hours and the induction to the delivery interval was slightly shorter with the Foley catheter (18.15 hours) as compared to 21.06 hours with the PGE2 gel. There was no case of uterine rupture or scar dehiscence. CONCLUSION: In this study, both the modes of induction in women with previous one caesarean sections were safe, simple and effective. The main advantages of the cervical ripening with the Foley catheter over the Prostaglandin E2 gel are the low cost, reversibility and the lower risk of systemic and serious side effects like uterine hyperstimulation and rupture, as well as it induces a significant ripening and dilatation of the cervix and a shorter induction to the delivery interval. So, the cervical ripening effect of the Foley catheter is as good as that of the Prostaglandin E2 gel in women with previous one caesarean sections. PMID- 23450273 TI - Clinically undiagnosed enteropathy associated T-cell lymphoma type II presenting with prolonged lower gastrointestinal tract symptoms: report of an autopsy case and review of diagnostic challenges and clinicopathological correlation. AB - An elderly patient with watery diarrhea for 3 months received extensive laboratory, radiographic and upper and lower gastrointestinal (GI) endoscopic work up including colonic biopsies, but a diagnosis was not established before death. At autopsy enteropathy associated T-cell lymphoma-type II (EATL-II) with multifocal mucosal involvement of the jejunum was identified. The colon was completely uninvolved grossly and microscopically. The stomach showed only subtle lesions grossly but microscopic examination revealed involvement by lymphoma in the stomach as well as other organs in abdomen and chest. The relationship between celiac disease and enteropathy associated T-cell lymphoma, the practical difficulties in establishing the diagnosis and the pathology of T-cell lymphomas affecting the gastrointestinal tract are discussed. PMID- 23450274 TI - Herpes simplex virus type 1 is the leading cause of genital herpes in New Brunswick. AB - INTRODUCTION: Little is known about the role of herpes simplex virus (HSV) type 1 (HSV1) in the epidemiology of genital herpes in Canada. Data on herpes viral cultures for two consecutive years obtained from L'Hopital Dr GL Dumont, which performs all the viral culture testing in New Brunswick, were reviewed. It was hypothesized that HSV1 was the main cause of genital herpes in New Brunswick. METHODS: Samples of genital origin sent to the laboratory for HSV culture testing between July 2006 and June 2008 were analyzed. Samples from an unspecified or a nongenital source were excluded from analysis. Multiple positive samples collected from the same patient were pooled into a single sample. RESULTS: HSV was isolated from 764 different patients. HSV1 was isolated in 62.6% of patients (male, 55%; female, 63.8%). HSV1 was isolated in 73.2% of patients 10 to 39 years of age and in 32% of patients >=40 years of age. The difference in rates of HSV1 infection between the 10 to 39 years of age group and the >=40 years of age group was statistically significant (P<0.001 [chi(2)]). In a similar Canadian study performed in Nova Scotia, HSV1 was recovered in 53.7% of positive cultures (male, 36.7%; female, 58.1%). The rates of HSV1 infection reported by this study and the present study were significantly different (P<0.001 [chi(2)] for male, P=0.012 for female). CONCLUSION: In New Brunswick, HSV1 is the dominant type of HSV isolated in samples collected from a genital site. Significant rate differences were demonstrated between the groups 10 to 39 years of age and >=40 years of age. INTRODUCTION: Little is known about the role of herpes simplex virus (HSV) type 1 (HSV1) in the epidemiology of genital herpes in Canada. Data on herpes viral cultures for two consecutive years obtained from L'Hopital Dr GL Dumont, which performs all the viral culture testing in New Brunswick, were reviewed. It was hypothesized that HSV1 was the main cause of genital herpes in New Brunswick. METHODS: Samples of genital origin sent to the laboratory for HSV culture testing between July 2006 and June 2008 were analyzed. Samples from an unspecified or a nongenital source were excluded from analysis. Multiple positive samples collected from the same patient were pooled into a single sample. RESULTS: HSV was isolated from 764 different patients. HSV1 was isolated in 62.6% of patients (male, 55%; female, 63.8%). HSV1 was isolated in 73.2% of patients 10 to 39 years of age and in 32% of patients >=40 years of age. The difference in rates of HSV1 infection between the 10 to 39 years of age group and the >=40 years of age group was statistically significant (P<0.001 [chi2]). In a similar Canadian study performed in Nova Scotia, HSV1 was recovered in 53.7% of positive cultures (male, 36.7%; female, 58.1%). The rates of HSV1 infection reported by this study and the present study were significantly different (P<0.001 [chi2] for male, P=0.012 for female). CONCLUSION: In New Brunswick, HSV1 is the dominant type of HSV isolated in samples collected from a genital site. Significant rate differences were demonstrated between the groups 10 to 39 years of age and >=40 years of age. PMID- 23450275 TI - What's in the black box of arthritis rehabilitation? A comparison of rehabilitation practice for patients with inflammatory arthritis in northern Europe. AB - BACKGROUND: In evaluating complex interventions, it is a challenge for researchers to provide transparent reporting of the intervention content with sufficient detail and clarity such that effects can be compared across studies or countries. OBJECTIVE: To describe and compare the content of current rehabilitation for patients with inflammatory arthritis across 4 northern European countries. PATIENTS AND METHODS: A total of 731 patients with inflammatory rheumatic diseases participated in a multicentre, longitudinal observational study carried out in Sweden, The Netherlands, Denmark and Norway. Data on context, structure and process were reported by patients and teams at the different participating study sites according to the Scandinavian Team Arthritis Register-European Team Intiative for Care Research (STAR-ETIC) framework. RESULTS: Although large similarities were found in the context, there were important differences between the Netherlands and the Scandinavian countries. Regarding structure, there were considerable differences in the length of the rehabilitation period across settings and countries. The most evident differences concerned process variables, especially the type and dosage of individual treatment modalities. CONCLUSION: The variation in important aspects of arthritis rehabilitation found in the present study underline the need for transparent and standardized description of these variables when comparing effects across settings and countries. A standardized description of current practice can be achieved by the STAR-ETIC framework. PMID- 23450276 TI - pH luminescence switch, DNA binding and photocleavage, and cytotoxicity of a dinuclear ruthenium complex. AB - The ground- and excited-state acid-base properties of [Ru2(bpy)4(H2bipt)]Cl4 1 {bpy = 2,2'-bipyridine, H2bipt = 2,5-bis[1,10]phenanthrolin[4,5-f]-imidazol-2 yl)thiophene} are investigated by emission and UV-visible absorption spectrophotometric pH titrations. The DNA binding properties of 1 are studied by means of DNA viscosity and optical spectroscopic techniques of UV-visible absorption and emission spectral titrations, steady-state emission quenching with ferrocyanide, ethidium bromide competitive binding, and DNA thermal denaturation as well as density functional theoretical calculations. The DNA photocleavage and singlet oxygen generation properties as well as in vitro anticancer activities against five cancer cell lines are studied as well. The results demonstrated that pH-induced luminescence switching, DNA binding, and anticancer properties of 1 are much improved with respect to those of the mononuclear analog [Ru(bpy)2(Htip)]Cl2 {Htip = 2-(thiophen-2-yl)-1H-imidazo[4,5 f][1,10]phenanthroline}. PMID- 23450278 TI - Epirubicin and docetaxel as neoadjuvant treatment of hormone receptor positive, HER-2 negative breast cancer: findings from two successive phase II studies. AB - BACKGROUND: We report on the activity of the combination of epirubicin and docetaxel given in neoadjuvant setting for 4 and 8 cycles respectively in 2 successive series of patients with large operable or locally advanced, hormone receptor positive, HER-2 negative breast cancer. PATIENTS AND METHODS: Patients were treated from 2002 to 2006 with epirubicin 90 mg/m(2) and docetaxel 75 mg/m(2) intravenously, every 3 weeks for 4 cycles before and 4 cycles after surgery (Series I - 13 patients), and from 2006 to 2010 with the same regimen administered for 8 cycles preoperatively (Series II - 37 patients), plus hormonal therapy for 5 years and radiation therapy if indicated. All Series I and 32 Series II patients were able to complete the preoperative chemotherapy. RESULTS: A complete response was found in 1 patient from Series I and 13 patients from Series II and the partial remission in 10 patients from Series I and 21 patients from Series II. Two Series I and 3 Series II patients did not respond clinically. Response rate (Series I/Series II) was 84/92%. All 50 patients underwent surgery. In Series I patients, 3 pCR occurred in the breast and the axilla was histologically negative in 2 cases. No evidence of disease both in the breast and in the axilla was achieved in 7.6% (1/13) of patients. In Series II patients, 8 pCR occurred in the breast and axilla was histologically negative in 15 patients. No evidence of disease both in the breast and in the axilla occurred in 10.8% (4/37) of patients. G3-G4 toxicity included myelosuppression in 3 patients from Series I and all patients from Series II, and mucositis in 1 patient from Series I and 4 patients from series II. No other G3-4 toxicities or toxic deaths occurred. Five-year progression free survival was 38% and 90% in Series I and Series II patients respectively. CONCLUSIONS: The incidence of pathologic complete remissions was lower in our patient population, compared to reported data. A longer duration of the preoperative treatment might be associated with a longer progression-free survival. PMID- 23450279 TI - Sporadic VACTERL association in a Japanese family with Sjogren-Larsson syndrome. PMID- 23450277 TI - How to engage the right brain hemisphere in aphasics without even singing: evidence for two paths of speech recovery. AB - There is an ongoing debate as to whether singing helps left-hemispheric stroke patients recover from non-fluent aphasia through stimulation of the right hemisphere. According to recent work, it may not be singing itself that aids speech production in non-fluent aphasic patients, but rhythm and lyric type. However, the long-term effects of melody and rhythm on speech recovery are largely unknown. In the current experiment, we tested 15 patients with chronic non-fluent aphasia who underwent either singing therapy, rhythmic therapy, or standard speech therapy. The experiment controlled for phonatory quality, vocal frequency variability, pitch accuracy, syllable duration, phonetic complexity and other influences, such as the acoustic setting and learning effects induced by the testing itself. The results provide the first evidence that singing and rhythmic speech may be similarly effective in the treatment of non-fluent aphasia. This finding may challenge the view that singing causes a transfer of language function from the left to the right hemisphere. Instead, both singing and rhythmic therapy patients made good progress in the production of common, formulaic phrases-known to be supported by right corticostriatal brain areas. This progress occurred at an early stage of both therapies and was stable over time. Conversely, patients receiving standard therapy made less progress in the production of formulaic phrases. They did, however, improve their production of non-formulaic speech, in contrast to singing and rhythmic therapy patients, who did not. In light of these results, it may be worth considering the combined use of standard therapy and the training of formulaic phrases, whether sung or rhythmically spoken. Standard therapy may engage, in particular, left perilesional brain regions, while training of formulaic phrases may open new ways of tapping into right-hemisphere language resources-even without singing. PMID- 23450280 TI - A triamido-uranium(V) inverse-sandwich 10pi-toluene tetraanion arene complex. AB - Reduction of [U(Ts(Tol))(Cl)(MU-Cl)U(Ts(Tol))(THF)2] [2, Ts(Tol) = HC(SiMe2NAr')3; Ar' = 4-MeC6H4)] with KC8 in toluene afforded the new arene bridged diuranium complex [{U(Ts(Tol))}2(MU-eta(6):eta(6)-C6H5Me)] (3); combined structural, spectroscopic, magnetic, and computational analyses unambiguously confirm that the uranium centres in 3 are in the +5 oxidation state and the toluene is a 10pi-tetraanion. PMID- 23450281 TI - Poisoning of bubble propelled catalytic micromotors: the chemical environment matters. AB - Self-propelled catalytic microjets have attracted considerable attention in recent years and these devices have exhibited the ability to move in complex media. The mechanism of propulsion is via the Pt catalysed decomposition of H2O2 and it is understood that the Pt surface is highly susceptible to poisoning by sulphur-containing molecules. Here, we show that important extracellular thiols as well as basic organic molecules can significantly hamper the motion of catalytic microjet engines. This is due to two different mechanisms: (i) molecules such as dimethyl sulfoxide can quench the hydroxyl radicals produced at Pt surfaces and reduce the amount of oxygen gas generated and (ii) molecules containing -SH, -SSR, and -SCH3 moieties can poison the catalytically active platinum surface, inhibiting the motion of the jet engines. It is essential that the presence of such molecules in the environment be taken into consideration for future design and operation of catalytic microjet engines. We show this effect on catalytic micromotors prepared by both rolled-up and electrodeposition approaches, demonstrating that such poisoning is universal for Pt catalyzed micromotors. We believe that our findings will contribute significantly to this field to develop alternative systems or catalysts for self-propulsion when practical applications in the real environment are considered. PMID- 23450282 TI - Limited support for the efficacy of nonpharmacological treatments for the core symptoms of ADHD. PMID- 23450283 TI - Prevention of schizophrenia: an impossible dream? PMID- 23450284 TI - Premenstrual dysphoric disorder and the brain. PMID- 23450285 TI - Why do children with disruptive behavior disorders keep making bad choices? PMID- 23450286 TI - Telepsychiatry: videoconferencing in the delivery of psychiatric care. AB - The provision of psychiatric treatment via live interactive videoconferencing, frequently termed telepsychiatry, is a viable option for psychiatrists to provide care to individual patients, populations, and communities faced with limited access and to move the point of care delivery into patients' living environments. Psychiatric providers new to videoconferencing should not be intimidated by the technology or its encompassing logistics, but they do need to develop an awareness of the salient regulatory, administrative, and clinical issues that arise in the practice of videoconferencing-based telepsychiatry. This article provides an overview of the current evidence base in telepsychiatry and reviews administrative and clinical issues in videoconferencing-based treatment. These points are then highlighted in a case example. PMID- 23450287 TI - Depicting depersonalization disorder. PMID- 23450288 TI - Disrupted expected value and prediction error signaling in youths with disruptive behavior disorders during a passive avoidance task. AB - OBJECTIVE: Youths with disruptive behavior disorders, including conduct disorder and oppositional defiant disorder, show major impairments in reinforcement-based decision making. However, the neural basis of these difficulties remains poorly understood. This partly reflects previous failures to differentiate responses during decision making and feedback processing and to take advantage of computational model-based functional MRI (fMRI). METHOD: Participants were 38 community youths ages 10-18 (20 had disruptive behavior disorders, and 18 were healthy comparison youths). Model-based fMRI was used to assess the computational processes involved in decision making and feedback processing in the ventromedial prefrontal cortex, insula, and caudate. RESULTS: Youths with disruptive behavior disorders showed reduced use of expected value information within the ventromedial prefrontal cortex when choosing to respond and within the anterior insula when choosing not to respond. In addition, they showed reduced responsiveness to positive prediction errors and increased responsiveness to negative prediction errors within the caudate during feedback. CONCLUSIONS: This study is the first to determine impairments in the use of expected value within the ventromedial prefrontal cortex and insula during choice and in prediction error-signaling within the caudate during feedback in youths with disruptive behavior disorders. PMID- 23450289 TI - Social and nonsocial cognition in bipolar disorder and schizophrenia: relative levels of impairment. AB - OBJECTIVE: This study aimed to determine the relative extent of impairment in social and nonsocial cognitive domains in patients with bipolar disorder compared with schizophrenia patients and healthy comparison subjects. METHODS: Sixty-eight clinically stable outpatients with bipolar disorder, 38 clinically stable outpatients with schizophrenia, and 36 healthy comparison subjects completed a range of social (facial affect perception, emotional regulation, empathic accuracy, mental state attribution, and self-referential memory) and nonsocial (speed of processing, attention/vigilance, working memory, verbal memory, visual memory, and reasoning/problem solving) cognitive tasks. RESULTS: For each social cognitive task, patients with bipolar disorder did not differ significantly from comparison subjects, and both groups performed better than schizophrenia patients. Within the bipolar group, clinical features and medication status were not related to social cognitive performance. Bipolar patients showed performance patterns across tasks (i.e., profiles) that were similar to those of comparison subjects on both social and nonsocial cognitive domains, whereas both groups differed from schizophrenia patients for both domains. Regarding relative impairment across the two cognitive domains, results revealed a significant group by-domain interaction in which bipolar patients showed less impaired social than nonsocial cognition, while schizophrenia patients showed the opposite pattern. CONCLUSIONS: Bipolar patients showed less impairment on social relative to nonsocial cognitive performance, whereas schizophrenia patients showed more impairment on social relative to nonsocial cognitive performance. These results suggest that these two cognitive domains play different roles in bipolar disorder compared with in schizophrenia. PMID- 23450296 TI - Characterization of a portable method for the collection of exhaled breath condensate and subsequent analysis of metal content. AB - Using exhaled breath condensate (EBC) as a biological media for analysis of biomarkers of exposure may facilitate the understanding of inhalation exposures. In this study, we present method validation for the collection of EBC and analysis of metals in EBC. The collection method was designed for use in a small scale longitudinal study with the goal of improving reproducibility while maintaining economic feasibility. We incorporated the use of an Rtube with additional components as an assembly, and trained subjects to breathe into the apparatus. EBC was collected from 8 healthy adult subjects with no known elevated exposures to Mn, Cr, Ni, and Cd repeatedly (10 times) within 7 days and analyzed for these metals via ICP-MS. Method detection limits were obtained by mimicking the process of EBC collection with ultrapure water, and resulted in 46-62% of samples falling in a range less than the method detection limit. EBC metal concentrations were found to be statistically significantly associated (p < 0.05) with room temperature and relative humidity during collection, as well as with the gender of the subject. The geometric mean EBC metal concentrations in our unexposed subjects were 0.57 MUg Mn per L, 0.25 MUg Cr per L, 0.87 MUg Ni per L, and 0.14 MUg Cd per L. The overall standard deviation was greater than the mean estimate, and the major source in EBC metals concentrations was due to fluctuations in subjects' measurements over time rather than to the differences between separate subjects. These results suggest that measurement and control of EBC collection and analytical parameters are critical to the interpretation of EBC metals measurements. In particular, rigorous estimation of method detection limits of metals in EBC provides a more thorough evaluation of accuracy. PMID- 23450297 TI - A novel keratin 5 mutation in an African family with epidermolysis bullosa simplex indicates the importance of the amino acid located at the boundary site between the H1 and coil 1A domains. PMID- 23450298 TI - Development of a multiplexing fingerprint and high wavenumber Raman spectroscopy technique for real-time in vivo tissue Raman measurements at endoscopy. AB - We report on the development of a novel multiplexing Raman spectroscopy technique using a single laser light together with a volume phase holographic (VPH) grating that simultaneously acquires both fingerprint (FP) and high wavenumber (HW) tissue Raman spectra at endoscopy. We utilize a customized VPH dual-transmission grating, which disperses the incident Raman scattered light vertically onto two separate segments (i.e., -150 to 1950 cm-1; 1750 to 3600 cm-1) of a charge coupled device camera. We demonstrate that the multiplexing Raman technique can acquire high quality in vivo tissue Raman spectra ranging from 800 to 3600 cm-1 within 1.0 s with a spectral resolution of 3 to 6 cm-1 during clinical endoscopy. The rapid multiplexing Raman spectroscopy technique covering both FP and HW ranges developed in this work has potential for improving in vivo tissue diagnosis and characterization at endoscopy. PMID- 23450300 TI - Collaborative effects of electric field and fluid shear stress on fibroblast migration. AB - Cells are inherently exposed to a number of different biophysical stimuli such as electric fields, shear stress, and tensile or compressive stress from the extracellular environment in vivo. Each of these biophysical cues can work simultaneously or independently to regulate cellular functions and tissue integrity in both physiological and pathological conditions. Thus, it is vital to understand the interaction of multiple stimuli on cells by decoupling and coupling the stimuli in simple combinations and by investigating cellular behaviors in response to these cues. Here, we report a novel microfluidic platform to apply the combinatorial stimulation of an electric field and fluid shear stress by controlling two directional cues independently. An integrated microfluidic platform was developed using soft lithography to monitor the cellular migration in real-time in response to an electric field and fluid shear stress in single, simultaneous, and sequential modes. When each of these stimulations is applied separately, normal human dermal fibroblasts migrate toward the anode and in the direction of fluid flow in a dose-dependent manner. Simultaneous stimulation with an electric field and shear stress, which mimics a wound in vivo, enhances the directional migration of fibroblasts by increasing both directedness and trajectory speed, suggesting the plausible scenario of cooperation between two physical cues to promote wound healing. When an electric field and shear stress are applied sequentially, migration behavior is affected by the applied stimulation as well as pre-existing stimulating conditions. This microfluidic platform can be utilized to understand other microenvironments such as embryogenesis, angiogenesis and tumor metastasis. PMID- 23450299 TI - Current genomics in cardiovascular medicine. AB - Cardiovascular disease (CVD) is a heterogeneous, complex trait that has a major impact on human morbidity and mortality. Common genetic variation may predispose to common forms of CVD in the community, and rare genetic conditions provide unique pathogenetic insights into these diseases. With the advent of the Human Genome Project and the genomic era, new tools and methodologies have revolutionised the field of genetic research in cardiovascular medicine. In this review, we describe the rationale for the current emphasis on large-scale genomic studies, elaborate on genome wide association studies and summarise the impact of genomics on clinical cardiovascular medicine and how this may eventually lead to new therapeutics and personalised medicine. PMID- 23450301 TI - A case of tuberculous cellulitis lacking epithelioid granuloma. PMID- 23450303 TI - The many faces of solitary and multiple erythema migrans. AB - Case definitions for European Lyme disease have been published. However, multiple erythema migrans may pose a diagnostic challenge. Therefore, we retrospectively reviewed the clinical and serological findings and response to therapy in a cohort of consecutive 54 patients with PCR-confirmed erythema migrans, referred to a university dermatology clinic. The proportion of patients with multiple erythema migrans lesions (usually 2 or 3) was almost equal (46%) to the proportion of patients with single erythema migrans lesions (54%). All patients, except for 2 multiple erythema migrans patients with a concomitant autoimmune disease, completely responded to treatment. In conclusion, multiple erythema migrans may be more common than anticipated, and since only 50% of the patients were seropositive when seeking medi-cal help, PCR testing of skin lesions is helpful to confirm the diagnosis in clinically atypical cases. PMID- 23450302 TI - Percent emphysema and right ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis-Lung and Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies. AB - BACKGROUND: Severe COPD can lead to cor pulmonale and emphysema and is associated with impaired left ventricular (LV) filling. We evaluated whether emphysema and airflow obstruction would be associated with changes in right ventricular (RV) structure and function and whether these associations would differ by smoking status. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI on 5,098 participants without clinical cardiovascular disease aged 45 to 84 years. RV and emphysema measures were available for 4,188 participants. Percent emphysema was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac CT scans. Generalized additive models were used to control for confounders and adjust for respective LV parameters. RESULTS: Participants consisted of 13% current smokers, 36% former smokers, and 52% never smokers. Percent emphysema was inversely associated with RV end-diastolic volume, stroke volume, cardiac output, and mass prior to adjustment for LV measures. After adjustment for LV end-diastolic volume, greater percent emphysema was associated with greater RV end-diastolic volume (+1.5 mL, P=.03) among current smokers, smaller RV end-diastolic volume (-0.8 mL, P=.02) among former smokers, and similar changes among never smokers. CONCLUSIONS: Percent emphysema was associated with smaller RV volumes and lower mass. The relationship of emphysema to cardiac function is complex but likely involves increased pulmonary vascular resistance, predominantly with reduced cardiac output, pulmonary hyperinflation, and accelerated cardiopulmonary aging. PMID- 23450304 TI - Droplet-based lipid bilayer system integrated with microfluidic channels for solution exchange. AB - This paper proposes a solution exchange of a droplet-based lipid bilayer system, in which the inner solution of a droplet is replaced for the purpose of efficient ion channel analyses. In our previous report, we successfully recorded the channel conductance of alpha-hemolysin in a bilayer lipid membrane using a droplet contact method that can create a spontaneous lipid bilayer at the interface of contacting droplets; this method is widely used as highly efficient method for preparing planar lipid membranes. When only pipetting droplets of the solution, this method is highly efficient for preparing lipid membranes. However, the drawback of droplet-based systems is their inability to exchange the solution within the droplets. To study the effect of inhibitors and promoters of ion channels in drug discovery, it would be beneficial to conduct a solution exchange of droplets to introduce membrane proteins and to apply or wash-out the chemicals. In this study, we propose a droplet contact method that allows for the solution exchange of droplets via microfluidic channels. We experimentally and numerically investigated the bilayer stability with respect to exchanging flow rates, and then demonstrated a binding assay of an alpha-hemolysin using one of its blockers. The solution exchange in this system was conducted in less than 20 s without rupturing the membrane. We believe that the proposed system will enhance the efficiency of ion channel analyses. PMID- 23450305 TI - Quality assessment of asthma clinical practice guidelines: a systematic appraisal. AB - BACKGROUND: The quality and potential impact of available clinical guidelines for asthma management have not been systematically evaluated. We, therefore, evaluated the quality of clinical practice guidelines (CPGs) for asthma. METHODS: We performed a systematic search of scientific literature published between 2000 and 2010 to identify and select CPGs related to asthma management. We searched guideline databases, guideline developers' websites, and the MEDLINE database of the US National Library of Medicine. Four independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines Research & Evaluation (AGREE) II instrument. We calculated the overall agreement among reviewers with the intraclass correlation coefficient (ICC). RESULTS: Eighteen CPGs published between the years 2000 and 2010 were selected from a total of 1,005 references. The overall agreement among reviewers was moderate (ICC: 0.78; 95% CI, 0.62 0.90). The mean scores for each AGREE domain were: scope and purpose, 44.1% (range: 10.0%-79.0%); stakeholder involvement, 33.8% (range: 4.0%-66.0%); rigor of development, 32.4% (range: 8.0%-64.0%); clarity and presentation, 52.1% (range: 17.0%-85.0%); applicability, 21.1% (range: 3%-55%); and editorial independence, 25% (range: 0%-58%). None of the appraised guidelines had a score > 60% (recommended). One-half of the appraised guidelines were recommended with modifications (nine of 18) or not recommended (nine of 18) for use in clinical practice. We observed improvement over time in overall quality of the guidelines (P = .01; guidelines published in the period 2001-2006 vs 2007-2009). CONCLUSIONS: The quality of guidelines for asthma care is low, although it has improved over time. Greater efforts are needed to provide high-quality guidelines that can be used as reliable tools for clinical decision-making in this field. PMID- 23450307 TI - Acute generalized exanthematous pustulosis induced by paroxetine in an adolescent girl. PMID- 23450308 TI - Rapid fabrication of nickel molds for prototyping embossed plastic microfluidic devices. AB - The production of hot embossed plastic microfluidic devices is demonstrated in 1 2 h by exploiting vinyl adhesive stickers as masks for electroplating nickel molds. The sticker masks are cut directly from a CAD design using a cutting plotter and transferred to steel wafers for nickel electroplating. The resulting nickel molds are used to hot emboss a variety of plastic substrates, including cyclo-olefin copolymer and THV fluorinated thermoplastic elastomer. Completed devices are formed by bonding a blank sheet to the embossed layer using a solvent assisted lamination method. For example, a microfluidic valve array or automaton and a droplet generator were fabricated with less than 100 MUm x-y plane feature resolution, to within 9% of the target height, and with 90 +/- 11% height uniformity over 5 cm. This approach for mold fabrication, embossing, and bonding reduces fabrication time and cost for research applications by avoiding photoresists, lithography masks, and the cleanroom. PMID- 23450309 TI - Feasibility and effectiveness of prone position in morbidly obese patients with ARDS: a case-control clinical study. AB - BACKGROUND: Obese patients are at risk for developing atelectasis and ARDS. Prone position (PP) may reduce atelectasis, and it improves oxygenation and outcome in severe hypoxemic patients with ARDS, but little is known about its effect in obese patients with ARDS. METHODS: Morbidly obese patients (BMI >= 35 kg/m2) with ARDS (Pao2/FIo2 ratio <= 200 mm Hg) were matched to nonobese (BMI < 30 kg/m2) patients with ARDS in a case-control clinical study. The primary end points were safety and complications of PP; the secondary end points were the effect on oxygenation (Pao2/FIo2 ratio at the end of PP), length of mechanical ventilation and ICU stay, nosocomial infections, and mortality. RESULTS: Between January 2005 and December 2009, 149 patients were admitted for ARDS. Thirty-three obese patients were matched with 33 nonobese patients. Median (25th-75th percentile) PP duration was 9 h (6-11 h) in obese patients and 8 h (7-12 h) in nonobese patients (P = .28). We collected 51 complications: 25 in obese and 26 in nonobese patients. The number of patients with at least one complication was similar across groups (n = 10, 30%). Pao2/FIo2 ratio increased significantly more in obese patients (from 118 +/- 43 mm Hg to 222 +/- 84 mm Hg) than in nonobese patients (from 113 +/- 43 mm Hg to 174 +/- 80 mm Hg; P = .03). Length of mechanical ventilation, ICU stay, and nosocomial infections did not differ significantly, but mortality at 90 days was significantly lower in obese patients (27% vs 48%, P < .05). CONCLUSIONS: PP seems safe in obese patients and may improve oxygenation more than in nonobese patients. Obese patients could be a subgroup of patients with ARDS who may benefit the most of PP. PMID- 23450310 TI - The prevalence of inducible clindamycin resistance among staphylococci in a tertiary care hospital - a study from the garhwal hills of uttarakhand, India. AB - OBJECTIVE: This study was undertaken to assess the frequency of the phenotypic expression of the inducible resistance to clindamycin which was due to the expression of the erm genes in various clinical isolates of the Staphylococcus species. MATERIALS AND METHODS: This was a cross sectional study conducted in the Dept. of Microbiology and Immunology, Veer Chandra Singh Garhwali Govt. Medical Sciences and Research Institute, Srikot, Uttarakhand, from July 2010 to December 2011. A total of 373 consecutive, non duplicate strains of Staphylococci isolated from various clinical samples like pus, wound swab, blood, urine and other body fluids, were tested. The isolates which had a discordant resistance pattern (clindamycin-sensitive and erythromycin-resistant) by Kirby Bauer Disk Diffusion method were selected and subjected to the D-test for inducible clindamycin resistance, as per the Clinical and Laboratory Standards Institutes (CLSI) guidelines. RESULTS: Among the 373 clinical isolates of Staphylococci which were studied, 134 isolates showed a discordant resistance pattern. Among these discordant strains, 45 (33.6%) isolates were D-test positive, which had inducible clindamycin resistance and belonged to the inducible macrolide lincosamide streptogramin- B phenotype (MLSBi). 89 (66.4%) isolates were D-test negative and they belonged to the macrolide streptogramin phenotype (MS). Among the MLSBi phenotypes, 6 (13.3%) isolates were methicillin-resistant Staphylococcus aureus (MRSA), 13 (28.9%) were Methicillin-sensitive S.aureus (MSSA) and 26 (57.8%) were coagulase negative staphylococci (CONS). CONCLUSION: The D-test is a simple, effective and an important method for the phenotypic detection of inducible clindamycin resistance and it should be used routinely, as it will help in guiding the empirical therapy. The possible clinical failures can thus be avoided. PMID- 23450313 TI - Recurrent keratoacanthomas developing after spontaneous resolution. PMID- 23450314 TI - Cytokine-induced killer cells co-cultured with complete tumor antigen-loaded dendritic cells, have enhanced selective cytotoxicity on carboplatin-resistant retinoblastoma cells. AB - Retinoblastoma (RB) is a challenging disease that affects mostly young children. Chemical therapy has been shown to have limitations during clinical practice, principally because of the ability of RB to become resistant to the treatment. Nevertheless, chemotherapy is still the main treatment for RB, and immunotherapy has become a promising treatment for most solid tumors with fewer side effects than traditional therapies. In this study, we explored the antitumor effects of cytokine-induced killer (CIK) cells co-cultured with dendritic cells (DCs) pulsed with complete tumor antigens (DC-Ag). Cytotoxicity and specificity were evaluated on an RB cell line (RB-Y79), on a human normal retina cell line (hTERT-RPE1) and a carboplatin-resistant RB cell line. Our results showed that CIK differentiation and cytotoxicity were enhanced by co-culturing CIKs with DC-Ag. Moreover, the co culture improved the CIK proliferation rate by increasing IL-6 and decreasing IL 10 levels in the culture medium. Furthermore, the use of DC-Ag-CIK cells had little effect on normal retinal cells but high cytotoxicity on RB cells even on carboplatin-resistant retinoblastoma cells. This is the first study showing that DC cells pulsed with the complete tumor antigen improve proliferation, differentiation and cytotoxic activity of CIKs specific not only for RB but also for the chemotherapy-resistant form of the malady. Thus highly efficient immunotherapy based on DC-Ag-CIK cells may be a potential effective and safe mean of treating RB especially to patients where traditional chemical therapy has failed. PMID- 23450315 TI - The Epworth Sleepiness Scale: conventional self vs physician administration. AB - BACKGROUND: The Epworth Sleepiness Scale (ESS) is a simple, self-administered questionnaire that provides a measurement of the subject's level of daytime sleepiness, and is widely used for patients with obstructive sleep apnea (OSA). Some works undermined its accuracy. The aim of this study was to compare self administered ESS scores to physician-administered scores in a sample of patients with suspicion of OSA. METHODS: Patients were randomly divided into two groups: group 1, or the self-administered group (n = 113); and group 2, or the physician administered group (n = 112). Patients in group 1 were asked to complete the ESS in the traditional way; in group 2, the ESS was administered by a sleep-medicine physician. Subjects in both groups underwent diagnostic in-laboratory portable monitoring (PM) within 1 week's time. RESULTS: The percentage of questionnaires properly completed was significantly different between groups: 77% (87 of 113) in the group 1 vs 100% (112 of 112) in the group 2 (P = .00). Scores obtained when a physician administered the questionnaire (ESSp) were higher than those when the ESS was self administered (ESSs) (ESSp:12.09 +/- 4.1 vs ESSs:10.37 +/- 5.49; P = .01). The ESSp was more highly correlated with apnea-hypopnea index and oxygen desaturation index than the ESSs. CONCLUSIONS: Our results lead us to consider the physician-administered ESS to be more accurate than the traditional ESS; thus, our suggestion is to validate this new method of administration. PMID- 23450318 TI - Skin cancer after solid organ transplantation. PMID- 23450319 TI - Sorting, identification and enrichment of side population cells in THP-1 acute monocytic leukemia cells. AB - The objective of the present study was to examine and determine whether the human acute monocytic leukemia cell line THP-1 contains side population (SP) cells, and, if so, to increase the proportion of SP cells using arabinosylcytosine (Ara C). Fluorescent microscopy and flow cytometry were employed to detect the percentage of SP cells in THP-1 cells. Then, SP and non-SP (NSP) cell subpopulations were collected and identified. THP-1 cells were incubated with different concentrations of Ara-C for 24 h and the proportion of SP cells was detected. Our results demonstrated that the percentage of SP cells was 1.81 +/- 0.99% in THP-1 cells. A majority of the SP cells remained in the G0/G1 phase, and the expression of CD34+ and CD34+CD38- and the proliferation ability of the SP cells were higher compared to NSP cells (P<0.05). The mRNA expression of multidrug resistance genes (ABCG2 and ABCB1), apoptosis regulation genes (Bcl-2) and the Bcl-2/Bax value of SP cells were higher than those of NSP cells. SP cells have been shown to be more tumorigenic than NSP cells. Following co-culture with Ara-C, the proportion of SP cells increased significantly and subsequently the Ara-C concentration increased. These findings suggest that the THP-1 cell line contains SP cells and that SP cells possess certain intrinsic stem cell properties and may contain a larger proportion of leukemia stem cells (LSCs). The concentrations of SP cells can be increased with Ara-C by co-culture, and this technique is a useful and important application for the study of LSCs. PMID- 23450320 TI - Implementation of multifamily group treatment for veterans with traumatic brain injury. AB - OBJECTIVE: This study evaluated the initial efficacy and feasibility of implementing multifamily group treatment for veterans with traumatic brain injury (TBI). METHODS: Veterans at two Veterans Affairs medical centers were prescreened by their providers for participation in an open trial of multifamily group treatment for TBI. Enrollment was limited to consenting veterans with a clinical diagnosis of TBI sustained during the Operation Enduring Freedom-Operation Iraqi Freedom era, a family member or partner consenting to participate, and a score >=20 on the Mini-Mental State Examination. The nine-month (April 2010-March 2011) trial consisted of individual family sessions, an educational workshop, and bimonthly multifamily problem-solving sessions. Interpersonal functioning and symptomatic distress among veterans and family burden, empowerment, and symptomatic distress among families were assessed before and after treatment. RESULTS: Providers referred 34 (58%) of 59 veterans screened for the study; of those, 14 (41%) met criteria and consented to participate, and 11 (32%) completed the study. Severity of TBI, insufficient knowledge about the benefits of family involvement, and access problems influenced decisions to exclude veterans or refuse to participate. Treatment was associated with decreased veteran anger expression (p<=.01) and increased social support and occupational activity (p<=.05), with effect sizes ranging from .6 to 1.0. Caregivers reported decreased burden (p<=.05) and increased empowerment (p<=.01). CONCLUSIONS: The results supported implementation of a randomized controlled trial, building in education at the provider and family level. PMID- 23450321 TI - Echocardiographic and hemodynamic predictors of mortality in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) can lead to the development of pulmonary hypertension, which is associated with an increased risk of death. In pulmonary arterial hypertension, survival is directly related to the capacity of the right ventricle to adapt to elevated pulmonary vascular load. The relative importance of right ventricular function in IPF is not well understood. Our objective was to evaluate right ventricular echocardiographic and hemodynamic predictors of mortality in a cohort of patients with IPF referred for lung transplant evaluation. METHODS: We performed a retrospective cohort study of 135 patients who met 2011 American Thoracic Society/European Respiratory Society criteria for IPF and who were evaluated for lung transplantation at the Hospital of the University of Pennsylvania. RESULTS: Right ventricle:left ventricle diameter ratio (hazard ratio [HR], 4.5; 95% CI, 1.7-11.9), moderate to severe right atrial and right ventricular dilation (HR, 2.9; 95% CI, 1.4-5.9; and HR, 2.7; 95% CI, 1.4-5.4, respectively) and right ventricular dysfunction (HR, 5.5; 95% CI, 2.6-11.5) were associated with an increased risk of death. Higher pulmonary vascular resistance was also associated with increased mortality (HR per 1 Wood unit, 1.3; 95% CI, 1.1-1.5). These risk factors were independent of age, sex, race, height, weight, FVC, and lung transplantation status. Other hemodynamic indices, such as mean pulmonary artery pressure and cardiac index, were not associated with outcome. CONCLUSIONS: Right-sided heart size and right ventricular dysfunction measured by echocardiography and higher pulmonary vascular resistance by invasive hemodynamic assessment predict mortality in patients with IPF evaluated for lung transplantation. PMID- 23450324 TI - Incidence and determinants of chronic pruritus: a population-based cohort study. AB - Epidemiological data on chronic pruritus (> 6 weeks) in the general population are sparse. We aimed to provide data on the incidence and prevalence of chronic pruritus, and identify its determinants based on cross-sectional and longitudinal analyses. A cohort of 1,190 participants from a cross-sectional baseline-study (response rate: 57.8%) was followed up after one year. The questionnaire assessed occurrence of chronic pruritus, medical, lifestyle and psychosocial variables. Incident chronic pruritus was defined as reported chronic pruritus at follow-up in those subjects free-of-the-symptom at baseline. Cross-sectional analyses of data from the follow-up assessments addressed potential associations of medical, lifestyle and psychosocial factors with prevalent chronic pruritus. Longitudinal analyses examined sociodemographic factors as potential predictors of incident chronic pruritus. The follow-up response rate was 83.1%. The mean age of subjects was 56 years, and 58% were female. The 12-month cumulative-incidence equalled 7.0% (95% confidence interval (95% CI) 5.2-9.2%. Lifetime prevalence was 25.5% (95% CI 21.8-27.8%). Incidence was significantly associated with age. Determinants of prevalent chronic pruritus in multi-variable analyses were: liver disease, asthma, eczema and dry skin within the medical domain, an elevated body mass index within the lifestyle domain and higher anxiety scores within the psychosocial domain. Findings suggest a considerable 12-month incidence and lifetime prevalence and provide important directions for future research. PMID- 23450325 TI - Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells. AB - Salivary adenoid cystic carcinoma (SACC) is a common type of salivary gland cancer. The poor long-term prognosis for patients with SACC is mainly due to local recurrence, perineural invasion (PNI) and distant metastasis. Notch signaling plays a critical role in determining cell fate such as proliferation, differentiation and apoptosis. Accumulating evidence indicates that aberrant Notch-4 expression has a tumor-promoting function in SACC. In the present study, we used lentiviral-mediated RNA interference (RNAi) targeted against Notch-4 to determine the effects of decreased levels of this protein in the human highly metastatic adenoid cystic carcinoma cell line ACC-M. Furthermore, the proliferative capability as well as the PNI potential of the treated cells were observed in vitro. Our studies demonstrated that RNAi directed against Notch-4 markedly decreased Notch-4 gene expression, resulting in the inhibition of cell proliferation, and G0/G1 to S phase arrest in ACC-M cells. Knockdown of Notch-4 also resulted in a decrease in the in vitro PNI activity in ACC-M cells. To conclude, RNAi targeting against Notch-4 induces the suppression of cell growth and inhibition of PNI in vitro in ACC-M cells. Notch-4 may play an important role in regulating proliferation and PNI activity of SACC. PMID- 23450326 TI - Multifamily group treatment for veterans with traumatic brain injury: what is the value to participants? AB - OBJECTIVE: This study evaluated the feasibility, acceptability, and helpfulness of implementation of multifamily group treatment for traumatic brain injury (TBI) among veterans who sustained a TBI during the wars in Iraq and Afghanistan and their families or caregivers. METHODS: Veterans and their family members who participated in an open clinical trial (August 2010-March 2011) of multifamily psychoeducation for TBI at two Veterans Affairs medical centers were invited to one of three focus groups. Participants were asked about problems experienced before and during the intervention, aspects of treatment that were helpful, and improvements that would facilitate effective implementation of multifamily group treatment for TBI. Postintervention focus group transcripts were analyzed by utilizing qualitative content analysis. RESULTS: Participants included eight veterans with TBI and eight family members. Five themes emerged: exploring common struggles and reducing isolation, building skills to cope with TBI and related problems, restoring relationships through communication and understanding, increasing understanding of the interconnection between TBI and posttraumatic stress disorder, and improving the multifamily group experience and increasing treatment engagement of veterans and families. Veterans and family members found multifamily group treatment for TBI highly acceptable and offered recommendations to improve and increase access to the program. CONCLUSIONS: The results supported the feasibility and acceptability of multifamily group treatment for TBI. Specific recommendations to improve this psychoeducational intervention and its implementation are offered. PMID- 23450327 TI - Influence of interstitial lung disease on outcome in systemic sclerosis: a population-based historical cohort study. AB - BACKGROUND: Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) and a major cause of SSc-related deaths. This study aimed to determine the influence of ILD on SSc in a population-based historical cohort study. The hypothesis was that patients with SSc who develop ILD have increased morbidity and mortality when compared with patients with SSc without ILD. METHODS: Using the record linkage system of the Rochester Epidemiology Project in Olmsted County, Minnesota, this study identified the incidence of SSc between 1980 and 2010 and point prevalence on December 31, 2010 and determined the progression of organ involvement and its influence on outcome. RESULTS: During the 30-year interval, we identified 64 incident cases of SSc: 57 women and seven men, median age 49.1 years (interquartile range [IQR], 39.8-67.6 years). There were 43 prevalent cases. ILD occurred in 19 cases, usually after the diagnosis of SSc (median, 2 years; IQR, 0-10 years), with only three cases occurring 6 to 24 months beforehand. Pulmonary arterial hypertension (PAH) was diagnosed in 14 cases, heart failure in 27 cases, and chronic kidney disease (CKD) in 21 cases. Seventeen patients died during the study period, with a median survival time after diagnosis of 22.9 years. ILD, PAH, and CKD were associated with an increased risk of death. CONCLUSIONS: The incidence of ILD associated with SSc was relatively low in this population-based cohort. ILD appeared to be a contributing factor to mortality. Other factors, including age, PAH, and CKD, were also associated with poor outcome. PMID- 23450328 TI - Postsynaptic protein synthesis is required for presynaptic enhancement in persistent forms of long-term potentiation. AB - Long-term potentiation (LTP) in the hippocampus is a fundamental process underlying learning and memory in the brain. At CA3-CA1 synapses, three discrete forms of LTP (LTP1, 2, and 3) have been differentiated on the basis of their persistence, maintenance mechanisms, Ca(2+) signaling pathways, expression loci, and electrophysiological requirements. We previously showed that LTP2 and LTP3 involve a presynaptic expression component that is established in a translation dependent manner. Here we investigate the locus of translation required for presynaptic expression. Neurotransmitter release rate was estimated via FM 1-43 destaining from CA3 terminals in hippocampal slices from male Wistar rats (6-8 weeks). Destaining was measured at sites making putative contact with CA1 dendritic processes in stratum radiatum that had been filled with a membrane impermeable translation inhibitor and a fluorescent indicator. Our results suggest that inhibition of postsynaptic translation eliminates the enhanced release ordinarily observed at 160 min post-LTP induction, and that this effect is limited to sites closely apposed to the filled postsynaptic cell. We conclude that postsynaptic translation is required for the presynaptic component of LTP2 and LTP3 expression. These data considerably strengthen the mechanistic separation of LTP1, 2, and 3 and provide evidence for an expanded repertoire of communication between synaptic elements. PMID- 23450330 TI - Large- and small-for-gestational-age neonates born by women with gestational diabetes mellitus diagnosed by the new IADPSG criteria: a case-control study of 289 patients and 1 108 controls. AB - BACKGROUND: The primary aim of this case-control study was to compare women whose pregnancy was complicated with gestational diabetes mellitus (GDM), diagnosed by the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria, with a control group of healthy, pregnant women in terms of incidence of large- (LGA) and small-for-gestational-age (SGA) neonates. Our secondary aim was to compare intrauterine growth of fetuses between the same 2 populations. PATIENTS AND METHODS: The study included 289 women diagnosed as having GDM in the current pregnancy and 1 108 pregnant controls. Women were followed-up every 2 (GDM group) or 4 weeks (control group). The main metabolic parameters recorded were body mass index, fasting plasma glucose, home blood glucose and glycated hemoglobin A1c. The main ultrasonographic parameters were estimated fetal weight (EFW), head (HC) and abdominal circumferences (AC). Decisions on treatment modification in the GDM group were based on both metabolic and ultrasonographic parameters. RESULTS: There was no evidence for a difference in the incidence of LGA (9.9 vs. 9.2%, Chi-square, p=0.745) or SGA (10.5 vs. 9.0%, p=0.524) in GDM and in control group, respectively. No significant differences were found in EFW or AC between GDM and control groups during the second and third trimester. CONCLUSIONS: Incidence of LGA and SGA neonates is similar among healthy pregnant women and women with GDM, diagnosed by the new IADPSG criteria and treated according to both metabolic and ultrasonographic parameters. PMID- 23450331 TI - Association of lipid peroxidation with endothelial dysfunction in patients with overt hypothyroidism. AB - Hypothyroidism is associated with increased oxidative stress. The mechanism underlying the endothelial dysfunction in thyroid disease is not yet clear. This study aims to investigate lipid peroxidation and its association with endothelial dysfunction in overt hypothyroidism (OHT).Plasma malondialdehyde (MDA) as a marker of oxidative stress and plasma nitrates and asymmetric dimethyl arginine levels (ADMA) as markers of endothelial dysfunction were estimated in 25 OHT patients in comparison to 25 euthyroid controls. Plasma MDA, ADMA levels were significantly increased, whereas plasma nitrates were significantly decreased in the patient group compared to control group (p<0.01). Moreover, a significant positive association between plasma MDA and ADMA was found in the patient group (rho=0.472, p=0.036). Our results reveal the presence of endothelial dysfunction in OHT patients as evidenced by decreased plasma nitrates and increased ADMA levels. Increased levels of MDA represent an increased generation of reactive oxygen species in these patients. A finding of significant direct relation of plasma MDA with ADMA indicates that oxidative stress has a strong impact on endothelial dysfunction in overt hypothyroidism. Further studies focusing on the role of oxidative stress in endothelial dysfunction and the effects of antioxidant supplementation on endothelial function in OHT patients are required. PMID- 23450332 TI - Multiple statistical methods for assessing differential gene expression in microarray data of diabetic model rats to predict the molecular mechanism of atorvastatin on anti-atherogenesis. AB - BACKGROUND: Many evidences indicate that statins have pleiotropic effects that are lipid-lowering independent. These effects could suggest attenuation of many of the stages critical to atherosclerosis. However, the specific molecular mechanisms of statins on atherogenesis are still unknown. The goal is to detect and analyze the altered gene expression of the artery after atorvastatin treatment in streptozocin (STZ)-induced diabetic rats, and to predict the possible cholesterol-independent effects of atorvastatin on anti-atherogenesis. METHODS: A total of 33 Sprague Dawley (SD) rats were randomly divided into 3 groups: control group, diabetic group, and diabetic group with atorvastatin treatment (receiving 50 mg/kg qd atorvastatin). Rats were sacrificed at the end of 4 weeks, and the aortas were obtained. The pathological changes were observed by Hematoxylin and eosin (HE) staining. A cDNA microarray analysis was carried out, and the results were analyzed by the random variance model (RVM) t-test, Stc analysis, Stc-Gene Ontology (GO) analysis, Stc-pathway analysis, and GeneFunNet analysis. Then reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate the mRNA expression of Cathepsin S (Cat S),Which was one of the significant genes obtained by statistical analysis, in the aortas of rats in control group (Wistar rats), DM group (Goto Kakisaki rats) and atorvastatin treated DM group (Goto Kakisaki rats with 50 mg/kg qd atorvastatin) for 12 weeks. RESULTS: A total of 1 073 differential expression genes were found in the 3 groups. 2 tendency profiles of gene expression, which represented the medicine effect, were picked out by Stc analysis of gene expression. The main functions of genes and the significant pathways in the 2 profiles were figured out by Stc-go analysis and Stc-pathway analysis. The core regulatory factors in the co expression network were shown by GeneFunNet analysis. Among these significant genes, Cat S was chosen to be further evaluated as a target gene. Expression of Cat S was upregulated in the aortas of the diabetic rats and downregulated with statistical significance by atorvastatin treatment. CONCLUSIONS: Atorvastatin can influence the expression of many genes and signal pathways, some may be significant and produce their marked effects on all of the processes of atherogenesis. Cat S is one of them. These data thus predict the possible molecular mechanism of pleiotropic effects of atorvastatin, which is useful for further experimental design. PMID- 23450333 TI - Lack of evidence on Tai Chi-related effects in patients with type 2 diabetes mellitus: a meta-analysis. AB - AIMS: Whether Tai Chi (TC) benefits patients with type 2 diabetes mellitus (T2DM) remains controversial. Thus, we performed a meta-analysis to assess the efficacy of TC in T2DM patients. METHODS: A computerised search through PubMed and Embase was performed to identify relevant studies. The primary outcomes were fasting blood glucose (FBG), haemoglobin A1c (HbA1c) and insulin resistance (HOMA). Secondary outcomes included total cholesterol, high-density lipoprotein cholesterol (HDL-C) and triglyceride. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated. RESULTS: 4 randomised controlled trials (RCTs) and 5 non-randomised controlled trials (NRCTs) met the inclusion criteria. The pooled WMDs from RCTs were -14.82 mg/dL (95% CI: -49.17 to 19.53; P=0.40) for FBG, -0.19% (95% CI: -0.41 to 0.03; P=0.09) for HbA1c and -0.34 units (95% CI: -3.02 to 2.34; P=0.80) for HOMA. The WMDs from NRCTs were -11.22 mg/dL (95% CI: -18.58 to -3.86; P=0.003) for FBG, -0.41% (95% CI: -0.53 to -0.29; P<0.00001) for HbA1c and -0.60 units (95% CI: -1.46 to 0.25; P=0.16) for HOMA. Furthermore, the pooled results of serum lipids suggest that TC significantly reduced triglyceride (P=0.006) instead of total cholesterol (P=0.77), and failed to improve HDL-C (P=0.12). CONCLUSIONS: Sufficient evidence to support the benefits of TC to T2DM patients is lacking. Further large-scale studies are needed to investigate the long-term efficacy of TC. PMID- 23450334 TI - Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia. AB - OBJECTIVE: To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. METHODS: Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher's exact test. RESULTS: Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%-2%). CONCLUSIONS: Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials. PMID- 23450335 TI - Automated volumes-of-interest identification for classical and atypical Parkinsonian syndrome differentiation using T2' MR imaging. AB - OBJECTIVES: In clinical routine, patients with classical Parkinsonian syndromes (CPS) need to be differentiated from those with atypical Parkinsonian syndromes (APS), particularly with respect to prognosis and treatment decision. To date, this diagnosis is mainly based on clinical criteria, leading to failure rates up to 25%, motivating the development of image-based decision support systems. Magnetic resonance imaging (MRI) and in particular T2' image sequences have been suggested as a potential marker for differential diagnosis. The aim of this study was to investigate whether automatically identified T2' volumes-of-interest (VOIs) can be used for an automatic differentiation of CPS and APS patients. MATERIAL AND METHODS: 74 MRI datasets were available for this hypothesis generating trial, including image sequences from 24 healthy subjects, 33 CPS and 17 APS patients. First, a problem-specific reference atlas was generated using the healthy control datasets. Next, patients' datasets were registered to the atlas. Voxel-wise t-tests, reflecting significance levels of T2' value differences between CPS and APS patients, were then applied for calculation of a p-map. Finally, the calculated p-map was thresholded and a connected component analysis was performed for final VOI detection. In parallel, manually defined VOIs were determined in grey and white matter for comparison. RESULTS: Three VOIs in parts of the basal ganglia and the left occipital lobe were automatically identified by the presented method. There was a trend for higher area under the curve on multivariable receiver operating characteristic curves for automatically determined VOIs over manually defined VOIs (0.939 vs. 0.818, p = 0.0572). CONCLUSION: The diagnostic role of automatically defined VOIs in differentiation of CPS and APS patients based on T2' image sequences should be further investigated. PMID- 23450337 TI - "Partial duplication of lower lip and hemimandible" A rare case. AB - Duplication of mandible and lower lip is a very rare congenital entity. We report an extremely uncommon case of Congenital Duplication of Lower lip and Mandible in a 3 year old girl, who was treated surgically in a single stage for correction of both lip and mandible. This was a commissure preserving single staged procedure. The Surgical procedure, the problems related to this anomaly and the embryology are discussed. PMID- 23450336 TI - Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. AB - BACKGROUND: Experience from influenza pandemics suggested that convalescent plasma treatment given within 4 to 5 days of symptom onset might be beneficial. However, robust treatment data are lacking. METHODS: This is a multicenter, prospective, double-blind, randomized controlled trial. Convalescent plasma from patients who recovered from the 2009 pandemic influenza A(H1N1) (A[H1N1]) infection was fractionated to hyperimmune IV immunoglobulin (H-IVIG) by CSL Biotherapies (now BioCSL). Patients with severe A(H1N1) infection on standard antiviral treatment requiring intensive care and ventilatory support were randomized to receive H-IVIG or normal IV immunoglobulin manufactured before 2009 as control. Clinical outcome and adverse effects were compared. RESULTS: Between 2010 and 2011, 35 patients were randomized to receive H-IVIG (17 patients) or IV immunoglobulin (18 patients). One defaulted patient was excluded from analysis. No adverse events related to treatment were reported. Baseline demographics and viral load before treatment were similar between the two groups. Serial respiratory viral load demonstrated that H-IVIG treatment was associated with significantly lower day 5 and 7 posttreatment viral load when compared with the control (P = .04 and P = .02, respectively). The initial serum cytokine level was significantly higher in the H-IVIG group but fell to a similar level 3 days after treatment. Subgroup multivariate analysis of the 22 patients who received treatment within 5 days of symptom onset demonstrated that H-IVIG treatment was the only factor that independently reduced mortality (OR, 0.14; 95% CI, 0.02 0.92; P = .04). CONCLUSIONS: Treatment of severe A(H1N1) infection with H-IVIG within 5 days of symptom onset was associated with a lower viral load and reduced mortality. TRIAL REGISTRY: ClinialTrials.gov; No.: NCT01617317; URL: www.clinicaltrials.gov. PMID- 23450338 TI - Relationships among veteran status, gender, and key health indicators in a national young adult sample. AB - OBJECTIVE: Although many risk behaviors peak during young adulthood, little is known about health risk factors and access to care. This study assessed health indicators and health care access in a national sample of young adult veterans and civilians. METHODS: Data were from the 2010 Behavioral Risk Factor Surveillance System, a national telephone survey. Of 27,471 participants, ages 19 30 years, 2.2% were veterans (74.6% were male) and 97.7% were civilians (37.6% were male). Gender-stratified comparisons assessed health indicators and health care access by veteran status. Multivariate logistic regression was used to examine health indicators and health care access as a function of gender and veteran status. RESULTS: In the overall sample, women were more likely than men to have insurance, to have a regular physician, and to have had a routine checkup and yet were more likely to report financial barriers to care. Women also were more likely than men to report general medical and mental distress and higher lifetime anxiety and depressive disorders, whereas men were more likely to be overweight or obese and to report tobacco use and high-risk drinking. Adjusted analyses revealed a higher likelihood of general medical distress and higher rates of lifetime anxiety disorders among veterans compared with civilians, although there were no differences between veterans and civilians regarding health care utilization and hazardous drinking. CONCLUSIONS: Findings extend the literature on health care status and modifiable risk factors for young adults by identifying differences between men and women and between veterans and civilians. Interventions may need to be tailored on the bases of gender and veteran status because of several differences in mental health and general health needs. PMID- 23450339 TI - An aerobic oxidation/homolytic substitution-cascade for stereoselective methylsulfanyl-cyclization of 4-pentenols. AB - 4-Pentenols (dihomoallylic alcohols) are oxidized by cobalt(II)-activated dioxygen in solutions of dimethyl disulfide and cyclohexa-1,4-diene to afford methylsulfanyl (CH3S)-functionalized tetrahydrofurans in up to 74% yield. The reaction is a cascade, composed of oxidative alkenol cyclization providing tetrahydrofuryl-2-methyl radicals, which are trapped in dimethyl disulfide. Homolytic methylsulfanyl substitution by carbon radicals is a slow reaction, as exemplified by the rate constant of k(SCH(3)) = 3 * 10(4) M(-1) s(-1) (70 degrees C) derived from competition kinetics for the reaction between dimethyl disulfide and the trans-2-phenyltetrahydrofuryl-5-methyl radical. Methylsulfanyl cyclizations therefore are experimentally performed in neat dimethyl disulfide, containing the minimum amount of cyclohexa-1,4-diene necessary for attaining almost quantitative alkenol conversion. The oxidative tetrahydrofuran synthesis occurs with noteworthy (>99%) 2,5-trans-stereoselectivity, as shown by the synthesis of diastereomerically pure 2,3- and 2,3,3-substituted 5 (methylsulfanyl)methyltetrahydrofurans from stereodefined 1,2-di- and 1,2,2 trisubstituted 4-pentenols. Changing the chemical nature of the disulfide reagent or the alkenol extends the scope of alkylsulfanyl-cyclization to ethylsulfanyl cyclization, allylsulfanyl-transfer, or tetrahydropyran synthesis. PMID- 23450340 TI - Measured gain in projection with the extended columellar strut-tip graft in endonasal rhinoplasty. AB - IMPORTANCE: The extended columellar strut-tip graft was designed to improve nasal tip projection and tip definition in patients undergoing rhinoplasty. OBJECTIVE: To determine whether the extended columellar tip graft leads to a true and measurable increase in nasal tip projection or simply gives the illusion of an increase in projection. DESIGN: Retrospective case review. The mean time of follow-up photographs was 32 months after surgery (range, 8 months to 10 years). PARTICIPANTS: The study population comprised 15 patients who underwent primary or revision rhinoplasty during the last 10 years. INTERVENTION: Primary or revision rhinoplasty. MAIN OUTCOME MEASURE: The outcome measure was the long-term gain in nasal tip projection. Preoperative and postoperative images were cropped and sized equally for accurate comparison. All measurements were made from the alar facial crease to the tip defining point. RESULTS: In all 15 patients, an increase in tip projection was obtained. The mean increase in projection was 19% compared with the preoperative projection. After applying a paired t test for analysis, there was a statistically significant increase in nasal projection (P < .05). CONCLUSIONS AND RELEVANCE: The extended columellar strut-tip graft effectively corrected poor nasal tip projection. The effect is maintained years later. The extended columellar strut-tip graft is an excellent choice in endonasal rhinoplasty to improve poor tip projection and definition. LEVEL OF EVIDENCE: 4. PMID- 23450341 TI - A case of recurrent acute encephalopathy with febrile convulsive status epilepticus with carnitine palmitoyltransferase II variation. AB - Acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) is the most common type of acute encephalopathy in childhood in Japan, which develops with prolonged febrile convulsion, followed by mild unconsciousness. It is generally sporadic and nonrecurrent. In this report, a 1-year-old girl showed signs of AEFCSE triggered by respiratory syncytial virus infection. Two years later, she presented with AEFCSE triggered by influenza virus infection, resulting in severe neurologic sequelae. The patient had a thermolabile genotype of carnitine palmitoyltransferase II (CPT II) variations consisting of three single nucleotide polymorphisms in exons 4 [1055T > G/F352C and 1102G > A/V368I] and 5 [1939A > G/M647V]. The polymorphism has been identified as a genetic predisposition for acute encephalopathy. This report presents the first case of recurrent encephalopathy with CPT II variations that may partially associate with pathogenesis of recurrent AEFCSE. PMID- 23450342 TI - Supporting translational research on inherited cardiomyopathies through information technology. AB - OBJECTIVES: The INHERITANCE project, funded by the European Commission, is aimed at studying genetic or inherited Dilated cardiomyopathies (DCM) and at understanding the impact and management of the disease within families that suffer from heart conditions that are caused by DCMs. The biomedical informatics research activity of the project aims at implementing information technology solutions to support the project team in the different phases of their research, in particular in genes screening prioritization and new gene-disease association discovery. METHODS: In order to manage the huge quantity of scientific, clinical and patient data generated by the project several advanced biomedical informatics tools have been developed. The paper describes a layer of software instruments to support translation of the results of the project in clinical practice as well as to support the scientific discovery process. This layer includes data warehousing, intelligent querying of the phenotype data, integrated search of biological data and knowledge repositories, text mining of the relevant literature, and case based reasoning. RESULTS: At the moment, a set of 1,394 patients and 9,784 observations has been stored into the INHERITANCE data warehouse. The literature database contains more than 1,100,000 articles retrieved from the Pubmed and generically related to cardiac diseases, already analyzed for extracting medical concepts and genes. CONCLUSIONS: After two years of project the data warehouse has been completely set up and the text mining tools for automatic literature analysis have been implemented and tested. A first prototype of the decision support tool for knowledge discovery and gene prioritization is available, but a more complete release is still under development. PMID- 23450343 TI - Characteristics of adults with substance use disorders expected to be eligible for Medicaid under the ACA. AB - OBJECTIVES: Provisions in the Affordable Care Act (ACA) are likely to expand access to substance use disorder treatment for low-income individuals. The aim of the study was to provide information on the need for substance use disorder treatment among individuals who may be eligible for Medicaid under the ACA. METHODS: The 2008 and 2009 National Survey on Drug Use and Health provided data on demographic characteristics, health status, and substance use disorders for comparison of current low-income Medicaid enrollees (N=3,809) with currently uninsured individuals with household incomes that may qualify them for Medicaid coverage beginning in 2014 (N=5,049). The incomes of the groups compared were 138% of the federal poverty level (133% provided in the ACA plus a 5% income "disregard" allowed by the law). RESULTS: The rate of substance use disorders among currently uninsured income-eligible individuals was slightly higher than the rate among current Medicaid enrollees (14.6% versus 11.5%, p=.03). Although both groups had significant unmet need for substance use disorder treatment, the treatment rate among those who needed treatment was significantly lower in the income-eligible group than in the currently enrolled group (31.3% versus 46.8%, p<.01). When the analysis excluded informal care received outside the medical sector, treatment rates among those with treatment needs were much lower in both groups (12.8% in the income-eligible group and 30.7% among current enrollees). CONCLUSIONS: Findings suggest that Medicaid insurance expansions under the ACA will reduce unmet need for substance use disorder treatment. PMID- 23450345 TI - Distinct roles of different fragments of PDCD4 in regulating the metastatic behavior of B16 melanoma cells. AB - Melanoma is an aggressive cutaneous malignancy. In this study, we demonstrated that the levels of the programmed cell death 4 (PDCD4) protein and mRNA were lower in tumor tissues compared with normal tissues. In order to further investigate the effects of PDCD4 and its fragments in B16 melanoma cells, we established B16 clones with expression of different PDCD4 fragments. Intact PDCD4, PDCD4?164-469 and PDCD4?327-440 expression, respectively, decreased proliferation and migration and increased apoptosis in B16 cells in vitro. We found that intact PDCD4, PDCD4?164-469 or PDCD4?327-440 can inhibit the activity of MMP-2 and the expression of CXCR4. However, PDCD4?164-275 showed no effects on B16 cells. These results may prove helpful for the development of novel therapies for melanoma treatment. PMID- 23450344 TI - Actin dosage lethality screening in yeast mediated by selective ploidy ablation reveals links to urmylation/wobble codon recognition and chromosome stability. AB - The actin cytoskeleton exists in a dynamic equilibrium with monomeric and filamentous states of its subunit protein actin. The spatial and temporal regulation of actin dynamics is critical to the many functions of actin. Actin levels are remarkably constant, suggesting that cells have evolved to function within a narrow range of actin concentrations. Here we report the results of screens in which we have increased actin levels in strains deleted for the ~4800 nonessential yeast genes using a technical advance called selective ploidy ablation. We detected 83 synthetic dosage interactions with actin, 78 resulted in reduced growth, whereas in 5 cases overexpression of actin suppressed the growth defects caused by the deleted genes. The genes were highly enriched in several classes, including transfer RNA wobble uridine modification, chromosome stability and segregation, cell growth, and cell division. We show that actin overexpression sequesters a limited pool of eEF1A, a bifunctional protein involved in aminoacyl-transfer RNA recruitment to the ribosome and actin filament cross-linking. Surprisingly, the largest class of genes is involved in chromosome stability and segregation. We show that actin mutants have chromosome segregation defects, suggesting a possible role in chromosome structure and function. Monomeric actin is a core component of the INO80 and SWR chromatin remodeling complexes and the NuA4 histone modification complex, and our results suggest these complexes may be sensitive to actin stoichiometry. We propose that the resulting effects on chromatin structure can lead to synergistic effects on chromosome stability in strains lacking genes important for chromosome maintenance. PMID- 23450346 TI - The effects of alar batten grafts on nasal airway obstruction and nasal steroid use in patients with nasal valve collapse and nasal allergic symptoms: a prospective study. AB - IMPORTANCE: Clinical management of nasal airway obstruction (NAO) in patients with and without nasal allergic symptoms and nasal valve collapse (NVC). OBJECTIVE: To examine the impact that autologous alar batten grafts have on patients with NAO owing to NVC and their affect on nasal steroid use and allergic symptoms. DESIGN: A prospective study. SETTING: Indiana University Medical Center, Indianapolis. PARTICIPANTS: Patients with NAO due to NVC with or without symptoms of nasal allergic symptoms. INTERVENTIONS: All of the patients had placement of autologous batten grafts during the study period. STUDY SELECTION: Prospective study of patients with dynamic NVC undergoing alar batten graft treatment. DATA EXTRACTION: Nasal Obstruction Symptom Evaluation survey preoperatively and postoperatively, prospective outpatient questionnaire to determine use of nasal steroids and presence of nasal allergic symptoms preoperatively and postoperatively. RESULTS: A total of 126 patients underwent surgical intervention for the treatment of NAO due to NVC. All of these patients were using nasal steroid sprays, and 78 patients (62%) also reported nasal allergic symptoms at their initial presentation. At 6-month and 1-year postoperative evaluations, 118 (94%) and 122 (97%), respectively, reported significant improvement of their NAO, regardless if they had presented with or without allergic nasal symptoms. Sixty-two of the 78 patients (79%) who initially presented with NAO owing to NVC and nasal allergic symptoms preoperatively reported significant improvement in their NAO and nasal allergic symptoms postoperatively. Eight of 126 (6%) restarted their use of nasal steroids postoperatively. All 8 of these patients reported nasal allergic symptoms preoperatively. No patients in the nonallergic group continued the use of nasal steroids postoperatively. There was no increase in nasal steroid use at the 12 month follow-up visit. CONCLUSIONS AND RELEVANCE: Nasal airway obstruction due to NVC in patients can be surgically treated with autologous alar batten grafts. In addition, the use of alar batten grafts may improve NAO in patients with nasal allergic symptoms and reduces their use of nasal steroids. These results support the idea of potential surgical repair of the nasal valve to treat patients with NAO due to nasal allergic symptoms and NVC. LEVEL OF EVIDENCE: 4. PMID- 23450347 TI - Toll-like receptor 2 is required for autoantibody production and development of renal disease in pristane-induced lupus. AB - OBJECTIVE: The mechanisms involved in breaking immunologic tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in nonautoimmune mice provided evidence of an important role of Toll-like receptor 2 (TLR-2) in antichromatin autoantibody induction by high mobility group box chromosomal protein 1-nucleosome complexes derived from apoptotic cells. The objective of this study was to investigate whether TLR-2 signaling is required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus. METHODS: Lupus like disease in C57BL/6 and TLR-2(-/-) mice was induced by pristane injection. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histologic analyses, and enzyme-linked immunospot assay. RESULTS: Pristane injected TLR-2(-/-) mice generated reduced numbers of splenic CD138+/cytoplasmic kappaL/lambdaL chain-positive plasma cells and displayed diminished IgG responses against double-stranded DNA, histones, nucleosomes, some extractable nuclear autoantigens, and cardiolipin when compared with wild- type controls. TLR-2 deficiency prevented the pristane-induced systemic release of interleukin-6 (IL 6) and IL-10. The absence of TLR-2 attenuated peritoneal recruitment of CD11c+ cells and formation of lipogranulomas. Importantly, the renal disease that developed in pristane-treated TLR-2(-/-) mice was less severe than that in control mice, as reflected by milder proteinuria, reduced glomerular deposition of IgG and complement, and decreased renal infiltration of autoantibody-secreting cells. CONCLUSION: TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE. PMID- 23450348 TI - [Acute disseminated encephalomyelitis]. PMID- 23450349 TI - [Mammography - the influence of contrast enhancement]. PMID- 23450350 TI - [CT-colonoscopy - computer-aided diagnosis]. PMID- 23450351 TI - [Suspicious pulmonary findings - digital tomosynthesis can save ct]. PMID- 23450352 TI - [Detection of incorporated cocaine-ct more reliable than conventional radiography]. PMID- 23450353 TI - [Vein thrombosis in hormonally inactive neuroendocrine pancreatic tumors confirmation may affect surgical planning]. PMID- 23450354 TI - [Nerve compression in trigeminal neuralgia-with high -resolution mri anatomical structures are clearly visible]. PMID- 23450355 TI - [Complex renal cysts-assessment using dual-source two spectra ct]. PMID- 23450356 TI - [Fibrotic idiopathic interstitial pneumonia - the extent of pulmonary fibrosis predicts survival]. PMID- 23450357 TI - [Radiogenomic analysis in breast cancer using mri - a new approach to the understanding of the underlying molecular biology]. PMID- 23450359 TI - ["Radiology is the future" - 94th German Roentgen Congress 20 May to 1 June - FFF, continuing specialty education, DeGIR/DGNR - certification, MTRA program]. PMID- 23450363 TI - [Minister of Science Schulze awards the Merit Cross to Prof. Otmar Schober]. PMID- 23450366 TI - Health providers' perceptions of novel approaches to visualizing integrated health information. AB - OBJECTIVES: We evaluated the design of three novel visualization techniques for integrated health information with health care providers in older adult care. Through focus groups, we identified generalizable themes related to the visualization and interpretation of health information. Using these themes we address challenges with visualizing integrated health information and provide recommendations for designers. METHODS: We recruited ten health care providers to participate in three focus groups. We applied a qualitative descriptive approach to code and extract themes related to the visualization of graphical displays. RESULTS: We identified a set of four common themes across focus groups related to: 1) Trust in data for decision-making; 2) Perceived level of detail for visualization (subthemes: holistic, individual components); 3) Cognitive issues (subthemes: training and experience; cognitive overload; contrast); and 4) Application of visual displays. Furthermore, recommendations are provided as part of the iterative design process for the visualizations. CONCLUSIONS: Data visualization of health information is an important component of care, impacting both the accuracy and speed of decision making. There are both functional and cognitive elements to consider during the development of appropriate visualizations that integrate different components of health. PMID- 23450367 TI - Use of intervention strategies by assertive community treatment teams to promote patients' engagement. AB - OBJECTIVE: This study explored the range of interventions and the use of more intrusive techniques by staff of assertive community treatment (ACT) teams to promote engagement, manage problem behaviors, and reinforce positive behaviors among patients. Individual and organizational characteristics that may be associated with these practices were identified. METHODS: Between January and March 2006, clinicians (N=239) from 34 ACT teams participated in a one-time survey about their intervention strategies with patients, perceptions about the ACT team environment, and beliefs about persons with severe mental illness. RESULTS: Significant variation existed in the types of interventions employed across teams. The less intrusive strategies, including positive inducements and verbal guidance, were the most common. Other strategies that placed limits on patients but that were still considered less intrusive-such as medication monitoring and money management-were also common. Clinicians who reported working in more demoralized climates and having negative perceptions of mental illness were more likely to endorse leveraged or intrusive interventions. CONCLUSIONS: The findings of this study suggest significant variation across teams in the use of intervention strategies. Both perceptions of a demoralized organizational climate and stigmatizing beliefs about mental illness were correlated with the use of more intrusive intervention strategies. Future research on the role and appropriateness of more intrusive interventions in mental health treatment and the impact of such interventions on patient outcomes is warranted. PMID- 23450368 TI - The hepatitis B virus X protein downregulates NF-kappaB signaling pathways through decreasing the Notch signaling pathway in HBx-transformed L02 cells. AB - Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma, which has been found to be associated with Notch and NF kappaB signaling. This study aimed to investigate the crosstalk between Notch and NF-kappaB pathways in HBx-related hepatocellular carcinoma. An HBx-transformed non-tumor hepatic cell line L02 (L02/HBx) was previously established. Immunofluorescence assays were performed to visualize HBx and the Notch intracellular domain (NICD) in cell nuclei. Co-immunoprecipitation assays were used to investigate physical interactions between HBx and components of the Notch signaling pathway (NICD and JAG1), NF-kappaB signaling pathway (p65 and p50) or IkappaBalpha. L02/HBx cells were treated with the Notch signal inhibitor DAPT or Notch1 siRNA to inhibit the Notch1 pathway. qRT-PCR was used to quantify the expression of the p65, p50 and IkappaBalpha genes. Protein expression changes in cytoplasm and nuclei after treatment with DAPT or Notch1 siRNA were analyzed by western blotting and EMSA assays. We found that HBx directly regulated Notch1 signaling, which cross-talked with the NF-kappaB pathway. Downregulation of Notch1 decreased the binding of NF-kappaB p65 to its target gene promoter, reduced NF-kappaB expression and enhanced IkappaBalpha expression. The results suggest that HBx functions through the Notch signaling pathway; Notch contributes to hepatocarcinogenesis partially by regulating the NF-kappaB pathway. Our findings provide new insights into the role of Notch and NF-kappaB signaling in the progression of hepatocellular carcinoma related to HBx. PMID- 23450370 TI - APhA2013 abstracts of contributed papers. PMID- 23450369 TI - Thiol-yne radical reaction mediated site-specific protein labeling via genetic incorporation of an alkynyl-L-lysine analogue. AB - Three alkyne-containing pyrrolysine derivatives were synthesized and genetically encoded into proteins by a mutant PylRS-tRNA pair with high efficiencies. With these alkyne handles, site-specific dual labeling of proteins can be achieved via a bioorthogonal thiol-yne ligation reaction. PMID- 23450371 TI - [Misplacement of central venous catheters in the subclavian artery: safe retrieval with a percutaneous closure device (AngioSeal)]. AB - PURPOSE: To evaluate the feasibility of retrieval of misplaced central venous catheters in the subclavian artery with a percutaneous closure device (AngioSeal). MATERIALS AND METHODS: According to the radiologic information system of a university hospital, 7 patients (6 women, 1 child) underwent removal of a misplaced central venous catheter (4 * 7 F, 1 * 8 F, 2 * 13 F) in the subclavian artery between January 2008 and June 2012 with the 8 F percutaneous closure device AngioSeal. The body mass index (BMI) of 7 patients was available, 3 of whom were obese (BMI 2 * 35.7 and 1 * 33.0). Both 13 F catheters were removed in a balloon-supported manner as described elsewhere. The Broviak catheter of a 21-month-old boy was removed by surgical support with preparation of the catheter to its vessel entry. Success control was done by a transfemoral DSA in 5 of the 7 patients. 2 patients received clinical follow-up. RESULTS: In all cases the misplaced catheter could be removed successfully. In all 7 patients, there was no arterial bleeding after catheter removal. Complications were not observed. CONCLUSION: Removal of misplaced central venous catheters in the subclavian artery by the percutaneous closure device AngioSeal is safe. Percutaneous catheter removal should be regarded as the method of choice, even in obese patients. PMID- 23450372 TI - [Iron quantification in iron overload disease using MRI]. AB - Iron as an essential nutrient is involved in multiple metabolic activities. The importance of a sufficient iron supply is stressed by the fact that, according to WHO data, about 30 % of the global population suffers from iron deficiency and resulting anemia. In contrast, hereditary hemochromatosis is the most common monogeneous inherited disease (prevalence of homozygous genotype 1:200 - 300 in Germany). While iron-induced anemia can be handled by relatively simple diagnostic and therapeutic management, the diagnosis and quantification of organ iron overload is far more challenging. This is of great clinical impact, as the overall body and organ iron concentration is the crucial prognostic parameter in iron overload disease. In 2001 the international workshop of NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) concluded that a quantitative, noninvasive, safe, and accurate approach for the assessment of body iron storage is needed to improve the diagnosis and management of patients with iron overload. PMID- 23450373 TI - Prefabrication of vascularized bone graft using an interconnected porous calcium hydroxyapatite ceramic in presence of vascular endothelial growth factor and bone marrow mesenchymal stem cells: Experimental study in rats. AB - OBJECTIVES: The purpose of this experimental pilot study was to create a prefabricated vascularized bone graft using interconnected porous calcium hydroxyapatite ceramic (PCHC) block by combining vascular bundle implantation, rat bone marrow mesenchymal stem cells and administration of vascular endothelial growth factor (VEGF) in a rat model. MATERIALS AND METHODS: Sixty male Sprague Dawley rats were used. Experimental animals were divided into six groups, each of which comprised 10 rats. The PCHC blocks were implanted in the medial thigh region in groups I, III, and V without vascular bundle implantation. The PCHC blocks were vascularized by the superficial inferior epigastric artery and vein in groups II, IV and VI. These vessels were passed through the hole of the PCHC blocks. Mesenchymal stem cells were administered into the PCHC in groups III, IV, V and VI. In addition, both mesenchymal stem cells and VEGF were administered in group V and VI. The presence and density of any new bone formation and neovascularization from the vascular bundle was evaluated by X-ray, microangiography, scintigraphy, biochemical analysis and histomorphometry. RESULTS: The newly formed vessels and bone formations were significantly greater in group VI, in which both mesenchymal stem cells and VEGF were applied. CONCLUSION: THIS PRELIMINARY STUDY SUGGESTS THAT: Both mesenchymal stem cells and VEGF provide vascularized bone prefabrication by enhancing neovascularization and osteogenesis in a shorter time compared to only VEGF application. PMID- 23450374 TI - Exploiting online discussions to discover unrecognized drug side effects. AB - BACKGROUND: Drugs can treat human diseases through chemical interactions between the ingredients and intended targets in the human body. However, the ingredients could unexpectedly interact with off-targets, which may cause adverse drug side effects. Notifying patients and physicians of potential drug effects is an important step in improving healthcare quality and delivery. OBJECTIVE: With the increasing popularity of Web 2.0 applications, more and more patients start discussing drug side effects in many online sources. These online discussions form a valuable source for mining interesting knowledge about side effects. The main goal of this paper is to investigate the feasibility of exploiting these discussions to discover unrecognized drug side effects. METHODS: We propose methods that can 1) build a knowledge base for drug side effects by automatically integrating the information related to drug side effects from different sources; and 2) monitor online discussions about drugs and discover potential unrecognized drug side effects. RESULTS: Experiment results show that the online discussions indeed provide useful information discovering unrecognized drug side effects. We find that the integrated knowledge base contains more information than individual online sources. Moreover, both proposed detection methods can identify the side effects related to the four recently recalled drugs, and the information from online discussions makes it possible to make the detection much earlier than official announcements. Finally, the proposed generative modeling method is shown to be more effective than the discriminative method. CONCLUSIONS: We find that it is possible to monitor online discussions to detect unrecognized drug side effects. The developed system is expected to serve as a complementary tool for drug companies and FDA to receive feedbacks from the patients, and it has the potentials to expedite the discovery process of unrecognized drug side effects and to improve the quality of healthcare. PMID- 23450375 TI - Current and future funding sources for specialty mental health and substance abuse treatment providers. AB - OBJECTIVES: Goals were to describe funding for specialty behavioral health providers in 1986 and 2005 and examine how the recession, parity law, and Affordable Care Act (ACA) may affect future funding. METHODS: Numerous public data sets and actuarial methods were used to estimate spending for services from specialty behavioral health providers (general hospital specialty units; specialty hospitals; psychiatrists; other behavioral health professionals; and specialty mental health and substance abuse treatment centers). RESULTS: Between 1986 and 2005, hospitals-which had received the largest share of behavioral health spending-declined in importance, and spending shares trended away from specialty hospitals that were largely funded by state and local governments. Hospitals' share of funding from private insurance decreased from 25% in 1986 to 12% in 2005, and the Medicaid share increased from 11% to 23%. Office-based specialty providers continued to be largely dependent on private insurance and out-of-pocket payments, with psychiatrists receiving increased Medicaid funding. Specialty centers received increased funding shares from Medicaid (from 11% to 29%), and shares from other state and local government sources fell (from 64% to 46%). CONCLUSIONS: With ACA's full implementation, spending on behavioral health will likely increase under private insurance and Medicaid. Parity in private plans will also push a larger share of payments for office-based professionals from out-of-pocket payments to private insurance. As ACA provides insurance for formerly uninsured individuals, funding by state behavioral health authorities of center-based treatment will likely refocus on recovery and support services. Federal Medicaid rules will increase in importance as more people needing behavioral health treatment become covered. PMID- 23450376 TI - Evaluation of polyhexamethylene biguanide (PHMB) as a disinfectant for adenovirus. AB - IMPORTANCE: Swimming pools can be a vector for transmission of adenovirus ocular infections. Polyhexamethylene biguanide (PHMB) is a disinfectant used in swimming pools and hot tubs. OBJECTIVE: To determine whether PHMB is an effective disinfectant against ocular adenovirus serotypes at a concentration used to disinfect swimming pools and hot tubs. DESIGN: In vitro laboratory study. INTERVENTIONS: The direct disinfecting activity of PHMB was determined in triplicate assays by incubating 9 human adenovirus types (1, 2, 3, 4, 5, 7a, 8, 19, and 37) with PHMB concentrations of 50 and 0 ppm (micrograms per milliliter) for 24 hours at room temperature to simulate swimming pool temperatures or 40oC to simulate hot tub temperatures. MAIN OUTCOME MEASURES: Plaque assays were performed to determine adenovirus titers after incubation. Titers were log10 converted and mean (SD) log10 reductions relative to controls were calculated. Virucidal (>99.9%) decreases in mean adenovirus titers after PHMB treatment were determined for each adenovirus type and temperature tested. RESULTS At room temperature, 50 ppm of PHMB produced mean reductions in titers less than 1 log10 for all adenovirus types tested. At 40 degrees C, 50 ppm of PHMB produced mean reductions in titers less than 1 log10 for 2 adenovirus types and greater than 1 but less than 3 log10 for 7 of 9 adenovirus types. CONCLUSIONS AND RELEVANCE: At a concentration of 50 ppm, PHMB was not virucidal against adenovirus at temperatures consistent with swimming pools or hot tubs. Recreational water maintained and sanitized with PHMB can serve as a vector for the transmission of ocular adenovirus infections. PMID- 23450377 TI - The use of CEUS in the diagnosis of retinal/choroidal detachment and associated intraocular masses - preliminary investigation in patients with equivocal findings at conventional ultrasound. AB - PURPOSE: To investigate whether contrast-enhanced ultrasound (CEUS) may help to diagnose retinal/choroidal detachment and may help to differentiate intraocular lumps in cases with equivocal features on conventional grayscale and Doppler modes. MATERIALS AND METHODS: The institutional review board approved this retrospective study. The need for informed consent was waived. A computerized data search was performed in the database of our institution for patients with vitreous hemorrhage who underwent CEUS of the eye to assess retinal/choroidal detachment and/or associated masses. This process yielded a total of 31 patients (18 men, 13 women, age range: 39 - 88 years) in whom CEUS was performed because the findings on conventional grayscale and Doppler modes were equivocal. CEUS was performed using low acoustic power contrast-specific modes. A 2.4 - 4.8 mL bolus of SonoVue was injected, followed by a saline flush. All examinations were digitally recorded for retrospective analysis. Confirmation of CEUS findings was obtained at surgery (n = 20) or with binocular indirect fundoscopy performed after clearance of the ocular media (n = 11). Two readers with different levels of ultrasound experience independently reviewed the imaging features. A five degree scale ranging from definitely absent (score 1) to definitely present (score 5) was used to assess the presence or absence of retinal/choroidal detachment on conventional ultrasound modes alone and with the addition of CEUS. ROC curve analysis was performed to assess the diagnostic accuracy of both methods. The inter-reader agreement was also evaluated. In patients with associated intraocular lumps, conventional Doppler modes and CEUS were used to differentiate non-tumor masses from tumor masses. RESULTS: According to the reference standard, 13 patients had retinal detachment, 4 had choroidal detachment, and 3 had both retinal and choroidal detachment. There were 8 associated intraocular lumps (4 subretinal hemorrhages, 3 malignant melanomas, 1 metastasis). The inter-reader agreement was good (K = 0.644) and very good (K = 0.833) for conventional modes and CEUS, respectively. The diagnostic performance of CEUS was high for both readers (area +/- standard error under the ROC curve: 0.966 +/- 0.031 and 0.900 +/- 0.055 for readers 1 and 2, respectively). There were 2 false-positive results and 1 false-negative result in patients with proliferative diabetic retinopathy. CEUS was effective in differentiating subretinal hemorrhage from hypovascular tumors. CONCLUSION: CEUS can be used as a problem-solving technique when conventional ultrasound modes are not diagnostic for retinal/choroidal detachment and when intraocular lumps cannot be characterized as tumor or non-tumor masses on conventional modes. The evaluation of patients with proliferative diabetic retinopathy, however, may be problematic. PMID- 23450378 TI - The role of taxonomies in social media and the semantic web for health education. A study of SNOMED CT terms in YouTube health video tags. AB - BACKGROUND: An increasing amount of health education resources for patients and professionals are distributed via social media channels. For example, thousands of health education videos are disseminated via YouTube. Often, tags are assigned by the disseminator. However, the lack of use of standardized terminologies in those tags and the presence of misleading videos make it particularly hard to retrieve relevant videos. OBJECTIVES: i) Identify the use of standardized medical thesauri (SNOMED CT) in YouTube Health videos tags from preselected YouTube Channels and demonstrate an information technology (IT) architecture for treating the tags of these health (video) resources. ii) Investigate the relative percentage of the tags used that relate to SNOMED CT terms. As such resources may play a key role in educating professionals and patients, the use of standardized vocabularies may facilitate the sharing of such resources. iii) Demonstrate how such resources may be properly exploited within the new generation of semantically enriched content or learning management systems that allow for knowledge expansion through the use of linked medical data and numerous literature resources also described through the same vocabularies. METHODS: We implemented a video portal integrating videos from 500 US Hospital channels. The portal integrated 4,307 YouTube videos regarding surgery as described by 64,367 tags. BioPortal REST services were used within our portal to match SNOMED CT terms with YouTube tags by both exact match and non-exact match. The whole architecture was complemented with a mechanism to enrich the retrieved video resources with other educational material residing in other repositories by following contemporary semantic web advances, in the form of Linked Open Data (LOD) principles. RESULTS: The average percentage of YouTube tags that were expressed using SNOMED CT terms was about 22.5%, while one third of YouTube tags per video contained a SNOMED CT term in a loose search; this analogy became one tenth in the case of exact match. Retrieved videos were then linked further to other resources by using LOD compliant systems. Such results were exemplified in the case of systems and technologies used in the mEducator EC funded project. CONCLUSION: YouTube Health videos can be searched for and retrieved using SNOMED CT terms with a high possibility of identifying health videos that users want based on their search criteria. Despite the fact that tagging of this information with SNOMED CT terms may vary, its availability and linked data capacity opens the door to new studies for personalized retrieval of content and linking with other knowledge through linked medical data and semantic advances in (learning) content management systems. PMID- 23450380 TI - Engaging to improve engagement. PMID- 23450379 TI - Functional outcome following intramedullary nailing or plate and screw fixation of paediatric diaphyseal forearm fractures: a systematic review. AB - PURPOSE: Unstable paediatric diaphyseal both-bone forearm fractures requiring fixation have traditionally been treated with rigid internal fixation with plate and screws. Intramedullary stabilisation has grown in popularity over the last 25 years but may be associated with rotational deformity and subsequent loss of pronosupination. This systematic review aims to establish which treatment method provides better functional outcome. METHODS: A systematic review of the published literature was performed, searching Medline, Embase, Pubmed and the Cochrane Library for English-language studies comparing intramedullary nailing with plate and screws in patients less than 18 years old with both-bone diaphyseal forearm fractures. RESULTS: Seven studies met the inclusion criteria. They were all retrospective comparative studies (level III or IV). One was age- and sex matched. Three looked specifically at older children. No study reported a significant difference in functional outcome with either treatment. CONCLUSIONS: The currently available literature shows no difference in functional outcome between intramedullary nailing and plate and screw fixation, even in older children with less remodelling potential. Intramedullary nailing may therefore be the treatment of choice for simple fracture patterns due to shorter operative time, better cosmesis and ease of removal. Plating may still have a role in more complex injuries. PMID- 23450382 TI - Antidepressant use in the European union: perceived indications and patterns. PMID- 23450383 TI - The feasibility of standardized patient assessments as a best practice in an academic training program. AB - The use of standardized patient assessments (SPAs) in psychiatry is an emerging best practice. This column describes a survey of resident and faculty supervisors at a large academic department examining current practices, attitudes, and perceived barriers to incorporating SPAs into clinical practice. Although the study found that SPAs were not routinely used in clinical practice or supervision, residents and faculty were fairly optimistic about their potential value. The results suggest that educational initiatives should be integrated into clinical practice, start early within training, include both trainees and faculty supervisors, and set use of SPAs as an expected standard of care. PMID- 23450384 TI - Recovery constructs and the continued debate that limits consumer recovery. AB - It is generally agreed that the concept of recovery is the result of two primary influences: longitudinal studies and the work, writing, perspectives, and advocacy of the consumer-survivor movement. To clarify what is actually meant by recovery, investigators have compared and contrasted the constructs being conveyed through each primary influence. This process has resulted in the proposal of two main taxonomies-"recovery from" as opposed to "recovery in" and "recovery as an outcome" as opposed to "recovery as a process." The author draws on her experience as a consumer to examine the efficacy of distinguishing the recovery constructs in each of these ways, concluding that both taxonomies limit the consumer recovery paradigm in a way that is neither valid nor helpful. It is essential to the progress of recovery-based services that the mental health field avoid the trap of a dualistic, either-or approach to recovery that was once so prevalent. PMID- 23450385 TI - Treatment-seeking barriers for veterans of the Iraq and Afghanistan conflicts who screen positive for PTSD. AB - OBJECTIVES: Barriers associated with the decision not to seek treatment for symptoms of combat-related posttraumatic stress disorder (PTSD) were examined. METHODS: Participants were 143 military men and women who served in Operation Enduring Freedom or Operation Iraqi Freedom (OEF/OIF) and who screened positive for posttraumatic stress disorder (PTSD), as assessed by the PTSD Checklist Military Version, and who had not sought treatment for PTSD. During a cognitive behavioral telephone intervention, participants were asked about their beliefs concerning seeking PTSD treatment. RESULTS: Four categories of beliefs were associated with the decision to seek treatment, including concerns about treatment (40%), emotional readiness for treatment (35%), stigma (16%), and logistical issues (8%). CONCLUSIONS: This work suggests areas for intervention efforts to minimize barriers to treatment for PTSD for OEF/OIF veterans. PMID- 23450386 TI - Public stigma associated with psychosis risk syndrome in a college population: implications for peer intervention. AB - OBJECTIVES: This study compared stigma associated with the psychosis risk label and diagnostic labels for nonpsychotic and psychotic mental disorders among young adult peers. METHODS: Urban college respondents (N=153) read an experimental vignette describing a young adult experiencing prodromal symptoms who was randomly assigned a diagnostic label (major depression, generalized anxiety disorder, schizophrenia, or psychosis risk with and without accurate information about the psychosis risk label) and answered questions about stigma toward the individual in the vignette. RESULTS: Compared with labels for nonpsychotic disorders, schizophrenia elicited more negative stereotyping and the at-risk label invoked greater social distance and less willingness to help. Any increased social distance appeared to be reduced by accurate information about the at-risk state. No differences in stigma were found for the psychosis risk and schizophrenia labels. CONCLUSIONS: The psychosis risk label alone appeared to evoke greater status loss and discrimination. Accurate information may minimize some stigmatizing attitudes among college peers. PMID- 23450387 TI - Rainbow beneath the sky: mental health help for Chinese Americans. PMID- 23450388 TI - Concurrent care at an academic psychiatric hospital. PMID- 23450389 TI - Kaiser 50-state Medicaid survey finds states gearing up for 2014. PMID- 23450391 TI - Ocular complications in children within 1 year after hematopoietic stem cell transplantation. AB - IMPORTANCE: It is essential to have insights into the risk of ocular involvement after hematopoietic stem cell transplantation (HSCT) in the pediatric population because young and severely ill children are unaware of their ocular problems. OBJECTIVE: To study the development of ocular complications in children within 1 year after HSCT. DESIGN AND SETTING: This prospective study includes all consecutive patients who had undergone an HSCT at the Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands, in 2009 and 2010. PARTICIPANTS: Forty-nine consecutive patients underwent systematic ophthalmologic evaluations before HSCT, before leaving the HSCT unit after HSCT, and 3, 6, and 12 months after HSCT. Additional examinations were performed during systemic viral reactivations. MAIN OUTCOME MEASURE: Development of ocular complications, including uveitis, hemorrhagic complications, optic disc edema, and dry eye syndrome. RESULTS: Thirteen patients (27%) developed an ocular complication after HSCT. These complications included DES (n = 7 [14%]), (sub)retinal hemorrhage (n = 6 [12%]), optic disc edema (n = 3 [6%]), chorioretinal lesions (n = 2 [4%]), vitritis (n = 1 [2%]), and increased intraocular pressure (n = 1 [2%]). Median time to the development of dry eye syndrome was 5 months after HSCT, whereas all other ocular complications were detected within the first 3 months after HSCT. In most cases, the symptoms were mild and self-limiting. Children with malignant disease had a higher risk of the development of ocular complications compared with children with nonmalignant disease. CONCLUSIONS AND RELEVANCE: Ocular complications in pediatric HSCT patients are common, although mostly mild. The risk of viral uveitis development during systemic viral reactivations is low; however, the potential risk of vision threatening complications in this population cannot be ruled out. PMID- 23450392 TI - Interaction between cAMP, volume-regulated anion channels and the Na+-HCO3- cotransporter, NBCe1, in the regulation of nutrient- and hypotonicity-induced insulin release from isolated rat pancreatic islets and tumoral insulin-producing BRIN-BD11 cells. AB - Soluble adenylyl cyclase (sAC) has been hypothesized to play a role in insulin secretion. The present study aimed to investigate the interaction between adenosine 3',5'-cyclic monophosphate (cAMP), volume-regulated anion channels (VRACs) and the electrogenic sodium bicarbonate (Na+-HCO3-) cotransporter, NBCe1, in the regulation of nutrient- and hypotonicity-induced insulin release from rat pancreatic islets and tumoral insulin-producing BRIN-BD11 cells. In the islets, 5 nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and 5-chloro-2-hydroxy-3 (thiophene-2-carbonyl)indole-1-carboxamide (tenidap) reduced glucose-stimulated insulin release, however, only NPPB suppressed the enhancing action of cAMP analogs upon such a release. Insulin output from the BRIN-BD11 cells was stimulated by 2-ketoisocaproate (KIC) or extracellular hypoosmolarity. cAMP analogs and 3-isobutyl-1-methylxanthine increased the insulin output recorded in the isotonic medium to a greater relative extent than that in the hypotonic medium. The secretory response to KIC or hypotonicity was inhibited by NPPB or tenidap, which both also opposed the enhancing action of cAMP analogs. Inhibitors of mitogen-activated protein (MAP) kinase decreased insulin output in isotonic and hypotonic media. The inhibitor of sAC, 2-hydroxyestriol, caused only a modest inhibition of insulin release, whether in the isotonic or hypotonic medium, even when tested at a concentration of 100 uM. The omission of NaHCO3 markedly decreased the secretory response to KIC or extracellular hypotonicity. The omission of Na+ suppressed the secretory response to extracellular hypotonicity. The observations of the present study do not support the hypothesis of a major role for sAC in the regulation of insulin release. PMID- 23450393 TI - [Prof. Dr. Dr. h. c. Karl-Walter Jauch -- chairman of the German Society of Surgery 2012/2013]. PMID- 23450394 TI - [Pancreatic anastomosis -- a video comparison of different techniques]. AB - INTRODUCTION: The pancreatic anastomosis seems to be the most difficult and dangerous anastomosis in general surgery, especially in a soft pancreas. Many techniques have been described. The techniques most often used are: anastomosis of the pancreas to the jejunum as a pancreatico-jejunostomy (duct-to-mucosa anastomosis) or as a pancreato-jejunostomy (invaginating anastomosis). Another widely used anastomosis for reconstruction after pancreatic head resection is from the stomach to the pancreas, i.e., pancreato-gastrostomy. In literature the data concerning postoperative complications (pancreatic fistula, postoperative bleeding and others) are not consistent. INDICATIONS: Reconstruction after pancreatic head resection. PROCEDURE: Anastomosis between small intestine or stomach and the pancreas. CONCLUSION: There is no gold standard for pancreatic anastomosis. Thus, of the different commonly used techniques, in our opinion, the best technique for each surgeon seems to be the one that he/she is most familiar with. PMID- 23450395 TI - ["Surgery with passion and good judgment"]. PMID- 23450396 TI - [Interventional radiological procedures in the therapy for colorectal liver metastases]. AB - Microtherapeutic procedures performed by interventional radiologists pose a viable alternative or additive to systemic chemotherapy for local tumour control in cases of non-operable (for technical, functional, and comorbidity reasons or at the patient's wish) liver metastases. A main focus includes local therapies such as radiofrequency ablation and interstitial brachytherapy which are performed under ultrasound, CT or MRI guidance to achieve a thermal or radiogenic ablation of the malignancy. Although highly effective, these procedures are limited to oligonodular manifestations. For disseminated metastases, locoregional techniques like the yttrium-90 radioembolisation have become established. Here, the active principle in the form of radioactively labelled microspheres is introduced into the liver through an arterial catheter under angiographic guidance. The present article focuses on metastases of colorectal cancer as the most frequent tumour entity encountered in interventional radiotherapy. PMID- 23450397 TI - [Occupational medicine aspects in general and abdominal surgery -- risk of infection attributable to needlestick injuries (what the surgeon should know)]. AB - Needlestick, stab, scratch, and cut injuries are a common problem and a significant health hazard among healthcare workers. The aim of this review is to give an overview on the risk of infection in general, abdominal and vascular surgery and to suggest occupational safety measures. Furthermore, we want to discuss insurance-related aspects. If medical devices are contaminated with blood or other body fluids, there is a relevant risk of infection with hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The risk of transmission depends on the infection status of the patient, and on the immune status of the healthcare worker. In addition, the risk of infection is affected by the type and severity of injuries, by the quantity (volume) of blood, the time between injury and cleaning, and the administration of post-exposure prophylaxis. Prevention measures are an important focus in occupational medicine. Comprehensive programmes to prevent injuries (usage of safety devices, surgical gloves, and of disposal containers) have to be continuously considered to minimize risk of infection of healthcare workers. PMID- 23450398 TI - [Work strain by anaesthetic gas and surgical smoke due to tissue coagulation as well as safety measures in surgical operating rooms - what the surgeon needs to know]. AB - Exposure of the respiratory tract during surgical interventions is an important topic of occupational medicine, which has only rarely been investigated. Based on a literature search, relevant information on the possible health risk is summarised. Within the operating room, an exposure of the respiratory tract to gas (volatile anaesthetics) and aerosols (smoking gas by coagulation) can occur. This exposure needs to be considered as a potential health risk if safety measures are not sufficient. Health risks comprise possible disturbances of gravidity and fertility, neurotoxicity and cancer generation. Such health risks can be prevented with primary preventive measures and can be early recognised/diagnosed by preventive investigations of occupational medicine (secondary prevention). Safety measures are developed according to the STOP principle (substitution, technical, organisatory and personal measures). Assessment of the potential danger begins with an appropriate description of the working procedure and detection of the toxic features of the drugs and medical products, which helps to determine individual exposure and to estimate risk potential. Required occupational safety measures can be derived from this and, subsequently, the work organisation can be optimised. In addition, employees in the operating room are to be instructed about the indicated preventive mode of behaviour. Due to better implementation of the above-mentioned basic principles, introduction of novel narcotics and technological developments, potential exposure of the respiratory tract within the operating room has been reduced over the last 10 years. Thus, risks for gravidity and possible disturbances of fertility by exposure to volatile narcotics are currently assessed to be low. However, available data on health risks of the chronic exposure to smoking gases are still deficient although toxic and cancerogenic organic pyrolysis products are generated. The protection effect of modern air conditioning (e.g., laminar air flow) is only insufficiently investigated. Therefore, further studies on these problems are required. PMID- 23450400 TI - [Off to pastures new]. PMID- 23450401 TI - [100 years resection of the complete trachea]. PMID- 23450402 TI - [Injuries to the tracheo-bronchial tree]. AB - Tracheobronchial injuries are rare events but often life-threatening. A great expertise in the field of thoracic surgery is necessary to manage these events. The aetiology of the injury - traumatic or iatrogenic - allows immediate considerations about the pattern of damage. The flexible or rigid bronchoscopy is the central diagnostic procedure to classify the injury. Whereas iatrogenic tracheal lacerations can be treated by conservative or operative means depending on severity, traumatic injuries of the tracheo-bronchial system need technically challenging operative reconstructions in almost every case. PMID- 23450403 TI - [Potential influence of recent modifications in Chilean legislation for medical research]. PMID- 23450404 TI - [Patient readmission for surgical site infection: integrative review]. AB - BACKGROUND: Surgical site infections (SSI) represent an inherent risk after surgical procedures associated both to the surgical procedure and to the patient clinical conditions. AIM: To analyze in an integrative review the studies related to patient readmission due to SSI. MATERIAL AND METHOD: The review was carried out by LILACS, CINHAL, MEDLINE and COCHRANE databases and articles published from 1966 to 2010 were selected. RESULTS: It was analyzed 13 studies classified as transversal (7), cohort (4) and longitudinal (2). Few studies analyzed only the readmissions related to the SSI. Time to define the readmission ranged from 28 to 90 days after surgery and studies related to orthopedic procedures were more frequent. The ISS readmission rates were lower than 5%. The main aetiological agents isolated from ISS were Staphylococcus aureus and coagulase-negative staphylococci. CONCLUSION: Monitoring readmissions due to SSI could contribute to dimension the occurrence of ISS post-discharge, once about half of the SSI post discharge was diagnosed at the readmission moment. PMID- 23450405 TI - [Detection of virulence genes in aminoglycoside susceptible and resistant Enterococcus faecalis]. AB - BACKGROUND: Enterococcus spp. is an important cause of nosocomial infections A number of virulence factors that may enhance its ability to colonize have been described. Enterococcus is capable of acquiring resistance genes, including high level resistance (HLR) to aminoglycoside antibiotics. AIM: to investigate the prevalence of genes encoding virulence factors in aminoglycosides susceptible and resistant E. faecalis. MATERIALS AND METHODS: A total of 80 E. faecalis isolates from clinical (n: 52) and poultry samples (n: 28) were included in this study. Bacterial identification was performed by biochemical tests and phenotypificationwas done using the Phene-PlateTM system. Susceptibility to different antimicrobial agents was determined by the agar dilution method. Virulence genes aceI, agg, gelE and efaA were detected by multiplex PCR. RESULTS: All isolates were susceptible to vancomycin and ampicillin. HLR to gentamicin (13.5%) and streptomycin (9.6%) was detected only in clinical isolates. The phenotyping revealed a great diversity of PhP-types, but only one clone with 7 strains of similar characteristics was found. The efaA gen was detected in 100% of the isolates. aceI gene was present in 94.2% and 75%, agg gene in 73.1%, and 67.9%, and gelE gene in 57.5% and 28.6% of the clinical and chicken isolates, respectively. Only 6 strains with HLR to aminoglycosides, belonging to the same phenotype, had the aceI, agg, gelE and efaA genes. CONCLUSIONS: E. faecalis with virulence genes and HLR to aminoglycosides were isolated from clinical and chicken samples in Antofagasta. More studies will be necessary to establish an association. PMID- 23450406 TI - [Lymphomas associated with HIV infection in patients at the Hospital San Borja Arriaran /Fundacion Arriaran 2001-2008, Santiago, Chile]. AB - INTRODUCTION: Hodgkin lymphomas (HL) and non Hodgkin lymphomas (NHL) are frequently associated to acquired immunodeficiency syndrome in adults. OBJECTIVE: To systematize the clinical features and histological characteristics of lymphomas in AIDS patients, its treatment and outcomes in our institution. PATIENTS AND METHODS: Retrospective analysis of patients with HIV-associated lymphoma between January 2001 and December 2008 at the San Borja Arriaran Hospital complex. RESULTS: Information was obtained from 30 patients with NHL and 7 with HL, with a median of 40 years. The majority of tumors were Burkitt lymphoma (47%), diffuse large cell lymphoma B-cell (37%) and NHL of T lineage (10%). There was no CNS or cavities lymphoma. Almost all patients (86.7%) with NHL were treated with CHOP chemotherapy, 57% of those receiving treatment had progression or relapse from complete remission. A rescue chemotherapy was indicated in 4 patients. 73% of patients receiving CHOP, complete 5 to 6 cycles of chemotherapy. The use of CHOP chemotherapy for the subgroup of patients with Burkitt lymphoma achieved low rates of complete remission and frequent relapse and disease progression, showing that CHOP was ineffective in improving survival, especially in high risk patients. We found statistically significant differences in survival according to IPIae (International prognostic Index age-adjusted). CONCLUSION: Non-Hodgkin lymphoma in HIV patients treated with chemotherapy protocols PAlNDA persists in our environment as a disease with a poor prognosis compared with findings in the international literature. The incorporation of new drugs of proven utility as rituximab and specific schemes chemotherapy could improve these results. The establishment of prognostic groups established by IPIae can guide clinical work for the use of chemotherapy tailored to their specific risk and optimized according to histological type. PMID- 23450407 TI - [Interaction between HIV-1 and GB virus type-C during coinfection status]. AB - The human immunodeficiency virus (HIV) infection is one of the most important problems in public health. It is estimated that 3 3 million people are infected around the world. HIV and GBV-C share the same transmission route, being frequent the co-infection. Since both viruses replicate in CD4+ lymphocytes, recent studies have described an interaction. Decreasing of HIV viral load and higher CD4 counts have been observed in co-infected patients, leading a better clinical outcome. Nevertheless, some epidemiological studies have shown contradictory results. Additionally, in vitro models report inhibition of HIV by E1, E2, NS3 and NS5A GBV-C proteins, resulting in a decreasing of p24 antigen. This review summarizes the principal findings about co-infection and mechanisms that have been proposed for HIV-1 inhibition. PMID- 23450409 TI - [Sphingomonas paucimobilis]. PMID- 23450408 TI - [Risk factors associated with virologic failure in HIV- infected patients receiving antiretroviral therapy at a public hospital in Peru]. AB - OBJECTIVE: To describe clinical and biological characteristics of subjects with virologic failure who participated in the sexually transmitted diseases HIV/AIDS National Program from a Peruvian public hospital. MATERIALS AND METHODS: An exploratory descriptive study was performed with data from subjects older than 18 who started high activity antiretroviral therapy (HAART) between May 2004 and December 2009 and who had a viral load control after 24 weeks of HAART. Virologic failure was defined as a viral load value above 1000 copies/mL on follow up after 24 weeks on HAART. RESULTS: Of 1478 records of patients on HAART analyzed, the median age was 35 years [IQR, 29-41] and 69.6% were male. Also, virologic failure occurred in 24% and 3.7% died. Of subjects with virologic failure, 9.5% died. On multivariate analysis, age, history of antiretroviral use before starting HAART, change of antiretroviral therapy due to toxicity, opportunistic infections during HAART, level of CD4 + lymphocytes below 100 cells/ml at start of HAART, adherence and clinical stage were independently associated with virologic failure. In the group of patient with no history of antiretroviral use before starting HAART, age, opportunistic infections during HAART were associated with virologic failure. CONCLUSION: This study identified factors associated with virologic failure. Further studies are needed to evaluate whether the use of these factors can help to identify prospectively patients at high risk of failure, and to design interventions aimed to reduce this risk. PMID- 23450411 TI - [Pet ownership in inmunocompromised patients: update and veterinary and medical considerations]. AB - Pet ownership offers undisputed benefits to immunocompromised (IC) patients, however, it poses the risk for potentially serious zoonoses. Mechanisms of transmission and manifestation of major zoonotic infections in dogs and cats that may affect IC patients are described. We also provide updated international information and local data. Recommendations are given to choose and care for pets ensuring safe and responsible ownership. This will help to prevent, detect and treat infections timely. PMID- 23450413 TI - [Bacteremic colangitis in adults in a general hospital in Chile]. AB - BACKGROUND: Some aspects of bacteremic cholangitis are unknown in Chile. AIM: To gather more information on clinical, microbiological aspects as well as risk factors for ICU admission, recurrence and antimicrobial resistance. MATERIAL AND METHODS: A retrospective research was performed using medical records of adult patients in a general hospital. RESULTS: Between 2006-2012, 22 patients with 29 bacteremic events were identified. Previous cholangitis events were reported by 27.3%, 45.5% had recent admissions and, 50% had used antimicrobial compounds. Coledocholithiasis was the most common cause of obstruction (45.5%) followed by cancer (36.4%). One third developed shock (31%), the only factor associated with ICU admission (OR 30, p < 0.05). In 24 of the 29 bacteremic events, the biliary tract was intervened (82.8%) and in 80.8% during the first 72 hours. Gram negative bacilli were predominant (> 80%) and some infrequent agents such as Staphylococcus warneri, Shewanella spp. and, Aeromonas spp. were observed. Among enteric gram negative bacilli, 29.2% presented fluoroquinolone resistance and, 26.1% resistance to third generation cephalosporins, both associated with previous endoscopic retrograde cholangiography (OR 35 and 16.5, respectively p < 0.05). A favorable response was observed in 93.1% of bacte-remic events but in 31.8% of patients cholangitis recurred with or without bacteremia. Recurrence was associated to recent admission (OR 16.5, p = 0.01) and in all cases occurred before 81 days. In-hospital mortality was 9.1% (n = 2), but in only one case associated to sepsis. Average length of stay (LOS) was 17.8 days. CONCLUSIONS: Early intervention of the biliary tract allows a favorable response in patients affected by bacteremic cholangitis, but this condition use intensive care resources, had a prolonged LOS, a recurrent pattern, and is associated with several bacterial species, some of them resistant. PMID- 23450414 TI - [The pneumococcal connection]. AB - The resistance of gram-negative bacilli is one of the most important areas in modern medicine, however it hasn't been highlighted the role of the third generation cephalosporins and in particularly ceftriaxone in the selection of gram-negative bacilli resistant to these agents. Paradoxically, ceftriaxone, like the rest of the molecules of this generation, whose initial indication were gram- negative infections began to be used as an agent of choice in pneumococcal infections. The broad spectrum activity of this molecule with its favorable pharmacokinetic properties replaces other agents by this antibiotic in the treatment of a wide range of community acquired infections. However, it wasn't considered the action of this cephalosporin on the microbiome, particularly the intestinal flora, which allowed the selection of enterobacteria that by genetic events, especially parental beta-lactamases mutations (TEM-1, TEM-2, SHV-1), developed resistance to third-generation cephalosporins. The decreased susceptibility to penicillin in Streptococcus pneumoniae isolates that stimulated the growing use of ceftriaxone, was one of the main drivers for the development of resistance to third-generation cephalosporins in gram-negative bacilli. PMID- 23450417 TI - [Cedecea lapagei traumatic wound infection: case report and literature review]. AB - Cedecea lapagei is a gram-negative, facultative anaerobic, non-spore-forming bacteria, belonging to the family Enterobacteriaceae. It has been reported as a pathogen in few cases of bacterial peritonitis, wound infection, chemicals burns and pneumonia. We report a case of traumatic wound infection by this pathogen with a pertinent review. PMID- 23450416 TI - [Pyomyositis in children: report of two cases]. AB - Pyomyositis (PM) is an uncommon pyogenic infection of skeletal muscle and, when not properly treated, it can progress to a high-risk clinical situation with high mortality. Because it usually has a subacute presentation, diagnosis is often delayed. We present two cases of PM of the paraspinal muscles in healthy children and discuss the current state of knowledge of this disease. PMID- 23450418 TI - [Tinea nigra: a allochthonous case report in Chile]. AB - Tinea nigra is a superficial mycosis caused by Hortaea werneckii. It is an infrequent asymptomatic infection that affects mainly human palms and soles, and it is mostly seen in tropical countries. It has not been reported in Chile yet. The clinical presentation is generally a single macule, not symptomatic, of brown color in palms and soles. We report a case of a Chilean woman that developed brown macules on both soles after travel to the United States and Central America. The diagnosis of Tinea nigra was confirmed by direct microscopic examination and mycological culture. She had a good response to treatment with oral itraconazol. PMID- 23450419 TI - [Bacteraemia due to Shigella flexneri serotype 6 in two patients with AIDS]. AB - Infections due to Shigella usually remain localized to the digestive tract and are self-limited. Bacteremia is a potentially lethal complication that can occur in immunocompromised patients. We describe two episodes of bacteremia caused by Shigella in two adults with AIDS. In both patients, S. flexneri was recovered from stool and blood samples. The isolates belonged to serotype 6, were resistant only to trimethoprim-sulfamethoxazole and showed a similar band profile by pulsed field gel electrophoresis. Patients received prolonged antimicrobial treatment with a favorable outcome. There were no cases of diarrhea in other individuals admitted to the emergency room. We hypothesized that patient No. 2 was infected at the hospital from patient No. 1. However, we could not establish the way of transmission. Although rare, it is important to take into account the possible occurrence of bacteremia due to Shigella or other bacterial enteropathogens in immunocompromised patients with diarrhea. PMID- 23450420 TI - [Literature memories about diphtheria: Mark Twain, W.G. Sebald and Stendhal syndrome]. AB - Memories of W.G. Sebald from the diphtheria he suffered as a child, gave rise to a discussion about the origin of classic clinical descriptions and the traps memory tends. Good examples of the latter are some experiences of Stendhal, who must also be distrusted given his hypersensitivity, which gave name to a psychosomatic syndrome. Mark Twain, a more practical man, brings us back to reality with a funny story about the terror the disease caused in the late nineteenth century. This leads us to remember isolation measures and topical treatments from the period immediately preceding the antitoxin. They included manual removal of the pseudo membranes, maneuver that led Maranon to misinterpret a painting by Goya on a scene of "Lazarillo de Tormes". PMID- 23450421 TI - [Surveillance of carbapenem-resistant enterobacteria in stool cultures in a university hospital in Santiago, Chile]. AB - BACKGROUND: Clinical cultures detect only one-third of colonized patients with carbapenem-resistant Enterobacteriaceae. Early identification and contact precautions implementation would help to interrupt transmission. In our hospital no carbapenemase-producing enterobacteria infections have been described. AIM: To perform stool surveillance cultures in patients hospitalized in critical care unit with the purpose to detect carbapenemase-producing Enterobacteriacea. MATERIAL AND METHODS: Rectal swabs were obtained of patients after five or more days of hospital stay, on a monthly basis from July to December 2011. Phenotypic assays (modified test Hodge and phenylboronic acid test) and polymerase chain reaction (PCR) searching for six carbapenemases of group A and B of Ambler's classification were performed. RESULTS: During this period, 241 surveillance rectal cultures were performed. Thirty eight enterobacteria isolated from 30 patients presented a decreased susceptibility to carbapenems by agar dilution method. All PCR were negative. CONCLUSION: We found that despite the significant number of resistant isolates, patients hospitalized in our institution are not colonized with carbapenemase-producing Enterobacteriaceae. We highlight the importance of screening before having the problem in place. PMID- 23450423 TI - [NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults]. PMID- 23450424 TI - Illness beliefs and treatment beliefs as predictors of short-term and medium-term outcome in chronic back pain. AB - OBJECTIVE: Patients' illness beliefs were shown to be more relevant than other psychosocial factors of influence for predicting outcome in back pain in primary care. The aim of this study was to determine whether illness beliefs and beliefs about rehabilitation are predictors of functioning, pain intensity, and coping with pain after rehabilitation in a population with longstanding chronic back pain. DESIGN AND PATIENTS: The study included 110 patients with longstanding chronic back pain in a longitudinal study design with 3 measurement points (before rehabilitation, end of rehabilitation, and 6 months follow-up). METHODS: Hierarchical multiple regression analyses were conducted to test the relative contribution of illness beliefs and beliefs about rehabilitation to the rehabilitation outcomes while adjusting for baseline values of outcome measures, mental health, sociodemographic, and illness-related variables. RESULTS: Illness beliefs and beliefs about rehabilitation made a significant contribution to the prediction of rehabilitation outcomes. In the short and medium term, incremental variance for coping with pain was as much as 13%, for functioning up to 14%, and for pain intensity between 6% and 9%. CONCLUSION: Further studies should be conducted as a confirmatory test of our preliminary results and to test the relative relevance of these constructs compared with other yellow flags for chronic patient samples. PMID- 23450425 TI - Association between rates of binocular visual field loss and vision-related quality of life in patients with glaucoma. AB - IMPORTANCE: It is reasonable to hypothesize that for 2 patients with similar degrees of integrated binocular visual field (BVF) loss, the patient with a history of faster disease progression will report worse vision-related quality of life (VRQOL) than the patient with slowly progressing damage. However, to our knowledge, this hypothesis has not been investigated in the literature. OBJECTIVE: To evaluate the association between binocular rates of visual field change and VRQOL in patients with glaucoma. DESIGN Observational cohort study. SETTING: Patients were recruited from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. PARTICIPANTS: The study included 796 eyes of 398 patients with diagnosed or suspected glaucoma followed up from October 1, 1998, until January 31, 2012, for a mean (SD) of 7.3 (2.0) years. MAIN OUTCOME MEASURES: The VRQOL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) at the last follow-up visit. The NEI VFQ-25 was completed for all patients during the period extending from December 1, 2009, through January 31, 2012. Integrated BVFs were calculated from the monocular fields of each patient. Linear regression of mean deviation values was used to evaluate rates of BVF change during the follow-up period. Logistic regression models were used to investigate the association between abnormal VRQOL and rates of BVF change, while adjusting for potentially confounding socioeconomic and demographic variables. RESULTS: Thirty-two patients (8.0%) had abnormal VRQOL as determined by the results of the NEI VFQ-25. Patients with abnormal VRQOL had significantly faster rates of BVF change than those with normal VRQOL (-0.18 vs -0.06 dB/y; P < .001). Rates of BVF change were significantly associated with abnormality in VRQOL (odds ratio = 1.31 per 0.1 dB/y faster; P = .04), after adjustment for confounding variables. CONCLUSIONS AND RELEVANCE: Patients with faster rates of BVF change were at higher risk of reporting abnormal VRQOL. Assessment of rates of BVF change may provide useful information in determining risk of functional impairment in glaucoma. PMID- 23450426 TI - Muscarinic acetylcholine receptor activation prevents disinhibition-mediated LTP in the hippocampus. AB - Disinhibition-mediated long-term potentiation (LTP) in the CA1 region of the hippocampus involves GABAergic synaptic plasticity at feedforward inhibitory inputs, resulting in the reduced shunting of glutamatergic excitatory currents. The GABAergic plasticity which underlies disinhibition-mediated LTP results from a Ca(2+)-dependent decrease in the activity of the K(+)-Cl(-) cotransporter (KCC2), depolarizing the reversal potential for GABAA receptor-mediated currents (EGABA), thereby attenuating inhibition. Muscarinic acetylcholine receptor (mAChR) activation has previously been shown to regulate classic glutamatergic LTP, modulate intracellular [Ca(2+)] and signaling, and facilitate the excitability of GABAergic interneurons in the CA1. Based on these effects, and the ability of mAChR activation to regulate CA1 pyramidal neuron KCC2 expression, we proposed that mAChR activation would modulate disinhibition-mediated LTP. To test this prediction, we made whole cell recordings from CA1 pyramidal neurons in hippocampal slices. Disinhibition-mediated LTP was induced using a spike timing dependent plasticity (STDP) protocol, which involved coincident pre-synaptic stimulation and post-synaptic current injection (at 5 Hz for 60 s). We found that mAChR activation via carbachol (CCh) prevented the induction of disinhibition mediated LTP. Moreover, in the presence of CCh, EGABA failed to depolarize following plasticity induction. Lastly, we recorded the paired-pulse ratio (PPR) during the induction of disinhibition-mediated LTP and found that in the presence of CCh, plasticity induction induced a significant paired-pulse depression. This suggests that pre-synaptic mAChR activation may prevent the post-synaptic expression of disinhibition-mediated LTP. PMID- 23450427 TI - Activation of spinal ERK1/2 contributes to mechanical allodynia in a rat model of postoperative pain. AB - Extracellular signal-regulated kinase (ERK) 1/2 in the spinal cord has been implicated in the development of neuropathic pain and inflammatory pain. However, a limited number of studies have investigated the role of spinal ERK in incisional pain. The present study aimed to determine the role of ERK in the spinal cord in incisional pain. Incisional pain was established in rats by a unilateral hind paw incision. ERK1/2 expression was analyzed by immunohistochemistry. Hypersensitivity to pain was evaluated by measuring the paw withdrawal threshold using the von Frey test. The mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, was administered 20 min prior to or 10 min following the incision by intrathecal or intraperitoneal injection. Phosphorylated ERK1/2 in the ipsilateral L4-5 spinal superficial dorsal horn was activated 1 min following the incision, reached its peak level at 5 min and then returned to the basal level 20 min following the incision. Pretreatment, but not post-treatment with U0126 markedly attenuated the pain hypersensitivity induced by the incision. Therefore, the present study indicates that the transient activation of spinal ERK1/2 contributes to the initiation of pain hypersensitivity following surgical incision. PMID- 23450428 TI - Functional effects of robotic-assisted locomotor treadmill thearapy in children with cerebral palsy. AB - OBJECTIVE: The aim of this study was to assess gait in children with spastic diplegic cerebral palsy rehabilitated with the use of Lokomat active orthosis. DESIGN: A randomized controlled trial. SUBJECTS: Fifty-two children with spastic diplegic cerebral palsy. METHODS: Temporospatial parameters of gait and selected kinematic parameters were assessed. Children from the study group used active orthosis in addition to following a programme of individual exercises. Children in the control group participated only in individual exercises. RESULTS: The difference between the initial and control examinations was statistically insignificant. After the programme was finished, there was a slight improvement in walking speed in both groups. Improvement in the mean walking speed was not significantly different between the groups (p = 0.5905). Range of motion decreased slightly in both groups, and the difference between mean amounts of change was not significant (p = 0.8676). There was significant improvement in maximal range of flexion in the hip joint (p = 0.0065) in the study. It was shown that with a decrease in the mean value of adduction in hip joint, the mean walking speed increased (r = -0.53, p = 0.0011). CONCLUSION: There are several limitations to this study, therefore these results should be regarded as preliminary. Further research consistent with the above indications is needed to investigate the impact of this new treatment option in patients with cerebral palsy. PMID- 23450429 TI - Nonarteritic anterior ischemic optic neuropathy in a 35-year-old postpartum woman with recent preeclampsia. PMID- 23450430 TI - Keratins in the human trophoblast. AB - Besides microfilaments and microtubules, intermediate filaments are major components of the cytoskeleton. In epithelial cells intermediate filaments are formed by heterodimers of specific keratins, whose expression pattern highly depends on the type of epithelium and differentiation degree of the cell. During the process of blastocyst implantation and subsequent development of the human placenta a very specialized epithelium appears at the feto-maternal interface. Arising from the trophectoderm of the blastocyst, the epithelium-like layer surrounding the early embryoblast, different trophoblast subtypes differentiate. They either develop into polar cells fulfilling real epithelial functions, or apolar tumor-like cells invading the maternal uterine wall to adapt the maternal tissue to progressing pregnancy. Thus, the whole trophoblast population, with all its subtypes, can be considered as an epithelial compartment and hence expresses keratin filaments. However, differentiation of trophoblast into different phenotypes may be linked to remodeling of the cytoskeletal composition, depending on spatiotemporal requirements of the respective cells. Here, we focus on the keratin composition of different trophoblast subtypes, how these keratins are used in trophoblast research and what is known about placental keratins in pregnancy pathologies. PMID- 23450431 TI - Mesenchymal stem cells overexpressing integrin-linked kinase attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions. AB - Mesenchymal stem cells (MSCs) transfected by integrin-linked kinase (ILK) transplantation may improve the function and compliance of the post-infarct cardiac ventricle. We investigated the effect of ILK-modified MSC contiditioned medium (ILK-MSC-CM) on the proliferation of cardiac fibroblasts (CFBs) and collagen synthesis in vitro and in vivo. Myocardial infarction (MI)-induced animals received mesenchymal stem cell conditioned medium (MSC-CM), ILK-MSC-CM, or complete medium alone, subepicardially. A group of animals with MI and no other former intervention served as controls. ILK-MSC-CM inhibited CFB proliferation, reduced the gene expression of type I (Col1a1) and type III collagen (Col3a1), tissue inhibitors of metalloproteinase-1 (TIMP-1) and -2 (TIMP 2), alpha smooth muscle actin (alpha-SMA), and connective tissue growth factor (CTGF). It also increased the gene expression of matrix metalloproteinase-2 (MMP 2) and -9 (MMP-9), as measured by qRT-PCR. Four weeks after the left anterior descending (LAD) coronary artery ligation, echocardiographic analysis demonstrated preserved cardiac geometry and contractility in the ILK-MSC-CM treated animals. Decreased infarct size and reduced fibrosis were observed in the ILK-MSC-CM group. Overexpression of ILK regulates paracrine actions of MSCs, and ILK-MSC-CM attenuates CFB proliferation and collagen synthesis through paracrine actions in vitro and in vivo. PMID- 23450432 TI - Malawian prosthetic and orthotic users' mobility and satisfaction with their lower limb assistive device. AB - OBJECTIVE: To investigate patients' mobility and satisfaction with their lower limb prosthetic or orthotic device and related service delivery in Malawi and to compare groups of patients regarding type and level of device and demographics. METHODS: Questionnaires were used to collect self-report data from 83 patients. RESULTS: Ninety percent of prostheses or orthoses were in use by patients, but approximately half of these needed repair. Thirty-nine percent reported pain when using their assistive device. The majority of patients were able to rise from a chair (77%), move around the home (80%), walk on uneven ground (59%) and travel by bus or car (56%). However, patients had difficulties walking up and down hills (78%) and stairs (60%). In general, patients were quite satisfied with their assistive device (mean of 3.9 out of 5) and very satisfied with the service provided (mean of 4.4 out of 5). Access to repairs and servicing were rated as most important, followed by durability and follow-up services. Lack of finances to pay for transport was a barrier to accessing the prosthetic and orthotic centre. CONCLUSION: Patients were satisfied with the assistive device and service received, despite reporting pain associated with use of the device and difficulties ambulating on challenging surfaces. PMID- 23450433 TI - One-year course and effects of insomnia in rural Chinese adolescents. AB - STUDY OBJECTIVES: We aimed to explore the incidence and persistence of insomnia, the associated risk factors, and the potential bidirectional association of insomnia with depression, anxiety, and sleepiness in rural Chinese adolescents. DESIGN: School-based prospective study. SETTING: Five high schools in rural China. PARTICIPANTS: There were 2,787 adolescents studied. INTERVENTIONS: N/A. MEASURES AND RESULTS: Insomnia was defined as having a score of equal to or higher than nine in the Insomnia Severity Index as validated in Chinese adolescents. Depression, anxiety, and sleepiness were determined by the Beck Depression Inventory (BDI), Zung Self-Rating Anxiety Scale (SAS), and Epworth Sleepiness Scale (ESS), respectively. The incidence and persistence rates of insomnia were 16.0% and 41.0%, respectively. Multivariate analyses in logistic regression models revealed that new incidence of insomnia was significantly associated with age, living in a rural area, habitual daytime napping, high life events, anxiety, and depression at baseline (range adjusted odds ratio = 1.12 1.61), whereas the persistence of insomnia was positively associated with age, female sex, high life events, and depression at baseline (range adjusted odds ratio = 1.26-1.55) but negatively associated with living in a rural area (odds ratio = 0.59). Insomnia at baseline could predict new onsets of both depression (odds ratio = 1.45) and anxiety (odds ratio = 1.98) but not sleepiness at follow up after adjustment for age, sex, and baseline symptoms. The results in cross lagged analyses further supported these observations in the bidirectional associations of insomnia with depression, anxiety, and sleepiness. CONCLUSIONS: Insomnia has considerable incidence and persistence rates in Chinese adolescents. We have identified several risk factors for the incidence and persistence of insomnia. There are bidirectional associations of insomnia with depression and anxiety but not sleepiness. CITATION: Luo C; Zhang J; Pan J. One-year course and effects of insomnia in rural Chinese adolescents. SLEEP 2013;36(3):377-384. PMID- 23450434 TI - A unique case of female pseudohermaphroditism with 21-hydroxylase deficiency and small supernumerary marker chromosome 7. AB - Small supernumerary marker chromosomes (sSMCs) are present in ~2.6x106 individuals worldwide. Concerning their clinical consequences as well as their chromosomal origin and shape, sSMCs are a heterogeneous group of derivative chromosomes; 70% of sSMC carriers are clinically normal. In the present study, we report on a female with mosaicism (45%) of a de novo sSMC derived from chromosome 7, in which the observed clinical signs do not correspond to comparable cases in the literature. She is clinically normal apart from problems in gender determination, a uterus without ovaries and an external penis, pointing overall towards an adrenogenital syndrome (AGS). 21-Hydroxylase deficiency (21-OHD) is the most common cause of AGS. A corresponding analysis for underlying mutations in the CYP21A2 gene revealed a homozygous mutation c.518T>A (p.Ile173Asn) inherited from both non-related parents. Overall, in this study, we report a unique case of female pseudohermaphroditism, classified as a simple virilization form of 21-OHD having an additional minute-shaped chromosome 7 [min(7)(:p11.1 >q11.23:)]. Notably, AGS was due to a mutation in the CYP21A2 gene located on chromosome 6. This is a further example that detection of an sSMC does not always resolve the clinical case. PMID- 23450435 TI - Exstrophy epispadias complex- Issues beyond the initial repair. AB - Despite advances in the management of exstrophy epispadias complex (EEC), the quality of life of these patients is far from good. The post-operative period is complicated by numerous and variable events - infection, dehiscence, upper tract dilatation with deterioration, fistulas, stone formation and incontinence to name a few of the major complications. Redo surgery for bladder closure, bladder neck reconstruction, epispadias repair and closure of fistulas are frequently required. The current focus is on limiting the frequency and morbidity of the reconstructive procedures. A successful initial closure and early satisfactory cosmetic and functional results are gratifying for the family and the health care team, but this is only the beginning of the lifelong care necessary for bladder exstrophy (BE) patients. In this article, the long-term outcome of various treatment options and the continent procedures in BE has been reviewed, tracing the journey of these patients into adolescence and adulthood. PMID- 23450436 TI - The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. AB - Treatment of patients with B-cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B-cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m(2) , Day 1), plus bendamustine (70 mg/m(2) , days 1-2), and cytarabine (800 mg/m(2) , Day 1-3; R-BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high-risk R/R CLL. All patients (median age 60 years, range 53-74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy-chain variable region, and were heavily pretreated (1-5, median three previous lines). Overall, R-BAC was well tolerated with limited non-hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow-up of 17 months, median progression-free survival was 16 months while median overall survival (OS) was not reached (1-year OS: 75 +/- 13%). R-BAC is an active regimen in R/R heavily pretreated high-risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy. PMID- 23450437 TI - Hierarchical heterostructures of MnO2 nanosheets or nanorods grown on Au-coated Co3O4 porous nanowalls for high-performance pseudocapacitance. AB - The rational design and fabrication of more multi-component (material combination) 3D hierarchical heterostructures for high-performance pseudocapacitor applications still remains a challenge. Herein, we have designed and synthesized a 3D hierarchical heterostructure of MnO2 nanosheets or nanorods grown on an Au-coated Co3O4 porous nanowall array, resembling a sandwich configuration of Co3O4@Au@MnO2, by a facial and controllable electrochemical deposition process. Due to their unique self-assembling architecture and characteristics including porous Co3O4 nanowalls, ultrathin MnO2 nanosheets, and a high conductivity Au layer sandwiched between them, each component provides a much-needed critical function for the efficient use of metal oxides for energy storage. The synthesized 3D hierarchical heterostructures exhibited favorable electrochemical performances, such as a high specific capacitances of 851.4 F g( 1) at 10 mV s(-1) and 1532.4 F g(-1) at 1 A g(-1), good rate performance and an excellent long-term cycling stability (almost no degradation after 5000 cycles), which are better than those of the reported Co3O4 or MnO2 based electrode materials, and thus could be considered as perspective materials for high performance electrochemical capacitors. PMID- 23450438 TI - A mathematical model of forgetting and amnesia. AB - We describe a mathematical model of learning and memory and apply it to the dynamics of forgetting and amnesia. The model is based on the hypothesis that the neural systems involved in memory at different time scales share two fundamental properties: (1) representations in a store decline in strength (2) while trying to induce new representations in higher-level more permanent stores. This paper addresses several types of experimental and clinical phenomena: (i) the temporal gradient of retrograde amnesia (Ribot's Law), (ii) forgetting curves with and without anterograde amnesia, and (iii) learning and forgetting curves with impaired cortical plasticity. Results are in the form of closed-form expressions that are applied to studies with mice, rats, and monkeys. In order to analyze human data in a quantitative manner, we also derive a relative measure of retrograde amnesia that removes the effects of non-equal item difficulty for different time periods commonly found with clinical retrograde amnesia tests. Using these analytical tools, we review studies of temporal gradients in the memory of patients with Korsakoff's Disease, Alzheimer's Dementia, Huntington's Disease, and other disorders. PMID- 23450439 TI - Staphylococcus aureus- the predominant pathogen in the neonatal ICU of a tertiary care hospital in amritsar, India. AB - BACKGROUND: An early treatment and the appropriate and the rational use of antibiotics would minimize the risk of severe morbidity and mortality in neonatal sepsis, and reduce the emergence of multi-drug resistant organisms in intensive care units. For the success of an early empiric treatment, a periodic review of the cases to assess any changing trends in the infecting organisms and their antimicrobial susceptibility is important. AIM: To study the most commonly encountered bacterial pathogens which caused neonatal sepsis and their sensitivity patterns, so that guidelines could be prepared for a rational antibiotic therapy. SETTING AND DESIGN: This was a retrospective study which was conducted in the Department of Microbiology and the Neonatal Intensive Care Unit (NICU) at SGRDIMSAR, Amritsar, during June 2011 to June 2012. METHODS AND MATERIALS: Blood specimens for culture were drawn from 311 newborns who were admitted in an NICU with sepsis. The specimens were inoculated into brain heart infusion broth. Subcultures were performed on days 1, 2, 3, 5, 7 and 10. The isolates were identified by doing standard biochemical tests. The antibiotic resistance patterns of the isolates were studied by the Kirby Bauer disc diffusion technique. RESULTS: A total of 131 organisms were isolated from the 311 blood cultures. These included Staphylococcus aureus (n=68), Coagulase Negative Staphylococcus (CoNS) (n=30), Klebsiella pneumoniae (n=10), Acinetobacter baumannii (n=9), Escherichia coli (n=05), Enterobacter cloacae (n=04), Citrobacter diversus (n=02), Pseudomonas aeruginosa (n=02) and Candida (n=01). Staphylococcus aureus was the main pathogen in both early and late-onset sepsis. On antibiotic sensitivity testing, 57.35% of the Staphylococcus aureus isolates were found to be methicillin resistant. More than 90% gram negative rods were resistant to amikacin. The resistance to the third generation cephalosporins varied between 50-55%. The resistance to ciprofloxacin was quite high; however, most of the isolates were susceptible to levofloxacin. A majority of the isolates were susceptible to piperacillin- tazobactum and imipenem. CONCLUSION: The present study emphasized the importance of periodic surveys on the microbial flora which was encountered in particular neonatal settings to recognize the trend. PMID- 23450440 TI - Personal history of obesity matters. Adolescent adiposity may influence the late results of gastric bypass performed in adults. AB - INTRODUCTION: The influence of adolescent obesity on weight loss following bariatric surgery in adults has not been evaluated. The purpose of this study was to determine the impact of prior adolescent obesity on long-term weight changes following Roux-en-Y gastric bypass (RYGB) in adulthood. MATERIAL AND METHODS: This single centre retrospective cohort study evaluated changes in body mass index (BMI) after RYGB within 9-13 years. Questionnaires were sent by post to patients (n = 147) operated on between January 1999 and December 2003 in the Department of General and Transplant Surgery of Medical University, Lodz, Poland. Long-term data was obtained from 33.33% (n = 49, mean age 46.1 +/- 10.7 years). Preoperative, nadir and actual BMI and differences between these values were calculated. Data was analysed with a cut-off BMI at 18 years old of 30 and 35 units (U). RESULTS: Patients with a BMI of more than 30 and 35 U in adulthood regained more weight after initial achievement of nadir total weight loss compared to their only adult obese counterparts. Preoperative BMI varied by weight at 18 years old (p = 0.02), while value and time to nadir postoperative BMI and actual BMI were comparable. CONCLUSION: Adolescent obesity may be a risk factor for long-term RYGB failure. Surgery cannot be definitively curative in this group of patients, and continued active conservative treatment is required. PMID- 23450441 TI - The impact of the repair of staple line dehiscence in post-RYGB patients on glucose homeostasis and gut hormones--a preliminary study. AB - INTRODUCTION: Staple-line disruption (SLD) following Roux-en-Y gastric bypass (RYGB) results in weight regain. This study evaluated glucose homeostasis and gut hormonal changes following surgical repair of gastrogastric fistula. MATERIAL AND METHODS: Three patients with SLD underwent an oral 75 g glucose tolerance test (OGTT) before (baseline) and one week after gastric pouch restoration. Plasma glucose, insulin and glucagon glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) were measured in the OGTT samples. Fasting plasma levels of ghrelin and leptin were assessed. RESULTS: Restoration of gastric pouch provided moderate amelioration of glucose metabolism and gut hormones, yet without complete normalisation of glucose homeostasis at one week after surgery. Duodenal passage exclusion resulted in early improvement of control fasting plasma glucose with decrease of glucagon from 18.5 to 15 (ng/mL, by 19%), relatively stable insulin and decline of incretin hormones (GIP and GLP 1). Post-challenge measurements confirmed amelioration of glycaemic control with decrease of plasma glucose from 182 to 158 mg/dL at 60 minutes. Surgical re intervention resulted in exacerbation of GIP response with brisk rise in plasma level, accompanied by considerable increase of peak insulin concentration. The overall post-challenge glucagon and GLP-1 responses were decreased. Marked decrease in fasting plasma ghrelin and leptin were observed. CONCLUSIONS: Our report gives further insight into the hormonal mechanisms underlying the effects of surgically altered anatomy of different parts of the small intestine on glucose homeostasis that is highly important, since it may facilitate novel conservative therapies of diabetes without the need for surgery. PMID- 23450442 TI - Nephrotoxicity after PRRT - still a serious clinical problem? Renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATATE and 90Y/177Lu DOTATATE. AB - INTRODUCTION: The kidneys play an essential role in PRRT. The infusion of amino acids could reduce uptake in the kidney of radiolabelled peptides. The purpose of this study was to determine the extent of kidney damage post PRRT. MATERIAL AND METHODS: 53 patients, with disseminated neuroendocrine tumours (NET), received 3 5 cycles of up to a maximum 7.4 GBq/m2 calculated dose of 90Y-DOTATATE (n = 25) and 90Y/177Lu-DOTATATE (n = 28). Creatinine levels were measured and glomerular filtration rates (GFR) were calculated. A mixed amino acid infusion was used for nephroprotection. RESULTS: Patients treated with 90Y-DOTATATE had a mean creatinine level of 0.77 +/- 0.19 mg/dL and a mean GFR (mL/min/1.73 m2) of 103.6 +/- 30.8. Patients treated with 90Y/177Lu-DOTATATE had a mean creatinine level of 0.92 +/- 0.33 mg/dL and a mean GFR of 84.7 +/- 26.3. In the follow up, among patients treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE, the mean GFR level at 12 months was 101.2 +/- 31.3 v. 83.9 +/- 25.2, at 24 months 80.2 +/- 32.7 v. 77.2 +/- 31.1, at 36 months 78.9 +/- 42.1 v. 67.5 +/- 9.7, and 48 months 59.7 +/- 15.2 v. 72.6 +/- 11.2. The mean yearly decrease in GFR was 4.5 mL in all treated patients; for patients treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE it was 6.8 v. 3.0, respectively. CONCLUSIONS: 90Y/177Lu-DOTATATE treatment induced statistically significantly less change in kidney function compared to 90Y DOTATATE. PMID- 23450443 TI - Factors associated with glucose metabolism disorders after kidney transplantation. AB - INTRODUCTION: Post-transplant diabetes mellitus (PTDM), pre-diabetes-impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are frequent complications after organ transplantation. The aim of this study was to assess the frequency of PTDM, IFG and IGT in a group of renal transplant recipients, to compare the frequency of glucose metabolism disorders in subjects treated with tacrolimus and with cyclosporine, and to establish the influence of different risk factors on the development of glucose metabolism disorders. MATERIAL AND METHODS: We examined 206 non-diabetic kidney allograft recipients (age 46.4 +/- 12.3 years, time since transplantation 45.5 +/- +/- 33.6 months, BMI 26.3 +/- 4.5 kg/m2). Glucose metabolism disorders were diagnosed using an oral glucose tolerance test. Logistic regression was used to assess the influence of each risk factor (age, BMI, waist circumference, physical activity, the presence of cardiovascular disease, positive family history of diabetes, cholesterol and triglycerides concentration) on the development of glucose metabolism disorders. RESULTS: In 103 patients (50%), we diagnosed glucose metabolism disorders. 19% of patients had PTDM, 14% IFG, and 17% IGT. We did not find any differences in the frequency of glucose metabolism disorders between patients treated with tacrolimus and with cyclosporine. Multivariate analysis identified BMI and a family history of diabetes as independent risk factors of glucose metabolism disorders. CONCLUSIONS: We found a high prevalence of glucose metabolism disorders in the examined group. This suggests that kidney transplant recipients should be screened for these disturbances. Patients with higher BMI and with first-degree relatives with diabetes had an increased risk of glucose metabolism disorders after kidney transplantation. PMID- 23450444 TI - Relationships between adiponectin, sex hormone binding globulin and insulin resistance in hyperthyroid Graves' disease women. AB - INTRODUCTION: Adiponectin and sex hormone binding globulin (SHBG) play a role in glucose metabolism. Hyperthyroidism has an impact on carbohydrate metabolism and could affect insulin resistance. The aim of this study was to assess the associations between insulin resistance, adiponectin and SHBG among hyperthyroid Graves' disease (GD) women. MATERIAL AND METHODS: The study was undertaken in 60 women with hyperthyroidism in the course of GD; 32 healthy women matched by BMI and age formed the control group. The concentrations of: free thyroxine (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), SHBG, insulin, adiponectin and glucose were measured, and the homeostasis model assessment (HOMA I) was calculated. RESULTS: Compared to euthyroid subjects, hyperthyroid GD women had elevated glucose, fT4, fT3, adiponectin and SHBG concentrations, but there were no differences in HOMA-I. When we explored the relations between adiponectin as well as SHBG with glucose and HOMA-I, we observed that HOMA-I was associated with adiponectin and SHBG only in the control group, and in hyperthyroidism there were no such connections. We found positive associations between adiponectin, SHBG, fT4 and fT3 in the GD group. CONCLUSIONS: Elevated concentrations of adiponectin and SHBG were observed in hyperthyroidism but they were not related to insulin resistance. PMID- 23450445 TI - Transsphenoidal surgery for Cushing's disease: the role of early post-operative serum cortisol measurements as a predictor of success--a prospective study. AB - INTRODUCTION: Transsphenoidal surgery (TSS) is the treatment of choice for Cushing's disease (CD). A proper assessment of the efficacy of surgical treatment is crucial in terms of patient prognosis. The aim of this study was to evaluate the usefulness of serum cortisol measurements performed on the first post operative day as a predictor of TSS outcome. MATERIAL AND METHODS: This prospective study involved 36 patients with CD who were operated on using the same surgical protocol and followed up for at least 18 months (median: 30 months). We investigated the relationship between serum cortisol measurements performed on the first post-operative day and the hormonal assessment of the pituitary-adrenal axis performed after 18 months of follow-up. The adopted criteria for remission were: serum cortisol within the referral range, normal circadian rhythm, and the ability of serum cortisol to suppress to values <= 1.8 MUg/dL after 1 mg of dexamethasone. RESULTS: The median serum cortisol on the first post-operative day was 1.98 MUg/dL. 23 patients (63.9%) were regarded as cured. In all these cured cases, the post-op cortisol was <= 2.5. On the other hand, in the cases of the 13 patients (36.1%) for whom the remission of CD was not confirmed, the post-op cortisol was >= 2.5. CONCLUSION: Our prospective study demonstrated that early post-operative serum cortisol measurements can serve as a simple and useful test that predicts the remission of CD. Furthermore, a post operative cortisol <= 2.5 can be considered as a forecast of CD remission. PMID- 23450446 TI - Assessment of bone metabolism in premenopausal females with hyperthyroidism and hypothyroidism. AB - INTRODUCTION: Osteoporosis is one of the commonest metabolic diseases of bone. Its possible causes may include thyroid hormonal dysfunction. The objective of this study was to evaluate the effects of hyperthyroidism and hypothyroidism on osseous tissue metabolism in premenopausal women. MATERIAL AND METHODS: 38 women with hyperthyroidism, 40 with hypothyroidism and 41 healthy women participated in this study. Initially after 6 and 12 months, each patient underwent selected hormonal, immunological and biochemical tests, measurement of concentrations of bone turnover markers and densitometry were also performed. RESULTS: On initial evaluation, lower cortical bone density was found in patients with hyperthyroidism (femoral neck). After 12 months, an increase in BMD was seen, but it was still lower than in the control group. Statistically significantly higher concentrations of bone turnover markers, decreasing from the sixth month of treatment, were noted only in the group with hyperthyroidism. Statistically significant differences were not noted in the femoral neck nor in the lumbar spine BMD in patients with hypothyroidism. CONCLUSIONS: Hyperthyroidism poses a negative effect on bone metabolism. Hypothyroidism in premenopausal females does not have any influence on bone density. PMID- 23450448 TI - Spontaneous regression of non-functioning pituitary adenoma due to pituitary apoplexy following anticoagulation treatment - a case report and review of the literature. AB - Pituitary apoplexy (PA) is a rare, potentially life-threatening medical condition due to acute ischaemia or haemorrhage of the pituitary gland. The main clinical features are: abrupt onset of severe headache, nausea, vomiting, deteriorating level of consciousness, visual impairment and/or endocrine deficiency. Correct and prompt diagnosis is essential for effective therapy, but there are no randomised studies or strict recommendations defining treatment modalities. We present the case of a 59 year-old woman with pituitary tumour apoplexy, presenting with severe headache, vomiting and visual field deterioration. The patient was treated conservatively because of her refusal of surgery and was followed-up for five years. In the course of treatment, recovery of the visual field defects, as well as right sixth cranial nerve paresis, was observed. Repeated magnetic resonance imaging (MRI) revealed regression of the tumour without signs of its re-growth. We discuss therapeutic modalities with particular emphasis on morbidity and review the literature relating to the management of pituitary tumour apoplexy. PMID- 23450447 TI - Links between growth hormone and aging. AB - Studies in mutant, gene knock-out and transgenic mice have demonstrated that growth hormone (GH) signalling has a major impact on ageing and longevity. Growth hormone-resistant and GH-deficient animals live much longer than their normal siblings, while transgenic mice overexpressing GH are short lived. Actions of GH in juvenile animals appear to be particularly important for life extension and responsible for various phenotypic characteristics of long-lived hypopituitary mutants. Available evidence indicates that reduced GH signalling is linked to extended longevity by multiple interacting mechanisms including increased stress resistance, reduced growth, altered profiles of cytokines produced by the adipose tissue, and various metabolic adjustments such as enhanced insulin sensitivity, increased oxygen consumption (VO2/g) and reduced respiratory quotient. The effects of removing visceral fat indicate that increased levels of adiponectin and reduced levels of pro-inflammatory cytokines in GH-resistant mice are responsible for their increased insulin sensitivity. Increased VO2 apparently represents increased energy expenditure for thermogenesis, because VO2 of mutant and normal mice does not differ at thermoneutral temperature. Recent studies identified GH- and IGF-1-dependent maintenance of bone marrow populations of very small embryonic-like stem cells (VSELs) as another likely mechanism of delayed ageing and increased longevity of GH-deficient and GH-resistant animals. Many of the physiological characteristics of long-lived, GH-related mouse mutants are shared by exceptionally long-lived people and by individuals genetically predisposed to longevity. PMID- 23450449 TI - Current concepts in the diagnosis and management of poorly differentiated gastrointestinal neuroendocrine carcinomas. AB - Poorly differentiated neuroendocrine carcinomas (PDNEC) are rare tumours that can originate from any site of the gastrointestinal tract exhibiting an overall aggressive behaviour that may vary between tumours according to the degree of cellular proliferation. The majority of PDNEC are locally advanced or metastatic at presentation, and are only infrequently associated with secretory hormonal syndromes. PDNEC exhibit aggressive histological features (high mitotic rate, high Ki67 labelling index and presence of necrosis) and are further subdivided into two morphological subgroups, small and large cell variants. As PDNEC express somatostatin receptors less frequently, somatostatin receptor scintigraphy is usually negative, whereas 18F-fluorodeoxyglucose positron emission tomography appears to be the best method of evaluating disease spread and guiding further treatment. PDNEC have traditionally been treated similarly to small cell lung carcinoma, although they show a number of different clinical and histopathologic features. First line systemic chemotherapy with a platinum-based agent and etoposide is used for patients with metastatic disease, leading to variable response rates that are often of relative short duration. Sequential or concurrent chemoradiation is recommended for patients with locoregional disease. In patients with localised disease, complete surgical resection should be offered followed by adjuvant treatment (chemotherapy with or without radiotherapy); the value of neoadjuvant chemotherapy has not been evaluated as yet. The role of second line therapies is evolving, with temozolomide being a promising agent. However, the majority of data regarding PDNEC is hampered by the small number of series and their retrospective nature, making it important that multicentre co operative studies be performed. PMID- 23450451 TI - The memory on Prof. Aldo Pinchera M.D., Ph.D. PMID- 23450450 TI - Recommendations of the Polish Society of Endocrinology and Polish Diabetes Association for the management of thyroid dysfunction in type 1 and type 2 diabetes. AB - Thyroid disorders are more frequently observed in diabetic patients. These conditions have been shown to be mainly of autoimmune origin and all of them may lead to hormonal imbalance. Especially strong links exist between autoimmune thyroid diseases (AITD) and type 1 diabetes. Importantly, both hypothyroidism and hyperthyroidism can adversely affect metabolic control of diabetes. These recommendations propose diagnostic and therapeutic algorithms for thyroid dysfunction in diabetic patients. PMID- 23450452 TI - Analysis of new N-category on prognosis of oesophageal cancer with positive lymph nodes in a Chinese population. AB - BACKGROUND: The 7(th) edition of the new TNM classification system for oesophageal cancer (EC) has been published. N-category is now divided into N0, N1, N2 and N3. In this study, we aimed to validate the prognostic ability of the new N classification system in EC with positive lymph nodes in a Chinese population, and evaluate whether the new N classification system can help the decision-making for postoperative adjuvant therapy. PATIENTS AND METHODS: From 2002 to 2008, thoracic EC who underwent oesophagectomy were retrospectively analysed. Patients pathological stage 6(th) edition of the American Joint Committee on Cancer / Union International Against Cancer (AJCC/UICC) TNM classification were switched to pathological stage 7(th) edition for this analysis. Patients with pathological stage T1-4N1-3M0 EC were selected. Kaplan Meier method and Cox regression analysis were employed to compare overall survival (OS). RESULTS: A total of 545 patients met the inclusion criteria: 346 (63.5%) received oesophagectomy alone, 199 (36.5%) received oesophagectomy and adjuvant radiotherapy, and 36.1% (197/545) received oesophagectomy and adjuvant chemotherapy. Univariate analysis and multivariate analysis revealed significant difference in OS among patients at different postoperative pN-category (p<0.001). This was also present in patients receiving postoperative radiotherapy (p<0.001) and those undergoing postoperative chemotherapy (p<0.001). There was no marked difference in OS between patients receiving postoperative adjuvant therapy and surgery alone at the same postoperative pN-category, except that postoperative radiotherapy marginally improved OS in patients with pN2 and pN3 disease. CONCLUSIONS: Our results validated the prognostic ability of new N classification system. The N-category is an independent prognostic factor in patients with resectable thoracic EC who were positive for lymph nodes in a Chinese population. Further studies are required to clarify the role of new N classification system in the decision-making for postoperative adjuvant therapy. PMID- 23450453 TI - Diminished sensitivity of audiovisual temporal order in autism spectrum disorder. AB - We examined sensitivity of audiovisual temporal order in adolescents with autism spectrum disorder (ASD) using an audiovisual temporal order judgment (TOJ) task. In order to assess domain-specific impairments, the stimuli varied in social complexity from simple flash/beeps to videos of a handclap or a speaking face. Compared to typically-developing controls, individuals with ASD were generally less sensitive in judgments of audiovisual temporal order (larger just noticeable differences, JNDs), but there was no specific impairment with social stimuli. This suggests that people with ASD suffer from a more general impairment in audiovisual temporal processing. PMID- 23450455 TI - Nonsurgical management of bilateral adrenal abscess in newborn with therapeutic aspiration under ultrasonographic guidance. AB - Neonatal adrenal abscess is a rare condition. Bilateral adrenal abscess are extremely rare. We present this case focusing on the usefulness of needle aspiration under ultrasonographic guidance. The bilateral suprarenal cystic masses are identified by ultrasonography and different sequences of magnetic resonance imaging. PMID- 23450456 TI - Left atrial diameter, aortic mean gradient, and hemoglobin for risk stratification in patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an alternative treatment of severe symptomatic aortic stenosis (AS) in patients with high operative risk. In spite of favorable entire results, long-term mortality of patients is high. HYPOTHESIS: The present study aims to identify independent preprocedural risk factors to improve risk stratification in these highly selected patients. METHODS: This prospective study included 202 consecutive patients with severe symptomatic AS and high operative risk (mean logistic European System for Cardiac Operative Risk Evaluation, 22+/-17%; mean age, 79+/-6 years; 107 female). Preprocedural comprehensive examinations were performed (laboratory, electrocardiography, echocardiography, cardiac catheterization). All patients received transfemoral or transaxillary TAVI with a CoreValve prosthesis (Medtronic, Minneapolis, MN). RESULTS: During a follow-up of 535+/-333 days, 56 patients (28%) reached the primary study end point (all-cause mortality). Independent predictors of long-term mortality were as follows: hemoglobin<12.5 g/dL (hazard risk [HR], 3.62; 95% confidence interval [CI], 2.025-6.468; P<0.001), aortic mean gradient<=41 mm Hg (HR, 2.16; 95% CI, 1.272-3.655; P=0.004), and left atrial diameter>42 mm (HR, 3.09; 95% CI, 1.588-6.019; P=0.001). Our risk-stratification model based on these independent predictors separated patients into 4 groups with high (74%), intermediate (37%), low (18%), and very low (3%) all-cause mortality. CONCLUSIONS: In patients undergoing TAVI, preprocedural assessment of hemoglobin, aortic mean gradient, and left atrial diameter provides independent prognostic information and therefore contributes to improved risk stratification in TAVI. PMID- 23450454 TI - Soft tissue tumors of the anorectum: rare, complex and misunderstood. AB - Anorectal soft tissue tumors are uncommon and often present both diagnostic and therapeutic challenges. Although many of these tumors are identified with imaging performed for unrelated reasons, most present with nonspecific symptoms that can lead to a delay in diagnosis. Historically, radical surgery (abdominoperineal resection) has been the mainstay of treatment for both benign and malignant anorectal soft tissue tumors. However, a lack of proven benefit in benign disease along with changes in technology has called this practice into question. In addition, the role of radiation and/or chemotherapy remains controversial. In this manuscript, we review the history and current status of anorectal soft tissue tumor management, with a particular focus on challenges in optimizing survival. PMID- 23450457 TI - High-resolution multishot spiral diffusion tensor imaging with inherent correction of motion-induced phase errors. AB - PURPOSE: To develop and compare three novel reconstruction methods designed to inherently correct for motion-induced phase errors in multishot spiral diffusion tensor imaging without requiring a variable-density spiral trajectory or a navigator echo. THEORY AND METHODS: The first method simply averages magnitude images reconstructed with sensitivity encoding from each shot, whereas the second and third methods rely on sensitivity encoding to estimate the motion-induced phase error for each shot and subsequently use either a direct phase subtraction or an iterative conjugate gradient algorithm, respectively, to correct for the resulting artifacts. Numerical simulations and in vivo experiments on healthy volunteers were performed to assess the performance of these methods. RESULTS: The first two methods suffer from a low signal-to-noise ratio or from residual artifacts in the reconstructed diffusion-weighted images and fractional anisotropy maps. In contrast, the third method provides high-quality, high resolution diffusion tensor imaging results, revealing fine anatomical details such as a radial diffusion anisotropy in cortical gray matter. CONCLUSION: The proposed sensitivity encoding + conjugate gradient method can inherently and effectively correct for phase errors, signal loss, and aliasing artifacts caused by both rigid and nonrigid motion in multishot spiral diffusion tensor imaging, without increasing the scan time or reducing the signal-to-noise ratio. PMID- 23450458 TI - Neural substrates of social emotion regulation: a FMRI study on imitation and expressive suppression to dynamic facial signals. AB - Emotion regulation is crucial for successfully engaging in social interactions. Yet, little is known about the neural mechanisms controlling behavioral responses to emotional expressions perceived in the face of other people, which constitute a key element of interpersonal communication. Here, we investigated brain systems involved in social emotion perception and regulation, using functional magnetic resonance imaging (fMRI) in 20 healthy participants. The latter saw dynamic facial expressions of either happiness or sadness, and were asked to either imitate the expression or to suppress any expression on their own face (in addition to a gender judgment control task). fMRI results revealed higher activity in regions associated with emotion (e.g., the insula), motor function (e.g., motor cortex), and theory of mind (e.g., [pre]cuneus) during imitation. Activity in dorsal cingulate cortex was also increased during imitation, possibly reflecting greater action monitoring or conflict with own feeling states. In addition, premotor regions were more strongly activated during both imitation and suppression, suggesting a recruitment of motor control for both the production and inhibition of emotion expressions. Expressive suppression (eSUP) produced increases in dorsolateral and lateral prefrontal cortex typically related to cognitive control. These results suggest that voluntary imitation and eSUP modulate brain responses to emotional signals perceived from faces, by up- and down-regulating activity in distributed subcortical and cortical networks that are particularly involved in emotion, action monitoring, and cognitive control. PMID- 23450459 TI - Fine-mapping and identification of a candidate gene underlying the d2 dwarfing phenotype in pearl millet, Cenchrus americanus (L.) Morrone. AB - Pearl millet is one of the most important subsistence crops grown in India and sub-Saharan Africa. In many cereal crops, reduced height is a key trait for enhancing yield, and dwarf mutants have been extensively used in breeding to reduce yield loss due to lodging under intense management. In pearl millet, the recessive d2 dwarfing gene has been deployed widely in commercial germplasm grown in India, the United States, and Australia. Despite its importance, very little research has gone into determining the identity of the d2 gene. We used comparative information, genetic mapping in two F2 populations representing a total of some 1500 progeny, and haplotype analysis of three tall and three dwarf inbred lines to delineate the d2 region by two genetic markers that, in sorghum, define a region of 410 kb with 40 annotated genes. One of the sorghum genes annotated within this region is ABCB1, which encodes a P-glycoprotein involved in auxin transport. This gene had previously been shown to underlie the economically important dw3 dwarf mutation in sorghum. The cosegregation of ABCB1 with the d2 phenotype, its differential expression in the tall inbred ICMP 451 and the dwarf inbred Tift 23DB, and the similar phenotype of stacked lower internodes in the sorghum dw3 and pearl millet d2 mutants suggest that ABCB1 is a likely candidate for d2. PMID- 23450460 TI - Effects of hyperbaric oxygen and N-acetylcysteine in survival of random pattern skin flaps in rats. AB - OBJECTIVE: Our aim is to investigate the role of HBO (hyperbaric oxygen), NAC (N acetylcysteine), and HBO plus NAC on the necrosis area of random rat's skin flaps of a modified McFarlane flap design. MATERIALS AND METHODS: Thirty-two male Wistar rats were randomly divided into four groups: G-S (sham: n = 8), G-NAC (NAC: n = 8), G-HBO (HBO: n = 8), and G-HN (HBO plus NAC: n = 8). A rectangular skin flap (2 * 8 cm(2)) was dissected from the muscular dorsal layer, preserving the cranial pedicle. Polyethylene film was placed over the muscular layer and an interrupted 3.0 nylon suture was employed to fix the flap into the original place. On the eighth day, full-thickness biopsy samples (2 * 1 cm(2)) were collected from the proximal, middle, and cranial areas of the skin flap, and in a site away from the flap labelled as the control area. RESULTS: The measurements of necrotic areas in the groups were 18.3% in G-S, 24.3% in G-NAC, 12.6% in G HBO, and 14.9% in G-HN. Significant difference was observed between the groups G HBO and G-HN as well as G-NAC. CONCLUSION: HBO is associated with reduced area of necrosis of skin flap. The G-NAC group was associated with poor results when examined in isolation. The association between HBO and NAC did not produce favourable results with respect to the use of HBO alone. These findings suggest that the diffusion of oxygen through the interstitial space was the determining factor of more favourable results of HBO. PMID- 23450461 TI - Ultra-robust graphene oxide-silk fibroin nanocomposite membranes. PMID- 23450462 TI - The effect of telomerase activity on vascular smooth muscle cell proliferation in type 2 diabetes in vivo and in vitro. AB - Serious complications as a result of type 2 diabetes mellitus (T2DM) are becoming a major health concern. In the present study, it was hypothesized that telomerase activity is upregulated in vascular smooth muscle cells (VSMCs) during proliferation in T2DM and that the application of telomerase inhibitors impedes the proliferation of VSMCs in vitro. Male Wistar rats were randomly allocated into the normal control (NC) or diabetic (DM) group. Diabetes was induced by high fat feeding and a low dose of streptozotocin (STZ; 30 mg/kg). Primary VSMC cultures were exposed to normal (5.5 mM) or high (25 mM) glucose and insulin (100 nM) in the presence and absence of various concentrations of antisense oligoribonucleotides (ASODNs) for varying lengths of time. Telomerase activity and the proliferation of VSMCs were measured. Results showed that there was a significant increase in the levels of fasting glucose, insulin, triglycerides (TG) and free fatty acids (FFAs) in the diabetic group. Telomerase activity and the proliferation of VSMCs were significantly higher in the diabetic group in vivo and in the high glucose and insulin (HGI)-treated group in vitro (P<0.01). ASODNs significantly inhibited the proliferation of VSMCs in a concentration- and time-dependent manner (P<0.01). In conclusion, hyperglycemia and hyperinsulinemia stimulate telomerase activity and the proliferation of VSMCs, while the inhibition of telomerase activity reduces the proliferation of VSMCs, indicating that telomerase may be involved in the pathological process of diabetic vascular disease. PMID- 23450463 TI - Congenital fusion of jaw and ankyloblepharon filiforme adnatum: malformation and multiple systems anomaly. AB - Congenital fusion of jaw and its association with ankyloblepharon filiforme adnatum is reported but is a quite rare congenital benign anomaly. It may be unilateral or bilateral and can present with a single system or multiple systems involvement. This report concentrates on describing the clinical features of above disease, likely aetiological causes, and embryogenesis with classification, diagnostic, and, treatment modality, anesthesia problems and review of literature. PMID- 23450464 TI - Is gait speed a valid measure to predict community ambulation in patients with Parkinson's disease? AB - OBJECTIVE: To investigate the predictive value of gait speed for community walking in Parkinson's disease and to develop a multivariate prediction model for community walking. DESIGN: Data from baseline assessments in a randomized clinical trial were used. SUBJECTS: A total of 153 patients with Parkinson's disease were included. METHODS: Community walking was evaluated using the mobility domain of the Nottingham extended activities of daily living index (NEAI). Patients who scored 3 points on item 1 ("Did you walk around outside?") and item 5 ("Did you cross roads?") were considered community walkers. Gait speed was measured with the 6-m or 10-m timed walking test. Age, gender, marital status, disease duration, disease severity, motor impairment, balance, freezing of gait, fear of falling, previous falls, cognitive function, executive function, fatigue, anxiety and depression were investigated for their contribution to the multivariate model. RESULTS: Seventy patients (46%) were classified as community walkers. A gait speed of 0.88 m/s correctly predicted 70% of patients as community walkers. The multivariate model, including gait speed and fear of falling, correctly predicted 78% of patients as community walkers. CONCLUSION: Timed walking tests are valid measurements to predict community walking in Parkinson's disease. However, evaluation of community walking should include an assessment of fear of falling. PMID- 23450465 TI - A clinical study on the management of inguinal hernias in children on the general surgical practice. AB - BACKGROUND: Inguinal and scrotal swellings are frequently encountered in the surgical practice, especially in children. It is also important to study the factors which are associated with inguinal hernia, especially in children, for its effective management. OBJECTIVE: To study the factors which are associated with inguinal hernia in children. SETTING AND DESIGN: A prospective hospital based study was undertaken in the Department of Surgery for a period of one year between 2001 to 2002. Children who were aged one day to 12 years were selected for the study. Out of 960 children who were admitted to the surgical ward, 50 children had inguinal hernia and they constituted the sample. METHODOLOGY: The details regarding the clinical history and the examination details were collected by using a predesigned proforma. The data which was thus collected was analyzed by using the appropriate statistical tests. RESULTS: The inguinal hernia in the study group was common in the 1-5 years age group. 90% of the study group was males; a swelling in the inguinal region was the commonest symptom. 70% of the study group was term deliveries; the swelling of the inguinal hernia was elastic in consistency in 35 cases. The swelling of the inguinal hernia was irreducible in two cases. The testis was palpable in 48 cases; a cough impulse was seen and felt in 48 cases. Tenderness of the swelling was present in 2 cases. CONCLUSIONS: Inguinal hernia is a common congenital condition in children. Difficulties are commonly encountered by the surgeons to identify and to confirm the presence of inguinal hernia. This study will help in a better management of hernia in the paediatric age group by understanding the features of inguinal hernia. PMID- 23450466 TI - Reduction in weight and BMI and changes in Co-morbidities following laparoscopic adjustable gastric banding procedure for morbidly obese patients in Bahrain: a five year longitudinal study. AB - BACKGROUND: Obesity and its related illnesses are pan-endemic health problems which require intervention. Laparoscopic Adjustable Gastric Banding (LAGB) is seen as a safe surgical procedure with satisfactory results on weight reduction and improvement in obesity related illness. METHODS: Data were collected in a repeated-measures longitudinal five year study for 143 morbidly obese patients who underwent laparoscopic adjustable gastric banding (LAGB). Follow up was continued from 3 to 60 months post operatively. Patients were assessed for diabetes, hypertension and dyslipidemia. RESULTS: Repeated measures ANOVAs revealed that both men and women lose weight and reduce their BMIs at a consistent rate. At 3, 6 and 9 months post-operative there are no differences in percent weight loss between men and women with mean weight loss at 8.9%, 13.1% and 16.0% respectively of pre-operative weight. At 12, 24 and 60 months post operatively, however, men significantly increase the percentage of weight loss as well as improve their BMI compared to women (p < .05). At 24 months post operative, men and women have BMIs of 36.03 and 32.85, both still in the obese range. By 60 months men have achieved a BMI that is slightly under the obese range into the overweight range (30.76) while women (BMI = 36.61) were still in the obese range. At 60 months, men have lost a total of 33.75% of their pre operative body weight while women have lost a total of 21.50. Diabetes, hypertension and dyslipidemia were significantly reduced in the sample post operatively (p < .01). CONCLUSION: LAGB is a safe and effective surgical procedure for morbidly obese patients resulting in weight loss, BMI decrease and reduction in co-morbid illnesses. PMID- 23450467 TI - In vivo T-cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA mismatched haploidentical transplantation. AB - We evaluated the efficacy of in vivo T-cell depletion with alemtuzumab in two prospective studies according to the International Conference on Harmonisation (ICH)-Good Clinical Practice (ICH-GCP) guidelines; one was for patients with aplastic anemia (AA study) and the other was for patients who were undergoing hematopoietic stem cell transplantation (HSCT) from a 2- or 3-antigen-mismatched haploidentical donor (MM study). The final dose of alemtuzumab in these studies was 0.16 mg/kg/day for 6 days. At this dose, all of the 12 and 11 patients in the AA and MM studies, respectively, achieved initial engraftment and the incidences of Grade II-IV acute graft-versus-host disease (GVHD) were 0% and 18%. While cytomegalovirus (CMV) frequently reactivated, none of the patients developed fatal CMV disease. Transplantation-related mortality within 1 year after HSCT was observed in only two and one patients, respectively. The numbers of CD4+ and CD8+ T-cells and T-cell receptor rearrangement excision circles remained low within 1 year after HSCT. These findings suggest that the use of alemtuzumab at this dose in a conditioning regimen enables safe allogeneic HSCT even from a 2- or 3 antigen-mismatched donor. However, the use of a lower dose of alemtuzumab should be explored in future studies to accelerate immune recovery after HSCT. PMID- 23450469 TI - [Genome-wide linkage scan for an ethnic Han Chinese pedigree affected with schizophrenia]. AB - OBJECTIVE: To perform genome-wide linkage analysis for an ethnic Han Chinese pedigree with schizophrenia in order to locate the susceptibility genes. METHODS: Genomic DNA was extracted from 4 mL of peripheral blood using conventional phenol chloroform method. Illumina Infinium Linkage 24 BeadChips chip was used for determining the genotypes through detection of single nucleotide polymorphisms (SNPs). After processing the raw data using Illumina BeadStudio software, two point nonparametric linkage analysis and two-point parametric linkage analysis were performed with Merlin software. RESULTS: By two-point nonparametric linkage analysis, 27 sites with high LOD scores (LOD=0.63-0.75, P U+003C 0.05) were identified. Among these, 3 SNPs(rs993694, rs992690 rs1861577) were located in 12p12.3 region, whilst the remainders were located in 4p12-q22 region. Two-point parametric linkage analysis under a dominant model has yielded almost identical results. CONCLUSION: Chromosomal regions 4p12-q22 and 12p12.3 probably contain susceptibility genes for schizophrenia. PMID- 23450468 TI - [A pilot study on spinal muscular atrophy carrier screening in Shanghai region using real-time PCR]. AB - OBJECTIVE: To develop a screening program for spinal muscular atrophy (SMA) carriers, and to assess the carrier frequency and detection rate in Shanghai region. METHODS: Quantitative analysis of the SMN1 gene by real-time PCR was developed using specimens from 15 SMA patients and 76 SMA parents from 38 affected nuclear families. A pilot screening was carried out for 1741 asymptomatic pregnant women. Frequencies of SMN1 alleles were determined with the Hardy-Weinberg equilibrium. RESULTS: Forty five out of the 1741 women were identified as SMA carriers by the presence of single copy of SMN1. The frequencies of no copy, 1 copy, 2 copy and 3 copy alleles were 1.37 U+00D7 10-2, 9.45 U+00D7 10-1, 2.80 U+00D7 10-2 and 1.27 U+00D7 10-2, respectively. The adjusted SMA carrier frequency was 1:35 with a detection rate of 94.49%. For those with a negative screening result, individuals with 3 copies carried a higher residual risk. CONCLUSION: The incidence of SMA carriers in Shanghai region is similar with that in Caucasian populations. Carrier screening has high detection efficiency. An effort should be made to further distinguish SMN1 gene copy numbers for those with more than 2 copies, since accurate determination of 2 and 3 copy allele frequencies is essential for post-screening genetic consulting. PMID- 23450470 TI - [Construction of wild-type and mutant SPAST vectors for the study of molecular mechanism of hereditary spastic paraplegia]. AB - OBJECTIVE: To construct wild-type and mutant pEGFP SPAST vectors and to explore the molecular mechanism of hereditary spastic paraplegia. METHODS: Mutant SPAST vector was constructed using overlap PCR method following construction of wild type SPAST vector. Wild-type and mutant constructs were transfected to COS7 cells and subcellular localization of spastin was observed. Co-localizations of spastin and microtubule, spastin and mitochondria were viewed by immunofluorescence staining. RESULTS: Wild-type spastin is localized in plasma, and mutant spastin did not change its cellular localization. Wild-type and mutant spastins did not co-localize with microtubules and mitochondria by immunofluorescence analysis. CONCLUSION: Wild-type and mutant SPAST constructs were successfully generated. Mutant spastin did not change its localization in cells. Spastin does not co localize with microtubules and mitochondria. This study may facilitate further studies on molecular mechanism of hereditary spastic paraplegia. PMID- 23450471 TI - [Association of vitamin D receptor gene polymorphisms with Parkinson disease]. AB - OBJECTIVE: Vitamin D receptor (VDR) has been proposed as a candidate gene for susceptibility to Parkinson's disease (PD). This study was set to assess the association between VDR gene Apa I and Taq I polymorphisms and PD in a Chinese Han population. METHODS: Two hundred and eighty five sporadic PD patients and 285 healthy controls were genotyped for the Apa I and Taq I polymorphisms in VDR gene using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method. RESULTS: No significant difference was detected in genotype or allele distribution of both Apa I and Taq I polymorphisms between PD patients and controls (P U+003E 0.05). No TT genotype for Taq I was found in the studied population. For Taq I, the distribution of genotype was significantly different between male PD patients and controls (U+03C7 2=4.187, P=0.032, OR=2.149, 95%CI: 1.011-4.567), and the frequency of T allele was significantly higher in male PD patients than male controls (U+03C7 2=3.867, P=0.036, OR=2.064, 95%CI: 0.989 4.307). CONCLUSION: VDR gene Apa I polymorphisms are not associated with sporadic Parkinson's disease, but Taq I may be a risk factor for male PD. PMID- 23450472 TI - [Association between mutations of SCN9A gene and pain related to Parkinsonism]. AB - OBJECTIVE: To screening mutations of exons 15, 18 and 26 of sodium channel Nav1.7 (SCN9A) gene, and to assess its association with pain related to Parkinsonism. METHODS: Respectively, 101 patients with primary Parkinson's disease (PD) and 104 similar-aged volunteers without PD were recruited from March, 2008 to January, 2011. Mutations of above 3 exons in SCN9A gene was detected with PCR and direct sequencing. For 100 patients with Parkinsonism, the pain was scored with a McGill pain rating scale. Statistical analysis was performed with SPSS. RESULTS: The prevalence of pain in Parkinsonian was 57%. 43.86% patients with pain were males, and 56.14% were females. Based on Chaudhuri criteria, the pain symptoms may be classified as musculoskeletal pain (10.52%), radicular pain (10.52%), dyskinesis pain (54.38%), pain from akathisia and restlessness (14.04%), dyskinesis combined with radicular pain (5.26%), skeletal muscles pain and headache (1.75%), and arthralgia (3.50%). Two missense mutations were identified, which included 2794A/C (0.941/0.059) (rs12478318) (M932L) in exon 15 and 3448C/T (0.988/0.012) (rs6746030) (R1150W) in exon 18. The wild type A/C for the 2794 locus had a higher prevalence in PD patients with pain, but this was not statistically different. All of the 5 heterozygotes for 3448 (C/T) were found in Parkinsonian patients with pain. No homozygotes were found. CONCLUSION: The prevalence of pain was higher in Parkinsonian patients than general population, and the proportion of males to females was similar. More patients have suffered dyskinesis pain. A 3448 (C/T) mutation of SCN9A gene may be related to pathogenesis of pain in Parkinsonism. PMID- 23450473 TI - [Association between ESR1 gene polymorphisms and haplotypes with schizophrenia]. AB - OBJECTIVE: To assess the association between single nucleotide polymorphisms (SNPs) and haplotypes of estrogen receptor 1 (ESR1) gene with schizophrenia. METHODS: Three SNPs (rs2234693, rs9340799 and rs3798759) were determined in 333 schizophrenic patients and 315 healthy subjects with polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Allelic and genotypic frequencies and particular haplotypes were compared between the two groups using Chi-square test. RESULTS: The allelic and genotypic frequencies of rs2234693 and rs9340799 showed no significant difference between the two groups (P U+003E 0.05). However, a significant difference was detected in the frequencies of rs3798759 G allele and GG genotype between the two groups (P U+003C 0.01). Single factor analysis stratified by sex also found that frequencies of rs3798759 GG and TG genotypes and G allele were significantly higher in female schizophrenia patients compared with healthy females (P U+003C 0.05). Haplotypes C-A-G and C-G G were more common in schizophrenia group (P U+003C 0.05). CONCLUSION: polymorphisms of rs3798759 may be a risk factor for female patients with schizophrenia, and haplotypes C-A-G and C-G-G may be risk factors for schizophrenia. PMID- 23450474 TI - [Influence of methylenetetrahydrofolate reductase gene polymorphisms on antidepressant response]. AB - OBJECTIVE: To assess the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene on response to antidepressant treatment. METHODS: Two hundred and eight one Chinese Han patients have received single antidepressant drugs for at least 6 weeks, among whom 275 were followed up for 8 weeks. Hamilton depression scale 17 (HAMD-17) was used to evaluate the severity of depressive symptoms and therapeutic effects. Single nucleotide polymorphisms (SNPs) of the MTHFR gene were determined using gene chips. Associations of single loci and haplotypes with response to treatment were analyzed using an Unphased 3.0.13 software. RESULTS: No significant differences in gender, age, year of education, family history, episode times, and antidepressant agents were found between responders and non-responders (all P U+003E 0.05), while the baseline scores of HAMD-17 was significantly different(t=2.891, P=0.004). There was also no significant difference between age, years of education, family history, baseline scores of HAMD-17 and antidepressant agents between remitters and non-remitters (both P U+003E 0.05), while proportion of male patients was significantly higher in non-remission group than remission group (t=2.381, P=0.018), and episode times in non-remission group was significantly higher (t=-1.983, P=0.049). Single locus association analysis has found no significant association between SNPs rs1801131 and rs1801133 in the MTHFR gene with antidepressant response (P U+003E 0.05). On the other hand, haplotype A-C of MTHFR gene (rs1801131 and rs1801133) was significantly associated with antidepressant response in total group (U+03C7 2=11.39, P=0.0007), male subgroup (U+03C7 2=8.767, P=0.003) and serotonin noradrenaline reuptake inhibitors (SNRIs) subgroup (U+03C7 2=10.51, P=0.001). CONCLUSION: Particular haplotype of MTHFR gene may be related with antidepressant effect, in which the haplotype (rs1801131, rs1801133) A-C type may be associated with better antidepressant efficacy, particularly in males and patients receiving SNRIs drugs. PMID- 23450475 TI - [Genetics and clinical study of Chinese kindreds with dentatorubral pallidoluysian atrophy]. AB - OBJECTIVE: To investigate genetics and clinical characteristics of dentatorubral pallidoluysian atrophy (DRPLA) in Chinese kindreds. METHODS: Fragment analysis with laser-induced fluorescence in capillary electrophoresis was performed for the cytosine-adenine-guanine (CAG) repeats of DRPLA gene in 708 probands of autosomal dominant ataxia pedigrees and 119 sporadic ataxia cases. RESULTS: Expanded CAG repeats of DRPLA gene were detected in probands of three ataxia pedigrees, with the numbers of repeats being 16/58, 16/58 and 14/54, respectively. In addition to ataxia, patients with adult-onset disease also exhibited spasm and neck torsion. CONCLUSION: Only three cases of DRPLA have been identified among 827 cases, which suggested that DRPLA is a relatively rare subtype of SCA in Chinese population. Clinical variation among the patients suggested DRPLA has a wide spectrum of phenotype. PMID- 23450476 TI - [Study on Duchenne muscular dystrophy gene mutation and prenatal diagnosis]. AB - OBJECTIVE: To explore the characteristics of DNA mutations underlying Duchenne muscular dystrophy and provide prenatal diagnosis. METHODS: Multiplex ligation dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) were applied for analyzing DMD gene mutations in 388 unrelated Chinese patients and 53 fetuses. RESULTS: Respectively, 230 and 43 subjects were found to harbor a deletion (59.28%) or duplication (11.08%). Two deletion hotspots were identified, which have located at exons 45-54 and exons 3 19. Duplications were mainly detected at exons 2-43. Point mutations were identified in 29.64% of patients. Fifty three fetuses were prenatal diagnosed, among which 18 were identified as patients. CONCLUSION: Frequencies of DMD gene deletions and duplications in China are similar to global data. Prenatal diagnosis can help to reduce births of DMD patients. PMID- 23450477 TI - [Efficiency of multiplex ligation-dependent probe amplification combined with short tandem repeat linkage analysis for the prenatal diagnosis for Duchenne muscular dystrophy]. AB - OBJECTIVE: To investigate the efficiency of multiplex ligation-dependent probe amplification (MLPA) combined with short tandem repeat (STR) linkage analysis for the prenatal diagnosis for Duchenne muscular dystrophy (DMD). METHODS: Gender of the fetus was first determined by the presence of Y chromosome sex-determining gene (SRY). Subsequently, combined MLPA and STR linkage analysis were applied for the probands, pregnant women and fetuses in 45 affected families. RESULTS: Among the 45 families, 31 SRY-positive fetuses were identified, among whom six were diagnosed with DMD. For 14 SRY-negative fetuses, four were diagnosed as carriers. The remainders were normal. CONCLUSION: MLPA can detect mutations in the exons of dystrophin gene, whilst STR linkage analysis can determine whether the fetus has inherited the maternal X chromosome bearing the mutant gene. As the result, the method can detect affected fetuses in which no exonic mutations are detected with MLPA. By combining the two methods, the diagnostic rate for DMD can be greatly improved. PMID- 23450478 TI - [Mutation analysis and prenatal diagnosis of families affected with Duchenne and Becker muscular dystrophy]. AB - OBJECTIVE: To detect potential mutations for probands from families affected with Duchenne/Becker muscular dystrophy (DMD/BMD), and to carry out prenatal diagnosis through identification of female carriers. METHODS: A total of 43 DMD/BMD families were recruited. Multiplex PCR was used to analyze 18 exons within hotspots for DMD gene deletions. Multiplex ligation-dependent probe amplification (MLPA) was used to detect potential deletions and duplications of DMD gene for 43 patients and 36 females from 32 families. Prenatal diagnosis was performed for 27 families. RESULTS: Deletional mutations were detected in 26 patients with multiplex PCR. In addition, MLPA has detected 3 deletions and 6 duplicational mutations, and the ranges of mutations were all determined. Among 36 female members, 18 were determined as carriers of deletional mutations, 10 were excluded as mutation carriers. The status of remaining 8 could not be determined. For prenatal diagnosis, 3 out of 18 male fetuses were diagnosed as patients and 1 female fetus was identified as carrier. CONCLUSION: MLPA is an accurate and reliable method for detecting deletional/duplicational mutations of DMD gene as well as for prenatal diagnosis and detection of female carriers. PMID- 23450479 TI - [Development and application of a method for molecular diagnosis of 21 hydroxylase deficiency]. AB - OBJECTIVE: To develop a method for elucidating genetic basis of 21-hydroxylase deficiency. METHODS: Sanger sequencing of entire 21-hydroxylase coding gene CYP21A2 was carried out to detect point mutations, and multiplex ligation dependent probe amplification (MLPA) and locus-specific PCR/enzyme restriction method were used to detect large deletions and conversion mutations. RESULTS: Nine children were analyzed. Point mutations of the CYP21A2 gene have been identified as: IVS2 13A/C>G (9 alleles), p.Arg356Trp (1 allele), Cluster E6 (1 allele), p.Gln318X (1 allele), and Prom conv (1 allele). While the former 4 mutations are pathogenic, the role of Prom conv mutation in the pathogenesis was uncertain. Three cases had entire CYP21A2 gene deletions (3 alleles), three had CYP21A1P/CYP21A2 chimeric mutations (3 alleles). The genotypes of all patients were determined. And all of the mutations were inherited from parents. CONCLUSION: A rational method for detecting point mutations and large deletions/conversions of CYP21A2 gene has been established. PMID- 23450480 TI - [Association between SIRT1 gene polymorphisms and longevity of populations from Yongfu region of Guangxi]. AB - OBJECTIVE: To assess the association between SIRT1 gene polymorphisms and the longevity phenomena in Yongfu region of Guangxi. In this case-control study, 500 individuals from Yongfu region of Guangxi were recruited. The subjects were divided into a longevity group (n=223, average age=93.17 U+00B1 3.08 yr) and a healthy control group (n=277, average age=46.92 U+00B1 17.12 yr). Polymerase chain reaction-high resolution melting curve (PCR-HRM) and DNA sequencing were used to determine the allelic and genotypic frequencies of rs3758391, rs3740051, rs2273773, rs4746720 and rs10997870 polymorphisms of SIRT1 gene in the two groups. The association between above polymorphisms and longevity was assessed. RESULTS: In the longevity group, CT genotype of the rs4746720 locus was significantly more common than CC and TT genotypes (P=0.000, OR=2.098, 95%CI:1.412-4.117). However, no significant difference was found in the allelic and genotypic frequencies of rs3758391, rs3740051 and rs2273773 between the two groups. CONCLUSION: There is an association between rs4746720 of SIRT1 gene and longevity in Yongfu region of Guangxi. PMID- 23450481 TI - [Methylation analysis of CpG island DNA of FMR1 gene in the fragile X syndrome]. AB - OBJECTIVE: To establish a method of methylation-sensitive restriction enzymes based quantitative PCR (MSRE-qPCR) for analysis of CpG island DNA of FMR1 gene, and to assess its value for molecular diagnosis of fragile X syndrome. METHODS: Thirty boys with mental retardation and abnormal repeats of 5'(CGG)n in the FMR1 gene and 20 mothers were analyzed by conventional PCR screening. Eag I was used to digest genomic DNA, and qPCR was performed to amplify CpG island in the FMR1 gene using both undigested and digested templates. Raw Ct values were obtained through quantitative PCR amplification. The degree of CpG island methylation was calculated by 2 - U+0394 U+0394 Ct. The result of MSRE-qPCR was verified by Southern blotting. 30 healthy females and 30 healthy males were used as controls to optimize the established MSRE-qPCR method. RESULTS: The ranges of 2 - U+0394 U+0394 Ct value for normal methylation, partial methylation and full methylation were determined. Among the 30 patients, 3 were found to have partial methylation of CpG island of the FMR1 gene, and 27 were found to have full methylation (3/30 results were verified by Southern blotting). Only 7 mothers were found abnormal methylation of CpG island of FMR1 gene, whilst the remaining 13 mothers were normal. CONCLUSION: MSRE-qPCR is a quick and reliable method for quantitative analysis of CpG island methylation status in FMR1 gene, which may provide a new strategy for the diagnosis of fragile X syndrome. PMID- 23450482 TI - [Progress of research on microRNA and Alzheimer's disease]. AB - MicroRNA are a group of non-coding RNA which, through regulating expression of proteins at post-transcription level, plays an important role in modulating growth and development of nervous system, cell differentiation and functions. Altered expression of microRNA in the brain may influence development and advance of Alzheimer's disease from multiple perspectives. Research on microRNA will facilitate in depth understanding of the pathogenesis of Alzheimer's disease. PMID- 23450483 TI - [Research on X-linked growth hormone deficiency and related genes]. AB - Growth hormone deficiency (GHD) is a common cause of dwarfism. Most GHD patients are sporadic, whilst 5%-30% are of familial type. X-linked GHD patients are relatively rare. We hereby provide a literature review and report on our latest findings of the disease. PMID- 23450484 TI - [Lung cancer and its epigenetics association with chronic obstructive pulmonary disease]. AB - Lung cancer and chronic obstructive pulmonary disease (COPD) are the leading causes of morbidity and mortality worldwide. Development of lung cancer involves both genetic and environment factors. In addition to genetic alterations, epigenetic mechanism is closely involved in pathogenesis of lung cancer. Characterized by an abnormal persistent inflammatory response to noxious environmental stimulation, COPD has shown to increase the susceptibility for lung tumorigenesis in previous research. Current research on epigenetics of lung cancer and COPD has focused on aberrant DNA methylation, histone acetylation and non-coding RNAs regulation. The aberrant DNA methylation associated with lung cancer and COPD has included overexpression of DNA methyltransferase, global DNA hypomethylation and DNA hypermethylation in promoter regions, while histone acetylation and histone methylation are the major changes for histone modification, in which histone acetyltransferases, histone deacetylases, histone methyltransferases and histone demethylases play the most important roles. RNA interference and microRNAs are both hot topics of research on non-coding RNAs regulation. Understanding of concurrent epigenetic alterations in the pathogenesis of lung cancer and COPD may facilitate identification of specific therapeutic targets and development of effective treatment. PMID- 23450485 TI - [Analysis of DCX gene mutation in a patient featuring X-linked subcortical laminar heterotopia and epilepsy]. AB - OBJECTIVE: To detect potential mutation of Doublecortin (DCX) gene in a patient featuring X-linked subcortical laminar heterotopia (X-SCLH) and epilepsy. METHODS: Mutation of the DCX gene was screened by PCR and direct sequencing. Pathogenicity of the mutation was analyzed with a PolyPhen-2 software. RESULTS: A de novo missense mutation c.971T>C (p.Phe324Ser) was discovered. CONCLUSION: A diagnostic method for X-SCLH has been established, which may facilitate diagnosis and genetic counseling of patients featuring this disease. PMID- 23450486 TI - [Significance of miR-155, miR-34a and miR-30a expression in diffuse large B-cell lymphoma]. AB - OBJECTIVE: To determine the expressions of miR-155, miR-34a and miR-30a in diffuse large B-cell lymphoma (DLBCL) and to explore their potential correlation with clinicopathological characteristics. METHODS: The expression level of miR 155, miR-34a and miR-30a in 46 DLBCL samples were determined with TaqMan real time polymerase chain reaction. Interphase fluorescence in situ hybridization (I FISH) was performed to detect MYC and p53 genes' status, and immunohistochemistry (Envision method) was used to evaluate the expression of CD3, CD10, CD20, BCL-6 and MUM-1 in DLBCL. The DLBCLs were classified into germinal center B cell-like (GCB) and non germinal center B cell-like (non-GCB) subtypes according to Hans' criteria. RESULTS: Compared with normal controls, miR-155 expression level was significantly higher in DLBCL. The expression level of miR-155 in non-GCB type was higher than that in GCB type. It was shown that the patients with MYC rearrangement had lower expression level of miR-155 than the negative controls. Compared with p53 normal group, the expression level of miR-34a was significantly lower in p53 deletion group. It was also shown that the patients with BCL-6 protein expression had lower expression of miR-30a compared with the negative group. CONCLUSION: miR-155 expression level is different in normal controls, DLBCL and patients with subtype DLBCL. It therefore has a diagnosis value for DLBCL. miR-34a is of great prognostic significance. miR-155, miR-34a and miR-30a may be potential therapy targets for DLBCL. PMID- 23450487 TI - [Clinical features and therapeutic response of aplastic anemia patients with or without cytogenetic abnormalities]. AB - OBJECTIVE: To compare clinical features and therapeutic response of patients with aplastic anemia with and without cytogenetic abnormalities. METHODS: Clinical features of 133 patients with successful chromosomal analysis were retrospectively studied, and therapeutic response between patients with and without cytogenetic abnormalities was compared. RESULTS: Cytogenetic abnormalities were found in 9 patients, which included trisomy 8 (4 cases), monosomy 7 (2 cases) and Xq- (1 case), 1q- (1 case) and 7q- (1 case). No significant difference was detected between patients with or without cytogenetic abnormalities in terms of age (50 vs. 58, P=0.337), sex ratio (male 55.56% vs. 62.10%, female 44.44% vs. 37.90%, P=0.762), or episode of acute aplastic anemia (44.44% vs. 37.10%, P=0.728). Patients with cytogenetic abnormalities had a tendency towards poorer rate of therapeutic response, which was however not significantly different from those without (55.56% vs. 79.03%, P=0.116). All of the 4 patients with +8 responded to treatment, whilst none of those with -7 or 7q did. CONCLUSION: No significant difference was found between aplastic anemia patients with or without cytogenetic abnormalities in terms of clinical features and therapeutic response. Patients with trisomy 8 seem to have a favorable response towards treatment. PMID- 23450488 TI - [A de novo partial 5p deletion and cryptic 18p duplication detected by SNP-Array in a boy featuring Cri du Chat syndrome]. AB - OBJECTIVE: To determine the karyotype of a boy suspected to have Cri du Chat syndrome with severe clinical manifestations, and to assess the recurrence risk for his family. METHODS: High-resolution GTG banding was performed to analyze the patient and his parents. Fluorescence in situ hybridization (FISH) with Cri du Chat syndrome region probe as well as subregional probes mapped to 5pter, 5qter, 18pter, 18qter, and whole chromosome painting probe 18 was performed to analyze the patient and his parents. In addition, single nucleotide polymorphism-based arrays (SNP-Array) analysis with Affymetrix GeneChip Genome-wide Human SNP Nsp/Sty 6.0 were also performed to analyze the patient. RESULTS: Karyotype analysis indicated that the patient has carried a terminal deletion in 5p. FISH with Cri du Chat syndrome region probe confirmed that D5S23 and D5S721 loci are deleted. SNP-Array has detected a 15 Mb deletion at 5p and a 2 Mb duplication at 18p. FISH with 5p subtelomeric probes and 18p subtelomeric probe further confirmed that the derivative chromosome 5 has derived from a translocation between 5p and 18p, which has given rise to a 46,XY,der(5)t(5;18)(p15.1;p11.31)dn karyotype. CONCLUSION: A de novo 5p partial deletion in conjunction with a cryptic 18p duplication has been detected in a boy featuring Cri-du-Chat syndrome. His parents, both with negative findings, have a low recurrence risk. For its ability to detect chromosomal imbalance, SNP-Array has a great value for counseling of similar patients and assessment of recurrence risks. PMID- 23450489 TI - [Identification of human small supernumerary marker chromosomes and discussion of its research value]. AB - OBJECTIVE: To identify the origin of human small supernumerary marker chromosomes (sSMCs) using fluorescent in situ hybridization (FISH) combined with G-banding karyotype analysis, and to discuss their mechanisms of formation and research value. METHODS: Cep-FISH and SubcenM-FISH were used to analyze sSMCs in 3 patients for whom the result of G-banding was 47,XN,+mar. RESULTS: The FISH result of case 1 was 47,XY,+mar.ish inv dup(22)(q11.1)(D22Z4++,D14/22Z1+, RP11 172D7-). The marker has formed exclusively by heterochromatin. A boy was delivered later with no apparent clinical abnormalities. The FISH result of case 2 was 47,XX,+mar.ish r(10)(p11.2q11.2) (cep10+, RP11-232C13+, RP11 178A10+)[25]/46,XX[10]. The marker has formed by heterochromatin and nearby centromere. A girl was delivered later with no clinical abnormalities. The FISH result of case 3 was 47,XY,+mar.ish inv dup(22)(q11.1)(D22Z4+,D14/22Z1+). The marker has also formed exclusively by euchromatin. Fetal abnormalities were detected by type B ultrasonography, but were not necessarily related with the marker. CONCLUSION: The diversity of sSMCs has posed a great challenge for prenatal diagnosis. Identification of sSMCs will require combined karyotype analysis and FISH or other molecular techniques such as microarray based comparative genomic hybridization or sequencing. For its specific structure, the sSMCs may also provide a valuable tool for gene mapping, heterochromatin research and gene therapy. PMID- 23450490 TI - [Screening for EXT1 and EXT2 gene mutations in a ethnic Han Chinese family from Shanxi with hereditary multiple exostoses]. AB - OBJECTIVE: To screen for potential mutations in an ethnic Han Chinese family from Shanxi with hereditary multiple exostoses. METHODS: Polymerase chain reaction and DNA sequencing were used to screen potential mutations in EXT1 and EXT2 genes. RESULTS: For EXT1 gene, two synonymous mutations (P477P and E587E), three intronic mutations (c.1537 -48A>G, c.1721 +203A>G and c.1722 -103C>G) were detected. For EXT2 gene, five intronic mutations (c.-29 -148A>T, c.1080 -18T>A, c.1336 -93C>T, c.1526 -166C>T, and c.1526 -195C>T) were identified. Among these, EXT1 P477P, EXT1 E587E and EXT2 c.1080 -18T>A are polymorphisms listed by Multiple Osteochondroma Mutation Database, whilst the other 7 sites have not been reported. CONCLUSION: No mutations have been found among all exons of the EXT1 and EXT2 genes in this family. Linkage analysis is necessary for identifying the cause of this disease. PMID- 23450491 TI - [Identification of a novel frameshift mutation of human androgen receptor gene in a patient featuring complete androgen insensitivity syndrome]. AB - OBJECTIVE: To identify potential mutation of human androgen receptor (AR) gene in a patient with complete androgen insensitivity syndrome (CAIS). METHODS: DNA sequences of 8 exons and exon/intron boundaries of the AR gene were amplified with PCR and directly sequenced. RESULTS: DNA sequencing has revealed a frameshift mutation due to deletion of nucleotide C at position 3507 in exon 6, which gave rise to a stop codon resulting premature termination for translation. CONCLUSION: A novel frameshift mutation in exon 6 of AR gene probably underlies the disease in our patient. PMID- 23450492 TI - [Association between glutathione-S-transferase gene polymorphisms (GSTM1, GSTT1 and GSTP1) and idiopathic azoospermia]. AB - OBJECTIVE: To assess the association between glutathione-S-transferase gene polymorphisms GSTT1, GSTM1 and GSTP1 and onset of azoospermia. METHODS: Multi-PCR was used to detect GSTM1 and GSTT1 gene deletions. Polymorphisms of GSTP1 were determined with restriction fragment length polymorphism (RFLP) method in 236 azoospermia patients and 142 healthy fertile male controls. RESULTS: The frequency of M1 (-/-) and P1 (Ile/Val or Val/Val) genotype was 24.65% in the control group, which was significantly higher than that of the patient group (15.68%, P=0.031). Frequency of M1 (-/-), T1 (+/+) and P1 (Ile/Val or Val/Val) genotype was 12.68% in the control group, which was significantly higher than that of the patient group (5.51%, P=0.014). CONCLUSION: The M1(-/-) and P1(Ile/Val or Val/Val) genotype and the M1(-/-), T1(+/+) and P1 (Ile/Val or Val/Val) genotype are associated with reduced risk of azoospermia in ethnic Chinese Han population. PMID- 23450493 TI - [Association of FOXP3 gene polymorphism in Chinese women with endometriosis]. AB - OBJECTIVE: To assess the association between single nucleotide polymorphisms (SNPs) of forkhead box P3 gene (FOXP3) and endometriosis in Chinese Han women from central China. METHODS: MassARRAY IPLEX and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) technique was used to determine the genotypes of FOXP3 gene in 314 patients with endometriosis and 358 healthy controls. RESULTS: Genotypes of C/T polymorphism for the rs2280883 locus, A/C for the rs3761548 locus, and C/T for the rs3761549 locus were determined. No significant difference was detected in distribution of genotypes CC, CT and TT (P=0.770, OR=0.960; P=0.923, OR=1.013) and frequencies of C and T alleles (P=0.772, OR=0.960; P=0.925, OR=1.013) for rs2280883 and rs3761549 between the two groups. And no significant difference was detected in distribution of genotypes AA, AC and CC (P=0.762, OR=0.958) and frequencies of A and C alleles (P=0.715, OR=0.950) for rs3761548 was detected between the two groups. Based on r-AFS classification, the patients were divided into two groups (respectively with I-II stage and III-IV stage endometriosis). Again, no significant difference was detected in distribution of genotypes CC, CT and TT (P=0.454, OR=1.198, P=0.526, OR=0.909; P=0.220, OR=0.750, P=0.548, OR=1.094) and frequencies of C and T alleles (P=0.473, OR=1.215, P=0.532, OR=0.912; P=0.204, OR=0.737, P=0.558, OR=1.089) for rs22080883 and rs3761549 loci between the two patient groups. No association was found between distribution of genotypes AA, AC and CC (P=0.431, OR=1.211; P=0.508, OR=0.905) and frequencies of A and C alleles (P=0.417, OR=1.226; P=0.516, OR=0.908) for rs3761548 locus between the two patient groups. CONCLUSION: Our study has failed to found any association between FOXP3 gene polymorphisms rs2280883, rs3761548 and rs3761549 with endometriosis in Chinese Han patients. PMID- 23450494 TI - [Association of polymorphisms of PTPN22 and PADI4 genes with rheumatoid arthritis in Yunnan]. AB - OBJECTIVE: To assess the association between genetic polymorphisms of 7 SNPs in PTPN22 and PADI4 genes and susceptibility to rheumatoid arthritis in Yunnan. METHODS: A case-control study was carried out on 192 patients of rheumatoid arthritis and 288 healthy controls. Genotypes of rs33996649 and 1858 loci within PTPN22 gene, and rs11203366 and rs874881 loci within PADI4 gene were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method. Genotypes of rs1635579, rs2428736 and rs2240340 in PADI4 gene were determined with pyrosequencing. RESULTS: The frequencies of alleles and genotypes of rs2240340 locus in PADI4 gene showed a significant difference between rheumatoid arthritis and controls in Yunnan population (P U+003C 0.05). CONCLUSION: Our results suggested that rs2240340 in PADI4 gene is associated with susceptibility to rheumatoid arthritis in Yunnan. PMID- 23450495 TI - [A study of interleukin-10 gene polymorphisms in Miao, Dong and Buyi ethnics of Guizhou]. AB - OBJECTIVE: To investigate allelic frequencies of interluekin-10 (IL-10) gene promoter in Miao, Dong and Buyi ethnics of Guizhou. METHODS: TaqMan MGB-based real-time PCR was used to determine the genotypes of IL-10 -819 and IL-10 -592 in 589 Miao, Dong and Buyi ethnics of Guizhou. RESULTS: The allelic frequency of IL 10 -819 in Miao ethnics was significantly different from those in Dong or Buyi ethnics. Allelic frequencies of IL-10 -592 in Miao ethnics was significantly different from those in Dong or Buyi ethnics. In Miao, Dong and Buyi ethnics, the distributions of genotype frequencies of IL-10 -819 and IL-10 -592 were statistically different from Han ethnics from Guizhou and Taiwan of China as well as South Koreans. CONCLUSION: There is a heterogeneity in the frequencies of polymorphisms of IL-10 promoter among different ethnic groups. PMID- 23450496 TI - [A pedigree with X-linked congenital adrenal dysplasia]. PMID- 23450497 TI - [A family with hereditary coagulation factor deficiency]. PMID- 23450498 TI - ESBL, MBL and Ampc beta Lactamases Producing Superbugs - Havoc in the Intensive Care Units of Punjab India. AB - BACKGROUND: An alarming rise in the rates of the antibiotic resistance has now become a serious and an increasingly common public health concern, with severe implications, especially in the intensive care units. A variety of beta lactamases which include ESBLs, AmpC beta-lactamases and metallo-betalactamases, have emerged as the most worrisome mechanism of resistance among the gram negative bacteria, which pose a therapeutic challenge to the health care settings. MATERIALS AND METHODS: The present study was aimed at knowing the prevalence of various beta-lactamases in the gram negative isolates which were obtained from ICU patients. A total 273 gram negative isolates from 913 clinical samples which were received over a period of one year were processed for their identification and their antimicrobial susceptibility pattern was determined. They were then screened for the beta-lactamase production. RESULTS: Among the 273 isolates, the beta-lactamase production was observed in 193 strains. 96 (35.16%) strains were ESBL producers, followed by 30 (10.98%) metallo beta- lactamase (MBL) producers and 15(5.4%) AmpC producers. The major ESBL and AmpC producer was Escherichia coli, while Klebsiella pneumonia was the predominant MBL producer. The co production of the ESBL/MBL/ AmpC beta- lactamases was observed in 52 (19.04%) strains and it was more common in Escherichia coli. A multidrug resistance to the fluoroquinolones and the aminoglycosides was also observed in the beta- lactamase producing organisms. CONCLUSION: The high prevalence of the beta- lactamases in the ICU isolates emphasizes the need for a continuous surveillance in the ICUs to detect the resistant strains, strict guidelines for the antibiotic therapy and the implementation of infection control measures to reduce the increasing burden of antibiotic resistance. PMID- 23450499 TI - Functional impairment in adult sleepwalkers: a case-control study. AB - STUDY OBJECTIVES: To investigate the restorative quality of sleep and daytime functioning in sleepwalking adult patients in comparison with controls. DESIGN: Prospective case-control study. SETTING: Data were collected at the Sleep Disorders Center, Hopital-Gui-de Chauliac, Montpellier, France between June 2007 and January 2011. PARTICIPANTS: There were 140 adult sleepwalkers (100 (median age 30 y, 55% male) in whom primary SW was diagnosed) who underwent 1 night of video polysomnography. All patients participated in a standardized clinical interview and completed a battery of questionnaires to assess clinical characteristics of parasomnia, daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and health-related quality of life. Results were compared with those of 100 sex- and age-matched normal controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Of the sleepwalkers, 22.3% presented with daily episodes and 43.5% presented with weekly episodes. Median age at sleepwalking onset was 9 y. Familial history of sleepwalking was reported in 56.6% of sleepwalkers and violent sleep related behaviors in 57.9%, including injuries requiring medical care for at least one episode in 17%. Significant associations were found between sleepwalking and daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and altered quality of life. Early-onset sleepwalkers had higher frequency of violent behaviors and injuries. Sleepwalkers with violent behaviors had higher frequency of sleep terrors and triggering factors, with greater alteration in health-related quality of life. CONCLUSION: Adult sleepwalking is a potentially serious condition that may induce violent behaviors, self-injury or injury to bed partners, sleep disruption, excessive daytime sleepiness, fatigue, and psychological distress, all of which affect health-related quality of life. CITATION: Lopez R; Jaussent I; Scholz S; Bayard S; Montplaisir J; Dauvilliers Y. Functional impairment in adult sleepwalkers: a case-control study. SLEEP 2013;36(3):345-351. PMID- 23450500 TI - New developments in the study of the microbiota of raw-milk, long-ripened cheeses by molecular methods: the case of Grana Padano and Parmigiano Reggiano. AB - Microorganisms are an essential component of cheeses and play important roles during both cheese manufacture and ripening. Both starter and secondary flora modify the physical and chemical properties of cheese, contributing and reacting to changes that occur during the manufacture and ripening of cheese. As the composition of microbial population changes under the influence of continuous shifts in environmental conditions and microorganisms interactions during manufacturing and ripening, the characteristics of a given cheese depend also on microflora dynamics. The microbiota present in cheese is complex and its growth and activity represent the most important, but the least controllable steps. In the past, research in this area was dependent on classical microbiological techniques. However, culture-dependent methods are time-consuming and approaches that include a culturing step can lead to inaccuracies due to species present in low numbers or simply uncultivable. Therefore, they cannot be used as a unique tool to monitor community dynamics. For these reasons approaches to cheese microbiology had to change dramatically. To address this, in recent years the focus on the use of culture-independent methods based on the direct analysis of DNA (or RNA) has rapidly increased. Application of such techniques to the study of cheese microbiology represents a rapid, sound, reliable, and effective way for the detection and identification of the microorganisms present in dairy products, leading to major advances in understanding this complex microbial ecosystem and its impact on cheese ripening and quality. In this article, an overview on the recent advances in the use of molecular methods for thorough analysis of microbial communities in cheeses is given. Furthermore, applications of culture independent approaches to study the microbiology of two important raw-milk, long ripened cheeses such as Grana Padano and Parmigiano Reggiano, are presented. PMID- 23450501 TI - Physiological basis of copper tolerance of Saccharomyces cerevisiae nonsense mediated mRNA decay mutants. AB - The eukaryotic nonsense-mediated mRNA decay pathway (NMD) is a specialized pathway that contributes to the recognition and rapid degradation of mRNA with premature termination codons. In addition to mRNAs containing premature termination codons, NMD degrades non-nonsense-containing, natural mRNAs. Approximately 5-10% of the total Saccharomyces cerevisiae transcriptome is affected when NMD is inactivated. The regulation of natural mRNAs by NMD has physiological consequences. However, the physiological outcomes associated with the degradation of specific natural mRNAs by NMD are not fully understood. Here, we examined the physiological consequences resulting from the NMD-mediated regulation of an mRNA involved in copper homeostasis, in an attempt to understand why nmd mutant strains are more tolerant of toxic copper levels than wild-type yeast strains. We found that wild-type (UPF1) and upf1Delta mutants accumulate similar amounts of total copper when grown in medium containing elevated levels of copper; however, the copper levels in the cytoplasm of wild-type yeast cells were higher than in the upf1Delta mutant. Copper tolerance by the upf1Delta mutant is dependent on the presence of CTR2. Deletion of CTR2 resulted in similar cytoplasmic copper levels in wild-type and upf1Delta mutant strains, regardless of the environmental copper levels. This suggests that CTR2 plays a role in regulating the level of copper in the cytoplasm. We also found that the upf1Delta mutant contained elevated copper levels in the vacuole relative to wild-type yeast cells, after both strains were exposed to elevated copper levels. PMID- 23450502 TI - Evaluation of the CHADS2 risk score on short- and long-term all-cause and cardiovascular mortality after syncope. AB - BACKGROUND: Syncope risk stratification is difficult and has not been implemented clinically. HYPOTHESIS: The CHADS2 score can be applied as a risk stratification tool for predicting mortality after an episode of syncope. METHODS: All patients discharged from emergency departments with a first-time diagnosis of syncope from 2001 to 2009 where identified from nationwide registers in Denmark and matched on sex and age with a control population. Risk of all-cause or cardiovascular death was analyzed by multivariable Cox models. RESULTS: A total of 37,705 patients were included. There were a total of 7761 deaths (21%), of which 52% were cardiovascular vs 27 862 (15%) deaths in the control population. The risk of cardiovascular death was significantly increased with increasing CHADS2 score (CHADS2 score: 1-2, hazard ratio [HR]: 9.11, 95% confidence interval [CI]: 8.25 10.07; CHADS2 score: 3-4, HR: 17.32, 95% CI: 15.42-19.47; CHADS2 score: 5-6, HR: 26.66, 95% CI: 21.40-33.21) relative to CHADS2 score of 0. A CHADS2 score of 0 was associated overall with very low event rates (15.1 deaths per 1000 person years) but was associated with increased relative risk in the syncope population compared to controls. Syncope predicted 1-week, 1-year, and long-term mortality across CHADS2 scores compared to controls but did not reach significance in CHADS2 scores of 5 to 6. CONCLUSIONS: Increasing CHADS2 score significantly predicts mortality in patients discharged with a diagnosis of syncope, and a CHADS2 score of 0 was associated with a very low absolute mortality. Compared to controls, syncope was associated with increased short- and long-term mortality, particularly in the lower CHADS2 scores. PMID- 23450503 TI - Proteus: Mythology to modern times. AB - AIMS: It is common knowledge that proteus bacteria are associated with urinary tract infections and urinary stones. Far more interesting however, is the derivation of the word proteus. This study examines the origin of the word proteus, its mythological, historical and literary connections and evolution to present-day usage. MATERIALS AND METHODS: A detailed search for primary and secondary sources was undertaken using the library and internet. RESULTS: Greek mythology describes Proteus as an early sea-god, noted for being versatile and capable of assuming many different forms. In the 8(th) century BC, the ancient Greek poet, Homer, famous for his epic poems the Iliad and Odyssey, describes Proteus as a prophetic old sea-god, and herdsman of the seals of Poseidon, God of the Sea. Shakespeare re-introduced Proteus into English literature, in the 15(th) century AD, in the comedy The Two Gentleman of Verona, as one of his main characters who is inconstant with his affections. The 'elephant man' was afflicted by a severely disfiguring disease, described as 'Proteus syndrome'. It is particularly difficult to distinguish from neurofibromatosis, due to its various forms in different individuals. The Oxford English Dictionary defines the word 'protean' as to mean changeable, variable, and existing in multiple forms. Proteus bacteria directly derive their name from the Sea God, due to their rapid swarming growth and motility on agar plates. They demonstrate versatility by secreting enzymes, which allow them to evade the host's defense systems. CONCLUSIONS: Thus proteus, true to its name, has had a myriad of connotations over the centuries. PMID- 23450504 TI - Modifying native nanocellulose aerogels with carbon nanotubes for mechanoresponsive conductivity and pressure sensing. AB - Mechanically excellent native cellulose nanofibers that are cleaved from plant cell walls have been modified by functionalized few-walled carbon nanotubes for hybrid nanofiber/nanotube aerogels. They show elastic mechanical behavior in combination with reversible electrical response under compression allowing responsive conductivity and pressure sensing. The concept combines wide availability of nanocellulosics and electrical functionality of carbon nanotubes synergistically. PMID- 23450505 TI - Melatonin modulates aromatase activity and expression in endothelial cells. AB - Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens. The presence of aromatase on endothelial cells indicates that endothelial cells may contribute to tumor growth by producing estrogens. Since human umbilical vein endothelial cells (HUVECs) express both aromatase and melatonin receptors, the aim of the present study was to evaluate the ability of melatonin to regulate the activity and expression of aromatase on endothelial cells, thus, modulating local estrogen biosynthesis. In the present study, we demonstrated that melatonin inhibits the growth of HUVECs and reduces the local biosynthesis of estrogens through the downregulation of aromatase. These results are supported by three lines of evidence. Firstly, 1 mM of melatonin counteracted the testosterone-induced cell proliferation of HUVECs, which is dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. Secondly, we found that 1 mM of melatonin reduced the aromatase activity of HUVECs. Finally, by real-time RT-PCR, we demonstrated that melatonin significantly downregulated the expression of aromatase as well as its endothelial-specific aromatase promoter region I.7. We conclude that melatonin inhibits aromatase activity and expression in HUVECs by regulating gene expression of specific aromatase promoter regions, thereby reducing the local production of estrogens. PMID- 23450506 TI - Radiotherapy for inverted papilloma: a case report and review of the literature. AB - BACKGROUND: Sinonasal inverted papilloma (IP) is a rare, usually benign tumor arising from the respiratory mucosa of the sinonasal tract. Surgical resection is the treatment of choice. In histologically overt benign IPs (i.e. without associated malignancy) irradiation was employed only anecdotally. The patient with gross residual of benign IP after up-front surgery that was subsequently treated with irradiation is presented and the literature reports on the use of radiotherapy (RT) in this tumor type are reviewed. CASE REPORT: After the surgical treatment the residuum in the region of the sphenoid and adjacent cavernous sinus was irradiated to 54 Gy in 1.8 Gy daily fractions. No recurrence or deterioration of olfaction, hearing or vision was observed 2.6 years post-RT. REVIEW OF THE LITERATURE: In the literature, six reports were identified with 16 patients describing necessary details on RT and outcome. Twelve of 14 cases (our case included) with gross or subtotal tumor resection and postoperative RT were locally controlled. The lowest and the median irradiation doses were 47.15 Gy and 56.5 Gy, respectively, and the follow-up period ranged between 0.5-20.5 years (median 7.8 years). CONCLUSIONS: RT is safe and valuable treatment option in histologically overt benign IPs. It is indicated when the risk of tumor recurrence after surgery is increased and in inoperable tumors. PMID- 23450507 TI - Structural abnormalities in the thalamus of migraineurs with aura: a multiparametric study at 3 T. AB - BACKGROUND AND OBJECTIVES: The thalamus exerts a pivotal role in pain processing and cortical excitability control, and migraine is characterized by repeated pain attacks and abnormal cortical habituation to excitatory stimuli. This work aimed at studying the microstructure of the thalamus in migraine patients using an innovative multiparametric approach at high-field magnetic resonance imaging (MRI). DESIGN: We examined 37 migraineurs (22 without aura, MWoA, and 15 with aura, MWA) as well as 20 healthy controls (HC) in a 3-T MRI equipped with a 32 channel coil. We acquired whole-brain T1 relaxation maps and computed magnetization transfer ratio (MTR), generalized fractional anisotropy, and T2* maps to probe microstructural and connectivity integrity and to assess iron deposition. We also correlated the obtained parametric values with the average monthly frequency of migraine attacks and disease duration. RESULTS: T1 relaxation time was significantly shorter in the thalamus of MWA patients compared with MWoA (P < 0.001) and HC (P <= 0.01); in addition, MTR was higher and T2* relaxation time was shorter in MWA than in MWoA patients (P < 0.05, respectively). These data reveal broad microstructural alterations in the thalamus of MWA patients compared with MWoA and HC, suggesting increased iron deposition and myelin content/cellularity. However, MWA and MWoA patients did not show any differences in the thalamic nucleus involved in pain processing in migraine. CONCLUSIONS: There are broad microstructural alterations in the thalamus of MWA patients that may underlie abnormal cortical excitability control leading to cortical spreading depression and visual aura. PMID- 23450508 TI - Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia. AB - The immunoglobulin heavy chain variable (IGHV) gene mutational status represents a major prognostic marker in chronic lymphocytic leukemia (CLL). Usually, the prognostic implications of IGHV gene analysis can be reliably ascertained but, occasionally, double productive rearrangements have been detected. Clinical presentation and biological features of such cases are unknown. Sixty patients with morphologically and phenotypically monoclonal CLL but double productive IGHV rearrangements were retrospectively identified by mRNA analysis from three Hematology Institutions. Clinical and biological features and survival of these 60 patients were compared with a control group of patients with CLL and single IGHV rearrangement. A prospective registry was used to assess the epidemiology of double productive IGHV among incidental patients with CLL. Using standard criteria to define IGHV-mutated (M) or unmutated (U) cases, 39 of the 60 patients (65%) with double productive IGHV rearrangement had concordant status (23 MM, 16 UU), while 21 (35%) had discordant IGHV status. As compared with M patients, the MM ones had lower CD38 expression, more favorable cytogenetics and more indolent clinical behavior. Cases with UU had similar characteristics of U patients. Discordant cases presented with adverse prognostic features and had an aggressive clinical behavior requiring early treatment, similar to U patients. The prevalence of double IGHV was 3.1%. Patients with CLL with double concordant mutational status (MM or UU) have a clinical course similar to that of the corresponding single IGHV status, while those exhibiting discordant status represent a high risk population. This may help correct stratification within clinical trials. PMID- 23450509 TI - Studying 18 MDa virus assemblies with native mass spectrometry. PMID- 23450510 TI - Different mechanisms contributing to savings and anterograde interference are impaired in Parkinson's disease. AB - Reinforcement and use-dependent plasticity mechanisms have been proposed to be involved in both savings and anterograde interference in adaptation to a visuomotor rotation (cf. Huang et al., 2011). In Parkinson's disease (PD), dopamine dysfunction is known to impair reinforcement mechanisms, and could also affect use-dependent plasticity. Here, we assessed savings and anterograde interference in PD with an A1-B-A2 paradigm in which movement repetition was (1) favored by the use of a single-target, and (2) manipulated through the amount of initial training. PD patients and controls completed either limited or extended training in A1 where they adapted movement to a 30 degrees counter-clockwise rotation of visual feedback of the movement trajectory, and then adapted to a 30 degrees clockwise rotation in B. After subsequent washout, participants readapted to the first 30 degrees counter-clockwise rotation in A2. Controls showed significant anterograde interference from A1 to B only after extended training, and significant A1-B-A2 savings after both limited and extended training. However, despite similar A1 adaptation to controls, PD patients showed neither anterograde interference nor savings. That extended training was necessary in controls to elicit anterograde interference but not savings suggests that savings and anterograde interference do not result from equal contributions of the same underlying mechanism(s). It is suggested that use-dependent plasticity mechanisms contributes to anterograde interference but not to savings, while reinforcement mechanisms contribute to both. As both savings and anterograde interference were impaired in PD, dopamine dysfunction in PD might impair both reinforcement and use-dependent plasticity mechanisms during adaptation to a visuomotor rotation. PMID- 23450511 TI - Review of the quality of pediatric medications in developing countries. AB - The quality of essential medicines for pediatric populations in developing countries is largely unknown. This review examines quality studies (2000-2011) of medicines on the WHO Essential Medicine List for Children, the quality of a subset of pediatric formulations, and the association of these poor quality medicines with adverse clinical outcomes. We searched Embase, Medline, BIOSIS, and IPA using MeSH subject terms for quality measures, medicine formulations, and substandard medicines and combined these with 267 medicines, and 91 low-income and lower-middle-income countries. Seventy articles met our inclusion criteria examining the quality of 75 medicines from 28 countries. Content and dissolution tests were utilized most often. Results indicate that antibacterials, antifungals, and antiretrovirals were consistently of good quality. Quality tests on pediatric formulations were performed on 55 of 75 of the medicines studied and followed the general trend of quality results. Three studies were included that examined clinical consequences of substandard medicines-two cases of diethylene glycol poisoning and one case of substandard malaria drugs. We conclude that there is a need for more quality studies of pediatric formulations of essential medicines in developing countries and their clinical consequences. PMID- 23450512 TI - Anatomical and functional connectivity as a tool to study brain networks in Parkinson's disease. PMID- 23450513 TI - Sildenafil and diastolic dysfunction after acute myocardial infarction trial: rationale and design. AB - AIMS: Diastolic dysfunction following myocardial infarction is an important predictor of outcome, irrespective of left ventricular systolic function. Previous studies suggest that phosphordiesterase-5 inhibition has a favorable effect on the myocardium as well as on the pulmonary and systemic vasculature. METHODS: Patients>=50 years old with recent myocardial infarction, preserved left ventricular ejection fraction (>=45%), and echocardiographic evidence of diastolic dysfunction (ratio between early [E] transmitral filling velocity and early diastolic tissue Doppler velocity [e']>=8 and left atrial volume>=34 mL/m2) will be double-blindly randomized 1:1 to receive 9 weeks of treatment with 40 mg sildenafil, 3 times per day, or comparable placebo. Before randomization and after 9 weeks of treatment, resting Doppler echocardiography, resting right heart catheterization, and symptom-limited supine cycle exercise testing with simultaneous echocardiography and right heart catheterization will be performed. The primary end point is filling pressure at rest and at peak exercise. STATISTICS: With a power of 80% and a significance level of .05, a study group of 60 patients is needed to detect a 15% reduction at peak exercise, which is considered clinically relevant. To account for dropouts and noncompliance, 70 patients will be enrolled in the study. CONCLUSIONS: In addition to determining if sildenafil can reduce filling pressure at rest and at peak exercise, the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction trial will provide additional hemodynamic information to help phenotypically classify this growing population of patients with diastolic dysfunction and preserved ejection fraction following myocardial infarction. PMID- 23450514 TI - Efficient solution-processed small-molecule solar cells with inverted structure. AB - We successfully demonstrate inverted structure small-molecule (SM) solar cells with an efficiency of 7.88% using ZnO and PEIE as an interfacial layer. Modification of ZnO with a cost-effective PEIE thin layer increases the efficiency of the inverted cell as a result of reducing the work function of the cathode and suppressing the trap-assisted recombination. In addition to the high efficiency, the inverted SM solar cells are relatively stable in air compared to conventional cells. PMID- 23450515 TI - Health effects of olive oil polyphenols: recent advances and possibilities for the use of health claims. AB - The Mediterranean diet and consumption of olive oil have been connected in several studies with longevity and a reduced risk of morbidity and mortality. Lifestyle, such as regular physical activity, a healthy diet, and the existing social cohesion in Southern European countries have been recognised as candidate protective factors that may explain the Mediterranean Paradox. Along with some other characteristics of the Mediterranean diet, the use of olive oil as the main source of fat is common in Southern European countries. The benefits of consuming olive oil have been known since antiquity and were traditionally attributed to its high content in oleic acid. However, it is now well established that these effects must also be attributed to the phenolic fraction of olive oil with its anti-oxidant, anti-inflammatory and anti-microbial activities. The mechanisms of these activities are varied and probably interconnected. For some activities of olive oil phenolic compounds, the evidence is already strong enough to enable the legal use of health claims on foods. This review discusses the health effects of olive oil phenols along with the possibilities of communicating these effects on food labels. PMID- 23450516 TI - Slow biasing of processing resources in early visual cortex is preceded by emotional cue extraction in emotion-attention competition. AB - In our previous studies on competition for attentional processing resources in early visual cortex between a foreground task and distracting emotional background images we found that emotional background images withdraw attentional resources from the foreground task after about 400 ms. Costs in behavioral data and a significant reduction of the steady state visual evoked potential (SSVEP) amplitude that was elicited by the foreground task lasted for several hundred milliseconds. We speculated that the differential effect in SSVEP amplitudes is preceded by the extraction of the emotional cue. Event related potential (ERP) studies to emotional and neutral complex images identified an early posterior negativity (EPN) as a robust neural signature of emotional cue extraction. The late positive potential (LPP) was related to in-depth processing of the emotional image. We extracted ERPs that were evoked by the onset of background images concurrently with the SSVEP that was elicited by the foreground task. Emotional compared to neutral background pictures evoked a more negative EPN at about 190 ms and a more positive LPP at about 700 ms after image onset. SSVEP amplitudes became significantly smaller with emotional background images after about 400 ms lasting for several hundred ms. Interestingly, we found no significant correlations between the three components, indicating that they act independently. Source localizations resulted in nonoverlapping cortical generators. Results suggest a cascade of perceptual processes: Extraction of the emotional cue preceded biasing of attentional resources away from the foreground task towards the emotional image for an evaluation of the picture content. PMID- 23450517 TI - Oxidative cyclodimerization after tandem cyclization of dehydrobenzo[14]annulenes induced by alkyllithium. PMID- 23450518 TI - Magnetic resonance imaging: a biomarker for cognitive impairment in Parkinson's disease? AB - Dementia is a frequent and disabling complication of Parkinson's disease (PD). Clinicians and researchers lack a biomarker capable of tracking the structural and functional changes that underlie the evolution of cognitive dysfunction in PD. Magnetic resonance imaging (MRI) has been adopted as a biomarker in natural history and interventional studies of Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), but its utility as a biomarker for PD and Parkinson's disease dementia (PDD) is unclear. In this review, the authors summarize the studies that have used MRI to investigate cognitive decline in PD, outline limitations of those studies, and suggest directions for future research. PD dementia is associated with extensive cortical atrophy, which may be quantified with structural MRI. More promisingly, patterns of atrophy may be present in those who have PD with MCI (PD-MCI). Subcortical white matter tract degeneration is detectable early in the disease with diffusion tensor imaging and may precede changes observed on conventional structural MRI. Although less well studied, other MR techniques, such as functional MRI, MR perfusion imaging with arterial spin labeling, and MR spectroscopy, have demonstrated differences in activation and metabolism between PD and PDD. In this review, the ability to compare studies was limited by the heterogeneity of study populations, cognitive testing methods, and imaging protocols. Future work should adopt agreed scan protocols, should be adequately powered, and should use carefully phenotyped patients to fully maximize the contribution of MRI as a biomarker for PDD. PMID- 23450519 TI - Skin necrosis induced by generic enoxaparin. PMID- 23450520 TI - Prenatal chromosomal microarray analysis: a survey of prenatal genetic counselors' experiences and attitudes. AB - OBJECTIVE: Studies showing the efficacy and accuracy of chromosomal microarray analysis (CMA) in prenatal diagnosis may position it as a first-tier prenatal test. This study seeks to characterize the practices and attitudes of North American prenatal genetic counselors regarding CMA. METHOD: Genetic counselors (N = 196) in Canada and the USA responded to an anonymous online survey. Completed surveys were analyzed (n = 160). RESULTS: Most respondents viewed CMA as useful (73%), presented CMA to patients (84%), and had ordered CMA at least once (69%). The use of full versus targeted arrays varied. Logistic regression analyses identified three significant predictors for the view that prenatal CMA is useful: more prenatal counseling experience, younger age, and previously presenting CMA to a patient. Three factors predicted the likelihood of offering CMA to prenatal patients: percentage of time spent in prenatal practice, belief that CMA is useful, and practicing in the USA (versus Canada). Reasons cited for not using CMA included financial concerns, the possibility of ambiguous results, and ethical concerns. Most respondents (n = 111) believed that ambiguous results are an ethical issue. CONCLUSION: Clinical guidelines for prenatal CMA, further research on specific copy number variants, and broader availability of targeted arrays to reduce ambiguous results are needed. PMID- 23450522 TI - Ultrasensitive non-resonant detection of ultrasound with plasmonic metamaterials. PMID- 23450521 TI - pH-sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability. AB - Tombusviruses, such as Carnation Italian ringspot virus (CIRV), encode a protein homodimer called p19 that is capable of suppressing RNA silencing in their infected hosts by binding to and sequestering short-interfering RNA (siRNA) away from the RNA silencing pathway. P19 binding stability has been shown to be sensitive to changes in pH but the specific amino acid residues involved have remained unclear. Using constant pH molecular dynamics simulations, we have identified key pH-dependent residues that affect CIRV p19-siRNA binding stability at various pH ranges based on calculated changes in the free energy contribution from each titratable residue. At high pH, the deprotonation of Lys60, Lys67, Lys71, and Cys134 has the largest effect on the binding stability. Similarly, deprotonation of several acidic residues (Asp9, Glu12, Asp20, Glu35, and/or Glu41) at low pH results in a decrease in binding stability. At neutral pH, residues Glu17 and His132 provide a small increase in the binding stability and we find that the optimal pH range for siRNA binding is between 7.0 and 10.0. Overall, our findings further inform recent experiments and are in excellent agreement with data on the pH-dependent binding profile. PMID- 23450523 TI - Combining the Marangoni effect and the pH-responsive superhydrophobicity superhydrophilicity transition to biomimic the locomotion process of the beetles of genus Stenus. PMID- 23450524 TI - Iontophoresis-targeted, follicular delivery of minoxidil sulfate for the treatment of alopecia. AB - Although minoxidil (MX) is a drug known to stimulate hair growth, the treatment of androgenic alopecia could be improved by delivery strategies that would favor drug accumulation into the hair follicles. This work investigated in vitro the potential of iontophoresis to achieve this objective using MX sulfate (MXS), a more water-soluble derivative of MX. Passive delivery of MXS was first determined from an ethanol-water solution and from a thermosensitive gel. The latter formulation resulted in greater accumulation of MXS in the stratum corneum (skin's outermost layer) and hair follicles and an overall decrease in absorption through the skin. Anodal iontophoresis of MXS from the same gel formulation was then investigated at pH 3.5 and pH 5.5. Compared with passive delivery, iontophoresis increased the amount of drug reaching the follicular infundibula from 120 to 600 ng per follicle. In addition, drug recovery from follicular casts was threefold higher following iontophoresis at pH 5.5 compared with that at pH 3.5. Preliminary in vivo experiments in rats confirmed that iontophoretic delivery of MXS facilitated drug accumulation in hair follicles. Overall, therefore, iontophoresis successfully and significantly enhanced follicular delivery of MX suggesting a useful opportunity for the improved treatment of alopecia. PMID- 23450525 TI - Nanotechnology for implantable sensors: carbon nanotubes and graphene in medicine. AB - Implantable sensors utilizing nanotechnology are at the forefront of diagnostic, medical monitoring, and biological technologies. These sensors are often equipped with nanostructured carbon allotropes, such as graphene or carbon nanotubes (CNTs), because of their unique and often enhanced properties over forms of bulk carbon, such as diamond or graphite. Because of these properties, the fundamental and applied research of these carbon nanomaterials have become some of the most cited topics in scientific literature in the past decades. The age of carbon nanomaterials is simply budding, however, and is expected to have a major impact in many areas. These areas include electronics, photonics, plasmonics, energy capture (including batteries, fuel cells, and photovoltaics), and--the emphasis of this review--biosensors and sensor technologies. The following review will discuss future prospects of the two most commonly used carbon allotropes in implantable sensors for nanomedicine and nanobiotechnology, CNTs and graphene. Sufficient further reading and resources have been provided for more in-depth and specific reading that is outside the scope of this general review. PMID- 23450526 TI - Anti-D administration in pregnancy for preventing Rhesus alloimmunisation. AB - BACKGROUND: During pregnancy, a Rhesus negative (Rh-negative) woman may develop antibodies when her fetus is Rhesus positive (Rh-positive). These antibodies may harm Rh-positive babies. OBJECTIVES: To assess the effects of antenatal anti-D immunoglobulin on the incidence of Rhesus D alloimmunisation when given to Rh negative women without anti-D antibodies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2012). SELECTION CRITERIA: Randomised trials in Rh-negative women without anti-D antibodies given anti-D after 28 weeks of pregnancy, compared with no treatment, placebo or a different regimen of anti-D. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and extracted the data. MAIN RESULTS: Two trials with moderate to high risk of bias, involving over 4500 women, compared anti-D prophylaxis with no anti-D during pregnancy. When women received anti-D at 28 and 34 weeks' gestation, risks of immunisation were not significantly different than for women not given antenatal anti-D: risk ratio (RR) of immunisation during pregnancy was 0.42 (95% confidence interval (CI) 0.15 to 1.17); after the birth of a Rh-positive infant the RR was 0.42 (95% CI 0.15 to 1.17); and within 12 months after birth of a Rh-positive infant the RR was 0.39 (95% CI 0.10 to 1.62).However, women receiving anti-D during pregnancy were significantly less likely to register a positive Kleihauer test (which detects fetal cells in maternal blood) in pregnancy (RR 0.60, 95% CI 0.41 to 0.88) and at the birth of a Rh-positive infant (RR 0.60, 95% CI 0.46 to 0.79). No data were available for the risk of Rhesus D alloimmunisation in a subsequent pregnancy. No significant differences were seen for neonatal jaundice, and no adverse effects were reported in either trial. AUTHORS' CONCLUSIONS: The risk of Rhesus D alloimmunisation during or immediately after a first pregnancy is about 1%. Administration of 100 ug (500 IU) anti-D to women in their first pregnancy can reduce this risk to about 0.2% without, to date, any adverse effects. Although unlikely to confer benefit in the current pregnancy, fewer women may have Rhesus D antibodies in any subsequent pregnancy, but the effects of this needs to be tested in studies of robust design. PMID- 23450527 TI - Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that mainly affects the small joints of the hands and feet. Erythropoiesis-stimulating agents have been used to treat anemia, one of the extra-articular manifestations of RA. Although anemia is less of a problem now because of the reduction in inflammation due to disease-modifying antirheumatic drugs (DMARDs), it could still be an issue in countries where DMARDs are not yet accessible. OBJECTIVES: We assessed the clinical benefits and harms of erythropoiesis-stimulating agents for anemia in rheumatoid arthritis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 7 2012), Ovid MEDLINE and Ovid MEDLINE(R) In Process & Other Non-Indexed Citations (1948 to 7 August 2012), OVID EMBASE (1980 to 7 August 2012), LILACS (1982 to 7 August 2012), the Clinical Trials Search Portal of the World Health Organization, reference lists of the retrieved publications and review articles. We did not apply any language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in patients aged 16 years or over, with a diagnosis of rheumatoid arthritis affected by anemia. We considered health-related quality of life, fatigue and safety as the primary outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently performed trial selection, risk of bias assessment, and data extraction. We estimated difference in means with 95% confidence intervals (CIs) for continuous outcomes. We estimated risk ratios with 95% CIs for binary outcomes. MAIN RESULTS: We included three RCTs with a total of 133 participants. All trials compared human recombinant erythropoietin (EPO), for different durations (8, 12 and 52 weeks), versus placebo. All RCTs assessed health-related quality of life. All trials had high or unclear risk of bias for most domains, and were sponsored by the pharmaceutical industry. Two trials administered EPO by a subcutaneous route while the other used an intravenous route.We decided not to pool results from trials, due to inconsistencies in the reporting of results.Health-related quality of life: subcutaneous EPO - one trial with 70 patients at 52 weeks showed a statistically significant difference in improvement of patient global assessment (median and interquartile range 3.5 (1.0 to 6.0) compared with placebo 4.5 (2.0 to 7.5) (P = 0.027) on a VAS scale (0 to 10)). The other shorter term trials (12 weeks with subcutaneous EPO and eight weeks with intravenous administration) did not find statistically significant differences between treatment and control groups in health-related quality of life outcomes.Change in hemoglobin: both trials of subcutaneous EPO showed a statistically significant difference in increasing hemoglobin levels; (i) at 52 weeks (one trial, 70 patients), intervention hemoglobin level (median 134, interquartile range 110 to 158 g/litre) compared with the placebo group level (median 112, interquartile range; 86 to 128 g/litre) (P = 0.0001); (ii) at 12 weeks (one trial, 24 patients) compared with placebo (difference in means 8.00, 95% CI 7.43 to 8.57). Intravenous EPO at eight weeks showed no statistically significant difference in increasing hematocrit level for EPO versus placebo (difference in means 4.69, 95% CI -0.17 to 9.55; P = 0.06).Information on withdrawals due to adverse events was not reported in two trials, and one trial found no serious adverse events leading to withdrawals. None of the trials reported withdrawals due to high blood pressure, or to lack of efficacy or to fatigue. AUTHORS' CONCLUSIONS: We found conflicting evidence for erythropoiesis-stimulating agents to increase quality of life and hemoglobin level by treating anemia in patients with rheumatoid arthritis. However, this conclusion is based on randomized controlled trials with a high risk of bias, and relies on trials assessing human recombinant erythropoietin (EPO). The safety profile of EPO is unclear. Future trials assessing erythropoiesis-stimulating agents for anemia in rheumatoid arthritis should be conducted by independent researchers and reported according to the CONSORT statements. Trials should be based on Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and The Patient-Centered Outcomes Research Institute (PCORI) approaches for combining both clinician and patient perspectives. PMID- 23450528 TI - Extramedullary fixation implants and external fixators for extracapsular hip fractures in adults. AB - BACKGROUND: Extramedullary fixation of hip fractures involves the application of a plate and screws to the lateral side of the proximal femur. In external fixators, the stabilising component is held outside the thigh by pins or screws driven into the bone. This is an update of a Cochrane review first published in 1998, and last updated in 2005. OBJECTIVES: To assess the relative effects of different types of extramedullary fixation implant, as well as external fixators, for treating extracapsular proximal femoral (hip) fractures in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (July 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2011, Issue 2), MEDLINE (1966 to June Week 4 2011), EMBASE (1988 to 2011 Week 25), various other databases, conference proceedings and reference lists. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing extramedullary implants or external fixators for fixing extracapsular hip fracture in adults were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias and extracted data. Data were pooled where appropriate. MAIN RESULTS: The 18 included trials tested seven comparisons in a total of 2615 mainly female and older participants with a total of 2619 fractures. All trials had methodological flaws that may affect the validity of their results.Three trials of 355 participants comparing a fixed nail plate (Jewett or McLaughlin) with the sliding hip screw (SHS) found an increased risk of fixation failure for fixed nail plates.The two trials of 433 participants comparing the Resistance Augmented Bateaux (RAB) plate with the SHS had contrasting results, notably in terms of operative complications, fixation failure and anatomical restoration.One trial of 100 participants comparing the Pugh nail and the SHS found no significant difference between implants.Three trials of 458 participants compared the Medoff plate with the SHS. There was a trend to higher blood losses and longer operation times for the Medoff plate along with a trend to a lower risk of fixation failure with the Medoff plate for unstable trochanteric fractures.Two trials of 676 participants compared the Medoff plate with three different screw-plate systems. There were no statistically significant differences in outcome for trochanteric fractures. For subtrochanteric fractures, there was a lower fixation failure rate for the Medoff plate but no evidence for differences in longer-term outcomes.Four trials of 396 participants comparing the Gotfried percutaneous compression plate (PCCP) with a SHS found a trend to lower blood loss and transfusion requirements for the PCCP but no other confirmed differences in outcomes between implants. Three of the trials reported intra-operative problems with the PCCP, some of which precluded its use.Three trials of 200 participants comparing external fixation with a SHS found less operative trauma for the external fixation. Final outcome appeared similar. AUTHORS' CONCLUSIONS: The markedly increased fixation failure rate of fixed nail plates compared with the SHS is a major consideration and thus the SHS appears preferable.There was insufficient evidence from other comparisons of extramedullary implants or on the use of external fixators to draw definite conclusions. PMID- 23450529 TI - Vaccines for preventing influenza in people with asthma. AB - BACKGROUND: Influenza vaccination is recommended for asthmatic patients in many countries as observational studies have shown that influenza infection can be associated with asthma exacerbations. However, influenza vaccination has the potential to cause wheezing and adversely affect pulmonary function. While an overview concluded that there was no clear benefit of influenza vaccination in patients with asthma, this conclusion was not based on a systematic search of the literature. OBJECTIVES: The objective of this review was to assess the efficacy and safety of influenza vaccination in children and adults with asthma. SEARCH METHODS: We searched the Cochrane Airways Group trials register and reviewed reference lists of articles. The latest search was carried out in November 2012. SELECTION CRITERIA: We included randomised trials of influenza vaccination in children (over two years of age) and adults with asthma. We excluded studies involving people with chronic obstructive pulmonary disease. DATA COLLECTION AND ANALYSIS: Inclusion criteria and assessment of trial quality were applied by two review authors independently. Data extraction was done by two review authors independently. Study authors were contacted for missing information. MAIN RESULTS: Nine trials were included in the first published version of this review, and nine further trials have been included in four updates. The included studies cover a wide diversity of people, settings and types of influenza vaccination, and we pooled data from the studies that employed similar vaccines. PROTECTIVE EFFECTS OF INACTIVATED INFLUENZA VACCINE DURING THE INFLUENZA SEASON: A single parallel-group trial, involving 696 children, was able to assess the protective effects of influenza vaccination. There was no significant reduction in the number, duration or severity of influenza-related asthma exacerbations. There was no difference in the forced expiratory volume in one second (FEV) although children who had been vaccinated had better symptom scores during influenza positive weeks. Two parallel-group trials in adults did not contribute data to these outcomes due to very low levels of confirmed influenza infection. ADVERSE EFFECTS OF INACTIVATED INFLUENZA VACCINE IN THE FIRST TWO WEEKS FOLLOWING VACCINATION: Two cross-over trials involving 1526 adults and 712 children (over three years old) with asthma compared inactivated trivalent split-virus influenza vaccine with a placebo injection. These trials excluded any clinically important increase in asthma exacerbations in the two weeks following influenza vaccination (risk difference 0.014; 95% confidence interval -0.010 to 0.037). However, there was significant heterogeneity between the findings of two trials involving 1104 adults in terms of asthma exacerbations in the first three days after vaccination with split-virus or surface-antigen inactivated vaccines. There was no significant difference in measures of healthcare utilisation, days off school/symptom-free days, mean lung function or medication usage.EFFECTS OF LIVE ATTENUATED (INTRANASAL) INFLUENZA VACCINATION: There were no significant differences found in exacerbations or measures of lung function following live attenuated cold recombinant vaccine versus placebo in two small studies on 17 adults and 48 children. There were no significant differences in asthma exacerbations found for the comparison live attenuated vaccine (intranasal) versus trivalent inactivated vaccine (intramuscular) in one study on 2229 children (over six years of age). AUTHORS' CONCLUSIONS: Uncertainty remains about the degree of protection that vaccination affords against asthma exacerbations that are related to influenza infection. Evidence from more recently published randomised trials of inactivated split-virus influenza vaccination indicates that there is no significant increase in asthma exacerbations immediately after vaccination in adults or children over three years of age. We were unable to address concerns regarding possible increased wheezing and hospital admissions in infants given live intranasal vaccination. PMID- 23450530 TI - Drugs for treating Schistosoma mansoni infection. AB - BACKGROUND: Schistosoma mansoni is a parasitic infection common in the tropics and sub-tropics. Chronic and advanced disease includes abdominal pain, diarrhoea, blood in the stool, liver cirrhosis, portal hypertension, and premature death. OBJECTIVES: To evaluate the effects of antischistosomal drugs, used alone or in combination, for treating S. mansoni infection. SEARCH METHODS: We searched MEDLINE, EMBASE and LILACS from inception to October 2012, with no language restrictions. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2012) and mRCT. The reference lists of articles were reviewed and experts were contacted for unpublished studies. SELECTION CRITERIA: Randomized controlled trials of antischistosomal drugs, used alone or in combination, versus placebo, different antischistosomal drugs, or different doses of the same antischistosomal drug for treating S. mansoni infection. DATA COLLECTION AND ANALYSIS: One author extracted data and assessed eligibility and risk of bias in the included studies, which were independently checked by a second author. We combined dichotomous outcomes using risk ratio (RR) and continuous data weighted mean difference (WMD); we presented both with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Fifty-two trials enrolling 10,269 participants were included. The evidence was of moderate or low quality due to the trial methods and small numbers of included participants.Praziquantel: Compared to placebo, praziquantel 40 mg/kg probably reduces parasitological treatment failure at one month post-treatment (RR 3.13, 95% CI 1.03 to 9.53, two trials, 414 participants, moderate quality evidence). Compared to this standard dose, lower doses may be inferior (30 mg/kg: RR 1.52, 95% CI 1.15 to 2.01, three trials, 521 participants, low quality evidence; 20 mg/kg: RR 2.23, 95% CI 1.64 to 3.02, two trials, 341 participants, low quality evidence); and higher doses, up to 60 mg/kg, do not appear to show any advantage (four trials, 783 participants, moderate quality evidence).The absolute parasitological cure rate at one month with praziquantel 40 mg/kg varied substantially across studies, ranging from 52% in Senegal in 1993 to 92% in Brazil in 2006/2007. Oxamniquine: Compared to placebo, oxamniquine 40 mg/kg probably reduces parasitological treatment failure at three months (RR 8.74, 95% CI 3.74 to 20.43, two trials, 82 participants, moderate quality evidence). Lower doses than 40 mg/kg may be inferior at one month (30 mg/kg: RR 1.78, 95% CI 1.15 to 2.75, four trials, 268 participants, low quality evidence; 20 mg/kg: RR 3.78, 95% CI 2.05 to 6.99, two trials, 190 participants, low quality evidence), and higher doses, such as 60 mg/kg, do not show a consistent benefit (four trials, 317 participants, low quality evidence).These trials are now over 20 years old and only limited information was provided on the study designs and methods. Praziquantel versus oxamniquine: Only one small study directly compared praziquantel 40 mg/kg with oxamniquine 40 mg/kg and we are uncertain which treatment is more effective in reducing parasitological failure (one trial, 33 participants, very low quality evidence). A further 10 trials compared oxamniquine at 20, 30 and 60 mg/kg with praziquantel 40 mg/kg and did not show any marked differences in failure rate or percent egg reduction.Combination treatments: We are uncertain whether combining praziquantel with artesunate reduces failures compared to praziquantel alone at one month (one trial, 75 participants, very low quality evidence).Two trials also compared combinations of praziquantel and oxamniquine in different doses, but did not find statistically significant differences in failure (two trials, 87 participants). Other outcomes and analyses: In trials reporting clinical improvement evaluating lower doses (20 mg/kg and 30 mg/kg) against the standard 40 mg/kg for both praziquantel or oxamniquine, no dose effect was demonstrable in resolving abdominal pain, diarrhoea, blood in stool, hepatomegaly, and splenomegaly (follow up at one, three, six, 12, and 24 months; three trials, 655 participants).Adverse events were not well-reported but were mostly described as minor and transient.In an additional analysis of treatment failure in the treatment arm of individual studies stratified by age, failure rates with 40 mg/kg of both praziquantel and oxamniquine were higher in children. AUTHORS' CONCLUSIONS: Praziquantel 40 mg/kg as the standard treatment for S. mansoni infection is consistent with the evidence. Oxamniquine, a largely discarded alternative, also appears effective.Further research will help find the optimal dosing regimen of both these drugs in children.Combination therapy, ideally with drugs with unrelated mechanisms of action and targeting the different developmental stages of the schistosomes in the human host should be pursued as an area for future research. PMID- 23450531 TI - Colloids versus crystalloids for fluid resuscitation in critically ill patients. AB - BACKGROUND: Colloid solutions are widely used in fluid resuscitation of critically ill patients. There are several choices of colloid, and there is ongoing debate about the relative effectiveness of colloids compared to crystalloid fluids. OBJECTIVES: To assess the effects of colloids compared to crystalloids for fluid resuscitation in critically ill patients. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register (17 October 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library) (Issue 10, 2012), MEDLINE (Ovid) 1946 to October 2012, EMBASE (Ovid) 1980 to October 2012, ISI Web of Science: Science Citation Index Expanded (1970 to October 2012), ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to October 2012), PubMed (October 2012), www.clinical trials.gov and www.controlled trials.com. We also searched the bibliographies of relevant studies and review articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of colloids compared to crystalloids, in patients requiring volume replacement. We excluded cross-over trials and trials involving pregnant women and neonates. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and rated quality of allocation concealment. We analysed trials with a 'double intervention', such as those comparing colloid in hypertonic crystalloid to isotonic crystalloid, separately. We stratified the analysis according to colloid type and quality of allocation concealment. MAIN RESULTS: We identified 78 eligible trials; 70 of these presented mortality data.COLLOIDS COMPARED TO CRYSTALLOIDS: Albumin or plasma protein fraction - 24 trials reported data on mortality, including a total of 9920 patients. The pooled risk ratio (RR) from these trials was 1.01 (95% confidence interval (CI) 0.93 to 1.10). When we excluded the trial with poor-quality allocation concealment, pooled RR was 1.00 (95% CI 0.92 to 1.09). Hydroxyethyl starch - 25 trials compared hydroxyethyl starch with crystalloids and included 9147 patients. The pooled RR was 1.10 (95% CI 1.02 to 1.19). Modified gelatin - 11 trials compared modified gelatin with crystalloid and included 506 patients. The pooled RR was 0.91 (95% CI 0.49 to 1.72). (When the trials by Boldt et al were removed from the three preceding analyses, the results were unchanged.) Dextran - nine trials compared dextran with a crystalloid and included 834 patients. The pooled RR was 1.24 (95% CI 0.94 to 1.65). COLLOIDS IN HYPERTONIC CRYSTALLOID COMPARED TO ISOTONIC CRYSTALLOID: Nine trials compared dextran in hypertonic crystalloid with isotonic crystalloid, including 1985 randomised participants. Pooled RR for mortality was 0.91 (95% CI 0.71 to 1.06). AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery. Furthermore, the use of hydroxyethyl starch might increase mortality. As colloids are not associated with an improvement in survival and are considerably more expensive than crystalloids, it is hard to see how their continued use in clinical practice can be justified. PMID- 23450532 TI - Psychosocial and psychological interventions for preventing postpartum depression. AB - BACKGROUND: Epidemiological studies and meta-analyses of predictive studies have consistently demonstrated the importance of psychosocial and psychological variables as postpartum depression risk factors. While interventions based on these variables may be effective treatment strategies, theoretically they may also be used in pregnancy and the early postpartum period to prevent postpartum depression. OBJECTIVES: Primary: to assess the effect of diverse psychosocial and psychological interventions compared with usual antepartum, intrapartum, or postpartum care to reduce the risk of developing postpartum depression. Secondary: to examine (1) the effectiveness of specific types of psychosocial and psychological interventions, (2) the effectiveness of professionally-based versus lay-based interventions, (3) the effectiveness of individually-based versus group based interventions, (4) the effects of intervention onset and duration, and (5) whether interventions are more effective in women selected with specific risk factors. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2011), scanned secondary references and contacted experts in the field. We updated the search on 31 December 2012 and added the results to the awaiting classification section of the review for assessment at the next update. SELECTION CRITERIA: All published and unpublished randomised controlled trials of acceptable quality comparing a psychosocial or psychological intervention with usual antenatal, intrapartum, or postpartum care. DATA COLLECTION AND ANALYSIS: Review authors and a research co-ordinator with Cochrane review experience participated in the evaluation of methodological quality and data extraction. Additional information was sought from several trial researchers. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. MAIN RESULTS: Twenty-eight trials, involving almost 17,000 women, contributed data to the review. Overall, women who received a psychosocial or psychological intervention were significantly less likely to develop postpartum depression compared with those receiving standard care (average RR 0.78, 95% confidence interval (CI) 0.66 to 0.93; 20 trials, 14,727 women). Several promising interventions include: (1) the provision of intensive, individualised postpartum home visits provided by public health nurses or midwives (RR 0.56, 95% CI 0.43 to 0.73; two trials, 1262 women); (2) lay (peer)-based telephone support (RR 0.54, 95% CI 0.38 to 0.77; one trial, 612 women); and (3) interpersonal psychotherapy (standardised mean difference -0.27, 95% CI -0.52 to -0.01; five trials, 366 women). Professional- and lay-based interventions were both effective in reducing the risk to develop depressive symptomatology. Individually-based interventions reduced depressive symptomatology at final assessment (RR 0.75, 95% CI 0.61 to 0.92; 14 trials, 12,914 women) as did multiple-contact interventions (RR 0.78, 95% CI 0.66 to 0.93; 16 trials, 11,850 women). Interventions that were initiated in the postpartum period also significantly reduced the risk to develop depressive symptomatology (RR 0.73, 95% CI 0.59 to 0.90; 12 trials, 12,786 women). Identifying mothers 'at-risk' assisted the prevention of postpartum depression (RR 0.66, 95% CI 0.50 to 0.88; eight trials, 1853 women). AUTHORS' CONCLUSIONS: Overall, psychosocial and psychological interventions significantly reduce the number of women who develop postpartum depression. Promising interventions include the provision of intensive, professionally-based postpartum home visits, telephone-based peer support, and interpersonal psychotherapy. PMID- 23450533 TI - Drug therapy for preventing post-dural puncture headache. AB - BACKGROUND: Post-dural (post-lumbar or post-spinal) puncture headache (PDPH) is one of the most common complications of diagnostic, therapeutic or inadvertent lumbar punctures. Many drug options have been used to prevent headache in clinical practice and have also been tested in some clinical studies, but there are still some uncertainties about their clinical effectiveness. OBJECTIVES: To assess the effectiveness and safety of drugs for preventing PDPH in adults and children. SEARCH METHODS: The search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 5), MEDLINE (from 1950 to May 2012), EMBASE (from 1980 to May 2012) and CINAHL (from 1982 to June 2012). There was no language restriction. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that assessed the effectiveness of any drug used for preventing PDPH. DATA COLLECTION AND ANALYSIS: Review authors independently selected studies, assessed risks of bias and extracted data. We estimated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous outcomes. We calculated a 95% confidence interval (CI) for each RR and MD. We did not undertake meta-analysis because participants' characteristics or assessed doses of drugs were too different in the included studies. We performed an intention-to-treat (ITT) analysis. MAIN RESULTS: We included 10 RCTs (1611 participants) in this review with a majority of women (72%), mostly parturients (women in labour) (913), after a lumbar puncture for regional anaesthesia. Drugs assessed were epidural and spinal morphine, spinal fentanyl, oral caffeine, rectal indomethacin, intravenous cosyntropin, intravenous aminophylline and intravenous dexamethasone.All the included RCTs reported data on the primary outcome, i.e. the number of participants affected by PDPH of any severity after a lumbar puncture. Epidural morphine and intravenous cosyntropin reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to placebo. Also, intravenous aminophylline reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to no intervention, while intravenous dexamethasone increased it. Spinal morphine increased the number of participants affected by pruritus when compared to placebo, and epidural morphine increased the number of participants affected by nausea and vomiting when compared to placebo. Oral caffeine increased the number of participants affected by insomnia when compared to placebo.The remainder of the interventions analysed did not show any relevant effect for any of the outcomes.None of the included RCTs reported the number of days that patients stayed in hospital. AUTHORS' CONCLUSIONS: Morphine and cosyntropin have shown effectiveness for reducing the number of participants affected by PDPH of any severity after a lumbar puncture, when compared to placebo, especially in patients with high risk of PDPH, such as obstetric patients who have had an inadvertent dural puncture. Aminophylline also reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to no intervention in patients undergoing elective caesarean section. Dexamethasone increased the risk of PDPH, after spinal anaesthesia for caesarean section, when compared to placebo. Morphine also increased the number of participants affected by adverse events (pruritus and nausea and vomiting)There is a lack of conclusive evidence for the other drugs assessed (fentanyl, caffeine, indomethacin and dexamethasone).These conclusions should be interpreted with caution, owing to the lack of information, to allow correct appraisal of risk of bias and the small sample sizes of studies. PMID- 23450534 TI - Personalised risk communication for informed decision making about taking screening tests. AB - BACKGROUND: There is a trend towards greater patient involvement in healthcare decisions. Although screening is usually perceived as good for the health of the population, there are risks associated with the tests involved. Achieving both adequate involvement of consumers and informed decision making are now seen as important goals for screening programmes. Personalised risk estimates have been shown to be effective methods of risk communication. OBJECTIVES: To assess the effects of personalised risk communication on informed decision making by individuals taking screening tests. We also assess individual components that constitute informed decisions. SEARCH METHODS: Two authors searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2012), MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EbscoHOST) and PsycINFO (OvidSP) without language restrictions. We searched from 2006 to March 2012. The date ranges for the previous searches were from 1989 to December 2005 for PsycINFO and from 1985 to December 2005 for other databases. For the original version of this review, we also searched CancerLit and Science Citation Index (March 2001). We also reviewed the reference lists and conducted citation searches of included studies and other systematic reviews in the field, to identify any studies missed during the initial search. SELECTION CRITERIA: Randomised controlled trials incorporating an intervention with a 'personalised risk communication element' for individuals undergoing screening procedures, and reporting measures of informed decisions and also cognitive, affective, or behavioural outcomes addressing the decision by such individuals, of whether or not to undergo screening. DATA COLLECTION AND ANALYSIS: Two authors independently assessed each included trial for risk of bias, and extracted data. We extracted data about the nature and setting of interventions, and relevant outcome data. We used standard statistical methods to combine data using RevMan version 5, including analysis according to different levels of detail of personalised risk communication, different conditions for screening, and studies based only on high risk participants rather than people at 'average' risk. MAIN RESULTS: We included 41 studies involving 28,700 people. Nineteen new studies were identified in this update, adding to the 22 studies included in the previous two iterations of the review. Three studies measured informed decision with regard to the uptake of screening following personalised risk communication as a part of their intervention. All of these three studies were at low risk of bias and there was strong evidence that the interventions enhanced informed decision making, although with heterogeneous results. Overall 45.2% (592/1309) of participants who received personalised risk information made informed choices, compared to 20.2% (229/1135) of participants who received generic risk information. The overall odds ratios (ORs) for informed decision were 4.48 (95% confidence interval (CI) 3.62 to 5.53 for fixed effect) and 3.65 (95% CI 2.13 to 6.23 for random effects). Nine studies measured increase in knowledge, using different scales. All of these studies showed an increase in knowledge with personalised risk communication. In three studies the interventions showed a trend towards more accurate risk perception, but the evidence was of poor quality. Four out of six studies reported non-significant changes in anxiety following personalised risk communication to the participants. Overall there was a small non-significant decrease in the anxiety scores. Most studies (32/41) measured the uptake of screening tests following interventions. Our results (OR 1.15 (95% CI 1.02 to 1.29)) constitute low quality evidence, consistent with a small effect, that personalised risk communication in which a risk score was provided (6 studies) or the participants were given their categorised risk (6 studies), increases uptake of screening tests. AUTHORS' CONCLUSIONS: There is strong evidence from three trials that personalised risk estimates incorporated within communication interventions for screening programmes enhance informed choices. However the evidence for increasing the uptake of such screening tests with similar interventions is weak, and it is not clear if this increase is associated with informed choices. Studies included a diverse range of screening programmes. Therefore, data from this review do not allow us to draw conclusions about the best interventions to deliver personalised risk communication for enhancing informed decisions. The results are dominated by findings from the topic area of mammography and colorectal cancer. Caution is therefore required in generalising from these results, and particularly for clinical topics other than mammography and colorectal cancer screening. PMID- 23450535 TI - Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. AB - BACKGROUND: Neuropsychiatric involvement in systemic lupus erythematosus (SLE) is complex and it is an important cause of morbidity and mortality. Management of nervous system manifestations of SLE remains unsatisfactory. This is an update of a Cochrane review first published in 2000 and previously updated in 2006. OBJECTIVES: To assess the benefits and harms of cyclophosphamide and methylprednisolone in the treatment of neuropsychiatric manifestations of SLE. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, SCOPUS and WHO up to and including June 2012. We sought additional articles through handsearching in relevant journals as well as contact with experts. There were no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials that compared cyclophosphamide to methylprednisolone in patients with SLE of any age and gender and presenting with any kind of neuropsychiatric manifestations. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted, assessed and cross-checked data. We produced a 'Summary of findings' table. We presented dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: We did not include any new trials in this update. One randomised controlled trial of 32 patients is included. Concerning risk of bias, generation of the allocation sequence was at low risk; however, allocation concealment, blinding and selective reporting were at high risk. Treatment response, defined as 20% improvement from basal conditions by clinical, serological and specific neurological measures, was found in 94.7% (18/19) of patients using cyclophosphamide compared with 46.2% (6/13) in the methylprednisolone group at 24 months (RR 2.05, 95% CI 1.13 to 3.73). This was statistically significant and the number needed to treat for an additional beneficial outcome (NNTB) of treatment response is three. We found no statistically significant differences between the groups in damage index measurements (Systemic Lupus International Collaborating Clinics (SLICC)). The median SLE Disease Activity Index (SLEDAI) rating favoured the cyclophosphamide group. Cyclophosphamide use was associated with a reduction in prednisone requirements. All the patients in the cyclophosphamide group had electroencephalographic improvement but there was no statistically significant difference in decrease between groups in the number of monthly seizures. No statistically significant differences in adverse effects, including mortality, were reported between the groups. AUTHORS' CONCLUSIONS: This systematic review found one randomised controlled trial with a small number of patients in the different clinical subgroups of neurological manifestation. There is very low quality evidence that cyclophosphamide is more effective in reducing symptoms of neuropsychiatric involvement in SLE compared with methylprednisolone. However, properly designed randomised controlled trials that involve large numbers of individuals, with explicit clinical and laboratory diagnostic criteria, sufficient duration of follow-up and description of all relevant outcome measures, are necessary to guide practice. As we did not find any new trials to include in this review at update, the conclusions of the review did not change. PMID- 23450536 TI - Electromagnetic therapy for treating venous leg ulcers. AB - BACKGROUND: Leg ulceration is a common, chronic, recurring condition. The estimated prevalence of leg ulcers in the UK population is 1.5 to 3 per 1000. Venous ulcers (also called stasis or varicose ulcers) comprise 80% to 85% of all leg ulcers. Electromagnetic therapy (EMT) is sometimes used as a treatment to assist the healing of chronic wounds such as venous leg ulcers. OBJECTIVES: To assess the effects of EMT on the healing of venous leg ulcers. SEARCH METHODS: For this third update, we searched The Cochrane Wounds Group Specialised Register (searched 12 November 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10); Ovid MEDLINE (2011 to November Week 1 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, November 12, 2012); Ovid EMBASE (2011 to 2012 Week 45); and EBSCO CINAHL (2011 to 9 November 2012). SELECTION CRITERIA: Randomised controlled trials comparing EMT with sham-EMT or other treatments. DATA COLLECTION AND ANALYSIS: At least two review authors independently scrutinised search results and obtained full reports of potentially eligible studies for further assessment. We extracted and summarised details of eligible studies using a data extraction sheet, and made attempts to obtain missing data by contacting study authors. A second review author checked data extraction, and we resolved disagreements after discussion between review authors. MAIN RESULTS: Three randomised controlled trials (RCTs) of variable quality involving 94 people were included in the original review; subsequent updates have identified no new trials. All the trials compared the use of EMT with sham-EMT. In the two trials that reported healing rates; one small trial (44 participants) reported that significantly more ulcers healed in the EMT group than the sham-EMT group however this result was not robust to different assumptions about the outcomes of participants who were lost to follow up. The second trial that reported numbers of ulcers healed found no significant difference in healing. The third trial was also small (31 participants) and reported significantly greater reductions in ulcer size in the EMT group however this result may have been influenced by differences in the prognostic profiles of the treatment groups. AUTHORS' CONCLUSIONS: There is no high quality evidence that electromagnetic therapy increases the rate of healing of venous leg ulcers, and further research is needed. PMID- 23450537 TI - Treatment of Lennox-Gastaut syndrome. AB - BACKGROUND: The Lennox-Gastaut syndrome (LGS) is an age-specific disorder, characterised by epileptic seizures, a characteristic electroencephalogram (EEG), psychomotor delay and behavioural disorder. It occurs more frequently in males and onset is usually before the age of eight years, with a peak between three and five years of age. Late cases occurring in adolescence and early adulthood have rarely been reported. Language is frequently affected, with both slowness in ideation and expression in addition to difficulties of motor dysfunction. Severe behavioural disorders (e.g. hyperactivity, aggressiveness and autistic tendencies) and personality disorders are nearly always present. There is also a tendency for psychosis to develop with time. The long-term prognosis is poor; although the epilepsy often improves, complete seizure freedom is rare and conversely the mental and psychiatric disorders tend to worsen with time. OBJECTIVES: To compare the effects of pharmaceutical therapies used to treat LGS in terms of control of seizures and adverse effects. Many people who suffer from this syndrome will already be receiving other antiepileptic medications at the time of their entry into a trial. However, for the purpose of this review we will only consider the effect of the single therapeutic agent being trialled (often as add-on therapy). SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialized Register (18 October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 10 of 12, 2012) and MEDLINE (1946 to October week 2, 2012). We also searched EMBASE (1980 to March 2003). We imposed no language restrictions. We searched the International Standard Randomised Controlled Trial Number (ISRCTN) register (18 October 2012) for ongoing trials and in addition, we contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: All randomised controlled trials (RCTs) of the administration of drug therapy to patients with LGS. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. Analysis included assessing study quality, as well as statistical analysis of the effects on overall seizure rates and effects on specific seizure types (e.g. drop attacks), adverse effects and mortality. MAIN RESULTS: We found nine RCTs, but were unable to perform any meta-analysis, because each trial looked at different populations, different therapies and considered different outcomes. AUTHORS' CONCLUSIONS: The optimum treatment for LGS remains uncertain and no study to date has shown any one drug to be highly efficacious; rufinamide, lamotrigine, topiramate and felbamate may be helpful as add-on therapy, clobazam may be helpful for drop seizures. Until further research has been undertaken, clinicians will need to continue to consider each patient individually, taking into account the potential benefit of each therapy weighed against the risk of adverse effects. PMID- 23450538 TI - WITHDRAWN: Therapeutic ultrasound for treating patellofemoral pain syndrome. AB - BACKGROUND: Therapeutic ultrasound is one of several rehabilitation interventions suggested for the management of pain due to patellofemoral knee pain syndrome. OBJECTIVES: To assess the effectiveness and side effects of ultrasound therapy for treating patellofemoral knee pain syndrome. SEARCH METHODS: We searched the Cochrane Musculoskeletal Review Group register, Cochrane Field of Physical and Related Therapies register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, HealthSTAR, Sports Discus, CINAHL,and PEDro databases (to December 2000) according to the sensitive search strategy for RCTs designed for the Cochrane Collaboration. The search was complemented with handsearching of the reference lists. Key experts in the area were contacted for any further articles. SELECTION CRITERIA: All randomized controlled trials (RCTs), controlled clinical trials (CCTs), case-control and cohort studies comparing therapeutic ultrasound against placebo or another active intervention in people with patellofemoral pain syndrome were selected according to an a priori protocol. DATA COLLECTION AND ANALYSIS: Two reviewers determined the studies to be included based on a priori inclusion criteria. Data were independently extracted by the same two reviewers and checked by a third reviewer (BS) using a previously developed form. The same two reviewers independently assessed the methodological quality of the RCTs and CCTs using a validated scale. The data analysis was performed using Peto odds ratios. MAIN RESULTS: The search retrieved 85 articles. Of the eight that were potentially relevant, only one RCT, including 53 participants with patellofemoral pain syndrome, was identified for this review. All participants received an exercise program as concurrent therapy. Ultrasound combined with ice massage contrast (n of 13), where n equals the number of participants, was not statistically different from ice massage alone (n = 16) in terms of participant rated pain relief or quadriceps and hamstring strengthening. In the ultrasound and ice massage group, 46% (6 of 13) reported improved pain relief compared to 31% (4 of 13) in the ice massage alone group. This difference of 15% does not meet international standards for clinically important improvements in osteoarthritis, which is 20%. Side effects were not reported. AUTHORS' CONCLUSIONS: Ultrasound therapy was not shown to have a clinically important effect on pain relief for people with patellofemoral pain syndrome. These conclusions are limited by the poor reporting of the therapeutic application of the ultrasound and low methodological quality of the one trial included. No conclusions can be drawn concerning the use, or non-use, of ultrasound for treating patellofemoral pain syndrome. More well-designed studies are needed. PMID- 23450539 TI - Pulmonary artery catheters for adult patients in intensive care. AB - BACKGROUND: Since pulmonary artery balloon flotation catheterization was first introduced in 1970, by HJ Swan and W Ganz, it has been widely disseminated as a diagnostic tool without rigorous evaluation of its clinical utility and effectiveness in critically ill patients. A pulmonary artery catheter (PAC) is inserted through a central venous access into the right side of the heart and floated into the pulmonary artery. PAC is used to measure stroke volume, cardiac output, mixed venous oxygen saturation and intracardiac pressures with a variety of additional calculated variables to guide diagnosis and treatment. Complications of the procedure are mainly related to line insertion. Relatively uncommon complications include cardiac arrhythmias, pulmonary haemorrhage and infarct, and associated mortality from balloon tip rupture. OBJECTIVES: To provide an up-to-date assessment of the effectiveness of a PAC on mortality, length of stay (LOS) in intensive care unit (ICU) and hospital and cost of care in adult intensive care patients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 12); MEDLINE (1954 to January 2012); EMBASE (1980 to January 2012); CINAHL (1982 to January 2012), and reference lists of articles. We contacted researchers in the field. We did a grey literature search for articles published until January 2012. SELECTION CRITERIA: We included all randomized controlled trials conducted in adults ICUs, comparing management with and without a PAC. DATA COLLECTION AND ANALYSIS: We screened the titles and abstracts and then the full text reports identified from our electronic search. Two authors (SR and MG) independently reviewed the titles, abstracts and then the full text reports for inclusion. We determined the final list of included studies by discussion among the group members (SR, ND, MG, AK and SC) with consensus agreement. We included all the studies that were in the original review. We assessed seven domains of potential risk of bias for the included studies. We examined the clinical, methodological and statistical heterogeneity and used random-effects model for meta-analysis. We calculated risk ratio for mortality across studies and mean days for LOS. MAIN RESULTS: We included 13 studies (5686 patients). We judged blinding of participants and personnel and blinding of outcome assessment to be at high risk in about 50% of the included studies and at low risk in 25% to 30% of the studies. Regardless of the high risk of performance bias these studies were included based on the low weight the studies had in the meta-analysis. We rated 75% of the studies as low risk for selection, attrition and reporting bias. All 13 studies reported some type of hospital mortality (28-day, 30-day, 60-day or ICU mortality). We considered studies of high-risk surgery patients (eight studies) and general intensive care patients (five studies) separately as subgroups for meta-analysis. The pooled risk ratio (RR) for mortality for the studies of general intensive care patients was 1.02 (95% confidence interval (CI) 0.96 to 1.09) and for the studies of high-risk surgery patients the RR was 0.98 (95% CI 0.74 to 1.29). Of the eight studies of high-risk surgery patients, five evaluated the effectiveness of pre-operative optimization but there was no difference in mortality when these studies were examined separately. PAC did not affect general ICU LOS (reported by four studies) or hospital LOS (reported by nine studies). Four studies, conducted in the United States (US), reported costs based on hospital charges billed, which on average were higher in the PAC groups. Two of these studies qualified for analysis and did not show a statistically significant hospital cost difference (mean difference USD 900, 95% CI -2620 to 4420, P = 0.62). AUTHORS' CONCLUSIONS: PAC is a diagnostic and haemodynamic monitoring tool but not a therapeutic intervention. Our review concluded that use of a PAC did not alter the mortality, general ICU or hospital LOS, or cost for adult patients in intensive care. The quality of evidence was high for mortality and LOS but low for cost analysis. Efficacy studies are needed to determine if there are optimal PAC-guided management protocols, which when applied to specific patient groups in ICUs could result in benefits such as shock reversal, improved organ function and less vasopressor use. Newer, less-invasive haemodynamic monitoring tools need to be validated against PAC prior to clinical use in critically ill patients. PMID- 23450540 TI - Methadone at tapered doses for the management of opioid withdrawal. AB - BACKGROUND: The evidence of tapered methadone's efficacy in managing opioid withdrawal has been systematically evaluated in the previous version of this review that needs to be updated OBJECTIVES: To evaluate the effectiveness of tapered methadone compared with other detoxification treatments and placebo in managing opioid withdrawal on completion of detoxification and relapse rate. SEARCH METHODS: We searched: Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 4), PubMed (January 1966 to May 2012), EMBASE (January 1988 to May 2012), CINAHL (2003- December 2007), PsycINFO (January 1985 to December 2004), reference lists of articles. SELECTION CRITERIA: All randomised controlled trials that focused on the use of tapered methadone versus all other pharmacological detoxification treatments or placebo for the treatment of opiate withdrawal. DATA COLLECTION AND ANALYSIS: Two review authors assessed the included studies. Any doubts about how to rate the studies were resolved by discussion with a third review author. Study quality was assessed according to the criteria indicated in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Twenty-three trials involving 2467 people were included. Comparing methadone versus any other pharmacological treatment, we observed no clinical difference between the two treatments in terms of completion of treatment, 16 studies 1381 participants, risk ratio (RR) 1.08 (95% confidence interval (CI) 0.97 to 1.21); number of participants abstinent at follow-up, three studies, 386 participants RR 0.98 (95% CI 0.70 to 1.37); degree of discomfort for withdrawal symptoms and adverse events, although it was impossible to pool data for the last two outcomes. These results were confirmed also when we considered the single comparisons: methadone with: adrenergic agonists (11 studies), other opioid agonists (eight studies), anxiolytic (two studies), paiduyangsheng (one study). Comparing methadone with placebo (two studies) more severe withdrawal and more drop-outs were found in the placebo group. The results indicate that the medications used in the included studies are similar in terms of overall effectiveness, although symptoms experienced by participants differed according to the medication used and the program adopted. AUTHORS' CONCLUSIONS: Data from literature are hardly comparable; programs vary widely with regard to the assessment of outcome measures, impairing the application of meta-analysis. The studies included in this review confirm that slow tapering with temporary substitution of long- acting opioids, can reduce withdrawal severity. Nevertheless, the majority of patients relapsed to heroin use. PMID- 23450541 TI - Naloxone for opiate-exposed newborn infants. AB - BACKGROUND: Naloxone, a specific opiate antagonist, is available for the treatment of newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opiate. It is unclear whether newborn infants may benefit from this therapy and whether naloxone has any harmful effects. OBJECTIVES: To determine the effect of naloxone as a treatment for newborn infants who have been exposed in utero to opiate. SEARCH METHODS: We searched the following databases in June 2012 for new studies published since the previous search in 2007: The Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 6), MEDLINE (OvidSP), MEDLINE In process & Other Non Indexed Citations (OvidSP), EMBASE (OvidSP), CINAHL (EBSCO), Maternity and Infant Care (OvidSP) and PubMed. We searched for ongoing and completed trials in Clinical Trials.gov, metaRegister of Controlled Trials, WHO International Clinical Trials Registry Platform and the EU Clinical Trials Register. We checked the reference lists of relevant articles to identify further potentially relevant studies. SELECTION CRITERIA: Randomised controlled trials comparing the administration of naloxone versus placebo, or no drug, or another dose of naloxone to newborn infants with suspected or confirmed in utero exposure to opiate. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors and synthesis of data using risk ratio, risk difference and weighted mean difference. MAIN RESULTS: We included nine trials that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opiate analgesia prior to delivery. None of these trials specifically recruited infants with cardiorespiratory or neurological depression. The main outcomes reported were measures of respiratory function in the first six hours of life. There is some evidence that naloxone increases alveolar ventilation. The trials did not assess the effect on the primary outcomes of this review (admission to a neonatal unit and failure to establish breastfeeding). AUTHORS' CONCLUSIONS: The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opiate. Given concerns about the safety of naloxone in this context it may be appropriate to limit its use to randomised controlled trials that aim resolve these uncertainties. PMID- 23450542 TI - Transpyloric versus gastric tube feeding for preterm infants. AB - BACKGROUND: Enteral feeding tubes for preterm infants may be placed in the stomach (gastric tube feeding) or in the upper small bowel (transpyloric tube feeding). There are potential advantages and disadvantages to both routes. OBJECTIVES: To determine the effect of feeding via the transpyloric route versus feeding via the gastric route on feeding tolerance, growth and development, and adverse consequences (death, gastro-intestinal disturbance including necrotising enterocolitis, aspiration pneumonia, chronic lung disease, pyloric stenosis) in preterm infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 3), MEDLINE, EMBASE, and CINAHL (to June 2012), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing transpyloric with gastric tube feeding in preterm infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. We synthesised data using a fixed-effect model and reported typical risk ratio (RR), risk difference (RD), and mean difference (MD). MAIN RESULTS: We found nine eligible trials in which a total of 359 preterm infants participated. All of the trials contained methodological weaknesses with lack of allocation concealment, absence of blinding of caregivers or assessors, and incomplete follow-up being the major potential sources of bias. The included trials did not detect any statistically significant effects on feeding tolerance or in-hospital growth rates. Meta-analyses found that infants allocated to receive transpyloric feeding had a higher risk of gastro-intestinal disturbance (typical RR 1.48 (95% confidence interval (CI) 1.05 to 2.09); typical RD 0.09 (95% CI 0.02 to 0.17); number needed to treat for an additional harmful outcome (NNTH) 10 (95% CI 6 to 50); six studies, 245 infants) and all-case mortality (typical RR 2.46 (95% CI 1.36 to 4.46); typical RD 0.16 (95% CI 0.07 to 0.26); NNTH 6 (95% CI 4 to 14); six studies, 217 infants). However, the trial that contributed most weight to these findings was likely to have been affected by selective allocation of the less mature and sicker infants to transpyloric feeding. We did not find any statistically significant differences in the incidence of other adverse events, including necrotising enterocolitis, intestinal perforation, and aspiration pneumonia. AUTHORS' CONCLUSIONS: The available data do not provide evidence of any beneficial effect of transpyloric feeding for preterm infants. Some evidence of harm exists, including a higher risk of gastrointestinal disturbance and mortality, but these findings should be interpreted and applied cautiously because of methodological weaknesses in the included trials. PMID- 23450543 TI - Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. AB - BACKGROUND: The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis with the aim of preventing the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008. OBJECTIVES: To determine the benefits and harms of antiviral medications to prevent CMV disease and all cause mortality in solid organ transplant recipients. SEARCH METHODS: We searched MEDLINE, EMBASE and the Cochrane Central Registry of Controlled Trials (CENTRAL) in The Cochrane Library to February 2004 for the first version of this review. The Cochrane Renal Group's specialised register was searched to February 2007 and to July 2011 for the first and current updates of the review without language restriction. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications and comparing different regimens of the same antiviral medications in recipients of any solid organ transplant. Studies examining pre-emptive therapy were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and by mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed using restricted maximum-likelihood to estimate the between study variance. Multivariate meta-regression was performed to investigate whether the results were altered after allowing for differences in drugs used, organ transplanted, and recipient CMV serostatus at the time of transplantation. MAIN RESULTS: We identified 37 studies (4342 participants). Risk of bias attributes were poorly performed or reported with low risk of bias reported for sequence generation, allocation concealment, blinding and selective outcome reporting in 25% or fewer studies.Prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment significantly reduced the risk for CMV disease (19 studies; RR 0.42, 95% CI 0.34 to 0.52), CMV infection (17 studies; RR 0.61, 95% CI 0.48 to 0.77), and all-cause mortality (17 studies; RR 0.63, 95% CI 0.43 to 0.92) primarily due to reduced mortality from CMV disease (7 studies; RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduced the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but not fungal infection, acute rejection or graft loss.Meta-regression showed no significant difference in the relative benefit of treatment (risk of CMV disease or all-cause mortality) by organ transplanted or CMV serostatus; no conclusions were possible for CMV negative recipients of negative organs.Neurological dysfunction was more common with ganciclovir and valaciclovir compared with placebo/no treatment. In direct comparison studies, ganciclovir was more effective than aciclovir in preventing CMV disease (7 studies; RR 0.37, 95% CI 0.23 to 0.60) and leucopenia was more common with aciclovir. Valganciclovir and IV ganciclovir were as effective as oral ganciclovir. The efficacy and adverse effects of valganciclovir/ganciclovir did not differ from valaciclovir in three small studies. Extended duration prophylaxis significantly reduced the risk of CMV disease compared with three months therapy (2 studies; RR 0.20, 95% CI 0.12 to 0.35). Leucopenia was more common with extended duration prophylaxis but severe treatment associated adverse effects did not differ between extended and three month durations of treatment. AUTHORS' CONCLUSIONS: Prophylaxis with antiviral medications reduces CMV disease and CMV-associated mortality in solid organ transplant recipients. These data suggest that antiviral prophylaxis should be used routinely in CMV positive recipients and in CMV negative recipients of CMV positive organ transplants. PMID- 23450544 TI - Lung protective ventilation strategy for the acute respiratory distress syndrome. AB - BACKGROUND: Patients with acute respiratory distress syndrome and acute lung injury require mechanical ventilatory support. Acute respiratory distress syndrome and acute lung injury are further complicated by ventilator-induced lung injury. Lung protective ventilation strategies may lead to improved survival. This systematic review is an update of a Cochrane review originally published in 2003 and updated in 2007. OBJECTIVES: To assess the effects of ventilation with lower tidal volume on morbidity and mortality in patients aged 16 years or older affected by acute respiratory distress syndrome and acute lung injury. A secondary objective was to determine whether the comparison between low and conventional tidal volume was different if a plateau airway pressure of greater than 30 to 35 cm H20 was used. SEARCH METHODS: In our previous 2007 updated review, we searched databases from inception until 2006. In this third updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and the Web of Science from 2006 to September 2012. We also updated our search of databases of ongoing research and of reference lists from 2006 to September 2012. SELECTION CRITERIA: We included randomized controlled trials comparing ventilation using either a lower tidal volume (Vt) or low airway driving pressure (plateau pressure 30 cm H2O or less), resulting in a tidal volume of 7 ml/kg or less, versus ventilation that used Vt in the range of 10 to 15 ml/kg in adults (16 years old or older) with acute respiratory distress syndrome and acute lung injury. DATA COLLECTION AND ANALYSIS: We independently assessed trial quality and extracted data. Wherever appropriate, results were pooled. We applied fixed-effect and random-effects models. MAIN RESULTS: We did not find any new study which were eligible for inclusion in this update. The total number of studies remained unchanged, six trials involving 1297 patients. Five trials had a low risk of bias. One trial had an unclear risk of bias. Mortality at day 28 was significantly reduced by lung-protective ventilation with a relative risk (RR) of 0.74 (95% confidence interval (CI) 0.61 to 0.88); hospital mortality was reduced with a RR of 0.80 (95% CI 0.69 to 0.92). Overall mortality was not significantly different if a plateau pressure less than or equal to 31 cm H2O in the control group was used (RR 1.13, 95% CI 0.88 to 1.45). There was insufficient evidence for morbidity and long-term outcomes. AUTHORS' CONCLUSIONS: Clinical heterogeneity, such as different lengths of follow up and higher plateau pressure in control arms in two trials, makes the interpretation of the combined results difficult. Mortality was significantly reduced at day 28 and at the end of the hospital stay. The effects on long-term mortality are unknown, although the possibility of a clinically relevant benefit cannot be excluded. Ventilation with lower tidal volumes is becoming a routine strategy of treatment of acute respiratory distress syndrome and acute lung injury, stopping investigators from carrying out additional trials. PMID- 23450545 TI - Partial liquid ventilation for the prevention of mortality and morbidity in paediatric acute lung injury and acute respiratory distress syndrome. AB - BACKGROUND: Acute lung injury and acute respiratory distress syndrome are syndromes of severe respiratory failure. Children with acute lung injury or acute respiratory distress syndrome have high mortality and the survivors have significant morbidity. Partial liquid ventilation is proposed as a less injurious form of respiratory support for these children. Uncontrolled studies in adults have shown improvements in gas exchange and lung compliance with partial liquid ventilation. A single uncontrolled study in six children with acute respiratory syndrome showed some improvement in gas exchange during three hours of partial liquid ventilation. This review was originally published in 2004, updated in 2009 and again in 2012. OBJECTIVES: To assess whether partial liquid ventilation reduces mortality or morbidity, or both, in children with acute lung injury or acute respiratory distress syndrome. SEARCH METHODS: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11); CINAHL (Cumulative Index to Nursing & Allied Health Literature) via Ovid (1982 to November 2011); Ovid MEDLINE (1950 to November 2011); and Ovid EMBASE (1982 to November 2011). The search was last performed in August 2008. SELECTION CRITERIA: We included randomized controlled trials (RCTs) which compared partial liquid ventilation with other forms of ventilation in children (aged 28 days to 18 years) with acute lung injury or acute respiratory distress syndrome. Trials had to report one or more of the following: mortality; duration of mechanical ventilation, respiratory support, oxygen therapy, stay in the intensive care unit, or stay in hospital; infection; long-term cognitive impairment, neurodevelopmental progress, or other long-term morbidities. DATA COLLECTION AND ANALYSIS: We independently evaluated the quality of the relevant studies and extracted the data from the included studies. MAIN RESULTS: Only one study enrolling 182 patients (reported as an abstract in conference proceedings) was identified and found eligible for inclusion; the authors reported only limited results. The trial was stopped prematurely and was, therefore, under-powered to detect any significant differences and at high risk of bias. The only available outcome of clinical significance was 28-day mortality. There was no statistically significant difference between groups, with a relative risk for 28-day mortality in the partial liquid ventilation group of 1.54 (95% confidence interval 0.82 to 2.9). AUTHORS' CONCLUSIONS: There is no evidence from RCTs to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome. Adequately powered, high quality RCTs are still needed to assess its efficacy. Clinically relevant outcome measures should be assessed (mortality at discharge and later, duration of both respiratory support and hospital stay, and long-term neurodevelopmental outcomes). The studies should be published in full. PMID- 23450546 TI - Nasal versus oral route for placing feeding tubes in preterm or low birth weight infants. AB - BACKGROUND: Enteral feeding tubes for preterm or low birth weight infants may be placed via either the nose or mouth. Nasal placement may compromise respiration. However, orally placed tubes may be more prone to displacement, local irritation, and vagal stimulation. OBJECTIVES: To determine the effect of nasal versus oral placement of enteral feeding tubes on feed tolerance, growth and development, and the incidence of adverse events in preterm or low birth weight infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012, Issue 10), MEDLINE, EMBASE, and CINAHL (to September 2012), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared nasal versus oral placement of enteral feeding tubes in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. We synthesised data using a fixed-effect model and reported typical risk ratio (RR), risk difference (RD), and weighted mean difference (WMD). MAIN RESULTS: Three studies fulfilled the review eligibility criteria. Two were parallel group trials (van Someren 1984; Dsilna 2005) and one was a cross-over trial (Bohnhorst 2010). The two parallel group randomised controlled trials enrolled 88 preterm infants. Only one trial reported data on the pre-specified primary outcomes for this review. This trial found no evidence of effect on the time taken to establish enteral feeding or the time taken to regain birth weight. However, the trial was underpowered to exclude modest effect sizes. We identified one randomised cross-over trial in which 35 very preterm infants participated. This study did not find any statistically significant effects on the incidence of apnoea, desaturation, and bradycardia during the study period. AUTHORS' CONCLUSIONS: There are insufficient data available to inform practice. A large randomised controlled trial would be required to determine if the use of naso- versus oro-enteric feeding tubes affects feeding, growth and development, and the incidence of adverse events in preterm or low birth weight infants. PMID- 23450547 TI - Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia. AB - BACKGROUND: Patients suffering from inoperable chronic critical leg ischaemia (NR CCLI) face amputation of the leg. Spinal cord stimulation (SCS) has been proposed as a helpful treatment in addition to standard conservative treatment. OBJECTIVES: To find evidence for an improvement on limb salvage, pain relief, and the clinical situation using SCS compared to conservative treatment alone. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). SELECTION CRITERIA: Controlled studies comparing the addition of SCS with any form of conservative treatment to conservative treatment alone in patients with NR-CCLI. DATA COLLECTION AND ANALYSIS: Both authors independently assessed the quality of the studies and extracted data. MAIN RESULTS: Six studies comprising nearly 450 patients were included. In general the quality of the studies was good. No study was blinded due to the type of intervention.Limb salvage after 12 months was significantly higher in the SCS group (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.56 to 0.90; risk difference (RD) -0.11, 95% CI -0.20 to -0.02). Significant pain relief occurred in both treatment groups, but was more prominent in the SCS group where the patients required significantly less analgesics. In the SCS group, significantly more patients reached Fontaine stage II than in the conservative group (RR 4.9, 95% CI 2.0 to 11.9; RD 0.33, 95% CI 0.19 to 0.47). Overall, no significantly different effect on ulcer healing was observed with the two treatments.Complications of SCS treatment consisted of implantation problems (9%, 95% CI 4 to 15%) and changes in stimulation requiring re-intervention (15%, 95% CI 10 to 20%). Infections of the lead or pulse generator pocket occurred less frequently (3%, 95% CI 0 to 6%). Overall risk of complications with additional SCS treatment was 17% (95% CI 12 to 22%), indicating a number needed to harm of 6 (95% CI 5 to 8).Average overall costs (one study) at two years were EUR 36,500 (SCS group) and EUR 28,600 (conservative group). The difference (EUR 7900) was significant (P < 0.009). AUTHORS' CONCLUSIONS: There is evidence to favour SCS over standard conservative treatment alone to improve limb salvage and clinical situations in patients with NR-CCLI. The benefits of SCS must be considered against the possible harm of relatively mild complications and the costs. PMID- 23450548 TI - Pessaries (mechanical devices) for pelvic organ prolapse in women. AB - BACKGROUND: Pelvic organ prolapse is common, with some degree of prolapse seen in up to 50% of parous women in a clinic setting, although many are asymptomatic. The use of pessaries (a passive mechanical device designed to support the vagina) to treat prolapse is very common, and up to 77% of clinicians use pessaries for the first line management of prolapse. A number of symptoms may be associated with prolapse and treatments include surgery, pessaries and conservative therapies. A variety of pessaries are described which aim to alleviate the symptoms of prolapse and avert or delay the need for surgery. OBJECTIVES: To determine the effectiveness of pessaries (mechanical devices) for pelvic organ prolapse. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register of trials (searched 13 March 2012), which includes searches of CENTRAL, MEDLINE, PREMEDLINE and handsearching of conference proceedings, and handsearched the abstracts of two relevant conferences held in 2011. We also searched the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi randomised controlled trials which included a pessary for pelvic organ prolapse in one arm of the study. DATA COLLECTION AND ANALYSIS: Abstracts were assessed independently by two authors with arbitration from a third if necessary. Data extraction was completed independently for included studies by two review authors. MAIN RESULTS: To date there is only one published randomised controlled trial assessing the use of pessaries in the treatment of pelvic organ prolapse. AUTHORS' CONCLUSIONS: The review authors identified one randomised controlled trial comparing ring and Gellhorn pessaries. The results of the trial showed that both pessaries were effective for the approximately 60% of women who completed the study with no significant differences identified between the two types of pessary. However, methodological flaws were noted in the trial, as elaborated under risk of bias assessment. There is no consensus on the use of different types of device, the indications nor the pattern of replacement and follow-up care. There is an urgent need for randomised studies to address the use of pessaries in comparison with no treatment, surgery and conservative measures. PMID- 23450549 TI - High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome. AB - BACKGROUND: High frequency oscillation is an alternative to conventional mechanical ventilation that is sometimes used to treat patients with acute respiratory distress syndrome, but effects on oxygenation, mortality and adverse clinical outcomes are uncertain. This review was originally published in 2004 and was updated in 2011. OBJECTIVES: To determine clinical and physiological effects of high frequency oscillation (HFO) in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) compared to conventional ventilation. SEARCH METHODS: We electronically searched CENTRAL (Ovid), MEDLINE (Ovid), EMBASE (Ovid), and ISI (from inception to March 2011). The original search was performed in 2002. We manually searched reference lists from included studies and review articles; searched conference proceedings of the American Thoracic Society (1994 to 2010), Society of Critical Care Medicine (1994 to 2010), European Society of Intensive Care Medicine (1994 to 2010), and American College of Chest Physicians (1994 to 2010); contacted clinical experts in the field; and searched for unpublished and ongoing trials in clinicaltrials.gov and controlled-trials.com. SELECTION CRITERIA: Randomized controlled clinical trials comparing treatment using HFO with conventional mechanical ventilation for children and adults diagnosed with ALI or ARDS. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. We used random-effects models in the analyses. MAIN RESULTS: Eight RCTs (n = 419) were included; almost all patients had ARDS. The risk of bias was low in six studies and unclear in two studies. The quality of evidence for hospital and six-month mortality was moderate and low, respectively. The ratio of partial pressure of oxygen to inspired fraction of oxygen at 24, 48, and 72 hours was 16% to 24% higher in patients receiving HFO. There were no significant differences in oxygenation index because mean airway pressure rose by 22% to 33% in patients receiving HFO (P < 0.01). In patients randomized to HFO, mortality was significantly reduced (RR 0.77, 95% CI 0.61 to 0.98; P = 0.03; 6 trials, 365 patients, 160 deaths) and treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) was less likely (RR 0.67, 95% CI 0.46 to 0.99; P = 0.04; 5 trials, 337 patients, 73 events). Other risks, including adverse events, were similar. We found substantial between-trial statistical heterogeneity for physiological (I(2) = 21% to 95%) but not clinical (I(2) = 0%) outcomes. Pooled results were based on few events for most clinical outcomes. AUTHORS' CONCLUSIONS: The findings of this systematic review suggest that HFO was a promising treatment for ALI and ARDS prior to the uptake of current lung protective ventilation strategies. These findings may not be applicable with current conventional care, pending the results of large multi-centre trials currently underway. PMID- 23450550 TI - WITHDRAWN: Intensity of exercise for the treatment of osteoarthritis. AB - BACKGROUND: Therapeutic exercise is used as one modality to treat people with osteoarthritis (OA). OBJECTIVES: To evaluate the effectiveness of therapeutic exercise of differing intensities on objective and subjective measures of disease activity in people with OA. SEARCH METHODS: We searched MEDLINE, EMBASE, Pedro, Current Contents, Sports Discus and CINAHL up to and including December 2002. The Cochrane Field of Rehabilitation and Related Therapies and the Cochrane Musculoskeletal Review Group were also contacted for a search of their specialized registers. Handsearching was conducted on all retrieved articles for additional studies. SELECTION CRITERIA: Comparative controlled studies, such as randomized controlled trials, controlled clinical trials, cohort studies or case/control studies, of therapeutic exercises compared to control or active interventions in people with OA were eligible. No language restrictions were applied. Abstracts were also accepted. DATA COLLECTION AND ANALYSIS: Two independent reviewers identified potential articles from the literature search. These reviewers extracted data using pre-defined extraction forms. Consensus was reached on all data extraction. The two reviewers used a five point scale to assess the quality of the selected articles. Randomization, double-blinding and description of withdrawals were assessed. MAIN RESULTS: One study involving 39 participants met the inclusion criteria. The review indicates that there were no significant differences between high intensity and low intensity aerobic exercise on participants with OA of the knee for functional status, gait, pain and aerobic capacity (Mangione 1999). AUTHORS' CONCLUSIONS: Both high intensity and low intensity aerobic exercise appear to be equally effective in improving a patient's functional status, gait, pain and aerobic capacity for people with OA of the knee. Further research involving a greater number of subjects, and a larger number of studies involving a control group is needed to further substantiate these results. PMID- 23450551 TI - Physical rehabilitation for older people in long-term care. AB - BACKGROUND: The worldwide population is progressively ageing, with an expected increase in morbidity and demand for long-term care. Physical rehabilitation is beneficial in older people, but relatively little is known about effects on long term care residents. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To evaluate the benefits and harms of rehabilitation interventions directed at maintaining, or improving, physical function for older people in long-term care through the review of randomised and cluster randomised controlled trials. SEARCH METHODS: We searched the trials registers of the following Cochrane entities: the Stroke Group (May 2012), the Effective Practice and Organisation of Care Group (April 2012), and the Rehabilitation and Related Therapies Field (April 2012). In addition, we searched 20 relevant electronic databases, including the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2009, Issue 4), MEDLINE (1966 to December 2009), EMBASE (1980 to December 2009), CINAHL (1982 to December 2009), AMED (1985 to December 2009), and PsycINFO (1967 to December 2009). We also searched trials and research registers and conference proceedings; checked reference lists; and contacted authors, researchers, and other relevant Cochrane entities. We updated our searches of electronic databases in 2011 and listed relevant studies as awaiting assessment. SELECTION CRITERIA: Randomised studies comparing a rehabilitation intervention designed to maintain or improve physical function with either no intervention or an alternative intervention in older people (over 60 years) who have permanent long-term care residency. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. The primary outcome was function in activities of daily living. Secondary outcomes included exercise tolerance, strength, flexibility, balance, perceived health status, mood, cognitive status, fear of falling, and economic analyses. We investigated adverse effects, including death, morbidity, and other events. We synthesised estimates of the primary outcome with the mean difference; mortality data, with the risk ratio; and secondary outcomes, using vote-counting. MAIN RESULTS: We included 67 trials, involving 6300 participants. Fifty-one trials reported the primary outcome, a measure of activities of daily living. The estimated effects of physical rehabilitation at the end of the intervention were an improvement in Barthel Index (0 to 100) scores of six points (95% confidence interval (CI) 2 to 11, P = 0.008, seven studies), Functional Independence Measure (0 to 126) scores of five points (95% CI -2 to 12, P = 0.1, four studies), Rivermead Mobility Index (0 to 15) scores of 0.7 points (95% CI 0.04 to 1.3, P = 0.04, three studies), Timed Up and Go test of five seconds (95% CI -9 to 0, P = 0.05, seven studies), and walking speed of 0.03 m/s (95% CI -0.01 to 0.07, P = 0.1, nine studies). Synthesis of secondary outcomes suggested there is a beneficial effect on strength, flexibility, and balance, and possibly on mood, although the size of any such effect is unknown. There was insufficient evidence of the effect on other secondary outcomes. Based on 25 studies (3721 participants), rehabilitation does not increase risk of mortality in this population (risk ratio 0.95, 95% CI 0.80 to 1.13). However, it is possible bias has resulted in overestimation of the positive effects of physical rehabilitation. AUTHORS' CONCLUSIONS: Physical rehabilitation for long-term care residents may be effective, reducing disability with few adverse events, but effects appear quite small and may not be applicable to all residents. There is insufficient evidence to reach conclusions about improvement sustainability, cost-effectiveness, or which interventions are most appropriate. Future large-scale trials are justified. PMID- 23450552 TI - Endothelin receptor antagonists for pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension. SEARCH METHODS: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012. SELECTION CRITERIA: We included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Five review authors independently selected studies, assessed study quality and extracted data. MAIN RESULTS: We included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide. AUTHORS' CONCLUSIONS: Endothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists. PMID- 23450553 TI - Methotrexate for ankylosing spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown cause, characterized by sacroiliitis and spondylitis. Methotrexate (MTX), a widely used disease-modifying antirheumatic drug (DMARD), is effective for rheumatoid arthritis (RA), and so might work for AS. This is an update of a Cochrane review first published in 2004, and previously updated in 2006. OBJECTIVES: To evaluate the benefits and harms of MTX for treating AS. SEARCH METHODS: We searched CENTRAL (The Cochrane Library Issue 6, 2012), MEDLINE (2005 to June 25, 2012), EMBASE (2005 to June 25, 2012), Ovid MEDLINE Scopus, World Health Organization International Clinical Trials Registry Platform and the reference sections of retrieved articles. Trials published in any language were acceptable. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi randomized controlled trials (qRCTs) examining the benefits and harms of MTX versus placebo, other medication, or no medication for treatment of AS. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We resolved any disagreements through discussions with a third review author. In the absence of significant heterogeneity, we combined results for continuous data using mean difference or standardized mean difference values. We calculated the risk ratio for dichotomous data. MAIN RESULTS: We identified three RCTs (no additional new studies), which included 116 participants. Of these three trials, one was a 12-month trial that compared naproxen plus MTX with naproxen alone. Also, there were two 24-week trials that compared different doses of MTX with placebo. We included the outcomes of response, physical function, pain, spinal mobility, peripheral joints/entheses pain, swelling and tenderness, changes in spine radiographs, and patient and physician global assessment. We judged only one trial to be at low risk of bias. Across these three trials, we did not identify any statistically significant differences favoring MTX treatment over no MTX treatment apart from one exception. The response rate in one trial showed a statistically significant absolute benefit of 36% and a number to treat for benefit (NNT) of three in the MTX group compared to the placebo group (RR 3.18, 95% CI 1.03 to 9.79). This response rate was based on a composite index that included assessments of morning stiffness, physical well-being, Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire for spondyloarthropathies (HAQ-S), and physician and patient global assessment. We did not identify any outcome that showed a statistically significant difference between the MTX treated and no MTX treatment groups when endpoint results were compared. Furthermore, no serious side effects were reported in any of the included trials. AUTHORS' CONCLUSIONS: There is not enough evidence to support any benefit of MTX in the treatment of AS. High quality RCTs of larger sample sizes are needed to clarify the effect(s) of MTX on AS. PMID- 23450554 TI - Nutritional interventions for reducing morbidity and mortality in people with HIV. AB - BACKGROUND: Adequate nutrition is important for optimal immune and metabolic function. Dietary support may, therefore, improve clinical outcomes in HIV infected individuals by reducing the incidence of HIV-associated complications and attenuating progression of HIV disease, improving quality of life and ultimately reducing disease-related mortality. OBJECTIVES: To evaluate the effectiveness of various macronutrient interventions, given orally, in reducing morbidity and mortality in adults and children living with HIV infection. SEARCH METHODS: We searched CENTRAL (up to August 2011), MEDLINE (1966 to August 2011), EMBASE (1988 to August 2011), LILACS (up to February 2012), and Gateway (March 2006-February 2010). We also scanned reference lists of articles and contacted authors of relevant studies and other researchers. SELECTION CRITERIA: Randomised controlled trials evaluating the effectiveness of macronutrient interventions compared with no nutritional supplements or placebo in the management of adults and children infected with HIV. DATA COLLECTION AND ANALYSIS: Three reviewers independently applied study selection criteria, assessed study quality, and extracted data. Effects were assessed using mean difference and 95% confidence intervals. Homogenous studies were combined wherever it was clinically meaningful to do so and a meta-analysis using the random effects model was conducted. MAIN RESULTS: Fourteen trials (including 1725 HIV positive adults and 271 HIV positive children), were included in this review. Neither supplementary food nor daily supplement of Spirulina significantly altered the risk of death compared with no supplement or placebo in malnourished, ART naive adult participants in the two studies which reported on this outcome. A nutritional supplement enhanced with protein did not significantly alter the risk of death compared to standard nutritional care in children with prolonged diarrhoea. Supplementation with macronutrient formulas given to provide protein and/or energy and fortified with micronutrients, in conjunction with nutrition counselling, significantly improved energy intake (3 trials; n=131; MD 393.57 kcal/day; 95% CI: 224.66 to 562.47;p<0.00001) and protein intake (2 trials; n=81; MD 23.5 g/day; 95% CI: 12.68, 34.01; p<0.00001) compared with no nutritional supplementation or nutrition counselling alone in adult participants with weight loss. In general supplementation with specific macronutrients such as amino acids, whey protein concentration or Spirulina did not significantly alter clinical, anthropometric or immunological outcomes compared with placebo in HIV-infected adults and children. AUTHORS' CONCLUSIONS: Given the current evidence base, which is limited to fourteen relatively small trials all evaluating different macronutrient supplements in different populations at different stages of HIV infection and with varying treatment status, no firm conclusions can be drawn about the effects of macronutrient supplementation on morbidity and mortality in people living with HIV. It is, however, promising to see more studies being conducted in low-income countries, and particularly in children, where macronutrient supplementation both pre-antiretroviral treatment and in conjunction with antiretroviral treatment might prove to be beneficial. PMID- 23450555 TI - Laparoscopic repair for perforated peptic ulcer disease. AB - BACKGROUND: Perforated peptic ulcer is a common abdominal disease that is treated by surgery. The development of laparoscopic surgery has changed the way to treat such abdominal surgical emergencies. The results of some clinical trials suggest that laparoscopic surgery could be a better strategy than open surgery in the correction of perforated peptic ulcer but the evidence is not strongly in favour for or against this intervention. OBJECTIVES: To measure the effect of laparoscopic surgical treatment versus open surgical treatment in patients with a diagnosis of perforated peptic ulcer in relation to abdominal septic complications, surgical wound infection, extra-abdominal complications, hospital length of stay and direct costs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2004, Issue 2), PubMed/MEDLINE (1966 to July 2004), EMBASE (1985 to November 2004) and LILACS (1988 to November 2004) as well as the reference lists of relevant articles. Searches in all databases were updated in December 2009 and January 2012. We did not confine our search to English language publications. SELECTION CRITERIA: Randomized clinical trials comparing laparoscopic surgery versus open surgery for the repair of perforated peptic ulcer using any mechanical method of closure (suture, omental patch or fibrin sealant). DATA COLLECTION AND ANALYSIS: Primary outcome measures included proportion of septic and other abdominal complications (surgical site infection, suture leakage, intra-abdominal abscess, postoperative ileus) and extra-abdominal complications (pulmonary). Secondary outcomes included mortality, time to return to normal diet, time of nasogastric aspiration, hospital length-of-stay and costs. Outcomes were summarized by reporting odds ratios (ORs) and 95% confidence intervals (CIs), using the fixed-effect model. MAIN RESULTS: We included three randomized clinical trials of acceptable quality. We found no statistically significant differences between laparoscopic and open surgery in the proportion of abdominal septic complications (OR 0.66; 95% CI 0.30 to 1.47), pulmonary complications (OR 0.43; 95% CI 0.17 to 1.12) or number of septic abdominal complications (OR 0.60; 95% CI 0.32 to 1.15). Heterogeneity was significant for pulmonary complications and operating time. AUTHORS' CONCLUSIONS: This review suggests that a decrease in septic abdominal complications may exist when laparoscopic surgery is used to correct perforated peptic ulcer. However, it is necessary to perform more randomized controlled trials with a greater number of patients to confirm such an assumption, guaranteeing a long learning curve for participating surgeons. With the information provided it could be said that laparoscopic surgery results are not clinically different from those of open surgery. PMID- 23450556 TI - Multinutrient fortification of human breast milk for preterm infants following hospital discharge. AB - BACKGROUND: Preterm infants are usually growth restricted at hospital discharge. Feeding preterm infants after hospital discharge with multinutrient fortified breast milk rather than unfortified breast milk may facilitate more rapid catch up growth and improve neurodevelopmental outcomes. OBJECTIVES: To determine the effect of feeding preterm infants following hospital discharge with multinutrient fortified human breast milk versus unfortified breast milk on growth and development. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials Register (CENTRAL, The Cochrane Library, 2012, Issue 3), MEDLINE, EMBASE and CINAHL (until August 2012), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared feeding preterm infants following hospital discharge with multinutrient fortified breast milk compared with unfortified human breast milk. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors and synthesis of data using risk ratio, risk difference and mean difference. MAIN RESULTS: We identified two small trials involving a total of 246 infants. These did not provide evidence that multinutrient fortification of breast milk for three to four months after hospital discharge affected rates of growth during infancy. One trial assessed infants at 18 months corrected age and did not find any statistically significant effects on neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: The limited available data do not provide convincing evidence that feeding preterm infants with multinutrient fortified breast milk compared with unfortified breast milk following hospital discharge affects important outcomes including growth rates during infancy. There are no data on long-term growth. Since fortifying breast milk for infants fed directly from the breast is logistically difficult and has the potential to interfere with breast feeding, it is important to determine if mothers would support further trials of this intervention. PMID- 23450557 TI - Honey as a topical treatment for wounds. AB - BACKGROUND: Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee, Apis mellifera. Honey has been used since ancient times as a remedy in wound care. Evidence from animal studies and some trials has suggested that honey may accelerate wound healing. OBJECTIVES: The objective was to determine whether honey increases the rate of healing in acute wounds (e.g. burns, lacerations) and chronic wounds (e.g. skin ulcers, infected surgical wounds). SEARCH METHODS: For this first update of the review we searched the Cochrane Wounds Group Specialised Register (searched 13 June 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5); Ovid MEDLINE (2008 to May Week 5 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 12 June 2012); Ovid EMBASE (2008 to 2012 Week 23); and EBSCO CINAHL (2008 to 8 June 2012). SELECTION CRITERIA: Randomised and quasi randomised trials that evaluated honey as a treatment for any sort of acute or chronic wound were sought. There was no restriction in terms of source, date of publication or language. Wound healing was the primary endpoint. DATA COLLECTION AND ANALYSIS: Data from eligible trials were extracted and summarised by one review author, using a data extraction sheet, and independently verified by a second review author. MAIN RESULTS: We identified 25 trials (with a total of 2987 participants) that met the inclusion criteria, including six new trials that were added to this update. In acute wounds, three trials evaluated the effect of honey in acute lacerations, abrasions or minor surgical wounds and 12 trials evaluated the effect of honey in burns. In chronic wounds, two trials evaluated the effect of honey in venous leg ulcers, and single trials investigated its effect in infected post-operative wounds, pressure injuries, cutaneous Lieshmaniasis, diabetic foot ulcers and Fournier's gangrene. Three trials recruited people into mixed groups of chronic or acute wounds. Most trials were at high or unclear risk of bias. In acute wounds, specifically partial-thickness burns, honey might reduce time to healing compared with some conventional dressings (WMD -4.68 days, 95%CI -4.28 to -5.09 days), but, when compared with early excision and grafting, honey delays healing in partial- and full-thickness burns (WMD 13.6 days, 95% CI 10.02 to 17.18 days). In chronic wounds, honey does not significantly increase healing in venous leg ulcers when used as an adjuvant to compression (RR 1.15, 95% CI 0.96 to 1.38), and may delay healing in cutaneous Leishmaniasis when used as an adjuvant to meglumine antimoniate compared to meglumine antimoniate alone (RR 0.72, 95% CI 0.51 to 1.01). AUTHORS' CONCLUSIONS: Honey dressings do not increase rates of healing significantly in venous leg ulcers when used as an adjuvant to compression. Honey may delay healing in partial- and full-thickness burns in comparison to early excision and grafting, and in cutaneous Leishmaniasis when used as an adjuvant with meglumine antimoniate. Honey might be superior to some conventional dressing materials, but there is considerable uncertainty about the replicability and applicability of this evidence. There is insufficient evidence to guide clinical practice in other types of wounds, and purchasers should refrain from providing honey dressings for routine use until sufficient evidence of effect is available. PMID- 23450558 TI - Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ transplant recipients. Pre-emptive treatment of patients with CMV viraemia using antiviral agents has been suggested as an alternative to routine prophylaxis to prevent CMV disease. This is an update of a Cochrane review first published in 2005. OBJECTIVES: This review was conducted to evaluate the efficacy of pre-emptive treatment with antiviral medications in preventing symptomatic CMV disease. SEARCH METHODS: For this update, we searched the Cochrane Renal Group's Specialised Register (to 16 January 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of pre emptive treatment compared with placebo, no specific treatment or with antiviral prophylaxis in solid organ transplant recipients. DATA COLLECTION AND ANALYSIS: Four authors assessed the quality and extracted all data. Analyses used a random effects model and results were expressed as risk ratio (RR) and 95% confidence intervals (CI). MAIN RESULTS: We identified 15 eligible studies (1098 participants). Of these, six investigated pre-emptive treatment versus placebo or treatment of CMV when disease occurred (standard care), eight looked at pre emptive treatment versus antiviral prophylaxis, and one reported on oral versus intravenous pre-emptive treatment.Assessment of risk of bias identified that the processes reported for sequence generation and allocation concealment were at low risk of bias in only five and three studies, respectively. All studies were considered to be at low risk of attrition bias, and seven studies were considered to be at low risk of bias for selective reporting. Only one study reported adequate blinding of participants and personnel; no study reported blinding of outcome assessment.Compared with placebo or standard care, pre-emptive treatment significantly reduced the risk of CMV disease (6 studies, 288 participants: RR 0.29, 95% CI 0.11 to 0.80) but not acute rejection (3 studies, 185 participants: RR 1.21, 95% CI 0.69 to 2.12) or all-cause mortality (3 studies, 176 participants: RR 1.23, 95% CI 0.35 to 4.30). Comparative studies of pre-emptive therapy versus prophylaxis showed no significant differences in preventing CMV disease between pre-emptive and prophylactic therapy (7 studies, 753 participants: RR 1.00, 95% CI 0.36 to 2.74) but there was significant heterogeneity (I2 = 63%). Leucopenia was significantly less common with pre emptive therapy compared with prophylaxis (6 studies, 729 participants: RR 0.42, 95% CI 0.20 to 0.90). Other adverse effects did not differ significantly or were not reported. There were no significant differences in the risks of all-cause mortality, graft loss, acute rejection and infections other than CMV. AUTHORS' CONCLUSIONS: Few RCTs have evaluated the effects of pre-emptive therapy to prevent CMV disease. Pre-emptive therapy is effective compared with placebo or standard care. Despite the inclusion of five additional studies in this update, the efficacy of pre-emptive therapy compared with prophylaxis to prevent CMV disease remains unclear due to significant heterogeneity between studies. Additional head-to-head studies are required to determine the relative benefits and harms of pre-emptive therapy and prophylaxis to prevent CMV disease in solid organ transplant recipients. PMID- 23450559 TI - Training to recognise the early signs of recurrence in schizophrenia. AB - BACKGROUND: Schizophrenia has a lifetime prevalence of less than one per cent. Studies have indicated that early symptoms that are idiosyncratic to the person with schizophrenia (early warning signs) often precede acute psychotic relapse. Early warning signs interventions propose that learning to detect and manage early warning signs of impending relapse might prevent or delay acute psychotic relapse. OBJECTIVES: To compare the effectiveness of early warning signs interventions plus treatment as usual involving and not involving a psychological therapy on time to relapse, hospitalisation, functioning, negative and positive symptomatology. SEARCH METHODS: Search databases included the Cochrane Schizophrenia Group Trials Register (July 2007 and May 2012) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were reviewed for inclusion. We inspected the UK National Research Registe and contacted relevant pharmaceutical companies and authors of trials for additional information. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing early warning signs interventions plus treatment as usual to treatment as usual for people with schizophrenia or other non-affective psychosis DATA COLLECTION AND ANALYSIS: We assessed included studies for quality and extracted data. If more than 50% of participants were lost to follow-up, the study was excluded. For binary outcomes, we calculated standard estimates of risk ratio (RR) and the corresponding 95% confidence intervals (CI), for continuous outcomes, we calculated mean differences (MD) with standard errors estimated, and for time to event outcomes we calculated Cox proportional hazards ratios (HRs) and associated 95 % CI. We assessed risk of bias for included studies and assessed overall study quality using the GRADE approach. MAIN RESULTS: Thirty-two RCTs and two cluster-RCTs that randomised 3554 people satisfied criteria for inclusion. Only one study examined the effects of early warning signs interventions without additional psychological interventions, and many of the outcomes for this review were not reported or poorly-reported. Significantly fewer people relapsed with early warning signs interventions than with usual care (23% versus 43%; RR 0.53, 95% CI 0.36 to 0.79; 15 RCTs, 1502 participants; very low quality evidence). Time to relapse did not significantly differ between intervention groups (6 RCTs, 550 participants; very low quality evidence). Risk of re-hospitalisation was significantly lower with early warning signs interventions compared to usual care (19% versus 39%; RR 0.48, 95% CI 0.35 to 0.66; 15 RCTS, 1457 participants; very low quality evidence). Time to re hospitalisation did not significantly differ between intervention groups (6 RCTs; 1149 participants; very low quality evidence). Participants' satisfaction with care and economic costs were inconclusive because of a lack of evidence. AUTHORS' CONCLUSIONS: This review indicates that early warning signs interventions may have a positive effect on the proportions of people re-hospitalised and on rates of relapse, but not on time to recurrence. However, the overall quality of the evidence was very low, indicating that we do not know if early warning signs interventions will have similar effects outside trials and that it is very likely that further research will alter these estimates. Moreover, the early warning signs interventions were used along side other psychological interventions, and we do not know if they would be effective on their own. They may be cost effective due to reduced hospitalisation and relapse rates, but before mental health services consider routinely providing psychological interventions involving the early recognition and prompt management of early warning signs to adults with schizophrenia, further research is required to provide evidence of high or moderate quality regarding the efficacy of early warning signs interventions added to usual care without additional psychological interventions, or to clarify the kinds of additional psychological interventions that might aid its efficacy. Future RCTs should be adequately-powered, and designed to minimise the risk of bias and be transparently reported. They should also systematically evaluate resource costs and resource use, alongside efficacy outcomes and other outcomes that are important to people with serious mental illness and their carers. PMID- 23450560 TI - Laparoscopy versus laparotomy for FIGO stage I ovarian cancer. AB - BACKGROUND: This is an updated version of the original review that was first published in the Cochrane Database of Systematic Reviews 2008, Issue 4. Laparoscopy has become an increasingly common approach to surgical staging of apparent early-stage ovarian tumours. This review was undertaken to assess the available evidence on the benefits and risks of laparoscopy compared with laparotomy for the management of International Federation of Gynaecology and Obstetrics (FIGO) stage I ovarian cancer. OBJECTIVES: To evaluate the benefits and risks of laparoscopy compared with laparotomy for the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic). SEARCH METHODS: For the original review, we searched the Cochrane Gynaecological Cancer Group Trials (CGCRG) Register, Cochrane Central Register of Controlled Trials (CENTRAL 2007, Issue 2), MEDLINE, EMBASE, LILACS, Biological Abstracts and CancerLit from 1 January 1990 to 30 November 2007. We also handsearched relevant journals, reference lists of identified studies and conference abstracts. For this updated review, we extended the CGCRG Specialised Register, CENTRAL, MEDLINE, EMBASE and LILACS searches to 6 December 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and prospective case-control studies comparing laparoscopic staging with open surgery (laparotomy) in women with stage I ovarian cancer according to FIGO. DATA COLLECTION AND ANALYSIS: There were no studies to include, therefore we tabulated data from non-randomised studies (NRS) for discussion. MAIN RESULTS: We performed no meta-analyses. AUTHORS' CONCLUSIONS: This review has found no good-quality evidence to help quantify the risks and benefits of laparoscopy for the management of early-stage ovarian cancer as routine clinical practice. PMID- 23450561 TI - Surgery for scoliosis in Duchenne muscular dystrophy. AB - BACKGROUND: Scoliosis in people with Duchenne muscular dystrophy is usually progressive and treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most people with Duchenne muscular dystrophy and scoliosis. This is an updated review and an updated search was undertaken in which no new studies were found. OBJECTIVES: To determine the effectiveness and safety of spinal surgery in people with Duchenne muscular dystrophy with scoliosis. We intended to test whether spinal surgery is effective in increasing survival, improving respiratory function, improving quality of life and overall functioning; and whether spinal surgery is associated with severe adverse effects. SEARCH METHODS: We searched the specialized registers of the Cochrane Neuromuscular Disease Group (31 July 2012), MEDLINE (January 1966 to July 2012), EMBASE (January 1947 to July 2012), CENTRAL (2012, Issue 7 in the Cochrane Library), CINAHL Plus(January 1937 to July 2012), Proquest Dissertation and Thesis Database (January 1980 to July 2012), and the National Institute of Health Clinical Trials Database (July 2012). No language restrictions were imposed. SELECTION CRITERIA: We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in people with Duchenne muscular dystrophy in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. DATA COLLECTION AND ANALYSIS: Two authors independently examined the search results and evaluated the study characteristics against inclusion criteria to decide which ones would be included in the review. MAIN RESULTS: On searching, 47 studies were relevant but none met the inclusion criteria for the review, because they were not clinical trials but prospective or retrospective reviews of case series. AUTHORS' CONCLUSIONS: Since there were no randomized controlled clinical trials available to evaluate the effectiveness of scoliosis surgery in people with Duchenne muscular dystrophy, no evidence-based recommendation can be made for clinical practice. People with scoliosis should be informed about the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function and life expectancy. PMID- 23450562 TI - Surgery for Meniere's disease. AB - BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 1, 2010.Meniere's disease is characterised by three major symptoms: vertigo, deafness, and tinnitus or aural fullness, all of which are discontinuous and variable in intensity. A number of surgical modalities, of varying levels of invasiveness, have been developed to reduce the symptoms of Meniere's disease, but it is not clear whether or not these are effective. OBJECTIVES: To assess the effectiveness of surgical options for the treatment of Meniere's disease. All surgical interventions used in the treatment of Meniere's disease, either to alter the natural history of the disease or to abolish vestibular function, were considered for this review. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 7 November 2012. SELECTION CRITERIA: Randomised or quasi-randomised controlled studies of a surgical modality versus a placebo therapy in Meniere's disease. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for further information. MAIN RESULTS: The only surgical intervention which has been evaluated in randomised controlled trials and met the inclusion criteria was endolymphatic sac surgery. We identified two randomised trials, involving a total of 59 patients; one comparing endolymphatic sac surgery with ventilation tubes and one with simple mastoidectomy. Neither study reported any beneficial effect of surgery either in comparison to placebo surgery or grommet insertion. AUTHORS' CONCLUSIONS: The two trials included in this review provide insufficient evidence of the beneficial effect of endolymphatic sac surgery in Meniere's disease. PMID- 23450563 TI - Antibiotics for mastitis in breastfeeding women. AB - BACKGROUND: Mastitis can be caused by ineffective positioning of the baby at the breast or restricted feeding. Infective mastitis is commonly caused by Staphylococcus aureus. The prevalence of mastitis in breastfeeding women may reach 33%. Effective milk removal, pain medication and antibiotic therapy have been the mainstays of treatment. OBJECTIVES: This review aims to examine the effectiveness of antibiotic therapies in relieving symptoms for breastfeeding women with mastitis with or without laboratory investigation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2012), contacted investigators and other content experts known to us for unpublished trials and scanned the reference lists of retrieved articles. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) and quasi RCTs comparing the effectiveness of various types of antibiotic therapies or antibiotic therapy versus alternative therapies for the treatment of mastitis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. When in dispute, we consulted a third author. MAIN RESULTS: Two trials met the inclusion criteria. One small trial (n = 25) compared amoxicillin with cephradine and found no significant difference between the two antibiotics in terms of symptom relief and abscess formation. Another, older study compared breast emptying alone as 'supportive therapy' versus antibiotic therapy plus supportive therapy, and no therapy. The findings of the latter study suggested faster clearance of symptoms for women using antibiotics, although the study design was problematic. AUTHORS' CONCLUSIONS: There is insufficient evidence to confirm or refute the effectiveness of antibiotic therapy for the treatment of lactational mastitis. There is an urgent need to conduct high quality, double-blinded RCTs to determine whether antibiotics should be used in this common postpartum condition. PMID- 23450564 TI - Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals. AB - BACKGROUND: Squamous cell carcinoma of the conjunctiva is described in the ophthalmic literature as a rare, slow-growing tumour of the eye, normally affecting elderly men around 70 years of age. In Africa, however, the disease is different. The incidence is rising rapidly, affecting young persons (around 35 years of age), and usually affecting women. It is more aggressive, with a mean history of three months at presentation. This pattern is related to the co existence of the HIV/AIDS pandemic, high HPV exposure, and solar radiation in the region. Various interventions exist, but despite therapy, there is a high recurrence rate (up to 43%) and poor cosmetic results in late disease. This review was conducted to evaluate the interventions for treatment of conjunctival squamous cell carcinoma in HIV-infected individuals. OBJECTIVES: To evaluate the effect of interventions for treating squamous cell carcinoma of the conjunctiva in HIV-infected individuals on local control, recurrence, death, time to recurrence, and adverse events. SEARCH METHODS: Using a sensitive search strategy, we attempted to identify all relevant trials, regardless of language or publication status, from the following electronic databases; PubMedPubMed, EMBASE and The Cochrane Library. We also searched clinical trial registries; WHO International Clinical Trials Registry Platform (ICTRP) and the US National Institutes of Health Clinicaltrials.gov. We searched the international conference proceedings of HIV/AIDS and AIDS-related cancers from the AIDS Education Global Education System (AEGIS). Searches were conducted between January and February 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving HIV infected individuals with ocular surface squamous neoplasia. DATA COLLECTION AND ANALYSIS: We independently screened the results of the search to select potentially relevant studies and to retrieve the full articles. We independently applied the inclusion criteria to the potentially relevant studies. No studies were identified that fulfilled the selection criteria. MAIN RESULTS: No RCTs of interventions currently used against conjunctival squamous cell carcinoma in HIV infected individuals were identified.There is one ongoing RCT in Kenya that was registered in July 2012. AUTHORS' CONCLUSIONS: IMPLICATIONS FOR PRACTICE: Current clinical practice in treatment of squamous cell carcinoma of the conjunctiva rests on a weak evidence base of case series and case reports. IMPLICATIONS FOR RESEARCH: Randomised controlled trials for treatment of this disease are needed in settings where it occurs most frequently. Preventive interventions also need to be identified. HIV/AIDS research has not focused on treatment of this tumour. PMID- 23450565 TI - Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. AB - BACKGROUND: Preoperative radiotherapy (RT) decreases local recurrence rate and improves survival in stage II and III rectal cancer patients. The combination of chemotherapy with RT has a sound radiobiological rationale, and phase II trials of combined chemoradiation (CRT) have shown promising activity in rectal cancer. OBJECTIVES: To compare preoperative RT with preoperative CRT in patients with resectable stage II and III rectal cancer. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until June 2012. A manual search was performed of Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys and the proceedings of ASTRO, ECCO and ASCO from 1990 until June 2012. SELECTION CRITERIA: Relevant studies randomized resectable stage II or III rectal cancer patients to at least one arm of preoperative RT alone or at least one arm of preoperative CRT. DATA COLLECTION AND ANALYSIS: Primary outcome parameters included overall survival (OS) at 5 years and local recurrence (LR) rate at 5 years. Secondary outcome parameters included disease free survival (DFS) at 5 years, metastasis rate, pathological complete response rate, clinical response rate, sphincter preservation rate, acute toxicity, postoperative mortality and morbidity, and anastomotic leak rate. Outcome parameters were summarized using the Odds Ratio (OR) and associated 95% confidence interval (CI) using the fixed effects model. MAIN RESULTS: Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68 10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67 1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92 1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years. AUTHORS' CONCLUSIONS: Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials. PMID- 23450566 TI - Prenatal education for congenital toxoplasmosis. AB - BACKGROUND: Congenital toxoplasmosis is considered a rare but potentially severe infection. Prenatal education about congenital toxoplasmosis could be the most efficient and least harmful intervention, yet its effectiveness is uncertain. OBJECTIVES: To assess the effects of prenatal education for preventing congenital toxoplasmosis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 January 2012), PubMed (1966 to 15 January 2012), EMBASE (1980 to 15 January 2012), CINAHL (1982 to 15 January 2012), LILACS (1982 to 15 January 2012), IMEMR (1984 to 15 January 2012), and reference lists of relevant papers, reviews and websites. SELECTION CRITERIA: Randomized and quasi randomized controlled trials (RCTs) of all types of prenatal education on toxoplasmosis infection during pregnancy. Cluster-randomized trials were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and study quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: Two cluster-randomized controlled trials (involving a total of 5455 women) met the inclusion criteria. The two included trials measured the effectiveness of the intervention in different ways which meant that meta-analysis of the results was not possible One trial (432 women enrolled) conducted in Canada was judged of low methodological quality. The authors did not report measure of association but only provided P values (P less than 0.05) for all outcomes. Moreover, losses to follow-up were high (34%, 147 out of 432 women initially enrolled). The authors concluded that prenatal education can effectively change pregnant women's behavior as it increased pet, personal and food hygiene. The second trial conducted in France was also judged of low methodological quality. Losses to follow-up were high (44.5%, 2233 out of 5023 women initially enrolled) and differential (40% in the intervention group and 52% in the control group). The authors concluded that prenatal education for congenital toxoplasmoses has a significant effect on improving women's knowledge whereas it has no effect on changing women's behavior. In this trial 17/3949 pregnant women seroconverted for toxoplasmosis: 13/2591 (0.5%) in the intervention group and 4/1358 (0.3%) in the control group. The number of events was too small to reach conclusions about the effect of prenatal education on seroconversion rate during pregnancy.No other randomized trials on the effect of prenatal education on congenital toxoplasmosis rate, or toxoplasmosis seroconversion rate during pregnancy were detected. AUTHORS' CONCLUSIONS: Even though primary prevention of congenital toxoplasmosis is considered a desirable intervention, given the lack of related risks compared to secondary and tertiary prevention, its effectiveness has not been adequately evaluated. There is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis even though evidence from observational studies suggests it is. Given the lack of good evidence supporting prenatal education for congenital toxoplasmosis prevention, further RCTs are needed to confirm any potential benefits and to further quantify the impact of different sets of educational intervention. PMID- 23450567 TI - Chemotherapy and/or radiotherapy in combination with surgery for ovarian carcinosarcoma. AB - BACKGROUND: Ovarian carcinosarcoma, also known as malignant mixed Mullerian tumour, is a rare malignant gynaecological tumour constituting about 1% or less of all ovarian cancers. In over 80% of cases, there is extra-ovarian intra abdominal spread at diagnosis. The primary treatment has traditionally been surgical cytoreduction followed by radiotherapy and chemotherapy or chemotherapy alone. Regimes have included cisplatin alone; a combination of doxorubicin, ifosfamide, dacarbazine, cyclophosphamide, taxol; and various other combinations. The effectiveness of these various regimens appears to be mixed. Therefore, there is a need to clarify if there is an optimum neoadjuvant or adjuvant therapy after surgical cytoreduction for this rare tumour. Also, it is important to address quality of life (QoL) issues related to treatment, particularly toxicity, as the overall prognosis appears to be poor. OBJECTIVES: To assess the effectiveness and safety of various adjuvant and neoadjuvant chemotherapy and radiotherapy options or chemotherapy alone in combination with surgery in the management of ovarian carcinosarcoma. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to February 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of review articles and contacted experts in the field. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared neoadjuvant or adjuvant chemotherapy and radiotherapy, or chemotherapy alone, in women with ovarian carcinosarcoma (malignant mixed Mullerian sarcoma of the ovary). We also reviewed non-randomised studies (NRS) for discussion in the absence of RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found and therefore no data were analysed. MAIN RESULTS: The search strategy identified 297 unique references of which all were excluded. AUTHORS' CONCLUSIONS: We found no evidence to inform decisions about neoadjuvant and adjuvant chemotherapy and radiotherapy regimens, or chemotherapy alone, for women with ovarian carcinosarcoma. Ideally, an RCT that is multicentre or multinational, or well designed non-randomised studies that use multivariate analysis to adjust for baseline imbalances, are needed to compare treatment modalities and improve current knowledge. Further research in genetic and molecular signalling pathways might improve understanding of this tumour subtype. PMID- 23450568 TI - Chest physiotherapy for pneumonia in adults. AB - BACKGROUND: Despite conflicting evidence, chest physiotherapy has been widely used as an adjunctive treatment for adults with pneumonia. OBJECTIVES: To assess the effectiveness and safety of chest physiotherapy for pneumonia in adults. SEARCH METHODS: We searched CENTRAL 2012, Issue 11, MEDLINE (1966 to November week 2, 2012), EMBASE (1974 to November 2012), Physiotherapy Evidence Database (PEDro) (1929 to November 2012), CINAHL (2009 to November 2012) and CBM (1978 to November 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the efficacy of chest physiotherapy for treating pneumonia in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and appraised trial quality. Primary outcomes were mortality and cure rate. We used risk ratios (RR) and mean difference (MD) for individual trial results in the data analysis. We performed meta-analysis and measured all outcomes with 95% confidence intervals (CI). MAIN RESULTS: Six RCTs (434 participants) appraised four types of chest physiotherapy (conventional chest physiotherapy; osteopathic manipulative treatment (which includes paraspinal inhibition, rib raising and myofascial release); active cycle of breathing techniques (which include active breathing control, thoracic expansion exercises and forced expiration techniques); and positive expiratory pressure).None of the physiotherapies (versus no physiotherapy or placebo) improved mortality rates of adults with pneumonia.Conventional chest physiotherapy (versus no physiotherapy), active cycle of breathing techniques (versus no physiotherapy) and osteopathic manipulative treatment (versus placebo) did not increase the cure rate or chest X ray improvement rate.Osteopathic manipulative treatment (versus placebo) and positive expiratory pressure (versus no physiotherapy) reduced the mean duration of hospital stay by 2.0 days (mean difference (MD) -2.0 days, 95% CI -3.5 to 0.6) and 1.4 days (MD -1.4 days, 95% CI -2.8 to -0.0), respectively. Conventional chest physiotherapy and active cycle of breathing techniques did not.Positive expiratory pressure (versus no physiotherapy) reduced fever duration (MD -0.7 day, 95% CI -1.4 to -0.0). Osteopathic manipulative treatment did not.Osteopathic manipulative treatment (versus placebo) reduced the duration of intravenous (MD 2.1 days, 95% CI -3.4 to -0.9) and total antibiotic treatment (MD -1.9 days, 95% CI -3.1 to -0.7).Limitations of this review are that the studies addressing osteopathic manipulative treatment were small, and that six published studies which appear to meet the inclusion criteria are awaiting classification. AUTHORS' CONCLUSIONS: Based on current limited evidence, chest physiotherapy might not be recommended as routine additional treatment for pneumonia in adults. PMID- 23450570 TI - Aripiprazole versus other atypical antipsychotics for schizophrenia. AB - BACKGROUND: In most western industrialised countries, second generation (atypical) antipsychotics are recommended as first line drug treatments for people with schizophrenia. In this review we specifically examine how the efficacy and tolerability of one such agent - aripiprazole - differs from that of other comparable second generation antipsychotics. OBJECTIVES: To evaluate the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (November 2011), inspected references of all identified studies for further trials, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing aripiprazole (oral) with oral and parenteral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. Where possible, we calculated illustrative comparative risks for primary outcomes. For continuous data, we calculated mean differences (MD), again based on a random-effects model. We assessed risk of bias for each included study. MAIN RESULTS: We included 12 trials involving 6389 patients. Aripiprazole was compared to olanzapine, risperidone and ziprasidone. All trials were sponsored by an interested drug manufacturer. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differences between groups).When compared with olanzapine no differences were apparent for global state (no clinically important change: n = 703, 1 RCT, RR short-term 1.00 95% CI 0.81 to 1.22; n = 317, 1 RCT, RR medium-term 1.08 95% CI 0.95 to 1.22) but mental state tended to favour olanzapine (n = 1360, 3 RCTs, MD total Positive and Negative Syndrome Scale (PANSS) 4.68 95% CI 2.21 to 7.16). There was no significant difference in extrapyramidal symptoms (n = 529, 2 RCTs, RR 0.99 95% CI 0.62 to 1.59) but fewer in the aripiprazole group had increased cholesterol levels (n = 223, 1 RCT, RR 0.32 95% CI 0.19 to 0.54) or weight gain of 7% or more of total body weight (n = 1095, 3 RCTs, RR 0.39 95% CI 0.28 to 0.54).When compared with risperidone, aripiprazole showed no advantage in terms of global state (n = 384, 2 RCTs, RR no important improvement 1.14 95% CI 0.81 to 1.60) or mental state (n = 372, 2 RCTs, MD total PANSS 1.50 95% CI -2.96 to 5.96).One study compared aripiprazole with ziprasidone (n = 247) and both the groups reported similar change in the global state (n = 247, 1 RCT, MD average change in Clinical Global Impression-Severity (CGI-S) score -0.03 95% CI -0.28 to 0.22) and mental state (n = 247, 1 RCT, MD change PANSS -3.00 95% CI -7.29 to 1.29).When compared with any one of several new generation antipsychotic drugs the aripiprazole group showed improvement in global state in energy (n = 523, 1 RCT, RR 0.69 95% CI 0.56 to 0.84), mood (n = 523, 1 RCT, RR 0.77 95% CI 0.65 to 0.92), negative symptoms (n = 523, 1 RCT, RR 0.82 95% CI 0.68 to 0.99), somnolence (n = 523, 1 RCT, RR 0.80 95% CI 0.69 to 0.93) and weight gain (n = 523, 1 RCT, RR 0.84 95% CI 0.76 to 0.94). Significantly more people given aripiprazole reported symptoms of nausea (n = 2881, 3 RCTs, RR 3.13 95% CI 2.12 to 4.61) but weight gain (7% or more of total body weight) was less common in people allocated aripiprazole (n = 330, 1 RCT, RR 0.35 95% CI 0.19 to 0.64). Aripiprazole may have value in aggression but data are limited. This will be the focus of another review. AUTHORS' CONCLUSIONS: Information on all comparisons are of limited quality, are incomplete and problematic to apply clinically. Aripiprazole is an antipsychotic drug with a variant but not absent adverse effect profile. Long-term data are sparse and there is considerable scope for another update of this review as new data emerges from the many Chinese studies as well as from ongoing larger, independent pragmatic trials. PMID- 23450571 TI - Enzyme replacement therapy for Anderson-Fabry disease. AB - BACKGROUND: Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers. OBJECTIVES: To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease. SEARCH METHODS: We searched 'Clinical Trials' on The Cochrane Library, MEDLINE, EMBASE, LILACS and the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 11 September 2012). The original search was performed in September 2008.Date of the most recent search of the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register: 11 September 2012. SELECTION CRITERIA: Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease. DATA COLLECTION AND ANALYSIS: Two authors selected relevant trials, assessed methodological quality and extracted data. MAIN RESULTS: Six trials comparing either agalsidase alfa or beta in 223 participants fulfilled the selection criteria.Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval (CI) -3.79 to -0.41); at up to five months, mean difference -1.90 (95% CI -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% CI -3.66 to 0.34). There was a significant difference in pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% CI -3.92 to -0.28) but not at other time-points. Neither trial reported deaths.One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% CI -2.09 to -1.31); heart, mean difference -0.90 (95% CI -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% CI -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain.Only one trial compared agalsidase alfa to agalsidase beta. There was no significant difference between the groups for any adverse events, risk ratio 0.36 (95% CI 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; 95% CI 0.03 to 2.57). AUTHORS' CONCLUSIONS: Six small, poor quality randomised controlled trials provide no robust evidence for use of either agalsidase alfa and beta to treat Anderson-Fabry disease. PMID- 23450569 TI - Neuroprotection for treatment of glaucoma in adults. AB - BACKGROUND: Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the commonest form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death. OBJECTIVES: The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents for slowing the progression of OAG in adults. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to October 2012), EMBASE (January 1980 to October 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 16 October 2012. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which topical or oral treatments were used for neuroprotection in adults with OAG. Minimum follow up time was four years. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed titles and abstracts from the literature searches. Full text copies of potentially relevant studies were obtained and re-evaluated for inclusion. Two review authors independently extracted data related study characteristics, risk of bias, and outcome data. One trial was identified for this review, thus we performed no meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until additional study details are provided. We documented reasons for excluding studies from the review. MAIN RESULTS: We included one multi-center RCT of adults with low-pressure glaucoma (Low-pressure Glaucoma Treatment Study, LoGTS) conducted in the USA. The primary outcome was visual field progression after four years of treatment with either brimonidine or timolol. Of the 190 adults enrolled in the study, 12 (6.3%) were excluded after randomization and 77 (40.5%) did not complete four years of follow up. The rate of attrition was unbalanced between groups with more participants dropping out of the brimonidine group (55%) than the timolol group (29%). Of those remaining in the study at four years, participants assigned to brimonidine showed less visual field progression than participants assigned to timolol (5/45 participants in the brimonidine group compared with 18/56 participants in the timolol group). Since no information was available for the 12 participants excluded from the study, or the 77 participants who dropped out of the study, we cannot draw any conclusions from these results as the participants for whom data are missing may or may not have progressed. The mean IOP was similar in both groups at the four-year follow up among those for whom data were available: 14.2 mmHg (standard deviation (SD) = 1.9) among the 43 participants in the brimonidine group and 14.0 mmHg (SD = 2.6) among the 48 participants in the timolol group. Among the participants who developed progressive visual field loss, IOP reduction of 20% or greater was not significantly different between groups: 4/9 participants in the brimonidine group and 12/31 participants in the timolol group. The study authors did not report data for visual acuity or vertical cup disc ratio. The most frequent adverse event was ocular allergy to study drug, which occurred more frequently in the brimonidine group (20/99 participants) than the timolol group (3/79 participants). AUTHORS' CONCLUSIONS: Although neuroprotective agents are intended to act as pharmacological antagonists to prevent cell death, this trial did not provide evidence that they are effective in preventing retinal ganglion cell death, and thus preserving vision in people with OAG. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. Since OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents would require long-term follow up (more than four years) in order to detect clinically meaningful effects. PMID- 23450572 TI - Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma. AB - BACKGROUND: Uterine carcinosarcomas are uncommon with about 35% not confined to the uterus at diagnosis. The survival of women with advanced uterine carcinosarcoma is poor with a pattern of failure indicating greater likelihood of upper abdominal and distant metastatic recurrence. OBJECTIVES: To evaluate the effectiveness and safety of adjuvant radiotherapy and/or systemic chemotherapy in the management of uterine carcinosarcoma. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), 2012, Issue 10, MEDLINE and EMBASE up to November 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant radiotherapy and/or chemotherapy in women with uterine carcinosarcoma. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) comparing adverse events in women who received radiotherapy and/or chemotherapy were pooled in random-effects meta-analyses. MAIN RESULTS: Three trials met the inclusion criteria and these randomised 579 women, of whom all were assessed at the end of the trials. Two trials assessing 373 participants with stage III to IV persistent or recurrent disease, found that women who received combination therapy had a significantly lower risk of death and disease progression than women who received single agent ifosfamide, after adjustment for performance status (HR = 0.75, 95% confidence interval (CI): 0.60 to 0.94 and HR = 0.72, 95% CI: 0.58 to 0.90 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of nausea and vomiting, where significantly more women experienced these ailments in the combination therapy group than the Ifosamide group (RR = 3.53, 95% CI: 1.33 to 9.37).In one trial there was no statistically significant difference in the risk of death and disease progression in women who received whole body irradiation and chemotherapy, after adjustment for age and FIGO stage (HR = 0.71, 95% CI: 0.48 to 1.05 and HR = 0.79, 95% CI: 0.53 to 1.18 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of haematological and neuropathy morbidities, where significantly less women experienced these morbidities in the whole body irradiation group than the chemotherapy group (RR= 0.02, 95% CI: 0.00 to 0.16) for haematological morbidity and all nine women in the trial experiencing neuropathy morbidity were in the chemotherapy group). AUTHORS' CONCLUSIONS: In advanced stage metastatic uterine carcinosarcoma as well as recurrent disease adjuvant combination, chemotherapy with ifosfamide should be considered. Combination chemotherapy with ifosfamide and paclitaxel is associated with lower risk of death compared with ifosfamide alone. In addition, radiotherapy to the abdomen is not associated with improved survival. PMID- 23450573 TI - Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome. AB - BACKGROUND: Maternal caffeine consumption during pregnancy may have adverse effects on fetal, neonatal and maternal outcomes. OBJECTIVES: This review investigates the effects of restricting caffeine intake by mothers on fetal, neonatal and pregnancy outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2012), scanned bibliographies of published studies and corresponded with investigators. SELECTION CRITERIA: Randomised controlled trials (RCTs) including quasi-RCTs investigating the effect of caffeine and/or supplementary caffeine versus restricted caffeine intake or placebo on pregnancy outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Two studies met the inclusion criteria but only one contributed data for the prespecified outcomes. Caffeinated instant coffee (568 women) was compared with decaffeinated instant coffee (629 women) and it was found that reducing the caffeine intake of regular coffee drinkers (3+ cups/day) during the second and third trimester by an average of 182 mg/day did not affect birthweight or length of gestation. AUTHORS' CONCLUSIONS: There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high-quality, double-blinded RCTs to determine whether caffeine has any effect on pregnancy outcome. PMID- 23450574 TI - Interventions for smoking cessation and reduction in individuals with schizophrenia. AB - BACKGROUND: Individuals with schizophrenia smoke more heavily than the general population and this contributes to their higher morbidity and mortality from smoking-related illnesses. It remains unclear what interventions can help them to quit or to reduce smoking. OBJECTIVES: To evaluate the benefits and harms of different treatments for nicotine dependence in schizophrenia. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and PsycINFO from inception to October 2012, and the Cochrane Tobacco Addiction Group Specialized Register in November 2012. SELECTION CRITERIA: We included randomised trials for smoking cessation or reduction, comparing any pharmacological or non pharmacological intervention with placebo or with another therapeutic control in adult smokers with schizophrenia or schizoaffective disorder. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the eligibility and quality of trials, as well as extracted data. Outcome measures included smoking abstinence, reduction in the amount smoked and any change in mental state. We extracted abstinence and reduction data at the end of treatment and at least six months after the intervention. We used the most rigorous definition of abstinence or reduction and biochemically validated data where available. We noted any reported adverse events. Where appropriate, we pooled data using a random-effects model. MAIN RESULTS: We included 34 trials (16 trials of cessation; nine trials of reduction; one trial of relapse prevention; eight trials that reported smoking outcomes for interventions aimed at other purposes). Seven trials compared bupropion with placebo; meta-analysis showed that cessation rates after bupropion were significantly higher than placebo at the end of treatment (seven trials, N = 340; risk ratio [RR] 3.03; 95% confidence interval [CI] 1.69 to 5.42) and after six months (five trials, N = 214, RR 2.78; 95% CI 1.02 to 7.58). There were no significant differences in positive, negative and depressive symptoms between bupropion and placebo groups. There were no reports of major adverse events such as seizures with bupropion.Smoking cessation rates after varenicline were significantly higher than placebo, at the end of treatment (2 trials, N = 137; RR 4.74, 95% CI 1.34 to 16.71). Only one trial reported follow-up at six months and the CIs were too wide to provide evidence of a sustained effect (one trial, N = 128, RR 5.06, 95% CI 0.67 to 38.24). There were no significant differences in psychiatric symptoms between the varenicline and placebo groups. Nevertheless, there were reports of suicidal ideation and behaviours from two people on varenicline.Two studies reported that contingent reinforcement (CR) with money may increase smoking abstinence rates and reduce the level of smoking in patients with schizophrenia. However, it is uncertain whether these benefits can be maintained in the longer term. There was no evidence of benefit for the few trials of other pharmacological therapies (including nicotine replacement therapy (NRT)) and psychosocial interventions in helping smokers with schizophrenia to quit or reduce smoking. AUTHORS' CONCLUSIONS: Bupropion increases smoking abstinence rates in smokers with schizophrenia, without jeopardizing their mental state. Varenicline may also improve smoking cessation rates in schizophrenia, but its possible psychiatric adverse effects cannot be ruled out. CR may help this group of patients to quit and reduce smoking in the short term. We failed to find convincing evidence that other interventions have a beneficial effect on smoking in schizophrenia. PMID- 23450575 TI - Antiepileptic drugs as prophylaxis for post-craniotomy seizures. AB - BACKGROUND: The incidence of seizures following supratentorial craniotomy for non traumatic pathology has been estimated to be 15% to 20%; however, the risk of experiencing a seizure may vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials. OBJECTIVES: To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialized Register (September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 9, 2012), and MEDLINE (1946 to September 2012). No language restrictions were imposed. SELECTION CRITERIA: Randomised controlled trials of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons were included. Trials with adequate randomisation methods and concealment were included; these could either be blinded or unblinded parallel trials. No minimum treatment period was stipulated, trials using active drugs or placebo as a control group were included. DATA COLLECTION AND ANALYSIS: Two review authors (JP and JG) independently selected trials for inclusion and carried out data extraction and risk of bias assessments. Any disagreements were resolved through discussion. Outcomes investigated included the number of patients experiencing seizures (early - occurring within first week following craniotomy and late - occurring after first week following craniotomy), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, data from the trials were not combined in a meta-analysis; the findings of the review are presented in narrative format. MAIN RESULTS: Six RCTs (N = 1398) were eligible for inclusion within the review with publication dates ranging between 1983 and 1999. Two trials compared a single AED (phenytoin) with a placebo. One three-arm trial compared two AEDs (carbamazepine, phenytoin) with no treatment. A second three-arm trial compared phenytoin, phenobarbital and no treatment. Two other trials were head-to-head trials of AEDs (phenytoin vs. valproate and zonisamide vs. phenobarbital). Of the four trials comparing AEDs with controls only one trial reported a significant difference between AED treatment and controls for early seizure occurrence. All other comparisons were non-significant. Of the head-to-head trials, none reported statistically significant differences between treatments for either early or late seizures. One head-to-head trial showed an increase in the number of deaths following one AED treatment compared to another AED treatment. Incidences of adverse effects of treatment were poorly reported, no significant differences between treatment groups were found due to the limited number of reported occurrences. AUTHORS' CONCLUSIONS: There is little evidence to suggest that AED treatment administered prophylactically is effective or not effective in preventing post-craniotomy seizures. The current evidence base is limited due to the differing methodologies employed in the trials and inconsistencies in reporting of outcomes. Further evidence from good-quality, contemporary trials is required in order to assess the effectiveness of prophylactic AED treatment compared to control groups or other AEDs in preventing post-craniotomy seizures properly. PMID- 23450576 TI - Topical capsaicin (high concentration) for chronic neuropathic pain in adults. AB - BACKGROUND: Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams.High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, normally under local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made. OBJECTIVES: To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-concentration (8%) capsaicin in chronic neuropathic pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and clinicaltrials.gov to December 2012. SELECTION CRITERIA: Randomised, double blind, placebo-controlled studies of at least six weeks' duration, using topical capsaicin to treat neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and validity, and extracted data on numbers of participants with pain relief (clinical improvement) after at least six weeks, and with local skin reactions. We calculated risk ratio and numbers needed to treat to benefit (NNT) and harm (NNH). We sought details of definition of pain relief and specific adverse events.Efficacy outcomes reflecting long duration pain relief after a single drug application were from the patient global impression of change (PGIC) at specific points, usually eight and 12 weeks. We regarded these outcomes as first-tier evidence. We regarded average pain scores over weeks 2 to 8 and 2 to 12 and the number and/or percentage of participants with pain intensity reduction of at least 30% or at least 50% over baseline as second-tier evidence. MAIN RESULTS: We included six studies, involving 2073 participants; they were of generally good reporting quality; the control was 0.04% topical capsaicin to help maintain blinding. Efficacy outcomes were inconsistently reported between studies, however, resulting in analyses for most outcomes being based on less than complete data.Four studies involved 1272 participants with postherpetic neuralgia. All efficacy outcomes were significantly better than control. At both eight and 12 weeks there was a significant benefit for high-concentration over low-concentration topical capsaicin for participants reporting themselves to be much or very much better, with point estimates of the NNTs of 8.8 (95% confidence interval (CI) 5.3 to 26) and 7.0 (95% CI 4.6 to 15) respectively. More participants had average 2 to 8 week and 2 to 12-week pain intensity reductions over baseline of at least 30% and at least 50% with active treatment than control, with NNT values between 10 and 12.Two studies involved 801 participants with painful HIV-neuropathy. In a single study the NNT at 12 weeks for participants to be much or very much better was 5.8 (95% CI 3.8 to 12). Over both studies more participants had average 2 to 12-week pain intensity reductions over baseline of at least 30% with active treatment than control, with an NNT of 11.Local adverse events were common, but not consistently reported. Serious adverse events were no more common with active treatment (4.1%) than control (3.2%). Adverse event withdrawals did not differ between groups, but lack of efficacy withdrawals were somewhat more common with control than active treatment, based on small numbers of events. No deaths were judged to be related to study medication. AUTHORS' CONCLUSIONS: High concentration topical capsaicin used to treat postherpetic neuralgia and HIV neuropathy generates more participants with high levels of pain relief than does control treatment using a much lower concentration of capsaicin. The additional proportion who benefit over control is not large, but for those who do obtain high levels of pain relief there are additional improvements in sleep, fatigue, depression and an improved quality of life. High-concentration topical capsaicin is therefore similar to other therapies for chronic pain. In this case, the high cost of single and repeated applications suggest that high-concentration topical capsaicin is likely to be used when other available therapies have failed, and that it should probably not be used repeatedly without substantial documented pain relief. Even when efficacy is established, there are unknown risks, especially on epidermal innervation, of repeated application of long periods. PMID- 23450577 TI - School-based physical activity programs for promoting physical activity and fitness in children and adolescents aged 6 to 18. AB - BACKGROUND: The World Health Organization (WHO) estimates that 1.9 million deaths worldwide are attributable to physical inactivity and at least 2.6 million deaths are a result of being overweight or obese. In addition, WHO estimates that physical inactivity causes 10% to 16% of cases each of breast cancer, colon, and rectal cancers as well as type 2 diabetes, and 22% of coronary heart disease and the burden of these and other chronic diseases has rapidly increased in recent decades. OBJECTIVES: The purpose of this systematic review was to summarize the evidence of the effectiveness of school-based interventions in promoting physical activity and fitness in children and adolescents. SEARCH METHODS: The search strategy included searching several databases to October 2011. In addition, reference lists of included articles and background papers were reviewed for potentially relevant studies, as well as references from relevant Cochrane reviews. Primary authors of included studies were contacted as needed for additional information. SELECTION CRITERIA: To be included, the intervention had to be relevant to public health practice (focused on health promotion activities), not conducted by physicians, implemented, facilitated, or promoted by staff in local public health units, implemented in a school setting and aimed at increasing physical activity, included all school-attending children, and be implemented for a minimum of 12 weeks. In addition, the review was limited to randomized controlled trials and those that reported on outcomes for children and adolescents (aged 6 to 18 years). Primary outcomes included: rates of moderate to vigorous physical activity during the school day, time engaged in moderate to vigorous physical activity during the school day, and time spent watching television. Secondary outcomes related to physical health status measures including: systolic and diastolic blood pressure, blood cholesterol, body mass index (BMI), maximal oxygen uptake (VO2max), and pulse rate. DATA COLLECTION AND ANALYSIS: Standardized tools were used by two independent reviewers to assess each study for relevance and for data extraction. In addition, each study was assessed for risk of bias as specified in the Cochrane Handbook for Systematic Reviews of Interventions. Where discrepancies existed, discussion occurred until consensus was reached. The results were summarized narratively due to wide variations in the populations, interventions evaluated, and outcomes measured. MAIN RESULTS: In the original review, 13,841 records were identified and screened, 302 studies were assessed for eligibility, and 26 studies were included in the review. There was some evidence that school-based physical activity interventions had a positive impact on four of the nine outcome measures. Specifically positive effects were observed for duration of physical activity, television viewing, VO2 max, and blood cholesterol. Generally, school-based interventions had little effect on physical activity rates, systolic and diastolic blood pressure, BMI, and pulse rate. At a minimum, a combination of printed educational materials and changes to the school curriculum that promote physical activity resulted in positive effects.In this update, given the addition of three new inclusion criteria (randomized design, all school-attending children invited to participate, minimum 12-week intervention) 12 of the original 26 studies were excluded. In addition, studies published between July 2007 and October 2011 evaluating the effectiveness of school-based physical interventions were identified and if relevant included. In total an additional 2378 titles were screened of which 285 unique studies were deemed potentially relevant. Of those 30 met all relevance criteria and have been included in this update. This update includes 44 studies and represents complete data for 36,593 study participants. Duration of interventions ranged from 12 weeks to six years.Generally, the majority of studies included in this update, despite being randomized controlled trials, are, at a minimum, at moderate risk of bias. The results therefore must be interpreted with caution. Few changes in outcomes were observed in this update with the exception of blood cholesterol and physical activity rates. For example blood cholesterol was no longer positively impacted upon by school-based physical activity interventions. However, there was some evidence to suggest that school based physical activity interventions led to an improvement in the proportion of children who engaged in moderate to vigorous physical activity during school hours (odds ratio (OR) 2.74, 95% confidence interval (CI), 2.01 to 3.75). Improvements in physical activity rates were not observed in the original review. Children and adolescents exposed to the intervention also spent more time engaged in moderate to vigorous physical activity (with results across studies ranging from five to 45 min more), spent less time watching television (results range from five to 60 min less per day), and had improved VO2max (results across studies ranged from 1.6 to 3.7 mL/kg per min). However, the overall conclusions of this update do not differ significantly from those reported in the original review. AUTHORS' CONCLUSIONS: The evidence suggests the ongoing implementation of school-based physical activity interventions at this time, given the positive effects on behavior and one physical health status measure. However, given these studies are at a minimum of moderate risk of bias, and the magnitude of effect is generally small, these results should be interpreted cautiously. Additional research on the long-term impact of these interventions is needed. PMID- 23450578 TI - Morning versus evening induction of labour for improving outcomes. AB - BACKGROUND: Induction of labour is a common intervention in obstetric practice. Traditionally, in most hospitals induction of labour with medication starts early in the morning, with the start of the working day for the day shift. In human and animal studies spontaneous onset of labour is proven to have a circadian rhythm with a preference for start of labour in the evening. Moreover, when spontaneous labour starts in the evening, the total duration of labour and delivery shortens and fewer obstetric interventions are needed. Based on these observations one might assume that starting induction of labour in the evening, in harmony with the circadian rhythm of natural birth, is more beneficial for both mother and child. OBJECTIVES: To assess whether induction of labour starting in the evening, coinciding with the endogenous circadian rhythm, improves the outcome of labour compared with induction of labour starting in the early morning, organised to coincide with office hours. SEARCH METHODS: We contacted the Trials Search Co ordinator to search the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012). In addition, we searched MEDLINE (1966 to 16 February 2012) and EMBASE (1980 to 16 February 2012). SELECTION CRITERIA: We included all published and unpublished randomised controlled trials. We excluded trials that employed quasi-random methods of treatment allocation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias. Two review authors independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. MAIN RESULTS: The search resulted in 2693 articles that we screened on title and abstract for eligibility.Thirteen studies were selected for full text assessment. We included three randomised trials involving 1150 women. Two trials compared the administration of prostaglandins in the morning versus the evening in women with an unfavourable cervix, and one trial compared induction of labour in the morning versus the evening in women with a favourable cervix and/or ruptured membranes with intravenous oxytocin. Because of the different mechanism, we have reported results for these two comparisons separately.In the two trials comparing prostaglandins in the morning versus the evening there were few clinically significant differences between study groups for maternal or neonatal outcomes. One study reported a statistically significant preference by women to start induction of labour with prostaglandins in the morning.In the trial examining induction of labour with intravenous oxytocin, the number of neonatal admissions was statistically significantly increased in the group of women that started induction in the morning. This finding was unexpected, and while the trial authors offered some possible explanations for this, it is important that any future trials examine neonatal outcomes. AUTHORS' CONCLUSIONS: Taking into account women's preferences that favoured administration of prostaglandins in the morning, we conclude that caregivers should preferably consider administering prostaglandins in the morning.There is no strong evidence that induction of labour with intravenous oxytocin in the evening is more or less effective than induction in the morning. Consideration may be given to start induction of labour with oxytocin in the evening when indicated. PMID- 23450579 TI - Macrolides for diffuse panbronchiolitis. AB - BACKGROUND: Diffuse panbronchiolitis (DPB) is a chronic airways disease predominantly affecting East Asians. Macrolides, a class of antibiotics, have been used as the main treatment for DPB, based on evidence from retrospective and non-randomised studies. OBJECTIVES: To assess the efficacy and safety of macrolides for DPB. SEARCH METHODS: We searched CENTRAL 2012, Issue 7, MEDLINE (1966 to July week 2, 2012), EMBASE (1974 to July 2012), Chinese Biomedical Literature Database (CBM) (1978 to July 2012), China National Knowledge Infrastructure (CNKI) (1974 to July 2012), KoreaMed (1997 to July 2012) and Database of Japana Centra Revuo Medicina (1983 to July 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs assessing the effect of macrolides for DPB. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality and subsequent risk of bias according to the Cochrane Collaboration's tool for assessing risk of bias. The primary outcomes were five-year survival rate, lung function and clinical response. We used risk ratios (RR) for individual trial results in the data analysis and measured all outcomes with 95% confidence intervals (CI). MAIN RESULTS: Only one RCT (19 participants) with significant methodological limitations was included in this review. It found that the computerised tomography images of all participants treated with a long-term, low-dose macrolide (erythromycin) improved from baseline, while the images of 71.4% of participants in the control group (with no treatment) worsened and 28.6% remained unchanged. Adverse effects were not reported. AUTHORS' CONCLUSIONS: There is little evidence for macrolides in the treatment of DPB. We are therefore unable to make any new recommendations. It may be reasonable to use low-dose macrolides soon after diagnosis is made and to continue this treatment for at least six months, according to current guidelines. PMID- 23450580 TI - Oral H1 antihistamines as monotherapy for eczema. AB - BACKGROUND: Eczema is a common skin disease in many countries, and although the majority of cases of eczema occur before the age of five years and often resolve during childhood or adolescence, it can also persist into adulthood. Itch is the most important aspect of eczema, often impacting significantly on the quality of life of an affected individual. OBJECTIVES: To assess the effects of oral antihistamines (H1 antagonists) as monotherapy in children and adults with eczema. SEARCH METHODS: We searched the following databases up to March 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We examined the reference lists of excluded studies in order to identify further references to relevant trials. We searched trials registers for ongoing and unpublished trials. We also handsearched the abstracts of the International Research Workshops on eczema, as well as the conference proceedings of the European Academy of Dermatology and Venereology (EADV) and the European Academy of Allergology and Clinical Immunology (EAACI), from 2000 to 2011. SELECTION CRITERIA: We sought to include randomised controlled trials that assessed the effects and safety of oral H1 antihistamines as monotherapy in children and adults with eczema. We excluded studies that compared an antihistamine versus another antihistamine and had no placebo control arm. We also excluded topical antihistamines and oral H1 antihistamines as 'add-on' therapy and studies using any concomitant therapy other than emollients or moisturisers, principally because some of these forms of concomitant therapy may be considered treatment modifiers in assessments of the effects of antihistamines on eczema. DATA COLLECTION AND ANALYSIS: Our search retrieved 409 references to studies. Based on assessments of their titles, abstracts, or both, we excluded all except 36 of these studies. After evaluation of the full text of each report, we excluded a further 35 studies, and 1 study is awaiting classification pending a response from the trial investigators. MAIN RESULTS: No randomised controlled trials met our inclusion criteria. AUTHORS' CONCLUSIONS: There is currently no high-level evidence to support or refute the efficacy or safety of oral H1 antihistamines used as monotherapy for eczema. Because most of the studies allowed the use of concomitant medications and involved multi-therapeutic approaches, meaningful assessments of the individual effects of oral H1 antihistamines on eczema were not feasible. Although well-designed randomised controlled trials excluding concomitant medications appear to be needed, consideration should be given to the potential ethical issues raised with the use of antihistamines as monotherapy for the management of eczema by withholding the use of rescue or additional therapies. A further systematic review of studies in which concomitant therapies were permitted might be of value in determining the potential benefits of oral H1 antihistamines as add-on therapy. PMID- 23450581 TI - Perianal injectable bulking agents as treatment for faecal incontinence in adults. AB - BACKGROUND: Faecal incontinence is a complex and distressing condition with significant medical and social implications. Injection of perianal bulking agents has been used to treat the symptoms of passive faecal incontinence. However, various agents have been used without a standardised technique and the supposed benefit of the treatment is largely anecdotal with a limited clinical research base. OBJECTIVES: To determine the effectiveness of perianal injection of bulking agents for the treatment of faecal incontinence in adults. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register of trials (25 May 2012), ZETOC (3 May 2012), clinical trials registries (3 May 2012) and the reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi randomised controlled trials comparing the use of injectable bulking agents for faecal incontinence with any alternative treatments or placebo were reviewed to evaluate the therapeutic effects. Case-control and cohort studies were also reviewed to assess risks and complications associated with the treatments. DATA COLLECTION AND ANALYSIS: Two review authors (YM and CN) assessed the methodological quality of eligible trials and independently extracted data from the included trials using a range of pre-specified outcome measures. MAIN RESULTS: Five eligible randomised trials with a total of 382 patients were identified. Four of the trials were at an uncertain or high risk of bias.Most trials reported a short term benefit from injections regardless of the material used, including placebo saline injection. One study demonstrated dextranomer in stabilised hyaluronic acid (NASHA Dx) to be more effective than sham injection but with more adverse effects. Dextranomer in stabilised hyaluronic acid (NASHA Dx) was better than sham injections at six months (65/136, 48% versus 48/70, 69% participants not improved, defined as less than 50% reduction in incontinence episodes, RR 0.70, 95% CI 0.55 to 0.88; with more incontinence free days (3.1 days compared with 1.7 in the sham treatment group, MD 1.40 days, 95% CI 0.33 to 2.47). Another study comparing silicone material (PTQTM) to saline injections was too small to demonstrate a clinical benefit compared to the control injection of normal saline.A silicone biomaterial (PTQTM) was shown to provide some advantages and was safer in treating faecal incontinence than carbon-coated beads (Durasphere(r)) in the short term.Similarly, there were short term benefits from injections delivered under ultrasound guidance compared with digital guidance.No long term evidence on outcomes was available and further conclusions were not warranted from the available data. None of the studies reported patient evaluation of outcomes and thus it is difficult to gauge whether the improvement in incontinence scores matched practical symptom improvements that mattered to the patients. AUTHORS' CONCLUSIONS: One large randomised controlled trial has shown that this form of treatment using dextranomer in stabilised hyaluronic acid (NASHA Dx) improves continence for a little over half of patients in the short term. However, the number of identified trials was limited and most had methodological weaknesses. PMID- 23450582 TI - Baclofen for alcohol withdrawal. AB - BACKGROUND: The treatment baclofen can rapidly reduce symptoms of severe alcohol withdrawal syndrome (AWS) in alcoholic patients, with a significant reduction in the cost. Baclofen is easy to manage, and rare euphoria, craving and other pleasant effects are reported by patients treated with baclofen. OBJECTIVES: To assess the efficacy and safety of baclofen for patients with AWS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (October 2012), MEDLINE (1966 to October 2012), EMBASE (1980 to October 2012) and CINAHL (1982 to October 2012). We also searched registers of ongoing trials, for example ClinicalTrials.gov, Controlled-trials.com, EUDRACT, etc. At the same time, we handsearched the references quoted in the identified trials, and contacted researchers, pharmaceutical companies and relevant trial authors seeking information about unpublished or uncompleted trials. All searches included the non-English language literature. SELECTION CRITERIA: All randomized controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for patients with AWS. Uncontrolled, non-randomized or quasi-randomized trials were excluded. Both parallel group and cross-over design were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed references retrieved for possible inclusion. All disagreements were resolved by an independent party. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: We identified a total of 113 references from all electronic databases searched excluding duplicates. After screening of titles and abstracts, full papers of 10 studies were obtained and assessed for eligibility. Finally, two RCTs with 81 participants were eligible according to the inclusion criteria. Regarding the efficacy, one study suggested that both baclofen and diazepam significantly decreased the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar) score, without any significant difference between the two interventions. The other study showed no significant difference in CIWA-Ar score between baclofen and placebo but a significantly decreased dependence on high dose benzodiazepines with baclofen compared to placebo. Meanwhile, only one study reported the safety outcomes and there were no side effects in either the baclofen or diazepam groups. AUTHORS' CONCLUSIONS: The evidence for recommending baclofen for AWS is insufficient. More well designed RCTs are needed to prove its efficacy and safety. PMID- 23450583 TI - Prophylactic gastrojejunostomy for unresectable periampullary carcinoma. AB - BACKGROUND: The role of prophylactic gastrojejunostomy in patients with unresectable periampullary cancer is controversial. OBJECTIVES: To determine whether prophylactic gastrojejunostomy should be performed routinely in patients with unresectable periampullary cancer. SEARCH METHODS: For the initial version of this review, we searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, issue 3), MEDLINE, EMBASE and Science Citation Index Expanded until April 2010. Literature searches were re-run in August 2012. SELECTION CRITERIA: We included randomised controlled trials comparing prophylactic gastrojejunostomy versus no gastrojejunostomy in patients with unresectable periampullary cancer (irrespective of language or publication status). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and independently extracted data. We analysed data with both the fixed-effect and the random-effects models using Review Manager (RevMan). We calculated the hazard ratio (HR), risk ratio (RR), and mean difference (MD) with 95% confidence intervals (CI) based on an intention-to-treat or available case analysis. MAIN RESULTS: We identified two trials (of high risk of bias) involving 152 patients randomised to gastrojejunostomy (80 patients) and no gastrojejunostomy (72 patients). In both trials, patients were found to be unresectable during exploratory laparotomy. Most of the patients also underwent biliary-enteric drainage. There was no evidence of difference in the overall survival (HR 1.02; 95% CI 0.84 to 1.25), peri-operative mortality or morbidity, quality of life, or hospital stay (MD 0.97 days; 95%CI -0.18 to 2.12) between the two groups. The proportion of patients who developed long-term gastric outlet obstruction was significantly lower in the prophylactic gastrojejunostomy group (2/80; 2.5%) compared with no gastrojejunostomy group (20/72; 27.8%) (RR 0.10; 95%CI 0.03 to 0.37). The operating time was significantly longer in the gastrojejunostomy group compared with no gastrojejunostomy group (MD 45.00 minutes; 95%CI 21.39 to 68.61). AUTHORS' CONCLUSIONS: Routine prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary cancer undergoing exploratory laparotomy (with or without hepaticojejunostomy). PMID- 23450584 TI - Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain-Barre syndrome. AB - BACKGROUND: Plasma exchange and intravenous immunoglobulin, but not corticosteroids, are beneficial in Guillain-Barre syndrome (GBS). The efficacy of other pharmacological agents is unknown. This review was first published in 2011 and this update in 2013. OBJECTIVES: To review systematically the evidence from randomised controlled trials (RCTs) for pharmacological agents other than plasma exchange, intravenous immunoglobulin and corticosteroids. SEARCH METHODS: On 28 August 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register CENTRAL (2012, Issue 8 in The Cochrane Library), MEDLINE (January 1966 to August 2012) and EMBASE (January 1980 to August 2012) for treatments for GBS. We considered evidence from non-randomised studies in the Discussion. SELECTION CRITERIA: We included all randomised or quasi-RCTs of acute (within four weeks from onset) GBS of all types, ages and degrees of severity. We discarded trials which only tested corticosteroids, intravenous immunoglobulin or plasma exchange. We included other pharmacological treatments or combinations of treatments compared with no treatment, placebo treatment or another treatment. DATA COLLECTION AND ANALYSIS: Change in disability after four weeks was the primary outcome. Two authors checked references and extracted data independently. One author entered and another checked data in Review Manager (RevMan). We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated mean differences and risk ratios with their 95% confidence intervals. We assessed strength of evidence with GradePro software. MAIN RESULTS: Only very low quality evidence was found for four different interventions. This update of the review found no new trials. One RCT with 13 participants showed no significant difference in any outcome between interferon beta-1a and placebo. Another with 10 participants showed no significant difference in any outcome between brain-derived neurotrophic factor and placebo. A third with 37 participants showed no significant difference in any outcome between cerebrospinal fluid filtration and plasma exchange. In a fourth with 20 participants, the risk ratio of improving by one or more disability grades after eight weeks was significantly greater with the Chinese herbal medicine tripterygium polyglycoside than with corticosteroids (risk ratio 1.47; 95% confidence interval 1.02 to 2.11). Serious adverse events were uncommon with each of these treatments and not significantly commoner in the treated than the control groups. AUTHORS' CONCLUSIONS: The quality of the evidence was very low. Three small RCTs, of interferon beta-1a, brain-derived neurotrophic factor and cerebrospinal fluid filtration, showed no significant benefit or harm. A fourth small trial showed that the Chinese herbal medicine tripterygium polyglycoside hastened recovery significantly more than corticosteroids but this result needs confirmation. It was not possible to draw useful conclusions from the few observational studies. PMID- 23450585 TI - Housing improvements for health and associated socio-economic outcomes. AB - BACKGROUND: The well established links between poor housing and poor health indicate that housing improvement may be an important mechanism through which public investment can lead to health improvement. Intervention studies which have assessed the health impacts of housing improvements are an important data resource to test assumptions about the potential for health improvement. Evaluations may not detect long term health impacts due to limited follow-up periods. Impacts on socio-economic determinants of health may be a valuable proxy indication of the potential for longer term health impacts. OBJECTIVES: To assess the health and social impacts on residents following improvements to the physical fabric of housing. SEARCH METHODS: Twenty seven academic and grey literature bibliographic databases were searched for housing intervention studies from 1887 to July 2012 (ASSIA; Avery Index; CAB Abstracts; The Campbell Library; CINAHL; The Cochrane Library; COPAC; DH-DATA: Health Admin; EMBASE; Geobase; Global Health; IBSS; ICONDA; MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; NTIS; PAIS; PLANEX; PsycINFO; RIBA; SCIE; Sociological Abstracts; Social Science Citations Index; Science Citations Index expanded; SIGLE; SPECTR). Twelve Scandinavian grey literature and policy databases (Libris; SveMed+; Libris uppsok; DIVA; Artikelsok; NORART; DEFF; AKF; DSI; SBI; Statens Institut for Folkesundhed; Social.dk) and 23 relevant websites were searched. In addition, a request to topic experts was issued for details of relevant studies. Searches were not restricted by language or publication status. SELECTION CRITERIA: Studies which assessed change in any health outcome following housing improvement were included. This included experimental studies and uncontrolled studies. Cross sectional studies were excluded as correlations are not able to shed light on changes in outcomes. Studies reporting only socio-economic outcomes or indirect measures of health, such as health service use, were excluded. All housing improvements which involved a physical improvement to the fabric of the house were included. Excluded interventions were improvements to mobile homes; modifications for mobility or medical reasons; air quality; lead removal; radon exposure reduction; allergen reduction or removal; and furniture or equipment. Where an improvement included one of these in addition to an included intervention the study was included in the review. Studies were not excluded on the basis of date, location, or language. DATA COLLECTION AND ANALYSIS: Studies were independently screened and critically appraised by two review authors. Study quality was assessed using the risk of bias tool and the Hamilton tool to accommodate non-experimental and uncontrolled studies. Health and socio-economic impact data were extracted by one review author and checked by a second review author. Studies were grouped according to broad intervention categories, date, and context before synthesis. Where possible, standardized effect estimates were calculated and statistically pooled. Where meta-analysis was not appropriate the data were tabulated and synthesized narratively following a cross-study examination of reported impacts and study characteristics. Qualitative data were summarized using a logic model to map reported impacts and links to health impacts; quantitative data were incorporated into the model. MAIN RESULTS: Thirty nine studies which reported quantitative or qualitative data, or both, were included in the review. Thirty-three quantitative studies were identified. This included five randomised controlled trials (RCTs) and 10 non-experimental studies of warmth improvements, 12 non-experimental studies of rehousing or retrofitting, three non-experimental studies of provision of basic improvements in low or mIddle Income countries (LMIC), and three non-experimental historical studies of rehousing from slums. Fourteen quantitative studies (42.4%) were assessed to be poor quality and were not included in the synthesis. Twelve studies reporting qualitative data were identified. These were studies of warmth improvements (n = 7) and rehousing (n = 5). Three qualitative studies were excluded from the synthesis due to lack of clarity of methods. Six of the included qualitative studies also reported quantitative data which was included in the review.Very little quantitative synthesis was possible as the data were not amenable to meta analysis. This was largely due to extreme heterogeneity both methodologically as well as because of variations in the intervention, samples, context, and outcome; these variations remained even following grouping of interventions and outcomes. In addition, few studies reported data that were amenable to calculation of standardized effect sizes. The data were synthesised narratively.Data from studies of warmth and energy efficiency interventions suggested that improvements in general health, respiratory health, and mental health are possible. Studies which targeted those with inadequate warmth and existing chronic respiratory disease were most likely to report health improvement. Impacts following housing led neighbourhood renewal were less clear; these interventions targeted areas rather than individual households in most need. Two poorer quality LMIC studies reported unclear or small health improvements. One better quality study of rehousing from slums (pre-1960) reported some improvement in mental health. There were few reports of adverse health impacts following housing improvement. A small number of studies gathered data on social and socio-economic impacts associated with housing improvement. Warmth improvements were associated with increased usable space, increased privacy, and improved social relationships; absences from work or school due to illness were also reduced.Very few studies reported differential impacts relevant to equity issues, and what data were reported were not amenable to synthesis. AUTHORS' CONCLUSIONS: Housing investment which improves thermal comfort in the home can lead to health improvements, especially where the improvements are targeted at those with inadequate warmth and those with chronic respiratory disease. The health impacts of programmes which deliver improvements across areas and do not target according to levels of individual need were less clear, but reported impacts at an area level may conceal health improvements for those with the greatest potential to benefit. Best available evidence indicates that housing which is an appropriate size for the householders and is affordable to heat is linked to improved health and may promote improved social relationships within and beyond the household. In addition, there is some suggestion that provision of adequate, affordable warmth may reduce absences from school or work.While many of the interventions were targeted at low income groups, a near absence of reporting differential impacts prevented analysis of the potential for housing improvement to impact on social and economic inequalities. PMID- 23450586 TI - Red flags to screen for malignancy in patients with low-back pain. AB - BACKGROUND: The identification of serious pathologies, such as spinal malignancy, is one of the primary purposes of the clinical assessment of patients with low back pain (LBP). Clinical guidelines recommend awareness of "red flag" features from the patient's clinical history and physical examination to achieve this. However, there are limited empirical data on the diagnostic accuracy of these features and there remains very little information on how best to use them in clinical practice. OBJECTIVES: To assess the diagnostic performance of clinical characteristics identified by taking a clinical history and conducting a physical examination ("red flags") to screen for spinal malignancy in patients presenting with LBP. SEARCH METHODS: We searched electronic databases for primary studies (MEDLINE, EMBASE, and CINAHL) and systematic reviews (PubMed and Medion) from the earliest date until 1 April 2012. Forward and backward citation searching of eligible articles was also performed. SELECTION CRITERIA: We considered studies if they compared the results of history taking and physical examination on patients with LBP with those of diagnostic imaging (magnetic resonance imaging, computed tomography, myelography). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the quality of each included study with the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and extracted details on patient characteristics, study design, index tests, and reference standard. Diagnostic accuracy data were presented as sensitivities and specificities with 95% confidence intervals for all index tests. MAIN RESULTS: We included eight cohort studies of which six were performed in primary care (total number of patients; n = 6622), one study was from an accident and emergency setting (n = 482), and one study was from a secondary care setting (n = 257). In the six primary care studies, the prevalence of spinal malignancy ranged from 0% to 0.66%. Overall, data from 20 index tests were extracted and presented, however only seven of these were evaluated by more than one study. Because of the limited number of studies and clinical heterogeneity, statistical pooling of diagnostic accuracy data was not performed.There was some evidence from individual studies that having a previous history of cancer meaningfully increases the probability of malignancy. Most "red flags" such as insidious onset, age > 50, and failure to improve after one month have high false positive rates.All of the tests were evaluated in isolation and no study presented data on a combination of positive tests to identify spinal malignancy. AUTHORS' CONCLUSIONS: For most "red flags," there is insufficient evidence to provide recommendations regarding their diagnostic accuracy or usefulness for detecting spinal malignancy. The available evidence indicates that in patients with LBP, an indication of spinal malignancy should not be based on the results of one single "red flag" question. Further research to evaluate the performance of different combinations of tests is recommended. PMID- 23450588 TI - Surgical cytoreduction for recurrent epithelial ovarian cancer. AB - BACKGROUND: The standard management of primary ovarian cancer is optimal cytoreductive surgery followed by platinum-based chemotherapy. Most women with primary ovarian cancer achieve remission on this combination therapy. For women achieving clinical remission after completion of initial treatment, most (60%) with advanced epithelial ovarian cancer will ultimately develop recurrent disease. However, the standard treatment of women with recurrent ovarian cancer remains poorly defined. Surgery for recurrent ovarian cancer has been suggested to be associated with increased overall survival. OBJECTIVES: To evaluate the effectiveness and safety of optimal secondary cytoreductive surgery for women with recurrent epithelial ovarian cancer. To assess the impact of various residual tumour sizes, over a range between 0 cm and 2 cm, on overall survival. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to December 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. For databases other than MEDLINE, the search strategy has been adapted accordingly. SELECTION CRITERIA: Retrospective data on residual disease, or data from randomised controlled trials (RCTs) or prospective/retrospective observational studies that included a multivariate analysis of 50 or more adult women with recurrent epithelial ovarian cancer, who underwent secondary cytoreductive surgery with adjuvant chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm. DATA COLLECTION AND ANALYSIS: Two review authors (KG, TA) independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis. MAIN RESULTS: There were no RCTs; however, we found nine non randomised studies that reported on 1194 women with comparison of residual disease after secondary cytoreduction using a multivariate analysis that met our inclusion criteria. These retrospective and prospective studies assessed survival after secondary cytoreductive surgery in women with recurrent epithelial ovarian cancer.Meta- and single-study analyses show the prognostic importance of complete cytoreduction to microscopic disease, since overall survival was significantly prolonged in these groups of women (most studies showed a large statistically significant greater risk of death in all residual disease groups compared to microscopic disease).Recurrence-free survival was not reported in any of the studies. All of the studies included at least 50 women and used statistical adjustment for important prognostic factors. One study compared sub-optimal (> 1 cm) versus optimal (< 1 cm) cytoreduction and demonstrated benefit to achieving cytoreduction to less than 1 cm, if microscopic disease could not be achieved (hazard ratio (HR) 3.51, 95% CI 1.84 to 6.70). Similarly, one study found that women whose tumour had been cytoreduced to less than 0.5 cm had less risk of death compared to those with residual disease greater than 0.5 cm after surgery (HR not reported; P value < 0.001).There is high risk of bias due to the non randomised nature of these studies, where, despite statistical adjustment for important prognostic factors, selection is based on retrospective achievability of cytoreduction, not an intention to treat, and so a degree of bias is inevitable.Adverse events, quality of life and cost-effectiveness were not reported in any of the studies. AUTHORS' CONCLUSIONS: In women with platinum sensitive recurrent ovarian cancer, ability to achieve surgery with complete cytoreduction (no visible residual disease) is associated with significant improvement in overall survival. However, in the absence of RCT evidence, it is not clear whether this is solely due to surgical effect or due to tumour biology. Indirect evidence would support surgery to achieve complete cytoreduction in selected women. The risks of major surgery need to be carefully balanced against potential benefits on a case-by-case basis. PMID- 23450589 TI - Antiplatelet agents for chronic kidney disease. AB - BACKGROUND: Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet treatment may be different in people with chronic kidney disease (CKD) for whom occlusive atherosclerotic events are less prevalent, and bleeding hazards might be increased. OBJECTIVES: To summarise the effects of antiplatelet treatment (antiplatelet agent versus control or other antiplatelet agent) for the prevention of cardiovascular and adverse kidney outcomes in individuals with CKD. SEARCH METHODS: In January 2011 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cochrane Renal Group's Specialised Register without language restriction. SELECTION CRITERIA: We selected randomised controlled trials of any antiplatelet treatment versus placebo or no treatment, or direct head-to-head antiplatelet agent studies in people with CKD. Studies were included if they enrolled participants with CKD, or included people in broader at-risk populations in which data for subgroups with CKD could be disaggregated. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from primary study reports and any available supplementary information for study population, interventions, outcomes, and risks of bias. Risk ratios (RR) and 95% confidence intervals (CI) were calculated from numbers of events and numbers of participants at risk which were extracted from each included study. The reported RRs were extracted where crude event rates were not provided. Data was pooled using the random-effects model. MAIN RESULTS: We included 50 studies, enrolling 27,139 participants; 44 studies (21,460 participants) compared an antiplatelet agent with placebo or no treatment, and six studies (5679 participants) directly compared one antiplatelet agent with another. Compared to placebo or no treatment, antiplatelet agents reduced the risk of myocardial infarction (17 studies; RR 0.87, 95% CI 0.76 to 0.99), but not all-cause mortality (30 studies; RR 0.93, 95% CI 0.81 to 1.06), cardiovascular mortality (19 studies; RR 0.89, 95% CI 0.70 to 1.12) or stroke (11 studies; RR 1.00, 95% CI 0.58 to 1.72). Antiplatelet agents increased the risk of major (27 studies; RR 1.33, 95% CI 1.10 to 1.65) and minor bleeding (18 studies; RR 1.49, 95% CI 1.12 to 1.97). In terms of dialysis access outcomes, antiplatelet agents reduced access thrombosis or patency failure but had no effect on suitability for dialysis. Meta-regression analysis indicated no differences in the relative benefit or harms of treatment (risk of all-cause mortality, myocardial infarction, or major bleeding) by type of antiplatelet agent or stage of CKD. Limited data were available for direct head-to-head comparisons of antiplatelet drugs, treatment in kidney transplant recipients, primary prevention, or risk of ESKD. AUTHORS' CONCLUSIONS: Antiplatelet agents reduce myocardial infarction but increase major bleeding. Risks may outweigh harms among people with low annual risks of cardiovascular events, including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease. PMID- 23450590 TI - Dental extractions prior to radiotherapy to the jaws for reducing post radiotherapy dental complications. AB - BACKGROUND: Radiotherapy as part of head and neck cancer treatment leaves patients requiring much dental rehabilitation in a compromised environment that is difficult for the patient and the dental team to manage. OBJECTIVES: To assess the effects of maintaining the patient's natural dentition during radiotherapy in comparison to extracting teeth before radiotherapy in areas that are difficult to access by the patient and the dentist, should reduction in mouth opening occur after radiotherapy to the jaws. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 22 November 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 11), MEDLINE via OVID (1946 to 22 November 2012), EMBASE via OVID (1980 to 22 November 2012), CANCERLIT via PubMed (1950 to 22 November 2012), CINAHL via EBSCO (1980 to 22 November 2012) and reference lists of articles. We advertised for currently ongoing studies via the Cochrane Oral Health Group website and the Cochrane Oral Health Group Twitter feed. SELECTION CRITERIA: Randomised controlled trials comparing extraction of teeth prior to radiotherapy with leaving teeth in situ during radiotherapy to the jaws. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the results of the searches for inclusion in the review. MAIN RESULTS: No randomised controlled trials were found. AUTHORS' CONCLUSIONS: There are no randomised controlled trials to assess the effect of extracting teeth prior to radiotherapy compared to leaving teeth in the mouth during radiotherapy to the jaws. PMID- 23450587 TI - Interventions to enhance adherence to dietary advice for preventing and managing chronic diseases in adults. AB - BACKGROUND: It has been recognized that poor adherence can be a serious risk to the health and wellbeing of patients, and greater adherence to dietary advice is a critical component in preventing and managing chronic diseases. OBJECTIVES: To assess the effects of interventions for enhancing adherence to dietary advice for preventing and managing chronic diseases in adults. SEARCH METHODS: We searched the following electronic databases up to 29 September 2010: The Cochrane Library (issue 9 2010), PubMed, EMBASE (Embase.com), CINAHL (Ebsco) and PsycINFO (PsycNET) with no language restrictions. We also reviewed: a) recent years of relevant conferences, symposium and colloquium proceedings and abstracts; b) web based registries of clinical trials; and c) the bibliographies of included studies. SELECTION CRITERIA: We included randomized controlled trials that evaluated interventions enhancing adherence to dietary advice for preventing and managing chronic diseases in adults. Studies were eligible if the primary outcome was the client's adherence to dietary advice. We defined 'client' as an adult participating in a chronic disease prevention or chronic disease management study involving dietary advice. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of the studies. They also assessed the risk of bias and extracted data using a modified version of the Cochrane Consumers and Communication Review Group data extraction template. Any discrepancies in judgement were resolved by discussion and consensus, or with a third review author. Because the studies differed widely with respect to interventions, measures of diet adherence, dietary advice, nature of the chronic diseases and duration of interventions and follow-up, we conducted a qualitative analysis. We classified included studies according to the function of the intervention and present results in a narrative table using vote counting for each category of intervention. MAIN RESULTS: We included 38 studies involving 9445 participants. Among studies that measured diet adherence outcomes between an intervention group and a control/usual care group, 32 out of 123 diet adherence outcomes favoured the intervention group, 4 favoured the control group whereas 62 had no significant difference between groups (assessment was impossible for 25 diet adherence outcomes since data and/or statistical analyses needed for comparison between groups were not provided). Interventions shown to improve at least one diet adherence outcome are: telephone follow-up, video, contract, feedback, nutritional tools and more complex interventions including multiple interventions. However, these interventions also shown no difference in some diet adherence outcomes compared to a control/usual care group making inconclusive results about the most effective intervention to enhance dietary advice. The majority of studies reporting a diet adherence outcome favouring the intervention group compared to the control/usual care group in the short-term also reported no significant effect at later time points. Studies investigating interventions such as a group session, individual session, reminders, restriction and behaviour change techniques reported no diet adherence outcome showing a statistically significant difference favouring the intervention group. Finally, studies were generally of short duration and low quality, and adherence measures varied widely. AUTHORS' CONCLUSIONS: There is a need for further, long-term, good quality studies using more standardized and validated measures of adherence to identify the interventions that should be used in practice to enhance adherence to dietary advice in the context of a variety of chronic diseases. PMID- 23450591 TI - Inhaled corticosteroids for subacute cough in children. AB - BACKGROUND: Cough is the most common symptom presenting to primary healthcare services. Cough in children is associated with significant morbidity for both children and their parents. While inhaled corticosteroids (ICS) can potentially reduce cough associated with airway inflammation and airway hyper-reactivity, use of ICS in children is not without potential adverse effects. Therefore, it would be beneficial to clinical practice to evaluate the evidence for the efficacy of ICS in reducing the severity of cough in children with subacute cough (defined as cough duration of two to four weeks) systematically. OBJECTIVES: To evaluate the efficacy of ICS in reducing the severity of cough in children with subacute cough. SEARCH METHODS: The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE, review articles and reference lists of relevant articles were searched. The latest searches were performed in November 2011. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing ICS with a control group in children with subacute cough were considered for inclusion. DATA COLLECTION AND ANALYSIS: Search results were reviewed against pre-determined criteria for inclusion. Two sets of review authors independently selected, extracted and assessed the data for inclusion. Study authors were contacted for further information where required. Data were analysed as 'intention to treat'. MAIN RESULTS: The search identified 1178 potentially relevant titles; however, there were no published studies that were specifically designed to answer this question. Two studies met criteria for inclusion in the review and 98 children were included in the meta-analysis. There was no significant difference between groups in the proportion of children 'not cured' at follow-up (primary outcome measure), with a pooled odds ratio (OR) of 0.61 (95% confidence interval (CI) 0.24 to 1.55). However, the included studies were limited in their ability to answer the review question by the fact that all participants were infants, post acute bronchiolitis illness, and cough duration at the start of study medication was ill-defined. AUTHORS' CONCLUSIONS: There is currently no evidence to support the use of ICS for treatment of subacute cough in children. However, this systematic review is limited by the small number of studies available for analysis and the size, quality and design of these studies. Further well-designed RCTs are required to support or refute the efficacy of treatment with ICS in children with subacute cough. PMID- 23450592 TI - Restorative justice conferencing for reducing recidivism in young offenders (aged 7 to 21). AB - BACKGROUND: Restorative justice is "a process whereby parties with a stake in a specific offence resolve collectively how to deal with the aftermath of the offence and its implications for the future" (Marshall 2003). Despite the increasing use of restorative justice programmes as an alternative to court proceedings, no systematic review has been undertaken of the available evidence on the effectiveness of these programmes with young offenders. Recidivism in young offenders is a particularly worrying problem, as recent surveys have indicated the frequency of re-offences for young offenders has ranged from 40.2% in 2000 to 37.8% in 2007 (Ministry of Justice 2009) OBJECTIVES: To evaluate the effects of restorative justice conferencing programmes for reducing recidivism in young offenders. SEARCH METHODS: We searched the following databases up to May 2012: CENTRAL, 2012 Issue 5, MEDLINE (1978 to current), Bibliography of Nordic Criminology (1999 to current), Index to Theses (1716 to current), PsycINFO (1887 to current), Social Sciences Citation Index (1970 to current), Sociological Abstracts (1952 to current), Social Care Online (1985 to current), Restorative Justice Online (1975 to current), Scopus (1823 to current), Science Direct (1823 to current), LILACS (1982 to current), ERIC (1966 to current), Restorative Justice Online (4 May 2012), WorldCat (9 May 2012), ClinicalTrials.gov (19 May 2012) and ICTRP (19 May 2012). ASSIA, National Criminal Justice Reference Service and Social Services Abstracts were searched up to May 2011. Relevant bibliographies, conference programmes and journals were also searched. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of restorative justice conferencing versus management as usual, in young offenders. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of included trials and extracted the data. Where necessary, original investigators were contacted to obtain missing information. MAIN RESULTS: Four trials including a total of 1447 young offenders were included in the review. Results failed to find a significant effect for restorative justice conferencing over normal court procedures for any of the main analyses, including number re-arrested (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.59 to 1.71; P = 0.99), monthly rate of reoffending (standardised mean difference (SMD) -0.06, 95% CI -0.28 to 0.16; P = 0.61), young person's remorse following conference (OR 1.73, 95% CI 0.97 to 3.10; P = 0.06), young person's recognition of wrongdoing following conference (OR 1.97, 95% CI 0.81 to 4.80; P = 0.14), young person's self-perception following conference (OR 0.95, 95% CI 0.55 to 1.63; P = 0.85), young person's satisfaction following conference (OR 0.42, 95% CI 0.04 to 4.07; P = 0.45) and victim's satisfaction following conference (OR 4.05, 95% CI 0.56 to 29.04; P = 0.16). A small number of sensitivity analyses did indicate significant effects, although all are to be interpreted with caution. AUTHORS' CONCLUSIONS: There is currently a lack of high quality evidence regarding the effectiveness of restorative justice conferencing for young offenders. Caution is urged in interpreting the results of this review considering the small number of included studies, subsequent low power and high risk of bias. The effects may potentially be more evident for victims than offenders. The need for further research in this area is highlighted. PMID- 23450593 TI - Medication review in hospitalised patients to reduce morbidity and mortality. AB - BACKGROUND: Pharmacotherapy in the elderly population is complicated by several factors that increase the risk of drug related harms and poorer adherence. The concept of medication review is a key element in improving the quality of prescribing and the prevention of adverse drug events. While no generally accepted definition of medication review exists, it can be defined as a systematic assessment of the pharmacotherapy of an individual patient that aims to evaluate and optimise patient medication by a change (or not) in prescription, either by a recommendation or by a direct change. Medication review performed in adult hospitalised patients may lead to better patient outcomes. OBJECTIVES: We examined whether the delivery of a medication review by a physician, pharmacist or other healthcare professional improves the health outcomes of hospitalised adult patients compared to standard care. SEARCH METHODS: We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group's Specialised Register (August 2011); The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library 2011, Issue 8; MEDLINE (1946 to August 2011); EMBASE (1980 to August 2011); CINAHL (1980 to August 2011); International Pharmaceutical Abstracts (1970 to August 2011); and Web of Science (August 2011). In addition we searched reference lists of included trials and relevant reviews. We searched trials registries and contacted experts to identify additional published and unpublished trials. We did not apply any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of medication review in hospitalised adult patients. We excluded trials of outclinic and paediatric patients. Our primary outcome was all-cause mortality and secondary outcomes included hospital readmission, emergency department contacts and adverse drug events. DATA COLLECTION AND ANALYSIS: Two review authors independently included trials, extracted data and assessed trials for risk of bias. We contacted trial authors for clarification of data and additional unpublished data. We calculated relative risks for dichotomous data and mean differences for continuous data (with 95% confidence intervals (CIs)). MAIN RESULTS: We identified 4647 references and included five trials (1186 participants). Follow up ranged from 30 days to one year. We found no evidence of effect on all-cause mortality (risk ratio (RR) 0.98; 95% CI 0.78 to 1.23) and hospital readmissions (RR 1.01; 95% CI 0.88 to 1.16), but a 36% relative reduction in emergency department contacts (RR 0.64; 95% CI 0.46 to 0.89). AUTHORS' CONCLUSIONS: It is uncertain whether medication review reduces mortality or hospital readmissions, but medication review seems to reduce emergency department contacts. However, the cost-effectiveness of this intervention is not known and due to the uncertainty of the estimates of mortality and readmissions and the short follow-up, important treatment effects may have been overlooked. Therefore, medication review should preferably be undertaken in the context of clinical trials. High quality trials with long follow-up are needed before medication review should be implemented. PMID- 23450594 TI - Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. AB - BACKGROUND: Uterine fibroids are the most common premenopausal benign uterine tumours. Fibroids can cause symptoms including heavy menstrual bleeding, pelvic pressure and pain. Progestogens can be administered by various routes. Intramuscular injection of depot medroxyprogesterone acetate (DMPA) has dual actions (stimulatory or inhibitory) on fibroid cell growth. Progestogen-releasing intrauterine systems (IUS) decrease menstrual blood loss associated with fibroids by inducing endometrial atrophy and reduction of uterine fibroid size. Currently, their effectiveness for the treatment of uterine fibroids has not been evaluated. OBJECTIVES: To determine the effectiveness of progestogens or progestogen releasing intrauterine systems in treating premenopausal women with uterine fibroids. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Specialised Register (inception to 17 August 2012), CENTRAL (inception to 17 August 2012) and Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library, MEDLINE (inception to 17 August 2012), Ovid EMBASE (1 January 2010 to 17 August 2012), Ovid PsycINFO (inception to 17 August 2012), CINAHL database, and trials registers for ongoing and registered trials. SELECTION CRITERIA: All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. DATA COLLECTION AND ANALYSIS: We assessed all potentially eligible studies identified as a result of the search strategy. Two review authors extracted data from each included study using an agreed form and assessed the risk of bias. We resolved discrepancies through discussion. MAIN RESULTS: This review included three studies. However, data for progestogen-releasing intrauterine systems were available from only one study that compared 29 women with a levonorgestrel (LNG) IUS versus 29 women with a combined oral contraceptive (COC) for treating uterine fibroids. There was a significant reduction of menstrual blood loss (MBL) in women receiving the LNG-IUS compared to the COC using the alkaline hematin test (mean difference (MD) 77.5%, 95% CI 71.3% to 83.67%, 58 women) and a pictorial assessment chart (PBAC) (MD 34.5%, 95% CI 14.9% to 54.1%, 58 women). The reduction in uterine fibroid size was significantly greater in the leuprorelin group at 16 weeks compared to the progestogen lynestrenol group (MD -15.93 mm, 95% CI -18.02 to -13.84 mm, 46 women). There was no RCT evaluating the effect of DMPA on uterine fibroids. AUTHORS' CONCLUSIONS: Progestogen-releasing intrauterine systems appear to reduce menstrual blood loss in premenopausal women with uterine fibroids. Oral progestogens did not reduce fibroid size or fibroid- related symptoms. However, there was a methodological limitation and the one included study with data had a small sample size. This evidence is insufficient to support the use of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. PMID- 23450595 TI - Optimal timing for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis. AB - BACKGROUND: Currently, initiation of antiretroviral therapy (ART) in most patients with human immunodeficiency virus (HIV) infection is based on the CD4 positive-t-lymphocyte count. However, the point during the course of HIV infection at which ART should be initiated in patients with concurrent cryptococcal meningitis remains unclear. The aim of this systematic review was to summarise the evidence on the optimal timing of ART initiation in patients with cryptococcal meningitis for use in clinical practice and guideline development. OBJECTIVES: To compare the clinical and immunologic outcomes for early initiation ART (less than four weeks after starting antifungal treatment) versus later initiation of HAART (four weeks or more after starting antifungal treatment) in HIV-positive patients with concurrent cryptococcal meningitis. SEARCH METHODS: We searched the following databases from January 1980 to February 2011: PubMed, EMBASE, and WHO International Clinical Trials Registry Platform, AEGIS database for conference abstracts, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. A total of 35 full text articles were identified and supplemented by a bibliographic search. We contacted researchers and relevant organizations and checked reference lists of all included studies. SELECTION CRITERIA: Randomized controlled trials that compared the effect of ART (consisting of three drug combinations) initiated early or delayed in HIV patients with cryptococcal meningitis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful, we performed a meta-analysis of dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs). MAIN RESULTS: Two eligible randomized controlled trials were included (N = 89). In our pooled analysis, we combined the clinical data for both trials comparing early initiation ART versus delayed initiation of ART. There was no statistically significant difference in mortality (RR=1.40, 95% CI [0.42, 4.68]) in the group with early initiation of ART compared to the group with delayed initiation of ART. AUTHORS' CONCLUSIONS: This systematic review shows that there is insufficient evidence in support of either early or late initiation of ART. For the moment, because of the high risk of immune reconstitution syndrome in patients with cryptococcal meningitis, we recommend that ART initiation should be delayed until there is evidence of a sustained clinical response to antifungal therapy. However, large studies with appropriate comparison groups, and adequate follow-up are warranted to provide the evidence base for effective decision making. PMID- 23450596 TI - Conservative interventions for treating hyperextension injuries of the proximal interphalangeal joints of the fingers. AB - BACKGROUND: Immobilisation and early motion (protected or unrestricted) are both used following hyperextension injuries to the proximal interphalangeal (PIP) joint of the finger. OBJECTIVES: To assess the effects of conservative interventions (non-surgical management) for treating hyperextension injuries of the proximal interphalangeal joints of the fingers. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (January 2012), the Cochrane Central Register of Controlled Trials (in The Cochrane Library 2012, Issue 1), MEDLINE (1946 to January Week 2 2012), EMBASE (1980 to 2012 Week 03), CINAHL (1950 to 24 January 2012), PEDro (1929 to March 2012), trial registers and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing immobilisation/protected mobilisation/unrestricted mobilisation in participants with PIP joint hyperextension injuries managed non-surgically. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. There was no pooling of data. MAIN RESULTS: Three trials involving 366 people were identified. All three trials, which were over 15 years old, were methodologically flawed with unclear or high risk of bias. None of the studies reported on self assessment of function. One trial compared unrestricted mobility with immobilisation; one trial compared protected mobilisation with immobilisation; and the remaining trial compared immobilisation for one week versus three weeks. None of these trials found statistically significant differences between their intervention groups in various measures of poor outcome, pain and range of movement at six months follow-up. This lack of difference applied at three years for the comparison between unrestricted mobility with immobilisation. AUTHORS' CONCLUSIONS: There is insufficient evidence from trials testing the need for, and the extent and duration of, immobilisation to inform on the key conservative management decisions for treating hyperextension injuries of the proximal interphalangeal joints. PMID- 23450597 TI - Interventions to optimise prescribing for older people in care homes. AB - BACKGROUND: There is a substantial body of evidence that prescribing for care home residents is suboptimal and requires improvement. Consequently, there is a need to identify effective interventions to optimise prescribing and resident outcomes in this context. OBJECTIVES: The objective of the review was to determine the effect of interventions to optimise prescribing for older people living in care homes. SEARCH METHODS: We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library (Issue 11, 2012); Cochrane Database of Systematic Reviews, The Cochrane Library (Issue 11, 2012); MEDLINE OvidSP (1980 on); EMBASE, OvidSP (1980 on); Ageline, EBSCO (1966 on); CINAHL, EBSCO (1980 on); International Pharmaceutical Abstracts, OvidSP (1980 on); PsycINFO, OvidSP (1980 on); conference proceedings in Web of Science, Conference Proceedings Citation Index - SSH & Science, ISI Web of Knowledge (1990 on); grey literature sources and trial registries; and contacted authors of relevant studies. We also reviewed the references lists of included studies and related reviews (search period November 2012). SELECTION CRITERIA: We included randomised controlled trials evaluating interventions aimed at optimising prescribing for older people (aged 65 years or older) living in institutionalised care facilities. Studies were included if they measured one or more of the following primary outcomes, adverse drug events; hospital admissions;mortality; or secondary outcomes, quality of life (using validated instrument); medication related problems; medication appropriateness (using validated instrument); medicine costs. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts, assessed studies for eligibility, assessed risk of bias and extracted data. A narrative summary of results was presented. MAIN RESULTS: The eight included studies involved 7653 residents in 262 (range 1 to 85) care homes in six countries. Six studies were cluster-randomised controlled trials and two studies were patient-randomised controlled trials. The interventions evaluated were diverse and often multifaceted. Medication review was a component of seven studies, three studies involved multidisciplinary case-conferencing, two studies involved an educational element for care home staff and one study evaluated the use of clinical decision support technology. Due to heterogeneity, results were not combined in a meta-analysis. There was no evidence of an effect of the interventions on any of the primary outcomes of the review (adverse drug events, hospital admissions and mortality). No studies measured quality of life. There was evidence that the interventions led to the identification and resolution of medication-related problems. There was evidence from two studies that medication appropriateness was improved. The evidence for an effect on medicine costs was equivocal. AUTHORS' CONCLUSIONS: Robust conclusions could not be drawn from the evidence due to variability in design, interventions, outcomes and results. The interventions implemented in the studies in this review led to the identification and resolution of medication-related problems, however evidence of an effect on resident-related outcomes was not found. There is a need for high-quality cluster randomised controlled trials testing clinical decision support systems and multidisciplinary interventions that measure well-defined, important resident related outcomes. PMID- 23450598 TI - Minimally invasive versus open surgery for reversal of tubal sterilization. AB - BACKGROUND: Although tubal sterilization procedures are considered to be permanent, requests for reversal of the procedure (re-canalisation) are not infrequent. The reversal procedure can be done either by an open laparotomy or by minimally invasive surgery (laparoscopic or robotic approach). OBJECTIVES: To compare the relative effectiveness and safety of reversal of tubal sterilization by open laparotomy, laparoscopy and robotically assisted endoscopy. SEARCH METHODS: On 23 October 2012 we searched the Cochrane Menstrual Disorders and Subfertility Review Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 10, 2012); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references for relevant published, unpublished and ongoing trials. SELECTION CRITERIA: Randomised trials comparing the different methods of surgical reversal of tubal sterilisation. DATA COLLECTION AND ANALYSIS: No trials that met the selection criteria were identified. MAIN RESULTS: No data for evaluation were obtained AUTHORS' CONCLUSIONS: Currently there is no evidence from randomised controlled trials to recommend or refute the use of a minimally invasive surgical approach (laparoscopic or robotic) or open surgery for reversal of tubal sterilization. There is a need for well conducted and reported randomised clinical trials to generate reliable evidence to inform clinical practice. PMID- 23450599 TI - Nurse versus physician-led care for the management of asthma. AB - BACKGROUND: Asthma is the most common chronic disease in childhood and prevalence is also high in adulthood, thereby placing a considerable burden on healthcare resources. Therefore, effective asthma management is important to reduce morbidity and to optimise utilisation of healthcare facilities. OBJECTIVES: To review the effectiveness of nurse-led asthma care provided by a specialised asthma nurse, a nurse practitioner, a physician assistant or an otherwise specifically trained nursing professional, working relatively independently from a physician, compared to traditional care provided by a physician. Our scope included all outpatient care for asthma, both in primary care and in hospital settings. SEARCH METHODS: We carried out a comprehensive search of databases including The Cochrane Library, MEDLINE and EMBASE to identify trials up to August 2012. Bibliographies of relevant papers were searched, and handsearching of relevant publications was undertaken to identify additional trials. SELECTION CRITERIA: Randomised controlled trials comparing nurse-led care versus physician led care in asthma for the same aspect of asthma care. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Five studies on 588 adults and children were included concerning nurse-led care versus physician-led care. One study included 154 patients with uncontrolled asthma, while the other four studies including 434 patients with controlled or partly controlled asthma. The studies were of good methodological quality (although it is not possible to blind people giving or receiving the intervention to which group they are in). There was no statistically significant difference in the number of asthma exacerbations and asthma severity after treatment (duration of follow-up from six months to two years). Only one study had healthcare costs as an outcome parameter, no statistical differences were found. Although not a primary outcome, quality of life is a patient-important outcome and in the three trials on 380 subjects that reported on this outcome, there was no statistically significant difference (standardised mean difference (SMD) -0.03; 95% confidence interval (CI) -0.23 to 0.17). AUTHORS' CONCLUSIONS: We found no significant difference between nurse-led care for patients with asthma compared to physician-led care for the outcomes assessed. Based on the relatively small number of studies in this review, nurse led care may be appropriate in patients with well-controlled asthma. More studies in varied settings and among people with varying levels of asthma control are needed with data on adverse events and health-care costs. PMID- 23450600 TI - Spinal cord stimulation for cancer-related pain in adults. AB - BACKGROUND: Cancer-related pain places a heavy burden on public health with related high expenditure. Severe pain is associated with a decreased quality of life in patients with cancer. A significant proportion of patients with cancer related pain are under-treated.There is a need for more effective control of cancer-related pain. Spinal cord stimulation (SCS) may have a role in pain management. The effectiveness and safety of SCS for patients with cancer-related pain is currently unknown. OBJECTIVES: This systematic review evaluated the effectiveness of SCS for cancer-related pain compared with standard care using conventional analgesic medication. We also appraised risk and potential adverse events associated with the use of SCS. SEARCH METHODS: We searched the following bibliographic databases in order to identify relevant studies: the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Libary (from inception to 2012, Issue 6); MEDLINE; EMBASE; and CBM (Chinese Biomedical Database) (from inception to July, 2012). We also handsearched relevant journals. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) that directly compared SCS with other interventions with regards to the effectiveness of pain management. We also planned to include cross-over trials that compared SCS with another treatment. We planned to identify non-randomised controlled trials but these would only be included if no RCTs could be found. DATA COLLECTION AND ANALYSIS: The initial search strategy yielded 430 articles. By scrutinising titles and abstracts, we found 412 articles irrelevant to the analytical purpose of this systematic review due to different scopes of diseases or different methods of intervention (intrathecal infusion system; oral medication) or aims other than pain control (spinal cord function monitoring, bladder function restoration or amelioration of organ metabolism). The remaining 18 trials were reviewed as full manuscripts. No RCTs were identified. Fourteen sporadic case reports and review articles were excluded and four before-and-after case series studies (92 participants) were included. Two review authors independently selected the studies to be included in the review according to the pre-specified eligibility criteria. A checklist for methodological quality of non randomised controlled trials was used (STROBE checklist) and all review authors discussed and agreed on the inclusion of trials and the results of the quality assessment. MAIN RESULTS: Four before-and-after case series studies (a total of 92 participants) met our criteria for inclusion. All included trials adopted a visual analogue scale (VAS) to evaluate pain relief. Heterogeneity existed in terms of baseline characteristics, electrode and stimulator parameters, level of implantation and route of implantation; data reporting was different among all trials. In two trials, pain relief was achieved in 76% (48/63) of patients at the end of the follow-up period. In the third trial, pre-procedure VAS was 6 to 9 (mean 7.43 ); the one-month post-implant VAS was 2 to 4 (mean 3.07); the 12-month post-implant VAS was 1 to 3 (mean 2.67). In the fourth trial, the pre-procedure VAS was 6 to 9 (mean 7.07); 1 to 4 (mean 2.67) at one-month; 1 to 4 (mean 1.87) at 12 months. Analgesic use was largely reduced. The main adverse events were infection of sites of implantation, cerebrospinal fluid (CSF) leakage, pain at the sites of electrodes, dislodgement of the electrodes and system failure, however, the incidence in patients with cancer could not be calculated. Since all trials were non-randomised controlled trials, they carried risk of all types of bias. AUTHORS' CONCLUSIONS: Current evidence is insufficient to establish the role of SCS in treating refractory cancer-related pain. Future randomised studies should focus on the implantation of SCS in patients with cancer-related pain. PMID- 23450601 TI - Magnesium sulphate for women at term for neuroprotection of the fetus. AB - BACKGROUND: Magnesium sulphate is extensively used in obstetrics for the treatment and prevention of eclampsia. A recent meta-analysis has shown that magnesium sulphate is an effective fetal neuroprotective agent when given antenatally to women at risk of very preterm birth. Term infants account for more than half of all cases of cerebral palsy, and the incidence has remained fairly constant. It is important to assess if antenatal administration of magnesium sulphate to women at term protects the fetus from brain injury, and associated neurosensory disabilities including cerebral palsy. OBJECTIVES: To assess the effectiveness of magnesium sulphate given to women at term as a neuroprotective agent for the fetus. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trial Register (31 July 2012) and the reference lists of other Cochrane reviews assessing magnesium sulphate in pregnancy. SELECTION CRITERIA: Randomised controlled trials comparing antenatally administered magnesium sulphate to women at term with placebo, no treatment or a different fetal neuroprotective agent. We also planned to include cluster-randomised trials, and exclude cross-over trials and quasi-randomised trials. We planned to exclude studies reported as abstracts only. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and for risk of bias. Two authors independently extracted data. Data were checked for accuracy. MAIN RESULTS: We included one trial (involving 135 women with mild pre-eclampsia at term). An additional six studies are awaiting further assessment.The included trial compared magnesium sulphate with a placebo and was at a low risk of bias. The trial did not report any of this review's prespecified primary outcomes. There was no significant difference between magnesium sulphate and placebo in Apgar score less than seven at five minutes (risk ratio (RR) 0.51; 95% confidence interval (CI) 0.05 to 5.46; 135 infants), nor gestational age at birth (mean difference (MD) -0.20 weeks; 95% CI -0.62 to 0.22; 135 infants).There were significantly more maternal side effects (feeling warm and flushed) in the magnesium sulphate group than in the placebo group (RR 3.81; 95% CI 2.22 to 6.53; 135 women). However, no significant difference in adverse effects severe enough to cease treatment was observed (RR 3.04; 95% CI 0.13 to 73.42; 135 women). There were no significant differences seen between groups in the rates of postpartum haemorrhage (RR 4.06; 95% CI 0.47 to 35.38; 135 women) and caesarean section (RR 0.80; 95% CI 0.39 to 1.63; 135 women). AUTHORS' CONCLUSIONS: There is currently insufficient evidence to assess the efficacy and safety of magnesium sulphate when administered to women for neuroprotection of the term fetus. As there has been recent evidence for the use of magnesium sulphate for neuroprotection of the preterm fetus, high-quality randomised controlled trials are needed to determine the safety profile and neurological outcomes for the term fetus. Strategies to reduce maternal side effects during treatment also require evaluation. PMID- 23450602 TI - Treatment of recurrent stress urinary incontinence after failed minimally invasive synthetic suburethral tape surgery in women. AB - BACKGROUND: Surgery is a common treatment modality for stress urinary incontinence (SUI), usually offered for women who fail conservative treatments. Suburethral tapes have superseded colposuspension because cure rates are comparable and recovery time reduced. However, some women will not be cured after suburethral tape surgery, and currently there is no consensus on how to manage these women. OBJECTIVES: To obtain and examine evidence supporting different management strategies for recurrent/persistent stress urinary incontinence (SUI) in women after failed suburethral tape surgery. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register of controlled trials (searched 18 December 2012), which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and PreMEDLINE; and handsearched journals and conference proceedings, and the reference lists of included studies and previous Cochrane reviews for randomised or quasi-randomised studies treating patients with recurrent incontinence, either as the sole population or a subset. Conservative, medical and surgical treatments were included. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials in women who had recurrent urinary incontinence after previous minimally invasive suburethral tape surgery. DATA COLLECTION AND ANALYSIS: Abstracts of identified studies were checked by two authors to confirm eligibility. Full text reports of relevant studies were obtained, and authors were contacted directly where necessary. Outcome data were extracted onto a standard proforma and processed according to the methods in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Twelve studies were identified, but all were excluded because they did not meet the eligibility criteria. Six were randomised controlled trials (RCTs) but were not eligible because the previous incontinence surgery was not a suburethral tape. A subset of one RCT may have been eligible for inclusion because some of the women were having repeat surgery, but we were unable to obtain from the authors the data according to primary surgery for this cohort. AUTHORS' CONCLUSIONS: There were no data to recommend or refute any of the different management strategies for recurrent or persistent stress incontinence after failed suburethral tape surgery. Evidence is urgently required to address this deficiency, ideally from RCTs. PMID- 23450603 TI - Interventions for preventing or reducing domestic violence against pregnant women. AB - BACKGROUND: Domestic violence during pregnancy is a major public health concern. This preventable risk factor threatens both the mother and baby. Routine perinatal care visits offer opportunities for healthcare professionals to screen and refer abused women for effective interventions. It is, however, not clear which interventions best serve mothers during pregnancy and postpartum to ensure their safety. OBJECTIVES: To examine the effectiveness and safety of interventions in preventing or reducing domestic violence against pregnant women. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (19 June 2012), scanned bibliographies of published studies and corresponded with investigators. SELECTION CRITERIA: We included randomised controlled trials (RCTs) including cluster-randomised trials, and quasi randomised controlled trials (e.g. where there was alternate allocation) investigating the effect of interventions in preventing or reducing domestic violence during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: We included nine trials with a total of 2391 women; however, for most outcomes very few studies contributed data and results were predominantly based on findings from single studies. There was evidence from one study that the total number of women reporting episodes of partner violence during pregnancy, and in the postpartum period was reduced for women receiving a psychological therapy intervention (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.48 to 0.88). There were few statistically significant differences between intervention and control groups for depression during pregnancy and the postnatal period. Only one study reported findings for neonatal outcomes such as preterm delivery and birthweight, and there were no clinically significant differences between groups. None of the studies reported results for other secondary outcomes: Apgar score less than seven at one minute and five minutes, stillbirth, neonatal death, miscarriage, maternal mortality, antepartum haemorrhage, and placental abruption. AUTHORS' CONCLUSIONS: There is insufficient evidence to assess the effectiveness of interventions for domestic violence on pregnancy outcomes. There is a need for high-quality, RCTs with adequate statistical power to determine whether intervention programs prevent or reduce domestic violence episodes during pregnancy, or have any effect on maternal and neonatal mortality and morbidity outcomes. PMID- 23450604 TI - Hypothermia for neuroprotection in children after cardiopulmonary arrest. AB - BACKGROUND: Cardiopulmonary arrest in paediatric patients often results in death or survival with severe brain injury. Therapeutic hypothermia, lowering of the core body temperature to 32 degrees C to 34 degrees C, may reduce injury to the brain in the period after the circulation has been restored. This therapy has been effective in neonates with hypoxic ischaemic encephalopathy and adults after witnessed ventricular fibrillation cardiopulmonary arrest. The effect of therapeutic hypothermia after cardiopulmonary arrest in paediatric patients is unknown. OBJECTIVES: To assess the clinical effectiveness of therapeutic hypothermia after paediatric cardiopulmonary arrest. SEARCH METHODS: We searched the Cochrane Anaesthesia Review Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11); Ovid MEDLINE (1966 to December 2011); Ovid EMBASE (1980 to December 2011); Ovid CINAHL (1982 to December 2011); Ovid BIOSIS (1923 to December 2011); and Web of Science (1945 to December 2011). We searched the trials registry databases for ongoing trials. We also contacted international experts in therapeutic hypothermia and paediatric critical care to locate further published and unpublished studies. SELECTION CRITERIA: We planned to include randomized and quasi-randomized controlled trials comparing therapeutic hypothermia with normothermia or standard care in children, aged 24 hours to 18 years, after paediatric cardiopulmonary arrest. DATA COLLECTION AND ANALYSIS: Two authors independently assessed articles for inclusion. MAIN RESULTS: We found no studies that satisfied the inclusion criteria. We found four on-going randomized controlled trials which may be available for analysis in the future. We excluded 18 non-randomized studies. Of these 18 non-randomized studies, three compared therapeutic hypothermia with standard therapy and demonstrated no difference in mortality or the proportion of children with a good neurological outcome; a narrative report was presented. AUTHORS' CONCLUSIONS: Based on this review, we are unable to make any recommendations for clinical practice. Randomized controlled trials are needed and the results of on-going trials will be assessed when available. PMID- 23450605 TI - Hydralazine in infants with persistent hypoxemic respiratory failure. AB - BACKGROUND: Most deaths of infants with chronic lung disease (CLD) are caused by respiratory failure, unremitting pulmonary artery hypertension (PAH) with cor pulmonale, or infection. Although the exact prevalence of PAH in infants with CLD is unknown, infants with CLD and severe PAH have a high mortality rate. Except for oxygen supplementation, no specific interventions have been established as effective in the treatment for PAH in premature infants with CLD. Little has been proven regarding the clinical efficacy of vasodilators and concerns remain regarding adverse effects. OBJECTIVES: To review current evidence for the benefits and harms of hydralazine therapy to infants with persistent hypoxemic respiratory failure. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE via PubMed and EMBASE, and other clinical trials registries through November 2011 using the standard search strategy of the Cochrane Neonatal Review Group. We searched these databases using a strategy combining a variation of the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE; sensitivity maximising version with selected MeSH and free-text terms: hydralazine, vasodilator agent, antihypertensive agent, heart diseases, lung diseases, respiratory tract diseases, infant, and randomised controlled trial. SELECTION CRITERIA: We considered only randomised controlled trials and quasi-randomised trials for inclusion. We included low birth weight (LBW) infants with persistent hypoxemic respiratory failure who were treated with any type of hydralazine therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality according to pre-specified criteria. MAIN RESULTS: We found no studies meeting the criteria for inclusion in this review. AUTHORS' CONCLUSIONS: There was insufficient evidence to determine the safety and efficacy of hydralazine in LBW infants with persistent hypoxemic respiratory failure. Since hydralazine is inexpensive and potentially beneficial, randomised controlled trials are recommended. Such trials are particularly needed in settings where other medications such as sildenafil, inhaled nitric oxide (iNO), or extracorporeal membrane oxygenation (ECMO) are not available. PMID- 23450606 TI - Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults. AB - BACKGROUND: Daily inhaled corticosteroids (ICS) are the recommended mainstay of treatment in children and adults with persistent asthma. However, often, ICS are used intermittently by patients or recommended by physicians to be used only at the onset of exacerbations. OBJECTIVES: The aim of this review was to compare the efficacy and safety of intermittent versus daily ICS in the management of children and adults with persistent asthma and preschool-aged children suspected of persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov web site up to October 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared intermittent ICS versus daily ICS in children and adults with persistent asthma. No co-interventions were permitted other than rescue relievers and oral corticosteroids used during exacerbations. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, methodological quality and extracted data. The primary efficacy outcome was the number of patients with one or more exacerbations requiring oral corticosteroids and the primary safety outcome was the number of patients with serious adverse health events. Secondary outcomes included exacerbations, lung function tests, asthma control, adverse effects, withdrawal rates and inflammatory markers. Equivalence was assumed if the risk ratio (RR) estimate and its 95% confidence interval (CI) were between 0.9 and 1.1. Quality of the evidence was assessed using GRADE. MAIN RESULTS: Six trials (including one trial testing two relevant protocols) met the inclusion criteria for a total of seven group comparisons. The four paediatric trials (two involving preschool children and two school-aged children) and two adult parallel-group trials, lasting 12 to 52 weeks, were of high methodological quality. A total of 1211 patients with confirmed, or suspected, persistent asthma contributed to the meta-analyses. There was no statistically significant group difference in the risk of patients experiencing one or more exacerbations requiring oral corticosteroids (1204 patients; RR 1.07; 95% CI 0.87 to 1.32; the large confidence interval translates into a risk of exacerbations in the intermittent ICS group varying between 17% and 25%, assuming a 19% risk with daily ICS). Age, severity of airway obstruction, step-up protocol used during exacerbations and trial duration did not significantly influence the primary efficacy outcome. No group difference was observed in the risk of patients with serious adverse health events (1055 patients; RR 0.82; 95% CI 0.33 to 2.03). Compared to the daily ICS group, the intermittent ICS group displayed a smaller improvement in change from baseline peak expiratory flow rate (PEFR) by 2.56% (95% CI -4.49% to -0.63%), fewer symptom-free days (standardised mean difference (SMD) -0.15 (95% CI -0.28 to -0.03), fewer asthma control days -9% (95% CI -14% to -4%), more use of rescue beta2-agonists by 0.12 puffs/day (95% CI 0 to 0.23) and a greater increase from baseline in exhaled nitric oxide of 16.80 parts per billion (95% CI 11.95 to 21.64). There was no significant group difference in forced expiratory volume in one second (FEV1), quality of life, airway hyper reactivity, adverse effects, hospitalisations, emergency department visits or withdrawals. In paediatric trials, intermittent ICS (budesonide and beclomethasone) were associated with greater growth by 0.41 cm change from baseline (532 children; 95% CI 0.13 to 0.69) compared to daily treatment. AUTHORS' CONCLUSIONS: In children and adults with persistent asthma and in preschool children suspected of persistent asthma, there was low quality evidence that intermittent and daily ICS strategies were similarly effective in the use of rescue oral corticosteroids and the rate of severe adverse health events. The strength of the evidence means that we cannot currently assume equivalence between the two options.. Daily ICS was superior to intermittent ICS in several indicators of lung function, airway inflammation, asthma control and reliever use. Both treatments appeared safe, but a modest growth suppression was associated with daily, compared to intermittent, inhaled budesonide and beclomethasone. Clinicians should carefully weigh the potential benefits and harm of each treatment option, taking into account the unknown long-term (> one year) impact of intermittent therapy on lung growth and lung function decline. PMID- 23450607 TI - Gamma aminobutyric acid (GABA) receptor agonists for acute stroke. AB - BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebral ischemia. However, the sedation effects of GABA receptor agonists have limited their wider application in acute stroke patients due to the potential risk of stupor. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (January 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1949 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), AMED (1985 to March 2012) and 11 Chinese databases (March 2012). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for acute stroke patients (within 12 hours after stroke onset), with the outcomes of death or dependency, functional independence and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality. MAIN RESULTS: We included five trials with 3838 patients. The methodological quality of the included trials was generally good, with low risk of bias. Four trials measured death and dependency at three months in chlormethiazole versus placebo without significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.95 to 1.11). One trial measured this outcome between diazepam and placebo (RR 0.94, 95% CI 0.82 to 1.07). In the subgroup analysis of total anterior circulation syndrome (TACS), a higher percentage of functional independence was found in the chlormethiazole group (RR 1.33, 95% CI 1.09 to 1.64). The frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46). AUTHORS' CONCLUSIONS: This review does not provide the evidence to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of patients with acute ischemic or hemorrhagic stroke. Chlormethiazole appeared to be beneficial in improving functional independence in patients with TACS according to the subgroup analysis, but this result must be interpreted with great caution. More well-designed RCTs with large samples of TACS would be required for further confirmation. However, somnolence and rhinitis are frequent adverse events related to chlormethiazole. PMID- 23450608 TI - Interventions for the eradication of methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers.Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as, not only an important infection in long-term hospitalised patients, but also as a potentially harmful pathogen in cystic fibrosis, and has been increasing steadily in prevalence internationally. Chronic pulmonary infection with MRSA is thought to confer cystic fibrosis patients with a worse overall clinical outcome and, in particular, result in an increased rate of decline in lung function. Clear guidance for the eradication of MRSA in cystic fibrosis, supported by robust evidence from good quality trials, is urgently needed. OBJECTIVES: To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. SEARCH METHODS: Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, EMBASE, handsearching article reference lists and through contact with local and international experts in the field.Date of the last search of the Group's Cystic Fibrosis Trials Register: 24 January 2013. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment. DATA COLLECTION AND ANALYSIS: The authors independently assessed all search results for eligibility. No eligible trials were identified. MAIN RESULTS: No current published eligible trials were identified, although two ongoing clinical trials are likely to be eligible for inclusion in future updates of this review. AUTHORS' CONCLUSIONS: We did not identify any randomised trials which would allow us to make any evidence-based recommendations. Although the results of several non-randomised studies would suggest that, once isolated, the eradication of MRSA is possible; whether this has a significant impact on clinical outcome is still unclear. Further research is required to guide clinical decision making in the management of MRSA infection in cystic fibrosis. PMID- 23450609 TI - Interventions for promoting reintegration and reducing harmful behaviour and lifestyles in street-connected children and young people. AB - BACKGROUND: Numbers of street-connected children and young people run into many millions worldwide and include children and young people who live or work in street environments. Whether or not they remain connected to their families of origin, and despite many strengths and resiliencies, they are vulnerable to a range of risks and are excluded from mainstream social structures and opportunities. OBJECTIVES: To summarise the effectiveness of interventions for street-connected children and young people that promote inclusion and reintegration and reduce harms. To explore the processes of successful intervention and models of change in this area, and to understand how intervention effectiveness may vary in different contexts.. SEARCH METHODS: We searched the following bibliographic databases, from inception to 2012, and various relevant non-governmental and organisational websites: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE and PreMEDLINE; EMBASE and EMBASE Classic; CINAHL; PsycINFO; ERIC; Sociological Abstracts; Social Services Abstracts; Social Work Abstracts; Healthstar; LILACS; System for Grey literature in Europe (OpenGrey); ProQuest Dissertations and Theses; EconLit; IDEAS Economics and Finance Research; JOLIS Library Catalog of the holdings of the World Bank Group and IMF Libraries; BLDS (British Library for Development Studies); Google, Google Scholar. SELECTION CRITERIA: The review included data from harm reduction or reintegration promotion intervention studies that used a comparison group study design and were all randomised or quasi-randomised studies. Studies were included if they evaluated interventions aimed to benefit street-connected children and young people, aged 0 to 24 years, in all contexts. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies. Data were extracted on intervention delivery, context, process factors, equity and outcomes. Outcome measures were grouped according to whether they measured psychosocial outcomes, risky sexual behaviours or substance use. A meta-analysis was conducted for some outcomes though it was not possible for all due to differences in measurements between studies. Other outcomes were evaluated narratively. MAIN RESULTS: We included 11 studies evaluating 12 interventions from high income countries. We did not find any sufficiently robust evaluations conducted in low and middle income countries (LMICs) despite the existence of many relevant programmes. Study quality overall was low to moderate and there was great variation in the measurement used by studies, making comparison difficult. Participants were drop-in and shelter based. We found no consistent results on a range of relevant outcomes within domains of psychosocial health, substance misuse and sexual risky behaviours despite the many measurements collected in the studies. The interventions being evaluated consisted of time limited therapeutically based programmes which did not prove more effective than standard shelter or drop-in services for most outcomes and in most studies. There were favourable changes from baseline in outcomes for most particpants in therapy interventions and also in standard services. There was considerable heterogeneity between studies and equity data were inconsistently reported. No study measured the primary outcome of reintegration or reported on adverse effects. The review discussion section included consideration of the relevance of the findings for LMIC settings. AUTHORS' CONCLUSIONS: Analysis across the included studies found no consistently significant benefit for the 'new' interventions compared to standard services for street-connected children and young people. These latter interventions, however, have not been rigorously evaluated, especially in the context of LMICs. Robustly evaluating the interventions would enable better recommendations to be made for service delivery. There is a need for future research in LMICs that includes children who are on the streets due to urbanisation, war or migration and who may be vulnerable to risks such as trafficking. PMID- 23450610 TI - Interventions for improving outcomes for pregnant women who have experienced genital cutting. AB - BACKGROUND: Female genital cutting (FGC) refers to all procedures that involve the partial or total removal of the external female genitalia, or other injury to the female genital organs for cultural or other non-therapeutic reasons. There are no known medical benefits to FGC, and it can be potentially dangerous for the health and psychological well-being of women and girls who are subjected to the practice resulting in short- and long-term complications. Health problems of significance associated with FGC faced by most women are maternal and neonatal mortality and morbidity, the need for assisted delivery and psychological distress. Under good clinical guidelines for caring for women who have undergone genital cutting, interventions could provide holistic care that is culturally sensitive and non-judgemental to improve outcomes and overall quality of life of women. This review focuses on key interventions carried out to improve outcome and overall quality of life in pregnant women who have undergone FGC. OBJECTIVES: To evaluate the impact of interventions to improve all outcomes in pregnant women or women planning a pregnancy who have undergone genital cutting. The comparison group consisted of those who have undergone FGC but have not received any intervention. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2012) and organisations engaged in projects regarding FGC. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster randomised trials or quasi-RCTs with reported data comparing intervention outcomes among pregnant women or women planning a pregnancy who have undergone genital cutting compared with those who did not receive any intervention. DATA COLLECTION AND ANALYSIS: We did not identify any RCTs, cluster-randomised trials or quasi-RCTs. MAIN RESULTS: There are no included studies. AUTHORS' CONCLUSIONS: FGC research has focused mainly on observational studies to describe the social and cultural context of the practice, and we found no intervention trials conducted to improve outcomes for pregnant women presenting with complications of FGC. While RCTs will provide the most reliable evidence on the effectiveness of interventions, there remains the issue of what is considered ethically appropriate and the willingness of women to undergo randomisation on an issue that is enmeshed in cultural traditions and beliefs. Consequently, conducting such a study might be difficult. PMID- 23450611 TI - Interventions for supporting parents' decisions about autopsy after stillbirth. AB - BACKGROUND: Stillbirth remains one of the least understood areas of infant death and accurate data on the causes of stillbirth are the cornerstone of stillbirth prevention. An autopsy examination remains the gold standard post-mortem investigation for stillbirth. However, decisions about post-mortem investigations, particularly autopsy are difficult. The purpose of this review is to examine the effectiveness of methods to help parents who have experienced a stillbirth decide whether to have post-mortem investigations, including whether to have an autopsy performed. OBJECTIVES: The primary objectives were a) to examine the effectiveness of interventions to support parents' decisions about autopsy consent after a stillbirth on outcomes for parents, and b) to determine autopsy rates. Secondary objectives were to identify issues related to the acceptability of any interventions to parents and the feasibility of their implementation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1966 to 24 July 2012) and EMBASE (1980 to 24 July 2012), Current Controlled Trials metaRegister (mRCT) (18 September 2012) and the WHO International Clinical Trials Registry Platform Search Portal (ICTRP) (18 September 2012). We also searched the websites of the Stillbirth and Neonatal Death Charity (SANDS) and International Stillbirth Alliance (ISA) (18 September 2012) and then subsequently searched the websites of all the ISA member organisations. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions designed specifically to support parents who have experienced a stillbirth make decisions about their options for post-mortem investigations including all investigations after stillbirth compared with usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently screened citations against the selection criteria. MAIN RESULTS: No studies meeting the review inclusion criteria were identified. A search of 40 websites associated with supporting parents who experience stillbirth also found little reference to, or information about autopsy or other post-mortem examinations. AUTHORS' CONCLUSIONS: Support for parents making decisions about autopsy or other post-mortem examinations after stillbirth must rely on the ad hoc knowledge and experience of those involved at the time. PMID- 23450612 TI - Non pharmacological interventions for spasticity in multiple sclerosis. AB - BACKGROUND: Spasticity is commonly experienced by people with multiple sclerosis (MS), and it contributes to overall disability in this population. A wide range of non pharmacological interventions are used in isolation or with pharmacological agents to treat spasticity in MS. Evidence for their effectiveness is yet to be determined. OBJECTIVES: To assess the effectiveness of various non pharmacological interventions for the treatment of spasticity in adults with MS. SEARCH METHODS: A literature search was performed using the Specialised Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Review Group on using the Cochrane MS Group Trials Register which among other sources, contains CENTRAL, Medline, EMBASE, CINAHL, LILACS, PEDRO in June 2012. Manual searching in the relevant journals and screening of the reference lists of identified studies and reviews were carried out. Abstracts published in proceedings of conferences were also scrutinised. SELECTION CRITERIA: Randomised controlled trials (RCTs) that reported non pharmacological intervention/s for treatment of spasticity in adults with MS and compared them with some form of control intervention (such as sham/placebo interventions or lower level or different types of intervention, minimal intervention, waiting list controls or no treatment; interventions given in different settings), were included. DATA COLLECTION AND ANALYSIS: Three review authors independently selected the studies, extracted data and assessed the methodological quality of the studies using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) tool for best-evidence synthesis. A meta-analysis was not possible due to methodological, clinical and statistical heterogeneity of included studies. MAIN RESULTS: Nine RCTs (N = 341 participants, 301 included in analyses) investigated various types and intensities of non pharmacological interventions for treating spasticity in adults with MS. These interventions included: physical activity programmes (such as physiotherapy, structured exercise programme, sports climbing); transcranial magnetic stimulation (Intermittent Theta Burst Stimulation (iTBS), Repetitive Transcranial Magnetic Stimulation (rTMS)); electromagnetic therapy (pulsed electromagnetic therapy; magnetic pulsing device), Transcutaneous Electrical Nerve Stimulation (TENS); and Whole Body Vibration (WBV). All studies scored 'low' on the methodological quality assessment implying high risk of bias. There is 'low level' evidence for physical activity programmes used in isolation or in combination with other interventions (pharmacological or non pharmacological), and for repetitive magnetic stimulation (iTBS/rTMS) with or without adjuvant exercise therapy in improving spasticity in adults with MS. No evidence of benefit exists to support the use of TENS, sports climbing and vibration therapy for treating spasticity in this population. AUTHORS' CONCLUSIONS: There is 'low level' evidence for non pharmacological interventions such as physical activities given in conjunction with other interventions, and for magnetic stimulation and electromagnetic therapies for beneficial effects on spasticity outcomes in people with MS. A wide range of non pharmacological interventions are used for the treatment of spasticity in MS, but more robust trials are needed to build evidence about these interventions. PMID- 23450613 TI - Ciclesonide versus other inhaled corticosteroids for chronic asthma in children. AB - BACKGROUND: Inhaled corticosteroids (ICS) are the cornerstone of asthma maintenance treatment in children. Particularly among parents, there is concern about the safety of ICS as studies in children have shown reduced growth. Small particle-size ICS targeting the smaller airways have improved lung deposition and effective asthma control might be achieved at lower daily doses.Ciclesonide is a relatively new ICS. This small-particle ICS is a pro-drug that is converted in the airways to an active metabolite and therefore with potentially less local (throat infection) and systemic (reduced growth) side effects. It can be inhaled once daily, thereby possibly improving adherence. OBJECTIVES: To assess the efficacy and adverse effects of ciclesonide compared to other ICS in the management of chronic asthma in children. SEARCH METHODS: We searched the Cochrane Airways Group Register of trials with pre-defined terms. Additional searches of MEDLINE (via PubMed), EMBASE and Clinical study results.org were undertaken. Searches are up to date to 7 November 2012. SELECTION CRITERIA: Randomised controlled parallel or cross-over studies were eligible for the review. We included studies comparing ciclesonide with other corticosteroids both at nominally equivalent doses or lower doses of ciclesonide. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Six studies were included in this review (3256 children, 4 to 17 years of age). Two studies were published as conference abstracts only. Ciclesonide was compared to budesonide and fluticasone.Ciclesonide compared to budesonide (dose ratio 1:2): asthma symptoms and adverse effect were similar in both groups. Pooled results showed no significant difference in children who experience an exacerbation (risk ratio (RR) 2.20, 95% confidence interval (CI) 0.75 to 6.43). Both studies reported that 24-hour urine cortisol levels showed a statistically significant decrease in the budesonide group compared to the ciclesonide group.Ciclesonide compared to fluticasone (dose ratio 1:1): no significant differences were found for the outcome asthma symptoms. Pooled results showed no significant differences in number of patients with exacerbations (RR 1.37, 95% CI 0.58 to 3.21) and data from a study that could not be pooled in the meta-analysis reported similar numbers of patients with exacerbations in both groups. None of the studies found a difference in adverse effects. No significant difference was found for 24-hour urine cortisol levels between the groups (mean difference 0.54 nmol/mmol, 95% CI 5.92 to 7.00).Ciclesonide versus fluticasone (dose ratio 1:2) was assessed in one study and showed similar results between the two corticosteroids for asthma symptoms. The number of children with exacerbations was significantly higher in the ciclesonide group (RR 3.57, 95% CI 1.35 to 9.47). No significant differences were found in adverse effects (RR 0.98, 95% CI 0.81 to 1.14) and 24-hour urine cortisol levels (mean difference 1.15 nmol/mmol, 95% CI 0.07 to 2.23).The quality of evidence was judged 'low' for the outcomes asthma symptoms and adverse events and 'very low' for the outcome exacerbations for ciclesonide versus budesonide (dose ratio 1:1). The quality of evidence was graded 'moderate' for the outcome asthma symptoms, 'very low' for the outcome exacerbations and 'low' for the outcome adverse events for ciclesonide versus fluticasone (dose ratio 1:1). For ciclesonide versus fluticasone (dose ratio 1:2) the quality was rated 'low' for the outcome asthma symptoms and 'very low' for exacerbations and adverse events (dose ratio 1:2). AUTHORS' CONCLUSIONS: An improvement in asthma symptoms, exacerbations and side effects of ciclesonide versus budesonide and fluticasone could be neither demonstrated nor refuted and the trade-off between benefits and harms of using ciclesonide instead of budesonide or fluticasone is unclear. The resource use or costs of different ICS should therefore also be considered in final decision making. Longer-term superiority trials are needed to identify the usefulness and safety of ciclesonide compared to other ICS. Additionally these studies should be powered for patient relevant outcomes (exacerbations, asthma symptoms, quality of life and side effects). There is a need for studies comparing ciclesonide once daily with other ICS twice daily to assess the advantages of ciclesonide being a pro-drug that can be administered once daily with possibly increased adherence leading to increased control of asthma and fewer side effects. PMID- 23450614 TI - The effect of pharmacist-provided non-dispensing services on patient outcomes, health service utilisation and costs in low- and middle-income countries. AB - BACKGROUND: The role of pharmacists has expanded beyond dispensing and packaging over the past two decades, and now includes ensuring rational use of drugs, improving clinical outcomes and promoting health status by working with the public and other healthcare professionals. OBJECTIVES: To examine the effect of pharmacist-provided non-dispensing services on patient outcomes, health service utilisation and costs in low- and middle-income countries. SEARCH METHODS: Studies were identified by electronically searching the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (February 2010), MEDLINE (1949 to February 2010), Scopus (1960 to March 2010) and International Pharmaceutical Abstracts (1970 to January 2010) databases. An update of this review is currently ongoing. The search was re-run September 2012 and the potentially relevant studies are awaiting classification. SELECTION CRITERIA: Randomised controlled trials, non-randomised controlled trials, controlled before after studies and interrupted time series analyses comparing 1. pharmacist provided non-dispensing services targeted at patients versus (a) the same services provided by other healthcare professionals, (b) the same services provided by untrained health workers, and (c) usual care; and 2. pharmacist provided non-dispensing services targeted at healthcare professionals versus (a) the same services provided by other healthcare professionals, (b) the same services provided by untrained health workers, and (c) usual care in low- and middle-income countries. The research sites must have been located in low or middle income countries according to World Bank Group 2009 at the time of the study, regardless of the location or the origin of the researchers. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for inclusion in the review. Two review authors independently extracted data for each study. Risk of bias of the included studies was also assessed independently by two authors. MAIN RESULTS: Twelve studies comparing pharmacist-provided services versus usual care were included in this review. Of the 12 studies, seven were from lower middle income countries and five were from upper middle income countries. Eleven studies examined pharmacist-provided services targeted at patients and one study evaluated pharmacist interventions targeted at healthcare professionals. Pharmacist-provided services targeting patients resulted in a small improvement of clinical outcomes such as blood pressure (-25 mm Hg/-6 mm Hg and -4.56 mm Hg/-2.45 mm Hg), blood glucose (-39.84 mg/dl and -16.16 mg/dl), blood cholesterol (-25.7 mg/dl)/ triglyceride levels (-80.1 mg/dl) and asthma outcomes (peak expiratory flow rate 1.76 l/min). Moreover, there was a small improvement in the quality of life, although four studies did not report the effect size explicitly. Health service utilisation, such as rate of hospitalisation and general practice and emergency room visits, was also found to be reduced by the patient targeted pharmacist-provided services. A single study examined the effect of patient targeted pharmacist interventions on medical expenses and the cost was found to be reduced. A single study that examined pharmacist services that targeted healthcare professionals demonstrated a very small impact on asthma symptom scores. No studies assessing the impact of pharmacist-provided non-dispensing services that targeted healthcare professionals reported health service utilisation and cost outcomes. Overall, five studies did not adequately report the numerical data for outcomes but instead reported qualitative statements about results, which prevented an estimation of the effect size.Studies for the comparison of patient targeted services provided by pharmacists versus the same services provided by other healthcare professionals or untrained healthcare workers were not found. Similarly, studies for the comparison of healthcare professional targeted services provided by pharmacists versus the same services provided by other healthcare professionals or untrained healthcare workers were not found. AUTHORS' CONCLUSIONS: Pharmacist-provided services that target patients may improve clinical outcomes such as management of high glucose levels among diabetic patients, management of blood pressure and cholesterol levels and may improve the quality of life of patients with chronic conditions such as diabetes, hypertension and asthma. Pharmacist services may reduce health service utilisation such as visits to general practitioners and hospitalisation rates. We are uncertain about the effect of educational sessions by pharmacists for healthcare professionals due to the imprecision of a single study included in this review. Similarly, conclusions could not be drawn for health service utilisation and costs due to lack of evidence on interventions delivered by pharmacists to healthcare professionals. These results were heterogenous in the types of outcomes measured, clinical conditions and approaches to measurement of outcomes, and require cautious interpretation. All eligible studies were from middle income countries and the results may not be applicable to low income countries. PMID- 23450615 TI - Changes to the Cochrane Library during the Cochrane Collaboration's first 20 years. PMID- 23450616 TI - Evidence supports TB test, so what now? PMID- 23450617 TI - A new search interface for the Cochrane Library. PMID- 23450618 TI - Photo- and thermoresponsive supramolecular assemblies: reversible photorelease of K+ ions and constitutional dynamics. PMID- 23450619 TI - Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis. AB - Iron homeostasis is dysregulated in primary myelofibrosis (PMF), given the high prevalence of anemia, need for red blood cell (RBC) transfusions, and disease associated inflammatory state. We measured plasma hepcidin levels in 203 consecutive PMF patients at the time of first referral; hepcidin levels were significantly higher as compared to healthy controls (P < 0.0001), and were correlated with hemoglobin of <10 g/dL, RBC transfusion requirement, serum ferritin of >500 ug/L, higher dynamic international prognostic scoring system (DIPSS)-plus risk category, the presence of circulating blasts, age of >65 years, and leukocyte count of <4 * 10(9) /L. Increased hepcidin levels predicted for inferior survival independent of six out of the eight DIPSS-plus prognostic parameters (hazard ratio [HR] = 1.8; P = 0.02), but not when RBC transfusion requirement, hemoglobin of <10 g/dL, or increased serum ferritin were included in the Cox model. Multivariable analysis that considered the four overlapping prognostic variables revealed that increased hepcidin (HR = 1.9; P = 0.03) and increased ferritin (HR = 2.3; P = 0.04), but not hemoglobin of <10 g/dL or RBC transfusion requirement, independently retained their significance for predicting survival. Accordingly, increased levels of both hepcidin and serum ferritin (seen in 29% of patients) predicted inferior survival independent of DIPSS-plus or increased inflammatory cytokine levels (HR = 2.4; P = 0.002), and could be considered in future prognostic models for PMF. PMID- 23450620 TI - Prevalence and clinical classification of tremor in elderly--a community-based survey in Brazil. AB - Prevalence data on different types of tremor among the elderly population are very scarce. The objective of this study was to study the prevalence of tremor in a community-dwelling elderly population in the town of Bambui, Brazil. The authors studied 1186 inhabitants aged>=64 years. This was a 2-phase study in which all participants who screened positive in a questionnaire for tremor and parkinsonism or who used drugs capable of causing/suppressing tremor were examined. In this population, the prevalence rate was 17.4% for tremor, 7.4% for essential tremor, 5.6% for parkinsonian tremor, 2.8% for enhanced physiological tremor, and 1.6% for other causes. There were no gender differences in prevalence rates for all types. Patients who had Parkinson's disease with tremor were older than those who had essential tremor, whereas patients who had enhanced physiological tremor were significantly younger. The age-specific prevalence of tremor increased with advancing age for both men and women. The prevalence of tremor in the studied population was high and increased with advancing age. Essential tremor, parkinsonian tremor, and enhanced physiological tremor were the most commonly identified causes. (c) 2013 Movement Disorder Society. PMID- 23450621 TI - A simple model for the fate of the cytokinesis midbody remnant: implications for remnant degradation by autophagy. AB - When a cell divides, it produces two daughter cells initially connected by a cytokinesis bridge, which is eventually cut through abscission. One of the two daughter cells inherits a bridge "remnant", which has been proposed to be degraded by autophagy. The fate and function of remnants is attracting increasing attention, as their accumulation appears to influence proliferation versus differentiation of the daughter cells. Here, we present a simple model for bridge and remnant turnover in a dynamic cell population. We demonstrate that remnant proportions depend on the ratio of remnant and bridge lifetimes to the cell population doubling time. Our results yield new alternative interpretations for published experimental data, leading us to believe that autophagy-independent pathways for remnant degradation may exist. In addition, using the model, we determined experimentally inaccessible parameters such as remnant lifetime. Our model proves to be a useful tool for studying bridge and remnant populations. PMID- 23450623 TI - Synthesis of porous, nitrogen-doped adsorption/diffusion carbonaceous membranes for efficient CO2 separation. AB - A porous, nitrogen-doped carbonaceous free-standing membrane (TFMT-550) is prepared by a facile template-free method using letrozole as an intermediate to a triazole-functionalized-triazine framework, followed by carbonization. Such adsorption/diffusion membranes exhibit good separation performance of CO2 over N2 and surpassing the most recent Robeson upper bound. An exceptional ideal CO2 /N2 permselectivity of 47.5 was achieved with a good CO2 permeability of 2.40 * 10( 13) mol m m(-2) s(-1) Pa(-1) . The latter results arise from the presence of micropores, narrow distribution of small mesopores and from the strong dipole quadrupole interactions between the large quadrupole moment of CO2 molecules and the polar sites associated with N groups (e.g., triazine units) within the framework. PMID- 23450624 TI - Effects of packaging and heat transfer kinetics on drug-product stability during storage under uncontrolled temperature conditions. AB - To predict the stability of pharmaceutical preparations under uncontrolled temperature conditions accurately, a method to compute the average reaction rate constant taking into account the heat transfer from the atmosphere to the product was developed. The average reaction rate constants computed with taken into consideration heat transfer (kappa(re) ) were then compared with those computed without taking heat transfer into consideration (kappa(in) ). The apparent thermal diffusivity (kappa(a) ) exerted some influence on the average reaction rate constant ratio (R, R = kappa(re) /kappa(in) ). In the regions where the kappa(a) was large (above 1 h(-1) ) or very small, the value of R was close to 1. On the contrary, in the middle region (0.001-1 h(-1) ), the value of R was less than 1.The kappa(a) of the central part of a large-size container and that of the central part of a paper case of 10 bottles of liquid medicine (100 mL) fell within this middle region. On the basis of the above-mentioned considerations, heat transfer may need to be taken into consideration to enable a more accurate prediction of the stability of actual pharmaceutical preparations under nonisothermal atmospheres. PMID- 23450626 TI - Engineering multifunctional nanoparticles: all-in-one versus one-for-all. AB - Multifunctional nanoparticles have been developed to overcome the conventional hurdles associated with the diagnosis and treatment of disease. However, there are often caveats involved with the development and clinical translation of multifunctional nanoparticles largely regarding the notion that additional functionality increases nanoparticle complexity. Here, we discuss two design concepts, a conventional approach, 'all-in-one', and introduce the concept of 'one-for-all' to suggest that multifunctionality does not necessarily result in multicomponent complex nanoparticles. This review focuses on the design concepts of all-in-one and one-for-all with examples of each approach and a discussion on the implications for clinical translation. PMID- 23450627 TI - Optimization of hydrophilic interaction LC by univariate and multivariate methods and its combination with salting-out liquid-liquid extraction for the determination of antihypertensive drugs in the environmental waters. AB - Hydrophilic interaction LC for the separation of four antihypertensive drugs was optimized by both univariate and multivariate methods. The column efficiency, resolution, and separation time were used as the three assessment parameters. The best separation condition of 97% ACN with 3% aqueous buffer containing 50 mM ammonium acetate at a pH of 3.0 was obtained by the two optimization methods. The multivariate optimization, orthogonal array design herein, was demonstrated to be a little tedious, but afforded a much better understanding of underlying separation factors. The content of ACN in the mobile phase contributed most significantly to separation. Furthermore, sample diluent and injection volume were found to influence the chromatographic performance. To match the hydrophilic interaction LC mobile phase, a proper sample pretreatment method, salting-out liquid-liquid extraction, in which ACN was the extractant, was chosen. Since reserpine was unstable under both acidic and alkaline conditions, it was not studied in this part. The optimal salting-out liquid-liquid extraction parameters were as follows: 400 MUL ACN was added to 1 mL sample solution containing 500 mg NH4 Cl at a pH of 14.0. The linearity ranged from 0.01 to 1.00 MUg/mL with r(2) > 0.9937. The LODs were between 1.9 and 2.5 ng/mL. The developed method was applied to the environmental water sample with good performance. PMID- 23450628 TI - Joint hypermobility is a risk factor for musculoskeletal pain during adolescence: findings of a prospective cohort study. AB - OBJECTIVE: To determine whether joint hypermobility (JH) in childhood is a risk factor for the subsequent development of musculoskeletal pain. METHODS: JH was determined according to the Beighton score at age 13.8 years in children from the Avon Longitudinal Study of Parents and Children (ALSPAC), using a cutoff of >=6 for the presence of hypermobility. Musculoskeletal pain was evaluated by questionnaire at age 17.8 years. Logistic regression analysis was performed in 2,901 participants (1,267 boys and 1,634 girls) who had complete data. RESULTS: A total of 4.6% of participants had JH at age 13.8 years. Moderately troublesome musculoskeletal pain at age 17.8 years was reported most commonly in the lower back (16.1%), shoulder (9.5%), upper back (8.9%), knee (8.8%), neck (8.6%), and ankle/foot (6.8%). JH was associated with an increased risk of at least moderately troublesome musculoskeletal pain at the shoulder (odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.04, 2.72]), knee (OR 1.83 [95% CI 1.10, 3.02]), and ankle/foot (OR 1.82 [95% CI 1.05, 3.16]) (adjusted for sex, maternal education, and body mass index). An equivalent relationship was not observed at other sites, including the spine, elbows, hands, and hips. In analyses examining interactions with obesity, associations between JH and knee pain showed higher ORs in obese participants (OR 11.01) as compared with nonobese participants (OR 1.57) (P=0.037 for the interaction of hypermobility and obesity). CONCLUSION: JH represents a risk factor for musculoskeletal pain during adolescence, comprising a specific distribution, namely, the shoulder, knee, and ankle/foot. These relationships were strongest in the presence of obesity, which is consistent with a causal pathway whereby JH leads to pain at sites exposed to the greatest mechanical forces. PMID- 23450629 TI - Nanomechanics of cation-pi interactions in aqueous solution. PMID- 23450630 TI - Recent developments in asymmetric phase-transfer reactions. AB - Phase-transfer catalysis has been recognized as a powerful method for establishing practical protocols for organic synthesis, because it offers several advantages, such as operational simplicity, mild reaction conditions, suitability for large-scale synthesis, and the environmentally benign nature of the reaction system. Since the pioneering studies on highly enantioselective alkylations promoted by chiral phase-transfer catalysts, this research field has served as an attractive area for the pursuit of "green" sustainable chemistry. A wide variety of asymmetric transformations catalyzed by chiral onium salts and crown ethers have been developed for the synthesis of valuable organic compounds in the past several decades, especially in recent years. PMID- 23450631 TI - Elongated hindguts in desert-living dung beetles (Scarabaeidae: Scarabaeinae) feeding on dry dung pellets or plant litter. AB - Most adult dung beetles (Scarabaeidae: Scarabaeinae) feed on fresh, wet dung of larger herbivorous or omnivorous mammals. As refractory plant fragments are selected out before ingestion, the food is presumed easily digestible. However, members of the desert-living scarabaeine genus Pachysoma (probably evolved from an ancestor closely related to the wet-dung feeding genus Scarabaeus) select dry dung pellets and/or plant litter. Thus, they ingest a much higher proportion of structural plant material, which nevertheless appears to be digested rather efficiently. This study investigates morphological modifications of the gut for this digestion in adults of eight Pachysoma species, both pellet and litter feeders. To ascertain hypothesized ancestral conditions, four fresh-dung feeding Scarabaeus species were also examined. The latter have the usual dung beetle gut consisting of a long, simple midgut, followed by an equally simple, much shorter hindgut of the same width. Lengths of midguts (M) and hindguts (H) divided by body length (B) for comparison between species of different size are: 4.9-6.3 (M/B) and 0.7-0.8 (H/B), which is normal for dung feeders. In Pachysoma, lengths are 6.3-6.5 (M/B) and 1.0-1.4 (H/B) in pellet feeders, and 4.4-5.0 (M/B) and 2.0 2.5 (H/B) for litter feeders. Hindguts are still morphologically undifferentiated and of midgut width, but clearly longer, particularly in litter feeders. Presumably, plant fragments in the food are digested, at least partly, in the hindgut. If so, the morphological adaptation is unusual: simple elongation rather than the expansion of part of the hindgut, as found in several other plant- or detritus-feeding scarabaeids. PMID- 23450632 TI - Simultaneous separation of hydrophobic and polar bases using a silica hydride stationary phase. AB - In this study, the retention behavior of selected hydrophobic and polar bases on a minimally modified silica hydride phase was investigated. From these results and the associated retention plots, significant differences in the chromatographic dependencies of these two classes of basic compounds were evident. The polar bases exhibited strong retention with mobile phases of high organic solvent content, but displayed weak retention with mobile phases of high water content. In contrast, the hydrophobic bases showed "U-shape" retention dependencies, indicative of the interplay of both RP and normal-phase retention characteristics. These studies have demonstrated that hydrophobic and polar bases can be simultaneously separated on the same column either under typical RP-like or aqueous normal-phase-like conditions, respectively, with distinctive selectivity. Finally, the effects of temperature on the RP and aqueous normal phase modality of separations with these analytes were investigated, where discrete changes in retention behavior were also observed. PMID- 23450634 TI - Synthesis, characterization, and liposome partition of a novel tetracycline derivative using the ionic liquids framework. AB - Recently, efforts have been put on the development of new drug formulations using ionic liquid framework. In this work, two different species of abroad-spectrum polyketide antibiotic, tetracycline, are studied in terms of some important properties for antibiotics such as solubility in water and hydrophilic hydrophobic balance. Tetracycline was used as cation, whereas docusate, a biocompatible anion, which enables the tailoring of the hydrophilicity of salts, was chosen as the anion. The developed innovative ion pair, tetracycline docusate, was characterized in terms of its thermal stability, water solubility, octanol-water, and liposome-water partition coefficients, using UV-vis spectrophotometry because of the absorbance of tetracycline around 270 nm. Egg yolk phosphatidylcholine liposomes were used as cell membrane models, and the interactions of both tetracycline hydrochloride and tetracycline docusate with the liposomes were quantified by determination of the partition coefficient using derivative spectrophotometry. A theoretical model based on simple partition drugs between two different media was used to determine the partition coefficient in liposomes. PMID- 23450633 TI - G protein-coupled receptors engage the mammalian Hippo pathway through F-actin: F Actin, assembled in response to Galpha12/13 induced RhoA-GTP, promotes dephosphorylation and activation of the YAP oncogene. AB - The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell-cell contact or determine epithelial cell polarity which, in a tissue-specific manner, use intracellular complexes containing FERM domain and actin-binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 such as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F )actin. Morever, cell architectures that promote F-actin assembly per se also activate YAP by kinase-dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. PMID- 23450635 TI - Adenomyoepithelial adenosis associated with breast cancer: a case report and review of the literature. AB - Adenomyoepithelial adenosis of the breast is an extremely rare type of adenosis. We herein present the case of a 35-year-old woman, who presented with a small painless hard lump and elastic soft induration of 5 cm in diameter in her left breast. Clinical examination and diagnostic workup were suggestive of a breast carcinoma, and a modified radical mastectomy and sentinel node biopsy were performed. Histopathological examination revealed adenomyoepithelial adenosis along with fibrocystic change and small invasive ductal carcinoma, slightly away from the adenosis. The presented case was thought to be initial-stage adenomyoepithelial adenosis and independently developing breast cancer. From a review of five reported cases of adenomyoepithelial adenosis, complete resection of the tumor and coexisting malignant disease may be recommended, owing to the tendency to develop breast cancer or malignant adenomyoepithelioma, or recurrence. PMID- 23450636 TI - Socioeconomic status, p53 abnormalities, and colorectal cancer. AB - BACKGROUND: Low socioeconomic status (SES) has been associated with abnormal expression of p53 in breast cancer, but this relationship has not been evaluated for colorectal cancer (CRC). A cohort of CRC patients was evaluated to determine if SES is associated with abnormal p53 expression. METHODS: The study population consisted of 249 patients who underwent curative or palliative resections for CRCs at the University of Alabama at Birmingham Hospital. Measures of SES and potential confounders were abstracted from medical records. Abnormal nuclear accumulation of p53 (p53(nac)) was measured in CRCs by immunohistochemistry. Logistic regression was used to assess the relationship between low SES and p53(nac). RESULTS: Over half (56.2%) of the patients exhibited p53(nac) in their CRCs. After adjustment, the odds ratio for p53(nac) was 1.28 (95% CI =0.55, 2.99) for Medicaid patients relative to those without Medicaid coverage. There was no association between the prevalence of p53(nac) and unemployment, private insurance coverage, or having Medicare due to disability. CONCLUSIONS: The odds of having p53(nac) were 1.28 times higher for patients with Medicaid coverage, although these findings were not statistically significant. The results of this pilot study, however, provide evidence of a molecular basis for the decreased survival of low SES patients with CRC. PMID- 23450637 TI - Asymmetric hydroamination: a survey of the most recent developments. AB - Asymmetric hydroamination allows the direct and selective formation of a new C-N bond as a simple procedure towards valuable scalemic synthons. Huge efforts have recently been made to overcome the challenges associated with this transformation. This non-comprehensive Concept article aims at pointing out the most recent and original progresses, offering nearby developments, and addressing the next challenges. PMID- 23450639 TI - A system for individualized prosthetic modeling of the femoral head. AB - The matching quality between the femoral head prosthesis and the acetabulum plays an important role in the operative treatment of femoral head prosthetics and femoral head replacement. To obtain the optimal model of the femoral head prosthesis for the target sufferer, an individualized modeling system is shown in this paper. It can recover the necrotic femoral heads into the satisfactory models. These models can well match with the acetabulum. This new system affords a theoretical model for the accurate operation position fixing in the orthopedic clinic. And this system also provides an innovative practical means for the individualized modeling of the artificial femoral head prosthesis. PMID- 23450638 TI - Internal dynamics of the homotrimeric HIV-1 viral coat protein gp41 on multiple time scales. PMID- 23450640 TI - Prospective evaluation of complications using the modified Clavien grading system, and of success rates of percutaneous nephrolithotomy using Guy's Stone Score: A single-center experience. AB - INTRODUCTION AND OBJECTIVES: To prospectively document the perioperative complications of percutaneous nephrolithotomy (PCNL) using the modified Clavien grading system. Evaluation of complications and clearance rates according to stone complexity using the validated Guy's Stone Score (GSS) was also done. MATERIALS AND METHODS: A total of 221 renal units underwent 278 PCNL procedures at a urology resident training center between September 2010 and September 2011 and data were recorded prospectively in our registry. Patients with co morbidities like diabetes, renal failure, hypertension and cardiopulmonary diseases were excluded. Stone complexity was classified according to the GSS while peri-operative complications were recorded using the modified Clavien grading system. RESULTS: Two hundred and forty-five complications were encountered in 278 PCNL procedures involving 116 renal units (41.72%). Complications of Grades 1, 2, 3a, 3b, 4a, 4b and 5 were seen in 52 (18.7%), 122 (43.8%), 42 (15.1%), 18 (6.4%), 6 (2.1%), 4 (1.4%) and 1 (0.3%) renal units respectively. There were 68, 98, 50 and 5 renal units in GSS I, II, III and IV groups, respectively. All grades of complications were more common in GSS III and IV (P<0.05). For GSS I, II, III and IV 100%, 74%, 56% and 0% of renal units, respectively, were stone-free after one session and 0%, 24%, 44% and 60% respectively needed two sessions to be stone-free. CONCLUSION: Although the complication rates were higher most were of low grade and self-limiting. Complications were significantly more common with higher GSS and the GSS effectively predicted stone-free rates. PMID- 23450641 TI - Anaesthetic Management of a Geriatric Patient with Parkinson's Disease, who was Posted for Emergency Laparotomy- A Case Report. AB - Parkinson's Disease (PD) is a relatively common neuro degenerative disorder in the geriatric age group. The pathophysiological changes in these patients predispose to major systemic complications like aspiration pneumonitis, respiratory depression, myocardial depression and postural hypotension. Anaesthetic agents interact with the anti-Parkinsonian medication and this may lead to adverse effects. Here, we are presenting a case report of the anaesthetic management of a patient with a history of Parkinson's disease, who was posted for emergency laparotomy. PMID- 23450644 TI - A genetically encoded 19F NMR probe for tyrosine phosphorylation. PMID- 23450645 TI - Intravenous urography supplemented with computerised tomography urogram: A pragmatic hybrid imaging approach to hydronephrosis. AB - BACKGROUND: Image quality in an Intravenous Urogram (IVU) can occasionally be compromised by variables like bowel preparation, renal function and radiographic factors, posing a challenge to all Uroradiologists. The Computerised Tomography Urogram (CTU) yields better diagnostic information than an IVU, due to its inherent superior anatomic delineation and contrast sensitivity, against a trade off involving radiation dose and cost. Our study was conducted to assess the utility and timing of performing a single-phase CTU, as a problem-solving tool, to clear the diagnostic dilemma in a selected subset of patients, in whom an ongoing IVU could potentially be inconclusive. MATERIAL AND METHODS: Five hundred and twelve patients who underwent IVU studies for urologic referrals at a tertiary care hospital, during the period of January to December 2009, formed the subject of the study, of whom 33 patients with inconclusive IVU findings after the first three radiographs underwent a single-phase CTU, to reach definitive imaging diagnoses. RESULTS: The percentage of inconclusive IVU studies amounted to only 33 / 512 (6.4%), in whom a CTU study revealed definitive diagnoses in 30 patients and no abnormality in three patients, thus conclusively clearing the ambiguities raised on the IVU in all the selected patients. CONCLUSIONS: The concept of a CTU limited to a single-phase study to supplement an inconclusive IVU optimizes the contrast and radiation dose to the affected patients. It is a cost-effective, timely, and definitive 'imaging intervention' and should be considered a viable hybrid technique to be utilized selectively and judiciously. PMID- 23450643 TI - Cell-cycle perturbations suppress the slow-growth defect of spt10Delta mutants in Saccharomyces cerevisiae. AB - Spt10 is a putative acetyltransferase of Saccharomyces cerevisiae that directly activates the transcription of histone genes. Deletion of SPT10 causes a severe slow growth phenotype, showing that Spt10 is critical for normal cell division. To gain insight into the function of Spt10, we identified mutations that impair or improve the growth of spt10 null (spt10Delta) mutants. Mutations that cause lethality in combination with spt10Delta include particular components of the SAGA complex as well as asf1Delta and hir1Delta. Partial suppressors of the spt10Delta growth defect include mutations that perturb cell-cycle progression through the G1/S transition, S phase, and G2/M. Consistent with these results, slowing of cell-cycle progression by treatment with hydroxyurea or growth on medium containing glycerol as the carbon source also partially suppresses the spt10Delta slow-growth defect. In addition, mutations that impair the Lsm1-7-Pat1 complex, which regulates decapping of polyadenylated mRNAs, also partially suppress the spt10Delta growth defect. Interestingly, suppression of the spt10Delta growth defect is not accompanied by a restoration of normal histone mRNA levels. These findings suggest that Spt10 has multiple roles during cell division. PMID- 23450642 TI - Lessons for inductive germline determination. AB - Formation of the germline in an embryo marks a fresh round of reproductive potential, yet the developmental stage and location within the embryo where the primordial germ cells (PGCs) form differs wildly among species. In most animals, the germline is formed either by an inherited mechanism, in which maternal provisions within the oocyte drive localized germ-cell fate once acquired in the embryo, or an inductive mechanism that involves signaling between cells that directs germ-cell fate. The inherited mechanism has been widely studied in model organisms such as Drosophila melanogaster, Caenorhabditis elegans, Xenopus laevis, and Danio rerio. Given the rapid generation time and the effective adaptation for laboratory research of these organisms, it is not coincidental that research on these organisms has led the field in elucidating mechanisms for germline specification. The inductive mechanism, however, is less well understood and is studied primarily in the mouse (Mus musculus). In this review, we compare and contrast these two fundamental mechanisms for germline determination, beginning with the key molecular determinants that play a role in the formation of germ cells across all animal taxa. We next explore the current understanding of the inductive mechanism of germ-cell determination in mice, and evaluate the hypotheses for selective pressures on these contrasting mechanisms. We then discuss the hypothesis that the transition between these determination mechanisms, which has happened many times in phylogeny, is more of a continuum than a binary change. Finally, we propose an analogy between germline determination and sex determination in vertebrates-two of the milestones of reproduction and development-in which animals use contrasting strategies to activate similar pathways. PMID- 23450646 TI - Short latency afferent inhibition: a biomarker for mild cognitive impairment in Parkinson's disease? AB - BACKGROUND: Mild cognitive impairment in Parkinson's disease (PD) is common and predicts those at risk of dementia. Cholinergic dysfunction may contribute to its pathophysiology and can be assessed using short latency afferent inhibition. METHODS: Twenty-two patients with PD (11 cognitively normal; 11 with mild cognitive impairment) and 22 controls participated. Short latency afferent inhibition was measured by conditioning motor evoked potentials, which were elicited by transcranial magnetic stimulation of the motor cortex with electrical stimuli delivered to the contralateral median nerve at varying interstimulus intervals. RESULTS: There was no significant difference between cognitively normal PD and controls for short latency afferent inhibition (62.8+/-30.3% vs. 55.7+/-21.7%; P=0.447). The PD-mild cognitive impairment group had significantly less inhibition (88.4+/-25.8%) than both cognitively normal PD (P=0.021) and controls (P=0.01). CONCLUSIONS: Cholinergic dysfunction occurs early in those with PD-mild cognitive impairment. Short latency afferent inhibition may be a useful biomarker of increased risk of dementia in PD patients. (c) 2013 Movement Disorder Society. PMID- 23450647 TI - Processes linking cultural ingroup bonds and mental health: the roles of social connection and emotion regulation. AB - Cultural and ethnic identities influence the relationships individuals seek out and how they feel and behave in these relationships, which can strongly affect mental and physical health through their impacts on emotions, physiology, and behavior. We proposed and tested a model in which ethnocultural identifications and ingroup affiliations were hypothesized explicitly to enhance social connectedness, which would in turn promote expectancy for effective regulation of negative emotions and reduce self-reported symptoms of depression and anxiety. Our sample comprised women aged 18-30 currently attending college in the Southwestern US, who self-identified as Hispanic of Mexican descent (MAs; n = 82) or as non-Hispanic White/European American (EAs; n = 234) and who completed an online survey. In the full sample and in each subgroup, stronger ethnocultural group identity and greater comfort with mainstream American culture were associated with higher social connectedness, which in turn was associated with expectancy for more effective regulation of negative emotions, fewer depressive symptoms, and less anxiety. Unexpectedly, preference for ingroup affiliation predicted lower social connectedness in both groups. In addition to indirect effects through social connection, direct paths from mainstream comfort and preference for ingroup affiliation to emotion regulation expectancy were found for EAs. Models of our data underscore that social connection is a central mechanism through which ethnocultural identities-including with one's own group and the mainstream cultural group-relate to mental health, and that emotion regulation may be a key aspect of this linkage. We use the term ethnocultural social connection to make explicit a process that, we believe, has been implied in the ethnic identity literature for many years, and that may have consequential implications for mental health and conceptualizations of processes underlying mental disorders. PMID- 23450648 TI - Identity profiles and well-being of multicultural immigrants: the case of canadian immigrants living in quebec. AB - Studies worldwide point toward increased risk of mental health issues among immigrants. Immigrants' ability to integrate the cultural identity of their new country has been found to be a key factor in their psychological well-being. Even though researchers agree on the crucial role of identity integration in immigrants' well-being, the current literature has two main limitations: (1) researchers do not agree on the importance that should be allocated to each of the cultural identities, and (2) research has focused on bicultural individuals as opposed to multicultural individuals. The present paper proposes to study Canadians immigrants living in the province of Quebec who, because of the political and linguistic situation of the province, face the challenge of integrating two new cultural identities (Quebecer and Canadian) to their original one. Specifically, cluster analysis was used to observe identity profiles that naturally emerge among 120 Canadian immigrants from the province of Quebec. Identity profiles were then compared on various indices of well-being to identify the optimal identity structure. In total, four identity profiles emerged, differing in their levels of identity coherence (i.e., similar levels of identification with each group) and identification to either the original group or the Quebecers. ANOVA results confirmed that identity profiles differed in their average level of well-being. First, immigrants with coherent profiles displayed higher levels of well-being. Second, among incoherent profiles, the profile where identification to the original group is the highest showed the greatest well-being. Implications suggest that in order to maximize immigrants' well-being, psychologists should focus on the coherence between cultural groups as well as identification to the original group. PMID- 23450649 TI - Current perspectives on systems immunology approaches to rheumatic diseases. PMID- 23450650 TI - The Diagnostic Utility of Bact/ALERT and Nested PCR in the Diagnosis of Tuberculous Meningitis. AB - OBJECTIVE: The early laboratory diagnosis of Tuberculous Meningitis (TBM) is crucial, to start the antitubercular chemotherapy and to prevent its complications. However, the conventional methods are either less sensitive or time consuming. Hence, the diagnostic potentials of BacT/ALERT and Polymerase Chain Reaction (PCR) was evaluated in this study. MATERIAL AND METHOD: The study group comprised of 62 cases and 33 controls. The cases were divided according to Ahuja's criteria into the confirmed (two cases), highly probable (19 cases), probable (26 cases) and the possible (15 cases) subgroups. Ziehl Neelsen's (ZN) and Auramine Phenol (AP) staining, Lowenstein Jensen (LJ) medium culture, BacT/ALERT and nested Polymerase Chain Reaction (PCR) which targeted IS6110 were carried out on all the patients. OBSERVATION AND RESULTS: The sensitivity of the LJ culture was 3.22%. BacT/ALERT showed a sensitivity and a specificity of 25.80% and 100% and those of nested PCR were found to be 40.32% and 96.97% respectively. The mean detection time of growth of the LJ culture was 31.28 days, whereas that of BacT/ALERT was 20.68 days. The contamination rate in the LJ culture and BacT/ALERT were 7.2% and 5.8% respectively. CONCLUSION: Nested PCR was found to be more sensitive, followed by BacT/ALERT as compared to the LJ culture and smear microscopy. As both false negative and false positive results have been reported for nested PCR, so it should not be used alone as a criterion for initiating or terminating the therapy, but it should be supported by clinical, radiological, cytological and other microbiological findings. PMID- 23450651 TI - Post-traumatic aneurysm of the radial artery: A case report. AB - An aneurysm is defined as a permanent localized dilation of an artery with a diameter increased by more than 50% compared to the normal diameter. An aneurism arising from the radial artery of the wrist is a rare injury and it usually occurs after a blunt trauma or as an iatrogenic injury. This paper presents the case of a 47-year-old patient with a pulsating swelling at the volar surface of the right wrist. Clinical diagnosis of aneurysm of the radial artery was confirmed by ultrasound (US) imaging. This case is reported because of the rarity of the pathology and to highlight the effectiveness of US as an important tool for further investigation and confirmation of clinical diagnosis. PMID- 23450653 TI - Two in one: Double free flap from a single free fibula osteocutaneous unit. AB - In the past two decades, the advancement in the microsurgical techniques has revolutionised the reconstruction of post-oncological head and neck defects. Free fibula osteocutaneous flap (FFOCF) has been considered as the treatment of choice by many for mandible reconstruction. The improvement in the surgical resection and adjuvant treatment has improved the survival rates even in patients with advanced cancer. Simultaneously the reconstruction is addressed towards more functional and aesthetic aspects to improve the quality of life in these patients. In this respect, a double free flap is advocated in certain cases of extensive composite oromandibular defects (COMDs). But in our institute, we have managed two such cases of extensive COMD with a single FFOCF unit - fibula bone with a skin paddle for inner lining and a perforator-based skin paddle from the proximal part of the FFOCF unit, anastomosed separately for outer cover. Compared to two separate free flaps, this method has the advantage of single donor site and reduction in reconstruction time. Though the technique of divided paddle, deepithelisation and supercharging has been mentioned for FFOCF, no such clinical cases of two free flaps from a single FFOCF unit have been mentioned in the literature. PMID- 23450652 TI - Extrasynaptic GABAA receptors in rat pontine reticular formation increase wakefulness. AB - STUDY OBJECTIVES: Gamma-aminobutyric acid (GABA) causes phasic inhibition via synaptic GABAA receptors and tonic inhibition via extrasynaptic GABAA receptors. GABA levels in the extracellular space regulate arousal state and cognition by volume transmission via extrasynaptic GABAA receptors. GABAergic transmission in the pontine reticular formation promotes wakefulness. No previous studies have determined whether an agonist at extrasynaptic GABAA receptors administered into the pontine reticular formation alters sleep and wakefulness. Therefore, this study used gaboxadol (THIP; agonist at extrasynaptic GABAA receptors that contain a delta subunit) to test the hypothesis that extrasynaptic GABAA receptors within the pontine reticular formation modulate sleep and wakefulness. DESIGN: Within/between subjects. SETTING: University of Michigan. PATIENTS OR PARTICIPANTS: Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 10). INTERVENTIONS: Microinjection of gaboxadol, the nonsubtype selective GABAA receptor agonist muscimol (positive control), and saline (negative control) into the rostral pontine reticular formation. MEASUREMENTS AND RESULTS: Gaboxadol significantly increased wakefulness and decreased both nonrapid eye movement sleep and rapid eye movement sleep in a concentration-dependent manner. Relative to saline, gaboxadol did not alter electroencephalogram power. Microinjection of muscimol into the pontine reticular formation of the same rats that received gaboxadol increased wakefulness and decreased sleep. CONCLUSION: Tonic inhibition via extrasynaptic GABAA receptors that contain a delta subunit may be one mechanism by which the extracellular pool of endogenous GABA in the rostral pontine reticular formation promotes wakefulness. CITATION: Vanini G; Baghdoyan HA. Extrasynaptic GABAA receptors in rat pontine reticular formation increase wakefulness. SLEEP 2013;36(3):337-343. PMID- 23450655 TI - Use of a halo frame for optimum intra- and post-operative management after scalp replantation/revascularization. AB - We present a new technique for stabilizing an avulsed scalp during and after replantation/revascularization. We used an aluminium "halo" frame with 4 screws. This technique can rigidly stabilize an avulsed scalp and eliminate the possibility of shearing/pressure necrosis. This device can make perioperative management easier and more comfortable for the patient and caregivers. PMID- 23450654 TI - How adaptation shapes spike rate oscillations in recurrent neuronal networks. AB - Neural mass signals from in-vivo recordings often show oscillations with frequencies ranging from <1 to 100 Hz. Fast rhythmic activity in the beta and gamma range can be generated by network-based mechanisms such as recurrent synaptic excitation-inhibition loops. Slower oscillations might instead depend on neuronal adaptation currents whose timescales range from tens of milliseconds to seconds. Here we investigate how the dynamics of such adaptation currents contribute to spike rate oscillations and resonance properties in recurrent networks of excitatory and inhibitory neurons. Based on a network of sparsely coupled spiking model neurons with two types of adaptation current and conductance-based synapses with heterogeneous strengths and delays we use a mean field approach to analyze oscillatory network activity. For constant external input, we find that spike-triggered adaptation currents provide a mechanism to generate slow oscillations over a wide range of adaptation timescales as long as recurrent synaptic excitation is sufficiently strong. Faster rhythms occur when recurrent inhibition is slower than excitation and oscillation frequency increases with the strength of inhibition. Adaptation facilitates such network based oscillations for fast synaptic inhibition and leads to decreased frequencies. For oscillatory external input, adaptation currents amplify a narrow band of frequencies and cause phase advances for low frequencies in addition to phase delays at higher frequencies. Our results therefore identify the different key roles of neuronal adaptation dynamics for rhythmogenesis and selective signal propagation in recurrent networks. PMID- 23450656 TI - Musculoskeletal determinants of pelvic sucker function in Hawaiian stream gobiid fishes: interspecific comparisons and allometric scaling. AB - Gobiid fishes possess a distinctive ventral sucker, formed from fusion of the pelvic fins. This sucker is used to adhere to a wide range of substrates including, in some species, the vertical cliffs of waterfalls that are climbed during upstream migrations. Previous studies of waterfall-climbing goby species have found that pressure differentials and adhesive forces generated by the sucker increase with positive allometry as fish grow in size, despite isometry or negative allometry of sucker area. To produce such scaling patterns for pressure differential and adhesive force, waterfall-climbing gobies might exhibit allometry for other muscular or skeletal components of the pelvic sucker that contribute to its adhesive function. In this study, we used anatomical dissections and modeling to evaluate the potential for allometric growth in the cross-sectional area, effective mechanical advantage (EMA), and force generating capacity of major protractor and retractor muscles of the pelvic sucker (m. protractor ischii and m. retractor ischii) that help to expand the sealed volume of the sucker to produce pressure differentials and adhesive force. We compared patterns for three Hawaiian gobiid species: a nonclimber (Stenogobius hawaiiensis), an ontogenetically limited climber (Awaous guamensis), and a proficient climber (Sicyopterus stimpsoni). Scaling patterns were relatively similar for all three species, typically exhibiting isometric or negatively allometric scaling for the muscles and lever systems examined. Although these scaling patterns do not help to explain the positive allometry of pressure differentials and adhesive force as climbing gobies grow, the best climber among the species we compared, S. stimpsoni, does exhibit the highest calculated estimates of EMA, muscular input force, and output force for pelvic sucker retraction at any body size, potentially facilitating its adhesive ability. PMID- 23450657 TI - Thoracobiliary fistulas: literature review and a case report of fistula closure with omentum majus. AB - BACKGROUND: Thoracobiliary fistulas are pathological communications between the biliary tract and the bronchial tree (bronchobiliary fistulas) or the biliary tract and the pleural space (pleurobiliary fistulas). REVIEW OF THE LITERATURE: We have reviewed aetiology, pathogenesis, predilection formation points, the clinical picture, diagnostic possibilities, and therapeutic options for thoracobiliary fistulas. CASE REPORT: A patient with an iatrogenic bronchobiliary fistula which developed after radiofrequency ablation of a colorectal carcinoma metastasis of the liver is present. We also describe the closure of the bronchobiliary fistula with the greater omentum as a possible manner of fistula closure, which was not reported previously according to the knowledge of the authors. CONCLUSIONS: Newer papers report of successful non-surgical therapy, although the bulk of the literature advocates surgical therapy. Fistula closure with the greater omentum is a possible method of the thoracobiliary fistula treatment. PMID- 23450658 TI - An interesting two-phase solvent system and its use in preparative isolation of aconitines from aconite roots by counter-current chromatography. AB - Two-phase solvent system plays crucial role in successful separation of organic compounds using counter-current chromatography (CCC). An interesting two-phase solvent system, composed of chloroform/ethyl acetate/methanol/water, is reported here, in which both phases contain sufficient organic solvents to balance their dissolving capacities. Adjusting the solvent system to get satisfactory partition coefficients (K values) for target compounds becomes relatively simple. This solvent system succeeded in sample preparation of aconitine (8.07 mg, 93.69%), hypaconitine (7.74 mg, 93.17%), mesaconitine (1.95 mg, 94.52%) from raw aconite roots (102.24 mg, crude extract), benzoylmesaconine (34.79 mg, 98.67%) from processed aconite roots (400.01 mg, crude extract), and yunaconitine (253.59 mg, 98.65%) from a crude extract of Aconitum forrestii (326.69 mg, crude extract). PMID- 23450659 TI - From deep sequencing to viral tagging: recent advances in viral metagenomics. AB - Culture-independent high-throughput sequencing has provided unprecedented insights into microbial ecology, particularly for Earth's most ubiquitous and diverse inhabitants - the viruses. A plethora of methods now exist for amplifying the vanishingly small amounts of nucleic acids in natural viral communities in order to sequence them, and sequencing depth is now so great that viral genomes can be detected and assembled even amid large concentrations of non-viral DNA. Complementing these advances in amplification and sequencing is the ability to physically link fluorescently labeled viruses to their host cells via high throughput flow sorting. Sequencing of such isolated virus-host pairs facilitates cultivation-independent exploration of the natural host range of viruses. Within the next decade, as these technologies become widespread, we can expect to see a systematic expansion of our knowledge of viruses and their hosts. PMID- 23450661 TI - Strained alkenes in natural product synthesis. AB - Strained molecules continue to challenge the ingenuity of chemists as their high energy bonds serve as fuel for the promotion of complex synthetic transformations. Developments in this area have resulted in the recent emergence of strained alkenes as intermediates in natural product synthesis. This Minireview highlights these recent advances along with current developments toward understanding the unique reactivity of strained alkenes. PMID- 23450660 TI - A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease. AB - We examined the effects of 3 dosages of pridopidine, a dopamine-stabilizing compound, on motor function and other features of Huntington's disease, with additional evaluation of its safety and tolerability. This was a randomized, double-blind, placebo-controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty-seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntington's Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was -1.2 points (95% confidence interval [CI], -2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was -2.8 points (95% CI, -5.4 to -0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntington's disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated. PMID- 23450663 TI - Shotgun proteomic analysis of two Bartonella quintana strains. AB - This study reports the first extensive shotgun analysis of the Bartonella quintana proteome. Proteins extracted from two B. quintana strains, Oklahoma and JK31, were analyzed in triplicate analyses by a bottom-up approach consisting of tryptic digestion in SDS-containing buffer, strong cation-exchange StageTip fractionation, and nano-LC-MS/MS analysis. By setting spectral false discovery rate below 0.5%, 548 unique proteins were identified overall, of which 409 protein identifications were shared between the two strains. The data set, which achieves the highest proteome coverage for B. quintana to date, could be exploited for the quantitative analysis of a selected subset of target proteins. PMID- 23450662 TI - The Peripheral NK Cell Repertoire after Kidney Transplantation is Modulated by Different Immunosuppressive Drugs. AB - In the context of kidney transplantation, little is known about the involvement of natural killer (NK) cells in the immune reaction leading to either rejection or immunological tolerance under immunosuppression. Therefore, the peripheral NK cell repertoire of patients after kidney transplantation was investigated in order to identify NK cell subsets that may be associated with the individual immune status at the time of their protocol biopsies for histopathological evaluation of the graft. Alterations in the peripheral NK cell repertoire could be correlated to the type of immunosuppression, i.e., calcineurin-inhibitors like Cyclosporin A vs. Tacrolimus with or without addition of mTOR inhibitors. Here, we could demonstrate that the NK cell repertoire in peripheral blood of kidney transplant patients differs significantly from healthy individuals. The presence of donor-specific antibodies was associated with reduced numbers of CD56(dim) NK cells. Moreover, in patients, down-modulation of CD16 and CD6 on CD56(dim) NK cells was observed with significant differences between Cyclosporin A- and Tac treated patients. Tac-treatment was associated with decreased CD69, HLA-DR, and increased CD94/NKG2A expression in CD56(dim) NK cells indicating that the quality of the immunosuppressive treatment impinges on the peripheral NK cell repertoire. In vitro studies with peripheral blood mononuclear cells of healthy donors showed that this modulation of CD16, CD6, CD69, and HLA-DR could also be induced experimentally. The presence of calcineurin or mTOR inhibitors had also functional consequences regarding degranulation and interferon-gamma-production against K562 target cells, respectively. In summary, we postulate that the NK cell composition in peripheral blood of kidney transplanted patients represents an important hallmark of the efficacy of immunosuppression and may be even informative for the immune status after transplantation in terms of rejection vs. drug-induced allograft tolerance. Thus, NK cells can serve as sensors for immunosuppression and may be utilized for future strategies of an individualized adjustment of immunosuppression. PMID- 23450664 TI - A right ectopic kidney with bilateral multiple anomalies of the renal vasculature - a case report. AB - The renal anatomy and its development is complex. This complexity is associated with numerous variations. Each renal variation has its own clinical and surgical importance. There is a good correlation between the ascent of the kidney, the level of its origin and number of the renal arteries. Any anomaly in the renal artery development may be due to a delay in the kidney ascension and it can lead to an ectopic kidney. Ectopic kidneys are more frequent in males and they are observed commonly on the left side. In the present study, we came across a rare case of a unilateral right renal ectopia and bilateral multiple renal arteries, with 5 renal arteries on the right side and 2 on the left side. The renal veins were 3 on the right side and two on the left side, with the retro aortic left renal vein, which were observed during the routine dissection of a male cadaver. This observation would be of immense importance for surgeons, interventional radiologists, nephrologists and vascular surgeons. PMID- 23450665 TI - Histology of melanic flank and opercular color pattern elements in the Firemouth Cichlid, Thorichthys meeki. AB - Dark melanic color pattern elements, such as bars, stripes, and spots, are common in the skin of fishes, and result from the differential distribution and activity of melanin-containing chromatophores (melanophores). We determined the histological basis of two melanic color pattern elements in the integument of the Firemouth Cichlid, Thorichthys meeki. Vertical bars on the flanks were formed by three layers of dermal melanophores, whereas opercular spots were formed by four layers (two lateral and two medial) in the integument surrounding the opercular bones. Pretreatment of opercular tissue with potassium and sodium salts effectively concentrated or dispersed intracellular melanosomes. Regional differences in epidermal structure, scale distribution, and connective tissues were also identified. PMID- 23450666 TI - Process analytical technology to understand the disintegration behavior of alendronate sodium tablets. AB - Various adverse events including esophagus irritations have been reported with the use of alendronate tablets, likely attributed to the rapid tablet disintegration in the mouth or esophagus. Accordingly, the disintegration of six alendronate tablet drug products was studied using a newly developed testing device equipped with in-line sensors, in addition to the official compendial procedure for measuring the disintegration time. The in-line sensors were used to monitor the particle count and solution pH change to assess the onset and duration of disintegration. A relatively large variation was observed in the disintegration time of the tested drug products using the compendial method. The data collected using the in-line sensors suggested that all tested drug products exhibited almost instantaneous onset of disintegration, under 2 s, and a sharp drop in solution pH. The drop in pH was slower for tablets with slower disintegration. The in-house prepared alendronate test tablets also showed similar trends suggesting rapid solubilization of the drug contributed to the fast tablet disintegration. This research highlights the usefulness of the newly developed in-line analytical method in combination with the compendial method in providing a better understanding of the disintegration and the accompanying drug solubilization processes for fast disintegrating tablet drug products. PMID- 23450667 TI - Investigating reduction of dimensionality during single-joint elbow movements: a case study on muscle synergies. AB - A long standing hypothesis in the neuroscience community is that the central nervous system (CNS) generates the muscle activities to accomplish movements by combining a relatively small number of stereotyped patterns of muscle activations, often referred to as "muscle synergies." Different definitions of synergies have been given in the literature. The most well-known are those of synchronous, time-varying and temporal muscle synergies. Each one of them is based on a different mathematical model used to factor some EMG array recordings collected during the execution of variety of motor tasks into a well-determined spatial, temporal or spatio-temporal organization. This plurality of definitions and their separate application to complex tasks have so far complicated the comparison and interpretation of the results obtained across studies, and it has always remained unclear why and when one synergistic decomposition should be preferred to another one. By using well-understood motor tasks such as elbow flexions and extensions, we aimed in this study to clarify better what are the motor features characterized by each kind of decomposition and to assess whether, when and why one of them should be preferred to the others. We found that three temporal synergies, each one of them accounting for specific temporal phases of the movements could account for the majority of the data variation. Similar performances could be achieved by two synchronous synergies, encoding the agonist antagonist nature of the two muscles considered, and by two time-varying muscle synergies, encoding each one a task-related feature of the elbow movements, specifically their direction. Our findings support the notion that each EMG decomposition provides a set of well-interpretable muscle synergies, identifying reduction of dimensionality in different aspects of the movements. Taken together, our findings suggest that all decompositions are not equivalent and may imply different neurophysiological substrates to be implemented. PMID- 23450668 TI - Lewis acid catalyzed enlargement of cyclic beta-alkoxyenals and one-pot synthesis of polyfunctional enoxysilanes derived from aucubin with trimethylsilyldiazomethane. PMID- 23450669 TI - Distance deviation measure of contouring variability. AB - BACKGROUND: Several methods that are currently used for contouring analysis have problems providing reliable and/or meaningful results. In this paper a solution to these problems is proposed in a form of a novel measure, which was developed based on requirements defined for contouring studies. MATERIALS AND METHODS: The proposed distance deviation measure can be understood as an extension of the closest point measures in such a way that it does not measure only distances between points on contours but rather analyse deviation of distances to both/all contours from each image point/voxel. The obtained result is information rich, reliable and provided in a form of an image, enabling detailed topographic analysis. In addition to image representation, results can be further processed into angular representation for compact topographic analysis or into overall scalar estimates for quick assessment of contour disagreement. RESULTS: Distance deviation method is demonstrated on a multi observer contouring example with complex contour shapes, i.e., with pronounced extremes and void interior. The results are presented using the three proposed methods. CONCLUSIONS: The proposed method can detect and measure contour variation irrespective of contour complexity and number of contour segments, while the obtained results are easy to interpret. It can be used in various situations, regarding the presence of reference contour or multiple test contours. PMID- 23450670 TI - Congenital urethrocutaneous fistula: Case report with review of literature. AB - We are presenting two cases of congenital urethrocutaneous fistula on ventral penile shaft. Congenital urethral fistula is an extremely rare, but easily manageable anomaly that may be confused with hypospadias. Awareness of the entity will avoid complications. This condition may be associated with other anomalies like congenital hernias and anorectal malformations. Treatment of this entity is individualized according to site of fistula, associated anomalies and condition of the distal urethra. All the principles of hypospadias surgery should be strictly followed. PMID- 23450671 TI - Unroofed coronary sinus and persistent left superior vena cava: A case report. AB - The unroofed coronary sinus is a spectrum of cardiac anomalies in which part or all of the common wall between the coronary sinus and the left atrium is absent. Most cases are associated with anomalous systemic venous return, such as persistent left superior vena cava.The diagnosis of this lesion is important to the prognosis of the patient, but it is often difficult because of nonspecific clinical features.Here we report a case of a complete unroofed coronary sinus and persistent left superior vena cava discovered during a computed tomographic investigation for pulmonary hypertension. PMID- 23450672 TI - Pneumoconiosis and malignant mesothelioma in a family operated metal casting business that used industrial talc from New York state. AB - BACKGROUND: The United States is second only to the People's Republic of China in annual talc production. U.S. talc is used in the production of ceramics, paint, paper, plastics, roofing, rubber, cosmetics, flooring, caulking, and agricultural applications. A number of U.S. talc deposits consistently contain talc intergrown with amphiboles such as tremolite and/or anthophyllite. It has long been recognized that miners and millers of talc deposits are at risk for pneumoconiosis and it has recently been reported that it is prudent, on the balance of probabilities, to conclude that dusts from New York State talc ores are capable of causing mesothelioma in exposed workers. This is a report of the diagnosis of pneumoconiosis and mesothelioma in a husband and wife who operated a small metal casting business that used industrial talc from New York as a parting agent. METHODS: Case reports, including medical records and exposure histories, were provided by an attorney who had also commissioned laboratory investigation of the industrial talc product used in the factory. RESULTS: Mrs X was diagnosed with pneumoconiosis characterized by interstitial fibrosis and heavily calcified pleural plaques. Mr X had calcified pleural plaques and developed a fatal pleural mesothelioma. Samples of the industrial talc contained fibrous tremolite and anthophyllite. CONCLUSIONS: The author concludes that end users of industrial talc from New York State may be at risk of pneumoconiosis and malignant disease. End users of talcs from other regions of the United States, where talc formation arose from processes driven by regional metamorphism, might also be at risk. PMID- 23450673 TI - Optimization of the production and characterization of milk clotting enzymes by Bacillus subtilis natto. AB - Suitable medium for production of milk clotting enzyme (MCE) by Bacillus subtilis (natto) Takahashi in submerged liquid-state fermentation was screened, the nutrient factors affecting MCE production was optimized by response surface methodology. The MCE production by B. subtilis (natto) Takahashi was increased significantly by 428% in the optimal medium developed. The MCE was filtered and concentrated by ultrafiltration. The retentate after tandem filtration carried out with the combined membranes of MWCO 50kDa and 5 kDa showed two major bands between 25kDa and 30kDa on SDS-PAGE, and the MCA and MCA/PA improved significantly in comparison with those in the initial broth. The crude enzyme thus obtained showed MCA and MCA/PA ratio of 48,000 SU/g and 6,400, which are commensurate with those (MCA 26,667 SU/g and MCA/PA 6,667) of the commercial rennet. It had optimal pH and temperature at pH 6 and 60 degrees C, and showed excellent pH and thermal stability. PMID- 23450674 TI - Bone densitometric assessment and management of fracture risk in Indian men of prostate cancer on androgen deprivation therapy: Does practice pattern match the guidelines? AB - OBJECTIVE: Estimation of baseline bone mineral density (BMD) at the time of instituting androgen deprivation therapy (ADT) for metastatic prostate cancer is recommended by several specialty groups and expert panels. The present study was carried out to analyze the practice pattern of Indian urologists with regard to bone densitometric assessment and management of fracture risk in men of prostate cancer on ADT, and their degree of adherence to currently available guidelines. MATERIALS AND METHODS: Telephonic interviews of 108 qualified urologists, randomly selected from the member database of Urological Society of India was carried out with a predefined questionnaire. The responses were analyzed and compared with the available evidences and recommendations. RESULTS: Only 19.4% urologists routinely perform a baseline BMD before starting ADT. Although majority of them prescribe calcium and vitamin D supplementation, only few tell regarding fracture risk and life-style modification to their patients. While 59.6% of the respondents use Zoledronic acid (ZA) in their patients on ADT, half of them prescribe it without knowing the BMD status, which may lead to overuse of ZA. CONCLUSION: Majority of the urologists in India do not follow the guidelines for BMD measurement in prostate cancer. A baseline BMD may help in reducing the unnecessary use of ZA. PMID- 23450675 TI - Experience with free fibula transfer with screw fixation as a primary modality of treatment for congenital pseudarthosis of tibia in children - Series of 26 cases. AB - BACKGROUND: Congenital pseudarthrosis is one of the greatest challenges of paediatric orthopaedic practice. Treatment options and literature addressing this condition are numerous, reflecting the difficulty in management. We aimed to study the effectiveness of free fibula transfer as a primary modality of treatment in children with this condition in terms of achieving length, union, and normal axis of the involved leg. MATERIALS AND METHODS: During the period of 2001 to 2010, 26 children with congenital pseudarthrosis of tibia between age group of 2-8 years were evaluated and were reconstructed using contra-lateral free fibula graft, and then patients were followed up for 5 years subsequently. Patients were examined and time of bony union, weight bearing ability and walking without support were noted. Any complication directly or indirectly related to surgery with any complication seen in the due course of follow up of 5 years was also taken care of. RESULTS: In our experience with treatment of congenital pseudarthrosis over a span of 10 years with free fibula transfer, the results have been gratifying with no flap loss. All our patients had UNEVENTFUL post-op recovery. Only 2 patients out of 26 had non-union, for which cancellous bone grafting was done (7.6%). Most of the patients were ambulatory with support by 3 6 months and continued to walk without support after a span of 18-24 months. The incidence of stress fracture in our study over the follow-up period was 4 out of 26 pts (15.3%). None of them had any deformity in the donor leg. CONCLUSION: When compared to other surgical modalities of treatment of the problem in question, vascularised free fibula transfer has emerged as a real saviour with good patient compliance and less complication rate in our study. It achieves the desired target with no residual deformities and near normal to normal gait with no stigma of bone removal from other leg. PMID- 23450676 TI - Are competition and extrinsic motivation reliable predictors of academic cheating? AB - Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356). Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast, extrinsic motivation had no significant effect. Indirect positive influence on cheating, based on some characteristics of hypercompetition, was also found, whereas attitudes toward self-developmental competition had a mediated negative influence. Neither constructive nor destructive competitive classroom climate had a significant impact on academic dishonesty. Acceptance of cheating and guilt has significant and direct effect on self-reported cheating. In comparison with them, the effects of motivational and competition-related variables are relatively small, even negligible. These results suggest that extrinsic motivation and competition are not amongst the most reliable predictors of academic cheating behavior. PMID- 23450677 TI - Tongue and lateral upper airway movement with mandibular advancement. AB - STUDY OBJECTIVES: To characterize tongue and lateral upper airway movement and to image tongue deformation during mandibular advancement. DESIGN: Dynamic imaging study of a wide range of apnea hypopnea index (AHI), body mass index (BMI) subjects. SETTING: Not-for-profit research institute. PARTICIPANTS: 30 subjects (aged 31-69 y, AHI 0-75 events/h, BMI 17-39 kg/m(2)). INTERVENTIONS: Subjects were imaged using dynamic tagged magnetic resonance imaging during mandibular advancement. Tissue displacements were quantified with the harmonic phase technique. MEASUREMENTS AND RESULTS: Mean mandibular advancement was 5.6 +/- 1.8 mm (mean +/- standard deviation). This produced movement through a connection from the ramus of the mandible to the pharyngeal lateral walls in all subjects. In the sagittal plane, 3 patterns of posterior tongue deformation were seen with mandibular advancement-(A) en bloc anterior movement, (B) anterior movement of the oropharyngeal region, and (C) minimal anterior movement. Subjects with lower AHI were more likely to have en bloc movement (P = 0.04) than minimal movement. Antero-posterior elongation of the tongue increased with AHI (R = 0.461, P = 0.01). Mean anterior displacements of the posterior nasopharyngeal and oropharyngeal regions of the tongue were 20% +/- 13% and 31% +/- 17% of mandibular advancement. The posterior tongue compressed 1.1 +/- 2.2 mm supero inferiorly. CONCLUSIONS: Mandibular advancement has two mechanisms of action which increase airway size. In subjects with low AHI, the entire tongue moves forward. Mandibular advancement also produces lateral airway expansion via a direct connection between the lateral walls and the ramus of the mandible. CITATION: Brown EC; Cheng S; McKenzie DK; Butler JE; Gandevia SC; Bilston LE. Tongue and lateral upper airway movement with mandibular advancement. SLEEP 2013;36(3):397-404. PMID- 23450678 TI - Resistance to PARP-Inhibitors in Cancer Therapy. AB - The pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) family of proteins have shown promising results in preclinical studies and clinical trials as a monotherapy or in combination therapy for some cancers. Thus, usage of PARP inhibitors (PARPi) in cancer therapy is bound to increase with time, but resistance of cancer cells to PARPi is also beginning to be observed. Here we review different known and potential mechanisms by which: (i) PARPi kill cancer cells; and (ii) cancer cells develop resistance to PARPi. Understanding the lethality caused by PARPi and the countermeasures deployed by cancers cells to survive PARPi will help us rationalize the use of this new class of drugs in cancer therapy. PMID- 23450679 TI - Highly photoluminescent carbon dots for multicolor patterning, sensors, and bioimaging. PMID- 23450680 TI - Xanthoma of the urinary bladder - A rare entity. AB - Xanthomas of the urinary bladder are rare. They may be associated with metabolic disorders. We hereby report a case of bladder xanthoma. PMID- 23450681 TI - Adenocarcinoma associated with tail gut cyst. AB - Primary adenocarcinomas of the presacral (retrorectal) space are rare. The diagnosis is usually delayed because of non-specific symptoms, and is made after a biopsy or surgery. These carcinomas arise from cystic lesions developing from remnants of the embryological postanal gut containing mucous-secreting epithelium, known as tail gut cysts. The potential for infection, perianal fistulas and most importantly, malignant change warrants an early complete surgical resection. From an oncologist's perspective, the management of these carcinomas has varied, and has included adjuvant chemotherapy and/or radiation therapy. We describe here a rare case of adenocarcinoma associated with a tail gut cyst that was discovered incidentally and resected by a posterior approach (Kraske procedure). The patient has had clinical and periodic radiologic surveillance without any evidence of cancer recurrence for over a year and a half. PMID- 23450682 TI - A study on the biochemical and the morphological changes in the liver in renal transplant recipients with an evidence of the HBV and the HCV infections. AB - CONTEXT: Renal transplantation is the definitive treatment in renal failure patients. Liver disease is a known problem in renal transplant recipients. They may be consequent to immunosuppression, drug toxicity, altered immune response to viruses and hemodialysis. AIMS: The aim of this study was to analyze and correlate the biochemical parameters and histopathology of liver biopsy among renal transplant recipients with both HBV and HCV infection and to correlate them. SETTING: The study group had thirty cases. Enrolment criteria included coinfection with HBV and HCV ; elevated liver enzymes and recipient of renal allograft. There was acontrol group of ten patients who were HBC and HCV positive but had not undergone renal transplant. MATERIAL & METHODS: Liver function tests including alkaline phosphatase, SGOT, SGPT and serum bilirubin levels were donet. Percutaneous liver biopsies were carried out using Menghini's needle.. Stains done included hematoxylin and eosin (H & E), vanGieson, reticulin and Perl's stain. Histopathological grading was performed using Metavir scoring system. Immunohistochemistry (IHC) was done where required for ground glass hepatocytes. Correlation of SGOT, SGPT and Alkaline phosphatase of the study group and the controls was carried out with the grading. STATISTICAL ANALYSIS: Statistical tests done included paired "t" test at 5% and test of probability. RESULTS: There was no statistically significant correlation between the controls and the transplanted patients. It was concluded that serum enzyme levels could be used to predict histological grade in the control group but not in the transplant recipients (p>0.05). PMID- 23450684 TI - Rapid eye movement sleep behavior disorder in Parkinson's disease: magnetic resonance imaging study. AB - BACKGROUND: Rapid eye movement sleep behavior disorder has poor prognostic implications for Parkinson's disease. The authors recruited 124 patients with early Parkinson's disease to compare clinical and neuroimaging findings based on the presence of this sleep disorder. METHODS: The presence of rapid eye movement sleep behavior disorder was assessed with the Mayo Sleep Questionnaire. Magnetic resonance imaging sequences were obtained for voxel-based morphometry and diffusion tensor imaging. RESULTS: Patients with sleep disorder had more advanced disease, but groups had similar clinical characteristics and cognitive performance. Those with sleep disorder had areas of reduced cortical grey matter volume and white matter changes compared with those who did not have sleep disorder. However, differences were slight and were not significant when the analyses were adjusted for multiple comparisons. CONCLUSIONS: Rapid eye movement sleep behavior disorder was associated with subtle changes in white matter integrity and grey matter volume in patients with early Parkinson's disease. PMID- 23450683 TI - Dysregulation of CD4+CD25(high) T cells in the synovial fluid of patients with antibiotic-refractory Lyme arthritis. AB - OBJECTIVE: To examine the role of immune dysregulation in antibiotic-refractory Lyme arthritis by comparing the phenotype, frequency, and function of CD4+ Teff cells and Treg cells in patients with antibiotic- responsive arthritis and patients with antibiotic-refractory arthritis. METHODS: Matched peripheral blood and synovial fluid samples from 15 patients with antibiotic-responsive arthritis were compared with those from 16 patients with antibiotic-refractory arthritis, using flow cytometry, suppression assays, and cytokine assays. RESULTS: Critical differences between the 2 patient groups were observed in the synovial fluid CD4+CD25(high) population, a cell subset usually composed of FoxP3-positive Treg cells. In patients with antibiotic-refractory arthritis, this cell population often had fewer FoxP3-positive cells and a greater frequency of FoxP3-negative (Teff) cells compared with patients with antibiotic-responsive arthritis. Moreover, the expression of glucocorticoid-induced tumor necrosis factor receptor and OX40 on CD4+CD25(high) cells was significantly higher in the antibody refractory group. Suppression assays showed that CD4+CD25(high) cells in patients with antibiotic-refractory arthritis did not effectively suppress proliferation of CD4+CD25- cells or secretion of interferon-gamma and tumor necrosis factor alpha, whereas those cells in patients with antibiotic-responsive arthritis did suppress proliferation of CD4+CD25- cells and secretion of interferon-gamma and tumor necrosis factor alpha. Finally, in the antibiotic-refractory group, higher ratios of CD25(high) FoxP3-negative cells to CD25(high) FoxP3-positive cells correlated directly with a longer duration of arthritis after antibiotic treatment. CONCLUSION: Patients with antibiotic-refractory Lyme arthritis often have lower frequencies of Treg cells, higher expression of activation coreceptors, and less effective inhibition of proinflammatory cytokines. This suggests that immune responses in these patients are excessively amplified, leading to immune dysregulation and antibiotic-refractory arthritis. PMID- 23450685 TI - Systemic delivery of microRNA-34a for cancer stem cell therapy. PMID- 23450686 TI - Making ends meet: coordination between RNA 3'-end processing and transcription initiation. AB - RNA polymerase II (RNAPII)-mediated gene transcription initiates at promoters and ends at terminators. Transcription termination is intimately connected to 3'-end processing of the produced RNA and already when loaded at the promoter, RNAPII starts to become configured for this downstream event. Conversely, RNAPII is 'reset' as part of the 3'-end processing/termination event, thus preparing the enzyme for its next round of transcription--possibly on the same gene. There is both direct and circumstantial evidence for preferential recycling of RNAPII from the gene terminator back to its own promoter, which supposedly increases the efficiency of the transcription process under conditions where RNAPII levels are rate limiting. Here, we review differences and commonalities between initiation and 3'-end processing/termination processes on various types of RNAPII transcribed genes. In doing so, we discuss the requirements for efficient 3'-end processing/termination and how these may relate to proper recycling of RNAPII. PMID- 23450687 TI - Tumor-positive resection margins reflect an aggressive tumor biology in pancreatic cancer. AB - BACKGROUND: Resection margin status has been shown to impact outcomes for pancreatic adenocarcinoma (PAC), yet it remains unknown whether margin status is a reflection of tumor biology or surgical technique. METHODS: Two hundred eighty three consecutive patients with pancreatic adenocarcinoma were identified in a prospectively maintained database. Only patients with R0 (n = 207) or R1 (n = 76) tumors were included. Each operative surgeon's first 50 cases were excluded to control for technical inexperience. Univariable and multivariable analyses of clinicopathologic and intra-operative factors were performed. RESULTS: The median follow-up for the cohort was 30.3 months with a median overall survival (OS) of 19.0 months. The R1 group had a higher rate of lymph node ratio >0.2 (41% vs. 25%; P = 0.013), and more microvascular invasion (64% vs. 44%; P = 0.007). R0 resections had both improved overall survival (22.7 months vs. 15.0 months, P = 0.004) and disease free survival (13.5 months vs. 10.7 months, P = 0.026). Factors independently associated with overall survival were microvascular invasion (HR 2.26; P = 0.001), pre-existing pulmonary disease (HR 2.18, P = 0.043), and cardiac disease (HR 1.78, P = 0.033). CONCLUSION: Factors associated with an R1 resection reflect a biologically more aggressive tumor, with a higher likelihood of microvascular invasion and increased positive lymph node ratio. PMID- 23450688 TI - Morphological variation in the appendicular skeleton of Atlantic Forest sigmodontine rodents. AB - Rodents of the subfamily Sigmodontinae comprise a highly diversified group in the Atlantic Forest, with semifossorial, terrestrial, semiaquatic, scansorial, and arboreal forms. In this study, we analyzed morphometric variation in humerus, scapula, ulna, radius, femur, tibia, and pelvis to investigate its possible relationship with the different types of locomotion recorded in the literature. Skeletal characters were measured in 321 specimens belonging to 29 species and 19 genera either restricted to or recorded in this ecoregion. Multivariate morphometric analyses (principal component and canonical variate analyses) arranged individuals of different genera in groups congruent with the different types of locomotion. This arrangement was more clearly defined when analyses included only forelimb measurements, indicating that most of the variation in appendicular traits associated with the different locomotor modes occurs in the forelimb skeleton. Semifossorial forms exhibited the most distinct appendicular morphology, as well as the greatest frequency of endemism among analyzed species. These results suggest that this mode of locomotion led to greater differentiation in semifossorial Atlantic forest sigmodontines than in terrestrial and arboreal forms, which were found to have more subtle differentiation and fewer endemics. Scansorial species could not be set apart from terrestrial ones in terms of appendicular morphology, suggesting that these two modes of locomotion are the most similar and generalized for the group, as they occur in most lineages in the subfamily. The results of this study corroborate previous observations on the relevance of appendicular characters in the differentiation of species and genera in the subfamily Sigmodontinae. PMID- 23450689 TI - Main-chain organometallic microporous polymers based on triptycene: synthesis and catalytic application in the Suzuki-Miyaura coupling reaction. PMID- 23450690 TI - Fatalities due to dichloromethane in paint strippers: a continuing problem. AB - BACKGROUND: Exposure to dichloromethane (DCM or methylene chloride - CH2 Cl2 ) in paint strippers continues to be an avoidable source of morbidity and mortality. DCM has been under regulatory scrutiny by occupational and consumer product agencies since the identification of its carcinogenicity in the mid-1980s. METHODS: We investigated two independent workplace incidents that resulted in three cases of DCM intoxication from paint stripper use. RESULTS: Each incident investigated resulted in a fatality. A third worker suffered obtundation requiring hospitalization and intubation. CONCLUSIONS: The continued occurrence of fatalities and other serious injuries due to DCM-containing paint strippers in the United States calls for a re-evaluation of existing regulatory strategies. PMID- 23450692 TI - Continuous-flow synthesis of 1-substituted benzotriazoles from chloronitrobenzenes and amines in a C-N bond formation/hydrogenation/diazotization/cyclization sequence. PMID- 23450691 TI - Reliability and validity of a MR-based volumetric analysis of the intrinsic foot muscles. AB - PURPOSE: To describe a semi-automated program that will segment subcutaneous fat, muscle, and adipose tissue in the foot using MR imaging, determine the reliability of the program between and within raters, and determine the validity of the program using MR phantoms. MATERIALS AND METHODS: MR images were acquired from 19 subjects with and without diabetes and peripheral neuropathy. Two raters segmented and measured volumes from single MR slices at the forefoot, midfoot, and hindfoot at two different times. Intra- and inter-rater correlation coefficients were determined. Muscle and fat MR phantoms of known volumes were measured by the program. RESULTS: Most ICC reliability values were over 0.950. Validity estimates comparing MR estimates and known volumes resulted in r(2) values above 0.970 for all phantoms. The root mean square error was less than 5% for all phantoms. CONCLUSION: Subcutaneous fat, lean muscle, and adipose tissue volumes in the foot can be quantified in a reliable and valid way. This program can be applied in future studies investigating the relationship of these foot structures to functions in important pathologies, including the neuropathic foot or other musculoskeletal problems. PMID- 23450693 TI - Anti-citrullinated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients. AB - OBJECTIVE: First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients sharing genetic and environmental risk factors for RA may represent a pre-RA state. Since anti-cyclic citrullinated protein/peptide antibodies (ACPAs) appear years before the onset of RA, the purpose of this study was to determine the prevalence of various ACPAs in FDRs of RA patients. METHODS: We evaluated 88 RA patients, 50 unaffected FDRs, and 20 healthy control subjects. Six different types of ACPAs were determined by enzyme-linked immunosorbent assay. Joint and periodontal disease symptoms were self-reported. Patients and FDRs were HLA typed for the shared epitope (SE) and the RA-protective alleles HLA-DRB*1301/1302. RESULTS: FDRs had a high prevalence of ACPAs (48%) as compared to controls (10%). Prevalence of the SE and smoking in FDRs was also high (62% and 49%, respectively). Of all of the ACPAs in the FDRs, 13 of 32 (41%) were of the IgA isotype. The most commonly expressed IgG ACPA targeted citrullinated vimentin, occurring in 20% of FDRs. The FDRs had an average of 1 type of ACPA, whereas the RA patients expressed a median of 5 different ACPAs. The only FDR to later develop RA expressed 4 different ACPAs. Joint and periodontal disease symptoms in the FDRs were significantly associated with smoking (OR 5.714 [95% confidence interval (95% CI) 1.151-28.3] and OR 12.25 [95% CI 2.544-58.99], respectively), but not with ACPAs. CONCLUSION: The rate of ACPA positivity in unaffected FDRs of RA patients with a high prevalence of the SE and smoking was 48%, whereas ACPAs were rare in the healthy controls. ACPAs in the FDRs of RA patients was most commonly of the IgA isotype, but IgG ACPA targeting citrullinated vimentin was also frequently found. PMID- 23450694 TI - Three simple clinical tests to accurately predict falls in people with Parkinson's disease. AB - Falls are a major cause of morbidity in Parkinson's disease (PD). The objective of this study was to identify predictors of falls in PD and develop a simple prediction tool that would be useful in routine patient care. Potential predictor variables (falls history, disease severity, cognition, leg muscle strength, balance, mobility, freezing of gait [FOG], and fear of falling) were collected for 205 community-dwelling people with PD. Falls were monitored prospectively for 6 months using monthly falls diaries. In total, 125 participants (59%) fell during follow-up. A model that included a history of falls, FOG, impaired postural sway, gait speed, sit-to-stand, standing balance with narrow base of support, and coordinated stability had high discrimination in identifying fallers (area under the receiver-operating characteristic curve [AUC], 0.83; 95% confidence interval [CI], 0.77-0.88). A clinical tool that incorporated 3 predictors easily determined in a clinical setting (falling in the previous year: odds ratio [OR], 5.80; 95% CI, 3.00-11.22; FOG in the past month: OR, 2.39; 95% CI, 1.19-4.80; and self-selected gait speed < 1.1 meters per second: OR, 1.86; 95% CI, 0.96-3.58) had similar discrimination (AUC, 0.80; 95% CI, 0.73-0.86) to the more complex model (P = 0.14 for comparison of AUCs). The absolute probability of falling in the next 6 months for people with low, medium, and high risk using the simple, 3-test tool was 17%, 51%, and 85%, respectively. In people who have PD without significant cognitive impairment, falls can be predicted with a high degree of accuracy using a simple, 3-test clinical tool. This tool enables individualized quantification of the risk of falling. (c) 2013 Movement Disorder Society. PMID- 23450695 TI - Reduced mortality rates in a cohort of long-term underground iron-ore miners. AB - BACKGROUND: Historically, working in iron-ore mines has been associated with an increased risk of lung cancer and silicosis. However, studies on other causes of mortality are inconsistent and in the case of cancer incidence, sparse. The aim of this study was to examine the association between iron-ore mining, mortality and cancer incidence. METHODS: A 54-year cohort study on iron-ore miners from mines in northern Sweden was carried out comprising 13,000 workers. Standardized rate ratios were calculated comparing the disease frequency, mortality, and cancer incidence with that of the general population of northern Sweden. Poisson regression was used to evaluate the association between the durations of employment and underground work, and outcome. RESULTS: Underground mining was associated with a significant decrease in adjusted mortality rate ratios for cerebrovascular and digestive system diseases, and stroke. For several outcomes, elevated standardized rate ratios were observed among blue-collar workers relative to the reference population. However, only the incidence of lung cancer increased with employment time underground (P < 0.001). CONCLUSIONS: Long-term iron-ore mining underground was associated with lower rates regarding several health outcomes. This is possibly explained by factors related to actual job activities, environmental exposure, or the selection of healthier workers for long-term underground employment. PMID- 23450696 TI - Epigenetic regulation of NK cell differentiation and effector functions. AB - Upon maturation, natural killer (NK) cells acquire effector functions and regulatory receptors. New insights suggest a considerable functional heterogeneity and dynamic regulation of receptor expression in mature human NK cell subsets based on different developmental axes. Such processes include acquisition of lytic granules as well as regulation of cytokine production in response to exogenous cytokine stimulation or target cell interactions. One axis is regulated by expression of inhibitory receptors for self-MHC class I molecules, whereas other axes are less well defined but likely are driven by different activating receptor engagements or cytokines. Moreover, the recent identification of long-lived NK cell subsets in mice that are able to expand and respond rapidly following a secondary viral challenge suggest previously unappreciated plasticity in the programming of NK cell differentiation. Here, we review advances in our understanding of mature NK cell development and plasticity with regards to regulation of cellular function. Furthermore, we highlight some of the major questions that remain pertaining to the epigenetic changes that underlie the differentiation and functional specialization of NK cells and the regulation of their responses. PMID- 23450697 TI - Like (CO)4, Do (CS)4 and (CSe)4 have a triplet ground state? AB - Cyclobutane-1,2,3,4-tetraone, (CO)4, was computationally predicted and, subsequently, experimentally confirmed to have a triplet ground state, in which a b2g sigma MO and an a2u pi MO were each singly occupied. In contrast, the (U)CCSD(T) calculations reported herein found that cyclobutane-1,2,3,4 tetrathione, (CS)4, and cyclobutane-1,2,3,4-tetraselenone, (CSe)4, both had singlet ground states, in which the b2g sigma MO was doubly occupied and the a2u pi MO was empty. Our calculations showed that both the longer C=X distances and smaller coefficients on the carbon atoms in the b2g and a2u MOs of (CS)4 and (CSe)4 contributed to the difference between the ground states of these two molecules and the ground state of (CO)4. An experimental test of the prediction of a singlet ground state for (CS)4 is proposed. PMID- 23450698 TI - Photon-upconverting nanoparticles for optical encoding and multiplexing of cells, biomolecules, and microspheres. AB - Photon-upconverting nanoparticles (UCNPs) are lanthanide-doped nanocrystals that emit visible light under near-infrared excitation (anti-Stokes emission). This unique optical property precludes background fluorescence and light scattering from biological materials. The emission of multiple and narrow emission lines is an additional hallmark of UCNPs that opens up new avenues for optical encoding. Distinct emission signatures can be obtained if the multiple emission of UCNPs is tuned by their dopant composition or by surface modification with dyes. Tuning the intensity of only one of the multiple emission lines and using another one as a constant reference signal enables the design of ratiometric codes that are resistant to fluctuations in absolute signal intensities. Combining several UCNPs each displaying a distinct set of emission lines expands the coding capacity exponentially and lays the foundation for highly multiplexed analyte detection. This Review highlights the potential of UCNPs for labeling and encoding biomolecules, microspheres, and even whole cells. PMID- 23450699 TI - Optimization-driven identification of genetic perturbations accelerates the convergence of model parameters in ensemble modeling of metabolic networks. AB - The ensemble modeling (EM) approach has shown promise in capturing kinetic and regulatory effects in the modeling of metabolic networks. Efficacy of the EM procedure relies on the identification of model parameterizations that adequately describe all observed metabolic phenotypes upon perturbation. In this study, we propose an optimization-based algorithm for the systematic identification of genetic/enzyme perturbations to maximally reduce the number of models retained in the ensemble after each round of model screening. The key premise here is to design perturbations that will maximally scatter the predicted steady-state fluxes over the ensemble parameterizations. We demonstrate the applicability of this procedure for an Escherichia coli metabolic model of central metabolism by successively identifying single, double, and triple enzyme perturbations that cause the maximum degree of flux separation between models in the ensemble. Results revealed that optimal perturbations are not always located close to reaction(s) whose fluxes are measured, especially when multiple perturbations are considered. In addition, there appears to be a maximum number of simultaneous perturbations beyond which no appreciable increase in the divergence of flux predictions is achieved. Overall, this study provides a systematic way of optimally designing genetic perturbations for populating the ensemble of models with relevant model parameterizations. PMID- 23450700 TI - Morphological analysis of rat ureteric terminal arterioles in situ. AB - Confocal imaging of Fluo-4, Propidium iodide, and di-8-Anepps loaded ureter were used to study the morphology of terminal arterioles with an inner diameter <50 MUm in intact rat ureter. Optical sectioning showed that the muscle coat of the terminal arterioles consisted of a monolayer of highly curved smooth muscle cells which run circumferentially around the endothelium. This technique allowed not only to measure the inner diameter of the terminal arterioles but also to define the orientation and number of revolutions an individual smooth muscle cell made around the endothelium. We measured thickness, width, length, and morphological profile of the myocytes and endothelial cells. Propidium iodide staining showed nuclei of individual cells by continuous imaging at high resolution in serial optical sections. Conventional haematoxylin-eosin, Masson's tri-chrome staining, and transmission electron microscopy were also used in this study to compare the measurements obtained from live confocal imaging with histological standard methods. Parameters obtained from live imaging were significantly different. This technique of live staining allowed measuring the cellular and nuclear dimensions of the terminal arterioles in their natural environment which are important in studying the effects of vascular disease or aging on vascular structure. PMID- 23450701 TI - Giant congenital melanocytic nevi: a case report. AB - Congenital melanocytic naevi which are formed by the overgrowth of melanocytes, are present at birth, which are called as bathing trunk, coat-sleeve or stocking naevi, which are commonly found over the back and the thigh areas . The giant congenital naevi of sizes which are greater than 20 cm are pigmented and are often hairy. The risk of malignant melanoma for the giant naevi is approximately 6% and 50% of the melanomas that develop by the age of two years, and 80% of those that develop by the age of seven years. So, an early removal is recommended The objective of this paper is to present a unique case of giant naevi along with a review of the literature. PMID- 23450702 TI - Inherited epidermolysis bullosa: Case report of finger localization. AB - Inherited epidermolysis bullosa is a rare condition that often present at birth with skin blisters and erosions. They are associated with defective cohesion of the dermis and epidermis. There are 3 principal types: Simple, junctional and dystrophic. The severity of the condition is quite variable. The most severe forms are incompatible with life. The most common types in our country are the severe ones such as the Hallopeau -Siemens subtype. Hands and mucosal areas can develop synechia. We report here a case of dystrophic epidermolysis bullosa in a 27-year-old woman whose finger lesion was managed surgically. This treatment consisted of complete removal of constrictions and adhesions, accompanied by use of a Hueston flap and skin graft to repair the tissue deficit. The patient's clinical course required several repeat operations. This surgery allowed the possible total loss of hand function to be delayed but the inevitable progression of the illness made the treatment somewhat disappointing. Psychosocial implications are very significant in our setting. PMID- 23450704 TI - An assessment of feeding jejunostomy tube placement at the time of resection for gastric adenocarcinoma. AB - BACKGROUND: Feeding jejunostomy tubes (J-tube) are often placed during gastrectomy for cancer to decrease malnutrition and promote delivery of adjuvant therapy. We hypothesized that J-tubes actually are associated with increased complications and do not improve nutritional status nor increase rates of adjuvant therapy. METHODS: One hundred thirty-two patients were identified from a prospectively maintained database that underwent gastric resection for gastric adenocarcinoma between 1/00 and 3/11 at one institution. Pre- and postoperative nutritional status and relevant intraoperative and postoperative parameters were examined. RESULTS: Median age was 64 years (range 23-85). Forty-six (35%) underwent a total and 86 (65%) a subtotal gastrectomy. J-tubes were placed in 66 (50%) patients, 34 of whom underwent a subtotal and 32 a total gastrectomy. Preoperative nutritional status was similar between J-tube and no J-tube groups as measured by serum albumin (3.5 vs. 3.4 g/dL). Tumor grade, T, N, and overall stage were similar between groups. J-tube placement was associated with increased postop complications (59% vs. 41%, P = 0.04) and infectious complications (36% vs. 17%, P = 0.01), of which majority were surgical site infections. J-tubes were associated with prolonged length of stay (13 vs. 11 days; P = 0.05). There was no difference in postoperative nutritional status as measured by 30, 60, and 90-day albumin levels and the rate of receiving adjuvant therapy was similar between groups (J-tube: 61%, no J-tube: 53%, P = 0.38). Multivariate analyses revealed J tubes to be associated with increased postop complications (HR: 4.8; 95% CI: 1.3 17.7; P = 0.02), even when accounting for tumor stage and operative difficulty and extent. Subset analysis revealed J-tubes to have less associated morbidity after total gastrectomy. CONCLUSION: J-tube placement after gastrectomy for gastric cancer may be associated with increased postoperative complications with no demonstrable advantage in receiving adjuvant therapy. Routine use of J-tubes after subtotal gastrectomy may not be justified, but may be selectively indicated in patients undergoing total gastrectomy. A prospective trial is needed to validate these results. PMID- 23450703 TI - Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients. AB - PURPOSE: To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. MATERIALS AND METHODS: Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues. RESULTS: Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field. CONCLUSION: Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage. PMID- 23450705 TI - Variations in risk assessment models may contribute to the existing gap between venous thromboembolism prophylaxis guidelines and adherence. AB - BACKGROUND: Risk assessment models (RAMs) may allow the clinician to determine need for deep vein thrombosis (DVT) prophylaxis. Individual healthcare facilities often develop their own RAMs. The purpose of this study was to determine: 1.) inter-RAM variability in DVT risk factors and contraindications; 2.) inter-rater variability and inter-RAM variability when applying a RAM to a standard case; and 3.) inter-rater and inter-RAM variability in outcome as far as type of prophylaxis. A convenience sample of RAMs was obtained from various institutions and ten reviewers were recruited to apply the RAMs to three patient cases. FINDING: The review resulted in 390 separate assessments. Patient 1 did not receive any chemoprophylaxis in 67% of the evaluations, patient 2 in 27% of the evaluations and patient 3 in 2.3% of the evaluations. There was statistically significant variation in the provision of chemoprophylaxis per RAM for patient 1 (p=0.001) and no significant variation for patients 2 and 3. When analyzing the rate of chemoprophylaxis per reviewer, there was statistically significant variation for patients 1 and 2 (p=0.026 and <0.0001 respectively) but not for patient 3 (p=0.123). CONCLUSION: There may be significant inter-RAM and inter reviewer variability when utilizing RAMs for assessing DVT risk. PMID- 23450707 TI - US and MRI features in venous vascular malformation of the abdominal wall. A case report. AB - Vascular anomalies are classified as vascular tumors and vascular malformations. Venous vascular malformations are the most common type of vascular malformation. They may be isolated or multiple and they rarely affect the trunk. The authors report a rare case of isolated venous vascular malformation of the abdominal wall with an emphasis on the related MRI and ultrasound (US) features. PMID- 23450706 TI - Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy. AB - While glioblastoma multiforme (GBM) is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs) remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed "glioma stem cells" (GSCs), "glioma progenitor cells," or "glioma-initiating cells," which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGG must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses (oHSV), genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oHSV. PMID- 23450708 TI - Luminescent conjugated oligothiophenes for sensitive fluorescent assignment of protein inclusion bodies. AB - Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands. PMID- 23450709 TI - MicroRNA-30a promotes B cell hyperactivity in patients with systemic lupus erythematosus by direct interaction with Lyn. AB - OBJECTIVE: To investigate why the level of Lyn is significantly decreased in B cells from a majority of patients with systemic lupus erythematosus (SLE) and to determine the role of microRNA-30a (miR-30a) in SLE B cell hyperactivity. METHODS: Luciferase reporter gene assays were performed to identify the interaction between miR-30a and the 3'-untranslated region (3'-UTR) of Lyn. Levels of miR-30a in B cells were determined by TaqMan quantitative polymerase chain reaction (qPCR), Lyn messenger RNA levels were tested with real-time qPCR, and protein levels of Lyn were determined using Western blotting. The quantity of IgG was determined by enzyme-linked immunosorbent assay. The proliferation of B cells was measured using (3) H-thymidine incorporation. RESULTS: In B cell lines, miR-30a, but not miR-30b, miR-30c, miR-30d, or miR-30e, could specifically bind the 3'-UTR of Lyn, and overexpression of miR-30a inhibited the levels of Lyn. The level of miR-30a in B cells was significantly higher in SLE patients compared to healthy donors. The level of miR-30a was negatively associated with the level of Lyn in B cells. Overexpression of miR-30a was found to promote B cell proliferation and the production of IgG antibodies. The effect of miR-30a could be abrogated by inducing overexpression of Lyn in B cells. CONCLUSION: These results reveal that elevated expression of miR-30a is responsible for the reduction in levels of Lyn in B cells from patients with SLE, suggesting that miR 30a plays an important role in B cell hyperactivity. PMID- 23450710 TI - Plastinated knee specimens: a novel educational tool. AB - INTRODUCTION: During the routine dissection of knee joints in an anatomy dissection hall, it was observed that the specimens had deteriorated overtime, due to their repeated handling and the use of high concentrations of formalin for their fixation. In order to stop their further deterioration, we decided to plastinate these specimens. Thus, the present study was undertaken to prepare plastinated knee specimens from old embalmed cadavers and to compare them with freshly fixed, plastinated specimens. OBJECTIVES: 1. To plastinate old embalmed and fresh formalin fixed knee regions.2. To demonstrate the extra and the intracapsular structures around both the plastinated knee regions.3. To compare their morphological features in terms of their colours, dilatation and flexibility. METHODS: A total of 15 knee joint specimens from among fresh formalin (5-8%) fixed (group I) and old embalmed bodies (group II) were collected, washed and plastinated by using the standard S-10 silicon technique and they were compared for their colours, dilatation and flexibility. RESULTS: All the plastinated specimens showed an accurate reproduction of the tissue details that were comparable to those of the natural unfixed specimens. A comparison among the two groups showed a significant difference in terms of the colour, dilatation and the flexibility of the specimens. The plastinated knee joint specimens from group I were of good quality, with negligible shrinkage, more flexibility and well preserved morphologies. CONCLUSION: Plastinated knee specimens can serve as an excellent educational tool for the undergraduate and postgraduate students of anatomy, radiology and orthopaedics, as they are dry, odourless and nontoxic, with a good structural preservation and a higher instructional value. The fresh knee regions, when they were plastinated, were aesthetically superior in terms of their colours, dilatation and flexibility, thus making them ideal for teaching and hands-on experiences. PMID- 23450711 TI - Voiding dysfunction after repair of giant trigonal vesicovaginal or urethrovesicovaginal fistulae: A need for long-term follow-up. AB - INTRODUCTION: Urodynamic findings of lower urinary tract of women presenting with voiding dysfunction after successful repair of complex trigonal vesicovaginal fistulas at our institute are presented. MATERIALS AND METHODS: In this retrospective case series, women presenting with voiding dysfunction after successful repair of obstetric fistulae were evaluated. In addition of standard clinical evaluation with history and clinical examination, all underwent kidney ureter-bladder ultrasonography, renal function test, urine culture, and multichannel urodynamics. The latter consisted of free uroflowmetry, filling and voiding cystometry. RESULTS: Five women (median age 35 years; range 30-45) presented with difficulty in voiding after the successful repair; two presented within 1 year and 3 after 10 years. The latter three presented with bilateral hydroureteronephrosis; one of these had chronic kidney disease (CKD) grade IV at presentation. Urodynamics (UDS) of all patients revealed poor detrusor compliance (median 11 ml/cm H2O; range 5-22), high-end filling detrusor pressures (median 41 cm H2O; range 11-46) and no detrusor overactivity. All patients attempted voiding with abdominal straining; with little contribution of detrusor contraction (median 6 cm H2O; range 0-9). Two patients could not void during the study, one with Tanagho reconstruction and another with CKD. CONCLUSION: Even after successful repair, patients with complex trigonal or urethra-vesicovaginal fistulae warrant indefinite long-term follow-up for voiding dysfunction in view of possibility of developing poorly compliant bladder. PMID- 23450712 TI - Randomized controlled trial of telephone-delivered cognitive behavioral therapy for chronic insomnia. AB - STUDY OBJECTIVES: To compare the efficacy of telephone-delivered cognitive behavioral therapy for insomnia to an information pamphlet control on sleep and daytime functioning at pretreatment, posttreatment, and 12-wk follow-up. DESIGN: Randomized controlled parallel trial. SETTING: N/A. PARTICIPANTS: Thirty individuals with chronic insomnia (27 women, age 39.1 +/- 14.4 years, insomnia duration 8.7 +/- 10.7 years). INTERVENTIONS: Cognitive behavioral therapy for insomnia (CBTI) delivered in up to eight weekly telephone sessions (CBTI-Phone, n = 15) versus an information pamphlet control (IPC, n = 15). MEASUREMENTS AND RESULTS: Sleep/wake diary, sleep-related questionnaires (Insomnia Severity Index, Pittsburgh Sleep Quality Index, 16-item Dysfunctional Beliefs and Attitudes about Sleep), and daytime symptom assessments (fatigue, depression, anxiety, and quality of life) were completed at pretreatment, posttreatment, and 12-wk follow up. Linear mixed models indicated that sleep/wake diary sleep efficiency and total sleep time improved significantly at posttreatment in both groups and remained stable at 12-wk follow-up. More CBTI-Phone than IPC patients showed posttreatment improvements in unhelpful sleep-related cognitions (P < 0.001) and were classified as "in remission" from insomnia at follow-up (P < 0.05). Posttreatment effect sizes on most daytime symptoms were large (Cohen d = 0.8 2.5) for CBTI-Phone patients and small to moderate (Cohen d = -0.1-0.6) for IPC patients. All CBTI-Phone patients completed posttreatment and 12-wk follow-up assessments, but three IPC patients discontinued the study. CONCLUSIONS: The findings provide preliminary support for telephone-delivered CBTI in the treatment of chronic insomnia. Future larger-scale studies with more diverse samples are warranted. Some individuals with insomnia may also benefit from pamphlet-delivered CBTI with brief telephone support. CITATION: Arnedt JT; Cuddihy L; Swanson LM; Pickett S; Aikens J; Chervin RD. Randomized controlled trial of telephone-delivered cognitive behavioral therapy for chronic insomnia. SLEEP 2013;36(3):353-362. PMID- 23450713 TI - Ventral striatal dopamine synthesis capacity predicts financial extravagance in Parkinson's disease. AB - Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson's disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait "disinhibition" is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[(18)F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders. PMID- 23450715 TI - Thoracodorsal artery perforator fasciocutaneous flap: A versatile alternative for coverage of various soft tissue defects. AB - OBJECTIVE: The thoracodorsal artery perforator (TDAP) flap has contributed to the efficient reconstruction of tissue defects that require a large amount of cutaneous tissue. The optimal reconstruction method should provide thin, and well vascularized tissue with minimal donor-site morbidity. The indications for the use of this particular flap with other flaps are discussed in this article. MATERIALS AND METHODS: Thirteen patients underwent soft tissue reconstruction using TDAP flaps between 2009 and 2011. Of those, there were four cases of antecubital burn contracture, three cases of axillary burn contracture, two cases of giant hair cell nevus of upper extremity, two cases of axillary reconstruction following severe recurrent hidradenitis, and two cases of crush injury. All patients were male and their ages ranged from 20 to 23 (average, 21 years). The mean follow-up period was 8 months (range, 4-22 months). RESULTS: All reconstructive procedures were completed without any major complications. Minor complications related to transfered flaps were wound dehiscence in one case, transient venous congestion in two cases. Minor complication related to the donor site was seroma in one case. The success rate was 100%, with satisfactory cosmetic results. CONCLUSIONS: The TDAP flap is a safe and extremely versatile flap that offers significant advantages in acute and delayed reconstruction. Although the vascular anatomy may be variable, free and pedicled TDAP flap is a versatile alternative for soft tissue defects. It adapts very well to the soft tissue defects with acceptable donor site scar. PMID- 23450716 TI - The efficiency of the serum prostate specific antigen levels in diagnosing prostatic enlargements. AB - BACKGROUND: The objective of this study was to evaluate the serum PSA levels in patients presenting with enlarged prostate and to evaluate the efficiency of serum PSA to diagnose and differentiate benign and malignant enlargements. METHODS: The authors evaluated the patients coming in surgical OPD with enlarged prostate and were advised to undergo serum PSA testing. RESULTS: The efficiency of serum PSA to differentiate Benign and malignant lesions was 97.18% and 83.33% respectively. PMID- 23450714 TI - Development in Aspergillus. AB - The genus Aspergillus represents a diverse group of fungi that are among the most abundant fungi in the world. Germination of a spore can lead to a vegetative mycelium that colonizes a substrate. The hyphae within the mycelium are highly heterogeneous with respect to gene expression, growth, and secretion. Aspergilli can reproduce both asexually and sexually. To this end, conidiophores and ascocarps are produced that form conidia and ascospores, respectively. This review describes the molecular mechanisms underlying growth and development of Aspergillus. PMID- 23450718 TI - Noncovalent tagging proteins with paramagnetic lanthanide complexes for protein study. AB - The site-specific labeling of proteins with paramagnetic lanthanides offers unique opportunities for NMR spectroscopic analysis in structural biology. Herein, we report an interesting way of obtaining paramagnetic structural restraints by employing noncovalent interaction between a lanthanide metal complex, [Ln(L)3](n-) (L=derivative of dipicolinic acid, DPA), and a protein. These complexes formed by lanthanides and DPA derivatives, which have different substitution patterns on the DPA derivatives, produce diverse thermodynamic and paramagnetic properties when interacting with proteins. The binding affinity of [Ln(L)3](n-) with proteins, as well as the determined paramagnetic tensor, are tunable by changing the substituents on the ligands. These noncovalent interactions between [Ln(L)3](n-) and proteins offer great opportunities in the tagging of proteins with paramagnetic lanthanides. We expect that this method will be useful for obtaining multiple angles and distance restraints of proteins in structural biology. PMID- 23450717 TI - Second hand smoke and COPD: lessons from animal studies. AB - Exposure to second hand smoke is a major cause of chronic obstructive pulmonary disease (COPD) in the non-smoker. In this review we explore the use of animal smoke exposure models and their insight into disease pathogenesis. The methods of smoke exposure, including exposure delivery systems, are described. Key findings from the acute and chronic smoke exposure models are outlined, including descriptions of the inflammation processes, proteases involved, oxidative stress, and apoptosis. Finally, alternatives to rodent models of lung disease are presented. PMID- 23450719 TI - Distally based cross-finger flaps for amputation stumps in avulsion amputations. AB - BACKGROUND: Though advances in microsurgery have resulted in better survival rates of replants, replanting crushed and avulsed digits are difficult. If replantation is not possible these digits need local tissue cover to retain length. PATIENTS AND METHODS: Twenty seven patients underwent distally based cross finger flaps for coverage of exposed vital structures over the amputation stumps. RESULTS: All the flaps survived well. They provide good quality thin pliable tissue over the fingertips and help in achieving near normal range of movements in injured digits. CONCLUSION: Distally based cross finger flap gives tissues of right dimensions, at the most desired site, making reconstruction of these difficult problems quiet easy. PMID- 23450720 TI - Occupational health outcomes for workers in the agriculture, forestry and fishing sector: implications for immigrant workers in the southeastern US. AB - BACKGROUND: Workers in the Agriculture, Forestry, and Fisheries (AgFF) sector experience exposures directly related to the work itself, as well as the physical environment in which the work occurs. Health outcomes vary from immediate to delayed, and from acute to chronic. METHODS: We reviewed existing literature on the health outcomes of work in the AgFF sector and identified areas where further research is needed to understand the impact of these exposures on immigrant Latino workers in the southeastern US. RESULTS: Outcomes related to specific body systems (e.g., musculoskeletal, respiratory) as well as particular exposure sources (e.g., pesticides, noise) were reviewed. The most extensive evidence exists for agriculture, with a particular focus on chemical exposures. Little research in the southeastern US has examined health outcomes of exposures of immigrant workers in forestry or fisheries. CONCLUSION: As the AgFF labor force includes a growing number of Latino immigrants, more research is needed to characterize a broad range of exposures and health outcomes experienced by this population, particularly in forestry and fisheries. PMID- 23450721 TI - Reply to Letter: Identical twins with leucine rich repeat kinase type 2 mutations discordant for Parkinson's disease. PMID- 23450722 TI - Determination of heavy metal content and lipid profiles in mussel extracts from two sites on the moroccan atlantic coast and evaluation of their biological activities on MIN6 pancreatic cells. AB - Mussels may concentrate pollutants, with possibly significant side effects on human health. Therefore, mussels (Mytilus galloprovincialis) from two sites of the Moroccan Atlantic coast (Jorf Lasfar [JL], an industrial site, and Oualidia [OL], a vegetable-growing area), were subjected to biochemical analyses to quantify the presence of heavy metals (Cd, Cr, and Pb) and to establish the lipid profile: fatty acid, cholesterol, oxysterol, phytosterol and phospholipid content. In addition, mussel lipid extracts known to accumulate numerous toxic components were tested on murine pancreatic beta-cells (MIN6), and their biological activities were measured with various flow cytometric and biochemical methods to determine their impacts on cell death induction, organelle dysfunctions (mitochondria, lysosomes, and peroxisomes), oxidative stress and insulin secretion. The characteristics of JL and OL lipid extracts were compared with those of commercially available mussels from Spain (SP) used for human consumption. OL and JL contained heavy metals, high amounts of phospholipids, and high levels of oxysterols; the [(unsaturated fatty acids)/(saturated fatty acids)] ratio, which can be considered a sign of environmental stress leading to lipid peroxidation, was low. On MIN6 cells, JL and OL lipid extracts were able to trigger cell death. This event was associated with overproduction of H2 O2 , increased catalase activity, a decreased GSH level, lipid peroxidation and stimulation of insulin secretion. These effects were not observed with SP lipid extracts. These data suggest that some components from OL and JL lipid extracts might predispose to pancreatic dysfunctions. Epidemiological studies would be needed to assess the global risk on human health and the metabolic disease incidence in a context of regular seafood consumption from the OL and JL areas. PMID- 23450723 TI - Anticholinergic agents result in weaker and shorter suppression of uterine contractility compared with intestinal motion: time course observation with cine MRI. AB - PURPOSE: To evaluate the time course effects of anticholinergic agents on uterine contractility and intestinal motion with cine magnetic resonance imaging (MRI). MATERIALS AND METHODS: Using a 1.5 T MRI scanner, 60 T2-weighted half-Fourier rapid acquisitions with relaxation enhancement images of the uterus were serially acquired over 3 minutes in 25 healthy women in the periovulatory phase, at four instances, prior to and 2-5, 5-8, and 10-13 minutes after intravenous injection of 20 mg of hyoscine butylbromide. Uterine peristalsis frequency (waves / 3 min) and degrees of endometrial transformation, subendometrial conduction, outer myometrial conduction, sporadic myometrial contraction, and intestinal movement were independently evaluated by three readers. RESULTS: Uterine peristalsis frequency of 6.14 +/- 2.34 decreased the most at 2-5 minutes (P < 0.001) by 1.41 (95% confidential interval [CI] = 0.59-2.22), or 23.0% ([6.14-4.73]/6.14) and remained reduced at 5-8 minutes (P = 0.013) by 0.97 (95% CI = 0.15-1.78), or 15.8% ([6.14-5.17]/6.14) after injection. The degree of intestinal movement was 3.32 +/- 0.54 and was prominently reduced at every phase (P < 0.001 for all) and maximally decreased to 0.67 +/- 0.65 at 5-8 min. It increased to 1.36 +/- 0.72 at 10-13 minutes compared with the degrees of motion at 2-5 minutes (P = 0.04) and 5 8 minutes (P = 0.004). CONCLUSION: Suppression of uterine peristalsis was weaker and shorter compared with the stronger and longer suppression of intestinal movement by the intravenous administration of anticholinergic agents. PMID- 23450724 TI - Catalytic disproportionation of formic acid to generate methanol. PMID- 23450725 TI - Susceptibility to childhood-onset rheumatoid arthritis: investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci. AB - OBJECTIVE: Children with childhood-onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. To test the hypothesis that adult-onset RA-associated variants are also associated with childhood-onset RA, we investigated RA associated variants at 5 loci in a cohort of patients with childhood-onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood-onset RA using a weighted genetic risk score (wGRS). METHODS: A total of 155 children with childhood-onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood-onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood-onset RA. RESULTS: Childhood-onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44-0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11-2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06 1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 * 10(-16) ). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood onset RA, especially among males. CONCLUSION: The magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood-onset RA are similar to those observed in RA, suggesting that adult-onset RA and childhood onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA-associated variants with susceptibility to childhood-onset RA. PMID- 23450726 TI - Saponins extracted from by-product of Asparagus officinalis L. suppress tumour cell migration and invasion through targeting Rho GTPase signalling pathway. AB - BACKGROUND: The inedible bottom part (~30-40%) of asparagus (Asparagus officinalis L.) spears is usually discarded as waste. However, since this by product has been reported to be rich in many bioactive phytochemicals, it might be utilisable as a supplement in foods or natural drugs for its therapeutic effects. In this study it was identifed that saponins from old stems of asparagus (SSA) exerted potential inhibitory activity on tumour growth and metastasis. RESULTS: SSA suppressed cell viability of breast, colon and pancreatic cancers in a concentration-dependent manner, with half-maximum inhibitory concentrations ranging from 809.42 to 1829.96 ug mL(-1). However, SSA was more functional in blocking cell migration and invasion as compared with its cytotoxic effect, with an effective inhibitory concentration of 400 ug mL(-1). A mechanistic study showed that SSA markedly increased the activities of Cdc42 and Rac1 and decreased the activity of RhoA in cancer cells. CONCLUSION: SSA inhibits tumour cell motility through modulating the Rho GTPase signalling pathway, suggesting a promising use of SSA as a supplement in healthcare foods and natural drugs for cancer prevention and treatment. PMID- 23450728 TI - Steric control in the pi-dimerization of oligothiophene radical cations annelated with bicyclo[2.2.2]octene units. AB - A Two series of oligothiophenes 2(nT) (n=4,5), annelated with bicyclo[2.2.2]octene (BCO) units at both ends, and quaterthiophenes 3 a-c, annelated with various numbers of BCO units at different positions, were newly synthesized to investigate the driving forces of pi-dimerization and the structure-property relationships of the pi-dimers of oligothiophene radical cations. Their radical-cation salts were prepared through chemical one-electron oxidation by using nitrosonium hexafluoroantimonate. From variable-temperature electron spin resonance and electronic absorption measurements, the pi dimerization capability was found to vary among the members of the 2(nT)(+)(.)SbF6(-) series and 3(+)(.)SbF6(-) series of compounds. To examine these results, density functional theory (DFT) calculations at the M06-2X/6 31G(d) level were conducted for the pi-dimers. This level of theory was found to successfully reproduce the previously reported X-ray structure of (2(3T))2(2+) having a bent pi-dimer structure with cis-cis conformations. The absorption bands obtained by time-dependent DFT calculations for the pi-dimers were in reasonable agreement with the experimental spectra. The attractive and repulsive forces for the pi-dimerization were divided into four factors: 1) SOMO-SOMO interactions, 2) van der Waals forces, 3) solvation, and 4) Coulomb repulsion, and the effects of each factor on the structural differences and chain-length dependence are discussed in detail. PMID- 23450727 TI - Evaluating the influence of selection markers on obtaining selected pools and stable cell lines in human cells. AB - Selection markers are common genetic elements used in recombinant cell line development. While several selection systems exist for use in mammalian cell lines, no previous study has comprehensively evaluated their performance in the isolation of recombinant populations and cell lines. Here we examine four antibiotics, hygromycin B, neomycin, puromycin, and ZeocinTM, and their corresponding selector genes, using a green fluorescent protein (GFP) as a reporter in two model cell lines, HT1080 and HEK293. We identify ZeocinTM as the best selection agent for cell line development in human cells. In comparison to the other selection systems, ZeocinTM is able to identify populations with higher fluorescence levels, which in turn leads to the isolation of better clonal populations and less false positives. Furthermore, ZeocinTM-resistant populations exhibit better transgene stability in the absence of selection pressure compared to other selection agents. All isolated ZeocinTM-resistant clones, regardless of cell type, exhibited GFP expression. By comparison, only 79% of hygromycin B resistant, 47% of neomycin-resistant, and 14% of puromycin-resistant clones expressed GFP. Based on these results, we rank ZeocinTM > hygromycin B ~ puromycin > neomycin for cell line development in human cells. Furthermore, this study demonstrates that selection marker choice does indeed impact cell line development. PMID- 23450729 TI - Assessment of work-related exposure to polycyclic aromatic hydrocarbons in Italy. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are generally present in the workplace environment as complex mixtures and often difficult to identify a priori. OBJECTIVES: The aim of this study is to evaluate the level and coverage of occupational exposure to PAHs in Italy. METHODS: Data were collected from exposure registries of companies with mandatory reporting to the National Workers' Compensation Authority. Statistical analyses were carried out on the retrieved information and the number of workers potentially exposed was estimated for some industrial sectors. RESULTS: Overall 12,849 measurements of exposure levels to individual PAHs were selected from the database of registries in the period 1996-2010. Most exposures occurred in the manufacture of chemicals (N = 5,383, 51%), and the occupational group most frequently measured was chemical processing-plant operator (N = 3,930, 31%). Measurements were associated to various PAHs, including benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, dibenz[a,h]anthracene, and benzo[j]fluoranthene. Overall, 39,230 workers were estimated as potentially at risk of exposure to PAHs in the selected industrial sectors. CONCLUSIONS: This study summarized data recorded in the Italian occupational exposure database and identified specific exposure patterns to PAHs. The systematic recording of occupational exposures is a source of data that allows the recognition, control, and prevention of high-risk situations for workers' health. PMID- 23450730 TI - Quantitative tractography and tract shape modeling in amyotrophic lateral sclerosis. AB - PURPOSE: To investigate brain-wide white matter structural changes associated with amyotrophic lateral sclerosis (ALS) using an automatic single seed point tractography-based segmentation method, probabilistic neighborhood tractography (PNT), which provides quantitative measures of both tract integrity and shape. MATERIALS AND METHODS: Diffusion MRI data were acquired from 30 patients with ALS (ALS Functional Rating Scale-Revised score > 20) and 30 matched controls. PNT was used to segment 12 major projection, commissural and association fibers, and assess differences in how the shape of an individual subject's tract compares to that of a predefined reference tract, in addition to providing tract-average mean diffusivity () and fractional anisotropy (FA) data. RESULTS: Across all 12 tracts, group-averaged was larger, while group-averaged FA was equal to or smaller in value for patients than controls. These differences were significant for right cingulum , and left and right corticospinal tract (CST) and FA (P-values 6 * 10(-5) to 0.03). Tract shape modeling indicated that there were significantly greater topological differences from the reference tract in left and right CST, and right uncinate fasciculus (P-values 0.02 to 0.04) for patients than controls. The rate of disease progression was significantly negatively correlated with bilateral CST FA (P-values 0.01 to 0.02). CONCLUSION: ALS, although particularly affecting CST, is associated with subtle changes in white matter tract integrity and shape in several other major fibers within the brain. Correlations between CST integrity and disease progression rate suggest that quantitative tractography may provide useful biomarkers of disease evolution in ALS. PMID- 23450731 TI - Calcium-catalyzed cyclopropanation. PMID- 23450732 TI - Fusarium graminearum and Its Interactions with Cereal Heads: Studies in the Proteomics Era. AB - The ascomycete fungal pathogen Fusarium graminearum (teleomorph stage: Gibberella zeae) is the causal agent of Fusarium head blight in wheat and barley. This disease leads to significant losses of crop yield, and especially quality through the contamination by diverse fungal mycotoxins, which constitute a significant threat to the health of humans and animals. In recent years, high-throughput proteomics, aiming at identifying a broad spectrum of proteins with a potential role in the pathogenicity and host resistance, has become a very useful tool in plant-fungus interaction research. In this review, we describe the progress in proteomics applications toward a better understanding of F. graminearum pathogenesis, virulence, and host defense mechanisms. The contribution of proteomics to the development of crop protection strategies against this pathogen is also discussed briefly. PMID- 23450733 TI - A host-plant-derived volatile blend to attract the apple blossom weevil Anthonomus pomorum - the essential volatiles include a repellent constituent. AB - BACKGROUND: Plant volatiles are promising cues for trapping pest insects. This study started with a recently identified complex blend released by prebloom apple trees and aimed to reduce the number of compounds in the blend while maintaining the attraction of the target pest, the apple blossom weevil Anthonomus pomorum. An evaluation was made to determine whether attraction to plant volatiles is a general feature in this species. RESULTS: Laboratory-based bioassays with field collected weevils demonstrated repellency by volatiles from the non-host walnut, indicating that preference for plant odours is not a general feature in this species. By a subtractive bioassay approach, the original number of compounds in the apple-plant-released blend was stepwise reduced from 12 to 6 while maintaining weevil attraction. This resulting blend was as attractive as the full blend and as a blossom-bud-carrying apple twig. It was found to be composed of two synergistically interacting constituents, of which the first containing benzenoids was behaviourally inactive, and the second comprising the remaining compounds was even repellent. CONCLUSIONS: This study enhances knowledge of the interaction of behaviourally effective constituents in complex odour blends and contributes to the development of an efficient monitoring system involving plant volatiles for the apple blossom weevil. PMID- 23450734 TI - Sarcoptic mange: a zoonotic ectoparasitic skin disease. AB - A 56-year old man attended the Dermatology Outpatients Department with the complaint of a localized, extremely itchy, erythematous papular lesion of acute onset on the ventral aspect of the right thigh. The patient was referred to the Microbiology Lab for the microscopic detection of the fungal elements. The KOH mount from the skin scrapings showed no fungal elements, but it showed the mites of Sarcopetes scabiei mange. The Sarcoptic Mange is noteworthy because of the fact that it is a zoonotic disease which can easily be passed on to humans. A close contact with infested pet dogs was considered as the main predisposing factor in this case. The response to the antiscabietic treatment was dramatic. PMID- 23450736 TI - Positive and negative impacts of specialty malts on beer foam: a comparison of various cereal products for their foaming properties. AB - BACKGROUND: The foam stability of beer is dependent on the presence of foam stabilizing polypeptides derived from the cereals from which it is made. It has long been argued that there is a tendency to boost the foam-stabilizing capabilities of these polypeptides at the heating stages involved in the production of the grist materials. The present study started with the intent to confirm whether these changes occurred and to assess the extent to which different cereal products differed in their foam-stabilizing tendencies. RESULTS: Cereal products differ enormously in their foam-stabilizing capabilities. Heavily roasted grains, notably black malt and roast barley, do have superior foaming properties. However, certain specialty malts, notably crystal malts, display inferior foam performance. The observed foaming pattern is a balance between their content of foam-positive and foam-negative components. Products such as pale malt do contain foam-negative materials but have a net balance in favour of foam-stabilizing entities. By contrast, wheat malt and especially black malt have a heavy preponderance of foam-positive components. Crystal malt displays the converse behaviour: it contains low-molecular-weight foam-negative species. Several of the cereal products appear to contain higher-molecular-weight foam inhibitors, but it appears that they are merely species that are of inherently inferior foam-stabilizing capability to the foaming polypeptides from egg white that were employed to probe the system. The foam-damaging species derived from crystal malt carried through to beers brewed from them. CONCLUSION: Intense heating in the production of cereal products does lead to enhanced foam performance in extracts of those products. However, not all speciality malts display superior foam performance, through their development of foam-negative species of lower molecular weight. PMID- 23450735 TI - How cholesterol interacts with membrane proteins: an exploration of cholesterol binding sites including CRAC, CARC, and tilted domains. AB - The plasma membrane of eukaryotic cells contains several types of lipids displaying high biochemical variability in both their apolar moiety (e.g., the acyl chain of glycerolipids) and their polar head (e.g., the sugar structure of glycosphingolipids). Among these lipids, cholesterol is unique because its biochemical variability is almost exclusively restricted to the oxidation of its polar -OH group. Although generally considered the most rigid membrane lipid, cholesterol can adopt a broad range of conformations due to the flexibility of its isooctyl chain linked to the polycyclic sterane backbone. Moreover, cholesterol is an asymmetric molecule displaying a planar alpha face and a rough beta face. Overall, these structural features open up a number of possible interactions between cholesterol and membrane lipids and proteins, consistent with the prominent regulatory functions that this unique lipid exerts on membrane components. The aim of this review is to describe how cholesterol interacts with membrane lipids and proteins at the molecular/atomic scale, with special emphasis on transmembrane domains of proteins containing either the consensus cholesterol binding motifs CRAC and CARC or a tilted peptide. Despite their broad structural diversity, all these domains bind cholesterol through common molecular mechanisms, leading to the identification of a subset of amino acid residues that are overrepresented in both linear and three-dimensional membrane cholesterol binding sites. PMID- 23450737 TI - A microbial-mineralization approach for syntheses of iron oxides with a high specific surface area. AB - Of minerals and microbes: A microbial-mineralization-inspired approach was used to facilitate the syntheses of iron oxides with a high specific surface area, such as 253 m(2)g(-1) for maghemite (gamma-Fe(2)O(3)) and 148 m(2)g(-1) for hematite (alpha-Fe(2)O(3)). These iron oxides can be applied to electrode material of lithium-ion batteries, adsorbents, and catalysts. PMID- 23450738 TI - Creation of a synthetic indicator of quality of care as a clinical management standard in primary care. AB - INTRODUCTION: The development of electronic medical records has allowed the creation of new quality indicators in healthcare. Among them, synthetic indicators facilitate global interpretation of results and comparisons between professionals. METHODS: A healthcare quality standard (EQA, the Catalan acronym for Estandard de Qualitat Assistencial) was constructed to serve as a synthetic indicator to measure the quality of care provided by primary care professionals in Catalonia (Spain). The project phases were to establish the reference population; select health problems to be included; define, select and deliberate about subindicators; and construct and publish the EQA. RESULTS: Construction of the EQA involved 107 healthcare professionals, and 91 health problems were included. In addition, 133 experts were consulted, who proposed a total of 339 indicators. After systematic paired comparison, 61 indicators were selected to create the synthetic indicator. The EQA is now calculated on a monthly basis for more than 8000 healthcare professionals using an automated process that extracts data from electronic medical records; results are published on a follow-up website. Along with the use of the online EQA results tool, there has been an ongoing improvement in most of the quality of care indicators. CONCLUSIONS: Creation of the EQA has proven to be useful for the measurement of the quality of care of primary care services. Also an improvement trend over 5 years is shown across most of the measured indicators. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-1801-2-51) contains supplementary material, which is available to authorized users. PMID- 23450739 TI - European studies on the prevalence of dementia in the elderly: time for a step towards a methodological consensus. AB - OBJECTIVE: The aim of this study was to discuss methodological limitations in studies on the prevalence of dementia across European countries with particular attention to post-EURODEM studies. METHODS: Two people independently focused on an iterative literature search for studies published in the years 2000-2012 using the following keywords: 'dementia', 'Alzheimer', 'incidence', 'prevalence' that were cross-linked with names of European countries. After that, the results obtained were compared and publications in English were included in a subsequent analysis. RESULTS: We included 26 studies published in the years 2000-2012. The majority of epidemiological studies come from Spain and Italy. The past decade has not provided prevalence rates from a considerable number of countries. There is also a lack of nationwide surveys on the prevalence of dementia. Predominantly, epidemiological studies on the prevalence of dementia follow a two stage approach that consists of a screening phase and a subsequent confirmation of dementia. However, several differences, particularly with regard to the neuropsychological instruments used, still exist and contribute to inconsistent prevalence rates. CONCLUSIONS: Although the EURODEM study was a milestone in the epidemiology of dementia in Europe and provided several future directions for research, methodological limitations are apparent in a number of European studies on the prevalence of dementia and require particular attention. In particular, a variety of diagnostic instruments requires unification for future studies. On the other hand, given the lack of epidemiological studies from a number of countries and the increasing prevalence of dementia, the need for population-based surveys should be emphasized. PMID- 23450740 TI - Functional reconstruction of complex tendo Achilles defect by free latissimus dorsi muscle flap. AB - Managing the complex tendo Achilles defect involves reconstructing the Achilles tendon as well as providing soft tissue cover to the heel area. The advent of microsurgery has revolutionised the reconstruction of this difficult defect providing a number of options to the reconstructive surgeon. We present a case of complex tendo Achilles defect reconstructed by the latissimus dorsi free flap. PMID- 23450741 TI - Comparative binding energy COMBINE analysis for understanding the binding determinants of type II dehydroquinase inhibitors. AB - Herein we report comparative binding energy (COMBINE) analyses to derive quantitative structure-activity relationship (QSAR) models that help rationalize the determinants of binding affinity for inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway. Independent COMBINE models were derived for Helicobacter pylori and Mycobacterium tuberculosis DHQ2, which is an essential enzyme in both these pathogenic bacteria that has no counterpart in human cells. These studies quantify the importance of the hydrogen bonding interactions between the ligands and the water molecule involved in the DHQ2 reaction mechanism. They also highlight important differences in the ligand interactions with the interface pocket close to the active site that could provide guides for future inhibitor design. PMID- 23450742 TI - Overview of immigrant worker occupational health and safety for the agriculture, forestry, and fishing (AgFF) sector in the southeastern United States. AB - BACKGROUND: Manual labor in the Agriculture, Forestry, and Fishing (AgFF) Sector is provided primarily by immigrant workers. Limited information is available that documents the demographic characteristics of these manual workers, the occupational illnesses, injuries and fatalities they experience; or the risk factors to which they are exposed. METHODS: A working conference of experts on occupational health in the AgFF Sector was held to address information limitations. This paper provides an overview of the conference. Other reports address organization of work, health outcomes, healthcare access, and safety policy. CONTENTS: This report addresses how best to define the population and the AgFF Sector, occupational exposures for the sector, data limitations, characteristics of immigrant workers, reasons for concern for immigrant workers in the AgFF Sector, regulations, a conceptual model for occupational health, and directions for research and intervention. PMID- 23450744 TI - Disgust and contamination: a cross-national comparison of ghana and the United States. AB - The emotion of disgust, with feelings of revulsion and behavioral withdrawal, make it a prime emotion to aid in the avoidance of sources of contamination, including sources of potential infectious disease. We tested the theory that living in a region with a historically high prevalence of infectious diseases would promote higher levels of disgust and contamination sensitivity as a protective measure. A sample of undergraduates from Ghana (n = 103, 57 women), a country with a historically high prevalence of infectious diseases, showed significantly higher scores on scales assessing disgust, contamination, and disease susceptibility than a sample of undergraduates from the United States (n = 96, 58 women), a country with lower levels of disease threat. Contamination sensitivity mediated the national differences in disgust. Disgust connoting contamination also produced larger cross-national effect sizes than other types of disgust. Finally, a factor analysis on the Ghanaian responses to one of the disgust scales did not resemble the usual three-factor solution found in West. Taken together, the results were consistent with the hypothesis that a region with a higher prevalence of infectious disease threats would produce greater sensitivity to disgust and contamination than seen in lower disease threat regions. This first study on disgust in Africa showed that disgust sensitivity could differ considerably from that in the West. PMID- 23450743 TI - Cell and neuron densities in the primary motor cortex of primates. AB - Cell and neuron densities vary across the cortical sheet in a predictable manner across different primate species (Collins et al., 2010b). Primary motor cortex, M1, is characterized by lower neuron densities relative to other cortical areas. M1 contains a motor representation map of contralateral body parts from tail to tongue in a mediolateral sequence. Different functional movement representations within M1 likely require specialized microcircuitry for control of different body parts, and these differences in circuitry may be reflected by variation in cell and neuron densities. Here we determined cell and neuron densities for multiple sub-regions of M1 in six primate species, using the semi-automated flow fractionator method. The results verify previous reports of lower overall neuron densities in M1 compared to other parts of cortex in the six primate species examined. The most lateral regions of M1 that correspond to face and hand movement representations, are more neuron dense relative to medial locations in M1, which suggests differences in cortical circuitry within movement zones. PMID- 23450745 TI - Cytosolic streaming in vegetative mycelium and aerial structures of Aspergillus niger. AB - Aspergillus niger forms aerial hyphae and conidiophores after a period of vegetative growth. The hyphae within the mycelium of A. niger are divided by septa. The central pore in these septa allows for cytoplasmic streaming. Here, we studied inter- and intra-compartmental streaming of the reporter protein GFP in A. niger. Expression of the gene encoding nuclear targeted GFP from the gpdA or glaA promoter resulted in strong fluorescence of nuclei within the vegetative hyphae and weak fluorescence in nuclei within the aerial structures. These data and nuclear run on experiments showed that gpdA and glaA are higher expressed in the vegetative mycelium when compared to aerial hyphae, conidiophores and conidia. Notably, gpdA or glaA driven expression of the gene encoding cytosolic GFP resulted in strongly fluorescent vegetative hyphae and aerial structures. Apparently, GFP streams from vegetative hyphae into aerial structures. This was confirmed by monitoring fluorescence of photo-activatable GFP (PA-GFP). In contrast, PA-GFP did not stream from aerial structures to vegetative hyphae. Streaming of PA-GFP within vegetative hyphae or within aerial structures of A. niger occurred at a rate of 10-15 MUm s(-1). Taken together, these results not only show that GFP streams from the vegetative mycelium to aerial structures but it also indicates that its encoding RNA is not streaming. Absence of RNA streaming would explain why distinct RNA profiles were found in aerial structures and the vegetative mycelium by nuclear run on analysis and micro-array analysis. PMID- 23450746 TI - Cephalic vein: Saviour in the microsurgical reconstruction of breast and head and neck cancers. AB - BACKGROUND: Reconstruction with microvascular free flaps is considered the reconstructive option of choice in cancer of the head and neck regions and breast. Rarely, there is paucity of vessels, especially the veins, at the recipient site. The cephalic vein with its good caliber and constant anatomy is a reliable recipient vein available in such situations. MATERIALS AND METHODS: It is a retrospective study from January 2010 to July 2012 and includes 26 patients in whom cephalic vein was used for free-flap reconstruction in head and neck (3 cases) and breast cancers (23 cases). RESULTS: All flaps in which cephalic vein was used survived completely. CONCLUSION: Cephalic vein can be considered as a reliable source of venous drainage when there is a non-availability/unusable of veins during free-flap reconstruction in the head and neck region and breast and also when additional source of venous drainage is required in these cases. PMID- 23450748 TI - The influence of misclassification bias on the reported rates of congenital anomalies on the birth certificates for West Virginia--a consequence of an open ended query. AB - BACKGROUND: Passive surveillance for congenital anomalies using birth certificates are generally considered to have biased reporting, though the sources of those biases are not well-known nor controlled for. We have analyzed the congenital anomaly reporting data for 418,385 live births in West Virginia (1990-2009) from the 1989 US standard birth certificate and have newly identified a particular source of bias. METHODS: Congenital anomaly prevalence rates per 100 live births have been determined for both specified birth defects and for other congenital anomalies by county, by hospital, and by year. Extreme outliers were identified by z score. Text strings for "other congenital anomaly" reports recorded for 1998-2009 were assessed for information on congenital anomalies. RESULTS: While rates for specified birth defects reported in checked-box format showed little variation, rates for "other congenital anomaly" collected in open ended format showed much variation. Nearly half of the "other congenital anomaly" reports were for neonatal conditions rather than for major structural congenital anomalies. This misclassification alone had elevated the state-wide congenital anomaly reporting rate from 1.1 to 1.8% of live births. Geographic clustering and a temporal bulge in congenital anomaly reports disappeared after misclassified data were removed. CONCLUSIONS: Data collected in checked-box format on specified birth defects showed consistent patterns over time and space, while data collected in open-ended format on "other congenital anomalies" showed an epidemiological pattern reflecting neonatal conditions rather than birth defects. The 2003 US standard birth certificate wisely limits data collection to specified birth defects using the checked-box format. PMID- 23450747 TI - Markedly increased volume of distribution of gadolinium in cardiac amyloidosis demonstrated by T1 mapping. AB - PURPOSE: To perform myocardial T1 mapping pre- and post-gadolinium (Gd) administration and determine the volume of distribution of Gd (VdGd ) in patients with cardiac amyloidosis to assess extracellular space expansion from amyloid protein deposition. MATERIALS AND METHODS: T1 mapping was performed before contrast and 20 minutes following bolus administration of 0.15 mmol/kg of gadopentetate dimeglumine (Magnevist) in five subjects with cardiac amyloidosis and in eight healthy volunteers using previously validated 3-5 Modified Look Locker Inversion (MOLLI) pulse sequence. The partition coefficient (lambda) and VdGd were determined and compared between groups. RESULTS: Before contrast the T1 of the blood and myocardium are longer in amyloidosis as compared to controls (1665 vs. 1509 msec; P = 0.03 and 1144 vs. 963 msec; P < 0.001, respectively). Postcontrast blood T1 was also significantly longer in amyloidosis (486 vs. 408 msec; P = 0.003) with a trend towards shorter T1 in the myocardium (503 vs. 544 msec; P = 0.15). The VdGd was 83% higher in amyloidosis than in controls (0.51 vs. 0.28; P = 0.005). CONCLUSION: Myocardial VdGd is markedly increased in cardiac amyloidosis, reflecting the increased extracellular space occupied by amyloid proteins. The precontrast T1 of blood and myocardium are increased in amyloidosis extending diagnostic utility in patients who cannot receive Gd. PMID- 23450749 TI - Long-term efficacy of a program to prevent beryllium disease. AB - BACKGROUND: In 2000, a manufacturer of beryllium materials and products introduced a comprehensive program to prevent beryllium sensitization and chronic beryllium disease (CBD). We assessed the program's efficacy in preventing sensitization 9 years after implementation. METHODS: Current and former workers hired since program implementation completed questionnaires and provided blood samples for the beryllium lymphocyte proliferation test (BeLPT). Using these data, as well as company medical surveillance data, we estimated beryllium sensitization prevalence. RESULTS: Cross-sectional prevalence of sensitization was 0.7% (2/298). Combining survey results with surveillance results, a total of seven were identified as sensitized (2.3%). Early Program workers were more likely to be sensitized than Late Program workers; one of the latter was newly identified. All sensitization was identified while participants were employed. One worker was diagnosed with CBD during employment. CONCLUSIONS: The combination of increased respiratory and dermal protection, enclosure and improved ventilation of high-risk processes, dust migration control, improved housekeeping, and worker and management education showed utility in reducing sensitization in the program's first 9 years. The low rate (0.6%, 1/175) among Late Program workers suggests that continuing refinements have provided additional protection against sensitization compared to the program's early years. PMID- 23450750 TI - Substituent effect of bis(pyridines)iodonium complexes as iodinating reagents: control of the iodocyclization/oxidation process. PMID- 23450751 TI - Probing slow chemical exchange at carbonyl sites in proteins by chemical exchange saturation transfer NMR spectroscopy. PMID- 23450752 TI - Enantiomeric separation of racemic 4-aryl-1,4-dihydropyridines and 4-aryl-1,2,3,4 tetrahydropyrimidines on a chiral tetraproline stationary phase. AB - The chromatographic chiral resolution of 4-aryl-1,4-dihydropyridines (1-32), 4 aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38), and 4-aryl-2-oxo-1,2,3,4 tetrahydropyrimidines (39-41) was studied on a tetraproline-immobilized chiral column synthesized in our lab. This tetraproline chiral stationary phase can resolve most of these compounds. The 4-aryl-2-thioxo-1,2,3,4 tetrahydropyrimidines (33-38) and 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39 41) were more efficiently resolved than the racemic 4-aryl-1,4-dihydropyridines on the tetraproline chiralstationary phase. Analytes with 5,5-dimethyl groups (39 41) were less efficiently resolved than analytes without 5,5-dimethyl substituents (1-16). The 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) without a sulfur atom were much more efficiently resolved than 4-aryl-2-thioxo 1,2,3,4-tetrahydropyrimidines (33-38). No obvious electronic effects on the resolution of any of these analytes (1-41) were observed on the tetraproline chiral stationary phase. The tetraproline chiral stationary phase separated enantiomers mainly via hydrogen bonding interactions. PMID- 23450753 TI - Infections in hospitalized children and young adults with acute leukemia in Morocco. AB - BACKGROUND: Overall survival from leukemia is less in low and middle-income countries than in high-income countries. Our purpose was to describe the incidence, clinical features, and mortality of febrile illness with or without documented infection in children and young adults treated for AML and ALL in two centers in Rabat and Casablanca during 2011. METHODS: This retrospective cohort study included patients <30 years of age who were newly diagnosed with AML and ALL in 2011 in Casablanca and Rabat. Each patient's chart was evaluated for patient demographics, febrile episodes, chemotherapy regimen, and clinical or microbiological evidence of infection, neutropenia, antibiotics, and mortality. RESULTS: One hundred sixty-six evaluable patients had 228 inpatient febrile episodes. The median number of febrile episodes in AML was three per patient, and for ALL, one per patient. Clinically identified infections mainly included pneumonitis and mucositis. Coagulase negative staphylococcus was the most commonly isolated bacterium, followed by gram-negative bacteria. Fifty-three percent of febrile episodes were classified as fever of undetermined origin. Broad-spectrum antibiotics were routinely used, with the addition of antifungals in 62 episodes and vancomycin in 83 episodes. The rate of deaths per febrile illness was 11.3% (16/141) in patients with AML, and 9.2% (8/87) in patients with ALL. CONCLUSION: The higher rate of infectious deaths in leukemia compared to that reported in high-income countries, suggests that improvements in infection care and prevention, including consistent access to rapid hospitalization, diagnostics and antibiotics; and standardizing quality of patient care are necessary to improve as well as survival in patients with leukemia in Morocco. PMID- 23450754 TI - Reproductive impacts of tributyltin (TBT) and triphenyltin (TPT) in the hermaphroditic freshwater gastropod Lymnaea stagnalis. AB - Tributyltin (TBT) and triphenyltin (TPT) are emblematic endocrine disruptors, which have been mostly studied in gonochoric prosobranchs. Although both compounds can simultaneously occur in the environment, they have mainly been tested separately for their effects on snail reproduction. Because large discrepancies in experimental conditions occurred in these tests, the present study aimed to compare the relative toxicity of TBT and TPT under similar laboratory conditions in the range of 0 ng Sn/L to 600 ng Sn/L. Tests were performed on the simultaneous hermaphrodite Lymnaea stagnalis, a freshwater snail in which effects of TPT were unknown. Survival, shell length, and reproduction were monitored in a 21-d semistatic test. Frequency of abnormal eggs was assessed as an additional endpoint. Triphenyltin hampered survival while TBT did not. Major effects on shell solidity and reproduction were observed for both compounds, reproductive outputs being more severely hampered by TBT than by TPT. Considering the frequency of abnormal eggs allowed increasing test sensitivity, because snail responses to TBT could be detected at concentrations as low as 19 ng Sn/L. However, the putative mode of action of the 2 compounds could not be deduced from the structure of the molecules or from the response of apical endpoints. Sensitivity of L. stagnalis to TBT and TPT was compared with the sensitivity of prosobranch mollusks with different habitats and different reproductive strategies. PMID- 23450755 TI - Performance of wood-rotting fungi-based enzymes on enzymic saccharification of rice straw. AB - BACKGROUND: For effective saccharification of rice straw we focused on enzyme preparations from wood-rotting fungi that have the ability to degrade cell wall polysaccharides and lignin. We tested extracellular enzyme preparations from 14 species of fungi for saccharification activity and examined the factor for saccharification by statistical analysis. RESULTS: An enzyme preparation from Schizophyllum commune had the highest saccharification activity of rice straw. This preparation contained highly active endo-beta-xylanase, endo-beta-glucanase (CMCase), beta-d-glucosidase and acetylxylan esterase. Correlation analysis of the 14 enzyme preparations demonstrated that acetylxylan esterase was closely related to saccharification activity in rice straw. Multiple regression analysis also showed that acetylxylan esterase had an important role in saccharification. Ligninolytic enzymes, which are characteristic of white-rot fungi, did not contribute to saccharification activity of rice straw. CONCLUSION: Deacetylation is an essential factor for saccharification of rice straw and enzyme preparations for saccharification need to contain highly active acetylxylan esterase as well as highly active cellulolytic and xylanolytic enzymes, but not ligninolytic ones. PMID- 23450756 TI - Ultrastructure of the bullfrog (Lithobates catesbeianus-Shaw, 1802) oviduct in different seasons. AB - The bullfrog (Lithobates catesbeianus) is an exotic animal that adapted perfectly to the climatic conditions of Brazil after introduction in the country. These climatic conditions favor the reproduction and fattening of bullfrogs. However, the development of the bullfrog is significantly reduced in colder regions because low temperatures affect the secretion of gonadotropins and change the sensitivity of the germinal epithelium to gonadotropic hormones. Thus, the temperature and photoperiod are abiotic factors that influence the life cycle of this species, especially with regard to reproduction. Samples from different regions of the oviducts (the infundibulum, magnum, and isthmus) of 9 bullfrogs were collected in the different seasons of the year. The samples were fixed and processed for analysis with scanning and transmission electron microscopy. A comparison of the morphology of the oviducts collected during different seasonal periods suggests that the frogs have greater reproductive potential in the spring due to the development of the structures related to the oviduct, presence of developed cilia, and electron-dense granules. However, seasonal changes were noted in the animal throughout the year in preparation for reproduction during the spring and summer. PMID- 23450757 TI - Brain activity during driving with distraction: an immersive fMRI study. AB - INTRODUCTION: Non-invasive measurements of brain activity have an important role to play in understanding driving ability. The current study aimed to identify the neural underpinnings of human driving behavior by visualizing the areas of the brain involved in driving under different levels of demand, such as driving while distracted or making left turns at busy intersections. MATERIALS AND METHODS: To capture brain activity during driving, we placed a driving simulator with a fully functional steering wheel and pedals in a 3.0 Tesla functional magnetic resonance imaging (fMRI) system. To identify the brain areas involved while performing different real-world driving maneuvers, participants completed tasks ranging from simple (right turns) to more complex (left turns at busy intersections). To assess the effects of driving while distracted, participants were asked to perform an auditory task while driving analogous to speaking on a hands-free device and driving. RESULTS: A widely distributed brain network was identified, especially when making left turns at busy intersections compared to more simple driving tasks. During distracted driving, brain activation shifted dramatically from the posterior, visual and spatial areas to the prefrontal cortex. CONCLUSIONS: Our findings suggest that the distracted brain sacrificed areas in the posterior brain important for visual attention and alertness to recruit enough brain resources to perform a secondary, cognitive task. The present findings offer important new insights into the scientific understanding of the neuro-cognitive mechanisms of driving behavior and lay down an important foundation for future clinical research. PMID- 23450758 TI - Bull gore injury of the vagina. AB - Although an obstetrically related trauma is the most common cause of the injuries to the female genital tract, non obstetric causes also lead to a significant number of vaginal and vulval injuries. We present 2 cases of vaginal injury, due to bull goring, one of which was associated with massive vulval haematoma. The 2 cases presented in a span of 2 months, in a rural medical college in South India. Both of them were managed surgically, following an initial haemodynamic resuscitation. They also required blood transfusions and an antibiotic prophylaxis. The postoperative period was uneventful. PMID- 23450759 TI - Cdc13 at a crossroads of telomerase action. AB - Telomere elongation by telomerase involves sequential steps that must be highly coordinated to ensure the maintenance of telomeres at a proper length. Telomerase is delivered to telomere ends, where it engages single-strand DNA end as a primer, elongates it, and dissociates from the telomeres via mechanism that is likely coupled to the synthesis of the complementary C-strand. In Saccharomyces cerevisiae, the telomeric G-overhang bound Cdc13 acts as a platform for the recruitment of several factors that orchestrate timely transitions between these steps. In this review, we focus on some unresolved aspects of telomerase recruitment and on the mechanisms that regulate telomere elongation by telomerase after its recruitment to chromosome ends. We also highlight the key regulatory modifications of Cdc13 that promote transitions between the steps of telomere elongation. PMID- 23450760 TI - Bisphenol A stimulates human prostate cancer cell migration via remodelling of calcium signalling. AB - Bisphenol A (BPA), the principal constituent of reusable water bottles, metal cans, and plastic food containers, has been shown to be involved in human prostate cancer (PCa) cell proliferation. The aim of the present study was to explore the effect of BPA on PCa cell migration and the pathways involved in these processes. Using the transwell technique, we clearly show for the first time that the pre-treatment of the cells with BPA (1-10 nM) induces human PCa cell migration. Using a calcium imaging technique, we show that BPA pre-treatment induces an amplification of Store-Operated Calcium Entry (SOCE) in LNCaP cells. RT-PCR and Western blot experiments allowed the identification of the ion channel proteins which are up-regulated by BPA pre-treatments. These include the Orai1 protein, which is known as an important SOCE actor in various cell systems, including human PCa cells. Using a siRNA strategy, we observed that BPA-induced amplification of SOCE was Orai1-dependent. Interestingly, the BPA-induced PCa cell migration was suppressed when the calcium entry was impaired by the use of SOCE inhibitors (SKF96365, BTP2), or when the extracellular calcium was chelated. Taken together, the results presented here show that BPA induces PCa cells migration via a modulation of the ion channel protein expression involved in calcium entry and in cancer cell migration. The present data provide novel insights into the molecular mechanisms involved in the effects of an environmental factor on cancer cells and suggest both the necessity of preventive measures and the possibility of targeting ion channels in the treatment of PCa cell metastasis. PMID- 23450761 TI - Tuberculous uveitis. AB - Tuberculous uveitis is an underdiagnosed form of uveitis. Absence of pulmonary signs and symptoms does not rule out the disease. In an era of reduced immunity from human immunodeficiency virus and acquired immunodeficiency syndrome, the disease is becoming more prevalent. This review discusses the common manifestations of tuberculous uveitis, pointing out helpful diagnostic criteria in suspicious cases of uveitis. Physicians need to be aware that ocular manifestations of tuberculosis may be independent of systemic disease. PMID- 23450762 TI - Systematic evaluation of reference protein normalization in proteomic experiments. AB - Quantitative comparative analyses of protein abundances using peptide ion intensities and their modifications have become a widely used technique in studying various biological questions. In the past years, several methods for quantitative proteomics were established using stable-isotope labeling and label free approaches. We systematically evaluated the application of reference protein normalization (RPN) for proteomic experiments using a high mass accuracy LC-MS/MS platform. In RPN all sample peptide intensities were normalized to an average protein intensity of a spiked reference protein. The main advantage of this method is that it avoids fraction of total based relative analysis of proteomic data, which is often very much dependent on sample complexity. We could show that reference protein ion intensity sums are sufficiently reproducible to ensure a reliable normalization. We validated the RPN strategy by analyzing changes in protein abundances induced by nutrient starvation in Arabidopsis thaliana. Beyond that, we provide a principle guideline for determining optimal combination of sample protein and reference protein load on individual LC-MS/MS systems. PMID- 23450763 TI - CT angiographic evaluation of perforators in the lower limb and their reconstructive implication. AB - BACKGROUND: The perforator flaps evolved on the knowledge of the vascular tree from the main vascular trunk up to the subdermal plexus. Therefore, we thought that it's necessary to map the whole vascular arcade by CT angiography. The aim of this study is to evaluate the perforators and the whole vascular tree of the lower limb by peripheral CT angiography with 3D reconstruction and intraoperative evaluation. This study helps in designing flaps of different constituents based on the selected perforators. MATERIALS AND METHODS: Twenty patients having lower limb defects were selected. CT angiography was done using a non-ionic iodinated contrast media injected through the antecubital vein. The lower limbs were imaged using volume rendering CT scan machine. Three dimensional reconstructions were made. The whole arterial tree, along with the perforators, were mapped. Findings of the audio-Doppler were correlated with the CT angiographic observations. Further these evaluations were confirmed by intraoperative findings. RESULTS: The three dimensional CT angiographic reconstruction with bone and soft tissue provided advanced knowledge of this vascular network. It delineated the main vessel, the perforators, their caliber, distance from fixed bony landmarks and course up to the subdermal plexus. These findings were confirmed during dissection of the proposed flap. The perforators were mainly musculocutaneous in the proximal leg and septocutaneous distally. CONCLUSIONS: The vascular details visualized by this technique made advancement over the existing methods namely color Doppler, audio Doppler, two dimensional angiography etc. It improved the understanding of perforator flaps and their successful clinical application. PMID- 23450765 TI - Temporal and spatial variation in bird and human use of beaches in southern California. AB - Southern California's beaches can support a remarkable diversity of birds along the Pacific Flyway. We asked whether seasonal, annual, and spatial factors affect bird richness and abundance on public beaches. To do so, we conducted three years of monthly bird surveys on 12 sandy beaches in Ventura California. Across all surveys, we counted 22 shorebird species, 8 gull species, 24 other water bird species, and 24 landbird species. Sanderling, western gull, Heerman's gull, willet, marbled godwit, and whimbrel were the most abundant members of the bird community. Beach wrack was uncommon, particularly where beaches were groomed, and did not have a large effect on bird abundance, though it was positively associated with overall bird richness. Beaches near estuaries tended to be wide, and such beaches had a higher richness and abundance of birds. Beaches with shallow slopes tended to have more gulls and shorebirds. People and (illegal) unleashed dogs were common, particularly at beaches fronted by houses. The abundance and richness of shorebirds and the richness of other waterbirds was lower where human activity was high. Bird richness and abundance was strongly affected by season, with the highest density of birds being seen during the fall shorebird migration. Gull abundance peaked earlier (August-September) than shorebird abundance (October through December). A brief pulse of shorebirds also occurred in May due to spring migration. Comparing these data with surveys in the 1990's found no evidence for a decline in shorebirds over time, though black bellied plover appear to still be recovering from the strong 1997-1998 ENSO. Opportunities to conserve birds on these beaches are limited, but could include enforcing leash laws and setting up human exclosures near estuary mouths. PMID- 23450764 TI - Strain specific genotype-environment interactions and evolutionary potential for body mass in brook charr (Salvelinus fontinalis). AB - Discriminating between genetic and environmental causes of phenotypic variation is an essential requirement for understanding the evolutionary potential of populations. However, the extent to which genetic variation differs among conspecific groups and environments during ontogeny has rarely been investigated. In this study, the genetic basis of body mass was measured in three divergent strains of brook charr (Salvelinus fontinalis) in different rearing environments and at different time periods. The results indicate that body mass was a heritable trait in all strains but that the level of heritability greatly differed among strains. Moreover, heritability estimates of each strain varied differently according to environmental rearing conditions, and cross-environments correlations were all significantly lower than unity, indicating strain-specific patterns of genotype-environment interactions. Heritability estimates also varied throughout ontogeny and decreased by 50% from 9 to 21 months of age. This study highlights the divergence in genetic architecture and evolutionary potential among these strains and emphasizes the importance of considering the strain specific potential of the response to selection according to environmental variation. PMID- 23450766 TI - Precarious employment, psychosocial working conditions, and health: Cross sectional associations in a population-based sample of working Australians. AB - BACKGROUND: Precarious employment has been associated with poor health, but the potential mechanisms are unclear. We examined the relationships between precarious employment and health, and investigated psychosocial working conditions as potential mediators. METHODS: A cross-sectional population-based survey was conducted in South Australia in 2009 (N = 1,016 employed). SF-12 measures of mental and physical health were modeled using logistic regression in relation to employment arrangement, controlling for socio-demographics, years in job and psychosocial working conditions. RESULTS: There was no association between casual full-time or part-time employment and poor mental health in multivariate analyses. Conversely, there was a significant association between casual full-time employment and poor physical health (compared to permanent full time workers, OR = 3.14, 95% CI 1.26-7.85). The association with physical health was unaffected by adjustment for psychosocial working conditions. CONCLUSIONS: Casual full-time employment was strongly associated with poor physical health but not with poor mental health. This association was not mediated by the psychosocial working conditions measured in this study, but may be related to other (unmeasured) working conditions. PMID- 23450767 TI - Decametallic Co(II)-cluster-based microporous magnetic framework with a semirigid multicoordinating ligand. AB - We have synthesized a microporous magnetic framework that contained supertetrahedral decametallic cobalt clusters as nodes and 4 (tris(hydroxymethyl)methyl)pyridine ligands as linkers in a NaCl-like network. This complex shows canted antiferromagnetism with spin-glass behavior. After the removal of the guest molecules, the spin-canting and spin-glass behaviors are maintained. The permanent porosity was evaluated by N2-adsorption measurements. This complex mainly shows a hydrophobic nature, as validated by MeOH- and water adsorption measurements, which is consistent with the grand canonical Monte Carlo (GCMC) theoretical simulation. PMID- 23450768 TI - Organocatalytic, regioselective nucleophilic "click" addition of thiols to propiolic acid esters for polymer-polymer coupling. PMID- 23450769 TI - Dynamic molecular processes detected by microtubular opto-chemical sensors self assembled from prestrained nanomembranes. PMID- 23450770 TI - Co-registered pulse-echo/photoacoustic transvaginal probe for real time imaging of ovarian tissue. AB - We present the design and construction of a prototype imaging probe capable of co registered pulse-echo ultrasound and photoacoustic (optoacoustic) imaging in real time. The probe consists of 36 fibers of 200 micron core diameter each that are distributed around a commercial transvaginal ultrasound transducer, and housed in a protective shield. Its performance was demonstrated by two sets of experiments. The first set involved imaging of blood flowing through a tube mimicking a blood vessel, the second set involved imaging of human ovaries ex vivo. The results suggest that the system along with the probe has great potential for imaging and characterizing of ovarian tissue in vivo. PMID- 23450771 TI - Evaluation of PCB bioaccumulation by Lumbriculus variegatus in field-collected sediments. AB - Review of data from several contaminated sediment sites suggested that biota sediment accumulation factors (BSAFs) declined with increasing contaminant concentrations in the sediment. To evaluate the consistency and possible causes of this behavior, polychlorinated biphenyl (PCB)-contaminated sediment samples from the Hudson, Grasse, and Fox River Superfund sites were used in sediment bioaccumulation tests with the freshwater oligochaete, Lumbriculus variegatus, with PCB concentrations in interstitial water (IW) quantified using polyoxymethylene passive samplers. Measured BSAFs tended to decrease with increasing PCB concentration in sediment, especially for the more highly chlorinated congeners. Measures of partitioning between sediment, IW, and oligochaetes showed that measured sediment-IW partition coefficients (KTOC ) tended to increase slightly with increasing sediment contamination, whereas the ratio of tissue PCB to IW PCB tended to decrease with increasing concentration in IW. Variation in accumulation among sediments was clearly influenced by bioavailability, as reflected by IW measurements, although the specific cause of varying KTOC was not clear. Calculated partitioning between IW and organism lipid (Klipid ) indicated that accumulation was generally 5 to 10-fold higher than would be predicted if Klipid was approximately equal to the n-octanol-water partition coefficient (KOW ). While affirming previous observations of decreasing BSAFs with increasing PCB contamination, the relatively shallow slope of the observed relationship in the current data may suggest that this concentration dependence is not a major uncertainty in sediment risk assessment, particularly if measurements of PCBs in IW are incorporated. PMID- 23450772 TI - Three-dimensional aspects of the structural characteristics and kidney angioarchitecture of adult and aged Wistar rats: a scanning electron microscopy study. AB - The aim of this study was to describe the structural morphological characteristics and organization of the kidney angioarchitecture in adult and aged Wistar rats using different scanning electron microscopy (SEM) methods. Twenty male Wistar rats (Rattus norvegicus) were divided into two groups: the Adult Group (n = 10), which included animals at 3 months of age, and the Aged Group (n = 10), which included animals at 24 months of age. Kidney samples from both groups were analyzed using three distinct SEM methods: coronal sections, cryofracturing and vascular corrosion casts/angioarchitecture. This study demonstrates the specificity of each technique for three-dimensional morphological analyses of the kidney using SEM. In the coronal sections, it was possible to view the structures on a given plane; the stratigraphy was best observed in the cryofracture method, and the vascular corrosion casts showed the organization and arrangement of the angioarchitecture. Thus, we concluded that the SEM methods together provide the best description of the morphological characteristics of normal and pathological kidneys of adult and aged Wistar rats. PMID- 23450773 TI - Exploring variation in proanthocyanidin composition and content of sainfoin (Onobrychis viciifolia). AB - BACKGROUND: To maximise the potential benefits to ruminants from sainfoin, plant breeding should focus on developing varieties with predictable condensed tannin (CT) profiles. Little is known about whether and to what extent accession and environment influence sainfoin CT structures. We sought to investigate the likely extent of accession and environment effects on CT characteristics of sainfoin. Four single-flowering (Communis) accessions and two multiple-flowering (Bifera) accessions, grown at three sites and collected at two harvest times were used. Sainfoin CTs were characterised by thiolytic degradation and by high-performance liquid chromatography-gel permeation chromatography (HPLC-GPC). Also, CT concentration measured earlier by the HCl-butanol method was compared with that from thiolysis. RESULTS: Thiolysis revealed that accession and harvest influenced most CT structural attributes. Bifera CTs eluted as single peaks (Mp < 6220 Da) in HPLC-GPC across the two harvests and two sites, whereas Communis generated two to three CT peaks, which included a peak (Mp <= 9066 Da) in the second harvest. A discrepancy was observed in CT concentrations measured by the two methods. CONCLUSION: CTs from Bifera accessions had more stable and predictable characteristics across harvests and sites and this could be of interest when breeding sainfoin. PMID- 23450774 TI - Essential medicines for pediatric oncology in developing countries. AB - The burden of cancer in children in low and middle income countries (LMICs) is substantial, comprising at least 80% of incident cases globally, and an even higher proportion of cancer-related deaths. With survival rates exceeding 80% in high income countries, it is imperative to transfer these successes to LMICs. A major challenge is the poor availability of safe, cost-effective chemotherapy. A list of 51 drugs-chemotherapeutics, infectious disease agents, and supportive care medications-is proposed as essential to improving the survival of children with cancer in LMICs with an additional 13 drugs identified as being of further value. PMID- 23450776 TI - N-heterocyclic carbene catalyzed [4+2] cycloaddition of nitroalkenes with oxodienes. AB - NHC catalysis: N-heterocyclic carbenes were found to be efficient catalysts for the unprecedented [4+2] cycloaddition of nitroalkenes and oxodienes, giving the corresponding dihydropyrans in good yield with good diastereoselectivity (see scheme). Deuteration experiment reveals that the reaction is possibly initiated by the addition of N-heterocylic carbene to nitroalkenes. PMID- 23450777 TI - Exfoliated graphitic carbon nitride nanosheets as efficient catalysts for hydrogen evolution under visible light. AB - Graphitic carbon nitride nanosheets are extracted, produced via simple liquid phase exfoliation of a layered bulk material, g-C3N4. The resulting nanosheets, having ~2 nm thickness and N/C atomic ratio of 1.31, show an optical bandgap of 2.65 eV. The carbon nitride nanosheets are demonstrated to exhibit excellent photocatalytic activity for hydrogen evolution under visible light. PMID- 23450778 TI - Plateletpheresis for postsplenectomy rebound thrombocytosis in a patient with chronic immune thrombocytopenic purpura on romiplostim. AB - Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG coated platelets are removed from circulation by the spleen, and platelet production is impaired due to increased thrombopoietin (TPO) clearance. Romiplostim, a novel TPO-mimetic agent, is approved for patients with ITP that are unresponsive to traditional treatments. However, there is little experience when using this drug before splenectomy. We describe herein the case of a young female with chronic ITP who was treated with romiplostim, underwent splenectomy shortly thereafter, and required plateletpheresis for postoperative rebound thrombocytosis with concomitant neurologic symptoms. PMID- 23450779 TI - The nature of hydrogen bonding in protic ionic liquids. AB - The size, direction, strength, and distribution of hydrogen bonds in several protic ionic liquids (PILs) has been elucidated using neutron diffraction and computer simulation. There is significant variation in PIL hydrogen bond interactions ranging from short and linear to long and bi-/trifurcated. The nature of the PIL's hydrogen bonds reflects its macroscopic properties. PMID- 23450780 TI - Photoacoustically-guided photothermal killing of mosquitoes targeted by nanoparticles. AB - In biomedical applications, nanoparticles have demonstrated the potential to eradicate abnormal cells in small localized pathological zones associated with cancer or infections. Here, we introduce a method for nanotechnology-based photothermal (PT) killing of whole organisms considered harmful to humans or the environment. We demonstrate that laser-induced thermal, and accompanying nano- and microbubble phenomena, can injure or kill C. elegans and mosquitoes fed carbon nanotubes, gold nanospheres, gold nanoshells, or magnetic nanoparticles at laser energies that are safe for humans. In addition, a photoacoustic (PA) effect was used to control nanoparticle delivery. Through the integration of this technique with molecular targeting, nanoparticle clustering, magnetic capturing and spectral sharpening of PA and PT plasmonic resonances, our laser-based PA-PT nano-theranostic platform can be applied to detection and the physical destruction of small organisms and carriers of pathogens, such as malaria vectors, spiders, bed bugs, fleas, ants, locusts, grasshoppers, phytophagous mites, or other arthropod pests, irrespective of their resistance to conventional treatments. PMID- 23450782 TI - Assessment of communication modes in patients and families with sickle cell disease. PMID- 23450781 TI - Death inducing and cytoprotective autophagy in T-47D cells by two common antibacterial drugs: sulphathiazole and sulphacetamide. AB - The broad spectrum of the pharmacological effects of sulphonamide family of drugs motivated us to investigate the cellular mechanisms for anti-cancer effects of sulphathiazole and sulphacetamide on T-47D breast cancer cells. Fluorescent microscopy, flow cytometric analysis, caspase-3 activity and DNA fragmentation assays were used to detect apoptosis. The distribution of the cells among different phases of the cell cycle was measured by flow cytometry. The expression of several genes with important roles in some critical cellular pathways including apoptosis, mTOR/AKT pathway and autophagy were determined by real-time RT-PCR analysis. Sulphathiazole and sulphacetamide induced anti-proliferative effects on T-47D cells were independent of apoptosis and cell cycle arrest. The overexpression of critical genes involved in autophagy including ATG5, p53 and DRAM indicated that the main effect of the drug-induced anti-proliferative effects was through induction of autophagy. This process was induced in two different forms, including death inducing and cytoprotective autophagy. Sulphathiazole treatment was followed by higher expression of p53/DRAM and downregulation of Akt/mTOR pathway resulting in death autophagy. In contrast, sulphacetamide treatment lowered expression of p53/DRAM pathway in parallel with upregulation of Akt/mTOR pathway promoting cytoprotective autophagy. The results indicated that autophagy is the main mechanism mediating the anti-cancer effects of sulphathiazole and sulphacetamide on T-47D cells. Alignment of the p53 and DRAM expression along with activation level of Akt survival pathway therefore determines the type of autophagy that occurs. PMID- 23450783 TI - Triggering mechanisms for oxygen-scavenging function of ascorbic acid incorporated whey protein isolate films. AB - BACKGROUND: Incorporation of ascorbic acid (AA) into whey protein isolate (WPI) films has been shown to increase the film's ability to protect foods from oxidation. The O2-scavenging function of AA-WPI films could be triggered upon being placed in contact with food products. Several food-related factors hypothesized to act as triggering mechanisms for activating the O2-scavenging function of AA-WPI films were investigated, including change of water activity (a(w)), pH and/or metal catalyst presence. RESULTS: Rate of O2 scavenging of AA WPI films was observed to most closely follow first-order kinetics. The film a(w) level was found to control the O2-scavenging rate. At high a(w) levels, O2 scavenging occurred at a desirably rapid rate. Food models with pH 7.4 produced the fastest O2-scavenging rate. The slowest rate at pH 3.0 was due to the lower concentration of O2-sensitive ascorbate monoanion. The presence of Cu2+ accelerated AA oxidation at high a(w) level. CONCLUSION: The desirable activation of oxygen scavenging in AA-WPI film at high a(w) and neutral pH in the presence of metal catalyst suggests that such AA-WPI films can be used to protect foods that have the highest vulnerability to oxidation. PMID- 23450785 TI - Predictors of respiratory sickness absence: an international population-based study. AB - BACKGROUND: Respiratory tract-related occupational disability is common among adults of working age. We examined occupational vapors, gas, dust, or fume (VGDF) exposure as a predictor of disability, based on respiratory sickness absence among the actively employed, at an early point at which prevention may be most relevant. METHODS: Currently employed European Community Respiratory Health Survey II participants (n = 6,988) were classified into three mutually exclusive, condition/symptom-based categories: physician-diagnosed asthma, self-reported rhinitis, and wheeze/breathlessness (n = 4,772). Logistic regression analysis estimated the odds of respiratory sickness absence (past 12 months) by VGDF exposure. RESULTS: In the condition/symptom groups, 327 (6.9%) reported respiratory sickness absence. Exposure to VGDF was associated with increased odds of respiratory sickness absence: asthma odds ratio [OR] 2.0 (95% confidence interval [CI] 1.1-3.6), wheeze/breathlessness OR 2.2 (95% CI 1.01-4.8); rhinitis OR 1.9 (95% CI 1.02-3.4). CONCLUSION: One in 15 currently employed with asthma, breathlessness, or rhinitis reported respiratory sickness absence. VGDF exposure doubled the odds of respiratory sickness absence, suggesting a focus for disability prevention. PMID- 23450784 TI - Silica-based branched hollow microfibers as a biomimetic extracellular matrix for promoting tumor cell growth in vitro and in vivo. AB - A novel scaffold composed of loosely branched hollow silica microfibers that has been proven to be highly biocompatible is proposed for the 3D culture of cancer cells. The MCF-7 cancer cells can grow and proliferate freely inside the scaffold in the form of multicellular spheroids. MCF-7 cancer cells cultured on the current 3D silica scaffold retained significantly more oncological characters than those cultured on the conventional 2D substrate and can serve as in vitro tumor model for studying cancer treatment. PMID- 23450786 TI - A R2p /R1p ratiometric procedure to assess matrix metalloproteinase-2 activity by magnetic resonance imaging. PMID- 23450787 TI - Label-free detection of microRNA: two-step signal enhancement with a hairpin probe-based graphene fluorescence switch and isothermal amplification. AB - A label-free approach with multiple enhancement of the signal for microRNA detection has been introduced. The key idea of this strategy is achieved by taking advantage of a novel graphene oxide (GO)/intercalating dye based fluorescent hairpin probe (HP) and an isothermal polymerization reaction. In this paper, we used microRNA-21 (mir-21) as the target to examine the desirable properties of this assay. When the target, as a "trigger", was hybridized with the HP and caused a conformation change, an efficient isothermal polymerization reaction was activated to achieve the first step of the "signal" amplification. After incubation with the platform of GO/intercalating dye, the formed complex of DNA interacted with the high-affinity dye and then detached from the surface of the GO, a process that was accompanied by distinguishable fluorescence recovery. Further signal enhancement has been accomplished by a mass of intercalating dye inserting into the minor groove of the long duplex replication product. Due to the efficient and multiple amplification steps, this approach exerted a substantial enhancement in sensitivity and could be used for rapid and selective detection of Mir-21 at attomole levels. Proof-of-concept evidence has been provided for the proposed cost-effective strategy; thus, this strategy could expand the application of GO-material-based bioanalysis for nucleic acid studies. PMID- 23450789 TI - Acquired hemoglobin variants and exposure to glucose-6-phosphate dehydrogenase deficient red blood cell units during exchange transfusion for sickle cell disease in a patient requiring antigen-matched blood. AB - Red blood cell exchange (RBCEx) is frequently used in the management of patients with sickle cell disease (SCD) and acute chest syndrome or stroke, or to maintain target hemoglobin S (HbS) levels. In these settings, RBCEx is a category I or II recommendation according to guidelines on the use of therapeutic apheresis published by the American Society for Apheresis. Matching donor red blood cells (RBCs) to recipient phenotypes (e.g., C, E, K-antigen negative) can decrease the risk of alloimmunization in patients with multi-transfused SCD. However, this may select for donors with a higher prevalence of RBC disorders for which screening is not performed. This report describes a patient with SCD treated with RBCEx using five units negative for C, E, K, Fya, Fyb (prospectively matched), four of which were from donors with hemoglobin variants and/or glucose-6-phosphate dehydrogenase (G6PD) deficiency. Pre-RBCEx HbS quantification by high performance liquid chromatography (HPLC) demonstrated 49.3% HbS and 2.8% hemoglobin C, presumably from transfusion of a hemoglobin C-containing RBC unit during a previous RBCEx. Post-RBCEx HPLC showed the appearance of hemoglobin G Philadelphia. Two units were G6PD-deficient. The patient did well, but the consequences of transfusing RBC units that are G6PD-deficient and contain hemoglobin variants are unknown. Additional studies are needed to investigate effects on storage, in-vivo RBC recovery and survival, and physiological effects following transfusion of these units. Post-RBCEx HPLC can monitor RBCEx efficiency and detect the presence of abnormal transfused units. PMID- 23450790 TI - An ectopic pregnancy in the tubal interstitium: beware! AB - An interstitial ectopic pregnancy is a rare and a dangerous form of an ectopic pregnancy. It presents late clinically and it is difficult to be imaged radiographically. We are presenting a case of an interstitial pregnancy which was a surprise intra operative finding.As Assisted Reproductive Technology (ART) procedures are becoming popular, the incidence of ectopic pregnancies is likely to increase. The clinicians should be well equipped to diagnose and to treat this unusual form of ectopic pregnancies at the earliest. PMID- 23450788 TI - Proteomics: a biotechnology tool for crop improvement. AB - A sharp decline in the availability of arable land and sufficient supply of irrigation water along with a continuous steep increase in food demands have exerted a pressure on farmers to produce more with fewer resources. A viable solution to release this pressure is to speed up the plant breeding process by employing biotechnology in breeding programs. The majority of biotechnological applications rely on information generated from various -omic technologies. The latest outstanding improvements in proteomic platforms and many other but related advances in plant biotechnology techniques offer various new ways to encourage the usage of these technologies by plant scientists for crop improvement programs. A combinatorial approach of accelerated gene discovery through genomics, proteomics, and other associated -omic branches of biotechnology, as an applied approach, is proving to be an effective way to speed up the crop improvement programs worldwide. In the near future, swift improvements in -omic databases are becoming critical and demand immediate attention for the effective utilization of these techniques to produce next-generation crops for the progressive farmers. Here, we have reviewed the recent advances in proteomics, as tools of biotechnology, which are offering great promise and leading the path toward crop improvement for sustainable agriculture. PMID- 23450791 TI - Genetics of Sleep Timing, Duration and Homeostasis in Humans. PMID- 23450792 TI - Combination treatment using percutaneous transluminal angioplasty and low-density lipoprotein apheresis in a patient with peripheral arterial disease and a history of chronic hemodialysis. AB - Peripheral arterial disease (PAD) is very common in dialysis patients, who tend to have diffuse calcification and severe peripheral arterial stenosis that make it difficult to treat limbs using only surgical or endovascular interventions. Better ways to treat this condition are therefore required and also follow-up studies to evaluate the effects of these treatments on the microcirculation. A 59 year-old man who had a cadaveric kidney transplant five years previously after 25 years of regular hemodialysis complained of pain at rest in his right lower limb and subsequently developed an intractable decubitus ulcer on his right fifth toe (Fontaine IV). Digital subtraction angiography revealed a severe obstruction of the right femoral artery and diffuse stenosis of the right superficial femoral artery. The patient underwent percutaneous transluminal angioplasty (PTA) and six sessions of low-density lipoprotein apheresis (LDL apheresis). At the end of these sessions his complaints were almost completely alleviated. The mean elevation in skin temperature after each session was (1.58 +/- 0.99) degrees C [mean +/- SD] over the right dorsalis pedis artery and (1.52 +/- 0.88) degrees C at the tip of the right fifth toe. Ultrasound-measured blood flow rates in the right dorsalis pedis artery were 9.2 cm/s before PTA and 20.2 cm/s one month after PTA. Hemodialysis was resumed 3 days after the PTA due to contrast-induced nephropathy. The combination of PTA and LDL apheresis is useful for treating PAD in hemodialysis patients, with the changes in peripheral artery patency are able to be evaluated effectively by measuring skin temperature. PMID- 23450793 TI - Prognostic abilities of different calculation formulas for the glomerular filtration rate in elderly Chinese patients with coronary artery disease. AB - OBJECTIVE: As a standard indicator of renal function, the glomerular filtration rate (GFR) is vital for the prognostic analysis of elderly patients with coronary artery disease (CAD). Thus, the search for the calculation equation of GFR with the best prognostic ability is an important task. The most commonly used Modification of Diet in Renal Disease (MDRD) equation and the Chinese version (CMDRD) of the MDRD equation has many shortcomings. The newly developed Mayo Clinic quadratic (Mayo) and Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) equations may overcome these shortcomings. Because the populations involved in these equation-related studies are almost completely devoid of subjects > 70 years of age, there are more debates on the performance of these equations in the elderly. This study was designed to compare the prognostic abilities of different calculation formulas for the GFR in elderly Chinese patients with CAD. METHODS: This study included 1050 patients (>=60 years of age) with CAD. The endpoint was all-cause mortality over a mean follow-up period of 417 days. RESULTS: The median age was 86 years (60-104 years). The median values for the MDRD-GFR, CMDRD-GFR, CKD-EPI-GFR, and Mayo-GFR were 66.0, 69.2, 65.6, and 75.8 mL/minute/1.73 m(2), respectively. The prevalence of GFR < 60 mL/minute/1.73 m(2) based on these measures was 39.3%, 35.4%, 43.0%, and 28.7%, respectively. Their area under the curve values for predicting death were 0.611, 0.610, 0.625, and 0.632, respectively. Their cut-off points for predicting death were 54.1, 53.5, 48.0, and 57.4 mL/minute/1.73 m(2), respectively. Compared with the MDRD-GFR, the net reclassification improvement values of the CMDRD-GFR, CKD-EPI-GFR, and Mayo-GFR were 0.02, 0.10, and 0.14, respectively. CONCLUSION: The prognostic abilities of the CKD-EPI and Mayo equations were significantly superior to the MDRD and CMDRD equations; the Mayo equation had a mild, but not statistically significant superiority compared with the CKD-EPI equation in elderly Chinese patients with CAD. PMID- 23450795 TI - Reply: To PMID 23042084. PMID- 23450794 TI - Accurate identification and analysis of human mRNA isoforms using deep long read sequencing. AB - Precise identification of RNA-coding regions and transcriptomes of eukaryotes is a significant problem in biology. Currently, eukaryote transcriptomes are analyzed using deep short-read sequencing experiments of complementary DNAs. The resulting short-reads are then aligned against a genome and annotated junctions to infer biological meaning. Here we use long-read complementary DNA datasets for the analysis of a eukaryotic transcriptome and generate two large datasets in the human K562 and HeLa S3 cell lines. Both data sets comprised at least 4 million reads and had median read lengths greater than 500 bp. We show that annotation independent alignments of these reads provide partial gene structures that are very much in-line with annotated gene structures, 15% of which have not been obtained in a previous de novo analysis of short reads. For long-noncoding RNAs (i.e., lncRNA) genes, however, we find an increased fraction of novel gene structures among our alignments. Other important aspects of transcriptome analysis, such as the description of cell type-specific splicing, can be performed in an accurate, reliable and completely annotation-free manner, making it ideal for the analysis of transcriptomes of newly sequenced genomes. Furthermore, we demonstrate that long read sequence can be assembled into full length transcripts with considerable success. Our method is applicable to all long read sequencing technologies. PMID- 23450796 TI - OMIP-017: human CD4(+) helper T-cell subsets including follicular helper cells. PMID- 23450797 TI - Atomic force microscopy of chronic lymphatic leukaemia cells activation induced by Staphylococcus aureus. AB - Activation of lymphatic cells is associated with changes in morphology, ultrastructure and adhesion force. We have investigated the activation efficiency of Staphylococcus aureus (SAC) on B-cell chronic lymphatic leukaemia (B-CLL) cells using atomic force microscopy (AFM), and found changes in the above properties. Cell viability and proliferation were measured using Cell Counting Kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA). AFM clearly showed that the volume and nuclear-cytoplasm ratio of cells increased significantly with activated time. It also showed that pseudopodia and immunological synapses began to appear at 24 h. In the activation process, nano-structures of the cell surface became aggregated, and adhesion increased. In conclusion, the results indicate a close relationship between membrane reconstruction and multiplication process of B-CLL cells. PMID- 23450798 TI - An unusual case report on the possible role of Warfarin in migraine prophylaxis. AB - BACKGROUND: Migraine is a complex disease whose physiopathological mechanisms are still not completely revealed. FINDINGS: We describe an unusual case, not yet described in literature, of a patient who reported migraine remission, but still presented aura attacks, since starting a therapy with Warfarin. CONCLUSIONS: This case report brings out new questions on the role of the coagulation, especially the blood coagulation pathway, in migraine with aura pathogenesis, and on the possibility to use vitamin K synthesis inhibitors, Warfarin or new generation drugs, as possible therapy to use in migraine prophylaxis. PMID- 23450799 TI - Noninvasive cross-sectional imaging of proximal caries using swept-source optical coherence tomography (SS-OCT) in vivo. AB - The aim of this study was to determine the diagnostic accuracy of swept-source optical coherent tomography (SS-OCT) in detecting and estimating the depth of proximal caries in posterior teeth in vivo. SS-OCT images and bitewing radiographs were obtained from 86 proximal surfaces of 53 patients. Six examiners scored the locations according to a caries lesion depth scale (0-4) using SS-OCT and the radiographs. The results were compared with clinical observations obtained after the treatment. SS-OCT could detect the presence of proximal caries in tomograms that were synthesized based on the backscatter signal obtained from the proximal carious lesion through occlusal enamel. SS-OCT showed significantly higher sensitivity and larger area under the receiver operating characteristic curve than radiographs for the detection of cavitated enamel lesions and dentin caries (Student's t -test, p < 0.05). SS-OCT appears to be a more reliable and accurate method than bitewing radiographs for the detection and estimation of the depth of proximal lesions in the clinical environment. PMID- 23450801 TI - Remote monitoring of videourodynamics using smart phone and free instant messaging software. AB - AIMS: To evaluate the feasibility of using smart phones plus free instant messaging software for remote monitoring of videourodynamics. METHODS: From November 2011 to October 2012, 85 females with voiding disorders were enrolled for videourodynamic tests. The patients were assigned to videourodynamics remotely monitored by the attending physician by using iPhone/iPad and Skype (group 1) and videourodynamics with the attending physician present (group 2). The procedural time and videourodynamic qualities, assessed by the frequency of adherence to the modified Sullivan criteria, in each group were recorded and compared. RESULTS: There were 44 and 41 patients in group 1 and group 2, respectively. The mean procedural time was comparable between group 1 and group 2 (56.3 vs. 54.4 min, P = 0.25). The frequencies of adherence to the modified Sullivan criteria were similar in each group. CONCLUSIONS: The qualities of videourodynamics under the attending physician's remote or direct monitoring were both appropriate. Based on the convenience of Internet, the popularity of smart phones and the intention to make the urologists use their time more efficiently, our study provides remote monitoring as an alternative way for performing videourodynamics. PMID- 23450800 TI - Young and intense: FoxP2 immunoreactivity in Area X varies with age, song stereotypy, and singing in male zebra finches. AB - FOXP2 is a transcription factor functionally relevant for learned vocalizations in humans and songbirds. In songbirds, FoxP2 mRNA expression in the medium spiny neurons of the basal ganglia song nucleus Area X is developmentally regulated and varies with singing conditions in different social contexts. How individual neurons in Area X change FoxP2 expression across development and in social contexts is not known, however. Here we address this critical gap in our understanding of FoxP2 as a link between neuronal networks and behavior. We used a statistically unbiased analysis of FoxP2-immunoreactivity (FoxP2-IR) on a neuron-by-neuron basis and found a bimodal distribution of FoxP2-IR neurons in Area X: weakly-stained and intensely-stained. The density of intensely-stained FoxP2-IR neurons was 10 times higher in juveniles than in adults, exponentially decreased with age, and was negatively correlated with adult song stability. Three-week old neurons labeled with BrdU were more than five times as likely to be intensely-stained than weakly-stained. The density of FoxP2-IR putative migratory neurons with fusiform-shaped nuclei substantially decreased as birds aged. The density of intensely-stained FoxP2-IR neurons was not affected by singing whereas the density of weakly-stained FoxP2-IR neurons was. Together, these data indicate that young Area X medium spiny neurons express FoxP2 at high levels and decrease expression as they become integrated into existing neural circuits. Once integrated, levels of FoxP2 expression correlate with singing behavior. Together, these findings raise the possibility that FoxP2 levels may orchestrate song learning and song stereotypy in adults by a common mechanism. PMID- 23450803 TI - Selective ruthenium-catalyzed transfer hydrogenations of nitriles to amines with 2-butanol. AB - Transfer your hydrogen: Fast and general transfer hydrogenation of nitriles to form primary amines is possible with a homogeneous Ru/1,4 bis(diphenylphosphino)butane (DPPB) catalyst (see scheme). The use of 2-butanol as the hydrogen-transfer reagent is essential for the selective reduction of aromatic, heteroaromatic, and aliphatic nitriles with this system. PMID- 23450804 TI - The effect of trazodone on standardized field sobriety tests. AB - STUDY OBJECTIVE: To evaluate the effects of a single dose of trazodone on the standardized field sobriety test (SFST). DESIGN: A randomized, double-blinded, repeated-measures study. PARTICIPANTS: Forty-five healthy adult subjects. SETTING: University campus. MEASUREMENTS AND MAIN RESULTS: The SFST consists of the horizontal gaze nystagmus, walk-and-turn, and one-leg stand tests. Subjects were administered a baseline SFST and at 2 hours after the administration of either trazodone 100 mg (30 subjects) or acetaminophen 650 mg (15 subjects). At 2 hours post drug administration, there were no statistical differences in failure rates between the trazodone and acetaminophen groups (53.3% vs 20.0%, p=0.054). However, the trazodone group exhibited more impairment clues within the individual tests of the SFST than the acetaminophen group. CONCLUSIONS: A one time dose of trazodone 100 mg does not result in an increased SFST failure rate at 2 hours postdosing compared to acetaminophen 650 mg. However, the number of individual impairment clues detected is increased with trazodone. Trazodone 100 mg may cause cognitive driving impairment. PMID- 23450802 TI - Fluorescence lifetime imaging of biosensor peptide phosphorylation in single live cells. PMID- 23450805 TI - The effect of temporal perception on weight perception. AB - A successful catch of a falling ball requires an accurate estimation of the timing for when the ball hits the hand. In a previous experiment in which participants performed ball-catching task in virtual reality environment, we accidentally found that the weight of a falling ball was perceived differently when the timing of ball load force to the hand was shifted from the timing expected from visual information. Although it is well known that spatial information of an object, such as size, can easily deceive our perception of its heaviness, the relationship between temporal information and perceived heaviness is still not clear. In this study, we investigated the effect of temporal factors on weight perception. We conducted ball-catching experiments in a virtual environment where the timing of load force exertion was shifted away from the visual contact timing (i.e., time when the ball hit the hand in the display). We found that the ball was perceived heavier when force was applied earlier than visual contact and lighter when force was applied after visual contact. We also conducted additional experiments in which participants were conditioned to one of two constant time offsets prior to testing weight perception. After performing ball-catching trials with 60 ms advanced or delayed load force exertion, participants' subjective judgment on the simultaneity of visual contact and force exertion changed, reflecting a shift in perception of time offset. In addition, timing of catching motion initiation relative to visual contact changed, reflecting a shift in estimation of force timing. We also found that participants began to perceive the ball as lighter after conditioning to 60 ms advanced offset and heavier after the 60 ms delayed offset. These results suggest that perceived heaviness depends not on the actual time offset between force exertion and visual contact but on the subjectively perceived time offset between them and/or estimation error in force timing. PMID- 23450806 TI - Biological design for simultaneous optical transparency and mechanical robustness in the shell of Placuna placenta. PMID- 23450807 TI - Comparison of Two Methods for the Determination of the Effects of Ionizing Radiation on Blood Cell Counts in Mice. AB - A reliable technique is needed to determine the effect of ionizing radiation on white blood cell (WBC) counts. Facilities that utilize automated methods can provide this service. However, utilizing external facilities can introduce additional variables, such as differences between time of sample collection and time of sample processing, which may affect the results. The purpose of the present study was to determine whether an automated method at an external facility can accurately determine radiation-induced changes in total WBC, lymphocyte and granulocyte counts when samples are analyzed at periods of time up to 24 hours after collection and stored either at room temperature or at 4 degrees C. To accomplish this, we compared automated blood cell counts determined at an external facility with our manual blood cell counts processed immediately after sample collection or 24 h after sample collection and stored either at room temperature or 4 degrees C from mice exposed to 2 Gy proton or 2 Gy gamma radiation. Our results show a close correlation and good agreement between the two methods, indicating that neither a delay of 24 hours in sample processing nor storage temperature affected white blood cell counts. Analysis of the effects of radiation on blood cell counts by either manual or automated cell counts revealed a statistically significant decrease in lymphocyte and granulocyte counts at different days post-irradiation, with no statistically significant difference between the methods employed; therefore both manual and automated blood cell counts are reliable methods to determine the effects of ionizing radiation in blood cells. PMID- 23450809 TI - An algorithm for the safety of costal diaphragm electromyography derived from ultrasound. PMID- 23450808 TI - Stable learning of functional maps in self-organizing spiking neural networks with continuous synaptic plasticity. AB - This study describes a spiking model that self-organizes for stable formation and maintenance of orientation and ocular dominance maps in the visual cortex (V1). This self-organization process simulates three development phases: an early experience-independent phase, a late experience-independent phase and a subsequent refinement phase during which experience acts to shape the map properties. The ocular dominance maps that emerge accommodate the two sets of monocular inputs that arise from the lateral geniculate nucleus (LGN) to layer 4 of V1. The orientation selectivity maps that emerge feature well-developed iso orientation domains and fractures. During the last two phases of development the orientation preferences at some locations appear to rotate continuously through +/-180 degrees along circular paths and referred to as pinwheel-like patterns but without any corresponding point discontinuities in the orientation gradient maps. The formation of these functional maps is driven by balanced excitatory and inhibitory currents that are established via synaptic plasticity based on spike timing for both excitatory and inhibitory synapses. The stability and maintenance of the formed maps with continuous synaptic plasticity is enabled by homeostasis caused by inhibitory plasticity. However, a prolonged exposure to repeated stimuli does alter the formed maps over time due to plasticity. The results from this study suggest that continuous synaptic plasticity in both excitatory neurons and interneurons could play a critical role in the formation, stability, and maintenance of functional maps in the cortex. PMID- 23450810 TI - Automatic cell cloning assay for determining the clonogenic capacity of cancer and cancer stem-like cells. AB - The clonogenic assay is a well-established in vitro method for testing the survival and proliferative capability of cells. It can be used to determine the cytotoxic effects of various treatments including chemotherapeutics and ionizing radiation. However, this approach can also characterize cells with different phenotypes and biological properties, such as stem cells or cancer stem cells. In this study, we implemented a faster and more precise method for assessing the cloning efficiency of cancer stem-like cells that were characterized and separated using a high-speed cell sorter. Cell plating onto a microplate using an automatic cell deposition unit was performed in a single-cell or dilution rank mode by the fluorescence-activated cell sorting method. We tested the new automatic cell-cloning assay (ACCA) on selected cancer cell lines and compared it with the manual approach. The obtained results were also compared with the results of the limiting dilution assay for different cell lines. We applied the ACCA to analyze the cloning capacity of different subpopulations of prostate and colon cancer cells based on the expression of the characteristic markers of stem (CD44 and CD133) and cancer stem cells (TROP-2, CD49f, and CD44). Our results revealed that the novel ACCA is a straightforward approach for determining the clonogenic capacity of cancer stem-like cells identified in both cell lines and patient samples. PMID- 23450811 TI - Neural correlates of sensory preconditioning: a preliminary fMRI investigation. AB - Sensory preconditioning (SPC; also known as behaviorally silent learning) consists of a combination of two neutral stimuli, none of which elicits an unconditional response. After one of them is later paired with an unconditional stimulus (US), the other neutral stimulus also yields a conditional response although it has never been paired with the US. In this study, an event-related functional magnetic resonance imaging (fMRI) paradigm was used to specify brain regions involved in SPC. The results demonstrated that SPC was associated with significant changes in activity of several regions, notably, the left amygdala, the left hippocampus, the bilateral thalamus, the bilateral medial globus pallidus, the bilateral cerebellum, the bilateral premotor cortex, and the bilateral middle frontal gyrus. This is a first effort to use fMRI to examine the effects of SPC on brain activation. Our data suggest that there is a distributed network of structures involved in SPC including both cortical and subcortical regions, therefore add to our understanding of the neural mechanisms underlying the ability to associative learning. PMID- 23450812 TI - Sensitivity enhanced nanothermal sensors for photoacoustic temperature mapping. AB - Photoacoustic imaging can be used to guide and validate the therapeutic outcome of nanoparticle-mediated photothermal therapy through its ability to visualize the delivery of nanoparticle contrast agents, image the temperature distribution inside living tissue, and confirm tissue coagulation. In this image-guided process, temperature mapping plays a critical role for thermal dosage control. Therefore, developing a sensitive and accurate photoacoustic technique to quantitatively measure the temperature distribution during thermal therapy is essential. In this study, we investigated and demonstrated that silica-coated gold nanorods, can provide a multi-fold improvement in sensitivity of the photoacoustic temperature mapping compared to gold nanorods without silica coating, and serve as a nanothermal sensor to accurately and quantitatively visualize temperature distributions during photothermal therapy. PMID- 23450813 TI - Aerobic oxidative coupling of arenes and olefins through a biomimetic approach. AB - Arenes and electron-deficient olefins can be oxidatively coupled through a biomimetic Pd(OAc)2-catalyzed transformation. C-H activation of the arene partner is effected under reaction conditions of low catalyst loading, normal oxygen pressure, and using p-benzoquinone and iron phthalocyanine as electron-transfer mediators (ETMs). By controlling catalyst loading, the reaction can be made selective for either mono- or diarylation. PMID- 23450814 TI - Asthma drugs and the risk of congenital anomalies. AB - STUDY OBJECTIVE: To estimate the prevalence of congenital anomalies between the offspring of women exposed and unexposed to asthma drugs during early pregnancy. DESIGN: Matched cohort study. DATABASE: The United Kingdom's General Practice Research Database. PATIENTS: Women exposed to asthma drugs during early pregnancy and a sample of matched unexposed pregnant women. MEASUREMENTS AND MAIN RESULTS: The prevalence of any anomaly among unexposed and exposed women was 27.8 (95% confidence interval [CI] 25.4-30.6)/1000 pregnancies and 31.3 (95% CI 27.7 35.5)/1000 pregnancies, respectively (relative risk [RR] 1.1 95% CI 1.0-1.3). CONCLUSION: Our findings suggest that asthma drugs, overall, do not increase the risk of congenital anomalies in the offspring when taken during the first trimester of pregnancy. PMID- 23450815 TI - Crystal-structure analysis of cis-X-Pro-containing peptidomimetics: understanding the steric interactions at cis X-Pro amide bonds. PMID- 23450816 TI - Chemical degradation in organic light-emitting devices: mechanisms and implications for the design of new materials. AB - Degradation of the materials in organic light-emitting devices (OLEDs) is the major impediment for the development of economically feasible, highly efficient and durable devices for commercial applications. Even though this chemical degradation is complex and the least understood of the different degradation modes in OLEDs, scientists were successful in providing insight into some of the responsible processes. In this progress report we will review recent advances in the elucidation of chemical degradation mechanisms: First possible reasons for defect formation and the most common and important methods to investigate those processes are covered before discussing the reactions and their products for the different types of materials present in a device. We summarize commonalities in the occurring mechanisms, and identify structural features and moieties that can be detrimental to operational stability. Some of the resulting implications on the development of new materials are presented and backed by concrete examples from literature. PMID- 23450817 TI - Acceleration apportionment: a method of improved 2D SENSE acceleration applied to 3D contrast-enhanced MR angiography. AB - PURPOSE: In 2D SENSE-accelerated 3D Cartesian acquisition, the net acceleration factor R is the product of the two individual accelerations, R = RY * RZ. Acceleration Apportionment tailors acceleration parameters (RY, RZ) to improve parallel imaging performance on a patient- and coil-specific basis and is demonstrated in contrast-enhanced MR angiography. METHODS: A performance metric is defined based on coil sensitivity information which identifies the (RY, RZ) pair that optimally trades off image quality with scan time reduction on a patient-specific basis. Acceleration Apportionment is evaluated using retrospective analysis of contrast-enhanced MR angiography studies, and prospective studies in which optimally apportioned parameters are compared with standard acceleration parameters. RESULTS: The retrospective studies show strong variability in optimal acceleration parameters between anatomic regions and between patients. Prospective application of apportionment to foot contrast enhanced MR angiography with an 8-channel receiver array provides a 20% increase in net acceleration with improved contrast-to-noise ratio. Application to 16 channel contrast-enhanced MR angiography of the feet and calves suggests 10% acceleration increase to R > 13 and no contrast-to-noise ratio loss. The specific implementation allows the optimum (RY, RZ) pair to be determined within one minute. CONCLUSION: Optimum 2D SENSE acceleration parameters can be automatically chosen on a per-exam basis to allow improved performance without disrupting the clinical workflow. PMID- 23450818 TI - Blast cell deficiency of CD11a as a marker of acute megakaryoblastic leukemia and transient myeloproliferative disease in children with and without Down syndrome. AB - BACKGROUND: The classification of acute myeloid leukemia (AML) FAB subtype M7 relies on immunophenotypic assessment. CD41 is expressed throughout all stages of maturation of megakaryocytes and has therefore been described as a specific blast cell marker in AML M7 as well as in transient myeloproliferative disease (TMD) of patients with Down syndrome (DS). However, technical difficulties underlie the need for new markers for these entities. METHODS: We evaluated the expression of human lymphocyte function-associated antigen 1 (CD11a) in a large cohort of pediatric AML and TMD patients (n = 91) of the Austrian AML-BFM 98 and 2004 studies. RESULTS: We found a consistent deficiency of CD11a as assessed by mean fluorescence intensity in all patients with non-DS AML M7 (n = 8) and M6 (n = 1), all cases of classical DS-AML (n = 12) as well as TMD (n = 15) that was statistically significant in comparison to non-DS AML M0-M5 patients (n = 55; P < 0.001, sensitivity 100%). Only three of 55 Non-DS M0-5 patients were CD11a deficient (specificity 95%). Monocytic leukemias (M4/5) and normal monocytes typically showed a high CD11a expression, FAB types M1/2 and normal neutrophils an intermediate expression level, while all M3 leukemias were rather low in CD11a expression. CONCLUSIONS: We conclude, that deficiency of CD11a expression should be added to the diagnostic criteria of AML-M7, classical DS-AML and TMD. PMID- 23450819 TI - Genetic and clinical characteristics of skeletal and cardiac muscle in patients with lamin A/C gene mutations. AB - Alterations of the lamin A/C (LMNA) gene are associated with different clinical entities, including disorders that affect skeletal and cardiac muscle, peripheral nerves, metabolism, bones, and disorders that cause premature aging. In this article we review the clinical and genetic characteristics of cardiac and skeletal muscle diseases related to alterations in the LMNA gene. There is no single explanation of how LMNA gene alterations may cause these disorders; however, important goals have been achieved in understanding the pathogenic effects of LMNA gene mutations on cardiac and skeletal muscle. PMID- 23450820 TI - Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease, which primarily targets the motor system. The structural integrity of the motor network and the way it is embedded in the overall brain network is essential for motor functioning. We studied the longitudinal effects of ALS on the brain network using diffusion tensor imaging and questioned whether over time an increasing number of connections become involved or whether there is progressive impairment of a limited number of connections. The brain network was reconstructed based on "whole brain" diffusion tensor imaging data. We examined: (1) network integrity in 24 patients with ALS at baseline (T = 1) and at a more advanced stage of the disease (T = 2; interval 5.5 months) compared with a group of healthy controls and (2) progressive brain network impairment comparing patients at two time points in a paired-analysis. These analyses demonstrated an expanding subnetwork of affected brain connections over time with a central role for the primary motor regions (P-values T = 1 0.003; T = 2 0.001). Loss of structural connectivity mainly propagated to frontal and parietal brain regions at T = 2 compared with T = 1. No progressive impairment of the initially affected (motor) connections could be detected. The main finding of this study is an increasing loss of network structure in patients with ALS. In contrast to the theory of ALS solely affecting a fixed set of primary motor connections, our findings show that the network of impaired connectivity is expanding over time. These results are in support of disease spread along structural brain connections. PMID- 23450821 TI - Quantitative approach to skin field cancerization using a nanoencapsulated photodynamic therapy agent: a pilot study. AB - BACKGROUND: This paper introduces a new nanoformulation of 5-aminolevulinic acid (nano-ALA) as well as a novel quantitative approach towards evaluating field cancerization for actinic keratosis and/or skin photodamage. In this pilot study, we evaluated field cancerization using nano-ALA and methyl aminolevulinate (MAL), the latter being commercialized as Metvix((r)). METHODS AND RESULTS: Photodynamic therapy was used for the treatment of patients with selected skin lesions, whereas the fluorescence of the corresponding photosensitizer was used to evaluate the time evolution of field cancerization in a quantitative way. Field cancerization was quantified using newly developed color image segmentation software. Using photodynamic therapy as the precancer skin treatment and the approach introduced herein for evaluation of fluorescent area, we found that the half-life of field cancerization reduction was 43.3 days and 34.3 days for nano ALA and MAL, respectively. We also found that nano-ALA targeted about 45% more skin lesion areas than MAL. Further, we found the mean reduction in area of skin field cancerization was about 10% greater for nano-ALA than for MAL. CONCLUSION: Although preliminary, our findings indicate that the efficacy of nano-ALA in treating skin field cancerization is higher than that of MAL. PMID- 23450822 TI - Tyramine Reveals Failing alpha2-Adrenoceptor Control of Catecholamine Release and Total Peripheral Vascular Resistance in Hypertensive Rats. AB - alpha2-Adrenoceptor-activation lowers central sympathetic output, peripheral, vesicular norepinephrine release, epinephrine secretion, and modulates vascular tension. We previously demonstrated that alpha2-adrenoceptor-mediated inhibition of basal norepinephrine release was not reflected in plasma unless re-uptake through the norepinephrine transporter (NET) was blocked. Tyramine activates reverse norepinephrine transport through NET. Here we tested the hypothesis that tyramine, by engaging NET in release, also blocks re-uptake, and therefore allows manipulation of pre-junctional alpha2-adrenoceptors to directly regulate norepinephrine overflow to plasma. We compared in anesthetized spontaneously hypertensive rats (SHRs) and normotensive controls (WKYs), the effect of alpha2 adrenoreceptor antagonist (L-659,066) and/or agonist (clonidine) on norepinephrine overflow and increase in total peripheral vascular resistance (TPR) evoked by tyramine-infusion (1.26 MUmol/min/kg, 15 min) and epinephrine secretion activated by the surgical stress. TPR was computed as blood pressure divided by cardiac output, recorded as ascending aortic flow. Plasma catecholamine concentrations after tyramine were higher in SHRs than WKYs. Pre treatment with L-659,066 increased the catecholamine concentrations in WKYs, but only if combined with clonidine in SHRs. Clonidine alone reduced tyramine-induced norepinephrine overflow in SHRs, and epinephrine in both strains. Tyramine induced increase in TPR was not different after clonidine, eliminated after L 659,066 and L-659,066 + clonidine in WKYs, but only after L-659,066 + clonidine in SHRs. We conclude that tyramine-infusion does allow presynaptic regulation of vesicular release to be accurately assessed by measuring differences in plasma norepinephrine concentration. Our results indicate that presynaptic alpha2 adrenoceptor regulation of norepinephrine release from nerve vesicles and epinephrine secretion is dysfunctional in SHRs, but can be restored by clonidine. PMID- 23450823 TI - On the mutational topology of the bacterial genome. AB - By sequencing the genomes of 34 mutation accumulation lines of a mismatch-repair defective strain of Escherichia coli that had undergone a total of 12,750 generations, we identified 1625 spontaneous base-pair substitutions spread across the E. coli genome. These mutations are not distributed at random but, instead, fall into a wave-like spatial pattern that is repeated almost exactly in mirror image in the two separately replicated halves of the bacterial chromosome. The pattern is correlated to genomic features, with mutation densities greatest in regions predicted to have high superhelicity. Superimposed upon this pattern are regional hotspots, some of which are located where replication forks may collide or be blocked. These results suggest that, as they traverse the chromosome, the two replication forks encounter parallel structural features that change the fidelity of DNA replication. PMID- 23450824 TI - Acoustic analyses of speech sounds and rhythms in Japanese- and english-learning infants. AB - The purpose of this study was to explore developmental changes, in terms of spectral fluctuations and temporal periodicity with Japanese- and English learning infants. Three age groups (15, 20, and 24 months) were selected, because infants diversify phonetic inventories with age. Natural speech of the infants was recorded. We utilized a critical-band-filter bank, which simulated the frequency resolution in adults' auditory periphery. First, the correlations between the power fluctuations of the critical-band outputs represented by factor analysis were observed in order to see how the critical bands should be connected to each other, if a listener is to differentiate sounds in infants' speech. In the following analysis, we analyzed the temporal fluctuations of factor scores by calculating autocorrelations. The present analysis identified three factors as had been observed in adult speech at 24 months of age in both linguistic environments. These three factors were shifted to a higher frequency range corresponding to the smaller vocal tract size of the infants. The results suggest that the vocal tract structures of the infants had developed to become adult-like configuration by 24 months of age in both language environments. The amount of utterances with periodic nature of shorter time increased with age in both environments. This trend was clearer in the Japanese environment. PMID- 23450825 TI - Adult-onset Idiopathic Focal Lower Extremity Dystonia: A Rare Task-Specific Dystonia. AB - BACKGROUND: Adult-onset focal lower extremity (LE) dystonia is rare, but there have recently been a number of case series that have reported an idiopathic variant triggered during ambulation. METHODS: We describe nine patients with idiopathic, focal task-specific LE dystonia. We conducted a comparative analysis that included our cohort and several recently published case series to further characterize the disorder. RESULTS: A total of 48 patients (37 female, 11 male) were compared. The average age of onset was 48 years; 36 patients had distal extremity involvement (75%), 5 proximal (10%), and 7 both proximal and distal (15%). Among 33 patients in which the dystonic side was known, 20 were affected on the left (61%). Inversion of the foot with flexion of one or more toes was the most prevalent pattern in those with distal extremity involvement. DISCUSSION: This is a novel task-specific dystonia triggered during ambulation that is often misdiagnosed as an orthopedic or psychogenic issue. PMID- 23450826 TI - Dual-wavelength excitation for fluorescence-based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood. AB - Quantification of erythrocyte zinc protoporphyrin IX (ZnPP) and protoporphyrin IX (PPIX), individually or jointly, is useful for the diagnostic evaluation of iron deficiency, iron-restricted erythropoiesis, lead exposure, and porphyrias. A method for simultaneous quantification of ZnPP and PPIX in unwashed blood samples is described, using dual-wavelength excitation to effectively eliminate background fluorescence from other blood constituents. In blood samples from 35 subjects, the results of the dual-wavelength excitation method and a reference high performance liquid chromatography (HPLC) assay were closely correlated both for ZnPP (rs = 0.943, p < 0.0001; range 37-689 MUmol ZnPP/mol heme, 84-1238 nmol/L) and for PPIX (rs = 0.959, p < 0.0001; range 42-4212 MUmol PPIX/mol heme, 93-5394 nmol/L). In addition, for ZnPP, the proposed method is compared with conventional single-wavelength excitation and with commercial front-face fluorimetry of washed erythrocytes and whole blood. We hypothesize that dual wavelength excitation fluorimetry will provide a new approach to the suppression of background fluorescence in blood and tissue measurements of ZnPP and PPIX. PMID- 23450827 TI - Over-the-counter access to emergency contraception without age restriction: an opinion of the Women's Health Practice and Research Network of the American College of Clinical Pharmacy. AB - Family planning remains a high priority area for the United States, with goals to increase the proportion of pregnancies that are intended, reduce pregnancy rates among adolescents, and increase contraceptive use prioritized in the Healthy People 2020 objectives. Contraception intended for use after unprotected intercourse, known as emergency contraception, remains underutilized. Levonorgestrel is one method of oral emergency contraception, which prevents fertilization and does not disrupt an already established pregnancy; thus, timing of administration is critical. Despite data demonstrating safety and efficacy, evidence-based decision making has been overshadowed by politically charged actions involving levonorgestrel emergency contraception for over a decade. The Women's Health Practice and Research Network of the American College of Clinical Pharmacy supports expanded access to levonorgestrel emergency contraception and removal of barriers such as age restrictions on the nonprescription drug product. Pharmacists remain a key provider of emergency contraceptive services and can help ensure timely access. In states where direct pharmacy access to emergency contraception is available, pharmacists are encouraged to participate. Education, research, and advocacy are other important responsibilities for pharmacists in this arena. PMID- 23450828 TI - Resolving multiple non-equivalent metal sites in magnesium-containing metal organic frameworks by natural abundance (25)Mg solid-state NMR spectroscopy. AB - In a spin: Directly differentiating multiple Mg sites in Mg-containing MOFs by (25)Mg solid-state NMR spectroscopy is very challenging at natural abundance. By performing (25)Mg two-dimensional triple-quantum magic-angle spinning solid-state NMR experiments at a magnetic field of 21.1 T at natural abundance, four non equivalent Mg sites with very similar local environments in alpha-Mg(3)(HCOO)(6) were unambiguously resolved (see figure). PMID- 23450829 TI - Hierarchically structured nanotubes for highly efficient dye-sensitized solar cells. AB - Hierarchical TiO2 nanotube arrays grown on Ti foil are yielded by subjecting electrochemically anodized, vertically oriented TiO2 nanotube arrays to hydrothermal processing. The resulting DSSCs exhibit a significantly enhanced power conversion efficiency of 7.24%, which is a direct consequence of the synergy of higher dye loading, superior light-scattering ability, and fast electron transport. PMID- 23450830 TI - Chemical tricks to stabilize silanones and their heavier homologues with E=O bonds (E=Si-Pb): from elusive species to isolable building blocks. AB - In contrast to the well-established chemistry of ketones (R2C=O), the reactivity of the elusive heavier congeners R2E=O (E=Si, Ge, Sn, Pb) is far less explored because of the high polarity of the E=O bonds and hence their tendency to oligomerize with no activation barrier. Very recently, great advances have been achieved in the synthesis of isolable compounds with E=O bonds, including the investigation of donor-stabilized isolable silanones and the first stable "genuine" germanone. These compounds show drastically different reactivities compared to ketones and represent versatile building blocks in silicon-oxygen and germanium-oxygen chemistry. This and other exciting achievements are described in this Minireview. PMID- 23450831 TI - Potential therapeutic biomarkers in plasma cell myeloma: a flow cytometry study. AB - OBJECTIVE: To investigate the expression profile of potential therapeutic biomarkers in plasma cell myeloma (PCM) by multicolor flow cytometry analysis. METHODS: Bone marrow (BM) specimens were collected consecutively and analyzed using a routine PCM panel (CD38/CD138/CD45/CD19/CD20/CD28/CD56/CD117, cyto kappa/lambda). The specimens were further assessed for CD30, CD44, CD49d, CD70, CD105, and CD184 expression in cases containing a substantial number of neoplastic plasma cells. RESULTS: Totally, 101 patient BM samples were assessed, including 58 men and 43 women, with a median age of 64 years (34-89). Twenty-nine patients had newly diagnosed/untreated PCM, 40 had persistent/residual disease undergoing various therapies and 32 had relapsed disease. CD49d was expressed brightly and uniformly in all 45 patients tested. Expression of CD44 and CD184 was more variable with a median percentage of 77% (1-100) and 65% (5-100) respectively. Using an arbitrary 20% cutoff, CD44 was positive in 74 (73%) and CD184 in 92 (91%) cases with a mean fluorescence intensity ratio of 42.8 and 21.4. A higher CD44 expression was observed in patients with recurrent/persistent disease (P = 0.028). Additionally, both CD44 (P = 0.002) and CD184 (P = 0.026) showed higher expressions in CD117-positive cases, but there was no correlation with cytogenetic groups. The CD30, CD70, and CD105 were expressed very infrequently in PCM, with a median expression of 0.2%, 0.2%, and 0.4% respectively. CONCLUSIONS: CD49d, CD44, and CD184, are highly expressed in PCM. CD49d expression is bright and uniform, whereas CD44 and CD184 are more heterogeneous. In contrast, surface CD30, CD70, and CD105 are infrequent. These data provide useful preclinical information for the design of potential novel targeted therapies in PCM patients. PMID- 23450832 TI - Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivo--a systematic review. AB - BACKGROUND: There is considerable debate about whether concomitant use of proton pump inhibitors (PPIs) should be recommended for patients who are prescribed clopidogrel after acute coronary syndrome. Most pharmacokinetic and pharmacodynamic studies in vivo were conducted using small sample sizes and were single centered, resulting in conflicting data. HYPOTHESIS: PPIs may attenuate the antiplatelet effect of clopidogrel in vivo and lead to an increased risk of cardiovascular events. METHODS: PubMed, the Cochrane Library, Embase, Web of Science, and China Biology Medicine Disc were searched. Randomized controlled trials that compared pharmacodynamic impacts of a PPI on the efficacy of clopidogrel in vivo were included. Two independent reviewers evaluated study quality and extracted data for meta-analysis. RESULTS: We identified 8 eligible studies. Compared to clopidogrel treatment alone, patients who received both a PPI and clopidogrel had less of a decrease in the platelet reactivity index (weighted mean difference [WMD]: 8.18; 95% confidence interval [CI]: 6.81-9.56; P<0.00001), less adenosine 5'-diphosphate-induced platelet aggregation inhibition (WMD: 7.28; 95% CI: 2.44-12.11; P=0.003), higher P2Y12 reaction units (WMD: 40.58; 95% CI: 19.31-61.86; P=0.0002), and higher risks of clopidogrel resistance (odds ratio [OR]: 2.49; 95% CI: 1.49-4.14; P=0.0005). There were no significant differences, however, for the incidences of major adverse cardiovascular events between the 2 groups (OR: 1.07; 95% CI: 0.44-2.59; P=0.88), and treatment with a PPI and clopidogrel significantly reduced the risk of adverse gastrointestinal events (OR: 0.16; 95% CI: 0.04-0.62; P=0.008). CONCLUSIONS: Concomitant use of a PPI with clopidogrel attenuated the antiplatelet effect of clopidogrel, but may be clinically unimportant because there were no clinical differences in the risk for major adverse cardiovascular events. PMID- 23450833 TI - Differences in cortical coding of heat evoked pain beyond the perceived intensity: an fMRI and EEG study. AB - Imaging studies have identified a wide network of brain areas activated by nociceptive stimuli and revealed differences in somatotopic representation of highly distinct stimulation sites (foot vs. hand) in the primary (S1) and secondary (S2) somatosensory cortices. Somatotopic organization between adjacent dermatomes and differences in cortical coding of similarly perceived nociceptive stimulation are less well studied. Here, cortical processing following contact heat nociceptive stimulation of cervical (C4, C6, and C8) and trunk (T10) dermatomes were recorded in 20 healthy subjects using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Stimulation of T10 compared with the C6 and C8 revealed significant higher response intensity in the left S1 (contralateral) and the right S2 (ipsilateral) even when the perceived pain was equal between stimulation sites. Accordingly, contact heat evoked potentials following stimulation of T10 showed significantly higher N2P2 amplitudes compared to C6 and C8. Adjacent dermatomes did not reveal a distinct somatotopical representation. Within the assessed cervical and trunk dermatomes, nociceptive cortical processing to heat differs significantly in magnitude even when controlling for pain perception. This study provides evidence that controlling for pain perception is not sufficient to compare directly the magnitude of cortical processing [blood oxygen level dependence (BOLD) response and amplitude of evoked potentials] between body sites. PMID- 23450834 TI - Evaluation of the effect of beetroot juice on DMBA-induced damage in liver and mammary gland of female Sprague-Dawley rats. AB - Red beetroot contains a specific class of antioxidants collectively named betalains, which have been shown to have anticarcinogenic and anti-inflamatory potential. We investigated the effect of beetroot juice on the hepatic and mammary gland carcinogen metabolizing enzymes, DNA damage and liver injury, altered by 7,12-dimethylbenz[a]anthracene (DMBA). In the liver, pretreatment with beetroot juice significantly decreased levels and activities of the majority of tested biochemical parameters, elevated by DMBA. Feeding with beetroot juice decreased the activities of CYP1A1 and 1A2 and increased phase II enzymes. The activities of all enzymes tested were enhanced in the animals treated with DMBA alone and in combination with beetroot juice. The most significant changes in the level of the enzymes tested were observed for NAD(P)H: quinone oxidoreductase-1. In mammary gland, beetroot juice induced the level of glutathione S-transferase pi, enzyme involved in active metabolites of DMBA detoxification. The final effects of beetroot juice are tissue specific and depend on the class of carcinogen. PMID- 23450835 TI - Supported noble metals on hydrogen-treated TiO2 nanotube arrays as highly ordered electrodes for fuel cells. AB - Hydrogen-treated TiO2 nanotube (H-TNT) arrays serve as highly ordered nanostructured electrode supports, which are able to significantly improve the electrochemical performance and durability of fuel cells. The electrical conductivity of H-TNTs increases by approximately one order of magnitude in comparison to air-treated TNTs. The increase in the number of oxygen vacancies and hydroxyl groups on the H-TNTs help to anchor a greater number of Pt atoms during Pt electrodeposition. The H-TNTs are pretreated by using a successive ion adsorption and reaction (SIAR) method that enhances the loading and dispersion of Pt catalysts when electrodeposited. In the SIAR method a Pd activator can be used to provide uniform nucleation sites for Pt and leads to increased Pt loading on the H-TNTs. Furthermore, fabricated Pt nanoparticles with a diameter of 3.4 nm are located uniformly around the pretreated H-TNT support. The as-prepared and highly ordered electrodes exhibit excellent stability during accelerated durability tests, particularly for the H-TNT-loaded Pt catalysts that have been annealed in ultrahigh purity H2 for a second time. There is minimal decrease in the electrochemical surface area of the as-prepared electrode after 1000 cycles compared to a 68 % decrease for the commercial JM 20 % Pt/C electrode after 800 cycles. X-ray photoelectron spectroscopy shows that after the H-TNT-loaded Pt catalysts are annealed in H2 for the second time, the strong metal-support interaction between the H-TNTs and the Pt catalysts enhances the electrochemical stability of the electrodes. Fuel-cell testing shows that the power density reaches a maximum of 500 mWcm(-2) when this highly ordered electrode is used as the anode. When used as the cathode in a fuel cell with extra-low Pt loading, the new electrode generates a specific power density of 2.68 kWg(Pt) (-1) . It is indicated that H-TNT arrays, which have highly ordered nanostructures, could be used as ordered electrode supports. PMID- 23450836 TI - Influences of the non-covalent interaction strength on reaching high solid-state order and device performance of a low bandgap polymer with axisymmetrical structural units. AB - A high organic field-effect transistor mobility (0.29 cm(2) V(-1) s(-1) ) and bulk-heterojunction polymer solar cell performance (PCE of 6.82%) have been achieved in a low bandgap alternating copolymer consisting of axisymmetrical structural units, 5,6-difluorobenzo-2,1,3-thiadiazole. Introducing the fluorine substituents enhanced intermolecular interaction and improved the solid-state order, which consequently resulted in the highest device performances among the 2,1,3-thiadiazole-quarterthiophene based alternating copolymers. PMID- 23450837 TI - De novo design of nanostructured iron-cobalt Fischer-Tropsch catalysts. PMID- 23450838 TI - Basophilic histamine content and release during venom immunotherapy: insights by flow cytometry. AB - BACKGROUND: Despite the efficiency of venom immunotherapy, the effects on basophils and mast cells remain incompletely understood and probably vary according to the treatment phase. OBJECTIVES: To study the effect of build-up and maintenance venom immunotherapy on individual basophils. METHODS: Intracellular histamine and its release was analyzed flow cytometrically by a new enzyme affinity method using diamine oxidase conjugated to laser-excitable fluorochromes. Phenotyping of cells included flow cytometric quantification of CD63 and CD203c. Analyses of basophil activation experiments were performed before the start of treatment, after build-up therapy and during maintenance therapy. RESULTS: Before the start of therapy, patients demonstrated significantly higher numbers of basophils when compared with stung control individuals. At the end of build-up therapy a decrease of basophil numbers was observed, whereas during maintenance therapy basophil counts returned to pretreatment values. Before the start of therapy, the intracellular histamine content per cell in patients was significantly higher when compared with stung control individuals. During maintenance therapy intracellular histamine content decreased to values observed in stung control individuals. In addition, maintenance therapy lowered the net release of histamine per cell in response to optimal stimulation with wasp venom. CONCLUSIONS: We introduce a novel technique that enables to assess the effects of venom immunotherapy on basophils. This new technique may help to monitor treatment effects in individual patients and could aid in the development of more efficient and better tolerated immunotherapy protocols. PMID- 23450839 TI - An intraoral thermoregulatory organ in the bowhead whale (Balaena mysticetus), the corpus cavernosum maxillaris. AB - The novel observation of a palatal retial organ in the bowhead whale (Balaena mysticetus) is reported, with characterization of its form and function. This bulbous ridge of highly vascularized tissue, here designated the corpus cavernosum maxillaris, runs along the center of the hard palate, expanding cranially to form two large lobes that terminate under the tip of the rostral palate, with another enlarged node at the caudal terminus. Gross anatomical and microscopic observation of tissue sections discloses a web-like internal mass with a large blood volume. Histological examination reveals large numbers of blood vessels and vascular as well as extravascular spaces resembling a blood filled, erectile sponge. These spaces, as well as accompanying blood vessels, extend to the base of the epithelium. We contend that this organ provides a thermoregulatory adaptation by which bowhead whales (1) control heat loss by transferring internal, metabolically generated body heat to cold seawater and (2) protect the brain from hyperthermia. We postulate that this organ may play additional roles in baleen growth and in detecting prey, and that its ability to dissipate heat might maintain proper operating temperature for palatal mechanoreceptors or chemoreceptors to detect the presence and density of intraoral prey. PMID- 23450841 TI - Group cognitive behavioral therapy for patients with generalized social anxiety disorder in Japan: outcomes at 1-year follow up and outcome predictors. AB - BACKGROUND: Social anxiety disorder (SAD) is one of the most common psychiatric disorders worldwide. Cognitive behavioral therapy (CBT) is an effective treatment option for patients with SAD. In the present study, we examined the efficacy of group CBT for patients with generalized SAD in Japan at 1-year follow-up and investigated predictors with regard to outcomes. METHODS: This study was conducted as a single-arm, naturalistic, follow-up study in a routine Japanese clinical setting. A total of 113 outpatients with generalized SAD participated in group CBT from July 2003 to August 2010 and were assessed at follow-ups for up to 1 year. Primary outcome was the total score on the Social Phobia Scale/Social Interaction Anxiety Scale (SPS/SIAS) at 1 year. Possible baseline predictors were investigated using mixed-model analyses. RESULTS: Among the 113 patients, 70 completed the assessment at the 1-year follow-up. The SPS/SIAS scores showed significant improvement throughout the follow-ups for up to 1 year. The effect sizes of SPS/SIAS at the 1-year follow-up were 0.68 (95% confidence interval 0.41 0.95)/0.76 (0.49-1.03) in the intention-to-treat group and 0.77 (0.42-1.10)/0.84 (0.49-1.18) in completers. Older age at baseline, late onset, and lower severity of SAD were significantly associated with good outcomes as a result of mixed model analyses. CONCLUSIONS: CBT for patients with generalized SAD in Japan is effective for up to 1 year after treatment. The effect sizes were as large as those in previous studies conducted in Western countries. Older age at baseline, late onset, and lower severity of SAD were predictors for a good outcome from group CBT. PMID- 23450842 TI - Uremia and chronic kidney disease: the role of the gut microflora and therapies with pro- and prebiotics. AB - Uremia is an illness that accompanies kidney failure and chronic kidney disease (CKD). Uremic illness is considered to be due largely to the accumulation of organic waste products that are normally cleared by the kidneys. However, uremic retention solutes are generated in part in the gastrointestinal tract (GIT), with the gut microbiota and the ensuing micro-biometabolome playing a significant role in the proliferation of uremic retention solutes. Toxins generated in, or introduced into the body via the intestine, such as advanced glycation end products, phenols, and indoles, all may contribute to the pathogenesis of CKD. Hence, it is biologically plausible, but not well recognized, that an important participant in the toxic load that contributes to CKD originates in the GIT. The microbiota that colonize the GIT perform a number of functions that include regulating the normal development and function of the mucosal barriers; assisting with maturation of immunological tissues, which in turn promotes immunological tolerance to antigens from foods, the environment, or potentially pathogenic organisms; controlling nutrient uptake and metabolism; and preventing propagation of pathogenic micro-organisms. Here, we develop a hypothesis that probiotics and prebiotics have a therapeutic role in maintaining a metabolically balanced GIT, and reducing progression of CKD and associated uremia. PMID- 23450843 TI - Resilience in shock and swim stress models of depression. AB - Experimental models of depression often entail exposing a rodent to a stressor and subsequently characterizing changes in learning and anhedonia, which may reflect symptoms of human depression. Importantly, not all people, and not all laboratory rats, exposed to stressors develop depressed behavior; these "resilient" individuals are the focus of our review. Herein we describe research from the "learned helplessness" and "intermittent swim stress" (ISS) models of depression in which rats that were allowed to control the offset of the aversive stimulus with a behavioral response, and in a subset of rats that were not allowed to control the stressor that appeared to be behaviorally and neurochemically similar to rats that were either naive to stress or had controllability over the stressor. For example, rats exposed to inescapable tailshock, but do not develop learned helplessness, exhibit altered sensitivity to the behavioral effects of GABAA receptor antagonists and reduced in vitro benzodiazepine receptor ligand binding. This pattern suggested that resilience might involve activation of an endogenous benzodiazepine-like compound, possibly an allostatic modulator of the GABAA receptor like allopregnanolone. From the ISS model, we have observed in resilient rats protection from stressor-induced glucocorticoid increases and immune activation. In order to identify the neural mediators of these correlates of resilience, non-invasive measures are needed to predict the resilient or vulnerable phenotype prior to analysis of neural endpoints. To this end, we found that ultrasonic vocalizations (USVs) appear to predict the resilient phenotype in the ISS paradigm. We propose that combining non-invasive predictive measures, such as USVs with biological endpoint measures, will facilitate future research into the neural correlates of resilience. PMID- 23450844 TI - Reviewing the effectiveness of pre-pregnancy counseling protocol on pregnancy and labor indices. AB - BACKGROUND: Pre-pregnancy care is considered as the services assessing and reducing the pregnancy risks through providing medical care and mental support. Therefore, a pre-pregnancy counseling protocol was prepared based on a series of guidelines. This study aimed to determine the effect of the protocol on pregnancy and labor indices. METHODS: This was a four-phase field study conducted in four randomly selected urban and rural health centers in Shahreza. In the first phase, the information including pregnancy and labor indices was extracted. The participants were all the women who had a delivery in the year before the study (census). In the second and third phases (3 and 6 months after implementing the protocol in the case centers), the process of implementing the protocol was assessed. In the fourth phase (a year later), pregnancy and labor indices were determined in case and control centers (on all the women who had labor in the year before) again and the results were compared in case and control groups as well as before and after implementing the protocol. Data was collected by reviewing documentations and using data collection forms. It was then analyzed by descriptive and analytical statistics using SPSS13. RESULTS: The obtained results indicated the positive effects of pre-pregnancy cares on cesarean indices, percentage of underlying diseases, pregnancy over the age of 35, and pregnancy intervals of less than 3 years. In addition, the protocol had been implemented correctly in 8.2% of the cases in the second phase, and in 30.2% of the cases in the third phase. CONCLUSIONS: The positive effects of pre-pregnancy cares on some of the indices raised the necessity of seriously considering and integrating this program in the routine women's health care programs. Considering that less than one-third of the staff members of the case centers had completely conducted the pre-pregnancy cares, monitoring the staff's performance is essential for improving the effectiveness of the care. PMID- 23450846 TI - Seeing is Believing but is Hearing? Comparing Audio and Video Communication for Young Children. AB - Video communication has been shown to create a sense of proximity between young children and parents. To determine if video affords a stronger sense of proximity and engagement than a traditional telephone, the current experiment employed a Separation and Reunion Paradigm with either a video-link or an audio-link available to the separated dyad. Results revealed that during the separation with a video-link, more children remained content to be physically alone than during the audio-link, children played more and displayed more positive affect. This is the first empirical demonstration that video provides a stronger sense of proximity and enjoyment for young children than audio, suggesting that video is a more appropriate medium to meaningfully connect children to relatives during geographical separation. PMID- 23450845 TI - A mosaic genetic screen for genes involved in the early steps of Drosophila oogenesis. AB - The first hours of Drosophila embryogenesis rely exclusively on maternal information stored within the egg during oogenesis. The formation of the egg chamber is thus a crucial step for the development of the future adult. It has emerged that many key developmental decisions are made during the very first stages of oogenesis. We performed a clonal genetic screen on the left arm of chromosome 2 for mutations affecting early oogenesis. During the first round of screening, we scored for defects in egg chambers morphology as an easy read-out of early abnormalities. In a second round of screening, we analyzed the localization of centrosomes and Orb protein within the oocyte, the position of the oocyte within the egg chamber, and the progression through meiosis. We have generated a collection of 71 EMS-induced mutants that affect oocyte determination, polarization, or localization. We also recovered mutants affecting the number of germline cyst divisions or the differentiation of follicle cells. Here, we describe the analysis of nine complementation groups and eight single alleles. We mapped several mutations and identified alleles of Bicaudal-D, lethal(2) giant larvae, kuzbanian, GDP-mannose 4,6-dehydratase, tho2, and eiF4A. We further report the molecular identification of two alleles of the Drosophila homolog of Che-1/AATF and demonstrate its antiapoptotic activity in vivo. This collection of mutants will be useful to investigate further the early steps of Drosophila oogenesis at a genetic level. PMID- 23450848 TI - Longitudinal Relationships Between Self-Management Skills and Substance Use in an Urban Sample of Predominantly Minority Adolescents. AB - We explored changes in self-management skills and substance use from 7th to 11th grade in a multiwave study of predominantly minority adolescents (N = 1,756). Using latent growth curve analysis, we found that substance use significantly increased, whereas self-management skills significantly decreased. In a parallel process model, we found that participants who reported higher self-management skills in the 7th grade had smaller increases in substance use. Participants who had larger decreases in self-management skills tended to have greater increases in substance use. We also explored the influence of grades and gender and found that (a) participants with higher grades at baseline had lower initial substance use, higher initial self-management skills, and smaller increases in substance use, and (b) male participants had greater increases in substance use. These results suggest that the provision of self-management skills may be an effective strategy for preventing substance-use initiation and escalation during adolescence. PMID- 23450847 TI - Classification of fMRI patterns--a study of the language network segregation in pediatric localization related epilepsy. AB - This article describes a pattern classification algorithm for pediatric epilepsy using fMRI language-related activation maps. 122 fMRI datasets from a control group (64) and localization related epilepsy patients (58) provided by five children's hospitals were used. Each subject performed an auditory description decision task. Using the artificial data as training data, incremental Principal Component Analysis was used in order to generate the feature space while overcoming memory requirements of large datasets. The nearest-neighbor classifier (NNC) and the distance-based fuzzy classifier (DFC) were used to perform group separation into left dominant, right dominant, bilateral, and others. The results show no effect of age, age at seizure onset, seizure duration, or seizure etiology on group separation. Two sets of parameters were significant for group separation, the patient vs. control populations and handedness. Of the 122 real datasets, 90 subjects gave the same classification results across all the methods (three raters, LI, bootstrap LI, NNC, and DFC). For the remaining datasets, 18 cases for the IPCA-NNC and 21 cases for the IPCA-DFC agreed with the majority of the five classification results (three visual ratings and two LI results). Kappa values vary from 0.59 to 0.73 for NNC and 0.61 to 0.75 for DFC, which indicate good agreement between NNC or DFC with traditional methods. The proposed method as designed can serve as an alternative method to corroborate existing LI and visual rating classification methods and to resolve some of the cases near the boundaries in between categories. PMID- 23450849 TI - Morphology of 9p21 homozygous deletion-positive pleural mesothelioma cells analyzed using fluorescence in situ hybridization and virtual microscope system in effusion cytology. AB - BACKGROUND: In malignant pleural mesothelioma (MPM), most patients first present with pleural effusion; thus, cytologic analysis is the primary diagnostic approach. However, the cytologic distinction between MPM and reactive mesothelial cells (RMCs) in effusions can be extremely difficult due to the lack of both well established immunocytochemical markers and definite cytological criteria for MPM. Moreover, the existence of both MPM cells and RMCs in effusions from the same patient makes the differentiation even more challenging. Homozygous deletion of the 9p21 locus, the site of the cyclin-dependent kinase inhibitor 2A/p16 (CDKN2A/p16) gene, frequently occurs in MPM but has never been reported in RMCs. The aim of this study was to define the cytomorphological characteristics of MPM cells, identified by the presence of 9p21 homozygous deletion by fluorescence in situ hybridization (FISH). METHODS: For this purpose, cells on smear preparations were recorded using a virtual microscope system and were subjected to FISH analysis. Thereafter, 9p21 homozygous deletion-positive cells were identified in the recorded virtual slides, followed by analysis of their morphological characteristics. RESULTS: Mesothelioma cells positive for the 9p21 homozygous deletion exhibited significantly more frequent cell-in-cell engulfment, multinucleation (more than 2 nuclei), and larger multicellular clusters composed of more than 10 cells than did 9p21 deletion-negative RMCs. Possible cutoff values are also proposed for these morphological markers to differentiate MPM cells from RMCs. CONCLUSIONS: These morphological differences and cutoff values are useful for cytological differentiation of mesothelioma cells from RMCs. In addition, the novel technique of a combination of virtual microscopy and FISH is introduced for tumor morphological analysis. PMID- 23450850 TI - In vivo profiling and visualization of cellular protein-lipid interactions using bifunctional fatty acids. PMID- 23450851 TI - Emerging treatment options for early mycosis fungoides. AB - Mycosis fungoides is a candidate for skin-directed therapies in its initial stages. In recent years, therapeutic options outside of the normal treatment recommendations such as topical imiquimod, topical tazarotene, topical methotrexate, excimer light sources, and photodynamic therapy have been published with variable results. These alternatives have been useful in cases of localized mycosis fungoides that do not respond to routine treatments; nevertheless, more studies on these methods are still needed. This article summarizes the literature and data that are known so far about these treatments. PMID- 23450853 TI - Comparison of patients' and nurses' viewpoints about responsiveness among a sample from public and private hospitals of Isfahan. AB - BACKGROUND: Health systems search for ways of making their services more responsive to patients and the public The new framework of the World Health Organization (WHO) for assessment of health system performance has determined health, responsiveness and fairness of financing as the main goals. This study aimed to compare patients' and nurses' view points about responsiveness among a sample of public and private hospitals of Isfahan, Iran. METHODS: A descriptive study was conducted on 160 nurses and also equal number of patients. Data were collected by a valid and reliable questionnaire designed by WHO. Data were analyzed using SPSS software. Scores were reported as mean (standard deviation). RESULTS: Mean score of responsiveness was 2.4(0.58) in nurses and 2.3(0.54) in patients but the difference was not statistically significant (out of a maximum of 4). The corresponding figures were significantly different (p = 0.009) regarding patients' viewpoints in public [2.2(0.4)] and private hospitals [2.3(0.5)]. CONCLUSIONS: Proper satisfaction about responsiveness was not provided in studied hospitals, based on the nurses' and patients' points of view. Public hospitals, in spite of their high costs, had a worse situation about responsiveness; the improvement of this situation necessitates managerial policies. PMID- 23450856 TI - An ethicist's commentary on euthanasia for tooth problem. PMID- 23450854 TI - Should high-risk adolescents have Papanicolaou tests? AB - BACKGROUND: The current American College of Obstetricians and Gynecologists guidelines state that cervical cancer screening should begin at age 21 years, regardless of sexual or obstetric history. However, previous studies have demonstrated that there is a small but significant subset of high-risk adolescents with extensive sexual and obstetric history who harbor a significant squamous cervical lesion. The objective of the current study was to use histologic and demographic data from adolescents (aged <21 years) who received Papanicolaou (Pap) tests to determine whether they benefited from early cervical cancer screening. METHODS: Adolescent girls who had Pap tests between 2000 and 2010 were included in the study. Demographic data, including obstetric history, number of sexual partners, age of first coitus, age at first pregnancy, menarche, smoking history, and Chlamydia and syphilis infection, were analyzed for associations with levels of cervical dysplasia. RESULTS: Of 56,785 adolescent Pap tests, 277 (0.5%) were diagnosed as high-grade squamous HSIL, and 56 of those Pap tests (20%) were from patients who had grade 3 cervical intraepithelial neoplasia (CIN-3) on subsequent biopsy and/or excision. One patient had microinvasive cervical carcinoma identified on loop electrosurgical excision procedure at age 27 years after an HSIL Pap test. Increased parity was associated significantly with higher rates of CIN-3. CONCLUSIONS: The study findings indicated that current American College of Obstetricians and Gynecologists guidelines to begin Pap testing at age 21 years are appropriate for the majority of adolescents, because the rate of HSIL is very low, and the risk for invasive carcinoma is minimal. Although higher parity was associated with a significantly increased grade of CIN, the conclusions are questionable because of the significant amount of missing demographic data points. That being said, this study should lead to other similar studies to determine any association of higher grade CIN with adolescent sexual and obstetric history. PMID- 23450857 TI - Castration of the Vietnamese pot-bellied boar: 8 cases. AB - Surgical techniques for castration of the Vietnamese pot-bellied boar and outcome are described. Vietnamese pot-bellied pig (VPBP) boars (n = 8) were admitted for castration. Data retrieved from medical records (2002-2011) for these pigs included signalment, history, reason for castration, perioperative management, surgical technique, and complications. Follow-up information was obtained from owners. A scrotal approach with closed technique was used for 6 boars with normally descended testes. A scrotal approach and open technique was used in 1 inguinal cryptorchid boar. In a hemicastrated abdominal cryptorchid boar an ipsilateral parainguinal approach was used. No complications occurred. Castration of the Vietnamese pot-bellied boar is associated with minimal complications and a satisfactory cosmetic outcome. We recommend the routine closure of the external inguinal rings, a simple and fast procedure that may prevent post-castration inguinal herniation. PMID- 23450852 TI - MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA. AB - Maintenance of genetic stability is crucial for all organisms in order to avoid the onset of deleterious diseases such as cancer. One of the many proveniences of DNA base damage in mammalian cells is oxidative stress, arising from a variety of endogenous and exogenous sources, generating highly mutagenic oxidative DNA lesions. One of the best characterized oxidative DNA lesion is 7,8-dihydro-8 oxoguanine (8-oxo-G), which can give rise to base substitution mutations (also known as point mutations). This mutagenicity is due to the miscoding potential of 8-oxo-G that instructs most DNA polymerases (pols) to preferentially insert an Adenine (A) opposite 8-oxo-G instead of the appropriate Cytosine (C). If left unrepaired, such A:8-oxo-G mispairs can give rise to CG->AT transversion mutations. A:8-oxo-G mispairs are proficiently recognized by the MutY glycosylase homologue (MUTYH). MUTYH can remove the mispaired A from an A:8-oxo-G, giving way to the canonical base-excision repair (BER) that ultimately restores undamaged Guanine (G). The importance of this MUTYH-initiated pathway is illustrated by the fact that biallelic mutations in the MUTYH gene are associated with a hereditary colorectal cancer syndrome termed MUTYH-associated polyposis (MAP). In this review, we will focus on MUTYH, from its discovery to the most recent data regarding its cellular roles and interaction partners. We discuss the involvement of the MUTYH protein in the A:8-oxo-G BER pathway acting together with pol lambda, the pol that can faithfully incorporate C opposite 8-oxo-G and thus bypass this lesion in a correct manner. We also outline the current knowledge about the regulation of MUTYH itself and the A:8-oxo-G repair pathway by posttranslational modifications (PTM). Finally, to achieve a clearer overview of the literature, we will briefly touch on the rather confusing MUTYH nomenclature. In short, MUTYH is a unique DNA glycosylase that catalyzes the excision of an undamaged base from DNA. PMID- 23450858 TI - Serological status of Canadian cattle for brucellosis, anaplasmosis, and bluetongue in 2007-2008. AB - A national bovine serological survey was conducted to confirm that the prevalence of brucellosis, bluetongue, and anaplasmosis does not exceed 0.02% (95% confidence) in live cattle in Canada. Sampling consisted of a systematic random sample of 15 482 adult cattle slaughtered in federally inspected abattoirs, stratified by province. Samples were tested to detect antibodies for brucellosis, bluetongue, and anaplasmosis. All samples were negative for brucellosis. Three samples were seroreactors to bluetongue, 2 of which originated from the Okanagan Valley in British Columbia and 1 from Ontario, which after follow-up, was considered an atypical result. A total of 244 samples were seroreactors to Anaplasma and follow-up identified infection in Saskatchewan, Manitoba, and Quebec. In conclusion, the Canadian cattle population remains free of brucellosis and free of bluetongue outside the Okanagan Valley. Canada is no longer free of anaplasmosis and will be unable to claim freedom until eradication measures are completed. PMID- 23450859 TI - A retrospective study of 29 cases of otitis media/interna in dairy calves. AB - Epidemiological data, clinical findings, laboratory data, medical imaging, and outcomes were reviewed in 29 dairy calves with otitis media/interna. Age at admission ranged from 1 to 24 wk. The majority of calves were referred during winter. Clinical signs included drooping ear, ptosis, head tilt, abnormal nystagmus, strabismus, dysphagia, regurgitation, stiff neck, opisthotonos, facial hyperesthesia, and purulent aural discharge. Intranasal endoscopic examination of 5 animals revealed nasopharyngeal collapse in 4. Cerebrospinal fluid (CSF) was abnormal in all of 7 cases. Mycoplasma bovis was cultured from all but 1 case with external ear or tympanic bullae samples (n = 12), and Mycoplasma arginini was cultured from the remaining ear sample. Radiographs of the tympanic bullae were performed in 24 calves, tomodensitometry (CT) in 3 calves and ultrasound in 4 calves. According to medical imaging techniques or necropsy, 69% of the cases were classified as chronic. Mean duration of treatment was 23.3 d. The rate of clinical recovery was 75%. PMID- 23450860 TI - Risk factors for herds to test positive for Mycobacterium avium ssp. paratuberculosis-antibodies with a commercial milk enzyme-linked immunosorbent assay (ELISA) in Ontario and western Canada. AB - The objectives of this study were to identify risk factors associated with i) a Mycobacterium avium subsp. paratuberculosis (MAP)-antibody milk enzyme-linked immunosorbent assay (MAP milk ELISA)-positive herd status, and ii) the within herd MAP milk ELISA-positive prevalence in Canadian dairy herds. This prospective cohort study was conducted between 2005 and 2009 on 226 herds in Ontario and western Canada, which participated in a voluntary risk assessment (RA)-based Johne's disease control program. Two MAP milk ELISA and risk assessments and a previsit survey were available per herd. The overall farm RA scores alone could not be used to predict whether a herd would test positive for MAP antibodies. However, the results of this study indicated that increasing the likelihood of exposing calves to MAP through certain management practices, as assessed with the RA, increased the likelihood of a herd being test-positive for MAP antibodies. PMID- 23450861 TI - Evaluating the effect of intraoperative peritoneal lavage on bacterial culture in dogs with suspected septic peritonitis. AB - This pilot study describes the effect of intraoperative peritoneal lavage (IOPL) on bacterial counts and outcome in clinical cases of septic peritonitis. Intraoperative samples were cultured before and after IOPL. Thirty-three dogs with presumed septic peritonitis on the basis of cytology were managed surgically during the study period. Positive pre-lavage bacterial cultures were found in 14 cases, 13 of which were a result of intestinal leakage. The post-lavage cultures showed fewer isolates in 9 cases and in 1 case became negative. The number of dogs with a decrease in the concentration of bacteria cultured from pre-lavage to post-lavage samples was not statistically significant. There was no significant effect of the change in pre- to post-lavage culture, single versus multiple types of bacteria, selection of an appropriate empiric antimicrobial on survival or the need for subsequent surgery. PMID- 23450862 TI - Near-fatal misuse of medical tape around an endotracheal tube connector during inhalation anesthesia in a horse. AB - A 7-year-old gelded Irish sports horse weighing 650 kg was anesthetized on 2 consecutive days for lavage of a septic right radio-carpal joint. On both occasions the endotracheal tube connector, which had been bound in medical tape to produce an airtight seal, functioned as a unidirectional valve during mechanical ventilation, retarding expiration, imposing positive end expiratory pressure (PEEP), and probably continuous positive airway pressure (CPAP). The equipment dysfunction was not identified on either occasion despite close inspection prompted by progressive increases in airway pressure and thoracic distension. Whilst the PEEP and CPAP exerted unexpectedly modest cardiovascular effects and the horse recovered uneventfully on both occasions, the improvisation may have proven fatal in a higher-risk subject. PMID- 23450863 TI - Severe pruritus and myoclonus following intrathecal morphine administration in a dog. AB - During epidural needle placement in a 32-kg dog the subarachnoid space was punctured and half the intended dose of lidocaine, bupivacaine, and morphine was injected. After recovery from anesthesia the dog showed signs of severe pruritus of the tail base and limbs and myoclonus of the tail and hind limbs. Methadone, acepromazine, ketamine, buprenorphine, and butorphanol were administered to control myoclonus and pruritus, but were unsuccessful. Diazepam was used to control myoclonus until the effects of morphine abated. PMID- 23450864 TI - Clinical evaluation of a closed, one-stage, stapled, functional, end-to-end jejuno-ileal anastomosis in 5 horses. AB - This study describes the outcome and complications in horses that had a closed, one-stage, stapled, functional, end-to-end (COSFE) jejuno-ileal anastomosis (JIA) following resection of compromised small intestine. Medical records were reviewed to identify all horses that had a COSFE JIA performed during exploratory laparotomy and to determine post-operative complications and final outcome. All 5 horses that were identified had successful COSFE JIA with resection of various amounts of distal jejunum and proximal ileum. Post-operative ileus occurred in 1 of the 5 horses. All horses survived at least 1 year after surgery. The survival times and incidence of post-operative ileus compared favorably with published results for other types of small intestinal resection and anastomoses. A COSFE JIA is a viable surgical procedure to correct lesions of the distal jejunum and proximal ileum. PMID- 23450865 TI - Surgery and radiation therapy for extramedullary plasmacytoma of the penile mucosa in a dog. AB - A 10-year-old neutered male Italian greyhound dog was presented because it had a penile plasmacytoma. Surgery followed by radiation therapy resulted in local control and survival for 1688 days. This is the first report of surgery and definitive radiation therapy for curative intent therapy of extramedullary penile plasmacytoma in a dog. PMID- 23450866 TI - Bilateral iliac arterial thrombosis in an alpaca (Vicugna pacos) cria. AB - A 3-month-old male alpaca was presented for acute onset of non-weight-bearing left hind limb lameness. Antemortem diagnostics revealed a mass to the right of the urinary bladder and no blood flow in the left femoral artery. Necropsy revealed bilateral iliac arterial thrombi and an abscess near the urinary bladder. PMID- 23450867 TI - The first reported case of rabbit hemorrhagic disease in Canada. AB - In March 2011, rabbit hemorrhagic disease (RHD) was suspected in a 1-year-old male neutered lop-eared rabbit that had acute onset liver failure. Gross pathology, histopathology, immunohistochemistry, partial nucleic acid sequencing and phylogenetic analysis of the major capsid protein (VP60) and animal inoculation studies all supported this diagnosis making it the first confirmed case of RHD in Canada. PMID- 23450868 TI - Time to practice smarter. PMID- 23450870 TI - A message from the editor. PMID- 23450871 TI - A plan to address Alzheimer's disease. PMID- 23450872 TI - Protecting the public's health: critical functions of the Section 317 Immunization Program-a report of the National Vaccine Advisory Committee. PMID- 23450873 TI - Section 317 immunization program: protecting a national asset. PMID- 23450874 TI - Area-level socioeconomic disadvantage and severe pulmonary tuberculosis: U.S., 2000-2008. AB - OBJECTIVES: Lower socioeconomic status (SES) is associated with increased risk of tuberculosis (TB) and diagnostic delays, but the extent to which this association reflects an underlying gradient in advanced status of pulmonary TB is unknown. We conducted a multilevel retrospective cohort analysis examining the relationship between socioeconomic characteristics and pulmonary TB disease status, as measured via sputum smears and chest radiography results. METHODS: We included 862 incident TB patients reported in King County, Washington, from 2000-2008. We abstracted patient-level measures from charts and surveillance data. We obtained socioeconomic characteristics of TB patients, as well as those of the areas where TB patients lived, from the 2000 U.S. Census. A socioeconomic position (SEP) index was derived to measure SES. RESULTS: Of those with known results, 814 of 849 patients (96%) displayed abnormal radiography findings. A total of 239 graded patients (39%) had positive smears, 136 (57%) of whom had grades of moderate (3+) or numerous (4+) acid-fast bacilli. In unadjusted analyses, patients living in lower SEP areas did not appear to have higher probabilities of more advanced disease. In multivariate models adjusting for individual demographic and socioeconomic measures, as well as area-based demographic variables, block-group SEP was not significantly associated with more advanced pulmonary disease. CONCLUSIONS: Lower SEP was not significantly associated with greater pulmonary disease severity after controlling for individual age, race, sex, and origin, and block-group race, ethnicity, and origin. These findings suggest that the severity of pulmonary TB at diagnosis is not synonymous with delayed diagnosis. PMID- 23450875 TI - Mortality rates and age at death from sickle cell disease: U.S., 1979-2005. AB - OBJECTIVES: Improvements in survival for children with sickle cell disease (SCD) during the last 30 years have been well established. Whether similar improvements for adults with the disease have occurred is unknown. We investigated mortality rates for children and adults with SCD. METHODS: We used the National Center for Health Statistics multiple-cause-of-death files to examine age at death and calculate mortality rates from 1979 to 2005. We examined trends in mortality rates using negative binomial regression, and we examined age at death using t tests and linear regression. RESULTS: We identified 16,654 sickle cell-related deaths. Mean age at death was significantly different for males (33.4 years, 95% confidence interval [CI] 33.0, 33.7) than for females (36.9 years, 95% CI 36.5, 37.4). In a regression model controlling for gender, the mean age at death increased by 0.36 years for each year of the study. The median age at death in 2005 was 42 years for females and 38 years for males. The overall mortality rate increased 0.7% (p<0.001) each year during the time period studied. The adult (>19 years of age) mortality rate increased by 1% (p<0.001) each year during the time period studied. The pediatric mortality rate decreased by 3% (p<0.001) each year during the time period studied. CONCLUSIONS: These data confirm prior findings of a significant decrease in mortality for children with SCD. The mortality rate for adults appears to have increased during the same time period. It seems unlikely that this increase is due merely to an influx of younger patients surviving to adulthood and may reflect a lack of access to high-quality care for adults with SCD. PMID- 23450880 TI - Understanding sexual health and its role in more effective prevention programs. PMID- 23450876 TI - Missed connections: HIV-infected people never in care. AB - OBJECTIVE: Clinical interventions that lengthen life after HIV infection and significantly reduce transmission could have greater impact if more HIV-diagnosed people received HIV care. We tested a surveillance-based approach to investigating reasons for delayed entry to care. METHODS: Health department staff in three states and two cities contacted eligible adults diagnosed with HIV four to 24 months previously who had no reported CD4+ lymphocyte (CD4) or viral load (VL) tests. The staff conducted interviews, performed CD4 and VL testing, and provided referrals to HIV medical care. Reported CD4 and VL tests were prospectively monitored to determine if respondents had entered care after the interview. RESULTS: Surveillance-based follow-up uncovered problems with reporting CD4 and VL tests, resulting in surveillance improvements. However, reporting problems led to misspent effort locating people who were already in care. Follow-up proved difficult because contact information in surveillance case records was often outdated or incorrect. Of those reached, 37% were in care and 29% refused participation. Information from 132 people interviewed generated ideas for service improvements, such as emphasizing the benefits of early initiation of HIV care, providing coverage eligibility information soon after diagnosis, and leveraging other medical appointments to provide assistance with linkage to HIV care. CONCLUSIONS: Surveillance-based follow-up of HIV-diagnosed individuals not linked to care provided information to improve both surveillance and linkage services, but was inefficient because of difficulties identifying, locating, and recruiting eligible people. Inefficiencies attributable to missing, incomplete, or inaccurate surveillance records are likely to diminish as data quality is improved through ongoing use. PMID- 23450881 TI - Socioeconomic disadvantage as a social determinant of teen childbearing in the U.S. AB - OBJECTIVES: We reviewed the literature focused on socioeconomic influences on teen childbearing and suggested directions for future research and practice related to this important indicator of teen sexual health. METHODS: We conducted an electronic search of Medline, ERIC, PsychLit, and Sociological Abstracts databases for articles published from January 1995 to November 2011. Selected articles from peer-reviewed journals included original quantitative analyses addressing socioeconomic influences on first birth among teen women in the U.S. Articles were abstracted for key information, ranked for quality according to the U.S. Preventive Services Task Force guidelines, assessed for bias, and synthesized. RESULTS: We selected articles with a range of observational study designs. Risk for bias varied across studies. All 12 studies that considered socioeconomic factors as influences on teen childbearing (vs. moderators or mediators of other effects) reported at least one statistically significant association relating low socioeconomic status, underemployment, low income, low education levels, neighborhood disadvantage, neighborhood physical disorder, or neighborhood-level income inequality to teen birth. Few reports included any associations contradicting this pattern. CONCLUSIONS: This review suggests that unfavorable socioeconomic conditions experienced at the community and family levels contribute to the high teen birth rate in the U.S. Future research into social determinants of sexual health should include multiple levels of measurement whenever possible. Root causes of teen childbearing should be evaluated in various populations and contexts. Interventions that address socioeconomic influences at multiple levels could positively affect large numbers of teens and help eliminate disparities in teen childbearing. PMID- 23450882 TI - Racial differences in age at first sexual intercourse: residential racial segregation and the black-white disparity among U.S. adolescents. AB - OBJECTIVES: The age of adolescents at first sexual intercourse is an important risk factor for sexually transmitted diseases (STDs) and adolescent pregnancy. Black adolescents are at higher risk than white adolescents for first sexual intercourse at younger ages as well as STDs and pregnancy. Individual- and family level factors do not fully explain this disparity. We examined whether five dimensions of black-white residential racial segregation can help explain the racial disparity in age at first sexual intercourse. METHODS: Using the National Longitudinal Survey of Youth 1997 and U.S. Census 2000 data, we performed multiple hierarchical discrete time-to-event analyses on a nationally representative cohort of adolescents followed since 1997. Although the cohort study is ongoing, we used data from 1997 through 2005. RESULTS: Concentration and unevenness significantly modified the association of race and age at first sexual intercourse. However, stratified results suggested differences in the effect of race on age at first sexual intercourse at each level of segregation across dimensions of segregation. CONCLUSIONS: Residential racial segregation may modify the black-white disparity in risk of first sexual intercourse at younger ages, but these associations are complex. Future studies should be conducted to elucidate the causal mechanisms. PMID- 23450883 TI - In their own words: romantic relationships and the sexual health of young African American women. AB - OBJECTIVE: We assessed young African American women's understanding of "dual protection" (DP) (i.e., strategies that simultaneously protect against unintended pregnancies and sexually transmitted diseases [STDs]) and how relationship factors influence their use of DP methods. METHODS: We conducted 10 focus groups with African American women (n=51) aged 15-24 years in Atlanta, Georgia, to identify barriers to and facilitators of their DP use. Focus group participants also completed a brief self-administered questionnaire that assessed demographics and sexual behaviors. We analyzed focus group data by theme: relationships, planning for sex, pregnancy intentions, STD worries, the trade-off between pregnancy and STDs, attitudes toward condoms and contraceptives, and understanding of DP. RESULTS: From the questionnaire, 51% of participants reported that an STD would be the "worst thing that could happen," and 26% reported that being pregnant would be "terrible." Focus group data suggested that most participants understood what DP was but thought it was not always feasible. Relationship factors (e.g., trust, intimacy, length of relationship, and centrality) affected pregnancy intentions, STD concerns, and use of DP. Social influences (e.g., parents) and pregnancy and STD history also affected attitudes about pregnancy, STDs, and relationships. CONCLUSIONS: Although participants identified risks associated with sex, a complex web of social and relationship factors influenced the extent to which they engaged in protective behavior. The extent to which relationship factors influence DP may reflect developmental tasks of adolescence and should be considered in any program promoting sexual health among young African American women. PMID- 23450884 TI - On the road to well-being: the development of a communication framework for sexual health. AB - OBJECTIVES: Recognizing the need to work with all partners who have an interest in addressing sexual health issues, we explored values held by diverse stakeholders in the United States. Based on these findings, we developed a framework for use in communicating about sexual health issues and potential solutions. METHODS: Our methods included an environmental scan, small-group metaphor elicitation and message framing assessments, interviews, and online surveys with diverse members of the public and health professionals. RESULTS: Of four overarching value-based themes, two were best accepted across audiences: the first theme emphasized the importance of protecting health along the road of life through enabling good choices, and the second called for adding health promotion approaches to traditional disease prevention control. Nearly all supporting statements evaluated were effective and can be used to support either of the two best accepted overarching themes. CONCLUSIONS: Although there is a great diversity of opinion regarding how to address sexual health issues in the U.S., among diverse stakeholders we found some common values in our exploratory work. These common values were translated into message frameworks. In particular, the idea of broadening sexual health programs to include wellness-related approaches to help expand disease control and prevention efforts resonated with stakeholders across the political spectrum. These findings show promise for improved sexual health communication and a foundation on which to build support across various audiences, key opinion leaders, and stakeholders. PMID- 23450885 TI - The development and validation of sexual health indicators of Canadians aged 16 24 years. AB - OBJECTIVES: We developed and validated a set of self-administered, multi dimensional indicators of sexual health among Canadians aged 16-24 years. METHODS: This study used a mixed-method qualitative and quantitative approach to develop and validate indicators of sexual health. We used the four-stage Dillman method to identify, focus-test, pilot-test, and validate key metrics to measure sexual health. We collected quantitative data to validate the measures through a computer-assisted self-interviewing program among a purposive sample of 1,158 people aged 16-24 years recruited from four Canadian provinces. RESULTS: The survey contained 75 items measuring five dimensions of sexual health: (1) physical, mental, emotional, and social well-being in relation to sexuality; (2) approach to sexuality; (3) sexual relationships; (4) sexual experiences; and (5) discrimination, coercion, and violence. Principal components analysis for composite measures found seven components with eigenvalues >=1. The factor structure was stable across gender, age, size of area of residence, and language in which the survey was completed. Cronbach's alpha coefficients ranged from 0.79 to 0.90. Indicators of condom use at last vaginal sex, protection self-efficacy, sexually transmitted infection/HIV testing self-efficacy, and sexual orientation also showed good construct validity. CONCLUSIONS: The indicators constituted a conceptually grounded survey that is easy for young adults to complete and contains valid, reliable, and psychometrically robust measures. The survey instrument provides a tool for future research to collect population-level data to measure and monitor trends in the sexual health of young people in Canada. PMID- 23450886 TI - Measurement of sexual health in the U.S.: an inventory of nationally representative surveys and surveillance systems. AB - OBJECTIVES: To identify opportunities within nationally representative surveys and surveillance systems to measure indicators of sexual health, we reviewed and inventoried existing data systems that include variables relevant to sexual health. METHODS: We searched for U.S. nationally representative surveys and surveillance systems that provided individual-level sexual health data. We assessed the methods of each data system and catalogued them by their measurement of the following domains of sexual health: knowledge, communication, attitudes, service access and utilization, sexual behaviors, relationships, and adverse health outcomes. RESULTS: We identified 18 U.S.-focused, nationally representative data systems: six assessing the general population, seven focused on special populations, and five addressing health outcomes. While these data systems provide a rich repository of information from which to assess national measures of sexual health, they present several limitations. Most importantly, apart from data on service utilization, routinely gathered, national data are currently focused primarily on negative aspects of sexual health (e.g., risk behaviors and adverse health outcomes) rather than more positive attributes (e.g., healthy communication and attitudes, and relationship quality). CONCLUSION: Nationally representative data systems provide opportunities to measure a broad array of domains of sexual health. However, current measurement gaps indicate the need to modify existing surveys, where feasible and appropriate, and develop new tools to include additional indicators that address positive domains of sexual health of the U.S. population across the life span. Such data can inform the development of effective policy actions, services, prevention programs, and resource allocation to advance sexual health. PMID- 23450887 TI - Community attitudes about discussing sexual health: assessing public opinion of local STD prevention campaigns. AB - OBJECTIVES: We assessed public views about the acceptability of and need for sexually transmitted disease (STD) and sexual health-related educational messaging in local campaigns. METHODS: A 28-item state-added module was included in the 2008 New York Behavioral Risk Factor Surveillance System survey (n=3,751). Respondents rated acceptability of venues/dissemination channels and messaging and agreement with attitudinal/need statements. Additional data were analyzed from a separate state survey with individual county samples (n=36,257). We conducted univariate, bivariate, and multivariable modeling analyses. RESULTS: Each venue was acceptable to more than three-quarters of respondents (range: 79% for billboards to 95% for teaching STD prevention in high school). All message areas were acceptable to at least 85% of respondents (acceptability rating range: 85% to 97%). More than 70% agreed that there is a need for more open discussion about STDs. Bivariate analyses identified areas where messaging tailored to specific subgroups may be helpful (e.g., 26% of white people, 44% of African Americans, and 45% of Hispanic people agreed with the statement, "I need ideas about how to talk to my partner about protection from STDs"). Little geographic variation was seen. Results of multivariable modeling on opposition showed limited interaction effects. CONCLUSION: These data provide key information about current community norms and reflect the public's approval for hearing and seeing more about sexual health and STDs in a range of public forums. PMID- 23450888 TI - Sexual Health and Responsibility Program (SHARP): preventing HIV, STIs, and unplanned pregnancies in the navy and marine corps. AB - In 1999, the Navy and Marine Corps Public Health Center converted an HIV train the-trainer program into a broader effort of preventing not just HIV, but also other sexually transmitted infections (STIs) and unplanned pregnancies. The premise for this broader approach was that a more comprehensive sexual health promotion message of STI, HIV, and unplanned pregnancy prevention is more likely to include at least one personally relevant concern for any given individual and is, therefore, more likely to be internalized and acted upon by the greatest number of individuals, and that risk reduction for any one of these consequences of sexual activity may reduce risk for all. This new effort was labeled the Sexual Health and Responsibility Program (SHARP). Within the Navy and Marine Corps, SHARP has become a focal and trusted source of sexual health promotion products, consultative services, and training, as well as a conduit for multidisciplinary collaboration and coordination. The existence of this central sexual health program normalizes integrated and comprehensive sexual health messages, enables efficiencies, promotes program and policy uniformity, and provides a forum for cross-organizational collaboration and continuous improvement. PMID- 23450889 TI - Shifting the paradigm in Oregon from teen pregnancy prevention to youth sexual health. AB - Oregon's work on teen pregnancy prevention during the previous 20 years has shifted from a risk-focused paradigm to a youth development model that places young people at the center of their sexual health and well-being. During 2005, the Oregon Governor's Office requested that an ad hoc committee of state agency and private partners develop recommendations for the next phase of teen pregnancy prevention. As a result of that collaborative effort, engagement of young people, and community input, the Oregon Youth Sexual Health Plan was released in 2009. The plan focuses on development of young people and embraces sexuality as a natural part of adolescent development. The plan's five goals and eight objectives guide the work of state agencies and partners addressing youth sexual health. Oregon's development of a statewide plan can serve as a framework for other states and entities to address all aspects of youth sexual health. PMID- 23450890 TI - Sexual health training and education in the U.S. PMID- 23450891 TI - Considerations for national public health leadership in advancing sexual health. AB - Nations across the globe face significant public heath challenges in optimizing sexual health, including reducing human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), sexually transmitted infections (STIs), unintended pregnancies, and sexual violence, and mitigating the associated adverse social and economic impacts. In response, some countries have implemented national strategies and other efforts focused on promoting more holistic and integrated approaches for addressing these syndemics. This article describes opportunities for national leadership to use a more holistic approach to improve the sexual health of individuals and communities. PMID- 23450892 TI - Addressing sexual health: looking back, looking forward. PMID- 23450893 TI - Individual genome assembly from metagenome: resolving the unknown genotypic microdiversity at the sharpened focus. PMID- 23450894 TI - Recruiting environmental genomes from metagenomes. PMID- 23450895 TI - HIV in Elderly. PMID- 23450896 TI - 111th ASM 2011 General Meeting Highlights with Opportunity for Microbiologists to Participate in Upcoming ASM 2012. PMID- 23450897 TI - The need for a greater focus on obesity and its treatment in sleep medicine. PMID- 23450898 TI - Clock genes and sleep homeostasis: a fundamental link within the two-process model? PMID- 23450899 TI - The future of insomnia treatment--the challenge of implementation. PMID- 23450900 TI - Are we ready to define central hypopneas? PMID- 23450901 TI - Do C. elegans sleep? A closer look. PMID- 23450902 TI - Sleep needs a MOP, or two MOPs! PMID- 23450905 TI - Social Services for Sexual Minority Youth: Preferences for What, Where, and How Services are Delivered. PMID- 23450906 TI - Cancer rehabilitation: opportunities and challenges. PMID- 23450907 TI - Commentary on Wilson et Al.(1.). PMID- 23450908 TI - Clinicians' commentary on you et Al.(1.). PMID- 23450909 TI - Clinicians' commentary on ottensmeyer et Al.(1.). PMID- 23450910 TI - What Does the Cochrane Collaboration Say about Respiratory Physiotherapy? PMID- 23450911 TI - Editorial. PMID- 23450912 TI - Introduction to "the behavior-analytic origins of constraint-induced movement therapy: an example of behavioral neurorehabilitation". PMID- 23450913 TI - Is variability an operant?: introductory remarks. PMID- 23450914 TI - Reinforcement and induction of operant variability. PMID- 23450915 TI - Operant variability: some random thoughts. PMID- 23450916 TI - Variability as an operant? PMID- 23450917 TI - Operant variability: procedures and processes. PMID- 23450918 TI - Variability as a subject matter in a science of behavior: reply to commentaries. PMID- 23450919 TI - Commentary on "what happened to analysis in applied behavior analysis" (pierce & epling, 1980). PMID- 23450920 TI - Farewell and kudos. PMID- 23450922 TI - Teach aesthetic plastic surgery in medical colleges. PMID- 23450921 TI - How I do it: triaging patients with hepatocellular carcinoma. PMID- 23450923 TI - Dr. C. V. Mehendale: A plastic surgeon in the true mould. PMID- 23450924 TI - Free perforator flaps on the peroneal vascular system. PMID- 23450926 TI - Plastic surgical audit: The need of the hour. PMID- 23450925 TI - The forked flap repair for hypospadias: The reality away from ideality. PMID- 23450927 TI - Congenital anterior urethrocutaneous fistula. PMID- 23450928 TI - Reconstruction of foot extensor tendons with gracilis tendon graft. PMID- 23450929 TI - Breast reconstruction awareness among educated women in a metropolitan city. PMID- 23450930 TI - Bilateral pneumothorax following breast augmentation: Beware and be aware. PMID- 23450931 TI - Evidence-based demerits on the use of rectus abdominis musculo-peritoneal flap for bladder augmentation in children with exstrophy bladder. PMID- 23450932 TI - Snapping wrist due to lunate malformation. PMID- 23450933 TI - Isolated closed rupture of the flexor digitorum superficialis tendon. PMID- 23450934 TI - An unusual form of 'finger stuck in a hole' injury in a child. PMID- 23450935 TI - Preparation of a partially avulsed scalp. PMID- 23450936 TI - The Lucknow splint. PMID- 23450937 TI - Comments: A useful modification of the plaster backslab to off-load pressure from reconstructions of the heel and elbow. PMID- 23450938 TI - Syringe-based wound irrigating device. PMID- 23450939 TI - Age weight, quality of muscle and speech! PMID- 23450940 TI - Chaperones and plastic surgery practice in India. PMID- 23450941 TI - The rise and rise of technology in urology- Cost-effective medicine vs. new treatments. PMID- 23450942 TI - May hegglin anomaly: rare entity with review of literature. AB - We present a brief review of a rare entity, May Hegglin anomaly. We also put forth a few pictures characterizing it. PMID- 23450943 TI - Falsely reported malaria parasites in otherwise normal peripheral blood smears. PMID- 23450944 TI - Editorial. PMID- 23450945 TI - From the desk of the editor. PMID- 23450946 TI - Building the IJSO: An International Editorial Perspective. PMID- 23450947 TI - Giant Adrenal Non-functioning Tumor: A Case Report and Review of Literature. PMID- 23450948 TI - Adrenal myelolipoma-a management dilemma. PMID- 23450949 TI - Inguinal lymphnode metastatic testicular seminoma: a case report and review of literature. PMID- 23450950 TI - Metastatic squamous cell carcinoma of oesophagus presenting as solitary nodule thyroid; a case report. PMID- 23450951 TI - Rare presentation of malignant porcelain gallbladder with intrahepatic ductal calcification and surgical obstructive jaundice. PMID- 23450953 TI - Message from the Editor-in-Chief. PMID- 23450954 TI - Message from Co-Editor-in-Chief. PMID- 23450955 TI - International journal of angiology: past, present, and future. PMID- 23450956 TI - Grateful for the past and excited for the future! PMID- 23450957 TI - Welcome to YOUR new Canadian Journal of Plastic Surgery. PMID- 23450958 TI - The Journal comes home. PMID- 23450959 TI - Are you Holt Renfrew or Walmart? Applied economics in pricing plastic surgery. PMID- 23450960 TI - Case 1: Breast reduction / Case 2: Flexor tenosynovitis. PMID- 23450961 TI - The challenge of periodic fevers in children. PMID- 23450962 TI - Case 1: Multifocal bone lesions in a teenager. PMID- 23450963 TI - Case 2: A neonate in shock. PMID- 23450964 TI - Genetics and risk assessment. PMID- 23450966 TI - Functional bowel disease. PMID- 23450965 TI - Introduction to guest editor. PMID- 23450969 TI - Martyrs for better care. PMID- 23450970 TI - Oncology and the Internet: regulatory failure and reform. PMID- 23450971 TI - Promise and perils of guidelines in quality cancer care. PMID- 23450972 TI - Physician quality reporting system enters penalty phase: practices urged to prepare now to avoid Medicare payment reductions. PMID- 23450973 TI - Response to payer coverage for patients enrolled onto clinical trials. PMID- 23450974 TI - National Oncology Practice Benchmark, 2012 report on 2011 data. PMID- 23450975 TI - Haemophilus influenzae serotype a as the causative agent of a pediatric upper extremity infection. PMID- 23450976 TI - Synovial chondromatosis in a child's thumb: a case report and review of the literature. PMID- 23450977 TI - Palmar radiocarpal dislocation: a case report and novel treatment method. PMID- 23450978 TI - Locking of the ring finger at proximal interphalangeal joint due to a sesamoid bone: a case report. PMID- 23450979 TI - Flexor tendon lacerations due to high-pressure water injection injury: a case report. PMID- 23450980 TI - Extraskeletal osteosarcoma of the hand. PMID- 23450981 TI - How plausible is a subcortical account of rapid visual recognition? PMID- 23450982 TI - Mentalizing in schizophrenia is more than just solving theory of mind tasks. PMID- 23450983 TI - Molecular and cell-biological mechanisms of antigen cross-presentation. PMID- 23450984 TI - Health Systems Performance Measurement Systems in Canada: How Well do They Perform in First Nations, Inuit, and Metis Contexts? AB - OBJECTIVE: To inventory and describe currently available health performance measurement systems for First Nations, Inuit, and Metis people in Canada to identify why current measurement systems are inadequate to inform community or regional level health planning. METHODS: Inventory, classification, and synthesis of strengths and weaknesses among existing health system performance measures through systematic literature review and key informant interviews. RESULTS: Indigenous-specific health indicators are available at national, provincial, regional, and community levels, but there is a paucity of data for non-registered First Nations, Metis, and Inuit people. Barriers to the effective use of these indicators include: indicator selection driven by accountability rather than public health requirements; poor data quality; inadequate infrastructure and human resources; minimal information returned to communities; tension between agencies collecting universal indicators and Indigenous-determined processes; and, mistrust by Indigenous communities of externally imposed processes. The focus on national systems results in greater attention to disease-based measures and less focus on regional cultural diversity and Indigenous-specific values and priorities. CONCLUSION: Indigenous health system performance measurement infrastructure in Canada is underdeveloped, particularly at the local level, and hence deficient in its ability to support community or regional health planning. PMID- 23450985 TI - Olfactory dysfunction: common in later life and early warning of neurodegenerative disease. AB - BACKGROUND: Disturbances of smell and taste are common. About 5% of the general population have anosmia (absence of the sense of smell). Olfactory dysfunction can markedly impair the quality of life. METHODS: Review of pertinent literature retrieved by a selective search. RESULTS: In recent years, simple and reliable tests of the sense of smell have been introduced in otorhinolaryngology. Olfactory testing has become a new focus of attention in neurology as well, mainly because many patients with neurodegenerative diseases-including the majority of those with Parkinson's or Alzheimer's disease-have olfactory loss early on in the course of their disorder. Olfactory dysfunction is thus regarded as an early sign of neurodegenerative disease that may allow a tentative diagnosis to be made years before the motor or cognitive disturbances become evident. As for the treatment of olfactory loss, anti-inflammatory drugs and surgery can help in some cases, and olfactory training can lead to significant improvement of post-viral olfactory deficits. CONCLUSION: Olfactory dysfunction is common and becomes more common with advancing age. It is increasingly receiving attention as an important sign for the early diagnosis and the differential diagnosis of neurodegenerative disorders. PMID- 23450986 TI - Eliminate noxious agents acting as triggers. PMID- 23450987 TI - Echocardiography is not a basic diagnostic test. PMID- 23450988 TI - In reply: Echocardiography is not a basic diagnostic test. PMID- 23450989 TI - Low-dose analgesic radiotherapy is a real alternative. PMID- 23450990 TI - In reply: Low-dose analgesic radiotherapy is a real alternative. PMID- 23450991 TI - Awareness should be raised among doctors. PMID- 23450992 TI - Somatic causes were omitted. PMID- 23450993 TI - Evidence needs to be presented. PMID- 23450994 TI - Oxytocin concentrations are crucial. PMID- 23450995 TI - Metabolic derailment should be considered. PMID- 23450996 TI - Successful bonding is important. PMID- 23450997 TI - In reply: Successful bonding is important. PMID- 23450998 TI - Competitive sports and the heart: benefit or risk? AB - BACKGROUND: Controversy surrounds the cardiac effects of competitive sports and the athlete's heart. In this review, we present and discuss the main cardiological findings in competitive athletes. METHOD: Selective review of pertinent literature retrieved by a search with the keywords "athlete's heart," "ECG," "echocardiography," "endurance exercise," "longevity," and others. RESULTS: Regular exercise leads to functional and structural adaptations that improve cardiac function. Athlete's heart, which develops rarely, is a typical finding in endurance athletes. This condition is characterized by physiological, harmonically eccentric hypertrophy of all cardiac chambers. The athlete's ECG can be used to distinguish physiological, training-related changes from pathological training-unrelated changes. The athlete's heart function is normal at rest and increases appropriately during exercise. The cardiac markers troponin and B-type natriuretic peptide are within the normal range in healthy athletes at rest, but can temporarily be mildly elevated after exhausting endurance-exercise, without evidence of myocardial damage. The epidemiological data suggest that participation in competitive sports increases life expectancy. CONCLUSION: Competitive exercise does not induce cardiac damage in individuals with healthy hearts, but does induce physiological functional and structural cardiac adaptations which have positive effects on life expectancy. PMID- 23450999 TI - Liver cirrhosis, transplantation and organ shortage. PMID- 23451000 TI - The etiology, diagnosis and prevention of liver cirrhosis: part 1 of a series on liver cirrhosis. AB - BACKGROUND: Cirrhosis of the liver is the end stage of chronic liver disease. Among the many liver disorders that can lead to cirrhosis, some progress rapidly (years) and others more slowly (decades). In Germany, cirrhosis is often a consequence of fatty liver disease due to alcoholism or other causes, but can also be caused by hepatitis B and hepatitis C. Cirrhosis is more common in overweight persons and smokers. The underlying causes of cirrhosis determine its rate of progression and are the focus of preventive efforts and treatment. The prevalence of cirrhosis in Germany is rising; it now ranks among the top 20 causes of death in the country. METHODS: This article is based on a selective review of pertinent literature, including reviews and current guidelines. RESULTS: Strictly speaking, cirrhosis is a pathological diagnosis; it is, nevertheless, usually diagnosed clinically, by history, physical examination (e.g., cutaneous signs of liver disease), ancillary testing (e.g., ultrasonography, transient elastography) and laboratory analyses (e,g., APRI, which is the quotient of the GOT concentration and the platelet count). There are no laboratory cutoff values for the diagnosis of cirrhosis. Early detection of chronic liver disease, followed by individually tailored, risk-adapted treatment, is the best way to prevent it. Esophagogastroduodenoscopy can be performed early on to assess the risk of variceal bleeding. In most patients, the progression of fibrosis can be averted by early detection and appropriate treatment. CONCLUSION: Screening for chronic liver disease should include history and physical examination, serum transaminase measurement, upper abdominal ultrasonography, and, in some cases, transient elastography. PMID- 23451001 TI - The diagnosis and treatment of bipolar disorder: recommendations from the current s3 guideline. AB - BACKGROUND: Bipolar disorder is a serious mental illness, characterized by frequent recurrences and major comorbidities. Its consequences can include suicide. METHODS: An S3 guideline for the treatment of bipolar disorder was developed on the basis of a systematic literature search, evaluation of the retrieved publications, and a formal consensus-finding procedure. Several thousand publications were screened, and 611 were included in the analysis, including 145 randomized controlled trials (RCT). RESULTS: Bipolar disorder should be diagnosed as early as possible. The most extensive evidence is available for pharmacological monotherapy; there is little evidence for combination therapy, which is nonetheless commonly given. The appropriate treatment may include long-term maintenance treatment, if indicated. The treatment of mania should begin with one of the recommended mood stabilizers or antipsychotic drugs; the number needed to treat (NNT) is 3 to 13 for three weeks of treatment with lithium or atypical antipsychotic drugs. The treatment of bipolar depression should begin with quetiapine (NNT = 5 to 7 for eight weeks of treatment), unless the patient is already under mood-stabilizing treatment that can be optimized. Further options in the treatment of bipolar depression are the recommended mood stabilizers, atypical antipsychotic drugs, and antidepressants. For maintenance treatment, lithium should be used preferentially (NNT = 14 for 12 months of treatment and 3 for 24 months of treatment), although other mood stabilizers or atypical antipsychotic drugs can be given as well. Psychotherapy (in addition to any pharmacological treatment) is recommended with the main goals of long-term stabilization, prevention of new episodes, and management of suicidality. In view of the current mental health care situation in Germany and the findings of studies from other countries, it is clear that there is a need for prompt access to need-based, complex and multimodal care structures. Patients and their families need to be adequately informed and should participate in psychiatric decision-making. CONCLUSION: Better patient care is needed to improve the course of the disease, resulting in better psychosocial function. There is a need for further high-quality clinical trials on topics relevant to routine clinical practice. PMID- 23451002 TI - Updating our skills in Doppler sonography. PMID- 23451023 TI - H3K56me3 is a novel, conserved heterochromatic mark that largely but not completely overlaps with H3K9me3 in both regulation and localization. AB - Histone lysine (K) methylation has been shown to play a fundamental role in modulating chromatin architecture and regulation of gene expression. Here we report on the identification of histone H3K56, located at the pivotal, nucleosome DNA entry/exit point, as a novel methylation site that is evolutionary conserved. We identify trimethylation of H3K56 (H3K56me3) as a modification that is present during all cell cycle phases, with the exception of S-phase, where it is underrepresented on chromatin. H3K56me3 is a novel heterochromatin mark, since it is enriched at pericentromeres but not telomeres and is thereby similar, but not identical, to the localization of H3K9me3 and H4K20me3. Possibly due to H3 sequence similarities, Suv39h enzymes, responsible for trimethylation of H3K9, also affect methylation of H3K56. Similarly, we demonstrate that trimethylation of H3K56 is removed by members of the JMJD2 family of demethylases that also target H3K9me3. Furthermore, we identify and characterize mouse mJmjd2E and its human homolog hKDM4L as novel, functionally active enzymes that catalyze the removal of two methyl groups from trimethylated H3K9 and K56. H3K56me3 is also found in C. elegans, where it co-localizes with H3K9me3 in most, but not all, tissues. Taken together, our findings raise interesting questions regarding how methylation of H3K9 and H3K56 is regulated in different organisms and their functional roles in heterochromatin formation and/or maintenance. PMID- 23451024 TI - Optimising use of electronic health records to describe the presentation of rheumatoid arthritis in primary care: a strategy for developing code lists. AB - BACKGROUND: Research using electronic health records (EHRs) relies heavily on coded clinical data. Due to variation in coding practices, it can be difficult to aggregate the codes for a condition in order to define cases. This paper describes a methodology to develop 'indicator markers' found in patients with early rheumatoid arthritis (RA); these are a broader range of codes which may allow a probabilistic case definition to use in cases where no diagnostic code is yet recorded. METHODS: We examined EHRs of 5,843 patients in the General Practice Research Database, aged >= 30 y, with a first coded diagnosis of RA between 2005 and 2008. Lists of indicator markers for RA were developed initially by panels of clinicians drawing up code-lists and then modified based on scrutiny of available data. The prevalence of indicator markers, and their temporal relationship to RA codes, was examined in patients from 3 y before to 14 d after recorded RA diagnosis. FINDINGS: Indicator markers were common throughout EHRs of RA patients, with 83.5% having 2 or more markers. 34% of patients received a disease specific prescription before RA was coded; 42% had a referral to rheumatology, and 63% had a test for rheumatoid factor. 65% had at least one joint symptom or sign recorded and in 44% this was at least 6-months before recorded RA diagnosis. CONCLUSION: Indicator markers of RA may be valuable for case definition in cases which do not yet have a diagnostic code. The clinical diagnosis of RA is likely to occur some months before it is coded, shown by markers frequently occurring >= 6 months before recorded diagnosis. It is difficult to differentiate delay in diagnosis from delay in recording. Information concealed in free text may be required for the accurate identification of patients and to assess the quality of care in general practice. PMID- 23451025 TI - Reference cluster normalization improves detection of frontotemporal lobar degeneration by means of FDG-PET. AB - Positron emission tomography with [18F] fluorodeoxyglucose (FDG-PET) plays a well established role in assisting early detection of frontotemporal lobar degeneration (FTLD). Here, we examined the impact of intensity normalization to different reference areas on accuracy of FDG-PET to discriminate between patients with mild FTLD and healthy elderly subjects. FDG-PET was conducted at two centers using different acquisition protocols: 41 FTLD patients and 42 controls were studied at center 1, 11 FTLD patients and 13 controls were studied at center 2. All PET images were intensity normalized to the cerebellum, primary sensorimotor cortex (SMC), cerebral global mean (CGM), and a reference cluster with most preserved FDG uptake in the aforementioned patients group of center 1. Metabolic deficits in the patient group at center 1 appeared 1.5, 3.6, and 4.6 times greater in spatial extent, when tracer uptake was normalized to the reference cluster rather than to the cerebellum, SMC, and CGM, respectively. Logistic regression analyses based on normalized values from FTLD-typical regions showed that at center 1, cerebellar, SMC, CGM, and cluster normalizations differentiated patients from controls with accuracies of 86%, 76%, 75% and 90%, respectively. A similar order of effects was found at center 2. Cluster normalization leads to a significant increase of statistical power in detecting early FTLD-associated metabolic deficits. The established FTLD-specific cluster can be used to improve detection of FTLD on a single case basis at independent centers - a decisive step towards early diagnosis and prediction of FTLD syndromes enabling specific therapies in the future. PMID- 23451026 TI - Efficacy, compliance and reasons for refusal of postoperative chemotherapy for elderly patients with colorectal cancer: a retrospective chart review and telephone patient questionnaire. AB - BACKGROUND: Numerous clinical trials have demonstrated that elderly patients with colorectal cancer (CRC) can benefit from chemotherapy, yet compliance in real world practice is low. The purpose of this study is to investigate the efficacy, compliance and reasons for refusal of postoperative chemotherapy for elderly patients with CRC and to provide corresponding strategies. PATIENTS AND METHODS: The clinico-pathological and biochemical data of the chemotherapy group and chemo refusing group were compared among 386 elderly patients (>70 years old) with CRC who underwent surgery. 226 patients received chemotherapy and 160 patients refused. Follow-up of the subjective reasons for refusal was investigated using the elderly caner patients' chemo-refusal reason questionnaire (ECPCRRQ) prepared by the authors and a group of psychologists. The questionnaire is administrated by telephone. A predictive model for 5-year disease-free survival (DFS) and 5 year overall survival (OS) was constructed by using Kaplan-Meier analysis, logistic and Cox regression. RESULTS: Among stage III patients, receiving chemotherapy was associated with a significantly higher OS (68%) compared to those who refused ( OS 50%) (HR: 2.05, 95%CI: 1.12-3.77, P = 0.02). The Chemo refusal group had more female and elderly patients, significantly higher rate of severe complications, and lower body mass index (BMI). Follow-up phone questionnaire analysis showed the doctors' uncertainty of chemotherapy benefit, economic difficulties, uncomfortable feeling, superstition of Traditional Chinese Medicine, concealing information and lack of social support were the main factors for elderly CRC patients to decline chemotherapy. CONCLUSION: The receipt of post operative chemotherapy in elderly patients with resected stage III CRC was associated with a more favorable survival. The low compliance rate (160/386) of postoperative chemotherapy was influenced by various subjective and objective factors. PMID- 23451027 TI - Recruiting at the edge: kinetic energy inhibits anchovy populations in the western Mediterranean. AB - The Strait of Gibraltar replenishes the Mediterranean with Atlantic waters through an intense eastward current known as the Atlantic Jet (AJ). The AJ fertilizes the southwestern Mediterranean and is considered to be the ultimate factor responsible for the comparatively high fish production of this region. Here, we perform an analysis of the available historical catches and catch per unit effort (CPUE), together with a long series of surface currents, kinetic energy and chlorophyll concentration. We show that the high kinetic energy of the AJ increases primary production but also negatively impacts the recruitment of anchovy. We contend that anchovy recruitment in the region is inhibited by the advection and dispersion of larvae and post-larvae during periods of strong advection by the AJ. The inhibitory impact of kinetic energy on anchovy landings is not a transient but rather a persistent state of the system. An exceptional combination of events creates an outbreak of this species in the Alboran Sea. These events depend on the Mediterranean-Atlantic exchange of water masses and, therefore, are highly sensitive to climate changes that are projected, though not always negatively, for fish landings. PMID- 23451028 TI - Interventions to increase the uptake of mammography amongst low income women: a systematic review and meta-analysis. AB - BACKGROUND: Two previous reviews found that access-enhancing interventions were effective in increasing mammography uptake amongst low-income women. The purpose of this study was to estimate the magnitude of the effect of interventions used to increase uptake of mammography amongst low-income women. METHODS: Searches were conducted in MEDLINE and EMBASE (2002-April 2012) using relevant MeSH terms and keywords. Randomised controlled trials which aimed to increase mammography use in an asymptomatic low-income population and which had as an outcome receipt of a mammogram, were eligible for inclusion. The primary outcome was the post intervention difference in the proportion of women who had a mammogram in the intervention and control groups. The quality of the studies was assessed using the Cochrane risk of bias tool. We calculated summary estimates using random effects meta-analyses. Possible reasons for heterogeneity were investigated using sub-group analyses and meta-regression. Publication bias was assessed using Egger's test. RESULTS: Twenty-one studies met the inclusion criteria, including 33 comparisons. Interventions increased the uptake of mammography in low income women by an additional 8.9% (95% CI 7.3 to 10.4%) compared to the control group. There was some evidence that interventions with multiple strategies were more effective than those with single strategies (p = 0.03). There was some suggestion of publication bias. The quality of the included studies was often unclear. Omitting those with high risk of bias has little effect on the results. CONCLUSIONS: Interventions can increase mammography uptake among low-income women, multiple interventions being the most effective strategy. Given the robustness of the results to sensitivity analyses, the results are likely to be reliable. The generalisability of the results beyond the US is unclear. PMID- 23451029 TI - Availability and readability of emergency preparedness materials for deaf and hard-of-hearing and older adult populations: issues and assessments. AB - A major public health challenge is to communicate effectively with vulnerable populations about preparing for disasters and other health emergencies. People who are Deaf or Hard of Hearing (Deaf/HH) and older adults are particularly vulnerable during health emergencies and require communications that are accessible and understandable. Although health literacy studies indicate that the readability of health communication materials often exceeds people's literacy levels, we could find no research about the readability of emergency preparedness materials (EPM) intended for Deaf/HH and older adult populations. The objective of this study was to explore issues related to EPM for Deaf/HH and older adult populations, to assess the availability and readability of materials for these populations, and to recommend improvements. In two California counties, we interviewed staff at 14 community-based organizations (CBOs) serving Deaf/HH clients and 20 CBOs serving older adults selected from a stratified, random sample of 227 CBOs. We collected 40 EPM from 10 CBOs and 2 public health departments and 40 EPM from 14 local and national websites with EPM for the public. We used computerized assessments to test the U.S. grade reading levels of the 16 eligible CBO and health department EPM, and the 18 eligible website materials. Results showed that less than half of CBOs had EPM for their clients. All EPM intended for clients of Deaf/HH-serving CBOs tested above the recommended 4(th) grade reading level, and 91% of the materials intended for clients of older adult-serving CBOs scored above the recommended 6(th) grade level. EPM for these populations should be widely available through CBOs and public health departments, adhere to health literacy principles, and be accessible in alternative formats including American Sign Language. Developers should engage the intended users of EPM as co-designers and testers. This study adds to the limited literature about EPM for these populations. PMID- 23451030 TI - Cytomegalovirus seropositivity is associated with increased arterial stiffness in patients with chronic kidney disease. AB - BACKGROUND: Patients with chronic kidney disease have an increased cardiovascular risk that is not fully explained by traditional risk factors but appears to be related to increased arterial stiffness. Cytomegalovirus (CMV) infection is associated with increased cardiovascular risk although the mechanisms for this are unknown. We examined whether CMV seropositivity was associated with increased arterial stiffness in patients with chronic kidney disease. METHODOLOGY AND PRINCIPAL FINDINGS: In 215 non-diabetic patients with chronic kidney disease, CMV seropositivity was determined using an anti-CMV IgG ELISA. Pulse wave velocity was measured and aortic distensibility assessed in the ascending, proximal descending and distal descending thoracic aorta. Patients seropositive for CMV had a higher pulse wave velocity and lower aortic distensibility at all 3 levels. These differences (except for ascending aortic distensibility) persisted in a subcohort matched for age, gender and renal function, and when the whole cohort was divided into quartiles of age. In multivariable analyses, CMV seropositivity was an independent determinant of pulse wave velocity and proximal and distal descending aortic distensibility. CONCLUSIONS: In patients with chronic kidney disease, CMV seropositivity is associated with increased arterial stiffness and decreased distensibility of the proximal descending and distal aorta. These findings suggest that further research is required to examine CMV as a possible cause of arterial disease and increased cardiovascular risk in patients with CKD and may be relevant more widely for CMV seropositive patients with normal renal function. PMID- 23451031 TI - Bridging HIV-1 cellular latency and clinical long-term non-progressor: an interactomic view. AB - Development of an effective HIV management is enticed by the fact that long-term non-progressors (LTNP) restrict viral replication spontaneously, but is hindered by HIV-1 latency. Given that the most overlapping characteristics found between HIV-1 LTNP and latency, detailed analysis of the difference would disclose the essentials of latency. In this study, microarray data from our previous study was combined with HIV-1 latency and LTNP data obtained from NCBI GEO database. Principal variance component analysis and hierarchical clustering verified the removal of batch effect across platform. The analysis revealed a total of 456 differential expressed genes with >2-fold change and B-statistic >0. Bayesian inference was used to reconstitute the transcriptional network of HIV-1 latency or LTNP, respectively. Gene regulation was reprogrammed under different disease condition. By network interference, KPNA2 and ATP5G3 were identified as the hubs in latency network which mediate nuclear export and RNA processing. These data offer comparative insights into HIV-1 latency, which will facilitate the understanding of the genetic basis of HIV-1 latency in vivo and serve as a clue for future treatment dealing with key targets in HIV-1 latency. PMID- 23451032 TI - Visual phenotype matching: cues to paternity are present in rhesus macaque faces. AB - The ability to recognize kin and thus behaviourally discriminate between conspecifics based on genetic relatedness is of importance both in acquiring inclusive fitness benefits and to enable optimal inbreeding. In primates, mechanisms allowing recognition of paternal relatives are of particular interest, given that in these mating systems patrilineal information is unlikely to be available via social familiarity. Humans use visual phenotype matching based on facial features to identify their own and other's close relatives, and recent studies suggest similar abilities may be present in other species. However it is unclear to what extent familial resemblances remain detectable against the background levels of relatedness typically found within demes in the wild - a necessary condition if facial cues are to function in kin recognition under natural conditions. Here, we experimentally investigate whether parent-offspring relationships are discernible in rhesus macaque (Macaca mulatta) faces drawn from a large free-ranging population more representative of the latter scenario, and in which genetic relatedness has been well quantified from pedigrees determined via molecular markers. We used the human visual system as a means of integrating multiple types of facial cue simultaneously, and demonstrate that paternal, as well as maternal, resemblance to both sons and daughters can be detected even by human observers. Experts performed better than participants who lacked previous experience working with nonhuman primates. However the finding that even naive individuals succeeded at the task underlines the strength of the phenotypic cues present in faces. PMID- 23451033 TI - Characterization of a chromosomal type II toxin-antitoxin system mazEaFa in the Cyanobacterium Anabaena sp. PCC 7120. AB - Cyanobacteria have evolved to survive stressful environmental changes by regulating growth, however, the underlying mechanism for this is obscure. The ability of chromosomal type II toxin-antitoxin (TA) systems to modulate growth or cell death has been documented in a variety of prokaryotes. A chromosomal mazEaFa locus of Anabaena sp. PCC 7120 has been predicted as a putative mazEF TA system. Here we demonstrate that mazEaFa form a bicistronic operon that is co-transcribed under normal growth conditions. Overproduction of MazFa induced Anabaena growth arrest which could be neutralized by co-expression of MazEa. MazFa also inhibited the growth of Escherichia coli cells, and this effect could be overcome by simultaneous or subsequent expression of MazEa via formation of the MazEa-MazFa complex in vivo, further confirming the nature of the mazEaFa locus as a type II TA system. Interestingly, like most TA systems, deletion of mazEaFa had no effect on the growth of Anabaena during the tested stresses. Our data suggest that mazEaFa, or together with other chromosomal type II TA systems, may promote cells to cope with particular stresses by inducing reversible growth arrest of Anabaena. PMID- 23451034 TI - Place-based attributes predict community membership in a mobile phone communication network. AB - Social networks can be organized into communities of closely connected nodes, a property known as modularity. Because diseases, information, and behaviors spread faster within communities than between communities, understanding modularity has broad implications for public policy, epidemiology and the social sciences. Explanations for community formation in social networks often incorporate the attributes of individual people, such as gender, ethnicity or shared activities. High modularity is also a property of large-scale social networks, where each node represents a population of individuals at a location, such as call flow between mobile phone towers. However, whether or not place-based attributes, including land cover and economic activity, can predict community membership for network nodes in large-scale networks remains unknown. We describe the pattern of modularity in a mobile phone communication network in the Dominican Republic, and use a linear discriminant analysis (LDA) to determine whether geographic context can explain community membership. Our results demonstrate that place-based attributes, including sugar cane production, urbanization, distance to the nearest airport, and wealth, correctly predicted community membership for over 70% of mobile phone towers. We observed a strongly positive correlation (r = 0.97) between the modularity score and the predictive ability of the LDA, suggesting that place-based attributes can accurately represent the processes driving modularity. In the absence of social network data, the methods we present can be used to predict community membership over large scales using solely place based attributes. PMID- 23451035 TI - Key role of group v secreted phospholipase A2 in Th2 cytokine and dendritic cell driven airway hyperresponsiveness and remodeling. AB - BACKGROUND: Previous work has shown that disruption of the gene for group X secreted phospholipase A2 (sPLA2-X) markedly diminishes airway hyperresponsiveness and remodeling in a mouse asthma model. With the large number of additional sPLA2s in the mammalian genome, the involvement of other sPLA2s in the asthma model is possible - in particular, the group V sPLA2 (sPLA2-V) that like sPLA2-X is highly active at hydrolyzing membranes of mammalian cells. METHODOLOGY AND PRINCIPAL FINDINGS: The allergen-driven asthma phenotype was significantly reduced in sPLA2-V-deficient mice but to a lesser extent than observed previously in sPLA2-X-deficient mice. The most striking difference observed between the sPLA2-V and sPLA2-X knockouts was the significant impairment of the primary immune response to the allergen ovalbumin (OVA) in the sPLA2-V(-/ ) mice. The impairment in eicosanoid generation and dendritic cell activation in sPLA2-V(-/-) mice diminishes Th2 cytokine responses in the airways. CONCLUSIONS: This paper illustrates the diverse roles of sPLA2s in the immunopathogenesis of the asthma phenotype and directs attention to developing specific inhibitors of sPLA2-V as a potential new therapy to treat asthma and other allergic disorders. PMID- 23451036 TI - Intermittent preventive treatment in pregnant women is associated with increased risk of severe malaria in their offspring. AB - BACKGROUND: In areas of widespread sulfadoxine-pyrimethamine resistance, intermittent treatment in pregnancy (IPTp) fails to prevent placental malaria (PM) and may exacerbate drug resistant infections. Because PM predicts increased susceptibility to parasitemia during infancy, we hypothesized that IPTp would also increase susceptibility to malaria infection and disease in the offspring. METHODS: In a birth cohort from NE Tanzania, we evaluated the association between maternal IPTp use and risk of parasitemia and severe malaria in the offspring. Using Cox Proportional Hazards Models as well as Generalized Estimating Equations, we evaluated the effects of IPTp on the entire cohort and on subgroups stratified by PM status at delivery. RESULTS AND CONCLUSIONS: Offspring of PM+ women who received IPTp had a dose-dependent decrease in time to first parasitemia (AHR = 2.13, p = 0.04 [95%CI: 1.04, 4.38]). Among all offspring, IPTp was associated with earlier first severe malaria episode (AHR = 2.32, p = 0.02 [95%CI: 1.12, 4.78]) as well as increased overall odds of severe malaria (AOR = 2.31, p = 0.03 [95%CI: 1.09, 4.88]). Cost-benefit analyses of IPTp regimens should consider the long term effects on offspring in addition to pregnancy outcomes. PMID- 23451037 TI - Cell-autonomous and non-cell-autonomous roles for IRF6 during development of the tongue. AB - Interferon regulatory factor 6 (IRF6) encodes a highly conserved helix-turn-helix DNA binding protein and is a member of the interferon regulatory family of DNA transcription factors. Mutations in IRF6 lead to isolated and syndromic forms of cleft lip and palate, most notably Van der Woude syndrome (VWS) and Popliteal Ptyerigium Syndrome (PPS). Mice lacking both copies of Irf6 have severe limb, skin, palatal and esophageal abnormalities, due to significantly altered and delayed epithelial development. However, a recent report showed that MCS9.7, an enhancer near Irf6, is active in the tongue, suggesting that Irf6 may also be expressed in the tongue. Indeed, we detected Irf6 staining in the mesoderm derived muscle during development of the tongue. Dual labeling experiments demonstrated that Irf6 was expressed only in the Myf5+ cell lineage, which originates from the segmental paraxial mesoderm and gives rise to the muscles of the tongue. Fate mapping of the segmental paraxial mesoderm cells revealed a cell autonomous Irf6 function with reduced and poorly organized Myf5+ cell lineage in the tongue. Molecular analyses showed that the Irf6-/- embryos had aberrant cytoskeletal formation of the segmental paraxial mesoderm in the tongue. Fate mapping of the cranial neural crest cells revealed non-cell-autonomous Irf6 function with the loss of the inter-molar eminence. Loss of Irf6 function altered Bmp2, Bmp4, Shh, and Fgf10 signaling suggesting that these genes are involved in Irf6 signaling. Based on these data, Irf6 plays important cell-autonomous and non cell-autonomous roles in muscular differentiation and cytoskeletal formation in the tongue. PMID- 23451038 TI - Low thalamic NAA-concentration corresponds to strong neural activation in working memory in Kleine-Levin syndrome. AB - BACKGROUND: Kleine Levin Syndrome (KLS) is a rare disorder of periodic hypersomnia and behavioural disturbances in young individuals. It has previously been shown to be associated with disturbances of working memory (WM), which, in turn, was associated with higher activation of the thalamus with increasing WM load, demonstrated with functional magnetic resonance imaging (fMRI). In this study we aimed to further elucidate how these findings are related to the metabolism of the thalamus. METHODS: fMRI and magnetic resonance spectroscopy were applied while performing a WM task. Standard metabolites were examined: n acetylaspartate (NAA), myo-inositol, choline, creatine and glutamate-glutamine. Fourteen KLS-patients and 15 healthy controls participated in the study. The patients with active disease were examined in asymptomatic periods. RESULTS: There was a statistically significant negative correlation between thalamic fMRI activation and thalamic NAA, i.e., high fMRI-activation corresponded to low NAA levels. This correlation was not seen in healthy controls. Thalamic levels of NAA in patients and controls showed no significant differences between the groups. None of the other metabolites showed any co-variation with fMRI-activation. CONCLUSION: This study shows negative correlation between NAA-levels and fMRI activity in the left thalamus of KLS-patients while performing a WM task. This correlation could not be found in healthy control subjects, primarily interpreted as an effect of increased effort in the patient group upon performing the task. It might indicate a disturbance in the neuronal networks responsible for WM in KLS patients, resulting in higher effort at lower WM load, compared with healthy subjects. The general relationship between NAA and BOLD-signal is also discussed in the article. PMID- 23451039 TI - New approaches of PARP-1 inhibitors in human lung cancer cells and cancer stem like cells by some selected anthraquinone-derived small molecules. AB - Poly (ADP-ribose) polymerase-1 (PARP-1) and telomerase, as well as DNA damage response pathways are targets for anticancer drug development, and specific inhibitors are currently under clinical investigation. The purpose of this work is to evaluate anticancer activities of anthraquinone-derived tricyclic and tetracyclic small molecules and their structure-activity relationships with PARP 1 inhibition in non-small cell lung cancer (NSCLC) and NSCLC-overexpressing Oct4 and Nanog clone, which show high-expression of PARP-1 and more resistance to anticancer drug. We applied our library selected compounds to NCI's 60 human cancer cell-lines (NCI-60) in order to generate systematic profiling data. Based on our analysis, it is hypothesized that these drugs might be, directly and indirectly, target components to induce mitochondrial permeability transition and the release of pro-apoptotic factors as potential anti-NSCLC or PARP inhibitor candidates. Altogether, the most active NSC747854 showed its cytotoxicity and dose-dependent PARP inhibitory manner, thus it emerges as a promising structure for anti-cancer therapy with no significant negative influence on normal cells. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and telomerase inhibitors, in particular. Together, the data presented here expand our insight into the PARP inhibitors and support the resource demanding lead optimization of structurally related small molecules for human cancer therapy. PMID- 23451040 TI - Immune-related gene expression profile in laboratory common marmosets assessed by an accurate quantitative real-time PCR using selected reference genes. AB - The common marmoset (Callithrix jacchus) is considered a novel experimental animal model of non-human primates. However, due to antibody unavailability, immunological and pathological studies have not been adequately conducted in various disease models of common marmoset. Quantitative real-time PCR (qPCR) is a powerful tool to examine gene expression levels. Recent reports have shown that selection of internal reference housekeeping genes are required for accurate normalization of gene expression. To develop a reliable qPCR method in common marmoset, we used geNorm applets to evaluate the expression stability of eight candidate reference genes (GAPDH, ACTB, rRNA, B2M, UBC, HPRT, SDHA and TBP) in various tissues from laboratory common marmosets. geNorm analysis showed that GAPDH, ACTB, SDHA and TBP were generally ranked high in stability followed by UBC. In contrast, HPRT, rRNA and B2M exhibited lower expression stability than other genes in most tissues analyzed. Furthermore, by using the improved qPCR with selected reference genes, we analyzed the expression levels of CD antigens (CD3epsilon, CD4, CD8alpha and CD20) and cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12beta, IL-13, IFN-gamma and TNF-alpha) in peripheral blood leukocytes and compared them between common marmosets and humans. The expression levels of CD4 and IL-4 were lower in common marmosets than in humans whereas those of IL-10, IL-12beta and IFN-gamma were higher in the common marmoset. The ratio of Th1-related gene expression level to that of Th2-related genes was inverted in common marmosets. We confirmed the inverted ratio of CD4 to CD8 in common marmosets by flow cytometric analysis. Therefore, the difference in Th1/Th2 balance between common marmosets and humans may affect host defense and/or disease susceptibility, which should be carefully considered when using common marmoset as an experimental model for biomedical research. PMID- 23451041 TI - BCG-mediated bladder cancer immunotherapy: identifying determinants of treatment response using a calibrated mathematical model. AB - Intravesical Bacillus Calmette Guerin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy - using cure rate as the primary endpoint. Based on available clinical and in vitro experimental data, we constructed and parameterized a stochastic mathematical model describing the interactions between BCG, the immune system, the bladder mucosa and tumor cells. The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy. PMID- 23451042 TI - IDH1-associated primary glioblastoma in young adults displays differential patterns of tumour and vascular morphology. AB - Glioblastoma is a highly aggressive tumour with marked heterogeneity at the morphological level in both the tumour cells and the associated highly prominent vasculature. As we begin to develop an increased biological insight into the underlying processes driving the disease, fewer attempts have thus far been made to understand these phenotypic differences. We sought to address this by carefully assessing the morphological characteristics of both the tumour cells and the associated vasculature, relating these observations to the IDH1/MGMT status, with a particular focus on the early onset population of young adults who develop primary glioblastoma. 276 primary glioblastoma specimens were classified into their predominant cell morphological type (fibrillary, gemistocytic, giant cell, small cell, oligodendroglial, sarcomatous), and assessed for specific tumour (cellularity, necrosis, palisades) and vascular features (glomeruloid structures, arcades, pericyte proliferation). IDH1 positive glioblastomas were associated with a younger age at diagnosis, better clinical outcome, prominent oligodendroglial and small cell tumour cell morphology, pallisading necrosis and glomeruloid vascular proliferation in the absence of arcade-like structures. These features widen the phenotype of IDH1 mutation-positive primary glioblastoma in young adults and provide correlative evidence for a functional role of mutant IDH1 in the differential nature of neo-angiogenesis in different subtypes of glioblastoma. PMID- 23451043 TI - Prevention of canine leishmaniosis in a hyper-endemic area using a combination of 10% imidacloprid/4.5% flumethrin. AB - BACKGROUND: Dogs are the main reservoir hosts of Leishmania infantum, the agent of human zoonotic visceral leishmaniosis. This study investigated the efficacy of a polymer matrix collar containing a combination of 10% imidacloprid and 4.5% flumethrin as a novel prophylactic measure to prevent L. infantum infections in young dogs from a hyper-endemic area of southern Italy, with a view towards enhancing current control strategies against both human and canine leishmaniosis. METHODOLOGY/PRINCIPAL FINDINGS: The study was carried out on 124 young dogs, of which 63 were collared (Group A) while 61 were left untreated (Group B), from March-April 2011 until March 2012. Blood and skin samples were collected at baseline (April 2011) and at the first, second, third and fourth follow-up time points (July, September 2011 and November 2011, and March 2012, respectively). Bone marrow and conjunctiva were sampled at baseline and at the fourth follow-up. Serological, cytological and molecular tests were performed to detect the presence of L. infantum in the different tissues collected. At the end of the trial, no dog from Group A proved positive for L. infantum at any follow-up, whereas 22 dogs from Group B were infected (incidence density rate = 45.1%); therefore, the combination of 10% imidacloprid and 4.5% flumethrin was 100% efficacious for the prevention of L. infantum infection in young dogs prior to their first exposure to the parasite in a hyper-endemic area for CanL. CONCLUSIONS: The use of collars containing 10% imidacloprid and 4.5% flumethrin conferred long-term protection against infection by L. infantum to dogs located in a hyper-endemic area, thus representing a reliable and sustainable strategy to decrease the frequency and spread of this disease among the canine population which will ultimately result in the reduction of associated risks to human health. PMID- 23451044 TI - Effect of isovolemic, isothermic hemodialysis on cerebral perfusion and vascular stiffness using contrast computed tomography and pulse wave velocity. AB - BACKGROUND: Patients undergoing hemodialysis treatment have a six-fold increased risk for stroke relative to the general population. However, the effect of hemodialysis on cerebral blood flow is poorly studied and confounding factors like blood pressure and ultrafiltration as well as temperature changes have rarely been accounted for. The aim of our study was to use state-of-the-art technology to evaluate the effect of a single dialysis session on cerebral perfusion as well as on vascular stiffness. METHODS: Chronic hemodialysis patients (7 male/3 female, mean age 58 years) were recruited. Cerebral blood flow and arterial pulse wave velocity were measured before and immediately after a hemodialysis session. To exclude effects of volume changes we kept ultrafiltration to a minimum, allowing no change in body weight. Isothermic conditions were maintained by using the GENIUS single-pass batch-dialysis system with a high-flux polysulfone dialyser. Cerebral blood flow was measured by contrast-enhanced computed tomography. Pulse wave velocity was measured using the SphygmoCor (AtCor Medical, USA) device by a single operator. RESULTS: This study shows for the first time that isovolemic, isothermic hemodialysis neither affected blood pressure or heart rate, nor total or regional cerebral perfusion. There was also no change in pulse wave velocity. CONCLUSIONS: Mechanisms other than the dialysis procedure itself might be causative for the high incidence of ischemic strokes in this patient population. Moreover, the sole removal of uremic toxins does not lead to short-term effects on vascular stiffness, underlying the importance of volume control in this patient population. PMID- 23451045 TI - The Populus superoxide dismutase gene family and its responses to drought stress in transgenic poplar overexpressing a pine cytosolic glutamine synthetase (GS1a). AB - BACKGROUND: Glutamine synthetase (GS) plays a central role in plant nitrogen assimilation, a process intimately linked to soil water availability. We previously showed that hybrid poplar (Populus tremula X alba, INRA 717-1B4) expressing ectopically a pine cytosolic glutamine synthetase gene (GS1a) display enhanced tolerance to drought. Preliminary transcriptome profiling revealed that during drought, members of the superoxide dismutase (SOD) family were reciprocally regulated in GS poplar when compared with the wild-type control, in all tissues examined. SOD was the only gene family found to exhibit such patterns. RESULTS: In silico analysis of the Populus genome identified 12 SOD genes and two genes encoding copper chaperones for SOD (CCSs). The poplar SODs form three phylogenetic clusters in accordance with their distinct metal co factor requirements and gene structure. Nearly all poplar SODs and CCSs are present in duplicate derived from whole genome duplication, in sharp contrast to their predominantly single-copy Arabidopsis orthologs. Drought stress triggered plant-wide down-regulation of the plastidic copper SODs (CSDs), with concomitant up-regulation of plastidic iron SODs (FSDs) in GS poplar relative to the wild type; this was confirmed at the activity level. We also found evidence for coordinated down-regulation of other copper proteins, including plastidic CCSs and polyphenol oxidases, in GS poplar under drought conditions. CONCLUSIONS: Both gene duplication and expression divergence have contributed to the expansion and transcriptional diversity of the Populus SOD/CCS families. Coordinated down regulation of major copper proteins in drought-tolerant GS poplars supports the copper cofactor economy model where copper supply is preferentially allocated for plastocyanins to sustain photosynthesis during drought. Our results also extend previous findings on the compensatory regulation between chloroplastic CSDs and FSDs, and suggest that this copper-mediated mechanism represents a common response to oxidative stress and other genetic manipulations, as in GS poplars, that affect photosynthesis. PMID- 23451046 TI - Small intestine inflammation in Roquin-mutant and Roquin-deficient mice. AB - Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquin(san/san) mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquin(san/san) mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquin(gt/gt) mice) had small intestinal inflammation that mimicked that of Roquin(san/san) mice. MLN cells in Roquin(san/san) mice consisted of activated proliferating T cells, and had increased numbers of CD44(hi) CD62L(lo) KLRG1(+) short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquin(san/san) mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquin(san/san) mice consisted of a high proportion of Gr-1(+) T cells that included IL-17A(+) cells and CD8(+) IFN-gamma(+) cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquin(san/san) mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn's disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process. PMID- 23451047 TI - Organic carbon storage in four ecosystem types in the karst region of southwestern China. AB - Karst ecosystems are important landscape types that cover about 12% of the world's land area. The role of karst ecosystems in the global carbon cycle remains unclear, due to the lack of an appropriate method for determining the thickness of the solum, a representative sampling of the soil and data of organic carbon stocks at the ecosystem level. The karst region in southwestern China is the largest in the world. In this study, we estimated biomass, soil quantity and ecosystem organic carbon stocks in four vegetation types typical of karst ecosystems in this region, shrub grasslands (SG), thorn shrubbery (TS), forest - shrub transition (FS) and secondary forest (F). The results showed that the biomass of SG, TS, FS, and F is 0.52, 0.85, 5.9 and 19.2 kg m(-2), respectively and the corresponding organic cabon storage is 0.26, 0.40, 2.83 and 9.09 kg m( 2), respectively. Nevertheless, soil quantity and corresponding organic carbon storage are very small in karst habitats. The quantity of fine earth overlaying the physical weathering zone of the carbonate rock of SG, TS, FS and F is 38.10, 99.24, 29.57 and 61.89 kg m(-2), respectively, while the corresponding organic carbon storage is only 3.34, 4.10, 2.37, 5.25 kg m(-2), respectively. As a whole, ecosystem organic carbon storage of SG, TS, FS, and F is 3.81, 4.72, 5.68 and 15.1 kg m(-2), respectively. These are very low levels compared to other ecosystems in non-karst areas. With the restoration of degraded vegetation, karst ecosystems in southwestern China may play active roles in mitigating the increasing CO2 concentration in the atmosphere. PMID- 23451048 TI - 1'-Acetoxychavicol acetate isolated from Alpinia galanga ameliorates ovalbumin induced asthma in mice. AB - The World Health Organization reports that 235 million people are currently affected by asthma. This disease is associated with an imbalance of Th1 and Th2 cells, which results in the upregulation of cytokines that promote chronic inflammation of the respiratory system. The inflammatory response causes airway obstruction and can ultimately result in death. In this study we evaluated the effect of 1'-acetoxychavicol acetate (ACA) isolated from Alpinia galanga rhizomes in a mouse model of ovalbumin (OVA)-induced asthma. To generate the mouse model, BALB/c mice were sensitized by intraperitoneal injection of OVA and then challenged with OVA inhalation for 5 days. Mice in the vehicle control group were sensitized with OVA but not challenged with OVA. Treatment groups received dexamethasone, 25 mg/kg/day ACA, or 50 mg/kg/day ACA for 5 days. Asthma-related inflammation was assessed by bronchoalveolar lavage fluid cell counts and histopathological and immunohistochemical analysis of lung tissues. Our results showed that ACA reduced the infiltration of white blood cells (especially eosinophils) and the level of IgE in the lungs of mice challenged with OVA and suppressed histopathological changes such as airway remodeling, goblet-cell hyperplasia, eosinophil infiltration, and glycoprotein secretion. In addition, ACA inhibited expression of the Th2 cytokines interleukin (IL)-4 and IL-13, and Th1 cytokines IL-12alpha and interferon-gamma. Because asthmatic reactions are mediated by diverse immune and inflammatory pathways, ACA shows promise as an antiasthmatic drug candidate. PMID- 23451049 TI - Population densities, vegetation green-up, and plant productivity: impacts on reproductive success and juvenile body mass in reindeer. AB - Global warming is expected to cause earlier springs and increased primary productivity in the Arctic. These changes may improve food availability for Arctic herbivores, but may also have negative effects by generating a mismatch between the surge of high quality food in the spring and the timing of reproduction. We analyzed a 10 year dataset of satellite derived measures of vegetation green-up, population densities, calf body masses and female reproductive success in 19 reindeer (Rangifer tarandus) populations in Northern Norway. An early onset of spring and high peak plant productivity had positive effects on calf autumn body masses and female reproductive success. In addition, body masses and reproductive success were both negatively related to population density. The quantity of food available, as determined by the onset of vegetation green-up and plant productivity over the summer were the main drivers of body mass growth and reproductive success. We found no evidence for an effect of the speed of spring green-up. Nor did we detect a negative mismatch between early springs and subsequent recruitment. Effects of global warming on plant productivity and onset of spring is likely to positively affect sub-Arctic reindeer. PMID- 23451050 TI - Decision rules and group rationality: cognitive gain or standstill? AB - Recent research in group cognition points towards the existence of collective cognitive competencies that transcend individual group members' cognitive competencies. Since rationality is a key cognitive competence for group decision making, and group cognition emerges from the coordination of individual cognition during social interactions, this study tests the extent to which collaborative and consultative decision rules impact the emergence of group rationality. Using a set of decision tasks adapted from the heuristics and biases literature, we evaluate rationality as the extent to which individual choices are aligned with a normative ideal. We further operationalize group rationality as cognitive synergy (the extent to which collective rationality exceeds average or best individual rationality in the group), and we test the effect of collaborative and consultative decision rules in a sample of 176 groups. Our results show that the collaborative decision rule has superior synergic effects as compared to the consultative decision rule. The ninety one groups working in a collaborative fashion made more rational choices (above and beyond the average rationality of their members) than the eighty five groups working in a consultative fashion. Moreover, the groups using a collaborative decision rule were closer to the rationality of their best member than groups using consultative decision rules. Nevertheless, on average groups did not outperformed their best member. Therefore, our results reveal how decision rules prescribing interpersonal interactions impact on the emergence of collective cognitive competencies. They also open potential venues for further research on the emergence of collective rationality in human decision-making groups. PMID- 23451051 TI - Characterization of DNA topoisomerase-1 in Spodoptera exigua for toxicity evaluation of camptothecin and hydoxy-camptothecin. AB - Camptothecin (CPT), a plant alkaloid originally isolated from the native Chinese tree, Camptotheca acuminate, exerts the toxic effect by targeting eukaryotic DNA topoisomerase 1 (DNA Topo1). Besides as potent anti-cancer agents, CPT and its derivatives are now being explored as potential pesticides for insect control. In this study, we assessed their toxicity to an insect homolog, the Topo1 protein from beet armyworms (Spodoptera exigua Hubner), a worldwide pest of many important crops. The S. exigua Topo1 gene contains an ORF of 2790 base pairs that is predicted to encode a polypeptide of 930 amino acids. The deduced polypeptide exhibits polymorphism at residue sites V420, L530, A653 and T729 (numbered according to human Topo1) among insect species, which are predicted to confer sensitivity to CPT. The DNA relaxation activity of this protein was subsequently examined using a truncated form that contained the residues 337-930 and was expressed in bacteria BL21 cells. The purified protein retained the ability to relax double-stranded DNA and was susceptible to CPT and its derivative hydroxy camptothecin (HCPT) in a dose-dependent manner. The same inhibitory effect was also found on the native Topo1 extracted from IOZCAS-Spex-II cells, a cell line established from beet armyworms. Additionally, CPT and HCPT treatment reduced the steady accumulation of Topo1 protein despite the increased mRNA expression in response to the treatment. Our studies provide information of the S. exigua Topo1 gene and its amino acid polymorphism in insects and uncover some clues about potential mechanisms of CPT toxicity against insect pests. These results also are useful for development of more effective Topo1-targeted CPT insecticides in the future. PMID- 23451052 TI - An albumin-derived peptide scaffold capable of binding and catalysis. AB - We have identified a 101-amino-acid polypeptide derived from the sequence of the IIA binding site of human albumin. The polypeptide contains residues that make contact with IIA ligands in the parent protein, and eight cysteine residues to form disulfide bridges, that stabilize the polypeptide structure. Seventy-four amino acids are located in six alpha-helical regions, while the remaining thirty seven amino acids form six connecting coil/loop regions. A soluble GST fusion protein was expressed in E. coli in yields as high as 4 mg/l. This protein retains the IIA fragment's capacity to bind typical ligands such as warfarin and efavirenz and other albumin's functional properties such as aldolase activity and the ability to direct the stereochemical outcome of a diketone reduction. This newly cloned polypeptide thus represents a valuable starting point for the construction of libraries of binders and catalysts with improved proficiency. PMID- 23451053 TI - Recognition in a social symbiosis: chemical phenotypes and nestmate recognition behaviors of neotropical parabiotic ants. AB - Social organisms rank among the most abundant and ecologically dominant species on Earth, in part due to exclusive recognition systems that allow cooperators to be distinguished from exploiters. Exploiters, such as social parasites, manipulate their hosts' recognition systems, whereas cooperators are expected to minimize interference with their partner's recognition abilities. Despite our wealth of knowledge about recognition in single-species social nests, less is known of the recognition systems in multi-species nests, particularly involving cooperators. One uncommon type of nesting symbiosis, called parabiosis, involves two species of ants sharing a nest and foraging trails in ostensible cooperation. Here, we investigated recognition cues (cuticular hydrocarbons) and recognition behaviors in the parabiotic mixed-species ant nests of Camponotus femoratus and Crematogaster levior in North-Eastern Amazonia. We found two sympatric, cryptic Cr. levior chemotypes in the population, with one type in each parabiotic colony. Although they share a nest, very few hydrocarbons were shared between Ca. femoratus and either Cr. levior chemotype. The Ca. femoratus hydrocarbons were also unusually long-chained branched alkenes and dienes, compounds not commonly found amongst ants. Despite minimal overlap in hydrocarbon profile, there was evidence of potential interspecific nestmate recognition -Cr. levior ants were more aggressive toward Ca. femoratus non-nestmates than Ca. femoratus nestmates. In contrast to the prediction that sharing a nest could weaken conspecific recognition, each parabiotic species also maintains its own aggressive recognition behaviors to exclude conspecific non-nestmates. This suggests that, despite cohabitation, parabiotic ants maintain their own species-specific colony odors and recognition mechanisms. It is possible that such social symbioses are enabled by the two species each using their own separate recognition cues, and that interspecific nestmate recognition may enable this multi-species cooperative nesting. PMID- 23451054 TI - A multifaceted independent performance analysis of facial subspace recognition algorithms. AB - Face recognition has emerged as the fastest growing biometric technology and has expanded a lot in the last few years. Many new algorithms and commercial systems have been proposed and developed. Most of them use Principal Component Analysis (PCA) as a base for their techniques. Different and even conflicting results have been reported by researchers comparing these algorithms. The purpose of this study is to have an independent comparative analysis considering both performance and computational complexity of six appearance based face recognition algorithms namely PCA, 2DPCA, A2DPCA, (2D)(2)PCA, LPP and 2DLPP under equal working conditions. This study was motivated due to the lack of unbiased comprehensive comparative analysis of some recent subspace methods with diverse distance metric combinations. For comparison with other studies, FERET, ORL and YALE databases have been used with evaluation criteria as of FERET evaluations which closely simulate real life scenarios. A comparison of results with previous studies is performed and anomalies are reported. An important contribution of this study is that it presents the suitable performance conditions for each of the algorithms under consideration. PMID- 23451055 TI - Centre selection for clinical trials and the generalisability of results: a mixed methods study. AB - BACKGROUND: The rationale for centre selection in randomised controlled trials (RCTs) is often unclear but may have important implications for the generalisability of trial results. The aims of this study were to evaluate the factors which currently influence centre selection in RCTs and consider how generalisability considerations inform current and optimal practice. METHODS AND FINDINGS: Mixed methods approach consisting of a systematic review and meta summary of centre selection criteria reported in RCT protocols funded by the UK National Institute of Health Research (NIHR) initiated between January 2005 January 2012; and an online survey on the topic of current and optimal centre selection, distributed to professionals in the 48 UK Clinical Trials Units and 10 NIHR Research Design Services. The survey design was informed by the systematic review and by two focus groups conducted with trialists at the Birmingham Centre for Clinical Trials. 129 trial protocols were included in the systematic review, with a total target sample size in excess of 317,000 participants. The meta summary identified 53 unique centre selection criteria. 78 protocols (60%) provided at least one criterion for centre selection, but only 31 (24%) protocols explicitly acknowledged generalisability. This is consistent with the survey findings (n = 70), where less than a third of participants reported generalisability as a key driver of centre selection in current practice. This contrasts with trialists' views on optimal practice, where generalisability in terms of clinical practice, population characteristics and economic results were prime considerations for 60% (n = 42), 57% (n = 40) and 46% (n = 32) of respondents, respectively. CONCLUSIONS: Centres are rarely enrolled in RCTs with an explicit view to external validity, although trialists acknowledge that incorporating generalisability in centre selection should ideally be more prominent. There is a need to operationalize 'generalisability' and incorporate it at the design stage of RCTs so that results are readily transferable to 'real world' practice. PMID- 23451056 TI - Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways. AB - The tumor suppressor kinase LKB1 is mutated in a broad range of cancers however, the role of LKB1 mammary gland tumorigenesis is not fully understood. Evaluation of human breast cancer tissue microarrays, indicate that 31% of HER2 positive samples lacked LKB1 expression. To expand on these observations, we crossed STK11 (fl/fl) mice with mice genetically engineered to express activated Neu/HER2-MMTV Cre (NIC) under the endogenous Erbb2 promoter, to generate STK11 (-/-/) NIC mice. In these mice, the loss of lkb1 expression reduced the latency of ErbB2-mediated tumorigenesis compared to the latency of tumorigenesis in NIC mice alone. Analysis of STK11(-/-/)NIC mammary tumors revealed hyperactivation of mammalian target of rapamycin (mTOR) through both mTORC1 and mTORC2 pathways as determined by the phosphorylation status of ribosomal protein S6 and AKT. Furthermore, STK11(-/-/)NIC mammary tumors had elevated ATP levels along with changes in metabolic enzymes and metabolites. The treatment of primary mammary tumor cells with specific mTOR inhibitors AZD8055 and Torin1, that target both mTOR complexes, attenuated mTOR activity and decreased expression of glycolytic enzymes. Our findings underscore the existence of a molecular interplay between LKB1-AMPK-mTORC1 and ErbB2-AKT-mTORC2 pathways with mTOR at its epicenter, suggestive that loss of LKB1 expression may serve as a marker for hyperactivated mTOR in HER2 positive breast cancer and warranting further investigation into therapeutics that target LKB1-AMPK-mTOR and glycolytic pathways. PMID- 23451057 TI - Efficient E. coli expression strategies for production of soluble human crystallin ALDH3A1. AB - Aldehyde dehydrogenase 3A1 (ALDH3A1) is a recently characterized corneal crystallin with its exact functions still being unclear. Expressing recombinant human ALDH3A1 has been difficult in Escherichia coli (E. coli) because of low solubility, yield and insufficient purity issues. In this report, we compared different E. coli expression strategies (namely the maltose binding protein; MBP- and the 6-his-tagged expression systems) under conditions of auto-induction and co-expression with E. coli's molecular chaperones where appropriate. Thus, we aimed to screen the efficiency of these expression strategies in order to improve solubility of recombinant ALDH3A1 when expressed in E. coli. We showed that the MBP- tagged expression in combination with lower-temperature culture conditions resulted in active soluble recombinant ALDH3A1. Expression of the fused 6-his tagged-ALDH3A1 protein resulted in poor solubility and neither lowering temperature culture conditions nor the auto-induction strategy improved its solubility. Furthermore, higher yield of soluble, active native form of 6-his tagged-ALDH3A1 was facilitated through co-expression of the two groups of E. coli's molecular chaperones, GroES/GroEL and DnaK/DnaJ/GrpE. Convenient one step immobilized affinity chromatography methods were utilized to purify the fused ALDH3A1 hybrids. Both fusion proteins retained their biological activity and could be used directly without removing the fusion tags. Taken together, our results provide a rational option for producing sufficient amounts of soluble and active recombinant ALDH3A1 using the E. coli expression system for conducting functional studies towards elucidating the biological role(s) of this interesting corneal crystallin. PMID- 23451058 TI - Identification of novel AR-targeted microRNAs mediating androgen signalling through critical pathways to regulate cell viability in prostate cancer. AB - MicroRNAs (miRNAs) have been recognized as significantly involved in prostate cancer (PCa). Since androgen receptor (AR) plays a central role in PCa carcinogenesis and progression, it is imperative to systematically elucidate the causal association between AR and miRNAs, focusing on the molecular mechanisms by which miRNAs mediate AR signalling. In this study, we performed a series of time course microarrays to observe the dynamic genome-wide expressions of mRNAs and miRNAs in parallel in hormone-sensitive prostate cancer LNCaP cells stimulated by androgen. Accordingly, we introduced Response Score to identify AR target miRNAs, as well as Modulation Score to identify miRNA target mRNAs. Based on theoretical identification and experimental validation, novel mechanisms addressing cell viability in PCa were unravelled for 3 miRNAs newly recognized as AR targets. (1) miR-19a is directly up-regulated by AR, and represses SUZ12, RAB13, SC4MOL, PSAP and ABCA1, respectively. (2) miR-27a is directly up-regulated by AR, and represses ABCA1 and PDS5B. (3) miR-133b is directly up-regulated by AR, and represses CDC2L5, PTPRK, RB1CC1, and CPNE3, respectively. Moreover, we found miR 133b is essential to PCa cell survival. Our study gives certain clues on miRNAs mediated AR signalling to cell viability by influencing critical pathways, especially by breaking through androgen's growth restriction effect on normal prostate tissue. PMID- 23451059 TI - Sequence variation analysis of HPV-18 isolates in southwest China. AB - Intratypic variations of HPV-18 are known to differ in the persistence of the infection, frequency of carcinogenesis and the progression of precursor lesions to advanced cervical cancer. This study was designed to analyze sequence variations of HPV-18 isolates in order to discover novel HPV-18 variants and to evaluate the variations among infected women in southwest China. Cervical biopsies from 56 HPV-18-positive women with cervical neoplasia were assayed by PCR amplification and sequencing of all eight genes (E1, E2, E4, E5, E6, E7, L1, L2) of the HPV-18 genome. The most frequently observed variation was a C to G transversion at nucleotide 287 of E6, which was found in 48.2% of samples. Analysis of E7 revealed only one specimen as having sequence variations. In addition, we have identified several novel variations: A551C in E6, G6906A in L1, and C4915T and C5147A in L2. The mutations in E6 and L2 are silent, while the E7 mutation results in a single amino acid change. This study complements and expands on previous descriptions of HPV-18 variants. The sequence variation data presented here provides a foundation for future research on HPV-induced oncogenesis and may prove valuable for developing diagnostic probes and in the design of HPV vaccines for targeted populations. PMID- 23451060 TI - Prognostic implications of micoRNA miR-195 expression in human tongue squamous cell carcinoma. AB - BACKGROUND: miR-195 is aberrantly expressed in multiple types of disease. But little is known about the dysregulation of miR-195 in tongue squamous cell carcinoma (TSCC). In this study, we investigated the roles of miR-195 in the development and progression of TSCC. METHODS: Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we evaluated miR-195 expression in TSCC samples from 81 patients. Overall survival of these patients was examined using Kaplan-Meier curves with log-rank tests and the Cox proportional hazards model. The expression of two known miR-195 target genes, Cyclin D1 and Bcl-2, was also examined in the TSCC samples by immunohistochemistry. The effects of miR-195 overexpression on cell cycle progression and apoptosis and its effects on the expression of Cyclin D1 and Bcl 2 were examined in transfected TSCC cell lines (SCC-15 and Cal27) using fluorescence-activated cell sorting assays, luciferase reporter assays, and Western blots. RESULTS: Reduced miR-195 expression was associated with tumor size and the clinical stage of TSCC tumors. Kaplan-Meier survival analysis indicated that the TSCC patients with reduced expression of miR-195 had poor overall survival and in multivariable analyses low levels of miR-195 emerged as an independent prognostic factor for this clinical outcome. Levels of miR-195 expression were inversely correlated with the expression of Cyclin D1 and Bcl-2. Overexpression of miR-195 inhibited cell cycle progression, promoted apoptosis, and reduced Cyclin D1 and Bcl-2 expression in two TSCC cell lines. CONCLUSIONS: miR-195 may have potential applications as a prognostic factor for TSCC patients. PMID- 23451062 TI - Artificial environments for the co-translational stabilization of cell-free expressed proteins. AB - An approach for designing individual expression environments that reduce or prevent protein aggregation and precipitation is described. Inefficient folding of difficult proteins in unfavorable translation environments can cause significant losses of overexpressed proteins as precipitates or inclusion bodies. A number of chemical chaperones including alcohols, polyols, polyions or polymers are known to have positive effects on protein stability. However, conventional expression approaches can use such stabilizing agents only post-translationally during protein extraction and purification. Proteins that already precipitate inside of the producer cells cannot be addressed. The open nature of cell-free protein expression systems offers the option to include single chemicals or cocktails of stabilizing compounds already into the expression environment. We report an approach for systematic screening of stabilizers in order to improve the solubility and quality of overexpressed proteins co-translationally. A comprehensive list of representative protein stabilizers from the major groups of naturally occurring chemical chaperones has been analyzed and their concentration ranges tolerated by cell-free expression systems have been determined. As a proof of concept, we have applied the method to improve the yield of proteins showing instability and partial precipitation during cell-free synthesis. Stabilizers that co-translationally improve the solubility and functional folding of human glucosamine 6-phosphate N-acetyltransferase have been identified and cumulative effects of stabilizers have been studied. PMID- 23451061 TI - Milano summer particulate matter (PM10) triggers lung inflammation and extra pulmonary adverse events in mice. AB - Recent studies have suggested a link between particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS), cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17) for a putative pro-carcinogenic marker (Cyp1B1) and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-alpha, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1) and for inflammation markers (TNF-alpha, MIP-2, IL-1beta, MPO). Genes up-regulation (HMOX1, Cyp1B1, IL-1beta, MIP-2, MPO) and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET 1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity of PM10sum and could facilitate shedding light on mechanisms underlying the development of urban air pollution related diseases. PMID- 23451063 TI - Association between the rs2910164 polymorphism in pre-Mir-146a sequence and thyroid carcinogenesis. AB - BACKGROUND: Rs2910164, a Single nucleotide polymorphism (SNP) located in the precursor microRNA sequence of miR-146a, is the only MicroRNA sequence SNP studied in papillary thyroid cancer (PTC). Association studies had been performed in US and UK-Northern European populations, but results were inconsistence. This study evaluated the association between rs2910164 and the risk of PTC as well as benign thyroid tumor (BN), and examined the clinicopathological characteristics of PTC and BN for different genotypes. METHODS: This case-control study genotyped rs2910164 in 753 PTCs, 484 BNs and 760 controls in a Chinese Han population. Clinicopathological and genetic data were collected and compared. Multivariate logistic regression was performed to calculate adjusted odds ratios (ORs). RESULTS: There were no differences in rs2910164 genotype distributions between the three groups. PTC cases with three genotypes (CC, CG, GG) had similar clinicopathological characteristics except the existence of "para-cancer" BN (PTC/BN, P = 0.006). PTC/BN patients were older (P = 0.009), and had smaller cancer lesions (P<0.001), lower serum thyrotropin levels (1.82+/-1.42 vs. 2.21+/ 1.74, P = 0.04), and lower rates of level VI lymph node metastasis (20.8% vs. 52.7%, P<0.001) and lateral neck lymph node metastasis (11.5% vs. 23.0%, P = 0.011) compared with PTC only. Then we supposed a possible progression from BN to PTC which may involve rs2910164 in and performed a multivariate logistic regression analysis of PTC/BN and BN cases to determine risk factors of this progression. Results showed that the rs2910164 GG homozygote (OR = 2.25, 95% CI 1.22-4.14, P = 0.01) was the only risk factor in this study. CONCLUSION: Rs2910164 was not associated with increased risk of PTC and BN in Chinese patients, but may play a latent role in the transformation from BN to PTC. PMID- 23451064 TI - Causes and implications of codon usage bias in RNA viruses. AB - Choice of synonymous codons depends on nucleotide/dinucleotide composition of the genome (termed mutational pressure) and relative abundance of tRNAs in a cell (translational pressure). Mutational pressure is commonly simplified to genomic GC content; however mononucleotide and dinucleotide frequencies in different genomes or mRNAs may vary significantly, especially in RNA viruses. A series of in silico shuffling algorithms were developed to account for these features and analyze the relative impact of mutational pressure components on codon usage bias in RNA viruses. Total GC content was a poor descriptor of viral genome composition and causes of codon usage bias. Genomic nucleotide content was the single most important factor of synonymous codon usage. Moreover, the choice between compatible amino acids (e.g., leucine and isoleucine) was strongly affected by genomic nucleotide composition. Dinucleotide composition at codon positions 2-3 had additional effect on codon usage. Together with mononucleotide composition bias, it could explain almost the entire codon usage bias in RNA viruses. On the other hand, strong dinucleotide content bias at codon position 3 1 found in some viruses had very little effect on codon usage. A hypothetical innate immunity sensor for CpG in RNA could partially explain the codon usage bias, but due to dependence of virus translation upon biased host translation machinery, experimental studies are required to further explore the source of dinucleotide bias in RNA viruses. PMID- 23451065 TI - Mitotic arrest and apoptosis in breast cancer cells induced by Origanum majorana extract: upregulation of TNF-alpha and downregulation of survivin and mutant p53. AB - BACKGROUND: In the present study, we investigated the effect of Origanum majorana ethanolic extract on the survival of the highly proliferative and invasive triple negative p53 mutant breast cancer cell line MDA-MB-231. RESULTS: We found that O. majorana extract (OME) was able to inhibit the viability of the MDA-MB-231 cells in a time- and concentration-dependent manner. The effect of OME on cellular viability was further confirmed by the inhibition of colony growth. We showed, depending on the concentration used, that OME elicited different effects on the MDA-MB 231 cells. Concentrations of 150 and 300 ug/mL induced an accumulation of apoptotic-resistant population of cells arrested in mitotis and overexpressing the cyclin-dependent kinase inhibitor, p21 and the inhibitor of apoptosis, survivin. On the other hand, higher concentrations of OME (450 and 600 ug/mL) triggered a massive apoptosis through the extrinsic pathway, including the activation of tumor necrosis factor-alpha (TNF-alpha), caspase 8, caspase 3, and cleavage of PARP, downregulation of survivin as well as depletion of the mutant p53 in MDA-MB-231 cells. Furthermore, OME induced an upregulation of gamma-H2AX, a marker of double strand DNA breaks and an overall histone H3 and H4 hyperacetylation. CONCLUSION: Our findings provide strong evidence that O. majorana may be a promising chemopreventive and therapeutic candidate against cancer especially for highly invasive triple negative p53 mutant breast cancer; thus validating its complementary and alternative medicinal use. PMID- 23451067 TI - Interacting coastal based ecosystem services: recreation and water quality in Puget Sound, WA. AB - Coastal recreation and water quality are major contributors to human well-being in coastal regions. They can also interact, creating opportunities for ecosystem based management, ecological restoration, and water quality improvement that can positively affect people and the environment. Yet the effect of environmental quality on human behavior is often poorly quantified, but commonly assumed in coastal ecosystem service studies. To clarify this effect we investigate a water quality dataset for evidence that environmental condition partially explains variation in recreational visitation, our indicator of human behavior. In Puget Sound, WA, we investigate variation in visitation in both visitation rate and fixed effects (FE) models. The visitation rate model relates the differences in annual recreational visitation among parks to environmental conditions, park characteristics, travel cost, and recreational demand. In our FE model we control for all time-invariant unobserved variables and compare monthly variation at the park level to determine how water quality affects visitation during the summer season. The results of our first model illustrate how visitation relates to various amenities and costs. In the FE analysis, monthly visitation was negatively related to water quality while controlling for monthly visitation trends. This indicates people are responding to changes in water quality, and an improvement would yield an increase in the value of recreation. Together, these results could help in prioritizing water quality improvements, could assist the creation of new parks or the modification of existing recreational infrastructure, and provide quantitative estimates for the expected benefits from potential changes in recreational visitation and water quality improvements. Our results also provide an example of how recreational visitation can be quantified and used in ecosystem service assessments. PMID- 23451066 TI - Highly pathogenic H5N1 influenza A virus strains provoke heterogeneous IFN alpha/beta responses that distinctively affect viral propagation in human cells. AB - The fatal transmissions of highly pathogenic avian influenza A viruses (IAV) of the H5N1 subtype to humans and high titer replication in the respiratory tract indicate that these pathogens can overcome the bird-to-human species barrier. While type I interferons (IFN-alpha/beta) are well described to contribute to the species barrier of many zoonotic viruses, current data to the role of these antiviral cytokines during human H5N1 IAV infections is limited and contradictory. We hypothesized an important role for the IFN system in limiting productive infection of avian H5N1 strains in human cells. Hence, we examined IFN alpha/beta gene activation by different avian and human H5N1 isolates, if the IFN alpha/beta response restricts H5N1 growth and whether the different strains were equally capable to regulate the IFN-alpha/beta system via their IFN-antagonistic NS1 proteins. Two human H5N1 isolates and a seasonal H3N2 strain propagated efficiently in human respiratory cells and induced little IFN-beta, whereas three purely avian H5N1 strains were attenuated for replication and provoked higher IFN secretion. Replication of avian viruses was significantly enhanced on interferon deficient cells, and exogenous IFN potently limited the growth of all strains in human cells. Moreover, IFN-alpha/beta activation by all strains depended on retinoic acid-inducible gene I excluding principal differences in receptor activation between the different viruses. Interestingly, all H5N1 NS1 proteins suppressed IFN-alpha/beta induction comparably well to the NS1 of seasonal IAV. Thus, our study shows that H5N1 strains are heterogeneous in their capacity to activate human cells in an NS1-independent manner. Our findings also suggest that H5N1 viruses need to acquire adaptive changes to circumvent strong IFN-alpha/beta activation in human host cells. Since no single amino acid polymorphism could be associated with a respective high- or low induction phenotype we propose that the necessary adaptations to overcome the human IFN-alpha/beta barrier involve mutations in multiple H5N1 genes. PMID- 23451068 TI - SGLT5 reabsorbs fructose in the kidney but its deficiency paradoxically exacerbates hepatic steatosis induced by fructose. AB - Although excessive fructose intake is epidemiologically linked with dyslipidemia, obesity, and diabetes, the mechanisms regulating plasma fructose are not well known. Cells transfected with sodium/glucose cotransporter 5 (SGLT5), which is expressed exclusively in the kidney, transport fructose in vitro; however, the physiological role of this transporter in fructose metabolism remains unclear. To determine whether SGLT5 functions as a fructose transporter in vivo, we established a line of mice lacking the gene encoding SGLT5. Sodium-dependent fructose uptake disappeared in renal brush border membrane vesicles from SGLT5 deficient mice, and the increased urinary fructose in SGLT5-deficient mice indicated that SGLT5 was the major fructose reabsorption transporter in the kidney. From this, we hypothesized that urinary fructose excretion induced by SGLT5 deficiency would ameliorate fructose-induced hepatic steatosis. To test this hypothesis we compared SGLT5-deficient mice with wild-type mice under conditions of long-term fructose consumption. Paradoxically, however, fructose induced hepatic steatosis was exacerbated in the SGLT5-deficient mice, and the massive urinary fructose excretion was accompanied by reduced levels of plasma triglycerides and epididymal fat but fasting hyperinsulinemia compared with fructose-fed wild-type mice. There was no difference in food consumption, water intake, or plasma fructose between the two types of mice. No compensatory effect by other transporters reportedly involved in fructose uptake in the liver and kidney were indicated at the mRNA level. These surprising findings indicated a previously unrecognized link through SGLT5 between renal fructose reabsorption and hepatic lipid metabolism. PMID- 23451069 TI - Label-free detection of neuronal differentiation in cell populations using high throughput live-cell imaging of PC12 cells. AB - Detection of neuronal cell differentiation is essential to study cell fate decisions under various stimuli and/or environmental conditions. Many tools exist that quantify differentiation by neurite length measurements of single cells. However, quantification of differentiation in whole cell populations remains elusive so far. Because such populations can consist of both proliferating and differentiating cells, the task to assess the overall differentiation status is not trivial and requires a high-throughput, fully automated approach to analyze sufficient data for a statistically significant discrimination to determine cell differentiation. We address the problem of detecting differentiation in a mixed population of proliferating and differentiating cells over time by supervised classification. Using nerve growth factor induced differentiation of PC12 cells, we monitor the changes in cell morphology over 6 days by phase-contrast live-cell imaging. For general applicability, the classification procedure starts out with many features to identify those that maximize discrimination of differentiated and undifferentiated cells and to eliminate features sensitive to systematic measurement artifacts. The resulting image analysis determines the optimal post treatment day for training and achieves a near perfect classification of differentiation, which we confirmed in technically and biologically independent as well as differently designed experiments. Our approach allows to monitor neuronal cell populations repeatedly over days without any interference. It requires only an initial calibration and training step and is thereafter capable to discriminate further experiments. In conclusion, this enables long-term, large scale studies of cell populations with minimized costs and efforts for detecting effects of external manipulation of neuronal cell differentiation. PMID- 23451071 TI - Diagnostic performance of an Aspergillus-specific nested PCR assay in cerebrospinal fluid samples of immunocompromised patients for detection of central nervous system aspergillosis. AB - Central nervous system (CNS) invasive aspergillosis (IA) is a fatal complication in immunocompromised patients. Confirming the diagnosis is rarely accomplished as invasive procedures are impaired by neutropenia and low platelet count. Cerebrospinal fluid (CSF) cultures or galactomannan (GM) regularly yield negative results thus suggesting the need for improving diagnostic procedures. Therefore the performance of an established Aspergillus-specific nested polymerase chain reaction assay (PCR) in CSF samples of immunocompromised patients with suspicion of CNS IA was evaluated. We identified 113 CSF samples from 55 immunocompromised patients for whom CNS aspergillosis was suspected. Of these patients 8/55 were identified as having proven/probable CNS IA while the remaining 47 patients were classified as having either possible (n = 22) or no CNS IA (n = 25). PCR positivity in CSF was observed for 8/8 proven/probable, in 4/22 possible CNS IA patients and in 2/25 NoIA patients yielding sensitivity and specificity values of 1.0 (95% CI 0.68-1) and 0.93 (95% CI 0.77-0.98) and a positive likelihood ratio of 14 and negative likelihood ratio of 0.0, respectively, thus resulting in a diagnostic odds ratio of infinity. The retrospective analysis of CSF samples from patients with suspected CNS IA yielded a high sensitivity of the nested PCR assay. PCR testing of CSF samples is recommended for patients for whom CNS IA is suspected, especially for those whose clinical condition does not allow invasive procedures as a positive PCR result makes the presence of CNS IA in that patient population highly likely. PMID- 23451070 TI - Safety and immunogenicity of neonatal pneumococcal conjugate vaccination in Papua New Guinean children: a randomised controlled trial. AB - BACKGROUND: Approximately 826,000 children, mostly young infants, die annually from invasive pneumococcal disease. A 6-10-14-week schedule of pneumococcal conjugate vaccine (PCV) is efficacious but neonatal PCV may provide earlier protection and better coverage. We conducted an open randomized controlled trial in Papua New Guinea to compare safety, immunogenicity and priming for memory of 7 valent PCV (PCV7) given in a 0-1-2-month (neonatal) schedule with that of the routine 1-2-3-month (infant) schedule. METHODS: We randomized 318 infants at birth to receive PCV7 in the neonatal or infant schedule or no PCV7. All infants received 23-valent pneumococcal polysaccharide vaccine (PPV) at age 9 months. Serotype-specific serum IgG for PCV7 (VT) serotypes and non-VT serotypes 2, 5 and 7F were measured at birth and 2, 3, 4, 9, 10 and 18 months of age. Primary outcomes were geometric mean concentrations (GMCs) and proportions with concentration >= 0.35 ug/ml of VT serotype-specific pneumococcal IgG at age 2 months and one month post-PPV. RESULTS: We enrolled 101, 105 and 106 infants, respectively, into neonatal, infant and control groups. Despite high background levels of maternally derived antibody, both PCV7 groups had higher GMCs than controls at age 2 months for serotypes 4 (p<0.001) and 9V (p<0.05) and at age 3 months for all VTs except 6B. GMCs for serotypes 4, 9V, 18C and 19F were significantly higher (p<0.001) at age 2 months in the neonatal (one month post dose2 PCV7) than in the infant group (one month post-dose1 PCV7). PPV induced significantly higher VT antibody responses in PCV7-primed than unprimed infants, with neonatal and infant groups equivalent. High VT and non-VT antibody concentrations generally persisted to age 18 months. CONCLUSIONS: PCV7 is well tolerated and immunogenic in PNG neonates and young infants and induces immunologic memory to PPV booster at age 9 months with antibody levels maintained to age 18 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT00219401. PMID- 23451072 TI - Comparative analysis of CpG islands among HBV genotypes. AB - DNA methylation is being increasingly recognized to play a role in regulation of hepatitis B virus (HBV) gene expression. The aim of this study was to compare the CpG island distribution among different HBV genotypes. We analyzed 176 full length HBV genomic sequences obtained from the GenBank database, belonging to genotypes A through J, to identify the CpG islands in the HBV genomes. Our results showed that while 79 out of 176 sequences contained three conventional CpG islands (I-III) as previously described, 83 HBV sequences harbored only two of the three known islands. Novel CpG islands were identified in the remaining 14 HBV isolates and named as CpG island IV, V, and VI. Among the eight known HBV genotypes and two putative genotypes, while HBV genomes containing three CpG islands were predominant in genotypes A, B, D, E, and I; genotypes C, F, G, and H tended to contain only two CpG islands (II and III). In conclusion, the CpG islands, which are potential targets for DNA methylation mediated by the host functions, differ among HBV genotypes, and these genotype-specific differences in CpG island distribution could provide new insights into the understanding of epigenetic regulation of HBV gene expression and hepatitis B disease outcome. PMID- 23451073 TI - Sex-specific correlations of individual heterozygosity, parasite load, and scalation asymmetry in a sexually dichromatic lizard. AB - Heterozygosity-fitness correlations (HFCs) provide insights into the genetic bases of individual fitness variation in natural populations. However, despite decades of study, the biological significance of HFCs is still under debate. In this study, we investigated HFCs in a large population of the sexually dimorphic lizard Takydromus viridipunctatus (Lacertidae). Because of the high prevalence of parasitism from trombiculid mites in this lizard, we expect individual fitness (i.e., survival) to decrease with increasing parasite load. Furthermore, because morphological asymmetry is likely to influence individuals' mobility (i.e., limb asymmetry) and male biting ability during copulation (i.e., head asymmetry) in this species, we also hypothesize that individual fitness should decrease with increasing morphological asymmetry. Although we did not formally test the relationship between morphological asymmetry and fitness in this lizard, we demonstrated that survival decreased with increasing parasite load using a capture-mark-recapture data set. We used a separate sample of 140 lizards to test the correlations between individual heterozygosity (i.e., standardized mean d(2) and HL based on 10 microsatellite loci) and the two fitness traits (i.e., parasite load and morphological asymmetry). We also evaluated and excluded the possibility that single-locus effects produced spurious HFCs. Our results suggest male-only, negative correlations between individual heterozygosity and parasite load and between individual heterozygosity and asymmetry, suggesting sex specific, positive HFCs. Male T. viridipunctatus with higher heterozygosity tend to have lower parasite loads (i.e., higher survival) and lower asymmetry, providing a rare example of HFC in reptiles. PMID- 23451074 TI - Global and stage specific patterns of Kruppel-associated-box zinc finger protein gene expression in murine early embryonic cells. AB - Highly coordinated transcription networks orchestrate the self-renewal of pluripotent stem cell and the earliest steps of mammalian development. KRAB containing zinc finger proteins represent the largest group of transcription factors encoded by the genomes of higher vertebrates including mice and humans. Together with their putatively universal cofactor KAP1, they have been implicated in events as diverse as the silencing of endogenous retroelements, the maintenance of imprinting and the pluripotent self-renewal of embryonic stem cells, although the genomic targets and specific functions of individual members of this gene family remain largely undefined. Here, we first generated a list of Ensembl-annotated KRAB-containing genes encoding the mouse and human genomes. We then defined the transcription levels of these genes in murine early embryonic cells. We found that the majority of KRAB-ZFP genes are expressed in mouse pluripotent stem cells and other early progenitors. However, we also identified distinctively cell- or stage-specific patterns of expression, some of which are pluripotency-restricted. Finally, we determined that individual KRAB-ZFP genes exhibit highly distinctive modes of expression, even when grouped in genomic clusters, and that these cannot be correlated with the presence of prototypic repressive or activating chromatin marks. These results pave the way to delineating the role of specific KRAB-ZFPs in early embryogenesis. PMID- 23451075 TI - Biochemical and mutational analysis of a novel nicotinamidase from Oceanobacillus iheyensis HTE831. AB - Nicotinamidases catalyze the hydrolysis of nicotinamide to nicotinic acid and ammonia, an important reaction in the NAD(+) salvage pathway. This paper reports a new nicotinamidase from the deep-sea extremely halotolerant and alkaliphilic Oceanobacillus iheyensis HTE831 (OiNIC). The enzyme was active towards nicotinamide and several analogues, including the prodrug pyrazinamide. The enzyme was more nicotinamidase (kcat/Km = 43.5 mM(-1)s(-1)) than pyrazinamidase (kcat/Km = 3.2 mM(-1)s(-1)). Mutational analysis was carried out on seven critical amino acids, confirming for the first time the importance of Cys133 and Phe68 residues for increasing pyrazinamidase activity 2.9- and 2.5-fold, respectively. In addition, the change in the fourth residue involved in the ion metal binding (Glu65) was detrimental to pyrazinamidase activity, decreasing it 6 fold. This residue was also involved in a new distinct structural motif DAHXXXDXXHPE described in this paper for Firmicutes nicotinamidases. Phylogenetic analysis revealed that OiNIC is the first nicotinamidase described for the order Bacillales. PMID- 23451076 TI - Prior infection does not improve survival against the amphibian disease Chytridiomycosis. AB - Many amphibians have declined globally due to introduction of the pathogenic fungus Batrachochytrium dendrobatidis (Bd). Hundreds of species, many in well protected habitats, remain as small populations at risk of extinction. Currently the only proven conservation strategy is to maintain species in captivity to be reintroduced at a later date. However, methods to abate the disease in the wild are urgently needed so that reintroduced and wild animals can survive in the presence of Bd. Vaccination has been widely suggested as a potential strategy to improve survival. We used captive-bred offspring of critically endangered booroolong frogs (Litoria booroolongensis) to test if vaccination in the form of prior infection improves survival following re exposure. We infected frogs with a local Bd isolate, cleared infection after 30 days (d) using itraconazole just prior to the onset of clinical signs, and then re-exposed animals to Bd at 110 d. We found prior exposure had no effect on survival or infection intensities, clearly showing that real infections do not stimulate a protective adaptive immune response in this species. This result supports recent studies suggesting Bd may evade or suppress host immune functions. Our results suggest vaccination is unlikely to be useful in mitigating chytridiomycosis. However, survival of some individuals from all experimental groups indicates existence of protective innate immunity. Understanding and promoting this innate resistance holds potential for enabling species recovery. PMID- 23451078 TI - Game theory, conditional preferences, and social influence. AB - Neoclassical noncooperative game theory is based on a simple, yet powerful synthesis of mathematical and logical concepts: unconditional and immutable preference orderings and individual rationality. Although this structure has proven useful for characterizing competitive multi-player behavior, its applicability to scenarios involving complex social relationships is problematic. In this paper we directly address this limitation by the introduction of a conditional preference structure that permits players to modulate their preference orderings as functions of the preferences of other players. Embedding this expanded preference structure in a formal and graphical framework provides a systematic approach for characterizing a complex society. The result is an influence network that allows conditional preferences to propagate through the community, resulting in an emergent social model which characterizes all of the social relationships that exist and which leads to solution concepts that account for both group and individual interests. The Ultimatum game is presented as an example of how social influence can be modeled with conditional preferences. PMID- 23451077 TI - MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia. AB - Mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome) cause X-linked familial hypophosphatemic rickets (XLH), a disorder having severe bone and tooth dentin mineralization defects. The absence of functional PHEX leads to abnormal accumulation of ASARM (acidic serine- and aspartate-rich motif) peptide - a substrate for PHEX and a strong inhibitor of mineralization - derived from MEPE (matrix extracellular phosphoglycoprotein) and other matrix proteins. MEPE-derived ASARM peptide accumulates in tooth dentin of XLH patients where it may impair dentinogenesis. Here, we investigated the effects of ASARM peptides in vitro and in vivo on odontoblast differentiation and matrix mineralization. Dental pulp stem cells from human exfoliated deciduous teeth (SHEDs) were seeded into a 3D collagen scaffold, and induced towards odontogenic differentiation. Cultures were treated with synthetic ASARM peptides (phosphorylated and nonphosphorylated) derived from the human MEPE sequence. Phosphorylated ASARM peptide inhibited SHED differentiation in vitro, with no mineralized nodule formation, decreased odontoblast marker expression, and upregulated MEPE expression. Phosphorylated ASARM peptide implanted in a rat molar pulp injury model impaired reparative dentin formation and mineralization, with increased MEPE immunohistochemical staining. In conclusion, using complementary models to study tooth dentin defects observed in XLH, we demonstrate that the MEPE-derived ASARM peptide inhibits both odontogenic differentiation and matrix mineralization, while increasing MEPE expression. These results contribute to a partial mechanistic explanation of XLH pathogenesis: direct inhibition of mineralization by ASARM peptide leads to the mineralization defects in XLH teeth. This process appears to be positively reinforced by the increased MEPE expression induced by ASARM. The MEPE-ASARM system can therefore be considered as a potential therapeutic target. PMID- 23451079 TI - Patients are paying too much for tuberculosis: a direct cost-burden evaluation in Burkina Faso. AB - BACKGROUND: Paying for health care may exclude poor people. Burkina Faso adopted the DOTS strategy implementing "free care" for Tuberculosis (TB) diagnosis and treatment. This should increase universal health coverage and help to overcome social and economic barriers to health access. METHODS: Straddling 2007 and 2008, in-depth interviews were conducted over a year among smear-positive pulmonary tuberculosis patients in six rural districts of Burkina Faso. Out-of-pocket expenses (direct costs) associated with TB were collected according to the different stages of their healthcare pathway. RESULTS: Median direct cost associated with TB was US$101 (n = 229) (i.e. 2.8 months of household income). Respectively 72% of patients incurred direct costs during the pre-diagnosis stage (i.e. self-medication, travel, traditional healers' services), 95% during the diagnosis process (i.e. user fees, travel costs to various providers, extra sputum smears microscopy and chest radiology), 68% during the intensive treatment (i.e. medical and travel costs) and 50% during the continuation treatment (i.e. medical and travel costs). For the diagnosis stage, median direct costs already amounted to 35% of overall direct costs. CONCLUSIONS: The patient care pathway analysis in rural Burkina Faso showed substantial direct costs and healthcare system delay within a "free care" policy for TB diagnosis and treatment. Whether in terms of redefining the free TB package or rationalizing the care pathway, serious efforts must be undertaken to make "free" health care more affordable for the patients. Locally relevant for TB, this case-study in Burkina Faso has a real potential to document how health programs' weaknesses can be identified and solved. PMID- 23451080 TI - KIR gene content in amerindians indicates influence of demographic factors. AB - Although the KIR gene content polymorphism has been studied worldwide, only a few isolated or Amerindian populations have been analyzed. This extremely diverse gene family codifies receptors that are expressed mainly in NK cells and bind HLA class I molecules. KIR-HLA combinations have been associated to several diseases and population studies are important to comprehend their evolution and their role in immunity. Here we analyzed, by PCR-SSP (specific sequencing priming), 327 individuals from four isolated groups of two of the most important Brazilian Amerindian populations: Kaingang and Guarani. The pattern of KIR diversity among these and other ten Amerindian populations disclosed a wide range of variation for both KIR haplotypes and gene frequencies, indicating that demographic factors, such as bottleneck and founder effects, were the most important evolutionary factors in shaping the KIR polymorphism in these populations. PMID- 23451081 TI - Distinct spatiotemporal expression of serine proteases Prss23 and Prss35 in periimplantation mouse uterus and dispensable function of Prss35 in fertility. AB - PRSS23 and PRSS35 are homologous proteases originally identified in mouse ovaries. In the periimplantation mouse uterus, Prss23 was highly expressed in the preimplantation gestation day 3.5 (D3.5) uterine luminal epithelium (LE). It disappeared from the postimplantation LE and reappeared in the stromal compartment next to the myometrium on D6.5. It was undetectable in the embryo from D4.5 to D6.5 but highly expressed in the embryo on D7.5. Prss35 became detectable in the uterine stromal compartment surrounding the embryo on D4.5 and shifted towards the mesometrial side of the stromal compartment next to the embryo from D5.5 to D7.5. In the ovariectomized uterus, Prss23 was moderately and Prss35 was dramatically downregulated by progesterone and 17beta-estradiol. Based on the expression of Prss35 in granulosa cells and corpus luteum of the ovary and the early pregnant uterus, we hypothesized that PRSS35 might play a role in female reproduction, especially in oocyte development, ovulation, implantation, and decidualization. This hypothesis was tested in Prss35((-/-)) mice, which proved otherwise. Between wild type (WT) and Prss35((-/-)) mice, superovulation of immature females produced comparable numbers of cumulus-oocyte complexes; there were comparable numbers of implantation sites detected on D4.5 and D7.5; there were no obvious differences in the expression of implantation and decidualization marker genes in D4.5 or D7.5 uteri. Comparable mRNA expression levels of a few known protease-related genes in the WT and Prss35((-/-)) D4.5 uteri indicated no compensatory upregulation. Comparable litter sizes from WT * WT and Prss35((-/-))* Prss35((-/-)) crosses suggested that Prss35 gene was unessential for fertility and embryo development. Prss35 gene has been linked to cleft lip/palate in humans. However, no obvious such defects were observed in Prss35((-/-)) mice. This study demonstrates the distinct expression of Prss23 and Prss35 in the periimplantation uterus and the dispensable role of Prss35 in fertility and embryo development. PMID- 23451082 TI - Cathepsin E is a marker of gastric differentiation and signet-ring cell carcinoma of stomach: a novel suggestion on gastric tumorigenesis. AB - Gastric cancer (GC) presents various histological features, though the mechanism underlying its diversity is seldom elucidated. It is mainly classified into well differentiated tubular adenocarcinoma (tub1), moderately differentiated tubular adenocarcinoma (tub2), poorly differentiated adenocarcinoma (por), signet-ring cell carcinoma (sig), mucinous adenocarcinoma (muc), and papillary adenocarcinoma (pap). By screening, we found cathepsin E (CTSE) expresses universally in sig type, occasionally in por-type, and rarely in tub1/tub2-type GC cell lines. In surgically-resected specimens, CTSE was immunostained in 50/51 sig-type (98.0%), 3/10 tub1-type (30.0%), 7/18 tub2-type (38.9%), 15/26 por-type (57.7%), 4/10 pap type (40.0%), and 0/3 muc-type (0.0%) GC. In endoscopically-resected specimens, 6/7 sig-type (85.7%), 7/52 tub1-type (13.7%), 5/12 tub2-type (41.7%), 2/7 pap type (28.6%) GC and 0/6 adenoma (0.0%) expressed CTSE. For non-malignant tissues, CTSE is universally expressed in normal fundic, pyloric, and cardiac glands of stomach, but hardly in other digestive organs. In the precancerous intestinal metaplasia of stomach, CTSE is mostly observed in mixed gastric-and-intestinal type and deficient in solely-intestinal type. CTSE expression is positively correlated with gastric marker MUC5AC (p<0.0001) and negatively correlated with intestinal marker MUC2 (p = 0.0019). For sig-type GC, in both tumors and background mucosa, expression of MUC5AC and CTSE is high whereas that of MUC2 is low, indicating that sig-type GC reflects the features of background mucosa. For gastric adenoma and tub1/tub2-type GC, more undifferentiated tumors tend to show higher expression of CTSE with MUC5AC and lower expression of MUC2 in tumors, but they tend to present lower expression of CTSE, MUC5AC and MUC2 in background mucosa. These suggest that more malignant gastric adenocarcinoma with stronger gastric and weaker intestinal properties tend to arise from background mucosa with decreased both gastric and intestinal features. In conclusion, CTSE is a marker of both gastric differentiation and signet-ring cell carcinoma, which should shed light on the mechanism of gastric tumorigenesis. PMID- 23451083 TI - Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells. AB - BACKGROUND AIMS: Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. METHODS: 12-O-tetradecanoylphorbor-13 acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. RESULTS: Telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan. Telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. CONCLUSIONS: The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation. PMID- 23451084 TI - Mast cell dependent vascular changes associated with an acute response to cold immersion in primary contact urticaria. AB - BACKGROUND: While a number of the consequences of mast cell degranulation within tissues have been documented including tissue-specific changes such as bronchospasm and the subsequent cellular infiltrate, there is little known about the immediate effects of mast cell degranulation on the associated vasculature, critical to understanding the evolution of mast cell dependent inflammation. OBJECTIVE: To characterize the microcirculatory events that follow mast cell degranulation. METHODOLOGY/PRINCIPAL FINDINGS: Perturbations in dermal blood flow, temperature and skin color were analyzed using laser-speckle contrast imaging, infrared and polarized-light colorimetry following cold-hand immersion (CHI) challenge in patients with cold-induced urticaria compared to the response in healthy controls. Evidence for mast cell degranulation was established by documentation of serum histamine levels and the localized release of tryptase in post-challenge urticarial biopsies. Laser-speckle contrast imaging quantified the attenuated response to cold challenge in patients on cetirizine. We found that the histamine-associated vascular response accompanying mast cell degranulation is rapid and extensive. At the tissue level, it is characterized by a uniform pattern of increased blood flow, thermal warming, vasodilation, and recruitment of collateral circulation. These vascular responses are modified by the administration of an antihistamine. CONCLUSIONS/SIGNIFICANCE: Monitoring the hemodynamic responses within tissues that are associated with mast cell degranulation provides additional insight into the evolution of the acute inflammatory response and offers a unique approach to assess the effectiveness of treatment intervention. PMID- 23451085 TI - Insights on the functional impact of microRNAs present in autism-associated copy number variants. AB - Autism spectrum disorder is a complex neurodevelopmental disorder that appears during the first three years of infancy and lasts throughout a person's life. Recently a large category of genomic structural variants, denoted as copy number variants (CNVs), were established to be a major contributor of the pathophysiology of autism. To date almost all studies have focussed only on the genes present in the CNV loci, but the impact of non-coding regulatory microRNAs (miRNAs) present in these regions remain largely unexplored. Hence we attempted to elucidate the biological and functional significance of miRNAs present in autism-associated CNV loci and their target genes by using a series of computational tools. We demonstrate that nearly 11% of the CNV loci harbor miRNAs and a few of these miRNAs were previously reported to be associated with autism. A systematic analysis of the CNV-miRNAs based on their interactions with the target genes enabled the identification of top 10 miRNAs namely hsa-miR-590-3p, hsa-miR-944, hsa-miR-570, hsa-miR-34a, hsa-miR-124, hsa-miR-548f, hsa-miR-429, hsa-miR-200b, hsa-miR-195 and hsa-miR-497 as hub molecules. Further, the CNV miRNAs formed a regulatory loop with transcription factors and their downstream target genes, and annotation of these target genes indicated their functional involvement in neurodevelopment and synapse. Moreover, miRNAs present in deleted and duplicated CNV loci may explain the difference in dosage of the crucial genes controlled by them. These CNV-miRNAs can also impair the global processing and biogenesis of all miRNAs by targeting key molecules in the miRNA pathway. To our knowledge, this is the first report to highlight the significance of CNV microRNAs and their target genes to contribute towards the genetic heterogeneity and phenotypic variability of autism. PMID- 23451087 TI - Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase. AB - The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two Mg(2+) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows N(1) glutathionylation of N(8)-glutathionylspermidine, classifying N(8) glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N(8)-glutathionylspermidine was characterised as druggable. PMID- 23451088 TI - Identification of a disulfide bridge important for transport function of SNAT4 neutral amino acid transporter. AB - SNAT4 is a member of system N/A amino acid transport family that primarily expresses in liver and muscles and mediates the transport of L-alanine. However, little is known about the structure and function of the SNAT family of transporters. In this study, we showed a dose-dependent inhibition in transporter activity of SNAT4 with the treatment of reducing agents, dithiothreitol (DTT) and Tris(2-carboxyethyl)phosphine (TCEP), indicating the possible involvement of disulfide bridge(s). Mutation of residue Cys-232, and the two highly conserved residues Cys-249 and Cys-321, compromised the transport function of SNAT4. However, this reduction was not caused by the decrease of SNAT4 on the cell surface since the cysteine-null mutant generated by replacing all five cysteines with alanine was equally capable of being expressed on the cell surface as wild type SNAT4. Interestingly, by retaining two cysteine residues, 249 and 321, a significant level of L-alanine uptake was restored, indicating the possible formation of disulfide bond between these two conserved residues. Biotinylation crosslinking of free thiol groups with MTSEA-biotin provided direct evidence for the existence of a disulfide bridge between Cys-249 and Cys-321. Moreover, in the presence of DTT or TCEP, transport activity of the mutant retaining Cys-249 and Cys-321 was reduced in a dose-dependent manner and this reduction is gradually recovered with increased concentration of H2O2. Disruption of the disulfide bridge also decreased the transport of L-arginine, but to a lesser degree than that of L-alanine. Together, these results suggest that cysteine residues 249 and 321 form a disulfide bridge, which plays an important role in substrate transport but has no effect on trafficking of SNAT4 to the cell surface. PMID- 23451086 TI - Lineage divergence and historical gene flow in the Chinese horseshoe bat (Rhinolophus sinicus). AB - Closely related taxa living in sympatry provide good opportunities to investigate the origin of barriers to gene flow as well as the extent of reproductive isolation. The only two recognized subspecies of the Chinese rufous horseshoe bat Rhinolophus sinicus are characterized by unusual relative distributions in which R. s. septentrionalis is restricted to a small area within the much wider range of its sister taxon R. s. sinicus. To determine the history of lineage divergence and gene flow between these taxa, we applied phylogenetic, demographic and coalescent analyses to multi-locus datasets. MtDNA gene genealogies and microsatellite-based clustering together revealed three divergent lineages of sinicus, corresponding to Central China, East China and the offshore Hainan Island. However, the central lineage of sinicus showed a closer relationship with septentrionalis than with other lineages of R. s. sinicus, in contrary to morphological data. Paraphyly of sinicus could result from either past asymmetric mtDNA introgression between these two taxa, or could suggest septentrionalis evolved in situ from its more widespread sister subspecies. To test between these hypotheses, we applied coalescent-based phylogenetic reconstruction and Approximate Bayesian Computation (ABC). We found that septentrionalis is likely to be the ancestral taxon and therefore a recent origin of this subspecies can be ruled out. On the other hand, we found a clear signature of asymmetric mtDNA gene flow from septentrionalis into central populations of sinicus yet no nuclear gene flow, thus strongly pointing to historical mtDNA introgression. We suggest that the observed deeply divergent lineages within R. sinicus probably evolved in isolation in separate Pleistocene refugia, although their close phylogeographic correspondence with distinct eco-environmental zones suggests that divergent selection might also have promoted broad patterns of population genetic structure. PMID- 23451089 TI - High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. AB - BACKGROUND: Breast cancer is a leading cause of death among women worldwide. Increasing evidence implies that human cytomegalovirus (HCMV) infection is associated with several malignancies. We aimed to examine whether HCMV is present in breast cancer and sentinel lymph node (SLN) metastases. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens from breast cancer and paired sentinel lymph node (SLN) samples were obtained from patients with (n = 35) and without SLN metastasis (n = 38). HCMV immediate early (IE) and late (LA) proteins were detected using a sensitive immunohistochemistry (IHC) technique and HCMV DNA by real-time PCR. RESULTS: HCMV IE and LA proteins were abundantly expressed in 100% of breast cancer specimens. In SLN specimens, 94% of samples with metastases (n = 34) were positive for HCMV IE and LA proteins, mostly confined to neoplastic cells while some inflammatory cells were HCMV positive in 60% of lymph nodes without metastases (n = 35). The presence of HCMV DNA was confirmed in 12/12 (100%) of breast cancer and 10/11 (91%) SLN specimens from the metastatic group, but was not detected in 5/5 HCMV-negative, SLN-negative specimens. There was no statistically significant association between HCMV infection grades and progesterone receptor, estrogen receptor alpha and Elston grade status. CONCLUSIONS: The role of HCMV in the pathogenesis of breast cancer is unclear. As HCMV proteins were mainly confined to neoplastic cells in primary breast cancer and SLN samples, our observations raise the question whether HCMV contributes to the tumorigenesis of breast cancer and its metastases. PMID- 23451090 TI - Climate and pH predict the potential range of the invasive apple snail (Pomacea insularum) in the southeastern United States. AB - Predicting the potential range of invasive species is essential for risk assessment, monitoring, and management, and it can also inform us about a species' overall potential invasiveness. However, modeling the distribution of invasive species that have not reached their equilibrium distribution can be problematic for many predictive approaches. We apply the modeling approach of maximum entropy (MaxEnt) that is effective with incomplete, presence-only datasets to predict the distribution of the invasive island apple snail, Pomacea insularum. This freshwater snail is native to South America and has been spreading in the USA over the last decade from its initial introductions in Texas and Florida. It has now been documented throughout eight southeastern states. The snail's extensive consumption of aquatic vegetation and ability to accumulate and transmit algal toxins through the food web heighten concerns about its spread. Our model shows that under current climate conditions the snail should remain mostly confined to the coastal plain of the southeastern USA where it is limited by minimum temperature in the coldest month and precipitation in the warmest quarter. Furthermore, low pH waters (pH <5.5) are detrimental to the snail's survival and persistence. Of particular note are low-pH blackwater swamps, especially Okefenokee Swamp in southern Georgia (with a pH below 4 in many areas), which are predicted to preclude the snail's establishment even though many of these areas are well matched climatically. Our results elucidate the factors that affect the regional distribution of P. insularum, while simultaneously presenting a spatial basis for the prediction of its future spread. Furthermore, the model for this species exemplifies that combining climatic and habitat variables is a powerful way to model distributions of invasive species. PMID- 23451091 TI - Genetic and genomic analysis of Rhizoctonia solani interactions with Arabidopsis; evidence of resistance mediated through NADPH oxidases. AB - Rhizoctonia solani is an important soil-borne necrotrophic fungal pathogen, with a broad host range and little effective resistance in crop plants. Arabidopsis is resistant to R. solani AG8 but susceptible to R. solani AG2-1. A screen of 36 Arabidopsis ecotypes and mutants affected in the auxin, camalexin, salicylic acid, abscisic acid and ethylene/jasmonic acid pathways did not reveal any variation in response to R. solani and demonstrated that resistance to AG8 was independent of these defense pathways. The Arabidopsis Affymetrix ATH1 Genome array was used to assess global gene expression changes in plants infected with AG8 and AG2-1 at seven days post-infection. While there was considerable overlap in the response, some gene families were differentially affected by AG8 or AG2-1 and included those involved in oxidative stress, cell wall associated proteins, transcription factors and heat shock protein genes. Since a substantial proportion of the gene expression changes were associated with oxidative stress responses, we analysed the role of NADPH oxidases in resistance. While single NADPH oxidase mutants had no effect, a NADPH oxidase double mutant atrbohf atrbohd resulted in an almost complete loss of resistance to AG8, suggesting that reactive oxidative species play an important role in Arabidopsis's resistance to R. solani. PMID- 23451092 TI - Parent-offspring conflict and the persistence of pregnancy-induced hypertension in modern humans. AB - Preeclampsia is a major cause of perinatal mortality and disease affecting 5-10% of all pregnancies worldwide, but its etiology remains poorly understood despite considerable research effort. Parent-offspring conflict theory suggests that such hypertensive disorders of pregnancy may have evolved through the ability of fetal genes to increase maternal blood pressure as this enhances general nutrient supply. However, such mechanisms for inducing hypertension in pregnancy would need to incur sufficient offspring health benefits to compensate for the obvious risks for maternal and fetal health towards the end of pregnancy in order to explain why these disorders have not been removed by natural selection in our hunter-gatherer ancestors. We analyzed >750,000 live births in the Danish National Patient Registry and all registered medical diagnoses for up to 30 years after birth. We show that offspring exposed to pregnancy-induced hypertension (PIH) in trimester 1 had significantly reduced overall later-life disease risks, but increased risks when PIH exposure started or developed as preeclampsia in later trimesters. Similar patterns were found for first-year mortality. These results suggest that early PIH leading to improved postpartum survival and health represents a balanced compromise between the reproductive interests of parents and offspring, whereas later onset of PIH may reflect an unbalanced parent offspring conflict at the detriment of maternal and offspring health. PMID- 23451093 TI - Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. AB - Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented. PMID- 23451094 TI - High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma. AB - Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD(+) in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor. PMID- 23451095 TI - Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab induced death and chemosensitization in B-cell lymphoma. AB - Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma. PMID- 23451096 TI - Patterns and drivers of tree mortality in iberian forests: climatic effects are modified by competition. AB - Tree mortality is a key process underlying forest dynamics and community assembly. Understanding how tree mortality is driven by simultaneous drivers is needed to evaluate potential effects of climate change on forest composition. Using repeat-measure information from c. 400,000 trees from the Spanish Forest Inventory, we quantified the relative importance of tree size, competition, climate and edaphic conditions on tree mortality of 11 species, and explored the combined effect of climate and competition. Tree mortality was affected by all of these multiple drivers, especially tree size and asymmetric competition, and strong interactions between climate and competition were found. All species showed L-shaped mortality patterns (i.e. showed decreasing mortality with tree size), but pines were more sensitive to asymmetric competition than broadleaved species. Among climatic variables, the negative effect of temperature on tree mortality was much larger than the effect of precipitation. Moreover, the effect of climate (mean annual temperature and annual precipitation) on tree mortality was aggravated at high competition levels for all species, but especially for broadleaved species. The significant interaction between climate and competition on tree mortality indicated that global change in Mediterranean regions, causing hotter and drier conditions and denser stands, could lead to profound effects on forest structure and composition. Therefore, to evaluate the potential effects of climatic change on tree mortality, forest structure must be considered, since two systems of similar composition but different structure could radically differ in their response to climatic conditions. PMID- 23451097 TI - Comparing the immunogenicity of AS03-adjuvanted 2009 pandemic H1N1 vaccine with clinical protection in priority risk groups in England. AB - In England, during pandemic 2009 H1N1, vaccine efficacy and immunogenicity population studies in priority groups were rolled out in parallel to evaluate the pandemic vaccination programme. This provided a unique opportunity to compare immunogenicity and clinical protection in the same population and thus provide insights into the correlates of protection for the pandemic H1N1 2009 vaccine in risk groups. While clinical protection from AS03-adjuvanted pandemic 2009 H1N1 vaccine was high in those aged <25 years and pregnant women, effectiveness in older adults with chronic conditions has been found to be surprisingly poor. Here we present results from the immunogenicity study derived from the same population. Individuals from priority groups eligible for pandemic vaccination attending participating general practices were recruited. Pre and post vaccination blood samples were collected and HI antibody testing to assess immune response to vaccination performed. The final cohort consisted of 610 individuals: 60 healthy children aged <5 years; 32 healthy pregnant women; 518 individuals from risk groups. Seroconversion rate in healthy children aged <5 years (87%, 95% CI: 75% to 94%) was higher than that of risk groups combined (65%, 95% CI: 61% to 69%) (p<0.001). Multivariable analysis of risk groups showed that the size of response in those who did seroconvert was lower in those who received the 2009/10 seasonal TIV (Fold effect: 0.52, 0.35 to 0.78). Predicted immunological boosting from higher pre-vaccine titres after 2009 pandemic H1N1 vaccination only occurred in children (seroconversion rate = 92%) and not in individuals aged 10 to 39 from risk groups (seroconversion rate = 74%). The lack of clinical protection identified in the same population in older adults from risk groups could be attributed to these lower seroresponses. Current immunogenicity licensing criteria for pandemic influenza vaccine may not correlate with clinical protection in individuals with chronic disease or immunocompromised. PMID- 23451098 TI - Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection. AB - Understanding the pathology resulting from Staphylococcus aureus and Pseudomonas aeruginosa polymicrobial wound infections is of great importance due to their ubiquitous nature, increasing prevalence, growing resistance to antimicrobial agents, and ability to delay healing. Methicillin-resistant S. aureus USA300 is the leading cause of community-associated bacterial infections resulting in increased morbidity and mortality. We utilized a well-established porcine partial thickness wound healing model to study the synergistic effects of USA300 and P. aeruginosa on wound healing. Wound re-epithelialization was significantly delayed by mixed-species biofilms through suppression of keratinocyte growth factor 1. Pseudomonas showed an inhibitory effect on USA300 growth in vitro while both species co-existed in cutaneous wounds in vivo. Polymicrobial wound infection in the presence of P. aeruginosa resulted in induced expression of USA300 virulence factors Panton-Valentine leukocidin and alpha-hemolysin. These results provide evidence for the interaction of bacterial species within mixed-species biofilms in vivo and for the first time, the contribution of virulence factors to the severity of polymicrobial wound infections. PMID- 23451099 TI - Stronger tests of mechanisms underlying geographic gradients of biodiversity: insights from the dimensionality of biodiversity. AB - Inference involving diversity gradients typically is gathered by mechanistic tests involving single dimensions of biodiversity such as species richness. Nonetheless, because traits such as geographic range size, trophic status or phenotypic characteristics are tied to a particular species, mechanistic effects driving broad diversity patterns should manifest across numerous dimensions of biodiversity. We develop an approach of stronger inference based on numerous dimensions of biodiversity and apply it to evaluate one such putative mechanism: the mid-domain effect (MDE). Species composition of 10,000-km(2) grid cells was determined by overlaying geographic range maps of 133 noctilionoid bat taxa. We determined empirical diversity gradients in the Neotropics by calculating species richness and three indices each of phylogenetic, functional and phenetic diversity for each grid cell. We also created 1,000 simulated gradients of each examined metric of biodiversity based on a MDE model to estimate patterns expected if species distributions were randomly placed within the Neotropics. For each simulation run, we regressed the observed gradient onto the MDE-expected gradient. If a MDE drives empirical gradients, then coefficients of determination from such an analysis should be high, the intercept no different from zero and the slope no different than unity. Species richness gradients predicted by the MDE fit empirical patterns. The MDE produced strong spatially structured gradients of taxonomic, phylogenetic, functional and phenetic diversity. Nonetheless, expected values generated from the MDE for most dimensions of biodiversity exhibited poor fit to most empirical patterns. The MDE cannot account for most empirical patterns of biodiversity. Fuller understanding of latitudinal gradients will come from simultaneous examination of relative effects of random, environmental and historical mechanisms to better understand distribution and abundance of the current biota. PMID- 23451100 TI - Adherence to chemoprophylaxis and Plasmodium falciparum anti-circumsporozoite seroconversion in a prospective cohort study of Dutch short-term travelers. AB - BACKGROUND: We conducted a prospective study in a cohort of short-term travelers assessing the incidence rate of anti-circumsporozoite seroconversion, adherence to chemoprophylaxis, symptoms of malaria during travel, and malaria treatment abroad. METHODS: Adults were recruited from the travel clinic of the Public Health Service Amsterdam. They kept a structured daily travel diary and donated blood samples before and after travel. Blood samples were serologically tested for the presence of Plasmodium falciparum anti-circumsporozoite antibodies. RESULTS: Overall, the incidence rate (IR) of anti-circumsporozoite seroconversion was 0.8 per 100 person-months. Of 945 travelers, 620 (66%) visited high-endemic areas and were advised about both chemoprophylaxis and preventive measures against mosquito bites. Most subjects (520/620 = 84%) took at least 75% of recommended prophylaxis during travel. Travel to Africa, use of mefloquine, travel duration of 14-29 days in endemic areas, and concurrent use of DEET (N,N diethyl-meta-toluamide) were associated with good adherence practices. Four travelers without fever seroconverted, becoming anti-circumsporozoite antibody positive. All four had been adherent to chemoprophylaxis; two visited Africa, one Suriname, one India. Ten subjects with fever were tested for malaria while abroad and of these, three received treatment. All three were adherent to chemoprophylaxis and tested negative for anti-circumsporozoite antibodies. CONCLUSION: Travel to Africa, using mefloquine, travel duration of 14-29 days in endemic areas, and use of DEET were associated with good adherence to chemoprophylaxis. The combination of chemoprophylaxis and other preventive measures were sufficient to protect seroconverting travelers from clinical malaria. Travelers who were treated for malaria abroad did not seroconvert. PMID- 23451101 TI - Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. AB - Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior. PMID- 23451102 TI - Health-related financial catastrophe, inequality and chronic illness in Bangladesh. AB - BACKGROUND: Bangladesh has a high proportion of households incurring catastrophic health expenditure, and very limited risk sharing mechanisms. Identifying determinants of out-of-pocket (OOP) payments and catastrophic health expenditure may reveal opportunities to reduce costs and protect households from financial risk. OBJECTIVE: This study investigates the determinants of high healthcare expenditure and healthcare- related financial catastrophe. METHODS: A cross sectional household survey was conducted in Rajshahi city, Bangladesh, in 2011. Catastrophic health expenditure was estimated separately based on capacity to pay and proportion of non-food expenditure. Determinants of OOP payments and financial catastrophe were estimated using double hurdle and Poisson regression models respectively. RESULTS: On average households spent 11% of their total budgets on health, half the residents spent 7% of the monthly per capita consumption expenditure for one illness, and nearly 9% of households faced financial catastrophe. The poorest households spent less on health but had a four times higher risk of catastrophe than the richest households. The risk of financial catastrophe and the level of OOP payments were higher for users of inpatient, outpatient public and private facilities respectively compared to using self-medication or traditional healers. Other determinants of OOP payments and catastrophic expenses were economic status, presence of chronic illness in the household, and illness among children and adults. CONCLUSION: Households that received inpatient or outpatient private care experienced the highest burden of health expenditure. The poorest members of the community also face large, often catastrophic expenses. Chronic illness management is crucial to reducing the total burden of disease in a household and its associated increased risk of level of OOP payments and catastrophic expenses. Households can only be protected from these situations by reducing the health system's dependency on OOP payments and providing more financial risk protection. PMID- 23451103 TI - Drug absorption efficiency in Caenorhbditis elegans delivered by different methods. AB - BACKGROUND: Caenorhbditis elegans has being vigorously used as a model organism in many research fields and often accompanied by administrating with various drugs. The methods of delivering drugs to worms are varied from one study to another, which make difficult in comparing results between studies. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the drug absorption efficiency in C. elegans using five frequently used methods with resveratrol with low aqueous solubility and water-soluble 5-Fluoro-2'-deoxyuridine (FUDR) as positive compounds. The drugs were either applied to the LB medium with bacteria OP50, before spreading onto Nematode Growth Medium (NGM) plates (LB medium method), or to the NGM with live (NGM live method) or dead bacteria (NGM dead method), or spotting the drug solution to the surface of plates directly (spot dead method), or growing the worms in liquid medium (liquid growing method). The concentration of resveratrol and FUDR increased gradually within C. elegans and reached the highest during 12 hours to one day and then decreased slowly. At the same time point, the higher the drug concentration, the higher the metabolism rate. The drug concentrations in worms fed with dead bacteria were higher than with live bacteria at the same time point. Consistently, the drug concentration in medium with live bacteria decreased much faster than in medium with dead bacteria, reach to about half of the original concentration within 12 hours. CONCLUSION: Resveratrol with low aqueous solubility and water-soluble FUDR have the same absorption and metabolism pattern. The drug metabolism rate in worms was both dosage and time dependent. NGM dead method and liquid growing method achieved the best absorption efficiency in worms. The drug concentration within worms was comparable with that in mice, providing a bridge for dose translation from worms to mammals. PMID- 23451104 TI - Suppression of the macrophage proteasome by ethanol impairs MHC class I antigen processing and presentation. AB - Alcohol binge-drinking (acute ethanol consumption) is immunosuppressive and alters both the innate and adaptive arms of the immune system. Antigen presentation by macrophages (and other antigen presenting cells) represents an important function of the innate immune system that, in part, determines the outcome of the host immune response. Ethanol has been shown to suppress antigen presentation in antigen presenting cells though mechanisms of this impairment are not well understood. The constitutive and immunoproteasomes are important components of the cellular proteolytic machinery responsible for the initial steps critical to the generation of MHC Class I peptides for antigen presentation. In this study, we used an in-vitro cell culture model of acute alcohol exposure to study the effect of ethanol on the proteasome function in RAW 264.7 cells. Additionally, primary murine peritoneal macrophages obtained by peritoneal lavage from C57BL/6 mice were used to confirm our cell culture findings. We demonstrate that ethanol impairs proteasome function in peritoneal macrophages through suppression of chymotrypsin-like (Cht-L) proteasome activity as well as composition of the immunoproteasome subunit LMP7. Using primary murine peritoneal macrophages, we have further demonstrated that, ethanol-induced impairment of the proteasome function suppresses processing of antigenic proteins and peptides by the macrophage and in turn suppresses the presentation of these antigens to cells of adaptive immunity. The results of this study provide an important mechanism to explain the immunosuppressive effects of acute ethanol exposure. PMID- 23451105 TI - A possible role for the asymmetric C-terminal domain dimer of Rous sarcoma virus integrase in viral DNA binding. AB - Integration of the retrovirus linear DNA genome into the host chromosome is an essential step in the viral replication cycle, and is catalyzed by the viral integrase (IN). Evidence suggests that IN functions as a dimer that cleaves a dinucleotide from the 3' DNA blunt ends while a dimer of dimers (tetramer) promotes concerted integration of the two processed ends into opposite strands of a target DNA. However, it remains unclear why a dimer rather than a monomer of IN is required for the insertion of each recessed DNA end. To help address this question, we have analyzed crystal structures of the Rous sarcoma virus (RSV) IN mutants complete with all three structural domains as well as its two-domain fragment in a new crystal form at an improved resolution. Combined with earlier structural studies, our results suggest that the RSV IN dimer consists of highly flexible N-terminal domains and a rigid entity formed by the catalytic and C terminal domains stabilized by the well-conserved catalytic domain dimerization interaction. Biochemical and mutational analyses confirm earlier observations that the catalytic and the C-terminal domains of an RSV IN dimer efficiently integrates one viral DNA end into target DNA. We also show that the asymmetric dimeric interaction between the two C-terminal domains is important for viral DNA binding and subsequent catalysis, including concerted integration. We propose that the asymmetric C-terminal domain dimer serves as a viral DNA binding surface for RSV IN. PMID- 23451106 TI - Mangiferin, a natural xanthone, protects murine liver in Pb(II) induced hepatic damage and cell death via MAP kinase, NF-kappaB and mitochondria dependent pathways. AB - One of the most well-known naturally occurring environmental heavy metals, lead (Pb) has been reported to cause liver injury and cellular apoptosis by disturbing the prooxidant-antioxidant balance via oxidative stress. Several studies, on the other hand, reported that mangiferin, a naturally occurring xanthone, has been used for a broad range of therapeutic purposes. In the present study, we, therefore, investigated the molecular mechanisms of the protective action of mangiferin against lead-induced hepatic pathophysiology. Lead [Pb(II)] in the form of Pb(NO3)2 (at a dose of 5 mg/kg body weight, 6 days, orally) induced oxidative stress, hepatic dysfunction and cell death in murine liver. Post treatment of mangiferin at a dose of 100 mg/kg body weight (6 days, orally), on the other hand, diminished the formation of reactive oxygen species (ROS) and reduced the levels of serum marker enzymes [alanine aminotranferase (ALT) and alkaline phosphatase (ALP)]. Mangiferin also reduced Pb(II) induced alterations in antioxidant machineries, restored the mitochondrial membrane potential as well as mutual regulation of Bcl-2/Bax. Furthermore, mangiferin inhibited Pb(II) induced activation of mitogen-activated protein kinases (MAPKs) (phospho-ERK 1/2, phosphor-JNK phospho- p38), nuclear translocation of NF-kappaB and apoptotic cell death as was evidenced by DNA fragmentation, FACS analysis and histological assessment. In vitro studies using hepatocytes as the working model also showed the protective effect of mangiferin in Pb(II) induced cytotoxicity. All these beneficial effects of mangiferin contributes to the considerable reduction of apoptotic hepatic cell death induced by Pb(II). Overall results demonstrate that mangiferin exhibit both antioxidative and antiapoptotic properties and protects the organ in Pb(II) induced hepatic dysfunction. PMID- 23451108 TI - The deep atmospheric boundary layer and its significance to the stratosphere and troposphere exchange over the Tibetan Plateau. AB - In this study the depth of the atmospheric boundary layer (ABL) over the Tibetan Plateau was measured during a regional radiosonde observation campaign in 2008 and found to be deeper than indicated by previously measurements. Results indicate that during fair weather conditions on winter days, the top of the mixed layers can be up to 5 km above the ground (9.4 km above sea level). Measurements also show that the depth of the ABL is quite distinct for three different periods (winter, monsoon-onset, and monsoon seasons). Turbulence at the top of a deep mixing layer can rise up to the upper troposphere. As a consequence, as confirmed by trajectory analysis, interaction occurs between deep ABLs and the low tropopause during winter over the Tibetan Plateau. PMID- 23451107 TI - Dissociated primary human prostate cancer cells coinjected with the immortalized Hs5 bone marrow stromal cells generate undifferentiated tumors in NOD/SCID-gamma mice. AB - Reconstitution of tumor development in immunodeficient mice from disaggregated primary human tumor cells is always challenging. The main goal of the present study is to establish a reliable assay system that would allow us to reproducibly reconstitute human prostate tumor regeneration in mice using patient tumor derived single cells. Using many of the 114 untreated primary human prostate cancer (HPCa) samples we have worked on, here we show that: 1) the subcutaneum represents the most sensitive site that allows the grafting of the implanted HPCa pieces; 2) primary HPCa cells by themselves fail to regenerate tumors in immunodeficient hosts; 3) when coinjected in Matrigel with rUGM (rat urogenital sinus mesenchyme), CAF (carcinoma-associated fibroblasts), or Hs5 (immortalized bone marrow derived stromal) cells, primary HPCa cells fail to initiate serially transplantable tumors in NOD/SCID mice; and 4) however, HPCa cells coinjected with the Hs5 cells into more immunodeficient NOD/SCID-IL2Rgamma(-/-) (NSG) mice readily regenerate serially transplantable tumors. The HPCa/Hs5 reconstituted 'prostate' tumors present an overall epithelial morphology, are of the human origin, and contain cells positive for AR, CK8, and racemase. Cytogenetic analysis provides further evidence for the presence of karyotypically abnormal HPCa cells in the HPCa/Hs5 tumors. Of importance, HPCa/Hs5 xenograft tumors contain EpCAM(+) cells that are both clonogenic and tumorigenic. Surprisingly, all HPCa/Hs5 reconstituted tumors are undifferentiated, even for HPCa cells derived from Gleason 7 tumors. Our results indicate that primary HPCa cells coinjected with the immortalized Hs5 stromal cells generate undifferentiated tumors in NSG mice and we provide evidence that undifferentiated HPCa cells might be the cells that possessed tumorigenic potential and regenerated HPCa/Hs5 xenograft tumors. PMID- 23451109 TI - Genetic variation of ITGB3 is associated with asthma in Chinese Han children. AB - Previous studies have demonstrated that integrins are involved in the aetiology of asthma. Several single-nucleotide polymorphisms (SNPs) in the integrin beta3 (ITGB3) gene are significantly associated with asthma in Western populations. Given the important roles of environmental exposures in the development of asthma, we evaluated the associations between six SNPs in ITGB3 and asthma in Chinese Han children. A total of 321 unrelated Chinese children with asthma and 315 healthy children were recruited for the study. SNP genotyping was performed by high-resolution melting analysis (HRM). The selected SNPs were well genotyped by HRM, and SNP rs3809865 in the 3' untranslated region (3'UTR) of ITGB3 was found to be strongly associated with asthma (adjusted p = 0.004). The minor allele of rs3809865 showed a protective effect against asthma (OR: 0.59; 95% CI: 0.43-0.8). The seed regions of two miRNAs (hsa-mir-124 and hsa-mir-506) were predicted to bind to the sequence containing rs3809865 by TargetScan and PITA. Luciferase reporter assays demonstrated that the T allele of rs3809865 was more efficiently targeted by hsa-mir-124 than was the A allele, which suggested that rs3809865 could affect the binding of hsa-mir-124 to ITGB3. Furthermore, the transfection of A549 cells with hsa-mir-124 resulted in the downregulation of ITGB3 expression. Our results revealed that rs3809865 was significantly associated with asthma due to its effect on the binding of hsa-mir-124 to ITGB3. PMID- 23451111 TI - MDM2 SNP309 rs2279744 polymorphism and gastric cancer risk: a meta-analysis. AB - BACKGROUND: MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 has been demonstrated to be associated with an increased MDM2 expression and a significantly earlier age of onset of several tumors, including gastric cancer. Several studies were published to evaluate the association between SNP309 and gastric cancer risk. However, the results remain conflicting rather than conclusive. OBJECTIVE: The aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk. METHODS: We performed a meta-analysis to investigate this relationship. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. RESULTS: Five published case-control studies, including 1,621 gastric cancer cases and 2,639 controls were identified. We found that the MDM2 SNP309 polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR = 1.54; 95%CI = 1.04 2.29, and GG versus GT/TT, OR = 1.49, 95%CI = 1.30-1.72). Furthermore, Egger's test did not show any evidence of publication bias (P = 0.799 for GG versus TT). CONCLUSION: Our results suggest that the MDM2 SNP309 polymorphism may be a low penetrant risk factor for the development of gastric cancer. PMID- 23451112 TI - The impact of gene duplication, insertion, deletion, lateral gene transfer and sequencing error on orthology inference: a simulation study. AB - The identification of orthologous genes, a prerequisite for numerous analyses in comparative and functional genomics, is commonly performed computationally from protein sequences. Several previous studies have compared the accuracy of orthology inference methods, but simulated data has not typically been considered in cross-method assessment studies. Yet, while dependent on model assumptions, simulation-based benchmarking offers unique advantages: contrary to empirical data, all aspects of simulated data are known with certainty. Furthermore, the flexibility of simulation makes it possible to investigate performance factors in isolation of one another.Here, we use simulated data to dissect the performance of six methods for orthology inference available as standalone software packages (Inparanoid, OMA, OrthoInspector, OrthoMCL, QuartetS, SPIMAP) as well as two generic approaches (bidirectional best hit and reciprocal smallest distance). We investigate the impact of various evolutionary forces (gene duplication, insertion, deletion, and lateral gene transfer) and technological artefacts (ambiguous sequences) on orthology inference. We show that while gene duplication/loss and insertion/deletion are well handled by most methods (albeit for different trade-offs of precision and recall), lateral gene transfer disrupts all methods. As for ambiguous sequences, which might result from poor sequencing, assembly, or genome annotation, we show that they affect alignment score-based orthology methods more strongly than their distance-based counterparts. PMID- 23451110 TI - Safety and efficacy of co-trimoxazole for treatment and prevention of Plasmodium falciparum malaria: a systematic review. AB - INTRODUCTION: Cotrimoxazole (CTX) has been used for half a century. It is inexpensive hence the reason for its almost universal availability and wide clinical spectrum of use. In the last decade, CTX was used for prophylaxis of opportunistic infections in HIV infected people. It also had an impact on the malaria risk in this specific group. OBJECTIVE: We performed a systematic review to explore the efficacy and safety of CTX used for P.falciparum malaria treatment and prophylaxis. RESULT: CTX is safe and efficacious against malaria. Up to 75% of the safety concerns relate to skin reactions and this increases in HIV/AIDs patients. In different study areas, in HIV negative individuals, CTX used as malaria treatment cleared 56%-97% of the malaria infections, reduced fever and improved anaemia. CTX prophylaxis reduces the incidence of clinical malaria in HIV-1 infected individuals from 46%-97%. In HIV negative non pregnant participants, CTX prophylaxis had 39.5%-99.5% protective efficacy against clinical malaria. The lowest figures were observed in zones of high sulfadoxine pyrimethamine resistance. There were no data reported on CTX prophylaxis in HIV negative pregnant women. CONCLUSION: CTX is safe and still efficacious for the treatment of P.falciparum malaria in non-pregnant adults and children irrespective of HIV status and antifolate resistance profiles. There is need to explore its effect in pregnant women, irrespective of HIV status. CTX prophylaxis in HIV infected individuals protects against malaria and CTX may have a role for malaria prophylaxis in specific HIV negative target groups. PMID- 23451113 TI - DNA methylation dynamics in blood after hematopoietic cell transplant. AB - Epigenetic deregulation is considered a common hallmark of cancer. Nevertheless, recent publications have demonstrated its association with a large array of human diseases. Here, we explore the DNA methylation dynamics in blood samples during hematopoietic cell transplant and how they are affected by pathophysiological events during transplant evolution. We analyzed global DNA methylation in a cohort of 47 patients with allogenic transplant up to 12 months post-transplant. Recipients stably maintained the donor's global methylation levels after transplant. Nonetheless, global methylation is affected by chimerism status. Methylation analysis of promoters revealed that methylation in more than 200 genes is altered 1 month post-transplant when compared with non-pathological methylation levels in the donor. This number decreased by 6 months post transplant. Finally, we analyzed methylation in IFN-gamma, FASL, IL-10, and PRF1 and found association with the severity of the acute graft-versus-host disease. Our results provide strong evidence that methylation changes in blood are linked to underlying physiological events and demonstrate that DNA methylation analysis is a viable strategy for the study of transplantation and for development of biomarkers. PMID- 23451114 TI - Health-related quality of life among children with recurrent respiratory tract infections in Xi'an, China. AB - OBJECTIVE: The aim of this study was to investigate the health-related quality of life (HRQOL) in 2-7-year-old children diagnosed with recurrent respiratory tract infections (RRTIs) and the impact of RRTIs on affected families. METHODS: This was a cross-sectional case-control study evaluating 2-7-year-old children with RRTIs (n = 352), 2-7-year-old healthy children (n = 376), and associated caregivers (parents and/or grandparents). A Chinese version of the PedsQLTM 4.0 Generic Core Scale was used to assess childhood HRQOL, and a Chinese version of the Family Impact Module (FIM) was used to assess the impact of RRTIs on family members. HRQOL scores were compared between children with RRTIs and healthy children. In addition, a multiple step-wise regression with demographic variables of children and their caregivers, family economic status, and caregiver's HRQOL as independent variables determined factors that influenced HRQOL in children with RRTIs. RESULTS: Children with RRTIs showed significantly lower physical, emotional, social, and school functioning scores than healthy children (p<0.05). Caregivers for children with RRTIs also scored significantly lower than caregivers for healthy children on physical, emotional, social, cognitive, and communication functioning (p<0.05). Caregivers for RRTIs affected children also reported significantly higher levels of worry. Multivariate analyses showed that children's age, children's relation with caregivers, the frequency of respiratory tract infections in the preceding year, caregiver's educational level, and caregiver's own HRQOL influenced HRQOL in children with RRTIs. CONCLUSIONS: The current data demonstrated that RRTIs were associated with lower HRQOL in both children and their caregivers and negatively influenced family functioning. In addition, caregivers' social characteristics also significantly affected HRQOL in children with RRTIs. PMID- 23451115 TI - Identification of chemokines associated with the recruitment of decidual leukocytes in human labour: potential novel targets for preterm labour. AB - Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL. PMID- 23451116 TI - CSF-1 receptor-dependent colon development, homeostasis and inflammatory stress response. AB - The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) directly regulates the development of Paneth cells (PC) and influences proliferation and cell fate in the small intestine (SI). In the present study, we have examined the role of CSF 1 and the CSF-1R in the large intestine, which lacks PC, in the steady state and in response to acute inflammation induced by dextran sulfate sodium (DSS). As previously shown in mouse, immunohistochemical (IHC) analysis of CSF-1R expression showed that the receptor is baso-laterally expressed on epithelial cells of human colonic crypts, indicating that this expression pattern is shared between species. Colons from Csf1r null and Csf1(op/op) mice were isolated and sectioned for IHC identification of enterocytes, enteroendocrine cells, goblet cells and proliferating cells. Both Csf1r(-/-) and Csf1(op/op) mice were found to have colon defects in enterocytes and enteroendocrine cell fate, with excessive goblet cell staining and reduced cell proliferation. In addition, the gene expression profiles of the cell cycle genes, cyclinD1, c-myc, c-fos, and c-myb were suppressed in Csf1r(-/-) colonic crypt, compared with those of WT mice and the expression of the stem cell marker gene Lgr5 was markedly reduced. However, analysis of the proliferative responses of immortalized mouse colon epithelial cells (lines; Immorto-5 and YAMC) indicated that CSF-1R is not a major regulator of colonocyte proliferation and that its effects on proliferation are indirect. In an examination of the acute inflammatory response, Csf1r(+/-) male mice were protected from the adverse affects of DSS-induced colitis compared with WT mice, while Csf1r(+/-) female mice were significantly less protected. These data indicate that CSF-1R signaling plays an important role in colon homeostasis and stem cell gene expression but that the receptor exacerbates the response to inflammatory challenge in male mice. PMID- 23451117 TI - Loss of GGN leads to pre-implantation embryonic lethality and compromised male meiotic DNA double strand break repair in the mouse. AB - The integrity of male germ cell genome is critical for the correct progression of spermatogenesis, successful fertilization, and proper development of the offspring. Several DNA repair pathways exist in male germ cells. However, unlike somatic cells, key components of such pathways remain largely unidentified. Gametogenetin (GGN) is a testis-enriched protein that has been shown to bind to the DNA repair protein FANCL via yeast-two-hybrid assays. This finding and its testis-enriched expression pattern raise the possibility that GGN plays a role in DNA repair during spermatogenesis. Herein we demonstrated that the largest isoform GGN1 interacted with components of DNA repair machinery in the mouse testis. In addition to FANCL, GGN1 interacted with the critical component of the Fanconi Anemia (FA) pathway FANCD2 and a downstream component of the BRCA pathway, BRCC36. To define the physiological function of GGN, we generated a Ggn null mouse line. A complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos. Moreover, pachytene spermatocytes of the Ggn heterozygous knockout mice showed an increased incidence of unrepaired DNA double strand breaks (DSBs). Together, our results suggest that GGN plays a role in male meiotic DSB repair and is absolutely required for the survival of pre-implantation embryos. PMID- 23451118 TI - Identification of a small molecule that selectively inhibits mouse PC2 over mouse PC1/3: a computational and experimental study. AB - The calcium-dependent serine endoproteases prohormone convertase 1/3 (PC1/3) and prohormone convertase 2 (PC2) play important roles in the homeostatic regulation of blood glucose levels, hence implicated in diabetes mellitus. Specifically, the absence of PC2 has been associated with chronic hypoglycemia. Since there is a reasonably good conservation of the catalytic domain between species translation of inhibitory effects is likely. In fact, similar results have been found using both mouse and human recombinant enzymes. Here, we employed computational structure-based approaches to screen 14,400 compounds from the Maybridge small molecule library towards mouse PC2. Our most remarkable finding was the identification of a potent and selective PC2 inhibitor. Kinetic data showed the compound to be an allosteric inhibitor. The compound identified is one of the few reported selective, small-molecule inhibitors of PC2. In addition, this new PC2 inhibitor is structurally different and of smaller size than those reported previously. This is advantageous for future studies where structural analogues can be built upon. PMID- 23451119 TI - Community intelligence in knowledge curation: an application to managing scientific nomenclature. AB - Harnessing community intelligence in knowledge curation bears significant promise in dealing with communication and education in the flood of scientific knowledge. As knowledge is accumulated at ever-faster rates, scientific nomenclature, a particular kind of knowledge, is concurrently generated in all kinds of fields. Since nomenclature is a system of terms used to name things in a particular discipline, accurate translation of scientific nomenclature in different languages is of critical importance, not only for communications and collaborations with English-speaking people, but also for knowledge dissemination among people in the non-English-speaking world, particularly young students and researchers. However, it lacks of accuracy and standardization when translating scientific nomenclature from English to other languages, especially for those languages that do not belong to the same language family as English. To address this issue, here we propose for the first time the application of community intelligence in scientific nomenclature management, namely, harnessing collective intelligence for translation of scientific nomenclature from English to other languages. As community intelligence applied to knowledge curation is primarily aided by wiki and Chinese is the native language for about one-fifth of the world's population, we put the proposed application into practice, by developing a wiki-based English-to-Chinese Scientific Nomenclature Dictionary (ESND; http://esnd.big.ac.cn). ESND is a wiki-based, publicly editable and open-content platform, exploiting the whole power of the scientific community in collectively and collaboratively managing scientific nomenclature. Based on community curation, ESND is capable of achieving accurate, standard, and comprehensive scientific nomenclature, demonstrating a valuable application of community intelligence in knowledge curation. PMID- 23451120 TI - A cis-acting element present within the Gag open reading frame negatively impacts on the activity of the HIV-1 IRES. AB - Translation initiation from the human immunodeficiency virus type-1 (HIV-1) mRNA can occur through a cap or an IRES dependent mechanism. Cap-dependent translation initiation of the HIV-1 mRNA can be inhibited by the instability element (INS)-1, a cis-acting regulatory element present within the gag open reading frame (ORF). In this study we evaluated the impact of the INS-1 on HIV-1 IRES-mediated translation initiation. Using heterologous bicistronic mRNAs, we show that the INS-1 negatively impact on HIV-1 IRES-driven translation in in vitro and in cell based experiments. Additionally, our results show that the inhibitory effect of the INS-1 is not general to all IRESes since it does not hinder translation driven by the HCV IRES. The inhibition by the INS-1 was partially rescued in cells by the overexpression of the viral Rev protein or hnRNPA1. PMID- 23451121 TI - Red meat and poultry intakes and risk of total and cause-specific mortality: results from cohort studies of Chinese adults in Shanghai. AB - Most previous studies of meat intake and total or cause-specific mortality were conducted in North America, whereas studies in other areas have been limited and reported inconsistent results. This study investigated the association of red meat or poultry intake with risk of total and cause-specific mortality, including cancer and cardiovascular disease (CVD), in two large population-based prospective cohort studies of 134,290 Chinese adult women and men in Shanghai. Meat intakes were assessed through validated food frequency questionnaires administered in person at baseline. Vital status and dates and causes of deaths were ascertained through annual linkage to the Shanghai Vital Statistics Registry and Shanghai Cancer Registry databases and home visits every 2-3 years. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of death associated with quintiles of meat intake. During 803,265 person-years of follow up for women and 334,281 person-years of follow up for men, a total of 4,210 deaths in women and 2,733 deaths in men accrued. The median intakes of red meat were 43 g/day among women and 54 g/day among men, and pork constituted at least 95% of total meat intake for both women and men. Red meat intake was associated with increased total mortality among men, but not among women; the HR (95% CI) comparing the highest with the lowest quintiles were 1.18 (1.02-1.35) and 0.92 (0.82-1.03), respectively. This sex difference was statistically significant (P = 0.01). Red meat intake was associated with increased risk of ischemic heart disease mortality (HR = 1.41, 95% CI = 1.05 1.89) and with decreased risk of hemorrhagic stroke mortality (HR = 0.62, 95% CI = 0.45-0.87). There were suggestive inverse associations of poultry intake with risk of total and all-CVD mortality among men, but not among women. Further investigations are needed to elucidate the sex-specific associations between red meat intake and mortality. PMID- 23451122 TI - Barrier-protective effects of activated protein C in human alveolar epithelial cells. AB - Acute lung injury (ALI) is a clinical manifestation of respiratory failure, caused by lung inflammation and the disruption of the alveolar-capillary barrier. Preservation of the physical integrity of the alveolar epithelial monolayer is of critical importance to prevent alveolar edema. Barrier integrity depends largely on the balance between physical forces on cell-cell and cell-matrix contacts, and this balance might be affected by alterations in the coagulation cascade in patients with ALI. We aimed to study the effects of activated protein C (APC) on mechanical tension and barrier integrity in human alveolar epithelial cells (A549) exposed to thrombin. Cells were pretreated for 3 h with APC (50 ug/ml) or vehicle (control). Subsequently, thrombin (50 nM) or medium was added to the cell culture. APC significantly reduced thrombin-induced cell monolayer permeability, cell stiffening, and cell contraction, measured by electrical impedance, optical magnetic twisting cytometry, and traction microscopy, respectively, suggesting a barrier-protective response. The dynamics of the barrier integrity was also assessed by western blotting and immunofluorescence analysis of the tight junction ZO-1. Thrombin resulted in more elongated ZO-1 aggregates at cell-cell interface areas and induced an increase in ZO-1 membrane protein content. APC attenuated the length of these ZO-1 aggregates and reduced the ZO-1 membrane protein levels induced by thrombin. In conclusion, pretreatment with APC reduced the disruption of barrier integrity induced by thrombin, thus contributing to alveolar epithelial barrier protection. PMID- 23451124 TI - Metabolic profiling for detection of Staphylococcus aureus infection and antibiotic resistance. AB - Due to slow diagnostics, physicians must optimize antibiotic therapies based on clinical evaluation of patients without specific information on causative bacteria. We have investigated metabolomic analysis of blood for the detection of acute bacterial infection and early differentiation between ineffective and effective antibiotic treatment. A vital and timely therapeutic difficulty was thereby addressed: the ability to rapidly detect treatment failures because of antibiotic-resistant bacteria. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were used in vitro and for infecting mice, while natural MSSA infection was studied in humans. Samples of bacterial growth media, the blood of infected mice and of humans were analyzed with combined Gas Chromatography/Mass Spectrometry. Multivariate data analysis was used to reveal the metabolic profiles of infection and the responses to different antibiotic treatments. In vitro experiments resulted in the detection of 256 putative metabolites and mice infection experiments resulted in the detection of 474 putative metabolites. Importantly, ineffective and effective antibiotic treatments were differentiated already two hours after treatment start in both experimental systems. That is, the ineffective treatment of MRSA using cloxacillin and untreated controls produced one metabolic profile while all effective treatment combinations using cloxacillin or vancomycin for MSSA or MRSA produced another profile. For further evaluation of the concept, blood samples of humans admitted to intensive care with severe sepsis were analyzed. One hundred thirty-three putative metabolites differentiated severe MSSA sepsis (n = 6) from severe Escherichia coli sepsis (n = 10) and identified treatment responses over time. Combined analysis of human, in vitro, and mice samples identified 25 metabolites indicative of effective treatment of S. aureus sepsis. Taken together, this study provides a proof of concept of the utility of analyzing metabolite patterns in blood for early differentiation between ineffective and effective antibiotic treatment in acute S. aureus infections. PMID- 23451123 TI - Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. AB - The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease. PMID- 23451125 TI - Interhemispheric inhibition during mental actions of different complexity. AB - Several investigations suggest that actual and mental actions trigger similar neural substrates. Yet, neurophysiological evidences on the nature of interhemispheric interactions during mental movements are still meagre. Here, we asked whether the content of mental images, investigated by task complexity, is finely represented in the inhibitory interactions between the two primary motor cortices (M1s). Subjects' left M1 was stimulated by means of transcranial magnetic stimulation (TMS) while they were performing actual or mental movements of increasing complexity with their right hand and exerting a maximum isometric force with their left thumb and index. Thus, we simultaneously assessed the corticospinal excitability in the right opponent pollicis muscle (OP) and the ipsilateral silent period (iSP) in the left OP during actual and mental movements. Corticospinal excitability in right OP increased during actual and mental movements, but task complexity-dependent changes were only observed during actual movements. Interhemispheric motor inhibition in the left OP was similarly modulated by task complexity in both mental and actual movements. Precisely, the duration and the area of the iSP increased with task complexity in both movement conditions. Our findings suggest that mental and actual movements share similar inhibitory neural circuits between the two homologous primary motor cortex areas. PMID- 23451126 TI - Serologic vaccination response after solid organ transplantation: a systematic review. AB - BACKGROUND: Infectious diseases after solid organ transplantation (SOT) are one of the major complications in transplantation medicine. Vaccination-based prevention is desirable, but data on the response to active vaccination after SOT are conflicting. METHODS: In this systematic review, we identify the serologic response rate of SOT recipients to post-transplantation vaccination against tetanus, diphtheria, polio, hepatitis A and B, influenza, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides, tick-borne encephalitis, rabies, varicella, mumps, measles, and rubella. RESULTS: Of the 2478 papers initially identified, 72 were included in the final review. The most important findings are that (1) most clinical trials conducted and published over more than 30 years have all been small and highly heterogeneous regarding trial design, patient cohorts selected, patient inclusion criteria, dosing and vaccination schemes, follow up periods and outcomes assessed, (2) the individual vaccines investigated have been studied predominately only in one group of SOT recipients, i.e. tetanus, diphtheria and polio in RTX recipients, hepatitis A exclusively in adult LTX recipients and mumps, measles and rubella in paediatric LTX recipients, (3) SOT recipients mount an immune response which is for most vaccines lower than in healthy controls. The degree to which this response is impaired varies with the type of vaccine, age and organ transplanted and (4) for some vaccines antibodies decline rapidly. CONCLUSION: Vaccine-based prevention of infectious diseases is far from satisfactory in SOT recipients. Despite the large number of vaccination studies preformed over the past decades, knowledge on vaccination response is still limited. Even though the protection, which can be achieved in SOT recipients through vaccination, appears encouraging on the basis of available data, current vaccination guidelines and recommendations for post SOT recipients remain poorly supported by evidence. There is an urgent need to conduct appropriately powered vaccination trials in well-defined SOT recipient cohorts. PMID- 23451127 TI - Further characterization of functional domains of PerA, role of amino and carboxy terminal domains in DNA binding. AB - PerA is a key regulator of virulence genes in enteropathogenic E. coli. PerA is a member of the AraC/XylS family of transcriptional regulators that directly regulates the expression of the bfp and per operons in response to different environmental cues. Here, we characterized mutants in both the amino (NTD) and carboxy (CTD) terminal domains of PerA that affect its ability to activate the expression of the bfp and per promoters. Mutants at residues predicted to be important for DNA binding within the CTD had a significant defect in their ability to bind to the regulatory regions of the bfp and per operons and, consequently, in transcriptional activation. Notably, mutants in specific NTD residues were also impaired to bind to DNA suggesting that this domain is involved in structuring the protein for correct DNA recognition. Mutations in residues E116 and D168, located in the vicinity of the putative linker region, significantly affected the activation of the perA promoter, without affecting PerA binding to the per or bfp regulatory sequences. Overall these results provide additional evidence of the importance of the N-terminal domain in PerA activity and suggest that the activation of these promoters involves differential interactions with the transcriptional machinery. This study further contributes to the characterization of the functional domains of PerA by identifying critical residues involved in DNA binding, differential promoter activation and, potentially, in the possible response to environmental cues. PMID- 23451128 TI - Antineoplastic effects of alpha-santalol on estrogen receptor-positive and estrogen receptor-negative breast cancer cells through cell cycle arrest at G2/M phase and induction of apoptosis. AB - Anticancer efficacy and the mechanism of action of alpha-santalol, a terpenoid isolated from sandalwood oil, were investigated in human breast cancer cells by using p53 wild-type MCF-7 cells as a model for estrogen receptor (ER)-positive and p53 mutated MDA-MB-231 cells as a model for ER-negative breast cancer. alpha Santalol inhibited cell viability and proliferation in a concentration and time dependent manner in both cells regardless of their ER and/or p53 status. However, alpha-santalol produced relatively less toxic effect on normal breast epithelial cell line, MCF-10A. It induced G2/M cell cycle arrest and apoptosis in both MCF-7 and MDA-MB-231 cells. Cell cycle arrest induced by alpha-santalol was associated with changes in the protein levels of BRCA1, Chk1, G2/M regulatory cyclins, Cyclin dependent kinases (CDKs), Cell division cycle 25B (Cdc25B), Cdc25C and Ser 216 phosphorylation of Cdc25C. An up-regulated expression of CDK inhibitor p21 along with suppressed expression of mutated p53 was observed in MDA-MB-231 cells treated with alpha-santalol. On the contrary, alpha-santalol did not increase the expression of wild-type p53 and p21 in MCF-7 cells. In addition, alpha-santalol induced extrinsic and intrinsic pathways of apoptosis in both cells with activation of caspase-8 and caspase-9. It led to the activation of the executioner caspase-6 and caspase-7 in alpha-santalol-treated MCF-7 cells and caspase-3 and caspase-6 in MDA-MB-231 cells along with strong cleavage of poly(ADP-ribose) polymerase (PARP) in both cells. Taken together, this study for the first time identified strong anti-neoplastic effects of alpha-santalol against both ER-positive and ER-negative breast cancer cells. PMID- 23451129 TI - Different brain activation under left and right ventricular stimulation: an fMRI study in anesthetized rats. AB - BACKGROUND: Myocardial ischemia in the anterior wall of the left ventricule (LV) and in the inferior wall and/or right ventricle (RV) shows different manifestations that can be explained by the different innervations of cardiac afferent nerves. However, it remains unclear whether information from different areas of the heart, such as the LV and RV, are differently processed in the brain. In this study, we investigated the brain regions that process information from the LV or RV using cardiac electrical stimulation and functional magnetic resonance imaging (fMRI) in anesthetized rats because the combination of these two approaches cannot be used in humans. METHODOLOGY/PRINCIPAL FINDINGS: An electrical stimulation catheter was inserted into the LV or RV (n = 12 each). Brain fMRI scans were recorded during LV or RV stimulation (9 Hz and 0.3 ms width) over 10 blocks consisting of alternating periods of 2 mA for 30 sec followed by 0.2 mA for 60 sec. The validity of fMRI signals was confirmed by first and second-level analyses and temporal profiles. Increases in fMRI signals were observed in the anterior cingulate cortex and the right somatosensory cortex under LV stimulation. In contrast, RV stimulation activated the right somatosensory cortex, which was identified more anteriorly compared with LV stimulation but did not activate the anterior cingulate cortex. CONCLUSION/SIGNIFICANCE: This study provides the first evidence for differences in brain activation under LV and RV stimulation. These different brain processes may be associated with different clinical manifestations between anterior wall and inferoposterior wall and/or RV myocardial ischemia. PMID- 23451130 TI - The methanol dehydrogenase gene, mxaF, as a functional and phylogenetic marker for proteobacterial methanotrophs in natural environments. AB - The mxaF gene, coding for the large (alpha) subunit of methanol dehydrogenase, is highly conserved among distantly related methylotrophic species in the Alpha-, Beta- and Gammaproteobacteria. It is ubiquitous in methanotrophs, in contrast to other methanotroph-specific genes such as the pmoA and mmoX genes, which are absent in some methanotrophic proteobacterial genera. This study examined the potential for using the mxaF gene as a functional and phylogenetic marker for methanotrophs. mxaF and 16S rRNA gene phylogenies were constructed based on over 100 database sequences of known proteobacterial methanotrophs and other methylotrophs to assess their evolutionary histories. Topology tests revealed that mxaF and 16S rDNA genes of methanotrophs do not show congruent evolutionary histories, with incongruencies in methanotrophic taxa in the Methylococcaceae, Methylocystaceae, and Beijerinckiacea. However, known methanotrophs generally formed coherent clades based on mxaF gene sequences, allowing for phylogenetic discrimination of major taxa. This feature highlights the mxaF gene's usefulness as a biomarker in studying the molecular diversity of proteobacterial methanotrophs in nature. To verify this, PCR-directed assays targeting this gene were used to detect novel methanotrophs from diverse environments including soil, peatland, hydrothermal vent mussel tissues, and methanotroph isolates. The placement of the majority of environmental mxaF gene sequences in distinct methanotroph-specific clades (Methylocystaceae and Methylococcaceae) detected in this study supports the use of mxaF as a biomarker for methanotrophic proteobacteria. PMID- 23451131 TI - Fatal stroke after the death of a sibling: a nationwide follow-up study from Sweden. AB - BACKGROUND: Although less studied than other types of familial losses, the loss of a sibling could be a potential trigger of stroke as it represents a stressful life event. We studied the association between loss of a sibling and fatal stroke up to 18 years since bereavement. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a follow-up study between 1981 and 2002, based on register data covering the total population of Swedes aged 40-69 years (n = 1,617,010). An increased risk of fatal stroke (1.31 CI: 1.05, 1.62) was found among women who had experienced the loss of a sibling. No increase in the overall mortality risk was found in men (1.11 CI: 0.92, 1.33). An elevated risk in the short term (during the second and third half-year after the death) was found among both men and women, whereas longer term elevation in risk was found primarily for women. Both external (1.47 CI: 1.00, 2.17) and not external (1.26 CI: 1.00, 1.60) causes of sibling death showed associations among women. In men, an association was found only if the sibling also died from stroke (1.78 CI: 1.00, 3.17). However, among women, we found an increased risk of stroke mortality if the sibling died from causes other than stroke (1.30 CI: 1.04, 1.62). CONCLUSIONS/SIGNIFICANCE: The findings suggest an increased risk of dying from stroke mortality after the death of a sibling, and that bereavement affects particularly women. It is important for health care workers to follow bereaved siblings and recognize potential changes of stress levels and health related behaviours that could lead to risk of stroke. PMID- 23451132 TI - Involvement of crosstalk between Oct4 and Meis1a in neural cell fate decision. AB - Oct4 plays a critical role both in maintaining pluripotency and the cell fate decision of embryonic stem (ES) cells. Nonetheless, in the determination of the neuroectoderm (NE) from ES cells, the detailed regulation mechanism of the Oct4 gene expression is poorly understood. Here, we report that crosstalk between Oct4 and Meis1a, a Pbx-related homeobox protein, is required for neural differentiation of mouse P19 embryonic carcinoma (EC) cells induced by retinoic acid (RA). During neural differentiation, Oct4 expression was transiently enhanced during 6-12 h of RA addition and subsequently disappeared within 48 h. Coinciding with up-regulation of Oct4 expression, the induction of Meis1a expression was initiated and reached a plateau at 48 h, suggesting that transiently induced Oct4 activates Meis1a expression and the up-regulated Meis1a then suppresses Oct4 expression. Chromatin immunoprecipitation (ChIP) and luciferase reporter analysis showed that Oct4 enhanced Meis1a expression via direct binding to the Meis1 promoter accompanying histone H3 acetylation and appearance of 5-hydoxymethylcytosine (5hmC), while Meis1a suppressed Oct4 expression via direct association with the Oct4 promoter together with histone deacetylase 1 (HDAC1). Furthermore, ectopic Meis1a expression promoted neural differentiation via formation of large neurospheres that expressed Nestin, GLAST, BLBP and Sox1 as neural stem cell (NSC)/neural progenitor markers, whereas its down-regulation generated small neurospheres and repressed neural differentiation. Thus, these results imply that crosstalk between Oct4 and Meis1a on mutual gene expressions is essential for the determination of NE from EC cells. PMID- 23451134 TI - Variance and covariance of actual relationships between relatives at one locus. AB - The relationship between pairs of individuals is an important topic in many areas of population and quantitative genetics. It is usually measured as the proportion of the genome identical by descent shared by the pair and it can be inferred from pedigree information. But there is a variance in actual relationships as a consequence of mendelian sampling, whose general formula has not been developed. The goal of this work is to develop this general formula for the one-locus situation,. We provide simple expressions for the variances and covariances of all actual relationships in an arbitrary complex pedigree. The proposed method relies on the use of the nine identity coefficients and the generalized relationship coefficients; formulas have been checked by computer simulation. Finally two examples for a short pedigree of dogs and a long pedigree of sheep are given. PMID- 23451133 TI - MCM-BP is required for repression of life-cycle specific genes transcribed by RNA polymerase I in the mammalian infectious form of Trypanosoma brucei. AB - Trypanosoma brucei variant surface glycoprotein (VSG) expression is a classic example of allelic exclusion. While the genome of T. brucei contains >2,000 VSG genes and VSG pseudogenes, only one allele is expressed at the surface of each infectious trypanosome and the others are repressed. Along with recombinatorial VSG switching, allelic exclusion provides a major host evasion mechanism for trypanosomes, a phenomenon known as antigenic variation. To extend our understanding of how trypanosomes escape host immunity by differential expression of VSGs, we attempted to identify genes that contribute to VSG silencing, by performing a loss-of-silencing screen in T. brucei using a transposon-mediated random insertional mutagenesis. One identified gene, which we initially named LOS1, encodes a T. brucei MCM-Binding Protein (TbMCM-BP). Here we show that TbMCM BP is essential for viability of infectious bloodstream-form (BF) trypanosome and is required for proper cell-cycle progression. Tandem affinity purification of TbMCM-BP followed by mass spectrometry identified four subunits (MCM4-MCM7) of the T. brucei MCM complex, a replicative helicase, and MCM8, a subunit that is uniquely co-purified with TbMCM-BP. TbMCM-BP is required not only for repression of subtelomeric VSGs but also for silencing of life-cycle specific, insect-stage genes, procyclin and procyclin-associated genes (PAGs), that are normally repressed in BF trypanosomes and are transcribed by RNA polymerase I. Our study uncovers a functional link between chromosome maintenance and RNA pol I-mediated gene silencing in T. brucei. PMID- 23451135 TI - Storage and release of spermatozoa from the pre-uterine tube reservoir. AB - In mammals, after coitus a small number of spermatozoa enter the uterine tube and following attachment to uterine tube epithelium are arrested in a non-capacitated state until peri-ovulatory signalling induces their detachment. Whilst awaiting release low numbers of spermatozoa continually detach from the epithelium and the uterine tube reservoir risks depletion. There is evidence of attachment of spermatozoa to uterine epithelium in several species which might form a potential pre-uterine tube reservoir. In this study we demonstrate that: (1) dog spermatozoa attach to uterine epithelium and maintain flagellar activity, (2) in non-capacitating conditions spermatozoa progressively detach with a variety of motility characteristics, (3) attachment is not influenced by epithelial changes occurring around ovulation, (4) attachment to uterine epithelium slows capacitation, (5) capacitated spermatozoa have reduced ability to attach to uterine epithelium, (6) under capacitating conditions increased numbers of spermatozoa detach and exhibit transitional and hyperactive motility which differ to those seen in non-capacitating conditions, (7) detachment of spermatozoa and motility changes can be induced by post-ovulation but not pre-ovulation uterine tube flush fluid and by components of follicular fluid and solubilised zona pellucida, (8) prolonged culture does not change the nature of the progressive detachment seen in non-capacitating conditions nor the potential for increased detachment in capacitating conditions. We postulate that in some species binding of spermatozoa to uterine epithelium is an important component of the transport of spermatozoa. Before ovulation low numbers of spermatozoa continually detach, including those which are non-capacitated with fast forward progressive motility allowing the re-population of the uterine tube, whilst around the time of ovulation, signalling from as-yet unknown factors associated with follicular fluid, oocytes and uterine tube secretion promotes the detachment of large numbers of capacitated spermatozoa with hyperactive motility that may contribute to the fertilising pool. PMID- 23451137 TI - Facilitation or competition? Tree effects on grass biomass across a precipitation gradient. AB - Savanna ecosystems are dominated by two distinct plant life forms, grasses and trees, but the interactions between them are poorly understood. Here, we quantified the effects of isolated savanna trees on grass biomass as a function of distance from the base of the tree and tree height, across a precipitation gradient in the Kruger National Park, South Africa. Our results suggest that mean annual precipitation (MAP) mediates the nature of tree-grass interactions in these ecosystems, with the impact of trees on grass biomass shifting qualitatively between 550 and 737 mm MAP. Tree effects on grass biomass were facilitative in drier sites (MAP<=550 mm), with higher grass biomass observed beneath tree canopies than outside. In contrast, at the wettest site (MAP = 737 mm), grass biomass did not differ significantly beneath and outside tree canopies. Within this overall precipitation-driven pattern, tree height had positive effect on sub-canopy grass biomass at some sites, but these effects were weak and not consistent across the rainfall gradient. For a more synthetic understanding of tree-grass interactions in savannas, future studies should focus on isolating the different mechanisms by which trees influence grass biomass, both positively and negatively, and elucidate how their relative strengths change over broad environmental gradients. PMID- 23451136 TI - Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity. AB - The arginine methyltransferase PRMT5-MEP50 is required for embryogenesis and is misregulated in many cancers. PRMT5 targets a wide variety of substrates, including histone proteins involved in specifying an epigenetic code. However, the mechanism by which PRMT5 utilizes MEP50 to discriminate substrates and to specifically methylate target arginines is unclear. To test a model in which MEP50 is critical for substrate recognition and orientation, we determined the crystal structure of Xenopus laevis PRMT5-MEP50 complexed with S adenosylhomocysteine (SAH). PRMT5-MEP50 forms an unusual tetramer of heterodimers with substantial surface negative charge. MEP50 is required for PRMT5-catalyzed histone H2A and H4 methyltransferase activity and binds substrates independently. The PRMT5 catalytic site is oriented towards the cross-dimer paired MEP50. Histone peptide arrays and solution assays demonstrate that PRMT5-MEP50 activity is inhibited by substrate phosphorylation and enhanced by substrate acetylation. Electron microscopy and reconstruction showed substrate centered on MEP50. These data support a mechanism in which MEP50 binds substrate and stimulates PRMT5 activity modulated by substrate post-translational modifications. PMID- 23451138 TI - Wild relatives of the eggplant (Solanum melongena L.: Solanaceae): new understanding of species names in a complex group. AB - BACKGROUND: The common or brinjal eggplant (Solanum melongena L.) belongs to the Leptostemonum Clade (the "spiny" solanums) of the species-rich genus Solanum (Solanaceae). Unlike most of the genus, the eggplant and its relatives are from the Old World; most eggplant wild relatives are from Africa. An informal system for naming eggplant wild relatives largely based on crossing and other biosystematics data has been in use for approximately a decade. This system recognises several forms of two broadly conceived species, S. incanum L. and S. melongena. Recent morphological and molecular work has shown that species-level differences exist between these entities, and a new species-level nomenclature has been identified as necessary for plant breeders and for the maintenance of accurately named germplasm. METHODOLOGY/PRINCIPAL FINDINGS: We examined herbarium specimens from throughout the wild species ranges as part of a larger revision of the spiny solanums of Africa. Based on these morphological and molecular studies, we delimited species in the group to which the common eggplant belongs and constructed identification keys for the group. We also examined the monophyly of the group considered as the eggplant relatives by previous authors. CONCLUSIONS/SIGNIFICANCE: WE RECOGNISE TEN SPECIES IN THIS GROUP: S. aureitomentosum Bitter, S. campylacanthum A.Rich., S. cerasiferum Dunal, S. incanum L., S. insanum L., S. lichtensteinii Willd., S. linnaeanum Hepper & P. M.L.Jaeger, S. melongena L., S. rigidum Lam. and S. umtuma Voronts. & S.Knapp. We review the history of naming and provide keys and character lists for all species. Ploidy level differences have not been investigated in the eggplant wild relatives; we identify this as a priority for improvement of crop wild relative use in breeding. The application of species-level names to these entities will help focus new collecting efforts for brinjal eggplant improvement and help facilitate information exchange. PMID- 23451139 TI - In vivo imaging of transplanted islets labeled with a novel cationic nanoparticle. AB - To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a beta-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients. PMID- 23451140 TI - A systems-level approach for investigating Pseudomonas aeruginosa biofilm formation. AB - Prevention of the initiation of biofilm formation is the most important step for combating biofilm-associated pathogens, as the ability of pathogens to resist antibiotics is enhanced 10 to 1000 times once biofilms are formed. Genes essential to bacterial growth in the planktonic state are potential targets to treat biofilm-associated pathogens. However, the biofilm formation capability of strains with mutations in these essential genes must be evaluated, since the pathogen might form a biofilm before it is eliminated. In order to address this issue, this work proposes a systems-level approach to quantifying the biofilm formation capability of mutants to determine target genes that are essential for bacterial metabolism in the planktonic state but do not induce biofilm formation in their mutants. The changes of fluxes through the reactions associated with the genes positively related to biofilm formation are used as soft sensors in the flux balance analysis to quantify the trend of biofilm formation upon the mutation of an essential gene. The essential genes whose mutants are predicted not to induce biofilm formation are regarded as gene targets. The proposed approach was applied to identify target genes to treat Pseudomonas aeruginosa infections. It is interesting to find that most essential gene mutants exhibit high potential to induce the biofilm formation while most non-essential gene mutants do not. Critically, we identified four essential genes, lysC, cysH, adk, and galU, that constitute gene targets to treat P. aeruginosa. They have been suggested by existing experimental data as potential drug targets for their crucial role in the survival or virulence of P. aeruginosa. It is also interesting to find that P. aeruginosa tends to survive the essential-gene mutation treatment by mainly enhancing fluxes through 8 metabolic reactions that regulate acetate metabolism, arginine metabolism, and glutamate metabolism. PMID- 23451141 TI - Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFbeta1 cascade involved in fibrogenesis. AB - AIM: Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice. METHODS AND RESULTS: ApoE-/- and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX). Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy) occurred in both strains of mice. Low dose irradiation (0.2 Gy) induced premature death in ApoE-/- mice (47% died at 20 weeks). Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-beta1 and PAI-1) was measured earlier in cardiomyocytes isolated from ApoE-/- than in wt animals. CONCLUSION: The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages. PMID- 23451142 TI - Peripheral immune cell gene expression changes in advanced non-small cell lung cancer patients treated with first line combination chemotherapy. AB - INTRODUCTION: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. METHODS: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. RESULTS: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. CONCLUSIONS: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC. PMID- 23451143 TI - Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment. AB - High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors. PMID- 23451144 TI - Impact of methicillin resistant Staphylococcus aureus contact isolation units on medical care. AB - BACKGROUND: Patient isolation using contact precautions has gained widespread use to halt MRSA transmission, however supportive data is scarce and concerns regarding patient safety and satisfaction have been raised. At our institution, MRSA patients are isolated on a dedicated ward (cohort isolation), rather than in separate rooms. Our objectives were (1) to determine the proportion of bedside medical visits to patients on an isolation ward, (2) to quantify complications in those patients and (3) to determine if those complications are related to isolation and if they can be prevented. METHODS: This retrospective case-control study was performed on the two sites of a tertiary teaching hospital in Sherbrooke, QC, Canada. We matched MRSA patients with an admission diagnosis of heart failure or chronic obstructive pulmonary disease to similar non-isolated controls. The proportion of bedside visits was ascertained through the number of progress notes with subjective elements or with a physical examination. Complications were sought through an extensive file review, and events were analysed according to Baker's CAES causality and preventability scales. RESULTS: Overall, 111 patient pairs were analysed (35 with heart failure and 76 with COPD). Isolated patients received less bedside visits (subjective notes/1,000 patient-days: 849.6 vs. 983.3, p = 0,001). Attending physicians (454.5 vs. 451.4, p = 0,02) and residents (347.0 vs. 416.9, p = 0.01) are responsible for this discrepancy, while medical students appear to visit isolated and non-isolated patients equally (116.5 vs. 114.9, p = 0.90). Isolated patients showed a tendency towards longer stay and more preventable complications, although no difference in the total number of complications was observed. CONCLUSION: Isolated patients have less documented care that suggests less bedside visits from the medical staff, which could hamper the therapeutical relationship. Further studies are needed to explain this finding. PMID- 23451145 TI - Predominance of HA-222D/G polymorphism in influenza A(H1N1)pdm09 viruses associated with fatal and severe outcomes recently circulating in Germany. AB - Influenza A(H1N1)pdm09 viruses cause sporadically very severe disease including fatal clinical outcomes associated with pneumonia, viremia and myocarditis. A mutation characterized by the substitution of aspartic acid (wild-type) to glycine at position 222 within the haemagglutinin gene (HA-D222G) was recorded during the 2009 H1N1 pandemic in Germany and other countries with significant frequency in fatal and severe cases. Additionally, A(H1N1)pdm09 viruses exhibiting the polymorphism HA-222D/G/N were detected both in the respiratory tract and in blood. Specimens from mild, fatal and severe cases were collected to study the heterogeneity of HA-222 in A(H1N1)pdm09 viruses circulating in Germany between 2009 and 2011. In order to enable rapid and large scale analysis we designed a pyrosequencing (PSQ) assay. In 2009/2010, the 222D wild-type of A(H1N1)pdm09 viruses predominated in fatal and severe outcomes. Moreover, co circulating virus mutants exhibiting a D222G or D222E substitution (8/6%) as well as HA-222 quasispecies were identified (10%). Both the 222D/G and the 222D/G/N/V/Y polymorphisms were confirmed by TA cloning. PSQ analyses of viruses associated with mild outcomes revealed mainly the wild-type 222D and no D222G change in both seasons. However, an increase of variants with 222D/G polymorphism (60%) was characteristic for A(H1N1)pdm09 viruses causing fatal and severe cases in the season 2010/2011. Pure 222G viruses were not observed. Our results support the hypothesis that the D222G change may result from adaptation of viral receptor specificity to the lower respiratory tract. This could explain why transmission of the 222G variant is less frequent among humans. Thus, amino acid changes at HA position 222 may be the result of viral intra-host evolution leading to the generation of variants with an altered viral tropism. PMID- 23451146 TI - The N-terminal beta-sheet of peroxiredoxin 4 in the large yellow croaker Pseudosciaena crocea is involved in its biological functions. AB - Peroxiredoxins (Prxs) are thiol-specific antioxidant proteins that exhibit peroxidase and peroxynitrite reductase activities involved in the reduction of reactive oxygen species. The peroxiredoxin Prx4 from the large yellow croaker Pseudosciaena crocea is a typical 2-Cys Prx with an N-terminal signal peptide. We solved the crystal structure of Prx4 at 1.90 A and revealed an N-terminal antiparallel beta-sheet that contributes to the dimer interface. Deletion of this beta-sheet decreased the in vitro peroxidase activity to about 50% of the wild type. In vivo assays further demonstrated that removal of this beta-sheet led to some impairment in the ability of Prx4 to negatively regulate nuclear factor kappaB (NF-kappaB) activity and to perform its role in anti-bacterial immunity. These results provide new insights into the structure and function relationship of a peroxiredoxin from bony fish. PMID- 23451147 TI - Meta-analysis of microsomal epoxide hydrolase gene polymorphism and risk of hepatocellular carcinoma. AB - BACKGROUND: Hepatocarcinogenesis is a complex process that may be influenced by many factors, including polymorphism in microsomal epoxide hydrolase (mEH). Previous work suggests an association between the Tyr113His and His139Arg mEH polymorphisms and susceptibility to hepatocellular carcinoma (HCC), but the results have been inconsistent. METHODS: PubMed, EMBASE, Google Scholar and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His and His139Arg mEH polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Eleven studies were included in the meta-analysis, involving 1,696 HCC cases and 3,600 controls. The 113His- mEH allele was significantly associated with increased risk of HCC based on allelic contrast (OR = 1.35, 95% CI = 1.04 1.75, p = 0.02), homozygote comparison (OR = 1.65, 95% CI = 1.07-2.54, p = 0.02) and a recessive genetic model (OR = 1.54, 95% CI = 1.21-1.96, p<0.001), while individuals carrying the Arg139Arg mEH genotype had no association with increased or decreased risk of HCC. CONCLUSION: The 113His- allele polymorphism in mEH may be a risk factor for hepatocarcinogenesis, while the mEH 139Arg- allele may not be a risk or protective factor. There is substantial evidence that mEH polymorphisms interact synergistically with other genes and the environment to modulate risk of HCC. Further large and well-designed studies are needed to confirm these conclusions. PMID- 23451148 TI - Non-LTR R2 element evolutionary patterns: phylogenetic incongruences, rapid radiation and the maintenance of multiple lineages. AB - Retrotransposons of the R2 superclade specifically insert within the 28S ribosomal gene. They have been isolated from a variety of metazoan genomes and were found vertically inherited even if their phylogeny does not always agree with that of the host species. This was explained with the diversification/extinction of paralogous lineages, being proved the absence of horizontal transfer. We here analyze the widest available collection of R2 sequences, either newly isolated from recently sequenced genomes or drawn from public databases, in a phylogenetic framework. Results are congruent with previous analyses, but new important issues emerge. First, the N-terminal end of the R2-B clade protein, so far unknown, presents a new zinc fingers configuration. Second, the phylogenetic pattern is consistent with an ancient, rapid radiation of R2 lineages: being the estimated time of R2 origin (850-600 Million years ago) placed just before the metazoan Cambrian explosion, the wide element diversity and the incongruence with the host phylogeny could be attributable to the sudden expansion of available niches represented by host's 28S ribosomal genes. Finally, we detect instances of coexisting multiple R2 lineages showing a non-random phylogenetic pattern, strongly similar to that of the "library" model known for tandem repeats: a collection of R2s were present in the ancestral genome and then differentially activated/repressed in the derived species. Models for activation/repression as well as mechanisms for sequence maintenance are also discussed within this framework. PMID- 23451149 TI - miR-153 regulates SNAP-25, synaptic transmission, and neuronal development. AB - SNAP-25 is a core component of the trimeric SNARE complex mediating vesicle exocytosis during membrane addition for neuronal growth, neuropeptide/growth factor secretion, and neurotransmitter release during synaptic transmission. Here, we report a novel microRNA mechanism of SNAP-25 regulation controlling motor neuron development, neurosecretion, synaptic activity, and movement in zebrafish. Loss of miR-153 causes overexpression of SNAP-25 and consequent hyperactive movement in early zebrafish embryos. Conversely, overexpression of miR-153 causes SNAP-25 down regulation resulting in near complete paralysis, mimicking the effects of treatment with Botulinum neurotoxin. miR-153-dependent changes in synaptic activity at the neuromuscular junction are consistent with the observed movement defects. Underlying the movement defects, perturbation of miR-153 function causes dramatic developmental changes in motor neuron patterning and branching. Together, our results indicate that precise control of SNAP-25 expression by miR-153 is critically important for proper neuronal patterning as well as neurotransmission. PMID- 23451150 TI - Elevated phospholipase A2 activities in plasma samples from multiple cancers. AB - Only in recent years have phospholipase A2 enzymes (PLA2s) emerged as cancer targets. In this work, we report the first detection of elevated PLA2 activities in plasma from patients with colorectal, lung, pancreatic, and bladder cancers as compared to healthy controls. Independent sets of clinical plasma samples were obtained from two different sites. The first set was from patients with colorectal cancer (CRC; n = 38) and healthy controls (n = 77). The second set was from patients with lung (n = 95), bladder (n = 31), or pancreatic cancers (n = 38), and healthy controls (n = 79). PLA2 activities were analyzed by a validated quantitative fluorescent assay method and subtype PLA2 activities were defined in the presence of selective inhibitors. The natural PLA2 activity, as well as each subtype of PLA2 activity was elevated in each cancer group as compared to healthy controls. PLA2 activities were increased in late stage vs. early stage cases in CRC. PLA2 activities were not influenced by sex, smoking, alcohol consumption, or body-mass index (BMI). Samples from the two independent sites confirmed the results. Plasma PLA2 activities had approximately 70% specificity and sensitivity to detect cancer. The marker and targeting values of PLA2 activity have been suggested. PMID- 23451151 TI - Phagocytosis is the main CR3-mediated function affected by the lupus-associated variant of CD11b in human myeloid cells. AB - The CD11b/CD18 integrin (complement receptor 3, CR3) is a surface receptor on monocytes, neutrophils, macrophages and dendritic cells that plays a crucial role in several immunological processes including leukocyte extravasation and phagocytosis. The minor allele of a non-synonymous CR3 polymorphism (rs1143679, conversation of arginine to histidine at position 77: R77H) represents one of the strongest genetic risk factor in human systemic lupus erythematosus, with heterozygosity (77R/H) being the most common disease associated genotype. Homozygosity for the 77H allele has been reported to reduce adhesion and phagocytosis in human monocytes and monocyte-derived macrophages, respectively, without affecting surface expression of CD11b. Herein we comprehensively assessed the influence of R77H on different CR3-mediated activities in monocytes, neutrophils, macrophages and dendritic cells. R77H did not alter surface expression of CD11b including its active form in any of these cell types. Using two different iC3b-coated targets we found that the uptake by heterozygous 77R/H macrophages, monocytes and neutrophils was significantly reduced compared to 77R/R cells. Allele-specific transduced immortalized macrophage cell lines demonstrated that the minor allele, 77H, was responsible for the impaired phagocytosis. R77H did not affect neutrophil adhesion, neutrophil transmigration in vivo or Toll-like receptor 7/8-mediated cytokine release by monocytes or dendritic cells with or without CR3 pre-engagement by iC3b-coated targets. Our findings demonstrate that the reduction in CR3-mediated phagocytosis associated with the 77H CD11b variant is not macrophage-restricted but demonstrable in other CR3-expressing professional phagocytic cells. The association between 77H and susceptibility to systemic lupus erythematosus most likely relates to impaired waste disposal, a key component of lupus pathogenesis. PMID- 23451152 TI - Heat shock-induced accumulation of translation elongation and termination factors precedes assembly of stress granules in S. cerevisiae. AB - In response to severe environmental stresses eukaryotic cells shut down translation and accumulate components of the translational machinery in stress granules (SGs). Since they contain mainly mRNA, translation initiation factors and 40S ribosomal subunits, they have been referred to as dominant accumulations of stalled translation preinitiation complexes. Here we present evidence that the robust heat shock-induced SGs of S. cerevisiae also contain translation elongation factors eEF3 (Yef3p) and eEF1Bgamma2 (Tef4p) as well as translation termination factors eRF1 (Sup45p) and eRF3 (Sup35p). Despite the presence of the yeast prion protein Sup35 in heat shock-induced SGs, we found out that its prion like domain is not involved in the SGs assembly. Factors eEF3, eEF1Bgamma2 and eRF1 were accumulated and co-localized with Dcp2 foci even upon a milder heat shock at 42 degrees C independently of P-bodies scaffolding proteins. We also show that eEF3 accumulations at 42 degrees C determine sites of the genuine SGs assembly at 46 degrees C. We suggest that identification of translation elongation and termination factors in SGs might help to understand the mechanism of the eIF2alpha factor phosphorylation-independent repression of translation and SGs assembly. PMID- 23451153 TI - New insights for native production of MSP1(19), the disulfide-rich C-terminal fragment from Plasmodium falciparum merozoite surface protein 1. AB - Malaria represents a major public health problem and an important cause of mortality and morbidity. The malaria parasites are becoming resistant to drugs used to treat the disease and still no efficient vaccine has been developed. One promising vaccine candidate is the merozoite surface protein 1 (MSP1), which has been extensively investigated as a vaccine target. The surface protein MSP1 plays an essential role in the erythrocyte invasion process and is an accessible target for the immune system. Antibodies to the carboxy-terminal region of the protein, named MSP119, can inhibit erythrocyte invasion and parasite growth. In order to develop an effective MSP119- based vaccine against malaria, production of an antigen that is recognized by protective antibodies is mandatory. To this aim, we propose a method to produce the disulfide-rich MSP119 in its native conformation based on its in vitro oxidative refolding. The native conformation of the renatured MSP119 is carefully established by immunochemical reactivity experiments, circular dichroism and NMR. MSP119 can successfully be refolded in vitro as an isolated protein or as a fusion with the maltose binding protein. The possibility to properly fold MSP119in vitro paves the way to new approaches for high titer production of native MSP119 using Escherichia coli as a host. PMID- 23451154 TI - Morphological similarity and ecological overlap in two rotifer species. AB - Co-occurrence of cryptic species raises theoretically relevant questions regarding their coexistence and ecological similarity. Given their great morphological similitude and close phylogenetic relationship (i.e., niche retention), these species will have similar ecological requirements and are expected to have strong competitive interactions. This raises the problem of finding the mechanisms that may explain the coexistence of cryptic species and challenges the conventional view of coexistence based on niche differentiation. The cryptic species complex of the rotifer Brachionus plicatilis is an excellent model to study these questions and to test hypotheses regarding ecological differentiation. Rotifer species within this complex are filtering zooplankters commonly found inhabiting the same ponds across the Iberian Peninsula and exhibit an extremely similar morphology-some of them being even virtually identical. Here, we explore whether subtle differences in body size and morphology translate into ecological differentiation by comparing two extremely morphologically similar species belonging to this complex: B. plicatilis and B. manjavacas. We focus on three key ecological features related to body size: (1) functional response, expressed by clearance rates; (2) tolerance to starvation, measured by growth and reproduction; and (3) vulnerability to copepod predation, measured by the number of preyed upon neonates. No major differences between B. plicatilis and B. manjavacas were found in the response to these features. Our results demonstrate the existence of a substantial niche overlap, suggesting that the subtle size differences between these two cryptic species are not sufficient to explain their coexistence. This lack of evidence for ecological differentiation in the studied biotic niche features is in agreement with the phylogenetic limiting similarity hypothesis but requires a mechanistic explanation of the coexistence of these species not based on differentiation related to biotic niche axes. PMID- 23451155 TI - The association between subclinical atherosclerosis and uterine fibroids. AB - OBJECTIVES: To explore the atherogenic hypothesis of uterine fibroids among Chinese women. METHODS: In a case-control study, 335 patients confirmed by ultrasound or hysterectomy surgery and 539 controls were enrolled between October 1, 2009 and April 1, 2012. Unconditional logistic regressions were used to calculate the odds ratios (ORs) for the associations of subclinical atherogenic and cardiovascular risk parameters with uterine fibroids in the overall case group and hysterectomy-confirmed case group, respectively. RESULTS: Higher level of ankle-brachial index (ABI) was independently associated with increased odds of uterine fibroids. The odds of UF among women in the highest tertile of ABI were 1.88 times higher (95%CI: 1.17, 3.02, Ptrend = 0.008) compared to those in the lowest tertile. The serum concentration of homocysteine was inversely related to fibroids (middle vs. low: OR 0.56, 95%CI: 0.36, 0.85; high vs. low: OR 0.50, 95% CI: 0.32, 0.79; Ptrend = 0.002). In the hysterectomy-confirmed group, an inverse association was suggested between high-density lipoprotein cholesterol (HDL-C) and fibroids (OR 0.46, 95% CI: 0.25, 0.84, Ptrend = 0.014). Moreover, the effect of homocysteine concentration was not observed in this group. CONCLUSIONS: These findings suggest that women with uterine fibroids might have an increased risk of subclinical atherosclerosis. PMID- 23451156 TI - A novel cancer testis antigen, A-kinase anchor protein 4 (AKAP4) is a potential biomarker for breast cancer. AB - BACKGROUND: Breast cancer is the second leading cause of cancer related deaths in women worldwide. Reports about the early diagnosis of breast cancer are suggestive of an improved clinical outcome and overall survival rate in cancer patients. Therefore, cancer screening biomarker for early detection and diagnosis is urgently required for timely treatment and better cancer management. In this context, we investigated an association of cancer testis antigen, A-Kinase anchor protein 4 (AKAP4) with breast carcinoma. METHODOLOGY/FINDINGS: We first compared the AKAP4 gene and protein expression in four breast cancer cells (MCF7, MDA-MB 231, SK-BR3 and BT474) and normal human mammary epithelial cells. In addition, 91 clinical specimens of breast cancer patients of various histotypes including ductal carcinoma in situ, infiltrating ductal carcinoma and infiltrating lobular carcinoma and 83 available matched adjacent non-cancerous tissues were examined for AKAP4 gene and protein expression by employing in situ RNA hybridization and immunohistochemistry respectively. Humoral response against AKAP4 was also investigated in breast cancer patients employing ELISA. Our in vitro studies in all breast cancer cells revealed AKAP4 gene and protein expression whereas, normal human mammary epithelial cells failed to show any expression. Using in situ RNA hybridization and immunohistochemistry, 85% (77/91) tissue specimens irrespective of histotypes, stages and grades of breast cancer clinical specimens revealed AKAP4 gene and protein expression. However, matched adjacent non cancerous tissues failed to display any AKAP4 gene and protein expression. Furthermore, humoral response was observed in 79% (72/91) of total breast cancer patients. Interestingly, we observed that 94% (72/77) of breast cancer patients found positive for AKAP4 protein expression generated humoral response against AKAP4 protein. CONCLUSIONS: Collectively, our data suggests that AKAP4 may be used as serum based diagnostic test for an early detection and diagnosis of breast cancer and may be a potential target for immunotherapeutic use. PMID- 23451157 TI - Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. AB - INTRODUCTION: Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. METHODS: In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, gammaH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. RESULTS: ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. CONCLUSIONS: Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells. PMID- 23451158 TI - An intracellular threonine of amyloid-beta precursor protein mediates synaptic plasticity deficits and memory loss. AB - Mutations in Amyloid-beta Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPbeta and beta-CTF. beta-CTF is cleaved by gamma-secretase to produce Abeta. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPbeta/beta-CTF but not Abeta. We have investigated further the pathogenic function of beta-CTF focusing on Thr(668) of beta-CTF because phosphorylation of Thr(668) is increased in AD cases. We created a knock-in mouse bearing a Thr(668)Ala mutation (APP(TA) mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr(668) is a viable therapeutic strategy for human dementias. PMID- 23451159 TI - Expansion of pathogen-specific mono- and multifunctional Th1 and Th17 cells in multi-focal tuberculous lymphadenitis. AB - BACKGROUND: Th1 and Th17 responses are known to play an important role in immunity to pulmonary tuberculosis (PTB), although little is known about their role in extrapulmonary forms of tuberculosis (TB). METHODS: To identify the role of Th1, Th17, and Th22 cells in multi-focal TB lymphadenitis (TBL), we examined mycobacteria-specific immune responses in the whole blood of individuals with PTB (n = 20) and compared them with those with TBL (n = 25). RESULTS: Elevated frequencies of CD4(+) T cells expressing IFN- gamma, TNF-alpha, and IL-2 were present in individuals with TBL compared with those with PTB at baseline and in response to ESAT-6 and CFP-10. Similarly, increased frequencies of CD4(+) T cells expressing IL-17A, IL-17F, and IFN-gamma were also present in individuals with TBL at baseline and following ESAT-6 and CFP-10 stimulation although no significant difference in frequency of Th22 cells was observed. Finally, frequencies of Th1 (but not Th17) cells exhibited a significantly negative correlation with natural regulatory T cell frequencies at baseline. CONCLUSIONS: Multi-focal TB lymphadenitis is therefore characterized by elevated frequencies of Th1 and Th17 cells, indicating that Th1 and Th17 responses in TB disease are probably correlates of disease severity rather than of protective immunity. PMID- 23451160 TI - Functional capacity of Shiga-toxin promoter sequences in eukaryotic cells. AB - Shiga toxins (Stx) are the main virulence factors in enterohemorrhagic Escherichia coli (EHEC) infections, causing diarrhea and hemolytic uremic syndrome (HUS). The genes encoding for Shiga toxin-2 (Stx2) are located in a bacteriophage. The toxin is formed by a single A subunit and five B subunits, each of which has its own promoter sequence. We have previously reported the expression of the B subunit within the eukaryotic environment, probably driven by their own promoter. The aim of this work was to evaluate the ability of the eukaryotic machinery to recognize stx2 sequences as eukaryotic-like promoters. Vero cells were transfected with a plasmid encoding Stx2 under its own promoter. The cytotoxic effect on these cells was similar to that observed upon incubation with purified Stx2. In addition, we showed that Stx2 expression in Stx2 insensitive BHK eukaryotic cells induced drastic morphological and cytoskeletal changes. In order to directly evaluate the capacity of the wild promoter sequences of the A and B subunits to drive protein expression in mammalian cells, GFP was cloned under eukaryotic-like putative promoter sequences. GFP expression was observed in 293T cells transfected with these constructions. These results show a novel and alternative way to synthesize Stx2 that could contribute to the global understanding of EHEC infections with immediate impact on the development of treatments or vaccines against HUS. PMID- 23451161 TI - NDRG2 is a novel p53-associated regulator of apoptosis in C6-originated astrocytes exposed to oxygen-glucose deprivation. AB - N-myc downstream-regulated gene 2 (NDRG2) has been documented to be a pro differentiative and anti-proliferative gene in cancer research. Our previous study found a significant NDRG2 up-regulation in reactive astrocytes of penumbra after transient focal cerebral ischemia, which was parallel to the enhancement of TUNEL-positive signals. However, it is still uncertain whether NDRG2 participates in cellular apoptosis induced by ischemia-reperfusion injury in brain. In this study, we investigated the role of NDRG2 in cellular apoptosis induced by oxygen glucose deprivation (OGD) in IL-6-differentiated C6 glioma cells. The results showed that NDRG2 was up-regulated and translocated from the cytoplasm to the nucleus after OGD exposure. NDRG2 over-expression exhibited an anti-proliferative effect and increased the Bax/Bcl-2 ratio after OGD exposure, while NDRG2 silencing promoted the cellular proliferation and attenuated the up-regulation of Bax/Bcl-2 ratio. The pro-apoptotic effect of p53 was verified by the results in which p53 silencing greatly reduced the percentage of OGD-induced apoptotic cells. p53 silencing also reduced the OGD-induced NDRG2 up-regulation. However, over-expression of p53 did not further improve the NDRG2 up-regulation. In conclusion, NDRG2 is a p53-associated regulator of apoptosis in C6-originated astrocytes after OGD exposure. These findings bring insight to the roles of NDRG2 in ischemic-hypoxic injury and provide potential targets for future clinical therapies on stroke. PMID- 23451162 TI - Addressing dichotomous data for participants excluded from trial analysis: a guide for systematic reviewers. AB - INTRODUCTION: Systematic reviewer authors intending to include all randomized participants in their meta-analyses need to make assumptions about the outcomes of participants with missing data. OBJECTIVE: The objective of this paper is to provide systematic reviewer authors with a relatively simple guidance for addressing dichotomous data for participants excluded from analyses of randomized trials. METHODS: This guide is based on a review of the Cochrane handbook and published methodological research. The guide deals with participants excluded from the analysis who were considered 'non-adherent to the protocol' but for whom data are available, and participants with missing data. RESULTS: Systematic reviewer authors should include data from 'non-adherent' participants excluded from the primary study authors' analysis but for whom data are available. For missing, unavailable participant data, authors may conduct a complete case analysis (excluding those with missing data) as the primary analysis. Alternatively, they may conduct a primary analysis that makes plausible assumptions about the outcomes of participants with missing data. When the primary analysis suggests important benefit, sensitivity meta-analyses using relatively extreme assumptions that may vary in plausibility can inform the extent to which risk of bias impacts the confidence in the results of the primary analysis. The more plausible assumptions draw on the outcome event rates within the trial or in all trials included in the meta-analysis. The proposed guide does not take into account the uncertainty associated with assumed events. CONCLUSIONS: This guide proposes methods for handling participants excluded from analyses of randomized trials. These methods can help in establishing the extent to which risk of bias impacts meta-analysis results. PMID- 23451163 TI - Intravital immunofluorescence for visualizing the microcirculatory and immune microenvironments in the mouse ear dermis. AB - Visualizing the dynamic behaviors of immune cells in living tissue has dramatically increased our understanding of how cells interact with their surroundings, contributing important insights into mechanisms of leukocyte trafficking, tumor cell invasion, and T cell education by dendritic cells, among others. Despite substantial advances with various intravital imaging techniques including two-photon microscopy and the generation of multitudes of reporter mice, there is a growing need to assess cell interactions in the context of specific extracellular matrix composition and microvascular functions, and as well, simpler and more widely accessible methods are needed to image cell behaviors in the context of living tissue physiology. Here we present an antibody based method for intravital imaging of cell interactions with the blood, lymphatic, and the extracellular matrix compartments of the living dermis while simultaneously assessing capillary permeability and lymphatic drainage function. Using the exposed dorsal ear of the anesthetized mouse and a fluorescence stereomicroscope, such events can be imaged in the context of specific extracellular matrix proteins, or matrix-bound chemokine stores. We developed and optimized the method to minimize tissue damage to the ear, rapidly immunostain for multiple extracellular or cell surface receptors of interest, minimize immunotoxicity with pre-blocking Fcgamma receptors and phototoxicity with extracellular antioxidants, and highlight the major dermal tissue structures with basement membrane markers. We demonstrate differential migration behaviors of bone marrow-derived dendritic cells, blood-circulating leukocytes, and dermal dendritic cells, with the latter entering sparse CCL21-positive areas of pre collecting lymphatic vessels. This new method allows simultaneous imaging of cells and tissue structures, microvascular function, and extracellular microenvironment in multiple skin locations for 12 hours or more, with the flexibility of immunolabeling in addition to genetic-based fluorescent reporters. PMID- 23451164 TI - Early activation of rat skeletal muscle IL-6/STAT1/STAT3 dependent gene expression in resistance exercise linked to hypertrophy. AB - Cytokine interleukin-6 (IL-6) is an essential regulator of satellite cell mediated hypertrophic muscle growth through the transcription factor signal transducer and activator of transcription 3 (STAT3). The importance of this pathway linked to the modulation of myogenic regulatory factors expression in rat skeletal muscle undergoing hypertrophy following resistance exercise, has not been investigated. In this study, the phosphorylation and nuclear localization of STAT3, together with IL-6/STAT3-responsive gene expression, were measured after both a single bout of resistance exercise and 10 weeks of training. Flexor Digitorum Profundus muscle samples from Wistar rats were obtained 2 and 6 hours after a single bout of resistance exercise and 72 h after the last bout of either 2, 4, or 10 weeks of resistance training. We observed an increase in IL-6 and SOCS3 mRNAs concomitant with phosphorylation of STAT1 and STAT3 after 2 and 6 hours of a single bout of exercise (p<0.05). STAT3-dependent early responsive genes such as CyclinD1 and cMyc were also upregulated whereas MyoD and Myf5 mRNAs were downregulated (p<0.05). BrdU-positive satellite cells increased at 2 and 6 hours after exercise (p<0.05). Muscle fiber hypertrophy reached up to 100% after 10 weeks of training and the mRNA expression of Myf5, c-Myc and Cyclin-D1 decreased, whereas IL-6 mRNA remained upregulated. We conclude that the IL 6/STAT1/STAT3 signaling pathway and its responsive genes after a single bout of resistance exercise are an important event regulating the SC pool and behavior involved in muscle hypertrophy after ten weeks of training in rat skeletal muscle. PMID- 23451165 TI - WormSizer: high-throughput analysis of nematode size and shape. AB - The fundamental phenotypes of growth rate, size and morphology are the result of complex interactions between genotype and environment. We developed a high throughput software application, WormSizer, which computes size and shape of nematodes from brightfield images. Existing methods for estimating volume either coarsely model the nematode as a cylinder or assume the worm shape or opacity is invariant. Our estimate is more robust to changes in morphology or optical density as it only assumes radial symmetry. This open source software is written as a plugin for the well-known image-processing framework Fiji/ImageJ. It may therefore be extended easily. We evaluated the technical performance of this framework, and we used it to analyze growth and shape of several canonical Caenorhabditis elegans mutants in a developmental time series. We confirm quantitatively that a Dumpy (Dpy) mutant is short and fat and that a Long (Lon) mutant is long and thin. We show that daf-2 insulin-like receptor mutants are larger than wild-type upon hatching but grow slow, and WormSizer can distinguish dauer larvae from normal larvae. We also show that a Small (Sma) mutant is actually smaller than wild-type at all stages of larval development. WormSizer works with Uncoordinated (Unc) and Roller (Rol) mutants as well, indicating that it can be used with mutants despite behavioral phenotypes. We used our complete data set to perform a power analysis, giving users a sense of how many images are needed to detect different effect sizes. Our analysis confirms and extends on existing phenotypic characterization of well-characterized mutants, demonstrating the utility and robustness of WormSizer. PMID- 23451166 TI - Importance of weight loss maintenance and risk prediction in the prevention of type 2 diabetes: analysis of European Diabetes Prevention Study RCT. AB - BACKGROUND: Prevalence of type 2 diabetes (T2D) is increasing worldwide. T2D prevention by lifestyle intervention is effective. Pragmatic scalable interventions are needed, with evidence to efficiently target and monitor such interventions. We report pooled analyses of data from three European trial cohorts: to analyse T2D incidence, sustained weight loss and utility of risk predictors. METHODS: We analysed data on 749 adults with impaired glucose tolerance (278 men and 471 women, mean age 56 years, mean BMI 31 kgm(-2)) recruited between 1993 and 2003, and randomised to intensive lifestyle intervention (I) or lifestyle advice control (C). The intervention aimed to increase physical activity, modify diet, and promote weight loss>=5%. Using Cox regression survival analysis, we assessed T2D incidence and the impact on T2D incidence of sustained weight loss, and of baseline cut-point values of FINDRISC score, fasting plasma glucose (FPG), and HbA1c. RESULTS: Mean follow-up duration was 3.1 years. T2D was diagnosed in 139 participants (I = 45/379, C = 94/370). Cumulative T2D incidence was 57% lower in the intervention compared with the control group (HR 0.42 (95% CI 0.29 to 0.60) P<0.001). Participants with >=5% weight loss at one year had 65% lower T2D incidence (HR 0.35 (95% CI 0.22 to 0.56) P<0.001); maintaining >=5% weight loss for two and three years further reduced T2D incidence. Recommended cut-points to identify those at high risk for T2D would have identified different proportions of European Diabetes Prevention Study (EDIPS) participants with similar hazard-ratios for intervention effect. CONCLUSIONS: Pooled analysis of EDIPS trial data reinforces evidence for T2D prevention by lifestyle intervention. Analysis showed the preventive effect of >=5% weight loss, especially if maintained long term, which has utility for intervention monitoring. Analysis of proposed cut-points demonstrates difficulties in balancing risk and benefit, to efficiently target interventions and suggests evidence is needed to define clinical policy. TRIAL REGISTRATIONS: THE FINNISH DIABETES PREVENTION STUDY, HELSINKI, FINLAND: ClinicalTrials.gov; NCT00518167 The SLIM diabetes prevention study, Maastricht, The Netherlands: Clinical Trials.gov; NCT00381186 The EDIPS-Newcastle diabetes prevention study, Newcastle upon Tyne, UK: International Standard Randomised Controlled Trial Number; ISRCTN15670600. PMID- 23451168 TI - Variation of the linkage of root function with root branch order. AB - Mounting evidence has shown strong linkage of root function with root branch order. However, it is not known whether this linkage is consistent in different species. Here, root anatomic traits of the first five branch order were examined in five species differing in plant phylogeny and growth form in tropical and subtropical forests of south China. In Paramichelia baillonii, one tree species in Magnoliaceae, the intact cortex as well as mycorrhizal colonization existed even in the fifth-order root suggesting the preservation of absorption function in the higher-order roots. In contrast, dramatic decreases of cortex thickness and mycorrhizal colonization were observed from lower- to higher-order roots in three other tree species, Cunninghamia lanceolata, Acacia auriculiformis and Gordonia axillaries, which indicate the loss of absorption function. In a fern, Dicranopteris dichotoma, there were several cortex layers with prominently thickened cell wall and no mycorrhizal colonization in the third- and fourth order roots, also demonstrating the loss of absorptive function in higher-order roots. Cluster analysis using these anatomic traits showed a different classification of root branch order in P. baillonii from other four species. As for the conduit diameter-density relationship in higher-order roots, the mechanism underpinning this relationship in P. baillonii was different from that in other species. In lower-order roots, different patterns of coefficient of variance for conduit diameter and density provided further evidence for the two types of linkage of root function with root branch order. These linkages corresponding to two types of ephemeral root modules have important implication in the prediction of terrestrial carbon cycling, although we caution that this study was pseudo-replicated. Future studies by sampling more species can test the generality of these two types of linkage. PMID- 23451167 TI - Effects of plasma membrane cholesterol level and cytoskeleton F-actin on cell protrusion mechanics. AB - Protrusions are deformations that form at the surface of living cells during biological activities such as cell migration. Using combined optical tweezers and fluorescent microscopy, we quantified the mechanical properties of protrusions in adherent human embryonic kidney cells in response to application of an external force at the cell surface. The mechanical properties of protrusions were analyzed by obtaining the associated force-length plots during protrusion formation, and force relaxation at constant length. Protrusion mechanics were interpretable by a standard linear solid (Kelvin) model, consisting of two stiffness parameters, k0 and k1 (with k0>k1), and a viscous coefficient. While both stiffness parameters contribute to the time-dependant mechanical behavior of the protrusions, k0 and k1 in particular dominated the early and late stages of the protrusion formation and elongation process, respectively. Lowering the membrane cholesterol content by 25% increased the k0 stiffness by 74%, and shortened the protrusion length by almost half. Enhancement of membrane cholesterol content by nearly two-fold increased the protrusion length by 30%, and decreased the k0 stiffness by nearly two-and-half-fold as compared with control cells. Cytoskeleton integrity was found to make a major contribution to protrusion mechanics as evidenced by the effects of F-actin disruption on the resulting mechanical parameters. Viscoelastic behavior of protrusions was further characterized by hysteresis and force relaxation after formation. The results of this study elucidate the coordination of plasma membrane composition and cytoskeleton during protrusion formation. PMID- 23451169 TI - Simultaneous detection of oseltamivir- and amantadine-resistant influenza by oligonucleotide microarray visualization. AB - Presently, the resistance of Influenza A virus isolates causes great difficulty for the prevention and treatment of influenza A virus infection. It is important to establish a drug-resistance detection method for epidemiological study and personalized medicine in the clinical setting. Consequently, a cost-effective oligonucleotide microarray visualization method, which was based on quantum dot catalyzed silver deposition, was developed and evaluated for the simultaneous detection of neuraminidase H275Y and E119V; matrix protein 2 V27A and S31N mutations of influenza A (H3N2), seasonal influenza A (H1N1), and 2009 influenza A (H1N1). Then, 307 clinical throat swab specimens were detected and the drug resistance results showed that 100% (17/17) of influenza A (H3N2) and 100% (259/259) of 2009 influenza A (H1N1) samples were resistant to amantadine and susceptible to oseltamivir; and 100% (5/5) of seasonal influenza A (H1N1) samples were resistant to both amantadine and oseltamivir. PMID- 23451170 TI - Molecular analysis of Anaplasma phagocytophilum isolated from patients with febrile diseases of unknown etiology in China. AB - Although anaplasmosis cases have been nationally identified in China, no human isolates of A. phagocytophilum have been obtained, which limits the analysis of any molecular and genetic contributions to patients' severe clinical manifestations and the study of the bacteria's pathogeneses in China. Given this situation, a joint project was conducted in 2009-2010. A total of 421 febrile cases of unknown etiology were collected and the patients' blood samples were collected for laboratory diagnoses including serologic diagnosis based on the four-fold rise in the anti- A. phagocytophilum IgG titer by indirect micro immunofluorescence assay (IFA), positive PCR assay and confirmation of A. phagocytophilum DNA and positive culture of A. phagocytophilum and confirmed by amplification and sequencing of the 16S rRNA and ank A genes of the A. phagocytophilum isolates. A total of 570 ticks were collected from the patients' domestic animals (456) and from wild fields (114) for culturing and amplifying and sequencing the 16S rRNA gene of A. phagocytophilum. Phylogenetic analyses were performed on the 16S rRNA and ank A gene sequences of the isolates and the ticks tested in the study. A total of 46 (10.9%) confirmed and 16 (3.8%) probable cases were diagnosed and severe clinical features and higher mortality rates were observed in these Chinese patients. Five isolates were obtained and the 16S rRNA genes of the 5 isolates were conserved but variety for ank A genes. Two human isolates and 1 tick isolate from Shandong Peninsula, where all patients exhibited severe clinical manifestations, were grouped as one clan based on the phylogenetic analyses, while 2 other human isolates were clustered in a second clan. 43.5% of H. longicornis were infected with A. phagocytophilum.The present study is the first to obtain clinical isolates of A. phagocytophilum in China. The diversity of the ank A genes of Chinese isolates will help us to further discern the relationship between the variations in the ank A genes and the severity of the disease's clinical manifestations in China. PMID- 23451171 TI - Differentially expressed miRNAs after GnRH treatment and their potential roles in FSH regulation in porcine anterior pituitary cell. AB - Hypothalamic gonadotropin-releasing hormone (GnRH) is a major regulator of follicle-stimulating hormone (FSH) secretion in gonadotrope cell in the anterior pituitary gland. microRNAs (miRNAs) are small RNA molecules that control gene expression by imperfect binding to the 3'-untranslated region (3'-UTR) of mRNA at the post-transcriptional level. It has been proven that miRNAs play an important role in hormone response and/or regulation. However, little is known about miRNAs in the regulation of FSH secretion. In this study, primary anterior pituitary cells were treated with 100 nM GnRH. The supernatant of pituitary cell was collected for FSH determination by enzyme-linked immunosorbent assay (ELISA) at 3 hours and 6 hours post GnRH treatment respectively. Results revealed that GnRH significantly promoted FSH secretion at 3 h and 6 h post-treatment by 1.40-fold and 1.80-fold, respectively. FSHbeta mRNA at 6 h post GnRH treatment significantly increased by 1.60-fold. At 6 hours, cells were collected for miRNA expression profile analysis using MiRCURY LNA Array and quantitative PCR (qPCR). Consequently, 21 up-regulated and 10 down-regulated miRNAs were identified, and qPCR verification of 10 randomly selected miRNAs showed a strong correlation with microarray results. Chromosome location analysis indicated that 8 miRNAs were mapped to chromosome 12 and 4 miRNAs to chromosome X. Target and pathway analysis showed that some miRNAs may be associated with GnRH regulation pathways. In addition, In-depth analysis indicated that 10 up-regulated and 3 down-regulated miRNAs probably target FSHbeta mRNA 3'-UTR directly, including miR-361-3p, a highly conserved X-linked miRNA. Most importantly, functional experimental results showed that miR-361-3p was involved in FSH secretion regulation, and up regulated miR-361-3p expression inhibited FSH secretion, while down-regulated miR 361-3p expression promoted FSH secretion in pig pituitary cell model. These differentially expressed miRNAs resolved in this study provide the first guide for post-transcriptional regulation of pituitary gonadotrope FSH secretion in pig, as well as in other mammals. PMID- 23451172 TI - Coevolution between male and female genitalia in the Drosophila melanogaster species subgroup. AB - In contrast to male genitalia that typically exhibit patterns of rapid and divergent evolution among internally fertilizing animals, female genitalia have been less well studied and are generally thought to evolve slowly among closely related species. As a result, few cases of male-female genital coevolution have been documented. In Drosophila, female copulatory structures have been claimed to be mostly invariant compared to male structures. Here, we re-examined male and female genitalia in the nine species of the D. melanogaster subgroup. We describe several new species-specific female genital structures that appear to coevolve with male genital structures, and provide evidence that the coevolving structures contact each other during copulation. Several female structures might be defensive shields against apparently harmful male structures, such as cercal teeth, phallic hooks and spines. Evidence for male-female morphological coevolution in Drosophila has previously been shown at the post-copulatory level (e.g., sperm length and sperm storage organ size), and our results provide support for male-female coevolution at the copulatory level. PMID- 23451173 TI - Differential activity of Drosophila Hox genes induces myosin expression and can maintain compartment boundaries. AB - Compartments are units of cell lineage that subdivide territories with different developmental potential. In Drosophila, the wing and haltere discs are subdivided into anterior and posterior (A/P) compartments, which require the activity of Hedgehog, and into dorsal and ventral (D/V) compartments, needing Notch signaling. There is enrichment in actomyosin proteins at the compartment boundaries, suggesting a role for these proteins in their maintenance. Compartments also develop in the mouse hindbrain rhombomeres, which are characterized by the expression of different Hox genes, a group of genes specifying different structures along their main axis of bilaterians. We show here that the Drosophila Hox gene Ultrabithorax can maintain the A/P and D/V compartment boundaries when Hedgehog or Notch signaling is compromised, and that the interaction of cells with and without Ultrabithorax expression induces high levels of non-muscle myosin II. In the absence of Ultrabithorax there is occasional mixing of cells from different segments. We also show a similar role in cell segregation for the Abdominal-B Hox gene. Our results suggest that the juxtaposition of cells with different Hox gene expression leads to their sorting out, probably through the accumulation of non-muscle myosin II at the boundary of the different cell territories. The increase in myosin expression seems to be a general mechanism used by Hox genes or signaling pathways to maintain the segregation of different groups of cells. PMID- 23451175 TI - Oxygen mediates vascular smooth muscle relaxation in hypoxia. AB - The activation of soluble guanylate cyclase (sGC) by nitric oxide (NO) and other ligands has been extensively investigated for many years. In the present study we considered the effect of molecular oxygen (O2) on sGC both as a direct ligand and its affect on other ligands by measuring cyclic guanosine monophosphate (cGMP) production, as an index of activity, as well as investigating smooth muscle relaxation under hypoxic conditions. Our isolated enzyme studies confirm the function of sGC is impaired under hypoxic conditions and produces cGMP in the presence of O2, importantly in the absence of NO. We also show that while O2 could partially affect the magnitude of sGC stimulation by NO when the latter was present in excess, activation by the NO independent, haem-dependent sGC stimulator 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was unaffected. Our in vitro investigation of smooth muscle relaxation confirmed that O2 alone in the form of a buffer bolus (equilibrated at 95% O2/5% CO2) had the ability to dilate vessels under hypoxic conditions and that this was dependent upon sGC and independent of eNOS. Our studies confirm that O2 can be a direct and important mediator of vasodilation through an increase in cGMP production. In the wider context, these observations are key to understanding the relative roles of O2 versus NO-induced sGC activation. PMID- 23451174 TI - Nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma. AB - Vasculogenic mimicry (VM) describes functional vascular channels composed only of tumor cells and its presence predicts poor prognosis in melanoma patients. Inhibition of this alternative vascularization pathway might be of clinical importance, especially as several anti-angiogenic therapies targeting endothelial cells are largely ineffective in melanoma. We show the presence of VM structures histologically in a series of human melanoma lesions and demonstrate that cell cultures derived from these lesions form tubes in 3D cultures ex vivo. We tested the ability of nicotinamide, the amide form of vitamin B3 (niacin), which acts as an epigenetic gene regulator through unique cellular pathways, to modify VM. Nicotinamide effectively inhibited the formation of VM structures and destroyed already formed ones, in a dose-dependent manner. Remarkably, VM formation capacity remained suppressed even one month after the complete withdrawal of Nicotimamid. The inhibitory effect of nicotinamide on VM formation could be at least partially explained by a nicotinamide-driven downregulation of vascular endothelial cadherin (VE-Cadherin), which is known to have a central role in VM. Further major changes in the expression profile of hundreds of genes, most of them clustered in biologically-relevant clusters, were observed. In addition, nicotinamide significantly inhibited melanoma cell proliferation, but had an opposite effect on their invasion capacity. Cell cycle analysis indicated moderate changes in apoptotic indices. Therefore, nicotinamide could be further used to unravel new biological mechanisms that drive VM and tumor progression. Targeting VM, especially in combination with anti-angiogenic strategies, is expected to be synergistic and might yield substantial anti neoplastic effects in a variety of malignancies. PMID- 23451177 TI - Association between TNF alpha gene polymorphisms and the risk of duodenal ulcer: a meta-analysis. AB - BACKGROUND: Epidemiological studies have evaluated the association between tumor necrosis factor alpha (TNF-alpha) single nucleotide polymorphisms (SNPs) and duodenal ulcer (DU), but the results remain inconclusive. The aim of this study was to perform a meta-analysis to investigate a more authentic association between TNF-alpha SNPs and DU. METHODS: We performed the meta-analysis by searching PubMed, Embase, and Web of Science databases from the first available year to Sep. 5, 2012. Additionally, checking reference lists from identified articles, reviews, and the abstracts presented at related scientific societies meetings were also performed. All case-control studies investigating the association between TNF-alpha SNPs and DU risk were included. The association was assessed by odds ratio (OR) with 95% confidence interval (CI). Publication bias was analyzed by Begg's funnel plot and Egger's regression test. RESULTS: A total of sixteen studies reporting TNF-alpha -308G/A, -1031T/C, -863C/A, -857C/T, and 238G/A polymorphism were included in our final meta-analysis. There was no statistically significant association between -308G/A polymorphism and DU in the overall study population, as well as subgroup analyses by ethnicity, study design, and H. pylori status. As for -1031T/C, -863C/A, -857C/T, and -238G/A, results of our meta-analyses showed no statistical evidence of significant association. Power calculation on the combined sample size showed that the statistical powers were all lower than 80% for all the meta-analyses. CONCLUSIONS: The data suggests that there is no statistical evidence of significant association between the studied TNF-alpha SNPs and DU. However, this conclusion should be interpreted with caution as low statistical powers were revealed by power calculations. In future, larger sample-size studies with homogeneous DU patients and well-matched controls are required. PMID- 23451176 TI - Differential intrahepatic phospholipid zonation in simple steatosis and nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34:1 and PC 36:2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH. PMID- 23451178 TI - Distinct genomic aberrations between low-grade and high-grade gliomas of Chinese patients. AB - BACKGROUND: Glioma is a type of tumor that develops in the central nerve system, mainly the brain. Alterations of genomic sequence and sequence segments (such as copy number variations or CNV and copy neutral loss of heterozygosities or cnLOH) are thought to be a major determinant of the tumor grade. METHODS: We mapped genomic variations between low-grade and high-grade gliomas (LGG and HGG) in Chinese population based on Illumina's Beadchip and validated the results using real-time qPCR. RESULTS: AT THE CYTOBAND LEVEL, WE DISCOVERED: (1) unique losses in LGG on 5q, 8p and 11q, and in HGG on 6q, 11p, 13q and 19q; (2) unique gains in the LGG on 1p and in HGG at 5p, 7p, 7q and 20q; and (3) cnLOH in HGG only on 3q, 8q, 10p, 14q, 15q, 17p, 17q, 18q and 21q. Subsequently, we confirmed well characterized oncogenes among tumor-related loci (such as EGFR and KIT) and detected novel genes that gained chromosome sequences (such as AASS, HYAL4, NDUFA5 and SPAM1) in both LGG and HGG. In addition, we found gains, losses, and cnLOH in several genes, including VN1R2, VN1R4, and ZNF677, in multiple samples. Mapping grade-associated pathways and their related gene ontology (GO) terms, we classified LGG-associated functions as "arachidonic acid metabolism", "DNA binding" and "regulation of DNA-dependent transcription" and the HGG-associated as "neuroactive ligand-receptor interaction", "neuronal cell body" and "defense response to bacterium". CONCLUSION: LGG and HGG appear to have different molecular signatures in genomic variations and our results provide invaluable information for the diagnosis and treatment of gliomas in patients with variable duration or diverse tumor differentiation. PMID- 23451179 TI - Autophagy and cellular senescence mediated by Sox2 suppress malignancy of cancer cells. AB - Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the "stemness" of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2 induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a), p21 and phosphorylated p53 (Ser15). Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers. PMID- 23451180 TI - Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. AB - Several unclassified variants (UVs) have been identified in splicing regions of disease-associated genes and their characterization as pathogenic mutations or benign polymorphisms is crucial for the understanding of their role in disease development. In this study, 24 UVs located at BRCA1 and BRCA2 splice sites were characterized by transcripts analysis. These results were used to evaluate the ability of nine bioinformatics programs in predicting genetic variants causing aberrant splicing (spliceogenic variants) and the nature of aberrant transcripts. Eleven variants in BRCA1 and 8 in BRCA2, including 8 not previously characterized at transcript level, were ascertained to affect mRNA splicing. Of these, 16 led to the synthesis of aberrant transcripts containing premature termination codons (PTCs), 2 to the up-regulation of naturally occurring alternative transcripts containing PTCs, and one to an in-frame deletion within the region coding for the DNA binding domain of BRCA2, causing the loss of the ability to bind the partner protein DSS1 and ssDNA. For each computational program, we evaluated the rate of non-informative analyses, i.e. those that did not recognize the natural splice sites in the wild-type sequence, and the rate of false positive predictions, i.e., variants incorrectly classified as spliceogenic, as a measure of their specificity, under conditions setting sensitivity of predictions to 100%. The programs that performed better were Human Splicing Finder and Automated Splice Site Analyses, both exhibiting 100% informativeness and specificity. For 10 mutations the activation of cryptic splice sites was observed, but we were unable to derive simple criteria to select, among the different cryptic sites predicted by the bioinformatics analyses, those actually used. Consistent with previous reports, our study provides evidences that in silico tools can be used for selecting splice site variants for in vitro analyses. However, the latter remain mandatory for the characterization of the nature of aberrant transcripts. PMID- 23451181 TI - Comparison of sum absolute QRST integral, and temporal variability in depolarization and repolarization, measured by dynamic vectorcardiography approach, in healthy men and women. AB - BACKGROUND: Recently we showed the predictive value of sum absolute QRST integral (SAI QRST) and repolarization lability for risk stratification of sudden cardiac death (SCD) in heart failure patients. The goal of this study was to compare SAI QRST and metrics of depolarization and repolarization variability in healthy men and women. METHODS: Orthogonal ECGs were recorded at rest for 10 minutes in 160 healthy men and women (mean age 39.6+/-14.6, 80 men). Mean spatial TT' angle, and normalized variances of T loop area, of spatial T vector amplitude, of QT interval and Tpeak-Tend area were measured for assessment of repolarization lability. Normalized variances of spatial QRS vector and QRS loop area characterized variability of depolarization. In addition, variability indices (VI) were calculated to adjust for normalized heart rate variance. SAI QRST was measured as the averaged arithmetic sum of areas under the QRST curve. RESULTS: Men were characterized by shorter QTc (430.3+/-21.7 vs. 444.7+/-22.2 ms; P<0.0001) and larger SAI QRST (282.1+/-66.7 vs. 204.9+/-58.5 mV*ms; P<0.0001). Repolarization lability negatively correlated with spatial T vector amplitude. Adjusted by normalized heart rate variance, QT variability index was significantly higher in women than in men (-1.54+/-0.38 vs. -1.70+/-0.33; P = 0.017). However, in multivariate logistic regression after adjustment for body surface area, QTc, and spatial T vector amplitude, healthy men had 1.5-3 fold higher probability of having larger repolarization lability, as compared to healthy women (T vector amplitude variability index odds ratio 3.88 (95%CI 1.4 11.1; P = 0.012). CONCLUSIONS: Healthy men more likely than women have larger repolarization lability. PMID- 23451182 TI - Polymicrobial infection with major periodontal pathogens induced periodontal disease and aortic atherosclerosis in hyperlipidemic ApoE(null) mice. AB - Periodontal disease (PD) and atherosclerosis are both polymicrobial and multifactorial and although observational studies supported the association, the causative relationship between these two diseases is not yet established. Polymicrobial infection-induced periodontal disease is postulated to accelerate atherosclerotic plaque growth by enhancing atherosclerotic risk factors of orally infected Apolipoprotein E deficient (ApoE(null)) mice. At 16 weeks of infection, samples of blood, mandible, maxilla, aorta, heart, spleen, and liver were collected, analyzed for bacterial genomic DNA, immune response, inflammation, alveolar bone loss, serum inflammatory marker, atherosclerosis risk factors, and aortic atherosclerosis. PCR analysis of polymicrobial-infected (Porphyromonas gingivalis [P. gingivalis], Treponema denticola [T. denticola], and Tannerella forsythia [T. forsythia]) mice resulted in detection of bacterial genomic DNA in oral plaque samples indicating colonization of the oral cavity by all three species. Fluorescent in situ hybridization detected P. gingivalis and T. denticola within gingival tissues of infected mice and morphometric analysis showed an increase in palatal alveolar bone loss (p<0.0001) and intrabony defects suggesting development of periodontal disease in this model. Polymicrobial infected mice also showed an increase in aortic plaque area (p<0.05) with macrophage accumulation, enhanced serum amyloid A, and increased serum cholesterol and triglycerides. A systemic infection was indicated by the detection of bacterial genomic DNA in the aorta and liver of infected mice and elevated levels of bacterial specific IgG antibodies (p<0.0001). This study was a unique effort to understand the effects of a polymicrobial infection with P. gingivalis, T. denticola and T. forsythia on periodontal disease and associated atherosclerosis in ApoE(null) mice. PMID- 23451184 TI - Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes. AB - BACKGROUND: The relationship between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) in type 2 diabetes is currently unknown. We examined the relationship between NAFLD and risk of incident AF in people with type 2 diabetes. METHODS AND RESULTS: We prospectively followed for 10 years a random sample of 400 patients with type 2 diabetes, who were free from AF at baseline. A standard 12-lead electrocardiogram was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. At baseline, NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases. During the 10 years of follow-up, there were 42 (10.5%) incident AF cases. NAFLD was associated with an increased risk of incident AF (odds ratio [OR] 4.49, 95% CI 1.6-12.9, p<0.005). Adjustments for age, sex, hypertension and electrocardiographic features (left ventricular hypertrophy and PR interval) did not attenuate the association between NAFLD and incident AF (adjusted-OR 6.38, 95% CI 1.7-24.2, p = 0.005). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Other independent predictors of AF were older age, longer PR interval and left ventricular hypertrophy. CONCLUSIONS: Our results indicate that ultrasound-diagnosed NAFLD is strongly associated with an increased incidence of AF in patients with type 2 diabetes even after adjustment for important clinical risk factors for AF. PMID- 23451183 TI - Elevated serum levels of macrophage migration inhibitory factor are associated with progressive chronic cardiomyopathy in patients with Chagas disease. AB - Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression.Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-alpha and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients. PMID- 23451185 TI - Changes in expression of manganese superoxide dismutase, copper and zinc superoxide dismutase and catalase in Brachionus calyciflorus during the aging process. AB - Rotifers are useful model organisms for aging research, owing to their small body size (0.1-1 mm), short lifespan (6-14 days) and the relative easy in which aging and senescence phenotypes can be measured. Recent studies have shown that antioxidants can extend the lifespan of rotifers. In this paper, we analyzed changes in the mRNA expression level of genes encoding the antioxidants manganese superoxide dismutase (MnSOD), copper and zinc SOD (CuZnSOD) and catalase (CAT) during rotifer aging to clarify the function of these enzymes in this process. We also investigated the effects of common life-prolonging methods [dietary restriction (DR) and resveratrol] on the mRNA expression level of these genes. The results showed that the mRNA expression level of MnSOD decreased with aging, whereas that of CuZnSOD increased. The mRNA expression of CAT did not change significantly. This suggests that the ability to eliminate reactive oxygen species (ROS) in the mitochondria reduces with aging, thus aggravating the damaging effect of ROS on the mitochondria. DR significantly increased the mRNA expression level of MnSOD, CuZnSOD and CAT, which might explain why DR is able to extend rotifer lifespan. Although resveratrol also increased the mRNA expression level of MnSOD, it had significant inhibitory effects on the mRNA expression of CuZnSOD and CAT. In short, mRNA expression levels of CAT, MnSOD and CuZnSOD are likely to reflect the ability of mitochondria to eliminate ROS and delay the aging process. PMID- 23451186 TI - Expression of fungal cutinase and swollenin in tobacco chloroplasts reveals novel enzyme functions and/or substrates. AB - In order to produce low-cost biomass hydrolyzing enzymes, transplastomic lines were generated that expressed cutinase or swollenin within chloroplasts. While swollenin expressing plants were homoplasmic, cutinase transplastomic lines remained heteroplasmic. Both transplastomic lines showed interesting modifications in their phenotype, chloroplast structure, and functions. Ultrastructural analysis of chloroplasts from cutinase- and swollenin-expressing plants did not show typical lens shape and granal stacks. But, their thylakoid membranes showed unique scroll like structures and chloroplast envelope displayed protrusions, stretching into the cytoplasm. Unusual honeycomb structures typically observed in etioplasts were observed in mature chloroplasts expressing swollenin. Treatment of cotton fiber with chloroplast-derived swollenin showed enlarged segments and the intertwined inner fibers were irreversibly unwound and fully opened up due to expansin activity of swollenin, causing disruption of hydrogen bonds in cellulose fibers. Cutinase transplastomic plants showed esterase and lipase activity, while swollenin transplastomic lines lacked such enzyme activities. Higher plants contain two major galactolipids, monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG), in their chloroplast thylakoid membranes that play distinct roles in their structural organization. Surprisingly, purified cutinase effectively hydrolyzed DGDG to MGDG, showing alpha galactosidase activity. Such hydrolysis resulted in unstacking of granal thylakoids in chloroplasts and other structural changes. These results demonstrate DGDG as novel substrate and function for cutinase. Both MGDG and DGDG were reduced up to 47.7% and 39.7% in cutinase and 68.5% and 67.5% in swollenin expressing plants. Novel properties and functions of both enzymes reported here for the first time should lead to better understanding and enhanced biomass hydrolysis. PMID- 23451187 TI - P-selectin glycoprotein ligand-1 forms dimeric interactions with E-selectin but monomeric interactions with L-selectin on cell surfaces. AB - Interactions of selectins with cell surface glycoconjugates mediate the first step of the adhesion and signaling cascade that recruits circulating leukocytes to sites of infection or injury. P-selectin dimerizes on the surface of endothelial cells and forms dimeric bonds with P-selectin glycoprotein ligand-1 (PSGL-1), a homodimeric sialomucin on leukocytes. It is not known whether leukocyte L-selectin or endothelial cell E-selectin are monomeric or oligomeric. Here we used the micropipette technique to analyze two-dimensional binding of monomeric or dimeric L- and E-selectin with monomeric or dimeric PSGL-1. Adhesion frequency analysis demonstrated that E-selectin on human aortic endothelial cells supported dimeric interactions with dimeric PSGL-1 and monomeric interactions with monomeric PSGL-1. In contrast, L-selectin on human neutrophils supported monomeric interactions with dimeric or monomeric PSGL-1. Our work provides a new method to analyze oligomeric cross-junctional molecular binding at the interface of two interacting cells. PMID- 23451188 TI - Acceptability of HPV vaccines and associations with perceptions related to HPV and HPV vaccines among men who have sex with men in Hong Kong. AB - HPV vaccines are available to men but there are few studies investigating the acceptability of HPV vaccines among men who have sex with men (MSM), a high risk group. We assessed the intention to take up HPV vaccines among MSM in Hong Kong and the associated factors related to cognitions on HPV and HPV vaccines, basing on the Health Belief Model (n = 542). The acceptability of HPV vaccines was 20% (unconditional on efficacies and price), 29.2% (conditional on efficacies and market price), 51.7% (conditional on efficacies and discounted price) and 79.1% (conditional on efficacies and free price). Adjusting for background variables, composite scores of perceived susceptibility, perceived severity, perceived barriers and cue to actions were significantly associated with acceptability of HPV vaccines conditional on specific efficacies and the market price. Acceptability of HPV vaccines was highly price sensitive. Future studies need to use conditional measures. Implementation and translational researches are warranted. PMID- 23451189 TI - Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-kappaB and Src protein kinase signaling pathways. AB - OBJECTIVE: Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells. METHODS: Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins. RESULTS: The individual IC50 of curcumin and 5-FU were approximately 20 uM and 5 uM in HCT116 cells and 5 uM and 1 uM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 uM and 1 uM in HCT116 and 5 uM and 0.1 uM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-kappaB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation. CONCLUSIONS: Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-kappaB/PI-3K/Src pathways and NF kappaB regulated gene products. PMID- 23451190 TI - Unlocking the genetic diversity of maize landraces with doubled haploids opens new avenues for breeding. AB - Landraces are valuable genetic resources for broadening the genetic base of elite germplasm in maize. Extensive exploitation of landraces has been hampered by their genetic heterogeneity and heavy genetic load. These limitations may be overcome by the in-vivo doubled haploid (DH) technique. A set of 132 DH lines derived from three European landraces and 106 elite flint (EF) lines were genotyped for 56,110 single nucleotide polymorphism (SNP) markers and evaluated in field trials at five locations in Germany in 2010 for several agronomic traits. In addition, the landraces were compared with synthetic populations produced by intermating DH lines derived from the respective landrace. Our objectives were to (1) evaluate the phenotypic and molecular diversity captured within DH lines derived from European landraces, (2) assess the breeding potential (usefulness) of DH lines derived from landraces to broaden the genetic base of the EF germplasm, and (3) compare the performance of each landrace with the synthetic population produced from the respective DH lines. Large genotypic variances among DH lines derived from landraces allowed the identification of DH lines with grain yields comparable to those of EF lines. Selected DH lines may thus be introgressed into elite germplasm without impairing its yield level. Large genetic distances of the DH lines to the EF lines demonstrated the potential of DH lines derived from landraces to broaden the genetic base of the EF germplasm. The comparison of landraces with their respective synthetic population showed no yield improvement and no reduction of phenotypic diversity. Owing to the low population structure and rapid decrease of linkage disequilibrium within populations of DH lines derived from landraces, these would be an ideal tool for association mapping. Altogether, the DH technology opens new opportunities for characterizing and utilizing the genetic diversity present in gene bank accessions of maize. PMID- 23451191 TI - Efficient methods for targeted mutagenesis in zebrafish using zinc-finger nucleases: data from targeting of nine genes using CompoZr or CoDA ZFNs. AB - Recently, it has been shown that targeted mutagenesis using zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) can be used to generate knockout zebrafish lines for analysis of their function and/or developing disease models. A number of different methods have been developed for the design and assembly of gene-specific ZFNs and TALENs, making them easily available to most zebrafish researchers. Regardless of the choice of targeting nuclease, the process of generating mutant fish is similar. It is a time consuming and multi-step process that can benefit significantly from development of efficient high throughput methods. In this study, we used ZFNs assembled through either the CompoZr (Sigma-Aldrich) or the CoDA (context-dependent assembly) platforms to generate mutant zebrafish for nine genes. We report our improved high throughput methods for 1) evaluation of ZFNs activity by somatic lesion analysis using colony PCR, eliminating the need for plasmid DNA extractions from a large number of clones, and 2) a sensitive founder screening strategy using fluorescent PCR with PIG-tailed primers that eliminates the stutter bands and accurately identifies even single nucleotide insertions and deletions. Using these protocols, we have generated multiple mutant alleles for seven genes, five of which were targeted with CompoZr ZFNs and two with CoDA ZFNs. Our data also revealed that at least five-fold higher mRNA dose was required to achieve mutagenesis with CoDA ZFNs than with CompoZr ZFNs, and their somatic lesion frequency was lower (<5%) when compared to CopmoZr ZFNs (9-98%). This work provides high throughput protocols for efficient generation of zebrafish mutants using ZFNs and TALENs. PMID- 23451192 TI - Fine-needle aspirates CYFRA 21-1 is a useful tumor marker for detecting axillary lymph node metastasis in breast cancer patients. AB - INTRODUCTION: To assess whether the value of CYFRA21-1 in the aspirates of ultrasonography-guided fine-needle aspiration biopsy (US-FNAB) can contribute to improving the performances of US-FNAB in the diagnosis of axillary lymph node (LN) metastasis in breast cancer patients. METHODS: US-FNAB was performed in 156 axillary LNs in 152 breast cancer patients (mean age: 51.4 years, range: 17-92 years). Concentrations of CYFRA21-1 were measured from washouts of the syringe used during US-FNAB. Tumor marker concentrations, US-FNAB, intraoperative sentinel node biopsy (SNB), and surgical pathology results were reviewed and analyzed. For comparison, the values of CEA and CA15-3 were also measured from washouts. RESULTS: Among the 156 LNs, 75 (48.1%) were benign, and 81 (51.9%) were metastases. Mean concentrations of CYFRA21-1 were significantly higher in metastasis compared to benign LNs (P<0.001). US-FNAB combined to CYFRA21-1 showed significantly higher sensitivity, NPV, and accuracy compared to US-FNAB alone (all values P<0.05). All diagnostic indices of US-FNAB combined to CYFRA21-1 were significantly higher compared to US-FNAB combined with CEA or CA15-3 (all P<0.001). Of the 28 metastatic LNs which showed metastasis on SNB, CYFRA21-1 showed higher positive rate of 75.0% (CEA or CA15-3?60.7%, P = 0.076). CONCLUSION: Measuring CYFRA 21-1 concentrations from US-FNAB aspirates improves sensitivity, NPV, and accuracy of US-FNAB alone, and may contribute to reducing up to 75.0% of unnecessary intraoperative SNB. Compared to CEA or CA15-3, CYFRA21 1 shows significantly higher performances when combined to US-FNAB in the preoperative diagnosis of LN metastasis in breast cancer patients. PMID- 23451193 TI - Prevalence of HIV, syphilis, HCV and their high risk behaviors among migrant workers in eastern China. AB - OBJECTIVE: The goal of this study was to understand the knowledge about AIDS, identify the correlates and determine the prevalence of HIV infection, syphilis, HCV among migrant workers in Zhejiang, China. METHODS: A cross-sectional study using face-to-face anonymous questionnaire interviews was conducted and blood samples were collected for HIV, syphilis and Hepatitis C infection screening. RESULTS: 17,377 (92.8%) of 18,730 migrant workers approached were interviewed. Among 17,377 participants, the HIV/AIDS knowledge rate was 66.2%. A total of 12,694 (73%) of the participants reported having ever had sexual intercourse, with 30.1% of single participants reporting having had sexual intercourse. Among those respondents with sexual experiences, 7.5% admitted they had two or more sexual partners and 4.9% reported having had sex with casual (unpaid) partners in the previous 12 months, whilst 3.7% had paid for sex. More than half of those who had paid for sex (59.4%) had not used a condom every time in their sexual acts with the sex workers. Multiple logistic regression analysis indicated that high risk sexual behavior (defined as sex with a casual or commercial sex partner without using a condom consistently) was associated with being divorced or widowed (P<0.05 for single); male gender; shorter duration of stay in Zhejiang; working in factory, market or domestic service (P<0.05 for odd job); having a province of origin inside Zhejiang; and drug use. The prevalence of HIV and HCV infections were 0.02% (95% CI: 0.01%-0.06%) and 0.40% (95%CI: 0.31%-0.51%), respectively. The prevalence of syphilis among those who were sexually active was 0.55% (95% CI: 0.43%-0.70%). Risk factors for syphilis included shorter duration of stay in Zhejiang, ethnic minority status, being divorced or widowed and having had multiple sex partners. CONCLUSIONS: Much greater efforts are needed to promote safer sex, and programs for the control of syphilis need to be tailored for migrant workers in China. PMID- 23451194 TI - Sudden collapse of vacuoles in Saintpaulia sp. palisade cells induced by a rapid temperature decrease. AB - It is well known that saintpaulia leaf is damaged by the rapid temperature decrease when cold water is irrigated onto the leaf surface. We investigated this temperature sensitivity and the mechanisms of leaf damage in saintpaulia (Saintpaulia sp. cv. 'Iceberg') and other Gesneriaceae plants. Saintpaulia leaves were damaged and discolored when subjected to a rapid decrease in temperature, but not when the temperature was decreased gradually. Sensitivity to rapid temperature decrease increased within 10 to 20 min during pre-incubation at higher temperature. Injury was restricted to the palisade mesophyll cells, where there was an obvious change in the color of the chloroplasts. During a rapid temperature decrease, chlorophyll fluorescence monitored by a pulse amplitude modulated fluorometer diminished and did not recover even after rewarming to the initial temperature. Isolated chloroplasts were not directly affected by the rapid temperature decrease. Intracellular pH was monitored with a pH-dependent fluorescent dye. In palisade mesophyll cells damaged by rapid temperature decrease, the cytosolic pH decreased and the vacuolar membrane collapsed soon after a temperature decrease. In isolated chloroplasts, chlorophyll fluorescence declined when the pH of the medium was lowered. These results suggest that a rapid temperature decrease directly or indirectly affects the vacuolar membrane, resulting in a pH change in the cytosol that subsequently affects the chloroplasts in palisade mesophyll cells. We further confirmed that the same physiological damage occurs in other Gesneriaceae plants. These results strongly suggested that the vacuoles of palisade mesophyll cells collapsed during the initial phase of leaf injury. PMID- 23451195 TI - Liver-targeting of interferon-alpha with tissue-specific domain antibodies. AB - Interferon alpha (IFNalpha) is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNalpha therapy. We genetically fused IFN to a domain antibody (dAb) specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR). Our results show that the murine IFNalpha2 homolog (mIFNalpha2) fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNalpha2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNalpha2 or mIFNalpha2 fused to an isotype control dAb VHD2 (which does not bind ASGPR) was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections. PMID- 23451196 TI - Cell volume regulation in cultured human retinal Muller cells is associated with changes in transmembrane potential. AB - Muller cells are mainly involved in controlling extracellular homeostasis in the retina, where intense neural activity alters ion concentrations and osmotic gradients, thus favoring cell swelling. This increase in cell volume is followed by a regulatory volume decrease response (RVD), which is known to be partially mediated by the activation of K(+) and anion channels. However, the precise mechanisms underlying osmotic swelling and subsequent cell volume regulation in Muller cells have been evaluated by only a few studies. Although the activation of ion channels during the RVD response may alter transmembrane potential (Vm), no studies have actually addressed this issue in Muller cells. The aim of the present work is to evaluate RVD using a retinal Muller cell line (MIO-M1) under different extracellular ionic conditions, and to study a possible association between RVD and changes in Vm. Cell volume and Vm changes were evaluated using fluorescent probe techniques and a mathematical model. Results show that cell swelling and subsequent RVD were accompanied by Vm depolarization followed by repolarization. This response depended on the composition of extracellular media. Cells exposed to a hypoosmotic solution with reduced ionic strength underwent maximum RVD and had a larger repolarization. Both of these responses were reduced by K(+) or Cl(-) channel blockers. In contrast, cells facing a hypoosmotic solution with the same ionic strength as the isoosmotic solution showed a lower RVD and a smaller repolarization and were not affected by blockers. Together, experimental and simulated data led us to propose that the efficiency of the RVD process in Muller glia depends not only on the activation of ion channels, but is also strongly modulated by concurrent changes in the membrane potential. The relationship between ionic fluxes, changes in ion permeabilities and ion concentrations -all leading to changes in Vm- define the success of RVD. PMID- 23451197 TI - Genes ycfR, sirA and yigG contribute to the surface attachment of Salmonella enterica Typhimurium and Saintpaul to fresh produce. AB - Salmonella enterica is a frequent contaminant of minimally-processed fresh produce linked to major foodborne disease outbreaks. The molecular mechanisms underlying the association of this enteric pathogen with fresh produce remain largely unexplored. In our recent study, we showed that the expression of a putative stress regulatory gene, ycfR, was significantly induced in S. enterica upon exposure to chlorine treatment, a common industrial practice for washing and decontaminating fresh produce during minimal processing. Two additional genes, sirA involved in S. enterica biofilm formation and yigG of unknown function, were also found to be differentially regulated under chlorine stress. To further characterize the roles of ycfR, sirA, and yigG in S. enterica attachment and survival on fresh produce, we constructed in-frame deletions of all three genes in two different S. enterica serovars, Typhimurium and Saintpaul, which have been implicated in previous disease outbreaks linked to fresh produce. Bacterial attachment to glass and polystyrene microtiter plates, cell aggregation and hydrophobicity, chlorine resistance, and surface attachment to intact spinach leaf and grape tomato were compared among wild-type strains, single-gene deletion mutants, and their respective complementation mutants. The results showed that deletions of ycfR, sirA, and yigG reduced bacterial attachment to glass and polystyrene as well as fresh produce surface with or without chlorine treatment in both Typhimurium and Saintpaul. Deletion of ycfR in Typhimurium significantly reduced bacterial chlorine resistance and the attachment to the plant surfaces after chlorinated water washes. Deletions of ycfR in Typhimurium and yigG in Saintpaul resulted in significant increase in cell aggregation. Our findings suggest that ycfR, sirA, and yigG collectively contribute to S. enterica surface attachment and survival during post-harvest minimal processing of fresh produce. PMID- 23451198 TI - Involvement of ERK phosphorylation of trigeminal spinal subnucleus caudalis neurons in thermal hypersensitivity in rats with infraorbital nerve injury. AB - To evaluate the involvement of the mitogen-activated protein kinase (MAPK) cascade in orofacial neuropathic pain mechanisms, this study assessed nocifensive behavior evoked by mechanical or thermal stimulation of the whisker pad skin, phosphorylation of extracellular signal-regulated kinase (ERK) in trigeminal spinal subnucleus caudalis (Vc) neurons, and Vc neuronal responses to mechanical or thermal stimulation of the whisker pad skin in rats with the chronic constriction nerve injury of the infraorbital nerve (ION-CCI). The mechanical and thermal nocifensive behavior was significantly enhanced on the side ipsilateral to the ION-CCI compared to the contralateral whisker pad or sham rats. ION-CCI rats had an increased number of phosphorylated ERK immunoreactive (pERK-IR) cells which also manifested NeuN-IR but not GFAP-IR and Iba1-IR, and were significantly more in ION-CCI rats compared with sham rats following noxious but not non noxious mechanical stimulation. After intrathecal administration of the MEK1 inhibitor PD98059 in ION-CCI rats, the number of pERK-IR cells after noxious stimulation and the enhanced thermal nocifensive behavior but not the mechanical nocifensive behavior were significantly reduced in ION-CCI rats. The enhanced background activities, afterdischarges and responses of wide dynamic range neurons to noxious mechanical and thermal stimulation in ION-CCI rats were significantly depressed following i.t. administration of PD98059, whereas responses to non-noxious mechanical and thermal stimulation were not altered. The present findings suggest that pERK-IR neurons in the Vc play a pivotal role in the development of thermal hypersensitivity in the face following trigeminal nerve injury. PMID- 23451199 TI - Functional investigation of the plant-specific long coiled-coil proteins PAMP INDUCED COILED-COIL (PICC) and PICC-LIKE (PICL) in Arabidopsis thaliana. AB - We have identified and characterized two Arabidopsis long coiled-coil proteins PAMP-INDUCED COILED-COIL (PICC) and PICC-LIKE (PICL). PICC (147 kDa) and PICL (87 kDa) are paralogs that consist predominantly of a long coiled-coil domain (expanded in PICC), with a predicted transmembrane domain at the immediate C terminus. Orthologs of PICC and PICL were found exclusively in vascular plants. PICC and PICL GFP fusion proteins are anchored to the cytoplasmic surface of the endoplasmic reticulum (ER) membrane by a C-terminal transmembrane domain and a short tail domain, via a tail-anchoring mechanism. T-DNA-insertion mutants of PICC and PICL as well as the double mutant show an increased sensitivity to the plant abiotic stress hormone abscisic acid (ABA) in a post-germination growth response. PICC, but not PICL gene expression is induced by the bacterial pathogen associated molecular pattern (PAMP) flg22. T-DNA insertion alleles of PICC, but not PICL, show increased susceptibility to the non-virulent strain P. syringae pv. tomato DC3000 hrcC, but not to the virulent strain P. syringae pv. tomato DC3000. This suggests that PICC mutants are compromised in PAMP-triggered immunity (PTI). The data presented here provide first evidence for the involvement of a plant long coiled-coil protein in a plant defense response. PMID- 23451200 TI - Cellular targets of nitric oxide in the hippocampus. AB - In the hippocampus, as in many other CNS areas, nitric oxide (NO) participates in synaptic plasticity, manifested as changes in pre- and/or postsynaptic function. While it is known that these changes are brought about by cGMP following activation of guanylyl cyclase-coupled NO receptors attempts to locate cGMP by immunocytochemistry in hippocampal slices in response to NO have failed to detect the cGMP elevation where expected, i.e. in the pyramidal neurones. Instead, astrocytes, unidentified varicose fibres and GABA-ergic nerve terminals are reported to be the prominent NO targets, raising the possibility that NO acts indirectly via other cells. We have re-investigated the distribution of cGMP generated in response to endogenous and exogenous NO in hippocampal slices using immunohistochemistry and new conditions designed to optimise cGMP accumulation and, hence, its detectability. The conditions included use of tissue from the developing rat hippocampus, a potent inhibitor of phosphodiesterase-2, and an allosteric enhancer of the NO-receptive guanylyl cyclase. Under these conditions, cGMP was formed in response to endogenous NO and was found in a population of pyramidal cell somata in area CA3 and subiculum as well as in structures described previously. The additional presence of exogenous NO resulted in hippocampal cGMP reaching the highest level recorded for brain tissue (1700 pmol/mg protein) and in cGMP immunolabelling throughout the pyramidal cell layer. Populations of axons and interneurones were also stained. According with these results, immunohistochemistry for the common NO receptor beta1-subunit indicated widespread expression. A similar staining pattern for the alpha1-subunit with an antibody used previously in the hippocampus and elsewhere, however, proved to be artefactual. The results indicate that the targets of NO in the hippocampus are more varied and extensive than previous evidence had suggested and, in particular, that the pyramidal neurones participating in NO-dependent synaptic plasticity are direct NO targets. PMID- 23451201 TI - EEG source reconstruction reveals frontal-parietal dynamics of spatial conflict processing. AB - Cognitive control requires the suppression of distracting information in order to focus on task-relevant information. We applied EEG source reconstruction via time frequency linear constrained minimum variance beamforming to help elucidate the neural mechanisms involved in spatial conflict processing. Human subjects performed a Simon task, in which conflict was induced by incongruence between spatial location and response hand. We found an early (~200 ms post-stimulus) conflict modulation in stimulus-contralateral parietal gamma (30-50 Hz), followed by a later alpha-band (8-12 Hz) conflict modulation, suggesting an early detection of spatial conflict and inhibition of spatial location processing. Inter-regional connectivity analyses assessed via cross-frequency coupling of theta (4-8 Hz), alpha, and gamma power revealed conflict-induced shifts in cortical network interactions: Congruent trials (relative to incongruent trials) had stronger coupling between frontal theta and stimulus-contrahemifield parietal alpha/gamma power, whereas incongruent trials had increased theta coupling between medial frontal and lateral frontal regions. These findings shed new light into the large-scale network dynamics of spatial conflict processing, and how those networks are shaped by oscillatory interactions. PMID- 23451202 TI - Foam cell specific LXRalpha ligand. AB - OBJECTIVE: The liver X receptor alpha (LXRalpha) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis. METHODS AND RESULTS: We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRalpha reporter-gene assays. STX4 displayed the unique property to activate LXRalpha effectively but not its subtype LXRbeta. The potential of STX4 to increase transcriptional activity as an LXRalpha ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09. CONCLUSIONS: STX4 is a new LXRalpha-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development. PMID- 23451203 TI - A megafauna's microfauna: gastrointestinal parasites of New Zealand's extinct moa (Aves: Dinornithiformes). AB - WE PERFORM THE FIRST MULTIDISCIPLINARY STUDY OF PARASITES FROM AN EXTINCT MEGAFAUNAL CLADE USING COPROLITES FROM THE NEW ZEALAND MOA (AVES: Dinornithiformes). Ancient DNA and microscopic analyses of 84 coprolites deposited by four moa species (South Island giant moa, Dinornis robustus; little bush moa, Anomalopteryx didiformis; heavy-footed moa, Pachyornis elephantopus; and upland moa, Megalapteryx didinus) reveal an array of gastrointestinal parasites including coccidians (Cryptosporidium and members of the suborder Eimeriorina), nematodes (Heterakoidea, Trichostrongylidae, Trichinellidae) and a trematode (Echinostomida). Parasite eggs were most prevalent and diverse in coprolites from lowland sites, where multiple sympatric moa species occurred and host density was therefore probably higher. Morphological and phylogenetic evidence supports a possible vicariant Gondwanan origin for some of the moa parasites. The discovery of apparently host-specific parasite taxa suggests paleoparasitological studies of megafauna coprolites may provide useful case studies of coextinction. PMID- 23451204 TI - Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. AB - The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders. PMID- 23451205 TI - Individual differences in the recognition of facial expressions: an event-related potentials study. AB - Previous studies have shown that early posterior components of event-related potentials (ERPs) are modulated by facial expressions. The goal of the current study was to investigate individual differences in the recognition of facial expressions by examining the relationship between ERP components and the discrimination of facial expressions. Pictures of 3 facial expressions (angry, happy, and neutral) were presented to 36 young adults during ERP recording. Participants were asked to respond with a button press as soon as they recognized the expression depicted. A multiple regression analysis, where ERP components were set as predictor variables, assessed hits and reaction times in response to the facial expressions as dependent variables. The N170 amplitudes significantly predicted for accuracy of angry and happy expressions, and the N170 latencies were predictive for accuracy of neutral expressions. The P2 amplitudes significantly predicted reaction time. The P2 latencies significantly predicted reaction times only for neutral faces. These results suggest that individual differences in the recognition of facial expressions emerge from early components in visual processing. PMID- 23451206 TI - Genome wide mapping reveals PDE4B as an IL-2 induced STAT5 target gene in activated human PBMCs and lymphoid cancer cells. AB - IL-2 is the primary growth factor for promoting survival and proliferation of activated T cells that occurs following engagement of the Janus Kinase (JAK)1 3/and Signal Transducer and Activator of Transcription (STAT) 5 signaling pathway. STAT5 has two isoforms: STAT5A and STAT5B (commonly referred to as STAT5) which, in T cells, play redundant roles transcribing cell cycle and survival genes. As such, inhibition of STAT5 by a variety of mechanisms can rapidly induce apoptosis in certain lymphoid tumor cells, suggesting that it and its target genes represent therapeutic targets to control certain lymphoid diseases. To search for these molecules we aligned IL-2 regulated genes detected by Affymetrix gene expression microarrays with the STAT5 cistrome identified by chip-on-ChIP analysis in an IL-2-dependent human leukemia cell line, Kit225. Select overlapping genes were then validated using qRT(2)PCR medium-throughput arrays in human PHA-activated PBMCs. Of 19 putative genes, one key regulator of T cell receptor signaling, PDE4B, was identified as a novel target, which was readily up-regulated at the protein level (3 h) in IL-2 stimulated, activated human PBMCs. Surprisingly, only purified CD8+ primary T-cells expressed PDE4B, but not CD4+ cells. Moreover, PDE4B was found to be highly expressed in CD4+ lymphoid cancer cells, which suggests that it may represent a physiological role unique to the CD8+ and lymphoid cancer cells and thus might represent a target for pharmaceutical intervention for certain lymphoid diseases. PMID- 23451207 TI - Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8). AB - We have identified the zinc-finger transcription factor Kruppel-like factor 4 (Klf4) among the transcription factors that are significantly downregulated in their expression during epithelial-mesenchymal transition (EMT) in mammary epithelial cells and in breast cancer cells. Loss and gain of function experiments demonstrate that the down-regulation of Klf4 expression is required for the induction of EMT in vitro and for metastasis in vivo. In addition, reduced Klf4 expression correlates with shorter disease-free survival of subsets of breast cancer patients. Yet, reduced expression of Klf4 also induces apoptosis in cells undergoing TGFbeta-induced EMT. Chromatin immunoprecipitation/deep sequencing in combination with gene expression profiling reveals direct Klf4 target genes, including E-cadherin (Cdh1), N-cadherin (Cdh2), vimentin (Vim), beta-catenin (Ctnnb1), VEGF-A (Vegfa), endothelin-1 (Edn1) and Jnk1 (Mapk8). Thereby, Klf4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. Specifically, increased expression of Jnk1 (Mapk8) upon down-regulation of its transcriptional repressor Klf4 is required for EMT cell migration and for the induction of apoptosis. The data demonstrate a central role of Klf4 in the maintenance of epithelial cell differentiation and the prevention of EMT and metastasis. PMID- 23451208 TI - Design maps for the hyperthermic treatment of tumors with superparamagnetic nanoparticles. AB - A plethora of magnetic nanoparticles has been developed and investigated under different alternating magnetic fields (AMF) for the hyperthermic treatment of malignant tissues. Yet, clinical applications of magnetic hyperthermia are sporadic, mostly due to the low energy conversion efficiency of the metallic nanoparticles and the high tissue concentrations required. Here, we study the hyperthermic performance of commercially available formulations of superparamagnetic iron oxide nanoparticles (SPIOs), with core diameter of 5, 7 and 14 nm, in terms of absolute temperature increase DeltaT and specific absorption rate (SAR). These nanoparticles are operated under a broad range of AMF conditions, with frequency f varying between 0.2 and 30 MHz; field strength H ranging from 4 to 10 kA m(-1); and concentration cMNP varying from 0.02 to 3.5 mg ml(-1). At high frequency field (~30 MHz), non specific heating dominates and DeltaT correlates with the electrical conductivity of the medium. At low frequency field (<1 MHz), non specific heating is negligible and the relaxation of the SPIO within the AMF is the sole energy source. We show that the DeltaT of the medium grows linearly with cMNP , whereas the SARMNP of the magnetic nanoparticles is independent of cMNP and varies linearly with f and H(2) . Using a computational model for heat transport in a biological tissue, the minimum requirements for local hyperthermia (Ttissue >42 degrees C) and thermal ablation (Ttissue >50 degrees C) are derived in terms of cMNP , operating AMF conditions and blood perfusion. The resulting maps can be used to rationally design hyperthermic treatments and identifying the proper route of administration - systemic versus intratumor injection - depending on the magnetic and biodistribution properties of the nanoparticles. PMID- 23451209 TI - European Phaseolus coccineus L. landraces: population structure and adaptation, as revealed by cpSSRs and phenotypic analyses. AB - Relatively few studies have extensively analysed the genetic diversity of the runner bean through molecular markers. Here, we used six chloroplast microsatellites (cpSSRs) to investigate the cytoplasmic diversity of 331 European domesticated accessions of the scarlet runner bean (Phaseolus coccineus L.), including the botanical varieties albiflorus, bicolor and coccineus, and a sample of 49 domesticated and wild accessions from Mesoamerica. We further explored the pattern of diversity of the European landraces using 12 phenotypic traits on 262 individuals. For 158 European accessions, we studied the relationships between cpSSR polymorphisms and phenotypic traits. Additionally, to gain insights into the role of gene flow and migration, for a subset of 115 accessions, we compared and contrasted the results obtained by cpSSRs and phenotypic traits with those obtained in a previous study with 12 nuclear microsatellites (nuSSRs). Our results suggest that both demographic and selective factors have roles in the shaping of the population genetic structure of the European runner bean. In particular, we infer the existence of a moderate-to-strong cytoplasmic bottleneck that followed the expansion of the crop into Europe, and we deduce multiple domestication events for this species. We also observe an adaptive population differentiation in the phenology across a latitudinal gradient, which suggests that selection led to the diversification of the runner bean in Europe. The botanical varieties albiflorus, bicolor and coccineus, which are based solely on flower colour, cannot be distinguished based on these cpSSRs and nuSSRs, nor according to the 12 quantitative traits. PMID- 23451210 TI - Modulation in Wistar rats of blood corticosterone compartmentation by sex and a cafeteria diet. AB - In the metabolic syndrome, glucocorticoid activity is increased, but circulating levels show little change. Most of blood glucocorticoids are bound to corticosteroid-binding globulin (CBG), which liver expression and circulating levels are higher in females than in males. Since blood hormones are also bound to blood cells, and the size of this compartment is considerable for androgens and estrogens, we analyzed whether sex or eating a cafeteria diet altered the compartmentation of corticosterone in rat blood. The main corticosterone compartment in rat blood is that specifically bound to plasma proteins, with smaller compartments bound to blood cells or free. Cafeteria diet increased the expression of liver CBG gene, binding plasma capacity and the proportion of blood cell-bound corticosterone. There were marked sex differences in blood corticosterone compartmentation in rats, which were unrelated to testosterone. The use of a monoclonal antibody ELISA and a polyclonal Western blot for plasma CBG compared with both specific plasma binding of corticosterone and CBG gene expression suggested the existence of different forms of CBG, with varying affinities for corticosterone in males and females, since ELISA data showed higher plasma CBG for males, but binding and Western blot analyses (plus liver gene expression) and higher physiological effectiveness for females. Good cross reactivity to the antigen for polyclonal CBG antibody suggests that in all cases we were measuring CBG. The different immunoreactivity and binding affinity may help explain the marked sex-related differences in plasma hormone binding as sex linked different proportions of CBG forms. PMID- 23451211 TI - Bombesin analogue-mediated delivery preferentially enhances the cytotoxicity of a mitochondria-disrupting peptide in tumor cells. AB - Tumor-homing peptides that recognize specific markers on tumor cells have shown potential as drug carriers for targeted cancer therapy. Bombesin receptors are frequently overexpressed or ectopically expressed in a wide range of human tumors. Bombesin and its analogues have been widely used as drug carriers for tumor imaging and tumor therapy. However, the cargos used in previous studies, including radioactive and chemotherapeutic agents, are usually small molecules. Mitochondrial-disrupting peptides depolarize the mitochondria and trigger apoptosis after entering tumor cells. We are interested in whether the bombesin analogue, Bn(6-14), which contains a bombesin receptor-binding motif, can specifically deliver the mitochondria-disrupting peptide, B28, to tumor cells. To this end, we created a chimeric peptide, B28Bn(6-14), by conjugating B28 to Bn(6 14) at its N-terminus. The cytotoxicity of B28Bn(6-14) in tumor cells was much stronger than unconjugated B28. The IC50 values of B28Bn(6-14) in tumor cells (1.7-3.5 uM) were approximately 10 times lower than B28. However, conjugation of B28 to Bn(2-7), which lacks the bombesin receptor-binding motif, did not increase its cytotoxicity. In addition, the IC50 values of B28Bn(6-14) in tumor cells (1.7 3.5 uM) was 3-10 times lower than in normal cells (10.8-16.8 uM). We found that selective binding of B28Bn(6-14) to tumor cells is Bn(6-14)-dependent. Upon entering the tumor cell, B28Bn(6-14) accumulated in the mitochondria and triggered caspase-dependent apoptosis. Intratumoral and intraperitoneal administration of B28Bn(6-14) substantially suppressed the growth of DU145 tumor xenografts in mice. These results demonstrate that Bn(6-14) is able to deliver the mitochondria-disrupting peptide to tumor cells, and B28Bn(6-14) should be further developed as novel anti-cancer agent. PMID- 23451212 TI - Analysis of metal element distributions in rice (Oryza sativa L.) seeds and relocation during germination based on X-ray fluorescence imaging of Zn, Fe, K, Ca, and Mn. AB - Knowledge of mineral localization within rice grains is important for understanding the role of different elements in seed development, as well as for facilitating biofortification of seed micronutrients in order to enhance seeds' values in human diets. In this study, the concentrations of minerals in whole rice grains, hulls, brown rice, bran and polished rice were quantified by inductively coupled plasma mass spectroscopy. The in vivo mineral distribution patterns in rice grains and shifts in those distribution patterns during progressive stages of germination were analyzed by synchrotron X-ray microfluorescence. The results showed that half of the total Zn, two thirds of the total Fe, and most of the total K, Ca and Mn were removed by the milling process if the hull and bran were thoroughly polished. Concentrations of all elements were high in the embryo regions even though the local distributions within the embryo varied between elements. Mobilization of the minerals from specific seed locations during germination was also element-specific. High mobilization of K and Ca from grains to growing roots and leaf primordia was observed; the flux of Zn to these expanding tissues was somewhat less than that of K and Ca; the mobilization of Mn or Fe was relatively low, at least during the first few days of germination. PMID- 23451213 TI - A geometric morphometric approach to the analysis of lip shape during speech: development of a clinical outcome measure. AB - Objective assessments of lip movement can be beneficial in many disciplines including visual speech recognition, for surgical outcome assessment in patients with cleft lip and for the rehabilitation of patients with facial nerve impairments. The aim of this study was to develop an outcome measure for lip shape during speech using statistical shape analysis techniques. Lip movements during speech were captured from a sample of adult subjects considered as average using a three-dimensional motion capture system. Geometric Morphometrics was employed to extract three-dimensional coordinate data for lip shape during four spoken words decomposed into seven visemes (which included the resting lip shape). Canonical variate analysis was carried out in an attempt to statistically discriminate the seven visemes. The results showed that the second canonical variate discriminated the resting lip shape from articulation of the utterances and accounted for 17.2% of the total variance of the model. The first canonical variate was significant in discriminating between the utterances and accounted for 72.8% of the total variance of the model. The outcome measure was created using the 95% confidence intervals of the canonical variate scores for each subject plotted as ellipses for each viseme. The method and outcome model is proposed as reference to compare lip movement during speech in similar population groups. PMID- 23451214 TI - Application of massively parallel sequencing to genetic diagnosis in multiplex families with idiopathic sensorineural hearing impairment. AB - Despite the clinical utility of genetic diagnosis to address idiopathic sensorineural hearing impairment (SNHI), the current strategy for screening mutations via Sanger sequencing suffers from the limitation that only a limited number of DNA fragments associated with common deafness mutations can be genotyped. Consequently, a definitive genetic diagnosis cannot be achieved in many families with discernible family history. To investigate the diagnostic utility of massively parallel sequencing (MPS), we applied the MPS technique to 12 multiplex families with idiopathic SNHI in which common deafness mutations had previously been ruled out. NimbleGen sequence capture array was designed to target all protein coding sequences (CDSs) and 100 bp of the flanking sequence of 80 common deafness genes. We performed MPS on the Illumina HiSeq2000, and applied BWA, SAMtools, Picard, GATK, Variant Tools, ANNOVAR, and IGV for bioinformatics analyses. Initial data filtering with allele frequencies (<5% in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFT scores (>0.95) prioritized 5 indels (insertions/deletions) and 36 missense variants in the 12 multiplex families. After further validation by Sanger sequencing, segregation pattern, and evolutionary conservation of amino acid residues, we identified 4 variants in 4 different genes, which might lead to SNHI in 4 families compatible with autosomal dominant inheritance. These included GJB2 p.R75Q, MYO7A p.T381M, KCNQ4 p.S680F, and MYH9 p.E1256K. Among them, KCNQ4 p.S680F and MYH9 p.E1256K were novel. In conclusion, MPS allows genetic diagnosis in multiplex families with idiopathic SNHI by detecting mutations in relatively uncommon deafness genes. PMID- 23451215 TI - Dexamethasone attenuates VEGF expression and inflammation but not barrier dysfunction in a murine model of ventilator-induced lung injury. AB - BACKGROUND: Ventilator-induced lung injury (VILI) is characterized by vascular leakage and inflammatory responses eventually leading to pulmonary dysfunction. Vascular endothelial growth factor (VEGF) has been proposed to be involved in the pathogenesis of VILI. This study examines the inhibitory effect of dexamethasone on VEGF expression, inflammation and alveolar-capillary barrier dysfunction in an established murine model of VILI. METHODS: Healthy male C57Bl/6 mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with an inspiratory pressure of 10 cmH2O ("lower" tidal volumes of ~7.5 ml/kg; LVT) or 18 cmH2O ("higher" tidal volumes of ~15 ml/kg; HVT). Dexamethasone was intravenously administered at the initiation of HVT-ventilation. Non-ventilated mice served as controls. Study endpoints included VEGF and inflammatory mediator expression in lung tissue, neutrophil and protein levels in bronchoalveolar lavage fluid, PaO2 to FiO2 ratios and lung wet to dry ratios. RESULTS: Particularly HVT-ventilation led to alveolar-capillary barrier dysfunction as reflected by reduced PaO2 to FiO2 ratios, elevated alveolar protein levels and increased lung wet to dry ratios. Moreover, VILI was associated with enhanced VEGF production, inflammatory mediator expression and neutrophil infiltration. Dexamethasone treatment inhibited VEGF and pro-inflammatory response in lungs of HVT-ventilated mice, without improving alveolar-capillary permeability, gas exchange and pulmonary edema formation. CONCLUSIONS: Dexamethasone treatment completely abolishes ventilator-induced VEGF expression and inflammation. However, dexamethasone does not protect against alveolar-capillary barrier dysfunction in an established murine model of VILI. PMID- 23451216 TI - A minimal optical trapping and imaging microscopy system. AB - We report the construction and testing of a simple and versatile optical trapping apparatus, suitable for visualizing individual microtubules (~25 nm in diameter) and performing single-molecule studies, using a minimal set of components. This design is based on a conventional, inverted microscope, operating under plain bright field illumination. A single laser beam enables standard optical trapping and the measurement of molecular displacements and forces, whereas digital image processing affords real-time sample visualization with reduced noise and enhanced contrast. We have tested our trapping and imaging instrument by measuring the persistence length of individual double-stranded DNA molecules, and by following the stepping of single kinesin motor proteins along clearly imaged microtubules. The approach presented here provides a straightforward alternative for studies of biomaterials and individual biomolecules. PMID- 23451217 TI - New insights from the oyster Crassostrea rhizophorae on bivalve circulating hemocytes. AB - Hemocytes are the first line of defense of the immune system in invertebrates, but despite their important role and enormous potential for the study of gene environment relationships, research has been impeded by a lack of consensus on their classification. Here we used flow cytometry combined with histological procedures, histochemical reactions and transmission electron microscopy to characterize the hemocytes from the oyster Crassostrea rhizophorae. Transmission electron microscopy revealed remarkable morphological characteristics, such as the presence of membranous cisternae in all mature cells, regardless of size and granulation. Some granular cells contained many cytoplasmic granules that communicated with each other through a network of channels, a feature never previously described for hemocytes. The positive reactions for esterase and acid phosphatase also indicated the presence of mature cells of all sizes and granule contents. Flow cytometry revealed a clear separation in complexity between agranular and granular populations, which could not be differentiated by size, with cells ranging from 2.5 to 25 um. Based on this evidence we suggest that, at least in C. rhizophorae, the different subpopulations of hemocytes may in reality be different stages of one type of cell, which accumulates granules and loses complexity (with no reduction in size) as it degranulates in the event of an environmental challenge. PMID- 23451218 TI - Susceptibility to declarative memory interference is pronounced in primary insomnia. AB - Sleep has been shown to stabilize memory traces and to protect against competing interference in both the procedural and declarative memory domain. Here, we focused on an interference learning paradigm by testing patients with primary insomnia (N = 27) and healthy control subjects (N = 21). In two separate experimental nights with full polysomnography it was revealed that after morning interference procedural memory performance (using a finger tapping task) was not impaired in insomnia patients while declarative memory (word pair association) was decreased following interference. More specifically, we demonstrate robust associations of central sleep spindles (in N3) with motor memory susceptibility to interference as well as (cortically more widespread) fast spindle associations with declarative memory susceptibility. In general the results suggest that insufficient sleep quality does not necessarily show up in worse overnight consolidation in insomnia but may only become evident (in the declarative memory domain) when interference is imposed. PMID- 23451219 TI - Diabetes self-management and education of people living with diabetes: a survey in primary health care in Muscat Oman. AB - BACKGROUND: Although the prevalence of type 2 diabetes in Oman is high and rising, information on how people were self-managing their disease has been lacking. The objective of this study was therefore to assess diabetes self management and education (DSME) among people living with type 2 diabetes in Oman. METHODS: A questionnaire survey was conducted in public primary health care centres in Muscat. Diabetes self-management and education was assessed by asking how patients recognized and responded to hypo- and hyperglycaemia, and if they had developed strategies to maintain stable blood glucose levels. Patients' demographic information, self-treatment behaviours, awareness of potential long term complications, and attitudes concerning diabetes management were also recorded. Associations between these factors and diabetes self-management and education were analysed. RESULTS: In total, 309 patients were surveyed. A quarter (26%, n = 83) were unaware how to recognize hypoglycaemia or respond to it (26%, n = 81). Around half (49%, n = 151), could not recognize hyperglycaemia and more than half could not respond to it (60%, n = 184). Twelve percent (n = 37) of the patients did not have any strategies to stabilize their blood glucose levels. Patients with formal education generally had more diabetes self-management and education than those without (p<0.001), as had patients with longer durations of diabetes (p<0.01). Self-monitoring of blood glucose was practiced by 38% (n = 117) of the patients, and insulin was used by 22% (n = 67), of which about one third independently adjusted dosages. Patients were most often aware of complications concerning loss of vision, renal failure and cardiac problems. Many patients desired further health education. CONCLUSIONS: Many patients displayed dangerous diabetes self-management and education knowledge gaps. The findings suggest a need for improving knowledge transfer to people living with diabetes in the Omani clinical setting. PMID- 23451221 TI - Dynamic similarity in titanosaur sauropods: ichnological evidence from the Fumanya dinosaur tracksite (southern Pyrenees). AB - The study of a small sauropod trackway from the Late Cretaceous Fumanya tracksite (southern Pyrenees, Catalonia) and further comparisons with larger trackways from the same locality suggest a causative relationship between gait, gauge, and body proportions of the respective titanosaur trackmakers. This analysis, conducted in the context of scaling predictions and using geometric similarity and dynamic similarity hypotheses, reveals similar Froude numbers and relative stride lengths for both small and large trackmakers from Fumanya. Evidence for geometric similarity in these trackways suggests that titanosaurs of different sizes moved in a dynamically similar way, probably using an amble gait. The wide gauge condition reported in trackways of small and large titanosaurs implies that they possessed similar body (trunk and limbs) proportions despite large differences in body size. These results strengthen the hypothesis that titanosaurs possessed a distinctive suite of anatomical characteristics that are well reflected in their tracks and trackways. PMID- 23451220 TI - Mycobacterium abscessus induces a limited pattern of neutrophil activation that promotes pathogen survival. AB - Mycobacterium abscessus is a rapidly growing mycobacterium increasingly detected in the neutrophil-rich environment of inflamed tissues, including the cystic fibrosis airway. Studies of the immune reaction to M. abscessus have focused primarily on macrophages and epithelial cells, but little is known regarding the neutrophil response despite the predominantly neutrophillic inflammation typical of these infections. In the current study, human neutrophils released less superoxide anion in response to M. abscessus than to Staphylococcus aureus, a pathogen that shares common sites of infection. Exposure to M. abscessus induced neutrophil-specific chemokine and proinflammatory cytokine genes. Although secretion of these protein products was confirmed, the quantity of cytokines released, and both the number and level of gene induction, was reduced compared to S. aureus. Neutrophils mediated killing of M. abscessus, but phagocytosis was reduced when compared to S. aureus, and extracellular DNA was detected in response to both bacteria, consistent with extracellular trap formation. In addition, M. abscessus did not alter cell death compared to unstimulated cells, while S. aureus enhanced necrosis and inhibited apoptosis. However, neutrophils augment M. abscessus biofilm formation. The response of neutrophils to M. abscessus suggests that the mycobacterium exploits neutrophil-rich settings to promote its survival and that the overall neutrophil response was reduced compared to S. aureus. These studies add to our understanding of M. abscessus virulence and suggest potential targets of therapy. PMID- 23451222 TI - Dynamic biomechanical examination of the lumbar spine with implanted total spinal segment replacement (TSSR) utilizing a pendulum testing system. AB - BACKGROUND: Biomechanical investigations of spinal motion preserving implants help in the understanding of their in vivo behavior. In this study, we hypothesized that the lumbar spine with implanted total spinal segment replacement (TSSR) would exhibit decreased dynamic stiffness and more rapid energy absorption compared to native functional spinal units under simulated physiologic motion when tested with the pendulum system. METHODS: Five unembalmed, frozen human lumbar functional spinal units were tested on the pendulum system with axial compressive loads of 181 N, 282 N, 385 N, and 488 N before and after Flexuspine total spinal segment replacement implantation. Testing in flexion, extension, and lateral bending began by rotating the pendulum to 5 degrees ; resulting in unconstrained oscillatory motion. The number of rotations to equilibrium was recorded and bending stiffness (N-m/ degrees ) was calculated and compared for each testing mode. RESULTS: The total spinal segment replacement reached equilibrium with significantly fewer cycles to equilibrium compared to the intact functional spinal unit at all loads in flexion (p<0.011), and at loads of 385 N and 488 N in lateral bending (p<0.020). Mean bending stiffness in flexion, extension, and lateral bending increased with increasing load for both the intact functional spinal unit and total spinal segment replacement constructs (p<0.001), with no significant differences in stiffness between the intact functional spinal unit and total spinal segment replacement in any of the test modes (p>0.18). CONCLUSIONS: Lumbar functional spinal units with implanted total spinal segment replacement were found to have similar dynamic bending stiffness, but absorbed energy at a more rapid rate than intact functional spinal units during cyclic loading with an unconstrained pendulum system. Although the effects on clinical performance of motion preserving devices is not fully known, these results provide further insight into the biomechanical behavior of this device under approximated physiologic loading conditions. PMID- 23451223 TI - Prostatic cell-specific regulation of the synthesis of MUC1-associated sialyl Lewis a. AB - Sialyl Lewis antigens are selectin ligands involved in leukocyte trafficking and cancer metastasis. Biosynthesis of these selectin ligands occurs by the sequential actions of several glycosyltransferases in the Golgi apparatus following synthesis of the protein backbone in the endoplasmic reticulum. In this study, we examine how the synthesis of sialyl Lewis a (sLe(a)) is regulated in prostatic cells and identify a mucin that carries this glycotope. We treat human prostatic cells including one normal and three cancerous cells with histone deacetylase inhibitors, valproic acid, tricostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA), and then monitor the expression of sLe(a). We have found that SAHA enhances the production of sLe(a) in normal prostatic RWPE-1 cells but not prostatic cancer cells. Employing siRNA technology and co immunoprecipitation, we show that the sLe(a) is associated with MUC1, which is confirmed by confocal immunofluorescence microscopy and proximity ligation assay. The SAHA-induced production of sLe(a) in RWPE-1 cells is resulted from upregulation of B3GALT1 gene via enhancement of acetylated histone-3 and histone 4. Interestingly, PC3 and LNCaP C-81 cells do not produce detectable amounts of sLe(a) despite expressing high levels of B3GALT1. However, the MUC1-associated sLe(a) is generated in these cells after introduction of MUC1 cDNA. We conclude that the synthesis of sLe(a) is controlled by not only peptide backbone of the glycoprotein but also glycoprotein-specific glycosyltransferases involved in the synthesis of sLe(a). Further, the SAHA induction of this selectin ligand in normal prostatic cells may pose a potentially serious side effect of this drug recently approved by the US Food and Drug Administration. PMID- 23451224 TI - Sustained attention in intellectually gifted children assessed using a continuous performance test. AB - This study aimed to investigate two aspects of sustained attention in intellectually gifted children: first, the differences to intellectually average children; second, the differences between receiving standard education and enrichment education. Study 1 compared sustained attention between 24 intellectually gifted and 26 intellectually average children. The results showed that intellectually gifted children had better performance than their average peers, not only for the whole task but also on all indices. Study 2 compared sustained attention between 24 intellectually gifted children who received standard education and 24 intellectually gifted children who received enrichment education. The results showed that intellectually gifted children who received enrichment education performed better than those who received standard education. These findings are consistent with previous work and provide support for the implementation of enrichment education for intellectually gifted children. PMID- 23451225 TI - Increased gastric IL-1beta concentration and iron deficiency parameters in H. pylori infected children. AB - Association between H. pylori infection, iron deficiency and iron deficiency anaemia has been described, but the mechanisms involved have not been established. We hypothesized that in H. pylori infected children increased gastric concentrations of IL-1beta and/or TNF-alpha, both potent inhibitors of gastric acid secretion that is essential for iron absorption, are predictors for low blood concentrations of ferritin and haemoglobin, markers of early depletion of iron stores and anaemia, respectively. We evaluated 125 children undergoing endoscopy to clarify the origin of gastrointestinal symptoms. Gastric specimens were obtained for H. pylori status and cytokine evaluation and blood samples for determination of iron deficiency/iron deficiency anaemia parameters and IL1 cluster and TNFA polymorphisms that are associated with increased cytokine secretions. Higher IL-1beta and TNF-alpha gastric concentrations were observed in H. pylori-positive (n = 47) than in -negative (n = 78) children. Multiple linear regression models revealed gastric IL-1beta, but not TNF-alpha, as a significant predictor of low ferritin and haemoglobin concentrations; results were reproduced in young children in whom IL1RN polymorphic genotypes associated with higher gastric IL-1beta expression and lower blood ferritin and haemoglobin concentrations. In conclusion, high gastric levels of IL-1beta can be the link between H. pylori infection and iron deficiency/iron deficiency anaemia in childhood. PMID- 23451226 TI - Cooperation or competition of the two hemispheres in processing characters presented at vertical midline. AB - Little is known about how the hemispheres interact in processing of stimuli presented at vertical midline. Processing might be mutually independent or cooperative. Here we measured target identification and visually evoked EEG potentials while stimulus streams containing two targets, T1 and T2, were either presented at vertical midline above and below fixation, or laterally, left and right. With left and right streams, potentials evoked by filler stimuli and by T2 were earlier at the right than the left visual cortex, and T2 was better identified left than right, confirming earlier results and suggesting better capabilities of the right hemisphere in this task. With streams above and below fixation, EEG potentials evoked by filler stimuli and by T2 were likewise earlier at the right than the left hemisphere, and T2 was generally identified as well as, but not better than left T2, in one target constellation even worse (T2 in lower stream preceded by T1 in upper stream). These results suggest right hemisphere preference for this task even with stimuli at vertical midline, and no added value through hemispheric cooperation. Lacking asymmetry for T1 amidst asymmetries for filler stimuli and for T2 might indicate alternating access of the hemispheres to midline stimuli as one means of hemispheric division of labor. PMID- 23451227 TI - High energy diets-induced metabolic and prediabetic painful polyneuropathy in rats. AB - To establish the role of the metabolic state in the pathogenesis of polyneuropathy, an age- and sex-matched, longitudinal study in rats fed high-fat and high-sucrose diets (HFSD) or high-fat, high-sucrose and high-salt diets (HFSSD) relative to controls was performed. Time courses of body weight, systolic blood pressure, fasting plasma glucose (FPG), insulin, free fatty acids (FFA), homeostasis model assessment-insulin resistance index (HOMA-IR), thermal and mechanical sensitivity and motor coordination were measured in parallel. Finally, large and small myelinated fibers (LMF, SMF) as well as unmyelinated fibers (UMF) in the sciatic nerves and ascending fibers in the spinal dorsal column were quantitatively assessed under electron microscopy. The results showed that early metabolic syndrome (hyperinsulinemia, dyslipidemia, and hypertension) and prediabetic conditions (impaired fasting glucose) could be induced by high energy diet, and these animals later developed painful polyneuropathy characterized by myelin breakdown and LMF loss in both peripheral and central nervous system. In contrast SMF and UMF in the sciatic nerves were changed little, in the same animals. Therefore the phenomenon that high energy diets induce bilateral mechanical, but not thermal, pain hypersensitivity is reflected by severe damage to LMF, but mild damage to SMF and UMF. Moreover, dietary sodium (high-salt) deteriorates the neuropathic pathological process induced by high energy diets, but paradoxically high salt consumption, may reduce, at least temporarily, chronic pain perception in these animals. PMID- 23451228 TI - FcStuA from Fusarium culmorum controls wheat foot and root rot in a toxin dispensable manner. AB - Fusarium culmorum is one of the most harmful pathogens of durum wheat and is the causal agent of foot and root rot (FRR) disease. F. culmorum produces the mycotoxin deoxynivalenol (DON) that is involved in the pathogenic process. The role of the gene FcStuA, a StuA ortholog protein with an APSES domain sharing 98.5% homology to the FgStuA protein (FGSG10129), was determined by functional characterisation of deletion mutants obtained from two F. culmorum wild-type strains, FcUk99 (a highly pathogenic DON producer) and Fc233B (unable to produce toxin and with a mild pathogenic behavior). The DeltaFcStuA mutants originating from both strains showed common phenotypic characters including stunted vegetative growth, loss of hydrophobicity of the mycelium, altered pigmentation, decreased activity of polygalacturonic enzymes and catalases, altered and reduced conidiation, delayed conidial germination patterns and complete loss of pathogenicity towards wheat stem base/root tissue. Glycolytic process efficiency [measured as growth on glucose as sole carbon (C) source] was strongly impaired and growth was partially restored on glutamic acid. Growth on pectin-like sources ranked in between glucose and glutamic acid with the following order (the lowest to the highest growth): beechwood xylan, sugarbeet arabinan, polygalacturonic acid, citrus pectin, apple pectin, potato azogalactan. DON production in the mutants originating from FcUK99 strain was significantly decreased (-95%) in vitro. Moreover, both sets of mutants were unable to colonise non-cereal plant tissues, i.e. apple and tomato fruits and potato tubers. No differences between mutants, ectopic and wild-type strains were observed concerning the level of resistance towards four fungicides belonging to three classes, the demethylase inhibitors epoxiconazole and tebuconzole, the succinate dehydrogenase inhibitor isopyrazam and the cytochrome bc1 inhibitor trifloxystrobin. StuA, given its multiple functions in cell regulation and pathogenicity control, is proposed as a potential target for novel disease management strategies. PMID- 23451229 TI - Effect of heavy atoms on the thermal stability of alpha-amylase from Aspergillus oryzae. AB - Currently, there are no versatile and established methods for improving stability of proteins. In an entirely different approach from conventional techniques such as mutagenesis, we attempted to enhance enzyme stability of alpha-amylase from Aspergillus oryzae using a heavy-atom derivatization technique. We evaluated changes in stability using differential scanning calorimetry (DSC). Candidate heavy atoms were identified using the Heavy-Atom Database System HATODAS, a Web based tool designed to assist in heavy-atom derivatization of proteins for X-ray crystallography. The denaturation temperature of alpha-amylase derivatized with gadolinium (Gd) or samarium (Sm) ions increased by 6.2 or 5.7 degrees C, respectively, compared to that of the native protein (60.6 degrees C). The binding of six Gd ions was confirmed by X-ray crystallography of the enzyme at 1.5 A resolution. DSC and dynamic light-scattering data revealed a correlation between stability and the aggregation state upon addition of Gd ions. These results show that HATODAS search is an effective tool for selecting heavy atoms for stabilization of this protein. PMID- 23451230 TI - Landscape genetics of leaf-toed geckos in the tropical dry forest of northern Mexico. AB - Habitat fragmentation due to both natural and anthropogenic forces continues to threaten the evolution and maintenance of biological diversity. This is of particular concern in tropical regions that are experiencing elevated rates of habitat loss. Although less well-studied than tropical rain forests, tropical dry forests (TDF) contain an enormous diversity of species and continue to be threatened by anthropogenic activities including grazing and agriculture. However, little is known about the processes that shape genetic connectivity in species inhabiting TDF ecosystems. We adopt a landscape genetic approach to understanding functional connectivity for leaf-toed geckos (Phyllodactylus tuberculosus) at multiple sites near the northernmost limit of this ecosystem at Alamos, Sonora, Mexico. Traditional analyses of population genetics are combined with multivariate GIS-based landscape analyses to test hypotheses on the potential drivers of spatial genetic variation. Moderate levels of within population diversity and substantial levels of population differentiation are revealed by FST and Dest. Analyses using structure suggest the occurrence of from 2 to 9 genetic clusters depending on the model used. Landscape genetic analysis suggests that forest cover, stream connectivity, undisturbed habitat, slope, and minimum temperature of the coldest period explain more genetic variation than do simple Euclidean distances. Additional landscape genetic studies throughout TDF habitat are required to understand species-specific responses to landscape and climate change and to identify common drivers. We urge researchers interested in using multivariate distance methods to test for, and report, significant correlations among predictor matrices that can impact results, particularly when adopting least-cost path approaches. Further investigation into the use of information theoretic approaches for model selection is also warranted. PMID- 23451231 TI - The effectiveness of Internet cognitive behavioural therapy (iCBT) for depression in primary care: a quality assurance study. AB - BACKGROUND: Depression is a common, recurrent, and debilitating problem and Internet delivered cognitive behaviour therapy (iCBT) could offer one solution. There are at least 25 controlled trials that demonstrate the efficacy of iCBT. The aim of the current paper was to evaluate the effectiveness of an iCBT Program in primary care that had been demonstrated to be efficacious in two randomized controlled trials (RCTs). METHOD: Quality assurance data from 359 patients prescribed the Sadness Program in Australia from October 2010 to November 2011 were included. RESULTS: Intent-to-treat marginal model analyses demonstrated significant reductions in depressive symptoms (PHQ9), distress (K10), and impairment (WHODAS-II) with medium-large effect sizes (Cohen's d = .51-1.13.), even in severe and/or suicidal patients (Cohen's d = .50-1.49.) Secondary analyses on patients who completed all 6 lessons showed levels of clinically significant change as indexed by established criteria for remission, recovery, and reliable change. CONCLUSIONS: The Sadness Program is effective when prescribed by primary care practitioners and is consistent with a cost-effective stepped-care framework. PMID- 23451232 TI - Increased rate of arterial stiffening with obesity in adolescents: a five-year follow-up study. AB - BACKGROUND: We prospectively and longitudinally determined the effects of childhood obesity on arterial stiffening and vascular wall changes. Changes in arterial stiffness measured as pulse wave velocity (PWV) and vascular morphology of the radial (RA) and dorsal pedal arteries (DPA) were examined in obese adolescents compared to lean subjects in a 5-year follow-up study. METHODOLOGY/PRINCIPAL FINDINGS: A total of 28 obese subjects and 14 lean controls participated in both baseline (14 years old) and follow-up studies. PWV was measured by tonometer (SphygmoCor(r)) and recorded at RA and carotid artery, respectively. Intima thickness (IT), intima-media thickness (IMT) and RA and DPA diameters were measured using high-resolution ultrasound (Vevo 770TM). Over the course of 5 years, PWV increased by 25% in the obese subjects as compared to 3% in the controls (p = 0.01). Diastolic blood pressure (DBP) increased by 23% in the obese subjects as opposed to 6% in controls (p = 0.009). BMI increased similarly in both groups, as did the IT and IMT. The change in PWV was strongly associated to the baseline BMI z -score (r = 0.51, p<0.001), as was the change in DBP (r = 0.50, p = 0.001). CONCLUSIONS/SIGNIFICANCE: During the transition from early to late adolescence, there was a general increase in arterial stiffness, which was aggravated by childhood obesity. The increase in arterial stiffness and DBP after 5 years was closely correlated to the baseline BMI z -score, indicating that childhood obesity has an adverse impact on vascular adaptation. PMID- 23451233 TI - Estrogen signalling and the metabolic syndrome: targeting the hepatic estrogen receptor alpha action. AB - An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ERalpha) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ERalpha recapitulates metabolic phenotypes of ERKO mice we generated a liver selective ERalphaKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERalpha selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERalpha action may not be the responsible factor for the previously identified hepatic insulin resistance in ERalphaKO mice. PMID- 23451234 TI - An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions. AB - Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36. PMID- 23451235 TI - A new multiplex assay of 17 autosomal STRs and Amelogenin for forensic application. AB - This paper describes a newly devised autosomal short tandem repeat (STR) multiplex polymerase chain reaction (PCR) systems for 17 autosomal loci (D1S1656, D2S441, D3S1358, D3S3045, D6S477, D7S3048, D8S1132, D10S1435, D10S1248, D11S2368, D13S325, D14S608, D15S659, D17S1290, D18S535, D19S253 and D22-GATA198B05) and Amelogenin. Primers for the loci were designed and optimized so that all of the amplicons were distributed from 50 base pairs (bp) to less than 500 bp within a five-dye chemistry design with the fifth dye reserved for the sizing standard. Strategies were developed to overcome challenges that encountered in creating the final assay. The limits of the multiplex were tested, resulting in the successful amplification of genomic DNA range from 0.25-4 ng with 30 PCR cycles. A total of 681 individuals from the Chinese Han population were studied and forensic genetic data were present. No significant deviations from Hardy-Weinberg equilibrium were observed. A total of 180 alleles were detected for the 17 autosomal STRs. The cumulative mean exclusion chance in duos (CMECD) was 0.999967, and cumulative mean exclusion chance in trios (CMECT) was 0.99999995. We conclude that the present 17plex autosomal STRs assay provides an additional powerful tool for forensic applications. PMID- 23451236 TI - The NF-kappaB RelB protein is an oncogenic driver of mesenchymal glioma. AB - High-grade gliomas, such as glioblastomas (GBMs), are very aggressive, invasive brain tumors with low patient survival rates. The recent identification of distinct glioma tumor subtypes offers the potential for understanding disease pathogenesis, responses to treatment and identification of molecular targets for personalized cancer therapies. However, the key alterations that drive tumorigenesis within each subtype are still poorly understood. Although aberrant NF-kappaB activity has been implicated in glioma, the roles of specific members of this protein family in tumorigenesis and pathogenesis have not been elucidated. In this study, we show that the NF-kappaB protein RelB is expressed in a particularly aggressive mesenchymal subtype of glioma, and loss of RelB significantly attenuated glioma cell survival, motility and invasion. We find that RelB promotes the expression of mesenchymal genes including YKL-40, a marker of the MES glioma subtype. Additionally, RelB regulates expression of Olig2, a regulator of cancer stem cell proliferation and a candidate marker for the cell of origin in glioma. Furthermore, loss of RelB in glioma cells significantly diminished tumor growth in orthotopic mouse xenografts. The relevance of our studies for human disease was confirmed by analysis of a human GBM genome database, which revealed that high RelB expression strongly correlates with rapid tumor progression and poor patient survival rates. Thus, our findings demonstrate that RelB is an oncogenic driver of mesenchymal glioma tumor growth and invasion, highlighting the therapeutic potential of inhibiting the noncanonical NF-kappaB (RelB-mediated) pathway to treat these deadly tumors. PMID- 23451237 TI - Effectiveness of a randomized school-based intervention involving families and teachers to prevent excessive weight gain among adolescents in Brazil. AB - OBJECTIVE: To evaluate the effectiveness of a school-based intervention involving the families and teachers that aimed to promote healthy eating habits in adolescents; the ultimate aim of the intervention was to reduce the increase in body mass index (BMI) of the students. DESIGN: Paired cluster randomized school based trial conducted with a sample of fifth graders. SETTING: Twenty classes were randomly assigned into either an intervention group or a control group. PARTICIPANTS: From a total of 574 eligible students, 559 students participated in the study (intervention: 10 classes with 277 participants; control: 10 classes with 282 participants). The mean age of students was 11 years. INTERVENTION: Students attended 9 nutritional education sessions during the 2010 academic year. Parents/guardians and teachers received information on the same subjects. MAIN OUTCOME MEASUREMENT: Changes in BMI and percentage of body fat. RESULTS: Intention-to-treat analysis showed that changes in BMI were not significantly different between the 2 groups (beta = 0.003; p = 0.75). There was a major reduction in the consumption of sugar-sweetened beverages and cookies in the intervention group; students in this group also consumed more fruits. CONCLUSION: Encouraging the adoption of healthy eating habits promoted important changes in the adolescent diet, but this did not lead to a reduction in BMI gain. Strategies based exclusively on the quality of diet may not reduce weight gain among adolescents. TRIAL REGISTRATION: Clinicaltrials.gov NCT01046474. PMID- 23451238 TI - Whole genome association mapping of Fusarium head blight resistance in European winter wheat (Triticum aestivum L.). AB - A total of 358 recent European winter wheat varieties plus 14 spring wheat varieties were evaluated for resistance to Fusarium head blight (FHB) caused by Fusarium graminearum and Fusarium culmorum in four separate environments. The FHB scores based on FHB incidence (Type I resistance)*FHB severity (Type II resistance) indicated a wide phenotypic variation of the varieties with BLUE (best linear unbiased estimation) values ranging from 0.07 to 33.67. Genotyping with 732 microsatellite markers resulted in 782 loci of which 620 were placed on the ITMI map. The resulting average marker distance of 6.8 cM allowed genome wide association mapping employing a mixed model. Though no clear population structure was discovered, a kinship matrix was used for stratification. A total of 794 significant (-log10(p)-value>=3.0) associations between SSR-loci and environment specific FHB scores or BLUE values were detected, which included 323 SSR alleles. For FHB incidence and FHB severity a total of 861 and 877 individual marker-trait associations (MTA) were detected, respectively. Associations for both traits co located with FHB score in most cases. Consistent associations detected in three or more environments were found on all chromosomes except chromosome 6B, and with the highest number of MTA on chromosome 5B. The dependence of the number of favourable and unfavourable alleles within a variety to the respective FHB scores indicated an additive effect of favourable and unfavourable alleles, i.e. genotypes with more favourable or less unfavourable alleles tended to show greater resistance to FHB. Assessment of a marker specific for the dwarfing gene Rht-D1 resulted in strong effects. The results provide a prerequisite for designing genome wide breeding strategies for FHB resistance. PMID- 23451239 TI - Study of USH1 splicing variants through minigenes and transcript analysis from nasal epithelial cells. AB - Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital profound deafness, vestibular areflexia and prepubertal retinitis pigmentosa. The first purpose of this study was to determine the pathologic nature of eighteen USH1 putative splicing variants found in our series and their effect in the splicing process by minigene assays. These variants were selected according to bioinformatic analysis. The second aim was to analyze the USH1 transcripts, obtained from nasal epithelial cells samples of our patients, in order to corroborate the observed effect of mutations by minigenes in patient's tissues. The last objective was to evaluate the nasal ciliary beat frequency in patients with USH1 and compare it with control subjects. In silico analysis were performed using four bioinformatic programs: NNSplice, Human Splicing Finder, NetGene2 and Spliceview. Afterward, minigenes based on the pSPL3 vector were used to investigate the implication of selected changes in the mRNA processing. To observe the effect of mutations in the patient's tissues, RNA was extracted from nasal epithelial cells and RT-PCR analyses were performed. Four MYO7A (c.470G>A, c.1342_1343delAG, c.5856G>A and c.3652G>A), three CDH23 (c.2289+1G>A, c.6049G>A and c.8722+1delG) and one PCDH15 (c.3717+2dupTT) variants were observed to affect the splicing process by minigene assays and/or transcripts analysis obtained from nasal cells. Based on our results, minigenes are a good approach to determine the implication of identified variants in the mRNA processing, and the analysis of RNA obtained from nasal epithelial cells is an alternative method to discriminate neutral Usher variants from those with a pathogenic effect on the splicing process. In addition, we could observe that the nasal ciliated epithelium of USH1 patients shows a lower ciliary beat frequency than control subjects. PMID- 23451240 TI - tmRNA is essential in Shigella flexneri. AB - Nonstop mRNAs pose a challenge for bacteria, because translation cannot terminate efficiently without a stop codon. The trans-translation pathway resolves nonstop translation complexes by removing the nonstop mRNA, the incomplete protein, and the stalled ribosome. P1 co-transduction experiments demonstrated that tmRNA, a key component of the trans-translation pathway, is essential for viability in Shigella flexneri. tmRNA was previously shown to be dispensable in the closely related species Escherichia coli, because E. coli contains a backup system for trans-translation mediated by the alternative release factor ArfA. Genome sequence analysis showed that S. flexneri does not have a gene encoding ArfA. E. coli ArfA could suppress the requirement for tmRNA in S. flexneri, indicating that tmRNA is essential in S. flexneri because there is no functional backup system. These data suggest that resolution of nonstop translation complexes is required for most bacteria. PMID- 23451241 TI - Adaptive controller for dynamic power and performance management in the virtualized computing systems. AB - Power and performance management problem in large scale computing systems like data centers has attracted a lot of interests from both enterprises and academic researchers as power saving has become more and more important in many fields. Because of the multiple objectives, multiple influential factors and hierarchical structure in the system, the problem is indeed complex and hard. In this paper, the problem will be investigated in a virtualized computing system. Specifically, it is formulated as a power optimization problem with some constraints on performance. Then, the adaptive controller based on least-square self-tuning regulator(LS-STR) is designed to track performance in the first step; and the resource solved by the controller is allocated in order to minimize the power consumption as the second step. Some simulations are designed to test the effectiveness of this method and to compare it with some other controllers. The simulation results show that the adaptive controller is generally effective: it is applicable for different performance metrics, for different workloads, and for single and multiple workloads; it can track the performance requirement effectively and save the power consumption significantly. PMID- 23451242 TI - Enhanced insight into the autoimmune component of glaucoma: IgG autoantibody accumulation and pro-inflammatory conditions in human glaucomatous retina. AB - BACKGROUND: There is accumulating evidence that autoimmune components, such as autoantibodies and autoantibody depositions, play a role in the pathogenesis of neurodegenerative diseases like Alzheimers disease or Multiple Sclerosis. Due to alterations of autoantibody patterns in sera and aqueous humor, an autoimmune component is also assumed in the pathogenesis of glaucoma, a common reason for irreversible blindness worldwide. So far there has been no convincing evidence that autoantibodies are accumulated in the retina of glaucoma patients and that the local immune homeostasis might be affected. METHODS AND RESULTS: Six human glaucomatous donor eyes and nine samples from donors with no recorded ocular disease were included. Antibody microarrays were used to examine the patterns of pro-inflammatory proteins and complement proteins. Analysis of TNF-alpha and interleukin levels revealed a slight up-regulation exclusively in the glaucomatous group, while complement protein levels were not altered. IgG autoantibody accumulations and/or cellular components were determined by immunohistology (n = 4 per group). A significantly reduced number of retinal ganglion cells was found in the glaucomatous group (healthy: 104+/-7 nuclei/mm, glaucoma: 67+/-9 nuclei/mm; p = 0.0007). Cell loss was accompanied by strong retinal IgG autoantibody accumulations, which were at least twice as high as in healthy subjects (healthy: 5.0+/-0.5 IgG deposits/100 cells, glaucoma: 9.4+/-1.9 IgG deposits/100 cells; p = 0.004). CD27(+) cells and CD27(+)/IgG(+) plasma cells were observed in all glaucomatous subjects, but not in controls. CONCLUSION: This work provides serious evidence for the occurrence of IgG antibody deposition and plasma cells in human glaucomatous retina. Moreover, the results suggest that these IgG deposits occurred in a pro-inflammatory environment which seems to be maintained locally by immune-competent cells like microglia. Thereby, glaucoma features an immunological involvement comparable to other neurodegenerative diseases, but also shows a multifactorial pathomechanism, which diverges and might be linked to the specific nature of both eye and retina. PMID- 23451243 TI - The combined propranolol/TSST paradigm--a new method for psychoneuroendocrinology. AB - Upon perception of a stimulus as stressful, the human brain reacts with the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), to mobilize energy resources to better cope with the stressor. Since the perception of the stressor is the initial stimulus, a synchronicity between the subjective perception of stress and the physiological stress reactivity should be expected. However, according to a recent meta analysis, these associations are weak and inconsistent. The goal of the current study was to investigate the interaction between the SNS, HPA and subjective stress perceptions, by introducing an experimental manipulation of this interaction. For this purpose, we combined the SNS inhibitor propranolol with the Trier Social Stress Test, and measured endocrinological and psychological responses to the stressor. Thirty healthy male participants were recruited and randomly assigned to either a propranolol (PROP; n = 15) or placebo (PLC; n = 15) group. All subjects were administered 80 mg of propranolol 60 minutes prior to exposure to psychosocial stress. Salivary cortisol and alpha amylase (sAA), heart rate, blood pressure and subjective stress responses were assessed throughout the study. We observed significantly reduced sAA levels and heart rate increases in the PROP group in response to stress, with no effects of the drug on systolic or diastolic blood pressure changes. In line with previous studies, a significant increase in cortisol was seen in response to the stress exposure. Importantly, the cortisol increase was significantly higher in the PROP group. A typical increase in subjective stress could be seen in both groups, with no significant group differences emerging. Complementing previous work, this study further demonstrates a significant interaction between the HPA and the SNS during acute stress. The HPA activity was found to be elevated in the presence of a suppressed SNS in reactivity to the TSST. PMID- 23451244 TI - VPO1 mediates ApoE oxidation and impairs the clearance of plasma lipids. AB - OBJECTIVE: ApoE is an abundant component of chylomicron, VLDL, IDL, and HDL. It binds to multiple types of lipids and is implicated in cholesterol and triglyceride homeostasis. Oxidation of ApoE plays a crucial role in the genesis of atherosclerosis. It is proposed that heme-containing peroxidases (hPx) are major mediators of lipoprotein oxidization. Vascular peroxidase 1 (VPO1) is a recently-discovered hPx, which is expressed in cardiovascular system, lung, liver etc. and secreted into plasma. Its plasma concentration is three orders of magnitude of that of myeloperoxidase. If VPO1 mediates ApoE oxidation and affects the lipid metabolism remains to be elucidated. METHODS: Recombinant ApoE and VPO1 were expressed and purified from stably-expressing cell lines deriving from HEK293 cells. ApoE oxidation was carried out by VPO1 in the presence of H2O2 and chloride. ApoE oxidation was verified by a variety of approaches including immunoblot and amino acid analyses. To evaluate the functional changes in VPO1 oxidized ApoE, lipid emulsion particle binding assays were employed. RESULTS: Oxidized ApoE binds weaker to lipid emulsion particles, which mimic the large lipid complexes in vivo. In lipid efflux assay, oxidized ApoE showed reduced capability in efflux of lipids from foam cells. Mice administrated with oxidized ApoE via blood exhibited weaker clearance ability of plasma lipids. CONCLUSIONS: Our data suggest that VPO1 is a new mediator regulating lipid homeostasis, implying a role in genesis and development of atherosclerosis. PMID- 23451245 TI - Dose-risk and duration-risk relationships between aspirin and colorectal cancer: a meta-analysis of published cohort studies. AB - BACKGROUND: In previous meta-analyses, aspirin use has been associated with reduced risk of colorectal cancer. However, uncertainty remains on the exact dose risk and duration-risk relationships. METHODS: We identified studies by searching several English and Chinese electronic databases and reviewing relevant articles. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Subgroup analyses were conducted to explore possible heterogeneity among studies. Potential heterogeneity was calculated as Q statistic and I(2) value. Publication bias was evaluated using funnel plots and quantified by the Begg's and Egger's test. RESULTS: Twelve studies were included in this meta-analysis. An inverse association between aspirin use and colorectal cancer was observed in both the overall group (RR = 0.74, 95% CI 0.64-0.83 for aspirin dose; RR = 0.80, 95% CI 0.75-0.85 for frequency of aspirin use; RR = 0.75, 95% CI 0.68-0.81 for years of aspirin use) and subgroups stratified by sex and cancer site. The dose-response meta-analysis showed that there was a 20% statistically significant decreased risk of colorectal cancer for 325 mg aspirin per day increment, 18% decreased risk for 7 times aspirin per week increment and 18% decreased risk for 10 years aspirin increment. CONCLUSION: Long-term (>5 years), low-dose (75-325 mg per day) and regular aspirin use (2-7 times per week) can effectively reduce the risk of colorectal cancer. PMID- 23451246 TI - Human SCARB2 transgenic mice as an infectious animal model for enterovirus 71. AB - Enterovirus 71 (EV71) and coxsackievirus (CVA) are the most common causative factors for hand, foot, and mouth disease (HFMD) and neurological disorders in children. Lack of a reliable animal model is an issue in investigating EV71 induced disease manifestation in humans, and the current clinical therapies are symptomatic. We generated a novel EV71-infectious model with hSCARB2-transgenic mice expressing the discovered receptor human SCARB2 (hSCARB2). The challenge of hSCARB2-transgenic mice with clinical isolates of EV71 and CVA16 resulted in HFMD like and neurological syndromes caused by E59 (B4) and N2838 (B5) strains, and lethal paralysis caused by 5746 (C2), N3340 (C4), and CVA16. EV71 viral loads were evident in the tissues and CNS accompanied the upregulated pro-inflammatory mediators (CXCL10, CCL3, TNF-alpha, and IL-6), correlating to recruitment of the infiltrated T lymphocytes that result in severe diseases. Transgenic mice pre immunized with live E59 or the FI-E59 vaccine was able to resist the subsequent lethal challenge with EV71. These results indicate that hSCARB2-transgenic mice are a useful model for assessing anti-EV71 medications and for studying the pathogenesis induced by EV71. PMID- 23451247 TI - Changes of AM fungal abundance along environmental gradients in the arid and semi arid grasslands of northern China. AB - Arbuscular mycorrhizal (AM) fungi are ubiquitous symbionts of higher plants in terrestrial ecosystems, while the occurrence of the AM symbiosis is influenced by a complex set of abiotic and biotic factors. To reveal the regional distribution pattern of AM fungi as driven by multiple environmental factors, and to understand the ecological importance of AM fungi in natural ecosystems, we conducted a field investigation on AM fungal abundance along environmental gradients in the arid and semi-arid grasslands of northern China. In addition to plant parameters recorded in situ, soil samples were collected, and soil chemo physical and biological parameters were measured in the lab. Statistical analyses were performed to reveal the relative contribution of climatic, edaphic and vegetation factors to AM fungal abundance, especially for extraradical hyphal length density (HLD) in the soil. The results indicated that HLD were positively correlated with mean annual temperature (MAT), soil clay content and soil pH, but negatively correlated with both soil organic carbon (SOC) and soil available N. The multiple regressions and structural equation model showed that MAT was the key positive contributor and soil fertility was the key negative contributor to HLD. Furthermore, both the intraradical AM colonization (IMC) and relative abundance of AM fungi, which was quantified by real-time PCR assay, tended to decrease along the increasing SOC content. With regard to the obvious negative correlation between MAT and SOC in the research area, the positive correlation between MAT and HLD implied that AM fungi could potentially mitigate soil carbon losses especially in infertile soils under global warming. However, direct evidence from long-term experiments is still expected to support the AM fungal contribution to soil carbon pools. PMID- 23451248 TI - Whole-brain CT perfusion and CT angiography assessment of Moyamoya disease before and after surgical revascularization: preliminary study with 256-slice CT. AB - BACKGROUND/AIMS: The 256-slice CT enables the entire brain to be scanned in a single examination. We evaluated the application of 256-slice whole-brain CT perfusion (CTP) in determining graft patency as well as investigating cerebral hemodynamic changes in Moyamoya disease before and after surgical revascularization. METHODS: Thirty-nine cases of Moyamoya disease were evaluated before and after surgical revascularization with 256-slice CT. Whole-brain perfusion images and dynamic 3D CT angiographic images generated from perfusion source data were obtained in all patients. Cerebral blood flow (CBF), cerebral blood volume (CBV), time to peak (TTP) and mean transit time (MTT) of one hemisphere in the region of middle cerebral artery (MCA) distribution and contralateral mirroring areas were measured. Relative CTP values (rCBF, rCBV, rTTP, rMTT) were also obtained. Differences in pre- and post- operation perfusion CT values were assessed with paired t test or matched-pairs signed-ranks test. RESULTS: Preoperative CBF, MTT and TTP of potential surgical side were significantly different from those of contralateral side (P<0.01 for all). All graft patencies were displayed using the 3D-CTA images. Postoperative CBF, rCBF and rCBV values of surgical side in the region of MCA were significantly higher than those before operation (P<0.01 for all). Postoperative MTT, TTP, rMTT and rTTP values of the surgical side in the region of MCA were significantly lower than those before operation (P<0.05 for all). CONCLUSION: The 256-slice whole brain CTP can be used to evaluate cerebral hemodynamic changes in Moyamoya disease before and after surgery and the 3D-CTA is useful for assessing the abnormalities of intracranial arteries and graft patencies. PMID- 23451249 TI - Changing climate and overgrazing are decimating Mongolian steppes. AB - Satellite observations identify the Mongolian steppes as a hotspot of global biomass reduction, the extent of which is comparable with tropical rainforest deforestation. To conserve or restore these grasslands, the relative contributions of climate and human activities to degradation need to be understood. Here we use a recently developed 21-year (1988-2008) record of satellite based vegetation optical depth (VOD, a proxy for vegetation water content and aboveground biomass), to show that nearly all steppe grasslands in Mongolia experienced significant decreases in VOD. Approximately 60% of the VOD declines can be directly explained by variations in rainfall and surface temperature. After removing these climate induced influences, a significant decreasing trend still persists in the VOD residuals across regions of Mongolia. Correlations in spatial patterns and temporal trends suggest that a marked increase in goat density with associated grazing pressures and wild fires are the most likely non-climatic factors behind grassland degradation. PMID- 23451250 TI - Neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71 genotype C4 inhibit infection at pre- and post-attachment steps. AB - BACKGROUND: Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease, which has been prevalent in Asia-Pacific regions, causing significant morbidity and mortality in young children. Antibodies elicited by experimental EV71 vaccines could neutralize infection in vitro and passively protect animal models from lethal challenge, indicating that neutralizing antibodies play an essential role in protection. However, how neutralizing antibodies inhibit infection in vitro remains unclear. METHODS/FINDINGS: In the present study, we explored the mechanisms of neutralization by antibodies against EV71 virus-like particles (VLPs). Recombinant VLPs of EV71 genotype C4 were produced in insect cells using baculovirus vectors. Immunization with the VLPs elicited a high-titer, EV71-specific antibody response in mice. Anti-VLP mouse sera potently neutralized EV71 infection in vitro. The neutralizing antibodies in the anti-VLP mouse sera were found to target mainly an extremely conserved epitope (FGEHKQEKDLEYGAC) located at the GH loop of the VP1 protein. The neutralizing anti-VLP antisera were able to inhibit virus binding to target cells efficiently. In addition, post-attachment treatment of virus-bound cells with the anti-VLP antisera also neutralized virus infection, although the antibody concentration required was higher than that of the pre-attachment treatment. CONCLUSIONS: Collectively, our findings represent a valuable addition to the understanding of mechanisms of EV71 neutralization and have strong implications for EV71 vaccine development. PMID- 23451251 TI - Identification of sensitive serum microRNA biomarkers for radiation biodosimetry. AB - Exposure to ionizing radiation through environmental, occupational or a nuclear reactor accident such as the recent Fukushima Daiichi incident often results in major consequences to human health. The injury caused by radiation can manifest as acute radiation syndromes within weeks in organs with proliferating cells such as hematopoietic and gastrointestinal systems. Cancers, fibrosis and degenerative diseases are also reported in organs with differentiated cells, months or years later. Studies conducted on atom bomb survivors, nuclear reactor workers and animal models have shown a direct correlation of these effects with the absorbed dose. Physical dosimeters and the available radio-responsive biologics in body fluids, whose responses are rather indirect, have limitations to accurately evaluate the extent of post exposure damage. We have used an amplification-free, hybridization based quantitative assay utilizing the nCounter multiplex platform developed by nanoString Technologies to compare the levels of over 600 miRNAs in serum from mice irradiated at a range of 1 to 12 Gy at 24 and 48 hr time points. Development of a novel normalization strategy using multiple spike-in oligonucleotides allowed accurate measurement of radiation dose and time dependent changes in serum miRNAs. The response of several evolutionarily conserved miRNAs abundant in serum, were found to be robust and sensitive in the dose range relevant for medical triage and in patients who receive total body radiation as preparative regimen for bone marrow transplantation. Notably, miRNA 150, abundant in lymphocytes, exhibited a dose and time dependent decrease in serum, which we propose as a sensitive marker indicative of lymphocyte depletion and bone marrow damage. Our study has identified several markers useful for evaluation of an individual's response by minimally invasive methods, relevant to triage in case of a radiation accident and evaluation of toxicity and response during and after therapeutic radiation. PMID- 23451252 TI - Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma. AB - Normal tissues express the M1 isoform of pyruvate kinase (PK) that helps generate and funnel pyruvate into the mitochondria for ATP production. Tumors, in contrast, express the less active PKM2 isoform, which limits pyruvate production and spares glycolytic intermediates for the generation of macromolecules needed for proliferation. Although high PKM2 expression and low PK activity are considered defining features of tumors, very little is known about how PKM expression and PK activity change along the continuum from low grade to high grade tumors, and how these changes relate to tumor growth. To address this issue, we measured PKM isoform expression and PK activity in normal brain, neural progenitor cells, and in a series of over 100 astrocytomas ranging from benign grade I pilocytic astrocytomas to highly aggressive grade IV glioblastoma multiforme (GBM). All glioma exhibited comparably reduced levels of PKM1 expression and PK activity relative to normal brain. In contrast, while grade I III gliomas all had modestly increased levels of PKM2 RNA and protein expression relative to normal brain, GBM, regardless of whether they arose de novo or progressed from lower grade tumors, showed a 3-5 fold further increase in PKM2 RNA and protein expression. Low levels of PKM1 expression and PK activity were important for cell growth as PKM1 over-expression and the accompanying increases in PK activity slowed the growth of GBM cells. The increased expression of PKM2, however, was also important, because shRNA-mediated PKM2 knockdown decreased total PKM2 and the already low levels of PK activity, but paradoxically also limited cell growth in vitro and in vivo. These results show that pyruvate kinase M expression, but not pyruvate kinase activity, is regulated in a grade-specific manner in glioma, but that changes in both PK activity and PKM2 expression contribute to growth of GBM. PMID- 23451253 TI - The therapeutic role of monocyte chemoattractant protein-1 in a renal tissue engineering strategy for diabetic patients. AB - In this study we aim to boost the functional output of the intra-kidney islet transplantation for diabetic patients using a tissue engineered polymeric scaffold. This highly porous electrospun scaffold featured randomly distributed fibers composed of polycaprolactone (PCL) and poliglecaprone (PGC). It successfully sustained murine islets in vitro for up to 4 weeks without detected cytotoxicity. The in vivo study showed that the islet population proliferated by 89% within 12 weeks when they were delivered by the scaffold but only 18% if freely injected. Correspondingly, the islet population delivered by the scaffold unleashed a greater capability to produce insulin that in turn further drove down the blood glucose within 12 weeks after the surgery. Islets delivered by the scaffold most effectively prevented diabetic deterioration of kidney as evidenced by the lack of a kidney or glomerular enlargement and physiological levels of creatinine, urea nitrogen and albumin through week 12 after the surgery. Unlike traditional wisdom in diabetic research, the mechanistic study suggested that monocytes chemoattractant protein-1 (MCP-1) was responsible for the improved preservation of renal functions. This study revealed a therapeutic role of MCP-1 in rescuing kidneys in diabetic patients, which can be integrated into a tissue engineered scaffold to simultaneously preserved renal functions and islet transplantation efficacy. Also, this study affords a simple yet effective solution to improve the clinical output of islet transplantation. PMID- 23451254 TI - Multi-proxy temperature reconstruction from the West Qinling Mountains, China for the past 500 years. AB - A total of 290 tree-ring samples, collected from six sites in the West Qinling Mountains of China, were used to develop six new standard tree-ring chronologies. In addition, 73 proxy records were assembled in collaboration with Chinese and international scholars, from 27 publically available proxy records and 40 tree ring chronologies that are not available in public datasets. These records were used to reconstruct annual mean temperature variability in the West Qinling Mountains over the past 500 years (AD 1500-1995), using a modified point-by-point regression (hybrid PPR) method. The results demonstrate that the hybrid PPR method successfully integrates the temperature signals from different types of proxies, and that the method preserves a high degree of low-frequency variability. The reconstruction shows greater temperature variability in the West Qinling Mountains than has been found in previous studies. Our temperature reconstruction for this region shows: 1) five distinct cold periods, at approximately AD 1520-1535, AD 1560-1575, AD 1610-1620, AD 1850-1875 and AD 1965 1985, and four warm periods, at approximately AD 1645-1660, AD 1705-1725, AD 1785 1795 and AD 1920-1945; 2) that in this region, the 20(th) century was not the warmest period of the past 500 years; and 3) that a dominant and persistent oscillation of ca. 64 years is significantly identified in the 1640-1790 period. PMID- 23451255 TI - High adhesion of tumor cells to mesothelial monolayers derived from peritoneal wash of disseminated gastrointestinal cancers. AB - The role of the mesothelial layer in the peritoneal spreading of cancer cells is only partially clarified. Here we attempted to better define the mesothelial contribution to the tumor cell adhesion using a direct adhesion test applied to human primary cultures of mesothelial cells (HPMCs) derived from the peritoneal washes of patients with gastric and colorectal cancers. Gastric and colon carcinoma cells were seeded on different mesothelial monolayers and quantitative fluorescence analysis was performed to analyze their growth and adhesive properties. The adhesion of the cancer cells was not affected by the origin of the HPMCs when derived from patients with different cancers or with benign disease. In contrast, the high levels of ICAM1 expression and ROS production, which characterize these senescent mesothelial cells, enhanced the tumor cell adhesion. These results suggest that the mesothelial adhesive properties are dependent on the cell senescence, while are not affected by the tumor environment. The use of peritoneal washes as a source to isolate HPMCs provides a practical and reliable tool for the in vitro analysis of the mesothelial conditions affecting the peritoneal carcinomatosis. PMID- 23451256 TI - Aberrant gene expression in dogs with portosystemic shunts. AB - Congenital portosystemic shunts are developmental anomalies of the splanchnic vascular system that cause portal blood to bypass the liver. Large-breed dogs are predisposed for intrahepatic portosystemic shunts (IHPSS) and small-breed dogs for extrahepatic portosystemic shunts (EHPSS). While the phenotype resulting from portal bypass of the liver of the two types of shunt is identical, the genotype and molecular pathways involved are probably different. The aim of this study was to gain insight into the pathways involved in the different types of portosystemic shunting. Microarray analysis of mRNA expression in liver tissue from dogs with EHPSS and IHPSS revealed that the expression of 26 genes was altered in either IHPSS or EHPSS samples compared with that in liver samples from control dogs. Quantitative real-time PCR of these genes in 14 IHPSS, 17 EHPSS, and 8 control liver samples revealed a significant differential expression of ACBP, CCBL1, GPC3, HAMP, PALLD, VCAM1, and WEE1. Immunohistochemistry and Western blotting confirmed an increased expression of VCAM1 in IHPSS but its absence in EHPSS, an increased WEE1 expression in IHPSS but not in EHPSS, and a decreased expression of CCBL1 in both shunt types. Regarding their physiologic functions, these findings may indicate a causative role for VCAM1 in EHPSS [corrected] and WEE1 for IHPSS. CCBL1 could be an interesting candidate to study not yet elucidated aspects in the pathophysiology of hepatic encephalopathy. PMID- 23451257 TI - Moderate heat challenge increased yolk steroid hormones and shaped offspring growth and behavior in chickens. AB - BACKGROUND: Environmental challenges might affect the maternal organism and indirectly affect the later ontogeny of the progeny. We investigated the cross generation impact of a moderate heat challenge in chickens. We hypothesized that a warm temperature--within the thermotolerance range--would affect the hormonal environment provided to embryos by mothers, and in turn, affect the morphology and behavioral phenotype of offspring. METHODOLOGY/PRINCIPAL FINDINGS: Laying hens were raised under a standard thermal condition at 21 degrees C (controls) or 30 degrees C (experimental) for 5 consecutive weeks. A significant increase was observed in the internal temperature of hens exposed to the warm treatment; however plasma corticosterone levels remained unaffected. The laying rate was not affected, but experimental hens laid lighter eggs than the controls during the treatment. As expected, the maternal thermal environment affected yolk hormone contents. Eggs laid by the experimental hens showed significantly higher concentrations of yolk progesterone, testosterone, and estradiol. All chicks were raised under standard thermal conditions. The quality of hatchlings, growth, feeding behavior and emotional reactivity of chicks were analyzed. Offspring of experimental hens (C30 chicks) were lighter but obtained better morphological quality scores at hatching than the controls (C21 chicks). C30 chicks expressed lesser distress calls when exposed to a novel food. Unlike C21 chicks, C30 chicks expressed no preference for energetic food. CONCLUSION/SIGNIFICANCE: Our findings suggest that moderate heat challenge triggers maternal effects and modulate the developmental trajectory of offspring in a way that may be adaptive. This suggests that the impact of heat challenges on captive or wild populations might have a cross-generation effect. PMID- 23451258 TI - Interaction of motor training and intermittent theta burst stimulation in modulating motor cortical plasticity: influence of BDNF Val66Met polymorphism. AB - Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities. PMID- 23451259 TI - Evaluating hemorrhage in renal cell carcinoma using susceptibility weighted imaging. AB - BACKGROUND: Intratumoral hemorrhage is a frequent occurrence in renal cell carcinoma and is an indicator of tumor subtype. We hypothesize that susceptibility weighted imaging (SWI) is sensitive to hemorrhage in renal cell carcinoma and can give a more diagnostic image when compared to conventional imaging techniques. MATERIALS AND METHODS: A retrospective review of 32 patients with clear cell renal cell carcinoma was evaluated. All patients underwent magnetic resonance imaging (MRI) and 22 out of 32 patients also underwent a computed tomography (CT) scan. Hemorrhage was classified into 3 different categories according to shape and distribution. Histopathology was obtained from all masses by radical nephrectomy. The ability to detect the presence of hemorrhage using CT, non-contrast conventional MRI and SWI was evaluated, and the patterns of hemorrhage were compared. RESULTS: Using pathologic results as the gold standard, the sensitivities of non-contrast conventional MRI, SWI and CT in detecting hemorrhage in clear cell renal cell carcinoma were 65.6%, 100% and 22.7%, respectively. Accuracy of non-contrast conventional MRI and SWI in evaluating hemorrhagic patterns were 31.3% and 100%, respectively. CONCLUSION: These results demonstrate that SWI can better reveal hemorrhage and characterize the pattern more accurately than either non-contrast conventional MRI or CT. This suggests that SWI is the technique of choice for detecting hemorrhagic lesions in patients with renal cancer. PMID- 23451261 TI - Intake of dairy products, calcium, magnesium, and phosphorus in childhood and age at menarche in the Tehran Lipid and Glucose Study. AB - PURPOSE: Studies indicate that milk intake is associated with insulin-like growth factor 1 (IGF-1) concentrations and height in childhood, whether milk and other dairy products promote puberty remains unclear. This study aimed to investigate influences of pre-pubertal intakes of milk, yogurt and cheese on menarcheal age in Tehranian girls. The associations of total dietary calcium (Ca), magnesium (Mg), and phosphorus (P) with menarcheal age were also examined. METHODS: This prospective study was conducted on 134 pre-pubertal girls, aged 4-12 years at baseline, who participated in the Tehran Lipid and Glucose Study (TLGS), and were followed for a median of 6.5 years. Dietary intakes were determined at initiation of the study using two non-consecutive 24-h dietary recalls and the age of menarche was documented during the follow-up. Logistic regression was used to calculate the risk of reaching menarche <= 12 years according to pre-pubertal levels of dairy or mineral intakes. RESULTS: The risk of earlier menarche was higher in girls with higher intakes of milk [OR: 2.28 (95% CI: 1.03-5.05)], Ca [OR: 3.20 (95%CI: 1.39-7.42)], Mg [OR: 2.43 (95% CI: 1.12-5.27)] and P [OR: 3.37 (95 % CI: 1.44-7.87) after controlling for energy and protein intake, interval between the age at study initiation and the age of menarche, and maternal age at menarche (Model 1). Girls in the middle tertile of cheese intakes had a lower risk of reaching menarche <= 12 years than those in the lowest tertile after controlling for covariates in model 1. These associations remained significant after further adjustment of BMI Z-score at baseline. The relationship of Ca, Mg, and P with menarche remained after further adjustment for height Z-score at baseline, whereas the association between milk and cheese intakes became non significant. CONCLUSIONS: Pre-pubertal intake of milk, but not cheese and yogurt, may hasten age at menarche. PMID- 23451260 TI - Hypoxia inducible factor 3alpha plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development. AB - Lung development occurs under relative hypoxia and the most important oxygen sensitive response pathway is driven by Hypoxia Inducible Factors (HIF). HIFs are heterodimeric transcription factors of an oxygen-sensitive subunit, HIFalpha, and a constitutively expressed subunit, HIF1beta. HIF1alpha and HIF2alpha, encoded by two separate genes, contribute to the activation of hypoxia inducible genes. A third HIFalpha gene, HIF3alpha, is subject to alternative promoter usage and splicing, leading to three major isoforms, HIF3alpha, NEPAS and IPAS. HIF3alpha gene products add to the complexity of the hypoxia response as they function as dominant negative inhibitors (IPAS) or weak transcriptional activators (HIF3alpha/NEPAS). Previously, we and others have shown the importance of the Hif1alpha and Hif2alpha factors in lung development, and here we investigated the role of Hif3alpha during pulmonary development. Therefore, HIF3alpha was conditionally expressed in airway epithelial cells during gestation and although HIF3alpha transgenic mice were born alive and appeared normal, their lungs showed clear abnormalities, including a post-pseudoglandular branching defect and a decreased number of alveoli. The HIF3alpha expressing lungs displayed reduced numbers of Clara cells, alveolar epithelial type I and type II cells. As a result of HIF3alpha expression, the level of Hif2alpha was reduced, but that of Hif1alpha was not affected. Two regulatory genes, Rarbeta, involved in alveologenesis, and Foxp2, a transcriptional repressor of the Clara cell specific Ccsp gene, were significantly upregulated in the HIF3alpha expressing lungs. In addition, aberrant basal cells were observed distally as determined by the expression of Sox2 and p63. We show that Hif3alpha binds a conserved HRE site in the Sox2 promoter and weakly transactivated a reporter construct containing the Sox2 promoter region. Moreover, Hif3alpha affected the expression of genes not typically involved in the hypoxia response, providing evidence for a novel function of Hif3alpha beyond the hypoxia response. PMID- 23451262 TI - Economic analysis of a pine plantation receiving repeated applications of biosolids. AB - Treated biosolids have been applied to 750-ha of a Pinus radiata forest plantation on Rabbit Island near Nelson City in New Zealand since 1996. A long term research trial was established in 1997 to investigate the effects of the biosolids applications on the receiving environment and tree growth. An analysis of the likely economic impact of biosolids application shows that biosolids application has been beneficial. Stem volume of the high treatment (biosolids applied at 600 kg N ha(-1) every three years) was 36% greater than the control treatment (no biosolids applied), and stem volume of the standard treatment (300 kg N ha(-1)) was 27% greater than the control treatment at age 18 years of age. Biosolids treatments have effectively transformed a low productivity forest site to a medium productivity site. Although this increased productivity has been accompanied by some negative influences on wood quality attributes with reduced wood stiffness, wood density, and larger branches, an economic analysis shows that the increased stem volume and greater average log diameter in the biosolids treatments outweighs these negative effects. The high and standard biosolids treatments are predicted to increase the net stumpage value of logs by 24% and 14% respectively at harvesting, providing a large positive impact on the forest owner's economic return. PMID- 23451263 TI - Effectiveness of a government-organized and hospital-initiated treatment for multidrug-resistant tuberculosis patients--a retrospective cohort study. AB - BACKGROUND: In contrast to the conventional model of hospital-treated and government directly observed treatment (DOT) for multidrug-resistant tuberculosis (MDR-TB) patient care, the Taiwan MDR-TB Consortium (TMTC) was launched in May 2007 with the collaboration of five medical care groups that have provided both care and DOT. This study aimed to determine whether the TMTC provided a better care model for MDR-TB patients than the conventional model. METHODS AND FINDINGS: A total of 651 pulmonary MDR-TB patients that were diagnosed nation-wide from January 2000-August 2008 were enrolled. Of those, 290 (45%) MDR-TB patients whose initial sputum sample was taken in January 2007 or later were classified as patients in the TMTC era. All others were classified as patients in the pre-TMTC era. The treatment success rate at 36 months was better in the TMTC era group (82%) than in the pre-TMTC era group (61%) (p<0.001). With multiple logistic regressions, diagnosis in the TMTC era (adjusted odds ratio (aOR) 2.8, 95% confidence interval (CI) 1.9-4.2) was an independent predictor of a higher treatment success rate at 36 months. With the time-dependent proportional hazards method, a higher treatment success rate was still observed in the TMTC era group compared to the pre-TMTC era group (adjusted hazard ratio 6.3, 95% CI 4.2-9.5). CONCLUSION: The improved treatment success observed in the TMTC era compared to the pre-TMTC era is encouraging. The detailed TMTC components that contribute the most to the improved outcome will need confirmation in follow-up studies with large numbers of MDR-TB patients. PMID- 23451265 TI - Association between prostate cancer and urinary calculi: a population-based study. AB - BACKGROUND: Understanding the reasons underlying the emerging trend and the changing demographics of Asian prostate cancer (PC) has become an important field of study. This study set out to explore the possibility that urinary calculi (UC) and PC may share an association by conducting a case-control study on a population-based database in Taiwan. METHODS: The cases of this study included 2,900 subjects >= 40 years-old who had received their first-time diagnosis of PC and 14,500 randomly selected controls without PC. Conditional logistic regressions were employed to explore the association between PC and having been previously diagnosed with UC. RESULTS: We found that prior UC was found among 608 (21.0%) cases and 2,037 (14.1%) controls (p<0.001). Conditional logistic regression analysis revealed that compared to controls, the odds ratio (OR) of prior UC for cases was 1.63 (95% CI = 1.47-1.80). Furthermore, we found that cases were more likely to have been previously diagnosed with kidney calculus (OR = 1.71; 95% CI = 1.42-2.05), bladder calculus (OR = 2.06; 95% CI = 1.32-3.23), unspecified calculus (OR = 1.66; 95% CI = 1.37-2.00), and >=2 locations of UC (OR = 1.73; 1.47-2.02) than controls. However, there was no significant relationship between PC and prior ureter calculus. We also found that of the patients with UC, there was no significant difference between PC and treatment method. CONCLUSIONS: This investigation detected an association between PC and prior UC. These results highlight a potential target population for PC screening. PMID- 23451264 TI - Expression of lysophosphatidic acid receptor 1 and relation with cell proliferation, apoptosis, and angiogenesis on preneoplastic changes induced by cadmium chloride in the rat ventral prostate. AB - BACKGROUND: Lysophosphatidic acid (LPA) is a phospholipid growth factor involved in cell proliferation, differentiation, migration, inflammation, angiogenesis, wound healing, cancer invasion, and survival. This study was directed to evaluate the immunoexpression of LPA-1, cell proliferation, apoptosis, and angiogenesis markers in preneoplastic lesions induced with cadmium chloride in rat prostate. METHODS: The following parameters were calculated in ventral prostate of normal rats and rats that received Cd in drinking water during 24 months: percentages of cells immunoreactive to LPA-1 (LILPA1), PCNA (LIPCNA), MCM7 (LIMCM7), ubiquitin (LIUBI), apoptotic cells (LIAPO), and p53 (LIp53); volume fraction of Bcl-2 (VFBcl-2); and length of microvessels per unit of volume (LVMV/mm3). Data were analyzed using Student's t-test and Pearson correlation test. RESULTS: The LILPA1 in dysplastic lesions and normal epithelium of Cd-treated rats was significantly higher than those in the control group. Markers of proliferation were significantly increased in dysplastic lesions, whereas some apoptotic markers were significantly decreased. No significant differences between groups were found in VFBcl-2. Dysplastic lesions showed a significant increase of LIp53. The length of microvessels per unit of volume was elevated in dysplastic acini. Statistically significant correlations were found only between LILPA1 and LIUBI. CONCLUSIONS: Our results suggest that LPA-1 might be implicated in dysplastic lesions induced by cadmium chloride development. More studies are needed to confirm its potential contribution to the disease. PMID- 23451266 TI - Inferring kangaroo phylogeny from incongruent nuclear and mitochondrial genes. AB - The marsupial genus Macropus includes three subgenera, the familiar large grazing kangaroos and wallaroos of M. (Macropus) and M. (Osphranter), as well as the smaller mixed grazing/browsing wallabies of M. (Notamacropus). A recent study of five concatenated nuclear genes recommended subsuming the predominantly browsing Wallabia bicolor (swamp wallaby) into Macropus. To further examine this proposal we sequenced partial mitochondrial genomes for kangaroos and wallabies. These sequences strongly favour the morphological placement of W. bicolor as sister to Macropus, although place M. irma (black-gloved wallaby) within M. (Osphranter) rather than as expected, with M. (Notamacropus). Species tree estimation from separately analysed mitochondrial and nuclear genes favours retaining Macropus and Wallabia as separate genera. A simulation study finds that incomplete lineage sorting among nuclear genes is a plausible explanation for incongruence with the mitochondrial placement of W. bicolor, while mitochondrial introgression from a wallaroo into M. irma is the deepest such event identified in marsupials. Similar such coalescent simulations for interpreting gene tree conflicts will increase in both relevance and statistical power as species-level phylogenetics enters the genomic age. Ecological considerations in turn, hint at a role for selection in accelerating the fixation of introgressed or incompletely sorted loci. More generally the inclusion of the mitochondrial sequences substantially enhanced phylogenetic resolution. However, we caution that the evolutionary dynamics that enhance mitochondria as speciation indicators in the presence of incomplete lineage sorting may also render them especially susceptible to introgression. PMID- 23451267 TI - Functional and structural neural network characterization of serotonin transporter knockout rats. AB - Brain serotonin homeostasis is crucially maintained by the serotonin transporter (5-HTT), and its down-regulation has been linked to increased vulnerability for anxiety- and depression-related behavior. Studies in 5-HTT knockout (5-HTT(-/-)) rodents have associated inherited reduced functional expression of 5-HTT with increased sensitivity to adverse as well as rewarding environmental stimuli, and in particular cocaine hyperresponsivity. 5-HTT down-regulation may affect normal neuronal wiring of implicated corticolimbic cerebral structures. To further our understanding of its contribution to potential alterations in basal functional and structural properties of neural network configurations, we applied resting state functional MRI (fMRI), pharmacological MRI of cocaine-induced activation, and diffusion tensor imaging (DTI) in 5-HTT(-/-) rats and wild-type controls (5 HTT(+/+)). We found that baseline functional connectivity values and cocaine induced neural activity within the corticolimbic network was not significantly altered in 5-HTT(-/-) versus 5-HTT(+/+) rats. Similarly, DTI revealed mostly intact white matter structural integrity, except for a reduced fractional anisotropy in the genu of the corpus callosum of 5-HTT(-/-) rats. At the macroscopic level, analyses of complex graphs constructed from either functional connectivity values or structural DTI-based tractography results revealed that key properties of brain network organization were essentially similar between 5 HTT(+/+) and 5-HTT(-/-) rats. The individual tests for differences between 5 HTT(+/+) and 5-HTT(-/-) rats were capable of detecting significant effects ranging from 5.8% (fractional anisotropy) to 26.1% (pharmacological MRI) and 29.3% (functional connectivity). Tentatively, lower fractional anisotropy in the genu of the corpus callosum could indicate a reduced capacity for information integration across hemispheres in 5-HTT(-/-) rats. Overall, the comparison of 5 HTT(-/-) and wild-type rats suggests mostly limited effects of 5-HTT genotype on MRI-based measures of brain morphology and function. PMID- 23451268 TI - Blood and dried blood spot telomere length measurement by qPCR: assay considerations. AB - Measurement of telomere length is crucial for the study of telomere maintenance and its role in molecular pathophysiology of diseases and in aging. Several methods are used to measure telomere length, the choice of which usually depends on the type and size of sample to be assayed, as well as cost and throughput considerations. The goal of this study was to investigate the factors that may influence the reliability of qPCR-based relative telomere length measurements in whole blood. Day to day intra-individual variability, types of blood anticoagulant, sample storage conditions, processing and site of blood draw were investigated. Two qPCR-based methods to measure telomere length (monoplex vs. multiplex) were also investigated and showed a strong correlation between them. Freezing and thawing of the blood and storage of the blood at 4 degrees C for up to 4 days did not affect telomere length values. Telomere lengths in dried blood spots were significantly higher than both whole blood and peripheral mononuclear blood cells, and were highly correlated with both. We found that telomere length measurements were significantly higher in dried blood spots collected directly from fingertip prick compared to dried blood spots prepared with anticoagulated whole blood collected from the finger, and non-blotted whole blood taken from both finger and arm venipuncture. This suggests that DNA from cells blotted on paper is not equivalent to that collected from venipuncture whole blood, and caution should be taken when comparing between blood sample types. PMID- 23451269 TI - Deltex-1 activates mitotic signaling and proliferation and increases the clonogenic and invasive potential of U373 and LN18 glioblastoma cells and correlates with patient survival. AB - Glioblastoma (GBM) is a highly malignant primary tumor of the central nervous system originating in glial cells. GBM results in more years of life lost than any other cancer type. Low levels of Notch receptor expression correlates with prolonged survival in various high grade gliomas independent of other markers. Different downstream pathways of Notch receptors have been identified. We tested if the Notch/Deltex pathway, which is distinct from the canonical, CSL-mediated pathway, has a role in GBM. We show that the alternative or non-canonical Notch pathway functioning through Deltex1 (DTX1) mediates key features of glioblastoma cell aggressiveness. For example, DTX1 activates the RTK/PI3K/PKB and the MAPK/ERK mitotic pathways and induces anti-apoptotic Mcl-1. The clonogenic and growth potential of established glioma cells correlated with DTX1 levels. Microarray gene expression analysis further identified a DTX1-specific, MAML1 independent transcriptional program - including microRNA-21- which is functionally linked to the changes in tumor cell aggressiveness. Over-expression of DTX1 increased cell migration and invasion correlating to ERK activation, miR 21 levels and endogenous Notch levels. In contrast to high and intermediate expressors, patients with low DTX1 levels have a more favorable prognosis. The alternative Notch pathway via DTX1 appears to be an oncogenic factor in glioblastoma and these findings offer new potential therapeutic targets. PMID- 23451270 TI - The angiotensin II type 1 receptor C-terminal Lys residues interact with tubulin and modulate receptor export trafficking. AB - The physiological and pathological functions of angiotensin II are largely mediated through activating the cell surface angiotensin II type 1 receptor (AT1R). However, the molecular mechanisms underlying the transport of newly synthesized AT1R from the endoplasmic reticulum (ER) to the cell surface remain poorly defined. Here we demonstrated that the C-terminus (CT) of AT1R directly and strongly bound to tubulin and the binding domains were mapped to two consecutive Lys residues at positions 310 and 311 in the CT membrane-proximal region of AT1R and the acidic CT of tubulin, suggestive of essentially ionic interactions between AT1R and tubulin. Furthermore, mutation to disrupt tubulin binding dramatically inhibited the cell surface expression of AT1R, arrested AT1R in the ER, and attenuated AT1R-mediated signaling measured as ERK1/2 activation. These data demonstrate for the first time that specific Lys residues in the CT juxtamembrane region regulate the processing of AT1R through interacting with tubulin. These data also suggest an important role of the microtubule network in the cell surface transport of AT1R. PMID- 23451271 TI - Comparative analysis of the expression profile of Wnk1 and Wnk1/Hsn2 splice variants in developing and adult mouse tissues. AB - The With No lysine (K) family of serine/threonine kinase (WNK) defines a small family of kinases with significant roles in ion homeostasis. WNK1 has been shown to have different isoforms due to what seems to be largely tissue specific splicing. Here, we used two distinct in situ hybridization riboprobes on developing and adult mouse tissues to make a comparative analysis of Wnk1 and its sensory associated splice isoform, Wnk1/Hsn2. The hybridization signals in developing mouse tissues, which were prepared at embryonic day e10.5 and e12.5, revealed a homogenous expression profile with both probes. At e15.5 and in the newborn mouse, the two probes revealed different expression profiles with prominent signals in nervous system tissues and also other tissues such as kidney, thymus and testis. In adult mouse tissues, the two expression profiles appeared even more restricted to the nervous tissues, kidney, thymus and testis, with no detectable signal in the other tissues. Throughout the nervous system, sensory tissues, as well as in Cornu Ammonis 1 (CA1), CA2 and CA3 areas of the hippocampus, were strongly labeled with both probes. Hybridization signals were also strongly detected in Schwann and supporting satellite cells. Our results show that the expression profiles of Wnk1 isoforms change during the development, and that the expression of the Wnk1 splice variant containing the Hsn2 exon is prominent during developing and in adult mouse tissues, suggesting its important role in the development and maintenance of the nervous system. PMID- 23451272 TI - Decreased functional brain connectivity in adolescents with internet addiction. AB - BACKGROUND: Internet addiction has become increasingly recognized as a mental disorder, though its neurobiological basis is unknown. This study used functional neuroimaging to investigate whole-brain functional connectivity in adolescents diagnosed with internet addiction. Based on neurobiological changes seen in other addiction related disorders, it was predicted that connectivity disruptions in adolescents with internet addiction would be most prominent in cortico-striatal circuitry. METHODS: Participants were 12 adolescents diagnosed with internet addiction and 11 healthy comparison subjects. Resting-state functional magnetic resonance images were acquired, and group differences in brain functional connectivity were analyzed using the network-based statistic. We also analyzed network topology, testing for between-group differences in key graph-based network measures. RESULTS: Adolescents with internet addiction showed reduced functional connectivity spanning a distributed network. The majority of impaired connections involved cortico-subcortical circuits (~24% with prefrontal and ~27% with parietal cortex). Bilateral putamen was the most extensively involved subcortical brain region. No between-group difference was observed in network topological measures, including the clustering coefficient, characteristic path length, or the small-worldness ratio. CONCLUSIONS: Internet addiction is associated with a widespread and significant decrease of functional connectivity in cortico-striatal circuits, in the absence of global changes in brain functional network topology. PMID- 23451273 TI - Parental influences on pathogen resistance in brown trout embryos and effects of outcrossing within a river network. AB - Phenotypic plasticity can increase tolerance to heterogeneous environments but the elevations and slopes of reaction norms are often population specific. Disruption of locally adapted reaction norms through outcrossing can lower individual viability. Here, we sampled five genetically distinct populations of brown trout (Salmo trutta) from within a river network, crossed them in a full factorial design, and challenged the embryos with the opportunistic pathogen Pseudomonas fluorescens. By virtue of our design, we were able to disentangle effects of genetic crossing distance from sire and dam effects on early life history traits. While pathogen infection did not increase mortality, it was associated with delayed hatching of smaller larvae with reduced yolk sac reserves. We found no evidence of a relationship between genetic distance (W, FST) and the expression of early-life history traits. Moreover, hybrids did not differ in phenotypic means or reaction norms in comparison to offspring from within-population crosses. Heritable variation in early life-history traits was found to remain stable across the control and pathogen environments. Our findings show that outcrossing within a rather narrow geographical scale can have neutral effects on F1 hybrid viability at the embryonic stage, i.e. at a stage when environmental and genetic effects on phenotypes are usually large. PMID- 23451274 TI - Comparative genomics identifies the mouse Bmp3 promoter and an upstream evolutionary conserved region (ECR) in mammals. AB - The Bone Morphogenetic Protein (BMP) pathway is a multi-member signaling cascade whose basic components are found in all animals. One member, BMP3, which arose more recently in evolution and is found only in deuterostomes, serves a unique role as an antagonist to both the canonical BMP and Activin pathways. However, the mechanisms that control BMP3 expression, and the cis-regulatory regions mediating this regulation, remain poorly defined. With this in mind, we sought to identify the Bmp3 promoter in mouse (M. musculus) through functional and comparative genomic analyses. We found that the minimal promoter required for expression in resides within 0.8 kb upstream of Bmp3 in a region that is highly conserved with rat (R. norvegicus). We also found that an upstream region abutting the minimal promoter acts as a repressor of the minimal promoter in HEK293T cells and osteoblasts. Strikingly, a portion of this region is conserved among all available eutherian mammal genomes (47/47), but not in any non eutherian animal (0/136). We also identified multiple conserved transcription factor binding sites in the Bmp3 upstream ECR, suggesting that this region may preserve common cis-regulatory elements that govern Bmp3 expression across eutherian mammals. Since dysregulation of BMP signaling appears to play a role in human health and disease, our findings may have application in the development of novel therapeutics aimed at modulating BMP signaling in humans. PMID- 23451275 TI - GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid stimulated expression and novel nuclear role. AB - Members of the large G protein-coupled receptor (GPCR) clan are implicated in many physiological and disease processes, making them important therapeutic drug targets. In the present study, we follow up on results of a pilot study suggesting a functional relationship between glucocorticoid (GC)-induced ocular hypertension and GPR158, one of three orphan members of the GPCR Family C. GC treatment increases levels of GPR158 mRNA and protein through transcriptional mechanisms, in cultured trabecular meshwork (TBM) cells derived from the eye's aqueous outflow pathway. Like treatment with GCs, transient overexpression of GPR158 stimulates cell proliferation, while siRNA knockdown of endogenous GPR158 has the opposite effect. Both endogenous and overexpressed GPR158 show an unusual subcellular localization pattern, being found almost entirely in the nucleus. However, when cells are treated with inhibitors of clathrin-mediated endocytosis, GPR158 is shifted to the plasma membrane. Mutation of a bipartite nuclear localization signal (NLS) in the 8(th) helix also shifts GPR158 out of the nucleus, but in this case the protein is found in vesicles localized in the cytoplasm. These results suggest that newly synthesized GPR158 first traffics to the plasma membrane, where it rapidly undergoes endocytosis and translocation to the nucleus. Significantly, mutation of the NLS abrogates GPR158-mediated enhancement of cell proliferation, indicating a functional requirement for nuclear localization. GPR158 overexpression upregulates levels of the cell cycle regulator cyclin D1, but mutation of the NLS reverses this. Overexpression of GPR158 enhances the barrier function of a TBM cell monolayer, which is associated with an increase in the levels of tight junction proteins ZO-1 and occludin, similar to reported studies on GC treatment. Regulated paracellular permeability controls aqueous outflow facility in vivo. Since GCs stimulate GPR158 expression, the result is consistent with a role for elevation of GPR158 expression in GC induced ocular hypertension. PMID- 23451276 TI - Maintenance of islet morphology is beneficial for transplantation outcome in diabetic mice. AB - We have previously shown that co-transplantation of islets and Mesenchymal Stem Cells (MSCs) improves islet graft function and revascularisation, which was associated with the maintenance of normal islet morphology. The aim of the current study was to determine whether maintaining islet morphology in the absence of additional islet-helper cells would improve transplantation outcome in diabetic mice. Islets were isolated from C57BL/6 mice. Recipient streptozotocin diabetic C57BL/6 mice were transplanted with a minimal mass of 150 islets as a single pellet or islets that were either manually dispersed or dispersed within a matrigel plug beneath the kidney capsule. Blood glucose concentrations were monitored for one month. Islet graft morphology and vascularisation were analysed by histology. Islets dispersed either alone or within matrigel plugs maintained near normal morphology, in contrast to pelleted islets, where individual islets fused to form large endocrine aggregates. The vascularisation of manually dispersed islets and islets dispersed within matrigel plugs was increased relative to respective control pelleted islet grafts. After one month 1/6 mice transplanted with pelleted islets cured compared to 5/6 mice transplanted with manually dispersed islets. The curative capacity of islets dispersed in matrigel was also better than that of pelleted islets (5/8 islet-matrigel implanted mice vs. 1/7 mice transplanted with pelleted islets cured by one month). Therefore, this study demonstrates that the maintenance of islet morphology is associated with improved graft function and revascularisation in diabetic mice. PMID- 23451277 TI - The SHOCT domain: a widespread domain under-represented in model organisms. AB - We have identified a new protein domain, which we have named the SHOCT domain (Short C-terminal domain). This domain is widespread in bacteria with over a thousand examples. But we found it is missing from the most commonly studied model organisms, despite being present in closely related species. It's predominantly C-terminal location, co-occurrence with numerous other domains and short size is reminiscent of the Gram-positive anchor motif, however it is present in a much wider range of species. We suggest several hypotheses about the function of SHOCT, including oligomerisation and nucleic acid binding. Our initial experiments do not support its role as an oligomerisation domain. PMID- 23451278 TI - Contribution of common PCSK1 genetic variants to obesity in 8,359 subjects from multi-ethnic American population. AB - Common PCSK1 variants (notably rs6232 and rs6235) have been shown to be associated with obesity in European, Asian and Mexican populations. To determine whether common PCSK1 variants contribute to obesity in American population, we conducted association analyses in 8,359 subjects using two multi-ethnic American studies: the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Multi-Ethnic Study of Atherosclerosis (MESA). By evaluating the contribution of rs6232 and rs6235 in each ethnic group, we found that in European-American subjects from CARDIA, only rs6232 was associated with BMI (P = 0.006) and obesity (P = 0.018) but also increased the obesity incidence during the 20 years of follow-up (HR = 1.53 [1.07-2.19], P = 0.019). Alternatively, in African-American subjects from CARDIA, rs6235 was associated with BMI (P = 0.028) and obesity (P = 0.018). Further, by combining the two case-control ethnic groups from the CARDIA study in a meta-analysis, association between rs6235 and obesity risk remained significant (OR = 1.23 [1.05-1.45], P = 9.5*10(-3)). However, neither rs6232 nor rs6235 was associated with BMI or obesity in the MESA study. Interestingly, rs6232 was associated with BMI (P = 4.2*10(-3)) and obesity (P = 3.4*10(-3)) in the younger European-American group combining samples from the both studies [less than median age (53 years)], but not among the older age group (P = 0.756 and P = 0.935 for BMI and obesity, respectively). By combining all the case-control ethnic groups from CARDIA and MESA in a meta-analysis, we found no significant association for the both variants and obesity risk. Finally, by exploring the full PCSK1 locus, we observed that no variant remained significant after correction for multiple testing. These results indicate that common PCSK1 variants (notably rs6232 and rs6235) contribute modestly to obesity in multi ethnic American population. Further, these results suggest that the association of rs6232 with obesity may be age-dependent in European-Americans. However, multiple replication studies in multi-ethnic American population are needed to confirm our findings. PMID- 23451279 TI - Caspase-2 is upregulated after sciatic nerve transection and its inhibition protects dorsal root ganglion neurons from apoptosis after serum withdrawal. AB - Sciatic nerve (SN) transection-induced apoptosis of dorsal root ganglion neurons (DRGN) is one factor determining the efficacy of peripheral axonal regeneration and the return of sensation. Here, we tested the hypothesis that caspase-2 (CASP2) orchestrates apoptosis of axotomised DRGN both in vivo and in vitro by disrupting the local neurotrophic supply to DRGN. We observed significantly elevated levels of cleaved CASP2 (C-CASP2), compared to cleaved caspase-3 (C CASP3), within TUNEL+DRGN and DRG glia (satellite and Schwann cells) after SN transection. A serum withdrawal cell culture model, which induced 40% apoptotic death in DRGN and 60% in glia, was used to model DRGN loss after neurotrophic factor withdrawal. Elevated C-CASP2 and TUNEL were observed in both DRGN and DRG glia, with C-CASP2 localisation shifting from the cytosol to the nucleus, a required step for induction of direct CASP2-mediated apoptosis. Furthermore, siRNA-mediated downregulation of CASP2 protected 50% of DRGN from apoptosis after serum withdrawal, while downregulation of CASP3 had no effect on DRGN or DRG glia survival. We conclude that CASP2 orchestrates the death of SN-axotomised DRGN directly and also indirectly through loss of DRG glia and their local neurotrophic factor support. Accordingly, inhibiting CASP2 expression is a potential therapy for improving both the SN regeneration response and peripheral sensory recovery. PMID- 23451280 TI - ICAD deficiency in human colon cancer and predisposition to colon tumorigenesis: linkage to apoptosis resistance and genomic instability. AB - We previously showed that DNA fragmentation factor, which comprises a caspase-3 activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency may be associated with colon malignancy in humans. Indeed, an examination of ICAD expression using immunohistochemistry in an array of both colon cancer and normal tissues revealed that ICAD expression levels were severely compromised in the cancerous tissues. Upon DNA damage caused by a low dose of irradiation, ICAD cells acquire a tumorigenic phenotype. Colon epithelial cells derived from ICAD mice showed a significant resistance to death induced by the colon carcinogen dimethylhydrazine in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of dimethylhydrazine-induced colon tumorigenesis, ICAD(-/-) mice developed significantly higher numbers of tumors with markedly larger sizes than the wild type counterparts. Interestingly, the phenotype of the ICAD(-/-) mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a potential link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability as assessed by array comparative genomic hybridization. Such genomic instability consisted most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Altogether, our results present a viable case for the involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis. PMID- 23451281 TI - Lamin A/C haploinsufficiency modulates the differentiation potential of mouse embryonic stem cells. AB - BACKGROUND: Lamins are structural proteins that are the major determinants of nuclear architecture and play important roles in various nuclear functions including gene regulation and cell differentiation. Mutations in the human lamin A gene cause a spectrum of genetic diseases that affect specific tissues. Most available mouse models for laminopathies recapitulate disease symptoms for muscle diseases and progerias. However, loss of human lamin A/C also has highly deleterious effects on fetal development. Hence it is important to understand the impact of lamin A/C expression levels on embryonic differentiation pathways. METHODOLOGY AND PRINCIPAL FINDINGS: We have investigated the differentiation potential of mouse embryonic stem cells containing reduced levels of lamin A/C by detailed lineage analysis of embryoid bodies derived from these cells by in vitro culture. We initially carried out a targeted disruption of one allele of the mouse lamin A/C gene (Lmna). Undifferentiated wild-type and Lmna(+/-) embryonic stem cells showed similar expression of pluripotency markers and cell cycle profiles. Upon spontaneous differentiation into embryoid bodies, markers for visceral endoderm such as alpha-fetoprotein were highly upregulated in haploinsufficient cells. However, neuronal markers such as beta-III tubulin and nestin were downregulated. Furthermore, we observed a reduction in the commitment of Lmna(+/-) cells into the myogenic lineage, but no discernible effects on cardiac, adipocyte or osteocyte lineages. In the next series of experiments, we derived embryonic stem cell clones expressing lamin A/C short hairpin RNA and examined their differentiation potential. These cells expressed pluripotency markers and, upon differentiation, the expression of lineage-specific markers was altered as observed with Lmna(+/-) embryonic stem cells. CONCLUSIONS: We have observed significant effects on embryonic stem cell differentiation to visceral endoderm, neuronal and myogenic lineages upon depletion of lamin A/C. Hence our results implicate lamin A/C level as an important determinant of lineage-specific differentiation during embryonic development. PMID- 23451282 TI - 4-aminopyridine does not enhance flocculus function in tottering, a mouse model of vestibulocerebellar dysfunction and ataxia. AB - The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP's ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering's deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug's mechanism of action on cerebellar motor dysfunction. PMID- 23451283 TI - Intestinal parasitic infections in HIV infected and non-infected patients in a low HIV prevalence region, West-Cameroon. AB - The magnitude of intestinal parasitic infection in acquired immunodeficiency syndrome patients requires careful consideration in the developing world where poor nutrition is associated with poor hygiene and several tropical diseases. However, there have been very few studies addressing this issue in Cameroon. This study was conducted to determine the prevalence of intestinal parasitosis in HIV/AIDS patients in Dschang -Cameroon. Stool and blood specimens from HIV/AIDS patients and control group were screened respectively for intestinal parasites and for HIV antibodies. Intestinal parasites were identified using direct microscopy, formalin-ether concentration and Ziehl Neelsen methods. Out of 396 participants recruited among patients consulting at hospital, 42 (10.6%) were HIV positive, thirty of them treatment naive. The overall prevalence of intestinal parasites was 14.64%. Out of 42 HIV/AIDS patients, 59.5% (25/42) were infected with intestinal parasites, while only 9.32% (33/354) of the HIV negative patients were infected with intestinal parasites. The parasites detected in our study population included Crystosporidium parvum (2.53%), Entamoeba histolytica (7.52%), Entamoeba coli (4.04%), Giardia lamblia (0.25%), Trichuris trichura (0.25%), Strongyloides stercoralis (0.25%) and Taenia spp. (0.25%). In the HIV infected group, Crystosporidium parvum (19.04%), Entamoeba histolytica (19.04%), Entamoeba coli (21.42%), Giardia lamblia (2.38%), Strongyloides stercoralis (0.25%) and Taenia spp. (0.25%) were found. Crystosporidium parvum was found to be significantly higher in HIV/AIDS patients than in controls (P<0.05). Multivariate analysis showed that the HIV status and the quality of water were the major risk factors for intestinal parasitosis. Routine examinations of stool samples for parasites would significantly benefit the HIV patients by contributing in reducing morbidity and improving the efficiency of antiretroviral treatment. Even after the introduction of free anti-retroviral drugs, opportunistic intestinal infections are still a threat. HIV patients should be screened routinely for intestinal parasites and treated for their overall well being. PMID- 23451284 TI - Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice. AB - Obesity and type 2 diabetes are associated with increased production of Galectin 3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute phase proteins, number of circulating pro-inflammatory Ly6C(high) monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARgamma, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1alpha and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation. PMID- 23451285 TI - Energetic benefits of sociality offset the costs of parasitism in a cooperative mammal. AB - Sociality and particularly advanced forms of sociality such as cooperative breeding (living in permanent groups with reproductive division of labour) is relatively rare among vertebrates. A suggested constraint on the evolution of sociality is the elevated transmission rate of parasites between group members. Despite such apparent costs, sociality has evolved independently in a number of vertebrate taxa including humans. However, how the costs of parasitism are overcome in such cases remains uncertain. We evaluated the potential role of parasites in the evolution of sociality in a member of the African mole-rats, the only mammal family that exhibits the entire range of social systems from solitary to eusocial. Here we show that resting metabolic rates decrease whilst daily energy expenditure and energy stores (i.e. body fat) increase with group size in social Natal mole rats (Cryptomys hottentotus natalensis). Critically, larger groups also had reduced parasite abundance and infested individuals only showed measurable increases in energy metabolism at high parasite abundance. Thus, in some circumstances, sociality appears to provide energetic benefits that may be diverted into parasite defence. This mechanism is likely to be self-reinforcing and an important factor in the evolution of sociality. PMID- 23451286 TI - Inhibition of TGF-beta signaling enables human corneal endothelial cell expansion in vitro for use in regenerative medicine. AB - Corneal endothelial dysfunctions occurring in patients with Fuchs' endothelial corneal dystrophy, pseudoexfoliation syndrome, corneal endotheliitis, and surgically induced corneal endothelial damage cause blindness due to the loss of endothelial function that maintains corneal transparency. Transplantation of cultivated corneal endothelial cells (CECs) has been researched to repair endothelial dysfunction in animal models, though the in vitro expansion of human CECs (HCECs) is a pivotal practical issue. In this study we established an optimum condition for the cultivation of HCECs. When exposed to culture conditions, both primate and human CECs showed two distinct phenotypes: contact inhibited polygonal monolayer and fibroblastic phenotypes. The use of SB431542, a selective inhibitor of the transforming growth factor-beta (TGF-beta) receptor, counteracted the fibroblastic phenotypes to the normal contact-inhibited monolayer, and these polygonal cells maintained endothelial physiological functions. Expression of ZO-1 and Na(+)/K(+)-ATPase maintained their subcellular localization at the plasma membrane. Furthermore, expression of type I collagen and fibronectin was greatly reduced. This present study may prove to be the substantial protocol to provide the efficient in vitro expansion of HCECs with an inhibitor to the TGF-beta receptor, and may ultimately provide clinicians with a new therapeutic modality in regenerative medicine for the treatment of corneal endothelial dysfunctions. PMID- 23451289 TI - Perceptions of emergency department crowding in the commonwealth of pennsylvania. AB - INTRODUCTION: The state of emergency department (ED) crowding in Pennsylvania has not previously been reported. METHODS: We assessed perceptions of ED crowding by surveying medical directors/chairs from Pennsylvania EDs in the spring of 2008. RESULTS: A total of 106 completed the questionnaire (68% response rate). A total of 83% (86/104) agreed that ED crowding was a problem; 26% (27/105) reported that at least half of admitted patients boarded for more than 4 hours. Ninety-eight percent (102/104) agreed that patient satisfaction suffers during crowding and 79% (84/106) stated that quality suffers. Sixty-five percent (68/105) reported that crowding had worsened during the past 2 years. Several hospital interventions were used to alleviate crowding: expediting discharges, 81% (86/106); prioritizing ED patients for inpatient beds, 79% (84/106); and ambulance diversion, 55% (57/105). Almost all respondents who had improved ED operations reported that it had reduced crowding. CONCLUSION: ED crowding is a common problem in Pennsylvania and is worsening in the majority of hospitals, despite the implementation of a variety of interventions. PMID- 23451290 TI - Accuracy of Handheld Point-of-Care Fingertip Lactate Measurement in the Emergency Department. AB - INTRODUCTION: Early recognition of elevated lactate levels in sepsis may hasten the detection of those patients eligible for aggressive resuscitation. Point-of care (POC) testing is now increasingly available for use in the emergency department (ED). We examined the accuracy and time-saving effect of a handheld POC device for the measurement of fingertip and whole blood lactate as compared with reference laboratory testing in critically ill ED patients. METHODS: A convenience sample of adult ED patients receiving serum lactate testing was prospectively enrolled at an urban, tertiary care US hospital. Consenting patients underwent fingertip POC lactate measurement with a portable device and simultaneous whole blood sampling for analysis by both the POC device and standard laboratory analyzer ("reference method"). Lactate measurements were compared by intraclass correlation (ICC) and Bland and Altman plots. Differences in time to test result were compared by paired t test. RESULTS: Twenty-four patients, 19 (79%) with sepsis and 21 (88%) with lactate levels below 4 mmol/L, were included from April 2005 to May 2005. Fingertip POC and whole blood POC lactate measurements each correlated tightly with the reference method (ICC = 0.90 and ICC = 0.92, respectively). Mean time between obtaining fingertip lactate samples and whole blood reference lactate samples was 8 +/- 13 minutes. Mean time between obtaining POC and reference laboratory lactate results was 65 minutes (95% confidence interval, 30-103). CONCLUSION: Fingertip POC lactate measurement is an accurate method to determine lactate levels in infected ED patients with normal or modestly elevated lactate values and significantly decreases time to test results. These findings should be verified in a larger, more critically ill, ED population. PMID- 23451291 TI - Fatality and injury severity of older adult motor vehicle collisions in orange county, california, 1998-2007. AB - INTRODUCTION: Injuries and fatalities in adult drivers 18-65 years of age have decreased in recent years due to safer vehicles, enhanced medical policies, and implementation of injury prevention policies. However, adult drivers over 65 years of age are continuing to suffer from motor vehicle collision-related injuries and fatalities at a more constant rate. A number of physiological factors contribute to the deterioration in visual acuity, slower reaction speeds, and decreased awareness in older drivers. The objective of this study was to examine injury severity and fatality rates in older drivers compared to their younger counterparts in Orange County, California. METHODS: This study used the Statewide Integrated Traffic Record System data for Orange County for the years 1998-2007. Drivers were categorized into 4 age groups: 25-64, 65-74, 75-84, and older than 85 years of age. Injury severity was assessed by the investigating officer. RESULTS: Of the 197,814 drivers involved in motor vehicle collisions, 178,481 (90.2%) were in the 25-64 age group; 11,397 (5.8%) were 65-74; 6,592 (3.3%) were 75-84; and 1,344 drivers (0.7%) were over 85. Those aged 25-64 had the lowest fatality rate per 100,000 people, 2.5, whereas those 75-84 had the highest fatality rate, 4.9. The percent of crashes involving a left turn increased with age, and the percent that were stopped in the road decreases with age. Change in injury collision involvement ratio in the 3 younger age groups decreased by 26% to 32%, but decreased by 18% among drivers aged 85 years and older. CONCLUSION: The decrease in collision fatalities was greater in the 25-64 year-old group compared to the older adult population. This disparity highlights the need for further injury prevention efforts for older drivers. PMID- 23451292 TI - Report from the first snake genomics and integrative biology meeting. AB - This report summarizes the proceedings of the 1st Snake Genomics and Integrative Biology Meeting held in Vail, CO USA, 5-8 October 2011. The meeting had over twenty registered participants, and was conducted as a single session of presentations. Goals of the meeting included coordination of genomic data collection and fostering collaborative interactions among researchers using snakes as model systems. PMID- 23451293 TI - RCN4GSC Workshop Report: Modeling a Testbed for Managing Data at the Interface of Biodiversity and (Meta)Genomics, April 2011. AB - At the GSC11 meeting (4-6 April 2011, Hinxton, England, the GSC's genomic biodiversity working group (GBWG) developed an initial model for a data management testbed at the interface of biodiversity with genomics and metagenomics. With representatives of the Global Biodiversity Information Facility (GBIF) participating, it was agreed that the most useful course of action would be for GBIF to collaborate with the GSC in its ongoing GBWG workshops to achieve common goals around interoperability/data integration across (meta)-genomic and species level data. It was determined that a quick comparison should be made of the contents of the Darwin Core (DwC) and the GSC data checklists, with a goal of determining their degree of overlap and compatibility. An ad-hoc task group lead by Renzo Kottman and Peter Dawyndt undertook an initial comparison between the Darwin Core (DwC) standard used by the Global Biodiversity Information Facility (GBIF) and the MIxS checklists put forward by the Genomic Standards Consortium (GSC). A term-by-term comparison showed that DwC and GSC concepts complement each other far more than they compete with each other. Because the preliminary analysis done at this meeting was based on expertise with GSC standards, but not with DwC standards, the group recommended that a joint meeting of DwC and GSC experts be convened as soon as possible to continue this joint assessment and to propose additional work going forward. PMID- 23451294 TI - RCN4GSC Workshop Report: Managing Data at the Interface of Biodiversity and (Meta)Genomics, March 2011. AB - Building on the planning efforts of the RCN4GSC project, a workshop was convened in San Diego to bring together experts from genomics and metagenomics, biodiversity, ecology, and bioinformatics with the charge to identify potential for positive interactions and progress, especially building on successes at establishing data standards by the GSC and by the biodiversity and ecological communities. Until recently, the contribution of microbial life to the biomass and biodiversity of the biosphere was largely overlooked (because it was resistant to systematic study). Now, emerging genomic and metagenomic tools are making investigation possible. Initial research findings suggest that major advances are in the offing. Although different research communities share some overlapping concepts and traditions, they differ significantly in sampling approaches, vocabularies and workflows. Likewise, their definitions of 'fitness for use' for data differ significantly, as this concept stems from the specific research questions of most importance in the different fields. Nevertheless, there is little doubt that there is much to be gained from greater coordination and integration. As a first step toward interoperability of the information systems used by the different communities, participants agreed to conduct a case study on two of the leading data standards from the two formerly disparate fields: (a) GSC's standard checklists for genomics and metagenomics and (b) TDWG's Darwin Core standard, used primarily in taxonomy and systematic biology. PMID- 23451295 TI - Meeting Report: Hackathon-Workshop on Darwin Core and MIxS Standards Alignment (February 2012). AB - The Global Biodiversity Information Facility and the Genomic Standards Consortium convened a joint workshop at the University of Oxford, 27-29 February 2012, with a small group of experts from Europe, USA, China and Japan, to continue the alignment of the Darwin Core with the MIxS and related genomics standards. Several reference mappings were produced as well as test expressions of MIxS in RDF. The use and management of controlled vocabulary terms was considered in relation to both GBIF and the GSC, and tools for working with terms were reviewed. Extensions for publishing genomic biodiversity data to the GBIF network via a Darwin Core Archive were prototyped and work begun on preparing translations of the Darwin Core to Japanese and Chinese. Five genomic repositories were identified for engagement to begin the process of testing the publishing of genomic data to the GBIF network commencing with the SILVA rRNA database. PMID- 23451297 TI - Qualitative Research Part II: Participants, Analysis, and Quality Assurance. PMID- 23451296 TI - Cephalopod genomics: A plan of strategies and organization. AB - The Cephalopod Sequencing Consortium (CephSeq Consortium) was established at a NESCent Catalysis Group Meeting, "Paths to Cephalopod Genomics- Strategies, Choices, Organization," held in Durham, North Carolina, USA on May 24-27, 2012. Twenty-eight participants representing nine countries (Austria, Australia, China, Denmark, France, Italy, Japan, Spain and the USA) met to address the pressing need for genome sequencing of cephalopod mollusks. This group, drawn from cephalopod biologists, neuroscientists, developmental and evolutionary biologists, materials scientists, bioinformaticians and researchers active in sequencing, assembling and annotating genomes, agreed on a set of cephalopod species of particular importance for initial sequencing and developed strategies and an organization (CephSeq Consortium) to promote this sequencing. The conclusions and recommendations of this meeting are described in this white paper. PMID- 23451298 TI - Shift-to-Shift Handoff Research: Where Do We Go From Here? PMID- 23451299 TI - Serious play in the virtual world: can we use games to train young doctors? PMID- 23451300 TI - Knowing the Science Is Not Enough: Integrating Health Care Delivery and Services Into GME. PMID- 23451301 TI - Assessing the impact of innovative training of family physicians for the patient centered medical home. AB - BACKGROUND: New approaches to enhance access in primary care necessitate change in the model for residency education. PURPOSE: To describe instrument design, development and testing, and data collection strategies for residency programs, continuity clinics, residents, and program graduates participating in the Preparing the Personal Physician for Practice (P(4)) project. METHODS: We developed and pilot-tested surveys to assess demographic characteristics of residents, clinical and operational features of the continuity clinics and educational programs, and attitudes about and implementation status of Patient Centered Medical Home (PCMH) characteristics. Surveys were administered annually to P(4) residency programs since the project started in 2007. Descriptive statistics were used to profile data from the P(4) baseline year. RESULTS: Most P(4) residents were non-Hispanic white women (60.7%), married or partnered, attended medical school in the United States and were the first physicians in their families to attend medical school. Nearly 85% of residency continuity clinics were family health centers, and about 8% were federally qualified health centers. The most likely PCMH features in continuity clinics were having an electronic health record and having fully secure remote access available; both of which were found in more than 50% of continuity clinics. Approximately one-half of continuity clinics used the electronic health record for safety projects, and nearly 60% used it for quality-improvement projects. CONCLUSIONS: We created a collaborative evaluation model in all 14 P(4) residencies. Successful implementation of new surveys revealed important baseline features of residencies and residents that are pertinent to studying the effects of new training models for the PCMH. PMID- 23451302 TI - Simulation-based education with mastery learning improves paracentesis skills. AB - BACKGROUND: Paracentesis is a commonly performed bedside procedure that has the potential for serious complications. Therefore, simulation-based education for paracentesis is valuable for clinicians. OBJECTIVE: To assess internal medicine residents' procedural skills before and after simulation-based mastery learning on a paracentesis simulator. METHODS: A team with expertise in simulation and procedural skills developed and created a high fidelity, ultrasound-compatible paracentesis simulator. Fifty-eight first-year internal medicine residents completed a mastery learning-based intervention using the paracentesis simulator. Residents underwent baseline skill assessment (pretest) using a 25-item checklist. Residents completed a posttest after a 3-hour education session featuring a demonstration of the procedure, deliberate practice, ultrasound training, and feedback. All residents were expected to meet or exceed a minimum passing score (MPS) at posttest, the key feature of mastery learning. We compared pretest and posttest checklist scores to evaluate the effect of the educational intervention. Residents rated the training sessions. RESULTS: Residents' paracentesis skills improved from an average pretest score of 33.0% (SD = 15.2%) to 92.7% (SD = 5.4%) at posttest (P < .001). After the training intervention, all residents met or exceeded the MPS. The training sessions and realism of the simulation were rated highly by learners. CONCLUSION: This study demonstrates the ability of a paracentesis simulator to significantly improve procedural competence. PMID- 23451303 TI - Results from a transitional-year program director survey: identifying crucial issues and concerns. AB - BACKGROUND: Transitional Year (TY) programs meet an important need by preparing residents for specialties that accept individuals after an initial preparatory year. To our knowledge, no surveys to date have been conducted to identify attributes of TY programs and concerns of TY program directors. PURPOSE: The purpose of this study was to review TY program characteristics and identify critical issues and concerns of TY program directors (TYPDs). METHODS: A web based, 22-question survey was sent to all 114 TYPDs of programs accredited by the Accreditation Council for Graduate Medical Education between January and April 2011. The survey included open-formatted and closed-formatted questions addressing program and institution demographics, program director time, administrative support, satisfaction, and future plans. RESULTS: The survey response rate was 86%. The median age of TY programs was 28 years, with few new programs. More than 80% of TY programs were conducted at community hospitals and university-affiliated community hospitals. Of the responding TYPDs, 17% had served less than 2 years, and 32% had served 10 years or more. Common sponsoring TY programs included internal medicine (88%), general surgery (42%), family medicine (25%), emergency medicine (24%), and pediatrics (18%). Overall, TYPDs were satisfied with their positions. They expressed concerns about inadequate time to complete duties, salary support, and administrative duties assigned to program coordinators. Forty-nine percent of TYPDs reported they planned to leave the position within the next 5 years. CONCLUSIONS: Our survey provides useful information to assist institutions and the graduate medical education community in meeting the needs of TYPDs and strengthening TY programs. PMID- 23451304 TI - Impact of a Resident-as-Teacher Workshop on Teaching Behavior of Interns and Learning Outcomes of Medical Students. AB - BACKGROUND: Residents and interns are recognized as important clinical teachers and mentors. Resident-as-teacher training programs are known to improve resident attitudes and perceptions toward teaching, as well as their theoretical knowledge, skills, and teaching behavior. The effect of resident-as-teacher programs on learning outcomes of medical students, however, remains unknown. An intervention cohort study was conducted to prospectively investigate the effects of a teacher-training workshop on teaching behavior of participating interns and on the clerkship learning outcomes of instructed fourth-year medical students. METHODS: The House Officer-as-Teacher Training Workshop was implemented in November 2009 over 1.5 days and attended by all 34 interns from one teaching hospital. Subsequently, between February and August 2010, 124 fourth-year medical students rated the observable teaching behavior of interns during 6-week general surgery clerkships at this intervention hospital as well as at 2 comparable hospitals serving as control sites. Ratings were collected using an anonymous 15 item Intern Clinical Teaching Effectiveness Instrument. Student achievement of clerkship learning outcomes during this period was evaluated using a validated and centralized objective structured clinical examination. RESULTS: Medical students completed 101 intern clinical teaching effectiveness instruments. Intern teaching behavior at the intervention hospital was found to be significantly more positive, compared with observed behavior at the control hospitals. Objective structured clinical examination results, however, did not demonstrate any significant intersite differences in student achievement of general surgery clerkship learning outcomes. CONCLUSIONS: The House Officer-as-Teacher Training Workshop noticeably improved teaching behavior of surgical interns during general surgery clerkships. This improvement did not, however, translate into improved achievement of clerkship learning outcomes by medical students during the study period. PMID- 23451305 TI - Effect of audit and feedback on improving handovers: a nonrandomized comparative study. AB - BACKGROUND: High-quality, shift-to-shift handovers by residents are critical to ensuring to patient safety. The 2011 Accreditation Council for Graduate Medical Education duty hour requirements have increased the number of handovers occurring daily, necessitating new approaches to this challenge. Research suggests standardized approaches, electronic systems, and education programs can improve the handover process. METHODS: We conducted a 2-phase, observational study comparing an electronic handover system (experimental) in one clinical setting to a standard card-based system (control) at a second site. Outcome data included an objective assessment of the completeness and accuracy of handovers, and resident assessment of the handover systems. In phase 1, data were recorded at both sites and not shared with residents. In phase 2, data from the experimental system were used to provide standardized feedback to residents on the quality of their handovers. RESULTS: A total of 3184 individual patient sign-outs were evaluated during the 11-month period. Following introduction of a feedback intervention in the experimental arm, errors were present in only 5.2% of handovers, compared with 16.1% of controls (P < .001), and 67% of the 38 residents responding reported they perceived the experimental system as facilitating better patient care. CONCLUSION: Regular, real-time feedback through an electronic handover system can improve the accuracy and completeness of handovers in patient care. PMID- 23451306 TI - Determining need for remediation through postrotation evaluations. AB - INTRODUCTION: Postrotation evaluations are frequently used by residency program directors for early detection of residents with academic difficulties; however, the accuracy of these evaluations in assessing resident performance has been questioned. METHODS: This retrospective case-control study examines the ability of postrotation evaluation characteristics to predict the need for remediation. We compared the evaluations of 17 residents who were placed on academic warning or probation, from 2000 to 2007, with those for a group of peers matched on sex, postgraduate year (PGY), and entering class. RESULTS: The presence of an outlier evaluation, the number of words written in the comments section, and the percentage of evaluations with negative or ambiguous comments were all associated with the need for remediation (P = .01, P = .001, P = .002, P = < .001, respectively). In contrast, United States Medical Licensing Examination step 1 and step 2 scores, total number of evaluations received, and percentage of positive comments on the evaluations were not associated with the need for remediation (P = .06, P = .87, P = .55, respectively). DISCUSSION: Despite ambiguous evaluation comments, the length and percentage of ambiguous or negative comments did indicate future need for remediation. CONCLUSIONS: Our study demonstrates that postrotation evaluation characteristics can be used to identify residents as risk. However, larger prospective studies, encompassing multiple institutions, are needed to validate various evaluation methods in measuring resident performance and to accurately predict the need for remediation. PMID- 23451307 TI - Narrative, written sign-outs and interns' and senior medical students' confidence: a randomized, controlled crossover trial. AB - BACKGROUND: Failures of communication during the transfer of patient care errors. METHODS: We created a new format for written sign-out material, based on aviation industry practice and cognitive psychology theory, designed to improve interns' and senior medical students' communication during transfers of patient care responsibility. We carried out a randomized, blinded, crossover trial, comparing a new, narrative, written sign-out report to a usual written sign-out. Thirty-two interns and fourth-year medical students rated their confidence across various clinical tasks and answered clinical questions regarding hypothetical patients presented to them in written, new, narrative sign-out compared with the customary format. RESULTS: There was no statistical difference in confidence when interns and senior medical students received usual versus narrative sign-outs. CONCLUSIONS: Although a limited measure suggested some improvement in competence, the narrative format did not improve participants' self-rated confidence during patient-care transfer. PMID- 23451308 TI - Equipping Residents to Address Alcohol and Drug Abuse: The National SBIRT Residency Training Project. AB - BACKGROUND: The Screening, Brief Intervention and Referral to Treatment (SBIRT) service for unhealthy alcohol use has been shown to be one of the most cost effective medical preventive services and has been associated with long-term reductions in alcohol use and health care utilization. Recent studies also indicate that SBIRT reduces illicit drug use. In 2008 and 2009, the Substance Abuse Mental Health Service Administration funded 17 grantees to develop and implement medical residency training programs that teach residents how to provide SBIRT services for individuals with alcohol and drug misuse conditions. This paper presents the curricular activities associated with this initiative. METHODS: We used an online survey delivery application (Qualtrics) to e-mail a survey instrument developed by the project directors of 4 SBIRT residency programs to each residency grantee's director. The survey included both quantitative and qualitative data. RESULTS: All 17 (100%) grantees responded. Respondents encompassed residency programs in emergency medicine, family medicine, pediatrics, obstetrics-gynecology, psychiatry, surgery, and preventive medicine. Thirteen of 17 (76%) grantee programs used both online and in-person approaches to deliver the curriculum. All 17 grantees incorporated motivational interviewing and validated screening instruments in the curriculum. As of June 2011, 2867 residents had been trained, and project directors reported all residents were incorporating SBIRT into their practices. Consistently mentioned challenges in implementing an SBIRT curriculum included finding time in residents' schedules for the modules and the need for trained faculty to verify resident competence. CONCLUSIONS: The SBIRT initiative has resulted in rapid development of educational programs and a cohort of residents who utilize SBIRT in practice. Skills verification, program dissemination, and sustainability after grant funding ends remain ongoing challenges. PMID- 23451309 TI - Using a commercially available web-based evaluation system to enhance residents' teaching. AB - BACKGROUND: Residents-as-teachers (RATs) programs have been shown to improve trainees' teaching skills, yet these decline over time. INTERVENTION: We adapted a commercial Web-based system to maintain resident teaching skills through reflection and deliberate practice and assessed the system's ability to (1) prevent deterioration of resident teaching skills and (2) provide information to improve residents' teaching skills and teaching program quality. METHODS: Ten first-year obstetrics-gynecology (Ob-Gyn) residents participated in a RATs program. Following the program, they used a commercial evaluation system to complete self-assessments of their teaching encounters with medical students. Students also evaluated the residents. To assess the system's effectiveness, we compared these residents to historical controls with an Objective Structured Teaching Examination (OSTE) and analyzed the ratings and the free text comments of residents and students to explore teaching challenges and improve the RATs program. RESULTS: The intervention group outscored the control group on the OSTE (mean score +/- SD = 81 +/- 8 versus 74 +/- 7; P = .05, using a 2-tailed Student t-test). Rating scale analysis showed resident self-assessments were consistently lower than student evaluations, with the difference reaching statistical significance in 3 of 6 skills (P < .05). Comments revealed that residents most valued using innovative teaching techniques, while students most valued a positive educational climate and interpersonal connections with residents. Recommended targets for RATs program improvement included teaching feedback, time-limited teaching, and modeling professionalism behaviors. CONCLUSIONS: Our novel electronic Web-based reinforcement system shows promise in preventing deterioration of resident teaching skills learned during an Ob-Gyn RATs program. The system also was effective in gaining resident and student insights to improve RATs programs. Because our intervention was built upon a commercially available program, our approach could prove useful to the large population of current subscribers. PMID- 23451311 TI - Training residents to address cancer health disparities. AB - INTRODUCTION: Cancer is the source of significant morbidity and mortality in the United States, and eliminating cancer-related racial and ethnic disparities has become an ever-increasing focus of public health efforts. Increasing workforce diversity plays a major role in the reduction of health disparities, and a well trained professional workforce is essential for the prevention, control, and ultimate elimination of this disease. METHODS: To help address this need, the Public Health/General Preventive Medicine residency program at Morehouse School of Medicine (MSM) developed an innovative Cancer Prevention and Control Track (CPCT). We describe the structure of the track, funding, examples of resident activities, and program successes. RESULTS: Since the development of the track in 2007, there have been 3 graduates, and 2 residents are currently enrolled. Residents have conducted research projects and have engaged in longitudinal community-based activities, cancer-focused academic experiences, and practicum rotations. There have been 3 presentations at national meetings, 1 research grant submitted, and 1 research award. CONCLUSION: The CPCT provides residents with comprehensive cancer prevention and control training with emphasis in community engagement, service, and research. It builds on the strengths of the diversity training already offered at MSM and combines resources from academia, the private sector, and the community at large. PMID- 23451310 TI - An interactive handoff workshop to improve intern readiness in patient care transitions. AB - INTRODUCTION: Patient handoffs are common during residency and are often performed with little or no training. We devised a simple intervention to improve the readiness of interns to perform handoffs. METHODS: We administered a 90 minute interactive workshop during intern orientation in 2009 and 2010. It consisted of a discussion, a case presentation, and a trigger video, followed by debriefing and a role-play exercise. The workshop required minimal technology and materials. Interns were surveyed on their readiness to perform handoffs before and after the workshop as well as 3 to 6 months after the workshop. RESULTS: Eighty-nine interns participated in the workshop during a 2-year period. Seventy four survey responses were collected. Self-reported readiness to perform a handoff increased by 26%. A total of 91% and 81% of respondents in 2010 and 2009, respectively, reported using aspects of the workshop up to 6 months later. CONCLUSION: A brief workshop can improve interns' readiness to perform handoffs. PMID- 23451312 TI - Integrative medicine in residency education: developing competency through online curriculum training. AB - INTRODUCTION: The Integrative Medicine in Residency (IMR) program, a 200-hour Internet-based, collaborative educational initiative was implemented in 8 family medicine residency programs and has shown a potential to serve as a national model for incorporating training in integrative/complementary/alternative medicine in graduate medical education. INTERVENTION: The curriculum content was designed based on a needs assessment and a set of competencies for graduate medical education developed following the Accreditation Council for Graduate Medical Education outcome project guidelines. The content was delivered through distributed online learning and included onsite activities. A modular format allowed for a flexible implementation in different residency settings. EVALUATION: TO ASSESS THE FEASIBILITY OF IMPLEMENTING THE CURRICULUM, A MULTIMODAL EVALUATION WAS UTILIZED, INCLUDING: (1) residents' evaluation of the curriculum; (2) residents' competencies evaluation through medical knowledge testing, self-assessment, direct observations, and reflections; and (3) residents' wellness and well-being through behavioral assessments. RESULTS: The class of 2011 (n = 61) had a high rate of curriculum completion in the first and second year (98.7% and 84.2%) and course evaluations on meeting objectives, clinical utility, and functioning of the technology were highly rated. There was a statistically significant improvement in medical knowledge test scores for questions aligned with content for both the PGY-1 and PGY-2 courses. CONCLUSIONS: The IMR program is an advance in the national effort to make training in integrative medicine available to physicians on a broad scale and is a success in terms of online education. Evaluation suggests that this program is feasible for implementation and acceptable to residents despite the many pressures of residency. PMID- 23451313 TI - Incorporating evidence into clinical teaching: enhanced geriatrics specialty case based residency presentations. AB - INTRODUCTION: Case-based presentations are widely used in medical education and are a preferred education modality to teach about the care of geriatric patients across a range of medical specialties. METHODS: We incorporated evidence-based materials from topical literature syntheses into case-based presentations on the care of geriatric patients for use by specialty residents. These enhanced case based presentations were used to augment learning and to facilitate detection of additional educational needs for future resident training sessions. RESULTS: Forty case-based presentations were presented to 11 specialty programs during a 4 year period. The program was popular, and program directors and residents requested additional presentations. Geriatric evidence-based summaries were viewed online 375 times during the course of the project. Geriatric clinical consults increased from an average of 10 consults a year to 141 from 64 different providers during the first year. DISCUSSION: Case-based presentation, enhanced with evidence-based summaries of research literature generated by information specialists, is a feasible and effective approach to teaching clinical content. These presentations can be used to target geriatrics educational competencies for resident trainees in nongeriatric specialties. PMID- 23451314 TI - A structured workshop to improve the quality of resident discharge summaries. AB - BACKGROUND: Poor communication at hospital discharge can increase the risk of adverse events. The hospital discharge summary is the most common tool for detailing events related to hospitalization in preparation for postdischarge follow-up, yet deficiencies in discharge summaries have been widely reported. Resident physicians are expected to dictate discharge summaries but receive little formal training in this arena. We hypothesized that implementation of an educational program on chart documentation skills would result in improvements in the quality of hospital discharge summaries in a community hospital internal medicine residency program. METHODS: A monthly, 1-hour workshop was launched in August 2007 to provide consistent and ongoing instruction on chart documentation. Guided by a faculty moderator, residents reviewed 2 randomly selected peer chart notes per session using instruments developed for that purpose. After the workshop had been in place for 2 years, 4 faculty members reviewed 63 randomly selected discharge summaries from spring 2007, spring 2008, and spring 2009 using a 14-item evaluation tool. RESULTS: Mean scores for 10 of the 14 individual items improved in a stepwise manner during the 3 years of the study. Items related to overall quality of the discharge summary showed statistically significant improvement, as did the portion of the summaries "carbon copied" to the responsible outpatient physician. CONCLUSIONS: The quality of hospital discharge summaries improved following the implementation of a novel, structured program to teach chart documentation skills. Ongoing improvement was seen 1 and 2 years into the program, suggesting that continuing instruction in those skills was beneficial. PMID- 23451315 TI - A new tool for testing and training ophthalmoscopic skills. AB - INTRODUCTION: The direct fundoscopic examination is an important clinical skill, yet the examination is difficult to teach and competency is difficult to assess. Currently there is no defined proficiency assessment for this physical examination, and the objective of this study was to assess the feasibility of a simulation model for evaluating the fundoscopic skills of residents. METHODS: Emergency medicine and ophthalmology residents participated in simulation sessions using a commercially available eye simulator that was modified with customized slides. The slides were designed with the goal of having a quantifiable measure of visualization in addition to a more traditional descriptive outcome. To assess feasibility, participants' ease of use, time to perform the examination, and user satisfaction were assessed. RESULTS: The simulation could be completed in a timely fashion (mean time per slide, 61-95 seconds), and there were no significant differences in performance between emergency medicine and ophthalmology residents in completion of this task. Residents expressed an interest in fundoscopy through simulation but found this model technically challenging. CONCLUSIONS: This simulation model has potential as a means of training and testing fundoscopy. A concern was low user satisfaction, and further refinement of the model is needed. PMID- 23451316 TI - Redesign of an internal medicine ward rotation: operational challenges and outcomes. AB - INTRODUCTION: In anticipation of the 2011 ACGME duty hour requirements, we redesigned our internal medicine resident ward experience. Our previous ward structure included a maximum 30-hour duty period for postgraduate year-1 (PGY-1) residents. In the redesigned ward structure, PGY-1 residents had a maximum 18 hour duty period. METHODS: We evaluated resident conference attendance and duty hour violations before and after implementation of our new ward redesign. We administered a satisfaction survey to residents and faculty 6 months after implementation of the new ward redesign. RESULTS: Before implementation of the ward redesign, 30-hour continuous and 80-h/wk duty violations were each 2/year, and violations of the 10-hour rest between duty periods were 10/year for 74 residents. After implementation of the ward redesign, there were no 30-hour continuous or 80-h/wk duty violations, but violations of the 10-hour rest between duty periods more than doubled (26/year for 75 residents). Duty hours were reported by different mechanisms for the 2 periods. Conference attendance improved. Resident versus faculty satisfaction scores were similar. Both groups judged overall professional satisfaction as slightly worse after implementation. CONCLUSION: Our ward rotation redesign eliminated 30-hour continuous and 80-h/wk duty violations as well as improved conference attendance. These benefits occurred at the cost of more faculty hires, decreased resident elective time, and slightly worse postimplementation satisfaction scores. PMID- 23451317 TI - Education in professionalism: results from a survey of pediatric residency program directors. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires pediatric residency programs to teach professionalism but does not provide concrete guidance for fulfilling these requirements. Individual programs, therefore, adopt their own methods for teaching and evaluating professionalism, and published research demonstrating how to satisfy the ACGME professionalism requirement is lacking. METHODS: We surveyed pediatric residency program directors in 2008 to explore the establishment of expectations for professional conduct, the educational experiences used to foster learning in professionalism, and the evaluation of professionalism. RESULTS: Surveys were completed by 96 of 189 program directors (51%). A majority reported that new interns attend a session during which expectations for professionalism are conveyed, either verbally (93%) or in writing (65%). However, most program directors reported that "None or Few" of their residents engaged in multiple educational experiences that could foster learning in professionalism. Despite the identification of professionalism as a core competency, a minority (28%) of programs had a written curriculum in ethics or professionalism. When evaluating professionalism, the most frequently used assessment strategies were rated as "very useful" by only a modest proportion (26%-54%) of respondents. CONCLUSIONS: Few programs have written curricula in professionalism, and opportunities for experiential learning in professionalism may be limited. In addition, program directors express only moderate satisfaction with current strategies for evaluating professionalism that were available through 2008. PMID- 23451318 TI - Variability in obtaining institutional review board approval for quality improvement activities in residency programs. AB - INTRODUCTION: Quality improvement (QI) activities are an important part of residency training. National studies are needed to inform best practices in QI training and experience for residents. The impact of the Institutional Review Board (IRB) process on such studies is not well described. METHODS: This observational study looked at time, length, comfort level, and overall quality of experience for 42 residency training programs in obtaining approval or exemption for a nationally based educational QI study. RESULTS: For the 42 programs in the study, the time period to IRB approval/exemption was highly variable, ranging from less than 1 week to 56.5 weeks; mean and median time was approximately 18 weeks (SD, 10.8). Greater reported comfort with the IRB process was associated with less time to obtain approval (r = -.50; P < .01; 95% CI, -0.70 to -0.23). A more positive overall quality of experience with the IRB process was also associated with less time to obtain IRB approval (r = -.60; P < .01; 95% CI, 0.74 to -0.36). DISCUSSION: The IRB process for residency programs initiating QI studies shows considerable variance that is not explained by attributes of the projects. New strategies are needed to assist and expedite IRB processes for QI research in educational settings and reduce interinstitutional variability and increase comfort level among educators with the IRB process. PMID- 23451319 TI - Meeting the Scholarly Project Requirement-Application of Scholarship Criteria beyond Research. PMID- 23451320 TI - The education data warehouse: a transformative tool for health education research. PMID- 23451321 TI - Journal club 102: enhancing evidence-based medicine learning using a virtual journal club. PMID- 23451322 TI - "Over the shoulder" training: impact on the experience of local iraqi physicians. PMID- 23451323 TI - An observational study of junior neurosurgery resident call at a large teaching hospital. PMID- 23451324 TI - I have been changed for good. PMID- 23451326 TI - Top reviewers for 2011. PMID- 23451325 TI - Satisfiers and hygiene factors: residents' perceptions of strengths and limitations of their learning environment. AB - BACKGROUND: Efforts are underway to enhance learner input into the accreditation of educational programs, including residencies and fellowships. OBJECTIVES: To aggregate the perspectives of residents and fellows from a cross-section of specialties to highlight common dimensions in learners' perceptions of strengths and opportunities for improvement (OFIs) in their program and to assess whether the ACGME Resident Survey captures areas important to residents' perceptions of their learning environment. RESULTS: The data set included 206 core and 193 subspecialty programs representing a wide range of specialties and subspecialties. Comments on strengths and OFIs addressed most of the items in the Resident Survey, with items not addressed in the survey also not represented in the ACGME requirements. The findings suggest that some program attributes are mentioned only in their absence (hygiene factors), whereas other dimensions (satisfiers), particularly quality and quantity of residents' interactions with faculty, procedural volume, and variety and didactic offerings, are critical to learners' perceptions of the quality of their learning environment. For some strengths, residents indicated their programs exceeded the ACGME standards, and for areas identified as OFIs, comments suggested programs were in compliance, but the residents desired more. Mentioned in this context were opportunities to perform research, access to board preparation courses and career counseling, and availability of new technology, including new patient care modalities. CONCLUSIONS: The findings allow insight into program attributes important to residents' perceptions of their learning environment. Programs may find the results helpful in suggesting areas for improvement in their learning environment. PMID- 23451327 TI - The role of local excision in invasive adenocarcinoma of the ampulla of Vater. PMID- 23451328 TI - Assessment of clinical benefit and quality of life in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of peritoneal carcinomatosis. PMID- 23451329 TI - Fine needle aspiration biopsy of malignant mass lesions in the liver: a revisit of diagnostic profiles and challenges. PMID- 23451331 TI - A molecularly confirmed neuroendocrine tumor resulting from Lynch Syndrome. PMID- 23451330 TI - The role of EGFR monoclonal antibodies (MoABs) cetuximab/panitumab, and BRAF inhibitors in BRAF mutated colorectal cancer. PMID- 23451332 TI - Adenocarcinoma of the proximal rectum and synchronous non-Hodgkin's lymphoma. PMID- 23451333 TI - Primary hepatic anaplastic large cell ki-1 lymphoma and celiac disease: a casual association? PMID- 23451334 TI - Classification of Allergic Rhinitis: What is Most Suitable in Korea? PMID- 23451336 TI - Valproic acid-induced hyperammonemic encephalopathy - a potentially fatal adverse drug reaction. AB - BACKGROUND: A patient with an early diagnosed epilepsy Valproic acid is one of the most widely used antiepileptic drugs. Hyperammonemic encephalopathy is a rare, but potentially fatal, adverse drug reaction to valproic acid. CASE DESCRIPTION: A patient with an early diagnosed epilepsy, treated with valproic acid, experienced an altered mental state after 10 days of treatment. Valproic acid serum levels were within limits, hepatic function tests were normal but ammonia levels were above the normal range. Valproic acid was stopped and the hyperammonemic encephalopathy was treated with lactulose 15 ml twice daily, metronidazole 250 mg four times daily and L-carnitine 1 g twice daily. DISCUSSION AND EVALUATION: Monitoring liver function and ammonia levels should be recommended in patients taking valproic acid. The constraints of the pharmaceutical market had to be taken into consideration and limited the pharmacological options for this patient's treatment. CONCLUSIONS: Idiosyncratic symptomatic hyperammonemic encephalopathy is completely reversible, but can induce coma and even death, if not timely detected. Clinical pharmacists can help detecting adverse drug reactions and provide evidence based information for the treatment. PMID- 23451337 TI - Headache after exposure to 'date-rape' drugs. AB - SUMMARY: We report two patients who developed a prolonged featureless headache, they think after a drink was 'spiked'. We speculate that each was exposed to scopolamine, resulting in enhanced trigeminal release of vasodilator neuropeptides, including Calcitonin Gene-Related Peptide (CGRP), and thus the headache. PMID- 23451335 TI - Distinct 3-O-sulfated heparan sulfate modification patterns are required for kal 1-dependent neurite branching in a context-dependent manner in Caenorhabditis elegans. AB - Heparan sulfate (HS) is an unbranched glycosaminoglycan exhibiting substantial molecular diversity due to multiple, nonuniformly introduced modifications, including sulfations, epimerization, and acetylation. HS modifications serve specific and instructive roles in neuronal development, leading to the hypothesis of a HS code that regulates nervous system patterning. Although the in vivo roles of many of the HS modifications have been investigated, very little is known about the function of HS 3-O-sulfation in vivo. By examining patterning of the Caenorhabditis elegans nervous system in loss of function mutants of the two 3-O sulfotransferases, hst-3.1 and hst-3.2, we found HS 3-O-sulfation to be largely dispensable for overall neural development. However, generation of stereotypical neurite branches in hermaphroditic-specific neurons required hst-3.1, hst-3.2, as well as an extracellular cell adhesion molecule encoded by kal-1, the homolog of Kallmann Syndrome associated gene 1/anosmin-1. In contrast, kal-1-dependent neurite branching in AIY neurons required catalytic activity of hst-3.2 but not hst-3.1. The context-dependent requirement for hst-3.2 and hst-3.1 indicates that both enzymes generate distinct types of HS modification patterns in different cell types, which regulate kal-1 to promote neurite branching. We conclude that HS 3-O-sulfation does not play a general role in establishing the HS code in C. elegans but rather plays a specialized role in a context-dependent manner to establish defined aspects of neuronal circuits. PMID- 23451338 TI - Acute Myeloid Leukaemia (AML) Presenting as a Bilateral Pleural Effusion. PMID- 23451339 TI - Rapid and selective access to three distinct sets of indole-based heterocycles from a single set of Ugi-adducts under microwave heating. AB - Three distinct sets of indole-based heterocycles were rapidly and selectively synthesized from the same set of Ugi-adducts under microwave heating in a reaction-condition-controlled manner. Notably, an unprecedented metal-free intramolecular sp(3)-hybridized C-H arylation using only cesium carbonate was discovered. PMID- 23451340 TI - Erythema multiforme minor after ibuprofen use for menstrual pain. PMID- 23451341 TI - [Nursing care]. PMID- 23451342 TI - [Research study regarding the benefits of nursing care in the twilight syndrome]. AB - The twilight syndrome manifests with the appearance of a severe confusional state which damages the patient's cognitive potential. The aim of this study was to evaluate whether nursing care focused on the patient's space-time orientation could reduce or even prevent the onset of this syndrome. The study comprised 48 patients, 17 in the action group and 31 in the control group. The results of the study showed that the nursing strategies implemented, aimed at maintaining the patient's cognitive, perceptive and orientation functions, not only slowed down the progression of the syndrome but also made early recognition possible. PMID- 23451343 TI - The role of the poor in medical research and the physician's duty to protect. PMID- 23451344 TI - Sustainability: Environmental puzzle solvers. PMID- 23451345 TI - [Nine reasons not to recommend protein rich diet]. PMID- 23451346 TI - [From KRAM to KRAMS: Is the holy grave well preserved?]. PMID- 23451347 TI - [The prohibited diagnoses--state authorized age discrimination?]. PMID- 23451348 TI - Response to letter regarding article, "critique of closure or medical therapy for cryptogenic stroke with patent foramen ovale: the hole truth?". PMID- 23451349 TI - Response to letter regarding article, "smartphone teleradiology application is successfully incorporated into a telestroke network environment". PMID- 23451350 TI - Gold on hold. PMID- 23451351 TI - Starvation diet. PMID- 23451352 TI - Prize drawback. PMID- 23451353 TI - Characterization of the oligomerization and ligand-binding properties of recombinant rat lipocalin 11. AB - Lipocalin 11 (Lcn11), a recently identified member of the lipocalin family, potentially plays crucial physiological roles in male reproduction. In this present work, we cloned, expressed and purified the rat Lcn11 (rLcn11) protein Escherichia coli. A C59A/C156A substitution was introduced to ameliorate the misfolding and aggregation problem associated with the wild-type protein. From circular dichroism and non-reducing SDS-PAGE, we characterized the conformational properties of rLcn11 as a typical lipocalin scaffold with the conserved disulfide bridge. The results obtained from size-exclusion chromatography, cross-linking experiment and dynamic light scattering analysis indicate that the recombinant rLcn11 protein forms dimer in neutral solution. By using fluorescent probe anilino-1 napthahlene sulfonic acid (ANS), we found rLcn might contain multiple hydrophobic binding sites for ligand binding. Similarly to the odorant-binding protein, rLcn11 processes a moderate affinity for binding 1-aminoanthracene (AMA), implying that Lcn11 might work as a dimeric chemoreception protein in male reproductive. PMID- 23451354 TI - Reply to A. Levy et al. PMID- 23451355 TI - Reply to P.H. Sugarbaker. PMID- 23451356 TI - National Highway Traffic Safety Administration. An analysis of recent improvements to vehicle safety. PMID- 23451357 TI - How can clinicians measure safety and quality in acute care? AB - The demand for high quality care is increasing and warranted. Evidence suggests that the quality of care in hospitals can be improved. The greatest opportunity to improve outcomes for patients over the next quarter century will probably come not from discovering new treatments but from learning how to deliver existing effective therapies. To improve, caregivers need to know what to do, how they are doing, and be able to improve the processes of care. The ability to monitor performance, though challenging in healthcare, is essential to improving quality of care. We present a practical method to assess and learn from routine practice. Methods to evaluate performance from industrial engineering can be broadly applied to efforts to improve the quality of healthcare. One method that may help to provide caregivers frequent feedback is time series data--ie, results are graphically correlated with time. Broad use of these tools might lead to the necessary improvements in quality of care. PMID- 23451358 TI - This month in aerospace medicine history. PMID- 23451359 TI - Increased 5-bromo-2'-deoxyuridine incorporation in various brain structures following passive avoidance training in mice. AB - We studied the effects of training on DNA synthesis intensity in mouse brain. Brain cells where DNA synthesis-associated processes took place under the influence of training were detected by immunohistochemical labeling of DNA molecules with synthetic thymine analogue 5-bromo-2'-deoxyuridine. The number of 5-bromo-2'-deoxyuridine-positive cell increased in various structures of the brain under the influence of training. PMID- 23451360 TI - Clinical leadership for commissioning. PMID- 23451361 TI - Educational scholarships: an innovative addition to GP training. PMID- 23451362 TI - Ciencia & Saude Coletiva: what has been achieved to date and what has yet to be done. PMID- 23451363 TI - Evidence-Based Toxicology Collaboration (EBTC). Editorial. PMID- 23451364 TI - Aging out of autism. A new study suggest symptoms can fade with time. PMID- 23451365 TI - Determination of total folates in infant formula and adult nutritionals by trienzyme extraction and UPLC-MS/MS Quantitation: First Action 2011.06. AB - The method for "Determination of Total Folates in Infant Formula and Adult Nutritionals by Trienzyme Extraction and UPLC-MS/MS Quantitation" was submitted to the Folate Working Group for consideration for adoption as Official First Action by AOAC INTERNATIONAL. This method uses ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) to determine the total folates in infant formulas and adult nutritionals after trienzyme digestion. Deconjugation of the various folate polyglutamates to folate monoglutamates is achieved by using rat plasma conjugase after the sample digestion with protease and a-amylase during the trienzyme digestion process. This method shows linearity of folate concentrations in the range of 10-19 100 microg/100 g. Extension of the range to cover folate concentrations of 5-2 000 000 microg/100 g can be achieved with appropriate adjustment of the sample weight and SPE cleanup loading volume. The recoveries ranged from 94.10 to 101.34%. PMID- 23451366 TI - Expert review panel approves First Action methods for antioxidants in foods. PMID- 23451367 TI - AOAC SMPR 2011.011. Standard method performance requirements for in vitro determination of total antioxidant activity in foods, beverages, food ingredients, and dietary supplements. PMID- 23451368 TI - Application of a microplate-based ORAC-pyrogallol red assay for the estimation ofantioxidant capacity: First Action 2012.03. AB - A method was developed for microplate-based oxygen radicals absorbance capacity (ORAC) using pyrogallol red (PGR) as probe (ORAC-PGR). The method was evaluated for linearity, precision, and accuracy. In addition, the antioxidant capacity of commercial beverages, such as wines, fruit juices, and iced teas, was measured. Linearity of the area under the curve (AUC) versus Trolox concentration plots was [AUC = (845 +/- 110) + (23 +/- 2) [Trolox, microM]; R = 0.9961, n = 19]. Analyses showed better precision and accuracy at the highest Trolox concentration (40 microM) with RSD and recovery (REC) values of 1.7 and 101.0%, respectively. The method also showed good linearity for red wine [AUC = (787 +/- 77) + (690 +/- 60) [red wine, microL/mL]; R = 0.9926, n = 17], precision and accuracy with RSD values from 1.4 to 8.3%, and REC values that ranged from 89.7 to 103.8%. Red wines showed higher ORAC-PGR values than white wines, while the ORAC-PGR index of fruit juices and iced teas presented a wide range of results, from 0.6 to 21.6 mM of Trolox equivalents. Product-to-product variability was also observed for juices of the same fruit, showing the differences between brands on the ORAC-PGR index. PMID- 23451369 TI - Determination of antioxidant activity in foods and beverages by reaction with 2,2'-diphenyl-1-picrylhydrazyl (DPPH): collaborative study First Action 2012.04. AB - A colorimetric method for the determination of total antioxidant activity in a variety of foods and beverages was validated in both a single-laboratory validation and a collaborative laboratory validation study. The procedure involved extraction of the antioxidants directly into a methanol-water solution containing a known amount of 2,2'-diphenyl-1-picrylhydrazyl (DPPH), thus promoting the rapid reaction of extracted materials with DPPH. The reaction was monitored by spectrophotometric measurement of the absorbance loss at 517 nm. Antioxidant activity was quantified relative to a dilution series of vitamin E analog standards (Trolox), which were analyzed in parallel simultaneously with the food and beverage samples. The antioxidant activities of the samples ranged from 131 to 131 000 micromole Trolox equivalents/100 g. Statistical analysis of the results showed that nine of the 11 matrixes gave acceptable HorRat values, indicating that the method performed well in these cases. The acceptable matrixes include pomegranate juice, blueberry juice, carrot juice, green tea, wine, rosemary spice, ready-to-eat cereal, and yogurt. Two samples failed the HorRat test: the first was an almond milk that had an antioxidant level below the practical LOQ for the method; the second was a sample of canola oil with added omega-3 fatty acid that was immiscible in the reaction medium. PMID- 23451370 TI - Rapid determination of free fatty acid content in waste deodorizer distillates using single bounce-attenuated total reflectance-FTIR spectroscopy. AB - A simple, rapid, economical, and environmentally friendly analytical method was developed for the quantitative assessment of free fatty acids (FFAs) present in deodorizer distillates and crude oils by single bounce-attenuated total reflectance-FTIR spectroscopy. Partial least squares was applied for the calibration model based on the peak region of the carbonyl group (C=O) from 1726 to 1664 cm(-1) associated with the FFAs. The proposed method totally avoided the use of organic solvents or costly standards and could be applied easily in the oil processing industry. The accuracy of the method was checked by comparison to a conventional standard American Oil Chemists' Society (AOCS) titrimetric procedure, which provided good correlation (R = 0.99980), with an SD of +/- 0.05%. Therefore, the proposed method could be used as an alternate to the AOCS titrimetric method for the quantitative determination of FFAs especially in deodorizer distillates. PMID- 23451371 TI - Validation of HPTLC and HPLC methods for the quantitative determination of allyl disulfide in some polyherbal oils. AB - Allium sativum L (garlic) is an essential component of many polyherbal oils used in traditional systems of medicine. Allyl disulfide has been a major component found in vegetable oil macerate of garlic, and can be used as reliable marker for determination of garlic in oil macerates of garlic. The HPLC separation of allyl disulfide was achieved on a Phenomenex Luna C18 (25 cm x 4.6 mm id x 5 pm particle size) column using acetonitrile-water-tetrahydrofuran (70 + 27 + 3, v/v/v) mobile phase at a flow rate of 1.0 mL/min. Quantitation was achieved with UV detection at 298 nm over the concentration range 8-48 microg/mL. HPTLC separation of allyl disulfide was achieved on an aluminum-backed layer of silica gel 60 F254 using n-hexane mobile phase. Quantitation was achieved by densitometric analysis at 298 nm over the 200-1200 ng/band concentration range. The methods were validated according to International Conference on Harmonization guidelines. PMID- 23451372 TI - Detection of adulterated Ginkgo biloba supplements using chromatographic and spectral fingerprints. AB - The fingerprints of 18 commercially available Ginkgo biloba supplements, 12 samples of raw G. biloba leaves, and three G. biloba standard reference materials from the National Institute of Standards and Technology were acquired directly (no chromatography) by UV spectrometry and after separation using HPLC with a diode array detector. The fingerprints consisted of the UV spectral images, the chromatographic images, and the areas of the 21 most prominent chromatographic peaks. Data were analyzed by principal component analysis and one-class soft independent modeling of class analogy (SIMCA). It was determined that three of the commercial products were adulterated with rutin, four with quercetin, and one with an unidentified flavonol glycoside. One-class SIMCA of the authentic products allowed the adulterated products to be easily distinguished using Q residuals. Authentic supplements and raw leaf materials were easily distinguished. The finely powdered samples were also analyzed by near-IR (NIR) spectrometry. The authentic and adulterated products could not be distinguished by NIR spectrometry because of the excipients. PMID- 23451373 TI - Simultaneous analysis of steviol and steviol glycosides by liquid chromatography with ultraviolet detection on a mixed-mode column: application to Stevia plant material and Stevia-containing dietary supplements. AB - Simultaneous separation of steviol and steviol glycosides is challenging because of differences in their polarity and chemical structure. In this study, simultaneous analysis of steviol and steviol glycosides was achieved by LC with UV detection using a mixed-mode RP weak anion exchange chromatography column. Steviol and seven steviol glycosides were analyzed on an Acclaim Mixed-Mode Wax-1 (Dionex) column with a linear gradient of deionized water adjusted to pH 3.00 with phosphoric acid and acetonitrile. The extraction was performed by sonicating dry plant material at 40 degreesC in acetonitrile-water (30 + 70, v/v). LOQ values (mg/g dry weight of plant material) were rebaudioside B, 0.50; steviol, 0.70, dulcoside A, 1.0; steviolbioside, 1.2; stevioside and rebaudioside C, 2.0; rebaudioside D, 3.3; and rebaudioside A, 5.0. The method demonstrated suitable performance for all analytes tested with respect to accuracy (mean recoveries 95 99%), intraday and interday precision for retention times (0.070-0.28% and 0.33 1.0% RSD, respectively), and linearity. The method was used to authenticate steviol glycosides in several samples of Stevia plant material as well as to quantitate steviol glycosides in dietary supplements containing Stevia. PMID- 23451374 TI - Quantitative determination of cucurbitane-type triterpenes and triterpene glycosides in dietary supplements containing bitter melon (Momordica charantia) by HPLC-MS/MS. AB - Momordica charantia L. (Cucurbitaceae), commonly known as bitter melon, is widely cultivated in many tropical and subtropical areas of the world. It is a common food staple; its fruits, leaves, seeds, stems, and roots also have a long history of use in traditional medicine. In the United States, dietary supplements labeled as containing bitter melon can be purchased over-the-counter and from Internet suppliers. Currently, no quantitative analytical method is available for monitoring the content of cucurbitane-type triterpenes and triterpene glycosides, the major constituents of bitter melon, in such supplements. We investigated the use of HPLC-electrospray ionization (ESI)-MS/MS for the quantitative determination of such compounds in dietary supplements containing bitter melon. Values for each compound obtained from external calibration were compared with those obtained from the method of standard additions to address matrix effects associated with ESI. In addition, the cucurbitane-type triterpene and triterpene glycoside contents of two dietary supplements determined by the HPLC-ESI-MS/MS method with standard additions were compared with those measured by an HPLC method with evaporative light scattering detection, which was recently developed for quantification of such compounds in dried fruits of M. charantia. The contents of five cucurbitane-type triterpenes and triterpene glycosides in 10 dietary supplements were measured using the HPLC-ESI-MS/MS method with standard additions. The total contents of the five compounds ranged from 17 to 3464 microg/serving. PMID- 23451375 TI - Evaluation of cyanocobalamin in multivitamin tablets and their Standard Reference Material 3280 by HPLC with visible detection. AB - As a part of the development of an alternative to microbiological assay for vitamin B12, we performed a quantitative analysis of cyanocobalamin (CN-cbl) in a National Institute of Standards and Technology Standard Reference Material (SRM 3280) by HPLC. Using this method, the observed value (4.64 microg/g) of CN-cbl in SRM 3280 was found to be in good agreement with the certified value (4.80 microg/g). The accuracy was over 95%, with a corresponding measurement precision value of 5%. To evaluate the applicability of the method on commercial multivitamin tablets, the method was applied to a variety of these samples. The present method has a good accuracy and precision to evaluate CN-cbl with respect to all of the examined tablets. PMID- 23451376 TI - Thin-layer chromatography-densitometry analysis of dimethoxyphenylbutadiene content in Zingiber cassumunar rhizomes. AB - Zingiber cassumunar (Zingiberaceae) has been widely used as a traditional medicine in southeast Asia, especially Thailand, for treatment of asthma, inflammation, and joint pain. (E)-4-(3,4-dimethoxyphenyl)butadiene, or DMPBD, a major component in the rhizome, has been reported to be an active anti inflammatory agent. This research developed a TLC-densitometry method for the simultaneous quantification of DMPBD in the rhizome extracts of four varieties of Z. cassumunar. DMPBD (dimethoxyphenylbutadiene) was found in the range of 0.90 +/ 0.01 to 1.61 +/- 0.05% (w/w). [corrected] The method was validated for linearity, precision, accuracy, robustness, LOD, and LOQ. The linearity was indicated by a good regression coefficient 0.9940 and covered the range of 130 to 703 ng/band. Intraday and interday precision (RSD) were less than 2%. Accuracy of the method was evaluated by a recovery study conducted at three different levels; the average recovery was 103.1%. The LOD and LOQ were 10 and 40 ng, respectively. The proposed TLC-densitometry method was simple, precise, specific, sensitive, and inexpensive. This method can be used for routine QC of raw materials of Z. cassumunar rhizomes, extracts, and its products, especially Prasaplai, a Thai traditional medicine for relieving dysmenorrhea. PMID- 23451377 TI - Performance of the AOAC use-dilution method with targeted modifications: collaborative study. AB - The U.S. Environmental Protection Agency (EPA), in collaboration with an industry work group, spearheaded a collaborative study designed to further enhance the AOAC use-dilution method (UDM). Based on feedback from laboratories that routinely conduct the UDM, improvements to the test culture preparation steps were prioritized. A set of modifications, largely based on culturing the test microbes on agar as specified in the AOAC hard surface carrier test method, were evaluated in a five-laboratory trial. The modifications targeted the preparation of the Pseudomonas aeruginosa test culture due to the difficulty in separating the pellicle from the broth in the current UDM. The proposed modifications (i.e., the modified UDM) were compared to the current UDM methodology for P. aeruginosa and Staphylococcus aureus. Salmonella choleraesuis was not included in the study. The goal was to determine if the modifications reduced method variability. Three efficacy response variables were statistically analyzed: the number of positive carriers, the log reduction, and the pass/fail outcome. The scope of the collaborative study was limited to testing one liquid disinfectant (an EPA registered quaternary ammonium product) at two levels of presumed product efficacies, high and low. Test conditions included use of 400 ppm hard water as the product diluent and a 5% organic soil load (horse serum) added to the inoculum. Unfortunately, the study failed to support the adoption of the major modification (use of an agar-based approach to grow the test cultures) based on an analysis of method's variability. The repeatability and reproducibility standard deviations for the modified method were equal to or greater than those for the current method across the various test variables. However, the authors propose retaining the frozen stock preparation step of the modified method, and based on the statistical equivalency of the control log densities, support its adoption as a procedural change to the current UDM. The current UDM displayed acceptable responsiveness to changes in product efficacy; acceptable repeatability across multiple tests in each laboratory for the control counts and log reductions; and acceptable reproducibility across multiple laboratories for the control log density values and log reductions. Although the data do not support the adoption of all modifications, the UDM collaborative study data are valuable for assessing sources of method variability and a reassessment of the performance standard for the UDM. PMID- 23451378 TI - Determination of ambroxol hydrochloride, guaifenesin, and theophylline in ternary mixtures and in the presence of excipients in different pharmaceutical dosage forms. AB - Determination of ternary mixtures of ambroxol hydrochloride, guaifenesin, and theophylline with minimum sample pretreatment and without analyte separation has been successfully achieved by using chemometric and RP-HPLC methods. The developed chemometric models are partial least squares (PLS) and genetic algorithm coupled with PLS. Data of the analyses were obtained from UV-Vis spectra of the studied drugs in different concentration ranges. These models have been successfully updated to be applied for determination of the proposed drugs in Farcosolvin syrup and in the presence of a syrup excipient (methyl paraben). In the developed RP-HPLC method, chromatographic runs were performed on an RP-C18 analytical column with the isocratic mobile phase 0.05 M phosphate buffer methanol-acetonitrile-triethylamine (63.5 + 27.5 + 9 + 0.25, v/v/v/v, pH 5.5 adjusted with orthophosphoric acid) at a flow rate of 1.2 mL/min. The analytes were detected and quantified at 220 nm. The method was optimized in order to obtain good resolution between the studied components and to prevent interference from methyl paraben. Method validation was performed with respect to International Conference on Harmonization guidelines and the validation acceptance criteria were met in all cases. The proposed methods can be considered acceptable for QC of the studied drugs in pharmaceutical capsules and syrup. The results obtained by the suggested chemometric methods for determination of the studied mixture in different pharmaceutical preparations were statistically compared to those obtained by applying the developed RP-HPLC method, and no significant difference was found. PMID- 23451379 TI - Chiral chromatography studies of chemical behavior of cinacalcet on polysaccharide chiral reversed-phase HPLC stationary phases. AB - A rapid HPLC method for the analytical resolution of cinacalcet enantiomers was developed. Four chiral columns (two amylose and two cellulose type) were evaluated in RP systems. Excellent enantioseparation with a resolution of more than 6 was achieved on Chiralpak AY (amylose 5-chloro-2-methylphenylcarbamate chiral stationary phase) using 10 mM triethylamine (pH 8.0)-acetonitrile (40 + 60, v/v) mobile phase. Validation of the HPLC method, including linearity, LOD, LOQ, precision, accuracy, and selectivity, was performed according to the International Conference on Harmonization guidelines. The method was successfully applied for the determination of (S)-cinacalcet in enantiopure active pharmaceutical ingredient (R)-cinacalcet. PMID- 23451380 TI - Application of quantitative nuclear magnetic resonance spectroscopy for the determination ofamantadine and acyclovir in plasma and pharmaceutical samples. AB - Rapid, simple, and selective methods for determining amantadine HCI and acyclovir antiviral drugs in pharmaceutical and plasma samples were developed using 1H-NMR spectroscopy with dimethyl sulfoxide (DMSO-d6) as the solvent. Integrations of the 1H-NMR signals at 2.07 and 7.82 ppm were used, respectively, for quantifying the two drugs, with the malonic acid signal at 3.24 ppm as the internal reference signal. Average recoveries of 98.24-101.00 +/- 4.82% and 97.7-100.38 +/- 3.36% were obtained for amantadine HCI and acyclovir in pharmaceutical samples, respectively. Average recoveries of 97.36-103.68 +/- 2.99 and 93.81-99.80 +/- 2.93 were obtained, respectively, for both drugs in plasma samples. The statistical Student's t-test gave t-values < or = 1.41 for analyzed pharmaceutical samples and t-values < or = 0.29 for analyzed plasma samples. These values indicated insignificant difference between the real and measured contents at the 95% confidence level. Application of the statistical F-test for the analytical results of amantadine HCI gave F-values < or = 6.44 and 2.80 in pharmaceutical and plasma samples, respectively. F-values < or = 6.82 and 3.86 were obtained for acyclovir in pharmaceutical and plasma, respectively. These values indicated insignificant differences in precisions between the developed NMR methods and arbitrarily chosen HPLC methods reported for determining both drugs in pharmaceutical and plasma samples. PMID- 23451381 TI - Digoxigenin-labeled probe-based colony blotting assay for rapid quantification of Salmonella serovars in seafood and water. AB - A non-radio-labeled probe-based detection method was developed for rapid enumeration of Salmonella in seafood and water samples. A Salmonella-specific invA gene probe was developed using a digoxigenin-based non-radio labeling assay, which was evaluated with naturally contaminated seafood and water samples. The probe-based technique was further compared with the quantitative PCR assay. The method was specific for detection of different Salmonella serovars without any nonspecific hybridization with other Salmonella-related Enterobacteriaceae. The optimum labeling efficiency was determined for the labeled probe, and 10 pg/microL probe concentration was observed to be most efficient for detection of Salmonella colonies on nylon membrane. Quantification of Salmonella in naturally contaminated seafood and water samples (n = 21) was in the range 10-10(2) CFU/mL. The assay successfully quantified Salmonella in spiked seafood and water samples in the presence of background flora, and the entire assay was completed within 48 h. The probe-based assay was further evaluated with real-time PCR, and results showed that the assay was comparable to real-time PCR assay. Thus, this probe based assay can be a rapid, useful, and alternative technique for quantitative detection of Salmonella in food, feed, and water samples. PMID- 23451382 TI - Samsung Salmonella Detection Kit. AOAC Performance Tested Method(SM) 021203. AB - Salmonella, one of the most common causes of foodborne illness, is a significant public health concern worldwide. There is a need in the food industry for methods that are simple, rapid, and sensitive for the detection of foodborne pathogens. In this study, the Samsung Salmonella Detection Kit, a real-time PCR assay for the detection of Salmonella, was evaluated according to the current AOAC guidelines. The validation consisted of lot-to-lot consistency, stability, robustness, and inclusivity/exclusivity studies, as well as a method comparison of 10 different food matrixes. In the validation, the Samsung Salmonella Detection Kit was used in conjunction with the Applied Biosystems StepOnePlus PCR system and the Samsung Food Testing Software for the detection of Salmonella species. The performance of the assays was compared to the U.S. Department of Agriculture/Food Safety and Inspection Service-Microbiology Laboratory Guidebook (USDA/FSIS-MLG) 4.05: Isolation and Identification of Salmonella from Meat, Poultry, Pasteurized Egg, and Catfish and the and U.S. Food and Drug Administration/Bacteriological Analytical Manual (FDA/BAM) Chapter 5 Salmonella reference methods. The validation was conducted using an unpaired study design for detection of Salmonella spp. in raw ground beef, raw pork, raw ground pork, raw chicken wings, raw salmon, alfalfa sprouts, pasteurized orange juice, peanut butter, pasteurized whole milk, and shell eggs. The Samsung Salmonella Detection Kit demonstrated lot-to-lot consistency among three independent lots as well as ruggedness with minor modifications to changes in enrichment incubation time, enrichment incubation temperature, and DNA sample volume for PCR reaction. Stability was observed for 13 months at -20 degrees C and 3 months at 5 degrees C. For the inclusivity/exclusivity study, the Samsung Salmonella Detection Kit correctly identified 147 Salmonella species isolates out of 147 isolates tested from each of three different enrichment broths (a total of 441 isolates detected), and correctly excluded all 31 nontarget strains analyzed. For the method comparison, statistical analysis was conducted according to the Mantel Haenszel Chi-square formula for unpaired test portions, and there was no significant difference in the number of positive samples detected between the Samsung Salmonella Detection Kit and the USDA/FSIS-MLG and FDA/BAM reference methods for all 10 food matrixes. PMID- 23451383 TI - Comparative evaluation of a phage protein ligand assay with VIDAS and BAX methodology for detection of Escherichia coli O157:H7 using a standard nonproprietary enrichment broth. AB - Escherichia coli O157:H7 is a major foodborne pathogen of concern worldwide. This study was conducted to compare the sensitivity and minimum enrichment time for detection of E. coli O157:H7 by the VIDAS ultraperformance E. coli test (VIDAS ECPT UP) with that of two other commercial detection kits, the ELISA-based VIDAS ECO system and the PCR-based BAX system. Only VIDAS ECPT UP detected all 18 positive results of bacterial suspensions at the level of 10(4) CFU/mL E. coli O157:H7 and 10(6) CFU/mL E. coli as background flora, whereas the BAX system PCR assay detected six positive results and VIDAS ECO detected no positive results. A 6 h enrichment at 42 degrees C is enough for detection of all 18 strains in artificial contaminated raw beef meat, raw milk, and raw chicken, and for detection of most of them in soybean sprout and fresh papaya juice with VIDAS ECPT UP, whereas enrichment of more than 8 h was required for detection of the strains with the VIDAS ECO and PCR-BAX systems. These results indicate that the VIDAS ECPT UP is superior to the other two alternative methods when a standard enrichment broth is used that is different from the broths recommended by the manufacturers. PMID- 23451384 TI - Roka Listeria detection method using transcription mediated amplification to detect Listeria species in select foods and surfaces. Performance Tested Method(SM) 011201. AB - The Roka Listeria Detection Assay was compared to the reference culture methods for nine select foods and three select surfaces. The Roka method used Half-Fraser Broth for enrichment at 35 +/- 2 degrees C for 24-28 h. Comparison of Roka's method to reference methods requires an unpaired approach. Each method had a total of 545 samples inoculated with a Listeria strain. Each food and surface was inoculated with a different strain of Listeria at two different levels per method. For the dairy products (Brie cheese, whole milk, and ice cream), our method was compared to AOAC Official Method(SM) 993.12. For the ready-to-eat meats (deli chicken, cured ham, chicken salad, and hot dogs) and environmental surfaces (sealed concrete, stainless steel, and plastic), these samples were compared to the U.S. Department of Agriculture/Food Safety and Inspection Service Microbiology Laboratory Guidebook (USDA/FSIS-MLG) method MLG 8.07. Cold-smoked salmon and romaine lettuce were compared to the U.S. Food and Drug Administration/Bacteriological Analytical Manual, Chapter 10 (FDA/BAM) method. Roka's method had 358 positives out of 545 total inoculated samples compared to 332 positive for the reference methods. Overall the probability of detection analysis of the results showed better or equivalent performance compared to the reference methods. PMID- 23451385 TI - Determination of aflatoxins B1, B2, G1, and G2 in olive oil, peanut oil, and sesame oil using immunoaffinity column cleanup, postcolumn derivatization, and liquid chromatography/fluorescence detection: collaborative study. AB - The accuracy, repeatability, and reproducibility characteristics of a method using immunoaffinity column (IAC) cleanup with postcolumn derivatization and LC with a fluorescence detector (FLD) for determination of aflatoxins (AFs; sum of AFs B1, B2, G1, and G2) in olive oil, peanut oil, and sesame oil have been established in a collaborative study involving 15 laboratories from six countries. Blind duplicate samples of blank, spiked at levels ranging from 0.25 to 20.0 microg/kg for AF, were analyzed. A naturally contaminated peanut oil sample was also included. Test samples were extracted with methanol-water (55 + 45, v/v). After shaking and centrifuging, the lower layer was filtered, diluted with water, and filtered through glass microfiber filter paper. The filtrate was then passed through an IAC, and the toxins were eluted with methanol. The toxins were then subjected to RPLC-FLD analysis after postcolumn derivatization. Average recoveries of AFs from olive oil, peanut oil, and sesame oil ranged from 84 to 92% (at spiking levels ranging from 2.0 to 20.0 microg/kg); of AFB1 from 86 to 93% (at spiking levels ranging from 1.0 to 10.0 microg/kg); of AFB2 from 89 to 95% (at spiking levels ranging from 0.25 to 2.5 microg/kg); of AFG1 from 85 to 97% (at spiking levels ranging from 0.5 to 5.0 microg/kg); and of AFG2 from 76 to 85% (at spiking levels ranging from 0.25 to 2.5 microg/kg). RSDs for within laboratory repeatability (RSD(r)) ranged from 3.4 to 10.2% for AF, from 3.5 to 10.9% for AFB1, from 3.2 to 9.5% for AFB2, from 6.5 to 14.9% for AFG1, and from 4.8 to 14.2% for AFG2. RSDs for between-laboratory reproducibility (RSDR) ranged from 6.1 to 14.5% for AF, from 7.5 to 15.4% for AFB1, from 7.1 to 14.6% for AFB2, from 10.8 to 18.1% for AFG1, and from 7.6 to 23.7% for AFG2. Horwitz ratio values were < or = 2 for the analytes in the three matrixes. PMID- 23451386 TI - Analysis of deoxynivalenol, zearalenone, T-2, and HT-2 toxins in animal feed by LC/MS/MS--a critical comparison of immunoaffinity column cleanup with no cleanup. AB - A comparison has been made of an LC/MS/MS method using direct analysis of acetonitrile extracts of feed and cereal samples and a method using acetonitrile extraction and subsequent immunoaffinity column (IAC) cleanup. Naturally contaminated samples containing one or more of deoxynivalenol, zearalenone, T-2, and HT-2 toxins were analyzed together with test materials containing known toxin levels. LC/MS/MS ion ratios and peak profiles, repeatability, and LOQs were used as the basis for comparing the two approaches. The method without cleanup had poorer performance than the method with IAC cleanup in terms of identification based on ion ratios compared to standards. Without cleanup, there was more evidence of background interference, and monitored ions were invariably seen against a noisy background. Nevertheless, quantification of samples analyzed without cleanup gave reasonable agreement with the levels found in the same samples that had received IAC cleanup. Repeatability was poorer with no cleanup, and LOQ values were higher for HT-2 and T-2 toxins, but there was no evidence of any adverse effects on MS performance with repeated injections of crude extracts. Overall, it was concluded that LC/MS/MS analysis of samples with no cleanup is adequate for screening, but for definitive measurements (e.g., for food regulatory control purposes) IAC cleanup remains essential. PMID- 23451387 TI - A sensitive gas chromatography-mass spectrometry method for the determination of patulin in apple juice. AB - A simple and sensitive GC/MS method was developed for the detection of patulin in apple juice. The method utilized a common laboratory chemical, 3-nitrobenzyl alcohol, as an internal standard. The calibration curve, ranging from 5 to 100 microg/L, showed good linearity with a correlation coefficient of 0.999. The LOD and LOQ were 2 and 5 microg/L, respectively. The significant advantage of the method was removal of the need for in-house synthesis of appropriate internal standards as reported by other researchers. The method also eliminated the need for careful sample preparation procedures, as outlined in some AOAC methods in which no internal standard was utilized. The streamlined extraction process and the improved sensitivity warrant the developed method to be a useful alternative for drug testing laboratories, especially those with large specimen volume and throughput to determine patulin levels in apple juice. PMID- 23451388 TI - GMOMETHODS: the European Union database of reference methods for GMO analysis. AB - In order to provide reliable and harmonized information on methods for GMO (genetically modified organism) analysis we have published a database called "GMOMETHODS" that supplies information on PCR assays validated according to the principles and requirements of ISO 5725 and/or the International Union of Pure and Applied Chemistry protocol. In addition, the database contains methods that have been verified by the European Union Reference Laboratory for Genetically Modified Food and Feed in the context of compliance with an European Union legislative act. The web application provides search capabilities to retrieve primers and probes sequence information on the available methods. It further supplies core data required by analytical labs to carry out GM tests and comprises information on the applied reference material and plasmid standards. The GMOMETHODS database currently contains 118 different PCR methods allowing identification of 51 single GM events and 18 taxon-specific genes in a sample. It also provides screening assays for detection of eight different genetic elements commonly used for the development of GMOs. The application is referred to by the Biosafety Clearing House, a global mechanism set up by the Cartagena Protocol on Biosafety to facilitate the exchange of information on Living Modified Organisms. The publication of the GMOMETHODS database can be considered an important step toward worldwide standardization and harmonization in GMO analysis. PMID- 23451389 TI - Changes of the wax contents in mixtures of olive oils as determined by gas chromatography with a flame ionization detector. AB - Mixing of refined olive-pomace oil with virgin olive oil is a fraud that has been tried often. Normally, the tests that detected the fraud were determinations of wax esters, erythrodiol+uvaol, and stigmastadienes contents. The most common is the determination of wax esters content (extra virgin olive oil is very poor in wax esters, usually less than 100 mg/kg). In this work, the variations of individual wax esters (C40, C42, C44, and C46), with different degrees of unsaturation content, and total wax esters were studied when extra virgin olive oil and refined pomace-olive oil were mixed. The following mixtures were prepared: extra virgin olive oil plus 1, 2, 4, 6, 8, 10, 12, 15, 18, 25, 35, 45, 50, and 80% of refined olive-pomace oil. In all cases, individual and total wax ester content variation was linear with increasing percentage of refined olive pomace oil in the mixture. The variation of the total wax esters content can be adjusted according to the equation: Total wax esters, mg/kg = 14.3 x (% refined olive-pomace oil) + 83.9. PMID- 23451390 TI - Analytical determination of bioactive compounds as an indication of fruit quality. AB - The aim of this investigation was to determine the bioactive compounds in kiwifruit as an indication of quality after extraction using methanol and ethyl acetate. Using FTIR and three-dimensional fluorescence spectroscopy and electrospray ionization/MS, the contents of polyphenols, flavonoids, flavanols, and tannins, and the level of the antioxidant activity by 2, 2-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt, 1, 1-diphenyl-2-picrylhydrazyl, ferric-reducing/ antioxidant power, and cupric reducing antioxidant capacity assays were determined and compared. It was found that the methanol extracts of kiwifruit showed significantly higher amounts of bioactive acetate extracts. The cultivar Bidan, in comparison compounds and antioxidant activities than the ethyl with the classic Hayward, showed significantly higher bioactivity. For the first time, Bidan organic kiwifruit was analyzed for its antioxidant activities and compared with the widely consumed Hayward organic based on its bioactive compounds and fluorescence properties. Relatively high content of bioactive compounds and positive antioxidant and antiproliferative properties of kiwifruit determined by the advanced analytical methods justify its use as a source of valuable antioxidants. The methods used are applicable for bioactivity determination, in general, for any food products. PMID- 23451391 TI - Qualitative and event-specific real-time PCR detection methods for Bt brinjal event EE-1. AB - Bt brinjal event EE-1 with cry1Ac gene, expressing insecticidal protein against fruit and shoot borer, is the first genetically modified food crop in the pipeline for commercialization in India. Qualitative polymerase chain reaction (PCR) along with event-specific conventional as well as real-time PCR methods to characterize the event EE-1 is reported. A multiplex (pentaplex) PCR system simultaneously amplifying cry1Ac transgene, Cauliflower Mosaic Virus (CaMV) 35S promoter, nopaline synthase (nos) terminator, aminoglycoside adenyltransferase (aadA) marker gene, and a taxon-specific beta-fructosidase gene in event EE-1 has been developed. Furthermore, construct-specific PCR, targeting the approximate 1.8 kb region of inserted gene construct comprising the region of CaMV 35S promoter and cry1Ac gene has also been developed. The LOD of developed EE-1 specific conventional PCR assay is 0.01%. The method performance of the reported real-time PCR assay was consistent with the acceptance criteria of Codex Alimentarius Commission ALINORM 10/33/23, with the LOD and LOQ values of 0.05%. The developed detection methods would not only facilitate effective regulatory compliance for identification of genetic traits, risk assessment, management, and postrelease monitoring, but also address consumer concerns and resolution of legal disputes. PMID- 23451392 TI - Inconsistencies in a highly polar capillary gas chromatography column and necessity of column performance checks for trans fatty acid measurement. AB - GC with a capillary column (60-100 m length) is widely used to measure trans fatty acids in dietary fats and biological tissues. Recently, we have occasionally observed that isothermal operation of an SP-2560 column at 180 degrees C results in incomplete separation of gondoic acid (11c-20:1) and one of the geometric isomers of alpha-linolenic acid (9t,12c,15c-18:3), although it has been known to produce their baseline separation in American Oil Chemists' Society Official Method Ce 1h-05, as well as in previous studies. Thus, trans isomer (9t,12c,15c-18:3) is one of the main components of trans fatty acids in refined edible oils, and the baseline separation of this peak from that of 11c-20:1 is indispensable. We demonstrate in this study that an isothermal operating temperature of 175 degrees C for an SP-2560 column results in satisfactory resolution of these two fatty acids. Because of the inconsistency in the separation provided by SP-2560 columns, careful monitoring of the relative elution order of different fatty acid methyl esters using standards is necessary for the exact evaluation of trans fatty acid contents in oils and fats. PMID- 23451393 TI - Method development and validation for ultra-high-pressure LC/MS/MS determination of hop prenylflavonoids in human serum. AB - Hops (Humulus lupulus L.) are used in the brewing of beer, and hop extracts containing prenylated compounds, such as xanthohumol (XN) and 8-prenylnaringenin (8-PN), are under investigation as dietary supplements for cancer chemoprevention and the management of hot flashes in menopausal women. To facilitate clinical studies of hop safety and efficacy, a selective, sensitive, and fast ultra-high pressure LC (UHPLC) tandem MS method was developed and validated for the simultaneous determination of the hop prenylflavonoids XN, isoxanthohumol (IX), 6 prenylnaringenin (6-PN), and 8-PN in human serum. The analytical method requires 300 microL of human serum, which is processed using liquid-liquid extraction. UHPLC separation was carried out in 2.5 min with gradient elution using an RP C18 column containing 1.6 pm particle size packing material. Prenylflavonoids were measured using negative ion electrospray MS with collision-induced dissociation and selected reaction monitoring. The method was validated and showed good accuracy and precision with an LOQ of 0.50 ng/mL for XN (1.4 nM) and 1.0 ng/mL for 6-PN, 8-PN (2.94 nM), and IX (2.82 nM) in serum. PMID- 23451394 TI - Analysis of the bacterial diversity existing on animal hide and wool: development of a preliminary PCR-restriction fragment length polymorphism fingerprint database for identifying isolates. AB - Twenty-one bacterial strains were isolated from imported cattle hide and rabbit wool using two types of media, nutrient broth, and nutrient broth with serum. The bacteria identified were Brevibacillus laterosporus, Leclercia adecarboxylata, Peptococcus niger, Bacillus circulans, Raoultella ornithinolytica, Bacillus subtilis, Bacillus cereus, Bacillus thermobacillus, Bacillus choshinensis, Bacillus sphaericus, Acinetobacter haemolyticus, Sphingomonas paucimobilis, Bacillus thuringiensis, Staphylococcus intermedius, Mycobacteria, Moraxella, Klebsiella pneumoniae, Ralstonia pickettii, Staphylococcus chromogenes, Comamonas testosteroni, and Cupriavidus pauculus. The 16s rDNA gene of each bacterium was amplified using the universal primers 27f and 1492r. The amplicons were digested with AvaI, BamHI, BgII, DraI, EcoRI, EcoRV, HindIII, HinfI, HpaI, PstI, SmaI, TaqII, XbaI, XmaI, AluI, XhoI, and PvuI individually. A specific fingerprint from the PCR-restriction fragment length polymorphism method based on 16s rDNA was obtained for each bacterium. The results showed that the method developed was useful not only for bacterial identification but also for the etiological investigation of pathogens in imported animal hair and wool. PMID- 23451395 TI - Quantification of arsenic in dialysate solution and scalp hair samples of kidney failure patients by cloud point extraction and electrothermal atomic absorption spectroscopy. AB - A method has been developed for the determination of arsenic (As) in pharmaceutical and scalp hair samples of kidney failure patients by cloud point extraction (CPE). The scalp hair samples were subjected to microwave-assisted digestion in nitric acid-hydrogen peroxide (2 + 1, v/v). Then, dialysate and digested scalp hair solutions were preconcentrated by CPE using pyronine B as a complexing agent. The resulting complex was entrapped in nonionic surfactant (Triton X-114) prior to its determination by electrothermal atomic absorption spectroscopy. The validity of the CPE method for As was checked by analysis of a certified reference material of human hair and a standard addition method for dialysate solution. The chemical variables affecting the analytical performance of the CPE methods were studied and optimized. After optimization of the complexation and extraction conditions, a preconcentration factor of 52 was obtained for As in 10 mL of dialysate solution and acid digested samples of scalp hair. Under the optimum experimental conditions, the LOD and LOQ of As for the preconcentration of 10 mL of solution were 0.022 and 0.073 microg/L, respectively. The level of As in scalp hair samples of kidney failure patients was higher than in healthy controls. PMID- 23451396 TI - Comparison of activated carbon and oxidized multiwalled carbon nanotubes modified with bis(3-nitrobenzylidene)-1,2-ethanediamine for enrichment of trace amounts of some metal ions. AB - The efficiency of modified activated carbon (AC) and multiwalled carbon nanotubes (MWCNTs) for the separation/preconcentration and determination of Co, Cd, Pb, Zn, and Cu following their complexation by bis(3-nitrobenzylidene)-1,2-ethanediamine has been described and compared. A one-at-a-time optimization method investigated the influence of various parameters that significantly influence the recoveries of the studied metal ions. At the optimum values of all variables, the response was linear over the range of 0.01-0.3 microg/mL, and detection limit (3 SDb/m, n = 10) was between 1.41-2.05 ng/mL for both sorbents while the preconcentration factor was 100 for AC and 500 for MWCNTs. The method was successfully applied for preconcentration and determination of trace amount of the aforementioned ions in various real samples such as orange, lettuce, bread, and pear. PMID- 23451397 TI - Analysis of triazole-based metabolites in plant materials using differential mobility spectrometry to improve LC/MS/MS selectivity. AB - Triazole-derivative metabolites can occur in plant and animal materials and in water. Due to their physical-chemical properties, their analysis in complex matrixes is very difficult. The objective of this work was to develop a method for the analysis of these analytes that is easy to handle, quick, and enables quantification at a residue level of 0.01 mg/kg. Using the LC-differential mobility spectrometry/MS/MS system, cleanup and derivatization processes became unnecessary. For more than 10 representative plant materials it could be shown that the new method is valid and reproducible, thus leading to accurate and reliable results. PMID- 23451398 TI - Multiresidue method for pesticide residue analysis in food of animal and plant origin based on GC or LC and MS or MS/MS. AB - A multiresidue method based on GC or LC and MS or MS/MS for the determination of 204 pesticides in diverse food matrixes of animal and plant origin is described. The method can include different stages of cleanup according to the chemical characteristics of each sample. Samples were extracted using accelerated solvent extraction. Those with a high fat content or that contained chlorophyll required further purification by gel permeation chromatography and/or SPE (ENVI-Carb). The methodology developed here was fully validated; the LOQs for the 204 pesticides are presented. The LOQ values lie between 0.01 to 0.02 mg/kg. However, in some cases, mainly in baby food, they were as low as 0.003 mg/kg, thereby meeting European Union requirements on maximum residue levels for pesticides, as outlined in European regulation 396/2005 and the Commission Directive 2003/13/EC. The procedure has been accredited for a wide scope of pesticides and matrixes by the Spanish Accreditation Body (ENAC) following ISO/IEC 17025:2005, as outlined in ENAC technical note NT-19. PMID- 23451399 TI - Cloud point extraction and flame atomic absorption spectrometry determination of lead (II) in environmental and food samples. AB - A cloud point extraction procedure for the preconcentration of Pb2+ in various samples following complexation with 2,2'-(1E,1'E)-1,1'-(2,2'-azanediylbis(ethane 2,1-diyl)bis(azan-1-yl-1-ylidene)) bis(ethan-1-yl-1-ylidene)diphenol in Triton X 114 after centrifugation is reported. A 0.5 mL portion of methanol acidified with 1.0 M HNO3 was added to the surfactant-rich phase prior to analysis by flame atomic absorption spectrometry. The influence of analytical parameters--including pH, concentrations of ligand, Triton X-114, and HNO3, bath temperature, heating time, and centrifugation rate and time--were optimized, and the effect of the matrix ions on the recovery of Pb2+ was investigated. An LOD of 1.9 ng/mL along with a preconcentration factor of 50 with RSD of 1.0% for Pb2+ were achieved. The proposed procedure was applied to the analysis of various real samples. PMID- 23451400 TI - The characteristic function, a method-specific alternative to the Horwitz function. AB - The Horwitz function is compared with the characteristic function as a descriptor of the precision of individual analytical methods. The Horwitz function describes the trend of reproducibility SDs observed in collaborative trials in the food sector over a wide range of concentrations of the analyte. However, it is imperfectly adaptable for describing the precision of individual methods, which is the role of the characteristic function. An essential difference between the two functions is that the characteristic function can accommodate a detection limit. This makes it a useful alternative when the precision of a method down to a detection limit is of interest. Many characteristic functions have a simple mathematical form, the parameters of which can be estimated with the usual resources. The Horwitz function serves an additional role as a fitness-for purpose criterion in the form of the Horwitz ratio (HorRat). This use also has some shortcomings. The functional form of the characteristic function (with suitable prescribed parameters) is better adapted to this task. PMID- 23451401 TI - Validation of the Delvotest SP NT. Performance Tested Methods(SM) 011102. AB - Delvotest SP NT is designed to test milk for the presence of antibacterial substances such as antibiotics. The test is made of an agar gel containing bacterial spores and a pH indicator. The milk sample is added onto the agar gel, and the test is placed for incubation at 64 degrees C. The principle of the test is based on the diffusion of possible inhibitory substances that may be present in the milk sample into the agar. This reduces growth and acid production by the test organism and delays or prevents the agar from changing color from purple to yellow. The present report includes all technical details about the Delvotest SP NT and the results of the validation study. The validation study demonstrates that the Delvotest SP NT conforms to the product performance claims and confirms the robustness of the test. The Delvotest SP NT is therefore granted Performance Tested Method(SM) certification. PMID- 23451402 TI - The new year begins! PMID- 23451404 TI - Your colleagues at work in the general assembly. Two AMS friends talk about their new roles in the Arkansas legislature. PMID- 23451403 TI - Paradise lost. PMID- 23451405 TI - Reducing avoidable hospitalizations among nursing home residents: 'INTERACT' with your staff. PMID- 23451406 TI - Paraneoplastic myasthenia gravis. PMID- 23451407 TI - The current state of non-accidental head injury in Arkansas. AB - Child maltreatment syndrome (CMS) and non-accidental head injury (NAHI) are frequent causes of death and disability with national incidences reported as high as 24.6 per 100,000 children. At this time the true incidence of CMS is unknown in Arkansas. The purpose of this review is to illustrate the severity of non accidental head injury and increase awareness in the state of Arkansas. This paper is the first in a planned series to determine the incidence, risk factors, presentation, best effective treatment strategies and outcomes of CMS and NAHI in Arkansas. PMID- 23451408 TI - [Suzanne Carriere: a passionate journey]. PMID- 23451409 TI - [Steps in the right direction: World Day against elder abuse]. PMID- 23451410 TI - [Bringing back the hope]. PMID- 23451411 TI - [Insulin at 90 years: a Canadian discovery that revolutionized medicine]. PMID- 23451412 TI - [Disabled persons: a new guide to help find assistance programs]. PMID- 23451413 TI - [Myths and reality: coffee]. PMID- 23451415 TI - [Not Available]. PMID- 23451414 TI - [Not Available]. PMID- 23451416 TI - [Not Available]. PMID- 23451417 TI - [The forgotten child: living in the shadow of a chronically ill sibling]. PMID- 23451418 TI - [Sjogren syndrome: are you familiar with it?]. PMID- 23451419 TI - [Are you familiar with the poison center? Concise evidence-based information for optimal management of poisonings ]. PMID- 23451420 TI - [Metabolic syndrome: precursor to diabetes and cardiovascular diseases]. PMID- 23451421 TI - [Bed bugs]. PMID- 23451422 TI - [Recognition of delirium in elderly patients. A study of home nurses]. PMID- 23451423 TI - [A screening questionnaire for delirium]. PMID- 23451424 TI - [Overtraining in the young athlete: an increase in anterior cruciate ligament and meniscal injuries]. PMID- 23451425 TI - [Resotran. A new agent for the treatment of chronic constipation]. PMID- 23451426 TI - [Abilify: a new antipsychotic for adolescents]. PMID- 23451427 TI - [Renard, a child soldier]. PMID- 23451428 TI - [Some precautions for travel will prevent problems]. PMID- 23451429 TI - King in a car park. The ignominious fate of Richard III. PMID- 23451430 TI - Computer assisted surgery evaluation of femoral component rotation in well balanced and well-aligned total knee arthroplasty using gap technique. AB - OBJECTIVE: Using computer assisted surgery (CAS) to assess femoral component rotation in well-balanced, well-aligned total knee arthroplasty (TKA) implanted with Posterior Cruciate Ligament (PCL) excision type prosthesis using gap technique. MATERIAL AND METHOD: Using CAS, well-balanced TKA was defined by both flexion/extension and medial/lateral gap difference of less than 2 mm and well aligned TKA was defined by final mechanical axis within +/- 3 degrees deviation and flexion contracture of less than 5 degrees without hyper extension. Femoral component rotation was determined by posterior condylar axis versus proximal tibia resection plane. The present study analyzed data from January 1, 2009 to September 30, 2009. RESULTS: Out of 65 knees, 34 knees (14 fixed and 20 mobile bearing prosthesis) were considered well-balanced and well-aligned. Mean femoral component rotation was 2.12 +/- 3.38 degrees. Seven knees were within 2-4 degrees external rotation. There was no statistically significant difference of femoral component rotation between fixed and mobile bearing. CONCLUSION: Wide range of femoral component rotation occurred in well-aligned and well-balanced TKA using PCL excision type prosthesis. PMID- 23451431 TI - The rotational axis of the tibia and relationship to the tibial torsion in varus osteoarthritic knee. AB - BACKGROUND: A transepicondylar axis is a useful reference for femoral component rotation and is demonstrated as a functional flexion-extension axis of a knee. Conversely, a rotational orientation of the tibial component was less clearly demonstrated and many anatomical landmarks were proposed. It has been reported that Asian people had more medial torsion of the tibia particularly with an osteoarthritic knee. The present study aims to address the relationship between the torsion variation of the tibia and the rotational axis of the tibia. MATERIAL AND METHOD: Forty knees of 32 women (mean age of 73.3) with varus osteoarthritis underwent a preoperative CT images to identify a surgical epicondylar axis, an axis perpendicular to this line (femoral reference line), lines connecting between the PCL insertion and 3 reference point on the patellar tendon, an AP axis of the ankle and a tibial torsion angle. RESULTS: The mean value of the angle between the line connecting the PCL insertion and 3 different point of the patellar tendon including the medial border medial one-third and middle of the patellar tendon and the femoral reference line was -4.22, +4.37 and +8.47 degree, respectively. The mean of a tibial torsion angle was +16.51 degree. There were 6 cases having the femoral reference line rotated internally to the medial border of the patellar tendon and having less torsion angle (medial tibial torsion) with a mean of +13.78 degree. CONCLUSION: The femoral reference line in the Thai osteoarthritic knee is passed between medial edge of patellar tendon and medial 1/3 of patellar tendon. This line rotates more internally compared with the patellar tendon if the degree of medial tibial torsion is more severe. An excessive externally rotated tibial component when using the patellar tendon as guidance should be avoided in the knee presenting with medial tibial torsion. PMID- 23451432 TI - Intertrochanteric valgus-lengthening-femoral neck osteotomy for developmental and posttraumatic conditions of the hips. AB - OBJECTIVE: To review the results of the treatment of coxa vara associated with femoral neck shortening and high-standing greater trochanter using the new technique of intertrochanteric valgus-lengthening-femoral neck osteotomy. MATERIAL AND METHOD: Twelve of the fifteen hips treated by the present technique of osteotomy were reviewed. Seven of the twelve cases were posttraumatic (four malunion, two nonunion and one childhood fracture of the femoral neck) and five were developmental conditions (three ischemic necrosis of the femoral head and one physeal dysplasia, all of which secondary to DDH and one coxa plana). The mean follow-up period was 34.3 months (range, 12-106). There were 5 male, 7 female. The mean age of the patients at the time of surgery was 26.6 years (range, 13-50). The operation consisted of intertrochanteric opening wedge valgus osteotomy,femoral neck lengthening by lateralization of femoral shaft and trochanteric lateralization. No bone grafting or substitute was used. RESULTS: Mean preoperative Harris hip score of 51.8 points (range, 32-67) was significantly improved to 94.8 points (range, 60-100) at the last follow-up study (p = 0.002). The mean femoral shaft-neck angle was changed from 113 degrees (range, 70-140) preoperatively to 138.2 (range, 110-165) degrees at the last follow-up (p = 0.002). Mean length gain at the last follow-up was 12.7 mm (range 5-29 mm). No complications, including delayed or non-union, implant failure and neurovascular injuries were encountered. CONCLUSION: The newly present technique could simultaneously address coxa vara associated with femoral neck shortening, and high-standing greater trochanter. The technique is safe and reliable. PMID- 23451433 TI - Radiographic assessment in bilateral primary total knee arthroplasty: computer assisted surgery vs. conventional surgery. AB - OBJECTIVE: The purpose of this retrospective study is to compare the efficiency of computer-assisted surgery (CAS) and conventional method (CONV) in TKA using mechanical axis (MA) and component alignment measured on the post-operative radiograph in the same patient by different technique for TKA on both sides of the knee. MATERIAL AND METHOD: Fifty-two TKA in twenty-six patients with primary osteoarthritis of both knees that underwent stage bilateral TKA by computer assisted surgery one side and conventional method on the other side were inclusion criteria. Digital long-leg weight-bearing radiographs were taken. The mechanical axis (MA), femoral component in coronal plane (FFC), tibial component in coronal plane (FTC), femoral component in sagittal plane (SFC) and tibial component in sagittal plane (STC) were measured and compared. RESULTS: The MA indicated that computer-assisted surgery (CAS) is significantly improved accuracy compared with conventional method (178.12 degrees +/- 1.56 degrees and 176.15 degrees +/- 1.85 degrees respectively p = 0.00). For FFC alignment, the results showed that CAS group is significantly more accurate than CONV group (88.58 degrees +/- 1.30 degrees and 87.38 degrees +/- 2.02 degrees respectively, p = 0.07). CAS group showed less distribution and fewer outliers of data than CONV group. For FTC, SFC and STC alignment, the means of both groups were no difference (p > 0.05). Otherwise, the numbers of outlier CONV group trend toward greater than CAS group (FTC 3.8% and 0%, SFC 30.8% and 0%, respectively). There was no report of change in the navigator group procedure to conventional method during surgery and no perioperative or postoperative complications were noted. CONCLUSION: Computer-assisted surgery (CAS) is a safe and useful intraoperative tool for total knee arthroplasty to improve accuracy of mechanical axis, good implant position and reduce number of postoperative implant outlier. Clinical studies will be required for clinical outcome assessment. PMID- 23451434 TI - Initial clinical and radiographic results with the short stem THA. AB - BACKGROUND: The patient who suitable for short stem THA must has good neck quality for initial stable fixation. In Thailand, the majority of patients are end stage osteonecrosis and have relatively narrow neck diameter so it's may be increased risk of intraoperative femoral fractures and leading to stem failure. OBJECTIVE: Evaluate the initial clinical and radiographic results of short stem THA over a maximum follow-up period of about 24 months, paying special attention to early problem. MATERIAL AND METHOD: The case series of 50 patients receiving short stem THA during March 2010 to September 2011. There were 15 cases of Mayo stem and 35 cases of Metha stem. The appearance of bone trabeculae development and radiolucent line at 1 year postoperative was reviewed using Gruen's classification. The Harris hip score was recorded at 6 months, 12 months and 24 months postoperative for evaluated the clinical results. RESULTS: In Mayo stem group, the mean age of patient was 44.2 years (range, 19-58) with the mean BMI of 20.9 (range, 16.9-28.1). There were 2 cases of intraoperative fractures and were treated with cerclage wires, 1 case had 3 mm subsidence with radiolucent line in zone 1, 2. Bone trabeculae was developed at zone 2 (60%), 6 (86.7%), 7 (53.3%) and radiolucent line was observed at zone 1 (6.7%) and zone 2 (6.7%). In Metha stem group, the mean age of patient was 43.9 years (range, 24-59) with the mean BMI of 22.2 (range, 16.5-32.3). There was 1 case of intraoperative fracture and was treated with cerclage wire, no further subsidence was observed. Bone trabeculae was developed at zone 1 (15.4%), 3 (79.9%), 6 (100%), 7 (92.3%) and no radiolucent line was observed. The mean Harris hip score was significantly improved from 44.9 (range, 22.7-59.7) preoperatively to 95.9 (range, 87-100) at 6 months (p < 0.01) in both stem design. CONCLUSION: The clinical results of short stem THA are generally satisfactory. The short-term results are promising and the learning curve acceptable. Its design enable preservation of the bone stock and the bone trabeculae appears to confirm the assumption of proximal force transmission. It is a promising option for young and active patients. PMID- 23451435 TI - Radiographic measurement to restore femoral head center in hip arthroplasty. AB - OBJECTIVE: The purpose of the present study was to find the anatomical landmarks used as a reference for restoration of the femoral head center in hip arthroplasty patients. MATERIAL AND METHOD: One hundred anterior-posterior digital radiographs of the hip with no magnification were analyzed to measure the correlation between the distance from the center of the femoral head to the most prominent part of lesser trochanter and the femoral head diameter, and the relationship between the level of tip of the greater trochanter and the level of femoral head center. RESULTS: The authors found the linear correlation between the distance from the femoral head center to the lesser trochanter and the femoral head diameter (Pearson's correlation coefficient = 0.95) with the average ratio of 1.023. The level of tip of the greater trochanter was found 75% higher than the femoral head center 15% below the femoral head center, and 10% at the same level. The average level of the tip of greater trochanter was 8 mm above the femoral head center. CONCLUSION: The distance from the center of the femoral head to the most prominent part of the lesser trochanter is approximately equal to the diameter of the femoral head. The use of the level of the tip of greater trochanter as a reference point for the level of the femoral head center should be carefully evaluated because of the variability of anatomy. PMID- 23451436 TI - Comparative study of anatomical landmark technique and self-aligned tibial component rotation determined by computer-assisted TKA. AB - BACKGROUND: An improper femoral and tibial component rotation is one of a major reason leading to a failed TKA. There is controversial on determination of rotational alignment particularly on a tibial component. An anatomical landmarks and a self-aligned technique have been proposed. It is the authors' purpose to determine the difference between two techniques in setting the rotation of tibial component. MATERIAL AND METHOD: The authors conducted a prospective, comparative study of 30 consecutive primary total knee arthroplasty. There were 4 men and 26 women with mean age of 68.6 years. All procedures were performed by a single surgeon with a navigation system. The degree of rotation of the tibial trial component established by a just-medial to the tibial tuberosity and self-aligned technique was compared. RESULTS: A mean of the degree of the tibial component rotation with the self-aligned of the center-post technique was 3 degrees more externally rotated than the just-medial to the tibial tuberosity technique. The self-aligned technique had standard deviations of 4.41 degrees, of which was significantly less variable (p < 0.05) than 5.94 degrees of the just-medial to the tibial tuberosity technique. CONCLUSION: The authors conclude that establishment of the tibial component rotation by using the self-aligned of the center-post technique will rotate the component more external compared with the just-medial to the tibial tuberosity technique. PMID- 23451437 TI - Cost analysis of peri-operative antibiotic administration in total knee arthroplasty. AB - BACKGROUND: Rationale perioperative antibiotic for prevent infection in total knee arthroplasty is well established. The recommendation are preoperative antibiotic should be administered within 1 h before skin incision and prophylactic antibiotics should be administered within 1 h before skin incision, if prolong surgery more than 4-6 hours need addition doses and duration of prophylactic antibiotic administration should not exceed the 24-hour postoperative period then not need for additional antibiotic. If there is evidences of infection, intravenous antibiotic and follow by oral antibiotic is mandatory in acute infection in conjuction with scrub and debridement. Because the burden of infection in joint replacement is disaster, it seemed to increase the antibiotic uses and impact about the cost concerned after total knee arthroplasty. No data available about the pharmaco-economical study of perioperative antibiotic in total knee arthroplasty have been established. OBJECTIVE: Primary outcomes is cost anaylsis of perioperative antibiotic uses in real clinical practice for total knee arthroplasty. Secondary outcome is infectioned total knee that need to reoperative for scrub and debridement. MATERIAL AND METHOD: Prospective opened lable study from joint registry in Police General Hospital from June, 2010 till March, 2011. With minimum 12 months follow up. Total Knee Arthroplasty was enrolled in the present study about 218 cases. 3 patients lossed follow-up in each groups, so the total number in the present study are 209 patients. Perioperative antibiotic consumption initial doses and followed for 48 hour is divided in 3 group: group 1 Fosmycin 4 g (2 g initially plus 2 g intraoperatively) for 70 patients group 2: Fosmycin 2 g for 68 patients. Group 3: Cefalosporin group for 71 patients. The cost of subsequence uses of intravenous and oral antibiotic were record. And also the cases that need to scrub debridement with the indication of infected total knee arthroplasty were recorded. The minimum follow-up about 12 months (range 12-18 months). RESULTS: The extend of intravenous antibiotic administration postop more than 48 hours in group 1 is 38 patients (54.28%) and oral antibiotic 42 patients (60%), in group 2 is 45 patients (66.18%) and oral antibiotic 40 patients (58.2%), in group 3 58 patients (81.7%) and oral antibiotic 60 patients (84.51%). The percentage of expenses preoperative intravenous and postoperative 48 hour: intravenous antibiotic during hospitalization: post operative antibiotic in group 1 is 19.82%: 59.69%: 20.49%; group 2 is 10.41%: 68.40%: 21.19% and group 3 is 1.39% 80.85%: 17.76%. The average total perioperative cost antibiotic (baht) in group 1: group 2: group 3 are 4,068: 4,776: 5,468. The infected case need operated for scrub and debridement in group 1 is 1 cases, group 2 is one cases and group 3 is 1 cases. CONCLUSION: Overall expense increased in both intravenous and oral antibiotic prophylaxis in total knee arthtroplasty for prevention of infection. The major cost of perioperative antibiotic is intravenous antibiotic more than 48 hours during hospitalization, the least number of patients and percentages of cost is in group 1 than group 2 and 3. The percentage of patients oral antibiotics are least in group 2 than group 1, 3 but the average cost is likely to be quite substantially lower in group 1 then group 2, 3. PMID- 23451438 TI - Results of peri-articular steroid injection in the treatment of chronic extra articular pain after total knee arthroplasty. AB - OBJECTIVE: The authors conducted study to analyze results of peri-articular steroid injection in the treatment of chronic pain from soft tissue inflammation after total knee arthroplasty (TKA). MATERIAL AND METHOD: The authors retrieved data from all patients underwent TKA whom suffered with chronic extra-articular pain and received local peri-articular steroid injection by 2 senior authors during January 1, 2008 to June 30, 2010. Clinical evaluation such as pain score, knee score and functional score were recorded pre-injection and three months after injection. RESULTS: 554 TKA cases were operated during January 1, 2008 and June 30, 2010. 29 knees from 28 female patients were injected with steroid injection and included in the present study. Mean age of 64.7 year and mean BMI of 27.7. Three patients in this group were diagnoses as Diabetes. The most common site of injection was in Tibia, with either Anserinus bursa or around Gerdy's tubercle. Mean time to injection after operation was 5 months. Mean VAS was reduced from 56.5 +/- 20.32 to 20.57 +/- 16.1. Mean knee score and functional score were improved from 74.62 +/- 14.24 to 85.71 +/- 11.85 and from 53.4 +/- 22.57 to 67.04 +/- 21.17 consecutively. All clinical difference has statistically significant with p-value < 0.05. There was no incident of superficial or deep infection at mean follow-up time of 2 years and 5 months. CONCLUSION: Local steroid injection is a safe and effective choice for treatment of pain from chronic soft tissue inflammation after TKA. PMID- 23451439 TI - Comparison of clinical and radiographic outcomes between minimally invasive lateral approach and mini-midvastus approach in total knee arthroplasty. AB - OBJECTIVE: To compare clinical and radiographic outcome between minimally invasive lateral approach and mini-midvastus approach in total knee arthroplasty. MATERIAL AND METHOD: Patients with 28 knees were underwent total knee arthroplasty. They were divided into two groups. 14 knees were underwent total knee arthroplasty with lateral approach and the other 14 knees were operated with mini-midvastus approach. Clinical evaluation was done with visual analog scale from the second day to the fifth day after surgery. WOMAC score and range of motion was recorded at the third month. Including operative time and incision length was evaluated. Prosthetic component angles was measured with radiographic evaluation at the third month. RESULTS: The results revealed no significant difference between lateral approach and mini-midvastus approach in terms of visual analog scale, incision length, operative time, range of motion, WOMAC score and prosthetic alignment. CONCLUSION: Lateral approach in total knee arthroplasty had no difference clinical and radiographic outcomes compare with mini-midvastus approach. PMID- 23451440 TI - The effect of preoperative quadriceps exercise on functional outcome after total knee arthroplasty. AB - OBJECTIVE: To compare the level of pain scores, range of motion, quadriceps strength and quality of life after TKA patients between preoperative quadriceps exercise group and usual care group. STUDY DESIGN: A randomized controlled trial study. MATERIAL AND METHOD: From January 2011-January 2012, 60 patients undergoing primary TKA were included. The patients were randomized into two groups with the use of blocking letter in 30 patients for each. The patients assigned to the preoperative quadriceps exercise group were asked to participate in three weeks home quadriceps strengthening exercise program until their TKA. The patients assigned to the usual care group were asked to continue their normal activities until their TKA. Preoperative data were collected within three weeks prior to the TKA. Should be 4 data collection included visual analog scale (VAS), quadriceps strength, knee range of motion and Modified WOMAC score. Both groups were evaluated four times: three weeks before surgery, 1 month, 3 months and 6 months after surgery. RESULTS: 60 patients was divided into 2 groups, the preoperative quadriceps exercise group and the usual care group. Most patients were female, older than 60 years, primary school educated, housekeeper occupation. Body mass index, duration of knee pain, Paracetamal and NSAIDs use were not statistically significant different. The quadriceps exercise group had statistically significant decreased pain in the postoperative 3 months (p = 0.003). The quadriceps exercise group had statistically significant decreased mean Modified WOMAC score in the postoperative 1, 3 months (p < or = 0.001, 0.001) and quadriceps strength better than the usual care group during the follow up in the postoperative 3 months. CONCLUSION: Preoperative quadriceps exercise at least three weeks prior total knee replacement result in short-term benefit such as decreased pain, improved quadriceps strength and improved quality of life after elective TKA. PMID- 23451441 TI - Can total knee arthroplasty (TKA) achieve its goal in knee flexion floor activity of Thai Buddhist monks? AB - OBJECTIVE: To study knee's angulation required for Thai Buddhist monks whose activity based on floor sitting basis. And to identify an inter-observer reliability of knee flexion measurement based on radiologic reading. MATERIAL AND METHOD: Descriptive analysis study comprised of measuring bilateral knee flexing angulation in 4 postures of floor activities; kneeling, monk's position in both right and left manner and sit cross-legged position, in 35 Thai Buddhist monks at Priest Hospital using plain radiograph image. The radiograph imaging for each patient was performed by one radiologist and two orthopedics. The measurement result was also analyzed for inter-observer reliability. RESULTS: Mean knee flexion angle in kneel, left monk's position, right monk's position and sit cross legged postures were 163.21, 146.49, 148.89 and 138.38 degree, respectively. No statistical difference between knee flexion measurements among 3 investigators. CONCLUSION: Daily floor activity of Thai Buddhist monks need more flexion capacity than that can achieve by total knee arthroplasty instrument using nowadays. PMID- 23451442 TI - A comparison of accuracy between step and non-step reamers of femoral intramedullary alignment system in total knee arthroplasty evaluated by computer assisted navigation. AB - Limb alignment after total knee replacement has been demonstrated to be one of the most influential in determining long-term survival of the implants. Malalignment can contribute to early prosthesis failure through point loading and premature polyethelene wear. Alignment guides have been developed to improve the accuracy of femoral and tibial cuts during surgery. Recently, there are at least two groups of femoral intramedullary reamer. The first group uses step reamer (8 mm drill with 10 mm step) and another one uses non-step reamer (8 mm drill). The purpose of this cadaveric study was to analyse the accuracy of both design by compared with computer navigation system. Eight cadaveric lower extremities were used for the present study in four cadaveric bodies. The step reamer was applied on the left side and the non-step reamer was applied on the right side of the same cadaver. The distal femoral cuts, using femoral valgus angle 6 degrees, were performed. The resection angles between the cutting surface and the mechanical axis were measured and collected by means of computer navigation system. The results show that the step reamer resulted in 0.125 degrees +/- 0.25 degrees of varus, whereas the non-step reamer resulted in 0.5 degrees +/- 1.08 degrees of varus compared with the calculated mechanical axis by computer-assisted navigation. These data suggest that step reamer has the accuracy more than non step reamer when evaluated by computer-assisted navigation. PMID- 23451443 TI - A prospective study comparing mobile-bearing versus fixed-bearing type in total knee arthroplasty using the free-hand-cutting technique. AB - BACKGROUND: The mobile-bearing knee prosthesis was claimed to get more flexion in the laboratory testing and may provide better functional outcome than the conventional fixed-bearing prosthesis in patients. To prove this hypothesis in the patients between those two type prosthesis about flexion and functional out come was our study goal. MATERIAL AND METHOD: The prospective randomized control trial. The Free-Hand-Cutting technique underwent TKR (100 mobile bearing and 100 fixed bearing). Post operative clinical outcomes were compared in range of movement, Knee Society Score, Function Knee Score and Oxford Knee Score at 2 months, 6 months, 1 year and 2 years. RESULTS: The mobile-bearing type prosthesis provided more flexion than the fixed-bearing knee prosthesis. But the same clinical out come was observed. CONCLUSION: The mobile-bearing type prosthesis gave more functional out come but not significant in daily patient activity compare to the fixed bearing knee prosthesis. PMID- 23451444 TI - Comparing alignment of proximal tibia first cut between narrow and wide saw blade in CAS TKA. AB - OBJECTIVE: The primary aim of the present study is to comparison between using narrow and wide saw blade of proximal tibial bone cut in close slot cutting block guide verified by computer navigation system. MATERIAL AND METHOD: The authors evaluated 80 knees in 80 patients. After cutting the proximal tibia, the cutting surface was validated using the navigated cutting block adapter, and the angular difference between the cutting surface and that preoperatively planned in the sagittal and coronal planes was recorded. RESULTS: The average cutting error of all knees was 1.8 degrees +/- 2.7 degrees in use narrow blade and 1.2 degrees +/- 2.2 degrees in use wide blade. The authors did not find statistically significant difference between the first 40 patients and the next 40 patients. The average cutting error of sclerotic bone was 2.3 degrees +/- 2.7 degrees in use narrow blade and 1.1 degrees +/- 2.1 degrees in use wide blade. The authors find statistically significant. The average error in the coronal plane was 1.5 degrees +/- 1.1 degrees in valgus and 2 (2.5%) in varus of the 80 knees had a malalignment of more than 1 degrees with respect to the targeted cutting plan. DISCUSSION: Alignment of cutting surface should be checked after cut proximal tibia and recut to reach target alignment and should be cut with wide saw blade especially in sclerotic bone. PMID- 23451445 TI - Prospective randomized trial comparing the efficacy of single 6-ml injection of hylan G-F 20 and hyaluronic acid for primary knee arthritis: a preliminary study. AB - OBJECTIVE: To compare the efficacy of single 6-ml intraarticular injection between hylan G-F 20 and hyaluronic acid (HA) for knee osteoarthritis. MATERIAL AND METHOD: Thirty-two patients with primary knee arthritis, who were randomly received single intraarticular injection of 6-ml hylan G-F 20 (Synvisc) or HA (Hyalgan), were prospectively evaluated for clinical outcomes at a minimum 26 week follow-up. The parameters, including visual analog scale (VAS) during walking, the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and Short-Form 36 (SF-36) questionnaires, were evaluated at pre-injection, then at 1 week, 4 weeks, 8 weeks, 12 weeks and 26 weeks, post-injection. RESULTS: There were 15 patients in both groups who were available for final follow-up with no statistical differences in demographic data, VAS during walking, WOMAC score and SF-36 score at pre-injection. There was no adverse event related to viscosupplementation using in is better than of both agents. At 26-week follow up, patients in both groups had significantly improved VAS during walking (p < 0.01), WOMAC score (p < 0.01) and SF-36 (p < 0.05) with no statistical differences between groups. However the cost of hylan G-F 20 was much more expensive than that of HA (534 USD vs. 252 USD). CONCLUSION: A single intraarticular injection of both hylan G-F 20 and HA for primary knee arthritis had no adverse event related to 6-ml volume. At 26-week follow-up of the present preliminary study, both groups had similarly improved clinical outcomes post injection. Further study in larger population is required. As the cost of hylan G F 20 was 2 times higher than HA, a single 6-ml intraarticular injection of HA (Hyalgan) provided better cost-effectiveness than hylan G-F 20 (Synvisc). PMID- 23451446 TI - Cost-utility analysis and economic burden of knee osteoarthritis treatment: the analysis from the real clinical practice. AB - BACKGROUND: Non-steroidal anti-inflammatory drug (tNSAIDs) or selective COX-II inhibitor (COXIBs) are generally used as the first-line intervention of knee osteoarthritis (OA). Total knee arthroplasty (TKA) is suggested for those who dissatisfy from non-surgical treatment. However the long-term usage of tNSAIDs may lead to articular cartilage and resulted in higher rate of TKA. The evaluation of real clinical practice needs to be scrutinized as the inappropriate treatment will be socially burden. OBJECTIVE: To evaluate cost-utility of selective COX-II inhibitors (COXIBs) compared to traditional NSAIDs in patients with knee osteoarthritis (OA) and to estimate health and economic burden of disease of knee OA. MATERIAL AND METHOD: The present study is an economic evaluation alongside a prospective observational study. The data of cost and treatment outcomes were collected from real clinical practice. EQ-5D questionnaire was employed to calculate utility values at baseline and 6 months after treatment. RESULTS: Total 939 patients were prescribed tNSAIDs and 380 patients received celecoxib. Eleven cases (1.17%) of all tNSAIDs usages and 3 cases (0.79%); p = 0.56 of celecoxib usages were detected GI complication. Two cases of tNSAIDs group were dead from severe GI bleeding. TKA was markedly reported with 12.99% of tNSAIDs and 9.80% of celecoxib; p = 0.06. QALYs gained from 6 months was 0.34 (+/- 0.11) for tNSAIDs and 0.36 (+/- 0.11) for celecoxib; p = 0.004. Average direct medical expenses per patient were comparable with 17,468.97 THB for tNSAIDs and 17,495.07 THB for celecoxib. Cost of TKA was a key element in both groups with 90% and 67% of total expenses in tNSAIDs and celecoxib groups, respectively. Incremental cost-effectiveness ratio (ICER) per Quality-adjusted life years (QALY) gained comparing celecoxib and tNSAIDs was 1,382.70 THB. CONCLUSION: The finding from our study can be a concrete evidence to support the appropriate future decision of clinical judgment and health care provider. PMID- 23451447 TI - Perception of leg length discrepancy after total hip replacement and its impact on quality of life. AB - OBJECTIVE: To assess the leg length discrepancy (LLD) in the patients who underwent primary total hip replacement both the actual inequality (anatomical LLD) and the perceived feeling of inequality (perceived LLD). Moreover the impact of the perceived LLD on quality of life was evaluated. MATERIAL AND METHOD: From January 2011-January 2012, 151 hips from 151 consecutive patients were studied about the post-operative LLD by measuring the post-operative radiographs at follow-up time. Questionnaires concerning the perception of LLD and the Harris hip score (HSS) were completed. Assessing the postoperative quality of life with the EQ-5D patient self-rating tool also was done. RESULTS: Seventy nine patients had anatomical LLD and 41 patients could perceive LLD. Age, gender, post operative time at follow-up and the HSS were not significantly different between both perceived LLD and non-perceived LLD patients. After 12 months post operatively all non-anatomical LLD patients perceived no LLD. Only the EQ-5D of non-perceived LLD group was significantly better. CONCLUSION: Perception of LLD after total hip replacement is a significant factor that influences the patients quality of life. However, this frustration could resolve or improve with time. PMID- 23451448 TI - Fall with and without fracture in elderly: what's different? AB - Falling fracture was one of the health problems in elderly. This presentation aimed to identify the factors of fall that caused fractures. The retrospective case-control study was designed. Samples were all who experienced fall within 1 year in Lamphun. Factors included age, gender underlying diseases, chronic drugs used, history of parent fragility fracture, age of menopause, steroid used, body mass index, visual acuity and time up and go test were studied. Multivariate regression analysis was used. 336 cases of fractures in 1,244 cases of fall were found. Significant factors of falling fracture group that were different from fall without fracture group included age, female gender, menopause before age of 45 and visual impairment. Visual impairment was the other key factor rather than osteoporosis that caused fall with fracture. The author suggested that falling fracture prevention programs should be included correction of visual impairment other than osteoporosis treatment. PMID- 23451449 TI - The efficacy of Plygersic gel for use in the treatment of osteoarthritis of the knee. AB - OBJECTIVE: An evaluation of the efficacy of the combination of ginger (Zingiber officinale) and plai (Zingiber cassumunar) gel for the treatment of osteoarthritis of the knee using 1% diclofenac gel as a comparator. MATERIAL AND METHOD: A double-blind, randomized, controlled trial of the combination of 4% ginger and plai extract in a gel (Plygersic gel) as compared with a 1% solution of diclofenac in patients with osteoarthritis knees. The number of participants in each group totaled fifty. The length of treatment was a 6 week period. The efficacy of the drugs was monitored by using the Knee Injury and Osteoarthritis Outcome Score (KOOS). The t-test was used to compare the scores before and after treatments in each group. The repeated ANOVA was used to compare the scores between the two groups. RESULTS: Both Plygersic gel and diclofenac gel could significantly improve knee joint pain, symptoms, daily activities, sports activities and quality of life measured by KOOS following 6 weeks of treatment. In the repeated ANOVA, there were no differences in the results between the Plygersic and diclofenac gel groups. CONCLUSION: Plygersic gel relieves joint pain and improves problematic symptoms and improves the quality of life in osteoarthritis knees during a 6 week treatment regimen with no differences to the 1% Diclofenac gel group. PMID- 23451450 TI - Non-union and avascular necrosis of delayed reduction and screw fixation in displaced femoral neck fracture in young adults. AB - OBJECTIVE: Management of displaced femoral neck fracture is crucial and vulnerable to develop complications. The present study was performed to evaluate the clinical outcome of delayed reduction with multiple screw fixations in young patients who had displaced femoral neck fracture. MATERIAL AND METHOD: The authors conducted a retrospective study in young patients, aged less than 50 years old, who underwent delayed fixation for traumatic displaced femoral neck fracture (Garden classification III or IV) at Phetchabun Hospital between 1997 and 2002. Either closed or open reduction was performed to achieve an acceptable alignment and fixed with 2 or 3 cancellous screws. Study factors were age, gender Garden classification, time to reduction, type of reduction, number of screw fixation and Garden alignment index. Non-union and avascular necrosis was assessed by clinical and radiographic findings. RESULTS: There were 26 eligible patients. The average duration of delayed surgery was 13 days (range 2 to 30 days). Twenty-three patients had completed followed-up at average 28.4 months (range 14-52 months). All patients revealed complete union and independently ambulated within 10-16 months postoperatively. Clinical and radiographic avascular necroses of the femoral head developed in 2 patients (8.7%) at 20 and 24 months after surgery. Three patients who had early fixation failure underwent hemiarthroplasty except one patient refused to re-operate. CONCLUSION: Within 30 day delayed reduction and screw fixation for the treatment of displaced femoral neck fracture in the young is still good alternative treatment to preserve the femoral head with low rate of avascular necrosis. PMID- 23451451 TI - Combined osteotomy in patients with severe Legg-Calve-Perthes disease. AB - OBJECTIVE: The purpose of the present study was to describe the clinical and radiographic results obtained with the combined osteotomy in patients with severe Legg-Calve-Perthes disease. MATERIAL AND METHOD: During 2000 to 2010 patients with Legg-Calve-Perthes disease who intervened with combined osteotomy at Siriraj Hospital were evaluated. Clinical evaluation was categorized by Ratliff classification and radiographic evaluation was performed by Moss index, Lloyd Roberts classification and Stulberg classification. RESULTS: Twenty patients intervened with combined osteotomy. There were nineteen males and one female with a mean age of 7.7 years. The average follow-up was 49 months. Nine had a Catterall III and eleven had a Catterall IV. According to Herring classification, fourteen patients were Herring B and six were Herring C. In accordance with the Ratliff classification, the postoperative clinical results: fifteen good, three fair and two poor. According to Mose scale, eight patients had good results, nine had fair results and three had poor results. According to the Lloyd-Roberts classification eight patients had good results, nine had fair results and three had poor results. Based on the Stulberg classification, there were ten patients in class II, nine in class III and one in class V. CONCLUSION: The surgical treatment for severe Perthes disease with the best expected outcome is still a challenge. According to the results reported here, the combined osteotomy is safe and effective procedure for patients with severe Perthes disease in whom the femoral head cannot be contained by conventional forms of treatment. PMID- 23451452 TI - The remodeling of the neck-shaft angle after proximal femoral varus osteotomy for the treatment of Legg-Calve-Perthes syndrome. AB - OBJECTIVE: To study the corrections of the neck-shaft angle (NSA) and the related clinical symptoms after proximal femoral varus osteotomy (PFVO) for the treatment of Legg-Calve-Perthes syndrome (LCPS). MATERIAL AND METHOD: Retrospective cohort study. Consecutive cases of LCPS treated at Lerdsin General Hospital during 1999 to 2010 were reviewed. The patients were excluded if they had less than 3 years of follow-up, there was incomplete data, and bilateral involvement. Demographic data and clinical symptoms were collected. The NSA were measured before and after PFVO. RESULTS: Twenty-two patients were treated by PFVO. The mean pre-operative NSA was 140 degrees. The mean varus angle created by PFVO was 20 degrees. The mean post-operative NSA at 6 weeks, 6 months, 1 year, 2 years and 3 years were 119, 119, 118, 120 and 120 degrees respectively. No statistical difference between the mean NSA at 6 weeks and 3 years (p = 0.65). There were 9 patients whose NSA increased more than 5 degrees at 3 years after operation. This group of patients had a more varus angulation at the early post-operative period. No physeal arrest was detected in any cases at 3 years after PFVO. No correlation between the NSA and pain or limitation of the hip abduction were observed. There were 3 patients, who had NSA less than 110 degrees after PFVO, had limping gait. CONCLUSION: It is difficult to predict the degree of remodeling of an individual hip after proximal femoral varus osteotomy. Special attention should be paid to avoid excessive varus of the proximal femur less than 110 degrees whenever PFVO is performed. PMID- 23451453 TI - Correlation between the length of gracilis and semitendinosus tendon and physical parameters in Thai males. AB - BACKGROUND: As anterior cruciate ligament (ACL) injuries became more common, ACL reconstruction using hamstring tendons autograft (i.e. semitendinosus and gracilis) has become increasingly popular. One of the problems encountered during operation is insufficient size of the graft. OBJECTIVE: In order to determine the size of hamstring graft preoperatively, the authors collect anthropometric data from the patients and compare them with the actual hamstring tendon length harvested from the patient during ACL reconstruction. STUDY DESIGN: Cross sectional diagnostic study. MATERIAL AND METHOD: Seventy-five consecutive patients with torn ACL scheduled for reconstruction using hamstring autograft were prospectively evaluated. Preoperatively the authors recorded height, weight, body mass index, age, leg length, thigh length, thigh circumference, length and width of the femur. Intraoperative measurements of both the gracilis and semitendinosus tendons length were made after trimming the useless thin border of the graft and final diameter of the quadrupled graft. Bivariate correlation coefficients (Pearson r) were calculated to identify relationships among clinical data and hamstring graft length and diameter measured intraoperatively. RESULTS: Strongest correlations for graft lengths were height and leg length measurements from both physical examination and x-rays. In contrast, graft diameter was not correlated with any physical parameters. CONCLUSION: Simple parameter such as height can be used for preoperative identification of patients at risk for insufficient graft tissue and would be useful for patient counseling and alternative graft source planning. Thai male who is taller than 170 cm have a good potential to have semitendinosus tendon longer than 250 mm and maybe candidates to have ACL reconstruction with semitendinosus alone. X-ray of the whole leg did not provide any better prediction of graft length. PMID- 23451454 TI - Outcome of plantar fasciitis treatment using monochrome infrared irradiation. AB - BACKGROUND: Plantar fasciitis is one of the most common causes of heel pain. Conservative treatment yields a good result, but it takes long time to accomplish the goal. Physical therapy modality, i.e. Infrared ray is one of the options that maybe help for quicker recovery. OBJECTIVE: To study the results of infrared rays for the treatment of plantar fasciitis. MATERIAL AND METHOD: 70 patients with diagnosis of plantar fasciitis at Phramongkutklao Hospital were divided in 2 groups. First group received a conservative treatment by NSAIDS, achiles tendon stretching. The second group is like the first group, with addition of infrared rays. The pain was measured at initial and 6 months post treatment using visual analog scale (VAS). RESULTS: In control group, 34 from 39 feet had lower VAS at 6 months, from 8.41 to 5.28. In the studied group, 35 from 44 feet had lower VAS at 6 months, from 8.70 to 3.38. No patient had the worse symptoms since the using of infrared rays. CONCLUSION: Application of infrared rays for the treatment of plantar fasciitis is effective. Infrared rays are safe and easy to use. PMID- 23451455 TI - Sensitivity and specificity of magnetic resonance imaging for knee injury and clinical application for the Naresuan University Hospital. AB - BACKGROUND: The accuracy of MRI evaluation for the traumatic knee injury may help the physician selecting the treatment options and informing patient about the prognosis. The purpose of the present study was to analyze the result of the MRI reported from a center in Phitsanulok which would be valuable for orthopaedic surgeons who practicing in the lower northern region of Thailand. MATERIAL AND METHOD: The 1.5 Tesla MRI of 51 injured knees that underwent subsequent arthroscopic knee surgery was independently reviewed by one from the group of radiologists. The sensitivity, specificity accuracy and negative predictive value of the MRI evaluation for menisci and cruciate ligament pathology compared to the arthroscopic finding is determined. RESULTS: There were 50 patients with the mean age of 36.7 year old (ranging from 18-75 years) and 30 were males and 20 were females. The sensitivity, specificity accuracy and negative predictive value (NPV) in detecting the complete tear of the ACL injury were 90.9%, 84.6%, 88.6% and 84.6%, respectively. There were 100%, 97.1%, 97.5% and 100%, respectively, for diagnosis of complete PCL tear. The MRI evaluation for definite medial meniscus tear revealed 100% in sensitivity, 52.6% in specificity, 64% in accuracy and 100% in NPV. For the lateral meniscus, it yielded 55.6%, 83.3%, 75.8% and 83.3%, respectively. Among the 22 patients who underwent the ACL reconstruction without the PCL or collateral ligament injury, there was 50% of associated meniscal injury with similar ratio between medial and lateral side. CONCLUSION: The MRI report from the center in Phitsanulok could be useful in detecting the cruciate ligament tear particularly with uncertain clinical examination. With a high negative predictive value, the MRI could be used as a negative diagnostic tool for the meniscal injury. PMID- 23451456 TI - A comparison of lateral radiograph of the knee in extended weight bearing and 30 degrees flexion to predict a patellar tendon length. AB - BACKGROUND: Anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstruction with bone patellar tendon bone graft (BPTB) are commonly performed. Lack of precision in patellar tendon length measurement may result in a graft-tunnel mismatch. Presently, preoperative planning needs to evaluate the limb alignment from knee extended weight bearing radiograph and the length of the patellar tendon from knee 30 degrees flexion radiograph. OBJECTIVE: To compare knee extended weight bearing radiograph and knee 30 degrees flexion radiograph to find which one can predict the patellar tendon length with more precision. STUDY DESIGN: Cross-sectional diagnostic study. MATERIAL AND METHOD: Thirty-six patients who received a cruciate ligament reconstruction with BPTB graft at Phramongkutklao Hospital were enrolled. Patellar tendon lengths were measured from knee extended weight bearing radiograph and knee 30 degress flexion radiograph and then compared to a real intraoperative patellar tendon length. Analysis using intra-class correlation coefficient and paired t-test was done. RESULTS: The mean patellar tendon length from radiographic taken at 30 degrees of knee flexion and extended weight bearing were 43.90 mm and 42.95 mm respectively. The difference was less than 1 mm which might not be clinically significant. The prediction of patellar tendon length from 30 degrees flexed film is statistically closer (ICC 0.760: 0.717, p-value < 0.001). By the way, they were both in intermediate reliability level (0.6 < ICC < 0.8). It also seems not clinically different. CONCLUSION: Preoperative film knee extended weight bearing alone is enough for evaluation both limb alignment and length of the patella tendon leading to decreasing cost, time and radiation exposure of patients. PMID- 23451457 TI - Tibial footprint for single anatomical anterior cruciate ligament reconstruction by the meniscal reference point: the cadaveric study. AB - OBJECTIVE: ACL reconstruction is the gold standard for the torn ACL. To perform the anatomic reconstruction, knowledge of the footprint location is important. The femoral footprint was described in many studies, but the tibial footprint has less information. The authors study the relationship of ACL tibial footprint by using the meniscuses as landmark. MATERIAL AND METHOD: 20 knee specimens from the anatomy department were obtained and dissected. The footprint area was determined by locating the tibial stump of ACL first, isolated it from another structures, the footprint size was measured and then the mid portion of the footprint was identified. The relationship between the meniscuses to the mid portion of the ACL tibial footprint was determined. RESULTS: The authors have found that the mid portion of the A CL tibial footprint in all of specimens was located anterior to the posterior border of anterior horn of lateral meniscus, with the average of 3.2 +/- 0.25 millimeters. CONCLUSION: The meniscuses can be used as landmark to locate the footprint of the tibial part of the ACL. The mid portion of the ACL tibial footprint is anterior to the posterior border of anterior horn of lateral meniscus. This information will help the surgeons to locate the footprint with more accuracy while performing the anatomic ACL reconstruction. PMID- 23451458 TI - The study of anterior cruciate ligament footprint in Thai population: a human cadaveric study. AB - BACKGROUND: Identification of the anterior cruciate ligament (ACL) footprint is critical for an anatomical ACL reconstruction. The osseous landmarks of the ACL footprint is one of the methods that can be used to determine the ACL insertion site. The size of ACL footprint on femur and tibia are also important for surgical decision. The purposes of the present study represent the existing of osseous landmarks and size of ACL footprint in Thai population. OBJECTIVE: Study the presence of the osseous landmarks and the size of ACL footprint both at femur and Tibia in Thai population. MATERIAL AND METHOD: 77 knees from 39 cadavers (38 paired and 1 unpaired) from Department of Anatomy, Phramongkutklao College of Medicine were dissected to identify bony landmarks of ACL at both tibia and femoral attachment. The resident's ridge and lateral bifurcate ridge were identified. The metallic markers were then inserted into the defined anatomic footprint points and size of ACL footprint on tibia and femur were measured and recorded in length and width. RESULTS: The present study found resident's ridge in 75/77 knees (97.40%) and lateral bifurcate ridge (bony landmark between anteromedial and posterolateral bundle), 50/77 knees (64.94%). The average ACL length and width at the femoral attachment were 12.01 +/- 1.66 mm and 9.52 +/- 1.37 mm respectively. At the tibial attachment, the average length was 15.36 +/- 2.33 mm and the width was 11.03 +/- 1.77 mm. However, when performed an analysis between male and female footprint, there were significant difference in length and width of both Femoral and tibial attachment. In male, the size of ACL at femoral attachment, average length was 12.68 +/- 1.48 mm and average width was 9.99 +/- 1.38 mm. At tibial attachment, average length was 16.84 +/- 1.07 mm and width was 11.32 +/- 1.43 mm. In female, the size of ACL at right femur attachment, average length and width were 10.68 +/- 1.1 mm, 8.64 +/- 0.79 mm respectively. At tibial attachment, average length and width were 12.48 +/- 1.08 mm and 10.1 +/- 0.96 mm respectively. CONCLUSION: Infemoral footprints of the ACL, the lateral bifurcate ridge can be found in 64.94% and resident's ridge can be found in 97.40% of the specimens. Then the authors can use the resident's ridge as a primary osseous landmark for anatomic ACL surgery in Thai patients, then locate the center of femoral tunnel at the lateral bifurcate ridge later in case of the authors could identify them. Gender has an effect on both femoral and tibial footprint size. The average size of ACL tibial footprint among Thai female are smaller than 14 mm, then the single anatomical ACL reconstruction may be preferred than double bundle technique. On the other hand, the average size of ACL femoral footprint in Thai male is greater than 14 mm. These findings alert the surgeon that double bundle technique could be performed in Thai male patients. PMID- 23451459 TI - Insall-Salvati ratio after arthroscopic anterior cruciate ligament reconstruction with patellar tendon graft. AB - BACKGROUND: Arthroscopic anterior cruciate ligament (ACL) reconstruction with patellar tendon graft has been considered to be the gold standard treatment of anterior cruciate ligament injuries. Much morbidity could occur after this graft was harvested, such as the patellar tendon length change and anterior knee pain. Insall-Salvati ratio is one of the tools to determine the patella tendon length. OBJECTIVE: To study the patella tendon length change after arthroscopic ACL reconstruction with patellar tendon graft by using Insall-Salvati ratio. MATERIAL AND METHOD: Descriptive study was conducted. Patients who were diagnosed ACL injury and underwent arthroscopic ACL reconstruction with patellar tendon graft were included. All patients had standardized preoperative and postoperative lateral knee radiographs. The patellar tendon length, patellar height, Insall Salvati ratio and Tegner Lysholm knee score were measured by the same person for all subjects at preoperative and 6 months postoperative period. RESULTS: In a series of 22 patients, the length of the patellar tendon lengthened by an average of 0.95 mm (6 mm shortening to 5 mm lengthening) or 1.82% and not statistically significant (p = 0.101). The Insall-Salvati ratio increased by 2.75% (16.32% shortening to 18.6% lengthening) which was also not statistically significant (p = 0.218). The Tegner Lysholm knee score was improved to 20.36 (5 to 45), which was statistically significant (p < 0.05). The amount of the Insall-Salvati ratio change was not related to Lysholm score (p = 0.571). CONCLUSION: The present study indicated that there was no significant change of patellar tendon length after arthroscopic ACL reconstruction with patellar tendon graft. No correlations with postoperative Insall-Salvati ratio and Tegner Lysholm knee score, however, the clinical results was improved in all of the patients. PMID- 23451460 TI - The relevant level to estimate girth difference between thighs after anterior cruciate ligament deficiency. AB - BACKGROUND: Manual thigh girth measurement is a simple tool to roughly estimate capacity change of the thigh. Yet, there is no good evidence supporting the most relevant anatomical landmarks to detect girth difference from the normal limb. MATERIAL AND METHOD: The present study consecutively enrolled 30 patients sustaining unilateral anterior cruciate ligament deficiency and measured both thigh girths in series at 2-cm intervals from anteromedial joint line until 30 cm cephalad. The measurements were also performed in intervals at 1/16 ratio of the thigh length marked between the tibial tuberosity (TT) and the anterior superior iliac spine (ASIS). The results from both normal and the injured side were compared by analyzing means and standard deviations for the statistical difference. RESULTS: Levels of significant mean girth difference between the two thighs were located at 18 cm and 20 cm above the anteromedial joint line or at 6/16 (3/8 or approximately 1/3) the thigh length measured from the TT towards the ASIS. CONCLUSION: In patients with knee problems using deficient ACL as the prototype, the most relevant level to detect thigh girth difference from the normal side is located at 18 cm and 20 cm above the anteromedial knee joint line or at 6/16 (3/8 or approximately 1/3) the thigh length measured from the TT towards the ASIS. PMID- 23451461 TI - Randomized controlled trial local injection for treatment of lateral epicondylitis, 5 and 10 mg triamcinolone compared. AB - OBJECTIVE: To compare the efficacy and adverse effects between 5 and 10 mg triamcinolone local injection for treatment of the lateral epicondylitis. The primary outcome was the improvement of pain after 12 weeks of treatment. The secondary outcome was the adverse effects rate. MATERIAL AND METHOD: One hundred and four patients with lateral epicondylitis were randomly allocated into 2 groups. Group A were injected with 5 mg triamcinolone and group B were injected with 10 mg triamcinolone at the maximum tenderness point at the lateral aspect of the elbow. All the patients were followed-up to 12 weeks. Patient satisfaction, pain score (VAS), degree of tenderness, pain on wrist extension against resistance, grip strength and adverse effects were recorded at 12 weeks after the injection. RESULTS: Group A (n = 51) had excellent result 80.39%, good 11.76%, slightly improved 1.96% and not improved 5.88%. Group B (n = 53) had excellent result 73.58%, good 16.98%, slightly improved 3.77% and not improved 5.66%. The adverse effects rate were 9.8% in group A and 13.2% in group B. There were no statistically significant in terms of patient satisfaction, pain score, tenderness at lateral epicondyle, grip strength and adverse effect rate. CONCLUSION: The use of 5 mg triamcinolone was comparable to 10 mg triamcinolone injected locally to treatment of lateral epicondylitis. PMID- 23451462 TI - Growth kinetics of rat mesenchymal stem cells from 3 potential sources: bone marrow, periosteum and adipose tissue. AB - OBJECTIVE: Mesenchymal stem cells (MSCs) have potential in orthopaedic applications as they are able to differentiate into bone and cartilage. These cells can be isolated from a variety of adult tissues. Three sources that are relevant for orthopaedic applications are bone marrow, periosteum and adipose tissue. The purpose of the present study was to compare the growth kinetics and colony forming potency of rat MSCs from these sources. MATERIAL AND METHOD: Bone marrow from the femur periosteum from the femoral diaphysis and adipose tissue from the inguinal area of Wistar rats were harvested for MSC isolation. The cells from 2nd-4th passage from primary culture were selected for study of their growth curves, population doubling time and colony forming ability using the percentage of colony forming units and colony forming area as the outcome measure. RESULTS: The isolated cells from these 3 sources were capable of osteogenesis, chondrogenesis and adipogenesis. The growth kinetics were compared using the growth curve and the population doubling time (PDT): bone marrow derived cells (PDT = 3.99 days, SD = 1.19) and periosteum derived cells (PDT = 3.55 days, SD = 1.21) had faster growth kinetics than adipose derived cells (PDT = 4.65 days, SD = 1.53). The percentage of colony forming units and the colony forming area from bone marrow derived cells (% colony forming unit = 8.58, SD = 1.35 and % colony forming area = 25.12, SD = 7.31) and periosteum derived cells (% colony forming units = 9.92, SD = 2.06, % colony forming area = 32.45, SD = 10.74) were significantly greater (p < 0. 05) than adipose derived cells (% colony forming units = 5.92, SD = 0.78, % colony forming area = 15.80, SD = 9.035). CONCLUSION: The growth kinetics and colony forming potency of MSCs from bone marrow and periosteum were comparable. The bone marrow and periosteum should be a suitable source for MSC isolation. The growth kinetics of MSCs derived from adipose tissue was lower than the other sources. Adipose tissue can be used as an alternative source as it is readily available and dispensable. PMID- 23451463 TI - Result of percutaneous disc decompression using nucleoplasty in Thailand: a randomized controlled trial. AB - BACKGROUND: Chronic low back pain is a major social, economic and healthcare issue in the Thailand. Percutaneous techniques are rapidly replacing traditional open surgery in operations requiring discectomy, decompression and fusion. The percutaneous access to the disc was first used in the 1950s to biopsy the disc with needles. Percutaneous access to the disc using endoscopic techniques was developed in the 1970s. Nucleoplasty has emerged as one of the minimally invasive techniques for treatment of low back pain and lower extremity pain due to contained herniated discs which utilizes coblation technology for ablating and coagulating the nucleus for a partial disc removal. OBJECTIVE: Evaluate the effectiveness of Nucleoplasty on pain in activity and improvement in MRI in patients with radicular or axial low back pain secondary to contained herniated discs. DESIGN: Prospective, Randomized, Control Trial. MATERIAL AND METHOD: Sixty four patients were randomized in two groups equally. Thirty-two patients had undergone Nucleoplasty and another thirty-two patients had undergone conservative treatment. Patients were evaluated at 1, 3, 6 and 12 months postoperatively and were asked to quantify their pain using a visual analog scale ranging from 0 to 10. Data were compared between baselines and at 1, 3, 6 and 12 months post treatment. Pre-nucleoplasty MRI and Post-nucleoplasty 3 months were compared to evaluate the decrease of bulging disc. RESULTS: Reported pain and medication use were significantly decreased and functional status was improved at 1, 3, 6 and 12 months following Nucleoplasty (p-values < or = 0. 001 for all outcome measures at all time periods) and also the bulging disc was significantly decreased 3 months following nucleoplasty. CONCLUSION: Nucleoplasty appears to be safe and effective in Thailand. Is an effective procedure for patients presenting with discogenic back and/or radicular pain that have failed conservative therapies and are not considered candidates for open surgical interventions. A result of this analysis indicated that PDD using Coblation technology, also referred to as nucleoplasty, is an effective procedure for patients presenting with discogenic back and/or leg pain who have failed conservative therapies and are not considered candidates for open surgical interventions. PMID- 23451464 TI - The effect of learning curve on the results of percutaneous transforaminal endoscopic lumbar discectomy. AB - OBJECTIVE: To demonstrate the correlation of postoperative visual analog scale (VAS) of leg pain and adequacy of disc decompression with the learning curve of the surgeon who performed PTELD. MATERIAL AND METHOD: The authors retrospectively reviewed 50 matched criteria patients arranged into 5 groups which were categorized by the period of operation from January 2010 to May 2011 successively. Each patient's preoperative and postoperative VAS of leg pain at 1 week, 3-week, and 6-week follow-up were analyzed and demonstrated the correlation with the learning curve. Additionally, the authors also showed the alteration of thecal sac expansion between the preoperative and the postoperative MRI to demonstrate the learning curve during the different operative period. RESULTS: The VAS of leg pain as well as the mean differences of VAS of leg pain in each groups of patient were improved at each postoperative period follow-up and have a statistically significant improvement at 6-week follow-up. When the authors analyzed the mean differences VAS at pre- and post-operative 6-week follow-up among each groups of patients, it demonstrated that the learning curve had the progressive effect on the result of the operation. Also for the adequacy of disc decompression, the improvement of the thecal sac expansion was established when the amount of surgical volume was increased. CONCLUSION: The amount of surgical volume in focus of PTELD has an influence in the improvement of the VAS of leg pain and the adequacy of disc decompression. However, the patient selection such as types of disc herniation is also play an important role in accomplishment. PMID- 23451465 TI - Flexor pollicis longus injury after corrective osteotomy of distal radius malunion with volar fixed-angle plating: case report and review literature of the flexor tendon injuries after volar plating. AB - Flexor tendon injury is a potential complication after volar plating of distal radius fracture. This article reports a case of flexor pollicis longus tendon rupture after corrective osteotomy of a distal radius malunion with volar fixed angle plating. Thirty-three cases of flexor tendon injuries after fixed-angle volar plating and eleven cases of flexor tendon injuries after non-fixed-angle volar plating were also reviewed. The clinical presentation, injured tendons, type of the plate, causes of the injuries and preventions of this complication were discussed. PMID- 23451466 TI - Modified uniportal endoscopic plantar fasciotomy: a technical report. AB - OBJECTIVE: Several authors have reported the benefits of the recent procedure of the dual portal endoscopic plantar fasciotomy (EPF). However, very little is known concerning its potential capability via the single portal EPF without special cutting device. The present study aimed to demonstrate the effectiveness of uniportal EPF in a patient with severe intractable plantar fasciitis following a failure of several conservative treatments. The recent technique; uniportal EPF under modified method, without a special cutting device, was reviewed in an effort to improve its capability for plantar release and to provide information for the avoidance of this procedure's complications. CASE REPORT: A patient, with the recalcitrant conditions and the progression of the severe plantar fasciitis of bilateral feet after a failure of the conservative treatments for 13-month period, was included in this report. All data of the preoperative and each successive postoperative period (1, 6 months and last follow-up) were prospectively collected including American Orthopedic Foot and Ankle Society (AOFAS) score, Visual Analogue Scale-Foot and Ankle (VAS-FA) score and any related complications. The operations were carried out by a single surgeon with the modified uniportal EPF via a simple hooked soft-tissue blade, without a special cutting device, on both feet simultaneously. All feet had uniportal EPF with transection of the medial 50% of the plantar fascia. Postoperatively, a patient was instructed to have partial-weight bearing for the first 2 weeks with wearing of full-length silicone insoles. Then, she is allowed to start to fully weightbear with the insoles. She is advised to cautiously return to daily activities and works at 2nd week after the operation. In regard to the EPF in two feet, there were clearly improvements in the comparison between preoperative and last follow-up period in terms of the increasing AOFAS scores, and VAS-FA scores. There were no significant iatrogenic-related complications including the lateral column pain in the present report. CONCLUSION: The recalcitrant condition of severe plantar fasciitis is not uncommon for several orthopedic surgeons. Regarding the emerging of several minimally invasive procedures for this condition, our modified uniportal EPF with a simple device was encouraging as a treatment option in releasing the plantar fascia with satisfactory effectiveness and lower risks of complications. PMID- 23451467 TI - Result of arthroscopic removal of an enchondroma at the talar dome: a case report. AB - Enchondroma is a benign tumor that is generally asymptomatic and rarely found in the talus. A forty-nine-year-old man, had a chronic left ankle pain which related to moderate to heavy activity. A plain radiograph and magnetic resonance imaging (MRI) revealed a 1.3 cm benign lobulated intramedullary lesion at the middle 1/3 of medial part of talar dome with sclerotic rim. An arthroscopic intralesional curettage of the ankle joint was performed without bone grafting. Histologic examination was consistent with the diagnosis of an enchondroma. The patient was asymptomatic and without restriction on his job at 6 months. At 1 year of follow up, the CT scan and MRI demonstrated no recurrence of the tumor but the defect was not filled up. PMID- 23451468 TI - Review article: management of bone loss in revision knee arthroplasty. AB - The number of total knee arthroplasty (TKA) has been increasing during the past few years, as this procedure is reliable and efficacious for patients who suffered from late stage knee osteoarthritis. According to higher number this procedure on varies patient's age, there has been increasing number of younger patients. Thus, there is potential to increase incidence of revision TKA in the future. In revision TKA, one of the major problems to deal with is the bone loss, which may affect the prosthesis placement, the alignment of the limb and prosthesis longevity. Bone loss in revision TKA varies according to the degree of severity. Management options are based on the severity and the principle of bone reconstruction, which range from bone cement, autogenous graft, allograft, metal augment, and mega prosthesis. Recently new alloys with high porosity have been introduced with satisfactory short-term results. In this review article, the authors summarized the scientific evidences of current treatment options and outcomes of bone loss according to the degree of severity. PMID- 23451469 TI - Contemporary pain management in total knee arthroplasty. AB - Pain management has become a very important part of postoperative care for total knee arthroplasty patients. Contemporary pain control has evolved from high-dose opioid in the past to state-of-the-art multimodal regimens. These include multiple non-opioid medication such as NSAIDs, COX-2 inhibitors, and gabapentinoid, and novel anesthetic techniques such as preemptive analgesia and ultrasound-guided peripheral nerve blocks. Another method which is gaining popularity is intraarticular injection of anesthetic cocktail during surgery. Pre op education can also help patients cope with their pain better. PMID- 23451470 TI - [Reconstruction of large external nose defect with forehead flap]. AB - OBJECTIVE: To discuss the role of forehead flap in large external nasal defect reconstruction. METHOD: We retrospectively reviewed the clinical and follow-up data of 11 patients with large or full-thickness external nasal defects, which were reconstructed with single-or two-stage interpolated or island forehead flaps from January 2007 to June 2011. All patients were male,defects of 9 cases were resulted from resection of skin malignant tumor and traumatic defect in 2 cases. The average diameter of defects was 3.3 cm (2.5-5.0 cm). Four cases had alar full thickness defect. The supratrochlear and angular artery of the elders (>70 yrs) and patients with suspicious peripheral blood vessel lesions were scanned before the surgery by Doppler ultrasonic. The defects were reconstructed by two-stage interpolated flap in 7 cases; five cases were reconstructed by single-stage island flap technique. A nasolabial flap based on piriform aperture was turned into the nasal cavity to reconstruct the lining. RESULT: All defects were repaired successfully. All tissue flap survived and the scar was not conspicuous. One patient had nostril stenosis with mild nasal congestion complain at the 6th postoperative month. CONCLUSION: The forehead flap, interpolated or island, can be used safely and effectively to repair the large external nasal defect in experienced hands. PMID- 23451471 TI - [Clinicopathological analysis of sinonasal ectopic meningioma]. AB - OBJECTIVE: To evaluate the diagnostic and therapeutic methods of sinonasal ectopic meningioma. METHOD: The clinical data of 8 patients treated in our department from Jan 1990 to Oct 2011 were retrospectively analysed. Among these patients, 5 cases were treated by lateral rhinotomy approach; 2 cases were treated by endoscopic plus modified Caldwell-Luc technique; 1 case was treated by endoscopic plus modified Caldwell-Luc technique. All patients were followed up postoperatively. RESULT: All patients had no complications after operation. All patients were followed up from six months to 22 years. Among them, two cases had recurred 18 months and one year postoperatively. The two cases did not recur after the second operation. CONCLUSION: Although sinonasal ectopic meningioma is difficult to diagnose because of their infrequent occurrence in this ectopic site and of their non-specific clinical appearance. The final diagnosis rests on the histological examination. Immunohistochemical studies are helpful to establish the accurate diagnosis. Prognosis is excellent after complete surgical resection. PMID- 23451472 TI - [The characteristics and treatment of empty sella combined cerebrospinal fluid leakage of nasal]. AB - OBJECTIVE: To study the feature and treatment method of patients with empty sella merger cerebro-spinal fluid leakage of nasal. METHOD: There were 8 cases with empty sella merger cerebrospinal fluid leakage of nasal, 2 cases were accepted the repairing surgery of cerebrospinal fluid leakage one time, 4 cases were accepted the repairing surgery of cerebrospinal fluid leakage used endoscope 2 times, 1 case was accepted repairing surgery of cerebrospinal fluid leakage used endoscope merge craniotomy and ventricle celiac bypass, 1 case recurrences after repairing surgery of cerebrospinal fluid was recurred after conservative treatment. Some postoperative were stayed in bed for three weeks and lumbar drainage for 1 week. RESULT: One case of cerebral hemorrhage after surgery was cured with craniotomy, followed for 2 years without recurrence. One case was recurred after conservative treatment. Two cases recurrences after surgery 3 years ago were accepted surgery again followed by one year without recurrence. One case who recurrence 1 year later was accepted repairing surgery of cerebrospinal fluid leakage used endoscope merge craniotomy and ventricle celiac bypass followed six months without recurrence. One cash after once surgery was followed half a year without recurrence. One case with recurrence 5 years later was accepted repairing surgery again. CONCLUSION: The patient with empty sella combined cerebrospinal fluid leakage of nasal was rare, the main method was endoscopic sinus surgery treatment, but it recurred usually. The patients with repeatedly recurrence can be considered to accepted the surgery of ventricle celiac bypass. It required long-term postoperative follow-up and review. PMID- 23451473 TI - [Analysis on the allergens in allergic rhinitis patients in Changzhou district of Jiangsu]. AB - OBJECTIVE: To investigate the distribution of positive allergens in patients with allergic rhinitis in Changzhou. METHOD: A total of 4242 cases with allergic symptoms and signs underwent skin prick test with 16 kinds of standardized allergens. The common allergens were found out. The samples were stratified on seven age groups to analysis the distributive characteristics of allergens responsible for each group. The samples were also stratified on children group and adults group to analysis their response degree to dust mite. RESULT: 2638 cases (62.19%) had the positive reaction, including male 1380 (52.3%) cases, female 1258 (47.7%) cases. Dermatophagoides farinae and dermatophagoides pteronyssinus had the highest positive ratio (85.86%, 83.55%) in inhalation group, followed cockroach (11.49%) and Humulus L. (9.82%), fungus (2.92%) in the lower positive ratio. Shrimp (5.76%) was the most common allergen in food group. The distribution of common allergens in different age groups was variable. There was significantly higher sensitivity to dust mite between children group compared to adults group (P < 0.01). CONCLUSION: The study shows that Dust mite was the mostly responsible common allergen in Changzhou district. The distribution of common allergens in children group and adults group was variable. PMID- 23451474 TI - [Combined middle meatus and expand pre-lacrimal recess-maxillary sinus approach for endoscopic maxillary sinus surgery]. AB - OBJECTIVE: To study surgical techniques and clinical applications of the intranasal endoscopic combined approach in maxillary sinus benign lesions surgery. METHOD: A retrospective clinical analysis of 27 patients "whose unilateral maxillary sinus benign lesions operated by the intranasal endoscopic middle meatus with inferior meatus tears recess approach surgical treatment was studied. RESULT: Benign lesions were confirmed by pathology in all patients before and after surgery as to rule out malignancy. All patients had been followed up for 12 to 24 months. Twenty-seven cases resulted in normal luminal epithelium and inferior turbinate shape after surgery. Only one case of papilloma relapsed 2 months after operation. So far, the papilloma has not recurred after the second surgery. There were no epiphora in all cases. CONCLUSION: Endonasal endoscopic expand anterior tears recess approach have great and clear view. This approach made us accurately, mini-invade and completely remove the maxillary sinus benign lesions. It is a physiological and functional surgery and has great advantage in the nasal cavity disease treatment. PMID- 23451475 TI - [Th1/Th2 cytokines and its clinical significance in obstructive sleep apnea hypopnea syndrome children without allergic rhinitis and asthma]. AB - OBJECTIVE: To analyze Th1 and Th2 immune balance related cytokines and clinical significance in obstructive sleep apnea hypopnea syndrome children without allergic rhinitis and asthma. METHOD: Collected 91 cases of obstructive sleep apnea hypopnea syndrome children with obstructive level data, and measured the serum Th1 cytokine TNF-beta and IFN-gamma, Th2 cytokines IL-4 and IL-5 levels. One hundred and five normal children were enrolled for the same detection of serum cytokines. RESULT: Non-allergic rhinitis and asthma children serum levels of IFN-gamma was lower than control group children, the difference was statistically significant (P < 0. 01). Other cytokines (TNF-beta, IL-4 and IL-5) were no significant difference with the control group. CONCLUSION: Th1 and Th2 immune response was imbalance in non-allergic rhinitis and asthma obstructive sleep apnea hypopnea syndrome children. The decline in Th1 cell-mediated protective immune response cells may cause disease. PMID- 23451476 TI - [Expression and correlational research of mTOR and 4EBP1 in laryngeal carcinoma]. AB - OBJECTIVE: This study aimed to explore the expression and their correlation of mammalian target of rapamycin (mTOR) and EIF4E binding protein1 (4EBP1) in laryngeal squamous cell carcinoma (LSCC). METHOD: MTOR and 4EBP1 expression was studied using immunohistochemical methods in LSCC tissues of 77 cases and adjacent tissues of 18 cases,and then the relationship of their expression and clinical pathological factors were analyzed. RESULT: The positive expression rates of mTOR and 4EBP1 were 54.5% and 48.1% in laryngeal carcinoma, which was significantly higher than those in para-carcinoma (P < 0.05). Expression of mTOR and 4EBP1 was associated with metastases to lymph nodes and histopathology classification (P < 0.05), but was not associated with clinic stages (P > 0.05). There was significant positive correlation between the expression level of mTOR and 4EBP1 in LSCC (P < 0.05). CONCLUSION: (1) The high expression of mTOR and 4EBP1 is closely related with clinicopathology and lymph node metastases. It may play an important role in the development and progression of laryngeal carcinoma. (2) The positive correlation on expression level of mTOR and 4EBP1 in LSCC tissue shows that it has clinical significance on clinical therapy and prognosis. PMID- 23451477 TI - [The effects of hearing level on auditory performance in infants with hearing aids]. AB - OBJECTIVE: The purpose of this study is to investigate the effects of hearing level on auditory performance in infants with hearing aids and provide a clinical database for their hearing and speech habilitation. METHOD: A total of 32 infants with prelingual hearing loss participated in this study, ranging in age at hearing aid fitting from 3 to 34 months with a mean of 16 months. According to their hearing level, they were divided into three groups. Infants in group A were with moderate hearing loss (41-60 dB HL). Infants in group B were with severe hearing loss (61-80 dB HL). Infants in group C were with profound hearing loss (>81 dB HL). The infant-toddler meaningful auditory integration scale (IT-MAIS) was used to evaluate their auditory performance. The evaluation was performed before hearing aid fitting and 1, 3, 6, 9, 12 months after fitting. RESULT: The mean scores of auditory performance showed significant improvements with time of hearing aid use for the three groups of infants (P < 0.05). The mean score of auditory performance for group A at 3 months after fitting was significantly superior in comparison with the scores before hearing aid fitting and at 1 month after fitting (P < 0.05). The mean score of auditory performance for group B at 6 months after fitting was significantly superior in comparison with the scores before hearing aid fitting and at 1, 3 months after fitting (P < 0.05). The mean score of auditory performance for group C at 9 months after fitting was significantly superior in comparison with the scores before hearing aid fitting and at 1, 3, 6 months after fitting (P < 0.05). There were no significant differences in mean scores between group A and B at each evaluating interval (P > 0.05). However, significant differences were observed between group A and C at 3, 6, 9, 12 months after fitting (P < 0.05). Significant differences were also shown between group B and C at 1, 3, 6, 9, 12 months after fitting (P < 0.05). CONCLUSION: Auditory performance of infants with prelingual hearing loss developed significantly with the use of hearing aids within the first year after fitting. The degree of hearing loss in infants had significant influence on the development of auditory performance. PMID- 23451478 TI - [Analysis of food allergens in patients with allergic rhinitis in Guangzhou]. AB - OBJECTIVE: To investigate the distribution of multiple food allergens in patients with allergic rhinitis in Guangzhou area. METHOD: Skin prick tests were performed in 1529 patients with allergic rhinitis. The result was discussed by the age of patients, the types of allergens and the response intensity. RESULT: Five hundred and eighty-seven cases were positive. The most important food allergens were crab (25.6%), prawn (19.4%). There were statistical differences of positive reactions among three age groups (P < 0. 05). The main food allergen was seafood. CONCLUSION: Crab and prawn are the main food allergens in patients with allergic rhinitis in Guangzhou. It is helpful for clinical diagnosis and treatment. PMID- 23451479 TI - [Quantitative analysis of psychiatric disorders in patients with intractable Meniere's disease]. AB - OBJECTIVE: To investigate the correlation between psychological disorder and vestibular dysfunction in patients suffering from peripheral vertigo. METHOD: Retrospective review of 17 peripheral vertiginous patients with intractable Meniere's disease recruited from the EENT hospital whom underwent intratympanic gentamicin injection. Hospital anxiety and depression scale, self-rating anxiety scale, self-rating depression scale, symptom checklist-90 were used in this study. Pre- and postoperative scores where compared. RESULT: The vertigo control rate of 17 patients reached 88%, with hearing impairment noted only in 17.6% of the patients. 33.3% of the preoperative tinnitus patients and 76.9% of the preoperative aural fullness patients had their symptoms relieved respectively. The outcomes of hospital anxiety and depression scale, self-rating anxiety scale, self-rating depression scale, symptom checklist-90 are significantly greater in vertiginous group than that in normal controls (P < 0. 01). The preoperative scores of these 4 questionnaires are greater than the postoperative scores in vertiginous patients (P < 0.05). No significant difference was noted between male and female participants in all the questionnaires used (P > 0.05). CONCLUSION: Significant differences were noted between peripheral vertiginous patients and normal controls in psychiatric questionnaires, suggesting that psychological dysfunction may contribute to the vertigo attack. PMID- 23451480 TI - [Comparison of plasma radiofrequency ablation to the total inferior turbinate with its anterior extremity]. AB - OBJECTIVE: To compare the curative effect and complications between plasma radiofrequency ablation to the anterior extremity of the inferior turbinate and the treatment to the total of the inferior turbinate for the treatment of hypertrophic inferior turbinate. METHOD: One hundred and fifty-three patients were randomly divided into two groups, and all of the patients had obviously nasal obstruction due to isolated inferior turbinate hypertrophy. In the experimental group, plasma radiofrequency ablation was only applied to the anterior extremity of the inferior turbinate, whereas the whole concha was ablated in the control group. Visual analogue scale (VAS) for nasal obstruction were obtained both before the treatment and 1 year after surgery, and during the follow-up period, their recovery of nasal mucosa and complications were evaluated. RESULT. VAS scores before and after treatment were statistically significant in both groups (P < 0.01), but decreased value of VAS scores between the two groups was insignificant (P > 0.05). Complications between the two groups were statistically significant (P < 0.01). CONCLUSION: Compare to radiofrequency ablation to the total of the inferior turbinate, the application to the anterior extremity of the inferior turbinate could provide adequate curative effect. The treatment to the anterior extremity of the inferior turbinate is simpler, which induce less complications, and which is safer for there is less risk of damage of continuity of the nasal mucosa. So it has a higher clinical application value. PMID- 23451481 TI - [Epithelial-myoepithelial carcinoma arising in the nasal cavity: a case report and literature review]. AB - OBJECTIVE: To seek pathological features, diagnosis, treatment, prognosis of Epithelial-myoepithelial carcinoma arising in the nasal cavity. METHOD: One case of Epithelial-myoepithelial carcinoma arising in the nasal cavity was analyzed retrospectively and studied with immunohistochemical Staining and light microscopy, as well as review of the literature. RESULT: The clinical feature of epithelial-myoepithelial carcinoma in the nasal cavity was atypical and diagnosis relied on pathologic features. Epithelial-myoepithelial carcinoma consisted of myoepithelial and epithelial cells. Immunohistochemical staining demonstrated that cytokeratin P, cytokeratin L, S-100 protein, a-smooth muscle actin expressed positively. CONCLUSION: Epithelial-myoepithelial carcinoma in the nasal cavity is a rare neoplasm. Wide surgical excision with a clear margin is the main therapy,and these tumors have the potential for metastasis and recurrence. PMID- 23451482 TI - [The longterm effect of coblation combined lateral fracture in the treatment of inferior turbinate hypertrophy]. PMID- 23451483 TI - [Crus of helix condyloma: report of one case]. AB - Discovery and study of condyloma acuminatum in the ear with the occurrence of clinical symptoms. Mainly for thwart protuberance, and discomfort, no pain. The pathology report showed: (The left crus of helix) squamous papilloma. PMID- 23451484 TI - [A case of fibrous dysplasia of temporal bone]. AB - Osteofibrous dysplasia is a kind of innocent bone tumor derived from fibrous tissue. Its pathogens has not been identified, it rarely affects the temporal bone, its clinical manifestations mainly is hearing loss. Imageological examination, for example, CT and MRI, is valuable for the diagnosis of this disease,the histopathological evidence is absolutely necessary to make definite diagnosis. Surgery is an effective method to treat the fibrous dysplasia of temporal bone. PMID- 23451485 TI - [Research progress on role of chemokine receptor CCR3 signaling in allergic airway diseases]. AB - Allergic airway diseases have been identified as chronic inflammatory diseases of respiratory membranes, characterized by infiltration of many inflammatory cells, especially eosinophils. The expression of CCR3 is abundant on the cell surface of eosinophils. Increased accumulation of CCR3-driven inflammatory cells is thought to favor the development of allergy. In this review, we survey the properties of CCR3 and its ligands and highlight the roles of CCR3 signaling in allergic airway diseases. PMID- 23451486 TI - [Advances in cytokine immune mechanisms of allergic rhinitis]. AB - Allergic rhinitis is a common disease, which was released by the IgE-mediated atopic individuals exposed to allergens in the earlier researches. However, there are variety of immunocompetent cells and cytokines involved in the nasal mucosa immunologic mechanism in nowadays researches. The mechanism of AR is caused by the imbalance of the Th1/Th2, a kind of allergic inflammation who is characterized by the nasal Th2 immune response dominant. Th1 cells mainly produce of IFN-gamma (does not include IL-4 and IL-5), Th2 cells produce IL-4, IL-5, IL-9 and IL-13 (not including IFN-gamma). Recently it was found that regulatory T cells (T regulatory cells, Treg) and Th17 cell research played a crucial role in the occurrence of allergic inflammation. PMID- 23451487 TI - [Effect of activated charcoal on rooting in tissue culture seedling of Begonia fimbristipula on Dinghushan Mountain]. AB - OBJECTIVE: To study the effect of different plant growth substance and activated charcoal on rooting in culture seedling of Begonia fimbristpula on Dinghushan mountain. METHODS: Tissue culture single factor experiment method was used. RESULTS: NAA 0. 3 mg/L + IBA 0. 2 mg/L preferably induction adventitious bud clump with corm to take rooting, but the number of adventitious root were less, short and small, callow shoot more germination. 300 mg/L activated carbon obviously increased radicate quality and inhibited fine buds point differentiation, root number up to 15.5 institia, root length range was 2.0-5.1 cm, root system developed. Tissue culture seedlings were higher, corn and leaf were good quality, strong growth. Took root of seedling cultivation with bulb for bush in the form of scattered bud planted to peat soil: perlite (3:1) mixed in matrix, after the transplant survival rate reached 100%, plant form seedlings fast, grew exuberant. CONCLUSION: MS with sucrose 30 g/L + NAA 0.3 mg/L + IBA 0.2 mg/L + activated carbon 300 mg/L + carrageenan 7.0 g/L as the tissue culture seedling of Begonia fimbristipula radicate system, is rapid propagation and preserve local unique plant in an effective way. PMID- 23451488 TI - [Cryopreservation and plantlet regeneration of dormant buds of Gentiana straminea by vitrification]. AB - OBJECTIVE: To investigate the detailed techniques for cryopreservation of Gentiana straminea dormant buds by vitrification. METHODS: Dormant buds as an experimental material,the influence of the different size of dormant buds,preculture and PVS etc. on cryopreservation of Gentiana straminea were studied. RESULTS: The optimal procedures were as follows: 10-11 mm long dormant buds which were cultured on MS medium supplemented with different sucrose concentration (0. 3,0. 5 or 0.7 mol/L) for 1 day respectively. The buds were immersed in loading solution for 20 min at 20 degrees C, and then treated in PVS2 solution for 40 min at 0 degrees C and finally plunged into liquid nitrogen quickly. After 24 hours, the buds were rapidly thawed in a water bath at 40 degrees C for 2 - 3 min and washed twice with MS medium supplemented with 1/2 MS liquid medium containing 1. 2 mol/L sucrose. Finally the buds were transferred to regeneration medium (MS + 0.5 mg/L 6-BA + 0.1 mg/L NAA + 3% sucrose + 0.7% agar), the survival rate was up to 83.3%. CONCLUSION: A high-efficiency cryopreservation protocol of Gentiana straminea is set up. PMID- 23451489 TI - [Study on the processing technique of enzyme hydrolysis Eupolyphaga sinensis peptide and innunoregulatory effect]. AB - OBJECTIVE: Using papain to prepare polypeptide from Eupolyphaga sinensis, then study the immune function of polypeptide from Eupolyphaga sinensis in vivo. METHODS: Used hydrolysis degree as index, pH value, enzyme dosage, thermometer reaction time were optimized. Studied the influence of polyeptide on the mice immune functions through mice immune organs index, phagocytic function and the level of IL-2. RESULTS: The optimum enzymolysis condition was as follows: pH 8.0, enzyme 1%, temperature 55 degrees C, reaction time 4. 5 h. In vivo test of mice demonstraed that, Eupolyphaga sinensis could elevate index of thymus and spleen, enhance the phagocytic function of macrophage and promote the level of IL-2 in serum. CONCLUSION: Eupolyphaga sinensis has immunoregulatory effect. PMID- 23451490 TI - [Full-length cDNA clone and sequence analysis of Cu/Zn-SOD gene from Evodia rutaecarpa]. AB - OBJECTIVE: To clone full-length sequence of Cu/Zn-SOD gene of Evodia rutaecarpa. METHODS: The genes ORF,3,and 5,noncoding regions were achieved using the RACE technology. RESULTS: This genes full-length was 717 bp, the open reading frame was 459 bp and 152 amino acids were encoded. The accession number of GenBank was JQ285851. CONCLUSION: This Cu/Zn-SOD gene is full-length cDNA sequence of Evodia rutaecarpa and it has high homology than other plants. PMID- 23451491 TI - [Identification of herba rabdosiae serrae from different plant resources by RAPD method]. AB - OBJECTIVE: To identify the different plant resources of Herba Rabdosiae Serrae by using Random Amplified Polymorphic DNA ( RAPD ) Analysis. METHODS: The mini spin columns were used to extract the genomic DNA from five different plants of Herba Rabdosiae Serrae. With the DNA extracted from these plants as template,the 85 oligo nucleic acids (10 bp)as random primers,the polymer chain reaction (PCR) was done and the results were analysed by electro-pharoses. RESULTS: 12 primers were selected with polymorphism and 7 of them showed good polymorphism in RAPD map. CONCLUSION: RAPD method can be used to identify the plant resources of Herba Rabdosiae Serrae. PMID- 23451492 TI - [Influence of processing methods on the chemical composition of the essential oil from Aucklandia lappa]. AB - OBJECTIVE: To investigate the effects of different processing methods on chemical compositions of essential oil from Aucklandia lappa. METHODS: 4 different methods, frying without additional ingredients (1), stir-heating with bran (2), roasting surrounded with bran (3), and roasting wrapped in wet paper (4) were used to process raw Radix Aucklandiae and the contents and chemical compositions of essential oil were compared in the processed products with those in the raw drug. The essential oils were extracted wtih supercritical CO2 and analyzed by GC MS. RESULTS: Except method 1, processing lowered the content of the essential oil in Radix Aucklandiae significantly. 29, 33, 32, 34, and 33 compounds were identified, respectively, in the essential oils from raw Radix Aucklandiae and the processed products of Radix Aucklandia with method 1, 2, 3, and 4. The chemical compositions of essential oil of Radix Aucklandiae changed a lot in processing,some components disappeared, such as alpha-phellandrene; Some came into being, such as alpha-ionone, alpha-caryophyllene, beta-sesquiphellandrene, alpha-longifolene,and so on, some increased in contents,such as elemene, dihydro a-ionone, beta-caryophyllene, and so on. The contents of costunolide and dehydrocostuslactone in Radix Aucklandiae decreased in processing with method 2, 3, and 4. CONCLUSION: As a perfume meterial, Radix Aucklandiae should be processed by roasting surrounded with wheat bran, while as a drug to treat epigastric pain, the raw drug should be processed by stir-heating. PMID- 23451493 TI - [Affect regularity of medicinal species and heating time on flavonoids contents in Epimedium cut crude drug]. AB - OBJECTIVE: To study the affect regularity of medicinal species and heating time on flavonoids contents in Epimedium cut crude drug. METHODS: Setting processing temperature at 170 degrees C, 39 batches Epimedium cut crude drug of different species were heated for 0, 5, 10 minutes. The contents of epimedin A, B, C, icariin, Baohuoside I in different species of Epimedium were determined by HPLC. The variance analysis was used to study the effect of medicinal species and heating time on the contents change of five major flavonoids. RESULTS: The contents of Epimedin A, B, C were significantly impacted by medicinal species (P < 0.01), and Baohuoside I was also impacted (P < 0. 05). The contents of Epimedin A, B, icariin and Baohuoside I were significantly impacted by heating time (P < 0.01). But the flavonoids contents in Epimedium were not impacted by the interaction effect of heating time and species (P > 0.05). CONCLUSION: The medicinal species and heat processed time are two important influence factors on the flavonoids contents in Epimedium. The contents of Epimedin A, C are abundant in Epimedium pubescens, and the contents of Epimedin B, Baohuoside I are higher in Epimedium brevicornu. After heating, the contents of Epimedin A, B, C are decreased, and icariin, Baohuoside I are increased. This study provides scientific evidences for variety certification, optimizing processing technology, exploring processing mechanism and clinical rational administration. PMID- 23451494 TI - [Study on ITS sequences of Aconitum vilmorinianum and its medicinal adulterant]. AB - OBJECTIVE: To analyze and compare the ITS sequences of Aconitum vilmorinianum and its medicinal adulterant Aconitum austroyunnanense. METHODS: Total genomic DNA were extracted from sample materials by improved CTAB method, ITS sequences of samples were amplified using PCR systems, directly sequenced and analyzed using software DNAStar, ClustalX1.81 and MEGA 4.0. RESULTS: 299 consistent sites, 19 variable sites and 13 informative sites were found in ITS1 sequences, 162 consistent sites, 2 variable sites and 1 informative sites were found in 5.8S sequences, 217 consistent sites, 3 variable sites and 1 informative site were found in ITS2 sequences. Base transition and transversion was not found only in 5.8S sequences, 2 sites transition and 1 site transversion were found in ITS1 sequences, only 1 site transversion was found in ITS2 sequences comparting the ITS sequences data matrix. By analyzing the ITS sequences data matrix from 2 population of Aconitum vilmorinianum and 3 population of Aconitum austroyunnanense, we found a stable informative site at the 596th base in ITS2 sequences, in all the samples of Aconitum vilmorinianum the base was C, and in all the samples of Aconitum austroyunnanense the base was A. CONCLUSION: Aconitum vilmorinianum and Aconitum austroyunnanense can be identified by their characters of ITS sequences, and the variable sites in ITS1 sequences are more than in ITS2 sequences. PMID- 23451495 TI - [Study on HPCE-DAD fingerprint of Salviae Miltiorrhizae Radix et Rhizoma]. AB - OBJECTIVE: To establish the analytical method for the fingerprint of Salviae Miltiorrhizae Radix et Rhizoma by HPCE-DAD and estimate its quality. METHODS: Salviae Miltiorrhizae Radix et Rhizoma were analyzed and the chromatographic fingerprint were determined by HPCE-DAD. The data were analysed by fuzzy cluster and fingerprint similarity evaluation software was used to compare the similarity of samples. RESULTS: HPCE-DAD fingerprint of 10 main common peaks was established preliminarily. It was discovered that a small number of samples were different from the others. CONCLUSION: The method is reliable, accurate and can be used for the quality control of Salviae Miltiorrhizae Radix et Rhizoma PMID- 23451496 TI - [Study on the chemical constituents of the active fraction of Polygonum capitatum]. AB - OBJECTIVE: To investigate the chemical constituents of the active fraction of Polygonum capitatum. METHODS: Various preparative chromatographic techniques were used for the isolation and purification of the compounds in the flavonoid enriched fraction and their structures were determined by comparison of their physicochemical and chromatographic data with those of the authentic samples and spectral analysis. RESULTS: Fourteen compounds were obtained and identified as 1 O-P-D-(6'-O-galloyl)-glucopyranosyl-3-methoxy-5-hydroxybenzene (1) ,5,7-dihydroxy 4H-chromen-4-one (2), ellagic acid (3), myricetrin (4), hirsutine (5), rutin (6), quercetin-3-O-(2"-O-galloyl)-beta-D-glucopyranoside (7) , quercetin-3-O-( 3"-O galloyl) -/3-D-glucopyranoside (8), quercitrin (9) , kaempferol-3-O-alpha-L rhamnopyranoside (10), quercetin-3-O-(2"-O-galloyl) -alpha-L-rhamnopyranoside (11), quercetin-3-O-(3"-O-galloyl) -alpha-L-rhamnopyranoside (12), quercetin (13), kaempferol (14). CONCLUSION: The flavonoid-enriched fraction contains flavonols and their glycosides as its major components,which might be responsible for the biological effects of Polygonum capitatum. Compounds 1, 8 and 12 are isolated from the genus Polygonum for the first time; Compound 3 is isolated from Polygonum capitatum for the first time. PMID- 23451497 TI - [Chemical constituents from stems of Ilex pubescens]. AB - OBJECTIVE: To study the chemical constituents from the stems of Ilex pubescens Hook. et Am. METHODS: The chemical constituents were isolated and purified by various column chromatographic methods with diatomite, silica gel, ODS and Sephadex LH-20. Their structures were identified on physical properties and spectroscopic methods. RESULTS: Nine compounds were isolated and determined as luteolin(1), quercetin(2), hyperoside(3), rutin(4), 1, 5-dihydroxy-3-methyl anthraquinone(5),3,5-dimethoxy-4-hydroxy-benzoic acid-1-O-beta-D-glucoside(6), hexadecanoic acid(7), stearic acid(8), n-tetratriacontanol(9), respectively. CONCLUSION: All the compounds are isolated from this plant for the first time, and compounds 5 and 6 are isolated from this genus for the first time. PMID- 23451498 TI - [GC-MS study on fingerprint of volatile oil from Kadsura heteroclita]. AB - OBJECTIVE: To study the fingerprint of volatile oil from Kadsura heteroclita by GC-MS. METHODS: 10 batches of Kadsura heteroclita were analyzed by GC-MS. TIC profiles were evaluated by" computer aided similarity evaluation system". The characteristic peaks in chromatograms were identified. Hierarchical clustering analysis was performed by SPSS. RESULTS: 23 main peaks was established preliminarily from 10 batches. Resemblance values of 10 batches were a little low. 10 batches were divided into three main clusters based on hierarchical clustering analysis. CONCLUSION: With Good reproducibility, fingerprints established for volatile oil from Kadsura heteroclita provides an effective method for quality control. PMID- 23451499 TI - [Novaeguineside G, A new aasterosaponine from the starfish Culcita novaeguineae]. AB - OBJECTIVE: To study the bioactive asterosaponin from the starfish Culcita novaeguineae. METHODS: Guided by Pyricularia oryzae bioassay method with a combination of multi-chromatographies, the bioactive asterosaponins were separated from the srarfish Culcita novaeguineae. RESULTS: A asterosaponin was obtained and identified by chemical methods and spectral analyses especially ESI MS and 2D-NMR techniques, its structure was elucidated as: sodium (20R,22R,23S,24S)-6alpha-O-{beta-D- fucopyranosyl-(1-->2 )--beta-D quinovopyranosyl-(1-->4)-[beta-D-quinovopyranosyl-(1-->2)] -beta-D quinovopyranosyl-(1-->3)-beta-D-glucopyranosyl}-22,23-epoxy-20-hydroxy24-methyl 5a-cholest-9 (11)-en-3P-yl-sulfate. CONCLUSION: The compound is a new asterosaponin,named as novaeguineside G. PMID- 23451500 TI - [Chemical constituents from Coptis chinensis]. AB - OBJECTIVE: To study the chemical constituents of Coptis chinensis. METHODS: The compounds were separated and purified by column chromatography and their structures were identified by spectroscopic methods. RESULTS: Seven compounds were isolated from the chloroform extract of Coptis chinensis, whose structures were determined as worenine (1),8,9-dihydroxy-1,5,6, 10b-tetrahydro-2H pyrrolo[2,1 -alpha] isoquinolin-3-one (2),(+/-) -5,5'-dimethoxy-lariciresinol (3),3,4-dihydroxy-phenylethylalcohol(4), methyl-5-O-feruloylquinate (5), ethyl-5 O- feruloylquinate (6), apocynol (7). CONCLUSION: Compounds (3) is isolated from this genus for the first time, compounds (5), (6), (7) are isolated from this plant for the first time. PMID- 23451501 TI - [Experimental research on prevention and treatment of fatty liver rats with Abrus cantoniensis]. AB - OBJECTIVE: To investigate the effects of Abrus cantoniensis (AC) on blood lipid metabolism, pathomorphological change of the liver and fenestrae of liver sinus endothelial cell (LSEC) in fatty liver disease rats. METHODS: SD rats were divided into 7 groups: blank control group,fatty liver model group, simvastatin group (7.2 mg/kg), Gynostemma pentaphyllum group (16.2 mg/kg), high dose (40 g/kg), middle dose (20 g/kg) and low dose (10 g/kg) of AC groups. All rats except blank control group were fed with high fat diet for the first 3 weeks, then treated with different conditions as previously mentioned for the next 3 weeks while keep on feeding with high fat diet. At the 43rd day,the abdominal aortic blood was collected for measuring the serum concentration of AST, ALT, TC, TG, HDL-C, LDL-C, and liver tissues were taken to make pathological sections for observation by optical microscope or were prepared for scanning electronic microscope. RESULTS: The levels of AST, ALT, TC, TG, LDL-C were obviously decreased while HDL-C were increased in fatty liver rats by AC high dose. Meanwhile the cell morphology of liver tissues and the fenestraes of LSEC were improved as well. CONCLUSION: AC can ameliorate the levels of blood lipid in fatty liver rats and improve the pathological change of liver tissues. To some extent AC has the function of prevention and treatment of fatty liver. PMID- 23451502 TI - [The effect of oxymatrine on aging mice caused by D+ -galactose]. AB - OBJECTIVE: To investigate the effect of oxymatrine (OMT) on aging mouse caused by D (+)-Galactose. METHODS: Healthy Kunming mouse were randomly divided into control, model and treated groups. The treated group was divided into three subgroups which were given oxymatrine 5 mg/kg, 10 mg/kg,20 mg/kg (OMT5, OMT10, OMT20). After 30 days of administration,the stand-jumping test and the Morris water maze test of each group were used to observe the learning and memory ability. After the behavior indicators test, 1-2 mL blood were got from ophthalmic vein plexus,and then got the serum by centrifuge. The super oxide dismutase (SOD) activity and malondialdehyde (MDA) content were determined by SOD and MDA kit. RESULTS: In the water maze test, the model group was significantly longer in the latency than that of the control group (P < 0.01), and the number of the crossing platforms was significantly reduced (P < 0.01), but compared with the model group, the OMT5, OMT10, OMT20 groups were significantly shorter in the latency to the end (P < 0.05, P < 0.05, P < 0.01), and the number of the crossing platforms was significantly increased (P < 0.05, P < 0.05, P < 0.01); In the stand-jumping test,the OMT groups all could extend the platform latency and reduce the error reaction times, the learning ability of the OMT groups was better than the model group, but the statistical tests failed (P > 0.05); In the serum biochemical indicators test,the SOD activity of the model group was significantly lower than that of the control group (P < 0.01), but the SOD activity of OMT5, OMTIO, OMT20 groups was significant higher than that of the model group (P < 0.05, P < 0.05, P < 0.01); The MDA content of the model group was significantly higher than that of the control group (P < 0.01) but the MDA content of OMT5, OMT1O, OMT20 groups was significant lower than that of the model group (P < 0.05, P < 0.05, P < 0.01). CONCLUSION: Oxymatrine could improve the learning and memory ability of aging mice caused by intraperitoneal injection D(+)-Galactose,and the anti-aging effect is related to the oxygen free radicals and reducing the lipid peroxidation. PMID- 23451503 TI - [Cellular absorption of the active ingredients in different compatibilities of gegenqinlian decoction in human intestinal Caco-2 cells]. AB - OBJECTIVE: To study the intestinal dynamics characteristics of puerarin and other active ingredients in Gegenqinlian decoction. METHODS: Caco-2 cell monolayer model was used to research the transport of puerarin and baicalin, berberine hydrochloride, liquiritin when they were used in different compatibilities, meanwhile a ultra performance liquid chromato-graphic method was also developed. RESULTS: The concentration of puerarin, haicalin, berberine hydrochloride, liqpiritin in cell culture medium was measured and the apparent permeahility coefficients (Papp) as well as percent absorption (%) from apical side to basolateral side were calculated. The absorption characteristics of the four components were different when they were used in different compatibilities. Furthermore the Papp sequence of puerarin in specific groups were puerarin baicalin-berberine-liquiritin group > puerarin-baicalin group > puerarin berberine > puerarin-liquiritin group > single puerarin (P < 0. 05). CONCLUSION: The intestinal absorption dynamics process of the active ingredients in Gegenqinlian decoction changes as the change of prescription compatibilities. And the intestinal absorption characteristics of puerarin is enhanced by the use of other components. PMID- 23451504 TI - [The pharmacokinetics of long-circulating beta-elemene liposomes]. AB - OBJECTIVE: To study the pharmacokinetics of long-circulating beta-elemene liposomes. METHODS: Gas chromatography was established to determine the concentration of beta-elemene in plasma of rats. RESULTS: The alpha, T(1/2beta), K12 and AUC of long-circulating beta-elemene liposomes groups were higher compared with those of the conventional liposomes,and the T(1/2alpha), Vc, CL, K10 of the latter were lower. CONCLUSION: Long-circulating beta-elemene liposomes can prolong the duration of beta-elemene in the body and improve the efficacy of drugs. PMID- 23451505 TI - [Study on the flax seed enzymatic degumming process by central composite design and response surface method]. AB - OBJECTIVE: To optimize extraction condition of degumming from flax seed by the response surface method. METHODS: The central composite design-response surface method selected the best technology and forecasting analysis with the ratio of material to liquid, sodium chloride dosage, soaks time as the independent variable and flax seed dry rubber weight for the dependent variable, through to the level of the independent variable multiple linear regression and binomial fitting. RESULTS: The optimum process condition was as follows: ratio of liquid to materials was 37:1, sodium chloride dosage was 2 g, soaks time was 120 min. CONCLUSION: The method is simple, reasonable, stable and predictability. PMID- 23451506 TI - [Study on the extraction of mycelium polysaccharides from selenium-rich Morchella esculenta with neutral proteinase method]. AB - OBJECTIVE: To study the extraction conditions of mycelium polysaccharides from selenium-rich Morchella esculenta with neutral proteinase for increasing of yield. METHODS: On the basis of single factor tests, orthogonal experiment design was applied to analyze the influence of factors including enzyme dosage, enzymolysis time, enzymolysis temperature and material/liquid ratio on the extraction rate of the polysaccharides. RESULTS: The optimal extraction conditions of mycelium polysaccharides from selenium-rich Morchella esculenta was as follows: enzyme dosage was 1.5%, enzymolysis time was 2 h, enzymolysis temperature was 40 degrees C, and material/liquid ratio was 1:15. The extraction rate of polysaccharide was 11.26% under the extraction conditions. CONCLUSION: The process is simple, stable and practicable, and can be used for the extraction of mycelium polysaccharides from selenium-rich Morchella esculenta. PMID- 23451507 TI - [Study on the release and mechanism of carbon nanotubes loaded with verapamil hydrochloride in vitro]. AB - OBJECTIVE: The aim of this study was to load Verapamil Hydrochloride to carboxylated multi-walled carbon nanotubes( c-CNTs) and discuss the mechanism of drug release which could act as an effective basis for c-MWNTs used as drug carriers of controlled and sustained release delivery system. METHODS: Raw CNTs were treated with mixed strong acid to obtain c-CNTs. Raman, IR, SEM and HR-TEM were used to characterize the CNTs and investigate the loading sites for drugs. The release behavior of the drug delivery system in vitro and the release model were studied. RESULTS: The raw CNTs were successfully grafted with carboxyl group by acid treatment. The water-soluble ability of c-CNTs was greatly improved. The length of c-CNTs was 200-300nm. Meanwhile, the ends of c-CNTs were opened. The results of the drug loading experiment showed that the more adding drugs, the larger loading content of drugs. Most of the drugs were loaded into the inner pores of c-CNTs when adding drugs was no more than 0.1 as quantity as c-CNTs. As the quantity of adding drugs increased, the drugs were loaded both in the inner pores and on the out-wall of c-CNTs. The release results in vitro showed release mechanism had something with the quantity of adding drugs. CONCLUSION: C-CNTs can be used as carriers of sustained and controlled release delivery system. Ideal release behavior of drugs can be achieved by choosing appropriate formula. PMID- 23451508 TI - [Study on prescription of self-microemulsifying drug delivery system of mangiferin phospholipid complex]. AB - OBJECTIVE: To study formulation of self-microemulsifying drug delivery system (SMEDDS) of mangiferin phospholipid complex and improve dissolution and bioavailability of mangiferin. METHODS: Ternary phase diagram was applied to optimize the prescription of self-microemulsifying drug delivery system of mangiferin phospholipid complex, and the best recipe was selected by comprehensive evaluation of the speed of microemulsifying, microemulsion size and electric potential. RESULTS: The optimum formulation of SMEDDS was composed of IPM-Cremphor EL35-labrasol = 2 : 4.8 : 3.2. CONCLUSION: Self-microemulsifying drug delivery system of mangiferin phospholipid complex can effectively improve the dissolution of Mangiferin. PMID- 23451509 TI - [A novel method for the identification of illegal cooking oil (1): detection of three capsaicinoids with liquid chromatography-mass spectrometry]. AB - Illegal cooking oil (ICO, also named swill-cooked dirty oil) has recently become a serious food safety problem in China. Now, the identification method of ICO is also a hot research area. Owning to the special eating habits of Chinese people, cayenne is widely used in catering business. Capsaicinoids are main spicy compounds in cayenne. So, they are potential evaluation indices for the identification of ICO. In this study, a solid phase extraction-liquid chromatography-mass spectrometry (SPE-LC-MS) method has been developed to detect the trace residues of three capsaicinoids (capsaicin, dihydrocapsaicin and nonylic acid vanillylamide) in cooking oil. The oil sample was first extracted with 20 g/L sodium hydroxide, the C18 SPE cartridge was then used to clean-up the sample and enrich the analytes before the liquid chromatography-mass spectrometry (LC-MS) detection. With this method, sixty seven blind samples provided by China National Center for Food Safety Risk Assessment were analyzed. The results showed that the capsaicinoids are good evaluation indices for the identification of ICO. In all the 48 ICO samples, 36 samples were successfully recognized. All the 19 normal oil samples were accurately identified. This method has been chosen and authorized as one of the four standard instrumental identification methods for ICO by the National Ministry of Health of China. PMID- 23451510 TI - [Novel method for the identification of illegal cooking oil (2) : determination of special odd-chain fatty acids by multidimensional gas chromatography-mass spectrometry]. AB - Endogenesis referents from illegal cooking oil (ICO), namely, 13-methyl tetradecanoic acid and undecanoic acid have been confirmed via non-target and target screening of fatty acids. The former is mainly originated from animal oil, and the later from heated vegetable oil. Based on the retention interactions between gas chromatographic columns with different polarities and alkyl acids, the alkyl acids with various carbon chain or their isomers with the same carbon chains can be separated effectively using multidimensional gas chromatographymass spectrometry. And the accurate quantification of 13-methyl-tetradecanoic acid and undecanoic acid was obtained. The target compounds can be cleaned up online and enriched with the developed method. Subsequently, the fourth and fifth assessments organized by China National Center for Food Safety Risk Assessment were performed in our laboratory. After continuous improvement, the precision of the method was increased. In detail, 100% vegetable oils, 71% ICO (the 4th batch) and 75% ICO (the 5th batch) have been identified. In combination with the capsaicinoid contents, edible oils can be identified in a comprehensive way, and the precision for ICO samples was increased to 89% and 100% for the 4th batch and the 5th batch samples, respectively. Owing to the aforementioned advantages, the developed method has been chosen as one of the four instrumental methods for the identification of ICO by China Ministry of Public Health, waiting for the validation from authoritative departments. PMID- 23451511 TI - [Determination of capsaicinoids and eugenol in waste-edible-oil by liquid-liquid extraction and liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the determination of capsaicinoids (capsaicin, dihydrocapsaicin and synthetic capsaicin) and eugenol in waste-edible-oil extracted by liquid-liquid extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The capsaicinoids and eugenol in waste-edible-oil were extracted by methanol, and then separated by a SUPEL COSIL ABZ + Plus dC18 column (150 mm x4.6 mm, 5 microm). The analysis was performed by MS/MS with electrospray ionization in positive and negative ion modes with multiple reaction monitoring (MRM). The limits of detection for capsaicin, dihydrocapsaicin, synthetic capsaicin and eugenol were 0.02, 0.03, 0.03 and 0.6 microg/L, respectively. The good linear relationships were obtained in certain concentration ranges of capsaicinoids and eugenol. The relative standard deviations (RSDs, n=5) of same worker and different-worker were less than 5%. The method is exclusive, sensitive and accurate, and can be used in waste-edible-oil determination. PMID- 23451512 TI - [Determination of sodium and chloride in hogwash oil and their molar ratio by ion chromatography]. AB - By reference to edible oil using process as well as hogwash oil refining technology, a method is presented to determine the contents of the sodium and chloride in hogwash oil based on ion chromatography. The molar ratio of the sodium and chloride was analyzed in order to determine whether the sample contained hogwash oil. A hogwash oil sample was extracted by deionized water before analysis. The ion chromatographic separation of the chloride was carried out on an AS19 column (250 mm x4 mm) at 30 degrees C, using 20 nmol/L KOH solution as mobile phase at a flow rate of 1 mL/min and suppressor current of 112 mA. The ion chromatographic separation of the sodium was carried out on a CS12 column (250 mm x 4 mm) at 30 degrees C, using 20 nmol/L methanesulfonic acid (MSA) as mobile phase at a flow rate of 1 mL/min and suppressor current of 59 mA. The injection volume was 25 microL and the detector was an electron capture detector (ECD). The external standard method was used to quantify chloride and sodium. The detection limits of this method were 0.005 mg/L for chloride and 0.001 mg/L for sodium. The linear range was from 0 to 5 mg/L with r2 = 0.999988 for chloride and r2 = 0.999926 for sodium. The average recoveries and relative standard deviations were 94.2% and 2.4% for chloride and 92.5% and 2.7% for sodium, respectively. The molar ratio of sodium and chloride in edible oil was approximately 1, while that in hogwash oil was more than 4. The determination of the contents and molar ratio of the chloride and sodium in hogwash oil can be used as an important basis for the judgment of hogwash oil. PMID- 23451513 TI - [Recent advances in the application of high performance capillary electrophoresis for food safety]. AB - In recent years, food safety incidents become a serious social problem. Foods are usually complex mixtures consisting of a large diversity of molecules. Analysis of foods is a topic that demands the development of rapid, robust, efficient, sensitive and cost-effective analytical methodologies. Therefore, new techniques for food safety purpose are required by analytical chemists. Capillary electrophoresis (CE) is a popular separation technique that possesses fast and efficient performances in an automated way with minimum consumption of sample and reagents. Nowadays, CE represents a desired strategy for the determination of many compounds or molecules in various kinds of food. In this paper, the review intends to provide the recent innovative developments reported in food safety analysis using CE methods for a full overview. As a fundamental review, it focuses on the introduction and detection of several common hazardous materials existing in food such as non-food additives, pesticide residues, veterinary drug residues, heavy metal ion contaminants, toxins, biphenol A and phthalates in packaging materials and so on. Furthermore, this review prospects the main development direction of CE in this field for the future. A total of 63 papers published during the period of Jan 2009 - Jun 2012 are included in the present review. PMID- 23451514 TI - [An enzyme reactor based on aptamer modified microfluidic chip for protein analysis]. AB - As a kind of recognition molecule, aptamer has been studied and applied widely in numerous science fields in recent years. Immobilized enzymatic reactor has drawn much attention because of its striking advantages, such as high digestion efficiency and ease in coupling with the separation and detection systems. In this study, a novel microfluidic enzymatic chip, which immobilized trypsin based on aptamer, was prepared and proposed. An online analysis platform, which consisted of an aptamer-based chip and high performance liquid chromatography tandem mass spectrometry, was established by using a 6-port valve and applied to protein analysis. The enzymatic capacity and stability performance of chip reactor were characterized by using mixed protein sample, which consisted of bovine serum albumin (BSA), myoglobin (Mb) and cytochrome c (Cyt. c). The sample digestion time of the chip reactor was about 5.76 s while 1 microL/min of flow rate was adopted; and moreover, 5 ng of Mb was identified successfully with the sequence coverage of 37%. Furthermore, the sequence coverages and the relative standard deviations were 44.3% and 6.5% for BSA, 65.0% and 2.7% for Mb, 62.0% and 5.6% for Cyt. c respectively when 500 ng digest of mixed proteins were analyzed in three runs. According to experimental results, the online analysis platform possesses the ability of high sensitivity and good stability, which can provide a promising tool for rapid and high-throughput proteomics study in the near future. PMID- 23451515 TI - Preparation of a stir bar sorptive extraction coating based on molecularly imprinted polymer and its application in the extraction of dienestrol and hexestrol in complicated samples. AB - A new stir bar sorptive extraction (SBSE) coating based on molecularly imprinted polymer (MIP) with diethylstilbestrol as replaced template molecule was prepared. The influences of the contents of template molecule and monomer in the polymerization mixture on the extraction performance of MIP-SBSE were investigated thoroughly. The MIP was characterized by elemental analysis, scanning electron microscopy and infrared spectroscopy. In order to evaluate the usability of the new coating, the MIP-SBSE was combined with high performance liquid chromatography (HPLC) and diode array detector (DAD) with dienestrol (DS) and hexestrol (HS) as detected solutes. To achieve optimally selective extraction performance for DS and HS, several parameters, including extraction and desorption times, desorption solvent, ionic strength and pH value in sample matrix were investigated. The results showed that under the optimized experimental conditions, the present method has high selectivity and sensitivity. When drying-redissolving procedure was taken during sample preparation, the limits of detection for DS and HS were as low as 0.04 microg/L and 0.14 micorg/L, respectively. Good linearities were obtained for analytes with the correlation coefficients (R2) above 0.99. Finally, the proposed method was successfully applied to the determination of DS and HS in wastewater, honey and cow urine samples. The recoveries of spiked target compounds in real samples ranged from 61.3% to 120%. The developed method is simple, selective, sensitive and applicable for the analysis of trace DS and HS in complicated samples. PMID- 23451516 TI - [Determination of ten aminoglycoside residues in milk and dairy products using high performance liquid chromatography-tandem mass spectrometry]. AB - A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/ MS) analytical method was developed for the simultaneous determination of ten aminoglycoside residues (streptomycin, dihydrostrepmycin, neomycin, kanamycin, tobramycin, gentamycin, apramycin, hygromycin B, paromomycin, and amkacin) in milk and dairy products. The sample was extracted with 5% trichloroacetic acid aqueous solution, then the extract was purified by a hydrophilic-lipophilic balance (HLB) cartridge. The ten aminoglycoside residues were separated by ion pair reversed phase high performance liquid chromatography. Heptafluorobutyric acid was used as ion pair agent due to its volatility. Then the analytes were detected by electrospray ionization tandem mass spectrometry. The pretreatment condition of the sample, the HPLC condition and the MS operation parameters were optimized. The results showed that the linearities of the ten aminoglycoside residues in 20-1000 microg/L had the correlation coefficient between 0.9946 0.9997. The recoveries ranged from 71.2% and 101.7% with the relative standard deviations of 3.4%-13.8%. The proposed method was successfully applied to the determination of the mass concentrations of the analytes in related samples, which provides a simple, and convenient method for the quality control of milk and dairy products. Furthermore, this method is effective for the safety monitoring of aminoglycoside residues in milk and dairy products. PMID- 23451517 TI - [Determination of three drugs and their metabolites in saliva by ultra performance liquid chromatography-tandem mass spectrometry]. AB - An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/ MS) method has been developed for the methamphetamine, morphine and O6-acetylmorphine in saliva. The sample was extracted and the protein was precipitated with acetonitrile. The matrix-matched standard solutions were used to prepare the curve of quantitative analysis. The drugs were separated on a BEH HILIC UPLC column. The mass spectrometric acquisition was carried out by means of electrospray ionization in positive mode (ESI+ ) with multiple reaction monitoring (MRM) method. The isotope internal standards were used to check the drugs. The average recoveries at four levels of 10, 20, 50 and 100 microg/L ranged from (68.7 +/- 6.5)% to (110.8 +/- 4.6)%. The intraday precisions were lower than 16.5% and interday precisions were lower than 16.3%. The detection limits (LOD, S/N > 3) and the quantification limits (LOQ, S/N > 10) of the three drugs were 0.02-0.05 microg/L and 0.1-0.2 microg/L, respectively. The saliva matrix effect was investigated. The method is rapid, simple, accurate and highly sensitive. The qualitative analysis and quantitative analysis of the collected saliva samples for the drugs can be finished within one hour, which is conducive to the rapid identification of the suspected drug addicts. PMID- 23451518 TI - [Simultaneous determination of nine effective components in jiaweizuojin pills by ultra performance liquid chromatography with tandem mass spectrometry]. AB - A method for the simultaneous determination of paeoniflorin, tetrahydropalmatine, jatrorrhizine, berberine, palmatine, evodiamine, saikosaponin C, saikosaponin A and saikosaponin D in Jiaweizuojin Pills was established by ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). The UPLC separation was performed on a Zorbax RRHD Eclipse Plus C18 column (50 mm x 2.1 mm, 1.8 microm) by using 0.2% (v/v) formic acid aqueous solution and methanol as mobile phases with the gradient elution at a flow rate of 0.4 mL/min. The analytes were detected by tandem mass spectrometry under the positive ion mode with the electrospray ionization (ESI) source and in the multiple reaction monitoring (MRM) mode. Under the optimized conditions, the calibration curves were linear in the ranges of 0.025 -5.0 mg/L for paeoniflorin, 0.0010-2.0 mg/L for tetrahydropalmatine, 0.0023-7.2 mg/L for jatrorrhizine, 0.0027-28.9 mg/L for berberine, 0. 002 3 - 9. 1 mg/L for palmatine, 0. 005 0 -1.0 mg/L for evodiamine, 0.050-10 mg/L for saikosaponin C, 0.0050-1.0 mg/L for saikosaponin A and 0.0075 1.5 mg/L for saikosaponin D with the detection limits of 5.0, 0.20, 0.45, 0.54, 0.45, 1.0, 10, 1.0, 1.5 microg/L, respectively. The average recoveries of the nine effective components were between 99.3% and 105% with the relative standard deviations not more than 2.6%. The developed method is simple, rapid and accurate, and suitable for the quality control of the nine effective components in jiaweizuojin pills. PMID- 23451519 TI - [Determination of multi-pesticides in black tea by subcritical water extraction and gas chromatography-tandem mass spectrometry]. AB - A gas chromatography-tandem mass spectrometry (GC-MS/MS) method with subcritical water extraction was developed for the determination of 21 organochlorine and pyrethroid pesticides in black tea. Under the extraction pressure of 5 MPa, the target compounds were extracted with subcritical water at the temperature of 150 degrees C for 15 min, transferred into acetone-n-hexane (1:1, v/v), and cleaned up by an ENVI-Carb solid phase extraction (SPE) column. The GC separation was performed on a DB-5 capillary column. The pesticides were determined by MS/MS in multiple reaction monitoring (MRM) mode and quantified by matrix-matched internal standard method. The calibration curves showed good linearities in the range of 5.0-320.0 microg/L with the correlation coefficients greater than 0.99. The limit of quantification (S/N > 10) was 50 ng/g, and the limit of detection (S/N > 3) was 10 ng/g. The recoveries of pesticides spiked in the tea at three levels of 50, 100 and 200 ng/g were ranged from 70. 18% to 119.98% with the relative standard deviations (RSDs) of 5.01%-11.76%. The sensitivity, accuracy and precision of the method meet the technical standard of the pesticide determination. The method can be applied to the determination of organochlorine and pyrethroid pesticides in black tea. PMID- 23451520 TI - [Determination of fatty acids in vegetable oils using comprehensive two dimensional gas chromatography coupled to quadropole mass spectrometry]. AB - Comprehensive two-dimensional gas chromatography with quadropole mass spectrometry (GC x GC-qMS) was applied to the detection of 31 fatty acids in vegetable oils. The sets of columns, modulation period, scan range of quadropole mass spectrometer were optimized. The results demonstrated that the separation was achieved in 50 min with the column set of DB-1 (30 m x0. 25 mm x 0.25 microm) as the 1st column and DB-Wax (3.2 m x 0.1 mm x 0. 1 microm) as the 2nd column. All fatty acids were accurately and sensitively determined while the modulation period was 3.5 s and the scan range of quadropole MS was m/z 40-350. Most of the fatty acids were identified by NIST library spectra search, the other fatty acid isomers were identified by single standard injection analysis. When applying this method to the real vegetable oil samples, not only the sensitivities were 100 times higher than those obtained with GC-qMS methods, but also some minor fatty acids were identified. This work suggested a new technical approach in analyzing fatty acid components in vegetable oils, which is meaningful to prohibit adulteration and ensuring the quality safety of edible vegetable oils. PMID- 23451521 TI - [Determination of 17 pyrethroid pesticide residues in vegetables by gas chromatography-mass spectrometry with negative chemical ionization]. AB - A method was established for the determination of 17 pyrethroid pesticide residues in vegetables using QuEChERS (quick, easy, cheap, effective, rugged and safe) clean-up method and gas chromatography-mass spectrometry (GC-MS) with negative chemical ionization (NCI). The pyrethroid pesticides in the sample were extracted with acetonitrile. After QuEChERS clean-up with a mixture of primary secondary amine and graphitized carbon black packings, the extract was analyzed by GC-NCI-MS in selected ion monitoring (SIM) mode. An isotope internal standard of cypermethrin was employed to the quantification. The limits of quantification ranged from 0.02 to 5 microg/kg. The recoveries of the pyrethroid pesticides spiked in three different matrixes (peas, broccoli and Chinese onion green) at four spiked levels of 10, 20, 30 and 100 microg/kg were from 71.0% to 139.0%, and the relative standard deviations were less than 12.8%. This method can be used as a conclusive evidence method of the 17 pyrethroid pesticide residues in vegetables. PMID- 23451522 TI - [Determination of synthetic nitro-musks in cosmetics by gas chromatography coupled with negative chemical ionization-triple quadrupole mass spectrometry]. AB - A confirmatory method is presented for the determination of five nitro-musks (musk ambrette, musk xylene, musk moskene, musk tibeten and musk ketone) in different cosmetics by gas chromatography coupled with negative chemical ionization (NCI)-triple quadrupole mass spectrometry (GC-MS/MS). The samples were extracted under ultrasonication using a mixture of acetone and hexane. The extract was concentrated and then cleaned up by CNWBOND Si solid phase extraction cartridge. Five different instrument parameters such as the temperature programmed, ion source temperature, reagent gas pressure, collision energy, monitoring ion pairs were optimized for higher sensitivity. Then the analytes were qualitatively and quantitatively analyzed under the multiple reaction monitoring (MRM) mode after the chromatographic separation on an HP-5MS capillary column (30 m x 0.25 mm, 0.25 microm), and employing d15-musk xylene as internal standard. The mixed standards were spiked in the blank cosmetics samples (each nitro-musk was about 500 ng/kg), and the recoveries were in the range of 85.81% 103.77% with the relative standard deviations (RSDs) not more than 5.32%. The limits of quantification of the method were about 50.0-500 ng/kg. The method is accurate, rapid, sensitive and can be used in the inspection of the five nitro musks in cosmetics. PMID- 23451523 TI - [Simultaneous determination of eight derivatives of propranolol in cornea perfusate in vitro by high performance liquid chromatography]. AB - A high performance liquid chromatographic method was developed for the simultaneous determination of eight derivatives of propranolol. Cassette dosing method was used in the epithelium side of cornea in vitro to get the effect of penetrant, and the perfusate was collected in the side of endothelium. The protein in the sample was precipitated and discarded by high speed centrifugation before injection. An Agilent Zorbax Extend column (150 mm x 3 mm, 5 microm) was used at 30 degrees C. The mobile phase system contained acetonitrile and 0.03% (v/v) phosphoric acid aqueous solution and the percentage of acetonitrile changed between 3% and 20% (v/v) in a linear gradient elution. The samples were detected by an ultraviolet (UV) detector at 205 nm. The results showed that the eight derivatives of propranolol were completely separated and determined in 31 min. The correlation coefficients were above 0.9970 and good linear relationships were obtained in the range of 0.2 (0.1)-40.0 micromol/L. Under the optimized conditions, the recoveries of the derivatives were in the range of 91.12% 105.73%. The intra-day relative standard deviations (RSDs) were in the range of 1.00%-11.63%, and the inter-day RSDs were in the range of 1.18%-18.58%. The sample showed stability under room temperature, freeze and three cycles of freeze thaw conditions. This method is fast and accurate for the quantitative analysis of the derivatives of propranolol in transmembrane absorption such as cornea perfusion in vitro or transwell cell system. PMID- 23451524 TI - [Separation of benzoxazine enantiomers on beta-cyclodextrin bonded chiral stationary phases]. AB - Chiral separation of benzoxazine enantiomers was studied on click chemistry based beta-cyclodextrin stationary phases under reversed-phase high performance liquid chromatographic mode. The effects of the type and percentage of the organic modifier, the concentration of triethylammonium acetate buffer (TEAA), and pH on enantioselective separation were examined and studied. It was demonstrated that acetonitrile was better for the chiral separation of benzoxazine enantiomers than methanol. It was observed that the retention time and the resolution of benzoxazine enantiomers decreased with the increase of the volume ratio of TEAA from 0.1% to 1.0%. The separation of benzoxazine enantiomers was of the maximum resolution at pH 4.1. With the optimized mobile phase of the mixture of acetonitrile and 0. 1% TEAA (pH 4.1), all the enantiomers were separated at the baseline. The chiral recognition mechanism is also discussed. The separation was probably based on the inclusion complex interaction and the hydrogen bonding between enantiomers and chiral stationary phases. This work provided the experience for the intensive study of click beta-cyclodextrin bonded stationary phases, and it also illustrated the potential of click chemistry in the preparation of beta-cyclodextrin based chiral stationary phase. PMID- 23451525 TI - Adsorption of endotoxins on Ca2+ -iminodiacetic acid by metal ion affinity chromatography. AB - Endotoxins (also known as lipopolysaccharides (LPS)) are undesirable by-products of recombinant proteins, purified from Escherichia coli. LPS can be considered stable under a wide range of temperature and pH, making their removal one of the most difficult tasks in downstream processes during protein purification. The inherent toxicity of LPS makes their removal an important step for the application of these proteins in several biological assays and for a safe parenteral administration. Immobilized metal affinity chromatography (IMAC) enables the affinity interactions between the metal ions (immobilized on the support through the chelating compound) and the target molecules, thus enabling high-efficiency separation of the target molecules from other components present in a mixture. Affinity chromatography is applied with Ca2+ -iminodiacetic acid (IDA) to remove most of the LPS contaminants from the end product (more than 90%). In this study, the adsorption of LPS on an IDA-Ca2+ was investigated. The adsorption Freundlich isotherm of LPS-IDA-Ca2+ provides a theoretical basis for LPS removal. It was found that LPS is bound mainly by interactions between the phosphate group in LPS and Ca2+ ligands on the beads. The factors such as pH (4.0 or 5.5) and ionic strength (1.0 mol/L) are essential to obtain effective removal of LPS for contaminant levels between endotoxin' concentration values less than 100 EU/mL and 100 000 EU/mL. This new protocol represents a substantial advantage in time, effort, and production costs. PMID- 23451526 TI - [Determination of deoxynivalenol in grain and its products by solid-phase extraction coupled with high performance liquid chromatography-tandem mass spectrometry]. AB - A method was established for the determination of deoxynivalenol (vomitoxin) in grain and its products based on solid-phase extraction coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The sample was firstly extracted by acetonitrile-water (84:16, v/v). The extract was then cleaned-up by an HLB solid phase extraction cartridge. The separation was carried out on a Phenomenex Kinetex C18 column (100 mm x4. 6 mm, 2.6 microm) with a gradient elution using 0.3% per hundred ammonia solution-acetonitrile as mobile phases. The analysis of deoxynivalenol was performed under electrospray negative ionization mode. The limit of detection (LOD, S/N= 3) and the limit of quantification (LOQ, S/N = 10) were 20 microg/kg and 50 microg/kg, respectively. A good linearity (r > 0.99) was achieved for the target compound over the range of 20-1000 pg/L. The recoveries at the three spiked levels (50, 100, 500 microg/kg) in the blank matrices such as flour, barley, soybean, rice, cornmeal, cassava and wheat, were varied from 75.6% to 111.0% with the relative standard deviations no more than 13. 0%. The method is accurate, efficient, sensitive and practical. The cost of pretreatment is obviously reduced by replacing immunoaffinity columns and Mycosep columns with HLB columns which have the same purification effect. PMID- 23451527 TI - Face-off. Can life technologies, which sells tools for genetics research, rise in a tough market? Interview by Ryan Derousseau. PMID- 23451528 TI - Cut your exposure to Medicare taxes. PMID- 23451529 TI - Advertising's new medium: human experience. AB - We live in a media-saturated world, where consumers are drowning in irrelevant messages delivered from the web, TV, radio, print, outdoor displays, and a proliferating array of mobile devices. Advertising strategies built on persuading through interruption, repetition, and brute ubiquity are increasingly ineffective. To win consumers' attention and trust, marketers must think less about what advertising says to its targets and more about what it does for them. Rayport outlines four domains of human experience: In the public sphere people move from one place or activity to another, both online and off. In the social sphere they interact with and relate to one another. In the tribal sphere they affiliate with groups to define or express their identity. In the psychological sphere they connect language with specific thoughts and feelings. Savvy marketers think about crafting messages that consumers will welcome in these domains. Zappos did that when it placed ads in airport security bins (the public sphere)- reaching people whose minds may be on their shoes. Nintendo identified young mothers who were willing to host Wii parties and provided them with everything they needed for these social-sphere events. Yelp's Elite Squad of reviewers have a heightened sense of tribal affiliation that makes them powerful brand ambassadors. Life is good Inc. is rooted in the psychological sphere: It advertises only through the optimism-promoting logo and slogan on its products. PMID- 23451530 TI - Do you play to win--or to not lose? AB - Some personality assessment tools are good at identifying what you like to do, but they tell you very little about whether you're good at it or how to improve if you're not. Fortunately, one way of grouping people into types is based on an attribute that does predict performance: promotion focus or prevention focus. Promotion-focused people see their goals as creating a path to advancement; they are comfortable taking chances, like to work quickly, dream big, and think creatively. Prevention-focused people see their goals as responsibilities; they are vigilant, risk-averse, thorough, and accurate, and like to maintain the status quo. Motivational focus affects how we approach life's challenges. It affects what we pay attention to, what we value, and how we feel when we succeed or fail. Once you know your focus, you can choose role models, frame goals, seek or give feedback, and provide incentives that will strengthen your motivation or your team's. This article details how you can create motivational fit, which enhances and sustains both the eagerness of the promotion-minded and the vigilance of the prevention-minded. PMID- 23451531 TI - Insurers expand usefulness of oncology pathway efforts. PMID- 23451532 TI - Physician assistants turn away from primary care. PMID- 23451533 TI - Aiming at a moving target in rheumatoid arthritis. PMID- 23451534 TI - Another cancer vaccine, another retreat. PMID- 23451535 TI - 2012 drug approvals won't be easy on pharmacy budgets. PMID- 23451536 TI - Hammurabi's Managed Health Care--circa 1700 B.C. PMID- 23451537 TI - Coverage with evidence development allows early adoption, better evaluation. PMID- 23451538 TI - More data in health care will enable predictive modeling advances. PMID- 23451539 TI - Highmark's accountable care future starts with expansion of PCMH model. PMID- 23451540 TI - Managing rapid change in the health care environment. PMID- 23451541 TI - Total knee replacement using patient-specific templates. PMID- 23451542 TI - Relapsing multiple sclerosis patients can look to second oral agent. PMID- 23451543 TI - Value-based insurance design helps cut plan's diabetes costs. PMID- 23451544 TI - Commonwealth Fund sings bundling's praises. PMID- 23451545 TI - Comparison between problem based and conventional curriculum. PMID- 23451546 TI - Perceptions of interns performance: a comparison between a problem based and a conventional curriculum. AB - BACKGROUND: Medical education is changing. Increasingly, there are calls for major curriculum reform based on premises of what might improve undergraduate medical education. Against this background, innovative methods of teaching and learning have emerged. Problem-based and student-centered approaches are increasingly being adopted with less reliance on the conventional didactic lecture forums. OBJECTIVE: To compare the effects of two different instructional methods (problem based learning and conventional teaching), on the professional competencies of pre-registration house officers (PRHOs) or interns, as perceived by the graduates themselves and their clinical supervisors. DESIGN: A cross sectional survey design was used to identify a causal relationship between the method of instruction and ratings on outcome for two different groups. SETTING: Selected medical board-accredited internship training centres throughout the country. SUBJECTS: Interns from Moi and Nairobi Universities who qualified in the academic year 2002/2003 and thus completed their internship in August/September 2004. For the supervisors, they needed to have supervised at least four groups of interns. RESULTS: Graduates from Moi University perceived themselves to be more prepared for two of the nineteen broad competencies and six of the twelve specific skills listed. The clinical supervisors perceived Moi graduates as better prepared in four of the broad competencies. They found no significant differences for any of the specific skills. CONCLUSION: Overall, the study showed that Moi University graduates, felt and are perceived as better prepared for their role as interns. The differences in curriculum contribute significantly to these findings. PMID- 23451547 TI - Cluster randomised trial of the uptake of a take-home infant dose of nevirapine in Kenya. AB - OBJECTIVE: To test whether a single take home dose of infant nevirapine increased infant uptake without decreasing institutional deliveries. DESIGN: Cluster randomised post-test only study with control group. SETTING: Ten hospitals in urban areas of Coast, Rift Valley, and Western provinces, Kenya. PARTICIPANTS: Pregnant women with HIV, 18 years and older, and at least 32 weeks gestation recruited during antenatal care and followed up at home approximately one week after delivery. INTERVENTION: In the intervention group, women were given a single infant's dose of nevirapine to take home prior to delivery. In the control group, no changes were made to the standard of care. MAIN OUTCOME MEASURES: Mothers' reports of infant uptake of nevirapine and place of delivery. RESULTS: Uptake of the infant's nevirapine dose was high, 94% in the intervention group and 88% in the control group (p=0.096). Among women who delivered at home, uptake was higher significantly among infants whose mothers got the take home dose compared to women who did not get the dose (93% vs. 53%, p<0.01). The intervention did not influence place of delivery. Providers were positive about the take home dose concept; difficulties were attributed to HIV-related stigma. CONCLUSIONS: Making take home infant nevirapine available, either as a single dose administered within 72 hours of birth or as part of a more complex six week postnatal regimen, will increase infant uptake especially among women who deliver at home without affecting place of delivery. PMID- 23451548 TI - Genito-urinary fistula patients at Bugando Medical Centre. AB - BACKGROUND: Information was collected on 1500 obstetric fistula patients attending Bugando Medical Centre (BMC) in Mwanza, Tanzania. OBJECTIVES: To identify high risk populations of fistula patients treated from 1998-2006. DESIGN: A prospective description study of 1294 patients treated for urine and faecal incontinence at BMC. SETTING: Obstetrics and Gynaecological ward at Bugando Medical Centre. INTERVENTIONS: A total of 1294 patients underwent surgical treatment of incontinence. MAIN OUTCOME MEASURES: Of the 1294 surgical repairs, 84% of the patients were cured, 12% had stress incontinence and 4% failed. CONCLUSIONS: The study shows that low education and poverty were the key factors in the development of fistula. Most obstetric fistulae can be cured, particularly during the first attempt by those properly trained in the skills. Prevention of genital fistula requires raising the education and social status of women including poverty reduction strategies, improving the quality of antenatal care. Increased access to Caesarean section is also needed for prevention of genitourinary fistulas. PMID- 23451549 TI - Task shifting in HIV clinics, Western Kenya. AB - BACKGROUND: United states Agency for International development-Academic Model for Providing Accesses to Healthcare (USAID-AMPATH) cares for over 80,000 HIV infected patients. Express care (EC) model addresses challenges of: clinically stable patient's adherent to combined-antiretroviral-therapy with minimal need for clinician intervention and high risk patients newly initiated on cART with CD4 counts < or = 100 cells/mm3 with frequent need for clinician intervention. OBJECTIVE: To improve patient outcomes without increasing clinic resources. DESIGN: A descriptive study of a clinician supervised shared nurse model. SETTING: USAID-AMPATH clinics, Western Kenya. RESULTS: Four thousand eight hundred and twenty four patients were seen during the pilot period, 90.4% were eligible for EC of whom 34.6% were enrolled. Nurses performed all traditional roles and attended to two thirds and three quarters of stable and high risk patient visits respectively. Clinicians attended to one third and one quarter of stable and high risk patient visits respectively and all visits ineligible for express care. CONCLUSION: The EC model is feasible. Task shifting allowed stable patients to receive visits with nurses, while clinicians had more time to concentrate on patients that were new as well as more acutely ill patients. PMID- 23451550 TI - Early childhood caries in Moshi, Tanzania. AB - OBJECTIVE: To determine the prevalence, severity and pattern of early childhood caries (ECC) in Moshi Municipality, Tanzania. DESIGN: Cross-sectional study. SETTING: Moshi Municipality, Kilimanjaro region, Tanzania. SUBJECTS: Three hundred and seventy two randomly selected children aged three to five years (157 males and 215 females) in 2008. RESULTS: Overall caries prevalence was 30.1% with no significant gender difference (p>0.05). The severe form of ECC that attacks primary maxillary incisors occurred in 21.2% of the children. The mean dmft score was 0.95 (SD +/- 1.81). The decay component was 0.87 (SD +/- 1.71), whereas the missing component was 0.08 (SD +/- 0.41). There was no significant gender difference in the mean dmft scores (p>0.05). Among the posterior teeth, mandibular last molars had the highest caries prevalence (12.4%) and for the anterior teeth, the maxillary central incisors had the highest caries prevalence (21%). Majority of the affected children had three or less teeth affected. The sample mean plaque score was 0.57 (SD +/- 0.46) with no statistical gender difference (p>0.05). A total of 174 (46.8%) parents/guardians responded to the questionnaire. Caries risk and experience was significantly higher in children with guardians and in children with history of falling asleep with the breast in the mouth respectively (p<0.05). CONCLUSION: Most of the affected children had ECC in the anterior and posterior segments. In the anterior segments, the maxillary teeth were affected more frequently than the mandibular teeth, while in the posterior segments the mandibular teeth were more frequently involved than the maxillary teeth. Significantly higher caries prevalence was found in children under the care of the guardians, children who had slept with breast in the mouth and those with higher sugar moments as the result of snacking. PMID- 23451551 TI - Bilharzia induced pathologies and techniques of detection in Uganda: a review. AB - BACKGROUND: Schistosoma S. mansoni was observed and reported in Uganda in 1902. Schistosoma S. mansoni is widely distributed in Uganda along permanent water bodies. OBJECTIVE: To review the literature on previous techniques and conventional ones used for the assessment and comparison of morbidity due to schistosomiasis in Uganda. DESIGN: Retrospective study. SETTING: Gulu University, Faculty of Medicine, Department of Microbiology and Immunology. RESULTS: Since its first detection in 1902 Schistosomiasis mansoni and later Schistosomiasis haematobium in Uganda, morbidity assessment was based on physical examination and intensity of eggs excretion. The first field study in Uganda of schistosomiasis pathologies using ultrasound was that conducted in West Nile in Obongi, Rhino Camp and Pundu in 1991 and reviewed in 1992. These armless and none invasive method of pathologies detection has the advantage of repeatability. It showed that after treatment there was reversibility of pathological conditions introduced by the parasites in the hosts. CONCLUSION: Schistosomiasis mansoni pathologies as detected by the none invasive ultrasound findings compared well with those of the more risky invasive liver biopsy. The detection of pathologies by clinical examination was less sensitive. Pathological lesions due to S. haematobium correlated with abnormalities of the urinary tract and intensity of eggs in urine. PMID- 23451553 TI - Obesity and its complications. PMID- 23451552 TI - Lingual thyroid: case report. AB - A sixteen year old male presented with progressive dysphagia, dysphonia and haemoptysis over eight months. Radionuclide studies and computed tomographic scans confirmed an only functional thyroid gland at the base of tongue which was excised wholly via mandibular split transoral route and patient put on thyroxin replacement therapy. PMID- 23451554 TI - Association of the ENPP1 rs997509 polymorphism with obesity in South African mixed ancestry learners. AB - BACKGROUND: The Ectonucleotide Pyrophosphatase Phosphodiesterasel (ENPP1) polymorphisms have been associated with metabolic traits. There is no data on the effect of ENPP1 in South African children or adults. OBJECTIVE: To investigate the role of K121Q (rs1044498), rs997509 and rs9402349 in obesity and other components of the metabolic syndrome. DESIGN: A case-control study. SUBJECTS: Sixty four obese and 64 lean mixed ancestry learners. SETTING: Western Cape, South Africa. MAIN OUTCOME MEASURE: The ENPP1 rs997509T allele is independently associated with obesity in children of mixed ancestry from South Africa. RESULTS: The T allele frequency of the rs997509 differed significantly between obese and controls, p=0.0100 and increased the risk of being obese, p = 0.0238. Furthermore, the estimated effect of the T allele was an increase of 8.6 cm in waist circumference, 10.2 kg in weight and a corresponding 4.9 kg/m2 in BMI. Individuals carrying both the 121Q and the T allele of rs997509 were more associated with obesity (odds ratio = 3.85, 95% CI: 1.13 to 13.09) whilst those carrying the C allele of rs997509 in the presence of 121Q were likely to be lean with odds ratio of obesity 0.41 (95% CI: 0.19 to 0.87). CONCLUSION: Our findings suggest that ENPP1 polymorphisms may contribute to different metabolic characteristics, all of which are associated with insulin resistance in mixed ancestry children of South Africa. However, a larger study is required to confirm findings of this study. PMID- 23451555 TI - Patterns of injuries in children who fall from a height as seen at Kenyatta National Hospital. AB - OBJECTIVE: To describe injuries and outcomes among children who fall from a height DESIGN: Prospective, convenience hospital based study. SETTING: Paediatric surgical wards of Kenyatta National Hospital, Nairobi, from November 2006 to February 2007. SUBJECTS: Children aged 1-13 years who sustained injuries after failing from any height. RESULTS: Eighty children were recruited. There were 61 male (76%) and 19 female (24%), with an age range 1-13 years. Most injuries occurred at home (78.75%) after falling from buildings (33.75%), and were of mild to-moderate severity. 13.4% sustained external haemorrhage, 16.5% sustained facial injuries, 25.2% sustained CNS injuries, 43.3% sustained various fractures, and 1.6% sustained abdominal trauma. The head and musculoskeletal systems were the mostlikely regions to be injured. The most common diagnoses were supracondylar fracture of humerus and mild head injury. No thoracic or pelvic fractures were recorded. Recovery was good in most instances. CONCLUSION: Most children who sustain injuries after a fall from height do so after falling from a building. The most common types of injuries sustained were to the head and distal limbs, especially fractures. They were mostly of mild-moderate severity and recovery usually complete. PMID- 23451556 TI - Perspectives on the practice of vaginal birth after caesarean section in East Africa. AB - BACKGROUND: The increasing Caesarean section rates being observed in most facilities will ultimately result in a larger proportion of women with previous scar. Choices need to be made by both the patient and the health worker between attempted Vaginal Birth after Caesarean section (VBAC) and Elective Repeat Caesarean section (ERCS). Both practices are associated with perinatal risks and benefits that call for certain objectivity and prudence in decision making especially where resources are scarce. OBJECTIVE: To determine perceptions on the practice of vaginal birth after Caesarean section among maternity service providers in East Africa. DESIGN: A semi-qualitative cross sectional survey using self administered questionnaires. SETTING: The study was undertaken among delegates attending a regional Obstetrics and Gynaecology conference in Mombasa, Kenya. SUBJECT: Sixty three consenting delegates were interviewed RESULTS: A majority (69.8%) of the respondents were consultants and midwives working in government facilities. Fifty eight out of the 63 respondents offered VBAC in their institutions despite acknowledging sub-optimal antenatal preparation. The main concerns identified were; deficiencies in healthcare delivery systems, inadequate human resources, lack of unit guidelines, inappropriate maternal education and inappropriate foetal monitoring tools. CONCLUSION: The practice of vaginal birth after Caesarean section was perceived to be sub-optimal with many existing deficiencies that need urgent action to ensure the safety of mothers and newborns. We therefore recommend that unless these concerns raised by maternity providers are addressed then the practice of VBAC in the region should not be encouraged. PMID- 23451557 TI - Acute medical conditions in under five year old children at a public hospital in Kenya. AB - OBJECTIVE: To determine the prevalence of childhood preventable and treatable medical conditions and the parent's/guardian's knowledge about the conditions and their management. DESIGN: A descriptive cross-sectional study. SETTING: Paediatric medical wards at Kenyatta National hospital SUBJECTS: All children aged 0-60 months with preventable conditions (that included pneumonia, malaria, diarrhoea/dehydration, meningitis and malnutrition) in paediatric wards who had stayed in the ward for 24 to 48 hours. RESULTS: Two hundred and fifty six parents/guardians staying with their children were recruited into the study. The vast majority (85.5%) of the children were aged less than two years. The prevalence of the acute treatable and preventable medical conditions was 88.6% over a one month period. The leading cause of admission for most children was pneumonia (31.6%) followed by malnutrition (16.8%) and gastro-enteritis (16%). Other conditions included neonatal sepsis (9.1%), measles (6%) and malaria (4.8%). The parents'/guardians' mean and median age was 26 years and the majority (89.8%) were mothers. A great proportion (46.5%) of the parents/guardians had attained at least some primary education. More than 70% of the parents/guardians were found to lack knowledge about their children's health problems and the drugs they were using. This was regardless of the parent's/guardians level of education and the frequency of admission of the child. CONCLUSION: Acute preventable and treatable medical conditions at KNH are highly prevalent, and the leading conditions include pneumonia, malnutrition and gastroenteritis. Most parents/guardians did not understand their children's health problems regardless of their level of education. PMID- 23451558 TI - Human papilloma virus genotypes in Ghanaian women with cervical carcinoma. AB - BACKGROUND: Humanpapilloma viruses (HPVs) have been considered to be the necessary and central agents of cervical cancer among women with nearly 80% of cases found in developing countries. OBJECTIVE: To determine HPV genotypes prevalent in Ghanaian women with cervical cancer. DESIGN: Retrospective study. SETTING: Pathology Department, University of Ghana Medical School, College of Health Sciences, University of Ghana. SUBJECTS: Ghanaian women 23 to 80 years diagnosed with cervical cancer. RESULTS: Of the 50 samples genotyped, 49 (98%) were determined as positive for HPV DNA. Eight out of 18 different HPV genotypes were detected and all were high-risk types. In decreasing order of prevalence, were HPV 18 in 42 (84%) samples, HPV 16 in 12 (24%) samples, HPV 45 in three (6%) samples, HPV 39 in two (4%) samples and HPV 35, 52,56 and 66 in one (2%) sample each. Multiple infections were detected in 13 (26%) of the 50 samples, the most common co-infections being HPV types 16/18 (18%). Triple infections were found in two (4%) samples with HPV types 16,18 and 39. HPV type 18 was more relatively frequent in adenocarcinomas and adenosquamous carcinomas than in squamous cell carcinomas. CONCLUSION: Eight high-risk HPV genotypes: 16,18, 35, 39, 45, 52, 56 and 66 were typed, with HPV type 18 being the most prevalent in Ghanaian women with cervical cancer. This is contrary to the worldwide prevalence where HPV 16 is the most common type associated with invasive cervical carcinoma. PMID- 23451559 TI - Conformity to the surviving sepsis campaign international guidelines among physicians in a general intensive care unit in Nairobi. AB - BACKGROUND: There are emerging therapies for managing septic critically-ill patients. There is little data from the developing world on their usage. OBJECTIVES: To determine the conformity rate for resuscitation and management bundles for septic patients amongst physicians in a general intensive care unit. DESIGN: Cross sectional observational study. SETTING: The general intensive care unit, Aga Khan University Hospital,Nairobi. SUBJECTS: Admitting physicians from all specialties in the general intensive care unit. RESULTS: The physicians had high conformity rates of 92% and 96% for the fluid resuscitation and use of va so pressors respectively for the initial resuscitation bundle. They had moderate conformity rates for blood cultures prior to administering antibiotics (57%) and administration of antibiotics within first hour of recognition of septic shock (54%). There was high conformity rate to the glucose control policy (81%), use of protective lung strategy in acute lung injury/Acute respiratory distress syndrome, venous thromboembolism prophylaxis (100%) and stress ulcer prophylaxis (100%) in the management bundle. Conformity was moderate for use of sedation, analgesia and muscle relaxant policy (69%), continuous renal replacement therapies (54%) and low for steroid policy (35%), administration ofdrotrecogin alfa (0%) and selective digestive decontamination (15%). CONCLUSION: There is varying conformity to the international sepsis guidelines among physicians caring for patients in our general ICU. Since increased conformity would improve survival and reduce morbidity, there is need for sustained education and guideline based performance improvement. PMID- 23451560 TI - Successful resuscitation of a three month old child with intralipid infusion, presumed to have bupivacaine induced seizures and cardiovascular complications: case report. AB - Anaesthetic agents used locally can be toxic especially if given as an inappropriate dose or route. Lipid infusion has been demonstrated in several animal models to successfully resuscitate bupivacaine induced toxicity. We present a case of successful use of 26% lipid infusion to resuscitate a paediatric patient with a presumed subcutaneous injection of bupivacaine and lignocaine which led to neurological and cardiologic consequences. PMID- 23451561 TI - Determinants of non-institutional deliveries in Malawi. AB - Malawi has one of the highest maternal mortality ratios in the world. One of the factors contributing to high maternal mortality is the non-use of health facilities during pregnancy and delivery. The aim of this study is to examine the factors associated with non-institutional deliveries in Malawi. Data from 2004 Malawi Demographic and Health Survey and multinomial logistic regression were used to assess the association between place of delivery and selected socio economic factors. The study population comprised of 7,218 women, who had at least one child, aged less than five years, at the time the survey. Of these women, 58% delivered at a health facility, 29.4% delivered at home and 12.6% delivered at the home of a traditional birth attendant. Multivariate analysis indicate that region (OR = 1.29 for Central Region), place of residence (OR=0.319 for urban areas), wealth status (OR=6.289 for poor, OR=4.683 for middle), education (OR=3.823 for no education, OR=2.265 for primary education), number of prenatal visits (OR=4.732 no visits, OR=1.696 1-3 visits) and ever use of family (OR=1.29 for never used) showed significant association with non-institutional deliveries. These factors should be considered in designing strategies to improve the maternal health care system in Malawi. PMID- 23451562 TI - The development of health policy in Malawi: the influence of context, evidence and links in the creation of a national policy for cotrimoxazole prophylaxis. AB - Within the health policy field, a growing literature is attempting to understand the diverse responses of policy makers to research, and to explain why certain research findings make their way into policy while others are effectively ignored. In this paper we apply a policy analysis framework to the development of cotrimoxazole prophylaxis national policy in Malawi. Arguing that Malawi was one of the early adopters of cotrimoxazole prophylaxis at a national level, we show how the research to policy process was influenced by national healthcare context, the networks of individuals involved, and the nature of the public health evidence itself. PMID- 23451563 TI - Underreporting of side effects of standard first-line ART in the routine setting in Blantyre, Malawi. AB - INTRODUCTION: In the Malawi ART programme, 92% of 250,000 patients are using the standard first-line regime of stavudine-lamivudine-nevaripine. National ART reports indicate <4% experience ART side effects, much less than expected from literature. METHODS: We interviewed adult patients on standard first-line ART for at least one year, after routine visits to an urban clinic in Blantyre, Malawi. We determined the prevalence of symptoms that are common side-effects, described discrepancies between symptoms that patients reported to us and those that had been recorded by attending staff as side-effects in the point-of-care electronic monitoring system, and studied factors associated with such discrepancies. RESULTS: Of 170 participants, 75 (44%) reported at least one symptom, most common were symptoms suggesting peripheral neuropathy (n=57) and lipodystrophy (n=16). Forty-six (66%) symptomatic patients said they reported symptoms to attending ART staff. Side-effects were recorded in the clinic database for just 4 patients. Toxicity recording was too low for meaningful analysis of factors associated with discrepancies between reporting and recording of side-effects. The prevalence of symptoms indicating characteristic side-effects of the standard first-line regimen was 39% based on interviews, and 2% in the electronic monitoring system. CONCLUSION: There was gross under-recording of side-effects in this setting, mainly due to not recording by ART staff. Pressure of work and insufficient perceived benefit of side-effect recording are suspected causes. Local and national ART reports do not reflect the true toxicity of the standard first line regimen. PMID- 23451564 TI - Cytosine arabinoside reduces the numbers of granulocyte macrophage colony forming cells (GM-CFC) and high proliferative potential colony forming cells (HPP-CFC) in vivo in mice. AB - BACKGROUND: Cytosine arabinoside (Ara-C) is an S-phase specific cytotoxic drug used in the treatment of malignancies. It is converted to Cytosine Arabinoside triphosphate (Ara-CTP) in the cell. Cytosine Arabinoside triphosphate, reversibly displaces deoxy cytidine triphosphate from DNA polymerase for incorporation into DNA. This process leads to cell death. OBJECTIVE: To investigate the in vivo effects of Ara-C on the Granulocyte Macrophage Colony Forming Cells (GM-CFC) and High Proliferative Potential Colony Forming Cells (HPP-CFC) respectively in mice. METHODOLOGY: Ara-C (150mg/kg) was administered intraperitoneally (i.p) once to mice and bone marrow cells sampled on days 1, 3 and 6. RESULTS: Ara-C reduced the numbers of both GM-CFC and HPP-CFC in the bone marrow. HPP-CFCs were initially more sensitive to Ara-C treatment than GM-CFCs. In the six days after treatment the effect on GM-CFC persisted, while there was a partial recovery in the number of HPP-CFCs. CONCLUSION: It is possible that Ara-C disturbs the stem cells niche by damaging the stromal cells of the bone marrow microenvironment. This would result in derangement of HPP-CFC proliferation. PMID- 23451565 TI - Case report: HIV test misdiagnosis. PMID- 23451566 TI - Case report: a difficult diagnosis to swallow. PMID- 23451567 TI - "I have worked in a field that was NOT adequately known, appreciated and resourced". Interview by Thengo Kavinya. PMID- 23451568 TI - Opinions on abortion as a viable way of improving reproductive health. PMID- 23451569 TI - [Evidence, experience and empathy: reflections on the medical profession]. PMID- 23451570 TI - [Physicians on the edge of burnout? Reflections on intersubjectivity]. PMID- 23451571 TI - [Chronic disease and collaborative care: when the healthcare system is lacking]. PMID- 23451572 TI - [Hidden shortness of breath or the difficulty of early diagnosis of pulmonary hypertension]. PMID- 23451573 TI - [Accidental falls: a new concern of physical activity?]. PMID- 23451574 TI - [The terminally ill copd patient: morphine, oxygen or both?]. PMID- 23451575 TI - [Muscle weakness, what's your diagnosis?]. PMID- 23451576 TI - [Chronic kidney disease]. PMID- 23451577 TI - [The role of complementary medicine along with traditional medicine]. PMID- 23451578 TI - [The lung and diving]. PMID- 23451579 TI - [Promotion of physical activity by the physician]. PMID- 23451580 TI - [What do we know about age-related changes in sports?]. PMID- 23451581 TI - [LAMal...a good or bad goodbye in 2013?]. PMID- 23451582 TI - [Are physicians on the edge of burnout?]. PMID- 23451583 TI - [When the child is no longer able to feed himself: enteral nutrition]. PMID- 23451584 TI - [The myth of Alzheimer disease]. PMID- 23451585 TI - [Oral health in the elderly]. PMID- 23451586 TI - [Update on parkinson disease]. PMID- 23451587 TI - [The lung and diving]. PMID- 23451588 TI - [Psychosomatic aspects of caring for diabetes]. PMID- 23451589 TI - [If the patient has mistletoe wishes]. PMID- 23451590 TI - [Asthma and allergy]. PMID- 23451591 TI - [Functional gastrointestinal disorders: are we pushing our resources?]. PMID- 23451592 TI - [Body weight, breathing, the environment, physical activity, the economy and health]. PMID- 23451593 TI - [Coping with the death of a child]. PMID- 23451594 TI - [Cardiogeriatrics: concept or reality?]. PMID- 23451595 TI - [Promises and fears of osteoporosis treatments]. PMID- 23451596 TI - [Poor and sick: what is the role of the physician?]. PMID- 23451597 TI - [Health coaching and neurolinguistic programming: useful techniques for the general physician]. PMID- 23451598 TI - [Prescribing and following up with psychotropic agents]. PMID- 23451599 TI - [Advanced lung cancer: supportive care]. PMID- 23451600 TI - [When our patients get on our nerves]. PMID- 23451601 TI - [Counseling the dependent patient]. PMID- 23451602 TI - [The role of the physician in caring for a handicapped child]. PMID- 23451603 TI - [End of life care]. PMID- 23451604 TI - [Critical care, appropriateness of care]. PMID- 23451605 TI - [The diabetic foot]. PMID- 23451606 TI - [Bariatric surgery and sleep apnea]. PMID- 23451607 TI - [What's new in multiple sclerosis therapy?]. PMID- 23451608 TI - [Thyroid autoimmunity]. PMID- 23451609 TI - ["From life...to death!" The Chrysalis Foundation disseminates a substantial, pertinent and useful document]. PMID- 23451610 TI - [Bisphenol A: a certain or verified toxin?]. PMID- 23451611 TI - [The last diagnosis from Dr. House]. PMID- 23451612 TI - [Health care reform and democracy]. PMID- 23451613 TI - He, robot. The high-tech future of the human body. PMID- 23451614 TI - Accuracy of vital status ascertainment using the Social Security Death Master File in a deceased population. AB - Both insurance and clinical studies depend on the Social Security Death Master File (SSDMF) to provide vital status on subjects that are unavailable for direct ascertainment. Using the Gen Re individual life claims data, we analyzed the accuracy of vital status determination in a population known to be deceased. Overall, only 75% of claims appeared in the SSDMF. The detection rate is highly skewed by age of the decedent. This systematically reduced ascertainment of mortality at younger ages could cause misleading conclusions in studies that measure absolute mortality rates, especially when they include a wide age span. PMID- 23451615 TI - Chronic condition mortality in the Medicare population. AB - The census and proportion of the US population that is age 65 years and older has never been as high. Medicare data files are a valuable source of data on medical conditions and care that can be used to study the older age population. We obtained access to The CMS Medicare data files including a 5% sample of annual Beneficiary Annual Summary (BASF) files for the years 1999-2009, and the most current Vital Status file available at the time of our request (2011). The Vital Status file enabled us to assess longitudinal follow-up for survival analysis. Data from over 3 million beneficiaries were available. The BASF files include summarized data pertaining to condition categories, defined by the Chronic Conditions Data Warehouse (CCW), which was of primary interest for this analysis. Cox regression models were used to assess the mortality risk associated with a set of 15 chronic conditions, as well as severity factors based on summary claims data. We were able to confirm a number of expectations, such as the high level of mortality risk with lung cancer, congestive heart failure, and in the oldest ages, Alzheimer's disease and related dementias. We were also able to identify chronic conditions that behave more as chronic conditions individuals may "live with" rather than "die of." Depression, diabetes, prostate and breast cancer are present for longer durations and/or are associated with low or no increased mortality risk in the Medicare population. Inpatient confinement or skilled nursing facility utilization were markers for increased risk, as expected. Unexpectedly, frequent physician visits (>10/year) was a marker for more favorable mortality, perhaps indicating that close supervision of chronic conditions lead to improved survival. PMID- 23451616 TI - Relationship between selected social factors and all-cause mortality. AB - OBJECTIVE: Evaluate the associations between several simple-to-measure social factors and all-cause mortality to determine whether selected social factors contribute useful mortality information. METHOD: Using the Third National Health and Nutritional Examination Survey (NHANES III) and the current NHANES III Linked Mortality File datasets, associations were evaluated among 18,460 survey participants at least 20 years of age, with 5408 deaths occurring during the 280,183 person-year follow-up. Selected social factors, including education level, current employment status, and frequency of interpersonal contact with friends/relatives, were analyzed using a Cox proportional hazard model, and the impact of the selected social factors on mortality was expressed as a hazard ratio. Associations were modeled adjusting for age and gender only and also in a multivariate regression analysis; furthermore, associations were evaluated when stratified by duration of follow up. RESULTS: In a multivariate Cox model, independent hazard ratios for higher education, being employed, being married, frequent phone conversations with friends, frequent visits with friends or relatives, frequent church attendance, and participation in a social group ranged between 0.56 and 0.99. All corresponding 95% confidence intervals exclude 1. Many of the associations between social factors and mortality were stronger at shorter follow-up durations. CONCLUSION: Several easy-to-measure social factors were shown to be significantly and independently associated with all-cause mortality. PMID- 23451617 TI - Laboratory and biometric predictors of cancer-related mortality in an insured population. AB - OBJECTIVES: Identification of statistically significant laboratory and biometric predictors of cancer-related mortality among insured individuals. BACKGROUND: Numerous clinical studies have identified correlations between various laboratory results and physical measurements and cancer risk, often of a uni-variate nature. A study of life insurance claims has permitted a broad multivariate analysis of laboratory and biometric risk factors for cancer mortality in an insured population. METHODS: Of the applicants with complete laboratory and physical measurement profiles, 1.25 million were available and followed for an average of 4.7 years. Dates of 518 life insurance claims resulting from cancer deaths were recorded, and the resulting data set analyzed by multivariate Cox Proportional Hazards regression to identify statistically significant predictors of cancer related mortality among insured individuals. RESULTS: Among demographic variables, cancer deaths were found to be strongly associated with age and tobacco use, but not with gender. Among serum and urine analytes, liver function tests (principally GGT and ALP), hypocholesterolemia, proteinurea, and low fructosamine were found to be independently predictive of cancer mortality. Among physical measurement variables, there was a positive relationship between cancer mortality risk and height and relatively weak relationships with pulse and blood pressure. Weight and body mass index (BMI) were not statistically significant covariates. CONCLUSIONS: The findings highlight the potential value of laboratory analytes and biometric measurements to cancer risk assessment including low to low-normal values in analytes (particularly cholesterol and fructosamine) whose diagnostic value in clinical practice and underwriting may be advantageous. PMID- 23451618 TI - Scoring life insurance applicants' laboratory results, blood pressure and build to predict all-cause mortality risk. AB - OBJECTIVE: Evaluate the degree of medium to longer term mortality prediction possible from a scoring system covering all laboratory testing used for life insurance applicants, as well as blood pressure and build measurements. METHOD: Using the results of testing for life insurance applicants who reported a Social Security number in conjunction with the Social Security Death Master File, the mortality associated with each test result was defined by age and sex. The individual mortality scores for each test were combined for each individual and a composite mortality risk score was developed. This score was then tested against the insurance applicant dataset to evaluate its ability to discriminate risk across age and sex. RESULTS: The composite risk score was highly predictive of all-cause mortality risk in a linear manner from the best to worst quintile of scores in a nearly identical fashion for each sex and decade of age. CONCLUSION: Laboratory studies, blood pressure and build from life insurance applicants can be used to create scoring that predicts all-cause mortality across age and sex. Such an approach may hold promise for preventative health screening as well. PMID- 23451619 TI - Human papillomavirus (HPV) and cervical cancer. PMID- 23451620 TI - Acute ischemia in an insurance applicant's electrocardiogram? AB - A life insurance applicant's electrocardiogram shows ST elevation and terminally negative T-waves suggestive of acute myocardial ischemia. PMID- 23451621 TI - Leg mass in a 19-year-old Afghan man. PMID- 23451623 TI - A research engine could drive the NHS to lead the world. PMID- 23451622 TI - Exclusive. Absence of technology ambition in efficiency plans. PMID- 23451624 TI - On technology in healthcare. PMID- 23451625 TI - On improving NHS performance. Is the government doing enough? PMID- 23451626 TI - How to make integration work. PMID- 23451627 TI - On removing workforce straitjackets. PMID- 23451628 TI - Conference. Long-term thinking. PMID- 23451629 TI - On the need for innovation in healthcare. PMID- 23451630 TI - Self-care. Home care approvals. PMID- 23451631 TI - Case studies. Remote controls. PMID- 23451632 TI - On health technology in the developing world. PMID- 23451633 TI - Networking. Making the connection. PMID- 23451634 TI - Case studies. Uniting in the act. PMID- 23451635 TI - On the challenge of providing care for prisoners. PMID- 23451636 TI - Offender health. Guarded prognosis. PMID- 23451637 TI - Case studies. Prison breaks. PMID- 23451638 TI - On the importance of partnerships. PMID- 23451639 TI - Care in the community. Sharing and caring. PMID- 23451640 TI - Case studies. Model of success. PMID- 23451641 TI - Ringing the changes. PMID- 23451642 TI - Careers. Stepping up to the plate. PMID- 23451643 TI - Post-authorisation. Looking ahead. PMID- 23451644 TI - NHS global. Is everyone getting on board for NHS exports? PMID- 23451645 TI - Community services. Reasons for redesigning care for older people. PMID- 23451646 TI - Commissioning. Minding the gap is key to change. PMID- 23451647 TI - Megatrends: Part 2 of 3. Feeling the heat of climate change. PMID- 23451648 TI - Special report. Developing an instinct for inquiry. PMID- 23451649 TI - Exclusive. Lamb to back integrated care 'experiments'. PMID- 23451650 TI - Workforce. NHS chief executives highlight the 'climate of fear'. PMID- 23451651 TI - Pay. Pay progress fails to halt consortium plan. PMID- 23451652 TI - On the NHS mandate. Will liberation come from the mandate? PMID- 23451653 TI - The importance of understanding evidence. PMID- 23451654 TI - On pathways. PMID- 23451655 TI - Service redesign. Beyond boundaries. PMID- 23451656 TI - Service improvement: case studies. Say your piece. PMID- 23451657 TI - On specialist care. PMID- 23451658 TI - External providers. General anxiety. PMID- 23451660 TI - On raising the bar. PMID- 23451659 TI - External providers: case studies. Special cases. PMID- 23451661 TI - Shared care. Fair share. PMID- 23451662 TI - Shared care case studies. Dose of confidence. PMID- 23451663 TI - Take action on NHS Change Day. PMID- 23451664 TI - Primary care. Defining a new model of sustainable leadership. PMID- 23451665 TI - Transport. NHS staff can play their part in carbon reduction. PMID- 23451666 TI - Primary care. Jumping through the wrong hoops. PMID- 23451667 TI - Sustainability. A radical response to the crash. PMID- 23451668 TI - Partnerships. Commercial break for the NHS. PMID- 23451669 TI - [Quality register--emperor with no clothes?]. PMID- 23451670 TI - [Swedish research needs Swedish innovation. The research and innovation strategy must strengthen Swedish competitiveness]. PMID- 23451671 TI - [Eruptive nevi after injection of drugs marketed as melanotan II. The first two Swedish cases described]. PMID- 23451672 TI - [Antibiotic prophylaxis in breast surgery? Yes, but not for everyone. Quality data from the Uppsala county council provides draft for guidelines]. PMID- 23451673 TI - [Too few patients get heart failure pacemakers. It can provide better treatment in heart failure and left bundle branch block]. PMID- 23451674 TI - [Ethical aspects to consider in observational studies]. PMID- 23451675 TI - [The biobanks are developed to meet research requirements]. PMID- 23451676 TI - [The coercion that affects us all]. PMID- 23451677 TI - [More randomized studies in health care can be made cheaper and more regularly]. PMID- 23451678 TI - [Public sector as engine for research and innovation]. PMID- 23451679 TI - [Care choice for specialized care--some proposals for action]. PMID- 23451681 TI - District general hospitals top 'efficiency league'. PMID- 23451680 TI - ["Fight against aging as a disease"]. PMID- 23451682 TI - Funding reform. We must beat our hospital addiction. PMID- 23451683 TI - On implementing the NHS mandate. PMID- 23451684 TI - On face-to- face facts. PMID- 23451685 TI - Efficiency. The NHS app store. PMID- 23451686 TI - On disruptive technology. PMID- 23451687 TI - Service redesign. A kinder system. PMID- 23451688 TI - On the friends and family test. PMID- 23451689 TI - Clinical governance. Engaged in delivering the quality agenda. PMID- 23451690 TI - Leadership. Learn the art of speech therapy. PMID- 23451691 TI - Acute care. Bridging the divide using liaison psychiatry. PMID- 23451692 TI - Nursing. Free nurses up to deliver care. PMID- 23451693 TI - Leadership starts with a vision. PMID- 23451694 TI - College raises concerns over community care plans. PMID- 23451695 TI - Patients given more input on quality of non-clinical services. PMID- 23451696 TI - Ambulatory care: it's all in a day's work. PMID- 23451697 TI - Meeting the needs of vulnerable patients. PMID- 23451698 TI - Role of facilitators in delivering high quality practice education. AB - Investment in the professional development of the nursing workforce is essential to enhance patient safety, quality of care, personal development and lifelong learning. When resources are scarce, however, education spending is often the first cost saving and this can reduce quality of care. This article explores the role of education facilitators, who are central to strategic representation of practice education issues, delivery of training and development, determining training needs, and the development of relevant education programmes. In addition, they provide support for mentors, practice educators and clinicians. PMID- 23451699 TI - Evolution of uniforms to cater for the needs of staff and patients. AB - Uniforms were originally developed to distinguish nurses from servants. However, with the arrival of the NHS in 1948, designs became less complex and an updated style of dress was created. This article examines how uniforms have changes since 1860 and how workwear has been adapted to meet developments in healthcare regulations. The styles have become more practical and comfortable, and modern materials incorporate properties that reduce risk of cross-contamination and infection. PMID- 23451700 TI - Encouraging nurses to take the lead on the information agenda. AB - This is the final in a series of four articles that discuss issues relating to the UK's growing reliance on health information technology. It is becoming increasingly clear that information and communication technologies are increasing the availability of health care, and improving the management, sharing and understanding of health care at a local and national level. This article explores the role of senior nurses in the management, delivery and support of care. PMID- 23451701 TI - The nature of health and social care partnerships. AB - Partnership, often wrongly used interchangeably with 'collaboration' and 'inter agency working', features regularly in government publications, and is often high on health and social care managers' agendas. With an increasing emphasis on partnership in politics, society and health care, managers need to understand the concept in relation to their practice, its challenges and the most effective ways of implementing it. This article discusses the multifaceted nature of partnership, explores the benefits and obstacles to achieving successful partnerships and looks at how these can be overcome. PMID- 23451702 TI - Quality comes first. PMID- 23451703 TI - [Expanded Recommendations for publication of clinical trials]. PMID- 23451704 TI - [Drugs in chronic venous insufficiency--the challenge of demonstrating clinical efficacy]. AB - Approximately 90% of German adults show alterations of their lower limb veins; about every fifth suffers from symptoms of chronic venous insufficiency (CVI). With compression therapy showing low compliance, CVI oedemas and accompanying subjective symptoms are frequently treated with anti-oedematous drugs of herbal origin. A guideline outlines the requirements for clinical studies with CVI drugs. Water displacement plethysmometry (volumetry) is the gold standard for determining the reduction ofoedemas. Besides reducing oedemas, drugs should also demonstrate effects on accompanying symptoms influencing quality of life. Despite assistance provided by the guideline, clinical studies in CVI are complex and subject to multiple error sources in planning and execution. The corroboration of successful studies in further confirmatory studies is good practice and demanded by regulatory authorities. This practice reduces the risk of drugs being accepted as effective just based on the play of chance. As an example, placebo controlled studies with an extract from red vine leaves show that a careful definition of patients as well as meticulous study planning and execution can reproducibly verify significant and clinically relevant treatment effects. When evaluating clinical studies it is recommended to refer to the CONSORT statement. Publications missing certain minimum information make interpretation difficult and may result in a biased judgment of the effects of therapy. PMID- 23451705 TI - [Clostridium difficile infection as interdisciplinary challenge. Current discussions in respect to epidemiology, diagnostic methods, risk classification as well as treatment options]. AB - Within the last decade, the incidence ofclostridium difficile infection (CDI) has increased in many regions all over the world including the highly virulent B1/NAP1/027 strain. Meanwhile, the value of predisposing risk factors and diagnostic measures as well as the spectrum of therapeutic options has been elucidated in more detail. Most commonly applied antiinfective agents include metronidazole, vancomycin and fidaxomicin, however, several questions remain unanswered in respect to their optimized use which is also true for some further drugs which have not yet been approved for this indication. Based on the complexity and potential severity of CID, antibiotic stewardships should be implemented more intensively in order to avoid a further spread of highly virulent and resistant strains in the near future. PMID- 23451706 TI - [Healthy nutrition in pregnancy]. AB - The right choices in eating when pregnant may influence the health of mother and child in the short and long term. Recent recommendations emphasize the intake of folic acid and iodide. The reader also obtains advice about the extent of weight gain, avoidance of alcohol and tobacco smoke and how to prevent food-borne infections. PMID- 23451708 TI - Chiral triazole fungicide difenoconazole: absolute stereochemistry, stereoselective bioactivity, aquatic toxicity, and environmental behavior in vegetables and soil. AB - In this study, the systemic assessments of the stereoisomers of triazole fungicide difenoconazole are reported for the first time, including absolute stereochemistry, stereoselective bioactivity toward pathogens (Alternaria sonali, Fulvia fulva, Botrytis cinerea, and Rhizoctonia solani), and toxicity toward aquatic organisms (Scenedesmus obliquus, Daphnia magna, and Danio rerio). Moreover, the stereoselective degradation of difenoconazole in vegetables (cucumber, Cucumis sativus and tomato, Lycopersicon esculentum) under field conditions and in soil under laboratory-controlled conditions (aerobic and anaerobic) was investigated. There were 1.33-24.2-fold and 1.04-6.78-fold differences in bioactivity and toxicity, respectively. Investigations on the stereoselective degradation of difenoconazole in vegetables showed that the highest-toxic and lowest-bioactive (2S,4S)-stereoisomer displays a different enrichment behavior in different plant species. Under aerobic or anaerobic conditions, (2R,4R)- and (2R,4S)-difenoconazole were preferentially degraded in the soil. Moreover, difenoconazole was configurationally stable in the test soil matrices. On the basis of biological activity, ecotoxicity, and environmental behavior, it is likely that the use of pure (2R,4S)-difenoconazole instead of the commercial stereoisomer mix may help to increase the bioactivity and reduce environmental pollution. PMID- 23451707 TI - Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site. AB - To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the Vmax of substrate hydrolysis without influencing the KM. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs. PMID- 23451709 TI - An integrative approach to the assessment of narcissism. AB - Narcissism research is poorly calibrated across fields of study in part due to confusion over how to integrate normal and pathological descriptions of narcissism. We argue that pathological and normal narcissism can be integrated in a single model that organizes around self-regulation mechanisms. We present theoretical and empirical support for this interpretation, and demonstrate that modeling pathological and normal narcissism as 2 dimensions underlying the narcissistic character can help to resolve some of the inconsistencies in the field regarding how to best assess adaptive and maladaptive expressions of narcissism. PMID- 23451710 TI - The complete mitochondrial genome structure of Schizothorax waltoni (Cypriniformes:Cyprinidae). AB - In this study, we sequenced and annotated the complete mitochondrial genome of Schizothorax waltoni (Cypriniformes:Cyprinidae). The mitogenome is 16,587 bp in length, which contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non-coding regions: origin of light-strand replication (O(L)) and control region (D-loop). The overall nucleotide base composition of S. waltoni mtDNA is A 29.96%, C 27.07%, G 17.58%, and T 25.39%, with an A + T content of 55.35%. Except for ND6 gene and eight tRNA genes, all other mitochondrial genes were encoded on the heavy strand. The mitochondrial genome of S. waltoni can contribute to the studies on conservation genetics and stock evaluation of S. waltoni resource, as well as molecular phylogeny and species identification of Cyprinidae. PMID- 23451711 TI - Geometric transition and electronic properties of titanium-doped aluminum clusters: Al(n)Ti (n = 2-24). AB - Equilibrium geometries of AlnTi (n = 2-24) clusters were studied using density functional theory with generalized gradient approximation. The resulting geometries showed that the titanium atom remains on the surface of clusters for n < 20 but is endohedrally doped from n = 20. This structural transition confirms the previous experiment results obtained by studying their abilities for argon physisorption (Lang, S. M.; Claes, P.; Neukermans, S.; Janssens, E. J. Am. Soc. Mass Spectrom.2011, 22, 1508). The average bond lengths, coordination numbers, relative stabilities, electronic properties, and other relevant properties were discussed. It was found that the doped titanium atoms strengthen the stabilities of the pure aluminum clusters. The coordination numbers of titanium atoms along with the average Al-Ti bond lengths undergo dramatic increases during the structural transition. The intra-atomic hybridization exists in both Ti and Al atoms, and charge transfer from Al atoms to Ti atom were found in these complexes, which should reflect the strength of Al-Ti interactions. Electronic structure analysis based on the partial density of states reveals stronger Al-Ti interactions for the endohedrally doped structures. PMID- 23451712 TI - Metabolic transit of dietary methylglyoxal. AB - Methylglyoxal (MGO) is responsible for the pronounced antibacterial activity of manuka honey, in which it may reach concentrations up to 800 mg/kg. As MGO formed in vivo is discussed to play a role in diabetic complications, the metabolic transit of dietary MGO was studied within a 3 day dietary recall with four healthy volunteers. Determination of MGO in 24 h urine was performed with GC-MS after derivatization with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine, and D lactate was quantified enzymatically. Following a diet virtually free from MGO and other glycation compounds, a defined amount of MGO (500 MUmol in manuka honey) was administered in the morning of day 2. Renal excretion was between 0.1 and 0.4 MUmol/day for MGO and between 50 and 220 MUmol/day for D-lactate. No influence on excretion of both compounds was observed following administration of MGO. To investigate the stability of MGO under physiological conditions, a simulated in vitro gastrointestinal digestion was performed with MGO-containing honey. After 8 h of in vitro digestion, only 5-20% of the initial methylglyoxal was recovered. This indicates that dietary MGO is rapidly degraded during the digestion process in the intestine and, therefore, exerts no influence on the MGO level in vivo. PMID- 23451713 TI - Journey describing applications of oxone in synthetic chemistry. PMID- 23451714 TI - Impact of new genomic tools on the practice of clinical genetics in consanguineous populations: the Saudi experience. AB - Consanguinity is practiced by around one tenth of the world population but its global distribution is far from uniform. In countries where consanguinity is common, a corresponding increase in the frequency of autosomal recessive diseases is usually observed owing to increased risk of homozygosity for ancestral haplotypes (autozygosity or identity by descent) that harbor pathogenic alleles. The burden of these diseases becomes more apparent as the healthcare system makes gains in its fight against communicable diseases in these countries. Recent advances in molecular genetics make it possible to leverage the mechanism by which consanguinity predisposes to the occurrence of autosomal recessive diseases in order to uncover the causal mutations at an efficient and cost-effective way compared to outbred populations. The identification of these mutations at an unprecedented scale has the potential to significantly reshape the practice of clinical genetics in these populations and to offer opportunities for innovative public health policies. This review discusses the impact that new genomic tools have had on a sample patient population and how they can inform future public health policies in ways that might be relevant to other consanguineous populations. PMID- 23451715 TI - Immune modulation and lack of alloimmunization following transfusion with pathogen-reduced platelets in mice. AB - BACKGROUND: Transfusion of allogeneic blood products can lead to alloimmunization, impacting success of subsequent transfusions and solid organ transplants. Pathogen reduction using riboflavin and ultraviolet B (UVB) light has been shown to eliminate the immunogenicity of white blood cells (WBCs) in vitro through down regulation of surface adhesion molecules, effectively blocking cell-cell conjugation and direct presentation. We sought to determine if this loss of immunogenicity is extended in vivo where indirect presentation of allogeneic antigens can occur. STUDY DESIGN AND METHODS: BALB/cJ mice were transfused with either untreated or riboflavin and UVB-treated C57Bl/6J platelet rich plasma (PRP) containing WBCs. Circulating alloantibody and allospecific splenocyte cytokine responses were measured. RESULTS: Pathogen reduction of allogeneic WBC-enriched PRP using riboflavin and UVB light before transfusion prevented alloimmunization, with a loss of both alloantibody generation and priming of secondary cytokine responses ex vivo. When mice given treated transfusions were subsequently given untreated transfusions, they produced normal levels of alloantibodies but had reduced secondary cytokine responses ex vivo. This immune modulation was antigen specific and was dependent on the presence of WBCs in the treated product. CONCLUSIONS: UVB plus riboflavin treatment of WBC enriched PRP effectively blocks alloimmunization and modulates immune responses to subsequent exposures. PMID- 23451716 TI - The Dorello canal: historical development, controversies in microsurgical anatomy, and clinical implications. AB - Interest in studying the anatomy of the abducent nerve arose from early clinical experience with abducent palsy seen in middle ear infection. Primo Dorello, an Italian anatomist working in Rome in the early 1900s, studied the anatomy of the petroclival region to formulate his own explanation of this pathological entity. His work led to his being credited with the discovery of the canal that bears his name, although this structure had been described 50 years previously by Wenzel Leopold Gruber. Renewed interest in the anatomy of this region arose due to advances in surgical approaches to tumors of the petroclival region and the need to explain the abducent palsies seen in trauma, intracranial hypotension, and aneurysms. The advent of the surgical microscope has allowed more detailed anatomical studies, and numerous articles have been published in the last 2 decades. The current article highlights the historical development of the study of the Dorello canal. A review of the anatomical studies of this structure is provided, followed by a brief overview of clinical considerations. PMID- 23451717 TI - New neonatal classification of unilateral cleft lip and palate-part 1: to predict primary lateral incisor agenesis and inherent tissue hypoplasia. AB - OBJECTIVES: To bring a neonatal classification system of unilateral cleft lip and palate (UCLP) and to correlate this classification with the distribution of the primary lateral incisor. DESIGN: Retrospective with longitudinal follow-up. Setting : Tertiary. Patients : One hundred twenty-one patients with treated UCLP. Thirteen plaster casts were used as controls. MAIN OUTCOME MEASURES: The UCLP patients were classified anatomically into four categories: class 1 corresponds to a maxillary arch with a narrow alveolar cleft, class 2 corresponds to a balanced form, class 3 corresponds to a wide cleft and short maxilla, and class 4 corresponds to a wide cleft and long maxilla. Clinical validity was evaluated with a concordance analysis (intra- and interexaminer). This anatomical classification was also corroborated with an automatic classification determined by morphometric parameters measured on neonatal maxillary plaster casts. The class was finally correlated with the distribution of the primary lateral incisor. RESULTS: Clinical classification of UCLP found 12 cases of class 1 (9.9%), 36 cases of class 2 (29.8%), 47 cases of class 3 (38.8%), and 26 cases of class 4 (21.5%). The clinical classification was validated with a good intra- and interexaminer concordance analysis (kappa > .6). The automatic classification was close to the clinical classification in 84%. The correlation was ideal in class 1 (100%), almost perfect in class 4 (92%), but lower for class 2 (74%) and class 3 (70%). The primary lateral incisor was usually duplicated in class 1, whereas class 2 and class 4 were correlated with a primary lateral incisor located on the lateral palatal segment. Class 3 was associated with an agenesis of the primary lateral incisor (P < .001). CONCLUSIONS: UCLP can be classified into four different classes at birth, which can all give information about the inherent tissue hypoplasia and the distribution of the primary lateral incisor. PMID- 23451718 TI - Multiplexed sensing and imaging with colloidal nano- and microparticles. AB - Sensing and imaging with fluorescent, plasmonic, and magnetic colloidal nano- and microparticles have improved during the past decade. In this review, we describe the concepts and applications of how these techniques can be used in the multiplexed mode, that is, sensing of several analytes in parallel or imaging of several labels in parallel. PMID- 23451720 TI - Nanobiodevices for biomolecule analysis and imaging. AB - Nanobiodevices have been developed to analyze biomolecules and cells for biomedical applications. In this review, we discuss several nanobiodevices used for disease-diagnostic devices, molecular imaging devices, regenerative medicine, and drug-delivery systems and describe the numerous advantages of nanobiodevices, especially in biological, medical, and clinical applications. This review also outlines the fabrication technologies for nanostructures and nanomaterials, including top-down nanofabrication and bottom-up molecular self-assembly approaches. We describe nanopillar arrays and nanowall arrays for the ultrafast separation of DNA or protein molecules and nanoball materials for the fast separation of a wide range of DNA molecules, and we present examples of applications of functionalized carbon nanotubes to obtain information about subcellular localization on the basis of mobility differences between free fluorophores and fluorophore-labeled carbon nanotubes. Finally, we discuss applications of newly synthesized quantum dots to the screening of small interfering RNA, highly sensitive detection of disease-related proteins, and development of cancer therapeutics and diagnostics. PMID- 23451721 TI - Enantioselective synthesis of (+)-obolactone based on a symmetry-breaking Wacker monooxidation of a diene. AB - A concise synthesis of the dihydro-alpha-pyrone/dihydro-gamma-pyrone natural product (+)-obolactone (13) is disclosed. The dienediol acetonide 23 (>=97% ee) was obtained from 1,5-dichloropentane-2,4-dione in four steps. A Wacker monooxidation of 23 furnished the monoketone 24 in 64% yield. The OH group of the ensuing dihydro-gamma-pyrone 31 was esterified under Mitsunobu conditions with cinnamic acid (-> 80% inversion and 20% retention of configuration). A ring closing metathesis formed the dihydro-alpha-pyrone moiety of the target in the terminating step. PMID- 23451719 TI - Synthetic nanoelectronic probes for biological cells and tissues. AB - Research at the interface between nanoscience and biology could yield breakthroughs in fundamental science and lead to revolutionary technologies. In this review, we focus on the interfaces between nanoelectronics and biology. First, we discuss nanoscale field effect transistors (nanoFETs) as probes to study cellular systems; specifically, we describe the development of nanoFETs that are comparable in size to biological nanostructures involved in communication through synthesized nanowires. Second, we review current progress in multiplexed extracellular sensing using planar nanoFET arrays. Third, we describe the designs and implementation of three distinct nanoFETs used to perform the first intracellular electrical recording from single cells. Fourth, we present recent progress in merging electronic and biological systems at the three-dimensional tissue level by use of macro-porous nanoelectronic scaffolds. Finally, we discuss future developments in this research area, unique challenges and opportunities, and the tremendous impact these nanoFET-based technologies might have on biological and medical sciences. PMID- 23451722 TI - Determinants of ocular deviation in esotropic subjects under general anesthesia. AB - PURPOSE: The authors attempted to identify the determinants of ocular deviation in a population of patients with esotropia under general anesthesia. METHODS: Forty-one patients with esotropia were included. Horizontal ocular deviation was evaluated by the photographic Hirschberg test both in the awakened state and under general anesthesia before surgery. Changes in ocular deviation were measured and a multivariate analysis was used to assess its clinical determinants. RESULTS: The mean age (+/- standard deviation [SD]) of study subjects was 13 +/- 11 years and 51% were females. The mean spherical equivalent refraction of the right eye was 2.44 +/- 2.50 diopters (D), with no significant difference between eyes (P = .26). The mean ocular deviation changed significantly, from 33.5 +/- 12.5 prism diopters (PD) at preoperative examination to 8.8 +/- 11.4 PD under general anesthesia (P = .0001). The changes in ocular deviation positively correlated with the pre-operative ocular deviation (correlation coefficient r = 0.59, P = .0001) and negatively correlated with patient age (correlation coefficient r = -0.53, P = .0001). These two determinants remained significant after multivariate adjustment of the following variables: preoperative ocular deviation; age; gender; spherical equivalent refraction; and number of previous strabismus surgeries (model r(2) = 0.49, P = .0001). CONCLUSIONS: The ocular position under general anesthesia was reported as a key factor in the surgical treatment of subjects with esotropia; therefore, its clinical determinants were assessed. The authors observed that preoperative ocular deviation and patient age were the main factors that influenced the ocular position under general anesthesia. PMID- 23451723 TI - A case of leukemia cutis presenting as histiocytoid Sweet's syndrome. AB - BACKGROUND: Leukemia cutis (LC) represents a skin infiltration by leukemic cells. Clinically, it can mimic a wide variety of dermatoses. METHODS: We report a case of LC presenting with a Sweet's syndrome-like eruption and a histiocytoid Sweet's syndrome histologic manifestation. RESULTS: This case may represent distinct and important cutaneous and histopathologic manifestations of LC. CONCLUSIONS: We believe that peripheral blood or bone marrow cytologic analysis is necessary in cases of LC to rule out the possibility of histiocytoid Sweet's syndrome. Additional study is needed to further elucidate the relationship between LC and histiocytoid Sweet's syndrome. PMID- 23451724 TI - Controlled supramolecular assembly of helical silica nanotube-graphene hybrids for chiral transcription and separation. AB - Chiral templating and enantioselective separations are demonstrated on graphene surfaces as directed by encapsulated silica nanotubes. Electrostatic assembly of helical silica nanotubes within graphene sheets results in a hybrid material with the electrochemical properties of graphene and the capability for chiral recognition. Control of the silica nanotube helicity within the graphene hybrid provides a means for directed chiral templating of guest molecules on the outer graphene surface as revealed in the chiral transcription of N(1),N(3),N(5)-tri(4 pyridinyl)cyclohexane-1,3,5-tricarboxamide as well as polyallylamine into supramolecular templated assemblies. Changing the helicity of the internal nanotube also provides control over enantiomer selectivity as demonstrated by the chiral separation of racemic mixtures of phenylalanine, tryptophan, and alanine derivatives. PMID- 23451725 TI - Higher order language competence and adolescent mental health. AB - BACKGROUND: Clinic and community-based epidemiological studies have shown an association between child psychopathology and language impairment. The demands on language for social and academic adjustment shift dramatically during adolescence and the ability to understand the nonliteral meaning in language represented by higher order language becomes essential. OBJECTIVES: : This article reports on the association between difficulties in higher order language skills, reading, cognition, and social-emotional adjustment in adolescents. METHOD: : 144 clinic referred and 186 comparison youth aged 12-18 years were administered a battery of standardized tests of intelligence, working memory, structural and higher order language, and reading achievement. Parent ratings on the Child Behavior Checklist were used as a measure of severity of social-emotional problems. RESULTS: : Clinic-referred youth scored significantly lower than comparison youth on measures of structural and higher order language, working memory, and reading. Of the clinic-referred youth, 45% had some type of higher order language impairment, whereas this was the case for 15% of youth in the comparison group. Lower levels of nonverbal ability and working memory as well as lower level of mothers' education were associated with greater risk of having higher order language impairment. CONCLUSIONS: : Findings have implications for practitioners' seeking to understand and treat adolescents since therapeutic techniques rely on skills where higher order language is at play including the ability to discuss opinions flexibly and to weigh interpretations. Therapists must be aware that there are areas that have potential for miscommunication with some adolescents and where inaccurate inferences may be made about their behavior. Furthermore, educators must consider resources for youth who may increasingly struggle in high school because of such difficulties. PMID- 23451726 TI - QTL and association analysis for skin and fibre pigmentation in sheep provides evidence of a major causative mutation and epistatic effects. AB - The pursuits of white features and white fleeces free of pigmented fibre have been important selection objectives for many sheep breeds. The cause and inheritance of non-white colour patterns in sheep has been studied since the early 19th century. Discovery of genetic causes, especially those which predispose pigmentation in white sheep, may lead to more accurate selection tools for improved apparel wool. This article describes an extended QTL study for 13 skin and fibre pigmentation traits in sheep. A total of 19 highly significant, 10 significant and seven suggestive QTL were identified in a QTL mapping experiment using an Awassi * Merino * Merino backcross sheep population. All QTL on chromosome 2 exceeded a LOD score of greater than 4 (range 4.4-30.1), giving very strong support for a major gene for pigmentation on this chromosome. Evidence of epistatic interactions was found for QTL for four traits on chromosomes 2 and 19. The ovine TYRP1 gene on OAR 2 was sequenced as a strong positional candidate gene. A highly significant association (P < 0.01) of grandparental haplotypes across nine segregating SNP/microsatellite markers including one non-synonymous SNP with pigmentation traits could be shown. Up to 47% of the observed variation in pigmentation was accounted for by models using TYRP1 haplotypes and 83% for models with interactions between two QTL probabilities, offering scope for marker assisted selection for these traits. PMID- 23451727 TI - Necrotizing fasciitis of the lower extremity caused by Shewanella algae. PMID- 23451730 TI - Clostridium difficile infection of a prosthetic knee joint requiring amputation. PMID- 23451729 TI - Effect of dietary monosaccharides on Pseudomonas aeruginosa virulence. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic, gram-negative pathogen associated with many hospital-acquired infections and disease states. In particular, P. aeruginosa has been identified as a crucial factor in the pathogenesis of neonatal necrotizing enterocolitis (NEC). This condition presents more frequently in infants fed a formula-based diet, which may be a result of the specific monosaccharide content of this diet. We hypothesized that P. aeruginosa would express virulence genes differentially when exposed to monosaccharides present in formula versus those in human milk. METHODS: Using the results of a metabolomics study on infant diets and their resulting fecal samples, we identified several monosaccharides that distinguished milk from formula diets. Of these compounds, four were found to be metabolized by P. aeruginosa. We subsequently grew P. aeruginosa in tryptic soy broth (TSB) supplemented with these four monosaccharides and used quantitative reverse transcriptase-polymerase chain reaction to measure the expression of 59 major P. aeruginosa virulence genes. The results were standardized to an external control of P. aeruginosa grown in TSB alone. RESULTS: P. aeruginosa did not respond differentially to the monosaccharides after 6 h of growth. However, after 24 h, the organism grown in arabinose (present in formula), xylose (present in human milk), and galactose (present in both formula and feces from milk-fed infants) displayed a significant increase in the expression of virulence genes in all categories. In contrast, P. aeruginosa grown in mannose (present in the feces of milk-fed infants) displayed a significant decrease in virulence gene expression. CONCLUSION: These results demonstrate the importance of nutrient content on the relative expression of virulence genes in pathogens that colonize commonly the gut of infants. Understanding the effect of current dietary formulas on virulence gene expression in various gut-colonizing pathogens may present a new approach to elucidating the differences between human milk and formula in the development of NEC. PMID- 23451731 TI - Exposure to bisphosphonates and risk of colorectal cancer. AB - Animal and in vitro studies suggest that the use of bisphosphonates (BPs) may be associated with reduced risk for colorectal cancer (CRC). However, results from these studies have been inconsistent. The aim of our study was to review and summarize the evidence provided by longitudinal studies on the association between BP use and CRC risk A comprehensive literature search for articles published up to October 2012 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risks (RRs) or odds ratios were calculated. Six reports (four case-control studies and two cohort studies) published between 2010 and 2012 were identified. There was evidence of an association between any use of BPs and CRC risk using a fixed effects model (RR = 0.80, 95% confidence interval = 0.74, 0.85) and a random effects model (RR = 0.80, 95% confidence interval = 0.71, 0.90). However, we did not observe any evidence of a trend with increasing duration of use. Our findings indicate that there is evidence of an association between any use of BP and reduced CRC risk. However, this subject deserves further investigation. PMID- 23451732 TI - Rosacea under the microscope: characteristic histological findings. AB - Rosacea is a common facial dermatosis that is seldom biopsied; thus, histological aspects have not been well described. Biopsies are generally performed in the presence of atypical symptoms (e.g. granulomas). Differential diagnosis with sarcoidosis, lupus miliaris or lupus erythematosus is another indication for biopsy. There are few published studies addressing the microscopic aspects of rosacea and describing the histological and immunohistochemical features of this disease. While some textbooks consider the microscopic signs of rosacea to be non diagnostic, experienced dermatopathologists are generally able to make the diagnosis via histology. This article discusses the specific combinations of histological features that are highly suggestive of rosacea. PMID- 23451733 TI - The influence of cis-acting P1 protein and translational elements on the expression of Potato virus Y helper-component proteinase (HCPro) in heterologous systems and its suppression of silencing activity. AB - In the Potyvirus genus, the P1 protein is the first N-terminal product processed from the viral polyprotein, followed by the helper-component proteinase (HCPro). In silencing suppression patch assays, we found that Potato virus Y (PVY) HCPro expressed from a P1-HCPro sequence increased the accumulation of a reporter gene, whereas protein expressed from an HCPro sequence did not, even with P1 supplied in trans. This enhancing effect of P1 has been noted in other potyviruses, but has remained unexplained. We analysed the accumulation of PVY HCPro in infiltrated tissues and found that it was higher when expressed from P1-HCPro than from HCPro sequences. Co-expression of heterologous suppressors increased the steady-state level of mRNA expressed from the HCPro sequence, but not that of protein. This suggests that, in the absence of P1 upstream, either HCPro acquires a conformation that affects negatively its activity or stability, or that its translation is reduced. To test these options, we purified HCPro expressed in the presence or absence of upstream P1, and found no difference in purification pattern and final soluble state. By contrast, alteration of the Kozak context in the HCPro mRNA sequence to favour translation increased partially suppressor accumulation and activity. Furthermore, protein activity was not lower than in protein expressed from P1-HCPro sequences. Thus, a direct role for P1 on HCPro suppressor activity or stability, by influencing its conformation during translation, can be excluded. However, P1 could still have an indirect effect favouring HCPro accumulation. Our data highlight the relevance of cis-acting translational elements in the heterologous expression of HCPro. PMID- 23451734 TI - Deployment of the Burkholderia glumae type III secretion system as an efficient tool for translocating pathogen effectors to monocot cells. AB - Genome sequences of plant fungal pathogens have enabled the identification of effectors that cooperatively modulate the cellular environment for successful fungal growth and suppress host defense. Identification and characterization of novel effector proteins are crucial for understanding pathogen virulence and host plant defense mechanisms. Previous reports indicate that the Pseudomonas syringae pv. tomato DC3000 type III secretion system (T3SS) can be used to study how non bacterial effectors manipulate dicot plant cell function using the effector detector vector (pEDV) system. Here we report a pEDV-based effector delivery system in which the T3SS of Burkholderia glumae, an emerging rice pathogen, is used to translocate the AVR-Pik and AVR-Pii effectors of the fungal pathogen Magnaporthe oryzae to rice cytoplasm. The translocated AVR-Pik and AVR-Pii showed avirulence activity when tested in rice cultivars containing the cognate R genes. AVR-Pik reduced and delayed the hypersensitive response triggered by B. glumae in the non-host plant Nicotiana benthamiana, indicative of an immunosuppressive virulence activity. AVR proteins fused with fluorescent protein and nuclear localization signal were delivered by B. glumae T3SS and observed in the nuclei of infected cells in rice, wheat, barley and N. benthamiana. Our bacterial T3SS enabled eukaryotic effector delivery and subcellular localization assays provide a useful method for identifying and studying effector functions in monocot plants. PMID- 23451735 TI - An overview of the DSM-5: changes, controversy, and implications for psychiatric nursing. AB - Scheduled for publication in May 2013, the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), will guide clinical diagnoses, treatment plans, medication choices and protocols, insurance reimbursements, and research agendas throughout the United States. It will also serve as a reference manual for clinicians around the world. This primary diagnostic source used by psychiatric and mental health providers is undergoing significant change in organization and content relative to the previous edition. This article provides a general overview of what to expect in the DSM-5, highlighting major aspects of the revision. Included is a list of the proposed diagnostic categories and an overview of some of the debate and discussion accompanying the changes. Implications for psychiatric nurses and psychiatric nursing are presented. PMID- 23451736 TI - DSM-5: historical perspectives. AB - The first major attempts to categorize psychiatric disorders in the United States occurred in the mid-1800s, when census data were collected that included "insanity" and "idiocy" of household members. In Europe, Florence Nightingale promoted the use of non-fatal disease classification for morbidity and treatment in 1860. By the late 1800s, Kraepelin categorized disorders, and his sixth edition of the Compendium der Psychiatrie was widely adopted by both Europeans and Americans. In 1952, the American Psychiatric Association published the first edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Since then, the manual has been periodically updated, expanded, and edited to reflect social and scientific beliefs about the etiology and categorization of psychiatric illness and care. In this article, we explore the historical and ongoing development of the DSM and its implications for psychiatric nurses. PMID- 23451737 TI - How culture is assessed in the DSM-5. AB - Reports regarding the proposed changes in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) indicate there will be expanded and more clearly defined mental health assessment information regarding culture and diversity. This change is in response to the concerns of educators, practitioners, and researchers regarding how culture was prioritized, defined, and assessed within the fourth edition, text revision (DSM-IV-TR) of the manual. The purposes of this article are to discuss (a) how culture was assessed in the DSM-IV-TR; (b) what new assessment cultural factors are proposed for inclusion in the DSM-5; and (c) implications for psychiatric-mental health nursing education, practice, and research based on the inclusion of the proposed cultural assessment changes. PMID- 23451738 TI - The complete mitochondrial genome sequence of Trichiurus nanhaiensis (Perciformes: Trichiuridae). AB - The Naihai cutlassfish (Trichiurus nanhaiensis, Wang and Xu, 1992) is an important commercial fish species in South China Sea, while the taxonomy is still controversial. The 17,060 base pair mitochondrial genome sequence of T. nanhaiensis was determined, which shared the features with the other bony fishes for gene arrangement, nucleotide composition, and tRNA structures except for tRNA(pro) gene. The termination-associated sequence, central conserved sequence blocks (CSB-F, CSB-E, CSB-D), and conserved sequence blocks (CSB-1, CSB-2, CSB 3), as well as tandem repeats were detected in the control region. Phylogenetic analyses revealed that T. nanhaiensis together with T. lepturus, T. japonicus, and T. brevis formed a clade of Trichiurus based on the complete Cyt b genes and partial CO I genes; meanwhile, the closest relationship was established between T. nanhaiensis and T. lepturus. PMID- 23451739 TI - Paget disease of the breast with invasion from nipple skin into the dermis. PMID- 23451741 TI - Second opinions: pathologists' preventive medicine. PMID- 23451740 TI - Soundalike test names create confusion. PMID- 23451742 TI - Anatomic winds of change blow in from Chicago: topics from faculty at Feinberg School of Medicine, Northwestern University, and Northwestern Memorial Hospital. PMID- 23451743 TI - Making the diagnosis of frontotemporal lobar degeneration. AB - CONTEXT: Autopsy evaluation of the brain of a patient with frontotemporal dementia (FTD) can be daunting to the general pathologist. At some point in their training, most pathologists learn about Pick disease, and can recognize Pick bodies, the morphologic hallmark of Pick disease. Pick disease is a type of frontotemporal lobar degeneration (FTLD), the general category of pathologic process underlying most cases of FTD. The 2 major categories of pathologic FTLD are tauopathies (FTLD-tau) and ubiquitinopathies (FTLD-U). Pick disease is one of the FTLD-tau subtypes and is termed FTLD-tau (PiD). OBJECTIVE: To "demystify" FTLDs, and to demonstrate that subtypes of FTLD-tau and FTLD-U can be easily determined by following a logical, stepwise, histochemical, and immunohistochemical investigation of the FTD autopsy brain. DATA SOURCES: Previously published peer-reviewed articles. CONCLUSIONS: The hope is that this article will be a useful reference for the general pathologist faced with performing a brain autopsy on a decedent with frontotemporal dementia. PMID- 23451744 TI - Pathologic examination of fetal and placental tissue obtained by dilation and evacuation. AB - CONTEXT: Dilation and evacuation (D&E) is an alternative method to induction of labor for pregnancy termination and intrauterine fetal demise, and it is the most common mode of second-trimester uterine evacuation in the United States. Many D&E specimens are examined in surgical pathology, and there is little information available in surgical pathology textbooks or the literature to assist pathologists in these examinations. OBJECTIVE: To provide an overview of the D&E procedure, discuss related legal issues, provide guidelines for routine pathologic examination of D&E specimens, and demonstrate the importance of careful pathologic examination of D&E specimens. DATA SOURCES: Case-derived material and literature review. CONCLUSIONS: Pathologic examination of D&E specimens has been understudied. However, the available literature and our experience support the fact that careful pathologic examination of D&E specimens can identify significant fetal and placental changes that can confirm clinical diagnoses or provide definitive diagnosis, assist in explaining the cause of intrauterine fetal demise, and identify unexpected anomalies that may provide further clues to a diagnostic syndrome or mechanism of anomaly formation. PMID- 23451745 TI - Dysplastic lesions in inflammatory bowel disease: molecular pathogenesis to morphology. AB - Context.-Inflammatory bowel disease (IBD) is a long-standing chronic active inflammatory process in the bowel with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic active inflammatory processes contribute to multistage progression of human cancer development, including reactive oxygen and nitrogen species, aberrant arachidonic acid metabolites and cytokines/growth factors, and immune dysfunction. These molecular events in IBD lead to genetic abnormality and promote aberrant cell proliferation, which further lead to epithelial changes encompassing a broad spectrum from inflammation-induced hyperplasia to dysplasia. Objective.-To review the (1) epidemiologic and molecular pathogenesis of the risk for colorectal cancer in IBD, (2) morphologic characterization, biomarker(s), and classification of dysplastic lesions, and (3) clinical management of dysplastic lesions arising in IBD. Data Sources.-The different IBD-related dysplastic lesions are illustrated by using morphology in conjunction with molecular pathways, and the "field cancerization" theory and its potential significance are discussed with a review of the literature. Conclusions.-Patients with IBD are at increased risk of developing colorectal cancer. The risk of developing carcinoma is related to the extent/duration/activity of the patient's disease. There is no consensus regarding the extent of carcinoma risk associated with IBD; however, all would agree that patients with IBD represent a group at significant risk for developing carcinoma and as such, warrant adequate surveillance and prevention. With better screening modalities and detection/characterization of dysplastic lesions, IBD associated serrated lesions, and "field cancerization," we will improve our understanding of and approach to risk stratification. PMID- 23451746 TI - Renal morphologic lesions reminiscent of diabetic nephropathy. AB - CONTEXT: Nodular, intercapillary glomerulosclerotic lesions resembling Kimmelstiel-Wilson nodules commonly observed in diabetic nephropathy can also be seen in patients without any clinical history or evidence of diabetes. OBJECTIVES: To discuss the pathobiology of lesions reminiscent of diabetes nephropathy, including light-chain deposition disease, amyloidosis, immunotactoid nephropathy, the membranoproliferative form of glomerulonephritis, and idiopathic nodular glomerulosclerosis, and how to differentiate them from diabetic nephropathy. DATA SOURCES: Published literature and authors' personal experience. CONCLUSIONS: The well-formed, intercapillary, nodular mesangial lesions, along with thickened glomerular basement membranes and tubular basement membranes, and hyaline arteriolosclerosis are virtually pathognomic of diabetic nephropathy. However, the pathologist must exclude lesions reminiscent of diabetic nephropathy by performing special stains on histologic sections, immunofluorescence, and electron microscopic studies. PMID- 23451747 TI - Lymphoid proliferations associated with human immunodeficiency virus infection. AB - CONTEXT: Individuals who are immune deficient are at an increased risk for developing lymphoproliferative lesions and lymphomas. Human immunodeficiency virus (HIV) infection is 1 of 4 clinical settings associated with immunodeficiency recognized by the World Health Organization (WHO) in which there is an increased incidence of lymphoma and other lymphoproliferative disorders. OBJECTIVES: To describe the major categories of benign lymphoid proliferations, including progressive HIV-related lymphadenopathy, benign lymphoepithelial cystic lesions, and multicentric Castleman disease, as well as the different types of HIV-related lymphomas as defined by the WHO. The characteristic morphologic, immunophenotypic, and genetic features of the different entities will be discussed in addition to some of the pathogenetic mechanisms. DATA SOURCES: The WHO classification of tumors of hematopoietic and lymphoid tissues (2001 and 2008), published literature from PubMed (National Library of Medicine), published textbooks, and primary material from the authors' current and previous institutions. CONCLUSIONS: HIV infection represents one of the clinical settings recognized by the WHO in which immunodeficiency-related lymphoproliferative disorders may arise. Although most lymphomas that arise in patients with HIV infection are diffuse, aggressive B-cell lesions, other lesions, which are "benign" lymphoid proliferations, may also be associated with significant clinical consequences. These lymphoproliferations, like many other immunodeficiency-associated lymphoproliferative disorders, are often difficult to classify. Studies of HIV-associated lymphoid proliferations will continue to increase our understanding of both the immune system and lymphomagenesis. PMID- 23451748 TI - Primary adenocarcinoma of the urinary bladder: differential diagnosis and clinical relevance. AB - CONTEXT: Glandular lesions of the urinary bladder include a broad spectrum of entities ranging from completely benign glandular lesions to primary and secondary malignancies. Common benign bladder lesions that exhibit glandular differentiation include cystitis cystica, cystitis glandularis, von Brunn nests, nephrogenic adenoma, intestinal metaplasia, urachal remnant, endometriosis, and prostatic-type polyp. The World Health Organization defines primary adenocarcinoma of the bladder as an epithelial malignancy with pure glandular differentiation without evidence of typical urothelial carcinoma. Malignant lesions that should be included in the differential diagnosis of a primary adenocarcinoma of the bladder include noninvasive and invasive urothelial carcinoma with glandular differentiation and secondary malignancies involving the bladder by direct extension or metastasis. The recognition and distinction of these different entities may be a challenge for pathologists, but they are of great clinical importance. OBJECTIVE: To review features of primary bladder adenocarcinoma as well as those entities that need to be differentiated from primary bladder adenocarcinoma, with emphasis on clinical findings, pathologic characteristics, and immunoprofiles. DATA SOURCES: Selected original articles published in the PubMed service of the US National Library of Medicine. CONCLUSIONS: The accurate diagnosis of adenocarcinoma of the urinary bladder is important and challenging. It has to prompt an extensive clinical workup to rule out other glandular lesions in the urinary bladder, especially the possibility of secondary involvement of the bladder by an adenocarcinoma from a different site. PMID- 23451749 TI - Lymphoproliferative neoplasms of the lung: a review. AB - CONTEXT: Diagnosis and classification of lymphomas are based on the morphologic, immunologic, and genetic features that the lesional cells share with their normal B and T lymphocyte counterparts. Primary pulmonary lymphomas account for 0.3% of primary lung neoplasms and less than 0.5% of all lymphomas. OBJECTIVE: To describe and summarize the clinical and histopathologic features of the primary pulmonary lymphoma and secondary involvement of the lung by lymphoma. DATA SOURCES: Peer-reviewed published literature and personal experience. CONCLUSIONS: Diagnosis of clonal lymphoid proliferations in the lung has evolved owing to the greater utility of molecular and flow cytometric analysis of tissue. Further studies are needed to best define the clinical and prognostic features, as well as search for targeted therapy for these patients with rare neoplasms. PMID- 23451750 TI - Radiology estimates of viable tumor percentage in hepatocellular carcinoma ablation cavities correlate poorly with pathology assessment. AB - CONTEXT: No study has evaluated radiology/pathology correlation of percentage viable tumor (PVT) estimates in ablated hepatocellular carcinoma (HCC) to examine the reliability of radiologic estimates. OBJECTIVE: To determine how well interdisciplinary PVT estimates correlate and identify pathologic factors that influence this correlation. DESIGN: Pathologists and radiologists established blinded PVT estimates in 22 HCC ablation cavities. Paired sample t tests examined the differences between the interdisciplinary estimates. RESULTS: Fifteen cavities had pathologic viable tumor (VT) (68%) and 6 had radiographic VT (22%). Radiology's sensitivity for detecting VT was 40% and the specificity was 100%. Pathology detected significantly more VT than radiology (pathology mean = 22.3% versus radiology mean = 2.6%; P = .005). Five cavities had tumor growth in a discontinuous rim pattern, 7 in a nodular pattern, and 3 in a solid pattern. Radiology did not detect VT in cavities with a discontinuous rim pattern (sensitivity = 0%) but did detect VT in 3 cavities with a nodular pattern (sensitivity = 43%), and in all cavities with a solid pattern (sensitivity = 100%). There was no significant difference in PVT estimates in cavities 3.5 cm or larger (P = .07), but there was a significant difference in cavities smaller than 3.5 cm (P = .01). CONCLUSION: This study clarifies that the risk of underestimation by imaging is greatest in small lesions (<3.5 cm), though the sensitivity of detection depends primarily on the tumor growth pattern within the cavity. This underestimation raises the question of whether basing treatment decisions on a radiologic impression of complete ablation is valid. PMID- 23451751 TI - Utility and diagnostic accuracy of ureteroscopic biopsy in upper tract urothelial carcinoma. AB - CONTEXT: Ureteroscopic biopsy is the gold standard for the histopathologic diagnosis of urothelial carcinoma of the upper urinary tract. OBJECTIVE: To assess the accuracy of endoscopically obtained biopsy samples in diagnosing, grading, and staging urothelial carcinoma and correlate diagnostic findings to biopsy sample size. DESIGN: We retrospectively reviewed endoscopic biopsies of the ureter, renal pelvis, and ureteropelvic junction from 2008 to 2011. Biopsy diagnoses that were discordant with follow-up pathology and/or ureteroscopic impression were re-reviewed and samples were immunohistochemically analyzed. RESULTS: Endoscopic biopsies (n = 118) yielded a sensitivity of 85.4% for the ureter (n = 79), 77.8% for the renal pelvis (n = 37), and 100% for the ureteropelvic junction (n = 2). A specificity of 100% for all locations and a diagnostic accuracy of 98.3% were identified. The median sample size was 0.3 cm for true positives, 0.3 cm for true negatives, and 0.2 cm for false negatives with no statistical significance. We found that 87.1% of tumors diagnosed on biopsy had concordant grade and 60.0% had concordant pT stage with follow-up surgical resections (n = 43) and biopsies (n = 24). Biopsy samples with concordant tumor grades (mean = 0.6 cm) compared with follow-up resection were larger than biopsy samples with discordant grades (mean = 0.3 cm) (P = .04). CONCLUSIONS: Though highly specific, endoscopic biopsy does provide a significant false-negative rate owing to both sampling and diagnostic errors when assessing the upper urinary tract for urothelial carcinoma. Tumor grading is accurate, particularly with larger tissue samples, but tumor staging is unreliable. PMID- 23451752 TI - Validation and optimization of criteria for manual smear review following automated blood cell analysis in a large university hospital. AB - CONTEXT: Each laboratory should have criteria for manual smear review that limit workload without affecting patient care. The International Consensus Group for Hematology Review established guidelines for action after automated blood cell analysis in 2005. OBJECTIVE: To compare the consensus group criteria with our laboratory criteria and optimize them for better efficiency. DESIGN: A total of 2114 first-time samples were collected consecutively from daily workload and were used to compare 2 criteria as well as establish the optimized criteria. Another set of 891 samples was used to validate the optimized criteria. All samples were run on either Sysmex XE-5000 or Coulter LH750 hematology analyzers and were investigated by manual smear review. The efficiency of each set of criteria was compared and optimized to obtain better efficiency, an acceptable review rate, and a low false-negative rate. RESULTS: From 2114 samples, 368 (17.40%) had positive smear results. Compared with that of our laboratory criteria, the efficiency of the consensus group criteria was higher (83.63% versus 78.86%, P < .001), the review rate was higher (29.33% versus 22.37%, P < .001), and the false negative rate was lower (2.22% versus 8.09%, P < .001). After optimizing the rules, we obtained an efficiency of 87.13%, a review rate of 24.22%, and a false negative rate of 2.98%. We validated the optimized criteria with another set of samples, and the efficiency, review rate, and false-negative rate were 87.32%, 25.25%, and 1.12%, respectively. CONCLUSIONS: Each laboratory should verify the criteria for smear review, based on the International Consensus Group for Hematology Review, and optimize them to maximize efficiency. PMID- 23451753 TI - Transcription factor E3 protein-positive perivascular epithelioid cell tumor of the appendix presenting as acute appendicitis: a case report and review of the literature. AB - Perivascular epithelioid cell tumors (PEComas) are a group of mesenchymal tumors that coexpress melanocytic and smooth muscle markers; their exact origin remains unknown. This group includes renal angiomyolipoma, clear cell sugar tumor, and lymphangioleiomyomatosis, although the term perivascular epithelioid cell tumors is currently used for lesions that exhibit a similar morphologic and immunohistochemical profile throughout the human body. Recently, a distinct subset of PEComas has been shown to harbor transcription factor E3 gene (TFE3) fusions. We report, for the first time, a unique case of TFE3-positive PEComa presenting as acute appendicitis in a 24-year-old woman. Microscopically, the tumor was composed of benign-appearing epithelioid cells with clear and eosinophilic cytoplasm, and arranged in nested and alveolar patterns. Immunohistochemical studies showed diffuse strong positivity for neuron-specific enolase, TFE3, and progesterone receptor and focal strong positivity for human melanoma black-45 (HMB-45) and melanocyte differentiation antigen (Melan-A) in the tumor cells. Although rare, PEComa should be included in the differential diagnosis of mesenchymal tumors of the appendix. PMID- 23451754 TI - Undifferentiated endometrial carcinoma: a diagnosis frequently overlooked. AB - Undifferentiated endometrial carcinoma (UEC) is a relatively uncommon neoplasm with only few studies published thus far. It has always been a diagnostic challenge because of the lack of proper definition cited in most of the standard textbooks. Recently however, a few studies have highlighted the clinicopathologic features of UEC. The distinctive morphology of UEC was noted by the group from MD Anderson Cancer Center, which enabled them to establish the defining criteria. It appears to be more aggressive than endometrial endometrioid adenocarcinoma, FIGO (International Federation of Gynecology and Obstetrics) grade 3, its main differential diagnosis. Proper recognition of this entity is important owing to its aggressive behavior. PMID- 23451755 TI - Separation anxiety in children ages 4 through 9 with oral clefts. AB - Background : Psychosocial research on children with oral clefts (OCs), i.e., clefts of the lip, palate, or lip and palate, has suggested that these children may have higher rates of anxiety in general, but overall results have been equivocal. In this study we estimated the prevalence of separation anxiety disorder (SAD) in a population-based sample of children with OCs and identified associated risk factors. Methods : Parents of 279 children with OCs, identified through three state birth defect registries, responded to a postal survey that included the Separation Anxiety subscale of the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and items regarding the child's OC and its sequelae, parent and child health, parent mental health, family structure, and socioeconomic status indicators. Associations with SA were evaluated using bivariate and multivariate statistics. Results : One quarter (24%) of the children screened positive for SAD, which was substantially higher than the U.S. child population estimates of 3% to 5%. OC-related impairments in speaking and eating more than doubled the risk of SAD, as did lower socioeconomic status and lower maternal health rating. Maternal mental health and marital status remained in the logistic model but were not significant. Conclusions : Children with OCs appear to be at increased risk for SAD as measured by the SCARED instrument. OC related problems with speech and eating more than doubled the risk of SAD. The use of targeted screening tools may help refine our understanding of psychosocial adjustment in children with OCs. PMID- 23451756 TI - Analysis of interpeak latencies of brainstem auditory evoked potential waveforms during microvascular decompression of cranial nerve VII for hemifacial spasm. AB - OBJECT: Microvascular decompression (MVD) of the facial nerve is an effective treatment for patients with hemifacial spasm. Intraoperative monitoring of brainstem auditory evoked potentials (BAEPs) during MVD can reduce the incidence of hearing loss. In this study the authors' goal was to evaluate changes in interpeak latencies (IPLs) of Waves I-V, Waves III-V, and Waves I-III of BAEP Waveforms I, III, and V during MVD and correlate them with postoperative hearing loss. To date, no such study has been performed. Hearing loss is defined as nonuseful hearing (Class C/D), which is a pure tone average of more than 50 dB and/or speech discrimination score of less than 50%. METHODS: The authors performed a retrospective analysis of IPLs of BAEPs in 93 patients who underwent intraoperative BAEP monitoring during MVD. Patients who did not have hearing loss were in Class A/B and those who had hearing loss were in Class C/D. RESULTS: Binary logistic regression analysis of independent IPL variables was performed. A maximum change in IPLs of Waves I-III and Waves I-V and on-skin change in IPLs of Waves I-V increases the odds of hearing loss. However, on adjusting the same variables for loss of response, change in IPLs did not increase the odds of hearing loss. CONCLUSIONS: Changes in IPL measurements did not increase the odds of postoperative hearing loss. This information might be helpful in evaluating the value of IPLs as alarm criteria during MVD to prevent hearing loss. PMID- 23451757 TI - Design and selection of soy breads used for evaluating isoflavone bioavailability in clinical trials. AB - To modulate isoflavone aglycone composition within a soy functional food, soy ingredients were processed and evaluated in a soy bread system intended for clinical trials. A soy flour/soy milk mixture (SM) was boiled, fermented, steamed, or roasted prior to dough preparation. The isoflavone compositions of five processed SM and their corresponding breads combined with and without beta glucosidase-rich almonds were examined using HPLC. Isoflavone malonyl-glucosides (>80%) were converted into acetyl and simple glucoside forms (substrates more favorable for beta-glucosidase) in steamed and roasted SM. Their corresponding breads had isoflavones predominately as aglycones (~75%) with soy-almond bread with steamed SM being more consumer acceptable than roasted. Isoflavone composition in soy bread was stable during frozen storage and toasting. A suitable glycoside-rich soy bread (31.6 +/- 2.1 mg aglycone equiv/slice) using unprocessed SM and an aglycone-rich soy-almond bread (31.1 +/- 1.9 mg aglycone equiv/slice) using steamed SM were developed to evaluate fundamental questions of isoflavone bioavailability in clinical trials. PMID- 23451758 TI - A new Raman spectroscopic probe of both the protonation state and noncovalent interactions of histidine residues. AB - The amino acid histidine (His) has a number of unique roles that can dictate function in proteins, and these roles are typically conferred through noncovalent interactions that depend on the protonation state of His's 4-substituted imidazole ring. His's protonation state can vary near physiological pH, and a probe of His's variable protonation state and its resulting noncovalent interactions that has both high time resolution and no sample limitations could find wide use in determining the role of particular His residues in proteins. Here we use a classic deuterium exchange reaction to replace the C2-H hydrogen atom of the His imidazole ring with deuterium, leading to a unique aromatic C2-D stretching vibration whose frequency is sensitive to environmental changes across the entire imidazole ring. Using nonresonant Raman spectroscopy, we demonstrate using model compounds that the frequency of this C2-D vibration shifts by 35 cm( 1) upon changes in the His protonation state. The C2-D band is a very weak infrared absorber, so this vibration is not expected to be useful in infrared transmission experiments for proteins. Solvent-dependent Raman experiments indicate that the C2-D band of the neutral imidazole ring is sensitive to H bonding interaction with donors and acceptors of varying strengths, suggesting that the C2-D frequency can be used to identify H-bonding partners of specific His residues. Raman spectra at varying concentrations of Cu(2+) also show the C2 D band's sensitivity to metal coordination, with differences due to changes in the coordination environment. The strong Raman signal of this band and the sampling flexibility of Raman spectroscopy suggest that this vibration could be very useful in documenting the local role of His residues in many His-containing proteins and protein assemblies. PMID- 23451759 TI - A comparison of health-related quality of life (health utility) between insulin degludec and insulin glargine: a meta-analysis of phase 3 trials. AB - AIM: To evaluate health-related quality of life (health utility) scores in patients with diabetes receiving insulin degludec (IDeg) or insulin glargine (IGlar). METHODS: Patient-level data from six, randomized, controlled, open label, multicentre, confirmatory, treat-to-target trials of 26- or 52 weeks' duration were pooled in this analysis. The Short Form 36 (SF-36) version-2 health questionnaire was completed by patients at baseline and end-of-trial. SF-36 scores for 4001 individual patients were then mapped onto the EuroQol-5D health utility scale, which has a range from -0.59 (a state worse than death) to 1.00 (perfect health). RESULTS: IDeg treatment exhibited a significant improvement in health status of 0.005 (CI: 0.0006; 0.009) points compared with IGlar (p < 0.024). Gender, region, trial and age also had a significant influence on estimated utility scores as did baseline utility scores, p < 0.05. Prior to the removal of interaction variables a difference of 0.008 points was observed, p < 0.045. Previous insulin treatment did not have an impact on the final outcome. CONCLUSION: This study shows that IDeg is associated with a modest, but statistically significant, improvement in health utility compared with IGlar in patients with diabetes. PMID- 23451761 TI - Nickel-catalyzed ring-opening alkylative coupling of enone with methylenecyclopropane in the presence of triethylborane. AB - Nickel-catalyzed alkylative coupling of an enone or enal with methylenecyclopropane in the presence of triethylborane was achieved via stereospecific proximal C-C bond cleavage of methylenecyclopropane. With the use of methylenecyclopropane possessing an acyclic alkyl substituent, this reaction was also accompanied by the beta-hydrogen elimination. PMID- 23451760 TI - Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. AB - Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs. PMID- 23451762 TI - Reduction in vasovagal reaction rate in young first-time blood donors by collecting 350 mL rather than 450 mL. AB - BACKGROUND: There is a paucity of studies on the magnitude of reduction of vasovagal reaction by reduced collection volume. This study was thus conducted to determine the difference in reaction rates between two collection volumes among the young first-time donors who are at particular risk of reaction. STUDY DESIGN AND METHODS: This retrospective study analyzed 38,436 whole blood donations made by young (aged 16 to 18 years) first-time donors. The effect of collection volume on vasovagal reaction was compared among different weight subgroups for both sexes by chi-square test. RESULTS: For females in all weight subgroups and two of the male lower-weight subgroups, the reduction percentages ranged from 35% to 58% (p < 0.05). It was also noted that, among the females, a higher weight was associated with a higher percent reduction in the reaction rate. CONCLUSION: With reduced collection volume, this study detected large and significant reduction in reaction rates among all females, as well as lower-weight males. PMID- 23451763 TI - A Myb transcription factor regulates genes of the phenylalanine pathway in maritime pine. AB - During the life cycles of conifer trees, such as maritime pine (Pinus pinaster Ait.), large quantities of carbon skeletons are irreversibly immobilized in the wood. In energetic terms this is an expensive process, in which carbon from photosynthesis is channelled through the shikimate pathway for the biosynthesis of phenylpropanoids. This crucial metabolic pathway is finely regulated, primarily through transcriptional control, and because phenylalanine is the precursor for phenylpropanoid biosynthesis, the precise regulation of phenylalanine synthesis and use should occur simultaneously. The promoters of three genes encoding the enzymes prephenate aminotransferase (PAT), phenylalanine ammonia lyase (PAL) and glutamine synthetase (GS1b) contain AC elements involved in the transcriptional activation mediated by R2R3-Myb factors. We have examined the capacity of the R2R3-Myb transcription factors Myb1, Myb4 and Myb8 to co regulate the expression of PAT, PAL and GS1b. Only Myb8 was able to activate the transcription of the three genes. Moreover, the expression of this transcription factor is higher in lignified tissues, in which a high demand for phenylpropanoids exits. In a gain-of-function experiment, we have shown that Myb8 can specifically bind a well-conserved eight-nucleotide-long AC-II element in the promoter regions of PAT, PAL and GS1b, thereby activating their expression. Our results show that Myb8 regulates the expression of these genes involved in phenylalanine metabolism, which is required for channelling photosynthetic carbon to promote wood formation. The co-localization of PAT, PAL, GS1b and MYB8 transcripts in vascular cells further supports this conclusion. PMID- 23451764 TI - Randomised clinical trial: the effects of daikenchuto, TU-100, on gastrointestinal and colonic transit, anorectal and bowel function in female patients with functional constipation. AB - BACKGROUND: Daikenchuto, a Japanese herbal medicine used for post-operative ileus and constipation, dose dependently stimulates gastrointestinal (GI) motility and decreases rectal compliance and sensation. Effects of TU-100 (commercial form of daikenchuto) in adults with constipation are unknown. AIM: To compare the effects of oral TU-100, 2.5 g t.d.s. or 5 g t.d.s. and placebo t.d.s. on GI and colonic transit (CT), rectal compliance (RC) and sensation thresholds (RST), anal sphincter pressures (ASP) and bowel function in female patients with functional constipation (FC). METHODS: We conducted a single-centre, randomised, parallel group, double-blind, pharmacodynamic study; 45 female patients with FC without evidence of rectal evacuation disorder were assigned to 28 days' treatment with oral placebo or TU-100 (Tsumura USA, Princeton, NJ, USA). Demographic data and CT were measured at baseline and randomisation stratified by baseline CT (GC> or <1.9) and by BMI (<25 or >=25 kg/m(2) ). At the end of treatment period, we measured GI and CT by scintigraphy, RST and RC by barostat, ASP by manometry, psychosensory sensations, bowel function by daily diary and quality of life (QOL). The study had power to detect effect sizes of 33% (CT), 40% (RC) and 46% (RST). Statistical analysis included BMI as covariate. RESULTS: TU-100 had no significant effects on GI or CT, RC, ASP, recto-anal pressure difference, or RST. The 5 g t.d.s./day dose was associated with lower RST for first sensation and gas (unadjusted P: 0.045 and 0.024 respectively). There were no treatment effects on psychosensory symptoms, stool frequency, stool consistency or QOL. CONCLUSION: Mechanisms underlying the observed clinical benefit of TU-100 remain unclear (ClinicalTrials.gov NCT01139216). PMID- 23451767 TI - Serum concentration of IL-17, IL-23 and TNF-alpha among patients with chronic spontaneous urticaria: association with disease activity and autologous serum skin test. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disorder, which is considered in a subset of patients to be an autoimmune disorder. T helper 17 (Th17) cells are crucially involved in the pathogenesis of some autoimmune diseases. OBJECTIVES: Our aim was to test the association of Th17 with CSU. We examined interleukin (IL)-17, IL-23 and tumor necrosis factor-alpha (TNF-alpha) serum levels in CSU patients and studied their association with urticaria activity and autologous serum skin test (ASST). SUBJECTS AND METHODS: Serum concentration of IL-17, IL-23 and TNF-alpha were measured in 75 patients with CSU and 30 healthy control subjects. Disease activity was assessed by using urticaria activity score (UAS) as recommended by EAACI/GA(2)LEN/EDF/WAO Guidelines. RESULTS: Serum concentration of IL-17, IL-23 and TNF-alpha were significantly higher in CSU patients as compared with the healthy control subjects (mean: 35.51 +/- 31.14 vs. 4.60 +/- 1.38 pg/mL; P < 0.001, 38.95 +/- 27.82 vs. 9.87 +/- 4.62 pg/mL; P > 0.001 and 17.93 +/- 6.05 vs. 6.87 +/- 3.73 pg/mL; P = 0.004, respectively). There were significant positive correlation between serum IL-17, IL-23, TNF-alpha and disease activity assessed by cumulative UAS for 7 days before blood sampling. The Serum concentration of IL-17, IL-23 and TNF-alpha were also significantly higher in ASST positive patients than in ASST negative patients. CONCLUSION: Our results showed high serum levels of IL-17, IL-23 and TNF-alpha among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of this important and common skin disease. It also may provide the rationale for new treatment strategies in chronic urticaria. PMID- 23451766 TI - Lipidomics of familial longevity. AB - Middle-aged offspring of nonagenarians, as compared to their spouses (controls), show a favorable lipid metabolism marked by larger LDL particle size in men and lower total triglyceride levels in women. To investigate which specific lipids associate with familial longevity, we explore the plasma lipidome by measuring 128 lipid species using liquid chromatography coupled to mass spectrometry in 1526 offspring of nonagenarians (59 years +/- 6.6) and 675 (59 years +/- 7.4) controls from the Leiden Longevity Study. In men, no significant differences were observed between offspring and controls. In women, however, 19 lipid species associated with familial longevity. Female offspring showed higher levels of ether phosphocholine (PC) and sphingomyelin (SM) species (3.5-8.7%) and lower levels of phosphoethanolamine PE (38:6) and long-chain triglycerides (TG) (9.4 12.4%). The association with familial longevity of two ether PC and four SM species was independent of total triglyceride levels. In addition, the longevity associated lipid profile was characterized by a higher ratio of monounsaturated (MUFA) over polyunsaturated (PUFA) lipid species, suggesting that female offspring have a plasma lipidome less prone to oxidative stress. Ether PC and SM species were identified as novel longevity markers in females, independent of total triglycerides levels. Several longevity-associated lipids correlated with a lower risk of hypertension and diabetes in the Leiden Longevity Study cohort. This sex-specific lipid signature marks familial longevity and may suggest a plasma lipidome with a better antioxidant capacity, lower lipid peroxidation and inflammatory precursors, and an efficient beta-oxidation function. PMID- 23451765 TI - Research review: Social motivation and oxytocin in autism--implications for joint attention development and intervention. AB - BACKGROUND AND SCOPE: The social motivation hypothesis (SMH) suggests that individuals with autism spectrum disorders (ASD) are less intrinsically rewarded by social stimuli than their neurotypical peers. This difference in social motivation has been posited as a factor contributing to social deficits in ASD. Social motivation is thought to involve the neuropeptide oxytocin. Here, we review the evidence for oxytocin effects in ASD, and discuss its potential role in one important social cognitive behavior. METHODS: Systematic searches were conducted using the PsychINFO and MEDLINE databases and the search terms 'oxytocin' and 'autism'; the same databases were used for separate searches for 'joint attention', 'intervention', and 'autism', using the same inclusion criteria as an earlier 2011 review but updating it for the period 2010 to October 2012. FINDINGS: Several studies suggest that giving oxytocin to both individuals with ASD and neurotypical individuals can enhance performance on social cognitive tasks. Studies that have attempted to intervene in joint attention in ASD suggest that social motivation may be a particular obstacle to lasting effects. CONCLUSIONS: The review of the evidence for the SMH suggests a potential role for oxytocin in social motivation deficits in ASD. Because of its importance for later communicative and social development, the focus here is on implications of oxytocin and social motivation in the development of and interventions in joint attention. Joint attention is a central impairment in ASD, and as a result is the focus of several behavioral interventions. In describing this previous research on joint attention interventions in ASD, we pay particular attention to problems encountered in such studies, and propose ways that oxytocin may facilitate behavioral intervention in this area. For future research, integrating behavioral and pharmacological interventions (oxytocin administration) would be a worthwhile experimental direction to improve understanding of the role of oxytocin in ASD and help optimize outcomes for children with ASD. PMID- 23451768 TI - Ferrate(VI)-induced arsenite and arsenate removal by in situ structural incorporation into magnetic iron(III) oxide nanoparticles. AB - We report the first example of arsenite and arsenate removal from water by incorporation of arsenic into the structure of nanocrystalline iron(III) oxide. Specifically, we show the capability to trap arsenic into the crystal structure of gamma-Fe2O3 nanoparticles that are in situ formed during treatment of arsenic bearing water with ferrate(VI). In water, decomposition of potassium ferrate(VI) yields nanoparticles having core-shell nanoarchitecture with a gamma-Fe2O3 core and a gamma-FeOOH shell. High-resolution X-ray photoelectron spectroscopy and in field (57)Fe Mossbauer spectroscopy give unambiguous evidence that a significant portion of arsenic is embedded in the tetrahedral sites of the gamma-Fe2O3 spinel structure. Microscopic observations also demonstrate the principal effect of As doping on crystal growth as reflected by considerably reduced average particle size and narrower size distribution of the "in-situ" sample with the embedded arsenic compared to the "ex-situ" sample with arsenic exclusively sorbed on the iron oxide nanoparticle surface. Generally, presented results highlight ferrate(VI) as one of the most promising candidates for advanced technologies of arsenic treatment mainly due to its environmentally friendly character, in situ applicability for treatment of both arsenites and arsenates, and contrary to all known competitive technologies, firmly bound part of arsenic preventing its leaching back to the environment. Moreover, As-containing gamma-Fe2O3 nanoparticles are strongly magnetic allowing their separation from the environment by application of an external magnet. PMID- 23451770 TI - Extraordinarily large, giant spider angioma in an alcoholic cirrhotic patient. PMID- 23451769 TI - Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. AB - AIM: Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. METHOD: This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). RESULTS: Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration time profile. CONCLUSION: Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. PMID- 23451771 TI - Self-assembled incorporation of modulated block copolymer nanostructures in phase change memory for switching power reduction. AB - Phase change memory (PCM), which exploits the phase change behavior of chalcogenide materials, affords tremendous advantages over conventional solid state memory due to its nonvolatility, high speed, and scalability. However, high power consumption of PCM poses a critical challenge and has been the most significant obstacle to its widespread commercialization. Here, we present a novel approach based on the self-assembly of a block copolymer (BCP) to form a thin nanostructured SiOx layer that locally blocks the contact between a heater electrode and a phase change material. The writing current is decreased 5-fold (corresponding to a power reduction by 1/20) as the occupying area fraction of SiOx nanostructures is increased from a fill factor of 9.1% to 63.6%. Simulation results theoretically explain the current reduction mechanism by localized switching of BCP-blocked phase change materials. PMID- 23451772 TI - The complete mitochondrial genome of a striped sole Zebrias zebrinus (Pleuronectiformes: Soleidae). AB - Zebrias zebrinus belongs in the family Soleidae of Pleuronectiformes. There are overlaps in the ranges of identification characters between Z. zebrinus and another striped sole Z. fasciatus. In this study, the complete mitochondrial genome of Z. zebrinus was first determined. The total length was 16,758 bp, including 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes (12S and 16S), as well as a putative control region and a putative L-strand replication origin (O(L)). Gene contents, locations, and arrangements were identical to those of typical bony fishes. The overall base composition of the mitogenome was 28.7%, 30.0%, 15.2%, and 26.1% for A, C, G, and T, respectively, with an A + T content of 54.8%. This result would expect the contribution to the molecular identification of this species and further phylogenetic study of Soleidae and Pleuronectiformes. PMID- 23451773 TI - Factors affecting pupation success of the small hive beetle, Aethina tumida. AB - Survivorship of larvae of the small hive beetle, Aethina tumida Murray (Coleoptera: Nitidulidae), was measured after they were raised on one of six diets. The effects of container shape (wide and shallow vs. narrow and deep), soil depth (0, 0.5, 1.0, 2.0, 4.0, and 8.0 cm), and temperature (28 degrees , 32 degrees , or 35 degrees C) on pupation success was measured. Diet influenced larval survivorship, but did not have a strong effect on larval weight. The larvae fed only bee brood survived the shortest period of time. The larvae that were denied pupation substrate, fed only honey and pollen, and no other food or water after 20 days, had a median survivorship of 47.6 days, with a maximum of 61 days, while those fed only brood had a median survivorship of 18.2 days. Pupation substrate was essential for successful pupation, and the depth of the substrate, not its top surface area, was the crucial factor. Pupation success in narrow and deep containers was 95.6% on average, but only 12.5% in wide and shallow containers, using the same soil volume. In narrow and deep containers, most or all larvae kept in 4-8 cm of soil pupated at all temperatures, few larvae kept at 2 cm soil depth pupated, one out of 240 kept at 1.0 cm pupated, and no larvae kept at soil depths of 0 or 0.5 cm pupated. PMID- 23451774 TI - Recalcitrant pemphigus vulgaris: aseptic meningitis associated with intravenous immunoglobulin therapy and successful treatment with rituximab. PMID- 23451775 TI - Evolving views of pectin biosynthesis. AB - Recent progress in the identification and characterization of pectin biosynthetic proteins and the discovery of pectin domain-containing proteoglycans are changing our view of how pectin, the most complex family of plant cell wall polysaccharides, is synthesized. The functional confirmation of four types of pectin biosynthetic glycosyltransferases, the identification of multiple putative pectin glycosyl- and methyltransferases, and the characteristics of the GAUT1:GAUT7 homogalacturonan biosynthetic complex with its novel mechanism for retaining catalytic subunits in the Golgi apparatus and its 12 putative interacting proteins are beginning to provide a framework for the pectin biosynthetic process. We propose two partially overlapping hypothetical and testable models for pectin synthesis: the consecutive glycosyltransferase model and the domain synthesis model. PMID- 23451776 TI - Network analysis of the MVA and MEP pathways for isoprenoid synthesis. AB - Isoprenoid biosynthesis is essential for all living organisms, and isoprenoids are also of industrial and agricultural interest. All isoprenoids are derived from prenyl diphosphate (prenyl-PP) precursors. Unlike isoprenoid biosynthesis in other living organisms, prenyl-PP, as the precursor of all isoprenoids in plants, is synthesized by two independent pathways: the mevalonate (MVA) pathway in the cytoplasm and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in plastids. This review focuses on progress in our understanding of how the precursors for isoprenoid biosynthesis are synthesized in the two subcellular compartments, how the underlying pathway gene networks are organized and regulated, and how network perturbations impact each pathway and plant development. Because of the wealth of data on isoprenoid biosynthesis, we emphasize research in Arabidopsis thaliana and compare the synthesis of isoprenoid precursor molecules in this model plant with their synthesis in other prokaryotic and eukaryotic organisms. PMID- 23451777 TI - The endodermis. AB - A Casparian strip-bearing endodermis is a feature that has been invariably present in the roots of ferns and angiosperms for approximately 400 million years. As the innermost cortical layer that surrounds the central vasculature of roots, the endodermis acts as a barrier to the free diffusion of solutes from the soil into the stele. Based on an enormous body of anatomical and physiological work, the protective endodermal diffusion barrier is thought to be of major importance for many aspects of root biology, reaching from efficient water and nutrient transport to defense against soil-borne pathogens. Until recently, however, we were ignorant about the genes and mechanisms that drive the differentiation of this intricately structured barrier. Recent work in Arabidopsis has now identified the first major players in Casparian strip formation. A mechanistic understanding of endodermal differentiation will finally allow us to specifically interfere with endodermal barrier function and study the effects on plant growth and survival under various stress conditions. Here, I critically review the major findings and models related to endodermal structure and function from other plant species and assess them in light of recent molecular data from Arabidopsis, pointing out where the older, descriptive work can provide a framework and inspiration for further molecular dissection. PMID- 23451778 TI - Transport and metabolism in legume-rhizobia symbioses. AB - Symbiotic nitrogen fixation by rhizobia in legume root nodules injects approximately 40 million tonnes of nitrogen into agricultural systems each year. In exchange for reduced nitrogen from the bacteria, the plant provides rhizobia with reduced carbon and all the essential nutrients required for bacterial metabolism. Symbiotic nitrogen fixation requires exquisite integration of plant and bacterial metabolism. Central to this integration are transporters of both the plant and the rhizobia, which transfer elements and compounds across various plant membranes and the two bacterial membranes. Here we review current knowledge of legume and rhizobial transport and metabolism as they relate to symbiotic nitrogen fixation. Although all legume-rhizobia symbioses have many metabolic features in common, there are also interesting differences between them, which show that evolution has solved metabolic problems in different ways to achieve effective symbiosis in different systems. PMID- 23451779 TI - Plant genome engineering with sequence-specific nucleases. AB - Recent advances in genome engineering provide newfound control over a plant's genetic material. It is now possible for most bench scientists to alter DNA in living plant cells in a variety of ways, including introducing specific nucleotide substitutions in a gene that change a protein's amino acid sequence, deleting genes or chromosomal segments, and inserting foreign DNA at precise genomic locations. Such targeted DNA sequence modifications are enabled by sequence-specific nucleases that create double-strand breaks in the genomic loci to be altered. The repair of the breaks, through either homologous recombination or nonhomologous end joining, can be controlled to achieve the desired sequence modification. Genome engineering promises to advance basic plant research by linking DNA sequences to biological function. Further, genome engineering will enable plants' biosynthetic capacity to be harnessed to produce the many agricultural products required by an expanding world population. PMID- 23451780 TI - Tapping the promise of genomics in species with complex, nonmodel genomes. AB - Genomics is enabling a renaissance in all disciplines of plant biology. However, many plant genomes are complex and remain recalcitrant to current genomic technologies. The complexities of these nonmodel plant genomes are attributable to gene and genome duplication, heterozygosity, ploidy, and/or repetitive sequences. Methods are available to simplify the genome and reduce these barriers, including inbreeding and genome reduction, making these species amenable to current sequencing and assembly methods. Some, but not all, of the complexities in nonmodel genomes can be bypassed by sequencing the transcriptome rather than the genome. Additionally, comparative genomics approaches, which leverage phylogenetic relatedness, can aid in the interpretation of complex genomes. Although there are limitations in accessing complex nonmodel plant genomes using current sequencing technologies, genome manipulation and resourceful analyses can allow access to even the most recalcitrant plant genomes. PMID- 23451781 TI - The number, speed, and impact of plastid endosymbioses in eukaryotic evolution. AB - Plastids (chloroplasts) have long been recognized to have originated by endosymbiosis of a cyanobacterium, but their subsequent evolutionary history has proved complex because they have also moved between eukaryotes during additional rounds of secondary and tertiary endosymbioses. Much of this history has been revealed by genomic analyses, but some debates remain unresolved, in particular those relating to secondary red plastids of the chromalveolates, especially cryptomonads. Here, I examine several fundamental questions and assumptions about endosymbiosis and plastid evolution, including the number of endosymbiotic events needed to explain plastid diversity, whether the genetic contribution of the endosymbionts to the host genome goes far beyond plastid-targeted genes, and whether organelle origins are best viewed as a singular transition involving one symbiont or as a gradual transition involving a long line of transient food/symbionts. I also discuss a possible link between transporters and the evolution of protein targeting in organelle integration. PMID- 23451782 TI - Growth mechanisms in tip-growing plant cells. AB - Tip growth is employed throughout the plant kingdom. Our understanding of tip growth has benefited from modern tools in molecular genetics, which have enabled the functional characterization of proteins mediating tip growth. Here we first discuss the evolutionary role of tip growth in land plants and then describe the prominent model tip-growth systems, elaborating on some advantages and disadvantages of each. Next we review the organization of tip-growing cells, the role of the cytoskeleton, and recent developments concerning the physiological basis of tip growth. Finally, we review advances in the understanding of the extracellular signals that are known to guide tip-growing cells. PMID- 23451783 TI - Photosystem II assembly: from cyanobacteria to plants. AB - Photosystem II (PSII) is an integral-membrane, multisubunit complex that initiates electron flow in oxygenic photosynthesis. The biogenesis of this complex machine involves the concerted assembly of at least 20 different polypeptides as well as the incorporation of a variety of inorganic and organic cofactors. Many factors have recently been identified that constitute an integrative network mediating the stepwise assembly of PSII components. One recurring theme is the subcellular organization of the assembly process in specialized membranes that form distinct biogenesis centers. Here, we review our current knowledge of the molecular components and events involved in PSII assembly and their high degree of evolutionary conservation. PMID- 23451784 TI - ROS-mediated lipid peroxidation and RES-activated signaling. AB - Nonenzymatic lipid oxidation is usually viewed as deleterious. But if this is the case, then why does it occur so frequently in cells? Here we review the mechanisms of membrane peroxidation and examine the genesis of reactive electrophile species (RES). Recent evidence suggests that during stress, both lipid peroxidation and RES generation can benefit cells. New results from genetic approaches support a model in which entire membranes can act as supramolecular sinks for singlet oxygen, the predominant reactive oxygen species (ROS) in plastids. RES reprogram gene expression through a class II TGA transcription factor module as well as other, unknown signaling pathways. We propose a framework to explain how RES signaling promotes cell "REScue" by stimulating the expression of genes encoding detoxification functions, cell cycle regulators, and chaperones. The majority of the known biological activities of oxygenated lipids (oxylipins) in plants are mediated either by jasmonate perception or through RES signaling networks. PMID- 23451785 TI - Plants, diet, and health. AB - Chronic disease is a major social challenge of the twenty-first century. In this review, we examine the evidence for discordance between modern diets and those on which humankind evolved as the cause of the increasing incidence of chronic diseases, and the evidence supporting consumption of plant foods as a way to reduce the risk of chronic disease. We also examine the evidence for avoiding certain components of plant-based foods that are enriched in Western diets, and review the mechanisms by which different phytonutrients are thought to reduce the risk of chronic disease. This body of evidence strongly suggests that consuming more fruits and vegetables could contribute both to medical nutrition therapies, as part of a package of treatments for conditions like type 2 diabetes, heart disease, cancer, and obesity, and to the prevention of these diseases. Plant science should be directed toward improving the quality of plant-based foods by building on our improved understanding of the complex relationships between plants, our diet, and our health. PMID- 23451786 TI - Seed-development programs: a systems biology-based comparison between dicots and monocots. AB - Seeds develop differently in dicots and monocots, especially with respect to the major storage organs. High-resolution transcriptome data have provided the first insights into the molecular networks and pathway interactions that function during the development of individual seed compartments. Here, we review mainly recent data obtained by systems biology-based approaches, which have allowed researchers to construct and model complex metabolic networks and fluxes and identify key limiting steps in seed development. Comparative coexpression network analyses define evolutionarily conservative (FUS3/ABI3/LEC1) and divergent (LEC2) networks in dicots and monocots. Finally, we discuss the determination of seed size--an important yield-related characteristic--as mediated by a number of processes (maternal and epigenetic factors, fine-tuned regulation of cell death in distinct seed compartments, and endosperm growth) and underlying genes defined through mutant analyses. Altogether, systems approaches can make important contributions toward a more complete and holistic knowledge of seed biology and thus support strategies for knowledge-based molecular breeding. PMID- 23451787 TI - Microgenomics: genome-scale, cell-specific monitoring of multiple gene regulation tiers. AB - The expression of nuclear protein-coding genes is controlled by dynamic mechanisms ranging from DNA methylation, chromatin modification, and gene transcription to mRNA maturation, turnover, and translation and the posttranslational control of protein function. A genome-scale assessment of the spatiotemporal regulation of gene expression is essential for a comprehensive understanding of gene regulatory networks. However, there are major obstacles to the precise evaluation of gene regulation in multicellular plant organs; these include the monitoring of regulatory processes at levels other than steady-state transcript abundance, resolution of gene regulation in individual cells or cell types, and effective assessment of transient gene activity manifested during development or in response to external cues. This review surveys the advantages and applications of microgenomics technologies that enable panoramic quantitation of cell-type-specific expression in plants, focusing on the importance of querying gene activity at multiple steps in the continuum, from histone modification to selective translation. PMID- 23451788 TI - A bountiful harvest: genomic insights into crop domestication phenotypes. AB - Human selection during crop domestication has resulted in remarkable transformations of plant phenotypes, providing a window into the genetic basis of morphological evolution. Recent progress in our understanding of the genetic architecture of novel plant traits has emerged from combining advanced molecular technologies with improved experimental designs, including nested association mapping, genome-wide association studies, population genetic screens for signatures of selection, and candidate gene approaches. These studies reveal a diversity of underlying causative mutations affecting phenotypes important in plant domestication and crop improvement, including coding sequence substitutions, presence/absence and copy number variation, transposon activation leading to novel gene structures and expression patterns, diversification following gene duplication, and polyploidy leading to altered combinatorial capabilities. The genomic regions unknowingly targeted by human selection include both structural and regulatory genes, often with results that propagate through the transcriptome as well as to other levels in the biosynthetic and morphogenetic networks. PMID- 23451789 TI - Future scenarios for plant phenotyping. AB - With increasing demand to support and accelerate progress in breeding for novel traits, the plant research community faces the need to accurately measure increasingly large numbers of plants and plant parameters. The goal is to provide quantitative analyses of plant structure and function relevant for traits that help plants better adapt to low-input agriculture and resource-limited environments. We provide an overview of the inherently multidisciplinary research in plant phenotyping, focusing on traits that will assist in selecting genotypes with increased resource use efficiency. We highlight opportunities and challenges for integrating noninvasive or minimally invasive technologies into screening protocols to characterize plant responses to environmental challenges for both controlled and field experimentation. Although technology evolves rapidly, parallel efforts are still required because large-scale phenotyping demands accurate reporting of at least a minimum set of information concerning experimental protocols, data management schemas, and integration with modeling. The journey toward systematic plant phenotyping has only just begun. PMID- 23451791 TI - It's time for a standard glucose report from CGM. PMID- 23451790 TI - Current neurosurgical management of glossopharyngeal neuralgia and technical nuances for microvascular decompression surgery. AB - Glossopharyngeal neuralgia (GPN) is an uncommon facial pain syndrome often misdiagnosed as trigeminal neuralgia. The rarity of this condition and its overlap with other cranial nerve hyperactivity syndromes often leads to a significant delay in diagnosis. The surgical procedures with the highest rates of pain relief for GPN are rhizotomy and microvascular decompression (MVD) of cranial nerves IX and X. Neurovascular conflict at the level of the root exit zone of these cranial nerves is believed to be the cause of this pain syndrome in most cases. Vagus nerve rhizotomy is usually reserved for cases in which vascular conflict is not evident. A review of the literature reveals that although the addition of cranial nerve X rhizotomy may improve the chances of long-term pain control, this maneuver also increases the risk of permanent dysphagia and vocal cord paralysis. The risks of this procedure have to be carefully weighed against its benefits. Based on the authors' experience, careful patient selection with a thorough exploratory operation most often leads to identification of the site of vascular conflict, obviating the need for cranial nerve X rhizotomy. PMID- 23451792 TI - It's time to move from the A1c to better metrics for diabetes control. PMID- 23451793 TI - Standardization of self-monitoring of blood glucose and continuous glucose monitoring reporting. PMID- 23451794 TI - Flavanols from evening primrose (Oenothera paradoxa) defatted seeds inhibit prostate cells invasiveness and cause changes in Bcl-2/Bax mRNA ratio. AB - In this study, we assessed the influence of an evening primrose flavanol preparation (EPFP) on proliferation and invasiveness of human prostate cancer cells (DU 145) and immortalized prostate epithelial cells (PNT1A). We report for the first time that EPFP reduces DU 145 cell proliferation (IC50 = 97 MUM GAE for 72 h incubation) and invasiveness (by 24% versus control at 75 MUM GAE). EPFP strongly inhibited PNT1A invasiveness in a concentration-dependent manner (by 67% versus control at 75 MUM GAE) and did not cause a reduction in their proliferation. Furthermore, EPFP inhibited the activities of MMP-2 and MMP-9 secreted to culture medium by PNT1A cells by 84% and 34% versus control at 100 MUM GAE, respectively. In the case of DU 145, MMP-9 activity at 100 MUM GAE was reduced by 37% versus control. Moreover, the evening primrose seed flavanols suppressed the expression of selected genes (MMP-1, MMP-9, MMP-14, c-Fos, c-Jun, and VEGF) and also caused favorable changes in Bcl-2/Bax mRNA ratio which render DU 145 cells more sensitive to apoptosis-triggering agents. An additional confirmation of the proapoptotic activity of EPFP toward DU 145 was visualization of characteristic apoptotic bodies by DAPI staining. In conclusion, this study suggests that EPFP may increase apoptosis and reduce angiogenesis of prostate cancer cells. PMID- 23451795 TI - Oligonucleotides conjugated to natural lipids: synthesis of phosphatidyl-anchored antisense oligonucleotides. AB - Antisense oligonucleotides are promising therapeutic agents against a variety of diseases. Effective delivery of these molecules is critical in view of their clinical application. Despite the richness of synthetic strategies addressed to the lipophilic modification of oligodeoxynucleotides (ODNs) for enhancing their pharmacokinetic behavior and trans-membrane delivery, the phosphatidyl group (1,2 di-O-acyl-sn-glycero-3-phosphoryl) has been never used as the lipophilic moiety of lipid-ODN conjugates. The present paper reports a general procedure for synthesizing 5'-phosphatidyl-ODNs. By this procedure, phosphatidyl conjugates of a VEGF antisense-ODN have been prepared, which differ in the fatty acid composition of their phosphatidyl moiety. These new lipid-ODN conjugates, which have been characterized on the basis of their physicochemical properties, showed an improved resistance to exonucleases and were able to lower the VEGF-mRNA expression in human SH-SY5Y neuroblastoma cells more effectively than the relevant free antisense-ODN did. PMID- 23451796 TI - Variability of glucose-lowering effect as a limiting factor in optimizing basal insulin therapy: a review. AB - Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles. PMID- 23451797 TI - Structural investigation and biological activity of sesquiterpene lactones from the traditional Chinese herb Inula racemosa. AB - Five new sesquiterpene lactones, racemosalactones A-E (1-5), along with 19 known sesquiterpene latones (6-24), were isolated from the roots of Inula racemosa. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configuration of 2 was deduced from X-ray diffraction analysis. Compounds 1, 6, 8, 10, 12, 14, and 17 exhibited antiproliferative activities with IC50 values ranging from 0.38 to 4.19 MUg/mL against human non-small-cell lung cancer A549, hepatocellular carcinoma HepG2, and human fibrosarcoma HT1080 cells. Compounds 6 and 8 exhibited antiproliferative activities against endothelial cells with IC50 values of 2.4 and 2.5 MUg/mL, respectively. Furthermore, compounds 6 and 8 both inhibited endothelial cell tube formation at 1.0 MUg/mL. A method for the rapid and straightforward preparative-scale isolation of compound 6 from alantolides is described. PMID- 23451798 TI - Screening blood donors for diabetes: analysis of use, accuracy, and cost. AB - BACKGROUND: The objective was to determine if a free, voluntary diabetes screening program as a part of the blood donation process might be cost effective. STUDY DESIGN AND METHODS: During the first 6 months of the program, 26,415 donors were screened using a single random plasma glucose (RPG) level. All donors were asked to eat before donation. Low-, moderate-, and high-risk groups were formed based on RPG levels (<140, 140-200, and >200 mg/dL). Contact with a telephone questionnaire was made with 139 of 178 (78%) of the persons in the high risk group with 33 new cases of diabetes diagnosed by the donor's physician and 26 donors indicating that they were not diagnosed with diabetes. Sex- and age matched donors in the low- and moderate-risk groups were contacted and administered the same questionnaire. RESULTS: The three risk groups were similar, except for body mass index (28.1 +/- 5.4 kg/m2 vs. 29.9 +/- 5.5 kg/m2 vs. 32.7 +/ 5.6 kg/m2 , p < 0.001). The discriminative effectiveness of screening was evaluated by the area under the receiver operating characteristics (AROC) curve. The AROC curve was 0.950 (95% confidence interval, 0.920-0.979) for the identification of diabetes. Using a RPG cutoff of 200 mg/dL, sensitivity was 100%, specificity was 82%, and positive predictive value was 56%. Cost analyses showed that the mean cost to screen, per donor, was less than $1. Cost per case identified was estimated to be less than $500 for a RPG cutoff of 200 mg/dL. CONCLUSIONS: Screening during the blood donation process appears to be accurate, convenient, and inexpensive. PMID- 23451799 TI - Retraction: Quitting smoking is perceived to have an effect on somatic health among pregnant and non-pregnant women. PMID- 23451800 TI - Synthesis of 2-aryl-3-fluoro-5-silylthiophenes via a cascade reactive sequence. AB - 2-Aryl-3-fluoro-5-silylthiophenes were readily prepared only in two steps from 2 bromo-3,3,3-trifluoropropene in good yields. These transformations include the first successful S(N)2'-type reaction of 2-bromo-3,3,3-trifluoropropene and benzylthiols and [2,3]sigmatropic rearrangement of 2-bromo-3,3-difluoroallyl benzyl sulfide. PMID- 23451801 TI - Hydrogen bonding in the prism face of ice I(h) via sum frequency vibrational spectroscopy. AB - The prism face of single crystal ice I(h) has been studied using sum frequency vibrational spectroscopy focusing on identification of resonances in the hydrogen bonded region. Several modes have been observed at about 3400 cm(-1); each mode is both polarization and orientation dependent. The polarization capabilities of sum frequency generation (SFG) are used in conjunction with the crystal orientation to characterize three vibrational modes. These modes are assigned to three-coordinated water molecules in the top-half bilayer having different bonding and orientation motifs. PMID- 23451802 TI - Arabidopsis transcription factor WRKY8 functions antagonistically with its interacting partner VQ9 to modulate salinity stress tolerance. AB - The WRKY transcription factors have been demonstrated to play crucial roles in regulating stress responses; however, the exact mechanisms underlying their involvement in stress responses are not fully understood. Arabidopsis WRKY8 was predominantly expressed in roots and was highly upregulated by salt treatment. Disruption of WRKY8 rendered plants hypersensitive to salt, showing delayed germination, inhibited post-germination development and accelerated chlorosis. Further investigation revealed that WRKY8 interacted with VQ9, and their interaction decreased the DNA-binding activity of WRKY8. The VQ9 protein was exclusively localized in the nucleus, and VQ9 expression was strongly responsive to NaCl treatment. Mutation of VQ9 enhanced tolerance to salt stress, indicating that VQ9 acts antagonistically with WRKY8 to mediate responses to salt stress. The antagonist functions of WRKY8 and VQ9 were consistent with an increased or reduced Na+/K+ concentration ratio, as well as contrasting expression patterns of downstream stress-responsive genes in salt-stressed wrky8 and vq9 mutants. Moreover, chromatin immunoprecipitation (ChIP) assays showed that WRKY8 directly bound the promoter of RD29A under salt conditions. These results provided strong evidence that the VQ9 protein acts as a repressor of the WRKY8 factor to maintain an appropriate balance of WRKY8-mediated signaling pathways to establish salinity stress tolerance. PMID- 23451803 TI - Digitized charge transfer magnitude determined by metal-organic coordination number. AB - Well-ordered metal-organic nanostructures of Fe-PTCDA (perylene-3,4,9,10 tetracarboxylic-3,4,9,10-dianhydride) chains and networks are grown on a Au(111) surface. These structures are investigated by high-resolution scanning tunneling microscopy. Digitized frontier orbital shifts are followed in scanning tunneling spectroscopy. By comparing the frontier energies with the molecular coordination environments, we conclude that the specific coordination affects the magnitude of charge transfer onto each PTCDA in the Fe-PTCDA hybridization system. A basic model is derived, which captures the essential underlying physics and correlates the observed energetic shift of the frontier orbital with the charge transfer. PMID- 23451805 TI - STXM and NanoSIMS investigations on EPS fractions before and after adsorption to goethite. AB - Extracellular polymeric substances (EPS) are expected to be an important source for the formation of mineral-organic associations in soil. Because such formations affect the composition of mobile and immobile organic matter as well as the reactivity of minerals, we investigated the composition of EPS before and after adsorption to goethite. Raman measurements on EPS extracted from Bacillus subtilis distinguished four fractions rich in proteins, polysaccharides, lipids, or lipids and proteins. Scanning transmission X-ray microscopy identified three different EPS-fractions that varied in their composition in proteins, nonaromatic proteins, and polysaccharides. Reaction of EPS with goethite led to a preferential adsorption of lipids and proteins. The organic coverage was heterogeneous, consisting of ~100 * 200 nm large patches of either lipid-rich or protein-rich material. Nanoscale secondary ion mass spectrometry showed a strong S enrichment in aggregates of ~400 nm in the goethite adsorbed EPS. From our simplified model system, we learned that only a small portion (<10%) of EPS was immobilized via adsorption to goethite. This fraction formed a coating of subMUm spaced protein-rich and lipid-rich domains, i.e., of two materials which will strongly differ in their reactive sites. This will finally affect further adsorption, the particle mobility and eventually also colloidal stability. PMID- 23451804 TI - Diagnostic transitions from childhood to adolescence to early adulthood. AB - BACKGROUND: Quantifying diagnostic transitions across development is needed to estimate the long-term burden of mental illness. This study estimated patterns of diagnostic transitions from childhood to adolescence and from adolescence to early adulthood. METHODS: Patterns of diagnostic transitions were estimated using data from three prospective, longitudinal studies involving close to 20,000 observations of 3,722 participants followed across multiple developmental periods covering ages 9-30. Common DSM psychiatric disorders were assessed in childhood (ages 9-12; two samples), adolescence (ages 13-18; three samples), and early adulthood (ages 19 to age 32; three samples) with structured psychiatric interviews and questionnaires. RESULTS: Having a disorder at an early period was associated with at least a threefold increase in odds for having a disorder at a later period. Homotypic and heterotypic transitions were observed for every disorder category. The strongest evidence of continuity was seen for behavioral disorders (particularly ADHD) with less evidence for emotional disorders such as depression and anxiety. Limited evidence was found in adjusted models for behavioral disorders predicting later emotional disorders. Adult substance disorders were preceded by behavioral disorders, but not anxiety or depression. CONCLUSIONS: Having a disorder in childhood or adolescence is a potent risk factor for a range of psychiatric problems later in development. These findings provide further support for prevention and early life intervention efforts and suggest that treatment at younger ages, while justified in its own right, may also have potential to reduce the risk for disorders later in development. PMID- 23451807 TI - Effects of rearing conditions, geographical origin, and selection on larval diapause in the Indianmeal moth, Plodia interpunctella. AB - The Indianmeal moth, Plodia interpunctella (Hubner) (Lepidoptera: Pyralidae), is a serious insect pest of stored products, and its late-instar larvae diapause as pre-pupae. Diapause induction in P. interpunctella was investigated for four populations obtained from Modesto, California, U.S.A.; Vancouver, British Columbia, Canada; and two locations from Winnipeg, Manitoba, Canada. Insects were reared at 25 degrees C and 16:8 L:D for 9 days. The larvae were then either continuously maintained under those conditions or transferred to 25 degrees C 8:16 L:D, 20 degrees C 16:8 L:D, or 20 degrees C 8:16 L:D, and the percent diapause was recorded. In the experiment with four populations, the highest diapause frequency was observed at 20 degrees C 8:16 L:D. The two Winnipeg populations had significantly higher frequency of diapause than the California populations, indicating the increased frequency of diapause in populations from higher latitudes. In a second experiment, the Vancouver population was selected for diapause. Larvae were reared at 25 degrees C 16:8 L:D for 9 days, then placed at 20 degrees C 8:16 L:D for the rest of their development, and percent diapause was determined. Eggs laid by moths that completed diapause in this first (parental) generation were used to obtain a second generation (F1), and the experiment was repeated as in the first generation. Selection increased the frequency of diapause to 91%, compared to 26% in the unselected population, after selecting over two generations. The narrow sense heritability of selection in P. interpunctella was 0.39 in the first selection, and 0.82 in the second. This study has shown that both low temperature and short photoperiod are required to induce diapause in North American populations of P. interpunctella, and that selection can increase diapause in a few generations. PMID- 23451806 TI - Randomised clinical trial: once- vs. twice-daily prolonged-release mesalazine for active ulcerative colitis. AB - BACKGROUND: Aminosalicylates are first-choice treatment for mild-to-moderately active ulcerative colitis (UC); however, multi-dosing regimens are inconvenient. AIM: To compare the efficacy and safety of once- (OD) vs. twice- (BD) daily prolonged-release mesalazine (Pentasa, Ferring, Saint-Prex, Switzerland) for active mild-to-moderate UC in a non-inferiority study. METHODS: Eligible patients (n = 206) were randomised to 8 weeks of mesalazine (4 g/day), either OD with two sachets of 2 g mesalazine granules in the morning (n = 102) or BD with one 2 g sachet in the morning and one in the evening (n = 104). Patients also received 4 weeks of mesalazine enema 1 g/day. Disease activity was assessed at randomisation, weeks 4, 8 and 12 using the UC Disease Activity Index (UC-DAI). Clinical and endoscopic remission (primary endpoint) was assessed after 8 weeks. Patients recorded stool frequency and rectal bleeding in a daily diary. RESULTS: The primary endpoint, non-inferiority in clinical and endoscopic remission with OD vs. BD mesalazine at 8 weeks, was met (intent-to-treat population: 52.1% vs. 41.8%, respectively, 95% confidence interval -3.4, 24.1; P = 0.14). Improvement of UC-DAI score (92% vs. 79%; P = 0.01) and mucosal healing (87.5% vs. 71.1%; P = 0.007) were significantly better, time to remission significantly shorter (26 vs. 28 days; P = 0.04) and safety similar with OD vs. BD dosing. CONCLUSIONS: When combined with mesalazine enema, prolonged-release mesalazine once-daily 4 g is as effective and well tolerated as 2 g twice-daily for inducing remission in patients with mild-to-moderately active ulcerative colitis (Clinicaltrials.gov: NCT00737789). PMID- 23451808 TI - Acute generalized exanthematous pustulosis induced by levetiracetam. PMID- 23451809 TI - Evaluation of histological grade and histologically tumour-free margins as predictors of local recurrence in completely excised canine mast cell tumours. AB - Completeness of mast cell tumour (MCT) excision is determined by assessment of histologically tumour-free margins (HTFM). The HTFM width necessary to prevent local recurrence (LR), recognized as histologic safety margin (HSM) in human oncology, has not been defined. We hypothesized that HTFM width would correlate with risk for LR and high-grade tumours would require wider HTFM than low-grade tumours. Records of dogs with completely excised MCTs were included. Signalment, two-tier tumour grade, tumour size, HTFM width, recurrence and therapy data was collected. High-grade (n = 39) tumours were more likely to recur than low-grade (n = 51) tumours (35.9% versus 3.9%), P < 0.0001, with no association between HTFM width and LR. Twenty-nine percent of low-grade tumours had HTFM less than 3 mm; none recurred. Narrow (<=3 mm) histologic margins are likely adequate to prevent LR of low-grade tumours. High-grade tumours have significant risk of LR regardless of HTFM width. PMID- 23451810 TI - Serum apelin levels in systemic sclerosis. PMID- 23451811 TI - Reaching rural communities with culturally appropriate care: a model for adapting remote monitoring to American Indian veterans with posttraumatic stress disorder. AB - OBJECTIVE: Providing specialized healthcare to rural communities can be extremely difficult, and consequently many health organizations are turning to the use of telehealth technologies for care delivery. One such technology, remote monitoring, has been successfully implemented with patients suffering from chronic and other medical conditions. A drawback, however, is that remote monitoring devices are programmed to reach a broad audience, and consequently the content may not be suitable for all patients-especially those who are not a part of the dominant culture. SUBJECTS AND METHODS: This report provides a model for adapting remote monitoring to specific populations who are undergoing care for posttraumatic stress disorder. Adaptation changes focus on (1) information gathering, (2) process and dialogue changes, (3) testing, and (4) patient and administrative feedback. Data for such modifications were gathered through a series of community meetings, patient interviews, and provider feedback. A case example highlights the successful implementation of the adaptation model for a rural American Indian Veteran population. RESULTS: Patients showed high acceptability of both the programmatic and cultural adaptations. Feasibility of the program also appeared positive, with most patients reporting that the readability of the program was appropriate, the dialogue duration was not burdensome, and technical problems were rare. CONCLUSIONS: Remote monitoring provides the ability to be modified for use with certain subpopulations. Procedural recommendations in this report highlight special considerations for working with American Indians living on or near reservation areas, although the model can be broadly adapted to several groups. PMID- 23451812 TI - Transcultural psychiatry made simple--asynchronous telepsychiatry as an approach to providing culturally relevant care. AB - OBJECTIVE: To examine the feasibility and diagnostic reliability of asynchronous telepsychiatry (ATP) consultations in Spanish and ATP consultation with Spanish to-English translation. SUBJECTS AND METHODS: Twenty-four interviews of Spanish speaking patients were videorecorded by a bilingual clinician who also collected patient history data and gave the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to each patient. The ATP data (video of the interview and patient history) were forwarded for psychiatric consultation and a diagnostic assessment by the investigators. The ATP data were then examined separately by two Spanish-speaking psychiatrists, before being translated into English and then re-examined by two English-speaking psychiatrists. Agreement between the expert diagnoses of the investigators and the diagnoses from the Spanish consultations, the Spanish-to-English translated consultations, and the SCID-I results was assessed using kappa statistics. RESULTS: We found acceptable levels of agreement for major diagnostic groupings among the Spanish- and English-speaking psychiatrists. Kappa values for diagnostic agreement between the expert and the translated consultations, the original language consultations, and the SCID-I were at least 0.52 (percentage agreement, 79%) and higher. CONCLUSIONS: ATP consultations in Spanish, and those translated from Spanish to English, are feasible, and broad diagnostic reliability was achieved. The ATP process allows for rapid language translation. This approach could be useful across national boundaries and in numerous ethnic groups. Cross-language ATP may also offer significant benefits over the use of real-time interpreting services and has the potential to improve the quality of care by allowing for the addition of culturally relevant information. PMID- 23451813 TI - Apocrine hidrocystoma on the penis of a 40-year-old man. PMID- 23451814 TI - Mediterranean dietary pattern adherence: associations with prediabetes, metabolic syndrome, and related microinflammation. AB - BACKGROUND: The adherence to the Mediterranean Diet (Med Diet) seems to reduce the incidence of metabolic syndrome. The present study aimed to explore whether the adherence to the overall Med Diet pattern and to specific Med Diet items is associated with the presence of metabolic syndrome, impaired fasting glucose (IFG), insulin resistance (IR), and microinflammation in subjects free of diabetes and cardiovascular diseases. MEASUREMENTS: Each patient underwent clinical assessment. Adherence to the Med Diet was measured by a previously validated 14-item questionnaire. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria; IR was defined by homeostasis model assessment of insulin resistance (HOMA-IR); inflammation was assessed through a high-sensitivity C-reactive protein (hsCRP) assay. RESULTS: A total of 120 subjects (64.2% women, mean age 59.8+/-10.2 years) were enrolled at this study. Subjects with lower Med Diet pattern adherence exhibited higher occurrence of metabolic syndrome and all its components and higher HOMA-IR and hsCRP values (P for all <0.0001). Subjects with metabolic syndrome were less likely to consume olive oil (P=0.002) and vegetables (P=0.023). By multivariable analyses, the overall Med Diet score was found to be strongly and inversely associated with the presence of metabolic syndrome [B= 0.066; 95% confidence interval (CI) -0.105 to -0.028; P=0.001], IFG (B=-0.076; 95% CI -0.114 to -0.038; p<0.0001), high HOMA-IR (B=-0.071; 95% CI -0.108 to 0.034; P<0.0001) and high hsCRP (B=-0.082; 95% CI -0.125 to -0.045; P<0.0001). None of specific Med Diet items independently predicted metabolic syndrome, IFG, and high HOMA-IR. Instead, the consumption of white meat over red meat (B=-0.324; 95% CI -0.467 to -0.178; P<0.0001) was found to be inversely associated with increased hsCRP. CONCLUSIONS: The inverse associations between adherence to Med Diet and the prevalence of metabolic syndrome and prediabetes may be due more to the effects of the entire dietary pattern rather than to individual food components. Metabolic syndrome-related microinflammation may further be linked to specific Med Diet components. PMID- 23451815 TI - Necessity of both waist circumference and waist-to-height ratio for better evaluation of central obesity. AB - BACKGROUND: Waist-to-height ratio (WHtR) has been shown to be a better discriminator of cardiovascular risk than waist circumference (WC). The purpose of this study was to determine whether cardiometabolic risk is increased in men showing large WC but not showing high WHtR. METHODS: Subjects (26,017 middle-aged men) were divided into four groups of normal WC (<85 cm) and normal WHtR (<0.5), large WC (>=85 cm) but normal WHtR, normal WC but high WHtR (>=0.5), and large WC and high WHtR. Odds ratios (ORs) of each group versus the group with normal WC and normal WHtR for each cardiometabolic risk factor were calculated after adjustment for age, alcohol drinking, smoking, and regular exercise. RESULTS: Subjects showing large WC but normal WHtR and subjects showing normal WC but high WHtR were 6.1% and 4.5%, respectively, of all subjects. ORs of subjects with large WC but normal WHtR versus subjects with normal WC and normal WHtR for hyperglycemia [1.80 (95% confidence interval, CI, 1.55- 2.09)], dyslipidemia [2.28 (95% CI 2.05-2.54)], high blood pressure [1.86 (95% CI 1.67-2.07)], and a cluster of these three risk factors [3.10 (95% CI 2.46-3.92)] were significantly higher than a reference level of 1.00 (p<0.01) and were comparable with the ORs of subjects with normal WC but high WHtR. CONCLUSION: Cardiometabolic risk was significantly increased in subjects with large WC and normal WHtR, and thus it is recommended to use both WC and WHtR for a more correct diagnosis of central obesity. PMID- 23451816 TI - Which liver enzymes are better indicators of metabolic syndrome in adolescents: the Fifth Korea National Health and Nutrition Examination Survey, 2010. AB - BACKGROUND: This study aimed to examine the relationships of liver enzyme levels with metabolic syndrome in adolescents. METHODS: A total of 808 adolescents (430 males and 378 females, aged 10-19 years) participated in the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1) in 2010, the relationships between liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), ratio of AST to ALT (AST/ALT), and gamma-glutamyltransferase (GGT)] and metabolic syndrome defined by the International Diabetes Federation criteria were assessed using logistic regression and receiver operating characteristic (ROC) curve analyses. RESULTS: After adjusting for age, higher ALT and GGT levels and a lower AST/ALT level were associated with clustering of metabolic syndrome components, whereas AST level was not associated with it in both sexes. The strength of association between the liver enzymes and clustering of metabolic syndrome components was higher in females than in males. In the non-overweight group, higher AST, ALT, and GGT levels and a lower AST/ALT level were associated with clustering of metabolic syndrome components, whereas none of the liver enzymes was associated with metabolic syndrome in the overweight group. The area under the ROC curve (AUC) of AST to determine metabolic syndrome was not significant and was significantly lower than AUCs of ALT, AST/ALT, and GGT in both sexes. The cutoff values of ALT, AST/ALT, and GGT to determine metabolic syndrome were higher in males than in females. CONCLUSIONS: ALT, AST/ALT, and GGT were found to be associated with clustering of metabolic syndrome components, and the relationships appear to be sex- and weight group-specific. PMID- 23451817 TI - Metformin synergistically enhances antitumor activity of histone deacetylase inhibitor trichostatin a against osteosarcoma cell line. AB - Oral hypoglycemic agent metformin is commonly used for treating type II diabetes; however, initial reports demonstrated that it could be used for suppressing tumor growth in vitro and in vivo. Moreover, novel potential anticancer drug histone deacetylase (HDAC) and inhibitor trichostatin A (TSA) have been extensively studied for inducing various malignancies growth inhibition, cell cycle arrest, and apoptosis. The object of the present study was to investigate the anti proliferation and apoptosis induction effects of metformin and TSA in osteosarcoma cell line, and to explore the mechanism of metformin and TSA in combination to inhibit the proliferation of osteosarcoma cells. After treating with metformin and TSA, the viability of osteosarcoma cell lines (MG-63 and LM8) was analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) at various concentrations, cell cycle analysis of MG-63 and LM8 cell was performed by flow cytometry. Real-time polymerase chain reaction and Western Blotting were performed to determine the expression of apoptosis-related genes and proteins such as Caspase-3, Bcl-2/Bax, Cyclin D1, and p21. Protein expression of the molecules involved in 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway after treatment with combination was determined by Western blotting. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish the murine model; tumor weight and tumor volume were monitored after drug administration separately or combined via the intraperitoneal (i.p.) route. MTT assays showed that the viability of osteosarcoma cell lines in the combination group (10 mM metformin, 0.3 MUM TSA) decreased in a concentration- and time-dependent manner; moreover, the cell cycle of MG-63 and LM8 in the combination group could be arrested in G1/G2 phase higher number compared with drug use separately. Furthermore, a combination of these drugs does not act via the AMPK signaling pathway to induce MG-63 osteosarcoma cell line growth inhibition and apoptosis. As data have showed here, metformin cotreatment increased TSA antitumor effects and have a synergistic effect on osteosarcoma cell line proliferation and apoptosis. PMID- 23451818 TI - Malignant peripheral nerve sheath tumors of the trigeminal nerve: a systematic review of 36 cases. AB - OBJECT: Malignant peripheral nerve sheath tumors (MPNSTs) are a rare form of malignancy arising from the Schwann cells of peripheral nerves. MPNSTs of the trigeminal nerve are exceptionally rare, with only a handful of reports in the literature. These tumors are typically very aggressive, resulting in significant patient morbidity and a generally grim prognosis. Most current reports suggest that radical resection with radiation therapy offers the best benefit. In this study, the authors systematically reviewed the world English-language literature on MPNSTs of the trigeminal nerve to analyze the presentations, treatment options, and outcomes for patients with this disease. METHODS: A literature search for MPNSTs of the trigeminal nerve confined to nonanimal, English-language articles was conducted utilizing the PubMed database, with additional cases chosen from the references of selected articles. Only cases of confirmed MPNSTs of the trigeminal nerve or its peripheral branches, based upon surgical, pathological, or radiological analysis, were included. RESULTS: From the literature search, 29 articles discussing 35 cases of MPNSTs of the trigeminal nerve were chosen. With the addition of 1 case from their own institution, the authors analyzed 36 cases of trigeminal MPNSTs. The average age of onset was 44.6 years. These tumors were more commonly seen in male patients (77.1%). The gasserian ganglion was involved in 36.1% of the cases. Of the cases in which the nerve distribution was specified (n = 25), the mandibular branch was most commonly involved (72.0%), followed by the maxillary branch (60.0%) and the ophthalmic branch (32.0%), with 44.0% of patients exhibiting involvement of 2 or more branches. Altered facial sensation and facial pain were the 2 most commonly reported symptoms, found in 63.9% and 52.8% of patients, respectively. Mastication difficulty and diplopia were seen in 22.2% of patients, facial weakness was seen in 19.4%, and hearing loss was present in 16.7%. With regard to the primary treatment strategy, 80.6% underwent resection, 16.7% underwent radiation therapy, and 2.9% received chemotherapy alone. Patients treated with complete resection followed by postoperative radiation therapy had the most favorable outcomes, with no patients showing evidence of disease recurrence with a mean follow-up of 34.6 months. Patients treated with incomplete resection followed by postoperative radiation therapy had more favorable outcomes than patients treated with incomplete resection without radiation therapy or radiation therapy alone. CONCLUSIONS: Trigeminal MPNSTs most commonly present as altered facial sensation or facial pain, although they exhibit a number of other clinical manifestations, including the involvement of other cranial nerves. While a variety of treatment options exist, due to their highly infiltrative nature, aggressive resection followed by radiation therapy appears to offer the greatest chance of recurrence-free survival. PMID- 23451819 TI - Role of donor and recipient sex in platelet transfusion. AB - BACKGROUND: H-Y proteins are ubiquitously expressed Y chromosome-encoded minor histocompatibility antigens, which are relevant in the transplantation of hematopoietic stem cells (HSCT) and solid organs. No studies have so far analyzed whether H-Y incompatibility influences the outcome of platelet (PLT) transfusion. STUDY DESIGN AND METHODS: We studied the effect of donor and recipient sex on outcome of 9038 single-donor PLT transfusions. RESULTS: Using standard corrected count increment or percent PLT recovery (PPR) calculations, male patients showed inferior recovery rates, irrespective of donor sex. Using an adjusted PPR, which takes into account differences in blood volume between males and females, neither donor nor recipient sex played any role in PLT recovery after transfusion. Similarly, the time to next PLT transfusion was unaffected by both donor and recipient sex. In a subgroup analysis of patients with graft-versus-host disease after allogeneic HSCT, male recipients of a female allograft-which may carry anti H-Y T cells and antibodies-had significantly lower time to next PLT transfusion. However, this occurred after both male donor and female donor PLT transfusions, arguing against an involvement of alloreactivity against H-Y antigens on PLTs. CONCLUSION: This large analysis found no evidence that donor-recipient sex matching influences the outcome of PLT transfusion. PMID- 23451820 TI - Cleavage of metal-ion-induced DNAzymes released from nanolabels for highly sensitive and specific immunoassay. AB - This work reports a novel electrochemical immunoassay protocol with signal amplification for determination of low-abundance protein (free prostate-specific antigen, PSA, used as a model) with high sensitivity and high selectivity by coupling metal sulfide (PbS)-based nanolabels with cleavage of the corresponding lead ion-induced DNAzymes. The assay mainly consists of an antigen-antibody immunoreaction with metal nanolabel in a transparent 96-well polystyrene microplate, the release of metal ions from the nanolabel, and cleavage of metal ion-induced DNAzyme. The signal is amplified by the labeled redox tag (ferrocene) on the DNAzyme-based sensor. In the presence of target analyte, the sandwiched immunocomplex can be formed between the primary antibody on the microplate and the corresponding metal sulfide nanolabel. The carried nanolabel can release numerous metal ions by acid, and induce the cleavage of the corresponding DNAzyme, thus resulting in the change of electrochemical signal. Under optimal conditions, the DNAzyme-based immunoassay presents an obvious electrochemical response for the detection of PSA, and allows detection of PSA at a concentration as low as 0.1 pg mL(-1). Intra-assay and interassay coefficients of variation (CV) were less than 9.5% and 10%, respectively. No significant differences at the 0.05 significance level were encountered in the analysis of 12 clinical serum specimens between the developed immunoassay and a commercially available enzyme linked immunosorbent assay (ELISA). PMID- 23451821 TI - Effects of 6 months glucagon-like peptide-1 receptor agonist treatment on endothelial function in type 2 diabetes mellitus patients. AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are used for treatment in type 2 diabetes mellitus (T2DM). Little is known about their cardiovascular (CV) impact. We sought to determine the effects of chronic treatment on vascular function in T2DM. Brachial artery endothelial-dependent flow-mediated dilation (FMD) and endothelial-independent glyceryl trinitrate (GTN) function and carotid intima-medial thickness (cIMT) were assessed in 11 severely obese T2DMs (4 females, 7 males: 55 +/- 8 years, diabetes duration 8.3 +/- 4.7 years mean +/- s.d.) before and after 6 months GLP-1 RA. Body weight (5.3 +/- 1.2 kg; p < 0.05) and magnetic resonance imaging determined total and subcutaneous fat, but not visceral fat, decreased. Glycaemic control improved. There were no significant changes in FMD, GTN and cIMT (-1.1 +/- 0.4%, 0.3 +/- 3.0% and 0.00 +/- 0.04 mm, respectively). Despite significant improvements in body composition and glycaemic control, 6 months GLP-1 RA treatment did not modulate vascular function. Alternative strategies may therefore be needed to reduce the burden of CV risk in severely obese patients with long-standing T2DM. PMID- 23451822 TI - The study of fetal neurobehavior in twins in all three trimesters of pregnancy. AB - AIM: The aim was to assess the onset and the frequencies of the first intertwin contacts by four-dimensional ultrasound (4D US) in the 1st trimester of pregnancy. In the second part of the study, fetal behavior and Kurjak Antenatal Neurodevelopmental Test (KANET) score of twins compared to singletons in the 2nd and the 3rd trimesters was assessed. PATIENTS AND METHODS: Transvaginal 4D assessment was performed in 20 women in the 1st trimester between 56 and 69 postmenstrual days (PMD), while trans-abdominal approach was performed from 70 PMD onwards and at weekly intervals until 112 PMD. Fetal behavior was assessed by 4D UD US between 28 and 36 gestational weeks in 49 twin pregnancies. RESULTS: The first intertwin contacts appeared at 61 PMD, while complex body movements appeared at 68 PMD. The complexity of intertwin contacts increased from 84 PMD. With increasing gestational age, a higher frequency of movements was observed. The number of abnormal, borderline, and normal KANET scores between singletons and twins was not statistically significant. Scores for isolated eye blinking, mouthing, grimacing, hand to head movement, finger movements, Gestalt perception and general movements differed significantly in twins and singletons. CONCLUSIONS: Two types of activities were observed: spontaneous and reactive. Although twins showed less activity and different behavioral pattern than singletons, a considerable proportion of overall motility was due to intertwin contacts. PMID- 23451823 TI - Cryptocapsinepoxide-type carotenoids from red mamey, Pouteria sapota. AB - New carotenoids, cryptocapsin-5,6-epoxide, 3'-deoxycapsanthin-5,6-epoxide, and cryptocapsin-5,8-epoxides, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Cryptocapsin-5,6-epoxide was prepared by partial synthesis via epoxidation of cryptocapsin, and the (5R,6S)- and (5S,6R)-stereoisomers were identified by HPLC-ECD analysis. Spectroscopic data of the natural (anti) and semisynthetic (syn) derivatives obtained by acid-catalyzed rearrangement of cryptocapsin-5,8-epoxide stereoisomers were compared for structural elucidation. Chiral HPLC separation of natural and semisynthetic samples of cryptocapsin-5,8 epoxides was performed, and HPLC-ECD analysis allowed configurational assignment of the separated stereoisomers. PMID- 23451824 TI - Modification of carotenoid levels by abscission agents and expression of carotenoid biosynthetic genes in 'valencia' sweet orange. AB - The effect of 5-chloro-3-methyl-4-nitro-1H-pyrazole (CMNP) and ethephon on peel color, flavedo carotenoid gene expression, and carotenoid accumulation was investigated in mature 'Valencia' orange ( Citrus sinensis L. Osbeck) fruit flavedo at three maturation stages. Abscission agent application altered peel color. CMNP was more effective than ethephon in promoting green-to-red (a) and blue-to-yellow (b) color at the middle and late maturation stages and total carotenoid changes at all maturation stages. Altered flow of carotenoid precursors during maturation due to abscission agents was suggested by changes in phytoene desaturase (Pds) and zeta-carotene desaturase (Zds) gene expression. However, each abscission agent affected downstream expression differentially. Ethephon application increased beta-carotene hydroxilase (beta-Chx) transcript accumulation 12-fold as maturation advanced from the early to middle and late stages. CMNP markedly increased beta- and epsilon-lycopene cyclase (Lcy) transcript accumulation 45- and 15-fold, respectively, at midmaturation. Patterns of carotenoid accumulation in flavedo were supported in part by gene expression changes. CMNP caused greater accumulation of total flavedo carotenoids at all maturation stages when compared with ethephon or controls. In general, CMNP treatment increased total red carotenoids more than ethephon or the control but decreased total yellow carotenoids at each maturation stage. In control fruit flavedo, total red carotenoids increased and yellow carotenoids decreased as maturation progressed. Trends in total red carotenoids during maturation were consistent with measured a values. Changes in carotenoid accumulation and expression patterns in flavedo suggest that regulation of carotenoid accumulation is under transcriptional, translational, and post-translational control. PMID- 23451825 TI - Reliable measurement of the receding contact angle. AB - Surface wettability is usually evaluated by the contact angle between the perimeter of a water drop and the surface. However, this single measurement is not enough for proper characterization, and the so-called advancing and receding contact angles also need to be measured. Measuring the receding contact angle can be challenging, especially for extremely hydrophobic surfaces. We demonstrate a reliable procedure by using the common needle-in-the-sessile-drop method. Generally, the contact line movement needs to be followed, and true receding movement has to be distinguished from "pseudo-movement" occurring before the receding angle is reached. Depending on the contact angle hysteresis, the initial size of the drop may need to be surprisingly large to achieve a reliable result. Although our motivation for this work was the characterization of superhydrophobic surfaces, we also show that this method works universally ranging from hydrophilic to superhydrophobic surfaces. PMID- 23451826 TI - Apocrine carcinoma of the scrotum with extramammary Paget's disease. PMID- 23451828 TI - The microtubule-associated kinase-like protein RUNKEL functions in somatic and syncytial cytokinesis. AB - The microtubule (MT)-associated putative kinase RUNKEL (RUK) is an important component of the phragmoplast machinery involved in cell plate formation in Arabidopsis somatic cytokinesis. Since loss-of-function ruk mutants display seedling lethality, it was previously not known whether RUK functions in mature sporophytes or during gametophyte development. In this study we utilized RUK proteins that lack the N-terminal kinase domain to further examine biological processes related to RUK function. Truncated RUK proteins when expressed in wild type Arabidopsis plants cause cellularization defects not only in seedlings and adult tissues but also during male meiocyte development, resulting in abnormal pollen and reduced fertility. Ultrastructural analysis of male tetrads revealed irregular and incomplete or absent intersporal cell walls, caused by disorganized radial MT arrays. Moreover, in ruk mutants endosperm cellularization defects were also caused by disorganized radial MT arrays. Intriguingly, in seedlings expressing truncated RUK proteins, the kinesin HINKEL, which is required for the activation of a mitogen-activated protein kinase signaling pathway regulating phragmoplast expansion, was mislocalized. Together, these observations support a common role for RUK in both phragmoplast-based cytokinesis in somatic cells and syncytial cytokinesis in reproductive cells. PMID- 23451829 TI - Facile synthesis of graphene/metal nanoparticle composites via self-catalysis reduction at room temperature. AB - Graphene/metal nanoparticle (NP) composites have attracted great interest for various applications as catalysts, electrodes, sensors, etc., due to their unique structures and extraordinary properties. A facile synthesis of graphene/metal NP composites with good control of size and morphology of metal NPs is critical to the practical applications. A simple method to synthesize graphene/metal NPs under a controllable manner via a self-catalysis reduction at room temperature has been developed in this paper. At first, metal NPs with desirable size and morphology were decorated on GO and then used as catalyst to accelerate the hydrolysis reaction of NaBH4 to reduce the graphene oxide. Compared to the existing methods, the method reported here features several advantages in which graphene/metal NPs are prepared without using toxic and explosive reductant, such as hydrazine or its derivatives, making it environmentally benign, and the reaction can be processed at room temperature with high efficiency and in a large range of pH values. The approach has been demonstrated to successfully synthesize graphene composites with various metal NPs in large quantity, which opens up a novel and simple way to prepare large-scale graphene/metal or graphene/metal oxide composites under mild conditions for practical applications. For example, graphene/AuNP composites synthesized by the method show excellent catalytic capability. PMID- 23451830 TI - Tumor-targeting and microenvironment-responsive smart nanoparticles for combination therapy of antiangiogenesis and apoptosis. AB - Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles' internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF-DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy. PMID- 23451831 TI - Oral clindamycin and rifampicin in the treatment of hidradenitis suppurativa-acne inversa: a prospective study on 23 patients. PMID- 23451832 TI - Systematic review of communication partner training in aphasia: methodological quality. AB - Twenty-three studies identified from a previous systematic review examining the effects of communication partner training on persons with aphasia and their communication partners were evaluated for methodological quality. Two reviewers rated the studies on defined methodological quality criteria relevant to each study design. There were 11 group studies, seven single-subject participant design studies, and five qualitative studies. Quality scores were derived for each study. The mean inter-rater reliability of scores for each study design ranged from 85-93%, with Cohen's Kappa indicating substantial agreement between raters. Methodological quality of research on communication partner training in aphasia was highly varied. Overall, group studies employed the least rigorous methodology as compared to single subject and qualitative research. Only two of 11 group studies complied with more than half of the quality criteria. No group studies reported therapist blinding and only one group study reported participant blinding. Across all types of studies, the criterion of treatment fidelity was most commonly omitted. Failure to explicitly report certain methodological quality criteria may account for low ratings. Using methodological rating scales specific to the type of study design may help improve the methodological quality of aphasia treatment studies, including those on communication partner training. PMID- 23451833 TI - Automated in-chamber specimen coating for serial block-face electron microscopy. AB - When imaging insulating specimens in a scanning electron microscope, negative charge accumulates locally ('sample charging'). The resulting electric fields distort signal amplitude, focus and image geometry, which can be avoided by coating the specimen with a conductive film prior to introducing it into the microscope chamber. This, however, is incompatible with serial block-face electron microscopy (SBEM), where imaging and surface removal cycles (by diamond knife or focused ion beam) alternate, with the sample remaining in place. Here we show that coating the sample after each cutting cycle with a 1-2 nm metallic film, using an electron beam evaporator that is integrated into the microscope chamber, eliminates charging effects for both backscattered (BSE) and secondary electron (SE) imaging. The reduction in signal-to-noise ratio (SNR) caused by the film is smaller than that caused by the widely used low-vacuum method. Sample surfaces as large as 12 mm across were coated and imaged without charging effects at beam currents as high as 25 nA. The coatings also enabled the use of beam deceleration for non-conducting samples, leading to substantial SNR gains for BSE contrast. We modified and automated the evaporator to enable the acquisition of SBEM stacks, and demonstrated the acquisition of stacks of over 1000 successive cut/coat/image cycles and of stacks using beam deceleration or SE contrast. PMID- 23451834 TI - Use of human embryonic stem cells and umbilical cord blood stem cells for research and therapy: a prospective survey among health care professionals and patients in Switzerland. AB - BACKGROUND: Scientific progress in the biology of hematopoietic stem cells (HSCs) provides opportunities for advances in therapy for different diseases. While stem cell sources such as umbilical cord blood (UCB) are unproblematic, other sources such as human embryonic stem cells (hESCs) raise ethical concerns. STUDY DESIGN AND METHODS: In a prospective survey we established the ethical acceptability of collection, research, and therapy with UCB HSCs versus hESCs among health care professionals, pregnant women, patients undergoing in vitro fertilization therapy, parents, and HSC donors and recipients in Switzerland. RESULTS: There was overall agreement about an ethical justification for the collection of UCB for research and therapy in the majority of participants (82%). In contrast, research and therapy with hESCs was acceptable only by a minority (38% of all responders). The collection of hESCs solely created for HSC collection purposes met overall with the lowest approval rates. Hematologists displayed among the participants the highest acceptance rates for the use of hESCs with 55% for collection, 63% for research, and 73% for therapy. CONCLUSIONS: This is the first study assessing the perception of hESCs for research and therapy in comparison with UCB HSCs in different target groups that are exposed directly, indirectly, or not at all to stem cell-based medicine. Our study shows that the debate over the legitimacy of embryo-destructive transplantation medicine is far from over as particularly hESC research continues to present an ethical problem to an overwhelming majority among laypersons and even among health care professionals. PMID- 23451835 TI - The effects of increasing body mass index on heartburn severity, frequency and response to treatment with dexlansoprazole or lansoprazole. AB - BACKGROUND: Higher body mass index (BMI) is a recognised risk factor for gastro oesophageal reflux disease (GERD). Data regarding the impact of BMI on proton pump inhibitor (PPI) therapy are conflicting. AIM: To assess the impact of BMI on baseline heartburn symptom severity and frequency and response to PPI therapy in patients with non-erosive GERD (NERD) or erosive oesophagitis (EO). METHODS: In post hoc analyses of phase 3 trial data, 621 NERD and 2692 EO patients were stratified by BMI (<25, 25 to <30 and >=30 kg/m(2) ). NERD patients received either dexlansoprazole MR 30 mg or placebo daily for 4 weeks. EO patients received either dexlansoprazole MR 60 mg or lansoprazole 30 mg for 8 weeks. Symptom frequency and severity were assessed at baseline and subsequently by daily diary. RESULTS: In both the NERD and EO cohorts, baseline heartburn severity increased with increasing BMI. The impact of PPI therapy on the reduction in heartburn symptom frequency and severity in both NERD and EO patients was similar across BMI categories. EO healing rates in patients treated with dexlansoprazole but not lansoprazole were higher in obese patients compared with those with a BMI <30 kg/m(2) . Differences between the PPIs were small. CONCLUSIONS: The PPIs evaluated in this study reduced the frequency and severity of 24-h heartburn regardless of baseline BMI. In addition, because patients with higher BMI have more severe symptoms at baseline, they may experience greater therapeutic gain with dexlansoprazole (NERD and erosive oesophagitis) and possibly lansoprazole (erosive oesophagitis) treatment. PMID- 23451836 TI - Effect of bait quantity and trap color on the trapping efficacy of the pheromone trap for the red palm weevil, Rhynchophorus ferrugineus. AB - The red palm weevil, Rhynchophorus ferrugineus (Olivier) (Curculionidae: Coleoptera), is not native to the United Arab Emirates (UAE). Since its arrival in 1985, it has been causing major damage to date palm trees. A primary control strategy has been the use of pheromone baited traps. The objectives of this study were to determine the quantity of bait, and the best trap color, to obtain the maximum catch of R. ferrugineus under field conditions in the UAE. Traps with 100, 300, or 500 g of dates as bait collected the same number of R. ferrugineus adults. Captures in black traps were significantly higher than captures in red, yellow, or white traps. Thus, using a black pheromone trap containing 100 g of dates can significantly enhance R. ferrugineus control efforts, and can help considerably in reducing the red palm weevil's deleterious impact on date palm production in UAE. PMID- 23451837 TI - Sleep quality in patients with alopecia areata: questionnaire-based study. PMID- 23451838 TI - Facile, efficient, and diastereoselective synthesis of heterohelicene-like molecules. AB - A concise and efficient route to new and interesting heterohelicene-like molecules has been developed through the one-pot, cascade reductive coupling reaction of o-hydroxydiimines or o-nitrodiimines and triphosgene in the presence of TiCl4/Sm. Purification of the final products only required a single recrystallization leading to high purity. High diastereoselectivity was also achieved, and two structures of the final products were confirmed by X-ray diffraction analysis. PMID- 23451839 TI - Congenital malformations in infants conceived following assisted reproductive technology in comparison with spontaneously conceived infants. AB - OBJECTIVE: To evaluate the risk for congenital malformations diagnosed at birth following assisted reproductive technology (ART) treatments compared with live births conceived spontaneously. METHODS: A retrospective cohort study including 9042 live births following ART and 213 288 spontaneously conceived (SC) live births during the period 1997-2004.The cohort was linked to the national live birth registry to determine the outcome of the pregnancies including congenital malformations. RESULTS: An increased adjusted risk for all congenital malformations was observed in ART compared with SC infants [2.4% versus 1.9%; ORadj = 1.45; 95% CI: 1.26, 1.68]. The increased risk was observed in singleton births [2.4% versus 1.8%; ORadj = 1.41; 95% CI: 1.14, 1.71] but not in the ART conceived multiple births [2.5% versus 2.6%.; ORadj = 1.15; 95% CI: 0.90, 1.46]. Significantly increased adjusted risks for nervous, circulatory, digestive and genital system malformations were evident in the ART singleton group compared to SC infants. In addition, increased risks were also observed in separate comparisons of IVF births versus SC [ORadj = 1.28; 95% CI: 1.00, 1.63] and ICSI births versus SC [ORadj = 1.56; 95% CI: 1.31, 1.84]. Data regarding pregnancy termination or congenital malformation diagnosed later in life were not included. CONCLUSION: Infants born following ART were at significantly increased risk for congenital malformations compared to live birth conceived spontaneously. PMID- 23451840 TI - Familial colorectal cancer risk assessment needs improvement for more effective cancer prevention in relatives. AB - AIM: Twelve to thirty % of colorectal cancer (CRC) patients and relatives with an increased familial risk of CRC are referred for preventive measures. New guidelines recommend genetic counselling for high-risk families and surveillance colonoscopy for moderate-risk families. Assessment of familial risk of CRC and referral rates for these preventive measures were determined 1 year after the introduction of new guidelines. METHOD: Assessment of familial risk of CRC and referral for preventive measures were measured in clinical practice among 358 patients with CRC in 18 hospitals using medical records and questionnaires. Additionally, a knowledge survey was performed among 312 clinicians. RESULTS: Sixty-seven % of patients with an increased familial risk (n = 65/97) were referred for preventive measures, as were 23% (61/261) of low-risk patients. The uptake of genetic counselling in high-risk families was 33% (12/36). The uptake of surveillance colonoscopy in moderate-risk families was 34% (21/61). In the knowledge survey clinicians correctly determined familial risk in 55% and preventive measures in 65% of cases. CONCLUSION: Currently 67% of individuals with an increased familial risk of CRC were referred for preventive measures. Only one-third were referred in accordance with guidelines. PMID- 23451842 TI - Preparation and oral bioavailability study of curcuminoid-loaded microemulsion. AB - Curcuminoid, a dietary polyphenolic compound, has poor water solubility and low bioavailability following oral administration. The aim of this study was to develop a formulation of curcuminoid-loaded microemulsion (Cur-ME) to improve its oral bioavailability. The optimized Cur-ME formulation was prepared by using labrafac lipophile WL 1349, cremophor RH 40, and glycerine as the oil phase, the surfactant, and the cosurfactant, respectively. Pharmacokinetics and bioavailability of curcuminoid suspension and Cur-ME were evaluated and compared in rats. Plasma bisdemethoxycurcumin (BDMC), treated as the representing component of curcuminoid, was determined by high-performance liquid chromatography with fluorescence detector. After gavage administration of curcuminoid suspension, the plasma BDMC level was very low, below 5 ng/mL, whereas for Cur-ME, double peak of maximum concentrations were observed. The relative bioavailability of Cur-ME was enhanced in an average of 9.6-fold that of curcuminoid suspension. It was concluded that the bioavailbility of curcuminoid was enhanced greatly by the microemulsion. PMID- 23451843 TI - The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. AB - It has been suggested that the intake of certain fatty acids may influence the risk of dementia. However, current reviews have focused only on the therapeutic effects of omega-3 fatty acids, mostly as supplements. To date, the evidence for the relevance of the omega-6/omega-3 ratio has been neglected. Therefore, we searched the databases Alois, Medline, Biosis, Embase, Cochrane Central Register of Controlled Trials, and The Cochrane Database of Systematic Reviews for "essential fatty acids" and "dementia" and aimed to conduct a comprehensive review across study types. All studies that reported on the association between the n-6/n-3 ratio and dementia or cognitive decline were selected. In the 13 animal studies we examined, the dietary n-6/n-3 ratio was shown to affect brain composition, Alzheimer's disease pathology, and behavior. Our review of the 14 studies in humans that fulfilled the selection criteria (7 prospective studies, 3 cross-sectional studies, 1 controlled trial, 3 case-control studies) provided evidence, albeit limited, supporting an association between the n-6/n-3 ratio, cognitive decline, and incidence of dementia. This review supports growing evidence of a positive association between the dietary n-6/n-3 ratio and the risk of Alzheimer's disease. PMID- 23451844 TI - Tackling the aging process with bio-molecules: a possible role for caloric restriction, food-derived nutrients, vitamins, amino acids, peptides, and minerals. AB - Aging is a multifactorial process leading to general deterioration in many tissues and organs, accompanied by an increased incidence and severity of a wide variety of chronic, incurable, and often fatal diseases. A possibility of slowing down the aging process and improving the quality of life in old age by nutritional intervention has renewed the interest of the scientific world in anti aging therapies. These include potential dietary interventions, adherence to nutrition, hormonal and cell-based therapies, genetic manipulations, and anti aging supplements or nutrients. This review addresses strategies to slow the aging process by caloric restriction and the use of nutritional supplements. PMID- 23451845 TI - Persistent food insecurity is associated with higher levels of cost-related medication nonadherence in low-income older adults. AB - The purpose of this study was to examine relationships between changes in food insecurity (FI) and cost-related medication nonadherence (CRN) among Older Americans Act Nutrition Program participants and wait-listed individuals in Georgia. This study used data collected from 3 waves of self-administered mail surveys conducted 4 months apart in 2008 and 2009 (n = 664, mean age 74.6 +/- 8.9 years, 71.5% female, 31.0% African American). FI was assessed by using a validated 6-item U.S. Household Food Security Survey Module. Practice of 5 CRN behaviors was evaluated. Changes in FI and CRN were determined based on >= 2 repeated measures. Participants with persistent FI and CRN were more likely to be younger, low-income, and in poorer health. After controlling for potential confounders, persistently food insecure individuals and those who became food insecure showed 8.2 (95% CI: 5.4-12.5) times and 5.3 (95% CI: 3.2-8.8) times increased odds of reporting higher levels of CRN than persistently food secure individuals. PMID- 23451846 TI - Fasting periods in older patients attending a South London emergency department. AB - There is increasing recognition of the deleterious effects of poor nutrition on health care outcomes. Older patients appear particularly vulnerable to the effects of undernutrition. This includes both low intake as patients and chronic preadmission undernutrition. This study investigates nutrition during a critical intervening period when patients present to a hospital emergency department (ED) in the first half of the day. One third of observed patients sustained periadmission fasts in excess of 18 hours. This fasting period showed significant positive correlation to age (correlation coefficient = 0.34, P < 0.05). Analysis of the results by gender showed that men who were older than the average cohort age of 53.6 years fasted for a significantly longer period in the hospital than their younger counterparts (P < 0.02). This comparison did not reach significant levels for female patients (P > 0.05). This study raises the question as to whether food should be routinely provided in the ED unless there is reason to withhold it. Particular care should be taken to avoid unnecessary delays in offering food to older patients. There may also be a need to ensure that geriatric care indicators are considered individually for each gender. PMID- 23451847 TI - Malnutrition and associated clinical outcomes in hospitalized patients aged 60 and older: an observational study in rural Wales. AB - This is a prospective observational study of malnutrition and six-week clinical outcomes on a previously unstudied population of older hospital inpatients in rural Wales. One hundred and twenty-six of 152 patients older than 60 years identified on the wards surveyed were included. Patients unable to give informed consent and those too ill to participate were excluded. The main findings were that 55 (44%) were malnourished at the first assessment, that nutrition risk predicted mortality (P = 0.019), length of hospital stay (P = 0.026), and discharge destination (P = 0.005), that only 17 patients had received nutritional support, and that many of those who received support nevertheless had lost weight at the 6-week follow-up. This confirms previous research which suggests that, while malnutrition is associated with poorer clinical outcomes, nutrition support for older patients in hospital nevertheless is often insufficient. PMID- 23451848 TI - Support for nutrition from the older Americans act programs: a clarification on its 40th anniversary. PMID- 23451849 TI - Epidemiological hurdles for the determination of the prevalence of chronic pain with neuropathic features. PMID- 23451850 TI - A comparison of stigma among patients with leprosy in rural Tanzania and urban United States: a role for public health in dermatology. AB - BACKGROUND: Leprosy is a chronic infection of the skin and peripheral nerves caused by the bacterium Mycobacterium leprae, which causes peripheral insensitivity and disfigurements of the skin, limbs, and digits. Social stigma is a common consequence of leprosy and may differ according to level of physical disfigurement and geographic location. The objective of this study was to assess social stigma encountered by patients with leprosy in clinical settings located in rural Tanzania and urban USA and to compare the social stigma reported in these regions. METHODS: A total of 56 respondents were recruited from one leprosy inpatient facility in Shirati, Tanzania (n = 28), and one outpatient clinic in Los Angeles, USA (n = 28). Cross-sectional data were obtained from face to-face interviews, which were conducted with respondents at each clinic location. Measures of perceived stigma were assessed in family relationship, vocational, social interaction, and interpersonal contexts. RESULTS: Patients in Tanzania, as compared with those in the USA, reported significantly higher levels of stigma in family relationship and vocational contexts. Tanzanian patients also reported higher levels of stigma in social interaction and self esteem contexts, but these differences were marginally significant and may reflect the small sample size. CONCLUSIONS: Leprosy-related social stigma is a major problem in regions of both developed and developing countries; however, patients with leprosy in developing countries reported higher levels of stigma in four social contexts. A public health role in dermatology is discussed as an agent of early diagnosis, control, and education in order to reduce social stigma and promote social rehabilitation. PMID- 23451851 TI - Embryo defective12 encodes the plastid initiation factor 3 and is essential for embryogenesis in maize. AB - Embryo-specific mutants in maize define a unique class of genetic loci that affect embryogenesis without a significant deleterious impact on endosperm development. Here we report the characterization of an embryo specific12 (emb12) mutant in maize. Embryogenesis in the emb12 mutants is arrested at or before transition stage. The mutant embryo at an early stage exhibits abnormal cell structure with increased vacuoles and dramatically reduced internal membrane organelles. In contrast, the mutant endosperm appears normal in morphology, cell structure, starch, lipid and protein accumulation. The Emb12 locus was cloned by transposon tagging and predicts a protein with a high similarity to prokaryotic translation initiation factor 3 (IF3). EMB12-GFP fusion analysis indicates that EMB12 is localized in plastids. The RNA in situ hybridization and protein immunohistochemical analyses indicate that a high level of Emb12 expression localizes in the embryo proper at early developmental stages and in the embryo axis at later stages. Western analysis indicates that plastid protein synthesis is impaired. These results indicate that Emb12 encodes the plastid IF3 which is essential for embryogenesis but not for endosperm development in maize. PMID- 23451852 TI - Pimecrolimus vs. tacrolimus for the topical treatment of unresponsive oral erosive lichen planus: a 8 week randomized double-blind controlled study. AB - BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease, affecting nearly 1-2% of the population; Proposed therapies are usually symptomatic and numerous drugs have been used, but recently, it has been published that there is insufficient evidence to support the effectiveness of any specific treatment as being superior. To the best of our knowledge, direct evaluation of the efficacy of topically applied pimecrolimus and tacrolimus in the treatment of atrophic erosive OLP, refractory to topical steroids, is still lacking. OBJECTIVES: To assess the efficacy and safety of topical calcineurin inhibitors for unresponsive OLP. An 8 week randomized, double-blind controlled trial, followed by a 6 month follow-up period. Patients were treated with either pimecrolimus 1% cream or tacrolimus 0.1% ointment, both mixed with an equivalent amount of 4% hydroxyethyl cellulose gel. The medications were to be applied twice daily for 2 months. Each patient was examined at the beginning of therapy, and then every 2 weeks during the treatment and every 3 months of follow-up. Main outcome measures were: (i) to compare the effectiveness of topically applied pimecrolimus and tacrolimus; (ii) to evaluate which is more cost-effective; (iii) to determine which drug is faster in reducing signs and symptoms and (iv) which gives the longest remission. RESULTS: Thirty patients were involved in the study. Both drugs were effective at inducing clinical improvement, with no statistical difference. Pimecrolimus creams revealed a significantly better stability of the therapeutic effectiveness (P = 0.031). CONCLUSION: Both medications would currently appear to be a treatment of choice for patients with unresponsive atrophic-erosive OLP. Pimecrolimus seemed to be more effective in providing long-term resolution of signs and symptoms. Future efforts are however needed to obtain more objective evidence of the benefit of these medications in the treatment of immunologically mediated oral mucosal lesion. PMID- 23451853 TI - Selective functionalization of the internal and the external surfaces of mesoporous silicon by liquid masking. AB - A general approach for selective, differential functionalization of the interior and exterior surfaces of mesoporous Si is reported. The method employs two immiscible liquids, one inert and the other chemically reactive with the porous Si nanostructure. First, a porous Si sample is prepared by electrochemical etch and then it is mildly oxidized, which places a thin layer of silicon oxide at the surface. The inner pore walls of the partially oxidized porous Si film are then infiltrated with an inert liquid (octane). The sample is then immersed in aqueous solution containing hydrogen fluoride (HF), which serves as the reactive liquid. The hydrophobic phase is retained in the interior of the porous nanostructure, and HF(aq) attacks only the exposed surfaces of the oxidized porous Si sample, generating a hydrophobic, hydrogen-terminated (Si-H) outer layer. The reaction is self-limiting due to the immiscibility of octane and water, and the extent of penetration of the Si-H surface into the porous layer is dependent on the time of exposure to HF(aq). The Si-H surface can then be modified by thermal hydrosilylation (1-dodecene or 10-bromo-1-decene) in a subsequent step, resulting in a bifunctional porous Si film containing hydrophobic pore entrances to hydrophilic inner pores. The hydrophobic dodecyl species at the mouths of the pores is found to form a barrier for molecular transport; it decreases the rate of leaching (into water) of a rhodamine test molecule that is preloaded into the sample by >8 fold. PMID- 23451854 TI - Facial nerve motor evoked potentials during skull base surgery to monitor facial nerve function using the threshold-level method. AB - OBJECT: During surgeries that put the facial nerve at risk for injury, its function can be continuously monitored by transcranial facial nerve motor evoked potentials (FNMEPs) in facial nerve target muscles. Despite their advantages, FNMEPs are not yet widely used. While most authors use a 50% reduction in FNMEP response amplitudes as a warning criterion, in this paper the authors' approach was to keep the response amplitude constant by increasing the stimulation intensity and to establish a warning criterion based on the "threshold-level" method. METHODS: The authors included 34 consecutive procedures involving 33 adult patients (median age 47 years) in whom FNMEPs were monitored. A threshold increase greater than 20 mA for eliciting FNMEPs in the most reliable facial nerve target muscle was considered a prediction of reduced postoperative facial nerve function, and subsequently a warning was issued to the surgeon. Preoperative and early postoperative function was documented using the House Brackmann grading system. RESULTS: Monitoring of FNMEPs was feasible in all 34 surgeries in at least one facial nerve target muscle. The mentalis muscle yielded the best results. The House-Brackmann grade deteriorated in 17 (50%) of 34 cases. The warning criterion was reached in 18 (53%) of 34 cases, which predicted an 83% risk of House-Brackmann grade deterioration. Sensitivity amounted to 88% (CI 64% 99%) and specificity to 82% (CI 57%-96%). Deterioration of FNMEPs and a worse House-Brackmann grade showed a high degree of association (p < 0.001). The impact of FNMEP monitoring on surgical strategy is exemplified in an illustrative case. CONCLUSIONS: In surgeries that put the facial nerve at risk, the intraoperative increase in FNMEP stimulation threshold was closely correlated to postoperative facial nerve dysfunction. Monitoring of FNMEPs is a valid indicator of facial nerve function in skull base surgery. It should be used as an adjunct to direct electrical facial nerve stimulation and continuous electromyographic monitoring of facial nerve target muscles. PMID- 23451855 TI - An invisible template method toward gold regular arrays of nanoflowers by electrodeposition. AB - A new approach, an invisible template method that is realized through controlling the interface electroconductivity of an electrode surface, is presented to synthesize gold regular arrays of nanoflowers with variable separations through further electrochemical deposition. Using polystyrene monolayer colloidal crystals as the first template, a hexagonally packed 1-hexadecanethiol pattern was self-assembled and used as an invisible template to control the interface electroconductivity. Further electrochemical deposition under appropriate conditions can easily lead to gold regular arrays of nanoflowers. This new approach demonstrates a simple route to the fabrication of novel gold micro/nanostructured arrays that may find applications as SERS active substrates, superhydrophobic materials, and so forth. PMID- 23451857 TI - Trichorhinophalangeal syndrome with low expression of TRPS1 on epidermal and hair follicle epithelial cells. AB - Trichorhinophalangeal syndrome (TRPS) is an autosomal-dominant congenital hair loss disease characterized by sparse and slow-growing scalp hair, craniofacial and skeletal abnormalities, pear-shaped nose, thin upper lip, brittle and thin toenails, and bilateral brachydactyly of the big toes. We report a case of TRPS1 exhibiting these clinical features with a novel heterozygous single nucleotide substitution in exon 3 of the TRPS1 gene. By immunohistochemical analysis of a biopsied specimen of the patient's alopecia lesion, we found for the first time that the expression level of TRPS1 was markedly reduced in the epidermis and the outer root sheath of hair follicles as compared to a normal subject. In addition, higher expression of phospho-Stat3 was found consequent to the loss of TRPS1 in the outer root sheath. PMID- 23451858 TI - [HPV and cervical cancer]. PMID- 23451859 TI - N-heterocyclic carbene-palladium(II)-1-methylimidazole complex catalyzed alpha arylation of oxindoles with aryl chlorides and aerobic oxidation of the products in a one-pot procedure. AB - NHC-Pd(II)-Im complex 1 was found to be an effective catalyst for the alpha arylation of unprotected oxindoles with aryl chlorides to give products 4 in 44 98% yields under a N2 atmosphere. Furthermore, if the reactions were first performed under conditions identical to those for the alpha-arylation reaction for 12 h and then exposed to air for another 3 h, 3-aryl-3-hydroxy-2-oxindoles 5 can be obtained in 49-84% yields in a one-pot procedure. PMID- 23451860 TI - Enzian classification: does it correlate with clinical symptoms and the rASRM score? AB - OBJECTIVE: To assess the extent to which the Enzian classification correlates with the revised American Society for Reproductive Medicine (rASRM) score and clinical symptoms in women with deeply infiltrating endometriosis. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Endometriosis competence center specializing in minimally invasive surgery. PATIENTS: Between 1 January 2009 and 31 December 2011, a total of 194 women underwent surgery due to deeply infiltrating endometriosis. After histological confirmation, they were classified using the rASRM and Enzian systems. Clinical symptoms were recorded preoperatively. INTERVENTIONS: Operative laparoscopy to treat endometriosis. MAIN OUTCOME MEASURES AND RESULTS: A clear correlation was seen between grades of severity in the rASRM score and the Enzian classification (p < 0.001). In addition, the rASRM severity grade and clinical symptoms correlated with the locations in the Enzian classification in relation to deeply infiltrating endometriosis. Pain and dysmenorrhea correlated strongly (p = 0.002, p < 0.001) with the severity grade in the Enzian classification. CONCLUSIONS: Deeply infiltrating endometriosis is well characterized using the Enzian classification as a supplement to the rASRM score. There is also a clear correlation between the rASRM and Enzian classifications, because of the way in which the disease crosses morphological boundaries. The locations in the Enzian classification correlate partially with clinical symptoms, and the classification's severity grades correlate substantially with pain and dysmenorrhea. In view of these clinical results, use of the Enzian classification can be recommended as a supplement to the rASRM score for detailed description of endometriosis. PMID- 23451861 TI - The characterisation and risk factors of ischaemic heart disease in patients with coeliac disease. AB - BACKGROUND: Studies have shown an increased risk of ischaemic heart disease (IHD) in patients with coeliac disease (CD), despite the patients' lack of traditional IHD risk factors. AIM: To characterise IHD according to CD status. METHODS: Data on duodenal or jejunal biopsies were collected in 2006-2008 from all 28 pathology departments in Sweden and were used to define CD (equal to villous atrophy; Marsh stage 3). We used the Swedish cardiac care register SWEDEHEART to identify IHD and to obtain data on clinical status and risk factors at time of first myocardial infarction for this case-only comparison. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). CD patients were compared with general population reference individuals. RESULTS: We identified 1075 CD patients and 4142 reference individuals with subsequent IHD. CD patients with myocardial infarction had lower body mass index (P < 0.001) and cholesterol values (P < 0.001) and were less likely to be active smokers (OR = 0.74; 95% CI = 0.56-0.98) than reference individuals with myocardial infarction. CD patients had less extensive coronary artery disease at angiography (any stenosis: OR = 0.80; 95% CI = 0.66-0.97; three-vessel disease: OR = 0.73; 95% CI = 0.57-0.94); but there was no difference in the proportions of CD patients with positive biochemical markers of myocardial infarction (CD: 92.2% vs. reference individuals: 91.5%, P = 0.766). CONCLUSION: Despite evidence of an increased risk of IHD and higher cardiovascular mortality, patients with coeliac disease with IHD have a more favourable cardiac risk profile compared with IHD in reference individuals. PMID- 23451862 TI - Canakinumab in pediatric rheumatic diseases. AB - INTRODUCTION: Hitherto, some of the most severe forms of arthritis with onset in the neonatal period and early childhood have been resistant to conventional and anti-tumour necrosis factor agents. Recent results from drug trials of novel monoclonal antibodies will significantly alter the treatment of two of these diseases. This review is for canakinumab, a new monoclonal antibody to interleukin 1beta that has been shown to be specifically efficacious in two groups of arthritis with systemic features. AREAS COVERED: The clinical features and treatment to-date in the autoinflammatory disease, cryopyrin associated periodic fever syndrome and systemic juvenile idiopathic arthritis are briefly reviewed. An overview of current IL-1 inhibitors is provided. Clinical trials of Canakinumab in the treatment of these two diseases are evaluated. EXPERT OPINION: The last decade has seen a major advance in treatment leading to remission while on therapy for many children with CAPS and sJIA. The outcomes of the anti-IL 1beta and the anti-IL-6 trials for sJIA are quite similar and do not enable preferential use of either biological in a given patient. PMID- 23451863 TI - Effects of eccentric exercise on branched-chain amino acid profiles in rat serum and skeletal muscle. AB - Supplementation of branched-chain amino acid (BCAA) is often used to attenuate exercise-induced skeletal muscle damage and promote adaptation, but no definitive conclusion on the benefits of BCAA on muscle recovery after injurious exercise can be drawn. Exploration of the systematic BCAA alteration in muscular injury repair stage per se without any BCAA supplement should provide some useful information in favour of BCAA application in muscle regeneration after injury. One bout of 90-min downhill-running exercise was performed to cause rat skeletal muscle injury. After exercise, myofibrillar BCAA concentrations showed minor changes compared with exercise before, while serum concentrations of BCAA were lower after exercise. Especially, serum leucine, isoleucine and total BCAA concentrations 2 weeks post-run were significantly lower than normal values of exercise before (p = 0.008, p = 0.041, p = 0.015). The data demonstrate that a single eccentric exercise can significantly decrease the serum BCAA concentrations, which mean high utilization of BCAA for myogenesis after injurious exercise. PMID- 23451864 TI - Age-related elevations in intraindividual variability on associative memory tasks. AB - Age-related elevations in cognitive intraindividual variability (IIV) have been linked to reduced executive control associated with decline in frontal lobe function. However, the theoretical conceptualization of IIV in cognitive aging may be constrained by limited study of the extent to which age-related elevations in IIV may be observed on cognitive processes sensitive to aging, but not primarily reliant on frontal systems. To address this empirical gap, the present study investigated age-related differences in IIV on two associative memory tasks. Older adults showed elevated IIV on both tasks compared to younger adults. Elevated IIV was correlated with slowed response speed across both groups and tasks; IIV-accuracy correlations were mixed. Findings suggest that IIV may reflect age-related decline in distributed neural networks, including medial temporal regions, in addition to frontal systems dysfunction. PMID- 23451865 TI - Oxo-functionalization and reduction of the uranyl ion through lanthanide-element bond homolysis: synthetic, structural, and bonding analysis of a series of singly reduced uranyl-rare earth 5f1-4f(n) complexes. AB - The heterobimetallic complexes [{UO2Ln(py)2(L)}2], combining a singly reduced uranyl cation and a rare-earth trication in a binucleating polypyrrole Schiff base macrocycle (Pacman) and bridged through a uranyl oxo-group, have been prepared for Ln = Sc, Y, Ce, Sm, Eu, Gd, Dy, Er, Yb, and Lu. These compounds are formed by the single-electron reduction of the Pacman uranyl complex [UO2(py)(H2L)] by the rare-earth complexes Ln(III)(A)3 (A = N(SiMe3)2, OC6H3Bu(t)2-2,6) via homolysis of a Ln-A bond. The complexes are dimeric through mutual uranyl exo-oxo coordination but can be cleaved to form the trimetallic, monouranyl "ate" complexes [(py)3LiOUO(MU-X)Ln(py)(L)] by the addition of lithium halides. X-ray crystallographic structural characterization of many examples reveals very similar features for monomeric and dimeric series, the dimers containing an asymmetric U2O2 diamond core with shorter uranyl U?O distances than in the monomeric complexes. The synthesis by Ln(III)-A homolysis allows [5f(1) 4f(n)]2 and Li[5f(1)-4f(n)] complexes with oxo-bridged metal cations to be made for all possible 4f(n) configurations. Variable-temperature SQUID magnetometry and IR, NIR, and EPR spectroscopies on the complexes are utilized to provide a basis for the better understanding of the electronic structure of f-block complexes and their f-electron exchange interactions. Furthermore, the structures, calculated by restricted-core or all-electron methods, are compared along with the proposed mechanism of formation of the complexes. A strong antiferromagnetic coupling between the metal centers, mediated by the oxo groups, exists in the U(V)Sm(III) monomer, whereas the dimeric U(V)Dy(III) complex was found to show magnetic bistability at 3 K, a property required for the development of single-molecule magnets. PMID- 23451866 TI - Does tuition for journal referees work? A quantitative evaluation of a half-day tuition course. AB - AIM: Most consultants participating as referees in the peer review process of papers submitted to scholarly journals have had no training or tuition. This study attempted to evaluate the effect on reviewing of a half-day course held at the Royal Society of Medicine. METHOD: Registered consultant delegates were sent two 'doctored' papers, a case report and an original paper, well before the meeting to review at home using the standard computerized score sheet issued with referee requests by Colorectal Disease. At the start of the meeting the scores were entered into a computer as 'Before'. After each paper had been presented and then discussed, it was re-marked to give the 'After' score. The Before and After scores were compared with the post-meeting feedback forms. RESULTS: The Before and After scores provided by the participants for the two papers each reviewed were not significantly different for the questions relating to the publication/rejection decision. The Before score was higher than the After score for questions relating to the Abstract, Introduction and Method sections. Feedback forms regarding the tuition were universally positive and appreciative. CONCLUSION: Consultants already have the expertise to decide whether a paper should be rejected. The study day appears to give an additional insight that may change an initial opinion. In general a paper scored before the meeting was scored lower after it was presented and discussed at the meeting (the tuition). PMID- 23451867 TI - Assembling tin dioxide quantum dots to graphene nanosheets by a facile ultrasonic route. AB - Nanocomposites have significant potential in the development of advanced materials for numerous applications. Tin dioxide (SnO2) is a functional material with wide-ranging prospects because of its high electronic mobility and wide band gap. Graphene as the basic plane of graphite is a single atomic layer two dimensional sp(2) hybridized carbon material. Both have excellent physical and chemical properties. Here, SnO2 quantum dots/graphene composites have been successfully fabricated by a facile ultrasonic method. The experimental investigations indicated that the graphene was exfoliated and decorated with SnO2 quantum dots, which was dispersed uniformly on both sides of the graphene. The size distribution of SnO2 quantum dots was estimated to be ranging from 4 to 6 nm and their average size was calculated to be about 4.8 +/- 0.2 nm. This facile ultrasonic route demonstrated that the loading of SnO2 quantum dots was an effective way to prevent graphene nanosheets from being restacked during the reduction. During the calcination process, the graphene nanosheets distributed between SnO2 nanoparticles have also prevented the agglomeration of SnO2 nanoparticles, which were beneficial to the formation of SnO2 quantum dots. PMID- 23451870 TI - Diversity of non-biting midge larvae assemblages in the Jacui River basin, Brazil. AB - The richness and composition of a mountain-river chironomid larvae assemblage in the Jacui River basin, Brazil were studied, and compared with other riverine non biting midge larvae assemblages previously studied in the country. Additionally, the influence of some regional-scale environmental characteristics on the spatial distribution of these assemblages was tested. The specimens were collected at 12 sites in the middle course of the Jacui River basin (in the state of Rio Grande do Sul) between April 2000 and May 2002. Around 100 taxa were recorded. The dominant taxa belonged to the genera Rheotanytarsus, Cricotopus, Polypedilum, and Pseudochironomus. Twenty-two rare taxa were found, representing 22% of the total of taxa inventoried. Fourteen genera (Aedokritus, Axarus, Endotribelos, Kiefferulus, Manoa, Oukuriella, Phaenopsectra, Stenochironomus, Xenochironomus, Xestochironomus, Cardiocladius, Metriocnemus, Paracladius, and Rheocricotopus) represent new occurrences in Rio Grande do Sul. The similarity analysis of the chironomid larvae assemblages inventoried in 32 regions of Brazil indicated five groups with similarity higher than 50%. The groups, when the effects of spatial autocorrelation were removed, displayed a weak positive correlation between the assemblage composition and the aquatic system or hydraulic conditions and the hydrographic basin, and a weak negative correlation in relation to the biome. The altitude showed no correlation with the composition of the assemblage. The relatively high richness of the region surveyed in relation to other Brazilian regions corroborates some tendencies already noted in other parts of the world, such as: i) lotic systems may constitute an exception to the rule that diversity is greater in tropical regions, ii) regions of transitional relief may contain the greatest richness of Chironomidae, and iii) in rivers, the group might have its spatial distribution influenced to a greater extent by local environmental characteristics than by regional ones. PMID- 23451868 TI - Flap endonuclease 1. AB - First discovered as a structure-specific endonuclease that evolved to cut at the base of single-stranded flaps, flap endonuclease (FEN1) is now recognized as a central component of cellular DNA metabolism. Substrate specificity allows FEN1 to process intermediates of Okazaki fragment maturation, long-patch base excision repair, telomere maintenance, and stalled replication fork rescue. For Okazaki fragments, the RNA primer is displaced into a 5' flap and then cleaved off. FEN1 binds to the flap base and then threads the 5' end of the flap through its helical arch and active site to create a configuration for cleavage. The threading requirement prevents this active nuclease from cutting the single stranded template between Okazaki fragments. FEN1 efficiency and specificity are critical to the maintenance of genome fidelity. Overall, recent advances in our knowledge of FEN1 suggest that it was an ancient protein that has been fine-tuned over eons to coordinate many essential DNA transactions. PMID- 23451869 TI - Systemic amyloidoses. AB - The amyloidoses are a group of protein misfolding diseases in which the precursor protein undergoes a conformational change that triggers the formation of amyloid fibrils in different tissues and organs, causing cell death and organ failure. Amyloidoses can be either localized or systemic. In localized amyloidosis, amyloid deposits form at the site of precursor protein synthesis, whereas in systemic amyloidosis, amyloid deposition occurs distant from the site of precursor protein secretion. We review the type of proteins and cells involved and what is known about the complex pathophysiology of these diseases. We focus on light chain amyloidosis to illustrate how biochemical and biophysical studies have led to a deeper understanding of the pathogenesis of this devastating disease. We also review current cellular, tissue, and animal models and discuss the challenges and opportunities for future studies of the systemic amyloidoses. PMID- 23451871 TI - Condom-use intentions and the influence of partner-related barriers among women at risk for HIV. AB - AIMS AND OBJECTIVES: To examine intentions to engage in condom use and potential partner-related barriers to condom use, including intimate partner violence (IPV), low levels of sexual relationship power and perceptions of monogamy, among women at risk for HIV. BACKGROUND: In the United States, women account for approximately one in four new HIV infections. Despite the effectiveness of consistent condom use, women often confront biological, cultural and psychosocial barriers that limit their ability to engage in condom-use. DESIGN: Cross sectional, quantitative study. METHODS: Participants (N = 90) were recruited from a domestic violence shelter, a domestic violence support organisation and an obstetrics/gynaecology clinic in Philadelphia, PA. Data were collected by questionnaires to assess women's condom-use intentions, actual condom-use behaviour, sexual partner risk factors, experience of IPV, level of sexual relationship power and perceptions of monogamy. RESULTS: Fifty-eight per cent of participants (n = 52) indicated a difference between their preference and intentions to use condoms vs. their actual use, with 62% (n = 32) using condoms less frequently than they would like. Significant differences in condom use emerged for women with low vs. high sexual relationship power and women who reported being in a monogamous relationship vs. those who did not. Of particular concern, a majority of these relationships were with high-risk partners, further increasing women's already elevated risk of acquiring HIV. CONCLUSIONS: Condom use is a multifaceted issue, particularly in sexual relationships involving power differentials and perceived monogamy. Condom use was complicated by women's own preferences, sexual relationship power differentials and by the perceived exclusivity of the relationship with their sexual partners. RELEVANCE TO CLINICAL PRACTICE: These findings have important implications for nurses as they are uniquely positioned to facilitate HIV risk reduction among their patients through the discussion of sexual health issues and barriers to negotiating condom use that women may confront. PMID- 23451872 TI - Localized toxic erythema of chemotherapy during treatment with paclitaxel. PMID- 23451873 TI - Antimicrobial susceptibility of Propionibacterium acnes isolates from acne patients in Colombia. AB - BACKGROUND: The increasing prevalence of antimicrobial resistance in Propionibacterium acnes poses a significant challenge to successful treatment outcomes in acne patients. Although P. acnes resistance has been demonstrated throughout the world, no previous data regarding the antimicrobial susceptibility of P. acnes in Colombia are available. OBJECTIVES: The aim of this study was to determine the antimicrobial susceptibility of P. acnes to common antibiotics used in the treatment of acne in a Colombian population. METHODS: Samples were collected from facial acne lesions of 100 dermatology patients. All samples were cultured in anaerobic conditions, and final identification of isolates was performed. Isolates of P. acnes were then subjected to antimicrobial susceptibility tests using erythromycin, clindamycin, tetracycline, doxycycline, and minocycline. RESULTS: Propionibacterium acnes isolates resistant to erythromycin (35%), clindamycin (15%), doxycycline (9%), tetracycline (8%), and minocycline (1%) were observed. Isolates with cross-resistance were also observed (to erythromycin and clindamycin [12%] and to doxycycline and tetracycline [6%]). Overall, 46% of isolates taken from patients with a history of antibiotic use demonstrated resistance, whereas 29% of isolates taken from patients who had never used antibiotics demonstrated resistance. CONCLUSIONS: Antimicrobial resistance in P. acnes in this Colombian population has a lower prevalence than those reported in Europe and follows a similar pattern to findings elsewhere in Latin America. Resistance is demonstrated even in isolates from patients with no previous history of antibiotic use. Resistance to erythromycin is most commonly observed. Minocycline emerges as the most effective antibiotic. PMID- 23451874 TI - Case of Darier's disease-associated skin eruption only at the site of heat stimulation with a heating pad. PMID- 23451875 TI - [Labor pain during childbirth]. PMID- 23451877 TI - Prediction and surprise in human fear conditioning (commentary on Boll et al.). PMID- 23451878 TI - Smoking is accompanied by a suppressed cervical nitric oxide release in women with high-risk human papillomavirus infection. AB - OBJECTIVE: Both smoking and the release of nitric oxide (NO) in the uterine cervix are determinants for high-risk human papillomavirus (hrHPV) infection. We compared the cervical NO release between smoking and non-smoking women with and without hrHPV infection. DESIGN: Open clinical cohort study. SETTING: University Hospital in Finland. POPULATION: One hundred and twenty-five smoking and 301 non smoking women, with (n = 244) and without (n = 182) hrHPV infection. In total, 264 women showed cytological and/or histological cervical epithelial changes. METHODS: The presence of hrHPV was tested by an HPV DNA test and the release of NO was assessed from NO metabolites in the cervical fluid by the Griess reaction. MAIN OUTCOME MEASURES: The difference in cervical NO release between smoking and non-smoking women with and without hrHPV. RESULTS: Infection with hrHPV in smokers (70%) was more frequent (p = 0.001) than in non-smokers (52%). As a whole, smoking was accompanied by a 35% decrease (p = 0.04) in NO release in hrHPV-infected women (35.9 MUmol/L, 95% confidence interval 27.0-44.2) compared with non-smoking hrHPV- infected women (48.3 MUmol/L, 95% confidence interval 38.0-56.2). No difference in NO release between smokers and non-smokers was seen in women with healthy cervical epithelium, but smoking was accompanied by a suppressed (26%) NO release (p = 0.03) in women with either cytological or histological changes. CONCLUSIONS: Smoking may suppress NO release in the uterine cervix in women with hrHPV infection. PMID- 23451879 TI - Prolonged ceftriaxone-induced immune thrombocytopenia due to impaired drug clearance: a case report. AB - BACKGROUND: Antibody-mediated drug-induced thrombocytopenia (DIT) typically requires the presence of the sensitizing drug in the plasma. Therefore, platelet (PLT) counts often start to recover 1 to 2 days after discontinuation of the offending medication. We present a case of ceftriaxone-induced DIT that resulted in severe, prolonged thrombocytopenia. CASE REPORT: A 65-year-old woman with liver and renal insufficiency was transferred to our hospital for liver transplant evaluation. Two days after a 5-day course of ceftriaxone, her PLT count declined from a stable baseline of approximately 70 * 10(9) /L to a value of 3 * 10(9) /L, with coincident onset of mucocutaneous purpura. Her PLT count remained in the 1 * 10(9) to 6 * 10(9) /L range until her death 13 days later, despite intravenous immune globulin, steroids, and PLT transfusions. The persistently low PLT count impeded central catheter placement for hemodialysis and possible therapeutic plasmapheresis. A strong ceftriaxone-dependent, PLT reactive antibody was identified in a sample drawn 7 days after ceftriaxone was last administered, and ceftriaxone remained detectable in her serum for at least 8 days after the last dose. CONCLUSION: A ceftriaxone-dependent, PLT-reactive antibody was responsible for the persistent thrombocytopenia in this patient. Although DIT is generally expected to improve within a few days of drug discontinuation, impaired drug clearance can significantly alter the outcome. This case highlights the importance of altered drug metabolism and clearance in critically ill patients, especially those with combined hepatic and renal dysfunction. DIT should be strongly suspected in patients with acute thrombocytopenia, and all treatment options to reduce serum drug levels should be seriously considered. PMID- 23451880 TI - Locating sweet spots for screening hits and evaluating pan-assay interference filters from the performance analysis of two lead-like libraries. AB - The efficiency of automated compound screening is heavily influenced by the design and the quality of the screening libraries used. We recently reported on the assembly of one diverse and one target-focused lead-like screening library. Using data from 15 enzyme-based screenings conducted using these libraries, their performance was investigated. Both libraries delivered screening hits across a range of targets, with the hits distributed across the entire chemical space represented by both libraries. On closer inspection, however, hit distribution was uneven across the chemical space, with enrichments observed in octants characterized by compounds at the higher end of the molecular weight and lipophilicity spectrum for lead-like compounds, while polar and sp(3)-carbon atom rich compounds were underrepresented among the screening hits. Based on these observations, we propose that screening libraries should not be evenly distributed in lead-like chemical space but be enriched in polar, aliphatic compounds. In conjunction with variable concentration screening, this could lead to more balanced hit rates across the chemical space and screening hits of higher ligand efficiency will be captured. Apart from chemical diversity, both screening libraries were shown to be clean from any pan-assay interference (PAINS) behavior. Even though some compounds were flagged to contain PAINS structural motifs, some of these motifs were demonstrated to be less problematic than previously suggested. To maximize the diversity of the chemical space sampled in a screening campaign, we therefore consider it justifiable to retain compounds containing PAINS structural motifs that were apparently clean in this analysis when assembling screening libraries. PMID- 23451881 TI - Certolizumab pegol in the treatment of Crohn's disease. AB - INTRODUCTION: The introduction of antibodies directed against tumour necrosis factor (anti-TNF) has dramatically changed the concept of treating patients with Crohn's disease (CD). Unfortunately, the long-term efficacy of anti-TNF agents may be hampered by immunogenicity. The availability of more anti-TNF agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti-TNF. In this review, the authors will focus on the efficacy of certolizumab pegol (CZP). AREAS COVERED: A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD. The authors first focused on the mechanism of action of CZP. Second, they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure. Next, they explored the influence of previous anti-TNF exposure and baseline C-reactive protein levels. Finally, they analysed the safety data on CZP, including the development of antibodies against CZP and the use of CZP during pregnancy. EXPERT OPINION: Based on the provided literature, CZP could be a good alternative in patients with moderate-to-severe CD failing another anti-TNF agent. More data are required to conclude on its impact on the long-term outcome of CD. PMID- 23451883 TI - Voice: the importance of diversity in healthcare. PMID- 23451882 TI - Weekend hospitalisations and post-operative complications following urgent surgery for ulcerative colitis and Crohn's disease. AB - BACKGROUND: There is increasing complexity in the management of patients with acute severe exacerbation of inflammatory bowel disease [IBD; Crohn's disease (CD), ulcerative colitis (UC)] with frequent requirement for urgent surgery. AIM: To determine whether a weekend effect exists for IBD care in the United States. METHODS: We used data from the Nationwide Inpatient Sample (NIS) 2007, the largest all-payer hospitalisation database in the United States. Discharges with a diagnosis of CD or UC who underwent urgent intestinal surgery within 2 days of hospitalisation were identified using the appropriate ICD-9 codes. The independent effect of admission on a weekend was examined using multivariate logistic regression adjusting for potential confounders. RESULTS: Our study included 7,112 urgent intestinal surgeries in IBD patients, 21% of which occurred following weekend admissions. There was no difference in disease severity between weekend and weekday admissions. Post-operative complications were more common following weekend than weekday hospitalisations in UC [odds ratio (OR) 1.71, 95% confidence interval (CI) 1.01-2.90]. The most common post-operative complication was post-operative infections (Weekend 30% vs. weekday 20%, P = 0.04). The most striking difference between weekend and weekday hospitalisations was noted for needing repeat laparotomy (OR 11.5), mechanical wound complications (OR 10.03) and pulmonary complications (OR 2.22). In contrast, occurrence of any post operative complication in CD was similar between weekday and weekend admissions. CONCLUSION: Patients with UC hospitalised on a weekend undergoing urgent surgery within 2 days have an increased risk for post-operative complications, in particular mechanical wound complications, need for repeat laparotomy and post operative infections. PMID- 23451884 TI - Solid lipid nanoparticles induced hematological changes and inflammatory response in mice. AB - Solid lipid nanoparticles (SLNs) are an alternative drug delivery system compared to emulsions, liposomes and polymeric nanoparticles. Due to their unique sizes and properties, SLNs offer possibility to develop new therapeutic approaches. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for drug targeting. However, toxicity of these new formulations has not been investigated thus far. In this study, we carried out an in vivo toxicity study. For that mice were divided into three groups and treated intraperitoneally with triestearin-based SLNs (TN), natural wax-based SLNs (VN) or vehicle for 10 days. After that, necropsies, histopathological and hematological analysis, as well as hepatic and renal functions were performed. Our results indicated that both TN and VN were absorbed post-exposure and induced an inflammatory response in adipose tissue. However, histopathological analysis demonstrated the absence of toxicity in both treated groups. In addition, the body weights were similar among the groups and low toxicity was also indicated by the unchanged serum biochemical parameters. This study provides a preliminary data for toxicological studies of two different SLNs in long-term in vivo exposure. However, further studies should be conducted in order to investigate the inflammatory response in order to establish the safety of these SLNs. PMID- 23451885 TI - Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and Ginkgo biloba extracts in healthy subjects. AB - 1. Ginkgo biloba extract (GBE) is one of the most commonly used herbal remedies worldwide. It is usually concomitantly administrated with statins to treat diseases in geriatric patients. We aim to determine the influence of GBE on the pharmacokinetics (PK) and pharmacodynamics of simvastatin, which is currently unknown. 2. An open-label, randomized, two-period, two-treatment, balanced, crossover study was performed in 14 healthy volunteers. Subjects received simvastatin 40 mg once daily, co-treated with placebo or GBE 120 mg twice daily. Each treatment was administered for 14 d, separated by a wash-out period of 1 month. Simvastatin, simvastatin acid and lipoprotein concentrations were assessed. 3. GBE administration reduced mean simvastatin area under the curve (AUC)0-24, AUC0-infinity and Cmax by 39% (p = 0.000), 36%(p = 0.001) and 32% (p = 0.002), respectively, but did not cause significant differences in simvastatin acid PK or its cholesterol-lowering efficacy. 4. GBE consumption decreased simvastatin system exposure, but did not affect simvastatin acid PK. However, we cannot rule out the possibility for a pharmacodynamic interaction between GBE and simvastatin in vivo. PMID- 23451886 TI - Influences of membrane mimetic environments on membrane protein structures. AB - The number of membrane protein structures in the Protein Data Bank is becoming significant and growing. Here, the transmembrane domain structures of the helical membrane proteins are evaluated to assess the influences of the membrane mimetic environments. Toward this goal, many of the biophysical properties of membranes are discussed and contrasted with those of the membrane mimetics commonly used for structure determination. Although the mimetic environments can perturb the protein structures to an extent that potentially gives rise to misinterpretation of functional mechanisms, there are also many structures that have a native-like appearance. From this assessment, an initial set of guidelines is proposed for distinguishing native-like from nonnative-like membrane protein structures. With experimental techniques for validation and computational methods for refinement and quality assessment and enhancement, there are good prospects for achieving native-like structures for these very important proteins. PMID- 23451887 TI - Quantitative modeling of bacterial chemotaxis: signal amplification and accurate adaptation. AB - We review the recent developments in understanding the bacterial chemotaxis signaling pathway by using quantitative modeling methods. The models developed are based on structural information of the signaling complex and the dynamics of the underlying biochemical network. We focus on two important functions of the bacterial chemotaxis signaling pathway: signal amplification and adaptation. We describe in detail the structure and the dynamics of the mathematical models and how they compare with existing experiments, emphasizing the predictability of the models. Finally, we outline future directions for developing the modeling approach to better understand the bacterial chemosensory system. PMID- 23451888 TI - Doing molecular biophysics: finding, naming, and picturing signal within complexity. AB - A macromolecular structure, as measured data or as a list of coordinates or even on-screen as a full atomic model, is an extremely complex and confusing object. The underlying rules of how it folds, moves, and interacts as a biological entity are even less evident or intuitive to the human mind. To do science on such molecules, or to relate them usefully to higher levels of biology, we need to start with a natural history that names their features in meaningful ways and with multiple representations (visual or algebraic) that show some aspect of their organizing principles. The two of us have jointly enjoyed a highly varied and engrossing career in biophysical research over nearly 50 years. Our frequent changes of emphasis are tied together by two threads: first, by finding the right names, visualizations, and methods to help both ourselves and others to better understand the 3D structures of protein and RNA molecules, and second, by redefining the boundary between signal and noise for complex data, in both directions-sometimes identifying and promoting real signal up out of what seemed just noise, and sometimes demoting apparent signal into noise or systematic error. Here we relate parts of our scientific and personal lives, including ups and downs, influences, anecdotes, and guiding principles such as the title theme. PMID- 23451889 TI - Structural insights into the evolution of the adaptive immune system. AB - The adaptive immune system, which is based on highly diverse antigen receptors that are generated by somatic recombination, arose approximately 500 Mya at the dawn of vertebrate evolution. In jawed vertebrates, adaptive immunity is mediated by antibodies and T cell receptors (TCRs), which are composed of immunoglobulin (Ig) domains containing hypervariable loops that bind antigen. In striking contrast, the adaptive immune receptors of jawless vertebrates, termed variable lymphocyte receptors (VLRs), are constructed from leucine-rich repeat (LRR) modules. Structural studies of VLRs have shown that these LRR-based receptors bind antigens though their concave surface, in addition to a unique hypervariable loop in the C-terminal LRR capping module. These studies have revealed a remarkable example of convergent evolution in which jawless vertebrates adopted the LRR scaffold to recognize as broad a spectrum of antigens as the Ig-based antibodies and TCRs of jawed vertebrates, with altogether comparable affinity and specificity. PMID- 23451890 TI - Energy functions in de novo protein design: current challenges and future prospects. AB - In the past decade, a concerted effort to successfully capture specific tertiary packing interactions produced specific three-dimensional structures for many de novo designed proteins that are validated by nuclear magnetic resonance and/or X ray crystallographic techniques. However, the success rate of computational design remains low. In this review, we provide an overview of experimentally validated, de novo designed proteins and compare four available programs, RosettaDesign, EGAD, Liang-Grishin, and RosettaDesign-SR, by assessing designed sequences computationally. Computational assessment includes the recovery of native sequences, the calculation of sizes of hydrophobic patches and total solvent-accessible surface area, and the prediction of structural properties such as intrinsic disorder, secondary structures, and three-dimensional structures. This computational assessment, together with a recent community-wide experiment in assessing scoring functions for interface design, suggests that the next generation protein-design scoring function will come from the right balance of complementary interaction terms. Such balance may be found when more negative experimental data become available as part of a training set. PMID- 23451892 TI - Advances, interactions, and future developments in the CNS, Phenix, and Rosetta structural biology software systems. AB - Advances in our understanding of macromolecular structure come from experimental methods, such as X-ray crystallography, and also computational analysis of the growing number of atomic models obtained from such experiments. The later analyses have made it possible to develop powerful tools for structure prediction and optimization in the absence of experimental data. In recent years, a synergy between these computational methods for crystallographic structure determination and structure prediction and optimization has begun to be exploited. We review some of the advances in the algorithms used for crystallographic structure determination in the Phenix and Crystallography & NMR System software packages and describe how methods from ab initio structure prediction and refinement in Rosetta have been applied to challenging crystallographic problems. The prospects for future improvement of these methods are discussed. PMID- 23451891 TI - Molecular traffic jams on DNA. AB - All aspects of DNA metabolism-including transcription, replication, and repair involve motor enzymes that move along genomic DNA. These processes must all take place on chromosomes that are occupied by a large number of other proteins. However, very little is known regarding how nucleic acid motor proteins move along the crowded DNA substrates that are likely to exist in physiological settings. This review summarizes recent progress in understanding how DNA-binding motor proteins respond to the presence of other proteins that lie in their paths. We highlight recent single-molecule biophysical experiments aimed at addressing this question, with an emphasis placed on analyzing the single-molecule, ensemble biochemical, and in vivo data from a mechanistic perspective. PMID- 23451894 TI - The underappreciated role of allostery in the cellular network. AB - Allosteric propagation results in communication between distinct sites in the protein structure; it also encodes specific effects on cellular pathways, and in this way it shapes cellular response. One example of long-range effects is binding of morphogens to cell surface receptors, which initiates a cascade of protein interactions that leads to genome activation and specific cellular action. Allosteric propagation results from combinations of multiple factors, takes place through dynamic shifts of conformational ensembles, and affects the equilibria of macromolecular interactions. Here, we (a) emphasize the well-known yet still underappreciated role of allostery in conveying explicit signals across large multimolecular assemblies and distances to specify cellular action; (b) stress the need for quantitation of the allosteric effects; and finally, (c) propose that each specific combination of allosteric effectors along the pathway spells a distinct function. The challenges are colossal; the inspiring reward will be predicting function, misfunction, and outcomes of drug regimes. PMID- 23451895 TI - Molecular mechanisms of drug action: an emerging view. AB - Volatile anesthetics serve as useful probes of a conserved biological process that is essential to the proper functioning of the central nervous system. A kinetic and thermodynamic analysis of their unusual pharmacological and physiological characteristics has led to a general, predictive theory in which small molecules that adsorb to membranes modulate ion channel function by altering physical properties of membrane bilayers. A kinetic model that is both parsimonious and falsifiable has been developed to test this mechanism. This theory leads to predictions about the structure, function, origin, and evolution of synapses, the etiology of several diseases and disease symptoms affecting the brain, and the mechanism of action of several drugs that are used therapeutically. Neuronal membranes may offer an appealing drug target, given the large number of compounds that adsorb to interfaces and hence membranes. PMID- 23451896 TI - Electrophysiological characterization of membrane transport proteins. AB - Active transport in biological membranes has been traditionally studied using a variety of biochemical and biophysical techniques, including electrophysiology. This review focuses on aspects of electrophysiological methods that make them particularly suited for the investigation of transporter function. Two major approaches to electrical recording of transporter activity are discussed: (a) artificial planar lipid membranes, such as the black lipid membrane and solid supported membrane, which are useful for studies on bacterial transporters and transporters of intracellular compartments, and (b) patch clamp and voltage clamp techniques, which investigate transporters in native cellular membranes. The analytical power of these methods is highlighted by several examples of mechanistic studies of specific membrane proteins, including cytochrome c oxidase, NhaA Na(+)/H(+) exchanger, ClC-7 H(+)/Cl(-) exchanger, glutamate transporters, and neutral amino acid transporters. These examples reveal the wealth of mechanistic information that can be obtained when electrophysiological methods are used in combination with rapid perturbation approaches. PMID- 23451897 TI - Coarse-graining methods for computational biology. AB - Connecting the molecular world to biology requires understanding how molecular scale dynamics propagate upward in scale to define the function of biological structures. To address this challenge, multiscale approaches, including coarse graining methods, become necessary. We discuss here the theoretical underpinnings and history of coarse-graining and summarize the state of the field, organizing key methodologies based on an emerging paradigm for multiscale theory and modeling of biomolecular systems. This framework involves an integrated, iterative approach to couple information from different scales. The primary steps, which coincide with key areas of method development, include developing first-pass coarse-grained models guided by experimental results, performing numerous large-scale coarse-grained simulations, identifying important interactions that drive emergent behaviors, and finally reconnecting to the molecular scale by performing all-atom molecular dynamics simulations guided by the coarse-grained results. The coarse-grained modeling can then be extended and refined, with the entire loop repeated iteratively if necessary. PMID- 23451898 TI - Asymmetric synthesis of cis-2,5-disubstituted pyrrolidine, the core scaffold of beta3-AR agonists. AB - A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N->C benzoyl migration, yields syn 1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of beta3-AR agonists is synthesized in 38% overall yield. PMID- 23451893 TI - Considering protonation as a posttranslational modification regulating protein structure and function. AB - Posttranslational modification is an evolutionarily conserved mechanism for regulating protein activity, binding affinity, and stability. Compared with established posttranslational modifications such as phosphorylation or ubiquitination, posttranslational modification by protons within physiological pH ranges is a less recognized mechanism for regulating protein function. By changing the charge of amino acid side chains, posttranslational modification by protons can drive dynamic changes in protein conformation and function. Addition and removal of a proton is rapid and reversible and, in contrast to most other posttranslational modifications, does not require an enzyme. Signaling specificity is achieved by only a minority of sites in proteins titrating within the physiological pH range. Here, we examine the structural mechanisms and functional consequences of proton posttranslational modification of pH-sensing proteins regulating different cellular processes. PMID- 23451899 TI - Telemonitoring for chronic heart failure: the views of patients and healthcare professionals - a qualitative study. AB - AIMS AND OBJECTIVES: To understand the views of patients and professionals on the acceptability and perceived usefulness of telemonitoring in the management of chronic heart failure in the context of day-to-day care provision. BACKGROUND: There is an increasing interest in the potential for telemonitoring to support the home-based management of patients with chronic heart failure. However, little is known about the views of patients and professionals on the use of telemonitoring in this context. A chronic heart failure telemonitoring service was set-up by NHS Lothian, Scotland, to evaluate the intervention. DESIGN: A qualitative design was adopted to explore the views of patients and professionals participating in the service. METHODS: Semi-structured interviews were undertaken with 18 patients (61% male, mean age 75 years) and five professionals participating at different time points in this new service. Interviews were audio recorded, coded and thematically analysed using the Framework approach. RESULTS: Five main themes were identified: 'information, support and reassurance'; 'compliance and dependence'; 'changes and challenges'; 'determining the criteria for patient applicability to telemonitoring'; and 'continuity of care'. CONCLUSION: Patients and professionals considered telemonitoring useful in the management of chronic heart failure, although with some caveats. Telemonitoring was popular with patients because they felt reassurance arising from what was perceived as continuous practitioner surveillance. Professionals expressed concern regarding perceived patient dependence on practitioner support. Increased workload was also a concern. Both groups acknowledged the need for improved technology and changes to service provision in order to better meet the intended objectives of the service. RELEVANCE TO CLINICAL PRACTICE: Although popular with patients, professionals emphasised the importance of case selection and adequate training and support, both for patients and themselves, in order to maximise the expected benefits of the service, particularly with regard to enabling self management. PMID- 23451900 TI - Does sacral nerve stimulation improve global pelvic function in women? AB - AIM: Many women undergoing sacral neuromodulation for faecal incontinence have coexisting pelvic floor dysfunction. We used a global pelvic-floor assessment questionnaire to evaluate the effect of sacral neuromodulation on non-bowel related symptomatology. METHOD: The electronic Personnel Assessment Questionnaire - Pelvic Floor (ePAQ-PF) is a validated Web-based electronic pelvic floor questionnaire. Women with faecal incontinence underwent assessment using the ePAQ. Pre- and poststimulator data were analysed over a 4.5-year period. RESULTS: Forty-three women (mean age 56.5 years; median follow up 6.8 months) were included. All (100%) had urinary symptoms, 81.4% had vaginal symptoms and 85.7% described some sexual dysfunction. There was a significant improvement in faecal incontinence and in bowel-related quality of life (P < 0.005) as well as in irritable bowel syndrome (IBS)-related symptoms (P < 0.01) and in bowel-related sexual heath (P < 0.01). Symptoms of vaginal prolapse significantly improved (P = 0.05). There was also improvement in symptoms of overactive bladder (P = 0.005) and in urinary-related quality of life (P < 0.05). A global health improvement was reported in 58.1%, mainly in bowel evacuation (P < 0.01) and in vaginal pain and sensation (P < 0.05). In sexually active female patients, significant improvements in vaginal and bowel-related sexual health were seen (P < 0.005). Improvement in general sex life following stimulation was reported in 53.3%. CONCLUSION: A Web-based electronic pelvic-floor assessment questionnaire has demonstrated global improvement in pelvic floor function in bowel, urinary, vaginal and sexual dimensions in women following sacral neuromodulation for faecal incontinence. PMID- 23451901 TI - Landscape analysis of drone congregation areas of the honey bee, Apis mellifera. AB - Male honey bees fly and gather at Drone Congregation Areas (DCAs), where drones and queens mate in flight. DCAs occur in places with presumably characteristic features. Using previously described landscape characteristics and observations on flight direction of drones in nearby apiaries, 36 candidate locations were chosen across the main island of Puerto Rico. At these locations, the presence or absence of DCAs was tested by lifting a helium balloon equipped with queen-sex pheromone-impregnated bait, and visually determining the presence of high numbers of drones. Because of the wide distribution of honey bees in Puerto Rico, it was expected that most of the potential DCAs would be used as such by drones and queens from nearby colonies. Eight DCAs were found in the 36 candidate locations. Locations with and without DCAs were compared in a landscape analysis including characteristics that were described to be associated with DCAs and others. Aspect (direction of slope) and density of trails were found to be significantly associated with the presence of DCAs. PMID- 23451902 TI - Subclinical ischemia verified by somatosensory evoked potential amplitude reduction during carotid endarterectomy: negative effects on cognitive performance. AB - OBJECT: Although the mechanisms underlying neurocognitive changes after carotid endarterectomy (CEA) are poorly understood, intraoperative ischemia and postoperative hemodynamic changes may play a role. METHODS: Data from 81 patients who underwent unilateral CEA with routine shunt use for carotid artery stenosis were retrospectively evaluated. These patients underwent neuropsychological examinations (NPEs), including assessment by the Wechsler Adult Intelligence Scale-Third Edition and the Wechsler Memory Scale-Revised before and 6 months after CEA. results of NPEs were converted into z scores, from which pre- and postoperative cognitive composite scores (CSpre and CSpost) were obtained. The association between the change of CS between pre- and postoperative NPEs (that is, CSpost - CSpre [CSpost - pre]) and various variables was assessed. These latter variables included ischemic or hemodynamic parameters such as 1) intraoperative hypoperfusion detected by somatosensory evoked potential (SSEP) change-that is, an SSEP amplitude reduction more than 50% and longer than 5 minutes (SSEP< 50%, > 5 min); 2) new lesions on postoperative diffusion-weighted imaging studies; and 3) preexisting hemodynamic impairment. Paired t-tests of the NPE scores were performed to determine the net effect of these factors on neurocognitive function at 6 months. RESULTS: A significant CSpost - pre decrease was observed in patients with SSEP< 50%, > 5 min when compared with those without SSEP< 50%, > 5 min (-0.225 vs 0.018; p = 0.012). Multiple regression analysis demonstrated that SSEP< 50%, > 5 min independently and negatively correlated with CSpost - pre (p = 0.0020). In the group-rate analysis, postoperative NPE scores were significantly improved relative to preoperative scores. CONCLUSIONS: Hypoperfusion during cross-clamping, as verified by SSEP amplitude reduction, plays a significant role in the subtle decline in cognition following CEA. However, this detrimental effect was small, and various confounding factors were present. Based on these observations and the group-rate analysis, the authors conclude that successful unilateral CEA with routine shunt use does not adversely affect postoperative cognitive function. PMID- 23451903 TI - Management of intracranial hemorrhage in patients with left ventricular assist devices. AB - OBJECT: The authors conducted a study to review outcomes and management in patients in whom intracranial hemorrhage (ICH) develops during left ventricular assist device (LVAD) therapy. METHODS: This retrospective cohort study included all adult patients (18 years of age or older) at a single institution who underwent placement of an LVAD between January 1, 2003, and March 1, 2012. The authors conducted a detailed medical chart review, and data were abstracted to assess outcomes in patients in whom ICH developed compared to those in patients in whom ICH did not develop; to compare management of antiplatelet agents and anticoagulation with outcomes; to describe surgical management employed and outcomes achieved; to compare subtypes of ICH (intraparenchymal, subdural, and subarachnoid hemorrhage) and their outcomes; and to determine any predictors of outcome. RESULTS: During the study period, 330 LVADs were placed and 36 patients developed an ICH (traumatic subarachnoid hemorrhage in 10, traumatic subdural hematoma in 8, spontaneous intraventricular hemorrhage in 1, and spontaneous intraparenchymal hemorrhage in 17). All patients were treated with aspirin and warfarin at the time of presentation. With suspension of these agents, no thromboembolic events or pump failures were seen and no delayed rehemorrhages occurred after resuming these medications. Intraparenchymal hemorrhages had the worst outcomes, with a 30-day mortality rate in 59% compared with a 30-day mortality rate of 0% in patients with traumatic subarachnoid hemorrhages and 13% in those with traumatic subdural hematomas. Five patients with intraparenchymal hemorrhages were managed with surgical intervention, 4 of whom died within 60 days. The only factor found to be predictive of outcome was initial Glasgow Coma Scale score. No patients with a Glasgow Coma Scale score less than 11 survived beyond 30 days. Overall, the development of an ICH significantly reduced survival compared with the natural history of patients on LVAD therapy. CONCLUSIONS: The authors' data suggest that withholding aspirin for 1 week and warfarin for 10 days is sufficient to reduce the risk of hemorrhage expansion or rehemorrhage while minimizing the risk of thromboembolic events and pump failure. Patients with intraparenchymal hemorrhage have poor outcomes, whereas patients with traumatic subarachnoid hemorrhage or subdural hematoma have better outcomes. PMID- 23451904 TI - Risk factors of aseptic bone resorption: a study after autologous bone flap reinsertion due to decompressive craniotomy. AB - OBJECT: In patients who have undergone decompressive craniectomy, autologous bone flap reinsertion becomes necessary whenever the cerebral situation has consolidated. However, aseptic necrosis of the bone flap remains a concern. The aim of this study was to report possible perioperative complications in patients undergoing autologous bone flap reinsertion and to identify the risk factors that may predispose the bone flap to necrosis. METHODS: All patients admitted to the authors' neurosurgical department between September 1994 and June 2011 and who received their own cryoconserved bone flap after decompressive craniectomy were studied. The grade of the bone flap necrosis was classified into 2 types. Type II bone necrosis was characterized by aseptic resorption with circumscribed or complete lysis of tabula interna and externa requiring surgical revision. To define predisposing factors, a multivariate analysis was performed using bone necrosis as the dependent variable. RESULTS: Among the 372 patients (mean age 48.6 years, 57.4% males) who received 414 bone flaps during the observation period, 134 (36.0%) had a diffuse traumatic brain injury, 69 (18.5%) had subarachnoid hemorrhage, 58 (15.6%) had cerebral infarction, 56 (15.1%) had extraaxial bleeding, 43 (11.6%) had intracerebral bleeding, and 12 (3.2%) had a neoplasm. Surgical relevant Type II bone flap necrosis occurred in 85 patients (22.8%) and 91 bone flaps, after a median time of 15 months (interquartile range [IQR], 10-33 months). In a multivariate analysis with Type II necrosis as the dependent variable, bone flap fragmentation with 2 (OR 3.35, 95% CI 1.59-7.01, p < 0.002) or more fragments (OR 24.00, 95% CI 10.13-56.84, p < 0.001), shunt dependent hydrocephalus (OR 1.76, 95% CI 0.99-3.12, p = 0.04), and a younger age (OR 0.98, 95% CI 0.96-0.99, p = 0.004) was associated with a higher risk for the development of an aseptic bone flap necrosis. CONCLUSIONS: In patients undergoing bone flap reinsertion after craniotomy, aseptic bone necrosis is an underestimated problem during long-term follow-up. Especially in younger patients with an expected good neurological recovery and a fragmented bone flap, an initial allograft should be considered because of an increased risk for aseptic bone flap necrosis. PMID- 23451905 TI - Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article. AB - OBJECT: The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors. METHODS: The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide. RESULTS: The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities. CONCLUSIONS: This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted. PMID- 23451906 TI - Predictive value of neuromarkers supported by a set of clinical criteria in patients with mild traumatic brain injury: S100B protein and neuron-specific enolase on trial: clinical article. AB - OBJECT: The role of the neuromarkers S100B protein and neuron-specific enolase (NSE) in minor head injury is well established. Moreover, there are sensitive decision rules available in the literature to identify clinically important brain lesions. However, it is not clear if using the biomarkers has an influence on the predictability of the decision rule. The purpose of this study was to determine if a set of preclinical and clinical parameters combined with 2 neuromarker levels could serve as reliable guidance for accurate diagnosis. METHODS: Prospective evaluation of a cohort of head trauma patients with Glasgow Coma Scale scores of 13-15 was performed at an academic, Level I trauma center. Blood samples and cranial CT studies were obtained for all patients within 3 hours after injury. The hypothesis of the study was whether the combination of an increase of S100B and NSE levels in serum and other defined risk factors are associated with a pathological finding on CT. A forward stepwise logistic regression model was used. RESULTS: The study included 107 head trauma patients with a mean age of 59 +/- 23 years. Twenty-five patients (23.4%) had traumatic lesions on CT. Eight patients underwent craniotomy. The analysis provided a model with good overall accuracy for discriminating cases with clinically important brain injury, including the 6 variables of S100B, NSE, nausea, amnesia, vomiting, and loss of consciousness. The area under the curve (AUC) was 0.88 (0.83-0.93). The receiver operating characteristic curve plots detecting clinically important brain injury for the single variables of S100B and NSE showed an AUC of 0.63 and 0.64, respectively. Conclusions The integration of the neuromarker panel as part of a diagnostic rule including the high-risk factors of nausea, vomiting, amnesia, and loss of consciousness is safe and reliable in determining a diagnosis, pending the availability of more brain-specific neuromarkers. CLINICAL TRIAL REGISTRATION NO.: NCT00622778 (ClinicalTrials.gov). PMID- 23451907 TI - Chicken embryonic brain: an in vivo model for verifying neural stem cell potency. AB - OBJECT: The multipotency of neural stem cells (NSCs) can be assessed in vitro by detection of stage-specific markers in response to a suitable differentiation signal. This test is frequently used because it is fast and affordable. However, it is not clear how the in vitro potential for multilineage differentiation and stem cell marker expression would reflect the ability of NSCs to engraft into the brain following transplantation. The authors undertook this study to directly compare the in vitro potency and in vivo migration of human NSCs (hNSCs) expanded under conditions of gradually increased concentration of fetal bovine serum (FBS) as a maturation factor. METHODS: Human NSCs isolated from fetal brain were propagated in serum free media (SF-hNSCs) and in media containing 0.1% and 0.2% serum. At Passage 4 in tissue culture the NSCs were harvested and either differentiated in vitro or transplanted into the lateral ventricle of chicken embryonic brain at the late stage of its development (Hamburger and Hamilton Stage 26). The in vitro differentiation was evaluated by immunostaining with neural or glial specific markers, and the in vivo migration was assessed using immunohistology. RESULTS: The authors found that SF-hNSCs successfully engrafted into the chicken embryonic brain, which correlated with their ability to differentiate in vitro. NSCs grown at as low as 0.1% concentration of FBS failed to demonstrate the robust in vivo migration pattern but still preserved the capability to differentiate in vitro. Furthermore, NSCs generated in media containing a higher concentration of FBS (0.2%) lost both the in vivo engraftment and in vitro differentiation potential. CONCLUSIONS: The present study suggests that marker expression and in vitro differentiation assays might not provide adequate information regarding the behavior of NSCs following their transplantation. The in vivo migration following injection into chicken embryonic brain may provide an important assay of the potency of NSCs. PMID- 23451908 TI - Editorial: Tumor and antiepileptic drugs: clinical article. PMID- 23451909 TI - Targeting accuracy of transcranial magnetic resonance-guided high-intensity focused ultrasound brain therapy: a fresh cadaver model. AB - OBJECT: This work aimed at evaluating the accuracy of MR-guided high-intensity focused ultrasound (MRgHIFU) brain therapy in human cadaver heads. METHODS: Eighteen heads of fresh human cadavers were removed with a dedicated protocol preventing intracerebral air penetration. The MR images allowed determination of the ultrasonic target: a part of the thalamic nucleus ventralis intermedius implicated in essential tremor. Osseous aberrations were corrected with simulation-based time reversal by using CT data from the heads. The ultrasonic session was performed with a 512-element phased-array transducer system operating at 1 MHz under stereotactic conditions with thermometric real-time MR monitoring performed using a 1.5-T imager. RESULTS: Dissection, imaging, targeting, and planning have validated the feasibility of this human cadaver model. The average temperature elevation measured by proton resonance frequency shift was 7.9 degrees C +/- 3 degrees C. Based on MRI data, the accuracy of MRgHIFU is 0.4 +/- 1 mm along the right/left axis, 0.7 +/- 1.2 mm along the dorsal/ventral axis, and 0.5 +/- 2.4 mm in the rostral/caudal axis. CONCLUSIONS: Despite its limits (temperature, vascularization), the human cadaver model is effective for studying the accuracy of MRgHIFU brain therapy. With the 1-MHz system investigated here, there is millimetric accuracy. PMID- 23451910 TI - Editorial: Predicting events in traumatic brain injury. PMID- 23451911 TI - Continuous equilibrated growth of ordered block copolymer thin films by electrospray deposition. AB - Deposition of block copolymer thin films is most often accomplished in a serial process where material is spin coated onto a substrate and subsequently annealed, either thermally or by solvent vapor, to produce a well-ordered morphology. Here we show that under appropriate conditions, well-ordered block copolymer films may be continuously grown under substrate equilibrated conditions by slow deposition of discrete subattoliter quantities of material using electrospray. We conduct time-resolved observations and investigate the effects of process parameters that underpin film morphology including solvent selectivity, substrate temperature, block-substrate selectivity, and flow rate of the feed solution. For a PEO cylinder-forming poly(styrene-b-ethylene oxide) block copolymer, we uncover a wide temperature window from 90 to 150 degrees C and an ideal flow rate of 2 MUL/min for ordered film deposition from dilute acetone solutions. PEO cylinders aligned with their long axes perpendicular to the film-air interface at optimal spray conditions. Using poly(styrene-b-methyl methacrylate) deposited onto neutrally selective surfaces, we show that the substrate-equilibrated process results in vertically oriented microdomains throughout the film, indicating a preservation of the initial substrate-dictated morphology during the film deposition. Electrospray offers a new and potentially exciting route for controlled, continuous growth of block copolymer thin films and manipulation of their microstructure. PMID- 23451912 TI - Pseudoporphyria induced by imatinib mesylate. PMID- 23451913 TI - Clinical features of axillary osmidrosis: a retrospective chart review of 723 Japanese patients. AB - Axillary osmidrosis often disturbs a person's social life, particularly in Asian countries. However, the clinical aspects of this condition have not been well documented in the English-language published work. This study aimed to provide information on the features of axillary osmidrosis, with a particular focus on sex differences. A retrospective review was made of the charts for 723 Japanese patients (492 female, 231 male). The mean age at initial presentation (29.1 years) was nearly the same for males and females. Almost all patients (96.1%) had wet earwax, which was extremely high compared to its frequency in the general Japanese population. An association with hyperhidrosis was seen in 61.8% of these patients. Subjective odor levels in female patients were significantly lower than those in males (P < 0.001). A positive family history was more frequent for females than for males (P < 0.001), and prior treatment history was also more frequent for females than for males (P < 0.015). Most patients (86.6%) had received some treatments in our clinic. There were significantly fewer females who underwent surgical treatments compared to males (P = 0.026), as females preferred less invasive techniques (P < 0.001). Several features, including male/female ratios, and associations of wet earwax and hyperhidrosis, corresponded to previously reported data on axillary osmidrosis. Female patients were more concerned with axillary odor than males, and females had a tendency for polysurgery. PMID- 23451914 TI - Alveolar rhabdomyosarcoma arising in a giant congenital melanocytic nevus in an adult--case report with review of literature. PMID- 23451915 TI - Incorporation of lapatinib into lipoprotein-like nanoparticles with enhanced water solubility and anti-tumor effect in breast cancer. AB - AIM: The poor water solubility of many active compounds is a serious deterrent to their use as commercial drugs. Lapatinib is a dual inhibitor of the EGF receptor and EGF receptor 2 approved by the US FDA to treat advanced breast cancer. This study prepares lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs) to enhance the water solubility and elevate the anti-tumor effect of lapatinib. MATERIALS & METHODS: Bovine albumin was used to bind with lapatinib, and egg yolk lecithin was used to stabilize the conjugation of bovine albumin and lapatinib. The characteristics of LTNPs were evaluated by several experiments. Cell uptake and toxicity were performed on BT-474 cells. In vivo anti-tumor effect was performed on BT-474 xenograft-bearing mice. RESULTS: LTNPs contained a lipid corona and a core of lapatinib and albumin. LTNPs could be effectively taken up by BT-474 cells and induced apoptosis. An in vivo study demonstrated that LTNPs could passively distribute into a tumor via the enhanced permeability and retention effect and induce anti-tumor activity in breast cancer. CONCLUSION: The authors present a convenient nanoformulation with improved anti-tumor effect, which is a promising candidate for clinical trials. PMID- 23451917 TI - Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. AB - BACKGROUND: Thrombopoietin receptor agonists (TRAs) are effective treatments for immune thrombocytopenia (ITP). However, continuous therapy is generally required to maintain platelet (PLT) count responses. STUDY DESIGN AND METHODS: In this case series, we describe ITP patients from our practice who achieved durable responses to the TRAs romiplostim and eltrombopag. Patients were classified as having a definite TRA-induced remission if PLT counts increased above 100 * 10(9) /L after TRA treatment and remained above 100 * 10(9) /L even after the medication was discontinued; or a possible TRA-induced remission if PLT counts increased above 100 * 10(9) /L, remained elevated for at least 3 months after the medication was discontinued, but a subsequent relapse occurred or the effect of other disease-modifying therapies could not be excluded. RESULTS: Of 31 patients with chronic ITP treated with TRAs in our practice, nine patients achieved a PLT count response with either romiplostim (n = 6) or eltrombopag (n = 3) that was maintained even after the medications were discontinued. Three patients met criteria for a definite TRA-induced remission, each after exposure to romiplostim. Patients had ITP for a median of 7.8 years and had failed a median of four prior therapies including eight patients who had a splenectomy. We documented a progressive decline in anti-glycoprotein IIbIIIa PLT autoantibodies in one patient while on treatment. CONCLUSION: Some patients with ITP can achieve sustained PLT count responses after the use of TRAs. This observation raises the possibility that these agents may restore immune tolerance to PLT antigens in some patients and supports the practice of down titrating the dose. PMID- 23451918 TI - Conservative medical treatment of ovarian hyperstimulation syndrome: a single center series and cost analysis study. AB - OBJECTIVE: To present the results of a large series of patients with ovarian hyperstimulation syndrome treated with a conservative medical approach and to compare the cost of this treatment with outpatient management with paracentesis according to published data. DESIGN: Retrospective case series and cost analysis study using a decision-tree model. SETTING: University hospital. POPULATION: 496 consecutive patients with ovarian hyperstimulation syndrome treated in our center from 1991 to 2010. METHODS: All patients were treated with a conservative medical approach: (a) conservative outpatient approach: bed rest and a low-sodium diet or (b) hospitalized patients: bed rest, low-sodium diet, 20% albumin (60 g/day) and furosemide (20 mg/8 h). MAIN OUTCOME MEASURES: Percentage of admissions, length of hospital stay and readmissions. Total cost of each therapeutic approach. RESULTS: (a) Conservative outpatient approach (n = 377): all cases solved without admission. (b) Hospitalized patients with conservative medical treatment (n = 119): 2.8 days of mean hospital stay, no patient required paracentesis or admission to intensive care unit. Readmissions: Five patients (4.2%) resolved on restarting medical treatment. (c) Cost-analysis comparison: Cost of the outpatient approach with paracentesis: US$980 (range US$519-3557). Cost of conservative medical treatment: US$570 (range US$232-1640). CONCLUSIONS: Ovarian hyperstimulation syndrome can be safely managed with a conservative medical approach, which was not found to be more expensive than outpatient management with paracentesis. PMID- 23451919 TI - Perturbations in cortical development and neuronal network excitability arising from prenatal exposure to benzodiazepines in mice. AB - During brain development, many factors influence the assembly and final positioning of cortical neurons, and this process is essential for proper circuit formation and normal brain function. Among many important extrinsic factors that guide the maturation of embryonic cortical neurons, the secreted neurotransmitter GABA has been proposed to influence both their migratory behaviour and their terminal differentiation. The full extent of the short-term and long-term changes in brain patterning and function caused by modulators of the GABA system is not known. In this study, we specifically investigated whether diazepam, a commonly used benzodiazepine that modulates the GABAA receptor, alters neuronal positioning in vivo, and whether this can lead to lasting effects on brain function. We found that fetal exposure to diazepam did not change cell positioning within the embryonic day (E)14.5 mouse cerebral cortex, but significantly altered neuron positioning within the E18.5 cortex. In adult mice, diazepam treatment affected the distribution of cortical interneurons that express parvalbumin or calretinin, and also led to a decrease in the numbers of calretinin-expressing interneurons. In addition, we observed that neonatal exposure to diazepam altered the sensitivity of mice to a proconvulsant challenge. Therefore, exposure of the fetal brain to benzodiazepines has consequences for the positioning of neurons and cortical network excitability. PMID- 23451920 TI - Call for papers: examination of basic nursing care. PMID- 23451921 TI - EcdGHK are three tailoring iron oxygenases for amino acid building blocks of the echinocandin scaffold. AB - The echinocandins are a small group of fungal N-acylated cyclic hexapeptides that are fungicidal for candida strains and fungistatic for aspergilli by targeting cell wall 1,3-beta-glucan synthases. The side chains of all six amino acid building blocks have hydroxyl groups, including the nonproteinogenic 4R,5R dihydroxy-Orn1, 4R-OH-Pro3, 3S,4S-dihydroxy-homoTyr4, and 3S-OH-4S-Me-Pro6. The echinocandin (ecd) gene cluster contains two predicted nonheme mononuclear iron oxygenase genes (ecdG,K) and one encoding a P450 type heme protein (ecdH). Deletion of the ecdH gene in the producing strain Emericella rugulosa generates an echinocandin scaffold (echinocandin D) lacking both hydroxyl groups on Orn1. Correspondingly, the DeltaecdG strain failed to hydroxylate C3 of the homoTyr residue, and purified EcdG hydroxylated free L-homoTyr at C3. The DeltaecdK strain failed to generate mature echinocandin unless supplemented with either 4R Me-Pro or 3S-OH-4S-Me-Pro, indicating blockage of a step upstream of Me-Pro formation. Purified EcdK is a Leu 5-hydroxylase, acting iteratively at C5 to yield gamma-Me-Glu-gamma-semialdehyde in equilibrium with the cyclic imine product. Evaluation of deshydroxyechinocandin scaffolds in the in vitro anticandidal assays revealed up to a 3-fold loss of potency for the DeltaecdG scaffolds, but a 3-fold gain of potency for the DeltaecdH scaffold, in line with prior results on deoxyechinocandin homologues. PMID- 23451922 TI - Cancer stem cell antigen-based vaccines: the preferred strategy for active specific immunotherapy of metastatic melanoma? AB - INTRODUCTION: There are now two chemotherapy agents, one tyrosine kinase inhibitor and three immunotherapy products approved for the treatment of metastatic melanoma, but an unmet need persists because these options are toxic and of limited therapeutic benefit. Active specific immunotherapy with therapeutic vaccines could be a useful addition to the therapeutic armamentarium, especially in patients whose tumor burden has been reduced by other treatment modalities. AREAS COVERED: This article reviews various sources of melanoma antigens, such as peptides, gangliosides, autologous tumor and cancer stem cells including allogeneic and autologous cell lines. The advantages and disadvantages of various antigen sources and allogeneic and autologous approaches are discussed with an emphasis on the theoretical benefits of immunizing against cancer stem cells. The results from published randomized trials testing the benefit of various vaccine approaches are summarized, as well as promising results from three Phase II trials (one randomized) of patient-specific stem cell antigen based products. EXPERT OPINION: Immune responses directed toward the unique neoantigens and stem cell antigens expressed on continuously proliferating, self renewing, autologous tumor cells could potentially overcome the limitations inherent in these other antigen-based approaches, that to date, have yielded disappointing results in randomized trials. PMID- 23451923 TI - First impressions: how to "wow" students into special care dentists. PMID- 23451924 TI - Assessment of dentally related functional competency for older adults with cognitive impairment--a survey for special-care dental professionals. AB - This survey was to study whether and how dental professional assess dental related function in older adults with cognitive impairment (OACI). An invitation was sent to 525 special-care dental professionals, followed by a reminder in 2 weeks. Thirteen percent of the targeted participants completed the survey. Among them, 88% completed a hospital dentistry, geriatric dentistry, or other postgraduate training program. Nearly 70% of the respondents considered somewhat to very difficult to assess dentally related function; 45% did not ever or did not regularly assess dental-related function for OACI. Dental-related functional assessments were often based on a subjective, unstructured approach. Only 6% of the respondents routinely used standard instruments to assess the patients' function. These results indicate that an objective functional assessment based on a standardized instrument has not been routinely incorporated into dental care for OACI, raising concerns for quality of care in this vulnerable population. PMID- 23451925 TI - Oral hygiene and associated factors among frail older assisted living residents. AB - The aim of this study was to determine the associations of older assisted living residents' tooth brushing habits with health and nutritional status. We assessed the tooth brushing habits, nutritional status, oral health, use of dental services, and morbidity of 1,447 assisted living residents in the Helsinki metropolitan area of Finland. Of the residents, 17% did not clean or had not cleaned their teeth and/or dentures daily. Those not cleaning their teeth and/or dentures daily were more often male, less educated and had a mean length of stay in assisted living longer than those who cleaned their teeth and/or dentures daily. They were more often malnourished and dependent in ADLs. In addition they more often had poorer oral health and used fewer dental services. Poor tooth brushing habits indicate poor oral and subjective health. More attention should focus on the oral hygiene of frail older assisted living residents. PMID- 23451926 TI - Quantitative estimation of vertical heights of maxillary and mandibular jawbones in elderly dentate and edentulous subjects. AB - The residual alveolar ridge resorption is inevitable with aging. The purpose of the study was to determine and compare differences in the vertical measurements of jaw bones in elderly dentate and edentulous subjects. The study sample included 51 elderly dentate subjects and 59 edentulous subjects. The panoramic radiographs were used to quantify the reduction in the alveolar ridges at 5 sites in each jaw. There were significant differences between elderly dentate and edentulous subjects in maxilla and mandible. The percentage reduction in the vertical height of edentulous subjects as compared to dentate subjects ranges from 29% to 39%. The reduction in the heights was greater in mandible than in maxilla in both the study groups. The vertical measurements were significantly greater in men than in women in maxilla and the mandible. Vertical heights of maxillary and mandibular jaw bones are important factors in planning complete denture and the implant supported prosthesis. Further studies would be necessary to determine the region specific resorption of jaw bones and its association with the duration of denture wear in edentulous subjects. PMID- 23451927 TI - Dental case manager encounters: the association with retention in dental care and treatment plan completion. AB - Little is known about dental case managers as few programs have been scientifically evaluated. The goal of this study was to explore the impact of dental case manager on retention in dental care and completion of treatment plans, while specifically exploring the number of dental case manager encounters. Fourteen programs enrolled people with HIV/AIDS (PLWHA) in dental care and a longitudinal study between 2007 and 2009. The 758 participants had a total of 2715 encounters with a dental case manager over twelve months: 29% had a single encounter; 21% had two; 27% had 3-4 and; 23% had 5-29 encounters. Adjusting for baseline characteristics, participants receiving more encounters were significantly more likely to complete their Phase 1 treatment plan, be retained in dental care, and experience improvements in overall oral health status. Organizations considering efforts to improve the oral health of vulnerable, hard to-engage populations should consider these findings when planning interventions. PMID- 23451928 TI - To evaluate the comparative status of oral health practices, oral hygiene and periodontal status amongst visually impaired and sighted students. AB - The aim of this study was to evaluate the comparative status of oral health practices, oral hygiene, and periodontal status amongst visually impaired and sighted students. In this study, 142 visually impaired children from a blind school in the age group of 6-18 years were enrolled with a similar number of age and sex matched sighted students studying in different schools of Chandigarh. The outcome variables were oral hygiene practices, oral hygiene status, and periodontal status. The visually impaired had been found to have better oral hygiene practices, a nonsignificant difference of oral hygiene scores but a significantly high value for bleeding scores as compared to sighted students. Age wise comparisons showed that bleeding scores were highly significant in 9-11 years and 12-14 years age group as compared to 6-8 years and 15-18 years age group. It could be related that the increased prevalence of bleeding sites despite of better oral hygiene practices in visually impaired group might be the result of their handicap to visualize plaque. PMID- 23451929 TI - Comparative assessment of dentition status among poliomyelitis children in Udaipur, India. AB - To determine and compare the dental caries experience and treatment needs of children with Poliomyelitis at Udaipur, India. Total sample comprised of 344 children with Poliomyelitis (upper limb disability: 33.4%; lower limb disability: 33.7%; both upper and lower limb disability: 32.8%) in the age group of 12-15 years. Clinical examination included recording Dentition Status and Treatment Needs. Chi-square test, Analysis of variance (ANOVA), multiple logistic and stepwise linear regressions were used for statistical analysis. The mean decayed, missing, filled teeth (DMFT) score (4.47 +/- 3.09) was found to be highest among children with Poliomyelitis having both upper and lower limb impairment (p < .05). Stepwise and logistic regression analysis showed that the best predictors for dental caries were disability, socioeconomic status and snacks in between meals. A significant relationship of dental caries with limb involved in impairment draws immediate attention for a planned approach in improving the oral health. PMID- 23451930 TI - Dentin decalcification during lithium treatment: case report. AB - Severe dental decay and changes in tooth structure have been reported in association with the use of lithium in Psychiatry, but lithium effects on tooth inorganic composition remain unknown. A 30-year-old woman with bipolar disorder, treated with lithium carbonate presented severe dental decay. Dentin samples from lithium and healthy volunteers were collected and submitted to ionic and ultrastructural analysis. Samples from the lithium patient exhibited irregular peritubular walls and the mineral crystals were irregularly arranged in the intertubular dentin. In addition, a decrease in Mg/P/Ca and an increase of Zn concentrations were detected. These data suggest that the severe dental decay and changes in the tooth structure observed for the lithium-treated patient are related to dentin mineral loss and that this pathological condition is different from caries lesions. PMID- 23451931 TI - Rapid endodontic management of type II dens invaginatus using an MTA plug: a case report. AB - Dens invaginatus is an anomaly characterized by an infolding of enamel and dentin that can lead to caries and pulpal death while the tooth is still immature, and present difficulties with diagnosis and treatment. Generally such open apices are managed by long term apexifaction procedures. This article demonstrated rapid management of a maxillary lateral incisor having a type 2 dens invaginatus, necrotic pulp, open apex and very large periradicular lesion using calcium hydroxide for one week prior to placement of a mineral trioxide aggregate (MTA) plug. After setting of the MTA, the remaining canal space was obturated using a warm vertical gutta percha technique. At 6 months follow-up the patient was asymptomatic, the lesion had almost entirely resolved, and, the root was already completely surrounded by bone. PMID- 23451933 TI - DFT and experimental exploration of intramolecular [2 + 2 + 2] cycloaddition of oxanorbornadienedicarboxylates and analogues. AB - The facile intramolecular [2 + 2 + 2] homo-Diels-Alder cycloadditions of oxanorbornadienedicarboxylates and analogues have been investigated by theoretical calculations using B3LYP and M06-2X density functional methods and experimental confirmation. The oxanorbornadienedicarboxylates formed from furans and but-2-ynedioates undergo the resulting intramolecular [2 + 2 + 2] cycloaddition in a concerted but asynchronous fashion, requiring energy barriers of about 30 kcal/mol to construct five- and three-membered rings simultaneously. Bridgehead substitutents have little influence on the regioselectivity, whereas 5 substitutents involving steric hindrance or electron-acceptor groups are predicted to attenuate the cycloaddition at the substituted side. Furthermore, the linker length, unsaturated bonds, and bridge-ring size are very sensitive to the cyclization rate. Additionally, aza- and norbornadienedicarboxylates demonstrate less reactivity, while thionorbornadienedicarboxylates show more reactivity with the challenge of their synthesis. The intermolecular version was also evaluated in comparison with the intramolecular version. Finally, our experimental tests verified the calculational prediction of the regioselectivity and reactivity. PMID- 23451932 TI - A survey of tobacco dependence treatment services in 121 countries. AB - AIMS: To report progress among Parties to the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in developing tobacco dependence treatment systems in accordance with FCTC Article 14 and the Article 14 guidelines recommendations. DESIGN: Cross-sectional study. SETTING: Electronic survey from December 2011 to August 2012. PARTICIPANTS: One hundred and sixty three of the 174 Parties to the FCTC at the time of our survey. MEASUREMENTS: The 51-item questionnaire contained 21 items specifically on treatment systems. Questions covered the availability of basic treatment infrastructure and national cessation support systems. FINDINGS: We received responses from 121 (73%) of the 166 countries surveyed. Fewer than half of the countries had national treatment guidelines (n = 53, 44%), a government official responsible for tobacco dependence treatment (n = 49, 41%), an official national treatment strategy (n = 53, 44%) or provided tobacco cessation support for health workers (n = 55, 46%). More than half encouraged brief advice in existing health care services (n = 68, 56%), while only 44 (36%) had quitlines and only 20 (17%) had a network of treatment support covering the whole country. Low- and middle-income countries had less tobacco dependence treatment provision than high-income countries. CONCLUSION: Most countries, especially low- and middle-income countries, have not yet implemented the recommendations of FCTC Article 14 or the FCTC Article 14 guidelines. PMID- 23451934 TI - Morphology and histology of Lyonet's gland of the tropical tasar silkworm, Antheraea mylitta. AB - The morphology and histology of Lyonet's gland in the second to fifth instar larvae of Antheraea mylitta Drury (Lepidoptera: Saturniidae) are described. Each of the paired silk glands of this silk worm were associated with a Lyonet's gland. The paired Lyonet's glands were located on the ventrolateral sides of the esophagus, close to the subesophageal ganglion. Whole mount and SEM observations revealed that each Lyonet's gland consisted of a rosette of glandular mass, and a short narrow tubular duct opening into the anterior part of the silk gland (ASG), close to the common excretory duct. In each instar, these glands were unequal in size. The glandular mass was innervated by fine nerves from the subesophageal ganglion, suggesting a neural control for the glandular activity. The glandular mass was made up of clustered long cells wrapped by a thin basal lamina, which was continuous over the non-secretory low columnar cells of the Lyonet's gland duct and ASG. The narrow bases of long cells of each glandular mass led into the lumen of the duct of the gland. Histochemical analysis of fully developed Lyonet's gland showed clustered lipid granules in the gland cells. PMID- 23451935 TI - Influence of nanohelical shape and periodicity on stem cell fate. AB - Microenvironments such as protein composition, physical features, geometry, and elasticity play important roles in stem cell lineage specification. The components of the extracellular matrix are known to subsequently assemble into fibrillar networks in vivo with defined periodicity. However, the effect of the most critical parameter, which involves the periodicity of these fibrillar networks, on the stem cell fate is not yet investigated. Here, we show the effect of synthetic fibrillar networks patterned with nanometric periodicities, using bottom-up approaches, on the response of stem cells. We have used helical organic nanoribbons based on self-assemblies of Gemini-type amphiphiles to access chiral silica nanoribbons with two different shapes and periodicities (twisted ribbons and helical ribbons) from the same native self-assembled organic nanostructure. We demonstrate the covalent grafting of these silica nanoribbons onto activated glass substrates and the influence of this programmed isotropically oriented matrix to direct the commitment of human mesenchymal stem cells (hMSCs) into osteoblast lineage in vitro, free of osteogenic-inducing media. The specific periodicity of 63 nm (+/-5 nm) with helical ribbon shape induces specific cell adhesion through the fibrillar focal adhesion formation and leads to stem cell commitment into osteoblast lineage. In contrast, the matrix of periodicity 100 nm (+/-15 nm) with twisted ribbon shape does not lead to osteoblast commitment. The inhibition of non-muscle myosin II with blebbistatin is sufficient to block this osteoblast commitment on helical nanoribbon matrix, demonstrating that stem cells interpret the nanohelical shape and periodicity environment physically. These results indicate that hMSCs could interpret nanohelical shape and periodicity in the same way they sense microenvironment elasticity. This provides a promising tool to promote hMSC osteogenic capacity, which can be exploited in a 3D scaffold for bone tissue engineering. PMID- 23451936 TI - Photochemical reaction containers as energy and electron-transfer agents. AB - Two deep cavity cavitands, octa acid and resorcinol-capped octa acid, have been established to be good triplet energy donors in the excited state and electron donors in the ground state to excited acceptors. This property endows them the capacity to be "active" reaction containers. The above recognition provides opportunities to investigate the excited state chemistry of host-encapsulated guests without the use of secondary triplet energy and electron donors. PMID- 23451938 TI - Chondroitinase injection improves keloid pathology by reorganizing the extracellular matrix with regenerated elastic fibers. AB - Keloids are a proliferative fibrotic disease characterized by abnormal accumulation of extracellular matrix in the dermis. Keloid lesions lack skin plasticity due to deficiencies in elastic fiber formation in the extracellular matrix. The loss of elastic fiber is caused by excessive accumulation of chondroitin sulfate (CS), a sulfated glycosaminoglycan. However, there is no radical cure for keloids. Using a model system, we show herein that treatment of keloid tissues with chondroitinase ABC, an enzyme that specifically digests CS, improves clinical features of keloids. Keloid tissues obtained from patients were grafted on nude mice, and chondroitinase ABC was injected into the grafted keloid tissues. Chondroitinase ABC treatment significantly reduced the volume of keloid implants concomitant with recovery of elastic fiber formation. These results suggest that chondroitinase ABC injection is an effective therapy for keloid. PMID- 23451940 TI - IDH mutation analysis in gliomas as a diagnostic and prognostic biomarker. AB - INTRODUCTION: There is a high rate of IDH1/2 mutations in low grade gliomas and in high grade gliomas deriving from them. IDH analysis of gliomas is a novel method of classification and an independent prognostic marker. We compared antibody and sequencing methods for the detection of IDH mutations. METHOD: 88 samples from 74 patients were identified. For immunohistochemistry: sections were stained with anti-IDH1R132H antibody. For sequencing: DNA was extracted from fresh, frozen tissue. RESULTS: 28% (20/71) of cases were positive for the R132H IDH1 mutation by antibody. An IDH1 mutation was detected by molecular genetics in 37% (21/57) of cases and no IDH2 mutations were detected. 24% (5/21) had rare IDH1 mutations not detected by immunohistochemistry. Where sufficient tissue was available, immunohistochemistry and DNA analysis were fully concordant for the p.Arg132His mutation. Both Grade II gliomas and anaplastic astrocytomas showed a statistically different distribution of IDH1 mutation load compared to GBMs (p < 0.0001; p = 0.0021 respectively). CONCLUSION: A rationalised combined approach involving R132H antibody testing and sequencing of negative cases would be ideal for the detection of IDH1 mutations--antibody testing is cheaper than sequencing but sequencing demonstrates rare IDH1 mutations not detected by immunohistochemistry. PMID- 23451941 TI - Thrombus formation in a dilated torcula following aneurysmal subarachnoid haemorrhage. AB - A case of thrombus formation occurring within a dilation of the dural venous sinuses following aneurysmal sub-arachnoid haemorrhage is presented. Acute neurological deterioration accompanied propagation of the thrombus. The patient was anticoagulated on day 5 post-SAH with no haemorrhagic complications and made a full recovery. The optimum time to commence anticoagulation is not clear and is discussed. PMID- 23451939 TI - Assessments of the extent to which health-care providers involve patients in decision making: a systematic review of studies using the OPTION instrument. AB - BACKGROUND: We have no clear overview of the extent to which health-care providers involve patients in the decision-making process during consultations. The Observing Patient Involvement in Decision Making instrument (OPTION) was designed to assess this. OBJECTIVE: To systematically review studies that used the OPTION instrument to observe the extent to which health-care providers involve patients in decision making across a range of clinical contexts, including different health professions and lengths of consultation. SEARCH STRATEGY: We conducted online literature searches in multiple databases (2001-12) and gathered further data through networking. INCLUSION CRITERIA: (i) OPTION scores as reported outcomes and (ii) health-care providers and patients as study participants. For analysis, we only included studies using the revised scale. DATA EXTRACTION: Extracted data included: (i) study and participant characteristics and (ii) OPTION outcomes (scores, statistical associations and reported psychometric results). We also assessed the quality of OPTION outcomes reporting. MAIN RESULTS: We found 33 eligible studies, 29 of which used the revised scale. Overall, we found low levels of patient-involving behaviours: in cases where no intervention was used to implement shared decision making (SDM), the mean OPTION score was 23 +/- 14 (0-100 scale). When assessed, the variables most consistently associated with higher OPTION scores were interventions to implement SDM (n = 8/9) and duration of consultations (n = 8/15). CONCLUSIONS: Whatever the clinical context, few health-care providers consistently attempt to facilitate patient involvement, and even fewer adjust care to patient preferences. However, both SDM interventions and longer consultations could improve this. PMID- 23451942 TI - Issues and challenges associated with nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory: a qualitative study. AB - AIMS AND OBJECTIVES: To explore issues and challenges associated with nurse administered procedural sedation and analgesia in the cardiac catheterisation laboratory from the perspectives of senior nurses. BACKGROUND: Nurses play an important part in managing sedation because the prescription is usually given verbally directly from the cardiologist who is performing the procedure and typically, an anaesthetist is not present. DESIGN: A qualitative exploratory design was employed. METHODS: Semi-structured interviews with 23 nurses from 16 cardiac catheterisation laboratories across four states in Australia and also New Zealand were conducted. Data analysis followed the guide developed by Braun and Clark to identify the main themes. RESULTS: Major themes emerged from analysis regarding the lack of access to anaesthetists, the limitations of sedative medications, the barriers to effective patient monitoring and the impact that the increasing complexity of procedures has on patients' sedation requirements. CONCLUSIONS: The most critical issue identified in this study is that current guidelines, which are meant to apply regardless of the clinical setting, are not practical for the cardiac catheterisation laboratory due to a lack of access to anaesthetists. Furthermore, this study has demonstrated that nurses hold concerns about the legitimacy of their practice in situations when they are required to perform tasks outside of clinical practice guidelines. To address nurses' concerns, it is proposed that new guidelines could be developed, which address the unique circumstances in which sedation is used in the cardiac catheterisation laboratory. RELEVANCE TO CLINICAL PRACTICE: Nurses need to possess advanced knowledge and skills in monitoring for the adverse effects of sedation. Several challenges impact on nurses' ability to monitor patients during procedural sedation and analgesia. Preprocedural patient education about what to expect from sedation is essential. PMID- 23451943 TI - Dermatologist-diagnosed skin diseases among immigrant Latino poultry processors and other manual workers in North Carolina, USA. AB - BACKGROUND: Immigrant Latino workers represent an expanding workforce in rural areas of the USA, where their employment is concentrated in occupations such as poultry processing that entail chemical, infectious, and mechanical skin exposures. Occupation-related skin illnesses in this vulnerable population are not well characterized. OBJECTIVES: This study was designed to describe the prevalences of skin diseases among immigrant Latino poultry processors and other manual workers in North Carolina. METHODS: Community-based sampling was used to recruit 742 immigrant Latino workers, 518 of whom underwent a physical examination supervised by a board-certified dermatologist. The presence or absence of skin disease on the face, neck, arms, hands, and feet was recorded. RESULTS: Workers ranged in age from 18 years to 68 years. Slightly over half of the sample were male (52.6%). Poultry workers represented 55.8% of the study sample. Infectious skin diseases were the most common diagnosis, present in 52.3% of workers. Inflammatory skin diseases were present in 28.2% and pigmentary disorders in 21.8% of workers. The most common skin conditions were tinea pedis (37.6%), onychomycosis (31.9%), scars (13.7%), acne (11.8%), and melasma (9.3%). Age, sex, first language, and work as a poultry processor accounted in part for the prevalence of these diseases. CONCLUSIONS: Several skin diseases are highly prevalent in immigrant Latino workers and may relate to work environment. These may impair the quality of life of these workers and predispose them to further illness. PMID- 23451945 TI - In search of a good ending. PMID- 23451944 TI - Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase. AB - The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands. Here we describe the application of the program AutoDock to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K(d) = ~100 fM). AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid side chains of the target protein. PMID- 23451946 TI - Neuroplasticity and pain: what does it all mean? PMID- 23451947 TI - Why e-health is so hard. PMID- 23451948 TI - Progressive multifocal leukoencephalopathy caused by BK virus? PMID- 23451951 TI - Closing the global gender gap. PMID- 23451952 TI - Meeting end-of-life care needs for people with chronic disease: palliative care is not enough. PMID- 23451953 TI - Advance care planning: lessons from a study of Tasmanian enduring guardianship forms. PMID- 23451955 TI - Doctors in support of law reform for voluntary euthanasia. PMID- 23451956 TI - Clinical effectiveness research: a critical need for health sector research governance capacity. PMID- 23451957 TI - Tiger snake (Notechis spp) envenoming: Australian Snakebite Project (ASP-13). Comment. PMID- 23451958 TI - Tiger snake (Notechis spp) envenoming: Australian Snakebite Project (ASP-13). PMID- 23451959 TI - A meta-analysis of "hospital in the home". Comment. PMID- 23451960 TI - A meta-analysis of "hospital in the home". PMID- 23451961 TI - Flexor digitorum profundus avulsion injuries in Oztag players. PMID- 23451963 TI - Effect of an electronic medical record information system on emergency department performance. AB - OBJECTIVE: To determine whether implementation of the Cerner FirstNet electronic medical record system was associated with any change in emergency department (ED) performance. DESIGN, SETTING AND PATIENTS: A retrospective observational study conducted during a 6-03 period in 2009 after the introduction of FirstNet and a corresponding 6-03 control period in 2008 when the Emergency Department Information System (EDIS) was operational. Data from all patients presenting to the ED during each period were extracted from each system and analysed for changes in key performance indicators (KPIs). Potential confounding variables, including total number of ED presentations, ED occupancy, ED staffing levels and triage category distribution, were also collected. MAIN OUTCOME MEASURES: Waiting time for all patients; waiting time, treatment time and total time for patients discharged from the ED; proportion of patients who did not wait to be seen by a doctor (DNW rate); and proportion of ambulance offload waiting times longer than 30 minutes. RESULTS: We found a reduction in performance with respect to ED KPIs after implementation of the FirstNet system. There were increases in the waiting time for all patients (median, 40 min v 78 min), and the waiting time (median, 49 min v 87 min), treatment time (median, 128 min v 147 min) and total time (median, 214 min v 280 min) for patients discharged from the ED. There were increases in the DNW rate (8.3% v 15.6%) and the proportion of ambulance offload times longer than 30 minutes (10.5% v 13.3%). All differences were statistically significant (P < 0.05). CONCLUSION: Implementation of the FirstNet electronic medical record system was associated with deterioration in ED KPIs. PMID- 23451962 TI - An update of consensus guidelines for warfarin reversal. AB - * Despite the associated bleeding risk, warfarin is the most commonly prescribed anticoagulant in Australia and New Zealand. Warfarin use will likely continue for anticoagulation indications for which novel agents have not been evaluated and among patients who are already stabilised on it or have severe renal impairment. * Strategies to manage over-warfarinisation and warfarin during invasive procedures can reduce the risk of haemorrhage. * For most warfarin indications, the target international normalised ratio (INR) is 2.0-3.0 (venous thromboembolism and single mechanical heart valve excluding mitral). For mechanical mitral valve or combined mitral and aortic valves, the target INR is 2.5-3.5. * Risk factors for bleeding with warfarin use include increasing age, history of bleeding and specific comorbidities. * For patients with elevated INR (4.5-10.0), no bleeding and no high risk of bleeding, withholding warfarin with careful subsequent monitoring seems safe. * Vitamin K1 can be given to reverse the anticoagulant effect of warfarin. When oral vitamin K1 is used for this purpose, the injectable formulation, which can be given orally or intravenously, is preferred. * For immediate reversal, prothrombin complex concentrates (PCC) are preferred over fresh frozen plasma (FFP). Prothrombinex-VF is the only PCC routinely used for warfarin reversal in Australia and New Zealand. It contains factors II, IX, X and low levels of factor VII. FFP is not routinely needed in combination with Prothrombinex-VF. FFP can be used when Prothrombinex-VF is unavailable. Vitamin K1 is essential for sustaining the reversal achieved by PCC or FFP. * Surgery can be conducted with minimal increased risk of bleeding if INR <= 1.5. For minor procedures where bleeding risk is low, warfarin may not need to be interrupted. If necessary, warfarin can be withheld for 5 days before surgery, or intravenous vitamin K1 can be given the night before surgery. Prothrombinex-VF use for warfarin reversal should be restricted to emergency settings. Perioperative management of anticoagulant therapy requires an evaluation of the risk of thrombosis if warfarin is temporarily stopped, relative to the risk of bleeding if it is continued or modified. PMID- 23451964 TI - Good HIT and bad HIT. PMID- 23451965 TI - Recent increase in detection of alprazolam in Victorian heroin-related deaths. AB - OBJECTIVES: To examine the rate of detection of alprazolam among cases of heroin related death (HRD) in Victoria, including the relationship between alprazolam supply and HRDs. DESIGN AND SETTING: Population-based study of community alprazolam supply in Victoria and HRDs reported to the Victorian coroner from January 1990 to December 2010. MAIN OUTCOME MEASURES: Number of prescriptions for alprazolam supplied; defined daily dose (DDD) per 1000 population per 04 of alprazolam; number of cases of HRD in which alprazolam was detected through postmortem toxicological testing. RESULTS: Alprazolam supply increased by 1426%, from 0.42 DDD/1000/04 in 1990, to 6.41 in 2010. For every 1 unit increase in DDD/1000/04, the proportion of cases of HRD in which alprazolam was detected increased at an incidence rate ratio of 2.4 (95% CI, 2.1-2.8; P < 0.001). Alprazolam was detected among increasing proportions of HRDs, from 5.3% in 2005 to a peak of 35.3% in 2009. CONCLUSION: The increase in detection of alprazolam among cases of HRD, particularly since 2005, and the disproportionate increase in prescribing of the high-dose 2 mg formulation compared with other formulations suggest a need to examine alprazolam prescribing and to identify inappropriate prescribing and the circumstances of diversion from licit to illicit use. PMID- 23451966 TI - Beyond injecting drug use: investigation of a Victorian cluster of hepatitis C among HIV-infected men who have sex with men. AB - OBJECTIVES: To examine increased notifications of hepatitis C virus (HCV) in men who have sex with men (MSM) infected with HIV in Victoria, and evaluate HCV transmission risk factors other than injecting drug use. DESIGN, SETTING AND PARTICIPANTS: Case series through retrospective review of all HCV cases in Victoria from 1 April 2010 to 30 June 2011, with clinical and laboratory data examined in likely MSM to identify a co-infected cohort. Patients with newly acquired HCV with HIV co-infection were invited to complete a questionnaire exploring novel risk factors for HCV transmission (non-injecting drug use, sexual practices with increased likelihood of trauma, and presence of genital ulcers). Sequencing was performed to determine the local molecular epidemiology of HCV co infection. MAIN OUTCOME MEASURES: Demographics of newly co-infected MSM, traditional versus novel risk factors for HCV acquisition, prior knowledge of potential for sexual transmission of HCV, and association between viral sequences. RESULTS: Thirty-one patients with HIV were identified from 3365 notifications of hepatitis C. The median age was 42 years, and median time from HIV to HCV diagnosis was 22 months. Most patients were asymptomatic, with abnormal liver function tests prompting HCV testing. Interviews with 14 patients identified a high prevalence of novel risk factors and limited knowledge of HCV risk. Two clusters of matching viral sequences were identified. CONCLUSIONS: Novel HCV transmission routes have emerged in Victoria. These data reinforce the need for targeted testing and prevention strategies among HIV-infected MSM. PMID- 23451967 TI - BK virus-associated progressive multifocal leukoencephalopathy. PMID- 23451968 TI - Ethics in medicine: is it a futile exercise? PMID- 23451969 TI - What is futile and who decides? The clinician's dilemma. PMID- 23451970 TI - Futile treatment: the ethicist's perspective. PMID- 23451971 TI - Legal perspectives on consent in disputes about futile care. PMID- 23451972 TI - Gaining a patient's perspective while becoming a doctor. PMID- 23451973 TI - Medicine on the walls of the art gallery. PMID- 23451974 TI - Unilateral nevoid telangiectasia--report of two cases. PMID- 23451975 TI - Managing critical incidents in grocery shopping by community-living people with Alzheimer's disease. AB - AIM: People with Alzheimer's disease (AD) remain in their ordinary housing and continue to use public space despite increasing disabilities. The aim of this study was to discover and describe problematic situations and critical incidents that took place when people with AD performed the ordinary outside-home activity of grocery shopping and how these were met by them. METHODS: Individual interviews (n = 12) and participant observations (n = 8) with six informants were performed and analysed using a grounded theory approach. RESULTS: The findings are presented in six categories and each category describes different critical incidents and actions used to meet these. The categories were: (a) Remembering to bring things when leaving home, (b) Finding the way to and from the grocery shop without getting lost, (c) Finding a way through traffic when not feeling safe, (d) Finding objects when organization is disrupted, (e) Choosing when a lot of objects and products are available, and (f) Finding a method to pay when payment opportunities are restricted. The core category, "A challenging and unstable process of meeting critical incidents in grocery shopping", was characterised by reflections and creativity to achieve relative harmony in each critical incident. CONCLUSIONS: In conclusion, it is important that relatives and professionals take into account relevant actions to help people with AD coordinate with their environment. PMID- 23451976 TI - Transient receptor potential TRP channels as therapeutic drug targets: next round! PMID- 23451977 TI - Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides. AB - INTRODUCTION: Therapeutic gene silencing is a huge promise for the treatment of a variety of diseases. The translation of this widely used scientific technique toward clinical application has been hindered by insufficient ADME properties of antisense and siRNA oligonucleotides. Despite reasonable therapeutic response after local administration, reaching adequate concentrations at the site of action after systemic application is still a major hurdle and this has resulted in poor efficiency in preclinical and clinical situations. AREAS COVERED: This review focuses on the influence on the ADME parameters of chemical modifications already tested in clinical trials, such as phosphorothioates (PSs), 2'-modified agents, including locked nucleic acids (LNA) and phosphorodiamidate morpholino oligomers (PMO). The dominating PS backbone modification, while conferring adequate nuclease resistance and improving biodistribution, has been shown to be involved in unspecific protein binding and off-target effects on apoptosis pathways. PS-free antisense agents such as PMO generally show poorer pharmacokinetic characteristics. EXPERT OPINION: In terms of pharmacokinetics and cell membrane permeation, there is currently no efficient alternative to PS, although doubts about long-term toxicity of this class still remain. Consequently, improved structural modifications or galenic formulations are deemed necessary to create entities with higher efficiency and lower toxicity. PMID- 23451978 TI - Isolation of an sigma-alkyl iridium hydride complex, formed in the (semi)hydrogenation of an beta-enamido ketone. AB - sigma-Alkyl iridium hydride complexes are generally postulated as intermediates in iridium-catalyzed hydrogenation. Fast reductive elimination results in the formation of the hydrogenation product. With an beta-enamido ketone as unsaturated substrate, such an intermediate could be trapped because the semihydrogenated product coordinates trifold to the iridium, generating a stable 18e(-) complex, which does not eliminate. PMID- 23451979 TI - Abundance of apple maggot, Rhagoletis pomonella, across different areas in central Washington, with special reference to black-fruited hawthorns. AB - The apple maggot fly, Rhagoletis pomonella (Walsh) (Diptera: Tephritidae), infests non-commercial apple (Malus domestica (Borkh.) Borkh.) and native black fruited hawthorns (mostly Crataegus douglasii Lindl.) in central Washington, but little has been published on the abundance of the fly in this region. In this paper, the abundance of R. pomonella across different sites near apple-growing areas in central Washington is documented in order to assess the threat of the fly to commercial apple orchards. The fly was first detected on traps in Klickitat, Yakima, and Kittitas Counties in 1981, 1995, and 1997, respectively. From 1981-2010 in Kittitas and Yakima Counties, only 0 to 4.7% of traps on apple, crabapple, and hawthorn trees were positive for flies, whereas in Klickitat County, located farther from commercial apple orchards, 0 to 41.9% of traps were positive. In 2008, in Yakima County and Goldendale in Klickitat County, 7.8% of black-fruited hawthorn trees were infested, with 0 to 0.00054 larvae per fruit. In 2010, in Kittitas and Yakima Counties and Goldendale in Klickitat County, 25.0% of C. douglasii trees were infested, with 0.00042 to 0.00248 larvae per fruit. In 2010, in a remote forested area of Klickitat County far from commercial apple orchards, 94.7% of C. douglasii trees were infested, with 0.20813 larvae per fruit. Overall results suggest R. pomonella is unlikely to develop high populations rapidly near major commercial apple-growing areas in central Washington, including in black-fruited hawthorns, increasing chances it can be kept out of commercial orchards. PMID- 23451980 TI - The effect of volume replacement during therapeutic leukapheresis on white blood cell reduction in patients with extreme leukocytosis. AB - BACKGROUND: Extreme leukocytosis, generally defined as a white blood cell (WBC) count of more than 100 * 10(9) /L consisting largely of blast cells, especially when accompanied by clinical signs and symptoms of leukostasis or hyperviscosity, often predicts a poor clinical outcome in patients with acute leukemia. In this study, we aimed to investigate the effect of volume replacement (VR) during therapeutic leukapheresis (TA) procedure on early mortality rate and WBC reduction. STUDY DESIGN AND METHODS: We retrospectively analyzed 29 patients who underwent TA from 2007 to 2011. Fifteen of the patients underwent TA procedure with VR and 14 of the patients underwent TA procedure without VR. RESULTS: WBC reduction was significantly higher in patients who underwent TA with VR (p < 0.001). Early mortality rate was significantly lower in leukemia patients who underwent TA with VR than in patients who underwent TA without VR (p < 0.01); early mortality rates were 6.7% for 7-day and 13.8% for 100-day survivals. The mortality rates in the TA without VR group, however, were 42.9 and 71.4% for 7- and 100-day survivals, respectively. CONCLUSION: Decreased early mortality rate in TA with VR group may be associated with prompt reduction of WBCs achieved with TA with VR and may also be associated with removal of the cytokines related to leukostasis. TA with VR would give more time for induction chemotherapy and increased overall survival rate. PMID- 23451981 TI - Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution. AB - Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To demonstrate the practical application of the RQSAR approach, the structure of vildagliptin, a high-CL and a high-Vdss compound, is modified based on the atomic contributions to its predicted CL and Vdss to propose compounds with lower CL and lower Vdss. PMID- 23451982 TI - Light saturated RuBP oxygenation by Rubisco is a robust predictor of light inhibition of respiration in Triticum aestivum L. AB - Plant respiratory metabolism is complicated by the fact that the rate of non photorespiratory mitochondrial CO2 release in the light (R light) may be lower than the rate of leaf respiration in the dark (R dark). A body of work on this topic implies a linkage between light inhibition of respiration and photorespiration, although the direction of effect and underlying mechanisms remain uncertain. In this study we used a variety of short- and long-term environmental manipulations to explicitly manipulate the rate of photorespiration (nuo) and quantify the effect on the inhibition of mitochondrial respiration in the light (R light:R dark). We address the following three questions: (i) will the R light:R dark ratio increase or decrease with high CO2 or low O2 and at low temperatures; (ii) does nuo correlate with R light:R dark, and if so, in what way; (iii) will suppression of respiration by light (the 'Kok effect') be seen to the same extent in Zea mays, a C4 plant, and in Triticum aestivum, a C3 plant? We found that Rlight :Rdark decreased under conditions that suppressed nuo in wheat, and this resulted in a positive relationship between R light:R dark and nuo. Inhibition of respiration by light in C4 maize did not respond to environmental treatment, and the fixed R light:R dark (0.46-0.72) was consistent with the wheat response, assuming a nuo approaching zero. The most likely mechanism to explain this finding is that R light increases (or the inhibition of respiration by light decreases) when there is an increase in photorespiration and thus an increase in the demand for TCA cycle substrates associated with the recovery of photorespiratory cycle intermediates in the peroxisome. This work is significant because it combines a comparison of C3 and C4 metabolism with a range of environmental treatments to independently suppress nuo. PMID- 23451983 TI - Efficient pro-survival/angiogenic miRNA delivery by an MRI-detectable nanomaterial. AB - Herein, we report the use of biodegradable nanoparticles (NPs) containing perfluoro-1,5-crown ether (PFCE), a fluorine-based compound (NP170-PFCE) with the capacity to track cells in vivo by magnetic ressonance imaging (MRI) and efficiently release miRNA. NP170-PFCE complexed with miRNAs accumulate whitin the cell's endolysosomal compartment and interact with higher frequency with argonaute2 (Ago2) and GW182 proteins, which are involved in the biological action of miRNAs, than commercial complexes formed by commercial reagents and miRNA, which in turn accumulate in the cell cytoplasm. The release of miRNA132 (miR132) from the NPs increased 3-fold the survival of endothelial cells (ECs) transplanted in vivo and 3.5-fold the blood perfusion in ischemic limbs relatively to control. PMID- 23451984 TI - How does robot-assisted radical prostatectomy (RARP) compare with open surgery in men with high-risk prostate cancer? AB - What's known on the subject? and what does the study add?: Previous studies have shown that robot-assisted radical prostatectomy (RARP) can be performed in men with high-risk prostate cancer with similar outcomes to that of open surgery. However, most of the literature consists of small case series and compares RARP outcomes to open outcomes from the literature. This study compared a cohort of high-risk patients undergoing open RP and RARP at a single institution with good follow up. We found no difference in positive margin rates or likelihood of prostate cancer recurrence. This adds to the growing evidence that RARP is a safe option for men with high-risk disease. OBJECTIVE: To compare oncological outcomes in high-risk patients who underwent open retropubic radical prostatectomy (RRP) and robot-assisted RP (RARP) at a single institution. Despite equivalent oncological outcomes between open RRP and RARP, the use of RARP in men with high risk tumours has been debated. PATIENTS AND METHODS: A retrospective analysis of high-risk patients treated with open RRP or RARP at UCSF from 2002 to 2011 was conducted. The relationship between surgical approach and positive margin rate was assessed by multivariate logistic regression Cox proportional hazards regression assessed the effect of surgical approach on time to tumour recurrence. RESULTS: In all, 177 open RRP and 233 RARP patients made up the final cohort for analyses. The mean (SD) age was 61.6 (6.6) years and the median (range) follow-up was 27 (2-112) months. RARP patients had less blood loss (median 200 vs 400 mL, P < 0.01) and underwent complete bilateral nerve sparing more often (54% vs 34%, P < 0.01) than those undergoing open RRP. There were no differences by approach in pathological grade, stage, or positive margin rates. However, there was a trend towards higher positive margin rates with RARP early on. Recurrence-free survival was similar at 2 years (84% and 79%) and 4 years (68% and 66%) after open RRP and RARP, respectively (log-rank P = 0.53). CONCLUSIONS: This study is novel in that it assesses outcomes of open RRP vs RARP in a cohort of high-risk men at a single institution. RARP appears to be a feasible option for men with high-risk prostate cancer and displayed equivalent oncological outcomes compared with open RRP. PMID- 23451985 TI - Blood lactate concentrations in ponies and miniature horses with gastrointestinal disease. AB - REASONS FOR PERFORMING STUDY: Clinical impression suggested that pony and miniature breeds (collectively referred to as ponies) presenting to a referral hospital for investigation of gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses. OBJECTIVES: The study tested the hypothesis that ponies with gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses with similar disease severity. STUDY DESIGN: Retrospective case-control study. METHODS: Medical records from September 2006 to July 2011 were reviewed for ponies with a primary presenting complaint of gastrointestinal disease. Two larger breed horses with gastrointestinal disease were selected as controls for each case. Data collected included case details, historical and clinicopathological findings, diagnosis and outcome. RESULTS: Information was collected on 50 ponies and 100 horses. Ponies had higher mean +/- s.d. respiratory rates (27 +/- 13 vs. 21 +/- 13 beats/min; P = 0.01) and rectal temperatures (37.9 +/- 0.6 vs. 37.4 +/- 0.6 degrees C; P = 0.006) and a longer median duration of clinical signs prior to presentation (10 h [1-72 h] vs. 6 h [1-120]; P<0.001). Median blood lactate concentrations on admission were higher in ponies than in horses (2.8 mmol/l [0.7-18.0] vs. 1.6 mmol/l [0.4-8.1]; P = 0.001). All other parameters relating to colic severity were not significantly different between groups, although more horses underwent exploratory laparotomy (19/50 ponies and 55/100 horses; P = 0.05). Median blood lactate concentrations in ponies with large intestinal disease, nonstrangulating lesions, undergoing medical treatment and surviving ponies were significantly higher than in horses in the same category. In contrast to horses, no differences in blood lactate concentrations exist between ponies with medical vs. surgical treatment, strangulating and nonstrangulating lesions and surviving and nonsurviving ponies. CONCLUSION AND POTENTIAL RELEVANCE: Ponies might present with higher blood lactate concentrations than horses and might falsely be suspected of having a surgical lesion or a poorer prognosis if veterinarians are not aware of breed differences. PMID- 23451986 TI - Association between low bone mineral density and clinical attachment loss in Japanese postmenopausal females. AB - BACKGROUND: Previous studies have shown conflicting results as to whether low bone mineral density (BMD) is associated with severe clinical attachment loss (AL). The effect of dental restoration on AL was not considered in most studies. In addition, studies of this association in Japanese individuals are limited. The aim of this cross-sectional study is to evaluate the possible association between BMD and AL with dental restoration information in Japanese community-dwelling postmenopausal females. METHODS: The participants were 397 females (average age: 68.2 years). BMDs of the lumbar spine and right proximal femur were measured by the dual-energy x-ray absorptiometry method. Based on lower BMD/young adult mean (YAM) among the two sites measured, participants were classified into three groups: 1) normal: BMD = 80% YAM or higher (n = 161); 2) osteopenia: BMD = 70% to 80% YAM (n = 136); and 3) osteoporosis: BMD = <70% YAM (n = 100). Multivariable analyses of the differences in AL values among three BMD groups was conducted using general linear models. Adjustments for the percentage of teeth restored and other covariates were considered. RESULTS: Individuals with osteopenia had significantly higher average AL than individuals with normal BMD (P = 0.022). Additionally, the osteoporosis group displayed significantly higher average AL (P = 0.003) and higher percentages of sites with AL >= 4 mm (P = 0.007). CONCLUSION: The results of the present study indicate that low systemic BMD was associated with severe AL in Japanese community-dwelling postmenopausal females. PMID- 23451987 TI - Periodontal tissue and serum concentration of clarithromycin after systemic administration in patients affected by chronic periodontitis. AB - BACKGROUND: During the past two decades, dentists and microbiologists have relied on periodontal antibiotic therapy in the management of periodontitis. This association has accumulated and strengthened exponentially. Macrolides attain high therapeutic concentrations in infected tissue, so they are potentially a good choice for inhibiting invasive periodontal pathogens. Clarithromycin accumulates in phagocytes, monocytes, fibroblasts, polymorphonuclear cells, macrophages, and lymphocytes. These cells are more numerous at inflamed sites, so it is reasonable to expect clarithromycin levels to be higher in periodontally diseased sites. This study determines the distribution profile of clarithromycin in the gingiva of patients with periodontitis compared to serum after systemic administration of clarithromycin. METHODS: Twenty patients (14 males and six females, aged 25 to 45 years) with chronic periodontitis were enrolled in the study. Gingival index and plaque index were recorded at baseline and 3 days after administration of 500 mg clarithromycin, twice daily, for 3 days. Intravenous blood and biopsy of periodontal tissue samples were taken on the third day. These samples were analyzed for detection of clarithromycin concentration using high performance liquid chromatography. RESULTS: Approximately 6 hours after the last dose of clarithromycin, mean clarithromycin concentrations in serum and periodontal tissue were 0.465 MUg/mL and 2.61 MUg/g, respectively, and the difference was statistically significant. CONCLUSIONS: Clarithromycin can attain higher levels in gingiva than serum of patients with periodontitis. This distribution profile of clarithromycin can thus be advantageous in the management of periodontal lesions. PMID- 23451988 TI - Do implant length and width matter for short dental implants (<10 mm)? A meta analysis of prospective studies. AB - BACKGROUND: This meta-analysis of prospective clinical trials was conducted to determine the effects of dental implant length and width on implant survival rate of short (<10 mm) implants. METHODS: An electronic search of the PubMed database for relevant studies published in English from November 1998 to March 2012 was performed. Selected studies were randomized clinical trials, human clinical trials, or prospective trials with a clear aim of investigating the success or survival rate of short (<10 mm) implants. RESULTS: Eight studies fulfilled the inclusion criteria and were subsequently analyzed. A total of 525 short (<10 mm) dental implants were analyzed, of which 253 were 3.5 mm in diameter (48.19%), 151 were 4.0 mm (28.76%), 90 were 4.1 mm (17.14%), 21 were 4.8 mm (4%), and 10 were 5.1 mm (1.9%). All implants included in this meta-analysis had a follow-up period of 12 to 72 months. The included studies reported on the survival rate and diameter of the implants. Six of the studies used "short implants" (7 to 9 mm), and the remaining were classified as "extra-short implants" (<= 6 mm). Five-year estimated failure rates were 1.61% and 2.92%, respectively, for extra-short and short implants (z = -3.49, P <0.001, 95% confidence interval = 0.51% to 4.10%). Furthermore, it was found that the wider the implant, the higher the failure rate (estimated failure rate = 2.36%, 95% confidence interval = 1.07% to 5.23%). CONCLUSIONS: Neither implant length nor width seemed to significantly affect the survival rate of short implants (<10 mm). Nonetheless, further well-designed randomized clinical trials are needed to confirm these findings. PMID- 23451989 TI - The significance of keratinized mucosa on implant health: a systematic review. AB - BACKGROUND: Whether a minimal width of keratinized mucosa (KM) is required to maintain peri-implant tissue health has been a topic of interest. This systematic review and meta-analysis aims to investigate the effect of KM on various peri implant health-related parameters. METHODS: An electronic search of five databases (from 1965 to October 2012) and a hand search of peer-reviewed journals for relevant articles were performed. Human cross-sectional or longitudinal studies with data on the relationship between the amount of KM around dental implants and various peri-implant parameters, with a follow-up period of at least 6 months, were included. RESULTS: Eleven studies, seven cross-sectional and four longitudinal, were included. Weighted mean difference (WMD) and confidence interval (CI) were calculated with meta-analyses for each clinical parameter. The results showed statistically significant differences in plaque index (PI) and modified PI (WMD = -0.27, 95% CI = -0.43 to -0.11), modified gingival index (mGI) (WMD = -0.48, 95% CI = -0.70 to -0.27), mucosal recession (MR) (WMD = -0.60 mm, 95% CI = -0.85 to -0.36 mm), and attachment loss (AL) (WMD = -0.35 mm, 95% CI = 0.65 mm to -0.06 mm), all favoring implants with wide KM. However, comparisons of other parameters (bleeding on probing, modified bleeding index, GI, probing depth, and radiographic bone loss) did not reach statistically significant differences. The result of heterogeneity test showed only one parameter (AL, P value for the chi(2) test = 0.30 and I(2) test = 18%) had a low degree of heterogeneity among analyzed studies; meta-analyses of other parameters presented moderate-to-high degree of heterogeneity. Limitations of the present review include limited number of selected studies (n = 11), existence of heterogeneity and publication bias, and only English-written articles searched. CONCLUSION: Based on current available evidence, a lack of adequate KM around endosseous dental implants is associated with more plaque accumulation, tissue inflammation, MR, and AL. PMID- 23451990 TI - Mixed nano/micro-sized calcium phosphate composite and EDTA root surface etching improve availability of graft material in intrabony defects: an in vivo scanning electron microscopy evaluation. AB - BACKGROUND: The use of nanoparticles of graft materials may lead to breakthrough applications for periodontal regeneration. However, due to their small particle size, nanoparticles may be eliminated from periodontal defects by phagocytosis. In an attempt to improve nanoparticle retention in periodontal defects, the present in vivo study uses scanning electron microscopy (SEM) to evaluate the potential of micrograft particles of beta-tricalcium phosphate (beta-TCP) to enhance the binding and retention of nanoparticles of hydroxyapatite (nHA) on EDTA-treated and non-treated root surfaces in periodontal defects after 14 days of healing. METHODS: Sixty patients having at least two hopeless periodontally affected teeth designated for extraction were randomly divided into four treatment groups (15 patients per group). Patients in group 1 had selected periodontal intrabony defects grafted with nHA of particle size 10 to 100 nm. Patients in group 2 were treated in a similar manner but had the affected roots etched for 2 minutes with a neutral 24% EDTA gel before grafting of the associated vertical defects with nHA. Patients in group 3 had the selected intrabony defects grafted with a composite graft consisting of equal volumes of nHA and beta-TCP (particle size 63 to 150 nm). Patients in group 4 were treated as in group 3 but the affected roots were etched with neutral 24% EDTA as in group 2. For each of the four groups, one tooth was extracted immediately, and the second tooth was extracted after 14 days of healing for SEM evaluation. RESULTS: Fourteen days after surgery, all group 1 samples were devoid of any nanoparticles adherent to the root surfaces. Group 2 showed root surface areas 44.7% covered by a single layer of clot-blended grafted particles 14 days following graft application. After 14 days, group 3 samples appeared to retain fibrin strands devoid of grafted particles. Immediately extracted root samples of group 4 had adherent graft particles that covered a considerable area of the root surfaces (88.6%). Grafted particles appeared to cover all samples in a multilayered pattern. After 14 days, the group 4 extracted samples showed multilayered fibrin-covered nano/micro-sized graft particles adherent to the root surfaces (78.5%). CONCLUSION: The use of a composite graft consisting of nHA and microsized beta-TCP after root surface treatment with 24% EDTA may be a suitable method to improve nHA retention in periodontal defects with subsequent graft bioreactivity. PMID- 23451992 TI - Determining the cost-effectiveness of hospital nursing interventions for patients undergoing a total hip replacement. AB - AIM: The purposes of the study were to (i) identify the types and amounts of nursing interventions and (ii) estimate the cost-effectiveness of nursing interventions for complications the patients experienced when undergoing a total hip replacement (THR). BACKGROUND: There has been little cost-effectiveness research into nursing interventions in hospitals, resulting in an inability to explain the economic value of hospital nursing interventions. METHOD: The direct effects of nursing interventions on hospital direct costs and complication rates were analysed using path modelling, controlling for multiple factors (patient characteristics and nursing contexts) influencing nursing care. Then, cost effectiveness ratios and the cost-effectiveness plane were used to identify cost effective interventions. RESULTS: Intramuscular (IM)/Subcutaneous (SC) Administration was the most cost-effective nursing intervention, followed by Orthotics Management. CONCLUSIONS: The study findings can be used to promote nurses' knowledge and attitudes about the economic value of nursing and cost effective care delivery. A sensitivity analysis with actual cost per nursing intervention and for specific complications will be necessary. IMPLICATIONS FOR NURSING MANAGEMENT: It is important for nurse administrators to support nurses' clear documentation in order to make nursing information available. Utilizing study methods and findings, nurse managers can compare the cost-effectiveness of new nursing interventions or manage dosages of nursing interventions to provide the most cost-effective nursing interventions. PMID- 23451993 TI - Antimonato polyoxovanadate based three-dimensional framework exhibiting ferromagnetic exchange interactions: synthesis, structural characterization, and magnetic investigation of {[Fe(C6H14N2)2]3[V15Sb6O42(H2O)]}.8H2O. AB - The new polyoxovanadate {[Fe(C6H14N2)2]3[V15Sb6O42(H2O)]}.8H2O (1) was obtained under solvothermal conditions using the amine that acts at the same time as the ligand, solvent, and reducing agent. The central structural motif of 1, [V15Sb6O42(H2O)](6-), is related to the {V18O42}-archetype cluster by replacing three VO5 square pyramids with three O2Sb-O-SbO2 moieties. Every [V15Sb6O42(H2O)](6-) cluster anion is expanded by six FeN4O2 octahedra, thus generating a rare three-dimensional network with differently sized pores hosting the crystal water molecules. In 1, two [V15Sb6O42(H2O)](6-) cluster anions with different orientations coexist. According to bond-valence-sum calculations, the anionic cluster can be formulated as [V(IV)15Sb(III)6O42(H2O)](6-), i.e., in line with the valence states of all other known {V15Sb6} clusters. The optical band gap of 1 was determined as 2.47 eV. Investigation of the magnetic behavior indicates dominating ferromagnetic exchange interactions between the V(4+) centers of the cluster and the Fe(2+) d(6) cations. PMID- 23451991 TI - Differences in HIV risk behavior of injection drug users in New York City by health care setting. AB - The purpose of this study is to examine the HIV risk behaviors and demographic characteristics of injection drug users (IDUs) by type of health care setting, which can inform development of tailored structural interventions to increase access to HIV prevention and medical treatment services. IDU syringe customers were recruited from pharmacies as part of the "Pharmacist As Resources Making Links to Community Services" (PHARM-Link) study, a randomized community-based intervention in New York City (NYC) aimed at connecting IDUs to HIV prevention, medical, and social services. An ACASI survey ascertained demographics, risk behavior, health-care utilization, and location where health care services were received in the past year. Data were analyzed using logistic regression. Of 602 participants, 34% reported receiving health care at a community clinic, 46% a private medical office, 15% a mobile medical unit, and 59% an emergency room (ER). After adjustment, participants who attended a community clinic were significantly more likely to have health insurance, report syringe sharing, and be HIV positive. Whites, nondaily injectors, insured, and higher income IDUs were more likely to attend a private medical office. Participants who recently used a case manager and had multiple sexual partners were more likely to use a mobile medical unit. ER attendees were more likely to be homeless and report recent drug treatment use. These findings show that IDU demographics and risk behaviors differ by health care setting, suggesting that risk reduction interventions should be tailored to health care settings. Specifically, these data suggest that community clinics and mobile medical units serve high-risk IDUs, highlighting the need for more research to develop and test innovative prevention and care programs within these settings. PMID- 23451994 TI - Extending the limits of precision polymer synthesis: giant polyphenylene dendrimers in the megadalton mass range approaching structural perfection. AB - The catalyst-free Diels-Alder synthesis of polyphenylene dendrimers with a chromophore core has now been demonstrated to achieve the seventh to ninth generations upon divergent growth. Since standard analytical tools such as size exclusion chromatography do not provide realistic molecular weights, MALDI-TOF mass spectrometry was applied to characterize the complete series of nine generations. Perfection and monodispersity were thus elucidated at such high masses. Transmission electron microscopy imaging was used to determine the size of these molecularly defined nanosized "particles" with diameters of up to 33 nm. PMID- 23451995 TI - Magnifying endoscopy combined with narrow band imaging may help to predict neoplasia coexisting with gastric hyperplastic polyps. AB - BACKGROUND AND STUDY AIM: Although focal cancer occasionally coexists with gastric hyperplastic polyps, previous studies have reported that white light endoscopy (WLE) and biopsy sampling cannot effectively predict the coexistence of cancer. The aim of this study was to elucidate efficacious predictors for cancer coexistence. PATIENTS AND METHODS: This retrospective single academic center study analyzed consecutive patients with gastric polyps diagnosed as hyperplastic before endoscopic resection. Using an image catalog of WLE and magnifying endoscopy combined with narrow band imaging (ME-NBI) performed as part of the preresection work-up, three endoscopists independently assessed the coexistence of cancer and the presence of predefined ME-NBI findings in the microvasculature (MV) and fine mucosal structure (FMS). RESULTS: Twelve of 64 gastric polyps (19%) resected from 51 patients enrolled in the study showed the coexistence of neoplasia. Polyps with coexisting neoplasia were significantly larger than those without (22.6 +/- 10.1 vs. 15.5 +/- 7.7 mm, respectively). Multivariate analysis of factors significantly associated with the coexistence of neoplasia identified lesion size and three specific endoscopic findings, that is, WLE diagnosis of cancer coexistence, ME-NBI findings of abnormal MV and micrification (size reduction) of the FMS. Combining lesion size (>=20 mm) and ME-NBI findings of FMS micrification had a diagnostic accuracy of 100% sensitivity and 58% specificity for coexisting neoplasia. However, combinations of WLE diagnosis and any other criteria could not achieve a diagnostic sensitivity of 100%. CONCLUSION: ME-NBI enhances the prediction of cancer coexistence in gastric hyperplastic polyps, with lesion size (>=20 mm) and FMS micrification the most effective predictive findings. PMID- 23451996 TI - Synthesis of the C1-C11 western fragment of madeirolide A. AB - The stereocontrolled synthesis of a fully elaborated C1-11 subunit of madeirolide A is described, utilizing an asymmetric boron aldol reaction and a cis-selective hetero-Michael cyclization to form the tetrahydropyran ring, followed by efficient formation of the required C5 alpha-glycoside. PMID- 23451997 TI - Amyopathic dermatomyositis-associated bilateral elbow ulcers successfully treated with autologous platelet-rich plasma. PMID- 23451998 TI - Editorial: Proceedings of the Fifth Stromboli Conference on Aging and Cancer "The primeval life-generating molecules. Therapeutic and aging-reversing properties". PMID- 23451999 TI - Cancer as the main aging factor for humans: the fundamental role of 5-methoxy tryptamine in reversal of cancer-induced aging processes in metabolic and immune reactions by non-melatonin pineal hormones. AB - Aging and advanced cancer are characterized by similar neuroendocrine and immune deficiencies; the most important of them consist of diminished nocturnal production of the pineal hormone melatonin (MLT) and decreased production of IL 2. At present, however, it is known that the pineal gland may produce indole hormones other than MLT. The most investigated of them is represented by 5 methoxy-tryptamine (5-MTT), which may exert antitumor, anticachectic, and immunomodulating effects under experimental conditions, in addition to those effects produced by MLT itself. In an attempt to obtain some preliminary data in human subjects about the potential therapeutic properties of 5-MTT, three different studies of 5-MTT have been carried out in advanced solid tumor patients. The first study of MLT plus 5-MTT included 14 thrombocytopenic cancer patients who did not respond to MLT alone. In the second study we have compared the clinical efficacy of MLT plus 5-MTT in a group of 25 untreatable metastatic cancer patients to the results obtained in a control group of 25 cancer patients receiving MLT alone. Finally, the third study of MLT plus 5-MTT included 14 untreatable metastatic cancer patients who did not respond to MLT alone. In all of these studies, MLT and 5-MTT were given orally at the level of 20 mg/day in the evening and at 5 mg/day during the period of maximum light. A normalization of platelet number was achieved by MLT plus 5-MTT in 5 of 14 (36%) thrombocytopenic cancer patients who did not respond to MLT alone. The percentage of disease control obtained by MLT plus 5-MTT in untreatable metastatic cancer patients was significantly higher than that achieved by MLT alone (15/25 [60%] vs. 8/25 [32%], P < 0.05). Finally, the association of 5-MTT with MLT induced disease stabilization in 4 of 14 (29%) untreatable metastatic cancer patients who did not respond to MLT alone. PMID- 23452000 TI - Acute generalized exanthematous pustulosis with overlap features of toxic epidermal necrolysis/Stevens-Johnson syndrome. PMID- 23452001 TI - Improving a measure of mobility-related fatigue (the mobility-tiredness scale) by establishing item intensity. AB - OBJECTIVES: To improve the construct validity of self-reported fatigue by establishing a formal hierarchy of scale items and to determine whether such a hierarchy could be maintained across time (aged 75-80), sex, and nationality. DESIGN: Cohort study. SETTING: Two Nordic urban locations: Jyvaskyla, Finland, and Glostrup, Denmark. PARTICIPANTS: Baseline (1989/90) consisted of a random sample of citizens of Finland or Denmark born in 1914 (n = 837). At 5-year follow up, excluding those lost to follow-up and with baseline disability resulted in a sample of n = 690. MEASUREMENTS: The Mobility-Tiredness (Mob-T) Scale is a six item scale that requires subjects to self-report on whether they become tired performing mobility-related tasks. Employing item response theory, an attempt was made to enhance construct validity by confirming a hierarchy of mobility-related fatigue. RESULTS: A formal hierarchy of fatigue tasks, maintained across time, was established using the revised Mob-T Scale. At age 75, the scalability statistics were a homogeneity coefficient (H) of 0.80, Ha T of 3.9% and an H(T) value of 0.66. The corresponding figures at age 80 were 0.75, 6.9% and 0.59. The property of invariant item ordering was maintained across subgroups based on sex and nationality. CONCLUSION: Establishing a formal hierarchy at age 75 allowed which tasks were most debilitating to be identified more clearly and the individual's "distance" from these tasks to be gauged. Because it was possible to confirm that the item hierarchy was maintained across time (aged 75-80), researchers or clinicians can be more confident that performance over time is the result of real change and has less to do with measurement error. PMID- 23452002 TI - Ocular biometric correlates of ciliary muscle thickness in human myopia. AB - PURPOSE: Anterior segment optical coherent tomography (AS-OCT) is used to further examine previous reports that ciliary muscle thickness (CMT) is increased in myopic eyes. With reference to temporal and nasal CMT, interrelationships between biometric and morphological characteristics of anterior and posterior segments are analysed for British-White and British-South-Asian adults with and without myopia. METHODS: Data are presented for the right eyes of 62 subjects (British White n = 39, British-South-Asian n = 23, aged 18-40 years) with a range of refractive error (mean spherical error (MSE (D)) -1.74 +/- 3.26; range -10.06 to +4.38) and separated into myopes (MSE (D) <-0.50, range -10.06 to -0.56; n = 30) and non-myopes (MSE (D) >=-0.50, -0.50 to +4.38; n = 32). Temporal and nasal ciliary muscle cross-sections were imaged using a Visante AS-OCT. Using Visante software, manual measures of nasal and temporal CMT (NCMT and TCMT respectively) were taken in successive posterior 1 mm steps from the scleral spur over a 3 mm distance (designated NCMT1, TCMT1 et seq). Measures of axial length and anterior chamber depth were taken with an IOLMaster biometer. MSE and corneal curvature (CC) measurements were taken with a Shin-Nippon auto-refractor. Magnetic resonance imaging was used to determine total ocular volume (OV) for 31 of the original subject group. Statistical comparisons and analyses were made using mixed repeated measures anovas, Pearson's correlation coefficient and stepwise forward multiple linear regression. RESULTS: MSE was significantly associated with CMT, with thicker CMT2 and CMT3 being found in the myopic eyes (p = 0.002). In non-myopic eyes TCMT1, TCMT2, NCMT1 and NCMT2 correlated significantly with MSE, AL and OV (p < 0.05). In contrast, myopic eyes failed generally to exhibit a significant correlation between CMT, MSE and axial length but notably retained a significant correlation between OV, TCMT2, TCMT3, NCMT2 and NCMT3 (p < 0.05). OV was found to be a significantly better predictor of TCMT2 and TCMT3 than AL by approximately a factor of two (p < 0.001). Anterior chamber depth was significantly associated with both temporal and nasal CMT2 and CMT3; TCMT1 correlated positively with CC. Ethnicity had no significant effect on differences in CMT. CONCLUSIONS: Increased CMT is associated with myopia. We speculate that the lack of correlation in myopic subjects between CMT and axial length, but not between CMT and OV, is evidence that disrupted feedback between the fovea and ciliary apparatus occurs in myopia development. PMID- 23452004 TI - The role of calling EMS versus using private transportation in improving the management of stroke in France. AB - OBJECTIVE: To compare the time from symptom onset to brain imaging between patients calling emergency medical services (EMS) and those using private means for transportation. METHODS: We focused on symptom onset-to-brain imaging times of <=2 hours and <=3 hours 30 minutes, assuming a one-hour interval between imaging and thrombolysis. Other variables were the patient's age, gender, stroke type, National Institutes of Health Stroke Scale (NIHSS) score, presence of an on site stroke unit, and period of symptom onset. Univariate analyses and a hierarchical linear regression model were used, as appropriate, and adjusted for these variables. RESULTS: A total of 1,105 stroke patients (28%) were included in the analyses, 40.6% of them transported by EMS. Patients using EMS were significantly older (72.8 vs. 70.5 years; p = 0.008), they had a higher NIHSS score (8 vs. 6.1; p = 0.0001), fewer were ischemic (85.1% vs. 90.6%; p = 0.005), and more of them reached hospitals with an on-site stroke unit (81.3% vs. 72.9%; p = 0.002). For the EMS-call patients, the median symptom onset-to-brain imaging time was significantly shorter (3 hours 21 minutes vs. 5 hours 57 minutes), and after adjustment, maximum delays of 2 hours and 3 hours 30 minutes were independently associated with EMS call: 28% vs. 18% (p = 0.015) and 66% vs. 45% (p < 0.0001) of patients, respectively, leading to an adjusted odds ratio of 2.77 (95% confidence interval, 2.007-3.828; p < 0.0001) for the threshold of 3 hours 30 minutes. CONCLUSIONS: The symptom onset-to-brain imaging time was significantly shorter in case of EMS transportation, but most patients did not reach the hospital in time to be eligible for thrombolysis. Efforts are still needed to reduce delays, especially public education and EMS activation. These efforts should be combined with new approaches for the quality management of stroke patients. PMID- 23452003 TI - Variation in prehospital use and uptake of the national Field Triage Decision Scheme. AB - BACKGROUND: The Field Triage Decision Scheme is a national guideline that has been implemented widely for prehospital emergency medical services (EMS) and trauma systems. However, little is known about the uptake, modification, or variation in field application of triage criteria between trauma systems. OBJECTIVE: To describe and compare the use of field triage criteria by EMS personnel in six regions, including the timing of guideline uptake and the use of nonguideline criteria. METHODS: This was a retrospective cohort study of injured children and adults transported by 48 EMS agencies to 105 hospitals (trauma centers and non-trauma centers) in six Western U.S. regions from 2006 through 2008. We used probabilistic linkage to match patient-level prehospital information from multiple sources, including EMS records, base-hospital phone communication records, and trauma registry data files. Triage criteria were evaluated individually and grouped by "steps" (physiologic, anatomic, mechanism, and special considerations). We used descriptive statistics to compare the frequency of triage criteria use (overall and between regions) and to evaluate the timing of guideline uptake across multiple versions of the guidelines. RESULTS: A total of 260,027 injured patients were evaluated and transported by EMS over the three-year study period, of whom 46,414 (18%) met at least one field triage criterion and formed the primary sample for analysis. The three most common criteria cited (of 33 in use) were EMS provider judgment (26%), age <5 or >55 years (10%), and Glasgow Coma Scale (GCS) score <14 (9%). Of the 33 criteria in use, five (15%) were previously retired from the guidelines and seven (21%) were never included in the guidelines. 11,048 (24%) patients had more than one criterion applied (range 1-21). There was large variation in the type and frequency of criteria used between systems, particularly among the nonphysiologic triage steps. Only one of six regions had translated the most recent guidelines into field use within two years after release. CONCLUSION: There is large variation between regions in the frequency and type of field triage criteria used. Field uptake of guideline revisions appears to be slow and variable, suggesting opportunities for improvement in dissemination and implementation of updated guidelines. PMID- 23452005 TI - Developing descriptors to predict mechanical properties of nanotubes. AB - Descriptors and quantitative structure property relationships (QSPR) were investigated for mechanical property prediction of carbon nanotubes (CNTs). 78 molecular dynamics (MD) simulations were carried out, and 20 descriptors were calculated to build quantitative structure property relationships (QSPRs) for Young's modulus and Poisson's ratio in two separate analyses: vacancy only and vacancy plus methyl functionalization. In the first analysis, C(N2)/C(T) (number of non-sp2 hybridized carbons per the total carbons) and chiral angle were identified as critical descriptors for both Young's modulus and Poisson's ratio. Further analysis and literature findings indicate the effect of chiral angle is negligible at larger CNT radii for both properties. Raman spectroscopy can be used to measure C(N2)/C(T), providing a direct link between experimental and computational results. Poisson's ratio approaches two different limiting values as CNT radii increases: 0.23-0.25 for chiral and armchair CNTs and 0.10 for zigzag CNTs (surface defects <3%). In the second analysis, the critical descriptors were C(N2)/C(T), chiral angle, and M(N)/C(T) (number of methyl groups per total carbons). These results imply new types of defects can be represented as a new descriptor in QSPR models. Finally, results are qualified and quantified against experimental data. PMID- 23452006 TI - Simple design for DNA nanotubes from a minimal set of unmodified strands: rapid, room-temperature assembly and readily tunable structure. AB - DNA nanotubes have great potential as nanoscale scaffolds for the organization of materials and the templation of nanowires and as drug delivery vehicles. Current methods for making DNA nanotubes either rely on a tile-based step-growth polymerization mechanism or use a large number of component strands and long annealing times. Step-growth polymerization gives little control over length, is sensitive to stoichiometry, and is slow to generate long products. Here, we present a design strategy for DNA nanotubes that uses an alternative, more controlled growth mechanism, while using just five unmodified component strands and a long enzymatically produced backbone. These tubes form rapidly at room temperature and have numerous, orthogonal sites available for the programmable incorporation of arrays of cargo along their length. As a proof-of-concept, cyanine dyes were organized into two distinct patterns by inclusion into these DNA nanotubes. PMID- 23452007 TI - Beliefs about cervical cancer and Pap test: a new Chilean questionnaire. AB - PURPOSE: The purpose of this study was to develop and validate a questionnaire to examine women's beliefs about cervical cancer and the Pap test in Chilean women. DESIGN AND METHODS: The questionnaire, developed following the guidelines by Robert de Vellis, is based on the Health Belief Model. The content validity index was 0.93 upon review by 10 Chilean experts. A cross-sectional design was implemented to validate the questionnaire. The sample included 333 women recruited from a women's healthcare center in Santiago, Chile. Exploratory factor analysis was used to evaluate validity and coefficient alpha to evaluate reliability. FINDINGS: After six models were computed, the questionnaire was reduced from 53 to 28 items. The new questionnaire, CPC-28 (in Spanish, Creencias, Papanicolaou, Cancer -28), includes six domains: the barriers domain to take a Pap test, the cues to action domain, the severity domain, the need to have a Pap test domain, the susceptibility to cervical cancer domain, and the benefit domain. The unexpected salient factor "need to have a Pap test" was found as part of the susceptibility domain proposed in the initial questionnaire. This finding is an important topic for future research. The CPC-28 questionnaire explained 49% of the total variance, and the reliability was .735. CONCLUSIONS: It was concluded that the CPC-28 questionnaire will have important implications on research, education, and administration across disciplines. CLINICAL RELEVANCE: Nursing curricula and healthcare providers must stress the importance and reinforce the importance of prevention of cervical cancer and regular Pap test screenings. PMID- 23452008 TI - Axitinib for the treatment of advanced non-small-cell lung cancer. AB - INTRODUCTION: Lung cancer is the most frequently diagnosed cancer in men and comprises 23% of total cancer deaths worldwide. The majority of patients present with advanced disease, for whom the 5-year survival is < 5%. Since angiogenesis plays a central role in tumourigenesis, inhibiting this pathway may improve outcomes in non-small-cell lung cancer (NSCLC). Axitinib is one of the latest and most potent anti-angiogenic tyrosine kinase inhibitors (TKI) currently being evaluated to treat NSCLC. AREAS COVERED: In this review, the rationale for targeting angiogenesis in lung cancer, other angiogenic agents in NSCLC, axitinib's mechanism of action, pharmacology and metabolism, and the preclinical and clinical data to date in NSCLC will be discussed. EXPERT OPINION: Several TKI which target angiogenesis pathways have resulted in improved response rates and progression-free survival in NSCLC, but no improvement in overall survival in clinical trials. Axitinib is a more potent inhibitor of vascular endothelial growth factor receptors than other TKI, but this has yet to translate into a clinical benefit. Phase II trials are ongoing, but the published data to date has yet to support a role for axitinib in the treatment algorithm for NSCLC. PMID- 23452009 TI - Falling behind: a substantive theory of care for older people with cognitive impairment in acute settings. AB - AIMS AND OBJECTIVES: To develop a theoretical understanding of the processes hindering person-centred care of older people with cognitive impairment in acute care settings. BACKGROUND: Although person-centred care with its holistic focus on the biopsychosocial needs of patients is commonly considered the gold standard care for older people with cognitive impairment, the extent to which care is person-centred can increase in acute care settings generally. DESIGN: Grounded theory inspired by Strauss and Corbin. METHOD: The study used a grounded theory approach to generate and analyse data from a Swedish sample of acute care staff, patients and family members. RESULTS: The substantive theory postulates that staff risks 'falling behind' in meeting the needs of older patients with cognitive impairment if working without consensus about the care of these patients, if the organisation is disease-oriented and efficiency-driven, and if the environment is busy and inflexible. This facilitated 'falling behind' in relation to meeting the multifaceted needs of older patients with cognitive impairment and contributed to patient suffering, family exclusion and staff frustration. CONCLUSIONS: The theory highlights aspects of importance in the provision of person-centred care of older people with cognitive impairment in acute settings and suggests areas to consider in the development of caring environments in which the place, pace and space can meet the needs of the older person. RELEVANCE TO CLINICAL PRACTICE: The proposed substantive theory can be used to critically examine current ward practices and routines, and the extent to which these support or inhibit high-quality person-centred care for older patients with known or unknown cognitive impairments. PMID- 23452010 TI - Weight loss interventions in asthma: EAACI evidence-based clinical practice guideline (part I). AB - BACKGROUND: Asthma and obesity are chronic multifactorial conditions that are associated with gene-environment interaction and immune function. Although the data are not fully consistent, it seems that obesity increases the risk of asthma and compromises asthma control. OBJECTIVE: To investigate the impact that weight changes have on asthma. METHODS: We carried out a systematic review of three large biomedical databases. Studies were scrutinized and critically appraised according to agreed exclusion and inclusion criteria. Quality assessment of eligible papers was conducted using the GRADE method. Meta-analyses of comparable studies were carried out. RESULTS: Thirty studies met the eligibility criteria of the review. Interventions were limited to dietary manipulation in three studies, one of which also used anti-obesity drugs, and bariatric surgery in four. All the other studies reported observational data. Becoming obese increased the odds for incident asthma by 1.82 (95% CI 1.47, 2.25) in adults and 1.98 (95% CI 0.71, 5.52) in children. Weight loss was associated with significant improvement in mean scores for symptoms, rescue medication score, and asthma exacerbations in the only randomized controlled trial. Similarly, evidence gathered from observational studies, with follow-up ranging between 8 weeks to 1 year, and from changes 1 year after bariatric surgery showed improvements in all asthma control related outcomes. Changes in lung function were reported in one randomized controlled and eight observational studies of asthmatic subjects, with conflicting results. Either improvement after weight loss, decline with weight gain, or no effects at all were reported. Changes in airway inflammation and responsiveness were reported only by observational studies. CONCLUSION: Weight increases above the obesity threshold significantly increase the risk of asthma. The available studies show weak evidence of benefits from weight reduction on asthma outcomes. PMID- 23452011 TI - Functional and numerical responses of the predatory mite, Neoseiulus longispinosus, to the red spider mite, Oligonychus coffeae, infesting tea. AB - Functional and numerical responses of the predatory mite, Neoseiulus longispinosus (Evans) (Acari: Phytoseiidae) to the red spider mite, Oligonychus coffeae Nietner (Acari: Tetranychidae), infesting tea were determined in a laboratory on leaf discs. Prey consumption increased with increases in temperature and prey density. Handling time decreased and successful attack rate increased with increased temperature. N. longispinosus was more voracious on larvae and nymphs than on adults of O. coffeae. Handling time was higher on adult females than on larvae. Rate of predation leveled off at temperatures greater than 25 degrees C. Functional responses to prey density at six temperatures and to each life stage of O. coffeae approximated the Holling type II model. The oviposition rate increased with prey consumption and temperature. On average, a predator consumed 1.62 adult female prey for every egg it laid. With a fixed number of prey available, predation rate per predator decreased with increased predator density. PMID- 23452012 TI - Exposure of mares to processionary caterpillars (Ochrogaster lunifer) in early pregnancy: an additional dimension to equine amnionitis and fetal loss. AB - REASONS FOR PERFORMING STUDY: Equine amnionitis and fetal loss (EAFL) is an unusual form of abortion in mid- to late-gestation mares, first identified in Australia in 2004. It has been shown that both whole processionary caterpillars (Ochrogaster lunifer) and their shed exoskeletons can induce abortion in mares during midgestation. These abortions exhibited gross pathology and bacteriology results consistent with field cases of EAFL. OBJECTIVES: To determine whether exposure of mares to the shed exoskeletons of processionary caterpillars can induce abortion in the preplacentation (<35 days' gestation) and early placentation (45-60 days) stages of pregnancy. STUDY DESIGN: In vivo experimental study. METHODS: Mares less than 35 days' gestation and between 45 and 60 days' gestation were exposed to a slurry of shed processionary caterpillar exoskeletons by nasogastric intubation. Mares were monitored by clinical examination daily. Transrectal ultrasonography was performed daily (control and treated preplacentation mares, treated early placentation mares) or every second day (control early placentation mares). Uterine swabs were collected from mares that aborted. All live foals underwent a clinical examination. Placentas were examined, with sampling for bacteriology and histopathology if appropriate. RESULTS: Abortions occurred in treated mares in both experiments without signs of impending abortion. One mare aborted in the embryonic stage experiment and 2 in the early placentation experiment. Embryonic and fetal death was detected on transrectal ultrasonography prior to abortion. In the early placentation experiment, one foal was born 5 weeks preterm and was very small, with laxity of the tendons in all limbs. Enteric or environmental bacteria, consistent with EAFL, were isolated from the mares that aborted. Focal mucoid placentitis lesions were present on the placentas of 2 treated mares, one from each experiment. CONCLUSIONS AND POTENTIAL RELEVANCE: Processionary caterpillar exposure may be associated with EAFL-related embryonic and early fetal loss in mares. Processionary caterpillars may also play a role in the occurrence of focal mucoid placentitis. PMID- 23452013 TI - The potential loss of the who and why of human suffering within evidence-based practice. PMID- 23452016 TI - FDA-approved drugs to treat ADHD. PMID- 23452019 TI - Emerging concept for the role of photorespiration as an important part of abiotic stress response. AB - When plants are exposed to stress, generation of reactive oxygen species (ROS) is often one of the first responses. In order to survive, cells attempt to down regulate the production of ROS, while at the same time scavenging ROS. Photorespiration is now appreciated as an important part of stress responses in green tissues for preventing ROS accumulation. Photorespiratory reactions can dissipate excess reducing equivalents and energy either directly (using ATP, NAD(P)H and reduced ferredoxin) or indirectly (e.g., via alternative oxidase (AOX) and providing an internal CO2 pool). Photorespiration, however, is also a source of H2 O2 that is possibly involved in signal transduction, resulting in modulation of gene expression. We propose that photorespiration can assume a major role in the readjustment of redox homeostasis. Protection of photosynthesis from photoinhibition through photorespiration is well known. Photorespiration can mitigate oxidative stress under conditions of drought/water stress, salinity, low CO2 and chilling. Adjustments to even mild disturbances in redox status, caused by a deficiency in ascorbate, AOX or chloroplastic NADP-malate dehydrogenase, comprise increases in photorespiratory components such as catalase, P-protein of glycine decarboxylase complex (GDC) and glycine content. The accumulation of excess reducing equivalents or ROS in plant cells also affects mitochondria. Therefore, a strong interaction between the chloroplast redox status and photorespiration is not surprising, but highlights interesting properties evident in plant cells. We draw attention to the fact that a complex network of multiple and dynamic systems, including photorespiration, prevents oxidative damage while optimising photosynthesis. Further experiments are necessary to identify and validate the direct targets of redox signals among photorespiratory components. PMID- 23452020 TI - Population-based trends in urinary diversion among patients undergoing radical cystectomy for bladder cancer. AB - What's known on the subject? and what does the study add?: Variations in the type of urinary diversion exist for patients undergoing radical cystectomy. Although its use has been increasing from 2001 to 2008, patients who are older, female, and primary insured by Medicaid are less likely to receive continent diversions. Furthermore, patients treated surgically at high-volume and teaching hospitals are more likely to receive continent diversions. OBJECTIVE: To describe the contemporary trends in urinary diversion among patients undergoing radical cystectomy (RC) for bladder cancer; and elucidate whether socioeconomic disparities persist in the type of diversion performed in the USA from a population-based cohort. PATIENTS AND METHODS: Using the Nationwide Inpatient Sample, we identified patients who underwent RC for bladder cancer between 2001 and 2008. Multivariable regression models were used to identify patient and hospital covariates associated with continent urinary diversion and enumerate predicted probabilities for statistically significant variables over time. RESULTS: Overall, 55635 (92%) patients undergoing RC for bladder cancer received incontinent urinary diversion, while 4552 (8%) patients received continent diversion from 2001 to 2008. Receipt of continent urinary diversion increased from 6.6% in 2001-2002 to 9.4% in 2007-2008 (P < 0.001 for trend). Patients who were older (odds ratio [OR] 0.93; P < 0.001), female (OR 0.52; P < 0.001) and insured by Medicaid (OR 0.54; P = 0.002) were less likely to receive continent urinary diversion. However, patients treated at teaching (OR 2.14; P < 0.001) and high-volume hospitals (OR 2.39; P = 0.04) had higher odds of continent urinary diversion. Predicted probabilities of continent diversion remained lower for female patients, Medicaid insurance status, and non-teaching and medium/low volume hospitals over time. CONCLUSIONS: In this nationally representative sample of hospitals from 2001 to 2008, the use of continent diversion in RC gradually increased. Although variations in urinary diversion exist by hospital teaching status, case volume, patient gender and primary health insurance, increased attention in expanding the use of continent diversions may help reduce these disparities for patients undergoing RC for bladder cancer. PMID- 23452021 TI - Changes in portal hemodynamics after TIPS in liver cirrhosis and portal hypertension. AB - OBJECTIVE: The objective of this study is to analyze the changes in portal hemodynamics that occurs in portal hypertension before and after transjugular intrahepatic portosystemic shunt (TIPS), to investigate the relationship between these changes and portal pressure (PP) and to determine the significance of sonographic parameters in measuring PP. METHODS: Ultrasonography of the portal and splenic veins and direct measurement of the PP were performed in 92 patients before and after TIPS. The differences observed in the portal and splenic vein diameters, the blood flow velocity in the portal and splenic veins and the PP were measured, and the correlations between PP and the other parameters were assessed using the SPSS 13 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant. RESULTS: We observed a significant decrease in the PP and the diameters of the portal and splenic veins compared to preoperative conditions (p < 0.001). The velocity of blood flow in the portal and splenic veins was significantly increased after TIPS (p < 0.001). The PP correlated with the diameter and velocity of blood flow in portal (r = 0.46, p = 0.020; r = 0.47, p = 0.017) and splenic vein (r = 0.57, p = 0.003; r = 0.33, p = 0.003) only in Child's A and was absent in Child's B cirrhosis patients. CONCLUSION: The PP is influenced by the complex interaction between intrahepatic vascular resistance, collaterals and the amount of portal blood flow, which varies considerably between individuals. Once a certain pressure threshold is reached, collaterals form, and the correlation between the ultrasonographic parameters and PP becomes limited. PMID- 23452022 TI - Protective and risk factors associated with stigma in a population of older adults living with HIV in Ontario, Canada. AB - Although the deleterious effects of HIV stigma are well documented, less is known about how various types of stigma impact older adults living with HIV disease and what factors exacerbate or lessen the effects of HIV stigma. Using cross sectional data from the OHTN cohort study (OCS), we undertook multiple linear regression to determine the predictors of overall HIV stigma, and enacted, anticipated, and internalized stigma subscales in a sample of OCS participants age 50 and over (n = 378). Being female, heterosexual, engaging in maladaptive coping, and having poor self-rated health were associated with greater overall stigma while being older, having greater mastery, increased emotional informational social support, and a longer time since HIV diagnosis were associated with lower levels of stigma. The final model accounted for 31% of the variance in overall stigma. Differences in these findings by subscale and implications for practice are discussed. PMID- 23452023 TI - Patterns of myopigenic activities with age, gender and ethnicity in Sydney schoolchildren. AB - PURPOSE: To examine the patterns of myopigenic activity (high near work, low time outdoors) in children growing up in Sydney, Australia, by age, ethnicity and gender. METHODS: The Sydney Adolescent Vascular and Eye Study (SAVES) re-examined children from the two age cohorts (6 and 12 years at baseline) from the Sydney Myopia Study (SMS). At 5-6 year follow-up, 863 in the younger cohort and 1196 in the older cohort had complete refraction data. Cycloplegic autorefraction (cyclopentolate 1%; Canon RK-F1) was measured at baseline and follow-up. Children who became myopic (<=-0.50 dioptres spherical equivalent refraction) were those classified as non-myopic at baseline and myopic at follow-up. A detailed questionnaire was administered to measure weekly activities, including time spent outdoors and near work at both baseline and follow-up examination. RESULTS: Overall, 128 (14.8%) children in the younger cohort and 210 (17.6%) in the older cohort became myopic. At follow-up, for both cohorts, children had significantly reduced the amount of time spent outdoors (younger cohort, p = 0.001, older cohort, p < 0.0001) and increased near work time (younger cohort, p < 0.0001, older cohort, p = 0.006). Children of East Asian ethnicity spent significantly less time outdoors by more than 7 h per week (both cohorts at baseline and follow up, all p < 0.0001) and more time in near work activities by close to 3 h compared to European Caucasian children at all ages examined (both cohorts at baseline and follow-up all, p < 0.03). The average pattern of activity for girls differed from that of boys in a similar way (both cohorts at baseline and follow up all, p < 0.0001). The two independent samples of 12 year-old children provided by follow-up in the younger cohort and baseline in the older cohort gave very similar answers to the questionnaire, with significant differences only evident for computer use (p = 0.001) and books read (p < 0.0001). CONCLUSIONS: Answers to the activity questionnaire were very similar in the two cohorts of 12 year-olds, suggesting that the questionnaire gives reproducible answers. However, further work is required for validation. Children's pattern of activities become more myopigenic with age, and differed by gender and by ethnicity at all ages, with girls having a more myopigenic activity pattern than boys, and children of East Asian ancestry having a more myopigenic activity pattern than European Caucasian children. PMID- 23452024 TI - A comparative study of aluminium and nutrient concentrations in mistletoes on aluminium-accumulating and non-accumulating hosts. AB - Mistletoes offer a unique model to study interactions among Al and nutrients in vascular plants, because they grow and reproduce on hosts with distinct Al uptake strategies. We investigated Al distribution and nutrient relations of mistletoes on Al-accumulating and non-accumulating hosts. We hypothesised that mistletoes would exhibit similar leaf nutrient and Al concentrations as their host plants, but a strong compartmentalisation of Al when growing on Al-accumulators. We measured concentrations of N, P, K, Ca, Mg, Cu, Fe, Mn, Zn in leaves and Al in leaves, seeds and branches of Phthirusa ovata and Psittacanthus robustus infecting Miconia albicans, an Al-accumulator, and Ph. ovata infecting Byrsonima verbascifolia, a non-Al-accumulator. High leaf concentrations of Al in Ph. ovata only occurred while parasitizing the Al-accumulating host; there was no accumulation in branches or seeds. In P. robustus, large concentrations of Al were found in leaves, branches and seeds. Mistletoe seed viability and leaf nutrient concentrations were not affected by Al accumulation. Passive uptake of Al, Ca, Mg, Mn and Cu in mistletoes was evidenced by significant correlations between mistletoes and host leaf concentrations, but not of N, P and K. Al was retranslocated to different plant organs in P. robustus, whereas it was mostly restricted to leaves in Ph. ovata. We suggest that Al might have some specific function in P. robustus, which only parasitizes Al-accumulator hosts, while the host generalist Ph. ovata can be considered a facultative Al-accumulator. PMID- 23452025 TI - Theranostic nanomedicine with functional nanoarchitecture. PMID- 23452026 TI - Half-and-half nail in Behcet's disease. PMID- 23452027 TI - Stem cell advances and challenges. PMID- 23452028 TI - Perinatal stem cells revisited: directions and indications at the crossroads between tissue regeneration and repair. PMID- 23452029 TI - Prospective histologic examinations in patients who practice traumatic hairstyling. AB - OBJECTIVES: Alopecia is the fifth most common dermatologic diagnosis in African American patients. Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia in this group. This study sought to evaluate clinical and histologic findings in patients without clinical alopecia who use chemical and/or thermal straighteners to determine whether follicular damage is evidenced histologically. METHODS: Eight African-American women with no clinical evidence of alopecia or scalp inflammation were included in the study. All participants had engaged in some form of traumatic hair care within the previous month. Participants submitted to clinical photography and 4-mm punch biopsy. Histologic examination was performed and the characteristics of each case recorded. RESULTS: There were no clinical signs of alopecia or inflammation in any patient. Histopathology showed peri-infundibular lymphocytic inflammation in all patients and mild superficial perivascular lymphocytic inflammation in three. Concentric infundibular fibrosis was observed in each hair follicle in all specimens. One sample showed additional focal peri-isthmus fibrosis. There was no evidence of complete follicular dropout, follicular epithelial thinning, or premature desquamation of inner root sheaths. The mean number of hair follicles was 4.88 per 4-mm punch. Hair cycling was consistently within normal ranges. CONCLUSIONS: Biopsy findings characteristic of CCCA suggest that a clinical prelude exists histologically. Further follow-up may provide a longitudinal timeframe for the potential progression, halting, or reversal of disease if hairstyling practices are, respectively, continued or discontinued. Central centrifugal cicatricial alopecia is likely to represent a common pathway of inflammation and scarring that can be instigated by traumatic hairstyling practices in genetically predisposed subjects. PMID- 23452030 TI - Pediatric bypasses for aneurysms and skull base tumors: short- and long-term outcomes. AB - OBJECT: Cerebral bypass is a useful microsurgical technique for the treatment of unclippable aneurysms and invasive skull base tumors. The authors present the largest reported series of cerebrovascular bypasses in the pediatric population. They describe the short- and long-term clinical and radiographic outcomes of extracranial-intracranial and local bypasses performed for complex cerebral aneurysms and recurrent, invasive, and malignant skull base tumors in pediatric patients. METHODS: A consecutive series of 17 pediatric patients who underwent revascularization were analyzed retrospectively for indications, graft patency, and neurological outcomes. RESULTS: The mean age was 12 years (median 11 years, range 4-17 years), and there were 7 boys (41%) and 10 girls (59%). A total of 18 bypasses were performed in 17 patients and included 10 aneurysm cases (55.5%) and 8 tumor cases (45%). Of these 18 bypasses, there were 11 (61.1%) extracranial intracranial bypasses (10 saphenous vein grafts [90%] and 1 radial artery graft [10%]), 1 side-to-side anastomosis (5.5%), 2 intracranial reimplants (11.1%), and 4 interposition bypass grafts (22.2%; 2 radial artery grafts, 1 saphenous vein graft, and 1 lingual artery graft). The mean clinical follow-up was 40.5 months (median 24 months, range 3-197 months). The mean radiographic follow-up was 40 months (median 15 months, range 9-197 months). Eighty-two percent of patients (14 of 17) achieved a modified Rankin Scale score between 0 and 2; however, 2 patients died of disease progression during long-term follow-up. The short-term (0- to 3-month) graft patency rate was 100%. Two patients had graft stenosis (11.7%) and underwent graft revisions. Two patients (11.1%) with giant middle cerebral artery aneurysms (> 25 mm) had strokes postoperatively but recovered without a persistent neurological deficit. One patient observed for 197 months showed a stable dysplastic change at the end of the graft. The long-term graft patency was 100% with a mean follow-up of 40 months. There were 2 deaths in the cohort during follow-up; both patients died of malignant tumors (osteogenic sarcoma and chondrosarcoma). CONCLUSIONS: The authors conclude that in properly selected cases, bypasses can be safely performed in patients with aneurysms and skull base tumors. The bypasses remained patent over long periods of time despite the growth of the patients. PMID- 23452031 TI - Neurosurgical management of neurenteric cysts in children. AB - OBJECT: Neurenteric cysts (NCs) are endothelium-lined structures of presumed endodermal origin. There have been few pediatric series of intracranial NCs reported previously. The authors present their experience in the management of these lesions. METHODS: A retrospective chart review of all cases of NCs identified between 1977 and 2007 was carried out. Demographics, details of clinical presentation, surgical therapy, and outcome data were extracted. RESULTS: Eleven cases were identified, involving 6 girls and 5 boys. The patients' average age was 4.6 years (range 1 day-14 years). Limb weakness was the most common presenting symptom. The location of the cysts was cervical in 2 cases, cervicothoracic in 4 cases, and thoracic in 3 cases. One cyst was anterior to the pons with extension to the left cerebellopontine angle and 1 cyst was at the craniocervical junction. Five patients had an apparently complete initial excision, with 1 recurrence. Four patients were initially treated with incomplete excision and/or cyst drainage, usually into an Ommaya reservoir. A neonate with a large cervicothoracic cyst died of multiple congenital anomalies without any intervention. All other patients were alive at last follow-up. One patient with a radiologically identified presumed cyst, which remained stable, was simply followed up. Several patients required multiple procedures and 1 patient developed hydrocephalus after aseptic meningitis and was treated with CSF shunting. CONCLUSIONS: Neurenteric cysts are rare in the pediatric population. Total resection, if possible, provides the best long-term outcome. Incomplete excision may lead to multiple procedures, including cyst drainage, but can lead to long-term stability. PMID- 23452032 TI - Spinal dysraphism. PMID- 23452033 TI - Silver-promoted, palladium-catalyzed direct arylation of cyclopropanes: facile access to spiro 3,3'-cyclopropyl oxindoles. AB - The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane C-H bonds is described. Various spiro 3,3'-cyclopropyl oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a C-H arylation pathway. PMID- 23452035 TI - Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified many risk loci for asthma, but effect sizes are small, and in most cases, the biological mechanisms are unclear. Targeted metabolite quantification that provides information about a whole range of pathways of intermediary metabolism can help to identify biomarkers and investigate disease mechanisms. Combining genetic and metabolic information can aid in characterizing genetic association signals with high resolution. This work aimed to investigate the interrelation of current asthma, candidate asthma risk alleles and a panel of metabolites. METHODS: We investigated 151 metabolites, quantified by targeted mass spectrometry, in fasting serum of asthmatic and nonasthmatic individuals from the population-based KORA F4 study (N = 2925). In addition, we analysed effects of single-nucleotide polymorphisms (SNPs) at 24 asthma risk loci on these metabolites. RESULTS: Increased levels of various phosphatidylcholines and decreased levels of various lyso-phosphatidylcholines were associated with asthma. Likewise, asthma risk alleles from the PDED3 and MED24 genes at the asthma susceptibility locus 17q21 were associated with increased concentrations of various phosphatidylcholines with consistent effect directions. CONCLUSIONS: Our study demonstrated the potential of metabolomics to infer asthma-related biomarkers by the identification of potentially deregulated phospholipids that associate with asthma and asthma risk alleles. PMID- 23452034 TI - Geriatric syndromes and incident disability in older women: results from the women's health initiative observational study. AB - OBJECTIVES: To determine how the number of geriatric syndromes is associated with incident disability in community-based populations of older adults. DESIGN: Longitudinal analysis from the Women's Health Initiative Observational Study (WHI OS). SETTING: Community. PARTICIPANTS: Twenty-nine thousand five hundred forty four women aged 65 and older enrolled in the WHI-OS and free of disability in activities of daily living (ADLs) at baseline. MEASUREMENTS: Geriatric syndromes (high depressive symptoms, dizziness, falls, hearing or visual impairment, osteoporosis, polypharmacy, syncope, sleep disturbance, and urinary incontinence) were self-reported at baseline and 3-year follow-up. Disability was defined as dependence in any ADL and was assessed at baseline and follow-up. Chronic diseases were measured according to a modified Charlson Index. RESULTS: Geriatric syndromes were common in this population of women; 76.3% had at least one syndrome at baseline. Greater number of geriatric syndromes at baseline was significantly associated with greater risk of incident ADL disability at follow up (P <= .001). Adjusted risk ratios were 1.21 (95% confidence interval (CI) = 0.78-1.87) for a single syndrome and 6.64 (95% CI = 4.15-10.62) for five or more syndromes compared with no syndromes. These results were only slightly attenuated after adjustment for number of chronic diseases or pain. CONCLUSION: Geriatric syndromes are significantly associated with onset of disability in older women; this association is not simply a result of chronic disease or pain. A better understanding of how these conditions contribute to disablement is needed. Geriatric syndrome assessment should be considered along with chronic disease management in the prevention of disability in older women. PMID- 23452036 TI - Exploring creativity and critical thinking in traditional and innovative problem based learning groups. AB - AIMS AND OBJECTIVES: To explore students' attitude towards problem-based learning, creativity and critical thinking, and the relevance to nursing education and clinical practice. BACKGROUND: Critical thinking and creativity are crucial in nursing education. The teaching approach of problem-based learning can help to reduce the difficulties of nurturing problem-solving skills. However, there is little in the literature on how to improve the effectiveness of a problem-based learning lesson by designing appropriate and innovative activities such as composing songs, writing poems and using role plays. DESIGN: Exploratory qualitative study. METHODS: A sample of 100 students participated in seven semi structured focus groups, of which two were innovative groups and five were standard groups, adopting three activities in problem-based learning, namely composing songs, writing poems and performing role plays. The data were analysed using thematic analysis. RESULTS: There are three themes extracted from the conversations: 'students' perceptions of problem-based learning', 'students' perceptions of creative thinking' and 'students' perceptions of critical thinking'. Participants generally agreed that critical thinking is more important than creativity in problem-based learning and clinical practice. Participants in the innovative groups perceived a significantly closer relationship between critical thinking and nursing care, and between creativity and nursing care than the standard groups. CONCLUSIONS: Both standard and innovative groups agreed that problem-based learning could significantly increase their critical thinking and problem-solving skills. Further, by composing songs, writing poems and using role plays, the innovative groups had significantly increased their awareness of the relationship among critical thinking, creativity and nursing care. RELEVANCE TO CLINICAL PRACTICE: Nursing educators should include more types of creative activities than it often does in conventional problem-based learning classes. The results could help nurse educators design an appropriate curriculum for preparing professional and ethical nurses for future clinical practice. PMID- 23452037 TI - Bacteriopheophytin a in the active branch of the reaction center of rhodobacter sphaeroides is not disturbed by the protein matrix as shown by 13C photo-CIDNP MAS NMR. AB - The electronic structure of bacteriopheophytin a (BPhe a), the primary electron acceptor (PhiA) in photosynthetic reaction centers (RCs) of the purple bacterium Rhodobacter sphaeroides, is investigated by photochemically induced dynamic nuclear polarization (photo-CIDNP) magic-angle spinning (MAS) NMR spectroscopy at atomic resolution. By using various isotope labeling systems, introduced by adding different (13)C selectively labeled delta-aminolevulinic acid precursors in the growing medium of R. sphaeroides wild type (WT), we were able to extract light-induced (13)C NMR signals originating from the primary electron acceptor. The assignments are backed by theoretical calculations. By comparison of these chemical shifts to those obtained from monomeric BPhe a in solution, it is demonstrated that PhiA in the active branch appears to be electronically close to free bacteriopheophytin. Hence, there is little effect of the protein surrounding on the cofactor functionally which contributes with its standard redox potential to the electron transfer process that is asymmetric. PMID- 23452038 TI - Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system. AB - Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all P < 0.01) were significantly associated with worse progression-free survival (PFS), while extensive ependymal canal formation was not (P = 0.89). Similar to the PF tumors, microvascular proliferation (P = 0.01) and elevated mitotic rate (P = 0.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (P = 0.03) were associated with worse clinical outcome in ST ependymomas, but hypercellularity (P = 0.57) and necrosis (P = 0.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site-specific grading criteria be considered in future classification systems. PMID- 23452039 TI - Simultaneous discrimination of diameter, handedness, and metallicity of single walled carbon nanotubes with chiral diporphyrin nanocalipers. AB - We have been developing the methodology to discriminate the handedness and diameter of single-walled carbon nanotubes (SWNTs) through molecular recognition using chiral diporphyrin nanotweezers. Although relatively small diameters of SWNTs (<1.0 nm) were recognized well, nanotweezers were not able to form stable complexes with the SWNTs having the diameters >1.0 nm. In this context, we designed chiral diporphyrin with a much larger cavity, namely, "nanocalipers". The feature of the newly designed host molecule is: (1) long spacer with more than 1.4 nm consisting of three aromatic moieties; (2) nearly parallel orientation of the two porphyrins; (3) restricted conformation by biaryl linkages of the porphyrin-carbazole and carbazole-anthracene; (4) strong interaction of two porphyrins and anthracene with the surface of a SWNT through pi-pi stacking; and (5) stereogenic centers at the periphery of porphyrins discriminating helicity of SWNTs. As expected, we obtained optically active SWNTs with >1.0 nm in diameter and, unexpectedly, enriched metallic SWNTs over semiconducting ones. The optically active metallic SWNTs are identified for the first time, in addition to the optically active semiconducting SWNTs with such large diameters. The nanocalipers are found to recognize the diameter, handedness, and metallicity of SWNTs simultaneously. PMID- 23452040 TI - Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies. AB - Alpha-synuclein (ASYN) is a major constituent of the typical protein aggregates observed in several neurodegenerative diseases that are collectively referred to as synucleinopathies. A causal involvement of ASYN in the initiation and progression of neurological diseases is suggested by observations indicating that single-point (e.g., A30P, A53T) or multiplication mutations of the gene encoding for ASYN cause early onset forms of Parkinson's disease (PD). The relative regional specificity of ASYN pathology is still a riddle that cannot be simply explained by its expression pattern. Also, transgenic over-expression of ASYN in mice does not recapitulate the typical dopaminergic neuronal death observed in PD. Thus, additional factors must contribute to ASYN-related toxicity. For instance, synucleinopathies are usually associated with inflammation and elevated levels of oxidative stress in affected brain areas. In turn, these conditions favor oxidative modifications of ASYN. Among these modifications, nitration of tyrosine residues, formation of covalent ASYN dimers, as well as methionine sulfoxidations are prominent examples that are observed in post-mortem PD brain sections. Oxidative modifications can affect ASYN aggregation, as well as its binding to biological membranes. This would affect neurotransmitter recycling, mitochondrial function and dynamics (fission/fusion), ASYN's degradation within a cell and, possibly, the transfer of modified ASYN to adjacent cells. Here, we propose a model on how covalent modifications of ASYN link energy stress, altered proteostasis, and oxidative stress, three major pathogenic processes involved in PD progression. Moreover, we hypothesize that ASYN may act physiologically as a catalytically regenerated scavenger of oxidants in healthy cells, thus performing an important protective role prior to the onset of disease or during aging. PMID- 23452041 TI - Classification of diapause status by color phenotype in Lygus hesperus. AB - Recent studies on adult diapause in the western tarnished plant bug, Lygus hesperus Knight (Heteroptera: Miridae), have highlighted the need to identify a reliable external marker for the internal changes that differentiate a normal animal from one that is overwintering. To test the efficacy of a color based discrimination system, L. hesperus of both genders were reared from eggs through day 10 of adulthood under a 10 hour photophase at a constant temperature. They were separated into three color groups (yellow, pale green, dark green), then dissected for diapause categorization based on internal development. Most yellow individuals were in diapause, dark green individuals were not, and pale green ones were mixed. A group of 25 assessors, naive with regard to L. hesperus development, were then asked to use a simplified color criteria (yellow = diapause, green = non-diapause) to estimate the status of a mixture of diapausing and non-diapausing adults of both genders aged two to seven days post-eclosion. After dissection to verify diapause status, assessor accuracy was found to be ineffective for assessing adults of both sexes younger than four days because color differences, which increased with age, were subtle or non-existent at this stage. For four to seven-day-old bugs, 84% of females and 67% of males were correctly categorized, on average. Incorrect assessments in all but the youngest males over-identified diapause, but for females there was no trend in miscategorizations. Overall, the results indicate that diapause status can be adequately discriminated by color assessment, and with greatest accuracy when sampling older females. However, factors other than photoperiod appear to also influence coloration. PMID- 23452042 TI - Reversibly acetylated lysine residues play important roles in the enzymatic activity of Escherichia coli N-hydroxyarylamine O-acetyltransferase. AB - CobB is a bacterial NAD(+)-dependent protein deacetylase. Although progress has been made in functional studies of this protein in recent years, its substrates and biological functions are still largely unclear. Using proteome microarray technology, potential substrates of Escherichia coli CobB were screened and nine proteins were identified, including N-hydroxyarylamine O-acetyltransferase (NhoA). In vitro acetylation/deacetylation of NhoA was verified by western blotting and mass spectrometry, and two acetylated lysine residues were identified. Site-specific mutagenesis experiments showed that mutation of each acetylated lysine decreased the acetylation level of NhoA in vitro. Further analysis showed that variant NhoA proteins carrying substitutions at the two acetylated lysine residues are involved in both the O-acetyltransferase and N acetyltransferase activity of NhoA. Structural analyses were also performed to explore the effects of the acetylated lysine residues on the activity of NhoA. These results suggest that reversible acetylation may play a role in the activity of Escherichia coli NhoA. PMID- 23452043 TI - A systematic review of the interventions for nipple trauma in breastfeeding mothers. AB - PURPOSE: To identify the most effective interventions to treat nipple trauma in breastfeeding mothers. DESIGN AND METHODS: Systematic literature review using the PICO strategy. The search was conducted on the electronic information systems Medline-PubMed, Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), World Health Organization Library Information System (WHOLIS), Cochrane, ScienceDirect (Elsevier), Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), using standardized and unstandardized descriptors. Studies were selected if they were controlled or uncontrolled randomized clinical trials written in English, Portuguese, or Spanish. Two reviewers evaluated the studies independently using a guide, and in case there were disagreements, a third reviewer was called on to reach a consensus. Of the 496 studies located, five were included. FINDINGS: The treatments investigated were lanolin, lanolin in association with breast protection shells, breast milk, hydrogel, adhesive polyethylene film dressings, a spray containing chlorhexidine with alcohol, and distilled water. All the groups in every study received breastfeeding education. The best outcomes for the treatment of nipple trauma used lanolin (recommendation B, evidence level 2) and breast milk (recommendation B, evidence level 2). Although one clinical study was found with positive outcomes resulting from treatment using a spray containing alcohol and chlorhexidine 0.2% (recommendation B, evidence level 2), this treatment modality should be further investigated since literature is not in favor of using antiseptic substances in skin wound treatment. CONCLUSIONS: Considering the treatments investigated, the most favorable evidence indicates the use of lanolin alone or in association with breast protection shells and breast milk expressed and rubbed into the nipple and areola after each feeding session. However, the results obtained in this review are inconclusive, indicating the need for further studies in order to clarify the action of breast milk and lanolin on the damaged tissues, as well as studies involving samples representative of the number needed to treat. CLINICAL RELEVANCE: This study provides evidence for nursing practice, thus contributing to the improvement of lactating mothers with nipple trauma care and, consequently, improving the rates of successful breastfeeding as well as the quality of life of breastfeeding mothers. PMID- 23452044 TI - Detection of A/B toxin and isolation of Clostridium difficile and Clostridium perfringens from foals. AB - REASONS FOR PERFORMING THE STUDY: Toxin detection and screening could contribute to knowledge of the transmission patterns, risk factors and epidemiology of Clostridium difficile and Clostridium perfringens. OBJECTIVE: To isolate C. difficile and C. perfringens and to detect A/B toxins in faecal samples from diarrhoeic and nondiarrhoeic foals. STUDY DESIGN: Cross-sectional observational study. METHODS: A total of 153 samples from foals were collected: 139 samples from farms and 14 samples from diarrhoeic foals admitted to a veterinary hospital. The A/B toxins were detected by cytotoxicity assay. All suspected colonies of C. perfringens were subjected to polymerase chain reaction for detection of the major toxin genes (alpha, beta, epsilon and iota) and for detection of beta2-, NetB- and enterotoxin-encoding genes. Furthermore, C. difficile and C. perfringens isolates were evaluated for in vitro antimicrobial susceptibility. RESULTS: Seven of 153 (4.6%) samples, all from diarrhoeic foals, were positive for C. difficile A/B toxin. Of these, 5 of 14 (35.7%) were from hospitalised foals, and only 2 of 63 (3.2%) diarrhoeic foal samples were from farms (P = 0.002). Clostridium perfringens was isolated from 31 (20.3%) foals, of which 21 of 76 (27.6%) were diarrhoeic and 10 of 76 (13.2%) were nondiarrhoeic, demonstrating a difference between these 2 groups (P = 0.045). Only 4 strains were positive for the beta2-encoding gene (cpb2). All C. difficile and C. perfringens isolates were susceptible to metronidazole and vancomycin. CONCLUSIONS: The present report highlights the need for laboratory diagnostics to differentiate C. difficile-associated infection in foals from other causes of diarrhoea to facilitate adequate antimicrobial therapy. POTENTIAL RELEVANCE: More studies are needed to clarify the role of C. perfringens as a primary agent of diarrhoea in foals. PMID- 23452045 TI - Solvent-induced structural dynamics in noninterpenetrating porous coordination polymeric networks. AB - Three novel soft porous coordination polymer (PCP) or metal-organic framework (MOF) compounds have been synthesized with a new rigid ligand N-(4-pyridyl) 1,4,5,8-naphathalenetetracarboxymonoimide (PNMI) by partial hydrolysis of N,N'-di (4-pyridyl)-1,4,5,8-naphthalenete-tracarboxydiimide (DPNI) during solvothermal reactions with Zn(II), Cd(II), and Mn(II) salts, and they are [Zn(PNMI)].2DMA (1.2DMA, 1a), [Cd(PNMI)].0.5DMA.5H2O (2.0.5DMA.5H2O), and [Mn(PNMI)].0.75DMF (3.0.75DMF). The structure of 1 is based on paddle-wheel secondary building unit (SBU) with a 3,6-connected rtl net topology, whereas 2 and 3 are isotypical but the M(O2C-C)2 fragments aggregate in one-dimension and the overall connectivity is the same rtl net topology. All these three MOFs have one-dimensional rhombic channels filled with guest molecules. The guest molecules in 1a can be exchanged with EtOH in a single-crystal to single-crystal (SCSC) manner to 1.1.25EtOH.0.375H2O (1b). Further, the guest molecules in 1b can be replaced with ethylene glycol, triethylene glycol and allyl alcohol without destroying its single crystal nature. These guest exchanges are accompanied by reduction in volume of the unit cell up to 16%, as well as the void volume up to 33.1%. Similarly, triethylene glycol (TEGly) selectively exchanges EtOH in a mixture of the above solvents, which might be the result of correct fit of the hydrogen bonded TEGly dimer in the channel of 1. While activated 1 and 3 exhibit no uptake of N2 and H2 at 1 bar and 77 K and very low uptake of CO2 gas at 1 bar and 196 K, activated 2 shows selective CO2 uptake, 278 cm(2).g(-1), over N2 and H2 at 1 bar and 196 K, which corresponds to 5.87 molecules of CO2 per formula unit of 2. PMID- 23452046 TI - Risk of repeat biopsy and prostate cancer detection after an initial extended negative biopsy: longitudinal follow-up from a prospective trial. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Even after a negative set of prostate biopsies, the risk of undetected prostate cancer remains clinically significant. Predictive markers of such a risk are undefined. In addition to PSA and PSAD, low prostate volume and %fPSA are interesting time varying risk factors and are relevant in biopsy decision-making. OBJECTIVE: To assess prospectively the time-varying risk of rebiopsy and of prostate cancer (PCa) detection after an initial negative biopsy protocol. PATIENTS AND METHODS: Over a period of 10 years, 1995 consecutive patients with initially negative biopsies were followed. Rebiopsies were performed in patients who had a persistent suspicion of PCa. Predictive factors for rebiopsy and for PCa detection were tested using univariate, multivariate and time-dependent models. RESULTS: A total of 617 men (31%) underwent at least one rebiopsy after a mean follow-up of 19 months. PCa detection rates during second, third, and fourth sets of biopsies were 16.7, 16.9 and 12.5%, respectively. The overall rate of detected PCa was 7.0%. The 5-year rebiopsy-free and PCa-free survival rates were 65.9 and 92.5%, respectively. Indications for rebiopsy were more frequently reported in patients having a high prostate-specific antigen (PSA) level (P = 0.006) or a high PSA density (PSAD; P < 0.001) and in younger patients (P = 0.008). The risk of PCa on rebiopsies was not correlated with age, but significantly increased more than twofold in cases of PSA >6 ng/mL, PSAD >0.15 ng/mL/g, free-to-total PSA ratio (%fPSA) <15, and/or prostate volume <50 mL. Time-dependent analyses were in line with these findings. The main study limitation was the lack of control of the absence of PCa and PSA kinetics in men not rebiopsied. CONCLUSIONS: The overall risk of detected PCa after an initial negative biopsy was low. In addition to PSA and PSAD, which are well-used in rebiopsy indications, low prostate volume and %fPSA are interesting time-varying risk factors for PCa on rebiopsy and could be relevant in biopsy decision-making. PMID- 23452047 TI - Enzymatic rate enhancements: a review and perspective. PMID- 23452048 TI - Wolf2Pack--portal based atomistic force-field development. AB - In this contribution we introduce the technical concept and implementation details concerning the front end of our force-field optimization workflow package for intramolecular degrees of freedom, called Wolf2Pack. The package's design follows our belief that parameter optimization should be a user-driven, but program guided, workflow with specific modular tasks that reduce human errors and save time. Through this design, parameter optimization becomes more reliable and reproducible. Wolf2Pack can integrate common force fields from different research areas, allowing the user to optimize balanced parameters; alternatively users can develop highly specialized force fields that suite their chemical systems. Included in the package's front end is a force-field and molecular database whose contents facilitate parameter optimization. Wolf2Pack can be accessed at www.wolf2pack.com. PMID- 23452049 TI - Properties of capsaicinoids for the control of fungi and oomycetes pathogenic to pepper. AB - Capsaicinoids are pungent compounds found in pepper (Capsicum spp.) fruits. Capsaicin showed antimicrobial activity in plate assays against seven isolates of five species of fungi and nine isolates of two species of oomycetes. The general trend was that oomycetes were more inhibited than fungi. Assays of capsaicin biosynthetic precursors suggest that the lateral chain of capsaicinoids has more inhibitory activity than the phenolic part. In planta tests of capsaicinoids (capsaicin and N-vanillylnonanamide) applied to the roots demonstrated that these compounds conferred protection against the pathogenic fungus Verticillium dahliae and induced both chitinase activity and expression of several defence-related genes, such as CASC1, CACHI2 and CABGLU. N-Vanillylnonanamide infiltrated into cotyledons confers systemic protection to the upper leaves of pepper against the fungal pathogen Botrytis cinerea. In wild-type tomato plants such cotyledon infiltration has no protective effect, but is effective in the Never-ripe tomato mutant impaired in ethylene response. A similar effect was observed in tomato after salicylic acid infiltration. PMID- 23452050 TI - Antiretroviral treatment adherence in childhood and adolescence: multidisciplinary team as an associated factor in Brazil. AB - Our aim was to analyze factors associated with non-adherence to antiretroviral (ARV) treatment among children and adolescents. A cross-sectional study was carried out involving non-institutionalized children and adolescents between 2 and 20 years of age, addressing non-adherence to ARV treatment, which was defined as taking <=89% of the medications on the day of the interview and the three previous days. The investigation into the association between non-compliance and the variables of interest was performed using unconditional logistic regression. The independent factors associated with non-adherence were forgetfulness (OR = 3.22; 95%CI = 1.75-5.92), difficulties coping with treatment (OR = 2.65; 95%CI = 1.03-6.79), and living with grandparents (OR = 2.28; 95%CI = 1.08-4.83), whereas a protective effect was found with participation in multidisciplinary activities (OR = 0.49; 95%CI = 0.25-0.96), i.e., this factor indicates that the exposure to the variable is beneficial, promoting adherence. We concluded that forgetting to take the medications and reporting having difficulty coping with ARV treatment are potentially modifiable factors through educational and programmatic actions. Residing with one's grandparents may strongly impact adherence to ARV treatment, indicating the need for the systematic support of these family members. Participation in multidisciplinary activities should be stimulated at health-care services. PMID- 23452051 TI - Functional variants of eNOS and iNOS genes have no relationship to the portal hypertension in patients with liver cirrhosis. AB - OBJECTIVE: Nitric oxide is an important vasoactive mediator. Changes in NO production, caused by functional variants of both endothelial and inducible NO synthase (eNOS, iNOS), might play a role in portal hypertension. The aim was to study the significance of functional eNOS and iNOS gene variants in cirrhotic patients and their interrelationship to both inflammatory and endothelial activation parameters. MATERIAL AND METHODS: One hundred and thirty-two patients with liver cirrhosis (age 36-72 years) and 101 controls were examined for functional variants of eNOS (E298D, 27bpintr4, 786T/C) and iNOS (R221W, S608L) genes. Inflammatory (IL6, IL8, IL10) and vasoactive (sVCAM-1, E-selectin) cytokines were measured using ELISA kits. RESULTS: The frequency of E298D (GG 12%, GT 41%, TT 47%), 28bpintr4 (AA 6%, AB 28%, BB 66%), 786T/C genotypes (CC 17%, CT 45%, TT 38%), as well as R221W (CC 93%, CT 7%, TT 0%), and S608L (CC 65%, CT 32%, TT 3%) genotypes in cirrhotic patients did not differ from the controls (p > 0.05 for all comparisons). No relationship was found between the frequency of these genotypes and the severity of portal hypertension, or either inflammatory or vasoactive cytokines. A positive correlation was found between hepatic venous pressure gradient and cytokine concentration: sVCAM-1, IL6, IL8, IL10. CONCLUSIONS: Examined eNOS and iNOS variants have no relationship to pathogenesis of liver cirrhosis. Severity of portal hypertension was associated with the changes in endothelial activation. PMID- 23452052 TI - Calculation of power and field of view of keratoprostheses. AB - PURPOSE: To demonstrate a mathematical algorithm for calculating the refractive power of keratoprostheses and to estimate vignetting effects. METHODS: A paraxial calculation scheme based on vergence transformation is developed for determination of the front surface radius or front surface refractive power of a Boston type I or II keratoprosthesis based on the design data of the manufacturer. A concept for derivation of lateral magnification (ratio of image size to slope of the incident ray) is presented based on 2 * 2 matrix representation of the eye. For estimation of vignetting effects, numerical ray tracing was used and the maximum half field angle and half luminance half field angle was extracted. RESULTS: Simulation calculations were performed in MATLAB. The front surface radius or refractive power is given in explicit form as a function of axial length, target refraction, as well as the principal design data of the keratoprosthesis such as posterior refractive power, length, or refractive index. With variation of the back surface radius it was shown that lateral magnification can be modulated e.g. to match the magnification of the fellow eye. The Boston type I does not restrict the field angle substantially, whereas type II shows significant vignetting effects. CONCLUSION: We present a strategy on the calculation of keratoprostheses and variation of the design (e.g. back surface curvature) to help to avoid aniseikonia in case of binocular vision (e.g. one phakic eye and one with keratoprosthesis). PMID- 23452053 TI - Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of agents for the treatment of type 2 diabetes mellitus (T2DM). By inhibiting SGLT2, they prevent renal glucose reabsorption, resulting in glucosuria. AREAS COVERED: The rationale for development of SGLT2 inhibitors is reviewed, with particular focus on the nine SGLT2 inhibitors currently in development. The authors compare the potency and SGLT2 selectivity of the agents, as well as the results from both animal and clinical studies, considering the potential implications they may have for clinical use. EXPERT OPINION: Current evidence suggests that SGLT2 inhibitors have similar efficacy in terms of glycemic control and also demonstrate benefits beyond glycemic reductions, including reductions in body weight and modest reductions in blood pressure. Additionally, they appear to preserve beta-cell function and improve insulin sensitivity. Their mechanism of action allows for combination of SGLT2 inhibitors with other antidiabetic drugs and use across the treatment continuum for T2DM. Potential differences in safety and efficacy based on observed differences in potency and selectivity among the SGLT2 inhibitors, particularly versus SGLT1, remain to be seen. Further long-term data, including post-marketing surveillance, are required to fully determine the safety profile of SGLT2 inhibitors in large patient groups. PMID- 23452055 TI - Spontaneous appearance of multiple asymptomatic papules and/or nodules over an apparently normal skin of the trunk. Fibrosing lepromatous leprosy (LL) evolving to histoid leprosy. PMID- 23452054 TI - Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. AB - OBJECTIVES: To evaluate the changes in types of medications prescribed for pain before and after withdrawal of certain selective cyclooxygenase 2 (COX-2) inhibitors in 2004 and to determine whether there was an association with fall events in elderly adults with a diagnosis of osteoarthritis (OA). DESIGN: A nested case-control design using electronic medical records compiled between 2001 and 2009. SETTING: Electronic medical records for care provided in an integrated health system in rural Pennsylvania over a 9-year period (2001-09), the midpoint of which rofecoxib and valdecoxib were pulled from the market. PARTICIPANTS: Thirteen thousand three hundred fifty-four individuals aged 65 to 89 with a diagnosis of OA. MEASUREMENTS: The incidence of falls and fractures was examined in relation to analgesics prescribed: narcotics, COX-2 inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). The comparison sample of individuals who did not fall was matched 3:1 with those who fell according to age, sex, and comorbidity. RESULTS: Narcotic analgesic prescriptions were associated with a significantly greater risk of falls and fractures. The likelihood of experiencing a fall/fracture was higher in participants prescribed narcotic analgesics than those prescribed a COX-2 inhibitor (odds ratio (OR) = 3.3, 95% confidence interval (CI) = 2.5-4.3) or NSAID (OR = 4.1, 95% CI = 3.7 4.5). CONCLUSION: Use of narcotic analgesics is associated with risk of falls and fractures in elderly adults with OA, an observation that suggests that the current guidelines for the treatment of pain, which include first-line prescription of narcotics, should be reevaluated. PMID- 23452056 TI - Synthesis of functionalized spiroindolines via palladium-catalyzed methine C-H arylation. AB - The synthesis of cyclopropyl spiroindolines is described using an intramolecular palladium(0)-catalyzed C-H functionalization of a methine C(sp(3))-H bond. This transformation can be coupled with intermolecular Suzuki couplings or direct arylations of heteroaromatics to access functionalized indoline scaffolds in a single step. PMID- 23452057 TI - Characterization of different courses of atopic dermatitis in adolescent and adult patients. AB - BACKGROUND: Atopic dermatitis (AD) starts most often during the first years of life and goes into remission in a high proportion of cases during childhood. However, in severe cases, AD persists until adulthood or starts and relapses later in life. So far, studies investigating the natural course of AD during adolescence and adulthood are rare. The aim of our study was to classify different courses of AD and to correlate these with specific risk factors for severe variants of AD. METHODS: A detailed clinical examination and retrospective evaluation of the history of the disease were performed in a collective of 725 adolescent and adult patients with AD. Laboratory data including total and specific IgE were evaluated. RESULTS: Six hundred and seven patients of 725 patients could be classified into course types. Of these 607 patients 85.7% could be classified into five main different course types of all 31 course types recorded. The highest differences in the number of sensitizations, total immunoglobulin E serum levels and predilection of the skin lesions were observed between patients with an early type of onset of AD and a chronic persisting course until adulthood and patients with a late type of onset of AD, that is, after the 20th year of life. CONCLUSION: Our data show that the natural course of AD can be divided into subgroups that display different clinical features. The data support the assumption of a broad heterogeneity of AD in adolescence and adulthood and emphasize the future need for careful stratification of patients with AD. PMID- 23452060 TI - Interplay between BDF1 and BDF2 and their roles in regulating the yeast salt stress response. AB - The homologous genes BDF1 and BDF2 in Saccharomyces cerevisiae encode bromodomain containing transcription factors. Although double deletion of BDF1 and BDF2 is lethal, single deletion does not affect cell viability. The bdf2? cells showed normal growth upon salt stress. However, the absence of Bdf1p resulted in a salt sensitive phenotype, and the salt sensitivity was suppressed by overexpression of BDF2. In this study, we further demonstrated that BDF2 shows dosage compensation in suppressing the salt sensitivity of bdf1?. None of the tested domains replaced the function of intact Bdf1p. The 494-626 region in Bdf1p was more important than the other domains for salt resistance. In addition, Bdf1p negatively regulated the expression of BDF2 by binding its promoter at loci -387 to -48. However, Bdf2p did not affect the expression of BDF1. In addition, Bdf1p and its defective functional domain mutants could combine with Bdf2p. This physical interaction increased the salt tolerance of bdf1?. The mitochondrial dysfunctions caused by BDF1 deletion were restored by overexpression of BDF2 under salt stress conditions. PMID- 23452061 TI - A single in vivo cocaine administration impairs 5-HT(1B) receptor-induced long term depression in the nucleus accumbens. AB - The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward based decision-making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5-hydroxytryptamine (5 HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5 HT or 5-HT1B receptor agonist CP 93129 induced a long-term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5-HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5-HT or CP 93129. The inhibition was blocked when a selective dopamine D1 receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129 induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP-dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5-HT1B receptor-mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5-HT1B receptors and thereby impairs the induction of LTD by 5-HT. PMID- 23452062 TI - Sexual health information seeking: a survey of adolescent practices. AB - AIMS AND OBJECTIVES: To identify sources of information and support preferred by young people to understand adolescent practices as adolescents develop a sexual health knowledge base. BACKGROUND: Statistics suggest that adolescents are not always making safe sexual health decisions. It is essential to develop an understanding of preferred sources of information and support to structure health and education services so that adolescents develop skills and knowledge to make safer choices. DESIGN: A cross-sectional survey design. METHODS: A wide-ranging questionnaire was developed using validated questions, drawn from similar adolescent lifestyle surveys and adapted with guidance from an advisory group; 2036 13-16-year-olds responded. Two questions, reporting information sources adolescents find useful and sources of approachable support, are considered here. RESULTS: Adolescents find informal sources more useful and experience higher levels of comfort accessing informal support especially from their best friends and mothers. Of formal provision, school-based sources are preferred; however, sexual health information seeking is gendered and changes across year groups. The range of sexual health information sources adolescents access increases with age, and how they access these information sources changes as sexual activity increases and the information becomes more relevant. CONCLUSIONS: The findings support the targeting of sexual health provision in relation to age and gender and suggest a youth-focused approach to formal provision, including outreach working and a collaborative relationship with adolescents and parents. RELEVANCE TO CLINICAL PRACTICE: The findings contribute to an understanding of sources of information and support preferred by adolescents. In particular, they need to reconsider how services external to the school may be developed so they are youth focused and approachable. Nurses need to consider how best to work in partnership with adolescents and their families to disseminate accurate information and develop relevant services. PMID- 23452063 TI - Diurnal rhythm and effects of feeding, exercise and recombinant equine growth hormone on serum insulin concentrations in the horse. AB - REASONS FOR PERFORMING THE STUDY: As growth hormone increases lean body mass, it could be a therapy for obese horses. However, growth hormone use induces hyperinsulinaemia in some species, so further investigation is warranted. OBJECTIVES: To investigate the effects of feeding, exercise and growth hormone therapy on basal insulin concentrations in healthy horses. STUDY DESIGN: In vivo experimental study. METHODS: Blood samples were obtained every 30 min from 12 geldings over 24 h, to establish basal serum insulin concentrations, before they underwent a 3-week exercise programme. Horses were allocated into 2 groups and exercised for another 4 weeks. Group A received daily i.m. injections of recombinant equine growth hormone; 5 mg/day for 5 days, then 12.5 mg/day for 16 days. Blood samples were taken daily before feeding. Insulin vs. time area under curve of Groups A and B were compared using a Student's unpaired t test. RESULTS: Horses demonstrated insulin peaks within 2 h of feeding of 577 +/- 108.3 pmol/l at 09.30 h and 342.4 +/- 75.7 pmol/l at 17.30 h, despite receiving the same meal. The nadir was between midnight and 07.30 h. Exercise had no effect on basal insulin concentrations prior to equine growth hormone administrations. The equine growth hormone injections increased serum insulin concentrations (P = 0.01) within Group A, from 44.4 +/- 15.3 pmol/l initially to 320.9 +/- 238.2 pmol/l by Day 12. Exogenous growth hormone caused variable hyperinsulinaemia, which was alleviated once equine growth hormone administration ceased. CONCLUSIONS: Single serum samples taken prior to the morning meal provide basal insulin concentrations. Exercise did not change basal insulin concentrations. However, equine growth hormone injections increased basal insulin concentrations, which were not ameliorated by exercise. POTENTIAL RELEVANCE: This therapy is not recommended to address obesity in insulin-resistant equids. PMID- 23452064 TI - Enantioselective total synthesis of plectosphaeroic acid B. AB - The first total synthesis of a member of the plectosphaeroic acid family of fungal natural products is reported. Key steps include the late-stage formation of the hindered N6-C9" bond and stereoselective introduction of the two methylthio substituents. PMID- 23452065 TI - Phenytoin therapy in a neonate diagnosed with epidermolysis bullosa. PMID- 23452066 TI - Enigmatic liaisons in Lepidoptera: a review of same-sex courtship and copulation in butterflies and moths. AB - Same-sex sexual interactions (SSSI) have been observed in many animal groups and have intrigued evolutionists. In this paper, reports on SSSI in Lepidoptera are reviewed and evolutionary hypotheses that could explain these behaviors are discussed. SSSI have been documented in males of 25 species and in females from role-reversed populations of one species. Four types of SSSI have been reported: pupal guarding, courtship, copulation attempt, and copulation. Although the hypotheses cannot be tested with the limited data, evidence suggests that in some Lepidoptera SSSI could result from selection for imposing costs on other males, or could be a by-product of sexual selection favoring individuals that exhibit high sexual willingness. In agreement with both hypotheses, in the 17 species whose mating systems are known, there is intense competition for mates in the sex exhibiting SSSI. We propose lines of research on SSSI in Lepidoptera. PMID- 23452067 TI - Conduction in a biological sodium selective channel. AB - The crystal structure of NavAb, a bacterial voltage gated Na(+) channel, exhibits a selectivity filter (SF) wider than that of K(+) channels. This new structure provides the opportunity to explore the mechanism of conduction and help rationalize its selectivity for sodium. Recent molecular dynamics (MD) simulations of single- and two-ion permeation processes have revealed that a partially hydrated Na(+) permeates the channel by exploring three SF binding sites while being loosely coupled to other ions and/or water molecules; a finding that differs significantly from the behavior of K(+) selective channels. Herein, we present results derived from a combination of metadynamics and voltage-biased MD simulations that throws more light on the nature of the Na(+) conduction mechanism. Conduction under 0 mV bias explores several distinct pathways involving the binding of two ions to three possible SF sites. While these pathways are very similar to those observed in the presence of a negative potential (inward conduction), a completely different mechanism operates for outward conduction at positive potentials. PMID- 23452068 TI - Important considerations when applying for a postdoctoral fellowship. AB - PURPOSE: To examine important decision points that graduates should consider before applying for a postdoctoral fellowship. METHODS: A literature review was performed. FINDINGS AND CONCLUSIONS: A synthesis of the present data on the postdoctoral fellowship, eligibility criteria, application process, and important considerations was provided. Experiential knowledge from four present postdoctoral fellows was included. The goals, advantages, and disadvantages of the fellowship were discussed. In conclusion, the postdoctoral fellowship was examined to offer important considerations in the decision to pursue this opportunity. CLINICAL RELEVANCE: The clinical relevance of this article is related to the training and education of nurses to become the next generation of independent, successful scholars and scientists. Postdoctoral training adds valuable contributions and quality to the field of nursing. PMID- 23452069 TI - In their own words: racial/ethnic and gender differences in sources and preferences for HIV prevention information among young adults. AB - The purpose of this study was to examine where young adults were obtaining their HIV prevention information, and determine if there were consumption preferences based on gender and race/ethnicity. We conducted a series of race/ethnic and gender-concordant 2-hour focus groups, and qualitative analyses identified common domains. Sixty adolescents attended 6 focus groups. Findings revealed that primary informational sources were television and advertisements, educational settings, community health care centers, and family and friends. However, television commercials and advertisements were viewed as an ineffective approach, with mistrust of the "mainstream" media being very high for Black males. Recommendations centered on the need for more realistic scenarios related to living with HIV by other adolescents, greater parental involvement with HIV education, especially for minority youth, and the use of social media. Special attention should be given to the importance of social media for adolescents, and how the fear of HIV-related stigma influences HIV information consumption patterns among males. PMID- 23452070 TI - Synthesis, structure, spectroscopic characterization, and protein binding affinity of new water-soluble hetero- and homometallic tetranuclear [Cu(II)2Zn(II)2] and [Cu(II)4] clusters. AB - Two new water-soluble hetero- and homometallic tetranuclear clusters, Na4[Cu2Zn2(ccdp)2(MU-OH)2].CH3OH.6H2O (1) and K3[Cu4(ccdp)2(MU-OH)(MU-OH2)].14H2O (2), have been synthesized in methanol-water at room temperature by exploiting the flexibility, chelating ability, and bridging potential of a carboxylate-rich dinucleating ligand, N,N'-bis(2-carboxybenzomethyl)-N,N'-bis(carboxymethyl)-1,3 diaminopropan-2-ol (H5ccdp). Complex 1 is obtained through the self-assembly of two monoanionic [CuZn(ccdp)](-)fragments, which are, in turn, exclusively bridged by two MU-OH(-)groups. Similarly, complex 2 is formed through the self-assembly of two monoanionic [Cu2(ccdp)](-) species exclusively bridged by one MU-OH(-) and one MU-OH2 groups. Complexes 1 and 2 are fully characterized in the solid state as well as in solution using various analytical techniques including a single crystal X-ray diffraction study. The X-ray crystal structure of 1 reveals that two Cu(II) centers are in a distorted square-pyramidal geometry, whereas two Zn(II) centers are in a distorted trigonal-bipyramidal geometry. The solid-state structure of 2 contains two dinuclear [Cu2(ccdp)](-) units having one Cu(II) center in a distorted square-pyramidal geometry and another Cu(II) center in a distorted trigonal-bipyramidal geometry within each dinuclear unit. In the powder state, the high-field EPR spectrum of complex 1 indicates that two Cu(II) ions are not spin-coupled, whereas that of complex 2 exhibits at least one noninteracting Cu(II) center coordinated to a nitrogen atom of the ligand. Both complexes are investigated for their binding affinity with the protein bovine serum albumin (BSA) in an aqueous medium at pH ~7.2 using fluorescence spectroscopy. Synchronous fluorescence spectra clearly reveal that complexes 1 and 2 bind to the active sites in the protein, indicating that the effect is more pronounced toward tyrosine than tryptophan. Density functional theory calculations have been carried to find the Fukui functions at the metal sites in complexes 1 and 2 to predict the possible metal centers involved in the binding process with BSA protein. PMID- 23452071 TI - Is there a difference between women with or without detrusor overactivity complaining of symptoms of overactive bladder? AB - What's known on the subject? and what does the study add?: Overactive bladder syndrome (OAB) is a highly prevalent medical condition, which is linked to the urodynamic observation of detrusor overactivity (DO). Urodynamics detect DO in about half of female patients with OAB. Our study detects significant differences between female patients with OAB with and without DO. DO could be considered as a more severe form in the wide OAB spectrum and the two terms should not be used interchangeably. The detected differences should be taken into account in the design of studies for the assessment of new selective or combination treatments of OAB and in the provision of treatment in everyday clinical practice. OBJECTIVE: To determine if there are differences between female patients complaining of symptoms of overactive bladder (OAB) with and without detrusor overactivity (DO). PATIENTS AND METHODS: The present study was a cross-sectional study of consecutive women attending a one-stop urodynamic assessment clinic with OAB symptoms. The King's Health Questionnaire (KHQ) and a 3-day bladder diary incorporating the Patient's Perception of Intensity of Urgency Scale (PPIUS) were used to assess symptoms and health-related quality of life (HRQoL). The participants underwent multichannel urodynamics (UDS) according to the International Continence Society (ICS) recommendations. Patients whose symptom of urgency was not reproduced during the laboratory test underwent a 4-h ambulatory UDS test. RESULTS: Of the 556 patients who were included in the study, 43% were diagnosed with DO by either laboratory (227/556) or ambulatory UDS (11/39). There was no difference between the groups in age, body mass index (BMI), menopausal status or the presence of prolapse. Patients with DO had a smaller functional bladder capacity (P < 0.001), higher urgency episode frequency (P < 0.001) and larger maximum and mean urge ratings (P < 0.001). No significant differences were found in daytime or nocturnal micturitions between the groups. The presence of DO had a more negative impact on the quality of life, with a statistically significant difference between the groups in six of the domains of the KHQ. CONCLUSIONS: The present study detects objective and subjective differences between female patients with OAB with and without DO. Women with DO experience more significant impairment to their quality of life and have a greater degree of bladder dysfunction. PMID- 23452072 TI - Hepatic encephalopathy is related to anemia and fat-free mass depletion in liver transplant candidates with cirrhosis. AB - BACKGROUND: Although muscle wasting may lead to decreased ammonia detoxification in cirrhosis, the potential role of lean mass depletion in hepatic encephalopathy (HE) has not been explored. Anemia, hormonal abnormalities, and psychological distress may contribute to cognitive dysfunction, but data on their potential relation to HE are limited. METHODS: Data on 108 cirrhotic liver transplant candidates enrolled in a prospective study on fatigue were retrospectively analyzed. HE was assessed clinically and with the number connection tests (NCT) A and B. Psychosocial distress was assessed with a validated questionnaire. Fasting serum glucose, insulin, ammonia, and the glomerular filtration rate (GFR) were measured. Fat and fat-free mass was evaluated with dual-energy X-ray absorptiometry. Serum cortisol, testosterone, dehydroepiandrosterone, thyroid function tests, interleukin-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in a subgroup of 80 patients. RESULTS: A total of 28% of patients had (overt or minimal) HE. Anemia was present in 59%, diabetes in 29%, renal impairment in 16%, and fat-free mass depletion in 14%. In multivariate analysis, fat-free mass depletion was an independent predictor of HE and NCT-A; renal impairment of NCT-A and -B; and anemia of NCT-B (p < 0.05 for all). HE was also independently related to international normalized ratio and TNF-alpha (p < 0.05 for both), but not to other hormonal abnormalities or psychological distress. Plasma ammonia was independently associated to anemia (beta = 15.24, p = 0.049), fasting insulin (beta = 0.26, p < 0.05), and GFR (beta = -0.43, p = 0.003). CONCLUSIONS: Anemia and fat-free mass depletion are predictors of HE in cirrhotic liver transplant candidates along with liver failure, renal impairment, and systemic inflammation. PMID- 23452073 TI - A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women. AB - BACKGROUND: Kisspeptin is a novel hypothalamic peptide which stimulates endogenous gonadotrophin releasing hormone (GnRH) secretion. A single subcutaneous bolus injection of kisspeptin-54 increases circulating luteinizing hormone (LH) levels in women, but its acute effects on LH pulsatility are not known. AIMS: To investigate the effects of a single subcutaneous (sc) injection of kisspeptin-54 administration on LH pulsatility in healthy female volunteers. METHODS: Six healthy female adult volunteers underwent 10-minute blood sampling for serum LH measurement for 8 h during the follicular phase of menstrual cycle. Sc bolus injection of saline or kisspeptin-54 (0.15, 0.30 or 0.60 nmol/kg) was administered 4 h after commencing the study. A previously described, blinded deconvolution method was used to detect LH pulses. RESULTS: Mean number of LH pulses was increased significantly following 0.30 and 0.60 nmol/kg kisspeptin-54 when compared with saline (mean increase in number of LH pulses per 4 h, following injection: -0.17 +/- 0.54, saline; +2.33 +/- 0.56, 0.30 nmol/kg kisspeptin-54, P < 0.05 vs saline; +2.33 +/- 0.80, 0.60 nmol/kg kisspeptin-54, P < 0.05 vs saline). LH pulse secretory mass increased following injection of 0.60 nmol/kg in five of six subjects, but the mean change in all subjects was non significant when compared with saline (mean increase in pulse secretory mass in IU/l following injection: +0.35 +/- 0.40, saline; +2.61 +/- 1.17, 0.60 nmol/kg kisspeptin-54, P = 0.10 vs saline). CONCLUSIONS: A single injection of kisspeptin 54 temporarily stimulates the number of LH pulses in healthy women. Further studies are required to investigate the therapeutic potential of kisspeptin-54 injection to restore LH pulsatility in patients with reproductive disorders caused by impaired GnRH secretion. PMID- 23452074 TI - Association of sarcopenia with functional decline in community-dwelling elderly subjects in Japan. AB - AIM: The present study aimed to determine the association of sarcopenia, defined by muscle mass, muscle strength and physical performance, with functional disability from a 2-year cohort study of community-dwelling elderly Japanese people. METHOD: Participants were 743 community-dwelling elderly Japanese people aged 65 years or older. We used bioelectrical impedance analysis (BIA) to measure muscle mass, grip strength to measure muscle strength, and usual walking speed to measure physical performance in a baseline study. Functional disability was defined using an activities of daily living (ADL) scale and instrumental activities of daily living (IADL) scale at baseline and during follow-up examinations 2 years later. Logistic regression analysis, adjusted for age and body mass index, was used to examine the association between sarcopenia and the occurrence of functional disability. RESULTS: In the present study, 7.8% of men and 10.2% of women were classified as having sarcopenia. Among sarcopenia patients in the baseline study, 36.8% of men and 18.8% of women became dependent in ADL at 2-year follow up. From the logistic regression analysis adjusted by age and body mass index, sarcopenia was significantly associated with the occurrences of physical disability compared with normal subjects in both men and women. CONCLUSIONS: Sarcopenia, defined by muscle mass, muscle strength and physical performance, was associated with functional decline over a 2-year period in elderly Japanese. Interventions to prevent sarcopenia are very important to prevent functional decline among elderly individuals. PMID- 23452075 TI - Generalized erythematous-violaceous plaques in a patient with a history of dyslipidemia. Interstitial granulomatous drug reaction (IGDR). PMID- 23452078 TI - The role of culture and self-construal in autobiographical memories of US and Turkish college students. AB - This study examined memory variables both cross-culturally and across four cultural self-construal types. US (N=240) and Turkish (N=174) college students described their earliest childhood memory, and another significant childhood memory, and completed the Balanced Integration-Differentiation (BID) Scale (Imamoglu, 1998; 2003), which measured relatedness and individuation, and allowed for the classification of students into four different self-construal types (Related-Individuated, Separated-Individuated, Related-Patterning, Separated Patterning). At the cultural level US students' earliest memories were dated approximately 6 months earlier, had greater volume, and were more positive. US students also reported memories as more important. Turkish students' memories had more detail, a higher proportion of propositions, self-, other- and we-related words, and higher other-self ratios, and they were clearer than those of US students. Turkish students also reported greater ease in describing their earliest memory in words. At the level of self-construal the primary differences were between students high in both relatedness and individuation and those low in both. The culture by BID interaction was significant in only 1 of the more than 24 analyses. PMID- 23452077 TI - Refining physician quality indicators for screening mammography in older women: distinguishing appropriate use from overuse. AB - OBJECTIVES: To assess the feasibility of refining physician quality indicators of screening mammography use based on patient life expectancy. DESIGN: Retrospective population-based cohort study. SETTING: Texas. PARTICIPANTS: Three thousand five hundred ninety-five usual care providers (UCPs) with at least 10 female patients aged 67 and older on January 1, 2008, with an estimated life expectancy of 7 years or more (222,584 women) and at least 10 women with an estimated life expectancy of less than 7 years (90,903 women), based on age and comorbidity. MEASUREMENTS: Screening mammography use in 2008-09 by each provider in each population. RESULTS: The average adjusted mammography screening rates for UCPs were 31.1% for women with a life expectancy of less than 7 years and 55.2% for women with a life expectancy of 7 years or longer. For women with limited life expectancy, 3.7% of UCPs had significantly lower and 9.2% had significantly higher than average adjusted mammography screening rates. For women with longer life expectancy, 16.7% of UCPs had significantly lower and 19.7% had significantly higher than average rates. UCP adjusted screening rates were stable over time (2006-07 vs 2008-09, correlation coefficient (r) = 0.65, P < .001). There was a strong correlation between UCP screening rates for their female patients with a life expectancy of less than 7 years and 7 years or longer (r = 0.67, P < .001). Most physician characteristics associated with higher screening rates (e.g., being female and foreign trained) in women with longer life expectancy were also associated with higher screening rates in women with limited life expectancy. CONCLUSION: Providers with high mammography screening rates for women with longer life expectancy also tend to screen women with limited life expectancy. Quality indicators for screening practice can be improved by distinguishing appropriate use from overuse based on patient life expectancy. PMID- 23452076 TI - Attenuated allergic airway inflammation in Cd39 null mice. AB - BACKGROUND: Extracellular Adenosine-5'-Triphosphate (ATP) is known to accumulate in the lung, following allergen challenge, and contributes via activation of purinergic receptors on dendritic cells (DC), to the development of allergic airway inflammation (AAI). Extracellular ATP levels in the airways are normally tightly regulated by CD39. This ectonucleotidase is highly expressed by DC purified from skin (Langerhans cells) and bone marrow, and has been shown to modulate DC adaptive/haptenic immune responses. In this study, we have evaluated the impact of Cd39 deletion and associated perturbation of purinergic signaling in AAI. METHODS: Standard ovalbumin (OVA)-alum and house dust mite (HDM) bone marrow-derived DC (BMDC)-dependent models of AAI were used to study effects of Cd39. Migration assays, time lapse microscopy, and T-cell priming assays were further used to determine functional relevance of Cd39 expression on BMDC in the setting of immune and Th2-mediated responses in these models. RESULTS: Cd39(-/-) mice exhibited marked increases in BALF ATP levels but paradoxically exhibited limited AAI in both OVA-alum and HDM models. These pathophysiological abnormalities were associated with decreased myeloid DC activation and chemotaxis toward ATP, and were linked to purinergic receptor desensitization responses. Further, Cd39(-/-) DCs exhibited limited capacity to both prime Th2 responses and form stable immune synaptic interactions with OVA-transgenic naive T cells. CONCLUSIONS: Cd39-deficient DCs exhibit limited capacity to induce Th2 immunity in a DC-driven model of AAI in vivo. Our data demonstrate a role of CD39 and perturbed purinergic signaling in models of AAI. PMID- 23452080 TI - New insights into the pathobiology of Down syndrome--hyaluronan synthase-2 overexpression is regulated by collagen VI alpha2 chain. AB - Down syndrome (DS) is a common birth defect characterized by the trisomy of chromosome 21. DS-affected umbilical cords (UCs) of fetuses show altered architecture of the extracellular matrix. Overexpression of the chromosome 21 genes encoding the collagen type VI (COLVI) chains alpha1(VI) and alpha2(VI), COL6A1 and COL6A2, respectively, has also reported to occur in the nuchal skin of DS fetuses. The aim of this study was therefore to evaluate the COLVI content in euploid and DS-affected UCs and human skin fibroblasts, and to investigate the relationships between COLVI and hyaluronan (HA) and HA synthase-2 (HAS2). We found that the UCs of DS fetuses showed denser staining of COLVI and increased COL6A2 expression at both early and term gestational ages. In vitro expression studies in DS-derived fibroblasts showed similarly increased amounts of alpha1(VI) and alpha2(VI) chains at the protein and transcriptional level, supporting the hypothesis of the gene dosage effect. Furthermore, increased levels of HA and HAS2 were also found in DS-derived skin fibroblast cultures. Notably, silencing of COL6A2 in DS-derived cells resulted in downregulation of HAS2, with a simultaneous decrease in secreted HA. Exogenous addition of COLVI to normal fibroblasts did not have any effect on HAS2 expression. In conclusion, UCs and skin fibroblasts in DS show significant increases in COLVI and HA; the overexpression of COL6A2 in DS tissue and cells is closely related to the increased expression of HAS2. These data may explain the DS phenotypes and their effects in organ tissue maturation. PMID- 23452079 TI - Structural analysis of aliphatic versus aromatic substrate specificity in a copper amine oxidase from Hansenula polymorpha. AB - Copper amine oxidases (CAOs) are responsible for the oxidative deamination of primary amines to their corresponding aldehydes. The CAO catalytic mechanism can be divided into two half-reactions: a reductive half-reaction in which a primary amine substrate is oxidized to its corresponding aldehyde with the concomitant reduction of the organic cofactor 2,4,5-trihydroxyphenylalanine quinone (TPQ) and an oxidative half-reaction in which reduced TPQ is reoxidized with the reduction of molecular oxygen to hydrogen peroxide. The reductive half-reaction proceeds via Schiff base chemistry, in which the primary amine substrate first attacks the C5 carbonyl of TPQ, forming a series of covalent Schiff base intermediates. The X ray crystal structures of copper amine oxidase-1 from the yeast Hansenula polymorpha (HPAO-1) in complex with ethylamine and benzylamine have been determined to resolutions of 2.18 and 2.25 A, respectively. These structures reveal the two amine substrates bound at the back of the active site coincident with TPQ in its two-electron-reduced aminoquinol form. Rearrangements of particular amino acid side chains within the substrate channel and specific protein-substrate interactions provide insight into the substrate specificity of HPAO-1. These changes begin to account for this CAO's kinetic preference for small, aliphatic amines over the aromatic amines or whole peptides preferred by some of its homologues. PMID- 23452081 TI - Sandwich-cultured hepatocytes: utility for in vitro exploration of hepatobiliary drug disposition and drug-induced hepatotoxicity. AB - INTRODUCTION: The sandwich-cultured hepatocyte (SCH) model has become an invaluable in vitro tool for studying hepatic drug transport, metabolism, biliary excretion and toxicity. The relevant expression of many hepatocyte-specific functions together with the in vivo-like morphology favor SCHs over other preclinical models for evaluating hepatobiliary drug disposition and drug-induced hepatotoxicity. AREAS COVERED: In this review, the authors highlight recommended procedures required for reproducibly culturing hepatocytes in sandwich configuration. It also provides an overview of the SCH model characteristics as a function of culture time. Lastly, the article presents a summary of the most prominent applications of the SCH model, including hepatic drug clearance prediction, drug-drug interaction potential and drug-induced hepatotoxicity. EXPERT OPINION: When human (cryopreserved) hepatocytes are used to establish sandwich cultures, the model appears particularly valuable to quantitatively investigate clinically relevant mechanisms related to in vivo hepatobiliary drug disposition and hepatotoxicity. Nonetheless, the SCH model would largely benefit from better insight into the fundamental cell signaling mechanisms that are critical for long-term in vitro maintenance of the hepatocytic phenotype. Studies systematically exploring improved cell culture conditions (e.g., co-cultures or extracellular matrix modifications), as well as in vitro work identifying key transcription factors involved in hepatocyte differentiation are currently emerging. PMID- 23452082 TI - Parental influences of sexual risk among urban African American adolescent males. AB - PURPOSE: This study examined the influence of parental marital status, parent child sexual communication, parent-child closeness on the HIV-related knowledge, safer-sex intentions, and behaviors of late adolescent urban African American males. DESIGN: The study employed a cross-sectional design with retrospective recall of salient parental influences and behaviors. METHODS: Data were collected via paper-and-pencil questionnaire from 134 late adolescent African American males, 18 to 22 years of age, recruited from urban communities in and around Boston, Massachusetts. Data were analyzed using bivariate correlations, paired t tests, and regression modeling. FINDINGS: Young men reported greater amounts of sexual communication with mothers than fathers (p < .001). Parent-child closeness was positively correlated with amount of parent-child sexual communication with both mothers and fathers (p < .001 for both). Parent-child closeness was, in turn, associated with greater condom use self-efficacy (p < .01), less permissive sexual attitudes (p < .001), fewer sexual partners (p < .01), and less unprotected sex (p < .01). Greater amounts of parent-child sexual communication were associated with fewer sexual risk behaviors, more consistent condom use, and greater intentions to use condoms in the future. There was evidence that parental influences on sexual risk behaviors and condom use intentions were mediated through young men's condom use self-efficacy, attitudes, and beliefs. CONCLUSIONS: These findings highlight the importance of the parent-child relationship and the role of parent-child communication between parents and sons. Further studies are needed to better understand the nature of father-son communication and develop strategies to help parents communicate effectively with sons. CLINICAL RELEVANCE: Evidence has shown that African American adolescent males are more likely to engage in high-risk sexual behaviors. Understanding the sexual risk communication between African American adolescent males and their parents is important to developing strategies in reducing sexual risk behavior. PMID- 23452083 TI - Highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of diynes to sulfonimines. AB - A new asymmetric [2+2+2] cycloaddition of diynes to sulfonimines under rhodium catalysis that provides the corresponding enantioenriched 1,2-dihydropyridines in good yields is described. PMID- 23452084 TI - Perceptions and acceptability of mHealth interventions for improving patient care at a community-based HIV/AIDS clinic in Uganda: a mixed methods study. AB - Mobile technologies for health (mHealth) represents a growing array of tools being applied in diverse health care settings. mHealth interventions for improving HIV/AIDS care is a promising strategy, but its evidence base is limited. We conducted a formative research evaluation to inform the development of novel mHealth HIV/AIDS care interventions to be used by community health workers (CHWs) in Kampala, Uganda. A mixed methods formative research approach was utilized. Qualitative methods included 20 in-depth interviews (IDIs) and six focus groups with CHWs, clinic staff, and patients. Thematic analysis was performed and selected quotations used to illustrate themes. Quantitative methods consisted of a survey administered to CHWs and clinic staff, using categorical and Likert scale questions regarding current mobile phone and internet access and perceptions on the potential use of smartphones by CHWs. Qualitative results included themes on significant current care challenges, multiple perceived mHealth benefits, and general intervention acceptability. Key mHealth features desired included tools to verify CHWs' task completions, clinical decision support tools, and simple access to voice calling. Inhibiting factors identified included concerns about CHWs' job security and unrealistic expectations of mHealth capabilities. Quantitative results from 27 staff participants found that 26 (96%) did not have internet access at home, yet only 2 (7.4%) did not own a mobile phone. Likert scale survey responses (1-5, 1 = Strongly Disagree, 5 = Strongly Agree) indicated general agreement that smartphones would improve efficiency (Mean = 4.35) and patient care (4.31) but might be harmful to patient confidentiality (3.88) and training was needed (4.63). Qualitative and quantitative results were generally consistent, and, overall, there was enthusiasm for mHealth technology. However, a number of potential inhibiting factors were also discovered. Findings from this study may help guide future design and implementation of mHealth interventions in this setting, optimizing their chances for success. PMID- 23452085 TI - Editorial: recent advances on molecular improvement of bio-energy plants. PMID- 23452086 TI - Molecular dynamics simulations of yeast F1-ATPase before and after 16 degrees rotation of the gamma subunit. AB - We have recently proposed the "packing exchange mechanism" for F1-ATPase, wherein the perturbation by a substrate binding/release or an ATP hydrolysis is followed by the reorganization of the asymmetric packing structure of the alpha3beta3 complex, accompanying the gamma subunit rotation. As part of a further investigation of this rotational mechanism, we performed all-atom molecular dynamics simulations for yeast F1-ATPase both before and after a 16 degrees rotation of the gamma subunit triggered by a Pi release. We analyzed the structural fluctuations, the subunit interface interactions, and the dynamics of the relative subunit arrangements before and after the rotation. We found that with the Pi release the alphaEbetaE subunit interface becomes looser, which also allosterically makes the alphaDPbetaDP subunit interface looser. This structural communication between these interfaces takes place through a tightening of the alphaTPbetaTP subunit interface. The gamma subunit interacts less strongly with alphaDP and betaDP and more strongly with alphaTP and betaTP. After the Pi release, the tightly packed interfaces are reorganized from the interfaces around betaDP to those around betaTP, inducing the 16 degrees rotation. These results, which are consistent with the packing exchange mechanism, allow us to deduce a view of the structural change during the 40 degrees rotation. PMID- 23452087 TI - Methylenediphosphonotetrathioate: synthesis, characterization, and chemical properties. AB - Metal chelators are potential therapeutic agents for treating diseases such as Wilson's and Alzheimer's where the pathology involves an excess of metal-ions (Cu(II) and Zn(II)/Cu(II)/Fe(II/III), respectively). In addition to the high affinity of the metal-ion to the chelators, metal selectivity of the chelators is essential to achieve the therapeutic goal, that is, the successful removal of excess of harmful metal-ions in a physiological extracellular medium rich in alkali and alkali earth metal-ions. For this purpose, we synthesized a novel chelator, methylenediphosphonotetrathioate (MDPT) which is the tetrathio analogue of methylenediphosphonic acid (MDP). MDPT was synthesized from bis methylene(phosphonicdichloride) in a 3-step synthesis and a 31% overall yield. MDPT formed a stable complex with Zn(II) (log K = 10.84), which is 10(7) times more stable than the corresponding Ca(II) complex. Moreover, the MDPT-Zn(II) complex was 50-fold more stable than the MDP-Zn(II) complex. In addition, MDPT was found to inhibit the Cu(I)-catalyzed Fenton reaction (IC50 26 MUM) 2.5 times more potently than a Fe(II)-catalyzed Fenton reaction, and 2.5 times more potently than EDTA (IC50 64 MUM) in the Cu(I)/H2O2 system, as monitored by electron spin resonance (ESR). Furthermore, MDPT was found to be relatively stable in both acidic (pD 1.9, t(1/2) = 71.5 h) and basic media (pD 12.4, t(1/2) = 81 h) as monitored by (31)P/(1)H NMR. However, MDPT was not stable in air because of intramolecular oxidation and disulfide formation (33% oxidation after 27 h). In conclusion, MDPT was found to be a water-soluble chelator showing a clear preference to soft/borderline metal-ions and a remarkable selectivity to those metal-ions vs Ca(II) ions. The relative sensitivity of MDPT to oxidation may limit its use; however, the application of MDPT in acidic or basic media will increase its lifetime. PMID- 23452088 TI - beta-Adrenergic signaling promotes posteriorization in Xenopus early development. AB - Adrenaline (also known as Epinephrine) is a hormone, which works as major regulator of various biological events such stages of vertebrate, the role of adrenaline for early embryogenesis has been as heart rate, blood vessel and air passage diameters, and metabolic shifts. Although its specific receptors are expressing at the early developmental stage those functions are poorly understood. Here, we show that loss-of-functional effects of adrenergic receptor beta-2 (Adrbeta2), which was known as the major receptor for adrenaline and highly expressed in embryonic stages, led posterior defects at the tadpole stage of Xenopus embryos, while embryos injected with Adrbeta2 mRNA or treated with adrenaline hormone adversely lost anterior structures. This posteriorization effect by adrenaline hormone was dose-dependently increased but effectively rescued by microinjection of antisense morpholino oligomer for Adrbeta2 (Adrbeta2 MO). Combination of adrenaline treatments and microinjection of Adrbeta2 mRNA maximized efficiency in its posteriorizing activity. Interestingly, both gain- and loss-of-functional treatment for beta-adrenergic signaling could not influence anterior neural fate induced by overexpression of Chordin mRNA in presumptive ectodermal region, meaning that it worked via mesoderm. Taken together with these results, we conclude that adrenaline is a novel regulator of anteroposterior axis formation in vertebrates. PMID- 23452089 TI - Chemoselective hydrogenation reaction of unsaturated bonds in the presence of an o-nitrobenzenesulfonyl group. AB - Chemoselective hydrogenation of unsaturated compounds bearing an o nitrobenzenesulfonyl (Ns)-amide moiety, affording the corresponding saturated compounds, was accomplished efficiently without loss of the nitro group by using the Pd/MS3A catalyst and a H2 balloon. Partial hydrogenation of alkynes bearing an Ns group to corresponding cis alkenes was achieved with the combination of the Pd/BN catalyst and an additive (diethylenetriamine or acetic acid). PMID- 23452090 TI - Age-related skeletal muscle mass loss and physical performance in Taiwan: implications to diagnostic strategy of sarcopenia in Asia. AB - AIM: Skeletal muscle loss is a common feature of aging, and is associated with unfavorable outcomes. Although several indexes of skeletal muscle mass measurement have been developed, the most optimal index for sarcopenia diagnosis among Asian populations has remained unclear. The present study aimed to evaluate the relationship between skeletal muscle mass and physical performance among community-dwelling people in Taiwan. METHODS: Data of the I-Lan Longitudinal Aging Study (ILAS) were retrieved for study. Comparisons between demographic profiles, physical performance and skeletal muscle mass (measured by dual-energy X-ray absorptiometry) were carried out. Skeletal muscle mass expressed by lean body mass divided by squared height (LBM/ht(2) ), appendicular muscle mass divided by squared height (ASM/ht(2) ) and percent skeletal muscle index (SMI%) were compared between measurements of physical performance. RESULTS: Overall, the data of 532 participants (mean age 64.6 +/- 9.5 years, male 53.0%) were retrieved for analysis. Age was associated with poorer physical performance, and decreased ASM/ht(2) and LBM/ht(2) , but not SMI%. Skeletal muscle mass (SMI%) was less significantly related to slow walking speed than ASM/ht(2) in men. In women, all three muscle indexes showed no significant association between slow walking speed. In contrast, low handgrip strength was strongly associated with decreased skeletal muscle mass (measured by ASM/ht(2) and LBM/ht(2) , but not SMI%) in both men and women. CONCLUSIONS: Skeletal muscle mass was significantly associated with handgrip strength along with aging, but the association of skeletal muscle mass and walking speed was less significant. In sarcopenia diagnosis among Asian populations, ASM/ht(2) should be the most suitable index for skeletal muscle mass measurements, and physical performance should be measured universally beyond measurements of skeletal muscle mass. PMID- 23452091 TI - Bart syndrome. PMID- 23452092 TI - Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture. AB - Drosophila melanogaster is widely used to study genetic factors causing Parkinson's disease (PD) largely because of the use of sophisticated genetic approaches and the presence of a high conservation of gene sequence/function between Drosophila and mammals. However, in Drosophila, little has been done to study the environmental factors which cause over 90% of PD cases. We used Drosophila primary neuronal culture to study degenerative effects of a well-known PD toxin MPP(+) . Dopaminergic (DA) neurons were selectively degenerated by MPP(+) , whereas cholinergic and GABAergic neurons were not affected. This DA neuronal loss was because of post-mitotic degeneration, not by inhibition of DA neuronal differentiation. We also found that MPP(+) -mediated neurodegeneration was rescued by D2 agonists quinpirole and bromocriptine. This rescue was through activation of Drosophila D2 receptor DD2R, as D2 agonists failed to rescue MPP(+) -toxicity in neuronal cultures prepared from both a DD2R deficiency line and a transgenic line pan-neuronally expressing DD2R RNAi. Furthermore, DD2R autoreceptors in DA neurons played a critical role in the rescue. When DD2R RNAi was expressed only in DA neurons, MPP(+) toxicity was not rescued by D2 agonists. Our study also showed that rescue of DA neurodegeneration by Drosophila DD2R activation was mediated through suppression of action potentials in DA neurons. PMID- 23452093 TI - Comparative effectiveness, costs and trends in treatment of small renal masses from 2005 to 2007. AB - What's known on the subject? and what does the study add?: Retrospective data have suggested an increased survival benefit for patients undergoing partial nephrectomy compared to radical nephrectomy, possibly as a result of the avoidance of long-term renalin sufficiency and subsequent sequelae. However, recent level-one evidence has questioned this benefit. Both retrospective studies and randomized controlled trials are not without limitations. There are few population-based data available with respect to the outcomes of partial nephrectomy vs radical nephrectomy. Additionally, there are no population-based studies analyzing the surgical approach (minimally-invasive vs open), as well as other modalities, such as ablation and surveillance. Finally, there is very little information available on the potential differences in cost for each approach. The present study comprises the first comprehensive population-based analysis of the trends, outcomes and costs of all treatment modalities for T1a renal masses from 2005 to 2007. OBJECTIVE: To perform a comprehensive analysis of the outcomes and costs for treatments for small renal masses (SRM) using a population-based approach. Partial nephrectomy may be associated with improved survival, although level-one evidence has questioned this survival advantage. PATIENTS AND METHODS: Using Surveillance, Epidemiology and End Results-Medicare data, we identified 1682 subjects who were diagnosed with SRM from 2005 to 2007. Treatment included open radical nephrectomy (ORN; n = 404), minimally-invasive radical nephrectomy (MIRN; n = 535), open partial nephrectomy (OPN; n = 330), minimally-invasive partial nephrectomy (MIPN; n = 160), ablation (n = 211) and surveillance (n = 42). Postoperative complications, renal insufficiency diagnosis, overall mortality, cancer-specific mortality and postoperative costs were compared. Covariates were balanced before outcomes analysis using propensity score methods. RESULTS: Although the use of nephron-sparing surgery (NSS) increased over the study period, radical nephrectomy remained the predominant approach for SRM in 2007. Minimally-invasive approaches had shorter lengths of stay (P < 0.001), whereas open approaches had more overall complications, respiratory complications and intensive care unit admissions (all P < 0.003). MIRN and ORN were associated with more peri-operative medical complications, acute renal failure, haemodialysis use and long-term chronic renal insufficiency diagnosis vs NSS (all P < 0.001). Ablation, MIRN and ORN were associated with the highest overall mortality rates (P < 0.001), whereas MIRN and ORN were associated with the highest cancer-specific mortality rates (P < 0.001). Treatment costs were lowest for surveillance ($2911) followed by ablation ($10730), MIRN ($15373), MIPN ($15695), OPN ($16986) and ORN ($17803). CONCLUSIONS: Although not the predominant treatment approach for SRM over the study period, the use of NSS increased and was associated with improved survival, fewer complications and less renal insufficiency. Minimally-invasive approaches confer lower costs. PMID- 23452094 TI - A qualitative evaluation of a telemedicine-enhanced emergency care program for older adults. AB - OBJECTIVES: To document the experiences of patients, their caregivers, healthcare personnel, and staff members with a program that provides telemedicine-enhanced emergency care to older adults residing in senior living communities (SLCs) and to delineate perceived barriers and facilitators. DESIGN: Qualitative study. SETTING: A primary care geriatric medicine practice. PARTICIPANTS: Stakeholders associated with telemedicine visits: patients, family caregivers, telemedicine dispatcher, certified telemedicine assistants, telemedicine providers, and SLC staff. MEASUREMENTS: Between June and August 2011, telemedicine encounters were observed, and field notes were recorded. After each telemedicine visit, all participants were interviewed using a semistructured guide. Discrete statements from interviews and field notes were coded and arranged into themes. Concordance or discordance in field notes and stakeholder responses were grouped for analysis. RESULTS: After 10 telemedicine visits and 34 interviews from 21 unique participants, redundancy was achieved. Participants and their families overwhelmingly reported satisfaction with their care, remarking particularly on the convenience, speed, and completeness of the evaluation. Participants reported some unmet expectations regarding provider presence at home and visit length. Providers thought telemedicine made them more efficient overall and improved diagnostic certainty but considered in-person visits to be superior. All stakeholders, including patients, noted inadequate telemedicine technician training, leading to low confidence levels and performance difficulties. Participants, providers, and telemedicine technicians cited problems with the reliability, weight, and size of the equipment as serious challenges, decreasing their satisfaction and increasing their frustration. CONCLUSION: Telemedicine enhanced emergency care is an acceptable method of providing emergency care to older adults in SLCs. Stakeholders report a number of advantages. Training and technology barriers require particular attention. PMID- 23452095 TI - IL-27 inhibits lymphatic endothelial cell proliferation by STAT1-regulated gene expression. AB - OBJECTIVE: IL-27 belongs to the IL-12 family of cytokines and is recognized for its role in Th cell differentiation and as an inhibitor of tumor angiogenesis. The purpose of this study was to investigate the effect of IL-27 on proliferation of lymphatic endothelial cells to gain insight into the interplay between the immune system and development of the lymphatic system. METHODS: IL-27-stimulated signal transduction in human dermal lymphatic endothelial cells was measured by western blotting and synthesis of CXCL10 and CXCL11 by use of RT-PCR and ELISA. Proliferation was measured using MTT and BrdU kits and the role of STAT1 and chemokines was determined by use of siRNA and recombinant proteins. RESULTS: Stimulation of lymphatic endothelial cell cultures with IL-27 induced JAK dependent phosphorylation of STAT1 and STAT3 and inhibited lymphatic endothelial cell proliferation and migration. Expression of CXCL10 and CXCL11, both STAT1 target genes, was profoundly up-regulated upon IL-27 stimulation, and recombinant CXCL10 and CXCL11 inhibited FGF-2-induced proliferation in vitro. siRNA targeting of STAT1 almost completely abrogated CXCL10 and CXCL11 expression as well as the proliferative effect of IL-27. CONCLUSIONS: IL-27 function as an anti lymphangiogenic regulator in vitro by up-regulating chemokines and interfering with the mitogenic effect of growth factors through STAT1 activation. PMID- 23452097 TI - How avoidant attachment influences subjective well-being: an investigation about the age and gender differences. AB - Intimate relationship is a significant factor that influences older adults' subjective well-being. Avoidant attachment reflects a basic working model regarding interpersonal relationships. The current study aims to test how age and gender moderate the effect of avoidant attachment to spouse on subjective well being. Fifty-six married couples aged from 20 to 79 years in Hong Kong were recruited for the study. Their avoidant attachment to spouse and subjective well being were measured by questionnaires. In general, avoidant attachment to spouse was found to undermine subjective well-being. More importantly, age significantly moderated the negative association between avoidant attachment and subjective well-being, but the direction of the moderating effect was opposite for husbands and wives. Compared with their younger counterparts, the detrimental effect of avoidant attachment on subjective well-being was weaker for older wives but stronger for older husbands. The results suggest that marital relationship may play different roles in different life stages for the two genders. In later adulthood, males may become more dependent on the marital relationship to maintain subjective well-being, whereas females can be relatively independent. PMID- 23452096 TI - Advancing genomic research and reducing health disparities: what can nurse scholars do? AB - PURPOSE: Advances in genomic research are improving our understanding of human diseases and evoking promise of an era of genomic medicine. It is unclear whether genomic medicine may exacerbate or attenuate extant racial group health disparities. We delineate how nurse scholars could engage in the configuration of an equitable genomic medicine paradigm. ORGANIZING CONSTRUCT: We identify as legitimate subjects for nursing scholarship the scientific relevance, ethical, and public policy implications for employing racial categories in genomic research in the context of reducing extant health disparities. FINDINGS: Since genomic research is largely population specific, current classification of genomic data will center on racial and ethnic groups. Nurse scholars should be involved in clarifying how putative racial group differences should be elucidated in light of the current orthodoxy that genomic solutions may alleviate racial health disparities. CONCLUSIONS: Nurse scholars are capable of employing their expertise in concept analysis to elucidate how race is used as a variable in scientific research, and to use knowledge brokering to delineate how race variables that imply human ancestry could be utilized in genomic research pragmatically in the context of health disparities. CLINICAL RELEVANCE: In an era of genomic medicine, nurse scholars should recognize and understand the challenges and complexities of genomics and race and their relevance to health care and health disparities. PMID- 23452098 TI - Parathyroid hormone changes following denosumab treatment in postmenopausal osteoporosis. AB - OBJECTIVE: Denosumab is a new potent antiresorptive treatment of osteoporosis that can potentially induce a compensatory increase in parathyroid hormone (PTH) levels. We aimed to evaluate the alteration of PTH 1 and 6 months after denosumab's administration with different regimens of calcium and vitamin D (Ca/D) supplementation. DESIGN: Prospective, multicenter, study in a relatively small, heterogeneous sample of postmenopausal women followed for 6 months. PATIENTS: Forty seven postmenopausal women followed in 2 outpatient clinics, requiring onset or continuation of osteoporosis treatment. We administered 1 g calcium carbonate and 800 IU cholecalciferol daily for 6 months (Group A) or the double dose for the first month followed by the 1 g/800 IU Ca/D regimen for the next 5 months (Group B). MEASUREMENTS: Parathyroid hormone (PTH) alterations between and within groups, and their associations with serum Ca and bone markers. RESULTS: Parathyroid hormone (PTH) levels were significantly higher at month 1 and 6 only in Group A; Ca levels were significantly decreased at month 1 and returned to baseline values at month 6 within the same Group. The mean per cent change between month 1 and baseline for PTH [Delta(PTH1-0 )] was significantly higher in Group A than B (63.5% +/- 28.2% vs -3.0% +/- 4.7%, P = 0.029). Delta(PTH1-0 ) was correlated with the reciprocal Delta-changes of Ca (rs = 0.610; P = 0.002) and collagen type I C-terminal telopeptide (rs = -0.697; P = 0.003) only in Group A. CONCLUSIONS: An increase in PTH should be expected, at least following the first administration of denosumab in common clinical practice. The effect of this compensatory onsequence in bone metabolism warrants further investigation. PMID- 23452099 TI - Short-term clinical outcomes in delirious older patients: a study at general medical wards in a university hospital in Thailand. AB - AIM: Delirium, a common disorder in hospitalized older patients, frequently results in unfavorable consequences. Previous studies in different settings have provided conflicting results regarding clinical outcomes and mortality. We aimed to study three clinical outcomes--length of stay (LOS), in-hospital mortality and 3-month mortality--among delirious Thai older patients. METHODS: A prospective observational study was carried out in a university hospital in Thailand. All patients aged older than 70 years admitted to general medical wards were included. Delirium assessments were undertaken within the first 24 h of admission and serially until discharge. Subsequent assessments were carried out at 3 months after discharge. Delirium was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria. Factors associated with mortality were determined by using logistic regression models. RESULTS: LOS was significantly longer in the delirium group (10 and 8 days, P = 0.001). Furthermore, the delirium group had higher in-hospital and 3-month mortality (P < 0.001). Factors significantly associated with in-hospital mortality in multivariate analysis were age more than 80 years (AOR 2.74, 95% CI 1.05-7.15), malignancy (AOR 3.11, 95% CI 1.16-8.33), severe illness (AOR 3.75, 95% CI 1.38 10.20) and delirium (AOR 7.34, 95% CI 1.51-35.69). Delirium remained a strong predictor for 3-month mortality in multivariate analysis with AOR of 3.33 (95% CI 1.45-7.62) CONCLUSIONS: Delirium was associated with prolonged hospital-stay and was the strongest predictor for mortality among older hospitalized patients. It requires serious attention from physicians, healthcare administrators and policy makers to implement an appropriate management plan for this high-burden issue. PMID- 23452100 TI - Overcoming the effect of letter confusability in letter-by-letter reading: a rehabilitation study. AB - Patients who read in a letter-by-letter manner can demonstrate effects of lexical variables when reading words comprised of low confusability letters, suggesting the capacity to process low-confusability words in parallel across the letters (Fiset, Arguin, & McCabe, 2006). Here a series of experiments is presented investigating letter confusability effects in MAH, a patient with expressive and receptive aphasia who shows reduced reading accuracy with longer words, and DM, a relatively "pure" alexic patient. Two rehabilitation studies were employed: (i) a word-level therapy and (ii) a letter-level therapy designed to improve discrimination of individual letters. The word-level treatment produced generalised improvement to low-confusability words only, but the serial processing treatment produced improvement on both high and low confusability words. The results add support to the hypothesis that letter confusability plays a key role in letter-by-letter reading, and suggest that a rehabilitation method aimed at reducing ambiguities in letter identification may be particularly effective for treating letter-by-letter reading. PMID- 23452101 TI - A case of CD20-positive peripheral T-cell lymphoma treated with rituximab and multiagent chemotherapy. PMID- 23452102 TI - Septic shock: new pharmacotherapy options or better trial design? AB - INTRODUCTION: Over the last two decades, many of the mechanisms underlying the pathophysiology of sepsis have been uncovered, but this has not led to the development of effective therapies for sepsis. Despite improvements in the general care of critically ill patients in recent years, mortality rates for patients with severe sepsis and septic shock remain high at 30 to 50% and there is an urgent need to develop new, effective therapeutic strategies. AREAS COVERED: Attempts to develop a therapy for sepsis have focused on modulating this immune response. Past and present clinical research in this field are reviewed and promising candidates and approaches for the future are discussed. EXPERT OPINION: Many reasons have been put forward over the years to explain the many negative results from trials of immunomodulatory therapies. Future studies need to be designed to specifically target patients who can benefit from the intervention being studied rather than at the sepsis population in general. The timing of administration of potential therapies also needs to be taken more into consideration. PMID- 23452103 TI - Public health nursing certification exam on the verge of extinction? Act fast! PMID- 23452104 TI - Health promotores' perceptions of their communities' health needs, knowledge, and resource needs in rural Nicaragua. AB - OBJECTIVES: This study was conducted to determine rural Nicaraguan health promotores' perceptions of their community's health problems, their self identified learning needs, and resource needs. Despite the valuable contributions of promotores, there is limited research regarding unpaid volunteer promotores' perceptions of their needs in providing care to remote communities. DESIGN AND SAMPLE: A qualitative descriptive study of 13 unpaid, volunteer promotores in Waslala, Nicaragua, was conducted. MEASURES: Data were collected during individual interviews with seven promotores and two focus groups with 13 promotores. Data were analyzed by reading verbatim transcripts repeatedly and establishing general themes. Promotores confirmed the findings. RESULTS: Waslalan promotores described a synergy of traditional folk health beliefs and natural practices along with use of modern medications while working to meet the health needs of their communities. Without much formal training, the promotores used public health strategies to influence health behaviors and address health disparities in the communities they serve. Serving their communities and God were their motivation in their work. CONCLUSIONS: Recommendations include supporting efforts to meet promotores' needs regarding community health education with messages from community leaders and nurses, finding methods to financially compensate promotores, and including promotores in health program planning and evaluation. PMID- 23452105 TI - Factors influencing health behaviors of younger women after menopause-inducing cancer treatment. AB - OBJECTIVE: To investigate the health promotion and risk reduction behaviors of younger women previously treated for cancer. DESIGN AND SAMPLE: Guided by the "Precede-Proceed" framework, a mixed-method descriptive investigation of the health behaviors of younger women with cancer treatment-induced menopause in one health jurisdiction in Australia was undertaken. MEASURES: This article reports the results of the qualitative interview component of the study. RESULTS: Of the 85 women who responded to surveys that quantified their health behaviors, 22 consented to interviews that explored how and why these behaviors might occur. CONCLUSIONS: Several predisposing, enabling and reinforcing factors that influenced participants' will or ability to engage with health-promoting behaviors after cancer treatment were identified in the interviews. These include entrenched precancer diagnosis health behaviors, the disabilities resulting from cancer treatments, perceptions of risk, focused intervention by health professionals and the nature of participants' social support. The results indicate a need for flexibility when planning public health initiatives to prepare this cohort for a healthy life after cancer, which accounts for their developmental, knowledge and posttreatment needs. PMID- 23452106 TI - Sexually transmitted disease testing misconceptions threaten the validity of self reported testing history. AB - OBJECTIVE: Sexually transmitted disease (STD) testing is fundamental to STD prevention and control. We sought to comprehensively examine young women's beliefs about the STD testing process. DESIGN AND SAMPLE: Descriptive, cross sectional, survey investigation. Women aged 18-24 (n = 302) drawn from four women's health clinics and one university classroom. MEASURES: Participants completed the RoTEST, which measures five domains of women's STD testing beliefs and a demographic survey. RESULTS: Many women believed they would be screened for all STDs when they receive STD testing (40%) and that visual inspection by a provider was a valid method of STD screening for gonorrhea (35%), chlamydia (32%) and HSV (77%). More than a quarter believed that a Pap test screens for gonorrhea (23%) and chlamydia (26%). Twenty-one percent reported that discussing STD testing with a provider is difficult and most reported feeling more comfortable seeking STD testing from an STD specialist rather than a family doctor (79%). CONCLUSIONS: Young women have numerous misconceptions about the STD testing process that may interfere with the validity of their self-reported STD testing history and subsequently undermine public health efforts to improve STD prevention and control. Innovative approaches to educating women about the testing process are needed. PMID- 23452107 TI - Heavy and light/moderate smoking among building trades construction workers. AB - OBJECTIVE: The purpose of the study was to identify the correlates of heavy smoking (defined as more than one pack of cigarettes per day) in building trades construction workers. DESIGN AND SAMPLE: This study used cross-sectional data from the MassBUILT smoking cessation intervention study at Massachusetts building trades unions with the sample of 763 smokers. MEASURES: Data collected included information about smoking behavior, individual, psychological, interpersonal, and occupational factors obtained through self-reported questionnaires. RESULTS: Approximately 21% of smokers were heavy smokers. Significant factors related to heavy smoking were: older age (OR = 1.10; 95% CI: 1.06-1.14), male gender (OR = 4.55; 95% CI: 1.62-12.79), smoking the first cigarette of the day within 30 min of waking (OR = 4.62; 95% CI: 2.81-7.59), smoking initiation at earlier age (OR = 0.93; 95% CI: 0.87-1.00), higher temptation to smoke (OR = 1.55; 95% CI: 1.17 2.05), household smoking (OR = 1.90; 95% CI: 1.18-3.06) or living alone (OR = 4.11; 95% CI: 1.70-9.92), and exposure to chemicals at work (OR = 1.61; 95% CI: 1.06-2.53). CONCLUSION: Addressing the influence of these factors on heavy smoking could lead to the development of targeted, multiple components in comprehensive cessation strategies for blue-collar smokers. PMID- 23452108 TI - A nutrition education intervention for anthropometric and biochemical profiles of rural older Malays with metabolic syndrome. AB - OBJECTIVE: This study aimed to determine the effectiveness of a nutrition education intervention package in improving anthropometric, clinical and biochemical indicators of rural older Malays with metabolic syndrome (MS). DESIGN AND SAMPLE: In this study, 47 older Malays diagnosed with MS were assigned to either the intervention group (n = 24) or the control group (n = 23) based on their geographical site. INTERVENTION: The intervention group received nutrition education via group counselling sessions, talks, and cooking and exercise demonstrations using a specifically developed healthy aging package for 6 months. MEASURES: The efficacy of the nutrition education intervention on anthropometric and biochemical parameters was assessed. RESULTS: Women in the nutrition education group showed a significant reduction in waist circumference (p < .01) compared to the control group. Men who received the nutrition education intervention maintained their total cholesterol (TC) level (p < .05) compared to the control group. CONCLUSIONS: The nutrition education intervention showed potential for improving TC levels in men and waist circumference in women with MS. Similar intervention studies could be initiated among the older adults in the community as a preventive measure. PMID- 23452109 TI - The maternal self-efficacy scale for preventing early childhood diarrhea: validity and reliability. AB - OBJECTIVE: This study aimed to develop and validate a psychometric scale for preventing early childhood diarrhea in endemic areas. DESIGN AND SAMPLE: Before applying to the field, the scale was subjected to content validity by a panel of experts and piloting. The final version was applied to 448 mothers of children 0- to 5-year-olds, living in Fortaleza, northeast Brazil. Structured interviews were conducted to identify diarrheal episodes in the study children. RESULTS: Significant negative correlations were found between higher maternal self efficacy scores and previous childhood diarrhea (p = .001). In addition, positive correlations were found with maternal age (p = .018). The frequency of children (6-36 months old) with diarrhea was significantly lower when scale scores were higher (p = .015). The predictive validity revealed that high levels of maternal self-efficacy were a protective factor against childhood diarrhea. Cronbachs alpha was .84. CONCLUSIONS: The scale was found reliable. Cultural adjustments may be needed to extrapolate the scale to other endemic areas worldwide. PMID- 23452110 TI - Recruitment and retention of African American and Hispanic girls and women in research. AB - Recruiting women and girls into research studies, especially minority women, continues to be a major challenge that impacts health policy and delivery systems. This article discusses various strategies to recruit and retain African American and Hispanic girls and women in studies. Strategies for successful recruitment focus on trust, familiarity and visibility, racial and ethnic similarities, environmental context, and convenience. Retention strategies include issues of transportation, language, literacy, cultural appropriateness, safety, flexibility, incentives, communication, and veracity. All strategies assist in meeting the challenge of engaging minority women in research to decrease health disparities. PMID- 23452111 TI - Application and modification of the integrative model for environmental health. AB - The Integrative Model for Environmental Health (IMEH) has guided research, literature reviews, and practice initiatives since 2002. This article presents the Modified IMEH that was developed based on using the IMEH as a guiding conceptual framework in a community-based participatory research environmental health project. Concepts from the Model of Risk Information Seeking and Processing as well as emergent themes from the data analysis were instrumental in this process. The Modified IMEH alters the structure of the IMEH in that the Vulnerability and Epistemological Domains are more prominent and feedback between domains is included. PMID- 23452112 TI - The nurse's first visit. 1918. AB - Home visiting was an important component of the Public Health Nurse's (PHN) role in the early twentieth century. In this reprint, originally published in 1918 and reprinted in 1926, Edna Foley discusses the significance of the first visit the PHN makes to a family. Critical themes in the paper include the importance of first impressions, communication and observation skills, obtaining the statistical data needed by the agency and collaboration with other community social service agencies. Many of the themes and strategies discussed by Foley are cogent to PHNs and visiting nurses in the contemporary health care arena. PMID- 23452113 TI - Store-operated Ca2+ entry is involved in transforming growth factor-beta1 facilitated proliferation of rat airway smooth muscle cells. AB - OBJECTIVE: To investigate the role and underlying mechanisms of store-operated Ca(2+) entry (SOCE) in mediating the promoting effect of transforming growth factor (TGF)-beta1 on the proliferation of airway smooth muscle cells (ASMCs). METHODS: Rat bronchial smooth muscle cells were cultured as we described previously. The intracellular Ca(2+) concentration ([Ca(2+)]i) of ASMCs was measured by laser confocal microscope Ca(2+) fluorescence imaging with Fluo-3/AM. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and p27 expression assay were used to determine the proliferation rate of ASMCs. RESULTS: We demonstrated that TGF-beta1 (10 ng/ml) increased basal (Ca(2+)]i) level, [Ca(2+)]i rise induced by thapsigargin-induced Ca(2+) release and SOCE in rat ASMCs. This effect of TGF-beta1 on SOCE was not inhibited by glucocorticoid dexamethasone (DXM, 100 nM), antioxidant alpha-tocopherol (100 MUM), and intermediate-conductance Ca(2+)-activated K(+) channels (IKCa) inhibitor charybdotoxin (100 nM), suggesting that reactive oxygen species and IKCa channels might not mediate the effect of TGF-beta1. TGF-beta1 slightly increased the expression of Orai1 and STIM1, two important molecules involved in the molecule component and regulation of SOC channels, in the presence of 10% fetal bovine serum (FBS). The proliferation of ASMC stimulated with 2.5% FBS was promoted by TGF-beta1, and partly inhibited by non-specific Ca(2+) channel blocker SKF-96365 (10 MUM) and Ni(2+) (100 MUM). DXM, alpha-tocopherol, and charybdotoxin had no effect on the proliferation promoted by TGF-beta1. CONCLUSION: TGF-beta1 promotes ASMC proliferation partly through increasing the expression and activity of SOC channels. PMID- 23452114 TI - Transmission dynamics of pancreas disease (PD) in a Norwegian fjord: aspects of water transport, contact networks and infection pressure among salmon farms. AB - Pancreas disease (PD) in marine salmon farming is caused by salmon pancreas disease virus (SPDV). Virus survival, infection pressure and contact networks among farms influence the potential of PD to spread. The present study aims to explore contact networks and infection pressure and their ability to explain transmission dynamics of PD in a Norwegian fjord. In this study, we included all records of PD by subtype 3 (SPDV3) in the study population from the first reported in August 2006 to the last reported in November 2009. Using logistic regression analyses, we found that contact network by water transport explained better transmission of PD than contact networks defined by ownership or close distance to infected farms. Hydrodynamic modelling can be a valuable tool to forecast the spread of PD and thereby take actions to reduce the transmission. Knowing the risk of getting infected, it is important to avoid water transport from infected farms when new cohorts are transferred to sea water, and to have conscious control regarding management operations between farms. PMID- 23452115 TI - Upgrading of Gleason score and prostate volume: a clinicopathological analysis. AB - OBJECTIVE: To more clearly elucidate the association between prostate volume and Gleason score (GS) upgrading. PATIENT AND METHODS: We reviewed 451 patients with prostate cancer with a GS of 6 on biopsy, who underwent radical prostatectomy without neoadjuvant treatment. As a preoperative variable, we assessed the independent effect of prostate volume on GS upgrading. To evaluate the association between prostate volume and GS upgrading, we developed multivariate models with volumetric pathological variables, including postoperative tumour volume and percent tumour volume (tumour volume as a percentage of prostate volume). RESULTS: GS upgrading was observed in 194 patients (43.0%). As a preoperative variable, smaller prostate volume was an independent predictor of GS upgrading. In regression analysis, prostate volume and postoperative tumour volume were inversely correlated. On multivariate analysis including volumetric pathological variables, tumour volume was a strong independent factor influencing GS upgrading, and prostate volume lost statistical significance after adjusting for tumour volume. Percent tumour volume was inversely correlated with GS upgrading after adjusting for tumour volume. CONCLUSIONS: Smaller prostate volume was an independent predictor of GS upgrading as a preoperative variable. The inverse relationship between prostate volume and GS upgrading seems to be attributable to cancer biology, which was represented by tumour volume in our study. Percent tumour volume was also inversely associated with GS upgrading. These results suggest that biological factors and sampling error both play important roles in GS upgrading. PMID- 23452116 TI - Immunophenotypic profile of nucleated erythroid progenitors during maturation in regenerating bone marrow. AB - This study introduces an in-depth flow cytometric method for the analysis of nucleated erythroid progenitors during bone marrow regeneration. Initial immunophenotypic analysis with the conventional erythroid-associated markers CD36, CD71 and CD235a was supplemented with the analysis of additional markers, including CD105, CD117, CD45, CD38 and cell-scattered light characteristics. Our data show that the expression of CD105 and CD117 is critical for the distinction between four phenotypically different developmental stages of nucleated erythroid progenitors: pro-erythroblasts, basophilic erythroblasts, polychromatophilic erythroblasts and orthochromatophilic erythroblasts. CD105 antigen expression was specifically associated with pro-erythroblasts and basophilic erythroblasts, whereas CD117 was expressed at the earliest pro-erythroblast stage. Both antigens were progressively lost throughout the course of differentiation. These data allow for the identification of aberrant erythroid development in acute erythroid leukemia or myelodysplastic syndrome. PMID- 23452117 TI - Efficacy and tolerability of reduced-dose 21-day cycle rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone therapy for elderly patients with diffuse large B-cell lymphoma. AB - Rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) is regarded as the first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL), but it is often necessary to reduce the dose or prolong the intervals between doses. In our center, dose reduction is performed with elderly patients with DLBCL on an individual basis: for patients in their 70s and 80s, the initial CHOP dose is reduced to 70% and 50%, respectively, and the subsequent doses are adjusted so that the patients receive, at 21-day intervals, the highest dose they can tolerate (reduced-dose R CHOP21). To verify this practice, a retrospective analysis was performed. Between January 2004 and January 2011, 109 >= 70-year-old patients with DLBCL received reduced-dose R-CHOP21 with curative intent. The 2-year overall survival rates of the 70-79- and >= 80-year-old patients were 75.2% and 64.6%, respectively. Of 35 deaths, 20 were due to disease progression and five were related to treatment toxicity. Multivariate analysis revealed that an age of 75-79 years and an age of 80 years or older were associated with shorter survival. Given that many patients had poor performance status and comorbidities, reduced-dose R-CHOP21 may provide a reasonable balance between efficacy and tolerability for elderly patients with DLBCL. PMID- 23452118 TI - Disruption of E627 and R683 interaction is responsible for B-cell acute lymphoblastic leukemia caused by JAK2 R683G(S) mutations. AB - Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays key roles in hematopoietic and immune responses. The acquired JAK2 R683G(S) somatic mutations are detected in 15% of patients with B-cell acute lymphoblastic leukemia (B-ALL) and are presumed to be a biomarker for B-ALL. However, how JAK2 R683G(S) mutations lead to B-ALL is still unclear. Our results indicated that the E627 and R683 interaction played a vital role in JAK2 autoinhibition. Mutations (R683S, R683G and E627A) disrupting this interaction led to JAK2 constitutive activation, while mutations (R683K, E627D) restoring this interaction decreased its activity. Furthermore, spectroscopy experiments implied that disruption of the E627 and R683 interaction abolished JH1/JH2 domain interactions and forced the JH1 domain into the open, active conformation. Mutations abolishing this interaction promoted the proliferation of Ba/F3 cells. The results herein may provide clues to understanding the mechanism of JAK2 R683G(S) mutation-associated B-ALL. PMID- 23452119 TI - Combination of celecoxib and doxorubicin increases growth inhibition and apoptosis in acute myeloid leukemia cells. AB - Cyclooxygenase-2 (COX-2) inhibitors have been shown to enhance antitumor activity of therapeutic agents in a variety of solid tumor cells. However, this has not been well established in hematopoietic tumors, especially in acute myeloid leukemia (AML). This study was designed to investigate the effects of the combination of celecoxib, a specific COX-2 inhibitor, and doxorubicin on cell growth and apoptosis in human leukemia cells. Co-treatment with celecoxib and doxorubicin significantly inhibited cell growth and induced cell apoptosis in the acute leukemia cell line HL60 and primary AML cells. The growth inhibition effect was accompanied by down-regulation of the expression of cyclin E and cyclin dependent kinase 2 (CDK2), the key regulators of cell cycle progression, which was associated with arrest of cells at G0/G1 phase. The pro-apoptotic effect was accompanied by down-regulation of the expression of survivin, an inhibitor of apoptosis protein, which mediated anti-apoptosis in AML cells. These results provide the first evidence that the growth inhibitory and pro-apoptotic effects of celecoxib and doxorubicin on AML cells are synergistic. PMID- 23452120 TI - Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells. AB - Aging of an organism is associated with the functional decline of tissues and organs, as well as a sharp decline in the regenerative capacity of stem cells. A prevailing view holds that the aging rate of an individual depends on the ratio of tissue attrition to tissue regeneration. Therefore, manipulations that favor the balance towards regeneration may prevent or delay aging. Skeletal muscle is a specialized tissue composed of postmitotic myofibers that contract to generate force. Satellite cells are the adult stem cells responsible for skeletal muscle regeneration. Recent studies on the biology of skeletal muscle and satellite cells in aging have uncovered the critical impact of systemic and niche factors on stem cell functionality and demonstrated the capacity of aged satellite cells to rejuvenate and increase their regenerative potential when exposed to a youthful environment. Here we review the current literature on the coordinated relationship between cell extrinsic and intrinsic factors that regulate the function of satellite cells, and ultimately determine tissue homeostasis and repair during aging, and which encourage the search for new anti-aging strategies. PMID- 23452121 TI - Adipose-derived mesenchymal stem cells and regenerative medicine. AB - Adipose tissue-derived mesenchymal stem cells (ADSCs) are multipotent and can differentiate into various cell types, including osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic beta-cells, and hepatocytes. Compared with the extraction of other stem cells such as bone marrow derived mesenchymal stem cells (BMSCs), that of ADSCs requires minimally invasive techniques. In the field of regenerative medicine, the use of autologous cells is preferable to embryonic stem cells or induced pluripotent stem cells. Therefore, ADSCs are a useful resource for drug screening and regenerative medicine. Here we present the methods and mechanisms underlying the induction of multilineage cells from ADSCs. PMID- 23452122 TI - Chitosan and platelet-derived growth factor synergistically stimulate cell proliferation in gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Chitosan is a naturally derived polymer that may be applied in periodontal therapy for tissue-reconstruction purposes. Previous studies have shown that chitosan may stimulate tissue healing. However, reports exploring the cellular responses stimulated by chitosan are lacking. In the present study we analyzed whether chitosan may promote cell proliferation in primary cultures of human gingival fibroblasts. MATERIAL AND METHODS: Chitosan particles were generated, and their size, zeta potential and morphology were characterized using transmission and scanning electron microscopy and zetasizer analysis. The biocompatibility of chitosan particles was analyzed using the 3 (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium (MTS) cell-viability assay and by detecting the release of lactate dehydrogenase into the cell-culture medium. The total number of cells was estimated by staining with crystal violet followed by measurement of the absorbance at 560 nm on a microplate reader. Cell proliferation was studied by detecting proliferating cell nuclear antigen protein levels, immunofluorescence for Ki67 and incorporation of 5'-bromo-2'-deoxyuridine. RESULTS: The sizes of the chitosan particles generated were in the micrometer and nanometer ranges. Cell viability was increased in the presence of chitosan. Moreover, the combination of chitosan and platelet-derived growth factor (PDGF-BB) potently stimulated cell viability, cell proliferation and activation of the ERK1/2 pathway involved in cell proliferation. CONCLUSIONS: The present study shows that chitosan is well tolerated by gingival fibroblasts and is able to stimulate cell proliferation through the ERK1/2 signaling pathway. A synergistic response between chitosan and growth factors (such as PDGF-BB) may stimulate cell proliferation in gingival fibroblasts exposed to this biomaterial. PMID- 23452123 TI - Larval settlement and metamorphosis of the mussel Mytilus coruscus in response to monospecific bacterial biofilms. AB - The effects of bacterial biofilms (BFs) on larval settlement and metamorphosis of the mussel, Mytilus coruscus, were investigated in the laboratory. Of nine different isolates, Shewanella sp.1 BF induced the highest percentage of larval settlement and metamorphosis, whereas seven other isolates had a moderate inducing activity and one isolate, Pseudoalteromonas sp. 4, had a no inducing activity. The inducing activity of individual bacterial isolates was not correlated either with their phylogenetic relationship or with the surfaces from which they were isolated. Among the eight bacterial species that demonstrated inducing activity, bacterial density was significantly correlated with the inducing activity for each strain, with the exception of Vibrio sp. 1. The Shewanella sp. 1 BF cue that was responsible for inducing larval settlement and metamorphosis was further investigated. Treatment of the BFs with formalin, antibiotics, ultraviolet irradiation, heat, and ethanol resulted in a significant decrease in their inducing activities and cell survival. BF-conditioned water (CW) did not induce larval metamorphosis, but it triggered larval settlement behavior. A synergistic effect of CW with formalin-fixed Shewanella sp. 1 BF significantly promoted larval metamorphosis. Thus, a cocktail of chemical cues derived from bacteria may be necessary to stimulate larval settlement and metamorphosis in this species. PMID- 23452124 TI - Mechanism and specificity of an acyltransferase domain from a modular polyketide synthase. AB - Acyltransferase (AT) domains of modular polyketide synthases exercise tight control over the choice of alpha-carboxyacyl-CoA substrates, but the mechanistic basis for this specificity is unknown. We show that whereas the specificity for the electrophilic malonyl or methylmalonyl component is primarily expressed in the first half-reaction (formation of the acyl-enzyme intermediate), the second half-reaction shows comparable specificity for the acyl carrier protein that carries the nucleophilic pantetheine arm. We also show that currently used approaches for engineering AT domain specificity work mainly by degrading specificity for the natural substrate rather than by enhancing specificity for alternative substrates. PMID- 23452125 TI - Editorial: Technologies in meat traceability, authenticity and safety. PMID- 23452126 TI - Ketyl radical cyclization of beta-disubstituted acrylates: formal syntheses of (+)-secosyrin 1 and longianone and the total synthesis of (+)-4-epi-secosyrin 1. AB - A novel approach to the synthesis of a series of 1,7-dioxaspirononanes that applies a ketyl radical cyclization strategy is described. Radical cyclization of the beta-disubstituted acrylate 23, prepared in five steps from (R)-1,2 isopropylideneglycerol, gives both 2,3-syn- and 2,3-anti-furan products. The densely functionalized furan heterocycles are used to complete a concise formal synthesis of secosyrin 1, a metabolite of Pseudomonas syringae, and the total synthesis of 4-epi-secosyrin 1. PMID- 23452128 TI - Electronic health records in an occupational health setting-Part II. Global deployment. AB - Electronic medical record systems are being used by more multi-national corporations. This article describes one corporation's considerations and process in successfully deploying a global electronic medical record system to international facilities in Brazil, Mexico, Singapore, and Taiwan. This article summarizes feedback from the experiences of occupational health nurse superusers in these countries. PMID- 23452127 TI - Body mass index, change in body mass index, and survival in old and very old persons. AB - OBJECTIVES: To examine how body mass index (BMI) and change in BMI are associated with mortality in old (70-79) and very old (>=80) individuals. DESIGN: Pooled data from three multidisciplinary prospective population-based studies: OCTO twin, Gender, and NONA. SETTING: Sweden. PARTICIPANTS: Eight hundred eighty-two individuals aged 70 to 95. MEASUREMENTS: BMI was calculated from measured height and weight as kg/m(2) . Information about survival status and time of death was obtained from the Swedish Civil Registration System. RESULTS: Mortality hazard was 20% lower for the overweight group than the normal-underweight group (relative risk (RR) = 0.80, P = .011), and the mortality hazard for the obese group did not differ significantly from that of the normal-underweight group (RR = 0.93, P = .603), independent of age, education, and multimorbidity. Furthermore, mortality hazard was 65% higher for the BMI loss group than for the BMI stable group (RR = 1.65, P < .001) and 53% higher for the BMI gain group than for the BMI stable group (RR = 1.53, P = .001). Age moderated the BMI change differences. That is, the higher mortality risks associated with BMI loss and gain were less severe in very old age. CONCLUSION: Old persons who were overweight had a lower mortality risk than old persons who were of normal weight, even after controlling for weight change and multimorbidity. Persons who increased or decreased in BMI had a greater mortality risk than those who had a stable BMI, particularly those aged 70 to 79. This study lends further support to the belief that the World Health Organization guidelines for BMI are overly restrictive in old age. PMID- 23452129 TI - Respirators and surgical masks-exploring the differences. AB - Filtering facepiece respirators (FFRs) and surgical masks may appear similar in design, but are quite different. When worker protection from inhalation hazards is necessary, a respirator, not a surgical mask, must be selected. For FFRs to protect wearers, however, wearers must be trained in wearing and using them properly, determine they fit by being fit tested, perform a user seal check each time FFRs are put on, and be medically evaluated to ensure they are physically able to wear FFRs while working. PMID- 23452130 TI - Psychosocial stress and multi-site musculoskeletal pain: a cross-sectional survey of patient care workers. AB - The aim of this study was to assess the relationship between psychosocial factors at work and multi-site musculoskeletal pain among patient care workers. In a survey of 1,572 workers from two hospitals, occupational psychosocial factors and health outcomes of workers with single and multi-site pain were evaluated using items from the Job Content Questionnaire that was designed to measure psychological demands, decision latitude, and social support. An adapted Nordic Questionnaire provided data on the musculoskeletal pain outcome. Covariates included body mass index, age, gender, and occupation. The analyses revealed statistically significant associations between psychosocial demands and multi site musculoskeletal pain among patient care associates, nurses, and administrative personnel, both men and women. Supervisor support played a significant role for nurses and women. These results remained statistically significant after adjusting for covariates. These results highlight the associations between workplace psychosocial strain and multi-site musculoskeletal pain, setting the stage for future longitudinal explorations. PMID- 23452132 TI - Diabetic foot examination. AB - The 60-second tool (2012)((c)) uses a cost-effective, simple, standardized approach to identifying, in a timely fashion, which individuals are at high risk for diabetic foot complications. Using this tool, occupational health nurses can screen for diabetic foot complications in varied clinical settings. PMID- 23452133 TI - Recommendations for thromboprophylaxis in the 2012 focused update of the ESC guidelines on atrial fibrillation: a commentary. AB - The objective of this article is to provide a commentary on the recommendations for stroke prevention from the 2012 focused update of the European Society of Cardiology guidelines on the management of atrial fibrillation and the evidence (or lack of it) supporting these recommendations. These guidelines strongly advocate a major clinical practice shift towards initially focusing on the identification of 'truly low risk' patients who do not need any antithrombotic therapy. After this initial decision-making step, effective stroke prevention - that is, oral anticoagulation therapy (whether as well-controlled adjusted dose warfarin or with one of the novel oral anticoagulants) - could be offered to patients with atrial fibrillation with >= 1 stroke risk factors. The 2012 focused update guideline also provides additional guidance on advances in stroke and bleeding risk assessment that are evident since publication of the 2010 guideline, as well as recommendations on the use of the novel oral anticoagulants and the left atrial appendage occlusion devices that have been increasingly used in European clinical practice over the last 2 years. PMID- 23452134 TI - The elegant ellipse-running subcuticular closures. PMID- 23452135 TI - Glucocorticoid-induced osteoporosis: lessons from Cushing's syndrome. AB - Glucocorticoid-induced osteoporosis (GIO) is the most frequent form of secondary bone disorders. Most of our knowledge on its pathogenesis and treatment has been obtained by investigating patients treated with exogenous glucocorticoids. This review will focus on the bone disorder in endogenous Cushing's syndrome, updating recent advances in its pathophysiology, diagnostic aspects and the various predictors which are important in determining bone mineral density (BMD) and fracture risk. We now know strong evidence that beside BMD, bone microarchitecture, one of the most important elements of bone quality, is a key factor in determining fracture risk. Recently, two new methods (spinal deformity index and trabecular bone score) have been shown to be useful markers of bone microarchitecture in GIO. Investigations of GIO in endogenous Cushing's syndrome have also contributed to our understanding on its natural history and reversibility. Relying on recently published guidelines for management of exogenous GIO, a short list of suggestions is provided regarding the optimal diagnostic and therapeutic approach to patients with endogenous GIO. PMID- 23452136 TI - Examining an emotion enhancement effect in working memory: evidence from age related differences. AB - The aim of the present study was to examine age-related differences between young, young-old and old-old adults in an affective version of the classical Working Memory Operation Span Test. The affective version of the Working Memory Operation Span Test included neutral words (as in the classical version) as well as negative and positive ones. Results showed that while young adults performed better than the young-old and old-old with neutral words, age-related differences between young and young-old with positive words were no longer significant, and age-related differences were nullified with negative ones. Altogether, results indicate that emotional words can reduce age-related decline when maintenance and manipulation of information in working memory in older adults are required. PMID- 23452137 TI - Medication adherence: is it a hidden drug-related problem in hidden elderly? AB - AIM: The present study aimed to identify the health needs of the hidden elderly in Hong Kong, and to investigate the impacts of pharmacist and nursing interventions on medication management and well-being in hidden elderly. METHODS: Participants were recruited by social workers if they were aged 65 years or older; did not have normal social life and network; did not have family support; and were not linked to the existing network of community support. Pharmacists identified drug-related problems. The health needs of participants were assessed by observations and interviews. Outcome measurements were scores of Morisky 8 item Medication Adherence Scale and EuroQoL (Quality of Life) 5-D Questionnaire. RESULTS: A total of 93 participants were recruited and 86 participants completed the study. The mean age was 81.46 +/- 5.70 years, the mean number of chronic disease was 3.29 +/- 1.45 and the mean number of chronic medications was 6.36 +/- 2.96. The most commonly observed chronic diseases were hypertension, cardiac problems, diabetes, hyperlipidemia and arthritis. Drug non-adherence and storage problems were found in 61.63% and 69.77% of participants. The mean total EuroQoL score increased by 1.05 (P <= 0.001). The mean Morisky score decreased by 0.61, signifying improvement of medication adherence (P< 0.001). Female sex (P = 0.045), polypharmacy with more than nine concurrent medications (P = 0.013), arthritis (P = 0.006) and drug storage problems (P = 0.002) were identified as factors associated with poor medication adherence. CONCLUSIONS: The majority of hidden elderly suffered from multiple chronic diseases, and the prevalence of drug-related problems was high. Pharmacist and nursing interventions improved drug-related problems, drug compliance and quality of life in hidden elderly. PMID- 23452138 TI - Synthesis of gold hexagonal bipyramids directed by planar-twinned silver triangular nanoprisms. AB - The direct growth of planar-twinned Au nanoparticles (NPs) in high yield remains a challenge in shape-controlled NP synthesis largely because suitable planar twinned seeds for Au NP growth have not been identified to date. Herein we describe the use of planar-twinned Ag triangular nanoprisms as a means to dictate Au NP twin structure. In a one-pot process, the Ag triangular nanoprisms first undergo oxidative Au replacement, forming Ag-Au alloy nanoframes and concomitantly releasing Ag(+) into solution, which then directs subsequent Au NP growth through an underpotential deposition process. The planar-twinned structure of the initial Ag nanoprism is maintained throughout particle growth. Using this method, we have successfully synthesized Au hexagonal bipyramids in high yield for the first time. PMID- 23452139 TI - Eltrombopag in patients with chronic liver disease. AB - INTRODUCTION: Thrombocytopenia may represent a barrier to optimal management of chronic liver disease patients undergoing invasive procedures, or who need to be treated with interferon-based antiviral therapy. Eltrombopag is a thrombopoietic drug that acts upon binding thrombopoietin receptor and stimulates megakaryocytopoiesis and platelet production. AREAS COVERED: A summary of the preclinical studies and of studies carried out in patients with chronic liver disease with eltrombopag are presented in this paper. Data are based on abstracts from journal articles and international conferences found in a PubMed search of literature published up to November 2012. EXPERT OPINION: Eltrombopag has shown to be capable of reducing the need for platelet transfusion in thrombocytopenic patients with advanced liver disease undergoing invasive procedures and help increase the sustained virological response rate to interferon-based antiviral therapy in patients with chronic hepatitis C who were poor candidates to treatment because of thrombocytopenia. In chronic liver disease patients, the possible benefits of eltrombopag administration should be accurately weighed against the adverse events profile of the drug due to possible concerns regarding the occurrence of thromboembolic events and the potential for decompensation of chronic liver disease. PMID- 23452140 TI - Usefulness of high-frequency sonography for the diagnosis of asymptomatic myopathy in Lofgren's syndrome. PMID- 23452142 TI - The role of tissue Doppler imaging in predicting left ventricular filling pressures in patients undergoing cardiac surgery: an intraoperative study: can we use transesophageal echocardiography in predicting the left ventricular filling pressures? PMID- 23452143 TI - Reply: To PMID 23190400. PMID- 23452146 TI - Occurrence and source of chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs) in tidal flats of the Ariake Bay, Japan. AB - In this study, we hypothesize that natural photochemical reactions of polycyclic aromatic hydrocarbons (PAHs) in tidal flats are responsible for the occurrence of chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs). This study aims to survey the impact of photochemical reactions using a combination of field surveys and lab-scale experiments. Concentrations and profiles of PAHs and Cl-PAHs in road dust and sediments collected from seven tunnels and two watersheds, respectively, were determined. In the lab-scale experiments, anthracene was irradiated with ultraviolet (UV) light under various salinity conditions. No detectable Cl-PAHs were found in the road dust. However, Cl-PAHs were detected in the sediments from 700 to 6.1 * 10(3) pg g(-1) and specifically from downstream sites. 2 Monochloroanthracene (2-Cl-ANT) and 9,10-dichloroanthracene (9,10-di-Cl-ANT) were dominant in the sediments. In the Domen River watershed, the ?Cl-PAHs and the salinity showed a significant positive correlation (p < 0.01) in the sediments, while such a correlation was not found for PAHs. 2-Cl-ANT, 9 monochloroanthracene, and 9,10-di-Cl-ANT were identified as transformation products in the UV irradiation experiments. Production of these Cl-PAHs was dependent on the solution salinity. These results support our hypothesis, and we conclude that photochemical reactions significantly contribute to the occurrence of Cl-PAHs in the studied tidal flats. PMID- 23452147 TI - Autoprocessing mechanism of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CLpro) from its polyproteins. AB - Like many other RNA viruses, severe acute respiratory syndrome coronavirus (SARS CoV) produces polyproteins containing several non-structural proteins, which are then processed by the viral proteases. These proteases often exist within the polyproteins, and are excised by their own proteolytic activity ('autoprocessing'). It is important to investigate the autoprocessing mechanism of these proteases from the point of view of anti-SARS-CoV drug design. In this paper, we describe a new method for investigating the autoprocessing mechanism of the main protease (M(pro)), which is also called the 3C-like protease (3CL(pro)). Using our method, we measured the activities, under the same conditions, of the mature form and pro-forms with the N-terminal pro-sequence, the C-terminal pro sequence or both pro-sequences, toward the pro-form with both N- and C-terminal pro-sequences. The data indicate that the pro-forms of the enzyme have proteolytic activity, and are stimulated by the same proteolytic activity. The stimulation occurs in two steps, with approximately eightfold stimulation by N terminal cleavage, approximately fourfold stimulation by C-terminal cleavage, and 23-fold stimulation by the cleavage of both termini, compared to the pro-form with both the N- and C-terminal pro-sequences. Such cleavage mainly occurs in a trans manner; i.e. the pro-form dimer cleaves the monomeric form. The stimulation by N-terminal pro-sequence removal is due to the cis (intra-dimer and inter protomer) effect of formation of the new N-terminus, whereas that by C-terminal cleavage is due to removal of its trans (inter-dimer) inhibitory effect. A numerical simulation of the maturation pathway is presented. PMID- 23452148 TI - Effect of remote ischaemic preconditioning on renal protection in patients undergoing laparoscopic partial nephrectomy: a 'blinded' randomised controlled trial. AB - OBJECTIVE: To evaluate whether remote ischaemic preconditioning (RIPC) reduces renal injury in patients undergoing laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS: In all, 82 patients undergoing LPN were randomly assigned to either the RIPC or control group, with 40 and 38 patients, respectively completing 6-months follow-up. RIPC was conducted after induction of anaesthesia, which consisted of three 5-min cycles of right lower limb ischaemia and 5 min of reperfusion during each cycle. The primary outcome was the absolute change in glomerular filtration rate (GFR) of the affected kidney by renal scintigraphy from baseline to 6 months. The secondary outcomes included urinary retinol binding protein (RBP) levels measured at 24 and 48 h, serum creatinine, and estimated GFR (eGFR) at 1 and 6 months, and changes in GFR by renal scintigraphy. RESULTS: There were no differences in the change of GFR of the affected kidney at 6 months, while it was significantly decreased by 15.0% in the control group vs 8.8% in the RIPC group at 1 month (P = 0.034). The urinary RBP levels increased 8.4-fold at 24 h in the control group compared with a lower increase of 3.9-fold in the RIPC group (P < 0.001). There were no differences in the serum creatinine level or eGFR at 1 and 6 months between the two groups. CONCLUSIONS: In patients undergoing LPN, RIPC using transient lower limb ischaemia may reduce renal impairment in the short term, but failed in the longer term despite a non significant trend in favour of RIPC. These novel data support the need for a larger study of RIPC during LPN surgery. PMID- 23452149 TI - The influence of leaf-atmosphere NH3(g ) exchange on the isotopic composition of nitrogen in plants and the atmosphere. AB - The distribution of nitrogen isotopes in the biosphere has the potential to offer insights into the past, present and future of the nitrogen cycle, but it is challenging to unravel the processes controlling patterns of mixing and fractionation. We present a mathematical model describing a previously overlooked process: nitrogen isotope fractionation during leaf-atmosphere NH3(g ) exchange. The model predicts that when leaf-atmosphere exchange of NH3(g ) occurs in a closed system, the atmospheric reservoir of NH3(g ) equilibrates at a concentration equal to the ammonia compensation point and an isotopic composition 8.10/00 lighter than nitrogen in protein. In an open system, when atmospheric concentrations of NH3(g ) fall below or rise above the compensation point, protein can be isotopically enriched by net efflux of NH3(g ) or depleted by net uptake. Comparison of model output with existing measurements in the literature suggests that this process contributes to variation in the isotopic composition of nitrogen in plants as well as NH3(g ) in the atmosphere, and should be considered in future analyses of nitrogen isotope circulation. The matrix-based modelling approach that is introduced may be useful for quantifying isotope dynamics in other complex systems that can be described by first-order kinetics. PMID- 23452150 TI - Phylogeography and adaptation genetics of stickleback from the Haida Gwaii archipelago revealed using genome-wide single nucleotide polymorphism genotyping. AB - Threespine stickleback populations are model systems for studying adaptive evolution and the underlying genetics. In lakes on the Haida Gwaii archipelago (off western Canada), stickleback have undergone a remarkable local radiation and show phenotypic diversity matching that seen throughout the species distribution. To provide a historical context for this radiation, we surveyed genetic variation at >1000 single nucleotide polymorphism (SNP) loci in stickleback from over 100 populations. SNPs included markers evenly distributed throughout genome and candidate SNPs tagging adaptive genomic regions. Based on evenly distributed SNPs, the phylogeographic pattern differs substantially from the disjunct pattern previously observed between two highly divergent mtDNA lineages. The SNP tree instead shows extensive within watershed population clustering and different watersheds separated by short branches deep in the tree. These data are consistent with separate colonizations of most watersheds, despite underlying genetic connections between some independent drainages. This supports previous suppositions that morphological diversity observed between watersheds has been shaped independently, with populations exhibiting complete loss of lateral plates and giant size each occurring in several distinct clades. Throughout the archipelago, we see repeated selection of SNPs tagging candidate freshwater adaptive variants at several genomic regions differentiated between marine freshwater populations on a global scale (e.g. EDA, Na/K ATPase). In estuarine sites, both marine and freshwater allelic variants were commonly detected. We also found typically marine alleles present in a few freshwater lakes, especially those with completely plated morphology. These results provide a general model for postglacial colonization of freshwater habitat by sticklebacks and illustrate the tremendous potential of genome-wide SNP data sets hold for resolving patterns and processes underlying recent adaptive divergences. PMID- 23452152 TI - External validation of a risk model of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma. AB - Febrile neutropenia (FN) is a common and serious complication of chemotherapy treatment. Clinical risk models may help to identify patients at high risk of FN but must undergo external validation before implementation in medical practice. Therefore, this study externally validated previously published clinical models of FN occurrence during chemotherapy in 240 patients with non-Hodgkin lymphoma by using an independent observational dataset (n = 1829). The models demonstrated predictive ability, and validation criteria for predicting any cycle of FN were partially met but a larger than expected decrease in performance was noted (area under the receiver operating characteristic curve was 0.71 in the validation dataset and 0.83 in the training dataset). Age, weight, baseline white blood cell count and planned chemotherapy parameters were confirmed to predict FN risk. Chemotherapy dose reductions, dose delays and colony-stimulating factor use were confirmed as risk modifiers during treatment. Further work is needed to improve the predictive ability of FN risk models. PMID- 23452151 TI - GA101 induces NK-cell activation and antibody-dependent cellular cytotoxicity more effectively than rituximab when complement is present. AB - Both complement and antibody-dependent cellular cytotoxicity (ADCC) contribute to the clinical efficacy of anti-CD20 monoclonal antibody (mAb) therapy. Paradoxically, the C3b component of complement can block interaction between mAb and natural killer (NK) cells. The present study compared the effect of complement on the ability of two anti-CD20 mAbs, rituximab and GA101, to activate NK cells and mediate ADCC. Complement blocked adherence of NK cells to rituximab, but had little effect on NK binding to GA101. Target cells coated with rituximab or GA101 were able to activate NK cells in the absence of serum. Complement in serum blocked NK activation induced by rituximab, but not GA101. Complement blocked rituximab-induced NK-cell mediated ADCC, but not GA101-induced ADCC. These results demonstrate that the decreased ability of GA101 to fix complement relative to rituximab results in an enhanced ability of GA101 to bind to NK cells, activate NK cells and induce ADCC when serum is present. PMID- 23452153 TI - On the adaptive significance of circadian clocks for their owners. AB - Circadian rhythms are believed to be an evolutionary adaptation to daily environmental cycles resulting from Earth's rotation about its axis. A trait evolved through a process of natural selection is considered as adaptation; therefore, rigorous demonstration of adaptation requires evidence suggesting evolution of a trait by natural selection. Like any other adaptive trait, circadian rhythms are believed to be advantageous to living beings through some perceived function. Circadian rhythms are thought to confer advantage to their owners through scheduling of biological functions at appropriate time of daily environmental cycle (extrinsic advantage), coordination of internal physiology (intrinsic advantage), and through their role in responses to seasonal changes. So far, the adaptive value of circadian rhythms has been tested in several studies and evidence indeed suggests that they confer advantage to their owners. In this review, we have discussed the background for development of the framework currently used to test the hypothesis of adaptive significance of circadian rhythms. Critical examination of evidence reveals that there are several lacunae in our understanding of circadian rhythms as adaptation. Although it is well known that demonstrating a given trait as adaptation (or setting the necessary criteria) is not a trivial task, here we recommend some of the basic criteria and suggest the nature of evidence required to comprehensively understand circadian rhythms as adaptation. Thus, we hope to create some awareness that may benefit future studies in this direction. PMID- 23452155 TI - Towards a further understanding of childhood dystonia. PMID- 23452154 TI - Computational, structural, and kinetic evidence that Vibrio vulnificus FrsA is not a cofactor-independent pyruvate decarboxylase. AB - The fermentation-respiration switch (FrsA) protein in Vibrio vulnificus was recently reported to catalyze the cofactor-independent decarboxylation of pyruvate. We now report quantum mechanical/molecular mechenical calculations that examine the energetics of C-C bond cleavage for a pyruvate molecule bound within the putative active site of FrsA. These calculations suggest that the barrier to C-C bond cleavage in the bound substrate is 28 kcal/mol, which is similar to that estimated for the uncatalyzed decarboxylation of pyruvate in water at 25 degrees C. In agreement with the theoretical predictions, no pyruvate decarboxylase activity was detected for recombinant FrsA protein that could be crystallized and structurally characterized. These results suggest that the functional annotation of FrsA as a cofactor-independent pyruvate decarboxylase is incorrect. PMID- 23452156 TI - Effect of ozone therapy on autogenous bone graft healing in calvarial defects: a histologic and histometric study in rats. AB - AIM: The purpose of this study was to analyze histologically the effect of ozone therapy in combination with autogenous bone graft on bone healing in rat calvaria. METHODS: Critical size defects were created in calvaria of 27 male Wistar rats. The animals were divided into three groups of nine animals each: autogenous bone graft group (n = 9); autogenous bone graft with ozone therapy group (80%, 30 s 3 d for 2 wk, n = 9); non-treatment (control) group (n = 9). Animals were killed after 8 wk. Histomorphometric assessments, using image analysis software, and histological analyses were performed. Primary outcome was total bone area. Secondary outcomes (osteoblast number, new bone formation) were also measured. RESULTS: Histomorphometrically, the total bone area in the autogenous bone graft with ozone therapy group (9.3 +/- 2.2) were significantly higher than that of the autogenous bone graft group (5.1 +/- 1.8) (p < 0.05). Also, the ozone therapy group significantly increased the percentage of total bone area compared to the autogenous bone graft group (p < 0.05). The osteoblast number significantly increased in the autogenous bone graft with the ozone therapy group (58 +/- 12.3) compared to the autogenous bone graft group (9.3 +/- 3.5) (p < 0.05). Also, it was observed that autogenous bone graft with ozone therapy group showed significant new bone formation when compared to the autogenous bone graft group (p < 0.05). CONCLUSION: Ozone therapy enhances new bone formation by autogenous bone graft in the rat calvarial defect model. PMID- 23452157 TI - Lentiginous mosaicism and mosaic generalized neurofibromatosis type 1. PMID- 23452158 TI - Plastics and priority pollutants: a multiple stressor in aquatic habitats. PMID- 23452159 TI - Species-area relationships and extinctions caused by habitat loss and fragmentation. AB - The species-area relationship (SAR) has been used to predict the numbers of species going extinct due to habitat loss, but other researchers have maintained that SARs overestimate extinctions and instead one should use the endemics-area relationship (EAR) to predict extinctions. Here, we employ spatially explicit simulations of large numbers of species in spatially heterogeneous landscapes to investigate SARs and extinctions in a dynamic context. The EAR gives the number of species going extinct immediately after habitat loss, but typically many other species have unviable populations in the remaining habitat and go extinct soon afterwards. We conclude that the EAR underestimates extinctions due to habitat loss, the continental SAR (with slope ~0.1 or somewhat less) gives a good approximation of short-term extinctions, while the island SAR calculated for discrete fragments of habitat (with slope ~0.25) predicts the long-term extinctions. However, when the remaining area of land-covering habitat such as forest is roughly less than 20% of the total landscape and the habitat is highly fragmented, all current SARs underestimate extinction rate. We show how the 'fragmentation effect' can be incorporated into a predictive SAR model. When the remaining habitat is highly fragmented, an effective way to combat the fragmentation effect is to aggregate habitat fragments into clusters rather than to place them randomly across the landscape. PMID- 23452160 TI - Finite element analysis of the meniscectomised tibio-femoral joint: implementation of advanced articular cartilage models. AB - The article presents advanced computer simulations aimed at the accurate modelling of human tibio-femoral joints (TFJs) in terms of anatomy, physiological loading and constitutive behaviour of the tissues. The main objective of this research is to demonstrate the implications that the implementation of different articular cartilage models have on the prediction of the joint response. Several biphasic material constitutive laws are tested using a finite element package and compared to the monophasic linear elastic description, often still used to predict the instantaneous response of the cartilage in 3D knee models. Thus, the importance of adequately capturing the contribution of the interstitial fluid support is proved using a simplified 3D model; subsequently, a biphasic poroviscoelastic non-linear constitutive law is implemented to study the response of a patient-specific TFJ subjected to simplified walking cycles. The time evolution of stresses, pore pressure, contact areas and joint displacements is captured and compared with existing meniscectomised knee models. Contact pressures and areas obtained using the developed numerical simulations are in agreement with the existing experimental evidence for meniscectomised human knee joints. The results are then used to predict the most likely site for the origin of mechanical damage, i.e. the medial cartilage surface for the specific case analysed in the present contribution. Finally, future research directions are suggested. PMID- 23452161 TI - Successful treatment of complex traumatic and surgical wounds with a foetal bovine dermal matrix. AB - A foetal bovine dermal repair scaffold (PriMatrix, TEI Biosciences) was used to treat complex surgical or traumatic wounds where the clinical need was to avoid skin flaps and to build new tissue in the wound that could be reepithelialised from the wound margins or closed with a subsequent application of a split thickness skin graft (STSG). Forty-three consecutive cases were reviewed having an average size of 79.3 cm(2) , 50% of which had exposed tendon and/or bone. In a subset of wounds (44.7%), the implantation of the foetal dermal collagen scaffold was also augmented with negative pressure wound therapy (NPWT). Complete wound healing was documented in over 80% of the wounds treated, whether the wound was treated with the foetal bovine dermal scaffold alone (95.2%) or when supplemented with NPWT (82.4%). The scaffold successfully incorporated into wounds with exposed tendon and/or bone to build vascularised, dermal-like tissue. The new tissue in the wound supported STSGs however, in the majority of the cases (88.3%); wound closure was achieved through reepithelialisation of the incorporated dermal scaffold by endogenous wound keratinocytes. The foetal bovine dermal repair scaffold was found to offer an effective alternative treatment strategy for definitive closure of challenging traumatic or surgical wounds on patients who were not suitable candidates for tissue flaps. PMID- 23452163 TI - Gut microbiota and non-alcoholic fatty liver disease: new insights. AB - Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. A 'two-hit' mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. PMID- 23452162 TI - Iron oxide magnetic nanoparticles highlight early involvement of the choroid plexus in central nervous system inflammation. AB - Neuroinflammation during multiple sclerosis involves immune cell infiltration and disruption of the BBB (blood-brain barrier). Both processes can be visualized by MRI (magnetic resonance imaging), in multiple sclerosis patients and in the animal model EAE (experimental autoimmune encephalomyelitis). We previously showed that VSOPs (very small superparamagnetic iron oxide particles) reveal CNS (central nervous system) lesions in EAE which are not detectable by conventional contrast agents in MRI. We hypothesized that VSOP may help detect early, subtle inflammatory events that would otherwise remain imperceptible. To investigate the capacity of VSOP to reveal early events in CNS inflammation, we induced EAE in SJL mice using encephalitogenic T-cells, and administered VSOP prior to onset of clinical symptoms. In parallel, we administered VSOP to mice at peak disease, and to unmanipulated controls. We examined the distribution of VSOP in the CNS by MRI and histology. Prior to disease onset, in asymptomatic mice, VSOP accumulated in the choroid plexus and in spinal cord meninges in the absence of overt inflammation. However, VSOP was undetectable in the CNS of non-immunized control mice. At peak disease, VSOP was broadly distributed; we observed particles in perivascular inflammatory lesions with apparently preserved glia limitans. Moreover, at peak disease, VSOP was prominent in the choroid plexus and was seen in elongated endothelial structures, co-localized with phagocytes, and diffusely disseminated in the parenchyma, suggesting multiple entry mechanisms of VSOP into the CNS. Thus, using VSOP we were able to discriminate between inflammatory events occurring in established EAE and, importantly, we identified CNS alterations that appear to precede immune cell infiltration and clinical onset. PMID- 23452164 TI - Prospective association of 25(OH)D with metabolic syndrome. AB - CONTEXT: Vitamin D may play a role in the aetiology of the metabolic syndrome (MetS), yet the majority of previous studies have been cross-sectional, and the limited number of prospective studies has yielded inconsistent results. OBJECTIVE: To examine the prospective association of vitamin D [25-hydroxyvitamin D, 25(OH)D] with MetS in a multi-ethnic cohort of adults in Ontario, Canada. DESIGN: Nondiabetic individuals with pre-existing MetS risk factors were recruited for participation in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, a longitudinal study of the determinants of insulin resistance and MetS. METHODS: Of the 654 participants enrolled at baseline, 489 attended a 3-year follow-up visit. There were 301 participants eligible for the analysis of 25(OH)D with incident MetS (age 49.2 +/- 9.3 years old, 75.4% female), after excluding 188 (38.5%) prevalent MetS cases at baseline. Longitudinal change in MetS components was assessed in the entire follow-up cohort. RESULTS: There were 76 (15.5%) participants who developed MetS over the 3 years of follow-up. Multivariate logistic regression analyses indicated a decreased risk of MetS at follow-up per standard deviation increase in baseline 25(OH)D after adjustment for sociodemographics, season, baseline and change in supplement use and physical activity and insulin resistance (OR = 0.63, 95% CI 0.44-0.90). Multivariate linear regression analyses revealed a significant inverse association of baseline 25(OH)D with fasting glucose at follow-up (beta = -0.0005, P = 0.025). CONCLUSIONS: There was a significant inverse association of baseline 25(OH)D with incident MetS, which may be partly driven by its association with glucose homoeostasis. PMID- 23452165 TI - Sympatric diversification vs. immigration: deciphering host-plant specialization in a polyphagous insect, the stolbur phytoplasma vector Hyalesthes obsoletus (Cixiidae). AB - The epidemiology of vector transmitted plant diseases is highly influenced by dispersal and the host-plant range of the vector. Widening the vector's host range may increase transmission potential, whereas specialization may induce specific disease cycles. The process leading to a vector's host shift and its epidemiological outcome is therefore embedded in the frameworks of sympatric evolution vs. immigration of preadapted populations. In this study, we analyse whether a host shift of the stolbur phytoplasma vector, Hyalesthes obsoletus from field bindweed to stinging nettle in its northern distribution range evolved sympatrically or by immigration. The exploitation of stinging nettle has led to outbreaks of the grapevine disease bois noir caused by a stinging nettle-specific phytoplasma strain. Microsatellite data from populations from northern and ancestral ranges provide strong evidence for sympatric host-race evolution in the northern range: Host-plant associated populations were significantly differentiated among syntopic sites (0.054 < F(HT) < 0.098) and constant over 5 years. While gene flow was asymmetric from the old into the predicted new host race, which had significantly reduced genetic diversity, the genetic identity between syntopic host-race populations in the northern range was higher than between these populations and syntopic populations in ancestral ranges, where there was no evidence for genetic host races. Although immigration was detected in the northern field bindweed population, it cannot explain host-race diversification but suggests the introduction of a stinging nettle-specific phytoplasma strain by plant-unspecific vectors. The evolution of host races in the northern range has led to specific vector-based bois noir disease cycles. PMID- 23452166 TI - Ureteroscopic management of upper tract urothelial carcinoma (UTUC) in patients with Lynch Syndrome (hereditary nonpolyposis colorectal cancer syndrome). AB - OBJECTIVES: To report our experience with ureteroscopic laser ablation of upper tract urothelial carcinoma (UTUC) in patients with Lynch Syndrome (LS), as defined by a documented germline mutation in the MSH-2 gene. To increase awareness among urologists about UTUC in this unique patient population and refer to genetic counselling when appropriate. PATIENTS AND METHODS: Demographic, clinical and pathological data on 13 consecutive patients with UTUC and documented MSH-2 mutation comprising 15 involved renal units were retrospectively collected. Ureteroscopic evaluations involved biopsy and laser treatment with combination holmium/neodymium yttrium aluminum garnet (YAG) lasers. Tumours were graded from 1 to 3 according to the 1973 World Health Organisation classification by a single pathologist evaluating cell block preparations. RESULTS: The mean patient age at initial presentation was 56.5 years, with six of 13 patients having metachronous bilateral UT disease. The mean follow-up was 59 months with a mean number of surveillances of 12. Of 15 affected renal units, 10/15 (67%) of initial tumours involved the ureter with mean lesion size of 17.5 mm, while five of 15 (33%) involved the intrarenal collecting system with mean lesion size of 25 mm. Ureteroscopy cleared 13/15 (87%) lesions and four of those 13 (31%) needed staged procedures. Renal preservation rate was 14/15 (93%) with one nephroureterectomy and one segmental ureterectomy performed. One patient developed metastatic UTUC after 40 months surveillance. No patient presented with bladder tumours but seven of the 13 (54%) developed them within 10 months of the initial ureteroscopy. CONCLUSIONS: Patients with LS who develop UTUC present at younger ages and appear to be more likely to have bilateral UT disease over their lifetimes vs sporadic UTUC patients. Ureteroscopic laser ablation offers a good renal preservation rate with reasonable cancer control in patients willing to undergo endoscopic surveillance. Development of new bladder tumours is common. PMID- 23452168 TI - Cu-catalyzed multicomponent polymerization to synthesize a library of poly(N sulfonylamidines). AB - We report a versatile Cu-catalyzed multicomponent polymerization (MCP) technique that enables the synthesis of high-molecular-weight, defect-free poly(N sulfonylamidines) from monomers of diynes, sulfonyl azides, and diamines. Through a series of optimizations, we discovered that the addition of excess triethylamine and the use of N,N'-dimethylformamide as a solvent are key factors to ensure efficient MCP. Formation of cyclic polyamidines was a side reaction during polymerization, but it was readily controlled by using diynes or diamines with long or rigid moieties. In addition, this polymerization is highly selective for three-component reactions over click reactions. The combination of the above factors enables the synthesis of high-molecular-weight polymers, which was challenging in previous MCPs. All three kinds of monomers (diynes, sulfonyl azides, and diamines) are readily accessible and stable under the reaction conditions, with various monomers undergoing successful polymerization regardless of their steric and electronic properties. Thus, we synthesized various high molecular-weight, defect-free polyamidines from a broad range of monomers while overcoming the limitations of previous MCPs, such as low conversion and defects in the polymer structures. PMID- 23452167 TI - Challenges of antibiotic prescribing for assisted living residents: perspectives of providers, staff, residents, and family members. AB - OBJECTIVES: To better understand the antibiotic prescribing process in assisted living (AL) communities given the growing rate of antibiotic resistance. DESIGN: Cross-sectional survey. SETTING: Four AL communities in North Carolina. PARTICIPANTS: Assisted living residents who received antibiotics (n = 30) from October 20, 2010, to March 31, 2011, a primary family member, staff, and the prescribing medical provider. MEASUREMENTS: Semistructured interviews that were conducted regarding prescribing included the information available at the time of prescribing and the perceptions of the quality of communication between providers, staff, residents and family members about the resident. Providers were asked an open-ended question regarding how to improve the communication process related to antibiotic prescribing for AL residents. RESULTS: For the 30 residents who received antibiotic prescriptions, providers often had limited information about the case and lacked familiarity with the residents, the residents' families, and staff. They also felt that cases were less severe and less likely to require an antibiotic than did residents, families, and staff. Providers identified several ways to improve the communication process, including better written documentation and staff and family presence. CONCLUSION: In a small sample of AL communities, providers faced an array of challenges in making antibiotic prescribing decisions. This work confirms the complex nature of antibiotic prescribing in AL communities and indicates that further work is needed to determine how to improve the appropriateness of antibiotic prescribing. PMID- 23452169 TI - Construction of octaalkyl-substituted and decasubstituted all-cis-octatetraenes via linear dimerization of 1,4-dicopper-1,3-butadienes and subsequent cross coupling with halides. AB - Lithium iodide-assisted linear dimerization of 1,4-dicopper-1,3-butadienes and subsequent Pd-catalyzed cross-coupling reaction with halides provide an efficient way to construct octaalkyl-substituted and decasubstituted all-cis octatetraenes. PMID- 23452170 TI - Equilibrium theory-based analysis of nonlinear waves in separation processes. AB - Different areas of engineering, particularly separation process technology, deal with one-dimensional, nonstationary processes that under reasonable assumptions, namely negligible dispersion effects and transport resistances, are described by mathematical models consisting of systems of first-order partial differential equations. Their behavior is characterized by continuous or discontinuous composition (or thermal) fronts that propagate along the separation unit. The equilibrium theory (i.e., the approach discussed here to determine the solution to these model equations) predicts this with remarkable accuracy, despite the simplifications and assumptions. Interesting applications are in adsorption, chromatography and ion-exchange, distillation, gas injection, heat storage, sedimentation, precipitation, and dissolution waves. We show how mathematics can enlighten the engineering aspects, and we guide the researcher not only to reach a synthetic understanding of properties of fundamental and applicative interest but also to discover new, unexpected, and fascinating phenomena. The tools presented here are useful to teachers, researchers, and practitioners alike. PMID- 23452171 TI - CO2 mineralization-bridge between storage and utilization of CO2. AB - CO2 mineralization comprises a chemical reaction between suitable minerals and the greenhouse gas carbon dioxide. The CO2 is effectively sequestered as a carbonate, which is stable on geological timescales. In addition, the variety of materials that can be produced through mineralization could find applications in the marketplace, which makes implementation of the technology more attractive. In this article, we review recent developments and assess the current status of the CO2 mineralization field. In an outlook, we briefly describe a few mineralization routes, which upon further development have the potential to be implemented on a large scale. PMID- 23452172 TI - Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature: a reply to a rebuttal. PMID- 23452173 TI - Comment on degradation of ascorbic acid in ethanolic solutions. PMID- 23452174 TI - Cinacalcet hydrochloride for the treatment of hyperparathyroidism. AB - INTRODUCTION: Effective therapeutic strategies are warranted to reduce the burden of parathyroid hormone excess related morbidity and mortality. The calcimimetic agent cinacalcet hydrochloride is a promising treatment strategy in hyperparathyroidism. AREAS COVERED: This review provides an overview of the pharmacokinetics, clinical efficacy, cost-effectiveness, safety and the efficacy profile of cinacalcet in the setting of primary and secondary hyperparathyroidism (p/sHPT). The authors searched PubMed database for English language articles related to cinacalcet in human subjects, published till Dec 2012 - focusing on the period between 2008 and 2012. EXPERT OPINION: The use of cinacalcet in pHPT can be considered on those hypercalcemic patients in whom parathyroidectomy is not performed. However, data on the impact of cinacalcet on hard clinical outcomes in pHPT are missing. Despite effective improvements of biochemical parameters of sHPT, the intention-to-treat-based analysis of the EVOLVE trial did not support the notion that cinacalcet significantly reduces the risk of death or major cardiovascular events in dialysis patients with moderate-to-severe sHPT. Considering the strong evidence indicating beneficial effects of cinacalcet in the setting of HPT, further randomized controlled trials are definitely warranted to evaluate whether calcimimetic treatment might improve mortality and cardiovascular risk in patients with parathyroid hormone excess over a broad spectrum of kidney function. PMID- 23452175 TI - Combination treatment of CO2 fractional laser, pulsed dye laser, and triamcinolone acetonide injection for refractory keloid scars on the upper back. AB - Keloids and hypertrophic scars are common lesions, which typically present as a cosmetic concern; however, they also can cause significant pruritus and pain. These lesions pose as a particular therapeutic challenge among clinicians due to a lack of complete knowledge of the formation of keloids and hypertrophic scars. Multiple treatments are widely accepted, yet all have shown limited benefit. In this case, we describe the treatment combination of the Affirm CO2 fractional laser (10 600 nm, Cynosure), Cynergy Pulsed dye laser (585 nm, Cynosure), and triamcinolone acetonide injection for keloids refractory to solitary treatments of triamcinolone acetonide injection and other laser modalities. PMID- 23452176 TI - Therapeutic efficacy of endoscopic retrograde cholangiopancreatography among pregnant women with severe acute biliary pancreatitis. AB - OBJECTIVE: To explore the feasibility of endoscopic retrograde cholangiopancreatography (ERCP) in pregnant women with severe acute biliary pancreatitis. SUBJECTS AND METHODS: In total, 24 pregnant patients with severe acute biliary pancreatitis were enrolled in our study between January 2003 and January 2008. Emergency ERCP and endoscopic nasobiliary drainage (ENBD) without fluoroscopy were performed successfully in all 24 patients within 12-72 hours of admission. Once stabilized, 15 patients in late pregnancy underwent a second ERCP with fluoroscopy to remove common bile duct (CBD) stones after pregnancy termination. Nine patients in early or mid-pregnancy continued gestating and underwent endoscopic retrograde biliary drainage (ERBD) with a second ERCP without fluoroscopy, and their stents and CBD stones were removed during a third ERCP with fluoroscopy 1 week after parturition. RESULTS: Among the mothers, all 24 patients were cured, and none of them died. The CBD stones in all 24 patients were completely removed with a two-step ERCP, and no serious post-ERCP complications occurred, although 2 patients had mild hemorrhage in the final ERCP to remove CBD stones. No recurrent pancreatitis or cholangitis occurred in patients who underwent ERBD. Among the infants, all survived without developmental problems or abnormality. Twenty infants were born at term; four infants were born prematurely at 35-37 weeks of gestation without developmental problems or complications. CONCLUSIONS: Emergency ERCP and ENBD without fluoroscopy in pregnant women with severe acute biliary pancreatitis are feasible and safe for both mothers and infants. It is also appropriate to remove CBD stones with two-step ERCP in pregnant women according to the stage of pregnancy. PMID- 23452177 TI - Starch metabolism and antiflorigenic signals modulate the juvenile-to-adult phase transition in Arabidopsis. AB - The physiology and genetics underlying juvenility is poorly understood. Here, we exploit Arabidopsis as a system to understand the mechanisms that regulate floral incompetence during juvenility. Using an experimental assay that allows the length of juvenility to be estimated and mutants impaired in different pathways, we show that multiple inputs influence juvenility. Juvenile phase lengths of wild type (WT) accessions Col-0, Ler-0 and Ws-4 are shown to differ, with Col-0 having the shortest and Ws-4 the longest length. Plants defective in sugar signalling [gin1-1, gin2-1, gin6 (abi4)] and floral repressor mutants [hst1, tfl1, tfl2 (lhp1)] showed shortened juvenile phase lengths compared to their respective WTs. Mutants defective in starch anabolism (adg1-1, pgm1) and catabolism (sex1, sex4, bam3) showed prolonged juvenile phase lengths compared to Col-0. Examination of diurnal metabolite changes in adg1-1 and sex1 mutants indicates that their altered juvenile phase length may be due to lack of starch turnover, which influences carbohydrate availability. In this article, we propose a model in which a variety of signals including floral activators and repressors modulate the juvenile-to-adult phase transition. The role of carbohydrates may be in their capacity as nutrients, osmotic regulators, signalling molecules and/ or through their interaction with phytohormonal networks. PMID- 23452178 TI - Surgical management of recurrent cervical sialoceles in four dogs. AB - Recurrent cervical sialoceles were diagnosed in four dogs associated with inadequate excision of the sublingual gland. Three dogs were managed by resection of the remnants of the sublingual gland via an oral approach. One dog was managed through a ventral approach as identification of the sublingual gland was not possible with the oral approach. The outcome was favourable in all cases and no relapses were detected after a median follow-up time of 10 months. PMID- 23452179 TI - Development of a generic fidelity measure for rehabilitation intervention research for children with physical disabilities. AB - AIM: To increase research rigour and create a plausible way to assess clinical effectiveness, it is necessary to measure the degree to which interventions are delivered as intended (fidelity). Generic fidelity measures enable evaluation of more than one intervention through observation of unique and general characteristics relevant across interventions. This study describes the first generic fidelity measure in paediatrics. METHOD: Items were constructed from multiple sources to create a general attributes domain and two paediatric cerebral palsy (CP) intervention-specific domains. After a pre-testing procedure, raters were trained and videos of clinical interventions were rated to test the measure's psychometric properties. RESULTS: The Paediatric Rehabilitation Observational measure of Fidelity (PROF) consisted of 30 items. Six raters were trained on the PROF and rated 25 videos. Internal consistency (alpha) and interrater reliability (IRR) for the frequency scale showed the following results: context therapy: alpha=0.71, IRR=0.75; child therapy: alpha=0.85, IRR=0.87; and general attributes; alpha=0.78, IRR=0.82. Quality scale scores across domains demonstrated internal consistency greater than 0.80 and interrater reliability of less than 0.40. Pearson's correlations (r=-0.71, p<0.001) and analyses of variance (p=0.01) validated that each intervention domain was an independent construct. INTERPRETATION: The PROF is reliable and valid for evaluating interventions used for children with CP. Future studies may use the measure's framework, general attributes domain, and procedures to test the psychometric properties of other interventions. PMID- 23452181 TI - Unilateral pigmented purpuric dermatosis associated with deep thrombosis. PMID- 23452180 TI - PCBs and OH-PCBs in serum from children and mothers in urban and rural U.S. communities. AB - East Chicago, Indiana is a heavily industrialized community bisected by the Indiana Harbor and Ship Canal, which volatilizes ~7.5 kg/yr polychlorinated biphenyls (PCBs). In contrast, the rural Columbus Junction, Iowa area has no known current or past PCB industrial sources. Blood from children and their mothers from these communities were collected April 2008 to January 2009 (n = 177). Sera were analyzed for all 209 PCBs and 4 hydroxylated PCBs (OH-PCBs). Sum PCBs ranged from nondetect to 658 ng/g lw (median = 33.5 ng/g lw). Sum OH-PCBs ranged from nondetect to 1.2 ng/g fw (median = 0.07 ng/g fw). These concentrations are similar to those reported in other populations without high dietary PCB intake. Differences between the two communities were subtle. PCBs were detected in more East Chicago mothers and children than Columbus Junction mothers and children, and children from East Chicago were enriched in lower molecular weight PCBs. East Chicago and Columbus Junction residents had similar levels of total and individual PCBs and OH-PCBs in their blood. Concentrations of parent PCBs correlated with concentrations of OH-PCBs. This is the first temporally and methodologically consistent study to evaluate all 209 PCBs and major metabolites in two generations of people living in urban and rural areas of the United States. PMID- 23452182 TI - Aldo-keto reductase and sorbitol dehydrogenase enzymes in Egyptian diabetic patients with and without proliferative diabetic retinopathy. AB - BACKGROUND: Activation of the polyol pathway due to increased aldo-keto reductase (AKR) activity has been implicated in the development of diabetic complications, including proliferative diabetic retinopathy (PDR); however, the relationship between hyperglycaemia-induced activation of the polyol pathway in the retina and PDR is still uncertain. METHODS: This study was conducted on 73 individuals, who were categorised into three groups: healthy individuals as normal control (15 age matched subjects), diabetic patients treated with oral hypoglycaemic drugs (OHD, 34 patients), six of whom (17.7 per cent) were diagnosed with PDR and the rest were diagnosed with non-proliferative diabetic retinopathy (NPDR) and diabetic patients treated with insulin (INS, 24 patients), 12 of whom (50 per cent) were diagnosed with PDR and the rest had NPDR. RESULTS: The AKR level in diabetic subjects showed a significant increase compared with the normal controls. Interestingly, AKR levels were significantly increased in the INS compared with the OHD group. Also the AKR level was significantly increased in the patients with proliferative compared with the non-proliferative retinopathy in both the insulin and oral diabetic groups. The sorbitol dehydrogenase (SDH) level in diabetic patients showed a significant decrease compared with the normal control level. Interestingly, the SDH level was significantly decreased in the INS compared with the OHD group. Also, the SDH level was significantly decreased in patients with proliferative compared with non-proliferative retinopathy in both INS and OHD groups. The HbA(1c) level in both INS and OHD subjects showed a significant increase compared with normal controls. In addition, the triglyceride level in insulin proliferative retinopathy showed a significant increase compared with other groups. CONCLUSIONS: The AKR level was significantly increased in patients with proliferative compared with non-proliferative retinopathy in both insulin and oral diabetic groups. The SDH level was significantly decreased in patients with proliferative compared with non-proliferative retinopathy in both insulin and oral diabetic groups. Both AKR and SDH could be used as indicators for diabetic control. PMID- 23452183 TI - Location-dependent intracellular particle tracking using a cell-based coordinate system. AB - Intracellular structure and active processes have been studied by particle tracking using the motion of internalised probes. Intracellular particle motion is driven by a complex combination of active and thermal processes within heterogeneous and dynamically changing micro-environments. Regions in the cells may react differently to environmental changes or following treatment, exhibiting location-dependent responses. Hence, to reveal such responses, we introduce cell specific polar coordinate systems. The coordinates are defined for each cell by its nucleus location and orientation, providing relative particle locations in the cytoplasm. The utility of our approach is demonstrated by comparing Adenosine Triphosphate (ATP)-depleted and control cells. In both cells, we observe differences in particle transport with the distance from the nucleus. Following ATP depletion, basic particle motion analysis shows an expected reduction in activity driving particle transport. However, it is our location-dependent approach which reveals that while morphology changes primarily at the cortex, the cell response is actually nearly uniform across the cytoplasm. PMID- 23452184 TI - Parasite consumption and host interference can inhibit disease spread in dense populations. AB - Disease dynamics hinge on parasite transmission among hosts. However, canonical models for transmission often fit data poorly, limiting predictive ability. One solution involves building mechanistic yet general links between host behaviour and disease spread. To illustrate, we focus on the exposure component of transmission for hosts that consume their parasites, combining experiments, models and field data. Models of transmission that incorporate parasite consumption and foraging interference among hosts vastly outperformed alternatives when fit to experimental data using a zooplankton host (Daphnia dentifera) that consumes spores of a fungus (Metschnikowia bicuspidata). Once plugged into a fully dynamic model, both mechanisms inhibited epidemics overall. Foraging interference further depressed parasite invasion and prevalence at high host density, creating unimodal (hump-shaped) relationships between host density and these indices. These novel results qualitatively matched a unimodal density prevalence relationship in natural epidemics. Ultimately, a mechanistic approach to transmission can reveal new insights into disease outbreaks. PMID- 23452185 TI - 1,3,4-thiadiazole and its derivatives: a review on recent progress in biological activities. AB - The 1,3,4-thiadiazole nucleus is one of the most important and well-known heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents. Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents. The broad and potent activity of thiadiazole and their derivatives has established them as pharmacologically significant scaffolds. In this study, an attempt has been made with recent research findings on this nucleus, to review the structural modifications on different thiadiazole derivatives for various pharmacological activities. PMID- 23452186 TI - Obesity, non-alcoholic fatty liver disease, and atherothrombosis: a role for the intestinal microbiota? AB - Whereas the association between intestinal microorganisms and health has been widely accepted in the area of infectious disease, recent advances have now implied a role for the intestinal microbiota in human energy balance. In fact, numerous studies support an intricate relationship between the intestinal microbiota and obesity, as well as subsequent insulin resistance and non alcoholic fatty liver disease. Intestinal microorganisms also seem to be involved in haemostatic tone and atherogenesis. However, as most of the findings stem from observational data, intervention studies in humans using interventions selectively aimed at altering the composition and activity of the intestinal microbiota are crucial to prove causality. If substantiated, this could open the arena for modulation of the intestinal microbiota as a future target in obesity associated disease, both as a diagnostic test for personalized algorithms and for selective therapeutic strategies. PMID- 23452188 TI - Novel software for quantitative evaluation and graphical representation of masticatory efficiency. AB - Blending of chewing gums of different colours is used in the clinical setting, as a simple and reliable means for the assessment of chewing efficiency. However, the available software is difficult to use in an everyday clinical setting, and there is no possibility of automated classification of the patient's chewing ability in a graph, to facilitate visualisation of the results and to evaluate potential chewing difficulties. The aims of this study were to test the validity of ViewGum - a novel image analysis software for the evaluation of boli derived from a two-colour mixing ability test - and to establish a baseline graph for the representation of the masticatory efficiency in a healthy population. Image analysis demonstrated significant hue variation decrease as the number of chewing cycles increased, indicating a higher degree of colour mixture. Standard deviation of hue (SDHue) was significantly different between all chewing cycles. Regression of the log-transformed values of the medians of SDHue on the number of chewing cycles showed a high statistically significant correlation (r2 = 0.94, P < 0.01). ViewGum eliminates drawbacks of previous two-colour chewing gum test methods by the simplicity of its application. The newly developed ViewGum software provides speed, ease of use and immediate extraction of clinically useful conclusions to the already established method of chewing efficiency evaluation and is a valid adjunct for the evaluation of masticatory efficiency with two-colour chewing gum. PMID- 23452187 TI - Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guerin (BCG): results of an international individual patient data survey (IPDS). AB - OBJECTIVES: To examine the management of intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC), particularly with regard to the use of bacillus Calmette-Guerin (BCG) therapy, in North America and Europe. To compare NMIBC management practices to European Association of Urology (EAU) and American Urological Association (AUA) guideline recommendations for the management of intermediate- and high-risk NMIBC. PATIENTS AND METHODS: In all, 102 urologists from Europe and North America participated in this retrospective on-line chart review, which was conducted between 1 April 2011 and 30 April 2012. Participants selected the charts of the first 10 intermediate- (defined as multiple or recurrent low-grade tumours) or high-risk (defined as any T1 and/or high-grade/G3 tumours and/or carcinoma in situ) patients who underwent transurethral resection of bladder tumour in 2009. Physicians retrospectively reviewed the charts and completed an on-line survey consisting of questions related to diagnosis, planned treatment, treatment status and follow-up. In all, 971 patients (197 intermediate risk; 774 high-risk) were included in the analysis; frequency counts and associated percentages were used to analyse treatment variables. RESULTS: In all, 47% of intermediate-risk patients received EAU or AUA guideline-recommended intravesical therapy: intravesical chemotherapy, BCG induction therapy or BCG induction plus maintenance. Of the high-risk patients, 50% received maintenance BCG as recommended by the EAU and the AUA; although not recommended for high-risk NMIBC, 12.5% received intravesical chemotherapy. Of patients prescribed maintenance BCG, 93% were scheduled for at least 1 year of therapy. Notably, only 15% discontinued BCG maintenance and, of these discontinuations, 65% were due to reasons unrelated to BCG-associated adverse events. CONCLUSIONS: There is significant non-adherence to EAU and AUA guideline recommendations for BCG use in intermediate- and high-risk NMIBC. However, most of those patients prescribed BCG maintenance therapy are scheduled for at least 1 year of therapy, as recommended by current guidelines for NMIBC management, and BCG maintenance discontinuation is low. PMID- 23452189 TI - Effects of the aromatic substitution pattern in cation-pi sandwich complexes. AB - A computational study investigating the effects of the aromatic substitution pattern on the structure and binding energies of cation-pi sandwich complexes is reported. The correlation between the binding energies (Ebind) and Hammett substituent constants is approximately the same as what is observed for cation-pi half-sandwich complexes. For cation-pi sandwich complexes where both aromatics contain substituents the issue of relative conformation is a possible factor in the strength of the binding; however, the work presented here shows the Ebind values are approximately the same regardless of the relative conformation of the two substituted aromatics. Finally, recent computational work has shown conflicting results on whether cation-pi sandwich Ebind values (Ebind,S) are approximately equal to twice the respective half-sandwich Ebind values (Ebind,HS), or if cation-pi sandwich Ebind,S values are less than double the respective half-sandwich Ebind,HS values. The work presented here shows that for cation-pi sandwich complexes involving substituted aromatics the Ebind,S values are less than twice the respective half-sandwich Ebind,HS values, and this is termed nonadditive. The extent to which the cation-pi sandwich complexes investigated here are nonadditive is greater for B3LYP calculated values than for MP2 calculated values and for sandwich complexes with electron-donating substituents than those with electron-withdrawing groups. PMID- 23452190 TI - Women with pre-existing diabetes under the care of diabetes specialist prior to pregnancy: are their outcomes better? AB - In this retrospective study, pregnant women with type 1 diabetes under the care of diabetes specialists pre-conception were found to have better glycaemic control and pregnancy outcomes than those not under specialist care prior to pregnancy. These differences were not seen in women with type 2 diabetes. The study showed that tight glycaemic control in women with pre-existing diabetes was associated with better pregnancy outcomes, and we believe women with type 1 diabetes should be managed by a diabetes specialist before pregnancy. PMID- 23452191 TI - Thermal adaptation and acclimation of ectotherms from differing aquatic climates. AB - To elucidate the mechanisms of thermal adaptation and acclimation in ectothermic aquatic organisms from differing climates, we used a common-garden experiment for thermal stress to investigate the heat shock response of redband trout (Oncorhynchus mykiss gairdneri) from desert and montane populations. Evidence for adaptation was observed as expression of heat shock genes in fish from the desert population was more similar to control (unstressed) fish and significantly different (P <= 0.05) from those from the montane population, while F1 crosses were intermediate. High induction of heat shock proteins (Hsps) in the montane strain appeared to improve short-term survival during first exposure to high water temperatures, but high physiological costs of Hsp production may have led to lower long-term survival. In contrast, the desert strain had significantly lower heat shock response than the montane fish and F1 crosses, suggesting that these desert fish have evolved alternative mechanisms to deal with thermal stress that provide better balance of physiological costs. Genomewide tests of greater than 10 000 SNPs found multiple SNPs that were significantly associated with survival under thermal stress, including Hsp47 which consistently appeared as a strong candidate gene for adaption to desert climates. Candidate SNPs identified in this study are prime targets to screen more broadly across this species' range to predict the potential for adaptation under scenarios of climate change. These results demonstrate that aquatic species can evolve adaptive responses to thermal stress and provide insight for understanding how climate change may impact ectotherms. PMID- 23452192 TI - Embedding plasmonic nanostructure diodes enhances hot electron emission. AB - When plasmonic nanostructures serve as the metallic counterpart of a metal semiconductor Schottky interface, hot electrons due to plasmon decay are emitted across the Schottky barrier, generating measurable photocurrents in the semiconductor. When the plasmonic nanostructure is atop the semiconductor, only a small percentage of hot electrons are excited with a wavevector permitting transport across the Schottky barrier. Here we show that embedding plasmonic structures into the semiconductor substantially increases hot electron emission. Responsivities increase by 25* over planar diodes for embedding depths as small as 5 nm. The vertical Schottky barriers created by this geometry make the plasmon induced hot electron process the dominant contributor to photocurrent in plasmonic nanostructure-diode-based devices. PMID- 23452193 TI - Think before you flush! A sustainable aquatic eco-system's relation to human health. AB - What we do every day at work and in our home lives can make a difference in the quality of our environment. Consider, for example, the flushing of pharmaceuticals into the sewer system can lead to water pollution resulting in a threat to aquatic and human life. In contrast, keeping aquatic life healthy may contribute to human health. Some aquatic-based medications are currently on the market. Others are in various stages of development. In this article the authors argue that, for the benefit of both human and marine life, it is time to implement safer disposal methods for unwanted medications. The authors begin by sharing nursing's guiding principles for environmental health; after which they review research related to pharmaceutical pollution of water resources; describe health care treatments derived from marine life; and discuss suggestions for promoting aquatic health. They conclude that by taking care to preserve aquatic life, we contribute to the quality of our own human lives. PMID- 23452194 TI - Nursing shortage: the facts and strategies in Macao society. AB - Historically, Macao, a Special Administrative Region (SAR) in the People's Republic of China, has been troubled by a shortage of nurses. This shortage became especially severe during the period immediately after the handover of Macao from Portugal to the People's Republic of China in 1999. A fast-growing population, an aging population, the risk of epidemics, and competition for personnel with other industries have all contributed to this shortage. In recent years, Macao has implemented the following successful strategies to address the shortage: increased school enrollments, benefits, and professional development, along with the development of a clinical specialist program, a transition program for new graduates, and training for more certified nursing assistants. Strong government support and collaboration among all stakeholders have also served to enhance the nursing work force. In this article, the authors describe the nursing shortage in Macao SAR, discuss factors contributing to the shortage, and present strategies used to manage the shortage. They conclude by emphasizing the importance of increasing salary and professional status and providing transition programs for new graduates. PMID- 23452195 TI - Facilitating change among nursing assistants in long term care. AB - In this article, the authors consider the implementation of change in long term care organizations (LTCOs) and present their study describing the process by which new nursing assistants are informally integrated into LTCOs in Quebec, Canada. The study method included 23 in-depth interviews with nursing assistants in two long term care centres. The findings enabled the authors to describe the informal process by which new nursing assistants are integrated into LTCOs and the manner in which informal work strategies enhance the work of nursing care, thus enabling the nursing assistants to manage heavy workloads. The authors discuss whether this teamwork is a deterrent to change or a lever for change and address issues regarding the collective structure of nursing assistant teams. Implications for practice include a Five-Step Innovation Plan. In conclusion, the authors propose that organizational change among nursing assistants in a LTCO is best accomplished when the leaders consider the nursing assistants' strong sense of community to be a change engine rather than a change obstacle. PMID- 23452196 TI - Ethics: the Patient Protection and Affordable Care Act: ethical perspectives in 21st century health care. PMID- 23452197 TI - Workplace violence prevention policies in home health and hospice care agencies. AB - Workplace violence in the home health industry is a growing concern, but little is known about the content of existing workplace violence prevention programs. The authors present the methods for this study that examined workplace violence prevention programs in a sample of 40 California home health and hospice agencies. Data was collected through surveys that were completed by the branch managers of participating facilities. Programs were scored in six different areas, including general workplace violence prevention components; management commitment and employee involvement; worksite analysis; hazard prevention and control; safety and health training; and recordkeeping and program evaluation. The results and discussion sections consider these six areas and the important gaps that were found in existing programs. For example, although most agencies offered workplace violence training, not every worker performing patient care was required to receive the training. Similarly, not all programs were written or reviewed and updated regularly. Few program differences were observed between agency characteristics, but nonetheless several striking gaps were found. PMID- 23452198 TI - Stressful incidents of physical violence against emergency nurses. AB - Physical violence against nurses has become an endemic problem affecting nurses in all settings. The purpose of this study was to describe acts of physical violence against emergency nurses perceived as stressful using a qualitative descriptive design with a national sample of emergency nurses. The guiding conceptual model for the study was the Ecological Occupational Health Model of Workplace Assault. Narrative accounts of physical violence were analyzed using a constant comparative analysis method. Key findings included risks related to employee, workplace, and aggressor factors, and descriptions of physical violence. Discussion of the study findings suggests that efforts to prevent violence and promote workplace safety need to focus on designing work environments that allow for the quick egress of employees, establishing and consistently enforcing policies aimed at violence prevention, and maintaining positive working relationships with security officers. While patients with mental health or substance use complaints are deemed most likely to commit physical violence, they are not the only patients to become violent. Risk reduction efforts should target all patients and visitors. PMID- 23452199 TI - Measurement and monitoring of health care worker aggression exposure. AB - Aggression exposure is highly prevalent in healthcare workers, and is a complex problem that negatively impacts patient and worker safety and health. Typically only events of high severity (e.g., use of physical restraint or incident reports) are monitored in healthcare settings. Unfortunately, these events are likely a small fraction of all aggressive events that range from verbal to physical. Improved measurement and monitoring of healthcare worker aggression exposure may lead to improved patient and worker safety and health. This article provides an overview of aggression exposure in healthcare and reviews the measurement of aggression, including challenges and common measures. Discussion of a pilot study presents insights gained from using a novel measure of aggression, handheld counters. The conclusion offers implications for research and clinical practice. PMID- 23452200 TI - A framework for translating workplace violence intervention research into evidence-based programs. AB - Workplace violence, a dangerous and complex occupational hazard in the modern health care work environment, presents challenges for nurses, other health care employees, management, labor unions, and regulators. Violence from patients, visitors, and coworkers is often tolerated and explained as part of the job in the fast-paced, stressful health care delivery workplace. Addressing violence in health care requires very purposeful organizational processes conducted by very specific organizational structures. The strength of the scientific evidence for workplace violence prevention strategies is well past the "emerging" evidence stage but has not achieved the "unequivocal" stage. It is unlikely that workplace violence interventions will be tested using randomized controlled experimental conditions. Consequently, educated and aware nurses often provide key leadership for organizations undertaking the development of workplace violence prevention programs, but must do so using local evidence generated at the facility level. In some cases, tools such as state regulations and federal workplace safety policies provide important impetus and support for nurses and hospitals undertaking these transformational programs. This article provides background information about workplace violence and offers a framework for developing comprehensive workplace violence prevention programs built on the existing scientific evidence, regulatory guidance, and locally generated practice evidence. PMID- 23452201 TI - Workplace violence in healthcare: strategies for advocacy. AB - The Occupational Safety and Health Administration (OSHA) reports that over 2 million American workers are victims of workplace violence each year. Violence can strike any workplace; no area is immune. But who may be more at risk? Commonly, violence occurs at work and refers to a broad spectrum of behaviors (e.g., violent acts by patients, visitors, and/or coworkers) that result in a concern for personal safety. This article provides a brief overview of workplace violence, and discusses the settings where it often occurs. The authors consider the direct and indirect financial impact of violent acts, such as jury awards for injuries; higher than average turnover; increased requests for medical leaves; unusually high time and attendance issues; and stress related illnesses. Advocacy strategies for nurses are offered to address workplace violence on several levels, such as legislative advocacy, workplace policy, and education. PMID- 23452202 TI - mRNA encoding WAVE-Arp2/3-associated proteins is co-localized with foci of active protein synthesis at the leading edge of MRC5 fibroblasts during cell migration. AB - During cell spreading, mammalian cells migrate using lamellipodia formed from a large dense branched actin network which produces the protrusive force required for leading edge advancement. The formation of lamellipodia is a dynamic process and is dependent on a variety of protein cofactors that mediate their local regulation, structural characteristics and dynamics. In the present study, we show that mRNAs encoding some structural and regulatory components of the WAVE [WASP (Wiskott-Aldrich syndrome protein) verprolin homologous] complex are localized to the leading edge of the cell and associated with sites of active translation. Furthermore, we demonstrate that steady-state levels of ArpC2 and Rac1 proteins increase at the leading edge during cell spreading, suggesting that localized protein synthesis has a pivotal role in controlling cell spreading and migration. PMID- 23452203 TI - Evaluation of microparticles in whole blood by multicolour flow cytometry assay. AB - OBJECTIVE: To develop and evaluate a multicolour flow cytometry method for analysis of microparticles (MPs) in fresh whole blood without any centrifugation steps or freezing/thawing procedure. MATERIALS AND METHODS: Flow cytometry was performed using a FC500 MPL cytometer. The compensation in the protocol was performed based on the platelet population. Polystyrene microspheres 0.50-1.27 MUm were used for size position, and the MP gate was set as particles 0.5-1.0 MUm. Whole blood was incubated with annexin V and antibodies to tissue factor (TF), platelets (CD41 and CD62P), monocyte (CD14) and endothelial cells (CD144). For comparison, MPs from platelet free supernatant was used. The TF activity was evaluated by Calibrated Automated Thrombogram. RESULTS: Annexin V was used to distinguish true events from background noise. For standardization, each analysis included 10,000 events in the gate of platelets. There were 622(462-1001) MP(annV+)/10,000 platelets and of these, 66 (49-82)/10,000 platelets expressed TF. After correction for the individual platelet counts, the amount of circulating MP(annV+) was 17.1 (12.1-24.9) * 10(9)/L in whole blood, and of these, 10% (6-12%) expressed TF. The majority of the MPs expressed CD41, and 5.6% (2.2-6.9%) of these co-expressed TF. The amount of CD41 + MP(annV+) tended to correlate to the TF activity in whole blood. There was no correlation between the MP(annV+) in whole blood and MPs derived from platelet free supernatant. Patients with pulmonary arterial hypertension and stable coronary artery disease had increased concentrations of CD41 + MP(annV+) in whole blood. CONCLUSION: This multicolour flow cytometry assay in whole blood mimics the in vivo situation by avoiding several procedure steps interfering with the MP count. By standardized quantification of MPs a reference interval of MPs can be created. PMID- 23452205 TI - mGluR2 positive allosteric modulators: a patent review (2009 - present). AB - INTRODUCTION: The mGlu2 receptor, which belongs to the group II subfamily of metabotropic glutamate receptors (mGlu) along with the mGlu3 receptor, has proven to be of particular importance in neuropharmacology. Preferentially expressed on presynaptic nerve terminals, the mGlu2 receptor negatively modulates glutamate and GABA release and is widely distributed in the brain. High levels of mGlu2 receptors are seen in brain areas such as prefrontal cortex, hippocampus and amygdala where glutamate hyperfunction may be implicated in disorders and diseases such as anxiety and schizophrenia. Given the promise offered by mGlu2/3 receptor activation, there is increased interest in identifying small molecules which activate the receptor. A preferred approach is via positive allosteric modulators (PAMs) which bind at an alternative site to agonists. AREAS COVERED: This review covers the patent applications which were published between April 2009 and December 2012 on PAMs of the mGlu2, and it is a continuation of an earlier review published in this journal. EXPERT OPINION: Advances in medicinal chemistry and pharmacology have set the stage in the field of mGlu2 receptor PAMs. Compounds currently advancing in clinical trials will soon establish the therapeutic potential of this allosteric approach. PMID- 23452204 TI - Cost-effectiveness of additional catheter-directed thrombolysis for deep vein thrombosis. AB - BACKGROUND: Additional treatment with catheter-directed thrombolysis (CDT) has recently been shown to reduce post-thrombotic syndrome (PTS). OBJECTIVES: To estimate the cost effectiveness of additional CDT compared with standard treatment alone. METHODS: Using a Markov decision model, we compared the two treatment strategies in patients with a high proximal deep vein thrombosis (DVT) and a low risk of bleeding. The model captured the development of PTS, recurrent venous thromboembolism and treatment-related adverse events within a lifetime horizon and the perspective of a third-party payer. Uncertainty was assessed with one-way and probabilistic sensitivity analyzes. Model inputs from the CaVenT study included PTS development, major bleeding from CDT and utilities for post DVT states including PTS. The remaining clinical inputs were obtained from the literature. Costs obtained from the CaVenT study, hospital accounts and the literature are expressed in US dollars ($); effects in quality adjusted life years (QALY). RESULTS: In base case analyzes, additional CDT accumulated 32.31 QALYs compared with 31.68 QALYs after standard treatment alone. Direct medical costs were $64,709 for additional CDT and $51,866 for standard treatment. The incremental cost-effectiveness ratio (ICER) was $20,429/QALY gained. One-way sensitivity analysis showed model sensitivity to the clinical efficacy of both strategies, but the ICER remained < $55,000/QALY over the full range of all parameters. The probability that CDT is cost effective was 82% at a willingness to pay threshold of $50,000/QALY gained. CONCLUSIONS: Additional CDT is likely to be a cost-effective alternative to the standard treatment for patients with a high proximal DVT and a low risk of bleeding. PMID- 23452206 TI - Cigarette smoke condensate extracts induce IL-1-beta production from rheumatoid arthritis patient-derived synoviocytes, but not osteoarthritis patient-derived synoviocytes, through aryl hydrocarbon receptor-dependent NF-kappa-B activation and novel NF-kappa-B sites. AB - Cigarette smoking is a major established environmental risk factor for rheumatoid arthritis (RA), and synoviocyte-derived proinflammatory cytokines are implicated in the pathogenesis of RA. We have reported that aryl hydrocarbon or cigarette smoke condensate (CSC) is able to upregulate the production of proinflammatory cytokines from an RA patient-derived synovial fibroblast cell line MH7A. In this study, we compared the effect of CSC on induction of interleukin-1beta (IL-1beta) from RA or osteoarthritis (OA) patient-derived synovial fibroblasts, and studied the mechanism of the effect of CSC. CSC induced IL-1beta mRNA from RA patient derived synoviocytes and MH7A, but not from OA patient-derived synoviocytes. CSC induced the mRNA and both precursor and mature forms of IL-1beta, and caspase-1 activity in MH7A. The mechanism of CSC-induced IL-1beta mRNA expression was investigated in MH7A. Reporter gene analyses and promoter pull-down assay indicated that 3 novel NF-kappaB sites at -3771 to -3762 bp, -3105 to -3096 bp, and -2787 to -2778 bp in the promoter region of the IL-1beta gene, especially the far distal NF-kappaB site and NF-kappaB activation, are critical for the gene activation by CSC. CSC-induced NF-kappaB activation, IL-1beta promoter activity, IL-1beta mRNA upregulation, and CYP1A1 mRNA induction were all inhibited by an aryl hydrocarbon receptor (AhR) antagonist alpha-naphthoflavone. These results indicate that CSC induced IL-1beta production from RA patient-derived synoviocytes, but not OA patient-derived synoviocytes, through AhR-dependent NF kappaB activation and novel NF-kappaB sites. PMID- 23452207 TI - Review of advances in the thin layer chromatography of pesticides: 2010-2012. AB - Techniques and applications of thin layer chromatography (planar chromatography) for the separation, detection, qualitative and quantitative determination, and preparative isolation of pesticides and their metabolites and some related pollutants are reviewed for the period from November 1, 2010 to November 1, 2012. Analyses are described for a variety of samples types and pesticide classes. In addition to references on residue analysis, studies such as pesticide structure - retention relationships, identification and characterization of natural and synthesized pesticides, metabolism, degradation, mobility, lipophilicity, and mechanism of action are covered. PMID- 23452208 TI - Evaluation of sorption-desorption processes for metalaxyl in natural and artificial soils. AB - The main process controlling soil-pesticide interaction is the sorption desorption as influenced by active soil surfaces. The sorption phenomena can influence translocation, volatility, persistence and bioactivity of a pesticide in soil. The present investigation was conducted on natural and artificial soils in order to enumerate the effect of soil components such as montmorillonite and ferrihydrite on the sorption behaviour of the fungicide metalaxyl and if sorption desorption of the chiral pesticide affects the enantiomeric ratio. The sorption desorption characteristics of metalaxyl were investigated by batch equilibration technique in a natural soil, two artificial soils, and in pure montmorillonite and ferrihydrite. After extraction, pesticide residues were analyzed by conventional and chiral chromatography using tandem mass spectrometry. A KdSorp (2.3-6.5) suggests low level sorption of metalaxyl with an appreciable risk of run-off and leaching. Thus, metalaxyl poses a threat to surface and ground water contamination. Furthermore, desorption tests revealed a hysteretic effect (H <= 0.8) in natural and artificial soils. Significant amount of metalaxyl was found tightly bound to the adsorbents without desorbing readily after desorption cycle. Desorption of 22-56% of the total amount of the retained metalaxyl was determined. This study reveals that an artificial soil derived from different soil constituents can be used to assess their influence on sorption/desorption processes. The present investigation showed that both montmorillonite and ferrihydrite play a significant role in the sorption of metalaxyl. The sorption doesn't influence the enantiomeric ratio of racemic metalaxyl. PMID- 23452209 TI - Sublethal contaminant exposure alters behavior in a common insect: important implications for trophic transfer. AB - This study examined the effects of sub-lethal exposure of the ubiquitous pesticide malathion on the behavior of the model orthopteran species, the house cricket (Acheta domesticus). Increasing concentrations of malathion caused male crickets to increase periods of non-directional movement, such as twitching and grooming, directional movement, and to seek out shelter less. These are all behavioral alterations that may increase the cricket's chances of being preyed upon, and thus have the potential for serious ecological consequences through trophic transfer. This study also revealed that female crickets appeared to be less affected by malathion than their male conspecifics, indicating a potential sex-bias in both susceptibility and possible predator attack. PMID- 23452210 TI - Optimization of methyl parathion biodegradation and detoxification by cells in suspension or immobilized on tezontle expressing the opd gene. AB - The goal of this study was to optimize methyl parathion (O,O-dimethyl-O-4-p nitrophenyl phosphorothioate) degradation using a strain of Escherichia coli DH5alpha expressing the opd gene. Our results indicate that this strain had lower enzymatic activity compared to the Flavobacterium sp. ATCC 27551 strain from which the opd gene was derived. Both strains were assessed for their ability to degrade methyl parathion (MP) in a mineral salt medium with or without the addition of glucose either as suspended cells or immobilized on tezontle, a volcanic rock. MP was degraded by both strains with similar efficiencies, but immobilized cells degraded MP more efficiently than cells in suspension. However, the viability of E. coli cells was much higher than that of the Flavobacterium sp. We confirmed the decrease in toxicity from the treated effluents through acetylcholinesterase activity tests, indicating the potential of this method for the treatment of solutions containing MP. PMID- 23452211 TI - Enhanced biodegradation of endosulfan and its major metabolite endosulfate by a biosurfactant producing bacterium. AB - The present study was carried out to isolate bacteria capable of producing biosurfactant that solublize endosulfan (6,7,8,9,10,10-Hexachloro-1,5,5a,6,9,9a hexahydro- 6,9-methano-2,4,3-benzodioxathiepine-3-oxide) and for enhanced degradation of endosulfan and its major metabolite endosulfate. The significance of the study is to enhance the bioavailability of soil-bound endosulfan residues as its degradation is limited due to its low solubility. A mixed bacterial culture capable of degrading endosulfan was enriched from pesticide-contaminated soil and was able to degrade about 80% of alpha-endosulfan and 75% of beta endosulfan in five days. Bacterial isolates were screened for biosurfactant production and endosulfan degradation. Among the isolates screened, four strains produced biosurfactant on endosulfan. ES-47 showed better emulsification of endosulfan and degraded 99% of endosulfan and 94% of endosulfate formed during endosulfan degradation. The strain reduced the surface tension up to 37 dynes/cm. The study reveals that the strain was capable of degrading endosulfan and endosulfate with simultaneous biosurfactant production. PMID- 23452212 TI - Simultaneous detection and degradation patterns of kresoxim-methyl and trifloxystrobin residues in citrus fruits by HPLC combined with QuEChERS. AB - This study aimed to investigate the residues, kinetics and dissipation patterns of kresoxim-methyl, (E)-methoxyimino[alpha-(o-tolyloxy)-o-tolyl]acetate, and trifloxystrobin, methyl(E)-methoxyimino-{(E)-alpha[1-(alpha,alpha,alpha-trifluoro m-tolyl)ethylideneaminooxy]-o-tolyl}acetate". A simple and sensitive liquid chromatography-ultraviolet detection (LC-UV) method combined with the 'Quick Easy Cheap Effective Rugged and Safe' (QuEChERS) protocol was developed to quantify the levels of kresoxim-methyl and trifloxystrobin residues in citrus. More than 97% of the kresoxim-methyl and trifloxystrobin deposists gradually dissipated from the citrus peels within 15 days. The half-lives of kresoxim-methyl and trifloxystrobin in the peels were in the ranges of 2.63-2.66 d and 3.12-3.15 d, respectively, and the pattern of decline in the peels followed first-order kinetics. The kresoxim-methyl and trifloxystrobin residues in the pulp dissipated below the detectable level of 0.01 mg kg(-1) after 9 days. Kresoxim-methyl and trifloxystrobin were easily decomposed (T1/2 < 30 d), and the observed dissipation patterns could support the application of these two fungicides in the postharvest storage of citrus fruits. PMID- 23452213 TI - Kinetics study of fermentative hydrogen production from liquid swine manure supplemented with glucose under controlled pH. AB - Kinetics of H2 production from liquid swine manure supplemented with glucose by mixed anaerobic cultures was investigated using batch experiments under four different pH conditions (4.4, 5.0, 5.6, and uncontrolled). The temperature for the experiments was controlled at 37 +/- 1 degrees C and the length of experiments varied between 50 and 120 hours, depending upon the time needed for completion of each individual experiment. The modified Gompertz model was evaluated for its suitability for describing the H2 production potential, H2 production rate, and substrate consumption rate for all the experiments. The results showed that the Gompertz model could adequately fit the experimental results. The effect of pH was significant on all kinetic parameters for H2 production including yield, production rate and lag time, and the substrate utilization rate. The optimal pH was found to be 5.0, at which a maximum H2 production rate (0.64 L H2/h) was obtained, and deviation from the optimal pH could result in substantial reductions in H2 production rate (0.32 L H2/h for pH 4.0 and 0.43 L H2/h for pH 5.6). The results also showed that if pH was not controlled for the batch fermentation process, the substrate utilization efficiency could steeply decrease from 98.8% to 33.7%. PMID- 23452214 TI - Synthesis of novel hapten and production of generic monoclonal antibody for immunoassay of penicillins residues in milk. AB - The objective of this study was to produce a generic monoclonal antibody for determination of penicillins residues in milk. The compound 6-aminopenicillanic acid was used as the template to synthesize two novel generic haptens that were used to produce the monoclonal antibodies. The obtained monoclonal antibodies simultaneously recognized 11 penicillin drugs (amoxicillin, ampicillin, penicillin G, penicillin V, sulbenicillin, carbencillin, methicillin, cloxacillin, dicloxacillin, oxacillin, and nafcillin). After evaluation of different reagent combinations, a heterologous indirect competitive enzyme immunoassay was developed to multi-determine the 11 drugs in milk. The crossreactivities to the 11 drugs were in a range of 16%-117% and the limits of detection were in a range of 0.7-9.3 ng/mL depending on the drug. The recoveries from the fortified blank milk were in a range of 77.6%-99.4% with coefficients of variation lower than 13.5%. This method could be used as a rapid screen tool for routine monitoring the residues of the 11 penicillin drugs in animal derived foods. PMID- 23452215 TI - Antibiotic resistance in bacteria isolated from freshwater aquacultures and prediction of the persistence and toxicity of antimicrobials in the aquatic environment. AB - The occurrence of antibiotic-resistant bacteria isolated from freshwater aquaculture effluents was investigated. The bacterial strains were collected from four different freshwater aquaculture effluents (catfish, trout, eel, and loach). Based on sequence of 16S rRNA, a total of 20 bacterial strains was isolated and one half of the isolated bacteria were Aeromonas sp. The antimicrobial sensitivity test was performed using the disc diffusion method. Individual antibiotic-resistant bacteria to antimicrobials were 41.7% and multiple antibiotic resistant bacteria were 58.3%. The disinfection of antibiotic resistant bacteria by electron beam (E-beam) irradiation was carried out using an electron accelerator. Antibiotic-resistant bacteria were effectively disinfected by E-beam irradiation. The isolated bacteria were completely disinfected at a dose of less than 2 kGy. The persistence and toxicity of each antimicrobial in the aquatic environment was estimated due to the human health and ecosystems. In order to estimate the persistence and toxicity of antimicrobials in the aquatic environment, two quantitative structure activity relationship (QSAR) models were used. The persistence and toxicity of each antimicrobial were influenced on its hydrophobicity. In addition, QSAR models showed that isoelectric point and hydrogen bonding acceptor are key parameters to estimate the persistence and toxicity of antimicrobials in the aquatic environment. PMID- 23452216 TI - Response of the soil microbial community to imazethapyr application in a soybean field. AB - The objective of this study was to determine the effects of imazethapyr on soil microbial communities combined with its effect on soybean growth. A short-term field experiment was conducted, and imazethapyr was applied to the soil at three different doses [1-fold, 10-fold, and 50-fold of the recommended field rate (H1, H10, H50)] during the soybean seedling period (with two leaves). Soil sampling was performed after 1, 7, 30, 60, 90, and 120 days of application to determine the imazethapyr concentration and microbial community structure by investigating phospholipid fatty acids (PLFA) and microbial biomass carbon (MBC). The half lives of the imazethapyr in the field soil varied from 30.1 to 43.3 days. Imazethapyr at H1 was innocuous to soybean plants, but imazethapyr at H10 and H50 led to a significant inhibition in soybean plant height and leaf number. The soil MBC, total PLFA, and bacterial PLFA were decreased by the application of imazethapyr during the initial period and could recover by the end of the experiment. The ratio of Gram-negative/Gram-positive (GN/GP) bacteria during the three treatments went through increases and decreases, and then recovered at the end of the experiment. The fungal PLFA of all three treatments increased during the initial period and then declined, and only the fungal PLFA at H50 recovered by the end of the treatment. A principal component analysis (PCA) of the PLFA clearly separated the treatments and sampling times, and the results demonstrate that imazethapyr alters the microbial community structure. This is the first systemic study reporting the effects of imazethapyr on the soil microbial community structure under soybean field conditions. PMID- 23452217 TI - Acridine orange as an alternative to optical density to study growth kinetics of Lactobacillus bulgaricus ATCC 7517. AB - In this study we assessed the use of acridine orange as an alternative to optical density to quantify the growth of Lactobacillus bulgaricus ATCC 7517. The growth of bacteria in Lactobacillus de Man Rogosa Sharpe (MRS) medium was measured by both acridine orange (AO) and optical density (OD) measurements for 24 h. The relationship between both methods was compared via correlation analysis. The doubling time of bacteria based on the values of OD600 and AO obtained during 24 h growth were also calculated. The result shows strong correlation of cell growth between OD600 and AO during the first 10 hours of growth, but the correlation was less strong when analyzing the data from 0 to 24 hours. Growth rates, generation time and lag time were also similar. This study indicates that AO could be used in place of OD to prepare growth curves of Lactobacillus bulgaricus during the exponential phase of growth, and to compare growth rates, generation times or lag times. PMID- 23452218 TI - Cadinene sesquiterpenes from Eupatorium adenophorum and their antifungal activity. AB - Bioactive constituents of Eupatorium adenophorum were investigated for antifungal activity. A structure-antifungal activity relationship of cadinene sesquiterpenes was predicted by evaluating individual derivatives. Cadinene derivatives were extracted from leaves of Eupatorium adenophorum using ethyl acetate. Five cadinene sesquiterpenes were isolated by column chromatography and Preparative Thin Layer Chromatography. Bioactivity of these cadinene sesquiterpenes were evaluated in vitro against four phytopathogenic fungi using poison food technique. Purified sesquiterpenes were spectroscopically elucidated as cadinan-3 ene-2,7-dione (1), 7-hydroxycadinan-3-ene-2-one (2), 5,6-dihydroxycadinan-3-ene 2,7-dione (3), cadinan-3,6-diene-2,7-dione (4) and 2-acetyl-cadinan-3,6-diene-7 one (5). Antifungal evaluation of these compounds against pathogenic fungi was found to be selective. Compound 1 was highly inhibitory towards S. rolfsii (ED50 181.60 +/- 0.58 MUgmL(-1)) and R. solani (ED50 189.74 +/- 1.03 MUgmL(-1)). Availability of plant material and significant antifungal activity makes the plant a potential source of antifungal agent and that can be exploited for the development of a natural fungicide. PMID- 23452219 TI - Computational design and biosensor applications of small molecule-sensing allosteric ribozymes. AB - Here I describe accurate and time-efficient computational methods for designing small molecule-sensing allosteric ribozymes that serve as logic gates with NOT or YES Boolean logic functions. Theophylline-sensing ribozymes are engineered to have a high cleavage rate of 1.3 min(-1) under physiologically relevant conditions. They are highly specific to theophylline and do not respond to caffeine, which differs in a single methyl group. These ribozymes are designed by fusing a theophylline aptamer with an extended version of the hammerhead ribozyme by modeling secondary structures. Purine-sensing ribozymes are designed by fusing the minimal version of the hammerhead ribozyme with bacterial guanine or adenine aptamers by modeling 3D interactions. I have developed high-throughput compatible arrays based on purine RNA sensors that can be used for antibacterial drug discovery. The ribozymes can be employed as molecular sensors in various applications, including exogenous control of gene expression, high-throughput screening arrays, and molecular computing. PMID- 23452220 TI - Exploiting plant virus-derived components to achieve in planta expression and for templates for synthetic biology applications. AB - This review discusses the varying roles that have been played by many plant-viral regulatory sequences and proteins in the creation of plant-based expression systems and virus particles for use in nanotechnology. Essentially, there are two ways of expressing an exogenous protein: the creation of transgenic plants possessing a stably integrated gene construction, or the transient expression of the desired gene following the infiltration of the gene construct. Both depend on disarmed strains of Agrobacterium tumefaciens to deliver the created gene construction into cell nuclei, usually through the deployment of virus-derived components. The importance of efficient mRNA translation in the latter process is highlighted. Plant viruses replicate to sustain an infection to promote their survival. The major product of this, the virus particle, is finding increasing roles in the emerging field of bionanotechnology. One of the major products of plant-viral expression is the virus-like particle (VLP). These are increasingly playing a role in vaccine development. Similarly, many VLPs are suitable for the investigation of the many facets of the emerging field of synthetic biology, which encompasses the design and construction of new biological functions and systems not found in nature. Genetic and chemical modifications to plant generated VLPs serve as ideal starter templates for many downstream synthetic biology applications. PMID- 23452221 TI - Biocompatibility assessment of a long-term wearable artificial pump-lung in sheep. AB - The purpose of this study was to assess the biocompatibility of a newly developed long-term wearable artificial pump-lung (APL) in a clinically relevant ovine animal model. The wearable APL device was implanted in five sheep through left thoracotomy. The device was connected between the right atrium and pulmonary artery and evaluated for 30 days. Three sheep were used as the sham control. Platelet activation was assessed by measuring platelet surface P-selectin (CD62P) expression with flow cytometry and plasma soluble P-selectin with an enzyme linked immunosorbent assay. Thrombotic deposition on the device components and hollow fiber membranes were analyzed with digital imaging and scanning electron microscopy. Surface P-selectin of the APL and sham groups changed significantly over the study period, but without significant differences between the two groups. Soluble P-selectin for the two groups peaked in the first 24 h after the surgery. Soluble P-selectin of the APL group remained slightly elevated over the study period compared to the presurgical baseline value and was slightly higher compared to that of the sham group. Plasma free hemoglobin remained in the normal ranges in all the animals. In spite of the surgery-related alteration in laboratory tests and elevation of platelet activation status, the APL devices in all the animals functioned normally (oxygen transfer and blood pumping) during the 30-day study period. The device flow path and membrane surface were free of gross thrombus. Electron microscopy images showed only scattered thrombi on the fibers (membrane surface and weft). In summary, the APL exhibited excellent biocompatibility. Two forms of platelet activation, surgery-related and device induced, in the animals implanted with the wearable APL were observed. The limited device-induced platelet activation did not cause gross thrombosis and impair the long-term device performance. PMID- 23452222 TI - Proportion of life lived with dystonia inversely correlates with response to pallidal deep brain stimulation in both primary and secondary childhood dystonia. AB - AIM: The aim of this study was to examine the impact of dystonia aetiology and duration, contracture, and age at deep brain stimulation (DBS) surgery on outcome in a cohort of children with medically refractory, disabling primary, secondary static, or secondary-progressive dystonias, including neurodegeneration with brain iron accumulation (NBIA). METHOD: Dystonia severity was assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score at baseline and 6 and 12 months postoperatively in a cohort of 70 consecutive children undergoing DBS between June 2005 and July 2011. RESULTS: Two children (3%) received unilateral DBS for hemidystonia and were excluded and five (7%) developed infections requiring part-DBS removal within 6 months, leaving 63 children (90%) undergoing bilateral DBS for follow-up (34 males, 29 females; mean age at surgery for the whole group 10y 4mo, SD 4y 2mo, range 1-14y). Seventeen children were classified with primary dystonia: mean age 12 years 11 months, SD 4 years 6 months range 4 years 6 months to 17 years 3 months; 28 as having secondary-static dystonia: mean age 10 years 2 months, SD 4 years 9 months (range 3y 3mo-20y); five as having secondary-progressive dystonia: mean age 8 years 11 months, SD 3 years 9 months (range 5y 5mo-13y 1mo); and 13 as having NBIA dystonia: mean age 10 years 2 months, SD 3 years 11 months (range 1-14y). Children with primary dystonias demonstrated greater improvements in BFMDRS motor score than those in the other aetiological categories (Kruskal-Wallis test, p<0.001), which correlated negatively with dystonia duration and more strongly still against the ratio of dystonia duration normalized to age at surgery (DD/AS ratio) at 1 year (Spearman's rank correlation coefficient 0.4752 and -0.599 respectively). A similar significant negative correlation was found in the secondary-static dystonia group between outcome at 1 year and DD/AS ratio (-0.461). Poorer outcome in secondary dystonia coincided with the absence of a period of normal motor development in comparison with the primary dystonia group. A significant improvement in BFMDRS motor score was seen in the NBIA group at 6, but not 12 months (Wilcoxon signed rank test p=0.028, p=0.85 respectively). No reduction in efficacy was seen in children with a musculoskeletal deformity at the time of surgery. CONCLUSION: Response to pallidal DBS in the treatment of dystonia declines with the proportion of life lived with dystonia in primary and secondary dystonia. Other intrinsic factors reduce the median magnitude of reduction in secondary dystonia after DBS. DBS should be offered early, preferably within 5 years of onset, to maximize benefits and reduce the childhood experience of dystonia, including musculoskeletal deformity. Other multidimensional assessments are required to understand how DBS improves the lives of children with dystonia. PMID- 23452223 TI - Marfan's syndrome: a refractive challenge for optometrists. AB - We present an interesting case of a child with Marfan's syndrome with ectopia lentis, who was followed for five years. The changes in refractive and visual findings of this child during this period are discussed. The importance of careful oculo-visual examination and possible management options in such children are highlighted. PMID- 23452224 TI - Longitudinal melanonychia in a northern Polish population. PMID- 23452225 TI - Ethical, legal, social, and policy implications of behavioral genetics. AB - The field of behavioral genetics has engendered a host of moral and social concerns virtually since its inception. The policy implications of a genetic basis for behaviors are widespread and extend beyond the clinic to the socially important realms of education, criminal justice, childbearing, and child rearing. The development of new techniques and analytic approaches, including whole-genome sequencing, noninvasive prenatal genetic testing, and optogenetics, has clearly changed the study of behavioral genetics. However, the social context of biomedical research has also changed profoundly over the past few decades, and in ways that are especially relevant to behavioral genetics. The ever-widening scope of behavioral genetics raises ethical, legal, social, and policy issues in the potential new applications to criminal justice, education, the military, and reproduction. These issues are especially critical to address because of their potentially disproportionate effects on vulnerable populations such as children, the unborn, and the incarcerated. PMID- 23452226 TI - Distribution of phosphodiesterase type 5 (PDE5) in the lateral wall of the guinea pig urinary bladder. AB - OBJECTIVE: To study PDE5 localisation by visualising the product of phosphodiesterase type 5 (PDE5) inhibition, namely cGMP, to determine the site of action of inhibitors in the urinary bladder. MATERIALS AND METHODS: Bladders of nine male guinea pigs were dissected and treated in wells containing 2 mL Krebs' solution and 1 MUM of the specific PDE5 inhibitor vardenafil at 36 degrees C for 30 min. After stimulating tissues with 100 MUM of the nitric oxide (NO) donor diethylamine-NONOate for 10 min, the tissues were snap-frozen and 9-10 MUm sections were cut. Sections were examined for cGMP immunoreactivity and also stained for vimentin, a marker for interstitial cells and the neuromarkers protein gene product 9.5 (PGP9.5), synaptic vesicle protein 2 (SV2), neurofilament (NF) and calcitonin gene-related peptide (CGRP), using the two-step indirect immunohistochemistry technique. RESULTS: After PDE5 inhibition, cGMP was found to be present in the urothelium, suburothelial interstitial cells and endothelium of blood vessels. cGMP was not expressed in nerves positive for CGRP, NF and SV2, and was expressed only in very few efferent nerves positive for PGP9.5. CONCLUSION: Our data show that the possible sites of action of PDE5 inhibition in the bladder are the urothelium, suburothelial interstitial cells and blood vessels, rather than the bladder nerve fibres. PMID- 23452227 TI - Mitigating amphibian chytridiomycosis with bioaugmentation: characteristics of effective probiotics and strategies for their selection and use. AB - Probiotic therapy through bioaugmentation is a feasible disease mitigation strategy based on growing evidence that microbes contribute to host defences of plants and animals. Amphibians are currently threatened by the rapid global spread of the pathogen, Batrachochytrium dendrobatidis (Bd), which causes the disease chytridiomycosis. Bioaugmentation of locally occurring protective bacteria on amphibians has mitigated this disease effectively in laboratory trials and one recent field trial. Areas still naive to Bd provide an opportunity for conservationists to proactively implement probiotic strategies to prevent further amphibian declines. In areas where Bd is endemic, bioaugmentation can facilitate repatriation of susceptible amphibians currently maintained in assurance colonies. Here, we synthesise the current research in amphibian microbial ecology and bioaugmentation to identify characteristics of effective probiotics in relation to their interactions with Bd, their host, other resident microbes and the environment. To target at-risk species and amphibian communities, we develop sampling strategies and filtering protocols that result in probiotics that inhibit Bd under ecologically relevant conditions and persist on susceptible amphibians. This filtering tool can be used proactively to guide amphibian disease mitigation and can be extended to other taxa threatened by emerging infectious diseases. PMID- 23452229 TI - Gut bacterial microbiota and obesity. AB - Although probiotics and antibiotics have been used for decades as growth promoters in animals, attention has only recently been drawn to the association between the gut microbiota composition, its manipulation, and obesity. Studies in mice have associated the phylum Firmicutes with obesity and the phylum Bacteroidetes with weight loss. Proposed mechanisms linking the microbiota to fat content and weight include differential effects of bacteria on the efficiency of energy extraction from the diet, and changes in host metabolism of absorbed calories. The independent effect of the microbiota on fat accumulation has been demonstrated in mice, where transplantation of microbiota from obese mice or mice fed western diets to lean or germ-free mice produced fat accumulation among recipients. The microbiota can be manipulated by prebiotics, probiotics, and antibiotics. Probiotics affect the microbiota directly by modulating its bacterial content, and indirectly through bacteriocins produced by the probiotic bacteria. Interestingly, certain probiotics are associated with weight gain both in animals and in humans. The effects are dependent on the probiotic strain, the host, and specific host characteristics, such as age and baseline nutritional status. Attention has recently been drawn to the association between antibiotic use and weight gain in children and adults. We herein review the studies describing the associations between the microbiota composition, its manipulation, and obesity. PMID- 23452228 TI - Monsoon-driven transport of organochlorine pesticides and polychlorinated biphenyls to the Tibetan Plateau: three year atmospheric monitoring study. AB - Due to the influence of the Indian monsoon system, air mass transport in and to the Tibetan Plateau shows obvious seasonality. In order to assess the responses of atmospheric concentrations of persistent organic pollutants (POPs) to the Indian Monsoon fluctuation patterns, a three year air monitoring program (2008 2011) was conducted in an observation station close to the Yarlung Tsangpo Grand Canyon, southeastern Tibetan Plateau. The air concentrations of polychlorinated biphenyls (PCBs) and hexachlorocyclohexanes (HCHs) are generally comparable to those of other remote regions, whereas the concentrations of DDTs are much higher than reported for the polar regions, the North American Rocky Mountains, and the European Alps. The concentrations of DDTs and PCBs were strongly linked to the cyclic patterns of the Indian monsoon, displaying higher values in the monsoon season (May-September) and lower values in the nonmonsoon season (November March). A "bimodal" pattern was observed for alpha- and gamma-HCH, with higher concentrations in spring and autumn and lower concentrations in the summer (monsoon season). Rain scavenging in the monsoon season likely resulted in the lower HCH concentrations in the atmosphere. This paper sheds lights on the role the Indian monsoon plays on the atmospheric transport of POPs to the Tibetan Plateau. PMID- 23452230 TI - What can we learn about dispersion from the conformer surface of n-pentane? AB - In earlier work [Gruzman, D. ; Karton, A.; Martin, J. M. L. J. Phys. Chem. A 2009, 113, 11974], we showed that conformer energies in alkanes (and other systems) are highly dispersion-driven and that uncorrected DFT functionals fail badly at reproducing them, while simple empirical dispersion corrections tend to overcorrect. To gain greater insight into the nature of the phenomenon, we have mapped the torsional surface of n-pentane to 10-degree resolution at the CCSD(T) F12 level near the basis set limit. The data obtained have been decomposed by order of perturbation theory, excitation level, and same-spin vs opposite-spin character. A large number of approximate electronic structure methods have been considered, as well as several empirical dispersion corrections. Our chief conclusions are as follows: (a) the effect of dispersion is dominated by same spin correlation (or triplet-pair correlation, from a different perspective); (b) singlet-pair correlation is important for the surface, but qualitatively very dissimilar to the dispersion component; (c) single and double excitations beyond third order are essentially unimportant for this surface; (d) connected triple excitations do play a role but are statistically very similar to the MP2 singlet pair correlation; (e) the form of the damping function is crucial for good performance of empirical dispersion corrections; (f) at least in the lower-energy regions, SCS-MP2 and especially MP2.5 perform very well; (g) novel spin-component scaled double hybrid functionals such as DSD-PBEP86-D2 acquit themselves very well for this problem. PMID- 23452231 TI - Attitudes and barriers to the introduction of umbilical cord blood gas and lactate analysis at birth. AB - BACKGROUND: Despite a growing body of evidence demonstrating the value of universal umbilical cord blood gas analysis (UCBGA), there remains reluctance in some maternity units to adopt universal testing. AIMS: Identify perceived barriers and benefits of universal UCBGA. METHODS: Medical and midwifery staff involved in intrapartum care at four level two maternity units (one metropolitan and three regional) completed questionnaires evaluating attitudes to UCBGA. Questionnaires included 13 statements with responses ranging from strongly agree to strongly disagree and background demographic data. RESULTS: Most respondents considered UCBGA beneficial to perinatal care (n = 72; 67.3%), with only nine individuals (8.4%) believing UCBGA had no place in perinatal care. The majority of respondents considered benefits of UCBGA to include being an effective and objective marker of neonatal status (n = 64; 59.8%), as well as playing a role in medicolegal issues (n = 74; 69.2%) and audit and teaching (n = 64; 59.8%). Respondents considered that barriers to universal UCBGA introduction included insufficient time following delivery, increased workload and encroachment of technology into birth. CONCLUSIONS: The majority of respondents indicated support for UCBGA. Information derived from this study may be useful in identifying and resolving concerns prior to the introduction of UCBGA. Further, it could be useful in the preparation of education and implementation packages necessary for introduction of UCBGA. PMID- 23452232 TI - Chaperone-mediated autophagy components are upregulated in sporadic inclusion body myositis muscle fibres. AB - AIMS: Sporadic inclusion-body myositis (s-IBM) is an age-associated degenerative muscle disease. Characteristic features are muscle-fibre vacuolization and intramuscle-fibre accumulations of multiprotein aggregates, which may result from the demonstrated impairments of the 26S proteasome and autophagy. Chaperone mediated autophagy (CMA) is a selective form of lysosomal degradation targeting proteins carrying the KFERQ motif. Lysosome-associated membrane protein type 2A (LAMP2A) and the heat-shock cognate protein 70 (Hsc70) constitute specific CMA components. Neither CMA components nor CMA activity has been studied in normal or disease human muscle, to our knowledge. METHODS: We studied CMA components by immunocytochemistry, immunoblots, real-time PCR and immunoprecipitation in: (a) 16 s-IBM, nine aged-matched normal and nine disease control muscle biopsies; and (b) cultured human muscle fibres (CHMFs) with experimentally inhibited activities of either the 26S proteasome or autophagy. RESULTS: Compared with age-matched controls, in s-IBM muscle, LAMP2A and Hsc70 were on a given transverse section accumulated as aggregates in approximately 5% of muscle fibres, where they (a) colocalized with each other and alpha-synuclein (alpha-syn), a CMA-targeted protein; and (b) were bound to each other and to alpha-syn by immunoprecipitation. By immunoblots, LAMP2A was increased sevenfold P < 0.001 and Hsc70 2.6-fold P < 0.05. LAMP2A mRNA was increased 4.4-fold P < 0.001 and Hsc70 mRNA 1.9-fold P < 0.05. In CHMFs inhibition of either the 26S proteasome or autophagy induced CMA, evidenced by a significant increase of both LAMP2A and Hsc70. CONCLUSIONS: Our study demonstrates, for the first time, up-regulation of CMA components in s-IBM muscle, and it provides further evidence that altered protein degradation is likely an important pathogenic aspect in s-IBM. PMID- 23452234 TI - Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results. AB - The aim of the study was to define specific genetic profile in Ta and T1 urinary bladder carcinoma patients with and without recurrence by gene expression microarrays. Eleven patients with the time to recurrence shorter than one year (patients with recurrence) and 11 patients with time to recurrence longer than 4 years (patients without recurrence) were enrolled. Data from microarrays were subjected to a panel of statistical analyses to identify bladder cancer recurrence-associated gene signatures. Initial screening using the GeneSpring and Bioconductor software tools revealed a putative set 47 genes differing in gene expression in both groups. After the validation, 33 genes manifested significant differences between both groups. The significant expression was observed in the group of patients without recurrence by 30 genes of which the highest differences were detected by ANXA1, ARHGEF4, FLJ32252, GNE, NINJ1, PRICKLE1, PSAT1, RNASE1, SPTAN1, SYNGR1, TNFSF15, TSPAN1, and WDR34. These genes code for signal transduction, vascular remodeling and vascular endothelial growth inhibition mainly. In the group with recurrence, 3 genes had significant differences, the highest differences were identified by two genes (PLOD2 and WDR72). Loci of genes with significant changes of gene expression were located on characteristic chromosomes for bladder cancer: 7 loci on chromosome 9, 8 loci on chromosomes 1, 2, 3, 12,14,15,16, and 22. We have selected and validated 15 genes that are differentially expressed in superficial bladder cancer. We hope that this cohort of genes will serve as a promising pool of candidate biomarkers for early stage bladder cancer. Our results indicate that it may be possible to identify patients with a low and high risk of disease recurrence at an early stage using a molecular profile. PMID- 23452235 TI - PbSe quantum dot field-effect transistors with air-stable electron mobilities above 7 cm2 V(-1) s(-1). AB - PbSe quantum dot (QD) field effect transistors (FETs) with air-stable electron mobilities above 7 cm(2) V(-1) s(-1) are made by infilling sulfide-capped QD films with amorphous alumina using low-temperature atomic layer deposition (ALD). This high mobility is achieved by combining strong electronic coupling (from the ultrasmall sulfide ligands) with passivation of surface states by the ALD coating. A series of control experiments rule out alternative explanations. Partial infilling tunes the electrical characteristics of the FETs. PMID- 23452236 TI - General approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors: enantioselective total syntheses of (+)- and (-)-gliocladine C, (+) leptosin D, (+)-T988C, (+)-bionectin A, and (+)-gliocladin A. AB - A common strategy for preparing tryptophan-derived epidithiodioxopiperazine (ETP) natural products containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter is reported. This strategy is exemplified by enantioselective total syntheses of four heptacyclic ETP natural products--gliocladine C (6), leptosin D (7), T988C (8), and bionectin A (9)--starting with the di-(tert butoxycarbonyl) derivative 17 of the trioxopiperazine natural product gliocladin C, which is readily available by enantioselective chemical synthesis. In addition, total syntheses of the enantiomer of gliocladine C (ent-6) and gliocladin A (11), the di(methylthio) congener of bionectin A, are reported. These syntheses illustrate a synthetic strategy wherein diversity in the dioxopiperazine unit of ETP natural products is introduced at a late stage in a synthetic sequence. In vitro cytotoxicity of compounds in this series against invasive human prostrate (DU145) and melanoma (A2058) cancer cell lines is described and compared to that of chaetocin A (4). PMID- 23452237 TI - Characterization of a pre-export enzyme-chaperone complex on the twin-arginine transport pathway. AB - The Tat (twin-arginine translocation) system is a protein targeting pathway utilized by prokaryotes and chloroplasts. Tat substrates are produced with distinctive N-terminal signal peptides and are translocated as fully folded proteins. In Escherichia coli, Tat-dependent proteins often contain redox cofactors that must be loaded before translocation. Trimethylamine N-oxide reductase (TorA) is a model bacterial Tat substrate and is a molybdenum cofactor dependent enzyme. Co-ordination of cofactor loading and translocation of TorA is directed by the TorD protein, which is a cytoplasmic chaperone known to interact physically with the TorA signal peptide. In the present study, a pre-export TorAD complex has been characterized using biochemical and biophysical techniques, including SAXS (small-angle X-ray scattering). A stable, cofactor-free TorAD complex was isolated, which revealed a 1:1 binding stoichiometry. Surprisingly, a TorAD complex with similar architecture can be isolated in the complete absence of the 39-residue TorA signal peptide. The present study demonstrates that two high-affinity binding sites for TorD are present on TorA, and that a single TorD protein binds both of those simultaneously. Further characterization suggested that the C-terminal 'Domain IV' of TorA remained solvent-exposed in the cofactor free pre-export TorAD complex. It is possible that correct folding of Domain IV upon cofactor loading is the trigger for TorD release and subsequent export of TorA. PMID- 23452238 TI - A new cell culture-based assay quantifies vitamin K 2,3-epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol-driven VKOR assay. AB - BACKGROUND: Warfarin directly inhibits the vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) enzyme to effect anticoagulation. VKORC1 function has historically been assessed in vitro using a dithiothreitol (DTT)-driven vitamin K 2,3-epoxide reductase (VKOR) assay. Warfarin inhibits wild-type VKORC1 function by the DTT-VKOR assay. However, VKORC1 variants with warfarin resistance associated missense mutations often show low VKOR activities and warfarin sensitivity instead of resistance. OBJECTIVES: A cell culture-based, indirect VKOR assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild-type and variant VKORC1 proteins. METHODS: Human coagulation factor (F)IX and VKORC1 variants were coexpressed in HEK 293T cells under standardized conditions at various warfarin concentrations. Secreted FIX activity served as surrogate marker to report wild-type and variant VKORC1 inhibition by warfarin. RESULTS AND CONCLUSIONS: Warfarin dose-response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild-type, Val29Leu, Val45Ala and Leu128Arg variants. The corresponding calculated IC50 values were 24.7, 136.4, 152.0 and 1226.4 nm, respectively. Basal activities in the absence of warfarin for all VKORC1 variants were similar to that of wild-type VKORC1. Ranked IC50 values from the cell culture-based assay accurately reflect elevated warfarin dosages for patients with VKORC1 missense mutation-associated warfarin resistance. PMID- 23452239 TI - Establishment of the Lotus japonicus Gene Expression Atlas (LjGEA) and its use to explore legume seed maturation. AB - Lotus japonicus is a model species for legume genomics. To accelerate legume functional genomics, we developed a Lotus japonicus Gene Expression Atlas (LjGEA), which provides a global view of gene expression in all organ systems of this species, including roots, nodules, stems, petioles, leaves, flowers, pods and seeds. Time-series data covering multiple stages of developing pod and seed are included in the LjGEA. In addition, previously published L. japonicus Affymetrix data are included in the database, making it a 'one-stop shop' for transcriptome analysis of this species. The LjGEA web server (http://ljgea.noble.org/) enables flexible, multi-faceted analyses of the transcriptome. Transcript data may be accessed using the Affymetrix probe identification number, DNA sequence, gene name, functional description in natural language, and GO and KEGG annotation terms. Genes may be discovered through co expression or differential expression analysis. Users may select a subset of experiments and visualize and compare expression profiles of multiple genes simultaneously. Data may be downloaded in a tabular form compatible with common analytical and visualization software. To illustrate the power of LjGEA, we explored the transcriptome of developing seeds. Genes represented by 36 474 probe sets were expressed at some stage during seed development, and almost half of these genes displayed differential expression during development. Among the latter were 624 transcription factor genes, some of which are orthologs of transcription factor genes that are known to regulate seed development in other species, while most are novel and represent attractive targets for reverse genetics approaches to determine their roles in this important organ. PMID- 23452233 TI - Extensive paternal mtDNA leakage in natural populations of Drosophila melanogaster. AB - Strict maternal inheritance is considered a hallmark of animal mtDNA. Although recent reports suggest that paternal leakage occurs in a broad range of species, it is still considered an exceptionally rare event. To evaluate the impact of paternal leakage on the evolution of mtDNA, it is essential to reliably estimate the frequency of paternal leakage in natural populations. Using allele-specific real-time quantitative PCR (RT-qPCR), we show that heteroplasmy is common in natural populations with at least 14% of the individuals carrying multiple mitochondrial haplotypes. However, the average frequency of the minor mtDNA haplotype is low (0.8%), which suggests that this pervasive heteroplasmy has not been noticed before due to a lack of power in sequencing surveys. Based on the distribution of mtDNA haplotypes in the offspring of heteroplasmic mothers, we found no evidence for strong selection against one of the haplotypes. We estimated that the rate of paternal leakage is 6% and that at least 100 generations are required for complete sorting of mtDNA haplotypes. Despite the high proportion of heteroplasmic individuals in natural populations, we found no evidence for recombination between mtDNA molecules, suggesting that either recombination is rare or recombinant haplotypes are counter-selected. Our results indicate that evolutionary studies using mtDNA as a marker might be biased by paternal leakage in this species. PMID- 23452240 TI - Introduction: cranial nerve surgery. PMID- 23452241 TI - Effects of sulfate groups on the adsorption and activity of cellulases on cellulose substrates. AB - Pretreatment of lignocellulosic biomass with sulfuric acid may leave sulfate groups on its surface that may hinder its biochemical conversion. This study investigates the effects of sulfate groups on cellulase adsorption onto cellulose substrates and the enzymatic hydrolysis of these substrates. Substrates with different sulfate group densities were prepared from H2SO4- and HCl-hydrolyzed and partially and fully desulfated cellulose nanocrystals. Adsorption onto and hydrolysis of the substrates was analyzed by quartz crystal microbalance with dissipation monitoring (QCM-D). The surface roughness of the substrates, measured by atomic force microscopy, increased with decreasing sulfate group density, but their surface accessibilities, measured by QCM-D H2O/D2O exchange experiments, were similar. The adsorption of cellulose binding domains onto sulfated substrates decreased with increasing sulfate group density, but the adsorption of cellulases increased. The rate of hydrolysis of sulfated substrates decreased with increasing sulfate group density. The results indicated an inhibitory effect of sulfate groups on the enzymatic hydrolysis of cellulose, possibly due to nonproductive binding of the cellulases onto the substrates through electrostatic interactions instead of their cellulose binding domains. PMID- 23452242 TI - Complete mitochondrial genome of the larch hawk moth, Sphinx morio (Lepidoptera: Sphingidae). AB - The larch hawk moth, Sphinx morio, belongs to the lepidopteran family Sphingidae that has long been studied as a family of model insects in a diverse field. In this study, we describe the complete mitochondrial genome (mitogenome) sequences of the species in terms of general genomic features and characteristic short repetitive sequences found in the A + T-rich region. The 15,299-bp-long genome consisted of a typical set of genes (13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes) and one major non-coding A + T-rich region, with the typical arrangement found in Lepidoptera. The 316-bp-long A + T-rich region located between srRNA and tRNA(Met) harbored the conserved sequence blocks that are typically found in lepidopteran insects. Additionally, the A + T-rich region of S. morio contained three characteristic repeat sequences that are rarely found in Lepidoptera: two identical 12-bp repeat, three identical 5-bp-long tandem repeat, and six nearly identical 5-6 bp long repeat sequences. PMID- 23452243 TI - beta-Sheet nanocrystalline domains formed from phosphorylated serine-rich motifs in caddisfly larval silk: a solid state NMR and XRD study. AB - Adhesive silks spun by aquatic caddisfly (order Trichoptera) larvae are used to build both intricate protective shelters and food harvesting nets underwater. In this study, we use (13)C and (31)P solid-state NMR and wide angle X-ray diffraction (WAXD) as tools to elucidate molecular protein structure of caddisfly larval silk from the species Hesperophylax consimilis . Caddisfly larval silk is a fibroin protein based biopolymer containing mostly repetitive amino acid motifs. NMR and X-ray results provide strong supporting evidence for a structural model in which phosphorylated serine repeats (pSX)4 complex with divalent cations Ca(2+) and Mg(2+) to form rigid nanocrystalline beta-sheet structures in caddisfly silk. (13)C NMR data suggests that both phosphorylated serine and neighboring valine residues exist in a beta-sheet conformation while glycine and leucine residues common in GGX repeats likely reside in random coil conformations. Additionally, (31)P chemical shift anisotropy (CSA) analysis indicates that the phosphates on phosphoserine residues are doubly ionized, and are charge-stabilized by divalent cations. Positively charged arginine side chains also likely play a role in charge stabilization. Finally, WAXD results finds that the silk is at least 7-8% crystalline, with beta-sheet interplane spacings of 3.7 and 4.5 A. PMID- 23452244 TI - A common partitioning strategy for photosynthetic products in evolutionarily distinct phytoplankton species. AB - . We compare the nutrient-dependent photosynthetic efficiencies of the chlorophyte, Dunaliella tertiolecta, with those of the marine diatom, Thalassiosira weissflogii. Despite considerable evolutionary and physiological differences, these two species appear to use nearly identical growth strategies under a wide range of nutrient limitation. . Using a variety of physiological measurements, we find that, for both species and across all growth rates, 75% of the gross photosynthetic electron flow is invested in carbon fixation and only 30% is retained as net carbon accumulation. A majority of gross photosynthesis (70%) is ultimately used as reductant for biosynthetic pathways and for the generation of ATP. . In both species, newly formed carbon products exhibit much shorter half-lives at slow growth rates than at fast growth rates. We show that this growth rate dependence is a result of increased polysaccharide storage during the S phase of the cell cycle. . We present a model of carbon utilization that incorporates this growth rate-dependent carbon allocation and accurately captures (r(2) = 0.94) the observed time-resolved carbon retention. Together, our findings suggest a common photosynthetic optimization strategy in evolutionarily distinct phytoplankton species and contribute towards a systems-level understanding of carbon flow in photoautotrophs. PMID- 23452245 TI - Changes in CSF flow after one-stage posterior vertebral column resection in scoliosis patients with syringomyelia and Chiari malformation type I. AB - OBJECT: Phase contrast-cine MRI (PC-cine MRI) studies in patients with syringomyelia and Chiari malformation Type I (CM-I) have demonstrated abnormal CSF flow across the foramen magnum, which can revert to normal after craniocervical decompression with syrinx shrinkage. In order to investigate the mechanisms leading to postoperative syringomyelia shrinkage, the authors studied the hydrodynamic changes of CSF flow in the craniocervical junction and spinal canal in patients with scoliosis associated with syringomyelia after one-stage deformity correction by posterior vertebral column resection. METHODS: Preoperative and postoperative CSF flow dynamics at the levels of the foramen magnum, C-7, T-7 (or apex), and L-1 were assessed by electrocardiogram synchronized cardiac-gated PC-cine MRI in 8 adolescent patients suffering from severe scoliosis with syringomyelia and CM-I (scoliosis group) and undergoing posterior vertebral column resection. An additional 8 patients with syringomyelia and CM-I without spinal deformity (syrinx group) and 8 healthy volunteers (control group) were also enrolled. Mean values were obtained for the following parameters: the duration of a CSF cycle, the duration of caudad CSF flow (CSF downflow [DF]) and cephalad CSF flow (CSF upflow [UF]), the ratio of DF duration to CSF cycle duration (DF%), and the ratio of UF duration to CSF cycle duration (UF%). The ratio of the stationary phase (SP) duration to CSF cycle duration was calculated (SP%). The maximum downflow velocities (VD max) and maximum upflow velocities (VU max) were measured. SPSS (version 14.0) was used for all statistical analysis. RESULTS: Patients in the scoliosis group underwent one stage posterior vertebral column resection for deformity correction without suboccipital decompression. The mean preoperative coronal Cobb angle was 102.4 degrees (range 76 degrees -138 degrees ). The mean postoperative Cobb angle was 41.7 degrees (range 12 degrees -75 degrees ), with an average correction rate of 59.3%. During the follow-up, 1 patient with hypermyotonia experienced a significant decrease of muscle tension and 1 patient with reduced anal sphincter tone manifested recovery. A total of 5 patients demonstrated a significant decrease (> 30%) in syrinx size. With respect to changes in CSF flow dynamics, the syrinx group was characterized by slower and shorter downflow than the control group, and the difference was more significant at the foramen magnum and C-7 levels. In patients with scoliosis, CSF downflow at the foramen magnum level was significantly restricted, and a prolonged stationary phase indicated increased obstruction of CSF flow. After posterior vertebral column resection, the peak velocity of CSF flow at the foramen magnum increased, and the downflow phase duration was markedly prolonged. The parameters showed a return to almost normal CSF dynamics at the craniocervical region, and this improvement was maintained for 6-12 months of follow-up. CONCLUSIONS: There were distinct abnormalities of CSF flow at the craniocervical junction in patients with syringomyelia. Abnormal dynamics of downflow could be aggravated by associated severe spinal deformity and improved by correction via posterior vertebral column resection. PMID- 23452246 TI - Transpedicular N-butyl cyanoacrylate-mediated percutaneous embolization of symptomatic vertebral hemangiomas. AB - OBJECT: The resection of spinal hemangiomas is often challenging because of characteristic high-volume and potentially prohibitive intraoperative blood loss. Although transarterial embolization can mitigate this risk, it can be suboptimal when tumor arterial supply is diffuse or poorly defined. The authors present their experience in the use of preoperative percutaneous direct injection of spinal hemangiomas with N-butyl cyanoacrylate (NBCA) as an effective preoperative adjunct that may reduce operative blood loss and facilitate resection of these vascular tumors. METHODS: Four patients with symptomatic spinal hemangiomas were treated using percutaneous transpedicular direct NBCA-Lipiodol injection; 2 patients had undergone prior spinal angiography, with suboptimal transarterial embolization in 1. Each patient underwent percutaneous bilateral transpedicular NBCA-assisted tumor embolization prior to resection. Retrospective analysis of operative times, blood loss, and clinical data is presented. RESULTS: There were no complications associated with the percutaneous NBCA embolization technique. The procedure was effective at facilitating tumor removal and minimizing intraoperative blood loss, especially at the vertebral body resection stage. Improved tumor filling was achieved as the filling characteristics of dilute NBCA Lipiodol mixture within large-channel, high-flow hemangiomas were appreciated with experience. CONCLUSIONS: Transpedicular NBCA direct-puncture embolization of spinal hemangiomas is an effective preoperative adjunct that facilitates resection of these highly vascular tumors. It is particularly useful when transarterial embolization is unsafe or suboptimal due to constraints imposed by the local angioarchitecture. PMID- 23452247 TI - The rib head as a landmark in the anterolateral approach to the thoracic spine: a computed tomography-based morphometric study. AB - OBJECT: The rib head is an important landmark in the anterolateral approach to the thoracic spine. Resection of the rib head is typically the first step in gaining access to the underlying pedicle and ultimately the spinal canal. The goal of this work is to quantify the relationship of the rib head to the spinal canal and adjacent aorta at each thoracic level using CT-based morphometric measurements. METHODS: One hundred thoracic spine CT scans (obtained in 50 male and 50 female subjects) were evaluated in this study. The width and depth of each vertebra body were measured from T-1 to T-12. In addition, the distance of each rib head to the spinal canal was determined by drawing a line connecting the rib heads bilaterally and measuring the distance to this line from the most ventral aspect of the spinal canal. Finally, the distance of the left rib head to the thoracic aorta was measured at each thoracic level below the aortic arch. RESULTS: The vertebral body depth progressively increased in a rostral to caudal direction. The vertebral body width was at its minimum at T-4 and progressively increased to T-12. The rib head extended beyond the spinal canal maximally at T 1. This distance incrementally decreased toward the caudal levels, with the tip of the rib head lying approximately even with the ventral canal at T-11 and T-12. The distance between the aorta and the left rib head increased in a rostral to caudal direction as well. CONCLUSIONS: The rib head is an important landmark in the anterolateral approach to the thoracic spine. At more cephalad levels, a larger portion of rib head requires resection to gain access to the spinal canal. At more caudad levels, there is a safer working distance between the rib head and aorta. PMID- 23452248 TI - Herpes myelitis after thoracic spine surgery. AB - Herpes simplex or herpes zoster reactivation after spinal surgery is rarely reported. This case report and review of the literature describes patients in whom this reactivation occurs to clarify the diagnosis and management. In addition to reporting their case, the authors reviewed case reports and series published between 1980 and 2012 found through a PubMed search. Herpes reactivation is generally confined to a vesicular rash that can be treated with acyclovir. However, occasional dissemination has occurred and has led to myelitis or encephalitis. Atypical presentations led to delays in diagnosis, delayed treatment, and poor neurological outcome. While rare, herpes simplex or herpes zoster reactivation is a complication of spine surgery that must be considered in the face of new-onset focal neurological symptoms in a dermatome pattern without a structural cause, even without a rash. PMID- 23452249 TI - Long-term outcome of laminectomy for cervical ossification of the posterior longitudinal ligament. AB - OBJECT: Although laminectomy is an effective surgical technique for the treatment of multilevel cervical stenotic lesions, postoperative kyphosis and neurological deterioration have been frequently reported after laminectomy. Hence, laminectomy without fusion is seldom performed nowadays. However, the clinical impression from the long-term follow-up of patients who had undergone laminectomy does not support that postoperative kyphosis is common in patients with ossification of the posterior longitudinal ligament (OPLL). In this paper, the authors assessed the long-term outcome of laminectomy for cervical OPLL in terms of the changes in the cervical curvature and in the neurological status. METHODS: The authors retrospectively reviewed medical records and radiological images in patients who had undergone cervical laminectomy between 1999 and 2009. The preoperative and the final follow-up status recovery rate were assessed using the Japanese Orthopaedic Association (JOA) scale. The cervical global angle and range of motion (ROM) were measured preoperatively and at the last follow-up. The cervical spine was classified into 3 types: lordotic, straight, and kyphotic. RESULTS: A total of 34 patients were available for medical record review and telephone interviews. There were 28 men and 6 women, whose mean age at the time of surgery was 57.8 years. The mean follow-up period was 57.5 months. The mean preoperative JOA score was 10.7, and the JOA score at the last follow-up was significantly improved to 14.3 (p < 0.001) with a recovery rate of 56.3%. The JOA score at each postoperative follow-up point increased until 6 years postoperatively; thereafter, it gradually decreased. The mean preoperative global angle was -11.3 degrees and the most recent global angle was -8.4 degrees . The preoperative ROM was 33.9 degrees and the most recent ROM was 27.4 degrees . There was no statistical significance in the change of cervical curvature or ROM. Preoperatively, 29 of the 34 patients had a lordotic cervical curvature and 5 patients had a straight spine. At last follow-up, 24 patients had a lordotic curvature, 3 patients changed from lordosis to kyphosis, and 7 patients had a straight spine. One patient whose cervical curvature changed from lordosis to kyphosis during the follow-up period underwent cervical fusion 9 years after the laminectomy procedure. CONCLUSIONS: The long-term outcome of laminectomy for cervical OPLL is satisfactory in terms of the clinical and radiological aspects. The risk of postlaminectomy kyphosis was not high, raising the possibility that the OPLL itself may serve as a support for the spinal column. PMID- 23452250 TI - Dielectric properties of polymer-particle nanocomposites influenced by electronic nature of filler surfaces. AB - The interface between the polymer and the particle has a critical role in altering the properties of a composite dielectric. Polymer-ceramic nanocomposites are promising dielectric materials for many electronic and power devices, combining the high dielectric constant of ceramic particles with the high dielectric breakdown strength of a polymer. Self-assembled monolayers of electron rich or electron poor organophosphate coupling groups were applied to affect the filler-polymer interface and investigate the role of this interface on composite behavior. The interface has potential to influence dielectric properties, in particular the leakage and breakdown resistance. The composite films synthesized from the modified filler particles dispersed into an epoxy polymer matrix were analyzed by dielectric spectroscopy, breakdown strength, and leakage current measurements. The data indicate that significant reduction in leakage currents and dielectric losses and improvement in dielectric breakdown strengths resulted when electropositive phenyl, electron-withdrawing functional groups were located at the polymer-particle interface. At a 30 vol % particle concentration, dielectric composite films yielded a maximum energy density of ~8 J.cm(-3) for TiO2-epoxy nanocomposites and ~9.5 J.cm(-3) for BaTiO3-epoxy nanocomposites. PMID- 23452251 TI - Distribution of biomolecules in porous nitrocellulose membrane pads using confocal laser scanning microscopy and high-speed cameras. AB - The main focus of our research was to study the distribution of inkjet printed biomolecules in porous nitrocellulose membrane pads of different brands. We produced microarrays of fluorophore-labeled IgG and bovine serum albumin (BSA) on FAST, Unisart, and Oncyte-Avid slides and compared the spot morphology of the inkjet printed biomolecules. The distribution of these biomolecules within the spot embedded in the nitrocellulose membrane was analyzed by confocal laser scanning microscopy in the "Z" stack mode. By applying a "concentric ring" format, the distribution profile of the fluorescence intensity in each horizontal slice was measured and represented in a graphical color-coded way. Furthermore, a one-step diagnostic antibody assay was performed with a primary antibody, double labeled amplicons, and fluorophore-labeled streptavidin in order to study the functionality and distribution of the immune complex in the nitrocellulose membrane slides. Under the conditions applied, the spot morphology and distribution of the primary labeled biomolecules was nonhomogenous and doughnut like on the FAST and Unisart nitrocellulose slides, whereas a better spot morphology with more homogeneously distributed biomolecules was observed on the Oncyte-Avid slide. Similar morphologies and distribution patterns were observed when the diagnostic one-step nucleic acid microarray immunoassay was performed on these nitrocellulose slides. We also investigated possible reasons for the differences in the observed spot morphology by monitoring the dynamic behavior of a liquid droplet on and in these nitrocellulose slides. Using high speed cameras, we analyzed the wettability and fluid flow dynamics of a droplet on the various nitrocellulose substrates. The spreading of the liquid droplet was comparable for the FAST and Unisart slides but different, i.e., slower, for the Oncyte-Avid slide. The results of the spreading of the droplet and the penetration behavior of the liquid in the nitrocellulose membrane may (partly) explain the distribution of the biomolecules in the different slides. To our knowledge, this is the first time that fluid dynamics in diagnostic membranes have been analyzed by the use of high-speed cameras. PMID- 23452252 TI - Ventricular septal rupture following an acute inferior wall myocardial infarction detected by computed tomography imaging. PMID- 23452254 TI - TDDFT studies on the determination of the absolute configurations and chiroptical properties of Strandberg-type polyoxometalates. AB - The electronic circular dichroism (ECD) and UV-visible absorption (UV-vis) spectra of Strandberg-type polyoxometalates (POMs) (R, R)-[(R*PO3)2M5O15](2-) (R* = CH3CH(NH3), (M = Mo, W)) have been explored using the time-dependent density functional theory (TDDFT) method. It demonstrates that the absolute configurations of chiral systems can be determined by chiroptical spectroscopic methods combined with DFT calculations. The calculated ECD spectra of the Strandberg-type molybdate were produced over the range of 3.3-6.5 eV, which are generally in agreement with the experimental spectra. In addition, the ECD spectra of (R, R)-[(R*PO3)2W5O15](2-) (R* = CH3CH(NH3)) were produced over the range of 4.5-8.5 eV. The Becke's half-and-half hybrid exchange-correlation functional (BHandHLYP) with the HF exchange fraction to 55% hybrid functional was found to well predict the excitation energies of studied systems. The origins of the ECD bands of two systems are mainly ascribed to charge-transfer (CT) transitions from oxygen atoms to metal atoms in polyanion. The results suggest that the polyanion are chiroptical chromophores. The polyanion plays a role as an optically active chromophore and contribute to the absorptions of ECD spectra. The difference of the UV-vis/ECD spectra between two systems shows that the transition metal atom significantly influences on the chiroptical properties of the studied Strandberg-type POMs. PMID- 23452253 TI - Diversity of bacterial endosymbionts and bacteria-host co-evolution in Gondwanan relict moss bugs (Hemiptera: Coleorrhyncha: Peloridiidae). AB - Many hemipterans are associated with symbiotic bacteria, which are usually found intracellularly in specific bacteriomes. In this study, we provide the first molecular identification of the bacteriome-associated, obligate endosymbiont in a Gondwanan relict insect taxon, the moss bugs (Hemiptera: Coleorrhyncha: Peloridiidae), which represents one of the oldest lineages within the Hemiptera. Endosymbiotic associations of fifteen species of the family were analysed, covering representatives from South America, Australia/Tasmania and New Zealand. Phylogenetic analysis based on four kilobases of 16S-23S rRNA gene fragments showed that the obligate endosymbiont of Peloridiidae constitute a so far unknown group of Gammaproteobacteria which is named here 'Candidatus Evansia muelleri'. They are related to the sternorrhynchous endosymbionts Candidatus Portiera and Candidatus Carsonella. Comparison of the primary-endosymbiont and host (COI + 28S rRNA) trees showed overall congruence indicating co-speciation the hosts and their symbionts. The distribution of the endosymbiont within the insect body and its transmission was studied using FISH. The endosymbionts were detected endocellularly in a pair of bacteriomes as well as in the 'symbiont ball' of the posterior pole of each developing oocyte. Furthermore, ultrastructural analysis of the Malpighian tubules revealed that most host nuclei are infected by an endosymbiotic, intranuclear bacterium that was determined as an Alphaproteobacterium of the genus Rickettsia. PMID- 23452255 TI - Pathological effects of processed bovine pericardial scaffolds--a comparative in vivo evaluation. AB - The objective of the present study was to assess the biocompatibility and regenerative potential of decellularized bovine pericardial scaffold in comparison with glutaraldehyde-treated and fresh bovine pericardial implants using short-term intramuscular implantation testing in a rat model. The inflammatory and immune responses were assessed using histopathological examination, special stains for connective tissue, histomorphometric evaluation, and immunohistochemistry. The decellularized pericardium showed an active tissue remodeling response with complete cellular invasion, minimum connective tissue encapsulation, extensive fibrovascular tissue formation, and collagen deposition. On the contrary, the glutaraldehyde-treated pericardial implants showed incomplete degradation and cellular invasion, while the fresh pericardial implants elicited a severe foreign body reaction. The results of immunohistochemical staining revealed a minimum T helper (CD4+) lymphocyte response in decellularized pericardial implants compared with its glutaraldehyde treated and fresh counterparts. The decellularized bovine pericardium was better accepted as a prosthetic scaffold, which permitted maximum collagen deposition and active tissue remodeling by invading host cells and showed good tissue integration in vivo compared with glutaraldehyde-treated and fresh/untreated pericardium. PMID- 23452256 TI - A rare case of cellulitis-like cutaneous metastasis of gastric adenocarcinoma. PMID- 23452257 TI - Differential effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated immune reactions on murine P0106-125 -induced experimental autoimmune neuritis. AB - AIM: The role of chemokines and their receptors, which regulate trafficking and homing of leucocytes to inflamed organs in human or murine autoimmune neuritis, has not yet been elucidated in detail, Therefore, the role of the chemokine receptors CXCR4 and CXCR7 and their ligand CXCL12 was studied in autoimmune mediated inflammation of the peripheral nervous system. METHODS: CXCL12/CXCR4 and/or CXCL12/CXCR7 interactions were specifically inhibited by the compounds AMD3100 or CCX771, respectively, in experimental autoimmune neuritis (EAN) of C57BL/6J mice immunized with P0106-125 peptide. RESULTS: Disease activity was significantly suppressed by blocking CXCR7 while antagonization of CXCR4 enhanced disease activity. Enhanced disease activity was accompanied by significantly increased transcription of IFN-gamma, IL-12 and TNF-alpha mRNA in regional lymph nodes and spleen as well as by increased serum levels of IFN-gamma. Furthermore, by blocking CXCR4, expression of the cell adhesion molecules ICAM-1 and VCAM-1 was upregulated on vascular endothelial cells of the sciatic nerve, which coincided with significantly increased infiltration of the sciatic nerve by CD4+ T cells and macrophages. Remarkably, combined antagonization of both CXCR4 and CXCR7 significantly suppressed disease activity. This was accompanied by increased frequencies of activated and highly IFN-gamma-expressing, P0106-125 specific T cells in regional lymph nodes and spleen; however, these cells were unable to infiltrate the sciatic nerve. CONCLUSION: These data suggest differential and hierarchically ordered roles for CXCR4/CXCL12- vs. CXCR7/CXCL12 dependent effects during EAN: CXCR7/CXCL12 interaction is a gatekeeper for pathogenic cells, regardless of their CXCR4/CXCL12-dependent state of activation. PMID- 23452258 TI - Lumped pathway metabolic model of organic carbon accumulation and mobilization by the alga Chlamydomonas reinhardtii. AB - Phototrophic microorganisms have significant potential as bioenergy feedstocks, but the sustainability of large-scale cultivation will require the use of wastewater as a renewable resource. A key barrier to this advancement is a lack of bioprocess understanding that would enable the design and implementation of efficient and resilient mixed community, naturally lit cultivation systems. In this study, a lumped pathway metabolic model (denoted the phototrophic process model or PPM) was developed for mixed phototrophic communities subjected to day/night cycling. State variables included functional biomass (XCPO), stored carbohydrates (XCH), stored lipids (XLI), nitrate (SNO), phosphate (SP), and others. PPM metabolic reactions and stoichiometry were based on Chlamydomonas reinhardtii , but experiments for model calibration and validation were performed in flat panel photobioreactors (PBRs) originally inoculated with biomass from a phototrophic system at a wastewater treatment plant. PBRs were operated continuously as cyclostats to poise cells for intrinsic kinetic parameter estimation in batch studies, which included nutrient-available conditions in light and dark as well as nitrogen-starved and phosphorus-starved conditions in light. The model was calibrated and validated and was shown to be a reasonable predictor of growth, lipid and carbohydrate storage, and lipid and carbohydrate mobilization by a mixed microbial community. PMID- 23452259 TI - Pelvic floor trauma in childbirth. AB - The investigation of female pelvic floor function and anatomy is moving from the fringes to the mainstream of urogynaecology and female urology, and it is becoming increasingly relevant for obstetrics. We are coming to realise that pelvic floor trauma in labour is common, usually overlooked, and a major factor in the causation of pelvic organ prolapse. Modern imaging methods such as magnetic resonance and 3D/4D ultrasound have enabled us to diagnose such trauma reliably and accurately, most commonly in the form of an avulsion of the puborectalis muscle; that is, a disconnection of the muscle from its insertion on the os pubis. Such damage to the levator muscle is macroscopically evident and can also be palpated, a skill that is available to every clinician, requiring neither investment nor specialised equipment. In this review, I will describe pelvic floor assessment by palpation and ultrasound and illustrate the commonest abnormalities and their clinical consequences. This paper will not focus on magnetic resonance imaging due to technical restrictions, cost and access issues in most jurisdictions, and because several papers have recently shown that ultrasound is at least as effective in diagnosing such trauma. Anal sphincter trauma is generally well covered in the literature and hence not subject of this review. PMID- 23452260 TI - Spatial scale affects landscape genetic analysis of a wetland grasshopper. AB - Most landscape genetic studies assess the impact of landscape elements on species' dispersal and gene flow. Many of these studies perform their analysis on all possible population pairs in a study area and do not explicitly consider the effects of spatial scale and population network topology on their results. Here, we examined the effects of spatial scale and population network topology on the outcome of a landscape genetic analysis. Additionally, we tested whether the relevant spatial scale of landscape genetic analysis could be defined by population network topology or by isolation-by-distance (IBD) patterns. A data set of the wetland grasshopper Stethophyma grossum, collected in a fragmented agricultural landscape, was used to analyse population network topology, IBD patterns and dispersal habitats, using least-cost transect analysis. Landscape genetic analyses neglecting spatial scale and population network topology resulted in models with low fits, with which a most likely dispersal habitat could not be identified. In contrast, analyses considering spatial scale and population network topology resulted in high model fits by restricting landscape genetic analysis to smaller scales (0-3 km) and neighbouring populations, as represented by a Gabriel graph. These models also successfully identified a likely dispersal habitat of S. grossum. The above results suggest that spatial scale and potentially population network topology should be more explicitly considered in future landscape genetic analyses. PMID- 23452261 TI - Evaluation of spatial and seasonal radioactivity dose fluctuations in a Wierzchowska Gorna limestone cave. AB - Measurements of the dose rate changes were carried out in order to assess seasonal and spatial radioactivity variations in the largest limestone cave of the Polish Jura Wierzchowska Gorna. Thermoluminescence detectors, which were annealed, calibrated and protected against humidity were used. Measurements were repeated four times in 13 locations to observe possible changes. The external dose rate was in the range of 0.004-0.106 mGy/quarter. The results were influenced by the detector locations - lower doses were estimated closer to the cave entrance and the highest doses were in the so-called 'primitive man room'. Doses measured in four periods were statistically significantly different. The external dose level as well as seasonal and spatial dose changes measured in the cave were low. In other caves where external doses are higher, seasonal and spatial dose changes may have a stronger impact on radiological hazard. PMID- 23452262 TI - A comparison of patient and tumour characteristics in two UK bladder cancer cohorts separated by 20 years. AB - OBJECTIVES: To compare patient and tumour characteristics at presentation from two large bladder cancer cohorts, with recruitment separated by 15-20 years To identify significant differences in the West Midlands' urothelial cancer of the bladder (UCB) population during this period. PATIENTS AND METHODS: Data were collected prospectively from 1478 patients newly diagnosed with UCB in the West Midlands from January 1991 to June 1992 (Cohort 1), and from 1168 patients newly diagnosed with UBC within the same region from December 2005 to April 2011 (Cohort 2). Gender, age, smoking history, and tumour grade, stage, type, multiplicity and size at presentation were compared using a Pearson chi-square test or Cochran-Armitage trend test, as appropriate. RESULT: Cohort 2 had a higher proportion of male patients (P = 0.021), elderly patients (P < 0.001), grade 3 tumours (P < 0.001), Ta/T1 tumours (P = 0.008), multiple tumours (P < 0.001), and tumours of <=2 cm in diameter (P < 0.001). CONCLUSIONS: There were significant differences between the cohorts. These differences are potentially explained by an ageing population, changes in grading practices, improved awareness of important symptoms, improved cystoscopic technology, and reductions in treatment delays. Regional cohorts remain important for identifying changes in tumour and patient characteristics that may influence disease management in the UK and beyond. PMID- 23452263 TI - Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms. AB - A cohort of 154 French Hajj pilgrims participating in the 2012 Hajj were systematically sampled with nasal swabs prior to returning to France, and screened for the novel HCoV-EMC coronavirus by two real-time RT-PCR assays. Despite a high rate of respiratory symptoms (83.4%), including 41.0% influenza like illness, no case of HCoV-EMC infection was detected. Despite the fact that zoonotic transmission was suspected in the first few cases, a recent family cluster in the Kingdom of Saudi Arabia suggests that the virus might show at least limited spread from person to person, which justifies continuing epidemiological surveillance. PMID- 23452264 TI - Increased responsivity of suspended graphene photodetectors. AB - The responsivity of graphene photodetectors depends critically on the elevated temperature of the electronic subsystem upon photoexcitation. We investigate the role of the substrate in providing cooling pathways for photoexcited carriers under ambient conditions by partially suspending few-layer graphene over a trench. Through photocurrent microscopy, we observe p-n junctions near the supported/suspended interfaces that produce photothermoelectric currents. Most importantly, we find the photocurrent in suspended p-n junctions to be an order of magnitude larger than in supported structures. This enhancement is attributed to the elimination of a dominant electronic cooling channel via the surface phonons of the polar substrate. Our work documents this mechanism of energy exchange between graphene and its environment, and it points to the importance of dielectric engineering for future improved graphene photodetectors. PMID- 23452265 TI - Post-operative hypercapnia-induced hyperpnoea accelerates recovery from sevoflurane anaesthesia: a prospective randomised controlled trial. AB - BACKGROUND: The time to recovery from vapour anaesthesia is shortened by an increase in ventilation while maintaining normocapnia. Hypercapnia during emergence from anaesthesia in spontaneously breathing patients also increases anaesthetic clearance from the brain by increasing cerebral blood flow. We hypothesised that hypercapnia-induced hyperpnoea accelerates emergence from sevoflurane anaesthesia compared to the standard anaesthesia protocol. METHODS: After Ethics Review Board approval, 44 ASA I-III patients undergoing elective gynaecological surgery were randomised after surgery to either hypercapnic hyperpnoea or control groups. In the hypercapnic hyperpnoea group, the end-tidal CO2 was adjusted to a range of 6.0-7.3 kPa to maintain a minute ventilation of 10 15 l/min. Recovery indices were compared using unpaired t-tests and ANOVA. RESULTS: Prior to extubation, minute ventilation and end-tidal CO2 in hypercapnic hyperpnoea and control groups were 10.3 +/- 1.7 l/min vs. 5.4 +/- 1.2 l/min (P < 0.001) and 6.6 +/- 0.6 kPa and 5.2 +/- 0.5 kPa (P < 0.001), respectively. Compared to control, the study group had shorter time to extubation [4.4 +/- 1.3 (SD) vs. 9.8 +/- 4.4 min, P < 0.01], BIS recovery to > 75 (2.4 +/- 0.9 vs. 6.1 +/ 3.1 min, P < 0.01), eye opening (3.9 +/- 1.6 vs. 9.8 +/- 6.2 min, P < 0.01), eligibility for leaving operating room (5.1 +/- 1.2 vs. 11.1 +/- 4.6 min, P < 0.01), and post-anaesthesia care unit (73.9 +/- 14.2 vs. 89.4 +/- 22.6) CONCLUSION: Hypercapnic hyperpnoea in spontaneously breathing patients halves the time of recovery from sevoflurane-induced anaesthesia in the operating room. PMID- 23452266 TI - Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing syndrome secondary to an epidermoid tumor in the cerebellopontine angle. AB - Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome is classified under trigeminal autonomic cephalalgias. This rare headache syndrome is infrequently associated with secondary pathologies. In this paper the authors report on a patient with paroxysmal left retroorbital pain with associated autonomic symptoms of ipsilateral conjunctival injection and lacrimation, suggestive of SUNCT syndrome. After failed medical treatment an MRI sequence was obtained in this patient, demonstrating an epidermoid tumor in the left cerebellopontine angle. The patient's symptoms completely resolved after a gross-total resection of the tumor. This case demonstrates the effectiveness of resection as definitive treatment for SUNCT syndrome associated with tumoral compression of the trigeminal nerve. Early MRI studies should be considered in all patients with SUNCT, especially those with atypical signs and symptoms. PMID- 23452267 TI - Diversity of proteobacterial endosymbionts in hemlock woolly adelgid (Adelges tsugae) (Hemiptera: Adelgidae) from its native and introduced range. AB - Knowledge of intraspecific variation in symbioses may aid in understanding the ecology of widespread insects in different parts of their range. We investigated bacterial symbionts of Adelges tsugae, a pest of hemlocks in eastern North America introduced from Asia. Amplification, cloning, and sequencing of bacterial 16S rDNA, in situ hybridizations, and electron microscopy revealed that A. tsugae harbours up to five bacterial phylotypes, according to population. Three Gammaproteobacteria species are maternally transmitted. The first, designated 'Ca. Pseudomonas adelgestsugas' resides in the haemocoel, and was detected in all populations except Taiwan. The second phylotype, 'Ca. Serratia symbiotica', resides in bacteriocytes of populations on Tsuga sieboldii in Japan and in E. North America. The third phylotype, designated 'Ca. Annandia adelgestsuga', clustered within a lineage of several insect endosymbionts that included Buchnera aphidicola. It was detected in bacteriocytes in all populations, and in salivary glands of first instars. Two Betaproteobacteria phylotypes were detected in some Japanese T. sieboldii and eastern North America populations, and were observed only in salivary glands with no evidence of maternal transmission. Our results support the ideas that symbiont gain and loss has been volatile in adelgids, and that symbionts may help to trace the source of invasive species. PMID- 23452268 TI - Electrostatically embedded generalized molecular fractionation with conjugate caps method for full quantum mechanical calculation of protein energy. AB - An electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method is developed for efficient linear-scaling quantum mechanical (QM) calculation of protein energy. This approach is based on our previously proposed GMFCC/MM method (He; et al. J. Chem. Phys. 2006, 124, 184703), In this EE-GMFCC scheme, the total energy of protein is calculated by taking a linear combination of the QM energy of the neighboring residues and the two-body QM interaction energy between non-neighboring residues that are spatially in close contact. All the fragment calculations are embedded in a field of point charges representing the remaining protein environment, which is the major improvement over our previous GMFCC/MM approach. Numerical studies are carried out to calculate the total energies of 18 real three-dimensional proteins of up to 1142 atoms using the EE-GMFCC approach at the HF/6-31G* level. The overall mean unsigned error of EE-GMFCC for the 18 proteins is 2.39 kcal/mol with reference to the full system HF/6-31G* energies. The EE-GMFCC approach is also applied for proteins at the levels of the density functional theory (DFT) and second-order many-body perturbation theory (MP2), also showing only a few kcal/mol deviation from the corresponding full system result. The EE-GMFCC method is linear-scaling with a low prefactor, trivially parallel, and can be readily applied to routinely perform structural optimization of proteins and molecular dynamics simulation with high level ab initio electronic structure theories. PMID- 23452269 TI - Hyperkeratotic variant of inflammatory disseminated superficial porokeratosis with lichenoid reaction and extensive amyloid deposition. PMID- 23452270 TI - Poly(acrylic acid)-grafted fluoropolymer films for highly sensitive fluorescent bioassays. AB - In this study, a facile and effective method for the surface functionalization of inert fluoropolymer substrates using surface grafting was demonstrated for the preparation of a new platform for fluorescence-based bioassays. The surface of perfluorinated poly(ethylene-co-propylene) (FEP) films was functionalized using a 150 keV ion implantation, followed by the graft polymerization of acrylic acid, to generate a high density of carboxylic acid groups on the implanted surface. The resulting functionalized surface was investigated in terms of the surface density of carboxylic acid, wettability, chemical structure, surface morphology, and surface chemical composition. These results revealed that poly(acrylic acid) (PAA) was successfully grafted onto the implanted FEP surface and its relative amount depended on the fluence. To demonstrate the usefulness of this method for the fabrication of bioassays, the PAA-grafted FEP films were utilized for the immobilization of probe DNA for anthrax toxin, followed by hybridization with Cy3 labeled target DNA. Liver cancer-specific alpha-feto-protein (AFP) antigen was also immobilized on the PAA-grafted FEP films. Texas Red-labeled secondary antibody was reacted with AFP-specific primary antibody prebound to the AFP antigen using an immunoassay method. The results revealed that the fluorescence intensity clearly depended on the concentration of the target DNA hybridized to the probe DNA and the AFP antigen immobilized on the FEP films. The lowest detectable concentrations of the target DNA and the AFP antigen were 10 fg/mL and 10 pg/mL, respectively, with the FEP films prepared at a fluence of 3 * 10(14) ions/cm(2). PMID- 23452271 TI - Adhesion of mussel foot protein-3 to TiO2 surfaces: the effect of pH. AB - The underwater adhesion of marine mussels relies on mussel foot proteins (mfps) rich in the catecholic amino acid 3,4-dihydroxyphenylalanine (Dopa). As a side chain, Dopa is capable of strong bidentate interactions with a variety of surfaces, including many minerals and metal oxides. Titanium is among the most widely used medical implant material and quickly forms a TiO2 passivation layer under physiological conditions. Understanding the binding mechanism of Dopa to TiO2 surfaces is therefore of considerable theoretical and practical interest. Using a surface forces apparatus, we explored the force-distance profiles and adhesion energies of mussel foot protein 3 (mfp-3) to TiO2 surfaces at three different pHs (pH 3, 5.5 and 7.5). At pH 3, mfp-3 showed the strongest adhesion force on TiO2, with an adhesion energy of ~-7.0 mJ/m(2). Increasing the pH gives rise to two opposing effects: (1) increased oxidation of Dopa, thus, decreasing availability for the Dopa-mediated adhesion, and (2) increased bidentate Dopa-Ti coordination, leading to the further stabilization of the Dopa group and, thus, an increase in adhesion force. Both effects were reflected in the resonance enhanced Raman spectra obtained at the three deposition pHs. The two competing effects give rise to a higher adhesion force of mfp-3 on the TiO2 surface at pH 7.5 than at pH 5.5. Our results suggest that Dopa-containing proteins and synthetic polymers have great potential as coating materials for medical implant materials, particularly if redox activity can be controlled. PMID- 23452272 TI - Concurrent and prospective effects of psychopathic traits on affective and cognitive empathy in a community sample of late adolescents. AB - BACKGROUND: A deficit in affective rather than cognitive empathy is thought to be central to psychopathic traits. However, empirical evidence for empathy deficits in adolescents with psychopathic traits is limited. We investigated the concurrent and prospective effects of psychopathic traits on affective and cognitive trait empathy in late adolescence. METHODS: A community sample of 107 males and 126 females who were approximately 16-year olds at Time 1 participated in four annual waves. Sex-specific classes of adolescents' psychopathic traits were created using Latent Class Analyses. Subsequently, we investigated class differences in level and development of empathy. RESULTS: For both sexes, Latent Class Analyses produced two classes: one class with low and one with moderate levels of psychopathic traits. Consistent with our hypothesis, for both sexes, adolescents with moderate levels of psychopathic traits reported lower mean levels of affective empathy than adolescents with low levels of psychopathic traits. In addition, female adolescents with moderate psychopathic traits reported lower mean levels of cognitive empathy. Male adolescents showed a trend in this direction. No differences between classes were found in development of empathy, which increased over years. CONCLUSIONS: This is the first study to show that male and female adolescents with higher levels of psychopathic traits have lower levels of affective empathy not only concurrently but also prospectively over a 3-year period. Females additionally showed a similar pattern on cognitive empathy. In this community sample, developmental results suggest that adolescents with higher levels of psychopathic traits have relative rather than absolute empathy deficits. PMID- 23452273 TI - Probing single-molecule fluorescence spectral modulation within individual hotspots with subdiffraction-limit image resolution. AB - The enhancement of the electromagnetic field on the rough metallic nanostructure has been extensively applied to obtain chemical or biological information about molecules with high sensitivity and has received much attention due to its potential applications in new types of devices based on nanoelectronics and nanophotonics. The typical size of the field enhancement area, the so-called hotspot, is approximately 1 order of magnitude smaller than the optical diffraction limit. In the present study, an optical super-resolution microscopic and spectroscopic approach is introduced to explore single-molecule fluorescence within a hotspot where nonhomogeneous spectral modulation is resolved beyond the optical diffraction limit for the first time. Distinct Stokes shifts from individual dyes were directly observed within single hotspots, which were found to be independent of the local electromagnetic field strength. The method reported here provides a robust tool to probe the optical properties of nanoresonantors with high temporal and spatial resolution. PMID- 23452274 TI - Body mass index (BMI) as predictor of ALSFRS-R score decline in ALS patients. AB - Recent studies of amyotrophic lateral sclerosis (ALS) suggest that body mass index (BMI) predicts patients' survival in a curvilinear manner. We sought to determine the relationship of initial BMI to decline in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score over time. We used data from the high dose Coenzyme-Q10 in ALS (QALS) clinical trial, with in-person ALSFRS-R interviews at baseline and nine months (n = 150). Multiple regression analysis allowed adjustment for a range of predictors. The final analysis, adjusted for age and FVC, indicated a significant, non-linear association of BMI with the change of ALSFRS-R over time (p < 0.01). The smallest decline was at BMI of 30. Among non-obese patients (BMI < 30, n = 126), higher BMI was associated with slower ALSFRS-R decline (p = 0.03). Among obese patients (BMI >= 30, n = 24), higher BMI was associated, although not significantly, with faster decline (p = 0.17). In conclusion, for ALS patient with BMI less than 30, higher initial BMI predicts slower functional decline. For patients with BMI greater than 30, higher initial BMI predicts more rapid decline. These results indicate that previous, apparently contradictory results can be reconciled, and suggest that initial BMI may help predict disease progression in ALS patients. PMID- 23452275 TI - The impact of a serum based proteomic mass spectrometry test on treatment recommendations in advanced non-small-cell lung cancer. AB - OBJECTIVE: To assess the impact of a serum-based proteomic test for non-small cell lung cancer (NSCLC) on physician treatment recommendations. RESEARCH DESIGN AND METHODS: A multivariate, serum-based proteomic test (VeriStrat) is commercially available to assist physicians when determining treatment using epidermal growth factor receptor inhibitor (EGFRi) therapy, such as erlotinib (Tarceva), by stratifying patients into two categories: those with significantly better ('good') and those with significantly worse ('poor') outcomes following treatment with EGFRi therapy. All tests ordered from August 9, 2011 to November 26, 2012, were considered for this study. Pre- and post-test treatment recommendations were prospectively collected from ordering physicians on a voluntary basis. Only those tests that had both pre- and post-test treatment information were included in the analysis group. MAIN OUTCOME MEASURES: Proportional change and correlation of treatment recommendations before and after receipt of the test results. RESULTS: Over the duration of the study, 724 physicians ordered 2854 tests. The analysis group comprised the 226 physicians who provided pre- and post-test treatment information (n = 403 tests). Following receipt of the test results, 90.3% (95% CI: 86.4-93.3%) of patients who tested as 'good' received erlotinib recommendations versus 9.6% (95% CI: 4.5-17.4%, p < 0.0001) of patients who tested as 'poor'. Ninety percent of post-test treatment recommendations positively correlated with test results, with 40% showing a change from pre-test considerations. STUDY LIMITATIONS: Data based on physicians willing to submit recommendations and endpoint limited to therapy recommendations. CONCLUSIONS: Among test orderers, serum-based proteomic mass spectrometry testing significantly influenced therapy recommendations in NSCLC. Usage patterns should be monitored as use expands. PMID- 23452276 TI - Modified proximal perineal urethrostomy technique for treatment of urethral stricture in goats. AB - OBJECTIVE: To report a modified procedure for perineal urethrostomy (PU) in goats. STUDY DESIGN: Case series. ANIMALS: Adult castrated male pet goats (n = 11) that had recurrence of urinary tract obstruction after one or more surgical procedures for obstructive urolithiasis. METHODS: Medical records (May 2008 February 2011) of goats that had a modified proximal PU were reviewed for history, signalment, and intraoperative and postoperative complications. Follow up was obtained through clinical examination or by telephone interview of owners or referring veterinarians. RESULTS: Ten goats survived to discharge. Postoperative complications included hemorrhage (n = 7), misdirected urine stream (3), obstructive urolithiasis (2), and bladder atony, dysuria, dehiscence, or delayed healing (1 each). One goat died acutely 15 hours after surgery from peritonitis, pleuritis, hemorrhagic cystitis, and hepatic lipidosis, and 1 goat was euthanatized 14 months after surgery because of renal failure and persistent cystitis. Urethrostomy sites were patent and functional in 9 goats available for long-term follow-up (>12 months). CONCLUSIONS: Transection of penile body attachments from the pelvis and careful mucocutaneous apposition may decrease the risk of postoperative urethral stricture formation in goats after PU. Hemorrhage is common after the procedure but does not affect clinical outcome. PMID- 23452277 TI - Protein phosphatase 2A regulatory subunits perform distinct functional roles in the maize pathogen Fusarium verticillioides. AB - Fusarium verticillioides is a pathogen of maize causing ear rot and stalk rot. The fungus also produces fumonisins, a group of mycotoxins linked to disorders in animals and humans. A cluster of genes, designated FUM genes, plays a key role in the synthesis of fumonisins. However, our understanding of the regulatory mechanism of fumonisin biosynthesis is still incomplete. We have demonstrated previously that Cpp1, a protein phosphatase type 2A (PP2A) catalytic subunit, negatively regulates fumonisin production and is involved in cell shape maintenance. In general, three PP2A subunits, structural A, regulatory B and catalytic C, make up a heterotrimer complex to perform regulatory functions. Significantly, we identified two PP2A regulatory subunits in the F. verticillioides genome, Ppr1 and Ppr2, which are homologous to Saccharomyces cerevisiae Cdc55 and Rts1, respectively. In this study, we hypothesized that Ppr1 and Ppr2 are involved in the regulation of fumonisin biosynthesis and/or cell development in F. verticillioides, and generated a series of mutants to determine the functional role of Ppr1 and Ppr2. The PPR1 deletion strain (Deltappr1) resulted in drastic growth defects, but increased microconidia production. The PPR2 deletion mutant strain (Deltappr2) showed elevated fumonisin production, similar to the Deltacpp1 strain. Germinating Deltappr1 conidia formed abnormally swollen cells with a central septation site, whereas Deltappr2 showed early hyphal branching during conidia germination. A kernel rot assay showed that the mutants were slow to colonize kernels, but this is probably a result of growth defects rather than a virulence defect. Results from this study suggest that two PP2A regulatory subunits in F. verticillioides carry out distinct roles in the regulation of fumonisin biosynthesis and fungal development. PMID- 23452278 TI - The cis-acting CTTC-P1BS module is indicative for gene function of LjVTI12, a Qb SNARE protein gene that is required for arbuscule formation in Lotus japonicus. AB - The majority of land plants live in symbiosis with arbuscular mycorrhizal fungi from the phylum Glomeromycota. This symbiosis improves acquisition of phosphorus (P) by the host plant in exchange for carbohydrates, especially under low-P availability. The symbiosome, constituted by root cortex cells accommodating arbuscular mycorrhizal fungal hyphae, is the site at which bi-directional exchange of nutrients and metabolites takes place. Uptake of orthophosphate (Pi) in the symbiosome is facilitated by mycorrhiza-specific plant Pi transporters. Modifications of the potato Pi transporter 3 (StPT3) promoter were analysed in transgenic mycorrhizal roots, and it was found that the CTTC cis-regulatory element is necessary and sufficient for a transcriptional response to fungal colonization under low-Pi conditions. Phylogenetic footprinting also revealed binary combination of the CTTC element with the Pi starvation response-associated PHR1-binding site (P1BS) in the promoters of several mycorrhiza-specific Pi transporter genes. Scanning of the Lotus japonicus genome for gene promoters containing both cis-regulatory elements revealed a strong over-representation of genes involved in transport processes. One of these, LjVTI12, encoding a member of the SNARE family of proteins involved in membrane transport, exhibited enhanced transcript levels in Lotus roots colonized with the arbuscular mycorrhizal fungus Glomus intraradices. Down-regulation of LjVTI12 by RNA interference resulted in a mycorrhiza-specific phenotype characterized by distorted arbuscule morphology. The results highlight cooperative cis-regulation which integrates mycorrhiza and Pi starvation signaling with vesicle trafficking in symbiosome development. PMID- 23452279 TI - Standardizing skin biopsy sampling to assess rejection in vascularized composite allotransplantation. AB - Over 70 hands and 20 faces have been transplanted during the past 13 yr, which have shown good to excellent functional and esthetic outcomes. However, (skin) rejection episodes complicate the post-operative courses of hand and face transplant recipients and are still a major obstacle to overcome after reconstructive allotransplantation. This article summarizes all relevant information on the skin component and rejection of a vascularized composite allograft. As more and more centers plan to implement a vascularized composite allotransplantation (VCA) program, we further develop guidelines and recommendations on collection and processing of skin biopsies from hand and face allograft recipients. This will help to standardize post-operative monitoring, avoid pitfalls for those new in the field and facilitate comparison of data on VCA between centers. PMID- 23452280 TI - The complete mitochondrial genome sequence of Ancherythroculter nigrocauda (Cypriniformes:Cyprinidae). AB - Ancherythroculter nigrocauda is a fish endemic to the upper reaches of the Yangtze River in China. In this study, we determined and analyzed the complete mitochondrial DNA (mtDNA) sequence of this species. The mitogenome is 16,623 bp in length. It consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non-coding regions: origin of light-strand replication (O(L)) and control region (D-loop). This mitogenome sequence data can contribute to elucidate the evolutionary mechanisms, molecular systematics, and biogeography of Ancherythroculter and is useful to conservation genetics and stock evaluation for A. nigrocauda. PMID- 23452281 TI - What are the health implications associated with the consumption of energy drinks? A systematic review. AB - There is increasing interest regarding the potential health effects of energy drink (ED) consumption. The aim of the present review was to investigate the existing evidence on health outcomes associated with ED consumption. Studies published between 1966 and February 2011 were retrieved and included if they met the following criteria: were randomized or pseudo randomized control trials; studied a human population; reported a health-related measure; and investigated a whole ED (as opposed to individual ingredients). Study quality was evaluated and data extracted using standardized tools. Fifteen studies were identified, the majority of which had less than 30 participants and included a short term of follow-up (range: 30 min-3 h). The following outcome measures were included: cardiorespiratory effects, physiological measures, pathological measures, and body composition. The mean dosage of ED was 390 mL (range: 250-750 mL). Commercial ED funding and/or study associations were identified in six studies. Studies investigating long-term consumption and follow-up were lacking. The findings from this review do not allow definitive dietary recommendations to be made regarding safe levels of ED consumption; caution should be exercised when consuming these drinks until further high-quality research is undertaken to substantiate findings. PMID- 23452282 TI - Dairy and blood pressure: a fresh look at the evidence. AB - The Dietary Guidelines for Americans, 2010 indicated there is moderate evidence for an association between the consumption of dairy foods and lower blood pressure in adults; however, it also stated that more evidence was needed, especially in clinical trials, to fully delineate a causal relationship. The purpose of this review is to provide background by examining the historical literature and the evidence reviewed by the 2010 Dietary Guidelines Advisory Committee, to examine the gaps in knowledge indicated by that committee, and to determine if recently published evidence is sufficient to elucidate or dismiss an association between dairy foods and blood pressure maintenance. Examination of the newly published literature, together with evaluation of the evidence as a whole, shows that the preponderance of evidence indicates dairy foods are beneficially associated with blood pressure; however, additional research is necessary to identify the mechanism of action of dairy foods. New evidence should come from carefully designed clinical trials that examine not only blood pressure outcomes but also the ability of dairy foods to affect the vasculature. PMID- 23452283 TI - Vitamin D and gestational diabetes mellitus. AB - The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM can be responsible for an important proportion of adverse fetal and maternal outcomes during pregnancy, and it is associated with long-term health deterioration for both mother and child. Therefore, it is important to identify potentially modifiable risk factors for GDM. Accumulating evidence links vitamin D deficiency with abnormal glucose metabolism, and epidemiological studies have shown that women who develop GDM are more likely to be vitamin D deficient. This review discusses the prevalence, risk factors, and outcomes of GDM and vitamin D deficiency in pregnant women, outlines the possible mechanism of action of vitamin D in glucose homeostasis, and summarizes emerging evidence that associates vitamin D deficiency with the risk of developing GDM. This critical review of the literature indicates there is a need for intervention trials to test the possible beneficial effect of vitamin D supplementation in pregnant women with low vitamin D status to reduce the risk of developing GDM. PMID- 23452284 TI - Overweight and obesity: a review of their relationship to metabolic syndrome, cardiovascular disease, and cancer in South America. AB - Socioeconomic and demographic transformations are occurring very rapidly in some areas of the world, especially in South America, and are accompanied by changes in lifestyle, dietary patterns, and the epidemiological profile of prevalent diseases. This review examines whether obesity and overweight are related to metabolic syndrome, cardiovascular disease, and cancer in South America. Research carried out in more than 6,000 cases and controls was evaluated, along with most of the available publications related to South America. In South America, obesity and risk factors for cardiovascular disease are related mainly to aging, ethnicity effects, and preventable risky lifestyle conditions. Most of the studies that found an association between cancer and obesity are from the Southern Cone, the geographic area most affected by this pathology. Overall, the prevalence of metabolic syndrome was highest in Chile, followed in decreasing order by Colombia, Peru, Argentina, and Ecuador, with differences noted between urban and rural areas or between urban and periurban areas. Obesity and cancer may be preventable, at least in part, by healthy behavior; hence, exercise, weight control, and healthy dietary habits are important to reduce the risk of these major chronic diseases. PMID- 23452285 TI - Primary and secondary coenzyme Q10 deficiency: the role of therapeutic supplementation. AB - Coenzyme Q10 (CoQ10) is the only lipid-soluble antioxidant that animal cells synthesize de novo. It is found in cell membranes and is particularly well known for its role in the electron transport chain in mitochondrial membranes during aerobic cellular respiration. A deficiency in either its bioavailability or its biosynthesis can lead to one of several disease states. Primary deficiency has been well described and results from mutations in genes involved in CoQ10 biosynthesis. Secondary deficiency may be linked to hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), which are used for the treatment of hypercholesterolemia. Dietary contributions of CoQ10 are very small, but supplementation is effective in increasing plasma CoQ10 levels. It has been clearly demonstrated that treatment with CoQ10 is effective in numerous disorders and deficiency states and that supplementation has a favorable outcome. However, CoQ10 is not routinely prescribed in clinical practice. This review explores primary as well as statin-induced secondary deficiency and provides an overview of the benefits of CoQ10 supplementation. PMID- 23452286 TI - Does vitamin D affect timing of menarche? AB - In a recently published prospective study, Villamor et al. found increased risk of early menarche in vitamin D-deficient girls compared to vitamin D-sufficient girls in Bogota, Columbia. The association was not fully explained by differences in body mass index-for-age z-scores. The mechanism for the association, if real, has not been elucidated, but could potentially involve vitamin D receptor polymorphisms. Early menarche and vitamin D deficiency are both associated with poor health outcomes, and further exploration of their association is important for women's health. PMID- 23452287 TI - Impact of mycelia on the accessibility of fluorene to PAH-degrading bacteria. AB - Mycelia have been recently shown to actively transport polycyclic aromatic hydrocarbons (PAH) in water-unsaturated soil over the range of centimeters, thereby efficiently mobilizing hydrophobic PAH beyond their purely diffusive transport in air and water. However, the question if mycelia-based PAH transport has an effect on PAH biodegradation was so far unsolved. To address this, we developed a laboratory model microcosm mimicking air-water interfaces in soil. Chemical analyses demonstrated transport of the PAH fluorene (FLU) by the mycelial oomycete Pythium ultimum that was grown along the air-water interfaces. Furthermore, degradation of mycelia-transported FLU by the bacterium Burkholderia sartisoli RP037-mChe was indicated. Since this organism expresses eGFP in response to a FLU flux to the cell, it was also as a bacterial reporter of FLU bioavailability in the vicinity of mycelia. Confocal laser scanning microscopy (CLSM) and image analyses revealed a significant increase of eGFP expression in the presence of P. ultimum compared to controls without mycelia or FLU. Hence, we could show that physically separated FLU becomes bioavailable to bacteria after transport by mycelia. Experiments with silicon coated glass fibers capturing mycelia-transported FLU guided us to propose a three-step mechanism of passive uptake, active transport and diffusion-driven release. These experiments were also used to evaluate the contributions of these individual steps to the overall mycelial FLU transport rate. PMID- 23452288 TI - Anticancer activity of olive oil hydroxytyrosyl acetate in human adenocarcinoma Caco-2 cells. AB - The anticancer activity of hydroxytyrosyl acetate (HTy-Ac) has been studied in human colon adenocarcinoma cells. Gene expression of proteins involved in cell cycle (p21, p53, cyclin B1, and cyclin G2) and programmed cell death (BNIP3, BNIP3L, PDCD4, and ATF3), as well as phase I and phase II detoxifying enzymes CYPA1 and UGT1A10, were evaluated by reverse transcription polymerase chain reaction after 24 h of exposure of Caco-2/TC7 cells to 5, 10, and 50 MUM of HTy Ac. The results show that HTy-Ac inhibited cell proliferation and arrested cell cycle by enhancing p21 and CCNG2 and lowering CCNB1 protein expression. HTy-Ac also affected the transcription of genes involved in apoptosis up-regulating of BNIP3, BNIP3L, PDCD4, and ATF3 and activating caspase-3. In addition, HTy-Ac also up-regulated xenobiotic metabolizing enzymes CYP1A1 and UGT1A10, thus enhancing carcinogen detoxification. In conclusion, these results highlight that HTy-Ac has the potential to modulate biomarkers involved in colon cancer. PMID- 23452289 TI - Radioactivity in Montenegro beach sands and assessment of the corresponding environmental risk. AB - Activity concentrations of the naturally occurring radionuclides (226)Ra, (232)Th, (40)K and anthropogenic (137)Cs in sand samples collected from 20 renowned beaches on the Coast of Montenegro have been determined using an HPGe (high purity Ge spectrometer). The average activity concentrations were found to be 7.4, 5.2, 97.3 and 0.5 Bq kg(-1), respectively. For all sand samples, the radium equivalent activity has been evaluated and found to be lower than the limit of 370 Bq kg(-1). External and internal hazard indices were less than unity. The gonadal dose equivalent was estimated to be on average 75 MUSv y(-1), which is about four times lower than the global average for soil (0.3 mSv y(-1)). Calculated values of absorbed dose rates showed the range from 3.1 to 28 nGy h( 1), which is below the world median of average values (57 nGy h(-1)). The effective dose rate in the range from 3.8 to 34.4 MUSv y(-1) was significantly below the recommended limit value for the public (1 mSv y(-1)). The highest dose rate was found for the Velika Plaza locality, which also showed heavy metal contents (As, B, Cd, Hg, Cr, Cu, Mn, Ni, Pb, Zn and Ba) significantly higher than in the sand from Jaz, a locality with one of the lowest dose rates. PMID- 23452290 TI - Atypical tumors of the facial nerve: case series and review of the literature. AB - OBJECT: The authors present a series of 4 patients with rare facial nerve tumors. The relevant literature is reviewed and is discussed regarding diagnostic features, the role of operative management, and surgical approach. METHODS: A retrospective chart review was conducted for patients with tumors of the facial nerve that were treated between 2008 and 2011. Patients undergoing observation with serial MRI and those who were treated with up-front radiosurgery and for whom tissue diagnosis was not available were excluded. In addition, patients with suspected vestibular schwannoma, facial nerve schwannoma, neurofibromatosis Type 2, and metastatic disease were also excluded. The charts of 4 patients (2 men and 2 women) with "atypical" tumors were reviewed and analyzed. RESULTS: A total of 12 patients with tumors of the facial nerve were identified during the study period. Patient characteristics, preoperative imaging, operative approach, tumor histology, and outcomes are described. CONCLUSIONS: Atypical facial nerve tumors must be distinguished from the more common facial nerve schwannoma. How the authors of this study treat rare facial nerve tumors is based on their experience with the more common facial nerve schwannomas, characterized by a slow progression of symptoms and growth. Less is known about the rare lesions, and thus a conservative approach may be warranted. Open questions include the role of radiosurgery, facial nerve decompression, and indications for resection of tumor and cable grafting for these rare lesions. PMID- 23452291 TI - Overexpression of autophagic proteins in the skeletal muscle of sporadic inclusion body myositis. AB - AIMS: Sporadic inclusion body myositis (s-IBM) is characterized by rimmed vacuole formation and misfolded protein accumulation. Intracellular protein aggregates are cleared by autophagy. When autophagy is blocked aggregates accumulate, resulting in abnormal rimmed vacuole formation. This study investigated the autophagy-lysosome pathway contribution to rimmed vacuole accumulation. METHODS: Autophagy was studied in muscle biopsy specimens obtained from eleven s-IBM patients, one suspected hereditary IBM patient, nine patients with other inflammatory myopathies and nine non-myopathic patients as controls. The analysis employed morphometric methods applied to immunohistochemistry using the endosome marker Clathrin, essential proteins of the autophagic cascade such as AuTophaGy related protein ATG5, splicing variants of microtubule-associated protein light chain 3a (LC3a) and LC3b, compared with Beclin 1, the major autophagy regulator of both the initiation phase and late endosome/lysosome fusion of the autophagy lysosome pathway. RESULTS: In muscle biopsies of s-IBM patients, an increased expression of Clathrin, ATG5, LC3a, LC3b and Beclin 1 was shown. Moreover, the inflammatory components of the disease, essentially lymphocytes, were preferentially distributed around the Beclin 1(+) myofibres. These affected myofibres also showed a moderate sarcoplasmic accumulation of SMI-31(+) phospho tau paired helical filaments. CONCLUSION: The overexpression of autophagy markers linked to the decreased clearance of misfolded proteins, including SMI-31, and rimmed vacuoles accumulation may exhaust cellular resources and lead to cell death. PMID- 23452292 TI - Prevention of mother-to-child transmission of hepatitis B virus (HBV) during pregnancy and the puerperium: current standards of care. AB - BACKGROUND: Mother-to-child transmission (MTCT) of hepatitis B virus continues to occur despite the interventions of hepatitis B vaccination and immunoglobulin. The most significant risk factor in transmission is high maternal viral load. Being aware of viral replicative activity permits risk stratification and allows the opportunity for additional preventative measures such as antiviral therapy. METHODS: Retrospective audit of investigations and clinical management among hepatitis B surface antigen-positive pregnant women from three maternity services across Victoria over a five-year period from 2006 to 2011. RESULTS: Over the study period at the three institutions, there were 46,855 births, and 398 hepatitis B-positive pregnant women. 87% of the women were non-Australian-born. Viral load testing was performed in <20% of all pregnancies, and hepatitis B e antigen status assessed in 33%. Only 18% of the women with hepatitis B were referred for specialist care, but if referred, they were more likely to have an assessment of viral replicative status performed. Compliance with administration of neonatal hepatitis B immunoglobulin and birth-dose vaccination was high (>90%). CONCLUSION: There is scope for considerable improvement in referral and assessment of pregnant women with hepatitis B infection. Guidelines addressing the issue of maternal viral replicative status and the need for antiviral therapy may assist in guiding clinical management. PMID- 23452294 TI - State-to-state quantum mechanical calculations of rate coefficients for the D+ + H2 -> HD + H+ reaction at low temperature. AB - The dynamics of the D(+) + H2 -> HD + H(+) reaction on a recent ab initio potential energy surface (Velilla, L.; Lepetit, B.; Aguado, A.; Beswick, J. A.; Paniagua, M. J. Chem. Phys. 2008, 129, 084307) has been investigated by means of a time-independent quantum mechanical approach. Cross-sections and rate coefficients are calculated, respectively, for collision energies below 0.1 eV and temperatures up to 100 K for astrophysical application. An excellent accord is found for collision energy above 5 meV, while a disagreement between theory and experiment is observed below this energy. We show that the rate coefficients reveal a slightly temperature-dependent behavior in the upper part of the temperature range considered here. This is in agreement with the experimental data above 80 K, which give a temperature independent value. However, a significant decrease is found at temperatures below 20 K. This decrease can be related to quantum effects and the decay back to the reactant channel, which are not considered by simple statistical approaches, such as the Langevin model. Our results have been fitted to appropriate analytical expressions in order to be used in astrochemical and cosmological models. PMID- 23452293 TI - The significance of virulence factors in Helicobacter pylori. AB - Helicobacter pylori (H. pylori) infection is linked to various gastroduodenal diseases; however, only a small fraction of these patients develop associated diseases. Despite the high prevalence of H. pylori infection in Africa and South Asia, the incidence of gastric cancer in these areas is much lower than those in other countries. The incidence of gastric cancer tends to decrease from north to south in East Asia. Such geographical differences in the pathology can be explained, at least in part, by the presence of different types of H. pylori virulence factors in addition to host and environmental factors. Virulence factors of H. pylori, such as CagA, VacA, DupA, IceA, OipA and BabA, have been demonstrated to be the predictors of severe clinical outcomes. Interestingly, a meta-analysis showed that CagA seropositivity was associated with gastric cancer compared with gastritis, even in East Asian countries where almost the strains possess cagA. Another meta-analysis also confirmed the significance of vacA, dupA and iceA. However, it is possible that additional important pathogenic genes may exist because H. pylori consists of approximately 1600 genes. Despite the advances in our understanding of the development of H. pylori infection-related diseases, further work is required to clarify the roles of H. pylori virulence factors. PMID- 23452295 TI - The role of cytokines in the pathogenesis of systemic lupus erythematosus - from bench to bedside. AB - The pathogenesis of systemic lupus erythematosus (SLE) entails a complex interaction between the different arms of the immune system. While autoantibodies production and immune complex deposition are cornered as hallmark features of SLE, there is growing evidence to propose the pathogenic role of cytokines in this disease. Examples of these cytokines include BLys, interleukin-6, interleukin-17, interleukin-18, type I interferons and tumour necrosis factor alpha. These cytokines all assume pivotal functions to orchestrate the differentiation, maturation and activation of various cell types, which would mediate local inflammatory process and tissue injury. The knowledge on these cytokines not only fosters our understanding of the disease, but also provides insights in devising biomarkers and targeted therapies. In this review, we focus on cytokines which have substantial pathogenic significance and also highlight the possible clinical applications of these cytokines. PMID- 23452296 TI - Nevoid hypertrichosis, diffuse lipoatrophy and epidermal nevus: a new syndrome? PMID- 23452297 TI - Highly efficient and stereocontrolled construction of 3,3'-pyrrolidonyl spirooxindoles via organocatalytic domino Michael/cyclization reaction. AB - A wide range of structurally diverse 3,3'-thiopyrrolidonyl spirooxindoles bearing three contiguous stereogenic centers can be smoothly obtained via a domino Michael/cyclization reaction between 3-isothiocyanato oxindoles and 3-methyl-4 nitro-5-alkenyl-isoxazoles with commercially available quinine as the catalyst under mild conditions. The protocol is significantly characterized by high reactivity, a low catalyst loading (1 mol %), and an excellent diastereo- and enantioselectivity (up to >99:1 dr and 98% ee). PMID- 23452298 TI - A retrospective study of the clinical and economic burden during hospitalizations among cancer patients with febrile neutropenia. AB - OBJECTIVE: The objective of this study was to provide up-to-date estimates of the clinical and economic burden that occurs during inpatient treatment of cancer patients with febrile neutropenia (FN). METHODS: A retrospective cohort study was conducted using 2007-2010 hospital discharge data from the Premier database. The study population included adult patients with discharge diagnoses of neutropenia (ICD-9 code 288.0x) with fever or infection and receipt of intravenous antibiotics and female breast cancer, lung cancer, colorectal cancer, ovarian cancer, non-Hodgkin lymphoma (NHL), or Hodgkin lymphoma. Primary study outcomes were inpatient mortality, hospital length of stay (LOS), and total hospitalization cost for each patient's first FN-related hospitalization. Logistic regressions (for mortality) and multivariate linear regressions (for LOS and cost) were conducted to assess the effect of comorbidities and infection types on study outcomes, adjusting for other patient and hospital characteristics. RESULTS: Among 16,273 cancer patients hospitalized with FN, the inpatient case fatality rate was 10.6%, mean LOS was 8.6 days, and mean total hospitalization cost was $18,880. Lung cancer patients had the highest inpatient case fatality rate (15.7%), and NHL patients had the longest LOS (10.1 days) and the highest cost ($24,218). Multivariate analyses showed that most comorbidities were associated with a greater risk of mortality, longer LOS, and higher cost. Septicemia/bacteremia and pneumonia were associated with a greater risk of mortality, and most types of infection were associated with a longer LOS and higher cost. LIMITATIONS: The total burden of FN may be under-estimated in this study because outpatient treatment and any patient deaths or costs that occurred outside of Premier hospitals could not be captured. CONCLUSIONS: FN-related hospitalizations among cancer patients are costly and accompanied by considerable mortality risk. Substantial differences in the clinical and economic burden of FN exist depending on cancer types, comorbidities, and infection types. PMID- 23452300 TI - Comparative analyses of genetic trends and prospects for selection against hip and elbow dysplasia in 15 UK dog breeds. AB - BACKGROUND: Hip dysplasia remains one of the most serious hereditary diseases occurring in dogs despite long-standing evaluation schemes designed to aid selection for healthy joints. Many researchers have recommended the use of estimated breeding values (EBV) to improve the rate of genetic progress from selection against hip and elbow dysplasia (another common developmental orthopaedic disorder), but few have empirically quantified the benefits of their use. This study aimed to both determine recent genetic trends in hip and elbow dysplasia, and evaluate the potential improvements in response to selection that publication of EBV for such diseases would provide, across a wide range of pure bred dog breeds. RESULTS: The genetic trend with respect to hip and elbow condition due to phenotypic selection had improved in all breeds, except the Siberian Husky. However, derived selection intensities are extremely weak, equivalent to excluding less than a maximum of 18% of the highest risk animals from breeding. EBV for hip and elbow score were predicted to be on average between 1.16 and 1.34 times more accurate than selection on individual or both parental phenotypes. Additionally, compared to the proportion of juvenile animals with both parental phenotypes, the proportion with EBV of a greater accuracy than selection on such phenotypes increased by up to 3-fold for hip score and up to 13 fold for elbow score. CONCLUSIONS: EBV are shown to be both more accurate and abundant than phenotype, providing more reliable information on the genetic risk of disease for a greater proportion of the population. Because the accuracy of selection is directly related to genetic progress, use of EBV can be expected to benefit selection for the improvement of canine health and welfare. Public availability of EBV for hip score for the fifteen breeds included in this study will provide information on the genetic risk of disease in nearly a third of all dogs annually registered by the UK Kennel Club, with in excess of a quarter having an EBV for elbow score as well. PMID- 23452299 TI - CD64-Neutrophil expression and stress metabolic patterns in early sepsis and severe traumatic brain injury in children. AB - BACKGROUND: Critical illness constitutes a serious derangement of metabolism. The aim of our study was to compare acute phase metabolic patterns in children with sepsis (S) or severe sepsis/septic shock (SS) to those with severe traumatic brain injury (TBI) and healthy controls (C) and to evaluate their relations to neutrophil, lymphocyte and monocyte expressions of CD64 and CD11b. METHODS: Sixty children were enrolled in the study. Forty-five children with systemic inflammatory response syndrome (SIRS) were classified into three groups: TBI (n = 15), S (n = 15), and SS (n = 15). C consisted of 15 non- SIRS patients undergoing screening tests for minor elective surgery. Blood samples were collected within 6 hours after admission for flow cytometry of neutrophil, lymphocyte and monocyte expression of CD64 and CD11b (n = 60). Procalcitonin (PCT), C-reactive protein (CRP), glucose, triglycerides (TG), total cholesterol (TC), high (HDL) or low density-lipoproteins (LDL) were also determined in all groups, and repeated on day 2 and 3 in the 3 SIRS groups (n = 150). RESULTS: CRP, PCT and TG (p < 0.01) were significantly increased in S and SS compared to TBI and C; glucose did not differ among critically ill groups. Significantly lower were the levels of TC, LDL, and HDL in septic groups compared to C and to moderate changes in TBI (p < 0.0001) but only LDL differed between S and SS (p < 0.02). Among septic patients, PCT levels declined significantly (p < 0.02) with time, followed by parallel decrease of HDL (p < 0.03) and increase of TG (p < 0.02) in the SS group. Neutrophil CD64 (nCD64) expression was higher in patients with SS (81.2%) and S (78.8%) as compared to those with TBI (5.5%) or C (0.9%, p < 0.0001). nCD64 was positively related with CRP, PCT, glucose, and TG (p < 0.01) and negatively with TC, LDL, and HDL (p < 0.0001), but not with severity of illness, hematologic indices, length of stay or mechanical ventilation duration. CONCLUSIONS: In sepsis, the early stress-metabolic pattern is characterized by a high (nCD64, glucose, TG) - low (TC, HDL, LDL) combination in contrast to the moderate pattern of TBI in which only glucose increases combined with a moderate cholesterol - lipoprotein decrease. These early metabolic patterns persist the first 3 days of acute illness and are associated with the acute phase CD64 expression on neutrophils. PMID- 23452301 TI - Practitioner Review: The effectiveness of solution focused brief therapy with children and families: a systematic and critical evaluation of the literature from 1990-2010. AB - BACKGROUND AND SCOPE: Solution focused brief therapy (SFBT) is a strengths-based therapeutic approach, emphasizing the resources that people possess and how these can be applied to a positive change process. The current study provides a systematic review of the SFBT evidence base and a critical evaluation of the use and application of SFBT in clinical practice with children and families. METHODS: Between 21 December 2010 and 12 May 2011 forty-four database searches (including, PsychInfo, ISI Web of Knowledge, ASSIA, British Education Index, Medline and Scopus), web searches and consultation with experts in the field were used to identify reports of SFBT studies published between 1990 and 2010. Studies were then screened according to trialled qualitative and quantitative assessment frameworks and reported according to the PRISMA guidelines. RESULTS: A total of 38 studies were included in the review. Of these, 9 applied SFBT to internalizing child behaviour problems, 3 applied SFBT to both internalizing and externalizing child behaviour problems, 15 applied the approach to externalizing child behaviour problems and 9 evaluated the application of SFBT in relation to a range of other issues. CONCLUSIONS: Although much of the literature has methodological weaknesses, existing research does provide tentative support for the use of SFBT, particularly in relation to internalizing and externalizing child behaviour problems. SFBT appears particularly effective as an early intervention when presenting problems are not severe. Further well-controlled outcome studies are needed. Studies included in the review highlight promising avenues for further research. PMID- 23452302 TI - Programmable display of DNA-protein chimeras for controlling cell-hydrogel interactions via reversible intermolecular hybridization. AB - Extensive studies have been recently carried out to achieve dynamic control of cell-material interactions primarily through physicochemical stimulation. The purpose of this study was to apply reversible intermolecular hybridization to program cell-hydrogel interactions in physiological conditions based on DNA antibody chimeras and complementary oligonucleotides. The results showed that DNA oligonucleotides could be captured to and released from the immobilizing DNA functionalized hydrogels with high specificity via DNA hybridization. Accordingly, DNA-antibody chimeras were captured to the hydrogels, successfully inducing specific cell attachment. The cell attachment to the hydrogels reached the plateau at approximately half an hour after the functionalized hydrogels and the cells were incubated together. The attached cells were rapidly released from the bound hydrogels when triggering complementary oligonucleotides were introduced to the system. However, the capability of the triggering complementary oligonucleotides in releasing cells was affected by the length of intermolecular hybridization. The length needed to be at least more than 20 base pairs in the current experimental setting. Notably, because the procedure of intermolecular hybridization did not involve any harsh condition, the released cells maintained the same viability as that of the cultured cells. The functionalized hydrogels also exhibited the potential to catch and release cells repeatedly. Therefore, this study demonstrates that it is promising to regulate cell-material interactions dynamically through the DNA-programmed display of DNA-protein chimeras. PMID- 23452303 TI - Early detection of cutaneous melanoma by sequential digital dermatoscopy (SDD). AB - The early diagnosis and excision of cutaneous melanoma is essential for an improved prognosis of the disease. Besides the investigation of pigmented lesions with the unaided eye and conventional dermatoscopy, long-term sequential digital dermatoscopy has been shown to improve the sensitivity of melanoma detection, especially in high-risk patients. In addition to the static clinical and dermatoscopic assessment, the sequential digital dermatoscopy strategy helps to detect changes over time. This review summarizes the latest developments in the field of sequential digital dermatoscopy, describes current strategies for the selection of patients and lesions to monitor, and suggests objective criteria that should lead to an excisional biopsy. PMID- 23452304 TI - Do pathogens reduce genetic diversity of their hosts? Variable effects of sylvatic plague in black-tailed prairie dogs. AB - Introduced diseases can cause dramatic declines in-and even the loss of-natural populations. Extirpations may be followed by low recolonization rates, leading to inbreeding and a loss of genetic variation, with consequences on population viability. Conversely, extirpations may create vacant habitat patches that individuals from multiple source populations can colonize, potentially leading to an influx of variation. We tested these alternative hypotheses by sampling 15 colonies in a prairie dog metapopulation during 7 years that encompassed an outbreak of sylvatic plague, providing the opportunity to monitor genetic diversity before, during and after the outbreak. Analysis of nine microsatellite loci revealed that within the metapopulation, there was no change in diversity. However, within extirpated colonies, patterns varied: In half of the colonies, allelic richness after recovery was less than the preplague conditions, and in the other half, richness was greater than the preplague conditions. Finally, analysis of variation within individuals revealed that prairie dogs present in recolonized colonies had higher heterozygosity than those present before plague. We confirmed plague survivorship in six founders; these individuals had significantly higher heterozygosity than expected by chance. Collectively, our results suggest that high immigration rates can maintain genetic variation at a regional scale despite simultaneous extirpations in spatially proximate populations. Thus, virulent diseases may increase genetic diversity of host populations by creating vacant habitats that allow an influx of genetic diversity. Furthermore, even highly virulent diseases may not eliminate individuals randomly; rather, they may selectively remove the most inbred individuals. PMID- 23452305 TI - Long-term maintenance of arytenoid cartilage abduction and stability during exercise after laryngoplasty in 33 horses. AB - OBJECTIVES: To (1) assess long-term maintenance of arytenoid cartilage abduction (ACA) after laryngoplasty (LP); and (2) correlate the residual grade of ACA and postoperative abductory loss with arytenoid cartilage stability (ACS) during exercise. STUDY DESIGN: Case series. ANIMALS: Horses re-examined after laryngoplasty (n = 33). METHODS: Of 89 LP horses (2005-2010), 33 had historic ACA data available and upper airway endoscopy at rest and during over-ground exercise (mean, 33 months; range, 4-71 months) after surgery. ACA grade at 1 and 6 weeks postoperatively were correlated to long-term ACA grade. Effects of long-term ACA grade and magnitude of postoperative abductory loss on ACS during exercise were investigated. RESULTS: Median ACA grade at 1 week (n = 33) was 2, reducing to grade 3 by week 6 (n = 16). Grade 3 abduction was maintained in the long-term. Correlation between ACA at 1 week and the long-term was poor (rho = .43, P = .1), but there was good correlation between week 6 and long-term (rho = .89, P < .001). Arytenoid cartilage instability was observed during exercise in 7/33 of horses, and not significantly associated with the ACA grade (P = .50), or the number of grades of ACA lost (P = .64). CONCLUSIONS: Limited abductory loss occurs after 6 weeks postoperatively. Resting ACA grade was not a useful predictor of ACS during exercise. PMID- 23452306 TI - Improving sensitivity of machine learning methods for automated case identification from free-text electronic medical records. AB - BACKGROUND: Distinguishing cases from non-cases in free-text electronic medical records is an important initial step in observational epidemiological studies, but manual record validation is time-consuming and cumbersome. We compared different approaches to develop an automatic case identification system with high sensitivity to assist manual annotators. METHODS: We used four different machine learning algorithms to build case identification systems for two data sets, one comprising hepatobiliary disease patients, the other acute renal failure patients. To improve the sensitivity of the systems, we varied the imbalance ratio between positive cases and negative cases using under- and over-sampling techniques, and applied cost-sensitive learning with various misclassification costs. RESULTS: For the hepatobiliary data set, we obtained a high sensitivity of 0.95 (on a par with manual annotators, as compared to 0.91 for a baseline classifier) with specificity 0.56. For the acute renal failure data set, sensitivity increased from 0.69 to 0.89, with specificity 0.59. Performance differences between the various machine-learning algorithms were not large. Classifiers performed best when trained on data sets with imbalance ratio below 10. CONCLUSIONS: We were able to achieve high sensitivity with moderate specificity for automatic case identification on two data sets of electronic medical records. Such a high-sensitive case identification system can be used as a pre-filter to significantly reduce the burden of manual record validation. PMID- 23452307 TI - Programming of glucose-insulin homoeostasis: long-term consequences of pre-natal versus early post-natal nutrition insults. Evidence from a sheep model. AB - AIM: Exposure to adverse intra-uterine conditions can predispose for metabolic disorders later in life. By using a sheep model, we studied (i) how programming of glucose-insulin homoeostasis during late gestation is manifested later in life depending on the early post-natal dietary exposure and (ii) whether dietary alteration in obese individuals can prevent adverse outcomes of early life programming. METHODS: During late gestation, twin-pregnant sheep were fed 100% (NORM) or 50% (LOW) of energy and protein requirements. After birth, offspring were exposed to a moderate (CONV) or high-carbohydrate-high-fat (HCHF) diet until around puberty. Offspring remaining thereafter (exclusively females) were fed a moderate diet until young adulthood. RESULTS: LOW lambs had increased insulin secretory responses during intravenous glucose tolerance tests indicative of reduced insulin sensitivity. HCHF lambs were hypertriglyceridaemic, 75% had mild pancreatic collagen infiltration, and their acute insulin secretory response and insulin clearance during intravenous glucose and insulin tolerance tests, respectively, were reduced. However, NORM-HCHF in contrast to LOW-HCHF lambs had normal glucose tolerance, indicating that later health outcomes are highly influenced by pre-natal nutrition. Dietary alteration normalized glucose-insulin homoeostasis in adult HCHF females, whereas late-gestation undernutrition (LOW) permanently depressed insulin sensitivity. CONCLUSION: Maintenance of glucose tolerance in sheep exposed to pre-natal undernutrition relied on pancreatic hypersecretion of insulin to compensate for reduced insulin sensitivity. A mismatching high-fat diet in early post-natal life interfered with this pancreatic hypersecretion resulting in reduced glucose tolerance. Early post natal, but not late pre-natal, impacts on glucose-insulin homoeostasis could be reversed by dietary correction later in life. PMID- 23452308 TI - Quantitative measurements of small molecule mixtures using laser electrospray mass spectrometry. AB - Quantitative measurements of atenolol, tioconazole, tetraethylammonium bromide, and tetrabutylammonium iodide using laser electrospray mass spectrometry (LEMS) reveal monotonic signal response as a function of concentration for single analytes, two- and four-component equimolar mixtures, and two-component variable molarity mixtures. LEMS analyses of single analytes as a function of concentration were linear over ~2.5 orders of magnitude for all four analytes and displayed no sign of saturation. Corresponding electrospray ionization (ESI) measurements displayed a nonmonotonic increase as saturation occurred at higher concentrations. In contrast to the LEMS experiments, the intensity ratios from control experiments using conventional ESI-MS deviated from expected values for the equimolar mixture measurements due to ion suppression of less surface active analytes, particularly in the analysis of the four-component mixture. In the analyses of two-component nonequimolar mixtures, both techniques were able to determine the concentration ratios after adjustment with response factors although conventional ESI-MS was subject to a greater degree of saturation and ion suppression at higher analyte concentrations. PMID- 23452309 TI - Finding synergies in fuels properties for the design of renewable fuels- hydroxylated biodiesel effects on butanol-diesel blends. AB - This article describes the effects of hydroxylated biodiesel (castor oil methyl ester - COME) on the properties, combustion, and emissions of butanol-diesel blends used within compression ignition engines. The study was conducted to investigate the influence of COME as a means of increasing the butanol concentration in a stable butanol-diesel blend. Tests were compared with baseline experiments using rapeseed methyl esters (RME). A clear benefit in terms of the trade-off between NOX and soot emissions with respect to ULSD and biodiesel diesel blends with the same oxygen content was obtained from the combination of biodiesel and butanol, while there was no penalty in regulated gaseous carbonaceous emissions. From the comparison between the biodiesel fuels used in this work, COME improved some of the properties (for example lubricity, density and viscosity) of butanol-diesel blends with respect to RME. The existence of hydroxyl group in COME also reduced further soot emissions and decreased soot activation energy. PMID- 23452310 TI - Template-free synthesis of renewable macroporous carbon via yeast cells for high performance supercapacitor electrode materials. AB - The urgent need for sustainable development has forced material scientists to explore novel materials for next-generation energy storage devices through a green and facile strategy. In this context, yeast, which is a large group of single cell fungi widely distributed in nature environments, will be an ideal candidate for developing effective electrode materials with fascinating structures for high-performance supercapacitors. With this in mind, herein, we present the first example of creating three-dimensional (3D) interpenetrating macroporous carbon materials via a template-free method, using the green, renewable, and widespread yeast cells as the precursors. Remarkably, when the as prepared materials are used as the electrode materials for supercapacitors, they exhibit outstanding performance with high specific capacitance of 330 F g(-1) at a current density of 1 A g(-1), and good stability, even after 1000 charge/discharge cycles. The approach developed in this work provides a new view of making full use of sustainable resources endowed by nature, opening the avenue to designing and producing robust materials with great promising applications in high-performance energy-storage devices. PMID- 23452311 TI - The complete mitochondrial genome structure of Schizothorax oconnori (Cypriniformes: Cyprinidae). AB - Schizothorax oconnori is mainly distributed in the Yarlung Zangbo River drainage in Tibet, China. S. oconnori is assessed as least concern species in International Union for Conservation of Nature Red List. In this paper, we determined the complete mitochondrial DNA (mtDNA) sequence of S. oconnori. The mitogenome is 16,590 bp in length. It consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 2 non-coding regions: origin of light-strand replication (O(L)) and control region (D-loop). The complete mitogenome sequence information of S. oconnori can be used in the studies on molecular systematics, stock evaluation and conservation genetics and will be helpful in the development of rational management strategies and sustainable utilization for S. oconnori resource. PMID- 23452312 TI - Novel therapies for the management of type 2 diabetes mellitus: part 1. pramlintide and bromocriptine-QR. AB - Several classes of antidiabetic agents have been introduced into the market place over the past dozen years. As our understanding of the underlying pathophysiology of type 2 diabetes has advanced, attempts have been made to address these defects specifically. This brief review focuses on our experience with two such pharmacological approaches: (i) a synthetic amylin analog addressing amylin deficiency; and (ii) a dopaminergic agonist, focused on enhancing the lowered dopaminergic tone in patients with type 2 diabetes. Importantly, the use of these agents is not associated with hypoglycemia or weight gain. PMID- 23452313 TI - Analysis of sugar degradation products with alpha-dicarbonyl structure in carbonated soft drinks by UHPLC-DAD-MS/MS. AB - Sugar-sweetened carbonated soft drinks (CSDs) are broadly consumed worldwide. The added sugar, particularly high-fructose corn syrup (HFCS), can be an important source of sugar degradation products, such as alpha-dicarbonyl compounds. This study recorded the alpha-dicarbonyl profile in CSDs by ultrahigh-performance liquid chromatography with hyphenated diode array-tandem mass spectrometry after derivatization with o-phenylenediamine. Thus, 3-deoxy-D-erythro-hexos-2-ulose (3 DG), D-lyxo-hexos-2-ulose (glucosone), 3-deoxy-D-threo-hexos-2-ulose (3-DGal), 1 deoxy-D-erythro-hexos-2,3-diulose (1-DG), 3,4-dideoxyglucosone-3-ene (3,4-DGE), methylglyoxal, and glyoxal were identified as major alpha-dicarbonyls and, with the exception of glyoxal, quantified (recovery rates, 85.6-103.1%; RSD, 0.8 3.6%). Total alpha-dicarbonyl concentration in 25 tested commercial products ranged between 0.3 and 116 MUg/mL and was significantly higher in HFCS-sweetened CSDs compared to CSDs sweetened with HFCS and sucrose or with sucrose alone. Predominant was 3-DG (<=87 MUg/mL) followed by glucosone (<=21 MUg/mL), 3-DGal (<=7.7 MUg/mL), 1-DG (<=2.8 MUg/mL), methylglyoxal (<=0.62 MUg/mL), and 3,4-DGE (<=0.45 MUg/mL). PMID- 23452315 TI - Effect of growth hormone on dawn phenomenon in patients with type 2 diabetes. AB - We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients. PMID- 23452314 TI - MC1R major variants are a risk factor of sleep lines in Caucasian women. AB - BACKGROUND: Sleep lines are caused by individual's sleeping positions and should be differentiated from expression wrinkles. OBJECTIVE: The aim of the study was to investigate possible risk factors for sleep lines on a sizeable sample of middle-aged Caucasian women. METHODS: This study involved a sample of 542 French middle-aged women (44 to 70 years old) from Paris area. Three standardized facial photographs (face and profiles) were examined independently by two dermatologists allowing the identification of sleep lines and the evaluation of the severity of several facial skin features. Possible impacts of MC1R gene polymorphisms were tested using logistic regression models. RESULTS: Sixty women (11%) had facial sleep lines and showed generally more than one sleep line. The sleep lines were often located on the forehead, along the nose, on the cheeks and under the eyes, and more rarely on the chin. As expected, the sleep lines were associated with age, and the women with sleep lines showed also more severe signs of skin ageing. After adjustment on possible confounders, the presence of two major diminished function variants of the MC1R gene was identified as a strong risk factor for sleep lines [adjusted odds ratios (AOR) (95% CI): 8.25 (2.62-25.97)]. DISCUSSION/CONCLUSION: The data in the literature are scarce and this study is the first to be conducted on a sizeable sample of women. Our results suggest that genetic variations of MC1R are important determinants of the development of sleep lines. PMID- 23452316 TI - Effect of previous botulinum neurotoxin treatment on microvascular decompression for hemifacial spasm. AB - OBJECT: The objective of this study was to investigate the clinical characteristics, intraoperative findings, complications, and outcomes after the first microvascular decompression (MVD) in patients with and without previous botulinum neurotoxin treatment for hemifacial spasm (HFS). METHODS: The authors analyzed 246 MVDs performed at the University of Pittsburgh Medical Center between January 1, 2000, and December 31, 2007. One hundred and seventy-six patients with HFS underwent botulinum neurotoxin injection treatment prior to first MVD (Group I), and 70 patients underwent their first MVD without previous botulinum neurotoxin treatment (Group II). Clinical outcome data were obtained immediately after the operation, at discharge, and at follow-up. Follow-up data were collected from 177 patients with a minimum follow-up period of 9 months (mean 54.48 +/- 27.84 months). RESULTS: In 246 patients, 89.4% experienced immediate postoperative relief of spasm, 91.1% experienced relief at discharge, and 92.7% experienced relief at follow-up. There was no significant difference in outcomes and complications between Group I and Group II (p > 0.05). Preoperatively, patients in Group I had higher rates of facial weakness, tinnitus, tonus, and platysmal involvement as compared with Group II (p < 0.05). The posterior inferior cerebellar artery and vertebral artery were intraoperatively identified as the offending vessels in cases of vasculature compression in a significantly greater number of patients in Group II compared with Group I (p = 0.008 and p = 0.005, respectively, for each vessel). The lateral spread response (LSR) disappeared in 60.48% of the patients in Group I as compared with 74.19% in Group II (p > 0.05). No significant differences in complications were noted between the 2 groups. CONCLUSIONS: Microvascular decompression is an effective and safe procedure for patients with HFS previously treated using botulinum neurotoxin. Intraoperative monitoring with LSR is an effective tool for evaluating adequate decompression. PMID- 23452317 TI - Phenoscope: an automated large-scale phenotyping platform offering high spatial homogeneity. AB - Increased phenotyping accuracy and throughput are necessary to improve our understanding of quantitative variation and to be able to deconstruct complex traits such as those involved in growth responses to the environment. Still, only a few facilities are known to handle individual plants of small stature for non destructive, real-time phenotype acquisition from plants grown in precisely adjusted and variable experimental conditions. Here, we describe Phenoscope, a high-throughput phenotyping platform that has the unique feature of continuously rotating 735 individual pots over a table. It automatically adjusts watering and is equipped with a zenithal imaging system to monitor rosette size and expansion rate during the vegetative stage, with automatic image analysis allowing manual correction. When applied to Arabidopsis thaliana, we show that rotating the pots strongly reduced micro-environmental disparity: heterogeneity in evaporation was cut by a factor of 2.5 and the number of replicates needed to detect a specific mild genotypic effect was reduced by a factor of 3. In addition, by controlling a large proportion of the micro-environmental variance, other tangible sources of variance become noticeable. Overall, Phenoscope makes it possible to perform large-scale experiments that would not be possible or reproducible by hand. When applied to a typical quantitative trait loci (QTL) mapping experiment, we show that mapping power is more limited by genetic complexity than phenotyping accuracy. This will help to draw a more general picture as to how genetic diversity shapes phenotypic variation. PMID- 23452318 TI - A home-based intervention using augmentative and alternative communication (AAC) techniques in rural Kenya: what are the caregivers' experiences? AB - BACKGROUND: Caring for a child with complex communication needs associated with a developmental condition frequently adds stress to the caregiver. Furthermore, professional assistance is scarce in low-income rural settings. For such children speech is frequently unachievable. Augmentative and alternative communication provides options for supplementing or replacing speech with other techniques. The current study aimed to examine the experiences of caregivers in Kenya before and after a home-based intervention using augmentative and alternative communication techniques with children with complex communication needs. METHODS: Caregivers were interviewed pre- and post-intervention. The interviews were digitally recorded, transcribed and translated into English. Content analysis was applied through the stages of text familiarization and topic organization. Emergent themes and their sub-themes were identified and labelled. Connections between themes were established and interpretations made. The procedure was completed by a second researcher independently. Conflicting ideas were jointly discussed until consensus was achieved. RESULTS: Four themes emerged from the data: communication process; struggle; normality; and supernatural power. Before intervention, the caregivers acknowledged their expertise in communications with the child, while also revealing their sense of isolation, burden and pain. Normality was present as a source of comparison and also an aspirational goal. Post-intervention more positive language was used to describe the child. There was an 'opening up' of communication that recognized the child's strengths and some social support systems were re-established. The power of the supernatural was recognized before and after intervention. CONCLUSION: Caring of a child with complex communication needs presents many challenges. A home-based intervention using augmentative and alternative communication techniques appears to have been a catalyst for some positive transformations in the caregivers' experiences, although it is not possible to attribute this change to any one aspect. The potentials of the home based intervention would benefit from further investigation on a larger scale. PMID- 23452319 TI - Impact of a single human leucocyte antigen (HLA) allele mismatch on the outcome of unrelated bone marrow transplantation over two time periods. A retrospective analysis of 3003 patients from the HLA Working Group of the Japan Society for Blood and Marrow Transplantation. AB - A previous Japanese study revealed that a human leucocyte antigen (HLA)-A or -B allele mismatch was associated with higher overall mortality, whereas an HLA-C or -DRB1 allele mismatch did not affect mortality after serologically matched unrelated bone marrow transplantation (BMT). This study reanalysed 3003 adult patients who underwent unrelated BMT from a serologically HLA-A, -B, or -DR matched unrelated donor between 1993 and 2009 using the latest database, that included 1966 HLA-matched unrelated BMT and 187, 31, 524, and 295 unrelated BMT with a single HLA-A, -B, -C, or -DRB1 allele mismatch, respectively. As opposed to our previous findings, HLA-C and -DRB1 mismatches had a significant negative impact [hazard ratio (HR) 1.35, P < 0.001, and HR 1.45, P < 0.001] on survival in the period 2000-2009. The negative impact of each single HLA allele mismatch was not significantly different among the HLA-A, -B, -C, and -DRB1 mismatches (P = 0.79). An interaction test revealed that the effects of single HLA-C and -DRB1 allele mismatches significantly differed over the two time periods (P = 0.032 and P = 0.0072, respectively). In conclusion, the impact of a single HLA allele mismatch changed over time. In the recent cohort, the negative impact of HLA-DRB1 and -C mismatches became apparent. PMID- 23452320 TI - Correlation between global genome methylation and mutation at CpG codons of p53 gene. AB - OBJECTIVE: Hypomethylation within the body of the p53 gene, which is normally methylated, has been found in neoplasms. Also, the CG -> TA transition was not detected in the CpG codons of the p53 gene in gastritis lesions in Iranian patients. Therefore, an evaluation of the probable correlation between global genome methylation and alteration at CpG codons of p53 gene was needed. METHODS: For defining the genotypes of CpG codons, DNA sequencing was performed on 90 paired samples of gastritis and normal tissues. To measure global genome methylation status, the extracted DNA was digested with HpaII (methylation sensitive) and MspI (insensitive). Then, enzymatic digestion was quantitated using Pyrosequencing as peak height. By calculating the HpaII/ MspI peak ratio it is possible to evaluate the methylation level of normal and gastritis tissues. RESULTS: Codons 9, 245 and 248 underwent a CG -> AT transversion but not a CG -> TA transition. In addition, the mean methylation level was significantly different between the patients with GG and GT genotypes at codon 245 (P = 0.019). CONCLUSIONS: As CG -> AT transversion at codon 245 is associated with global genome methylation, GG hypomethylation may induce different pattern of mutations, for example, C -> A instead of C -> T at the CpG codons of the p53 gene during gastritis development in Iranian patients. PMID- 23452321 TI - Identifying national health research priorities in Timor-Leste through a scoping review of existing health data. AB - Health research is crucial to understand a country's needs and to improve health outcomes. We conducted a scoping review and analysis of existing health data in Timor-Leste to identify the health research priorities of the country. Published and unpublished health research in Timor-Leste from 2001 to 2011 that reported objectives, methods and results were identified. Key findings were triangulated with data from national surveys and the Health Management Information System; 114 eligible articles were included in the analysis, the leading topics of which were communicable (malaria, tuberculosis, HIV and sexually transmitted diseases and dengue) and non-communicable (eye and mental health) diseases. There were 28 papers (25%) on safe motherhood, child health and nutrition, of which 20 (71%) were unpublished. The review of national indicators showed high infant, under five and maternal mortality rates. Burden of disease is greatest in young children, with respiratory infections, febrile illnesses and diarrheal disease predominating. There is poor access to and utilization of health care. Childhood malnutrition is an important unresolved national health issue. There are several obstacles leading to under-utilization of health services. The following topics for future health research are suggested from the review: nutrition, safe motherhood, childhood illness (in particular identifying the causes and cause specific burden of severe respiratory, febrile and diarrheal diseases) and access to and use of health services. PMID- 23452322 TI - Development of simple and rapid assay to detect viral RNA of tick-borne encephalitis virus by reverse transcription-loop-mediated isothermal amplification. AB - BACKGROUND: Tick-borne encephalitis virus (TBEV) is a causative agent of acute central nervous system disease in humans. It has three subtypes, far eastern (FE), Siberian (Sib) and European (Eu) subtypes, which are distributed over a wide area of Europe and Asia. The objective of this study was to develop a simple and rapid assay for the detection of TBEV RNA by using reverse-transcriptase loop mediated isothermal amplification (RT-LAMP) method that can differentiate the three subtypes of TBEV and can be used for clinical diagnosis and epidemiological study. METHODS: Primers for TBEV-specific and subtype-specific RT-LAMP assay were designed to target the consensus sequence in NS1 of all subtypes and the consensus sequence in the E gene of each subtype, respectiveluy. In vitro transcribed RNA of Oshima strain that belongs to FE subtype was serially diluted and used to examine the sensitivity of the assay. Cross-reactivity of subtype specific RT-LAMP assay was tested by using the RNA of Oshima and Sofjin (FE), IR 99 (Sib) and Hochosterwitz (Eu) strains. RNA extracted from the mixtures of TBEV and ticks, and of TBEV and human blood, and the mouse tissues infected with TBEV, were evaluated in the assay. Positive amplification was observed by real-time monitoring of turbidity and by visual detection of color change. RESULTS: The sensitivity of TBEV-specific RT-LAMP assay was 102 copies of target RNA per reaction volume. FE-specific RT-LAMP assay amplified viral genes of Oshima and Sofjin strains but not of IR-99 and Hochosterwitz strains, and of Japanese encephalitis virus. RT-LAMP assay for Sib and for Eu specifically amplified viral genes of IR-99 and Hochosterwitz strains, respectively. We also showed that tick or human blood extract did not inhibit the amplification of viral gene during the assay. Furthermore, we confirmed that the TBEV RT-LAMP could detect virus RNA from peripheral and central nervous system tissues of laboratory mice infected with TBEV. CONCLUSION: TBEV RT-LAMP assay offers a sensitive, specific, rapid and easy-to-handle method for the detection of TBEV RNA in tick samples and this may be applied in the clinical samples collected from TBE-suspected patients. PMID- 23452323 TI - Investigating a socially anxious-impulsive subgroup of adolescents: a prospective community study. AB - Previous research has identified a subgroup of socially anxious adults who are both anxious and impulsive. To date, however, this subgroup has not been identified in adolescence. Therefore, in this study we aimed to identify this subgroup in a sample of adolescents. In addition, we hypothesized that this subgroup would be higher on problem behaviors, and that these processes would be moderated by gender. We used longitudinal data from 714 adolescents who were in the 7th and 8th grades at Time 1. They were followed annually for three years. Cluster analyses identified an anxious-inhibited subgroup as well as an anxious impulsive subgroup in early adolescence (Time 1). The socially anxious-impulsive adolescent boys were generally higher on both intoxication frequency and delinquency compared with all other adolescents in all clusters at each time point. Findings suggest that social anxiety subgroups may differ on problem behavior, and that early detection of an anxious-impulsive subgroup may be important to prevent maladjustment, especially for adolescent boys. PMID- 23452324 TI - Classical ethylene insensitive mutants of the Arabidopsis EIN2 orthologue lack the expected 'hypernodulation' response in Lotus japonicus. AB - Three independent ethylene insensitive mutants were selected from an EMS- mutagenized population of Lotus japonicus MG-20 (Miyakojima). The mutants, called 'Enigma', were mutated in the LjEIN2a gene from Lotus chromosome 1, sharing significant homology with Arabidopsis EIN2 (ethylene-insensitive2). All three alleles showed classical ethylene insensitivity phenotypes (e.g., Triple Response), but lacked the increased nodulation phenotype commonly associated with ethylene insensitivity. Indeed, all showed a marginal reduction in nodule number per plant, a phenotype that is enigmatic to sickle, an ethylene-insensitive EIN2 mutant in Medicago truncatula. In contrast to wild type, but similar to an ETR1-1 ethylene ethylene-insensitive transgenic of L. japonicus, enigma mutants formed nodules in between the protoxylem poles, demonstrating the influence of ethylene on radial positioning. Suppression of nodule numbers by nitrate and colonisation by mycorrhizal fungi in the enigma-1 mutant were indistinguishable from the wild type MG-20. However, reflecting endogenous ethylene feedback, the enigma-1 mutant released more than twice the wild-type amount of ethylene. enigma-1 had a moderate reduction in growth, greater root mass (and lateral root formation), delayed flowering and ripening, smaller pods and seeds. Expression analysis of ethylene-regulated genes, such as ETR1, NRL1 (neverripe-like 1), and EIL3 in shoots and roots of enigma-1 and MG-20 illustrated that the ethylene-insensitive mutation strongly affected transcriptional responses in the root. These mutants open the possibility that EIN2 in L. japonicus, a determinate nodulating legume, acts in a more complex fashion possibly through the presence of a duplicated copy of LjEIN2. PMID- 23452325 TI - Oxygen insertion of o-quinone under catalytic hydrogenation conditions. AB - An oxygen-insertion reaction that transforms an o-quinone and a conjugated alpha diketone substrate into an anhydride product or derivative under catalytic hydrogenation conditions is reported. The experiments and computations indicate that the oxygen insertion proceeds via a radical mechanism mediated by an acetoxyl radical. PMID- 23452327 TI - Validation of an analytical method based on the high-resolution continuum source flame atomic absorption spectrometry for the fast-sequential determination of several hazardous/priority hazardous metals in soil. AB - BACKGROUND: The aim of this paper was the validation of a new analytical method based on the high-resolution continuum source flame atomic absorption spectrometry for the fast-sequential determination of several hazardous/priority hazardous metals (Ag, Cd, Co, Cr, Cu, Ni, Pb and Zn) in soil after microwave assisted digestion in aqua regia. Determinations were performed on the ContrAA 300 (Analytik Jena) air-acetylene flame spectrometer equipped with xenon short arc lamp as a continuum radiation source for all elements, double monochromator consisting of a prism pre-monocromator and an echelle grating monochromator, and charge coupled device as detector. For validation a method-performance study was conducted involving the establishment of the analytical performance of the new method (limits of detection and quantification, precision and accuracy). Moreover, the Bland and Altman statistical method was used in analyzing the agreement between the proposed assay and inductively coupled plasma optical emission spectrometry as standardized method for the multielemental determination in soil. RESULTS: The limits of detection in soil sample (3sigma criterion) in the high-resolution continuum source flame atomic absorption spectrometry method were (mg/kg): 0.18 (Ag), 0.14 (Cd), 0.36 (Co), 0.25 (Cr), 0.09 (Cu), 1.0 (Ni), 1.4 (Pb) and 0.18 (Zn), close to those in inductively coupled plasma optical emission spectrometry: 0.12 (Ag), 0.05 (Cd), 0.15 (Co), 1.4 (Cr), 0.15 (Cu), 2.5 (Ni), 2.5 (Pb) and 0.04 (Zn). Accuracy was checked by analyzing 4 certified reference materials and a good agreement for 95% confidence interval was found in both methods, with recoveries in the range of 94-106% in atomic absorption and 97 103% in optical emission. Repeatability found by analyzing real soil samples was in the range 1.6-5.2% in atomic absorption, similar with that of 1.9-6.1% in optical emission spectrometry. The Bland and Altman method showed no statistical significant difference between the two spectrometric methods for 95% confidence interval. CONCLUSIONS: High-resolution continuum source flame atomic absorption spectrometry can be successfully used for the rapid, multielemental determination of hazardous/priority hazardous metals in soil with similar analytical performances to those in inductively coupled plasma optical emission spectrometry. PMID- 23452326 TI - Biomolecular signatures of diabetic wound healing by structural mass spectrometry. AB - Wound fluid is a complex biological sample containing byproducts associated with the wound repair process. Contemporary techniques, such as immunoblotting and enzyme immunoassays, require extensive sample manipulation and do not permit the simultaneous analysis of multiple classes of biomolecular species. Structural mass spectrometry, implemented as ion mobility-mass spectrometry (IM-MS), comprises two sequential, gas-phase dispersion techniques well suited for the study of complex biological samples because of its ability to separate and simultaneously analyze multiple classes of biomolecules. As a model of diabetic wound healing, poly(vinyl alcohol) sponges were inserted subcutaneously into nondiabetic (control) and streptozotocin-induced diabetic rats to elicit a granulation tissue response and to collect acute wound fluid. Sponges were harvested at days 2 or 5 to capture different stages of the early wound-healing process. Utilizing IM-MS, statistical analysis, and targeted ultraperformance liquid chromatography analysis, biomolecular signatures of diabetic wound healing have been identified. The protein S100-A8 was highly enriched in the wound fluids collected from day 2 diabetic rats. Lysophosphatidylcholine (20:4) and cholic acid also contributed significantly to the differences between diabetic and control groups. This report provides a generalized workflow for wound fluid analysis demonstrated with a diabetic rat model. PMID- 23452328 TI - HbA1c and the diagnosis of diabetes and prediabetes in a middle-aged and elderly Han population from northwest China (HbA1c). AB - OBJECTIVE: To identify the optimal threshold of HbA1c and to evaluate the predictive performance of HbA1c levels in diagnosing diabetes and prediabetes in a middle-aged and elderly Han Chinese population from northwest China. METHODS: In all, 3354 participants aged >= 40 years with no history of diabetes from northwest China were enrolled in the present cross-sectional study. All subjects underwent a 75-g oral glucose tolerance test (OGTT), as well as HbA1c testing. HbA1c thresholds for diagnosing diabetes and prediabetes were identified by the highest sum of sensitivity and specificity of each cut-off point, and the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic accuracy of the HbA1c threshold. RESULTS: The mean (+/- SD) age of the participants was 57 +/- 8 years, and 70.75% were women. Based on results of the OGTT, 1347 (40.16%) subjects had impaired fasting glucose and/or impaired glucose tolerance, and 725 (21.62%) had diabetes. The area under the ROC curve for detecting undiagnosed diabetes and prediabetes by HbA1c levels was 0.810 (95% confidence interval [CI] 0.796-0.823) and 0.732 (95% CI 0.717-0.747), respectively. HbA1c threshold of 6.4% and 6.1% produced the highest sum of sensitivity (60.00% and 61.49%) and specificity (87.33% and 73.24%) for diagnosing diabetes and prediabetes, respectively. CONCLUSION: HbA1c is an effective and convenient method for diagnosing diabetes and prediabetes. HbA1c thresholds of 6.4% and 6.1% may be used as diagnostic criteria for diabetes and prediabetes, respectively, in the Han Chinese population living in northwest China. PMID- 23452329 TI - Do different ADHD-related etiological risks involve specific neuropsychological pathways? An analysis of mediation processes by inhibitory control and delay aversion. AB - BACKGROUND: Inhibitory control (IC) has been regarded as a neuropsychological basic deficit and as an endophenotype of attention deficit/hyperactivity disorder (ADHD). Implicated here are mediation processes between etiological factors and ADHD symptoms. We thus analyze whether and to what extent executive IC and delay aversion (DA; i.e., reward-related IC) performance mediate the associations of familial, prenatal, and psychosocial risks with ADHD symptoms. METHODS: The study sample consisted of 130 preschool children (3-6 years; 50% boys), including 20% (n = 26) with a positive family history of ADHD (familial risk). Prenatal risks were mainly taken from medical records. Psychosocial risks were assessed by a structured interview. ADHD symptoms were assessed by structured interviews and questionnaires completed by parents and teachers. A set of neuropsychological tasks on IC and DA was conducted with the children. RESULTS: Familial, prenatal, and psychosocial risks were significantly associated with ADHD symptoms. IC and DA also correlated significantly with ADHD symptoms. While the familial risk significantly correlated with IC and DA, psychosocial and prenatal risks were only weakly associated with these measures. The link between the familial risk and ADHD symptoms was partially mediated by IC and DA. CONCLUSIONS: The results indicate different neuropsychological pathways related to 'positive family history of ADHD' and prenatal risks. Given a cross-validation in future studies, the results underscore the endophenotypic character of IC and DA in preschool ages. PMID- 23452330 TI - Complete mitochondrial genome of the Xiangjiang barbel chub Squaliobarbus curriculus: comparative analysis of the genetic variation associated with geographical population. AB - The barbel chub (Squaliobarbus curriculus), a kind of small commercial fish, is widespread in China. In this study, we sequenced the mitochondrial genome of the barbel chub from the Xiangjiang River. The total length of the mitochondrial genome is 16,619 bp, with the base composition of 31.19% A, 25.01% T, 27.68% C, and 16.12% G. The organization and arrangement of these genes are the same as that found in the teleosts, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and a major noncoding control region (D-loop region). Compared with the S. curriculus collected from Jiangsu province, there were 29 mutation sites in the mitogenome sequence of Xiangjiang S. curriculus. All the mutation sites were transitions and mainly occurred in protein-coding genes (21/29), two mutation sites occurred in transfer RNA, two occurred in ribosomal RNA, and four occurred in D-loop region. Among the 21 mutation sites in protein-coding genes, 6 mutation sites resulted in amino acid mutation in ND2, ATPase6, COX3, ND4, and Cytb genes, while the others were synonymous substitutions. These results indicated that there was genetic variation in different geographical populations of S. curriculus. PMID- 23452331 TI - On dihydroorotate dehydrogenases and their inhibitors and uses. AB - Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science. PMID- 23452332 TI - Modular access to complex prodiginines: total synthesis of (+)-roseophilin via its 2-azafulvene prototropisomer. AB - Ansa-bridged prodiginines are bioactive pigments produced by bacteria. Certain of these structures are reported to be antagonists of protein-protein interactions involved in apoptosis. We describe a new entry to alkaloids of this type, demonstrated with a concise asymmetric synthesis of (+)-roseophilin (3). Our route constructs the pyrrolophane motif via phosphoryl transfer-terminated macroaldolization and passes through a previously unexplored prototropic form of the natural product. PMID- 23452335 TI - Effect of functional groups on the sensing properties of silicon nanowires toward volatile compounds. AB - Molecular layers attached to a silicon nanowire field effect transistor (SiNW FET) can serve as antennas for signal transduction of volatile organic compounds (VOCs). Nevertheless, the mutual relationship between the molecular layers and VOCs is still a puzzle. In the present paper, we explore the effect of the molecular layer's end (functional) groups on the sensing properties of VOCs. Toward this end, SiNW FETs were modified with tailor-made molecular layers that have the same backbone but differ in their end groups. Changes in the threshold voltage (DeltaVth) and changes in the mobility (DeltaMUh) were then recorded upon exposure to various VOCs. Model-based analysis indicates that the interaction between molecular layers and VOCs can be classified to three main scenarios: (a) dipole-dipole interaction between the molecular layer and the polar VOCs; (b) induced dipole-dipole interaction between the molecular layers and the nonpolar VOCs; and (c) molecular layer tilt as a result of VOCs diffusion. Based on these scenarios, it is likely that the electron-donating/withdrawing properties of the functional groups control the dipole moment orientation of the adsorbed VOCs and, as a result, determine the direction (or sign) of the DeltaVth. Additionally, it is likely the diffusion of VOCs into the molecular layer, determined by the type of functional groups, is the main reason for the DeltaMUh responses. The reported findings are expected to provide an efficient way to design chemical sensors that are based on SiNW FETs to nonpolar VOCs, which do not exchange carriers with the molecular layers. PMID- 23452336 TI - Sirevirus LTR retrotransposons: phylogenetic misconceptions in the plant world. AB - Sireviruses are an ancient and plant-specific LTR retrotransposon genus. They possess a unique genome structure that is characterized by a plethora of highly conserved sequence motifs in key domains of the non-coding genome, and often, by the presence of an envelope-like gene. Recently, their crucial role in the organization of the maize genome, where Sireviruses occupy approximately 21% of its nuclear content, was revealed, followed by an analysis of their distribution across the plant kingdom. It is now suggested that Sireviruses have been a major mediator of the evolution of many plant genomes. However, the name 'Sirevirus' has caused confusion in the scientific community in regards to their classification within the LTR retrotransposon order and their relationship with viruses - a situation that is not unique to Sireviruses, but also affects other LTR retrotransposon genera. Here, we clarify the phylogenetic position of Sireviruses as typical LTR retrotransposons of the Copia superfamily and explain that the confusion stems from the discrepancy in the categorization of LTR retrotransposons by the two main classification systems: the International Committee on the Taxonomy of Viruses (ICTV) system and the unified classification system for eukaryotic transposable elements. While the name 'Sirevirus' has been given by ICTV, we show that the transposable element system, which is more suitable for eukaryotic genome studies, lacks an appropriate taxonomic level for describing them. We urge for this inconsistency to be addressed. Finally, we provide data suggesting that of the three ICTV-proposed genera of the Pseudoviridae (that is, Copia) family, only Sireviruses form a monophyletic group, while the phylogenetic distinction between Pseudoviruses and Hemiviruses is unclear. We conclude that because of their ongoing important contribution to the classification of transposable elements, these schemes need to be frequently revisited and revised - as shown by the example of the Sirevirus LTR retrotransposon genus. PMID- 23452337 TI - Rural-urban comparison in prevalence of overweight and obesity among adolescents in Shandong, China. AB - BACKGROUND: Prevalence of overweight and obesity has increased in both developed and developing countries. The increasing global prevalence of overweight and obesity among children and adolescents constitutes a public health crisis. AIM: The present study assessed the rural-urban differences in prevalence of overweight and obesity among adolescents in Shandong Province, China from 1985 2010. SUBJECTS AND METHODS: The BMI of adolescents aged 7-18 years was calculated using data from five national repeated cross-sectional surveys on students' constitution and health carried out by the government in 1985, 1995, 2000, 2005 and 2010 in Shandong Province, China. The prevalence of overweight and obesity was obtained according to the WGOC (Working Group on Obesity in China) reference norm and the International Obesity Task Force (IOTF) cut-offs. RESULTS: In the past 25 years, The prevalence of overweight and obesity increased rapidly: The rate of overweight plus obesity by WGOC reference norm increased from 3.60% (Urban male), 3.03% (Urban female), 0.77% (Rural male) and 1.47% (Rural female) in 1985 to 36.57% (Urban male), 19.39% (Urban female), 29.59% (Rural male) and 18.76% (Rural female) in 2010, respectively. The increasing trend is similar using IOTF cut-offs. Differences in prevalence by year of overweight and obesity between urban and rural areas were observed. CONCLUSION: Overweight and obesity increased remarkably among Shandong adolescents from 1985-2010 and has become a serious public health problem. Comprehensive evidence-based strategies of intervention should be introduced, including periodic monitoring. PMID- 23452338 TI - Open stomata 1 (OST1) kinase controls R-type anion channel QUAC1 in Arabidopsis guard cells. AB - Under drought stress, the stress hormone ABA addresses the SnR kinase OST1 via its cytosolic receptor and the protein phosphatase ABI1. Upon activation, OST1 phosphorylates the guard cell S-type anion channel SLAC1. Arabidopsis ABI1 and OST1 loss-of-function mutants are characterized by an extreme wilting 'open stomata' phenotype. Given the fact that guard cells express both SLAC- and R /QUAC-type anion channels, we questioned whether OST1, besides SLAC1, also controls the QUAC1 channel. In other words, are ABI1/OST1 defects preventing both of the guard cell anion channel types from operating properly in terms of stomatal closure? The activation of the R-/QUAC-type anion channel by ABA signaling kinase OST1 and phosphatase ABI1 was analyzed in two experimental systems: Arabidopsis guard cells and the plant cell-free background of Xenopus oocytes. Patch-clamp studies on guard cells show that ABA activates R-/QUAC-type currents of wild-type plants, but to a much lesser extent in those of abi1-1 and ost1-2 mutants. In the oocyte system the co-expression of QUAC1 and OST1 resulted in a pronounced activation of the R-type anion channel. These studies indicate that OST1 is addressing both S-/SLAC- and R-/QUAC-type guard cell anion channels, and explain why the ost1-2 mutant is much more sensitive to drought than single slac1 or quac1 mutants. PMID- 23452339 TI - AMH after laparoscopic surgery of the ovaries: a review. AB - Operative laparoscopy compared with laparotomy has been established as the gold standard surgical approach in treating ovarian cysts. However, the safety of a laparoscopic cystectomy has been questioned in what has to do with the subsequent damage to the ovarian reserve of the operated ovary. One of the best available methods to determine ovarian reserve, due to its biochemical and pathological characteristics is anti-Mullerian hormone (AMH). With this study, we are reviewing currently available studies examining the effect laparoscopic operations have on AMH levels. PMID- 23452340 TI - Tandem repeats derived from centromeric retrotransposons. AB - BACKGROUND: Tandem repeats are ubiquitous and abundant in higher eukaryotic genomes and constitute, along with transposable elements, much of DNA underlying centromeres and other heterochromatic domains. In maize, centromeric satellite repeat (CentC) and centromeric retrotransposons (CR), a class of Ty3/gypsy retrotransposons, are enriched at centromeres. Some satellite repeats have homology to retrotransposons and several mechanisms have been proposed to explain the expansion, contraction as well as homogenization of tandem repeats. However, the origin and evolution of tandem repeat loci remain largely unknown. RESULTS: CRM1TR and CRM4TR are novel tandem repeats that we show to be entirely derived from CR elements belonging to two different subfamilies, CRM1 and CRM4. Although these tandem repeats clearly originated in at least two separate events, they are derived from similar regions of their respective parent element, namely the long terminal repeat (LTR) and untranslated region (UTR). The 5' ends of the monomer repeat units of CRM1TR and CRM4TR map to different locations within their respective LTRs, while their 3' ends map to the same relative position within a conserved region of their UTRs. Based on the insertion times of heterologous retrotransposons that have inserted into these tandem repeats, amplification of the repeats is estimated to have begun at least ~4 (CRM1TR) and ~1 (CRM4TR) million years ago. Distinct CRM1TR sequence variants occupy the two CRM1TR loci, indicating that there is little or no movement of repeats between loci, even though they are separated by only ~1.4 Mb. CONCLUSIONS: The discovery of two novel retrotransposon derived tandem repeats supports the conclusions from earlier studies that retrotransposons can give rise to tandem repeats in eukaryotic genomes. Analysis of monomers from two different CRM1TR loci shows that gene conversion is the major cause of sequence variation. We propose that successive intrastrand deletions generated the initial repeat structure, and gene conversions increased the size of each tandem repeat locus. PMID- 23452341 TI - The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake. AB - The cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. The CB1R is also expressed peripherally, where its effects include promotion of liver fat accumulation, which consumes ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blockade of hepatic CB1Rs could contribute significantly to the weight-reducing and insulin sensitizing effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and bodyweight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may be effective in treating inflammatory liver disease, such as non-alcoholic steatohepatitis, reducing the likelihood of disease progression to cirrhosis or cancer. PMID- 23452342 TI - The intensity of physical activity influences bone mineral accrual in childhood: the childhood health, activity and motor performance school (the CHAMPS) study, Denmark. AB - BACKGROUND: Studies indicate genetic and lifestyle factors can contribute to optimal bone development. In particular, the intensity level of physical activity may have an impact on bone health. This study aims to assess the relationship between physical activity at different intensities and Bone Mineral Content (BMC), Bone Mineral Density (BMD) and Bone Area (BA) accretion. METHODS: This longitudinal study is a part of The CHAMPS study-DK. Whole-body DXA scans were performed at baseline and after two years follows up. BMC, BMD, and BA were measured. The total body less head (TBLH) values were used. Physical activity (PA) was recorded by accelerometers (ActiGraph, model GT3X). Percentages of different PA intensity levels were calculated and log odds of two intensity levels of activity relative to the third level were calculated. Multilevel regression analyses were used to assess the relationship between the categories of physical activity and bone traits. RESULTS: Of 800 invited children, 742 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow up. Complete datasets were obtained in 602/742 (81%) children. Mean (range) of age was 11.5 years (9.7-13.9). PA at different intensity levels was for boys and girls respectively, sedentary 62% and 64%, low 29% for both genders and moderate to high 9% and 7% of the total time. Mean (range) BMC, BMD, and BA was 1179 g (563-2326), 0.84 g/cm2 (0.64-1.15) and 1393 cm2 (851-2164), respectively. Valid accelerometer data were obtained for a mean of 6.1 days, 13 hours per day. CONCLUSIONS: There 7was a positive relationship between the log odds of moderate to high-level PA versus low level activity and BMC, BMD and BA. Children with an increased proportion of time in moderate to high-level activity as opposed to sedentary and low-level activity achieved positive effects on BMC, BMD and BA. PMID- 23452343 TI - The multiple roles of histidine in protein interactions. AB - BACKGROUND: Among the 20 natural amino acids histidine is the most active and versatile member that plays the multiple roles in protein interactions, often the key residue in enzyme catalytic reactions. A theoretical and comprehensive study on the structural features and interaction properties of histidine is certainly helpful. RESULTS: Four interaction types of histidine are quantitatively calculated, including: (1) Cation-pi interactions, in which the histidine acts as the aromatic pi-motif in neutral form (His), or plays the cation role in protonated form (His+); (2) pi-pi stacking interactions between histidine and other aromatic amino acids; (3) Hydrogen-pi interactions between histidine and other aromatic amino acids; (4) Coordinate interactions between histidine and metallic cations. The energies of pi-pi stacking interactions and hydrogen-pi interactions are calculated using CCSD/6-31+G(d,p). The energies of cation-pi interactions and coordinate interactions are calculated using B3LYP/6-31+G(d,p) method and adjusted by empirical method for dispersion energy. CONCLUSIONS: The coordinate interactions between histidine and metallic cations are the strongest one acting in broad range, followed by the cation-pi, hydrogen-pi, and pi-pi stacking interactions. When the histidine is in neutral form, the cation-pi interactions are attractive; when it is protonated (His+), the interactions turn to repulsive. The two protonation forms (and pKa values) of histidine are reversibly switched by the attractive and repulsive cation-pi interactions. In proteins the pi-pi stacking interaction between neutral histidine and aromatic amino acids (Phe, Tyr, Trp) are in the range from -3.0 to -4.0 kcal/mol, significantly larger than the van der Waals energies. PMID- 23452344 TI - Effect of variations in depth of neuromuscular blockade on rating of surgical conditions by surgeon and anesthesiologist in patients undergoing laparoscopic renal or prostatic surgery (BLISS trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Surgical conditions in laparoscopic surgery are largely determined by the depth of neuromuscular relaxation. Especially in procedures that are confined to a narrow working field, such as retroperitoneal laparoscopic surgery, deep neuromuscular relaxation may be beneficial. Until recently, though, deep neuromuscular block (NMB) came at the expense of a variety of issues that conflicted with its use. However, with the introduction of sugammadex, rapid reversal of a deep NMB is feasible. In the current protocol, the association between the depth of NMB and rating of surgical conditions by the surgeon and anesthesiologist is studied. METHODS/DESIGN: This is a single-center, prospective, randomized, blinded, parallel group and controlled trial. Eligible patients are randomly assigned to one of two groups: (1) deep NMB (post-tetanic count, one or two twitches; n = 12) and (2) moderate NMB (train-of-four, 1 to 2 twitches, n = 12) by administration of high-dose rocuronium in Group 1 and a combination of atracurium and mivacurium in Group 2. The NMB in Group 1 is reversed by 4 mg/kg sugammadex; the NMB in Group 2 by 1 mg neostigmine and 0.5 mg atropine. Patients are eligible if they are over 18 years, willing to sign the informed consent form, and are scheduled to undergo an elective laparoscopic renal procedure or laparoscopic prostatectomy. A single surgeon performs the surgeries and rates the surgical conditions on a five-point surgical rating scale (SRS) ranging from 1 (poor surgical conditions) to 5 (excellent surgical conditions). The intra-abdominal part of the surgeries is captured on video and a group of five anesthesiologists and ten surgical experts will rate the videos using the same SRS. The primary analysis will be an intention-to-treat analysis. Evaluation will include the association between the level of NMB and SRS, as obtained by the surgeon performing the procedure and the agreement between the scoring of the images by anesthesiologists and surgeons. DISCUSSION: We aim to show that under the right conditions the perceived opposing goals of surgeons and anesthesiologists (optimal surgical conditions vs. optimal postoperative conditions) may be met without compromise to either. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01631149. PMID- 23452346 TI - Knowledge and utilization of information communication technology (ICT) among health science students at the University of Gondar, North Western Ethiopia. AB - BACKGROUND: Despite the relatively huge ICT investment and policy deployment in higher institutions in Ethiopia, there is still scant information about the success of implementation of the Information Communication Technology (ICT) in the higher education. This study, therefore, was carried out with an aim to assess knowledge and utilization of Information Communication Technology (ICT) among medicine and health science students and its associated factors in Gondar College of Medicine and Health sciences, University of Gondar. METHODS: A cross sectional study was conducted at the College of Medicine and Health Sciences, University of Gondar, Ethiopia. Data regarding socio-demographic characteristics of the students, level of knowledge and utilization of ICT were collected by means of a self-administered questionnaire. Data was analyzed using SPSS version 13. RESULTS: A total of 1096 students responded giving a response rate of 97.8%. The mean age of the study participants was 20.3 (+/-1. 3) years. Females constitute only 26% of the respondents. The majority (79%) were fulltime students. Only half of the respondents (51%) had ICT knowledge and only 46% students utilized ICT while 47% of the respondents never used electronic communication (e.g. email or chat room) and 39% of the respondents never used Microsoft office (e.g. word ((r)) or WordPerfect ((r))). ICT knowledge [AOR = 2.5, 95% CI: 1.7-3.5], family educational background [AOR = 4.36, 95% CI: 2.16 8.80], and perceived quality of training [AOR = 1.9, 95% CI: 1.3-2.8] showed strong and positive associations with ICT utilization. Students from urban areas were more likely to utilize ICT compared with those from rural areas [AOR = 2.7, 95% CI: 2.097, 3.497], and information technology training was found to be positively associated with ICT utilization [AOR = 2. 07, 95% CI: 1.18, 3.62]. CONCLUSIONS: The result showed that students' knowledge was inadequate and utilization of ICT was poor. Therefore, the university should sustain professional development to improve teaching, to raise student performance and equip the college with student centered ICT computer labs to increase students' ICT utilization. PMID- 23452345 TI - What are the most effective techniques in changing obese individuals' physical activity self-efficacy and behaviour: a systematic review and meta-analysis. AB - Increasing self-efficacy is generally considered to be an important mediator of the effects of physical activity interventions. A previous review identified which behaviour change techniques (BCTs) were associated with increases in self efficacy and physical activity for healthy non-obese adults. The aim of the current review was to identify which BCTs increase the self-efficacy and physical activity behaviour of obese adults. A systematic search identified 61 comparisons with obese adults reporting changes in self-efficacy towards engaging in physical activity following interventions. Of those comparisons, 42 also reported changes in physical activity behaviour. All intervention descriptions were coded using Michie et al's (2011) 40 item CALO-RE taxonomy of BCTs. Meta-analysis was conducted with moderator analyses to examine the association between whether or not each BCT was included in interventions, and size of changes in both self efficacy and physical activity behaviour. Overall, a small effect of the interventions was found on self-efficacy (d = 0.23, 95% confidence interval (CI): 0.16-0.29, p < 0.001) and a medium sized effect on physical activity behaviour (d = 0.50, 95% CI 0.38-0.63, p < 0.001). Four BCTs were significantly associated with positive changes in self-efficacy; 'action planning', 'time management', 'prompt self-monitoring of behavioural outcome' and 'plan social support/social change'. These latter two BCTs were also associated with positive changes in physical activity. An additional 19 BCTs were associated with positive changes in physical activity. The largest effects for physical activity were found where interventions contained 'teach to use prompts/cues', 'prompt practice' or 'prompt rewards contingent on effort or progress towards behaviour'. Overall, a non significant relationship was found between change in self-efficacy and change in physical activity (Spearman's Rho = -0.18 p = 0.72). In summary, the majority of techniques increased physical activity behaviour, without having discernible effects on self-efficacy. Only two BCTs were associated with positive changes in both physical activity self-efficacy and behaviour. This is in contrast to the earlier review which found a strong relationship between changes in physical activity self-efficacy and behaviour. Mechanisms other than self-efficacy may be more important for increasing the physical activity of obese individuals compared with non-obese individuals. PMID- 23452347 TI - Nonscanning three-dimensional optical microscope based on the reflectivity-height transformation for biological measurements. AB - We propose a nonscanning three-dimensional (3D) optical microscope based on reflectivity-height transformation in applications of biological and transparent plate measurements. The reflectivity of a prism can be transformed to the surface height of the specimen based on geometrical optics and the principle of internal reflection. Thus, the pattern of reflectivity is representative of the surface profile. Using charge-coupled device cameras to obtain the two-dimensional image patterns and combining with its reflectivity pattern, the 3D profile can be generated. The lateral resolution is determined by the diffraction limit, and the vertical resolution is better than several nanometers according to the incident angle and polarization used. PMID- 23452348 TI - Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes. AB - Mutations in TRPM1, a calcium channel expressed in retinal bipolar cells and epidermal melanocytes, cause complete congenital stationary night blindness with no discernible skin phenotype. In the retina, TRPM1 activity is negatively coupled to metabotropic glutamate receptor 6 (mGluR6) signaling through Galphao and TRPM1 mutations result in the loss of responsiveness of TRPM1 to mGluR6 signaling. Here, we show that human melanocytes express mGluR6, and treatment of melanocytes with L-AP4, a type III mGluR-selective agonist, enhances Ca(2+) uptake. Knockdown of TRPM1 or mGluR6 by shRNA abolished L-AP4-induced Ca(2+) influx and TRPM1 currents, showing that TRPM1 activity in melanocytes is positively coupled to mGluR6 signaling. Galphao protein is absent in melanocytes. However, forced expression of Galphao restored negative coupling of TRPM1 to mGluR6 signaling, but treatment with pertussis toxin, an inhibitor of Gi /Go proteins, did not affect basal or mGluR6-induced Ca(2+) uptake. Additionally, chronic stimulation of mGluR6 altered melanocyte morphology and increased melanin content. These data suggest differences in coupling of TRPM1 function to mGluR6 signaling explain different cellular responses to glutamate in the retina and the skin. PMID- 23452349 TI - Eradication of superficial fungal infections by conventional and novel approaches: a comprehensive review. AB - During the last two decades, the occurrence of fungal infections either superficial or systemic has been increasing. Moreover, fungal infections become more difficult to treat when they show coupling with immunogenic diseases like AIDS. Superficial fungal infections are associated with skin, nail and eye and are less prominent to systemic infection. However, it may be dangerous if not treated properly. It is usually observed that conventional formulations including cream, powder, gels etc. are used to treat skin fungal infections even for the deep seated fungal infections. However, these formulations show various side effects on the application site like burning, redness and swelling. Further, due to the immediate release of drug from these formulations they can stimulate the immune system of body generating high impact allergic reactions. Deep seated fungal infections like invasive aspergillosis and invasive candidiasis may be more difficult to treat because the drug released from conventional topical formulation can not reach at the target site due to the low penetration capacity. Similarly, in case of fungal infection of nail and eye, conventional formulations show problem of less bioavailability. Thus, to overcome the drawbacks of conventional therapy a lot of research works have been carried out to develop novel formulations of antifungal drugs to deliver them superficially. Novel formulations explored for the skin delivery of antifungal drugs include liposomes, niosomes, ethosomes, microemulsions, nanoparticles, microspheres and micelles. These formulations show extended or sustained release of drug, minimizing the side effect on application site, enhancing bioavailability and reducing the dosing frequency. Further, these formulations also show penetration into the deep skin to treat invasive fungal infections. Novel formulations explored in treatment of fungal infections of eye are liposomes and nanoparticles and whether for nail fungal infections microemulsions are the choice. In present article, we have discussed about conventional treatment of superficial fungal infection and their comparison with the novel drug delivery systems. PMID- 23452350 TI - Where is the game? Wild meat products authentication in South Africa: a case study. AB - BACKGROUND: Wild animals' meat is extensively consumed in South Africa, being obtained either from ranching, farming or hunting. To test the authenticity of the commercial labels of meat products in the local market, we obtained DNA sequence information from 146 samples (14 beef and 132 game labels) for barcoding cytochrome c oxidase subunit I and partial cytochrome b and mitochondrial fragments. The reliability of species assignments were evaluated using BLAST searches in GenBank, maximum likelihood phylogenetic analysis and the character based method implemented in BLOG. The Kimura-2-parameter intra- and interspecific variation was evaluated for all matched species. RESULTS: The combined application of similarity, phylogenetic and character-based methods proved successful in species identification. Game meat samples showed 76.5% substitution, no beef samples were substituted. The substitutions showed a variety of domestic species (cattle, horse, pig, lamb), common game species in the market (kudu, gemsbok, ostrich, impala, springbok), uncommon species in the market (giraffe, waterbuck, bushbuck, duiker, mountain zebra) and extra continental species (kangaroo). The mountain zebra Equus zebra is an International Union for Conservation of Nature (IUCN) red listed species. We also detected Damaliscus pygargus, which is composed of two subspecies with one listed by IUCN as 'near threatened'; however, these mitochondrial fragments were insufficient to distinguish between the subspecies. The genetic distance between African ungulate species often overlaps with within-species distance in cases of recent speciation events, and strong phylogeographic structure determines within species distances that are similar to the commonly accepted distances between species. CONCLUSIONS: The reliability of commercial labeling of game meat in South Africa is very poor. The extensive substitution of wild game has important implications for conservation and commerce, and for the consumers making decisions on the basis of health, religious beliefs or personal choices.Distance would be a poor indicator for identification of African ungulates species. The efficiency of the character-based method is reliant upon availability of large reference data. The current higher availability of cytochrome b data would make this the marker of choice for African ungulates. The encountered problems of incomplete or erroneous information in databases are discussed. PMID- 23452351 TI - A switch of the oxidation state of graphene oxide on a surface plasmon resonance chip. AB - Controlling the assembly and manipulating the oxidation state of graphene nanosheets on surfaces are of essential importance for application of graphene related optical and biosensing devices. In this study, we assemble a graphene oxide (GO) film on a surface plasmon resonance chip surface and then convert it to reduced graphene by an in situ electrochemical method. The mechanism and application of surface-enhanced Raman spectroscopy and DNA sensing from graphene based substrates are investigated. The average thickness and dielectric constant of GO are varied significantly with the switch of its oxidation state. Electrochemical reduction decreases the distance between carbon atoms and the gold surface by removing the spacer of oxygen functional groups. The electromagnetic field of the graphene surface is therefore enhanced, resulting in an enhancement of the Raman signal. A p doping of electrochemically reduced GO (ERGO) that occurred from changes in the graphene electronic structure through interaction between gold and ERGO is also observed during electrochemical reduction. The GO and ERGO substrates perform different interaction abilities with single- and double-stranded DNA. This work may be valuable for graphene related research works on optoelectronics and biosensors. PMID- 23452352 TI - Rorschach scores in applied clinical practice: a survey of perceived validity by experienced clinicians. AB - We surveyed practicing clinicians who regularly used the Rorschach about the perceived clinical validity of specific Rorschach scores from many coding systems. The survey included quantitative feedback on the validity of specific variables as well as qualitative input in several areas, including the validity of specific variables, the potentially unique information that can be obtained from them, coding challenges associated with Comprehensive System (CS) codes, and recommendations for CS developments. Participants were recruited by applying a snowball sampling strategy. Based on responses from 246 experienced clinicians from 26 countries, composite judgments on rated variables were quite reliable (e.g., M alpha = .95 across 88 CS variables), despite limited agreement among any 2 judges. The aggregated judgments clearly differentiated among scores that were considered more and less clinically valid and the overall results aligned with recently obtained meta-analytic conclusions from the traditional validity literature (Mihura, Meyer, Dumitrascu, & Bombel, 2012). The judges also provided guidance concerning revisions and enhancements that would facilitate Rorschach based assessment in the future. We discuss the implication of the quantitative and qualitative findings and provide suggestions for future directions based on the results. PMID- 23452353 TI - Quality and value in cancer care. PMID- 23452354 TI - What can be done for patients with NSCLC without druggable targets? PMID- 23452355 TI - Ginseng: panacea among herbal remedies? PMID- 23452356 TI - Access to cancer medicine in Iran. PMID- 23452357 TI - Secondary haematological malignancies in the BCIRG 001 study. PMID- 23452358 TI - Genes, genes, genes. PMID- 23452359 TI - Education requirements and opportunities. PMID- 23452360 TI - Severe abdominal trauma in a 21-month-old child. PMID- 23452361 TI - Flying friendly. PMID- 23452363 TI - A different view: changing the way we learn. PMID- 23452364 TI - Helicopter emergency medical services crew administration of antibiotics for open fractures. AB - This study had 3 major aims: (1) to ascertain the degree to which helicopter emergency medical services (HEMS) administration of antibiotics (Abx) can streamline the time to Abx in open fracture patients, (2) to determine whether any clinical outcome improvements were associated with HEMS Abx therapy, and (3) to calculate the cost-effectiveness of prehospital HEMS Abx. The design of the study was a prospective, nonrandomized, nonintervention, natural study of timing and clinical outcomes for patients with suspected open extremity fracture. There were 138 scene trauma cases transported by 8 participating HEMS programs from July 2009 to June 2010. The participating HEMS programs were both urban and rural. The diagnosis of an open fracture by the HEMS crews had an accuracy rate of 97.8% (95% confidence interval, 90.8%-98.4%). The time from the incident to Abx was 30 minutes shorter (P = .0001) when Abx were administered by HEMS crews. There was no statistical significance (P = 1.0) regarding the endpoint of infection or nonunion development in HEMS- versus hospital-administered Abx. In conclusion, the administration of Abx by HEMS crews to patients diagnosed with open extremity fractures is feasible, it may decrease the time to Abx by 30 minutes, and the effect magnitude (40.3% relative risk reduction) was promising. PMID- 23452365 TI - Flight vibrations and bleeding in helicoptered patients with pelvic fracture. AB - Depending on their amplitude and frequency, vibrations may facilitate bleeding and worsen the prognosis of patients with pelvic fractures transported by helicopter emergency medical services (HEMS). We measured the range of frequencies and amplitudes of forced vibrations produced by the helicopter used by the HEMS of the Italian Friuli Venezia Giulia region on the pelvis of transported persons. We performed 3 flight tests with 3 different volunteers (mass 70, 80, and 90 kg, respectively) loaded on the helicopter's stretcher and recorded the amplitudes and frequencies of vibrations through a triaxis sensor placed on the HEMS stretcher in the pelvis area. The flight profile planned was identical for each of the 3 iterations. Over the whole flight, the frequencies of vibration were between 26.4 and 53.5 Hz, and the greastest amplitude was 0.035 mm. The vibrations recorded in the helicopter may facilitate bleeding in unstable fractures. In the management of patients with pelvic fractures, HEMS crews should provide prehospital care that includes the use of specific splinting devices in addition to the spinal board, which allows an early immobilization of fractures and the limitation of pelvic motion. PMID- 23452366 TI - Development of an educational program for the helicopter emergency medical services in Japan. AB - INTRODUCTION: The Japanese helicopter emergency medical service (HEMS) system provides advanced prehospital treatment at the scene. The education of the dispatched HEMS physicians is important for guaranteeing the quality of medical and safety management, but there is no nationally established training program. This study aimed to determine the validity of the HEMS educational program developed by our team. METHODS: A 3-step educational program was designed for HEMS trainees: step 1, 20 HEMS missions as an observer; step 2, 80 missions of on the-job training; and step 3, certifying examination conducted by a supervisor. As an evaluation standard, scene time, defined as time from landing at the scene to taking off for a hospital, was determined retrospectively. RESULTS: For trainees, scene time was significantly longer (16.3 +/- 5.4 min, 95% CI 15.5 17.1) than for experts (doctors who completed >200 HEMS missions; 15.2 +/- 6.7 min, 95% CI 14.7-15.8; P = 0.040) but was significantly shorter than for doctors trained before establishment of the HEMS program (17.5 +/- 7.0 min, 95% CI 16.9 18.2; P = 0.030). In cases of trauma or intrinsic disease, there was no significant difference in scene time between trainees (17.4 +/- 5.6 min and 14.9 +/- 4.8 min, respectively) and experts (16.4 +/- 7.8 min and 14.2 +/- 5.5 min, respectively). CONCLUSION: The finding that scene time was shortened for program trainees demonstrates the validity of our HEMS educational program. The quality of HEMS missions will be better ensured through this educational system. PMID- 23452367 TI - The Airtraq Optical Laryngoscope in helicopter emergency medical services: a pilot trial. AB - OBJECTIVE: To determine the degree of success helicopter emergency medical services personnel have in placing an endotracheal tube using a relatively new device for endotracheal intubation (ETI) known as the Airtraq (AT) Optical Laryngoscope (King Systems Corp, Noblesville, IN), and to determine the frequency with which flight crews had to resort to other means for advanced airway management. METHODS: This prospective, observational pilot trial evaluated the critical care flight team's ability to perform ETI using the AT as a first-line device in the prehospital setting. Flight crews were instructed to use the AT for any patient needing ETI. Teams completed a 30-minute training session followed by mannequin practice. They documented situations and outcomes: reason for ETI, success in placing the AT, reason for unsuccessful placement, end-tidal carbon dioxide concentration in expired air (ETCO2), and where patients were when they underwent intubation (field, ambulance, aircraft, hospital). Data were abstracted and analyzed using JMP software version 7.0 (SAS Institute, Inc, Cary, NC). RESULTS: Fifty cases involving use of the AT were analyzed. Median patient age was 51.5 years (range, 15-90; interquartile range, 36-64.5). Most patients were male (n = 37 [74%]). The primary reasons for intubation were unresponsiveness and altered loss of consciousness (n = 23 [46%]), respiratory distress or apnea (n = 8 [16%]), cardiac arrest (n = 10 [20%]), and combative behavior (n = 7 [14%]). AT was successful (n = 31[62%]) in 1 to 2 attempts. The primary reason for AT failure was blood or vomit in the airway (n = 8 [42.1%]); 48.1% (n = 25) of patients required a different management mode. CONCLUSIONS: HEMS crews had difficulty placing successful ET tubes with this device after minimal education with a single regular-sized device. Difficulty was pronounced when blood or vomit was present and obstructing the optical view. Further study is needed to evaluate the implementation time, training time required, and possible design advantages of the AT compared with those of traditional emergent airway management techniques. PMID- 23452368 TI - Supraglottic airway device use as a primary airway during rapid sequence intubation. AB - INTRODUCTION: This study compared first-attempt placement success rates of the King LTS-D as a primary airway for patients requiring medication-assisted airway management (MAAM) against historical controls. SETTING: Rotor-wing division of a single critical care transportation company METHODS: 53 providers (RNs/EMT-P) consented to participation and were trained in the use of the King LTS-D. All patients in need of MAAM per agency treatment guidelines were screened for inclusion and exclusion criteria. After each placement attempt, providers completed data collection via telephone. The primary endpoint was comparison of first-attempt placement success rate between the King LTS-D and historical control endotracheal intubation (ETI) MAAM patients. Overall placement success, time to placement, pre- and post-placement SaO2, ETCO2 at 2 minutes after placement, and complications were also analyzed. RESULTS: 38 patients received rapid sequence intubation with the King LTS-D by 23 of 58 consented providers. First-attempt success rate was 76% (29/38), with an overall success rate of 84% (32/38). The primary endpoint analysis showed no difference in first-attempt success rate between historical control ETI MAAM data and King LTS-D (71% vs 76%; OR = 0.1.34 [95% CI Intubation time to insertion was 26 seconds (IQR = 12-46). Pre- and post-insertion SaO(1)2 values were 88.9 +/- 12.6% and 92.1 +/- 12.7%, respectively. Mean ETCO2 at 2 minutes after placement was 34.8 +/- 4.0. Vomit in the patient's airway was the most frequently reported complication (46%). CONCLUSION: Success rates with the King LTS-D were not significantly different from historical control ETI data. Time to placement was comparable to previous reports. PMID- 23452369 TI - A 10-year analysis of 214 HEMS backcountry hoist rescues. AB - BACKGROUND: Few published studies on civilian helicopter emergency medical services (HEMS) hoist programs exist. This study provides a demographic analysis of hoist rescue operations performed by the only FAA Part 135 hoist-approved civilian HEMS operator in the United States. METHODS: All persons hoisted between May 29, 2001, and May 28, 2011, were retrospectively analyzed. RESULTS: Over a 10 year period, 212 of 214 victims were hoisted. The most common indications were fall injuries (38%) and being stranded (21%). Victim demographics showed an average age of 35 +/- 17years, predominantly male (79%), often associated with trauma (66%), with a majority (68%) of all victims requiring subsequent transport to a hospital by ground ambulance (24%) or flown by Life Flight (44%). Hoists occurred most often in the afternoon (14:07 +/- 3:47 hours), during the weekend (53%), in the months of May-September (71%), at an altitude of 7,488 +/- 1487 feet, with the seat harness (39%) being the most common mode of victim extraction. Hoist insertion of search and rescue (SAR) personnel occurred infrequently (5%). CONCLUSION: The results from this demographic study on hoist operations can provide important demographic information for HEMS contemplating backcountry hoist operations and programs that interface with SAR agencies. PMID- 23452370 TI - Surviving tragedy. PMID- 23452372 TI - Objectively measured light-intensity lifestyle activity and sedentary time are independently associated with metabolic syndrome: a cross-sectional study of Japanese adults. AB - BACKGROUND: Reducing sedentary time and increasing lifestyle activities, including light-intensity activity, may be an option to help prevent metabolic syndrome (MetS). The purpose of the present study was to examine whether objectively measured light-intensity lifestyle activity and sedentary time is associated with MetS, independent of moderate-vigorous intensity physical activity (MVPA). METHODS: The participants in this cross-sectional study were 483 middle-aged Japanese adults, aged 30-64 years. The participants were divided into those with or without MetS according to the Japanese criteria for MetS. A triaxial accelerometer was used to measure light-intensity lifestyle activity [1.6-2.9 metabolic equivalents (METs)] and sedentary time (<=1.5 METs). Logistic regression was used to predict MetS from the levels of light-intensity lifestyle activity and sedentary time with age, sex, smoking, calorie intake, accelerometer wear time, and MVPA as covariates. RESULTS: The odds ratios (OR) for MetS in the highest and middle tertiles of light-intensity lifestyle activity were 0.44 [95% confidence interval (CI): 0.24 to 0.81] and 0.51 (95% CI: 0.29 to 0.89) relative to the lowest tertile, after adjustment for age, sex, smoking, calorie intake, accelerometer wear time and MVPA (Ptrend = 0.012). Sedentary time was also associated with the risk of MetS (Ptrend = 0.018). Among participants in the highest tertile of sedentary time, the risk of MetS was 2.27-times greater than that in the lowest tertile (95% CI: 1.25 to 4.11). The risk of MetS was not significantly increased in subjects in the middle tertile of sedentary time. CONCLUSIONS: We found that light-intensity lifestyle activity and sedentary time were significantly associated with the risk of MetS, independent of MVPA. The results of our study suggest that public health messages and guidelines should be refined to include increases in light-intensity lifestyle activity and/or decreases in sedentary time, alongside promoting MVPA, to prevent MetS. PMID- 23452373 TI - Experience of nurses with using eHealth in Gilgit-Baltistan, Pakistan: a qualitative study in primary and secondary healthcare. AB - BACKGROUND: To improve the quality of health care in remote parts of Pakistan, a research project was initiated in the mountainous region of Gilgit-Baltistan using information and communication technology to improve patient care and support continuing education of health providers (eHealth). This paper describes the experience of nurses in using eHealth in their routine practices. METHODS: All health centres of Gilgit-Baltistan, Pakistan using eHealth as part of this study, were taken as a single case. These include four primary healthcare centres, three secondary care centres and one medical centre. In-depth interviews were conducted using semi-structured interview guide to study nurses' perspective about using eHealth, and its perceived impact on their professional lives. RESULTS: According to the respondents, eHealth enhanced access to care for remote communities, and improved quality of health services by providing opportunities for continuing learning. Nurses also appreciated eHealth for reducing their professional isolation, and providing exposure to new knowledge through teleconsultations and eLearning.The responses categorized under six major headings include: gaps in health services prior to eHealth; role of eHealth in addressing these gaps; benefits of eHealth; challenges in eHealth implementation; community's perception about eHealth; and future recommendations. CONCLUSIONS: Low-cost and simple eHealth solutions have shown to benefit nurses, and the communities in the remote mountainous regions of Pakistan. PMID- 23452374 TI - Abnormalities of cortical-limbic-cerebellar white matter networks may contribute to treatment-resistant depression: a diffusion tensor imaging study. AB - BACKGROUND: White matter abnormalities can cause network dysfunction that underlies major depressive disorder (MDD). Diffusion tensor imaging (DTI) is used to examine the neural connectivity and integrity of the white matter. Previous studies have implicated frontolimbic neural networks in the pathophysiology of MDD. Approximately 30% of MDD patients demonstrate treatment-resistant depression (TRD). However, the neurobiology of TRD remains unclear. METHODS: We used a voxel based analysis method to analyze DTI data in young patients with TRD (n = 30; 19 males, 11 females) compared with right-handed, age- and sex-matched healthy volunteers (n = 25; 14 males, 11 females). RESULTS: We found a significant decrease in fractional anisotropy (FA) (corrected, cluster size >50) in the left middle frontal gyrus (peak coordinates [-18 46-14]), left limbic lobe uncus (peak coordinates [-18 2-22]), and right cerebellum posterior lobe (peak coordinates [26-34 -40]). There was no increase in FA in any brain region in patients. We also found a significant negative correlation between mean regional FA values in the three areas and Beck Depression Inventory symptom scores. CONCLUSIONS: We found significant differences in white matter FA in the frontal lobe, limbic lobe and cerebellum between TRD patients and controls. These data suggest that abnormalities of cortical-limbic-cerebellar white matter networks may contribute to TRD in young patients. PMID- 23452375 TI - Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial. AB - BACKGROUND: Osteoarthritis (OA) is the most common type of arthritis, causing significant joint pain and disability. It is already a major cause of healthcare expenditure and its incidence will further increase with the ageing population. Current treatments for OA have major limitations and new analgesic treatments are needed. Synovitis is prevalent in OA and is associated with pain. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides, such as rheumatoid arthritis. We propose that treating patients with symptomatic hand OA with hydroxychloroquine will be a practical and safe treatment to reduce synovitis and pain. METHODS/DESIGN: HERO is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial. A total of 252 subjects with symptomatic hand OA will be recruited across primary and secondary care sites in the UK and randomized on a 1:1 basis to active treatment or placebo for 12 months. Daily medication dose will range from 200 to 400 mg according to ideal body weight. The primary endpoint is change in average hand pain during the previous two weeks (measured on a numerical rating scale (NRS)) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures and radiographic structural change at 12 months. A health economics analysis will also be performed. An ultrasound substudy will be conducted to examine baseline levels of synovitis. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis. DISCUSSION: The HERO trial is designed to examine whether hydroxychloroquine is an effective analgesic treatment for OA and whether it provides any long-term structural benefit. The ultrasound substudy will address whether baseline synovitis is a predictor of therapeutic response. This will potentially provide a new treatment for OA, which could be of particular use in the primary care setting. TRIAL REGISTRATION: ISRCTN91859104. PMID- 23452378 TI - Atomic-scale measurement of structure and chemistry of a single-unit-cell layer of LaAlO3 embedded in SrTiO3. AB - A single layer of LaAlO3 with a nominal thickness of one unit cell, which is sandwiched between a SrTiO3 substrate and a SrTiO3 capping layer, is quantitatively investigated by high-resolution transmission electron microscopy. By the use of an aberration-corrected electron microscope and by employing sophisticated numerical image simulation procedures, significant progress is made in two aspects. First, the structural as well as the chemical features of the interface are determined simultaneously on an atomic scale from the same specimen area. Second, the evaluation of the structural and chemical data is carried out in a fully quantitative way on the basis of the absolute image contrast, which has not been achieved so far in materials science investigations using high resolution electron microscopy. Considering the strong influence of even subtle structural details on the electronic properties of interfaces in oxide materials, a fully quantitative interface analysis, which makes positional data available with picometer precision together with the related chemical information, can contribute to a better understanding of the functionality of such interfaces. PMID- 23452377 TI - CpG oligonucleotides bind TLR9 and RRM-containing proteins in Atlantic salmon (Salmo salar). AB - BACKGROUND: Bacterial DNA is well-known for its potent immunostimulatory properties which have been attributed to the abundance of CpG dinucleotides within the genomes of prokaryotes. Research has found that mammalian TLR9 is a receptor which mediates the immune response to CpG DNA; however, its functional properties in non-mammalian vertebrates are still poorly characterized. Leukocytes isolated from lower vertebrates, including teleosts, respond to CpG DNA and TLR9 has been identified in many fish species; however, the ligand binding properties of fish TLR9 have, so far, not been studied. The fact that some vertebrates, like chicken, lack TLR9 and use an alternative molecule (TLR21) as a receptor for CpGs has questioned the functional conservation of TLR9 within vertebrates. RESULTS: In the current study, TLR9 from Atlantic salmon (SsTLR9) has been found to interact with synthetic oligonucleotides via a CpG-independent but a pH-dependent mechanism. The endogenous receptor, expressed by primary mononuclear phagocytes colocalizes with CpG oligonucleotides (ODNs) in vesicles that appear to be endosomes. When overexpressed in salmonid cell lines, SsTLR9 spontaneously activates ISRE-containing promoters of genes involved in the IFN response; however, the transgenic receptor fails to translocate to CpG-containing endosomes. This indicates that only specific immune cell types have the ability to relocate the receptor to the appropriate cellular compartments where it may become activated by its ligand. In addition, through co-precipitation and mass spectrometry, two salmon proteins - hnRNPA0 and NCOA5, which both contain RNA binding domains (RRM), were found to bind CpG ODNs, suggesting they may be involved in the CpG response in salmon leukocytes. CONCLUSION: The presented data are the first to demonstrate that the DNA-binding properties of TLR9 are conserved between teleosts and mammals. The current study also identifies additional molecules which may function as mediators of the immunostimulatory properties of foreign DNA. PMID- 23452376 TI - The PKD domain distinguishes the trafficking and amyloidogenic properties of the pigment cell protein PMEL and its homologue GPNMB. AB - Proteolytic fragments of the pigment cell-specific glycoprotein, PMEL, form the amyloid fibrillar matrix underlying melanins in melanosomes. The fibrils form within multivesicular endosomes to which PMEL is selectively sorted and that serve as melanosome precursors. GPNMB is a tissue-restricted glycoprotein with substantial sequence homology to PMEL, but no known function, and was proposed to localize to non-fibrillar domains of distinct melanosome subcompartments in melanocytes. Here we confirm that GPNMB localizes to compartments distinct from the PMEL-containing multivesicular premelanosomes or late endosomes in melanocytes and HeLa cells, respectively, and is largely absent from fibrils. Using domain swapping, the unique PMEL localization is ascribed to its polycystic kidney disease (PKD) domain, whereas the homologous PKD domain of GPNMB lacks apparent sorting function. The difference likely reflects extensive modification of the GPNMB PKD domain by N-glycosylation, nullifying its sorting function. These results reveal the molecular basis for the distinct trafficking and morphogenetic properties of PMEL and GPNMB and support a deterministic function of the PMEL PKD domain in both protein sorting and amyloidogenesis. PMID- 23452379 TI - APOA5 genotype influences the association between 25-hydroxyvitamin D and high density lipoprotein cholesterol. AB - OBJECTIVE: Circulating levels of 25-hydroxyvitamin D (25OHD) are positively associated with high density lipoprotein (HDL) cholesterol. We sought to replicate a previously reported interaction between APOA5 genotype and vitamin D, and to examine whether HDL-associated genetic loci modify the association between serum 25OHD and HDL cholesterol. METHODS: We examined whether 42 single nucleotide polymorphisms (SNPs) modify the association between serum 25OHD and HDL cholesterol in the 1958 British Birth cohort (aged 45 years, n = 4978). RESULTS: We identified a borderline interaction between the SNP rs12272004 (near the APOA5) and serum 25OHD on HDL cholesterol (P(interaction) = 0.05). The interaction was particularly prominent among the samples collected during winter (P(interaction) = 0.001). None of the other loci showed an interaction with serum 25OHD concentrations on HDL cholesterol. CONCLUSIONS: Our study in 4978 British Whites provides further support that APOA5 genotype modifies the association between vitamin D metabolites and HDL cholesterol. PMID- 23452380 TI - Simultaneous determination of seven hydrophilic bioactive compounds in water extract of Polygonum multiflorum using pressurized liquid extraction and short end injection micellar electrokinetic chromatography. AB - BACKGROUND: Polygoni Multiflori Radix, He-Shou-Wu in Chinese, is a widely used traditional Chinese medicine. Clinically, water decoction is the major application form of He-Shou-Wu. Therefore, simultaneous determination of bioactive compounds in water extract is very important for its quality control. RESULTS: A pressurized liquid extraction and short-end injection micellar electrokinetic chromatography (MEKC) were first developed for simultaneous determination of seven hydrophilic bioactive compounds in water extract of He Shou-Wu. The influence of parameters, such as pH, concentration of phosphate, SDS and HP-beta-CD, capillary temperature and applied voltage, on the analysis were carefully investigated. Optimum separation was obtained within 14 min by using 50 mM phosphate buffer containing 90 mM SDS and 2% (m/v) HP-beta-CD (pH 2.5) at 15 kV and 20 degrees C. All calibration curves showed good linearity (R2>0.9978) within test ranges. The overall LOD and LOQ were lower than 2.0 MUg/mL and 5.5 MUg/mL, respectively. The RSDs for intra- and inter-day of seven analytes were less than 3.2% and 4.6%, and the recoveries were 97.0%-104.2%. CONCLUSION: The validated method was successfully applied to the analysis of He-Shou-Wu samples, which is helpful for its quality control. PMID- 23452381 TI - Biomechanics of rising from a chair and walking in pregnant women. AB - The present study aimed to assess the changes in the pattern of rising from a chair and walking forward as pregnancy progressed. Twelve pregnant women and 10 nulliparous women were included in this study. Participants were videotaped with a digital video camera in the sagittal plane, and the coordinates of the markers attached to the subjects were identified using image analysis software. The peak trunk-flexion angle in pregnant women during rising was smaller, but the hip extension angle during the stance phase was larger than in controls. Also, the peak horizontal and vertical velocities of the center of mass were lower, and appeared earlier, in pregnant women than in controls. During rising, pregnant women dampened the propulsion attributable to increased uterus volume, and they enhanced the forward propulsion at gait initiation. To ensure safe motion, pregnant women should not initiate gait until reaching a stable standing position after rising. PMID- 23452382 TI - Effects of flow restoration on mussel growth in a Wild and Scenic North American River. AB - BACKGROUND: Freshwater mussels remain among the most imperiled species in North America due primarily to habitat loss or degradation. Understanding how mussels respond to habitat changes can improve conservation efforts. Mussels deposit rings in their shell in which age and growth information can be read, and thus used to evaluate how mussels respond to changes in habitat. However, discrepancies between methodological approaches to obtain life history information from growth rings has led to considerable uncertainty regarding the life history characteristics of many mussel species. In this study we compared two processing methods, internal and external ring examination, to obtain age and growth information of two populations of mussels in the St. Croix River, MN, and evaluated how mussel growth responded to changes in the operation of a hydroelectric dam. RESULTS: External ring counts consistently underestimated internal ring counts by 4 years. Despite this difference, internal and external growth patterns were consistent. In 2000, the hydroelectric dam switched from operating on a peaking schedule to run-of-the-river/partial peaking. Growth patterns between an upstream and downstream site of the dam were similar both before and after the change in operation. At the downstream site, however, older mussels had higher growth rates after the change in operation than the same sized mussels collected before the change. CONCLUSIONS: Because growth patterns between internal and external processing methods were consistent, we suggest that external processing is an effective method to obtain growth information despite providing inaccurate age information. External processing is advantageous over internal processing due to its non-destructive nature. Applying this information to analyze the influence of the operation change in the hydroelectric dam, we suggest that changing to run-of-the-river/partial peaking operation has benefited the growth of older mussels below the dam. PMID- 23452383 TI - The Draf III septal flap technique: a preliminary report. AB - AIM: The most prevalent complication of Draf III surgery is recurrence of frontal recess stenosis. The aim of this study is to introduce a method to prevent closure of the recess. TYPE OF THE STUDY AND SETTING: This is a retrospective study that was conducted in Ear, Nose and Throat Referral Center, Amir'Alam Hospital, Tehran. METHODS AND MATERIALS: We introduced a new technique for reconstructing frontal recess mucosa and prevention of restenosis following Draf III operation; we covered the posterior wall of the common recess with a vascular mucosal flap from nasal septum. RESULTS: During a 6-month period we used septal flaps based on anterior ethmoidal artery on four patients who had undergone endoscopic Draf III operation. During a 3-month follow-up period, frontal recess stenosis did recur in any of the patients. CONCLUSION: Applying a precise and astute surgical method along with reconstructing common recess mucosa will improve the outcomes of endoscopic frontal sinus drill-out. We strongly recommend application of septal mucosal flap based on the anterior ethmoidal artery during Draf III operation to decrease the incidence of scar and recurrence of common frontal recess stenosis. PMID- 23452384 TI - Evaluation of mucoadhesive carrier adjuvant: toward an oral anthrax vaccine. AB - The aim of present study was to evaluate the potential of mucoadhesive alginate coated chitosan microparticles (A-CHMp) for oral vaccine against anthrax. The zeta potential of A-CHMp was -29.7 mV, and alginate coating could prevent the burst release of antigen in simulated gastric fluid. The results indicated that A CHMp was mucoadhesive in nature and transported it to the peyer's patch upon oral delivery. The immunization studies indicated that A-CHMp resulted in the induction of potent systemic and mucosal immune responses, whereas alum adjuvanted rPA could induce only systemic immune response. Thus, A-CHMp represents a promising acid carrier adjuvant for oral immunization against anthrax. PMID- 23452385 TI - High sulfur loading cathodes fabricated using peapodlike, large pore volume mesoporous carbon for lithium-sulfur battery. AB - Porous carbon materials with large pore volume are crucial in loading insulated sulfur with the purpose of achieving high performance for lithium-sulfur batteries. In our study, peapodlike mesoporous carbon with interconnected pore channels and large pore volume (4.69 cm(3) g(-1)) was synthesized and used as the matrix to fabricate carbon/sulfur (C/S) composite which served as attractive cathodes for lithium-sulfur batteries. Systematic investigation of the C/S composite reveals that the carbon matrix can hold a high but suitable sulfur loading of 84 wt %, which is beneficial for improving the bulk density in practical application. Such controllable sulfur-filling also effectively allows the volume expansion of active sulfur during Li(+) insertion. Moreover, the thin carbon walls (3-4 nm) of carbon matrix not only are able to shorten the pathway of Li(+) transfer and conduct electron to overcome the poor kinetics of sulfur cathode, but also are flexible to warrant structure stability. Importantly, the peapodlike carbon shell is beneficial to increase the electrical contact for improving electronic conductivity of active sulfur. Meanwhile, polymer modification with polypyrrole coating layer further restrains polysulfides dissolution and improves the cycle stability of carbon/sulfur composites. PMID- 23452386 TI - Hormones and pain--a "rebirth". PMID- 23452387 TI - Trigeminal neuralgia secondary to giant Virchow-Robin spaces: a case report with neuroimaging. AB - Virchow-Robin spaces are pial-lined, interstitial, fluid-filled structures that accompany penetrating arteries and arterioles as they enter the cerebral substance. Occasionally they may enlarge and become giant Virchow-Robin spaces (GVRS) and produce mass effect. Various neurological symptoms have been described in association with GVRS, however, trigeminal neuralgia has not yet been reported in this context. We present a case of trigeminal neuralgia secondary to dorsal pontine giant Virchow-Robin spaces (GVRS) and highlight the diagnostic radiologic features. Routine 1.5 T MRI sequences were sufficient to diagnose the GVRS and a diffusion tensor imaging (DTI) study revealed distortion of the intrinsic trigeminal pathway. This study highlights the utility of routine MRI to study the intrinsic anatomy of the trigeminal pathway in pathological conditions. PMID- 23452388 TI - Effect of avidin-like proteins and biotin modification on mesenchymal stem cell adhesion. AB - The avidin-biotin system is a highly specific reaction that has been used in a wide range of biomedical applications, including surface modification and cell patterning. We systematically examined a number of avidin derivatives as the basis for a simple and cost effective tissue culture polystyrene substrate surface modification for human stem cell culture. Non-specific adhesion between human mesenchymal stem cells and various avidin derivatives, media conditions, and subsequent biotinylation reactions was quantified. We observed significant non-specific cell adhesion to avidin and strepthavidin, indicating that previous observations using this system may be artifactual. Seeding of cells in serum free media, blocking with bovine serum albumin, and the use of the avidin derivative neutravidin were all necessary for elimination of background adhesion. Neutravidin conjugated with biotinylated bsp-RGD(15) peptide provided the most robust cell adhesion, as well as the greatest increase in cell adhesion over background levels. PMID- 23452389 TI - Cellular uptake, intracellular trafficking, and antitumor efficacy of doxorubicin loaded reduction-sensitive micelles. AB - Reduction-sensitive micelles were prepared from monomethoxy-poly(ethylene glycol) S-S-hexadecyl (mPEG-S-S-C16), an amphiphilic poly(ethylene glycol) derivative containing a disulfide bond. The micelles were then used for the intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells, and the cellular uptake mechanisms of the micelles were determined. To serve as a control, monomethoxy-poly(ethylene glycol)-C-C-hexadecyl (mPEG-C-C-C16) with an analogous structure but without a disulfide bond was also prepared. The polymer could self-assemble into micelles in an aqueous solution and be loaded with high content DOX. In vitro release studies revealed that DOX-loaded mPEG-S-S-C16 micelles released DOX faster than DOX-loaded mPEG-C-C-C16 micelles in the presence of dithiothreitol (DTT), but showed similar release rates in the absence of DTT. MTT assay demonstrated significantly enhanced cytotoxicity of DOX-loaded mPEG-S-S-C16 micelles against the human cervical cancer cells (HeLa) compared with DOX-loaded mPEG-C-C-C16 micelles, but there was no significant difference in the cytotoxicity between the two DOX-loaded micelles against the african green monkey SV40-transformed kidney fibroblast cells (COS-7). Confocal laser scanning microscopy observation and flow cytometry analyses indicated that DOX-loaded mPEG S-S-C16 micelles were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. By contrast, in the case of DOX-loaded mPEG-C-C-C16 micelles, little DOX was found in the nuclei. Endocytosis inhibition results proved that both mPEG-S-S-C16 and mPEG-C-C-C16 micelles entered the HeLa cells mainly through the clathrin-mediated endocytosis pathway, and caveolae mediated endocytosis was involved to a small extent. These results indicated that the different behaviors of cell uptake between reduction-sensitive and insensitive micelles may occur after the micelles were internalized into the cells, but not during endocytosis, and the potential of this reduction-sensitive polymer for the effective intracellular delivery of anticancer drugs. PMID- 23452390 TI - Access to syringes for HIV prevention for injection drug users in St. Petersburg, Russia: syringe purchase test study. AB - BACKGROUND: The HIV epidemic in Russia is concentrated among injection drug users (IDUs). This is especially true for St. Petersburg where high HIV incidence persists among the city's estimated 80,000 IDUs. Although sterile syringes are legally available, access for IDUs may be hampered. To explore the feasibility of using pharmacies to expand syringe access and provide other prevention services to IDUs, we investigated the current access to sterile syringes at the pharmacies and the correlation between pharmacy density and HIV prevalence in St. Petersburg. METHODS: 965 pharmacies citywide were mapped, classified by ownership type, and the association between pharmacy density and HIV prevalence at the district level was tested. We selected two districts among the 18 districts--one central and one peripheral--that represented two major types of city districts and contacted all operating pharmacies by phone to inquire if they stocked syringes and obtained details about their stock. Qualitative interviews with 26 IDUs provided data regarding syringe access in pharmacies and were used to formulate hypotheses for the pharmacy syringe purchase test wherein research staff attempted to purchase syringes in all pharmacies in the two districts. RESULTS: No correlation was found between the density of pharmacies and HIV prevalence at the district level. Of 108 operating pharmacies, 38 (35%) did not sell syringes of the types used by IDUs; of these, half stocked but refused to sell syringes to research staff, and the other half did not stock syringes at all. Overall 70 (65%) of the pharmacies did sell syringes; of these, 49 pharmacies sold single syringes without any restrictions and 21 offered packages of ten. CONCLUSIONS: Trainings for pharmacists need to be conducted to reduce negative attitudes towards IDUs and increase pharmacists' willingness to sell syringes. At a structural level, access to safe injection supplies for IDUs could be increased by including syringes in the federal list of mandatory medical products sold by pharmacies. PMID- 23452391 TI - A (S)TEM gas cell holder with localized laser heating for in situ experiments. AB - The advent of aberration correction for transmission electron microscopy has transformed atomic resolution imaging into a nearly routine technique for structural analysis. Now an emerging frontier in electron microscopy is the development of in situ capabilities to observe reactions at atomic resolution in real time and within realistic environments. Here we present a new in situ gas cell holder that is designed for compatibility with a wide variety of sample type (i.e., dimpled 3-mm discs, standard mesh grids, various types of focused ion beam lamellae attached to half grids). Its capabilities include localized heating and precise control of the gas pressure and composition while simultaneously allowing atomic resolution imaging at ambient pressure. The results show that 0.25-nm lattice fringes are directly visible for nanoparticles imaged at ambient pressure with gas path lengths up to 20 MUm. Additionally, we quantitatively demonstrate that while the attainable contrast and resolution decrease with increasing pressure and gas path length, resolutions better than 0.2 nm should be accessible at ambient pressure with gas path lengths less than the 15 MUm utilized for these experiments. PMID- 23452392 TI - Visual and psychological morbidity among patients with autosomal dominant optic atrophy. PMID- 23452393 TI - The incidences and mortalities of major cancers in China, 2009. AB - In 2012, the National Central Cancer Registry (NCCR) of China collected cancer registration information for the year 2009 from local cancer registries and analyzed it to describe the incidences and mortalities of cancers in China. Based on the data quality criteria from NCCR, data from 104 registries covering 85,470,522 people (57,489,009 in urban areas and 27,981,513 in rural areas) were checked and evaluated. The data from 72 registries were qualified and accepted for the cancer registry annual report in 2012. The total cancer incident cases and cancer deaths were 244,366 and 154,310, respectively. The morphologically verified cases accounted for 67.23%, and 3.14% of the incident cases only had information from death certifications. The crude incidence in the Chinese cancer registration areas was 285.91/100,000 (317.97/100,000 in males and 253.09/100,000 in females). The age-standardized rates for incidences based on the Chinese standard population (ASRIC) and the world standard population (ASRIW) were 146.87/100,000 and 191.72/100,000, respectively, with a cumulative incidence of 22.08%. The cancer mortality in the Chinese cancer registration areas was 180.54/100,000 (224.20/100,000 in males and 135.85/100,000 in females). The age standardized rates for mortalities based on the Chinese standard population(ASRMC) and the world standard population (ASRMW) were 85.06/100,000 and 115.65/100,000, respectively, and the cumulative mortality was 12.94%. Lung cancer, gastric cancer, colorectal cancer, liver cancer, esophageal cancer, pancreatic cancer, encephaloma, lymphoma, female breast cancer, and cervical cancer were the most common cancers, accounting for 75% of all cancer cases. Lung cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, pancreatic cancer, breast cancer, encephaloma, leukemia, and lymphoma accounted for 80% of all cancer deaths. The cancer registration's population coverage has been increasing, and its data quality is improving. As the basis of the cancer control program, the cancer registry plays an important role in directing anticancer strategies in the medium and long term. Because cancer burdens are different in urban and rural areas in China, prevention and control efforts should be based on practical situations. PMID- 23452394 TI - Developing process guidelines for trauma care in the Netherlands for severely injured patients: results from a Delphi study. AB - BACKGROUND: In organised trauma systems the process of care is the key to quality. Nevertheless, the optimal process of trauma care remains unclear due to lack of or inconclusive evidence. Because monitoring and improving the performance of a trauma system is complex, this study aimed to develop consensus based process guidelines for trauma care in the Netherlands for severely injured patients. METHODS: A five-round Delphi study was conducted with 141 participants that represent all professions involved in trauma care. Sensitivity analyses were carried out to evaluate whether consensus extended across all professions and to detect possible bias. RESULTS: Consensus was reached on 21 guidelines within 4 categories: timeliness, actions, competent teams and interdisciplinary process. Timeliness guidelines set specific critical limits and definitions for 10 time intervals in the time period from an emergency call until the patient leaves the trauma room. Action guidelines reflect aspects of appropriate care and strongly rely on the international Advanced Trauma Life Support principles. Competence guidelines include flow charts to assess the competence of prehospital and emergency department teams. Essential to competent teams are education and experience of all team members. The interdisciplinary process guideline focuses on cooperation, communication and feedback within and between all professions involved. Consensus was extended across all professions and no bias was detected. CONCLUSIONS: In this Delphi study, a large expert panel agreed on a set of guidelines describing the optimal process of care for severely injured trauma patients in the Netherlands. In addition to time intervals and appropriate actions, these guidelines emphasise the importance of team competence and interdisciplinary processes in trauma care. The guidelines can be seen as a description of a best practice and a new field standard in the Netherlands. The next step is to implement the guidelines and monitor the performance of the Dutch trauma system based on the guidelines. PMID- 23452395 TI - SSX2IP promotes metastasis and chemotherapeutic resistance of hepatocellular carcinoma. AB - BACKGROUND: Synovial sarcoma, X breakpoint 2 interacting protein (SSX2IP), which has been identified as an acute myeloid leukemia associated antigen, is a potential target for leukemia immunotherapy. In rodents, its homologous gene, ADIP, plays an important role in the regulation of cell adhesion and migration, underlying its potential role in promoting metastasis of other cancers. METHODS: To investigate the correlation between the expression level of SSX2IP and the clinicopathologic factors of hepatocellular carcinoma (HCC), 53 cases were studied by qPCR and statisted. To directly testing SSX2IP's contribution to HCC in animal models, 45 nude mice were enrolled in peritoneal spreading and liver metastasis models. For the migration and invasion assays, cell culture experiments were performed using QCMTM 24-Well Colorimetric Migration Assay Kit and Cell Invasion Assay Kit (Millipore). Moreover we examined the influence of SSX2IP overexpression on the chemosensitivity of hepatocellular carcinoma cells to two most common chemotherapy drugs (5-Fu and CDDP) using Cell counting kit-8 (CCK-8). The chemotherapeutic drugs sensitivity was evaluated by IC50 parameter. RESULTS: Statistical analysis of clinical cases revealed that the SSX2IP high expression group had inclinations towards larger tumor size, more tumor thrombus and shorter survival period, implying a strong correlation between the expression level of SSX2IP and HCC tumorigenesis. Consistently in abdominal cavity metastasis and liver metastasis models of immune-deficient mice, SSX2IP was able to promote the metastasis of hepatoma cells. At the cytological level, SSX2IP stimulates the wound healing, metastasis and invasion of hepatoma cells, and reduces the sensitivity of hepatoma cells to 5-Fu and CDDP. CONCLUSIONS: Our results showed that SSX2IP promotes the development and metastasis of hepatocellular carcinoma and contributes to the drug resistance of hepatoma cells, suggesting that SSX2IP is expected to become a new diagnostic and prognostic marker and a new target of the treatment of hepatocellular carcinoma. PMID- 23452396 TI - Comparative transcription analysis and toxin production of two fluoroquinolone resistant mutants of Clostridium perfringens. AB - BACKGROUND: Fluoroquinolone use has been listed as a risk factor for the emergence of virulent clinical strains of some bacteria. The aim of our study was to evaluate the effect of fluoroquinolone (gatifloxacin) resistance selection on differential gene expression, including the toxin genes involved in virulence, in two fluoroquinolone-resistant strains of Clostridium perfringens by comparison with their wild-type isogenic strains. RESULTS: DNA microarray analyses were used to compare the gene transcription of two wild types, NCTR and ATCC 13124, with their gatifloxacin-resistant mutants, NCTRR and 13124R. Transcription of a variety of genes involved in bacterial metabolism was either higher or lower in the mutants than in the wild types. Some genes, including genes for toxins and regulatory genes, were upregulated in NCTRR and downregulated in 13124R. Transcription analysis by quantitative real-time PCR (qRT-PCR) confirmed the altered expression of many of the genes that were affected differently in the fluoroquinolone-resistant mutants and wild types. The levels of gene expression and enzyme production for the toxins phospholipase C, perfringolysin O, collagenase and clostripain had decreased in 13124R and increased in NCTRR in comparison with the wild types. After centrifugation, the cytotoxicity of the supernatants of NCTRR and 13224R cultures for mouse peritoneal macrophages confirmed the increased cytotoxicity of NCTRR and the decreased cytotoxicity of 13124R in comparison with the respective wild types. Fluoroquinolone resistance selection also affected cell shape and colony morphology in both strains. CONCLUSION: Our results indicate that gatifloxacin resistance selection was associated with altered gene expression in two C. perfringens strains and that the effect was strain-specific. This study clearly demonstrates that bacterial exposure to fluoroquinolones may affect virulence (toxin production) in addition to drug resistance. PMID- 23452398 TI - "The Chennai declaration" - Indian doctors' fight against antimicrobial resistance. AB - "The Chennai Declaration" is the result of the first ever joint meeting of medical societies in India addressing antibiotic resistance. The declaration is not a policy by itself, but a call for a national policy. The Declaration has looked into all major aspects of the problem of antimicrobial resistance, has suggested practical solutions, explained in detail the responsibility of each and every stakeholder. PMID- 23452397 TI - Study protocol for a randomized controlled trial for anterior inguinal hernia repair: transrectus sheath preperitoneal mesh repair compared to transinguinal preperitoneal procedure. AB - BACKGROUND: Anterior open treatment of the inguinal hernia with a tension-free mesh has reduced the incidence of hernia recurrence. The Lichtenstein procedure is the current reference technique for inguinal hernia treatment. Chronic pain has become the main postoperative complication after surgical inguinal hernia repair, especially following Lichtenstein. Preliminary experiences with a soft mesh positioned in the preperitoneal space (PPS) by transinguinal preperitoneal (TIPP) or total extraperitoneal (TEP) technique, showed promising results considering the reduction of postoperative chronic pain. Evolution of surgical innovations for inguinal hernia repair led to an open, direct approach with preperitoneal mesh position, such as TIPP. Based on the TIPP procedure, another preperitoneal repair has been recently developed, the transrectus sheath preperitoneal (TREPP) mesh repair. METHODS: The ENTREPPMENT trial is a multicentre randomized clinical trial. Patients will be randomly allocated to anterior inguinal hernia repair according to the TREPP mesh repair or TIPP procedure. All patients with a primary unilateral inguinal hernia, eligible for operation, will be invited to participate in the trial. The primary outcome measure will be the number of patients with postoperative chronic pain. Secondary outcome measures will be serious adverse events (SAEs), including recurrence, hemorrhage, return to daily activities (for example work), operative time and hospital stay. Alongside the trial health status, an economic evaluation will be performed. To demonstrate that inguinal hernia repair according to the TREPP technique reduces the percentage of patients with postoperative chronic pain from 12% to <6%, a sample size of 800 patients is required (two-sided test, alpha = 0.05, 80% power).The ENTREPPMENT trial aims to evaluate the TREPP and TIPP procedures from patients' perspective. It is hypothesized that the TREPP technique may reduce the number of patients with any form of postoperative chronic pain by 50% compared to the TIPP procedure. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN18591339. PMID- 23452399 TI - Distribution, frequency and clinical implications of napkin-ring sign assessed by multidetector computed tomography. AB - BACKGROUND: Plaque rupture and secondary thrombus formation play key roles in the onset of acute coronary syndrome (ACS). Plaques showing the napkin-ring sign in multidetector computed tomography (MDCT) have been reported as thin-cap fibroatheroma that is recognized as a precursor lesion for plaque rupture. The purpose of this study was to investigate distribution and frequency of napkin ring sign and its relationship to features indicating coronary plaque vulnerability on MDCT in patients with coronary artery disease. METHODS: We enrolled 273 patients with ACS (n=61) or stable angina pectoris (SAP, n=212) who were assessed by MDCT. The definition of the napkin-ring sign was the presence of a ring of high attenuation and the CT attenuation of a ring presenting higher than those of the adjacent plaque and no greater than 130HU. RESULTS: The culprit plaques with the napkin-ring sign show higher remodeling index and lower CT attenuation (1.15+/-0.12 vs. 1.02+/-0.12, p<0.01 and 39.9+/-22.8 vs. 72.7+/-26.6, p<0.01, respectively). Napkin-ring sign at culprit lesions was more frequent in patients with ACS than those with SAP (49.0% vs. 11.2%, p<0.01). Moreover, napkin ring sign at non-culprit lesions was more frequently observed in ACS patients compared with SAP patients (12.7% vs. 2.8%, p<0.01). The distribution of the napkin-ring sign in the right coronary arteries and left circumflex arteries of our population was relatively even, whereas the napkin-ring sign in the left anterior descending artery was common in the proximal sites (p<0.01). CONCLUSIONS: The napkin-ring sign assessed by MDCT represents similar clinical features of fibroatheroma. MDCT could contribute to the search for fibroatheroma. PMID- 23452400 TI - Impact of smoking status on early and late outcomes after isolated coronary artery bypass graft surgery. AB - BACKGROUND: There are limited data on the impact of smoking status on outcomes after isolated coronary artery bypass graft (CABG) surgery. METHODS: Data obtained prospectively between June 2001 and December 2009 by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program were retrospectively analyzed. Demographic and operative data were compared between patients who were non-smokers, previous smokers, and current smokers. The independent impact of smoking status on 14 short-term complications and long-term mortality was determined using binary logistic and Cox regression, respectively. RESULTS: Isolated CABG surgery was performed in 21 534 patients; smoking status was recorded in 21486 (99.8%). Of these, 7023 (32.6%) had no previous smoking history, 11183 (59.1%) were previous smokers, and 3290 (15.2%) were current smokers. The 30-day mortality rate was 1.8% in non-smokers, 1.5% in previous smokers, and 1.5% in current smokers (p=NS). The incidence of peri operative complications was generally similar in the three groups, but current smokers were at an increased risk of pneumonia (p<0.001), and multisystem failure (p=0.003). The mean follow-up period for this study was 37 months (range, 0-106 months). After adjusting for differences in patient variables, the incidence of late mortality was higher in previous smokers [hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.47-2.05; p<0.001] or current smokers (HR, 1.41; 95% CI, 1.26-1.59; p<0.001) compared to non-smokers. CONCLUSION: Smoking status is not associated with early mortality after isolated CABG. It is, however, associated with an increased risk of pulmonary complications and reduced long term survival. PMID- 23452401 TI - Self-assembly of tetrakis (3-trifluoromethylphenoxy) phthalocyaninato cobalt(II) on multiwalled carbon nanotubes and their amperometric sensing application for nitrite. AB - In this work, the soluble cobalt phthalocyanine functionalized multiwalled carbon nanotubes (MWCNTs) are synthesized by pi-pi stacking interaction between tetrakis (3-trifluoromethylphenoxy) phthalocyaninato cobalt(II) (CoPcF) complex and MWCNTs. The physical properties of CoPcF-MWCNTs hybrids are evaluated using spectroscopy (UV-vis, XPS, and Raman) and electron microscopy (TEM and SEM). Subsequently, an amperometric nitrite electrochemical sensor is designed by immobilizing CoPcF-MWCNTs hybrids on the glassy carbon electrode. The immobilized CoPcF complex shows the fast electron transfer rate and excellent electrocatalytic activity for the oxidation of nitrite. Under optimum experimental conditions, the proposed nitrite electrochemical sensor shows the fast response (less than 2 s), wide linear range (9.6 * 10(-8) to 3.4 * 10(-4) M) and low detection limit (6.2 * 10(-8) M) because of the good mass transport, fast electron transfer rate, and excellent electrocatalytic activity. PMID- 23452402 TI - Adenocarcinoma of the seminal vesicles complicated by antineutrophil cytoplasmic antibody vasculitis: a case report and review of the literature. AB - INTRODUCTION: Adenocarcinoma of the seminal vesicles is a very rare malignancy, with less than 100 cases reported worldwide. It is documented to have a poor prognosis, with the majority of patients developing metastatic disease, most commonly in the prostate, bladder and rectum. Currently there is no standard treatment for metastatic disease and the limited reports of treatment with radiotherapy, chemotherapy and hormonal (anti-androgenic) therapy show that they are generally of modest benefit. The association between malignancy and an increased risk of autoimmune vasculitis has been demonstrated in a number of malignancies, but to date there have been no documented cases of adenocarcinoma of the seminal vesicles associated with anti-neutrophil cytoplasmic antibody vasculitis. CASE PRESENTATION: In this report we describe the case of a 55-year old Caucasian man with metastatic adenocarcinoma of the seminal vesicles. He previously had received chemotherapy treatment for advanced testicular cancer and later presented with hemospermia. He subsequently developed c-antineutrophil cytoplasmic antibody vasculitis requiring intensive immunosuppression and renal dialysis. CONCLUSION: Adenocarcinoma of the seminal vesicles is a rare diagnosis and our case is more unusual in that our patient previously had chemotherapy treatment for advanced testicular cancer and went on to develop severe antineutrophil cytoplasmic antibody vasculitis when diagnosed with metastatic seminal vesicle cancer. This case illustrates that autoimmune vasculitis can occur in any patient with malignancy and an early referral to the renal team combined with renal biopsy can assist in the earlier diagnosis and more successful management of these rare events. This case should be of interest to oncologists, renal physicians, urologists and general physicians who encounter patients presenting with hemospermia or vasculitis. PMID- 23452403 TI - The nutrition transition: the same, but different. PMID- 23452404 TI - A qualitative study of a social and emotional well-being service for a remote Indigenous Australian community: implications for access, effectiveness, and sustainability. AB - BACKGROUND: People living in rural and remote Australia experience increased mental health problems compared with metropolitan Australians. Moreover, Indigenous Australians are twice as likely as non Indigenous Australians to report high or very high levels of mental health problems. It is imperative, therefore, that effective and sustainable social and emotional wellbeing services (Indigenous Australians prefer the term "social and emotional wellbeing" to "mental health") are developed for Indigenous Australians living in remote communities. In response to significant and serious events such as suicides and relationship violence in a remote Indigenous community, a social and emotional wellbeing service (SEWBS) was developed. After the service had been running for over three years, an independent evaluation was initiated by the local health board. The aim of the evaluation was to explore the impact of SEWBS, including issues of effectiveness and sustainability, from the experiences of people involved in the development and delivery of the service. METHODS: Purposive sampling was used to recruit 21 people with different involvement in the service such as service providers, service participants, and referrers. These people were interviewed and their interviews were transcribed. Interpretative Phenomenological Analysis (IPA) was used to analyse the interview transcripts to identify superordinate themes and subthemes in the data. RESULTS: Two superordinate themes and nine subthemes were developed from the interview transcripts. The first superordinate theme was called "The Big Picture" and it had the sub themes: getting started; organizational factors; funding; the future, and; operational problems. The second superordinate theme was called "On the Ground" and it had the subthemes: personal struggles; program activities; measuring outcomes, and; results. CONCLUSIONS: While the evaluation indicated that the service had been experienced as an effective local response to serious problems, recommendations and directions for future research and development emerged that were more broadly applicable. Issues such as appropriate staffing, localising decision making, identifying priorities and how they will be evaluated, and developing flexibility in terms of job descriptions and qualifications are highlighted. PMID- 23452405 TI - Topiramate-induced acute bilateral myopia. PMID- 23452407 TI - Communicating in the pre-hospital emergency environment. AB - AIM: To develop and evaluate the implementation of a communication board for paramedics to use with patients as an augmentative or alternative communication tool to address communication needs of patients in the pre-hospital setting. METHOD: A double-sided A4-size communication board was designed specifically for use in the pre-hospital setting by the Queensland Ambulance Service and Disability and Community Care Services. One side of the board contains expressive messages that could be used by both the patient and paramedic. The other side contains messages to support patients' understanding and interaction tips for the paramedic. The communication board was made available in every ambulance and patient transport vehicle in the Brisbane Region. RESULTS: A total of 878 paramedics completed a survey that gauged which patient groups they might use the communication board with. The two most common groups were patients from culturally and linguistically diverse backgrounds and children. Staff reported feeling confident in using the board, and 72% of interviewed paramedics agreed that the communication board was useful for aiding communication with patients. Feedback from paramedics suggests that the board is simple to use, reduces patient frustration and improves communication. CONCLUSION: These results suggest that a communication board can be applied in the pre-hospital setting to support communication success with patients. WHAT IS KNOWN ABOUT THE TOPIC? It is imperative that communication between patient and paramedic is clear and effective. Research has shown that communication boards have been effective with people with temporary or permanent communication difficulties. WHAT DOES THIS PAPER ADD? This is the first paper outlining the development and use of a communication board by paramedics in the pre-hospital setting in Australia. The paper details the design of the communication board for the unique pre-hospital environment. The paper provides some preliminary data on the use of the communication board with certain patient groups and its effectiveness as an alternative communication tool. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? The findings support the use of the tool as a viable option in supporting the communication between paramedics and a range of patients. It is not suggested that this communication board will meet the complete communication needs of any individual in this environment, but it is hoped that the board's presence within the Queensland Ambulance Service may result in paramedics introducing the board on occasions where communication with a patient is challenging. PMID- 23452408 TI - Surface oxide effect on optical sensing and photoelectric conversion of alpha In2Se3 hexagonal microplates. AB - The surface formation oxide assists of visible to ultraviolet photoelectric conversion in alpha-In2Se3 hexagonal microplates has been explored. Hexagonal alpha-In2Se3 microplates with the sizes of 10s to 100s of micrometers were synthesized and prepared by the chemical vapor transport method using ICl3 as a transport agent. Many vacancies and surface imperfection states have been found in the bulk and on the surface of the microplate because of the intrinsic defect nature of alpha-In2Se3. To discover physical and chemical properties and finding technological uses of alpha-In2Se3, several experiments including transmission electron miscopy (TEM), X-ray photoelectron spectroscopy (XPS), surface photovoltage (SPV), photoluminescence (PL), surface photoresponse (SPR), photoconductivity (PC), and thermoreflectance (TR) measurements have been carried out. Experimental results of TEM, XPS, SPV, PL, and SPR measurements show that a surface oxidation layer alpha-In2Se3-3xO3x (0 <= x <= 1) has formed on the crystal face of alpha-In2Se3 in environmental air with the inner layer content close to In2Se3 but the outermost layer content approaching In2O3. The near band edge transitions of alpha-In2Se3 microplates have been probed experimentally by TR and PC measurements. The direct band gap of alpha-In2Se3 has been determined to be 1.453 eV. The SPV result shows a maximum quantum efficiency of the surface oxide alpha-In2Se3-3xO3x (0 <= x <= 1) that presents a peak photoresponse near 2.18 eV. The analyses of SPV, SPR, PL, TR, and PC measurements revealed that the surface oxide layer facilitates the conversion of the ultraviolet to the visible range while the native defects (Se and In vacancies) sustain photoconductivity in the near-infrared region. On the basis of the experimental results a wide-energy range photodetector that combines PC- and SPR-mode operations for alpha-In2Se3 microplate has been made. The testing results show a well-behaved function of photoelectric conversion in the near-infrared to ultraviolet region via the auxiliary forming of surface oxide on the crystalline face of the alpha-In2Se3 microplates. PMID- 23452406 TI - Stem cells: a new paradigm for disease modeling and developing therapies for age related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in people over age 55 in the U.S. and the developed world. This condition leads to the progressive impairment of central visual acuity. There are significant limitations in the understanding of disease progression in AMD as well as a lack of effective methods of treatment. Lately, there has been considerable enthusiasm for application of stem cell biology for both disease modeling and therapeutic application. Human embryonic stem cells and induced pluripotent stem cells (iPSCs) have been used in cell culture assays and in vivo animal models. Recently a clinical trial was approved by FDA to investigate the safety and efficacy of the human embryonic stem cell-derived retinal pigment epithelium (RPE) transplantation in sub-retinal space of patients with dry AMD These studies suggest that stem cell research may provide both insight regarding disease development and progression, as well as direction for therapeutic innovation for the millions of patients afflicted with AMD. PMID- 23452409 TI - Co-synergism of endophyte Penicillium resedanum LK6 with salicylic acid helped Capsicum annuum in biomass recovery and osmotic stress mitigation. AB - BACKGROUND: Water-deficiency adversely affects crop growth by generating reactive oxygen species (ROS) at cellular level. To mitigate such stressful events, it was aimed to investigate the co-synergism of exogenous salicylic acid (SA) and symbiosis of endophytic fungus with Capsicum annuum L. (pepper). RESULTS: The findings of the study showed that exogenous SA (10-6 M) application to endophyte (Penicillium resedanum LK6) infected plants not only increased the shoot length and chlorophyll content but also improved the biomass recovery of pepper plants under polyethylene glycol (15%) induced osmotic stress (2, 4 and 8 days). Endophyte-infected plants had low cellular injury and high photosynthesis rate. SA also enhanced the colonization rate of endophyte in the host-plant roots. Endophyte and SA, in combination, reduced the production of ROS by increasing the total polyphenol, reduce glutathione, catalase, peroxidase and polyphenol oxidase as compared to control plants. Osmotic stress pronounced the lipid peroxidation and superoxide anions formation in control plants as compared to endophyte and SA treated plants. The endogenous SA contents were significantly higher in pepper plants treated with endophyte and SA under osmotic stress as compared to control. CONCLUSION: Endophytic fungal symbiosis and exogenous SA application can help the plants to relieve the adverse effects of osmotic stress by decreasing losses in biomass as compared to non-inoculated plants. These findings suggest that SA application positively impact microbial colonization while in combination, it reprograms the plant growth under various intervals of drought stress. Such symbiotic strategy can be useful for expanding agriculture production in drought prone lands. PMID- 23452410 TI - HIV risk perception and distribution of HIV risk among African, Caribbean and other Black people in a Canadian city: mixed methods results from the BLACCH study. AB - BACKGROUND: African, Caribbean and other Black (ACB) people are a priority group for HIV prevention in Canada, but little is known about the epidemiology of HIV risk in this population. This paper helps fill the knowledge gap by: presenting service providers' and ACB people's perceptions about HIV risk in ACB populations; describing the distribution of HIV risk behaviours among ACB people according to markers of social status and position; and comparing results from these two analyses. METHODS: The Black, African and Caribbean Canadian Health (BLACCH) Study is a mixed methods study that used semi-structured interviews and a cross-sectional quantitative questionnaire to collect information about HIV and health from 188 ACB people in London, Ontario, Canada. Qualitative content analysis was used to identify interview themes, and weighted bivariate statistical analyses were performed on the quantitative data. Behaviours related to HIV risk were stratified by sex, poverty status, immigration experience and employment status. RESULTS: Community members perceived that they were at low risk for HIV and mainly focused on sexual risks. They called for more information about HIV in Canada and culturally appropriate HIV services. Service providers cited marital infidelity and cultural and religious attitudes about condoms as barriers to women protecting themselves. They mentioned cultural norms, beliefs about masculinity and underrepresentation of heterosexual ACB men at AIDS service organizations as barriers to men protecting themselves. There were few statistically significant differences in risk behaviours reported by men and women. Those living in poverty were more likely to abstain from sex (p = 0.006) and use condoms (p = 0.027) in the past year. Those living in Canada longer reported higher prevalences of forced sex (p < 0.001), mixing alcohol or drugs with sex (p = 0.001) and past STI diagnoses (p = 0.032). Stable employment was associated with higher prevalences of not using condoms in the past year (p = 0.005) and past STI diagnoses (p = 0.018). CONCLUSIONS: The results show that perceptions about ACB people's HIV risk differ from actual risk, and those with higher social standing might be at greater risk. Furthermore, the social determinants of health are important factors in the epidemiology of HIV among ACB people. PMID- 23452412 TI - Structural reorganisation of cellulose fibrils in hydrothermally deconstructed lignocellulosic biomass and relationships with enzyme digestibility. AB - BACKGROUND: The investigation of structural organisation in lignocellulose materials is important to understand changes in cellulase accessibility and reactivity resulting from hydrothermal deconstruction, to allow development of strategies to maximise bioethanol process efficiencies. To achieve progress, wheat straw lignocellulose and comparative model wood cellulose were characterised following increasing severity of hydrothermal treatment. Powder and fibre wide-angle X-ray diffraction techniques were employed (WAXD), complemented by enzyme kinetic measurements up to high conversion. RESULTS: Evidence from WAXD indicated that cellulose fibrils are not perfectly crystalline. A reduction in fibril crystallinity occurred due to hydrothermal treatment, although dimensional and orientational data showed that fibril coherency and alignment were largely retained. The hypothetical inter-fibril spacing created by hydrothermal deconstruction of straw was calculated to be insufficient for complete access by cellulases, although total digestion of cellulose in both treated straw and model pulp was observed. Both treated straw and model pulps were subjected to wet mechanical attrition, which caused separation of smaller fibril aggregates and fragments, significantly increasing enzyme hydrolysis rate. No evidence from WAXD measurements was found for preferential hydrolysis of non-crystalline cellulose at intermediate extent of digestion, for both wood pulp and hydrothermally treated straw. CONCLUSIONS: The increased efficiency of enzyme digestion of cellulose in the lignocellulosic cell wall following hydrothermal treatment is a consequence of the improved fibril accessibility due to the loss of hemicellulose and disruption of lignin. However, incomplete accessibility of cellulase at the internal surfaces of fibrillar aggregates implies that etching type mechanisms will be important in achieving complete hydrolysis. The reduction in crystalline perfection following hydrothermal treatment may lead to an increase in fibril reactivity, which could amplify the overall improvement in rate of digestion due to accessibility gains. The lack of preferential digestion of non-crystalline cellulose is consistent with the existence of localised conformational disorder, at surfaces and defects, according to proposed semicrystalline fibril models. Cellulases may not interact in a fully selective manner with such disordered environments, so fibril reactivity may be considered as a function of average conformational states. PMID- 23452411 TI - The effect of robenacoxib on the concentration of C-reactive protein in synovial fluid from dogs with osteoarthritis. AB - BACKGROUND: Robenacoxib is a novel and highly selective inhibitor of COX-2 in dogs and cats and because of its acidic nature is regarded as being tissue selective. Thirty four dogs with stifle osteoarthritis secondary to failure of the cranial cruciate ligament were recruited into this study. Lameness, radiographic features, synovial cytology and C-reactive protein concentrations in serum and synovial fluid were assessed before and 28 days after commencing a course of Robenacoxib at a dose of 1 mg/kg SID. RESULTS: There was a significant reduction in the lameness score (P < 0.01) and an increase in the radiographic score (P < 0.05) between pre- and post-treatment assessments. There was no difference between pre- (median 1.49 mg/l; Q1-Q3 0.56-4.24 mg/L) and post - (1.10 mg/L; 0.31-1.78 mg/L) treatment serum C-reactive protein levels although synovial fluid levels were significantly reduced (pre- : 0.44 mg/L; 0.23-1.62 mg/L; post- : 0.17 mg/L; 0.05-0.49 mg/L) (P < 0.05). There was no correlation between C reactive protein concentrations in serum and matched synovial fluid samples. CONCLUSIONS: Robenacoxib proved effective in reducing lameness in dogs with failure of the cranial cruciate ligament and osteoarthritis of the stifle joint. The drug also reduced levels of C-reactive protein in the synovial fluid taken from the affected stifle joint. Robenacoxib appears to reduce articular inflammation as assessed by C-reactive protein which supports the concept that Robenacoxib is a tissue-selective non-steroidal anti-inflammatory drug. PMID- 23452413 TI - Correlation of vascular endothelial growth factor plasma levels and glycemic control in patients with diabetic retinopathy. AB - PURPOSE: To determine whether glycemic control of patients with diabetic retinopathy (DR) due to type 2 diabetes was related to VEGF plasma levels. METHODS: The prospective study included 30 patients with DR due to type 2 diabetes. Retinopathy was classified according to the international clinical DR disease severity scale. The concentrations of VEGF in the blood plasma were measured by ELISA. Glycosylated hemoglobin (HbA1c) was assessed all patients. Results were reported as DCCT/NGSP-HbA1c (%) values. RESULTS: The median plasma level of VEGF was 34.5 (range 15-217) pg/ml. Median HbA1c was 7.5 (range 5.3 10.6). The highest individual plasma VEGF measurements were found in patients with severe non-proliferative DR. HbA1c levels revealed a significant correlation with plasma VEGF concentrations (r = 0.573, p = 0.001). Age (r = 0.097, p = 0.611), gender (r = -0.315, p = 0.09) and severity of DR (r = 0.256, p = 0.172) were with no significant relationship to the VEGF measurements. CONCLUSION: Poor glycemic control is positively correlated with increased levels of plasma VEGF in patients with type 2 diabetes. As normalization of HbA1c is one of the most effective ways to prevent progression of DR and VEGF has been to shown to be clearly implicated in the development of DR, it affirms the importance of glycemic control in patients with DR. PMID- 23452414 TI - Impaired cardioprotective function of transplantation of mesenchymal stem cells from patients with diabetes mellitus to rats with experimentally induced myocardial infarction. AB - BACKGROUND: Diabetes mellitus (DM) exacerbates coronary artery disease (CAD) morbidity and mortality. Mesenchymal stem cells (MSCs) play an important therapeutic role in myocardial ischemic injury. However, little is known about changes in the cardioprotective characteristics of MSCs from patients with DM. METHODS: Sternal bone marrow aspirates were taken at the time of coronary artery bypass graft surgery. The morphology and growth characteristics of hMSCs were observed in passage 3. Differences in gene expression profiling were measured by Affymetrix GeneChipHuman Genome U133 Plus 2.0 Arrays. Forty two adult male rats with experimentally CAD were randomized into three groups. MSCs from patients with CAD+DM or CAD were injected into the infarcted myocardium. Control animals received culture medium. Echocardiography, TUNEL, immunohistochemistry and Western-blot analysis were performed 4 weeks after transplantation. RESULTS: Growth curves showed that proliferation of hMSCs in the CAD+DM group was significantly lower than in the CAD group. Nine transcripts of genes related to apoptosis containing Bcl-2 were found to differentiate the two groups. Transplantation of hMSCs in the infarcted border zone improved cardiac function, but DM partly impaired this effect. Similar results were observed from TUNEL, immunohistochemistry and Western-blot analysis. CONCLUSIONS: hMSCs from patients with CAD+DM and CAD alone both have proliferative properties. Transplantation of hMSCs ameliorate heart function, but proliferative ability and myocardial protection decrease significantly in MSCs obtained from patients with CAD+DM compared with cultures from patients with CAD alone, possibly as a result of differences in Bcl-2 protein expression and reduced anti-apoptosis. PMID- 23452415 TI - The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. AB - Recent investigations of the tumor microenvironment have shown that many tumors are infiltrated by inflammatory and lymphocytic cells. Increasing evidence suggests that the number, type and location of these tumor-infiltrating lymphocytes in primary tumors has prognostic value, and this has led to the development of an 'immunoscore. As well as providing useful prognostic information, the immunoscore concept also has the potential to help predict response to treatment, thereby improving decision- making with regard to choice of therapy. This predictive aspect of the tumor microenvironment forms the basis for the concept of immunoprofiling, which can be described as 'using an individual's immune system signature (or profile) to predict that patient's response to therapy' The immunoprofile of an individual can be genetically determined or tumor-induced (and therefore dynamic). Ipilimumab is the first in a series of immunomodulating antibodies and has been shown to be associated with improved overall survival in patients with advanced melanoma. Other immunotherapies in development include anti-programmed death 1 protein (nivolumab), anti-PD-ligand 1, anti-CD137 (urelumab), and anti-OX40. Biomarkers that can be used as predictive factors for these treatments have not yet been clinically validated. However, there is already evidence that the tumor microenvironment can have a predictive role, with clinical activity of ipilimumab related to high baseline expression of the immune-related genes FoxP3 and indoleamine 2,3-dioxygenase and an increase in tumor-infiltrating lymphocytes. These biomarkers could represent the first potential proposal for an immunoprofiling panel in patients for whom anti-CTLA-4 therapy is being considered, although prospective data are required. In conclusion, the evaluation of systemic and local immunological biomarkers could offer useful prognostic information and facilitate clinical decision making. The challenge will be to identify the individual immunoprofile of each patient and the consequent choice of optimal therapy or combination of therapies to be used. PMID- 23452416 TI - Acetabular fractures in children: a review of the literature. AB - Injury to the acetabular growth plate is rare. Accordingly, data on the incidence in the literature are controverse. Other difficulties include the clear definition of a pediatric acetabular injury. The modified classification according to Salter-Harris described by Bucholz is used in immature patients. The majority of these injuries can be treated conservatively. In severely displaced injuries or in the presence of intra-articular pathologies open procedures are recommended. The main long-term complication is the development of posttraumatic acetabular dysplasia which should be early detected by regular check-ups until the completion of growth. Overall, the long-term results are satisfactory. PMID- 23452417 TI - [Trochanteric femoral fractures]. AB - At the present time proximal femoral fractures account for 30% of all fractures referred to hospitals for treatment. Our population is ageing, the proportion of patients with post-menopausal or senile osteoporosis is increasing and therefore the number of proximal femoral fractures requiring urgent treatment is growing too. In the age category of 50 years and older, the incidence of these fractures has increased exponentially. Our department serves as a trauma centre for half of Prague and part of the Central Bohemia Region with a population of 1 150 000. Prague in particular has a high number of elderly citizens. Our experience is based on extensive clinical data obtained from the Register of Proximal Femoral Fractures established in 1997. During 14 years, 4280 patients, 3112 women and 1168 men, were admitted to our department for treatment of proximal femoral fractures. All patients were followed up until healing or development of complications. In the group under study, 82% were patients older than 70 years; 72% of those requiring surgery were in their seventies and eighties. Men were significantly younger than women (p<0.001) and represented 30% of the group. The fractures were 2.3-times more frequent in women than in men. In the category under 60 years, men significantly outnumbered women (p<0.001). The patients with pertrochanteric fractures were, on the average, eight years older than the patients with intertrochanteric fractures, which is a significant difference (p<0.001). The mortality rate within a year of injury was about 30%. Trochanteric fractures accounted for 54.7% and femoral neck fractures for 45.3% of all fractures. The inter-annual increase was 5.9%, with more trochanteric than femoral neck fractures. There was a non-significant decrease in intertrochanteric (AO 31-A3) fractures. On the other hand, the number of pertrochanteric (AO 31 A1+2) fractures increased significantly (p<0.001). A total of 1 394 fractures were treated with a proximal femoral nail; a short nail was used in 1260 and a long nail in 134 of them. A dynamic hip screw (DHS) was employed to treat 947 fractures. Distinguishing between pertrochanteric (21-A1, 31-A2) and intertrochanteric (31-A3) fractures is considered an important approach because of their different behaviour at reduction. Pertrochanteric fractures occurred more frequently (81.5%); the patients' age was higher (80 years on the average) and women outnumbered men at a ratio of 3:1. Intertrochanteric fractures were found in significantly younger patients (average, 72 years), with a women-to-men ratio of 1.3:1. Stable pertrochanteric fractures (31-A1) were preferably indicated for DHS surgery. Unstable pertrochanteric (31-A2) and intertrochanteric (31- A3) fractures were treated with a nail. The patients underwent surgery on the day of injury or the next day. In the case of contraindications to an urgent intervention, surgery was performed after the patient's medical condition had stabilised. The number of complications was largely related to technical errors, such as insufficient reduction or an incorrectly inserted implant. Intertrochanteric fractures were associated with a higher occurrence of complications. No implant can compensate for errors due to surgery. Serious complications can be reduced by the correct assessment of fracture type, the use of an appropriate operative technique and early treatment of potential complications. The necessity of restoring continuity in the medial cortex of the femoral neck (Adams' arch) is the requirement that should be observed. Pseudoarthrosis or varus malalignment in a healed hip should be managed by valgus osteotomy. When the femoral head or the acetabulum is damaged, total hip arthroplasty is indicated. A prerequisite for successful surgical outcome is urgently and correctly performed osteosynthesis allowing for early rehabilitation and mobilisation of the patient. PMID- 23452418 TI - Transverse + posterior wall fractures of the acetabulum: epidemiology, operative management and long-term results. AB - PURPOUSE OF THE STUDY: Associated transverse and posterior wall fractures account for approximately 20% of all acetabular fractures. To asses the risk of these concommitant bone injuries on early joint failure despite a high rate of postoperative congruency. MATERIAL: The analysis of 104 surgically treated patients with associated transverse and posterior wall fractures showed that more than half of these patients had associated injuries. The mean age was 35 years, and > 75% of these patients were male. A high energy trauma was the trauma mechanism in 94.2%. The mean ISS was 26.3 points. The majority of patients showed a juxta- or transtectal fracture line. The mean articular fracture displacement was 13.5 mm. 87.5% of the patients showed a femoral head dislocation. An acetabular roof comminution was present in 16.3%. 20.2% of patients received a fracture related preoperative nerve injury to the sciatic nerve. METHODS: Osteosynthesis was performed 9.9 days after trauma. The Kocher-Langenbeck approach was used in > 90% for stabilization with a combination of plate and screw fixation in 71.1%. The mean operative time was 190 minutes with a blood loss of 855 ml. Postoperatively the hip joint was congruent in 90.3% with anatomical or near-anatomical joint reconstruction in > 90%. Iatrogenic nerve injury occurred in 12 patients (8.9%). RESULTS: 67 patients (67.7%) could be followed after a mean of 42.7 months. The average subjective Visual Analog Scale pain score was 42.7. Mild or no pain was seen in 58.2%. The mean Merle d'Aubigne score was 15.4 with 56.7% of patients having a functionally perfect or good result. 52.2% had no post-traumatic osteoarthritic changes of their hip joint. A joint failure was diagnosed in 32.8% of the patients. Analyzing only patients with anatomically reconstructed hip joints, patients showed comparable results with 61.3% having no or mild pain and 59.2% a good or excellent functional result. Posttraumatic arthrotic changes occur in only 26.5% of these patients. A joint failure was present in 32.7%. In this group, a joint failure was significantly more likely to be present with an additional acetabular comminution zone. CONCLUSION: Associated transverse and posterior wall fractures have a significant risk of early joint failure despite a high rate of postoperative congruency. PMID- 23452419 TI - [Mid-term radiographic results in Th12 and L1 fractures after anterior column reconstruction with tibial shaft bone allograft]. AB - PURPOSE OF THE STUDY: Frozen tibial shaft bone allografts filled with autologous cancellous bone chips were used for anterior column reconstruction in Th12 and L1 fractures. The aim of this retrospective study was to evaluate the five-year results of the treatment on the basis of radiographic findings. MATERIAL AND METHODS: Twenty-six patients treated in 2005 and 2006 for isolated Th12 or L1 fractures, with no neurological deficit, were evaluated. In all patients, the spine was stabilised from an isolated anterior approach or through a combined posterior and anterior approach, and angle-stable implants were used. On radiographic examination the loss of correction and lateral compression of the segment involved were measured on standard X-ray views. Data on bone union at graft-bone interfaces were obtained from spiral CT scans. For assessment of the stage of bone healing, a scale of 0-25-50-75-100 % was established, and each patient was evaluated by two independent radiologists. Based on the average results, bone union was defined as non-union, 0-24 %; incomplete union, 25-74 %; complete union, 75-100 %. RESULTS: The average loss of correction measured by Beck's method was 0.77 degree. In four patients, the lateral compression angle deteriorated on the average by 1.1 degree (range, 0.7 degrees -1.8 degrees ) during the treatment. The proximal graft-bone interface showed complete union in 19 patients (73 %), and the distal interface was completely healed in 20 patients (77 %). Incomplete bone union at the proximal and the distal interface was found in seven (27 %) and six (23 %) patients, respectively. Nonunion was not recorded. No complications occurred. CONCLUSIONS: The use of tibial shaft bone allografts filled with autologous cancellous bone chips resulted in stable reconstruction of the anterior column of the thoracolumbar spine which showed a low loss of correction and good bone union. PMID- 23452420 TI - [Exactness of correction of proximal femoral deformities using conventional angled blade plates and the cannulated paediatric osteotomy system. Comparison of two methods]. AB - PURPOSE OF THE STUDY: The aim of the study was to compare the exactness of correction of proximal femoral deformities between the patients treated with AO angled blade plates and those managed by the cannulated paediatric osteotomy system (CAPOS). MATERIAL AND METHODS: In the period from 1994 to 2003, corrective osteotomy of the proximal femur using the conventional AO angled blade plate (90 degrees , 120 degrees , 130 degrees ) was performed on 57 hips in 42 children. In the period 2004-2012, 68 hips in 59 children were treated by the CAPOS method. In each child, the pre- and post-operative X-ray views were compared and a real deviation from the pre-operative plan was determined. A deviation larger than 10 degrees in the frontal plane was recorded as an error. Penetration of the blade into either the posterior or the anterior femoral neck cortex seen on axial views was regarded as an error as well. RESULTS: Corrective osteotomy with AO angled blade plates performed on 57 hips failed in 12 (21.1%) on anteroposterior views and six hips (10.5%) on axial views. Of 68 hips treated by the CAPOS, failure was recorded in four (5.9%) and one (1.5%) on anteroposterior and axial views, respectively. DISCUSSION No information on the CAPOS technique is available in either international or national literature, with the exception of our preliminary report. On the other hand, locking compression plates for paediatric hips, developed later, have been described in several publications. The authors appreciate a higher accuracy of bone correction and higher stability for the whole fixation, which results in earlier mobilisation of the treated extremity. These advantages are also true for CAPOS instrumentation. CONCLUSIONS: The CAPOS can be seen as an intermediate stage of development between conventional angled blade plates and locking compression plates for paediatric hips. However, it should be noted that surgery involving insertion of an angled blade plate takes less time than insertion of a locking compression plate. For this reason, in procedures combining femoral osteotomy with, for instance, triple pelvic osteotomy the use of CAPOS instrumentation is still preferred. PMID- 23452421 TI - [Evaluation of anterior cruciate ligament reconstruction using anterior tibial muscle tendon allograft]. AB - PURPOSE OF THE STUDY: Injury to the anterior cruciate ligament (ACL) frequently results in the development of knee instability. This is managed by ACL reconstruction using autogenous or allogeneic grafts. This study presents a comprehensive evaluation of the patients with ACL reconstruction using a tendon allograft harvested from the anterior tibial muscle (ATM). MATERIAL AND METHODS: The group under study comprised 53 patients, 33 men and 20 women, with unilateral ACL reconstruction while the other knee was intact. The average age was 32.4 years (17 to 51) and the average follow-up was 33,4 months (21 to 53). Clinical evaluation included the Tegner and Lysholm scores and questionnaire-based satisfaction rating. Functional assessment included measurements of the range of motion and thigh circumference. Knee stability was determined using the pivot shift test, Lachman test and one-leg hop test. ACL laxity was measured on a GNRB(r) arthrometer. Placement of the tibial and the femoral tunnel on radiographs was assessed by the method of Harner. RESULTS: All patients reported their willingness to undergo the surgery again. The average pre-operative Tegner score improved from 7.17 (4-10) to 6.45 (2-10; p = 0.0001). The average post operative Lysholm score was 87 points (47-100). At final follow-up, the full range of motion was recorded in 39 patients (74%), while the remaining patients exhibited only insignificant restriction of knee motion in comparison with the pre-operative status. The results of the Lachman test were negative in 38 patients (71.7%) while the pivot shift test was negative in 52 patients (98.1%). In the one-leg hop test, 44 patients (83%) were able to jump on the treated leg for a distance longer than 90% of the distance done on the healthy leg. The GNRB test at a force of 134N showed an anterior shift of the proximal tibia by 2.2 mm (0.1-9.3) on the average. The tibial tunnel was placed in zone B in 48 patients (90.6%) and the femoral tunnel was most often located to zone D (n = 47; 88.7%). DISCUSSION: The choice of tissue for ACL reconstruction is still being discussed. In some centres an ATM tendon allograft is used only in revision surgery while, in other centres, it is also employed in primary procedures. Recent studies on ACL surgery suggest that outcomes are relatively independent of the material used for reconstruction. In view of evidence-based medicine, more well-conducted multicentre clinical trials are needed to optimise indications for allograft ACL reconstruction. CONCLUSIONS: The ACL reconstruction using an ATM tendon allograft showed good clinical outcome at a minimum follow-up of 21 months. The method can be recommended not only for revision ACL reconstruction but also in primary reconstructions particularly in elderly patients. The present-day technology of producing allografts maintains tissue biomechanical characteristics and reduces risks for transmission of infection to a minimum. PMID- 23452422 TI - [Evaluation of the clinical results in patients with symptomatic partial tears of the anterior cruciate ligament diagnosed arthroscopically]. AB - PURPOSE OF THE STUDY: The study presents a retrospective evaluation of clinical data and arthroscopic findings in a group of our patients with symptomatic knee instability due to a partial tear of the anterior cruciate ligament (ACL). MATERIAL AND METHODS: The group included 31 patients diagnosed with symptomatic partial ACL tears, i.e. an isolated tear of the posterolateral (PL) or the anteromedial (AM) bundle. The patients' average age was 26.5 years. A side-to side difference in ventral knee laxity was assessed using the anterior drawer test and the Lachman test under general anaesthesia before arthroscopy was commenced; rotational knee laxity was evaluated by the pivot shift test. An objective evaluation of side-to-side ventral laxity differences in both knees was performed on the GNRB(r) arthrometer with an applied pressure of 134 N and 250 N in the conscious patient. During arthroscopic examination, findings on the two ACL bundles were recorded. RESULTS: All 31 patients were diagnosed with symptomatic partial ACL tears, of them 22 had a PL bundle lesion and nine had an AM bundle tear. All patients with PL bundle lesions only reported problems in association with pivot sports, and all patients with AM bundle tears had problems regardless of any sports activities. In all patients with isolated AM bundle tears, the lesion was located close to its femoral attachment. In the patients with PL bundle tears, femoral location was found in 68% and tibial location in 32% of the patients. In the patients with partial PL bundle lesions, + and ++ results in the pivot shift test were recorded in 32% and 68% of the treated patients, respectively. The Lachman test showed + and ++ results in 71% and 9% of the patients, respectively. The anterior drawer test had negative results in 87% and positive + results in 13% of the patients. The side-to-side difference on the GNRB arthrometer ranged from 0.4 to 2.3 mm at a pressure of 134 N and from 1.2 to 4.2 mm at 250 N in the patients with isolated PL bundle lesions. In the patients with AM bundle lesions, the results were as follows: pivot shift test, 89% negative. 11% positive +; Lachman test, 56% negative, 44% positive +; anterior drawer test, 89% +, 11% ++; GNRB test, 2.2 to 4.4 mm at 134 N, and 4.3 to 7.1 at 250 N. DISCUSSION: The diagnosis of partial ACL lesions, i.e., isolated tears of the AM or the PL bundle, requires accurate knowledge of knee anatomy and its biomechanics. In accordance with other authors our results showed that an arthroscopic examination of both bundles of the ligament as well as knee laxity evaluation under general anaesthesia are most essential for making the definite diagnosis in partial ACL tears. They also confirmed that, in isolated AM bundle lesions, ventral laxity is present more often particularly at a higher degree of knee flexion while, in PL bundle lesions, rotational laxity is more frequent and ranges from 0 to 30 degrees of knee flexion. CONCLUSIONS: To make the definite diagnosis of partial ACL tears, patient medical history, clinical knee examination including instability type and degree assessment under general anaesthesia and, most importantly, arthroscopic findings on both ACL bundles are necessary. PMID- 23452423 TI - [Pelvic injuries and acetabular fractures: differences in their severity]. AB - PURPOSE OF THE STUDY: The aim of the study was to assess differences in the number and severity of associated injuries between patients with pelvic injury and those with acetabular fracture. MATERIAL AND METHODS: The patients treated in the period from January 1, 2008, to December 31, 2010, were enrolled. The group comprised 249 patients (130 women and 119 men) with pelvic injuries and 58 patients (14 women and 44 men) with acetabular fractures. In the patients with pelvic injury, the average age was 52 years, 61 in women and 43 in men, in the range of 17 to 91 years. In the patients with acetabular fracture, the average age was 54 years, 59 in women and 53 in men, in the range of 21 to 96 years. The relevant data including age, sex, cause of injury, associated injuries and the overall severity of injury were obtained from the patient database. The results were statistically analysed using Pearson's .2 test at a 5% level of significance. RESULTS: Acetabular fractures were recorded in more men than women and this difference was significantly higher (p = 0.002) than in the patients with pelvic injury in whom similar numbers of men and women were affected. A fall from height was significantly more frequent as a cause of pelvic injury than that of acetabular fracture (p = 0.034). The patients with pelvic injury also had significantly more associated injuries (p = 0.016) and the number of these patients with an Injury Severity Score (ISS) higher than 16 was significantly higher compared with the number of patients with acetabular fractures (p < 0.001). DISCUSSION: Little published information is available on comparison of the severity of injuries in patients with pelvic injuries and those with acetabular fractures because these conditions are in fact two nosological units. In pelvic injuries, as conditions usually accompanied by multiple trauma, associated injuries, risk factors for death, requirements for primary life-saving measures, complications and treatment outcomes have been studied. Less attention has been paid to these issues in patients with acetabular fractures; the authors focused on determining the quality of intra-articular fracture treatment in relation to a subsequent risk of avascular necrosis of the femoral head or early arthritis. CONCLUSIONS: The study comparing the patients with pelvic injury with those having acetabular fracture showed a significantly higher proportion of men in the group with acetabular fractures. A fall from height significantly more often caused a pelvic injury than an acetabular fracture. In traffic accidents, drivers usually suffered acetabular fractures while pedestrians and cyclists had pelvic injuries. However, a significantly higher number of associated injuries and multiple trauma with an ISS > 16 recorded in the patients with pelvic injury in comparison with those with acetabular fractures was the most important difference between these two groups. PMID- 23452424 TI - First metatarsophalangeal joint replacement with modular three-component press fit implant. Preliminary report. AB - PURPOSE OF THE STUDY: The aim of this retrospective study was to assess functional and radiographic results of the first metatarsophalangeal joint replacement with use of unconstrained, modular, three components, porous titanium and hydroxyapatite coated, press-fit METIS(r) prosthesis. According to author's knowledge, results of that type of prosthesis have never been published before. MATERIAL AND METHODS: 25 prosthesis were implanted in 24 patients between February 2009 and May 2011. American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal Interphalangeal scoring system (AOFAS-HMI) was used to assess functional results. Patients were also asked if they would undergo procedure again or recommend it to other people. Weight bearing radiographs ware made at final follow up and analyzed for presence of osteolysis and radiolucencies. In 8 patients total joint replacement was introduced as a salvage after failure of previous surgery like Keller resection arthroplasty, failed arthrodesis, avascular necrosis and postoperative arthritis. In 11 patients the reason for prosthetic replacement were hallux rigidus, in 4 cases rheumatoid arthritis and gout in one patient. In two patients additional procedures like Akin phalangeal osteotomy and in one case fifth metatarsal osteotomy, was performed. There were 20 females and 4 males in presented group. The mean age at the operation was 56 years. The average follow up period was 18 months (from 12 to 36 months). RESULTS: The median postoperative value of AOFAS-HMI scores was 88 points (from 75 to 95 points). First metatarsophalangeal joint motion (dorsiflexion plus plantarflexion) was classified according to AOFAS-HMI ranges as: moderately restricted (between 30 to 70 degrees) in 19 patients 80% (20 prosthesis) and severely restricted (less then 30 degrees) in 5 patients (20%). 15 (64%) patients were completely satisfied, 5 (20%) reported moderate satisfaction and (16%) 4 were totally disappointed and would not undergo this procedure again. A limited hallux dorsiflexion was the main dissatisfaction reason. Partial radiolucent line was seen in one patient (4%). Authors noticed two serious complications. In one patient, with rheumatoid arthritis, deep infection occurred 12 months after prosthesis implantation. In second case phalangeal implant was revised due to misalignment. CONCLUSIONS: METIS(r) metatarsophalangeal joint replacement allows alleviate of pain relating to hallux rigidus and partial restoration of joint movement, even in patients after failures of primary metatarsophalangeal joint surgery. AOFAS-HMI results are better than previously reported in the literature in assessment of the first metatarsophalangeal joint replacement. Radiographic results imply satisfactory bone ingrowth into the cementless implants. PMID- 23452425 TI - [Microbial and pharmacological characteristics of VancogenX]. AB - PURPOSE OF THE STUDY: Prosthetic joint infection is a feared complication in total hip arthroplasty. The use of antibiotic-impregnated bone cement is the important part of preventive and therapeutic strategies. At present a number of commercial bone cements are available and support of their use by the results of experimental trials and clinical studies has varied. In relation to this issue we studied essential microbiological and pharmacological characteristics of VancogenX in comparison with gentamicin-loaded bone cement used conventionally. MATERIAL AND METHODS: Based on a previously described protocol, we tested pellets of four commercial bone cements, namely, Hi-Fatigue G, Palacos R+G, VancogenX, and Palacos R as a control. Bone cement was prepared in a vacuum-mixing system. The strains used for bacterial load included Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli. Each cement was tested for its antimicrobial and antibiofilm activities and the results were evaluated by standard methods. In addition, we investigated time-related release of gentamicin and vancomycin from the bone cements tested. RESULTS: All antibiotic-loaded cement pellets were able to prevent growth of the bacterial strains tested. The bactericidal effect lasted for several days in relation to the bacterial species and cement used, with the exception of S. epidermidis whose growth was inhibited by gentamicin-loaded cement only for one day. The antibiotic-loaded pellets also prevented the formation of a biofilm for 24 hours at least. The major amount of vancomycin (32.915 mg/l) was released from VancogenX to MH medium within 24 hours and the last measureable amount (4.327 mg/l) was recorded at 48 hours after the start of the experiment. In physiological saline the highest level of vancomycin was 139.852 mg/ml measured at 24 hours, and the antibiotic was detectable at a level of 2.334 mg/ml as late as 8 days after the experiment started. Release of gentamicin from VancogenX was as follows: the 24-hour level was higher in MH medium than physiological saline (178 versus 131.4 mg/ml); however, gentamicin was still detectable in physiological saline at 192 hours after the start of the experiment while no gentamicin was found in MH medium after 72 hours. DISCUSSION: The antimicrobial effect of VancogenX bone cement was not an unexpected finding since both gentamicin and vancomycin have been used with bone cement for a long time and their combination is optimal in terms of preventing prosthetic joint infection. However, there is a disputable issue of poor release of vancomycin from bone cement. In MH medium we were able to detect the vancomycin released from VancogenX only for two days after the initial rapid elution while its release into physiological saline seemed to be slower but much longer. It is possible that more vancomycin is released from bone cement, but this amount is immediately bound to proteins in the cement vicinity and this process is not detectable by any analytical method. CONCLUSIONS: The bone cement VancogenX showed excellent antimicrobial and antibiofilm properties and can be recommended for use in orthopaedic practice. Therapy of prosthetic joint infection is the main indication. Extension of the indication to the prevention of prosthetic joint infection in high-risk patients should be preceded by biomechanical studies demonstrating that the cement is appropriate for long-term implant fixation. PMID- 23452426 TI - [Systematic mediastinal lymphadenectomy in surgery for sarcomatous pulmonary metastases]. AB - PURPOSE OF THE STUDY: Systematic lymph node dissection is performed as standard curative resection for non-small cell lung cancer. Its role in lung metastasectomy is unknown. The aim of our study was to find out the frequency of lymph node metastases, the survival of patients with and without lymph node involvement, and to consider if routine lymph node dissection should be recommended. MATERIAL AND METHODS: The study was undertaken at three departments of surgery and included 14 patients undergoing lung metastasectomy between July 2008 and December 2011. In all patients systematic lymph node dissection was also performed. When wedge resection was done, N1 nodes were removed only as part of a local procedure at that anatomical site. Patients with mediastinal lymph node involvement detected by pre-operative CT or PET scans were not included in the study. RESULTS: Lung metastasectomy for metastatic sarcoma was performed in 14 patients. Nine patients had bilateral lung metastases. Solitary lung metastasis was found in only one case. The mean number of removed mediastinal lymph nodes was 14.8 (7-32). Mediastinal lymph node metastases were found in two patients (14.3%). The average disease free interval (DFI) was 79.6 months (median, 25.5 months). Using the Kaplan-Meier method, the 3-year survival rate was 46% (0.46+/ 0.15). The Cox-Mantel test for comparing the survival curves showed, at a 0.05 level of significance, better survival rates for the patients with no metastatic lymph node involvement (p=0.01). DISCUSSION: The frequency of mediastinal lymph node involvement in our study was 14.3% and this was in agreement with the data reported in the literature. The 3-year survival rate was 46% in our patients; the published 5-year survival is 15-50%. A systematic mediastinal lymphadenectomy during lung metastasectomy for metastatic sarcoma has been recommended, but also argued against because of a low incidence of mediastinal lymph node involvement in sarcomatous metastases reported by some authors. We showed that mediastinal lymph node involvement was a negative prognostic factor. Systematic mediastinal lymphadenectomy as a routine procedure provides for a better staging. This is important in association with the development of adjuvant modalities, such as monoclonal antibodies, at present or a gene therapy in the future. CONCLUSIONS: Even in a carefully selected group of patients, incidence of mediastinal lymph node metastases is high. Since no relevant data based on large patient groups are available, we recommend routine nodal dissection for all patients indicated for lung metastasectomy. Drawing a definite conclusion will require analyses of large numbers of data from multi-institutional studies and cooperation with the international database, if possible. PMID- 23452427 TI - [Injectable hydrogel functionalised with thrombocyte-rich solution and microparticles for accelerated cartilage regeneration]. AB - PURPOSE OF THE STUDY: Articular cartilage defects arise due to injury or osteochondral disease such as osteonecrosis or osteochondritis dissecans. In adult patients cartilage has minimal ability to repair itself and the lesions develop into degenerative arthritis. Overcoming the low regenerative capacity of the cartilage cells and the Hayflick limit poses a challenge for the therapy of osteochondral defects. Composite scaffolds with appropriate biomechanical properties combined with a suitable blend of proliferation and differentiation factors could be a solution. The aim of this in vitro study was to develop a novel functionalised hydrogel with an integrated drug delivery system stimulating articular cartilage regeneration. MATERIAL AND METHODS: Injectable collagen/ hyaluronic acid/fibrin composite hydrogel was mixed with nanofibre-based microparticles. These were loaded with ascorbic acid and dexamethasone. In addition, the effect of thrombocyte-rich solution (TRS) was studied. The gels seeded with mesenchymal stem cells (MSCs) were cultivated for 14 days. The viability, proliferation and morphology of the cells were evaluated using molecular and microscopic methods. Scaffold degradation was also assessed. RESULTS: The cultivation study showed that MSCs remained viable in all experimental groups, which indicated good biocompatibility of the gel. However, the number of cells in the groups enriched with microparticles was lower than in the other groups. On the other hand, confocal microscopy showed higher cell viability and rounded morphology of the cells, which can be associated with chodrogenic differentiation. The scaffolds containing microparticles showed significantly higher stability during the 14-day experiment. DISCUSSION: Our results suggest that the addition of microparticles to the scaffold improved cell differentiation into the chondrogenic lineage, resulting in a lower proliferation rate. Cell viability was better in the groups enriched with microparticles that served as an efficient drug delivery system. In addition, the presence of microparticles slowed down gel degradation which can help achieve sufficient stability of the system for the time frame required for cartilage regeneration. CONCLUSIONS: The novel approach described here produced an efficient system where microparticles served as a drug delivery system and stabilised the gel for prolonged periods of time. These characteristics play an important role in the development of scaffolds for cartilage regeneration. In the future the results of these in vitro experiments will be verified in an in vivo study. PMID- 23452428 TI - Alternative technique of cement augmentation of loosened pedicle screws -- technical note and presentation of two cases. AB - An alternative cement augmentation technique for pedicle screws is described, which was applied in two patients with mono- and bisegmental non-union after preceding multisegmental lumbar fusion. The correctly placed pedicle screws in S1 with diameters of 6 and 8.5 mm had severely enlarged the screw cavities due to segmental instability. Revision screws with 10 mm diameter demonstrated sufficient purchase only on the left side. Therefore, cement augmentation was performed for the right sided screws. After verification of intact pedicle borders, the cavity was filled up with PMMA bone cement. Afterwards, a Kirschner wire was positioned centrally, the hardening of the cement was awaited, the cement was gradually drilled and the screw was placed. In both patients, sufficient purchase of the cemented pedicle screws was documented. Screw insertion after awaiting the hardening of the bone cement in pedicles and vertebral bodies with huge defect situations seems to be an alternative to previous cement augmentation techniques of pedicle screws with the advantage, that the screws could be more easily unscrewed, if necessary. PMID- 23452430 TI - Novel cigarlike TiO2 nanofibers: fabrication, improved mechanical, and electrochemical performances. AB - By coupling the self-assembly of polystyrene-block-poly(ethylene oxide) (PS-b PEO) containing titanium precursors with the electrospinning technique, novel cigarlike nanofibers with an outer-shell and inner-continuous-pore structure and resultant fabrics were fabricated. Different from typical porous metal oxides, the prepared high-surface-area nonwoven fabrics show excellent mechanical properties. Not only are these fabrics self-supporting over a large area, but they can also be cut using scissors, which is important for large-scale applications. Furthermore, as electrode materials in Li-ion batteries, these fabrics exhibit much higher charge/discharge capacity and cycle stability compared with the commercially available nanosized TiO2 (P25). The improved mechanical and electrochemical performances are attributed to the presence of an outer-shell, inner-bicontinuous structures (including continuous TiO2 frame and continuous nanopores) and hierarchical pores from the cigarlike nanofibers. PMID- 23452429 TI - Mn (III) tetrakis (4-benzoic acid) porphyrin scavenges reactive species, reduces oxidative stress, and improves functional recovery after experimental spinal cord injury in rats: comparison with methylprednisolone. AB - BACKGROUND: Substantial experimental evidence supports that reactive species mediate secondary damage after traumatic spinal cord injury (SCI) by inducing oxidative stress. Removal of reactive species may reduce secondary damage following SCI. This study explored the effectiveness of a catalytic antioxidant - Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) - in removing reactive oxygen species (ROS), reducing oxidative stress, and improving functional recovery in vivo in a rat impact SCI model. The efficiency of MnTBAP was also compared with that of methylprednisolone - the only drug used clinically in treating acute SCI. RESULTS: In vivo measurements of time courses of ROS production by microdialysis and microcannula sampling in MnTBAP, methylprednisolone, and saline (as vehicle control)-treated SCI rats showed that both agents significantly reduced the production of hydrogen peroxide, but only MnTBAP significantly reduced superoxide elevation after SCI. In vitro experiments further demonstrated that MnTBAP scavenged both of the preceding ROS, whereas methylprednisolone had no effect on either. By counting the immuno-positive neurons in the spinal cord sections immunohistochemically stained with anti nitrotyrosine and anti-4-hydroxy-nonenal antibodies as the markers of protein nitration and membrane lipid peroxidation, we demonstrated that MnTBAP significantly reduced the numbers of 4-hydroxy-nonenal-positive and nitrotyrosine positive neurons in the sections at 1.55 to 2.55 mm and 1.1 to 3.1 mm, respectively, rostral to the injury epicenter compared to the vehicle-treated animals. By behavioral tests (open field and inclined plane tests), we demonstrated that at 4 hours post-SCI treatment with MnTBAP and the standard methylprednisolone regimen both significantly increased test scores compared to those produced by vehicle treatment. However, the outcomes for MnTBAP-treated rats were significantly better than those for methylprednisolone-treated animals. CONCLUSIONS: This study demonstrated for the first time in vivo and in vitro that MnTBAP significantly reduced the levels of SCI-elevated ROS and that MnTBAP is superior to methylprednisolone in removing ROS. Removal of ROS by MnTBAP significantly reduced protein nitration and membrane lipid peroxidation in neurons. MnTBAP more effectively reduced neurological deficits than did methylprednisolone after SCI - the first most important criterion for assessing SCI treatments. These results support the therapeutic potential of MnTBAP in treating SCI. PMID- 23452431 TI - Synthetic approaches to RBC mimicry and oxygen carrier systems. AB - Whole blood or red blood cell (RBC) transfusions are highly significant, clinically, for blood replacement therapies in traumatic injuries, presurgical conditions, and anemias. However, natural RBC-based products suffer from limited shelf life due to pathological contamination and also present risks of refractoriness, graft-versus-host disease, immunosuppression, and acute lung injury. These issues can be only partially resolved by pathogen reduction technologies, serological blood testing, leukoreduction, and specialized storage; hence, they severely affect the efficacy and safety of the blood products. Consequently, there is a significant interest in synthetic RBC analogues that can mimic its oxygen-transport properties while allowing convenient manufacture, reproducibility, long shelf life, and reduced biological risks. To this end, the current Review provides a comprehensive description and discussion of the various research approaches and current state-of-the-art in synthetically mimicking RBC's oxygen-carrying biochemical properties, as well as the biophysical parameters (shape, size and mechanical modulus) that influence RBCs' hemodynamic transport properties in blood flow. PMID- 23452432 TI - Prevalence and predictors of over-the-counter medication use among pregnant women: a cross-sectional study in the Netherlands. AB - BACKGROUND: Over-the-counter-medication (OTC-medication) use during pregnancy can be potentially harmful for the fetus. To successfully counsel the patient it is important to know if the patient is at risk. In this study possible predictors for OTC-medication use were identified and a model was designed to predict OTC medication use during pregnancy. METHODS: We performed a post-hoc analysis on data collected for a clustered clinical trial to study a screening strategy for Query fever. Pregnant women under supervision of a midwife were eligible for inclusion. These women filled out questionnaires during their pregnancy and post partum. These questionnaires were used to determine the prevalence and to select possible predictors for OTC-medication use. These predictors were included in a prediction model using multivariate analysis. The discrimination and calibration of the model were assessed with Receiver Operating Characteristic analysis and the Hosmer and Lemeshow test. RESULTS: Of the 1348 women enrolling in the clustered clinical trial, we included 1246 women in this analysis. The prevalence of OTC-medication use was 12.5%. The predictors for OTC-medication use in our cohort were: nulliparity, use of prescription medication, the presence of a comorbidity, Body Mass Index between 26 and 30 kg/m2 and General Practitioner visits. These predictors were used to design a prediction model for OTC medication use. The area under the Receiver Operating Characteristic-curve of the prediction model was 0.667 (95% CI 0.620-0.714 P<0.001) and the predictive probabilities ranged from 6.6% to 57.4%. The Hosmer and Lemeshow goodness-of-fit test indicated good calibration of the model (P = 0.640). CONCLUSION: It is possible to indicate women at risk for OTC-medication use during pregnancy, using five maternal characteristics that independently contribute to the prediction model. The predictors are easy to estimate and the model is easy to implement in daily practice. PMID- 23452433 TI - Novel indole-bearing combretastatin analogues as tubulin polymerization inhibitors. AB - BACKGROUND: The combretastatins are a class of natural stilbenoids. These molecules generally share three common structural features: a trimethoxy "A" ring, a "B"-ring containing substituent often at C3' and C4', and an ethene bridge between the two rings, which provides necessary structural rigidity. Members of the combretastatin family possess varying ability to cause vascular disruption in tumors. Combretastatin binds to the colchicine binding site of beta subunit of tubulin. Despite having a similar name, combretastatin is unrelated to statins, a family of cholesterol-lowering drugs. RESULTS: New combretastatin 2-(1 acetyl-1H-indole-3-yl)-3-(phenyl) propenoic analogues (2a to 2y), bearing indole moiety at the place of ring A of combretastatin (CA4), were synthesized and evaluated for anticancer activity against various cancer cell lines such as THP-1 (leukemia), A-549 (lung), IGROV-1 (ovary), HEP-2 (liver), MCF-7 (breast), and DU 145 (prostate). Compound 2d showed anti-cancer activity against THP-1 and MCF-7 with IC50 0.80 and 0.37 MUM, respectively, and 2y showed against MCF-7 with IC50 3.60 MUM comparable to paclitaxel. CONCLUSIONS: The target compounds bind to the colchicine binding site which is situated at alpha and beta interface of tubulin and prevent polymerization as it was confirmed by immunofluorescence technique. The molecular docking further confirmed the binding of the potent compound 2d to the colchicine binding site at alpha and beta interface of tubulin. PMID- 23452435 TI - Comparative proteomic analysis of a new adaptive Pichia Stipitis strain to furfural, a lignocellulosic inhibitory compound. AB - The development of inhibitor-tolerant ethanologenic yeast is one of the most significant challenges facing bio-ethanol production. Adaptation of Pichia stipitis to inhibitors is one of the most efficient ways for dealing with inhibitor problems. The molecular mechanisms involved in the tolerance and adaptation of P. stipitis are, however, still unclear. In the present study, we developed a yeast strain from P. stipitis Y7 that has improved tolerance against inhibitors. We performed comparative proteomic investigations with sodium dodecyl sulfate polyacrylamide gel electrophoresis and quadrupole time-of-flight mass spectrometry. These investigations gave insights into the tolerance of yeast strains to biomass conversion inhibitors at the protein level. Many proteins involved in glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle were found to be differentially expressed due to the presence of furfural. Quantitative real-time reverse transcription-PCR (RT-PCR) and metabolite analysis were utilized to provide orthogonal evidence for the results obtained. Our results provide a deeper understanding of the molecular mechanisms involved in the response of P. stipitis to furfural. These findings will benefit the design and development of inhibitor-tolerant yeast. PMID- 23452434 TI - Carcinoembryonic antigen (CEA) level, CEA ratio, and treatment outcome of rectal cancer patients receiving pre-operative chemoradiation and surgery. AB - BACKGROUND: To investigate serum carcinoembryonic antigen (CEA) as a prognostic factor for rectal cancer patients receiving pre-operative chemoradiotherapy (CRT). METHODS: Between 2000 and 2009, 138 patients with advanced rectal cancer receiving CRT before surgery at our hospital were retrospectively classified into 3 groups: pre-CRT CEA <6 ng/ml (group L; n = 87); pre-CRT CEA >= 6 ng/ml and post CRT CEA <6 ng/ml (group H-L; n = 32); and both pre- and post-CRT CEA >= 6 ng/ml (group H-H; n = 19). CEA ratio (defined as post-CRT CEA divided by pre-CRT CEA), post-CRT CEA level and other factors were reviewed for prediction of pathologic complete response (pCR). RESULTS: Five-year disease-free survival (DFS) was better in groups L (69.0%) and H-L (74.5%) than in group H-H (44.9%) (p = 0.024). Pathologic complete response was observed in 19.5%, 21.9% and 5.3% of groups L, H L and H-H respectively (p = 0.281). Multivariate analysis showed that ypN stage and pCR were independent prognostic factors for DFS and that post-CRT CEA level was independently predictive of pCR. As a whole, post-CRT CEA <2.61 ng/ml predicted pCR (sensitivity 76.0%; specificity 58.4%). For those with pre-CRT CEA >=6 ng/ml, post-CRT CEA and CEA ratio both predicted pCR (sensitivity 87.5%, specificity 76.7%). CONCLUSIONS: In patients with pre-CRT serum CEA >=6 ng/ml, those with "normalized" CEA levels after CRT may have similar DFS to those with "normal" (<6 ng/ml) pre-CRT values. Post-CRT CEA level is a predictor for pCR, especially in those with pre-CRT CEA >=6 ng/ml. PMID- 23452436 TI - A three-year follow-up of ranibizumab treatment of exudative AMD: impact on the outcome of carrying forward the last acuity observation in drop-outs. AB - PURPOSE: To analyse a 3-year clinical patient cohort of ranibizumab treatment of exudative age-related macular degeneration (AMD), to investigate the impact on visual outcome of carrying forward the last acuity observation in drop-outs and to explore possible differences between the early and the late phase of the study. METHODS: A retrospective study of 312 eyes with neovascular AMD. The patients were followed up monthly, received three initial monthly injections of 0.5 mg ranibizumab and were re-treated pro re nata (PRN). Time-domain optical coherence tomography (TD-OCT) was used until spectral-domain (SD)-OCT was introduced during the last year of enrolment. Sixty-five patients were discontinued from the study. PRIMARY OUTCOME: change in best corrected visual acuity (BCVA). RESULTS: Best corrected visual acuity was 58.4 (CI 56.9-59.9) ETDRS (Early Treatment Diabetic Retinopathy Study) letters. At three months, it had increased by 4.1 letters (p=0.0004), at 12 months by 1.8 letters, at 24 months by 1.0 letter and at 36 months by 0.1 letter. However, if the last available acuity of drop-outs was carried forward one step and included, acuity had increased by 3.9 letters at 3 months (p<0.0001) and by 1.0 letter at 12 months but had decreased by 3.8 letters at 24 months (p=0.019) and by 4.1 letters (p=0.003) at 36 months. At 24 months, the result was significantly (p=0.030) less favourable when drop-outs were included. In patients enrolled during the late phase, BCVA was 59.3 (CI 56.7-62.0). It had increased by 5.7 letters (p<0.0001) at three months and by 5.8 letters at 12 months (p=0.0016). In patients enrolled during the early phase, BCVA was 57.9 (CI 55.0-60.8). At three months, it had increased by 3.5 letters (p=0.0008), but at 12 months, it had decreased by 2.3 letters (ns). The result at 12 months was significantly (p=0.0033) better for the late than for the early phase. The number of injections was also significantly (p=0.011) higher in the late phase. Adverse events were similar to those in earlier clinical trials. CONCLUSIONS: The results of this 3-year cohort showed that the initial average acuity could be maintained over 36 months, which was comparable to those of many other clinical cohorts. However, if the last available acuity of drop-outs was carried forward one step and included, the acuity figures would have fallen significantly. The results in patients enrolled during the late phase of the study were fairly similar to those in clinical trials. PMID- 23452438 TI - Au/Pd core-shell nanoparticles with varied hollow Au cores for enhanced formic acid oxidation. AB - A facile method has been developed to synthesize Au/Pd core-shell nanoparticles via galvanic replacement of Cu by Pd on hollow Au nanospheres. The unique nanoparticles were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy, ultraviolet-visible spectroscopy, and electrochemical measurements. When the concentration of the Au solution was decreased, grain size of the polycrystalline hollow Au nanospheres was reduced, and the structures became highly porous. After the Pd shell formed on these Au nanospheres, the morphology and structure of the Au/Pd nanoparticles varied and hence significantly affected the catalytic properties. The Au/Pd nanoparticles synthesized with reduced Au concentrations showed higher formic acid oxidation activity (0.93 mA cm-2 at 0.3 V) than the commercial Pd black (0.85 mA cm-2 at 0.3 V), suggesting a promising candidate as fuel cell catalysts. In addition, the Au/Pd nanoparticles displayed lower CO-stripping potential, improved stability, and higher durability compared to the Pd black due to their unique core-shell structures tuned by Au core morphologies. PMID- 23452437 TI - Differential impact of metabolic syndrome on subclinical atherosclerosis according to the presence of diabetes. AB - BACKGROUND: Metabolic syndrome (MS) is associated with increased risks of diabetes and atherosclerotic cardiovascular disease. However, data on the impact of MS and its individual components on subclinical atherosclerosis (SCA) according to diabetes status are scarce. METHODS: Surrogate markers of SCA, brachial-ankle pulse wave velocity (baPWV), and carotid intima-medial thickness (IMT) and plaque were assessed in 2,560 subjects (60 +/- 8 years, 33% men) who participated in baseline health examinations for a community-based cohort study. RESULTS: The participants included 2,149 non-diabetics (84%) and 411 diabetics (16%); 667 non-diabetics (31%) and 285 diabetics (69%) had MS, respectively. Diabetics had significantly higher baPWV and carotid IMT, and more plaques than non-diabetics (p < 0.001, respectively). Individuals with MS had significantly higher baPWV and carotid IMT than those without MS only among non-diabetics (p < 0.001, respectively). Among MS components, increased blood pressure was significantly associated with the exacerbation of all SCA markers in non diabetics. The number of MS components was significantly correlated with both baPWV and carotid IMT in non-diabetics (baPWV: r = 0.302, p < 0.001; carotid IMT: r = 0.217, p < 0.001). Multiple regression showed both MS and diabetes were significantly associated with baPWV (p < 0.001, respectively), carotid IMT (MS: p < 0.001; diabetes: p = 0.005), and the presence of plaque (MS: p = 0.041; diabetes: p = 0.002). CONCLUSIONS: MS has an incremental impact on SCA in conditions without diabetes. The identification of MS and its individual components is more important for the risk stratification of CVD in non-diabetic individuals. PMID- 23452439 TI - Severe traumatic brain injury in adults. AB - Traumatic brain injury is the most common cause of death and disability in young people, with an annual financial burden of over $50 billion per year in the United States. Traumatic brain injury is defined by both the initial primary injury and the subsequent secondary injuries. Fundamental to emergency department management is ensuring brain perfusion, oxygenation, and preventing even brief or transient episodes of hypotension, hypoxia, and hypocapnia. Cerebral perfusion pressure is a function of intracranial pressure and systemic blood pressure, and it must be monitored and maintained. Current research is devoted towards the prevention and treatment of secondary injury. The emergency clinician must be vigilant in maintaining homeostasis while coordinating the downstream care of the patient, including the intensive care unit and/or the operating room. PMID- 23452441 TI - Unexplained antepartum stillbirth: a consequence of placental aging? AB - Unexplained antepartum stillbirth is a major obstetric health problem. Data demonstrate a rapid rise in risk per 1000 continuing pregnancies as gestation advances beyond 40 weeks. We review the evidence that such stillbirths are a consequence of aging related changes in the late gestation placenta. We suggest that the relatively small number of continuing pregnancies after 40 completed weeks means that negative effects of genes that produce aging affect so few pregnancies that polymorphisms in genes that produce these effects are retained in the population. Aging related changes likely represent a consequence of the damaging effects of oxidative stress, increased by cigarette smoking counteracted by the mitigating effects of oxidative defence pathways. The aging related changes are likely downstream from nutrient sensing units such as mTOR and include effects on production of telomerase and consequent shortening of telomere length. The late gestation changes occur in the context of increasing fetal growth and nutrient supply demands that can produce the rapid development of a mismatch between placental supply and fetal need resulting in fetal demise. Premature aging may also play an important role in antepartum stillbirth occurring earlier in pregnancy, especially in the context of growth restriction. PMID- 23452440 TI - High glucose induces apoptosis and suppresses proliferation of adult rat neural stem cells following in vitro ischemia. AB - BACKGROUND: Post-stroke hyperglycemia appears to be associated with poor outcome from stroke, greater mortality, and reduced functional recovery. Focal cerebral ischemia data support that neural stem cells (NSCs) play an important role in post-ischemic repair. Here we sought to evaluate the negative effects of hyperglycemia on the cellular biology of NSCs following anoxia, and to test whether high glucose affects NSC recovery from ischemic injury. RESULTS: In this study, we used immortalized adult neural stem cells lines and we induced in vitro ischemia by 6 h oxygen and glucose deprivation (OGD) in an anaerobic incubator. Reperfusion was performed by returning cells to normoxic conditions and the cells were then incubated in experimental medium with various concentrations of glucose (17.5, 27.75, 41.75, and 83.75 mM) for 24 h. We found that high glucose (>=27.75 mM) exposure induced apoptosis of NSCs in a dose-dependent manner after exposure to OGD, using an Annexin V/PI apoptosis detection kit. The cell viability and proliferative activity of NSCs following OGD in vitro, evaluated with both a Cell Counting kit-8 (CCK-8) assay and a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, were inhibited by high glucose exposure. Cell cycle analysis showed that high glucose exposure increased the percentage of cells in G0/G1-phase, and reduced the percentage of cells in S-phase. Furthermore, high glucose exposure was found to significantly induce the activation of c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) and suppress extracellular signal-regulated kinase 1/2 (ERK1/2) activity. CONCLUSIONS: Our results demonstrate that high glucose induces apoptosis and inhibits proliferation of NSCs following OGD in vitro, which may be associated with the activation of JNK/p38 MAPK pathways and the delay of G1-S transition in the cells. PMID- 23452442 TI - Energy disposition in reactive intermediates. PMID- 23452443 TI - Co-culturing a novel Bacillus strain with Clostridium tyrobutyricum ATCC 25755 to produce butyric acid from sucrose. AB - BACKGROUND: Currently, the most promising microorganism used for the bio production of butyric acid is Clostridium tyrobutyricum ATCC 25755T; however, it is unable to use sucrose as a sole carbon source. Consequently, a newly isolated strain, Bacillus sp. SGP1, that was found to produce a levansucrase enzyme, which hydrolyzes sucrose into fructose and glucose, was used in a co-culture with this strain, permitting C. tyrobutyricum ATCC 25755T to ferment sucrose to butyric acid. RESULTS: B. sp. SGP1 alone did not show any butyric acid production and the main metabolite produced was lactic acid. This allowed C. tyrobutyricum ATCC 25755T to utilize the monosaccharides resulting from the activity of levansucrase together with the lactic acid produced by B. sp. SGP1 to generate butyric acid, which was the main fermentative product within the co-culture. Furthermore, the final acetic acid concentration in the co-culture was significantly lower when compared with pure C. tyrobutyricum ATCC 25755T cultures grown on glucose. In fed batch fermentations, the optimum conditions for the production of butyric acid were around pH 5.50 and a temperature of 37 degrees C. Under these conditions, the final butyrate concentration was 34.2+/-1.8 g/L with yields of 0.35+/-0.03 g butyrate/g sucrose and maximum productivity of 0.3+/-0.04 g/L/h. CONCLUSIONS: Using this co-culture, sucrose can be utilized as a carbon source for butyric acid production at a relatively high yield. In addition, this co-culture offers also the benefit of a greater selectivity, with butyric acid constituting 92.8% of the acids when the fermentation was terminated. PMID- 23452444 TI - The prevalence of retinopathy in subjects with and without type 2 diabetes mellitus. AB - PURPOSE: To evaluate the prevalence of and risk factors for, retinopathy in a geographically defined population with type 2 diabetes mellitus compared with a control group of subjects without diabetes, matched by age, sex and residence in order to find the retinopathy attributable to type 2 diabetes. METHODS: The study populations are, on one hand, a prevalence cohort of subjects with type 2 diabetes resident in the community of Laxa, Sweden, and on the other a control group, matched by age, gender and residence with those with a diagnosis of type 2 diabetes mellitus. Retinopathy was graded from fundus photographs using a modification of the Early Treatment Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of diabetic retinopathy (DR). RESULTS: Any retinopathy was found in 34.6% in the type 2 diabetes cohort and in 8.8% in the control group without diabetes. Among the diabetic patients, any retinopathy was significantly associated with duration of diabetes (p = 0.0001), HbA1c (p = 0.0056), systolic blood pressure (p = 0.0091) and lower serum cholesterol (p = 0.0197) in multivariate logistic regression analyses. Having retinopathy in the control group was associated only with systolic blood pressure (p = 0.0014) in logistic regression analysis. CONCLUSIONS: The prevalence of retinopathy among patients with type 2 diabetes in Laxa, Sweden, was similar or somewhat lower compared with other studies in the Nordic countries. The prevalence of retinopathy in a control group without diabetes equalled numbers from population studies worldwide. Our study indicates that the retinopathy that can be attributed to hyperglycaemia in the diabetic state is less common than is usually accounted for. A considerable fraction of retinopathy in subjects with diabetes may instead be due to other factors such as hypertension and should thus be treated correspondingly. PMID- 23452445 TI - In reply to Fourney. PMID- 23452446 TI - In regard to Cunha et al. PMID- 23452447 TI - In reply to Olson. PMID- 23452448 TI - In regard to de Lima et al. PMID- 23452449 TI - In regard to Potters. PMID- 23452450 TI - In reply to Baer. PMID- 23452451 TI - In regard to Vogelius and Bentzen. PMID- 23452452 TI - In reply to Arcangeli et al. PMID- 23452453 TI - Why workforce diversity in oncology matters. PMID- 23452454 TI - Is selective neck irradiation safe for node-negative nasopharyngeal carcinoma? PMID- 23452455 TI - The addition of SPECT/CT lymphoscintigraphy to breast cancer radiation planning spares lymph nodes critical for arm drainage. AB - BACKGROUND: This prospective cohort study was designed to determine whether the amount of radiation delivered to the nonpathological lymph nodes (LNs) that drain the arm can be significantly reduced by integrating single-photon emission computed tomography (SPECT)/computed tomography (CT) scans into radiation treatment planning. METHODS: SPECT-CT scans were acquired for the 28 patients with stage I or II breast cancer and fused with the routinely obtained radiation oncology planning CT scans. Arm-draining LNs were contoured with 0.5-cm margins automatically using a threshold of 50% maximum intensity. Two treatment plans were generated: 1 per routine clinical practice (standard; STD) and the second (modified; MOD) with treatment fields modified to minimize dose to the arm draining LNs visible on SPECT/CT images without interfering with the dosage delivered to target tissues. Participants were treated per the MOD plans. Arm volumes were measured prior to radiation and thereafter at least three subsequent 6-month intervals. RESULTS: Sixty-eight level I-III arm-draining LNs were identified, 57% of which were inside the STD plan fields but could be blocked in the MOD plan fields. Sixty-five percent of arm-draining LNs in the STD versus 16% in the MOD plans received a mean of >=10 Gy, and 26% in the STD versus 4% in the MOD plans received a mean of >=40 Gy. Mean LN radiation exposure was 23.6 Gy (standard deviation 18.2) with the STD and 7.7 Gy (standard deviation 11.3) with the MOD plans (P<.001). No participant developed lymphedema. CONCLUSIONS: The integration of SPECT/CT scans into breast cancer radiation treatment planning reduces unnecessary arm-draining LN radiation exposure and may lessen the risk of lymphedema. PMID- 23452456 TI - Letter from the editor: effects of aging on the musculoskeletal system. PMID- 23452457 TI - Letter from the guest editor: musculoskeletal imaging update. PMID- 23452458 TI - Case of the season: Saturday Night Palsy. PMID- 23452459 TI - Magnetic resonance neurography-simple guide to performance and interpretation. PMID- 23452460 TI - Musculoskeletal computed tomography: current technology and clinical applications. PMID- 23452461 TI - Volumetric magnetic resonance imaging of the musculoskeletal system. PMID- 23452462 TI - Cartilage imaging: a review of current concepts and emerging technologies. PMID- 23452463 TI - Femoral acetabular impingement. PMID- 23452464 TI - Musculoskeletal ultrasonography: starting your practice. PMID- 23452465 TI - Current concepts in hip arthroplasty imaging: metal-on-metal prostheses, their complications, and imaging strategies. PMID- 23452466 TI - Identification of biomarkers for intake of protein from meat, dairy products and grains: a controlled dietary intervention study. AB - In the present controlled, randomised, multiple cross-over dietary intervention study, we aimed to identify potential biomarkers for dietary protein from dairy products, meat and grain, which could be useful to estimate intake of these protein types in epidemiological studies. After 9 d run-in, thirty men and seventeen women (22 (SD 4) years) received three high-protein diets (aimed at approximately 18% of energy (en%)) in random order for 1 week each, with approximately 14 en% originating from either meat, dairy products or grain. We used a two-step approach to identify biomarkers in urine and plasma. With principal component discriminant analysis, we identified amino acids (AA) from the plasma or urinary AA profile that were distinctive between diets. Subsequently, after pooling total study data, we applied mixed models to estimate the predictive value of those AA for intake of protein types. A very good prediction could be made for the intake of meat protein by a regression model that included urinary carnosine, 1-methylhistidine and 3-methylhistidine (98% of variation in intake explained). Furthermore, for dietary grain protein, a model that included seven AA (plasma lysine, valine, threonine, alpha-aminobutyric acid, proline, ornithine and arginine) made a good prediction (75% of variation explained). We could not identify biomarkers for dairy protein intake. In conclusion, specific combinations of urinary and plasma AA may be potentially useful biomarkers for meat and grain protein intake, respectively. These findings need to be cross-validated in other dietary intervention studies. PMID- 23452467 TI - An efficient method for the determination of furan derivatives in apple cider and wine by solid phase extraction and high performance liquid chromatography--diode array detector. AB - A reliable SPE-HPLC/DAD method was developed for the simultaneous separation and quantitation of 10 furan derivatives in apple cider and wine matrices, including 5-hydroxymethyl-2-furaldehyde (5-HMFD), 4-hydroxy-2,5-dimethyl-3(2H)-furanone (4 HDMF), 2-furoic acid (2-FA), 2-furaldehyde (2-F), 3-furaldehyde (3-F), 2 acetylfuran (2-AF), 5-methyl-2-furaldehyde (5-MFD), methyl 2-furoate (MFT), 2 propionylfuran (2-PF) and ethyl 2-furoate (EFT). All the compounds were satisfactorily separated on a C18 column in less than 30 min. The solid phase extraction parameters have been optimized, including the sorbent, sample volume, washing and elution solvent. The relative standard deviations (RSDs) (intra- and inter-day) of all analytes were less than 6.4% for apple cider at 5mg/L spiking level and less than 3.9% (except 2-FA) for wine at 0.5mg/L spiking level. The limits of detection (LOD) and limits of quantitation (LOQ) were low (LOD 0.002 0.093 mg/L, LOQ 0.01-0.31 mg/L) compared to the usual concentrations of these compounds in these food matrices. The absolute recoveries of all compounds were higher than 77.8% (most of them were 80.5-103%) at different spiking levels (apple cider 0.5-50mg/L). The results showed that the developed method was precise, sensitive, robust and of good selectivity. PMID- 23452468 TI - Direct quantification of fatty acids in human milk by gas chromatography. AB - Human milk provides the key nutrients necessary for the infants' growth and development. The fatty acid composition of human milk has been extensively studied over the last 20 years and the results obtained by analyzing the fatty acid profile followed by lipid extraction and expressing data as g per 100g of fatty acids. The main drawback is that normalizing data set does not give any information on the amount of fatty acid mother's milk and therefore the level of intake by the infant. The objective of the present study was to develop and validate a direct method to analyze the fatty acid content in liquid human milk samples. Hydrochloric acid in a solution of methanol was selected as the catalyst and methyl undecanoate (11:0) as the internal standard together with tritridecanoin (13:0 TAG) to monitor transesterification performance. The separation of fatty acid methyl esters (FAME) was performed using a 100 m highly polar capillary column and a certified calibration mixture used to calculate experimental response factors. The method is suitable to quantify fatty acids in human milk from a 250 MUL sample and allow expression of the data in mg of fatty acids per deciliter of human milk as well as weight % of fatty acids. The method has been validated and show a good repeatability [CV(r)<15% and CV(r)<20% for the concentrations close to the LOQ] and a good intermediate reproducibility [CV(iR)<15% and CV(iR)<20% for the concentrations close to the LOQ]. The method was applied to analyze human milk samples obtained from 50 mothers 4 weeks post partum and the data are provided in absolute and relative quantity. These results show that the inter-individual variability of the fatty acid content in human milk is of prime importance and such information cannot be captured with normalized data sets. PMID- 23452469 TI - Educational curriculum, assessment, research and outcomes: past, present and future directions. PMID- 23452470 TI - Medical student radiology curriculum: what skills do residency program directors believe are essential for medical students to attain? AB - RATIONALE AND OBJECTIVES: The purpose of this study was to identify radiology topics considered essential by residency program directors who will be working with our graduates. Secondary goals were to survey their satisfaction with incoming residents' radiology knowledge, inquire if radiology training was provided in their programs, and identify differences among specialties. MATERIALS AND METHODS: A questionnaire was mailed to all residency program directors in emergency medicine, family medicine, internal medicine, pediatrics, and general surgery programs that accepted our graduates between 2005 and 2010. Program directors were asked to rate a list of radiology knowledge and skills topics as essential or nonessential and to answer several questions regarding their residents and programs. RESULTS: Ninety-nine surveys were completed (51.3% response rate). Seven skills were considered essential by 90% or more of all respondents. On average, program directors identified 18/28 topics as essential prior to beginning their residency. The mean number identified as essential did not differ by program (F4, 93 = 0.732, P = .572). Based on analyses of variance comparing each topic by program, the importance of six topics differed significantly. Program directors generally agreed that incoming residents had adequate radiology skills and knowledge when they started their residencies. One hundred percent of the responding emergency medicine, family medicine, and pediatrics programs and 70% to 80% of the general surgery and internal medicine programs provide radiology training. CONCLUSION: There is high agreement among program directors regarding imaging topics they consider essential. Topics considered essential by more than 60% should comprise our core curriculum for all students while less essential topics can be included in elective or program specific curricula. PMID- 23452471 TI - Fourth-year medical student opinions and basic knowledge regarding the field of radiology. AB - RATIONALE AND OBJECTIVES: This study evaluates the opinions and knowledge of fourth-year US medical students regarding radiology and analyzes the influence of a required or nonrequired radiology rotation as a reflection of the effectiveness of radiology medical student education. METHODS AND MATERIALS: Our institutional review board granted exempt status. An invitation e-mail was sent to 137 US medical schools. Upon receiving approval a second email was sent containing our voluntary anonymous online survey hyperlink to forward to their fourth-year class. Survey topics included demographics, radiology educational experiences, attitudes toward the field, and basic radiology knowledge. Responses were collected between August 4 and September 26, 2011. RESULTS: A total of 444 fourth year medical students from 37 medical schools participated: 89% planned to enter a nonradiology specialty, 10.8% were required to take a dedicated radiology rotation, 34.9% completed one, 77% planned to complete one by graduation, 88.4% thought radiology often changes patient care or is at least as important as physical exam, 91.4% underestimated the cancer risk of an abdomen and pelvis computed tomography by at least one order of magnitude, and 72.9% by at least two orders. Seventy-seven percent had never heard of the American College of Radiology (ACR) Appropriateness Criteria. Respondents underestimated the potential risks of magnetic resonance imaging (MRI); with 58.3% aware intravenous gadolinium can cause nephrogenic systemic fibrosis and 79.4% aware of potential injury from metallic projectiles. 40.4% indicated that non-radiologist clinicians in specific medical specialties interpret their respective imaging studies at least as accurately as corresponding subspecialty radiologists. Other results include student opinions regarding teleradiology, radiologist lifestyle, and compensation. CONCLUSIONS: Fourth-year medical students recognize the importance of radiology but are poorly informed regarding radiation safety, MRI safety, and ACR Appropriateness Criteria, despite 34.9% having a dedicated rotation. This highlights the need for adoption of the Alliance of Medical Student Educators in Radiology curriculum. PMID- 23452472 TI - Radiology medical student education: an outcome-based survey of PGY-1 residents. AB - RATIONALE AND OBJECTIVES: Postgraduate year (PGY)-1 residents are frequently required to order imaging studies and make preliminary interpretations on them. This study determines whether PGY-1 residents feel their radiology education in medical school sufficiently trained them for the clinical responsibilities of internship. MATERIALS AND METHODS: This multicenter, institutional review board approved survey asked PGY-1 trainees three categories of questions: 1) extent of medical school training for ordering and interpreting imaging studies, 2) confidence levels in ordering appropriate imaging studies and making common/emergent diagnoses, and 3) rating the importance of radiologic interpretation by interns. Respondents also submitted ideas for medical school teaching topics deemed most useful for interns. RESULTS: A total of 175 questionnaires were returned with good representation across specialties. Although 63.7% of interns were frequently asked to independently preview radiology studies, 12.6% received no formal radiology training in medical school. Participants rated chest radiographs as the most important study for interns to competently interpret (93.4% reporting very or extremely important). However, only 60.2% of interns reported high confidence in recognizing common/emergent pulmonary findings, and 56.3% for evaluating line and tube position. With regard to ordering imaging studies, 81.0% had never used or never heard of the American College of Radiology Appropriateness Criteria(r). Only 33.1% had high confidence in knowing when to order oral/intravenous contrast. Similar low percentages had high confidence identifying and premedicating contrast allergies (36.4%) and knowing risk factors of nephrogenic systemic fibrosis (13.2%). CONCLUSIONS: PGY-1 residents feel that medical school curriculum emphasizing interpretation of chest radiographs and ordering appropriate imaging studies would better prepare students for the responsibilities of internship. PMID- 23452473 TI - Radiology ExamWeb: development and implementation of a national web-based examination system for medical students in radiology. AB - RATIONALE AND OBJECTIVES: Faculty are often limited in time, knowledge, and resources to develop efficient, effective, and valid computer-based examinations to evaluate students. Our purpose was to develop a web-based pool of standardized National Board of Medical Examiners (NBME)-format, peer-reviewed, and peer-tested questions based on the Alliance of Medical Student Educators in Radiology (AMSER) National Medical Student Curriculum to evaluate the radiologic knowledge of medical students. MATERIALS AND METHODS: Members of the AMSER Electronics Committee submitted questions they had written for their institutions and later developed a 113-question standardized examination. Questions were edited by 24 subspeciality editors and then further edited by the authors to NBME recommendations. Software was developed using commercially available software (www.ExamWeb.com) with extensive modifications and additions following initial deployment. Students take examinations online and receive their scores immediately. Items were validated by identifying those answered >30 times and analyzing the following: number of times deployed, number of times correctly answered, distractor-specific breakdown, difficulty level (P), and point biserial coefficient (rbi). RESULTS: Radiology ExamWeb (REW) is available online with 3500 registered students from 65 institutions and 1800 active questions. Instructors can create examinations or use "shared examinations" made by another instructor but enabled for other institutions to administer or modify. More than 300 shared examinations have been developed. The AMSER curriculum was converted into database format and crosschecked with question items to ensure that the question pool adequately covered the spectrum of the curriculum. An AMSER standardized examination has been developed and deployed within REW. CONCLUSIONS: REW has provided medical student educators with the means to evaluate students in a systematic way, using a nationally edited and regularly reviewed web-based process. PMID- 23452474 TI - The role of radiology in preclinical anatomy: a critical review of the past, present, and future. AB - RATIONALE AND OBJECTIVES: Radiology has been an increasingly important component of preclinical anatomy instruction since the 1960s. The global status of medical imaging pedagogies and radiologists' roles in medical anatomy education is not well established but is important in determining the specialty's contribution to undergraduate medical education. MATERIALS AND METHODS: PubMed was searched with various combinations of MeSH terms including "radiology," "undergraduate medical education," and "anatomy." Articles were reviewed for relevance, and referenced articles of possible relevance were hand-traced to ensure a wide capture of articles. RESULTS: Although more medical schools around the world are using medical imaging to teach anatomy, some regions, such as the United States, show a decline in the proportion of imaging taught by radiologists. Lectures, small group discussions, and self-instruction remain the mainstay of current pedagogies and have witnessed dramatic changes over the past few decades with respect to the types of imaging used. Newer pedagogies use contextual and hands-on experiences to improve spatial and application principles. Qualitative and quantitative studies report somewhat mixed results of pedagogical efficacies but demonstrate generally high acceptance by students and instructors and often significant exam score improvement. Radiology as a specialty must overcome several challenges for it to become more involved in anatomy education, including teaching incentives and protected academic time. CONCLUSIONS: As anatomy instruction and clinical medicine grow increasingly digital, it is ever more important that radiologists continue to develop new anatomy pedagogies and contribute to anatomy education in greater roles. PMID- 23452475 TI - Increased error rates in preliminary reports issued by radiology residents working more than 10 consecutive hours overnight. AB - RATIONALE AND OBJECTIVES: To determine if the rate of major discrepancies between resident preliminary reports and faculty final reports increases during the final hours of consecutive 12-hour overnight call shifts. MATERIALS AND METHODS: Institutional review board exemption status was obtained for this study. All overnight radiology reports interpreted by residents on-call between January 2010 and June 2010 were reviewed by board-certified faculty and categorized as major discrepancies if they contained a change in interpretation with the potential to impact patient management or outcome. Initial determination of a major discrepancy was at the discretion of individual faculty radiologists based on this general definition. Studies categorized as major discrepancies were secondarily reviewed by the residency program director (M.H.S.) to ensure consistent application of the major discrepancy designation. Multiple variables associated with each report were collected and analyzed, including the time of preliminary interpretation, time into shift study was interpreted, volume of studies interpreted during each shift, day of the week, patient location (inpatient or emergency department), block of shift (2-hour blocks for 12-hour shifts), imaging modality, patient age and gender, resident identification, and faculty identification. Univariate risk factor analysis was performed to determine the optimal data format of each variable (ie, continuous versus categorical). A multivariate logistic regression model was then constructed to account for confounding between variables and identify independent risk factors for major discrepancies. RESULTS: We analyzed 8062 preliminary resident reports with 79 major discrepancies (1.0%). There was a statistically significant increase in major discrepancy rate during the final 2 hours of consecutive 12 hour call shifts. Multivariate analysis confirmed that interpretation during the last 2 hours of 12-hour call shifts (odds ratio (OR) 1.94, 95% confidence interval (CI) 1.18-3.21), cross-sectional imaging modality (OR 5.38, 95% CI 3.22 8.98), and inpatient location (OR 1.81, 95% CI 1.02-3.20) were independent risk factors for major discrepancy. CONCLUSIONS: In a single academic medical center, major discrepancies in resident preliminary reports increased significantly during the final 2 hours of consecutive 12-hour overnight call shifts. This finding could be related to either fatigue or circadian desynchronization. Discrimination of these two potential etiologies requires additional investigation as major discrepancies in resident reports have the potential to negatively impact patient care/outcome. Cross-sectional imaging modalities including computed tomography and ultrasound (versus conventional radiography), as well as inpatient location (versus Emergency Department location), were also associated with significantly higher major discrepancy rates. PMID- 23452476 TI - Residents' perception of a novel end-of-rotation evaluation method. AB - RATIONALE AND OBJECTIVES: With the advent of the new core and certifying examinations, a need has arisen to restructure learning and assessment to better reflect the emphasis on continuous learning throughout residency. We developed a multiparametric end-of-rotation (EOR) evaluation tool to assess medical knowledge, oral presentation, and written communication skills administered to the residents at the end of each core subspecialty rotation. The benefit of continual assessment is obvious from a program perspective; the purpose of this article is to evaluate the residents' perception of the process. MATERIALS AND METHODS: All residents (n = 31, 28 postgraduate years two through five and 3 postgraduate year one) participate in the mandatory EOR evaluation as a required component of the residency program. After receiving Institutional Review Board approval, informed consent was obtained from the residents wishing to participate in quarterly 16-question online surveys assessing their experience. Each survey consists of 15 questions with Likert scale responses (1 through 5 from strongly disagree to strongly agree) and one free text answer. Data are collected quarterly, starting in September 2011. RESULTS: Overall, the residents' response has been positive. The new evaluation method is felt to be more meaningful than (average 3.9, standard deviation 0.9) and is favored by the residents over the traditional competency-based evaluation (average 4.0, standard deviation 1.0). However, residents retain neutral attitudes regarding preparation for boards or changes in study habits (average score 3.6, standard deviation 0.9 and 3.6, and standard deviation 1.1, respectively). CONCLUSION: Residents rate the EOR evaluation experience positively, although they do not report changes in study habits or increased preparedness for the new certifying examination. PMID- 23452477 TI - Results of the 2012 survey of the American Association of Academic Chief Residents in Radiology. AB - RATIONALE AND OBJECTIVE: Every year, the American Association of Academic Chief Residents in Radiology conducts a survey of the chief residents in accredited radiology training programs in North America. The survey serves as a tool for gathering information, sharing ideas, and voicing opinions. MATERIALS AND METHODS: An online survey was made available to the chief residents from 187 training programs in North America. Questions were presented in multiple-choice and free response formats, designed to address many issues ranging from program structure to on-call policies, changes for the new board examination format and fellowships, and the effects of health care reform on radiology practices. The results of the survey were tabulated and responses to the repeated questions were compared with those from earlier surveys dating to 2003. RESULTS: Among those surveyed, 185 individual responses representing 135 unique programs were completed, yielding a 73% response rate. Thirty-eight percent of programs responded from the northeast and 17% of programs responded from the southeast. Nineteen percent of responses were from central United States, 14% of responses were from western United States, and 12% of responses were from Canada. CONCLUSIONS: There is an increasing number of programs, which cover more hospitals, during the past decade. There are more programs providing ultrasound and magnetic resonance services after hours, with an associated increase in after hours attending physician coverage. Many changes are being made for the future board examination format. Health care reform is affecting how residents are preparing themselves for their future practices. PMID- 23452478 TI - Introductory lecture series for first-year radiology residents: implementation, investment and assessment. AB - RATIONALE AND OBJECTIVES: A lecture series aimed at providing new radiology residents a rapid course on the fundamental concepts of professionalism, safety, and interpretation of diagnostic imaging was established. Evaluation of the course's educational value was attempted through surveys. MATERIALS AND METHODS: Twenty-six live 45-minute lectures presented by 16 or 17 faculty members were organized exclusively for the first class of radiology residents, held over a 2 month period at the beginning of certain weekdays. Online surveys were conducted after the course to gather feedback from residents. Average resident rotation evaluation scores were measured over the first semester for the two classes before and after this new course implementation. RESULTS: The lecture series was successfully organized and implemented. A total of 33 residents sat through the course over three summers. Faculty reported a reasonable number of preparation hours, and 100% of residents indicated they valued the course. Comparison of class average evaluation scores before and after the existence of this 2-month course did not significantly change. CONCLUSIONS: This collection of introductory lectures on professionalism, safety, and diagnostic imaging, delivered early in the first year of the radiology residency, requires a reasonable number of invested preparation hours by the faculty but results in a universal increase in resident confidence. However, we were unable to demonstrate an objective improvement in resident performance on clinical rotations. PMID- 23452479 TI - A web based Foundations of Radiological Physics for diagnostic radiology residents. AB - RATIONALE AND OBJECTS: We describe a new web-based physics course for radiology residents preparing for the Exam of the Future (EOF). MATERIALS AND METHODS: A course was developed with a total of 12 web-based modules. Six modules were focused on "imaging" and six on "radiation." A module was subdivided into nine short "nuggets." Traditional lectures were replaced by modules using prerecorded lectures (Tegrity) to a secure website (WebCT). Each module was accompanied by three quizzes, each consisting of ten questions designed to reinforce covered materials. All online modules were accompanied by a noon conference that employed an Audience Response System (Turning Point). Seventeen first-year residents over 2 consecutive years beginning in July 2010 took this new course, and participated in an anonymous online follow-up survey (Survey Monkey). RESULTS: The recorded 12 modules had an overall average duration of 72 +/- 19 minutes. Ten of 17 residents expressed a preference of 15 minutes for nugget duration. Highest personal assessment scores of each resident's understanding were obtained in human radiation risks and radiation protection. Residents considered supplemental noon conferences to be important for learning radiological physics. Satisfaction level was largely positive, with five residents highly satisfied, nine residents somewhat satisfied, two residents neutral, and only one resident somewhat dissatisfied. CONCLUSIONS: Our Foundations of Radiological Physics course was well received and served as the springboard for mastering x-ray-based imaging modalities of radiography, mammography, fluoroscopy, interventional radiology, and computed tomography. PMID- 23452480 TI - Teaching medical management and operations engineering for systems-based practice to radiology residents. AB - RATIONALE AND OBJECTIVES: To better prepare radiology residents for providing care within the context of the larger health care system, this study evaluated the feasibility and impact of a curriculum to enhance radiology residents' understanding and ability to apply concepts from medical management and industrial and operational engineering to systems-based practice problems in radiology practice. MATERIALS AND METHODS: A multiprofessional team including radiology, medical education, and industrial and operational engineering professionals collaborated in developing a seven-module curriculum, including didactic lectures, interactive large-group analysis, and small-group discussions with case-based radiology examples, which illustrated real-life management issues and the roles physicians held. Residents and faculty participated in topic selection. Pre- and post-instruction formative assessments were administered, and results were shared with residents during teaching sessions. RESULTS: Attendance and participation in case-based scenario resolutions indicate the feasibility and impact of the interactive curriculum on residents' interest and ability to apply curricular concepts to systems-based practice in radiology. Paired t test analyses (P < .05) and effect sizes showed residents significantly increased their knowledge and ability to apply concepts to systems-based practice issues in radiology. CONCLUSIONS: Our iterative curriculum development and implementation process demonstrated need and support for a multiprofessional team approach to teach management and operational engineering concepts. Curriculum topics are congruent with Accreditation Council for Graduate Medical Education requirements for systems-based practice. The case-based curriculum using a mixed educational format of didactic lectures and small-group discussion and problem analysis could be adopted for other radiology programs, for both residents and continuing medical education applications. PMID- 23452481 TI - Improving accuracy in reporting CT scans of oncology patients: assessing the effect of education and feedback interventions on the application of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. AB - RATIONALE AND OBJECTIVES: In February 2010, our radiology department adopted the use of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for newly diagnosed oncology patients. Prior to staff used RECIST 1.1, we hypothesized that education and feedback interventions could help clarify differences between RECIST 1.0 and the newly adopted RECIST 1.1 guidelines and result in appropriate and accurate utilization of both reporting systems. This study evaluates the effect of education and feedback interventions on the accuracy of computed tomography (CT) reporting using RECIST criteria. MATERIALS AND METHODS: Consecutive CT scan reports and images were retrospectively reviewed during three different periods to assess for compliance and adherence to RECIST guidelines. Data collected included interpreting faculty, resident, type, and total number of errors per report. Significance testing of differences between cohorts was performed using an unequal variance t-test. Group 1 (baseline): RECIST 1.0 used; prior to adoption of RECIST 1.1 criteria. Group 2 (post distributed educational materials): Following adoption of RECIST 1.1 criteria and distribution of educational materials. Group 3 (post audit and feedback): Following the audit and feedback intervention. RESULTS: The percentage of reports with errors decreased from 30% (baseline) to 28% (group 2) to 22% (group 3). Only the difference in error rate between the baseline and group 3 was significant (P = .03). CONCLUSION: The combination of distributed educational materials and audit and feedback interventions improved the quality of radiology reports requiring RECIST criteria by reducing the number of studies with errors. PMID- 23452482 TI - Learning objectives in radiology education: why you need them and how to write them. AB - Learning objectives are a critical step in the creation and implementation of a radiology curriculum. Their use is mandated by the Liaison Committee on Medical Education, the Accreditation Council on Graduate Medical Education, and the Accreditation Council on Continuing Medical Education, but more importantly they can have a significant beneficial impact on quality of radiology education programs. Learning objectives guide student learning, help clarify our teaching goals, and simplify learner testing and evaluation. This article will review the components of a proper learning objective and provide a simple, straightforward approach to writing them effectively. PMID- 23452484 TI - Radiology education 2.0--on the cusp of change: part 2. eBooks; file sharing and synchronization tools; websites/teaching files; reference management tools and note taking applications. AB - Increasing use of smartphones and handheld computers is accompanied by a rapid growth in the other related industries. Electronic books have revolutionized the centuries-old conventional books and magazines markets and have simplified publishing by reducing the cost and processing time required to create and distribute any given book. We are now able to read, review, store, and share various types of documents via several electronic tools, many of which are available free of charge. Additionally, this electronic revolution has resulted in an explosion of readily available Internet-based educational resources for the residents and has paved the path for educators to reach out to a larger and more diverse student population. PMID- 23452483 TI - Radiology education 2.0--on the cusp of change: part 1. Tablet computers, online curriculums, remote meeting tools and audience response systems. AB - We are in the midst of an evolving educational revolution. Use of digital devices such as smart phones and tablet computers is rapidly increasing among radiologists who now regularly use them for medical, technical, and administrative tasks. These electronic tools provide a wide array of new tools to the radiologists allowing for faster, more simplified, and widespread distribution of educational material. The utility, future potential, and limitations of some these powerful tools are discussed in this article. PMID- 23452485 TI - Practical considerations to setting up a radiology CME conference: how we do it. AB - The authors describe our experience in planning, organizing, and running a radiology CME conference at a hotel (rather than at a stand-alone conference or convention center). Much of the information described should also be useful for other medical and nonmedical conferences. This experience should provide new conference organizers with useful information to ensure a more efficient and successful conference, so there are fewer "If I knew then what I know now" moments over the years. PMID- 23452486 TI - Teaching radiology in the millennial era. PMID- 23452487 TI - Quantum dots in bioanalysis: a review of applications across various platforms for fluorescence spectroscopy and imaging. AB - Semiconductor quantum dots (QDs) are brightly luminescent nanoparticles that have found numerous applications in bioanalysis and bioimaging. In this review, we highlight recent developments in these areas in the context of specific methods for fluorescence spectroscopy and imaging. Following a primer on the structure, properties, and biofunctionalization of QDs, we describe select examples of how QDs have been used in combination with steady-state or time-resolved spectroscopic techniques to develop a variety of assays, bioprobes, and biosensors that function via changes in QD photoluminescence intensity, polarization, or lifetime. Some special attention is paid to the use of Forster resonance energy transfer-type methods in bioanalysis, including those based on bioluminescence and chemiluminescence. Direct chemiluminescence, electrochemiluminescence, and charge transfer quenching are similarly discussed. We further describe the combination of QDs and flow cytometry, including traditional cellular analyses and spectrally encoded barcode-based assay technologies, before turning our attention to enhanced fluorescence techniques based on photonic crystals or plasmon coupling. Finally, we survey the use of QDs across different platforms for biological fluorescence imaging, including epifluorescence, confocal, and two-photon excitation microscopy; single particle tracking and fluorescence correlation spectroscopy; super-resolution imaging; near-field scanning optical microscopy; and fluorescence lifetime imaging microscopy. In each of the above-mentioned platforms, QDs provide the brightness needed for highly sensitive detection, the photostability needed for tracking dynamic processes, or the multiplexing capacity needed to elucidate complex systems. There is a clear synergy between advances in QD materials and spectroscopy and imaging techniques, as both must be applied in concert to achieve their full potential. PMID- 23452488 TI - Vibrational sum-frequency spectroscopy for trace chemical detection on surfaces at stand-off distances. AB - Vibrational sum-frequency spectroscopy (VSFS) has been used for some time as a laboratory-based surface chemical analytical tool. Here, theoretical considerations in applying the method as a remote-sensing probe for detecting trace levels of chemicals adsorbed on surfaces are presented. Additionally, a VSFS instrument is configured to operate at a stand-off distance of 2.2 m using near-nadir incidence angles. This system was used to measure VSFS spectra for films of pure 1-amino-4-nitrobenzene (p-nitroaniline, PNA) and pure 2-hydroxy 1,3,5-trinitrobenzene (picric acid, PA) adsorbed on polished T-6061 aluminum alloy. These spectra are used to investigate the effect of optical polarization on the sum-frequency response of these compounds at nadir optical geometries. Detection limits for each compound are also estimated and found to be 0.51 MUg cm(2) for PNA and 0.89 MUg cm(2) for PA. The implications of these results regarding remote sensing applications of VSFS are discussed. PMID- 23452489 TI - The water-hydrophobic interface: neutral and charged solute adsorption at fluorocarbon and hydrocarbon self-assembled monolayers (SAMs). AB - Adsorption of small molecular solutes in an aqueous solution to a soft hydrophobic surface is a topic relevant to many fields. In biological and industrial systems, the interfacial environment is often complex, containing an array of salts and organic compounds in the solution phase. Additionally, the surface itself can have a complex structure that can interact in unpredictable ways with small solutes in its vicinity. In this work, we studied model adsorption processes on hydrocarbon and fluorocarbon self-assembled monolayers by using vibrational sum frequency spectroscopy, with methanol and butylammonium chloride as adsorbates. The results indicate that differences in surface functionality have a significant impact on the organization of adsorbed organic species at hydrophobic surfaces. PMID- 23452490 TI - Potential of Fourier transform infrared spectroscopy (FT-IR) to differentiate environmental Aspergillus fungi species A. niger, A. ochraceus, and A. westerdijkiae using two different methodologies. AB - We assessed the ability of Fourier transform infrared spectroscopy (FT-IR) to differentiate three important and morphologically similar Aspergillus species: A. ochraceus and A. westerdijkiae, and A. niger. Fungi were processed by two methods, powdered mycelia and conidiospore-saline solution, and then recorded in a spectrometer. Second derivatives with nine points of smoothing were applied as spectra data pretreatment. Partial least squares regression was used for the species comparison models and a prediction test was used to evaluate the models. The powdered-mycelia methodology correctly identified 100% of the prediction test set to discriminate A. niger from A. ochraceus and A. westerdijkiae; in addition, it had a 86.6% success rate in discriminating A. ochraceus and A. westerdijkiae. This is the first time a study assessed the ability of FT-IR to differentiate A. niger, A. ochraceus, and A. westerdijkiae, and we believe this technique is very promising for classifying and distinguish fungi isolates. PMID- 23452491 TI - Photoluminescence and visible diffuse-reflection spectroscopic evidence of samarium reduction in air-fired samples of mixed samarium: strontium tetraborate precipitates. AB - Photoluminescence and visible diffuse-reflection spectroscopies have provided evidence of the reduction of samarium to the divalent state in samarium-doped strontium borate and pure samarium borate samples. The samples were prepared by the air firing of homogeneous precipitates of divalent strontium and trivalent samarium ions from aqueous solutions with saturated sodium tetraborate. The use of this method in the preparation of divalent lanthanide ions has not been reported previously. Reduced samarium was observed in fired tetraborate precipitates prepared with solutions containing 1, 5, 10, 25, 50, 75, and 90 mole percent samarium versus strontium. Divalent samarium also was identified in fired precipitates of trivalent samarium solutions precipitated with tetraborate. Sm(2+) was identified as the primary emitting species in each of the eight compositions. However, diffuse-reflection spectroscopy indicated the presence of trivalent samarium in the studied samples, ranging from minimal for samples prepared with low samarium concentrations to nearly exclusive when pure samarium was studied. Quenching of the characteristic emission associated with the trivalent species is believed to result in the absence of the emission features arising from residual samarium(III) in the products. Although the absence of trivalent samarium emission enhanced the ability of emission spectroscopy to identify small amounts of divalent samarium, indicating that reduction had occurred, it limited the ability of this method to determine the extent of the reduction. Diffuse-reflection spectroscopy's ability to look at both species provided a much better analysis of the extent of samarium reduction. PMID- 23452492 TI - Insight into resolution enhancement in generalized two-dimensional correlation spectroscopy. AB - Generalized two-dimensional correlation spectroscopy (2D-COS) can be used to enhance spectral resolution in order to help differentiate highly overlapped spectral bands. Despite the numerous extensive 2D-COS investigations, the origin of the 2D spectral resolution enhancement mechanism(s) is not completely understood. In the work here, we studied the 2D-COS of simulated spectra in order to develop new insights into the dependence of 2D-COS spectral features on the overlapping band separations, their intensities and bandwidths, and their band intensity change rates. We found that the features in the 2D-COS maps that are derived from overlapping bands were determined by the spectral normalized half intensities and the total intensity changes of the correlated bands. We identified the conditions required to resolve overlapping bands. In particular, 2D-COS peak resolution requires that the normalized half-intensities of a correlating band have amplitudes between the maxima and minima of the normalized half-intensities of the overlapping bands. PMID- 23452493 TI - A nonlinearized multivariate dominant factor-based partial least squares (PLS) model for coal analysis by using laser-induced breakdown spectroscopy. AB - A nonlinearized multivariate dominant factor-based partial least-squares (PLS) model was applied to coal elemental concentration measurement. For C concentration determination in bituminous coal, the intensities of multiple characteristic lines of the main elements in coal were applied to construct a comprehensive dominant factor that would provide main concentration results. A secondary PLS thereafter applied would further correct the model results by using the entire spectral information. In the dominant factor extraction, nonlinear transformation of line intensities (based on physical mechanisms) was embedded in the linear PLS to describe nonlinear self-absorption and inter-element interference more effectively and accurately. According to the empirical expression of self-absorption and Taylor expansion, nonlinear transformations of atomic and ionic line intensities of C were utilized to model self-absorption. Then, the line intensities of other elements, O and N, were taken into account for inter-element interference, considering the possible recombination of C with O and N particles. The specialty of coal analysis by using laser-induced breakdown spectroscopy (LIBS) was also discussed and considered in the multivariate dominant factor construction. The proposed model achieved a much better prediction performance than conventional PLS. Compared with our previous, already improved dominant factor-based PLS model, the present PLS model obtained the same calibration quality while decreasing the root mean square error of prediction (RMSEP) from 4.47 to 3.77%. Furthermore, with the leave-one-out cross validation and L-curve methods, which avoid the overfitting issue in determining the number of principal components instead of minimum RMSEP criteria, the present PLS model also showed better performance for different splits of calibration and prediction samples, proving the robustness of the present PLS model. PMID- 23452494 TI - Optimization of hollow waveguides as absorption cells for spectroscopic gas sensing. AB - Flexible and low-loss hollow waveguide has many advantages as an absorption cell for spectroscopic gas sensing. The characteristics of the sensing system are dependent on the parameters of the hollow waveguide cell. In this paper, a mathematical model was proposed to analyze the waveguide cell by considering waveguide loss, effective optical path length, and signal-to-noise ratio of the system. Simulation results show that the gas absorption intensity and system sensitivity are dependent not only on the waveguide length but also on the bore diameter, signal-to-noise ratio, and the concentration of the target gases. The results provide optimizing methods for the sensing system and algorithms for error compensation. Preliminary experiments on concentration detection of methane gas were carried out and measured data showed good agreements with the simulation results. PMID- 23452495 TI - Structural differences between cold- and melt-crystallized poly(trimethylene terephthalate) samples. AB - Time-resolved Fourier transform infrared spectroscopy was used to investigate the structural differences between cold- and melt-crystallized poly(trimethylene terephthalate) (PTT) samples. To elucidate the arrangement of different chain segments in the crystalline phase obtained through different crystallization processes, characteristic bands associated with the phenylene rings, the CH2 segments, and the C-O-C segments were followed during the cold and the melt crystallizations. The results show that the alignment of the phenylene rings and the C=O groups in the PTT crystals produced via cold- and melt-crystallization processes are essentially the same, while the alignment of the CH2 segments depends on the crystallization condition. It was found that the CH2 segments in the melt-crystallized sample were more stable than those in the cold-crystallized sample. This was ascribed to the different crystallization environment. Melt crystallized PTT chains have higher mobility, and the variation of flexible segments is quicker than that of the rigid segments. However, in cold crystallization, the CH2 segments are restricted by the adjacent environment in the glass state, which weakens their capability of transforming their conformation; this leads to a cooperative change of CH2 segments, phenylene rings, and C=O groups. Therefore, the stability of CH2 segments in crystalline structure is lowered accordingly. PMID- 23452496 TI - Comparison of three schemes of two-photon laser-induced fluorescence for CO detection in flames. AB - Two-photon excitation laser-induced fluorescence of carbon monoxide suffers from interference from mainly C2 and strong pressure quenching. This paper presents an investigation of three excitation/detection schemes for two-photon excitation laser-induced fluorescence on carbon monoxide. The schemes are evaluated for pressure and quenching partner dependencies and C2 interference. Three different emission bands lie in the Hopefield-Birge system: The Angstrom B(1)Sigma(+) >A(1)Piu band, with two-photon excitation through B(1)Sigma(+)<-X(1)Pi around 230 nm; the Herzberg band C(1)Sigma(+)->A(1)Piu, with two-photon excitation through, C(1)Sigma(+)<-X(1)Pi, around 217 nm; and the third positive group b(3)Sigma >a(3)Pi, also with excitation of B(1)Sigma(+)<-X(1)Pi around 230 nm. The measurements are performed in laminar premixed flames with various equivalence ratios as well as in a high-pressure cell, where pressure and species concentrations are varied in order to investigate the fluorescence quenching dependence. PMID- 23452497 TI - Investigation of temperature dependent multi-walled nanotube G and D doublet using pseudo-Voigt functions. AB - A pseudo-Voigt (PV) function is used as a representation of the Stoke's phonon frequency distributions for a multi-walled nanotube (MWNT) composite G and D doublet. Variable peak assignments with the PV function have been shown to enhance the resolution of these bands commonly used for characterization of carbon nanotube (CNT) composites. The peak assignment study was applied to an in situ temperature experiment where the addition of new sub-bands in the G and D doublet was determined to reduce the uncertainty of the Raman characteristics. Fitting the spectrum with five pseudo-Voigt bands was concluded to give the most consistent results, producing the lowest uncertainty values for G-peak position (nuG) and D/G intensity ratio. PMID- 23452498 TI - The effect of standing acoustic waves on the formation of laser-induced air plasmas. AB - The expected location of an air plasma produced by a focused YAG laser pulse has been found to be influenced by the acoustics of the surrounding environment. In open air, the expected location of a laser-induced air plasma is centered close to the focal point of the lens focusing the laser beam. When confining the same beam coaxially along the interior of a quartz tube, the expected location of the air plasma shifts away from the focal point, toward the focusing lens, in a region of less laser fluence. This shift is caused by an interaction between standing acoustic waves (formed from sound waves produced by previous laser induced plasmas) and the impinging laser pulse. Standing acoustic waves in a tube produce areas (antinodes) of slightly higher and slightly lower pressure than ambient atmospheric conditions, that in turn have a noticeable affect on the probability of creating an air plasma at a given location. This leads to two observed phenomena: Increased probability of air plasma formation before the optical focal point is reached, and the formation of distinct (separate) air plasmas at the antinodes themselves. PMID- 23452499 TI - Increasing the quantitative credibility of open-path Fourier transform infrared (FT-IR) spectroscopic data, with focus on several properties of the background spectrum. AB - The choice of the type of background spectrum affects the credibility of open path Fourier transform infrared spectroscopy (OP/FT-IR) data, and consequently, the quality of data analysis. We systematically investigated several properties of the background spectrum. The results show that a short-path background measured with the lowest amplifier gain could significantly reduce noise in the calculated absorbance spectrum, by at least 30% in our case. We demonstrated that by using a short-path background, data analysis is more resistant to interferences such as wavenumber shift or resolution alteration that occurs as a consequence of aging hardware or misalignment. We discussed a systematic error introduced into quantitative analyses by the short-path background and developed a procedure to correct that error. With this correction approach, a short-path background established five years ago was still found to be valid. By incorporating these findings into the protocol for quantitative analysis, we processed the measurements with two OP/FT-IR instruments set up side by side in the vicinity of a large dairy farm, to monitor NH3, CH4, and N2O. The two sets of calculated concentrations showed high agreement with each other. The findings of our investigations are helpful to atmospheric monitoring practitioners of OP/FT IR spectroscopy and could also be a reference for future amendments to the protocols outlined in the guidelines of the U.S. Environmental Protection Agency, the American Society for Testing and Materials, and the European Committee for Standardization. PMID- 23452500 TI - Pollen identification by Fourier transform infrared photoacoustic spectroscopy. AB - Fourier transform infrared photoacoustic spectroscopy (FT-IR-PAS) has been applied to the problem of identifying pollen samples. One hundred measurements were made on a set of pollen samples comprising five families and ten species. Chemometric analysis of the resulting spectra showed evidence of clustering. Construction of a spectral library allowed pollens in the set to be correctly identified as the first match on the basis of photoacoustic spectra at the species (99%) or family (100%) level. PMID- 23452501 TI - A subcutaneous Raman needle probe. AB - Raman spectroscopy is a powerful tool for studying the biochemical composition of tissues and cells in the human body. We describe the initial results of a feasibility study to design and build a miniature, fiber optic probe incorporated into a standard hypodermic needle. This probe is intended for use in optical biopsies of solid tissues to provide valuable information of disease type, such as in the lymphatic system, breast, or prostate, or of such tissue types as muscle, fat, or spinal, when identifying a critical injection site. The optical design and fabrication of this probe is described, and example spectra of various ex vivo samples are shown. PMID- 23452503 TI - Chemoprophylaxis and treatment of African canine trypanosomosis in French military working dogs: a retrospective study. AB - African trypanosomosis is a major threat to livestock production in sub-Saharan Africa. Although the disease mainly concerns cattle, dogs can also be infected by Trypanosoma spp. transmitted by tsetse flies. Between 1997 and 2003, the parasite Trypanosoma congolense was identified in French military dogs sent to Africa. On infected dogs, the diagnosis was made during the mission or just after the return to France, depending on when the symptoms appeared. The high incidence and mortality rate among these dogs led veterinarians of the French Health Service to implement a systematic chemoprophylaxis beginning in 2004. Between 2004 and 2011, the chemoprophylaxis was carried out on more than 400 military dogs. The protocol of chemoprophylaxis relies on the use of isometamidium chloride (Trypamidium((r)), Merial). The drug has been used successfully at the dosage of 1mg/kg body weight by deep intramuscular injection, every two or three months. In addition, dogs are given collars impregnated with deltamethrin (Scalibor((r)), MSD Animal Health). Isometamidium chloride was also used successfully in the treatment of military dogs infected with T. congolense, with a full recovery and without any relapses. PMID- 23452502 TI - Diabetes, perioperative ischaemia and volatile anaesthetics: consequences of derangements in myocardial substrate metabolism. AB - Volatile anaesthetics exert protective effects on the heart against perioperative ischaemic injury. However, there is growing evidence that these cardioprotective properties are reduced in case of type 2 diabetes mellitus. A strong predictor of postoperative cardiac function is myocardial substrate metabolism. In the type 2 diabetic heart, substrate metabolism is shifted from glucose utilisation to fatty acid oxidation, resulting in metabolic inflexibility and cardiac dysfunction. The ischaemic heart also loses its metabolic flexibility and can switch to glucose or fatty acid oxidation as its preferential state, which may deteriorate cardiac function even further in case of type 2 diabetes mellitus.Recent experimental studies suggest that the cardioprotective properties of volatile anaesthetics partly rely on changing myocardial substrate metabolism. Interventions that target at restoration of metabolic derangements, like lifestyle and pharmacological interventions, may therefore be an interesting candidate to reduce perioperative complications. This review will focus on the current knowledge regarding myocardial substrate metabolism during volatile anaesthesia in the obese and type 2 diabetic heart during perioperative ischaemia. PMID- 23452504 TI - Prevalence of sexual, physical and emotional abuse in the Norwegian mother and child cohort study. AB - BACKGROUND: Abuse of women occurs in every society of the world. Increased information about the prevalence in industrialized countries, like Norway, is required to make strategies to prevent abuse. Our aim was to investigate the prevalence of self-reported sexual, physical and emotional abuse in a large obstetric population in Norway, and the associations between exposure to adult abuse, socio-demographics and other characteristics. METHODS: Our study is based on the Norwegian Mother and Child (MoBa) Cohort study, conducted by the Norwegian Institute of Public Health. The current study included 65,393 women who responded to two extensive postal questionnaires during pregnancy. Any adult abuse is defined as being exposed to one or more types of adult abuse, any child abuse is defined as being exposed to one or more types of child abuse, and any lifetime abuse is defined as being exposed to abuse either as a child and/or as an adult. Perpetrators were categorized as known or stranger. RESULTS: Overall, 32% of the women reported any lifetime abuse, 20% reported any adult abuse, 19% reported any child abuse and 6% reported abuse both as adults and as children. Emotional abuse was the most frequently reported type of abuse both as adults (16%) and children (14%). Adult sexual abuse was reported by 5% and child sexual abuse by 7%. Physical abuse was reported by 6% as adults and by 6% as children. Approximately 30% of those reporting adult or child abuse reported exposure to two or three types of abuse. Five percent of the women reported exposure to any abuse during the last 12 months. For all types of abuse, a known perpetrator was more commonly reported. Logistic regression showed that being exposed to child abuse, smoking and drinking alcohol in the first trimester of pregnancy, living alone, and belonging to the eldest age group were significantly associated with being exposed to any adult abuse. CONCLUSION: The reported prevalence of any lifetime abuse was substantial in our low-risk pregnant population. Antenatal care is an opportunity for clinicians to ask about experiences of abuse and identify those at risk. PMID- 23452505 TI - Angry affect and violence in the context of a psychotic illness: a systematic review and meta-analysis of the literature. AB - A small but significant relationship between schizophrenia and violence is well established, but not yet fully explained. Research has highlighted anger as an important factor in precipitating actual violence in general and psychiatric populations. However, anger has not been extensively studied as a risk factor for violence in people with schizophrenia and related psychoses. We evaluated published evidence on the relationship between anger and violence in patients with schizophrenia and related psychoses by means of a systematic review of the literature. A search of main online databases from inception till January 2012 was performed and supplemented with correspondence with authors and data available online. 11 studies which measured angry affect in patients with schizophrenia who had been violent were included in the review. 5 studies with a total of 510 individuals had anger data that were suitable to be pooled in a meta analysis in form of standardised mean difference values comparing the anger scores of the non-violent groups with violent groups. All the studies included showed significantly higher scores for anger in the violent group compared with the non-violent group with the pooled result expressed as standardised mean difference of 0.74 95% CI (0.53, 0.94) and the Z value for overall effect=7.01. The studies not included in the meta-analysis which looked at 610 individuals, were analysed descriptively and all of them reported higher scores for anger for individuals with schizophrenia who acted violently. There is a consistency of significant association between angry affect and violent behaviour in the context of psychotic illness across various study designs, settings and populations. Theoretical support already exists for this relationship and this review lends further support to explore this relationship further. PMID- 23452506 TI - Adherence therapy following an acute episode of schizophrenia: a multi-centre randomised controlled trial. AB - BACKGROUND: Non-adherence with antipsychotic medication is common in patients with schizophrenia. AIMS: To establish the efficacy of adherence therapy (AT) compared to treatment as usual (TAU) in improving medication compliance in patients following an acute episode of schizophrenia. METHOD: The study was designed as a parallel group, single blind, randomised controlled trial. Fieldwork was conducted in four centres (3 in Germany and 1 in Switzerland) and involved a total of 161 patients. Patients received 8 sessions of AT in addition to treatment as usual. The main outcomes of this study were adherence and psychopathology at 12 weeks post discharge follow up. RESULTS: In total 80 patients received AT and 57 TAU. Intention-to-treat analysis included all randomised patients. Psychopathology, as determined using the PANSS-total, improved in the AT compared to TAU group by a mean of -6.16 points 12 weeks after discharge from hospital (p<.05). AT had no significant effects on patients' adherence, treatment attitudes or functioning. No significant adverse events were reported. CONCLUSION: AT improves psychopathology in patients recovering from an acute episode of schizophrenia. PMID- 23452507 TI - Improved orange and red Ca2+/- indicators and photophysical considerations for optogenetic applications. AB - We have used protein engineering to expand the palette of genetically encoded calcium ion (Ca(2+)) indicators to include orange and improved red fluorescent variants, and validated the latter for combined use with optogenetic activation by channelrhodopsin-2 (ChR2). These indicators feature intensiometric signal changes that are 1.7- to 9.7-fold improved relatively to the progenitor Ca(2+) indicator, R-GECO1. In the course of this work, we discovered a photoactivation phenomenon in red fluorescent Ca(2+) indicators that, if not appreciated and accounted for, can cause false-positive artifacts in Ca(2+) imaging traces during optogenetic activation with ChR2. We demonstrate, in both a beta cell line and slice culture of developing mouse neocortex, that these artifacts can be avoided by using an appropriately low intensity of blue light for ChR2 activation. PMID- 23452508 TI - Passivation mechanism of thermal atomic layer-deposited Al2O3 films on silicon at different annealing temperatures. AB - Thermal atomic layer-deposited (ALD) aluminum oxide (Al2O3) acquires high negative fixed charge density (Qf) and sufficiently low interface trap density after annealing, which enables excellent surface passivation for crystalline silicon. Qf can be controlled by varying the annealing temperatures. In this study, the effect of the annealing temperature of thermal ALD Al2O3 films on p type Czochralski silicon wafers was investigated. Corona charging measurements revealed that the Qf obtained at 300 degrees C did not significantly affect passivation. The interface-trapping density markedly increased at high annealing temperature (>600 degrees C) and degraded the surface passivation even at a high Qf. Negatively charged or neutral vacancies were found in the samples annealed at 300 degrees C, 500 degrees C, and 750 degrees C using positron annihilation techniques. The Al defect density in the bulk film and the vacancy density near the SiOx/Si interface region decreased with increased temperature. Measurement results of Qf proved that the Al vacancy of the bulk film may not be related to Qf. The defect density in the SiOx region affected the chemical passivation, but other factors may dominantly influence chemical passivation at 750 degrees C. PMID- 23452509 TI - Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety. AB - BACKGROUND: Concurrent chemoradiation is a standard option for locally advanced pancreatic cancer (LAPC). Concurrent conventional radiation with full-dose gemcitabine has significant toxicity. Stereotactic body radiation therapy (SBRT) may provide the opportunity to administer radiation in a shorter time frame with similar efficacy and reduced toxicity. This Pilot study assessed the safety of concurrent full-dose gemcitabine with SBRT for LAPC. METHODS: Patients received gemcitabine, 1000 mg/m2 for 6 cycles. During week 4 of cycle 1, patients received SBRT (25 Gy delivered in five consecutive daily fractions of 5 Gy prescribed to the 75-83% isodose line). Acute and late toxicities were assessed using NIH CTCAE v3. Tumor response was assessed by RECIST. Patients underwent an esophagogastroduodenoscopy at baseline, 2, and 6 months to assess the duodenal mucosa. Quality of life (QoL) data was collected before and after treatment using the QLQ-C30 and QLQ-PAN26 questionnaires. RESULTS: Between September 2009 and February 2011, 11 patients enrolled with one withdrawal during radiation therapy. Patients had grade 1 to 2 gastrointestinal toxicity from the start of SBRT to 2 weeks after treatment. There were no grade 3 or greater radiation-related toxicities or delays for cycle 2 of gemcitabine. On endoscopy, there were no grade 2 or higher mucosal toxicities. Two patients had a partial response. The median progression free and overall survival were 6.8 and 12.2 months, respectively. Global QoL did not change between baseline and immediately after radiation treatment. CONCLUSIONS: SBRT with concurrent full dose gemcitabine is safe when administered to patients with LAPC. There is no delay in administration of radiation or chemotherapy, and radiation is completed with minimal toxicity. PMID- 23452510 TI - A conceptual model for the impact of climate change on fox rabies in Alaska, 1980 2010. AB - The direct and interactive effects of climate change on host species and infectious disease dynamics are likely to initially manifest? at latitudinal extremes. As such, Alaska represents a region in the United States for introspection on climate change and disease. Rabies is enzootic among arctic foxes (Vulpes lagopus) throughout the northern polar region. In Alaska, arctic and red foxes (Vulpes vulpes) are reservoirs for rabies, with most domestic animal and wildlife cases reported from northern and western coastal Alaska. Based on passive surveillance, a pronounced seasonal trend in rabid foxes occurs in Alaska, with a peak in winter and spring. This study describes climatic factors that may be associated with reported cyclic rabies occurrence. Based upon probabilistic modelling, a stronger seasonal effect in reported fox rabies cases appears at higher latitudes in Alaska, and rabies in arctic foxes appear disproportionately affected by climatic factors in comparison with red foxes. As temperatures continue a warming trend, a decrease in reported rabid arctic foxes may be expected. The overall epidemiology of rabies in Alaska is likely to shift to increased viral transmission among red foxes as the primary reservoir in the region. Information on fox and lemming demographics, in addition to enhanced rabies surveillance among foxes at finer geographic scales, will be critical to develop more comprehensive models for rabies virus transmission in the region. PMID- 23452512 TI - Graphene: promises, facts, opportunities, and challenges in nanomedicine. PMID- 23452511 TI - Evaluation of the novel folate receptor ligand [18F]fluoro-PEG-folate for macrophage targeting in a rat model of arthritis. AB - INTRODUCTION: Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET). Images, however, also showed significant peri articular background activity. The folate receptor (FR)-beta is a potential alternative target for imaging activated macrophages. Therefore, the PET tracer [18F]fluoro-PEG-folate was synthesized and evaluated in both in vitro and ex vivo studies using a methylated BSA induced arthritis model. METHODS: [18F]fluoro-PEG folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5 methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [18F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic and normal rats and results were compared with those of the established macrophage tracer (R)-[11C]PK11195. RESULTS: [18F]fluoro-PEG-folate was synthesized with a purity >97%, a yield of 300 to 1,700 MBq and a specific activity between 40 and 70 GBq/umol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8-fold lower than that of folic acid, but 3-fold higher than that of 5-Me-THF. In the rat model, [18F]fluoro-PEG-folate uptake in arthritic knees was increased compared with both contralateral knees and knees of normal rats. Uptake in arthritic knees could be blocked by an excess of glucosamine-folate, consistent with [18F]fluoro-PEG folate being specifically bound to FR. Arthritic knee-to-bone and arthritic knee to-blood ratios of [18F]fluoro-PEG-folate were increased compared with those of (R)-[11C]PK11195. Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels increased absolute [18F]fluoro-PEG-folate uptake in arthritic joints, but without improving target-to-background ratios. CONCLUSIONS: The novel PET tracer [18F]fluoro-PEG-folate, designed to target FR on activated macrophages provided improved contrast in a rat model of arthritis compared with the accepted macrophage tracer (R)-[11C]PK11195. These results warrant further exploration of [18F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients. PMID- 23452513 TI - Incidence and pattern of technical complications in balloon-guided osteoplasty for depressed tibial plateau fractures: a pilot study in 20 consecutive patients. AB - BACKGROUND: Inflation bone tamps are becoming increasingly popular as a reduction tool for depressed tibial plateau fractures. A number of recent publications have addressed the technical aspects of balloon inflation osteoplasty. However, no study has yet been published to describe the technical limitations, intraoperative complications, and surgical bailout strategies for this new technology. METHODS: Observational retrospective study of all patients managed with inflatable bone tamps for depressed tibial plateau fractures between October 1, 2010 and December 1, 2012. The primary outcome parameter was the rate of complications, which were stratified into "minor" and "major" depending on the necessity for altering the surgical plan intraoperatively, and based on the risk for patient harm. This study was approved by the Institutional Review Board of the State of Colorado. RESULTS: A consecutive series of 20 patients were managed by balloon inflation osteoplasty for depressed tibial plateau fractures during the 15 months study period. The mean age was 42.8 years (range 20-79), with 9 females and 11 males. A total of 13 patients sustained an adverse intraoperative event (65%), with three patients sustaining multiple technical complications. Minor events (n = 8) included the burst of a balloon with extrusion of contrast dye, and the unintentional posterior wall displacement during balloon inflation. Major events (n = 5) included the intra-articular injection of calcium phosphate in the knee joint, and the inability to elevate the depressed articular fragment with the inflatable bone tamp. CONCLUSION: The observed intraoperative complication rate of 65% reflects a steep learning curve for the use of inflation bone tamps to reduce depressed tibial plateau fractures. Specific surgical bailout options are provided in this article, based on our early anecdotal experience in a pilot series of 20 consecutive cases. Patients should be advised on the benefits and risks of this new technology as part of the shared decision making process during the informed consent. PMID- 23452514 TI - Simultaneous removal of arsenate and arsenite by a nanostructured zirconium manganese binary hydrous oxide: behavior and mechanism. AB - Arsenate and arsenite typically co-exist in groundwater. Arsenite is more toxic than arsenate, while it is more difficult to be removed than arsenate. In order to effectively remove arsenate and arsenite simultaneously from water solution, a nanostructured zirconium-manganese binary hydrous oxide was successfully developed in this study. The amorphous sorbent was aggregate of nanoparticles with a high surface area of 213 m(2)g(-1). Our sorption experiments showed that the nano-scale particles could effectively oxidize As(III) to As(V) and greatly remove both As(V) and As(III). The maximal adsorption capacities of As(V) and As(III) were 80 and 104 mg g(-1) at pH 5.0, respectively. As(V) uptake may be mainly achieved through replacement of hydroxyl groups and sulfate anions on the surface of the oxide and formation of inner complexes. The As(III) removal was essentially due to a sorption coupled with oxidation process; the MnO2 was mainly responsible for oxidization of As(III) to As(V) that was subsequently adsorbed onto ZrO2. PMID- 23452515 TI - On the growth mechanisms of nanoemulsions. AB - The shelf stability of nanoemulsions made by ultrasound, phase inversion composition, and the Ouzo effect was studied using a range of hydrocarbons, as the model oils, and surfactants. The cube of the average drop radius of the nanoemulsions displayed a linear increase with time. Both Ostwald ripening and coalescence can exhibit such behaviour. A new approach, based on the time evolution of drop size distribution, is proposed for unravelling the aging mechanism of nanoemulsions. Sequences of fall and rise in the average drop size of nanoemulsions were clearly observed. The decrease in the drop size could unambiguously be attributed to Ostwald ripening, but the increase could be due to either Ostwald ripening or coalescence/flocculation. Coalescence was identified as the dominant growth mechanism at low surfactant concentrations evidenced by drop size distribution broadening with time associated with the rise in the average drop size. Ostwald ripening was the dominant mechanism at higher surfactant concentrations where the drop size distributions broadened with time during the falls and narrowed with time during the rises of the average drop size. The nanoemulsions produced via the Ouzo process, displayed a coalescence dependent transient stage and an Ostwald ripening dominated asymptotic regime in the absence of surfactant. The nanoemulsion produced via phase inversion was found to be the most stable one, however, still showed vulnerability to Ostwald ripening and flocculation in the long term. PMID- 23452516 TI - Comparative study of alkylthiols and alkylamines for the phase transfer of gold nanoparticles from an aqueous phase to n-hexane. AB - An efficient ligand-assisted phase transfer method has been developed to transfer gold nanoparticles (Au-NPs, d: 5-25 nm) from an aqueous solution to n-hexane. Four different ligands, namely 1-dodecanethiol (DDT), 1-octadecanethiol (ODT), dodecylamine (DDA), and octadecylamine (ODA) were investigated, and DDT was found to be the most efficient ligand. It appears that the molar ratio of DDT to Au-NPs is a critical factor affecting the transfer efficiency, and 270-310 is found to be the optimum range, under which the transfer efficiency is >96%. Moreover, the DDT-assisted phase transfer can preserve the shape and size of the Au-NPs, which was confirmed by UV-vis spectra and transmission electron microscopy (TEM). Additionally, the transferred Au-NPs still can be well dispersed in the n-hexane phase and remain stable for at least 2 weeks. On the other hand, the ODT-, DDA-, and ODA-assisted phase transfer is fraught with problems either related to transfer efficiency or NPs aggregation. Overall, the DDT-assisted phase transfer of Au-NPs provides a rapid and efficient method to recover Au-NPs from an aqueous solution to n-hexane. PMID- 23452517 TI - Synthesis and self-assembly of thermo/pH-responsive double hydrophilic brush-coil copolymer with poly(L-glutamic acid) side chains. AB - We report on the synthesis and self-assembly behavior of a well-defined double hydrophilic brush-coil copolymer with poly(N-isopropylacrylamide)-b-poly(glycidly methacrylate) (PNIPAM-b-PGMA) as backbone and poly(L-glutamic acid) (PLGA) as brush. The PNIPAM-b-PGMA was firstly prepared by the sequential reversible addition-fragmentation chain transfer polymerization of N-isopropylacrylamide and glycidly methacrylate. The obtained diblock copolymer was reacted with ethylenediamine (EDA) yielding the aminated macroinitiator (PNIPAM-b-PGMA-EDA), which was then used to initiate ring-opening polymerization of gamma-benzyl-L glutamate-N-carboxyanhydride (BLG-NCA) to give PNIPAM-b-(PGMA-g-PBLG) copolymer. After the deprotection of benzyl groups on PBLG, double hydrophilic brush-coil copolymer, PNIPAM-b-(PGMA-g-PLGA), was obtained. The thermo- and pH-responsive micellization behaviors of PNIPAM-b-(PGMA-g-PLGA) in aqueous solution were investigated by fluorescence spectroscopy, (1)H NMR, dynamic light scattering, scanning electron microscopy, and circular dichroism. It can self-assemble into PNIPAM-core micelles at pH 10 and elevated temperature and PLGA-core micelles at pH 4 and room temperature. Such brush-coil copolymers have the potential applications as biomedical and intelligent materials. PMID- 23452518 TI - A novel arsenic removal process for water using cupric oxide nanoparticles. AB - Recent studies suggest that the cupric oxide (CuO) nanoparticles effectively adsorb aqueous arsenic species under a wide range of water chemistries. However, to develop CuO nanotechnology to a field application level, further studies are necessary. Batch adsorption kinetic experiments were conducted to determine the time course of uptake of arsenic by CuO nanoparticles. A reactor with CuO nanoparticles was developed to conduct continuous flow-through experiments to filter arsenic from groundwater samples. Groundwater samples spiked with 100 MUg/L of arsenic were passed through (1L/h) the flow-through reactor. Samples from the flow-through reactor were collected at a regular interval and analyzed for arsenic and other chemical components (e.g., pH, major and trace elements). The CuO nanoparticles adsorbed with arsenic were regenerated with a sodium hydroxide (NaOH) solution and tested again in the flow-through reactor. Three natural groundwater samples with above 10 MUg/L of arsenic were also tested with the flow-through reactor. The arsenic adsorption process by CuO nanoparticles was kinetically rapid and followed the pseudo-second-order rate. The continuous flow through reactor with CuO nanoparticles was effective in filtering arsenic from spiked or natural groundwater. The regenerated CuO nanoparticles were also effective in filtering arsenic from groundwater. Arsenic mass balance data from regeneration studies suggested that 99% of input arsenic concentration was recovered. The CuO nanoparticle treatment did not show any discernible effects on the chemical quality of groundwater samples. Results of this study suggest that CuO nanoparticles show potential for developing a simple process for field applications to remove arsenic from water. PMID- 23452519 TI - Evolution of land plant genes encoding L-Ala-D/L-Glu epimerases (AEEs) via horizontal gene transfer and positive selection. AB - BACKGROUND: The L-Ala-D/L-Glu epimerases (AEEs), a subgroup of the enolase superfamily, catalyze the epimerization of L-Ala-D/L-Glu and other dipeptides in bacteria and contribute to the metabolism of the murein peptide of peptidoglycan. Although lacking in peptidoglycan, land plants possess AEE genes that show high similarity to those in bacteria. RESULTS: Similarity searches revealed that the AEE gene is ubiquitous in land plants, from bryophytas to angiosperms. However, other eukaryotes, including green and red algae, do not contain genes encoding proteins with an L-Ala-D/L-Glu_epimerase domain. Homologs of land plant AEE genes were found to only be present in prokaryotes, especially in bacteria. Phylogenetic analysis revealed that the land plant AEE genes formed a monophyletic group with some bacterial homologs. In addition, land plant AEE proteins showed the highest similarity with these bacterial homologs and shared motifs only conserved in land plant and these bacterial AEEs. Integrated information on the taxonomic distribution, phylogenetic relationships and sequence similarity of the AEE proteins revealed that the land plant AEE genes were acquired from bacteria through an ancient horizontal gene transfer (HGT) event. Further evidence revealed that land plant AEE genes had undergone positive selection and formed the main characteristics of exon/intron structures through gaining some introns during the initially evolutionary period in the ancestor of land plants. CONCLUSIONS: The results of this study clearly demonstrated that the ancestor of land plants acquired an AEE gene from bacteria via an ancient HGT event. Other findings illustrated that adaptive evolution through positive selection has contributed to the functional adaptation and fixation of this gene in land plants. PMID- 23452520 TI - Effects of conjugated linoleic acid on growth, non-specific immunity, antioxidant capacity, lipid deposition and related gene expression in juvenile large yellow croaker (Larmichthys crocea) fed soyabean oil-based diets. AB - The effects of conjugated linoleic acid (CLA) on growth performance, non-specific immunity, antioxidant capacity, lipid deposition and related gene expression were investigated in the large yellow croaker (Larmichthys crocea). Fish (7.56 (SEM 0.60) g) were fed soyabean oil-based diets with graded levels of CLA (0, 0.42, 0.83, 1.70%) for 70 d. Quantitative PCR was used to assess the effects of CLA on the transcription of inflammation- and fatty acid oxidation-related genes. Growth in fish fed the diet with 0.42% CLA was significantly higher. Also, phagocytic index and respiratory burst activity were significantly higher in fish fed the diets containing 0.42 and 0.83% CLA, respectively. Hepatic total antioxidative capacity and catalase activities increased significantly when CLA increased from 0 to 0.83%, and then decreased with further increase of CLA. However, hepatic malondialdehyde content decreased significantly as dietary CLA increased. Lipid concentration in the whole body and muscle increased significantly with increasing dietary CLA. Transcription of genes related to inflammation (cyclo oxygenase-2 and IL-b) in the liver and kidney and fatty acid oxidation (carnitine palmitoyl transferase I and acyl CoA oxidase) in the kidney decreased significantly as dietary CLA increased. PPAR alpha and acyl CoA oxidase expression in the liver decreased significantly as CLA increased from 0.42 to 1.70%. These results strongly suggest that dietary CLA could significantly affect growth performance, non-specific immunity, antioxidant capacity, lipid deposition and transcription of inflammation- and fatty acid oxidation-related genes of the large yellow croaker. This may contribute to our understanding of the mechanisms related to the physiological effects of dietary CLA in fish. PMID- 23452521 TI - Effect of methylprednisolone injection speed on the perception of intramuscular injection pain. AB - Pain originating from intramuscular (IM) injection should not be underestimated, because a painful injection might incite severe fear of injection, which may lead a patient to delay seeking medical help. The aim of this study was to determine the impact of two different IM methylprednisolone injection speeds on pain intensity and pain duration. A one-group quasiexperimental design was used to study 10-second versus 30-second injection durations. According to the formula for one sample using average values, 25 patients were recruited from a dermatology clinic. Data were collected using the "Patient Characteristics Form" and the visual analog scale (VAS). The mean difference in pain levels according to the VAS in the postinjection period was significantly higher with administration of IM methylprednisolone in 10 seconds compared with 30-second administration (VAS 1.9 vs. 1.3; p < .05). The severity of pain peaked at 0 minutes for both injection speeds, but the duration of pain was longer with 10 second injections. The data showed that at multiple time points after 10-second injections, men and patients >40 years old experienced greater pain severity. Pain severity after 30-second injections was greater for patients of normal or low weight who had completed higher levels of education. In conclusion, slow IM injection of steroids improves pain management. PMID- 23452522 TI - Pain management knowledge and attitudes of baccalaureate nursing students and faculty. AB - Pain affects approximately 76 million adults in the US. Though pain management has been targeted as a top priority, it continues to be inadequately addressed. Nursing faculty are in a unique position to significantly address the problem through facilitating the acquisition and utilization of knowledge by student nurses. The purpose of this study was to determine the knowledge of and attitudes toward pain in baccalaureate nursing students and faculty to establish a foundation for a systematic and comprehensive integration of pain content in the curricula. The descriptive design included a sample of 162 junior and senior students enrolled in a baccalaureate nursing program in Texas and 16 nursing faculty. The Knowledge and Attitudes Survey Regarding Pain (KASRP) was used to measure knowledge and attitudes toward pain. A direct correlation was found between the level of education and the percentage correct score. Differences found in knowledge and attitudes among the three levels of students and faculty were significant (df = 3.173; F = 14.07, p < .001). Senior students nearing graduation scored only 68% (SD = 6.8) with faculty scoring only slightly better with a mean of 71% (SD = 13). Significant differences also were found in assessment of pain through case scenarios of a patient who was smiling and talking as compared to a patient who was lying quietly and grimacing (X2 = 37.13, p < .05 (df = 24). Reevaluation of the way pain assessment and treatment are taught is indicated. Further studies are needed to assess changes in knowledge and attitudes toward pain as curricular revisions are made. PMID- 23452523 TI - Effect of music on postoperative pain and physiologic parameters of patients after open heart surgery. AB - The aim of this study was to investigate the effect of listening to personal choice of music on self-report of pain intensity and the physiologic parameters in patients who have undergone open heart surgery. The study design was quasiexperimental. Patients were selected through convenience sampling in the Cardiovascular Surgery Intensive Care Unit at a university hospital. The study was conducted with a total of 87 patients who underwent open heart surgery: 44 in the music group, 43 in the control group, ages between 18 and 78 years. Through pretest-posttest design, postoperative first-day data were collected. First, physiologic parameters (blood pressure, heart rate, oxygen saturation, and respiratory rate) were recorded and a unidimensional verbal pain intensity scale applied to all participants. Later, the control group had a rest in their beds while the music group listened to their choice of music for 30 minutes. Physiologic data were then collected and the pain intensity scale applied once more. In the music group, there was a statistically significant increase in oxygen saturation (p = .001) and a lower pain score (p = .001) than in the control group. There was no difference between the groups in the other physiologic parameters. Results of this research provide evidence to support the use of music. Music might be a simple, safe, and effective method of reducing potentially harmful physiologic responses arising from pain in patients after open heart surgery. PMID- 23452524 TI - Evaluation of the outcomes of ice application for the control of pain associated with chest tube irritation. AB - The aim of this study was to evaluate the effectiveness of the use of ice for the control of pain associated with chest tube irritation. The randomized and single blinded study consisted of 40 patients (20 in the control and 20 in the study group) who underwent thoracotomy with chest tube placement. The same general anesthesia protocol was used for all patients, and the procedure was performed by the same surgery team. Procedures such as decortication and thoracic wall resection were not included in the study. Standard postoperative analgesic methods were applied to all patients. Additionally, ice (in flexible and bendable cold gel packs wrapped in fine cloth sheaths) was applied to the chest tube insertion site at the 24th, 28th, 36th, and 40th postoperative hours for 20 minutes. To assess the effectiveness of ice application, Verbal Category Scale and Behavioral Pain Scale methods were used to measure the severity of pain. Average pain severity scores during the mobilization activities, including coughing and walking, were compared and found to be significantly lower in the study group patients who received cold therapy than in the control group patients (p < .05). Additionally, analgesic consumption was lower in the study group than in the control group patients (p < .05). As a result, the application of ice to the chest tube insertion site reduced pain associated with irritation along with the need for analgesics. PMID- 23452525 TI - Is pain assessment feasible as a performance indicator for Dutch nursing homes? A cross-sectional approach. AB - Quality of care gains transparency with the help of performance indicators. For Dutch nursing homes, the current set of performance indicators does not include pain. To determine the feasibility of pain assessment as performance indicator, information about pain prevalence and analgesic prescription in one nursing home was collected. Within the time span of 3 days, pain intensity was measured in 91% of the residents (201 out of 221), either with a numeric rating scale, a verbal rating scale, or the Rotterdam Elderly Pain Observation Scale (REPOS). Numerical rating was used for 72%, verbal rating for 3%, and REPOS observation for 25% of the residents. Pain was substantial in 65 residents (32%), who received the following analgesic prescription: World Health Organization (WHO) step 1, 45%; WHO step 3, 12%; and neuroactive agents, 5%. Thirty-eight percent of these residents were in pain and received no analgesics. Residents with substantial pain significantly more often received analgesics (p = .007). Results suggest that pain assessment is feasible in a nursing home and would stimulate staff attention to pain. Further investigation is necessary to find out if a pain algorithm is feasible and will lead to improved pain treatment. PMID- 23452527 TI - Adolescents' experience with scoliosis surgery: a qualitative study. AB - This article reports a study of adolescents' narrated experiences of undergoing scoliosis surgery. Six adolescents were interviewed. Open and semistructured questions were asked, and a qualitative content analysis of the text was performed. The results are presented in three main categories followed by subcategories. The three main categories of experience were emotional, physical, and social. The emotional aspects that emerged were fear, nightmares, nervousness, and helplessness. These had a great impact on adolescents' well being before, during, and after the hospital visit. The physical aspects were mobilization, scars, different hip levels, pain, nausea, appetite, and urinary catheter. These aspects caused much discomfort, mostly during the hospital visit. The social aspects were friends, power, coaching and comfort, and sports. Some of the social aspects had a strong negative impact on the adolescents' well-being mostly after the hospital visit. This study suggests that both before and long after the surgery adolescents have strong emotions that they should be better prepared and helped to manage. To optimize perioperative care an interdisciplinary, a holistic approach must be taken that incorporates the complexity and whole of the adolescent's experiences. The findings of this study suggest that perioperative care of adolescents during scoliosis surgery needs to be optimized. To improve patients' psychologic preparation before surgery pediatric nurses should learn more about the individual patient and make care plans from a holistic perspective. Follow-up after discharge should address emotional, social, and physical aspects of the adolescent's health. PMID- 23452526 TI - Psychologic and biologic factors associated with fatigue in patients with persistent radiculopathy. AB - Fatigue is a common symptom associated with neuropathic pain (NP) and can have negative consequences on psychosocial functioning, physical endurance, and quality of life. Recent evidence indicates that immune activation modulated through the increased release of proinflammatory cytokines can predict fatigue in some patient populations. Although earlier studies have shown that immune activation is a pathophysiologic feature of NP, there have been no studies to examine the relationship between immune activation and fatigue in persons with NP. Therefore, the purpose of this exploratory study was to: 1) determine the relationships among fatigue, pain, psychosocial factors, and selected biologic markers of immune activation (interleukin [IL] 6 and soluble IL-6 receptor [sIL 6R]) in participants with persistent radiculopathy; and 2) determine the differences in these variables based on fatigue severity. Participants (n = 80) were classified according to their level of fatigue as low (27.5%), moderate (32.5%), or high (40%), and significant differences were found between fatigue categories (p = .001). Multivariate analyses of variance revealed that individuals with moderate to high levels of fatigue differed from those with the lowest levels of fatigue in psychologic distress, depressive symptoms, IL-6, and sIL-6R, whereas the differences between moderate and high levels of fatigue were significant for psychologic distress and sIL-6R only. The findings suggest that immune activation affects fatigue severity and possibly other behavioral responses, offering important information when providing care to patients with persistent radiculopathy. The integration of biobehavioral nursing interventions in pain management may have a greater impact on quality of life than treatment focused only on pain. PMID- 23452528 TI - ASPMN survey--nurses' practice patterns related to monitoring and preventing respiratory depression. AB - The American Society for Pain Management Nursing convened a taskforce to develop guidelines on monitoring for opioid-induced sedation and respiratory depression. Part of the guideline development was the determination of nursing practice patterns related to monitoring and preventing respiratory depression during the administration of analgesics for pain. One hundred and forty-seven responses were received from 90 unique institutions across the United States. Monitoring adults with intermittent pulse oximetry while using intravenous patient-controlled analgesia (IV PCA) was 58%. Adults were monitored with continuous pulse oximetry by 25% of respondents. When using continuous epidural analgesia, 56% of patients were monitored intermittently, and 40% were monitored continuously. The use of end tidal CO2 (ETCO2) monitoring was much less, with 2.2% patients on epidural therapy, and 1.5% of institutions were using ETCO2 with IV PCA. The survey also included the location of the alarm, respiratory parameters for alarms, changes in procedures reported by institutions, and definitions of high-risk patients. PMID- 23452529 TI - [New indications and recommendations in the antihypertensive treatment]. PMID- 23452530 TI - [Analysis of the control of cardiovascular risk factors in patients with peripheral arterial disease]. AB - INTRODUCTION: The objective was to determine the percentage of patients with peripheral arterial disease (PAD) with good control of their cardiovascular risk factors (CVRF) (LDL cholesterol, blood pressure and smoke cessation). MATERIAL AND METHODS: Cross-sectional multicentre study. The location was Primary Care and other clinics that typically treat patients with peripheral arterial disease (Internal Medicine, Vascular Surgery, Cardiology, Endocrinology and Nephrology). The first 10 patients with peripheral arterial disease were systematically selected by 440 researchers from all regions. RESULTS: The study included 4087 patients. Blood pressure was controlled in 29.5% of the cases. The frequency of patients with optimal control was significantly better in primary care (p<.01). There was an optimal control of LDL-C levels in 30.4% of patients. Factors associated with optimal control of LDL-C was, being diabetic, stage I of La Fontaine, and being seen by a doctor that was not the primary care physician. Control was worse in women and in smokers. CONCLUSIONS: Primary care physicians better manage patients with hypertension. Patients seen in by a specialist as opposed to primary care are more likely to achieve optimal control of CVRF. The situation is far from the ideal, only 6% achieved optimal control of all CVRF. PMID- 23452531 TI - [Triage in primary care emergency services]. AB - OBJECTIVE: To design and validate a triage system for emergency services in primary care. METHODS: A classification of 5 priority levels was used (red, orange, yellow, green and blue). The first phase of the project was documentation, a classification based on the International Classification of Primary Care (ICPC2), and grouping the reasons for consultation with their respective decision trees into 97 different codes. The second phase was a pilot with 115 patients in which two independent evaluators performed triage. In the third stage of validation, triage was carried out on patients arriving at the emergency services (23,168 patients) over an eight month period, with continuous monitoring of the results. RESULTS: The level of concordance between two independent observers in the patients of the pilot obtained a Kappa of 0.7. The time of triage was 108.82sec (SD; 94.14). The main reasons for consultation were ear, nose and throat problems (27.6%), respiratory (15.7%), and musculoskeletal (14%). Distribution by priority: red (0.1%), orange (8.3%), yellow (17.9%), green (62.7%), blue (11%). Triage discharges/hospital admittance levels: 3.79/3.36 (P<.05). Professionals agreed with the triage level in more than 99% of cases. CONCLUSIONS: The triage system shows good interobserver agreement results, has a good correlation with the referral hospital, and there was no disagreement with the opinion of professionals. PMID- 23452532 TI - [Cost-effectiveness analysis of fixed dose antihypertensive drugs]. AB - OBJECTIVE: The aim of this study is to compare the efficiency of different fixed dose combinations of renin-angiotensin-aldosterone system (RAAS) blockers and calcium channel blockers, to use it as a guide to assist the rational prescribing in antihypertensive therapy. METHODS: The efficacy of each drug was obtained from intervention studies randomized, double-blind, made with these combinations and a utility-cost modeling from the model proposed and used by NICE. The perspective of our analysis is the National Health System and the time horizon is long enough to achieve therapeutic goals. MAIN OUTCOME MEASURES: Cost per mmHg reduction in BP, percentage of reduction necessary to achieve the therapeutic goals for hypertension control and cost, and finally quantity and quality of life gained with these treatments in patients with hypertension, diabetes. RESULTS: We studied three fixed-dose combinations: amlodipine/olmesartan, amlodipine/valsartan and manidipine/delapril. The cost per mmHg systolic BP ranged from 24.93 to 12.34 ?/mmHg, and diastolic BP ranged from 34.24 to 18.76 ?/mmHg, depending on the drug used. For an initial value of 165mmHg systolic BP the most efficient treatment to achieve the therapeutic goal of hypertension control (<140mmHg) is manidipine/delapril with a cost of 67.76 ?. The use of these drugs to control diabetic and hypertensive patients resulted in all cases being cost-effective (more effective and lower cost compared to "no treatment"). Manidipine/delapril showed the best relation cost-utility (1,970 ?/QALY (quality adjusted life year)) followed by amlodipine/olmesartan and amlodipine/valsartan (2,087 and 2,237 ?/QALY, respectively). PMID- 23452534 TI - [Reasons and determining factors for referrals between primary and specialised care]. AB - OBJECTIVES: To determine the reasons and characteristics of referrals from Primary to Specialised Care in the Health Area of Toledo (Spain). MATERIAL AND METHODS: A descriptive, cross-sectional study was conducted by reviewing a sample of the referrals to specialists made by 26 general practitioners from eight Teaching Health Centres during February 2011. All of them completed a questionnaire which recorded patient data, and reason and characteristics of the referral. RESULTS: A total of 332 referrals were recorded; the mean age of the patients was 51.3 years (SD; 17.9); 60.1% females; 30.7% pensioners; 54.8% had a chronic disease; 85.8% were from an urban environment. The most consulted specialists were: Traumatology (63), Gynaecology (53), and Ophthalmology (41). More than three-quarters (78.9%) were by the normal route, and 47.4% were first consultations. Around 12.7% were scheduled reviews, with a majority (51.4%) by a hospital specialist. More than two thirds (69.8%, 95% CI; 64.5-74.7%) required follow-up or treatment by the specialist. More than half (57.7%, 95% CI; 52.3 63.1%) required special diagnostic tests, and in 29.8% (95% CI; 25.0-35.1%) there was no clear diagnosis. There was a history of a repeated consultation for the same symptomatology in 28.9% of the referrals. Around 38.4% (95% CI; 33.0-43.7%) were requested specifically by the family or patient. Around 5.4% had a poor relationship with the patient. CONCLUSIONS: The majority of referrals are made by the normal route, and to surgical specialities. The need for hospital specialist follow-up and/or treatment, or the impossibility to request specific tests from Primary Care were the main reasons for requesting care from a second health care level. There were a high percentage of referrals requested by the family/patient. PMID- 23452533 TI - [Consensus on integrated care of acute exacerbations of chronic obstructive pulmonary disease (ATINA-EPOC). Part VI]. PMID- 23452535 TI - [Work disability criteria in breast cancer]. AB - Breast cancer is one of the most frequent neoplasia in women, with an increasing prevalence in Europe and also in Spain. Although the predominance over the male sex is clear, we should not forget the cases where men are affected, even more so when in this case the risks attached to the type of job become more important. The importance of the indirect costs of this illness arises from: the high prevalence in people of working age, long periods of work disability, and permanent disability when the limitations are incompatible with the work activity once all the options of job readjustment and return to work have been exhausted. We will review the current criteria in order to establish some orientating guidelines that can be useful in the daily practice for Occupational Medicine professionals, General Practitioners and other specialists, always in collaboration with the medical teams from the National Health Service in charge of the evaluation of disabilities. PMID- 23452536 TI - [Mondor's disease. Presentation of a case]. AB - Superficial thrombophlebitis is a common process. It usually affects lower limbs, but sometimes appears in rather special locations such as the anterior wall of the chest or in the penis, and is called Mondor's disease. It is important to identify it in order to exclude breast malignancy, with which it is often associated. PMID- 23452537 TI - [Aortic pseudoaneurysm as a complication of oesophageal perforation caused by a fish bone]. AB - We describe the case of a 41 year-old female patient with acute thoracic and epigastric pain associated with dysphagia. Due to the acute onset and the intensity of symptoms an urgent gastroscopy was requested. This was delayed and only performed when further serious complications appeared. This showed an oesophageal perforation due to ingestion of a fish bone, and an aortic pseudoaneurysm. Early determination of the cause and the extraction of fish bone would have avoided the subsequent worsening and long term stay in the hospital. Special tests limitations often delay diagnosis with severe consequences for the patients. PMID- 23452538 TI - [A case of upper extremity deep vein thrombosis]. AB - The case is presented of a 41 year-old women with a personal history of smoking and treated with oral contraceptives, who began taking analgesics and muscle relaxants due to a right cervical pain. As her clinical condition did not improve she was seen again. During the physical examination an increase of soft tissue in the right supraclavicular area was observed. The ultrasound revealed thrombosis of the internal jugular, subclavian, brachycephalic, axillar and humeral veins. We believe that upper-extremity deep venous thrombosis is a rare condition that must be considered in patients with oedema of the upper limbs. The key to a prompt diagnosis is to know the risk factors. Ultrasound is the standard approach. PMID- 23452539 TI - [Lipoid pneumonia: presentation of a case]. AB - We report a case of lipoid pneumonia treated in our Health Centre. It is a disease that occurs rarely, but is important in Primary Care. This condition has been known since 1925, when it was first described by Laughlen, who described a case of lipoid pneumonia secondary to an injection of oil in the nasopharyngeal area. Today it is a rarity, and it is most frequently associated with the use of oil-based nasal drops (which are now decreasing in use). Its aetiology may be endogenous or exogenous. Although the pathological diagnosis is generally the most important, sometimes a lesion in the chest X-ray can lead us to suspect it due to the patient's history. This was a case of acute lipoid pneumonia in a young patient, who periodically performed as a "fire eater". PMID- 23452540 TI - [Cutaneous horn, actinic keratosis and squamous cell carcinoma. Presentation of a clinical case]. AB - The cutaneous horn is defined as a tumour, usually of conical appearance which prevails over the length of its diameter, with large hyperkeratosis in its extreme and due to varied causes. It may be associated with benign, pre-malignant (actinic keratosis) and malignant (squamous cell carcinoma) skin, usually requiring complete excision of the lesion and a histopathological examination. We report a case of a 94 year old woman with a cutaneous horn and an initial pathological diagnosis of actinic keratosis, which subsequently progressed to squamous cell carcinoma, along with and a brief review of the literature. The treatment is complete excision of the lesion, deepening its base due to the likelihood of association with malignant lesions. PMID- 23452541 TI - [Bowel perforations due to fish bones: rare and curious]. PMID- 23452542 TI - [Considerations about the value of prostate specific antigen in patients treated with 5-alpha reductase]. PMID- 23452543 TI - [Radiology image of lanthanum carbonate]. PMID- 23452544 TI - Vitamin D-dependent cathelicidin inhibits Mycobacterium marinum infection in human monocytic cells. AB - BACKGROUND: 1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) up-regulates the production of human cathelicidin antimicrobial peptide (CAMP) from monocytes/macrophages infected with Mycobacterium tuberculosis (M. tbc). CAMP facilitates the co-localization of autophagolysosomes with M. tbc, promoting the antimicrobial activity of monocytes. Mycobacterium marinum (M. marinum) is an acid-fast bacillus that causes less severe granulomatous skin lesions compared with M. tbc. OBJECTIVE: We investigated whether autophagic antimicrobial activity is promoted by 1,25(OH)2D3 or C-terminal of cathelicidin LL-37 in human monocytes upon infection with M. marinum. METHODS: Human monocytes (THP-1) were infected with M. marinum. Effects of simultaneous treatments of 1,25(OH)2D3, exogenous LL 37 peptide, autophagolysosome inhibitors, 3-methyladenine or chloroquine, were examined. RESULTS: CAMP was strongly induced by adding 1,25(OH)2D3 to the culture of THP-1 cells. In the absence of 1,25(OH)2D3 M. marinum infection alone did not induce CAMP, however, simultaneous addition of 1,25(OH)2D3 to M. marinum infection accelerated CAMP production more than 1,25(OH)2D3 alone. Proliferation of M. marinum was markedly decreased in the presence of 1,25(OH)2D3 or exogenous LL-37 in THP-1 cells. Co-localization of CAMP with autophagolysosome was evident in 1,25(OH)2D3 and LL-37 treated THP-1 cells after M. marinum infection. Autophagolysosome inhibitors abrogated the antimicrobial effects of 1,25(OH)2D3 and exogenous LL-37 against M. marinum infection in THP-1 cells. CONCLUSIONS: Human monocytic cells, whose CAMP production is up-regulated by 1,25(OH)2D3 vitamin D receptor pathway, accelerate antimicrobial function of autophagolysosome in M. marinum infection. PMID- 23452545 TI - Differentially regulated microRNAs during human sebaceous lipogenesis. AB - BACKGROUND: MicroRNAs (miRNAs) regulate several aspects of the morphogenesis and homeostasis of the skin and its appendages, and miRNA deregulation has been shown to be associated or even causally related to several skin diseases. OBJECTIVE: To evaluate the differential expression of miRNAs during sebaceous lipogenesis. METHODS: Inhibition of global miRNA activity in human SZ95 sebaceous gland cells was achieved by transfection with siRNAs directed against the DICER transcript, encoding a key enzyme of miRNA biogenesis. Sebaceous lipogenesis was induced in SZ95 sebocytes by addition of linoleic acid (LA) and ciglitazone (CIG) and microarray-based miRNA expression profiles were obtained on an Agilent platform. The expression of selected miRNA candidates was measured by Taqman quantitative real-time RT-PCR. Increased activity of one validated miRNA was attained by transfecting SZ95 sebocytes with miR-574-3p mimics. RESULTS: Downregulation of sebaceous lipogenesis was detected in DICER-impaired SZ95 sebocytes. Using microarrays, we identified twelve significantly upregulated and nine significantly downregulated miRNAs in LA- and CIG-treated SZ95 sebocytes as compared to non-treated cells. Validation of a subset of miRNA candidates by qRT PCR confirmed upregulation of mIR-203 and miR-574-3p and downregulation of miR-7 during sebaceous lipogenesis. The two upregulated miRNAs have been previously implied in keratinocyte differentiation. Increased activity of miR-574-3p augmented lipogenesis in SZ95 sebocytes. CONCLUSION: Global miRNA activity is essential for lipid synthesis in human SZ95 sebocytes. Individual miRNAs are likely to play a significant role during sebaceous lipogenesis. PMID- 23452546 TI - beta-cryptoxanthin regulates bone resorption related-cytokine production in human periodontal ligament cells. AB - OBJECTIVE: beta-cryptoxanthin (beta-cry) is a type of carotenoid found in certain fruits and vegetables. Although it has been shown that beta-cry inhibits alveolar bone resorption, the molecular mechanisms for this have not yet been clarified. In the present study, we investigated the effects of beta-cry on bone resorption related-cytokine production in human periodontal ligament (hPDL) cells. DESIGN: hPDL cells were stimulated with beta-cry (1*10(-7)mol/l), mechanical stress (1 or 6MPa), and P. gingivalis. The production of interleukin (IL)-1beta, IL-6, IL-8, tumour necrosis factor (TNF)-alpha, osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) were analyzed by RT-PCR and ELISA. RESULTS: The production of IL-1beta, IL-6, IL-8, and TNF-alpha was not induced in hPDL cells after stimulation with beta-cry, although these cytokines were produced after stimulation with P. gingivalis. On the other hand, IL-6 and IL-8 were produced after exposure to 6MPa of mechanical stress. The production of IL-6 and IL-8 was significantly decreased by the addition of beta-cry. Furthermore, beta-cry up-regulated the production of OPG, but not RANKL. CONCLUSION: beta-cry inhibited the production of IL-6 and IL-8 induced by mechanical stress and periodontopathogenic bacteria in hPDL cells. Moreover, beta-cry up-regulated OPG production. These results suggest that beta-cry may prevent bone resorption in periodontitis. PMID- 23452548 TI - [European Association of Urology guidelines on assessment and nonsurgical management of urinary incontinence]. AB - CONTEXT: The previous European Association of Urology (EAU) guidelines on urinary incontinence comprised a summary of sections of the 2009 International Consultation on Incontinence. A decision was made in 2010 to rewrite these guidelines based on an independent systematic review carried out by the EAU guidelines panel, using a sustainable methodology. OBJECTIVE: We present a short version of the full guidelines on assessment, diagnosis, and nonsurgical treatment of urinary incontinence, with the aim of increasing their dissemination. EVIDENCE ACQUISITION: Evidence appraisal included a pragmatic review of existing systematic reviews and independent new literature searches, based on Population, Intervention, Comparator, Outcome questions. Appraisal of papers was carried out by an international panel of experts, who also collaborated on a series of consensus discussions, to develop concise structured evidence summaries and action-based recommendations using a modified Oxford system. EVIDENCE SUMMARY: The full version of the guidelines is available online (http://www.uroweb.org/guidelines/online-guidelines/). The guidelines include algorithms that refer the reader back to the supporting evidence, and they are more immediately useable in daily clinical practice. CONCLUSIONS: These new guidelines present an up-to-date summary of the available evidence, together with clear clinical algorithms and action-based recommendations based on the best available evidence. Where such evidence does not exist, they present a consensus of expert opinion. PMID- 23452547 TI - The effect of an anti-malarial subsidy programme on the quality of service provision of artemisinin-based combination therapy in Kenya: a cluster randomized, controlled trial. AB - BACKGROUND: Many patients with suspected malaria in sub-Saharan Africa seek treatment from private providers, but this sector suffers from sub-standard medicine dispensing practices. To improve the quality of care received for presumptive malaria from the highly accessed private retail sector in western Kenya, subsidized pre-packaged artemether-lumefantrine (AL) was provided to private retailers, together with a one day training for retail staff on malaria diagnosis and treatment, job aids and community engagement activities. METHODS: The intervention was assessed using a cluster-randomized, controlled design. Provider and mystery-shopper cross-sectional surveys were conducted at baseline and eight months post-intervention to assess provider practices. Data were analysed based on cluster-level summaries, comparing control and intervention arms. RESULTS: On average, 564 retail outlets were interviewed per year. At follow-up, 43% of respondents reported that at least one staff member had attended the training in the intervention arm. The intervention significantly increased the percentage of providers knowing the first line treatment for uncomplicated malaria by 24.2% points (confidence interval (CI): 14.8%, 33.6%; adjusted p=0.0001); the percentage of outlets stocking AL by 31.7% points (CI: 22.0%, 41.3%; adjusted p=0.0001); and the percentage of providers prescribing AL for presumptive malaria by 23.6% points (CI: 18.7%, 28.6%; adjusted p=0.0001). Generally outlets that received training and job aids performed better than those receiving one or none of these intervention components. CONCLUSION: Overall, subsidizing ACT and retailer training can significantly increase the percentage of outlets stocking and selling AL for the presumptive treatment of malaria, but further research is needed on strategies to improve the provision of counselling advice to retail customers. PMID- 23452549 TI - Perceived risks and benefits of cigarette smoking among Nepalese adolescents: a population-based cross-sectional study. AB - BACKGROUND: The perceived risks and benefits of smoking may play an important role in determining adolescents' susceptibility to initiating smoking. Our study examined the perceived risks and benefits of smoking among adolescents who demonstrated susceptibility or non susceptibility to smoking initiation. METHODS: In October-November 2011, we conducted a population-based cross-sectional study in Jhaukhel and Duwakot Villages in Nepal. Located in the mid-hills of Bhaktapur District, 13 kilometers east of Kathmandu, Jhaukhel and Duwakot represent the prototypical urbanizing villages that surround Nepal's major urban centers, where young people have easy access to tobacco products and are influenced by advertising. Jhaukhel and Duwakot had a total population of 13,669, of which 15% were smokers. Trained enumerators used a semi-structured questionnaire to interview 352 randomly selected 14- to 16-year-old adolescents. The enumerators asked the adolescents to estimate their likelihood (0%-100%) of experiencing various smoking-related risks and benefits in a hypothetical scenario. RESULTS: Principal component analysis extracted four perceived risk and benefit components, excluding addiction risk: (i) physical risk I (lung cancer, heart disease, wrinkles, bad colds); (ii) physical risk II (bad cough, bad breath, trouble breathing); (iii) social risk (getting into trouble, smelling like an ashtray); and (iv) social benefit (looking cool, feeling relaxed, becoming popular, and feeling grown-up). The adjusted odds ratio of susceptibility increased 1.20-fold with each increased quartile in perception of physical Risk I. Susceptibility to smoking was 0.27- and 0.90-fold less among adolescents who provided the highest estimates of physical Risk II and social risk, respectively. Similarly, susceptibility was 2.16-fold greater among adolescents who provided the highest estimates of addiction risk. Physical risk I, addiction risk, and social benefits of cigarette smoking related positively, and physical risk II and social risk related negatively, with susceptibility to smoking. CONCLUSION: To discourage or prevent adolescents from initiating smoking, future intervention programs should focus on communicating not only the health risks but also the social and addiction risks as well as counteract the social benefits of smoking. PMID- 23452550 TI - Evolution of foot-and-mouth disease virus intra-sample sequence diversity during serial transmission in bovine hosts. AB - RNA virus populations within samples are highly heterogeneous, containing a large number of minority sequence variants which can potentially be transmitted to other susceptible hosts. Consequently, consensus genome sequences provide an incomplete picture of the within- and between-host viral evolutionary dynamics during transmission. Foot-and-mouth disease virus (FMDV) is an RNA virus that can spread from primary sites of replication, via the systemic circulation, to found distinct sites of local infection at epithelial surfaces. Viral evolution in these different tissues occurs independently, each of them potentially providing a source of virus to seed subsequent transmission events. This study employed the Illumina Genome Analyzer platform to sequence 18 FMDV samples collected from a chain of sequentially infected cattle. These data generated snap-shots of the evolving viral population structures within different animals and tissues. Analyses of the mutation spectra revealed polymorphisms at frequencies >0.5% at between 21 and 146 sites across the genome for these samples, while 13 sites acquired mutations in excess of consensus frequency (50%). Analysis of polymorphism frequency revealed that a number of minority variants were transmitted during host-to-host infection events, while the size of the intra host founder populations appeared to be smaller. These data indicate that viral population complexity is influenced by small intra-host bottlenecks and relatively large inter-host bottlenecks. The dynamics of minority variants are consistent with the actions of genetic drift rather than strong selection. These results provide novel insights into the evolution of FMDV that can be applied to reconstruct both intra- and inter-host transmission routes. PMID- 23452551 TI - The severity of experimental arthritis is independent of IL-36 receptor signaling. AB - INTRODUCTION: Interleukin (IL)-36 refers to three related IL-1 family cytokines, IL-36alpha, IL-36beta, and IL-36gamma, that bind to the IL-36 receptor (IL-36R). IL-36 exerts proinflammatory effects in skin and lung and stimulates T cell responses. In the present study, we examined the expression and function of IL 36R and its ligands in experimental arthritis. METHODS: Collagen-induced arthritis (CIA), antigen-induced arthritis (AIA), and K/BxN serum transfer induced arthritis were induced according to standard protocols. Messenger RNA levels for IL-36R and its ligands in the joints of mice with CIA were determined by RT-qPCR. Mice with CIA were injected with a blocking monoclonal anti-IL-36R, a blocking anti-IL-1RI, or their isotype-matched control antibodies at the time of arthritis onset. Anti-IL-36R or control antibodies were also injected at the time of AIA induction. Finally, IL-36R-deficient mice were examined in AIA and serum transfer-induced arthritis. The development and severity of arthritis were assessed by clinical and histological scoring. RESULTS: IL-36R, IL-36Ra and IL 36gamma mRNA were detected in the joints of mice with CIA, but their levels did not correlate with arthritis severity. As opposed to anti-IL-1RI antibody treatment, the injection of an anti-IL-36R antibody was devoid of effect on the development and severity of CIA. The severity of joint inflammation and structural damage in AIA was also unaltered by anti-IL-36R antibody treatment. Finally, the severity of AIA and K/BxN serum transfer-induced arthritis was similar in IL-36R-deficient and wild-type mice. CONCLUSIONS: The development and severity of experimental arthritis are independent of IL-36R signaling. PMID- 23452552 TI - Identification of small hepatocellular carcinoma and tumor-feeding branches with cone-beam CT guidance technology during transcatheter arterial chemoembolization. AB - PURPOSE: To evaluate the performance of transcatheter arterial chemoembolization guidance software that uses cone-beam computed tomography (CT) technology in identifying small hepatocellular carcinoma (HCC) tumors and feeding branches. MATERIALS AND METHODS: Cone-beam CT and manual feeder vessel detection (MFD) software were used in chemoembolization of 68 HCCs 30 mm or smaller (mean +/- standard deviation, 15.3 mm +/- 5.2). Detectability of tumors and tumor-feeding sub-subsegmental arteries was compared versus that of nonselective digital subtraction angiography (DSA). Technical success of chemoembolization was divided into three grades according to 1-week CT findings: entire tumor embolized with at least a 5-mm-wide margin (ie, complete), tumor embolized without a margin in parts (ie, adequate), or entire tumor not embolized (ie, incomplete). All cone beam CT data were also reanalyzed with automatic feeder vessel detection (AFD) software that was developed later. RESULTS: Cone-beam CT could depict all tumors, including eight that were first discovered during chemoembolization. Sixty-one tumors (89.7%) were detected on CT during arterial portography and during hepatic arteriography, and seven (10.3%) were detected with one or the other. Nonselective DSA depicted 49 tumors (72.1%). Among 100 tumor-feeding vessels, 81 were identified with MFD and 38 with nonselective DSA. Detectability of tumors with CT and tumor-feeding branches with MFD was significantly better than with nonselective DSA (both P<.001). Fifty-nine tumors (86.8%) were completely embolized and nine (13.2%) were adequately embolized. AFD identified 96 feeder vessels; 88 (88%) represented true-positive findings. CONCLUSIONS: Transcatheter arterial chemoembolization guidance software with cone-beam CT technology has a sufficient performance level to detect small HCCs and their feeding branches. PMID- 23452553 TI - Transarterial chemoembolization with drug-eluting beads in hepatocellular carcinoma: usefulness of contrast saturation features on cone-beam computed tomography imaging for predicting short-term tumor response. AB - PURPOSE: To evaluate the predictability of the short-term tumor response and the clinical usefulness of cone-beam computed tomography (CT) performed immediately after drug-eluting bead (DEB) transarterial chemoembolization in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This retrospective study comprised 90 patients (male-to-female ratio = 66:24; mean age, 60.4 y) with 119 tumors (mean size, 3.2 cm). All patients underwent DEB transarterial chemoembolization and received cone-beam CT after embolization. The marginal contrast saturation was defined as a contrast stasis that was observed along the margin of the tumor on the cone-beam CT images. The degree of marginal contrast saturation was calculated as a percentage and was classified into five grades in 25% increments. The degree of marginal contrast saturation and the tumor response were correlated based on follow-up imaging. RESULTS: There was a complete response in 63.8% (n = 76) of all tumors. Partial response, stable disease, and progressive disease were identified in 21.8% (n = 26), 13.4% (n = 16), and 0.8% (n = 1) of tumors. Marginal contrast saturation by cone-beam CT was 86%+/- 16.3, 73.2%+/- 28.8, 16.9%+/- 27.2, and 0% for complete response, partial response, stable disease, and progressive disease, which indicated a significant correlation of a higher contrast saturation with a better response (P<.001) by follow-up imaging criteria. The positive predictive value of the G5 group showing a complete response was 98.1%. CONCLUSIONS: Marginal contrast saturation showed a high positive predictive value for short-term tumor response. This technique may improve the success rates of DEB transarterial chemoembolization procedures and may reduce technical difficulties and shorten procedural time. PMID- 23452554 TI - Readability assessment of internet-based patient education materials related to uterine artery embolization. AB - PURPOSE: To determine the readability of Internet-based patient education materials (IPEMs) created by United States hospitals and universities and clinical practices and miscellaneous health care-associated Web sites regarding uterine artery embolization (UAE) as a marker for IPEMs in general. METHODS AND METHODS: Two hundred unique Web sites were evaluated for patient-related articles on UAE. Web sites produced by US hospitals and universities and clinical practices, as well as miscellaneous health care-associated Web sites meeting the Health on the Net Foundation Code of Conduct criteria were included in the database. By using mathematical regression algorithms based on word and sentence length to quantitatively analyze reading materials for language intricacy, readability of 40 UAE-related IPEMs was assessed with four indices: Flesch Kincaid Grade Level (FKGL), Flesch Reading Ease Score (FRES), Simple Measure of Gobbledygook (SMOG), and Gunning Frequency of Gobbledygook (GFOG). Scores were evaluated against national recommendations, and intergroup analysis was performed. RESULTS: None of the IPEMs were written at or below the sixth-grade reading level, based on FKGL. The mean readability scores were as follows: FRES, 43.98; FKGL, 10.76; SMOG, 13.63; and GFOG, 14.55. These scores indicate that the readability of UAE IPEMs is written at an advanced level, significantly above the recommended 6th grade reading level (P<.05) determined by the United States Department of Health and Human Services. CONCLUSIONS: IPEMs related to UAE generated by hospitals, clinical practices, and miscellaneous health care associated Web sites are written above the recommended sixth grade level. IPEMs for other disease entities may also reflect similar results. PMID- 23452555 TI - Phononic and magnonic dispersions of surface waves on a permalloy/BARC nanostructured array. AB - Phononic and magnonic dispersions of a linear array of periodic alternating Ni80Fe20 and bottom anti-reflective coating nanostripes on a Si substrate have been measured using Brillouin light scattering. The observed phononic gaps are considerably larger than those of laterally patterned multi-component crystals previously reported, mainly a consequence of the high elastic and density contrasts between the stripe materials. Additionally, the phonon hybridization bandgap has an unusual origin in the hybridization and avoided crossing of the zone-folded Rayleigh and pseudo-Sezawa waves. The magnonic band structure features near-dispersionless branches, with unusual vortex-like dynamic magnetization profiles, some of which lie below the highly-dispersive fundamental mode branch. Finite element calculations of the phononic and magnonic dispersions of the magphonic crystal accord well with experimental data. PMID- 23452556 TI - Co-application of selenite and phosphate reduces arsenite uptake in hydroponically grown rice seedlings: toxicity and defence mechanism. AB - The study empirically evaluates the abatement of As(III) uptake in rice seedlings (7d), in presence of Se and phosphate (P) under hydroponic condition. Positive correlation between As(III) translocation to the shoots of As(III) and P treated seedlings, shows P dependent As(III) translocation in rice. Whereas, presence of both P (5 and 10MUgml(-1)) and (0.75MUgml(-1)) of Se significantly reduces the As(III) uptake in rice seedlings. Application of Se alone also reduces As(III) uptake both in shoots and roots significantly, however, the seedlings suffers from lipid peroxidation. Among all the studied treatments, lower rates of P (5MUgml(-1)) and Se (0.75MUgml(-1)) when co-applied, significantly reduced As(III) translocation to the shoots without inflicting much toxicity in the seedlings which is manifested as significant increase in biomass with lower thio barbituric reactive substances (TBARS). Also, significantly lower TBARS in seedlings receiving As(4)+Se(0.75) and higher TBARS in As(4)+Se(1.5), demonstrates that Se applied at lower rates (0.75MUgml(-1)), lowers As induced toxicity. Higher SOD, APX and guaiacol peroxidase (POD) activities in As(4)+P(5)+Se(0.75) compared to that of As(4)+P(5) and As(4)+Se(0.75), supports that lower rate of P and Se provides tolerance towards As induced stress. The nitrogen metabolism in As(4)+P+Se treated seedlings is affected adversely at higher rates of Se and P application. Overall study concluded that application of lower rates of P (5MUgml(-1)) and Se (0.75MUgml(-1)) provides maximum amelioration of As(III) toxicity in rice seedlings. PMID- 23452557 TI - The 21st century burn care team. AB - The 21st century burn care team epitomises integrated multidisciplinary care. The physical, psychological and socials needs of burn victims necessitates the close collaboration of a broad spectrum of health care professionals. The ultimate aim is to return the patient to the optimal level of physical and psychological health and social function. The modern burn care team must not only consider the staffing and structure of the team, but also the way in which the team is to be delivered to the patient. Furthermore, the 21st century burn care team must be willing to adapt and evolve during the likely NHS re-structuring that will come with the Health and Social Care Act 2012, as well as integrate with the new UK trauma networks. This paper discusses the staffing and structure of the 21st century burn care team along with the future challenges and opportunities it may be presented with. PMID- 23452558 TI - Breast reconstruction and post-mastectomy radiation practice. AB - PURPOSE: The goal of this study was to explore the perspectives and practice of radiation oncologists who treat breast cancer patients who have had breast reconstruction. METHODS: In 2010, an original electronic survey was sent to all physician members of the American Society of Radiation Oncology, National Cancer Research Institute-Breast Cancer Studies Group in the United Kingdom, Thai Society of Therapeutic Radiology and Oncology, Swiss Society of Radiation Oncology, and Turkish Radiation Oncology Society. We identified factors associated with radiation oncologists who treat breast cancer patients with reconstruction performed prior to radiation and obtained information regarding radiation management of the breast reconstruction. RESULTS: 358 radiation oncologists responded, and 60% of the physicians were from the United States. While 64% of participants agree or strongly agree that breast image affects a woman's quality of life during radiation, 57% feel that reconstruction challenges their ability to deliver effective breast radiation. Compared with other countries, treatment within the United States was associated with a high reconstruction rate (>/= 50% of mastectomy patients) prior to radiation (p < 0.05). Delayed-immediate reconstruction with a temporary tissue expander was more common in the United States than in other countries (52% vs. 23%, p = 0.01). Among physicians who treat patients with tissue expanders, the majority (60%) prefer a moderately inflated implant with 150-250 cc of fluid rather than a completely deflated (13%) or inflated expander (28%) during radiation. Among radiation oncologists who treat reconstructions, 49% never use bolus and 40% never boost a breast reconstruction. United States physicians were more likely than physicians from other countries to boost or bolus the reconstruction irrespective of the type of reconstruction seen in their clinic patients (p < 0.01). CONCLUSIONS: Great variation in practice is evident from our study of radiation treatment for breast cancer patients with reconstruction. Further research on the impact and delivery of radiation to a reconstructed breast may validate some of the observed practices, highlight the variability in treatment practice, and help create a treatment consensus. PMID- 23452559 TI - [Differences by age and gender in the incidence of type 1 diabetes in Navarre, Spain (2009-2011)]. AB - OBJECTIVE: To determine the incidence of type 1 diabetes in Navarre, irrespective of age, from 2009 to 2011, and its characteristics at onset by age and gender. METHOD: A descriptive cross-sectional study was conducted. Data were obtained from one primary and three secondary sources. Poisson regression models were used to analyze differences in incidence rates among age groups and between male and female patients. RESULTS: We detected 167 new cases (incidence: 8.7/100,000 inhabitants-year; 95%CI: 7.4-10.1). The incidence was higher in children than in adults and was highest in the group aged 10-14 years. The incidence was higher in males than in females. The incidence increased with age in boys under 15 years but not in girls. CONCLUSIONS: The incidence of type 1 diabetes in children and young adults in Navarre is among the highest in Europe. Differences were found by age and gender. PMID- 23452560 TI - [A celebrity can have as much impact in public health as an international awareness campaign]. PMID- 23452561 TI - Spatio-temporal analysis of malaria within a transmission season in Bandiagara, Mali. AB - BACKGROUND: Heterogeneous patterns of malaria transmission are thought to be driven by factors including host genetics, distance to mosquito breeding sites, housing construction, and socio-behavioural characteristics. Evaluation of local transmission epidemiology to characterize malaria risk is essential for planning malaria control and elimination programmes. The use of geographical information systems (GIS) techniques has been a major asset to this approach. To assess time and space distribution of malaria disease in Bandiagara, Mali, within a transmission season, data were used from an ongoing malaria incidence study that enrolled 300 participants aged under six years old". METHODS: Children's households were georeferenced using a handheld global position system. Clinical malaria was defined as a positive blood slide for Plasmodium falciparum asexual stages associated with at least one of the following signs: headache, body aches, fever, chills and weakness. Daily rainfall was measured at the local weather station.Landscape features of Bandiagara were obtained from satellite images and field survey. QGISTM software was used to map malaria cases, affected and non affected children, and the number of malaria episodes per child in each block of Bandiagara. Clusters of high or low risk were identified under SaTScan((r)) software according to a Bernoulli model. RESULTS: From June 2009 to May 2010, 296 clinical malaria cases were recorded. Though clearly temporally related to the rains, Plasmodium falciparum occurrence persisted late in the dry season. Two "hot spots" of malaria transmission also found, notably along the Yame River, characterized by higher than expected numbers of malaria cases, and high numbers of clinical episodes per child. Conversely, the north-eastern sector of the town had fewer cases despite its proximity to a large body of standing water which was mosquito habitat. CONCLUSION: These results confirm the existence of a marked spatial heterogeneity of malaria transmission in Bandiagara, providing support for implementation of targeted interventions. PMID- 23452562 TI - Porcine CD8alphadim/-NKp46high NK cells are in a highly activated state. AB - Natural Killer (NK) cells play a crucial role in the early phase of immune responses against various pathogens. In swine so far only little information about this lymphocyte population exists. Phenotypical analyses with newly developed monoclonal antibodies (mAbs) against porcine NKp46 recently revealed that in blood NKp46- and NKp46+ cells with NK phenotype exist with comparable cytotoxic properties. In spleen a third NKp46-defined population with NK phenotype was observed that was characterised by a low to negative CD8alpha and increased NKp46 expression. In the current study it is shown that this NKp46high phenotype was correlated with an increased expression of CD16 and CD27 compared to the CD8alpha+NKp46- and NKp46+ NK-cell subsets in spleen and blood. Additionally NKp46high NK cells expressed elevated levels of the chemokine receptor CXCR3 on mRNA level. Functional analyses revealed that splenic NKp46high NK cells produced much higher levels of Interferon-gamma and Tumor Necrosis Factor-alpha upon stimulation with cytokines or phorbol-12-myristate-13 acetate/Ionomycin compared to the other two subsets. Furthermore, cross-linking of NKp46 by NKp46-specific mAbs led to a superior CD107a expression in the NKp46high NK cells, thus indicating a higher cytolytic capacity of this subset. Therefore porcine splenic NKp46high NK cells represent a highly activated subset of NK cells and may play a profound role in the immune surveillance of this organ. PMID- 23452563 TI - Effects of acute detoxification of the herbal blend 'Spice Gold' on dopamine D2/3 receptor availability: a [18F]fallypride PET study. AB - We carried out dynamic [(18)F]fallypride PET scans to measure cerebral dopamine D2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from "Spice", a pre-packaged herbal smoking thought to contain synthetic cannabinoids. Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [(18)F]fallypride binding potential (BPND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [(18)F]fallypride BPND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BPND increased to normal values. This study shows substantial short-term alterations of dopamine D2/3 receptor availability in a patient before and after acute detoxification from "Spice Gold", thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend. PMID- 23452564 TI - International comparative performance of mental health research, 1980-2011. AB - Scientific understanding of mental illness, mental health and their neurobiological and psychosocial underpinnings has greatly increased in the last three decades. Yet, little is known about the landscape of this knowledge and how and where it is evolving. This paper provides a bibliometric assessment of mental health research (MHR) outputs from 1980 to 2011. MHR papers were retrieved using three strategies: from key mental health journals; using US National Library of Medicine Medical Subject Heading (MeSH) keywords; and from additional journals in which mental health topics accounted for over 75% of papers. The number of papers per year increased over time in absolute terms and as a proportion of total medical output. The US's proportion of world publication output dropped from 60% in 1980 to 42% in 2011, while the EU increased its share from 27% to 40%. Countries with greater research intensity in mental health generally had higher citation impact, such as the US, UK, Canada and the Netherlands. MHR also became more collaborative: 3% of all MHR papers published in 1980 were the result of international collaboration compared to 22% in 2011. We conclude by noting that the rise in MHR appears to be due to funding and that bibliometrics can help highlight the potential drivers of variation in performance of MHR systems. The paper provides an analytical basis for benchmarking MHR trends in the future. PMID- 23452565 TI - The personal and national costs of lost labour force participation due to arthritis: an economic study. AB - BACKGROUND: The costs of arthritis to the individuals and the state are considerable. METHODS: Cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model of 45 to 64 year old Australians built on data from the Australian Bureau of Statistics' Survey of Disability, Ageing and Carers and STINMOD, an income and savings microsimulation model. RESULTS: Individuals aged 45 to 64 years who had retired early due to arthritis had a median value of AU$260 in total weekly income whereas those who were employed full time were likely to average more than five times this. The large national aggregate impact of early retirement due to arthritis includes AU$9.4 billion in lost GDP, attributable to arthritis through its impact on labour force participation.When looking at the ongoing impact of being out of the labour force those who retired from the labour force early due to arthritis were estimated to have a median value of total savings by the time they are 65 of as little as $300 (for males aged 45-54). This is far lower than the median value of savings for those males aged 45-54 who remained in the labour force full time, who would have an estimated $339,100 of savings at age 65. CONCLUSIONS: The costs of arthritis to the individuals and the state are considerable. The impacts on the state include loss of productivity from reduced workforce participation, lost income taxation revenue, and increased government support payments - in addition to direct health care costs. Individuals bear the economic costs of lost income and the reduction of their savings over the long term. PMID- 23452566 TI - Commentary: Successful spinal fusion surgery: can we improve the odds? PMID- 23452567 TI - Commentary: Diagnostic tests for chronic low back pain--a dismal science. PMID- 23452568 TI - Commentary: Access to care affects the rate of spinal deformity surgery. PMID- 23452569 TI - Commentary: Therapies for osteoporosis: are they good for spinal fusion? PMID- 23452570 TI - Neurocritical care. PMID- 23452571 TI - Extent of acute hydrocephalus after subarachnoid hemorrhage as a risk factor for poor functional outcome. AB - OBJECTIVES: To evaluate the correlation between acute hydrocephalus after subarachnoid hemorrhage (SAH) and functional outcome 1 year after the event. METHODS: We retrospectively reviewed the clinical and radiological information on consecutive adult patients admitted to our hospital with a diagnosis of acute SAH between 1 January 2002 and 1 January 2008. Patients with early death of any cause, chronic hydrocephalus, or evidence of radiological infarction were excluded. Remaining patients were grouped based on the presence or absence of acute hydrocephalus. The extent of ventricular dilatation was expressed as a function of bicaudate distance. Functional outcomes at 1 year after the hemorrhage were compared between patients with and without acute hydrocephalus. RESULTS: We included 110 patients of whom 57 (52%) had acute hydrocephalus. Acute hydrocephalus was an independent risk factor for poor functional outcome in multivariate analysis (P = 0.006). Patients were categorized into quartiles based on the relative bicaudate index (RBCI). The proportion of patients with poor functional outcome increased in consecutive quartiles (P = 0.0001). The adjusted odds ratio for the highest quartile of RBCI versus the lowest was 7.2 (95% confidence interval: 2.1-25.2). Initiation of treatment at or above an RBCI value of 1.6 (+/- 0.3) did not significantly improve functional outcome (P = 0.15). CONCLUSION: The extent of ventricular dilatation after SAH is a strong risk factor for development of poor functional outcome in the year following the event. The proportion of patients with poor outcome was not significantly different with and without cerebrospinal fluid drainage, when treatment was initiated at an RBCI of ?1.6. Our results suggest that development of acute hydrocephalus after SAH adversely affects long-term functional outcome. Moreover, cerebrospinal fluid flow diversion strategies might best be aimed at preventing ventricular enlargement rather than at treating an established hydrocephalus. PMID- 23452572 TI - How we do it: acute management of subarachnoid hemorrhage. AB - OBJECTIVES: Acute subarachnoid hemorrhage (SAH) is a neurological emergency with significant potential for long-term morbidity and mortality. We review our management of acute SAH and some of the evidence base supporting our practices. METHODS: We reviewed our standardized and multi-disciplinary approach to the management of SAH. RESULTS: Management of SAH treatment can be divided into acute, aneurysmal, waiting, and post-waiting phases. Acute issues upon presentation include hemodynamic and respiratory stability, prevention of rebleeding, and treatment of hydrocephalus. The aneurysm must then be secured through endovascular or microsurgical methods. Observation for signs and symptoms of vasospasm must be closely undertaken. Prevention of subsequent medical complications must also be undertaken. Weaning from cerebrospinal fluid diversion and possible shunting is the final step. DISCUSSION: Standardized multi-modality management of rebleeding, hydrocephalus, aneurysmal obliteration, vasospasm, cerebral salt wasting, and other medical complications during these phases, is critical. PMID- 23452573 TI - Clinical relevance of negative initial angiogram in spontaneous subarachnoid hemorrhage. AB - BACKGROUND: We aimed to compare the presentation, management, and clinical course in patients with perimesencephalic and nonperimesencephalic (aneurysmal) bleeding patterns on noncontrast CT, but negative initial 4-vessel digital subtraction angiography (DSA). METHODS: We retrospectively reviewed clinical and imaging data for 280 patients presenting with spontaneous SAH admitted between 2005 and 2011. We identified 56 patients (20%) with SAH diagnosed on high resolution head CT performed within 48 hours of admission, and negative initial DSA, and divided them into perimesencephalic and non-perimesencephalic groups based on hemorrhage patterns. Patients with traumatic subarachnoid bleeding and those with initial positive DSA were excluded from this analysis. RESULTS: Perimesencephalic SAH was seen in 25 patients (45%); non-perimesencephalic bleeding patterns were seen in 31 (55%). All patients with perimesencephalic SAH presented with Hunt and Hess (HH) I, versus 45% HH I and 55% HH II-IV in those with non-perimecenphalic SAH. All patients with perimesencephalic SAH achieved modified Rankin score (mRS) 0 at discharge and 6-month follow-up, compared with 45% mRS 0 at discharge and 68% at 6-month follow-up in non-perimesencephalic SAH. Patients with perimesencephalic SAH presented a uniformly uncomplicated clinical course. Among non perimesencephalic SAH patients there were 19 neurological/neurosurgical and 10 medical complications, two small aneurysms diagnosed at follow-up DSA, and one death. CONCLUSIONS: In this series, perimesencephalic SAH was associated with good clinical grades, consistently negative initial and follow-up angiograms, and an excellent prognosis. In contrast, non-perimesencephalic SAH was associated with a worse clinical presentation, higher complication rates, higher rates of true aneurysm detection on follow-up angiogram, and a poorer outcome. PMID- 23452574 TI - Isolated cortical vein thrombosis: a rare cause of venous stroke with good prognosis after timely diagnosis and treatment. AB - BACKGROUND: Isolated cortical vein thrombosis (ICoVT) is a rare condition representing approximately 6% of cerebral vein thromboses (CVT). In all its forms, CVT is more prevalent in women. ICoVT shares the same group of predisposing conditions typical of other CVT. It may thus be easily missed due to its non-specific clinical presentation and confounding radiological findings, which may lead to a delay in appropriate diagnosis and treatment. METHODS: A comprehensive literature search was conducted to identify manuscripts discussing epidemiology, risk factors, clinical presentation, radiological techniques and presentation, management, and outcome in patients with ICoVT. RESULTS: We identified 40 papers published between 1991 and 2012 that met our criteria for review. DISCUSSION: MR techniques are essential in the diagnosis of this entity. Without appropriate therapy, these thromboses may extend bidirectionally and even compromise the dural sinuses. Correction of predisposing factors for venous thrombosis and anticoagulation is the therapy of choice for most patients. The overall prognosis with adequate and timely therapy is very good. PMID- 23452575 TI - Clinical course and treatment of vertebrobasilar dolichoectasia: a systematic review of the literature. AB - OBJECTIVES: Vertebrobasilar dolichoectasia is a rare condition with unsettled clinical course and treatment. We performed a systematic review of the literature on clinical course and treatment of vertebrobasilar dolichoectasia. METHODS: We systematically searched PUBMED, EMBASE, and the Cochrane Library and hand searched citations for studies on vertebrobasilar dolichoectasia with an average follow-up duration of at least 1 year and fulfilling predefined inclusion criteria. We pooled data to calculate proportions with corresponding 95% confidence intervals (CIs) for 5 year incidences of: (1) transient ischemic attack; (2) ischemic stroke; (3) subarachnoid hemorrhage; (4) other intracranial hemorrhage; (5) (progressive) brainstem compression; (6) clinical deterioration from (progressive) hydrocephalus; and (7) case fatality. We used the Cochrane collaboration five-item tool to assess risk of bias in treatment studies. RESULTS: From 958 citations identified, we included 12 manuscripts describing nine cohorts with 375 patients. Follow-up ranged 1.5-11.7 years. Estimated 5 year complication risks were for ischemic stroke 17.6% (95%CI: 12.4-22.8), brainstem compression 10.3% (95%CI: 6.4-14.1), transient ischemic attack 10.1% (95%CI: 6.3 14.0), hemorrhagic stroke 4.7% (95%CI: 2.4-8.3), hydrocephalus 3.3% (95%CI: 1.4 6.4), and subarachnoid hemorrhage 2.6% (95%CI: 1.1-5.1). The estimated five year case fatality was 36.2% (95%CI: 30.6-41.8). The 5 year prognosis is more favorable in patients who are asymptomatic at time of diagnosis. No randomized intervention trials were identified. In the included studies, treatment specifications were often not available for individual patients. None of the studies fulfilled any of the criteria to reduce risk of bias. CONCLUSION: Patients with vertebrobasilar dolichoectasia are at high risk of ischemic stroke, brainstem compression, and death. Hemorrhagic complications are less common. Risk of bias in the included studies was too high to make any recommendation regarding treatment. PMID- 23452576 TI - Optimal cerebral perfusion pressure: are we ready for it? AB - OBJECTIVES: Cerebral perfusion pressure (CPP)-oriented therapy and the Lund concept lie on opposite ends of the CPP scale, in the management of head injury. Optimization of CPP by monitoring cerebral vascular pressure reactivity is an alternative approach that may reconcile these two divergent approaches, preventing both injurious hypotension and hypertension with an individualized CPP target. METHODS: Indices describing cerebral vascular reactivity or cerebral blood flow autoregulation, derived from intracranial pressure, near-infrared spectroscopy, or transcranial Doppler are reviewed in this manuscript. RESULTS: Indices of cerebrovascular reactivity and autoregulation typically converge to a U-shape curve when viewed as a function of CPP, with the best reactivity metrics indicating optimal CPP. In a retrospective study of prospectively collected data from head-injured patients, Steiner et al. demonstrated that a greater distance between averaged over total monitoring time-CPP and optimal CPP, correlated with unfavourable outcome. A recent study of 300 head-injured patients (2003-2009) showed that hypotension below optimal CPP was associated with greater mortality rate, while hypertension above optimal CPP was associated with an increase in severe disability. DISCUSSION: Pilot studies indicating feasibility of autoregulation-oriented CPP optimization have been performed in adult and paediatric traumatic brain injury, aneurysmal subarachnoid haemorrhage, and in patients undergoing cardiothoracic surgery. It remains to be prospectively demonstrated whether optimal CPP management is able to improve outcome. PMID- 23452577 TI - Ultrasound-based imaging in neurocritical care patients: a review of clinical applications. AB - OBJECTIVE: To analyze the diagnostic, monitoring, and procedural applications of ultrasound (US) imaging in neurocritical care (NCC) patients. METHOD: US imaging has been extensively validated in various subset of critically ill patients, but not specifically in the NCC population. We reviewed the clinical applications of US imaging for heart, vascular, brain, and lung evaluation and for possible procedural uses in NCC patients. Major neurosurgical books, journals, testimonials, authors' personal experience, and scientific databases were analyzed. RESULTS: Cardiac US imaging provides accurate information at NCC arrival to stratify risk factors, including presence of atrial septal defect/patent formen ovale, abnormal ventricular function, or pericardial effusion, and to monitor cardiac anatomy and function during the NCC stay for guiding goal-directed therapy. Vascular US in NCC patients has three especially relevant indications: to screen anatomy and flow in extracranial supra-aortic arteries, to diagnose deep vein thrombosis, and to optimize the safety of central venous catheterization. Brain US has important clinical applications in the NCC, including transcranial Doppler and emerging techniques for cerebral blood flow evaluation with contrast-enhanced US imaging. Lung US, as demonstrated in other intensive care unit patients, provides accurate diagnosis of anatomical and functional abnormalities and enables diagnosis of pleural effusion, pneumothorax, lung consolidation, pulmonary abscess and interstitial-alveolar syndrome, and lung recruitment/derecruitment. US imaging can effectively guide percutaneous tracheostomy. CONCLUSION: In conclusion, US imaging is an important diagnostic tool that provides real-time information at the bedside to stratify risk, monitor for complications, and guide invasive procedures in NCC patients. PMID- 23452578 TI - QTc prolongation after brain surgery. AB - OBJECTIVE: Abnormalities observed in the electrocardiogram (ECG) after acute central nervous system (CNS) events have been reported. Our objective was to assess the incidence of heart rate-corrected QT interval (QTc) prolongation in patients admitted to the intensive care unit (ICU) after brain surgery. METHODS: Admission standard 12-lead ECGs were analyzed blinded to patient data. The QT interval was measured and Bazzett's formula was used to obtain QTc. Prolonged QTc was defined as ?450 ms. RESULTS: We included 114 patients in the study. The mean age was 49+/-17 years. Brain neoplasm was the surgical indication in 90% of the patients. The mean QTc was 470+/-42 ms. Prolonged QTc was found in 71% patients. The heart rate-corrected QT interval was between 450 ms and 500 ms in 52% and >500 ms in 19% of the patients. The heart rate and concentration of serum glucose were higher in the prolonged QTc group. Only 7.5% of all patients had hypokalemia (<=3 mEq/l). In the prolonged QTc group 9.2% had hypokalemia compared to 3.2% in normal QTc patients (P = 0.406). There were no significant associations between categories of QTc and the serum levels of creatinine, magnesium, calcium, sodium, or pH. Phenytoin and metoclopramide were not frequently used in patients with prolonged QTc. DISCUSSION: This study supports our hypothesis that prolonged QTc is frequently observed after a brain surgery. Hypokalemia, hypocalcaemia, and drugs such as metoclopramide or phenytoin could not explain the high incidence of prolonged QTc. Brain injury during a surgical procedure may be one of the primary causes of QTc prolongation after neurosurgery. PMID- 23452579 TI - Pitfalls and slip-ups in brain death determination. AB - Brain death (or brainstem death in the UK) is an uncommon result of a major catastrophic neurologic injury. The determination of brain death proceeds through a comprehensive and stepwise evaluation. There is no room for misinterpretations. Slip ups, however, could occur with brain death determination and this review discusses the most common concerns encountered by physicians. Problems may arise when a multitude of small errors accumulate and this may occur with an inexperienced physician who misjudges confounders, performs an incomplete evaluation, and misinterprets a confirmatory test. PMID- 23452580 TI - Comparative study among three different methods of bone marrow mesenchymal stem cell transplantation following cerebral infarction in rats. AB - The objective of this study was to investigate the effects of transplanted bone marrow mesenchymal stem cells (BMSCs) administered via internal jugular vein injection, carotid artery injection, or intraventricular transplantation for the treatment of cerebral infarction, which was modeled in rats. The neurological scores of the treated rats and the distribution of the transplanted cells (GFP labeled) in the infarction area were evaluated. The cerebral infarction model was produced by inserting a modified Zea-longa suture, which generated middle cerebral artery occlusion (MCAO). The GFP-labeled BMSCs were transplanted through the jugular vein or the carotid artery or by stereotactic intraventricular delivery to the infarction models 1 week after the cerebral infarction was established. The 'Nerve Function Score' of the model rats was recorded before and after BMSC transplantation. Brain tissue sections were examined under a fluorescence microscope. We determined that the transplanted BMSCs rescued brain function, which was indicated by a decrease in the neurological scores (P<0.05) following BMSC transplantation. The effect of BMSC transplantation was reflected in decreases in the neurological score in the intraventricular transplantation group, the carotid artery transplantation group, and the jugular vein graft group*. The transplanted BMSCs were able to migrate to the brain injury area and the cortex and survived the infarction; thus, BMSCs may promote the recovery of nerve function. PMID- 23452581 TI - Association of intronic repetition of SLC26A4 gene with Hashimoto thyroiditis disease. AB - Intronic microsatellites repeats were implicated in the pathogenic mechanisms of several diseases. SLC26A4 gene, involved in the genetic susceptibility of autoimmune thyroid disease (AITD), harbours large non-coding introns. Using the tandem repeat finder (TRF) Software, two new polymorphic microsatellite markers, rs59736472 and rs57250751, located at introns 10 and 20, respectively, were identified. A case-control design including 308 patients affected with AITD (146 GD, 90 HT and 72 PIM) and 212 unmatched healthy controls were performed for each marker (rs59736472, D7S2459 and rs57250751). Furthermore, we used PHASE 2.0 version to reconstruct haplotypes, Kolmogorov-Smirnov (KS) and the Clump analysis program for multivariate analysis. The fluorescent genotyping revealed three alleles (106,112 and 115 bp) for rs57250751 and 12 alleles for both D7S2459 and rs59736472 ranging from 134 to 156 bp and from 144 to 168 bp, respectively. The case-control analysis confirmed the positive association of D7S2459 with Hashimoto thyroiditis (HT) disease previously reported. Moreover, a significant association was found only with rs59736472 and HT disease. Haplotype-specific analysis showed that the 140-148-115 haplotype may increase the risk of HT (chi2=9.8, 1 df, P=0.0017, OR=2.07, IC [1.27-3.36]). Consequently, considering the number of repetitions of both D7S2459 and rs59736472, we found 15 alleles ranging from 45 to 59 repetitions. The case-control analysis showed a significant association of the 55 repetition with HT disease (chi2=6.32, 1 df, p c=0.012, OR=1.74, IC [1.1-2.76]). In conclusion, we suggest the association of longer alleles of intron 10 of SLC26A4 gene with HT disease. PMID- 23452582 TI - Grain protein content variation and its association analysis in barley. AB - BACKGROUND: Grain protein content (GPC) is an important quality determinant for barley used as malt, feed as well as food. It is controlled by a complex genetic system. GPC differs greatly among barley genotypes and is also variable across different environments. It is imperative to understand the genetic control of barley GPC and identify the genotypes with less variation under the different environments. RESULTS: In this study, 59 cultivated and 99 Tibetan wild barley genotypes were used for a genome-wide association study (GWAS) and a multi platform candidate gene-based association analysis, in order to identify the molecular markers associated with GPC. Tibetan wild barley had higher GPC than cultivated barley. The significant correlation between GPC and diastatic power (DP), and malt extract confirmed the importance of GPC in determining malt quality. Diversity arrays technology (DArT) markers associated with barley GPC were detected by GWAS. In addition, GWAS revealed two HvNAM genes as the candidate genes controlling GPC. No association was detected between HvNAM1 polymorphism and GPC, while a single nucleotide polymorphism (SNP) (798, P < 0.01), located within the second intron of HvNAM2, was associated with GPC. There was a significant correlation between haplotypes of HvNAM1, HvNAM2 and GPC in barley. CONCLUSIONS: The GWAS and candidate gene based-association study may be effectively used to determine the genetic variation of GPC in barley. The DArT markers and the polymorphism of HvNAM genes identified in this study are useful in developing high quality barley cultivars in the future. HvNAM genes could play a role in controlling barley GPC. PMID- 23452583 TI - Pediatric idiopathic intracranial hypertension and extreme childhood obesity: a role for weight gain. PMID- 23452584 TI - Comprehensive assessment of serious adverse events following immunization by health care providers. PMID- 23452585 TI - Tick-borne encephalitis carries a high risk of incomplete recovery in children. AB - OBJECTIVE: To examine long-term outcome after tick-borne encephalitis (TBE) in children. STUDY DESIGN: In this population-based cohort, 55 children with TBE with central nervous system involvement infected during 2004-2008 were evaluated 2-7 years later using the Rivermead post-concussion symptoms questionnaire (n = 42) and the Behavior Rating Inventory of Executive Functioning for parents and teachers (n = 32, n = 22, respectively). General cognitive ability was investigated in a subgroup (n = 20) using the Wechsler Intelligence Scale for Children, 4th edition. RESULTS: At long-term follow-up, two-thirds of the children experienced residual problems, the main complaints being cognitive problems, headache, fatigue, and irritability. More than one-third of the children were reported by parents or teachers to have problems with executive functioning on the Behavior Rating Inventory of Executive Functioning, mainly in areas involving initiating and organizing activities and working memory. Children who underwent Wechsler Intelligence Scale for Children, 4th edition testing had a significantly lower working memory index compared with reference norms. CONCLUSION: A large proportion of children experience an incomplete recovery after TBE with central nervous system involvement. Cognitive problems in areas of executive function and working memory are the most prevalent. Even if mortality and severe sequelae are low in children after TBE, all children should be followed after TBE to detect cognitive deficits. PMID- 23452587 TI - Encephalocraniocutaneous lipomatosis: magnetic resonance imaging findings in a child. PMID- 23452586 TI - Effects of different complementary feeding regimens on iron status and enteric microbiota in breastfed infants. AB - OBJECTIVE: To compare iron status in breastfed infants randomized to groups receiving complementary feeding regimens that provided iron from fortified infant cereals or meats, and to examine the development of the enteric microbiota in these groups. STUDY DESIGN: Forty-five exclusively breastfed 5-month-old infants were randomized to 1 of 3 feeding groups (FGs)-commercially available pureed meats, iron- and zinc-fortified infant cereals, or iron-only fortified infant cereals-as the first and primary complementary food through 9-10 months of age. Dietary iron was determined by monthly 3-day diet records. Iron status was assessed at the end of the study by measurements of hemoglobin, serum ferritin, and soluble transferrin receptor levels. In a subsample of 14 infants, enteric microbiota were profiled in monthly stool samples (5-9 months) by 16S ribosomal RNA gene pyrosequencing. RESULTS: Infants in the 2 cereal FGs had 2- to 3-fold greater daily iron intakes versus the meat FG (P < .0001). More than one-quarter (27%) of the infants had a low serum ferritin level, and 36% were mildly anemic, with no significant differences by FG; more infants in the meat FG had a high soluble transferrin receptor value (P = .03). Sequence analysis identified differences by time and FG in the abundances of several bacterial groups, including significantly more abundant butyrate-producing Clostridium group XIVa in the meat FG (P = .01) CONCLUSION: A high percentage of healthy infants who were breastfed-only were iron-deficient, and complementary feeding, including iron exposure, influenced the development of the enteric microbiota. If these findings are confirmed, then reconsideration of strategies to both meet infants' iron requirements and optimize the developing microbiome may be warranted. PMID- 23452588 TI - Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. AB - OBJECTIVE: To evaluate the electrographic seizure burden in neonates with hypoxic ischemic encephalopathy (HIE) treated with or without therapeutic hypothermia and stratified results by severity of HIE and severity of injury as assessed by magnetic resonance imaging (MRI). STUDY DESIGN: Between 2007 and 2011, video electroencephalography (EEG) monitoring was initiated in neonates with moderate to severe HIE. Seizure burden (in seconds) was calculated, and brain MRI scans were quantitatively scored. Data were analyzed by ANOVA, the Student t test, and the chi(2) test. RESULTS: Sixty-nine neonates with moderate or severe HIE were prospectively enrolled, including 51 who received therapeutic hypothermia and 18 who did not. The mean duration of video-EEG monitoring was longer in the therapeutic hypothermia group (72 +/- 34 hours vs 48 +/- 34 hours; P = .01). The therapeutic hypothermia group had a lower electrographic seizure burden (log units) after controlling for injury, as assessed by MRI (2.9 +/- 0.6 vs 6.2 +/- 0.9; P = .003). A reduction in seizure burden was seen in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80). Among neonates with injury assessed by MRI, seizure burden was lower in those with mild (P = .0004) and moderate (P = .02) injury, but not in those with severe injury (P = .90). CONCLUSION: Therapeutic hypothermia was associated with reduced electrographic seizure burden in neonatal HIE. This effect was detected on video-EEG in infants with moderate HIE, but not in those with severe HIE. When stratified by injury as assessed by MRI, therapeutic hypothermia was associated with a reduced seizure burden in infants with mild and moderate injury, but not in those with severe injury. PMID- 23452590 TI - [Too much evaluation kills evaluation]. PMID- 23452591 TI - [Mouse models of autism: a common basis for syndromic and non syndromic autisms ?]. PMID- 23452592 TI - [Noisy silent polymorphisms]. PMID- 23452593 TI - [The neurotrophic factor GDNF, a novel modulator of the semaphorin signaling pathway during axon guidance]. PMID- 23452594 TI - [An ionic channel involved in the skin protection against pressure]. PMID- 23452595 TI - [c-MYC, PARP1 and BIN1 as targets for therapy of cancer cell resistance]. PMID- 23452596 TI - [Inheritance of paramutation in plants and Drosophila]. PMID- 23452597 TI - [PSD-95 expression controls L-Dopa dyskinesia]. PMID- 23452598 TI - [Cellular communication between neurons and glial cells: an overview]. PMID- 23452599 TI - [Mucus clearance in the respiratory tract: a new concept?]. PMID- 23452600 TI - [Cell adhesion mechanics of zebrafish gastrulation]. PMID- 23452601 TI - [A new hope: restoration of auditory evoked responses]. PMID- 23452602 TI - [Micro-RNA miR-7a controls the production of dopaminergic neurons in the mouse forebrain]. PMID- 23452603 TI - [Genetic, immunological, and pharmacological strategies to generate improved oncolytic viruses]. AB - Since over a century, medical literature has reported cases of viral infections leading to tumour regression. This phenomenon, now understood, can be exploited for cancer therapy. It involves viruses defined as "oncolytic". These viruses, either wild-type or genetically engineered, replicate preferentially in malignant cells. They induce tumour regression through various mechanisms including direct cell lysis and stimulation of an anti-tumour immune response. Several oncolytic viruses have reached late-stage clinical investigation and could be approved soon for treating certain neoplasms. While already promising, there is still room for improvement and various genetic, immunological, and pharmacological strategies are currently under development to increase their therapeutic efficacy. PMID- 23452604 TI - [Vesicular stomatitis virus in the fight against cancer]. AB - Cancer is a complex disease that affects more and more people around the world. Unfortunately, existing treatments are only partially efficient and often induce major side effects. Thus, the use of viruses to selectively kill cancer cells is a new promising therapeutic approach. Recently, VSV has been used in oncolytic virotherapy because of its capacity to preferentially infect most human tumor cells. However, despite the availability of good oncolytic VSV mutants, the large variability of tumor cell types and the multiple ways in which they can evade viral infection suggests that therapeutic combinations of various viruses will be necessary to efficiently treat most cancers. A better understanding of the infection mechanisms and immune system recruitment by oncolytic viruses will be of great value for the development of safe and efficient strategies for cancer treatment. PMID- 23452605 TI - [Ischemia reperfusion control: the key of kidney graft outcome]. AB - During the transplantation procedure, ischemia reperfusion is an inevitable situation characterized by specific pathophysiological processes, which ultimately act synergistically to create injuries in the graft. These injuries are involved in early graft dysfunctions which promote chronic dysfunction and compromise graft outcome. Progresses in immunosuppressive drug regimens now place ischemia reperfusion injury control at the forefont for innovative therapeutic strategy to improve the quality of the graft. This review details these different processes and its consequences on renal graft function underlying the interest of novel therapeutic strategy. PMID- 23452606 TI - [Epilepsy pharmacogenetics : science or fiction?]. AB - Pharmacogenetics (PGX) is the study of how genetic variants influence individual responses to drugs. Although numerous candidate gene studies in epilepsy PGX have been published, to date only two validated associations exist: the association of the *2 and *3 alleles of CYP2C9 with phenytoin metabolism and the association of HLA-B*1502 with serious hypersensitivity reactions to carbamazepine. The advent of novel technologies such as genomewide association studies and next generation sequencing will likely lead to the identification of additional genetic biomarkers. The potential benefits of epilepsy PGX are multiple: epilepsy treatment in individual patients would become more rationalized, clinical trials could be stratified according to patients' genetic profiles and novel therapeutic pathways may be uncovered. Ultimately, it is hoped that PGX will improve the quality of life for people suffering from epilepsy worldwide. PMID- 23452607 TI - [Compartmentalization and plasticity of the microtubule network]. AB - Cytoplasm organization greatly depends on the cytoskeleton and especially on microtubules. Their multiple roles comprise for instance long-distance vesicular traffic or the organization of several signalling pathways. A variety of cellular functions require highly dynamic microtubules, which alternate between growing and shrinking phases. Meanwhile, other functions use stable microtubules, in which tubulin often bears multiple post-translational modifications like acetylation. Recent progress has been made in understanding some molecular mechanisms that control microtubule dynamics or tubulin acetylation. These mechanisms reveal the high plasticity of microtubules and point out the importance of their compartmentalization at structural and functional levels. PMID- 23452608 TI - [mTORC1 and sirolimus: a link with fertility]. AB - mTOR (mammalian target of rapamycin), a protein kinase highly conserved, is the catalytic subunit of two complexes, mTORC1 and mTORC2. These complexes are regulated by amino acids availability, by insulin and growth factors signaling pathways. Thus, mTORC1 and mTORC2 complexes are essential sensors of the cellular nutrient and energy levels in living organisms. mTORC1 is sensitive to rapamycin (also known as sirolimus), a drug prescribed in case of organ transplantation (kidney) due to its immunosuppressive and anti-proliferative properties. However, some studies have shown that the rapamycin treatment can induce fertility disorders. Thus, this article reviews the mTOR involvement in the male and female reproductive axis. PMID- 23452609 TI - [Ethics of biomedical research: questions about patient information]. AB - All recommendations and laws concerning biomedical research, including the most recent in France in 2012, emphasize the quality of patient information to justify its participation. To optimize practices, it is important to take into account the central issues: what limits of information? What role for the relatives and family in the decision in case of disability or vulnerability of a patient? What need for specific information for long protocol and follow-up cohort? What information about research results? PMID- 23452610 TI - [The dark side of science]. PMID- 23452611 TI - [Snips versus family history]. PMID- 23452612 TI - [X chromosome inactivation in human: XACT and XIST, a non coding RNA for each X]. PMID- 23452613 TI - An animal model of atherosclerotic plaque disruption and thrombosis in rabbit using pharmacological triggering to plaques induced by perivascular collar placement. AB - INTRODUCTION: Limited availability of suitable animal model of plaque disruption and thrombosis has hampered the study of mechanism and preclinical evaluation of plaque-stabilizing therapies. This study aims to develop an animal model of atherosclerotic plaque disruption and thrombosis in rabbit femoral artery. METHODS: Silastic collars were placed around the bilateral femoral arteries of rabbits, which had been fed with atherogenic diet for 7 days. After 28 days on the same diet, the rabbits received pharmacological triggering by intraperitoneal injection of Russell's viper venom (RVV, 0.15 mg/kg) followed by intravenous injection of histamine (0.02 mg/kg), and the animals were then processed for imageological and histological examinations. RESULTS: Perivascular collar placement of the femoral artery in high-cholesterol-fed rabbits for 28 days induced marked intimal hyperplasia, which was a lipid- and collagen-rich lesion that contained substantial amount of macrophages and smooth muscle cells. Subsequent histological analysis showed that the pharmacological triggering evoked plaque disruption and platelet- and fibrin-rich thrombi in the collared femoral arteries. CONCLUSION: We demonstrated, for the first time, a rabbit model of plaque disruption and thrombosis induced by the combination of perivascular collar placement, RVV, and histamine injections. This model can be rapidly formed, easily operated, and site controlled. PMID- 23452614 TI - Reduction of the domino effect in osteoporotic vertebral compression fractures through short-segment fixation with intravertebral expandable pillars compared to percutaneous kyphoplasty: a case control study. AB - BACKGROUND: Osteoporotic vertebral compression fracture is the leading cause of disability and morbidity in elderly people. Treatment of this condition remains a challenge. Osteoporotic vertebral compression fractures can be managed with various approaches, but each has limitations. In this study, we compared the clinical outcomes obtained using short-segment fixation with intravertebral expandable pillars (I-VEP) to those obtained with percutaneous kyphoplasty in patients who had suffered vertebral compression fractures. METHODS: The study included 46 patients with single-level osteoporotic thoracolumbar fractures. Twenty-two patients in Group I underwent short-segment fixation with I-VEP and 24 patients in Group II underwent kyphoplasty. All patients were evaluated pre- and postoperatively using a visual analogue scale, anterior height of the fractured vertebra, and kyphotic angle of the fractured vertebra. The latter 2 radiological parameters were measured at the adjacent segments as well. RESULTS: There was no significant difference between the groups in terms of gender or fracture level, but the mean age was greater in Group II patients (p = 0.008). At the 1-year follow-up, there were no significant differences in the visual analogue scale scores, anterior height of the fractured vertebra, or the value representing anterior height above the fractured vertebra and kyphotic angle below the fractured vertebra, after adjusting for the patients' gender, fracture level, and age. When considered separately, the anterior height below the fractured vertebra was significantly higher and the kyphotic angle above the fractured vertebra was significantly smaller in Group I than in Group II (p = 0.029 and p = 0.008, respectively). The kyphotic angle of the fractured vertebra was significantly smaller in Group II than in Group I (p < 0.001). CONCLUSIONS: In older individuals with vertebral compression fractures, kyphoplasty restored and maintained the collapsed vertebral body with less kyphotic deformity than that induced by short-segment fixation with I-VEP. Short-segment fixation with I-VEP was more effective in maintaining the integrity of adjacent segments, which prevented the domino effect often observed in patients with osteoporotic kyphotic spines. PMID- 23452615 TI - Molecular characterization of two insect nematode species (Oxyurida: Thelastomatidae) using small subunit (18S) ribosomal DNA sequence and secondary structure analyses. AB - Nematodes of the family Thelastomatidae are parasitic in the alimentary tract of many arthropods, including Periplaneta americana L. In Meerut, Uttar Pradesh, India, two nematode species, namely Hammerschmidtiella indicus and Thelastoma icemi, belonging to this family have been reported. In the present study, the molecular phylogeny of these two nematode species was derived using small subunit (18S) sequence and secondary-structure analyses. The small subunit sequence analyses were carried out to explore the validation and systematics of these species. Phylogenetic analyses were performed for primary sequence data as well as using neighbour-joining and maximum-parsimony approaches. In contrast, the inferred secondary structures for the two species, using free-energy modelling, showed structural identities. As well as this, motif sequences were also found to be a promising tool for nematode species identification. The study provides molecular characterization based on primary sequence data of the 18S ribosomal DNA region of the nematodes along with secondary-structure data and motif sequences for inferences at higher taxonomic levels. PMID- 23452616 TI - Temporal trend of short-term mortality in severely ill patients receiving parenteral glutamine supplementation. PMID- 23452617 TI - Importance of material evaluation prior to the construction of devices for in vitro techniques. AB - The development and validation of new in vitro methods in the field of toxicology have gained more importance in recent years due to stricter guidelines for animal testing, especially in the European Union. Consequently, advances in the construction of technical devices for the exposure of cell or tissue cultures to test substances are necessary. Here, to obtain reliable results, it is important to exclusively use materials that do not interfere with the cell viability. Thus, similar to the biomaterials testing of medical devices which is regulated in the Directive 93/42/EEC, the biocompatibility of the materials has to be verified prior to the construction of such devices. We present here a novel approach for biomaterials testing which allows the quantitative and qualitative assessment of cytotoxicity of material samples. Stainless steel and silicone are often used for laboratory equipment, due to their high chemical, thermal and mechanical resistance. However, our results highlight that some types of silicone may have adverse effects on cultured cells. Moreover, special methods for the surface treatment of metals may also be a critical factor for in vitro devices. Therefore, the testing of all materials coming in contact with cell cultures is highly recommended. PMID- 23452618 TI - Modulation in current density of metal/n-SiC contact by inserting Al2O3 interfacial layer. AB - Metal contact to SiC is not easy to modulate since the contact can be influenced by the metal, the termination of the SiC, the doping, and the fabrication process. In this work, we introduce a method by inserting a thin Al2O3 layer between metal and SiC to solve this problem simply but effectively. The Al2O3/n SiC interface composition was obtained with X-ray photoemission spectroscopy, and the electrical properties of subsequently deposited metal contacts were characterized by current-voltage method. We can clearly demonstrate that the insertion of Al2O3 interfacial layer can modulate the current density effectively and realize the transfer between the Schottky contact and ohmic contact. PMID- 23452619 TI - The Arabidopsis At1g30680 gene encodes a homologue to the phage T7 gp4 protein that has both DNA primase and DNA helicase activities. AB - BACKGROUND: The Arabidopsis thaliana genome encodes a homologue of the full length bacteriophage T7 gp4 protein, which is also homologous to the eukaryotic Twinkle protein. While the phage protein has both DNA primase and DNA helicase activities, in animal cells Twinkle is localized to mitochondria and has only DNA helicase activity due to sequence changes in the DNA primase domain. However, Arabidopsis and other plant Twinkle homologues retain sequence homology for both functional domains of the phage protein. The Arabidopsis Twinkle homologue has been shown by others to be dual targeted to mitochondria and chloroplasts. RESULTS: To determine the functional activity of the Arabidopsis protein we obtained the gene for the full-length Arabidopsis protein and expressed it in bacteria. The purified protein was shown to have both DNA primase and DNA helicase activities. Western blot and qRT-PCR analysis indicated that the Arabidopsis gene is expressed most abundantly in young leaves and shoot apex tissue, as expected if this protein plays a role in organelle DNA replication. This expression is closely correlated with the expression of organelle-localized DNA polymerase in the same tissues. Homologues from other plant species show close similarity by phylogenetic analysis. CONCLUSIONS: The results presented here indicate that the Arabidopsis phage T7 gp4/Twinkle homologue has both DNA primase and DNA helicase activities and may provide these functions for organelle DNA replication. PMID- 23452620 TI - Characterizing microclimate in urban malaria transmission settings: a case study from Chennai, India. AB - BACKGROUND: Environmental temperature is an important driver of malaria transmission dynamics. Both the parasite and vector are sensitive to mean ambient temperatures and daily temperature variation. To understand transmission ecology, therefore, it is important to determine the range of microclimatic temperatures experienced by malaria vectors in the field. METHODS: A pilot study was conducted in the Indian city of Chennai to determine the temperature variation in urban microclimates and characterize the thermal ecology of the local transmission setting. Temperatures were measured in a range of probable indoor and outdoor resting habitats of Anopheles stephensi in two urban slum malaria sites. Mean temperatures and daily temperature fluctuations in local transmission sites were compared with standard temperature measures from the local weather station. The biological implications of the different temperatures were explored using temperature-dependent parasite development models to provide estimates of the extrinsic incubation period (EIP) of Plasmodium vivax and Plasmodium falciparum. RESULTS: Mean daily temperatures within the urban transmission sites were generally warmer than those recorded at the local weather station. The main reason was that night-time temperatures were higher (and hence diurnal temperature ranges smaller) in the urban settings. Mean temperatures and temperature variation also differed between specific resting sites within the transmission environments. Most differences were of the order of 1-3 degrees C but were sufficient to lead to important variation in predicted EIPs and hence, variation in estimates of transmission intensity. CONCLUSIONS: Standard estimates of environmental temperature derived from local weather stations do not necessarily provide realistic measures of temperatures within actual transmission environments. Even the small differences in mean temperatures or diurnal temperature ranges reported in this study can lead to large variations in key mosquito and/or parasite life history traits that determine transmission intensity. Greater effort should be directed at quantifying adult mosquito resting behaviour and determining the temperatures actually experienced by mosquitoes and parasites in local transmission environments. In the absence of such highly resolved data, the approach used in the current study provides a framework for improved thermal characterization of transmission settings. PMID- 23452623 TI - Chemometric techniques in distribution, characterisation and source apportionment of polycyclic aromatic hydrocarbons (PAHS) in aquaculture sediments in Malaysia. AB - This study investigated polycyclic aromatic hydrocarbons (PAHs) pollution in surface sediments within aquaculture areas in Peninsular Malaysia using chemometric techniques, forensics and univariate methods. The samples were analysed using soxhlet extraction, silica gel column clean-up and gas chromatography mass spectrometry. The total PAH concentrations ranged from 20 to 1841 ng/g with a mean of 363 ng/g dw. The application of chemometric techniques enabled clustering and discrimination of the aquaculture sediments into four groups according to the contamination levels. A combination of chemometric and molecular indices was used to identify the sources of PAHs, which could be attributed to vehicle emissions, oil combustion and biomass combustion. Source apportionment using absolute principle component scores-multiple linear regression showed that the main sources of PAHs are vehicle emissions 54%, oil 37% and biomass combustion 9%. Land-based pollution from vehicle emissions is the predominant contributor of PAHs in the aquaculture sediments of Peninsular Malaysia. PMID- 23452621 TI - Molecular basis of 'hypoxic' breast cancer cell radio-sensitization: phytochemicals converge on radiation induced Rel signaling. AB - BACKGROUND: Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers (BCa) and generally associated with therapeutic resistance, metastases, and poor patient survival. About 50% of locally advanced BCa, where radiotherapy is less effective are suggested to be due to hypoxic regions. In this study, we investigated the potential of bioactive phytochemicals in radio-sensitizing hypoxic BCa cells. METHODS: Hypoxic (O2-2.5%; N2-92.5%; CO2-5%) MCF-7 cells were exposed to 4 Gy radiation (IR) alone or after pretreatment with Curcumin (CUR), curcumin analog EF24, neem leaf extract (NLE), Genistein (GEN), Resveratrol (RES) or raspberry extract (RSE). The cells were examined for inhibition of NFkappaB activity, transcriptional modulation of 88 NFkappaB signaling pathway genes, activation and cellular localization of radio responsive NFkappaB related mediators, eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIkappaBalpha, TNFalpha, Birc-1, -2, -5 and associated induction of cell death. RESULTS: EMSA revealed that cells exposed to phytochemicals showed complete suppression of IR-induced NFkappaB. Relatively, cells exposed EF24 revealed a robust inhibition of IR-induced NFkappaB. QPCR profiling showed induced expression of 53 NFkappaB signaling pathway genes after IR. Conversely, 53, 50, 53, 53, 53 and 53 of IR-induced genes were inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. In addition, 25, 29, 24, 16, 11 and 21 of 35 IR suppressed genes were further inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. Immunoblotting revealed a significant attenuating effect of IR modulated radio-responsive eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIkappaBalpha, TNFalpha, Birc-1, -2 and -5 with EF24, NLE, CUR, GEN, RES or RSE. Annexin V-FITC staining showed a consistent and significant induction of IR-induced cell death with these phytochemicals. Notably, EF24 robustly conferred IR-induced cell death. CONCLUSIONS: Together, these data identifies the potential hypoxic cell radio-sensitizers and further implies that the induced radio-sensitization may be exerted by selectively targeting IR-induced NFkappaB signaling. PMID- 23452622 TI - Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study. AB - INTRODUCTION: Hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased risk of mortality in critically ill patients. The role of diabetic status on modulating the relation of these three domains of glycemic control with mortality remains uncertain. The purpose of this investigation was to determine how diabetic status affects the relation of hyperglycemia, hypoglycemia, and increased glycemic variability with the risk of mortality in critically ill patients. METHODS: This is a retrospective analysis of prospectively collected data involving 44,964 patients admitted to 23 intensive care units (ICUs) from nine countries, between February 2001 and May 2012. We analyzed mean blood glucose concentration (BG), coefficient of variation (CV), and minimal BG and created multivariable models to analyze their independent association with mortality. Patients were stratified according to the diagnosis of diabetes. RESULTS: Among patients without diabetes, mean BG bands between 80 and 140 mg/dl were independently associated with decreased risk of mortality, and mean BG bands>or=140 mg/dl, with increased risk of mortality. Among patients with diabetes, mean BG from 80 to 110 mg/dl was associated with increased risk of mortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. An effect of center was noted on the relation between mean BG and mortality. Hypoglycemia, defined as minimum BG<70 mg/dl, was independently associated with increased risk of mortality among patients with and without diabetes and increased glycemic variability, defined as CV>or=20%, was independently associated with increased risk of mortality only among patients without diabetes. Derangements of more than one domain of glycemic control had a cumulative association with mortality, especially for patients without diabetes. CONCLUSIONS: Although hyperglycemia, hypoglycemia, and increased glycemic variability is each independently associated with mortality in critically ill patients, diabetic status modulates these relations in clinically important ways. Our findings suggest that patients with diabetes may benefit from higher glucose target ranges than will those without diabetes. Additionally, hypoglycemia is independently associated with increased risk of mortality regardless of the patient's diabetic status, and increased glycemic variability is independently associated with increased risk of mortality among patients without diabetes. PMID- 23452624 TI - Is the distribution of the lancelet Branchiostoma caribaeum affected by sewage discharges? An analysis at multiple scales of variability. AB - Spatial variation in the density and biomass of Branchiostoma caribaeum was analyzed along a sewage contamination gradient identified by fecal steroids in a subtropical estuary, southern Brazil. Sampling, repeated in the austral winter and summer, followed a hierarchical design nested at four spatial scales (sector>1 km; area>100 m; site>10 m; replicate<1 m). Density and biomass were significantly lower at sites characterized by high concentrations of fecal steroids. The best combinations of variables that explained the biological similarities among sites involved contamination indicators. Most of the variation of biological data was found at the smallest scales and could be related with the sediment texture. Our study highlighted the usefulness of a multi-scale perspective to evaluate distribution patterns of benthic invertebrates as a biological indication of environmental pollution. Gradient analyses at larger spatial scales may be invalidated by the patchy distribution of benthic fauna if they do not account for such small scale variability. PMID- 23452625 TI - Mast cells contribute to double-stranded RNA-induced augmentation of airway eosinophilia in a murine model of asthma. AB - BACKGROUND: Clinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13. METHODS: The effect of poly IC on allergen-induced airway eosinophilia was investigated for mast cell-conserved Kit+/+ mice and deficient KitW/KitW-v mice. The outcome of mast cell reconstitution was further investigated. RESULTS: Airway eosinophilia and IL-13 production were augmented by poly IC in Kit+/+ mice but not in KitW/KitW-v mice. When KitW/KitW-v mice were reconstituted with bone marrow-derived mast cells (BMMCs), the augmentation was restored. The augmentation was not induced in the mice systemically deficient for TIR domain-containing adaptor-inducing IFN-beta (TRIF) or interferon regulatory factor (IRF)-3, both mediate dsRNA-triggered innate immune responses. The augmentation was, however, restored in KitW/KitW-v mice reconstituted with TRIF deficient or IRF-3-deficient BMMCs. Although leukotriene B4 and prostaglandin D2 are major lipid mediators released from activated mast cells, no their contribution was shown to the dsRNA-induced augmentation of airway eosinophilia. CONCLUSIONS: We conclude that mast cells contribute to dsRNA-induced augmentation of allergic airway inflammation without requiring direct activation of mast cells with dsRNA or involvement of leukotriene B4 or prostaglandin D2. PMID- 23452626 TI - Negative pressure technology enhances bone regeneration in rabbit skull defects. AB - BACKGROUND: Bone is a slowly regenerating tissue influenced by various physiological processes, including proliferation, differentiation, and angiogenesis, under the control of growth factors. Shortening this healing time is an important and popular clinical research focus in orthopedics. Negative pressure can stimulate angiogenesis, improve blood circulation, promote granulation tissue growth and accelerate tissue wound healing. We sought to determine whether negative pressure could reduce bone healing time in a rabbit cranial defect model. METHODS: Four symmetrical holes (diameter, 3.5 mm) were drilled into the skulls of 42 New Zealand white rabbits, with two holes in each parietal bone. For each rabbit, the two sides were then randomly assigned into experimental and control groups. Using negative pressure suction tubes, experimental holes were treated with -50 kPa for 15 minutes, four times per day, whereas the control holes remained untreated. After 4 weeks, the negative pressure suction tubes were removed. At 2, 4, 6 and 8 weeks, three-dimensional (3D) reconstruction computed tomography (CT), X-ray radiopacity, and two-photon absorptiometry were used to evaluate new bone formation. Histological changes were determined by hematoxylin and eosin (H.E) staining. At weekly intervals until 6 weeks, the mRNA expression levels of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 were evaluated by RT-PCR. A paired student's t-test was employed to compare X-ray radiopacity and bone density measurements between the experimental and control groups. RESULTS: 3D reconstruction CT showed that new bone regeneration in the experimental group was greater than that in the control group at 4 and 6 weeks. At these time points, the experimental group presented with higher X-ray radiopacity and increased bone density (P < 0.05) as compared with the control group. Cartilage islands and new bone were observed by H.E staining at 2 weeks in the experimental group. By 6 weeks, the new bone had matured into lamellar bone in the experimental group. RT PCR results showed that VEGF and BMP-2 were highly expressed in the experimental group as compared with control. CONCLUSIONS: Intermittent negative pressure can promote the regeneration of bone possibly by enhancing the expression of VEGF and BMP-2. PMID- 23452627 TI - High-resolution manometry and esophageal pressure topography: filling the gaps of convention manometry. AB - Although conventional manometry set the basis for the diagnosis of esophageal motility disorders, the large axial spacing between recording sites leaves large portions of the esophagus unevaluated and vulnerable to movement artifact. However, continuous spatiotemporal representations of pressure through the esophagus recorded with high-resolution manometry offers greater detail and improved accuracy for many of the most important measurements of esophageal motor function. This review describes how the new classification schemes for esophageal pressure topography have evolved from conventional criteria and focuses on how esophageal pressure topography has improved the ability to subcategorize conventional manometric diagnoses into new functional phenotypes. PMID- 23452628 TI - Impedance-pH testing. AB - Pharmacologic treatment of gastroesophageal reflux disease is based upon gastric acid suppression with proton pump inhibitors (PPIs). In many patients, symptoms persist despite PPI treatment. For some, ongoing symptoms may be due to nonacid reflux. Accurate measurement of nonacid reflux is not possible with conventional ambulatory pH monitoring. Impedance-pH monitoring has advanced the ability to assess gastroesophageal reflux, because, in addition to detecting acid reflux, it enables measurement of nonacid reflux. This article discusses the principles of impedance-pH monitoring, catheter characteristics and placement, interpretation of studies, and clinical uses of this form of reflux monitoring. PMID- 23452630 TI - Management of achalasia. AB - Achalasia is a rare motility disorder of the esophagus characterized by the absence of peristalsis and defective relaxation of the lower esophageal sphincter. Patients present at all ages with dysphagia and regurgitation as main symptoms. The diagnosis is suggested by barium swallow and endoscopy and confirmed by manometry. Because there is no curative treatment for achalasia, treatment is confined to disruption of the lower esophageal sphincter to improve bolus passage. The most successful therapies are pneumodilation and laparoscopic Heller myotomy, with comparable short-term clinical rates of success. The prognosis of achalasia patients is good, but re-treatment is often necessary. PMID- 23452632 TI - Extraesophageal manifestations of gastroesophageal reflux disease. AB - This article discusses the current state of knowledge regarding the relationship between gastroesophageal reflux disease (GERD) and pulmonary and ear/nose/throat manifestations of reflux and outlines the recent developments in the diagnostic and treatment strategies for this difficult group of patients. Upper gastrointestinal endoscopy and pH monitoring are poorly sensitive for diagnosing reflux in this group of patients. Instead it is recommended that in those without warning symptoms, an empiric trial of proton-pump inhibitors be the initial approach to diagnosing and treating the potential underlying cause of these extraesophageal symptoms. PMID- 23452629 TI - Management of spastic disorders of the esophagus. AB - The concept of esophageal spastic disorders encompasses spastic achalasia, distal esophageal spasm, and jackhammer esophagus. These are conceptually distinct in that spastic achalasia and distal esophageal spasm are characterized by a loss of neural inhibition, whereas jackhammer esophagus is associated with hypercontractility. Hypercontractility may also occur as a result of esophagogastric junction outflow obstruction or inflammation. The diagnosis of jackhammer esophagus as a primary motility disorder is based on the characteristic manometric findings after ruling out mechanical obstruction and eosinophilic esophagitis. Despite the differences in pathophysiology among the esophageal spastic disorders, their management is similar. PMID- 23452631 TI - Gastroesophageal reflux disease and sleep. AB - There is strong evidence of a bidirectional relationship between gastroesophageal reflux disease and sleep disturbances. Gastroesophageal reflux (GER) events during the night result in sleep disturbances that include difficulty in falling asleep, sleep fragmentation, and early morning awakenings. In addition, sleep deprivation per se induces hyperalgesia of the esophageal mucosa in response to acid. Treatment includes lifestyle modifications, proton-pump inhibitors (PPIs), gamma-aminobutyric acidB agonists, hypnotics, and antireflux surgery. Among these, PPIs are considered first-line treatment for the control of nighttime gastric acid secretion; however, the timing and dosing of PPI administration should be individualized for each patient. PMID- 23452633 TI - Novel pharmaceutical approaches to reflux disease. AB - Acid suppression, with proton pump inhibitors (PPI), is the mainstay of therapy for reflux disease; despite this, symptoms and injury persist in many patients. Novel approaches have focused on (1) augmenting acid suppression with reformulated current PPIs, new PPIs or new acid pump blockers and (2) preventing reflux with reflux inhibitors. Other strategies to reduce reflux, improve gastric emptying or esophageal clearance, protect the mucosa, or reduce esophageal sensitivity are under investigation alone or in combination with PPIs; however, novel approaches face significant challenges. The safety and efficacy of current PPIs hamper demonstration of clinical superiority for new acid suppressants, and the multifactorial etiology of reflux disease means that monotherapy using a non acid suppressant is unlikely to match PPI therapy while combination therapy will be superior only if susceptible patients can be identified reliably. Advances will come, not from a 'one size fits all' approach but rather from novel pharmaceuticals allied to novel investigations to permit targeted, personalized reflux therapy. PMID- 23452634 TI - Surgical management of gastroesophageal reflux disease. AB - Antireflux surgery has become a well-established therapy for gastroesophageal reflux disease (GERD) and its complications. The popularization of minimally invasive surgical techniques has brought about a revolution in the use of fundoplication for the long-term management of GERD. A reliable and objective understanding of the outcomes following fundoplication is important for all physicians treating GERD, so that informed decisions can be made regarding the optimal treatment strategy for a given patient. With ongoing study, the appropriate indications for surgical intervention among the array of potential antireflux therapies will continue to be elucidated. PMID- 23452636 TI - Screening and risk stratification for Barrett's esophagus: how to limit the clinical impact of the increasing incidence of esophageal adenocarcinoma. AB - Barrett's esophagus (BE) and gastroesophageal reflux disease are the strongest risk factors for esophageal adenocarcinoma. To reduce the clinical impact of this disease, endoscopic screening to detect BE has been proposed and nonendoscopic diagnostic techniques are under investigation. Because screening would result in new diagnoses of BE and additional costs related to endoscopic surveillance, novel tools for risk stratification are also warranted. Dysplasia is the gold standard for risk stratification. Molecular biomarkers may provide a more objective and reproducible estimation of the individual risk, and further prospective studies are required as a prelude to introducing biomarkers into routine clinical practice. PMID- 23452635 TI - Eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition whereby infiltration of eosinophils into the esophageal mucosa leads to symptoms of esophageal dysfunction. EoE is encountered in a substantial proportion of patients undergoing diagnostic upper endoscopy. This review discusses the clinical, endoscopic, and histologic features of EoE and presents the most recent guidelines for its diagnosis. Selected diagnostic dilemmas are described, including distinguishing EoE from gastroesophageal reflux disease and addressing the newly recognized clinical entity of proton-pump inhibitor-responsive esophageal eosinophilia. Also highlighted is evidence to support both pharmacologic and nonpharmacologic treatments, including topical corticosteroids, dietary elimination therapy, and endoscopic dilation. PMID- 23452637 TI - Endoscopic therapy for Barrett's esophagus and early esophageal adenocarcinoma. AB - Endoscopic therapy for Barrett's esophagus is feasible and likely to decrease the future risk of development of esophageal adenocarcinoma. The most commonly used therapy is radiofrequency ablation, which has been shown to produce reproducible superficial injury in the esophagus. Other thermal therapies include multipolar coagulation, argon plasma coagulation, and thermal laser therapy. The other end of the ablative spectrum includes cryotherapy, which involves freezing tissue to produce mucosal necrosis. Photodynamic therapy has been used to photochemically eliminate abnormal mucosa. Endoscopic therapy has been demonstrated to be effective in high-risk situations such as Barrett's esophagus with high-grade dysplasia. PMID- 23452638 TI - Treatment strategies for esophageal cancer. AB - The treatment of esophageal cancer has evolved considerably in the past decade and depends largely on the extent of disease at the time of presentation. For disease confined to the esophageal mucosa, endoscopic therapy is replacing esophagectomy as the standard of care. For locoregional disease, neoadjuvant chemoradiation followed by esophagectomy is the best strategy for optimizing long term survival. In the minority of patents who present with metastatic disease, the prognosis is poor. Palliative therapies available for these patients include chemotherapy, radiation, endoscopic therapies to ameliorate obstruction or bleeding, and surgical intervention to optimize nutritional status or to relieve obstruction. PMID- 23452639 TI - Benign and malignant esophageal diseases. PMID- 23452641 TI - A clinicopathological and immunohistochemical study of minimal deviation adenocarcinoma of the uterine cervix. AB - OBJECTIVE: To investigate the clinical, pathological and immunohistochemical features of minimal deviation adenocarcinoma (MDA) of the uterine cervix by conducting a retrospective study of 25 cases consecutively treated in three institutes over a 10 years period. METHODS: Of 25 cases with MDA, clinical features were retrospectively reviewed, gross and micro appearances of surgical specimens of 17 operative cases were observed. Ki67, SMA, p53, PCNA, Vimentin, CEA, ER, CA125 and PR were detected on tissues from MDA and 50 cases common adenocarcinomas of the uterine cervix (AUCs) (differentiation rank: high 16, moderate 20, low 14). Their expressions were assessed in paraffin sections using the immunohistochemistry method. RESULTS: MDA accounted for only 1.2% of adenocarcinomas of the uterine cervix. The main clinical manifestations were vaginal profuse, watery or mucoid discharge and irregular bleeding. Signs were cervical hypertrophy or thickening. The gross appearance showed many similarities with common AUCs. Immunohistochemical results: the positive rates for p53 and Ki67 in >50% of the cell nuclei (Ki67/50(+)) were 88% and 64% in MDA respectively, significantly higher than common AUCs (38%, 18%, P<0.01), CA 125 was 18% in MDA, clearly lower than common AUCs (58%, P<0.01). There was no difference between MDA and common AUCs for CEA, PR, Vimentin, ER, PCNA and SMA (P>0.05). No significant difference was noticed among the high, moderate and low differentiation groups in common AUCs (P>0.05). CONCLUSIONS: For early stage diagnoses, MDA should be considered when cervical hypertrophy is present in patients complaining of a vaginal profuse watery or mucoid discharge and irregular bleeding. Positive immunohistochemical staining for p53, Ki67/50(+) and negative for CA125 can assist diagnosis and discrimination. PMID- 23452642 TI - Osteoporosis delays intervertebral disc degeneration by increasing intradiscal diffusive transport of nutrients through both mechanical and vascular pathophysiological pathways. AB - Several studies have demonstrated an inverse correlation between osteoporosis and degenerative disc disease, so that patients with lower bone mass index, despite presenting greater risks of vertebral fractures, would paradoxically present delayed intervertebral disc degeneration. However the exact pathophysiological mechanisms underlying such phenomenon are not yet completely elucidated. In this article the author provides a general scheme to explain the causal relation between osteoporosis and delayed intervertebral disc degeneration by two main pathophysiological pathways: a vascular and a mechanical one. According to such model, osteoporosis positively affects disc nutrient diffusion through several mechanisms such as: increased endplate vascularization, decreased endplate resistance and decreased intradiscal strain. In the sequence a comprehensive review of the current literature on the issue is performed in order to provide a general overview about the current degree of evidence about the role of each factor postulated to be involved in such pathophysiological scheme. Finally the author provides overall directions for future research on the issue with special attention to the causal links which are supported by weak scientific evidence or by evidence from single studies. PMID- 23452643 TI - Beyond the cliff of creativity: a novel key to Bipolar Disorder and creativity. AB - How brain processes translate into creativity is still an unsolved puzzle in science. Although a number of conceptual models of creativity has been proposed to date, the exact nature of the process is still unknown. Recent findings support the idea that creativity may reside upon a continuum with psychopathology. If creativity is meant as "the capability of generating novel and appropriate ideas to solve problems", the missing pieces of the puzzle might be nested in the link between creativity and Bipolar Disorder. The existence of such a link is widely accepted by the Scientific Community. What still remains unknown is the nature of this link. An unconventional perspective is adopted during the investigation. Starting from the observation that depression in Bipolar Disorder might possibly trace back to ancient survival strategies in extreme climatic conditions - i.e. hibernation - the paper analyses old and recent findings in different disciplines: paleo-anthropology, information technology, neurobiology. Hints from the related research fields are linked together. The unified framework that emerges, still as a set of hypotheses, is reported in the conclusions. A novel key of interpretation of both creativity and Bipolar Disorder is thus provided. The core result is that normal people, creative individuals and patients affected by Bipolar Disorder share the same mind mechanism for problem-solving. The mechanism consists of two specific components, which are described in detail in the paper. Dysfunctions in brain myelination, making signal interference possible, hold a big role. The conclusions of the paper are in agreement with reports by patients affected by Bipolar Disorder concerning their subjective experience during mania, which is traditionally described as prone to creativity. To make readers aware of such an experience, a synthesis was elaborated by the first author, in the unusual shape of a short story. The short story is the narrative version of a real diary of a real patient, tutored by the second author. The short story is available to readers on request. PMID- 23452644 TI - Pulmonary arteriovenous malformations etiologies in HHT patients and potential utility of thalidomide. AB - Thalidomide has shown its efficacy in the treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT) patients. We hypothetize that, owing to its anti inflammatory/antiangiogenic/vascular growth maturation properties, thalidomide should be useful in the prophylaxis and therapy of HHT patients presenting with initial lung involvement. PMID- 23452645 TI - Prevalence and associated factors of depression among people living with HIV in two cities in China. AB - OBJECTIVES: Depression has significant effects on morbidity and mortality in people living with HIV (PLWH). Current study estimated the rate of depressive disorder and identified the correlates of depressive disorder among PLWH in China. METHODS: 258 PLWH in China were recruited and interviewed with a structured questionnaire including measurements testing perceived stress, social support, perceived discrimination, and depression. Mediating effect of perceived stress between perceived discrimination and depression and moderating effect of social support on effect of perceived discrimination and perceived stress to depression were tested. Multivariate regression was used to examine the determinants of depression. RESULTS: The prevalence of mild to severe depression is 71.9%. The relationship between the perceived discrimination and depression is fully mediated by perceived stress (perceived discrimination that was statistically significant (beta=0.153) to depression became non-significant after adding perceived stress in the regression model). Interaction term between social support and perceived stress has negative effects (beta=-0.117) and explained a significant amount of variance (R(2)=0.018) in depression. Lower income, and higher perceived stress predicted more depressive symptoms. LIMITATIONS: Cross sectional study and self-report bias are major limitations of this study. CONCLUSION: Depression among PLWH is a severe problem in China. Primary health care workers need to be trained in recognition and treatment in depression. Stress management skills and social support for PLWH are warranted. PMID- 23452646 TI - Feeding practices, nutritional status and associated factors of lactating women in Samre Woreda, South Eastern Zone of Tigray, Ethiopia. AB - BACKGROUND: Lactating mothers from low-income settings are considered as a nutritionally vulnerable group. Due to the nursing process, mothers are subjected to nutritional stresses. Frequent pregnancies followed by lactation increase the health risk of mothers resulting in a high maternal mortality. OBJECTIVE: To assess the feeding practices, nutritional status and associated factors of lactating women from Samre Woreda, South Eastern Tigray, Ethiopia. DESIGN: Community based cross-sectional survey SETTING: Four kebeles of Samre Woreda (2 urban & 2 rural kebeles) METHODS: Four hundred lactating mothers were recruited from 400 randomly selected households. Data on socio-demographic characteristics, maternal characteristics, feeding practices, frequency of foods eaten and dietary diversity was collected using a pre-tested and structured questionnaire. Anthropometric measurements were taken from each mother using calibrated equipments and standardized techniques. A one-day weighed food record was also collected from randomly selected sub sample (n=60) of mothers. The nutrient and energy content of foods consumed by the mothers was calculated by using ESHA Food Processor and the Ethiopian Food Composition Tables. To investigate the socio economic and demographic factors affecting the nutritional status of the women, logistic regression was used. ANOVA and t-test were also used to see if there was a mean difference in nutritional status among the lactating mothers. RESULTS: Majority (71.2%) of the participants did not take additional meals during lactation. The median dietary diversity score of the study participants was 5 out of 14 food groups. The prevalence of underweight, chronic energy deficiency and stunting were 31%, 25% and 2.2% respectively. Using logistic regression model, factors significantly associated with the nutritional status of the study participants (as determined by BMI and MUAC) were size of farm land, length of years of marriage, maize cultivation, frequency of antenatal care visit and age of breastfeeding child. CONCLUSIONS: The feeding practices, dietary intakes and nutritional status of the lactating women were short of the national and international recommendations. Therefore, sustained health and nutrition education is recommended to the women and their families and communities on increased food intake, proper dietary practices and dietary diversification during lactation in order to improve health and nutrition outcomes of lactating women. PMID- 23452647 TI - Willing and able: a closer look at pain Willingness and Activity Engagement on the Chronic Pain Acceptance Questionnaire (CPAQ-8). AB - An 8-item version of the Chronic Pain Acceptance Questionnaire (CPAQ-8) has recently been proposed and validated. The aims of this study were to further investigate the reliability and validity of the CPAQ-8 in a new sample. Questionnaires were completed by 550 people with chronic pain (478 online survey, 72 paper survey). A demographic and pain history questionnaire was administered along with the CPAQ-8 and measures of pain self-efficacy, pain catastrophizing, psychological flexibility in pain, anxiety, and mood. In addition, 105 respondents completed the CPAQ-8 within 6 weeks to provide test-retest reliability data. The 2-factor structure of the CPAQ-8 (Activity Engagement [AE] and Pain Willingness [PW]) was confirmed and had reasonable-to-good scale score reliability and test-retest reliability. Pain acceptance as measured by the CPAQ 8 was associated with less depression, anxiety, pain interference, fear of reinjury, pain catastrophizing, and psychological inflexibility in pain, and higher levels of satisfaction with life, pain self-efficacy, and general acceptance. Furthermore, pain acceptance fully mediated the relationship between reported pain severity and emotional distress (anxiety and depression) and partially mediated the relationship between pain severity and pain interference in a structural equation model. The test-retest reliability after 4 to 6 weeks ranged from .68 for PW to .86 for AE; the overall score correlation was .81. We conclude that the CPAQ-8 is a reliable and valid measure of pain acceptance and that the 2 subscales of the measure each make an individual contribution to the prediction of adjustment in people with chronic pain. PERSPECTIVE: The present study provides further evidence for the reliability and validity of the CPAQ-8. Support was found for the 2 related subscales, PW and AE, which appear to work in synergy to influence levels of pain interference and emotional distress in people living with chronic pain. PMID- 23452648 TI - Anastrozole-associated joint pain and other symptoms in patients with breast cancer. AB - More than a third of breast cancer patients undergoing aromatase inhibitor (AI) treatment report joint pain. We conducted a longitudinal study to characterize the course of AI-induced joint pain and other symptoms and to identify potential predictors for developing these symptoms. Patients were recruited before AI initiation. The Brief Pain Inventory, M. D. Anderson Symptom Inventory, and a joint-pain questionnaire were administered at baseline and then biweekly for 1 year. Analysis included logistic regression, Cox models, and mixed-effects models. Of 47 patients assessed, 16 (34%) reported joint pain at least once. Median time to first report of joint pain was 7 weeks (range, 1-38). Baseline pain was the only predictor for both incidence of joint pain and time to first event. In the first 6 weeks, emergence of joint pain was associated with increase in general pain, fatigue, disturbed sleep, hot flashes, vaginal dryness, and decreased sexual activity. After week 6, having joint pain was associated with increase in general pain and with persistently high fatigue. Having AI-associated joint pain correlated with increase in or persistence of other symptoms likely related to AI therapy. Further research is needed to validate predictors of AI associated symptoms. PERSPECTIVE: We demonstrate for the first time that AI induced joint pain associates with development of other symptoms and that pretreatment pain level is a potential, measurable predictor of symptom development during treatment. Because baseline pain is easily assessed with a brief questionnaire, it can be applied clinically with minimal patient burden. PMID- 23452649 TI - The need to focus on pain management among sexual assault survivors. PMID- 23452650 TI - Anisakid larvae in the liver of cod (Gadus morhua) L. from the southern Baltic Sea. AB - In the present investigation a sample of 490 cod (Gadus morhua) was examined from three regions in the southern Baltic Sea (the Polish Exclusive Economic Zone, EEZ). Three species of anisakid nematodes with zoonotic potential, namely species of Contracaecum, Anisakis and Pseudoterranova, were found in the liver of cod, with Contracaecum being the most dominant species. The prevalence of infection was highest in the Western Baltic (22.5%) compared to the Central Baltic (10.4%) and the Gulf of Gdansk (3.4%). Generalized linear models (GLMs) were applied to analyse the prevalence of infection with Anisakis sp. and Contracaecum sp. relative to biological and spatial parameters. The effect of the sampling region, age and body length of the fish were significant in both GLMs. The effect of region was higher in the Western Baltic than in other regions. The prevalence of infection was correlated with the length of the fish and was higher in adult compared with sub-adult fish. These results suggest that the prevalence of infection with anisakid nematodes (especially Contracaecum sp.) in cod sampled in Polish waters of the Baltic Sea has significantly increased compared with previous studies undertaken over the past few decades. PMID- 23452652 TI - [Keratinocyte growth factor and its receptor in middle-ear cholesteatoma]. AB - AIM: Etiology of middle ear cholesteatoma is far from beeing elicidated. Current concepts postulate that cholesteatoma is the result of disturbed wound healing process. Keratinocyte growth factor (KGF) plays important role in wound healing, so it seemed interesting to assess the expression of KGF and its receptor in the cholesteatoma. MATERIAL AND METHODS: 25 cholesteatoma and 7 retraction pockets specimens were obtained from the patients during middle ear surgery. The expression of KGF and FGFR2 was evaluated by immunohistochemical staining using polyclonal antibodies. The results were analyzed depending on clinical features such as: localization, number of anatomic sites involved and presence of purulent discharge. RESULTS: KGF expression was detected in the cells of subepithelial tissue. It was observed in 4/7 (57%) of the specimens of retraction pockets and 11/25 (44%) of cholesteatoma specimens. FGFR2 expression was observed mainly in the cells of spinous layer of epithelium in 4/7 (57%) specimens of retraction pockets and 19/25 (76%) of specimens of cholesteatoma. Statistically significant (p=0.011) relationship between the presence of KGF expression in the subepithelial tissue and the presence of FGFR2 expression in the epithelium was found. There were no differences in the expression of KGF and FGFR2 between retraction pocket and cholesteatoma specimens. Also, no differences in the expression, depending on localization, extend of the cholesteatoma and presence of purulent discharge were observed. CONCLUSION: KGF and its receptor seem to play an important role in paracrine regulation of cholesteatoma growth. PMID- 23452653 TI - [Results of radical surgery in group of 355 patients with advanced laryngeal cancer]. AB - INTRODUCTION: The aim of the study was to evaluate the results of radical surgery in group of 355 patients with advanced laryngeal cancer. MATERIAL AND METHOD: The paper presents results of treatment in group of 355 patients with advanced laryngeal cancer treated in the ENT Clinical Department in Zabrze in the following years 1998-2007. The advancement stage was defined as III in 147 patients (42%), as IV in 208 patients (58%). Group of 250 patients (70%) underwent total laryngectomy and group of 105 patients (30%) underwent pharyngolaryngectomy. In the group of 327 patients (92%) operation was performed microscopically radically. 298 patients (84%) underwent postoperative radiotherapy. Median follow-up period was 5 years. Local recurrence, nodal recurrence and distant metastasis were rated as treatment failure. Treatment effectiveness was evaluated in relation to overall survival, disease-free survival, local control, locoregional control and observation free from metastases. All of these parameters were analyzed with the method of updated percentages. RESULTS: During observation period 177 patients (50%) died. Local recurrence occurred in 47 patients (13%), nodal recurrence occurred in 19 patients (5%). Distant metastases occurred in 26 patients (7%). 5-year overall survival rate (OS) was 50%. 5-year disease-free survival rate (DFS) was 47%. 5 year local control rate (LC) was 81%. 5-year locoregional control rate (LRC) was 75%. The updated 5-year observation free from metastases rate (FFM) was 89% respectively. CONCLUSION: Radical surgery is the chance of 5-year survival of 50% of patients with advanced cancer of the larynx and of 5-year locoregional control of 75% patients. PMID- 23452654 TI - [Anatomical anomalies of the vertebral and carotid arteries in patients with vertigo and hearing disorders]. AB - INTRODUCTION: The aim of this work was the analysis of the frequency and type of anatomical anomalies of the arteries to the cranium such as vertebral arteries and carotid arteries in patients with vertigo and hearing disorders. MATERIAL AND METHODS: Between 2007 and 2011, in the Department of Otolaryngology and Laryngological Oncology, the number of the patients diagnosed due to vertigo and hearing disorders amounted to 2,167. In CT-angiogram anatomical anomalies were confirmed in 29 of these patients. The studied group included 22 women aged 22-68 and 7 men aged 21-53. Each patient underwent a subjective and objective structured laryngological interview, audiological and otoneurological examinations, laboratory tests, USG and angio-CT of the arteries to the cranium. RESULTS: The most common anatomical anomaly of the arteries to the cranium was hypoplasia of the right vertebral artery in 58.7% of the cases, out of which 51.7% in women and 6.9% in men. Hypoplasia of the left vertebral artery was diagnosed in 24.7% of the studied group, 13.8% of women and 10.3% of men. Hypoplasia of the right internal carotid artery was found in 3.4% of the female patients while hypoplasia of the left internal carotid artery was identified in 6.8% of the studied cases, 3.4% of women and 3.4% of men. Hypoplasia of the right common carotid artery was confirmed in 3.4% of the male patients whereas critical stenosis of the left subclavian artery with the subclavian steal syndrome was found in 3.4% of the studied female patients. Tinnitus was reported in 88.2% of the patients with diagnosed right vertebral artery hypoplasia, and in 58.8% vertigo and in 52.9% hearing disorders were confirmed. Tinnitus was the most common complaint in the studied group, both in men and women. Less frequent complaints referred to vertigo (65.5% altogether) and hearing impairment (55.2% altogether). CONCLUSIONS: In the analyzed group, diagnosed anatomical anomalies were not indications for vascular surgery nor neurosurgery, therefore, the applied treatment was strictly conservative. PMID- 23452655 TI - [Embolization of carotid arteria branch in stanching of nasal bleeding]. AB - BACKGROUND: Epistaxis is a common clinical problem, especially in otolaryngology. This disorder affects equally both genders. Most cases manifest as spontaneous nasal bleeding. It can also appear as a result of trauma, high blood pressure, Osler-Rendu-Weber disease. When the bleeding is massive it can be potentially life-threatening. A great majority of epistaxis can be treated conservatively, if not it sometimes requires endovascular treatment. It is specially reserved for extensive, dangerous epistaxis. Angiography with selective embolization has become an accepted method of treating epistaxis that is not controlled with conservative methods. MATERIAL AND METHODS: Authors analyzed the efficacy of selective embolization treatment of epistaxis. 61 patients treated in the Department of Otolaryngology in Bialystok in years 1999-2011 were examined. There were 39 men and 22 women aged 24-48 years. Patients were referred for endovascular treatment when primary management was ineffective. Arteries suspected of bleeding were embolized superselectively. RESULTS: Immediate, complete control of bleeding was achieved in 100% patients. After few hours recurrent nasal bleeding occurred in 4 (7%) patients who underwent successful reembolization. There were no severe complications after procedure. Nine patients experienced few days lasting mild headache which disappeared after medicament treatment. Five patients suffered from unaided removing facial oedema. Out of 61 patients, 56 were available for 12-month follow-up evaluation. No neurological or otolaryngological complications were certified. There was also no relapse of epistaxis. CONCLUSIONS: Selective angiographic embolization is an effective method that should be considered in the treatment of refractory epistaxis. It is safe and not traumatic for patients. PMID- 23452656 TI - [Stapedotomie with the use of CO2 laser--"one shot" technique]. AB - INTRODUCTION: CO2 laser is used in stapes surgery due to good water absorption and quite optimal ablation of a bony structure without the influence of inner ear parameters. AIM OF THE STUDY: the assessment of the influence of CO2 - "one shot" laser on hearing results in the patients group with otosclerosis. MATERIAL AND METHOD: The study was carried out on a patients group after surgical treatment. The follow up time was at least 6 months. The hearing results were described according to the guidelines of the American Committee on Hearing and Equilibrium. The obtained results were statistically analysed with the use of the Wilcoxon sequence pair test. RESULTS: The CO2 - "one shot" laser has been used in Department of Otolaryngology in Poznan since July 2009. Using this system 101 operations were carried out to the end of December 2011. 54 patients were in the analysed group, there were 40 women and 14 men, the age range from 22 to 59. In the Wilcoxon sequence pair test there was a statistically significant correlation between the value of the hearing threshold in pre- and post-operative examinations at 0.5, 1, 2 and 3kHz for bone and air conduction. We found also a statistically significant correlation between the mean value of the air-bone gap before and after treatment. In the group after the surgery the cochlear reserved became closed or decreased (p<0.001). CONCLUSION: based of the hearing results we found great usefulness of CO2 - "one shot" laser in stapes surgery. PMID- 23452657 TI - [Extensive neck trauma in material of Otolaryngology Department of the Jagiellonian University in Krakow 2009-2012]. AB - Isolated laryngeal fractures quite rarely can occur following trauma to the neck region, but because of the variety and dynamic growth of symptoms or possible injury of the main structures on the neck may be life-threatening. The appropriate treatment of these patients is quick surgical intervention proceeded by imaging techniques. Here we report the cases of three patients treated in our Department between 2009 and 2012: two of them with penetrating injury and one with blunt trauma. The appropriate treatment of these patients requires that airway patency be the first priority and if possible quick reconstruction. These cases illustrate the individualized treatment and multidisciplinary approach in managing such cases. PMID- 23452658 TI - ["Starplasty" tracheotomy in children of Pediatric ENT Department of Poznan University of Medical Sciences]. AB - INTRODUCTION: Obvious anatomical differences between larynx and trachea of the adult and the child necessitate different surgical techniques. The "starplasty" technique of pediatric tracheotomy was introduced in 1998 as an alternative pediatric tracheotomy technique associated with several advantages such as easy recannulation in case of accidental decannulation, isolation of trachea secretions from the tracheotomy wound and the absence of stenosis and anterior wall collapse. AIM OF THE STUDY: The aim of this study was to compare the new technique of tracheotomy with the traditional one in pediatric patients. MATERIAL AND METHODS: 26 "starplasty" tracheotomies were performed in the Pediatric ENT Dept. from 2006-2010. There were two control groups. The first one consisted of 25 patients and their observation period was 3 years. In the second one there were 14 patients and the observation time was 7 years. In both, the tracheotomy was performed with use of traditional technique. RESULTS: The comparison of these groups of patients revealed significant differences in long-term complications such as presence of granuloma tissue (0 after "starplasty", 8% to 14,3% after traditional technique) and suprastomal collapse (0% after "starplasty", 8% to 78,6% after traditional tracheotomy). CONCLUSIONS: "Starplasty" is a safe and easy to perform pediatric tracheotomy technique. It decreases the incidence of short and long-term complications. But the persistence of postoperative tracheocutaneous fistula should limit the indications to perform it only in children in whom the tracheotomy will be permanent. PMID- 23452659 TI - [Melanoma of the nasal septum]. AB - Sinonasal mucosal melanoma is a rare neoplasm, accounting for less than 1% of all melanomas. It is more aggressive than its cutaneous counterpart, with a very poor prognosis. We report a case of melanoma arising from mucosae of the nasal septum in a 73-year-old man. Clinical features, diagnosis, and treatment are described and a review of literature is made. Nasal location and relatively nonspecific symptoms frequently delay diagnosis. Optimal treatment guidelines are not established because of its rare occurrence. PMID- 23452660 TI - [Sarcoidosis of the lacrimal sac as a cause of dacriostenosis]. AB - Sarcoidosis is a systemic granulomatous disease of unknown aetiology. The course of sarcoidosis ranges from asymptomatic to severe. It could affect people of all ages. The disease affects predominantly the lungs and lymph nodes, skin, abdominal organs or eyes. Sarcoidosis of lacrimal sac is very uncommon. We describe a young man with lacrimal sac and nasal mucosa sarcoidosis present with epiphora. Few years before the onset of dacriocystitis the patient was treated because of lymph nodes sarcoidosis. The lacrimal sac sarcoidosis developed five years after systemic disease remission. An endoscopic dacriocystorhinostomy with intubation of nasolacrimal duct was performed. We used postoperatively systemic and local steroids for 3 months period. The patient is under observation for over four years with good health. The abnormal looking nasal or lacrimal sac mucosa could be associated with granulomatous disease as sarcoidosis and Wegener's or malignancies. If the sarcoidosis is established, it could be the first manifestation of sarcoidosis leading to future systemic sarcoidosis development or it may develop many years after the onset of systemic disease. Endoscopic dacriocystorhinostomy with intubation followed by intensive therapy with systemic and local corticosteroids may be helpful to maintain lacrimal drainage patency. PMID- 23452661 TI - State of the science of maternal-infant bonding: a principle-based concept analysis. AB - OBJECTIVE: to provide a principle-based analysis of the concept of maternal infant bonding. DESIGN: principle-based method of concept analysis for which the data set included 44 articles published in the last decade from Pubmed, CINAHL, and PyschINFO/PsychARTICLES. SETTING: literature inclusion criteria were English language, articles published in the last decade, peer-reviewed journal articles and commentary on published work, and human populations. MEASUREMENT AND FINDINGS: after a brief review of the history of maternal-infant bonding, a principle-based concept analysis was completed to examine the state of the science with regard to this concept. The concept was critically examined according to the clarity of definition (epistemological principle), applicability of the concept (pragmatic principle), consistency in use and meaning (linguistic principle), and differentiation of the concept from related concepts (logical principle). Analysis of the concept revealed: (1) Maternal-infant bonding describes maternal feelings and emotions towards her infant. Evidence that the concept encompasses behavioural or biological components was limited. (2) The concept is clearly operationalised in the affective domain. (3) Maternal-infant bonding is linguistically confused with attachment, although the boundaries between the concepts are clearly delineated. KEY CONCLUSION: despite widespread use of the concept, maternal-infant bonding is at times superficially developed and subject to confusion with related concepts. Concept clarification is warranted. A theoretical definition of the concept of maternal-infant bonding was developed to aid in the clarification, but more research is necessary to further clarify and advance the concept. IMPLICATIONS FOR PRACTICE: nurse midwives and other practitioners should use the theoretical definition of maternal-infant bonding as a preliminary guide to identification and understanding of the concept in clinical practice. PMID- 23452662 TI - Maternal experience of musculoskeletal pain during pregnancy and birth outcomes: significance of lower back and pelvic pain. AB - AIM: to examine the association between back and pelvic pain during pregnancy and birth outcomes. BACKGROUND: back and pelvic pain during pregnancy is a common occurrence. It is known to affect maternal functioning and well-being during pregnancy and can persist postnatally and beyond. However, there has been little examination of the impact upon birth outcomes such as birth mode, duration of labour and pain experience. METHOD: five hundred and eighty mothers with an infant aged zero to six months completed a retrospective questionnaire documenting their pain during pregnancy and birth outcomes (e.g. mode, duration, interventions, perception of pain). Participants also rated overall pain and pain in specific body regions for each of the three trimesters. Estimations of fetal position before birth were given. FINDINGS: higher pain ratings during the third trimester of pregnancy were associated with increased incidence of caesarean section, assisted delivery and a longer duration of labour. Specifically, lower back and pelvic pain were associated with an increase in complications, potentially due to occurrence of malpositioning of the fetus during pregnancy. CONCLUSION: mothers who experience high levels of pain during pregnancy may be at increased risk of complications during labour. Explanations for this may be physiological, mechanical or psychological but greater awareness should be given to the potential impact of maternal pain ratings during pregnancy upon birth outcomes. PMID- 23452663 TI - Counterfactual processing of economic action-outcome alternatives in obsessive compulsive disorder: further evidence of impaired goal-directed behavior. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a disorder of automatic, uncontrollable behaviors and obsessive rumination. There is evidence that OCD patients have difficulties performing goal-directed actions, instead exhibiting repetitive stimulus-response habit behaviors. This might result from the excessive formation of stimulus-response habit associations or from an impairment in the ability to use outcome value to guide behavior. We investigated the latter by examining counterfactual decision making, which is the ability to use comparisons of prospective action-outcome scenarios to guide economic choice. METHODS: We tested decision making (forward counterfactual) and affective responses (backward counterfactual) in 20 OCD patients and 20 matched healthy control subjects using an economic choice paradigm that previously revealed attenuation of both the experience and avoidance of counterfactual emotion in schizophrenia patients and patients with orbitofrontal cortex lesions. RESULTS: The use of counterfactual comparison to guide decision making was diminished in OCD patients, who relied primarily on expected value. Unlike the apathetic affective responses previously shown to accompany this decision style, OCD patients reported increased emotional responsivity to the outcomes of their choices and to the counterfactual comparisons that typify regret and relief. CONCLUSIONS: Obsessive-compulsive disorder patients exhibit a pattern of decision making consistent with a disruption in goal-directed forward modeling, basing decisions instead on the temporally present (and more rational) calculation of expected value. In contrast to this style of decision making, emotional responses in OCD were more extreme and reactive than control subjects. These results are in line with an account of disrupted goal-directed cognitive control in OCD. PMID- 23452665 TI - Brain effects of cognitive remediation therapy in schizophrenia: a structural and functional neuroimaging study. AB - BACKGROUND: Cognitive remediation therapy positively affects cognition and daily functioning in patients with schizophrenia. However, studies on the underlying neurobiological mechanisms of this treatment are scarce. The aim of the current study was to investigate functional and structural connectivity brain changes in schizophrenia patients after cognitive remediation therapy using a whole-brain approach that combined functional magnetic resonance imaging and diffusion tensor imaging. METHODS: A randomized controlled trial with 30 schizophrenia outpatients and 15 healthy volunteers. A strategy-learning-based treatment was used as a cognitive remediation therapy. A social skills training that provides useful information about illness management was used as an active control. We investigated changes in the pattern of functional connectivity assessed during an n-back task by tensorial independent component analysis as implemented in the multivariate exploratory linear decomposition into independent components and in the fractional anisotropy index of white matter integrity using tract-based spatial statistics. RESULTS: Brain networks activation pattern significantly changed in patients exposed to the cognitive treatment in the sense of normalizing toward the patterns observed in healthy control subjects. Additionally, in white matter, they showed an increase in fractional anisotropy index in the anterior part of the genu of the corpus callosum. Cognitive improvement, functional, and also structural changes showed statistically significant correlations. CONCLUSIONS: Improvement in brain functioning detected after cognitive remediation therapy in schizophrenia patients might be based on an increase of the interhemispheric information transfer between the bilateral prefrontal cortexes via the corpus callosum. PMID- 23452667 TI - The study on the application of solid-state method for synthesizing the polyaniline/noble metal (Au or Pt) hybrid materials. AB - The solid-state method was applied for synthesizing polyaniline (PANI)/noble metal hybrid materials with the presence of HAuCl4.4H2O or H2PtCl6.6H2O in the reaction medium. The structure, morphology, and electrochemical activity of the composites were characterized by Fourier transform infrared (FTIR) spectra, UV visible (vis) absorption spectra, energy dispersive spectrum (EDS), X-ray powder diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and cyclic voltammetry. The results from FTIR and UV-vis spectra showed that the oxidation degree and doping level of the PANI in composites can be influenced by HAuCl4.4H2O and H2PtCl6.6H2O. The EDS data demonstrated that the composites contain a certain amount of Au (or Pt) element. XRD analysis indicated the presence of crystalline-state Au particles in PANI matrix prepared from the presence of HAuCl4.4H2O and revealed that the H2PtCl6.6H2O cannot be converted into metal Pt. The TEM and SEM images implied that the Au particles did exist in the polymer matrix with the size of about 20 nm. The enzymeless H2O2 sensor constructed with PANI/Au composite from the presence of HAuCl4.4H2O showed a short response time (within 5 s) and displayed an excellent performance in wide linear range. PMID- 23452666 TI - Carotid baroreceptors are mainly localized in the medial portions of the proximal internal carotid artery. AB - AIM: To visualize baroreceptors in the human carotid bifurcation by light microscopy. Baroreceptor location is investigated in order to provide recommendations for the extent of adventitial stripping in the treatment for carotid sinus syndrome (CSS). METHODS: Human carotid specimens were transversely cut in 20 MUm sections. After immunohistochemical staining using antibodies to vesicular glutamate transporter 2 (VGLUT2) and protein gene product 9.5 (PGP 9.5), the presence of baroreceptor tissue was studied using light microscopic techniques. RESULTS: Visual assessment indicated that VGLUT2 and PGP 9.5 immunoreactivity was present in the adventitia of the carotid arteries and that nerve density was highest in the medial wall of the proximal first cm of the internal carotid artery (ICA). CONCLUSION: Human carotid baroreceptors, as reflected in immunoreactivity for VGLUT2 and PGP 9.5, are mainly localized in the medial portions of the proximal ICA. If surgical carotid denervation is indicated in patients suffering from carotid sinus syndrome, adventitial stripping of the proximal portion of the ICA should be sufficient. PMID- 23452664 TI - Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress. AB - BACKGROUND: Social stress is a risk factor for affective disorders for certain vulnerable individuals. Stress and depression are linked in part through regulation of the dorsal raphe (DR)-serotonin (5-HT) system by the stress-related neuropeptide, corticotropin-releasing factor (CRF). We used a rat social stress model that shows individual differences in coping strategies to determine whether differences in CRF-5-HT interactions underlie individual differences in the vulnerability to social stress. METHODS: Rats were exposed to the resident intruder model of social stress for 5 days. In vivo single-unit recordings assessed DR-5-HT neuronal responses to CRF and immunoelectron microscopy assessed CRF1 and CRF2 cellular localization 24 hours after the last stress. RESULTS: Rats responded to social stress passively, assuming defeat with short latencies (48%), or actively, with proactive behaviors and longer defeat latencies (LL, 52%). Whereas CRF (30 ng, intra-DR) inhibited 5-HT neuronal activity of control and SL rats, it activated 5-HT neurons of LL rats, an effect that was CRF2-mediated. Consistent with this, social stress promoted CRF1 internalization together with CRF2 recruitment to the plasma membrane of DR neurons selectively in LL rats. CONCLUSIONS: These data suggest that a proactive coping strategy toward social stress is associated with a redistribution of CRF1 and CRF2 in DR-5-HT neurons that primes the system to be activated by subsequent stress. The lack of this adaptation in passive coping rats may contribute to their depressive-like phenotype. These studies provide a cellular mechanism for individual differences in stress responses and consequences. PMID- 23452668 TI - Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone. AB - BACKGROUND: Patients with ulcerative colitis (UC) are treated with prednisolone (PSL), which causes adverse side effects. Extracorporeal granulocyte/monocyte adsorption (GMA) with an Adacolumn depletes elevated/activated myeloid lineage leucocytes as sources of inflammatory cytokines. We were interested to evaluate the efficacy, safety and the treatment cost for PSL and GMA. METHODS: Forty-one patients with active UC had achieved remission with GMA, at 1 or 2 sessions/week, up to 10 sessions (n=24) or with orally administered PSL (1mg/kg bodyweight, n=17). Clinical activity index (CAI) <=4 was considered clinical remission. Following remission, patients received 5-aminosalicylic acid (2250-3000mg/day) or sulphasalazine (4000-6000mg/day) as maintenance therapy and were followed for 600 days. The total treatment cost was assessed based on 1?=150JPY. RESULTS: PSL was tapered after two weeks, and discontinued when a patient achieved remission. The average time to the disappearance of at least one major UC symptom (haematochezia, diarrhoea, or abdominal discomfort) was 15.3 days in the GMA group and 12.7 days in the PSL group, while time to remission was 27.9 days in the GMA group and 27.6 days in the PSL group, CAI 0.8 and 2.0, respectively. The Kaplan-Meier plots showed similar remission maintenance rates over the 600 days follow-up period. The average medical cost was 12739.4?/patient in the GMA group and 8751.3? in the PSL group (P<0.05). In the GMA group, 5 transient adverse events were observed vs 10 steroid related adverse events in the PSL group (P<0.001). CONCLUSIONS: In appropriately selected patients, GMA has significant efficacy with no safety concern. The higher cost of GMA vs PSL should be compromised by good safety profile of this non-pharmacological treatment intervention. PMID- 23452669 TI - Cortisol levels and neuropsychiatric diagnosis as markers of postoperative delirium: a prospective cohort study. AB - INTRODUCTION: The pathophysiology of delirium after cardiac surgery is largely unknown. The purpose of this study was to investigate whether increased concentration of preoperative and postoperative plasma cortisol predicts the development of delirium after coronary artery bypass graft surgery. A second aim was to assess whether the association between cortisol and delirium is stress related or mediated by other pathologies, such as major depressive disorder (MDD) or cognitive impairment. METHODS: The patients were examined 1 day preoperatively with the Mini International Neuropsychiatric Interview and the Montreal Cognitive Assessment and the Trail Making Test to screen for depression and for cognitive impairment, respectively. Blood samples for cortisol levels were collected both preoperatively and postoperatively. The Confusion Assessment Method for the Intensive Care Unit was used within the first 5 days postoperatively to screen for a diagnosis of delirium. RESULTS: Postoperative delirium developed in 36% (41 of 113) of participants. Multivariate logistic regression analysis revealed two groups independently associated with an increased risk of developing delirium: those with preoperatively raised cortisol levels; and those with a preoperative diagnosis of MDD associated with raised levels of cortisol postoperatively. According to receiver operating characteristic analysis, the most optimal cutoff values of the preoperative and postoperative cortisol concentration that predict the development of delirium were 353.55 nmol/l and 994.10 nmol/l, respectively. CONCLUSION: Raised perioperative plasma cortisol concentrations are associated with delirium after coronary artery bypass graft surgery. This may be an important pathophysiological consideration in the increased risk of postoperative delirium seen in patients with a preoperative diagnosis of MDD. PMID- 23452670 TI - Risk of second cancer from scattered radiation of intensity-modulated radiotherapies with lung cancer. AB - PURPOSE: To compare the risk of secondary cancer from scattered and leakage doses following intensity-modulated radiotherapy (IMRT), volumetric arc therapy (VMAT) and tomotherapy (TOMO) in patients with lung cancer. METHODS: IMRT, VMAT and TOMO were planned for five lung cancer patients. Organ equivalent doses (OEDs) are estimated from the measured corresponding secondary doses during irradiation at various points 20 to 80 cm from the iso-center by using radio-photoluminescence glass dosimeter (RPLGD). RESULTS: The secondary dose per Gy from IMRT, VMAT and TOMO for lung cancer, measured 20 to 80 cm from the iso-center, are 0.02~2.03, 0.03~1.35 and 0.04~0.46 cGy, respectively. The mean values of relative OED of secondary dose of VMAT and TOMO, which is normalized by IMRT, ranged between 88.63% and 41.59% revealing 88.63% and 41.59% for thyroid, 82.33% and 41.85% for pancreas, 77.97% and 49.41% for bowel, 73.42% and 72.55% for rectum, 74.16% and 81.51% for prostate. The secondary dose and OED from TOMO became similar to those from IMRT and VMAT as the distance from the field edge increased. CONCLUSIONS: OED based estimation suggests that the secondary cancer risk from TOMO is less than or comparable to the risks from conventional IMRT and VMAT. PMID- 23452671 TI - [Pocket echography performed by a family physician: yes to democratization, no to revolution]. PMID- 23452672 TI - [Erdheim-Chester disease: report of a case with retroperitoneal involvement treated with interferon alpha-2a]. PMID- 23452674 TI - In this issue. Abstract thinking: adolescence and adversity. PMID- 23452673 TI - Epidemiological characteristics of 778 patients who underwent surgical drainage of chronic subdural hematomas in Brasilia, Brazil. AB - BACKGROUND: Chronic subdural hematomas (CSDHs) are common in neurosurgical practice. There are no publications that report large series of the epidemiological characteristics of this pathology in Brazil. The purpose is to describe a large series of surgical cases and analyze the epidemiological and clinical characteristics. METHODS: We retrospectively analyzed patients with CSDH admitted into Neurosurgical Services at the Hospital de Base do Distrito Federal, Brasilia, Brazil from 2006 to 2011. Age, sex, clinical feature, etiology, surgical procedure, side, clinical outcome, and recurrence were reviewed. Statistical tests were used to analyze data, and P < 0.05 was considered statistically significant. RESULTS: The series included 778 patients. There were 643 (82.6%) male patients with a mean age of 64.3 +/- 15.9 (range, 14-93) years. The principal symptom was headache (58.9%). The most frequent origin was a fall (282 cases, 36.2%), but the origin remained unclear in 281 (36.1%) patients. Mild head injury occurred in 540 (69.4%) cases. Burr holes with drainage were used as the surgical procedure in 96.5% patients, and 687 (88.3%) patients had a positive outcome. Mortality was 0%. Recurrence was observed in 42 cases. CONCLUSIONS: The occurrence of CSDHs is more common in elderly men. Treatment with burr holes and drainage is a simple and safe method for treatment. In our experience, CSDH presents decreased morbidity and mortality. PMID- 23452675 TI - Telepsychiatry: time to connect. PMID- 23452676 TI - Mentalization-based treatment: can it be translated into practice in clinical settings and teams? PMID- 23452677 TI - Treating trichotillomania across the lifespan. PMID- 23452678 TI - Do stimulants prevent substance use and misuse among youth with attention deficit/hyperactivity disorder? The answer is still maybe. PMID- 23452679 TI - Finding the tools for effective early intervention for preschool attention deficit/hyperactivity disorder. PMID- 23452680 TI - N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. AB - OBJECTIVE: To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study. METHOD: A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of hairpulling as measured by the Massachusetts General Hospital-Hairpulling Scale (MGH-HPS). Secondary measures assessed hairpulling severity, automatic versus focused pulling, clinician-rated improvement, and comorbid anxiety and depression. Outcomes were examined using linear mixed models to test the treatment*time interaction in an intention-to-treat population. RESULTS: No significant difference between N-acetylcysteine and placebo was found on any of the primary or secondary outcome measures. On several measures of hairpulling, subjects significantly improved with time regardless of treatment assignment. In the NAC group, 25% of subjects were judged as treatment responders, compared to 21% in the placebo group. CONCLUSIONS: We observed no benefit of NAC for the treatment of children with trichotillomania. Our findings stand in contrast to a previous, similarly designed trial in adults with TTM, which demonstrated a very large, statistically significant benefit of NAC. Based on the differing results of NAC in pediatric and adult TTM populations, the assumption that pharmacological interventions demonstrated to be effective in adults with TTM will be as effective in children, may be inaccurate. This trial highlights the importance of referring children with TTM to appropriate behavioral therapy before initiating pharmacological interventions, as behavioral therapy has demonstrated efficacy in both children and adults with trichotillomania. PMID- 23452681 TI - Age and gender correlates of pulling in pediatric trichotillomania. AB - OBJECTIVE: Our goals were to examine clinical characteristics and age and gender correlates in pediatric trichotillomania. METHOD: A total of 62 children (8-17 years of age) were recruited for a pediatric trichotillomania treatment trial and characterized using structured rating scales of symptoms of hairpulling and common comorbid conditions. We analyzed the association between qualitative and quantitative characteristics of pulling, comorbidities, and age and gender. We also examined the type of treatments these children previously received in the community. RESULTS: We found lower rates of comorbid depression and anxiety disorders than have been reported in adult trichotillomania samples. Focused hairpulling significantly increased with age, whereas automatic pulling remained constant. Older children with hairpulling experienced more frequent urges and a decreased ability to refrain from pulling. Female participants reported greater distress and impairment associated with hairpulling, even though the severity of pulling did not differ from that of male participants. CONCLUSION: These results confirm several findings from the Children and Adolescent Trichotillomania Impact Project (CA-TIP). Our cross-sectional findings suggest there may be a developmental progress of symptoms in trichotillomania. Children appeared to develop more focused pulling, to become more aware of their urges, and to experience more frequent urges to pull, as they get older. Although these are important findings, they need to be confirmed in prospective longitudinal studies. PMID- 23452683 TI - The Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS) 6 year follow-up. AB - OBJECTIVE: To describe the clinical course of attention-deficit/hyperactivity disorder (ADHD) symptom severity and diagnosis from ages 3 to 5 up to 9 to 12 years during a 6-year follow-up after the original Preschool ADHD Treatment Study (PATS). METHOD: A total of 207 participants (75% male) from the original PATS, assessed at baseline (mean age, 4.4 years, when all met criteria for ADHD) and 3 months later (before medication treatment), were re-evaluated in three follow-up assessment visits (year 3, mean age 7.4 years; year 4, 8.3 years; and year 6, 10.4 years). Parents and teachers rated symptom severity, and clinicians established psychiatric diagnoses. Analyses examined longitudinal changes in symptom severity and ADHD diagnosis. RESULTS: Parent- and teacher-rated symptom severity decreased from baseline to year 3 but remained relatively stable and in the moderate-to-severe clinical range through year 6. Girls showed generally steeper decreases in symptom T-scores. At year 6, 89% (160/180) of remaining participants met ADHD symptom and impairment diagnostic criteria. Comorbidity of oppositional defiant disorder and/or conduct disorder was associated with a 30% higher risk of having an ADHD diagnosis at year 6 in the multiple logistic model. Medication status during follow-up, on versus off, did not predict symptom severity change from year 3 to year 6 after adjustment for other variables. CONCLUSIONS: ADHD in preschoolers is a relatively stable diagnosis over a 6-year period. The course is generally chronic, with high symptom severity and impairment, in very young children with moderate-to-severe ADHD, despite treatment with medication. Development of more effective ADHD intervention strategies is needed for this age group. PMID- 23452684 TI - Developmental meta-analysis of the functional neural correlates of autism spectrum disorders. AB - OBJECTIVE: There is a pressing need to elucidate the brain-behavior interactions underlying autism spectrum disorders (ASD) given the marked rise in ASD diagnosis over the past decade. Functional magnetic resonance imaging (fMRI) has begun to address this need, but few fMRI studies have evaluated age-related changes in ASD. Therefore, we conducted a developmental analysis of activation likelihood estimation (ALE) meta-analysis to compare child versus adult ASD fMRI studies. We hypothesized that children and adolescents with ASD (<18 years old) would rely less on prefrontal cortex structures than adults (>=18 years old). METHOD: PubMed and PsycInfo literature searches were conducted to identify task-dependent fMRI studies of children or adults with ASD. Then recent GingerALE software improvements were leveraged to perform direct comparisons of child (n = 18) versus adult (n = 24) studies. RESULTS: ALE meta-analyses of social tasks showed that children and adolescents with ASD versus adults had significantly greater hyperactivation in the left post-central gyrus, and greater hypoactivation in the right hippocampus and right superior temporal gyrus. ALE meta-analyses of nonsocial tasks showed that children with ASD versus adults had significantly greater hyperactivation in the right insula and left cingulate gyrus, and hypoactivation in the right middle frontal gyrus. CONCLUSION: Our data suggest that the neural alterations associated with ASD are not static, occurring only in early childhood. Instead, children with ASD have altered neural activity compared to adults during both social and nonsocial tasks, especially in fronto-temporal structures. Longitudinal neuroimaging studies are required to examine these changes prospectively, as potential targets for brain-based treatments for ASD. PMID- 23452682 TI - Adolescent substance use in the multimodal treatment study of attention deficit/hyperactivity disorder (ADHD) (MTA) as a function of childhood ADHD, random assignment to childhood treatments, and subsequent medication. AB - OBJECTIVE: To determine long-term effects on substance use and substance use disorder (SUD), up to 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA; n = 436); to test whether medication at follow-up, cumulative psychostimulant treatment over time, or both relate to substance use/SUD; and to compare substance use/SUD in the ADHD sample to the non-ADHD childhood classmate comparison group (n = 261). METHOD: Mixed-effects regression models with planned contrasts were used for all tests except the important cumulative stimulant treatment question, for which propensity score matching analysis was used. RESULTS: The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD. Substance use at all time points, including use of two or more substances and SUD, were each greater in the ADHD than in the non ADHD samples, regardless of sex. CONCLUSIONS: Medication for ADHD did not protect from, or contribute to, visible risk of substance use or SUD by adolescence, whether analyzed as randomized treatment assignment in childhood, as medication at follow-up, or as cumulative stimulant treatment over an 8-year follow-up from childhood. These results suggest the need to identify alternative or adjunctive adolescent-focused approaches to substance abuse prevention and treatment for boys and girls with ADHD, especially given their increased risk for use and abuse of multiple substances that is not improved with stimulant medication. Clinical trial registration information-Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://clinical trials.gov/; NCT00000388. PMID- 23452685 TI - Intrinsic functional connectivity of amygdala-based networks in adolescent generalized anxiety disorder. AB - OBJECTIVE: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala based circuitry; the present study examines this issue in adolescents with GAD. METHOD: Resting state fMRI scans were obtained from 15 adolescents with GAD and 20 adolescents without anxiety who were group matched on age, sex, scanner, and intelligence. Functional connectivity of the centromedial, basolateral, and superficial amygdala subdivisions was compared between groups. We also assessed the relationship between amygdala network dysfunction and anxiety severity. RESULTS: Adolescents with GAD exhibited disruptions in amygdala-based intrinsic functional connectivity networks that included regions in medial prefrontal cortex, insula, and cerebellum. Positive correlations between anxiety severity scores and amygdala functional connectivity with insula and superior temporal gyrus were also observed within the GAD group. There was some evidence of greater overlap (less differentiation of connectivity patterns) of the right basolateral and centromedial amygdala networks in the adolescents with, relative to those without, GAD. CONCLUSIONS: These findings suggest that adolescents with GAD manifest alterations in amygdala circuits involved in emotion processing, similar to findings in adults. In addition, disruptions were observed in amygdala-based networks involved in fear processing and the coding of interoceptive states. PMID- 23452686 TI - Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. AB - OBJECTIVE: First-degree relatives of persons with an autism spectrum disorder (ASD) are at increased risk for ASD-related characteristics. As little is known about the early expression of these characteristics, this study characterizes the non-ASD outcomes of 3-year-old high-risk (HR) siblings of children with ASD. METHOD: Two groups of children without ASD participated: 507 HR siblings and 324 low-risk (LR) control subjects (no known relatives with ASD). Children were enrolled at a mean age of 8 months, and outcomes were assessed at 3 years. Outcome measures were Autism Diagnostic Observation Schedule (ADOS) calibrated severity scores, and Mullen Verbal and Non-Verbal Developmental Quotients (DQ). RESULTS: At 3 years, HR siblings without an ASD outcome exhibited higher mean ADOS severity scores and lower verbal and non-verbal DQs than LR controls. HR siblings were over-represented (21% HR versus 7% LR) in latent classes characterized by elevated ADOS severity and/or low to low-average DQs. The remaining HR siblings without ASD outcomes (79%) belonged to classes in which they were not differentially represented with respect to LR siblings. CONCLUSIONS: Having removed a previously identified 18.7% of HR siblings with ASD outcomes from all analyses, HR siblings nevertheless exhibited higher mean levels of ASD severity and lower levels of developmental functioning than LR children. However, the latent class membership of four-fifths of the HR siblings was not significantly different from that of LR control subjects. One-fifth of HR siblings belonged to classes characterized by higher ASD severity and/or lower levels of developmental functioning. This empirically derived characterization of an early-emerging pattern of difficulties in a minority of 3-year-old HR siblings suggests the importance of developmental surveillance and early intervention for these children. PMID- 23452688 TI - Risks interpreting odds. PMID- 23452687 TI - Late preterm birth, maternal depression, and risk of preschool psychiatric disorders. AB - OBJECTIVE: Preterm children are at greater risk for psychiatric disorders, including anxiety disorders and attention-deficit/hyperactivity disorder (ADHD), than their term-born peers. Prior research has focused primarily on children born at early gestational ages. Less is known about the rate of psychiatric disorders among late preterm or early term children. In addition, whether a history of maternal depression also associated with prematurity has an impact on the risk for psychiatric disorders remains underexplored. METHOD: Preschoolers between ages 3 and 6 years (N = 306) were recruited for a study examining preschool depression that included healthy and disruptive preschoolers. Preschoolers were placed in the following groups: late preterm (34-36 weeks, n = 39), early term (37-39 weeks, n = 78), and full term (40-41 weeks, n = 154). DSM-IV psychiatric disorders were assessed via the Preschool Age Psychiatric Assessment. Maternal history of psychiatric disorders was assessed using the Family Interview for Genetic Studies. RESULTS: Late preterm children had higher rates of any Axis I psychiatric diagnosis (odds ratio = 3.18, 95% confidence interval = 1.09-4.76) and of any anxiety disorder (odds ratio = 3.74, 95% confidence interval = 1.59 8.78) than full term children after adjusting for gender, ethnicity, family income, and IQ. There were no differences in rates of psychiatric diagnoses between early term and full term children. A history of maternal depression mediated the relationship between late preterm birth and anxiety disorders in preschoolers. CONCLUSIONS: Late preterm children were at increased risk for anxiety disorders at preschool age. A history of maternal depression mediated this association. Findings confirm the extension of the risk of psychiatric disorders associated with prematurity to the late preterm group, and suggest that maternal depression may play a key role in this risk trajectory. PMID- 23452689 TI - Dr. Blackford and Ms. Clauss reply:. PMID- 23452691 TI - search GenBank: interactive orchestration and ad-hoc choreography of Web services in the exploration of the biomedical resources of the National Center For Biotechnology Information. AB - BACKGROUND: Due to the growing number of biomedical entries in data repositories of the National Center for Biotechnology Information (NCBI), it is difficult to collect, manage and process all of these entries in one place by third-party software developers without significant investment in hardware and software infrastructure, its maintenance and administration. Web services allow development of software applications that integrate in one place the functionality and processing logic of distributed software components, without integrating the components themselves and without integrating the resources to which they have access. This is achieved by appropriate orchestration or choreography of available Web services and their shared functions. After the successful application of Web services in the business sector, this technology can now be used to build composite software tools that are oriented towards biomedical data processing. RESULTS: We have developed a new tool for efficient and dynamic data exploration in GenBank and other NCBI databases. A dedicated search GenBank system makes use of NCBI Web services and a package of Entrez Programming Utilities (eUtils) in order to provide extended searching capabilities in NCBI data repositories. In search GenBank users can use one of the three exploration paths: simple data searching based on the specified user's query, advanced data searching based on the specified user's query, and advanced data exploration with the use of macros. search GenBank orchestrates calls of particular tools available through the NCBI Web service providing requested functionality, while users interactively browse selected records in search GenBank and traverse between NCBI databases using available links. On the other hand, by building macros in the advanced data exploration mode, users create choreographies of eUtils calls, which can lead to the automatic discovery of related data in the specified databases. CONCLUSIONS: search GenBank extends standard capabilities of the NCBI Entrez search engine in querying biomedical databases. The possibility of creating and saving macros in the search GenBank is a unique feature and has a great potential. The potential will further grow in the future with the increasing density of networks of relationships between data stored in particular databases. search GenBank is available for public use at http://sgb.biotools.pl/. PMID- 23452693 TI - Changing the delivery of health care. PMID- 23452694 TI - Noise can be harmful to patients as well as staff members. PMID- 23452695 TI - The safe and efficient use of forced-air warming systems. AB - Maintaining perioperative normothermia is important to ensure that a patient does not experience inadvertent hypothermia and its consequences, such as increased blood loss, cardiac abnormalities, prolonged recovery, and increased risk for wound infection. Many clinical guidelines recommend the use of forced-air warming as one of several techniques to prevent inadvertent perioperative hypothermia. Safe use of forced-air warming devices includes choosing the right device, assessing the patient for risks, protecting the patient from burn injuries, appropriately maintaining the patient's body temperature, and using the device as directed by the manufacturer's recommendations. Staff members should receive education on hypothermia and warming technology on a regular basis. PMID- 23452696 TI - A comparison of warming interventions on the temperatures of inpatients undergoing colorectal surgery. AB - This study compared the effects of two different warming interventions in the preoperative setting on the preoperative, intraoperative, and postoperative temperatures of patients undergoing colorectal surgery in an inpatient setting. The study was performed to determine whether prewarming patients for at least 30 minutes would result in postoperative temperatures of 36 degrees C (96.8 degrees F) or higher within 15 minutes of their arrival in the postanesthesia care unit. The results indicated that prewarming devices did not result in reduced proportions of patients who subsequently experienced hypothermia. One reason may be that all the patients were warmed with a forced-air warming device before induction in the OR. Our study does not recommend a specific intervention for a prewarming strategy but indicates that prewarming may contribute to normothermia in the immediate postoperative period. PMID- 23452697 TI - Effect of preoperative forced-air warming on postoperative temperature and postanesthesia care unit length of stay. AB - Unintended hypothermia in the surgical patient has been linked to numerous postoperative complications, including increased risk for surgical site infection, increased oxygen demands, and altered medication metabolism. The lack of literature on the subject was part of the impetus for perioperative nurses in one hospital to conduct a quality improvement project to evaluate the effectiveness of preoperative warming on patients' postoperative temperatures. We randomly assigned 128 patients to either a group that received a forced-air warming blanket preoperatively or a group that did not. Our results showed that prewarming patients before surgery did not have an effect on patients' postoperative temperatures. PMID- 23452698 TI - Developing effective drills in preparation for a malignant hyperthermia crisis. AB - A malignant hyperthermia (MH) crisis is a medical emergency. To give the patient the best possible chance for a successful outcome, a swift, coordinated, multidisciplinary team response is necessary. Malignant hyperthermia occurs infrequently and, as such, details about its diagnosis, treatment, and management must be reviewed and reinforced during periodic education sessions. An MH response plan should be developed to guide a multidisciplinary team during an MH crisis. This plan should be tailored to the needs of the individual health care organization and practiced and refined during periodic simulations of MH episodes, such as MH mock drills. PMID- 23452699 TI - Alleviating anxiety and preventing panic attacks in the surgical patient. PMID- 23452700 TI - Creating a culture of safety by using checklists. PMID- 23452702 TI - Say it again. PMID- 23452703 TI - Neuropsychiatric symptoms, seizure severity, employment, and quality of life of Jordanians with epilepsy. AB - RATIONALE: Depression and anxiety are more strongly associated with quality of life (QOL) than seizure frequency in several populations with epilepsy. However, QOL is culturally determined and may be influenced by cultural values and norms as well as local policies and resources. The goal of this study is to investigate the impact of neuropsychiatric symptoms and seizure severity on QOL and employment in people with epilepsy living in Jordan. METHODS: Seizure severity and complications, antiepileptic drug side effects, social stigma, neuropsychiatric symptoms, and mental health (MH-SF36) and physical health (PH SF36) domains of QOL were assessed in 45 adult patients with epilepsy in a university neurology clinic. Multivariate regression analysis was used to evaluate the relationship between these variables and the quality of life of Jordanians with epilepsy. RESULTS: Neuropsychiatric symptoms, seizure frequency, and history of injury due to seizure were associated with the MH-SF36. However, earlier age of seizure onset, longer duration of epilepsy, unemployment, and history of chronic disease was associated with lower PH-SF36 scores. Furthermore, there were no differences in QOL, neuropsychiatric symptoms, and seizure frequency in Jordanians who were employed versus unemployed in this study. CONCLUSIONS: Neuropsychiatric symptoms were significantly associated with mental health-related QOL measures, but not with physically-related QOL measures, in Jordanians with epilepsy. For studies across populations, it is critical to separate mental health from physical health QOL measures. Furthermore, regional differences in culture and policy may more strongly influence employment status than individuals' experiences of epilepsy, neuropsychiatric symptoms, or QOL in some populations. PMID- 23452704 TI - High circulating CD3+CD56+CD16+ natural killer-like T cell levels predict a better IVF treatment outcome. AB - The aim of this study was to determine whether there was any association between peripheral blood NKT-like cells and IVF treatment outcome. In this prospective study, 124 women who underwent IVF treatment for tubal factor were randomly selected in June and July 2011. Blood samples were obtained on the day of vaginal oocyte retrieval prior to the procedure. The percentages of peripheral blood NKT like cell subsets and the expression levels of mRNA encoding MCP-1 and TNFalpha in PBMCs were recorded, and their relation to IVF treatment outcomes was analyzed. CD3(+)CD56(+)CD16(+) NKT-like cells were significantly elevated in the pregnant group. The expression level of MCP-1 and TNFalpha mRNAs in PBMCs from the pregnant group was also increased. Furthermore, both MCP-1 and TNFalpha mRNA expression were positively correlated with the percentage of CD3(+)CD56(+)CD16(+) NKT-like cells (r=0.55 and r=0.70, respectively). A ROC analysis (AUC=0.634) found that in those women with CD3(+)CD56(+)CD16(+) NKT-like cells >1.85%, the pregnancy rate and live birth rate were higher than in women with cells below this level. An increase in CD3(+)CD56(+)CD16(+) NKT-like cells was associated with a better IVF treatment outcome (OR 4.89, 95% CI=1.86-12.88), with a sensitivity of 47%, specificity of 85%, PPV of 89%, and NPV of 56%. We conclude that an elevated level of circulating CD3(+)CD56(+)CD16(+) NKT-like cells is associated with increased rates of pregnancy and live births in IVF treatment. PMID- 23452705 TI - Estimation of cardiac output and systemic vascular resistance using a multivariate regression model with features selected from the finger photoplethysmogram and routine cardiovascular measurements. AB - BACKGROUND: Cardiac output (CO) and systemic vascular resistance (SVR) are two important parameters of the cardiovascular system. The ability to measure these parameters continuously and noninvasively may assist in diagnosing and monitoring patients with suspected cardiovascular diseases, or other critical illnesses. In this study, a method is proposed to estimate both the CO and SVR of a heterogeneous cohort of intensive care unit patients (N=48). METHODS: Spectral and morphological features were extracted from the finger photoplethysmogram, and added to heart rate and mean arterial pressure as input features to a multivariate regression model to estimate CO and SVR. A stepwise feature search algorithm was employed to select statistically significant features. Leave-one out cross validation was used to assess the generalized model performance. The degree of agreement between the estimation method and the gold standard was assessed using Bland-Altman analysis. RESULTS: The Bland-Altman bias +/-precision (1.96 times standard deviation) for CO was -0.01 +/-2.70 L min-1 when only photoplethysmogram (PPG) features were used, and for SVR was -0.87 +/-412 dyn.s.cm-5 when only one PPG variability feature was used. CONCLUSIONS: These promising results indicate the feasibility of using the method described as a non invasive preliminary diagnostic tool in supervised or unsupervised clinical settings. PMID- 23452706 TI - The millennium of consciousness: reflections on the one mind. PMID- 23452707 TI - Consortium honors Bravewell through Lectureship and Distinguished Service Award. PMID- 23452708 TI - Crossing the threshold: nonlocal consciousness and the burden of proof. PMID- 23452709 TI - Fatigue-recovering effect of a house designed with open space. AB - CONTEXT: Exposure to a natural environment has been reported to be associated with positive effects on mental well-being. However, no report has examined the effects of a house designed with an open space connected to nature on recovery from fatigue. OBJECTIVE: The purpose of this study was to examine the effects of such an open space on recovery from mental fatigue. DESIGN: Placebo-controlled, crossover design. SETTING: Participants were randomized into open (connected to nature) and closed (not connected to nature) conditions. PARTICIPANTS: Sixteen healthy female volunteers were enrolled. INTERVENTION: After a 30-minute fatigue inducing mental task, participants moved to an open or closed recovery room for 30 minutes. MAIN OUTCOME MEASURES: As fatigue-evaluating mental tasks, participants performed advanced trail making tests for 20 minutes. They were asked to rate their levels of fatigue, relaxation, comfort, and healing on a visual analogue scale from 0 (minimum) to 100 (maximum) to evaluate their subjective mental. They also underwent accelerated plethysmography. RESULTS: After the recovery session, lower total error counts of a cognitive test, greater levels of subjective relaxation, comfort, and healing, and lower levels of waveform index-1 assessed via accelerated plethysmography were observed in participants exposed to the open condition compared with the closed condition. These results provide evidence that the use of a house designed with an open space connected to nature during the recovery session improved cognitive function and subjective mental states. Hence, open space was effective for helping recovery from mental fatigue. PMID- 23452710 TI - Spiritual care of cancer patients by integrated medicine in urban green space: a pilot study. AB - BACKGROUND: Psycho-oncological care, including spiritual care, is essential for cancer patients. Integrated medicine, a therapy combining modern western medicine with various kinds of complementary and alternative medicine, can be appropriate for the spiritual care of cancer because of the multidimensional characteristics of the spirituality. In particular, therapies that enable patients to establish a deeper contact with nature, inspire feelings of life and growth of plants, and involve meditation may be useful for spiritual care as well as related aspects such as emotion. The purpose of the present study was to examine the effect of spiritual care of cancer patients by integrated medicine in a green environment. METHODS: The present study involved 22 cancer patients. Integrated medicine consisted of forest therapy, horticultural therapy, yoga meditation, and support group therapy, and sessions were conducted once a week for 12 weeks. The spirituality (the Functional Assessment of Chronic Illness Therapy-Spiritual well being), quality of life (Short Form-36 Health Survey Questionnaire), fatigue (Cancer Fatigue Scale), psychological state (Profile of Mood States, short form, and State-Trait Anxiety Inventory) and natural killer cell activity were assessed before and after intervention. RESULTS: In Functional Assessment of Chronic Illness Therapy-Spiritual well-being, there were significant differences in functional well-being and spiritual well-being pre- and postintervention. This program improved quality of life and reduced cancer-associated fatigue. Furthermore, some aspects of psychological state were improved and natural killer cell activity was increased. CONCLUSIONS: It is indicated that integrated medicine performed in a green environment is potentially useful for the emotional and spiritual well-being of cancer patients. PMID- 23452711 TI - Effect of the emotional freedom technique on perceived stress, quality of life, and cortisol salivary levels in tension-type headache sufferers: a randomized controlled trial. AB - OBJECTIVE: To evaluate the short-term effects of the emotional freedom technique (EFT) on tension-type headache (TTH) sufferers. DESIGN: We used a parallel-group design, with participants randomly assigned to the emotional freedom intervention (n = 19) or a control arm (standard care n = 16). SETTING: The study was conducted at the outpatient Headache Clinic at the Korgialenio Benakio Hospital of Athens. PARTICIPANTS: Thirty-five patients meeting criteria for frequent TTH according to International Headache Society guidelines were enrolled. INTERVENTION: Participants were instructed to use the EFT method twice a day for two months. OUTCOME MEASURES: Study measures included the Perceived Stress Scale, the Multidimensional Health Locus of Control Scale, and the Short-Form questionnaire-36. Salivary cortisol levels and the frequency and intensity of headache episodes were also assessed. RESULTS: Within the treatment arm, perceived stress, scores for all Short-Form questionnaire-36 subscales, and the frequency and intensity of the headache episodes were all significantly reduced. No differences in cortisol levels were found in any group before and after the intervention. CONCLUSIONS: EFT was reported to benefit patients with TTH. This randomized controlled trial shows promising results for not only the frequency and severity of headaches but also other lifestyle parameters. PMID- 23452712 TI - Effect of Johrei therapy on sleep in a murine model. AB - CONTEXT: Sleep deprivation is an underrecognized problem that afflicts our society and can lead to reductions in vitality. However, vitality can be improved by Johrei therapy. We experimented on animals to distinguish the potential benefits of Johrei therapy independent of placebo effects. OBJECTIVES: The central purpose of this study was to explore the sleep-promoting effects of Johrei in mice subjected to sleep interruption. The exploratory aim of the study was to determine the effect of Johrei on sleep as measured by tissue markers in the brain and electroencephalography-derived sleep in sleep-interrupted mice when compared with control mice. DESIGN, INTERVENTION, AND MEASUREMENTS: Mice (n = 45; C57BL/J6) were randomly allocated to one of five study arms with nine animals per arm: Johrei therapy alone, sham controls, negative controls, sleep interruption, and sleep interruption plus Johrei therapy. The amount of sleep was evaluated by measuring proportion of C-fos reactive neurons versus non-C-fos reactive neurons in the medial preoptic area of brain. RESULTS: The proportion of C-fos reactive cells in sleep-interrupted mice that received Johrei therapy (14.5 +/- 0.8%; sleep interruption plus Johrei therapy group) was greater than in sleep interrupted mice (2.4 +/- 1.3%; sleep interruption group) that received no such therapy (P < .0001). The sleep efficiency adjusted for baseline sleep in sleep interrupted mice that received Johrei therapy (sleep interruption plus Johrei therapy group; median 115%; interquartile range 68, 134%) was greater than mice receiving sleep interruption alone (sleep interruption group; median 89%; interquartile range 65, 110%; P = .07). CONCLUSIONS: Johrei treatment results in better sleep as measured by proportion of brain tissue markers of recent sleep. PMID- 23452713 TI - A randomized controlled pilot trial: the effects of EGb 761 on information processing and executive function in multiple sclerosis. PMID- 23452714 TI - Challenges of withdrawal from chronic antidepressant medication: a healing odyssey. AB - We report the case of a woman with posttraumatic stress disorder secondary to childhood sexual assault who attempted withdrawal from long-term use of antidepressant medication and experimented with a plethora of different therapies. The complex case history illustrates the potential difficulty of withdrawal from chronic antidepressant medication and the role of integrative therapies for posttraumatic stress disorder. PMID- 23452715 TI - Acupressure and postoperative vomiting, soy and breast cancer, gingko biloba and Alzheimer's disease, acupuncture and irritable bowel syndrome, mediterranean and low-carbohydrate diets. PMID- 23452716 TI - Patient-centeredness and caring in medical education. PMID- 23452717 TI - Innovation and collaboration: the First International Congress for Educators in Complementary and Integrative Medicine. PMID- 23452718 TI - Current status and future prospects for the prophylactic management of hemophilia patients with inhibitor antibodies. AB - Inhibitor antibodies to factor VIII arise in a substantial minority of patients with hemophilia A treated with replacement therapy; factor IX inhibitors in treated hemophilia B patients are considerably less common. As replacement therapy is not feasible in most such patients, hemostasis can generally only be achieved with "inhibitor bypassing agents", namely (activated) prothrombin complex concentrates and recombinant factor VIIa. These agents are widely used to treat active bleeding in inhibitor patients but they have been used relatively infrequently as prophylactic agents to prevent bleeding and its consequences, mainly progressive joint damage. This is in contrast to hemophilia patients without inhibitors, in whom prophylactic replacement with concentrates of factor VIII or IX has become widely accepted as the optimal strategy to prevent these adverse outcomes. This review addresses the current experience and evidence and the future prospects regarding prophylaxis in inhibitor patients. PMID- 23452719 TI - Isotopic discrimination of stable isotopes of nitrogen (delta15N) and carbon (delta13C) in a host-specific holocephalan tapeworm. AB - During the past decade, parasites have been considered important components of their ecosystems since they can modify food-web structures and functioning. One constraint to the inclusion of parasites in food-web models is the scarcity of available information on their feeding habits and host-parasite relationships. The stable isotope approach is suggested as a useful methodology to determine the trophic position and feeding habits of parasites. However, the isotopic approach is limited by the lack of information on the isotopic discrimination (ID) values of parasites, which is pivotal to avoiding the biased interpretation of isotopic results. In the present study we aimed to provide the first ID values of delta(15)N and delta(13)C between the gyrocotylidean tapeworm Gyrocotyle urna and its definitive host, the holocephalan Chimaera monstrosa. We also test the effect of host body size (body length and body mass) and sex of the host on the ID values. Finally, we illustrate how the trophic relationships of the fish host C. monstrosa and the tapeworm G. urna could vary relative to ID values. Similar to other studies with parasites, the ID values of the parasite-host system were negative for both isotopic values of N (Deltadelta(15)N = - 3.33 +/- 0.630/00) and C (Deltadelta(13)C = - 1.32 +/- 0.650/00), independent of the sex and size of the host. By comparing the specific ID obtained here with ID from other studies, we illustrate the importance of using specific ID in parasite-host systems to avoid potential errors in the interpretation of the results when surrogate values from similar systems or organisms are used. PMID- 23452721 TI - MethylPCA: a toolkit to control for confounders in methylome-wide association studies. AB - BACKGROUND: In methylome-wide association studies (MWAS) there are many possible differences between cases and controls (e.g. related to life style, diet, and medication use) that may affect the methylome and produce false positive findings. An effective approach to control for these confounders is to first capture the major sources of variation in the methylation data and then regress out these components in the association analyses. This approach is, however, computationally very challenging due to the extremely large number of methylation sites in the human genome. RESULT: We introduce MethylPCA that is specifically designed to control for potential confounders in studies where the number of methylation sites is extremely large. MethylPCA offers a complete and flexible data analysis including 1) an adaptive method that performs data reduction prior to PCA by empirically combining methylation data of neighboring sites, 2) an efficient algorithm that performs a principal component analysis (PCA) on the ultra high-dimensional data matrix, and 3) association tests. To accomplish this MethylPCA allows for parallel execution of tasks, uses C++ for CPU and I/O intensive calculations, and stores intermediate results to avoid computing the same statistics multiple times or keeping results in memory. Through simulations and an analysis of a real whole methylome MBD-seq study of 1,500 subjects we show that MethylPCA effectively controls for potential confounders. CONCLUSIONS: MethylPCA provides users a convenient tool to perform MWAS. The software effectively handles the challenge in memory and speed to perform tasks that would be impossible to accomplish using existing software when millions of sites are interrogated with the sample sizes required for MWAS. PMID- 23452722 TI - Microscopic polyangiitis complicated with ileal involvement detected by double balloon endoscopy: a case report. AB - BACKGROUND: Microscopic polyangiitis is characterized by pauci-immune, necrotizing small-vessel vasculitis and an anti-neutrophil cytoplasmic antibody associated vasculitis. Although gastrointestinal involvement in microscopic polyangiitis is not rare, endoscopic observation of it is extremely rare. To the best of our knowledge, this is the first case report of small intestinal involvement in microscopic polyangiitis detected and followed up by double balloon endoscopy. CASE PRESENTATION: A 70-year-old Japanese woman was transferred to our hospital for close examination of suspected small intestinal lymphoma. Retrograde double-balloon endoscopy revealed various forms of ulcers with redness and edema in the ileum. Histological findings suggested ischemic changes. Because mononeuritis multiplex and a fever spike appeared later, vasculitis was suspected. The perinuclear anti-neutrophil cytoplasmic antibody titer was elevated. Nerve biopsy results suggested vasculitis. From these findings, microscopic polyangiitis was diagnosed. It was suggested that microscopic polyangiitis caused the intestinal involvement. Intravenous pulse cyclophosphamide and oral predonisolone were started. After treatment, perinuclear anti-neutrophil cytoplasmic antibodies decreased to the normal range. Retrograde double-balloon endoscopy after treatment showed ulcer scars and no ulcer. CONCLUSION: The cause of gastrointestinal involvement in microscopic polyangiitis is ischemia due to vasculitis. It is difficult to diagnose small vessel vasculitis by endoscopic biopsy. Although histological evidence of microscopic polyangiitis is important, the treatment should not be delayed by repeating the biopsy, because such delay can result in adverse sequela.This case report shows that microscopic polyangiitis should be considered as a differential diagnosis when small intestinal changes like those in the present case are observed by endoscopy. PMID- 23452723 TI - Variation of C peptide decay rate in diabetic patients with positive glutamic acid decarboxylase antibody: better discrimination with initial fasting C peptide. AB - BACKGROUND: Diabetic patients with positive glutamic acid decarboxylase antibody (GAD-Ab) could be classified as autoimmune diabetes, which is discriminated into acute-onset classical type 1 diabetes (T1DM) and latent autoimmune diabetes in adults (LADA). However, whether the decay rate of beta cell function is relevant with the mode of onset (acute or latent-onset) is unclear. We aimed to investigate whether initial C peptide levels could help differentiate variation of C peptide decay rate. METHODS: Five hundred and twenty-seven newly diagnosed GAD-Ab positive diabetic patients were followed up to assess the natural course of beta cell function. Beta cell function failure was defined as fasting C peptide and postprandial C peptide levels less than 100 pmol/L and 150 pmol/L respectively. RESULTS: All these diabetic patients were discriminated according to initial fasting C peptide of 300 pmol/L, that is B+ (larger than 300 pmol/L) and B- (less than 300 pmol/L) group. The proportion of developing beta cell function failure was 13.1% in B+ group and 90.5% in B- group, which suggested that fasting C peptide levels made a good distinction of the heterogeneity in autoimmune diabetes. Receiver operator characteristic (ROC) analysis suggested that the fasting C peptide level of 300 pmol/L was optimal for determining beta cell function failure with sensitivity of 90.5% and specificity of 86.9%. CONCLUSIONS: Initial level of fasting C peptide is a good indicator for predicting beta cell function failure in GAD-Ab positive diabetic patients. PMID- 23452724 TI - How to write a research paper. PMID- 23452725 TI - Introducing a new series on effective writing and publishing of scientific papers. PMID- 23452726 TI - Effective writing and publishing scientific papers--part I: how to get started. PMID- 23452727 TI - Rapid screening and identification of dominant B cell epitopes of HBV surface antigen by quantum dot-based fluorescence polarization assay. AB - A method for quickly screening and identifying dominant B cell epitopes was developed using hepatitis B virus (HBV) surface antigen as a target. Eleven amino acid fragments from HBV surface antigen were synthesized by 9-fluorenylmethoxy carbonyl solid-phase peptide synthesis strategy, and then CdTe quantum dots were used to label the N-terminals of all peptides. After optimizing the factors for fluorescence polarization (FP) immunoassay, the antigenicities of synthetic peptides were determined by analyzing the recognition and combination of peptides and standard antibody samples. The results of FP assays confirmed that 10 of 11 synthetic peptides have distinct antigenicities. In order to screen dominant antigenic peptides, the FP assays were carried out to investigate the antibodies against the 10 synthetic peptides of HBV surface antigen respectively in 159 samples of anti-HBV surface antigen-positive antiserum. The results showed that 3 of the 10 antigenic peptides may be immunodominant because the antibodies against them existed more widely among the samples and their antibody titers were higher than those of other peptides. Using three dominant antigenic peptides, 293 serum samples were detected for HBV infection by FP assays; the results showed that the antibody-positive ratio was 51.9% and the sensitivity and specificity were 84.3% and 98.2%, respectively. In conclusion, a quantum dot-based FP assay is a very simple, rapid, and convenient method for determining immunodominant antigenic peptides and has great potential in applications such as epitope mapping, vaccine designing, or clinical disease diagnosis in the future. PMID- 23452728 TI - Concomitant sarcoidosis and a connective tissue disease: review of the clinical findings and postulations concerning their association. AB - INTRODUCTION: Known causes of granulomatous inflammation must be excluded before the diagnosis of sarcoidosis can be secured. We explored the possibility that connective tissue diseases (CTDs) could be a cause of granulomatous inflammation through an analysis of patients cared for in 2 medical centers and a review of the medical literature. METHODS: Patients with both a diagnosis of sarcoidosis and a CTD were identified at two medical centers. In addition, a literature search identified reported cases of patients with both diagnoses. RESULTS: We identified 15 patients at 2 medical centers plus 53 previous reported patients in the medical literature (total=68) with diagnoses of both sarcoidosis and a CTD. The patients were predominantly female. Scleroderma was the most common CTD. Only 2/59 (3%) with chest radiographs recorded had fibrocystic (stage 4) disease. In 48/67 (72%) patients where the time of diagnosis was recorded, sarcoidosis was diagnosed simultaneously or after the CTD. Sarcoidosis in only one organ ("isolated sarcoidosis") was associated with sarcoidosis being diagnosed simultaneously or after the CTD (p=0.0001). CONCLUSIONS: These data suggest that a significant portion of patients with CTDs and sarcoidosis may actually not have the latter disease. Rather, the CTD may "cause" granulomatous inflammation. Alternate explanations for these findings include that sarcoidosis and/or the connective tissue disease was misdiagnosed in these patients. The diagnosis of a concomitant connective tissue disease and sarcoidosis must be made with extreme caution. PMID- 23452729 TI - Providing nutritional support to patients with thoracic cancer: findings of a dedicated rehabilitation service. AB - BACKGROUND: National guidelines recommend screening patients with thoracic cancer to identify those requiring nutritional support. To help quantify this area of need, the associated workload and explore its impact, we report findings from a dedicated rehabilitation service. METHODS: Patients were screened soon after diagnosis to determine the prevalence of malnutrition, and various aspects compared between malnourished and not malnourished groups. A nutritional care plan was instigated and all contacts recorded, together with follow-up body weight. RESULTS: Of 243 patients seen, 35% were malnourished which was associated with a palliative treatment intent (P < 0.05) and a reduced survival (median 155 days less, 1-year survival 19% vs. 41%; P < 0.01 for both); nonetheless, for about one-fifth, treatment intent was curative. Overall, about two-thirds of patients were failing to meet their daily recommended energy intake. The dietitian provided over 870 episodes of care, a median of three per patient. More of the malnourished group received oral nutritional supplements, but also experienced problems tolerating them. Over one month, neither the pattern nor magnitude of the change in weight differed between malnourished and not malnourished groups. Overall, weight was stable, increased or decreased in 52 (27%), 80 (42%) and 59 (31%) respectively, with no difference in overall survival (P = 0.16). CONCLUSION: Our data provides a pragmatic insight into the implications of following national guidance on nutritional screening and support in this patient group. Nutritional support failed to prevent weight loss in some patients, and did not appear to impact on survival; new assessments and treatments for cachexia are required. PMID- 23452730 TI - Venous thrombosis during assisted reproduction: novel risk reduction strategies. AB - Ovarian hyperstimulation syndrome (OHSS) affects 5% of IVF cycles and incurs a 100-fold increase in risk of venous thrombosis over natural conceptions. Identification of women at risk of OHSS can be achieved using antral follicle count (AFC) and anti-Mullerian hormone (AMH). For those women with a high AFC or AMH combining a GnRH antagonist with a conventional hCG trigger will reduce the risk of OHSS and still allow a fresh transfer to occur. Complete abolition of OHSS is however now a reality by avoiding exposure to exogenous hCG. This can be achieved by segmentation of the IVF cycle using a GnRH agonist for final oocyte maturation and then freezing all oocytes or embryos with subsequent replacement of a single embryo in the context of a frozen embryo transfer. This novel approach will ensure a VTE risk equivalent to natural conception and can be combined with conventional thromboprophylaxis strategies. PMID- 23452731 TI - Management of pregnant women with myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are generally considered to be diseases of elderly population; however, 20% of subjects diagnosed with ET are younger than 40 years. Increase in gestational age in the Western world and improved diagnostic tools raise MPN incidence during pregnancy. MPNs are associated with a remarkable risk for thrombosis and the hypercoagulability milieu associated with pregnancy increases that risk even further. Pregnancies of women diagnosed with MPNs may be complicated with placental thrombosis, fetal growth restriction or loss, and increased risk for maternal thrombosis. The live birth rate in ET and PV is as low as 60 %, with first-trimester loss occurring in 20-30% of pregnancies and an increase in late placenta-mediated complications. Major maternal complications (thromboembolic events and bleeding) are more frequent in PV compared with ET. Therapeutic options range from no therapy, aspirin alone, low-molecular weight heparin (LMWH) to cytoreductive therapy, tailored according to patient-specific risk factors. PMID- 23452732 TI - Role of the coagulation system in development. AB - The generation of knock out mice urged researchers, not always voluntarily, to newly define developmental functions of the gene knocked out. Among others, this has led to the establishment of the field of developmental haemostasis. The work in this field identified a role of coagulation proteases and their regulators independent of haemostasis in the embryo proper. Rather, coagulation proteases regulate cellular function through receptor dependent signalling in the embryo proper, both within and outside the vasculature. Likewise, coagulation proteases modulate placental development independent of haemostasis through mechanisms involving the activation of maternal myeloid derived cells. The following review summarizes the current knowledge in the field of developmental haemostasis and pinpoints open questions within this evolving field. PMID- 23452733 TI - Placental vascular pathology as a mechanism of disease in pregnancy complications. AB - Inadequate placental development results in pregnancy complications. The extent and the degree of defective deep placentation may explain why a similar insult would result in different clinical presentations. The relative new categorization of the placental lesions, separating the non-infectious lesions into lesions that are consistent with maternal and fetal circulation abnormalities, and the infectious lesions into maternal and fetal inflammatory responses, provides us an additional tool to determine the placental maternal and fetal role in the various pregnancy complications. Placental vascular lesions are different in pregnancies complicated by preeclampsia (predominant maternal vascular supply lesions), by fetal growth restriction (FGR) (predominant fetal vascular supply lesions), and by preeclampsia with FGR (both maternal and fetal compartments are involved). Moreover, placental vascular lesions are also different in relation to gestational age at disease onset, as in early- and late-onset preeclampsia, FGR, Fetal death and preterm labor. PMID- 23452734 TI - Placenta-derived microparticles. AB - Microparticles (MPs), sub-micron membrane vesicles, participate in the placental and maternal crosstalk in normal pregnancies as well as in gestational vascular complications (GVC). The article will review the effects of MPs on placental physiological processes, including hemostasis, trophoblast migration, invasion, placental vasculature and their involvement in pathologic states such as thrombosis, inflammation and endothelial dysfunction, resulting in GVC. PMID- 23452735 TI - An update on thrombophilia and placenta mediated pregnancy complications: what should we tell our patients? AB - The placenta mediated pregnancy complications, including pre-eclampsia, birth of a small for gestational age child, placental abruption or late pregnancy loss, are common and often devastating pregnancy complications leading to important maternal/fetal/neonatal morbidity and mortality. In this narrative review I examine two common questions related to women with prior placenta mediated pregnancy complications. Do thrombophilias cause placenta mediated pregnancy complications? Does low molecular weight heparin prevent recurrent placenta mediated pregnancy complications? PMID- 23452736 TI - Antiphospholipid syndrome: looking for a refocusing. AB - The antiphospholipid syndrome (APS) is characterised by thrombotic or obstetric symptoms associated with persistent antiphospholipid antibodies (aPL). Despite an increasing standardisation of aPLs testing, which is prone to strong evolutions due to brilliant progresses in the understanding of APS pathophysiology, the specificity and sensitivity of the epidemiological associations between symptoms and aPLs are highly variable, with persistent strong equivocal evidences probably leading to over-diagnosis, particularly in the obstetrical presentations where consistent association studies are rare and levels of evidence limited. We propose to review the APS definition based on biological mechanisms, to abandon the clinical syndromes which are still molecularly unclassified like "unexplained recurrent pregnancy losses before week 10" and the aspecific markers like classic anticardiolipin antibodies, and finally to narrow APS criteria asa constructive promise for a determined move toward precision medicine. PMID- 23452737 TI - Pathogenesis and management of peripartum coagulopathic calamities (disseminated intravascular coagulation and amniotic fluid embolism). AB - Acute coagulopathic peripartum calamities are relatively rare but contribute importantly to maternal morbidity and mortality in the Western world. Abruptio placenta, amniotic fluid embolism, and retained fetal or placental material may lead to fulminant intravascular activation of coagulation which results in thromboembolic complications and consumption coagulopathy causing severe hemorrhage. The central underlying pathophysiological pathway in the coagulopathy associated with these syndromes is the occurrence of tissue factor, released from the placenta and amniotic fluid, in the circulation, in combination with low levels of physiological anticoagulant factors during pregnancy. The diagnosis of DIC may be made trough conventional composite scoring systems employing routine coagulation tests, whereas for the diagnosis of amniotic fluid embolism measurement of insulin like growth factor binding protein-1 seems promising. Therapy is aimed at removing the precipitating factor combined with supportive adjunctive treatment options. PMID- 23452738 TI - Intraventricular hemorrhage in preterm infants and coagulation--ambivalent perspectives? AB - Intraventricular hemorrhage (IVH) is a major complication of preterm birth, and large hemorrhages may yield significant future disability. During the last few decades, the survival of preterm infants has increased dramatically. Nevertheless, morbidity is still a major problem especially for very young and extremely low birth weight infants. As both, mortality and incidence of morbidities known to influence outcome, show a weekly decline with increasing gestational age, prematurity and low birth weight have been identified as major risk factors for IVH occurrence. This stems probably from the increased vulnerability of the premature germinal matrix as well as the physiologically impaired hemostasis, demonstrated in neonates. The hypothesis that a severe coagulation deficiency in the premature newborn could be a major contributing factor for IVH has been suggested, and small open label interventional studies targeting the premature coagulation system have been conducted with ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII and prothrombin complex concentrate. Nevertheless, potential venous origin of hemorrhages, which may be related to thrombophilic risk factors, has also been discussed. The following manuscript will focus upon IVH pathogenesis and address potential therapies. PMID- 23452739 TI - Venous thromboembolism in neonates and children--update 2013. AB - Thromboses (VTE) in children were associated with medical diseases with and without acquired or inherited thrombophilic risk factors (IT). Disease recurrence rates vary between 3% in children with a first event during the neonatal period and 21% in children with idiopathic VTE. Recently reported systematic reviews showed significant associations between VTE and factor V G1691A or factor II G20210A mutations, protein C, protein S and antithrombin deficiency, more pronounced when combined IT were involved. The factor II G20210A mutation, protein C, protein S, and antithrombin deficiency did also play an important role at VTE recurrence. Primarily asymptomatic family members of pediatric VTE index cases showed annual VTE incidence rates of 2.82% in carriers of antithrombin, protein C, or protein S deficiency, 0.42% and 0.25% in carriers of the factor II G202010A or V G1691A mutation, and 0.10% in relatives with no IT. PMID- 23452740 TI - Mechanisms of hormonal therapy related thrombosis. AB - There is now compelling evidence that use of oral contraceptives and postmenopausal hormonal therapies containing various estrogens is associated with a weak, but clinically relevant risk of both arterial and venous thrombosis. The increased risk is related to type and dose of both estrogen and combined progestagen and mode of delivery. Treatment induces mainly subtle changes in individual components of the coagulation and fibrinolytic systems, but the overall effect is the induction of a prothrombotic phenotype. This brief review summarizes some of the mechanisms responsible the prothrombotic effects of such treatment. PMID- 23452741 TI - Fetal/neonatal alloimmune thrombocytopenia. AB - In fetal/neonatal alloimmune thrombocytopenia (FNAIT), antibodies against paternal antigens present on fetal platelets are produced by the mother. These antibodies will cross the placenta and can cause thrombocytopenia of the unborn. One severe consequence of thrombocytopenia is intracranial bleeding which may lead to death or severe sequelae. FNAIT index cases in one family are usually detected at birth only since antenatal screening programmes have not been installed so far. Subsequent pregnancies of immunized mothers may require special diagnostic and prophylactic interventions, and interdisciplinary counselling and treatment involving obstetricians, pediatricians and immunohematologists may prove useful for optimized care. This short review covers pathogenesis, clinical presentation, diagnostic, and therapeutic options in FNAIT. PMID- 23452742 TI - Von Willebrand disease: pathogenesis and management. AB - Recent studies have suggested a unifying pathophysiological concept to explain the underlying defects of von Willebrand factor (VWF) causing von Willebrand disease (VWD) and have highlighted the relevance of simple VWF related activities in producing a useful diagnosis. A standardized bleeding history condensed into a final bleeding score and few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII (FVIII), in the index case and in his/her relatives are of critical importance. Ristocetin-induced platelet aggregation (RIPA) should also be tested. Trial with desmopressin should be carried out in patients, except those with virtual absence of VWF or with increased RIPA. Desmopressin should be used in all responsive patients as first choice. Substitutive treatment with VWF/FVIII containing products should be used in unresponsive patients, in those with heightened response to desmopressin or in those undergoing interventions requiring good hemostasis for more than 3-5 days. Special consideration should be deserved to the treatment of menorrhagia and parturition. PMID- 23452743 TI - Cerebral vein thrombosis. AB - The estimated annual incidence of cerebral vein thrombosis (CVT) is 3 to 4 cases per million in adults and 7 cases per million in neonates. Among the commonest risk factors there are oral contraceptive use, pregnancy and puerperium that make CVT more frequent in women than in men. Cerebral tumors, infections and traumas are less encountered local risk factors. In 15-20% of patients CVT remains unprovoked. Coagulation abnormalities causing thrombophilia, as well as hyperhomocysteinemia, are worthy to be investigated in patients with CVT. Rarely CVT can be the first clinical manifestation of a myeloproliferative neoplasm. The recurrence rate of CVT is low, but venous thromboembolism in the common sites (lower-limb deep vein thrombosis or pulmonary embolism) can recur, particularly in patients with a first idiopathic CVT. Early diagnosis and anticoagulant treatment reduce morbidity of CVT and improve survival, although the optimal duration of anticoagulant treatment is not well established. PMID- 23452744 TI - Pregnancy and travel-related thromboembolism. AB - Air travel is associated with an increased risk of venous thrombosis. The average risk in all travellers is not particularly high, but high-risk groups have been identified. One such high risk group could be pregnant women but no data are available on the exact magnitude of their risk. In this review we use results from studies performed in air travellers and pregnant women separately to estimate the risk of the combination, which leads to an estimated risk of 0.03 0.1%. Until real data are available, physicians will need to decide on a case-to case basis how to prevent thrombosis in these women. In most passengers, prevention can be limited to encouraging exercise, and avoid prolonged immobilization through sleeping or taking a window seat. Women perceived to be at high risk (history of venous thrombosis, known thrombophilia or other risk factors for thrombosis) may benefit from a short period of LMWH therapy. PMID- 23452745 TI - Mechanisms of thrombosis in cancer. AB - Patients with cancer are at high risk of developing thrombosis. The pathogenesis of blood coagulation activation in cancer patients is complex involves both clinical and biological factors. The thrombotic risk varies according to the type of malignancy and its disease stage, and is increased by concomitant patient related thrombotic risk factors (i.e. advanced age, infection, heart disease). In addition, the tumor cell-specific prothrombotic properties and the host cell inflammatory response dramatically contribute to the risk of thrombosis in these patients. The current development of risk assessment models to predict thrombosis in cancer is important for identifying high-risk patients and predispose the adequate preventive measures. In this review we provide an overview of the principal mechanisms of thrombosis in cancer, including clinical and biological risk factors, and a summary of risk assessment tools to predict thrombosis in the single patient. PMID- 23452746 TI - New anticoagulants in atrial fibrillation management. AB - Three new oral anticoagulants have been evaluated in large registration trials and are now available in many jurisdictions for patients with atrial fibrillation. Questions arise whether these drugs are equally effective and safe for all patients. Now when we are moving away from decades with only one orally available drug for anticoagulation there is opportunity to tailor the therapy according to patient characteristics and preferences. This review addresses the interaction of various patient characteristics with the treatment and what features can assist the physician in the choice of anticoagulant for the individual patient. PMID- 23452747 TI - Novel oral anticoagulants for the prevention of venous thromboembolism in surgical patients. AB - Pharmacologic prophylaxis with low-dose unfractionated heparin, low molecular weight heparin or fondaparinux has clearly demonstrated to reduce the rate of thromboembolic events in surgical patients. In the last decade, several novel oral anticoagulants have been tested in surgical patients, but only in the setting of major orthopedic surgery. Based on the results of the studies, dabigatran, rivaroxaban and apixaban have been approved by the European Medicines Agency for the prevention of venous thromboembolism after elective hip or knee replacement surgery. The novel anticoagulants represent an appealing alternative to current prophylaxis strategies that are mostly based on subcutaneous injection of low molecular weight heparin and have also been recommended by recently updated guidelines. Their role in other settings, such as hip fracture surgery, or in non-orthopedic surgery, may deserve future evaluation. PMID- 23452748 TI - Anticoagulant choices in pregnant women with mechanical heart valves: balancing maternal and fetal risks--the difference the dose makes. AB - Long-term anticoagulation is required in all patients with mechanical prosthetic heart valves to prevent complications with valve thrombosis and valve failure or systemic thromboembolism. The prothrombotic environment of pregnancy further increases the risks of these complications. Anticoagulant choices for pregnant women include oral vitamin K antagonists such as warfarin, or heparin - either unfractionated heparin (UFH) or low molecular weight heparin (LMWH). None of the options is without risk for the mother or her baby. Warfarin crosses the placenta and is associated with warfarin embryopathy and fetopathy but is very effective at preventing thromboembolic complications. The dose of warfarin may play a role in the risk of some, but not all fetal complications. Heparin does not cross the placenta but is less effective at preventing thrombosis and LMWH may be more effective than UFH. The optimal dose and target anti-Xa levels for LMWH have not been established. Measurement of trough anti-Xa levels in addition to peak anti Xa levels may be important. PMID- 23452749 TI - Polycystic ovary syndrome and depression in New Zealand adolescents. AB - OBJECTIVE: To determine whether adolescents with polycystic ovary syndrome (PCOS) are more depressed than adolescent girls in the community and to examine factors associated with depression. DESIGN: An observational study comparing clinical and community samples. SETTING: Two specialist reproductive endocrine clinics in Auckland, New Zealand. PARTICIPANTS: 102 girls aged 14-19 presenting for clinical assessment, fulfilling the Rotterdam consensus for PCOS. The comparison group was 1349 girls from a school-based survey of New Zealand youth. INTERVENTIONS: Clinically significant depression was identified by the long and short form Reynolds Adolescent Depression Scale. BMI, androgen levels, oral contraceptive use, objective symptom severity, age, ethnicity, and socioeconomic grouping were recorded. MAIN OUTCOME MEASURES: Clinically significant depression in the PCOS and community samples. Potential determinants of depression. RESULTS: Clinically significant depression in adolescent girls with PCOS was not increased compared with the community sample (OR 1.3; 95%CI 0.7-2.7, P = .42). Within the PCOS cohort, depression was correlated with increased BMI (P = .01) and possibly acne (P = .08). CONCLUSIONS: Lean adolescent girls with PCOS did not have more clinically significant depression than girls in the community. Within the PCOS cohort, however, there was a clear association between higher depression scores and elevated BMI. There is a potentially important interaction between obesity and depression in PCOS. PMID- 23452750 TI - Randomized blinded challenge study to assess association between Moraxella bovoculi and Infectious Bovine Keratoconjunctivitis in dairy calves. AB - The objective of this study was to evaluate if Moraxella bovoculi was associated with Infectious Bovine Keratoconjunctivitis (IBK) using a corneal scarification model in calves. A 3-arm single-eye block-randomized and blinded challenge study was designed as follows: corneal scarification only, corneal scarification and inoculation with M. bovoculi (ATCC strain: BAA-1259; origin: CA) and corneal scarification and inoculation with Moraxella bovis (strain Epp63-300; origin: NADC). The study was conducted in 3 replicates of 10-12 animals housed in individual pens with no nose-to-nose contact. Calves were enrolled after an ophthalmologist confirmed the absence of corneal, conjunctival, and eyelid abnormalities. Calves were scarified and inoculated in one randomly selected eye, then observed for the primary outcome of interest (corneal ulcers) until euthanized 10 days following scarification. Research group members assessing the outcome were blind to allocation status. The study was approved by the institutional animal care and use committee. Of 36 animals purchased for the study, 5 were excluded prior to enrollment due to ophthalmic abnormalities. Of the 31 enrolled calves, 9/10 (90%) of M. bovis calves, 0/10 (0%) of M. bovoculi calves and 1/11 (9%) of control calves developed corneal ulcerations consistent with IBK in the scarified eyes. The absence of corneal ulcerations in M. bovoculi BAA-1259 inoculated calves suggests it is not a causal organism for IBK in this model and the pathogenicity of this ATCC strain has not been established. Consistent corneal ulceration development in the M. bovis inoculated group demonstrates the ability of the model to induce IBK ulcers. PMID- 23452751 TI - Oral exposure, reinfection and cellular immunity to Schmallenberg virus in cattle. AB - Schmallenberg virus (SBV), a novel orthobunyavirus, was discovered in Germany in 2011. In adult ruminants SBV causes mild transient disease, but foetal infection can lead to severe malformations. Owing to its recent discovery, the knowledge about the pathogenesis is limited. In this study, two heifers seroconverted after a previous SBV infection and five SBV antibody-negative calves were subcutaneously inoculated, another two animals received SBV orally and three were kept as controls. In naive cattle infected subcutaneously viral RNA was detected in serum and blood samples for several days. Seropositive or orally inoculated animals as well as the uninfected controls remained negative throughout the study. Seroconversion was observed only after subcutaneous exposure of the naive animals to SBV. In lymphocytes from peripheral blood SBV genome was not detected, but the lymphocyte homeostasis in blood was influenced. PMID- 23452752 TI - "I am sane but he is mad": Insight and illness attributions to self and others in psychosis. AB - We attempted to explore whether lack of insight in patients with psychosis is related to their genuine inability to recognise symptoms of mental illness as opposed to denial. We addressed this by examining participants' judgments of illness in vignettes in which they were either the protagonist or were commenting on others' behaviour. We recruited 44 first episode psychosis patients and 23 healthy controls to make judgements of specially constructed vignettes describing psychotic symptoms. Insight, Theory of Mind (ToM) and IQ was also measured. Patients' and controls' rating of vignettes overall did not differ significantly with respect to their attribution of mental illness. Patients and controls rated 2nd person vignettes similarly; patients were less likely to attribute mental illness to a character described in the 3rd person. This effect correlated with insight scores. Vignette judgments were significantly correlated with ToM performance but this was moderated by IQ. In conclusion, patients with lower insight tend to make the same attributions to others as to themselves, whilst healthy controls tend to think of mental illness as something seen in other people. There was no support for a 'denial' explanation for lack of insight in these patients. PMID- 23452753 TI - The validity of patient- and clinician-rated measures of needs and the therapeutic relationship in psychosis: a pooled analysis. AB - Measuring outcomes of treatments for psychosis such as needs and the quality of the therapeutic relationship is important in research and routine care. However, evidence on the validity of existing outcome measures is limited. We aimed to test the convergent, discriminant, and predictive validity of two widely used patient- and clinician-rated measures of needs and the therapeutic relationship. Multitrait-multimethod (MTMM) analysis was conducted on the Camberwell Assessment of Need Short Appraisal Schedule (CANSAS) and the Helping Alliance Scale (HAS), both the clinician (CANSAS-C, HAS-C) and patient (CANSAS-P, HAS-P) versions, in a pooled sample of 605 psychotic patients and their clinicians. CANSAS-C and CANSAS P items loaded substantially into one common unmet needs factor. By comparison, substantial factor loadings were found for HAS-C and HAS-P items on two separate clinician- and patient-rated therapeutic relationship factors. Common unmet needs and clinician-rated therapeutic relationship factors significantly predicted reduced psychiatric in-patient days. Our findings support the convergent validity of the CANSAS, discriminant validity of the HAS, and predictive validity of CANSAS and HAS-C. The findings may inform the use of CANSAS and HAS as psychosis outcome measures in research and routine care. PMID- 23452754 TI - Socio-demographic and clinical correlates of subjective quality of life among Nigerian outpatients with schizophrenia. AB - This study aimed to measure the subjective quality of life (QOL) of Nigerian outpatients with schizophrenia and to examine its socio-demographic as well as clinical determinants. A total of 313 outpatients with schizophrenia participated in the study. Data were collected on socio-demographics, outpatient clinic attendance, perceived social support, perceived satisfaction with hospital care, medication adherence, illness severity and QOL. Multiple linear regression analysis was used to determine the amount of variance in the QOL domain scores explained by socio-demographic and clinical variables. Employment status, perceived social support, satisfaction with outpatient care, antipsychotic medication dose, Brief Psychiatric Rating Scale (BPRS) scores and medication adherence had significant relationships with all the QOL domains. Average monthly allowance and outpatient clinic default were significantly associated with all QOL domains except social relationship. Socio-demographic and clinical factors explained only a modest part (29.4%) of the variance in the QOL scores. It is likely that unmeasured 'internalised' determinants contribute in a much larger sense to the variation in subjective QOL. PMID- 23452755 TI - The impact of recovery-oriented day clinic treatment on internalized stigma: preliminary report. AB - Internalized stigma is a complicating feature in the treatment of schizophrenia spectrum disorders and considerably hinders the recovery process. The empowerment and recovery-oriented program of our day clinic might contribute to a reduction in internalized stigma. The aim of the study was to explore the influence of this day clinic program on internalized stigma and other subjectively important outcome measures such as quality of life and psychopathology. Data from two groups of patients had been collected twice, at baseline and after 5 weeks. The experimental group attended the day clinic treatment (N=40) and the control group waited for the day clinic treatment (N=40). The following significant differences between the two groups were found: Patients in day clinic treatment showed a reduction in internalized stigma while the control group showed a minimal increase (Cohen's d=0.446). The experimental group as compared with the control group also showed a greater improvement in the quality of life domain psychological health (Cohen's d=0.6) and in overall psychopathology (Cohen's d=0.452). Interestingly, changes in internalized stigma and psychological quality of life were not associated with changes in psychopathology. Results are encouraging but have to be confirmed in a randomized design. PMID- 23452756 TI - Variability of waist circumference and its relationship with cardiovascular risk factors in outpatients with schizophrenia. AB - The magnitude of waist circumference (WC) in schizophrenia patients was measured at three sites (above superior iliac crest, midpoint between lowest rib and iliac crest, and umbilical level), and correlated with lipid profiles, glucose, blood pressure and metabolic syndrome. The mean midpoint WC was significantly smaller than at the other sites. PMID- 23452757 TI - Phytoremediative urban design: transforming a derelict and polluted harbour area into a green and productive neighbourhood. AB - Many urban areas are polluted by industrial activities and waste disposal in landfills. Since conventional soil remediation techniques are costly and unsustainable, phytoremediation might offer an alternative. In this article, we explore how phytoremediation can be integrated into the transformation of urban post-industrial areas, while improving public space. Buiksloterham, a polluted and deprived industrial area in Amsterdam, serves as case study. Buiksloterham is polluted with heavy metals, with Zinc (Zn) concentrations being the highest. A regression-model for Alpine Pennycress (Thlaspi caerulescens) is used to estimate the time needed to remediate the site. This reveals a conflict in time between remediation and urban development. A research by design experiment shows how to overcome this conflict by dealing with polluted soil innovatively while emphasizing spatial and aesthetic qualities of the phytoremediation plant species. The resulting landscape framework integrates phytoremediation with biomass production and gives new ecological, economic and social value to Buiksloterham. PMID- 23452758 TI - DCJ-Indel sorting revisited. AB - BACKGROUND: The introduction of the double cut and join operation (DCJ) caused a flurry of research into the study of multichromosomal rearrangements. However, little of this work has incorporated indels (i.e., insertions and deletions of chromosomes and chromosomal intervals) into the calculation of genomic distance functions, with the exception of Braga et al., who provided a linear time algorithm for the problem of DCJ-indel sorting. Although their algorithm only takes linear time, its derivation is lengthy and depends on a large number of possible cases. RESULTS: We note the simple idea that a deletion of a chromosomal interval can be viewed as a DCJ that creates a new circular chromosome. This framework will allow us to amortize indels as DCJs, which in turn permits the application of the classical breakpoint graph to obtain a simplified indel model that still solves the problem of DCJ-indel sorting in linear time via a more concise formulation that relies on the simpler problem of DCJ sorting. Furthermore, we can extend this result to fully characterize the solution space of DCJ-indel sorting. CONCLUSIONS: Encoding indels as DCJ operations offers a new insight into why the problem of DCJ-indel sorting is not ultimately any more difficult than that of sorting by DCJs alone. There is still room for research in this area, most notably the problem of sorting when the cost of indels is allowed to vary with respect to the cost of a DCJ and we demand a minimum cost transformation of one genome into another. PMID- 23452759 TI - Identifying landscape features associated with Rift Valley fever virus transmission, Ferlo region, Senegal, using very high spatial resolution satellite imagery. AB - INTRODUCTION: Dynamics of most of vector-borne diseases are strongly linked to global and local environmental changes. Landscape changes are indicators of human activities or natural processes that are likely to modify the ecology of the diseases. Here, a landscape approach developed at a local scale is proposed for extracting mosquito favourable biotopes, and for testing ecological parameters when identifying risk areas of Rift Valley fever (RVF) transmission. The study was carried out around Barkedji village, Ferlo region, Senegal. METHODS: In order to test whether pond characteristics may influence the density and the dispersal behaviour of RVF vectors, and thus the spatial variation in RVFV transmission, we used a very high spatial resolution remote sensing image (2.4 m resolution) provided by the Quickbird sensor to produce a detailed land-cover map of the study area. Based on knowledge of vector and disease ecology, seven landscape attributes were defined at the pond level and computed from the land-cover map. Then, the relationships between landscape attributes and RVF serologic incidence rates in small ruminants were analyzed through a beta-binomial regression. Finally, the best statistical model according to the Akaike Information Criterion corrected for small samples (AICC), was used to map areas at risk for RVF. RESULTS: Among the derived landscape variables, the vegetation density index (VDI) computed within a 500 m buffer around ponds was positively correlated with serologic incidence (p<0.001), suggesting that the risk of RVF transmission was higher in the vicinity of ponds surrounded by a dense vegetation cover. The final risk map of RVF transmission displays a heterogeneous spatial distribution, corroborating previous findings from the same area. CONCLUSIONS: Our results highlight the potential of very high spatial resolution remote sensing data for identifying environmental risk factors and mapping RVF risk areas at a local scale. PMID- 23452760 TI - Molecular identification of species of Taenia causing bovine cysticercosis in Ethiopia. AB - Bovine cysticercosis causing damage to the beef industry is closely linked to human taeniasis due to Taenia saginata. In African countries, Taenia spp. from wildlife are also involved as possible sources of infections in livestock. To identify the aetiological agents of bovine cysticercosis in Ethiopia, cysticerci were collected from 41 cattle slaughtered in the eastern and central areas during 2010-2012. A single cysticercus per animal was subjected to the polymerase chain reaction (PCR)-based DNA sequencing of mitochondrial cytochrome c oxidase subunit 1 gene, and the resultant sequence was compared with those of members of the genus Taenia. Although 38 out of 41 cysticerci (92.7%) were identified as T. saginata, three samples (7.3%) showed the hitherto unknown sequences of Taenia sp., which is distantly related to Taenia solium, Taenia arctos and Taenia ovis. Old literatures suggest it to be Taenia hyaenae, but morphological identification of species could not be completed by observing only the larval samples. PMID- 23452761 TI - Cystic fibrosis papers of the year 2012. AB - This paper reviews a personal selection of three potentially important cystic fibrosis (CF) interventional studies that have been published in the 12 month period preceding the November 2012 RSM CF conference. The review highlights the difficulties in the interpretation of outcome measures in CF. PMID- 23452762 TI - Improved expression of Sirt1 on thymic epithelial cells of SAMP10 after Intrabone marrow-bone marrow transplantation. AB - Aging is accompanied by various forms of immune dysfunction, leading to an increase in frequency of infections and the development of malignant tumors in mice and humans. Sirt1 has been implicated in processes as varied as metabolism, differentiation, cancer, and the stress response and aging. Senescence accelerated mice prone 10 (SAMP10) show not only spontaneously occurring brain atrophy, with deficits in learning and memory, but also emotional disorders. We attempted in this study to clarify the deficits and found that the percentage of CD4/TNF-alpha T-cells in the spleen of 24-week-old (but not 6-week-old) SAMP10 to be significantly reduced. The thymus was significantly lighter, and the percentage of CD4+CD8+ cells was significantly lower in the 24-week-old SAMP10 than 6-week-old SAMP10. Microarray analyses indicated that genes related to transcription coactivator activity, growth factor activity, hormone activity, cytokine activity, receptor activity, and regulation of the immune system were downregulated in the thymus of 24-week-old SAMP10. Real-time PCR analysis showed that the expression of KGF, Aire, and Sirt1 was decreased on the thymic epithelial cells (TECs) of 24-week-old SAMP10. However, these parameters improved after the mice were treated with intrabone marrow-bone marrow transplantation. This is the first report of age-related changes in immune system dysfunction in 24-week-old SAMP10 and the first to show that dysfunction on the TECs of 24-week old SAMP10 was modulated by allogeneic bone marrow cells. PMID- 23452763 TI - Extending Barrett's esophagus cancer risk profile towards genetic abnormalities. PMID- 23452764 TI - [Rare diseases in neurology]. PMID- 23452765 TI - Rare neurological diseases: a Pandora's box for neurology (an European and Italian perspective). AB - Rare neurological diseases are a heterogeneous group of disorders mainly affecting the central and peripheral nervous systems and muscle, representing almost 50% of all rare diseases; this means that neurologists are among the main specialists involved in their diagnosis and research. However, the classical interest of neurologists is primarily directed towards the more common diseases such as dementia, multiple sclerosis, headache, epilepsy and stroke, while avoiding the follow-up of rare neurological diseases that have, taken altogether, had such a major impact on health systems in Europe as well as in other countries around the world. Rare diseases are also considered 'orphan' diseases, as only a few of them have treatments. In Europe as in the USA in recent years, considerable interest has been generated by these disorders, thereby stimulating more specific programs of care and management. In fact, the difficulty of diagnosis and the need for super-specialization in this field has led to the organization of dedicated centers in different countries to collect patients' data within a network for diagnosis, treatment and research. The present report describes our experience in Siena with such a reference center for these disorders and their diagnosis and treatment, and also includes a discussion of the organization of care for rare neurological diseases in Europe and Italy. Finally, this report also covers the new initiative of the Italian Neurological Society to promote an information center for rare neurological diseases to disseminate information and knowledge to all neurologists working in this field. PMID- 23452766 TI - [Have centers of rare neurological diseases modified practices and the care of Wilson's disease?]. AB - Wilson's disease is a particularly rare disease. It is a multisystemic affection related to a genetic abnormality of copper metabolism. Drug treatment is particularly effective if administered at an early stage of the disease and continued throughout life. The French Wilson's disease center, certified for only the one disorder, is easily identifiable by everyone, professionals and patients, which has allowed a rapid increase in the number of patients followed by the center, and considerably reduced the delay between first symptoms and diagnosis. Of its numerous ongoing research projects, it is important to mention the development of a new diagnostic test that would allow the speedy introduction of treatment of both the symptomatic forms and presymptomatic familial forms. Collaborations among professionals permit multidisciplinary care and improve the follow-up of patients in terms of all their medical and social aspects. In addition, the organization of the French Wilson's disease network serves as an exemplar for the implementation of Wilson's disease networks in other European countries and the development of collaborations between Wilson's disease patients'associations across Europe. At present, the center is also working to improve the care of patients presenting with other inherited or acquired pathologies related to copper and other heavy metals. PMID- 23452767 TI - [Have centers of rare neurological diseases changed their practices and management of the hereditary cerebellar ataxias?]. AB - The classification and management of hereditary cerebellar ataxias have been considerably changed by advances made in the field of genetics. Given the numerous genes implicated in the disorders, genetic analysis, which alone can confirm the diagnosis, needs to be based on phenotypically precise studies. Diagnostic algorithms including both recessive and dominant forms of ataxia have been proposed. The range of disease effects has been further expanded in the light of evidence of ataxias associated with permutations of the Fragile X gene, and ataxias linked to mutations of the nuclear genes coding for structural proteins of mitochondrial DNA. In the field of therapeutics, several studies are currently ongoing for Friedreich's ataxia. PMID- 23452768 TI - [Reference center for rare vascular diseases of the eye and brain]. AB - The reference center CERVCO (for rare diseases of the blood vessels in the brain and eye) is involved in the management of various rare vascular diseases of the brain and retina. Any progress made in recent years is variable and depends on the disease concerned. The reference center is also heavily involved in many of the research activities that have taken place over the past 5 years to improve the diagnosis and treatment of these diseases, but the challenges for the future are different for each of them. The reference center now needs simplified assessment tools, the formal recognition of a network of medical 'experts', and adaptation of its technical and human resources to achieve its objectives. PMID- 23452769 TI - [Orphanet and its consortium: where to find expert-validated information on rare diseases]. AB - There are approximately 6000 rare diseases, and 80% of them are genetic. In Europe, a disease is considered rare when it affects no more than one person in 2000. In France, two to three million people are affected, while nearly 30 million others are affected across Europe (5-8% of the whole European population). The majority of rare diseases are poorly understood by health professionals. Due to the lack of sufficient scientific and medical knowledge, many patients are misdiagnosed, which results in delays in care that can be harmful. Because many rare diseases are often associated with neurological manifestations, the neurologist in his daily practice may often encounter these complex diseases that require special care as well as a multidisciplinary approach. Orphanet is the reference portal for rare diseases. Freely accessible on the Internet, it is a non-profit service officially supported by the French Ministry of Health and the European Commission. Its mission is to keep healthcare professionals and patients informed and, by so doing, it contributes to improvements in the diagnosis and treatment of rare diseases. It is currently the only project that establishes a link between diseases and any published information concerning them, and the appropriate services for patients as well as healthcare professionals. Orphanet is currently the most comprehensive site in terms of referenced and documented data, and it has in just a few years become the global reference portal for rare diseases and orphan drugs for all audiences. Orphanet generates a million page views per month. The site is available in six languages (English, French, Spanish, Italian, German and Portuguese) and offers a range of services, including: an inventory, classification and peer-reviewed encyclopedia of rare diseases along with the associated genes (more than 2000 diseases with neurological manifestations are described); a diagnostic support tool; clinical and emergency guidelines; a directory of specialised services in 37 partner countries; an encyclopedia aimed at the general public; an inventory of orphan drugs; downloadable thematic studies and reports on such subjects as the prevalence of rare diseases, orphan drugs, aids and services for patients; and numerous links to other sources of information. Five to ten new rare diseases are described every month, which represents a major challenge for health professionals in terms of keeping their knowledge up to date. The Orphanet website content is expert-validated and updated continuously to respond in real time. PMID- 23452770 TI - Treatment of chronic immune-mediated neuropathies: impact of the rare diseases centers network in Italy. AB - Chronic immune-mediated neuropathies represent a heterogeneous group of mostly demyelinating neuropathies thought to be caused by an autoimmune response to peripheral nerve antigens. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and related variants, multifocal motor neuropathy (MMN) and neuropathy associated with an IgM monoclonal gammopathy with antibody activity against myelin-associated glycoprotein (MAG). Most of these neuropathies respond to immune therapy even though their response to therapy may be different, thereby confirming that their distinct characteristics have relevant clinical implications. While clinicians and scientists are intrigued by the desire to better clarify the cause and pathogenesis of these disorders, the need to allow affected patients to be reimbursed by insurance companies or the national health system can lead to the risk of lumping all these neuropathies under the umbrella term of 'CIDP' to facilitate patients' access to costly therapies. PMID- 23452771 TI - [Have ALS centers changed the care and management of amyotrophic lateral sclerosis?]. AB - The multidisciplinary care of amyotrophic lateral sclerosis (ALS) patients in clinics with expertise in the disease was created in the 1980s and 1990 s specifically to manage the severe functional impairment caused by the disorder. This specialized care for both diagnosis and management led to the creation of the ALS centers. To facilitate the continuity of care through close liaisons between primary-care physicians and community-based services, a specialized network was also developed. French ALS centers are now 10 years old, and their efficient national coordination has provided an improved and homogeneous care delivery in our country, while their recommendations for care have been published both nationally and internationally. Several studies have indicated positive effects on ALS patients'survival after attending ALS centers and receiving such specialized palliative treatments as assisted ventilation. PMID- 23452772 TI - [Congenital myasthenic syndromes: difficulties in the diagnosis, course and prognosis, and therapy--The French National Congenital Myasthenic Syndrome Network experience]. AB - Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by members of the national French CMS Network: the difficulties in making a proper diagnosis; the course and long-term prognosis; and the response to therapy, especially for CMS that do not respond to cholinesterase inhibitors. CMS diagnosis is late in most cases because of confusion with other entities such as: congenital myopathies, due to the frequent presentation in patients of myopathies such as permanent muscle weakness, atrophy and scoliosis, and the abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy) seen on biopsy; seronegative autoimmune myasthenia gravis, when CMS is of late onset; and metabolic myopathy, with the presence of lipidosis in muscle. The long-term prognosis of CMS was studied in a series of 79 patients recruited with the following gene mutations: CHRNA; CHRNE; DOK7; COLQ; RAPSN; AGRN; and MUSK. Disease-course patterns (progressive worsening, exacerbation, stability, improvement) could be variable throughout life in a given patient. DOK7 patients had the most severe disease course with progressive worsening: of the eight wheelchair-bound and ventilated patients, six had mutations of this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first-line therapy for CMS patients, except for cases of slow-channel CMS, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss or RAPSN gene mutations. Ephedrine was given to 18 patients (eight DOK7, five COLQ, four AGRN and one RAPSN). Tolerability was good. Therapeutic responses were encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient who was allergic to ephedrine. PMID- 23452773 TI - [Role and actions of the orphan rare diseases reference center for central hypersomnias in France]. AB - Narcolepsy (with or without cataplexy), idiopathic hypersomnia (with or without long sleep duration) and Kleine - Levin syndrome are the main central rare hypersomnias. They may be considered models to help us to better understand the mechanisms controlling sleep and waking regulation in humans. When creating the national centers for rare hypersomnias, the aims were: 1) screening and earlier treatment of patients with hypersomnia; 2) improving patient care with guidelines, a specific patient's card, coordination of treatments between centers and professionals, and the development of new treatments; 3) encouraging research studies into the epidemiology, pathophysiology and genotype/phenotype through the creation of clinical, DNA, sera and cerebrospinal fluid banks; 4) increasing public awareness among patients and their relatives, the general public and in the mass media of rare hypersomnias; and 5) regular evaluation of our activities. These goals appear to have been achieved over the past 5 years. However, there are now financial difficulties to be faced, given the increasing demands of patients and professionals while having to stay within the same limited budgets. PMID- 23452774 TI - [Inborn errors of metabolism in adult neurology]. AB - Inborn errors of metabolism (IEM) are caused by mutations in genes coding for enzymes and other proteins involved in cell metabolism. Many IEM can be treated effectively. Although IEM have usually been considered pediatric diseases, they can present at any age, mostly with neurological and psychiatric symptoms, and therefore constitute an integral subspeciality of neurology. However, although they are increasingly being recognized, IEM remain rare, and the care for patients should be optimized in specialized reference centers. Since the number of different diseases is very large, the diagnostic approach needs to be rigorous, starting at the clinics and calling upon the additional help of neuroradiology, biochemistry and molecular biology. In practice, it is important for the neurologist to recognize: (1) when to start suspecting an IEM; and (2) how to correlate a given clinical presentation with one of the five major groups of diseases affecting the nervous system. These five groups may be classified as: (a) energy metabolism disorders such as respiratory chain disorders, pyruvate dehydrogenase deficiency, GLUT1 deficiency, fatty-acid beta-oxidation defects, and disorders involving key cofactors such as electron transfer flavoprotein, thiamine, biotin, riboflavin, vitamin E and coenzyme Q10; (b) intoxication syndromes such as porphyrias, urea-cycle defects, homocystinurias, organic acidurias and amino acidopathies; (c) lipid-storage disorders such as lysosomal storage disorders (Krabbe disease, metachromatic leukodystrophy, Niemann - Pick disease type C, Fabry disease and Gaucher's disease), peroxisomal disorders (adrenomyeloneuropathy, Refsum disease, disorders of pristanic acid metabolism, peroxisome biogenesis disorders), Tangier disease and cerebrotendinous xanthomatosis; (d) metal-storage diseases such as iron, copper and manganese metabolic disorders; and (e) neurotransmitter metabolism defects, including defects of serotonin, dopamine and glycine metabolism. PMID- 23452775 TI - [The national plan for orphan rare diseases: nearly 10 years on]. AB - The management of orphan rare diseases has been the goal of two successive government plans since 2004. They allowed the management of these diseases to be handled initially through reference centers, then by specialized centers that were specifically created. The resulting benefits to patients, standardization of management protocols, dissemination of information through ORPHANET, and the development of both fundamental and clinical research have clearly justified the setting up of these plans. Other associated plans are expected to follow in the years to come. PMID- 23452776 TI - virtualArray: a R/bioconductor package to merge raw data from different microarray platforms. AB - BACKGROUND: Microarrays have become a routine tool to address diverse biological questions. Therefore, different types and generations of microarrays have been produced by several manufacturers over time. Likewise, the diversity of raw data deposited in public databases such as NCBI GEO or EBI ArrayExpress has grown enormously.This has resulted in databases currently containing several hundred thousand microarray samples clustered by different species, manufacturers and chip generations. While one of the original goals of these databases was to make the data available to other researchers for independent analysis and, where appropriate, integration with their own data, current software implementations could not provide that feature.Only those data sets generated on the same chip platform can be readily combined and even here there are batch effects to be taken care of. A straightforward approach to deal with multiple chip types and batch effects has been missing.The software presented here was designed to solve both of these problems in a convenient and user friendly way. RESULTS: The virtualArray software package can combine raw data sets using almost any chip types based on current annotations from NCBI GEO or Bioconductor. After establishing congruent annotations for the raw data, virtualArray can then directly employ one of seven implemented methods to adjust for batch effects in the data resulting from differences between the chip types used. Both steps can be tuned to the preferences of the user. When the run is finished, the whole dataset is presented as a conventional Bioconductor "ExpressionSet" object, which can be used as input to other Bioconductor packages. CONCLUSIONS: Using this software package, researchers can easily integrate their own microarray data with data from public repositories or other sources that are based on different microarray chip types. Using the default approach a robust and up-to-date batch effect correction technique is applied to the data. PMID- 23452777 TI - [Haemodynamic monitoring with a pulse-wave system during phaeochromocytoma surgery]. PMID- 23452778 TI - [Prevalence of pain in hospitalised paediatric patients in Spain]. PMID- 23452779 TI - Emergency cholecystectomy and hepatic arterial repair in a patient presenting with haemobilia and massive gastrointestinal haemorrhage due to a spontaneous cystic artery gallbladder fistula masquerading as a pseudoaneurysm. AB - BACKGROUND: Haemobilia usually occurs secondary to accidental or iatrogenic hepatobiliary trauma. It can occasionally present with cataclysmal upper gastrointestinal haemorrhage posing as a life threatening emergency. Haemobilia can very rarely be a complication of acute cholecystitis. Here we report a case of haemobilia manifesting as massive gastrointestinal haemorrhage in a patient without any prior history of biliary surgery or intervention and present a brief review of literature. CASE PRESENTATION: A 22 year old male admitted with history suggestive of acute cholecystitis subsequently developed waxing waning jaundice and recurrent episodes of upper gastrointestinal bleed. Endoscopy showed an ulcer in the first part of duodenum with a clot, no active bleed was visible. Angiography was suggestive of a ruptured pseudoaneurysm in the vicinity of the right hepatic artery probably originating from the cystic artery. Coil embolization was tried but the coil dislodged into the right branch of hepatic artery distal to the site of pseudoaneurysm. Review of angiographic video in light of operative findings demonstrated a fistulous communication between cystic artery and gallbladder as the cause, a simultaneous cholecystoduodenal fistula was also noted. Retrograde cholecystectomy, closure of cholecystoduodenal fistula and right hepatic arteriotomy with retrieval of the endo-coil and hepatic arterial repair was performed. CONCLUSION: Fistula between the cystic artery and gallbladder has been commonly reported to occur after laparoscopic cholecystectomy. Spontaneous fistulous communication, i.e. in the absence of any prior trauma or intervention, between cystic artery and gallbladder is rare with very few reports in literature. Aetiopathogenesis of the disease, in the context of current literature is reviewed. The diagnostic dilemma posed by the confounding finding of an ulcer in the duodenum, the iconic video angiographic depiction as also the therapeutic challenge of a failed embolization with consequent microcoil migration and primary hepatic arterial repair in the emergency situation is discussed. PMID- 23452780 TI - Efficacy of alogliptin in type 2 diabetes treatment: a meta-analysis of randomized double-blind controlled studies. AB - BACKGROUND: Alogliptin is a new dipeptidyl peptidase (DPP-4) inhibitor, which is under investigation for treatment of type 2 diabetes either alone or in combination with other antidiabetic drugs. The aim of this meta-analysis was to assess the efficacy and tolerability of alogliptin in patients with type 2 diabetes. METHODS: Computer based search was performed in MEDLINE, Cochrane library, and HINARI (Health InterNetwork Access to Research Initiative) databases. Meta-analysis was carried out by incorporating double-blind randomized controlled studies done on the efficacy of alogliptin in patients with type 2 diabetes. The efficacy and tolerability of alogliptin was determined by standardized mean differences (SMDs) and Mantel-Haenszel odds ratio. Heterogeneity was assessed by the chi-squared test (Cochran Q test) and I2 statistics. RESULTS: The pooled SMDs demonstrated a significant reduction in HbA1c in patients treated with alogliptin 12.5 mg (SMD = -0.81; 95% CI, -1.11 to 0.51) or alogliptin 25 mg (SMD= -0.98; 95%CI= -1.30 to -0.66) as compared with controls. The SMD for reduction in fasting plasma glucose level (FPG) from baseline was also statistically significant among alogliptin treated patients. However, the effect of alogliptin on body weight change was inconclusive. The proportion of patients who discontinued alogliptin due to adverse events was not different from controls. Similarly, the meta-analyses of specific adverse events did not demonstrate statistically significant differences. CONCLUSIONS: Alogliptin alone or in combination with other antidiabetic drug has shown a significant reduction in HbA1c and FPG level in patients with type 2 diabetes. However, its consistent efficacy for longer duration of therapy needs further investigation. PMID- 23452781 TI - Conductive polymer-based microextraction methods: a review. AB - Conductive polymers (CPs) are classified as materials which exhibit highly reversible redox behavior and the unusual combined properties of metal and plastics. CPs, due to their multifunctionality, ease of synthesis and their stability, have attracted more attentions in different fields of research, including sample preparation. CPs along with several commercial hydrophilic sorbents, are alternative to the commercially available hydrophobic sorbents which despite their high specific surface areas, have poor interactions and retentions in the extraction of polar compounds. This review covers a general overview regarding the recent progress and new applications of CPs toward their synthesis and use in novel extraction and microextraction techniques including solid phase microextraction (SPME), electrochemically controlled solid-phase microextraction (EC-SPME) and other relevant techniques. Furthermore the contribution of nano-structured CPs in these methodologies is also reviewed. PMID- 23452782 TI - Total introduction of microsamples in inductively coupled plasma mass spectrometry by high-temperature evaporation chamber with a sheathing gas stream. AB - A systematic study on the high-temperature Torch Integrated Sample Introduction System (TISIS) for use in Inductively Coupled Plasma Mass Spectrometry (ICP-MS) has been performed. The investigation included the optimization of the relevant parameters (chamber temperature, sheathing gas flow rate, nebulizer gas flow rate, sample uptake rate), the evaluation of its performance characteristics (sensitivity, limits of detection, stability, memory effects, use with the dynamic reaction cell) and representative applications to environmental, biological and clinical samples. Under the optimal conditions (T=150 degrees C; nebulizer gas flow rate of 0.7Lmin(-1) along with sheathing gas flow rate of 0.35Lmin(-1) and a sample uptake rate of 20MULmin(-1)), the sensitivity was from 2 to 8 times higher than that measured using a conventional micronebulizer/mini spray chamber system, due to the enhanced analyte mass transport toward the plasma and the solvent introduction in the vapour form. In addition, for several elements, TISIS provided lower limits of detection than the conventional system, even when the latter worked at 5-fold higher sample uptake rate. Short-term and long-term precision was better than 5%. Spectroscopic interferences arising from common matrices were efficiently removed by the dynamic reaction cell technique. The application of TISIS/ICP-MS to representative certified reference samples (spinach leaves, marine plankton, bone tissue, human blood) proved the suitability of this system for the accurate analysis of limited-size samples. PMID- 23452783 TI - Extent-based kinetic identification using spectroscopic measurements and multivariate calibration. AB - Extent-based kinetic identification is a kinetic modeling technique that uses concentration measurements to compute extents and identify reaction kinetics by the integral method of parameter estimation. This article considers the case where spectroscopic data are used together with a calibration model to predict concentrations. The calibration set is assumed to be constructed from reacting data that include pairs of concentration and spectral data. Alternatively, one can use the concentration- and spectral contributions of the reactions and mass transfers, which are obtained by pretreatment in reaction- and mass-transfer variant form. The extent-based kinetic identification using concentrations predicted from spectroscopic data is illustrated through the simulation of both a homogeneous and a gas-liquid reaction system. PMID- 23452784 TI - Identification of discriminatory variables in proteomics data analysis by clustering of variables. AB - This article presents a data analysis method for biomarker discovery in proteomics data analysis. In factor analysis-based discriminate models, the latent variables (LV's) are calculated from the response data measured at all employed instrument channels. Since some channels are irrelevant and their responses do not possess useful information, the extracted LV's possess mixed information from both useful and irrelevant channels. In this work, clustering of variables (CLoVA) based on unsupervised pattern recognition is suggested as an efficient method to identify the most informative spectral region and then it is used to construct a more predictive multivariate classification model. In the suggested method, the instrument channels (m/z value) are clustered into different clusters via self-organization map. Subsequently, the spectral data of each cluster are separately used as the input variables of classification methods such as partial least square-discriminate analysis (PLS-DA) and extended canonical variate analysis (ECVA). The proposed method is evaluated by the analysis of two experimental data sets (ovarian and prostate cancer data set). It is found that our proposed method is able to detect cancerous from healthy samples with much higher sensitivity and selectivity than conventional PLS-DA and ECVA methods. PMID- 23452785 TI - Multivariate analysis of chromatographic retention data and lipophilicity of phenylacetamide derivatives. AB - One of the most important physicochemical parameters of a molecule that determines its bioactivity is its lipophilicity. Cluster analysis (CA), principal component analysis (PCA), and sum of ranking differences (SRD) were used to compare the lipophilic parameters of twenty phenylacetamide derivatives, obtained experimentally as chromatographic retention data in the presence of different solvents and calculated by different mathematical methods. All the applied methods of multivariate analysis gave approximately similar grouping of the studied lipophilic parameters. In the attempt to group the investigated compounds in respect of their lipophilicity, the obtained results appeared to be dependent on the applied chemometric method. The CA and PCA, grouped the compounds on the basis of the nature of the substituents R1 and R2, indicating that they determine to a great extent the lipophilicity of the investigated molecules. Unlike them, the SRD method could not be used to group the studied compounds on the basis of their lipophilic character. PMID- 23452786 TI - A sandwich-type DNA biosensor based on electrochemical co-reduction synthesis of graphene-three dimensional nanostructure gold nanocomposite films. AB - A novel electrochemical DNA biosensor based on graphene-three dimensional nanostructure gold nanocomposite modified glassy carbon electrode (G-3D Au/GCE) was fabricated for detection of survivin gene which was correlated with osteosarcoma. The G-3D Au film was prepared with one-step electrochemical coreduction with graphite oxide and HAuCl4 at cathodic potentials. The active surface area of G-3D Au/GCE was 2.629cm(2), which was about 3.8 times compared to that of a Au-coated GCE under the same experimental conditions, and 8.8 times compared to a planar gold electrode with a similar geometric area. The resultant nanocomposites with high conductivity, electrocatalysis and biocompatibility were characterized by scanning electron microscopy (SEM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). A "sandwich-type" detection strategy was employed in this electrochemical DNA biosensor and the response of this DNA biosensor was measured by CV and amperometric current-time curve detection. Under optimum conditions, there was a good linear relationship between the current signal and the logarithmic function of complementary DNA concentration in a range of 50-5000fM with a detection limit of 3.4fM. This new biosensor exhibited a fast amperometric response, high sensitivity and selectivity and has been used in a polymerase chain reaction assay of real-life sample with a satisfactory result. PMID- 23452787 TI - Self-assembled oligo(phenylene ethynylene)s/graphene nanocomposite with improved electrochemical performances for dopamine determination. AB - In this work, a novel 1,4-bis (4- aminophenylethynyl)benzene (OPE-NH2, a symmetric linear conjugated oligo(phenylene ethynylene)s derive) and chemically reduced graphene oxide (rGO) nanocomposite (OPE-NH2/rGO) was synthesized by a simple self-assembly method. The OPE-NH2/rGO nanocomposite was stable and water soluble. The formation of OPE-NH2/rGO nanocomposite was ascribed to the pi-pi stacking interaction between the conjugated structure of OPE-NH2 and rGO as well as the electrostatic force between the amino group of OPE-NH2 and the carboxyl group on rGO, which was characterized by FT-IR, UV-vis spectra and fluorescence spectra. The OPE-NH2/rGO nanocomposite exhibited significantly improved electrocatalytic activity to the oxidization of dopamine (DA) than that of rGO or OPE-NH2. The electrochemical performances of OPE-NH2/rGO were dependent on the OPE-NH2 contents, and OPE-NH2 content of 5wt% exhibited the highest activity. Compared with that of rGO, the nanocomposite presented superior high sensitivity with detection limit of 5nM, excellent selectivity, wide linear range (0.01 60MUM) and good stability on the determination of DA. The practical application of the developed OPE-NH2/rGO nanocomposite modified electrode was successfully demonstrated for DA determination in human serum samples. PMID- 23452788 TI - Battery-triggered ultrasensitive electrochemiluminescence detection on microfluidic paper-based immunodevice based on dual-signal amplification strategy. AB - Dual-signal amplification strategy for ultrasensitive electrochemiluminescence (ECL) multiplexed immunoassay on microfluidic paper-based analytical devices (MU PADs) was demonstrated. This dual-signal amplification technique was achieved by employing graphene oxide-chitosan/gold nanoparticles (GCA) immunosensing platform and [4,4'-(2,5-dimethoxy-1,4-phenylene)bis(ethyne-2,1-diyl) dibenzoic acid] (P acid) functionalized nanoporous silver (P-acid/NPS) signal amplification label. For further low-cost and disposable applications, battery-triggered constant potential ECL (+1.0V for P-acid label (vs. Ag/AgCl auxiliary electrode)) was applied on this paper-based immunodevice with the aid of a home-made voltage tunable power device, allowing the traditional electrochemical workstation to be abandoned. We found that two tumor markers could be sequentially detected in the linear ranges of 0.003-20 and 0.001-10ngmL(-1) with the detection limits down to 1.0 and 0.8pgmL(-1), respectively, by simply reversing the connection mode on two working electrodes. The results exhibited excellent precision and high sensitivity of such immunoassay, and it also demonstrated that this battery triggered ECL paper-based immunodevice could provide a rapid, simple and simultaneous multiplex immunoassay with high throughput, low-cost and low detection limits for point-of-care testing. PMID- 23452789 TI - Development and application of carbon nanotubes assisted electromembrane extraction (CNTs/EME) for the determination of buprenorphine as a model of basic drugs from urine samples. AB - In this work carbon nanotubes assisted electromembrane extraction (CNTs/EME) coupled with capillary electrophoresis (CE) and ultraviolet (UV) detection was developed for the determination of buprenorphine as a model of basic drugs from urine samples. Carbon nanotubes reinforced hollow fiber was used in this research. Here the CNTs serve as a sorbent and provide an additional pathway for solute transport. The presence of CNTs in the hollow fiber wall increased the effective surface area and the overall partition coefficient on the membrane; and lead to an enhancement in the analyte transport. For investigating the influence of the presence of CNTs in the SLM on the extraction efficiency, a comparative study was carried out between EME and CNTs/EME methods. Optimization of the variables affecting these methods was carried out in order to achieve the best extraction efficiency. Optimal extractions were accomplished with NPOE as the SLM, with 200V as the driving force, and with pH 2.0 in the donor and pH 1.0 in the acceptor solutions with the whole assembly agitated at 750rpm after 25min and 15min for EME and CNTs/EME, respectively. Under the optimized conditions, in comparison with the conventional EME method, CNTs/EME provided higher extraction efficiencies in shorter time. This method provided lower limit of detection (1ngmL(-1)), higher preconcentration factor (185) and higher recovery (92). Finally, the applicability of this method was evaluated by the extraction and determination of buprenorphine in patients' urine samples. PMID- 23452790 TI - Rapid determination of triclosan in personal care products using new in-tube based ultrasound-assisted salt-induced liquid-liquid microextraction coupled with high performance liquid chromatography-ultraviolet detection. AB - This paper describes the development of a novel, simple and efficient in-tube based ultrasound-assisted salt-induced liquid-liquid microextraction (IT-USA-SI LLME) technique for the rapid determination of triclosan (TCS) in personal care products by high performance liquid chromatography-ultraviolet (HPLC-UV) detection. IT-USA-SI-LLME method is based on the rapid phase separation of water miscible organic solvent from the aqueous phase in the presence of high concentration of salt (salting-out phenomena) under ultrasonication. In the present work, an indigenously fabricated home-made glass extraction device (8-mL glass tube inbuilt with a self-scaled capillary tip) was utilized as the phase separation device for USA-SI-LLME. After the extraction, the upper extractant layer was narrowed into the self-scaled capillary tip by pushing the plunger plug; thus, the collection and measurement of the upper organic solvent layer was simple and convenient. The effects of various parameters on the extraction efficiency were thoroughly evaluated and optimized. Under optimal conditions, detection was linear in the concentration range of 0.4-100ngmL(-1) with correlation coefficient of 0.9968. The limit of detection was 0.09ngmL(-1) and the relative standard deviations ranged between 0.8 and 5.3% (n=5). The applicability of the developed method was demonstrated for the analysis of TCS in different commercial personal care products and the relative recoveries ranged from 90.4 to 98.5%. The present method was proven to be a simple, sensitive, less organic solvent consuming, inexpensive and rapid procedure for analysis of TCS in a variety of commercially available personal care products or cosmetic preparations. PMID- 23452791 TI - A rapid ultrasound-assisted dispersive liquid-liquid microextraction followed by ultra-performance liquid chromatography for the simultaneous determination of seven benzodiazepines in human plasma samples. AB - A simple and efficient ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) method has been developed for the determination of seven benzodiazepines (alprazolam, bromazepam, clonazepam, diazepam, lorazepam, lormetazepam and tetrazepam) in human plasma samples. Chloroform and methanol were used as extractant and disperser solvents, respectively. The influence of several variables (e.g., type and volume of dispersant and extraction solvents, pH, ultrasonic time and ionic strength) was carefully evaluated and optimized, using an asymmetric screening design 3(2)4(2)//16. Analysis of extracts was performed by ultra-performance liquid chromatography coupled with photodiode array detection (UPLC-PDA). Under the optimum conditions, two reversed-phases, Shield RP18 and C18 columns were successfully tested, obtaining good linearity in a range of 0.01-5MUgmL(-1), with correlation coefficients r>0.996. Quantification limits ranged between 4.3-13.2ngmL(-1) and 4.0-14.8ngmL(-1), were obtained for C18 and Shield RP18 columns, respectively. The optimized method exhibited a good precision level, with relative standard deviation values lower than 8%. The recoveries studied at two spiked levels, ranged from 71 to 102% for all considered compounds. The proposed method was successfully applied to the analysis of seven benzodiazepines in real human plasma samples. PMID- 23452792 TI - Preparation of hybrid soda-lime/quartz glass chips with wettability-patterned channels for manipulation of flow profiles in droplet-based analytical systems. AB - Profile switching of two-phase flows is often required in microfluidic systems. Manipulation of flow profiles can be realized by control of local surface energy of micro channel through wettability-patterning of channel surface. This article presents a facile approach for wettability-patterning of the micro channels of glass chips. Commercially available octadecyltrichlorosilane (OTS) was used to hydrophobilize the channels via the formation of OTS self-assembly monolayer (SAM), and a UV-source that mainly emits deep UV-light of 254 and 185 nm was employed to degrade the in-channel formed OTS-SAM. The architecture of soda-lime glass/quartz glass hybrid chip was designed to facilitate the deep UV-light effective degrading the OTS-SAM. The established approach, together with the side by-side laminar-flow patterning technique, was applied to prepare various finely patterned channel networks for different tasks of flow profile switching. The micro device capable of conducting the profile switch from W/O droplets to two separated continuous phases was demonstrated to perform on-chip quick liquid liquid extraction for the determination of partition coefficients of pharmaceuticals. PMID- 23452793 TI - Synthesis and application of ionic liquid matrices (ILMs) for effective pathogenic bacteria analysis in matrix assisted laser desorption/ionization (MALDI-MS). AB - Application of two new series of ionic liquid matrices (ILMs) based on the two most predominantly used conventional organic matrices (Sinapinic acid and 2,5 DHB) in conjugation with various bases (aniline (ANI), dimethyl aniline (DMANI), diethylamine (DEA), dicyclohexylamine (DCHA), pyridine (Pyr), 2-picoline(2-P), 3 picoline(3-P)) for bacterial analysis in matrix assisted laser desorption/ionisation mass spectrometry (MALDI-MS) are reported. The results reveal that ionic liquid matrices could significantly enhance the protein signals, reduce spot-to-spot variation and increase spot homogeneity. More importantly, these novel matrices would not produce any interference during MALDI MS analysis. Among these ILMs, 2,5-DHB/ANI, 2,5-DHB/DMANI and 2,5-DHB/Pyr can be successfully applied to intact bacterial studies compared with other ILMs. Base molecules when added to conventional matrix can promote proton transfer between the bacterial lysate and the matrices. Due to the enhanced proton transfer efficiency by the ionic liquid matrices, almost all the biomolecules of the intact bacterial cells can be ionized and detected in the MALDI-MS. All synthesized ILMs were characterized using ESI (+)/MS and UV-spectroscopy. PMID- 23452794 TI - Determination of dioxin-like polychlorinated biphenyls in 1 mL whole blood using programmable temperature vaporization large volume injection coupled to gas chromatogram and high-resolution mass spectrometry. AB - A sensitive method based on programmable temperature vaporization large volume injection coupled to gas chromatogram and high-resolution mass spectrometry (PTV GC-HRMS) has been developed for the determination of ultra trace levels of dioxin like polychlorinated biphenyls (DL PCBs) in small amounts of human blood. Blood samples (1mL) were first extracted by column extraction and then purified with column chromatorgraphies. Final extracts (20MUL) were introduced to the PTV injector under the solvent vent mode and detected by GC-HRMS (SIM mode). PTV parameters were observed by changing one factor at a time (practical conditions: vent flow: 50mLmin(-1), vent pressure: 0kPa and vent time: 0.1min), recoveries of most PCB congeners ranged from 55.1% to 108%, and method detection limits were in the range of 0.11-1.63pgg(-1). PMID- 23452795 TI - High resolution Orbitrap mass spectrometry in comparison with tandem mass spectrometry for confirmation of anabolic steroids in meat. AB - A prominent trend which has been observed in recent years in the analysis of veterinary drugs and growth-promoting agents is the shift from target-oriented procedures, mainly based on liquid chromatography coupled to triple-quadrupole mass spectrometry (LC-QqQ-MS), towards accurate mass full scan MS (such as time of flight (ToF) and Fourier Transform (FT) Orbitrap MS). In this study the applicability of high resolution single-stage-Orbitrap-MS for confirmatory analysis of growth-promoting agents in meat was compared to that of a QqQ-MS. Validation according to CD 2002/657/EC demonstrated that steroid analysis based on Orbitrap MS, operating at a resolution of 50,000 FWHM, is indeed capable to compete with QqQ-MS in terms of selectivity/specificity, while providing excellent linearity (for most compounds >0.99) but somewhat inferior sensitivity. Indeed, CCalphas reached from 0.04-0.88MUgkg(-1) for the 34 anabolic steroids upon MS/MS detection, while upon Orbitrap MS detection a range of 0.07-2.50MUgkg( 1) was observed. Using QqQ-MS adequate precision was obtained since relative standard deviations, associated with the repeatability and intra-laboratory reproducibility, were below 20%. In the case of Orbitrap MS, for some compounds (i.e. some estrogens) this threshold was exceeded and thus poor precision was observed, which is possibly caused by the lack in sensitivity. Overall, it may be concluded that Orbitrap-MS offers an adequate performance in terms of linearity and precision but lacks in sensitivity for some of the compounds. PMID- 23452796 TI - Amperometric biosensor based on reductive H2O2 detection using pentacyanoferrate bound polymer for creatinine determination. AB - Pentacyanoferrate-bound poly(1-vinylimidazole) (PVI[Fe(CN)5]) was selected as a mediator for amperometric creatinine determination based on the reductive H2O2 detection. Creatinine amidohydrolase (CNH), creatine amidohydrolase (CRH), sarcosine oxidase (SOD), peroxidase (POD), and PVI[Fe(CN)5] were crosslinked with poly(ethylene glycol) diglycidyl ether (PEGDGE) on a glassy carbon (GC) electrode for a creatinine biosensor fabrication. Reduction current was monitored at -0.1V in the presence of creatinine and O2. It is revealed that PVI[Fe(CN)5] is suitable as a mediator for a bioelectrocatalytic reaction of POD, since PVI[Fe(CN)5] neither reacts with reactants nor works as an electron acceptor of SOD. The amounts of PVI[Fe(CN)5], PEGDGE, and enzymes were optimized toward creatinine detection. Nafion as a protecting film successfully prevented the enzyme layer from interferences. The detection limit and linear range in creatinine determination were 12MUM and 12-500MUM (R(2)=0.993), respectively, and the sensitivity was 11mAcm(-2)M(-1), which is applicable for urine creatinine tests. The results of the creatinine determination for four urine samples measured with this proposed method were compared with Jaffe method, and a good correlation was obtained between the results. PMID- 23452797 TI - An improved method for ratiometric fluorescence detection of pH and Cd2+ using fluorescein isothiocyanate-quantum dots conjugates. AB - In this study, thioglycolic acid capped-CdTe quantum dots (QDs) were modified by polyethylenimine (PEI), and then combined with fluorescein isothiocyanate (FITC) to fabricate FITC-CdTe conjugates. The self-assembly of FITC, CdTe and PEI was ascribed to electrostatic interactions in aqueous solution. The resulting conjugates were developed toward two routes. In route one, ratiometric photoluminescence (PL) intensity of conjugates (IFITC/IQDs) was almost linear toward pH from 5.3 to 8.7, and a ratiometric PL sensor of pH was favorable obtained. In route two, firstly added S(2-) induced remarkable quenching of QDs PL peak (at the "OFF" state), which was restored due to following addition of Cd(2+) (at the "ON" state). In the conjugates, successive introduction of S(2-) and Cd(2+) hardly influenced on FITC PL peaks. According to this PL "OFF-ON" mode, a ratiometric PL method for the detection of Cd(2+) was achieved. Experimental results confirmed that the IFITC/IQDs exhibited near linear proportion toward Cd(2+) concentration in the range from 0.1 to 15MUM, and the limit of detection was 12nM. Interferential experiments adequately testified that the proposed sensors of pH and Cd(2+) were practicable in real samples and complex systems. In comparison with conventional analytical techniques, the ratiometric PL method was simple, rapid, economic and highly selective. PMID- 23452798 TI - Investigation on the application of titania nanorod arrays to the determination of chemical oxygen demand. AB - In the present paper, the TiO2 nanorod arrays electrode was developed as a sensor for the determination of chemical oxygen demand (COD) based on a photoelectrochemical degradation principle. Effects of common parameters, such as applied potential, light intensity and pH on its analytical performance were investigated. Under the optimized conditions, the nanorod arrays electrode was successfully applied in the COD determination for both synthetic and real samples. In the COD determination, the proposed method can achieve a practical detection limit of 18.3mgL(-1) and a linear range of 20-280mgL(-1). Furthermore, the results obtained by the proposed method were well correlated with those obtained using the conventional (i.e., dichromate) COD determination method. The main advantages of this COD determination method were its simplicity, long term stability and environmental friendly (corrosive and toxic reagents not consumed). This work would open a new application area (COD determination) of the TiO2 nanorod arrays. PMID- 23452799 TI - Simultaneous determination of fangchinoline and tetrandrine in Stephania tetrandra S. Moore by using 1-alkyl-3-methylimidazolium-based ionic liquids as the RP-HPLC mobile phase additives. AB - A reversed phase high performance liquid chromatography (RP-HPLC) method for simultaneous determination of fangchinoline (FAN) and tetrandrine (TET) in Stephania tetrandra S. Moore was established by using 1-hexyl-3-methylimidazolium tetrafluoroborate as the mobile phase additives in this paper. Four types of 1 alkyl-3-methylimidazolium-based ionic liquids (ILs) were used as additives of the mobile phase to separate FAN and TET by RP-HPLC. The effects of the length of the alkyl group on the imidazolium ring and its counterion, the concentrations of IL and the pH of the mobile phase, which influenced the chromatographic behaviors of FAN and TET, were investigated in detail. The linearity, sensitivity, accuracy and repeatability of the proposed method were also investigated. The probable mechanism of the separation with ILs as the mobile phase additives was explored and discussed. PMID- 23452800 TI - Molecularly imprinted nano particles combined with miniaturized homogenous liquid liquid extraction for the selective extraction of loratadine in plasma and urine samples followed by high performance liquid chromatography-photo diode array detection. AB - In this work a molecularly imprinted polymer was developed as a selective sorbent for extraction of loratadine (as a model) in complex matrices followed by miniaturized homogeneous liquid-liquid extraction (MHLLE) for the first time. The molecularly imprinted polymer (MIP) which is based on loratadine as the template was synthesized successfully by precipitation polymerization and was used as a selective sorbent. This technique was applied for preconcentration, sample preparation, and determination of loratadine using high performance liquid chromatography-photo diode array detection (HPLC-PDA). Optimization of various parameters affecting molecular imprinted solid phase extraction (MISPE), such as pH of adsorption, composition and volume of eluent, adsorption and desorption times were investigated. Besides, in the subsequent stage (MHLLE) the type and volume of extraction solvent, sodium hydroxide amount, surfactant concentration, and extraction time were investigated and optimized. Under the optimal condition, maximum enrichment capacity and Langmuir constant were 91mgg(-1) and 0.014Lmg( 1), respectively. Furthermore, enrichment factor and extraction recovery of MIP MHLLE method were 30 and 90%, respectively. The LOD of the proposed method was 0.2MUgL(-1) and a linear dynamic range of 1-1000MUgL(-1) was obtained with correlation coefficient of greater than 0.998. The present method was applied for extraction and determination of loratadine in plasma and urine samples in MUgL( 1) levels and satisfactory results were achieved (RSD <8% based on three replicate measurements). PMID- 23452801 TI - Biodegradation of alachlor in liquid and soil cultures under variable carbon and nitrogen sources by bacterial consortium isolated from corn field soil. AB - Alachlor, an aniline herbicide widely used in corn production, is frequently detected in water resources. The main objectives of this research were focused on isolating bacterial consortium capable of alachlor biodegradation, assessing the effects of carbon and nitrogen sources on alachlor biodegradation and evaluating the feasibility of using bacterial consortium in soil culture. Kavar corn field soil with a long history of alachlor application in Fars province of Iran has been explored for their potential of alachlor biodegradation. The influence of different carbon compounds (glucose, sodium citrate, sucrose, starch and the combination of these compounds), the effect of nitrogen sources (ammonium nitrate and urea) and different pH (5.5-8.5) on alachlor removal efficiency by the bacterial consortium in liquid culture were investigated. After a multi-step enrichment program 100 days of acclimation, a culture with the high capability of alachlor degradation was obtained (63%). Glucose and sodium citrate had the highest alachlor reduction rate (85%). Alachlor reduction rate increased more rapidly by the addition of ammonium nitrate (94%) compare to urea. Based on the data obtained in the present study, pH of 7.5 is optimal for alachlor biodegradation. After 30 days of incubation, the percent of alachlor reduction were significantly enhanced in the inoculated soils (74%) as compared to uninoculated control soils (17.67%) at the soil moisture content of 25%. In conclusion, bioaugmentation of soil with bacterial consortium may enhance the rate of alachlor degradation in a polluted soil. PMID- 23452802 TI - Challenges facing academic urology training programs: an impending crisis. AB - OBJECTIVE: To determine the most pressing issues facing academic urology training centers. The supply of urologists per capita in the United States continues to decrease. Stricter resident requirements, restriction of resident duty hours, and a Graduate Medical Education (GME) funding cap on resident education has led to significant challenges for academic centers. METHODS: A 32-question survey was sent to Society of University Urologists members. Respondents defined themselves as academic faculty tenure track, program director, academic chair, program director and academic chair, clinical faculty nontenure track, and community faculty member. RESULTS: A total of 143 of 446 members(32%) responded. A lack of funding was indicated as an obstacle to adding new residency positions (65% respondents) and recruiting new faculty (60% respondents). Residency positions not funded by GME (40% respondents) required either clinical or hospital dollars to support these slots. Most respondents (51%) indicated resident research rotations are funded with clinical dollars. Surgical skills laboratories are commonly used (85% respondents) and are supported mostly with hospital or clinical dollars. The majority of respondents (84%) indicated they would expand simulation laboratories if they had better funding. Other than urodynamics and ultrasound, urology residency training programs reported little income from ancillary dollars. CONCLUSION: There is a significant workforce shortage within urology training programs. Clinical revenue and hospital funding seem to be the main financial support engines to supplement the GME funding shortage, proficiency training, and faculty salary support for teaching. The current system of GME funding for urology residency programs is not sustainable. PMID- 23452803 TI - Establishment of a grading system for bladder trabeculation. AB - OBJECTIVE: To establish a grading system for bladder trabeculation. METHODS: A total of 228 patients who underwent videourodynamic studies were retrospectively reviewed. All fluoroscopic images included were gathered and were classified into 4 grades of trabeculation according to maximum depth and portion of bladder surface occupied: 0 (none), 1 (mild, depth <5 mm and area <1/2 of bladder), 2 (moderate, depth 5-10 mm and area >= 1/2 of bladder), and 3 (severe, depth >10 mm and area >= 1/2 of bladder). Presence of vesicoureteral refluxes, urethral leaks, and diverticula were evaluated. Grades were determined by 9 participants, and test-retest reliability was assessed over the span of 2 weeks. To evaluate interobserver and test-retest reliabilities, the intraclass correlation coefficient, Crohn's kappa, and Spearman's correlation coefficient were analyzed. RESULTS: We found the mean trabeculation depths to be 6.5 +/- 6.1 mm and with increasing trabeculation grade, refluxes, and urethral leaks increased. The number of diverticula, however, was unrelated to the grade. The interobserver reliability was almost perfect, with the intraclass correlation coefficients of 0.985 in fluoroscopy. Test-retest reliability was strong between repeated grading, and all values of Crohn's kappa showed almost perfect agreement (from 0.870 to 0.955). Urodynamic results of free uroflowmetry and voiding cystometry showed clinical significance of this trabeculation classification grade. CONCLUSION: Interobserver and test-retest reliabilities proved the reliability and validity of the grading system for bladder trabeculation using trabeculation depths and area covering the bladder surface. PMID- 23452804 TI - Patient-centered medical therapy for nephrolithiasis. AB - OBJECTIVE: To elucidate the effect of a patient-centered combined nutritional and medical therapy approach on stone disease management, guided by 24-hour urinary stone risk. MATERIALS AND METHODS: We retrospectively analyzed the records of patients treated at our multidisciplinary stone clinic from July 2007 to February 2009. Included were adult stone formers who presented with severe urinary abnormalities or whose urinary parameters failed to improve with dietary changes. Urinary risk factors for stone disease were evaluated before and after intervention with 24-hour urine collections. Hypercalciuria was treated with hydrochlorothiazide/indapamide, hypocitraturia with potassium/calcium citrate, and hyperuricosuria with allopurinol. The primary end point was the effect of combined dietary and medical intervention on levels of urinary metabolites. Statistical comparisons of postintervention urine collection values with baseline values were performed using a paired t test. Two-tailed P <.05 was considered statistically significant. RESULTS: Data for 137 patients with a mean follow-up of 14.39 months were analyzed. Mean age was 47.2 years, and the male-to-female ratio was 1.04. Hypocitraturia was detected in 70 patients (51%), hypercalciuria in 49 (37%) and hyperuricosuria in 18 (13%). A significant improvement was found in 67% of patients with hypocitraturia (urinary citrate levels: 380.28 to 663.96 mg/d; P <.0001), in 82% of patients with hypercalciuria (urinary calcium levels: 337.4 to 183.6 mg/d; P <.0001), and in 72% of patients with hyperuricosuria (urinary citric acid level: 927 to 600 mg/d; P <.0001). CONCLUSION: Medical management of stone disease instituted based on individual risk factors impacts subsequent urinary stone risk, supporting its use for stone disease when patients do not respond to lifestyle and dietary changes. PMID- 23452805 TI - Editorial comment. PMID- 23452806 TI - The impact of body mass index on the outcomes of retrograde intrarenal stone surgery. AB - OBJECTIVE: To compare the outcomes of using retrograde intrarenal surgery (RIRS) for treating renal stones among normal weight, overweight, and obese patients. MATERIALS AND METHODS: From December 2008 to March 2012, 207 patients who underwent RIRS were included in the study. Patients were categorized into 3 groups according to their body mass index (BMI): normal weight <25 kg/m(2) (group 1), overweight 25-29.9 kg/m(2) (group 2), and obese >=30 kg/m(2) (group 3). We compared the 3 groups with regard to preoperative characteristics, operative parameters, and postoperative outcomes. RESULTS: There were no significant differences in age, gender, or renal stone parameters (size, localization, laterality, multiplicity) among the 3 groups. The mean stone sizes were 18.6 +/- 7.1 mm in group 1, 16.9 +/- 7.0 mm in group 2, and 18.5 +/- 8.4 mm in group 3 (P = .365). The stone-free rates (SFRs) of a single procedure for the groups were 79.0%, 77.9%, and 75.5% for groups 1, 2, and 3, respectively (P = .897). After additional treatments, the final SFR for the groups increased to 85.2%, 84.4%, and 81.6% for groups 1, 2, and 3, respectively (P = .861). We did not find any significant differences among the groups with regard to the operation times, complication rates, and hospital length of stay (LOS). Major complications were not observed either during or after the operations. CONCLUSION: Our study demonstrates that the outcomes of RIRS for treating renal stones are similar in overweight and obese patients when compared with patients who are of normal weight. Therefore, these patients can be treated safely and successfully with RIRS. PMID- 23452807 TI - Perioperative complications of robot-assisted partial nephrectomy: analysis of 886 patients at 5 United States centers. AB - OBJECTIVE: To review complications of robot-assisted partial nephrectomy (RAPN) at 5 centers, as classified by the Clavien system. MATERIALS AND METHODS: A multi institutional analysis of prospectively maintained databases assessed RAPN complications. From June 2007 to November 2011, 886 patients at 5 United States centers underwent RAPN. Patient demographics, perioperative outcomes, and complications data were collected. Complication severity was classified by Clavien grade. RESULTS: Mean (standard deviation) data were patient age, 59.4 (11.4) years; age-adjusted Charlson Comorbidity Index, 3.0 (1.9); radiographic tumor size, 3.0 (1.6) cm; nephrometry score, 6.9 (2.0); and warm ischemia time, 18.8 (9.0) minutes. Median blood loss was 100 mL (interquartile range, 100-250 mL). Of the 886 patients, intraoperative complications occurred in 23 patients (2.6%) and 139 postoperative complications occurred in 115 patients (13.0%) for a total complication rate of 15.6%. Among the 139 postoperative complications, 43 (30.9%) were classified as Clavien 1, 64 (46.0%) were Clavien 2, 21 (15.1%) were Clavien 3, and 11 (7.9%) were Clavien 4. No complication-related deaths occurred. Intraoperative hemorrhage occurred in 9 patients (1.0%) and postoperative hemorrhage in 51 (5.8%). Forty-one patients (4.6%) required a perioperative blood transfusion, 10 (1.1%) required angioembolization, and 2 (0.2%) required surgical reexploration for postoperative hemorrhage. Urine leaks developed in 10 patients (1.1%): 3 (0.3%) required ureteral stenting, and 2 (0.2%) required percutaneous drainage. Acute postoperative renal insufficiency or renal failure developed in 7 patients (0.8%), 2 of whom required hemodialysis. The RENAL (radius, exophytic/endophytic properties of the tumor, nearness of tumor deepest portion to the collecting system or sinus, anterior/posterior descriptor and the location relative to polar lines) nephrometry scoring system accurately predicted RAPN complication rates. CONCLUSION: Complication rates in this large multicenter series of RAPN appear to be acceptable and comparable with other nephron-sparing modalities. Most complications (77.0%) are Clavien 1 and 2 and can be managed conservatively. PMID- 23452808 TI - Editorial comment. PMID- 23452810 TI - Does infertility treatment increase male reproductive tract disorder? AB - OBJECTIVE: To determine the association between assisted human reproduction and male reproductive disorders in infants conceived by this means. MATERIALS AND METHODS: Between January 2008 and December 2011, 15,332 neonates were born in our hospital. We assessed the birth weight, gestational age, and other characteristics of the 7752 male infants and determined the association between methods of conception and male reproductive disorders in the infants. We also analyzed the influence of male factor on the occurrence of these disorders. RESULTS: Ninety-nine newborns (1.3%) were diagnosed with cryptorchidism, 8 (0.1%) were diagnosed with hypospadias, and 4 (0.05%) were diagnosed with both. Cryptorchidism was more common in children conceived through in vitro fertilization (IVF) and IVF/intracytoplasmic sperm injection (IVF/ICSI; P <.05), and hypospadias was more common in children conceived through IVF/ICSI (P <.05). Children conceived through intrauterine insemination (IUI), IVF, and IVF/ICSI had higher rates of low birth weight and preterm birth. Logistic regression analysis showed that low birth weight and preterm birth were significantly associated with male reproductive disorders, whereas the method of conception was not. Male factor was not significantly associated with these disorders. CONCLUSION: IVF and IVF/ICSI increase the risks of low birth weight and preterm birth, resulting in increased rates of hypospadias and cryptorchidism. Male factor was not associated with reproductive disorders in male infants. PMID- 23452809 TI - Long-term follow-up of a phase II trial of chemotherapy plus hormone therapy for biochemical relapse after definitive local therapy for prostate cancer. AB - OBJECTIVE: To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse (BR). METHODS: Treatment was 4 cycles of docetaxel (70 mg/m(2)) every 3 weeks and estramustine 280 mg three times a day (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was the proportion with prostate specific antigen (PSA) <0.1 with recovered testosterone 5 years after completion of therapy. Secondary endpoints included time to progression (TTP), time to reinitiate androgen deprivation therapy (ADT), the proportion with castration resistant prostate cancer (CRPC), and overall survival (OS). RESULTS: Median follow-up was 8.6 years (range 1.3-11.1 years). At 5 year follow-up, 7 patients (11%) had PSA <0.1 (5 undetectable); 8 (13%) had PSA >0.1 but without reinitiation of ADT (median PSA 0.37). Of the 15 (24%) men without reinitiation of ADT, and 14 have recovered testosterone to normal range. Median TTP for the complete cohort was 35.0 months (95% confidence interval [CI] 31.7-39.2). Baseline PSA <3.0 ng/dL, no prior ADT, and prostatectomy (vs radiation) were associated with longer TTP (P = .0001, P = .0055, and P = .0398, respectively). At the time of analysis, 42 men (68%) had restarted ADT, 23 men had CRPC (37%), and 11 (18%) had chemotherapy. Median time to reinitiation of ADT was 32.6 months (range 0-107.6 months). Median OS has not been reached; there were 15 deaths. CONCLUSION: Chemotherapy plus ADT for BR resulted in durable (>5 years) complete responses (<0.1 ng/mL) in 7 men (11%). Twenty-four percent of men have not re initiated ADT 5 years from completion of protocol therapy. PMID- 23452811 TI - Delayed-onset ureteral obstruction after endoscopic dextranomer/hyaluronic acid copolymer (Deflux) injection for treatment of vesicoureteral reflux in children: a case series. AB - We report 4 patients with upper urinary tract (UUT) obstruction requiring ureteric reimplantation at 1, 7, 28, and 63 months after dextranomer/hyaluronic acid copolymer (Dx/HA) injection for vesicoureteric reflux. Histopathologic evaluation of ureteric segments revealed extensive foreign body formation in all cases. We conclude that UUT obstruction is a rare but serious complication after Dx/HA injection that can occur even years after surgery. The incidence of delayed onset UUT obstruction may be higher than previously noted. Long-term follow-up and a critical reappraisal of the method are needed to assess the late sequelae of Dx/HA injection therapy for vesicoureteric reflux. PMID- 23452812 TI - Access to the extrapleural space at the time of surgery for continuous paravertebral block after flank incision: description of the technique and case series. AB - OBJECTIVE: To test our hypothesis that surgeon-placed paravertebral block (PVB) placement during open renal surgery is effective, feasible, and safe. Neuraxial analgesia represents the current standard of care for perioperative anesthesia for open renal surgery. However, potential catastrophic complications such as neuraxial bleeding and infection may occur. An alternative to neuraxial analgesia widely used in thoracic surgery is the surgeon-placed PVB. TECHNICAL CONSIDERATIONS: The surgeon-placed catheter is directed in the paravertebral space through the flank incision at the time of surgery. The postoperative catheter management was directed by anesthesiologists. All patients undergoing open renal surgery by a single urologist were provided a PVB for this series. Twenty-nine consecutive patients undergoing open renal surgery were given PVBs. Patients received an average of 5.1 mg of subcutaneous equivalent hydromorphone in the 48-hour postoperative period. No complications because of the PVB were found. CONCLUSION: PVB represents a safe and effective surgeon-placed alternative to neuraxial analgesia for open renal operative procedures. PMID- 23452813 TI - Re: Netsch et al.: Impact of preoperative ureteral stenting on stone-free rates of ureteroscopy for nephroureterolithiasis: a matched-paired analysis of 286 patients (Urology 2012;80:1214-1220). PMID- 23452814 TI - Reply by the authors. PMID- 23452815 TI - Unusual retrovesical cystic mass in a male patient. AB - Primary tumors of the seminal vesicles are very rare, with most reported cases being malignant. Benign tumors of the seminal vesicles are even rarer. A spectrum of tumors is derived from both epithelium and stroma and constitutes a distinct subset termed "epithelial-stromal tumors." We present the classic imaging findings of a cystadenoma of the seminal vesicles in a 23-year-old man, who presented with lower abdominal pain and obstructive urinary symptoms. PMID- 23452817 TI - [Primary retroperitoneal hydatid cyst]. PMID- 23452818 TI - [Pancreatic pseudocyst fistulised to pleural space: a rare cause of a massive pleural effusion]. PMID- 23452816 TI - beta-Secretase: its biology as a therapeutic target in diseases. AB - beta-Secretase (BACE1, beta-site APP cleaving enzyme 1) is an aspartic proteinase that has multiple functions in various physiological processes, such as cell differentiation, immunoregulation, and cell death. There is increasing evidence that changes in BACE1 activity are involved in many diseases, such as Alzheimer's disease (AD), schizophrenia, epileptic behavior, and others. However, a deeper understanding of the molecular biology of BACE1 is necessary for further exploration of cell development, immunological regulation, and disease pathogenesis. Here, we review the molecular and cellular biology of BACE1, including its enzymatic properties, structure, biosynthesis, and physiological functions to provide a new perspective and rational assessment of drugability. Lastly, we discuss proposed strategies to control BACE1 activity for possible therapeutic application. PMID- 23452819 TI - [Gastroenteric reconstruction route after pancreaticoduodenectomy: antecolic versus retrocolic]. AB - INTRODUCTION: Delayed gastric emptying (DGE) is a relatively common complication after cephalic pancreaticoduodenectomy (CPD). Its origin is not very clear, and it is believed that its appearance is due to multiple factors (hormones, appearance of other complications, particularly pancreatic fistulas, and the surgical technique). Among the technical aspects associated with DGE, it has been proposed that the route of gastroenteric reconstruction (antecolic or retrocolic) could have an effect on its incidence. MATERIAL AND METHODS: A systemic review was made of the literature, searching for articles that compared both reconstruction routes after CPD, finding only 11 articles: 4 randomised clinical trials, one prospective study, and 6 retrospective studies. A meta-analysis could not be performed on them, due to the large methodological differences between them. RESULTS: In the 4 randomised studies, 2 were in favour of the antecolic route, and 2 did not observe any differences between either of them. The antecolic route obtained a much lower DGE rate than the retrocolic one in the only prospective study. In 4 of the retrospective studies the antecolic route obtained a very low rate. The results of both routes were similar in another 2 retrospective studies, with the retrocolic route slightly better in one of them. CONCLUSIONS: Using the published literature, the gastric reconstruction route associated with less DGE after CPD cannot currently be determined. PMID- 23452821 TI - Dedication of this special issue to Professor Jerry Keeler. PMID- 23452822 TI - Abstracts of the Combined Northern and Yorkshire Deaneries Rheumatology Annual Conference. York, United Kingdom. September 26, 2012. PMID- 23452820 TI - Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer. AB - BACKGROUND: New therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies. METHODS: We explored the combination of ABT-737 and chloroquine, an inhibitor of autophagy, in preclinical models of SCLC. These included cell culture analyses of viability and of autophagic and apoptotic pathway induction, as well as in vivo analyses of efficacy in multiple xenograft models. RESULTS: Combination treatment of SCLC lines with ABT-737 and chloroquine decreased viability and increased caspase-3 activation over treatment with either single agent. ABT-737 induced several hallmarks of autophagy. However, knockdown of beclin-1, a key regulator of entry into autophagy, diminished the efficacy of ABT 737, suggesting either that the effects of chloroquine were nonspecific or that induction but not completion of autophagy is necessary for the combined effect of ABT-737 and chloroquine. ABT-737 and chloroquine in SCLC cell lines downregulated Mcl-1 and upregulated NOXA, both of which may promote apoptosis. Treatment of tumor-bearing mice demonstrated that chloroquine could enhance ABT-737-mediated tumor growth inhibition against NCI-H209 xenografts, but did not alter ABT-737 response in three primary patient-derived xenograft models. CONCLUSION: These data suggest that although ABT-737 can induce autophagy in SCLC, autophagic inhibition by choroquine does not markedly alter in vivo response to ABT-737 in relevant preclinical models, arguing against this as a treatment strategy for SCLC. PMID- 23452824 TI - Endodermal stem cell populations derived from pluripotent stem cells. AB - The generation of functional endodermal lineages, such as hepatocytes and pancreatic endocrine cells, from pluripotent stem cells (PSCs) remains a challenge. One strategy to enhance the purity, yield and maturity of endodermal derivatives is to expand endoderm committed stem or progenitor cell populations derived from PSCs before final differentiation. Recent studies have shown that this is in fact a viable option both for expanding pure populations of endodermal cells as well as for generating more mature derivative tissues, as highlighted in the case of pancreatic beta cells. PMID- 23452825 TI - A randomized controlled pilot study of a cognitive-behavioral therapy approach for painful diabetic peripheral neuropathy. AB - The purpose of the present pilot study was to assess the efficacy of cognitive behavioral therapy (CBT) for painful diabetic peripheral neuropathy. This was a randomized, treatment as usual (TAU), controlled, nonblinded intervention pilot study with a 4-month follow-up conducted in a VA medical center. It was hypothesized that participants who received CBT, as compared to those who received TAU, would report significant decreases on self-report measures of pain severity, interference, and depressive symptoms from pretreatment to 4-month follow-up. Participants meeting inclusion criteria were randomly assigned to 1 of the study conditions. Of the 20 eligible participants, 12 were randomized to CBT and 8 were randomized to TAU. Participants randomized to CBT showed significant decreases on measures of pain severity (B = -.54) and pain interference (B = .77) from pretreatment to 4-month follow-up. There were no significant changes in the TAU participants' scores on measures of pain severity (B = .00) or pain interference (B = -.09). Neither CBT nor TAU participants showed significant changes in their levels of depressive symptoms from pretreatment to 4-month follow-up. CBT may be an effective treatment approach for reducing pain severity and interference associated with painful diabetic peripheral neuropathy. PERSPECTIVE: The results of this study suggest that engaging patients in CBT for painful diabetic peripheral neuropathy may provide them the skills to become more active and experience less pain. PMID- 23452826 TI - Lack of correlation between opioid dose adjustment and pain score change in a group of chronic pain patients. AB - Despite the increasing use of opioid analgesics for chronic pain management, it is unclear whether opioid dose escalation leads to better pain relief during chronic opioid therapy. In this study, we retrospectively analyzed clinical data collected from the Massachusetts General Hospital Center for Pain Medicine over a 7-year period. We examined 1) the impact of opioid dose adjustment (increase or decrease) on clinical pain score; 2) gender and age differences in response to opioid therapy; and 3) the influence of clinical pain conditions on the opioid analgesic efficacy. A total of 109 subjects met the criteria for data collection. We found that neither opioid dose increase, nor decrease, correlated with point changes in clinical pain score in a subset of chronic pain patients over a prolonged course of opioid therapy (an average of 704 days). This lack of correlation was consistent regardless of the type of chronic pain including neuropathic, nociceptive, or mixed pain conditions. Neither gender nor age differences showed a significant influence on the clinical response to opioid therapy in these subjects. These results suggest that dose adjustment during opioid therapy may not necessarily alter long-term clinical pain score in a group of chronic pain patients and that individualized opioid therapy based on the clinical effectiveness should be considered to optimize the treatment outcome. PERSPECTIVE: The study reports a relationship, or lack thereof, between opioid dose change and clinical pain score in a group of chronic pain patients. The study also calls for further investigation into the effectiveness of opioid therapy in the management of chronic nonmalignant pain conditions. PMID- 23452828 TI - [Hashimoto's encephalopathy: a rare cause of status epilepticus]. AB - Hashimoto's Encephalopathy (HE) is a rare condition defined by the association of encephalopathy and autoimmune thyroiditis with increased levels of antithyroid antibodies. Presenting symptoms of HE may be quite variable. Although seizures are rather frequent, status epilepticus seems very rare (10 reported cases to date) and exceptionally revealing. We report the case of a 48-year-old female, who presented with a series of status epilepticus. The only positive result of the initial exploration was an increased level of antithyroid antibodies. The patient's condition improved only after initiation of corticosteroid treatment, which provided a stable remission. HE pathophysiology still remains poorly understood and controversial. Pathological data are sparse and provide variable pictures. Although an autoimmune mechanism looks very likely, the precise role of antithyroid antibodies is still discussed. A direct toxicity has not been demonstrated and antibodies could simply be a marker of impaired immunity. Occurrence of status epilepticus in HE could be related to the presence of active inflammation of cortical or para-cortical tissue, although such a hypothesis remains to be demonstrated. The diagnosis of HE should be systematically considered in patients with unexplained episodes of status epilepticus. Search for abnormal thyroid function and increased levels of antithyroid antibodies allow both early diagnosis and treatment, with a clear benefit for the patients. PMID- 23452827 TI - BioTile, a Perl based tool for the identification of differentially enriched regions in tiling microarray data. AB - BACKGROUND: Genome-wide tiling array experiments are increasingly used for the analysis of DNA methylation. Because DNA methylation patterns are tissue and cell type specific, the detection of differentially methylated regions (DMRs) with small effect size is a necessary feature of tiling microarray 'peak' finding algorithms, as cellular heterogeneity within a studied tissue may lead to a dilution of the phenotypically relevant effects. Additionally, the ability to detect short length DMRs is necessary as biologically relevant signal may occur in focused regions throughout the genome. RESULTS: We present a free open-source Perl application, Binding Intensity Only Tile array analysis or "BioTile", for the identification of differentially enriched regions (DERs) in tiling array data. The application of BioTile to non-smoothed data allows for the identification of shorter length and smaller effect-size DERs, while correcting for probe specific variation by inversely weighting on probe variance through a permutation corrected meta-analysis procedure employed at identified regions. BioTile exhibits higher power to identify significant DERs of low effect size and across shorter genomic stretches as compared to other peak finding algorithms, while not sacrificing power to detect longer DERs. CONCLUSION: BioTile represents an easy to use analysis option applicable to multiple microarray platforms, allowing for its integration into the analysis workflow of array data analysis. PMID- 23452829 TI - [Intramedullary cavernoma revealed by Arnold's neuralgia]. PMID- 23452830 TI - Prevalence and socioeconomic correlates of chronic morbidity among elderly people in Kosovo: a population-based survey. AB - BACKGROUND: Our aim was to assess the prevalence and demographic and socioeconomic correlates of chronic morbidity in the elderly population of transitional Kosovo. METHODS: A cross-sectional study was conducted in Kosovo in 2011 including a representative sample of 1890 individuals aged >= 65 years (949 men, mean age 73 +/- 6 years; 941 women, mean age 74 +/- 7 years; response rate: 83%). A structured questionnaire inquired about the presence and the number of self-reported chronic diseases among elderly people, and their access to medical care. Demographic and socioeconomic data were also collected. Binary logistic regression was used to assess the association of demographic and socioeconomic characteristics with chronic conditions. RESULTS: In this nationwide population based sample in Kosovo, 42% of elderly people were unable to access medical care, of whom 88% due to unaffordable costs. About 83% of the elderly people reported at least one chronic condition (63% cardiovascular diseases), and 45% had at least two chronic diseases. In multivariable-adjusted models, factors associated with the presence of chronic conditions and/or multimorbidity were female sex, older age, self-perceived poverty and the inability to access medical care. CONCLUSION: This study provides important evidence on the magnitude and distribution of chronic conditions among the elderly population of Kosovo. Our findings suggest that, in this sample of elderly people from Kosovo, the oldest old (especially women) and the poor endure the vast majority of chronic conditions. These findings point to the urgent need to establish a social health insurance scheme including the marginalized segments of elderly people in this transitional country. PMID- 23452831 TI - Association of menstrual phase with smoking behavior, mood and menstrual phase associated symptoms among young Japanese women smokers. AB - BACKGROUND: Previous studies of the relationship between the menstrual phases and smoking behavior have been problematic, so the association of menstrual phases with smoking behavior and correlations among smoking, psychological and physical conditions in each phase of the menstrual cycle are unclear. METHODS: To accurately examine the association between menstrual phases and the amount of smoking (number of cigarettes smoked and breath CO concentration), craving of smoking on visual analogue scale (VAS), depression in the Center for Epidemiologic Studies Depression (CES-D) Scale, and menstrual phase-associated symptoms in the Menstrual Distress Questionnaire (MDQ), we improved various methodological issues, specifically, 1) Ovulation was confirmed by measuring the basal body temperature and identifying a urinary luteinizing hormone (LH) surge in two cycles; 2) The menstrual, follicular, and luteal phases were clearly defined for subjects with different menstrual cycles; 3) The breath CO concentration was measured every day. A notice was posted on public bulletin boards to recruit research subjects and twenty-nine young Japanese women smokers aged 19 to 25 years old were analyzed. RESULTS: The number of cigarettes smoked was greater and the CO concentration was higher in the luteal phase than in the follicular phase. The levels of craving for smoking (VAS), depressiveness (CES D), and menstrual phase-associated symptoms (MDQ) in the menstrual and luteal phases were higher than those in the follicular phase. The mean score for CES-D was 16 points (the cut-off value in screening for depression) or higher in the menstrual (16.9 +/- 8.2) and luteal phases (17.2 +/- 8.4).The number of cigarettes smoked and CO concentration were significantly correlated with the levels of craving for smoking, depressiveness, and menstrual phase-associated symptoms in all phases except for MDQ scores in follicular phase. The amount of smoking in the luteal phase was most strongly correlated with these symptoms. CONCLUSIONS: In the menstrual and luteal phases, young Japanese women smokers increased their amount of smoking and suffered from greater craving for smoking, depressiveness and menstrual phase-associated symptoms. The amount of smoking was correlated with these symptoms, but their cause-effect relationship has not been determined yet. PMID- 23452832 TI - Evaluation of reference genes for reverse transcription quantitative PCR analyses of fish-pathogenic Francisella strains exposed to different growth conditions. AB - BACKGROUND: Reverse transcription quantitative PCR has become a powerful technique to monitor mRNA transcription in response to different environmental conditions in many bacterial species. However, correct evaluation of data requires accurate and reliable use of reference genes whose transcription does not change during the course of the experiment. In the present study exposure to different growth conditions was used to validate the transcription stability of eight reference gene candidates in three strains from two subspecies of Francisella noatunensis, a pathogen causing disease in both warm and cold water fish species. RESULTS: Relative transcription levels for genes encoding DNA gyrase (gyrA), RNA polymerase beta subunit (rpoB), DNA polymerase I (polA), cell division protein (ftsZ), outer membrane protein (fopA), riboflavin biosynthesis protein (ribC), 16S ribosomal RNA (16S rRNA) and DNA helicases (uvrD) were quantified under exponential, stationary and iron-restricted growth conditions. The suitability of selected reference genes for reliable interpretation of gene expression data was tested using the virulence-associated intracellular growth locus subunit C (iglC) gene. CONCLUSION: Although the transcription stability of the reference genes was slightly different in the three strains studied, fopA, ftsZ and polA proved to be the most stable and suitable for normalization of gene transcription in Francisella noatunensis ssp. PMID- 23452833 TI - The effect of exogenous follicle stimulating hormone (FSH) and endogenous plasma leptin concentrations on the pregnancy rate of beef heifers subjected to fixed timed artificial insemination (FTAI). AB - In this study, 53 crossbred beef heifers were used to test the hypotheses that administration of exogenous FSH 2 days following CIDR insertion and administration of estradiol would increase the pregnancy rate in heifers synchronized for FTAI and that plasma leptin concentrations in beef heifers would be higher for heifers that became pregnant to FTAI. The heifers used in this study had a median age of 440 days, an average weight of 324 kg, an average body condition score of 5.1 and a mean reproductive tract score of 3.1. Heifers were stratified by weight and BCS into two groups and then treatments were randomly allotted to each group: (1) control (n=28) or (2) FSH (n=27). Both groups were administered 200mg estradiol benzoate (EB) and received an intravaginal controlled internal drug-releasing device (CIDR) on day 0. On day 2, females in the FSH treatment group were administered 20 mg of FSH, while the control group received 1 ml of saline. On day 7 all females were administered 25 MUg PGF2alpha and the CIDR was removed. Then 24h following CIDR removal all females were administered 1mg EB and 24h later were subjected to FTAI. Pregnancy diagnosis was performed via transrectal ultrasonography 43 days following insemination. Blood samples were collected via jugular venipuncture on days 2, 6-10, 13 and 52 and plasma leptin concentrations were determined by radioimmunoassay. Pregnancy rates were higher (P=0.01) for FSH-treated females (60%) compared with females not receiving FSH (25%). Circulating plasma leptin concentrations were higher (P=0.0051) for pregnant females compared with females that did not become pregnant following FTAI during the experiment. Mean plasma leptin concentration was also higher (P=0.04) from day 2 to day 9 during the synchronization protocol in heifers that became pregnant compared with heifers that did not become pregnant from FTAI. There was no difference (P=0.38) in reproductive tract scores for heifers that became pregnant compared with heifers that did not become pregnant from FTAI. Circulating leptin concentrations were not different (P=0.11) for females receiving FSH compared with females in the non FSH-treated group. Circulating leptin concentrations were affected by sampling day (P<0.0001). However, there was no interaction between sampling day and pregnancy status (P=0.80), treatment and pregnancy status (P=0.14) or treatment and sampling day (P=0.12). These results indicate that the administration of FSH on day 2 of the synchronization protocol may increase pregnancy rates in beef heifers and that increased circulating concentrations of plasma leptin during the synchronization protocol may be indicative of subsequent pregnancy outcome. PMID- 23452834 TI - Effects of genistein on oestrogen and progesterone receptor, proliferative marker Ki-67 and carbonic anhydrase localisation in the uterus and cervix of gilts after insemination. AB - Soya products are routinely fed to domestic animals as an important source of protein. The aim of this work was to study how the phytooestrogen genistein, supplemented at a feed relevant level, affects the morphology and distribution of reproductive hormone receptors, proliferative activities and carbonic anhydrase (CA) in the uterus and cervix of gilts. Eleven gilts were fed a soya-free diet. Six were given genistein (1 mg/kg bw) twice daily for eight days starting three days before expected oestrus. Five gilts were used as controls. All gilts were inseminated (AI) one day after signs of standing oestrus and euthanized three days after AI. Samples from the uterus and cervix were processed for morphometric evaluation, immunohistochemical localisation of oestrogen receptors alpha and beta (ERalpha and ERbeta), progesterone receptor (PR), proliferative marker Ki-67 and histochemical localisation of CA. Nuclear staining for ERbeta was detected in surface epithelial, glandular and some stromal cells in the uterus and in the cervix surface epithelial cells. ERalpha and PR were observed in surface epithelium, subepithelial stromal cells and smooth muscle cells of uterus and cervix, and glandular cells of the uterus. Ki-67 positive cells were recorded in uterine and cervical surface epithelium and subepithelial stromal layer. CA was mainly confined to glandular cells of the uterus. Immunohistochemical results were evaluated using semi-quantitative image analysis. Statistic comparison between groups revealed no differences. However, intra-treatment evaluation and correlations indicate that the supplementation of genistein modulates the expression pattern of all receptors and Ki-67, which may induce cellular activities in both the uterus and cervix of early pregnant gilts. PMID- 23452836 TI - Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. AB - Spinal cord injuries (SCI) cause sensory loss and motor paralysis. They are normally treated with physical therapy, but most patients fail to recover due to limited neural regeneration. Here we describe a strategy in which treatment with autologous adherent bone marrow cells is combined with physical therapy to improve motor and sensory functions in early stage chronic SCI patients. In a phase I/II controlled single-blind clinical trial (clinicaltrials.gov identifier: NCT00816803), 70 chronic cervical and thoracic SCI patients with injury durations of at least 12 months were treated with either intrathecal injection(s) of autologous adherent bone marrow cells combined with physical therapy or with physical therapy alone. Patients were evaluated with clinical and neurological examinations using the American Spinal Injury Association (ASIA) Impairment Scale (AIS), electrophysiological somatosensory-evoked potential, magnetic resonance imaging (MRI), and functional independence measurements. Chronic cervical and thoracic SCI patients (15 AIS A and 35 AIS B) treated with autologous adherent bone marrow cells combined with physical therapy showed functional improvements over patients in the control group (10 AIS A and 10 AIS B) treated with physical therapy alone, and there were no long-term cell therapy-related side effects. At 18 months posttreatment, 23 of the 50 cell therapy-treated cases (46%) showed sustained functional improvement. Compared to those patients with cervical injuries, a higher rate of functional improvement was achieved in thoracic SCI patients with shorter durations of injury and smaller cord lesions. Therefore, when combined with physical therapy, autologous adherent bone marrow cell therapy appears to be a safe and promising therapy for patients with chronic SCI of traumatic origin. Randomized controlled multicenter trials are warranted. PMID- 23452838 TI - SQUID-detected ultra-low field MRI. AB - MRI remains the premier method for non-invasive imaging of soft-tissue. Since the first demonstration of ULF MRI the trend has been towards ever higher magnetic fields. This is because the signal, and efficiency of Faraday detectors, increases with ever higher magnetic fields and corresponding Larmor frequencies. Nevertheless, there are many compelling reasons to continue to explore MRI at much weaker magnetic fields, the so-called ultra-low field or (ULF) regime. In the past decade many excellent proof-of-concept demonstrations of ULF MRI have been made. These include combined MRI and magnetoencephalography, imaging in the presence of metal, unique tissue contrast, and implementation in situations where a high magnetic field is simply impractical. These demonstrations have routinely used pulsed pre-polarization (at magnetic fields from ~10 to 100 mT) followed by read-out in a much weaker (1-100 MUT) magnetic fields using the ultra-sensitive Superconducting Quantum Interference Device (SQUID) sensor. Even with pre polarization and SQUID detection, ULF MRI suffers from many challenges associated with lower magnetization (i.e. signal) and inherently long acquisition times compared to conventional >1 T MRI. These are fundamental limitations imposed by the low measurement and gradient fields used. In this review article we discuss some of the techniques, potential applications, and inherent challenges of ULF MRI. PMID- 23452837 TI - Molecular basis for prey relocation in viperid snakes. AB - BACKGROUND: Vertebrate predators use a broad arsenal of behaviors and weaponry for overcoming fractious and potentially dangerous prey. A unique array of predatory strategies occur among snakes, ranging from mechanical modes of constriction and jaw-holding in non-venomous snakes, to a chemical means, venom, for quickly dispatching prey. However, even among venomous snakes, different prey handling strategies are utilized, varying from the strike-and-hold behaviors exhibited by highly toxic elapid snakes to the rapid strike-and-release envenomation seen in viperid snakes. For vipers, this mode of envenomation represents a minimal risk predatory strategy by permitting little contact with or retaliation from prey, but it adds the additional task of relocating envenomated prey which has wandered from the attack site. This task is further confounded by trails of other unstruck conspecific or heterospecific prey. Despite decades of behavioral study, researchers still do not know the molecular mechanism which allows for prey relocation. RESULTS: During behavioral discrimination trials (vomeronasal responsiveness) to euthanized mice injected with size-fractionated venom, Crotalus atrox responded significantly to only one protein peak. Assays for enzymes common in rattlesnake venoms, such as exonuclease, L-amino acid oxidase, metalloproteinase, thrombin-like and kallikrein-like serine proteases and phospholipase A(2), showed that vomeronasal responsiveness was not dependent on enzymatic activity. Using mass spectrometry and N-terminal sequencing, we identified the proteins responsible for envenomated prey discrimination as the non-enzymatic disintegrins crotatroxin 1 and 2. Our results demonstrate a novel and critical biological role for venom disintegrins far beyond their well established role in disruption of cell-cell and cell-extracellular matrix interactions. CONCLUSIONS: These findings reveal the evolutionary significance of free disintegrins in venoms as the molecular mechanism in vipers allowing for effective relocation of envenomated prey. The presence of free disintegrins in turn has led to evolution of a major behavioral adaptation (strike-and-release), characteristic of only rattlesnakes and other vipers, which exploits and refines the efficiency of a pre-existing chemical means of predation and a highly sensitive olfaction system. This system of a predator chemically tagging prey represents a novel trend in the coevolution of predator-prey relationships. PMID- 23452839 TI - Innate immunity. PMID- 23452840 TI - ERAP1 and ankylosing spondylitis. AB - The strong genetic association of ERAP1 (endoplasmic reticulum aminopeptidase 1) with ankylosing spondylitis (AS), which is restricted to HLA-B27 positive cases, has profound pathogenetic implications. ERAP1 is involved in trimming peptides to optimal length for binding to HLA class 1 molecules, thereby not only affecting the stability and processing of HLA-B27 but also influencing the peptide repertoire presented to the immune system. This could have secondary effects on specific adaptive or autoimmune responses in AS. However, it appears increasingly likely that the pathogenic effect of ERAP1 may be mediated through effects on innate immunity, such as altering the interaction between HLA-B27 and immune receptors such as the killer immunoglobulin-like receptors (KIR) found on a range of innate immune cells or via the endoplasmic reticulum unfolded protein response. ERAP1 variants associated with reduced endopeptidase activity appear to be protective against AS, raising the possibility that ERAP1 inhibition could represent a future treatment strategy. PMID- 23452842 TI - Immunoproteasomes are important for proteostasis in immune responses. PMID- 23452843 TI - Quit stalling or you'll be silenced. AB - The use of small RNAs to program gene regulation and genome defense necessitates ever-changing choices about the sequences used for small-RNA biogenesis. Dumesic et al. now reveal stalled spliceosomes as a trigger for small-RNA biogenesis in the pathogenic fungus Cryptococcus neoformans. PMID- 23452844 TI - By hook or by crook: multifaceted DNA-binding properties of MeCP2. AB - Two new studies reveal novel DNA-binding properties of MeCP2, mutations of which cause Rett syndrome. Baker et al. report critical roles for the AT-hook domain of MeCP2 in chromatin organization and clinical features of Rett syndrome. Mellen et al. find the methyl-CpG-binding domain of MeCP2 interacts with hydroxymethyl-CpG. PMID- 23452845 TI - Evolution of cell division: from shear mechanics to complex molecular machineries. AB - Cell division depends on sophisticated molecular machinery. However, wall-less forms of bacteria use a much simpler mechanism that mimics spontaneous division of synthetic lipid vesicles. Mercier et al. (2013) show that this "mechanical" division can be activated by increased lipid synthesis. Conceivably, the first cells divided via this route. PMID- 23452846 TI - Encoding and decoding cellular information through signaling dynamics. AB - A growing number of studies are revealing that cells can send and receive information by controlling the temporal behavior (dynamics) of their signaling molecules. In this Review, we discuss what is known about the dynamics of various signaling networks and their role in controlling cellular responses. We identify general principles that are emerging in the field, focusing specifically on how the identity and quantity of a stimulus is encoded in temporal patterns, how signaling dynamics influence cellular outcomes, and how specific dynamical patterns are both shaped and interpreted by the structure of molecular networks. We conclude by discussing potential functional roles for transmitting cellular information through the dynamics of signaling molecules and possible applications for the treatment of disease. PMID- 23452847 TI - A role for the nucleoporin Nup170p in chromatin structure and gene silencing. AB - Embedded in the nuclear envelope, nuclear pore complexes (NPCs) not only regulate nuclear transport but also interface with transcriptionally active euchromatin, largely silenced heterochromatin, as well as the boundaries between these regions. It is unclear what functional role NPCs play in establishing or maintaining these distinct chromatin domains. We report that the yeast NPC protein Nup170p interacts with regions of the genome that contain ribosomal protein and subtelomeric genes, where it functions in nucleosome positioning and as a repressor of transcription. We show that the role of Nup170p in subtelomeric gene silencing is linked to its association with the RSC chromatin-remodeling complex and the silencing factor Sir4p, and that the binding of Nup170p and Sir4p to subtelomeric chromatin is cooperative and necessary for the association of telomeres with the nuclear envelope. Our results establish the NPC as an active participant in silencing and the formation of peripheral heterochromatin. PMID- 23452849 TI - Excess membrane synthesis drives a primitive mode of cell proliferation. AB - The peptidoglycan cell wall is a hallmark of the bacterial subkingdom. Surprisingly, many modern bacteria retain the ability to switch into a wall-free state called the L-form. L-form proliferation is remarkable in being independent of the normally essential FtsZ-based division machinery and in occurring by membrane blebbing and tubulation. We show that mutations leading to excess membrane synthesis are sufficient to drive L-form division in Bacillus subtilis. Artificially increasing the cell surface area to volume ratio in wild-type protoplasts generates similar shape changes and cell division. Our findings show that simple biophysical processes could have supported efficient cell proliferation during the evolution of early cells and provide an extant biological model for studying this problem. PMID- 23452848 TI - An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. AB - Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2's key functions is to alter chromatin structure. PMID- 23452850 TI - Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate. AB - Metazoan evolution involves increasing protein domain complexity, but how this relates to control of biological decisions remains uncertain. The Ras guanine nucleotide exchange factor (RasGEF) Sos1 and its adaptor Grb2 are multidomain proteins that couple fibroblast growth factor (FGF) signaling to activation of the Ras-Erk pathway during mammalian development and drive embryonic stem cells toward the primitive endoderm (PrE) lineage. We show that the ability of Sos1/Grb2 to appropriately regulate pluripotency and differentiation factors and to initiate PrE development requires collective binding of multiple Sos1/Grb2 domains to their protein and phospholipid ligands. This provides a cooperative system that only allows lineage commitment when all ligand-binding domains are occupied. Furthermore, our results indicate that the interaction domains of Sos1 and Grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. This optimized system ensures that PrE lineage commitment occurs in a timely and selective manner during embryogenesis. PMID- 23452851 TI - H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. AB - Histone modifications regulate chromatin-dependent processes, yet the mechanisms by which they contribute to specific outcomes remain unclear. H3K4me3 is a prominent histone mark that is associated with active genes and promotes transcription through interactions with effector proteins that include initiation factor TFIID. We demonstrate that H3K4me3-TAF3 interactions direct global TFIID recruitment to active genes, some of which are p53 targets. Further analyses show that (1) H3K4me3 enhances p53-dependent transcription by stimulating preinitiation complex (PIC) formation; (2) H3K4me3, through TAF3 interactions, can act either independently or cooperatively with the TATA box to direct PIC formation and transcription; and (3) H3K4me3-TAF3/TFIID interactions regulate gene-selective functions of p53 in response to genotoxic stress. Our findings indicate a mechanism by which H3K4me3 directs PIC assembly for the rapid induction of specific p53 target genes. PMID- 23452852 TI - Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. AB - Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here, we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, whereas ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase dependent and -independent pathways. The latter pathway involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a, or p21, indicating that PHF20 is required for reprogramming. Our findings demonstrate, to the best of our knowledge, a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process. PMID- 23452853 TI - Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. AB - Endosomal protein trafficking is an essential cellular process that is deregulated in several diseases and targeted by pathogens. Here, we describe a role for ubiquitination in this process. We find that the E3 RING ubiquitin ligase, MAGE-L2-TRIM27, localizes to endosomes through interactions with the retromer complex. Knockdown of MAGE-L2-TRIM27 or the Ube2O E2 ubiquitin conjugating enzyme significantly impaired retromer-mediated transport. We further demonstrate that MAGE-L2-TRIM27 ubiquitin ligase activity is required for nucleation of endosomal F-actin by the WASH regulatory complex, a known regulator of retromer-mediated transport. Mechanistic studies showed that MAGE-L2-TRIM27 facilitates K63-linked ubiquitination of WASH K220. Significantly, disruption of WASH ubiquitination impaired endosomal F-actin nucleation and retromer-dependent transport. These findings provide a cellular and molecular function for MAGE-L2 TRIM27 in retrograde transport, including an unappreciated role of K63-linked ubiquitination and identification of an activating signal of the WASH regulatory complex. PMID- 23452855 TI - Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. AB - Period determination in the mammalian circadian clock involves the turnover rate of the repressors CRY and PER. We show that CRY ubiquitination engages two competing E3 ligase complexes that either lengthen or shorten circadian period in mice. Cloning of a short-period circadian mutant, Past-time, revealed a glycine to glutamate missense mutation in Fbxl21, an F-box protein gene that is a paralog of Fbxl3 that targets the CRY proteins for degradation. While loss of function of FBXL3 leads to period lengthening, mutation of Fbxl21 causes period shortening. FBXL21 forms an SCF E3 ligase complex that slowly degrades CRY in the cytoplasm but antagonizes the stronger E3 ligase activity of FBXL3 in the nucleus. FBXL21 plays a dual role: protecting CRY from FBXL3 degradation in the nucleus and promoting CRY degradation within the cytoplasm. Thus, the balance and cellular compartmentalization of competing E3 ligases for CRY determine circadian period of the clock in mammals. PMID- 23452854 TI - Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. AB - Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor stroma interaction-mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway. PMID- 23452856 TI - FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. AB - In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21(-/-) mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3(-/-) mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock. PMID- 23452857 TI - Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. AB - The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament alpha-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity. PMID- 23452858 TI - A network of cytosolic factors targets SRP-independent proteins to the endoplasmic reticulum. AB - Translocation into the endoplasmic reticulum (ER) is an initial and crucial biogenesis step for all secreted and endomembrane proteins in eukaryotes. ER insertion can take place through the well-characterized signal recognition particle (SRP)-dependent pathway or the less-studied route of SRP-independent translocation. To better understand the prevalence of the SRP-independent pathway, we systematically defined the translocational dependence of the yeast secretome. By combining hydropathy-based analysis and microscopy, we uncovered that a previously unappreciated fraction of the yeast secretome translocates without the aid of the SRP. Furthermore, we validated a family of SRP-independent substrates-the glycosylphosphatidylinositol (GPI)-anchored proteins. Studying this family, we identified a determinant for ER targeting and uncovered a network of cytosolic proteins that facilitate SRP-independent targeting and translocation. These findings highlight the underappreciated complexity of SRP independent translocation, which enables this pathway to efficiently cope with its extensive substrate flux. PMID- 23452859 TI - Profiling of ubiquitin-like modifications reveals features of mitotic control. AB - Ubiquitin and ubiquitin-like (Ubl) protein modifications affect protein stability, activity, and localization, but we still lack broad understanding of the functions of Ubl modifications. We have profiled the protein targets of ubiquitin and six additional Ubls in mitosis using a functional assay that utilizes active mammalian cell extracts and protein microarrays and identified 1,500 potential substrates; 80-200 protein targets were exclusive to each Ubl. The network structure is nonrandom, with most targets mapping to a single Ubl. There are distinct molecular functions for each Ubl, suggesting divergent biological roles. Analysis of differential profiles between mitosis and G1 highlighted a previously underappreciated role for the Ubl, FAT10, in mitotic regulation. In addition to its role as a resource for Ubl modifications, our study provides a systematic approach to analyze changes in posttranslational modifications at various cellular states. PMID- 23452860 TI - Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. AB - Targeted gene regulation on a genome-wide scale is a powerful strategy for interrogating, perturbing, and engineering cellular systems. Here, we develop a method for controlling gene expression based on Cas9, an RNA-guided DNA endonuclease from a type II CRISPR system. We show that a catalytically dead Cas9 lacking endonuclease activity, when coexpressed with a guide RNA, generates a DNA recognition complex that can specifically interfere with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This system, which we call CRISPR interference (CRISPRi), can efficiently repress expression of targeted genes in Escherichia coli, with no detectable off-target effects. CRISPRi can be used to repress multiple target genes simultaneously, and its effects are reversible. We also show evidence that the system can be adapted for gene repression in mammalian cells. This RNA-guided DNA recognition platform provides a simple approach for selectively perturbing gene expression on a genome wide scale. PMID- 23452862 TI - SnapShot: the intestinal crypt. PMID- 23452861 TI - Immuno- and constitutive proteasomes do not differ in their abilities to degrade ubiquitinated proteins. AB - Immunoproteasomes are alternative forms of proteasomes that have an enhanced ability to generate antigenic peptides. Recently, Seifert and colleagues reported surprising observations concerning the functions of immunoproteasomes and cellular responses to interferon-gamma: (1) that immunoproteasomes degrade ubiquitinated proteins faster than the constitutive proteasomes, (2) that polyubiquitin conjugates accumulate after interferon-gamma treatment but then are preferentially degraded by immunoproteasomes, and (3) that immunoproteasome deficiency causes the formation of inclusions and more severe experimental autoimmune encephalomyelitis (EAE). In contrast, we find that polyubiquitin conjugates do not transiently accumulate following IFNgamma-treatment and that immunoproteasomes do not prevent the formation of intracellular inclusions or protect against EAE. Furthermore, purified 26S constitutive and immunoproteasomes bind ubiquitin conjugates similarly and degrade them at similar rates. We conclude that, although immunoproteasomes can increase the generation of peptides appropriate for MHC class I presentation, they do not degrade ubiquitinated proteins more efficiently than constitutive particles. PMID- 23452863 TI - Promising insights into the health related quality of life for children with severe obesity. AB - BACKGROUND: Childhood obesity is a growing health concern known to adversely affect quality of life in children and adolescents. The Patient Reported Outcomes Measurement Information System (PROMIS) pediatric measures were developed to capture child self-reports across a variety of health conditions experienced by children and adolescents. The purpose of this study is to begin the process of validation of the PROMIS pediatric measures in children and adolescents affected by obesity. METHODS: The pediatric PROMIS instruments were administered to 138 children and adolescents in a cross-sectional study of patient reported outcomes in children aged 8-17 years with age-adjusted body mass index (BMI) greater than the 85th percentile in a design to establish known-group validity. The children completed the depressive symptoms, anxiety, anger, peer relationships, pain interference, fatigue, upper extremity, and mobility PROMIS domains utilizing a computer interface. PROMIS domains and individual items were administered in random order and included a total of 95 items. Patient responses were compared between patients with BMI 85 to<99th percentile versus >=99th percentile. RESULTS: 136 participants were recruited and had all necessary clinical data for analysis. Of the 136 participants, 5% ended the survey early resulting in missing domain scores at the end of survey administration. In multivariate analysis, patients with BMI >= 99th percentile had worse scores for depressive symptoms, anger, fatigue, and mobility (p<0.05). Parent-reported exercise was associated with better scores for depressive symptoms, anxiety, and fatigue (p<0.05). CONCLUSIONS: Children and adolescents ranging from overweight to severely obese can complete multiple PROMIS pediatric measures using a computer interface in the outpatient setting. In the 5% with missing domain scores, the missing scores were consistently found in the domains administered last, suggesting the length of the assessment is important. The differences in domain scores found in this study are consistent with previous reports investigating the quality of life in children and adolescents with obesity. We show that the PROMIS instrument represents a feasible and potentially valuable instrument for the future study of the effect of pediatric obesity on quality of life. PMID- 23452864 TI - A health equity critique of social marketing: where interventions have impact but insufficient reach. AB - Health interventions increasingly rely on formative qualitative research and social marketing techniques to effect behavioural change. Few studies, however, incorporate qualitative research into the process of program evaluation to understand both impact and reach: namely, to what extent behaviour change interventions work, for whom, in what contexts, and why. We reflect on the success of a community-based hygiene intervention conducted in the slums of Kathmandu, Nepal, evaluating both maternal behaviour and infant health. We recruited all available mother-infant pairs (n = 88), and allocated them to control and intervention groups. Formative qualitative research on hand-washing practices included structured observations of 75 mothers, 3 focus groups, and 26 in-depth interviews. Our intervention was led by Community Motivators, intensively promoting hand-washing-with-soap at key junctures of food and faeces contamination. The 6-month evaluation period included hand-washing and morbidity rates, participant observation, systematic records of fortnightly community meetings, and follow-up interviews with 12 mothers. While quantitative measures demonstrated improvement in hand-washing rates and a 40% reduction in child diarrhoea, the qualitative data highlighted important equity issues in reaching the ultra-poor. We argue that a social marketing approach is inherently limited: focussing on individual agency, rather than structural conditions constraining behaviour, can unwittingly exacerbate health inequity. This contributes to a prevention paradox whereby those with the greatest need of a health intervention are least likely to benefit, finding hand-washing in the slums to be irrelevant or futile. Thus social marketing is best deployed within a range of interventions that address the structural as well as the behavioural and cognitive drivers of behaviour change. We conclude that critiques of social marketing have not paid sufficient attention to issues of health equity, and demonstrate how this can be addressed with qualitative data, embedded in both the formative and evaluative phases of a health intervention. PMID- 23452865 TI - Abstracts of the 16th Annual SCMR (Society for Cardiovascular Magnetic Resonance) Scientific Sessions. San Francisco, California, USA. January 31-February 3, 2013. PMID- 23452867 TI - The OxyContin crisis: problematisation and responsibilisation strategies in addiction, pain, and general medicine journals. AB - BACKGROUND: OxyContin((r)) (Purdue Pharma, L.P., Stamford, CT) is now widely regarded as a drug of abuse fueling a larger opioid health crisis. While coverage in the North American press about OxyContin overwhelmingly focused upon the problems of related crime and addiction/misuse and the perspectives of law enforcement officials and police, coverage in those fields of medicine most intimately concerned with OxyContin-pain medicine and addiction medicine-was more nuanced. METHODS: In this article, we draw upon the constructivist social problems tradition and Hunt's theory of moral regulation in a qualitative analysis of 24 medical journal articles. We compare and contrast pain medicine and addiction medicine representations of the OxyContin problem, the agents responsible for it, and proposed solutions. RESULTS: While there are some significant differences, particularly concerning the nature of the problem and the agents responsible for it, both pain medicine and addiction medicine authors 'take responsibility' in ways that attempt to mitigate the potential appropriation of the issue by law enforcement and regulatory agencies. CONCLUSIONS: The responses of pain medicine and addiction medicine journal articles represent strategic moves to recapture lost credibility, to retain client populations and tools necessary to their jobs, and to claim a seat at the table in responding to the OxyContin crisis. PMID- 23452866 TI - Application of peripheral-blood-derived endothelial progenitor cell for treating ischemia-reperfusion injury and infarction: a preclinical study in rat models. AB - BACKGROUND: Our aim was to explore the therapeutic effects of peripheral blood derived endothelial progenitor cells (PB-EPC) in cardiac ischemia-reperfusion infarction models in rats and in in vitro culture systems. METHODS: Rat models of ischemia reperfusion and myocardial infarction were developed using male, Sprague Dawley rats. Cardiomyocyte and endothelial cell cultures were also established. Therapeutic effects of PB-EPCs were examined in vivo and in vitro in both models. Rats underwent either cardiac ischemia-reperfusion (n = 40) or infarction (n = 56) surgeries and were transplanted with genetically modified EPCs. Treatment efficacy in the ischemia-reperfusion group was measured by infarct size, myocardial contraction velocity, and myeloperoxidase activity after transplantation. Cardiomyocyte survival and endothelial cell apoptosis were investigated in vitro. Vascular growth-associated protein expression and cardiac function were evaluated in the myocardial infarction group by western blot and echocardiography, respectively. RESULTS: Infarct size and myeloperoxidase activity were significantly decreased in the ischemia-reperfusion group, whereas myocardial contractility was significantly increased in the EPC and Tbeta4 groups compared with that in the control group. In contrast, no differences were found between EPC + shRNA Tbeta4 and control groups. Rates of cardiomyocyte survival and endothelial cell apoptosis were significantly higher and lower, respectively, in the EPC and Tbeta4 groups than in the control group, whereas no differences were found between the EPC + shRNA Tbeta4 and control group. Four weeks after myocardial infarction, cardiac function was significantly better in the EPC group than in the control group. Expressions of PDGF, VEGF, and Flk-1 were significantly higher in EPC group than in control group. CONCLUSIONS: Study findings suggest that PB-EPCs are able to protect cardiomyocytes from ischemia reperfusion or infarction-induced damage via a Tbeta4-mediated mechanism. EPCs may also provide protection through increased expression of proteins involved in mediating vascular growth. Autologous peripheral-blood-derived EPCs are readily available for efficient therapeutic use without the concerns of graft rejection. PMID- 23452868 TI - Unlaid Xenopus eggs degrade by apoptosis in the genital tract. AB - BACKGROUND: In several species with external fertilization, including frogs, laid unfertilized eggs were found to die by apoptosis outside of the animal body. However, there is no apparent reason for the externally laid eggs to degrade by this process, considering that apoptosis developed as a mechanism to reduce the damaging effect of individual cell death to the whole organism. RESULTS: Here, we demonstrate that a number of eggs are retained in the genital tract of the African clawed frog Xenopus laevis after gonadotropin-induced ovulation. The majority of these eggs exit meiotic arrest within 24 hours of hormone administration. Subsequently, post-meiotic eggs die in the frog genital tract by a well-defined apoptotic process. The hallmarks of egg degradation include prominent morphological changes, cytochrome c release, caspase activation, increase in ADP/ATP ratio, progressive intracellular acidification, egg swelling and all-out proteolysis of egg proteins. The sustained presence of post-apoptotic eggs in the genital tract of ageing frogs evidenced age-associated worsening of apoptotic clearance. CONCLUSIONS: The direct observation of egg degradation in the Xenopus genital tract provides a clue to the physiological relevance of frog egg apoptosis. It works to eliminate the mature unlaid eggs retained in the animal body after ovulation. Our findings establish egg apoptosis as a major physiological process accompanying ovulation in frogs. PMID- 23452869 TI - Clinical factors associated with trabecular bone score. AB - Dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) is the reference standard for diagnosing osteoporosis but does not directly reflect deterioration in bone microarchitecture. The trabecular bone score (TBS), a novel grey-level texture measurement that can be extracted from DXA images, predicts osteoporotic fractures independent of BMD. Our aim was to identify clinical factors that are associated with baseline lumbar spine TBS. In total, 29,407 women >=50 yr at the time of baseline hip and spine DXA were identified from a database containing all clinical results for the Province of Manitoba, Canada. Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Multiple linear regression and logistic regression (lowest vs highest tertile) was used to define the sensitivity of TBS to other risk factors associated with osteoporosis. Only a small component of the TBS measurement (7-11%) could be explained from BMD measurements. In multiple linear regression and logistic regression models, reduced lumbar spine TBS was associated with recent glucocorticoid use, prior major fracture, rheumatoid arthritis, chronic obstructive pulmonary disease, high alcohol intake, and higher body mass index. In contrast, recent osteoporosis therapy was associated with a significantly lower likelihood for reduced TBS. Similar findings were seen after adjustment for lumbar spine or femoral neck BMD. In conclusion, lumbar spine TBS is strongly associated with many of the risk factors that are predictive of osteoporotic fractures. Further work is needed to determine whether lumbar spine TBS can replace some of the clinical risk factors currently used in fracture risk assessment. PMID- 23452870 TI - Selection of women aged 50-64 yr for bone density measurement. AB - The fracture risk assessment tool from the World Health Organization (FRAX((r))) estimates 10-yr major osteoporotic and hip fracture probabilities from multiple clinical risk factors and optionally femoral neck bone mineral density (BMD). FRAX without BMD has been proposed as a method to select postmenopausal women younger than 65yr for BMD measurement, but the efficiency of this strategy and its concordance with National Osteoporosis Foundation (NOF) treatment guidelines is unknown. The osteoporosis self-assessment test (OST) is another simple screening tool based on age and weight alone. A historical cohort of 18,315 women aged 50-64yr, drawn from the Manitoba Bone Density Program database, which contains clinical BMD results for the Province of Manitoba, Canada, was used to determine the performance of these screening tools in selecting postmenopausal women younger than 65yr for BMD testing. FRAX was closely aligned with indicators of high fracture risk (area under the receiver operating characteristic curve [AUROC]: 0.89), whereas OST was better for detecting women with osteoporotic BMD (AUROC: 0.72). The combination of major fracture probability 10% or higher from FRAX without BMD or OST less than 1 identified 42% of women for BMD testing, capturing 72% of women meeting any NOF treatment criteria (90% of women with NOF criteria for high risk from FRAX or prior fracture). The negative predictive value to exclude qualification for treatment under the NOF criteria was 90%. These data may help to inform an evidence-based approach for targeting BMD testing in postmenopausal women younger than 65yr under the NOF treatment guidelines. PMID- 23452871 TI - Precision errors, least significant change, and monitoring time interval in pediatric measurements of bone mineral density, body composition, and mechanostat parameters by GE lunar prodigy. AB - Dual-energy X-ray absorptiometry (DXA) method is widely used in pediatrics in the study of bone density and body composition. However, there is a limit to how precise DXA can estimate bone and body composition measures in children. The study was aimed to (1) evaluate precision errors for bone mineral density, bone mass and bone area, body composition, and mechanostat parameters, (2) assess the relationships between precision errors and anthropometric parameters, and (3) calculate a "least significant change" and "monitoring time interval" values for DXA measures in children of wide age range (5-18yr) using GE Lunar Prodigy densitometer. It is observed that absolute precision error values were different for thin and standard technical modes of DXA measures and depended on age, body weight, and height. In contrast, relative precision error values expressed in percentages were similar for thin and standard modes (except total body bone mineral density [TBBMD]) and were not related to anthropometric variables (except TBBMD). Concluding, due to stability of percentage coefficient of variation values in wide range of age, the use of precision error expressed in percentages, instead of absolute error, appeared as convenient in pediatric population. PMID- 23452872 TI - Body composition parameters in healthy Brazilian women differ from white, black, and Hispanic American women reference range. AB - Body composition (BC) seems to vary between populations, suggesting the need for regional reference data. The objective of this study was to determine BC in Brazilian women. Five hundred healthy non-black Brazilian women aged 20 yr or older were included. Women with fractures, chronic diseases, medications affecting bone and mineral metabolism, coronary heart disease, pregnancy, silicone prosthesis, and Asians or Indians were excluded. BC by dual-energy X-ray absorptiometry (DXA) included total lean mass, appendicular lean mass, skeletal muscle index, and total body fat (BF). Reference values were made for 10-yr age groups. Lean mass decreased with age reaching the lowest values in women aged 80 yr and older. BF showed a bimodal distribution: increased with age until 50-59 yr, with a slight subsequent decrease. BF in Brazilian women did not differ from American women, except in the age groups 75-79 and 80-84 yr, where BF was lower (p < 0.05). Fat mass index was consistently higher between African and Hispanic American women (p < 0.05). Lean mass was consistently lower in Brazilian women compared with Americans in almost all age and ethnic groups (p < 0.05). BC in Brazilian women differs from American reference data. Our findings support the notion that BC varies according to ethnicity. PMID- 23452873 TI - A socio-ecological perspective on behavioural interventions to influence food choice in schools: alternative, complementary or synergistic? AB - OBJECTIVE: An increasing focus on legislation, policy and guidance on the nutritional content of school food has in part been in response to the limited impact of more behavioural or educational approaches. However, there is a risk that a sole focus on policy-level action may lead to neglect of the important contribution that more behavioural approaches can make as components of effective, coordinated, multilevel action to improve the dietary intake of schoolchildren. The current paper aims to highlight the potential importance of viewing alternative approaches as complementary or synergistic, rather than competing. DESIGN: The socio-ecological and RE-AIM frameworks are used to provide a theoretical rationale and demonstrate the importance of explicitly identifying the interdependence of policies, interventions and contextual structures and processes. School food case study evidence is used to exemplify how understanding and exploiting these interdependencies can maximise impact on dietary outcomes. SETTING: Case studies of trials in schools in the UK (South West England and Wales) and Australia (Victoria). SUBJECTS: Schoolchildren. RESULTS: The case studies provide examples to support the hypothesis that the reach, effectiveness, adoption, implementation and maintenance of school food policies and interventions can be maximised by understanding and exploiting the interdependence between levels in the socio-ecological framework. CONCLUSIONS: Rather than being seen as competing alternatives, diverse approaches to improving the diets of schoolchildren should be considered in terms of their potential to be complementary and synergistic, acting at multiple levels to improve acceptability, fidelity, effectiveness and sustainability. PMID- 23452874 TI - Unusual suicide with a chainsaw. AB - A 39-year-old male, with a history of multiple suicidal attempts and psychiatric pathology, a professional lumberjack, was found dead at the meadow with his throat cut and a chainsaw beside him. Autopsy revealed that all physical injuries were confined to the head, neck and left shoulder. Two major (long and wide) wounds were found and documented on both sides of the neck and head. A wound on the posterior and right lateral side of his neck and head was noted. Medical examiner noted an irregular rupture on the posterior-right side of the atlanto occipital joint with impaired bone, but without any damage on the spinal cord. Another gaping cut was noted in the lower part on the left lateral side of his neck. Medical examiner noted that muscles of the left side of the neck, left common carotid artery, left internal jugular vein and left vagus nerve were completely cut off. The body of the C5 and C6 vertebra, with the spinal cord at that level, was completely cut. Also, there were multiple linear and striped parallel abrasions on the outer side of the left shoulder and one abrasion on the left lateral side of the neck. The conclusion of inquiries was "suicide by chainsaw". PMID- 23452875 TI - Inferior vena cava filters: what radiologists need to know. AB - Inferior vena cava (IVC) filters are a controversial mechanical adjunct in the prevention of pulmonary embolism, the most serious result of venous thromboembolism. Despite modern IVC filters being in clinical use for more than 45 years, there is still uncertainty amongst many radiologists about the indications for IVC filter placement and their removal, particularly the more recent prophylactic use in patients without confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). Recently published guidelines on filter use from the National Institute of Health and Clinical Excellence (NICE) and other professional bodies are discussed. The vast majority of IVC filters in the UK are inserted by interventional radiologists, so radiologists may be the first point of contact for information requested by other clinicians. The increasing use of filters means that radiologists will encounter filters increasingly often during abdominal cross-sectional imaging. Awareness of common filter-related complications, such as tilting, thrombosis, and caval perforation, is useful to reassure or alert other clinicians. The potential role of filters in upper extremity DVT and requirement for concomitant anticoagulation is discussed. PMID- 23452876 TI - Small solid renal masses: characterization by diffusion-weighted MRI at 3 T. AB - AIM: To describe the appearance of small solid renal lesions (<=3 cm) on diffusion-weighted magnetic resonance imaging (MRI) and to determine whether ADC measurements may help to differentiate benign from malignant small solid renal masses. METHODS AND MATERIALS: Thirty-five patients with 47 small renal masses (23 malignant, 24 benign) who underwent 3 T MRI of the kidney using diffusion weighted sequences (b values of 0 and 1000 s/mm(2)) were retrospectively evaluated. Qualitative and quantitative analysis of diffusion-weighted images was performed. RESULTS: Most lesions were hyperintense to kidney on high b-value diffusion-weighted images and hypointense on apparent diffusion coefficient (ADC) map. The mean ADC of the lesions was significantly lower than that of kidney (1.22 +/- 0.3 versus 1.85 +/- 0.12 mm(2)/s; p < 0.005). The mean ADC was significantly different between renal cell carcinomas (1.2 +/- 0.01 mm(2)/s), metastases (1.25 +/- 0.04 mm(2)/s), angiomyolipoma (1.07 +/- 0.3 mm(2)/s) and oncocytomas (1.56 +/- 0.08 mm(2)/s; p < 0.05). The mean ADC of clear cell renal cell carcinomas was significantly different from that of non-clear cell renal cell carcinomas (1.38 +/- 0.34 versus 0.83 +/- 0.34 mm(2)/s; p < 0.005). No significant difference was found between mean ADC of fat containing and minimal fat angiomyolipomas (1.06 +/- 0.48 versus 1.11 +/- 0.33 mm(2)/s). CONCLUSION: Small solid renal masses are hyperintense on high b value and have different ADC values. PMID- 23452878 TI - Jejunal diverticulosis as the obscure cause of acute abdominal pain. PMID- 23452879 TI - The impact of Rotavirus mass vaccination on hospitalization rates, nosocomial Rotavirus gastroenteritis and secondary blood stream infections. AB - BACKGROUND: The aim of the study was to evaluate the effects of universal mass vaccination (UMV) against rotavirus (RV) on the hospitalization rates, nosocomial RV infections and RV-gastroenteritis (GE)-associated secondary blood stream infections (BSI). METHODS: The retrospective evaluation (2002-2009) by chart analysis included all clinically diagnosed and microbiologically confirmed RV-GE cases in a large tertiary care hospital in Austria. The pre-vaccination period (2002-2005) was compared with the recommended and early funded (2006-2007) and the funded (2008-2009) vaccination periods. Primary outcomes were RV-GE associated hospitalizations, secondary outcomes nosocomial RV disease, secondary BSI and direct hospitalization costs for children and their accompanying persons. RESULTS: In 1,532 children with RV-GE, a significant reduction by 73.9% of hospitalized RV-GE cases per year could be observed between the pre-vaccination and the funded vaccination period, which was most pronounced in the age groups 0 11 months (by 87.8%), 6-10 years (by 84.2%) and 11-18 years (88.9%). In the funded vaccination period, a reduction by 71.9% of nosocomial RV-GE cases per year was found compared to the pre-vaccination period. Fatalities due to nosocomial RV-GE were only observed in the pre-vaccination period (3 cases). Direct costs of hospitalized, community-acquired RV-GE cases per year were reduced by 72.7% in the funded vaccination period. The reduction of direct costs for patients (by 86.9%) and accompanying persons (86.2%) was most pronounced in the age group 0-11 months. CONCLUSIONS: UMV may have contributed to the significant decrease of RV-GE-associated hospitalizations, to a reduction in nosocomial RV infections and RV-associated morbidity due to secondary BSI and reduced direct hospitalization costs. The reduction in nosocomial cases is an important aspect considering severe disease courses in hospitalized patients with co-morbidities and death due to nosocomial RV-GE. PMID- 23452880 TI - CCN2/CTGF attenuates myocardial hypertrophy and cardiac dysfunction upon chronic pressure-overload. AB - BACKGROUND: Myocardial CCN2/CTGF (connective tissue growth factor) is strongly induced in heart failure (HF) and acts as a cardioprotective factor in ischemia/reperfusion injury. However, its functional role in myocardial hypertrophy remains unresolved. METHODS AND RESULTS: Transgenic mice with cardiac restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate control (NLC) mice were subjected to chronic pressure-overload by abdominal aortic banding. After 4weeks of persistent pressure-overload, a time point at which compensatory hypertrophy of the left ventricle (LV) prevails, Tg-CTGF mice displayed diminished increase of LV mass compared with NLC. At study end-point after 12 weeks of sustained aortic constriction, the mice displayed LV dilatation and reduced cardiac function. Repeated transthoracic echocardiography during the 12 weeks of chronic pressure-overload, revealed attenuation of LV dilatation and virtually sustained systolic function in Tg-CTGF mice compared with NLC mice. Also, increase of LV mass was blunted in Tg-CTGF versus NLC mice at study end point. Consistently, increases of myocardial ANP, BNP and skeletal alpha-actin mRNA levels were blunted in Tg-CTGF mice subjected to chronic pressure-overload. Furthermore, cardiac myocytes from Tg-CTGF mice displayed increased phospho NFATc2 levels and attenuated hypertrophic response upon stimulation with alpha1 adrenoceptor agonist, indicating that CTGF attenuates hypertrophic signaling in cardiac myocytes. Increase of myocardial collagen contents in mice subjected to aortic banding was similar in Tg-CTGF and NLC mice, indicating that CTGF have minimal impact on myocardial collagen deposition. CONCLUSION: This study provides novel evidence that CTGF attenuates cardiac hypertrophy upon chronic pressure overload due to inhibition of signaling mechanisms that promote pathologic myocardial hypertrophy. PMID- 23452881 TI - Beware of putting too much trust in PubMed: a lesson from Hong-Lin Chen's article on adherence to CONSORT (2010) recommendations. PMID- 23452882 TI - Not just numbers, but years of science: putting the ACE inhibitor-ARB meta analyses into context. PMID- 23452883 TI - Conscious sedation and analgesia use in cardiac device implantation. PMID- 23452884 TI - Comparative cardiometabolic effects of fibrates and omega-3 fatty acids. AB - Even with the aggressive reduction of low-density lipoprotein cholesterol by statin therapy, a high residual risk of cardiovascular events remains substantially and attracts attention to the need for additional preventive therapies. Therefore, effective reductions of residual risk of cardiovascular disease have emerged as therapeutic targets. Fibrates and omega-3 fatty acids have been introduced to reduce triglycerides and to increase high-density lipoprotein cholesterol and have shown anti-atherosclerotic, vascular and metabolic effects. However, some effects are controversial and very recent randomized clinical trials report different results from the earlier ones. In this review, we address the vascular and metabolic effects and the results of recent clinical trials of fibrates and omega-3 fatty acids. We also compared their effects under modern guideline therapy regarding potential drugs to reduce a residual cardiometabolic risk of cardiovascular disease. PMID- 23452885 TI - Progressive left ventricular myocardial fat invasion in arrhythmogenic right ventricular cardiomyopathy. PMID- 23452886 TI - Left-atrial wall thickening may be an important-response in systemic hypertension as well as left-ventricular hypertrophy and more remarkable than left-ventricular diastolic dysfunction and left-atrial enlargement. PMID- 23452887 TI - C-reactive protein promotes vascular endothelial dysfunction partly via activating adipose tissue inflammation in hyperlipidemic rabbits. AB - BACKGROUND: Endothelial dysfunction is the basic and original sign of atherogenesis. Some evidences show that C-reactive protein (CRP) and perivascular adipose tissue (PVAT) play a pivotal role in atherosclerosis. However, the effects of CRP on atherosclerosis and the related mechanisms require elucidation. METHODS: The levels of basic total cholesterol, low-density lipoprotein cholesterol, triglyceride, CRP, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO) and endothelin-1 (ET-1) were respectively measured in rabbits, endothelium-dependent vasorelaxation function was also evaluated. Animals were randomly divided into two groups: PVAT(-) and PVAT(+) group (removing or keeping pericarotid adipose tissue (PCAT)). Both of the two groups were exposed to a high-fat diet for six-week, and then sustained CRP treatment was performed for a week, at this time point all the above parameters were remeasured. In addition, mRNA and protein expression of TNF-alpha, IL-6, and macrophage chemoattractant protein-1 (MCP-1) were respectively evaluated by Polymerase Chain Reaction and immunoblotting in PCAT and cultured adipocytes treated by CRP. RESULTS: High-fat diet greatly increased the serum lipids and inflammatory markers, induced endothelial dysfunction and imbalance between NO and ET-1, increased mRNA and protein expression of TNF-alpha, IL-6, MCP-1 and enhanced macrophage infiltration of PCAT. CRP treatment could further promote macrophage infiltration of PVAT, induce the imbalance between NO and ET-1, aggravate endothelial dysfunction especially in PVAT(+) arteries, and could also enhance the above-mentioned mRNA and protein expression in PCAT and cultured adipocytes. CONCLUSIONS: CRP could significantly promote endothelial dysfunction in high-fat diet rabbits especially in PVAT(+) groups, which may be partly mediated by activating inflammatory reaction of adipose tissue. PMID- 23452888 TI - The change in the atrial fibrillation type as a prognosis marker in a community study: long-term data from AFBAR (Atrial Fibrillation in the BARbanza) study. AB - BACKGROUND: The aim is to describe the prognosis role of the change in the atrial fibrillation (AF) type in an unselected population of patients with AF currently attending primary care in a single health-service area in Galicia, north-western Spain. METHODS: AFBAR is a cohort study that was carried out by 35 primary care providers in 2008. Participants were followed up for a mean of 2.8 +/- 0.7 years. 798 patients with the diagnosis of AF who presented at their clinics during a three-month period were recruited. Primary endpoint was mortality or hospital admission. RESULTS: 778 patients (413 male) were analyzed; mean age 74.8 years old. Hypertension was the most prevalent risk factor (76.5%). Permanent AF was diagnosed in 529 patients (68.0%). Change of AF status occurred in 76 patients (9.8%). During follow-up 52.1% of the patients underwent a primary endpoint and the overall survival was 83.4%. The following independent determinants of primary endpoint were identified: change in AF status (Hazard Ratio (HR) 1.41 (95% confidence interval (CI) 1.04-1.92); p=0.026); previous heart failure (HR 1.28 (95%-CI 1.00-1.65); p=0.050); previous cardiovascular admission (HR 1.54 (95%-CI 1.16-2.03); p=0.002); stroke (HR 2.02 (95%-CI 1.35-3.03); p=0.001);ischemic heart disease (HR 1.28 (95%-CI 1.00-1.65); p=0.050); chronic obstructive pulmonary disease (HR 1.28 (95%-CI 1.00-1.64);p=0.042); anemia (HR 1.37 (95% CI 1.08-1.75); p=0.010); or AF-related complications (HR 1.45 (95%-CI 1.18-1.78); p<0.001). CONCLUSIONS: The change in AF status showed to be an important prognosis marker for death or hospital admissions in a primary care cohort. PMID- 23452889 TI - Impaired cross-activation of beta3 integrin and VEGFR-2 on endothelial progenitor cells with aging decreases angiogenesis in response to hypoxia. AB - BACKGROUND: The mechanism by which vascular regeneration declines with aging is not fully understood. An interaction between integrin and vascular endothelial growth factor receptor-2 (VEGFR-2) plays a substantial role in angiogenesis. Here, we investigated whether aging impairs this interaction in endothelial progenitor cells (EPCs) under hypoxia. METHODS AND RESULTS: Aging reduced the blood flow and vessel density in ischemic muscles in mice. Levels of phosphorylated Src (p-Src), p-beta3, and p-VEGFR-2 in acute ischemia were reduced in the muscles of aged mice compared to young mice. The hypoxia-inducible factor (HIF)-1alpha stabilizer deferoxamine improved the age-related impairment of angiogenesis, but this effect was diminished by LY290004, an inhibitor of phosphatidylinositol 3-kinase. Deferoxamine improved the reduction in chronic ischemia-induced beta3-integrin and VEGFR-2 phosphorylation in the muscles of aged mice; this effect was also diminished by LY290004. In EPCs, we identified the molecular requirements for VEGF-mediated beta3-integrin and VEGFR-2 cross activation in vitronectin-induced cell adhesion under acute hypoxia. We demonstrated that c-Src controlled the adhesion- and VEGF-induced beta3 tyrosine phosphorylation in hypoxia. Aging enhanced the hypoxia-induced EPC apoptosis and impaired several c-Src-related VEGF-induced receptor events, including beta3 tyrosine activation, ligand binding, cell adhesion, and tubulogenesis in cultured EPCs of animals and those of humans. CONCLUSIONS: These data suggest that the aging-related decline in angiogenic action in response to ischemia is mediated by the impairment of cross-activation between beta3 and VEGFR-2 in EPCs, which is partially associated with decreased HIF-1alpha stability. PMID- 23452890 TI - Exploring the periodicity of cardiovascular events in Switzerland: variation in deaths and hospitalizations across seasons, day of the week and hour of the day. AB - PURPOSE: The purpose of this study is to explore the periodical patterns of events and deaths related to cardiovascular disease (CVD), acute myocardial infarction (AMI) and stroke in Swiss adults (>= 18 years). METHODS: Mortality data for period 1969-2007 (N=869,863 CVD events) and hospitalization data for period 1997-2008 (N=959,990 CVD events) were used. The annual, weekly and circadian distribution of CVD-related deaths and events were assessed. Multivariate analysis was conducted using multinomial logistic regression adjusting for age, gender and calendar year and considering deaths from respiratory diseases, accidents or other causes as competitive events. RESULTS: CVD deaths and hospitalizations occurred less frequently in the summer months. Similar patterns were found for AMI and stroke. No significant weekly variation for CVD deaths was found. Stratification by age and gender showed subjects aged <65 years to present a higher probability of dying on Mondays and Saturday, only for men. This finding was confirmed after multivariate adjustment. Finally, a circadian variation in CVD mortality was observed, with a first peak in the morning (8-12 am) and a smaller second peak in the late afternoon (2-6 pm). This pattern persisted after multivariate adjustment and was more pronounced for AMI than for stroke. CONCLUSION: There is a periodicity of hospitalizations and deaths related to CVD, AMI and stroke in Switzerland. This pattern changes slightly according to the age and sex of the subjects. Although the underlying mechanisms are not fully identified, preventive measures should take into account these aspects to develop better strategies of prevention and management of CVD. PMID- 23452891 TI - Valvular osteoclasts in calcification and aortic valve stenosis severity. AB - BACKGROUND: Bone remodeling in calcified aortic valves is thought to originate from microfractures at multiple sites of the valve, at which osteoclasts and osteoblasts are recruited. The aim of the present study was to assess circulating mediators of bone homeostasis, correlate them to the severity of stenosis and explore the spatio-temporal distribution of bone turnover in different parts of calcified aortic valve tissue. METHODS AND RESULTS: Plasma and explanted aortic valves were obtained from 46 patients undergoing aortic valve replacement surgery. Plasma levels of tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear-kappaB (RANK) ligand and Runt-related transcription factor 2 (Runx2/Cbfa1) exhibited a significant correlation to the severity of aortic stenosis. mRNA levels in normal, thickened and calcified parts of aortic valves assessed by quantitative real-time PCR were significantly elevated in calcified parts of valves for TRAP (5.08 +/- 1.6-fold, P<0.001) RANK ligand (8.6 +/- 4.2 fold, P<0.001) and RANK (1.98 +/- 0.78-fold, P=0.015). In an age, gender and aortic valve anatomy-adjusted multivariable regression analysis the local transcript levels of TRAP correlated significantly with echocardiographic parameters quantifying stenosis severity in early stages, whereas the expression level of Runx2/Cbfa1 was a predictor of the stenosis severity in advanced stages. CONCLUSIONS: These findings suggest a critical role of bone turnover as a determinant of aortic stenosis severity. PMID- 23452892 TI - Treatment with statins improves long-term survival in individuals with carotid artery stenosis. PMID- 23452893 TI - [The contraceptive pill in question?]. PMID- 23452894 TI - Combination cell therapy using mesenchymal stem cells and regulatory T-cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of TH1/TH2 and th17/treg cells in a murine acute graft-versus-host disease model. AB - Mesenchymal stem cells (MSCs) have been considered to be an ideal cellular source for graft-versus-host disease (GVHD) treatment due to their unique properties, including tissue repair and major histocompatibility complex (MHC)-unmatched immunosuppression. However, preclinical and clinical data have suggested that the immunomodulatory activity of MSCs is not as effective as previously expected. This study was performed to investigate whether the immunomodulatory capacity of MSCs could be enhanced by combination infusion of regulatory T (Treg) cells to prevent acute GVHD (aGVHD) following MHC-mismatched bone marrow transplantation (BMT). For GVHD induction, lethally irradiated BALB/c (H-2(d)) mice were transplanted with bone marrow cells (BMCs) and spleen cells of C57BL/6 (H-2(b)) mice. Recipients were injected with cultured recipient-derived MSCs, Treg cells, or MSCs plus Treg cells (BMT + day 0, 4). Systemic infusion of MSCs plus Treg cells improved clinicopathological manifestations and survival in the aGVHD model. Culture of MSCs plus Treg cells increased the population of Foxp3(+) Treg cells and suppressed alloreactive T-cell proliferation in vitro. These therapeutic effects were associated with more rapid expansion of donor-type CD4(+)CD25(+)Foxp3(+) Treg cells and CD4(+)IL-4(+) type 2 T-helper (Th2) cells in the early posttransplant period. Furthermore, MSCs plus Treg cells regulated CD4(+)IL-17(+) Th17 cells, as well as CD4(+)IFN-gamma(+) Th1 cells. These data suggest that the combination therapy with MSCs plus Treg cells may have cooperative effects in enhancing the immunomodulatory activity of MSCs and Treg cells in aGVHD. This may lead to development of new therapeutic approaches to clinical allogeneic hematopoietic cell transplantation. PMID- 23452895 TI - Sphaeromyxids form part of a diverse group of myxosporeans infecting the hepatic biliary systems of a wide range of host organisms. AB - BACKGROUND: Approximately 40 species of Sphaeromyxa have been described, all of which are coelozoic parasites from gall bladders of marine fish. They are unique amongst the myxosporeans as they have polar filaments that are flat and folded instead of being tubular and spirally wound. This unusual feature was used as a subordinal character to erect the suborder Sphaeromyxina, which contains one family, the Sphaeromyxidae, and a single genus Sphaeromyxa. METHODS: In the present study, we examine eelpout from the genus Lycodes from Iceland for the presence of myxosporean parasites in the gall bladder and perform morphological and DNA studies. RESULTS: A novel myxosporean, Sphaeromyxa lycodi n. sp., was identified in the gall bladders of five of the six species of Lycodes examined, with a prevalence ranging from 29 - 100%. The coelozoic plasmodia are large, polysporous and contain disporic pansporoblasts and mature spores which are arcuate. The pyriform polar capsules encase long and irregularly folded ribbon like polar filaments. Each spore valve has two distinct ends and an almost 180 degrees twist along the relatively indistinct suture line. The single sporoplasm is granular with two nuclei. Sphaeromyxa lycodi is phylogenetically related to other arcuate sphaeromyxids and is reproducibly placed with all known sphaeromyxids and forms part of a robustly supported clade of numerous myxosporean genera which infect the hepatic biliary systems of a wide range of hosts. CONCLUSIONS: Sphaeromyxa lycodi is a common gall bladder myxosporean in eelpout of the genus Lycodes from Northern Iceland. It has characteristics typical of the genus and develops arcuate spores. Molecular phylogenetic analyses confirm that sphaeromyxids form a monophyletic group, subdivided into straight and arcuate spore forms, within the hepatic biliary clade that infect a wide range of freshwater associated animals. The ancestral spore form for the hepatic biliary clade was probably a Chloromyxum morphotype; however, sphaeromyxids have more recently evolved from an ancestor with a spindle-shaped Myxidium spore form. We recommend that the suborder Sphaeromyxina is suppressed; however, we retain the family Sphaeromyxidae and place it in the suborder Variisporina. PMID- 23452896 TI - Health-related quality of life in a national cohort of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) experience impaired health-related quality of life (HRQL). The objective of this study was to evaluate HRQL in a nation-wide sample. PATIENTS AND METHODS: This is a prospective, multicenter, non interventional study of HRQL including 139 (89%) PAH and 17 (11%) CTEPH patients (women 70.5%; mean age, 52.2) recruited from 21 Spanish hospitals. 55% had idiopathic PAH, 34% other PAH and 11% CTEPH. HRQL was measured using the Short Form 36 Health Survey (SF-36) and EuroQoL-5D (baseline and after 6 months). RESULTS: HRQL in the patients with PAH or CTEPH was impaired. The physical component of SF-36 and the EuroQol-5D correlated with the functional class (FC). Mean EuroQol-5D visual analogical scale (EQ-5D VAS) scores were 73.5+/-18.4, 62.9+/-20.7 and 51.3+/-16.0 (P<.0001) in patients with FC I, II and III, respectively. Every increase of one FC represented a loss of 4.0 on the PCS SF-36 and a loss of 9.5 on the EQ-5D VAS. Eight patients who died or received a transplant during the study period presented poorer initial HRQL compared with the rest of the population. No significant changes in HRQL were observed in survivors after 6 months of follow-up. CONCLUSIONS: HRQL is impaired in this population, especially in PAH/CTEPH patients near death. HRQL measurements could help predict the prognosis in PAH and CTPH and provide additional information in these patients. PMID- 23452897 TI - Intracellular lactate signaling cascade in atrial remodeling of mitral valvular patients with atrial fibrillation. AB - BACKGROUND: Atrial remodeling has emerged as the structural basis for the maintenance and recurrence of atrial fibrillation. Lactate signaling cascade was recently linked to some cardiovascular disorders for its regulatory functions to myocardial structural remodeling. It was hypothesized that lactate signaling cascade was involved in the maintenance and recurrence of atrial fibrillation by regulating atrial structural remodeling. METHODS: Biopsies of right atrial appendage and clinical data were collected from sex- and age-matched 30 persistent atrial fibrillation, 30 paroxysmal atrial fibrillation, 30 sinus rhythm patients undergoing isolated mitral valve surgery and 10 healthy heart donors. RESULTS: Atrial fibrillation groups had higher atrial lactate expression and this upregulated expression was positively correlated with regulatory indicators of atrial structural remodeling as reflected by severe oxidative stress injury and mitochondrial control of apoptosis. CONCLUSIONS: The present findings suggest a potential role for lactate signaling cascade in the maintenance and recurrence of atrial fibrillation and possibly represent new targets for therapeutic intervention in this disorder. PMID- 23452898 TI - Clinicopathological characteristics and prognostic factors in young patients after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: The aim of this study was to analyze the clinicopathological characteristics and the prognostic factors for survival and recurrence of young patients who had undergone hepatectomy for hepatocellular carcinoma. METHODS: Between 1990 and 2010, 31 patients aged 40 years or younger (younger patient group) among 811 consecutive patients with hepatocellular carcinoma who had undergone primary hepatectomy were analyzed with regard to patient factors, including liver function, tumor factors and operative factors. The clinicopathological characteristics of the younger patients were compared with those of patients over the age of 40 (older patient group). Then the prognostic factors of the younger patients were analyzed. Continuous variables were expressed as the means +/- standard deviation and compared using the chi2 test for categorical variables. Overall survival and recurrence-free survival rates were determined by the Kaplan-Meier method and analyzed by the log-rank test. The Cox proportional hazards model was used for multivariate analysis. RESULTS: In the younger patients, the rates of HBs-antigen-positivity, high alpha fetoprotein, portal invasion, intrahepatic metastasis, large tumors, low indocyanin green retention rate at 15 minutes, and anatomical resection were significantly higher than the same measures in the older patients. The five-year overall survival rate of the young patients was 49.6%. The prognostic factors of survival were HCV-antibody-positivity and low albumin status. Prognostic factors of recurrence were multiple tumors and the presence of portal invasion. CONCLUSIONS: In younger patients, survival appeared to be primarily affected by liver function, while recurrence was affected by tumor factors. Young patients with hepatocellular carcinoma should be aggressively treated with hepatectomy due to their good pre-surgical liver function. PMID- 23452899 TI - In vitro biological effects of two anti-diabetic medicinal plants used in Benin as folk medicine. AB - BACKGROUND: Extracts from Polygonum senegalensis (Polygonaceae) and Pseudocedrela kotschyi (Meliaceae) are two important traditionally used medicinal plants in rural Benin to treat many diseases and notably type 2 diabetes. The aim of the study was to investigate the alpha-glucosidase inhibition, antioxidant and antibacterial activities of those plants extract: Polygonum senegalensis leaves, and Pseudocedrela kotschyi root. METHODS: Hydro-alcoholic (50%) extracts were analyzed for their phytochemical content and tested for their inhibition potency on alpha-glucosidase from Saccharomyces cerevisiae. Antioxidant activities were assessed using the DPPH, ORAC, FRAP and DCFH-DA (cell based) assay. Finally, the antibacterial activity was evaluated using MIC determination on four Gram positive cocci (Bacillus subtilis, Clostridium difficile, Enterococcus faecalis, Staphylococcus aureus), three Gram-negative bacilli (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae), and the yeast Candida albicans. RESULTS: Each extract presented significant alpha-glucosidase inhibition and antioxidant activities. Polygonum senegalensis leaf extracts were the most active in each in vitro assay with an IC50 = 1.5 MUg/ml for alpha-glucosidase inhibition and an IC50 = 6.8 MUg/ml for DPPH scavenging, - 4.5 MUmol Fe II/g of dry matter - 9366 MUmol Trolox / g DW - for FRAP and ORAC values, respectively. IC50 = 2.3 MUg GA / ml for DCFH-DA assay. Concerning its antibacterial activity, a growth inhibitory effect was observed only against three Gram negative bacilli: B. subtilis, E. faecalis, S. aureus and the yeast C. albicans at high concentration. CONCLUSION: The results showed that the semi alcoholic extract of the two studied plants possess alpha-glucosidase inhibitory activity, antioxidant potency, and low antibacterial effect. PMID- 23452900 TI - International conference for healthcare and medical students 2012 dublin, ireland. 2-3 november 2012. Abstracts. PMID- 23452903 TI - Natural history of cow's milk allergy. PMID- 23452904 TI - Reply: To PMID 22981788. PMID- 23452902 TI - Prenatal and postnatal bisphenol A exposure and asthma development among inner city children. AB - BACKGROUND: Bisphenol A (BPA) is used widely to manufacture food container linings. Mouse models suggest exposure to BPA might increase allergic inflammation. OBJECTIVES: We hypothesized that BPA exposure, as assessed based on urinary BPA concentrations, would be associated with increased odds of wheeze and asthma and increased fraction of exhaled nitric oxide (Feno) values in children. METHODS: The Columbia Center for Children's Environmental Health recruited pregnant women for a prospective birth cohort study (n = 568). Mothers during the third trimester and children at ages 3, 5, and 7 years provided spot urine samples. Total urinary BPA concentrations were measured by using online solid phase extraction, high-performance liquid chromatography, isotope-dilution tandem mass spectrometry. Wheeze in the last 12 months was measured by using questionnaires at ages 5, 6, and 7 years. Asthma was determined by a physician once between ages 5 and 12 years. Feno values were measured at ages 7 to 11 years. RESULTS: Prenatal urinary BPA concentrations were associated inversely with wheeze at age 5 years (odds ratio [OR], 0.7; 95% CI, 0.5-0.9; P = .02). Urinary BPA concentrations at age 3 years were associated positively with wheeze at ages 5 years (OR, 1.4; 95% CI, 1.1-1.8; P = .02) and 6 years (OR, 1.4; 95% CI, 1.0-1.9; P = .03). BPA concentrations at age 7 years were associated with wheeze at age 7 years (OR, 1.4; 95% CI, 1.0-1.9; P = .04) and Feno values (beta = 0.1; 95% CI, 0.02-0.2; P = .02). BPA concentrations at ages 3, 5, and 7 years were associated with asthma (OR, 1.5 [95% CI, 1.1-2.0], P = .005; OR, 1.4 [95% CI, 1.0 1.9], P = .03; and OR, 1.5 [95% CI, 1.0-2.1], P = .04, respectively). CONCLUSIONS: This is the first report of an association between postnatal urinary BPA concentrations and asthma in children. PMID- 23452905 TI - Prevalence and risk factors of female sexual dysfunction among healthcare personnel in Malaysia. AB - OBJECTIVE: To determine the prevalence and risk factors of female sexual dysfunction (FSD) among healthcare personnel in selected healthcare facilities in Malaysia. METHODS: This was a cross-sectional study carried out at three large healthcare facilities that were selected by convenience sampling. Within each facility, stratified random sampling was used to select suitable candidates to participate in the study (n=201). Validated questionnaires were used to assess depression, anxiety, sexual function in women and erectile dysfunction (ED) in their partners. RESULTS: The prevalence of FSD was 5.5%. Women with sexual dysfunction were more likely to be married longer (OR=4.08; 95% CI; 1.15-4.50), had lower frequency of sexual intercourse (OR=5.00; 95% C; 1.05-23.76) and had a spouse with ED (OR=24.35; 95% CI; 4.55-130.37). Multivariate analysis showed that ED was the strongest predictor for FSD (AOR=27.30; 95% CI; 4.706-159.08). CONCLUSION: One in eighteen female healthcare personnel suffered from FSD and presence of ED in the partner strongly impacted her sexual function, negatively. The findings highlight the importance of including the male partner in clinical assessment of FSD. PMID- 23452906 TI - Is dimensional scoring important only for subthreshold levels of severity in personality disorders other than borderline? AB - Research assessing the utility of dimensional and categorical models of personality disorders (PDs) overwhelmingly supports the use of continuous over categorical models. Using borderline PD as an example, recent studies from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project suggested that continuous (criteria count) scoring of PDs is most informative for "subthreshold" levels of pathology, but is less important once a patient meets the diagnostic threshold. Using PD criteria count, the current study compared 7 indices of psychosocial morbidity for patients above and below diagnostic threshold for 3 additional PDs: paranoid, avoidant, and obsessive compulsive. Results showed that for all tested PDs, only number of current Axis I disorders was more correlated with PD criteria in the sub-threshold group as compared to those who met criteria for the disorder. Results for the remaining 6 indices of psychosocial morbidity varied by PD tested. PMID- 23452907 TI - Clinical validation of a virtual environment for normalizing eating patterns in eating disorders. AB - The purpose of the present study was to examine the clinical validation of a Virtual Reality Environment (VRE) designed to normalize eating patterns in Eating Disorders (ED). The efficacy of VR in eliciting emotions, sense of presence and reality of the VRE were explored in 22 ED patients and 37 healthy eating individuals. The VRE (non-immersive) consisted of a kitchen room where participants had to eat a virtual pizza. In order to assess the sense of presence and reality produced by the VRE, participants answered seven questions with a Likert scale (0-10) during the experience, and then filled out the Reality Judgment and Presence Questionnaire (RJPQ) and ITC-Sense of Presence Inventory (ITC-SOPI). The results showed that the VRE induced a sense of presence and was felt as real for both groups, without differences in the experience of "ease" with the VRE, sense of physical space, or the ecological validity assigned to the virtual kitchen and eating virtually. However, the ED patients reported paying more attention and experiencing greater emotional involvement and dysphoria after virtual eating. The results suggest that the VRE was clinically meaningful to the ED patients and might be a relevant therapy tool for normalizing their eating patterns. PMID- 23452909 TI - Recent advances and challenges in the anode architecture and their modifications for the applications of microbial fuel cells. AB - Microbial fuel cells (MFC), the ergonomic technology connects the liaison of fuel cell architecture and biological resources. Many viable applications like wastewater treatment, biosensors and bioremediation can be made possible with the help of MFCs. This technology is still at its toddler stage and immense works are still in progress to increase the volumetric energy density of MFCs. The overall performance of MFC depends on the cardinal part of the system; anode. A number of anode materials are currently in research to adjudge the better one in terms of the startup time, power output and durability. A wide range of possibilities are now currently available in the fabrication and modification of anode materials to substantially increase the power performances. This review adumbrates the significant requirements of anodes that are essential to be fulfilled, encompasses the aspiring research efforts which have been devoted so far in the anode modification and fabrication strategies to increase the power output, durability and compatibility of the anode interface with the inoculated microorganisms. PMID- 23452908 TI - Continental phylogeography of an ecologically and morphologically diverse Neotropical songbird, Zonotrichia capensis. AB - BACKGROUND: The Neotropics are exceptionally diverse, containing roughly one third of all extant bird species on Earth. This remarkable species richness is thought to be a consequence of processes associated with both Andean orogenesis throughout the Tertiary, and climatic fluctuations during the Quaternary. Phylogeographic studies allow insights into how such events might have influenced evolutionary trajectories of species and ultimately contribute to a better understanding of speciation. Studies on continentally distributed species are of particular interest because different populations of such taxa may show genetic signatures of events that impacted the continent-wide biota. Here we evaluate the genealogical history of one of the world's most broadly-distributed and polytypic passerines, the rufous-collared sparrow (Zonotrichia capensis). RESULTS: We obtained control region DNA sequences from 92 Zonotrichia capensis individuals sampled across the species' range (Central and South America). Six additional molecular markers, both nuclear and mitochondrial, were sequenced for a subset of individuals with divergent control region haplotypes. Median-joining network analysis, and Bayesian and maximum parsimony phylogenetic analyses all recovered three lineages: one spanning Middle America, the Dominican Republic, and north western South America; one encompassing the Dominican Republic, Roraima (Venezuela) and La Paz (Bolivia) south to Tierra del Fuego, Argentina; and a third, including eastern Argentina and Brazil. Phylogenetic analyses suggest that the Middle American/north-western South American clade is sister to the remaining two. Bayesian and maximum likelihood coalescent simulations used to study lineage demographic history, diversification times, migration rates and population expansion together suggested that diversification of the three lineages occurred rapidly during the Pleistocene, with negligible gene flow, leaving genetic signatures of population expansions. CONCLUSIONS: The Pleistocene history of the rufous-collared sparrow involved extensive range expansion from a probable Central American origin. Its remarkable morphological and behavioral diversity probably represents recent responses to local conditions overlying deeper patterns of lineage diversity, which are themselves produced by isolation and the history of colonization of South America. PMID- 23452910 TI - Factors associated with stunting and overweight in Amazonian children: a population-based, cross-sectional study. AB - OBJECTIVE: To examine the prevalence of stunting and overweight in children and identify demographic, socio-economic and maternal characteristics, as well as biochemical indicators, associated with these outcomes. DESIGN: A population based, cross-sectional study was performed. Data from structured questionnaires, anthropometric measurements, and blood and stool samples were used in Poisson regression models to estimate prevalence ratios (PR) according to a hierarchical conceptual framework. SETTING: Acrelandia, western Brazilian Amazon. SUBJECTS: Children (n 1139) aged <10 years. RESULTS: Prevalence of stunting was 7.1 % (95 % CI 5.1, 9.6 %) and 3.7 % (95 % CI 2.4, 5.7 %) among children aged <5 years and >=5 years, respectively; overweight was detected in 20.6 % (95 % CI 17.4, 24.2 %) and 9.4 % (95 % CI 7.2, 12.1 %) of children aged <5 years and >=5 years, respectively. Among children <5 years of age, stunting was positively associated with the lowest maternal height tertile (PR = 3.09, 95 % CI 1.26, 7.63), low birth weight (PR = 2.70, 95 % CI 1.41, 5.19), diarrhoea for >=3d (PR = 2.21, 95 % CI 1.03, 4.77) and geohelminth infections (PR = 2.53, 95 % CI 1.02, 6.13). Overweight in children <5 years of age was positively associated with caesarean delivery (PR = 1.45, 95 % CI 1.02, 2.06), birth weight >=3500 g (PR = 1.82, 95 % CI 1.30, 2.55) and Fe deficiency (PR = 1.64, 95 % CI 1.07, 2.53). Among children aged >=5 years, land or livestock ownership (PR = 1.85, 95 % CI 1.07, 3.22), maternal overweight (PR = 2.06, 95 % CI 1.23, 3.47), high C-reactive protein concentration (PR = 2.43, 95 % CI 1.26, 4.70), vitamin A deficiency (PR = 1.97, 95 % CI 1.13, 3.41) and high serum TAG concentration (PR = 2.16, 95 % CI 1.27, 3.68) were associated with overweight. CONCLUSIONS: Overweight was more prevalent than stunting, being associated with higher household wealth, maternal overweight, caesarean delivery, high birth weight, micronutrient deficiencies and high TAG concentration. Improvements in maternal and child health care with sustainable access to healthy food are necessary to reduce short- and long-term health complications related to overweight in this population. PMID- 23452911 TI - Differentiating Enterococcus concentration spatial, temporal, and analytical variability in recreational waters. AB - Monitoring recreational waters for fecal contamination is an important responsibility of water resource management agencies throughout the world, yet fecal indicator bacteria (FIB)-based recreational water quality assessments rarely distinguish between analytical, spatial, and temporal variability. To address this gap in water resources research and management protocol, we compare two methods for quantifying FIB concentration variability at a frequently-used beach on Lake Huron (Michigan, USA). The first method calculates differences between most probable number (MPN) and colony-forming unit (CFU) values derived from conventional analysis procedures. The second method uses the "raw data" from these analysis procedures in a Bayesian hierarchical model to explicitly acknowledge analytical variability and subsequently infer the relative significance of the effect of sampling location and time on in situ FIB concentrations. Results of the Bayesian analysis indicate that in situ FIB concentrations do not vary significantly over small spatial and temporal scales, and that observed differences in MPN and CFU values over these same spatial and temporal scales are due almost entirely to intrinsic variability introduced by laboratory analysis procedures. Our findings underscore potential opportunities for incorporating Bayesian statistical models directly into routine recreational water quality assessments and for advancing the state of the art in methods for protecting humans from waterborne disease. PMID- 23452912 TI - Bachelor of midwifery graduates well educated to provide care in rural maternity units. PMID- 23452913 TI - Effect of a blackout in pediatric patients with home medical devices during the 2011 eastern Japan earthquake. AB - BACKGROUND: during the eastern Japan earthquake in 2011 and the following prolonged blackout, pediatric patients with home medical devices sought electricity at the pediatric department. We retrospectively studied the effect of this earthquake and the following blackout. METHODS: we hand-reviewed pediatric admission records in Tohoku University Hospital for new inpatients attributed to the earthquake from March 11, 2011 to April 12, 2011. A survey by questionnaire regarding the situation during the earthquake was performed for parents of technology-assisted patients. RESULTS: during the study period, 24 pediatric patients were admitted to the pediatric department. Eighteen technology-assisted pediatric patients, including those with home respirators, accounted for 75% of new pediatric admissions. Patients who were admitted for electricity shortage stayed in the hospital for a mean of 11.0days (3-25days). The questionnaire survey showed that 55% of technology-assisted patients were admitted to medical centers for evacuation. The majority of patients (89%) with ventilators were eventually admitted to medical centers during the earthquake. Most of the parents of technology-assisted patients experienced a prolonged petrol shortage and difficulty in communications with medical centers. CONCLUSION: the current study suggests that technology-assisted pediatric patients with neurological disorders as the primary disease can overwhelm the capacity of hospital inpatient facilities in certain situations. Disaster preparedness should consider assuring power requirements in healthcare facilities and preparing backup power generators lasting for at least 24h for these patients. Preparing alternative measures for emergent electricity and communications could remedy serious conditions during a disaster. PMID- 23452914 TI - Sulfite oxidase deficiency--an unusual late and mild presentation. AB - INTRODUCTION: Sulfite oxidase deficiency (SOD) is an autosomal recessive inherited disease usually presenting in the neonatal period with severe neurological symptoms including seizures, often refractory to anticonvulsant therapy, and a rapidly progressive encephalopathy resembling neonatal hypoxic ischemia, with premature death. Most patients develop dislocated ocular lenses. Later or milder presentations of SOD are being reported with increasing frequency. These presentations include neurological regression with loss of previously acquired milestones or movement disorders. CASE REPORT: We report a four years old girl presenting with intermittent ataxia and uncoordinated limb movements. A similar episode of ataxia had occurred previously, one year before, with complete neurologic recovery and normal developmental milestones. Bilateral lens dislocation had been recently diagnosed. Cranial MRI demonstrated bilateral globus pallidus enhancement. Low homocysteine was found in plasma and Sulfitest(R) was positive. Further investigations led to confirmation of isolated sulfite oxidase deficiency with no enzyme activity detected on skin fibroblasts culture. DISCUSSION: This case illustrates the clinical variability of SOD and it is not only atypical but also seems to be the mildest form described so far. The association of ectopia lentis with a movement disorder, even without psychomotor regression, should prompt us to look for this diagnosis. PMID- 23452915 TI - Immuno-virologic outcomes and immuno-virologic discordance among adults alive and on anti-retroviral therapy at 12 months in Nigeria. AB - BACKGROUND: Predictors of immuno-virologic outcomes and discordance and their associations with clinical, demographic, socio-economic and behavioral risk factors are not well described in Nigeria since HIV viral load testing is not routinely offered in public HIV treatment programs. METHODS: The HACART study was a multi-center observational clinic-based cohort study of 2585 adults who started HAART between April 2008 and February 2009. A total of 628 patients were randomly selected at 12 months for immuno-virologic analyses. RESULTS: Virologic suppression rate (<400 copies/ml) was 76.7%, immunologic recovery rate (CD4 change from baseline >=50 cells/mm3) was 77.4% and immuno-virologic discordance rate was 33%. In multivariate logistic regression, virologic failure was associated with age <30 years (OR 1.79; 95% CI: 1.17-2.67, p=0.03), anemia (Hemoglobin < 10 g/dl) (OR 1.71; 95% CI: 1.22-2.61, p=0.03), poor adherence (OR 3.82; 95% CI: 2.17-5.97, p=0.001), and post-secondary education (OR 0.60; 95% CI: 0.30-0.86, p=0.02). Immunologic failure was associated with male gender (OR 1.46; 95% CI: 1.04-2.45, p=0.04), and age <30 years (OR 1.50; 95% CI: 1.11-2.39, p=0.03). Virologic failure with immunologic success (VL-/CD4+) was associated with anemia (OR 1.80; 95% CI: 1.13-2.88, p=0.03), poor adherence (OR 3.90; 95% CI: 1.92-8.24, p=0.001), and post-secondary education (OR 0.40; 95% CI: 0.22 0.68, p=0.005). CONCLUSIONS: Although favorable immuno-virologic outcomes could be achieved in this large ART program, immuno-virologic discordance was observed in a third of the patients. Focusing on intensified treatment preparation and adherence, young patients, males, persons with low educational status and most importantly baseline anemia assessment and management may help address predictors of poor immuno-virologic outcomes, and improve overall HIV program impact. Viral load testing in addition to the CD4 testing should be considered to identify, characterize and address negative immuno-virologic outcomes and discordance. PMID- 23452916 TI - Effects of lifestyle on plasma levels of the IGF system and the antioxidants coenzyme Q10 and vitamin E in Kenyan rural and urban populations. AB - OBJECTIVE: Overnight fasting blood plasma insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1 (IGFBP-1), coenzyme Q10, (CoQ) vitamin E and plasma lipids were compared between a semi-nomadic Samburu population and relatively urbanized cohorts from Nairobi, Kenya. RESEARCH DESIGN AND METHODS: 143 middle aged subjects without known diabetes were included. IGF-I and IGFBP-1 were analyzed by RIA, and CoQ and vitamin E by HPLC. Plasma lipid levels were analyzed by standard laboratory methods routinely used in the clinics. RESULTS: The age adjusted IGF-I serum levels were low in the Samburu male and female populations, ranging from 0 to -4 IGFSD-score (SDS), and a minor part of the investigated population reaching as low as -5 and -7 SDS. The Nairobi cohorts showed significantly higher values reaching from -2.5 to +1 SDS (P<0.0001). The nomadic Samburu population showed fasting IGFBP-1 values ranging from 30-100 MUg/l, while that of the urbanized Nairobi cohorts was considerably lower (25-60 MUg/l) (P<0.0001). CoQ concentrations of the Nairobi cohorts were 1.5-2.0 nmol/ml similar to the levels found in several European countries. The Samburu population on the other hand showed extremely high CoQ values ranging from 2 to 9 nmol/ml (P<0.0001). Vitamin E levels of the Nairobi group were low (5 20 nmol/ml), but the Samburu population had even lower levels ranging from 3 to 15 nmol/ml (P<0.0001). Plasma lipid levels such as cholesterol, triglycerides, LDL/HDL, ApoB/ApoA ratios as well as BMI and weight were significantly higher in the Nairobi population (P<0.0001). CONCLUSIONS: Low IGF-I and high IGFBP-1 levels of the Samburu cohorts indicate malnutrition. High lipid levels of the Nairobi cohorts indicate that these groups have several risk factors for cardiovascular diseases and diabetes type2. PMID- 23452917 TI - Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced cervical cancer employing MRI with a tandem/ring applicator in situ and virtual preplanning of the interstitial component. AB - PURPOSE: To investigate the reproducibility of virtually planned needles, changes in DVH parameters and clinical feasibility of combined intracavitary/interstitial (IC/IS) pulsed dose rate brachytherapy (PDR-BT) for locally advanced cervical cancer based on 3D MRI preplanning. MATERIAL AND METHODS: Fifty-eight consecutively patients accrued in the EMBRACE study were included. Treatment was initiated with external beam radiotherapy and cisplatin. Three BT implants and MRI with the applicator in situ were performed in all patients, i.e. week 5 (BT0), week 6 (BT1) and week 7 (BT2) of the treatment. BT0 was only used for preplanning of subsequent implantations, whereas BT1 and BT2 comprised 2 equal sized fractions of PDR BT. RESULTS: Based on BT0, 24 patients (41%) were selected for a combined IC/IS implant at BT1 and BT2. Patients treated with IC/IS BT had significantly larger tumours compared with patients treated with IC BT only (p<0.03). Additional time in general anaesthesia for the IC/IS component was on average 16 min. The number of preplanned virtual needles was 5.3+/-2.7 compared to 5.3+/-2.9 and 5.4+/-3.0 needles implanted at BT1 and BT2, respectively (p=0.72). Planned needle implantation depth was 33+/-15 mm compared to 30+/-10 mm at BT1 and 29+/-11 mm at BT2 (p=0.04). In the 24 patients selected for IC/IS BT both the virtual IC/IS plan (BT0) and the actually delivered plan (BT1+BT2) significantly increased D90 and D100 for HR CTV (p<0.01) and reduced D2cc for sigmoid (p<0.01) and bowel (p=0.04) compared to the optimised IC preplan (BT0). IC/IS BT was only associated with minor morbidity, which was resolved at a 3 month follow up. CONCLUSION: Combined IC/IS BT based on full 3D MRI preplanning is clinically feasible. The virtual preplanned needle positions are reproducible at subsequent BT applications leading to significantly improved DVH parameters and a clinically feasible and fast implant procedure. PMID- 23452921 TI - Small bowel obstruction secondary to gastric banding migration. PMID- 23452918 TI - Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. AB - BACKGROUND: Macrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators. The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-gamma and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages. METHODS: For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry. This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples. RESULTS: Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions. M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status. CONCLUSIONS: Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status. PMID- 23452922 TI - Is the residual gastric volume after laparoscopic sleeve gastrectomy an objective criterion for adapting the treatment strategy after failure? AB - BACKGROUND: Causes of failure after laparoscopic sleeve gastrectomy (LSG) are not known but may include a high residual gastric volume (RGV). The aim of this study was to use gastric computed tomography volumetry (GCTV) to investigate the RGV and relate the latter parameter to the outcome of LSG. METHODS: A single-center, prospective study included patients with>24 months of follow-up after LSG. The RGV was measured with a unique GCTV technique. We determined the LSG outcomes according to a variety of criteria and examined potential relationships with the RGV. When the RGV was>250 cc, we offered a repeat LSG (RLSG). RESULTS: Seventy six patients were included. The mean RGV was 255 cc but differed significantly when comparing "failure" and "success" subgroups, regardless of whether the latter were defined by a percentage of excess weight loss>50 (309 cc versus 225 cc, respectively; P = .0003), a BAROS score>3 (312 cc versus 234 cc; P = .005), the Reinhold criteria (290 cc versus 235 cc; P = .019), or the Biron criteria (308 cc versus 237 cc; P = .008). The RGV threshold (corresponding to the volume above which the probability of failure after LSG is high) was 225 cc. Fifteen RLSGs were performed during the inclusion period. CONCLUSION: A high RGV 34 months after LSG is a risk factor for failure. Knowledge of the RGV can be of value in the management of failure after LSG. PMID- 23452923 TI - Asymptomatic colon cancer finding during open bariatric surgery in a 29-year-old female. PMID- 23452924 TI - Comment on: psychological assessment of the adolescent bariatric surgery candidate. PMID- 23452925 TI - Laparoscopic biliopancreatic diversion with duodenal switch (LBPD/DS) is a safe operation. PMID- 23452926 TI - The duodenal-jejunal bypass sleeve (EndoBarrier Gastrointestinal Liner) for weight loss and treatment of type 2 diabetes. AB - BACKGROUND: Surgical intervention is now the most effective modality with which to treat severe obesity. There is currently a lack of minimally invasive technology with which we can effectively treat obesity and reverse type 2 diabetes mellitus. The EndoBarrier is a fluoropolymer sleeve that is reversibly fixated to the duodenal bulb and extends 80 cm into the small bowel, usually terminating in the proximal jejunum. This endoscopically inserted device aids weight loss through malabsorption and activating hormonal triggers. METHODS: We conducted a nonsystematic review on worldwide articles published on the MEDLINE database to ascertain progress in the development and use of the EndoBarrier. RESULTS: Most studies used 12-week excess weight loss (EWL) as a primary outcome measure with results ranging from 11.9%-23.6%. One study to date used 52-week EWL as its primary measure with a significant outcome of 47%. Our group has seen this technology cause significant weight loss, resolution of type 2 diabetes mellitus, and improvement in cardiovascular risk factor profile. CONCLUSIONS: The EndoBarrier shows promise in the surgical weight loss arena. This review article summarizes the technical aspects of this new technology, provides preliminary efficacy results, and introduces the roles it may play in the future of bariatric surgery. PMID- 23452927 TI - Outcome of surgical treatment for proximal long segment post intubation tracheal stenosis. AB - BACKGROUND: Post intubation long segment tracheal stenosis is a serious problem which usually requires multiple methods of treatment. The aim of this study was to evaluate the results of surgical treatment in long segment post intubation tracheal stenosis. METHODS: Between 2004 to 2008, 20 patients with proximal long segment tracheal stenosis and resection of over 40% of tracheal length, were analyzed in terms of age, sex, clinical symptoms, etiology of stenosis, length of stenosis and resection, role of suprahyoeid release with bilateral hyoeid bone cutting maneuver, post operative complications and life quality 3 year after surgery. RESULTS: M/F was 2/5, with the average age of 23.5 +/- 0.5 years. Average length of stenosis was 4.2 +/- 0.4 cm and the average length of resected segment was 5.2 +/- 0.4 cm. Early postoperative complications occurred in 4 patients (20%), 5 patients (25%) had late stenosis and 4 of them were treated with multiple dilation and one patient needed tracheostomy and prolonged T. tube. We didn't have any mortality. 80% of patients had excellent surgical results in follow up period. CONCLUSION: Surgery is the best method of treatment in long and multi segment tracheal stenosis. PMID- 23452928 TI - Synaptic potentiation in the nociceptive amygdala following fear learning in mice. AB - BACKGROUND: Pavlovian fear conditioning is a classical form of associative learning, which depends on associative synaptic plasticity in the amygdala. Recent findings suggest that the central amygdala (CeA) plays an active role in the acquisition of fear learning. However, little is known about the synaptic properties of the CeA in fear learning. The capsular part of the central amygdala (CeC) receives direct nociceptive information from the external part of the lateral parabrachial nucleus (lPB), as well as highly processed polymodal signals from the basolateral nucleus of the amygdala (BLA). Therefore, we focused on CeC as a convergence point for polymodal BLA signals and nociceptive lPB signals, and explored the synaptic regulation of these pathways in fear conditioning. RESULTS: In this study, we show that fear conditioning results in synaptic potentiation in both lPB-CeC and BLA-CeC synapses. This potentiation is dependent on associative fear learning, rather than on nociceptive or sensory experience, or fear memory retrieval. The synaptic weight of the lPB-CeC and BLA-CeC pathways is correlated in fear-conditioned mice, suggesting that fear learning may induce activity dependent heterosynaptic interactions between lPB-CeC and BLA-CeC pathways. This synaptic potentiation is associated with both postsynaptic and presynaptic changes in the lPB-CeC and BLA-CeC synapses. CONCLUSIONS: These results indicate that the CeC may provide an important locus of Pavlovian association, integrating direct nociceptive signals with polymodal sensory signals. In addition to the well-established plasticity of the lateral amygdala, the multi-step nature of this association system contributes to the highly orchestrated tuning of fear learning. PMID- 23452929 TI - Guava leaf extracts promote glucose metabolism in SHRSP.Z-Leprfa/Izm rats by improving insulin resistance in skeletal muscle. AB - BACKGROUND: Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) have been associated with insulin-resistance; however, the effective therapies in improving insulin sensitivity are limited. This study is aimed at investigating the effect of Guava Leaf (GL) extracts on glucose tolerance and insulin resistance in SHRSP.Z-Leprfa/Izm rats (SHRSP/ZF), a model of spontaneously metabolic syndrome. METHODS: Male rats at 7 weeks of age were administered with vehicle water or treated by gavage with 2 g/kg GL extracts daily for six weeks, and their body weights, water and food consumption, glucose tolerance, and insulin resistance were measured. RESULTS: Compared with the controls, treatment with GL extracts did not modulate the amounts of water and food consumption, but significantly reduced the body weights at six weeks post treatment. Treatment with GL extracts did not alter the levels of fasting plasma glucose and insulin, but significantly reduced the levels of plasma glucose at 60 and 120 min post glucose challenge, also reduced the values of AUC and quantitative insulin sensitivity check index (QUICKI) at 42 days post treatment. Furthermore, treatment with GL extracts promoted IRS-1, AKT, PI3Kp85 expression, then IRS-1, AMKP, and AKT308, but not AKT473, phosphorylation, accompanied by increasing the ratios of membrane to total Glut 4 expression and adiponectin receptor 1 transcription in the skeletal muscles. CONCLUSIONS: These data indicated that GL extracts improved glucose metabolism and insulin sensitivity in the skeletal muscles of rats by modulating the insulin-related signaling. PMID- 23452930 TI - Automatic vessel network features quantification using local vessel pattern operator. AB - Automatic measurement and quantification of blood vessels' features and detection of vessel landmarks are key steps in the computer-aided diagnosis and diseases monitoring. This work proposes a novel and robust method for detecting vessel landmarks, i.e. bifurcation and crossovers, and measurement of different features, i.e. vessel orientation and vessel diameter as well as bifurcation angle, from the detected vessel network using simple and efficient local vessel pattern operator. The proposed method is applied to the publicly available DRIVE, STARE and ARIA databases and compared with existing state-of-the-art approaches. It shows higher accuracy in detection of vessel landmark and estimation of vessel features. PMID- 23452931 TI - A supervised orthogonal discriminant projection for tumor classification using gene expression data. AB - An important application of gene expression data is tumor classification. Dimensionality reduction is a key step of tumor classification, as gene expression data is of high dimensionality and small sample size (SSS) and it contains a large number of redundant genes irrelevant to tumor phenotypes. Manifold learning is an excellent tool for dimensionality reduction and it is promising for gene expression data analysis. In this paper, an improved supervised orthogonal discriminant projection (SODP) is proposed for tumor classification. In SODP, an effective weight measurement between two nodes of the weight graph is designed according to both sample class information and local information. With the novel measurement, SODP can maximize the weighted difference between the non-local scatter and the local scatter, on the basis of locality preserving. The experimental results with five public tumor datasets demonstrate that the proposed SODP is quite efficient and feasible for tumor classification. PMID- 23452932 TI - Nurturing tomorrow's clinician scientists. PMID- 23452933 TI - The researcher of the future...develops powerful networks. PMID- 23452934 TI - Science: a new generation. PMID- 23452935 TI - Anne Johnson and Patrick Vallance: same starting point, different outcomes. PMID- 23452936 TI - The researcher of the future...makes the most of social media. PMID- 23452937 TI - The researcher of the future...engages with industry. PMID- 23452938 TI - The researcher of the future...takes advantage of international opportunities. PMID- 23452939 TI - Combination of a GnRH agonist with an antagonist prevents flare-up effects and protects primordial ovarian follicles in the rat ovary from cisplatin-induced toxicity: a controlled experimental animal study. AB - BACKGROUND: With the continuous improvement of surgery and chemotherapeutic treatments, many tumour patients increasingly achieve long-term survival and can even be completely cured. However, platinum-containing drugs, which are widely used to treat a variety of types of cancer, cause menstrual disorders and ovarian failure, which in turn lead to infertility. Thus far, gonadotropin releasing hormone (GnRH) agonist (GnRHa) and antagonist (GnRHant) are reported to act as protective agents of the ovary in chemotherapy through the inhibition of the female gonadal axis. Nevertheless, they both have disadvantages that limit their use. GnRHa causes a flare-up effect during the first week after administration, and no long-acting GnRHant agent is available. GnRHa combined with GnRHant may prevent the flare-up effect of GnRHa and rapidly inhibit the female gonadal axis. Several clinical studies with small sample sizes have reported controversial conclusions. In this strictly controlled animal study, we investigated the advantages of combination treatment with GnRHa and GnRHant. METHODS: Rats aged 12 weeks were divided into six groups: Control, cisplatin (CDDP), GnRHa, GnRHant, Combination (sht, short-term) and Combination (lng, long-term) of GnRHa and GnRHant. The last four groups received Triptorelin (1 mg/kg.d, for 14 days), Cetrorelix (0.5 mg/kg.d, for 10 days), a combination of Triptorelin (1 mg/kg.d, for 10 days) and Cetrorelix (0.5 mg/kg.d, for 10 days) in the long-term group and for 3 days in the short-term group. The Control and CDDP groups received saline (1 ml/kg.d, for 10 day). Then, all groups apart from the Control group received cisplatin (1 mg/kg.d, for 10 days), and the Control group received another 10 days of saline as described above. Blood samples were collected to detect the serum levels of E2, LH and FSH. Observation of oestrous cyclicity was also performed after drug administration. Finally, bilateral ovaries were collected for histological study and follicle counting. RESULTS: We observed a flare-up effect in rats treated with GnRHa, but not in any of the combination groups. The percentage of normal cyclicity increased from 0% in the CDDP group to 25.0%, 33.3%, 66.7% and 41.7%, in the GnRHa, GnRHant, combination (lng) and combination (sht) groups, respectively. Pretreatment with GnRHa, GnRHant and combination (lng) significantly protected the primordial follicles from destruction by preserving 57.6%, 63.4%, 87.1% and 60.4% of the follicles, respectively. CONCLUSIONS: The combination of a GnRH agonist with antagonist completely prevented the flare-up effect and enhanced the protective effect of the ovary from cisplatin-induced gonadotoxicity in rats. PMID- 23452940 TI - A telephone-supported cardiovascular lifestyle programme (CLIP) for lipid reduction and weight loss in general practice patients: a randomised controlled pilot trial. AB - OBJECTIVE: To evaluate a primary prevention care model using telephone support delivered through an existing health call centre to general practitioner-referred patients at risk of developing CVD, using objective measures of CVD risk reduction and weight loss. DESIGN: Participants were randomised into two groups: (i) those receiving a telephone-supported comprehensive lifestyle intervention programme (CLIP: written structured diet and exercise advice, plus seven telephone sessions with the Heart Foundation Health Information Service); and (ii) those receiving usual care from their general practitioner (control: written general lifestyle advice). Fasting plasma lipids, blood pressure, weight, waist circumference and height were assessed on general practice premises by a practice nurse at Weeks 0 and 12. SETTING: Two general practices in Adelaide, South Australia. SUBJECTS: Forty-nine men and women aged 48.0 (sd 5.88) years identified by their general practitioner as being at future risk of CVD (BMI = 33.13 (sd 5.39) kg/m2; LDL cholesterol (LDL-C) = 2.66 (sd 0.92) mmol/l). RESULTS: CLIP participants demonstrated significantly greater reductions in LDL-C (estimated mean (EM) = 1.98 (se 0.17) mmol/l) and total cholesterol (EM = 3.61 (se 0.21) mmol/l) at Week 12 when compared with the control group (EM = 3.23 (se 0.18) mmol/l and EM = 4.77 (se 0.22) mmol/l, respectively). There were no significant treatment effects for systolic blood pressure (F(1,45) = 0.28, P = 0.60), diastolic blood pressure (F(1,43) = 0.52, P = 0.47), weight (F(1,42) = 3.63, P = 0.063) or waist circumference (F(1,43) = 0.32, P = 0.577). CONCLUSIONS: In general practice patients, delivering CLIP through an existing telephone health service is effective in achieving reductions in LDL-C and total cholesterol. While CLIP may have potential for wider implementation to support primary prevention of CVD, longer-term cost-effectiveness data are warranted. PMID- 23452942 TI - Addiction: failure of control over maladaptive incentive habits. AB - Drug addiction may be associated with a loss of executive control over maladaptive incentive habits. We hypothesize that these incentive habits result from a pathological coupling of drug-influenced motivational states and a rigid stimulus-response habit system by which drug-associated stimuli through automatic processes elicit and maintain drug seeking. Neurally, incentive habits may depend upon an interaction between the basolateral amygdala and nucleus accumbens core, together with the progressive development of a ventral-to-dorsolateral striatum functional coupling through the recruitment of striato-nigro-striatal dopamine dependent loop circuitry. Recent evidence suggests that both ventral striatal and central nucleus pathways from the amygdala may be required for the recruitment of DLS-dependent control over habitual behavior. PMID- 23452941 TI - Sleep and immune function: glial contributions and consequences of aging. AB - The reciprocal interactions between sleep and immune function are well-studied. Insufficient sleep induces innate immune responses as evidenced by increased expression of pro-inflammatory mediators in the brain and periphery. Conversely, immune challenges upregulate immunomodulator expression, which alters central nervous system-mediated processes and behaviors, including sleep. Recent studies indicate that glial cells, namely microglia and astrocytes, are active contributors to sleep and immune system interactions. Evidence suggests glial regulation of these interactions is mediated, in part, by adenosine and adenosine 5'-triphosphate actions at purinergic type 1 and type 2 receptors. Furthermore, microglia and astrocytes may modulate declines in sleep-wake behavior and immunity observed in aging. PMID- 23452943 TI - Effects of task complexity on rhythmic reproduction performance in adults. AB - The aim of the present study was to investigate the effect of task complexity on the capability to reproduce rhythmic patterns. Sedentary musically illiterate individuals (age: 34.8+/-4.2 yrs; M+/-SD) were administered a rhythmic test including three rhythmic patterns to be reproduced by means of finger-tapping, foot-tapping and walking. For the quantification of subjects' ability in the reproduction of rhythmic patterns, qualitative and quantitative parameters were submitted to analysis. A stereophotogrammetric system was used to reconstruct and evaluate individual performances. The findings indicated a good internal stability of the rhythmic reproduction, suggesting that the present experimental design is suitable to discriminate the participants' rhythmic ability. Qualitative aspects of rhythmic reproduction (i.e., speed of execution and temporal ratios between events) varied as a function of the perceptual-motor requirements of the rhythmic reproduction task, with larger reproduction deviations in the walking task. PMID- 23452944 TI - Characteristics of grasping movements in a laboratory and in an everyday-like context. AB - To understand the principles of motor control, it is useful to know whether movements with the same physical constraints can be governed by different rules depending on the behavioral context. We therefore have recently introduced a paradigm in which subjects grasp from the same starting position to the same final object, once as a typical laboratory task and once as part of everyday-like behavior. In the laboratory context, grasping was repetitive, externally triggered and purposeless; in the everyday-like context, it was embedded in a complex activity, intentionally initiated, and served a purpose. Here we present a comprehensive analysis of data from that paradigm. Among 38 response parameters that reflected hand transport, grip shaping and object manipulation, 20 differed significantly between groups. Factor analysis further reduced them to four orthogonal factors: response speed, finger-object contact, response variability, and hand path curvature. This shows, for the first time, that behavioral context influences the execution of grasping movements in four independent ways, possibly reflecting four distinct functional modules in the motor system. This fits well with the view - derived from neurological data - that grasping is controlled by a set of interconnected brain areas which are differentially recruited to achieve different behavioral goals. PMID- 23452945 TI - [Hemoptysis and Ehlers-Danlos vascular disease]. PMID- 23452946 TI - Oxidative state in idiophase links reactive oxygen species (ROS) and lovastatin biosynthesis: differences and similarities in submerged- and solid-state fermentations. AB - The present work was focused on finding a relationship between reactive oxygen species (ROS) and lovastatin biosynthesis (secondary metabolism) in Aspergillus terreus. In addition, an effort was made to find differences in accumulation and control of ROS in submerged (SmF) and solid-state fermentation (SSF), which could help explain higher metabolite production in the latter. sod1 expression, ROS content, and redox balance kinetics were measured during SmF and SSF. Results showed that A. terreus sod1 gene (oxidative stress defence enzyme) was intensely expressed during rapid growth phase (trophophase) of lovastatin fermentations. This high expression decreased abruptly, just before the onset of production (idiophase). However, ROS measurements detected high concentrations only in idiophase, suggesting a link between ROS and lovastatin biosynthesis. Apparently sod1 down regulation promotes the rise of ROS during idiophase. This oxidative state in idiophase was further supported by a high redox balance observed in trophophase that changed to a low value in idiophase (around six-fold lower). The patterns of ROS accumulation, sod1 expression, and redox balance behaviour were similar in SmF and SSF. However, sod1 expression and ROS concentration (ten fold), were higher in SmF. Our results indicate a link between ROS and lovastatin biosynthesis. Also, showed differences of physiology in SSF that yield lower but more steady ROS concentrations, which could be associated to higher lovastatin production. PMID- 23452947 TI - Species of Mycosphaerellaceae and Teratosphaeriaceae on native Myrtaceae in Uruguay: evidence of fungal host jumps. AB - Mycosphaerella species are well-known causal agents of leaf diseases on many economically and ecologically important plant species. In Uruguay, a relatively large number of Mycosphaerellaceae and Teratosphaeriaceae are found on Eucalyptus, but nothing is known of these fungi on native Myrtaceae. The aim of this study was to identify Mycosphaerellaceae and Teratosphaeriaceae species associated with leaf diseases on native Myrtaceae in Uruguay and to consider whether host jumps by the pathogen from introduced Eucalyptus to native Myrtaceae have occurred. Several native forests throughout the country were surveyed with special attention given to those located close to Eucalyptus plantations. Five species belonging to the Mycosphaerellaceae and Teratosphaeriaceae clades were found on native Myrtaceous trees and three of these had previously been reported on Eucalyptus in Uruguay. Those occurring both on Eucalyptus and native Myrtaceae included Pallidocercospora heimii, Pseudocercospora norchiensis, and Teratosphaeria aurantia. In addition, Mycosphaerella yunnanensis, a species known to occur on Eucalyptus but not previously recorded in Uruguay, was found on leaves of two native Myrtaceous hosts. Because most of these species occur on Eucalyptus in countries other than Uruguay, it appears that they were introduced in this country and have adapted to be able to infect native Myrtaceae. These apparent host jumps have the potential to result in serious disease problems and they should be carefully monitored. PMID- 23452948 TI - Viability of ectomycorrhizal fungi following cryopreservation. AB - The use of ectomycorrhizal (ECM) fungi in biotechnological processes requires their maintenance over long periods under conditions that maintain their genetic, phenotypic, and physiological stability. Cryopreservation is considered as the most reliable method for long-term storage of most filamentous fungi. However, this technique is not widespread for ECM fungi since many do not survive or exhibit poor recovery after freezing. The aim of this study was to develop an efficient cryopreservation protocol for the long-term storage of ECM fungi. Two cryopreservation protocols were compared. The first protocol was the conventional straw protocol (SP). The mycelium of the ECM isolates was grown in Petri dishes on agar and subsequently collected by punching the mycelium into a sterile straw before cryopreservation. In the second protocol, the cryovial protocol (CP), the mycelium of the ECM isolates was grown directly in cryovials filled with agar and subsequently cryopreserved. The same cryoprotectant solution, freezing, and thawing process, and re-growth conditions were used in both protocols. The survival (positive when at least 60 % of the replicates showed re-growth) was evaluated before and immediately after freezing as well as after 1 week, 1 m, and 6 m of storage at -130 degrees C. Greater survival rate (80 % for the CP as compared to 25 % for the SP) and faster re-growth (within 10 d for the CP compared to the 4 weeks for the SP) were observed for most isolates with the CP suggesting that the preparation of the cultures prior to freezing had a significant impact on the isolates survival. The suitability of the CP for cryopreservation of ECM fungi was further confirmed on a set of 98 ECM isolates and displayed a survival rate of 88 % of the isolates. Only some isolates belonging to Suillus luteus, Hebeloma crustuliniforme, Paxillus involutus and Thelephora terrestris failed to survive. This suggested that the CP is an adequate method for the ultra-low cryopreservation of a large set of ECM fungi and that further studies are necessary for the more recalcitrant ones. PMID- 23452949 TI - Survival of Phytophthora cinnamomi as oospores, stromata, and thick-walled chlamydospores in roots of symptomatic and asymptomatic annual and herbaceous perennial plant species. AB - Studies were conducted to determine how Phytophthora cinnamomi survives during hot and dry Mediterranean summers in areas with limited surviving susceptible hosts. Two Western Australian herbaceous perennials Chamaescilla corymbosa and Stylidium diuroides and one Western Australian annual Trachymene pilosa were collected weekly from a naturally infested site from the Eucalyptus marginata (jarrah) forest from winter to spring and less frequently during summer 2011/2012. Selfed oospores, thick-walled chlamydospores, and stromata of P. cinnamomi were observed in each species. Oospores and thick-walled chlamydospores germinated in planta confirming their viability. This is the first report of autogamy by P. cinnamomi in naturally infected plants. Stromata, reported for the first time for P. cinnamomi, were densely aggregated inside host cells, and germinated in planta with multiple germ tubes with hyphae capable of producing oospores and chlamydospores. Trachymene pilosa was completely asymptomatic, S. diuroides did not develop root lesions but some plants wilted, whilst C. corymbosa remained asymptomatic above ground but lesions developed on some tubers. The presence of haustoria suggests that P. cinnamomi grows biotrophically in some hosts. Asymptomatic, biotrophic growth of P. cinnamomi in some annual and herbaceous perennials and the production of a range of survival structures have implications for pathogen persistence over summer and its management. PMID- 23452950 TI - Geographic locality greatly influences fungal endophyte communities in Cephalotaxus harringtonia. AB - Although endophytes of conifers have been extensively studied, few data are available on Cephalotaxaceae. We examined foliar and stem endophytes of Cephalotaxus harringtonia, within its natural range in Japan and outside its natural range in France to study the effect of geography on endophyte community composition. In Japan, rapidly growing endophytes were dominant and may have masked the real diversity, in comparison to France where most endophytes were growing slowly. Analyses of ITS rDNA revealed 104 different Blast Groups among 554 isolates. Almost no overlap between endophyte assemblages of C. harringtonia from the two countries was observed. It seems that Japanese C. harringtonia trees, which should be well adapted to their native site, would host a specific, endemic endophyte community, while trees that have been introduced recently to a foreign site, in France, should have captured existing cosmopolitan and more generalist taxa. In Japan the majority of xylariaceous taxa, which dominated the communities, were unknown and, although closely related to Asian taxa, may be new to science. Dothideomycetes were more prevalent in France. Locally, urban environment, particularly in Japan, may have introduced some perturbations in the native endophyte community of C. harringtonia, with an abundance of generalist fungi such as Nigrospora and Colletotrichum. PMID- 23452951 TI - Metarhizium anisopliae chitinase CHIT30 is involved in heat-shock stress and contributes to virulence against Dysdercus peruvianus. AB - Entomopathogenic fungi are able to produce several chitinases, which serve a variety of biological functions, such as fungal cell wall organization and the degradation of exogenous chitin for nutrition or insect infection processes. In this study, we analyzed the contribution of the CHIT30 chitinase from Metarhizium anisopliae in morphogenetic development and virulence as a model of chitinase function. The analysis of chi3 gene expression revealed transcript accumulation in response to heat-shock stress conditions as well as cultivation in medium supplemented with chitin. Null chi3 mutants were constructed to determine the biological role of CHIT30. No substantial differences in the secreted chitinase activity could be detected between the wild type and the Deltachi3 mutant. However, both endochitinase and exochitinase activities were diminished in the mutant strain following heat-shock treatment, suggesting that CHIT30 is involved in heat-shock adaptation. Mutants lacking CHIT30 chitinase showed reduced virulence against the cotton stainer bug Dysdercus peruvianus, indicating that the CHIT30 chitinase plays a role in the infection process of M. anisopliae. PMID- 23452952 TI - A molecular contribution to the assessment of the Tricholoma equestre species complex. AB - In recent years, interest in the Tricholoma equestre species complex has increased because of several cases of severe and sometimes fatal rhabdomyolysis reported in France and Poland. These occurred after repeated consumption of large portions of T. equestre sporophores during consecutive meals, despite the fact that this species is renowned as a tasty edible wild mushroom. The T. equestre species complex includes three ectomycorrhizal species Tricholoma flavovirens (Pers.) S. Lundell, Tricholoma auratum (Paulet) Gillet, and T. equestre (L.) P. Kummer. All these species produce sporophores with intense yellow gills but are difficult to distinguish by morphological analyses at both the macroscopic and microscopic levels. In T. equestre, two additional varieties are recognized: T. equestre var. populinum (Christensen & Noordeloos) associated with Populus sp. and/or Betula sp. trees and sometimes recognized as Tricholoma frondosae (Kalamees & Shchukin) and T. equestre var. pallidifolia characterized by pale to white gills, frequently recognized as Tricholoma joachimii (Bon & Riva). To explore the taxonomic (species delimitation), ecological, and geographical extent and limits of the T. equestre species complex, we have carried out a molecular comparison of worldwide strains belonging to this complex by using sequences of two molecular markers: the internal transcript spacer (ITS)1/5.8S/ITS2 region of the nuclear ribosomal unit and the 5' part of the mitochondrial cox1 gene. Phylogenetic analyses support the placement of European T. equestre, T. flavovirens, and T. auratum strains as representatives of a single species. This species appears associated with various conifers trees, depending on the geographic origin (Pinus pinaster for T. auratum, Pinus sylvestris or Abies alba for T. equestre and T. flavovirens). However, in the context of a single T. equestre species, the geographical location could lead to the characterization of sub-species or varieties, as suggested by the gathering of the four Asian (Japanese) T. auratum strains in a strongly supported distinct phylogenetic clade. Moreover, our analysis strongly argues for considering T. joachimii and the synonymised T. equestre var. pallidifolia as two representatives of a different species not belonging to the T. equestre group. This species would be phylogenetically related to the Tricholoma columbetta species with which they share white gills. Similarly, the phylogenetic analysis of the molecular data and the lack of gene flow between the strains associated with broad-leaved trees and those of the T. equestre complex, rather argues for two distinct species depending on the ecological niche: T. frondosae under broad-leaved trees and T. equestre under conifers. PMID- 23452953 TI - Combining ethidium monoazide treatment with real-time PCR selectively quantifies viable Batrachochytrium dendrobatidis cells. AB - Detection of the lethal amphibian fungus Batrachochytrium dendrobatidis relies on PCR-based techniques. Although highly accurate and sensitive, these methods fail to distinguish between viable and dead cells. In this study a novel approach combining the DNA intercalating dye ethidium monoazide (EMA) and real-time PCR is presented that allows quantification of viable B. dendrobatidis cells without the need for culturing. The developed method is able to suppress real-time PCR signals of heat-killed B. dendrobatidis zoospores by 99.9 % and is able to discriminate viable from heat-killed B. dendrobatidis zoospores in mixed samples. Furthermore, the novel approach was applied to assess the antifungal activity of the veterinary antiseptic F10((r)) Antiseptic Solution. This disinfectant killed B. dendrobatidis zoospores effectively within 1 min at concentrations as low as 1:6400. PMID- 23452954 TI - The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. AB - OBJECTIVES: The objectives of this study are to quantify endurance and respiratory function and better characterize spectrum of symptoms and biochemical abnormalities in mucopolysaccharidosis IVA subjects. METHODS: MorCAP was a multicenter, multinational, cross sectional study amended to be longitudinal in 2011. Each study visit required collection of medical history, clinical assessments, and keratan sulfate (KS) levels. RESULTS: Data from the first visit of 325 subjects (53% female) were available. Mean age was 14.5 years. Mean +/- SD height z-scores were -5.6 +/- 3.1 as determined by the CDC growth charts. Mean +/ SD from the 6-minute-walk-test was 212.6 +/- 152.2m, revealing limitations in functional endurance testing, and 30.0 +/- 24.0 stairs/min for the 3-minute-stair climb test. Respiratory function showed limitations comparable to MPS VI patients; mean +/- SD was 1.2 +/- 0.9l based on forced vital capacity and 34.8 +/ 25.5l/min based on maximum voluntary ventilation. Mean urinary keratan sulfate (uKS) was elevated for all ages, and negatively correlated with age. Higher uKS correlated with greater clinical impairment based on height z-scores, endurance and respiratory function tests. The MPS Health Assessment Questionnaire reveals impairments in mobility and activities of daily living in comparison to an age matched control population. CONCLUSIONS: MPS IVA is a multisystem disorder with a continuum of clinical presentation. All affected individuals experience significant functional limitations and reduced quality of life. Older patients have more severe exercise and respiratory capacity limitations, and more frequent cardiac pathology illustrating the progressive nature of disease. PMID- 23452955 TI - Fabry disease peripheral blood immune cells release inflammatory cytokines: role of globotriaosylceramide. AB - Fabry disease is an X-linked lysosomal disorder (LD) due to deficiency of the enzyme alpha-galactosidase A (alphaGal), which leads to the accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb3). Several mechanisms contribute to the diverse physiopathological alterations observed in this disease, and it has been suggested that an underlying proinflammatory state could play a significant role. The aim of this study is to investigate the presence of a proinflammatory state in the different subsets of peripheral blood mononuclear cells (PBMC) and to understand the mechanisms that contribute to its onset and perpetuation. We have shown that cultured PBMC from Fabry patients present a higher proinflammatory cytokine expression and production. Moreover, we determined that among PBMC, dendritic cells and monocytes present a basal proinflammatory cytokine production profile, which is further exacerbated with an inflammatory stimulus. Finally we established that normal, monocyte-derived dendritic cells and macrophages display the same proinflammatory profile when cultured in the presence of Gb3 and an inhibitor of alphaGal. Furthermore, this effect can be abolished using a TLR4 blocking antibody, indicating that TLR4 is necessary in the process. In summary, our results demonstrate the presence of a proinflammatory state involving two key subsets of innate immunity, and provide direct evidence of Gb3 having a proinflammatory role, likely mediated by TLR4, a finding that could help in the understanding of the underlying causes of the inflammatory pathogenesis of Fabry disease. PMID- 23452956 TI - Understanding the comparative catarrhine context of human pelvic form: a 3D geometric morphometric analysis. AB - Comparative studies of catarrhine pelvic morphology in an evolutionary framework play an important role in paleoanthropology, especially since this is the context from which human bipedalism eventually arose. Given the abundance of potentially confounding evolutionary and mechanical factors influencing pelvic form, it is important to tease apart the effects of shape and size in the major component of the primate pelvis, the os coxae. However, os coxae form is difficult to assess via traditional morphometric methods. Here, we adopt a 3D geometric morphometric approach to landmark data. Our analyses included data from 30 extant catarrhine taxa. Data were transformed and registered using Procrustes analysis and analyzed via examination of principal components. Two analyses were performed: one excluding Homo sapiens, and a second including them. Results of the first analysis demonstrate that the total diversity of os coxae morphology is significantly greater in hominoids than it is in cercopithecoids. This appears to be driven by the greater effects of size diversity (i.e., allometric effects) in the case of the hominoids. This analysis also revealed a clear taxonomic/phylogenetic distinction between hominoids and cercopithecoids in terms of os coxae shape. The second analysis showed that Procrustes distances in shape space are significantly greater between extant Pan and Homo than they are between any two non-human catarrhine taxa. This analysis thus quantifies, on a comparative basis, the dramatic effect that the course of hominin evolution had upon the morphology of the human pelvis, within what is - even by catarrhine standards--a relatively short span of evolutionary time. PMID- 23452957 TI - Type-specific oncogenic human papillomavirus infection in high grade cervical disease in New Zealand. AB - BACKGROUND: The national Human Papillomavirus (HPV) Immunisation Programme in New Zealand was introduced in 2008, and involves routine vaccination of girls 12-13 years with a catch-up for females aged up to 19 years. The aims of this study were to measure the pre-vaccination prevalence of oncogenic HPV infection in women aged 20-69 years who were participating in the New Zealand National Cervical Screening Programme (NZ-NCSP) and who were: (1) referred with high grade cytology with a subsequent histologically-confirmed high grade cervical intraepithelial neoplasia (CIN2/3) or adenocarcinoma in situ (AIS); or (2) were in the wider group of women who had a cytological prediction of high grade squamous disease or glandular abnormality (ASC-H/ HSIL+/AGC/AIS). METHODS: Women aged 20-69 years appearing on the NZ-NCSP register between August 2009-February 2011 with a cytology record of ASC-H/HSIL+/AGC/AIS were invited to participate in the study. Liquid-based cytology specimens were tested for 37 HPV types using Linear Array genotyping. The prevalence of type-specific HPV infection was reported within women with histologically-confirmed CIN 2/3 and within the wider group with ASC-H/HSIL+/AGC/AIS cytology. Age-specific trends for the relative proportion of HPV 16/18 vs. other oncogenic types in CIN2/3 were assessed. RESULTS: A total of 594 women with ASC-H/HSIL+/AGC/AIS cytology and a valid HPV test were recruited; of these 356 (60%) had confirmed CIN2/3 and 6 (1%) had confirmed AIS or glandular dysplasia. Positivity rates for any oncogenic HPV infection and for HPV16 and/or 18 within confirmed CIN2/3-AIS were 95% (95%CI: 92 97%) and 60% (54-65%) respectively; in all women with ASC-H/HSIL+/AGC/AIS cytology it was 87% (84-89%) and 53% (49-57%), respectively. The most common reported HPV types in women with CIN 2/3 were 16 (51%), 52 (19%), 31 (17%), 33 (13%) and 18 (12%). A trend for higher rates of HPV 16/18 infection compared to other oncogenic types was observed in younger women (p=0.0006). CONCLUSIONS: The prevalence of HPV 16/18 in confirmed high grade disease in New Zealand is comparable to that observed in Australia and European countries. Test positivity rates for type 52 appear higher than in comparable studies in other developed countries. A greater proportion of high grade lesions in younger women appear to be associated with HPV 16/18 infection. PMID- 23452958 TI - Postural control as a function of time-of-day: influence of a prior strenuous running exercise or demanding sustained-attention task. AB - BACKGROUND: The current experiment investigated the impact of two potential confounding variables on the postural balance in young participants: the induced experimental activity prior to the static postural measurements and the well documented time-of-day effects. We mainly hypothesized that an exhaustive exercise and a high attention-demanding task should result in alterations of postural control. METHODS: Ten participants performed three experimental sessions (differentiated by the activity - none, cognitive or physical - prior of the assessment of postural stability), separated by one day at least. Each session included postural balance assessments around 8 a.m., 12.00 p.m. and 5 p.m. +/- 30 min. The physical and cognitive activities were performed only before the 12 o'clock assessment. The postural tests consisted of four conditions of quiet stance: stance on a firm surface with eyes open; stance on a firm surface with eyes closed; stance on a foam surface with eyes open and stance on a foam surface with eyes closed. Postural performance was assessed by various center of pressure (COP) parameters. RESULTS: Overall, the COP findings indicated activity-related postural impairment, with an increase in body sway in the most difficult conditions (with foam surface), especially when postural measurements are recorded just after the running exercise (physical session) or the psychomotor vigilance test (cognitive session). CONCLUSIONS: Even if no specific influence of time-of-day on static postural control is demonstrated, our results clearly suggest that the activities prior to balance tests could be a potential confounding variable to be taken into account and controlled when assessing clinical postural balance. PMID- 23452960 TI - Validating continued competency. PMID- 23452959 TI - Course and etiology of dysexecutive MCI in a community sample. AB - BACKGROUND: Amnestic mild cognitive impairment (aMCI) is associated with an elevated risk of progressing to Alzheimer's disease. Much less is known about the course of dysexecutive mild cognitive impairment (dMCI). The goals of this study were to determine how the profile of cognitive deficits differs over time between patients with dMCI and aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with stroke and white matter hyperintensity on magnetic resonance imaging (MRI) than aMCI. METHODS: The authors undertook a prospective evaluation of an inception cohort of 1167 ethnically diverse elders recruited from an urban community-based sample monitored with clinical and neuropsychological testing for an average of 4.5 years (standard deviation, 0.8 year). A subset of the subjects underwent MRI. We compared four groups of MCI patients: single-domain amnestic and dysexecutive MCI, and multiple-domain MCI with and without executive dysfunction. RESULTS: Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single-domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple-domain MCI did not increase risk of progression to dementia. Patients with multiple-domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer's type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to experience stroke, but not white matter hyperintensity, detected via MRI than patients with aMCI. CONCLUSIONS: dMCI appears to follow a different course, and is less associated with Alzheimer's disease and more associated with stroke than aMCI. PMID- 23452961 TI - The need to know. PMID- 23452963 TI - Information-seeking behavior of adolescent orthodontic patients. AB - INTRODUCTION: Health-information-seeking behavior is the purposive search for health-related information. The literature contains few articles examining this behavior as it relates to orthodontics; therefore, the aim of this study was to investigate how adolescent orthodontic patients seek information about their treatment, why they search for this information, and how they prefer the information to be available. METHODS: In-depth interviews were conducted with 15 subjects, 10 to 16 years old, who were considering orthodontic treatment. The purpose of the interviews was to identify themes that were then used to develop a questionnaire to investigate information-seeking behavior. The questionnaire was distributed to 50 adolescent orthodontic patients. RESULTS: The main sources of information were talking to a dentist or an orthodontist (84%), talking to peers (66%), and reading information leaflets (64%). Surprisingly few respondents had used the Internet (8%). The preferred sources of information were talking to an orthodontist (26%) and family members (12%), followed by talking with the general dentist (10%), viewing a DVD (10%), or reading information leaflets (10%). CONCLUSIONS: The preferred method of obtaining information was verbal, followed by audiovisual and written. Audiovisual information could be beneficial for those who find reading difficult or who struggle to retain verbal information. Few patients accessed information via the Internet, and this was attributed to concerns about the reliability of the information. PMID- 23452964 TI - Different manifestations of Class II Division 2 incisor retroclination: a morphologic study. AB - INTRODUCTION: The aims of this study were to investigate whether there is a different transverse morphologic pattern of dental arches among patients with different manifestations of Class II Division 2 incisor retroclination and to evaluate to what extent the pattern of smaller-than-average teeth in Class II Division 2 malocclusion is common to all groups studied. This information might clarify whether different Class II Division 2 phenotypes represent a single etiology or multiple etiologies. METHODS: The sample comprised 108 subjects with Class II Division 2 malocclusions, divided into 2 groups according to the type of incisor retroclination: group I included 43 Class II Division 2 subjects with retroclination exclusively of the maxillary central incisors, and group II included 65 Class II Division 2 subjects with retroclination of the 4 maxillary incisors. Maxillary and mandibular intercanine and intermolar widths as well as mesiodistal crown dimensions of the 4 maxillary and mandibular incisors were determined from the patients' initial study models. Mean values of all variables were compared between the 2 groups by sex with analysis of variance. RESULTS: From the comparison between these 2 groups, no statistically significant differences were found for all transverse measurements (P >0.05). For all mesiodistal measurements analyzed, statistically significant differences between the groups were only found for the mean value of both maxillary lateral incisors' mesiodistal dimensions in both sexes (P <0.05). CONCLUSIONS: It is not possible to attribute a characteristic pattern of dental arch-width and incisor mesiodistal dimensions to the different manifestations of incisor retroclination in Class II Division 2 malocclusion. PMID- 23452965 TI - Microbial contamination of "as received" and "clinic exposed" orthodontic materials. AB - INTRODUCTION: Our objective was to determine whether components of fixed orthodontic appliances as received from the manufacturers and after exposure to the clinical environment are free from microbial contamination before clinical use. A pilot molecular microbiologic laboratory study was undertaken at a dental hospital in the United Kingdom. METHODS: A range of orthodontic materials "as received" from the manufacturers and materials "exposed" to the clinical environment were studied for bacterial contamination. After growth on blood-rich media, cultured bacteria were identified by 16S rDNA polymerase chain reaction amplification and sequence phylogeny. RESULTS: Bacteria were isolated from "as received" bands, archwires, and impression trays, but the level of contamination was low (0.5 * 10(1) to 1.825 * 10(2) CFU/mL(-1)). Various bacterial species were isolated from "clinic exposed" bands, archwires, impression trays, coil springs, and elastomeric modules, but the level of contamination was low (0.5 * 10(1) to 8.0 * 10(1) CFU/mL(-1)). The most commonly identified bacterial species was Staphylococcus epidermidis, followed by Kocuria, Moraxella, and Micrococcus species. CONCLUSIONS: New materials "as received" from the manufacturers and those exposed to the clinical environment are not free from bacterial contamination before use in patients, but this contamination is low considering the potential for aerosol and operator contamination and could be considered insignificant. Further studies would be required to determine the level of risk that this poses. PMID- 23452966 TI - Change in maxillary incisor inclination during surgical-orthodontic treatment of skeletal Class III malocclusion: comparison of extraction and nonextraction of the maxillary first premolars. AB - INTRODUCTION: The purpose of this study was to investigate differences in preoperative decompensation and postoperative compensation of the maxillary incisors in patients with skeletal Class III malocclusion treated with 2-jaw surgery and extraction or nonextraction of the maxillary first premolars. METHODS: The subjects consisted of 50 skeletal Class III patients who had a normal maxillary position, prognathic mandible, and mild crowding in the maxillary arch (<=4 mm). All patients were treated with 2-jaw surgery. They were divided into 2 groups: group 1 (n = 25) had extraction of the maxillary first premolars, and group 2 (n = 25) had no extractions. Lateral cephalograms were analyzed before treatment (T0), 1 month before surgery (T1), 1 day after surgery (T2), and after debonding (T3). After measurement of the skeletodental variables, statistical analyses were performed. RESULTS: At T0, group 1 exhibited more compensated maxillary incisors compared with group 2 (U1-SN, P <0.001). Considerable preoperative decompensation in group 1 and negligible preoperative decompensation in group 2 occurred at T1 (DeltaU1-SN, -9.1 degrees vs 1.1 degrees ). Although maxillary incisor inclination significantly decreased with surgical movement of the maxilla at T2, this increased to compensate for the postsurgical skeletal relapse in both groups at T3. Although 24% of group 1 had a normal range of maxillary incisor inclination (U1-SN) at T0, it increased to 68% at T1. A dominant pattern of the subjects within the normal range of U1-SN was maintained in groups 1 and 2 (80% and 96% at T2, and 72% and 80% at T3, respectively). According to the achievement ratio, the U1-SN value became close to the norm mainly by preoperative decompensation in group 1 (95.5%) and by surgery in group 2 (130.2%). CONCLUSIONS: The results of this study might provide effective guidelines for predicting the amount and pattern of preoperative decompensation and postoperative compensation of the maxillary incisors in skeletal Class III patients treated with 2-jaw surgery. PMID- 23452967 TI - Evaluation of the severity of malocclusions in children affected by osteogenesis imperfecta with the peer assessment rating and discrepancy indexes. AB - INTRODUCTION: Osteogenesis imperfecta is a heritable disorder affecting bone and tooth development. Malocclusion is frequent in those affected by osteogenesis imperfecta, but this has not been studied in detail. The purpose of this study was to describe and quantify the severity of malocclusions in patients with osteogenesis imperfecta. METHODS: Articulated dental casts were obtained from 49 patients diagnosed with osteogenesis imperfecta (ages 5-19 years; 28 female) and 49 age- and sex-matched control subjects who did not have osteogenesis imperfecta. Both groups were seeking orthodontic treatment. Malocclusions were scored by using the peer assessment rating (PAR) and the discrepancy index (DI). RESULTS: The average United Kingdom weighted PAR scores were 31.1 (SD, 14.5) for the osteogenesis imperfecta group and 22.7 (SD, 10.7) for the control group (P <0.05). The mean United States weighted PAR scores were 32.2 (SD, 15.0) for patients with osteogenesis imperfecta and 21.6 (SD, 9.6) for the controls (P <0.05). The average modified DI scores were 29.8 (SD, 20.2) for the osteogenesis imperfecta group and 12.4 (SD, 6.8) for the control group (P <0.05). Group differences were greatest for lateral open bite (osteogenesis imperfecta group, 7.1; control group, 0.3) for the DI parameters and anterior crossbite (osteogenesis imperfecta group, 13.0; control group, 3.8 [United Kingdom]) for the PAR. CONCLUSIONS: Both the PAR and the DI showed that malocclusions were significantly more severe in patients with osteogenesis imperfecta than in the control group. There was a higher incidence of Class III malocclusion associated with anterior and lateral open bites in patients affected by osteogenesis imperfecta. PMID- 23452968 TI - Effect of surgical exposure technique, age, and grade of impaction on ankylosis of an impacted canine, and the effect of rapid palatal expansion on eruption: A prospective clinical study. AB - INTRODUCTION: This study had 2 aims: (1) to assess whether the surgical exposure technique, the patient's age, and the grade of impaction are associated with ankylosis of the impacted canine; and (2) to investigate the effect of rapid palatal expansion on an impacted canine's automatic eruption. METHODS: The sample for this prospective longitudinal study consisted of 118 orthodontic patients (72 female, 46 male) who were treated surgically and orthodontically by the first author (S.I.K.) over 18 years. The patients' ages at the beginning of therapy ranged from 11.2 to 46.1 years. They had 157 impacted canines (150 maxillary, 7 mandibular), grouped in 7 categories (grades I-VII) according to their radiographic position in the orthopantomogram at the onset of treatment. Univariate and multivariate generalized estimating equation logistic regression analyses were used to assess the effect of the predictors of interest on ankylosis. (In this research, a broad definition of "ankylosis" was used, to include impacted canines immobilized a priori or during traction, due to all the possible causes that could contribute to immobilization, such as all types of external tooth resorption and other known or unknown factors.) RESULTS: Thirty eight canines erupted spontaneously after space gaining, and the other 119 were treated surgically with an open (57 cases) or a closed (62 cases) exposure technique. Eleven canines of the 119 that were treated surgically had ankylosis, either a priori or during orthodontic traction. The percentages of ankylosis were 3.5% in the open technique and 14.5% in the closed technique. Evidence of statistical association was found between age and ankylosis, grade of impaction and ankylosis, and rapid palatal expansion and automatic eruption of the impacted canine. CONCLUSIONS: Evidence of an association between exposure technique and ankylosis was found. Additionally, there was evidence that the grade of impaction and the patient's age are significant predictors of ankylosis, as is the use of rapid palatal expansion a predictor of automatic eruption. PMID- 23452969 TI - Factors affecting the accuracy of buccal alveolar bone height measurements from cone-beam computed tomography images. AB - INTRODUCTION: The reasons for inaccuracies in alveolar bone measurement from cone beam computed tomography (CBCT) images might be multifactorial. In this study, we investigated the impact of software, the presence or absence of soft tissues, the voxel size of the scan, and the regions in the jaws on buccal alveolar bone height measurements in pigs at an age equivalent to human adolescents. METHODS: Marker holes, apical to the maxillary and mandibular molar roots, and mesiodistal molar occlusal reference grooves were created in 6 fresh pig heads (12 for each jaw), followed by CBCT scans at 0.4-mm and 0.2-mm voxel sizes under soft-tissue presence and soft-tissue absence conditions. Subsequently, buccolingual sections bisecting the marker holes were cut, from which the physical alveolar bone height and thickness were measured. One blinded rater, using Dolphin (version 11.5 Premium; Dolphin Imaging, Chatsworth, Calif) and OsiriX (version 3.9; www.osirix viewer.com) software, independently collected alveolar bone height measurements from the CBCT images. Differences between the CBCT and the physical measurements were calculated. The mean differences and the limit of agreement (LOA, +/-1.96 SD) for every jaw, voxel-size, soft-tissue, and software condition were depicted. Each measurement was then assessed for clinical inaccuracy by using 2 levels of criteria (absolute differences between CBCT and physical measurements >=1 mm, or absolute differences between CBCT and physical measurements >=0.5 mm), and the interactions between soft-tissue and voxel-size factors for every jaw and software condition were assessed by chi-square tests. RESULTS: Overall, the mean differences between the CBCT and the physical measurements for every jaw, voxel size, soft-tissue, and software condition were near 0. With all other conditions kept equal, the accuracy of the maxillary CBCT measurements was inferior (larger limit of agreement ranges and higher frequencies of clinical inaccuracy) to the mandibular measurements. The physical thickness of the maxillary alveolar crestal bone was less than 1 mm and significantly thinner than the mandibular counterparts. For every jaw and software condition, the accuracy of measurements from the 0.2-mm soft-tissue presence CBCT images was consistently superior (smaller limit of agreement ranges and lower frequencies of clinical inaccuracy) to those from the 0.4-mm soft-tissue presence, the 0.4-mm soft-tissue absence, and the 0.2-mm soft-tissue absence images; all showed similar accuracies. Qualitatively, the soft-tissue absence images demonstrated much brighter enamel and alveolar bone surface contours than did the soft-tissue presence images. CONCLUSIONS: At an adolescent age, the buccal alveolar bone height measured from the maxillary molar region based on 0.4-mm voxel-size CBCT images can have relatively large and frequently inaccurate measurements, possibly due to its thinness. By using 0.2-mm voxel-size scans, measurement accuracy might be improved, but only when the overlying facial and gingival tissues are kept intact. PMID- 23452970 TI - Association between gingival recession and proclination of maxillary central incisors near the cleft in patients with unilateral cleft lip and palate: A retrospective case-control study. AB - INTRODUCTION: The aim of this study was to investigate whether proclination of the maxillary central incisor near a cleft leads to gingival recession in patients born with unilateral cleft lip and palate. METHODS: Forty patients with unilateral cleft lip and palate were retrospectively enrolled. By using intraoral slides, casts, and cephalograms, changes in gingival recession and proclination were measured. The 2-sample t test, correlation, and stepwise logistic regression analyses were applied. RESULTS: There were statistically significant differences in proclination variations between subjects with and without increased gingival recession (P <0.0001). A positive correlation was shown between proclination and gingival recession. Bone grafting during treatment resulted in a significant difference in gingival recession (P <0.05). Every 2 degrees of increase in the angle between the long axis of the maxillary central incisors and the sella nasion plane had a 3.06 times greater risk for gingival recession (odds ratio, 3.06; 95% confidence interval, 1.329-7.046; P = 0.0086). CONCLUSIONS: Proclination of the maxillary central incisor adjacent to the cleft is positively correlated with gingival recession in patients with unilateral cleft lip and palate. Proclination should be limited to prevent gingival recession and its esthetic and functional problems. It is better for a borderline cleft patient to have orthognathic surgery rather than camouflage treatment. Bone grafting during treatment might benefit gingival recession. The angle between the long axis of the maxillary central incisors and the sella-nasion plane is considered the strongest predictor of gingival recession. PMID- 23452971 TI - Esthetic perception of black spaces between maxillary central incisors by different age groups. AB - INTRODUCTION: The aim of this research was to evaluate esthetic perceptions of the smile, especially regarding black spaces between the maxillary central incisors, by laypersons in 3 age groups. METHODS: Photographs were digitally manipulated to simulate black spaces in the region of the maxillary central incisor crenations. The images were printed on photographic paper and attached to a questionnaire that was given to 150 laypersons in 3 age groups: 15 to 19, 35 to 44, and 65 to74 years. They were asked to use a visual analog scale method to rate the smiles from a score of 0, corresponding to "not very attractive," to 10, "very attractive." Differences between the examiners were verified by the Mann Whitney test. All statistics were performed with a degree of confidence of 95%. RESULTS: The results showed that older persons had more difficulty perceiving black spaces. In the younger groups, the subjects were better able to perceive the black spaces, and the larger the black space, the less attractive they rated the photograph (P < 0.01). CONCLUSIONS: Younger people are more likely than older people to perceive black spaces in maxillary incisor crenations. The larger the black spaces, the less attractive they rate the smile. PMID- 23452972 TI - Effect of remineralizing agents on white spot lesions after orthodontic treatment: a systematic review. AB - INTRODUCTION: White spot lesions are a common complication after orthodontic treatment. The aim of this systematic review was to investigate which remineralizing agents are effective for the treatment of white spot lesions after orthodontic treatment. METHODS: According to predetermined criteria, 4 databases were searched for appropriate studies. References of the selected articles and relevant reviews were searched for any missed publications. RESULTS: Seven randomized controlled trials were selected as eligible studies, and only qualitative analyses were performed because of the diversity of the interventions and outcome measures. Two studies showed significant effects of 2 different fluoride preparations: one with a small sample size and several methodologic deficiencies, and the other using only nonconventional detection methods (ie, DIAGNOdent pen, KaVo, Biberach, Germany) to assess white spot lesions. Two studies involved casein phosphopeptide-amorphous calcium phosphate, which seemed to be effective for the regression of white spot lesions. However, the statistical analysis in 1 study was based on the tooth surfaces instead of the patient, and the visual examination used in the other study to assess the white spots was not reliable. CONCLUSIONS: Based on the literature, there is a lack of reliable evidence to support the effectiveness of remineralizing agents for the treatment of postorthodontic white spot lesions. PMID- 23452973 TI - Correction of Class II malocclusion with Class II elastics: a systematic review. AB - INTRODUCTION: Although Class II elastics have been widely used in the correction of Class II malocclusions, there is still a belief that their side effects override the intended objectives. The aim of this systematic review was to evaluate the true effects of Class II elastics in Class II malocclusion treatment. METHODS: A search was performed on PubMed, Scopus, Web of Science, Embase, Medline, and Cochrane databases, complemented by a hand search. Study eligibility criteria were the application of Class II elastics in Class II malocclusion treatment and the presentation of dental or skeletal outcomes of treatment. All age groups were included. RESULTS: The search identified 417 articles, of which 11 fulfilled the inclusion criteria. Four studied the isolated effects of Class II elastics, and 7 were comparisons between a single use of elastics and another method for Class II malocclusion correction. Because of the differences in treatment modalities in these articles, a meta-analysis was not possible. CONCLUSIONS: Based on the current literature, we can state that Class II elastics are effective in correcting Class II malocclusions, and their effects are primarily dentoalveolar. Therefore, they are similar to the effects of fixed functional appliances in the long term, placing these 2 methods close to each other when evaluating treatment effectiveness. Little attention has been given to the effects of Class II elastics on the soft tissues in Class II malocclusion treatment. PMID- 23452974 TI - Correction of bilateral impacted mandibular canines with a lip bumper for anchorage reinforcement. AB - Multiple treatment options are available to patients with impacted manibular canines in addition to a retained deciduous canine. This article describes the treatment of a prepubertal girl, aged 10 years 6 months, with a skeletal Class I, dental Class II Division 1 malocclusion, retrognathic mandible, deep overbite, proclined maxillary incisors, midline diastema, and bilateral mandibular canine impaction. The orthodontic treatment plan included extraction of the deciduous canine and forced eruption of the impacted canines. A modified lip bumper appliance was used both for forced eruption and to reinforce anchorage. Through the collaborative efforts of an orthodontist and an oral surgeon, an excellent esthetic and functional outcome was achieved. PMID- 23452975 TI - Bilateral craniofacial microsomia: orthognathic treatment for an advanced dentofacial deformity. AB - In this article, we report the combined surgical and orthodontic treatment for a patient with bilateral craniofacial microsomia and facial asymmetry. PMID- 23452976 TI - Combining traditional techniques to correct anterior open bite and posterior crossbite. AB - The treatment of anterior open bite often requires the use of skeletal anchorage to prevent excessive eruption of the posterior teeth and consequent downward rotation of the mandible. However, this procedure might not always be accomplished. This article reports the successful treatment of an anterior open bite and a posterior crossbite in a young boy, combining traditional techniques and involving high-pull maxillary traction to help growth to correct the skeletal Class II malocclusion without skeletal anchorage. The vertical dentoalveolar contribution of maxillary growth was also favorable to close the bite, whereas cross-elastics corrected the axial inclination of the mandibular posterior teeth, eliminating the inverted posterior crossbite. The open bite was completely closed with edgewise appliances, which also achieved normal overjet, intercuspation, and incisor exposure on smiling. Traditional mechanics for the treatment of open bite and crossbite remain a useful alternative when patients do not accept skeletal anchorage. PMID- 23452977 TI - Orthodontic treatment of a patient with dentin dysplasia type I. AB - Dentin dysplasia is a genetic disorder of the teeth that affects the dentin and the pulp. Type I is sometimes called "rootless teeth," because of the loss of organization of the root dentin, which often leads to a shortened root length. The purpose of this article was to present a rare clinical case of a girl who was diagnosed with dentin dysplasia type I when she was referred for an orthodontic evaluation. Panoramic and periapical radiographs showed defective root formation and areas with periapical radiolucencies in several teeth. Her Angle Class I malocclusion was successfully treated, providing esthetic and functional results, without clinical symptoms or signs of periodontitis or odontogenic infections. PMID- 23452978 TI - Application of a new viscoelastic finite element method model and analysis of miniscrew-supported hybrid hyrax treatment. AB - INTRODUCTION: In this study, we aimed to assess the ability of a new viscoelastic finite element method model to accurately simulate rapid palatal expansion with a miniscrew-supported hybrid hyrax appliance. METHODS: A female patient received 3 dimensional craniofacial imaging with computed tomography at 2 times: before expansion and immediately after expansion, with the latter serving as a reference model for the analysis. A novel approach was applied to the finite element method model to improve simulation of the viscoelastic properties of osseous tissue. RESULTS: The resulting finite element method model was a suitable approximation of the clinical situation and adequately simulated the forced expansion of the midpalatal suture. Specifically, it demonstrated that the hybrid hyrax appliance delivered a force via the 2 mini-implants at the center of resistance of the nasomaxillary complex. CONCLUSIONS: The newly developed model provided a suitable simulation of the clinical effects of the hybrid hyrax appliance, which proved to be a suitable device for rapid palatal expansion. PMID- 23452979 TI - Litigation and legislation. Qualifying the expert witness. PMID- 23452980 TI - Multiplicity 1: subgroup analyses. PMID- 23452981 TI - Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. AB - BACKGROUND: Measurement of genome-wide DNA methylation (DNAm) has become an important avenue for investigating potential physiologically-relevant epigenetic changes. Illumina Infinium (Illumina, San Diego, CA, USA) is a commercially available microarray suite used to measure DNAm at many sites throughout the genome. However, it has been suggested that a subset of array probes may give misleading results due to issues related to probe design. To facilitate biologically significant data interpretation, we set out to enhance probe annotation of the newest Infinium array, the HumanMethylation450 BeadChip (450 k), with >485,000 probes covering 99% of Reference Sequence (RefSeq) genes (National Center for Biotechnology Information (NCBI), Bethesda, MD, USA). Annotation that was added or expanded on includes: 1) documented SNPs in the probe target, 2) probe binding specificity, 3) CpG classification of target sites and 4) gene feature classification of target sites. RESULTS: Probes with documented SNPs at the target CpG (4.3% of probes) were associated with increased within-tissue variation in DNAm. An example of a probe with a SNP at the target CpG demonstrated how sample genotype can confound the measurement of DNAm. Additionally, 8.6% of probes mapped to multiple locations in silico. Measurements from these non-specific probes likely represent a combination of DNAm from multiple genomic sites. The expanded biological annotation demonstrated that based on DNAm, grouping probes by an alternative high-density and intermediate density CpG island classification provided a distinctive pattern of DNAm. Finally, variable enrichment for differentially methylated probes was noted across CpG classes and gene feature groups, dependant on the tissues that were compared. CONCLUSION: DNAm arrays offer a high-throughput approach for which careful consideration of probe content should be utilized to better understand the biological processes affected. Probes containing SNPs and non-specific probes may affect the assessment of DNAm using the 450 k array. Additionally, probe classification by CpG enrichment classes and to a lesser extent gene feature groups resulted in distinct patterns of DNAm. Thus, we recommend that compromised probes be removed from analyses and that the genomic context of DNAm is considered in studies deciphering the biological meaning of Illumina 450 k array data. PMID- 23452982 TI - Endovascular treatment for traumatic thoracic aortic pseudoaneurysm: a case report. AB - Cases of an endovascular treatment for traumatic aortic injury are extremely rare. A prompt diagnosis of traumatic thoracic aortic pseudoaneurysm through a 3 dimensional computed tomographic angiography of aorta and emergency repair are mandatory to rescue the life-threatening condition. An endovascular treatment is a trend for traumatic aortic injury because of lower invasivity, morbidity and mortality. We reported a rare case of traumatic aortic injury with thoracic aortic pseudoaneurysm definitively diagnosed by the reconstructional computed tomographic angiography of aorta and successfully treated with endovascular stent graft. PMID- 23452983 TI - Antioxidant and antiproliferative activities of Abrus precatorius leaf extracts- an in vitro study. AB - BACKGROUND: The use of traditional medicine at the primary health care level is widespread and plant-based treatments are being recommended for curing various diseases by traditional medical practitioners all over the world. The phytochemicals present in the fruits, vegetables and medicinal plants are getting attention day-by-day for their active role in the prevention of several human diseases. Abrus precatorius is a widely distributed tropical medicinal plant with several therapeutic properties. Therefore in the present study, A. precatorius leaf extracts were examined for their antioxidant and cytotoxic properties in vitro in order to discover resources for new lead structures or to improve the traditional medicine. METHODS: In this study, antioxidant and antiproliferative properties of the different leaf extracts (hexane, ethyl acetate, ethanol and water) from A. precatorius were investigated along with the quantification of the polyphenol and flavonoid contents. The ability of deactivating free radicals was extensively investigated with in vitro biochemical methods like DPPH(?), (?)OH, NO, SO(2-) scavenging assays and inhibition capability of Fe(II)-induced lipid peroxidation. Furthermore, antiproliferative activities using different human cancer cell lines and primary cell line was carried out by MTT method. RESULTS: Total phenolic content and total flavonoid content of the extracts were found in the range of 1.65 +/- 0.22 to 25.48 +/- 0.62 GAE mg/g dw and 6.20 +/- 0.41 to 17.16 +/- 1.04 QE mg/g dw respectively. The experimental results further revealed that A. precatorius extracts showed strong antiradical properties, capable to chelate Fe(2+) and possess good inhibition ability of lipid peroxidation. In addition, as a first step towards the identification of phytoconstituents endowed with potent chemopreventive activities, we evaluated the inhibitory effects of A. precatorius extracts on the proliferation of four different human tumour cell lines such as human colon adenocarcinoma cells (Colo-205), human retinoblastoma cancer cells (Y79), human hepatocellular carcinoma cells (HepG2) and Leukemia cells (SupT1). Ethanol extract (APA) and ethyl acetate extract (APE) of A. precatorius had apparent capabilities of inhibiting the survival of tested human cancer cell lines. Moreover, it was observed that the A. precatorius extracts did not inhibit the growth of mice peritoneal macrophages, thus confirming that plants extracts are selective against the cancer cell lines. CONCLUSION: This work provides a scientific support for the high antioxidant and antiproliferative activity of this plant and thus it may find potential applications in the treatment of the diseases caused by ROS. Further studies are needed to confirm in vivo anti-tumorgenicity and subsequent chemical characterization of the active molecule(s). PMID- 23452984 TI - Differential expression of beta-catenin and Dickkopf-1 in the third trimester placentas from normal and preeclamptic pregnancies: a comparative study. AB - BACKGROUND: Beta-catenin is a key nuclear effector of Wnt signaling which could be antagonized by dickkopf-1(DKK1). Beta-catenin and DKK1 are involved in a variety of biological processes; however, their expression in the placenta with severe preeclampsia (PE) has not been elucidated. This study was aimed to detect the localization and compare the expression of beta-catenin and DKK1 in normal and preeclamptic placenta. METHODS: Sixty pregnant women who underwent cesarean section were enrolled in this study, including 30 healthy pregnant women in the control group and 30 preeclamptic women in the severe PE group. Real-time polymerase chain reaction (real-time-PCR) and western blot were employed to detect the beta-catenin and DKK1 mRNA and protein expression levels, respectively, and their locations were evaluated by immunohistochemistry (IHC). RESULTS: Our results indicated that beta-catenin and DKK1 were expressed predominantly in the syncytiotrophoblast and the extravillous trophoblast (EVT). The beta-catenin mRNA and protein expressions were significantly decreased, whereas the DKK1 significantly increased in preeclamptic placental tissues compared to normal placental controls. CONCLUSIONS: In conclusion, decreased beta catenin expression, as well as DKK1 over-expression might be associated with the process of the pathogenesis of PE. Further studies would elucidate their exact roles in the pathogenesis of PE. PMID- 23452985 TI - Carbonic anhydrases. PMID- 23452987 TI - Accuracy of a clinical PET/CT vs. a preclinical MUPET system for monitoring treatment effects in tumour xenografts. AB - PURPOSE: Small animal imaging is of growing importance for preclinical research and drug development. Tumour xenografts implanted in mice can be visualized with a clinical PET/CT (cPET); however, it is unclear whether early treatment effects can be monitored. Thus, we investigated the accuracy of a cPET versus a preclinical MUPET using (18)F-FDG for assessing early treatment effects. MATERIALS AND METHODS: The spatial resolution and the quantitative accuracy of a clinical and preclinical PET were evaluated in phantom experiments. To investigate the sensitivity for assessing treatment response, A431 tumour xenografts were implanted in nude mice. Glucose metabolism was measured in untreated controls and in two therapy groups (either one or four days of antiangiogenic treatment). Data was validated by gamma-counting of explanted tissues. RESULTS: In phantom experiments, cPET enabled reliable separation of boreholes>=5mm whereas MUPET visualized boreholes>=2mm. In animal studies, MUPET provided significantly higher tumour-to-muscle ratios for untreated control tumours than cPET (3.41+/-0.87 vs. 1.60+/-.0.28, respectively; p<0.01). During treatment, cPET detected significant therapy effects at day 4 (p<0.05) whereas MUPET revealed highly significant therapy effects even at day one (p<0.01). Correspondingly, gamma-counting of explanted tumours indicated significant therapy effects at day one and highly significant treatment response at day 4. Correlation with gamma-counting was good for cPET (r=0.74; p<0.01) and excellent for MUPET (r=0.85; p<0.01). CONCLUSION: Clinical PET is suited to investigate tumour xenografts>=5mm at an advanced time-point of treatment. For imaging smaller tumours or for the sensitive assessment of very early therapy effects, MUPET should be preferred. PMID- 23452988 TI - Ovarian tissue cryopreserved for fertility preservation from patients with Ewing or other sarcomas appear to have no tumour cell contamination. AB - AIM: The chemotherapy required to treat patients with sarcoma may as a side effect induce infertility in girls and young women. If these patients have ovarian cortical tissue cryopreserved prior to chemotherapy, they may, if necessary, have the tissue transplanted and restore their fertility. The aim of this study was to evaluate the risk of residual cancer cells in the ovarian cortex intended for transplantation. PATIENTS AND METHODS: Ovarian tissue stored for fertility preservation from 16 surviving patients diagnosed with sarcoma (nine with Ewing sarcomas, four with osteosarcomas, two with synovial sarcomas and one with chondrosarcoma) was evaluated for the presence of malignant cells by histology and by transplantation to immunodeficient mice for 20 weeks. A fraction of the tissue from patients with Ewing sarcoma was also evaluated for the presence of the molecular marker EWS-FLI1 by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The transplant itself and selected murine organs were analysed for the presence of malignant cells by histology. RESULTS: All the mice accommodated the human tissue for 20 weeks of transplantation period with none of the mice developing any sign of cancer. In no instance were any cancer cells detected by histology or RT-qPCR. CONCLUSION: Ovarian tissue from patients with sarcoma appears to be without metastatic malignant cells in numbers that allow detection. Although the actual pieces of ovarian tissue used for transplantation remain unchecked, the current data indicate that the procedure is safe at least in patients that survive the sarcoma disease. PMID- 23452989 TI - Letter in response to the Wedlake et al. paper 'Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies'. PMID- 23452986 TI - Use of dietary supplements in pregnant women in relation to sociodemographic factors - a report from The Environmental Determinants of Diabetes in the Young (TEDDY) study. AB - OBJECTIVES: The aim of the present study was to examine the prevalence and associated factors of dietary supplement use, particularly supplements containing vitamin D and fatty acids, in pregnant women enrolled in a multi-national study. DESIGN: The Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective longitudinal cohort study. Maternal dietary supplement use was self reported through questionnaires at month 3 to 4 postpartum. SETTING: Six clinical research centres; three in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Sweden, Finland and Germany). SUBJECTS: Mothers (n 7326) to infants screened for high-risk HLA-DQ genotypes of type 1 diabetes. RESULTS: Ninety-two per cent of the 7326 women used one or more types of supplement during pregnancy. Vitamin D supplements were taken by 65% of the women, with the highest proportion of users in the USA (80.5 %). Overall, 16% of the women reported taking fatty acid supplements and a growing trend was seen in all countries between 2004 and 2010 (P,0.0001). The use was more common in Germany (32 %) and the USA (24 %) compared with Finland (8.5%) and Sweden (7.0 %). Being pregnant with the first child was a strong predictor for any supplement use in all countries. Low maternal age (<25 years), higher education, BMI<=25.0 kg/m2 and smoking during pregnancy were factors associated with supplement use in some but not all countries. CONCLUSIONS: The majority of the women used dietary supplements during pregnancy. The use was associated with sociodemographic and behavioural factors, such as parity, maternal age, education, BMI and maternal smoking. PMID- 23452990 TI - Comparison of human papillomavirus testing strategies for triage of women referred with low-grade cytological abnormalities. AB - AIM: To compare triage strategies using different human papillomavirus (HPV) consensus and genotyping tests and a p16(INK4a) test. METHODS: 1228 women referred with a borderline or single mildly dyskaryotic smear. Samples were taken at colposcopy using PreservCyt. Tests included Hybrid Capture 2, Abbott RealTime PCR, BD HPV, Cobas 4800, PreTect HPV-Proofer, APTIMA and p16(INK4a). Results were based on the worst histology within 9 months. RESULTS: 97/1228 (7.9%) women had CIN3+ (203/1228 (17%) CIN2+). HPV testing alone using Hybrid Capture 2, Abbott RealTime PCR, BD HPV, Cobas 4800 or APTIMA had a sensitivity for CIN3+ ranging from 99.0% to 100.0% and specificity for 0.05) in healthy controls and in T2DM patients with and without retinopathy. CONCLUSION: Aqueous humor from T2DM patients with retinopathy exhibits elevated antioxidant activity with significant suppressive effect on ROS production and enhanced levels of locally secreted VEGF and IL-6 in comparison with T2DM patients without retinopathy. These results suggest an inflammatory profile in the absence of typical oxidative stress for T2DM patients with retinopathy, possibly resulting from the compensatory antioxidant response detected in the aqueous humor improving the ocular redox state. PMID- 23452994 TI - Quantification of epicardial fat by computed tomography: why, when and how? AB - In the past decade, interest has grown in the relation between epicardial fat and cardiovascular disease. Several imaging modalities such as echocardiography, computed tomography, and magnetic resonance imaging can be used to quantify epicardial adipose tissue. Computed tomography provides high spatial resolution and true volume coverage of the heart; therefore, it constitutes an attractive approach to quantifying epicardial fat. An increasing body of evidence has been accumulated which shows a relation between epicardial fat volume and coronary atherosclerosis, cardiovascular outcomes, and even non-atherosclerotic heart disease such as atrial fibrillation. The association of increased epicardial fat volume with cardiac disease remains significant even after correction for weight, body mass index, and traditional cardiovascular risk factors. The mechanisms have not been reliably identified, but metabolic properties of epicardial fat may play a role. At the present time, epicardial fat quantification is not included in recommended algorithms for risk stratification. However, the available data are intriguing enough to warrant further research. PMID- 23452995 TI - Congenital absence of the pericardium and its mimics. AB - Congenital absence of the pericardium is a rare entity, with less than 400 cases reported in the literature. Pericardial absence is typically left sided, which results in herniation of the great vessels or portions of the heart. Patients may be asymptomatic, typical for complete defects, or can present with various degrees of chest pain in the setting of partial absence and strangulation. The finding may be isolated or associated with complex heart disease. We present a number of cases of pericardial absence that show isolated right- and left-sided defects, as well as entities in the differential diagnosis. Early recognition may decrease morbidity and mortality, resulting from delay in proper treatment. PMID- 23452996 TI - A prospective randomized trial comparing image quality, study interpretability, and radiation dose of narrow acquisition window with widened acquisition window protocols in prospectively ECG-triggered coronary computed tomography angiography. AB - BACKGROUND: Prospectively triggered coronary computed tomography angiography (CTA) is commonly performed with a widened acquisition window to provide flexibility in image reconstruction. OBJECTIVE: We conducted a randomized controlled trial to determine whether the use of a narrow acquisition window in prospectively triggered coronary CTA would allow lower radiation dose while preserving image quality and interpretability. METHODS: Prospective 2-center 2- platform randomized trial that evaluated 205 consecutive patients 96 with widened acquisition (WA) and 109 narrow acquisition (NA) referred for coronary CTA in sinus rhythm and heart rate <65 beats/min. Patients scanned with WA had phases reconstructed at 5% intervals, and each phase was assigned an individual study ID. Images were reviewed with individual phase reconstructions interpreted randomly by 2 level 3 readers with a third for consensus. Images were evaluated with a 5-point Likert scale on a per-vessel basis (best score on any phase). Scores were then dichotomized into diagnostic (score 3-5) compared with nondiagnostic (score 1-2). Readers also reported obstructive coronary artery disease on a per-patient basis. Agreement for the diagnosis of obstructive disease and per-artery interpretability was performed. Signal and noise measurements were also performed. RESULTS: No difference in demographics between groups (P = NS). The signal-to-noise ratio was comparable 12.99 +/- 3.4 NA and 12.53 +/- 4.13 for the WA (P = 0.45). The median effective dose was 1.78 mSv for NA compared with 3.26 mSv for WA (P < 0.001). Image quality, diagnostic interpretability, interreader agreement, and downstream testing were not significantly different between the 2 groups (P= NS for all). CONCLUSIONS: Coronary CTA with NA resulted in a 47% lower radiation dose without significant difference in study interpretability or image quality or increased downstream resource use or testing. PMID- 23452997 TI - First experience with monochromatic coronary computed tomography angiography from a 64-slice CT scanner with Gemstone Spectral Imaging (GSI). AB - BACKGROUND: New technology combining dual-energy CT with the latest gemstone detectors for spectral imaging (GSI) can be used to synthesize monochromatic images that mimic images as if different monochromatic x-ray sources were used. OBJECTIVE: The aim of the study was to evaluate the optimal combination of monochromatic image energy and adaptive statistical iterative reconstruction (ASiR) for monochromatic reconstruction of coronary CT angiography (CTA) images with the use of GSI. METHODS: Twenty consecutive patients underwent coronary CTA on a GSI capable 64-slice CT scanner (Discovery CT 750 High Definition, GE Healthcare). In 7 sets of monochromatic images (60, 65, 70, 75, 80, 90, and 110 keV; each with increasing contributions of ASiR, ie, 0%, 20%, 40%, 60%, and 80%; n = 35 reconstructions per patient), signal-to-noise (aortic root) and contrast to-noise (left main artery) ratios were assessed. Signal-to-noise ratio, contrast to-noise ratio, and image quality (graded on a 5-point Likert scale) were assessed in all above monochromatic reconstructions and compared with the respective standard (conventional polychromatic) image. RESULTS: Compared with conventional polychromatic images, reconstructions with 60 keV and 80% ASiR showed the highest improvement in contrast-to-noise (144%; P < 0.001) and signal to-noise ratio (173%; P < 0.001). Image quality reached a plateau at 65-75 keV with 40%-60% ASiR blending, yielding a maximal image quality score improvement of 50% compared with conventional imaging (P < 0.001). CONCLUSION: In coronary CTA with low radiation technique (mean radiation dose, 1.8 +/- 0.7 mSv), GSI with monochromatic reconstructions (65-75 keV) and ASiR (40%-60%) offers significant noise reduction and image quality improvement. PMID- 23452998 TI - The new healthcare payment system: can coronary CT angiography help? PMID- 23452999 TI - Modeling hydrology, groundwater recharge and non-point nitrate loadings in the Himalayan Upper Yamuna basin. AB - The mountainous Himalayan watersheds are important hydrologic systems responsible for much of the water supply in the Indian sub-continent. These watersheds are increasingly facing anthropogenic and climate-related pressures that impact spatial and temporal distribution of water availability. This study evaluates temporal and spatial distribution of water availability including groundwater recharge and quality (non-point nitrate loadings) for a Himalayan watershed, namely, the Upper Yamuna watershed (part of the Ganga River basin). The watershed has an area of 11,600 km(2) with elevation ranging from 6300 to 600 m above mean sea level. Soil and Water Assessment Tool (SWAT), a physically-based, time continuous model, has been used to simulate the land phase of the hydrological cycle, to obtain streamflows, groundwater recharge, and nitrate (NO3) load distributions in various components of runoff. The hydrological SWAT model is integrated with the MODular finite difference groundwater FLOW model (MODFLOW), and Modular 3-Dimensional Multi-Species Transport model (MT3DMS), to obtain groundwater flow and NO3 transport. Validation of various modules of this integrated model has been done for sub-basins of the Upper Yamuna watershed. Results on surface runoff and groundwater levels obtained as outputs from simulation show a good comparison with the observed streamflows and groundwater levels (Nash-Sutcliffe and R(2) correlations greater than +0.7). Nitrate loading obtained after nitrification, denitrification, and NO3 removal from unsaturated and shallow aquifer zones is combined with groundwater recharge. Results for nitrate modeling in groundwater aquifers are compared with observed NO3 concentration and are found to be in good agreement. The study further evaluates the sensitivity of water availability to climate change. Simulations have been made with the weather inputs of climate change scenarios of A2, B2, and A1B for end of the century. Water yield estimates under climate change scenarios have been made and implications on groundwater and groundwater quality have been assessed. The delicate groundwater resource balance that connects livelihoods of millions of people seems to be under tremendously increasing pressure due to the dynamic conditions of the natural environment of the region and the future climate changes. PMID- 23453000 TI - Quantification of heterogeneity observed in medical images. AB - BACKGROUND: There has been much recent interest in the quantification of visually evident heterogeneity within functional grayscale medical images, such as those obtained via magnetic resonance or positron emission tomography. In the case of images of cancerous tumors, variations in grayscale intensity imply variations in crucial tumor biology. Despite these considerable clinical implications, there is as yet no standardized method for measuring the heterogeneity observed via these imaging modalities. METHODS: In this work, we motivate and derive a statistical measure of image heterogeneity. This statistic measures the distance-dependent average deviation from the smoothest intensity gradation feasible. We show how this statistic may be used to automatically rank images of in vivo human tumors in order of increasing heterogeneity. We test this method against the current practice of ranking images via expert visual inspection. RESULTS: We find that this statistic provides a means of heterogeneity quantification beyond that given by other statistics traditionally used for the same purpose. We demonstrate the effect of tumor shape upon our ranking method and find the method applicable to a wide variety of clinically relevant tumor images. We find that the automated heterogeneity rankings agree very closely with those performed visually by experts. CONCLUSIONS: These results indicate that our automated method may be used reliably to rank, in order of increasing heterogeneity, tumor images whether or not object shape is considered to contribute to that heterogeneity. Automated heterogeneity ranking yields objective results which are more consistent than visual rankings. Reducing variability in image interpretation will enable more researchers to better study potential clinical implications of observed tumor heterogeneity. PMID- 23453001 TI - Sudden death in a case of sickle cell anemia: post-mortem computed tomography and autopsy correlation from a radiologist's perspective. AB - Sickle cell anemia (SCA) is a hemolytic disease characterized by the production of abnormal hemoglobin chains and distorted red blood cell morphology or sickling. "Sickle cell crisis" includes vaso-occlusive crisis, a plastic crisis, sequestration crisis, haemolytic crisis and often culminating in serious complications, organ damage and even sudden death. Post-mortem computed tomography (PMCT) findings of sickle cell disease have never been reported in literature. This case of sudden death from acute hemolytic crisis in SCA where post-mortem computed tomography (PMCT) and autopsy findings complemented each other, both revealing findings invisible to the other and both crucial to the case. PMID- 23453002 TI - Planning and adjustments for the control of reach extent in a virtual environment. AB - BACKGROUND: Skilled performance of reach actions includes both anticipatory planning and compensatory adjustments made while moving. The execution of reach actions in a virtual environment (VE) demonstrates similar characteristics to reaches performed in the real-world, however, it is unclear whether the VE itself significantly impacts movement planning or compensatory adjustments. The purpose of this study was to directly compare the use of planning and adjustments to control extent for unconstrained reach actions performed in an immersive VE to those performed in an analogous real-world environment (RWE). METHODS: Five non disabled adults (29+/-5 years) reached with the dominant, right arm to six targets presented in two directions (+45 degrees , -45 degrees ) and three distances (8, 16, 24 cm) in a VE and an analogous RWE. Position data were sampled at 120 Hz from an electromagnetic marker on the index finger and differentiated to determine velocity and acceleration. The control of reach extent was compared between the two environments (paired t-test) as to the use of planning (correlation of peak acceleration with movement distance), compensatory adjustments prior to peak velocity (correlation of time to peak velocity with movement distance), and compensatory adjustments after peak velocity (variance in movement distance accounted for by deterministic statistical model). RESULTS: Reach movements were relatively fast (<400 msec) and scaled to target distance in both the VE and RWE. Overall, the control of reach extent was similar in all respects between the two environments. In both environments, a hybrid control pattern was observed. That is, individuals utilized a combined strategy that relied on both planning and compensatory adjustments to capture the target. Adjustments to the reach were evident prior to peak velocity through changes in acceleration duration as well as after peak velocity based on target information. The two factor deterministic statistical model (peak velocity, target distance) explained >92% of the variance in movement distance across participants and environments. CONCLUSIONS: The VE did not impact movement planning or subsequent compensatory adjustments for the control of reach extent when directly compared to an analogous RWE. An immersive VE is a valid environment for the study of unconstrained reach actions. PMID- 23453004 TI - Chemical fingerprinting and quantitative constituent analysis of Siwu decoction categorized formulae by UPLC-QTOF/MS/MS and HPLC-DAD. AB - BACKGROUND: Siwu decoction categorized formulae (SWDCF) are widely used for treating gynecological diseases. This study aims to elucidate the differences of bioactive constituents in SWDCF by ultra-high performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC - QTOF - MS /MS) and HPLC DAD. METHODS: An efficient method based on UPLC - QTOF - MS /MS was developed for identifying the chemical profiles of SWDCF. HPLC-DAD method was used for quantifying seven chemical markers in SWDCF. RESULTS: Eighty four components were identified or characterized, including ten organic acids, thirty glycosides (monoterpene or iridoid or phenylpropanoids glycosides), fourteen lactones, eighteen flavonoids, and eleven alkaloids in the complex system. The datasets of tR-m/z pairs, ion intensities and sample codes were processed with supervised orthogonal partial least squared discriminant analysis to compare these decoction samples. After a clear classification was established, OPLS-DA was performed and 16 common components with relative quantity in SWDCF samples were determined. Gallic acid, protocatechuic acid, vanillic acid, caffeic acid, paeoniflorin, ferulic acid, and senkyunolide I were selected as the chemical markers to identify SWDCF by HPLC-DAD. CONCLUSION: The chemical profiles with 84 components in SWDCF, including monoterpene glycosides, acetophenones, galloyl glucoses, even some isomers in the complex system were characterized by UPLC-QTOF-MS/MS. PMID- 23453003 TI - Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. AB - Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures. PMID- 23453005 TI - Giant left atrium associated with massive thrombus formation. AB - Giant left atrium is a condition characterized by huge enlargement of the left atrium with a diameter exceeding 65mm. It is most commonly associated with long standing rheumatic mitral valve disease. We present a 45-year-old female patient with rheumatic mitral stenosis associated with giant left atrium occupied by an 11 * 10 * 5 cm thrombus weighing 500 gms. The patient underwent successful mitral valve replacement and thrombectomy through an inverted T-shaped biatrial incision. PMID- 23453007 TI - Associations among blood pressure, salt consumption and body weight status of students from south-western Ontario. AB - OBJECTIVE: The purpose was to examine the associations among body weight status, blood pressure and daily Na intake among grade 7 students from south-western Ontario, Canada. DESIGN: Cross-sectional. Data were collected using the Food Behaviour Questionnaire, including a 24 h diet recall. Measured height and weight were used to determine BMI. Blood pressure was taken manually using mercury sphygmomanometers. SETTING: Twenty-six schools in south-western Ontario, Canada. SUBJECTS: Grade 7 students (n 1068). RESULTS: Body weight status indicated 1 % were underweight, 56 % normal weight, 23 % overweight and 20 % were obese. Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 108.3 (sd 10.3) mmHg and 66.0 (sd 7.5) mmHg, respectively, and mean Na intake was 2799 (sd 1539) mg/d. Bivariate analyses suggested that SBP (P < 0.001) and DBP (P < 0.001) were significantly different by body weight status, yet no associations were observed for Na. Adjusted for gender, ethnicity and under-reporting, participants were more likely to be overweight/obese if they had higher SBP (v. lower: OR = 1.06, 95 % CI 1.05, 1.08, P < 0.001), higher DBP (v. lower: OR = 1.02, 95 % CI 1.00, 1.04, P = 0.043) and higher intakes of Na (3rd v. 1st quartile: OR = 1.72, 95 % CI 1.14, 2.59, P = 0.009; 4th v. 1st quartile: OR = 2.88, 95 % CI, 1.76, 4.73, P < 0.001). CONCLUSIONS: High intakes of Na, coupled with high SBP and DBP, were associated with overweight and obesity status among the grade 7 sample from south-western Ontario, Canada. PMID- 23453006 TI - Effects of ectopic HER-2/neu gene expression on the COX-2/PGE2/P450arom signaling pathway in endometrial carcinoma cells: HER-2/neu gene expression in endometrial carcinoma cells. AB - OBJECTIVES: To investigate the role of HER-2/neu-mediated COX-2/P450arom signal in estrogen-dependent endometrial carcinoma. METHODS: The recombinant eukaryotic expression vector, pcDNA3.1-HER-2/neu, was constructed and transfect to Ishikawa endometrial carcinoma cells. The expression of COX-2 and P450arom in transfected cells were detected by real-time PCR and western blotting. The levels of estrogen in cell supernatants were detected by ELISA. RESULTS: Over-expression of HER 2/neu in transfected cells was confirmed by real-time PCR and western blotting. The levels of autocrine estrogen in transfected cells was significantly increased which combination with the enhancement of COX-2 and P450arom expression in transfected cells. CONCLUSION: HER-2/neu induced the improvement of autocrine estrogen in endometrial carcinoma cell through triggering the COX-2/P450arom signal. PMID- 23453008 TI - Can mycobacterial katG genetic changes in isoniazid-resistant tuberculosis influence human disease features? AB - BACKGROUND: Isoniazid-resistant (INHr) Mycobacterium tuberculosis isolates often have katG mutations, and katG is a virulence factor in animal models. It is unclear if katG mutations or other mutations influence the characteristics of human disease. OBJECTIVE: To determine if the presence of INHr-conferring mutations were associated with distinct clinical features of tuberculosis (TB). METHODS: In a retrospective case-control study, INHr-conferring mutations were determined by DNA sequencing. We examined associations between clinical characteristics in patients with INHr M. tuberculosis (stratified by groups of relevant INHr-conferring mutations, including katG-S315T and inhA-C(-)15T mutations) and pan-susceptible (PS) isolates. RESULTS: Twenty-nine INHr TB cases and 50 PS controls were evaluated. Disease characteristics were not statistically different between INHr and PS cases. However, patients infected with non-katG mutants were associated with a higher rate of sputum culture conversion at 1 month after adjustment for relevant covariates (adjusted OR [aOR] 4.4, 95%CI 1.1 23.6, P = 0.04). Patients infected with katG mutants were associated with a higher rate of unilateral disease (aOR 4.7, 95%CI 1.0-34.3, P = 0.05). CONCLUSIONS: Most INHr TB cases with non-katG mutations have disease associated with faster response to treatment, and most cases with katG mutants have localized lung involvement. PMID- 23453009 TI - It takes a team.... PMID- 23453010 TI - Clinical and socio-demographic predictors of postoperative vital exhaustion in patients after cardiac surgery. AB - BACKGROUND: Vital exhaustion, a psychological state characterized by extreme fatigue, is an independent predictor of future cardiac events. However, the attributes of vital exhaustion following coronary artery bypass (CABG) surgery are poorly understood. OBJECTIVE: The study objective was to assess correlates of vital exhaustion following CABG surgery. METHODS: In a descriptive, exploratory study, 42 patients who had CABG surgery were evaluated for exhaustion 4-8 weeks post-hospital discharge. Demographic and clinical data were obtained from self report and medical chart review. RESULTS: Of the total sample (mean age 67.9 +/- 12.5, 90% male, 70% Caucasian, 3.12 +/- 1.3 grafts), approximately 41% reported exhaustion. When compared to their exhausted post-CABG counterpart, non-exhausted post-CABG patients had a significantly higher frequency of preoperative insulin use. Exhausted patients were significantly more likely to have higher left ventricular ejection fraction ([LVEF], OR: 1.07, p = 0.04), and elevated hemoglobin (OR: 2.98, p = 0.03) and eosinophils (OR: 1.02, p = 0.02) than those who were not exhausted. CONCLUSION: Clinicians should evaluate all patients for exhaustion post-CABG surgery; patients with elevated LVEF, hemoglobin, and eosinophil levels warrant increased scrutiny. PMID- 23453011 TI - Effects of intensive glycemic control on outcomes of cardiac surgery. AB - OBJECTIVES: To investigate the effects of postoperative intensive glycemic control on patient outcomes. BACKGROUND: Ineffective perioperative glycemic control has been associated with high mortality and morbidity rates among cardiac surgery patients. METHODS: 212 cardiac surgery patients were allocated by a quasi experimental design to: a) a control group (n = 107) with targeted blood glucose levels 161-200 mg/dl or b) a therapy group (n = 105) with blood glucose target 120-160 mg/dl. We compared the two groups on their mortality, length of stay, duration of intubation, incidence of severe hypoglycemia and frequency of postoperative infections. RESULTS: The mean postoperative blood glucose levels were significantly lower for the therapy group compared with the control group (153.9 mg/dl vs. 173.9 md/dl, p < 0.001). The intensive glycemic control was strongly associated with decreased in-hospital mortality (7 deaths/105 patients for the control group vs. 1 death/105 patients for the therapy group; p = 0.033). We did not identify any statistically significant associations regarding the other patient outcomes. CONCLUSIONS: This randomized quasi-experimental trial found lower in-hospital mortality with more intense blood glucose control. Effective postoperative glycemic control did not affect the other studied patient outcomes. PMID- 23453012 TI - Urinary incontinence in people with chronic heart failure. Reply to a letter to the Editor. PMID- 23453013 TI - Pentraxin 3: An early marker of severity in higher mortality disease. PMID- 23453014 TI - My journey to DNA repair. AB - I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have discovered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mammalian exonucleases DNase III (TREX1) and IV (FEN1). Interestingly, expression of TREX1 was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O(6)-methylguanine (O(6)mG) is repaired without removing the guanine from DNA, identifying a surprising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron dependent enzyme carrying out oxidative demethylation. PMID- 23453016 TI - Recent advances in computational methods for nuclear magnetic resonance data processing. AB - Although three-dimensional protein structure determination using nuclear magnetic resonance (NMR) spectroscopy is a computationally costly and tedious process that would benefit from advanced computational techniques, it has not garnered much research attention from specialists in bioinformatics and computational biology. In this paper, we review recent advances in computational methods for NMR protein structure determination. We summarize the advantages of and bottlenecks in the existing methods and outline some open problems in the field. We also discuss current trends in NMR technology development and suggest directions for research on future computational methods for NMR. PMID- 23453017 TI - Comparative analysis of microRNA promoters in Arabidopsis and rice. AB - Endogenously-encoded microRNAs (miRNAs) are a class of small regulatory RNAs that modulate gene expression at the post-transcriptional level. In plants, miRNAs have increasingly been identified by experiments based on next-generation sequencing (NGS). However, promoter organization is currently unknown for most plant miRNAs, which are transcribed by RNA polymerase II. This deficiency prevents a comprehensive understanding of miRNA-mediated gene networks. In this study, by analyzing full-length cDNA sequences related to miRNAs, we mapped transcription start sites (TSSs) for 62 and 55 miRNAs in Arabidopsis and rice, respectively. The average free energy (AFE) profiles in the vicinity of TSSs were studied for both species. By employing position weight matrices (PWM) for 99 plant cis-elements, we discovered that three cis-elements were over-represented in the miRNA promoters of both species, while four and ten cis-elements were over represented in Arabidopsis only and in rice only. Thus, comparison of miRNA promoters between Arabidopsis and rice provides a new perspective for studying miRNA regulation in plants. PMID- 23453015 TI - N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. AB - N(6)-methyl-adenosine (m(6)A) is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m(6)A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation of m(6)A may have a profound impact on gene expression regulation. The m(6)A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 (METTL3). m(6)A modification on messenger RNAs (mRNAs) mainly occurs in the exonic regions and 3'-untranslated region (3'-UTR) as revealed by high-throughput m(6)A-seq. One significant advance in m(6)A research is the recent discovery of the first two m(6)A RNA demethylases fat mass and obesity-associated (FTO) gene and ALKBH5, which catalyze m(6)A demethylation in an alpha-ketoglutarate (alpha-KG)- and Fe(2+)-dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from development and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role of m(6)A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m(6)A modification on RNA may also serve as a novel epigenetic marker of profound biological significances. PMID- 23453019 TI - Adults with congenital heart disease and previous interventions. PMID- 23453018 TI - Efficacy of modified LiuJunZi decoction on functional dyspepsia of spleen deficiency and qi-stagnation syndrome: a randomized controlled trial. AB - BACKGROUND: Chinese herbal medicine (CHM) has been used in China and some other countries for the treatment of patients with functional dyspepsia (FD). However, controlled studies supporting the efficacy of such treatments in patients with FD are lacking. In this trial, we aimed to assess the efficacy and safety of modified LiuJunZi decoction in patients with FD of spleen-deficiency and qi stagnation syndrome. METHODS: We performed a randomized, double-blind, placebo controlled trial with patients from five centers. Patients with FD of spleen deficiency and qi-stagnation syndrome (n = 160) were randomly assigned to groups given CHM modified LiuJunZi decoction or placebo in a 2:1 ratio. Herbal or placebo granules were dissolved in 300 ml of boiled water cooled to 70 degrees C. Patients in both groups were administered 150 ml (50 degrees C) twice daily. The trial included a 4-week treatment period and a 4-week follow-up period. The primary outcomes were dyspepsia symptom scores, measured by the total dyspepsia symptom scale and the single dyspepsia symptom scale at weeks 0, 1, 2, 3, 4 and 8. The secondary outcome was the change of radiopaque barium markers emptied from the stomach between week 0 and week 4 of treatment. RESULTS: Compared with patients in the placebo group, patients in the CHM group showed significant improvements according to the scores of total dyspepsia symptoms and single dyspepsia symptoms obtained from patients (P < 0.01) and investigators (P < 0.01). They also showed an improvement in the number of radiopaque barium markers emptied from the stomach (P < 0.05). CONCLUSIONS: CHM modified LiuJunZi decoction appears to offer symptomatic improvement in patients with FD of spleen-deficiency and qi-stagnation syndrome. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR): http://ChiCTR-TRC-10001074. PMID- 23453020 TI - Arrhythmogenic right ventricular dysplasia. AB - Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy and is also called ARVD/C. In most cases, ARVD is inherited in an autosomal dominant pattern and clinically is characterized by ventricular arrhythmias with an increased risk of sudden death. Although it is prominently a disease of the right ventricle (RV), involvement of the left ventricle is not uncommon. Pathologically, there is RV myocardial atrophy with thinning of the wall, aneurysm, and global RV dilatation. Genetic testing and magnetic resonance imaging of the RV are an increasing aspect of the diagnosis. Diagnosis relies on a scoring system with major or minor criteria. Prevention of sudden death is the primary goal of management. Pharmacologic treatment of arrhythmias, catheter ablation of ventricular tachycardia, and implantable cardioverter defibrillator are the mainstay of treatment of ARVD/C. PMID- 23453021 TI - WITHDRAWN: Ensifer psoraleae sp. nov. and Ensifer sesbaniae sp. nov., isolated from the root nodules of Psoralea corylifolia, Sesbania cannabina and other legumes. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23453022 TI - [Orthotopic liver transplantation in polycystic liver disease]. AB - INTRODUCTION: There is currently no effective medical therapy for polycystic liver (PCL). Cyst puncture and sclerotherapy, cyst fenestration, or partial hepatic resections have been used as palliative treatments. Orthotopic liver transplantation (OLT) has become the treatment of choice for terminal PCL, being indicated in patients with limiting symptoms not susceptible to any other medical treatment. It is also difficult to determine the priority on the waiting list using the Model for End-Stage Liver Disease (MELD). METHODS: A retrospective analysis of OLT for PCL was conducted in our centre. Inclusion criteria were patients with limiting symptoms, bilateral cysts liver, and insufficient remaining liver. In all cases a deceased donor liver transplantation with piggy back technique without veno-venous bypass was performed. RESULTS: Six patients underwent liver transplantation for PCL between April 1992 and April 2010, one of them a combined liver-kidney transplantation. The mean intraoperative packed red blood cell transfusion was 3.25 L and fresh frozen plasma was 1.200 cc. Mean operation time was 299 min, and 498 min in the liver-kidney transplantation. There was no peri-operative mortality. The mean hospital stay was 6.5 days. All patients are healthy after a mean follow-up of 71 months. CONCLUSION: OLT offers an excellent overall survival. Results are better when OLT is performed early; thus these patients should receive additional points to be able to use the MELD score as a valid prioritisation system for waiting lists. PMID- 23453023 TI - MLPA-based genotype-phenotype analysis in 1053 Chinese patients with DMD/BMD. AB - BACKGROUND: Large-scale analysis of the transmission, mutation characteristics and the relationship between the reading frame and phenotype of the DMD gene has previously been performed in several countries, however, analogous studies have yet to be performed in Chinese populations. METHODS: Clinical data from 1053 Chinese patients with DMD/BMD were collected, and the DMD gene was tested by MLPA in all patients and 400 proband mothers. In 20 patients with negative MLPA, sequencing was also performed. RESULTS: We found that 27.50% of cases had a family medical history of DMD/BMD, and large rearrangements were identified in 70.56% of the probands, of which 59.35% and 11.21% were deletions or duplications, respectively. The carrier status of the mothers in the study was determined to be 50.75%, and it was established that the DMD mutation was inherited from the mother in 51.72% of the probands. Exons 45-54 and 3-22 were the most frequently deleted regions, and exons 3-11 and 21-37 were the most prevalently duplicated regions of the gene. Breakpoints mainly occurred in introns 43-55 for deletion mutations and in introns 2 and 7 for duplication mutations. No breakpoints were found at the 5' or 3' end of introns 31, 35, 36, 40, 65, 68, and 74-78 in any of the deletion or duplication mutations. The reading frame rule held true for 86.4% of the DMD patients and 74.55% of the BMD patients. CONCLUSION: It is essential to increase physicians' understanding of DMD/BMD, to promote scientific information, and to increase awareness in regards to genetic counseling and prenatal diagnosis in pedigrees with a family history of the disease, particularly in families with small DMD lesions in China. In addition, such a large-scale analysis will prove to be instructive for leading translational studies between basic science and clinical medicine. PMID- 23453024 TI - Bio-oil from cassava peel: a potential renewable energy source. AB - In this work, liquid biofuel (bio-oil) was produced by pyrolizing cassava peel. The experiments were conducted isothermally in a fixed-bed tubular reactor at temperatures ranging from 400 to 600 degrees C with a heating rate of 20 degrees C/min. The chemical compositions of bio-oil were analyzed by a gas chromatography mass spectrometry (GC-MS) technique. For the optimization of liquid product, temperature was plotted to be the most decisive factor. The maximum yield of bio oil ca. 51.2% was obtained at 525 degrees C and the biofuel has a gross calorific value of 27.43 MJ/kg. The kinetic-based mechanistic model fitted well with experimental yield of pyrolysis products with the mean squared error (MSE) of 13.37 (R(2)=0.96) for solid (char), 16.24 (R(2)=0.95) for liquid (bio-oil), and 0.49 (R(2)=0.99) for gas. PMID- 23453025 TI - Toward monotasking in the dental school classroom? PMID- 23453026 TI - Gingival ulceration and exposed bone. PMID- 23453027 TI - Assessing the contribution of HRPT2 to the pathogenesis of jaw fibrous dysplasia, ossifying fibroma, and osteosarcoma. AB - OBJECTIVE: To investigate HRPT2 in jaw ossifying fibroma (OF), fibrous dysplasia (FD), and osteosarcoma (OS). STUDY DESIGN: We combined microsatellite loss of heterozygosity (LOH), HRPT2 sequence alterations at the mRNA level by reverse transcription polymerase chain reaction (PCR), cDNA sequencing, and quantitative PCR (qPCR) and immunohistochemistry (IHC) in a total of 19 OF, 15 FD, and 9 OS. Because HRPT2 (parafibromin) interacts with cyclin D1, we investigated cyclin D1 expression with the use of qPCR and IHC. RESULTS: LOH was detected in 3/5 FD, 6/9 OF, and 2/2 OS heterozygous samples. LOH was not associated with decreased mRNA levels or HRPT2 protein expression except for 1 OF which harbored an inactivating mutation. However, this tumor did not display altered transcription or protein levels of HRPT2 nor cyclin compared with the other OF. CONCLUSIONS: The contribution of HRPT2 inactivation to the pathogenesis of OF, FD, and OS is marginal at best and may be limited to progression rather than tumor initiation. PMID- 23453028 TI - Adenoid cystic carcinoma of the head and neck: clinicopathologic analysis of 218 cases in a Chinese population. AB - OBJECTIVE: The aim of this study was to analyze the clinicopathologic characteristics and prognostic factors of adenoid cystic carcinoma of the head and neck (ACCHN). STUDY DESIGN: This was a retrospective study of 218 patients with ACCHN. RESULTS: The cohort included 110 men and 108 women; the parotid and the palate were the most common site of involvement. Of 203 patients with follow up information (range 2-132 months), 57 had died of the tumor. Distant metastasis (DM) and local recurrence (LR) were documented in 83 (40.9%) and 34 (16.7%) patients, respectively. Cox regression analysis indicated that a solid pattern was a marker for LR and that positive margins and older age were risk factors for DM. Histologic pattern, T stage, N stage, LR, DM, and patient age contributed to the prediction of disease-specific survival. CONCLUSIONS: A solid pattern, metastasis, LR, and older age are the most important factors for predicting poor prognosis in Chinese patients with ACCHN. PMID- 23453029 TI - Promoter hypermethylation of the gene encoding heat shock protein B1 in oral squamous carcinoma cells. AB - OBJECTIVE: The mechanism responsible for the regulation of HSPB1 expression in oral squamous cell carcinoma was explored in this study. STUDY DESIGN: The expression and the methylation status of HSPB1 in oral squamous carcinoma cells were examined using real-time reverse transcription-PCR, methylation-specific PCR and pyrosequencing. RESULTS: HSPB1 expression was weakly expressed in oral squamous carcinoma cell lines (N = 4) as compared to that of normal human oral keratinocytes. The lower expressed HSPB1 was associated with promoter hypermethylation of the HSPB1 gene, and the expression of HSPB1 could be induced by treating the cells with a DNA methyltransferase inhibitor, RG108. Promoter hypermethylation of the HSPB1 gene was also noted in primary oral squamous carcinomas, concomitant with reduced levels of HSPB1 gene expression, as compared to those of the paired neighboring normal tissues. CONCLUSION: Aberrant promoter hypermethylation of the HSPB1 gene may explain the reduced expression of HSPB1 noted in oral cancer cells. PMID- 23453030 TI - SIRT1 expression is associated with good prognosis for head and neck squamous cell carcinoma patients. AB - OBJECTIVES: SIRT1, class III histone deacetylase, has been described to be up regulated in various malignancies. However, the opposite results have been reported in other malignancies. Therefore, we investigated SIRT1 expression to clarify its biological behavior and identify its usefulness as a biomarker for head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: SIRT1 expression was assessed by immunohistochemistry (IHC) conducted using samples from 437 consecutive HNSCC patients. Acetylated histone status and p53 expression were also examined. RESULTS AND CONCLUSION: IHC revealed 79.6% staining of SIRT1 in HNSCC, while almost all normal tissues showed positive staining. SIRT1 expression predominated in cases involving patients aged >65 years, lymph node negative, and early clinical stage cases. It was positively and statistically correlated with expression of acetylated histone H3K9 and H4K16, but not with p53. Multivariate analyses revealed that expression of SIRT1 was an independent and good indicator of prognosis. PMID- 23453031 TI - Interobserver variation of single-photon emission computed tomography bone scans in patients evaluated for unilateral condylar hyperactivity. AB - OBJECTIVE: This study assessed the quantitative evaluation of the region of interest (ROI) by mean and maximum pixel counts of single-photon emission computed tomography (SPECT) scans in patients with clinical suspicion of unilateral condylar hyperactivity (UCH); the interobserver reliability and the correlation of condylar activity with patient age was determined. METHODS: Two independent observers analyzed 67 bone SPECT scans. Maximum and mean activity values within an ROI on the mandibular condyle were analyzed; a cutoff value of 55% was used to determine the qualitative outcome. RESULTS: Excellent interobserver agreement was seen for both maximum (kappa 1.0) and mean activity analysis (kappa 0.94). Maximum and mean condylar activities were strongly correlated (r > 0.98). Maximum and mean condylar activity of the normal condyle decreased significantly with increasing age. CONCLUSIONS: Maximum and mean condylar activity levels were highly correlated in patients with mandibular asymmetry. An excellent interobserver agreement was found with either maximum or mean condylar activity. PMID- 23453032 TI - A 31P-magnet resonance spectroscopy study on the metabolism of human masseter in individuals with different vertical facial pattern. AB - OBJECTIVE: The objective of this study was to investigate differences in masseter metabolism by (31)P-Chemical Shift Imaging (CSI) in adult individuals with different vertical facial patterns. The clinical study should be supported by functional findings at the mRNA level after orthognathic surgery. STUDY DESIGN: Twenty-two male volunteers (mean age 24.6) were divided into a deep-bite (NL/ML 11.8 +/- 2.3 degrees ) and open-bite group (NL/ML 34.1 +/- 2.6 degrees ). Vertical jaw relationship, gonial angle, and masseter volume were defined and compared with the phosphate values obtained from the (31)P spectra. Student t test and regression analysis were used. RESULTS: Phosphocreatine related strongly to muscle volume (P < .001), gonial angle (P < .001), and ML/NL angle (P < .01). Pi was found to be related to gonial angle (P < .05). Muscle volume was found to be inversely related to ML/NL (P < .01) and to the gonial angle (P < .01). CONCLUSIONS: A difference in masseter muscle metabolism between long- and short faced subjects was confirmed at rest position. PMID- 23453033 TI - Gardner's syndrome: a clinical and genetic study of a family. AB - OBJECTIVE: Gardner syndrome (GS) is an autosomal dominant genetic disorder with almost complete penetrance (80%) and variable expression. GS is a variant of familial adenomatous polyposis and characterized by extracolonic manifestations including osteomas and soft tissue tumors (desmoid tumors, epidermoid cysts). We describe clinical and surgical approaches in a family in which the genetic disorder was diagnosed in 3 generations. STUDY DESIGN: The studied family underwent clinical history and instrumental and genomic studies. Two members of this family, affected with GS, underwent surgery for skeletal osteomas. RESULTS: The patients that we treated with clinical-instrumental monitoring for a period of 5 years had no major disturbances of the stomatognathic system and no clinical signs of pathology of the gastrointestinal tract, eyes, or endocrine systems. CONCLUSIONS: The orofacial complex disorders are exclusively functional and esthetic, concerning primarily the stomatognathic system. We had no cases of malignant transformation of osteomatosis lesions. Clinical sequelae are manly facial eumorphy and occlusion problems of the temporomandibular joint. PMID- 23453034 TI - Comparison of soft tissue healing around implants in beagle dogs: flap surgery versus flapless surgery. AB - OBJECTIVE: The objective of this study was to compare soft tissue healing after implant placement in flap and flapless surgery in the dog model. STUDY DESIGN: Mandibular premolars were extracted from 10 beagle dogs. The extraction sockets were allowed to heal for 8 weeks. After healing, 3 implants on each side of the mandible were implanted using either flap or flapless techniques. One implant was installed on each side at the 0-, 4-, and 6-week time point. Eight weeks later, the peri-implant soft tissue healing was subjected to clinical and immunohistochemical analysis. RESULTS: It was revealed that vascular endothelial growth factor (VEGF) expression, peri-implant crevicular fluid (PICF) volume, and the aspartate aminotransferase and alkaline phosphatase activity in PICF increased significantly in the 2-week flap group compared with the 2-week flapless group. Microvascular density and VEGF expression in the 8-week flap group was statistically significantly lower than the 8-week flapless group and normal group. Buccal gingival recession was less pronounced in the flapless group than in the flap group after 4 and 8 weeks. CONCLUSIONS: Within the limits of this study, the results demonstrate that flapless surgery contributes to better esthetic outcomes in implants compared with the flap approach. PMID- 23453035 TI - Novel nanoporous bioceramic spheres for drug delivery application: a preliminary in vitro investigation. AB - BACKGROUND: Bioceramics and their composites have found myriad applications in medicine as superlative osteoalloplasts. Their potential to function as a biocompatible resorbable drug delivery system is being explored. The present study is a preliminary investigation into the efficacy of these indigenously developed nanoporous materials as vehicles for therapeutic agents. An in vitro experiment was conducted with the goal of assessing this material and comparing it with a commercially available gentamicin-loaded polymethylmethacrylate cement. STUDY DESIGN: The drug-eluting characteristics of gentamicin bone cement and indigenously designed nanoporous bioceramic granules were analyzed spectrophotometrically and compared. Regression analysis was done. RESULTS: The first 5 days saw the elute from both samples containing drug concentrations >100 MUg/g. CONCLUSIONS: Both samples exhibit a high initial-burst release, which is ideal for prophylactic purposes. Drug eluent levels for both materials were >100 MUg/g, which is sufficient for bactericidal activity. PMID- 23453036 TI - Experimental acute myocardial infarction in rats: HIF-1alpha, caspase-3, erythropoietin and erythropoietin receptor expression and the cardioprotective effects of two different erythropoietin doses. AB - The cardioprotective effects of two different doses of erythropoietin administration were analyzed in rats with experimental myocardial infarction. None, saline, standard-dose (5000Ukg(-1)) and high-dose (10,000Ukg(-1)) of human recombinant erythropoietin alpha were administered intraperitoneally in Wistar rats with myocardial infarction induced by coronary artery ligation. Infarct sizes measured after triphenyltetrazolium chloride staining, levels of biochemical markers, histopathology examined by light and electron microscopy, and immunohistochemical expressions of erythropoietin, erythropoietin receptor, hypoxia inducible factor-1alpha and caspase-3, were analyzed. Lower scores of infarction and hemorrhage, lower number of macrophages and higher score of vascularization surrounding the infarct area were observed in the erythropoietin administered groups (p<0.05). Erythropoietin administration after myocardial infarction reduced the area of infarction and hemorrhage. There were hypoxia inducible factor-1alpha and caspase-3 expressions in the marginal area, and erythropoietin and erythropoietin receptor expression in both marginal and normal areas (p<0.001). Vascularization, erythropoietin expression in the normal area and vascular erythropoietin expression were positively correlated with human erythropoietin levels. The cardioprotective effects of erythropoietin treatment were independent of endogenous erythropoietin/erythropoietin receptor activity. Moreover exogenous erythropoietin treatment did not suppress endogenous erythropoietin. Erythropoietin administration after myocardial infarction reduced caspase 3 expression (apoptotic activity) and induced neovascularization around the infarct area. Higher erythropoietin administration did not provide an additional benefit over the standard-dose in myocardial protection. PMID- 23453037 TI - Reliability of ultrasound imaging in the assessment of the dorsal Lisfranc ligament. AB - BACKGROUND: The Lisfranc ligament plays an integral role in providing stability to the midfoot. Variable clinical presentations and radiographic findings make injuries to the Lisfranc ligament notoriously difficult to diagnose. Currently, radiographic evaluation is the mainstay in imaging such injuries; however, ultrasound has been suggested as a viable alternative. The objective of this study was to evaluate the intra-rater and inter-rater reliability in the measurement of the length of the dorsal Lisfranc ligament using ultrasound imaging in healthy, asymptomatic subjects. METHODS: The dorsal Lisfranc ligaments of fifty asymptomatic subjects (n = 100 feet) were imaged using a Siemens SONOLINE Antares Ultrasound Imaging System(c) under low, medium, and high stress loads at 0 degrees and 15 degrees abducted foot positions. The lengths of the ligaments were measured, and Interclass correlation coefficients were used to calculate within-session intra-rater reliability (n = 100 feet) as well as between-session intra-rater reliability (n = 40 feet) and between-session inter rater reliability (n = 40 feet). RESULTS: The within-session intra-rater reliability results for dorsal Lisfranc ligament length had an average ICC of 0.889 (min 0.873 max 0.913). The average ICC for between-session intra-rater reliability was 0.747 (min 0.607 max 0.811). The average ICC for between-session inter-rater reliability was 0.685 (min 0.638 max 0.776). CONCLUSIONS: The measurement of the dorsal Lisfranc ligament length using ultrasound imaging shows substantial to almost perfect reliability when evaluating asymptomatic subjects. This imaging modality methodology shows promise and lays the foundation for further work in technique development towards the diagnostic identification of pathology within the Lisfranc ligament complex. PMID- 23453038 TI - Green tea and coffee consumption is inversely associated with depressive symptoms in a Japanese working population. AB - OBJECTIVE: To examine the association between the consumption of green tea, coffee and caffeine and depressive symptoms. DESIGN: Cross-sectional study. Consumption of green tea and coffee was ascertained with a validated dietary questionnaire and the amount of caffeine intake was estimated from these beverages. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Multiple logistic regression analysis was performed to compute odds ratios and 95% confidence intervals for depressive symptoms with adjustments for potential confounders. SETTING: Two workplaces in north-eastern Kyushu, Japan, in 2009. SUBJECTS: A total of 537 men and women aged 20-68 years. RESULTS: Higher green tea consumption was associated with a lower prevalence of depressive symptoms. Compared with participants consuming <=1 cup/d, those consuming >=4 cups green tea/d had a 51% significantly lower prevalence odds of having depressive symptoms after adjustment for potential confounders, with significant trend association (P for trend = 0.01). Further adjustment for serum folate slightly attenuated the association. Coffee consumption was also inversely associated with depressive symptoms (>=2 cups/d v. <1 cup/d: OR = 0.61; 95% CI 0.38, 0.98). Multiple-adjusted odds for depressive symptoms comparing the highest with the lowest quartile of caffeine consumption was OR = 0.57 (95% CI 0.30, 1.05; P for trend = 0.02). CONCLUSIONS: Results suggest that higher consumption of green tea, coffee and caffeine may confer protection against depression. PMID- 23453039 TI - Involvement of regucalcin in lipid metabolism and diabetes. AB - Regucalcin (RGN/SMP30) was originally discovered in 1978 as a unique calcium binding protein that does not contain the EF-hand motif of calcium-binding domain. The regucalcin gene (rgn) is localized on the X chromosome and is identified in over 15 species consisting the regucalcin family. Regucalcin has been shown to play a multifunctional role in cell regulation; maintaining of intracellular calcium homeostasis and suppressing of signal transduction, translational protein synthesis, nuclear deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, proliferation, and apoptosis in many cell types. Moreover, regucalcin may play a pathophysiological role in metabolic disorder. The expression of regucalcin is stimulated through the action of insulin in liver cells in vitro and in vivo and it is decreased in the liver of rats with type I diabetes induced by streptozotocin administration in vivo. Overexpression of endogenous regucalcin stimulates glucose utilization and lipid production in liver cells with glucose supplementation in vitro. Regucalcin reveals insulin resistance in liver cells. Deficiency of regucalcin induces an impairment of glucose tolerance and lipid accumulation in the liver of mice in vivo. Overexpression of endogenous regucalcin has been shown to decrease triglyceride, total cholesterol and glycogen contents in the liver of rats, inducing hyperlipidemia. Leptin and adiponectin mRNA expressions in the liver tissues are decreased in regucalcin transgenic rats. Decrease in hepatic regucalcin is associated with the development and progression of nonalcoholic fatty liver disease and fibrosis in human patients. Regucalcin may be a key molecule in lipid metabolic disorder and diabetes. PMID- 23453040 TI - Supplementation of a grape seed and grape marc meal extract decreases activities of the oxidative stress-responsive transcription factors NF-kappaB and Nrf2 in the duodenal mucosa of pigs. AB - BACKGROUND: In pigs, enteric infections and the development of gut disorders such as diarrhoea are commonly observed, particularly after weaning. The present study investigated the hypothesis that feeding a grape seed and grape marc extract (GSGME) as a dietary supplement has the potential to suppress the inflammatory process in the small intestine of pigs by modulating the activities of NF-kappaB and Nrf2 due to its high content of flavonoids. METHODS: Twenty-four crossbred, 6 weeks old pigs were randomly assigned to 2 groups of 12 animals each and fed nutritionally adequate diets without or with 1% GSGME for 4 weeks. RESULTS: Pigs administered GSGME had a lower transactivation of NF-kappaB and Nrf2 and a lower expression of various target genes of these transcription factors in the duodenal mucosa than control pigs (P < 0.05). Concentrations of alpha-tocopherol and thiobarbituric acid reactive substances (TBARS) in liver and plasma and total antioxidant capacity of plasma and relative mRNA abundances of NF-kappaB and Nrf2 target genes in the liver did not differ between the two groups. However, the ratio of villus height:crypt depth and the gain:feed ratio was higher in the pigs fed GSGME than in control pigs (P < 0.05). CONCLUSIONS: This study shows that dietary supplementation of a polyphenol rich GSGME suppresses the activity of NF kappaB in the duodenal mucosa of pigs and thus might provide a useful dietary strategy to inhibit inflammation in the gut frequently occurring in pigs. Feeding GSGME did not influence vitamin E status and the antioxidant system of the pigs but improved the gain:feed ratio. In overall, the study suggests that polyphenol rich plant extracts such GSGME could be useful feed supplements in pig nutrition, in order to maintain animal health and improve performance. PMID- 23453041 TI - Cross recurrence quantification analysis of precision grip following peripheral median nerve block. AB - BACKGROUND: Precision grip by the thumb and index finger is vulnerable to sensorimotor deficits. Traditional biomechanical parameters offer limited insight into the dynamical coordination between digits during precision grip. In this study, the thumb and index finger were viewed as "coupled systems", and a cross recurrence quantification analysis (CRQA) was used to examine the changes of interdigit dynamics and synchronization caused by peripheral median nerve block. METHODS: Seven subjects performed a precision grip by holding an instrumented handle before and after median nerve block at the wrist. The forces and the torques at each digit-handle interface were recorded with two six-component transducers. For CRQA, the percentage of recurrence rate (%RR), percentage of determinism (%DET), longest diagonal line (Lmax) and percentage of laminarity (%LAM) were computed for the force, torque and center of pressure (COP) signals. Phase synchronization of the thumb and index finger was examined based on the tau recurrence rate. Paired t-tests and Wilcoxon signed-rank tests were used for statistical comparisons. The twin-surrogate hypothesis test was used to examine phase synchronization. RESULTS: Nerve block led to significant increases (p < 0.05) for %DET, Lmax and %LAM in all components of force, torque, and COP. Only the normal force met the conditions of phase synchronization for all successfully completed pre- and post-block grasping trials. The probability of synchronization with larger time lags (tau > 0.1 s) increased after nerve block. The percentage of trials that the thumb led the index finger increased from 52% (pre-block) to 86% (post-block). CONCLUSIONS: Nerve block caused more deterministic structures in force, torque and COP when the thumb interacted with the index finger. A compensatory mechanism may be responsible for this change. Phase synchronization between the opposite normal forces exerted by the thumb and index finger would be an essential dynamical principle for a precision grip. The nerve block resulted in an increased interdigit phase delay and increased probability that the thumb leads the index finger. The CRQA provides an effective tool to examine interdigit coordination during precision grip and has the potential for clinical evaluation of hand dysfunction. PMID- 23453042 TI - Skin temperature of the hand in multiple system atrophy and Parkinson's disease. AB - AIM: A previous study on a small number of patients showed that low skin temperature of the hands, the so called "cold hands sign", may be useful for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). We have further investigated skin temperature of the hand in a larger number of patients. METHODS: Skin temperature on the palm was measured in 50 MSA (11 MSA-P and 39 MSA-C patients) and 50 PD patients, and 25 normal healthy subjects. RESULTS: Palm skin temperature was significantly lower in MSA patients (32.0 +/- 2.7 degrees C) than in controls (34.1 +/- 0.9 degrees C, p = 0.0002), but was not different compared with the PD group (32.9 +/- 1.8 degrees C, p = 0.06). Temperatures of <28 degrees C were observed in 3 MSA patients (6%) and none of the PD patients and controls. There was no significant difference in palm skin temperature between patients with and without orthostatic hypotension for each patient group, or between MSA-P and MSA-C patients. CONCLUSION: The cold hand (<28 degrees C) is a useful marker for distinguishing MSA from PD, but it is not common in MSA patients, and its sensitivity may be low for differentiating between MSA and PD. PMID- 23453044 TI - The intrapleural volume threshold for ultrasound detection of pneumothoraces: an experimental study on porcine models. AB - BACKGROUND: Small pneumothoraxes (PTXs) may not impart an immediate threat to trauma patients after chest injuries. However, the amount of pleural air may increase and become a concern for patients who require positive pressure ventilation or air ambulance transport. Lung ultrasonography (US) is a reliable tool in finding intrapleural air, but the performance characteristics regarding the detection of small PTXs need to be defined. The study aimed to define the volume threshold of intrapleural air when PTXs are accurately diagnosed with US and compare this volume with that for chest x-ray (CXR). METHODS: Air was insufflated into a unilateral pleural catheter in seven incremental steps (10, 25, 50, 100, 200, 350 and 500 mL) in 20 intubated porcine models, followed by a diagnostic evaluation with US and a supine anteroposterior CXR. The sonographers continued the US scanning until the PTXs could be ruled in, based on the pathognomonic US "lung point" sign. The corresponding threshold volume was noted. A senior radiologist interpreted the CXR images. RESULTS: The mean threshold volume to confirm the diagnosis of PTX using US was 18 mL (standard deviation of 13 mL). Sixty-five percent of the PTXs were already diagnosed at 10 mL of intrapleural air; 25%, at 25 mL; and the last 10%, at 50 mL. At an air volume of 50 mL, the radiologist only identified four out of 20 PTXs in the CXR pictures; i.e., a sensitivity of 20% (95% CI: 7%, 44%). The sensitivity of CXR increased as a function of volume but leveled off at 67%, leaving one-third (1/3) of the PTXs unidentified after 500 mL of insufflated air. CONCLUSION: Lung US is very accurate in diagnosing even small amounts of intrapleural air and should be performed by clinicians treating chest trauma patients when PTX is among the differential diagnoses. PMID- 23453043 TI - Intrarenal resistance index for the assessment of acute renal injury in a rat liver transplantation model. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation (LT) and associated with a high mortality. The renal resistive index (RI) is used to assess early renal function impairment in critical care patients. However, limited data are available concerning changes of renal RI and the development of AKI early after reperfusion. We approached to investigate the changes of renal RI and AKI after reperfusion in a rat liver transplantation model. METHODS: Rats were randomly divided into sham group or LT group. Ten rats in each group were used for the hemodynamic study and twenty for Doppler measurements during the procedure. Ten rats were sacrificed 30 min or 2 h after the reperfusion. We harvested kidneys, serum and urine for further analysis of the renal function. RESULTS: The intrarenal RI increased significantly in the anhepatic stage and decreased significantly after the reperfusion in the LT group compared with sham group (P < 0.05). AKI was seen after the reperfusion in the LT group. No correlation was noted between the RI and renal function parameters 30 min after reperfusion. CONCLUSIONS: The intrarenal RI increased significantly during the anhepatic stage, and decreased significantly early after the reperfusion. Intrarenal RI was unable to assess renal function in a rat liver transplantation model. PMID- 23453045 TI - Can organizational justice help the retention of general practitioners? AB - In many countries, public sector has major difficulties in recruiting and retaining physicians to work as general practitioners (GPs). We examined the effects of taking up a public sector GP position and leaving public sector GP work on the changes of job satisfaction, job involvement and turnover intentions. In addition, we examined whether organizational justice in the new position would moderate these associations. This was a four-year prospective questionnaire study including two measurements among 1581 (948 women, 60%) Finnish physicians. A change to work as a public GP was associated with a substantial decrease in job satisfaction and job involvement when new GPs experienced that their primary care organization was unfair. However, high organizational justice was able to buffer against these negative effects. Those who changed to work as public GPs had 2.8 times and those who stayed as public GPs had 1.6 times higher likelihood of having turnover intentions compared to those who worked in other positions. Organizational justice was not able to buffer against this effect. Primary care organizations should pay more attention to their GPs - especially to newcomers - and to the fairness how management behaves towards employees, how processes are determined, and how rewards are distributed. PMID- 23453047 TI - The physiological response of the reef coral Pocillopora damicornis to elevated temperature: results from coral reef mesocosm experiments in Southern Taiwan. AB - Given the threat of climate change towards scleractinian corals, there is an urgent need to understand their physiological mechanisms of acclimation to increasing temperatures. To gain insight into this process, two mesocosm-based experiments were conducted in Southern Taiwan with the model reef-building coral Pocillopora damicornis. In the first study, temperature was gradually elevated to 32 degrees C, though reduced to ambient levels at night, in order to simulate a temperature profile that can characterize intertidal reefs of Southern Taiwan. All corals acclimated to such conditions over the course of the month-long experiment, as evidenced by a variety of physiological and sub-cellular responses. In the second experiment, corals were exposed continually to 31.5 degrees C for two weeks, and, in contrast to results from the first study, the majority of the corals died, revealing that prolonged exposure to this temperature is lethal for this dominant reef builder of many regions of the Pacific Ocean. PMID- 23453048 TI - The origins of tropical marine biodiversity. AB - Recent phylogeographic studies have overturned three paradigms for the origins of marine biodiversity. (i) Physical (allopatric) isolation is not the sole avenue for marine speciation: many species diverge along ecological boundaries. (ii) Peripheral habitats such as oceanic archipelagos are not evolutionary graveyards: these regions can export biodiversity. (iii) Speciation in marine and terrestrial ecosystems follow similar processes but are not the same: opportunities for allopatric isolation are fewer in the oceans, leaving greater opportunity for speciation along ecological boundaries. Biodiversity hotspots such as the Caribbean Sea and the Indo-Pacific Coral Triangle produce and export species, but can also accumulate biodiversity produced in peripheral habitats. Both hotspots and peripheral ecosystems benefit from this exchange in a process dubbed biodiversity feedback. PMID- 23453049 TI - Misconceptions of sexual selection and species recognition: a response to Knell et al. and to Mendelson and Shaw. PMID- 23453050 TI - Does the terrestrial biosphere have planetary tipping points? AB - Tipping points--where systems shift radically and potentially irreversibly into a different state--have received considerable attention in ecology. Although there is convincing evidence that human drivers can cause regime shifts at local and regional scales, the increasingly invoked concept of planetary scale tipping points in the terrestrial biosphere remains unconfirmed. By evaluating potential mechanisms and drivers, we conclude that spatial heterogeneity in drivers and responses, and lack of strong continental interconnectivity, probably induce relatively smooth changes at the global scale, without an expectation of marked tipping patterns. This implies that identifying critical points along global continua of drivers might be unfeasible and that characterizing global biotic change with single aggregates is inapt. PMID- 23453051 TI - Architecture of the subendothelial elastic fibers of small blood vessels and variations in vascular type and size. AB - Most blood vessels contain elastin that provides the vessels with the resilience and flexibility necessary to control hemodynamics. Pathophysiological hemodynamic changes affect the remodeling of elastic components, but little is known about their structural properties. The present study was designed to elucidate, in detail, the three-dimensional (3D) architecture of delicate elastic fibers in small vessels, and to reveal their architectural pattern in a rat model. The fine vascular elastic components were observed by a newly developed scanning electron microscopy technique using a formic acid digestion with vascular casts. This method successfully visualized the 3D architecture of elastic fibers in small blood vessels, even arterioles and venules. The subendothelial elastic fibers in such small vessels assemble into a sheet of meshwork running longitudinally, while larger vessels have a higher density of mesh and thicker mesh fibers. The quantitative analysis revealed that arterioles had a wider range of mesh density than venules; the ratio of density to vessel size was higher than that in venules. The new method was useful for evaluating the subendothelial elastic fibers of small vessels and for demonstrating differences in the architecture of different types of vessels. PMID- 23453052 TI - Utility of semiquantitative parameters to differentiate benign and malignant focal hepatic lesions. AB - OBJECTIVE: Any distinction and the usefulness of semiquantitative parameters derived from dynamic-contrast-enhanced (DCE) MRI obtained with extracellular gadolinium contrast agent in hemangiomas, hepatocellular carcinomas (HCC) and metastases of the liver was studied prospectively. METHODS: Seventy-four focal liver lesions (consisted of 34 hemangiomas, 23 HCC, and 17 metastases) of the 37 patients underwent DCE-MRI (six phases). Functional coloured maps and subsequently semiquantitative parameters were obtained using the FuncTool. Maximum and average (avg) values of mean time to enhancement (MTE), positive enhancement integral (PEI), time to peak (TP), maximum slope of increase (MSI), maximum slope of decrease (MSD) values were measured by placing the region of interest. The diagnosis of HCC and metastases were proven histopathologically and/or clinically. RESULTS: The mean values of the paremeters were: In hemangiomas, avgMTE: 271.2 +/- 4.7; avgPEI: 840.3 +/- 77.3; avgTP: 146.6 +/- 13.1; avgMSI: 999.1 +/- 108.4; avgMSD: 254.1 +/- 30.4. In HCC, avgMTE: 246 +/- 3.6; avgPEI: 424.9 +/- 31.6; avgTP: 132.8 +/- 9.5; avgMSI: 484.1 +/- 36.5; avgMSD: 109.1 +/- 13.3. In metastases, avgMTE: 248.1 +/- 8.2, avgPEI: 453.9 +/- 39.6; avgTP: 142.8 +/- 13.9; avgMSI: 472.6 +/- 50.4 and avg MSD: 200.1 +/- 38.2. Both maximum and avg values of MTE, PEI, MSI, and MSD were significantly higher in hemangiomas (P<.05). The most significant difference was found in avgPEI with 82.1% sensitivity and 67.6% specificity when 570 cutoff value was considered. The values however were not significantly different among HCC and metastases (P>.05). CONCLUSIONS: Semiquantitative DCE-MRI parameters provide useful, complementary, and quantitative information. This technique increases diagnostic value of extracellular gadolinium contrast agent to characterize focal liver lesions and may be useful for follow-up after local-regional therapies. PMID- 23453053 TI - Classification of EMG signals using PSO optimized SVM for diagnosis of neuromuscular disorders. AB - Support vector machine (SVM) is an extensively used machine learning method with many biomedical signal classification applications. In this study, a novel PSO SVM model has been proposed that hybridized the particle swarm optimization (PSO) and SVM to improve the EMG signal classification accuracy. This optimization mechanism involves kernel parameter setting in the SVM training procedure, which significantly influences the classification accuracy. The experiments were conducted on the basis of EMG signal to classify into normal, neurogenic or myopathic. In the proposed method the EMG signals were decomposed into the frequency sub-bands using discrete wavelet transform (DWT) and a set of statistical features were extracted from these sub-bands to represent the distribution of wavelet coefficients. The obtained results obviously validate the superiority of the SVM method compared to conventional machine learning methods, and suggest that further significant enhancements in terms of classification accuracy can be achieved by the proposed PSO-SVM classification system. The PSO SVM yielded an overall accuracy of 97.41% on 1200 EMG signals selected from 27 subject records against 96.75%, 95.17% and 94.08% for the SVM, the k-NN and the RBF classifiers, respectively. PSO-SVM is developed as an efficient tool so that various SVMs can be used conveniently as the core of PSO-SVM for diagnosis of neuromuscular disorders. PMID- 23453054 TI - BiNoM 2.0, a Cytoscape plugin for accessing and analyzing pathways using standard systems biology formats. AB - BACKGROUND: Public repositories of biological pathways and networks have greatly expanded in recent years. Such databases contain many pathways that facilitate the analysis of high-throughput experimental work and the formulation of new biological hypotheses to be tested, a fundamental principle of the systems biology approach. However, large-scale molecular maps are not always easy to mine and interpret. RESULTS: We have developed BiNoM (Biological Network Manager), a Cytoscape plugin, which provides functions for the import-export of some standard systems biology file formats (import from CellDesigner, BioPAX Level 3 and CSML; export to SBML, CellDesigner and BioPAX Level 3), and a set of algorithms to analyze and reduce the complexity of biological networks. BiNoM can be used to import and analyze files created with the CellDesigner software. BiNoM provides a set of functions allowing to import BioPAX files, but also to search and edit their content. As such, BiNoM is able to efficiently manage large BioPAX files such as whole pathway databases (e.g. Reactome). BiNoM also implements a collection of powerful graph-based functions and algorithms such as path analysis, decomposition by involvement of an entity or cyclic decomposition, subnetworks clustering and decomposition of a large network in modules. CONCLUSIONS: Here, we provide an in-depth overview of the BiNoM functions, and we also detail novel aspects such as the support of the BioPAX Level 3 format and the implementation of a new algorithm for the quantification of pathways for influence networks. At last, we illustrate some of the BiNoM functions on a detailed biological case study of a network representing the G1/S transition of the cell cycle, a crucial cellular process disturbed in most human tumors. PMID- 23453055 TI - Prostate Health Index (PHI): golden bullet or just another prostate cancer marker? PMID- 23453056 TI - Fixed or mixed: a comparison of three, four and mixed-option multiple-choice tests in a Fetal Surveillance Education Program. AB - BACKGROUND: Despite the widespread use of multiple-choice assessments in medical education assessment, current practice and published advice concerning the number of response options remains equivocal. This article describes an empirical study contrasting the quality of three 60 item multiple-choice test forms within the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Fetal Surveillance Education Program (FSEP). The three forms are described below. METHODS: The first form featured four response options per item. The second form featured three response options, having removed the least functioning option from each item in the four-option counterpart. The third test form was constructed by retaining the best performing version of each item from the first two test forms. It contained both three and four option items. RESULTS: Psychometric and educational factors were taken into account in formulating an approach to test construction for the FSEP. The four-option test performed better than the three-option test overall, but some items were improved by the removal of options. The mixed-option test demonstrated better measurement properties than the fixed-option tests, and has become the preferred test format in the FSEP program. The criteria used were reliability, errors of measurement and fit to the item response model. CONCLUSIONS: The position taken is that decisions about the number of response options be made at the item level, with plausible options being added to complete each item on both psychometric and educational grounds rather than complying with a uniform policy. The point is to construct the better performing item in providing the best psychometric and educational information. PMID- 23453057 TI - Respiratory infection of mice with mammalian reoviruses causes systemic infection with age and strain dependent pneumonia and encephalitis. AB - BACKGROUND: Because mammalian reoviruses are isolated from the respiratory tract we modeled the natural history of respiratory infection of adult and suckling mice with T1 Lang (T1L) and T3 Dearing (T3D) reoviruses. METHODS: Adult and suckling Balb/c mice were infected by the intranasal route and were assessed for dose response of disease as well as viral replication in the lung and other organs. Viral antigen was assessed by immunofluorescence and HRP staining of tissue sections and histopathology was assessed on formalin fixed, H + E stained tissue sections. RESULTS: Intranasal infection of adult mice resulted in fatal respiratory distress for high doses (10(7) pfu) of T1L but not T3D. In contrast both T1L and T3D killed suckling mice at moderate viral dosages (10(5) pfu) but differed in clinical symptoms where T1L induced respiratory failure and T3D caused encephalitis. Infections caused transient viremia that resulted in spread to peripheral tissues where disease correlated with virus replication, and pathology. Immunofluorescent staining of viral antigens in the lung showed reovirus infection was primarily associated with alveoli with lesser involvement of bronchiolar epithelium. Immunofluorescent and HRP staining of viral antigens in brain showed infection of neurons by T3D and glial cells by T1L. CONCLUSIONS: These mouse models of reovirus respiratory infection demonstrated age and strain dependent disease that are expected to be relevant to understanding and modulating natural and therapeutic reovirus infections in humans. PMID- 23453058 TI - An electrospun scaffold integrating nucleic acid delivery for treatment of full thickness wounds. AB - We developed a multi-functional construct capable of controlled delivery of bioactive substances that can improve wound repair by supporting the intrinsic ability of the skin to heal. We synthesized electrospun scaffolds-composed of a blend of the degradable polymers poly(l-lactide) (PLA) or polycaprolactone (PCL) that produce highly efficient non-viral in vivo gene delivery to cells in the wound bed, provide a protective barrier during early wound healing, and support cell migration and growth. This multi-functional material was tested for its influence on wound healing: scaffolds were loaded with plasmids encoding keratinocyte growth factor (KGF) and applied to full-thickness wounds in mice. Compared to scaffolds with control plasmids, animals receiving the KGF plasmid loaded scaffold produced significant enhancements in wound healing, which was quantified by improvements in the rate of wound re-epithelialization, keratinocyte proliferation, and granulation response. Further, we quantified the expression level of endogenous and plasmid-derived KGF in wound samples: qRT-PCR on wound sections revealed a correlation between the levels of plasmid-derived protein expression and histological analysis of wound healing, revealing an inverse relationship between the expression level of exogenous KGF and the size of the unhealed epithelial layer in wounds. Our findings suggest that engineered nanofiber PLA/PCL scaffolds are capable of highly efficient controlled DNA delivery and are promising materials for treatment of cutaneous wounds. PMID- 23453059 TI - Mechanism of drug release from double-walled PDLLA(PLGA) microspheres. AB - The drug release and degradation behavior of two double-walled microsphere formulations consisting of a doxorubicin-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) core (~46 kDa) surrounded by a poly(d,l-lactic acid) (PDLLA) shell layer (~55 and 116 kDa) were examined. It was postulated that different molecular weights of the shell layer could modulate the erosion of the outer coating and limit the occurrence of water penetration into the inner drug-loaded core on various time scales, and therefore control the drug release from the microspheres. For both microsphere formulations, the drug release profiles were observed to be similar. The degradation of the microspheres was monitored for a period of about nine weeks and analyzed using scanning electron microscopy, laser scanning confocal microscopy, and gel permeation chromatography. Interestingly, both microsphere formulations exhibited occurrence of bulk erosion of PDLLA on a similar time scale despite different PDLLA molecular weights forming the shell layer. The shell layer of the double-walled microspheres served as an effective diffusion barrier during the initial lag phase period and controlled the release rate of the hydrophilic drug independent of the molecular weight of the shell layer. PMID- 23453060 TI - Role of chitosan co-formulation in enhancing interleukin-12 delivery and antitumor activity. AB - Local delivery systems that provide sustained, high concentrations of antitumor cytokines in the tumor microenvironment while minimizing systemic dissemination are needed to realize the potential of cytokine-based immunotherapies. Recently, co-formulations of cytokines with chitosan solutions have been shown to increase local cytokine retention and bioactivity. In particular, intratumoral (i.t.) injections of chitosan/IL-12 can eliminate established tumors and generate tumor specific immune responses. In the present study, we explored the mechanisms by which chitosan potentiated IL-12's antitumor activity. The location of chitosan/IL-12 injection was found to be critical for optimal cytokine delivery. I.t. injections eliminated 9 of 10 MC38 adenocarcinomas while contralateral and peritumoral injections delayed tumor growth but could not eliminate tumors. Microdosing studies demonstrated that IL-12 depots, simulated through daily i.t. injections with IL-12 alone, were not as effective as weekly i.t. chitosan/IL-12. 50-75% of mice receiving daily IL-12 microdoses and 87.5% of mice receiving weekly chitosan/IL-12 were cured of MC38 tumors. Chitosan was found to increase IL-12-mediated leukocytic expansion in tumors and tumor-draining lymph nodes (TDLNs) by 40 and 100%, respectively. Immunophenotyping studies demonstrated that chitosan co-formulation amplified IL-12-induced increases in important effector populations, such as CD8(+)IFN-gamma(+) and NKT cells, in tumors and dendritic cell populations in TDLNs. Remarkable increases in Gr-1(+)CD11b(+) tumor infiltrates were also observed in mice receiving chitosan or chitosan/IL-12. This population does not appear be suppressive and may facilitate the local antitumor response. Presented data suggest that chitosan-mediated depot formation and enhanced local cytokine retention is significantly, but not entirely, responsible for increased cytokine bioactivity. PMID- 23453061 TI - Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration. AB - Development of effective non-invasive drug delivery systems is of great importance to the treatment of Alzheimer's diseases and has made great progress in recent years. In this work, lactoferrin (Lf), a natural iron binding protein, whose receptor is highly expressed in both respiratory epithelial cells and neurons is here utilized to facilitate the nose-to-brain drug delivery of neuroprotection peptides. The Lf-conjugated PEG-PCL nanoparticle (Lf-NP) was constructed via a maleimide-thiol reaction with the Lf conjugation confirmed by CBQCA Protein Quantitation and XPS analysis. Other important parameters such as particle size distribution, zeta potential and in vitro release of fluorescent probes were also characterized. Compared with unmodified nanoparticles (NP), Lf NP exhibited a significantly enhanced cellular accumulation in 16HBE14o-cells through both caveolae-/clathrin-mediated endocytosis and direct translocation. Following intranasal administration, Lf-NP facilitated the brain distribution of the coumarin-6 incorporated with the AUC0-8h in rat cerebrum (with hippocampus removed), cerebellum, olfactory tract, olfactory bulb and hippocampus 1.36, 1.53, 1.70, 1.57 and 1.23 times higher than that of coumarin-6 carried by NP, respectively. Using a neuroprotective peptide - NAPVSIPQ (NAP) as the model drug, the neuroprotective and memory improvement effect of Lf-NP was observed even at lower dose than that of NP in a Morris water maze experiment, which was also confirmed by the evaluation of acetylcholinesterase, choline acetyltransferase activity and neuronal degeneration in the mice hippocampus. In conclusion, Lf-NP may serve as a promising nose-to-brain drug delivery carrier especially for peptides and proteins. PMID- 23453062 TI - Codelivery of mTERT siRNA and paclitaxel by chitosan-based nanoparticles promoted synergistic tumor suppression. AB - Clinical applications of siRNA are being hindered by poor intracellular uptake and enzymatic degradation. To address these problems, we devised an oral delivery system for telomerase reverse transcriptase siRNA using N-((2-hydroxy-3 trimethylammonium) propyl) chitosan chloride (HTCC) nanoparticles (HNP). Both the porous structure and the positive charge of HNP facilitated siRNA encapsulation. The outer coating of HTCC not only protected siRNA from enzymatic degradation, but also improved siRNA permeability in intestine tract. In vivo and in vitro experiments proved that HNP could effectively deliver siRNA to lesion site and further into tumor cells. On the basis of confirming the antitumor activity of HNP:siRNA, we continued to encapsulate a hydrophobic chemotherapeutic drug paclitaxel (PTX) into HNP to form a "two-in-one" nano-complex (HNP:siRNA/PTX). We demonstrated that HNP:siRNA/PTX could simultaneously ferry siRNA and PTX into tumor cells and increase drug concentration, which, in particular, was much more effective in tumor suppression than that of traditional cocktail therapy. These results suggested that the HNP, as a powerful delivery system for both siRNA and chemotherapeutic drug, would have a far-reaching application in human cancer therapy. PMID- 23453064 TI - Publication of clinical trial protocols--what can we learn? PMID- 23453065 TI - Outcomes of intraductal papillary mucinous neoplasm with "Sendai-positive" criteria for resection undergoing non-operative management. AB - BACKGROUND: There are few data on the outcome of patients with intraductal papillary mucinous neoplasms of the pancreas meeting criteria for resection (Sendai-positive), and not operated. AIM: To evaluate outcome of patients with a resectable, Sendai-positive intraductal papillary mucinous neoplasm, and not operated. METHODS: Multicentre, retrospective analysis of prospectively enrolled patients, with resectable Sendai-positive, not-operated intraductal papillary mucinous neoplasm. Overall-survival and disease-specific survival were the primary end-point, and progression-free survival secondary. RESULTS: Thirty-five patients (60% male, median age 77) enrolled: 40% main-duct, 60% branch-duct intraductal papillary mucinous neoplasms. In 19 patients surgery was ruled out due to comorbidities, in 7 because aged > 80, 9 refused surgery. Twelve (34.3%) patients died after a mean of 32.5 months, 8 due to disease progression, 4 due to comorbidities. The median overall, disease-specific and progression-free survival were 52, 55, and 44 months respectively. Main duct involvement and age at diagnosis were associated with worse overall and progression-free survival, only main duct involvement with worse disease-specific survival (52 months main duct vs. 64 branch duct; P = 0.04). CONCLUSION: These results suggest that in elderly and comorbid patients with Sendai-positive intraductal papillary mucinous neoplasms, especially of the branch duct, a conservative approach could be reasonable, as associated with a relatively good outcome, and should be carefully discussed with the patients. PMID- 23453067 TI - Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2'-C methyl-6-O-methyl guanosine nucleoside and L-Alanine ester phosphoramidates. AB - 7-Deazapurines are known to possess broad antiviral activity, however the 2'-C methylguanosine analogue displays poor cell permeation and limited phosphorylation, thus is not an efficient inhibitor of hepatitis C virus (HCV) replication. We previously reported the 6-O-methyl entity as a prodrug moiety to increase liphophilicity of guanine nucleosides and the ProTide approach applied to 2'-C-methyl-6-O-methylguanosine has lead to potent HCV inhibitors now in clinical trials. In this Letter, we report the synthesis and biological evaluation of 2'-C-methyl-6-O-methyl-7-deaza guanosine and ProTide derivatives. In contrast to prior studies, removal of the N-7 of the nucleobase entirely negates anti-HCV activity compared to the 2'-C-methyl-6-O-methylguanosine analogues. To understand better this significant loss of activity, enzymatic assays and molecular modeling were carried out and suggested 2'-C-methyl-6-O methyl-7-deaza guanosine and related ProTides do not act as efficient prodrugs of the free nucleotide, in marked contrast to the case of the parent guanine analogue. PMID- 23453066 TI - Daptomycin plus trimethoprim/sulfamethoxazole combination therapy in post neurosurgical meningitis caused by linezolid-resistant Staphylococcus epidermidis. AB - Post-neurosurgical infection is a serious complication that occurs in approx. 4% of all patients undergoing neurosurgical procedures and is associated with high morbidity and mortality rates and prolonged length of intensive care unit (ICU) stay. Coagulase-negative staphylococci (CoNS), especially methicillin-resistant Staphylococcus epidermidis (MRSE), are the most frequent pathogens involved in CNS post-neurosurgical meningitis. Treatment is challenging especially in patients with meningitis due to multidrug- resistant (MDR) CONS. Herein, we report a unique case of post-neurosurgical meningitis due to MRSE resistant to linezolid (a molecular analysis revealed the presence of the mutation G2576T on domain V of the 23S rRNA gene) and with reduced susceptibility to glycopeptides, successfully treated with a combination of daptomycin at 10 mg/kg daily plus trimethoprim/sulfamethoxazole (TMP/SMX). This antibiotic combination showed an indifferent interaction in in vitro studies. Daptomycin serum and cerebrospinal fluid (CSF) concentrations, determined through blood and CSF samples drawn just prior to and 4 h after the third dose, were 18.9-0.78 and 51.65-3.1 mg/L, respectively. These values allowed us to approximate a 5-6% penetration rate of the drug through an inflamed blood-brain barrier. In conclusion, although further studies are needed, combination of high-dose daptomycin plus TMP/SMX is a reasonable option for treatment of meningitis caused by multidrug-resistant S. epidermidis. PMID- 23453068 TI - Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing. PMID- 23453070 TI - A series of thiazole derivatives bearing thiazolidin-4-one as non-competitive ADAMTS-5 (aggrecanase-2) inhibitors. AB - A series of thiazole bearing thiazolidin-4-one was discovered via high-throughput screening as non-competitive inhibitors of ADAMTS-5. Compound 31 appeared to give the best ADAMTS-5 inhibition and good selectivity over other metalloproteases. PMID- 23453071 TI - Synthesis and evaluation of nicotinamide derivative as anti-angiogenic agents. AB - Previously, we have found that BRN-103, a nicotinamide derivative, inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis signaling in human endothelial cells. During our continuous efforts to identify more potent anti-angiogenic agents, we synthesized various nicotinamide derivatives and evaluated their anti-angiogenic effects. We found that 2-{1-[1-(6-chloro-5 fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3 carboxamide (BRN-250) significantly inhibited human umbilical vascular endothelial cells (HUVECs) proliferation, migration, tube formation, and microvessel growth in a concentration range of 10-100 nM. Furthermore, BRN-250 inhibited the VEGF-induced phosphorylation and intracellular tyrosine kinase activity of VEGF receptor 2 (VEGFR2) and the activation of its downstream AKT pathway. Taken together, these findings suggest that BRN-250 be considered a potential lead compound for cancer therapy. PMID- 23453069 TI - Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase. AB - Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130. PMID- 23453072 TI - Design, synthesis and SAR investigation of thienosultam derivatives as ADAMTS-5 (aggrecanase-2) inhibitors. AB - A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1' pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability. PMID- 23453074 TI - Fluorescent probes designed for detecting human serum albumin on the basis of its pseudo-esterase activity. AB - We developed activity-based fluorescent probes for detecting human serum albumin (HSA) on the basis of its pseudo-esterase activity. These probes could also detect HSA in blood-contaminated tissue samples. PMID- 23453073 TI - Small molecule modulators of Wnt/beta-catenin signaling. AB - The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer. Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery. Recently, we reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/beta-catenin signaling by a unique mechanism, though the target responsible remains unknown. We interrogated the mechanism and structure-activity relationships to understand drivers of potency and to assist target identification efforts. We found inhibition of Wnt signaling by Niclosamide appears unique among the structurally-related anthelmintic agents tested and found the potency and functional response was dependent on small changes in the chemical structure of Niclosamide. Overall, these findings support efforts to identify the target of Niclosamide inhibition of Wnt/beta-catenin signaling and the discovery of potent and selective modulators to treat human disease. PMID- 23453075 TI - An extension of the Rescorla and Wagner Simulator for context conditioning. AB - This paper introduces R&W Simulator version 4, which extends previous work by incorporating context simulation within standard Pavlovian designs. This addition allows the assessment of: (1) context-stimulus competition, by treating contextual cues as ordinary background stimuli present throughout the whole experimental session; (2) summation, by computing compound stimuli with contextual cues as an integrating feature, with and without the addition of specific configural cues; and (3) contingency effects in causal learning. These new functionalities broaden the range of experimental designs that the simulator is able to replicate, such as some recovery from extinction phenomena (e.g., renewal effects). In addition, the new version permits specifying probe trials among standard trials and extracting their values. PMID- 23453076 TI - Embolism resistance as a key mechanism to understand adaptive plant strategies. AB - One adaptation of plants to cope with drought or frost stress is to develop wood that is able to withstand the formation and distribution of air bubbles (emboli) in its water conducting xylem cells under negative pressure. The ultrastructure of interconduit pits strongly affects drought-induced embolism resistance, but also mechanical properties of the xylem are involved. The first experimental evidence for a lower embolism resistance in stems of herbaceous plants compared to stems of their secondarily woody descendants further supports this mechanical functional trade-off. An integrative approach combining (ultra)structural observations of the xylem, safety-efficiency aspects of the hydraulic pipeline, and xylem-phloem interactions will shed more light on the multiple adaptive strategies of embolism resistance in plants. PMID- 23453077 TI - Urethral injury by an orthopedic screw: an unusual cause of hematuria. AB - Pelvic fractures are commonly associated with urethral disruption; however, urethral injury from the repair of these fractures is rarely reported. Thus, the management of these injuries has not been well defined. We report a case of urethral injury from orthopedic screw insertion presenting 3 months postoperatively and effectively managed with removal of the screw and temporary Foley catheterization. PMID- 23453078 TI - Gemstone spectral imaging dual-energy computed tomography: a novel technique to determine urinary stone composition. AB - OBJECTIVE: To assess the capability of determining the chemical composition of urinary stones using dual-energy spectral computed tomography (CT). MATERIALS AND METHODS: A total of 116 urinary stones with a known chemical composition determined by infrared spectroscopy were scanned using both gemstone spectral imaging and conventional polychromatic imaging (at 120 kVp) in vitro. The CT numbers of each stone were recorded from the 11 sets of monochromatic images (40 140 keV, 10-keV interval) and 120-kVp polychromatic images. The differences between the CT numbers obtained in the 12 sets were compared among the stone groups. RESULTS: The 116 urinary stones were classified into 7 groups: uric acid (n = 16), cystine (n = 10), brushite (n = 17), weddellite (n = 14), whewellite (n = 24), carbapatite (n = 12), and struvite (n = 23). The paired CT numbers (at 120 kVp and 50 keV, respectively) of each stone group were as follows: uric acid, 469.11 +/- 69.83 and 474.06 +/- 40.55 Hounsfield units (HU); cystine, 564.81 +/- 97.71 and 839.58 +/- 92.14 HU; brushite, 1830.94 +/- 59.19 and 2787.41 +/- 306.07 HU; weddellite, 1438.09 +/- 191.12 and 2100.79 +/- 202.32 HU; whewellite, 1493.48 +/- 259.90 and 2321.39 +/- 367.23 HU; carbapatite, 1784.58 +/- 106.42 and 2513.86 +/- 189.09 HU; and struvite, 833.037 +/- 9.91 and 1123.24 +/- 267.70 HU. The differences in the CT numbers at 120 kVp and 50 keV among the groups were statistically significant by binary comparison (P <.05), except for those at 120 kVp between uric acid and cystine (P = .121), whewellite and weddellite (P = .280), and brushite and carbapatite (P = .419). CONCLUSION: Gemstone spectral imaging dual-energy CT provides a novel method to better characterize pure urinary stones using the CT numbers at 50 keV. PMID- 23453079 TI - Does prostate morphology affect outcomes after holmium laser enucleation? AB - OBJECTIVE: To determine whether prostate morphology or technique used has any effect on postoperative outcomes after holmium laser enucleation of the prostate. MATERIALS AND METHODS: A retrospective review of prospectively collected data was completed for all patients undergoing a holmium laser enucleation of the prostate at our institution. Prostate morphology was classified as either "bilobar" or "trilobar" according to the cystoscopic appearance. The baseline characteristics, complications, and postoperative outcomes were collected. RESULTS: A total of 304 patients with either "bilobar" (n = 142) or "trilobar" (n = 162) prostate morphology were included. The trilobar group was more likely to have longer operative times (112 vs 100 minutes, P = .04), although this difference was not significant on multivariate analysis. The postoperative outcomes were similar between the 2 groups for American Urological Association symptom score, change in American Urological Association symptom score, bother score, maximal flow rate, change in maximal flow rate, postvoid residual urine volume, and complication rate. However, the trilobar group had a significantly greater decrease in their PVR urine volume (296 vs 176 mL, P = .01), a difference that persisted on multivariate analysis. A subset analysis of the trilobar prostates revealed that performing a 2-lobe technique achieved shorter operative and enucleation times, although the difference was not significant. CONCLUSION: Those patients with trilobar prostate morphology are more likely to achieve a greater decrease in the PVR urine volume after holmium laser enucleation of the prostate. All other outcomes appeared to be similar between the 2 groups. In addition, a 2-lobe technique can be safely used for trilobar prostates when deemed feasible by the surgeon. PMID- 23453080 TI - A review of contemporary data on surgically resected renal masses--benign or malignant? AB - OBJECTIVE: To clearly define the proportions of benign vs malignant histologic findings in resected renal masses through an in-depth review of the contemporary medical data to assist in preoperative risk assessment. MATERIALS AND METHODS: PubMed and select oncology congresses were searched for publications that identify the histologic classification of resected renal masses in a representative sample from the contemporary data: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit 2003-2011. RESULTS: We identified 26 representative studies meeting the inclusion criteria and incorporating 27,272 patients. The frequency of benign tumors ranged from 7% to 33%, with most studies within a few percentage points of the mean (14.5% +/- 5.2%, median 13.9%). Clear cell renal cell carcinoma occurred in 46% to 83% of patients, with a mean of 68.3% (median 61.3; SD = 11.9%). An inverse relationship between tumor size and benign pathologic features was identified in 14 of 19 (74%) studies that examined an association between tumor size and pathologic characteristics. A statistically significant correlation between clear cell renal cell carcinoma and tumor size was identified in 13 of 19 studies (63%). The accuracy of preoperative cross sectional imaging was low in the 2 studies examining computed tomography (17%). CONCLUSION: Benign renal tumors represent ~15% of detected surgically resected renal masses and are more prevalent among small clinical T1a lesions. Noninvasive preoperative differentiation between more and less aggressive renal masses would be an important clinical advance that could allow clinicians greater diagnostic confidence and guide patient management through improved risk stratification. PMID- 23453081 TI - Unilateral versus bilateral correction of unicoronal synostosis: an analysis of long-term results. AB - INTRODUCTION: Hollowing of the temporal region is a common problem after cranioplasty for unicoronal synostosis. In this study, first, the development of temporal hollowing pre- and postoperatively is evaluated. Second, the origin of temporal hollowing is investigated by comparing two operative techniques. Ultimately, the relation between timing of surgery and the development of hollowing is investigated. METHODS: From 1979 to 2010, 194 patients with unicoronal synostosis were operated at our center. Patients were treated with a unilateral or bilateral correction of the supraorbital rim. A total of 48 patients qualified for the present study. Mean age at follow-up was 7.5 years. Cephalic landmarks were identified on radiographs prior to and after surgery to determine the growth of the forehead. For visual analysis, two independent observers evaluated normal photographs for the presence and severity of temporal hollowing. RESULTS: Preoperative osseous asymmetry improved significantly after surgery. A total of 21 patients show an increase of temporal hollowing on photographs after surgery (46%). In 35 out of 48 patients, postoperative temporal hollowing was noted (73%). Bilaterally treated patients showed more severe temporal hollowing compared to unilaterally treated patients, though not significantly (23% vs. 6%, p = 0.229). Timing of surgery (before or after the age of 1 year) did not influence the occurrence of severe temporal hollowing. CONCLUSIONS: Fronto-supraorbital advancement was unable to achieve normal growth in the temporal region in a large proportion of patients, although more symmetry was achieved. The operative technique itself did not seem to influence the occurrence of temporal hollowing, nor did the timing of surgery. PMID- 23453082 TI - The relationship between oral conditions, masticatory performance and oral health related quality of life in children. AB - OBJECTIVE: To evaluate the association between oral conditions, masticatory performance (MP) and oral health-related quality of life (OHRQoL) in 8-12 year old children. DESIGN: 150 Brazilian scholars were examined for caries and malocclusions. MP was evaluated based on the ability to comminute an artificial test food followed by the determination of the median particle size (X50) and particle distribution in different-sized sieves ("b"). OHRQoL was measured using the Brazilian versions 8-10 and 11-14 of the child perceptions questionnaire (CPQ), considering the following domains: oral symptoms (OS), functional limitations (FL), emotional well-being (EW) and social well-being (SW). Higher scores indicated worse OHRQoL. Data were submitted to Spearman's correlation test and multiple linear regression analysis. RESULTS: There were significant positive correlations between the psychosocial and OS domains scores of the CPQ8-10 and the number of decayed and missing teeth, respectively. The number of decayed teeth positively correlated with the number of missing teeth and the CPQ11-14 scores. The number of decayed and missing teeth was significantly associated with higher CPQ8-10 scores. Higher CPQ11-14 overall scores were associated with female gender, higher FL domain scores were associated with the number of missing teeth, and higher X50 values and EW domain scores were associated with female gender and the number of decayed teeth. CONCLUSIONS: A higher number of missing teeth correlated with an inferior MP in older children. Children with a higher number of caries rated their oral health less favourably. Older females and those who broke the test material into smaller sizes were also more likely to report a worse OHRQoL, suggesting that the time allowed to reduce food appears to be a more influential factor on children' perception of oral health than their ability to break down the test material into smaller sizes. Moreover, the subjectivity of functional domain and artificial nature of chewable test material could have influenced the test sensitivity. PMID- 23453083 TI - 8-Isoprostane: a lipid peroxidation product in gingival crevicular fluid in healthy, gingivitis and chronic periodontitis subjects. AB - OBJECTIVE: The idea that reactive oxygen species (ROS) are associated with the pathogenesis of inflammatory periodontal diseases and have a role (direct or indirect) in tissue damage has become a major area of research over the last decade. The purpose of this study is to determine, presence of 8-isoprostane in gingival crevicular fluid (GCF) in healthy, gingivitis and chronic periodontitis (CP) subjects and to find an association, if any between GCF 8-isoprostane levels and clinical periodontal parameters. MATERIALS AND METHODS: 78 subjects (40 males and 38 females) were selected based on their clinical parameters into three groups: Group 1 (26 healthy), Group 2 (26 gingivitis subjects) and Group 3 (26 CP subjects). GCF 8-isoprostane levels were estimated by ELISA. RESULTS: The 8 isoprostane concentration in GCF was highest in subjects with chronic periodontitis as compared to gingivitis and healthy subjects and a significant association was observed between GCF 8-isoprostane levels and all periodontal parameters. CONCLUSIONS: There was increase in 8-isoprostane levels in GCF as the disease process progressed from health to gingivitis and chronic periodontitis, suggesting a role for increased oxidative stress in CP. PMID- 23453084 TI - Longitudinal change detection: inference on the diffusion tensor along white matter pathways. AB - Diffusion weighted magnetic resonance imaging (DW-MRI) makes it possible to probe brain connections in vivo. This paper presents a change detection framework that relies on white matter pathways with application to neuromyelitis optica (NMO). The objective is to detect local or global fiber diffusion property modifications between two longitudinal DW-MRI acquisitions of a patient. To this end, we develop two frameworks based on statistical tests on tensor eigenvalues to detect local or global changes along the white matter pathways: a pointwise test that compares tensor populations extracted in bundles cross sections and a fiberwise test that compares paired tensors along all the fiber bundles. Experiments on both synthetic and real data highlight the benefit of considering fiber based statistical tests compared to standard voxelwise strategies. PMID- 23453085 TI - Metabolic fingerprinting of Angelica sinensis during growth using UPLC-TOFMS and chemometrics data analysis. AB - BACKGROUND: The radix of Angelica sinensis is widely used as a medicinal herbal and metabolomics research of this plant during growth is necessary. RESULTS: Principal component analysis of the UPLC-QTOFMS data showed that these 27 samples could be separated into 4 different groups. The chemical markers accounting for these separations were identified from the PCA loadings plot. These markers were further verified by accurate mass tandem mass and retention times of available reference standards. The study has shown that accumulation of secondary metabolites of Angelica sinensis is closely related to the growth periods. CONCLUSIONS: The UPLC-QTOFMS based metabolomics approach has great potential for analysis of the alterations of secondary metabolites of Angelica sinensis during growth. PMID- 23453086 TI - Statement on matching language to the type of evidence used in describing outcomes data. PMID- 23453087 TI - Attribution of causality in clinical research: an important element for learning health systems. PMID- 23453088 TI - Radiation exposure with transradial and transfemoral procedures. PMID- 23453089 TI - Improving outcomes in patients with cardiogenic shock: achieving more through less. PMID- 23453091 TI - Determining the risks of clinically indicated nonthoracic magnetic resonance imaging at 1.5 T for patients with pacemakers and implantable cardioverter defibrillators: rationale and design of the MagnaSafe Registry. AB - BACKGROUND: Until recently, the presence of a permanent pacemaker or an implantable cardioverter-defibrillator has been a relative contraindication for the performance of magnetic resonance imaging (MRI). A number of small studies have shown that MRI can be performed with minimal risk when patients are properly monitored and device programming is modified appropriately for the procedure. However, the risk of performing MRI for patients with implanted cardiac devices has not been sufficiently evaluated to advocate routine clinical use. The aim of the present protocol is to prospectively determine the rate of adverse clinical events and device parameter changes in patients with implanted non-MRI conditional cardiac devices undergoing clinically indicated nonthoracic MRI at 1.5 T. METHODS: The MagnaSafe Registry is a multicenter, prospective cohort study of up to 1500 MRI examinations in patients with pacemakers or implantable cardioverter-defibrillators implanted after 2001 who undergo clinically indicated nonthoracic MRI following a specific protocol to ensure that preventable potential adverse events are mitigated. Adverse events and changes in device parameter measurements that may be associated with the imaging procedure will be documented. RESULTS: Through August 2012, 701 MRI studies have been performed, representing 47% of the total target enrollment. CONCLUSIONS: The results of this registry will provide additional documentation of the risk of MRI and will further validate a clinical protocol for screening and the performance of clinically indicated MRI for patients with implanted cardiac devices. PMID- 23453090 TI - INtensive versus standard ambulatory blood pressure lowering to prevent functional DeclINe in the ElderlY (INFINITY). AB - Reductions in mobility and cognitive function linked to accrual of brain microvascular disease related white matter hyperintensities (WMHs) on magnetic resonance imaging can occur in older hypertensive patients in as little as 2 years. We have designed a trial evaluating 2 levels of ambulatory blood pressure (ABP) control in individuals with normal or mildly impaired mobility and cognition who have detectable cerebrovascular disease (>0.5% WMH fraction of intracranial volume) on functional outcomes. The study is a prospective randomized, open-label trial with blinded end points, in patients ages >=75 years with elevated 24-hour systolic blood pressure (BP) (145 mm Hg in the untreated state) who do not have unstable cardiovascular disease, heart failure, or stroke. The primary and key secondary outcomes in the trial are change from baseline in mobility and cognitive function and damage to brain white matter as demonstrated by accrual of WMH volume and changes in diffusion tensor imaging. Approximately 300 patients will be enrolled, and 200 randomized to 1 of 2 levels of ABP control (intensive to achieve a goal 24-hour systolic BP of <=130 mm Hg or standard to achieve a goal 24-hour systolic BP of <=145 mm Hg) for a total of 36 months using similar antihypertensive regimens. The analytical approach provides 85% power to show a clinically meaningful effect in differences in mobility accompanied by quantitative differences in WMH between treatment groups. The INFINITY trial is the first to guide antihypertensive therapy using ABP monitoring rather than clinic BP to reduce cerebrovascular disease. PMID- 23453092 TI - Central versus local adjudication of myocardial infarction in a cardiac biomarker trial. AB - OBJECTIVES: The impact of regulatory requirements, which require central adjudication for the diagnosis of acute myocardial infarction (AMI) in cardiac biomarker studies, is unclear. We determined the impact of local (at the site of subject enrollment) versus central adjudication of AMI on final diagnosis. METHODS: This is a retrospective analysis of data from the Myeloperoxidase in the Diagnosis of Acute Coronary Syndromes Study, an 18-center prospective study of patients with suspected acute coronary syndromes, with enrollment from December 19, 2006, to September 20, 2007. Local adjudication of AMI was performed by a single site investigator at each center following the protocol-specified definition and according to the year 2000 definition of AMI, which based cardiac troponin (cTn) elevation on local cut points for each of the 13 different assays. After completion of the Myeloperoxidase in the Diagnosis of Acute Coronary Syndromes Study primary analysis and to evaluate a new troponin assay, a Food and Drug Administration-mandated central adjudication was performed by 3 investigators at different institutions. This adjudication used the 2007 Universal Definition of AMI, which differs by use of the manufacturer's 99th percentile cTn cut point. We describe the outcome of this process and compare it with the local adjudication. Central adjudicators were not blinded to local adjudications. For central adjudication, discrepant diagnoses were resolved by consensus. Local versus central cTn cut points differed for 6 assays. Both definitions required a rise and/or fall of cTn. Discrepant cases were reviewed by the lead author. Difficult cases were defined as having a difference between local and central adjudication, an elevated cTn with a temporal rise and fall, and a negative or absent risk stratification test. Statistics were by chi(2), kappa, and logistic regression. RESULTS: Of 1,107 patients enrolled, 11 had indeterminate central adjudication, leaving 1,096 for analysis. In spite of high agreement across central versus local adjudicators, kappa = 0.79 (95% CI [0.73, 0.85]), AMI was diagnosed more often by central adjudication, 134 (12.2%) versus 104 (9.5%), with 44 local diagnoses (4%) changed from non-AMI to AMI (n = 37) or AMI to non-AMI (n = 7) (P < .001). These 44 represented 34% (95% CI 26%-42%) of 141 cases in which either central or local adjudication was AMI. Of diagnoses changed to AMI, 3 reasons contributed approximately one-third each: the local use of a non-99th percentile cTn cutoff (32%), the possibility of human error (34%), and difficult cases (34%). CONCLUSION: Despite an acceptable kappa, over a third of patients with a diagnosis of AMI were not assigned that diagnosis by both sets of adjudicators. This supports the importance of 1 standard method for diagnosis of AMI. PMID- 23453093 TI - Transradial percutaneous coronary intervention in cardiogenic shock: a single center experience. AB - BACKGROUND: Use of the transradial approach (TRA) in percutaneous coronary intervention (PCI) has increased in recent years. TRA has a lower mortality rate than the transfemoral approach (TFA) in patients with acute coronary syndrome. Comparative studies have systematically excluded patients with cardiogenic shock (CS). METHODS: We performed a prospective, observational registry study of consecutive patients undergoing emergent revascularization between February 2007 and January 2012. An analysis of the clinical evolution of patients with CS during hospitalization was performed. RESULTS: Of 1,400 emergency procedures, 122 had CS, of which 80 underwent PCI by TRA (65.6%) and 42 underwent PCI by TFA (34.3%). The main reason for choosing TFA was the absence of radial pulse (54.9%). Mortality (64.3% vs 32.5%, P = .001), serious access site complications (11.9% vs 2.5%, P = .03), access site complications requiring blood transfusion (7.1% vs 0%, P = .04), and major adverse cardiac events (death, infarction, stroke, serious bleeding, and postanoxic encephalopathy) (73.8% vs 43.8%, P = .001) were greater in patients treated by TFA. In the multivariate analysis, TRA was a predictor of mortality (odds ratio [OR] 0.39 [0.15-0.97]); other predictive factors were age >=75 years (3.47 [1.35-8.92]), previous treatment with diuretics (3.67 [1.21-11.12]), and success of the procedure (0.07 [0.02-0.24]). CONCLUSIONS: Transradial approach for PCI is possible and safe in up to two thirds of patients with CS. Absence of radial pulse was the main factor preventing use of TRA. In multivariate analysis, TRA was associated with a lower risk of mortality. PMID- 23453094 TI - Radiation exposure during coronary angiography via transradial or transfemoral approaches when performed by experienced operators. AB - BACKGROUND: Studies demonstrate an increase in radiation exposure with transradial approach (TRA) when compared with transfemoral approach (TFA) for coronary angiography. Given the learning curve associated with TRA, it is not known if this increased radiation exposure to patients is seen when procedures are performed by experienced operators. METHODS: We retrospectively evaluated 1,696 patients who underwent coronary angiography with or without percutaneous coronary intervention (PCI) by experienced operators at a tertiary center from October 2010 to June 2011. Experienced operators were defined as those that perform >75 PCIs/year with >95% of cases performed using the TRA or TFA approach for >=5 years. The outcomes of interest were dose area product (DAP) and fluoroscopy time (FT). RESULTS: Of the 1,696 patients, 1,382 (81.5%) were performed by experienced femoral operators using TFA and 314 (18.5%) were performed by experienced radial operators using TRA. Most of these cases (65.4%) were diagnostic only (870 TFA and 240 TRA) with both DAP (6040 [3210-8786] vs 5019 [3377-6869] MUGy.m(2), P = .003] and FT [6.2 [4.0-10.3] vs 3.3 [2.6-5.0] minutes, P < .001) significantly higher using TRA versus TFA. For procedures involving PCI, despite similar baseline patient, procedural and lesion characteristics, DAP and FT remained significantly higher using TRA versus TFA (19,649 [11,996-25,929] vs 15,395 [10,078-21,617] MUGy.m(2), P = .02 and 22.1 [13.3-31.0] vs. 13.8 [9.8-20.3] minutes, P < .001). CONCLUSIONS: In a contemporary cohort of patients undergoing coronary angiography by experienced operators, TRA was associated with higher radiation exposure when compared with TFA. PMID- 23453095 TI - Reduction in operator radiation exposure during transradial catheterization and intervention using a simple lead drape. AB - BACKGROUND: Transradial access for cardiac catheterization and intervention is a recognized method for reducing complications and improving patient comfort. However, there are concerns over possible increased operator radiation exposure. We tested the hypothesis that a simple lead drape would reduce operator exposure in transradial procedures. METHODS: Patients undergoing either diagnostic or interventional procedures using transradial access were assigned in an alternating manner to the use of a 0.5-mm lead apron across the patient's abdomen in addition to standard operator protection. Patients were divided into 4 groups: (left enhanced shielding vs left standard shielding; right enhanced shielding vs right standard shielding). Dosimeters were taped to the primary and secondary operators' left wrist and outside the thyroid guard. The operator exposure was measured for each site on every case in centigray. RESULTS: In standard shielded patients, there was no increase in operator exposure between the left and right approach patients at any measurement site. Measured exposure was reduced with enhanced shielding at all dosimeter sites except the secondary operator's collar (both left and right) and the primary operator's collar from the right. There was no significant difference in fluoroscopy, air kerma, or dose area product between standard and enhanced shielded patients. CONCLUSIONS: The use of a lead drape reduces the rate of operator radiation exposure at multiple measurement sites. Use of the left radial approach was not associated with an increase in operator exposure compared with the right radial approach. PMID- 23453096 TI - Impact of a dedicated "radial lounge" for percutaneous coronary procedures on same-day discharge rates and bed utilization. AB - BACKGROUND: Two advantages of transradial coronary procedures are an increased potential for same-day discharge and better resource management. This study assessed the impact of a dedicated "radial lounge" (1) on the rate of same-day discharge after elective percutaneous coronary intervention (PCI) and coronary angiography and (2) on bed utilization. METHODS: We compared our unit's rates of same-day discharge in patients who underwent elective PCI or coronary angiography in the year before and in the year after the opening of a dedicated radial lounge for elective patients. RESULTS: In its first year of operation, 439 patients who underwent PCI and 1,109 patients who underwent angiography were managed in the radial lounge. Among these patients, the rate of same-day discharge was 84.7% after PCI and 97.0% after angiography. Requirement for overnight admission was significantly more common after femoral access compared with radial access for both angiography (4.1% vs 2.8%, P < .05) and PCI (20.3% vs 14.2%, P < .01). The unit's overall rate of same-day discharge increased from 2.3% to 51.2% after elective PCI (P < .0005) and from 72.7% to 84.9% after elective angiography (P < .005). An estimated 595 bed days were saved through reduced overnight admissions in elective patients. CONCLUSIONS: Our unit's overall rates of same-day discharge after elective PCI and coronary angiography increased dramatically in the year after the opening of a dedicated radial lounge. This was directly attributable to the high rates of same-day discharge in radial lounge patients. The radial lounge impacted favorably on in-patient bed capacity. PMID- 23453097 TI - Comparison of costs between transradial and transfemoral percutaneous coronary intervention: a cohort analysis from the Premier research database. AB - BACKGROUND: Transradial intervention (TRI) for percutaneous coronary intervention (PCI) is associated with shorter length of stay, fewer bleeding complications, and higher patient satisfaction. Less is known about the economic implications of TRI in contemporary practice. METHODS: This is a retrospective inpatient cohort analysis using medical data from the Premier research database (Premier Inc, Charlotte, NC), which contains approximately one-fifth of all acute care hospitalizations in the US annually. The database was queried to identify patients undergoing PCI from 2004 to 2009. Patients with TRI were identified by center-level charge codes for radial-specific devices and matched one-to-many with patients undergoing transfemoral intervention (TFI). Adjusted total hospitalization costs were compared between patients undergoing TRI and TFI. Patients were additionally classified by periprocedural risk of bleeding as low (<1%), moderate (1%-3%), and high (>3%). RESULTS: There were 609 TRI cases matched with 60,900 TFI cases. Total adjusted costs for TRI were $11,736 +/- $6,748 vs $12,288 +/- $23,418 for TFI, a difference of $553 favoring TRI (95% CI $45-$1,060, P = .033). Day-of-procedure costs were similar, at $17 higher for TRI compared with TFI (95% CI -$318 to $353, P = .37); however, costs from the following day until discharge were significantly lower for TRI (-$571, 95 % CI $912 to $229, P = .001). Postprocedure costs were lower for patients with TRI vs patients with TFI at moderate (-$478, 95% CI -$887 to $69, P = .022) and high ( $917, 95% CI -$1,814 to $19, P = .045) risk of bleeding. CONCLUSIONS: In a nationwide administrative hospital database, transradial compared with transfemoral PCI access was associated with lower average direct hospital costs and shorter length of hospital stay. Postprocedure costs associated with TRI were also lower in patients at greater bleeding risk. PMID- 23453098 TI - Transradial and transfemoral coronary angiography and interventions: 1-year outcomes after initiating the transradial approach in a cardiology training program. AB - BACKGROUND: Limited data are available regarding the safety and feasibility of initiating transradial (TR) diagnostic coronary angiography (CA) and percutaneous coronary intervention (PCI) in cardiology fellowship programs. METHODS: From July 2010 to June 2011, University of California, Davis Medical Center, adopted the TR approach with supervised cardiology fellows as the primary operators. Procedural variables and clinical outcomes of TR and transfemoral (TF) procedures were compared. To minimize confounding variables, ST-elevation myocardial infarction, bypass graft interventions, chronic total occlusions, and procedures with concomitant right heart catheterizations were excluded. To reflect the learning curve of the TR approach, this experience was assessed in 2 sequential 6-month periods. RESULTS: A total of 402 diagnostic CAs and 255 PCIs were included. Transradial access was used in 141 (35%) of the CAs and in 72 (28%) of PCIs. Within the TR-CA and TF-CA (n = 261) groups, there was no difference between fluoroscopy (10.4 +/- 6.0 vs 11.0 +/- 8.9, P = .63) or procedure (31.8 +/- 11.5 vs 33.2 +/- 13.8, P = .55) time throughout the academic year with a significant trend toward lower contrast use (128 +/- 52 vs 110 vs 50, P = .04) by the second half. In addition, during the second half of the academic year, the TR-CA showed significantly higher fluoroscopy (11.0 +/- 8.9 vs 6.7 +/- 6.8, P = .001) and procedure (33.2 +/- 13.8 vs 27.2 +/- 11.6, P = .0015) times when compared with TF CA. Transfemoral PCI (n = 183) and TR-PCI showed no significant difference between all fluoroscopy and procedure time and contrast use when comparing the 2 halves of the academic year. When comparing TF with TR within each academic half year, there was no difference within the PCI group. Vascular complications were less with the TR approach. Overall procedural success rates were high, and there were low rates of crossover and periprocedural complications in both the TR and the TF groups. CONCLUSION: A TR approach is safe for CA and PCI when performed by supervised operators in training. Although the learning curve for trainees appears slower for TR-CA compared with TF-CA, cardiology fellowship training programs should be encouraged to adopt TR procedures as part of their curriculum. PMID- 23453099 TI - Influence of access site choice on incidence of neurologic complications after percutaneous coronary intervention. AB - BACKGROUND: Neurologic complications (NCs) are a rare but potentially devastating complication that may follow percutaneous coronary intervention (PCI). In recent years, there has been an increase in use of transradial access, driven by a developing body of evidence that favors its use over femoral access. Concerns have been raised, however, that transradial access may increase the risk of NC compared with transfemoral access. We aimed to investigate the influence of access site selection on the occurrence of NCs through a period of transition during which transradial access became the dominant route for PCI procedures performed in the United Kingdom. METHODS: We performed a retrospective analysis of the British Cardiovascular Intervention Society database between January 2006 and December 2010. The data were split into 2 cohorts based on access site. An NC was defined as a periprocedural ischemic stroke, hemorrhagic stroke, or transient ischemic attack occurring before hospital discharge. Binary logistic multivariate analysis was used to investigate the influence of access site utilization on NCs and adjust for measured confounding factors. RESULTS: Between 2006 and 2010, the use of radial access increased from 17.2% to 50.8% of all PCI procedures. A total of 124,616 radial procedures and 223,476 femoral procedures were studied with a NC rate of 0.11% in each cohort. In univariate (odds ratio 1.01, 95% CI 0.82 1.24, P = .93) and multivariate analysis (odds ratio 0.99, 95% CI 0.79-1.23, P = .91), there was no significant association between the use of radial access and the occurrence of NCs. CONCLUSION: These results suggest that radial access is not associated with an increased risk of clinically detected NCs, even during a period when there was a rapid evolution in the preferred access site for PCI in the United Kingdom. These are reassuring results, particularly for operators embarking on a change to radial access for PCI. PMID- 23453100 TI - Successive transradial access for coronary procedures: experience of Quebec Heart Lung Institute. AB - BACKGROUND: Transradial approach (TRA) for cardiac catheterizations and interventions improves clinical outcomes compared with transfemoral access, and its use is increasing worldwide. However, there are limited data on successive use of same artery for repeat procedures. METHODS: Between May 2010 and May 2011, all consecutive patients undergoing a repeat TRA procedure (>=2) were retrospectively identified. Success rates and reasons for failure to use ipsilateral radial artery for repeat access were identified. RESULTS: A total of 519 patients underwent 1,420 procedures. In 480 patients (92%), right radial artery was used as initial access, and left radial artery, in 39 patients. All patients underwent >=2 procedures; 218 patients, >=3; 87 patients, >=4; 39 patients, >=5; 19 patients, >=6; 11 patients, >=7; and 5 patients, >=8 procedures. Two patients had, respectively, 9 and 10 procedures. The success rate for second attempt was 93%, 81% for third, and declining to 60% for >=8. Linear regression analysis estimated a 5% failure rate for each repeat attempt (R(2) = 0.87, P = .007). The main reason for failure was related to clinical radial artery occlusion (RAO) including absent or faint pulse, poor oximetry, and failed puncture. All patients with clinical RAO were asymptomatic. By multivariate analysis, female gender (odds ratio [OR] 3.08, 95% CI 1.78-5.39, P < .0001), prior coronary artery bypass graft (OR 5.26, 95% CI 2.67-10.42, P < .0001), and repeat radial access (OR 2.14, 95% CI 1.70-2.76, P < .0001) were independent predictors of radial access failure. CONCLUSION: Successive TRA is both feasible and safe in most cases for up to 10 procedures. However, failure rate for TRA increases with successive procedures, primarily due to clinical RAO. Strategies to minimize the risks of chronic clinical RAO and allow repeat use of ipsilateral radial artery need to be further defined. PMID- 23453101 TI - The practice of transradial percutaneous coronary intervention in the Washington State Clinical Outcomes Assessment Program. AB - BACKGROUND: Transradial percutaneous coronary intervention (tPCI) as opposed to the femoral approach (fPCI) is associated with lower rates of bleeding. The purposes of this study were to describe the use of tPCI in the Washington State Clinical Outcomes Assessment Program, identify the predictors of bleeding, and determine whether tPCI was associated with less bleeding in women vs men, age <75 years vs >=75 years, and baseline creatinine <2.0 mg/dL vs >=2.0 mg/dL. METHODS: This study included 23,599 individuals who had a first tPCI or fPCI performed in 30 centers in Washington State in 2010 and 2011. Data were collected according to specifications from the American College of Cardiology National Cardiovascular Data Registry Cath-PCI version 4.3. The American College of Cardiology National Cardiovascular Data Registry bleeding model was used to calculate adjusted rates. RESULTS: Transradial percutaneous coronary intervention was used in only 5% of procedures, and in just 3 centers, tPCI was used in >10% of cases. Patient demographics and medical histories were similar in tPCI and fPCI, although the percent of acute cases was higher in fPCI (68% vs 45%, P < .0001). The overall bleeding rate was 2.2%, and the 3 most important predictors of bleeding were acute procedure, women, and age >=75 years. For women, unadjusted rates of bleeding were 1.4% for tPCI and 4.0% for fPCI (P = .013). Among women, adjusted rates were almost 20% lower for tPCI (3.3% vs 4.1%). CONCLUSION: In Washington State, tPCI was used infrequently, although it was associated with lower bleeding rates in high-risk groups including women. PMID- 23453102 TI - Early and late outcomes after primary percutaneous coronary intervention by radial or femoral approach in patients presenting in acute ST-elevation myocardial infarction and cardiogenic shock. AB - BACKGROUND: Although radial approach is increasingly used in percutaneous coronary interventions (PCIs) including in acute myocardial infarction (MI), patients with cardiogenic shock have been excluded from comparisons with femoral approach. The aim of our study was to compare clinical outcomes in patients undergoing primary PCI with cardiogenic shock by radial and femoral approach. METHODS AND RESULTS: From 2,663 patients presenting with ST-elevation MI in 2 large volume radial centers, we identified 197 patients (7.4%) with signs of cardiogenic shock immediately before undergoing primary PCI. Radial approach was used in 55% of cases when at least 1 radial artery was weakly palpable, either spontaneously or after intravenous noradrenaline bolus. Patients in the radial group were older (69 +/- 12 vs 64 +/- 12 years, P = .010), had less diabetes (13% vs 26%, P = .028), and required less often intubation prior PCI (42% vs 66%, P = .0006) or intraaortic balloon pump (36% vs 55%, P = .0096). Mortality at 1 year was 44% in the radial group and 64% in the femoral group (P = .0044). Independent predictors of late mortality included radial approach (hazard ratio [HR] 0.65, 95% CI 0.42-0.98, P = .041), the use of glycoprotein IIb-IIIa receptor inhibitors (HR 0.63, 95% CI 0.40-0.96, P = .032), baseline creatinine >=110 MUmol/L (HR 3.34, 95% CI 2.20-5.12, P < .0001), initial glycemia >200 mg/dL (HR 2.02, 95% CI 1.34-3.11, P = .0008), and age >65 years (HR 1.80, 95% CI 1.18-2.79, P = .006). CONCLUSION: Radial approach was safe and feasible in more than half of the patients with ST-elevation MI and cardiogenic shock treated by primary PCI. After adjustment for baseline and procedural characteristics, radial approach remained associated with better survival. However, prognosis of patients undergoing primary PCI in cardiogenic shock remains poor. PMID- 23453103 TI - TransRadial Education and Therapeutics (TREAT): shifting the balance of safety and efficacy of antithrombotic agents in percutaneous coronary intervention: a report from the Cardiac Safety Research Consortium. AB - Percutaneous coronary intervention (PCI) is an integral part of the treatment of coronary artery disease. The most common complication of PCI, bleeding, typically occurs at the vascular access site and is associated with short-term and long term morbidity and mortality. Periprocedural bleeding also represents the primary safety concern of concomitant antithrombotic therapies essential for PCI success. Use of radial access for PCI reduces procedural bleeding and hence may change the risk profile and net clinical benefit of these drugs. This new drug-device safety interaction creates opportunities to advance the safe and effective use of antithrombotic agents during PCI. In June 2010 and March 2011, leaders from government, academia, professional societies, device manufacturing, and pharmaceutical industries convened for 2 think tank meetings. Titled TREAT I and II, these forums examined approaches to improve the overall safety of PCI by optimizing strategies for antithrombotic drug use and radial artery access. This article summarizes the content and proceedings of these sessions. PMID- 23453105 TI - Prehospital system delay in ST-segment elevation myocardial infarction care: a novel linkage of emergency medicine services and in hospital registry data. AB - BACKGROUND: Emergency medical services (EMS) are critical in the treatment of ST segment elevation myocardial infarction (STEMI). Prehospital system delays are an important target for improving timely STEMI care, yet few limited data are available. METHODS: Using a deterministic approach, we merged EMS data from the North Carolina Pre-hospital Medical Information System (PreMIS) with data from the Reperfusion of Acute Myocardial Infarction in Carolina Emergency Departments Emergency Response (RACE-ER) Project. Our sample included all patients with STEMI from June 2008 to October 2010 who arrived by EMS and who had primary percutaneous coronary intervention (PCI). Prehospital system delays were compared using both RACE-ER and PreMIS to examine agreement between the 2 data sources. RESULTS: Overall, 8,680 patients with STEMI in RACE-ER arrived at a PCI hospital by EMS; 21 RACE-ER hospitals and 178 corresponding EMS agencies across the state were represented. Of these, 6,010 (69%) patients were successfully linked with PreMIS. Linked and notlinked patients were similar. Overall, 2,696 patients were treated with PCI only and were taken directly to a PCI-capable hospital by EMS; 1,750 were transferred from a non-PCI facility. For those being transported directly to a PCI center, 53% reached the 90-minute target guideline goal. For those transferred from a non-PCI facility, 24% reached the 120-minute target goal for primary PCI. CONCLUSIONS: We successfully linked prehospital EMS data with in hospital clinical data. With this linked STEMI cohort, less than half of patients reach goals set by guidelines. Such a data source could be used for future research and quality improvement interventions. PMID- 23453104 TI - Dynamic modeling of 90-day mortality in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. AB - AIMS: Dynamic risk models update the risk profile of ST-elevation myocardial infarction (STEMI) patients over the acute period following the event and have implications to clinical practice and research. METHODS AND RESULTS: Multivariable survival models were developed in 5,745 STEMI patients undergoing primary percutaneous coronary intervention (PCI) enrolled in the APEX-AMI trial to predict 90-day mortality from 4 clinically relevant times: baseline, 2 hours, 24 hours, and 96 hours. Culprit coronary thrombolysis in myocardial infarction flow grade, 30-minute post-PCI worst-lead ST-elevation residual, and in-hospital clinical events were considered in the models. The 90-day mortality was 4.7%; the cumulative proportion of mortality occurring within 2, 24, and 96 hours was 8%, 22%, and 40% respectively. Relative to the baseline risk factors, age and systolic blood pressure remained highly ranked in the post-baseline models. However, the relative importance of heart rate, Killip class, and creatinine declined, whereas markers of coronary reperfusion and in-hospital events (shock, congestive heart failure) became increasingly influential. The c-index increased from 0.819 at baseline to 0.847 at 96 hours. Over the forecasting periods, the proportion of "low-risk" (<1.1% 90-day mortality) patients increased from 20% to 49%. This approach derived from an unfolding series of models reveals the shifting levels of mortality risk from baseline to 96 hours. CONCLUSION: This novel approach in STEMI patients undergoing primary PCI demonstrates the dynamic nature of risk over time and may prove useful in understanding risk and in clinical decision making. PMID- 23453106 TI - Risk stratification in patients with unstable angina using absolute serial changes of 3 high-sensitive troponin assays. AB - BACKGROUND: It is unknown whether unstable angina (UA) results in previously nondetectable low-level myocardial necrosis. We compared the pattern of myocardial necrosis between patients with UA, acute myocardial infarction (AMI), and noncardiac chest pain (NCCP) using 3 high-sensitive cardiac troponin (hs-cTn) assays. METHODS: In a multicenter study, we enrolled 842 unselected patients with acute chest pain in the emergency department. Roche hs-cTnT, Beckman Coulter hs cTnI, and Siemens hs-cTnI were determined in a blinded fashion at presentation and after 1, 2, 3, and 6 hours. The final diagnosis was adjudicated by 2 independent cardiologists. RESULTS: A change in hs-cTn of >=2 ng/L within the first hour after presentation as assessed with Roche hs-cTnT, Beckman Coulter hs cTnI, and Siemens hs-cTnI was observed in 26%, 31%, and 32% of patients with UA (n = 115) compared with 91%, 92%, and 96% in patients with AMI (n = 120) and 12%, 23%, and 16% in patients with NCCP (n = 415; P < .001 for all comparisons between UA and AMI, P > .05 for all comparisons between UA and NCCP). In patients with UA, such a 1-hour change in hs-cTn of >=2 ng/L was associated with an increased risk of death or AMI during the 30-day follow-up (P = .003, .03, .03) and 2-year follow-up (P < .001, .002, and .006). CONCLUSIONS: In marked contrast to patients with AMI, most patients with UA do not exhibit relevant hs-cTn changes. The minority of UA with hs-cTn changes, however, has a significantly worse short- and long-term outcome. PMID- 23453107 TI - Incidence of heart failure and mortality after acute coronary syndromes. AB - BACKGROUND: The long-term incidence of heart failure (HF) in ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA) patients is uncertain. We examined the 1-year incidence of HF and its association with mortality among patients surviving their first acute coronary syndrome (ACS) hospitalization. METHODS AND RESULTS: A retrospective cohort study of patients, aged >=20 years, with no prior HF, hospitalized for the first time with ACS between April 1, 2002, and December 31, 2008, in Alberta, Canada, and followed up for 1 year. Index HF was defined as HF that developed as a complication during the index ACS hospitalization, and post discharge HF, as HF developing after discharge from the index ACS hospitalization. Among 9,406 STEMI, 11,008 NSTEMI, and 4,910 UA patients, 13.6%, 14.8%, and 5.2% had index HF, respectively (P < .01). At 1-year, cumulative HF rates were 23.4% in STEMI, 25.4% in NSTEMI, and 16% in UA patients. Among hospital survivors, 1-year mortality rate was 13.9% in patients with index HF, 10.6% in patients with postdischarge HF, and 2.4% in patients with no HF. In multivariable analysis, both index HF (adjusted hazard ratio 3.2, 95% CI 2.7-3.7) and postdischarge HF (adjusted hazard ratio 4.6, 95% CI 3.9-5.4) were associated with 1-year mortality. CONCLUSIONS: There are significant differences in the incidence of HF among STEMI, NSTEMI, and UA patients. The increased mortality risk associated with index HF and postdischarge HF suggests a need for vigilant follow-up of all ACS patients for prompt detection and treatment of HF. PMID- 23453108 TI - Wearable defibrillators in uninsured patients with newly diagnosed cardiomyopathy or recent revascularization in a community medical center. AB - BACKGROUND: The wearable defibrillator (WD) can prevent sudden death in patients who are not candidates for an implantable cardioverter-defibrillator (ICD). OBJECTIVES: We studied outcomes of uninsured patients prescribed a WD. METHODS: A consecutive series of patients were prescribed a WD because of a new onset cardiomyopathy or coronary artery revascularization with a predischarge ejection fraction (EF) <=35%. Patients were followed up for WD compliance, events, EF changes, and subsequent ICD implants. RESULTS: Among 134 patients with cardiomyopathy diagnosed at a mean age of 52.7 +/- 11.6 years and with a mean EF of 22.5% +/- 7.3%, 125 patients (93%) were newly diagnosed with cardiomyopathy. There were 77 patients (57%) with nonischemic cardiomyopathy and 57 (43%) with ischemic cardiomyopathy. Patients wore the WD for a mean of 14.1 +/- 8.1 hours per day for 72 +/- 55 days. There were no shocks or detected arrhythmias. Forty eight patients (35%) were lost to follow-up. No ICDs were implanted in 33 (38%) of the other 86 patients, whose EF improved to above 35%. Of the 53 patients with persistent EF <=35%, 44 patients (83%) received an ICD. However, 12 (27%) of these 44 patients had ICD implant before 90 days after the index event. CONCLUSION: There was a high lost to follow-up rate in an uninsured population. There were no sustained ventricular tachyarrhythmia events. Wearable defibrillator utilization prevented ICD implant in the subgroup of patients with EF improvement, although there were still premature implants based on Centers for Medicare and Medicaid Guideline waiting periods. PMID- 23453109 TI - Outcome and safety of same-day-discharge percutaneous coronary interventions with femoral access: a single-center experience. AB - BACKGROUND: Ongoing development in percutaneous coronary intervention (PCI) techniques and closing devices facilitates same-day-discharge in patients undergoing uncomplicated PCI procedures. We examined the safety and outcome in low-risk patients discharged the same day as PCI with femoral access was performed. METHODS: From January 1, 2010, through December 31, 2010, the outcomes of same-day discharge in 355 (19.6%) of in total 1,809 patients undergoing PCI were analyzed. Composite end point included major adverse cardiac or cerebral events and/or bleeding/vascular complications within 24 hours and 30 days. Major adverse cardiac and cerebral events were defined as cardiac death, myocardial infarction, stroke, coronary artery bypass grafting, or repeat PCI. RESULTS: The mean age of the study population was 64.5 years (40.0-93.0 years), 17.3% of the patients were >=75 years old. The indication for PCI was: stable angina pectoris (n = 277, 78.0%) and unstable angina pectoris/non-ST-segment elevation myocardial infarction (n = 78, 22.0%). In all patients femoral access was used, and the puncture site was closed with the closing-device AngioSeal. No major adverse cardiac and cerebral events were seen within 24 hours or 30 days except in 1 patient who had target lesion revascularization done as PCI 4 days post procedure. Three patients had bleeding/vascular complications; 2 patients were re admitted within 24 hours due to access-site hematomas, which were treated with manual compression and bed-rest regimes. One patient developed a pseudoaneurysm within 12 hours post-procedure. CONCLUSIONS: Same-day-discharge after uncomplicated PCI using femoral access is safe when patients are properly selected. The strategy may improve and benefit health costs in the future. PMID- 23453110 TI - Characteristics of culprit atheromatous plaques obtained in vivo by intravascular ultrasound radiofrequency analysis: results from the CULPLAC study. AB - OBJECTIVES: We used virtual histology-intravascular ultrasound (VH-IVUS) to investigate the characteristics of culprit lesions in acute coronary syndromes (ACS). BACKGROUND: Autopsy studies of patients who died of ACS have shown that culprit atheromatous plaques almost always contain a large lipid-necrotic core covered by a ruptured thin fibrous cap. There are no studies of sufficient size that have assessed the in vivo characterization of plaques responsible for ACS. METHODS: Patients undergoing angiography for stable ischemic heart disease and ACS (with and without ST-segment elevation) were enrolled in a prospective study. Lesions in patients with stable angina were classified as stable and those in patients with ACS as culprit or nonculprit. RESULTS: The study included 189 patients: VH-IVUS was used to assess 253 lesions (73 stable, 82 nonculprit, and 98 culprit lesions). The thin-cap fibroatheroma phenotype (VH-TCFA) was more frequent among lesions in patients with ACS (55.1% in culprit lesions, 36.6% in nonculprit lesions and 14.4% in stable lesions; P = .007). The arc of the VH-TCFA exposed to the vessel lumen was significantly greater in culprit lesions than in nonculprit lesions (122.28 degrees +/- 58 vs 89.46 degrees +/- 52; respectively; P = .007). Multivariate analysis showed that VH-TCFA (OR 2.1; P = .033), calcified nodules (OR 2.1; P = .046), positive remodeling (OR 3.5; P < .001) and necrotic core volume (OR 1.02;P = .009) were independently associated with a clinically identified culprit lesion. CONCLUSIONS: Plaque phenotype, rather than the proportion of each tissue, appears to be associated with plaque instability. VH-TCFA, particularly subtype IV, is associated with lesions responsible for ACS. PMID- 23453111 TI - Effects of stem cell mobilization by granulocyte colony-stimulating factor on endothelial function after sirolimus-eluting stent implantation: a double-blind, randomized, placebo-controlled clinical trial. AB - BACKGROUND: Stem cell mobilization by granulocyte colony-stimulating factor (G CSF) has been shown to enhance endothelial healing after spontaneous or iatrogenic arterial disruption. Granulocyte colony-stimulating factor treatment might attenuate endothelial dysfunction after sirolimus-eluting stent (SES) implantation that may be associated with adverse cardiac events during follow-up. This prospective, double-blind, randomized, placebo-controlled study investigated whether G-CSF improved endothelial dysfunction after SES implantation. METHODS: One hundred patients who underwent SES implantation were randomly assigned to the G-CSF (n = 50) or the placebo group (n = 50). They received daily subcutaneous injection of 300 MUg G-CSF or saline for 5 days. Endothelial function was estimated by measuring the coronary vasoreactivity in the segments 15 mm proximal and distal to SES in response to intracoronary infusion of acetylcholine (10(-8) and 10(-7) mol/L) at 9-month follow-up. RESULTS: Follow-up angiography was performed in 41 G-CSF patients (82%) and 46 placebo patients (92%) (P = .14). Changes in coronary diameter in response to acetylcholine infusion in the proximal segment were not significantly different between the 2 groups. However, vasoconstriction in the distal segment in response to 10(-8) mol/L (-3.9% +/- 6.4% vs -7.0% +/- 8.1%, P < .05) and 10(-7) mol/L (-8.8% +/- 11.0% vs -15.2% +/- 7.6%, P < .01) acetylcholine infusion was attenuated in the G-CSF group. Endothelium-independent vasodilatation after nitrate infusion did not differ between the 2 groups. CONCLUSION: Granulocyte colony-stimulating factor attenuates endothelial dysfunction after SES implantation. PMID- 23453112 TI - Closed versus open cell stent for high-risk percutaneous coronary interventions in ST-elevation acute myocardial infarction: the Closed versus Open Cells stent for High risk percutaneous coronary Interventions in ST-Elevation acute myocardial infarction (COCHISE) pilot study. AB - BACKGROUND: Stent deployment may be associated with distal embolization and slow flow in coronary thrombotic lesions. There are no data on the risk of distal thrombus embolization according to the stent design. The aim was to evaluate coronary flow after percutaneous coronary interventions (PCI) in acute myocardial infarction according to the employed stent (closed versus open cell design). METHODS: From March 2010 to December 2011, 223 consecutive patients with acute ST elevation myocardial infarction were randomized to primary PCI either with an open cell (112 patients, 88 men) or with a closed cell stent design (111 patients, 92 men). The primary endpoint was the corrected TIMI frame count (cTFC) after the procedure. RESULTS: There were no significant differences in procedural success nor in-stent deployment in the 2 groups. At baseline, there were no significant differences in cTFC between the 2 groups (70 +/- 37 and 67 +/- 39, P = .65, respectively). After the procedure, the open cell group showed significantly higher cTFC compared to the closed cell group (18 +/- 11 and 15 +/- 5, P = .003 respectively). This difference was associated with a significant lower rate of TIMI 3 flow (87% and 95%, P = .037) and myocardial blush grade 3 (65% and 87%, P = .001) in the open compared to the closed cell group. There were 2 cases of death in the open cell and 1 case in the closed cell group. CONCLUSIONS: The use of a closed cell stent design rather than an open cell during PCI for acute ST-elevation myocardial infarction is associated with better coronary angiographic flow after PCI. PMID- 23453113 TI - Ischemic stroke associated with left cardiac catheterization: the importance of modifiable and non-modifiable risk factors. AB - BACKGROUND: Stroke associated with left cardiac catheterization is a devastating complication, and its incidence has not changed over the decades. We investigated the incidence, in-hospital outcomes and the modifiable and non-modifiable risk factors for periprocedural ischemic stroke. METHODS: Our retrospective cohort study included all patients experiencing periprocedural ischemic stroke among the 24,500 patients who underwent left cardiac catheterization between January 2003 and October 2010. The case group was compared with a group of control patients randomly selected among those who underwent the procedure during this period. RESULTS: Ischemic cerebrovascular events attested by brain imaging occurred in 37 patients (0.15% of procedures), transient ischemic attack occurred in 9 cases, and persistent neurological deficit occurred in 28 cases. Patients who developed strokes were more likely to be older and were more often female with a greater prevalence of comorbidities. Emergency and longer procedures were more frequent in patients in the case group who had more coronary complications. A multivariate analysis identified diabetes mellitus (adjusted odds ratio (OR) 4.2; 95% CI 1.8 9.9; P < .001), chronic renal dysfunction (OR 2.4; 95% CI 1.1-5.4; P < .001), known cerebrovascular disease (OR 5.1; 95% CI 2.3-11.5; P < .001), emergency procedure (OR 3.1; 95% CI 1.4-9.2; P < .01) and recent congestive heart failure (OR 6.1; 95% CI 2.9-13; P < .001) as independent predictors for stroke. The independent modifiable predictive factors were represented by left ventricular angiography (OR 7.5; 95% CI 2.7-21; P < .001), and low operator volume (OR 3.1; 95% CI 1.3-7.4; P < .01). CONCLUSION: Limiting the performance of left cardiac catheterization to high volume operators and avoiding unnecessary left ventricular angiography may reduce periprocedural ischemic stroke. PMID- 23453114 TI - Thrombotic and bleeding complications after orthopedic surgery. AB - BACKGROUND: Thrombotic and bleeding complications are major concerns during orthopedic surgery. Given the frequency of orthopedic surgical procedures and the limited data in the literature, we sought to investigate the incidence and risk factors for thrombotic (myocardial necrosis and infarction) and bleeding events in patients undergoing orthopedic surgery. METHODS AND RESULTS: We performed a retrospective cohort analysis of 3,082 consecutive subjects >=21 years of age undergoing hip, knee, or spine surgery between November 1, 2008, and December 31, 2009. Patient characteristics were ascertained using International Classification of Diseases, Ninth Revision, diagnosis coding and retrospective review of medical records, and laboratory/blood bank databases. In-hospital outcomes included myocardial necrosis (elevated troponin), major bleeding, coded myocardial infarction, and coded hemorrhage as defined by International Classification of Diseases, Ninth Revision, coding. Of the 3,082 subjects, mean age was 60.8 +/- 13.3 years, and 59% were female. Myocardial necrosis, coded myocardial infarction, major bleeding, and coded hemorrhage occurred in 179 (5.8%), 20 (0.7%), 165 (5.4%), and 26 (0.8%) subjects, respectively. Increasing age (P < .001), coronary artery disease (P < .001), cancer (P = .004), and chronic kidney disease (P = .01) were independent predictors of myocardial necrosis, whereas procedure type (P < .001), cancer (P < .001), female sex (P < .001), coronary artery disease (P < .001), and chronic obstructive pulmonary disease (P = .01) were independent predictors of major bleeding. CONCLUSION: There is a delicate balance between thrombotic and bleeding events in the perioperative period after orthopedic surgery. Perioperative risk of both thrombosis and bleeding deserves careful attention in preoperative evaluation, and future prospective studies aimed at attenuating this risk are warranted. PMID- 23453115 TI - Data quality of an electronic health record tool to support VA cardiac catheterization laboratory quality improvement: the VA Clinical Assessment, Reporting, and Tracking System for Cath Labs (CART) program. AB - BACKGROUND: Electronic health records (EHRs) have been identified as a key tool for quality improvement (QI) in health care. However, EHR data must be of sufficient quality to support QI efforts. In 2005, the Department of Veterans Affairs (VA) began using a novel EHR tool-the CART Program-to support QI in cardiac catheterization laboratories. We evaluated whether data collected by the CART Program were of sufficient quality to support QI. METHODS: We evaluated the data validity, completeness, and timeliness of CART Program data using a random sample of 200 coronary procedures performed in 10 geographically diverse VA medical centers. RESULTS: Of 1690 observations in the CART Program data repository, 1664 (98.5%) were valid, as compared to the VA medical record. The CART Program reports were more complete than cardiac catheterization laboratory reports generated prior to CART Program implementation (79% vs. 63.1%, P < .001). Finally, there was a trend toward earlier availability of completed procedure reports to treating providers after CART Program implementation, with 75% of CART Program reports available within 1 day compared to 4 days for reports generated prior to CART Program implementation (P = .06). CONCLUSIONS: Cardiac catheterization reports generated by the VA's CART Program demonstrate excellent data validity, superior completeness, and a trend toward more timely availability to referring providers relative to cardiac catheterization laboratory reports generated prior to CART Program implementation. This demonstration of data quality is a key step in realizing CART Program's aim of supporting QI efforts in VA catheter laboratories. PMID- 23453116 TI - Bilateral sagittal split osteotomy in a mandible previously reconstructed with a non-vascularized bone graft. AB - We report a bilateral sagittal split osteotomy (BSSO) in a reconstructed mandible. A 28-year-old woman underwent a segmental mandibulectomy due to a multicystic ameloblastoma in the left jaw. After primary plate reconstruction, final reconstruction was performed with a left posterior iliac crest cortico cancellous autograft. Due to a pre-existing Class II malocclusion, the patient was analyzed for combined orthodontic-surgical treatment. Subsequently, after 1 year of orthodontic treatment, the BSSO was planned. The sagittal split was performed in the remaining right mandible and on the left side in the iliac crest cortico-cancellous autograft. Ten months later, oral rehabilitation was completed with implant placement in the neomandible. Follow-up showed a Class I occlusion, with good function. The patient was very satisfied with the functional and aesthetic results. This case shows that a BSSO can be performed in a reconstructed mandible, without side effects and with good functional and aesthetic results. PMID- 23453117 TI - Surgical outcomes of 43 cases with adenoid cystic carcinoma of the external auditory canal. AB - PURPOSE: To evaluate surgical outcomes for adenoid cystic carcinoma (ACC) of the external auditory canal (EAC). METHODS: Forty-three patients with ACC of the EAC in Eye and ENT Hospital of Fudan University were analyzed retrospectively for survival. The patients were staged according to the modified Pittsburgh staging system. Thirteen patients with T1 stage underwent local resection (LR), 6 patients with T1 stage underwent lateral temporal bone resection (LTBR), and 8 patients with T1 stage underwent LTBR including superficial parotidectomy (SP). Two patients with T2 stage underwent LTBR, and 1 patient with T2 stage underwent LTBR+SP. Three patients with T3 stage underwent LTBR. One patient with T4 stage underwent LTBR, two patients with T4 stage underwent subtotal temporal bone resection (STBR), and 7 patients with T4 stage underwent LTBR+SP. RESULTS: Of all patients that underwent surgery, 13 died of their primary cancers during the follow-up time. The 5-year survival rates of patients with T stages 1 through 4 were 85%, 67%, 67%, and 30%, respectively. There was statistically significant difference in 5-year survival rate between T1 and other stages (T2, T3, T4) using the log-rank test (p<0.05). There was significant difference in 5-year survival rate between T4 and other stages using the log-rank test (p<0.05). The 5-year survival rates after LR, LTBR or LTBR plus SP for T1 were 77%, 87% and 100%, respectively. The 5-year survival rates after LTBR, STBR or LTBR plus SP for T4 were 0%, 50% and 29%, respectively. The 5-year survival rates for 19 patients with clear surgical margins and 24 patients with positive margins were 89% and 54%, respectively. The 5-year survival rates of patients with radiotherapy and without radiotherapy were 62% and 86%, respectively. CONCLUSION: An en bloc resection including superficial parotidectomy is favored in an effort to produce negative surgical margins for ACC of the EAC. Adjunctive radiotherapy is used for patients with positive margins and in advanced lesions. PMID- 23453118 TI - Comparison of oxygen desaturation patterns in children and adults with sleep disordered breathing. AB - PURPOSE: Although the number of apnea-hypopnea episodes per hour apnea-hypopnea index (AHI) is typically used to evaluate sleep-disordered breathing (SDB) in adults, it does not provide an accurate characterization of SDB in children. We investigated differences in SDB patterns in children and adults to evaluate SDB severity in children. MATERIALS AND METHODS: Fifteen adults (mean age, 45.3 +/- 8.4 years) and 15 children (mean age, 6.7 +/- 3.9 years) with adenotonsillar hypertrophy underwent standard polysomnography. The change of oxygen saturation (DeltaSpO2) was defined as the difference between baseline SpO2 during stable nighttime breathing and the lowest SpO2 accompanied by an apnea-hypopnea event. The number of apnea-hypopnea episodes was determined using two different criteria to define an episode (criterion 1: cessation of airflow for at least 10s; criterion 2: cessation of airflow for at least two consecutive breaths). RESULTS: Mean DeltaSpO2 accompanied by obstructive apneas lasting <=10 s was significantly greater in children than in adults, although there was no significant difference in the duration of apnea-hypopnea episodes. The slope of the regression line between DeltaSpO2 and apnea-hypopnea duration in children was greater than in adults (P<0.005). AHI in children was higher when calculated using criterion 2 compared to criterion 1 (10.9 +/- 9.4 vs. 6.5 +/- 4.9/h, P=0.003). CONCLUSIONS: DeltaSpO2 is a good indicator of SDB severity in children, and should therefore be considered in the diagnosis and treatment of pediatric SDB along with AHI. PMID- 23453120 TI - Granulocyte colony-stimulating factor with or without stem cell factor extends time to premature ovarian insufficiency in female mice treated with alkylating chemotherapy. AB - OBJECTIVE: To examine gonadal protective properties of granulocyte colony stimulating factor (G-CSF) alone or in combination with stem cell factor (SCF) in female mice treated with high-dose alkylating chemotherapy. DESIGN: Experimental laboratory animal study. SETTING: Tertiary care academic hospital and research institute. ANIMAL(S): Six- and 8-week-old C57Bl/6 female mice. INTERVENTION(S): Adult female mice were treated with [1] cyclophosphamide and busulfan (CTx), [2] CTx + G-CSF/SCF, [3] CTx + G-CSF, or [4] normal saline and dimethyl sulfoxide (DMSO; vehicle control). MAIN OUTCOME MEASURE(S): Follicle counts, microvessel density, cellular response to DNA damage, and litter production. RESULT(S): G-CSF +/- SCF increased microvessel density and decreased follicle loss in CTx-treated female mice compared with CTx-only treated female mice. Mice administered CTx alone exhibited premature ovarian insufficiency, with only 28% of mice producing two litters. However, 100% of mice receiving CTx with G-CSF + SCF, and 80% of mice receiving CTx + G-CSF alone produced at least three litters and 20% of mice in each group produced five litters. CONCLUSION(S): Treatment of mice with G-CSF decreases chemotherapy-induced ovarian follicle loss and extends time to premature ovarian insufficiency in female mice. Further studies are needed to validate these preclinical results in humans and compare efficacy with the established GnRH analogue treatments. PMID- 23453121 TI - Elective single embryo transfer trends and predictors of a good perinatal outcome -United States, 1999 to 2010. AB - OBJECTIVE: To assess trends in elective single ET and identify factors associated with a good perinatal outcome. DESIGN: Retrospective cohort study. SETTING: Clinic-based data. PATIENT(S): A total of 886,686 fresh, nondonor cycles reported to the National Assisted Reproductive Technology Surveillance System during 1999 2010, of which 17,166 met criteria for elective single ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of elective single ET and good perinatal outcome (term, singleton infant with normal birth weight). RESULT(S): In 2010, elective single ET comprised 5.6% of all fresh transfers, representing an eightfold increase since publication of first guidelines in 2004 recommending elective single ET. Compared with other ETs, elective single ETs were nearly twice as likely to result in a good perinatal outcome (37.1% vs. 18.9%, respectively). Among women using elective single ET, those aged <35 and 35-37 years had a good perinatal outcome (40.2% and 32.5%, respectively). In multivariable, log-binomial analyses, factors positively associated with a good perinatal outcome included male factor infertility, day 5 ET, and having >=3 supernumerary embryos for cryopreservation. CONCLUSION(S): Between 1999 and 2010, national rates of elective single ET increased. Given the frequency of good perinatal outcomes among women aged 35-37 years, guidelines for elective single ET could be expanded to include patients in this age group with favorable prognoses. PMID- 23453122 TI - High expression of cyclic nucleotide phosphodiesterase 7B mRNA predicts poor prognosis in mantle cell lymphoma. AB - In order to determine the relationship between expression of cyclic nucleotide phosphodiesterase isoform 7B (PDE7B) and mantle cell lymphoma (MCL) progression, PDE7B mRNA expression was measured by qRT-PCR in 21 untreated MCL patients with bone marrow involvement and 20 healthy donors. The expression level of PDE7B was markedly higher in MCL patients compared with normal controls (P=0.001), and the higher level of PDE7B expression was associated with unfavorable cytogenetic characteristics in MCL. It was showed that higher expression of PDE7B might be a novel unfavorable prognostic indicator in MCL, which possess important clinical significance. PMID- 23453123 TI - Usage of documented pre-hospital observations in secondary care: a questionnaire study and retrospective comparison of records. AB - BACKGROUND: The patient handover is important for the safe transition from the pre-hospital setting to secondary care. The loss of critical information about the pre-hospital phase may impact upon the clinical course of the patient. METHODS: University Hospital Emergency Care registrars answered a questionnaire about how they perceive clinical documentation from the ambulance services. We also reviewed patient records retrospectively, to investigate to what extent eight selected parameters were transferred correctly to hospital records by clinicians. Only parameters outside the normal range were selected. RESULTS: The registrars preferred a verbal handover with hand-written pre-hospital reports as the combined source of clinical information. Scanned report forms were infrequently used. Information from other doctors was perceived as more important than the information from ambulance crews. Less than half of the selected parameters in pre-hospital notes were transferred to hospital records, even for parameters regarded as important by the registrars. Abnormal vital signs were not transferred as often as mechanism of injury, medication administered and immobilisation of trauma patients. CONCLUSIONS: Data on pre-hospital abnormal vital signs are frequently not transferred to the hospital admission notes. This information loss may lead to suboptimal care. PMID- 23453124 TI - The limits for life under multiple extremes. AB - Life on Earth is limited by physical and chemical extremes that define the 'habitable space' within which it operates. Aside from its requirement for liquid water, no definite limits have been established for life under any extreme. Here, we employ growth data published for 67 prokaryotic strains to explore the limitations for microbial life under combined extremes of temperature, pH, salt (NaCl) concentrations, and pressure. Our review reveals a fundamental lack of information on the tolerance of microorganisms to multiple extremes that impedes several areas of science, ranging from environmental and industrial microbiology to the search for extraterrestrial life. PMID- 23453125 TI - Mass-gathering medicine: a descriptive analysis of a range of mass-gathering event types. AB - OBJECTIVE: To identify and evaluate the volume, nature, and severity of patient presentations encountered by emergency medical services (EMS) at all mass gathering events held at or near a southeastern US university. In addition, to compare the existing literature base (single mass-gathering event held in large urban population centers) with a broader variety of events varying in crowd size and locations. METHODS: This was a retrospective review of all EMS records from mass-gathering patient presentations (individual-patient cases) between October 24, 2009, and August 27, 2011. All patrons seen by event-based EMS were included. Events categories included the following: football, concerts, public exhibitions, and nonfootball athletic events. Event volumes were defined as follows: low (<1000 patrons), medium (between 1001 and 15 000 patrons), and large (>15 000 patrons). Case presentation-management categories included the following: trauma, medical, and support (minimal medical intervention required, eg, minor dressing for abrasion, water, etc). Severity categories included the following: mild, moderate, and severe based on the following definitions using both provider assessment and the use of transport to a hospital: minor cases were considered non-life threats and did not result in a transport to a hospital; moderate cases were associated with transports to a hospital; and severe cases were life threats with transport to a hospital. RESULTS: We studied 79 events over the study period. Event volumes were 16.45% high, 79.75% medium, and 3.80% low. A total of 670 cases presented, with a mean of 8.48 cases/event. The football category had the highest mean number of cases with 37.09 cases/event, for a total of 408 cases. The nonfootball, athletic event category had the lowest mean number of cases at 1.83 cases/event. Most (81.82%) of the football events were classified as large volume. Support cases were the most common presentation (43.13%), followed closely by medical complaints (41.94%). Most cases were mild in severity (95.97%). There were 27 cases requiring transport to hospital, with 3 cases being life-threatening. The average patient age was 33 years, with 60.3% female sex. These features are similar to the published information on large event medical attendance. CONCLUSIONS: In this retrospective, descriptive study of a broad range of event type, the most common patient presentations at mass-gathering events were mild in severity, requiring minimal medical intervention. Both transports from the event to a hospital and the occurrence of life threats were uncommon. Our findings are similar to the data found in the existing medical literature. PMID- 23453126 TI - Parent and young adult satisfaction with psychiatry consultation services in a children's hospital. AB - BACKGROUND: Quality of health care services can be improved by promoting patient- and family-centered care informed by patient and family satisfaction with services delivered. Few studies have been conducted looking at satisfaction with psychiatric consultation services within an inpatient pediatric hospital setting. OBJECTIVE: The objective of the quality improvement pilot project was to identify ways to enhance services delivered and to guide the development of more comprehensive quality improvement projects. METHOD: Forty-eight parents of forty eight patients and 10 adult patients were administered the Pediatric Psychiatry Consultation Satisfaction Survey, which surveyed satisfaction with the psychiatric consultation services received during their stay in a freestanding tertiary pediatric academic hospital. RESULTS: Sixty-nine percent of participants reported overall high satisfaction (i.e., reports of excellent or very good) with the psychiatric consultation service along with 88% reporting that they would recommend this service to a friend. Overall high satisfaction with the service was associated with positive ratings with three core components of a consultation: provisions of impressions and recommendations (P = 0.018), consultant-participant communication and working relationship (P < 0.001), and the helpfulness of the consultation (P < 0.001). CONCLUSIONS: This quality improvement project underscores the importance of having psychiatry consultants convey their clinical impressions and recommendations, communicate effectively, and provide helpful interventions to parents and young adults in the pediatric hospital. It serves as an initial step responding to national consumers' demand for higher levels of quality and service and will provide guidance in future design and implementation of more comprehensive quality improvement projects. PMID- 23453127 TI - The misdiagnosis of steroid-responsive encephalopathy associated with autoimmune thyroiditis as masked depression in an elderly euthyroid woman. PMID- 23453128 TI - The sensor kinase BfmS mediates virulence in Acinetobacter baumannii. AB - BACKGROUND/PURPOSE: BfmR, the response regulator component of the two-component system BfmRS, has important roles in biofilm formation and cellular morphology of Acinetobacter baumannii. Until now, the contribution of the sensor kinase BfmS to the virulence of this bacterium remains unknown. In this study, a bfmS knockout and complementation studies were performed to clarify the role of BfmS in A. baumannii virulence. METHODS: We constructed a bfmS knockout mutant in the A. baumannii 17978 type strain by transposon inactivation. To clarify the role of bfmS in A. baumannii virulence, the biofilm formation, adherence ability to eukaryotic cells, serum resistance, and antibiotic susceptibility tests were performed in A. baumannii 17978 and its derivative knockout and complementation strains. RESULTS: The bfmS knockout displayed a reduction in biofilm formation, loss of adherence to eukaryotic cells, and greater sensitivity to serum killing compared with the parent strain. Proteomic analysis of culture supernatants revealed that the release of outer membrane proteins (Omps), including CarO and outer membrane protein A (OmpA), was associated with the inactivation of BfmS in A. baumannii. CONCLUSION: This study is the first to demonstrate that the pathway regulated by the sensor kinase BfmS is associated with biofilm formation, adherence to biotic surfaces, serum resistance, and antibiotic susceptibility, which may be associated with the release of Omps in A. baumannii. PMID- 23453129 TI - Comparison of gastrotomy closure modalities for natural orifice transluminal surgery: a canine study. AB - BACKGROUND: Reliable closure of the gastrotomy after transgastric natural orifice transluminal endoscopic surgery (NOTES) remains unresolved. OBJECTIVE: To compare the technical aspects and clinical and histologic outcomes of NOTES gastrotomy closure techniques. DESIGN: Experimental study. SETTING: Animal laboratory. PATIENTS: Thirty-four dogs, 14 for nonsurvival study and 20 for survival study. INTERVENTIONS: The animals randomly received different gastrotomy closures after NOTES: endoclip, omentoplasty, over-the-scope-clip (OTSC), and hand-suturing. MAIN OUTCOME MEASUREMENTS: Procedure time, closure strength, survival, postoperative adverse events, and histologic evaluation of wound healing. RESULTS: Omentoplasty and OTSC groups needed shorter procedure times and fewer clips than the endoclip group. The endoclip and omentoplasty groups generated similar leakage pressures (34.5 +/- 2.6 vs 42.2 +/- 4.1 mm Hg, P > .05), both lower than OTSC and hand-suturing groups (81.5 +/- 2.1 and 87.0 +/- 3.0 mm Hg, respectively, P < .001). Of the 20 animals in the survival study (all 4 groups), only 2 of 6 in the endoclip group were killed prematurely due to sepsis. Necropsy revealed the OTSC group reached a 100% clip retention rate, higher than the endoclip (47.9%) and omentoplasty groups (44.4%, P < .05) rates. Complete healing, defined as intact and continuous gastric layers microscopically, was seen in 83.3% of animals (5 of 6) in the omentoplasty group, comparable with OTSC (4 of 6, 66.7%, P = .500) but higher than the endoclip group (1 of 6, 16.7%, P = .04). LIMITATIONS: Animal study. CONCLUSIONS: Omentoplasty is easier and safer for NOTES gastrotomy closure than endoclips and offers safety profile and efficacy similar to OTSC and hand-suturing. PMID- 23453130 TI - Delivery optimization of erlotinib according to toxicity: may clinical practice go beyond research? PMID- 23453131 TI - Fatty acids as biomarkers of microalgae. AB - Microalgae are primary producers of the food chain and hold prominence towards pharmaceutical and nutraceutical applications. Fatty acids (FAs) are one of the primary metabolites of microalgae, which enrich their utility both in the form of food and fuels. Additionally, the vast structural diversity coupled with taxonomic specificity makes these FAs as potential biomarkers. The determination of lipid and fatty acid profiling of 12 different strains of microalgae has been accomplished in this study and further discussed in respect to their chemotaxonomic perspective in microalgae. Palmitic acid (C16:0) and oleic acid (C18:1n9c) were found to be dominant among the members of Cyanophyceae whereas members of Chlorophyceae were rich in palmitic acid (C16:0), oleic acid (C18:1n9c) and linoleic acid (C18:2n6). The application of principal component analysis (PCA) and algorithmic hierarchical clustering (AHC) resulted in the segregation of the studied microalgal strains into 8 different orders belonging to 2 distinct phyla according to their phylogenetic classification. Nutritionally important FAs like eicosapentaenoic acid (EPA, C20:5n3) and docosahexaenoic acid (DHA, C22:6n3) were detected only in Chlorella sp. belonging to Chlorophyceaen family. Differential segregation of microalgae with respect to their fatty acid profile indicated the potential utility of FAs as biomarkers. PMID- 23453132 TI - Use of medical aural and encephalic glue-soaked gelfoam for frontal sinus repair: a single-centre experience. AB - BACKGROUND: Frontal sinus (FS) perforation is a common complication in frontal craniotomy. The primary goal of treatment is to seal the FS without destroying physiological function. OBJECTIVE: This article describes a new FS cavity reconstruction technique using medical aural and encephalic glue (EC glue)-soaked gelfoam. METHODS: Between 2007 and 2012, 118 patients underwent FS reconstruction using EC glue-soaked gelfoam. The FS cavity was reconstructed in all patients and no patient experienced intracranial infection, frontal sinusitis, or cerebrospinal fluid (CSF) leakage. RESULTS: Restoring physiological function is the primary goal of FS reconstruction. Difficulty often arises in sealing the sinus opening, especially when the mucosa is damaged. Mucosal border dissection and electric coagulation of the mucosal laceration can help to reconstruct the mucosal cavity. Sealing the sinus with autogenous or exogenous material, such as fascia, bone flap or gelfoam carries increased risks of intracranial infection, frontal sinusitis, and CSF leakage in the short term, and increased the occurrence of a FS mucocoele in the long term. Gelfoam saturated with EC glue obtained good results. CONCLUSION: We describe the application of gelfoam saturated with EC glue to treat an open FS with or without mucosal violation during frontal craniotomy. Gelfoam saturated with EC glue is a quick, effective, low-cost and reliable means of sealing the FS while preserving its physiological function. PMID- 23453133 TI - Preferences of AP position of the straight Caucasian facial profile. AB - INTRODUCTION: Several investigators have compared the perception of profile attractiveness between professional and non-professional people, different groups of clinicians, and different ethnic groups. Our aim was to study preferences for facial protrusion in the lateral view for a straight Class I profile and to study the influence of gender, age, sex preference, and profession. MATERIAL AND METHODS: Portrait images of one male and one female model with a Class I occlusal relationship were warped into nine different antero-posterior positions. An internet site was established to reach as many people as possible, and a request was sent by email to participate in a scientific experiment. Finally, 1707 Caucasion assessors could be grouped. RESULTS: The preferred male profile is the straight full ante profile. For a feminine facial profile, the straight average and the straight 2/3 ante profiles were perceived as the most attractive. Surgeons tended to give significantly higher scores to attractive (ante) profiles, which correlated strongly with scores of the orthodontists. CONCLUSION: Whenever possible with combined orthodontic/surgery treatment, straight ante profiles should be aimed for. PMID- 23453134 TI - Cannabinoid receptor 1 controls human mucosal-type mast cell degranulation and maturation in situ. AB - BACKGROUND: Because many chronic inflammatory and allergic disorders are intimately linked to excessive mast cell (MC) numbers and activation, it is clinically important to understand the physiologic mechanisms preventing excess MC accumulation/degranulation in normal human tissues. OBJECTIVE: Because endocannabinoids are increasingly recognized as neuroendocrine regulators of MC biology, we investigated how cannabinoid receptor (CB) 1 signaling affects human mucosal-type mast cells (hMMCs). METHODS: Using organ-cultured nasal polyps as a surrogate tissue for human bronchial mucosa, we investigated how CB1 stimulation, inhibition, or knockdown affects hMMC biology using quantitative (immuno)histomorphometry and electron microscopy. RESULTS: Kit(+) hMMCs express functional CB1 in situ. Blockade of CB1 signaling (with the specific CB1 antagonist N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl 1H-pyrazole-3-carboxamide [AM251] or CB1 gene knockdown) enhanced hMMC degranulation and increased total numbers without affecting their proliferation in situ. This suggests that inhibiting CB1 signaling induces hMMC maturation from resident progenitor cells within human mucosal stroma. hMMC maturation was induced at least in part through upregulating stem cell factor production. Both the prototypic endocannabinoid anandamide and the CB1-selective agonist arachidonyl-2-chloroethylamide effectively counteracted secretagogue-triggered excessive hMMC degranulation. CONCLUSIONS: The current serum-free nasal polyp organ culture model allows physiologically and clinically relevant insights into the biology and pharmacologic responses of primary hMMCs in situ. In human airway mucosa hMMC activation and maturation are subject to a potent inhibitory endocannabinoid tone through CB1 stimulation. This invites one to target the endocannabinoid system in human airway mucosa as a novel strategy in the future management of allergic diseases. PMID- 23453135 TI - IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. AB - BACKGROUND: IL-10-producing regulatory B cells suppress immune responses, and lack of these cells leads to exacerbated symptoms in mouse models of chronic inflammation, transplantation, and chronic infection. IgG4 is a blocking antibody isotype with anti-inflammatory potential that is induced in human high-dose antigen tolerance models. OBJECTIVE: We sought to characterize human inducible IL 10-secreting B regulatory 1 (BR1) cells and to investigate their immunoregulatory capacity through suppression of cellular immune responses and production of anti inflammatory immunoglobulins. METHODS: Highly purified IL-10-secreting B cells were phenotypically and functionally characterized by means of whole-genome expression analysis, flow cytometry, suppression assay, and antibody production. B cells specific for the major bee venom allergen phospholipase A2 (PLA) were isolated from beekeepers who displayed tolerance to bee venom antigens and allergic patients before and after specific immunotherapy. RESULTS: Human IL-10+ BR1 cells expressed high surface CD25 and CD71 and low CD73 levels. Sorting of CD73-CD25+CD71+ B cells allowed enrichment of human BR1 cells, which produced high levels of IL-10 and potently suppressed antigen-specific CD4+ T-cell proliferation. IgG4 was selectively confined to human BR1 cells. B cells specific for the major bee venom allergen PLA isolated from nonallergic beekeepers show increased expression of IL-10 and IgG4. Furthermore, the frequency of IL-10+ PLA specific B cells increased in allergic patients receiving allergen-specific immunotherapy. CONCLUSION: Our data show the characterization of IL-10+ BR1 cells and in vivo evidence for 2 essential features of allergen tolerance: the suppressive B cells and IgG4-expressing B cells that are confined to IL-10+ BR1 cells in human subjects. PMID- 23453136 TI - Asthma studies should be phenotype specific. PMID- 23453137 TI - Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome. PMID- 23453138 TI - Antihypertensive medication use is associated with increased organ system involvement and hospitalization in emergency department patients with anaphylaxis. AB - BACKGROUND: Risk factors for increased anaphylaxis severity are poorly understood. Angiotensin-converting enzyme (ACE) inhibitors have been associated with severe anaphylactic reactions in patients with hymenoptera venom allergy. Studies evaluating the association between beta-blockers and severe anaphylaxis have been conflicting. OBJECTIVE: To evaluate the association between antihypertensive medication use and increased anaphylaxis severity. METHODS: We included emergency department anaphylaxis patients aged 18 years and older. Markers of severe anaphylaxis were defined as (1) syncope, hypotension, or hypoxia; (2) signs and symptoms involving 3 or more organ systems; and (3) hospitalization. Antihypertensive medications evaluated included beta-blockers, ACE inhibitors, calcium channel blockers, angiotensin receptor blockers, and diuretics. Simple and multiple logistic regression analyses were conducted to estimate the association between antihypertensive medication use and markers of increased anaphylaxis severity. RESULTS: Among 302 patients with anaphylaxis, 55 (18%) had syncope, hypoxia, or hypotension, 57 (19%) required hospitalization, and 139 (46%) had 3 or more organ system involvement. After adjusting for age, gender, suspected trigger, and preexisting lung disease, beta-blocker, ACE inhibitor, diuretic, or antihypertensive medication use in aggregate remained associated with both 3 or more organ system involvement and need for hospital admission. The adjusted associations between antihypertensive medication use in aggregate and 3 or more organ system involvement yielded an odds ratio of 2.8 (95% CI, 1.5-5.2; P=.0008) and with hospitalization an odds ratio of 4.0 (95% CI, 1.9-8.4; P=.0001). CONCLUSIONS: In emergency department anaphylaxis patients, antihypertensive medication use is associated with increased organ system involvement and increased odds of hospital admission, independent of age, gender, suspected trigger, or preexisting lung disease. PMID- 23453139 TI - The history of veterinary cardiology. AB - Throughout civilization, animals have played a pivotal role in the advancement of science and medicine. From as early as 400 BC when Hippocrates recognized that diseases had natural causes, the steadfast advances made by biologists, scientists, physicians and scholars were fueled by timely and important facts and information- much of it gained through animal observations that contributed importantly to understanding anatomy, physiology, and pathology. There have been many breakthroughs and historic developments. For example, William Harvey in the 16th and 17th centuries clarified the importance of the circulatory system, aided by observations in dogs and pigs, which helped to clarify and confirm his concepts. The nineteenth century witnessed advances in physical examination techniques including auscultation and percussion. These helped create the basis for enhanced proficiency in clinical cardiology. An explosion of technologic advances that followed in the 20th century have made possible sophisticated, accurate, and non-invasive diagnostics. This permitted rapid patient assessment, effective monitoring, the development of new cardiotonic drugs, clinical trials to assess efficacy, and multi-therapy strategies. The latter 20th century has marshaled a dizzying array of advances in medical genetics and molecular science, expanding the frontiers of etiologies and disease mechanisms in man, with important implications for animal health. Veterinary medicine has evolved during the last half century, from a trade designed to serve agrarian cultures, to a diverse profession supporting an array of career opportunities ranging from private, specialty practice, to highly organized, specialized medicine and subspecialty academic training programs in cardiology and allied disciplines. PMID- 23453140 TI - Scanning through the pain: ergonomic considerations for performing echocardiography of animals. AB - Work-related musculoskeletal disorders (MSD) are a common problem among sonographers, with prevalence in human sonographers of 80-90%. However, this problem appears to be largely neglected in the veterinary literature. Awareness of MSDs, ergonomic redesign, workplace management, and physical self-care are components to reducing the risk of developing MSDs. Work-place redesign and alterations in work flow management are discussed, and a template for a more ergonomically favorable echocardiogram table is provided. PMID- 23453141 TI - Dysphagia in a young woman. PMID- 23453142 TI - Emerging threats to public health from regional trade agreements. PMID- 23453143 TI - A novel UV-MALDI-MS analytical approach for determination of halogenated phenyl containing pesticides. AB - The paper highlighted the capability of the UV-MALDI mass spectrometry, employing the Orbitrap analyzer for solid-state assay of halogenated phenyl-pesticides in mixtures. It is successfully applied for the analysis of eighteen (1)-(18) molecular objects of Fenarimol (1) type and their condensation products (P5) (P12). The full method and technique validation is performed using the dried droplet sample preparation technique on embedded analytes in novel organic matrix crystals of N-(1H-benzoimidazol-2-yl)-guanidine (M4) and (E)-phenyl-2-pyridyl ketone oxime (M5), resulting to successful ionization of the analytes. Since the sampling technique in the UV-MALDI method is a key step in the overall process impacting significantly the metrology through the reproducibility of the data, the crystallization of M4, M5 and matrix-analyte in situ morphology of the samples is controlled by single crystal X-ray diffraction. The achieved promising metrology of LODs, of 0.46ngkg(-1) (1.53ngkg(-1) LOQs), is several orders of magnitude lower than the reported ecotoxicological effect values of studied pesticides. It is confirmed by the partial validated protocol based on ESI-MS. Inasmuch that LC-MS/MS is a method of choice for foodstuffs monitoring of organic contaminations, due to its routine quantitative analytical procedures, it is often characterized with the difficulties of the chromatographic separation of the closely structured analytes at a large scale of experimental conditions, complex multi-step sampling pretreatments, which inevitably alert the variables through the systematic and random errors. In this respect, notwithstanding the complex quantitative UV-MALDI-Orbitrap-MS procedure, conceptually different from the LC-MS/MS one, its high resolving power, capability for achieving meaningful analytical qualitative, quantitative and structural information of low-molecular weight analytes, its instrumental and sampling operation flexibility, applicable for a large scale of foodstuff matrices, and operating at the analyte concentrations of up to fgg(-1) make UV-MALDI-Orbitrap-MS a perspective method of choice for an extensive implementation in the foodstuffs monitoring practice for control of the most essential task related to the assessment of the human health risks from environmental and foodstuff contaminations. PMID- 23453144 TI - Access to cochlear implantation. PMID- 23453145 TI - ACI Alliance--The American Cochlear Implant Alliance Foundation. PMID- 23453146 TI - Cochlear implantation in the world's largest medical device market: utilization and awareness of cochlear implants in the United States. AB - Provision of cochlear implants (CIs) for those within the criteria for implantation remains lower in the United States than in some other developed nations. When adults and children are grouped together, the rate of utilization/provision remains low at around 6%. For children, the provision rate is about 50% of those who could benefit from an implant, compared with figures of about 90% for the Flanders part of Belgium, the United Kingdom and other European countries. The probable reasons for this underprovision include: low awareness of the benefits of CIs among the population; low awareness among health-care professionals; the lack of specific referral pathways; some political issues relating to the Deaf Community; and financial issues related to health provision. Such financial issues result in situations which either fail to provide for access to implants or provide too low a level of the necessary funding, especially for low-income individuals covered by public health-care programs such as Medicaid. These issues might be mitigated by adoption and publication of standards for best clinical practices for CI provision, availability of current cost-effectiveness data, and the existence of an organization dedicated to cochlear implantation. Such an organization, the American Cochlear Implant Alliance (ACI Alliance), was recently organized and is described in the paper by Niparko et al. in this Supplement. PMID- 23453147 TI - New expectations: pediatric cochlear implantation in Japan. AB - FUNDING FOR COCHLEAR IMPLANTS: The Japanese health-care system provides universal health coverage for the entire 127 million population of Japan. This includes all aspects of cochlear implantation, from diagnosis to implantation to mapping and habilitation aftercare. Japan has the third largest developed economy; however, the uptake rate for cochlear implants is lower than that of countries with similar economic status. Japan has an uptake rate of approximately 1% of potentially suitable subjects of all ages, compared with 5.6% in the USA. COCHLEAR IMPLANT PROVISION FOR CHILDREN: In Japan, about 55% of cochlear implant recipients are children of less than 18 years of age. This represents an increase of 20% in the last 10 years, with a relative increase in the numbers of children receiving implants compared with the numbers of adults. However, only 3-4% of children under the age of 3 years are being implanted at less than 18 months of age. This is in accordance with the Japanese ENT Academy's guidelines, which currently puts the minimum age limit for implants in children at 18 months. NEONATAL SCREENING: For hearing loss was first piloted nationally in Japan in 2000. Funding for screening subsequently stopped in 2005, though the national treasury provided a further 2 years' funding. Since 2007 local government organizations have been given responsibility to support these screening programs, but there remains considerable variation in funding between different prefectures. In one prefecture, Okayama, 95% of babies were screened and followed up for 2 years. However, the support system for children who need further diagnostic testing after screening remains insufficient. REFERRAL: When diagnosed, children with hearing loss are referred for counselling, hearing aids and habilitation. The responsibility for these is divided between the Ministry of Health and Welfare (including surgery, device programming, and therapy) and the Ministry of Education. Schools for the deaf and preschool hearing impaired education centers have had most of the responsibility for early intervention, educational choices and referral for cochlear implantation. In the past 98% of schools for children with hearing loss have used communication methods relying mostly on visual cues. In recent years, however, there has been a shift toward 'inclusive' mainstream education. Between 2008 and 2011 the number of children with cochlear implants in special needs schools increased to 16%. It is now estimated that 67% of children with cochlear implants may now be in mainstream schools. There is still the need for support services for these implanted children attending mainstream schools, with adequate provision of resources. CONCLUSION: Cochlear Implantation has had a significant role in changing the medical management and education of children in Japan with hearing loss. Much remains to be done, though the situation has greatly improved in recent years and continues to do so. PMID- 23453149 TI - Enter the dragon--China's journey to the hearing world. AB - CONTEXT: China's population of 1.3 billion represents nearly 20% of the world's population. The current live birth rate in China is 17 million per year, compared with 4.1 million in the USA in 2009. Ministry of Health figures from China identify 115,000 children under the age of 7 years with severe-to-profound deafness and 30,000 babies born each year with hearing impairment. NEWBORN SCREENING: Universal Newborn Hearing Screening (UNHS) has been implemented in China since 1999. By 2010 UNHS was implemented in 20 of the 32 Chinese provinces. In large cities 95% of babies are screened in hospital-based programs. In more remote areas babies with high-risk factors for hearing loss are referred to screening centers within 1 month of birth and leaflets about identifying deafness are distributed. COCHLEAR IMPLANTS: Since 1995 more than 10,000 people in China have received cochlear implants (CIs) and 85% of these implant recipients have been children under the age of 7 years. FINANCING OF CIs: China is in the process of developing a national reimbursement scheme for medical care. The first multichannel implant was performed in 1995. In 2005, a private financier provided more than 1500 implants for children under the age of 5 years. In 2009, the Chinese government set up a project to implant 1500 children aged 1-5 years over the next 3 years, with provision of the equivalent of US$65.4 million to pay for the devices, surgery, mapping, and rehabilitation. By 2011, the government had agreed to fund implants for an additional 17,000 children over 4 years. TRAINING OF PROFESSIONALS: Schemes have been developed to train surgeons, Audiologists, and those involved in rehabilitation of implanted children in China. OUTCOME ASSESSMENT: Standardized outcome tests are being developed for CI recipients. There are two large-scale ongoing outcome studies in progress. CI penetration in China is currently less than 5% of potential pediatric candidates, but cochlear implantation is continuing to expand at great speed, and it is hoped that the infrastructure and capacity will continue to grow and develop. PMID- 23453148 TI - Accessibility to cochlear implants in Belgium: state of the art on selection, reimbursement, habilitation, and outcomes in children and adults. AB - Belgium, and especially the northern region called Flanders, has been a center of expertise in cochlear implants and early hearing screening for many years. Some of their surgeons and engineers were pioneers in the development of cochlear implants and in 1998 Flanders was the first region in Europe to implement a universal hearing screening program for all neonates. The Belgian National Institute for Health and Disability Insurance has reimbursed cochlear implants in children and adults since 1994 and bilateral implantation in children under the age of 12 years since February 2010. These deaf children, screened and implanted early, achieve higher auditory, speech and language outcomes and increasing numbers are going to regular schools using fewer interpreters. In 2010, 93% of severe-to-profound deaf preschool children in Flanders had received cochlear implants and 25% had bilateral implants. Although on average twice as many adults as children are implanted a year in Belgium, we have less research data available from this adult population. Also very little is published about the growth curves and minimal rehabilitation requirements (intensity, duration etc.) after implantation for both children and adults. So, there still remain many challenges for the future. PMID- 23453150 TI - Cochlear implants in the United Kingdom: awareness and utilization. AB - INTRODUCTION: Every child and adult in the United Kingdom who fulfils the criteria for cochlear implantation is entitled to receive treatment under the National Health Service (NHS); children since 2009 are eligible for bilateral simultaneous implants and adults single implants unless they have additional sensory needs. HISTORY: During a period between 1982 and 1990, when a number of individual teams ran programmes using charitable funding, the British Cochlear Implant Group approached the UK Department of Health, who agreed to set up a 4 year pilot study of 10 programmes, including one children's programme. The outcomes were collected and analysed by the Medical Research Council's Institute of Hearing Research. The results, showing positive outcomes for adults and children, were published in 1995 and subsequently funding was provided directly by the NHS. ACCESS: Between 2001 and 2006 the Universal Newborn Hearing Screen (UNHS) was implemented in England and Wales and also in Scotland and Northern Ireland. Data from UNHS and also data from the three main cochlear implant manufacturers have allowed estimates of access to cochlear implants for children and adults within the criteria for implantation. CHILDREN: Between 2006 and 2011 the figures show that 74% of estimated eligible children aged 0-3 years have received implants and 94% by the age of 17. ADULTS: For adults the figures are considerably lower, with only about 5% of those eligible for an implant actually receiving one. The reasons for this include, to a lesser degree, the fact that guidelines by the National Institute of Clinical Excellence (NICE) are stricter than in some other European countries, but chiefly because of lack of awareness among candidates and professionals, both of criteria for eligibility and of the potential advantages from cochlear implantation. PMID- 23453152 TI - Isolated brainstem cysticercosis. PMID- 23453151 TI - Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: a 6 year single institutional experience. AB - OBJECTIVES: Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Surgery and radiotherapy constitute the cornerstones for the therapeutic management of GBM. The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol. Despite the progress in neurosurgery, radiotherapy and oncology, the prognosis still results poor. In order to reduce the long time of standard treatment, maintaining or improving the clinical results, in our institute we have investigated the effects of hypo-fractionated radiation therapy for patients with GBM. PATIENTS AND METHODS: Sixty-seven patients affected by GBM who had previously undergone surgical resection (total, subtotal or biopsy) were enrolled between October 2005 and December 2011 in a single institutional study of hypo-fractionated intensity modulated radiation therapy (IMRT) followed or not by adjuvant chemotherapy with TMZ (6-12 cycles). The most important eligibility criteria were: biopsy-proven GBM, KPS >= 60, age >= 18 years, no previous brain irradiation, informed consensus. Hypo-fractionated IMRT was delivered to a total dose of 25 Gy in 5 fractions prescribed to 70% isodose. Response to treatment, OS, PFS, toxicity and patterns of recurrence were evaluated, and sex, age, type of surgery, Karnofsky performance status, Recursive Partitioning Analysis (RPA) classification, time between surgery and initiation of radiotherapy were evaluated as potential prognostic factors for survival. RESULTS: All patients have completed the treatment protocol. Median age was 64.5 years (range 41-82 years) with 31 females (46%) and 36 males (54%). Median KPS at time of treatment was 80. The surgery was gross total in 38 patients and subtotal in 14 patients; 15 patients underwent only biopsy. No grade 3-4 acute or late neurotoxicity was observed. With median follow-up of 14.9 months, the median OS and PFS were 13.4 and 7.9 months, respectively. CONCLUSIONS: The hypo fractionated radiation therapy can be used for patients with GBM, resulting in favourable overall survival, low rates of toxicity and satisfying QoL. Future investigations are needed to determine the optimal fractionation for GBM. PMID- 23453153 TI - Supraorbital trans-eyebrow craniotomy and fluorescence-guided resection of fronto basal high grade gliomas. AB - OBJECT: To determine the effectiveness of fluorescence-guided resection of fronto basal high grade gliomas by using the supraorbital trans-eyebrow craniotomy. METHODS: We present a single-institution experience of 6 consecutive patients presenting high grade brain glioma located on the fronto-basal area that were operated through a supraorbital trans-eyebrow craniotomy. Previous to surgery all patients were administered 20mg/kg of 5 aminolevulic acid so microscopic fluorescence-guided resection could be accomplished. Tumors were located on gyrus rectus (3 patients), medial orbital gyrus (2 patients), and anterior orbital gyrus (1 patient). RESULTS: Despite the narrow surgical corridor, fluorescence was useful in all cases. Fluorescence-guided resection allowed inclusion into the margins of resection of areas previously considered as normal under white light. Complete resection was obtained in 5 patients. No neurological postoperative new deficit was observed in this series. All six cases corresponded to glioblastoma. Only one case of superficial infection with delayed wound healing was reported as complication. All patients expressed a high level of satisfaction related to cosmetic result. CONCLUSIONS: Fluorescence-guided resection of fronto-basal high grade gliomas can be successfully achieved through supraorbital trans-eyebrow craniotomy. Benefits of supraorbital craniotomy in the management of fronto-basal high grade gliomas as well as usefulness of fluorescence-guided resection through a very narrow corridor are exposed. PMID- 23453154 TI - Intramedullary abscess of the upper cervical spinal cord. Unusual presentation and dilemmas of management: case report. PMID- 23453155 TI - The platelet amyloid precursor protein ratio as a diagnostic marker for Alzheimer's disease in Thai patients. AB - The platelet amyloid precursor protein (APP) ratio has recently been shown to be a promising diagnostic marker for Alzheimer's disease (AD). To evaluate its usefulness in Thai patients, platelet APP was analyzed by immunoblotting. The APP ratio was calculated as the ratio of the combined band density of the 120-kD and 130-kD isoforms compared to that of the 110-kD isoform. The mean ages (and ranges) of 27 normal and 13 AD-affected subjects were 68.3 (60-84) and 79.3 (70 97) years, respectively. The Thai Mental State Examination (TMSE) scores demonstrated that the AD patients had significantly poorer cognitive functions than the normal subjects, with mean TMSE scores of 20.3 and 27.6 (maximum score of 30 points), respectively (p<0.05). The platelet APP ratios of the AD patients were significantly lower than those of normal subjects: values (mean +/- standard deviation) were 7.32 +/- 1.29 and 9.13 +/- 3.00, respectively (p<0.05) for AD patients and normal subjects. However, the ranges of the APP ratios from both groups markedly overlapped, which precluded the establishment of a cutoff level to differentiate between the AD and normal subjects. In addition, no significant correlations were observed between the platelet APP ratio and the TMSE score or between the APP ratio and the serum cholesterol in this study, in contrast to previous reports. PMID- 23453156 TI - Asleep-awake-asleep craniotomy: a comparison with general anesthesia for resection of supratentorial tumors. AB - The anesthetic plan for patients undergoing awake craniotomy, when compared to craniotomy under general anesthesia, is different, in that it requires changes in states of consciousness during the procedure. This retrospective review compares patients undergoing an asleep-awake-asleep technique for craniotomy (group AW: n = 101) to patients undergoing craniotomy under general anesthesia (group AS: n = 77). Episodes of desaturation (AW = 31% versus AS = 1%, p < 0.0001), although temporary, and hypercarbia (AW = 43.75 mmHg versus AS = 32.75 mmHg, p < 0.001) were more common in the AW group. The mean arterial pressure during application of head clamp pins and emergence was significantly lower in AW patients compared to AS patients (pinning 91.47 mmHg versus 102.9 mmHg, p < 0.05 and emergence 84.85 mmHg versus 105 mmHg, p < 0.05). Patients in the AW group required less vasopressors intraoperatively (AW = 43% versus AS = 69%, p < 0.01). Intraoperative fluids were comparable between the two groups. The post anesthesia care unit (PACU) administered significantly fewer intravenous opioids in the AW group. The length of stay in the PACU and hospital was comparable in both groups. Thus, asleep-awake-asleep craniotomies with propofol-dexmedetomidine infusion had less hemodynamic response to pinning and emergence, and less overall narcotic use compared to general anesthesia. Despite a higher incidence of temporary episodes of desaturation and hypoventilation, no adverse clinical consequences were seen. PMID- 23453157 TI - Image-guided transoral biopsy in a boy with Grisel's syndrome. AB - Grisel's syndrome is a disease characterized by an atlanto-axial rotatory subluxation following acute inflammation of the upper respiratory tract. The syndrome has a good prognosis as it usually heals with antibiotics, despite the delayed serious complications that have been reported. When neuroradiological investigation does not allow an accurate differential diagnosis between a tumor and osteomyelitis, an image-guided transoral biopsy is a safe, fast, minimally invasive, as well as effective, procedure. PMID- 23453158 TI - Transoral penetrating craniocerebral injury by a bamboo chopstick in a child. AB - We present a 3-year-old girl with a transoral injury by a bamboo chopstick penetrating the middle skull base. The features of imaging are described and the management is discussed. The potential for injury to the cavernous sinus is emphasized, even if no there is no hemorrhage on the initial CT scan. Early intracranial infection in relation to penetrating injuries is a factor in planning treatment by craniotomy. PMID- 23453159 TI - Hemichorea caused by intracranial hemorrhage following contralateral herpes zoster ophthalmicus. AB - A healthy, 66-year-old, right-handed man was admitted to our university hospital and diagnosed with herpes zoster ophthalmicus (HZO). After 4 weeks, he complained of hemichorea on his left side. Brain MRI showed a focal hemorrhage in the right subthalamic area. No evidence of aneurysmal lesion or cerebral angiitis was observed on cerebral angiography. PMID- 23453160 TI - A patient with Parkinson's disease benefits from spinal cord stimulation. AB - We present a case of a 43-year-old woman with a history of Parkinson's disease and chronic neuropathic pain secondary to trauma. She was implanted with a spinal cord simulator to relieve her persistent intractable pain. After the implantation of the device the patient not only was relieved of her neuropathic pain but also found significant improvement in her Parkinson symptoms. PMID- 23453161 TI - Fatal injury as a function of rurality-a tale of two Norwegian counties. AB - BACKGROUND: Many studies indicate rural location as a separate risk for dying from injuries. For decades, Finnmark, the northernmost and most rural county in Norway, has topped the injury mortality statistics in Norway. The present study is an exploration of the impact of rurality, using a point-by-point comparison to another Norwegian county. METHODS: We identified all fatalities following injury occurring in Finnmark between 2000 and 2004, and in Hordaland, a mixed rural/urban county in western Norway between 2003 and 2004 using data from the Norwegian Cause of Death Registry. Intoxications and low-energy trauma in patients aged over 64 years were excluded. To assess the effect of a rural locale, Hordaland was divided into a rural and an urban group for comparison. In addition, data from Statistics Norway were analysed. RESULTS: Finnmark reported 207 deaths and Hordaland 217 deaths. Finnmark had an injury death rate of 33.1 per 100,000 inhabitants. Urban Hordaland had 18.8 deaths per 100,000 and rural Hordaland 23.7 deaths per 100,000. In Finnmark, more victims were male and were younger than in the other areas. Finnmark and rural Hordaland both had more fatal traffic accidents than urban Hordaland, but fewer non-fatal traffic accidents. CONCLUSIONS: This study illustrates the disadvantages of the most rural trauma victims and suggests an urban-rural continuum. Rural victims seem to be younger, die mainly at the site of injury, and from road traffic accident injuries. In addition to injury prevention, the extent and possible impact of lay people's first aid response should be explored. PMID- 23453162 TI - Statewide costs of health care-associated infections: estimates for acute care hospitals in North Carolina. AB - BACKGROUND: State-specific, health care-associated infection (HAI) cost estimates have not been calculated to guide Department of Public Health efforts and investments. METHODS: We completed a cost identification study by conducting a survey of 117 acute care hospitals in NC to collect surveillance data on patient days, device-days, and surgical procedures during 1 year. We then calculated expected rates and direct hospital costs of surgical site infections (SSI), Clostridium difficile infection, and 3 selected device-related HAIs for hospitals and the entire state using reference data sets such as the National Healthcare Safety Network. RESULTS: In total, 67 (53%) hospitals responded to the survey. The median bed size of respondent hospitals was 140 (interquartile range, 66 350). A "standard" NC hospital diagnosed approximately 100 HAI each year with estimated costs of $985,000 to $2.7 million. The most common HAI was SSI (73%). Costs related to SSI accounted for 87% to 91% of overall costs. In total, the overall direct annual cost of these 5 selected HAIs was estimated to be between $124.1 and $347.8 million in 2009 for the state of NC. CONCLUSION: Using conservative estimates, HAI led to costs of more than $100 million in acute care hospitals in the state of NC in 2009. The majority of costs were due to SSI. PMID- 23453164 TI - Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal. AB - The neuropeptide oxytocin has been implicated in a variety of social processes. However, recent studies indicate that oxytocin does not enhance prosocial behavior in all people in all circumstances. Here, we investigate effects of intranasal oxytocin administration on intrinsic functional brain connectivity with resting state functional magnetic resonance imaging. Participants were 42 women who received a nasal spray containing either 16 IU of oxytocin or a placebo and reported how often their mother used love withdrawal as a disciplinary strategy involving withholding love and affection after a failure or misbehavior. We found that oxytocin changes functional connectivity between the posterior cingulate cortex (PCC) and the brainstem. In the oxytocin group there was a positive connectivity between these regions, whereas the placebo group showed negative connectivity. In addition, oxytocin induced functional connectivity changes between the PCC, the cerebellum and the postcentral gyrus, but only for those participants who experienced low levels of maternal love withdrawal. We speculate that oxytocin enhances prosocial behavior by influencing complex brain networks involved in self-referential processing and affectionate touch, most prominently in individuals with supportive family backgrounds. PMID- 23453165 TI - The Urban Mining concept. PMID- 23453163 TI - Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol. AB - Alcohol and dietary fat both play an important role in alcohol-mediated multi organ pathology, including gut and liver. In the present study we hypothesized that the combination of alcohol and dietary unsaturated fat (USF) would result in intestinal inflammatory stress and mucus layer alterations, thus contributing to disruption of intestinal barrier integrity. C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil/linoleic acid) or SF (medium chain triglycerides: beef tallow) for 8 weeks. Intestinal histology, morphometry, markers of inflammation, as well as levels of mucus protective factors were evaluated. Alcohol and dietary USF triggered an intestinal pro inflammatory response, characterized by increase in Tnf-alpha, MCP1, and MPO activity. Further, alcohol and dietary USF, but not SF, resulted in alterations of the intestinal mucus layer, characterized by decreased expression of Muc2 in the ileum. A strong correlation was observed between down-regulation of the antimicrobial factor Cramp and increased Tnf-alpha mRNA. Therefore, dietary unsaturated fat (corn oil/LA enriched) is a significant contributing factor to EtOH-mediated intestinal inflammatory response and mucus layer alterations in rodents. PMID- 23453166 TI - The evolution of food donation with respect to waste prevention. AB - The donation of food which is still edible can be seen as a specific application of urban mining as food is recovered for its original purpose - human intake. There are several projects implemented worldwide but due to a lack of data, scientific literature about the topic is rare. This paper summarises briefly the evolution of food donation activities and gives information on the differences and similarities of current organisations distributing food to people in need as well as the political, legal, social and logistical barriers and incentives which occur with respect to this topic. A concept for a food donation network is presented and impact on ecology, economy and society is discussed. PMID- 23453169 TI - The 9th International Bode Hygiene Days - a unique meeting to discuss infectious disease prevention and control strategies. PMID- 23453170 TI - Three years of national hand hygiene campaign in Germany: what are the key conclusions for clinical practice? AB - The World Health Organization (WHO) started the 'Clean Care is Safer Care' campaign in 2005. Since then, more than 120 countries have pledged to improve hand hygiene as a keystone of their national or subnational healthcare-associated infection prevention programmes. Thirty-eight countries have implemented national campaigns. Germany started a national campaign to improve hand hygiene compliance on 1 January 2008. The campaign, 'AKTION Saubere Hande', is funded by the German Ministry of Health and was initiated by the National Reference Centre for the Surveillance of Nosocomial Infections, the Society for Quality Management in Health Care and the German Coalition for Patient Safety. The campaign is designed as a multi-modal campaign based on the WHO implementation strategy. Since the end of 2010, more than 700 healthcare institutions have been actively participating in the campaign, among which are 28 university hospitals. Voluntarily participating hospitals have to implement the following measures: active support by hospital administrators of local campaign implementation, participation in a one-day introductory course, education of healthcare workers at least once a year, measurement of alcohol-based hand-rub consumption (AHC) and feedback on resulting data, implementation of the WHO 'My Five Moments for Hand Hygiene' model, increase in hand-rub availability, participation in national hand hygiene day at least every two years, and participation in national campaign network workshops at least once every two years. Observational studies to measure hand hygiene compliance are optional. Overall, there has been a significant increase of 11% in hand hygiene compliance in 62 hospitals that observed compliance before and after intervention. A total of 129 hospitals provided AHC data for three years and achieved an overall increase of 30.7%. The availability of alcohol based hand rub increased from 86.8% to > 100% in intensive care units and from 63.6% to 91.3% in non-intensive care units. Overall, the implementation of a national campaign using the WHO multi-modal intervention strategy has led to improved hand hygiene compliance and hand-rub availability in participating settings. PMID- 23453171 TI - How can compliance with hand hygiene be improved in specialized areas of a university hospital? AB - Hand hygiene is considered to be the pillar of infection control and prevention. Despite national and international recommendations on hand hygiene, compliance remains low. Basic requirements allowing adequate hand hygiene compliance, in theory at least, are well known. Why then is it so hard to achieve acceptable compliance despite sufficient access to hand disinfectant dispensers, repeated training, and participation in national campaigns? Could it be that hand hygiene is regarded as too laborious, and changes to the established work-flow are needed to increase compliance? Some practicable examples are presented and pitfalls in defining compliance are discussed. Ownership for compliance must come from within clinical teams, and not solely driven from the infection control team. Support from the hospital management is essential. Ideally, the concepts presented allow a simple and efficient implementation of hand hygiene as part of the clinical work-flow to achieve an increase in compliance in the longer term. PMID- 23453172 TI - Impact of health campaign on hand hygiene with alcohol-based hand rubs in a non clinical setting. AB - BACKGROUND: Hand hygiene has been acknowledged as the single most important measure to prevent nosocomial infections. Likewise, for non-clinical settings, hand hygiene is recognized as a key element to prevent the spread of infectious diseases, nevertheless poor compliance has been documented. The feasibility of hand hygiene interventions in open-community settings with adults is mostly unclear. AIM: To investigate the acceptability and feasibility of a health campaign to promote hand hygiene with alcohol-based hand disinfectants at workplaces in a non-clinical setting. METHODS: The surveys were conducted as part of a prospective, controlled intervention study with volunteers from the administration of the Ernst-Moritz-Arndt-University Greifswald, the municipality of Greifswald and the state of Mecklenburg-West Pomerania. Participants in the intervention group were provided with alcohol-based hand disinfection; the control group was unchanged. Eleven volunteers filled out an initial survey at the beginning of the intervention regarding demographic and health-related questions as well as questions about the type of work, and a survey after completion of the intervention to evaluate the study's impact on the participants' attitudes toward hand hygiene. Participants in the experimental group filled out a monthly questionnaire regarding their compliance with hand hygiene measures, feasibility of hand disinfection and possible side-effects. FINDINGS: From 850 employees asked to participate, 134 were included in the study, and surveys from 129 participants (intervention: 64 vs control: 65) were accepted for analysis. Overall, datasets of 1230 person-months (79.46% of total possible follow-up surveys) were collected. Return rate and compliance remained high during the study period. Hand disinfection did not lead to skin problems in the majority of person-months. After the intervention, a majority of participants would favour a further use of hand disinfectants. CONCLUSION: Campaigns that enforce the use of alcohol-based hand disinfectants can have a sustainable effect on the compliance with hand hygiene measures in non-clinical settings. Campaigns have been shown to be feasible and effective in the prevention of transmissible diseases, therefore employers should consider whether hand hygiene campaigns to introduce waterless hand rubs could be included in companies' health programmes. PMID- 23453173 TI - Maintaining health by balancing microbial exposure and prevention of infection: the hygiene hypothesis versus the hypothesis of early immune challenge. AB - The human immune system is inseparably bonded to an individual's personal micro biome from birth to death. Since the beginning of life, commensal relationships have ensured the survival of micro- and macro-organisms within complex relationships. However, technological advances and altered lifestyle imposed new rules for this interaction during recent decades. It has been observed that reduced exposure to micro-organisms and parasites results in decreased morbidity and mortality, but is also associated with a rising prevalence of atopic disorders and autoimmune diseases, mostly in industrialized countries. This inverse relationship is described by the 'hygiene hypothesis', put forward in 1989, yet this term only imperfectly describes these observations, as excessive hygiene or hygienic measures may not directly be the central cause. The lack of appropriate immune stimulation during early childhood with the consequence of disturbed alignment in the sequence of encountering self- or non-self-antigens might account in the rise of atopy and autoimmune disease. For this reason we propose the term 'early immune challenge hypothesis'. This concept highlights the importance of immune priming in early life in the context of genetic, social, geographic, cultural, and economic background. Moreover, it emphasizes the central role of 'training' of regulatory T-cells through sufficient microbial exposure, leading to a robust, healthy balance between inflammation and anti inflammation or immune tolerance. Insufficient exposure might result in abnormal immune regulatory development. Finally, it incorporates the idea of encountering 'old friends' - organisms that shaped our immune system during human phylogeny. This article gives a comprehensive overview of the relationship between microbial exposure, and the incidence of asthma and hay fever is outlined. Although the outcomes of these studies originally were interpreted in the framework of the hygiene hypothesis, they may suit the concept of the hypothesis of early immune challenge even better. Moreover, recent studies have revealed that TH or TReg imbalances in disease may be partially corrected by the administration of helminthic or bacterial extracts. PMID- 23453174 TI - Hand hygiene and healthcare system change within multi-modal promotion: a narrative review. AB - Many factors may influence the level of compliance with hand hygiene recommendations by healthcare workers. Lack of products and facilities as well as their inappropriate and non-ergonomic location represent important barriers. Targeted actions aimed at making hand hygiene practices feasible during healthcare delivery by ensuring that the necessary infrastructure is in place, defined as 'system change', are essential to improve hand hygiene in healthcare. In particular, access to alcohol-based hand rubs (AHRs) enables appropriate and timely hand hygiene performance at the point of care. The feasibility and impact of system change within multi-modal strategies have been demonstrated both at institutional level and on a large scale. The introduction of AHRs overcomes some important barriers to best hand hygiene practices and is associated with higher compliance, especially when integrated within multi-modal strategies. Several studies demonstrated the association between AHR consumption and reduction in healthcare-associated infection, in particular, meticillin-resistant Staphylococcus aureus bacteraemia. Recent reports demonstrate the feasibility and success of system change implementation on a large scale. The World Health Organization and other investigators have reported the challenges and encouraging results of implementing hand hygiene improvement strategies, including AHR introduction, in settings with limited resources. This review summarizes the available evidence demonstrating the need for system change and its importance within multi-modal hand hygiene improvement strategies. This topic is also discussed in a global perspective and highlights some controversial issues. PMID- 23453175 TI - Surgical hand hygiene: scrub or rub? AB - Surgical hand hygiene is standard care prior to any surgical procedure. Per operative glove punctures are observed in almost 30% of all interventions, and a risk factor for postoperative infections. In the past, washing hands with antimicrobial soap and water (surgical scrub) was the norm, mainly with chlorhexidine or iodine. More recently, alcohol-based hand rub has been successfully introduced, showing greater effectiveness, less irritation to the hands, and requiring less time than washing hands. All products should have a remnant effect that delays microbial growth under the gloved hand. Some of the alcohol-based compounds are effective (as determined by the European Norm EN 12791) within 90 s whereas others require 3-5 min, similar to the scrub. The short procedure relies heavily on proper technique and timing, since lowering the exposure time to <90 s leads to significantly lower effectiveness of bacterial killing. Today, surgical hand hygiene should meet EN 12791 in Europe, or other standards, such as the US Food and Drug Administration tentative final monograph norm in the USA. It is best performed by using an alcohol-based hand rub, but a scrub with chlorhexidine-containing soap also meets these standards. PMID- 23453176 TI - Practical experience in a surgical unit when changing from scrub to rub. AB - Concurring with the move to a new facility at the end of 2008, alcohol-based hand rub (AHR) dispensers were allocated in all anterooms of operating theatres in a tertiary care hospital in Madrid, Spain. Routine educational sessions on surgical hand disinfection (SHD) were performed by infection control personnel, emphasizing the preferred method of AHR. Our aim was to evaluate the knowledge about SHD, as well as the performance of SHD and perceptions concerning the use of AHR or antiseptic soap hand scrub (ASHS) by surgeons and operating room nurses (ORNs). An anonymous survey on SHD was circulated to the surgeons, resident surgeons and nurses who perform SHD in our hospital. In all, 70 surveys were completed, corresponding to 27 ORNs (38.6%), 20 resident surgeons (29%), and 23 staff surgeons (33%), 41 (59%) of them being females. Forty percent of them perform mostly disinfectant soap hand scrub (DSHS) and 19% mostly hand rubs; 41% perform both methods. AHR rub is believed to be more efficacious than DSHS in reducing hand contamination (mean 6.5 vs 5.6; P > 0.001). Almost half of the personnel (49%) perform AHR >50% of the time (AHR users). AHR use is associated with ORNs (odds ratio: 3.4; 95% confidence interval [CI] 1.2-9.3; P = 0.018) but not with resident surgeons (odds ratio: 4.1; 95% CI 1.3-13.2; P = 0.017). When comparing both methods of SHD, personnel favour AHR for its colour (P > 0.01) and speed of drying (P > 0.01). Compared with surgeons, ORNs scored DSHS as more skin irritating (4.1 vs 5.2; P = 0.013), more associated with skin dryness (3.2 vs 4.7; P > 0.001), and inferior overall score (4.7 vs 5.6; P > 0.005). Most of the personnel agree that AHR (85%) improves compliance with SHD. Nevertheless ASHS is the method preferred for surgeons (63%) whereas AHR is the method preferred by nurses (70%; P< 0.001). According to auto-evaluation of hand skin after use, AHR has better outcomes in terms of lack of dryness (5.3 vs 4.6; P > 0.05). In addition, nurses scored ASHS lower than did surgeons in terms of skin redness (4.7 vs 6.0; P > 0.001), lack of skin integrity (4.8 vs 5.9; P = 0.004), skin dryness (3.6 vs 5.4; P > 0.001), and overall score (4.0 vs 5.2; P > 0.002). Change of perceptions and behaviours about SHD can be accomplished, and the AHR method is better adhered to by nursing personnel. PMID- 23453177 TI - Evaluating the risk of type 2 diabetes mellitus using artificial neural network: an effective classification approach. AB - AIM: To develop and evaluate an effective classification approach without biochemical parameters to identify those at high risk of T2DM in rural adults. METHODS: A cross-sectional survey was conducted. Of 8640 subjects who met inclusion criteria, 75% (N1=6480) were randomly selected to provide training set for constructing artificial neural network (ANN) and multivariate logistic regression (MLR) models. The remaining 25% (N2=2160) were assigned to validation set for performance comparisons of the ANN and MLR models. Predictive performance of different models was analyzed by the receiver operating characteristic (ROC) curve using the validation set. RESULTS: The prevalence rates of T2DM were 8.66% (n=561) and 9.21% (n=199) in training and validation sets, respectively. For ANN model, the sensitivity, specificity, positive and negative predictive value for identifying T2DM were 86.93%, 79.14%, 31.86%, and 98.18%, respectively, while MLR model were only 60.80%, 75.48%, 21.78%, and 94.52%, respectively. Area under the ROC curve (AUC) value for identifying T2DM when using the ANN model was 0.891, showing more accurate predictive performance than the MLR model (AUC=0.744) (P=0.0001). CONCLUSION: The ANN model is an effective classification approach for identifying those at high risk of T2DM based on demographic, lifestyle and anthropometric data. PMID- 23453178 TI - Community Diabetes Education (CoDE) for uninsured Mexican Americans: a randomized controlled trial of a culturally tailored diabetes education and management program led by a community health worker. AB - AIMS: The purpose of this randomized controlled trial was to determine the impact of a culturally tailored diabetes education program led by a community health worker (CHW) on the HbA1c, blood pressure, body mass index (BMI) and lipid status of uninsured Mexican Americans with diabetes. METHODS: Adult patients were recruited from a community clinic and randomized into intervention (n=90) and control (n=90) groups. Both groups received usual medical care from clinic physicians. The intervention group participated in the Community Diabetes Education (CoDE) program over 12 months. The primary outcome of interest was HbA1c. Secondary outcomes included blood pressure, BMI and lipid status. Variations in outcomes over time were assessed within groups and between groups using linear mixed-models and an intention-to-treat approach. Assessment of changes in HbA1c, blood pressure and lipid status over 12 months included variables to control for modifications made to antidiabetic, antihypertensive and lipid lowering medications. RESULTS: There was no difference in baseline characteristics between the intervention and control groups. Mean changes of HbA1c over 12 months showed a significant intervention effect (-.7%, p=.02) in the CoDE group compared with controls. HbA1c decreased significantly from baseline to 12 months within the intervention (-1.6%, p<.001) and control (-.9%, p<.001) groups. No differences between groups for secondary outcomes were found. CONCLUSIONS: This study supports the effectiveness of CHWs as diabetes educators/case managers functioning as integral members of the health care team in community clinic settings serving uninsured Mexican Americans. PMID- 23453179 TI - Usefulness of frequent electrocardiographic, echocardiographic, and serum catecholamine levels in takotsubo syndrome. PMID- 23453180 TI - All-cause mortality in patients with unprotected left main coronary disease: comparison between stenting and coronary artery bypass grafting. PMID- 23453181 TI - Use of drug-eluting stents or coronary artery bypass grafting in patients with unprotected left main coronary artery disease. PMID- 23453182 TI - Takotsubo cardiomyopathy: overrepresentation of cases. PMID- 23453184 TI - Effect of peroral endoscopic myotomy on esophagogastric junction physiology in patients with achalasia. AB - BACKGROUND: Pneumatic dilation and laparoscopic Heller myotomy improve parameters of esophageal function such as lower esophageal sphincter (LES) pressure, esophageal emptying, and esophagogastric junction (EGJ) distensibility. OBJECTIVE: To evaluate the effect of peroral endoscopic myotomy (POEM) on esophagogastric function. DESIGN: Prospective trial. SETTING: Endoscopy department at a university hospital. PATIENTS: All consecutive patients aged >17 years with achalasia and an Eckardt score of >=3. INTERVENTION: Before and 3 months after POEM, 10 consecutive patients underwent esophageal manometry, timed barium esophagograms, and EndoFLIP as well as an EGD. MAIN OUTCOME MEASUREMENTS: Eckardt symptom score, LES resting pressure, centimeters of barium stasis, EGJ distensibility, and reflux esophagitis. RESULTS: Compared with scores before POEM, patient symptom scores were significantly reduced (1, interquartile range [IQR 0-1] vs 8 [IQR 4-8]; P = .005). LES pressure decreased significantly (6.0 mm Hg [IQR 2.6-7.4] vs 19.0 mm Hg [IQR 13.0-28.0]; P = .008). Esophageal emptying increased significantly, and a 5-minute barium column measured 2.3 cm (IQR 0-3.2 cm) versus 10.1 cm (IQR 5.7-10.8 cm; P = .005). EGJ distensibility increased significantly (6.7 mm(2)/mm Hg [IQR 3.8-16.6] vs 1.0 mm(2)/mm Hg [IQR 0.4-2.3]; P = .02) at 50 mL. In 6 of 10 patients, reflux esophagitis was seen. Of these patients, 3 reported reflux symptoms. LIMITATIONS: Small number of patients, short-term follow-up. CONCLUSION: POEM improves esophagogastric function and suggests favorable long-term results based on Eckardt score, esophageal manometry, esophageal emptying, and EGJ distensibility. Long-term follow-up of larger series will determine whether the high rate of reflux esophagitis affects the clinical application of POEM. PMID- 23453183 TI - Preliminary report on a new, fully covered, metal stent designed for the treatment of pancreatic fluid collections. AB - BACKGROUND: Endoscopic transluminal treatment of pancreatic fluid collections (PFC) has been reported as an effective alternative approach to surgical treatment. A wide, short stent with an anti-migration system has been developed. OBJECTIVE: To evaluate a newly developed, fully covered, self-expandable metal stent (FCSEMS) customized for cystogastrostomy. DESIGN: Retrospective case series. SETTING: Tertiary-care academic medical centers and affiliated hospitals. PATIENTS: Nine patients who underwent endoscopic treatment of PFCs (5 with pseudocysts and 4 with walled-off pancreatic necrosis). INTERVENTION: Stent deployment after endoscopic US-guided puncture. Irrigation and necrosectomy were performed at the discretion of the endoscopist. MAIN OUTCOME MEASUREMENTS: Technical and clinical success rate, complications, and removability. RESULTS: The FCSEMS was inserted successfully in all cases (9/9, 100%). Clinical success was achieved in 7 of 9 cases (77.8%). No early complications associated with the procedure were observed. Late complications were observed in 2 cases (bleeding and asymptomatic migration). The FCSEMS was removed without any complications in all 6 cases where it was attempted after the procedure had been completed (100%). LIMITATIONS: This was a retrospective evaluation of a small number of cases. The FCSEMS was always inserted via the transgastric route. Follow-up duration was short. CONCLUSION: The endoscopic approach that uses this new FCSEMS is feasible for the treatment of PFCs. However, further evaluation is required. PMID- 23453185 TI - Risk stratification of upper GI bleeding with an esophageal capsule. AB - BACKGROUND: Analysis of upper GI bleeding (UGIB) presentations to our institutions suggests that many patients admitted for endoscopic investigation could be managed safely as outpatients. OBJECTIVE: To learn whether an esophageal capsule could identify a low-risk group of patients with UGIB who could safely wait for elective EGD. DESIGN: Diagnostic, nonrandomized, single-blind (investigator) study. SETTING: Three tertiary-care referral centers. PATIENTS: Eighty-three consecutive adult patients referred for management of UGIB. INTERVENTION: A capsule endoscopy (CE) was performed before EGD for the investigation and management of UGIB. MAIN OUTCOME MEASUREMENTS: Detection rates of UGIB source and identification of a low-risk group of patients who would have been suitable for outpatient EGD based on CE findings. RESULTS: In total, 62 of 83 patients (75%) had a cause for bleeding identified. Findings were concordant across both modalities in 34 patients (55%). Twenty-one patients (38%) with positive EGD results had negative CE results, 7 of whom were due to lack of duodenal visualization alone. However, 7 of 28 patients (25%) with normal EGD results had positive CE results. The subgroup of patients with duodenal visualization on CE, 23 of 25 (92%), were concordant with EGD for low-risk lesions that would have been suitable for outpatient management. LIMITATIONS: Low duodenal visualization rates with CE and low concordance between EGD and CE. CONCLUSION: Although CE is not currently ready to be used as a triage tool, when duodenal visualization was achieved CE correlated well with EGD findings and identified 92% of patients who may have been managed as outpatients. PMID- 23453186 TI - Creation of simulated papillae for endoscopic sphincterotomy and papillectomy training by using in vivo and ex vivo pig model (with videos). AB - BACKGROUND: There are few in vivo and ex vivo models for training in endoscopic sphincterotomy (ES) and endoscopic papillectomy (EP). OBJECTIVE: We describe in vivo and ex vivo training pig models that use a simulated papilla for hands-on teaching of ES and EP. DESIGN: Animal experiment. SETTING: A referral center. MATERIALS AND INTERVENTIONS: Hyaluronate solution (0.4%) was injected submucosally using a 25-gauge sclerotherapy needle to create a submucosal bleb by using porcine in vivo stomach, ex vivo stomach, and ex vivo rectum. ES and EP were then performed by using a pull-type sphincterotome and snare, respectively. MAIN OUTCOME MEASUREMENT: The feasibility of creating a simulated papilla for ES and EP procedures was tested by experienced and nonexperienced ERCP endoscopists. RESULTS: Creation of a hemispheroidal bulge was successful in 13 of 17 (76%) areas within an in vivo stomach, 13 of 16 (81%) areas of an ex vivo stomach, and 16 of 16 (100%) areas in an ex vivo rectum. In the in vivo stomach model, ES was successfully and realistically performed on the anterior wall of the stomach rather than in other walls. In the ex vivo stomach model, endoscopists experienced in ERCP and trainees performed ES without difficulty, whereas it was difficult or impossible for nonexperienced trainees to perform ES. In the ex vivo rectum model, all 3 endoscopists were able to complete not only ES but also EP. LIMITATIONS: Pilot study. CONCLUSIONS: Although further studies are necessary to evaluate the reproducibility and cost-effectiveness, this novel pig model appears useful for ES and EP training. PMID- 23453187 TI - Sex and age related non-metric variation of the human sternum in a Northwest Indian postmortem sample: a pilot study. AB - Nonmetric traits are quasi-continuous skeletal traits that cannot be measured, but are observed as ranks or scores. In the present study, 8 nonmetric traits of sternum were examined from 343 sternums collected from the autopsy cases. More males, particularly older subjects, had a mesosternal foramen. The frequency of mesosternal foramen, arch-shaped prominence on the manubrium and radial strips on mesosternum significantly increased but that of lateral projection of manubrium decreased in the 30+ year age-group (older individuals). The denticulate costal incisures were found mostly in females and younger subjects; however, the crescent incisures and arch shaped prominence of manubrium were noticed mainly in males and older subjects. Majority of subjects had 'deep and narrow' jugular notch and xiphi-sternum was 'bifid' or 'oblong' in males and 'small sized' in females and younger subjects. Xiphi-sternum was generally found absent in females and younger subjects. The different shapes of costal incisures, jugular notch and xiphoid process were found to have significant sex and age differences. The number of cases with fused elements significantly increased with advancing age in both sexes. The sternal elements' fusion showed a variable pattern and hence was not found to be a reliable criterion. Chi-square analysis revealed significant differences between two age-groups of individual sex in the distribution of 3 of the 8 nonmetric traits. Significant sex and age differences were noticed in the frequency of occurrence of mesosternal foramina between the younger and older age groups in both the sexes. The logistic regression analysis of the scores classified 73.8% sternums to their sex category and 70.0% sternums to their age group. Though present findings may not be enough for absolute personal identification, these traits can still serve as important identification tools if antemortem radiographs/CT or MRI scans are available for comparisons, or help classify an unknown sternum to its sex or age category based on the morphological features discussed in present study. PMID- 23453188 TI - Characterization of Citrus sinensis transcription factors closely associated with the non-host response to Xanthomonas campestris pv. vesicatoria. AB - Plants, when exposed to certain pathogens, may display a form of genotype independent resistance, known as non-host response. In this study, the response of Citrus sinensis (sweet orange) leaves to Xanthomonas campestris pv. vesicatoria (Xcv), a pepper and tomato pathogenic bacterium, was analyzed through biochemical assays and cDNA microarray hybridization and compared with Asiatic citrus canker infection caused by Xanthomonas citri subsp. citri. Citrus leaves exposed to the non-host bacterium Xcv showed hypersensitive response (HR) symptoms (cell death), a defense mechanism common in plants but poorly understood in citrus. The HR response was accompanied by differentially expressed genes that are associated with biotic stress and cell death. Moreover, 58 transcription factors (TFs) were differentially regulated by Xcv in citrus leaves, including 26 TFs from the stress-associated families AP2-EREBP, bZip, Myb and WRKY. Remarkably, in silico analysis of the distribution of expressed sequence tags revealed that 10 of the 58 TFs, belonging to C2C2-GATA, C2H2, CCAAT, HSF, NAC and WRKY gene families, were specifically over-represented in citrus stress cDNA libraries. This study identified candidate TF genes for the regulation of key steps during the citrus non-host HR. Furthermore, these TFs might be useful in future strategies of molecular breeding for citrus disease resistance. PMID- 23453189 TI - Factors related with the time to surgery in waiting-list patients for knee prostheses. AB - OBJECTIVE: In the year 2006 the Hospital Complex of Jaen began a new model of attention for consultation of knee osteoarthritis (CMAR), to offer quality treatment to the patient based on clinical practice guidelines. The objective of this study was to analyse the efficiency of the unit, in terms of delaying the time until a knee prostheses is needed. PATIENTS AND METHODS: An analysis of a retrospective cohort of patients seen at the CMAR was made, with a minimum available data set, and a Kaplan Meier analysis carried out in order to evaluate the time until the referral of the patient to surgery, as well as a Cox regression analysis in order to study the factors related with the time until the referral. RESULTS: 224 patients were included, with mean age of 65.7 years (95% CI 64 to 67), 67.9% women. 48.2% had a stage III affection (Kellgren-Lawrence), 27.5% stage 2, 15.3% stage 4, and 9% stage 1. 90.2% (202) received treatment with viscosupplementation (Hialuronic acid NASHA). Single joint affection (P<.0001; OR 0,267, 95% CI 0.130 to 0,549), a higher degree of osteoarthritis (P=.048; OR 0,410, 95% CI 0.169 to 0,992), and lower intensity of pain (P<.0001; OR 1,091, 95% CI 1.044 to 1,141), were the factors related with shorter time until surgery. Treatment with viscosupplementation increased the time until surgery in all patients. CONCLUSIONS: Factors like a lower age of the patient and the involvement of a single joint influenced the referral of the patient to surgery. The administration of viscosupplementation, delayed the time until the patient was finally referred to surgery. PMID- 23453190 TI - Which barriers affect morbidity registration performance of GP trainees and trainers? AB - BACKGROUND: Diagnosis coding percentages in the specialty training of general practitioners (GPs) are generally high, but not perfect, indicating barriers against coding still exist, possibly influencing the validity of data based on electronic patient records (EPRs). OBJECTIVE: To study the relationship between barriers to coding diagnoses with the International Classification of Primary Care (ICPC) of GP trainees and trainers and their self-reported and actual coding performance. METHODS: A questionnaire was developed, and returned by 71 (of 73, 97%) GP trainees and 103 (of 108, 95%) GP trainers, affiliated to the GP Specialty Training of the Academic Medical Center, University of Amsterdam. Their barriers to ICPC coding and self-reported coding performance were compared with EPR-derived data extractions that were collected during one year. RESULTS: Mean coding percentages were 88.3 (SD=11.5) and 82.3% (SD=19.0) (trainees/trainers). Most participants reported always registering ICPC codes for consultations and home visits, specifically in those situations pre-specified in the questionnaire. Telephone consultations, repeat prescriptions and administrative actions were coded less frequently. Most participants never or rarely experienced coding barriers, an exception being 'insufficient refinement of the ICPC system'. Most motivation and ICPC-related barriers correlated with self-reported and actual coding performance. Regression analyses showed that 'ICPC coding is unpleasant to use' predicted both trainees' and trainers' coding percentages. The trainers' coding percentage was also predicted by 'no personal gain from ICPC' and 'coding is difficult'. CONCLUSION: The mean coding percentages we found were high, but could further be improved by increasing GPs' motivation and by making ICPC coding more user-friendly. EPR-derived data seem biased by non-coded telephone consultations only. PMID- 23453191 TI - The treatment of glioblastomas: a systematic update on clinical Phase III trials. AB - Glioblastomas (GBMs) are invariably associated with unavoidable tumor recurrence and overall poor prognosis. The present study is to summarize the results of clinical Phase III studies on GBMs over the past seven years. A systematic literature search was performed using major electronic databases and by screening meeting abstracts. Totally, 16 studies of patients with newly diagnosed GBMs, recurrent GBMs, and elderly patients with GBMs were selected for this review. Although the outcomes of the experimental therapies were not encouraging, these studies produced a considerable amount of potentially clinically relevant information. Such aspects as surgical outcomes, radiation schedules, temozolomide (TMZ) schedules, methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene, combination of therapies, novel drug delivery methods and use of targeted agents have come to light and are being addressed here. In addition, we discuss the existing controversies of (1) surgical studies, (2) evaluations of recurrence, (3) salvage treatment bias, and (4) studies on elderly patients. PMID- 23453192 TI - Contribution of smoking to the gender gap in life expectancy in Japan. PMID- 23453193 TI - Human frailty and systemic failing in health care. PMID- 23453194 TI - Smoking and vascular risk: are all forms of smoking harmful to all types of vascular disease? AB - Smoking, both active and passive, is an established vascular risk factor. The present narrative review considers the effects of different forms of smoking (i.e. cannabis, cigar, pipe, smokeless tobacco and cigarette) on cardiovascular risk. Furthermore, the impact of smoking on several vascular risk factors [e.g. hypertension, diabetes mellitus (DM), dyslipidaemia and haemostasis] and on vascular diseases such as coronary heart disease (CHD), peripheral arterial disease (PAD), abdominal aortic aneurysms (AAA) and carotid arterial disease, is discussed. The adverse effects of all forms of smoking and the interactions between smoking and established vascular risk factors highlight the importance of smoking cessation in high-risk patients in terms of both primary and secondary vascular disease prevention. Healthcare providers should discourage people (especially the young) from becoming smokers, strongly encourage all vascular patients to stop smoking and support those who decide to quit by pharmaceutical and psychological interventions. In high-risk populations such as patients with CHD, DM and/or PAD, smoking cessation should always be a part of a multifactorial treatment to reduce vascular risk. PMID- 23453195 TI - Comparison of model-based and conventional controllers on a pilot-scale heat exchanger. AB - This pilot-scale heat exchanger demonstration compares two relatively simple nonlinear model-based control strategies to conventional proportional-integral (PI) control. The two nonlinear controllers, generic model control (GMC) and process-model based control (PMBC), use a first-principles model thereby providing characterization of the nonlinear process throughout the operating range. There are two approaches to GMC, one uses a dynamic model, the other a steady-state model. This work uses the steady-state model; accordingly, will use the term GMC-SS, which can be classified as output characterization for a PI controller, making it relatively simple to implement. PMBC uses a dynamic model and adapts to represent the process. These two nonlinear controllers were selected for this application evaluation because of their simplicity (they can be implemented in-house within many commercial control systems), diversity (steady state and dynamic models), and demonstrated utility for control of nonlinear single-input-single-output processes. The application and results are presented and discussed. Summarizing the results: Within a small temperature operating range PI provides good control, but over the full operating range, the nonlinear and variable delay of the process lead to poor control with PI. GMC can handle the nonlinear issues, but using the convenient steady-state model; it also, provides poor control because of the variable delay associated with flow rate. PMBC was able to provide good control throughout the entire operating range. PMBC has a further advantage of only having one tuning coefficient, while PI and GMC SS have two. PMID- 23453196 TI - [Unusual acute encephalopathy in a young patient with end-stage renal disease]. AB - Posterior reversible encephalopathy represents a neurotoxic state which can be associated to different pathological situations. The key to diagnosis are characteristic features on magnetic resonance imaging and rapidly evolving neurological symptoms if recognized and treated rapidly. Arterial hypertension and preeclampsia are the main causes of posterior reversible encephalopathy. Metabolic disorders including renal failure can also be associated with this syndrome. We report the clinical observation of an 18-year-old young patient on chronic hemodialysis who presented a status epilepticus associated with hypertensive crisis, two weeks after his transfer to peritoneal dialysis. Magnetic resonance imaging showed a typical aspect of posterior reversible encephalopathy with intracerebral haemorrhage. The evolution was favorable with a clear improvement of encephalic lesions. PMID- 23453197 TI - Correlation of ambient pollution levels and heavily-trafficked roadway proximity on the prevalence of smear-positive tuberculosis. AB - OBJECTIVES: Varying levels of evidence exist for the contribution of indoor air pollution and environmental tobacco smoke as a risk factor for tuberculosis (TB). Despite a similar mechanism of action, the influence of outdoor air pollution exposure as an independent contributor to TB disease has yet to be explored. This area of inquiry is of increasing importance given the level of pollution in the rising economies of many TB-endemic nations. Los Angeles' unique physical environs and traffic patterns mirror other global megacities with a greater burden of TB therefore allowing for preliminary correlative studies. This preliminary study hypothesizes that individuals who reside proximal to elevated pollutant exposures are likely to have a greater burden of disease--as evidenced by sputum smear-positive TB. STUDY DESIGN: Retrospective medical records review. METHODS: Medical records of non-homeless individuals (n = 196) diagnosed with culture positive TB at Los Angeles County and University of Southern California Medical Center Hospital were analyzed from January 2007 to December 2008. The study population was grouped according to acid-fast bacilli (AFB) smear-positive (n = 111) and smear-negative (n = 85) status. Air pollutant exposure was captured using measurements of ozone (O3) and particulate matter with an aerodynamic diameter of less than 2.5 (PM2.5). Individual assignment to O3 and PM2.5 exposures were based on residential proximity to the nearest US Environmental Protection Agency's monitoring station. Proximity of home residences to traffic related pollutants occurred by measurement of distance to the nearest freeway and major non-freeway road. RESULTS: Single factorial models yielded a significant correlation of smear-positive status and residential exposure to PM2.5. Residential distance to freeways and major arterial roads did not yield an association. CONCLUSIONS: This is the first report linking ambient pollution exposure as a risk factor for TB. PM2.5 may have the potential to impact TB lung pathology as evidenced by the linkage of fine particulate matter levels and smear positive TB. PMID- 23453198 TI - Factors associated with prolonged Escherichia coli O157 infection in a school outbreak. PMID- 23453199 TI - Treatment of diabetes mellitus with microencapsulated fetal human liver (FH-B TPN) engineered cells. AB - Transplantation of whole human pancreases or isolated islets into patients with type 1 diabetes mellitus has been severely hampered by the scarcity of cadaveric human donor organs, which mandates search for insulin producing cells/tissue source alternatives. Recent progress in stem cell biology has started looking into functionally competent, insulin-secreting progenitor cells. It had been previously observed that induced expression of the beta-cell transcriptional factor of the pancreatic and duodenal homeobox gene1 (PDX1), in human hepatocytes, may activate multiple features of the beta-cell phenotype. These "FH B-TPN" cells were shown to release insulin in response to physiological glucose stimulation both, in vitro and in vivo. However, because FH-B-TPNs lack the expression of a number of beta-cell or non beta-cell genes, and are associated with low insulin content, we aimed to determine whether these cells, upon physical manipulation and envelopment within "clinical grade" alginate-based microcapsules, would reverse hyperglycemia after graft into diabetic animal models. PMID- 23453200 TI - Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides. AB - Chemotherapeutic agents often cause severe side effects because they produce a similar cytotoxicity in both cancerous and healthy cells. In this study, a rational strategy was implemented to take advantage of a combination of both tumor microenvironment-sensitive polypeptides (TMSP) and folate to create a more selective and efficient drug delivery system to target cancer cells. TMSP and folate were conjugated to the distal ends of DSPE-PEG2000-maleimide and DSPE PEG5000-amine to create DSPE-PEG2000-TMSP and DSPE-PEG5000-folate, respectively, which were incorporated onto the surface of a docetaxel-loaded nanostructured lipid carrier (F/TMSP-DTX-NLC). TMSP are comprised of polycationic cell penetrating peptides (CPP) and polyanionic inhibitory peptides, which are coupled via a proteinase-sensitive cleavable linker. The linker can be cleaved in the presence of matrix metalloprotease-2 and -9 (MMP-2/9). TMSP provides the ability to enhance specific cancer cellular uptake after selectively unmasking polyanionic inhibitory peptides in MMP-2/9 protease-oversecretion tumor tissue, whereas in circulation, the penetration is shielded. The folate moiety binds selectively to folate receptor-positive tumors. The cleaved dual-modified nanocarriers are then taken up by the tumor cells via both receptor-mediated endocytosis and CPP penetrating action to overcome the higher interstitial pressure in the tumor. The nanocarrier system demonstrated a small size, high encapsulation efficiency (>95%), sustained release and targeted delivery. The strong cellular uptake and cytotoxic activity of dual-modified F/TMSP-DTX-NLC in KB, HT-1080, MCF-7 and A549 cells verified the correlation with folate receptor expression and MMP-2/9 secretion. The remarkable penetration into KB and HT-1080 multicellular tumor spheroids confirmed that the temporary mask of the polyanionic inhibitory peptide in TMSP does not disturb the penetration ability of CPP in the tumor microenvironment with abundant proteases. Furthermore, the active targeting and triggered activation exhibited higher antitumor efficacy and lower systemic toxicity with the KB tumor model in nude mice compared to the nonmodified DTX-NLC and Taxotere((r)). These results suggested that the application of combined TMSP and folate modifications may be an approach in the selectively targeted delivery of anticancer drugs with low systemic toxicity. PMID- 23453202 TI - Regulation of central carbon metabolism in Saccharomyces cerevisiae by metabolic inhibitors. AB - Metabolic inhibitors were applied for chemical regulation of central carbon metabolism in Saccharomyces cerevisiae. S. cerevisiae was treated with 10 metabolic inhibitors with various modes of action, and their activities were evaluated using a growth inhibition assay. Among the 6 active inhibitors, the effects of pyrazole (alcohol dehydrogenase inhibitor) and TTA (2 thenoyltrifluoloacetone, succinate dehydrogenase inhibitor) were analyzed in detail. The flask-scale batch-fermentation test showed that ethanol yield was reduced to 0.10 +/- 0.01 g g-1 and glycerol yield increased to 0.26 +/- 0.01 g g 1 on treatment with pyrazole at 5.0 g L-1, indicating that multiple isozymes of alcohol dehydrogenase were simultaneously inhibited. The multi-targeted metabolic profiling analysis revealed that, although the TTA and pyrazole treatments affected the profiles of all central carbon metabolites in distinct manners, the level of fructose-1,6-bisphosphate commonly increased in the TTA- and pyrazole treated S. cerevisiae by an unknown mechanism. These results demonstrate that chemical regulation of the central carbon metabolism could be used as an alternative tool to control microbial cell factories for bioproduction, or as a chemical probe to investigate the metabolic systems of useful microorganisms. PMID- 23453203 TI - TK1299, a highly thermostable NAD(P)H oxidase from Thermococcus kodakaraensis exhibiting higher enzymatic activity with NADPH. AB - Seven nicotinamide adenine dinucleotide oxidase homologs have been found in the genome of Thermococcus kodakaraensis. The gene encoding one of them, TK1299, consisted of 1326 nucleotides, corresponding to a polypeptide of 442 amino acids. To examine the molecular properties of TK1299, the structural gene was cloned, expressed in Escherichia coli and the gene product was characterized. Molecular weight of the recombinant protein was 49,375 Da when determined by matrix assisted laser desorption/ionization time-of-flight and 300 kDa when analyzed by gel filtration chromatography indicating that it existed in a hexameric form. The enzyme was highly thermostable even in boiling water where it exhibited more than 95% of the enzyme activity after incubation of 150 min. TK1299 catalyzed the oxidation of NADH as well as NADPH and predominantly converted O2 to H2O (more than 75%). K(m) value of the enzyme towards NADH and NADPH was almost same (24 +/ 2 MUM) where as specific activity was higher with NADPH compared to NADH. To our knowledge this is the most thermostable and unique NAD(P)H oxidase displaying higher enzyme activity with NADPH. PMID- 23453201 TI - Highly elastomeric poly(glycerol sebacate)-co-poly(ethylene glycol) amphiphilic block copolymers. AB - Poly(glycerol sebacate) (PGS), a tough elastomer, has been proposed for tissue engineering applications due to its desired mechanical properties, biocompatibility and controlled degradation. Despite interesting physical and chemical properties, PGS shows limited water uptake capacity (~2%), thus constraining its utility for soft tissue engineering. Therefore, a modification of PGS that would mimic the water uptake and water retention characteristics of natural extracellular matrix is beneficial for enhancing its utility for biomedical applications. Here, we report the synthesis and characterization of highly elastomeric poly(glycerol sebacate)-co-polyethylene glycol (PGS-co-PEG) block copolymers with controlled water uptake characteristics. By tailoring the water uptake property, it is possible to engineer scaffolds with customized degradation and mechanical properties. The addition of PEG results in almost 15 fold increase in water uptake capacity of PGS, and improves its mechanical stability under dynamic loading conditions. PGS-co-PEG polymers show elastomeric properties and can be subjected to serve deformation such as bending and stretching. The Young's modulus of PGS-co-PEG can be tuned from 13 kPa to 2.2 MPa by altering the amount of PEG within the copolymer network. Compared to PGS, more than six-fold increase in elongation was observed upon PEG incorporation. In addition, the rate of degradation increases with an increase in PEG concentration, indicating that degradation rate of PGS can be regulated. PGS-co PEG polymers also support cell proliferation, and thus can be used for a range of tissue engineering applications. PMID- 23453204 TI - L17. What can we expect from the revised Chapel Hill consensus conference nomenclature of vasculitis? PMID- 23453205 TI - [Bilateral gas gangrene of the lower limbs secondary to intramuscular injections of quinine]. PMID- 23453206 TI - L14. Immunomodulatory properties of apoptotic cells. PMID- 23453207 TI - S3. Rituximab for ANCA-associated vasculitides: the French experience. PMID- 23453208 TI - L18. Granuloma formation in granulomatosis with polyangiitis. PMID- 23453209 TI - L25. Medical treatment of subglottic stenosis in granulomatosis with polyangiitis (Wegener's). PMID- 23453210 TI - L51. From immunosuppression to selective treatments: the benefit-risk ratio. PMID- 23453211 TI - L39. Fulminant ANCA vasculitis. PMID- 23453212 TI - L15. EULAR/ACR 2012 classification criteria for polymyalgia rheumatica. PMID- 23453213 TI - L4. Eosinophils: how they contribute to endothelial damage and dysfunction. PMID- 23453214 TI - [A case of Marchiafava-Bignami disease]. PMID- 23453215 TI - L33. Neutrophil in immunity: a key modulator. PMID- 23453216 TI - Design, synthesis and pharmacological evaluation of omeprazole-like agents with anti-inflammatory activity. AB - A new series of novel benzimidazole derivatives containing substituted pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety has been synthesized and evaluated as orally bioavailable anti-inflammatory agents with anti-ulcerogenic activity. The anti-inflammatory and anti-ulcerogenic activities of these compounds were compared to diclofenac and omeprazole, respectively. In carrageenan-induced paw oedema assay, 2-methyl-N-((3,4-dimethoxypyridin-2 yl)methyl)-1H-benzimidazol-5-amine (12d) and 1-(1,2,3,5-tetrahydroxy-alpha-D mannofuranose)-5-(((3,4-dimethoxypyridin-2yl)methyl)amino)-2-methyl-1H benzimidazole (15d) displayed dose-dependent anti-inflammatory activities by decreasing the inflammation by 62% and 72%, respectively which is comparable to that of diclofenac (73%). In contrast to diclofenac, the anti-inflammatory activity of these compounds was not only free from any side effects on the gastric mucosa but also showed significant anti-ulcerogenic activity in rat pyloric ligation and ethanol-induced gastric ulcer models similar to that of omeprazole. Together, these findings suggest that 12d and 15d are potent anti inflammatory agents with concurrent anti-ulcerogenic activity and support its clinical promise as a component of therapeutic strategies for inflammation, for which the gastric side effects are always a major limitation. PMID- 23453217 TI - Discovery and structure-activity relationship of thienopyridine derivatives as bone anabolic agents. AB - A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4 phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day. PMID- 23453218 TI - A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy. AB - In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human. PMID- 23453219 TI - Novel leucine ureido derivatives as inhibitors of aminopeptidase N (APN). AB - Aminopeptidase N (APN/CD13) over expressed on tumor cells, plays a critical role in tumor invasion, metastasis, and tumor angiogenesis. Here we described the design, synthesis and preliminary activity studies of novel leucine ureido derivatives as aminopeptidase N (APN/CD13) inhibitors. The results showed that compound 8c had the most potent inhibitory activity against APN with the IC50 value to 0.06 +/- 0.041 MUM, which could be used for further anticancer agent research. PMID- 23453220 TI - The conversational skills of school-aged children with cochlear implants. AB - Children with cochlear implants have been shown to have language skills on a par with children with severe hearing losses who have hearing aids. Earlier implants, bilateral implantation, and focused intervention programmes may result in some children with cochlear implants displaying similar language skills to their hearing peers. The development of pragmatic skills is central to communication competence and underpins the development of friendships. Although some studies of pragmatic skills in children with cochlear implants have been reported, most have used a contrived referential communication task rather than free conversation. METHOD: This study investigated the conversational skills of 20 children with cochlear implants, aged between 9 and 12 years, in free conversation with their hearing peers. The pragmatic skills of these 20 deaf/hearing pairs or dyads were compared with the pragmatic skills of 20 hearing/hearing dyads. Pragmatic skills were analysed in terms of conversational balance, conversational turn types, and conversational maintenance. The impact of the participants' level of speech intelligibility was also investigated. RESULTS: Children with cochlear implants tend to dominate conversations with their hearing peers. They initiated more topics, took longer turns, asked more questions, and tended to make more personal comments while their hearing friends tended to use more conversational devices and minimal answers. In contrast, pairs of matched hearing children were very balanced in all of these aspects of conversation. Speech intelligibility did not appear to impact consistently on the pragmatic skills of the children with cochlear implants but all children had a relatively high level of speech intelligibility. DISCUSSION: Rather than being characterized by frequent conversational breakdown as in older studies, children with cochlear implants had a strong grasp of basic conversational rules. They conversed in a similar way to some deaf adults who also have been shown to take control of the conversation. Findings are discussed for their implications for intervention and future research. PMID- 23453221 TI - Children with bilateral cochlear implants identify emotion in speech and music. AB - OBJECTIVES: This study examined the ability of prelingually deaf children with bilateral implants to identify emotion (i.e. happiness or sadness) in speech and music. METHODS: Participants in Experiment 1 were 14 prelingually deaf children from 5-7 years of age who had bilateral implants and 18 normally hearing children from 4-6 years of age. They judged whether linguistically neutral utterances produced by a man and woman sounded happy or sad. Participants in Experiment 2 were 14 bilateral implant users from 4-6 years of age and the same normally hearing children as in Experiment 1. They judged whether synthesized piano excerpts sounded happy or sad. RESULTS: Child implant users' accuracy of identifying happiness and sadness in speech was well above chance levels but significantly below the accuracy achieved by children with normal hearing. Similarly, their accuracy of identifying happiness and sadness in music was well above chance levels but significantly below that of children with normal hearing, who performed at ceiling. For the 12 implant users who participated in both experiments, performance on the speech task correlated significantly with performance on the music task and implant experience was correlated with performance on both tasks. DISCUSSION: Child implant users' accurate identification of emotion in speech exceeded performance in previous studies, which may be attributable to fewer response alternatives and the use of child directed speech. Moreover, child implant users' successful identification of emotion in music indicates that the relevant cues are accessible at a relatively young age. PMID- 23453223 TI - A bile acid transporter as a candidate receptor for hepatitis B and D virus entry. PMID- 23453224 TI - [Analysis of the results of the SEIMC External Quality Control Program. Year 2011]. AB - The External Quality Control Program of the Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica [SEIMC]) includes controls for bacteriology, serology, mycology, parasitology, mycobacteria, virology, and molecular microbiology. This article presents the most relevant conclusions and lessons from the 2011 controls. Overall, the results obtained in 2011 confirm the excellent skill and good technical standards found in previous years. Nevertheless, erroneous results can be obtained in any laboratory and in clinically relevant determinations. The results of this program highlight the need to implement both internal and external controls, such as those offered by the SEIMC program, in order to ensure maximal quality of microbiological tests. PMID- 23453225 TI - [Analysis of the results of the HIV-1, HCV and HBV viral load of the SEIMC External Quality Control Program. Year 2011]. AB - Human immunodeficiency virus type 1 (HIV-1) and hepatitis B (HBV) and C virus (HCV) viral load determinations are among the most important markers in the follow-up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of the results obtained by microbiology laboratories. This article summarizes the results of the 2011 SEIMC External Quality Control Program for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of five standards were sent. One standard consisted of seronegative human plasma, while the remaining four contained plasma from three different viremic patients in the range of 2-5 log10 copies/mL; to determine repeatability, two of these standards were identical. A significant proportion of the laboratories (52.1% on average) obtained values outside the accepted range (mean +/- 0,25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was very good, with up to 94.9% of laboratories reporting results within the accepted range (Delta<0,5 log10 copies/ mL). The HBV and HCV program consisted of two standards with different viral load contents. In most of the participating laboratories (90% in the case of HCV and 86% in that of HBV), all the results were within the accepted range (mean +/- 1.96 SD log10UI/mL). Data from this analysis reinforce the utility of proficiency programs to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase in overall quality. Due to the marked interlaboratory variability found, use of the same method and the same laboratory for patient follow-up is advisable. PMID- 23453222 TI - Computational mass spectrometry for small molecules. AB - : The identification of small molecules from mass spectrometry (MS) data remains a major challenge in the interpretation of MS data. This review covers the computational aspects of identifying small molecules, from the identification of a compound searching a reference spectral library, to the structural elucidation of unknowns. In detail, we describe the basic principles and pitfalls of searching mass spectral reference libraries. Determining the molecular formula of the compound can serve as a basis for subsequent structural elucidation; consequently, we cover different methods for molecular formula identification, focussing on isotope pattern analysis. We then discuss automated methods to deal with mass spectra of compounds that are not present in spectral libraries, and provide an insight into de novo analysis of fragmentation spectra using fragmentation trees. In addition, this review shortly covers the reconstruction of metabolic networks using MS data. Finally, we list available software for different steps of the analysis pipeline. PMID- 23453226 TI - [Streptococcus bovis, taxonomic status, clinical relevance and antimicrobial susceptibility]. AB - Streptococcus bovis is a large bacterial complex of facultative anaerobic Gram positive cocci that includes distinct, genetically-related species. Traditionally, S. bovis was classified into three biotypes: I (mannitol fermentation-positive), II/1 (mannitol-negative and beta-glucuronidase-negative), and II/2 (mannitol-negative and beta-glucuronidase-positive). The introduction of molecular techniques in the last few decades has led to proposals for a genetic classification of this complex: S. bovis biotype I belongs to Streptococcus gallolyticus subsp. gallolyticus, S. bovis biotype II/1 is, in fact, Streptococcus infantarius subsp. infantarius, designated as Streptococcus lutetiensis, and S. bovis biotype II/2 is Streptococcus gallolyticus subsp. pasteurianus, commonly designated as Streptococcus pasteurianus. Although this modern taxonomy is currently accepted, many clinicians remain unfamiliar with these terms. The importance of correct identification lies in the strong association between bacteriemia, endocarditis and/or colon cancer and the various subspecies. In general, S. bovis is more susceptible to antimicrobial agents than other streptococci, but high levels of resistance to macrolides and tetracycline have been described. PMID- 23453227 TI - [Molecular typing methods for infection monitoring and control]. AB - Molecular typing methods are useful in the surveillance and control of nosocomial outbreaks because they can provide information on the clonal relatedness among isolates, identify reservoirs, and determine routes of transmission. The gold standard assay for molecular typing is pulsed-field gel electrophoresis (PFGE) due to its high discriminatory power. Some major disadvantages of PFGE include the high cost of the equipment, its labor intensiveness (the technique is not automated) and the time required to analyze the profiles of DNA bands (pulsotypes). Although there are many molecular typing methods based on polymerase-chain reaction (PCR), the most widely used is repetitive sequence based PCR (REP-PCR). Most of the PCR techniques used for molecular typing have none of the limitations of PFGE as they are less expensive and labor intensive (some, such as bioMerieux's Diversilab system, are commercially available) and generate DNA profiles that are easier to interpret, depending on the microorganism. The discriminatory power of PCR is generally lower than or similar to that of PFGE. Both PFGE and PCR require optimal laboratory standardization to guarantee good reproducibility. PCR methods are preferable in the study of small, timelimited outbreaks. In more complex outbreaks of longer duration, in which clonal evolution and dynamics are studied, the use of PFGE is preferable. Molecular typing methods based on DNA sequencing, such as multilocus sequence typing, are applicable in global epidemiological studies or in analyses of the population structure of microorganisms. PMID- 23453228 TI - [Diagnosis and treatment of Chagas disease]. AB - Trypanosoma cruzi infection, or Chagas disease, was discovered more than 100 years ago by Carlos Chagas. Although the infection kills more than 15,000 people each year, it is still classified as a neglected tropical disease. Today, this disease affects eight million people in 21 Latin American countries and, due to immigration, is also present in non-endemic countries. In recent years, the size of the immigrant population with chronic imported forms of Chagas disease has increased in Spain. In addition, several cases of congenital transmission have been reported. Some patients have severe infection and require specialized treatment such as pacemaker implantation or even heart transplantation, representing a considerable clinical, social and economic burden, particularly in areas with a large immigrant population. Since the 1960s, the only drugs available for the etiological treatment of this infection have been benznidazole and nifurtimox. Although new, more effective and better tolerated compounds are urgently needed, treatment with these trypanocidal drugs is recommended in both the acute and chronic stages of Chagas disease. New strategies for diagnosis and infection control in chronically infected patients have recently been reported, allowing the effectiveness of treatments to be assessed. PMID- 23453229 TI - [Detection of resistance mutations in proviral DNA in HIV-1 infection]. AB - Analysis of proviral DNA in HIV infection may have useful applications if techniques that are sufficiently sensitive to detect minor variants, such as single genome sequencing (SGS), are used. This technology, which is performed in DNA from whole blood, improves determination of co-receptor tropism and the detection of both circulating and archived resistance mutations (RM) that are undetectable in plasma. Many of these RM have clinical relevance and their identification could be useful in specific situations, such as the start of antiretroviral therapy to exclude the transmission of resistant strains, as information to be weighed in simplification strategies in patients with undetectable viral loads, and in antiretroviral-experienced patients with limited availability of clinical reports. Clonal analysis using SGS has yielded useful information on the pathogenesis and diagnosis of HIV-1 infection but, in its current design, is inappropriate for the clinical laboratory. The new generation of sequencing technology, which allows the simultaneous analysis of a large number of sequences, has begun to be applied in the analysis of the diversity of plasma HIV-1. The use of these highly sensitive, automated techniques in the analysis of HIV-1 cellular reservoirs will potentially allow all variants recorded during the history of the disease to become available. This information would be highly useful for the clinical management of HIV-1 infection at the individual and population level. PMID- 23453230 TI - [Update on hepatitis C therapy. New drugs, treatment response monitoring and emergence of resistance]. AB - The development of novel direct antiviral agents (DAAs) against hepatitis C virus (HCV) has represented a breakthrough in the treatment of chronic hepatitis C. Telaprevir and boceprevir are the first two protease inhibitor (PI) DAAs to be approved for combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). In genotype 1 monoinfected patients, triple PI therapy has increased sustained viral response (SVR) rates by approximately 30% compared with conventional combination therapy. The introduction of these drugs into clinical practice will modify the timing of monitoring parameters in diagnostic laboratories, especially with regard to stopping rules and to faster delivery of results. In the near future, new DAAs, directed against different targets of the HCV cycle (polymerase inhibitors, viral replication complex inhibitors and cyclophilin inhibitors), which are currently in various stages of clinical development, will be available. Some of these DAAs have already reached advanced phases of development, both in combination with PEG-IFN and RBV and in interferon free therapy, with very high rates of SVR. PMID- 23453231 TI - [Implementation of the technical requirements of the UNE-EN-ISO 15189 quality standard in a mycobacterial laboratory]. AB - The UNE-EN-ISO 15189:2007 standard defines the requirements for quality and competence that must be met by medical laboratories. These laboratories should use this international standard to develop their own quality management systems and to evaluate their own competencies; in turn, this standard will be used by accreditation bodies to confirm or recognize the laboratories' competence. In clinical microbiology laboratories, application of the standard implies the implementation of the technical and specific management requirements that must be met to achieve optimal quality when carrying out microbiological tests. In Spain, accreditation is granted by the Spanish Accreditation Body (Entidad Nacional de Acreditacion). This review aims to discuss the practical application of the standard's technical requirements in mycobacterial laboratory. Firstly, we define the scope of accreditation. Secondly, we specify how the items of the standard on personnel management, control of equipment, environmental facilities, method validation, internal controls and customer satisfaction surveys were developed and implemented in our laboratory. PMID- 23453232 TI - [Antifungal susceptibility testing in yeasts. Update and novelties]. AB - This text reviews and updates the uses of the reference procedures for antifungal susceptibility testing in yeasts, the reliability of the commercial methods and the guidelines for the use of these procedures for patient management and for epidemiological reasons to determine the susceptibility profile and the emergence of resistances. Novelties in the procedures of setting clinical breakpoints of antifungal agents by both the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the US Clinical Laboratory Standards Institute (CLSI) are also reviewed. PMID- 23453233 TI - Microalgae cultivation for bioenergy production using wastewaters from a municipal WWTP as nutritional sources. AB - In order to reduce input cost for microalgal cultivation, we investigated the feasibility of wastewater taken from a municipal WWTP in Busan, Korea as wastewater nutrients. The wastewaters used in this study were the effluent from a primary settling tank (PS), the effluent from an anaerobic digestion tank (AD), the conflux of wastewaters rejected from sludge-concentrate tanks and dewatering facilities (CR), and two combined wastewaters of AD:PS (10:90, v/v) and AD:CR (10:90, v/v). Chlorella sp. ADE5, which was isolated from the AD, was selected for the feasibility test. The highest biomass production (3.01 g-dry cell weight per liter) of the isolate was obtained with the combined wastewater ADCR, and it was 1.72 times higher than that with BG 11 medium. Interestingly, the cells cultivated with wastewater containing PS wastewater were easily separated from the culture and improved lipid content, especially oleic acid content, in their cells. PMID- 23453234 TI - Application of surface enzyme treatments using laccase and a hydrophobic compound to paper-based media. AB - A new approach for the hydrophobization of finished cellulosic substrates based on a previously reported enzymatic technique is proposed. Commercial finished paper was hydrophobized by using laccase from Trametes villosa in combination with lauryl gallate (LG) as hydrophobic compound. The efficiency of the method was increased by the use of a lignosulfonate as a natural dispersant to improve the surface distribution of LG on the paper, raise its hydrophobicity and help preserve the enzyme activity. No similar threefold effect from a single compound for the improvement of enzymatic treatments was previously reported. The influence of processing conditions including the LG dose, treatment time and temperature was also examined, resulting in further increased hydrophobicity. Efficient fiber bonding and chemical functionalization were confirmed by thorough washing and Soxhlet extraction of the paper. As shown here for the first time, enzyme treatments have the potential to improve the surface hydrophobicity of paper-based media. PMID- 23453235 TI - Design of adaptive fuzzy wavelet neural sliding mode controller for uncertain nonlinear systems. AB - This paper proposes novel adaptive fuzzy wavelet neural sliding mode controller (AFWN-SMC) for a class of uncertain nonlinear systems. The main contribution of this paper is to design smooth sliding mode control (SMC) for a class of high order nonlinear systems while the structure of the system is unknown and no prior knowledge about uncertainty is available. The proposed scheme composed of an Adaptive Fuzzy Wavelet Neural Controller (AFWNC) to construct equivalent control term and an Adaptive Proportional-Integral (A-PI) controller for implementing switching term to provide smooth control input. Asymptotical stability of the closed loop system is guaranteed, using the Lyapunov direct method. To show the efficiency of the proposed scheme, some numerical examples are provided. To validate the results obtained by proposed approach, some other methods are adopted from the literature and applied for comparison. Simulation results show superiority and capability of the proposed controller to improve the steady state performance and transient response specifications by using less numbers of fuzzy rules and on-line adaptive parameters in comparison to other methods. Furthermore, control effort has considerably decreased and chattering phenomenon has been completely removed. PMID- 23453236 TI - Reply to the article entitled "Ultrasound description of Pecs II (modified Pecs I): a novel approach to breast surgery". Reply of the authors. PMID- 23453237 TI - [Continuous paravertebral block for analgesia in minimally invasive cardiac surgery. Reply of the authors]. PMID- 23453238 TI - [Continuous paravertebral block for analgesia in minimally invasive cardiac surgery]. PMID- 23453239 TI - [Perioperative treatment of a pregnant woman with severe belonephobia]. PMID- 23453240 TI - The accuracy of human papillomavirus vaccination status based on adult proxy recall or household immunization records for adolescent females in the United States: results from the National Immunization Survey-Teen. AB - PURPOSE: We assessed the accuracy of human papillomavirus (HPV) vaccination status based on adult proxy recall and household immunization records for adolescent females in the United States. METHODS: We used data from the 2010 National Immunization Survey-Teen for females aged 13 to 17 years. The accuracy of HPV vaccination status (>=1 dose) based on adult proxy recall (unweighted n = 6868) and household immunization records (unweighted n = 2216) was assessed by estimating the sensitivity, specificity, and corresponding 95% confidence limits (CL) of these measures with provider-reported HPV vaccination status as the reference standard. Our analyses accounted for the complex survey design and population weights. RESULTS: The sensitivity and specificity of adult proxy recall were 83.9% (95% CL: 81.2%, 86.6%) and 90.4% (95% CL: 88.9%, 92.0%), respectively. Conversely, the sensitivity and specificity of household immunization records were 74.2% (95% CL: 69.1%, 79.2%) and 98.0% (95% CL: 96.8%, 99.1%), respectively. The accuracy of both measures varied by race/ethnicity, proxy respondent, and maternal education. CONCLUSIONS: Our results suggest that adult proxy recall and household immunization records have reasonable accuracy for classifying HPV vaccination status for females aged 13 to 17 years in the United States, but these measures present a trade-off between sensitivity and specificity. PMID- 23453241 TI - Tangential excision of pigmented nail matrix lesions responsible for longitudinal melanonychia: evaluation of the technique on a series of 30 patients. AB - OBJECTIVES: We sought to assess the shave biopsy technique, which is a new surgical procedure for complete removal of longitudinal melanonychia. We evaluated the quality of the specimen submitted for pathological examination, assessed the postoperative outcome, and ascertained its indication between the other types of matrix biopsies. DESIGN: This was a retrospective study performed at the dermatologic departments of the Universities of Liege and Brussels, Belgium, of 30 patients with longitudinal or total melanonychia. RESULTS: Pathological diagnosis was made in all cases; 23 patients were followed up during a period of 6 to 40 months. Seventeen patients had no postoperative nail plate dystrophy (74%) but 16 patients had recurrence of pigmentation (70%). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Shave biopsy is an effective technique for dealing with nail matrix lesions that cause longitudinal melanonychia over 4 mm wide. Recurrence of pigmentation is the main drawback of the procedure. PMID- 23453242 TI - Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients. AB - BACKGROUND: Scleromyxedema is associated with a monoclonal gammopathy and other comorbidities. Its prognostic and therapeutic features are poorly documented because most reports deal with single cases or small series. OBJECTIVE: We sought to describe the characteristics of patients with scleromyxedema regarding demographics, clinical characteristics, comorbidities, therapeutic interventions, and course. METHODS: We conducted a retrospective and prospective multicenter study. RESULTS: We identified 30 patients with scleromyxedema (17 men and 13 women). The mean age at diagnosis was 59 years. The mean delay between disease onset and diagnosis was 9 months. Monoclonal gammopathy was detected in 27 patients. Extracutaneous manifestations were present in 19 patients including neurologic (30%), rheumatologic (23.3%), and cardiac (20%) manifestations. Two patients developed hematologic malignancies. The most common therapies included oral steroids and intravenous immunoglobulins. Although corticosteroids were ineffective, intravenous immunoglobulins (alone or in combination with other drugs) induced complete remission in 4 and partial remission in 9 patients with a mean treatment duration of 2 years. In all, 21 patients were followed up for a mean period of 33.5 months, at which time 16 patients were alive, 12 with and 4 without skin disease. Five patients died: 2 with dermatoneuro syndrome and 1 each with myeloid leukemia, Hodgkin lymphoma, and myocardial insufficiency. LIMITATIONS: This is mainly a retrospective study. CONCLUSIONS: Our study confirms that scleromyxedema is a chronic and unpredictable disease with severe systemic manifestations leading to a guarded prognosis. There is no specific definitive treatment. Our data support the contention that intravenous immunoglobulin is a relatively effective and safe treatment. The response is not permanent and maintenance infusions are required. PMID- 23453243 TI - Low-dose high-dose-rate brachytherapy in the treatment of facial lesions of cutaneous T-cell lymphoma. AB - BACKGROUND: The use of many of the standard skin-directed mycosis fungoides (MF) therapies on facial skin may be limited by site-specific increased risks of side effects, excessive inflammation, and ocular toxicity. OBJECTIVE: Our study aimed to describe the levels of erythema, scale, and induration of facial lesions in MF before and after low-dose high-dose-rate surface applicator brachytherapy and to examine the overall clinical response to brachytherapy. METHODS: A total of 23 facial MF lesions in 10 patients were treated with high-dose-rate brachytherapy doses of 4 Gy per session for a total of 2 fractions at our multidisciplinary cutaneous oncology clinic between August 17, 2009, and March 12, 2012. RESULTS: In all 23 lesions, dramatic clinical improvement was observed. Patients were followed up for a median of 6.3 months. No recurrences were reported in the follow-up period. LIMITATIONS: Long-term follow-up is lacking. Reassessment of all included patients at annual intervals for a period of at least 5 years is the authors' goal. CONCLUSION: Low-dose high-dose-rate brachytherapy using custom made surface molds is a highly efficacious therapy in the treatment of facial lesions in MF. PMID- 23453244 TI - Residual neuromuscular block as a risk factor for critical respiratory events in the post anesthesia care unit. AB - OBJECTIVE: Residual neuromuscular block is an important postoperative complication associated to the use of neuromuscular blocking drugs. The purpose of this study was to access the incidence of residual neuromuscular block in a post-anesthesia care unit and to evaluate its association with critical respiratory events. MATERIAL AND METHODS: Prospective cohort study was conducted in a Post Anesthetic Care Unit (PACU) for a period of 3 weeks. Two hundred two adult patients who submitted to scheduled non-cardiac and non-intracranial surgery were eligible to the study. The primary outcome variable was residual neuromuscular block after arrival to PACU that was defined as train-of-four ratio <0.9 and objectively quantified using acceleromyography. Demographic data, perioperative variables, lengths of hospital and recovery room stay and critical respiratory events were recorded. Inadequate emergence was classified in its different forms according to the Richmond agitation and sedation scale 10 min after admission to the recovery room. RESULTS: Residual neuromuscular block incidence in the post-anesthesia care unit was 29.7% (95% confidence interval: 23.4, 36.1). Patients with residual neuromuscular block had more frequently overall critical respiratory events (51% versus 16%, P<0.001), airway obstruction (10% versus 2%, P=0.029), mild-moderate hypoxemia (23% versus 4%, P<0.001), severe hypoxemia (7% versus 1%, P=0.033), respiratory failure (8% versus 1%, P=0.031), inability to breathe deeply (38% versus 12%, P<0.001) and muscular weakness (16% versus 1%, P<0.001). Residual neuromuscular block was more common after high-risk surgery (53% versus 33%, P=0.011) and was more often associated with post-operative hypoactive emergence as defined by the Richmond Agitation and Sedation Scale (21% versus 6%, P=0.001). CONCLUSIONS: This study suggests that residual neuromuscular block is common in the PACU and is associated with more frequent critical respiratory events. PMID- 23453245 TI - Forbidden fruit: on the analysis of recurrent events in randomized clinical trials. AB - The conventional analysis of a typical clinical trial focuses on the time to occurrence of the first among a composite set of alternative events such as death or nonfatal myocardial infarction. Subsequent recurrent events are thereby excluded from consideration to ensure that all the observations were mutually exclusive of each other. Thus, not all events occurring during follow-up will be analyzed. Consequently, some investigators are now reporting additional analyses of previously published trials based on a naive comparison of the total number of events-first events plus recurrent events-and are recommending that these additional analyses be routinely conducted in future trials. We have summarized the potential limitations of this proposal and suggest other methods to analyze recurrent events, with a particular focus on kinetic modeling. The application of this approach to several previously published trials illustrates its facility to help elucidate the causal mechanisms underlying empirical demonstrations of safety and efficacy. PMID- 23453246 TI - First-onset psychosis, anti-NMDAR encephalitis, schizophrenia and Consultation Liaison psychiatry. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a new, severe and possibly life-threatening disorder as illustrated by a 25% mortality or severe disability rate. Its neuropsychiatric presentation closely resembles schizophrenia. In this paper, the relationship of anti-NMDAR encephalitis to schizophrenia and its consequences in Consultation-Liaison service for diagnostic workup in patients with first-episode psychosis are addressed. PMID- 23453247 TI - Human placental sulfate transporter mRNA profiling from term pregnancies identifies abundant SLC13A4 in syncytiotrophoblasts and SLC26A2 in cytotrophoblasts. AB - Sulfate is an important nutrient for fetal growth and development. The fetus has no mechanism for producing its own sulfate and is therefore totally reliant on sulfate from the maternal circulation via placental sulfate transport. To build a model of directional sulfate transport in the placenta, we investigated the relative abundance of the 10 known sulfate transporter mRNAs in human placenta from uncomplicated term pregnancies. SLC13A4 and SLC26A2 were the most abundant sulfate transporter mRNAs, which localized to syncytiotrophoblast and cytotrophoblast cells, respectively. These findings indicate important physiological roles for SLC13A4 and SLC26A2 in human placental sulfate transport. PMID- 23453249 TI - Do written mandatory accreditation standards for residential care positively model learning organizations? Textual and critical discourse analysis. AB - BACKGROUND: Unprecedented global population ageing accompanied by increasing complexity of aged care present major challenges of quality in aged care. In the business literature, Senge's theory of adaptive learning organisations offers a model of organisational quality. However, while accreditation of national standards is an increasing mechanism for achieving quality in aged care, there are anecdotal concerns it creates a 'minimum standards compliance mentality' and no evidence about whether it reinforces learning organisations. OBJECTIVE: The research question was 'Do mandatory national accreditation standards for residential aged care, as they are written, positively model learning organisations?'. METHOD: Automatic text analysis was combined with critical discourse analysis to analyse the presence of learning concepts from Senge's learning organisation theory in an exhaustive sample of national accreditation standards from 7 countries. The two stages of analysis were: (1) quantitative mapping of the presence of learning organisation concepts in standards using Bayesian-based textual analytics software and (2) qualitative critical discourse analysis to further examine how the language of standards so identified may be modelling learning organisation concepts. RESULTS: The learning concepts 'training', 'development', 'knowledge', and 'systems' are present with relative frequencies of 19%, 11%, 10%, and 10% respectively in the 1944 instances, in paragraph-sized text blocks, considered. Concepts such as 'team', 'integration', 'learning', 'change' and 'innovation' occur with 7%, 6%, 5%, 5%, and 1% relative frequencies respectively. Learning concepts tend to co-occur with negative rather than positive sentiment language in the 3176 instances in text blocks containing sentiment language. Critical discourse analysis suggested that standards generally use the language of organisational change and learning in limited ways that appear to model 'learning averse' communities of practice and organisational cultures. CONCLUSION: The aged care quality challenge and the role of standards need rethinking. All standards implicitly or explicitly model an organisation of some type. If standards can model a limited and negative learning organisation language, they could model a well-developed and positive learning organisation language. In the context of the global aged care crisis, the modelling of learning organisations is probably critical for minimal competence in residential aged care and certainly achievable in the language of standards. PMID- 23453248 TI - "Trophoblast islands of the chorionic connective tissue" (TICCT): a novel placental histologic feature. AB - INTRODUCTION: We found isolated or clustered trophoblasts in the chorionic connective tissue of the extraplacental membranes, and defined this novel histologic feature as the "trophoblast islands of the chorionic connective tissue" (TICCT). This study was conducted to determine the clinical significance of TICCT. METHODS: Immunohistochemistry for cytokeratin-7 was performed on the chorioamniotic membranes (N = 2155) obtained from singleton pregnancies of 1199 uncomplicated term and 956 preterm deliveries. The study groups comprised 1236 African-American and 919 Hispanic women. Gestational age ranged from 24(+0) weeks to 41(+6) weeks. Multiple logistic regression analysis was performed to investigate the magnitude of association between patient characteristics and the presence of TICCT. RESULTS: The likelihood of TICCT was significantly associated with advancing gestational age both in term (OR: 1.29, 95% CI: 1.16-1.45, p < 0.001) and preterm deliveries (OR: 1.19, 95% CI: 1.07-1.32, p = 0.001) . Hispanic women were less likely than African-American women to have TICCT across gestation in term (OR: 0.23, 95% CI: 0.18-0.31, p < 0.001) and preterm pregnancies (OR: 0.41, 95% CI: 0.29-0.58, p < 0.001). Women with a female fetus were significantly more likely to have TICCT than women with a male fetus, in both term (OR: 1.64, 95% CI: 1.28-2.11, p < 0.001) and preterm gestations (OR: 2.04, 95% CI: 1.46 2.85, p < 0.001). TICCT was 40% less frequent in the presence of chronic placental inflammation [term (OR: 0.60, 95% CI: 0.45-0.81, p = 0.001) and preterm gestations (OR: 0.58, 95% CI: 0.40-0.84, p = 0.003)] and in parous women at term (OR: 0.60, 95% CI: 0.44-0.81, p = 0.001). CONCLUSIONS: Our findings suggest that the duration of pregnancy, fetal sex, and parity may influence the behavior of extravillous trophoblast and placental mesenchymal cells. PMID- 23453251 TI - Validation of an automated algorithm for detecting apneas and hypopneas by acoustic analysis of breath sounds. AB - BACKGROUND: Sleep-disordered breathing (SDB) is common and is associated with increased risk for cardiovascular disease. However, most patients remain undiagnosed due to lack of access to sleep laboratories. We therefore tested the validity of a single-channel monitoring setup that captures and analyzes breath sounds (BSs) to detect SDB. METHODS: BS were recorded from 50 patients undergoing simultaneous polysomnography (PSG). Using custom-designed automatic software, BS were subjected to a set of pattern recognition rules to identify apneas and hypopneas from which the acoustic apnea-hypopnea index (AHI-a) was calculated. Apneas and hypopneas from PSG were scored blindly by three technicians according to two criteria; one relying solely on the drop of the respiratory signal by >90% for an apnea and by 50% to 90% for a hypopnea (TV50 criteria), and another that also required a desaturation or an arousal for a hypopnea (American Association of Sleep Medicine [AASM] criteria). PSG AHI (AHI-p) was calculated for each technician according to both criteria. RESULTS: There was no significant difference between AHI-p scores according to TV50 and AASM criteria. AHI-a was strongly correlated with AHI-p according to both TV50 (R=94%) and AASM criteria (R=93%). Bland-Altman plot analysis revealed that 98% and 92% of AHI-a fell within the limits of agreement for AHI-p according to TV50 and AASM criteria, respectively. Based on a diagnostic cutoff of AHI-p>=10 for SDB, overall accuracy of AHI-a reached 88% and negative predictive value reached 100%. CONCLUSION: Acoustic analysis of BS is a reliable method for quantifying AHI and diagnosing SDB compared to simultaneous PSG. PMID- 23453250 TI - Bilateral impairments in task-dependent modulation of the long-latency stretch reflex following stroke. AB - OBJECTIVE: Modulation of the long-latency reflex (LLR) is important for sensorimotor control during interaction with different mechanical loads. Transcortical pathways usually contribute to LLR modulation, but the integrity of pathways projecting to the paretic and non-paretic arms of stroke survivors is compromised. We hypothesize that disruption of transcortical reflex pathways reduces the capacity for stroke survivors to appropriately regulate the LLR bilaterally. METHODS: Elbow perturbations were applied to the paretic and non paretic arms of persons with stroke, and the dominant arm of age-matched controls as subjects interacted with Stiff or Compliant environments rendered by a linear actuator. Reflexes were quantified using surface electromyograms, recorded from biceps. RESULTS: LLR amplitude was significantly larger during interaction with the Compliant load compared to the Stiff load in controls. However, there was no significant change in LLR amplitude for the paretic or non-paretic arm of stroke survivors. CONCLUSION: Modulation of the LLR is altered in the paretic and non paretic arms after stroke. SIGNIFICANCE: Our results are indicative of bilateral sensorimotor impairments following stroke. The inability to regulate the LLR may contribute to bilateral deficits in tasks that require precise control of limb mechanics and stability. PMID- 23453252 TI - [Faulty implants: the court of appeal has ruled surgeon's responsibility]. AB - It is in this atmosphere fuelled by the recent scandal of the PIP implants that the final court of appeal has given a judgment on July 12, 2012 which reorients the debate. While patients seeked a shared responsibility between the provider of the implants and the surgeon, in this case of faulty testicular implants, the final court of appeal just ruled out the responsibility of the surgeon. But this jurisprudence can only be applied to private law, i.e. for private healthcare whereas lawsuits filed against public hospitals depend on a different legal liability system. PMID- 23453253 TI - Quercetin improves the postthaw characteristics of cryopreserved sex-sorted and nonsorted stallion sperm. AB - Excessive reactive oxygen species generation during sex sorting and cryopreservation of stallion sperm leads to DNA fragmentation, lipid peroxidation, and motility loss. In this study we investigated whether antioxidant supplementation during sex sorting and cryopreservation could ameliorate the effects of reactive oxygen species on stallion sperm. In experiment 1, the postthaw characteristics of stallion sperm (N = 9) cryopreserved in the presence or absence of catalase (200 U/mL), cysteine (0.2 mg/mL), or quercetin (0.15 mM) was examined. Motility and acrosome integrity were assessed at 0, 1, and 3 hours after thawing. The sperm chromatin structure assay (SCSA; detectable DNA fragmentation index [DFI], mean DFI, and DFI) was used to assess DNA integrity immediately after thawing. Quercetin increased the total postthaw motility (25.3% vs. 20.9%; P < 0.05), but there was no beneficial effect of catalase or cysteine. Based on these results, the effect of quercetin during cryopreservation on the postthaw zona binding ability of sperm was assessed using a heterologous (bovine) zona binding assay. Quercetin increased the number of sperm bound per oocyte (13.6 vs. 9.2; P < 0.05) compared with the control. In experiment 2, the effect of quercetin (0.15 mM) in the media used during semen storage and transport, Hoechst 33342 staining and cryopreservation of stallion sperm (N = 9) was investigated. Motility, acrosome integrity, and viability were assessed at 0, 1, and 3 hours after thawing and SCSA was performed at 0 hours after thawing. Quercetin supplementation during sex sorting and cryopreservation improved DNA integrity (SCSA; detectable DFI of 54.9% vs. 74.6%, P < 0.05; mean DFI of 270.2 vs. 288.1, P < 0.05; and DFI of 26.3% vs. 28.5%, P < 0.05) compared with control sex-sorted sperm. There was no beneficial effect of quercetin on the motility, acrosome integrity, or viability of sex-sorted sperm. In conclusion, quercetin significantly improved the motility and zona binding ability of cryopreserved stallion sperm, and reduced DNA fragmentation in sex-sorted, cryopreserved stallion sperm. PMID- 23453254 TI - Effect of porcine follicular fluid proteins and peptides on oocyte maturation and their subsequent effect on in vitro fertilization. AB - The follicular fluid (FF) is a microenvironment that contains molecules involved in oocyte maturation, ovulation, and fertilization. Characterizing the proteins and peptides present in the FF could be useful for determining which proteins and peptides to use as a supplement for culture media. Biologically active peptides produced during the maturation or degradation of functional proteins are called cryptides. The aim of this study was to identify the proteins and cryptides in porcine FF that could stimulate porcine oocyte in vitro maturation (IVM) and in vitro fertilization (IVF) when added to culture maturation medium. Five FF protein fractions (F1-F5) were obtained by ionic exchange chromatography, resolved by SDS-PAGE, and identified by tandem mass spectrometry. These fractions had effects on IVM and/or IVF. The F1 fraction, which was composed of immunoglobulin fragments, cytokeratin, transferrin, and plasminogen precursor increased IVM and IVF. The F2, F3, and F4 fractions reduced the percentage of oocytes in first metaphase. Additionally, the F3 fraction, which was composed of immunoglobulins and transthyretin, interfered with germinal vesicle breakdown. The F5 fraction, which was mainly composed of serum albumin and keratin, favored germinal vesicle breakdown and promoted IVM. Most of the 31 proteins which were associated with the immune response and inflammatory processes could be related to oocyte maturation and fertilization. Some of the identified proteins were present in more than one fraction; this could be explained by a change in their isoelectric points, because of the loss of part of the amino acid sequence or a change in the glycosylation status of the protein. Improved oocyte IVM and IVF will increase embryo production, which in turn will contribute to the efficiency of assisted reproduction in various mammalian species. PMID- 23453255 TI - Pregnancy per AI differences between primiparous and multiparous high-yield dairy cows after using Double Ovsynch or G6G synchronization protocols. AB - The objective of the present work was to determine the optimal protocol for timed AI on high-yield dairy cows. The pregnancy per AI (pregnancy/AI) arising from 7805 first timed artificial inseminations on 27 dairy farms in eastern Spain was examined after use of the Double Ovsynch (DOv; N = 6783) or G6G (N = 1022) synchronization protocols. Parity number, farm, prostaglandin analogue, and season (hot or cool) were examined for their possible association with postsynchronization fertility (in terms of pregnancy/AI). Mean pregnancy/AI overall was 36.1 +/- 8.4%, with no significant differences between the DOv or G6G protocols (36.3 +/- 8.3% vs. 34.8 +/- 9.1%). However, parity and synchronization treatment resulted in a significant interaction (P = 0.03). When DOv AIs (N = 6783) and G6G AIs (N = 1022) were analyzed separately it was observed that pregnancy/AI was significantly better in primiparous than in multiparous cows after DOv (44.3 +/- 11.4% vs. 31.4 +/- 8.2%; P < 0.0001), and pregnancy/AI was similar after G6G in primiparous and in multiparous cows (34.7 +/- 9.2% vs. 34.8 +/- 9.9%). Hot season significantly reduced pregnancy/AI to a similar extent for primiparous and multiparous cows and showed a significant interaction of protocol and season (P = 0.001). These results were similar across all farms, regardless that their overall pregnancy/AI was similar or significantly different from the average. These results indicate that G6G tended to be associated with a higher pregnancy/AI than DOv in multiparous cows, and the opposite was observed in primiparous cows. PMID- 23453256 TI - First multifocal bullous fixed drug eruption due to etodolac. PMID- 23453257 TI - Left ventricular apical hypoplasia: an unusual diagnosis. PMID- 23453259 TI - Male and female ecstasy users: differences in patterns of use, sleep quality and mental health outcomes. AB - BACKGROUND: Ecstasy users report a number of adverse effects following use including mood and sleep disturbances. The present study examined differences in characteristics of ecstasy use (amount, frequency of use, reported harm resulting from use) between males and females and assessed relationships between ecstasy use, sleep quality and mental health outcomes. METHODS: An online survey of 268 ecstasy users (54.1% male, 45.9% female) was conducted. Validated sleep instruments assessing sleep quality and excessive daytime sleepiness, as well as questionnaires regarding physical and mental health (measured using the short form health survey 12 (SF-12) and details of drug use were included. RESULTS: Male ecstasy users reported taking larger amounts of ecstasy, but were not more frequent users compared to females. Female ecstasy users were more likely to report increased harm following ecstasy including: feelings of guilt and remorse; failing to do what was normally expected of them; and having been told by others to cut down their ecstasy use. There were interactions between amount and gender and frequency and gender in predicting use of sleep medication and daytime dysfunction. There was a positive correlation between poorer sleep quality and negative mood, although this relationship was not moderated by sex. CONCLUSIONS: There is a significant association between sleep quality and mood disturbance in ecstasy users suggesting that these negative outcomes are co-morbid. These findings have implications for the treatment and advice given to ecstasy users who are experiencing sleep and/or mood related complaints. PMID- 23453258 TI - Coping and emotion regulation profiles as predictors of nonmedical prescription drug and illicit drug use among high-risk young adults. AB - BACKGROUND: Deficits in the ability to organize, integrate, and modulate emotions, thoughts, and behaviors when dealing with stress have been found to be related to the onset and escalation of substance use among adolescents and young adults. However, limited research has focused on understanding how coping and emotion regulation tendencies might be associated with different patterns of prescription and illicit drug use, particularly among high-risk young adults who may already face additional challenges relative to lower-risk populations. METHODS: Young adults aged 16-25 years who had misused prescription drugs within the past 90 days were interviewed in Los Angeles and New York. The current study utilized latent profile analysis to empirically derive coping and emotion regulation typologies/profiles that are then used to predict different patterns of substance use (N=560). RESULTS: Four latent classes/groups were identified: (1) suppressors, (2) others-reliant copers, (3) self-reliant copers and (4) active copers. Distinct patterns of prescription and illicit drug misuse were found among different coping/emotion regulation profiles, including differences in age of initiation of opiates, tranquilizers, and illicit drugs, recent injection drug use, substance use-related problems, and past 90-day use of tranquilizers, heroin, and cocaine. Specifically, suppressors and others-reliant copers evidenced more problematic patterns of substance use compared to active copers. CONCLUSION: This is among the first studies to show how coping and emotion regulation profiles predict distinct patterns of substance use. Results provide the groundwork for additional investigations that could have significant prevention and clinical implications for substance-using high-risk young adults. PMID- 23453260 TI - Development of Opioid Overdose Knowledge (OOKS) and Attitudes (OOAS) Scales for take-home naloxone training evaluation. AB - AIMS: To develop an Opioid Overdose Knowledge Scale (OOKS) and an Opioid Overdose Attitudes Scale (OOAS) to evaluate take-home naloxone training. METHODS: Psychometric instrument development study conducted in England using convenience samples. Forty-five items were selected for the OOKS organised in four sub-scales (risks, signs, actions and naloxone use). The OOAS was formed initially of 32 items grouped in three sub-scales (competence, concerns and readiness). Both scales were administered to 42 friends and family members of heroin users and 56 healthcare professionals to assess internal reliability and construct validity. The Brief Overdose Recognition and Response Assessment (BORRA) and the General Self-Efficacy Scale (GSE) were also administered to family members to test concurrent validity. Family members completed the OOKS and OOAS on a second occasion to assess test-retest reliability. RESULTS: The OOKS and OOAS were internally reliable (Cronbach's alpha=0.83 and 0.90, respectively). Retest was completed by 33 participants after 14 (SD 7) days (OOKS, ICC=0.90 and OOAS, ICC=0.82) with sub-scale item sets from each measure falling within the fair-to excellent range (ICC=0.53-0.92). Professionals reported significantly higher scores on both scales than family members. The OOKS total score was positively correlated with the BORRA's Overdose Recognition (r=0.5, P<0.01) and Naloxone Indication sub-scales (r=0.44, P<0.05), but the total score on the OOAS was not associated with the GSE (r=0.02, NS). CONCLUSION: The 45-item OOKS and 28-item OOAS are suitable as outcome measures of take-home naloxone training for friends and family members of opioid users. PMID- 23453261 TI - Is the HCV-HIV co-infection prevalence amongst injecting drug users a marker for the level of sexual and injection related HIV transmission? AB - BACKGROUND: Amongst injecting drug users (IDUs), HIV is transmitted sexually and parenterally, but HCV is transmitted primarily parenterally. We assess and model the antibody prevalence of HCV amongst HIV-infected IDUs (denoted as HCV-HIV co infection prevalence) and consider whether it proxies the degree of sexual HIV transmission amongst IDUs. METHODS: HIV, HCV and HCV-HIV co-infection prevalence data amongst IDU was reviewed. An HIV/HCV transmission model was adapted. Multivariate model uncertainty analyses determined whether the model's ability to replicate observed data trends required the inclusion of sexual HIV transmission. The correlation between the model's HCV-HIV co-infection prevalence and estimated proportion of HIV infections due to injecting was evaluated. RESULTS: The median HCV-HIV co-infection prevalence (prevalence of HCV amongst HIV-infected IDUs) was 90% across 195 estimates from 43 countries. High HCV-HIV co-infection prevalences (>80%) occur in most (75%) settings, but can be lower in settings with low HIV prevalence (<10%) or high HIV/HCV prevalence ratios (HIV prevalence divided by HCV prevalence>0.75). The model without sexual HIV transmission reproduced some data trends but could not reproduce any epidemics with high HIV/HCV prevalence ratios (>0.85) or low HCV-HIV co-infection prevalence (<60%) when HIV prevalence>10%. The model with sexual HIV transmission reproduced data trends more closely. The proportion of HIV infections due to injecting correlated with HCV-HIV co-infection prevalence; suggesting that up to 80/60/<20% of HIV infections could be sexually transmitted in settings with HCV-HIV co-infection prevalence between 50-60/70-80/>90%. CONCLUSION: Substantial sexual HIV transmission may occur in many IDU populations; HCV-HIV co-infection prevalence could signify its importance. PMID- 23453262 TI - Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus. AB - Epigenetic modifications, including DNA methylation, contribute to the transcriptional regulation of developmental genes that control growth and differentiation during embryogenesis. The methyl donor, S-adenosylmethionine (SAM), is biosynthesized from methionine and adenosine triphosphate by methionine adenosyltransferase 2a (Mat2a) in the one-carbon (C1) metabolism pathway. SAM biosynthesis requires a steady supply of nutrients, vitamins and cofactors obtained by the developing conceptus through histiotrophic nutrition pathways (HNPs). The visceral yolk sac (VYS) captures proteins and their substrate cargos by receptor-mediated endocytosis and degrades them using lysosomal proteases. We hypothesize that leupeptin, a protease inhibitor, reduces the availability of methionine and C1 substrates, restricting SAM biosynthesis and altering patterns of DNA methylation. Rat conceptuses were exposed to 50 and 100 MUM leupeptin in whole embryo culture for periods of 26 h from gestational day (GD) 10 or 6 h on GD11. After 6 h on GD11, the 100-MUM leupeptin treatment significantly decreased methionine in embryo (EMB) and VYS, reduced Mat2a protein levels and inhibited Mat2a specific activity, all of which produced a significant 52% reduction of SAM in the VYS. The 50- and 100-MUM leupeptin treatments significantly decreased global methylation levels by 6%-9% in EMB and by 11%-15% in VYS following both 6- and 26-h exposure periods. This study demonstrates that HNP disruption alters C1 activity and significantly reduces global DNA methylation during organogenesis. Because epigenetic reprogramming is crucial for normal differentiation and growth, these findings suggest a possible mechanism through which nutrients and environmental factors may alter early developmental regulation. PMID- 23453264 TI - The mid Staffordshire NHS Foundation trust inquiry. The Robert Francis Report. PMID- 23453263 TI - Does your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution. AB - The premise of genetic analysis is that a causal link exists between phenotypic and allelic variation. However, it has long been documented that mutant phenotypes are not a simple result of a single DNA lesion, but are instead due to interactions of the focal allele with other genes and the environment. Although an experimentally rigorous approach focused on individual mutations and isogenic control strains has facilitated amazing progress within genetics and related fields, a glimpse back suggests that a vast complexity has been omitted from our current understanding of allelic effects. Armed with traditional genetic analyses and the foundational knowledge they have provided, we argue that the time and tools are ripe to return to the underexplored aspects of gene function and embrace the context-dependent nature of genetic effects. We assert that a broad understanding of genetic effects and the evolutionary dynamics of alleles requires identifying how mutational outcomes depend upon the 'wild type' genetic background. Furthermore, we discuss how best to exploit genetic background effects to broaden genetic research programs. PMID- 23453265 TI - [Medical mystery: Febrile dyspnea. Febrile dyspnea. Leptospirosis]. PMID- 23453267 TI - Prediction of body mass index status from voice signals based on machine learning for automated medical applications. AB - OBJECTIVES: The body mass index (BMI) provides essential medical information related to body weight for the treatment and prognosis prediction of diseases such as cardiovascular disease, diabetes, and stroke. We propose a method for the prediction of normal, overweight, and obese classes based only on the combination of voice features that are associated with BMI status, independently of weight and height measurements. MATERIALS AND METHODS: A total of 1568 subjects were divided into 4 groups according to age and gender differences. We performed statistical analyses by analysis of variance (ANOVA) and Scheffe test to find significant features in each group. We predicted BMI status (normal, overweight, and obese) by a logistic regression algorithm and two ensemble classification algorithms (bagging and random forests) based on statistically significant features. RESULTS: In the Female-2030 group (females aged 20-40 years), classification experiments using an imbalanced (original) data set gave area under the receiver operating characteristic curve (AUC) values of 0.569-0.731 by logistic regression, whereas experiments using a balanced data set gave AUC values of 0.893-0.994 by random forests. AUC values in Female-4050 (females aged 41-60 years), Male-2030 (males aged 20-40 years), and Male-4050 (males aged 41-60 years) groups by logistic regression in imbalanced data were 0.585-0.654, 0.581 0.614, and 0.557-0.653, respectively. AUC values in Female-4050, Male-2030, and Male-4050 groups in balanced data were 0.629-0.893 by bagging, 0.707-0.916 by random forests, and 0.695-0.854 by bagging, respectively. In each group, we found discriminatory features showing statistical differences among normal, overweight, and obese classes. The results showed that the classification models built by logistic regression in imbalanced data were better than those built by the other two algorithms, and significant features differed according to age and gender groups. CONCLUSION: Our results could support the development of BMI diagnosis tools for real-time monitoring; such tools are considered helpful in improving automated BMI status diagnosis in remote healthcare or telemedicine and are expected to have applications in forensic and medical science. PMID- 23453268 TI - Primary fascial closure after damage control laparotomy: sepsis vs haemorrhage. AB - OBJECTIVE: To compare the outcomes of patients undergoing damage control laparotomy (DCL) for intra-abdominal sepsis vs intra abdominal haemorrhage. We hypothesize that patients undergoing DCL for sepsis will have a higher rate of septic complications and a lower rate of primary fascial closure. SETTINGS AND PATIENTS: Retrospective study of patients undergoing DCL from December 2006 to November 2009. Data are presented as medians and percentages where appropriate. RESULTS: 111 patients were identified (55 men), 79 with sepsis and 32 with haemorrhage. There was no difference in age (63 vs 62 years), body mass index (BMI, 27 vs 28), diabetes mellitus (13% vs 9%), or duration of initial operation (125 vs 117 min). Patients with sepsis presented with a lower serum lactate (2.2 vs 4.7 mmol/L, p<0.01), base deficit (4.0 vs 8.0, p <= 0.01) and ASA score (3.0 vs 4.0, p<0.01). There was no statistical difference in overall morbidity (81% vs 66), mortality (19% vs 22%), intra-abdominal abscess (18% vs 16%), deep wound infection (9% vs 9%), enterocutaneous fistula (ECF) (8% vs 6%) and primary fascial closure (58% vs 59%). Multivariable analysis demonstrated that intra abdominal abscess (OR 4.26, 95% CI 1.06-19.32), higher base deficit (OR 1.14, 95% CI 1.00-1.31) and more abdominal explorations (OR 1.54, 95% CI 1.23-2.07) were associated with lack of primary fascial closure, but BMI (OR 1.00, 95% CI 0.94 1.07), ECF (OR 2.02, 95% CI 0.23-19.98), wound infection (OR 0.93, 95% CI 0.15 5.27), amount of crystalloids infused within the first 24h (OR 1.00, 95% CI 0.99 1.00) and intra-abdominal sepsis (OR 1.14, 95% CI 0.35-3.80) were not. CONCLUSIONS: There was an equivalent rate of septic complications and primary fascial closure rates regardless of cause for DCL. Intra-abdominal abscess, worse base deficit and higher number of abdominal explorations were independently associated with the lack of primary fascial closure. PMID- 23453269 TI - Expression of beta-defensin 4 on temporomandibular joint discs with anterior displacement without reduction. AB - OBJECTIVES: beta-defensin-4 is a member of antimicrobial peptides (APs) of the immunity system. This molecule has antimicrobial activity but it seems to be involved in articular inflammatory processes too, as it happens during osteoarthritic disease (OA). Considering the possible relation existing between (OA) and temporomandibular disorders (TMD), the aim of our study was to evaluate immunohistochemically the presence of beta- defensin-4 in pathological temporomandibular joint (TMJ) discs affected by internal derangement without reduction (ADDwoR). DESIGN: Eighteen TMJ-displaced disc specimens were considered in this study and were analysed by immunohistochemical evaluation. They were compared with a control sample of sixteen healthy discs and two scores, intensity of staining (IS) and extent score (ES) were estimated. RESULTS: Findings of our analysis showed a significant difference between control and study sample (P < 0.001). IS and ES of control sample and pathological sample were 1 and 4 respectively. CONCLUSION: Our results confirmed the presence of beta-defensin-4 in human TMJ discs affected by ADDwoR, hypothesing a possible role of this molecule in articular bone disruption. PMID- 23453270 TI - Amplification of the PPFIA1 gene region on 11q13 in oral squamous cell carcinomas (OSCC). AB - INTRODUCTION: Analyzing chromosomal amplifications delivers valuable information for identification of oncogenes. For carcinomas of the oral cavity only few genes have been identified in amplified regions. The aim of this study was to search genes in amplified regions as possible biomarkers and targets for novel therapies. MATERIAL AND METHODS: DNA from 10 carcinomas of the floor of the oral cavity was examined using a 500K Array GeneChip (Affymetrix 6.0) to detect chromosomal losses, gains or amplifications. Suspicious alterations were validated on tissue microarrays using fluorescence in situ hybridization (FISH) with respective probes. RESULTS: FISH-validation on tissue arrays confirmed PPFIA1 amplifications as one of the most frequent events (32.6%). High (10-20 signals) and low (<10 signals) amplification of PPFIA1 was found in 10.9% (5/46) and 21.7% (10/46) tumours, respectively. Fine mapping with overlapping FISH probes showed co-amplification of PPFIA1 and the Cyclin D1 gene which are approximately 600 kb apart from each other, likely in the same amplicon. DISCUSSION: PPFIA1 was frequently co-amplified with the Cyclin D1 gene in oral carcinomas and could present a biomarker as well as a novel target for specific gene therapy. Further studies are necessary to investigate the role of PPFIA1 in development and pathogenesis of oral carcinomas. PMID- 23453271 TI - Anaesthesia of the inferior alveolar and lingual nerves following subcondylar fractures of the mandible. AB - A retrospective chart review of 387 patients with condylar and subcondylar fractures revealed 2 cases of inferior alveolar nerve (IAN) and lingual nerve (LN) anaesthesia following the subcondylar fracture. Only 5 cases have been reported previously. The mechanism of action remains unknown but a review of the literature and an analysis of 120 dry human skulls supported the hypothesis that compression of the mandibular nerve at a high level, close to the foramen ovale, could cause anaesthesia. This complication is rare, because it requires compression at a particular angle. The antero-median angulation of the condyle must be close to the foramen ovale, and the fracture must be a unilaterally displaced fracture. The presence of an enlarged lateral pterygoid plate appeared to enhance the risk of compression. The IAN and LN anaesthesia could be resolved after open reduction of the fracture and IAN and LN anaesthesia constitute a strict indication for an early open fracture reduction. PMID- 23453272 TI - Innovative tribometer for in situ spectroscopic analyses of wear mechanisms and phase transformation in ceramic femoral heads. AB - The literature on tribological assessments of artificial hip joints usually focuses on correlations between joint composition, size, and specific wear rates, but conspicuously ignores the physical aspects behind the occurrence of degradation mechanisms of friction and wear. Surface degradation in artificial joints occurs because of increases in temperature and local exacerbation of contact stresses inside the moving contact as a consequence of physical and chemical modifications of the sliding surfaces. This article reports about the development of a new pin-on-ball spectroscopy-assisted tribometer device that enables investigating also physical rather than merely engineering aspects of wear processes using in situ Raman and fluorescence techniques. This innovative tribometer is designed to bring about, in addition to conventional tribological parameters, also information of temperature, stress and phase transformations in the femoral heads as received from the manufacturer. Raman and fluorescence spectra at the point of sliding contact are recorded durilng reciprocating hard on-hard dry-sliding tests. Preliminary results were collected on two different commercially available ceramic-on-ceramic hip joint bearing couples, made of monolithic alumina and alumina-zirconia composites. Although the composite couple showed direct evidence of tetragonal-to-monoclinic phase transformation, which enhanced the coefficient of friction, the specific wear rate was significantly lower than that of the monolithic one (i.e., by a factor 2.63 and 4.48 on the pin and head side, respectively). In situ collected data compared to ex situ analyses elucidated the surface degradation processes and clarified the origin for the higher wear resistance of the composite as compared to the monolithic couple. PMID- 23453273 TI - In situ measurements of local temperature and contact stress magnitude during wear of ceramic-on-ceramic hip joints. AB - Fluorescence microprobe spectroscopy was applied to in situ assessments of contact stress and local temperature at the contact point of dry-sliding couples during wear tests of two commercially available ceramic-on-ceramic femoral heads. The investigated ceramic hip implants consisted of either monolithic Al2O3 or Al2O3/ZrO2 composite. A specially designed pin-on-ball tribometer was employed, which enabled directly testing the femoral head components as received from the maker without further manipulation. The strong fluorescence emission from Cr(3+) impurities contained in Al2O3 served as a responsive sensor for both temperature and stress. Analytical corrections for the averaging effects arising from the finite size of the laser probe were made according to a probe response formalism in which geometrical conditions of the sliding couple were incorporated as boundary conditions. The sample-probe interaction at the contact point was then experimentally calibrated by obtaining probe response functions for the two materials investigated. Based on such theoretical and experimental procedures, deconvolutive computational routines could be set up and the true variations of local temperature and stress at the contact point of the bearing surfaces retrieved from the observed time-dependent broadening and shift of a selected spectral band, respectively. The main result of the in situ investigation was that the monolithic sliding couple showed both significantly lower temperature and lower magnitude of compressive stress at the contact point as compared to the composite one, although the composite couple wore at a significantly lower specific wear rate than the monolithic one. PMID- 23453274 TI - [Mobile team of palliative care in a department of neurology: value of two multidisciplinary and professional groups fruit of a joint distribution of the palliative approach and ethical support]. AB - This article describes how a mobile team of palliative care and a department of neurology learned to cope with many complex end-of-life situations. After a brief introduction to inter-team cooperation, clinical work of the mobile team with patients and families and its cooperation with the neurology team are presented. The specificity of supportive care in neurology is also analyzed. Two interdisciplinary and multi-professional tools - the Palliative Care Resource Group and the Ethics Consultation Group - are described, with their activities and their goals. The Palliative Care Resource Group is a specific entity whose identity lies at the crossroads between commonly recognized organizational units: clinic staff, clinical practice, ethical or organizational analysis groups (Balint, 1960), discussion groups (Rusznievski, 1999), training groups. It has several objectives: 1) create a robust conceptual environment enabling the pursuit of palliative care practices without relying on the empty paradigm of stereotypical actions; if suffering cannot be avoided, psychic development and transformation can be promoted; 2) attempt to prevent caregiver burnout; 3) help support and strengthen the collective dimension of the team, learning a mode of care which goes beyond the execution of coded actions; 4) enhance the primary dimension of care, i.e. taking care, especially in clinical situations where conventional wisdom declares that "nothing more can be done."; 5) promote group work so new ideas arising from the different teams influence the behavior of all caregivers. The Ethics Consultation Group organizes its work in several steps. The first step is discernment, clearly identifying the question at hand with the clinical staff. This is followed by a consultation between the clinical team, the patient, the family and the referring physician to arrive at a motivated decision, respecting the competent patient's opinion. The final step is an evaluation of the decision and its consequences. The Ethical Consultation Group, which meets at a scheduled time at a set place, unites the different members of the neurology and palliative care teams who come to a common decision. These specific moments have an important impact on team cohesion, creating a common culture and a convergence of individual representations about making difficult decisions. Specific clinical cases are described to illustrate some of the difficulties encountered in palliative care decision-making. These cases provide insight about the decision to create a palliative care gastrostomy for a man with progressive supranuclear palsy, the suffering experienced by a medical team caring for a young woman with Creutzfeldt-Jacob encephalopathy, or a woman's experience with the post-stroke life-and-death seesaw. Theoretical divisions, illustrated with clinical stories, can be useful touchstones for neurology teams. PMID- 23453275 TI - [Address from the previous President, January 17, 2013]. PMID- 23453276 TI - The codon-optimization of cfaE gene and evaluating its high expression capacity and conserved immunogenicity in Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) is the most common cause of children diarrhea in the world. Adhesion of ETEC to small intestine is an important virulence trait. One of the most prevalent colonization factors (CFs) in human is CFA/I fimbriae and CfaE which is the required binding factor for adhesion of ETEC to intestinal mucosa. We optimized cfaE gene codons according to codon bias of E. coli to achieve a high level of recombinant protein expression. The optimized gene was expressed in E. coli and rCFaE protein was used for mice immunization. Blocking activity of the obtained antibody was examined by microplate agglutination inhibition test. SDS-PAGE analysis indicated that the optimized sequence of cfaE produces a suitable amount of rCFaE in comparison with native gene sequence. This optimized rCFaE protein could induces strong humoral response in mice and the antibody obtained against rCFaE inhibited the adhesion of ETEC to human group A erythrocytes. It is concluded that codon optimization is a useful approach for obtaining large quantities of recombinant rCFaE protein. With regard to the results of hemagglutination inhibition test, codon optimization and increased production of recombinant protein expressed in E. coli did not affect the immunogenicity potential of CFaE. PMID- 23453277 TI - L1 burst fracture with associated vertebral angioma. AB - Vertebral angioma is a common bone tumor. We report a case of L1 vertebral angioma revealed by type A3.2 traumatic pathological fracture of the same vertebra. Management comprised emergency percutaneous osteosynthesis and, after stabilization of the multiple trauma, arterial embolization and percutaneous kyphoplasty. PMID- 23453278 TI - Probing for depression and finding diabetes: a mixed-methods analysis of depression interviews with adults treated for type 2 diabetes. AB - BACKGROUND: Depression has increased prevalence and consistently predicts poor health outcomes among patients with diabetes. The impact of stressors related to diabetes and its treatment on depression assessment is infrequently considered. METHODS: We used mixed methods to evaluate depressive symptoms in adults with type 2 diabetes. We categorized responses related to diabetes and its treatment during interviews (n=70) using the Montgomery-Asberg Depression Rating Scale (MADRS) and administered questionnaires to measure diabetes-related distress and depressive symptoms. RESULTS: Participants (M age=56, SD=7; 67% female; 64% Black; 21% Latino) had mild depression on average (MADRS M=10, SD=9). Half of those with symptoms spontaneously mentioned diabetes context; 61% said diabetes contributed to their symptoms when questioned directly. Qualitative themes included: overlapping symptoms of diabetes and depression; burden of diabetes treatment; emotional impact of diabetes; and the bidirectional influence of depression and diabetes. Diabetes was mentioned more often at higher levels of depression severity (r=.38, p=.001). Higher HbA1c was associated with mentioning diabetes as a context for depressive symptoms (r=.32, p=.007). Insulin-users mentioned diabetes more often than those on oral medications only (p=.005). LIMITATIONS: MADRS is not a traditional qualitative interview so themes may not provide an exhaustive view of the role of diabetes context in depression assessment. CONCLUSIONS AND CLINICAL IMPLICATIONS: The burden of type 2 diabetes and its treatment often provide an explanatory context for depressive symptoms assessed by structured clinical interviews, the gold standard of depression assessment. Diabetes context may influence accuracy of assessment and should inform intervention planning for those needing treatment. PMID- 23453279 TI - Competitive advantage and tolerance of selected shochu yeast in barley shochu mash. AB - A shochu yeast strain, Saccharomyces cerevisiae BAW-6, was previously isolated from Kagoshima yeast strain Ko, and has since been utilized in shochu production. The BAW-6 strain carries pho3/pho3 homozygous genes in contrast to the heterozygous PHO3/pho3 genes in the parental Ko strain. However, absence of the PHO3 gene per se cannot explain the fermentation superiority of BAW-6. Here, we demonstrate the growth advantage of the BAW-6 strain over the Ko strain by competitive cultivation in barley shochu preparation, where alcohol yield and nihonshudo of the former strain were higher than those of the latter strain. In addition, the maximum growth rate of BAW-6 was less affected than that of Ko by high Brix values of barley koji medium, suggesting that BAW-6 is less sensitive to growth inhibitory compounds derived from barley or barley koji. The tolerance of BAW-6 to growth inhibitory compounds, cerulenin and diethylstilbestrol (an H+ ATPase inhibitor), was also higher than that of other yeast strains. Consistent with BAW-6's tolerance to diethylstilbestrol in the presence of 8% ethanol (pH 4.5), H+-ATPase activity, but not transcription of its gene, was higher in BAW-6 than in Ko. We conclude that the BAW-6 strain is associated with certain gene alterations other than PHO3, such that it can maintain cellular ion homeostasis under conditions of ethanol stress during the latter phase of fermentation. PMID- 23453280 TI - Topical linezolid 0.2% for the treatment of vancomycin-resistant or vancomycin intolerant gram-positive bacterial keratitis. AB - PURPOSE: To report the successful use of topical linezolid 0.2% in the treatment of gram-positive bacterial keratitis. STUDY DESIGN: Retrospective, interventional case series. METHODS: All cases of bacterial keratitis treated at the University of Illinois Eye and Ear Infirmary with topical linezolid were identified from the Cornea and External Disease Clinic and were reviewed for culture results, prior therapy, clinical course, and visual outcome. RESULTS: Three patients received topical linezolid, all for cases of culture-positive or presumed gram-positive keratitis. Cases consisted of 1 patient with recalcitrant vancomycin-resistant Enterococcus faecalis (VRE) and 2 patients with infectious crystalline keratitis, 1 previously culture-positive for an uncharacterized Staphylococcus and the other for Streptococcus mitis. All 3 patients had rapid resolution of their infectious keratitis and noted no pain or discomfort attributed to the topical therapy. The patient with VRE keratitis developed a consecutive Candida keratitis elsewhere in the same cornea at the end of therapy for her VRE keratitis. CONCLUSION: Topical linezolid 0.2% can be an effective ophthalmic antibiotic for the treatment of gram-positive keratitis, including VRE, and is both significantly more comfortable and less immediately toxic to the ocular surface than topical vancomycin. PMID- 23453281 TI - Visual outcomes in children with neurofibromatosis type 1 and orbitotemporal plexiform neurofibromas. AB - PURPOSE: To describe the visual outcomes and volumetric magnetic resonance imaging (3D MRI) in children with neurofibromatosis type 1 (NF1) and orbitotemporal plexiform neurofibromas. DESIGN: Multicenter retrospective case series. METHODS: Two institutions with dedicated NF1 clinical research programs queried their established clinical databases for children with orbitotemporal plexiform neurofibromas. Visual acuity, refractive error, ambylopia, and treatment history were abstracted. Extent of orbitotemporal plexiform neurofibroma involvement was assessed clinically and with 3D MRI analysis. Children with optic pathway gliomas or ocular causes of decreased visual acuity (ie, cataracts, glaucoma) other than strabismus or anisometropia were excluded. RESULTS: Twenty-one children met inclusion criteria (median age 8 years, range 0.33-23 years). Orbitotemporal plexiform neurofibroma location was classified as isolated eyelid (n = 6), eyelid and orbit (n = 7), orbit and temporal region (n = 7), or diffuse orbit (n = 1). Three subjects had bilateral orbital involvement. Amblyopia secondary to the orbitotemporal plexiform neurofibroma was present in 13 subjects (62%) and was caused by strabismus (n = 2, 10%), occlusion from ptosis (n = 9, 43%), or anisometropia (n = 9, 43%), or a combination of factors (n = 6, 29%). MRI-derived volumes were measured in 19 subjects (median 41.8 mL, range 2.7-754 mL). All subjects with amblyopia had orbitotemporal plexiform neurofibroma volumes greater than 10 mL. CONCLUSION: In our series, amblyopia occurs in more than half of NF1 children with orbitotemporal plexiform neurofibromas, most commonly because of ptosis and anisometropia. The 3D MRI analysis allowed for sensitive measurement of orbitotemporal plexiform neurofibroma size, and larger volumes were associated with development of amblyopia. PMID- 23453283 TI - Effects of unconditional and conditional cash transfers on child health and development in Zimbabwe: a cluster-randomised trial. AB - BACKGROUND: Cash-transfer programmes can improve the wellbeing of vulnerable children, but few studies have rigorously assessed their effectiveness in sub Saharan Africa. We investigated the effects of unconditional cash transfers (UCTs) and conditional cash transfers (CCTs) on birth registration, vaccination uptake, and school attendance in children in Zimbabwe. METHODS: We did a matched, cluster-randomised controlled trial in ten sites in Manicaland, Zimbabwe. We divided each study site into three clusters. After a baseline survey between July, and September, 2009, clusters in each site were randomly assigned to UCT, CCT, or control, by drawing of lots from a hat. Eligible households contained children younger than 18 years and satisfied at least one other criteria: head of household was younger than 18 years; household cared for at least one orphan younger than 18 years, a disabled person, or an individual who was chronically ill; or household was in poorest wealth quintile. Between January, 2010, and January, 2011, households in UCT clusters collected payments every 2 months. Households in CCT clusters could receive the same amount but were monitored for compliance with several conditions related to child wellbeing. Eligible households in all clusters, including control clusters, had access to parenting skills classes and received maize seed and fertiliser in December, 2009, and August, 2010. Households and individuals delivering the intervention were not masked, but data analysts were. The primary endpoints were proportion of children younger than 5 years with a birth certificate, proportion younger than 5 years with up-to-date vaccinations, and proportion aged 6-12 years attending school at least 80% of the time. This trial is registered with ClinicalTrials.gov, number NCT00966849. FINDINGS: 1199 eligible households were allocated to the control group, 1525 to the UCT group, and 1319 to the CCT group. Compared with control clusters, the proportion of children aged 0-4 years with birth certificates had increased by 1.5% (95% CI -7.1 to 10.1) in the UCT group and by 16.4% (7.8-25.0) in the CCT group by the end of the intervention period. The proportions of children aged 0-4 years with complete vaccination records was 3.1% (-3.8 to 9.9) greater in the UCT group and 1.8% (-5.0 to 8.7) greater in the CCT group than in the control group. The proportions of children aged 6-12 years who attended school at least 80% of the time was 7.2% (0.8-13.7) higher in the UCT group and 7.6% (1.2-14.1) in the CCT group than in the control group. INTERPRETATION: Our results support strategies to integrate cash transfers into social welfare programming in sub-Saharan Africa, but further evidence is needed for the comparative effectiveness of UCT and CCT programmes in this region. FUNDING: Wellcome Trust, the World Bank through the Partnership for Child Development, and the Programme of Support for the Zimbabwe National Action Plan for Orphans and Vulnerable Children. PMID- 23453284 TI - Metabolites of tryptophan catabolism are elevated in sera of patients with myelodysplastic syndromes and inhibit hematopoietic progenitor amplification. AB - Tryptophan catabolism, which is mediated by the enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), produces kynurenine. Kynurenine itself is converted by downstream enzymes into secondary catabolites. We evaluated the serum levels of primary and secondary tryptophan catabolites in a cohort of patients with myelodysplastic syndromes (MDS). The MDS patients showed significantly higher levels tryptophan catabolites which correlated with cytopenia. The tryptophan catabolites inhibited progenitor expansion during the in vitro culture of hematopoietic cells. Thus, MDS patients are characterized by high tryptophan catabolism resulting in elevated primary and secondary metabolites, which both have inhibitory effects on hematopoiesis. PMID- 23453282 TI - Breaking down protein degradation mechanisms in cardiac muscle. AB - Regulated protein degradation through the ubiquitin-proteasome and lysosomal/autophagy systems is critical for homeostatic protein turnover in cardiac muscle and for proper cardiac function. The discovery of muscle-specific components in these systems has illuminated how aberrations in their levels are pivotal to the development of cardiac stress and disease. New evidence suggests that equal importance in disease development should be given to ubiquitously expressed degradation components. These are compartmentalized within cardiac muscles and, when mislocalized, can be critical in the development of specific cardiac diseases. Here, we discuss how alterations in the compartmentalization of degradation components affect disease states, the tools available to investigate these mechanisms, as well as recent discoveries that highlight the therapeutic value of targeting these pathways in disease. PMID- 23453285 TI - Absolute lymphocyte count is associated with minimal residual disease level in childhood B-cell precursor acute lymphoblastic leukemia. AB - The prognostic value of absolute lymphocyte count (ALC) has been a recent matter of debate in childhood acute lymphoblastic leukemia (ALL). In the current study, ALCs at the time of diagnosis (ALC-0), after 7 days of initial therapy (ALC-8) and at interim of the induction therapy (ALC-22) were examined in Chinese children with B-cell precursor (BCP) ALL and correlated with the level of minimal residual disease (MRD) at day 22 of induction therapy. Medical and laboratory records of 140 patients diagnosed with childhood BCP ALL were retrieved and analyzed. ALC-22 is significantly correlated with MRD level at day 22 of therapy and can be a good prognostic factor for childhood BCP-ALL. Furthermore, lymphocyte count at initial diagnosis is correlated with MRD level at day 22 in childhood BCP-ALL with the immnunophenotype of CD19(pos)/CD10(pos)/CD34(pos)/CD45(neg) and role as a new prognostic factor was determined. PMID- 23453286 TI - IL10 inversely correlates with the percentage of CD8+ cells in MDS patients. AB - The role of the immune system in myelodysplastic syndrome (MDS) progression has been widely accepted, although mechanisms underlying this immune dysfunction are not clear. CD4(+) and CD8(+) lymphocyte profiles in the peripheral blood of MDS patients were evaluated and correlated with clinical characteristics, the expression of FOXP3 and the anti-inflammatory cytokines IL10, TGFbeta1 and CTLA4. IL10 expression inversely correlated with the percentage of CD8(+) cells and was higher in high-risk MDS. Our findings provide further evidence for the role of T cell-mediated IL10 production in MDS and strengthen the idea of distinct cytokine profiles in low and high-risk MDS. PMID- 23453287 TI - Modifying disease in CMML: who responds to Azacitidine? PMID- 23453288 TI - Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. AB - BACKGROUND: Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB. METHODS: Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. RESULTS: Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41). CONCLUSIONS: Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding. PMID- 23453290 TI - Glutamate-based antidepressants: preclinical psychopharmacology. AB - Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5 methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2). PMID- 23453289 TI - Polygenic risk and white matter integrity in individuals at high risk of mood disorder. AB - BACKGROUND: Bipolar disorder (BD) and major depressive disorder (MDD) are highly heritable and genetically overlapping conditions characterized by episodic elevation and/or depression of mood. Both demonstrate abnormalities in white matter integrity, measured with diffusion tensor magnetic resonance imaging, that are also heritable. However, it is unclear how these abnormalities relate to the underlying genetic architecture of each disorder. Genome-wide association studies have demonstrated a significant polygenic contribution to BD and MDD, where risk is attributed to the summation of many alleles of small effect. Determining the effects of an overall polygenic risk profile score on neuroimaging abnormalities might help to identify proxy measures of genetic susceptibility and thereby inform models of risk prediction. METHODS: In the current study, we determined the extent to which common genetic variation underlying risk to mood disorders (BD and MDD) was related to fractional anisotropy, an index of white matter integrity. This was conducted in unaffected individuals at familial risk of mood disorder (n = 70) and comparison subjects (n = 62). Polygenic risk scores were calculated separately for BD and MDD on the basis of genome-wide association study data from the Psychiatric GWAS Consortia. RESULTS: We report that a higher polygenic risk allele load for MDD was significantly associated with decreased white matter integrity across both groups in a large cluster, with a peak in the right-sided superior longitudinal fasciculus. CONCLUSIONS: These findings suggest that the polygenic approach to examining brain imaging data might be a useful means of identifying traits linked to the genetic risk of mood disorders. PMID- 23453291 TI - Chest wall reconstruction with methacrylate prosthesis in Poland syndrome. AB - Poland syndrome is a rare congenital malformation. This syndrome was described in 1841 by Alfred Poland at Guy's Hospital in London. It is characterized by hypoplasia of the breast and nipple, subcutaneous tissue shortages, lack of the costosternal portion of the pectoralis major muscle and associated alterations of the fingers on the same side. Corrective treatment of the chest and soft tissue abnormalities in Poland syndrome varies according to different authors. We report the case of a 17-year-old adolescent who underwent chest wall reconstruction with a methyl methacrylate prosthesis. This surgical procedure is recommended for large anterior chest wall defects, and it prevents paradoxical movement. Moreover it provides for individual remodeling of the defect depending on the shape of the patient's chest. PMID- 23453292 TI - Randomized comparison between the cemented Scientific Hip Prosthesis and Omnifit: 2-year DEXA and minimum 10-year clinical follow-up. AB - Radiostereometry (RSA) of the cemented Scientific Hip Prosthesis (SHP) reported excessive migration and predicted high failure rates. In a prospective randomized clinical trial we compared minimum 10 years results of the SHP (n=38) with the Omnifit-stem (n=37). Two-year bone remodelling, compared with dual energy x-ray absorptiometry and assessed in regions of interest A-D based on the 7 Gruen zones, showed better periprosthetic bone preservation around the SHP in all but one regions (P<.05). At 10 years Harris Hip Score was better for the SHP (P=.0001) but Oxford Hip Score was the same (P=.79). There were no revisions in either group, but radiographic loosening was definite in 1 SHP and 1 Omnifit. Based on earlier RSA studies, the rough surface finish of the SHP was expected to cause cement abrasion, osteolysis and inferior survival. However our clinical and remodelling results could not confirm these expectations, suggesting that the link of early migration and mid-term clinical results is not sufficiently clear for the SHP. PMID- 23453293 TI - A novel flexible cryoprobe for EUS-guided pancreatic biopsies. AB - BACKGROUND: EUS-guided FNA (EUS-FNA) is an established technique for the cytologic diagnosis of pancreatic disease. Attempts to obtain adequate histologic specimens have yielded variable and mostly insufficient results. OBJECTIVE: To evaluate the safety, feasibility, and quality of histologic biopsy specimens obtained by using a new cryobiopsy probe and to compare them with standard EUS FNA and (laparoscopic) trucut biopsy specimens of pancreatic tissue. DESIGN: Animal non-survival study. INTERVENTION: Eighty-four pancreatic biopsy specimens (12 per group) were obtained in 4 anesthetized pigs by using one of the following the 18-gauge flexible cryoprobe; a conventional, 19-gauge, EUS-FNA needle; or a rigid, trucut biopsy device (18 gauge). The latter, used in laparoscopic surgery, was considered as the criterion standard for obtaining histology specimens. MAIN OUTCOME MEASUREMENTS: Specimens were evaluated for artifacts and specimen quality by a blinded pathologist who used a 7-point Likert scale to assess histologic adequacy. Biopsy size and bleeding time after biopsy also were recorded. RESULTS: The new cryoprobe was equivalent to the rigid, trucut needle and superior (P < .001) to the conventional 19-gauge FNA needles with respect to artifacts, quality of the specimen, biopsy specimen size, and bleeding. LIMITATIONS: Animal model. CONCLUSION: EUS-guided cryobiopsy was associated with better specimen quality for histologic analysis and a shorter bleeding time compared with a conventional 19 gauge FNA needle in the animal model. It is a promising new technique for histologic examination of pancreatic tissue. PMID- 23453294 TI - Control of severe strictures after circumferential endoscopic submucosal dissection for esophageal carcinoma: oral steroid therapy with balloon dilation or balloon dilation alone. AB - BACKGROUND: Recent technological advances have allowed superficially spreading intramucosal carcinomas of the esophagus to be successfully resected by circumferential endoscopic submucosal dissection (cESD). After this procedure, esophageal strictures develop in most patients and are mainly treated by endoscopic balloon dilation (EBD). OBJECTIVE: To compare oral steroids plus EBD with EBD alone for the management of benign esophageal strictures after cESD. DESIGN: Retrospective cohort study. SETTING: Tertiary-care referral center. PATIENTS: We studied 23 consecutive patients who underwent complete cESD for superficial esophageal carcinoma (22 squamous cell carcinomas and 1 adenocarcinoma associated with Barrett's esophagus). INTERVENTION: After cESD, patients were managed with EBD alone (EBD, n = 13) or with EBD and oral prednisolone (steroid + EBD, n = 10), 30 mg daily, started 2 days after cESD and gradually tapered and discontinued after 8 weeks. MAIN OUTCOME MEASUREMENTS: Total number of EBD sessions and total EBD period (months). RESULTS: Steroid + EBD patients required fewer sessions (13.8 +/- 6.9 vs 33.5 +/- 22.9; P < .001) and a shorter management period (4.8 +/- 2.3 vs 14.2 +/- 17.5 months, P = .005) compared with the EBD group. An additional 3 patients received oral steroids a mean interval of 158 days after cESD. These patients required more EBD sessions (46.3 +/- 30.0; P = .002), and the EBD period was significantly longer (17.5 +/- 13.0 months; P = .005) than in the early steroid + EBD group. LIMITATIONS: Nonrandomized study; retrospective analysis. CONCLUSION: After cESD, oral steroid therapy dramatically reduced the need for EBD. We conclude that oral steroid therapy after EBD is an effective strategy for the management of esophageal strictures after complete cESD. PMID- 23453295 TI - Endogenous brain-machine interface based on the correlation of EEG maps. AB - In this paper, a non-invasive endogenous brain-machine interface (BMI) based on the correlation of EEG maps has been developed to work in real-time applications. The classifier is able to detect two mental tasks related to motor imagery with good success rates and stability. The BMI has been tested with four able-bodied volunteers. First, the users performed a training with visual feedback to adjust the classifier. Afterwards, the users carried out several trajectories in a visual interface controlling the cursor position with the BMI. In these tests, score and accuracy were measured. The results showed that the participants were able to follow the targets during the performed trajectory, proving that the EEG mapping correlation classifier is ready to work in more complex real-time applications aimed at helping people with a severe disability in their daily life. PMID- 23453296 TI - Maternal high-fat diets cause insulin resistance through inflammatory changes in fetal adipose tissue. AB - OBJECTIVES: Epidemiological and animal studies have shown that maternal obesity predisposes the offspring to obesity and the metabolic syndrome, possibly via late-onset metabolic programming of the fetus. Little is known, however, about the metabolic effect of maternal obesity on the fetus. This study investigated the effect of a maternal high-fat diet (HFD) on fetal growth and glucose metabolism using a diet-induced obesity mouse model. STUDY DESIGN: Female mice (6 weeks old; C57BL/6N) were fed either a normal chow diet (NCD, 10 kcal% fat) or an HFD (60 kcal% fat) for 4 weeks before mating and throughout pregnancy. At 17 days of gestation, gene expression of inflammatory markers and adipokines in fetal subcutaneous adipose tissue was analyzed by quantitative real-time polymerase chain reaction. RESULTS: HFD mice were overweight, glucose intolerant and insulin resistant compared with NCD mice of the same gestational age. Although fetal body weight was not significantly different, fetal plasma glucose and insulin levels were higher in the HFD group than the NCD group. Furthermore, examination of fetal subcutaneous adipose tissue in the HFD group revealed hypertrophy with an increase in the levels of cluster of differentiation-68, chemokine receptor-2 and tumor necrosis factor-alpha mRNA, but a decrease in the level of glucose transporter-4 mRNA. CONCLUSION: Maternal HFD causes inflammatory changes in the adipose tissue of offspring. PMID- 23453297 TI - Fluorescent in situ hybridization as a predictor of relapse in urothelial carcinoma. AB - OBJECTIVE: To assess the value of the study of chromosomal alterations by fluorescent in situ hybridization in a series of patients diagnosed of urothelial carcinoma and a minimum follow up of twenty four months, as well as evaluate its putative predictive potential. MATERIAL AND METHODS: The overall series includes 338 samples from 98 patients with 84 episodes of urothelial carcinoma. A subgroup of 24 patients who had at least one recurrence during the follow up was used to evaluate the predictive potential of the test. Three categories were considered (positive coherent episode, negative coherent episode, and incoherent episode) depending on the relationship between the fluorescent in situ hybridization result in the concomitant study of the new episode and those of the preceding samples. RESULTS: Fluorescent in situ hybridization showed higher sensitivity regardless of grade, negative predictive value and accuracy, while specificity and positive predictive value were superior with conventional cytology. In the recurrence, series 19/29 episodes were coherent, 11/19 were positive coherent with urothelial carcinoma all high grade and 8/19 negative coherent, most low grade. CONCLUSIONS: Fluorescent in situ hybridization test shows good sensitivity during a follow up of twenty four months and is able to predict recurrence, especially in cases of high grade. Our data demonstrate the existence of urothelial carcinomas without detectable chromosomal abnormalities by currently available methodology. The results support a multidisciplinary follow up combining fluorescent in situ hybridization, cytology and cystoscopy. PMID- 23453298 TI - Transumbilical single port surgery with conventional laparoscopic instruments in horseshoe kidney. AB - INTRODUCTION: Laparoscopic surgery is following a natural course as it decreases surgical aggression on the abdominal wall without undermining the curative and functional results. Although it is still being developed, single port surgery has meant an advance in this sense. MATERIAL AND METHODS: We present the first single port laparoscopic pyelolithectomy surgery in horseshoe kidney, using conventional rigid instruments. The case of an 18-year old patient with BMI of 19 in whom the imaging tests (urogram and computed tomography) showed a horseshoe kidney with left coralliform lithiasis and discrete calyceal ectasia is presented. The lithiasis was extracted using umbilical access with single port device and conventional rigid instruments. RESULTS: The surgery was performed without complications. Surgery time was 110 minutes and bleeding 50 cc. On incision of the urinary system, there was purulent urine extravasation that conditioned fever of 38 degrees C in the post-operatory period. During the intervention, a double J stent was placed via percutaneous approach. The patient was discharged on the third day of hospitalization. CONCLUSION: Single port laparoscopic access for pyelolithectomy surgery in horseshoe kidney is a reasonable alterative. The use of conventional rigid instruments facilitates the performance of this surgery with good triangulation, without conflict regarding hands and safety for the patient. PMID- 23453299 TI - Structural factors that promote stigmatization of drug users with hepatitis C in hospital emergency departments. AB - BACKGROUND: Interventions to mediate the stigmatization of people affected with HCV, particularly those who use illicit drugs, have been largely focused on changing health care practitioners' attitudes and knowledge regarding Hepatitis C and illicit drug use and these have had disappointing results. There is a need for research that examines factors beyond individual practitioners that explains why and how stigmatization of the population occurs within health care and informs interventions to mitigate these factors. METHODS: The research was intended to identify structural factors that contribute to the structural stigmatization of people within hospital Emergency Departments who are current users of illicit drugs and are HCV positive. The research had an interpretive description design and occurred in Nova Scotia, Canada. The year-long qualitative study entailed individual interviews of 50 service providers in hospital EDs or community organizations that served this population. RESULTS: The research findings generated a model of structural stigmatization that greatly expands the current understanding of stigmatization beyond individual practitioners' attitudes and knowledge and internal structures to incorporate structures external to hospitals, such as physician shortages within the community and the mandate of EDs to reduce wait times. CONCLUSIONS: The research reported herein has conceptualized stigmatization beyond an individualistic approach to incorporate the multifaceted ways that such stigmatization is fostered and supported by internal and external structures. PMID- 23453300 TI - An ambiguous monolith - the Swedish drug issue as a political battleground 1965 1981. AB - BACKGROUND: The drug problem has been a highly ideologized topic in the political debate in Sweden ever since the mid-1960s. The aim of the article is to investigate dominant conceptions of drugs, drug use, society and the individual in the political discussions on drug use in Sweden during the years 1965-1981. METHODS: The empirical basis for the textual analysis consists of 146 parliamentary bills and 135 parliamentary protocols. RESULTS: The unwanted drug appear as a sensitive litmus paper, an indication that something had gone wrong in society and as a suggestion of how the good society could be accomplished. The drug problem was connected to ideological core values such as class struggle, Christianity or criticism of urbanism and modernity. CONCLUSION: The analysis suggests that the drug problem was used as political ammunition, to pick holes in political opponents and to highlight one's own ideological stance. The hegemonic conversational order, the consensual spirit and the agreement that this was the most serious problem, did not hamper these political moves. Rather, the cross party conception of the problem's severity and accelerating deterioration contributed to a common ground for political arguments and ideological visions. It also meant that the political discussions moved away from the more obvious drug policy issues. PMID- 23453302 TI - Cognitive memory. AB - Regarding the workings of the human mind, memory and pattern recognition seem to be intertwined. You generally do not have one without the other. Taking inspiration from life experience, a new form of computer memory has been devised. Certain conjectures about human memory are keys to the central idea. The design of a practical and useful "cognitive" memory system is contemplated, a memory system that may also serve as a model for many aspects of human memory. The new memory does not function like a computer memory where specific data is stored in specific numbered registers and retrieval is done by reading the contents of the specified memory register, or done by matching key words as with a document search. Incoming sensory data would be stored at the next available empty memory location, and indeed could be stored redundantly at several empty locations. The stored sensory data would neither have key words nor would it be located in known or specified memory locations. Sensory inputs concerning a single object or subject are stored together as patterns in a single "file folder" or "memory folder". When the contents of the folder are retrieved, sights, sounds, tactile feel, smell, etc., are obtained all at the same time. Retrieval would be initiated by a query or a prompt signal from a current set of sensory inputs or patterns. A search through the memory would be made to locate stored data that correlates with or relates to the prompt input. The search would be done by a retrieval system whose first stage makes use of autoassociative artificial neural networks and whose second stage relies on exhaustive search. Applications of cognitive memory systems have been made to visual aircraft identification, aircraft navigation, and human facial recognition. Concerning human memory, reasons are given why it is unlikely that long-term memory is stored in the synapses of the brain's neural networks. Reasons are given suggesting that long term memory is stored in DNA or RNA. Neural networks are an important component of the human memory system, and their purpose is for information retrieval, not for information storage. The brain's neural networks are analog devices, subject to drift and unplanned change. Only with constant training is reliable action possible. Good training time is during sleep and while awake and making use of one's memory. A cognitive memory is a learning system. Learning involves storage of patterns or data in a cognitive memory. The learning process for cognitive memory is unsupervised, i.e. autonomous. PMID- 23453301 TI - The role of child protection in cannabis grow-operations. AB - BACKGROUND: This unique social work research examined the rationale for child protection interventions with families found living in illegal cannabis grow operations, based on the assumption of risk in the presence of probable medical harm. METHODS: The study examined the household, family and individual characteristics of 181 children found living in cannabis grow operations in two regions in British Columbia, Canada. Data was collected on-site on the physical characteristics of the homes, the health characteristics of the children, and their prescription drug history. Comparison of prescription drug use was also made with a group of children from the same geographic areas. RESULTS: This study found that there was no significant difference between the health of the children living in cannabis grow operations and the comparison group of children, based on their prescription history and their reported health at the time. CONCLUSION: The findings of this study challenge contemporary child welfare approaches and have implications for both child protection social workers and the policymakers who develop frameworks for practice. PMID- 23453303 TI - Protective effects of propolis on female rats' histopathological, biochemical and genotoxic changes during LPS induced endotoxemia. AB - In recent years, propolis has been the object of extensive research for its antibacterial, antioxidant, anti-inflammatory, and antitumoral activities. This study aims to determine the hepatoprotective efficiency of propolis on experimental endotoxemia in rats. In the current study, fifty adult Sprague Dawley rats (weighing 200-300 g) were randomly divided into five groups of ten rats each. Normal saline solution was administered to the rats in the control group, while in the second group LPS (30 mg/kg), in the third group propolis (250 mg/kg), in the fourth group first propolis and then LPS (30 mg/kg), and in the fifth group, first LPS (30 mg/kg) and then propolis were given. Six hours after the application, biochemical (MDA levels) and histopathological changes as well as global DNA methylation analysis in the liver tissue samples were determined, while in the blood tissue samples Genomic Template Stability (GTS, %) was evaluated using RAPD-PCR profiles. The results demonstrated that the administration of propolis could have a protective effect against changes of both genomic stability values and methylation profiles, and it minimized the increase in MDA and tissue damage caused by LPS. In conclusion, the application of propolis prior to LPS-induced endotoxemia has shown to reduce hepatic damage. PMID- 23453304 TI - Antihyperglycemic and sub-chronic antidiabetic actions of morolic and moronic acids, in vitro and in silico inhibition of 11beta-HSD 1. AB - Morolic (1) and moronic (2) acids are the main constituents of acetonic extract from Phoradendron reichenbachianum (Loranthaceae), a medicinal plant used in Mexico for the treatment of diabetes. The aim of the current study was to establish the sub-acute antidiabetic and antihyperlipidemic effects of compounds 1 and 2 over non insulin-dependent diabetic rat model. Also, to determine the antihyperglycemic action on normoglycemic rats by oral glucose tolerance test. Daily-administered morolic (1) and moronic (2) acids (50 mg/kg) significantly lowered the blood glucose levels at 60% since first day until tenth day after treatment than untreated group (p<0.05). Moreover, analyzed blood samples obtained from diabetic rats indicated that both compounds diminished plasmatic concentration of cholesterol (CHO) and triglycerides (TG), returning them to normal levels (p<0.05). Also, pretreatment with 50 mg/kg of each compound induced significant antihyperglycemic effect after glucose and sucrose loading (2 g/kg) compared with control group (p<0.05). In vitro studies showed that compounds 1 and 2 induced inhibition of 11beta-HSD 1 activity at 10 MUM. However, in silico analysis of the pentaclyclic triterpenic acids on 11beta-HSD 1 revealed that all compounds had high docking scores and important interactions with the catalytic site allowing them to inhibit 11beta-HSD 1 enzyme. In conclusion, morolic and moronic acids have shown sustained antidiabetic and antihyperglycemic action possibly mediated by an insulin sensitization with consequent changes of glucose, cholesterol and triglycerides, in part mediated by inhibition of 11beta-HSD 1 as indicated by in vitro and in silico studies. PMID- 23453305 TI - Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis. AB - Evidence suggests an important role of intestinal barrier dysfunction in the etiology of inflammatory bowel disease (IBD). Therefore stabilizing mucosal barrier function constitutes a new therapeutic approach in its management. Ectoine is a compatible solute produced by aerobic chemoheterotrophic and halophilic/halotolerant bacteria, where it acts as osmoprotectant and effective biomembrane stabilizer, protecting the producing cells from extreme environmental stress. Since this natural compound was also shown to prevent inflammatory responses associated with IBD, its potential usefulness was studied in a model of colitis. Groups of rats were treated orally with different doses of ectoine (30 300 mg/kg) or sulfasalazine (reference drug) daily for 11 days. On day 8 colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid, when overt signs of lesions develop within the next 3 days. On day 12, blood was withdrawn from the retro-orbital plexus of the rats and the animals were sacrificed. The colon was excised and examined macroscopically and microscopically. Relevant parameters of oxidative stress and inflammation were measured in serum and colon homogenates. Induction of colitis led to marked weight loss, significant histopathological changes of the colon, and variable changes in levels of myeloperoxidase, reduced glutathione, malondialdehyde, and all inflammatory markers tested. Treatment with ectoine ameliorated the inflammatory changes in TNBS-induced colitis. This effect was associated with reduction in the levels of TNF-alpha, IL-1beta, ICAM-1, PGE2 and LTB4. The findings suggest that intestinal barrier stabilizers from natural sources could offer new therapeutic measures for the management of IBD. PMID- 23453306 TI - Cytotoxic effect of leaf essential oil of Lippia gracilis Schauer (Verbenaceae). AB - Medicinal plants are one of the most important sources of drugs used in the pharmaceutical industry. Among traditional medicinal plants, Lippia gracilis Schauer (Verbenaceae) had been used for several medicinal purposes in Brazilian northeastern. In this study, leaf essential oil (EO) of L. gracilis was prepared using hydrodistillation. Followed by GC-MS analysis, its composition was characterized by the presence of thymol (55.50%), as major constituent. The effects of EO on cell proliferation and apoptosis induction were investigated in HepG2 cells. Furthermore, mice bearing Sarcoma 180 tumor cells were used to confirm its in vivo effectiveness. EO and its constituents (thymol, p-cymene, gamma-terpinene and myrcene) displayed cytotoxicity to different tumor cell lines. EO treatment caused G1 arrest in HepG2 cells accompanied by the induction of DNA fragmentation without affecting cell membrane integrity. Cell morphology consistent with apoptosis and a remarkable activation of caspase-3 were also observed, suggesting induction of caspase-dependent apoptotic cell death. In vivo antitumor study showed tumor growth inhibition rates of 38.5-41.9%. In conclusion, the tested essential oil of L. gracilis leaves, which has thymol as its major constituent, possesses significant in vitro and in vivo antitumor activity. These data suggest that leaf essential oil of L. gracilis is a potential medicinal resource. PMID- 23453308 TI - Jacaric acid and its octadecatrienoic acid geoisomers induce apoptosis selectively in cancerous human prostate cells: a mechanistic and 3-D structure activity study. AB - Plant-derived non-essential fatty acids are important dietary nutrients, and some are purported to have chemopreventive properties against various cancers, including that of the prostate. In this study, we determined the ability of seven dietary C-18 fatty acids to cause cytotoxicity and induce apoptosis in various types of human prostate cancer cells. These fatty acids included jacaric and punicic acid found in jacaranda and pomegranate seed oil, respectively, three octadecatrienoic geometric isomers (alpha- and beta-calendic and catalpic acid) and two mono-unsaturated C-18 fatty acids (trans- and cis-vaccenic acid). Jacaric acid and four of its octadecatrienoic geoisomers selectively induced apoptosis in hormone-dependent (LNCaP) and -independent (PC-3) human prostate cancer cells, whilst not affecting the viability of normal human prostate epithelial cells (RWPE-1). Jacaric acid induced concentration- and time-depedent LNCaP cell death through activation of intrinsic and extrinsic apoptotic pathways resulting in cleavage of PARP-1, modulation of pro- and antiapoptotic Bcl-2 family of proteins and increased cleavage of caspase-3, -8 and -9. Moreover, activation of a cell death-inducing signalling cascade involving death receptor 5 was observed. Jacaric acid induced apoptosis in PC-3 cells by activation of the intrinsic pathway only. The spatial conformation cis, trans, cis of jacaric and punicic acid was shown to play a key role in the increased potency and efficacy of these two fatty acids in comparison to the five other C-18 fatty acids tested. Three dimensional conformational analysis using the PubChem Database (http://pubchem.ncbi.nlm.nih.gov) showed that the cytotoxic potency of the C-18 fatty acids was related to their degree of conformational similarity to our cytotoxic reference compound, punicic acid, based on optimized shape (ST) and feature (CT) similarity scores, with jacaric acid being most 'biosimilar' (ST(ST opt)=0.81; CT(CT-opt)=0.45). This 3-D analysis of structural similarity enabled us to rank geoisomeric fatty acids according to cytotoxic potency, whereas a 2-D positional assessment of cis/trans structure did not. Our findings provide mechanistic evidence that nutrition-derived non-essential fatty acids have chemopreventive biological activities and Exhibit 3-D structure-activity relationships that could be exploited to develop new strategies for the prevention or treatment of prostate cancer regardless of hormone dependency. PMID- 23453307 TI - Modulatory effect of green tea extract on hepatic key enzymes of glucose metabolism in streptozotocin and high fat diet induced diabetic rats. AB - The study was undertaken to evaluate the antidiabetic effect of green tea extract on carbohydrate metabolic key enzymes in control and streptozotocin high fat diet -induced diabetic rats. The daily oral treatment of green tea extract (300 mg/kg body weight) to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, glycosylated hemoglobin (HbA1c) and increase in the levels of insulin and hemoglobin. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6 phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver of diabetic rats were significantly reverted to near normal levels by the administration of green tea extract. Further, green tea extract administration to diabetic rats improved muscle and hepatic glycogen content suggesting the antihyperglycemic potential of green tea extract in diabetic rats. The obtained results were compared with metformin, a standard oral hypoglycemic drug. Thus, this study indicates that the administration of green tea extract to diabetic rats resulted in alterations in the metabolism of glucose with subsequent reduction in plasma glucose levels. PMID- 23453309 TI - [Traumatic recurrence of idiopathic spinal cord herniation]. AB - Idiopathic spinal cord herniation is a rare cause of thoracic myelopathy and its recurrence is even more infrequent. Cord herniation is through an anterior dural defect in thoracic spine with unknown causes. Symptomatic cases must be surgically treated to reduce the hernia and seal the defect to prevent recurrences. We report a patient presenting a Brown-Sequard syndrome secondary to a D5 spinal cord herniation treated successfully and its posterior traumatic recurrence. PMID- 23453310 TI - [Congenital medulloblastoma associated with intracranial arachnoid cyst]. AB - Arachnoid cysts are very common lesions in paediatric patients, with treatment depending on their location and symptomatology. They are usually solitary cysts but may be associated with other central nervous system diseases such as tumours and congenital deformities. We describe the case of a neonate diagnosed with an arachnoid cyst of the quadrigeminal cistern treated by endoscopy. After the operation, the child's condition worsened; a CT scan revealed a midline posterior fossa tumour not visible in the preoperative neuroradiological tests. The tumour, a medulloblastoma, was partially removed. Given the child's age and the poor prognosis, oncological treatment was not undertaken. The association between medulloblastoma and arachnoid cyst is very rare, and we could find only one such case in the literature. PMID- 23453311 TI - Revisiting the Hispanic mortality advantage in the United States: the role of smoking. AB - More than three decades of health disparities research in the United States has consistently found lower adult mortality risks among Hispanics than their non Hispanic white counterparts, despite lower socioeconomic status among Hispanics. Explanations for the "Hispanic Paradox" include selective migration and cultural factors, though neither has received convincing support. This paper uses a large nationally representative survey of health and smoking behavior to examine whether smoking can explain life expectancy advantage of Hispanics over US-born non-Hispanics whites, with special attention to individuals of Mexican origin. It tests the selective migration hypothesis using data on smoking among Mexico-to-US migrants in Mexico and the United States. Both US-born and foreign-born Mexican Americans exhibit a life expectancy advantage vis-a-vis whites. All other Hispanics only show a longevity advantage among the foreign-born, while those born in the United States are disadvantaged relative to whites. Smoking attributable mortality explains the majority of the advantage for Mexican Americans, with more than 60% of the gap deriving from lower rates of smoking among Mexican-Americans. There is no evidence of selective migration with respect to smoking; Mexicans who migrate to the US smoke at similar rates to Mexicans who remain in Mexico, with both groups smoking substantially less than non-Hispanic whites in the US. The results suggest that more research is needed to effectively explain the low burden of smoking among Mexican-Americans in the United States. PMID- 23453312 TI - GPs and hospital expenditures. Should we keep expenditure containment programs alive? AB - Pay-for-Performance programs offering additional payments to GPs can be used not only to improve the quality of care but also for cost containment purposes. In this paper, we analyse the impact of removing financial incentives in primary care that were aimed at containing hospital expenditure in the Italian region of Emilia-Romagna during the period 2002-2004. Our analysis draws on regional databanks linking GPs' characteristics to those of their patients (including all sources of public payments made to GPs), together with information on the utilisation of hospital services. The dataset includes 2,936,834 patients, 3229 GPs and 39 districts belonging to 11 Local Health Authorities. We employ a difference-in-difference specification to assess changes in expenditures for avoidable and total hospital admissions. We identify the treatment group with GPs operating in districts where the program is withdrawn during the observation period ("Leavers"). Their performance is compared to that of two separate control groups, namely: GPs working in districts that grant incentives for the entire period ("Stayers") and those working in districts that never introduced measures for the containment of hospitalisations ("Non Participants"). The comparison between treatment and control groups shows that removing incentives does not result in a worse performance by Leavers compared to both control groups. This supports the policy of removing incentives, as such entail extra payments to GPs which, however, do not seem capable of significantly influencing their behaviour in the desired way. Our findings complement previous evidence from the same institutional context showing that only those programs that aim to improve disease management for specific conditions - rather than to simply contain expenditure - have proven successful in reducing avoidable admissions for the target population. PMID- 23453313 TI - Metaphors and myths in pharmaceutical advertising. AB - It should come as no surprise that the ancient Greek word for drug, pharmakon, meant remedy. But this same word also meant poison as well as magical charm. We speak of heart attacks and of a long road to recovery. These meanings and phrases are reflective of how society conceives of illness and medical therapies. Metaphors and myths of magic, sports and journey are prevalent in medical terminology and they permeate pharmaceutical advertising. This research investigates the conceptual metaphors that are present in advertisements for pharmaceuticals, both those directed to consumers as well as those directed to physicians, for a broad range of drugs and medical conditions. This research employed a content analysis of advertisements appearing in popular consumer magazines as well as in physician journals and an analysis of online consumer drug reviews. The research concludes with a discussion of the similarities and differences among the conceptual metaphors in consumer versus physician ads, across different medical conditions, and the impact of specific metaphors on consumers' understanding of illness and drug therapies. PMID- 23453314 TI - Addressing the unequal geographic distribution of specialist doctors in indonesia: the role of the private sector and effectiveness of current regulations. AB - As in many countries, the geographic distribution of the health workforce in Indonesia is unequal, with a concentration in urban and more developed areas, and a scarcity in rural and remote areas. There is less information on the distribution of specialist doctors, yet inequalities in their distribution could compromise efforts to achieve universal coverage by 2014. This paper uses data from 2007 and 2008 to describe the geographic distribution of specialist doctors in Indonesia, and to examine two key factors that influence the distribution and are targets of current policies: sources of income for specialist doctors, and specialist doctor engagement in private practice. The data demonstrates large differences in the ratio of specialist doctors to population among the provinces of Indonesia, with higher ratios on the provinces of the islands of Java, and much lower ratios on the more remote provinces in eastern Indonesia. Between 65% and 80% of specialist doctors' income derives from private practice in non-state hospitals or private clinics. Despite regulations limiting practice locations to three, most specialists studied in a provincial capital city were working in more than three locations, with some working in up to 7 locations, and spending only a few hours per week in their government hospital practice. Our study demonstrates that the current regulatory policies and financial incentives have not been effective in addressing the maldistribution of specialist doctors in a context of a growing private sector and predominance of doctors' income from private sources. A broader and more integrated policy approach, including more innovative service delivery strategies for rural and remote areas, is recommended. PMID- 23453315 TI - Provider and patient influences on the formation of socioeconomic health behavior disparities among pregnant women. AB - Socially advantaged individuals are better positioned to benefit from advances in biomedicine, which frequently results in the emergence of social inequalities in health. I use survey and in-depth interviews with pregnant women and their health care providers from four Midwestern clinics in the United States, conducted in 2009 and 2010. I compare socioeconomic differences in intake of two new prenatal supplements: Vitamin D and omega-3 fatty acid. Although socioeconomic differences in omega-3 fatty acid supplementation emerged, there were no differences in the use of vitamin D. I argue that providers may have contributed to the prevention of a health disparity in vitamin D supplementation by implementing an aggressive uniform protocol. These results suggest that providers not only serve as a conduit for the dissemination of new biomedical information, the strength and uniformity of their recommendations have the potential to prevent or exacerbate socioeconomic differences in health behaviors. PMID- 23453316 TI - Bedouin in Lebanon: Social discrimination, political exclusion, and compromised health care. AB - Global inequalities in health have long been associated with disparities between rich and poor nations. The middle-income countries of the Levant (Lebanon, Syria and Jordan) have developed models of health care delivery that mirror the often complex make-up of their states. In Lebanon, which is characterized by political clientelism and sectarian structures, access to health care is more contingent on ethnicity and religious affiliation than on poverty. This case study of the Bedouin of the Middle Bekaa Valley of Lebanon is based on interviews with policymakers, health care providers and the Bedouin as part of a study funded by the European Commission between 2006 and 2010. The study explores the importance of considering social discrimination and political exclusion in understanding compromised health care. Three decades after the Declaration of Alma Ata (1978), which declared that an acceptable level of health care for all should be attained by the year 2000, the Bedouin community of Lebanon remains largely invisible to the government and, thus, invisible to national health care policy and practice. They experience significant social discrimination from health practitioners and policymakers alike. Their unfair treatment under the health system is generally disassociated from issues of wealth or poverty; it is manifested in issues of access and use, discrimination, and resistance and agency. Overcoming their political exclusion and recognizing the social discrimination they face are steps that can be taken to protect and promote equal access to basic reproductive and child health care. This case study of the Bedouin in Lebanon is also relevant to the health needs of other marginalized populations in remote and rural areas. PMID- 23453317 TI - Prevalence and severity of intimate partner violence in women living in eight indigenous regions of Mexico. AB - The aim of this study was to identify the prevalence and severity of intimate partner violence (IPV) in eight indigenous regions of Mexico, as well as the socioeconomic and demographic variables that are associated with this phenomenon. A cross-sectional study was conducted in indigenous regions that have a greater availability of government medical services than other indigenous regions. Interviews were conducted with female patients (n = 3287) seeking medical care in either of the two public health institutions in these regions. The severity of intimate partner violence (SIPV) during the previous 12 months was measured using a 33-item scale. Multinomial logistic regression analyses were performed to explore the factors associated with SIPV. Intimate partner violence prevalence was 25.5% (95%CI 24.93-25.26). Female partner variables such as personal history of child abuse (ORA 3.48; 95%CI 2.48-4.89) and work outside the home (ORA 1.74; 95%CI 1.22-2.49) and male partner variables such as unemployment (ORA 2.31; 95%CI 1.34-3.97) and a high frequency of alcohol use (ORA 13.35; 95%CI 7.02-25.39) were the main predictors for IPV. We found a three-fold higher risk of IPV for women living in the Los Altos de Chiapas region (ORA 3.01; 95%CI 1.88-4.79) compared with women in the Mayan region (reference category). Such results should aid decision makers in the development of extended public policies and interventions to address violence against women in the indigenous populations of Mexico. PMID- 23453318 TI - Subjective socioeconomic status and health: relationships reconsidered. AB - Subjective status, an individual's perception of her socioeconomic standing, is a robust predictor of physical health in many societies. To date, competing interpretations of this correlation remain unresolved. Using longitudinal data on 8430 older adults from the 2000 and 2007 waves of the Indonesia Family Life Survey, we test these oft-cited links. As in other settings, perceived status is a robust predictor of self-rated health, and also of physical functioning and nurse-assessed general health. These relationships persist in the presence of controls for unobserved traits, such as difficult-to-measure aspects of family background and persistent aspects of personality. However, we find evidence that these links likely represent bi-directional effects. Declines in health that accompany aging are robust predictors of declines in perceived socioeconomic status, net of observed changes to the economic profile of respondents. The results thus underscore the social value afforded good health status. PMID- 23453319 TI - The impact of state-level nutrition-education program funding on BMI: evidence from the behavioral risk factor surveillance system. AB - Currently, there is insufficient evidence regarding which policies will improve nutrition, reduce BMI levels and the prevalence of obesity and overweight nationwide. This preliminary study investigates the impact of a nutrition education policy relative to price policy as a means to reduce BMI in the United States (US). Model estimations use pooled cross-sectional data at the individual level from the Centers for Disease Control's (CDC), Behavioral Risk Factor Surveillance System (BRFSS), state-level food prices from the American Chamber of Commerce Research Association (ACCRA) and funding for state-specific nutrition education programs from the United States Department of Agriculture (USDA) from 1992 to 2006. The total number of observations for the study is 2,249,713 over 15 years. During this period, federal funding for state-specific nutrition-education programs rose from approximately $660 thousand for seven states to nearly $248 million for all fifty-two states. In 2011, federal funding for nutrition education programs reached $375 million. After controlling for state-fixed effects, year effects and state specific linear and quadratic time trends, we find that nutrition education spending has the intended effect on BMI, obese and overweight in aggregate. However, we find heterogeneity as individuals from certain, but not all, income and education levels respond to nutrition-education funding. The results regarding nutrition-education programs suggest that large scale funding of nutrition-education programs may improve BMI levels and reduce obesity and overweight. However, more study is required to determine if these funds are able make the requisite dietary improvements that may ultimately improve BMI for individuals from low income and education-levels. PMID- 23453320 TI - A mental model of factors associated with subjective life expectancy. AB - The objective was to develop and test a framework based on a biopsychosocial model that can be used to identify factors associated with subjective (self estimated) life expectancy (SLE). SLE predicts important work and retirement decisions so a better understanding of the factors that contribute to an individual's thoughts about their likely age at death is essential for late career and financial planning and for developing interventions aimed at addressing inappropriate estimates. This is a sub-study of the Australian 45 and Up Study cohort. Survey data were collected at two time points (3 years apart) from 2579 participants aged over 55 years. Correlations and regression analyses tested the relationship of SLE with biomedical/genetic factors (age, health diagnoses, parental longevity), socioeconomic factors (income, education) health behaviors (exercise, smoking, alcohol use, diet), and psychosocial factors (optimism, distress, social connectedness). Variables within each set of factors except the socioeconomic set were significantly related to SLE. Healthy lifestyle behaviors significantly moderated the effect of parental longevity. The findings indicate that individuals construct an understanding of their personal life expectancy based on similar factors that predict actual life expectancy, but not all mortality risk factors appear to be weighted realistically. The findings imply that, at least to some extent, SLE is not a stable construct and might be amenable to intervention. PMID- 23453321 TI - Geospatial analysis of naturally occurring boundaries in road-transport emissions and children's respiratory health across a demographically diverse cityscape. AB - The motor-vehicle is accountable for emitting a substantial concoction of air quality objective pollutants and carcinogenic hydrocarbons within close proximity to urbanised residential districts. The spatial extent of health impacts associated with road-transport pollutants have traditionally been explored through the examination of artificially created buffers, defined by subjective distances from specified major road links. Within this paper an alternative approach is presented using boundary statistics, which describe naturally occurring shifts of magnitude in socio-environmental and health outcomes across the wider urban area. In contrast, previous distance-threshold investigations have used arbitrarily sized buffers placed upon predetermined locations in response to environmental attributes, without considering the combined influence of additional social burdens. The demographically diverse City of Leicester, situated within the heart of the United Kingdom's major road-transport network, was selected to showcase such methods. Descriptive multilevel modelling strategies accommodating for generalised spatial structures across Leicester, globally associated issues of deprivation, road-transport emissions and ethnic minorities with increased respiratory risks. Getis-Ord Gi* spatial pattern recognition statistics identified the existence of localised variations, with inner city neighbourhoods tending to house children of ethnic minority groups whom experience disproportionately large environmental and respiratory health burdens. Crisp polygon wombling boundary detection across Leicester appeared to broadly complement the Gi* statistics, identifying naturally occurring boundaries in road-transport emissions to result in elevated children's respiratory admissions within a distance of 283 m (P < 0.05). The designated threshold was identified to reduce in relation to certain ethnic groups, thus suggesting environmental injustices likely prevail within the model British multicultural City of Leicester. The study's findings have applications within healthcare management and urban planning for locating vulnerable populaces and for minimising health risks in future road network designs. PMID- 23453322 TI - Bringing politics and evidence together: policy entrepreneurship and the conception of the At Home/Chez Soi Housing First Initiative for addressing homelessness and mental illness in Canada. AB - An interesting question concerns how large-scale (mental) health services policy initiatives come into being, and the role of evidence within the decision-making process behind their origins. This paper illustrates the process by which motivation to address homelessness, in the context of the upcoming 2010 Vancouver Olympics, was leveraged into a pan-Canadian project including sites in Vancouver, Winnipeg, Toronto, Montreal and Moncton, New Brunswick. The aim of the initiative was to implement and evaluate an intervention, Housing First, to provide housing and support to previously homeless people with mental illness. This qualitative case study was conducted between December 2009 and December 2010, employing grounded theory, and drawing on archival documents and interviews with 19 key informants involved in the conception of the project. Overall, the findings affirm that policy-making does not follow a rational, linear process of knowledge translation/exchange (KTE) and implementation, whereby evidence-based "products" are brought forward to address objectively determined needs and then "placed into decision-making events" (Lomas, 2007, p. 130). Instead, evidence-based policy making should be understood within the much more complex context of "policy entrepreneurship" (Kingdon, 2003; Mintrom & Norman, 2009) which entails taking advantage of windows of opportunity, and helping to bring together the "streams" of problems, politics, and policy ideas (Kingdon, 2003). PMID- 23453323 TI - Virtual laparoscopy: Initial experience with three-dimensional ultrasonography to characterize hepatic surface features. AB - OBJECTIVE: To examine the potential utility of 3D-reconstructed sonograms to distinguish cirrhotic from non-cirrhotic livers by demonstrating hepatic surface characteristics. MATERIALS AND METHODS: A preliminary phantom study was performed to examine the potential resolution of 3D images, recognizing surface irregularities as a difference in height. In a prospective clinical study of 31 consecutive patients with ascites (21 cirrhosis, 10 non-cirrhosis), liver volume data were acquired by transabdominal mechanical scanning. The hepatic surface features of cirrhotic and non-cirrhotic patients were compared by 2 independent reviewers. Intra- and inter-operator/reviewer agreements were also examined. RESULTS: The phantom study revealed that 0.4mm was the minimum recognizable difference in height on the 3D sonograms. The hepatic surface image was successfully visualized in 74% patients (23/31). Success depended on the amount of ascites; visualization was 100% with ascites of 10mm or more between the hepatic surface and abdominal wall. The images showed irregularity of the hepatic surface in all cirrhotic patients. The surface appearance was confirmed as being very similar in 3 patients who had both 3D sonogram and liver resection for transplantation. The ability to distinguish cirrhotic liver from non-cirrhotic liver improved with the use of combination of 2D- and 3D-imaging versus 2D imaging alone (sensitivity, p=0.02; accuracy, p=0.02) or 3D-imaging alone (sensitivity, p=0.03). Intra-/inter-operator and inter-reviewer agreement were excellent (kappa=1.0). CONCLUSION: 3D-based sonographic visualization of the hepatic surface showed high reliability and reproducibility, acting as a virtual laparoscopy method, and the technique has the potential to improve the diagnosis of cirrhosis. PMID- 23453324 TI - Design, application and impact of quality improvement 'theme months' in orthopaedic nursing: a mixed method case study on pressure ulcer prevention. AB - BACKGROUND: While there is growing awareness of quality problems in healthcare systems, it remains uncertain how best to accomplish and sustain improvement over time. OBJECTIVE: To report on the design and application of quality improvement theme months in orthopaedic nursing, and evaluate the impact on pressure ulcer as an example. DESIGN: Retrospective mixed method case study with time series diagrams. SETTING: An orthopaedic department at a Swedish university hospital. METHOD: The interventions were led by nursing teams and focused on one improvement theme at a time in two-month cycles, hence the term 'improvement theme months'. These included defined objectives, easy-to-use follow-up measurement, education, changes to daily routines, "reminder months" and data feedback. The study draws on retrospective record data regarding one of the theme topics, pressure ulcer risk assessment and prevalence, in 2281 orthopaedic admissions during January 2007-October 2010 through point prevalence measurement one-day per month. Data were analysed in time series diagrams and through comparison to annual point prevalence data from mandatory county council-wide measurements prior to, during and after interventions from 2003 to 2010. By using document analysis we reviewed concurrent initiatives at different levels in the healthcare organisation and related them to the improvement theme months and their impact. RESULTS: The 46 monthly point prevalence samples ranged from 28 to 66 admissions. Substantial improvements were found in risk assessment rates for pressure ulcers both in the longitudinal follow-up (p<0.001) and in the annual county council-wide measurements. A reduction in pressure ulcer rate was observed in the annual county council-wide measurements. In the longitudinal data, wider variation in the pressure ulcer rate was seen (p<0.067); however, there was a significant decrease in pressure ulcer rates during the final ten-month period in 2010, compared to the baseline period in 2007 (p=0.004). Improvements were moderate the first years and needed reinforcement to be maintained. CONCLUSIONS: The theme month design and the way it was applied in this case showed potential, contributing to reduced pressure ulcer prevalence, as a way to conduct quality improvement initiatives in nursing. For sustainable improvement, multi component interventions are needed with regular monitoring and reminder efforts. PMID- 23453326 TI - Comments on the lannuzzi article. PMID- 23453325 TI - Age-related changes in neuromuscular function of the quadriceps muscle in physically active adults. AB - Substantial evidence exists for the age-related decline in maximal strength and strength development. Despite the importance of knee extensor strength for physical function and mobility in the elderly, studies focusing on the underlying neuromuscular mechanisms of the quadriceps muscle weakness are limited. The aim of this study was to investigate the contributions of age-related neural and muscular changes in the quadriceps muscle to decreases in isometric maximal voluntary torque (iMVT) and explosive voluntary strength. The interpolated twitch technique and normalized surface electromyography (EMG) signal during iMVT were analyzed to assess changes in neural drive to the muscles of 15 young and 15 elderly volunteers. The maximal rate of torque development as well as rate of torque development, impulse and neuromuscular activation in the early phase of contraction were determined. Spinal excitability was estimated using the H reflex technique. Changes at the muscle level were evaluated by analyzing the contractile properties and lean mass. The age-related decrease in iMVT was accompanied by a decline in voluntary activation and normalized surface EMG amplitude. Mechanical parameters of explosive voluntary strength were reduced while the corresponding muscle activation remained primarily unchanged. The spinal excitability of the vastus medialis was not different while M wave latency was longer. Contractile properties and lean mass were reduced. In conclusion, the age-related decline in iMVT of the quadriceps muscle might be due to a reduced neural drive and changes in skeletal muscle properties. The decrease in explosive voluntary strength seemed to be more affected by muscular than by neural changes. PMID- 23453327 TI - Physiologic tolerance of descending thoracic aortic balloon occlusion in a swine model of hemorrhagic shock. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an emerging technique in trauma; however, the physiologic sequelae have not been well quantified. The objectives of this study were to characterize the burden of reperfusion and organ dysfunction of REBOA incurred during 30 or 90 min of class IV shock in a survivable porcine model of hemorrhage. METHODS: After induction of shock, animals were randomized into 4 groups (n = 6): 30 min of shock alone (30 Shock) or with REBOA (30-REBOA) and 90 min of shock alone (90-Shock) or with REBOA (90-REBOA). Cardiovascular homeostasis was then restored with blood, fluid, and vasopressors for 48 h. Outcomes included mean central aortic pressure (MCAP), lactate concentration, organ dysfunction, histologic evaluation, and resuscitation requirements. RESULTS: Both REBOA groups had greater MCAPs throughout their shock phase compared to controls (P < .05) but accumulated a significantly greater serum lactate burden, which returned to control levels by 150 min in the 30-REBOA groups and 320 min in the 90-REBOA group. There was a greater level of renal dysfunction and evidence of liver necrosis seen in the 90 REBOA group compared to the 90-Shock group. There was no evidence of cerebral or spinal cord necrosis in any group. The 90-REBOA group required more fluid resuscitation than the 90-Shock group (P = .05). CONCLUSION: REBOA in shock improves MCAP and is associated with a greater lactate burden; however, this lactate burden returned to control levels within the study period. Ultimately, prolonged REBOA is a survivable and potentially life-saving intervention in the setting of hemorrhagic shock and cardiovascular collapse in the pig. PMID- 23453329 TI - Molecular cloning and protein characterization of swine 4-1BB. AB - 4-1BB is expressed on activated T cells and other immune and non-immune cells. It plays important roles in human and mouse T cell function. However, the swine 4 1BB sequence remains unknown and its role in swine T cell response has not been studied. In the present study, we for the first time described the cloning of the swine 4-1BB gene and the property of the protein. Two 4-1BB variants were detected in swine. The coding sequences of variant 1 and variant 2 were 768 and 726 nucleotides in length, respectively, and both variants were coded by 7 exons in the swine genome. Comparison of nucleotide and amino acid sequences showed that both swine 4-1BB variants were more closely related to bovine and human sequences than to either the mouse or rat sequence. Prediction analysis showed that swine 4-1BB belonged to the tumor necrosis factor receptor (TNFR) superfamily like human and mouse 4-1BB and the tertiary structures of the swine 4 1BB variants were much more similar to mouse 4-1BB than to human 4-1BB. The 1556bp 5' regulatory sequence cloned by nested PCR efficiently induced green fluorescent protein expression in porcine peripheral blood mononuclear cells (PBMC) post nucleofection. Moreover, 4-1BB protein was widely expressed in pig tissues and both variants of swine 4-1BB protein were transmembrane proteins and expressed on the membrane of porcine PBMCs. PMID- 23453328 TI - Contemporary trends in necrotizing soft-tissue infections in the United States. AB - BACKGROUND: Necrotizing soft-tissue infections (NSTI) are rare, potentially fatal, operative emergencies. We studied a national cohort of patients to determine recent trends in incidence, treatment, and outcomes for NSTI. METHODS: We queried the Nationwide Inpatient Sample (1998-2010) for patients with a primary diagnosis of NSTI. Temporal trends in patient characteristics, treatment (debridement, amputation, hyperbaric oxygen therapy [HBOT]), and outcomes were determined with Cochran-Armitage trend tests and linear regression. To account for trends in case mix (age, sex, race, insurance, Elixhauser index) or receipt of HBOT on outcomes, multivariable analyses were conducted to determine the independent effect of year of treatment on mortality, any major complication, and hospital length of stay (LOS) for NSTI. RESULTS: We identified 56,527 weighted NSTI admissions, with an incidence ranging from approximately 3,800-5,800 cases annually. The number of cases peaked in 2004 and then decreased between 1998 and 2010 (P < .0001). The percentage of female patients decreased slightly over time (38.6-34.1%, P < .0001). Patients were increasingly in the 18- to 34-year-old (8.8-14.6%, P < .0001) and 50- to 64-year-old age groups (33.2-43.5, P < .0001), Hispanic (6.8-10.5%, P < .0001), obese (8.9-24.6%, P < .0001), and admitted with >3 comorbidities (14.5-39.7%, P < .0001). The percentage of patients requiring only one operative debridement increased somewhat (43.2-46.2%, P < .0001), whereas the use of HBOT was rare and decreasing (1.6-0.8%, P < .0001). The percentage of patients requiring operative wound closure decreased somewhat (23.5 20.8%, P < .0001). Although major complication rates increased (30.9-48.2%, P < .0001), hospital LOS remained stable (18-19 days) and mortality decreased (9.0 4.9%, P < .0001) on univariate analyses. On multivariable analyses each 1-year incremental increase in year was associated with a 5% increased odds of complication (odds ratio 1.05), 0.4 times decrease in hospital LOS (coefficient 0.41), and 11% decreased odds of mortality (odds ratio 0.89). CONCLUSION: There were potentially important national trends in patient characteristics and treatment patterns for NSTI between 1998 and 2010. Importantly, though patient acuity worsened and complication rates increased, but LOS remained relatively stable and mortality decreased. Improvements in early diagnosis, wound care, and critical care delivery may be the cause. PMID- 23453330 TI - Multidisciplinary care of patients with brain tumors. AB - Patients with brain tumors are some of the most complex patients in the medical system, necessitating treatment teams of multiple subspecialists for optimal care. This article examines the roles of these subspecialists, with the goal of summarizing standard-of-care practices, recent therapeutic advances, and ongoing clinical investigations within each subspecialty. PMID- 23453331 TI - Multidisciplinary care of the patient with head and neck cancer. AB - Head and neck cancer is a heterogeneous group of cancers, which require a multidisciplinary approach to achieve excellent treatment results. This article focuses on current treatment guidelines and controversies in the management of head and neck cancer. It also provides insight into future directions and newest advances in the treatment of head and neck cancer. PMID- 23453332 TI - Multidisciplinary management of esophageal cancer. AB - This article reviews the current management of esophageal cancer, including staging and treatment options, as well as providing support for using multidisciplinary teams to better manage esophageal cancer patients. PMID- 23453333 TI - Multidisciplinary management of gastric cancer. AB - Treatment of gastric cancer involves a multidisciplinary approach to achieve long term outcome, including surgery, chemotherapy, and radiation therapy. Most patients present with advanced disease and are not candidates for a curative approach. Palliative chemotherapy is recommended for symptom control and for short-term advances in survival. Surgery combined with different chemotherapy and chemoradiation options improves survival. Initial studies focused on adjuvant chemoradiation and showed improved survival. More recent trials have demonstrated that perioperative chemotherapy before and after surgery provides a survival advantage. Such an approach may also downstage marginal patients who can then be selected to undergo curative resection and complete adjuvant chemotherapy. PMID- 23453335 TI - Colorectal cancer metastases: a surgical perspective. AB - Metastases from colorectal cancer occur to the regional lymph nodes, the liver, the peritoneal surfaces, and lung. These metastases may occur synchronously or metachronously and the timing of the metastatic process is important in terms of treatment possibilities. Each anatomic site for metastatic disease has a unique management strategy. Systemic chemotherapy as an adequate management plan for all sites of colorectal metastatic disease is not compatible with a high standard of care. Formulation of an individualized plan combining surgery with regional chemotherapy and systemic chemotherapy is a necessary function of the multidisciplinary team. PMID- 23453334 TI - Multidisciplinary management of pancreatic cancer. AB - Pancreatic cancer (pancreatic adenocarcinoma) remains one of the deadliest malignancies in the western hemisphere despite improved surgical technique, chemotherapy, and radiation therapy. The appropriate management of this malignancy should incorporate multiple treatment modalities for optimal opportunity for cure. Recent trials with a variety of treatment techniques confer improved survival of patients with pancreatic cancer, even in the metastatic setting. In this review, the importance of multidisciplinary management of pancreatic cancer based on disease stage is discussed. PMID- 23453336 TI - Multidisciplinary care of patients with early-stage breast cancer. AB - There is a compelling need for close coordination and integration of multiple specialties in the management of patients with early-stage breast cancer. Optimal patient care and outcomes depend on the sequential and often simultaneous participation and dialogue between specialists in imaging, pathologic and molecular diagnostic and prognostic stratification, and the therapeutic specialties of surgery, radiation oncology, and medical oncology. These are but a few of the various disciplines needed to provide modern, sophisticated management. The essential role for coordinated involvement of the entire health care team in optimal management of patients with early-stage breast cancer is likely to increase further. PMID- 23453337 TI - Multimodality approach to management of stage III non-small cell lung cancer. AB - Stage III non-small cell lung cancer represents a heterogeneous group of patients who are best managed with a multidisciplinary approach, including evaluation for surgical, radiation, and chemotherapeutic options. PMID- 23453338 TI - Multidisciplinary management of small cell lung cancer. AB - The standard treatment of limited-stage small cell lung cancer (SCLC) is concurrent cisplatin and etoposide with thoracic radiation therapy, whereas treatment of extensive-stage disease is typically chemotherapy alone with a platinum compound plus etoposide. Surgical resection of early disease is generally reserved for patients with small, node-negative disease. Prophylactic cranial irradiation reduces the development of brain metastases and prolongs survival in patients with both limited-stage and extensive-stage disease who have responded to chemotherapy. Further understanding of the molecular underpinnings of SCLC is necessary to develop better treatment options and improve outcomes for patients. PMID- 23453339 TI - Multimodality treatment of pleural mesothelioma. AB - Although the treatment of malignant pleural mesothelioma has been refined during the past two decades, overall survival from this rather uncommon disease is still extremely poor. Here we review the current multimodal diagnostic and treatment options for patients with mesothelioma and discuss promising new experimental concepts in this disease. PMID- 23453340 TI - Multidisciplinary management of patients with localized bladder cancer. AB - Multidisciplinary approach to muscle-invasive bladder cancer is imperative to achieve optimal long-term cancer control. Radical cystectomy, pelvic lymph node dissection, and urinary diversion have been the mainstay of therapy for decades. Laparoscopic and robotic-assisted surgical techniques are becoming increasingly prevalent, and have shown short-term benefits in terms of blood loss, less pain, and smaller incisions. Neoadjuvant chemotherapy plus surgery results in absolute survival advantage and this approach is encouraged in appropriate patients. A similar survival advantage with the use of adjuvant chemotherapy has yet to be convincingly demonstrated. Bladder-preservation protocols involving a visibly complete transurethral resection followed by chemoradiation may be a feasible option for select patients. PMID- 23453341 TI - Advances in the multimodality management of high-risk prostate cancer. AB - Prostate cancer is a heterogeneous disease with marked variability in its natural progression and response to therapeutic interventions. It is the most commonly diagnosed visceral cancer of men living in western countries, yet it is life threatening in only a minority of cases. Thus, appropriate patient selection for treatment based on tumor as well as patient characteristics is essential to achieve optimal outcomes. The combination of early cancer detection and technical improvements in local treatment has led to a reduction in disease burden and an increase in cancer survivorship. However, treatment failure remains common among high-risk cases. PMID- 23453342 TI - Surgical Oncology Clinics of North America. Multidisciplinary care of the cancer patient. Foreword. PMID- 23453343 TI - Multidisciplinary care of the cancer patient. PMID- 23453344 TI - [Possible prognostic value of atrial fibrillation and atrial flutter in Brugada syndrome]. AB - OBJECTIVE: To analyze the specific risk for the variables: type 1 spontaneous pattern, type 1 induced pattern, type 1 pattern with spontaneous variability, syncope, family history of sudden death, atrial fibrillation and atrial flutter with the subsequent development of malignant arrhythmic events. METHODS: Forty three Brugada patients (90% males; mean age 40.4 years), with a type 1 spontaneous pattern (74.4%) or induced by ajmaline (25.6%) were retrospectively analyzed. Of these, 58.1% presented spontaneous variability, 18.6% had family history of sudden death, 39.5% were symptomatic, and 18.6% presented atrial fibrillation or atrial flutter. The antecedents of resuscitated cardiac arrest, sudden death or appropriate shock from implantable automatic defibrillator were considered malignant arrhythmic events. During a mean follow up of 51 months, no deaths were recorded, 6.9% of the patients presented a malignant arrhythmic event, and all of them were appropriate shocks. The annual rate of events in patients with syncope was 1.7%, with a spontaneous type 1 pattern was 2.79%, and spontaneous variability was 2.87%. No malignant arrhythmic event was observed in asymptomatic patients or in those with a persistent pattern or induced type 1 pattern. The annual rate of events with positive or negative history of family sudden death was 2.94 and 1.7%, respectively. In the presence of atrial fibrillation, atrial flutter and atrial fibrillation/atrial flutter were 7.3, 15.69 and 10%, respectively. In the absence of atrial fibrillation/atrial flutter no malignant arrhythmic events were observed. CONCLUSION: Of the variables analyzed, the one that was most related to a malignant arrhythmic event was the presence of atrial fibrillation (P=.046) and atrial flutter (P=.03). PMID- 23453345 TI - [QTc interval prolongation and polymorphic ventricular tachycardia related to subarachnoid hemorrhage]. AB - A 55-yr-old woman was taken to the hospital after recovering from a presyncopal episode. The electrocardiogram showed sinus bradycardia with QTc interval of 840 msec. Few minutes later, the patient developed a polymorphic ventricular tachycardia and subsequent cardiac arrest requiring cardiopulmonary resuscitation. A week later she presented with severe headache, seizures and decerebrate movements. Cranial computed tomography scan showed subarachnoid hemorrhage with intracranial hypertension requiring decompressive craniectomy. On the follow- up the electrocardiograms always showed prolonged QTc interval, without any new arrhythmic event. The patient's clinical course was unfavorable and required maximum dose of vasoactive drugs. She died 13 days after admission. PMID- 23453346 TI - The final chapter of the ALS lithium saga. PMID- 23453348 TI - The influence of food quantity on metal bioaccumulation and reproduction in fathead minnows (Pimephales promelas) during chronic exposures to a metal mine effluent. AB - Metal mine effluents can impact fish in the receiving environment via both direct effects from exposure as well as indirect effects via food web. The main objective of the present study was to assess whether an indirect effect such as reduced food (prey) availability could influence metal accumulation and reproductive capacity in fish during chronic exposure to a metal mine effluent. Breeding pairs of fathead minnows (Pimephales promelas) were exposed to either reference water (RW) or an environmentally relevant metal mine effluent [45 percent process water effluent (PWE)] for 21 days and fed either low food quantities [LF (a daily ration of 6-10 percent body weight)] or normal food quantities [NF (a daily ration of 20-30 percent body weight)] in artificial stream systems. Fish in RW treatments were fed Chironomus dilutus larvae cultured in RW (Treatments: RW-NF or RW-LF), while fish in PWE treatments were fed C. dilutus larvae cultured in PWE (Treatments: PWE-NF or PWE-LF). Tissue-specific (gill, liver, gonad and carcass) metal accumulation, egg production, and morphometric parameters in fish were analyzed. Fathead minnows that were exposed to LF rations had significantly smaller body, gonad and liver sizes, and were in a relatively poor condition compared to fathead minnows exposed to NF rations, regardless of the treatment water type (RW or PWE) (two-way ANOVA; p<0.05). Although elevated concentrations of copper, nickel, rubidium, selenium, and thallium were recorded in C. dilutus cultured in PWE, only the concentrations of rubidium, selenium and thallium increased in tissues of fish in PWE treatments. Interestingly though, despite the greater abundance of metal-contaminated food in the PWE-NF treatment, tissue metal accumulation pattern were almost similar between the PWE-NF and PWE-LF treatments, except for higher liver barium, cobalt and manganese concentrations in the latter treatment. This indicated that a higher food ration could help reduce the tissue burden of at least some metals and thereby ameliorate the toxicity of metal-mine effluents in fish. More importantly, cumulative egg production in fish was found to be lowest in the PWE LF treatment, whereas fish egg production in the PWE-NF treatment was not impacted. Overall, these findings suggest that decreased food abundance could have a greater impact than metal accumulation in target tissues on the reproductive capacity of fish inhabiting metal-mine effluent receiving environments. PMID- 23453349 TI - Cancer and non-cancer risk assessment of trihalomethanes in urban drinking water supplies of Pakistan. AB - This study aims at monitoring and risk assessment of trihalomethanes (THMs) such as chloroform, bromodichloromethane, dibromochloromethane and bromoform, in the drinking water supplies of Rawalpindi and Islamabad. THMs were monitored at twenty locations in these twin cities using solid phase micro extraction-gas chromatography (SPME-GC). Total concentration of THMs was ranged between 21 and 373MUg/L, whereas both cities had an average total THMs concentration of 142 and 260MUg/L, respectively. Chloroform was found as one the major contributor to the THMs concentration (>85%). The occurrence of THMs followed the given order: chloroform, bromodichloromethane>dibromochloromethane>bromoform. Lifetime cancer risk assessment of THMs was carried out using prediction models via different exposure routes (ingestion, inhalation and dermal). An average lifetime cancer risk was found to be 0.74*10(-4) and 1.24*10(-4) for Rawalpindi and Islamabad, respectively. The number of expected cancer cases per year could reach two cases for each city. Hazard index values were found below unity for both the cities implying that there would be no considerable non-cancer risk. Oral ingestion was found to be one of the main routes of exposure for both types of risk which was followed by inhalation and dermal routes. PMID- 23453350 TI - Effect of carbon sources and of sulfate on microbial arsenic mobilization in sediments of West Bengal, India. AB - Arsenic (As) dissolution from sediments into groundwater in the Bengal Delta/West India was investigated. Two experimental sites were choosen with contrasting As concentrations in shallow groundwater. Apparently patches of high-As and low-As sediments occured in close neigbourhood. A fast As mobilization with lactate or ethanol as carbon sources and sulfate as an electron acceptor and a possible influence of indigenous flora because of higher As amounts and an increasing total cell count was observed over a peroid of 110 days. Sucrose was a less suitable carbon source. Inoculation of an arsenate-reducing Pseudomonas putida WB, that was isolated from the sediments did not improve arsenic mobilization. Maximal arsenic concentrations up to 160MUg/l were leached out from sediment columns with lactate or ethanol+sulfate in the water at natural groundwater flow, but the majority of the As remained in the sandy sediments. Some correlation of arsenic with Fe, but not with Mn dissolution seems to exist. PMID- 23453347 TI - Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log rank chi(2) on 1 df=1.64; p=0.20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0.71 (95% CI 0.40-1.24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland. PMID- 23453351 TI - Low-grade albuminuria is associated with carotid atherosclerosis in normotensive and euglycemic Chinese middle-aged and elderly adults: the Shanghai Changfeng Study. AB - BACKGROUND: Microalbuminuria is associated with cardiovascular disease (CVD). We investigated whether low-grade albuminuria (LGA) is independently associated with the carotid intima-media thickness (CIMT) and carotid plaques in normotensive and euglycemic Chinese middle-aged and elderly adults. METHODS: A total of 1341 normotensive and euglycemic participants (489 males and 852 females; mean age, 57.7 years) with normal urinary albumin-to-creatinine ratios (UACRs) (<30 MUg/mg) were enrolled from the Changfeng Study. A standard interview, anthropometric measurements and laboratory analyzes were performed for each participant. Bilateral CIMTs were measured using ultrasonography, and the presence of carotid plaques was assessed. The urinary albumin excretion rate was measured using an early morning urine sample to determine the UACR. RESULTS: The median UACRs were 4.2 (interquartile range, 2.9-6.0) MUg/mg and 5.6 (interquartile range, 4.0-8.2) MUg/mg for male and female subjects, respectively. Compared with subjects with UACRs in the first and second tertiles, subjects of both genders with UACRs in the third tertile had greater CIMTs. After adjusting for conventional CVD risk factors and the glomerular filtration rate (GFR), male and female participants with UACRs in the third tertile for each gender had a 1.696-fold and 1.911-fold increased risk, respectively, of carotid plaques relative to those in the lowest tertiles. The logUACR was positively associated with the CIMT (beta = 0.068 in males, P = 0.001; and beta = 0.034 in females, P = 0.012) after adjusting for conventional CVD risk factors and the GFR. The multiple logistic regression analysis showed that a 1-unit increase in the logUACR corresponded to an odds ratio (OR) of having a carotid plaque that was 1.875 (95% confidence interval (CI) 1.103-3.538; P = 0.022) and 2.389 (95% CI 1.244-4.391; P = 0.01) for male and female subjects, respectively, after adjusting for all potential confounders. CONCLUSIONS: These results suggest that the UACR is independently associated with carotid atherosclerosis in normotensive and euglycemic Chinese individuals and that even when well below the current microalbuminuria threshold, LGA contributes to the risk of atherosclerosis. PMID- 23453352 TI - Low dose chromium-polynicotinate or policosanol is effective in hypercholesterolemic children only in combination with glucomannan. AB - OBJECTIVE: A low-fat, fiber-rich diet is the first step in the management for hypercholesterolemic children. Glucomannan (GM) is a natural fiber that has been demonstrated to lower total and LDL-cholesterol. The use of high-dose chromium polynicotinate (CP) and policosanol (PC) has also shown cholesterol-lowering benefits. We aimed at investigating the effects of low-dose CP or PC and their GM combination in hypercholesterolemic children. METHODS: A double-blind trial was conducted in 120 children (60 M, 60 F, 9 +/- 4 years, median 9.6 years, range: 3 16 years) randomly assigned to 5 neutraceutical and 1 placebo (only resistant starch) 8-week treatment groups. Fasting blood glucose (FBG), total cholesterol (CholT), triglycerides (TG), HDL and LDL cholesterol were considered. RESULTS: GM combination of low-dose CP or PC reduced CholT and LDL without changing HDL, TG and FBG. The highest post-treatment changes were seen after GM combination with CP (CholT 85 +/- 3% and LDL 85 +/- 5%, of pretreatment) which was significantly (p < 0.01) less than with low-dose CP or PC and starch. When GM was associated with starch, there was no lipid lowering effect, which was an unexpected finding as compared to previous data with GM and no starch. No adverse effects were reported. CONCLUSION: This is the first report to show the cholesterol-lowering efficacy of GM combined treatment with low-dose CP or PC. Further studies are needed to investigate the best combinations and doses of nutraceutics to be added to the standard GM treatment. The potential negative association of GM and nutraceutics with starch is clearly shown. PMID- 23453353 TI - Aggressive angiomyxoma. PMID- 23453354 TI - Suitability analysis for siting MSW landfills and its multicriteria spatial decision support system: method, implementation and case study. AB - Multicriteria spatial decision support systems (MC-SDSS) have emerged as an integration of geographical information systems (GIS) and multiple criteria decision analysis (MCDA) methods for incorporating conflicting objectives and decision makers' (DMs') preferences into spatial decision models. This article presents a raster-based MC-SDSS that combines the analytic hierarchy process (AHP) and compromise programming methods, such as TOPSIS (technique for order preference by similarity to the ideal solution) and Ideal Point Methods. To the best of our knowledge it is the first time that a synergy of AHP and compromise programming methods is implemented in raster-driven GIS-based landfill suitability analysis. This procedure is supported by a spatial decision support system (SDSS) that was developed within a widely used commercial GIS software package. A real case study in the Thrace region in northeast Greece serves as a guide on how to conduct a suitability analysis for a MSW landfill site with the proposed MC-SDSS. Moreover, the procedure for identifying MSW disposal sites is accomplished by performing four computational models for synthesizing the DMs per criterion preferential system. Based on the case study results, a comparison analysis is performed according to suitability index estimations. According to them Euclidean distance metric and TOPSIS present strong similarities. When compared with Euclidean distance metric, TOPSIS seems to generate results closer to that derived by Manhattan distance metric. The comparison of Chebychev distance metric with all the other approaches revealed the greatest deviations. PMID- 23453355 TI - Aluminium recovery vs. hydrogen production as resource recovery options for fine MSWI bottom ash fraction. AB - Waste incineration bottom ash fine fraction contains a significant amount of aluminium, but previous works have shown that current recovery options based on standard on-step Eddy Current Separation (ECS) have limited efficiency. In this paper, we evaluated the improvement in the efficiency of ECS by using an additional step of crushing and sieving. The efficiency of metallic Al recovery was quantified by measuring hydrogen gas production. The ash samples were also tested for total aluminium content with X-ray fluorescence spectroscopy (XRF). As an alternative to material recovery, we also investigated the possibility to convert residual metallic Al into useful energy, promoting H2 gas production by reacting metallic Al with water at high pH. The results show that the total aluminium concentration in the <4 mm bottom ash fraction is on average 8% of the weight of the dry ash, with less than 15% of it being present in the metallic form. Of this latter, only 21% can be potentially recovered with ECS combined with crushing and sieving stages and subsequently recycled. For hydrogen production, using 10MNaOH at 1L/S ratio results in the release of 6-11l of H2 gas for each kilogram of fine dry ash, equivalent to an energy potential of 118 kJ. PMID- 23453356 TI - Measuring waste prevention. AB - The Waste Framework Directive (WFD-2008/98/EC) has set clear waste prevention procedures, including reporting, reviewing, monitoring and evaluating. Based on the WFD, the European Commission and will offer support to Member States on how to develop waste prevention programmes through guidelines and information sharing on best practices. Monitoring and evaluating waste prevention activities are critical, as they constitute the main tools to enable policy makers, at the national and local level, to build their strategic plans and ensure that waste prevention initiatives are effective and deliver behaviour change. However, how one can measure something that is not there, remains an important and unresolved research question. The paper reviews and attempts to evaluate the methods that are being used for measuring waste prevention and the impact of relevant implemented activities at the household level, as the available data is still limited. PMID- 23453357 TI - Autoinflammation: From monogenic syndromes to common skin diseases. AB - Autoinflammation is characterized by aberrant regulation of the innate immune system and often manifests as periodic fevers and systemic inflammation involving multiple organs, including the skin. Mutations leading to abnormal behavior or activity of the interleukin 1 beta (IL-1beta)-processing inflammasome complex have been found in several rare autoinflammatory syndromes, for which anticytokine therapy such as IL-1 or tumor necrosis factor-alfa inhibition may be effective. It is becoming clear that features of autoinflammation also affect common dermatoses, some of which were previously thought to be solely autoimmune in origin (eg, vitiligo, systemic lupus erythematosus). Recognizing the pathogenetic role of autoinflammation can open up new avenues for the targeted treatment of complex, inflammatory dermatoses. PMID- 23453358 TI - Dermatologists perform the majority of cutaneous reconstructions in the Medicare population: numbers and trends from 2004 to 2009. AB - BACKGROUND: Dermatologists are experts in skin cancer treatment. Their experience with cutaneous reconstruction may be underrecognized. OBJECTIVE: We sought to determine the percentage of skin reconstruction claims submitted to Medicare by dermatologists relative to other specialists. METHODS: The Medicare Physician Supplier Procedure Master File from 2004 to 2009 was accessed to determine the proportion of layered closures, grafts, and flaps by specialty. RESULTS: In 2009, dermatologic surgeons' (DS) claims accounted for 60.8% of intermediate closures, 75.1% of complex repairs, 55.5% of local tissue rearrangements, and 57.5% of full thickness skin grafts in the Medicare population. DS billed for the majority of skin reconstructions except simple repairs, split-thickness skin grafts, and interpolation flaps. DS claims represented far more reconstructions of aesthetically important regions of the head and neck-including ears, eyes, nose, and lips-than other fields including plastic surgery and otolaryngology. Over the study period, DS increased the percentage of skin reconstructions in nearly every category relative to other specialists. LIMITATIONS: This analysis is limited to the Medicare population and addresses claim volumes only. Cosmetic outcomes or appropriateness of closure selection or coding cannot be addressed. CONCLUSIONS: DS perform the highest volumes of repairs in the Medicare population. DS play a primary role in routine and advanced cutaneous reconstructive surgery, especially of aesthetically important regions. PMID- 23453359 TI - Epidemiology and risk factors for oesophageal adenocarcinoma. AB - Oesophageal adenocarcinoma will soon cease to be a rare form of cancer for people born after 1940. In many Western countries, its incidence has increased more rapidly than other digestive cancers. Incidence started increasing in the Seventies in England and USA, 15 years later in Western Europe and Australia. The cumulative risk between the ages of 15 and 74 is particularly striking in the UK, with a tenfold increase in men and fivefold increase in women in little more than a single generation. Prognosis is poor with a 5-year relative survival rate of less than 10%. The main known risk factors are gastro-oesophageal reflux, obesity (predominantly mediated by intra-abdominal adipose tissues) and smoking. Barrett's oesophagus is a precancerous lesion, however, the risk of degeneration has been overestimated. In population-based studies the annual risk of adenocarcinoma varied between 0.12% and 0.14% and its incidence between 1.2 and 1.4 per 1000 person-years. Only 5% of subjects with Barrett's oesophagus die of oesophageal adenocarcinoma. On the basis of recent epidemiological data, new surveillance strategies should be developed. The purpose of this review is to focus on the epidemiology and risk factors of oesophageal adenocarcinoma. PMID- 23453360 TI - Experimental assessment of a novel robotically-driven endoscopic capsule compared to traditional colonoscopy. AB - BACKGROUND: Despite colonoscopy represents the conventional diagnostic tool for colorectal pathology, its undeniable discomfort reduces compliance to screening programmes. AIMS: To evaluate feasibility and accuracy of a novel robotically driven magnetic capsule for colonoscopy as compared to the traditional technique. METHODS: Eleven experts and eleven trainees performed complete colonoscopy by robotic magnetic capsule and by conventional colonoscope in a phantom ex vivo model (artificially clean swine bowel). Feasibility, overall accuracy to detect installed pins, procedure elapsed time and intuitiveness were measured for both techniques in both operator groups. RESULTS: Complete colonoscopy was feasible in all cases with both techniques. Overall 544/672 pins (80.9%) were detected by experimental capsule procedure, while 591/689 pins (85.8%) were detected within conventional colonoscopy procedure (P=ns), thus establishing non-inferiority. With the experimental capsule procedure, experts detected 74.2% of pins vs. 87.6% detected by trainees (P<0.0001). Overall time to complete colon inspection by robotic capsule was significantly higher than by conventional colonoscopy (556+/ 188s vs. 194+/-158s, respectively; P=0.0001). CONCLUSION: With the limitations represented by an ex vivo setting (artificially clean swine bowel and the absence of peristalsis), colonoscopy by this novel robotically-driven capsule resulted feasible and showed adequate accuracy compared to conventional colonoscopy. PMID- 23453361 TI - [Liver transplantation in alcoholic hepatitis]. PMID- 23453362 TI - Baseline serum magnesium concentrations and neurodevelopmental outcomes of extremely low birth weight premature infants. AB - AIM: To test the hypothesis that, in ELBW infants who did not receive antenatal MgSO4, lower baseline serum Mg is associated with poorer neurodevelopmental outcomes (NDO). STUDY DESIGN: The study was conducted in two phases: phase 1-- retrospective, and phase 2--prospective. SUBJECTS: Extremely low birth weight infants. OUTCOME MEASURES: Mortality and adverse NDO were assessed in relation to initial serum Mg measured in the first 12 hours of age. RESULTS: We studied 156 ELBW infants. In phase 1 (n=102): initial serum Mg (median [IQ range]) was greater in the infants who died compared to those who survived (1.7 [1.5-2.2] mg/dL vs. 1.6 [1.4-1.7] mg/dL, p=0.034). In phase 2 (n=54): initial serum Mg was greater in infants who died or had adverse NDO at 9 months when compared to those who survived with better NDO (1.7 [1.55-2.1] mg/dL vs. 1.5 [1.4-1.68] mg/dL, p=0.008). Using receiver operating characteristic (ROC) curve, increased Mg concentration in the first 12 hours>1.6 mg/dL was associated with unfavorable outcomes with sensitivity of 73%, specificity of 67%, and odds ratio of 5.5 (CI=1.2-24.8, p=0.037). CONCLUSIONS: In a cohort of preterm infants without antenatal exposure to MgSO4, initial serum Mg concentrations associated positively with poor outcomes. Further studies are needed in ELBW infants with poor NDO to determine whether they have a dysfunctional transport system that prevents Mg from entering into cells, or they have an active process that excretes Mg extracellularly. PMID- 23453363 TI - Reply to: brain computed tomographic scan findings in acute opium overdose patients. PMID- 23453364 TI - Methylene blue for the treatment of refractory anaphylaxis without hypotension. PMID- 23453365 TI - Estimating Y-STR allelic drop-out rates and adjusting for interlocus balances. AB - Y chromosome short tandem repeats (Y-STRs) are valuable genetic markers in certain areas of forensic case-work. However, when the Y-STR DNA profile is weak, the observed Y-STR profile may not be complete--i.e. locus drop-out may have occurred. Another explanation could be that the stain DNA did not have a Y-STR allele that was detectable with the method used (the allele is a 'null allele'). If the Y-STR profile of a stain is strong, one would be reluctant to consider drop-out as a reasonable explanation of lack of a Y-STR allele and would maybe consider 'null allele' as an explanation. On the other hand, if the signal strengths are weak, one would most likely accept drop-out as a possible explanation. We created a logistic regression model to estimate the probability of allele drop-out with the Life Technologies/Applied Biosystems AmpFlSTR((r)) Yfiler((r)) kit such that the trade-off between drop-outs and null alleles could be quantified using a statistical model. The model to estimate the probability of drop-out uses information about locus imbalances, signal strength, the number of PCR cycles, and the fragment size of Yfiler. We made two temporarily separated experiments and found no evidence of temporal variation in the probability of drop-out. Using our model, we found that for 30 PCR cycles with a 150 bp allele, the probability of drop-out was 1:5000 corresponding to the average estimate of the probability of Y-STR null alleles at a signal strength of 1249 RFU. This means that the probability of a null allele is higher than that of an allele drop out at e.g. 4000 RFU and the probability of drop-out is higher than that of a null allele at e.g. 75 RFU. PMID- 23453366 TI - Welcome to our world of hand therapy... dare to make waves, dare to adapt! PMID- 23453367 TI - Effectiveness of cast immobilization in comparison to the gold-standard self removal orthotic intervention for closed mallet fingers: a randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. INTRODUCTION: Although orthotic immobilization has become the preferable treatment choice for closed mallet injuries, it is unclear whether orthosis self-removal has an impact on the final outcome. PURPOSE: To evaluate the treatment efficacy of cast immobilization of closed mallet fingers using Quickcast((r)) (QC) compared to a removable, lever type thermoplastic orthosis (LTTP). METHODS: 57 subjects were randomized in 2 groups. DIPj extensor lag and the Gaberman success scale were used as primary outcomes. RESULTS: LTTP subjects resulted in greater extensor lag than QC subjects (x = 5 degrees ; p = 0.05) at 12 weeks from baseline, and high edema and older age negatively affected DIPj extensor lag. No other differences were found between groups. CONCLUSION: Cast immobilization seems to be slightly more effective than the traditional approach probably for its greater capacity to reduce edema. LEVEL OF EVIDENCE: 1B. PMID- 23453368 TI - Evaluation of the Korean version of the patient-rated wrist evaluation. AB - STUDY DESIGN: Clinical measurements. Longitudinal. PURPOSE: To translate and cross-culturally adapt the original patient-rated wrist evaluation (PRWE) into a Korean version (K-PRWE), and to measure the reliability, validity, and responsiveness of the K-PRWE for the evaluation of distal radius fractures (DRFs). METHODS: K-PRWE was developed by forward and backward translations of the PRWE and resolution of cultural discrepancies. Sixty-three DRF patients that underwent open reduction and volar plate fixation completed the K-PRWE at 3 months and 6 months postoperatively. Grip strength, wrist range of motion, VAS for wrist pain and the Korean version of DASH were performed at 3 months postoperatively. Reliability was measured by determining test-retest reliability (intraclass correlation coefficient) and internal consistency (Cronbach's alpha coefficient). Criterion and construct validity testing was performed using Spearman's correlation test. Responsiveness was evaluated using effect size (ES) and standardized response mean (SRM). RESULTS: Cronbach's alpha coefficient and the intraclass correlation coefficient of the K-PRWE were 0.94 and 0.96, respectively, which indicated that the internal consistency of the questionnaire items was sound and reliable. The correlation coefficient between K-PRWE and K DASH scores was 0.74 and between K-PRWE and VAS scores was 0.69. Responsiveness was good with an ES of 0.84 and an SRM of 0.89. CONCLUSIONS: The Korean version of the PRWE was found to be reliable, valid, and responsive to evaluate the pain and disability associated with distal radius fractures. PMID- 23453369 TI - MicroRNA-497 is a potential prognostic marker in human cervical cancer and functions as a tumor suppressor by targeting the insulin-like growth factor 1 receptor. AB - BACKGROUND: Increasing evidence has shown that microRNAs function as oncogenes or tumor suppressors in human malignancies, but the roles of microRNA (miR)-497 in human cervical cancer still remain unclear. Our aim was to analyze the clinicopathologic and prognostic significance of miR-497 in human cervical cancer and to investigate the effects of miR-497 on the malignant phenotype of cervical cancer cells. METHODS: First, we detected miR-497 expression in the HPV-16 immortalized cervical epithelial cell lines and 4 other cervical cancer cell lines (HeLa, Caski, SiHa, and HeLa-S3). Then the expression of miR-497 was analyzed in cervical cancer tissues and paired nontumor tissues, and its correlation with clinicopathologic features and survival was analyzed. Finally, the roles of miR-497 in regulation of tumor proliferation, apoptosis, migration, invasion, and target gene expression were further investigated. RESULTS: MiR-497 was downregulated in cervical cancer cells or tissues compared with HPV-16 immortalized cervical epithelial cell lines or the paired nontumor tissues. Also, the decrease in miR-497 correlated closely with the criteria of the International Federation of Gynaecology and Obstetrics stage and lymph node metastases in patients with cervical cancer. Multivariate Cox analysis showed that low miR-497 expression appeared to be an unfavorable prognostic factor. Transient forced expression of miR-497 decreased the growth and colony-formation capacity of HeLa and SiHa cells by inducing Caspase-3-dependent apoptosis. Forced expression of miR-497 suppressed the migration and invasiveness of cervical cancer cells. By computational miRNA target prediction and functional analysis, miR-497 was demonstrated to bind to the 3' untranslated regions of IGF-1R mRNA, and upregulation of miR-497 downregulated IGF-1R protein expression. Further investigation showed that small interfering RNA-mediated IGF-1R knockdown could mimic the effect of enforced miR-497 expression on the malignant phenotypes of cervical cancer cells. CONCLUSION: MiR-497 may be a potential prognostic marker and functions as a tumor suppressor in human cervical cancer by post transcriptionally targeting IGF-1R. PMID- 23453370 TI - Repeat surgery following breast conservation and intra-operative sentinel lymph node analysis for breast cancer. AB - INTRODUCTION: Intra-operative sentinel node analysis (IOA) for breast cancer reduces the need for a second operation by revealing metastasis intra operatively, allowing immediate axillary clearance. Critics argue that the number of patients deriving benefit is limited, as further surgery is often required for reasons other than nodal status. AIM: To identify the proportion of women avoiding further surgery by using IOA excluding those who require further surgery for reasons other than axillary node metastasis. PATIENTS AND METHODS: All patients undergoing sentinel node biopsy with IOA over one year were reviewed. Patient demographics, margin positivity, sentinel node metastasis, requirement for further surgery, and cavity shave involvement were analysed. RESULTS: 322 patients were analysed: 253 undergoing breast-conserving surgery [BCS] and 69 undergoing mastectomy). IOA revealed metastasis in 81 (25.2.%) patients [25 undergoing mastectomy and 56 undergoing BCS], who underwent immediate axillary clearance. 43 BCS patients (17%) did not require further surgery other than for sentinel node involvement. 39 patients required further oncological surgery: 16 excision of margins; 13 completion mastectomy; 6 excision of margins followed by mastectomy; 3 completion axillary clearance; and 1 excision of recurrence. 20.6% had involvement of any circumferential histological margin. Cavity shaves were performed in 28.5% patients at initial surgery, the majority of which were clear of malignancy. 20 mastectomy patients had concordant definitive histology, avoiding a second operation. In total, 19.6% of this cohort avoided a second operation through the use of IOA. DISCUSSION: Approximately 15% of patients undergoing breast conservation surgery for breast cancer require further surgery. However, a further 17% were saved subsequent surgery by utilising IOA, since they had immediate axillary clearance. When also considering patients undergoing mastectomy, this proportion is even higher. PMID- 23453371 TI - [Healthcare workers need more training in hand hygiene]. PMID- 23453372 TI - Value of three-dimensional contrast-enhanced ultrasound in the diagnosis of small adnexal masses. AB - The main purpose of this study was to determine whether three-dimensional contrast-enhanced ultrasound (3D-CEUS) can provide useful information to distinguish malignant from benign adnexal masses (<=4 cm). Forty-seven patients with 51 adnexal masses were examined with 3D-CEUS. The sonographic features of masses were analyzed. All diagnoses were confirmed by surgical pathology and long term follow-up results. The 51 masses included 43 benign and 8 malignant lesions. On 3D-CEUS images, benign lesions appeared as round structures formed by sparse and straight capillary vessels. Malignant lesions showed irregular stereo structures with dense and tortuous vascular distribution. A 3D-CEUS scoring system was established. There were no statistically significant differences in scores at each time point between the 20th and 70th seconds, and the area under the receiver operating characteristic curve for this time period was the largest (0.995). A cut-off score of 8 was established, with scores >=8 being suggestive of malignancy. The 3D-CEUS scoring system had a high sensitivity (100%) and specificity (98%). 3D-CEUS is likely to be the new tool to distinguish malignant from benign small adnexal masses and diagnose early ovarian cancer. PMID- 23453373 TI - Effect of velocity profile skewing on blood velocity and volume flow waveforms derived from maximum Doppler spectral velocity. AB - Given evidence that fully developed axisymmetric flow may be the exception rather than the rule, even in nominally straight arteries, maximum velocity (V(max)) can lie outside the Doppler sample volume (SV). The link between V(max) and derived quantities, such as volume flow (Q), may therefore be more complex than commonly thought. We performed idealized virtual Doppler ultrasound on data from image based computational fluid dynamics (CFD) models of the normal human carotid artery and investigated how velocity profile skewing and choice of sample volume affected V(max) waveforms and derived Q variables, considering common assumptions about velocity profile shape (i.e., Poiseuille or Womersley). Severe velocity profile skewing caused substantial errors in V(max) waveforms when using a small, centered SV, although peak V(max) was reliably detected; errors with a long SV covering the vessel diameter were orientation dependent but lower overall. Cycle averaged Q calculated from V(max) was typically within +/-15%, although substantial skewing and use of a small SV caused 10%-25% underestimation. Peak Q derived from Womersley's theory was generally accurate to within +/-10%. V(max) pulsatility and resistance indexes differed from Q-based values, although the Q based resistance index could be predicted reliably. Skewing introduced significant error into V(max)-derived Q waveforms, particularly during mid-to late systole. Our findings suggest that errors in the V(max) and Q waveforms related to velocity profile skewing and use of a small SV, or orientation dependent errors for a long SV, could limit their use in wave analysis or for constructing characteristic or patient-specific flow boundary conditions for model studies. PMID- 23453374 TI - Effect of high-intensity focused ultrasound on Enterococcus faecalis planktonic suspensions and biofilms. AB - In this study, the effect of high-intensity focused ultrasound (HIFU) on Enterococcus faecalis on both planktonic suspensions and biofilms was investigated. E. faecalis persist in secondary dental infections as biofilms. Glass-bottom Petri dishes with biofilms were centered at the focal point of the HIFU wave generated by a 250-kHz transducer. Specimens were subjected to HIFU exposure at different periods of 30, 60 and 120 s. The viable bacteria, removal effect and bacterial viability of biofilms attached to the Petri dish surface were studied by colony-forming units (CFUs), scanning electron microscopy and confocal microscopy, respectively. The removal and bactericidal effects of HIFU are dependent on the exposure time. A significant reduction in biofilm thickness and CFU was found with the increase in HIFU exposure. The removal or bactericidal effect of HIFU was more significant starting from 60 s of exposure. This study highlighted the potential application of HIFU as a novel method for root canal disinfection. PMID- 23453375 TI - Real-time ultrasound perfusion imaging in acute stroke: assessment of cerebral perfusion deficits related to arterial recanalization. AB - We investigated whether real-time ultrasound perfusion imaging (rt-UPI) is able to detect perfusion changes related to arterial recanalization in the acute phase of middle cerebral artery (MCA) stroke. Twenty-four patients with acute territorial MCA stroke were examined with rt-UPI and transcranial color-coded duplex ultrasound (TCCD). Ultrasound studies were consecutively performed within 24 h and 72-96 h after stroke onset. Real-time UPI parameters of bolus kinetics (time to peak, rt-TTP) and of refill kinetics (plateau A and slope beta of the exponential replenishment curve) were calculated from regions of interest of ischemic versus normal brain tissue; these parameters were compared between early and follow-up examinations in patients who recanalized. At the early examination, there was a delay of rt-TTP in patients with MCA occlusion (rt-TTP [s]: 13.09 +/- 3.21 vs. 10.16 +/- 2.6; p = 0.01) and a lower value of the refill parameter beta (beta [1/s]: 0.62 +/- 0.34 vs. 1.09 +/- 0.58; p = 0.01) in ischemic compared with normal brain tissue, whereas there were no differences of the parameters A and Axbeta. At follow-up, the delay of rt-TTP was reversible once recanalization of an underlying MCA obstruction was demonstrated: rt-TTP [s], 13.09 +/- 3.21 at 24 h versus 10.95 +/- 1.5 at 72-96 h (p = 0.03). Correspondingly, beta showed a higher slope than at the first examination: beta [1/s]: 0.55 +/- 0.29 at 24 h versus 0.71 +/- 0.27 at 72-96 h (p = 0.04). We conclude that real-time UPI can detect hemodynamic impairment in acute MCA occlusion and subsequent improvement following arterial recanalization. This offers the chance for bedside monitoring of the hemodynamic compromise (e.g. during therapeutic interventions such as systemic thrombolysis). PMID- 23453377 TI - Potential femoral head osteonecrosis model induced by high-intensity focused ultrasound. AB - Osteonecrosis of the femoral head is a common disease that can result in complex hip replacement. To evaluate potential treatments, a model that consistently creates osteonecrosis is needed. We studied and demonstrated the possibility of developing an osteonecrosis model using high-intensity focused ultrasound (HIFU) on canine femora in vitro. To achieve these goals, the temperature in the medullary cavity of the femoral head was measured. A phenomenological model was developed to fit the measured temperature variations with the HIFU parameters for similar HIFU experiments on femoral heads. The average temperature discrepancy between model and measured values was less than 0.83 degrees C. Histology confirmed that the temperature in the medullary cavity can be elevated to a level at which an acute thermal injury is created. HIFU has the potential to be used in a non-invasive model of osteonecrosis. PMID- 23453376 TI - The mechanical properties of ex vivo bovine and porcine crystalline lenses: age related changes and location-dependent variations. AB - The mechanical properties of ex vivo animal lenses from three groups were evaluated: old bovine (25-30 mo old, n = 4), young bovine (6 mo old, n = 4) and young porcine (6 mo old, n = 4) eye globes. We measured the dynamics of laser induced microbubbles created at different locations within the crystalline lenses. An impulsive acoustic radiation force was applied to the microbubble, and the microbubble displacements were measured using a custom-built high pulse repetition frequency ultrasound system. Based on the measured dynamics of the microbubbles, Young's moduli of bovine and porcine lens tissue in the vicinity of the microbubbles were reconstructed. Age-related changes and location-dependent variations in the Young's modulus of the lenses were observed. Near the center, the old bovine lenses had a Young's modulus approximately fivefold higher than that of young bovine and porcine lenses. The gradient of Young's modulus with respect to radial distance was observed in the lenses from three groups. PMID- 23453378 TI - Developmental impact and lesion maturation of histotripsy-mediated non-invasive tissue ablation in a fetal sheep model. AB - Non-invasive histotripsy therapy has previously been used to achieve precise fetal tissue ablation in a sheep model. To further assess the clinical viability of the technique, this study investigated potential effects of histotripsy therapy during the remaining gestation and its local impact on fetal development. Five ewes (six lambs) at 95-107 d of gestation were treated and allowed to complete the full gestation period of 150 d. A 1-MHz focused transducer was used to treat the fetal kidney and liver with 5-MUs pulses at 500-Hz repetition rates and 10- to 16-MPa peak negative pressures; ultrasound imaging provided real-time treatment guidance. The lambs were euthanized after delivery and treated organs were harvested. Samples were examined by magnetic resonance imaging and histopathologic analysis. These data were compared with results from four other ewes (four lambs) that underwent similar treatments but were sacrificed immediately after the procedure. The sheep tolerated the treatment well, and acute lesion samples displayed well-defined ablated regions characterized by the presence of fractionated tissue and hemorrhage. All fetuses that were allowed to continue gestation survived and were delivered at full term. The lambs were healthy on delivery, with no signs of external injury. A minor indentation was observed in each of the treated kidneys with minimal presence of fibrous tissue, while no discernible signs of lesions were detected in treated livers. In a sheep model, histotripsy-mediated fetal tissue ablation caused no acute or pregnancy related complications, supporting the potential safety and effectiveness of histotripsy therapy as a tool in fetal intervention procedures. PMID- 23453379 TI - Inter- and intra-operator reliability and repeatability of shear wave elastography in the liver: a study in healthy volunteers. AB - This study assessed the reproducibility of shear wave elastography (SWE) in the liver of healthy volunteers. Intra- and inter-operator reliability and repeatability were quantified in three different liver segments in a sample of 15 subjects, scanned during four independent sessions (two scans on day 1, two scans 1 wk later) by two operators. A total of 1440 measurements were made. Reproducibility was assessed using the intra-class correlation coefficient (ICC) and a repeated measures analysis of variance. The shear wave speed was measured and used to estimate Young's modulus using the Supersonics Imagine Aixplorer. The median Young's modulus measured through the inter-costal space was 5.55 +/- 0.74 kPa. The intra-operator reliability was better for same-day evaluations (ICC = 0.91) than the inter-operator reliability (ICC = 0.78). Intra-observer agreement decreased when scans were repeated on a different day. Inter-session repeatability was between 3.3% and 9.9% for intra-day repeated scans, compared with to 6.5%-12% for inter-day repeated scans. No significant difference was observed in subjects with a body mass index greater or less than 25 kg/m(2). PMID- 23453380 TI - Toward ultrasound molecular imaging with phase-change contrast agents: an in vitro proof of principle. AB - Phase-change contrast agents (PCCAs), which normally consist of nanoscale or microscale droplets of liquid perfluorocarbons in an encapsulating shell, can be triggered to undergo a phase transition to the highly echogenic gaseous state upon the input of sufficient acoustic energy. As a result of the subsequent volumetric expansion, a number of unique applications have emerged that are not possible with traditional ultrasound microbubble contrast agents. Although many studies have explored the therapeutic aspects of the PCCA platform, few have examined the potential of PCCAs for molecular imaging purposes. In this study, we demonstrate a PCCA-based platform for molecular imaging using alpha(v)beta(3) targeted nanoscale PCCAs composed of low-boiling-point perfluorocarbons. In vitro, nanoscale PCCAs adhered to target cells, could be activated and imaged with a clinical ultrasound system and produced a six-fold increase in image contrast compared with non-targeted control PCCAs and a greater than fifty-fold increase over baseline. Data suggest that low-boiling-point nanoscale PCCAs could enable future ultrasound-based molecular imaging techniques in both the vascular and extravascular spaces. PMID- 23453381 TI - Quantitative shear wave elastography in the evaluation of metastatic cervical lymph nodes. AB - Our aim was to compare the diagnostic performance of shear wave elastography (SWE) with that of gray-scale ultrasound (US) in differentiating metastatic from benign lymph nodes in patients with head and neck malignancies. Maximum shear elasticity modulus (maxSM) was measured on SWE. The reference standard was pathologic diagnosis after surgery. We examined 67 lymph nodes (34 metastatic, 33 benign) from 15 patients (8 men and 7 women; mean age, 54.2 years). The maxSM value was significantly higher for metastatic than benign lymph nodes (41.06 +/- 36.34 kPa vs. 14.22 +/- 4.19 kPa, p < 0.0001) at a cutoff level of 19.44 kPa. Accuracy, sensitivity and specificity were 94, 91 and 97%, respectively, for SWE, and 91, 88 and 94%, respectively, for gray-scale US. Multiple regression analysis showed that the maxSM value (r = 0.882) and gray-scale US criteria (r = 0.837) were independent variables. SWE may be a valuable quantitative reproducible method for characterizing cervical lymph nodes. PMID- 23453382 TI - Reversal of the detrimental effects of simulated microgravity on human osteoblasts by modified low intensity pulsed ultrasound. AB - Microgravity (MG) is known to induce bone loss in astronauts during long-duration space mission because of a lack of sufficient mechanical stimulation under MG. It has been demonstrated that mechanical signals are essential for maintaining cell viability and motility, and they possibly serve as a countermeasure to the catabolic effects of MG. The objective of this study was to examine the effects of high-frequency acoustic wave signals on osteoblasts in a simulated microgravity (SMG) environment (created using 1-D clinostat bioreactor) using a modified low-intensity pulsed ultrasound (mLIPUS). Specifically, we evaluated the hypothesis that osteoblasts (human fetal osteoblastic cell line) exposure to mLIPUS for 20 min/d at 30 mW/cm(2) will significantly reduce the detrimental effects of SMG. Effects of SMG with mLIPUS were analyzed using the MTS proliferation assay for proliferation, phalloidin for F-actin staining, Sirius red stain for collagen, and Alizarin red for mineralization. Our data showed that osteoblast exposure to SMG results in significant decreases in proliferation (~ 38% and ~ -44% on days 4 and 6, respectively; p < 0.01), collagen content (~ 22%; p < 0.05) and mineralization (~ -37%; p < 0.05) and actin stress fibers. In contrast, mLIPUS stimulation in SMG condition significantly increases the rate of proliferation (~24% by day 6; p < 0.05), collagen content (~52%; p < 0.05) and matrix mineralization (~25%; p < 0.001) along with restoring formation of actin stress fibers in the SMG-exposed osteoblasts. These data suggest that the acoustic wave can potentially be used as a countermeasure for disuse osteopenia. PMID- 23453384 TI - Potentially missed detection with screening mammography: does the quality of radiologist's interpretation vary by patient socioeconomic advantage/disadvantage? AB - PURPOSE: We examined whether quality of mammography interpretation as performed by the original reading radiologist varied by patient sociodemographic characteristics. METHODS: For 149 patients residing in Chicago and diagnosed in 2005-2008, we obtained the original index mammogram that detected the breast cancer and at least one prior mammogram that did not detect the cancer performed within 2 years of the index mammogram. A single breast imaging specialist performed a blinded review of the prior mammogram. Potentially missed detection (PMD) was defined as an actionable lesion seen during a blinded review of the prior mammogram that was in the same quadrant as the cancer on the index mammogram. RESULTS: Of 149 prior mammograms originally read as nonmalignant, 46% (N = 68) had a potentially detectable lesion. In unadjusted analyses, PMD was greater among minority patients (54% vs. 39%, P = .07) and for patients with incomes below $30,000 (65% vs. 36%, P < .01), less education (58% vs. 39%, P = .02), and lacking private health insurance (63% vs. 40%, P = .02). Likelihood ratio tests for the inclusion of socioeconomic variables in multivariable logistic regression models were highly significant (P <= .02). CONCLUSIONS: Disadvantaged socioeconomic status appears to be associated with PMD of breast cancer at mammography screening. PMID- 23453383 TI - The association between excess weight and comorbidity and self-rated health in the Italian population. AB - PURPOSE: To evaluate the association of obesity with comorbidity and with subjective health perception in a large sample representative of the Italian population and how the association differs by age and gender. METHODS: Cross sectional data were obtained from nine waves of the "Multipurpose Household Survey," conducted by the Italian National Institute of Statistics. Self-reported height and weight, six weight-associated diseases and self-rated health (SRH) were evaluated on 352,020 subjects aged 20 to 89 years. Comorbidity was defined as the presence of two or more diseases. RESULTS: The prevalence of comorbidity was significantly different between obese and normal weight subjects in all age categories. SRH was worse in obese subjects than in those of normal weight; this difference persisted, at least in females, into older ages. CONCLUSIONS: Obesity is associated with comorbidity and self-rated health; this association varies across ages and genders. The results found for obese subjects of a given age category were similar to (or worse than) those found for older normal weight subjects of the next age class. For comorbidity, this was true both in males and in females of all the considered age categories; for SRH, this was true in particular for females and younger males. PMID- 23453385 TI - Socioeconomic mobility in adulthood and cardiovascular disease mortality. AB - PURPOSE: Life course models suggest that socioeconomic mobility is associated with decreased cardiovascular disease (CVD) mortality risk. We examined adult socioeconomic mobility measured by household income in relation to CVD mortality risk among older adults. METHODS: Data from 2691 (n(men) = 1157; n(women) = 1534) Alameda County Study respondents in 1994 were used in these analyses. Latent growth curve models were used to identify income patterns from 1965 to 1994. RESULTS: Income patterns were categorized as consistently low, moderately low, increasing, and high. Bivariate models showed that membership in the increasing compared with high pattern was associated with decreased hazards of CVD mortality (hazard ratio, 0.15; 95% confidence interval [CI], 0.04-0.53). Controlling for age, race/ethnicity, marital status, and gender, respondents in the consistently low (HR, 2.1; 95% CI, 1.5-3.1) and high pattern (HR, 2.2; 95% CI, 1.1-4.2) had increased hazards of CVD mortality than those in the moderately low income group. CONCLUSIONS: Patterns of association were consistent with social mobility models of socioeconomic position, indicating lower CVD mortality risk for those with increasing or higher incomes. Future work should continue to investigate measures that capture the variation in social mobility over the life course, and how these patterns shape chronic disease risk in later life. PMID- 23453386 TI - The male-female health-survival paradox and sex differences in cohort life expectancy in Utah, Denmark, and Sweden 1850-1910. AB - PURPOSE: In Utah, the prevalence of unhealthy male risk behaviors are lower than in most other male populations, whereas women experience higher mortality risk because of higher fertility rates. Therefore, we hypothesize that the Utah sex differential in mortality would be small and less than in Sweden and Denmark. METHODS: Life tables from Utah, Denmark, and Sweden were used to calculate cohort life expectancies for men and women born in 1850-1910. RESULTS: The sex difference in cohort life expectancy was similar or larger in Utah when compared with Denmark and Sweden. The change over time in the sex differences in cohort life expectancy was approximately 2 years smaller for active Mormons in Utah than for other groups suggesting lifestyle as an important component for the overall change seen in cohort life expectancy. Sex differences in cohort life expectancy at the age of 50 years were similar for individuals actively affiliated with the Church of Jesus Christ of Latter-day Saints and for Denmark and Sweden. CONCLUSIONS: The hypothesis that a smaller sex difference in cohort life expectancies in Utah would be detected in relation to Denmark and Sweden was not supported. In Utah, the male-female differences in life expectancy remain substantial pointing toward biological mechanisms or other unmeasured risk factors. PMID- 23453387 TI - A link between physician-diagnosed ulcer and anxiety disorders among adults. AB - PURPOSE: Previous studies have suggested an association between mood and anxiety disorders and peptic ulcer, yet extant work suffers from methodologic limitations. Centrally, previous epidemiologic studies have relied exclusively on self-report of ulcer. This study aimed to investigate the relationship between DSM-IV depression and anxiety disorders and physician-diagnosed ulcer among adults in the general population. METHODS: Data were drawn from a population based, representative sample of 4181 adults aged 18 to 79 in the German National Health Interview and Examination Survey. RESULTS: Any anxiety disorder (odds ratio [OR], 2.6), panic disorder (OR, 5.2), panic attacks (OR, 3.8), and social phobia (OR, 3.3) were associated with increased likelihood of physician-diagnosed ulcer, compared with those without ulcer. There was evidence of a dose-response relationship between number of mental disorders and likelihood of current ulcer. CONCLUSIONS: These findings provide initial evidence of a link between anxiety disorders and physician-diagnosed ulcer among adults in the community. Future work, ideally taking into account Helicobacter pylori infection, stress, and mental health problems is needed to improve our understanding of the possible mechanisms that can provide insight into the etiology of peptic ulcers. PMID- 23453388 TI - Effect of eicosapentaenoic acid-derived prostaglandin E3 on intestinal epithelial barrier function. AB - Prostaglandins (PG) are inflammatory mediators derived from arachidonic or eicosapentaenoic acid giving rise to the 2-series or the 3-series prostanoids, respectively. Previously, we have observed that PGE2 disrupts epithelial barrier function. Considering the beneficial effect of fish oil consumption in intestinal inflammatory processes, the aim of this study was to assess the role of PGE3 on epithelial barrier function assessed from transepithelial electrical resistance and dextran fluxes in Caco-2 cells. The results indicate that PGE3 increased paracellular permeability (PP) to the same extent as PGE2, through the interaction with EP1 and EP4 receptors and with intracellular Ca(2+) and cAMP as the downstream targets. Moreover, we observed a redistribution of tight junction proteins, occludin and claudin-4. In conclusion, PGE3 is able to increase PP thus leading to reconsider the role of PGE2/PGE3 ratio in the beneficial effects of dietary fish oil supplementation in the disruption of barrier function. PMID- 23453389 TI - Development and numerical characterization of a new standing wave ultrasonic motor operating in the 30-40kHz frequency range. AB - The purpose of this research is to present a new design of standing-wave ultrasonic motor. This motor uses three piezoelectric actuating blocks which deform appropriately when powered up. The deformations of the blocks in ultrasonic range are internally amplified via the design of the motor by about 80 times and collectively yield an elliptical trajectory for the driving head of the motor. Finite Element Analysis using ANSYS was performed for both dynamic analysis and optimization of a prototype motor. The numerical results verified that at steady state, the motor can achieve vibrations in micro-meter level and the velocity can reach decimeter scale, satisfying the fast speed requirement as a positioning actuator. PMID- 23453391 TI - The effect of ergocalciferol on uremic pruritus severity: a randomized controlled trial. AB - OBJECTIVE: Hemodialysis (HD) patients have a high prevalence of pruritus. 25 Hydroxy vitamin D deficiency is common in this population and may play a role in its etiology. Because of this, we studied whether vitamin D2 treatment with ergocalciferol is effective for relief of uremic pruritus severity as measured by pruritus severity surveys. DESIGN, SETTING, AND SUBJECTS: In this double-blind, placebo-controlled, randomized trial, the effect of 12 weeks of ergocalciferol administration on uremic pruritus severity was evaluated. INTERVENTION: Fifty HD patients randomly received either ergocalciferol 50,000 international units (IU) or placebo once weekly for 12 weeks. MAIN OUTCOME MEASURE: Pruritus severity surveys were completed every 2 weeks by all patients starting from baseline until 12 weeks and serve as the main outcome variable. RESULTS: Twenty-five study participants were randomized to ergocalciferol therapy and 25 were randomized to placebo. At baseline, the only significant difference between the two groups was time on dialysis and white blood cell count. Both groups experienced a decrease in pruritus scores from the beginning to the end of study (percent change -38.9% in the treatment group vs. -47.5% in the placebo group). By intention to treat, the treatment * time effect was not statistically significant (F = 0.71, df = (1, 282), P = .34), indicating that the pruritus score was not significantly lower in the treatment group than the placebo group throughout the study. CONCLUSION: In conclusion, we did not find ergocalciferol to be effective for the treatment of uremic pruritus. PMID- 23453390 TI - Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. AB - Drugs that cause liver injury often 'stress' mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and nuclear factor erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Owing to adaptation, drugs alone rarely cause liver injury, with acetaminophen (APAP) being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause 'stressed' hepatocytes to become injured, leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as c-Jun N-terminal kinase (JNK) become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI. PMID- 23453392 TI - Autonomic function is associated with health-related quality of life in patients with end-stage renal disease: a case-control study. AB - OBJECTIVE: In the present study, we assessed the associations among fatigue, quality of life (QOL), clinical parameters, and body mass index (BMI) with autonomic function in end-stage renal disease (ESRD) patients undergoing hemodialysis as well as fatigue-free healthy subjects. DESIGN AND METHODS: This was a case-control study. This study compared autonomic function in ESRD patients (n = 192) to that of healthy subjects (n = 282) and evaluated its association with fatigue, QOL, and clinical parameters such as glucose, albumin, cholesterol, and BMI. Fatigue was evaluated by a recently established fatigue questionnaire and performance status, and QOL was evaluated with the kidney disease QOL questionnaire. With regards to autonomic function, spontaneous beat-to-beat variations were measured, according to time- (standard deviation of all normal a wave intervals [CVa-a%]) and frequency domains (low frequency [LF] power, high frequency [HF] power, and LF/HF ratio) with acceleration plethysmography. RESULTS: CVa-a%, LF power, HF power, and LF/HF ratio were significantly lower in ESRD patients than healthy subjects. There were significant inverse correlations between these factors and age in healthy subjects, but not in ESRD patients. Although the fatigue score was not associated with any autonomic parameters, ESRD patients with impaired performance status exhibited a significantly lower LF/HF ratio. Moreover, in ESRD patients, the LF/HF ratio was significantly and positively associated with several components of QOL, including physical functioning and role emotional, independent of other clinical parameters and BMI. CONCLUSIONS: Impaired autonomic function is significantly associated with fatigue and impaired QOL in dialysis patients. PMID- 23453393 TI - Low risk of apparent transmission of vancomycin-resistant Enterococci from bacteraemic patients to hospitalized contacts. AB - BACKGROUND: Vancomycin-resistant enterococci (VRE) are primarily opportunistic pathogens with incalculable clinical significance. In addition, the effectiveness of isolation in VRE is often not easily assessed. The goals of this study were to estimate the transmissibility of VRE of patients with VRE bacteraemia to other hospitalized patients and to document reliable epidemiologic data on all VRE cases in a large health care center. METHODS: A prospective survey on in-patients colonized and/or systemically infected with VRE was conducted at a 2,000-bed tertiary care university hospital in Germany. All roommates of VRE bacteraemia patients were analyzed. Pulsed-field gel electrophoresis was performed to assess clonal relatedness. RESULTS: 16,507 Screening tests were performed on 9,258 patients, of which 560 tested positive for VRE (6.1%). Nineteen patients also suffered from VRE bacteraemia, an incidence of 3.4%. This cohort was multimorbid and had high rates of exposure to external risk factors (eg, previous hospital stay prior to admission, 78.9%). The transmission rate to contacts was low (3.5%). Contact time of negative contacts was significantly lower than that of VRE-positive contacts (19.3 hours vs 72.0 hours, respectively, P < .006). CONCLUSION: VRE bacteraemia was found exclusively in multimorbid patients, transmission occurred seldom, and average contact time of positive contacts was very high. The risk of transmission of VRE from bacteraemic patients to hospitalized contacts is low. PMID- 23453394 TI - A new discrete element analysis method for predicting hip joint contact stresses. AB - Quantifying cartilage contact stress is paramount to understanding hip osteoarthritis. Discrete element analysis (DEA) is a computationally efficient method to estimate cartilage contact stresses. Previous applications of DEA have underestimated cartilage stresses and yielded unrealistic contact patterns because they assumed constant cartilage thickness and/or concentric joint geometry. The study objectives were to: (1) develop a DEA model of the hip joint with subject-specific bone and cartilage geometry, (2) validate the DEA model by comparing DEA predictions to those of a validated finite element analysis (FEA) model, and (3) verify both the DEA and FEA models with a linear-elastic boundary value problem. Springs representing cartilage in the DEA model were given lengths equivalent to the sum of acetabular and femoral cartilage thickness and gap distance in the FEA model. Material properties and boundary/loading conditions were equivalent. Walking, descending, and ascending stairs were simulated. Solution times for DEA and FEA models were ~7 s and ~65 min, respectively. Irregular, complex contact patterns predicted by DEA were in excellent agreement with FEA. DEA contact areas were 7.5%, 9.7% and 3.7% less than FEA for walking, descending stairs, and ascending stairs, respectively. DEA models predicted higher peak contact stresses (9.8-13.6 MPa) and average contact stresses (3.0-3.7 MPa) than FEA (6.2-9.8 and 2.0-2.5 MPa, respectively). DEA overestimated stresses due to the absence of the Poisson's effect and a direct contact interface between cartilage layers. Nevertheless, DEA predicted realistic contact patterns when subject-specific bone geometry and cartilage thickness were used. This DEA method may have application as an alternative to FEA for pre-operative planning of joint preserving surgery such as acetabular reorientation during peri-acetabular osteotomy. PMID- 23453395 TI - The effects of confluency on cell mechanical properties. AB - Mechanical properties of cells depend on various external and internal factors, like substrate stiffness and surface modifications, cell ageing and disease state. Some other currently unknown factors may exist. In this study we used force spectroscopy by AFM, confocal microscopy and flow cytometry to investigate the difference between single non-confluent and confluent (in monolayer) Vero cells. In all cases the stiffness values were fitted by log-normal rather than normal distribution. Log-normal distribution was also found for an amount of cortical actin in cells by flow cytometry. Cells in the monolayer were characterized by a significantly lower (1.4-1.7 times) Young's modulus and amount of cortical actin than in either of the single non-confluent cells or cells migrating in the experimental wound. Young's modulus as a function of indentation speed followed a weak power law for all the studied cell states, while the value of the exponent was higher for cells growing in monolayer. These results show that intercellular contacts and cell motile state significantly influence the cell mechanical properties. PMID- 23453396 TI - Myoelectric stimulation on peroneal muscles with electrodes of the muscle belly size attached to the upper shank gives the best effect in resisting simulated ankle sprain motion. AB - Ankle sprain is a common sports related injury that may be caused by incorrect positioning of the foot prior to and at initial contact during landing from a jump or gait. Furthermore a delayed reaction of the peroneal muscle may also contribute to the injury mechanism. A recent study demonstrated that myoelectric stimulation of the peroneal muscles within 15 ms of a simulated inversion event would significantly resist an ankle spraining motion. This study further investigated its effect with three different electrode sizes and three different lateral shank attachment positions. Twelve male subjects with healthy ankles performed simulated ankle supination spraining motion on a pair of mechanical sprain simulators. A pair of electrodes of one of the three sizes (large, medium, small) was attached to one of the three positions (upper 1/4, middle, lower 1/4) along the lateral shank to deliver an electrical signal of 130 V for 0.5s when the sprain simulator started. Ankle kinematics data were collected by a tri-axial gyroscope motion sensor and the peak inward heel tilting velocity was obtained to represent the effect in resisting the simulated ankle spraining motion. Repeated measures one-way analysis of variance was performed and showed a significant drop from 273.3 (control, no stimulation) to 215.8 deg/s (21%) when small electrodes were attached to the upper 1/4 position. Decrease was found in all other conditions but the drops (11-18%) were not statistically significant. The small electrodes used in this study fitted the width of the peroneal muscle belly at the upper 1/4 position, so the electrical current may have well flowed to the motor points of the muscles to initiate quick contraction. PMID- 23453397 TI - 13C metabolic flux analysis: optimal design of isotopic labeling experiments. AB - Measuring fluxes by 13C metabolic flux analysis (13C-MFA) has become a key activity in chemical and pharmaceutical biotechnology. Optimal design of isotopic labeling experiments is of central importance to 13C-MFA as it determines the precision with which fluxes can be estimated. Traditional methods for selecting isotopic tracers and labeling measurements did not fully utilize the power of 13C MFA. Recently, new approaches were developed for optimal design of isotopic labeling experiments based on parallel labeling experiments and algorithms for rational selection of tracers. In addition, advanced isotopic labeling measurements were developed based on tandem mass spectrometry. Combined, these approaches can dramatically improve the quality of 13C-MFA results with important applications in metabolic engineering and biotechnology. PMID- 23453398 TI - Network, nodes and nexus: systems approach to multitarget therapeutics. AB - Systems biology is revealing multiple layers of regulatory networks that manifest spatiotemporal variations. Since genes and environment also influence the emergent property of a cell, the biological output requires dynamic understanding of various molecular circuitries. The metabolic networks continually adapt and evolve to cope with the changing milieu of the system, which could also include infection by another organism. Such perturbations of the functional networks can result in disease phenotypes, for instance tuberculosis and cancer. In order to develop effective therapeutics, it is important to determine the disease progression profiles of complex disorders that can reveal dynamic aspects and to develop mutitarget systemic therapies that can help overcome pathway adaptations and redundancy. PMID- 23453399 TI - [Recommendations for making decisions when parents refuse to vaccinate their children: ethical analysis]. AB - Vaccinating children is the most effective primary prevention activity and many lives have been saved due to vaccines. Anti-vaccine movements have spread doubts about the safety and effectiveness of childhood vaccines, leading to some parents refusing to vaccinate their children. This refusal raises a conflict of values between the right of parents to the upbringing of their children according to their beliefs and justice, putting the immunity of the group at risk. In Spain, the law protects this ability for parents to decide not to comply with the official vaccine program. Pediatricians play an essential role in a parent's decision, and must provide accurate information about vaccination. It is necessary to explore The values of the parents, their concerns need to be empathetically examined, in order to reach an agreement. Respect for freedom does not exempt us from using discussion and persuasion to achieve attitudes and healthy choices for children. Our commitment to responsability promotion is essential for maintaining high vaccination levels that protect the health of children. PMID- 23453401 TI - Quantitative analysis of in vivo confocal microscopy images: a review. AB - In vivo confocal microscopy (IVCM) is a non-invasive method of examining the living human cornea. The recent trend towards quantitative studies using IVCM has led to the development of a variety of methods for quantifying image parameters. When selecting IVCM images for quantitative analysis, it is important to be consistent regarding the location, depth, and quality of images. All images should be de-identified, randomized, and calibrated prior to analysis. Numerous image analysis software are available, each with their own advantages and disadvantages. Criteria for analyzing corneal epithelium, sub-basal nerves, keratocytes, endothelium, and immune/inflammatory cells have been developed, although there is inconsistency among research groups regarding parameter definition. The quantification of stromal nerve parameters, however, remains a challenge. Most studies report lower inter-observer repeatability compared with intra-observer repeatability, and observer experience is known to be an important factor. Standardization of IVCM image analysis through the use of a reading center would be crucial for any future large, multi-centre clinical trials using IVCM. PMID- 23453400 TI - Down but not out. AB - A 20-year-old Hispanic man with Down syndrome presented with progressively worsening headache, fluctuating decreased vision, and bilateral optic disk edema. Magnetic resonance imaging of the head showed an empty sella, and magnetic resonance venography showed thrombosis of left transverse and sigmoid sinuses. Catheter angiography angiogram showed a dural arteriovenous fistula in the wall of left transverse and sigmoid sinuses. The patient underwent Onyx endovascular embolization of the fistula, resulting in its angiographic obliteration, followed by resolution of his clinical signs and symptoms. PMID- 23453402 TI - Economic evaluation of fulvestrant 500 mg versus generic nonsteroidal aromatase inhibitors in patients with advanced breast cancer in the United Kingdom. AB - OBJECTIVE: The goal of this study was to examine the cost-effectiveness of fulvestrant 500 mg for the treatment of first progression or recurrence of advanced breast cancer in postmenopausal patients compared with generic nonsteroidal aromatase inhibitors (anastrozole and letrozole) in the United Kingdom. METHODS: A cost-utility model based on a time-in-state approach was used. Clinical effectiveness estimates used in the model were derived from a network meta-analysis for overall survival and serious adverse events. Overall survival was extrapolated by using a Weibull distribution, and progression-free survival (PFS) estimates were derived from a simultaneous network meta-analysis and extrapolation of PFS curves by using the log-normal distribution. Data on resource use, costs, and utilities were based on various sources, including expert opinion and published data. To explore uncertainty, 1-way and probability sensitivity analyses were conducted. The study was conducted from the perspective of the UK National Health Service, and costs are reported in 2010/2011 British pounds. RESULTS: The base case incremental cost-effectiveness ratio (ICER) for fulvestrant 500 mg versus letrozole was L34,528, with incremental costs of L14,383 and an incremental quality-adjusted life-year (QALY) of 0.417. Extended dominance occurred for anastrozole because the ICER for anastrozole versus letrozole was higher than the ICER for fulvestrant 500 mg versus anastrozole. Based on the probability sensitivity analyses, the probability that fulvestrant 500 mg was the most cost-effective treatment option was 3%, 20%, and 53% at a willingness-to-pay threshold of L20,000, L30,000, and L40,000 per QALY, respectively. According to the 1-way sensitivity analyses, the PFS estimates were the key drivers of the model results. CONCLUSIONS: Although fulvestrant 500 mg was found not to be a cost-effective option at a standard UK threshold of L20,000 to L30,000 per QALY, it may be relevant to apply a higher threshold due to the poor prognosis of patients with advanced breast cancer and the limited number of hormonal treatment options available for this stage of treatment. Certain subgroups may also benefit from fulvestrant as a treatment option; however, limited data are currently available to identify these subgroups. PMID- 23453403 TI - Impact of local administration of liposome bupivacaine for postsurgical analgesia on wound healing: a review of data from ten prospective, controlled clinical studies. AB - BACKGROUND: Liposome bupivacaine is a liposomal formulation that allows delivery of bupivacaine for 96 hours with a single local administration. It is indicated for the management of postsurgical pain. OBJECTIVE: This retrospective review of 10 clinical trials assessed the potential impact of local anesthetics on wound healing and chondrolysis. Various doses of liposome bupivacaine and bupivacaine hydrochloride (HCl) were evaluated. METHODS: Primary inclusion criteria across the 10 Phase 2 and Phase 3 randomized, double-blind studies required that patients be >=18 years of age at the screening visit and scheduled to undergo the specified surgical procedure in each study (inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, or bunionectomy). Key exclusion criteria were: a history of clinically significant medical conditions (including cardiovascular, hepatic, renal, neurologic, psychiatric, or metabolic disease) or laboratory results that indicated an increased vulnerability to the study drugs and/or procedures; medical condition(s) or concurrent surgery that may have required analgesic treatment in the postoperative period for pain that was not strictly related to the study surgery; and/or any clinically significant event or condition discovered during surgery that could have complicated the patient's postsurgical course. Assessments included the clinician's overall satisfaction with the patient's wound healing, wound status (erythema, drainage, edema, and induration), and wound scarring. Adverse events (AEs) potentially manifesting as wound complications and local AEs were also assessed. RESULTS: In total, 823 patients received liposome bupivacaine at doses ranging from 66 to 532 mg across the 5 different surgical settings; 446 patients received bupivacaine HCl (75-200 mg), and 190 patients received placebo. Few studies showed statistically significant differences between liposome bupivacaine and the comparator (bupivacaine HCl or placebo) with regard to the clinician's overall satisfaction with patient wound healing; the incidence of erythema, drainage, edema, and induration; and wound scarring. The incidences of local AEs were similar between treatments, ranging from 9% to 20% with liposome bupivacaine across the studies compared with 8% to 19% with bupivacaine HCl. CONCLUSIONS: Liposome bupivacaine given locally at the surgical wound site appeared to have no clinically evident impact on wound or bone healing at doses up to 532 mg across different surgical models. The wound-healing profile of liposome bupivacaine was similar to that of bupivacaine HCl. PMID- 23453404 TI - Effects of hepatic impairment on the pharmacokinetics of everolimus: a single dose, open-label, parallel-group study. AB - BACKGROUND: Although the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. OBJECTIVE: The goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. METHODS: A multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0-infinity geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. RESULTS: Thirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0-infinity for patients with mild, moderate, and severe hepatic impairment increased by 1.60 , 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 MUmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, <=1 day in duration, and not everolimus related. CONCLUSIONS: Everolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591. PMID- 23453405 TI - Development and initial assessment of the medication user self-evaluation (MUSE) tool. AB - BACKGROUND: Using patient-reported data to supplement claims-based indicators may be helpful in identifying Medicare beneficiaries likely to benefit from medication therapy management (MTM) services. OBJECTIVE: Our objective was to develop and initially assess a patient medication user self-evaluation (MUSE) tool to identify Medicare Part D beneficiaries who would benefit from a comprehensive medication review. METHODS: A random sample of 225 patient medication profiles was created from a survey of Medicare beneficiaries; the survey also included demographic characteristics, responses to adherence questions, and reported symptoms. Three clinical pharmacists used the patient profiles to make judgments regarding the likelihood (low, moderate, or high) that each patient would benefit from an MTM visit in the next 3 months. A total of 150 cases were used for model calibration, and 75 were used for validation. Ordinal logistic regression models were fit to predict the likelihood of benefit from an MTM visit by using different combinations of potential MUSE items. Final model selection was based on the Akaike information criterion and the percent agreement between model prediction and expert judgments in the validation data. Measures considered for inclusion in the MUSE tool were related to medication use, medical conditions, and health care utilization. RESULTS: The final MUSE items incorporated number of medications, number of physicians, number of pharmacies, number of hospitalizations in the past 6 months, having forgotten to take medications, cost-related problems, and number of medical conditions. CONCLUSION: The 7-item MUSE tool could be used in targeting MTM services, such as comprehensive medication reviews, among Medicare beneficiaries. PMID- 23453406 TI - Effect of azithromycin on anticoagulation-related outcomes in geriatric patients receiving warfarin. AB - BACKGROUND: Warfarin is known to have multiple pharmacokinetic and pharmacodynamic interactions. Of the macrolide family, erythromycin and clarithromycin have been shown to interact with warfarin, leading to an elevated international normalized ratio (INR). The incidence of overanticoagulation in patients prescribed azithromycin stabilized on a warfarin regimen is controversial. OBJECTIVES: The primary objective was to assess warfarin dosage adjustments and their effect on the INR after treatment with azithromycin. The secondary objective was to examine the occurrence of hemorrhage in patients taking warfarin who received azithromycin. METHODS: This retrospective review included 100 patients from the Western New York Veterans Affairs Healthcare System aged >=65 years who received a prescription for azithromycin and warfarin between January 1, 2004, and December 31, 2009. The inclusion criteria consisted of a stable warfarin dose (2 INR values within 0.2 of the therapeutic range and the last INR determined <=30 days before the introduction of azithromycin) and no medication changes in the 30 days before azithromycin therapy initiation. A repeated INR was determined 3 to 30 days after azithromycin therapy was initiated. Patients were excluded if they discontinued warfarin use, had a history of hemorrhage, or were taking antiplatelets, anti-inflammatory agents, or any other antibiotics. RESULTS: The impact on the INR was analyzed using a paired samples t test comparing INR values and warfarin doses before and after azithromycin exposure. There was a significant change in the INR between the 2 groups (before vs after azithromycin exposure, P < 0.001). This change was clinically significant given that the values before and after exposure to azithromycin lead to a decrease in warfarin from a mean weekly dose of 30 mg to 29.2 mg (P = 0.001). However, changes in the INR did not result in vitamin K administration or adverse bleeding events. CONCLUSIONS: The addition of azithromycin to a stable warfarin regimen resulted in a significant change in the INR and warfarin dosage alteration without an increase in bleeding. PMID- 23453407 TI - Re: Working together in placing the long term interests of the child at heart of the DSD evaluation, by Ellie Magritte, July 13, 2012. PMID- 23453408 TI - Clinical and microbiological observational study on AmpC beta-lactamase-producing Enterobacteriaceae in a hospital of Nepal. AB - Limited information is available regarding AmpC beta-lactamase (ABL)-producing Enterobacteriaceae compared to extended-spectrum beta-lactamase-producing enterobacteria. Since ABL-producing organisms are often resistant to multiple antimicrobial agents, therapeutic options against these pathogens are limited. Among 230 clinical Enterobacteriaceae isolates, 64 (27.8%) were found to produce ABL in our study. Escherichia coli (83.9%) was a predominant pathogen, followed by Citrobacter freundii (5.2%). A significant proportion of ABL-producing isolates (81.3%) were found to be multidrug resistant against commonly used antibiotics. Univariate analysis showed that prior history of taking antibiotics (odds ratio [OR], 5.278; confidence interval [CI], 2.838-9.817; p<0.001) and being inpatients (OR, 4.587; CI, 2.132-9.9; p<0.001) were associated with ABL positivity. Regular antimicrobial resistance surveillance for ABL-producing Enterobacteriaceae is warranted for proper antimicrobial treatment strategy and policy making due to ABL-positive infections. PMID- 23453409 TI - Congenitally transmitted visceral leishmaniasis: report of two Brazilian human cases. AB - Visceral leishmaniasis is a relevant public health problem worldwide. Most of the reported cases in Latin America are from Brazil. Herein we report two human cases of congenitally transmitted visceral leishmaniasis in two patients who developed symptoms during pregnancy. The diagnosis was made by visual examination of Leishmania parasites in bone marrow aspirates of the mothers and by detecting parasite kDNA in bone marrow samples of the newborn children using polymerase chain reaction. PMID- 23453410 TI - Co-infection cases of human common respiratory viruses in Beijing, 2010-2012. PMID- 23453411 TI - Successful use of gentamycin as an antibiotic prophylaxis regimen to reduce the rate of healthcare-associated infections after renal transplantation. AB - At our institution, we observed an increase in the incidence of healthcare associated infections (HAI) due to Gram-negative bacilli, including three cases of carbapenem-resistant Klebsiella pneumoniae, among patients who underwent renal transplantation. In addition to strengthening infection control measures, we chose to add gentamycin to the antibiotic prophylaxis regimen of patients undergoing renal transplantation. We assessed the number of HAI occurring within 30 days of renal transplantation during two time periods: (1) the pre intervention period, between September 2009 and June 2010, and (2) the post intervention period, between July 2010 and April 2011. The intervention consisted of the addition of gentamycin to the surgical antibiotic prophylaxis regimen. The percentage of patients with HAIs was 31% lower during the post-intervention period (p=0.03), with the greatest reductions observed for urinary tract infections (p=0.024). Carbapenem-resistant K. pneumoniae was not isolated during this period. The investigated patients did not exhibit worsening renal function. Further studies are needed to assess antibiotic prophylaxis in renal transplantation patients at institutions where there is a high prevalence of multidrug-resistant Gram-negative bacteria. PMID- 23453412 TI - Strong correlation by ultrasonography of hepatomegaly and the presence of co infection in HIV/HCV cirrhotic patients. AB - OBJECTIVES: Progression of hepatic fibrosis is accelerated in patients co infected with human immunodeficiency virus and hepatitis C virus compared to hepatitis C virus mono-infected patients. This study aimed to compare ultrasound features and selected clinical and biochemical variables between patients with human immunodeficiency virus/hepatitis C virus co-infection (n=16) versus hepatitis C virus mono-infection (n=16). METHODS: Each patient underwent abdominal ultrasound, and a specific evaluation was performed in order to detect findings consistent with chronic liver disease. Characterization of spleen size, liver structural pattern, diameter of the portal, spleen, and mesenteric veins was based on classical ultrasound parameters. Propensity score was used for control of selection bias and performed using binary logistic regression to generate a score for each patient. The Fisher and Mann-Whitney tests were used to evaluate categorical variables and continuous variables, respectively. RESULTS: On univariate analysis right hepatic lobe size was larger in human immunodeficiency virus/hepatitis C virus patients (157.06 +/- 17.56 mm) compared to hepatitis C virus mono-infected patients (134.94 +/- 16.95 mm) (p=0.0011). The left hepatic lobe was also significantly larger in human immunodeficiency virus/hepatitis C virus patients (115.88 +/- 22.69 mm) versus hepatitis C virus mono-infected patients (95.06 +/- 24.18 mm) (p=0.0177). Also, there was a strong correlation between hepatomegaly and co-infection (p=0.005). CONCLUSION: Human immunodeficiency virus infection was the primary variable influencing liver enlargement in this population. Hepatomegaly on ultrasound was more common among cirrhotic human immunodeficiency virus/hepatitis C virus co-infected patients than among cirrhotic hepatitis C virus mono-infected patients. This aspect is very important in the management of human immunodeficiency virus/hepatitis C virus co-infected patients, because screening for hepatocellular carcinoma is necessary in this population. PMID- 23453413 TI - Clinical implications of vancomycin susceptibility testing in Staphylococcus aureus. PMID- 23453414 TI - A comparative analysis between survivors and nonsurvivors patients treated with tigecycline. PMID- 23453415 TI - Immunoglobulin levels, cytology and microbiologic investigations of broncho alveolar lavage in children with cystic fibrosis. PMID- 23453416 TI - Multidrug resistant tuberculosis versus non-tuberculous mycobacterial infections: a CT-scan challenge. AB - INTRODUCTION: Clinical, laboratory and imaging findings in patients with multidrug resistant-tuberculosis (MDR-TB) and non-tuberculosis mycobacterium (NTM) are similar, and the majority of these patients present with positive smear for Acid Fast Bacilli (ADB) and no response to first line anti-TB treatment, so sputum culture and PCR are necessary, especially in NTM. OBJECTIVE: In this study we evaluate more details of imaging findings to help earlier diagnosis of pathogens. MATERIALS AND METHODS: 66 patients with positive smear for AFB and no response to first line anti-TB drugs were divided into two groups by PCR and culture: MDR-TB (43 patients) and NTM (23 patients). Age, sex, history of anti-TB treatment, smoking and CT-scan findings (parenchymal, pleural and mediastinal variables) by details and lobar distribution were analyzed. RESULTS: Mean age of NTM patients was slightly higher (52 versus 45) and there is no significant difference in sex and smoking. In MDR-TB group, history of anti-TB treatment and evidence of chronic pulmonary disease such as calcified and fibrodestructed parenchyma, volume loss and pleural thickening were higher significantly. Cavities in MDR-TB were thick-wall in the background of consolidation, while NTM cavities were more thin-walled with adjacent satellite nodules in same segment or lobe. Prevalence of bronchiectasis was similar in both groups, while bronchiectasis in MDR-TB group was in fibrobronchiectatic background in upper lobes, and in NTM group the distribution was more uniform with slightly middle lobes predominance. Prevalence and distribution of nodular infiltrations were similar more in Tree in Buds and scattered pattern. Calcified or non-calcified lymph nodes and also pleural changes were more frequent in MDR-TB but prevalence of lymphadenopathy was mildly higher in NTM. CONCLUSION: A check-list with multiple variables is helpful for differentiation between the two groups. PMID- 23453417 TI - The clinical features and outcomes of acute liver failure associated with dengue infection in adults: a case series. AB - OBJECTIVE: To describe the clinical manifestations and outcome of acute liver failure (ALF) associated with dengue viral infection, a rare but severe complication. METHODS: One hundred and fifty five consecutive patients with ALF admitted to the national liver centre from 2001 to 2009 were reviewed retrospectively. Eight cases due to dengue infection were identified and their clinical characteristics are described. RESULTS: All patients had severe dengue with one dengue shock syndrome. The median (minimum, maximum) age was 33.5 (17, 47) years with 50% female. The median (minimum, maximum) duration from the onset of fever to development of ALF was 7.5 (5, 13) days and the maximum hepatic encephalopathy (HE) grade were III in five patients and II in three patients. Three patients had systemic inflammatory responses (SIRS) on admission and were in grade III HE. The presence of SIRS on admission was associated with higher grade of HE and its development during the course of hospitalization was associated with worsening HE grade. The hepatitis was characterized by marked elevations in: alanine transaminase [median admission 1140.5 u/L (639, 4161); median peak 2487 u/L (998, 5181)], serum bilirubin [median admission 29 MUmol/L (23, 291); median peak 127 MUmol/L (72, 592)], and prothrombin time [median admission 16.8s (15.3, 26.2); median peak 22s (15.3, 40.7)]. The survival rate with standard medical therapy alone was 100%. CONCLUSIONS: Dengue associated ALF manifest about one week after the onset of fever with severe hepatitis and encephalopathy. In our experience, the outcome with standard medical therapy alone is excellent. PMID- 23453418 TI - Health issues among nurses in Taiwanese hospitals: National survey. AB - BACKGROUND: Few, if any, studies have compared the health issues of nurses working in different hospital settings. The objective of this study was to compare the health status and work-related health hazards among nurses working in different hospital units in Taiwan. METHODS: This study was a cross-sectional survey. The study participants were 21,095 full-time employees with a professional background in nursing, working at 100 hospitals across Taiwan. The study participants responded to a structured questionnaire from May to July, 2011. RESULTS: After adjustment for age, sex, educational level, accredited hospital level, and certification as a health promoting hospital, nurses who worked in administration and in outpatient clinics reported better overall health than nurses who worked in operating rooms/delivery rooms, and these nurses reported better overall health than nurses who worked in emergency rooms/intensive care units and general wards. Depressed mood followed the same trend. Nurses who worked in the operating rooms/delivery rooms, wards, and emergency rooms/intensive care units were at higher risk for occupational incidents than nurses who worked in outpatient clinics and administration. The most prevalent health hazards among nurses were low back pain, sprained/strained muscles, cuts, and verbal or sexual harassment/violence. CONCLUSIONS: Nurses who worked in emergency rooms/intensive care units and in wards had worse health and more depressed moods than nurses in other hospital units. Work-related health hazards were common and varied among nurses working in different hospital units. Worksite-based health promotion programs should take these differences into consideration to tailor wellness programs for nurses working in different hospital settings. PMID- 23453419 TI - Timing of curative treatment for prostate cancer: a systematic review. AB - CONTEXT: Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa). OBJECTIVE: To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes. EVIDENCE ACQUISITION: A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded. EVIDENCE SYNTHESIS: Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5-9 mo delay in higher risk patients (respectively defined as any with T >= 2b, prostate-specific antigen >10, Gleason score >6, >34-50% positive cores; or D'Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias. CONCLUSIONS: Treatment delay of several months or even years does not appear to affect outcomes of men with low risk PCa. Limited data suggest treatment delay may have an impact on men with non low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified. PMID- 23453420 TI - Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. AB - BACKGROUND: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) is associated with decreased insulin sensitivity and increased diabetes risk among nondiabetic men. Few data are available about the effects of ADT on diabetes control among men with diabetes. OBJECTIVE: We examined care for men who had diabetes at the time of PCa diagnosis to assess the effect of ADT on diabetes control, as measured by hemoglobin A1c (HbA1c) levels and the intensification of diabetes pharmacotherapy. DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study using US Department of Veterans Affairs registry data and administrative data to assess HbA1c levels and intensification of diabetes pharmacotherapy among 2237 pairs of propensity-matched men with PCa and diabetes who were or were not treated with ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We calculated the difference in difference of HbA1c levels at baseline and at 1 and 2 yr in the two groups, compared using a paired Student t test. We used a Cox proportional hazards model to estimate time to intensification of diabetes pharmacotherapy. RESULTS AND LIMITATIONS: The mean HbA1c at baseline was 7.24 (standard error [SE]: 0.05) for the ADT group and 7.24 (SE: 0.04) for the no ADT group. HbA1c increased at 1 yr for men treated with ADT to 7.38 (SE: 0.04) and decreased among men not treated with ADT to 7.14 (SE: 0.04), for a difference in differences of +0.24 (p=0.008). Results were similar at 2 yr (p=0.03). The worsening HbA1c control occurred despite ADT being associated with an increased hazard of addition of diabetes medication (adjusted hazard ratio: 1.20; 95% confidence interval, 1.09-1.32). The limitation of this study was that it was observational and relied on administrative data. CONCLUSIONS: ADT is associated with worsening of diabetes control and increases in HbA1c levels despite the use of additional diabetes medications. PMID- 23453421 TI - Indium-111-labeled girentuximab immunoSPECT as a diagnostic tool in clear cell renal cell carcinoma. AB - BACKGROUND: Improved and more frequent radiologic evaluation has resulted in increased identification of renal masses of unknown origin, which frequently pose a diagnostic dilemma for urologists. OBJECTIVE: Carbonic anhydrase IX (CAIX) is an antigen ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). The specific and high level of expression in ccRCC makes CAIX an excellent target for imaging ccRCC lesions. We present our experience with immuno-single-photon emission computed tomography (immunoSPECT) imaging with the indium-111 ((111)In) labeled anti-CAIX antibody girentuximab in patients presenting with either a primary renal tumor or a history of ccRCC and lesions suspect for metastases during follow-up. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine patients received 100-200 MBq (111)In-labeled girentuximab. Whole-body and single photon emission computed tomography (SPECT) images were acquired after 4-7 d. INTERVENTION: Injection with (111)In-girentuximab and image acquisition after 4-7 d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Accuracy of (111)In girentuximab immunoSPECT. RESULTS AND LIMITATIONS: Distinct uptake of (111)In girentuximab was seen in 16 of 22 patients presenting with a renal mass. All renal masses proven to be ccRCC after resection (n=15) were detected with (111)In girentuximab. Suspect lesions of six patients showed no uptake of (111)In girentuximab. In these patients, ccRCC was not found, nor progression occurred. Seven patients with a history of ccRCC and possible metastatic lesions on follow up computed tomography scans were imaged with (111)In-girentuximab. In four of these patients, the lesions showed preferential uptake of (111)In-girentuximab and local or systemic treatment was initiated. In three other cases, no (111)In girentuximab targeting was seen. During follow-up of these three patients, one showed progression, for which systemic treatment was started. In the two other patients, no progression occurred, suggesting a benign nature. CONCLUSIONS: (111)In-girentuximab immunoSPECT can be used to detect ccRCC lesions in patients with a primary renal mass and to clarify the nature of lesions suspect for metastases in patients with a history of ccRCC. PMID- 23453423 TI - Determinants of food label use among supermarket shoppers: a Singaporean perspective. AB - OBJECTIVE: Examining factors influencing food label use among Singapore's supermarket shoppers using the Theory of Planned Behavior. DESIGN: A point-of purchase survey among general shoppers in 2 supermarkets. SETTING: Singapore, a country whose population is exposed to a wide range of food labeling formats because of the import-dependent nature of the food industry. PARTICIPANTS: A total of 200 shoppers (Chinese [75.5%], Malays [8.5%], and Indians [7.0%]) participated in the survey. MAIN OUTCOME MEASURES: Independent variables composed of attitudes and subjective norms (both 5-point Likert); perceived behavioral control and diet-health concern (both 5-point semantic differential); and knowledge (18-item index). Dependent variables were intention to use food labels (5-point differential scale) and actual use of food labels (19-item index). ANALYSIS: Data were analyzed using descriptive statistics, mean analysis, and multivariate linear regression. RESULTS: Low levels of knowledge and health literacy were found. Attitudes, subjective norms, and behavioral control differed significantly by age and ethnicity. Subjective norms and diet-health concern were significant predictors of intention to use food labels. CONCLUSIONS AND IMPLICATIONS: Lack of knowledge but positive attitudes toward food labels make Singapore's consumers vulnerable to misusing or being misled by food label information. Demographic differences demonstrate the need to develop targeted educational interventions and enhance awareness of and ability to use food labels. PMID- 23453424 TI - Adverse events reported in randomized clinical trials of drug therapies: the information is still insufficient. PMID- 23453425 TI - [Resected non-small cell bronchogenic carcinoma stage pIIIA-N2. Which patients will benefit most from adjuvant therapy?]. AB - BACKGROUND: Controversy persists as regards the indications and results of surgery in the treatment of patients with stage pIIIA-N2 non-small cell lung cancer (NSCLC). The objective of this study was to analyze the overall survival of a multicentre series of these patients and the role of adjuvant treatment, looking for factors that may define subgroups of patients with an increased benefit from this treatment. METHODS: A retrospective study was conducted on 287 patients, with stage pIIIA-N2 NSCLC subjected to complete resection, taken from a multi-institutional database of 2.994 prospectively collected consecutive patients who underwent surgery for lung cancer. Adjuvant treatment was administered in 238 cases (82.9%). Analyses were made of the age, gender, histological type, administration of induction and adjuvant chemotherapy and/or radiation therapy treatments. RESULTS: The 5-year survival was 24%, with a median survival of 22 months. Survival was 26.5% among patients receiving with adjuvant treatment, versus 10.7% for those without it (P=.069). Age modified the effect of adjuvant treatment on survival (interaction P=.049). In patients under 70 years of age with squamous cell carcinoma, adjuvant treatment reduced the mortality rate by 37% (hazard ratio: 0,63; 95% CI; 0,42-0,95; P=.036). CONCLUSIONS: Completely resected patients with stage pIIIA-N2 NSCLC receiving adjuvant treatment reached higher survival rates than those who did not. Maximum benefit was achieved by the subgroup of patients under 70 years of age with squamous cell carcinoma. PMID- 23453426 TI - [Clinical and oncological results of the pathological complete response in rectal cancer after neoadjuvant treatment]. AB - INTRODUCTION: Neoadjuvant chemo-radiotherapy is the treatment of choice for rectal cancer in order to reduce local recurrence. Patients with a pathological complete response (PCR) have a better prognosis. The aim of this study was to determine the influence of PCR on the oncological outcomes in our patients. METHODS: All patients with stage ii/iii rectal cancer treated with neoadjuvant chemo-radiotherapy and radical resection between 2007 and 2011 were identified from a prospective database, and grouped based on whether they achieved PCR or not (non-PCR). Clinical, histological and oncological outcome data were compared. RESULTS: A total of 162 patients were included (62% men), with a mean age of 65 years. In terms of pre-operative TNM staging, 82 patients (50%) were T2, 75 (46%) were T3, and 5 (3%) were T4. Forty-two patients (25%) were N1, and 87 (53%) were N2. Low anterior resection and abdominoperineal resection were performed in 125 (77%) and 25 (15%) patients. Forty-three patients (26.5%) had postoperative morbidity. PCR was achieved in 19 patients (11.7%). After a median follow-up of 26 months, there are no recurrences in the PCR group, and in the non-PCR group, local recurrence was 1.4% (P=.78), and distant metastasis was 8.4% (P=.21). Overall survival (P=.39) and survival free of diseases (P=.23) were better in the PCR group, but the differences were not significant. CONCLUSION: Patients with pathological complete response have better oncological outcome. PMID- 23453427 TI - [Impact of thymic function in age-related immune deterioration]. AB - Age-related biological deterioration also includes immune system deterioration and, in consequence, a rise in the incidence and prevalence of infections and cancers, as well as low responses to vaccination strategies. Out of all immune cell subsets, T-lymphocytes seem to be involved in most of the age-related defects. Since T-lymphocytes mature during their passage through the thymus, and the thymus shows an age-related process of atrophy, thymic regression has been proposed as the triggering event of this immune deterioration in elderly people. Historically, it has been accepted that the young thymus sets the T-lymphocyte repertoire during the childhood, whereupon atrophy begins until the elderly thymus is a non-functional evolutionary trace. However, a rising body of knowledge points toward the thymus functioning during adulthood. In the elderly, higher thymic function is associated with a younger immune system, while thymic function failure is associated with all-cause mortality. Therefore, any new strategy focused on the improvement of the elderly quality of life, especially those trying to influence the immune system, should take into account, together with peripheral homeostasis, thymus function as a key element in slowing down age related decline. PMID- 23453428 TI - A novel cause of pneumocephalus. AB - BACKGROUND: Pneumocephalus is rare, mostly arising as a complication of surgery, trauma, infection, or neoplasm. OBJECTIVE: Our aim was to briefly discuss the etiology and Emergency Department evaluation of patients with pneumocephalus. CASE REPORT: We present a case of a spontaneous esophageal-arachnoid fistula in a patient with stage IV non-small cell carcinoma leading to spontaneous pneumocephalus with resulting meningitis and death. CONCLUSIONS: Although usually asymptomatic, pneumocephalus can lead to tension pneumocephalus, a potentially fatal condition, or septic meningitis, if it is the result of infection from gas producing bacteria. PMID- 23453429 TI - Sources of information and factual knowledge in Europeans with inflammatory bowel diseases: a cross-cultural comparison between German and Irish patients. AB - BACKGROUND: Disease related knowledge may be associated with quality of life, coping skills and medication adherence. However, little is known of cross cultural variations regarding inflammatory bowel disease knowledge or sources of information and no study has assessed knowledge in diverse European IBD populations. AIM: To assess sources of information and patient knowledge in Irish and German inflammatory bowel disease patients. METHODS: Three hundred and three disease, gender, age and education matched German and Irish patients completed a previously validated knowledge questionnaire. Additional data were collected on age, gender, education, disease type and duration, family history, smoking habits, medication use, previous surgery and quality of life. RESULTS: German patients obtained knowledge from a wider range of sources than Irish patients (p<0.001), most notably from the internet (p<0.001), newspapers and magazines (p=0.002). Both cohorts answered a similar number of questions correctly (Irish, mean 4.4 questions (Standard deviation (S.D.) 2.4); German, mean 4.3 (S.D. 2.2); p=0.67). In addition, both nationalities answered "don't know" to a similar number of questions (Irish, mean 3.3 (S.D. 3.1); German, mean 2.7 (S.D. 2.8); p=0.12) while Irish patients answered slightly fewer questions wrongly (Irish, mean 2.4 (S.D. 1.8); German, mean 3.1 (S.D. 1.9); p=0.002). A multivariate analysis included only Crohn's disease, female gender, young age and higher educational status as being significantly and independently associated with knowledge. CONCLUSIONS: Our data suggest few differences between German and Irish IBD patients, despite cultural and linguistic differences, with regard to disease related knowledge of IBD. PMID- 23453431 TI - Transplantation practice has been particularly suited to national, regional, specialist and global registries. PMID- 23453430 TI - Preoperative pelvic radiation increases the risk for ileal pouch failure in patients with colitis-associated colorectal cancer. AB - BACKGROUND AND AIMS: To evaluate the impact of preoperative radiation on pouch outcomes in patients with colitis-associated cancer (CAC). METHODS: CAC patients who underwent restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) from 1984 to 2009 were identified from our registry. The impact of preoperative pelvic radiation for CAC or other pelvic cancer on pouch related outcomes was evaluated. RESULTS: Sixty-three pouch patients with confirmed CAC were included (37 male, 58.7%). The mean age at pouch construction was 46.9+/ 10.6 years. Seven patients were excluded due to the presence of persistent diverting ileostomy (n=2) or no follow-up (n=5). The remaining 56 patients were analyzed, including 9 who received pelvic radiation prior to IPAA creation for CRC or other cancers. Preoperative pelvic radiation was significantly associated with chronic pouchitis (P=0.024). There was, however, no correlation between pelvic radiation and pouch/anal transitional zone neoplasia, pouch stricture, pelvic abscess and pouch fistula/sinus. Pouch failure occurred in 13 patients after a median follow-up of 66.4 (range: 2.7-322.2) months. Although a simple statistical analysis based on the number of patients with pouch failure did not achieve significance (4/9 vs. 9/47, P=0.19), Kaplan-Meier analysis showed a strong association between preoperative pelvic radiation and the risk for pouch failure (P<0.001). A subgroup analysis of rectal cancer patients revealed that 3/7 patients (42.9%) with radiation and 3/17 (17.6%) without had pouch failure (P=0.31). Again, the association between pelvic radiation and pouch failure was confirmed using Kaplan-Meier analysis (P=0.02). CONCLUSIONS: Pelvic radiation administered prior to IPAA creation appears to be associated with poor pouch outcomes. Oncological benefits and pouch functional outcomes should be carefully balanced before pelvic radiation is considered prior to restorative proctocolectomy. PMID- 23453432 TI - Biosorption and toxicity responses to arsenite (As[III]) in Scenedesmus quadricauda. AB - Toxicity and biosorption responses to arsenite (As[III]) were examined in a 96-h exposure study using Scenedesmus quadricauda, one of the most popular green algae distributed in freshwaters in China. Results indicated that the pH-dependent distribution of two arsenite species (H2AsO3(-) and H3AsO3) played an important role in biosorption and toxicity. The undissociated H3AsO3 was more toxic than its monoanionic H2AsO3(-) through comparison of algal cell numbers, chlorophyll-a contents, and algal ultrastructural changes observed with transmission electron microscopy. An effective biosorption of 89.0mgg(-1) at 100mgL(-1) As[III] was found in the treatments with an initial pH of 9.3 and 25.2MUgg(-1) at 0.03mgL(-1) As[III] at an initial pH of 8.2 as a result of the predominant species of H2AsO3( ) under the ambient pH and Eh conditions. Our results imply that S. quadricauda may provide a new means for the removal of toxic arsenite species present in contaminated surface water. PMID- 23453433 TI - Reduction of PCDDs/PCDFs in MSWI fly ash using microwave peroxide oxidation in H2SO4/HNO3 solution. AB - Microwave peroxide oxidation (MPO) is an energy-efficient and low GHG emission technology to destroy the hazardous organic compounds in solid waste. The objective of this paper is to explore the reduction feasibility of PCDDs/Fs in MSWI fly ash using the MPO in H2SO4/HNO3 solution. Nearly all PCDDs/Fs, 99% in the original fly ash, can be reduced in 120min at the temperature of 150 degrees C using the MPO treatment. It was also found that a change occurred in the content distribution profiles of 17 major PCDD/F congeners before and after MPO treatment. This provides the potential to reduce the actual PCDDs/Fs content more than I-TEQ contents of PCDDs/Fs. The percentile distribution profile has a tendency of higher chlorinated PCDDs/Fs moving to the lower ones. It concludes that a significant reduction efficiency of I-TEQ toxicity was achieved and showed sufficient reduction of toxic level to lower than 1.0ngI-TEQ(gdw)(-1). The treatment temperature would be a critical factor facilitating the dissolution because higher temperature leads more inorganic salt (parts of fly ash) dissolution. Some problems caused by the MPO method are also delineated in this paper. PMID- 23453434 TI - Concentrations of select persistent organic pollutants across pregnancy trimesters in maternal and in cord serum in Trujillo, Peru. AB - Although the production and use of some persistent organic pollutants (POPs) have been banned or highly restricted, human exposure remains a subject of investigation due to their environmental persistence. Physiological changes during pregnancy may affect the disposition of POPs in the mother's body, and thus fetal exposure. Changes in serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) across pregnancy trimesters, and trans-placental transfer to the fetus were investigated. Seventy-nine pregnant women in Trujillo, Peru were recruited in the first trimester of pregnancy, and provided blood samples for the analysis of 35 PCB congeners, 9 OCPs, and 11 polybrominated biphenyl diethers (PBDEs). Subsequently, maternal blood samples were collected in the second (n=64) and third trimesters (n=59), and cord blood samples (n=50) were collected at delivery. There were statistically significant changes across trimesters (p<0.05) for both fresh weight (increase) and lipid adjusted concentrations (decrease) of hexachlorobenzene (HCB), 2,2-Bis(4 chlorophenyl)-1,1-dichloroethene (p,p'-DDE), PCB-74, 118, 138-158, 153, 170, 180 and 194. Fresh weight concentrations of these POPs increased from first to third trimester by 10-28%. On the other hand lipid adjusted concentrations decreased from first to third trimester by 16-28%. Serum lipids increased from first to third trimester by 53% indicating the dilution of the POPs in the lipids. Concentrations of 2,2-Bis(4-chlorophenyl)-1,1,1-trichloroethane (p,p'-DDT), its metabolite p,p'-DDE, PCB-118, 138-158, 153, 170 and 180 above their limits of detection were measured in >60% of cord serum samples. Intra-individual correlations in maternal serum concentrations were high for most of the POPs (rho=0.62-0.99; p<0.05) while correlations between maternal and cord serum concentrations were also high (rho=0.68-0.99; p<0.05). Results indicate that the disposition in the body and blood concentrations of POPs may change during pregnancy, and show trans-placental transfer of DDT, DDE and PCBs. PMID- 23453435 TI - Spatial variability of nitrous oxide and methane emissions from an MBT landfill in operation: strong N2O hotspots at the working face. AB - Mechanical biological treatment (MBT) is an effective technique, which removes organic carbon from municipal solid waste (MSW) prior to deposition. Thereby, methane (CH4) production in the landfill is strongly mitigated. However, direct measurements of greenhouse gas emissions from full-scale MBT landfills have not been conducted so far. Thus, CH4 and nitrous oxide (N2O) emissions from a German MBT landfill in operation as well as their concentrations in the landfill gas (LFG) were measured. High N2O emissions of 20-200gCO2eq.m(-2)h(-1) magnitude (up to 428mgNm(-2)h(-1)) were observed within 20m of the working face. CH4 emissions were highest at the landfill zone located at a distance of 30-40m from the working face, where they reached about 10gCO2eq.m(-2)h(-1). The MBT material in this area has been deposited several weeks earlier. Maximum LFG concentration for N2O was 24.000ppmv in material below the emission hotspot. At a depth of 50cm from the landfill surface a strong negative correlation between N2O and CH4 concentrations was observed. From this and from the distribution pattern of extractable ammonium, nitrite, and nitrate it has been concluded that strong N2O production is associated with nitrification activity and the occurrence of nitrite and nitrate, which is initiated by oxygen input during waste deposition. Therefore, CH4 mitigation measures, which often employ aeration, could result in a net increase of GHG emissions due to increased N2O emissions, especially at MBT landfills. PMID- 23453436 TI - Extreme mobility in the Late Pleistocene? Comparing limb biomechanics among fossil Homo, varsity athletes and Holocene foragers. AB - Descriptions of Pleistocene activity patterns often derive from comparisons of long bone diaphyseal robusticity across contemporaneous fossilized hominins. The purpose of this study is to augment existing understanding of Pleistocene hominin mobility patterns by interpreting fossil variation through comparisons with a) living human athletes with known activity patterns, and b) Holocene foragers where descriptions of group-level activity patterns are available. Relative tibial rigidity (midshaft tibial rigidity (J)/midshaft humeral rigidity (J)) was compared amongst Levantine and European Neandertals, Levantine and Upper Palaeolithic Homo sapiens, Holocene foragers and living human athletes and controls. Cross-country runners exhibit significantly (p<0.05) greater relative tibial rigidity compared with swimmers, and higher values compared with controls. In contrast, swimmers displayed significantly (p<0.05) lower relative tibial rigidity than both runners and controls. While variation exists among all Holocene H. sapiens, highly terrestrially mobile Later Stone Age (LSA) southern Africans and cross-country runners display the highest relative tibial rigidity, while maritime Andaman Islanders and swimmers display the lowest, with controls falling between. All fossil hominins displayed relative tibial rigidity that exceeded, or was similar to, the highly terrestrially mobile Later Stone Age southern Africans and modern human cross-country runners. The more extreme skeletal structure of most Neandertals and Levantine H. sapiens, as well as the odd Upper Palaeolithic individual, appears to reflect adaptation to intense and/or highly repetitive lower limb (relative to upper limb) loading. This loading may have been associated with bipedal travel, and appears to have been more strenuous than that encountered by even university varsity runners, and Holocene foragers with hunting grounds 2000-3000 square miles in size. Skeletal variation among the athletes and foraging groups is consistent with known or inferred activity profiles, which support the position that the Pleistocene remains reflect adaptation to extremely active and mobile lives. PMID- 23453437 TI - How confident are we in the chronology of the transition between Howieson's Poort and Still Bay? PMID- 23453438 TI - Provenancing of silcrete raw materials indicates long-distance transport to Tsodilo Hills, Botswana, during the Middle Stone Age. AB - Lithic artifacts from the African Middle Stone Age (MSA) offer an avenue to explore a range of human behaviors, including mobility, raw material acquisition, trade and exchange. However, to date, in southern Africa it has not been possible to provenance the locations from which commonly used stone materials were acquired prior to transport to archaeological sites. Here we present results of the first investigation to geochemically fingerprint silcrete, a material widely used for tool manufacture across the subcontinent. The study focuses on the provenancing of silcrete artifacts from the MSA of White Paintings Shelter (WPS), Tsodilo Hills, in the Kalahari Desert of northwest Botswana. Our results suggest that: (i) despite having access to local quartz and quartzite at Tsodilo Hills, MSA peoples chose to transport silcrete over 220 km to WPS from sites south of the Okavango Delta; (ii) these sites were preferred to silcrete sources much closer to Tsodilo Hills; (iii) the same source areas were repeatedly used for silcrete supply throughout the 3 m MSA sequence; (iv) during periods of colder, wetter climate, silcrete may have been sourced from unknown, more distant, sites. Our results offer a new provenancing approach for exploring prehistoric behavior at other sites where silcrete is present in the archaeological record. PMID- 23453439 TI - Long-term benefits and risks of drug-eluting compared to bare-metal stents in patients with versus without chronic kidney disease. AB - AIMS: Chronic kidney disease (CKD) is associated with worse outcomes in patients with coronary artery disease (CAD). How CKD influences the benefit-risk balance of drug-eluting stents (DES) versus bare-metal stents (BMS) is less known. METHODS AND RESULTS: In the multicentre BASKET-PROVE trial, 2314 patients in need of large coronary stenting (>= 3.0mm) were randomised 2:1 to DES or BMS. In an a priori planned secondary analysis, outcomes were evaluated according to renal function defined by estimated glomerular filtration rates (eGFR; normal: eGFR >= 60 ml/min/1.73 m(2); CKD: eGFR<60 ml/min/1.73 m(2)). The primary endpoint was the first major adverse cardiac event (MACE: cardiac death, myocardial infarction, target vessel revascularisation) up to 2 years. A Cox proportional-hazard model was used to evaluate adjusted relative risks (hazard rates, HRs) for BMS versus DES. The interaction of stent type and renal function was tested. CKD patients (189 (11.2%)/1681 with such data) had a 2-year MACE rate of 8.5% versus 7.4% in those without CKD [HR 0.98 (0.56-1.72), p=0.95] with cardiac mortalities of 5.3% and 1.5%, respectively (p=0.002, non-significant after baseline adjustments). The MACE rate was lower in CKD patients with DES than with BMS [4.9% versus 15.2%, p=0.017, HR 0.29(0.10-0.80)] as was the MACE rate in patients without CKD [5.6% with DES versus 11.1% with BMS, p<0.0001, HR 0.51(0.35-0.75)]. No significant interaction between stent type and renal function was found. CONCLUSIONS: This analysis of patients needing large coronary artery stenting confirms the increased mortality of CKD patients and documents a long-term benefit of DES compared to BMS irrespective of kidney function. PMID- 23453440 TI - Life course socioeconomic conditions, adulthood risk factors and cardiovascular mortality among men and women: a 17-year follow up of the GLOBE study. AB - BACKGROUND: Our goal was to study associations between childhood socioeconomic position (SEP), adulthood SEP, adulthood risk factors and cardiovascular disease (CVD) mortality, by investigating the critical period and pathway models. METHODS: The prospective GLOBE study in the Netherlands, with baseline data from 1991, was linked with cause of death register data from Statistics Netherlands in 2007. At baseline, respondents reported information on childhood SEP (i.e. occupational level of respondent's father), adulthood SEP (educational level), and adulthood risk factors (health behaviours, material circumstances, and psychosocial factors). Analyses included 4894 men and 5572 women. Data were analysed by Cox proportional hazard ratios (HR) with CVD mortality as the outcome. RESULTS: Childhood SEP was associated with CVD mortality among men with the lowest childhood SEP only (HR 1.32, 95% CI 1.00-1.74), and not among women. The majority of childhood SEP inequalities in CVD mortality among men (88%) were explained by material, behavioural and psychosocial risk factors in adulthood, and adulthood SEP. This was mostly due to the association of childhood SEP with adulthood SEP, and the interrelations of adulthood SEP with risk factors, and partly via the direct association of childhood SEP with adulthood risk factors, independent of adulthood SEP. CONCLUSION: This study supports the pathway model for men, but found no evidence that socioeconomic conditions in childhood are critical for CVD mortality in later life independent of adulthood conditions. Developing effective methods to reduce material and behavioural risk factors among lower socioeconomic groups should be a top priority in cardiovascular disease prevention. PMID- 23453441 TI - Hemodialysis does not affect ventricular-arterial coupling beyond the reduction of blood pressure and preload. PMID- 23453442 TI - Usefulness of cardiopulmonary exercise testing to predict the development of arterial hypertension in adult patients with repaired isolated coarctation of the aorta. AB - BACKGROUND: Patients who underwent surgery for aortic coarctation (COA) have an increased risk of arterial hypertension. We aimed at evaluating (1) differences between hypertensive and non-hypertensive patients and (2) the value of cardiopulmonary exercise testing (CPET) to predict the development or progression of hypertension. METHODS: Between 1999 and 2010, CPET was performed in 223 COA patients of whom 122 had resting blood pressures of <140/90 mmHg without medication, and 101 were considered hypertensive. Comparative statistics were performed. Cox regression analysis was used to assess the relation between demographic, clinical and exercise variables and the development/progression of hypertension. RESULTS: At baseline, hypertensive patients were older (p=0.007), were more often male (p=0.004) and had repair at later age (p=0.008) when compared to normotensive patients. After 3.6 +/- 1.2 years, 29/120 (25%) normotensive patients developed hypertension. In normotensives, VE/VCO2-slope (p=0.0016) and peak systolic blood pressure (SBP; p=0.049) were significantly related to the development of hypertension during follow-up. Cut-off points related to higher risk for hypertension, based on best sensitivity and specificity, were defined as VE/VCO2-slope >= 27 and peak SBP >= 220 mmHg. In the hypertensive group, antihypertensive medication was started/extended in 48/101 (48%) patients. Only age was associated with the need to start/extend antihypertensive therapy in this group (p=0.042). CONCLUSIONS: Higher VE/VCO2 slope and higher peak SBP are risk factors for the development of hypertension in adults with COA. Cardiopulmonary exercise testing may guide clinical decision making regarding close blood pressure control and preventive lifestyle recommendations. PMID- 23453443 TI - Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. AB - BACKGROUND: Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG). METHODS AND RESULTS: Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 MUM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucose-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW. CONCLUSIONS: Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2-regulated antioxidant enzymes in cardiomyocytes exposed to HG. PMID- 23453444 TI - Impact of global hemodynamic load on exercise capacity in aortic stenosis. AB - BACKGROUND: The determinants of maximal exercise capacity (MEC) in aortic stenosis (AS) are, in large part, unknown. We hypothesized that the left ventricular (LV) global hemodynamic load--as assessed by the valvulo-arterial impedance (Zva)--is one of the main determinants of MEC and we sought to evaluate the factors associated with reduced MEC in AS. METHOD AND RESULTS: Asymptomatic patients with moderate or severe AS (n=62, aortic valve area <1.5 cm(2), 65 +/- 13 years, 68% men) and preserved LV systolic function (ejection fraction>50%) were prospectively referred for comprehensive resting echocardiography and cardiopulmonary exercise test. Absolute peak VO2 was 19.5 +/- 5.7 mL/kg/min (median 19.6 mL/kg/min; range 7.2-33.1 mL/kg/min). There were significant correlations between peak VO2 and: age, body mass index, LV stroke volumes, cardiac output, mean flow rate, mitral annulus s' and e' wave velocities, E/e' ratio and left atrial diameter (all p<0.05). Indexed mean flow rate and Zva were the strongest univariable echocardiographic determinants of peak VO2 (r=0.44, p<0.001 and r=-0.39, p=0.002, respectively). In addition, patients with reduced MEC (peak VO2=60 degrees had a hazard ratio of 1.35 (95% confidence interval 1.04 to 1.75; p <0.05) and a QRS-T angle of >=120 degrees had a hazard ratio of 1.45 (95% confidence interval 1.10 to 1.92, p <0.01). For men, a QRS-T angle of >=130 degrees had a hazard ratio of 1.53 (95% confidence interval 1.14 to 2.06, p <0.01). For the whole cohort, a QRS T angle of >=125 degrees gave a hazard ratio of 1.47 (95% confidence interval 1.20 to 1.80, p <0.0001). The QRS-T angle was also a predictor of increased cardiac-related hospitalizations. The QRS-T angle was a predictor in patients with reduced and preserved left ventricular function and in patients with a normal QRS interval. In conclusion, the QRS-T angle was a powerful predictor of outcome in patients with HF. We believe the QRS-T angle should be a part of the electrocardiographic evaluation of patients with HF. PMID- 23453458 TI - Characteristics and in-hospital outcomes of patients with non-ST-segment elevation myocardial infarction undergoing an invasive strategy according to hemoglobin levels. AB - The benefit of an invasive strategy in non-ST-segment elevation myocardial infarction (NSTEMI) was established from randomized trials that included few anemic patients. The aim of this study was to describe the characteristics, therapies, and mortality of patients with NSTEMIs who undergo an invasive strategy in relation to their admission hemoglobin levels. Data from 73,067 patients with NSTEMIs who underwent cardiac catheterization and who were captured by the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines (ACTION-GWTG) were examined. Patients were divided into 3 hemoglobin groups on the basis of initial hemoglobin level: (1) <10 g/dl, (2) 10 to 12 g/dl, or (3) >12 g/dl. Patients with hemoglobin <10 g/dl had more co morbidities and more 3-vessel coronary artery disease at catheterization compared with those with hemoglobin >12 g/dl (46.2% vs 33.9%, all p values <0.0001). They received fewer acute antithrombotic therapies, less often underwent revascularization (57.4% vs 74.1%), and had higher rates of red blood cell transfusion before catheterization (32.1% vs 0.3%, all p values <0.0001). After adjustment, in-hospital mortality was inversely associated with initial hemoglobin, with a 7% increase for each 1 g/dl decrease in hemoglobin lower than 15 g/dl (odds ratio 1.07, 95% confidence interval 1.02 to 1.11). In conclusion, in patients presenting with NSTEMIs and managed with an invasive strategy, a lower hemoglobin level is associated with more extensive coronary artery disease, less use of revascularization and evidence-based therapies, and increased mortality. PMID- 23453460 TI - Rapid freezing cryo-polymerization and microchannel liquid-flow focusing for cryogel beads: adsorbent preparation and characterization of supermacroporous bead-packed bed. AB - Cryogel beads, fabricated by the microchannel liquid-flow focusing and cryo polymerization method, have micron-scale supermacropores allowing the passage of crude feedstocks, and could be of interest as chromatographic adsorbents in bioseparation applications. In this work, we provide a rapid freezing and continuous formation method for cryogel beads by cryo-polymerization using dry ice particles as the freezing source and microchannel liquid-flow focusing using peristaltic pumps for the fluid supply. Polyacrylamide (pAAm)-based supermacroporous cryogel beads were prepared and grafted with N,N dimethylaminoethyl methacrylate (DMAEMA), which provided the anion-exchange cryogel beads with tertiary amine functional groups suitable for binding proteins. Properties of the supermacroporous cryogel-bead packed bed, i.e., permeability, bed voidage, protein breakthrough as well as protein adsorption performance by using bovine gamma-globulin as model protein, were experimentally investigated. A capillary-based model was employed to characterize the supermacroporous bed performance, and gave a reasonable description of the microstructure and thus an insight into the flow, dispersion and mass transfer behaviors within the cryogel bead-packed bed. The results also showed that by using dry ice as the freezing source, it is easy to reduce the temperature below 55 to -61 degrees C in the bulk solution, causing the rapid formation of ice crystals within the monomer drops, and finally effective cryo-polymerization to form supermacropores within the cryogel beads. By using peristaltic pumps, continuous preparation was achieved and the obtained cryogel beads had favorable properties similar to those prepared using syringe pumps in the microchannel liquid-flow focusing process. This method is thus expected to be interesting in the liter- or even larger-scale preparation of cryogel adsorbents. PMID- 23453459 TI - Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study]. AB - A first pilot study of interleukin-1 blockade in ST-segment elevation acute myocardial infarction showed improved remodeling. In the present second pilot study, we enrolled 30 patients with clinically stable ST-segment elevation acute myocardial infarction randomized to anakinra, recombinant interleukin-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blind fashion. The primary end point was the difference in the interval change in left ventricular (LV) end-systolic volume index between the 2 groups within 10 to 14 weeks. The secondary end points included changes in the LV end-diastolic volume index, LV ejection fraction, and C-reactive protein levels. No significant changes in end systolic volume index, LV end-diastolic volume index, or LV ejection fraction were seen in the placebo group. Compared to placebo, treatment with anakinra led to no measurable differences in these parameters. Anakinra significantly blunted the increase in C-reactive protein between admission and 72 hours (+0.8 mg/dl, interquartile range -6.4 to +4.2, vs +21.1 mg/dl, interquartile range +8.7 to +36.6, p = 0.002), which correlated with the changes in LV end-diastolic volume index and LV end-systolic volume index at 10 to 14 weeks (R = +0.83, p = 0.002, and R = +0.55, p = 0.077, respectively). One patient in the placebo group (7%) died. One patient (7%) in the anakinra group developed recurrent acute myocardial infarction. More patients were diagnosed with new-onset heart failure in the placebo group (4, 27%) than in the anakinra group (1, 7%; p = 0.13). When the data were pooled with those from the first Virginia Commonwealth University Anakinra Remodeling Trial (n = 40), this difference reached statistical significance (30% vs 5%, p = 0.035). In conclusion, interleukin-1 blockade with anakinra blunted the acute inflammatory response associated with ST-segment elevation acute myocardial infarction. Although it failed to show a statistically significant effect on LV end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction in this cohort of clinically stable patients with near-normal LV dimensions and function, anakinra led to a numerically lower incidence of heart failure. PMID- 23453461 TI - Evaluation of the asymmetric least squares baseline algorithm through the accuracy of statistical peak moments. AB - This manuscript evaluates the performance of the Eilers' smoothing algorithm by comparing the third central statistical peak moment of simulated peaks to their true value. Peaks were simulated by imposing an exponentially modified Gaussian peak profile onto a random segment of pre-recorded high performance liquid chromatography baseline. Prior to moment calculation the noise was removed from the simulated curves and the signal was subtracted by the approximated baseline. We found that with a signal to noise ratio of 1000 an 11% relative error was observed between the practical and true third statistical moment. The Eilers' smoothing algorithm was observed to both reduced noise and baseline correct without distorting the shape of the chromatographic peak. PMID- 23453462 TI - Novel reverse-phase ion pair-high performance liquid chromatography separation of heparin, heparan sulfate and low molecular weight-heparins disaccharides and oligosaccharides. AB - In this study, by using tetrabutylammonium bisulfate as ion-pairing reagent, we were able to separate all the main heparin/heparan sulfate disaccharides generated by the action of heparinases along with the main Hep tetrasaccharide possessing a 3-O-sulfate group on the sulfoglucosamine unit and resistant to enzymatic action. Moreover, this novel HPLC method was able to separate and quantify uncommon disaccharides/oligosaccharides present in low molecular weight heparins produced by chemical treatment with nitrous acid, dalteparin, or benzylation followed by alkaline hydrolysis, enoxaparin. Additionally, this procedure yields a sensitivity ~4-times higher compared to conventional strong anion exchange-HPLC separation. This was obtained by a common UV detector at 232 nm avoiding the use of complex procedures capable of increasing sensitivity by post-column derivatization. Finally, it is worth mentioning that disaccharide/oligosaccharide composition by HPLC and UV detection is a common analytical approach in quality control laboratories to evaluate heparins and low molecular weight-heparins structure and quality during their extraction and production. This simple HPLC approach offers high resolution and sensitivity for the rapid differentiation of pharmaceutical native heparins and derivatives and for the compositional analysis of small amounts of samples derived from biological sources at a glycosaminoglycans level of a few hundred nanogram. PMID- 23453463 TI - Optimising the design and operation of semi-continuous affinity chromatography for clinical and commercial manufacture. AB - This paper presents an integrated experimental and modelling approach to evaluate the potential of semi-continuous chromatography for the capture of monoclonal antibodies (mAb) in clinical and commercial manufacture. Small-scale single column experimental breakthrough studies were used to derive design equations for the semi-continuous affinity chromatography system. Verification runs with the semi-continuous 3-column and 4-column periodic counter current (PCC) chromatography system indicated the robustness of the design approach. The product quality profiles and step yields (after wash step optimisation) achieved were comparable to the standard batch process. The experimentally-derived design equations were incorporated into a decisional tool comprising dynamic simulation, process economics and sizing optimisation. The decisional tool was used to evaluate the economic and operational feasibility of whole mAb bioprocesses employing PCC affinity capture chromatography versus standard batch chromatography across a product's lifecycle from clinical to commercial manufacture. The tool predicted that PCC capture chromatography would offer more significant savings in direct costs for early-stage clinical manufacture (proof of-concept) (~30%) than for late-stage clinical (~10-15%) or commercial (~5%) manufacture. The evaluation also highlighted the potential facility fit issues that could arise with a capture resin (MabSelect) that experiences losses in binding capacity when operated in continuous mode over lengthy commercial campaigns. Consequently, the analysis explored the scenario of adopting the PCC system for clinical manufacture and switching to the standard batch process following product launch. The tool determined the PCC system design required to operate at commercial scale without facility fit issues and with similar costs to the standard batch process whilst pursuing a process change application. A retrofitting analysis established that the direct cost savings obtained by 8 proof-of-concept batches would be sufficient to pay back the investment cost of the pilot-scale semi-continuous chromatography system. PMID- 23453464 TI - Aortocaval compression during early pregnancy: are there other causes? PMID- 23453465 TI - A comparison of the haemodynamic effects of lateral and sitting positions during induction of spinal anaesthesia for caesarean section. AB - BACKGROUND: Hypotension during spinal anaesthesia occurs commonly in parturients. By influencing spread of local anaesthetic, maternal position may affect the speed of onset of sensory block and thus the haemodynamic effects. The aim of this study was to determine whether inducing spinal anaesthesia for caesarean section using plain bupivacaine in the lateral position would result in less hypotension compared with the sitting position. METHODS: One hundred American Society of Anesthesiologists physical status I and II patients undergoing elective caesarean section were randomised to receive spinal anaesthesia in the lateral position (Group L) or the sitting position (Group S). Using the L3-4 interspace, patients received intrathecal plain bupivacaine, 10mg or 12 mg according to their height, after which they were placed immediately in the supine position with left uterine displacement. Maternal blood pressure was measured every minute for 10 min, every three min for 20 min and 5-minutely thereafter. Hypotension was defined as a fall in systolic blood pressure >20% or a value <90 mmHg. RESULTS: There was no difference in the lowest recorded systolic blood pressure in Group L (99.2+/-8.9 mmHg) compared with Group S (95.4+/-12.3 mmHg, P=0.081). However, the lowest recorded mean arterial pressure was greater in Group L (72.9+/-11.2 mmHg) than in Group S (68.2+/-9.6 mmHg; P=0.025). The incidence of hypotension was lower in Group L (17/50, 34%) than in Group S (28/50, 56%; P=0.027). Onset of hypotension was similar between groups. CONCLUSION: Hypotension occurred less frequently when spinal anaesthesia for caesarean using plain bupivacaine was induced with patients in the lateral compared with the sitting position. Values for the lowest recorded mean arterial pressure were greater but values for the lowest recorded systolic blood pressure were similar for patients in the lateral position group. PMID- 23453466 TI - Misleading neurological symptoms during insertion of an epidural catheter in labour. PMID- 23453467 TI - Pain relief at the end of life: nurses' experiences regarding end-of-life pain relief in patients with dementia. AB - Patients with dementia receive suboptimal palliative care, and this patient group is at risk to have pain at the end of life. Because communicative impairments are common in this patient group, nurses play an important caregiver role in identifying, assessing, and relieving patients' pain. This study aimed to describe nurses' experiences regarding end-of-life pain relief in patients with dementia. This descriptive exploratory qualitative study was based on seven semistructured interviews. Burnard's content analysis inspired the data analysis. Two main categories were identified: (1) nurses' experience of difficulties concerning pain relief and (2) nurses' experience of resources concerning pain relief. Nurses experienced difficulties, such as feeling of powerlessness because of difficulties in obtaining adequate prescriptions for analgesics, ethical dilemmas, feeling of inadequacy because analgesia did not have the desired effect, and a feeling of not being able to connect with the patient. Factors, including knowledge about the patient, professional experience, utilization of pain assessment tools, interpersonal relationships, and interprofessional cooperation, served as resources and enabled end-of-life pain relief. The results of this study highlight the complexity of pain relief in patients with dementia at the end of life from a nursing perspective. The inability of patients with dementia to verbally communicate their pain makes them a vulnerable patient group, dependent on their caregivers. Knowing the life story of the patient, professional experience, teamwork based on good communication, and use of a pain assessment tool were reported by the nurses to improve pain relief at the end of life for patients with dementia. PMID- 23453469 TI - Three new cases of palmar fasciitis with polyarthritis including a patient with atypical mutilating osteolysis. AB - We managed three patients who had both palmar fasciitis and polyarthritis coexisting with gynecological malignancies. The first patient was followed up for 3 years, during which she experienced mutilating osteolysis of the fingers and very severe inflammation as assessed by osteoarticular ultrasonography. The second patient had active synovitis by ultrasonography without structural joint damage. Finally, in the last patient, magnetic resonance imaging showed synovitis and extensor tenosynovitis of the fingers. The many differential diagnoses of this paraneoplastic syndrome are discussed. PMID- 23453468 TI - Pathologic validation of renal cell carcinoma histology in the Surveillance, Epidemiology, and End Results program. AB - PURPOSE: The Surveillance, Epidemiology, and End Results (SEER) program is an important epidemiologic research tool to study cancer. No information is available on its pathologic accuracy for renal cell carcinoma (RCC). METHODS: Central pathology review was analyzed as a part of the United States Kidney Cancer Study. Cases previously identified through the Detroit SEER registry were reviewed. The sensitivity and specificity, and positive and negative predictive values were calculated for each SEER-assigned subtype, with the central review assignments used as the reference. RESULTS: Of the 498 cases included in this study, 490 (98.5%) were confirmed to be RCC. The overall agreement for histology was 78.2% (kappa = 0.55); however, individual cases were frequently reclassified. The sensitivity and specificity for SEER-assigned clear cell RCC were 79.1% and 88.1%, respectively, when based solely on the ICD-O-3 morphology code 8310 (n = 310), and 99.2% and 80.5% when 8312 (RCC not otherwise specified; n = 41) was also assumed to be clear cell. Although RCC not otherwise specified is frequently grouped with clear cell, only 78.1% had this histology. Assignments of papillary and chromophobe RCC had comparable sensitivities (73.5% and 72.4%, respectively) and specificities (97.5% and 97.6%). Positive predictive values for clear cell (excluding/including 8312), papillary, and chromophobe RCC were 95.5%/93.5%, 85.9%, and 65.6%, respectively. CONCLUSIONS: Our findings confirm that nearly all RCC cases are correctly classified in SEER. The positive predictive value was higher for clear cell RCC than for papillary or chromophobe RCC, suggesting that pathologic confirmation may be warranted for studies of non-clear cell tumors. PMID- 23453470 TI - Treatment responses in five patients with Ribbing disease including two with 466C>T missense mutations in TGFbeta1. AB - OBJECTIVE: To assess 5-year treatment responses and TGFB1 gene abnormalities in five patients with ribbing disease. METHODS: PCR analysis and bidirectional sequencing of TGFbeta1 exons 1 through 7 were performed in all five patients. RESULTS: The five patients, four women and one man with a mean age of 34 years at symptom onset, shared the following features: severe diaphyseal pain predominating in the lower limbs with diaphyseal hyperostosis; increased radionuclide uptake at sites of pain and, in some cases at other cortical sites; asymmetric or asynchronous lesions; long symptom duration (5-18 years) despite a variety of treatments; and a delay of several years (2-15) between symptom onset and the diagnosis. Of our five patients, two had a heterozygous missense mutation in exon 2 of TGFbeta1 (c.466C>T, p.Arg156Cys, previously described in Camurati Engelmann syndrome) and three had commonly found TGFbeta1 polymorphisms. Intravenous bisphosphonate therapy was used in all five patients but induced substantial improvements in a single patient. Of the three patients given bolus methylprednisolone therapy, two experienced a lasting response; the exception was one of the two women with a TGFbeta1 mutation. CONCLUSION: Considerable heterogeneity in the clinical presentations, genetic abnormalities, and treatment responses contribute to the diagnostic challenges raised by ribbing disease. Detailed genetic studies are needed. PMID- 23453471 TI - Validation of the TAGAP rs212389 polymorphism in rheumatoid arthritis susceptibility. PMID- 23453472 TI - When neutrophils cast their nets. PMID- 23453473 TI - Lichen planus under anti TNF therapy for ankylosing spondylitis. PMID- 23453474 TI - Sciatica with motor loss and hemi-cauda equina syndrome due to varicella-zoster virus meningoradiculitis. PMID- 23453475 TI - Successful use of antitumor necrosis factor-alpha biological therapy in managing human immunodeficiency virus-associated arthritis: three case studies from Saudi Arabia. AB - Arthralgic disorders involving various rheumatic manifestations are commonly observed in HIV patients. Available therapies for HIV-associated rheumatic syndromes include non-steroidal anti-inflammatory drugs for pain management, disease-modifying antirheumatic drugs (e.g., methotrexate), and antitumor necrosis factor-alpha therapies. However, treatment of HIV-associated arthritis can be challenging, particularly in patients with co-infections like hepatitis viruses, and therapeutic strategies are not well defined. Here, we present three case reports on the use of antitumor necrosis factor-alpha agents for HIV associated arthritis. We managed three cases of HIV-associated arthritis following initial presentation. All patients were on highly active antiretroviral therapy with stable HIV loads and CD4(+) cell counts. Data were reported for treatment of inflammatory arthritis using 5 months of etanercept followed by adalimumab for case 1, and 12 months of etanercept for case 2. In case 3, reactive arthritis was treated with 5 months of etanercept followed by adalimumab. In all three cases, significant improvement or resolution of arthritis was achieved following treatment with antitumor necrosis factor-alpha therapies. Moreover, these case studies demonstrated the safe and effective use of antitumor necrosis factor-alpha agents in HIV patients with hepatitis B and/or C virus co-infection. Our results indicate that antitumor necrosis factor-alpha therapies can be successfully used for HIV-infected patients with stable HIV loads and CD4(+) lymphocyte counts. PMID- 23453476 TI - Prospective assessment of bone texture parameters at the hand in rheumatoid arthritis. AB - OBJECTIVE: Fractal bone analysis (Hmean) is a texture parameter reflecting bone microarchitecture. The BMA device (D3ATM Medical Systems, Orleans, France) is a high-resolution X-ray device that allows assessment of bone texture analysis. We aimed to measure Hmean in rheumatoid arthritis patients at the second and third metacarpal bones, at baseline and after 1 year of follow-up, and to assess the relationship of Hmean and rheumatoid arthritis disease parameters. METHODS: Patients with rheumatoid arthritis according to ACR criteria were included. They were assessed over 1 year, in the context of a prospective study conducted in Maastricht. For this substudy, activity of the disease was assessed by erythrocyte sedimentation rate, C-reactive protein and Disease Activity Score 28 performed at each visit. Radiographic bone damage was assessed using hand and feet radiographs at baseline and on a 1-year basis. The bone texture parameters were evaluated on the second and third metacarpal heads of the left hand using BMA device. RESULTS: One hundred and sixty-five rheumatoid arthritis patients were included in this study. At baseline, Hmean was negatively correlated with age [r=-0.22 (P=0.013)] and erythrocyte sedimentation rate [r=-0.16 (P=0.039)]. No significant correlation was found between Hmean and Disease Activity Score, disease activity Visual Analog Scale, daily corticosteroid dose and C-reactive protein. There was a significant increase in Hmean of second and third metacarpal bones over 1 year (1.6% and 1.3%, P<0.01) except in patients with local second and third metacarpal bones erosion. CONCLUSION: The bone texture parameter Hmean is influenced by age, inflammation and local erosions in rheumatoid arthritis. PMID- 23453477 TI - Rheumatoid factor does not predict response to TNF antagonists in rheumatoid arthritis: three centers experience. PMID- 23453478 TI - Evaluation of spondylarthritis activity by patients and physicians: ASDAS, BASDAI, PASS, and flares in 200 patients. AB - OBJECTIVES: In patients with spondyloarthritis, to determine Ankylosing Spondylitis Disease Activity Score (ASDAS) cutoffs matching the patient acceptable symptom state (PASS) and patient-reported levels of disease activity, to assess associations between disease activity levels and presence of depression, and to identify ASDAS and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) cutoffs indicating a flare and indicating a remission. METHODS: Prospective single-center study of patients meeting ASAS criteria for spondyloarthritis receiving follow-up at the Besancon teaching hospital, France, between February 2011 and February 2012. In each patient, the BASDAI, ASDAS, Bath Ankylosing Spondylitis Functional Index (BASFI), patient-acceptable symptom state (PASS) and signs of depression were assessed. Receiver-operating characteristic (ROC) curves were drawn to identify the ASDAS cutoffs separating different levels of disease activity. The kappa coefficient was computed to evaluate agreement between patients and physicians regarding the presence of flares. RESULTS: Two hundred patients with a mean age of 44.4 +/- 12.5 years and mean disease duration of 12.9 +/- 10.5 years were included. Mean BASDAI was 4.1 +/- 2.2, mean ASDAS-C reactive protein (CRP) was 2.4 +/- 1, mean BASFI was 3.3 +/- 2.7, and 58.9% of patients reported being in the PASS. The PASS was associated with BASDAI values inferior or equal to 4.1 and ASDAS-CRP values inferior or equal to 2.3. Mild patient-reported disease activity was associated with BASDAI values inferior or equal to 3.8 and ASDAS-CRP values inferior or equal to 2.3; corresponding values for high patient-reported disease activity were superior to 5.2 and superior to 3.1. Among patients reporting high disease activity, 64.5% had Beck Depression Inventory scores consistent with severe depression. At the time of the visit, 36.9% of the patients and 28.3% of the physicians felt there was a flare. Cutoffs indicating a flare were superior or equal to 5.2 for the BASDAI and superior or equal to 2.3 for the ASDAS-CRP. Agreement between patients and physicians regarding flares was good (Kappa, 0.61). An evaluation in 43 patients indicated that an ASDAS-CRP cutoff inferior or equal to 2.2 separated the 25.6% of patients who reported being in remission from the other patients. CONCLUSION: Our results show a significant association between disease activity and depression severity, as well as good agreement between BASDAI and ASDAS. The ASDAS cutoffs for the various levels of patient-reported disease activity differed from the cutoffs suggested by ASAS; a 2.3 cutoff was found for both patient-reported absence of disease activity and PASS, indicating that achieving PASS should be included among our treatment objectives. PMID- 23453479 TI - Are immunoglobulin free light chains levels reliable to assess disease activity in rheumatoid arthritis? PMID- 23453480 TI - Rewarding early abstinence in Veterans Health Administration addiction clinics. AB - This study investigates the addition of a contingency management (CM) intervention to Veterans Health Administration substance use disorders treatment on during- and post-treatment outcomes for Veterans diagnosed with alcohol dependence only (n=191) or stimulant dependence (n=139). Participants were randomly assigned to 8weeks of usual care or usual care plus CM. Follow-up assessments occurred at 2, 6 and 12months. In the alcohol dependent subgroup, CM participants submitted significantly more negative samples (13 versus 11 samples, Cohen's d=0.54), were retained significantly longer (7 versus 6weeks, d=0.47), achieved significantly longer median durations of abstinence (16 versus 9 consecutive visits; median difference=7, 95% CI=4-8), and submitted significantly more negative samples at follow-ups (unstandardized effect size=0.669, se=0.2483) compared to usual care participants. Intervention effects were non-significant for the stimulant dependent subgroup. The study provides support for the effectiveness of CM interventions for alcohol dependent patients. PMID- 23453482 TI - Comparing statistical methods for analyzing skewed longitudinal count data with many zeros: an example of smoking cessation. AB - Count data with skewness and many zeros are common in substance abuse and addiction research. Zero-adjusting models, especially zero-inflated models, have become increasingly popular in analyzing this type of data. This paper reviews and compares five mixed-effects Poisson family models commonly used to analyze count data with a high proportion of zeros by analyzing a longitudinal outcome: number of smoking quit attempts from the New Hampshire Dual Disorders Study. The findings of our study indicated that count data with many zeros do not necessarily require zero-inflated or other zero-adjusting models. For rare event counts or count data with small means, a simpler model such as the negative binomial model may provide a better fit. PMID- 23453483 TI - Nanoparticle surface modification by amphiphilic polymers in aqueous media: role of polar organic solvents. AB - We investigate the role of three polar organic solvents (dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), and glycerol) on the interfacial behavior of Pluronic P105 poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) block copolymers on protonated silica nanoparticles in an aqueous dispersion. The polymer adsorption and self-assembly have been assessed from critical surface micelle concentration (csmc, measured by pyrene fluorescence spectroscopy) and adsorbed layer thickness (measured by capillary viscometry) data. Above its csmc, PEO-PPO-PEO block copolymers form hydrophobic domains on the nanoparticle surface. Below a critical concentration in water (known as critical displacer concentration, cdc), organic solvents act as displacers (molecules that can displace adsorbed polymer from a solid surface). The critical displacer concentration is obtained from the csmc and the polymer adsorbed layer thickness data. The cdc is found to be dependent on both the amount of nanoparticles present in the system as well as the nature of the displacer. Below the cdc, the csmc increases and the adsorbed polymer layer thickness decreases with increasing organic solvent concentration. Interfacial free energy calculations suggest that DMF, DMSO, and glycerol can adsorb onto the silica particles by displacing adsorbed PEO. These calculations are consistent with the experimental results in that, as a displacer, glycerol is the most effective and DMF is the least effective. Above the cdc, the influence of glycerol or DMSO on csmc is opposite to that of DMF which is attributed to the cosolvent effect. PMID- 23453481 TI - Identifying the substance abuse treatment needs of caregivers involved with child welfare. AB - Parental substance use significantly increases risk of child maltreatment, but is often under-identified by child protective services. This study examined how agency use of standardized substance use assessments and child welfare investigative caseworker education, experience, and caseload affected caseworkers' identification of parental substance abuse treatment needs. Data are from a national probability sample of permanent, primary caregivers involved with child protective services whose children initially remained at home and whose confidential responses on two validated instruments indicated harmful substance use or dependence. Investigative caseworkers reported use of a formal assessment in over two thirds of cases in which substance use was accurately identified. However, weighted logistic regression indicated that agency provision of standardized assessment instruments was not associated with caseworker identification of caregiver needs. Caseworkers were also less likely to identify substance abuse when their caseloads were high and when caregivers were fathers. Implications for agency practice are discussed. PMID- 23453484 TI - Sternal perforation with an intraosseous device and hemomediastinum infusion. PMID- 23453485 TI - [A step further to avoid the use of predefined transfusion triggers]. PMID- 23453486 TI - [Plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) predicts acute kidney injury in septic shock at ICU admission]. AB - PURPOSE: To validate plasma Neutrophil Gelatinase-Associated Lipocalin (pNGAL) as an early biomarker in intensive care unit (ICU) for acute kidney injury (AKI) in critically ill adult with septic shock. PATIENTS AND METHOD: Fifty consecutive patients with septic shock were included in this observational cohort study. AKI was defined if patients met any RIFLE or AKIN criteria. The main objective was to evaluate diagnosis value of pNGAL measured with a point-of-care device at admission (D0), at 24hours (D1) and at 48hours (D2). RESULTS: Among the 50 patients enrolled, 86% had AKI, 48% had persistent renal AKI and 30% required renal replacement therapy (RRT) during their ICU stay. At D0, pNGAL concentration was significantly higher in patients with AKI compared to patients without AKI (471ng/mL versus 134ng/mL, P<0.001). This level remained significantly higher in the AKI population at D1 and D2 and pNGAL concentration at D0 among AKI patients increased with kidney failure level. At D1, pNGAL was significantly higher for persistent renal AKI rather than transient prerenal (570ng/mL versus 337ng/mL, P=0.027). pNGAL concentration below 348ng/mL at D1 was never seen in patients with RRT. CONCLUSION: Plasma NGAL is a useful, sensitive and early biomarker to predict persistent AKI in septic shock at ICU admission and help to discuss RRT. PMID- 23453487 TI - [Knowing is not enough, we must apply...]. PMID- 23453488 TI - The development and outcomes of a pediatric palliative care program: a quality improvement process. PMID- 23453489 TI - Cationic lipid:DNA complexes allow bleomycin uptake by melanoma cells. AB - Bleomycin is a chemotherapeutic agent barely diffusible through the plasmatic membrane. We evaluated DNA/cationic lipids complexes (lipoplexes) as mediators of its uptake in four spontaneous canine melanoma derived cell lines (Ak, Bk, Br and Rkb). Cell survival after lipofection plus or minus bleomycin was determined by the acid phosphatase method and the cellular uptake of lipoplexes, carrying the E. coli beta-galactosidase gene, was evidenced by SYBR Green I staining. The four cell lines resulted sensitive to the bleomycin/lipoplexes system in both spatial configurations. Survival rates values were lower than 20% in monolayers of the four tested lines and lower than 30% in three lines (Ak, Bk and Rkb) when grown as spheroids. The sensitization to bleomycin depended on lipoplexes in Ak and Rkb while Bk (in both spatial configurations) and Br (as monolayers) were sensitive to bleomycin alone. Although some degree of sensitivity to bleomycin was induced by cationic lipids alone in Ak and Rkb monolayers, the maximal bleomycin effects appeared in the presence of lipoplexes. The sensitization was independent of transcriptional activity. The co-administration of lipoplexes diminished bleomycin IC50: 10-fold in Ak and Rkb monolayers; and sensitized the Ak and Rkb resistant spheroids. The bleomycin cytotoxic effects depended on lipoplexes concentration and diminished when cells were incubated at 8 degrees C. Our results suggest that lipoplexes sensitize cells to bleomycin, increasing its uptake by an active transport mechanism, such as endocytosis. The bleomycin/lipoplexes system appears as a promising combination of chemotherapy and non-viral cancer gene therapy. PMID- 23453490 TI - Pancreatic endocrine tumour with disseminated pulmonary thromboembolism in an owl monkey (Aotus nancymae). AB - Pulmonary thromboembolism associated with pancreatic endocrine neoplasia is extremely uncommon in man and animals. Post-mortem examination of an adult owl monkey (Aotus nancymae) revealed extensive pulmonary arterial thromboembolism and a well-demarcated mass attached to the pancreas. Microscopically, the mass consisted of areas of interstitial fibrosis with loss of acini and islets and replacement by nests and sheets of polygonal cells with amphophilic cytoplasm, an eccentric round nucleus with stippled chromatin and, in some cells, with a single prominent eccentric nucleolus. Clusters of these cells were noted within vessels and adjacent lymph nodes. The cells did not express S100 or insulin, but were labelled strongly with SP-1/chromogranin. Rare individual cells expressed glucagon and somatostatin. A few cells in pulmonary thrombi/emboli and the adjacent lymph node also expressed SP-1/chromogranin. Based on cell morphology, location and immunohistochemistry the tumour was classified as pancreatic endocrine (islet cell) carcinoma with metastasis to regional lymph nodes and lung. PMID- 23453491 TI - Immunohistochemical characterization of type II pneumocyte proliferation after challenge with type I porcine reproductive and respiratory syndrome virus. AB - The aim of this study was to characterize histologically and immunohistochemically the lung lesions developing in growing pigs, 10 and 21 days after experimental challenge with a field strain of porcine reproductive and respiratory syndrome virus (PRRSV). Lung lesions were scored for (1) pneumocyte hypertrophy and hyperplasia, (2) septal mononuclear infiltration, (3) intra alveolar necrotic debris, (4) intra-alveolar inflammatory cell accumulation and (5) perivascular inflammatory cell accumulation. Immunohistochemistry was performed using antibodies specific for cytokeratin, Ki67, thyroid transcription factor (TTF)-1, the myelomonocytic marker MAC387 and PRRSV. Anti-TTF-1 identified type II pneumocytes and there was marked proliferation of these cells compared with control lung (P <0.05). Anti-cytokeratin labelled type I and II pneumocytes as well as bronchial epithelial cells; however, this labelling was not suitable for cell counting purposes. There was a correlation between lesion severity and the number of cells expressing Ki67 (P <0.05). PMID- 23453492 TI - Active and latent ovine herpesvirus-2 (OvHV-2) infection in a herd of captive white-tailed deer (Odocoileus virginianus). AB - Malignant catarrhal fever (MCF) is the clinical manifestation of infection of certain ruminant species with one of a group of pathogenic gammaherpesviruses known as MCF viruses. Cattle and numerous exotic ruminant species are susceptible to clinical disease that may be sporadic or occasionally epidemic in nature. The most common MCF virus worldwide is ovine herpesvirus (OvHV)-2. Reservoir hosts such as sheep, carry and excrete OvHV-2, but do not develop clinical signs, while clinically susceptible species develop severe and often fatal disease. The existence of latent infection in clinically susceptible hosts is poorly understood, but is documented in some ruminant species. Twenty-six animals from a captive herd of white-tailed deer (Odocoileus virginianus) died and were examined from October 2006 to December 2010. Fifteen of these animals (58%) showed clinical signs and gross and microscopical lesions consistent with MCF, while 11 (42%) did not. Polymerase chain reaction (PCR) amplification yielded product consistent with OvHV-2 DNA in samples of spleen from all 26 deer. To examine the possibility of latent infection in this herd, peripheral blood mononuclear cells were examined by PCR for OvHV-2 DNA, and the test was positive in 23/32 (72%) clinically normal deer. Archived serum samples were used to examine the history of MCF exposure in the herd using a competitive enzyme-linked immunosorbent assay, which demonstrated that 10/40 (25%) deer tested had MCF viral antibodies, with nine deer being seropositive over multiple years. Combined with previous observations in deer and other species, these results suggest the existence of latent infection of white-tailed deer with OvHV-2. PMID- 23453493 TI - Littoral cell angiosarcoma in a dog. AB - This report describes the microscopical and immunohistochemical characteristics of littoral cell angiosarcoma in a 12-year-old, neutered female, beagle dog. The dog succumbed to metastatic disease 3 months after diagnosis of a mid-splenic mass. The tumour was characterized by two histological patterns: anastomosing microvascular channels and microvascular papillary fronds. The neoplastic cells expressed both endothelial and histiocytic markers and were erythrophagocytic. Immunohistochemical findings consistent with malignancy were CD34 expression and high Ki67 nuclear immunoreactivity. PMID- 23453494 TI - Chip-calorimetric monitoring of biofilm eradication with antibiotics provides mechanistic information. AB - Increased antibiotic resistance of pathogenic bacteria dwelling in biofilm structures has motivated the development of various monitoring tools specifically designed for biofilm investigations. In this study, the potential of the recently emerging chip calorimetry for this purpose was analysed. The activity of biofilms of Pseudomonas putida PaW340 was monitored chip-calorimetrically and compared with counts of colony forming units (CFU), bioluminescence-based ATP measurements, and quantitative confocal laser scanning microscopy (CLSM). The biofilms were treated with antibiotics differing in their mechanisms of action (bactericidal kanamycin vs. bacteriostatic tetracycline) and referenced to untreated biofilms. For untreated biofilms, all methods gave comparable results. Calorimetric killing curves, however, reflecting metabolic responses to biofilm eradication non-invasively in real time, differed from those obtained with the established methods. For instance, heat signals increased right after addition of the antibiotics. This transient increase of activity was not detected by the other methods, since only calorimetry delivers specific information about the catabolic part of the metabolism. In case of the bactericidal antibiotic, CFU misleadingly indicated successful biofilm eradication, whereas calorimetry revealed enduring activity. Our results show that calorimetry holds promise to provide valuable mechanistic information, thereby complementing other methods of biofilm analysis. PMID- 23453495 TI - Heparin-induced thrombocytopenia without thrombocytopenia in an intensive care unit. PMID- 23453496 TI - Tattooing and piercing: an underestimated issue for immunocompromised patients? PMID- 23453497 TI - L10. Animal models of ANCA-associated vasculitis: effector mechanisms and experimental therapies. PMID- 23453498 TI - [Rotator cuff syndrome--three clinical cases showing an interaction between work and the worker stature]. PMID- 23453499 TI - L11. Hepatitis C virus mixed cryoglobulinemia vasculitis: therapeutic options. PMID- 23453500 TI - L29. Relevance of anti-LAMP-2 in vasculitis: why the controversy. PMID- 23453501 TI - [Diagnosis and management of severe adverse events occurring during BCG therapy for non-muscle invasive bladder cancer (NMIBC)]. AB - BCG therapy, which is the standard treatment for non-muscle invasive bladder tumours with high risk of recurrence and progression, has potential life threatening adverse effects (AEs). Rapid deterioration of general condition in a patient with history of bladder tumour should question about an ongoing treatment with BCG and specify the date of the last instillation. Trauma during catheterization and untreated concomitant urinary infection upon instillations are risk factors of severe AEs. In emergency, the diagnosis of severe AEs of BCG therapy is only based on the medical questioning with the notion of current BCG treatment and risk-bearing event upon instillation. Management of AEs is related to their pathophysiological mechanisms and relies on a combination of antibiotics against BCG, the symptomatic treatment, and corticosteroid therapy which has shown to improve patient outcomes. PMID- 23453502 TI - [Patient hotel: Results of a satisfaction survey among 50 patients after ambulatory surgery]. PMID- 23453503 TI - L24. Local treatments of subglottic and tracheal stenoses in granulomatosis with polyangiitis (Wegener's). PMID- 23453504 TI - [Prazosin for sleep disturbance and nightmares in post-traumatic stress disorder]. PMID- 23453505 TI - [Acute kidney injury following naproxene use in an ultraendurance female athlete]. PMID- 23453506 TI - [Health impact of unicellular algae of the Ostreopsis genus blooms in Algeria during summer 2009]. PMID- 23453507 TI - [Sinonasal inverted papilloma: 43 cases]. AB - PURPOSE: Inverted papilloma (IP) is a common epithelial tumor arising from the nasal vault. The aim of our study was to evaluate the advantages, the results and the limits in the treatment of this tumor. PATIENTS AND METHOD: Retrospective study of 43 patients over the period 1989-2009. RESULTS: The mean age was 53.3 years. We found a maxillary sinus extension in 40 cases and ethmoidal extension in 27 cases. Twenty-nine patients were treated through an endoscopic endonasal approach. A vestibular approach was used in three patients. A paralateral nasal approach was used for 12 cases. We observed a recurrence in 9.3% of the all cases. CONCLUSION: The treatment of IP is surgical. Their high potential of local aggressiveness, fear of recurrence and the possibility of the occurrence of a malignancy require radical treatment. PMID- 23453508 TI - L6. Eosinophilic granulomatosis with polyangiitis: future therapies. PMID- 23453509 TI - Classification of secondary corneal amyloidosis and involvement of lactoferrin. AB - PURPOSE: To classify secondary corneal amyloidosis (SCA) by its clinical appearance, to analyze the demographics of the patients, and to determine the involvement of lactoferrin. DESIGN: Retrospective, observational, noncomparative, multicenter study. PARTICIPANTS: Twenty-nine eyes of 29 patients diagnosed with SCA by corneal specialists at 9 ophthalmologic institutions in Japan were studied. METHODS: The clinical appearance of SCA was determined by slit-lamp biomicroscopy and was classified into 3 types. The demographics of the patients, for example, age, gender, and the duration of the basic disease (trichiasis, keratoconus, and unknown), were determined for each clinical type. Surgically excised tissues were stained with Congo red and antilactoferrin antibody. The postoperative prognosis also was determined. MAIN OUTCOME MEASURES: Clinical appearance of the 3 types of SCA, along with the gender, age, and duration of the basic diseases were determined. RESULTS: Classification of SCA into 3 types based on clinical appearance found 21 cases with gelatinous drop-like dystrophy (GDLD) like appearance (GDLD type), 3 cases with lattice corneal dystrophy (LCD)-like appearance (LCD type), and 5 cases with the combined type. Patients with the GDLD type were younger (average age: 40.9 years for the GDLD type, 74.3 years for the LCD type, and 46.8 years for the combined type), predominantly women (85.7% for the GDLD type, 33.3% for the LCD type, and 60% for the combined type), and had the basic disease over a longer time (average duration: 22.1 years for the GDLD type, 14.0 for the LCD type, and 11.4 for the combined type). The distribution of the basic diseases (trichiasis vs. keratoconus vs. unknown) was not significantly different for each type. Surgical treatments, for example, phototherapeutic keratectomy, lamellar keratoplasty, and simple keratectomy, resulted in a good resolution in all surgically treated cases. One subject dropped out of the study. Spontaneous resolution was seen in one subject after epilation of the cilia. Amorphous materials in the excised tissues showed positive staining results by Congo red and by antilactoferrin antibody. CONCLUSIONS: Secondary corneal amyloidosis can be classified into 3 clinical types based on its clinical appearance. Larger numbers of females and lactoferrin expression were seen in all 3 types. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23453510 TI - Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an Australasian disease registry. AB - OBJECTIVES: To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset individuals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort. DESIGN: Cross sectional study using a national disease registry. PARTICIPANTS: One thousand sixty individuals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation. MAIN OUTCOME MEASURES: Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in individuals with advanced and nonadvanced POAG. RESULTS: This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six individuals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers. CONCLUSIONS: The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying individuals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23453511 TI - Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. AB - PURPOSE: To report the 1-year clinical outcomes of an outbreak of Streptococcus endophthalmitis after intravitreal injection of bevacizumab, including visual acuity outcomes, microbiological testing, and compound pharmacy investigations by the Food and Drug Administration (FDA). DESIGN: Retrospective consecutive case series. PARTICIPANTS: Twelve eyes of 12 patients who developed endophthalmitis after receiving intravitreal bevacizumab prepared by a single compounding pharmacy. METHODS: Medical records of patients were reviewed; phenotypic and DNA analyses were performed on microbes cultured from patients and from unused syringes. An inspection report by the FDA based on site visits to the pharmacy that prepared the bevacizumab syringes was summarized. MAIN OUTCOME MEASURES: Visual acuity, interventions received, time to intervention, microbiological consistency, and FDA inspection findings. RESULTS: Between July 5 and 8, 2011, 12 patients developed endophthalmitis after intravitreal bevacizumab from syringes prepared by a single compounding pharmacy. All patients received initial vitreous tap and injection, and 8 patients (67%) subsequently underwent pars plana vitrectomy (PPV). After 12 months follow-up, outcomes have been poor. Seven patients (58%) required evisceration or enucleation, and only 1 patient regained pre-injection visual acuity. Molecular testing using real-time polymerase chain reaction, partial sequencing of the groEL gene, and multilocus sequencing of 7 housekeeping genes confirmed the presence of a common strain of Streptococcus mitis/oralis in vitreous specimens and 7 unused syringes prepared by the compounding pharmacy at the same time. An FDA investigation of the compounding pharmacy noted deviations from standard sterile technique, inconsistent documentation, and inadequate testing of equipment required for safe preparation of medications. CONCLUSIONS: In this outbreak of endophthalmitis, outcomes have been generally poor, and PPV did not improve visual results at 1-year follow-up. Molecular testing confirmed a common strain of S. mitis/oralis. Contamination seems to have occurred at the compounding pharmacy, where numerous problems in sterile technique were noted by public health investigators. PMID- 23453512 TI - Glaucoma severity and medication adherence in a county hospital population. AB - OBJECTIVE: To assess the association between disease severity and adherence with glaucoma medications in a county hospital population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 126 patients diagnosed with glaucoma receiving intraocular pressure (IOP)-lowering medication were recruited from the San Francisco General Hospital Ophthalmology Clinic. METHODS: Subjects completed an oral questionnaire to assess demographic information, knowledge of glaucoma, and perceptions of glaucoma medication adherence. Glaucoma disease severity was classified according to the American Academy of Ophthalmology's Preferred Practice Pattern guidelines. Medication adherence was measured for each patient by obtaining pharmacy refill data and calculating medication possession ratio (MPR), that is, the ratio of total days' supply of medication during a 365-day period. Adherence was measured retrospectively over the 18-month period before study entry. Subjects with an MPR >80% were considered adherent. MAIN OUTCOME MEASURE: Medication adherence. RESULTS: Subjects with mild or moderate glaucoma were more likely to be nonadherent to their prescribed glaucoma medications than those with severe disease (adjusted odds ratio [OR], 1.54; 95% confidence interval [CI], 1.03-2.31; P = 0.04). Age, gender, race, education level, years of glaucoma, number of medications, and glaucoma diagnosis were not found to be statistically significantly associated with adherence. CONCLUSION: Patients with severe glaucoma were more likely to adhere to their topical IOP-lowering medication regimen than those with milder glaucomatous disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23453513 TI - Ranibizumab treatment outcomes in phakic versus pseudophakic eyes: an individual patient data analysis of 2 phase 3 trials. AB - OBJECTIVE: To compare visual outcomes in phakic and pseudophakic eyes treated with monthly intravitreal ranibizumab for exudative age-related macular degeneration (AMD). DESIGN: Meta-analysis of individual patient data from 2 phase 3 clinical trials of intravitreal ranibizumab in neovascular AMD (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration [ANCHOR], ClinicalTrials.gov number, NCT00061594; and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration [MARINA], ClinicalTrials.gov number NCT00056836). PARTICIPANTS AND CONTROLS: A total of 1137 patients from 2 phase 3 clinical trials. METHODS: Phakic and pseudophakic eyes were treated with monthly intravitreal ranibizumab (0.3 mg or 0.5 mg), sham injections plus verteporfin photodynamic therapy (ANCHOR), or sham injections alone (MARINA). MAIN OUTCOME MEASURES: Mean change from baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) and the proportion of patients gaining or losing 15 or more ETDRS letters. RESULTS: After adjusting for baseline covariates, no differences were seen in mean change in VA for phakic versus pseudophakic eyes. Pseudophakic eyes were more likely to lose 15 or more letters of vision than phakic eyes at 12 months, but not at 24 months. CONCLUSIONS: Overall, in this analysis, lens status did not demonstrate an independent influence on mean VA for eyes treated with monthly ranibizumab. It is possible that phakic eyes may be less prone to severe vision loss. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23453514 TI - A phenotype-genotype correlation study of X-linked retinoschisis. AB - PURPOSE: To compare the clinical phenotype and detailed electroretinographic parameters in X-linked retinoschisis (XLRS). DESIGN: Retrospective, comparative study. PARTICIPANTS: Fifty-seven patients (aged 1-67 years) with molecularly confirmed XLRS were clinically ascertained. METHODS: Pattern electroretinography (PERG) and full-field electroretinography (ERG), incorporating international standard recordings, were performed in 44 cases. Thirteen patients, mostly pediatric, were tested using a simplified ERG protocol. On-Off and S-cone ERGs were performed in most adults. Fundus autofluorescence (FAF) imaging and optical coherence tomography (OCT) were available in 17 and 21 cases, respectively. MAIN OUTCOME MEASURES: The clinical and electrophysiologic data associated with different types of mutation in the RS1 gene. RESULTS: Forty-three patients had missense changes (group A), and 14 patients had nonsense, splice-site, or frame shifting mutations in the RS1 gene (group B). The mean best-corrected visual acuity was better in group A than in group B (0.34 and 0.21, respectively). Fundus examination revealed foveal schisis in approximately half of both groups. The bright-flash dark-adapted (DA) ERG (11.0 candela.sec.m(-2)) waveform was electronegative in 62% of group A eyes and 100% of group B eyes. The photopic 30 Hz flicker ERG was delayed in all group B eyes and all except 6 group A eyes. On Off ERG b-waves were subnormal in 39% of group A and 89% of group B eyes; d-waves were delayed in 14 eyes (group A = 10, group B = 4). S-cone ERGs were abnormal in 50% of both groups. The PERG was abnormal in 88% of group A and 100% of group B eyes. A spoke-wheel pattern of high and low intensity was the most common FAF abnormality observed. The OCT showed intraretinal schitic cavities in the majority of eyes. CONCLUSIONS: There is profound phenotypic variability in patients with XLRS. Most patients have DA bright-flash ERGs with a low b:a ratio in keeping with inner retinal dysfunction. Generalized cone system dysfunction is common and associated with an abnormal On-response and less frequent additional Off-response involvement. Nonsense, splice-site, or frame-shifting mutations in RS1 consistently caused electronegative bright-flash ERG, delayed flicker response, and abnormal PERG; missense mutations result in a wider range of ERG abnormalities. PMID- 23453515 TI - The impact of endovascular lower-limb revascularisation on the aortic augmentation index in patients with peripheral arterial disease. AB - OBJECTIVES: The aortic augmentation index (AIx), a marker of arterial stiffness, and peripheral arterial disease (PAD) are associated with an increased cardiovascular risk. In claudicants, the effect of balloon angioplasty (percutaneous transluminal angioplasty, PTA) on AIx has not been determined so far. METHODS: Measurements of the ankle-brachial pressure index (ABI) and AIx were performed before and 3 months after PTA and compared to age- and sex-matched PAD patients under best medical treatment. RESULTS: The data of 61 patients (44% female, mean age 68 years) who underwent lower-limb PTA was compared to 48 conservatively treated patients (38% female, mean age 68 years). ABI significantly improved after PTA from 0.73 +/- 0.02 to 0.85 +/- 0.03 (p = 0.001), but remained unchanged in the control group (0.85 +/- 0.23 and 0.80 +/- 0.21; p = 0.16). Revascularisation was associated with a significant reduction of AIx from 31.5 +/- 1.1% to 28.8 +/- 1.1% after 3 months (p = 0.01). In the conservatively treated group, AIx did not change during follow-up (29.9 +/- 1.1% to 29.9 +/- 1.1%; p = 0.83). CONCLUSION: Lower-limb revascularisation in PAD Rutherford stage II-III is associated with an improvement of markers for arterial stiffness. PMID- 23453516 TI - Volatiles and sensory evaluation of goat milk cheese Gokceada as affected by goat breeds (Gokceada and Turkish Saanen) and starter culture systems during ripening. AB - The effect of goat breed and starter culture on volatile composition and sensory scores in goat milk cheese was studied during 90d of ripening. Milk from 2 goat breeds (Gokceada and Turkish Saanen) and different starter culture systems (no starter, mesophilic and thermophilic starters) were used in the manufacture of goat milk cheeses (called Gokceada goat cheese). Volatile composition was determined by a solid-phase microextraction-gas chromatography-mass spectrometric method. Sixty compounds including esters (13), carboxylic acids (7), aldehydes (6), ketones (8), alcohols (14), and miscellaneous compounds (12) were identified. Esters, alcohols, and carboxylic acids were the main classes of volatile components in the cheeses. Both qualitatively and quantitatively, the use of different starter cultures and goat breeds significantly influenced the volatile fraction of goat milk cheese. Decanoic, hexanoic, and octanoic (commonly named capric, caproic, and caprylic) acids were indicator compounds to distinguish the goat breeds. Principal component analysis grouped the cheeses based on the use of starter culture and goat breed. Starter-free cheeses were separately located on the plot and age-related changes were present in all samples. Sensory evaluation of 90-d-old cheeses showed that the cheeses from the Gokceada breed received higher odor, flavor, and quality scores than those from the Turkish Saanen breed, and cheeses made using mesophilic starters resulted in the most satisfactory scores for flavor and quality attributes. In conclusion, goat milk cheeses made using milk from Gokceada goats and mesophilic starter culture had the best quality in terms of volatile composition and sensory attributes. PMID- 23453517 TI - Presence of Campylobacter and Arcobacter species in in-line milk filters of farms authorized to produce and sell raw milk and of a water buffalo dairy farm in Italy. AB - The objectives of this study were to investigate the presence of Campylobacter spp. and Arcobacter spp. in dairy herds authorized for the production and sale of raw milk and in a water buffalo dairy farm, and to test the antimicrobial susceptibility of the isolates. A total of 196 in-line milk filters were collected from 14 dairy farms (13 bovine and 1 water buffalo) for detection of Campylobacter spp. and Arcobacter spp. by microbiological culture. For each farm investigated, 1 isolate for each Campylobacter and Arcobacter species isolated was tested using the Etest method (AB Biodisk, Solna, Sweden) to evaluate the susceptibility to ciprofloxacin, tetracycline, chloramphenicol, ampicillin, erythromycin, and gentamicin. A total of 52 isolates were detected in 49 milk filters in 12 farms (85.7%) out of 14 and the isolates were identified as Campylobacter jejuni (6), Campylobacter hyointestinalis ssp. hyointestinalis (8), Campylobacter concisus (1), Campylobacter fetus ssp. fetus (1), Arcobacter butzleri (22), and Arcobacter cryaerophilus (14). The small number of isolates tested for antimicrobial susceptibility precludes any epidemiological consideration but highlights that all Campylobacter isolates were susceptible to macrolides, which are the first-choice drugs for the treatment of campylobacteriosis, and that resistance to fluoroquinolones and tetracycline was detected; for Arcobacter isolates, resistance to ampicillin and chloramphenicol was detected. The sale of raw milk for human consumption by self-service automatic vending machines has been allowed in Italy since 2004 and the presence of C. jejuni in in-line milk filters confirms that raw milk consumption is a significant risk factor for human infection. The high occurrence of emerging Campylobacter spp. and Arcobacter spp. discovered in dairy farms authorized for production and sale of raw milk represents an emerging hazard for human health. PMID- 23453518 TI - Conditions associated with Clostridium sporogenes growth as a surrogate for Clostridium botulinum in nonthermally processed canned butter. AB - The objective of this study was to better understand the effect of butter composition and emulsion structure on growth and survival of Clostridium sporogenes, used as a surrogate for C. botulinum in canned butter. The lack of a thermal process step in commercially available canned butter raises questions of potential safety, because it is hermetically sealed and generally exhibits anaerobic growth conditions, which are optimal for Clostridium botulinum growth. Without thermal processing, low-acid canned foods must have inhibitory factors present to prevent C. botulinum growth. Some potential intrinsic inhibitory factors, or hurdles, within butter include: reduced water activity, acidity in cultured products, elevated salt content, and the micro-droplet nature of the aqueous phase in the butter emulsion. It was hypothesized that a normal, intact butter emulsion would have sufficient hurdles to prevent C. botulinum growth, whereas a broken butter emulsion would result in a coalesced aqueous phase that would allow for C. botulinum growth. Batch-churned butter was inoculated with C. sporogenes; butter samples with varying salt contents (0, 0.8, 1.6, and 2.4% wt/wt NaCl) were prepared and stored in coated steel cans for varying times (1 or 2 wk) and temperatures (22 or 41 degrees C) to determine temperature and emulsion structure effects on C. sporogenes growth. Samples stored at 41 degrees C showed a significant increase in C. sporogenes growth compared with those stored at 22 degrees C. Furthermore, NaCl addition was found to have a significant effect on C. sporogenes growth, with 0.8% NaCl promoting more growth than 0%, but with decreases in growth observed at 1.6 and 2.4%. Uninoculated control plates were also found to have bacterial growth; this growth was attributed to other anaerobic bacteria present within the cream. It was concluded that removal of the hurdle created by the micro-droplet size of the emulsion aqueous phase could result in C. botulinum growth even at elevated salt levels and, therefore, home preparation of canned butter is not advisable. It is also possible that commercially canned butter, if heat abused, could potentially allow for C. botulinum growth and, therefore, consumption is not recommended. PMID- 23453519 TI - Effect of treatment with human chorionic gonadotropin on day 5 after timed artificial insemination on fertility of lactating dairy cows. AB - Reproductive management programs that synchronize ovulation can ovulate a smaller than normal follicle, potentially resulting in inadequate progesterone (P4) concentrations after artificial insemination (AI). Ovulation of the dominant follicle of the first follicular wave with human chorionic gonadotropin (hCG) treatment can produce an accessory corpus luteum and increase circulating P4 concentrations. This manuscript reports the results of 2 separate analyses that evaluated the effect of hCG treatment post-AI on fertility in lactating dairy cows. The first study used meta-analysis to combine the results from 10 different published studies that used hCG treatment on d 4 to 9 post-AI in lactating dairy cows. Overall, pregnancies per artificial insemination (P/AI) were increased 3.0% by hCG treatment post-AI [34% (752/2,213) vs. 37% (808/2,184); Control vs. hCG treated, respectively]. The second study was a field research trial in which lactating Holstein cows (n=2,979) from 6 commercial dairy herds were stratified by parity and breeding number and then randomly assigned to one of 2 groups: control (no further treatment, n=1,519) or hCG [Chorulon i.m.: 2,000 IU (in 3 of the herds) or 3,300 IU (in 3 herds); n=1,460] on d 5 after a timed AI (ovulation synchronized with Ovsynch, Presynch-Ovsynch, or Double-Ovsynch). In a subset of cows, the hCG profile and P4 changes were determined. Treatment with hCG increased P4 (4.3 vs. 5.3 ng/mL on d 12). Pregnancies per AI were greater in cows treated with hCG (40.8%; 596/1,460) than control (37.3%; 566/1,519) cows. Interestingly, an interaction among treatment and parity was observed; primiparous cows had greater P/AI after hCG (49.7%; 266/535) than controls (39.5%; 215/544). In contrast, older cows receiving hCG (35.7%; 330/925) had similar P/AI to controls (36.0%; 351/975).Thus, targeted use of hCG on d 5 after TAI enhances fertility about 3.0% (based on meta-analysis) to 3.5% (based on our field trial). Surprisingly, this fertility-enhancing effect of hCG was very large in first-lactation cows but not observed in older cows in the field study. Future research is needed to confirm these intriguing results and to determine why older cows did not have improved fertility after hCG treatment. PMID- 23453520 TI - A multivariate and stochastic approach to identify key variables to rank dairy farms on profitability. AB - The economic efficiency of dairy farms is the main goal of farmers. The objective of this work was to use routinely available information at the dairy farm level to develop an index of profitability to rank dairy farms and to assist the decision-making process of farmers to increase the economic efficiency of the entire system. A stochastic modeling approach was used to study the relationships between inputs and profitability (i.e., income over feed cost; IOFC) of dairy cattle farms. The IOFC was calculated as: milk revenue + value of male calves + culling revenue - herd feed costs. Two databases were created. The first one was a development database, which was created from technical and economic variables collected in 135 dairy farms. The second one was a synthetic database (sDB) created from 5,000 synthetic dairy farms using the Monte Carlo technique and based on the characteristics of the development database data. The sDB was used to develop a ranking index as follows: (1) principal component analysis (PCA), excluding IOFC, was used to identify principal components (sPC); and (2) coefficient estimates of a multiple regression of the IOFC on the sPC were obtained. Then, the eigenvectors of the sPC were used to compute the principal component values for the original 135 dairy farms that were used with the multiple regression coefficient estimates to predict IOFC (dRI; ranking index from development database). The dRI was used to rank the original 135 dairy farms. The PCA explained 77.6% of the sDB variability and 4 sPC were selected. The sPC were associated with herd profile, milk quality and payment, poor management, and reproduction based on the significant variables of the sPC. The mean IOFC in the sDB was 0.1377 +/- 0.0162 euros per liter of milk (?/L). The dRI explained 81% of the variability of the IOFC calculated for the 135 original farms. When the number of farms below and above 1 standard deviation (SD) of the dRI were calculated, we found that 21 farms had dRI<-1 SD, 32 farms were between 1 SD and 0, 67 farms were between 0 and +1 SD, and 15 farms had dRI>+1 SD. The top 10% of the farms had a dRI greater than 0.170 ?/L, whereas the bottom 10% farms had a dRI lower than 0.116 ?/L. This stochastic approach allowed us to understand the relationships among the inputs of the studied dairy farms and to develop a ranking index for comparison purposes. The developed methodology may be improved by using more inputs at the dairy farm level and considering the actual cost to measure profitability. PMID- 23453521 TI - Evaluation of the Charm maximum residue limit beta-lactam and tetracycline test for the detection of antibiotics in ewe and goat milk. AB - The Charm maximum residue limit beta-lactam and tetracycline test (Charm MRL BLTET; Charm Sciences Inc., Lawrence, MA) is an immunoreceptor assay utilizing Rapid One-Step Assay lateral flow technology that detects beta-lactam or tetracycline drugs in raw commingled cow milk at or below European Union maximum residue levels (EU-MRL). The Charm MRL BLTET test procedure was recently modified (dilution in buffer and longer incubation) by the manufacturers to be used with raw ewe and goat milk. To assess the Charm MRL BLTET test for the detection of beta-lactams and tetracyclines in milk of small ruminants, an evaluation study was performed at Instituto de Ciencia y Tecnologia Animal of Universitat Politecnica de Valencia (Spain). The test specificity and detection capability (CCbeta) were studied following Commission Decision 2002/657/EC. Specificity results obtained in this study were optimal for individual milk free of antimicrobials from ewes (99.2% for beta-lactams and 100% for tetracyclines) and goats (97.9% for beta-lactams and 100% for tetracyclines) along the entire lactation period regardless of whether the results were visually or instrumentally interpreted. Moreover, no positive results were obtained when a relatively high concentration of different substances belonging to antimicrobial families other than beta-lactams and tetracyclines were present in ewe and goat milk. For both types of milk, the CCbeta calculated was lower or equal to EU-MRL for amoxicillin (4 ug/kg), ampicillin (4 ug/kg), benzylpenicillin (<= 2 ug/kg), dicloxacillin (30 ug/kg), oxacillin (30 ug/kg), cefacetrile (<= 63 ug/kg), cefalonium (<= 10 ug/kg), cefapirin (<= 30 ug/kg), desacetylcefapirin (<= 30 ug/kg), cefazolin (<= 25 ug/kg), cefoperazone (<= 25 ug/kg), cefquinome (20 ug/kg), ceftiofur (<= 50 ug/kg), desfuroylceftiofur (<= 50ug/kg), and cephalexin (<= 50 ug/kg). However, this test could neither detect cloxacillin nor nafcillin at or below EU-MRL (CCbeta >30 ug/kg). The CCbeta for tetracyclines was also lower than EU-MRL for chlortetracycline (ewe milk: <= 50 ug/kg; goat milk: 75 ug/kg), oxytetracycline (<= 50 ug/kg), and tetracycline (<= 50 ug/kg). Regarding the 4-epimers of these tetracyclines only 4-epioxytetracycline was detected by the Charm MRL BLTET test below EU-MRL (ewe milk: 75 ug/kg; goat milk: <= 50 ug/kg). Acidiol had no effect on the performance of the test. The Charm MRL BLTET test could be used routinely with adapted test procedure for the fast screening of ewe and goat milk. PMID- 23453522 TI - Diurnal patterns of grazing behavior and humoral factors in supplemented dairy cows. AB - Offering feed supplements to grazing dairy cows results in a reduction in grazing time. However, the effect differs depending on the time of day that feeds are offered. To understand the physiological basis for this, associations among circulating factors known to be associated with intake regulation in monogastric species and grazing behavior in the dairy cow were investigated. Seventeen multiparous cows at 28 +/- 5 d in milk grazed together and consumed 4.4 kg of dry matter/d of a pelleted concentrate feed supplement, equally split, at the a.m. and p.m. milking. Grazing behavior was recorded over 4 consecutive days in all 17 cows. Blood was sampled from 10 of the 17 cows every 4h over a 48-h period following the grazing behavior measurements; sampling times were staggered by 2h to provide a diurnal profile of humoral factors. Grazing profiles illustrated major grazing bouts after the a.m. and p.m. milking; however, the p.m. grazing bout was characterized as the most intensive and time spent grazing was unaffected by supplementation. Associations among proportion of cows grazing and circulating hormones and metabolites differed throughout the day. During the a.m., relationships were consistent with those reported in monogastric species, with ghrelin and nonesterified fatty acids decreasing and insulin increasing with feeding. In comparison, during the major grazing bout predusk, ghrelin concentrations increased until sunset, despite the large proportion of cows grazing, before declining; this is consistent with ghrelin stimulating the predusk grazing bout. Results indicate that humoral factors known to affect hunger and satiety in monogastric animals may also have a potential role in the physiological regulation of diurnal and feeding behavior in ruminants. PMID- 23453523 TI - Dilatation of the bile duct in patients after cholecystectomy: a retrospective study. AB - PURPOSE: Retrospective assessment of impact of cholecystectomy, age, and sex on bile duct (BD) diameter. MATERIALS AND METHODS: We retrospectively reviewed abdominal contrast-enhanced multidetector computed tomography and laboratory reports of 290 consecutive patients (119 men; mean age, 55.9 years) who presented without cholestasis to the emergency department of our institution between June 2009 and August 2010. BD diameters were measured in 3 locations, by 2 independent observers, twice, at 1-month intervals. Reproducibility and agreement were evaluated by intraclass correlation coefficients and Bland-Altman analyses. The effects of cholecystectomy, age, and sex on BD diameter were analysed with linear mixed models. RESULTS: BD diameter inter-reader reproducibility and agreement were excellent at the level of the right hepatic artery (intraclass correlation coefficient, 0.94). Sixty-one patients (21.0%) had a history of cholecystectomy. Among them, the 95th percentile of BD diameters at hepatic artery level was 7.9 mm (<50 years) and 12.3 mm (>=50 years). Among those without cholecystectomy, BD diameter was 6.2 mm (<50 years) and 7.7 mm (>=50 years). Cholecystectomy was associated with significantly larger BD diameters in both age groups (P < .001). Older age was associated with larger BD diameters (P = .004). Sex had no impact on BD diameter (P = .842). CONCLUSION: Patients after cholecystectomy may present with an enlarged BD unrelated to cholestasis. The BD diameter increases with age. Clinicians should rely on cholecystectomy status, age, and laboratory results to determine needs of further investigation. PMID- 23453524 TI - Transcatheter closure of the patent ductus arteriosus: an intention to treat analysis. AB - BACKGROUND: In patients with patent ductus arteriosus (PDA), transcatheter closure is the current procedure of choice. There are multiple devices available with limited current comparative data and varied recommendations for device selection. OBJECTIVE: To assess the efficacy and safety of the Flipper coil (FC) and the Amplatzer Duct Occluder (ADO). METHODS: An intention to treat analysis of all children admitted to the catheter laboratory at a single institution for occlusion of PDA from 2003 to 2011 was performed. Patient and device selection were determined by the treating physician. Standard techniques for FC and ADO implantation were used. RESULTS: Two hundred and twenty eight children with median weight of 14.2 kg (range; 5.5-68 kg) underwent cardiac catheterisation, with successful occlusion in 96.2% of patients when attempted. In 16 patients, median angiographic PDA diameter of 0.8 mm (range; 0.4-1.2 mm), was considered too small to warrant closure. Eight patients with large PDA's underwent surgical ligation. FC was successfully used in 70 (34.3%) and ADO in 134 (66.7%) patients. ADO patients were smaller (P=0.004) with larger PDA's (P<0.0001) than the FC group. Median fluoroscopy time was longer for ADO patients (10.1 min vs 8.0 min; P<0.0001). ADO had a lower embolisation rate (0% vs 6.6%; P=0.005) and a higher complete occlusion rate at follow-up (100% vs 73.4%; P<0.0001). Length of hospital admission decreased with time in both groups. CONCLUSION: Transcatheter closure of the PDA has a high degree of safety and efficacy. This study suggests that the ADO may be the device of first choice in the current era. PMID- 23453525 TI - Quality of life, family burden and associated factors in relatives with obsessive compulsive disorder. AB - OBJECTIVE: The aim of this study is to assess the quality of life (QoL), family burden and psychiatric disorders in first-degree relatives of patients with obsessive-compulsive disorder (OCD) and to compare them with healthy controls and their relatives. METHODS: Forty patients with OCD and 47 of their first-degree relatives as well as 40 healthy subjects and 45 of their first-degree relatives were recruited in this study. OCD and comorbid anxiety or mood disorders were determined by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Comorbid Axis II disorders were diagnosed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition Personality Disorders. Type and severity of obsessive-compulsive symptoms were assessed with the Yale-Brown Obsessive Compulsive Scale, and the disability of patients with OCD was evaluated with the WHO DAS II. Family burden and QoL in the relatives were evaluated with the Zarit Burden Interview (ZBI) protocol and the World Health Organization Quality of Life Assessment-Brief, respectively. RESULTS: The mean ZBI score of family members of OCD patients was higher than the control relatives. Linear regression analysis indicated that the independent factors associated with ZBI were duration of OCD, comorbid major depressive disorder and poorer insight. Compared with those of control relatives, the QoL of relatives of patients with OCD was significantly lower in all domains. While the diagnosis of major depressive disorder in relatives of OCD patients was significantly higher than the control relatives, the diagnosis of any anxiety disorder did not differ. CONCLUSIONS: Our study provides evidence that OCD not only affects the lives of patients but also their family members. PMID- 23453526 TI - Same, varied, or both? Contextual support aids young children in generalizing category labels. AB - Children have a difficult time in generalizing among changes in background context. We examined the role of two processes that may aid in generalizing category labels in new contexts. In this study, 2-year-old children were taught novel object categories in one type of contextual condition and were tested for category generalization in a new context. In Experiment 1, children (N=48) learned in one of three conditions: (a) all category instances presented in the same context, (b) all category instances presented in varied contexts, or (c) some category instances presented in the same context and some presented in varied contexts. In Experiment 2, children (N=48) learned in one of three conditions, all of which included presentations in the same context and varied contexts but differed in order. Results from both experiments revealed that children were significantly more likely to choose the correct object when training was in both same and varied contexts regardless of order. The results suggest that contextual factors, by providing both support for aggregation and support for decontextualization, contribute to word learning and generalization for novice word learners. PMID- 23453527 TI - Microfabricated devices in microbial bioenergy sciences. AB - Microbes provide a platform for the synthesis of clean energy from renewable resources. Significant investments in discovering new microbial systems and capabilities, discerning the molecular mechanisms that mediate microbial bioenergy production, and optimizing existing microbial bioenergy systems have been made. However, further development is needed to achieve the economically feasible large-scale production of value-added energy products. Microfabricated lab-on-a-chip systems provide cost- and time-efficient opportunities for analyzing microbe-mediated bioenergy synthesis. Here, we review developments in the application of lab-on-a-chip systems to the bioenergy sciences. We focus on systems that support the analysis of microbial generation of bioelectricity, biogas, and liquid transportation fuels. We conclude by suggesting possible future directions. PMID- 23453529 TI - Role of vitamin D receptor (VDR) polymorphisms in susceptibility to multiple myeloma in ethnic Kashmiri population. AB - BACKGROUND: Vitamin D regulates many biological processes including bone metabolism, innate immune response, and cell proliferation and differentiation by binding to its receptor VDR. Vitamin D receptor (VDR) gene polymorphisms have been associated with many cancers like breast, colorectal, prostate, and skin. The main aim of this study was to determine whether VDR polymorphisms (ApaI, BsmI and FokI) are associated with increased risk of multiple myeloma. METHODS: We designed a case control study where 75 multiple myeloma cases were studied for VDR polymorphisms (ApaI, BsmI and FokI) against 150 controls taken from general population. The polymorphisms of VDR gene were investigated using PCR-RFLP method. RESULTS: We did not find any significant association between ApaI and BsmI polymorphisms and multiple myeloma risk (P>0.05), but FokI polymorphism was significantly associated with increased risk for multiple myeloma. We also found a significant association between the ff variant genotype with creatinine levels, albumin levels, and Durie-Salmon stage III. CONCLUSION: Our findings suggest that the FokI polymorphism is involved in the increased susceptibility to development and progression in multiple myeloma in the ethnic Kashmiri population. Furthermore these results suggest that ff genotype is associated with higher risk for developing multiple myeloma. PMID- 23453530 TI - The relationship between psychosocial care and attitudes toward illness in adolescents with epilepsy. AB - Epilepsy is a significant health problem in Iran and other countries. Previous epilepsy studies conducted in Iran have often focused on physiological aspects and pharmacological therapy, and little attention has been paid to the psychological and social aspects of care, particularly in adolescence. This paper aims to fill this gap by assessing the relationship between psychosocial care and attitudes toward illness in adolescents with epilepsy. A descriptive correlational design was adopted, and 74 adolescents who experienced generalized seizures and were treated at the neurology clinic affiliated with the Tabriz University of Medical Sciences in 2010 were examined. The data were collected using instruments including (1) the patient demographic characteristics, (2) the Child Report of Psychosocial Care Scale, and (3) the Child's Attitude Toward Illness Scale. There was a significant positive correlation between psychosocial care and attitudes toward illness (p<.05). There is no evidence for routine psychological consultation for our sample; it would be helpful if psychological consultation with and without parents made available to adolescents with epilepsy. PMID- 23453531 TI - The "E" word: epilepsy and perceptions of unfair treatment from the 2010 Australian Epilepsy Longitudinal Survey. AB - AIM: The aim of the current study was to examine self-report data on perceptions of unfair treatment due to epilepsy. METHOD: We analyzed data from the 2010 Australian Epilepsy Longitudinal Survey, distributed to 621 registrants on the Australian Epilepsy Research Register. A total of 343 responses were received (55% response rate), providing insight into experiences of life with epilepsy in Australia. Responses relating to perceptions of unfair treatment in areas of employment, education and community participation as a result of epilepsy are reported in this article. RESULTS: Forty-eight percent of respondents reported perceptions of unfair treatment as a result of their epilepsy, with most providing details of their experiences. Discrimination in the workplace remains of key concern, with 47% citing examples of unfair treatment in this setting. CONCLUSIONS: In spite of Australian anti-discrimination laws, findings indicate that full-time employment rates for people with epilepsy are lower than previously reported, with further mechanisms for support required to improve education and reduce experiences of stigma. PMID- 23453528 TI - Hematopoietic stem cells are pluripotent and not just "hematopoietic". AB - Over a decade ago, several preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability (often referred to as HSC plasticity) of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired in controversy and remained dormant for almost a decade. This commentary provides a concise review of evidence for HSC plasticity, including more recent findings based on single HSC transplantation in mouse and clinical transplantation studies. There is strong evidence for the concept that HSCs are pluripotent and are the source for the majority, if not all, of the cell types in our body. Also discussed are some biological and experimental issues that need to be considered in the future investigation of HSC plasticity. PMID- 23453532 TI - Attitude toward epilepsy after media coverage of car accidents related to persons with epilepsy in Japan. AB - We compared the familiarity with and attitude toward epilepsy among nonmedical students before and after media coverage on car accidents related to persons with epilepsy in Japan. We have annually conducted a questionnaire survey on attitude toward epilepsy since 2008. We divided students into two groups: pre-accident era (years 2008-2010) and post-accident era (years 2011-2012). The rate of students who have read or heard about epilepsy was significantly higher in the post accident era. Students in the post-accident era answered more frequently that they do not oppose the idea of their kids playing or attending school with children with epilepsy, they think that people with epilepsy should be hired in the same way as other people, and they do not oppose the idea of their children one day marrying a person with epilepsy. The results of our study show that media coverage of car accidents related to persons with epilepsy positively affected familiarity with and attitude toward epilepsy. PMID- 23453533 TI - Suspected coronary artery disease and myocardial infarction with normal coronary angiography: a heterogeneous but benign condition? AB - INTRODUCTION: Previous follow-up studies of patients with symptoms and/or non invasive tests suggestive of ischemia or an acute coronary syndrome and a normal coronary angiogram have reported a good prognosis. OBJECTIVES: The aim of this study was to evaluate the clinical characteristics and outcome of a cohort of patients with suspected ischemic heart disease and normal coronary arteries. METHODS: A clinical follow-up was performed of 607 patients (mean age 62+/-11 years) with symptoms or non-invasive tests suggestive of ischemia (544) or myocardial infarction (63) and normal coronary angiography. The occurrence of major cardiac events or of readmission due to chest pain was recorded during a mean follow-up of 33.6+/-9.5 months after angiography. RESULTS: Patients with myocardial infarction were older (65.4+/-11.1 vs. 61.9+/-10.7, p=0.05), and the majority were women (68.3%). Hypertension was reported by 65.5% of patients, diabetes by 17.9%, dyslipidemia by 58.6%, smoking by 14% and family history of coronary artery disease in 11%. During follow-up no patient died from cardiovascular causes; three patients (0.5%) suffered myocardial infarction and 50 (8.3%) had recurrent chest pain leading to emergency admission. Patients with myocardial infarction had more events (20.6%) than those referred for angiography due to symptoms and/or positive non-invasive tests for ischemia (7.4%) (log-rank chi-square test: 13.6, p<0.0005). CONCLUSION: The incidence of risk factors was high. Our data suggest that patients with a normal angiogram had a good prognosis in spite of their baseline clinical presentation. A significant number of patients showed persistence of symptoms. PMID- 23453534 TI - [Cardiac rehabilitation after myocardial infarction: an invaluable intervention that is little used in Portugal]. PMID- 23453535 TI - [Long-term effects of a cardiac rehabilitation program in the control of cardiovascular risk factors]. AB - INTRODUCTION: Cardiac rehabilitation programs are designed to improve patients' functional capacity, as well as to educate them and to monitor their cardiovascular risk factors. AIM: The study aims to evaluate the effects of cardiac rehabilitation programs in patients with coronary disease over a 12-month follow-up period with regard to control of cardiovascular risk factors. METHODS: This was a prospective study of patients diagnosed with coronary disease who completed an exercise-based cardiac rehabilitation program between January 2008 and December 2009 and who were not lost to follow-up. Patients were evaluated at an early stage (first medical consultation in phase II of the program) and 3, 6 and 12 months later, the following parameters being assessed: weight and body mass index, waist circumference, lipid profile, HbA1c in diabetic patients, blood pressure, smoking status and physical activity (using the International Physical Activity Questionnaire). RESULTS: In the sample of 256 patients (76.2% male, mean age 67 years), dyslipidemia proved to be the most prevalent risk factor (74.2%), followed by overweight (71.5%). There was a statistically significant improvement (p<0,05) in all risk factors studied at the end of phase II of the program, which was maintained at 6 and 12 months of follow-up, with the exception of body mass index (loss of statistical significance at 6-month assessment, p=0,92). CONCLUSION: This study highlights the need for cardiac rehabilitation programs in the context of secondary prevention of cardiovascular disease and the importance of implementing strategies that promote long-term maintenance of their benefits. PMID- 23453536 TI - Ischemic rupture of the anterolateral papillary muscle. AB - We describe the case of a 59-year-old man who presented with chest pain and ST segment elevation in the inferior leads, R>S in V1 and ST depression in the anterior leads due to proximal occlusion of the first obtuse marginal. Primary coronary angioplasty and stenting of this artery were performed. Twelve hours later the patient became hemodynamically unstable and severe mitral regurgitation due to rupture of one of the heads of the anterolateral papillary muscle was diagnosed. Emergency surgery was performed (papillary muscle head reimplantation, mitral annuloplasty with a rigid ring, tricuspid annuloplasty and coronary artery bypass grafting). On surgical inspection, it was observed that the detached muscle head had become trapped in the left ventricle by a secondary cord attached to the other head. This case is unusual in presenting two uncommon features of ischemic papillary muscle: rupture of the anterolateral muscle in myocardial infarction involving the inferoposterior walls, and the fact that the ruptured muscle head did not prolapse because it had become trapped in the left ventricle by secondary cord attachment. PMID- 23453537 TI - Cavernous hemangioma of the cavernous sinus misdiagnosed as a meningioma: a case report and MR imaging findings. AB - Cavernous hemangioma (CH) is a benign vascular malformation. Intracranial CH is generally localized as an intracranial-intraaxial and responsible for 5-13% of all intracranial vascular malformations. Intracranial-extraaxial CHs are rare rather than intracranial-intraaxial CHs. Clinical findings, imaging characteristics, and surgical approach of extraaxial CHs are rather different than intraaxial CHs. Diagnosing cavernous sinus CH preoperatively is very important, but its radiological differential diagnosis is quite difficult. In this study, we present magnetic resonance imaging findings of a 48-year-old male who was considered preoperatively to have meningioma but was diagnosed with cavernous sinus CH during surgery by pathological examination. PMID- 23453538 TI - Factors affecting local progression after percutaneous cryoablation of lung tumors. AB - PURPOSE: To evaluate factors predicting local tumor progression after percutaneous cryoablation of lung tumors (PCLT). MATERIALS AND METHODS: Seventy one consecutive patients with 210 tumors (11 primary and 199 metastatic pulmonary neoplasms; mean maximum diameter, 12.8 mm) were treated with 102 sessions of PCLT. Rates of local tumor progression and technique effectiveness were estimated by Kaplan-Meier method. Multiple variables were evaluated with the log-rank test, followed by uni- and multivariate multilevel analyses to identify independent risk factors, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. All statistical tests were two-sided. RESULTS: Median follow-up period was 454 days (range, 79-2,467 d). Local tumor progression occurred in 50 tumors (23.8%). One-, 2-, and 3-year local progression-free rates were 80.4%, 69.0%, and 67.7%, respectively, and technique effectiveness rates were 91.4%, 83.0%, and 83.0%, respectively. Existence of a thick vessel (diameter>=3 mm) no more than 3 mm from the edge of the tumor was assessed as an independent factor (HR, 3.84; 95% CI, 1.59-9.30; P = .003) associated with local progression by multivariate analysis. CONCLUSIONS: Presence of a vessel at least 3 mm in diameter close to the tumor represents an independent risk factor for local progression after PCLT. PMID- 23453539 TI - Uncertainties of target volume delineation in MRI guided adaptive brachytherapy of cervix cancer: a multi-institutional study. AB - BACKGROUND AND AIM: We aimed to quantify target volume delineation uncertainties in cervix cancer image guided adaptive brachytherapy (IGABT). MATERIALS AND METHODS: Ten radiation oncologists delineated gross tumour volume (GTV), high- and intermediate-risk clinical target volume (HR CTV, IR CTV) in six patients. Their contours were compared with two reference delineations (STAPLE-Simultaneous Truth and Performance Level Estimation and EC- expert consensus) by calculating volumetric and planar conformity index (VCI and PCI) and inter-delineation distances (IDD). RESULTS: VCISTAPLE and VCIEC were 0.76 and 0.72 for HR CTV, 0.77 and 0.68 for IR CTV and 0.59 and 0.58 for GTV. Variation was most prominent caudally and cranially in all target volumes and posterolaterally in IR CTV. IDDSTAPLE and IDDEC for HR CTV (3.6+/-3.5 and 3.8+/-3.4 mm) were significantly lower than for GTV (4.8+/-4.2 and 4.2+/-3.5 mm) and IR CTV (4.7+/-5.2 and 5.2+/ 5.6 mm) (p<0.05). CONCLUSIONS: Due to lower delineation uncertainties when compared to GTV and IR CTV, HR CTV may be considered most robust volume for dose prescription and optimization in cervix cancer IGABT. Adequate imaging, training and use of contouring recommendations are main strategies to minimize delineation uncertainties. PMID- 23453540 TI - Aortic dose constraints when reirradiating thoracic tumors. AB - BACKGROUND AND PURPOSE: Improved radiation delivery and planning has allowed, in some instances, for the retreatment of thoracic tumors. We investigated the dose limits of the aorta wherein grade 5 aortic toxicity was observed after reirradiation of lung tumors. MATERIAL AND METHODS: In a retrospective analysis, 35 patients were identified, between 1993 and 2008, who received two rounds of external beam irradiation that included the aorta in the radiation fields of both the initial and retreatment plans. We determined the maximum cumulative dose to 1 cm(3) of the aorta (the composite dose) for each patient, normalized these doses to 1.8 Gy/fraction, and corrected them for long-term tissue recovery between treatments (NIDR). RESULTS: The median time interval between treatments was 30 months (range, 1-185 months). The median follow-up of patients alive at analysis was 42 months (range, 14-70 months). Two of the 35 patients (6%) were identified as having grade 5 aortic toxicities. There was a 25% rate of grade 5 aortic toxicity for patients receiving composite doses >=120.0 Gy (vs. 0% for patients receiving <120.0 Gy) (P=0.047). CONCLUSIONS: Grade 5 aortic toxicities were observed with composite doses >=120.0 Gy (NIDR >=90.0 Gy) to 1cm(3) of the aorta. PMID- 23453542 TI - Comparing rigid and deformable dose registration for high dose thoracic re irradiation. AB - For patients with locally-recurrent lung cancer, high dose thoracic re irradiation can prolong survival. Deformable image registration improves the accuracy with which initial treatments are accounted for compared to rigid image registration. Using deformable image registration will improve correlative toxicity data, and may reduce toxicity for selected patients undergoing re irradiation. PMID- 23453541 TI - Predictive value of hypoxia, proliferation and tyrosine kinase receptors for EGFR inhibition and radiotherapy sensitivity in head and neck cancer models. AB - BACKGROUND AND PURPOSE: EGFR-inhibitor Cetuximab (C225) improves the efficacy of radiotherapy in only a subgroup of HNSCC patients. Identification of predictive tumor characteristics is essential to improve patient selection. MATERIAL AND METHODS: Response to C225 and/or radiotherapy was assessed with tumor growth delay assays in 4 HNSCC xenograft models with varying EGFR-expression levels. Hypoxia and proliferation were quantified with immunohistochemistry and the expression of proteins involved in C225-resistance with Western blot. RESULTS: EGFR-expression did not predict response to C225 and/or radiotherapy. Reduction of hypoxia by C225 was only observed in SCCNij202, which was highly sensitive to C225. Proliferation changes correlated with response to C225 and C225 combined with radiotherapy, as proliferation decreased after C225 treatment in C225 sensitive SCCNij202 and after combined treatment in SCCNij185, which showed a synergistic effect to combined C225-radiotherapy. Furthermore, C225-resistant SCCNij153 tumors expressed high levels of (activated) HER3 and MET. CONCLUSIONS: EGFR-expression is needed for C225-response, but is not sufficient to predict response to C225 with or without radiotherapy. However, basal expression of additional growth factor receptors and effects on proliferation, but not hypoxia, correlated with response to combined C225-radiotherapy treatment and are potential clinically relevant predictive biomarkers. PMID- 23453543 TI - Inter-application variation of dose and spatial location of D(2cm(3)) volumes of OARs during MR image based cervix brachytherapy. AB - PURPOSE: Evaluation of Inter-application variation of doses and spatial location of D(2cm(3)) volumes of OARs during MR-image based cervix brachytherapy. MATERIALS AND METHODS: Twenty-seven patients treated with EMBRACE protocol were analyzed. Every patient had two applications, one week apart. For each application patient had undergone MR-imaging (MR-1 and MR-2), volume delineation, reconstruction, treatment planning (plan-1 and plan-2) and dose evaluation. Both the image series were then co-registered with applicator as the reference coordinate system (Eclipse planning system v8.6.14). Inter-application dose, volume and spatial location of D(2cm(3)) variation were evaluated. RESULTS: The largest inter-application systematic and random dose variations were observed for sigmoid as compared to rectum and bladder. The mean (+/-SD) of the relative D(2cm(3)) variations were 0.6(+/-15.1)%, 0.9(+/-13.1)% and 11.9(+/-37.5)% for rectum, bladder and sigmoid respectively. The overlap of D(2cm(3)) volumes was more than 50% in 16(59%), 8(30%) and 3(11%) patients for rectum, bladder and sigmoid, respectively. CONCLUSION: The 2cm(3) volumes between the applications/fractions are quite stable in topography for bladder and rectum, and hence the current practice of cumulative addition of D(2cm(3)) dose is expected to be valid for bladder and rectum. For sigmoid, significant topographical changes were seen, which need further validation in a larger patient population and in multi-centric settings. PMID- 23453544 TI - Evaluation of varicella zoster virus infection morbidity and mortality in pancreas and kidney-pancreas transplant recipients. AB - BACKGROUND: Solid organ transplant recipients are at increased risk of infection due to chronic immunosuppression. The incidence of varicella zoster virus (VZV) infection is known to be increased in these patients compared with the immunocompetent population. Previous reports suggested that these patients are likely to experience a morbid disease course. Few data currently exist on the course of VZV infections in pancreas or pancreas plus kidney (PK) transplant recipients. OBJECTIVE: The goal of this study was to evaluate the incidence and severity of VZV infections in pancreas or PK recipients. STUDY DESIGN: We analyzed the transplantation patient database of the Royal Victoria Hospital, identifying 137 pancreas or PK transplantation procedures performed between January 1999 and October 2010, among which we included 98 patients in the study. We subsequently performed a retrospective chart review to evaluate the incidence and severity of VZV infections posttransplantation. RESULTS: Our analysis revealed that 11/98 patients developed VZV infections. The majority of infections (~90.9%) occurred within the first 5 years. Most patients (63.6%) were treated on an outpatient basis, whereas only 4 (36.4%) were hospitalized with a mean hospital stay of 9.5 +/- 8.42 days. The initial immunosuppressive regimen remained unchanged for the majority of patients. All patients experienced a mild disease course without intensive care unit admission or death. Only 3 patients (27.3%) developed postherpetic neuralgia. CONCLUSION: These findings suggest that with timely diagnosis and proper treatment, most patients recover well from a VZV infection. PMID- 23453545 TI - The use of continuous positive airway pressure or non-invasive ventilation as forms of respiratory support in children with cystic fibrosis. AB - Non-invasive ventilation is used in patients with cystic fibrosis to treat respiratory failure, as a bridge to transplantation and as an adjunct to airway clearance techniques, despite a limited evidence base, particularly amongst the paediatric population. Where early CF lung disease is complicated by tracheobronchomalacia, we believe CPAP has good theoretical reasons for benefit and we describe a case which serves to illustrate these benefits in clinical practice. As time and technology move on we may begin to see more children with cystic fibrosis being treated with respiratory support. PMID- 23453546 TI - The Global School Adaptation score: a new neurodevelopmental assessment tool for very preterm children at five years of age. AB - OBJECTIVE: To determine the usefulness of a neurodevelopmental assessment tool consisting of a questionnaire administered to teachers to measure the Global School Adaptation (GSA) scores of very preterm children at the age of 5 years. STUDY DESIGN: A sample of 445 very preterm children (<35 weeks of gestation) was assessed at 5 years of age using GSA and IQ scores. According to the consistency between the scores, children were determined to be well classified, intermediately classified, or misclassified. The differences between groups were assessed through univariate and multivariate logistic regression. RESULTS: The GSA score was highly or intermediately consistent with the IQ score for 89.2% of the children, and 10.8% were considered misclassified. Children with a higher GSA than IQ score had more autonomy and self-confidence (P < .01), and those with a lower GSA than IQ score had more behavioral problems (P < .01). Analysis by logistic regression showed that sex and gestational age significantly affected the consistency between the 2 scores. Thus, girls were less likely to have a lower GSA than IQ score (aOR = 0.45; 95% CI: 0.24-0.84; P = .01), and a lower gestational age significantly increased the likelihood of having a higher GSA than IQ score (for children born between 24 and 28 weeks of gestation: aOR = 2.70; 95% CI: 1.23-5.92; P = .01). CONCLUSIONS: The GSA score is a simple, inexpensive, and reliable screening tool for assessing neurodevelopment in very preterm children at 5 years of age. PMID- 23453547 TI - Early enteral fat supplement and fish oil increases fat absorption in the premature infant with an enterostomy. AB - OBJECTIVE: To test the hypothesis that in the premature infant with an enterostomy, early enteral supplementation with Microlipid (fat supplement) and fish oil increases enteral fat absorption and decreases the requirement for Intralipid (intravenous fat emulsion). STUDY DESIGN: Premature infants (<2 months old) with an enterostomy after surgical treatment for necrotizing enterocolitis or spontaneous intestinal perforation and tolerating enteral feeding at 20 mL/kg/day were randomized to usual care (control 18 infants) or early supplementing enteral fat and fish oil (treatment 18 infants). Intravenous fat emulsion was decreased as enteral fat intake was increased. Daily weight, ostomy output, and nutrition data were recorded. Weekly 24-hour ostomy effluent was collected until bowel reanastomosis, and fecal fat, fecal liquid, and dry feces were measured. Fat absorption (g/kg/d) was calculated by subtracting fecal fat from dietary fat. The fecal liquid and dry feces were reported as mg/g wet stool. Date were analyzed by using ANOVA and mixed-effects model. RESULTS: The interval from initial postoperative feeding to bowel reanastomosis varied from 2 to 10 weeks. The treatment group received more dietary fat and less intravenous fat emulsion and had higher enteral fat absorption, less fecal liquid, and drier feces than the control group. These effects were greater among infants with a high ostomy compared with those with a low ostomy. Enteral fat intake was significantly correlated with fat absorption. CONCLUSION: Early enteral fat supplement and fish oil increases fat absorption and decreases the requirement for intravenous fat emulsion. This approach could be used to promote bowel adaptation and reduce the use of intravenous fat emulsion in the premature infant with an enterostomy. PMID- 23453548 TI - Spontaneous intracranial hypotension in childhood and adolescence. AB - OBJECTIVES: To describe the clinical and radiographic manifestations of spontaneous intracranial hypotension, a rarely diagnosed cause of headache in children. STUDY DESIGN: This study included patients 19 years of age or younger evaluated between January 1, 2001, and June 30, 2012, for spontaneous intracranial hypotension. RESULTS: We evaluated 24 children (18 girls and 6 boys) with spontaneous intracranial hypotension (age at onset of symptoms: 2-19 years, mean 14.3 years). Twenty-three patients presented with orthostatic headaches and 1 presented with a nonpositional headache. A generalized connective tissue disorder was diagnosed in 54% of patients. Magnetic resonance imaging showed the typical changes of spontaneous intracranial hypotension in most patients (79%). Spinal imaging demonstrated a cerebrospinal fluid (CSF) leak with or without an associated meningeal diverticulum in 12 patients (50%) and with dural ectasia or meningeal diverticula in 10 patients (42%), and it was normal in 2 patients (8%). Twenty-three patients initially underwent epidural blood patching, but 8 patients also were treated with percutaneous injections of fibrin glue and 11 patients eventually required surgical correction of the underlying CSF leak. There was no morbidity or mortality associated with any of the treatments, but 5 patients required acetazolamide for rebound high intracranial pressure headache. Overall, outcome was good in 22 patients (92%) and poor in 2 patients (8%). CONCLUSIONS: Spontaneous intracranial hypotension in childhood is rare. Most patients can be treated effectively using a combination of epidural blood patching and percutaneous injections of fibrin glue or surgical CSF leak repair in refractory cases. PMID- 23453549 TI - Changing the paradigm in pediatric acute kidney injury. PMID- 23453550 TI - Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults. AB - OBJECTIVE: To examine the effect on adult cognitive function of being born small for gestational age (SGA), and to evaluate whether cognitive function is related to intrauterine growth restriction (IUGR). STUDY DESIGN: Fifty-nine SGA subjects (birth weight <10th percentile) and 81 controls (birth weight >=10th percentile) born at term underwent cognitive assessment with the Wechsler Adult Intelligence Scale-Third Edition at age 19-20 years. Repeated ultrasound measures of fetal growth were available for weeks 25, 33, and 37 in a subgroup of 29 SGA subjects and 75 control subjects, and these were data used to dichotomize the 29 SGA subjects into those with IUGR and those without IUGR. IUGR was defined as growth deviating more than -2 SD from the mean value of the control group. The effect of maternal smoking during pregnancy was considered as well. Group differences were analyzed using a general linear model, controlling for sex and socioeconomic status. RESULTS: The SGA group had lower full IQ scores than the control group (mean difference, -6.3; 95% CI, -2.8 to -9.7; P = .001), including lower scores on 6 of the Wechsler Adult Intelligence Scale-Third Edition subtests. In the SGA subgroup with repeated ultrasound measures, 6 of 29 subjects (21%) had IUGR, and these subjects also had a lower IQ compared with controls (mean difference, 14.0; 95% CI: -4.8 to -23.3; P = .003). Maternal smoking during pregnancy was related to lower IQ in the control group but not in the SGA group, independent of IUGR or non-IUGR status. CONCLUSION: IQ scores were lower in young adults born SGA compared with controls. Our analysis suggest that this outcome is related to IUGR. PMID- 23453551 TI - What are we missing? Arrhythmia detection in the pediatric intensive care unit. AB - OBJECTIVES: To test the hypothesis that instituting a process of routine daily review of rhythm alarms in non-cardiac patients in the pediatric intensive care unit would yield clinically important disturbances that would otherwise go undetected. STUDY DESIGN: A prospective observational study was performed over a consecutive 28-day period. Total bedside monitor alarms, rhythm alarms, and heart rate (HR) trends were recorded. Rhythm alarm recordings were reviewed independently by two study team members. Medical records for patients with critical arrhythmias were reviewed to evaluate for prior knowledge of the event and to correlate with clinical data. RESULTS: We evaluated 86 patients (343 patient-days). There were 54,656 total monitor alarms (159.3 alarms/patient-day), of which 19,970 (37%) were rhythm alarms, including 4032 (20%) critical arrhythmias. Fifty-six percent of the critical alarms were artifactual. Seventeen of the 1786 ventricular tachycardia alarms represented true episodes that occurred in 5 patients. Two patients' care were altered as a result of detection of the arrhythmia in the review process. Eight hundred sixty-five (98%) of the 883 true critical alarms reviewed were for extreme HR. Eighty-three percent (5172) of the 6239 true non-critical alarms reviewed were HR alarms. CONCLUSIONS: Daily review of rhythm alarms improves detection of clinically relevant arrhythmias in non-cardiac pediatric intensive care unit patients. PMID- 23453552 TI - Multichannel intraluminal impedance to study gastroesophageal reflux in mechanically ventilated children in the first 48 h after PICU admission. AB - OBJECTIVE: The aim of this study was to determine the incidence, characteristics, related factors, and clinical implications of gastroesophageal reflux (GER) in critically ill children using esophageal pH monitoring and multichannel intraluminal impedance. METHODS: A prospective observational clinical study was performed including 36 non-enterally fed critically ill children with mechanical ventilation, aged 1 mo to 7 y, in the first 48 h after admission in the pediatric intensive care unit (PICU). Esophageal pH monitoring and multichannel intraluminal impedance were used. RESULTS: Multichannel intraluminal impedance detected 352 episodes of GER (20.1% acid, 53.8% weak acid, 26% alkaline), whereas pH monitoring detected 171 episodes (100% acid). There were no differences in the type of reflux according to age and no differences in the number or type of reflux according to the administration of inotropic or sedatives drugs or the duration of mechanical ventilation. Patients treated with vecuronium had fewer episodes of GER than those without muscle relaxant drugs. CONCLUSIONS: The incidence of GER in non-enterally fed critically ill children with mechanical ventilation is high in the first 48 h after admission to the PICU. Multichannel intraluminal impedance is more sensitive than pH monitoring for establishing the diagnosis of GER because the refluxate is alkaline or weak acid in the majority of episodes. Patients who received muscle relaxants had a lower frequency of GER. PMID- 23453553 TI - Novel diet for patients with impaired mastication evaluated by consumption rate, nutrition intake, and questionnaire. AB - OBJECTIVE: "iEat((r))" (EN Otsuka Pharmaceutical Co. Ltd.; study diet), a food product that resembles an ordinary meal in appearance but is cooked to soften, was compared with foods provided to patients with impaired mastication (modified traditional diet) to investigate the influence of the appearance of foods on the consumption rate, dietary nutrition intake, and satisfaction level. METHODS: After serving the study participants the modified traditional diet on days 1 and 2, the study diet on days 3, 4, and 5, and the modified traditional diet on days 6 and 7, the consumption rates were measured by weight difference. The amounts of dietary nutrition intake were calculated from the consumption rates. Satisfaction levels were evaluated by a questionnaire completed by the participants and their health care professionals after each meal. RESULTS: No significant difference in consumption rates was observed between the study diet and the modified traditional diet. The amounts of dietary nutrition intake of energy and protein were significantly higher for the study diet than for the modified traditional diet. The study diet showed higher satisfaction levels in terms of "appearance" when evaluated by the participants, and "joy of eating" and "overall satisfaction level" when evaluated by the health care professionals. CONCLUSION: The study diet has potential to become a new dietary option for patients with impaired mastication. PMID- 23453554 TI - Tea and coffee consumption and risk of oral cavity cancer: results of a large population-based case-control study, the ICARE study. AB - BACKGROUND: Results on the relationship between coffee and tea drinking and the risk of oral cavity cancer are contrasted. The aim of this study was to evaluate the relation between coffee and tea drinking and the risk of oral cavity cancer in France, a high incidence area. MATERIAL AND METHODS: We conducted a population based case-control study with face-to-face interviews and standardized questionnaires (the ICARE study, Investigation of occupational and environmental causes of respiratory cancers). We used data from 689 cases of oral cavity squamous cell carcinoma and 3481 controls. Odds-ratios (ORs) and 95% confidence intervals (95% CI) associated with tea and coffee consumption (quantity, duration, cumulative consumption) were estimated by unconditional logistic regression with adjustment for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking. RESULTS: We observed inverse associations between oral cavity cancer and tea or coffee consumption (odds ratio, 0.39; 95% CI 0.21-0.70, for the highest quartile of tea consumption, and 0.60, 95% CI 0.34-1.05, for the highest quartile of coffee consumption). Exclusive tea or coffee consumption was associated with a reduced risk of oral cavity cancer and their joint effect was multiplicative. No differences in risk between men and women or between consumers of tobacco and alcohol and non consumers were observed. The odds ratios related to the subsites usually included in the oropharynx (soft palate and base of the tongue) did not differ significantly from that observed for the other subsites of the oral cavity. CONCLUSIONS: Tea and coffee drinking may decrease the risk of oral cavity cancer through antioxidant components which play a role in the repair of cellular damages. These findings need further investigation in prospective studies and the underlying mechanisms in humans remain to be clarified. PMID- 23453555 TI - Is there a decreased risk of intracerebral hemorrhage and mortality in obese patients treated with intravenous thrombolysis in acute ischemic stroke? AB - BACKGROUND: The current guidelines do not recommend increasing the dose of intravenous recombinant tissue plasminogen activator (IV rt-PA) for ischemic stroke patients weighing >100 kg. Obese patients are therefore receiving an IV rt PA dose <0.9 mg/kg; however, the consequences of such underdosing are unknown. Our goal was to determine the relationship between obesity and clinical outcomes among acute ischemic stroke patients receiving IV rt-PA. METHODS: Data from all patients admitted to US hospitals between 2002 and 2009 who were treated with IV thrombolysis and who had a primary discharge diagnosis of stroke were included. The effect of obesity on rates of intracerebral hemorrhage and discharge outcomes was analyzed after adjusting for potential confounders using logistic regression analysis. RESULTS: Of the 81,579 patients with ischemic stroke treated with IV rt PA, 5174 (6.3%) were categorized as obese. The intracerebral hemorrhage rates in obese and nonobese patients were significantly different (4.5% v 6.3%; P = .01). After adjusting for age, sex, presence of hypertension, diabetes mellitus, location/teaching status and All Patient Refined Diagnosis Related Group severity scale, there was no difference in the rates of no to minimal disability between obese and nonobese patients (odds ratio [OR] 1.0; 95% confidence interval [CI] 0.8-1.2; P = .8). Obese patients had lower odds of in-hospital mortality (OR 0.6; 95% CI 0.5-0.8; P = .001) but also more likely to be discharged with moderate to severe disability (OR 1.2; 95% CI 1.01-1.3; P = .03). CONCLUSIONS: Obese patients receiving IV rt-PA treatment for acute ischemic stroke appear to have a higher survival rate most likely related to their decreased rates of intracerebral hemorrhage. PMID- 23453556 TI - Hemorrhagic transformation during thrombolytic therapy and reperfusion: effects of age, blood pressure, and matrix metalloproteinases. AB - BACKGROUND: Despite the increasing use of thrombolytic therapy for acute ischemic stroke, hemorrhagic transformation remains a significant complication. Transformation appears to occur more frequently with age, diabetes, and hypertension, but clinical data are mixed. In addition to risk factors, matrix metalloproteinase expression mediates hemorrhage. We sought to test the effects of age, hypertension, and matrix metalloproteinases during recombinant tissue plasminogen activator (rt-PA) treatment in a standard model of filament occlusion of the middle cerebral artery. METHODS: We compared young and aged rats who were genetically predisposed to hypertension to similar and dissimilar strains to separate the effect of hypertension and age. RESULTS: Hemorrhagic transformation occurred significantly more frequently in chronically hypertensive animals-23 of 53 (44%) compared to 2 of 23 (9%) normotensive, genetically similar rats (Chi square; P < .001; Mantel-Haenszel common odds ratio estimate 12.33 [95% confidence interval 2.7-57.0]). Hemorrhage rates were comparable in aged and young chronically hypertensive animals. Induced acute hypertension during reperfusion did not appear to alter rates of transformation. In hypertensive (n = 26) compared to genetically similar normotensive (n = 12) animals, rt-PA treatment increased mortality to 35% from 0% (Chi-square; P < .05), while hemorrhage occurred in 50% of the rt-PA-treated hypertensive subjects compared to 8% of the normotensive animals (Chi-square; P < .05). Two different inhibitors of matrix metalloproteinases significantly reduced mortality but not hemorrhage rates. CONCLUSIONS: Our data suggest for the first time an effect of chronic hypertension separate from age on the risk of hemorrhagic transformation. In addition, inhibitors of matrix metalloproteinases may protect the neurovascular unit directly, even without reducing hemorrhage risk. These findings will require additional research. PMID- 23453557 TI - Accuracy of image-free computer navigated total knee arthroplasty is not compromised in severely deformed varus knees. AB - In severe varus knee deformity, image-free computer navigated total knee arthroplasty (TKA) may result in a malaligned knee. The aim of this study was to compare the results of 17 severe varus knees (>= 20 degrees ) and 81 varus knees (< 20 degrees ) that underwent image-free computer navigated TKA and analyze postoperative malalignment. Computer navigated TKA was performed according to standard protocol, and component angles and mechanical axes were evaluated postoperatively with weight bearing full-length standing radiographs. All severe varus knees were corrected to within 3 degrees of neutral lower limb alignment despite having a mean preoperative varus deformities of 22.4 degrees . Neutral alignment was obtained in 88.9% of the varus group (mean preoperative varus deformity of 11.7 degrees ), without significant difference between the two groups. No significant difference was found in either the femoral or tibial component angles, or in the frequency of complications. Severity of varus deformity did not affect the accuracy of image-free computer navigated TKA. PMID- 23453558 TI - Determination of acoustical nonlinear parameter beta of water using the finite amplitude method. AB - The acoustic nonlinearity of water is investigated using a variation of the finite amplitude method with harmonic generation. The finite amplitude method provides information on the coefficient of nonlinearity, beta, through the ratio of the amplitude of the fundamental and that of the second harmonic. The pressure of both the fundamental, p1, and that of the second harmonic, p2, are determined experimentally at different transmitter-receiver separation distances, eliminating the need for knowledge of the sound absorption in the medium. It was found that the experimental relationship between the slope of p2(x)/p1(2)(x) and transmitter-receiver separation distance, x, follows a linear relationship only in the near-field, in good agreement with theoretical predictions. A beta of 3.5+/-0.1 is determined for water at room temperature, in good agreement with previous results from both the isentropic equation of state and finite amplitude method. PMID- 23453559 TI - [Screening for adenocarcinoma in Barrett's esophagus: yes or no, when and how?]. AB - Barrett's esophagus (BE) is the main recognized risk factor for the development of esophageal adenocarcinoma (EAC). The incidence of this cancer and its associated mortality has increased in developed countries during the last few years. Detection of EAC at earlier stages could potentially improve survival dramatically in these patients, which is especially important as mortality from EAC remains high despite the available treatments. Therefore, endoscopic surveillance is an attractive option for patients with Barrett's esophagus. Consequently, periodic endoscopic surveillance is recommended by all the International Gastroenterology Societies in an attempt to detect EAC at an early and potentially curable stage. Currently, the frequency of endoscopic surveillance and its need in Barrett's esophagus with low-grade dysplasia or without dysplasia are under discussion. This review presents the available evidence in order to assist clinicians in the decision-making process. PMID- 23453560 TI - [Diarrhea due to visceral leishmaniasis in a liver transplant recipient]. PMID- 23453561 TI - Resolution of refractory thrombotic thrombocytopenic purpura (TTP) after successful treatment of a fulminant colitis due to Entamoeba histolytica. PMID- 23453562 TI - Mere intention to perform painful movements elicits fear of movement-related pain: an experimental study on fear acquisition beyond actual movements. AB - Fresh empirical evidence supports the notion that fear of movement-related pain can be acquired through associative learning. In the context of these findings, 2 ideas are appealing, yet uninvestigated. The first is that merely the intention to perform a painful movement acts as a covert conditioned stimulus (CS) inducing defensive fear responses (ie, gaining excitatory properties following Pavlovian acquisition). The second idea is that after extinction, fear of movement-related pain can easily be reinstated after unexpected painful stimuli (ie, reinstatement). In a voluntary differential conditioning movement paradigm with movements as CSs and a painful electrocutaneous stimulus as the unconditioned stimulus (pain-US), 2 groups were included (Experimental/Control). One movement (CS+) was followed by the pain-US and another movement (CS-) was not during acquisition, while the CS+ was no longer reinforced during extinction. Next, the Experimental group received 2 reinstating pain-USs, whereas the Control group did not. The CS+ but not the CS- evoked fear of movement-related pain in self-reports and eye-blink startles. Intriguingly, the mere intention to perform the painful movement produced higher eye-blink startle responses than the intention to perform the nonpainful movement. We also demonstrated nondifferential reinstatement in the verbal fear ratings in the Experimental group only. PERSPECTIVE: This study demonstrates that the mere intention to perform a painful movement prior to the actual painful movement itself can come to elicit conditioned fear responses. These results suggest that actual movement may not be necessary to elicit pain-related fear responses, maintaining chronic pain-related fear, avoidance, and disability. PMID- 23453563 TI - Use of ClinicalTrials.gov to estimate condition-specific nocebo effects and other factors affecting outcomes of analgesic trials. AB - ClinicalTrials.gov is a registry and results database of federally and privately supported clinical trials conducted worldwide. We sought to answer: what are the characteristics of pain trials; how frequently are these trials stopped and why; what is the magnitude of attrition due to lack of efficacy or adverse events; and whether the withdrawal rates depend on pain syndrome. To facilitate this and subsequent studies, we have developed a system called Sherlock that automatically downloads data from ClinicalTrials.gov into a relational database. We included pain interventional trials. To evaluate attrition, we restricted consideration to prospective randomized, parallel, double-blind, placebo-controlled trials. Of the 82,867 trials, 6% reported results and 5.6% terminated before the planned number of subjects was accrued. Of these early terminations, 38% were due to enrollment difficulties. In the placebo arms, 3.8% of participants withdrew due to lack of efficacy and 4.9% due to adverse events, with proportions differing among pain conditions. Compared with migraine trials, in fibromyalgia trials 5.1% more participants withdrew due to lack of efficacy (95% confidence interval [CI], 2.5 7.8%), and 6.4% more withdrew due to adverse events (95% CI, 4.3-8.6%). Nonsteroidal anti-inflammatory drugs were the treatment class with the lowest adverse events withdrawals. Recruitment challenges account for the largest proportion of noncompleted trials. Attrition rates differ across pain conditions. Migraine studies had the lowest withdrawal rate. Tools like Sherlock facilitate conducting research in the ClinicalTrials.gov registry. PERSPECTIVE: ClinicalTrials.gov registry enables researchers to get a snapshot of a specific field and observe changes over time in trial design, including numbers of subjects accrued, and it can inform clinical trial design. We learned that recruitment challenges account for the largest proportion of noncompleted trials, attrition rates differed across pain conditions, and migraine studies had the lowest withdrawal rate. PMID- 23453564 TI - Changes resembling complex regional pain syndrome following surgery and immobilization. AB - The study of complex regional pain syndrome (CRPS) in humans is complicated by inhomogeneities in available study cohorts. We hoped to characterize early CRPS like features in patients undergoing hand surgery. Forty-three patients were recruited from a hand surgery clinic that had elective surgeries followed by cast immobilization. On the day of cast removal, patients were assessed for vasomotor, sudomotor, and trophic changes, and edema and pain sensitization using quantitative sensory testing. Pain intensity was assessed at the time of cast removal and after 1 additional month, as was the nature of the pain using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS). Skin biopsies were harvested for the analysis of expression of inflammatory mediators. We identified vascular and trophic changes in the surgical hands of most patients. Increased sensitivity to punctate, pressure, and cold stimuli were observed commonly as well. Moreover, levels of IL-6, TNF-alpha, and the mast cell marker tryptase were elevated in the skin of hands ipsilateral to surgery. Moderate-to-severe pain persisted in the surgical hands for up to 1 month after cast removal. Exploratory analyses suggested interrelationships between the physical, quantitative sensory testing, and gene expression changes and pain-related outcomes. PERSPECTIVE: This study has identified CPRS-like features in the limbs of patients undergoing surgery followed by immobilization. Further studies using this population may be useful in refining our understanding of CRPS mechanisms and treatments for this condition. PMID- 23453565 TI - Effect of experimental stress in 2 different pain conditions affecting the facial muscles. AB - Chronic facial muscle pain is a common feature in both fibromyalgia (FM) and myofascial (MF) pain conditions. In this controlled study, a possible difference in the mode of deregulation of the physiological response to a stressing stimulus was explored by applying an acute mental stress to FM and MF patients and to controls. The effects of the stress test were observed on pain, sympathetic variables, and both tonic and reflex electromyographic activities of masseteric and temporal muscles. The statistical analyses were performed through a generalized linear model including mixed effects. Painful reaction to the stressor was stronger (P < .001) and longer (P = .011) in FM than in MF independently of a higher pain level at baseline. The stress-induced autonomic changes only seen in FM patients did not reach significance. The electromyographic responses to the stress test were strongest for controls and weakest for FM. The stress test had no effect on reflex activity (area under the curve [AUC]) or latency, although AUC was high in FM and latencies were low in both pain groups. It is suggested that FM is characterized by a lower ability to adapt to acute stress than MF. PERSPECTIVE: This study showed that an acute psychosocial stress triggered several changes in 2 pain conditions including an increase in pain of larger amplitude in FM than in MF pain. Similar stress induced changes should be explored as possible mechanisms for differentiation between dysfunctional pain conditions. PMID- 23453567 TI - Variations in patient satisfaction with care for breast, lung, head and neck and prostate cancers in different cancer care settings. AB - PURPOSE OF THE RESEARCH: To assess cancer patients' satisfaction and the extent to which it varies between cancer care centres. METHODS AND SAMPLE: This is a multi-site descriptive study reporting on the satisfaction of patients with breast, prostate, head and neck and lung cancers in Cyprus. The sample consisted of 272 patients randomly selected. Data were retrieved with the Patient satisfaction Scale additionally to 7 single questions reflecting 7-care dimensions namely "access to care", "explanation at first visit", "understanding of diagnosis and treatment", "first treatment: respect communication and involvement", "first treatment: pain and discomfort", "first treatment: hospital management" and "discharged co-ordination". RESULTS: Participants were overall satisfied by the nursing care (mean 3.5) however, dissatisfaction was expressed in relation to the 7-care dimensions (p < 0.001). Variations in satisfaction were found across the oncology settings as well as across cancer types. The variables gender, age, marital status, level of education, length of stay in the department, previous hospitalization, tumour type and treatment type had an influence on patients' perceived satisfaction (p < 0.001). CONCLUSIONS: Seemingly identical nursing care can be measurably different between cancer care centres. Based on the findings the satisfaction variations can be attributed to factors personally experienced by the patients as well as to systemic hospital-level factors. The notion of patient satisfaction is important to clinical practice as a tool to assess and plan the nursing care and managers should bear in mind that patient satisfaction is sensitive to person specific variables as well as to many extraneous variables. PMID- 23453566 TI - Sex differences of gray matter morphology in cortico-limbic-striatal neural system in major depressive disorder. AB - Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naive participants with MDD. Participants included 29 medication-naive individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyzes of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p < 0.05, corrected) in the left ventral prefrontal cortex, right amygdala, right hippocampus and bilateral caudate when comparing the MDD and HC groups. Posthoc analyzes showed that females with MDD had significant GM decreases in limbic regions (p < 0.05, corrected), compared to female HC; while males with MDD demonstrated significant GM reduction in striatal regions, (p < 0.05, corrected), compared to HC males. The observed sex-related patterns of abnormalities within the cortico-limbic-strial neural system, such as predominant prefrontal-limbic abnormalities in MDD females vs. predominant prefrontal-striatal abnormalities in MDD males, suggest differences in neural circuitry that may mediate sex differences in the clinical presentation of MDD and potential targets for sex differentiated treatment of the disorder. PMID- 23453568 TI - Prerequisites required for the provision and use of web-based communication for psychosocial support in haematologic care. AB - PURPOSE: The purpose of this study was to describe the prerequisites required for the provision and use of web-based communication for psychosocial support within a haematology clinic, from a patient and family perspective. METHOD: A qualitative design using content analysis was used. A strategically selected sample of patients (n = 11) and family members (n = 6) were offered access to a web-based communication capability with a nurse. After four months, individual interviews were conducted with all participants, in order to identify necessary prerequisites. RESULTS: Preferences and characteristics of the individual patient or family member are crucial as to whether web-based communication for support is perceived as useful. To feel comfortable with writing and to self-identify the need for support are fundamental in getting motivated to use web-based communication. An effective organization around psychosocial support in general is another prerequisite. Goals and responsibilities must be clearly defined for patients and family members to understand their rights and enable the transformation of opportunities into practice. The use of web-based communication must also be a convenient and naturally incorporated part of both individual and organizational use of the web in general. CONCLUSIONS: Prerequisites of taking into account caretakers' different preferences and needs, providing highly structured psychosocial support activities and providing a congruent range of web services, are necessary for successful provision and use of web-based communication for psychosocial support. PMID- 23453569 TI - Introducing a new stop smoking service in an acute UK hospital: a qualitative study to evaluate service user experience. AB - PURPOSE: Smoking is a risk factor for numerous cancers yet many smokers do not become motivated to quit until they are admitted to hospital with a smoking related illness. The provision of smoking cessation services in hospitals could therefore be helpful to these patients. This study aimed to explore the user experience of one such service in a UK hospital and identify whether the service assisted patients to quit smoking. METHOD: A qualitative approach was used which incorporated face-to-face structured interviews with 44 patients across 4 clinical specialties in an acute hospital in the UK. Data collection also involved follow-up telephone interviews with nineteen participants approximately 6 weeks later. Data were analysed using a thematic analysis. RESULTS: Patients with a variety of diagnoses, including cancer, participated in the study and all welcomed the opportunity to access the hospital service. Hospital was seen as an appropriate venue, where it was easier to make a quit attempt and there was ready access to nicotine replacement therapy (NRT) and a supportive environment. A number of 'pushes' towards, and 'pulls' away from quitting emerged from the data and were demonstrated outwardly by how ready the patient was to quit. CONCLUSIONS: The hospital environment provided a prime opportunity to offer stop smoking advice, assessment and treatment to patients. The provision of this service outside of traditional locations broadened opportunities for access particularly when patients were ready to quit. This service therefore made a positive contribution to the stop smoking agenda. PMID- 23453570 TI - Long term effect of surgery and radiotherapy for colorectal cancer on defecatory function and quality of life. AB - PURPOSE: Survival from rectal cancer has improved substantially. Understanding the consequences of treatment is important to optimise patient support and minimise impact on daily life. We aimed to define the long-term prevalence of pelvic dysfunction following curative rectal cancer surgery (+/- radiotherapy) within the context of overall quality of life. METHODS: We evaluated bowel, urinary and sexual function and quality of life using three validated questionnaires in patients treated for rectal cancer. This group was compared to patients undergoing abdominal surgery without pelvic dissection for colon cancer during the same time period. RESULTS: The response rate was 57% (381/667) with a median time interval of 4.4 years. A subset of rectal patients documented persistent problems with faecal leakage (16%); requiring to alter daily activities (18%); always needing to wear a protective pad (17%); rarely or never emptying their bowels fully (31%); difficulty controlling the passage of gas (32%) and requiring to modify diet (30%). Altered bowel function was found to impact on overall quality of life. Men reported increased erectile function difficulties. Pre-operative radiotherapy was associated with increased defecation problems as was low level of anastomosis (<=6 cm). CONCLUSION: In keeping with emergent evidence, this study has quantified the extent of late adverse effects with a sub-set of rectal cancer patients reporting persistent bowel function problems. The implications are now to consider current follow-up services and to 'trial' new models of comprehensive assessment and interventions in patients who are 'at risk' of experiencing late adverse effects of treatment. PMID- 23453571 TI - Characterization of 25+ year survivors of cardiac transplantation. PMID- 23453573 TI - Prognostic utility of the Seattle Heart Failure Score and amino terminal pro B type natriuretic peptide in varying stages of systolic heart failure. AB - BACKGROUND: Cardiac transplantation represents the best procedure to improve long term clinical outcome in advanced chronic heart failure (CHF), if pre-selection criteria are sufficient to outweigh the risk of the failing heart over the risk of transplantation. Although the cornerstone of success, risk assessment in heart transplant candidates is still under-investigated. Amino terminal pro B-type natriuretic peptide (NT-proBNP) is regarded as the best predictor of outcome in CHF, and the Seattle Heart Failure Score (SHFS), including clinical markers, is widely used if NT-proBNP is unavailable. METHODS: The present study assessed the predictive value for all-cause death of the SHFS in CHF patients and compared it with NT-proBNP in a multivariate model including established baseline parameters known to predict survival. RESULTS: A total of 429 patients receiving stable HF specific pharmacotherapy were included and monitored for 53.4 +/- 20.6 months. Of these, 133 patients (31%) died during follow-up. Several established predictors of death on univariate analysis proved significant for the total study cohort. Systolic pulmonary arterial pressure (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.02-1.05); p < 0.001, Wald 15.1), logNT-proBNP (HR, 1.51; 95% CI, 1.22-1.86; p < 0.001, Wald 14.9), and the SHFS (HR, 0.99; 95% CI, 0.99-1.00; p < 0.001, Wald 12.6) remained within the stepwise multivariate Cox regression model as independent predictors of all-cause death. Receiver operating characteristic curve analysis revealed an area under the curve of 0.802 for logNT-proBNP and 0.762 for the SHFS. CONCLUSIONS: NT-proBNP is a more potent marker to identify patients at the highest risk. If the NT-proBNP measurement is unavailable, the SHFS may serve as an adequate clinical surrogate to predict all-cause death. PMID- 23453572 TI - Children with pulmonary arterial hypertension and prostanoid therapy: long-term hemodynamics. AB - BACKGROUND: Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil. METHODS: This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant. RESULTS: Mean age at baseline was 7.7 +/- 5.2 years, with follow-up of 4.3 +/- 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 +/- 0.4, 0.8 +/- 0.4, 0.8 +/- 0.4, 1.0 +/- 0.4, and 1.2 +/- 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 +/- 0.3, 0.7 +/- 0.3, 0.5 +/- 0.2, (p < 0.01 vs baseline), and 1.1 +/- 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%). CONCLUSION: There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies. PMID- 23453574 TI - Pirfenidone: a potential therapy for progressive lung allograft dysfunction? PMID- 23453576 TI - Spinal cord injuries related to cervical spine fractures in elderly patients: factors affecting mortality. AB - BACKGROUND CONTEXT: Spinal cord injuries (SCIs) related to cervical spine (C spine) fractures can cause significant morbidity and mortality. Aggressive treatment often required to manage instability associated with C-spine fractures is complicated and hazardous in the elderly population. PURPOSE: To determine the mortality rate of elderly patients with SCIs related to C-spine fractures and identify factors that contribute toward a higher risk for negative outcomes. STUDY DESIGN/SETTING: Retrospective cohort study at two Level 1 trauma centers. PATIENT SAMPLE: Thirty-seven consecutive patients aged 60 years and older who had SCIs related to C-spine fractures. OUTCOME MEASURES: Level of injury, injury severity, preinjury medical comorbidities, treatment (operative vs. nonoperative), and cause of death. METHODS: Hospital medical records were reviewed independently. Baseline radiographs and computed tomography or magnetic resonance imaging scans were examined to permit categorization according to the mechanistic classification by Allen and Ferguson of subaxial C-spine injuries. Univariate logistic regression analyses were performed to identify factors related to in-hospital mortality and ambulation at discharge. There were no funding sources or potential conflicts of interest to disclose. RESULTS: The in hospital mortality rate was 38%. Respiratory failure was the leading cause of death. Preinjury medical comorbidities, age, and operative versus nonoperative treatment did not affect mortality. Injury level at or above C4 was associated with a 7.1 times higher risk of mortality compared with injuries below C4 (p=.01). Complete SCI was associated with a 5.1 times higher risk of mortality compared with incomplete SCI (p=.03). Neurological recovery was uncommon. Apart from severity of initial SCI, no other factor was related to ambulatory disposition at discharge. CONCLUSIONS: In this elderly population, neurological recovery was poor and the in-hospital mortality rate was high. The strongest risk factors for mortality were injury level and severity of SCI. Although each case of SCI related to C-spine fractures is different, physicians may be able to use these findings to help better determine the prognosis and guide subsequent treatment. PMID- 23453575 TI - Endoscopic endonasal odontoidectomy with anterior C1 arch preservation in elderly patients affected by rheumatoid arthritis. AB - BACKGROUND CONTEXT: Rheumatoid arthritis is the most common inflammatory disease involving the spine with predilection for the craniovertebral segment. Surgery is usually reserved to patients with symptomatic craniovertebral junction (CVJ) instability, basilar invagination, or upper spinal cord compression by rheumatoid pannus. Anterior approaches are indicated in cases of irreducible ventral bulbo medullary compression. Classically performed through the transoral approach, the exposure of this region can be now achieved by a minimally invasive endonasal endoscopic approach (EEA). PURPOSE: The aim of this article is to demonstrate the feasibility of performing an odontoidectomy and a rheumatoid pannus removal by a minimally invasive EEA, preserving the anterior C1 arch continuity and avoiding a posterior fixation procedure. STUDY DESIGN: Technical description and cohort report. METHODS: We report three cases of elderly patients with a long history of rheumatoid arthritis and irreducible anterior bulbo-medullary compression secondary to basilar invagination and/or rheumatoid pannus. Anterior decompression was achieved by an endonasal image-guided fully endoscopic approach. RESULTS: Neurological improvement and adequate bulbo-medullary decompression were obtained in all cases. The anterior C1 arch continuity was preserved, and none of the patients required a subsequent posterior fixation. CONCLUSIONS: Anterior decompression by a minimally invasive EEA could represent an innovative option for the treatment of irreducible ventral CVJ lesions in elderly patients with rheumatoid arthritis. This approach permits the preservation of the anterior C1 arch and the avoidance of a posterior fixation, thus preserving the rotational movement at C0-C2 segment and reducing the risk of a subaxial instability development. PMID- 23453577 TI - Cutaneous hypersensitivity responses to Rhipicephalus tick larval antigens in pre sensitized cattle. AB - Nguni cattle are known to be more resistant to ticks than Bonsmara cattle, even if the immunological mechanisms responsible for this phenomenon are not fully understood. Cutaneous hypersensitivity responses to unfed larval extracts (ULE) of the ticks Rhipicephalus decoloratus and Rhipicephalus microplus were investigated in Nguni and Bonsmara cattle to improve knowledge on the immunity to ticks. Hypersensitivity reactions were induced by intradermal inoculation of 0.1ml of ULE of R. decoloratus and R. microplus ticks (50MUg protein) in the right and left ear, respectively, of 8-9-month-old Nguni (n=11) and Bonsmara (n=9) heifers. Ear thickness was measured using callipers before and 0.5, 1, 6, 24, 48, and 72h post inoculation (PI). Bonsmara cattle showed a more intense immediate reaction with maximum response at 1h PI and no delayed hypersensitivity reaction. Nguni heifers, conversely, presented a less intense immediate reaction with maximum response at 1h PI, and a delayed hypersensitivity reaction at 72h PI. Reactions to R. decoloratus ULE produced a more intense skin response than to R. microplus in both breeds at all time intervals. Nguni cattle showed lower tick infestation indicating higher tick resistance than Bonsmara cattle. Delayed hypersensitivity reaction could be associated with superior tick resistance in the Nguni breed, while immediate hypersensitivity reaction could be associated with increased tick susceptibility in the Bonsmara breed. This study indicates the need for further investigations on the correlation of tick resistance and cellular immune responses to tick infestation in Nguni cattle. PMID- 23453579 TI - HIV-1 Vpr activates both canonical and noncanonical NF-kappaB pathway by enhancing the phosphorylation of IKKalpha/beta. AB - The human immunodeficiency virus type I (HIV-1) Vpr plays an essential role in viral replication. A number of studies have reported that Vpr modulates the nuclear factor-kappaB (NF-kappaB) pathway. Yet, the reported effects of Vpr on NF kappaB signaling are controversial. In this study, we investigate the interplay between Vpr and NF-kappaB pathway. We discover that HIV-1 infection elevates the phosphorylation of IkappaBalpha and p100, and that this increase is greatly reduced when a Vpr-negative HIV-1 is used for infection. Our data further show that Vpr regulates the activity of IKKalpha/beta through interactions. In addition, Vpr modulates the phosphorylation of p65 and p100, suggesting that Vpr activates both canonical and noncanonical NF-kappaB pathway. Knock down of endogenous IKKalpha/beta result in a decrease in Vpr-mediated NF-kappaB and HIV-1 LTR activation. Given that Vpr is present in HIV-1 particles, our data suggest that Vpr activates the NF-kappaB pathway immediately after HIV-1 entry. PMID- 23453578 TI - The mechanism of differential neutralization of dengue serotype 3 strains by monoclonal antibody 8A1. AB - While previous studies have demonstrated that envelope (E) glycoprotein variation between dengue viruses (DENV) genotypes can influence antibody neutralization potency, the mechanisms of variable neutralization remain incompletely understood. Here we characterize epitope antibody interactions of a DENV-3 EDIII binding mouse mAb 8A1 which displays highly variable neutralizing activity against DENV-3 genotypes. Using a DENV-3 reverse genetics platform, we characterize ability of 8A1 to bind and neutralize naturally occurring DENV-3 E genotypic variant viruses. Introduction of single and multiple amino acid mutations into the parental clone background demonstrates that mutations at positions 301 and 383 on EDIII are responsible for 8A1 differential neutralization phenotypes. ELISA and surface plasmon resonance (SPR) studies indicate differences in binding are responsible for the variable neutralization. Variability at position 301 primarily determined binding difference through influencing antibody-EDIII dissociation rate. Our findings are relevant to many groups focusing on DENV EDIII as a vaccine target. PMID- 23453580 TI - Simvastatin and oseltamivir combination therapy does not improve the effectiveness of oseltamivir alone following highly pathogenic avian H5N1 influenza virus infection in mice. AB - Nonspecific anti-inflammatory drugs have been purported to reduce the burden of severe influenza disease. We demonstrate that, unlike oseltamivir administration, simvastatin administration did not reduce morbidity, mortality, or viral load of mice infected with H1N1 or H5N1 viruses. No added benefit to the efficacy of oseltamivir therapy was observed when mice were treated in combination with simvastatin. Modest reductions in lung cytokine production in H5N1 but not H1N1 virus-infected simvastatin-treated mice indicate a potential benefit for statin use in mitigating disease following severe virus infection. PMID- 23453581 TI - Replacement of the heterologous 5' untranslated region allows preservation of the fully functional activities of type 2 porcine reproductive and respiratory syndrome virus. AB - The 5' untranslated region (UTR) is believed to be vital for the replication of porcine reproductive and respiratory syndrome virus (PRRSV), yet its functional mechanism remains largely unknown. In this study, to define the cis-acting elements for viral replication and infectivity, The 5' UTR swapping chimeric clones pTLV8 and pSHSP5 were constructed based on two different genotypes full length infectious cDNA clone pAPRRS and pSHE backbones. Between them, vTLV8 could be rescued from pTLV8 and had similar virological properties to vAPRRS, including phenotypic characteristic and RNA synthesis level. However, pSHSP5 exhibited no evidence of infectivity. Taken together, the results presented here demonstrate that only the 5' UTR of type 1 PRRSV did not affect the infectivity and replication of type 2 PRRSV in vitro. The 5' UTR of type 2 PRRSV could be functionally replaced by its counterpart from type 1. PMID- 23453582 TI - Sustained virological response to pegylated interferon plus ribavirin leads to normalization of liver stiffness in hepatitis C virus-infected patients. AB - INTRODUCTION: Pegylated interferon plus ribavirin (Peg-IFN/RBV) therapy leads to improvements in liver stiffness measurements (LSM) in hepatitis C virus (HCV) infected patients. However, the rate of LSM return to normal values in response to Peg-IFN/RBV is unclear. Thus, our aim was to assess the probability and factors associated with LSM normalization in HCV-infected patients receiving Peg IFN/RBV. METHODS: This prospective observational longitudinal study included 160 HCV-infected patients, 111 (69%) with human immunodeficiency virus and receiving Peg-IFN/RBV, with baseline LSM >= 7kPa. The outcome variable was LSM normalization, i.e. a stable decrease in LSM below 7kPa after starting Peg IFN/RBV. RESULTS: After starting Peg-IFN/RBV, 56 [35%, 95% confidence interval (95% CI): 28-42%] patients showed LSM normalization. The probability of LSM normalization was 21% (95% CI: 13.2-32.4%) at 12 months, and 51.3% (95% CI: 39.9 63.9%) at 24 months after Peg-INF/RBV initiation for individuals with sustained virological response (SVR), and 8.3% (95% CI: 4-16.6%) at 12 months and 11.3% (95% CI: 6-20.7%) at 24 months for those without SVR (p<0.001). For individuals with LSM >= 7kPa 24 weeks after the pre-planned end of treatment, LSM normalizations were only observed among those with SVR. Achievement of SVR [Hazard ratio (HR, 95% CI): 6.84 (3.39-13.81)] and lack of baseline cirrhosis [HR (95% CI): 4.17 (1.69-10)] were independently associated with LSM normalization after starting Peg-IFN/RBV. CONCLUSIONS: LSM normalizations during Peg-IFN/RBV treatment are more likely, and occur earlier among patients with SVR. In addition, LSM normalizations continue 24 weeks after the scheduled end of therapy, but only among individuals who reach SVR. PMID- 23453583 TI - Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study. AB - BACKGROUND: Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat. METHODS: In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598. FINDINGS: 38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction. INTERPRETATION: Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned. FUNDING: Chroma Therapeutics. PMID- 23453584 TI - The auditory dorsal stream plays a crucial role in projecting hallucinated voices into external space. AB - INTRODUCTION: Verbal auditory hallucinations (VAHs) are experienced as spoken voices which seem to originate in the extracorporeal environment or inside the head. Animal and human research has identified a 'where' pathway for sound processing comprising the planum temporale, the middle frontal gyrus and the inferior parietal lobule. We hypothesize that increased activity of that 'where' pathway mediates the exteriorization of VAHs. METHODS: The fMRI scans of 52 right handed psychotic patients experiencing frequent VAHs were compared with the reported location of hallucinations, as rated with the aid of the PSYRATS-AHRS. For each subject, a unique VAH activation model was created based on the VAH timings, and subsequently convolved with a gamma function to model the hemodynamic response. In order to examine the neurofunctional equivalents of perceived VAH location, second-level group effects of subjects experiencing either internal (n = 24) or external (n = 28) VAHs were contrasted within planum temporale, middle frontal gyrus, and inferior parietal lobule regions of interest (ROIs). RESULTS: Three ROIs were tested for increased activity in relation with the exteriorization of VAHs. The analysis revealed a left-sided medial planum temporale and a right-sided middle frontal gyrus cluster of increased activity. No significant activity was found in the inferior parietal lobule. CONCLUSIONS: Our study indicates that internal and external VAHs are mediated by a fronto temporal pattern of neuronal activity while the exteriorization of VAHs stems from additional brain activity in the auditory 'where' pathway, comprising the planum temporale and prefrontal regions. PMID- 23453585 TI - Predictors of substance use disorder treatment outcomes among patients with psychotic disorders. AB - Although integrated approaches are recommended and effective for treating patients with co-occurring substance use and psychotic disorders (SUD-PSY), many patients receive standard, nonintegrated substance use disorder (SUD) treatment. Research has yet to investigate how patients with co-occurring substance use and psychotic disorders respond to standard SUD treatment, an issue we address here. In a naturalistic follow-up of 236 male SUD-PSY patients receiving 12-step facilitation or cognitive-behavioral-oriented SUD treatment, we found that patients (1) demonstrated significant improvements in proximal outcomes (e.g., approach coping) from treatment intake to discharge, and in distal outcomes (e.g., psychiatric symptoms, substance use frequency) from treatment intake to 1- and 5-year follow-ups, and (2) tended to have similar outcomes whether they received 12-step facilitation or cognitive-behavioral SUD treatment. Patients who (3) were more involved in treatment, as reflected by more positive perceptions of and more satisfaction, tended to experience better proximal outcomes and engage in more continuing care, and those who (4) experienced better proximal outcomes tended to have better psychiatric and substance use outcomes in the years following treatment. Our results suggest that SUD-PSY patients can benefit from standard SUD treatments, even though it may not directly address their psychiatric disorders. PMID- 23453586 TI - Characterization of a denture base using autopolymerized pour-type denture base resin and acrylic stain. PMID- 23453587 TI - NDMA formation from amine-based pharmaceuticals--impact from prechlorination and water matrix. AB - The presence of N-nitrosodimethylamine (NDMA) in drinking water is most commonly associated with the chloramination of amine-based precursors. One option to control the NDMA formation is to remove the precursors via pre-oxidation, and prechlorination is among the most effective options in reducing NDMA formation. However, most of the findings to-date are based on single-precursor scenarios using the model precursor dimethylamine (DMA) and natural organic matter (NOM), while few studies have considered the potential interactions between water matrix components and the target precursors when investigating the prechlorination impact. Specifically, little is known for the behaviour of amine-based pharmaceuticals which have recently been reported to contribute to NDMA formation upon chloramination. This work demonstrates that prechlorination can affect both the ultimate NDMA conversion and the reaction kinetics from selected pharmaceuticals, and the nature and extent of the impact was compound-specific and matrix-specific. In the absence of NOM, the NDMA formation from most pharmaceuticals was reduced upon prechlorination, except for sumatriptan which showed a consistent increase in NDMA formation with increasing free chlorine contact time. In the presence of NOM, prechlorination was shown to enhance initial reactions by reducing the binding between NOM and pharmaceuticals, but prolonged prechlorination broke down NOM into smaller products which could then form new bonds with pharmaceuticals and thus inhibit their further conversion into NDMA. PMID- 23453588 TI - Some factors affecting SPME analysis and PAHs in Philadelphia's urban waterways. AB - Solid phase microextraction (SPME) opened up a new era in separation science and the technique has developed quickly over the past two decades. However, there are still aspects deserving more study. In this study, the effects of salt-addition, SPME fiber thickness and sample vial size on the analysis of PAHs in the aqueous phase were evaluated. An analytical method based on EPA Method 8272 was devised for the analysis of PAHs in environmental water. PAHs were analyzed in selected waterways of the greater Philadelphia area. The results show the feasible application of this method to determine the range, spatial variation of PAH concentration, composition profile and relationship with dissolved organic matter for the Philadelphia watershed. Based on above information, PAH pollution sources were evaluated along with their dynamic backgrounds. Comparison of PAH concentration in the studied area with those of other urban waterways worldwide shows that PAHs in the studied waterways were found, in this study, to be within the low range of reported concentrations and meet the criteria of the World Health Organization (WHO). The results also demonstrate that this method is suitable and reliable in monitoring PAH concentrations in environmental water. PMID- 23453589 TI - Biotransformation kinetics and sorption of cocaine and its metabolites and the factors influencing their estimation in wastewater. AB - The quantitative analysis of human urinary metabolites as biomarkers in wastewater streams has been used to estimate the rates of illicit drug use in the wider community. The primary underlying assumption in such studies is that a sample of wastewater is equivalent to a cumulative sample of urine. Drug metabolism in humans is predominantly enzymatically mediated, but these processes are not exclusive to the human body, and are found to occur in the environment and the sewer network. Understanding what happens to drugs and their urinary metabolites in the sewer system between the point of excretion and sampling is particularly important since it is possible that in-sewer transformation may influence final biomarker concentration. The present study uses batch experiments to measure and assess the biotransformation processes of cocaine and its two major human metabolites, benzoylecgonine and ecgonine methyl ester. The activated sludge modelling framework for xenobiotic organic micro-pollutants (ASM-X) is used for model structure identification and calibration. Biotransformation was observed to follow pseudo first-order kinetics. The biodegradation kinetics of cocaine, benzoylecgonine and ecgonine methyl ester is not significantly affected by the availability of dissolved oxygen. Results obtained in this study show that omitting in-pipe biotransformation affects the accuracy of back-calculated cocaine use estimates. This varies markedly depending on the in-sewer hydraulic retention time, total biomass concentration and the relative concentration of each metabolite. However, back-calculated cocaine use estimates derived from wastewater concentrations of benzoylecgonine and ecgonine methyl ester do show very close agreement if ex-vivo biotransformation of these compounds is considered. PMID- 23453590 TI - Mineralization and defluoridation of 2,2,3,3-tetrafluoro -1-propanol (TFP) by UV oxidation in a novel three-phase fluidized bed reactor (3P-FBR). AB - 2,2,3,3-Tetrafluoro-1-propanol (TFP, C3H4F4O, M.W. = 132.06) is extensively used as the solvent in CD-R and DVD-R fabrication. Since it has a fluorinated alky chain configuration and is non-biodegradable, its treatment by conventional oxidation methods is typically very inefficient. In this work, novel three-phase fluidized bed reactor (3P-FBR, 7.5 cm in diameter, 50 cm high) that combines photo oxidation (UV/H2O2, one of AOPs (Advanced Oxidation Process) and adsorption (BT5 iron oxide as adsorbent) processes is designed for mineralizing and defluorinizing TFP wastewater. The experimental results reveal that TFP can be efficiently mineralized, and the BT5 that is circulated by aeration in the 3P-FBR system can remove the released fluoride ions in the reaction period. Irradiation with 254 nm UV and a 10 mM H2O2 dose yield a TOC removal of TFP (1.39 mM, equivalent to an initial TOC of 50 ppm) of over 99.95% in 2 h, and 99% of fluoride was removed by BT5 with an adsorption capacity of 24.1 mg-F g(-1). PMID- 23453591 TI - Terson syndrome and ocular ultrasound. PMID- 23453592 TI - Intonation and expressivity: a single case study of classical western singing. AB - Previous studies have shown that singers tend to sharpen phrase-peak tones as compared with equally tempered tuning (ETT). Here we test the hypothesis that this can serve the purpose of musical expressivity. Data were drawn from earlier recordings, where a professional baritone sang excerpts as void of musical expression as he could (Neutral) and as expressive as in a concert (Concert). Fundamental frequency averaged over tones was examined and compared with ETT. Phrase-peak tones were sharper in excited examples, particularly in the Concert versions. These tones were flattened to ETT using the Melodyne software. The manipulated and original versions were presented pairwise to a musician panel that was asked to choose the more expressive version. By and large, the original versions were perceived as more expressive, thus supporting the common claim that intonation is a means for adding expressivity to a performance. PMID- 23453593 TI - Vocal flexibility and prosodic strategies in a professional impersonator. AB - OBJECTIVES/HYPOTHESIS: Voice imitation of a famous personality results in detection and reproduction of some vocal features, including spectral characteristics but also prosody, speech flow, or articulatory patterns. The objective of this study was to describe vocal flexibility in one of the best French impersonators and determine his strategies. STUDY DESIGN: Prospective study. METHOD: We have downloaded the recording of a political speech by former French President Jacques Chirac, who we have chosen for his very specific and recognizable voice. After transcription, we asked one professional impersonator and four control subjects to do several readings in their natural voice and in a spontaneous imitation task (ie, without listening to any of Chirac's recording). To facilitate the control subject's task, we made an additional recording after having them listen to the target sample. Using Praat freeware, we have compared several prosodic measurements taken on each sample: pitch, pitch range, articulatory speed, duration of pauses, and number of pauses. RESULTS: Results showed significant modifications in the participant's prosody and significant differences in the strategies used by the professional impersonator and the control group. CONCLUSION: The professional impersonator's imitation strategy lies in the reproduction of global characteristics and instant alignment of prosodic variations. PMID- 23453594 TI - Formant tuning strategies in professional male opera singers. AB - The term "formant tuning" is generally used for the case that one of the lowest formant frequencies coincides with the frequency of a source spectrum partial. Some authors claim that such coincidence is favorable and belongs to the goals of classical opera voice training, whereas other authors have found evidence for advising against it. This investigation analyzes the relationships between formant frequencies and partials in professional singers, who sang scales on the vowels /a/, /u/, /i/, and /ae/ in a pitch range including the passaggio, that is, the fundamental frequency range of approximately 300-400Hz, applying either of the two singing strategies that are typically used (1) in classical and (2) in nonclassical singing, respectively. Formant frequencies of each note in the scales were measured by inverse-filtering the acoustic signal. In the classical style, the first formant tended to be lower than in the nonclassical style. Neither the first nor the second formant tended to change systematically between scale tones, such that on some scale tones either or both formants was just below, just above, or right on a spectrum partial. In many cases, singers produced similar spectrum characteristics of the top tones of the scales with different first and second formant frequencies. Regardless of whether the first formant was slightly lower, slightly higher, or right on a partial, the properties of the voice source did not seem to be affected. PMID- 23453595 TI - Reported barriers to evaluation in chronic care: experiences in six European countries. AB - INTRODUCTION: The growing movement of innovative approaches to chronic disease management in Europe has not been matched by a corresponding effort to evaluate them. This paper discusses challenges to evaluation of chronic disease management as reported by experts in six European countries. METHODS: We conducted 42 semi structured interviews with key informants from Austria, Denmark, France, Germany, The Netherlands and Spain involved in decision-making and implementation of chronic disease management approaches. Interviews were complemented by a survey on approaches to chronic disease management in each country. Finally two project teams (France and the Netherlands) conducted in-depth case studies on various aspects of chronic care evaluation. RESULTS: We identified three common challenges to evaluation of chronic disease management approaches: (1) a lack of evaluation culture and related shortage of capacity; (2) reluctance of payers or providers to engage in evaluation and (3) practical challenges around data and the heterogeity of IT infrastructure. The ability to evaluate chronic disease management interventions is influenced by contextual and cultural factors. CONCLUSIONS: This study contributes to our understanding of some of the most common underlying barriers to chronic care evaluation by highlighting the views and experiences of stakeholders and experts in six European countries. Overcoming the cultural, political and structural barriers to evaluation should be driven by payers and providers, for example by building in incentives such as feedback on performance, aligning financial incentives with programme objectives, collectively participating in designing an appropriate framework for evaluation, and making data use and accessibility consistent with data protection policies. PMID- 23453596 TI - Cost-effectiveness of pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: qualitative synthesis of scientific evidence. AB - OBJECTIVE: To describe the cost-effectiveness analyses of medications launched in Spain for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. MATERIAL AND METHODS: Systematic review of the literature without meta-analysis. A search was made in, PubMed/MEDLINE, SCOPUS, databases of the Centre for Reviews and Dissemination, and the websites of technology assessment agencies from Canada, the United Kingdom and the Spanish Platform AUnETS. Only full economic evaluations were included, considering at least methylphenidate or atomoxetine as pharmacological treatment alternatives in children and/or adolescents with ADHD. RESULTS: Eleven studies published in 9 articles or reports were included. The most frequent characteristics were: cost utility analysis (82%), health system perspective (82%), short-term horizon (91%), and private funding (50%). Methylphenidate was included in all studies, and atomoxetine in 4 studies. Methylphenidate and atomoxetine are cost-effective alternatives compared to placebo or no treatment, although incremental cost effectiveness ratios are variable. The few direct treatment-comparisons between methylphenidate and atomoxetine provided contradictory and potentially biased results. CONCLUSIONS: The pharmacological treatment of ADHD in children and adolescents, with the reservations arising from the generalization of results to different settings, is probably cost-effective in the short term. The existing studies do not allow the relative efficiency of different treatments to be established, either in the long-term treatment or in patient subgroups with specific characteristics or comorbidities. PMID- 23453598 TI - An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. AB - Fgf8 encodes a key signaling factor, and its precise regulation is essential for embryo patterning. Here, we identified the regulatory modules that control Fgf8 expression during mammalian embryogenesis. These enhancers are interspersed with unrelated genes along a large region of 220 kb; yet they act on Fgf8 only. Intriguingly, this region also contains additional genuine enhancer activities that are not transformed into gene expression. Using genomic engineering strategies, we showed that these multiple and distinct regulatory modules act as a coherent unit and influence genes depending on their position rather than on their promoter sequence. These findings highlight how the structure of a locus regulates the autonomous intrinsic activities of the regulatory elements it contains and contributes to their tissue and target specificities. We discuss the implications of such regulatory systems regarding the evolution of gene expression and the impact of human genomic structural variations. PMID- 23453597 TI - Syndecan-4 phosphorylation is a control point for integrin recycling. AB - Precise spatiotemporal coordination of integrin adhesion complex dynamics is essential for efficient cell migration. For cells adherent to fibronectin, differential engagement of alpha5beta1 and alphaVbeta3 integrins is used to elicit changes in adhesion complex stability, mechanosensation, matrix assembly, and migration, but the mechanisms responsible for receptor regulation have remained largely obscure. We identify phosphorylation of the membrane intercalated proteoglycan syndecan-4 as an essential switch controlling integrin recycling. Src phosphorylates syndecan-4 and, by driving syntenin binding, leads to suppression of Arf6 activity and recycling of alphaVbeta3 to the plasma membrane at the expense of alpha5beta1. The resultant elevation in alphaVbeta3 engagement promotes stabilization of focal adhesions. Conversely, abrogation of syndecan-4 phosphorylation drives surface expression of alpha5beta1, destabilizes adhesion complexes, and disrupts cell migration. These data identify the dynamic spatiotemporal regulation of Src-mediated syndecan-4 phosphorylation as an essential switch controlling integrin trafficking and adhesion dynamics to promote efficient cell migration. PMID- 23453599 TI - Induction of gene responses in St. Lawrence River northern pike (Esox lucius) environmentally exposed to perfluorinated compounds. AB - Municipal waste water effluents (MWWEs) are important sources of chemical contamination for aquatic environments. This study investigated the presence and effects of perfluorinated compounds (PFCs) in environmentally exposed northern pike (Esox lucius) collected upstream and downstream a major municipal waste water treatment plant (WWTP) in the St. Lawrence River, Canada. Twelve PFCs, including the newly detected perfluoroethylcyclohexane sulfonate (PFECHS), were quantified in fish muscle, liver, and plasma. Additionally, the expression of eight genes and the activity of three biomarkers were analyzed in fish tissues at both sites. Mean ?PFC concentration in fish plasma collected upstream the WWTP was 185ng/g w.w. compared to 545ng/g w.w. downstream the point of release. PFECHS was quantified for the first time in St. Lawrence River fish (mean plasma concentration in MWWE fish: 5.07+/-4.72ng/g w.w.). Results of transcriptomic responses were tissue-specific and indicated significant up-regulation for metallothionein (MT) in blood and MT, glutathion-S-transferase (GST), superoxide dismutase (SOD), and cytochromes P450 1A1 (CYP1A1) in gill tissue of fish collected in the MWWE suggesting greater stress responses for organisms at this location. Significant relationships were found between vitellogenin (Vtg) gene expression in liver, Vtg activity in plasma and perfluorotridecanoic acid (PFTrA), perfluorotetradecanoic acid (PFTeA), and perfluorodecane sulfonate (PFDS) plasma concentrations. The possible endocrine effects of these PFCs should be further investigated. PMID- 23453600 TI - Rapid analysis of multi-pesticide residues in lotus seeds by a modified QuEChERS based extraction and GC-ECD. AB - A modified quick, easy, cheap, efficient, rugged and safe method (QuEChERS) coupled to gas chromatography with electron capture detector (GC-ECD) was developed for rapid extraction and simultaneous determination of 36 pesticides in lotus seeds. The extraction solvent (acetone, ethyl acetate, acetonitrile, n hexane and n-hexane in combination with ethyl acetate) and purifying agent (neutral alumina, primary secondary amine, graphite carbon block and florisil) for QuEChERS extraction were optimized. The GC-ECD method was in-house validated in terms of linearity, selectivity, reproducibility, stability and recovery. The limits of detection (LODs) of the developed GC-ECD method for all investigated pesticides ranged from 0.01 to 3.0MUgL(-1) and limits of quantification (LOQs) from 0.05 to 10.0MUgL(-1). The satisfactory data demonstrated the good reproducibility and stability of the method with relative standard deviations (RSDs) lower than 15%. Recoveries for spiked lotus seed samples were from 60.84% to 119.91% with RSDs lower than 13.06%. Two out of 24 batches of lotus seeds collected in China were found to be contaminated with trans-chlordane, which were below LOQ. This is the first attempt in China using QuEChERS to GC-ECD to determine 36 major pesticides with differences in physio-chemical properties in lotus seeds. The method described here was found to be practicable in the routine residue analysis of pesticides in lotus seeds. PMID- 23453601 TI - Biodegradation of petroleum hydrocarbons in contaminated clayey soils from a sub arctic site: the role of aggregate size and microstructure. AB - This study investigates the extent of biodegradation of non-volatile petroleum hydrocarbons (C16-C34) and the associated microbial activity in predominant aggregate sizes during a pilot-scale biopile experiment conducted at 15 degrees C, with a clayey soil, from a crude oil-impacted site in northern Canada. The in situ aggregate microstructure was characterized by N2 adsorption and X-ray CT scanning. The soils in the nutrient (N)-amended and unamended biopile tanks were comprised of macroaggregates (>2 mm) and mesoaggregates (0.25-2 mm). Nutrient addition significantly enhanced petroleum hydrocarbon biodegradation in macroaggregates, but not in mesoaggregates. At the end of 65-d biopile experiment, 42% of the C16-C34 hydrocarbons were degraded in the nutrient-amended macroaggregates, compared to 13% in the mesoaggregates. Higher microbial activity in the macroaggregates of the nutrient amended biopile was inferred from a larger increase in extractable protein concentrations, compared to the other aggregates. Terminal Restriction Fragment Length Polymorphism (T-RFLP) of 16S rRNA genes showed that there was no selection of bacterial populations in any of the aggregates during biopile treatment, suggesting that the enhanced biodegradation in nutrient-amended macroaggregates was likely due to metabolic stimulation. X ray micro CT scanning revealed that the number of pores wider than 4 MUm, which would be easily accessible by bacteria, were an order of magnitude higher in macroaggregates. Also, N2 adsorption analyses showed that pore surface areas and pore volumes per unit weight were four to five-times larger, compared to the mesoaggregates. Thus the higher porosity microstructure in macroaggregates allowed greater hydrocarbon degradation upon biostimulation by nutrient addition and aeration. PMID- 23453602 TI - Calorimetric evaluation of interaction and absorption of polychlorinated biphenyls by biomembrane models. AB - Polychlorinated biphenyls (PCBs) are organic pollutants with lipophilic properties, due to their persistence, they are present in environment at potentially dangerous concentrations for humans health. In this work we investigated the interaction and absorption of 2,4,4'-trichlorobiphenyl (PCB 28), 2,3,3',4,4'-pentachlorobiphenyl (PCB 105) and 2,3,3',4,4',5,5'-eptachlorobiphenyl (PCB 189) with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV), chosen as biomembrane models, by differential scanning calorimetry technique (DSC). The obtained results indicate that the tested compounds affected the thermotropic behaviour of MLV to different degree, modifying the phase transition peak and shifting it towards lower temperature. The effect of an aqueous or lipophilic medium on the absorption process of these compounds by the biomembrane models was also investigated revealing that the process is hindered by the aqueous medium but favoured by the lipophilic medium. PMID- 23453603 TI - Heavy metal concentrations and contamination levels from Asian dust and identification of sources: a case-study. AB - The aims of this study were to determine concentrations of selected metals (As, Cd, Cr, Co, Cu, Ni, Sb, Pb and Zn) in Asian and non-Asian dust collected in Daejeon, Korea between February 2007 and December 2007 and to estimate the pollution sources. The geoaccumulation index (Igeo) and the enrichment factor (EF) show that the pollution levels of Cd, Pb, Zn, Sb, Cu, and As are much higher than those of Cr, Co and Ni. As, Cd, Cu, Sb, Pb, and Zn are the ones most strongly affected by anthropogenic inputs such as airborne pollutants. The (206)Pb/(207)Pb ratios of Asian and non-Asian dust are similar to those of the airborne particles in some heavily industrialized Chinese cities and the soils of the Alashan desert. To address the highly elevated levels of heavy metals found in Asian and non-Asian dust, studies should be performed to assess the potential impacts of settled particles on surface ecosystems, water resources, and human health in Korea. PMID- 23453604 TI - Effect of hydrogen sulfide on phosphorus lability in lake sediments amended with drinking water treatment residuals. AB - The use of drinking water treatment residuals (WTRs) to immobilize P in sediments is a novel approach for lake restoration. However, the lability of P in WTRs amended sediments may vary with many factors, e.g., hydrogen sulfide content. Earlier works in our laboratory have demonstrated that WTRs are effective sorbents for hydrogen sulfide in water. Thus, we hypothesized that the lability of P in WTRs-amended sediments would not be increased by hydrogen sulfide. The results of this work suggested that this hypothesis was tenable. Compared to the raw sediments, the amended sediments had significantly lower P desorption potential in the presence of hydrogen sulfide at different times, pH and concentrations. Moreover, the amended sediments were also better able to adsorb hydrogen sulfide. In the amended sediments, the P, which was easily desorbed due to the effect of hydrogen sulfide, was transformed into the Fe/Al bound P. PMID- 23453605 TI - Towards effective phosphorus recycling from wastewater: quantity and quality. AB - Precipitation in the Mg-Ca-NH3-PO4 system has been explored to improve understanding of likely phases recoverable from complex wastewaters. Over a range of Mg/Ca combinations (0-100%) and pH 5-11, at least seven identifiable crystalline phases could be precipitated from artificial wastewater including: struvite, hydroxylapatite, newberyite, brushite, merrilite/whitlockite, octocalcium phosphate, and monetite. This experimental study has outlined the physicochemical conditions required to produce various phosphate products from synthetic wastewater, and found that large differences exist between experimentally formed phases and thermodynamical predictions. Struvite formation is the most desirable precipitate for the recovery of phosphate based upon purity, growth characteristics, dewatering properties, phosphate removal efficiency, and its ability to simultaneously remove ammonia. This study has also demonstrated that in specific cases the preliminary precipitation of brushite is a possible means of decreasing calcium content such that subsequent struvite formation could achieve higher-purity. Utilising experimental results and information on current commodity prices, discussion on the choice of Mg and Ca sources for phosphorus recovery provides guidance on appropriate means to optimise the formation and yield of high quality cost-optimised products. PMID- 23453606 TI - The association of PTPN22 polymorphism with endometriosis: effect of genetic and clinical factors. AB - OBJECTIVE: To investigate the possible effect of clinical and genetic variables on the association between PTPN22 and endometriosis. METHODS: PTPN22, ACP1 and p53 codon 72 genetic polymorphisms and duration of previous pharmacological treatment were studied. The study sample consisted of 132 women hospitalized for endometriosis diagnosed by laparoscopic intervention and histologically confirmed: 359 healthy blood donors were studied as controls. PTPN22, ACP1 and p53 codon 72 genotypes were determined by DNA analysis. Discriminant statistical analysis, logistic regression analysis, chi square of independence, power test and linear correlation were performed using SPSS programs. RESULTS: A significant increase of PTPN22 *T allele in endometriosis is observed in women carrying ACP1*C allele, in women carrying p53 codon 72 *Pro allele and in women with prolonged pharmacological treatment. CONCLUSIONS: PTPN22 may not be a primary factor in the etiology of endometriosis but may cooperate with clinical and genetic factors influencing susceptibility and clinical course of disease. These new observations point to a multifactorial origin of endometriosis and help to explain the reported differences between human populations concerning the association between PTPN22 and endometriosis. PMID- 23453607 TI - Educating advanced level practice within complex health care workplace environments through transformational practice development. AB - Over the past 20 years health care reform has influenced the development of advanced level practitioner roles and expectations. How advanced level practitioners work to survive the highly stimulating, yet sometimes overwhelming aspects of balancing high quality provision with political reform agendas, amidst economic constraint is considered. Transformational approaches (encompassing education and practice led service development) can provide, promote and 'provoke' a harnessing of complex issues workplace environment to produce creative solutions. Transformational Practice Development provides a structured, rigorous, systematic approach that practitioners, teams and health care consumers alike can utilise to achieve skills and attributes needed for successful innovation. The authors present case study materials from action orientated locally delivered Practice Development, as a complex strategic intervention approach to influence and promote advanced level practice expertise. Initiated through facilitation of transformational leadership, and resultant team based improvements, we present how strategic collaborative processes can harness work chaos and complexity to provide sustainable and productive workplace cultures of effectiveness. PMID- 23453608 TI - Calcaneal Z osteotomy for extra-articular correction of hindfoot valgus. AB - The lateral column lengthening procedure has been used in the surgical management of congenital and adult-acquired pes planus. Lateral column lengthening allows correction of the abducted forefoot and subsequent improvement in the medial longitudinal arch. However, owing to the inconsistent healing times and complications, we opted to pursue a novel approach to the lateral column lengthening procedure, the calcaneal Z osteotomy. PMID- 23453609 TI - Repair of hypospadias fistula using a penile skin advancement flap with penile dartos interposition. AB - OBJECTIVE: We aim to report a single surgeon's experience of using a penile skin advancement flap with penile dartos interposition for hypospadias fistula repair. PATIENTS & METHODS: All hypospadias fistula repairs performed in our unit by this paediatric urologist between 2000 and 2012 were identified from a prospectively recorded database. Patients' case-notes were reviewed retrospectively gathering data on surgical technique, post-operative care and fistula recurrence on follow up. Only those boys having repair by this advancement flap technique were included. A urethral catheter was left in situ in all patients for 5-7 days. Repairs performed using other techniques were excluded. RESULTS: 20 consecutive patients had fistula repair by the advancement flap technique. This was the primary repair in 19 boys, and was repair of a third fistula occurrence in one. The median age at fistula repair was 3.7 years (1.6-15.3). The median follow-up was 4 months (3-73). One boy failed to attend any follow-up. No recurrence has yet been identified in any of the 20 patients. CONCLUSION: The penile skin advancement flap with dartos interposition technique was very successful in our series in both primary fistula repair, and in a patient who had multiple previous operations. PMID- 23453610 TI - Optical tomography reconstruction algorithm based on the radiative transfer equation considering refractive index--Part 1: Forward model. AB - The present study consists of two parts. The overall goal is to introduce and experimentally test the optical tomographic imaging algorithm based on the radiative transfer equation considering the refractive index. Considering that the high scattering medium with void-like regions has very low absorption and scattering coefficients, we use the radiative transfer equation to describe the optical parameters of the medium. In the process of photo propagation, not only the absorption and scattering coefficients have impact on the light radiance, but also the refractive index affect the light radiance. Therefore, we focus on the impact of the refractive index in this present study. We divide the refractive index into two cases: the uniform refractive index and the gradient refractive index. The paper is the first part of the present study, namely the forward model. We calculate the derivative of the fluency with the optical parameters by upwind-difference method, and a simpler mathematical framework is obtained in our study. In order to verify the accuracy of the forward model, we select the human brain phantom image with a void-like region and tumor as the experimental data. We found that the experimental measurements are in good agreement with the theoretical predictions of the measurements. PMID- 23453611 TI - Evaluation of postoperative discomfort following third molar surgery using submucosal dexamethasone - a randomized observer blind prospective study. AB - BACKGROUND: Surgical removal of impacted lower third molar is still the most frequent procedure done by Oral and Maxillofacial surgeons and is often associated with pain, swelling and trismus. These postoperative sequelae can cause distress to the patient as a result of tissue trauma and affect the patient's quality of life after surgery. Use of antiseptic mouthwashes, drains, muscle relaxants, cryotherapy, antibiotics, corticosteroids and physiotherapy seems to decrease postoperative discomfort. Among them corticosteroids are well known adjuncts to surgery for suppressing tissue mediators of inflammation, thereby reducing transudation of fluids and lessening edema. The rationale of this study is to determine the effectiveness of submucosal injection of dexamethasone in reducing postoperative discomfort after third molar surgery. PATIENTS AND METHODS: 100 patients requiring surgical removal of third molar under local anesthesia were randomly divided into 2 groups, group I receiving 4 mg dexamethasone as submucosal injection and the control group II received no steroid administration. Facial swelling was quantified by anatomical facial landmarks. Furthermore, pain and patient satisfaction, as well as neurological score and the degree of mouth opening were observed from each patient. RESULTS: Patients receiving dexamethasone showed significant reduction in pain, swelling, trismus, a tendency to less neurological complaints and improved quality of life compared with the control group. CONCLUSIONS: Submucosal injection of dexamethasone is more efficient to manage postoperative discomfort after removal of third molars compared to no steroid administration. PMID- 23453612 TI - The comparative efficacy of 0.12% chlorhexidine and amoxicillin to reduce the incidence and magnitude of bacteremia during third molar extractions: a prospective, blind, randomized clinical trial. AB - OBJECTIVE: The purpose of this study was to directly compare the incidence and magnitude of bacteremia of a 0.12% chlorhexidine pre-procedure rinse to the AHA and the ADA/AAOS recommended 2 g amoxicillin antibiotic prophylaxis during third molar extractions. STUDY DESIGN: This study was a randomized, blind, placebo controlled prospective clinical trial involving subjects assigned to a placebo, rinse, or antibiotic group. The incidence and magnitude of bacteremia were analyzed via chi(2) and Kruskal-Wallis/Friedman tests, respectively. RESULTS: There was no statistically significant difference in the incidence and magnitude of bacteremia between the three groups. However, the placebo group apparently resulted in the largest range and highest mean magnitude of bacteremia, followed by the rinse then the antibiotic group. CONCLUSIONS: The results of this novel study may reasonably conclude an oral rinse or systemic antibiotic antimicrobial intervention does not statistically reduce the incidence and magnitude of bacteremia compared to no antimicrobial intervention. PMID- 23453613 TI - Heterotopic gastrointestinal mucosa in the oral cavity of adults. AB - Heterotopic gastrointestinal mucosa (HGM) is a rare entity observed in the head and neck region and occurs more frequently in male infants and children. The floor of the mouth and anterior aspects of the tongue are the most commonly affected sites. Histologically, HGM resembles gastric, intestinal or colonic mucosa with areas of squamous epithelium, which can be cystic or solid. In the current report, 2 cases of HGM affecting the oral mucosa in patients over 35 years of age are presented, and one of these cases presented 2 nodules in different locations. Both cases represented solid lesions instead of the more common cystic presentation showing gastric glandular-type tissue that was lined with pseudostratified columnar epithelium containing crypts and fundic glands. Immunohistochemical analysis revealed positive expression of cytokeratins 7, 8 and 18 and smooth muscle actin (SMA). In both cases, the final diagnosis was HGM, and conservative surgical excision was performed. PMID- 23453614 TI - Qualitative and quantitative changes in saliva among patients with thyroid dysfunction prior to and following the treatment of the dysfunction. AB - OBJECTIVE: Animal studies have shown thyroid dysfunction affects salivary gland functioning, however conclusive human studies are lacking. We sought to assess the qualitative and quantitative changes in saliva among subjects with thyroid dysfunction prior to and following treatment. MATERIAL AND METHODS: A longitudinal observational study of 153 newly diagnosed subjects who had hypothyroidism (n = 107) or hyperthyroidism (n = 46), aged 18-45 years, fulfilling the inclusion/exclusion criteria was conducted. Analysis of salivary parameters (stimulated salivary flow rate (SSFR), pH and buffering capacity) was performed at diagnosis (baseline), on attaining euthyroid state and 3 months thereafter. RESULTS: Subjects were 86% females, and at baseline 13% of subjects had hyposalivation. Mean SSFR, pH, buffering capacity as well as percentage of hypothyroid subjects having normal salivation increased following thyroid treatment. CONCLUSIONS: Thyroid dysfunction affects salivary gland function. Subjects with chronic hyposalivation should have thyroid function assessment if the known established causes are excluded. PMID- 23453615 TI - Time to first antibiotic dose for patients hospitalised with community-acquired pneumonia. AB - Time to first antibiotic dose (TFAD) of 4h or 8h has been suggested as a quality measure for adult patients hospitalised with community-acquired pneumonia (CAP). Clinical evidence leading to implementation of this quality measure came from two large, retrospective studies. Following these studies, several prospective studies were conducted, with variable results. In a compilation of all observational studies to date, no significant benefit for short TFAD in terms of all-cause mortality was observed [unadjusted odds ratio (OR) = 1.01, 95% confidence interval (CI) 0.79-1.29, 13 studies; adjusted OR = 0.95, 95% CI 0.73 1.23, 14 studies]. Implementation of a requirement for short TFAD for CAP in the emergency department or other acute medical care setting may lead to unnecessary antibiotic treatment. We believe that attention should be shifted to early appropriate empirical antibiotic treatment for severe sepsis in hospital regardless of the source of infection, rather than focusing on CAP. PMID- 23453616 TI - Rapid selection of carbapenem-resistant Pseudomonas aeruginosa by clinical concentrations of ertapenem. PMID- 23453617 TI - Pharmacokinetics of linezolid during extracorporeal membrane oxygenation. PMID- 23453618 TI - Concurrent and transferable resistance to extended-spectrum cephalosporins, monobactam and fluoroquinolone in a Salmonella enterica serovar Worthington blood isolate from a neonate in Kolkata, India. PMID- 23453619 TI - An outcomes analysis of outpatient parenteral antibiotic therapy (OPAT) in a large Asian cohort. AB - Outpatient parenteral antibiotic therapy (OPAT) facilitates early discharge, easing demands on inpatient resources and allowing patients the opportunity to restore home life. In Singapore, two large hospitals established a common prospective database in 2006. This study presents an analysis of all enrolled cases over 6 years to consider factors potentially causing adverse outcomes. In this prospective observational study, patients' first OPAT episodes, from initiation to completion, re-admission or early cessation, were recorded and analysed using Cox regression to identify factors associated with clinical deterioration leading to unplanned hospital re-admission. Of 2229 first episodes, 1874 (84.1%) completed treatment in OPAT as planned; 201 episodes (9.0%) were complicated by clinical deterioration and re-admitted. Other patients who failed to complete treatment were either re-admitted for elective procedures, experienced adverse drug reactions or peripherally inserted central catheter related complications, or had other reasons for not completing treatment. Increased risk of clinical deterioration was associated with homecare OPAT (aHR=2.5, 95% CI 1.7-3.8; P<0.001), age >70 years (aHR=1.6, 95% CI 1.1-2.2; P=0.008) and non-private care (aHR=1.8, 95% CI 1.0-3.0; P=0.033). Diagnosis and type of antibiotic treatment were not significant risk factors for re-admission. OPAT provides intravenous antibiotics to those who would otherwise remain as hospital inpatients. In this large Asian cohort, clinical factors did not relate to the ability of patients to complete their treatment in OPAT. Criteria identified as significant warrant ongoing consideration as patients are assessed for acceptance into OPAT programmes. PMID- 23453620 TI - Association between atazanavir plasma levels and renal function in HIV-positive individuals on antiretroviral therapy with undetectable viral load. PMID- 23453621 TI - Evolving approaches to the ethical management of genomic data. AB - The ethical landscape in the field of genomics is rapidly shifting. Plummeting sequencing costs, along with ongoing advances in bioinformatics, now make it possible to generate an enormous volume of genomic data about vast numbers of people. The informational richness, complexity, and frequently uncertain meaning of these data, coupled with evolving norms surrounding the sharing of data and samples and persistent privacy concerns, have generated a range of approaches to the ethical management of genomic information. As calls increase for the expanded use of broad or even open consent, and as controversy grows about how best to handle incidental genomic findings, these approaches, informed by normative analysis and empirical data, will continue to evolve alongside the science. PMID- 23453622 TI - Genetic basis of cell-cell fusion mechanisms. AB - Cell-cell fusion in sexually reproducing organisms is a mechanism to merge gamete genomes and, in multicellular organisms, it is a strategy to sculpt organs, such as muscle, bone, and placenta. Moreover, this mechanism has been implicated in pathological conditions, such as infection and cancer. Studies of genetic model organisms have uncovered a unifying principle: cell fusion is a genetically programmed process. This process can be divided in three stages: competence (cell induction and differentiation); commitment (cell determination, migration, and adhesion); and cell fusion (membrane merging and cytoplasmic mixing). Recent work has led to the discovery of fusogens, which are cell fusion proteins that are necessary and sufficient to fuse cell membranes. Two unrelated families of fusogens have been discovered, one in mouse placenta and one in Caenorhabditis elegans (syncytins and F proteins, respectively). Current research aims to identify new fusogens and determine the mechanisms by which they merge membranes. PMID- 23453624 TI - Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. AB - Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC. PMID- 23453623 TI - Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal like breast cancer. AB - The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6 biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecule biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and reactive oxygen species production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of beta-catenin with T-cell factor. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC. PMID- 23453625 TI - Use of PAX8 and GATA3 in diagnosing sarcomatoid renal cell carcinoma and sarcomatoid urothelial carcinoma. AB - Immunohistochemistry for PAX8 and GATA3 are sensitive markers for renal cell carcinoma and urothelial carcinoma, respectively. However, there are limited data on these markers in sarcomatoid renal cell carcinoma (SARCRCC) and sarcomatoid urothelial carcinoma (SARCUC). Tissue microarrays (TMAs) were constructed from 45 cases of SARCRCC and 45 cases of SARCUC of the lower urinary tract, with an additional 11 SARCUCs of the upper tract. PAX8 and GATA3 were also evaluated in TMAs from 161 sarcomas from other sites, 14 atypical epithelioid angiomyolipomas (AMLs) of the kidney, 23 bladder inflammatory myofibroblastic tumors (IMTs), and 2 bladder and 4 renal leiomyosarcomas. In the SARCRCC, PAX8 and GATA3 were positive in the sarcomatoid areas in 31 (69%) and 0 (0%) of cases, respectively. In the bladder SARCUC, GATA3 and PAX8 were positive in 14 (31%) and 2 (4%) of cases, respectively. Of the 11 SARCUCs of the upper urinary tract, 2 (18%) cases were PAX8 positive and 2 (18%) separate cases were GATA3 positive. Only 1 tumor present on the sarcoma TMAs, a Ewing sarcoma/primitive neuroectodermal tumor, was PAX8 positive, and all sarcomas were GATA3 negative. Of the AMLs, IMTs, and leiomyosarcoma, only 1 case of IMT showed moderate GATA3 positivity, and all were negative for PAX8. PAX8 can be used to distinguish SARCCRCC from atypical epithelioid AMLs and primary renal or retroperitoneal sarcomas. However, in a kidney/renal pelvic tumor, PAX8 shows overlap in staining between SARCUC and SARCRCC. GATA3 lacks sensitivity but is more specific for SARCUC. PMID- 23453626 TI - Diagnosis of mitochondrial neurogastrointestinal encephalopathy disease in gastrointestinal biopsies. AB - A 14-year-old boy with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease had a lifelong history of failure to thrive and gastrointestinal symptoms including vomiting, pain, and diarrhea, leading to progressive cachexia. At the age of 9 years, after an extensive workup, the diagnosis of Crohn disease was strongly suspected, and he underwent colonoscopy with multiple biopsies. At 11 years of age, vision change and poor balance lead to a diagnosis of leukodystrophy by magnetic resonance imaging. Investigations for metachromatic leukodystrophy, adrenal leukodystrophy, and globoid cell leukodystrophy were all negative. A diagnosis of MNGIE disease was suspected when he continued deteriorating with gastrointestinal symptoms, multiple neurologic deficits, and encephalopathy. Markedly diminished thymidine phosphorylase activity and increased thymidine plasma levels confirmed the diagnosis of MNGIE. At autopsy, megamitochondria were observed by light microscopy in submucosal and myenteric ganglion cells and in smooth muscle cells of muscularis mucosae and muscularis propria, along the entire gastrointestinal tract from the esophagus to the rectum. Megamitochondria in ganglion cells were also observed in a retrospective review of the endoscopic intestinal biopsies taken at age 9 and 13 years and in the appendectomy specimen obtained 1 month before his demise. This study corroborates the presence of megamitochondria in gastrointestinal ganglion cells in MNGIE disease, better illustrates their detailed morphology, and describes for the first time similar structures in the cytoplasm of gastrointestinal smooth muscle cells. Pathologists should be able to recognize these structures by light microscopy and be aware of their association with primary mitochondriopathies. PMID- 23453627 TI - Dedifferentiated adenoid cystic carcinoma of the trachea: a case report with respect to the immunohistochemical analyses of mammalian target of rapamycin pathway proteins. AB - Dedifferentiated adenoid cystic carcinoma is an extremely rare and highly aggressive tumor. We describe the first reported case of dedifferentiated adenoid cystic carcinoma of the trachea and analyze the expression profiles of mammalian target of rapamycin pathway proteins. A 66-year-old Japanese man was incidentally found to have stenosis of the trachea, and a bronchial biopsy revealed low-grade adenoid cystic carcinoma. The resected specimen revealed dedifferentiated adenoid cystic carcinoma, which was composed of conventional low-grade adenoid cystic carcinoma with tubular and cribriform patterns, and a dedifferentiated carcinoma component (poorly differentiated adenocarcinoma). Immunohistochemical study showed that mammalian target of rapamycin and 4E-BP1 were expressed in both components; however, phosphorylated 4E-BP1 was expressed only in the dedifferentiated carcinoma component. This report clearly demonstrates that mammalian target of rapamycin pathway proteins were activated in dedifferentiated carcinoma. Mammalian target of rapamycin is a central protein involved in carcinogenesis, and administration of its inhibitors prolonged survival in some types of carcinoma. Therefore, mammalian target of rapamycin inhibitors may be a potential candidate for treatment of this highly aggressive carcinoma. PMID- 23453628 TI - Controlling the size distribution of lipid-coated bubbles via fluidity regulation. AB - Lipid-coated bubbles exhibit oscillation responses capable of enhancing the sensitivity of ultrasound imaging by improving contrast. Further improvements in performance enhancement require control of the size distribution of bubbles to promote correspondence between their resonance frequency and the frequency of the ultrasound. Here we describe a size-controlling technique that can shift the size distribution using a currently available agitation method. This technique is based on regulating the membrane dynamic fluidity of lipid mixtures and provides a general size-controlling variable that could also be applied in other fabrication methods. Three materials (1,2-dihexadecanoyl-sn-glycero-3 phosphocholine, 1,2-dioctadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) and polyethylene glycol 40 stearate) with distinct initial fluidities and phase behaviors were used to demonstrate the use of fluidity regulation to control bubble sizes. Bubble size distributions of different formulations were determined by electrical impedance sensing, and bubble volumes and surface areas were calculated. To confirm the relationship between regulated fluidity and mean bubble size, the membrane fluidity of each composition was determined by fluorescence anisotropy, with the results indicating linear relations in the compositions with similar main transition temperatures. Compositions with a higher molar proportion of polyethylene glycol 40 stearate showed higher fluidities and larger bubbles. B-mode ultrasound imaging was performed to investigate the echogenicity and lifetime of the fabricated bubbles, with the results indicating that co-mixing a high-transition-temperature charged lipid (i.e., 1,2-dioctadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol)) extends the tailoring range of this fluidity regulation technique, allowing refined and continuous changes in mean bubble size (from 0.93 to 2.86 MUm in steps of ~0.5 MUm), and also prolongs bubble lifetime. The polydispersity of each composition was also determined to evaluate practicality in particular applications. Our study demonstrates a feasible approach to naturally controling bubble size distribution and provides a practical reference for other fabrication systems and ultrasound imaging applications. PMID- 23453629 TI - Clot retraction affects the extent of ultrasound-enhanced thrombolysis in an ex vivo porcine thrombosis model. AB - We investigated ultrasound-enhanced thrombolysis in two whole-blood clot models using a Food and Drug Administration-approved contrast agent (Definity, Lantheus Medical Imaging; Billerica, MA USA) and thrombolytic drug (recombinant tissue type plasminogen activator [rt-PA]) (Genentech; South San Francisco, CA USA). Porcine venous blood was collected from donor hogs and coagulated in vials made of two different materials. This method produced clots with differing compositional properties, as determined by routine scanning electron microscopy and histology. Clots were deployed in an ex vivo porcine thrombosis model, and exposed to an intermittent ultrasound scheme previously developed to maximize stable cavitation while acoustic emissions were detected. Exposure to 3.15 MUg/mL rt-PA promoted lysis in both clot models, compared with exposure to plasma alone. However, only unretracted clots experienced significant enhancement of thrombolysis in the presence of rt-PA, Definity, and ultrasound, compared with treatment with rt-PA. In these clots, microscopy revealed loose erythrocyte aggregates, a significantly less extensive fibrin network and a higher porosity, which may facilitate increased penetration of thrombolytics by cavitation. PMID- 23453630 TI - Extended-field-of-view three-dimensional transesophageal echocardiography using image-based X-ray probe tracking. AB - The use of ultrasound imaging for guidance of cardiac interventional procedures is limited by the small field of view of the ultrasound volume. A larger view can be created by image-based registration of several partially overlapping volumes, but automatic registration is likely to fail unless the registration is initialized close to the volumes' correct alignment. In this article, we use X ray images to track a transesophageal ultrasound probe and thereby provide initial position information for the registration of the ultrasound volumes. The tracking is possible using multiple X-rays or just a single X-ray for each probe position. We test the method in a phantom experiment and find that with at least 50% overlap, 88% of volume pairs are correctly registered when tracked using three X-rays and 86% when using single X-rays. Excluding failed registrations with errors greater than 10 mm, the average registration accuracy is 2.92 mm between ultrasound volumes and 4.75 mm for locating an ultrasound volume in X-ray space. We conclude that the accuracy and robustness of the registrations are sufficient to provide useful images for interventional guidance. PMID- 23453631 TI - Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL 15-responsive IFN-gamma-producing cells. AB - Mucosal innate lymphoid cell (ILC) subsets promote immune responses to pathogens by producing distinct signature cytokines in response to changes in the cytokine microenvironment. We previously identified human ILC3 distinguished by interleukin-22 (IL-22) secretion. Here we characterized a human ILC1 subset that produced interferon-gamma (IFN-gamma) in response to IL-12 and IL-15 and had a unique integrin profile, intraepithelial location, hallmarks of TGF-beta imprinting, and a memory-activated phenotype. Because tissue-resident memory CD8(+) T cells share this profile, intraepithelial ILC1 may be their innate counterparts. In mice, intraepithelial ILC1 were distinguished by CD160 expression and required Nfil3- and Tbx21-encoded transcription factors for development, but not IL-15 receptor-alpha, indicating that intraepithelial ILC1 are distinct from conventional NK cells. Intraepithelial ILC1 were amplified in Crohn's disease patients and contributed to pathology in the anti-CD40-induced colitis model in mice. Thus, intraepithelial ILC1 may initiate IFN-gamma responses against pathogens but contribute to pathology when dysregulated. PMID- 23453632 TI - Enhanced apoptosis by disruption of the STAT3-IkappaB-zeta signaling pathway in epithelial cells induces Sjogren's syndrome-like autoimmune disease. AB - Sjogren's syndrome (SS) is an autoimmune disease characterized by exocrinopathy that leads to dry eye and mouth. Although lymphocyte infiltration into exocrine glands and the generation of autoantibodies have been reported in SS, its pathogenic mechanism remains elusive. Here, we show that mice lacking the transcriptional regulator IkappaB-zeta developed SS-like inflammation characterized by lymphocyte-infiltrated dacryoadenitis and SS-associated autoantibodies. In particular, epithelial cells, but not hematopoietic cells, lacking IkappaB-zeta were essential for the development of inflammation. IkappaB zeta-deficient epithelial cells in the lacrimal glands exhibited enhanced apoptosis even in the absence of lymphocytes. Administration of caspase inhibitors ameliorated the inflammation, indicating the critical role of caspase mediated apoptosis. Furthermore, epithelial cell-specific STAT3-deficient mice developed SS-like inflammation with impaired IkappaB-zeta expression in the lacrimal glands. Thus, this study reveals a pathogenic mechanism of SS in which dysfunction of epithelial cells caused by disruption of STAT3-mediated IkappaB zeta induction elicits the activation of self-reactive lymphocytes. PMID- 23453635 TI - The presentation of seizures and epilepsy in YouTube videos. AB - We evaluated videos on the social media website, YouTube, containing references to seizures and epilepsy. Of 100 videos, 28% contained an ictal event, and 25% featured a person with epilepsy recounting his or her personal experience. Videos most commonly fell into categories of Personal Experience/Anecdotal (44%) and Informative/Educational (38%). Fifty-one percent of videos were judged as accurate, and 9% were inaccurate; accuracy was not an applicable attribute in the remainder of the videos. Eighty-five percent of videos were sympathetic towards those with seizures or epilepsy, 9% were neutral, and only 6% were derogatory. Ninety-eight percent of videos were thought to be easily understood by a layperson. The user-generated content on YouTube appears to be more sympathetic and accurate compared to other forms of mass media. We are optimistic that with a shifting ratio towards sympathetic content about epilepsy, the amount of stigma towards epilepsy and seizures will continue to lessen. PMID- 23453633 TI - The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells. AB - Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21 induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive alpha-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon-gamma (IFN-gamma)-producing CD4+ T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response. PMID- 23453634 TI - The BAFF receptor transduces survival signals by co-opting the B cell receptor signaling pathway. AB - Follicular B cell survival requires signaling from BAFFR, a receptor for BAFF and the B cell antigen receptor (BCR). This "tonic" BCR survival signal is distinct from that induced by antigen binding and may be ligand-independent. We show that inducible inactivation of the Syk tyrosine kinase, a key signal transducer from the BCR following antigen binding, resulted in the death of most follicular B cells because Syk-deficient cells were unable to survive in response to BAFF. Genetic rescue studies demonstrated that Syk transduces BAFFR survival signals via ERK and PI3 kinase. Surprisingly, BAFFR signaling directly induced phosphorylation of both Syk and the BCR-associated Igalpha signaling subunit, and this Syk phosphorylation required the BCR. We conclude that the BCR and Igalpha may be required for B cell survival because they function as adaptor proteins in a BAFFR signaling pathway leading to activation of Syk, demonstrating previously unrecognized crosstalk between the two receptors. PMID- 23453636 TI - Knowledge, attitudes, and care techniques of caregivers of PWE in northeastern Thailand. AB - Caregivers of persons with epilepsy (PWEs) in developing countries do not always have access to correct information related to the affliction of the patients they are entrusted to care for. Epilepsy can be difficult to manage for all those involved, whether it is a family member, the PWEs themselves, or the caregiver. Misconceptions are common about epilepsy, especially in undeveloped countries where a majority of the population have lower educational levels. This study aims to acquire baseline data about caregivers of PWEs related to their knowledge, attitudes, and methods of giving care to PWEs. A cross-sectional survey was administered to 83 PWE caregivers at a university epilepsy clinic in northeastern Thailand. The caregivers believed that knowledge about epilepsy was paramount; however, they felt that their own knowledge of the condition was insufficient. Educational level, relationship to the PWEs, and sex were correlated to various aspects related to epilepsy knowledge and attitudes in caregivers. A slight negative correlation was found between caregiver knowledge and attitudes toward epilepsy with Pearson's correlation coefficient (r=-0.38, P-value 0.001). Education and improved epilepsy information need to be provided to the caregivers of PWEs in northeastern Thailand. PMID- 23453637 TI - A systematic review and meta-analysis of probiotics for the management of radiation induced bowel disease. AB - BACKGROUND & AIMS: A meta-analysis to estimate the efficacy of probiotics in prevention of radiation-induced bowel disease after pelvic radiotherapy has been performed. Previous attempts have arguably failed to provide a comprehensive analysis of clinical trials and their outcomes. METHODS: We searched for studies indexed in Medline, EMBASE, Cochrane Library, and on-line clinical trials registers. There was no language or time limit. Each study was evaluated for methodological quality and outcomes. We identified four outcomes on which to perform meta-analysis: incidence of diarrhoea, loperamide use, watery, and soft stools (Bristol Stool Chart). Odds ratio (OR) was used to compare efficacy, and the pooled OR was estimated using a random effects model; heterogeneity was assessed with Cochran's Q and Higgins I(2) test. Analyses were performed using Review Manager 5.2. RESULTS: Ten studies were included in our systematic review, of which six were subjected to meta-analysis to compare probiotics against placebo. Quality assessment showed an unclear risk due to incomplete outcome data and lack of performance of intention-to-treat analysis, while blinding and randomization issues were present in certain studies. Pooled results showed heterogeneity (Cochran's Q: p < 0.05; I(2): high). However the pooled OR for the incidence of diarrhoea, synthesized from 6 studies, significantly favoured the use of probiotics over control (OR = 0.44, 95% CI 0.21-0.92). Numerically, but not statistically, probiotics seem to decrease loperamide use (OR = 0.29, 95% CI 0.01-6.80) and the incidence of watery stools (OR = 0.36, 95% CI 0.05-2.81). CONCLUSIONS: In conclusion, probiotic supplementation shows a probable beneficial effect in the prevention, and possible benefit in the treatment, of radiation induced diarrhoea. PMID- 23453638 TI - The role of high fat diet in the development of complications of chronic pancreatitis. AB - BACKGROUND: Little is known about risk factors for complications in chronic pancreatitis (CP). High fat diet (HFD) has been demonstrated to aggravate pancreatic injury in animal models. The aim of this study was to investigate the role of HFD in age at diagnosis of CP and probability of CP related complications. METHODS: A cross-sectional case-case study was performed within a prospectively collected cohort of patients with CP. Diagnosis and morphological severity of CP was established by endoscopic ultrasound. Pancreatic exocrine insufficiency (PEI) was diagnosed by 13C mixed triglyceride breath test. Fat intake was assessed by a specific nutritional questionnaire. Odds ratios (OR) for CP related complications were estimated by multivariate logistic regression analysis. RESULTS: 168 patients were included (128 (76.2%) men, mean age 44 years (SD 13.5)). Etiology of CP was alcohol abuse in 89 patients (53.0%), other causes in 30 (17.9%) and idiopathic in the remaining 49 subjects (29.2%). 24 patients (14.3%) had a HFD. 68 patients (40.5%) had continuous abdominal pain, 39 (23.2%) PEI and 43 (25.7%) morphologically severe CP. HFD was associated with an increased probability for continuous abdominal pain (OR = 2.84 (95% CI, 1.06 7.61)), and a younger age at diagnosis (37.0 +/- 13.9 versus 45.8 +/- 13.0 years, p = 0.03) but not with CP related complications after adjusting for sex, years of follow-up, alcohol and tobacco consumption, etiology and body mass index. CONCLUSIONS: Compared with a normal fat diet, HFD is associated with a younger age at diagnosis of CP and continuous abdominal pain, but not with severity and complications of the disease. PMID- 23453639 TI - CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters. AB - The serotonin system and the hypothalamic-pituitary-adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters. PMID- 23453640 TI - Genetic variability at IMPA2, INPP1 and GSK3beta increases the risk of suicidal behavior in bipolar patients. AB - Bipolar patients (BP) are at high risk of suicide. Causal factors underlying suicidal behavior are still unclear. However, it has been shown that lithium has antisuicidal properties. Genes involved in its putative mechanism of action such as the phosphoinositol and the Wnt/beta-catenine pathways could be considered candidates for suicidal behavior (SB). Our aim was to investigate the association of the IMPA1 and 2, INPP1, GSK3alpha and beta genes with suicidal behavior in BP. 199 BP were recruited. Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432) and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 (rs3791809, rs4853694 and 909270), GSK3alpha (rs3745233) and GSK3beta (rs334558, rs1732170 and rs11921360) genes were genotyped. All patients were grouped and compared according to the presence or not of history of SB (defined as the presence of at least one previous suicidal attempt). Single SNP analyses showed that suicide attempters had higher frequencies of AA genotype of the rs669838 IMPA2 and GG genotype of the rs4853694-INPP1gene compared to non-attempters. Results also revealed that T-allele carriers of the rs1732170-GSK3beta gene and A allele carriers of the rs11921360-GSK3beta gene had a higher risk for attempting suicide. Haplotype analysis showed that attempters had lower frequencies of A:A haplotype (rs4853694:rs909270) at the INPP1 gene. Higher frequencies of the C:A haplotype and lower frequencies of the A:C haplotype at the GSK-3beta gene (rs1732170:rs11921360) were also found to be associated to SB in BP. Therefore, our results suggest that genetic variability at IMPA2, INPP1 and GSK3beta genes is associated with the emergence of SB in BP. PMID- 23453642 TI - Morphometry of the soft tissues of the orbital region in Northern Sudanese persons. AB - The orbital region plays a predominant role in the evaluation of the craniofacial complex. No current normative data exist for Northern Sudanese subjects. In the current study information about normal sex- and age-related dimensions of the orbital region was provided. The three-dimensional coordinates of ten landmarks on the orbital soft tissues were obtained using a hand-held laser scanner in 654 healthy Northern Sudanese subjects aged 4-30 years. From the landmarks, biocular and intercanthal widths, paired height and inclination of the orbit relative to both the true horizontal (head in natural head position) and Frankfurt plane, length and inclination of the eye fissure, the relevant ratios, were calculated, and averaged for age and sex. Comparisons were performed by factorial analysis of variance. All analysed linear soft-tissue orbital dimensions, except intercanthal width and left orbital height, were significantly larger in men than in women (p<0.01). A significant sexual dimorphism was found also for the height-to-width ratios (larger in women in most age groups), the orbital inclinations vs. the true horizontal and Frankfurt plane (both measurements were almost always larger in men than in women), and the right side inclination of the eye fissure vs. the true horizontal (larger in women than in men), while no sex-related differences were observed for the left side inclination of the eye fissure vs. the true horizontal. All measurements but the right side inclination of the eye fissure vs. the true horizontal underwent significant modifications as a function of age, with several significant age*sex interactions. Biocular and intercanthal widths, orbital height, length of the eye fissure, all increased from childhood to young adulthood; in the second decade of life all age-related increments were larger in men than in women. Overall, when compared to literature data for African and Caucasoid subjects, several differences were found, pointing to the necessity of ethnic-specific data. Data collected in the present investigation could serve as a database for the quantitative description of human orbital morphology during normal growth and development. Forensic applications (evaluations of traumas, craniofacial alterations, teratogenic-induced conditions, facial reconstruction, ageing of living and dead people, personal identification) may also benefit from age- and sex-based data banks. PMID- 23453641 TI - Sudden death due to a dissecting intramural hematoma of the esophagus (DIHE) in a woman with severe neurofibromatosis-related scoliosis. AB - Dissecting intramural hematoma of the esophagus (DIHE) is a rare condition in which intramural hemorrhage can lead to submucosal dissection of the esophageal wall. DIHE is generally considered a benign disease, and the only mortality associated with DIHE has been due to operative intervention or to the presence of another underlying, life-threatening condition. We report, however, a case of sudden death due to the spontaneous rupture of a DIHE that occurred in a 32-year old woman, affected by neurofibromatosis type 1. She was admitted to the local emergency room, presenting a 24-hour history of sudden onset, severe central chest and interscapular pain associated with dysphagia, odynophagia and vomiting. Her condition worsened and proved fatal within a 6-hour period. A complete autopsy was then conducted, showing a complete dissecting intramural hematoma with laceration of the third superior of the esophagus. We can hypothesize that abnormal variations of gastro-esophageal pressure during ingurgitation and during bolus movement could be predisposing factors in the pathogenesis of the dissection. On the other hand angular kyphoscoliosis deformity may have had play a role as precipitating factor while vomiting in the subject's medical history can then be interpreted as the likely activation phenomenon. PMID- 23453643 TI - Car-to-pedestrian accident with a unique decollement injury. AB - The authors present a unique case of decollement injury found on an 85-year-old victim that was run-over by a tank truck. While external examination evidenced multiple severe injuries, autopsy confirmed the preliminary findings and revealed also the presence of an extensive decollement that spread from the left hemithorax to a wound on the left ankle, through which parts of the small intestines and pertaining mesentery protruded. The article offers an interpretation of the injuries sustained by the victim, focusing on the most probable decollement mechanism. The forensic pathologist in this case could rely also on the valuable help of surveillance cameras of a nearby bank office that helped to better understand the events that brought to the fatal injuries. The authors concluded that the expulsion of the jejunum was produced by a combination of two movements: a forward passage that created the decollement and detachment of the jejunum and a backward movement that completed the expulsion of the jejunum through the open fracture of the ankle. This case report evidences the importance of the forensic pathologist and a correct and detailed investigation of injuries in reconstructing an accident, as well that of surveillance cameras as investigation tool in forensic cases. PMID- 23453644 TI - A closer look at the effects of postoperative radiotherapy by stage and nodal status: updated results of an individual participant data meta-analysis in non small-cell lung cancer. PMID- 23453645 TI - Efficacy of two fluorescence in situ hybridization (FISH) probes for diagnosing malignant pleural effusions. AB - It is difficult to differentiate tumor cells in pleural fluid from reactive benign mesothelium. Fluorescence in situ hybridization (FISH) can increase diagnostic accuracy. Two hundred pleural fluid samples were analyzed by using FISH probes for chromosomes 11 and 17. Histological analysis was used to diagnose cancer. Clinical, radiological, and histological data were used to exclude malignancy. Eighty-two pleural effusion samples had positive cytology, 51 were benign, and 67 were atypical, but inconclusive. The 82 positive cases were confirmed to be malignant. Among the 51 negative cytology cases, videothoracoscopy-guided pleural biopsy revealed malignancy in three; aneuploid cells were detected by FISH in all cases. In 43 of the 67 cases with inconclusive cytology, malignancy was confirmed based on histology and fluorescence in situ hybridization. One case of parapneumonic effusion with no evidence of cancer during clinical follow-up had a suspicious cytology and positive fluorescence in situ hybridization result. The remaining 23 cases had no histological, radiological, clinical, or genetic evidence of malignancy. This study demonstrated that cytogenetic analysis of fresh pleural fluid samples using only two FISH probes is a valuable ancillary method for the identification of malignant pleural effusion, particularly in cases in which oncotic cytology is inconclusive. PMID- 23453646 TI - CNS metastases in non-small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives. AB - A considerable proportion of non-small-cell lung cancer (NSCLC) patients will develop central nervous system (CNS) metastases throughout the course of their disease and these manifestations cause significant morbidity and mortality. Accordingly, novel therapies with high efficacy and low toxicity are needed for NSCLC-related CNS metastases. In NSCLC patients with activating epidermal growth factor receptor gene (EGFR) mutations EGFR-specific tyrosine kinase inhibitors (TKI) represent effective and well tolerated modes of therapy, however, it has been unclear whether these drugs are also able to cross the blood-brain-barrier (BBB) and cause remission of CNS metastases. Recent studies suggest that this might indeed be the case and intracerebral response rates of 70-80% in molecularly selected patients are considerably higher compared to what would be expected for standard approaches like systemic chemotherapy and whole brain radiation therapy. Limitations in the application of EGFR-TKI may arise from genetic heterogeneity between the primary tumor and CNS metastases. Accordingly, the acquisition of repeated biopsies from all relevant metastatic sites, including the CNS, may be necessary to guide therapeutic decisions. However, even in EGFR-wildtype patients EGFR-TKI seem to represent a valuable second line therapy with response rates of about 10%. Application of EGFR-TKI in a "pulsative" pattern may help to overcome insufficient delivery of TKI to the cerebro-spinal fluid and may further increase response rates and time until progression. In the future, combination of EGFR-TKI with radiation or chemotherapy and/or incorporation of next-generation TKI should be evaluated regarding their potential for further optimizing therapy of NSCLC patients with CNS metastases. PMID- 23453647 TI - ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer. AB - BACKGROUND: Increased incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) with ALK translocations was postulated, however, ALK gene aberrations in NSCLC-BM have not been investigated so far. METHODS: We investigated ALK and EML4 gene aberrations (amplifications, translocations, inversions) by fluorescent in situ hybridization (FISH) (n=175) and ALK and EML4 protein expression by immunohistochemistry (n=221) in NSCLC BM and corresponding primary tumors. RESULTS: ALK translocations were found in 4/151 (2.6%; 3 of them involving EML4) of BM of adenocarcinomas (AC), 1/9 (11.1%) of adenosquamous carcinomas (ASC), 0/5 of squamous cell carcinomas (SCC) and 0/10 of large cell carcinomas (LCC). Rearrangement of ALK without involvement of EML4 was seen in 1 AC-BM and rearrangement of EML4 without involvement of ALK in 3 AC-BM, 1 ASC-BM and 1 LCC. ALK amplifications without gene rearrangements were found in BM of 16/151 (10.6%) AC, 2/5 (40%) SCC, 0/9 ASC and one LCC. ALK translocation status was constant between BM and primary tumors in 16 evaluable cases including two cases with ALK-EML4 translocations Among these 16 cases ALK amplification was seen in two BM and none of the primary tumors. All cases with translocations but not with amplifications of ALK showed protein expression. We found no association of ALK gene status with patient age, gender or overall survival time. CONCLUSIONS: ALK translocations and amplifications are found in approximately 3% and 11% of NSCLC-BM, respectively. While ALK translocations appear to be constant between primary tumors and BM, amplifications seem to be more prevalent in BM. ALK translocation, but not ALK amplification is associated with ALK protein overexpression. Further studies are needed to determine whether NSCLC-BM patients with ALK gene aberrations may benefit from specific inhibitor therapy. PMID- 23453648 TI - Effects of tolterodine and trospium chloride on renal damage induced by partial upper urinary tract obstruction. AB - OBJECTIVE: To examine the efficacy of trospium chloride and tolterodine on the renal parenchymal inflammatory process and upper urinary dilation in rats with chronic partial upper urinary tract obstruction. MATERIALS AND METHODS: A total of 32 rats were divided into 4 groups: group 1, control; group 2, obstruction; group 3, obstruction plus tolterodine; and group 4, obstruction plus trospium chloride. In all groups, except for group 1, partial upper urinary tract obstruction was induced by embedding the upper quarter of the right ureter into the psoas muscle for 14 days. At the end of the experiment, the rats were killed. The catalase, malondialdehyde, and protein carbonyl levels were determined in renal tissue. Tubular dilation and parenchymal inflammation were evaluated using hematoxylin-eosin staining. Smooth muscle actin and cytoglobin were examined with immunohistochemical staining. RESULTS: The obstruction group demonstrated severe pelvic dilation and parenchymal inflammation and increased smooth muscle actin staining in the wall of upper urinary tract (P <.05). The treatment of the rats with tolterodine and trospium chloride markedly attenuated the inflammatory alterations and reduced tubular dilation. This treatment also reduced elevated oxidative stress product levels and restored the depleted renal antioxidant enzyme. CONCLUSION: These findings imply that increased renal pelvic pressure can contribute to renal parenchymal injury in chronic pelvic upper urinary tract obstruction. Antimuscarinic medications such as tolterodine and trospium chloride exert renoprotective effects, probably by prevention of pelvic pressure increases. PMID- 23453649 TI - Obesity is not associated with aggressive pathologic features or biochemical recurrence after radical prostatectomy. AB - OBJECTIVE: To determine whether obesity is associated with adverse pathologic characteristics, positive surgical margins, greater biochemical recurrence rates, and interval to death after primary treatment with radical prostatectomy (RP). MATERIALS AND METHODS: A 12-year, retrospective, single-institution analysis of patients treated with RP was performed. Patients were categorized by their body mass index (BMI) as normal weight (n = 533), overweight (n = 1342), obese (n = 603), and morbidly obese (n = 22). The associations among the BMI, clinicopathologic characteristics, and biochemical recurrence rates were assessed. RESULTS: After adjusting for multiple clinical preoperative characteristics, the BMI category was not associated with positive surgical margins (P = .66), organ-confined disease (P = .10), Gleason score (P = .22), extracapsular extension (P = .09), seminal vesicle invasion (P = .15), percentage of cancer in the prostate gland (P = .67), largest tumor nodule (P = .13), or lymph node metastasis (P = .39). Gleason score 4+3 (P <.001), Gleason score 9 and 10 (P <.001), and an increasing prostate-specific antigen level (P <.001) were associated with biochemical recurrence. At a mean overall follow-up of 55.6 months, 276 patients (11.0%) had developed biochemical recurrence (normal weight 11.3%, overweight 10.5%, obese 12.3%, and morbid obesity 4.5%). After multivariate adjustment for age, ethnicity, risk group, clinical stage, Gleason score, preoperative prostate-specific antigen level, and year of surgery, no association was found between the BMI and biochemical recurrence (P = .87). CONCLUSION: In men undergoing RP for clinically localized prostate adenocarcinoma, obesity was not associated with adverse pathologic features, positive surgical margins, or biochemical recurrence. These data provide evidence that obese men undergoing RP are not more likely to have aggressive prostate cancer. PMID- 23453650 TI - Wilms tumor with renal vein tumor thrombus treated with only 3-port retroperitoneal laparoscopic technique. AB - Wilms tumor is the most common malignant renal tumor in childhood, but it is rarely associated with a vascular tumor thrombus. We present a case of Wilms tumor with renal vein tumor thrombus treated with only a 3-port retroperitoneal laparoscopic technique in a 10-year-old girl. The patient was alive at the 12 month follow-up examination with adjuvant chemotherapy. To our knowledge, we present the first case of Wilms tumor with renal vein tumor thrombus treated with pure retroperitoneal laparoscopic management. Our technique can be recommended owing to the benefits of the superior recovery profile, a safer surgical route, and cosmetically more acceptable incisions. PMID- 23453651 TI - Can spongioplasty prevent fistula formation and correct penile curvature in TIP urethroplasty for hypospadias? AB - OBJECTIVE: To clarify whether spongioplasty decreases the complications rate and the degree of penile curvature in TIP urethroplasty. METHODS: From 2007 to 2011, 47 patients underwent TIP repair. Thirty-seven underwent spongioplasty, while 10 did not because their bifurcated spongy tissues could be not clearly identified. We investigated whether spongioplasty reduced the incidencerates of complications such as urethrocutaneous fistula. We also evaluated whether spongioplasty contributed to resolving or decreasing penile curvature. In addition, we assessed how many of the patients that underwent spongioplasty did not have to undergo dorsal plication. RESULTS: Among the 47 patients who underwent TIP repair, postoperative complications occurred in 3 (8%) of the 37 patients that underwent spongioplasty and 1 (10%) of the 10 who did not. Spongioplasty did not decrease the complications rate of TIP repair. As 15 of the 47 patients demonstrated a straight penis before spongioplasty, the effect of spongioplasty on the correction of penile curvature was analyzed in 32 patients. Dorsal plication was avoided in 19 patients (59%) because their penile curvature had been decreased to within the permissible range (<15 degrees ) by spongioplasty. CONCLUSION: We conclude that spongioplasty can not replace dartos flap coverage of the neourethra after TIP urethroplasty because it did not produce a significant reduction in the complications rate; however, spongioplasty could be used as an additional procedure because it reduced the degree of penile curvature and allowed dorsal plication to be avoided in more than half of the hypospadiac patients that displayed moderately severe curvature. PMID- 23453652 TI - SIU scholar: Dr. Samson Maina. PMID- 23453653 TI - Sensitivity and specificity of ultrasonography in predicting etiology of azoospermia. AB - OBJECTIVE: To determine the sensitivity and specificity of different ultrasound (US) modalities in predicting an obstructive vs a nonobstructive etiology of azoospermia. MATERIALS AND METHODS: A total of 268 azoospermic men with available histopathologic slides were separated into obstructive (n = 104) and nonobstructive (n = 164) groups. Scrotal US studies, including color Doppler and transrectal US examinations, were performed in all patients and compared with the testicular biopsy results as the reference standard. RESULTS: We found that a decreased testicular volume and intra- and extratesticular varicocele were the most common abnormalities detected using scrotal US in those with nonobstructive azoospermia. In contrast, epididymitis, spermatocele, and duct ectasia were the most common findings in those with obstructive azoospermia. The sensitivity and specificity of scrotal US in detecting nonobstructive azoospermia was 75% and 72%, respectively, and for detecting obstructive azoospermia was 29.8% and 87%, respectively. Prostatic midline cysts, ejaculatory duct calcification, dilated seminal vesicle, and/or vassal ampullae were the most common abnormalities detected using transrectal US for obstructive azoospermia. The sensitivity and specificity of transrectal US in detecting obstructive etiology was 45% and 83%, respectively, and for functional etiology was 39% and 88%, respectively. CONCLUSION: Scrotal US was more sensitive in detecting functional azoospermia and more specific in detecting obstructive azoospermia. However, transrectal US was more sensitive in detecting obstructive azoospermia and more specific in detecting functional azoospermia. Both tests had greater specificity than sensitivity for obstructive azoospermia, indicating that US has the ability to exclude more than to diagnose cases of obstructive azoospermia. However, US is unlikely to completely replace testicular biopsy. PMID- 23453655 TI - Editorial comment. PMID- 23453656 TI - Supernumerary phalanx-like bone formation posterior to C6 spinous process. PMID- 23453657 TI - Increased periostin gene expression in degenerative intervertebral disc cells. AB - BACKGROUND CONTEXT: Disc degeneration is a multifactorial disease that may cause clinical symptoms such as chronic back pain or radiculopathy in the extremities. Periostin, an extracellular matrix protein involved in the process of fibrosis, expressed in tissues subjected to mechanical stress such as intervertebral disc. However, the expression of periostin during disc degeneration has not yet been studied. PURPOSE: The aim of this study is to elucidate the difference in gene expression profiles between degenerative and nondegenerative intervertebral discs for a better understanding of disc degeneration. STUDY DESIGN: Degenerative and nondegenerative nucleus pulposus cells were isolated from elderly patients with degenerative disc disease and younger patients with adolescent idiopathic scoliosis, respectively. METHODS: Affymetrix GeneChip Human arrays were used to derive gene expression profiles for disc degeneration, and gene expressions of periostin and other degeneration-related markers were confirmed by reverse transcription-polymerase chain reaction (RT-PCR), real-time RT-PCR, and western blot analysis. Immunohistochemical analysis of periostin and Gomori trichrome stain was performed to show the relationship of periostin, fibrosis, and disc degeneration. The mechanical stress experiment was designed to demonstrate the relationship of periostin, stress, and disc degeneration. RESULTS: Fourteen genes were identified to express at significantly different levels between degenerative and nondegenerative groups. An increase of periostin gene expression was observed in human degenerative nucleus pulposus cells for the messenger RNA and protein levels. Histological examination demonstrated an increased positive staining of periostin in degenerative discs from human tissues and rat needle-punctured tails and more fibrosis with architectural disorder and fragmentation in human degenerative disc as compared with nondegenerative discs. The expression of periostin was significantly induced by stress in human degenerative nucleus pulposus cells but not in nondegenerative cells. CONCLUSIONS: This study demonstrates for the first time an upregulation of periostin in addition to the expression levels of Type I collagen and matrix metalloproteinase-2 in human disc degeneration. It suggests that periostin may be a candidate gene that shows promise as a new prognostic marker and a therapeutic target that is worth further study to expand our knowledge of its role in disc degeneration. PMID- 23453658 TI - Towards a dynamic assessment of raw materials criticality: linking agent-based demand--with material flow supply modelling approaches. AB - Emerging technologies such as information and communication-, photovoltaic- or battery technologies are expected to increase significantly the demand for scarce metals in the near future. The recently developed methods to evaluate the criticality of mineral raw materials typically provide a 'snapshot' of the criticality of a certain material at one point in time by using static indicators both for supply risk and for the impacts of supply restrictions. While allowing for insights into the mechanisms behind the criticality of raw materials, these methods cannot account for dynamic changes in products and/or activities over time. In this paper we propose a conceptual framework intended to overcome these limitations by including the dynamic interactions between different possible demand and supply configurations. The framework integrates an agent-based behaviour model, where demand emerges from individual agent decisions and interaction, into a dynamic material flow model, representing the materials' stocks and flows. Within the framework, the environmental implications of substitution decisions are evaluated by applying life-cycle assessment methodology. The approach makes a first step towards a dynamic criticality assessment and will enhance the understanding of industrial substitution decisions and environmental implications related to critical metals. We discuss the potential and limitation of such an approach in contrast to state-of-the-art methods and how it might lead to criticality assessments tailored to the specific circumstances of single industrial sectors or individual companies. PMID- 23453660 TI - The (137)Cs accumulation by forest-derived products in the Gomel region. AB - This paper reports basic features of the (137)Cs uptake by forest-derived products in the Gomel region. Even with the soil contamination density of 37 kBq m(-2) the radionuclide contents in 20-30% of mushrooms and berries were found to be higher than the admissible levels. The (137)Cs contamination density of soil, site type and meteorological parameters were observed as the major factors which govern the radiocaesium uptake by mushrooms and berries. The (137)Cs contents in forest-derived products were found to increase directly with the soil contamination density. Bilberries (Vaccinium myrtillus) growing on different site types differed significantly in the (137)Cs content. It was also determined that statistically significant differences in the (137)Cs radioactivity of forest foods growing on different natural sites were governed by the factor designated in the current study by "territorial". The differences are to be accounted for both by forms of the Chernobyl fallout and by the natural and climatic conditions determining variations in the availability of radionuclides in the soil. In dry years the (137)Cs concentrations in some mushroom species were higher than in normal years. PMID- 23453659 TI - The impact of hospital volume, residency, and fellowship training on perioperative outcomes after radical prostatectomy. AB - OBJECTIVES: Although high-volume hospitals have been associated with improved outcomes for radical prostatectomy (RP), the association of residency or fellowship teaching institutions or both and this volume-outcome relationship remains poorly described. We examine the effect of teaching status and hospital volume on perioperative RP outcomes. METHODS AND MATERIALS: Within the Nationwide Inpatient Sample, we focused on RPs performed between 2003 and 2007. We tested the rates of prolonged length of stay beyond the median of 3 days, in-hospital mortality, and intraoperative and postoperative complications, stratified according to teaching status. Multivariable logistic regression analyses further adjusted for confounding factors. RESULTS: Overall, 47,100 eligible RPs were identified. Of these, 19,193 cases were performed at non-teaching institutions, 24,006 at residency teaching institutions, and 3,901 at fellowship teaching institutions. Relative to patients treated at non-teaching institutions, patients treated at fellowship teaching institutions were healthier and more likely to hold private insurance. In multivariable analyses, patients treated at residency (OR = 0.92, P = 0.015) and fellowship (OR = 0.82, P = 0.011) teaching institutions were less likely to experience a postoperative complication than patients treated at non-teaching institutions. Patients treated at residency (OR = 0.73, P<0.001) and fellowship (OR = 0.91, P = 0.045) teaching institutions were less likely to experience a prolonged length of stay. CONCLUSIONS: More favorable postoperative complication profile and shorter length of stay should be expected at residency and fellowship teaching institutions following RP. Moreover, postoperative complication rates were lower at fellowship teaching than at residency teaching institutions, despite adjustment for potential confounders. PMID- 23453661 TI - High resolution monitoring system for IRE stack releases. AB - The main activity of IRE (Institute for Radio-Element) is radioisotope production of bulk (99)Mo and (131)I for medical application (diagnosis and therapy). Those isotopes are chemically extracted from HEU (High Enriched Uranium) targets activated in reactors. During this process, fission products are released from the targets, including noble gases isotopes (Xe and Kr). Like any nuclear plant, IRE has release limits which are given by the Belgium authority and moreover IRE is in the process of continuously reducing the level of its releases. To achieve this mission, the need of an accurate tool is necessary and IRE has developed a specific monitoring system using a high resolution detector in order to identify and accurately estimate its gaseous releases. This system has a continuous air sampling system in the plant main stack. The sampled gases cross charcoal cartridges where they are slowed down and concentrated for higher detection efficiency. In front of those cartridges is installed an HPGe detector with a detection chain connected to a specific analysis system allowing on-line spectrum analysis. Each isotope can be separately followed without interferences, especially during the production process where high activity can be released. Due to its conception, the system also allows to measure iodine isotopes by integration on the charcoal cartridges. This device is of great help for accurately estimate IRE releases and to help for understanding specific releases and their origin in the production or maintenance process. PMID- 23453662 TI - Pleural and pericardial effusion in a patient with polymyalgia rheumatica: a case presentation. AB - Polymyalgia rheumatica is an inflammatory rheumatic disease that presents with bilateral pain and stiffness affecting mainly proximal muscles. It affects individuals over 50 years of age and it is usually associated with a raised erythrocyte sedimentation rate. Classically, treatment with low-dose corticosteroids results in a dramatic improvement in both symptoms and laboratory findings. We report the case of an 80 years old patient presenting polymyalgia rheumatica coinciding with pleuropericardial effusion. The patient had a very good response to treatment with rapid improvement in the symptomatology and laboratory findings. Polymyalgia Rheumatica is a common disease but it is rarely associated to pleuropericardial effusion. It should be considered in the differential diagnostic in patients presenting with pericardial effusion over 50 of age years due to the good response to treatment. PMID- 23453663 TI - Increased concentrations of soluble CD40 ligand platelet in patients with primary antiphospholipidic syndrome. AB - OBJECTIVE: To determine the concentrations of sCD40L in patients with PAPS, and establish its association with the number of thrombosis. PATIENTS AND METHODS: We included patients with PAPS and healthy controls of the same age and sex. For analysis, patients with PAPS were divided into 2 groups: 1) patients with 1 thrombosis, and 2) patients with >1 thrombosis. Soluble CD40L concentrations were determined by ELISA method. RESULTS: sCD40L concentrations were significantly higher in patients with PAPS compared with the controls (9.72 ng +/- 11.23 ng/ml vs. 4.69 +/- 4.04 ng/ml) (P=.04) There was no association between serum levels of sCD40L and the number of thrombosis (1 thrombosis: 9.81 +/- 9.87 ng/ml vs 9.63 +/ 12.75 ng/ml in >= 1thrombosis (P=.13). In women with pregnancy and abortions, (13 patients) concentrations of sCD40L were higher than in those patients without a history of abortion (26 patients) but without statically significant difference (12.11 +/- 16.46 ng/ml vs. 8.80 +/- 8.61 ng/ml) (P=.33). There was no correlation between levels of sCD40L and the total number of thrombosis. CONCLUSIONS: Patients with PAPS have higher concentrations of sCD40L compared with healthy subjects, although this is not associated with a greater number of thrombosis. Among patients with PAPS, there is a tendency to higher concentrations of sCD40L in women with pregnancy and history of abortion. Since the platelet is the main cellular source of sCD40L, is possible that this pathway plays a pathogenic role in patients with PAPS. PMID- 23453664 TI - Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. AB - Dyskeratosis congenita (DC) and its phenotypically severe variant, Hoyeraal Hreidarsson syndrome (HHS), are multisystem bone-marrow-failure syndromes in which the principal pathology is defective telomere maintenance. The genetic basis of many cases of DC and HHS remains unknown. Using whole-exome sequencing, we identified biallelic mutations in RTEL1, encoding a helicase essential for telomere maintenance and regulation of homologous recombination, in an individual with familial HHS. Additional screening of RTEL1 identified biallelic mutations in 6/23 index cases with HHS but none in 102 DC or DC-like cases. All 11 mutations in ten HHS individuals from seven families segregated in an autosomal recessive manner, and telomere lengths were significantly shorter in cases than in controls (p = 0.0003). This group had significantly higher levels of telomeric circles, produced as a consequence of incorrect processing of telomere ends, than did controls (p = 0.0148). These biallelic RTEL1 mutations are responsible for a major subgroup (~29%) of HHS. Our studies show that cells harboring these mutations have significant defects in telomere maintenance, but not in homologous recombination, and that incorrect resolution of T-loops is a mechanism for telomere shortening and disease causation in humans. They also demonstrate the severe multisystem consequences of its dysfunction. PMID- 23453665 TI - Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia. AB - Microphthalmia is an important developmental eye disorder. Although mutations in several genes have been linked to this condition, they only account for a minority of cases. We performed autozygome analysis and exome sequencing on a multiplex consanguineous family in which colobomatous microphthalmia is associated with profound global developmental delay, intractable seizures, and corpus callosum abnormalities, and we identified a homozygous truncating mutation in C12orf57 [c.1A>G; p.Met1?]. In a simplex case with a similar phenotype, we identified compound heterozygosity for the same mutation and another missense mutation [c.152T>A; p.Leu51Gln]. Little is known about C12orf57 but we show that it is expressed in several mouse tissues, including the eye and brain. Our data strongly implicate mutations in C12orf57 in the pathogenesis of a clinically distinct autosomal-recessive syndromic form of colobomatous microphthalmia. PMID- 23453666 TI - Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. AB - The corpus callosum is the principal cerebral commissure connecting the right and left hemispheres. The development of the corpus callosum is under tight genetic control, as demonstrated by abnormalities in its development in more than 1,000 genetic syndromes. We recruited more than 25 families in which members affected with corpus callosum hypoplasia (CCH) lacked syndromic features and had consanguineous parents, suggesting recessive causes. Exome sequence analysis identified C12orf57 mutations at the initiator methionine codon in four different families. C12orf57 is ubiquitously expressed and encodes a poorly annotated 126 amino acid protein of unknown function. This protein is without significant paralogs but has been tightly conserved across evolution. Our data suggest that this conserved gene is required for development of the human corpus callosum. PMID- 23453667 TI - Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of alpha-dystroglycan. AB - Mutations in several known or putative glycosyltransferases cause glycosylation defects in alpha-dystroglycan (alpha-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of alpha-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in beta-1,3-N acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a beta-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of alpha-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement. PMID- 23453668 TI - An African American paternal lineage adds an extremely ancient root to the human Y chromosome phylogenetic tree. AB - We report the discovery of an African American Y chromosome that carries the ancestral state of all SNPs that defined the basal portion of the Y chromosome phylogenetic tree. We sequenced ~240 kb of this chromosome to identify private, derived mutations on this lineage, which we named A00. We then estimated the time to the most recent common ancestor (TMRCA) for the Y tree as 338 thousand years ago (kya) (95% confidence interval = 237-581 kya). Remarkably, this exceeds current estimates of the mtDNA TMRCA, as well as those of the age of the oldest anatomically modern human fossils. The extremely ancient age combined with the rarity of the A00 lineage, which we also find at very low frequency in central Africa, point to the importance of considering more complex models for the origin of Y chromosome diversity. These models include ancient population structure and the possibility of archaic introgression of Y chromosomes into anatomically modern humans. The A00 lineage was discovered in a large database of consumer samples of African Americans and has not been identified in traditional hunter gatherer populations from sub-Saharan Africa. This underscores how the stochastic nature of the genealogical process can affect inference from a single locus and warrants caution during the interpretation of the geographic location of divergent branches of the Y chromosome phylogenetic tree for the elucidation of human origins. PMID- 23453670 TI - [Description of patients with confirmed influenza A(H1N1)pdm09 admitted to an intensive care unit and identification of severity risk factors]. AB - OBJECTIVE: The authors had for objective to describe patients with confirmed influenza A(H1N1)pdm09 admitted to an intensive care unit (ICU) in a university hospital and to identify risk factors correlated with the severity of the disease. DESIGN: A prospective study was conducted in an university hospital during the A(H1N1)pdm09 influenza pandemic. Severe laboratory confirmed cases (admitted to an ICU) were described and compared with non-severe confirmed cases (not admitted to an ICU). RESULTS: Sixty-nine patients were included; 36 (52%) were 15 to 44 years of age. Sixteen (23%) cases were defined as severe, ten of these (63%) concerned patients 45 to 64 years of age. The independent factors associated with severity were: a history of heart disease, obesity, and tobacco abuse. CONCLUSIONS: This work reinforces the need to identify and protect groups at risk of severe outcomes. PMID- 23453671 TI - Is it time to write a prescription for coffee? Coffee and liver disease. PMID- 23453669 TI - Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. AB - Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin. PMID- 23453672 TI - Attachment and temperament profiles among the offspring of a parent with bipolar disorder. AB - INTRODUCTION: Attachment is associated both with the risk of developing a mood disorder and temperamental profile. Relatively little is known about these associations in children of a parent with bipolar disorder (BD). The present study is a preliminary analysis of the association between attachment, temperament and psychopathology among high-risk offspring. METHODS: As part of an ongoing prospective cohort study, offspring from families with one parent with BD (HR) and offspring from families with unaffected parents (C) were clinically assessed using KSADS-PL format interviews annually. Validated self-report measures of perceived attachment and temperament were completed. RESULTS: Perceived attachment did not differentiate HR from C offspring and did not predict psychopathology or mood disorder in particular. However, high emotionality significantly predicted the risk of psychopathology in HR offspring, where 1 standard deviation increase in emotionality significantly increased the hazard of psychopathology by a factor of 1.36 (p=0.0009) and mood disorder by a factor of 1.24 (p=0.02). LIMITATIONS: Use of retrospective measures and low sample size for some models. CONCLUSIONS: There may be no gross abnormalities in attachment among HR compared to C offspring. It remains unclear if emotionality is a barometer of illness or a true risk factor in this population. More longitudinal research is needed to advance understanding of the influential pathways by which psychosocial risk factors impact the development of BD. This research has implications for targeted early interventions in HR youth. PMID- 23453673 TI - Depressive symptoms and interpersonal needs as mediators of forgiveness and suicidal behavior among rural primary care patients. AB - BACKGROUND: Suicide is the 10th leading cause of death in the US, and rates of suicide are higher in rural than urban areas. As proposed by the Interpersonal Psychological Theory of Suicide, thwarted belongingness and perceived burdensomeness are risk factors for suicidal behavior, although protective individual-level characteristics such as forgiveness, may indirectly affect suicidal behavior by decreasing the deleterious effect of thwarted interpersonal needs. METHOD: A sample of uninsured adults recruited from a rural primary clinic (N=101) completed the Brief Multidimensional Measure of Religiousness and Spirituality; Suicidal Behaviors Questionnaire-Revised; Interpersonal Needs Questionnaire; and Center for Epidemiologic Studies Depression Scale. Parallel and serial multivariable mediation analyses were conducted to test for direct and indirect effects of forgiveness on suicidal behavior. RESULTS: In parallel mediation, covarying depressive symptoms, forgiveness of self had an indirect effect on suicidal behavior, through perceived burdensomeness. Inclusion of depressive symptoms as a mediator revealed an indirect effect of forgiveness of self and others on suicidal behavior via depression, thwarted belongingness, and perceived burdensomeness in a serial mediation model. LIMITATION: A longitudinal study, with an equal representation of males and diverse populations is needed to replicate our findings. DISCUSSION: Our findings have implications for the role health providers can play in addressing suicide with rural patients. Promoting forgiveness, may, in turn affect interpersonal functioning and decrease risk for suicidal behavior. PMID- 23453675 TI - Can repetition of deliberate self-harm be predicted? A prospective multicenter study validating clinical decision rules. AB - BACKGROUND: Clinical decision rules have been developed to help identify patients at high risk of repeating deliberate self-harm actions. The objective of this study was to prospectively validate the clinical decision rules', Sodersjukhuset Self-Harm Rule and Manchester Self-Harm Rule, ability to predict repetition of deliberate self-harm (DSH). METHODS: A consecutive series of 325 patients attending two large emergency departments in Stockholm, Sweden due to DSH were included and followed for six months. Predictive factors were collected from hospital charts at the emergency department. A nationwide register-based follow up of new DSH within six months was used. We calculated the sensitivity and specificity to evaluate the different decision rules' ability to identify repetition of DSH. Main outcome measure repeated DSH within six months. RESULTS: The cumulative incidence for patients repeating within six months was 24.6% (95% CI: 19.9-29.3). Application of Sodersjukhuset Self-Harm Rule yielded a sensitivity of 89% (95%CI: 79.2-94.4) and a specificity of 11% (95%CI: 7.9-16.2). Application of Manchester Self-Harm Rule to our material yielded a sensitivity of 94% (95%CI: 85.4-97.7) and a specificity of 18% (95%CI: 13.8-23.9). LIMITATIONS: If data regarding predictive factors were missing it was not possible to investigate this further and in the statistical analysis missing data was classified as no. This would imply that the predicted risks may be underestimated. CONCLUSION: Clinical decision rules could be used as a compliment providing important additional information regarding risk of repetition in an ED setting when focusing on high sensitivity. PMID- 23453676 TI - Status update: maladaptive Facebook usage predicts increases in body dissatisfaction and bulimic symptoms. AB - BACKGROUND: The current study examined the effects of online social evaluations and comparisons on body dissatisfaction and bulimic symptoms. METHODS: We tested the effects of maladaptive Facebook usage (defined as the tendency to seek negative social evaluations and/or engage in social comparisons via Facebook) on body dissatisfaction and bulimic symptoms in a sample of 232 college females followed for approximately 4 weeks. RESULTS: Results provided evidence that maladaptive Facebook usage significantly predicted increases in bulimic symptoms and episodes of over-eating approximately four weeks later. Body dissatisfaction was found to fully mediate the relationship between maladaptive Facebook usage and increases in over-eating episodes, whereas body dissatisfaction partially mediated the relationship between maladaptive Facebook usage and increases in bulimic symptoms more broadly. LIMITATIONS: Limitations include the use of a novel measure of maladaptive Facebook usage due to the absence of an existing measure and a non-clinical sample. CONCLUSIONS: The results of this study suggest that reducing maladaptive Facebook usage may be a fruitful target for interventions aimed at reducing body dissatisfaction and symptoms of eating pathology. PMID- 23453674 TI - A randomized, placebo-controlled proof-of-concept, crossover trial of phenytoin for hydrocortisone-induced declarative memory changes. AB - BACKGROUND: Corticosteroid excess is associated with declarative memory impairment and hippocampal atrophy. These findings are clinically important because approximately 1% of the population receives prescription corticosteroids at any time, and major depressive disorder is associated with elevated cortisol levels and hippocampal atrophy. In animals, hippocampal changes with corticosteroids are blocked by phenytoin. The objective of the current study was to extend these preclinical findings to humans. We examined whether phenytoin attenuated the effects of hydrocortisone on declarative memory. Functional magnetic resonance imaging (fMRI) assessed task-related hippocampal activation. METHODS: A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in 17 healthy adult volunteers. Participants received hydrocortisone (2.5 days), phenytoin (3.5 days), both medications together, or placebo, with 21-day washouts between conditions. Differences between treatments were estimated using a mixed-effects repeated measures analysis. RESULTS: Fifteen participants had data from at least two treatment conditions and were used in the analysis. Basal cortisol levels negatively correlated with fMRI BOLD activation in the para-hippocampus with a similar trend observed in the hippocampus. Decrease in declarative memory with hydrocortisone was blocked with concomitant phenytoin administration. Relative to the placebo condition, a significant decrease in hippocampal BOLD activation was observed with hydrocortisone and phenytoin alone, and the two medications in combination. Declarative memory did not show significant correlations with hippocampal activation. LIMITATIONS: The modest sample size, which limited our statistical power, was a limitation. CONCLUSIONS: Findings from this pilot study suggest phenytoin attenuated effects of corticosteroids memory in humans, but potentiated the reduction in hippocampal activation. PMID- 23453677 TI - Approaches to model the retention and peak profile in linear gradient reversed phase liquid chromatography. AB - The optimisation of the experimental conditions in gradient reversed-phase liquid chromatography requires reliable algorithms for the description of the retention and peak profile. As in isocratic elution, the linear relationship between the logarithm of the retention factor and the solvent contents is only acceptable in relatively small concentration ranges of modifier. However, more complex models may not allow an analytical integration of the general equation for gradient elution. Alternative approaches for modelling the retention in linear gradient elution are here proposed. Those based on the quadratic logarithmic model and a model proposed for normal liquid chromatography yielded accurate predictions of the retention time for a wide range of initial concentrations of organic modifier and gradient slopes, with errors usually below 1-2%. Based on the half-width changes of chromatographic peaks along one or more gradients, an approach is also reported to predict the peak profile with low errors (usually below 2-3%). The proposed approaches were applied to two sets of probe compounds (diuretics and flavonoids), eluted with acetonitrile-water gradients. The changes in retention and peak shape in isocratic and gradient elution are illustrated through diagrams that define triangular regions including all possible values of retention factors or peak half-widths (or widths) inside the selected working ranges. PMID- 23453678 TI - High resolution 19F{1H} nuclear magnetic resonance spectroscopy and liquid chromatography-solid phase extraction-offline 1H nuclear magnetic resonance spectroscopy for conclusive detection and identification of cyanide in water samples. AB - We report herein a new, sensitive and efficient method for detection, identification and quantification of cyanide in water samples. Cyanide was converted (>95% yield) to its versatile and stable derivative, 1-cyano-2,2,2 trifluoro-1-phenylethyl acetate (CTPA).The crude reaction mixture was directly subjected to high resolution fluorine-19 nuclear magnetic resonance ((19)F{(1)H} NMR) spectroscopy. In order to do away with signal overlap and dynamic range problems associated with (1)H NMR spectroscopy, liquid chromatography with UV detection hyphenated to online solid phase extraction (LC-UV-SPE) was performed. The trapped and enriched CTPA was thereafter subjected to offline (1)H NMR spectroscopy. In this way the delta(1)H, delta(19)F spectral signatures and LC-UV retention time were used for specific detection and identification and quantification of cyanide. The three techniques (viz. LC-UV and LC-UV-SPE followed by offline (1)H NMR and (19)F{(1)H} NMR spectroscopy) demonstrated good linearity (r(2)>0.99), reproducibility (inter-day RSD: 1.43-1.89%, 2.60-2.80%, 1.42-1.60; intra-day: RSD 1.20-1.38%, 3.21-3.25%, 1.00-1.19%), accuracy (recoveries: 95.1-97.2%, 77.5-82.8%, 96.8-98.9%) and LODs (1.31 MUg/mL, 4.24 MUg/mL, and 2.14 MUg/mL) respectively. Total time required for the analysis was ~3 h. Utility of the method was demonstrated by the detection and identification of spiked water samples. Since the derivative CTPA was volatile, could also be analyzed by GC-MS and GC-FTIR instruments. PMID- 23453679 TI - Urethral dosimetry and toxicity with high-dose-rate interstitial brachytherapy for vaginal cancer. AB - PURPOSE: The tolerance and complication rates of the urethra are unknown for the interstitial high-dose-rate brachytherapy (HDR-BT) for vaginal cancer. METHODS AND MATERIALS: Patients with vaginal cancer near/involving the urethra who were treated with HDR-BT between 2008 and 2011 were included. Patients received mean external beam dose of 48.0Gy followed by mean HDR-BT dose of 4.5Gy/fraction for five fractions. With CT-based planning, the urethra was contoured from the bladder neck to the meatus. Doses were converted to the biologically equivalent dose in 2Gy/fraction (EQD2). RESULTS: A total of 16 patients were included, and the EQD2D90 was 74.9Gy. The urethral volume was 1.31cm(3), and the EQD2 to 0.1 and 1cm(3) were 76.2 and 48.9Gy, respectively. Two of the 6 patients with urethral involvement developed urethral necrosis. The D90 for these 2 patients was 76.8Gy, and the urethral doses to 0.1 and 1cm(3) were 95.1 and 45.8, respectively. Those who developed severe urethral toxicity had a trend to urethral EQD2 (95.1Gy vs. 73.4Gy, p=0.1) and significantly higher dose per fraction of HDR-BT to 0.1cm(3) of the urethra (5.7Gy vs. 3.7Gy, p=0.02) when compared with those who did not develop severe urethral toxicity. CONCLUSIONS: This study is among the first to assess urethral dosimetry for patients treated with HDR-BT for vaginal cancer. Patients who received five fractions of higher than 5Gy/fraction to 0.1cm(3) of urethra (estimated EQD2 of 85Gy) are at increased risk of severe urethral toxicity. PMID- 23453680 TI - Online correction of catheter movement using CT in high-dose-rate prostate brachytherapy. AB - PURPOSE: To present a clinical procedure that readjusts catheters to its planned positions based on pretreatment computed tomography (CT) for patients undergoing high-dose-rate (HDR) prostate brachytherapy, and evaluate the magnitude and dosimetric impact of the adjustments. METHODS AND MATERIALS: Patients received a pretreatment verification CT (vCT) before each fraction. The vCT dataset was imported to the treatment-planning system and fused to the planning CT (pCT) by rigid-body registration based on the implanted fiducials within the prostate. Catheter positions in the vCT were then compared with catheter positions in the pCT in a reconstructed plane through each catheter. Any catheter with difference in penetration larger than 3 mm was manually adjusted by a radiation oncologist before treatment. To evaluate treatment quality, the patient's plan was applied to the vCT off-line and dose delivered to prostate and normal structures were compared with their planned value. RESULTS: Forty-four fractions of 13 consecutive patients were treated using this method. Thirty-nine fractions had at least one catheter adjusted before treatment. A total of 651 catheters were assessed, and 194 catheters (30%) were adjusted by an average amount of 5.8 +/- 1.9 mm. In eight fractions the prostate D90 would have decreased by more than 10% from the planned value (with a maximum of 32%) if the catheter displacements were not rectified. After the adjustment, the maximum deviation of D90 was 10.6%. The improvement in D90 is 24% per 1 cm of time-averaged adjustment. CONCLUSIONS: Interfraction catheter motion occurs without any particular pattern. Using pretreatment CTs and restoring each catheter to its planned position ensures that the delivered treatment closely matches the treatment plan and therefore enhances the overall quality of the HDR treatment. The procedure can be readily implemented in any clinical setting. PMID- 23453681 TI - American Brachytherapy Society-Groupe Europeen de Curietherapie-European Society of Therapeutic Radiation Oncology (ABS-GEC-ESTRO) consensus statement for penile brachytherapy. AB - PURPOSE: To develop a consensus statement between the American Brachytherapy Society (ABS) and Groupe Europeen de Curietherapie/European Society for Therapeutic Radiation and Oncology (GEC-ESTRO) for the use of brachytherapy in the primary management of carcinoma of the penis. METHODS AND MATERIALS: The American Brachytherapy Society and Groupe Europeen de Curietherapie/European Society for Therapeutic Radiation and Oncology convened a group of expert practitioners and physicists to develop a statement for the use of (192)Ir in low dose-rate (LDR), pulse-dose-rate, and high-dose-rate (HDR) brachytherapy for penile cancer. RESULTS: Decades of brachytherapy experience with LDR (192)Ir wire and pulse-dose-rate (192)Ir sources for this rare malignancy indicate a penile preservation rate of 70% at 10 years postimplant. Chief morbidities remain stenosis of the urethral meatus and soft tissue ulceration at the primary site. Nonhealing ulceration can be successfully managed with various measures including hyperbaric oxygen treatment. HDR brachytherapy implant procedures are technically similar to LDR. The optimal HDR dose and fractionation schemes are being developed. CONCLUSIONS: The good tumor control rates, acceptable morbidity, and functional organ preservation warrant recommendation of brachytherapy as the initial treatment for invasive T1, T2, and selected T3 penile cancers. PMID- 23453682 TI - First report of transperineal polyethylene glycol hydrogel spacer use to curtail rectal radiation dose after permanent iodine-125 prostate brachytherapy. AB - PURPOSE: To demonstrate the feasibility of transperineal polyethylene glycol (PEG) hydrogel insertion into anterior perirectal fat for reducing rectal radiation dose in patients with suboptimal rectal dosimetry after permanent iodine-125 prostate brachytherapy. METHODS AND MATERIALS: Five patients with suboptimal rectal dosimetry after iodine-125 seed brachytherapy implant underwent a single transperineal injection of PEG hydrogel into the anterior perirectal fat under general anesthetic using transrectal ultrasound guidance. Prostate-rectum separation and rectal radiation dose before and after PEG hydrogel spacer insertion were measured. Toxicity because of spacer insertion was assessed at Days 0-1 and 4-6 weeks using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS: All patients experienced a clinically significant reduction in the volume of rectum receiving greater than or equal to the prescription dose (RV100) on the postspacer postimplant dosimetry, compared with the prespacer postimplant dosimetry. Mean prostate rectum separation that was achieved with the insertion of the spacer was 15.1 mm (+/-3.4). The mean difference in separation from before to after spacer insertion was 12.5 mm (+/-4.5). This was associated with a reduction in mean RV100 from 3.04 (+/-1.2) to 0.06 (+/-0.1) cc. Toxicities were limited to Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) perineal pain and rectal discomfort (3/5 patients). There were no Grade 2 or greater toxicities reported after insertion of the spacer. CONCLUSIONS: PEG hydrogel is safe and effective at reducing rectal radiation dose in select patients with suboptimal rectal dosimetry after prostate seed brachytherapy. PMID- 23453683 TI - Risk of infections in rheumatoid arthritis patients switching from anti-TNF agents to rituximab, abatacept, or another anti-TNF agent, a retrospective administrative claims analysis. AB - OBJECTIVE: This study compared the incidence and hazard of ICD-9-CM-coded infections and severe infections in rheumatoid arthritis (RA) patients treated with subsequent-line (SL) BIOs (BIO) after switching from first-line (FL) anti TNF therapy (anti-TNF). METHODS: Retrospective analysis of a large U.S. claims database. RA patients initiating an FL anti-TNF between 1/1/2004 and 3/31/2010 were identified and followed forward in time to capture all SL BIO episodes through 3/31/2010. SL BIO episodes were classified into: abatacept, adalimumab, etanercept, infliximab, or rituximab. Multivariate mixed-effects survival models compared the hazard of infections and severe infections across the SL BIO episodes with adjustment for demographic and clinical confounders. RESULTS: In total, 4332 SL BIO episodes were identified: mean age 55 years; 80% female. In adjusted analyses: when compared to rituximab, the hazard of all infections was significantly higher for adalimumab (hazard ratio [HR] = 1.31, 95% confidence interval [CI] = 1.09-1.55), etanercept (HR = 1.44, 95% CI = 1.20-1.72), and infliximab (HR = 1.30, 95% CI = 1.07-1.57), and insignificantly different for abatacept (HR = 1.18, 95% CI = 0.98-1.41); when compared to rituximab, the hazard of severe infection was significantly higher for infliximab (HR = 1.62, 95% CI = 1.03-2.55), and insignificantly different for abatacept (HR = 1.21, 95% CI = 0.78 1.88), adalimumab (HR = 1.10, 95% CI = 0.72-1.68), and etanercept (HR = 1.27, 95% CI = 0.83-1.95). CONCLUSIONS: In RA patients treated with SL BIO, a 30-44% higher hazard of all infection was observed in anti-TNFs versus rituximab with a 62% higher hazard of severe infection observed in infliximab versus rituximab. This study used a non-randomized, observational design and is therefore subject to confounding from unmeasured factors that influence both treatment choice and infection risk. PMID- 23453684 TI - Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review. AB - OBJECTIVE: To report on the effectiveness of cyclophosphamide (CYC) to treat glucocorticoid (GC)-dependent giant-cell arteritis (GCA) and/or severe GC-related side effects. METHODS: Fifteen patients with GCA and treated with CYC were retrieved from the computerized patient-record system. Glucocorticoid dependence was defined as a prednisone dose of >20mg/day for 6 months or >10mg/day for 1 year in order not to relapse. Response to CYC was defined as improved clinical and biological findings. Remission was defined as a sustained absence (>12 months) of active signs of vasculitis at a daily GC dose of <7.5mg. A literature review searched PubMed for all patients diagnosed with GCA and who received CYC. RESULTS: Our 15 patients responded to monthly pulses of CYC, and all experienced a GC-sparing effect, including five patients who discontinued GC long term. At a median follow-up of 43 (range: 14-75) months after CYC, nine (53%) patients were still in remission and six (40%) had relapsed at 6 (3-36) months after the last CYC infusion. Twelve (80%) patients experienced side effects, leading to discontinuation of CYC in two (13%). A literature review retrieved 88 patients who received CYC: 66 for GC-dependent disease, 53 for GC toxicity, and 14 for severe organ involvement. Their median follow-up time was 24 (4-60) months. Among the 88 patients, 74 (84%) were responsive to CYC and 17 (19%) relapsed, although all were receiving a maintenance therapy with immunosuppressive agents (such as methotrexate). Twenty-nine (33%) patients experienced side effects and 11 (12.5%) discontinued treatment. CONCLUSION: Cyclophosphamide is an interesting option for GCA patients with GC-dependent disease or with severe GC-related side effects, especially when conventional immunosuppressive agents have failed. PMID- 23453685 TI - Allergen immunotherapy: Much more than a shot in the dark. PMID- 23453686 TI - Reply: To PMID 23142009. PMID- 23453687 TI - Reply: To PMID 22728082. PMID- 23453688 TI - The crucial task of defining a healthy immune response toward respiratory infections. PMID- 23453690 TI - Point mutations as a source of de novo genetic disease. AB - Family-based next generation sequencing (NGS) has recently pointed to an important role for de novo germline point mutations in both rare and common genetic disorders associated with reduced fitness. In this review we highlight the impact of the mutational target size on the frequency of diseases caused by these de novo point mutations. In addition, we will discuss the human per generation mutation rate, its relation to advanced paternal age and how these factors affect the frequency of genetic disease caused by de novo events. PMID- 23453689 TI - Multi-disciplinary methods to define RNA-protein interactions and regulatory networks. AB - The advent of high-throughput technologies including deep-sequencing and protein mass spectrometry is facilitating the acquisition of large and precise data sets toward the definition of post-transcriptional regulatory networks. While early studies that investigated specific RNA-protein interactions in isolation laid the foundation for our understanding of the existence of molecular machines to assemble and process RNAs, there is a more recent appreciation of the importance of individual RNA-protein interactions that contribute to post-transcriptional gene regulation. The multitude of RNA-binding proteins (RBPs) and their many RNA targets has only been captured experimentally in recent times. In this review, we will examine current multidisciplinary approaches toward elucidating RNA-protein networks and their regulation. PMID- 23453691 TI - ATRX and the replication of structured DNA. AB - Understanding the underlying molecular basis for disease can often be a prolonged and tortuous process with many false leads and blind alleys. Relating the cause of ATR-X syndrome to the function of the protein ATRX is a case in point. In this review we attempt to bring together the diverse biological phenomena associated with ATRX dysfunction with what has recently been discovered concerning the chromatin remodelling activity of this protein. This potentially casts light on how defective DNA replication/histone replacement can impact on transcription, telomere maintenance and also possibly chromosome segregation. PMID- 23453692 TI - Fatigue and quality of life in citrin deficiency during adaptation and compensation stage. AB - Citrin-deficient children and adolescents between adult-onset type II citrullinemia and neonatal intrahepatic cholestasis by citrin deficiency do not have clear clinical features except for unusual diet of high-fat, high-protein, and low-carbohydrate food. The aims of the present study are to characterize fatigue and quality of life (QOL) in citrin-deficient patients during adaptation and compensation stage, and to define the relationship between fatigue and QOL. The study subjects were 55 citrin-deficient patients aged 1-22years (29 males) and 54 guardians. Fatigue was evaluated by self-reports and proxy-reports of the PedsQL Multidimensional Fatigue Scale. QOL was evaluated by the PedsQL Generic Core Scales. Both scale scores were significantly lower in child self-reports (p<0.01 and p<0.05, respectively) and parent proxy-reports (p<0.01 and p<0.01, respectively) than those of healthy children. Citrin-deficient patients with scores of 50 percentile or less of healthy children constituted 67.5% of the sample for the Fatigue Scale and 68.4% for the Generic Core Scales. The PedsQL Fatigue Scale correlated with the Generic Core Scales for both the patients (r=0.56) and parents reports (r=0.71). Assessments by the patients and their parents showed moderate agreement. Parents assessed the condition of children more favorably than their children. The study identified severe fatigue and impaired QOL in citrin-deficient patients during the silent period, and that such children perceive worse fatigue and poorer QOL than those estimated by their parents. The results stress the need for active involvement of parents and medical staff in the management of citrin-deficient patients during the silent period. PMID- 23453693 TI - Characterization of ischemic index using ultra-widefield fluorescein angiography in patients with focal and diffuse recalcitrant diabetic macular edema. AB - PURPOSE: To explore the association of angiographic nonperfusion in focal and diffuse recalcitrant diabetic macular edema (DME) in diabetic retinopathy (DR). DESIGN: A retrospective, observational case series of patients with the diagnosis of recalcitrant DME for at least 2 years placed into 1 of 4 cohorts based on the degree of DR. METHODS: A total of 148 eyes of 76 patients met the inclusion criteria at 1 academic institution. Ultra-widefield fluorescein angiography (FA) images and spectral-domain optical coherence tomography (SD OCT) images were obtained on all patients. Ultra-widefield FA images were graded for quantity of nonperfusion, which was used to calculate ischemic index. Main outcome measures were mean ischemic index, mean change in central macular thickness (CMT), and mean number of macular photocoagulation treatments over the 2-year study period. RESULTS: The mean ischemic index was 47% (SD 25%; range 0%-99%). The mean ischemic index of eyes within Cohorts 1, 2, 3, and 4 was 0%, 34% (range 16%-51%), 53% (range 32%-89%), and 65% (range 47%-99%), respectively. The mean percentage decrease in CMT in Cohorts 1, 2, 3, and 4 were 25.2%, 19.1%, 11.6%, and 7.2%, respectively. The mean number of macular photocoagulation treatments in Cohorts 1, 2, 3, and 4 was 2.3, 4.8, 5.3, and 5.7, respectively. CONCLUSIONS: Eyes with larger areas of retinal nonperfusion and greater severity of DR were found to have the most recalcitrant DME, as evidenced by a greater number of macular photocoagulation treatments and less reduction in SD OCT CMT compared with eyes without retinal nonperfusion. Areas of untreated retinal nonperfusion may generate biochemical mediators that promote ischemia and recalcitrant DME. PMID- 23453695 TI - Factor structure of the Eating Disorder Examination Questionnaire (EDE-Q) in male and female college athletes. AB - The study explored the psychometric properties of the Eating Disorder Examination Questionnaire (EDE-Q) among 1637 university students. Participants were divided into male (n=432) and female (n=544) competitive athletes, and male (n=229) and female (n=429) comparison groups comprised of individuals who had not engaged in competitive sports for at least one year. All groups were subjected to confirmatory factor analysis (CFA) to test the fit of the published factor structure in this population, and then exploratory FA (EFA). A three-factor solution was the best fit for three out of four groups, with a two-factor solution providing best fit for the male comparison group. The first factor for all groups resembled a combined Shape and Weight Concern subscale. The factor structure among male and female competitive athletes was remarkably similar; however, non-competitive athletic/low activity males appear qualitatively different from other groups. PMID- 23453694 TI - Racial variations in the prevalence of refractive errors in the United States: the multi-ethnic study of atherosclerosis. AB - PURPOSE: To describe racial variations in the prevalence of refractive errors among adult white, Chinese, Hispanic, and black subjects in the United States. DESIGN: Cross-sectional data from a prospective cohort study-the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: A total of 6000 adults aged 45 to 84 years living in the United States participated in the study. Refractive error was assessed, without cycloplegia, in both eyes of all participants using an autorefractor. After excluding eyes with cataract, cataract surgery, or previous refractive surgery, the eye with the larger absolute spherical equivalent (SE) value for each participant was used to classify refractive error. Any myopia was defined as SE of -1.0 diopters (D) or less; high myopia was defined as SE of -5.0 D or less; any hyperopia was defined as SE of +1.0 D or more; clinically significant hyperopia was defined as SE of +3.0 D or more. Astigmatism was defined as a cylinder value of +1.0 D or more. RESULTS: After excluding 508 participants with cataracts in both eyes, 838 participants with cataract surgery, 90 participants with laser refractive surgery, and 134 participants who refused to remove their contact lenses for the refraction measurement, 4430 adults with refractive error assessment in at least 1 eye contributed to the analysis. The prevalence of myopia among MESA participants was 25.1%, with lowest rates in Hispanic participants (14.2%), followed by black (21.5%) and white participants (31.0%), and highest rates in Chinese participants (37.2%). The overall rates of high myopia and astigmatism were 4.6% and 45.0%, respectively, with Chinese subjects also having the highest rates of high myopia (11.8%) and astigmatism (53.4%). The overall prevalence of any hyperopia was 38.2% and clinically significant hyperopia was 6.1%, with Hispanic participants having the highest rates of hyperopia (50.2%) and clinically significant hyperopia (8.8%). In multivariate analyses adjusting for age, sex, race, and study site, higher education level, being employed, and being taller were associated with a higher prevalence of myopia. In contrast, lower educational level and being shorter were associated with a higher prevalence of hyperopia. CONCLUSIONS: Myopia and astigmatism were most prevalent in the Chinese population, with Chinese subjects having 3 times the prevalence of myopia as Hispanic subjects. Hyperopia was most common in Hispanic subjects. These findings provide further insights into variations in refractive errors among different racial groups and have important implications for the eye care services in the United States. PMID- 23453696 TI - Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II. AB - Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A mediated which justifies these observations. PMID- 23453697 TI - Quantitative morphology of the corpus callosum in obsessive-compulsive disorder. AB - Neuroimaging studies have implicated the corpus callosum (CC) in the pathophysiology of obsessive-compulsive disorder (OCD). Putative dysfunctions in prefrontal cortical regions suggest anomalies in anterior segments of the CC. However, recent studies have also implicated the middle and posterior CC. The present study soughts to examine the CC using parcellation scheme informed by diffusion tensor imaging. Anatomic brain magnetic resonance scans were obtained from 21 OCD subjects (mean age=26.9 +/- 9.93) and 42 healthy age- and sex-matched controls (mean age=26.6 +/- 9.46) between the ages of 14 and 49. Area and volume measures of five subregions of the CC were obtained via manual tracings. A multivariate analysis of variance (after correcting for multiple comparisons) identified smaller area and volume in the mid-anterior region of the CC in OCD patients relative to controls. These findings implicate medio-frontal regions of the cortex in the pathophysiology of OCD. PMID- 23453698 TI - Intrapartum uncertainty: a feature of normal birth, as experienced by midwives in Scotland. AB - OBJECTIVE: to explore midwives' perceptions of intrapartum uncertainty when caring for women in low risk labour. DESIGN: a grounded theory approach was used to capture the experiences of midwives practising in Scotland. Data were generated through unstructured in-depth one-to-one interviews and focus groups. SETTING: four Health Boards in Scotland. PARTICIPANTS: 19 midwives, practising in a range of maternity settings, participated in the study. The maternity settings included; obstetric led labour wards, along-side maternity units, stand-alone community maternity units, and community and independent practice. They also had a mixture of clinical experience, ranging from one to 20 years in practice. FINDINGS: Three categories emerged from the analysis, intrapartum uncertainty, the normality boundary and threshold pressures. Recognising the point at which a labour deviates away from normal constitutes 'intrapartum uncertainty'. In these situations midwives develop a normality boundary that shape their clinical judgements and decisions. The boundary becomes the limit, edge or border of what they accept as normal in a labour. Therefore if midwives tolerate intrapartum uncertainty they are more likely to construct labours as normal, than midwives with a lower tolerance of uncertainty. This can be mediated by threshold pressures that expand or contract their definitions of normality. So that supportive environments and good relationships with women enable midwives to tolerate uncertainty and thus maintain normality. IMPLICATIONS FOR PRACTICE: the reemphasise on midwifery practice as a means of supporting normal birth has been promoted as a way of 'demedicalising' birth for low risk women. However to maintain normality midwives need to understand the impact uncertainty has on their decision making. Supporting midwives to tolerate uncertainty, either at unit or national level, will expand definitions of normality so that birth can remain natural and dynamic. PMID- 23453699 TI - A systematic review of factors influencing uptake of invasive fetal genetic testing by pregnant women of advanced maternal age. AB - Women of advanced maternal age have a higher risk of having a child affected by a chromosomal disorder than younger childbearing women and are frequently offered invasive testing during pregnancy. The aim of our systematic review was to identify and analyse the current evidence base regarding factors that influence the uptake of invasive fetal testing by pregnant women of advanced maternal age. We conducted a systematic review. A search of The Cochrane Library, CINAHL, Embase and Medline databases was undertaken for papers published in English and Italian from January 2002 to May 2012. Eleven studies satisfied the inclusion criteria, were subjected to quality assessment and included in the review. We analysed the data using thematic analysis. The factors influencing women were classified as either external or psychosocial factors. External factors included the opportunity for screening, screening results and use of genetic counselling. Psychosocial factors related to ethnicity, socio-demographic status and attendance of partners during counselling. It is difficult to draw firm conclusions as to the principle factors that influence uptake of invasive tests by women of AMA. More research is needed to enhance understanding of relevant factors to ensure that services are offered in a way that acknowledges practical as well as psychosocial influences. This type of research will help to equip midwives and other professionals caring for women during pregnancy to ensure that women are supported to make the choices that are appropriate for them and their families. PMID- 23453700 TI - What factors influence midwives' decision to perform or avoid episiotomies? A focus group study. AB - OBJECTIVE: to explore midwives' reasons for performing or avoiding episiotomies and motivation to change episiotomy practice in a large tertiary maternity hospital. DESIGN: using purposive sampling, three focus groups were conducted to achieve theme saturation. Open-ended questions elicited personal reasons for performing or avoiding episiotomy, information sources, and opinions about past and future practice trends. Sessions were audiotaped, and transcripts independently examined by three researchers who coded for themes. An iterative process was used to achieve consensus. Grounded theory was used to interpret data and to derive a theoretical framework for understanding the reasoning that influences episiotomy practice. SETTING: a high volume delivery unit in Singapore. PARTICIPANTS: 20 of 79 licensed midwives, aged 28-70, who performed independent deliveries at the delivery unit. FINDINGS: participants recognised maternal, fetal and other factors affecting their own decision to perform episiotomies. Patient request, better healing, midwife's reputation and job satisfaction were cited as main reasons to avoid episiotomy. Key sources informing practice were past training, delivery experience, anecdotal learning and lack of a protocol. There was no consensus on current trends in episiotomy practice. There was an absence of recognition of individual roles in reducing episiotomy rates. Clinicians were perceived as having both positive and negative influence. CONCLUSIONS: midwives' reasons for performing episiotomies were attributed to midwifery training, fear of doing harm and perceived clinician expectation, and were not consistent with current international practice guidelines. Reasons for avoiding episiotomies were associated with patient centeredness and job satisfaction. Midwives agreed on the need to reduce episiotomy rates. IMPLICATIONS FOR PRACTICE: with reduction in episiotomy rates as a goal, a combination of guideline education, feedback, peer coaching and collaborative care with doctors may be needed to achieve desired outcomes. Views and experiences of midwives should also be incorporated into strategies to change episiotomy practice. PMID- 23453701 TI - Quinacrine-induced occlusive fibrosis in the human fallopian tube is due to a unique inflammatory response and modification of repair mechanisms. AB - Quinacrine has been widely used in treatment of parasitic diseases such as malaria and giardiasis, and in the treatment of autoimmune diseases. Quinacrine has also been used as an effective substitute for surgical contraception by causing occlusion of the fallopian tube. This minimally invasive treatment protocol involves intrauterine insertion of the drug in the form of pellets and has been studied in humans in a number of countries, including the United States. Despite its development in the 1970s, the cellular and molecular events induced by quinacrine in the human fallopian tube have not been described. Here we describe a plausible mechanism for quinacrine action in the fallopian tube. This is manifested as an acute pro-inflammatory response in the uterus and fallopian tube, characterized by loss of epithelial cell adhesion. This response relies on properties of gated channels found on the surface of epithelial cells in the reproductive tract. While the uterus returns to normal, the inflammatory response affects the uterotubal junction and transmural segment of the human fallopian tube, and initiates formation of mature collagen in the lumen of the fallopian tube, resulting in its permanent occlusion. The response within the fallopian tube appears similar to the protective mechanisms that have evolved in women to minimize the likelihood of systemic infection from Neisseria gonorrhoeae, and to some extent from Chlamydia trachomatis. This review could assist in development of experimental models used in investigating the mechanisms of fibrotic responses in humans as well as development of techniques for permanent non-surgical female contraception. PMID- 23453702 TI - TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury. AB - Even though neurogenic axis is well known in asthma pathogenesis much attention had not been given on this aspect. Recent studies have reported the importance of TRP channels, calcium-permeable ion channels and key molecules in neurogenic axis, in asthma therapeutics. The role of TRPV1 channels has been underestimated in chronic respiratory diseases as TRPV1 knockout mice of C57BL/6 strains did not attenuate the features of these diseases. However, this could be due to strain differences in the distribution of airway capsaicin receptors. Here, we show that TRPV1 inhibition attenuates IL-13 induced asthma features by reducing airway epithelial injury in BALB/c mice. We found that IL-13 increased not only the lung TRPV1 levels but also TRPV1 expression in bronchial epithelia in BALB/c rather than in C57BL/6 mice. TRPV1 knockdown attenuated airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and subepithelial fibrosis induced by IL-13 in BALB/c mice. Further, TRPV1 siRNA treatment reduced not only the cytosolic calpain and mitochondrial calpain 10 activities in the lung but also bronchial epithelial apoptosis indicating that TRPV1 siRNA might have corrected the intracellular and intramitochondrial calcium overload and its consequent apoptosis. Knockdown of IL-13 in allergen induced asthmatic mice reduced TRPV1, cytochrome c, and activities of calpain and caspase 3 in lung cytosol. Thus, these findings suggest that induction of TRPV1 with IL-13 in bronchial epithelia could lead to epithelial injury in in vivo condition. Since TRPV1 expression is correlated with human asthma severity, TRPV1 inhibition could be beneficial in attenuating airway epithelial injury and asthma features. PMID- 23453703 TI - Usefulness of HeLa cells to evaluate inverse agonistic activity of antihistamines. AB - Antihistamines are thought to antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). However, recent studies indicate that antihistamines are classified into two groups, i.e., inverse agonists and neutral antagonists on the basis of their ability to down-regulate the constitutive activity of H1R. As H1R is an allergy-sensitive gene whose expression influences the severity of allergic symptoms, inverse agonists should more potently alleviate allergic symptoms than neutral antagonists by inhibiting H1R constitutive activity. Therefore, it is important to assess inverse agonistic activity of antihistamines. Here we report a novel assay method using HeLa cells expressing H1R endogenously for evaluation of inverse agonistic activity of antihistamines. Pretreatment with inverse agonists down-regulated H1R gene expression below to its basal level. On the other hand, basal H1R mRNA expression was unchanged by neutral antagonist pretreatment. Both inverse agonists and neutral antagonists suppressed histamine-induced H1R mRNA elevation. Classification of antihistamines on the basis of their suppressive activity of basal H1R gene expression was consistent with that of inositol phosphate accumulation in H1R-overexpressed cells. Our data suggest that the assay method using HeLa cells is more convenient and useful than the existing methods and may contribute to develop new antihistamines with inverse agonistic activity. PMID- 23453704 TI - Evidence-based practice in radiology: knowledge, attitude and perceived barriers to practice among residents in radiology. AB - AIM: We examinted the attitude, knowledge and perceived barriers to evidence based practice of radiology (EBPR) among residents in radiology. STUDY DESIGN AND SETTING: We used the McColl questionnaire (1) and the BARRIERS scale (2) to assess the issues among radiology trainees attending an annual refresher course. Ninety six residents from 32 medical colleges from Southern India attended the course. RESULTS: Eighty (83.3%) residents, 55 male and 25 female of age range 24 34 years, consented and returned the questionnaire. The majority of the participants had a positive attitude towards EBPR. However, 45% were unaware of sources for evidence based literature although many had access to Medline (45%) and the internet (80%). The majority (70%) were aware of the common technical terms (e.g. odds ratio, absolute and relative risk) but other complex details (e.g. meta-analysis, clinical effectiveness, confidence interval, publication bias and number needed to treat) were poorly understood. Though majority of residents (59%) were currently following guidelines and protocols laid by colleagues within their departments, 70% of residents were interested in learning the skills of EBPR and were willing to appraise primary literature or systematic reviews by themselves. Insufficient time on the job to implement new ideas (70.1%); relevant literature is not being complied in one place (68.9%); not being able to understand statistical methods (68.5%) were considered to be the major barriers to EBPR. Training in critical appraisal significantly influence usage of bibliographic databases (p<0.0001). Attitude of collegues (p=0.006) influenced attitude of the trainees towards EBPR. Those with higher knowledge scores (p=0.02) and a greater awareness of sources for seeking evidence based literature (p=0.05) held stronger beliefs that EBPR significantly improved patient care. CONCLUSIONS: The large knowledge gap related to EBPR suggests the need to incorporate structured training into the core-curriculum of training programmes in radiology. PMID- 23453707 TI - Facile synthesis of single crystalline rhenium (VI) trioxide nanocubes with high catalytic efficiency for photodegradation of methyl orange. AB - Single-crystalline rhenium trioxide (ReO3) nanocubes have been prepared for the first time without the need of surfactants via controlled reduction of rhenium (VII) oxide (Re2O7), sandwiched between silicon wafers at 250 degrees C. The metallic ReO3 nanocubes are magnetic and possess surface plasmon resonance (SPR) bands down to the NIR region. The nanocubes also show very high catalytic activity toward the photodegradation of methyl orange (MO) under ambient conditions. A mechanism has been proposed to account for the photodegradation process. PMID- 23453706 TI - ABA transport and transporters. AB - Abscisic acid (ABA) metabolism, perception, and transport form a triptych allowing higher plants to use ABA as a signaling molecule. The molecular bases of ABA metabolism are now well described and, over the past few years, several ABA receptors have been discovered. Although ABA transport has long been demonstrated in planta, the first breakthroughs in identifying plasma membrane-localized ABA transporters came in 2010, with the identification of two ATP-binding cassette (ABC) proteins. More recently, two ABA transporters in the nitrate transporter 1/peptide transporter (NRT1/PTR) family have been identified. In this review, we discuss the role of these different ABA transporters and examine the scientific impact of their identification. Given that the NRT1/PTR family is involved in the transport of nitrogen (N) compounds, further work should determine whether an interaction between ABA and N signaling or nutrition occurs. PMID- 23453705 TI - Proton MR spectroscopy in patients with pyogenic brain abscess: MR spectroscopic imaging versus single-voxel spectroscopy. AB - PURPOSE: Single-voxel spectroscopy (SVS) has been the gold standard technique to diagnose the pyogenic abssess. Two-dimensional magnetic resonance spectroscopic imaging (MRSI) is able to provide spatial distribution of metabolic concentration, and is potentially more suitable for differential diagnosis between abscess and necrotic tumors. Therefore, the purpose of this study was to evaluate the equivalence of MRSI and SVS in the detection of the metabolites in pyogenic brain abscesses. MATERIALS AND METHODS: Forty-two patients with pyogenic abscesses were studied by using both SVS and MRSI methods. Two neuroradiologists reviewed the MRS data independently. A kappa value was calculated to express inter-reader agreement of the abscesses metabolites, and a correlation coefficient was calculated to show the similarity of two spectra. After consensus judgment of two readers, the binary value of metabolites of pyogenic abscesses (presence or absence) was compared between SVS and MRSI. RESULTS: The consistency of spectral interpretation of the two readers was very good (kappa ranged from 0.95 to 1), and the similarity of two spectra was also very high (cc=0.9+/-0.05). After consensus judgment of two readers, the sensitivities of MRSI ranged from 91% (acetate) to 100% (amino acids, succinate, lactate, lipid), and the specificities of MRSI were 100% for detecting all metabolites with SVS as reference. CONCLUSION: SVS and MRSI provide similar metabolites in the cavity of pyogenic brain abscess. With additional metabolic information of cavity wall and contralateral normal-appearing brain tissue, MRSI would be a more suitable technique to differentiate abscesses from necrotic tumors. PMID- 23453708 TI - Fabrication and characterization of II-VI semiconductor nanoparticles decorated electrospun polyacrylonitrile nanofibers. AB - Semiconductor nanoparticles incorporated highly aligned electrospun polyacrylonitrile (PAN) composite nanofibers were obtained via a simple, scalable and low-cost dip coating technique at room temperature. The resultant PAN nanofibers exhibited good incorporation of CdS, ZnS and CoS semiconductor nanoparticles. The detailed characterizations of these composite nanofibers were investigated. The incorporation of semiconductor nanoparticles on the surfaces of PAN nanofibers were confirmed by scanning electron microscopy (SEM), energy dispersive X-ray (EDX) spectroscopy and X-ray diffraction analysis. The current voltage (I-V) characteristics revealed that the electrical conductivity of these composite nanofibers were higher than that of the pristine PAN nanofibers. Overall, the feasibility of obtaining uniformly dispersed semiconductor nanoparticles on PAN nanofibers can be utilized for the realization of various nanotechnological device applications. PMID- 23453709 TI - Carotid pseudo-occlusion on CTA in patients with acute ischemic stroke: a concerning observation. AB - OBJECTIVE: Differentiation between an occluded and a patent extracranial internal carotid artery (ICA) is crucial in the diagnostic workup of patients with acute ischemic stroke; particularly in patients eligible for endovascular treatment. We report neurological and radiological findings of cases in which CTA in the acute phase incorrectly revealed an occlusion of the ICA. METHODS: In our image data base of 54 patients with acute ischemic stroke eligible for endovascular treatment, we searched for patients with an occluded extracranial ICA on CTA whereas DSA proved that this artery was patent. Of these patients, all available images were re-examined to investigate possible causes of these so-called pseudo occlusions. RESULTS: We detected 6 patients (11%) with a pseudo-occlusion. The pseudo-occlusions on CTA were associated with reduced flow due to carotid T occlusions (4 cases) or a combination of a high degree stenosis of the extracranial ICA and MCA occlusion (2 cases). CONCLUSION: CTA in the acute phase of ischemic stroke needs to be interpreted with severe caution, and in endovascular treatment decisions we should be aware that an extracranial ICA occlusion may be a false positive finding. PMID- 23453710 TI - The right scan, for the right patient, at the right time: the reorganization of major trauma service provision in England and its implications for radiologists. AB - Major trauma services in England are currently undergoing a radical overhaul with the formation of regional trauma networks and designated major trauma centres (MTCs). Radiology is scheduled to play a key role within major trauma care both in terms of 24/7 access to whole body computed tomography (WBCT) and interventional radiology (IR) services, as well as providing immediate expert imaging guidance to the trauma team. This review examines the rationale behind trauma networks, as well as drawing attention to the new Royal College of Radiologists' standards for major trauma imaging. It attempts to address radiologists' understandable concerns about the inappropriate use of WBCT, radiation dose, and intravenous contrast medium risks. Reporting whole-body CT for trauma patients is difficult, covering multiple body regions, with great pressure to provide a rapid and accurate report to the trauma team. The benefits of standardized reports, dual-radiologist reporting, and the use of organ injury severity grading are explored to aid succinct communication of findings and further guide patient management. PMID- 23453711 TI - Revised protocol for whole-body CT for multi-trauma patients applying triphasic injection followed by a single-pass scan on a 64-MDCT. AB - AIM: To evaluate a revised protocol for whole-body computed tomography (CT) for multi-trauma patients in an emergency department and compare it to conventional protocols. MATERIALS AND METHODS: Forty-two of 82 multi-trauma patients underwent unenhanced CT examinations of the head, cervical spine, and upper abdomen, followed by an arterial-phase contrast-enhanced CT examination of the thorax and a porto-venous scan of the abdomen and pelvis (conventional protocol). The other 40 patients underwent unenhanced CT examinations of the head, cervical spine, and upper abdomen, followed by a one-step acquisition of the thorax, abdomen, and pelvis using a 64-section multidetector CT (MDCT) system following a triphasic injection (revised protocol). Contrast enhancement was measured in the ascending, descending, and abdominal aorta, common iliac arteries, inferior vena cava (IVC), liver, spleen, and kidneys. Image count, radiation dose, total acquisition time, mediastinal artefacts, and image quality of each area were reviewed. RESULTS: Mean enhancement values in the ascending and descending aorta were significantly greater with the conventional protocol. Enhancement of the abdominal aorta, iliac arteries, IVC, liver, spleen, and kidneys was significantly greater with the revised protocol. Mediastinal streak artefacts were present in all conventional protocol images and absent in all revised protocol images. Image quality using the revised protocol was significantly better (p < 0.002). The mean effective radiation dose was significantly lower (p = 0.005), and image number reduced (p < 0.001). CONCLUSION: The revised triphasic injection single-pass whole-body imaging protocol was superior to the conventional protocol using 64-MDCT. It enabled better vascular and abdominal parenchymal imaging with reduction in radiation dose and image overload. PMID- 23453712 TI - Improvement of right ventricular dysfunction after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: utility of echocardiography to demonstrate restoration of the right ventricle during 2-year follow-up. AB - BACKGROUND: Pulmonary endarterectomy (PEA) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH) by dissecting the residual thrombus from the native vessel wall. The goal of PEA is to improve pulmonary hemodynamics and right ventricular dysfunction, and thus increase exercise capacity, alleviate symptoms and decrease mortality. The aim of this study, accordingly, was to assess the ability of echocardiography to provide a mechanism to monitor the time course of RV functional improvement after PEA. METHODS: Twenty-six consecutive adult patients who underwent PEA for CTEPH were included in the study. All the patients underwent transthoracic echocardiography and right heart catheterization before surgery. Follow-up echocardiography was performed within 3, 12, and 24 months of surgery. The parameters of right ventricle were compared with baseline data. RESULTS: In all cases, the RV was enlarged and systolic function was impaired before surgery. RV systolic pressure fell from 92+/-16 mm Hg before surgery to 41+/-9 mm Hg by the 3 month post-PEA follow-up (P<0.001). RV end diastolic area and end-systolic area likewise decreased from 35.8+/-4.4 cm(2) to 26.6+/-4.8 cm(2) (P<0.001) and from 27.1+/-3.8 cm(2) to 17.9+/-3.8 cm(2) (P<0.001), respectively. The RV myocardial performance index also decreased from a ratio of 0.8+/-0.1 to 0.5+/-0.1 (P<0.001). The tricuspid annular plane systolic excursion increased from 8.8+/-0.6mm to 10.1+/-0.9 mm (P<0.001). Tricuspid regurgitation (TR) improved from a mean grade of 3.1+/-0.5 to 2.2+/-0.7 (P<0.001). At the 12 and 24 month follow-up examinations, RV systolic pressure and function remained improved, respectively. The RV systolic pressure remained above 50 mmHg in only two cases. CONCLUSION: In patients with CTEPH who undergo PEA, echocardiography is a useful tool for the evaluation of RV function. Echocardiographic measurements of RV size, systolic pressure, systolic function, and TR show significant improvement, and this effect is sustained for up to 24 months after surgery. PMID- 23453713 TI - The multiple facets of opioid receptor function: implications for addiction. AB - Addiction is characterized by altered reward processing, disrupted emotional responses and poor decision-making. Beyond a central role in drug reward, increasing evidence indicate that opioid receptors are broadly involved in all these processes. Recent studies establish the mu opioid receptor as a main player in social reward, which attracts increasing attention in psychiatric research. There is growing interest in blocking the kappa opioid receptor to prevent relapse, and alleviate the negative affect of withdrawal. The delta opioid receptor emerges as a potent mood enhancer, whose involvement in addiction is less clear. All three opioid receptors are likely implicated in addiction depression comorbidity, and understanding of their roles in cognitive deficits associated to drug abuse is only beginning. PMID- 23453714 TI - Nocardia spp infections among hematological patients: results of a retrospective multicenter study. AB - OBJECTIVES: To describe the clinical characteristics and prognostic factors of hematological patients affected by Nocardia spp infections. METHODS: We retrospectively evaluated all the cases diagnosed in four Italian institutions. RESULTS: Between 2002 and 2012, 10 cases of nocardiosis were recorded. The median age of the patients was 66 years (range 24-85 years). The underlying hematological disease was a lymphoproliferative disorder in all but two patients. Eight patients (80%) showed active underlying hematological disease, relapsed or refractory in five (50%); one patient had a history of previous allogeneic bone marrow transplantation. Eight patients (80%) were on steroid therapy; lymphopenia was present in 8/10 (80%) patients. All patients showed lung involvement. Six patients were affected by disseminated nocardiosis. Three patients (30%) were nocardemic and three (30%) showed central nervous system involvement. Skin, lymph nodes, and bone were involved in one patient each. The median overall survival was 65 days. Older age, a longer period between hematological diagnosis and Nocardia spp infection, and relapsed/refractory hematological disease were associated with a worse prognosis. CONCLUSIONS: Although rare, nocardiosis should be considered in the differential diagnosis of pulmonary and central nervous system lesions among hematological patients. Lymphoproliferative disorders, prolonged steroid treatment, lymphopenia, and active hematological disease are the conditions that are worth considering as predisposing factors for the development of this disease. PMID- 23453715 TI - Group B streptococcal bacteremia in a major teaching hospital in Malaysia: a case series of eighteen patients. AB - BACKGROUND: Group B Streptococcus (GBS) is a leading cause of infections such as meningitis and septicemia in neonates and pregnant women; however the significance of invasive GBS disease has not been clearly defined in non-pregnant adults. METHODS: We reviewed the hospital records of 18 cases with GBS bacteremia who attended the Universiti Kebangsaan Malaysia Medical Centre from June 2010 to October 2011. We analyzed the clinical findings of both bacteremic adults and neonates and compared them to previous studies of GBS bacteremia. Serotyping was done by latex agglutination test using 10 distinct antisera (Ia, Ib, and II-IX). RESULTS: During the period of 1 year and 4 months, there were 18 patients with GBS bacteremia. Five cases occurred in neonates, one in a parturient woman, and 12 in other adults. All neonates with bacteremia were males and two of them were premature. Septicemia was the most common clinical presentation in neonates. They were treated with intravenous (IV) penicillin G and gentamicin. The adults included nine men (69%) and four women (31%). Their mean age was 60 years and all patients had more than two underlying conditions. The most common clinical syndrome was pneumonia (n=6, 46.5%). The others were peritonitis (n=3, 23.1%), primary bacteremia (n=2, 15.5%), septic arthritis (n=2, 15.5%), skin and soft tissue infection (n=1, 7.7%), meningitis (n=1, 8%), urinary tract infection (n=1, 8%), and intravascular device infection (n=1, 7.7%). Cardiovascular diseases (n=7, 53.8%) were the most common underlying conditions, and diabetes mellitus (n=5, 38.5%) was second. The other co-morbid conditions were hyperlipidemia (n=3, 23.1%), renal disease (n=3, 23.1%), liver disease and/or alcohol abuse (n=3, 23.1%), autoimmune disease or immunosuppressive condition (n=2, 15.5%), malignancy (n=2, 15.5%), respiratory disease (n=1, 8%), and postpartum condition (n=1, 8%), as well as miscellaneous conditions including intravenous drug abuse, HIV infection, and trauma (n=2, 15.5%). Polymicrobial bacteremia was found in five (45.4%) cases and Staphylococcus aureus was the most common concurrent bacterial isolate. Of the 18 GBS isolates in both adults and neonates, serotype Ia was predominant (38.9%), followed by VI (27.8%), V (11.1%), and III (5.5%); the remaining 16.7% were non-typeable. CONCLUSIONS: GBS bacteremia is a significant problem and is associated with serious underlying disease, which may result in a high rate of mortality, not only in neonates and pregnant women, but also in non-pregnant adults. PMID- 23453716 TI - Key considerations and current perspectives of epidemiological studies on human papillomavirus persistence, the intermediate phenotype to cervical cancer. AB - Persistent infection with human papillomavirus (HPV) causes essentially all precancerous cervical lesions and cervical cancer in females and thus is an important intermediate phenotype to cervical cancer. A majority of infected individuals naturally clear HPV viral infection, but the virus persists in a subset of infected hosts and the mechanism for this differential outcome is not well described. Most of the epidemiological studies have been cross-sectional in nature, and even with longitudinal studies, the definition of HPV persistence or clearance has not been well defined. There is no consensus on the correct time interval between HPV DNA tests, or how to utilize HPV persistence information in clinical management because there is no treatment for HPV. While most studies are performed with the endpoint of cancer, the intermediate phenotype has been overlooked. Epidemiological studies of HPV persistence suffer with several challenges in definitions, study designs, and analyses that undermine its importance in identifying and understanding the interactions between the viral and host genomes in the process of HPV infection pathogenesis. We have evaluated the current status of HPV persistence and provide perspectives on how the field would benefit from a research focus on intermediate phenotype in epidemiological studies. PMID- 23453717 TI - [Two uncommon extrapulmonary forms of Mycoplasma pneumoniae infection]. AB - Mycoplasma pneumonia is the second most frequent bacterium in pneumonia and the leading intracellular type. M. pneumoniae pulmonary infection is characterized by a slower onset profile and a lower biological inflammatory picture than pneumococcal infection. Both upper and lower respiratory tracts are often affected and sometimes a Kawasaki-like syndrome can be associated, with conjunctivitis or cheilitis. Extrapulmonary forms of the disease can occur, whether or not it is associated with pulmonary infection. We report two cases: in the first case, a renal form of M. pneumoniae disease developed in a 6-year-old girl, with membranous proliferative glomerulonephritis expressed as a picture of impure nephritic syndrome with decreased serum complement concentration, following an upper respiratory infection. Diagnosis was obtained by means of a kidney biopsy. The second case occurred in an 8-year-old girl who expressed, after a respiratory tract infection, neurological symptoms such as ocular flutter, perception disorder, and ataxia. This onset is typical of post infectious rhombencephalitis. Biological investigations and imaging were normal. In both cases, M. pneumoniae infection was diagnosed on the basis of immunoglobulin M-positive serology. Direct exploration of the bacterium was negative, due to its fragility and delayed diagnostic hypothesis. Several forms of M. pneumoniae infection are either the direct effect of the bacterium or are secondary to a cross-immunological reaction. As its frequency is increasing, M. pneumoniae infection should be raised as a cause of atypical, less well-known extrapulmonary forms of the disease. PMID- 23453718 TI - [Pediatric seizures and end-stage renal disease]. AB - Neonates and infants with hypocalcemia usually present with seizures, whereas this is less common in older children and teenagers. We report on a case of hypocalcemic seizures in a 16-year-old girl with undiagnosed end-stage renal disease with progressive growth retardation and bone deformations. We highlight the value of checking serum calcium, phosphate, and creatinine in children with growth retardation, seizures, and/or unexplained bone deformations. We also discuss the clinical consequences of pediatric renal osteodystrophy. PMID- 23453719 TI - [Cutaneous polymorph manifestations of familial Mediterranean fever in a child]. AB - We describe the case of a 4-year-old child with Mediterranean fever characterized by cutaneous features. Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent attacks of fever and polyserositis including peritonitis, pleuritis, and arthritis. Skin involvement is less common. In our case, the successively patient presented erysipelas-like erythema, edemas of the palmar and plantar regions, and purpuric lesions. From these clinical observations, several diagnoses were raised: infectious erysipelas, Kawasaki disease, Henoch-Schonlein purpura, and familial Mediterranean fever. Only the latter diagnosis was confirmed after exploration and then confirmed with genetic analysis, which found a M694V homozygous mutation. Erysipelas-like erythema is the most frequent cutaneous sign reported in the literature and the only one to be associated with the M694V homozygous mutation. The originality of this case is the dominancy and polymorphism of the skin lesions. PMID- 23453720 TI - [Vitamin D, Randall plaques and nephrolithiasis: are they related?]. PMID- 23453721 TI - [Multifocal osteoarticular infection caused by Salmonella non typhi in a child with sickle cell disease]. AB - INTRODUCTION: Sickle cell disease is the most common monogenic hereditary hemoglobinopathy. Its course is marked by vaso-occlusive crises (VOC), episodes of acute hemolytic anemia on a background of chronic hemolytic anemia, and severe infections. CASE REPORT: A 2-year-old child with sickle cell disease presented with severe sepsis caused by Salmonella non typhi. Control of the sepsis was difficult, with multifocal osteomyelitis and arthritis, which required prolonged intravenous antibiotic therapy. Prolonged treatment was complicated by cardiorespiratory arrest and severe neurological damage, as well as nosocomial infections. CONCLUSION: Osseous articular infections caused by Salmonella non typhi are a common complication in children with sickle cell disease, which need to be promptly recognized. Management remains a great concern. The clinical case reported herein is original in its multifocal evolution. It illustrates the vulnerability of patients with sickle cell disease and the need for urgent and intensive care in the case of infection. PMID- 23453722 TI - [Epidemiology of acute bacterial diarrhea in children in Libreville, Gabon]. PMID- 23453724 TI - What's brewing: how interventional radiologists can learn from the reinvention of Starbucks. PMID- 23453725 TI - Sharing a collection of radiology educational websites as bookmarks among radiologists. PMID- 23453726 TI - Bilateral coordination and gait symmetry after body-weight supported treadmill training for persons with chronic stroke. AB - BACKGROUND: Locomotor interventions are commonly assessed using functional outcomes, but these outcomes provide limited information about changes toward recovery or compensatory mechanisms. The study purposes were to examine changes in gait symmetry and bilateral coordination following body-weight supported treadmill training in individuals with chronic hemiparesis due to stroke and to compare findings to participants without disability. METHODS: Nineteen participants with stroke (>6 months) who ambulated between 0.4 and 0.8 m/s and 22 participants without disability were enrolled in this repeated-measures study. The stroke group completed 24 intervention sessions over 8 weeks with 20 minutes of walking/session. The non-disabled group served as a comparison for describing changes in symmetry and coordination. Bilateral 3-dimensional motion analysis and gait speed were assessed across 3 time points (pre-test, immediate post-test, and 6-month retention). Continuous relative phase was used to evaluate bilateral coordination (thigh-thigh, shank-shank, foot-foot) and gait symmetry was assessed with spatiotemporal ratios (step length, swing time, stance time). FINDINGS: Significant improvements in continuous relative phase (shank-shank and foot-foot couplings) were found at post-test and retention for the stroke group. Significant differences in spatiotemporal symmetry ratios were not found over time. Compared to the non-disabled group, changes in bilateral coordination moved in the direction of normal recovery. Most measures of continuous relative phase were more responsive to change after training than the spatiotemporal ratios. INTERPRETATIONS: After body-weight supported treadmill training, the stroke group made improvements toward recovery of normal bilateral coordination. Bilateral coordination and gait symmetry measures may assess different aspects of gait. PMID- 23453727 TI - Left paraduodenal hernia in an adult obese patient at the time of bariatric surgery. PMID- 23453728 TI - Using ultrasound lung comets in the diagnosis of high altitude pulmonary edema: fact or fiction? AB - High altitude pulmonary edema is a life-threatening condition that remains a concern for climbers and clinicians alike. Within the last decade, studies have shown ultrasonography to be valuable in the accurate diagnosis of a variety of lung pathologies, including cardiogenic pulmonary edema, pleural effusion, pneumothorax, and lung consolidation. Recently, studies conducted in remote areas have demonstrated that ultrasound lung comets can be used as a measure of subacute pulmonary edema and high altitude pulmonary edema in climbers ascending to altitude. This clinical review article provides an overview of lung ultrasonography and its relevance as a diagnostic aid to respiratory pathology. In addition, we describe a standardized technique for identifying ultrasound lung comets and its utility in recognizing the presence of extravascular lung water, as well as the results of studies that have used this approach at sea level and high altitude. PMID- 23453729 TI - Mercury toxicity in wildland firefighters. AB - OBJECTIVE: Recent studies have shown that significant levels of mercury are being released into the atmosphere by wildland fires throughout the United States. Eagle populations in the western United States are experiencing mercury toxicity in areas where many of these massive fires are occurring. We hypothesized that wildland firefighters exposed to smoke and other contaminates from these extensive fires would also reflect elevated blood levels of mercury. METHODS: Wildland firefighters in the western United States were studied during the summers of 2007, 2008, and 2009. Pre- and post-fire season blood samples were tested for mercury in a cohort of firefighters and control subjects. RESULTS: Over the course of 3 summers, 66 firefighters were studied (41 had pre- and postseason blood draws). In 2008 and 2009 a control group was added with a total of 39 subjects (24 had pre- and postseason blood draws). Detectable blood levels of mercury were found in 6 firefighters, and 1 elevated level was found over the course of the study period. Six control subjects had detectable mercury levels, and no elevated levels were found. CONCLUSIONS: This study did not show statistically significant elevated blood levels of mercury in our cohort of wildland firefighters. However, as forest fires continue to ignite, we recommend continued investigation to ensure the health and safety of firefighting crews. PMID- 23453731 TI - Different profile and distribution of antigen specific T cells induced by intranasal and intrarectal immunization with rotavirus 2/6-VLP with and without LT-R192G. AB - In this study, we compared both the profile and distribution of antigen specific primed T cells after intrarectal (IR) and intranasal (IN) immunization with rotavirus (RV) 2/6-VLP, alone or in the presence of LT-R192G, in order to highlight the differences between the two routes and the impact of the adjuvant. Adult BALB/c mice were immunized once with 2/6-VLP with or without adjuvant and the T cell response was analyzed in lymphoid tissues after in vitro restimulation with the antigen. IN, but not IR, immunization of mice with 2/6-VLP alone induced antigen-specific IL-10 and IL-17 secreting T cells. IL-10-, in contrast to IL-17 , secreting T cells did not migrate to the mesenteric lymph nodes (MLN) whereas they were detected in cervical lymph nodes (CLN) and spleen. With the IN route, the adjuvant allowed to complete this profile with the secretion of IL-2 and IL 4, increased IL-17 secretion and induced antigen specific CD4+CD25+Foxp3+ and Foxp3- T cells in all studied organs (CLN, spleen and MLN) but did not impact on IL-10 secreting T cells. With the IR route, the adjuvant induced IL-2 and IL-17 secretion but, in contrast to the IN route, did not allow IL-4 production. These results show that, for a same antigen, T cell priming not only depends on the presence of adjuvant but also on the mucosal route of administration. Moreover, they show a different dissemination of IL-10 secreting T cells compared to other subtypes. PMID- 23453730 TI - Probiotics and colostrum/milk differentially affect neonatal humoral immune responses to oral rotavirus vaccine. AB - Breast milk (colostrum [col]/milk) components and gut commensals play important roles in neonatal immune maturation, establishment of gut homeostasis and immune responses to enteric pathogens and oral vaccines. We investigated the impact of colonization by probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (Bb12) with/without col/milk (mimicking breast/formula fed infants) on B lymphocyte responses to an attenuated (Att) human rotavirus (HRV) Wa strain vaccine in a neonatal gnotobiotic pig model. Col/milk did not affect probiotic colonization in AttHRV vaccinated pigs. However, unvaccinated pigs fed col/milk shed higher numbers of probiotic bacteria in feces than non-col/milk fed colonized controls. In AttHRV vaccinated pigs, col/milk feeding with probiotic treatment resulted in higher mean serum IgA HRV antibody titers and intestinal IgA antibody secreting cell (ASC) numbers compared to col/milk fed, non-colonized vaccinated pigs. In vaccinated pigs without col/milk, probiotic colonization did not affect IgA HRV antibody titers, but serum IgG HRV antibody titers and gut IgG ASC numbers were lower, suggesting that certain probiotics differentially impact HRV vaccine responses. Our findings suggest that col/milk components (soluble mediators) affect initial probiotic colonization, and together, they modulate neonatal antibody responses to oral AttHRV vaccine in complex ways. PMID- 23453732 TI - Targeting TRPV1 and TRPV2 for potential therapeutic interventions in cardiovascular disease. AB - Cardiovascular disease is a leading cause of morbidity and mortality worldwide, encompassing a variety of cardiac and vascular conditions. Transient receptor potential vanilloid (TRPV) channels, specifically TRPV type 1 (TRPV1) and TRPV type 2 (TRPV2), are relatively recently described channels found throughout the body including within and around the cardiovascular system. They are activated by a variety of stimuli including high temperatures, stretch, and pharmacologic and endogenous ligands. The TRPV1 channel has been found to be an important player in the pathway of the detection of chest pain after myocardial injury. Activation of peripheral TRPV1 via painful stimuli or capsaicin has been shown to have cardioprotective effects, whereas genetic abrogation of TRPV1 results in increased myocardial damage after ischemia and reperfusion injury in comparison to wild-type mice. Furthermore, blood pressure changes have been noted upon TRPV1 stimulation. Similarly, the TRPV2 channel has also been associated with changes in blood pressure and cardiac function depending on how and where the channel is activated. Interestingly, overexpression of TRPV2 channels in the heart induces dystrophic cardiomyopathy; however, stimulation under physiologic conditions leads to improved cardiac function. Probenecid, a TRPV2 agonist, has been studied as a model therapy for its inotropic effects and potential use in the treatment of cardiomyopathy. In this review, we present an up to date account of the growing evidence that supports the study of TRPV1 and TRPV2 channels as targets for therapeutic agents of cardiovascular diseases. PMID- 23453733 TI - Koch's postulates and the pathogenesis of comparative infectious disease causation associated with Bartonella species. AB - In his homage to Lucretius ('Georgica'), Vergil is credited with stating: 'Felix qui potuit rerum cognoscere causas' ('Fortunate is he who knows the causes of things'). Based on numerous commentaries and publications it is obvious that clinicians, diagnosticians and biomedical research scientists continue to struggle with disease causation, particularly in the assessment of the pathogenic role of 'stealth pathogens' that produce persistent infections in the host. Bartonella species, because of their evolutionary ability to induce persistent intravascular infections, present substantial challenges for researchers attempting to clarify the ability of these stealth bacteria to cause disease. By studying the comparative biological and pathological behaviour of microbes across mammalian genera, researchers might be able more rapidly to advance medical science and, subsequently, patient care by undertaking focused research efforts involving a single mammalian species or by attempting to recapitulate a complex disease in an rodent model. Therefore, in an effort to further assist in the establishment of disease causation by stealth pathogens, we use recent research observations involving the genus Bartonella to propose an additional postulate of comparative infectious disease causation to Koch's postulates. PMID- 23453734 TI - The combating of tuberculosis in the light of the experience that has been gained in the successful combating of other infectious diseases. Journal of Comparative Pathology and Therapeutics (1901, Vol. 14, No. 3). PMID- 23453735 TI - The Journal of Comparative Pathology historical archive and Koch's postulates. PMID- 23453736 TI - Structural changes of gut microbiota in a rat non-alcoholic fatty liver disease model treated with a Chinese herbal formula. AB - Accumulating evidence indicates that disruption of the gut microbiota by a high fat diet (HFD) may play a pivotal role in the progression of metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). In this study, the structural changes of gut microbiota were analyzed in an HFD-induced NAFLD rat model during treatment with an ancient Chinese herbal formula (CHF) used in clinical practice Qushi Huayu Fang. CHF treatment significantly reduced body weight, alleviated hepatic steatosis, and decreased the content of triglycerides and free fatty acids in the livers of the rats. Gut microbiota of treated and control rats were profiled with polymerase chain reaction-denaturing gradient gel electrophoresis and bar-coded pyrosequencing of the V3 region of 16S rRNA genes. Both analyses indicated that the CHF-treated group harbored significantly different gut microbiota from that of model rats. Partial least squares discriminant analysis and taxonomy-based analysis were further employed to identify key phylotypes responding to HFD and CHF treatment. Most notably, the genera Escherichia/Shigella, containing opportunistic pathogens, were significantly enriched in HFD-fed rats compared to controls fed normal chow (P<0.05) but they decreased to control levels after CHF treatment. Collinsella, a genus with short chain fatty acid producers, was significantly elevated in CHF-treated rats compared to HFD-fed rats (P<0.05). The results revealed that the bacterial profiles of HFD-induced rats could be modulated by the CHF. Elucidation of these differences in microbiota composition provided a basis for further understanding the pharmacological mechanism of the CHF. PMID- 23453737 TI - Taxonomy becoming a driving force in genome sequencing projects. AB - We studied the possible impact of genomic projects by comparing the number of published articles before and after the completion of the project. We found that for most species, there is no significant change in the number of citations. Also our study remarks the growing importance of taxonomy as main motivation for the sequencing of genomes. PMID- 23453738 TI - Declining social support in adolescents prior to first episode psychosis: associations with negative and affective symptoms. AB - Social support for individuals with psychosis is associated with decreased symptom severity, improved outcomes, and recovery. In adolescents, declining social support prior to the first hospitalization has been shown to predict time to relapse, which may have implications for early intervention. Data were collected on adolescents (n=84) following a first hospitalization for a psychotic episode in order to examine how change in social support relates to the duration and type of untreated symptoms. Most adolescents experienced a decline in social support (n=46) prior to index hospitalization. Chi-square analyses showed that declining social support was related to negative symptoms and longer duration of untreated psychosis, whereas stable social support was associated with manic symptoms and diagnosis of Bipolar disorder. When entered together into a logistic regression model, the decline in social support was primarily explained by the type of symptoms, rather than by the duration of untreated symptoms. These findings are relevant for targeting psychosocial treatments toward adolescents who may have particular deficits in social support during the prodromal phase and first episode of psychosis. PMID- 23453739 TI - Lack of association between TNFalpha rs1800629 polymorphism and schizophrenia risk: a meta-analysis. AB - Evidence has suggested that tumour necrosis factor alpha (TNFalpha) may be involved in the aetiology of schizophrenia, but the underlying association between TNFalpha-308G/A polymorphism (rs1800629) and schizophrenia risk is still ambiguous. This meta-analysis was performed to quantitatively summarise the evidence for such a relationship. Eligible studies were identified by searching PubMed, EMBASE, CNKI (China National Knowledge Infrastructure), CBM (Chinese Biomedical Literature Database) and WANFANG databases within a range of published years from 1990 to July 2012. The odds ratio (OR) corresponding to the 95% confidence interval (CI) was used to assess the different associations. Twenty one studies with 4340 cases and 5745 controls were included in this meta analysis. The pooled examination displayed that there was no significant association between TNFalpha-308G/A polymorphism and susceptibility to schizophrenia overall (OR=1.047, 95% CI=0.876-1.253, P=0.614 for A vs. G), and no difference in Caucasian subgroup (OR=1.041, 95% CI=0.815-1.331, P=0.747) and Asian subgroup (OR=1.057, 95% CI=0.807-1.386, P=0.686). Lack of association was also found in males (OR=0.862, 95% CI=0.413-1.797, P=0.692) and females (OR=0.797, 95% CI=0.579-1.097, P=0.163) with a dominant model. Taken together, this meta-analysis suggests that TNFalpha-308G/A polymorphism may not be associated with schizophrenia susceptibility. PMID- 23453741 TI - Validation of new york operative mortality risk score for valve and valve/coronary artery bypass grafting operations. AB - BACKGROUND: New York (NY) valve and valve/coronary artery bypass grafting (CABG) mortality risk models, developed from operations performed in 2007 to 2009, have just been published. These models were validated using NY data from 2004 to 2006. The authors stated that their models "should also be validated by testing them against non-New York populations." Thus, we validated the NY models with the Providence Health & Services-Swedish Health Services (PH&S-SHS) cardiac surgical data and also compared them with The Society of Thoracic Surgeons (STS) mortality risk models. METHODS: The PH&S-SHS validation data set contained 4,021 isolated valve and 2,406 valve/CABG operations, performed from 2008 to 2012. The risk models (NY logistic and score models and the STS models) were recalibrated to equalize the expected and observed number of deaths. Discrimination was tested by C statistics and calibration by Hosmer-Lemeshow statistics. RESULTS: PH&S-SHS operative mortality rates were 2.6% and 5.5% in the valve and valve/CABG operations, respectively, and were lower than the NY rates. The C statistics for the NY logistic valve and valve/CABG models were 0.777 and 0.727, respectively, and were very similar for the NY score models. Calibration was good for the NY valve model (p=0.85), but not for the NY valve/CABG model (p=0.01). The STS models had better discrimination than NY models and good calibration. CONCLUSIONS: The NY logistic and score models for valve operations fit the PH&S SHS data well with acceptable discrimination and good calibration. The NY models for valve/CABG operations fit the PH&S-SHS data with acceptable discrimination and poor calibration. STS logistic regression models fit the PH&S-SHS data somewhat better. PMID- 23453740 TI - Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas. AB - BACKGROUND: Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. We aimed to clarify the mechanisms of epithelial-to-mesenchymal transition (EMT) in MPMs by analyzing the expressions of EMT-associated transcription factors and E-cadherin in relation to tumor proliferation rates and patient survival. METHODS: One hundred nine patients with MPMs were investigated. Among these patients, there were 61 epithelioid tumors, 21 sarcomatoid tumors, 20 biphasic tumors, and 7 desmoplastic tumors. Immunohistochemical analyses were performed to evaluate the expressions of Snail, ZEB1, Twist, E-cadherin, and the Ki-67 proliferation index. RESULTS: The expressions of Snail and ZEB1 were significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p<0.0001 and p=0.0051, respectively). Furthermore, the E-cadherin expression was significantly lower in the Snail-high tumors than in the Snail-low tumors (p=0.0423). The E-cadherin expression was significantly lower in the nonepithelioid tumors than in the epithelioid tumors (p=0.0126). The Ki-67 proliferation index was significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p=0.025). Patient survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs (p=0.0016), especially in patients with nonepithelioid tumors (p=0.0089). The multivariate analysis also demonstrated that nuclear Snail expression was a significant predictor of poor prognosis in patients with MPMs (p=0.0142). CONCLUSIONS: The Snail expression is associated with EMT and a poor prognosis in MPMs. Snail could be a potential molecular target for the treatment of patients with MPMs. PMID- 23453742 TI - Minimally invasive edge-to-edge mitral repair with or without artificial chordae. AB - BACKGROUND: This study aims to analyze the midterm outcomes of minimally invasive edge-to-edge mitral valve repair (MVR) with artificial chords (CHORD) or without artificial chords (noCHORD) in patients with mitral regurgitation (MR). METHODS: Records of all patients undergoing edge-to-edge MVR through minithoracotomy at a single institution over a 7-year period were retrospectively reviewed. RESULTS: A total of 186 patients underwent edge-to-edge MVR through minithoracotomy. Disease etiology was posterior prolapse in 73 (39%) and bileaflet prolapse in 77 (41%). Edge-to-edge sutures were used at A1-P1 in 20 patients (11%), A2-P2 in 136 (73%), and A3-P3 in 30 (16%). Annuloplasty rings were placed in 184 patients (99%), with a mean size of 36+/-5 mm. Mean follow-up was 2 years (range, 0 to 6), with mean mitral gradient 4+/-2 mm Hg, MR mild or less in 179 of 186 (96%), 4 (2%) late reoperations, and 1 (0.5%) late death. The CHORD patients (n=71) were more likely than the noCHORD patients (n=115) to have extensive posterior leaflet pathology (p<0.01), had longer clamp and pump times (p<0.01) and were less likely to need leaflet resection (p=0.002), but had similar postoperative courses. At 3 years, freedom from moderate MR was less in CHORD versus noCHORD patients (88+/-6 versus 100%, p=0.001), but freedom from reoperation was similar (96%+/-3% versus 99%+/ 1%, p=not significant). CONCLUSIONS: Early results suggest that edge-to-edge MVR can be safe and effective in patients with mitral regurgitation. Edge-to-edge MVR combined with artificial chordae may be useful in selected patients, but with some risk of recurrent moderate MR. PMID- 23453743 TI - Video-assisted thoracoscopic lobectomy in children: safety, efficacy, and risk factors for conversion to thoracotomy. AB - BACKGROUND: Video-assisted thoracoscopic lobectomy in small children has not been widely performed because of difficulties in single-lung ventilation and surgical technique. This study assessed the feasibility, outcomes, and risk factors for conversion to thoracotomy of thoracoscopic lobectomy in children. METHODS: From 2005 to 2011, thoracoscopic lobectomy was tried in 50 consecutive pediatric patients. The median age was 3.2 years and the median body weight was 16 kg. Congenital cystic adenomatoid malformation (CCAM) (78%) and pulmonary sequestration (18%) were the most common diagnoses. Prenatal diagnosis by ultrasonography was made in 34% of patients (17 of 50), and a previous history of pneumonia was present in 46% (23 of 50). The most commonly used single-lung ventilation modality was endobronchial blocking by balloon catheter through a single-lumen endotracheal tube. The use of a stapler was minimized, with endoscopic clipping devices and energy-based cutting instruments used instead. RESULTS: Thoracoscopic lobectomy without conversion was accomplished in 82% of patients (41 of 50). There was no in-hospital mortality and 1 major morbidity (2%) with postoperative bleeding. Comparison with a group from an earlier period (~2009) and a group from a later period (2010-2011) determined that thoracotomy conversion rates, mean operation times, and mean hospital days were 27% and 8%, 190+/-85 and 133+/-40 minutes, and 11.0+/-6.7 and 5.2+/-2.2 days, respectively. In univariate analysis, lower body weight (p=0.010), operations in the earlier period (p=0.040), single-lung ventilation failure (p=0.004), and a previous history of pneumonia (p<0.001) were related to conversion to thoracotomy. Multivariate analysis revealed a previous history of pneumonia to be the only independent risk factor for conversion to thoracotomy (p=0.0179). CONCLUSIONS: Thoracoscopic lobectomy in small children is a safe and effective treatment modality. Close cooperation with the anesthesiologist, use of adequate instruments, and selection of proper patients are important for the success of thoracoscopic lobectomy in small children. A previous history of pneumonia was an independent risk factor for conversion to thoracotomy. PMID- 23453744 TI - Hemodynamic assessment after complete repair of pulmonary atresia with major aortopulmonary collaterals. AB - BACKGROUND: Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals (PA/VSD/MAPCAs) is a complex form of congenital heart defect. There are limited data regarding late hemodynamics of patients after repair of PA/VSD/MAPCAs. This study evaluated the hemodynamics of patients who underwent complete repair of PA/VSD/MAPCSs and subsequently returned for a conduit change. METHODS: This was a retrospective review of 80 children undergoing a right ventricle (RV)-to-pulmonary artery conduit replacement after complete repair of PA/VSD/MAPCAs. All patients underwent preoperative cardiac catheterization to define the cardiac physiology. Patients were an average age of 6.5+/-1.2 years, and the average interval between complete repair and conduit change was 4.5+/-1.1 years. RESULTS: The preoperative cardiac catheterization demonstrated an average RV right peak systolic pressure of 70+/-22 mm Hg and pulmonary artery pressure of 38+/-14 mm Hg. This pressure gradient of 32 mm Hg reflects the presence of conduit obstruction. After conduit change, the intraoperative RV systolic pressure was 34+/-8 mm Hg, similar to 36+/-9 mm Hg at the conclusion of the previous complete repair. The corresponding RV/aortic pressure ratios were 0.36+/-0.07 and 0.39+/-0.09, respectively. CONCLUSIONS: The data demonstrate that patients who underwent complete repair of PA/VSD/MAPCAs had nearly identical pulmonary artery pressures when they returned for conduit change some 4.5 years later. This finding indicates that the growth and development of the unifocalized pulmonary vascular bed is commensurate with visceral growth. We would hypothesize that complete repair, along with low RV pressures, will confer a long-term survival advantage. PMID- 23453745 TI - Bilateral internal mammary artery grafting and risk of sternal wound infection: evidence from observational studies. AB - BACKGROUND: The advantageous survival outcome of bilateral internal mammary artery grafting (BIMA) has been well established. However, this meta-analysis aims to make clear whether BIMA grafting increases the risk of sternal wound infection (SWI) when compared with single internal mammary artery grafting (SIMA). METHODS: A literature search was performed in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. The observational studies reporting a comparison between SIMA and BIMA were included. The outcome of interest was the risk of SWI. Literature search, data extraction, and quality assessment were performed. Sensitivity and publication bias were also assessed in this research. RESULTS: We identified 4,701 titles and included 32 studies finally. The meta-analysis showed that the risk of SWI in the BIMA group was higher (relative risk [RR] 0.62, 95% confidence interval [CI] 0.55 to 0.71) than that in the SIMA group. Moreover, BIMA grafting was also associated with a higher risk of SWI in diabetic patients (RR 0.65, 95% CI 0.52 to 0.81) as well as elderly patients (RR 0.45, 95% CI 0.33 to 0.62). When skeletonization technique was adopted, the risk of SWI in BIMA patients was just a little higher than that in SIMA patients, but the difference did not reach statistical significance (RR 0.84, 95% CI 0.54 to 1.31). CONCLUSIONS: The BIMA grafting increases the risk of SWI when compared with SIMA grafting. This adverse effect further extends to diabetic and elderly patients. As regarding the method of procurement, skeletonized BIMA is safe and effective, thus it should be the procedure recommended. PMID- 23453746 TI - Application of intravascular dissection devices for closed chest coronary sinus lead extraction: an interdisciplinary approach. AB - BACKGROUND: Increasing application of cardiac resynchronization therapy is accompanied by an increase in patients requiring removal of coronary sinus (CS) leads. The aim of this study was to determine outcomes of closed chest CS lead extraction using intravascular dissection devices. METHODS: Between 2000 and 2011, 41 patients (80.5% men; aged 64.2+/-13.8 years) underwent transvenous CS lead extraction procedures. Reasons for lead extraction were infection in 9, CS lead dislodgement in 15, lead malfunction, including manufacturer-initiated product recall in 6, phrenic nerve stimulation in 5, combinations of causes in 5, and elective extraction concomitant with generator replacement for battery depletion in 1. RESULTS: In addition to 24 isolated CS lead extractions, we performed 17 multiple lead extractions (2 to 4 leads) after a mean of 30.6+/-32.5 months. The time elapsed from implantation was 4.6+/-9.1 months for isolated CS and 42.6+/-32.4 months for multiple lead extractions. Extraction by direct manual traction was feasible in 13 patients by locking stylets in 6. Escalation to mechanical sheaths was required in 17 patients and to electrosurgical sheaths in 5. More aggressive methods were associated with longer implantation times and positive infection status. No deaths or major periprocedural complications occurred. Six minor postprocedural complications, of which three were surgically related, occurred in 5 patients. CONCLUSIONS: Closed chest CS lead extraction can be safely performed with excellent results. We recommend an escalating approach from isolated manual traction over locking stylets to mechanical sheaths and, eventually, electrosurgical dissection devices. The application in mainly high risk patients demands an interdisciplinary approach to enhance safety and limit morbidity and death. PMID- 23453747 TI - Left atrial dissection: etiology and treatment. AB - BACKGROUND: Left atrial dissection (LatD) is a rare entity most commonly associated with mitral valve surgery. We have reviewed our experience with 4 patients to better define the etiology and the treatment of LatD. METHODS: From 1991 to 2012, 4 patients experienced LatD after surgery (1 of 6,302, or 0.02%, of isolated coronary artery bypass grafting patients and 3 of 1,895, or 0.16%, of mitral valve patients). Patient and perioperative data and management were reviewed. RESULTS: Two patients were women, and ages ranged from 49 to 80 years. Three patients underwent mitral procedures (two replacements with coronary artery bypass grafting and one repair) for mitral regurgitation. One patient underwent emergent isolated coronary artery bypass grafting after cardiopulmonary resuscitation for a left main dissection during percutaneous coronary intervention. Three LatDs were found during surgery, and one LatD was found 12 days after mitral repair and was successfully treated nonoperatively. The LatD was located along the posterior atrial wall originating from the atrioventricular junction in all cases and obstructed mitral valve inflow. Operative repair focused on the evacuation of hematoma, obliteration of the false lumen, and repair of the entry injury. No mortality occurred. CONCLUSIONS: Left atrial dissection is a rare complication of cardiac surgery, probably related to a contained atrioventricular separation allowing pressurized blood to separate the layers of the posterior left atrium. Prompt intraoperative diagnosis, obliterating the false cavity, and addressing the entry point are essential. In contrast, a nonoperative approach in a stable patient with a delayed LatD suggests healing of the dissection, and atrial remodeling occurs. PMID- 23453748 TI - Analysis of the risk factors for early failure after extracardiac Fontan operation. AB - BACKGROUND: We analyzed risks for severe morbidity in the early period after extracardiac Fontan operation. METHODS: Between November 1995 and May 2011, 140 patients (median age, 3.8 years) underwent extracardiac Fontan operation. We assumed as preoperative risk factors systemic right ventricle (n=51), heterotaxia (n=25), arterial oxygen saturation less than 75% (n=22), and adult age (>16 years, n=20) at time of surgery. Prolonged cardiopulmonary bypass time of longer than 120 minutes (n=30) and use of cardioplegia (n=26) were analyzed as intraoperative risks. RESULTS: Heterotaxia was revealed as a risk factor for postoperative prolonged inotropic support, acute renal failure, prolonged mechanical ventilation, prolonged pleural effusions, and tachyarrhythmias. With the exception of pleural effusions, the same held true for right ventricle morphology. Low preoperative arterial oxygen saturation was found to be associated with an increased risk of prolonged inotropic support, acute renal failure, and prolonged mechanical ventilation. Adult age was identified as a risk factor for acute renal failure. Of the intraoperative factors, prolonged cardiopulmonary bypass time longer than 120 minutes was a risk factor for acute renal failure and prolonged pleural effusions, whereas use of cardioplegia was associated with an increased risk of prolonged inotropic support, prolonged mechanical ventilation, acute renal failure, and tachyarrhythmias. Multivariate analysis demonstrated heterotaxia, right ventricular morphology, and low preoperative arterial oxygen saturation to be independent risk factors for postoperative prolonged inotropic support and prolonged mechanical ventilation. CONCLUSIONS: Patients with heterotaxia, systemic right ventricle, and low preoperative arterial oxygen saturation are still at high risk for early Fontan failure after extracardiac Fontan operation and require special management for optimal outcome. PMID- 23453749 TI - Differences in survival from prostate cancer in Denmark, Iceland and Sweden. AB - INTRODUCTION: Register-based studies have shown large survival differences among prostate cancer patients in the Nordic countries. The aim of this study was to determine the background of such differences in Denmark, Iceland and Sweden. MATERIAL AND METHODS: Patients with prostate cancer were identified through population-based cancer registers in the three countries. Clinical findings at diagnosis were retrieved from hospital records. In Sweden, clinical information was gathered from regional population-based prostate cancer registers. Country specific incidence and excess mortality rates were compared, with adjustment for prognostic factors. RESULTS: The relative survival in the cohorts was comparable to that in previous population-based studies. Significant differences in excess mortality rates were found across countries, which diminished or disappeared after adjustment for patient characteristics, i.e. metastatic status, clinical T stage and prostate-specific antigen level. A difference in the proportion of patients with metastatic disease was the main explanation of the differences in survival among countries, while the incidence rates of metastatic cancer were similar. DISCUSSION: Register-based studies of the relative survival of prostate cancer patients are influenced by national differences in clinical presentation at diagnosis. Differences in the proportion of patients with metastatic spread explained most of the difference in relative survival among patients in Denmark, Iceland and Sweden. Future country comparisons of relative survival should include adjustment for differences in patient characteristics, such as stage, prostate-specific antigen level and screening intensity. PMID- 23453751 TI - Mental time travel: continuities and discontinuities. PMID- 23453750 TI - Quantifying fatigue in (long-term) colorectal cancer survivors: a study from the population-based patient reported outcomes following initial treatment and long term evaluation of survivorship registry. AB - BACKGROUND: Few studies specifically focus on fatigue of (long-term) colorectal cancer (CRC) survivors or compare fatigue levels with a normative population. Association between surviving multiple primary cancers and fatigue is also explored. METHODS: Survivors diagnosed from 1998 to 2009 were identified from the Eindhoven Cancer Registry. In total, 3739 (79%) respondents and an age- and gender-matched normative population (n=338) completed questionnaires on fatigue and psychological distress. RESULTS: More survivors reported feeling fatigued than the normative population (39% versus 22%, p<0.0001). Short-term survivors (<5 years post-diagnosis) had the highest mean fatigue scores compared with long term survivors (>=5 years post-diagnosis) or the normative population (21+/-7 versus 20+/-7 versus 18+/-5, p<0.0001, respectively). Having primary cancers prior to CRC was associated with more fatigue. Surgery+chemoradiation was independently associated with fatigue (odds ratio (OR): 1.63, 95% confidence interval (CI): 1.17-2.29, p=0.004) as were anxiety (OR: 1.16, 95% CI: 1.12-1.19, p<0.0001) and depressive symptoms (OR: 1.38, 95% CI: 1.33-1.43, p<0.0001). CONCLUSIONS: Fatigue is a significant problem, especially for short-term CRC survivors. The association between chemoradiation and fatigue suggests that patients could benefit from better information on treatment side-effects. When treating fatigue, clinical care should also focus on survivors' psychological needs, especially survivors of multiple primary cancers. PMID- 23453752 TI - Loss of tyrosine hydroxylase expression within the nigro-striato-cortical pathways in the cirrhotic rat: the possible restorative effect of the neurosteroid dehydroepiandrosterone sulfate. AB - Hepatic encephalopathy (HE) is a neuropsychiatric disorder occurring as a consequence of both acute and chronic liver failure. Advanced HE is generally accompanied with extrapyramidal symptoms including rigidity and tremor, which may reflect alterations of the dopaminergic system. Recently we reported a beneficial effect of the neuroactive steroid dehydroepiandrosterone sulfate (DHEAS) in cirrhotic rats, however the mechanisms of such an effect by DHEAS were not addressed. In the present study, we describe the changes of the dopaminergic system occurring in the cirrhotic rats and concomitantly we investigated the effect of DHEAS on this system in Sprague-Dawley rats using the expression of tyrosine hydroxylase (TH) as a neuronal marker. Rats were submitted to bile duct ligation (BDL) surgery and TH immunohistochemistry was assessed in the Substantia nigra pars compacta (SNc), striatum, ventral tegmental area (VTA) and the cortex. TH immunoreactivity showed a significant diminution in both SNc and VTA concomitantly with the cortical and the striatal outputs in the BDL rats vs. controls. Three daily injections of 5mg/kg of DHEAS to BDL rats significantly normalized TH expression decrease in both SNc and VTA as well as dopaminergic projections to the striatum and the cortex of BDL rats. The present data support an involvement of the dopaminergic system in mild HE and a possible beneficial effect of the neurosteroid DHEAS as a potential pharmacological treatment of mild HE. PMID- 23453753 TI - Socio-demographic and psychosocial correlates of erectile dysfunction among hypertensive patients. AB - OBJECTIVE: The main aim of the study was to estimate the prevalence of ED and the associated socio-demographic and psychological correlates among hypertensive patients from a rural multiethnic community in Malaysia. METHODS: A cross sectional study was conducted among hypertensive patients attending rural primary care clinics. The socio-demographic, health characteristics, erectile function and levels of depression, anxiety and stress were recorded and analysed. The International Index of ErectileFunction-5 (IIEF-5) questionnaire and the Depression, Anxiety and Stress Scale (DASS-21) were used to assess erectile function and the levels of depression, anxiety and stress, respectively. RESULTS: A total of 253 hypertensive patients comprising 178 (70.4%) Malays, 56 (22.1%) Chinese and 18 (7.5%) Indians participated. The mean age of participants was 59.8 +/- 10.62 years. Overall, the prevalence rate of ED was 62%: 90 (35%) with moderate and 69 (27%) with severe ED. The prevalence rate of ED among those aged 65 years or older (83.1%) was significantly higher than those less than 65 years (51.8%), (p<0.001). Higher prevalence rates were also noted among the Chinese (78.6%) compared to Malays (59.6%) and Indians (50%) (p=0.021); lower education level (69.1%) (p=0.026), among hypertensive patients with concomitant diabetes mellitus (70.6%) (p=0.026) and WHR >= 0.9 (31.3%) (p=0.021). However, no significant association was found between depression, anxiety and stress scores with IIEF-5 score. CONCLUSION: The prevalence rate of ED among Malaysian hypertensive patients is high. The rate increases significantly with age, Chinese ethnicity, concomitant diabetes mellitus, lower education level, WHR and the number of pack years of smoking. ED should be properly recognized and managed in hypertensive patients. PMID- 23453754 TI - Re: "Impact of age over 75 years on outcomes after pancreaticoduodenectomy". PMID- 23453755 TI - [Brachytherapy of breast cancer]. AB - For breast cancer, interstitial brachytherapy remains an accurate irradiation technique for delivering a high dose (increasing the local control) in a small volume (decreasing the toxicity). In this article, we present the technical data related to the breast brachytherapy proceeding, from the implantation of the vectors to the treatment itself, including the planning. The different indications of breast brachytherapy include all the breast irradiations focusing on the initial tumour bed (partial irradiation of the breast), such as boost, accelerated and partial breast irradiation (APBI) and second conservative radiosurgical treatment in case of ipsilateral in-breast recurrence. The results in terms of efficacy and toxicity are presented for each indication. Interstitial breast brachytherapy, performed according with the standard rules, remains a major technique for breast cancer treatment. PMID- 23453756 TI - [Brachytherapy dose calculation]. AB - Brachytherapy dose distribution calculation has evolved from the simple use of charts to the TG-43 formalism. It depends on the physical and geometrical characteristics of each source, the position of the source relatively to the calculation point and on the medium composition. Its principles and limitations are presented as well as the different dosimetric systems associated with implementing rules and the definition of the prescribed dose. The new generation of algorithms and their contributions are discussed. PMID- 23453758 TI - Massively parallel MRI detector arrays. AB - Originally proposed as a method to increase sensitivity by extending the locally high-sensitivity of small surface coil elements to larger areas via reception, the term parallel imaging now includes the use of array coils to perform image encoding. This methodology has impacted clinical imaging to the point where many examinations are performed with an array comprising multiple smaller surface coil elements as the detector of the MR signal. This article reviews the theoretical and experimental basis for the trend towards higher channel counts relying on insights gained from modeling and experimental studies as well as the theoretical analysis of the so-called "ultimate" SNR and g-factor. We also review the methods for optimally combining array data and changes in RF methodology needed to construct massively parallel MRI detector arrays and show some examples of state of-the-art for highly accelerated imaging with the resulting highly parallel arrays. PMID- 23453757 TI - Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins. AB - The modular SCF (Skp1, cullin, and F box) ubiquitin ligases feature a large family of F box protein substrate receptors that enable recognition of diverse targets. However, how the repertoire of SCF complexes is sustained remains unclear. Real-time measurements of formation and disassembly indicate that SCF(Fbxw7) is extraordinarily stable, but, in the Nedd8-deconjugated state, the cullin-binding protein Cand1 augments its dissociation by one-million-fold. Binding and ubiquitylation assays show that Cand1 is a protein exchange factor that accelerates the rate at which Cul1-Rbx1 equilibrates with multiple F box protein-Skp1 modules. Depletion of Cand1 from cells impedes recruitment of new F box proteins to pre-existing Cul1 and profoundly alters the cellular landscape of SCF complexes. We suggest that catalyzed protein exchange may be a general feature of dynamic macromolecular machines and propose a hypothesis for how substrates, Nedd8, and Cand1 collaborate to regulate the cellular repertoire of SCF complexes. PMID- 23453760 TI - A knowledge-based clinical toxicology consultant for diagnosing multiple exposures. AB - OBJECTIVE: This paper presents continued research toward the development of a knowledge-based system for the diagnosis of human toxic exposures. In particular, this research focuses on the challenging task of diagnosing exposures to multiple toxins. Although only 10% of toxic exposures in the United States involve multiple toxins, multiple exposures account for more than half of all toxin related fatalities. Using simple medical mathematics, we seek to produce a practical decision support system capable of supplying useful information to aid in the diagnosis of complex cases involving multiple unknown substances. METHODS: The system is automatically trained using data mining techniques to extract prior probabilities and likelihood ratios from a database managed by the Florida Poison Information Center (FPIC). When supplied with observed clinical effects, the system produces a ranked list of the most plausible toxic exposures. During testing, the system diagnosed toxins at three levels: identifying the substance, identifying the toxin's major and minor categories, and identifying the toxin's major category alone. To enable comparison between these three levels, accuracy was calculated as the percentage of exposures correctly identified in top 10% of trained diagnoses. RESULTS: System evaluation utilized a dataset of 8901 multiple exposure cases and 37,617 single exposure cases. Initial system testing using only multiple exposure cases yielded poor results, with diagnosis accuracies ranging from 18.5% to 50.1%. Further investigation revealed that the system's inability to diagnose multiple disorders resulted from insufficient data and that the clinical effects observed in multiple exposures are dominated by a single substance. Including single exposures when training, the system achieved accuracies as high as 83.5% when diagnosing the primary contributors in multiple exposure cases by substance, 86.9% when diagnosing by major and minor categories, and 79.9% when diagnosing by major category alone. CONCLUSIONS: Although the system failed to completely diagnose exposures to multiple toxins, the ability to identify the primary contributor in such cases may prove valuable in aiding medical personnel as they seek to diagnose and treat patients. As time passes and more cases are added to the FPIC database, we believe system accuracy will continue to improve, producing a viable decision support system for clinical toxicology. PMID- 23453761 TI - Changes in health-related quality of life in off-pump versus on-pump cardiac surgery: Veterans Affairs Randomized On/Off Bypass trial. AB - BACKGROUND: The relative benefits of performing coronary artery bypass graft surgery off-pump versus on-pump continue to be debated. A critical, patient centered outcome is health-related quality of life; yet there has been limited evaluation in large-scale, multicenter trials of the off-pump versus on-pump impact upon quality of life. METHODS: The Veterans Affairs Randomized On/Off Bypass trial randomized 2,203 nonemergent patients to off-pump or on-pump from February 2002 to May 2007. Patients completed a general quality of life survey (VR-36) and a disease-specific quality of life survey, the Seattle Angina Questionnaire (SAQ), prior to surgery, then again at 3 and 12 months post-bypass. RESULTS: Of the 2,130 1-year survivors, 1,805 patients (85%) completed 1-year surveys. Randomization resulted in comparable baseline patient characteristics, including VR-36 and SAQ scores. At 3 months and 1-year post-procedure, there were no clinically relevant differences between off-pump and on-pump patients in any of the quality of life measures. Both groups had statistically significant, comparable improvements in the physical component scale of the VR-36, and in the SAQ scales. CONCLUSIONS: For this trial's male, low-to-moderate risk, veteran population, there were no significant differences between off-pump and on-pump with regard to 1-year general and disease-specific quality of life outcomes. Both treatment arms experienced some improvements by 3 months, with continued improvements through 1-year post-bypass. PMID- 23453759 TI - Strategies for rapid in vivo 1H and hyperpolarized 13C MR spectroscopic imaging. AB - In vivo MRSI is an important imaging modality that has been shown in numerous research studies to give biologically relevant information for assessing the underlying mechanisms of disease and for monitoring response to therapy. The increasing availability of high field scanners and multichannel radiofrequency coils has provided the opportunity to acquire in vivo data with significant improvements in sensitivity and signal to noise ratio. These capabilities may be used to shorten acquisition time and provide increased coverage. The ability to acquire rapid, volumetric MRSI data is critical for examining heterogeneity in metabolic profiles and for relating serial changes in metabolism within the same individual during the course of the disease. In this review we discuss the implementation of strategies that use alternative k-space sampling trajectories and parallel imaging methods in order to speed up data acquisition. The impact of such methods is demonstrated using three recent examples of how these methods have been applied. These are to the acquisition of robust 3D (1)H MRSI data within 5-10 min at a field strength of 3 T, to obtaining higher sensitivity for (1)H MRSI at 7 T and to using ultrafast volumetric and dynamic (13)C MRSI for monitoring the changes in signals that occur following the injection of hyperpolarized (13)C agents. PMID- 23453762 TI - The role of intraoperative magnetic resonance imaging in complex meningioma surgery. AB - Intraoperative magnetic resonance imaging (iMRI) has gained importance in the treatment of gliomas and sellar tumors. In intracranial meningiomas, the extent of surgical tumor removal is one of the most important factors in the prevention of tumor recurrence and patient survival. Complex meningiomas located at the skull base or near eloquent brain regions show higher recurrence rates, morbidity and mortality. The aim of this study was to evaluate whether iMRI contributes to more extensive surgical resection in these tumors. Patients undergoing complex meningioma resection using iMRI from January 2007 to January 2011 were included in this study. The indication for iMRI-guided tumor resection included patients presenting with meningiomas located in the skull base or compressing eloquent brain areas in whom a radical resection was considered to be difficult. Intraoperative 0.15-T MRI scan (PoleStar; Medtronic Navigation, Louisville, CO, USA) was performed before and after maximal possible resection using standard microsurgical and neuronavigation techniques. All patients underwent fluorescence guided resection. The following data were analyzed: tumor localization, histological grade, Simpson resection grade, duration of the procedure, iMRI scan time, iMRI findings, resection extent based on postresection iMRI, hospitalization time, surgical complications and outcome, and MRI follow-up 2 27months postoperation. Twenty-seven consecutive patients undergoing complex meningioma resection using iMRI were included. In this series, only one patient (3.4%) underwent resection of tumor remnant after iMRI, although without improvement of the Simpson resection grade. Temporary neurologic deficits were found in 8 patients (27.6%) postoperatively, whereas 11 patients (37.9%) had permanent postoperative neurologic deficits. In one case (3.4%), fatal postoperative bleeding occurred which was not detected by iMRI. Our results show that iMRI has no influence on intraoperative strategy in terms of resection grade or detection of early postoperative complications. The benefits of iMRI in complex meningioma surgery are therefore doubtful; however, it may still prove to be effective in certain subsets of complex meningiomas. PMID- 23453763 TI - Influence of thickening of the inner skull table on intracranial volume measurement in older people. AB - INTRODUCTION: It is generally assumed that intracranial volume (ICV) remains constant after peaking in early adulthood. Thus ICV is used as a 'proxy' for original brain size when trying to estimate brain atrophy in older people in neuroimaging studies. However, physiological changes in the skull, such as thickening of the frontal inner table, are relatively common in older age and will reduce ICV. The potential influence that inner table skull thickening may have on ICV measurement in old age has yet to be investigated. METHODS: We selected 60 (31 males, 29 females) representative older adults aged 71.1 74.3years from a community-dwelling ageing cohort, the Lothian Birth Cohort 1936. A semi-automatically derived current ICV measurement obtained from high resolution T1-weighted volume scans was compared to the estimated original ICV by excluding inner skull table thickening using expert manual image processing. RESULTS: Inner table skull thickening reduced ICV from an estimated original 1480.0ml to a current 1409.1ml, a median decrease of 7.3% (Z=-6.334; p<0.001), and this reduction was more prominent in women than men (median decrease 114.6 vs. 101.9ml respectively). This led to potential significant underestimations of brain atrophy in this sample by 5.3% (p<0.001) and obscured potential gender differences. CONCLUSIONS: The effects of skull thickening are important to consider when conducting research in ageing, as they can obscure gender differences and result in underestimation of brain atrophy. Research into reliable methods of determining the estimated original ICV is required for research into brain ageing. PMID- 23453764 TI - Robotic-assisted laparoscopic vs abdominal and laparoscopic myomectomy: systematic review and meta-analysis. AB - Herein is presented a systematic review and meta-analysis of evidence related to operative outcomes associated with robotic-assisted laparoscopic myomectomy (RLM) compared with abdominal myomectomy (AM) and laparoscopic myomectomy (LM). Outcome measures included estimated blood loss (EBL), blood transfusion, operating time, complications, length of hospital stay (LOHS), and costs. Meta-analysis 1 compared RLM vs AM, and meta-analysis 2 compared RLM vs LM. Studies scored moderately well on the Newcastle-Ottawa Quality Assessment Scale. No significant differences were found in age, body mass index, or number, diameter, and weight of myomas. In meta-analysis 1, EBL, blood transfusion, and LOHS were significantly lower; risk of complications was similar; and operating time and costs were significantly higher with RLM. In meta-analysis 2, no significant differences were noted in EBL, operating time, complications, and LOHS with RLM; however, blood transfusion risk and costs were higher. It was concluded that insofar as operative outcomes, RLM has significant short-term benefits compared with AM and no benefits compared with LM. Long-term benefits such as recurrence, fertility, and obstetric outcomes remain uncertain. PMID- 23453765 TI - Case-control study of complications associated with bipolar and monopolar hysteroscopic operations. AB - STUDY OBJECTIVE: To examine whether all hysteroscopic operations can be performed using bipolar technology and to compare the complication rates of hysteroscopic surgery performed using monopolar and bipolar technology. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: Endoscopic gynecology unit at a tertiary-care university hospital. PATIENTS: Women aged 17 to 88 years (median, 43.9 years) who underwent operative hysteroscopy to treat uterine disease. INTERVENTIONS: Operative hysteroscopy using bipolar technology and normal saline solution as irrigation medium. The control group was composed of women who underwent the procedure using monopolar technology, with glycine as irrigation medium, before adoption of bipolar technology. MEASUREMENTS AND MAIN RESULTS: Data regarding short-term complications were prospectively obtained during surgery and at 2-week follow-up. More than 1800 procedures were investigated (1318 in the study group and 524 in the control group). The complication rate was 4.1% in the study group and 2.8% in the control group (p = .08). CONCLUSION: Both monopolar and bipolar hysteroscopic techniques are safe and feasible. The bipolar hysteroscopic system has eliminated the need to use hypotonic solutions as irrigation medium, with its life-threatening complications. When limiting normal saline solution to 2 L, no serious complications associated with irrigation medium are expected. Therefore, we believe that when available, the bipolar system should be preferred. PMID- 23453766 TI - Vitamin D is not associated with serologic response to influenza vaccine in adults over 50 years old. AB - Vitamin D deficiency has been implicated in risk of respiratory illness. We determined whether serum vitamin D levels are related to influenza vaccine response measured by hemagglutination antibody inhibition (HAI) titer in adults aged >=50 years old. The study was a prospective cohort study conducted over two influenza seasons (fall 2008-spring 2009 and fall 2009-spring 2010) in Marshfield, WI and Nashville, TN including 1103 community-dwelling adult volunteers >=50 years of age. Pre-vaccination levels of serum vitamin D and HAI titer levels pre- and 21-28 days post-influenza vaccination were measured. Seroprotection was defined as HAI >=40; seroconversion was defined as >=4-fold rise in HAI titers from pre- to post-vaccination. More than 25% of participants were vitamin D deficient (<25ng/mL). Vitamin D measured as a continuous variable was not related to pre- or post-vaccination seroprotection or seroconversion for any vaccine strain in any year. Vitamin D deficiency was associated with a greater frequency of post-vaccination seroprotection for seasonal H1N1 in the first year of the study, but was not related to seroprotection or seroconversion for any other strain in either year. No consistent association was found between vitamin D levels or vitamin D deficiency and serologic response to influenza vaccination in older adults. Cell-mediated immune parameters should also be explored in order to further investigate possible relationships between micronutrient status and influenza vaccine response. PMID- 23453767 TI - The effects of natural and modified clinoptilolite on intestinal barrier function and immune response to LPS in broiler chickens. AB - The protection of intestinal barrier function and the anti-inflammatory effects of natural clinoptilolite (NCLI) and modified clinoptilolite (MCLI) were investigated in broilers that were repeatedly challenged with lipopolysaccharide (LPS). A total of 288 1-d-old broiler chicks were divided equally into three treatment groups: control, NCLI-treated (2%) and MCLI-treated (2%). Half of the birds from each treatment group were challenged with 0.9% NaCl solution or LPS (250MUg/kg body weight, administered orally) at 16, 18 and 21d of age. The results indicated that, prior to LPS challenge, the diet had no effect on bird growth performance (P>0.05). The oral administration of LPS was also not associated with any significant changes in poultry performance (P>0.05). In LPS challenged birds that were pretreated with NCLI (2%) or MCLI (2%), the LPS induced increases in the plasma and intestinal mucosa concentrations of TNF alpha, IL-1beta, IL-2, IL-6, IL-4 and IL-10 were dramatically attenuated. Additionally, significant decreases in the plasma d-lactic acid and diamine oxidase (DAO) levels were found in birds that were pretreated with NCLI or MCLI. Furthermore, both NCLI and MCLI reduced the sICAM-1 concentration in the intestinal mucosa. In conclusion, NCLI and MCLI are able to prevent the LPS induced intestinal mucosa damage and inflammatory response in vivo. These beneficial effects suggest that NCLI and MCLI act as anti-inflammatory agents in part by inhibiting neutrophil infiltration and hyperactivation and by suppressing the secretion of various plasma and intestinal mucosa inflammatory mediators. PMID- 23453768 TI - Infection with feline immunodeficiency virus alters intestinal epithelial transport and mucosal immune responses to probiotics. AB - HIV infection is associated with intestinal mucosal dysfunction and probiotics offer the therapeutic potential to enhance the mucosal barrier in HIV+ patients. To evaluate the response of immunocompromised hosts to probiotics, we orally administered Lactobacillus acidophilus to cats with chronic feline immunodeficiency virus (FIV) infection. FIV infection significantly affected transcellular, but not paracellular, transport of small molecules across the intestinal epithelium. Additionally, probiotic treatment of FIV+ cats resulted in changes in cytokine release and mucosal leukocyte percentages that were not paralleled in FIV- cats. These results suggest a novel role for FIV in upregulating transcellular transport across the gastrointestinal epithelial barrier and demonstrate the potential therapeutic use of probiotic bacteria to restore intestinal homeostasis. PMID- 23453769 TI - Risk of tuberculosis in high-rise and high density dwellings: an exploratory spatial analysis. AB - Studies have shown that socioeconomic and environmental factors have direct/indirect influences on TB. This research focuses on TB prevalence of Hong Kong in relation to its compact urban development comprising of high-rise and high-density residential dwellings caused by rapid population growth and limited land resources. It has been postulated that occupants living on higher levels of a building would benefit from better ventilation and direct sunlight and thus less likely to contract infectious respiratory diseases. On the contrary, those on lower floors amid the dense clusters of high-rises are more susceptible to TB infection because of poorer air quality from street-level pollution and lesser exposure to direct sunlight. However, there have not been published studies to support these claims. As TB continues to threaten public health in Hong Kong, this study seeks to understand the effects of housing development on TB occurrences in an urban setting. PMID- 23453770 TI - Reply: To PMID 22633290. PMID- 23453771 TI - A rapidly expanding orbital lesion. PMID- 23453772 TI - Genetics and pediatric unconjugated hyperbilirubinemia. PMID- 23453773 TI - The effect of design on the usability and real world effectiveness of medical devices: a case study with adolescent users. AB - Adolescents are currently overlooked in many fields of healthcare research and as a result are often required to use medical devices that have been designed for use by either children or adults. This can lead to poor adherence and a reduction in health outcomes. This study examines the role of device design in the real world effectiveness of a medical device used in the treatment of cystic fibrosis from the perspective of adolescent users. Interactive design interviews were carried out with 20 adolescent users of the acapella((r)) physiotherapy device to investigate user requirements and themes about the user-device relationship that are important to this user group. This study found that adolescent users of the acapella((r)) device do not use the device as regularly and correctly as is recommended by clinicians. A number of aspects of the current design of the acapella((r)) device were identified that affect how and how often it is used. Five factors are identified that may improve the real world effectiveness of the acapella((r)) device for adolescents with Cystic Fibrosis: engagement, information, confidence, aesthetics and compatibility with lifestyle. PMID- 23453774 TI - Making sense of complex electronic records: socio-technical design in social care. AB - Dealing with complex electronic documentation is an integral part of much contemporary professional work. In this paper, we address the design of electronic records for social care professionals in the UK. Recent reforms in UK child welfare have followed a top-down, managerial approach emphasizing conformance to standard processes. The vicissitudes of a major national IT project, the Integrated Children's System, show the limitations of this approach, in particular the detrimental effect it has had on professional autonomy. Following in the foot-steps of Ken Eason, we argue that socio-technical design, by focussing on innovative applications of technology to support users (rather than the interests of the bureaucracy) offers a more promising alternative. A user-centred design exercise is presented to illustrate this approach in action. A novel interface was developed for handling the heterogeneous bundle of documents which make up the social care record, helping social workers make better sense of case-files. The prototype draws on the metaphor of the dining room table as a way of overcoming the limitations of the computer display. We conclude that socio-technical thinking engenders a shift in mind-set, opening up a radically different design space compared to current design orthodoxy. PMID- 23453775 TI - Effectiveness and driver acceptance of a semi-autonomous forward obstacle collision avoidance system. AB - This paper proposes a semi-autonomous collision avoidance system for the prevention of collisions between vehicles and pedestrians and objects on a road. The system is designed to be compatible with the human-centered automation principle, i.e., the decision to perform a maneuver to avoid a collision is made by the driver. However, the system is partly autonomous in that it turns the steering wheel independently when the driver only applies the brake, indicating his or her intent to avoid the obstacle. With a medium-fidelity driving simulator, we conducted an experiment to investigate the effectiveness of this system for improving safety in emergency situations, as well as its acceptance by drivers. The results indicate that the system effectively improves safety in emergency situations, and the semi-autonomous characteristic of the system was found to be acceptable to drivers. PMID- 23453776 TI - Comment: the King-Devick test and sports-related concussion: study of a rapid visual screening tool in a collegiate cohort. PMID- 23453777 TI - CLIPPERS-like MRI findings in a patient with multiple sclerosis. AB - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) has been described as a clinically and radiologically distinct pontine-predominant encephalomyelitis with a favorable response to high dose corticosteroids and usually requiring chronic immunosuppresive therapy. Brain magnetic resonance imaging (MRI) reveals a characteristic pattern of punctate and curvilinear enhancement lesions in the pons extending variably to surrounding areas. We herein describe such imaging findings in a patient with a definite diagnosis of relapsing-remitting multiple sclerosis (MS). PMID- 23453778 TI - Compressive rib fracture: peri-mortem and post-mortem trauma patterns in a pig model. AB - Despite numerous studies on high impact fractures of ribs, little is known about compressive rib injuries. We studied rib fractures from a biomechanical and morphological perspective using 15, 5th ribs of domestic pigs Sus scrofa, divided into two groups, desiccated (representing post-mortem trauma) and fresh ribs with intact periosteum (representing peri-mortem trauma). Ribs were axially compressed and subjected to four-point bending in an Instron 3339 fitted with custom jigs. Morphoscopic analysis of resultant fractures consisted of standard optical methods, micro-CT (MUCT) and scanning electron microscopy (SEM). During axial compression, fresh ribs had slightly higher strength because of energy absorption capabilities of their soft and fluidic components. In flexure tests, dry ribs showed typical elastic-brittle behaviour with long linear load-extension curves, followed by relatively short non-linear elastic (hyperelastic) behaviour and brittle fracture. Fresh ribs showed initial linear-elastic behaviour, followed by strain softening, visco-plastic responses. During the course of loading, dry bone showed minimal observable damage prior to the onset of unstable fracture. In contrast, fresh bone showed buckling-like damage features on the compressive surface and cracking parallel to the axis of the bone. Morphologically, all dry ribs fractured precipitously, whereas all but one of the fresh ribs showed incomplete fracture. The mode of fracture, however, was remarkably similar for both groups, with butterfly fractures predominating (7/15, 46.6% dry and wet). Our study highlights the fact that under controlled loading, despite seemingly similar butterfly fracture morphology, fresh ribs (representing perimortem trauma) show a non-catastrophic response. While extensive strain softening observed for the fresh bone does show some additional micro-cracking damage, it appears that the periosteum may play a key role in imparting the observed pseudo ductility to the ribs. The presence of fibrous pull-out and grooving of the outer tensile surface associated with periosteal stretching suggests that the periosteum under tension is able to sustain very high strain and bridge the mouth of the extending butterfly crack, thereby contributing to the observed strain softening behaviour. PMID- 23453779 TI - Florigen in rice: complex gene network for florigen transcription, florigen activation complex, and multiple functions. AB - Regulation of flowering time directly influences successful rice grain production; thus, the long history of domestication and breeding has improved the genetic network of flowering. Recent advances using molecular genomic approaches have revealed the targets of these modifications and the underlying molecular mechanism for flowering. These efforts contributed to identifying the molecular nature of the systemic floral signal 'florigen' and have shown how florigen functions, how florigen expression is controlled, and how regulatory pathways are diversified. In this review, we summarize the advances in our understanding of the detailed molecular and genetic mechanisms that allow rice plants to produce flowers at the proper time to ensure grain production. PMID- 23453780 TI - Genetic mechanisms conferring adaptation to submergence and drought in rice: simple or complex? AB - Both high and low extremes in precipitation increasingly impact agricultural productivity and sustainability as a consequence of global climate change. Elucidation of the genetic basis underlying stress tolerance facilitates development of new rice varieties with enhanced tolerance. Submergence tolerance is conferred by a single master regulator that orchestrates various acclimation responses, whereas drought tolerance is regulated by a number of small-effect loci that are largely influenced by genetic background and environment. Detailed molecular studies have uncovered the functional importance of genes and signaling components which coordinate various morphological and physiological responses to submergence and drought, providing new insight into understanding the complex regulatory mechanisms of stress tolerance in rice. PMID- 23453781 TI - Succinate dehydrogenase: the complex roles of a simple enzyme. AB - Succinate dehydrogenase (SDH) oxidises succinate to fumarate as a component of the tricarboxylic acid cycle and ubiquinone to ubiquinol in the mitochondrial electron transport chain. Studies of SDH mutants have revealed far-reaching effects of altering succinate oxidation in plant cells. The plant SDH complex composition, structure and assembly are all beginning to be understood but the implications of the divergence across eukaryotes is still unclear. We propose an integration of the reported physiological roles of SDH in plants which influence photosynthesis, the function of stomata, root elongation and fungal defence. Future SDH research needed in plants should involve tissue-specific studies of mutants, analysis of the pathways induced by succinate-dependent reactive oxygen species generation and assessment of the impact of succinate accumulation on metabolism. PMID- 23453782 TI - Protective effects of Acanthopanax divaricatus vat. albeofructus and its active compound on ischemia-reperfusion injury of rat liver. AB - In the present study, the potential antioxidant and anti-inflammatory effects of Acanthopanax divaricatus vat. albeofructus (AE) and acanthoside-D (AD) isolated from AE against hepatic ischemia-reperfusion (I/R) injury were investigated in a rat model. Male Sprague-Dawley rats (200-220 g) were randomized into seven groups: normal controls; sham-operated controls; I/R injury model; I/R injury model with AE pretreatment at 150, 300, and 600 mg/kg body weight; and I/R injury model with AD pretreatment at 600 MUg/kg body weight (equivalent to high dose of AE). The AE and AD pretreatments were administered orally for 2 weeks prior to I/R injury surgery. All rats recovered for 1 week with AE and AD treatment after surgery. Compared to the normal control groups, the I/R injury model group without supplemental treatment showed a significantly lower level of serum superoxide dismutase (SOD) and significantly higher levels of tumor necrosis factor-alpha (TNF-alpha, interleukin (IL)-6, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), as well as lactate dehydrogenase (LDH) activity. The I/R-induced decrease in SOD and increases in TNF-alpha and IL-6 were resolved, at least partially, by AE and AD treatments, as evidenced by significantly higher antioxidant activities and significantly lower inflammatory cytokine levels in the treatment groups as compared to the I/R injury model group. The AE and AD treatment groups also showed significantly higher levels of serum IL-10 than I/R injury model group. Histological examination revealed that the AE and AD treated groups had less extensive liver necrosis than I/R injury model group. Concomitantly, AE lowered the I/R-induced increases in AST, ALT, ALP levels and LDH activity. In conclusion, AE and AD are capable of alleviating I/R-induced hepatic injury by inhibiting inflammatory cell infiltration, thereby mitigating the release of inflammatory cytokines and balancing the oxidant-antioxidant status mediated by p38 MAPK and JNK/SAPK signaling. PMID- 23453783 TI - The management of ductal carcinoma in situ: current controversies and future directions. AB - The incidence of ductal carcinoma in situ (DCIS) has increased in recent decades, primarily due to the widespread implementation of breast cancer screening. Traditionally, the management of DCIS has mirrored that of invasive breast cancer, with a focus on adequate surgical excision, breast-conserving surgery, adjuvant radiotherapy and endocrine therapy. However, an increasing understanding of the biology of this spectrum of conditions many mean that some cases may be managed more conservatively, reserving aggressive therapies for those patients at high risk of progression to invasive disease, ultimately aiming for a personalised approach based on individual risk factors. This overview highlights the key evidence behind current practice and discusses the rationale for current and future clinical trials in DCIS. PMID- 23453784 TI - Effect of a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) in women with menstrually-related migraine (MRM). AB - BACKGROUND: Combined hormonal contraception might worsen migraine in sensitive women, especially during the free-hormone interval, and raise concerns about the vascular risk. The characteristics of a contraceptive pill containing estradiol valerate/dienogest (E2V/DNG) might be of potential benefit in women with menstrually related migraine (MRM) who choose to use oral contraception for birth control. STUDY DESIGN: This was a prospective diary-based pilot study. Thirty-two women (age >35 years) [n=18 who had never used combined oral contraceptives (COCs) and n=14 who had previously used COCs] diagnosed with MRMs according to the International Headache Society criteria were included. During the observational period, women filled in a diary with the clinical characteristics of migraine attacks. After a three-cycle run-in period, each subject received a COC containing E2V/DNG (Qlaira(r)/Natazia(r); Bayer HealthCare, Berlin, Germany) administered using an estrogen step-down and progestogen step-up approach. Follow up evaluations were scheduled at the last cycle of run-in and at the third and sixth cycles of treatment. RESULTS: The number of migraine attacks was significantly reduced at the third (p<.001) and sixth cycles (p<.001) in comparison with the run-in period. A similar result was evident for the duration (p<.001 at the third and p<.001 at the sixth cycle) as well as for the severity of head pain (p<.001 at the third and p<.001 at the sixth month). Indeed, a significantly lower number of analgesics were used at the third cycle (p<.001) in comparison with baseline, and a further decrease was evident at the sixth cycle (p<.001) in comparison with the third cycle of E2V/DNG use. Interestingly, duration and severity of head pain were significantly correlated with the number of days of dysmenorrhea at the third cycle (r=.89, p=.000 and r=.67, p=.02; respectively) and at the sixth cycle (r=.76, p=.000 and r=.62, p=.04; respectively) in women without complete remission of menstrual cramps during the study period. CONCLUSIONS: The present diary-based pilot study indicates that the use of a pill containing EV2/DNG for six cycles has a positive effect in women with MRM and suggests an association between dysmenorrhea with COCs use as a potential feature of refractory head pain. PMID- 23453785 TI - Laparoscopic adjustable gastric banding versus Roux-en-Y gastric bypass: 10-year results of a prospective, randomized trial. AB - BACKGROUND: There are few studies of long-term outcomes for either laparoscopic adjustable gastric banding (LAGB) or laparoscopic Roux-en-Y gastric bypass (LRYGB). The objective of this study was to compare outcomes of patients randomly assigned to undergo LAGB or LRYGB at 10 years. METHODS: LAGB, using the pars flaccida technique, and standard LRYGB were performed. From January 2000 to November 2000, 51 patients (mean age 34.0 +/- 8.9 years; range 20-49) were randomly allocated to undergo either LAGB (n = 27, 5 men and 22 women; mean age 33.3 years; mean weight 120 kg; mean body mass index [BMI] 43.4 kg/m(2)) or LRYGB (n = 24, 4 men and 20 women; mean age 34.7; mean weight 120 kg; mean BMI 43.8 kg/m(2)). Data on complications, reoperations, weight, BMI, percentage of excess weight loss, and co-morbidities were collected yearly. The data were analyzed using Student's t test and Fisher's exact test, with P<.05 considered significant. RESULTS: Five patients in the LAGB group and 3 patients in the LRYGB group were lost to follow-up. No patient died. Conversion to laparotomy was performed in 1 (4.2%) of 24 LRYGB patients. Reoperations were required in 9 (40.9%) of 22 LAGB patients and in 6 (28.6%) of the 21 LRYGB patients. At 10-year follow-up, the LRYGB patients had a greater percentage of mean excess weight loss than did the LAGB patients (69+/-29% versus 46+/-27%; P = .03). CONCLUSION: LRYGB was superior to LAGB in term of excess weight loss results (76.2% versus 46.2%) at 10 years. However, LRYGB exposes patients to higher early complication rates than LAGB (8.3% versus 0%) and potentially lethal long-term surgical complications (internal hernia and bowel obstruction rate: 4.7%). PMID- 23453786 TI - Effect of ketoprofen treatment on the uterine inflammatory response after AI of jennies with frozen semen. AB - Artificial insemination (AI) involving the placing of frozen-thawed semen directly into the jenny uterine body is associated with very low pregnancy rates. This might be because of an exacerbation of the acute response of the endometrium to sperm, as seen in mares with persistent induced mating endometritis. Pregnancy rates can be increased in such mares, however, by including anti-inflammatory treatments in the insemination protocol (Bucca S, Carli A, Buckley T, Dolci G, Fogarty U. The use of dexamethasone administered to mares at breeding time in the modulation of persistent mating induced endometritis. Theriogenology 2008;70:1093 100; Rojer H, Aurich C. Treatment of persistent mating-induced endometritis in mares with the non-steroid anti-inflammatory drug vedaprofen. Reprod Domest Anim 2010;45:e458-60). To investigate the endometritis caused by the use of frozen thawed semen in jennies, and to assess the response to ketoprofen treatment, endometrial cytological samples and biopsies from six healthy jennies were examined in a crossover design experiment. Samples were taken from jennies in estrus (E; control) and at 6 hours after AI with or without ketoprofen (+K and K, respectively). Ketoprofen was administered iv 24 hours before and for 4 days after insemination (total = 2.2 mg/kg/24 hours for 5 days). All animals showed a severe inflammatory response to semen deposition. Polymorphonuclear neutrophil numbers in the cytological smears and biopsies differed significantly between the +K and E animals. No significant differences were recorded, however, between the +K and -K treatments. Eosinophils were observed in all sample types from all groups; these cells appear to be a feature of the normal jenny endometrium. Slight fibrosis was observed in some biopsies, but no significant relationship with inflammation was found. Intense cyclooxygenase-2 (COX-2) immunohistochemical labeling was detected in the -K biopsies. Less intense labeling was seen in those of the +K animals, and mainly localized in the stratum compactum. No differences in COX-2 labeling were observed between the +K and E animals. Plasma concentrations of ketoprofen remained detectable until 2 hours after administration, after which the compound was rapidly eliminated. In summary, jennies are susceptible to endometritis after insemination with frozen-thawed semen. Ketoprofen reduces this inflammation by inhibiting COX-2; no reduction in the number of polymorphonuclear neutrophils occurs. The physiological and pharmacological characteristics of jennies should be taken into account when designing treatments for acute endometritis aimed at enhancing pregnancy rates after insemination with frozen-thawed sperm. PMID- 23453787 TI - Dimethyl formamide improves the postthaw characteristics of sex-sorted and nonsorted stallion sperm. AB - Cryopreserved, sex-sorted stallion sperm has been shown to have poor fertility. During this study, the effects of cryoprotectant (glycerol [GLY] and dimethyl formamide [DMF]), cryoprotectant equilibration time (0, 30, 60, 90, or 120 minutes), and cryoprotectant concentration (2%, 3%, or 4% vol/vol) on stored sex sorted and stored nonsorted stallion sperm were evaluated. Total motility, viability, and DNA integrity (determined using sperm chromatin structure assay) of sperm were assessed after thawing. Equilibration for 90 minutes improved total motility (33.8%) compared with 0 (28.5%) or 120 minutes (29.8%; P < 0.05), though viability was higher after 120 minutes (33.1%) compared with 0 (30.5%) or 30 minutes (31.0%; P < 0.01). The viability of nonsorted sperm decreased as cryoprotectant concentration increased (P < 0.001), and total motility of nonsorted sperm was higher when DMF alone was used (15.8%, 16.6%, and 24.0% for GLY, GLY and DMF, and DMF respectively; P < 0.001). Sex sorting was detrimental to the postthaw quality of sperm; at 45 minutes after thawing, total motility of nonsorted sperm was higher than that of sex-sorted sperm (37.4% vs. 5.6%; P < 0.001), the viability of sex-sorted sperm was lower than that of nonsorted sperm (12.4% vs. 30.0%; P < 0.001, averaged over postthaw time), and sex-sorted sperm had higher detectable DNA fragmentation index (DFI) (63.6% vs. 11.3%, P < 0.001) and mean DFI (285.1 vs. 211.3, P < 0.001) than nonsorted sperm. The viability of sex-sorted sperm was improved by GLY and DMF or DMF compared with GLY (22.6%, 25.3%, and 19.3%, respectively; P < 0.05), and the DNA integrity of sex-sorted sperm was improved by the use of DMF compared with GLY (detectable DFI, 60.2 vs. 66.8, P < 0.05; and mean DFI, 280.9 vs. 289.2, P < 0.05, respectively). In conclusion, postthaw characteristics of stored sex-sorted and stored nonsorted stallion sperm were improved by the use of DMF as a cryoprotectant, though the parameters to benefit differed between sorted and nonsorted sperm. PMID- 23453788 TI - Emergence of blaNDM-1 among Klebsiella pneumoniae ST15 and novel ST1031 clinical isolates in China. AB - The emergence of NDM-1 has become established as a major public health threat and represents a new and major challenge in the treatment of infectious diseases. A total of 39 carbapenem-resistant Enterobacteriaceae isolates collected from patients receiving care at 5 teaching hospitals in Jiangxi province, central China, were analyzed for carriage of resistance genes, including bla(NDM-1). Two carbapenem-resistant Klebsiella pneumoniae isolates (NC12 and NC18) were found to harbor bla(NDM-1). In addition to bla(NDM-1), NC12 also carried bla(SHV-1), while NC18 harbored additional resistance genes, including bla(SHV-12), bla(CTX-M-14), armA and bla(TEM-1). NC12 and NC18 belonged to ST15 and novel ST1031 and were clonally unrelated. Carbapenem resistance for NC12 could be transferred to Escherichia coli recipients through conjugation and chemical transformation, while carbapenem resistance for NC18 was only transferred to E. coli recipients by chemical transformation. The EcoR1-digested DNA pattern of plasmids from the transformants of NC12 was identical to that for NC18. Taken together, this is the first report of bla(NDM-1) carriage by K. pneumoniae clinical isolates in mainland China, indicating that bla(NDM-1) is disseminated among Enterobacteriaceae in China. Systemic surveillance should focus on the dissemination of bla(NDM-1) among Gram-negative clinical isolates, especially some major clones, such as K. pneumoniae ST15 which is a major clone among CTX-M 15-producing isolates. PMID- 23453789 TI - Resolute zotarolimus-eluting stent to treat bifurcated lesions according to the provisional technique: a procedural performance comparison with sirolimus- and everolimus-eluting stents. AB - OBJECTIVES: Different drug-eluting stents (DES) may have different performance in bifurcation PCI. Thus, we compared the performance of a novel zotarolimus-eluting stent (ZRS) with that obtained using two other DES in bifurcation PCI. METHODS AND RESULTS: Consecutive patients with bifurcated lesions undergoing DES implantation were treated by a provisional approach with sirolimus-eluting stent (SES) or everolimus-eluting stent (EES) during a former period, and then by ZRS in a second period. The PCI procedural details were prospectively recorded and angiographic results were evaluated by a 3-dimensional quantitative coronary analysis software. Primary procedural end-point was "side-branch (SB) trouble" (occurrence, after MV stenting, of: SB TIMI flow<3 or need of specific wires for SB rewiring, or failure to re-wire/dilate the SB). Primary angiographic end-point was post-PCI minimal-lumen-diameter at SB-ostium. During the study, 225 patients were enrolled and treated by ZRS (n=75), by SES (n=75) or by EES (n=75). Among procedural characteristics, "SB trouble" occurred in 4% of patients treated by ZRS, a figure significantly lower compared to SES (16%, P=0.014) and non significantly lower compared to EES (11%, P=0.12). At multivariable analysis, DES type, pre-PCI SB flow <3 and bifurcation complexity were the only predictors of "SB trouble". After the procedure, minimal-lumen-diameter at SB ostium was significantly larger with ZRS compared to SES (1.94 vs. 1.64 mm, P=0.008) and similar to that of EES. CONCLUSIONS: ZRS is associated to improved performance and SB angiographic results compared to SES. These results support the hypothesis that DES selection may influence the procedural course and the acute angiographic result of bifurcation PCI. PMID- 23453790 TI - fMRI reveals a lower visual field preference for hand actions in human superior parieto-occipital cortex (SPOC) and precuneus. AB - Humans are more efficient when performing actions towards objects presented in the lower visual field (VF) than in the upper VF. The present study used slow event-related functional magnetic resonance imaging (fMRI) to examine whether human brain areas implicated in action would show such VF preferences. Participants were asked to fixate one of four different positions allowing objects to be presented in the upper left, upper right, lower left or lower right VF. In some trials they reached to grasp the object with the right hand while in others they passively viewed the object. Crucially, by manipulating the fixation position, rather than the position of the objects, the biomechanics of the movements did not differ across conditions. The superior parieto-occipital cortex (SPOC) and the left precuneus, brain areas implicated in the control of reaching, were significantly more activated when participants grasped objects presented in the lower VF relative to the upper VF. Importantly, no such VF preferences were observed in these regions during passive viewing. This finding fits well with evidence from the macaque neurophysiology that neurons within visuomotor regions over-represent the lower VF relative to the upper VF and indicate that the neural responses within these regions may reflect a functional lower VF advantage during visually-guided actions. PMID- 23453791 TI - Morphometric analyses of the visual pathways in macular degeneration. AB - INTRODUCTION: Macular degeneration (MD) causes central visual field loss. When field defects occur in both eyes and overlap, parts of the visual pathways are no longer stimulated. Previous reports have shown that this affects the grey matter of the primary visual cortex, but possible effects on the preceding visual pathway structures have not been fully established. METHODS: In this multicentre study, we used high-resolution anatomical magnetic resonance imaging and voxel based morphometry to investigate the visual pathway structures up to the primary visual cortex of patients with age-related macular degeneration (AMD) and juvenile macular degeneration (JMD). RESULTS: Compared to age-matched healthy controls, in patients with JMD we found volumetric reductions in the optic nerves, the chiasm, the lateral geniculate bodies, the optic radiations and the visual cortex. In patients with AMD we found volumetric reductions in the lateral geniculate bodies, the optic radiations and the visual cortex. An unexpected finding was that AMD, but not JMD, was associated with a reduction in frontal white matter volume. CONCLUSION: MD is associated with degeneration of structures along the visual pathways. A reduction in frontal white matter volume only present in the AMD patients may constitute a neural correlate of previously reported association between AMD and mild cognitive impairment. PMID- 23453792 TI - ERP-pupil size correlations reveal how bilingualism enhances cognitive flexibility. AB - A bilingual upbringing has been shown to enhance executive control, but the neural mechanisms underpinning such effect are essentially unknown. Here, we investigated whether monolingual and bilingual toddlers differ in semantic processing efficiency and their allocation of attention to expected and unexpected visual stimuli. We simultaneously recorded event-related brain potentials (ERPs) and pupil size in monolingual and bilingual toddlers presented with (spoken) word-picture pairs. Although ERP effects elicited by semantic relatedness were indistinguishable between the two children groups, pictures unrelated to the preceding word evoked greater pupil dilation than related pictures in bilinguals, but not in monolinguals. Furthermore, increasing pupil dilation to unrelated pictures was associated with decreasing N400 amplitude in bilinguals, whereas the monolingual toddlers showed the opposite association. Hence, attention to unexpected stimuli seems to hamper semantic integration in monolinguals, but to facilitate semantic integration in bilinguals, suggesting that bilingual toddlers are more tolerant to variation in word-referent mappings. Given the link between pupil dilation and norepinephrine-driven cognitive efficiency, correlations between ERP amplitude and concurrent pupil dilation provide new insights into the neural bases of the bilingual cognitive advantage. PMID- 23453793 TI - Grating-based X-ray phase contrast for biomedical imaging applications. AB - In this review article we describe the development of grating-based X-ray phase contrast imaging, with particular emphasis on potential biomedical applications of the technology. We review the basics of image formation in grating-based phase contrast and dark-field radiography and present some exemplary multimodal radiography results obtained with laboratory X-ray sources. Furthermore, we discuss the theoretical concepts to extend grating-based multimodal radiography to quantitative transmission, phase-contrast, and dark-field scattering computed tomography. PMID- 23453794 TI - Primary dilatation as a treatment for pediatric laryngotracheal stenosis: a systematic review. AB - OBJECTIVE: To identify and review original studies on balloon and rigid dilatation as primary therapy for laryngotracheal stenosis (LTS) in pediatric patients. DESIGN: Systematic review. METHODS: A comprehensive search strategy in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials was conducted and limited to human studies published in English after 1980. Two independent reviewers identified original studies on primary dilatation therapy for LTS in patients younger than 18 years. Studies on tracheobronchial stenosis or stents for tracheomalacia were excluded. 22 of 369 identified studies (6%) met the inclusion criteria. Two reviewers independently appraised the level of evidence of each study, using the Oxford clinical evidence-based medicine guidelines, and extracted raw data using a standardized form developed a priori. RESULTS: The patient population consisted of grades I-III LTS. Most studies used adjuvant therapy including laser or topical agents. The primary outcome of success was achieving a functional airway without open laryngo-tracheal surgery or ongoing need for a tracheostomy. In studies using balloon dilatation alone (6 studies, n=10) or rigid dilatation alone (5 studies, n=68), success rates were 50% and 53%, respectively. Success rates ranged from 50% to 78% for balloon dilatation with adjuvant therapy (6 studies, n=24) and 53%-100% for rigid dilatation with adjuvant therapy (5 studies, n=61). CONCLUSIONS: Dilatation was successful as primary therapy in the majority of low-grade pediatric LTS. Given the lack of comparative studies among other study limitations, it could not be determined whether one method of dilatation was superior to another. PMID- 23453795 TI - Benefits of frenulotomy in infants with ankyloglossia. AB - OBJECTIVES: Ankyloglossia is a common, congenital abnormality often causing feeding difficulties in infants. This study aimed to evaluate indications and outcomes of frenulotomy performed in infants with ankyloglossia for breast feeding difficulties. METHODS: 85 patients were prospectively identified as they underwent frenulotomy in Pinderfields Hospital ENT outpatient department between February 2008 and February 2011. 52 patients were successfully followed up with a telephone questionnaire about effects on breast-feeding and any complications. RESULTS: All mothers had experienced problems breast-feeding prior to frenulotomy. Following frenulotomy 40/52 (77%) of mothers reported an improvement in breast-feeding within 2 weeks of the procedure. No complications were reported. CONCLUSION: This study supports the view that ankyloglossia is a common cause of breast-feeding difficulties. However the lack of universal improvement in breast-feeding following frenulotomy suggests that it is not the only cause of problems and supports the clinician approaching these situations holistically and exploring other causes. PMID- 23453796 TI - Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis. AB - BACKGROUND: Chronic hypersensitivity pneumonitis is characterized by pulmonary inflammation and fibrosis in response to repeated inhalation of mainly organic antigens. It is recognized that IL-17A is crucial for the development of pulmonary inflammation in murine models of experimental hypersensitivity pneumonitis, but its role in the development of pulmonary fibrosis has not been determined. Furthermore, the main cell type(s) that produce IL-17A in experimental hypersensitivity pneumonitis have not yet been identified. OBJECTIVE: Our objectives were to test the hypothesis that IL-17A plays a central role in the development of pulmonary fibrosis in experimental hypersensitivity pneumonitis and to determine the main inflammatory cell type(s) responsible for IL-17A production. METHODS: We used a mouse model of experimental hypersensitivity pneumonitis in which IL-17A was inhibited or neutrophils were depleted. We also used IL-17RA-deficient and RAG-2-deficient mice. Lung IL-17A producing cells were identified by fluorescence-activated cell sorting of myeloid versus lymphoid cell populations, intracellular IL-17A staining, flow cytometry, and quantitative reverse transcription PCR for IL-17A mRNA. RESULTS: We found that the development of pulmonary fibrosis depended on IL-17A and was significantly attenuated by neutrophil depletion. Neutrophils and monocytes/macrophages were the main cell types that expressed IL-17A in our model. CONCLUSIONS: We have identified the central roles of IL-17A and neutrophils in the pathogenesis of fibrosis in experimental hypersensitivity pneumonitis. We have also established that nonlymphocytic innate immune cells, specifically neutrophils and monocytes/macrophages, rather than TH17 lymphocytes, are the predominant source of IL-17A in experimental hypersensitivity pneumonitis. PMID- 23453797 TI - Vitamin D insufficiency is associated with challenge-proven food allergy in infants. AB - BACKGROUND: Epidemiological evidence has shown that pediatric food allergy is more prevalent in regions further from the equator, suggesting that vitamin D insufficiency may play a role in this disease. OBJECTIVE: To investigate the role of vitamin D status in infantile food allergy. METHODS: A population sample of 5276 one-year-old infants underwent skin prick testing to peanut, egg, sesame, and cow's milk or shrimp. All those with a detectable wheal and a random sample of participants with negative skin prick test results attended a hospital-based food challenge clinic. Blood samples were available for 577 infants (344 with challenge-proven food allergy, 74 sensitized but tolerant to food challenge, 159 negative on skin prick test and food challenge). Serum 25-hydroxyvitamin D levels were measured by using liquid chromatography tandem mass spectrometry. Associations between serum 25-hydroxyvitamin D and food allergy were examined by using multiple logistic regression, adjusting for potential risk and confounding factors. RESULTS: Infants of Australian-born parents, but not of parents born overseas, with vitamin D insufficiency (<=50 nmol/L) were more likely to be peanut (adjusted odds ratio [aOR], 11.51; 95% CI, 2.01-65.79; P=.006) and/or egg (aOR, 3.79; 95% CI, 1.19-12.08; P=.025) allergic than were those with adequate vitamin D levels independent of eczema status. Among those with Australian-born parents, infants with vitamin D insufficiency were more likely to have multiple food allergies (>=2) rather than a single food allergy (aOR, 10.48; 95% CI, 1.60 68.61 vs aOR, 1.82; 95% CI, 0.38-8.77, respectively). CONCLUSIONS: These results provide the first direct evidence that vitamin D sufficiency may be an important protective factor for food allergy in the first year of life. PMID- 23453798 TI - Preparation and characterization of biomass carbon-based solid acid catalyst for the esterification of oleic acid with methanol. AB - A solid acid catalyst, prepared by sulfonating carbonized corn straw, was proved to be an efficient and environmental benign catalyst for the esterification of oleic acid and methanol. Various synthetic parameters, such as carbonization temperature and time were systematically examined. It was found that the catalyst exhibited the highest acid density of 2.64 mmol/g by NaOH titration. A quantitative yield (98%) of ester was achieved, using the most active sulfonated catalyst at 333 K with a 7 wt.% catalyst/oleic acid ratio for 4h, at a 7:1 M ratio of methanol/oleic acid, while the commercial available Amberlyst-15 only gave 85% yield under the same reaction condition. PMID- 23453799 TI - Livestock wastewater treatment using aerobic granular sludge. AB - The present study demonstrated that aerobic granular sludge is capable of treating livestock wastewater from a cattle farm in a sequencing batch reactor (SBR) without the presence of support material. A lab scale SBR was operated for 80 d using 4 h cycle time with an organic loading rate (OLR) of 9 kg COD m(-3) d( 1). Results showed that the aerobic granules were growing from 0.1 to 4.1 mm towards the end of the experimental period. The sludge volume index (SVI) was 42 ml g(-1) while the biomass concentration in the reactor grew up to 10.3 g L(-1) represent excellent biomass separation and good settling ability of the granules. During this period, maximum COD, TN and TP removal efficiencies (74%, 73% and 70%, respectively) were observed in the SBR system, confirming high microbial activity in the SBR system. PMID- 23453800 TI - Study of the adsorption of Cr(VI) by tannic acid immobilised powdered activated carbon from micro-polluted water in the presence of dissolved humic acid. AB - The adsorption of Cr(VI) (0.500 mg/L) onto food-grade tannic-acid immobilised powdered activated carbon (TA-PAC) in the presence of dissolved humic acid (DHA) was investigated at 280 K as a function of pH, along with the adsorption capacities and the adsorption isotherms for chromium ions. The results showed that the presence of DHA improved the adsorption capacities of Cr(VI) and its reduction product (Cr(III)) over a wide pH range (4.0-8.0). The main mechanism for metal-DHA complexation in the Cr(VI) system was the reduction of Cr(VI) followed by complexation between Cr(III) and DHA. The Freundlich isotherms yielded the best fits to all data (R(2)=0.9951, qm=5.639 mg/g) in the presence of DHA. The adsorption mechanisms of Cr(VI) onto TA-PAC in the presence of DHA were summarized into three categories: (i) binding by anion adsorption, (ii) Cr(VI) reduction followed by Cr(III) adsorption, and (iii) adsorption of Cr(III)-DHA complexes. PMID- 23453801 TI - Genetic investigations of kidney disease: core curriculum 2013. PMID- 23453802 TI - Intravenous fluid therapy: saline versus mixed electrolyte and organic anion solutions. PMID- 23453803 TI - Reply: To PMID 22360920. PMID- 23453804 TI - Factor V Leiden carriers taking oral contraceptives have an increased risk of thrombosis. PMID- 23453805 TI - ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes. AB - Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling. PMID- 23453806 TI - AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. AB - Thioredoxin-interacting protein (TXNIP) is an alpha-arrestin family protein that is induced in response to glucose elevation. It has been shown to provide a negative feedback loop to regulate glucose uptake into cells, though the biochemical mechanism of action has been obscure. Here, we report that TXNIP suppresses glucose uptake directly, by binding to the glucose transporter GLUT1 and inducing GLUT1 internalization through clathrin-coated pits, as well as indirectly, by reducing the level of GLUT1 messenger RNA (mRNA). In addition, we show that energy stress results in the phosphorylation of TXNIP by AMP-dependent protein kinase (AMPK), leading to its rapid degradation. This suppression of TXNIP results in an acute increase in GLUT1 function and an increase in GLUT1 mRNA (hence the total protein levels) for long-term adaptation. The glucose influx through GLUT1 restores ATP-to-ADP ratios in the short run and ultimately induces TXNIP protein production to suppress glucose uptake once energy homeostasis is reestablished. PMID- 23453807 TI - The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. AB - Parkin, a RING-between-RING-type E3 ubiquitin ligase associated with Parkinson's disease, has a wide neuroprotective activity, preventing cell death in various stress paradigms. We identified a stress-protective pathway regulated by parkin that links NF-kappaB signaling and mitochondrial integrity via linear ubiquitination. Under cellular stress, parkin is recruited to the linear ubiquitin assembly complex and increases linear ubiquitination of NF-kappaB essential modulator (NEMO), which is essential for canonical NF-kappaB signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-kappaB-responsive promoter elements for maintenance of mitochondrial integrity and protection from stress-induced cell death. Parkin induced stress protection is lost in the absence of either NEMO or OPA1, but not in cells defective for the mitophagy pathway. Notably, in parkin-deficient cells linear ubiquitination of NEMO, activation of NF-kappaB, and upregulation of OPA1 are significantly reduced in response to TNF-alpha stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway. PMID- 23453808 TI - The n-SET domain of Set1 regulates H2B ubiquitylation-dependent H3K4 methylation. AB - Past studies have documented a crosstalk between H2B ubiquitylation (H2Bub) and H3K4 methylation, but little (if any) direct evidence exists explaining the mechanism underlying H2Bub-dependent H3K4 methylation on chromatin templates. Here, we took advantage of an in vitro histone methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights. Combined with genetic analyses, we demonstrate that the n-SET domain within Set1, but not Swd2, is essential for H2Bub-dependent H3K4 methylation. Spp1, a homolog of human CFP1, is conditionally involved in this crosstalk. Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway. As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies draw attention to the n-SET domain as a predictor of an H2B ubiquitylation-sensing mechanism that leads to downstream H3K4 methylation. PMID- 23453811 TI - Canadian aquatic science and environmental legislation under threat. PMID- 23453809 TI - Different roles for Tet1 and Tet2 proteins in reprogramming-mediated erasure of imprints induced by EGC fusion. AB - Genomic imprinting directs the allele-specific marking and expression of loci according to their parental origin. Differential DNA methylation at imprinted control regions (ICRs) is established in gametes and, although largely preserved through development, can be experimentally reset by fusing somatic cells with embryonic germ cell (EGC) lines. Here, we show that the Ten-Eleven Translocation proteins Tet1 and Tet2 participate in the efficient erasure of imprints in this model system. The fusion of B cells with EGCs initiates pluripotent reprogramming, in which rapid re-expression of Oct4 is accompanied by an accumulation of 5-hydroxymethylcytosine (5hmC) at several ICRs. Tet2 was required for the efficient reprogramming capacity of EGCs, whereas Tet1 was necessary to induce 5-methylcytosine oxidation specifically at ICRs. These data show that the Tet1 and Tet2 proteins have discrete roles in cell-fusion-mediated pluripotent reprogramming and imprint erasure in somatic cells. PMID- 23453812 TI - Mixing and dispersion of pollutants emitted from an outboard motor. AB - This paper quantifies the mixing and dispersion from an outboard motor by field experiments in a small subtropical waterway. Organic dye was used as a surrogate for exhaust emissions and was mixed with uncontaminated creek water before being dispersed into the creek. Dye concentrations were measured with an array of concentration probes stationed in the creek. The data were then processed and fitted with a power law function. The corresponding dispersion constants agreed well with the literature. However, the amplitude was lower than the IMO equation but higher than the correlation from laboratory tests. Results for dye concentration intermittency (presence of dye) are presented for the first time from such field measurements and show significant mixing in-homogeneity. PMID- 23453810 TI - MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance. AB - The Raf/MEK/ERK and PI3K/Akt pathways are prominent effectors of oncogenic Ras. These pathways negatively regulate each other, but the mechanism involved is incompletely understood. We now identify MEK1 as an essential regulator of lipid/protein phosphatase PTEN, through which it controls phosphatidylinositol-3 phosphate accumulation and AKT signaling. MEK1 ablation stabilizes AKT activation and, in vivo, causes a lupus-like autoimmune disease and myeloproliferation. Mechanistically, MEK1 is necessary for PTEN membrane recruitment as part of a ternary complex containing the multidomain adaptor MAGI1. Complex formation is independent of MEK1 kinase activity but requires phosphorylation of T292 on MEK1 by activated ERK. Thus, inhibiting the ERK pathway reduces PTEN membrane recruitment, increasing phosphatidylinositol-3-phosphate accumulation and AKT activation. Our data offer a conceptual framework for the observation that activation of the PI3K pathway frequently mediate resistance to MEK inhibitors and for the promising results obtained by combined MEK/PI3K inhibition in preclinical cancer models. PMID- 23453813 TI - Estimating discharge rates of oily wastes and deterrence based on aerial surveillance data collected in western Canadian marine waters. AB - Illegal discharge of waste oil from ships is a major source of mortality for seabirds globally. Using linear and log-linear regression, we explored the relationship between detection rates of marine oily discharges and surveillance effort at different time scales, based on data collected in the Canadian Pacific Ocean by the National Aerial Surveillance Program (NASP) from 1997 to 2006. We introduce an approach for quantifying reductions in discharge rates with increased surveillance while controlling appropriately for surveillance effort, as standard linear correction for effort can introduce considerable bias. Despite low probabilities of detection (0.088-1.1%), we found evidence for reduced discharge rates with increasing surveillance effort for data summarized monthly and bimonthly in region A, which is closest to the NASP base airport. Using residuals derived from the best-fit log-linear models, we found detected discharge rates declined annually (-[0.070 spills/month]*year). PMID- 23453814 TI - Hydrogeochemical variables regionalization--applying cluster analysis for a seasonal evolution model from an estuarine system affected by AMD. AB - This study describes the spatial evolution of the hydrogeochemical parameters which characterise a strongly affected estuary by Acid Mine Drainage (AMD). The studied estuarine system receives AMD from the Iberian Pyrite Belt (SW Spain) and, simultaneously, is affected by the presence of an industrial chemical complex. Water sampling was performed in the year of 2008, comprising four sampling campaigns, in order to represent seasonality. The results show how the estuary can be divided into three areas of different behaviour in response to hydrogeochemical variables concentrations that define each sampling stations: on one hand, an area dominated by tidal influence; in the opposite end there is a second area including the points located in the two rivers headwaters that are not influenced by seawater; finally there is the area that can be defined as mixing zone. These areas are moved along the hydrological year due to seasonal chemical variations. PMID- 23453815 TI - Editorial: Poseidon's shame. PMID- 23453816 TI - Effects of green macroalgal blooms on the meiofauna community structure in the Bay of Cadiz. AB - The effect of macroalgal blooms on the abundance and community structure of intertidal sediment meiofauna was studied using an in situ enclosure experiments (Bay of Cadiz, Spain). Meiofaunal abundance (3500-41,000 ind 10 cm-2) was three to sevenfold higher in the presence of macroalgae. Nematoda were the dominant taxon both in Control (52-82%) and Macroalgae plots (92-96%), followed by Harpacticoida Copepoda and Ostracoda. Non-metric Multi-Dimensional Scaling (MDS) analysis clearly separated the meiofaunal community from Control and Macroalgae plots. Organic matter, organic carbon, total nitrogen, chlorophyll a and freeze lysable inorganic nutrients were higher in Macroalgae plots, and were highly correlated with the horizontal MDS axis separating Control and Macroalgae meiofaunal communities. Meiofaunal abundance and taxonomic composition in the Bay of Cadiz seem to be bottom-up controlled either through a grazer system based on microphytobenthos in bare sediments or through a decomposer system in macroalgae affected sediments. PMID- 23453817 TI - Carbon and nitrogen stable isotope ratios and mercury concentration in the scalp hair of residents from Taiji, a whaling town. AB - We analyzed stable isotope ratios of carbon (delta(13)C) and nitrogen (delta(15)N) as well as mercury (Hg) concentration in the scalp hair of Japanese who consumed whale meat and those who did not, and investigated the relationships among the delta(13)C and delta(15)N values and Hg concentration. The average delta(15)N and delta(13)C values of whale meat-eaters (10.110/00 and -18.50/00) were significantly higher than those of non-eaters (9.280/00 and -18.90/00), respectively. The average Hg concentration of whale meat-eaters (20.6 MUg/g) was significantly higher than that of non-eaters (2.20 MUg/g). Significant positive correlations were found between the delta(13)C and delta(15)N values and between the delta(15)N value and Hg concentration in the hair of whale meat-eaters, while the correlation between the delta(15)N value and Hg concentration was not statistically significant in the non-eaters. The consumption of whale meat may increase Hg concentration as well as delta(15)N and delta(13)C values in scalp hair. PMID- 23453818 TI - Antifouling biocides in water and sediments from California marinas. AB - Irgarol 1051 is a common antifouling biocide and is highly toxic to non-target plant species at low ng/L concentrations. We measured up to 254 ng/L Irgarol in water and up to 9 ng/g dry weight Irgarol in sediments from Southern California recreational marinas. Irgarol's metabolite, M1, concentrations were up to 62 ng/L in water and 5 ng/g dry weight in sediments. Another antifouling biocide, diuron, reached up to 68 ng/L in water and 4 ng/g dry weight in sediments. The maximum Irgarol concentrations in water were greater than the Irgarol concentration recommended as the plant toxicity benchmark (136 ng/L), suggesting that Irgarol concentrations may be high enough to cause changes in phytoplankton communities in the sampled marinas. Irgarol concentrations measured in sediments were greater than calculated Environmental Risk Limits (ERLs) for Irgarol in sediments (1.4 ng/g). Antifouling pesticide accumulation in sediments may present a potential undetermined risk for benthic organisms. PMID- 23453819 TI - ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. PMID- 23453821 TI - Ultrasound-assisted butyl acetate synthesis catalyzed by Novozym 435: enhanced activity and operational stability. AB - The influence of low-frequency ultrasound (40 kHz) in the esterification reaction between acetic acid and butanol for flavor ester synthesis catalyzed by the commercial immobilized lipase B from Candida antarctica (Novozym 435) was evaluated. A central composite design and the response surface methodology were used to analyze the effects of the reaction parameters (temperature, substrate molar ratio, enzyme content and added water) and their response (yields of conversion in 2.5 h of reaction). The reaction was carried out using n-hexane as solvent. The optimal conditions for ultrasound-assisted butyl acetate synthesis were found to be: temperature of 46 degrees C; substrate molar ratio of 3.6:1 butanol:acetic acid; enzyme content of 7%; added water of 0.25%, conditions that are slightly different from those found using mechanical mixing. Over 94% of conversion was obtained in 2.5h under these conditions. The optimal acid concentration for the reaction was determined to be 2.0 M, compared to 0.3 M without ultrasound treatment. Enzyme productivity was significantly improved to around 7.5-fold for each batch when comparing ultrasound and standard mechanical agitation. The biocatalyst could be directly reused for 14 reactions cycles keeping around 70% of its original activity, while activity was virtually zeroed in the third cycle using the standard mixing system. Thus, compared to the traditional mechanical agitation, ultrasound technology not only improves the process productivity, but also enhances enzyme recycling and stability in the presence of acetic acid, being a powerful tool to improve biocatalyst performance in this type of reaction. PMID- 23453820 TI - Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome. AB - BACKGROUND: Previous studies indicate that negative symptoms reflect a separable domain of pathology from other symptoms of schizophrenia. However, it is currently unclear whether negative symptoms themselves are multi-faceted, and whether sub-groups of patients who display unique negative symptom profiles can be identified. METHODS: A data-driven approach was used to examine the heterogeneity of negative symptom presentations in two samples: Study 1 included 199 individuals with schizophrenia assessed with a standard measure of negative symptoms and Study 2 included 169 individuals meeting criteria for deficit schizophrenia (i.e., primary and enduring negative symptoms) assessed with a specialized measure of deficit symptoms. Cluster analysis was used to determine whether different groups of patients with distinct negative symptoms profiles could be identified. RESULTS: Across both studies, we found evidence for two distinctive negative symptom sub-groups: one group with predominantly Avolition Apathy (AA) symptoms and another with a predominantly Diminished Expression (DE) profile. Follow-up discriminant function analyses confirmed the validity of these groups. AA and DE negative symptom sub-groups significantly differed on clinically relevant external validators, including measures of functional outcome, premorbid adjustment, clinical course, disorganized symptoms, social cognition, sex, and ethnicity. CONCLUSIONS: These results suggest that distinct subgroups of patients with elevated AA or DE can be identified within the broader diagnosis of schizophrenia and that these subgroups show clinically meaningful differences in presentation. Additionally, AA tends to be associated with poorer outcomes than DE, suggesting that it may be a more severe aspect of psychopathology. PMID- 23453822 TI - UPLC-MS/MS measurement of S-nitrosoglutathione (GSNO) in human plasma solves the S-nitrosothiol concentration enigma. AB - We developed and validated a fast UPLC-MS/MS method with positive electrospray ionization (ESI+) for the quantitative determination of S-nitrosoglutathione (GSNO) in human plasma. We used a published protocol for the inactivation of plasma gamma-glutamyltransferase (gammaGT) activity by using the gammaGT transition inhibitor serine/borate and the chelator EDTA for the stabilization of GSNO, and N-ethylmaleimide (NEM) to block SH groups and to avoid S transnitrosylation reactions which may diminish GSNO concentration. S [(15)N]Nitrosoglutathione (GS(15)NO) served as internal standard. Fresh blood was treated with NEM/serine/borate/EDTA, plasma spiked with GS(15)NO (50nM) was ultrafiltered (cut-off 10kDa) and 10MUL aliquots of the ultrafiltrate were analyzed by UPLC-MS/MS. Five HILIC columns and an Acquity UPLC BH amide column were tested. The mobile phase was acetonitrile-water (70:30, v/v), contained 20mM ammonium formate, had a pH value of 7, and was pumped isocratically (0.5mL/min). The Nucleoshell column allowed better LC performance and higher MS sensitivity. The retention time of GSNO was about 1.1min. Quantification was performed by selected-reaction monitoring the mass transition m/z 337 ([M+H](+))->m/z 307 ([M+H(14)NO](+)) for GSNO (i.e., GS(14)NO) and m/z 338 ([M+H](+))->m/z 307 ([M+H(15)NO](+)) for GS(15)NO. NEM/serine/borate/EDTA was found to stabilize GSNO in human plasma. The method was validated in human plasma (range, 0-300nM) using 50nM GS(15)NO. Accuracy and precision were in generally acceptable ranges. A considerable matrix effect was observed, which was however outweighed by the internal standard GS(15)NO. In freshly prepared plasma from heparinized blood donated by 10 healthy subjects, no endogenous GSNO was determined above 2.8nM, the limit of quantitation (LOQ) of the method. This study challenges previously reported GSNO plasma concentrations being far above the present method LOQ value and predicts that the concentration of low-molecular-mass and high-molecular-mass S-nitrosothiols are in the upper pM- and lower nM-range, respectively. PMID- 23453823 TI - Trichinella infections in different host species of an endemic district of Serbia. AB - Trichinella infections are endemic in the Balkan region of Europe. Though trichinellosis and agents thereof are serious problems for human health and animal husbandry, only a limited number of Trichinella isolates from Serbia have been identified at the species level so far. The aim of the present study was the surveillance and monitoring of Trichinella in domestic pigs and wild animals from the endemic district of Branicevo. Investigations performed during the 2009-2010 period revealed Trichinella infections in 344 out of 282,960 (0.12%) domestic pigs. Among wildlife, Trichinella infections were detected in 11 out of 94 (11.7%) wild boars (Sus scrofa), 7 out of 57 (12.3%) red foxes (Vulpes vulpes), 7 out of 13 (53.8%) golden jackals (Canis aureus), and in all three examined wolves (Canis lupus). Trichinella spiralis and Trichinella britovi were the only two species identified. T. britovi was identified in 31% of isolates from wildlife of the Branicevo district and T. spiralis was found in 53% of wild animals; mixed infections were observed in 16% of the animals examined. Findings form the basis of an information campaign for veterinary services, pig owners and the hunter's associations about the risk of the transmission of these zoonotic agents. The application of control programs as established at the Veterinary Specialist Institute of Pozarevac resulted in a decline in Trichinella infections among domestic pigs and the absence of human trichinellosis in the last three years in the Branicevo district. PMID- 23453824 TI - Cold exposure attenuates post exercise cardiovagal reactivation and sympathetic withdrawal. AB - In a crossover design we investigated cardiac autonomic responses (heart rate variability, HRV) to isometric handgrip exercise (IHG) in cold (4 degrees C) and temperate (24 degrees C, temp) conditions in 20 men that assumed the supine position for 30 min in an environmental chamber. After a 5 min rest, subjects performed 3 min of IHG followed by a 3 min recovery period (REC). During REC, the low frequency of HRV was lower while the high frequency and the square root of the mean squared differences of successive NN intervals were higher (P<0.05) than the rest in the temp compared to a full recovery in the cold. In conclusion, recovery from concurrent cold exposure and exercise impairs cardiovagal modulation which may precipitate cardiac events. PMID- 23453825 TI - Symbolic patterns of heart rate dynamics reflect cardiac autonomic changes during childhood and adolescence. AB - Symbolic dynamics derived from heart rate variability (HRV) is able to reflect changes of cardiac autonomic modulations in healthy subjects. It has been shown that linear measures of HRV in children and adolescents monotonically increase or decrease (depending on the measure) with age whereas non-linear measures show a local extreme value at the age of 7 to 9 years. In this study, the age-related variations of dynamical features of the R-R interval series during childhood and adolescence were addressed. In particular, the binary symbolic dynamics reflecting the sequence of acceleration (='1') and deceleration (='0') of heart rate was examined. The R-R interval series of 409 healthy children and adolescents (age range: 1 to 22 years, 220 females) was analyzed with respect to the regularity of binary patterns of length 8 using Approximate Entropy (ApEn). Binary patterns were grouped to patterns sets according to the level of their regularity as assessed by ApEn. Pattern sets containing regular binary patterns occurred more often with increasing age whereas irregular binary patterns occurred less often. Specific regular binary patterns show an unexpected behavior. They occurred fewest in the group 7 to 9 years. Furthermore, regular binary patterns occur more often during daytime whereas irregular binary patterns occur more often during nighttime. In conclusion, the analysis of binary symbolic dynamics is able to reflect age-related changes during childhood and adolescence in spite of the considerable reduction of information involved. As many binary patterns are linked to sympathetic or parasympathetic modulations of the autonomic nervous system e.g. spectral analysis of HRV may be complemented by this kind of analysis. PMID- 23453826 TI - Enhanced mechanical properties and blood compatibility of PDMS/liquid crystal cross-linked membrane materials. AB - A novel polydimethylsiloxane/liquid crystal cross-linked membrane (PDMS/LC) was prepared by using PDMS containing vinyl groups and LCs containing unsaturated linkages as matrix materials. Mechanical properties, liquid crystalline performance and blood compatibility of the PDMS/LC cross-linked membrane containing different LC contents and LC groups were investigated, respectively. The results showed that mechanical properties of the membrane increased more significantly than those of pure PDMS membranes. The PDMS/LC cross-linked membrane also possessed better membrane-forming ability, lower hemolysis rate, less platelets adhesion and more favorable anti-coagulant properties. Additionally, mechanical properties and blood compatibility of the membrane can be enhanced simultaneously and obviously due to the introduction of the cholesteric liquid crystals and the application of the preferred cross-linked reaction without byproducts. PMID- 23453827 TI - Fabrication and deformation behaviour of multilayer Al2O3/Ti/TiO2 nanotube arrays. AB - In this study, titanium thin films were deposited on alumina substrates by radio frequency (RF) magnetron sputtering. The mechanical properties of the Ti coatings were evaluated in terms of adhesion strength at various RF powers, temperatures, and substrate bias voltages. The coating conditions of 400W of RF power, 250 degrees C, and a 75V substrate bias voltage produced the strongest coating adhesion, as obtained by the Taguchi optimisation method. TiO2 nanotube arrays were grown as a second layer on the Ti substrates using electrochemical anodisation at a constant potential of 20V and anodisation times of 15min, 45min, and 75min in a NH4F electrolyte solution (75 ethylene glycol: 25 water). The anodised titanium was annealed at 450 degrees C and 650 degrees C in a N2 gas furnace to obtain different phases of titania, anatase and rutile, respectively. The mechanical properties of the anodised layer were investigated by nanoindentation. The results indicate that Young's modulus and hardness increased with annealing temperature to 650 degrees C. PMID- 23453828 TI - Large amplitude oscillatory shear properties of human skin. AB - Skin is a complex multi-layered tissue, with highly non-linear viscoelastic and anisotropic properties. Thus far, a few studies have been performed to directly measure the mechanical properties of three distinguished individual skin layers; epidermis, dermis and hypodermis. These studies however, suffer from several disadvantages such as skin damage due to separation, and disruption of the complex multi-layered composition. In addition, most studies are limited to linear shear measurements, i.e. measurements with small linear deformations (also called small amplitude oscillatory shear experiments), whereas in daily life skin can experience high strains, due to for example shaving or walking. To get around these disadvantages and to measure the non-linear mechanical (shear) behavior, we used through-plane human skin to measure large amplitude oscillatory shear (LAOS) deformation up to a strain amplitude of 0.1. LAOS deformation was combined with real-time image recording and subsequent digital image correlation and strain field analysis to determine skin layer deformations. Results demonstrated that deformation at large strains became highly non-linear by showing intra-cycle strain stiffening and inter-cycle shear thinning. Digital image correlation revealed that dynamic shear moduli gradually decreased from 8kPa at the superficial epidermal layer down to a stiffness of 2kPa in the dermis. From the results we can conclude that, from a mechanical point of view, skin should be considered as a complex composite with gradually varying shear properties rather than a three layered tissue. PMID- 23453829 TI - Rider-handlebar injury in two-wheel frontal collisions. AB - This work analyses blunt abdominal trauma produced by driver-handlebar collision, in low speed two-wheel accidents. A simplified dynamic model is introduced, whose parameters have been estimated on the basis of cadaver tests. This model allows calculating the peak impact force and the abdominal penetration depth; therefore the likelihood of occurrence of serious injuries can be estimated for different masses of contacting bodies and different speeds. Results have been checked against literature data and true-accident reports. Numerical simulations demonstrate that serious injuries (AIS>3) can occur even at low speeds (<20km/h), therefore the design of protective clothing is recommendable. The model can allow both the analysis of true accident data and the virtual testing of protective equipment in the conceptual design phase. PMID- 23453830 TI - Yokukansan (TJ-54) for treatment of very-late-onset schizophrenia-like psychosis: an open-label study. AB - BACKGROUND: Although schizophrenia affects all age groups, late or very-late onset schizophrenia-like psychosis has not been well studied, and various treatment issues remain unresolved. The objective of the present study was to evaluate the efficacy and safety of yokukansan (TJ-54), Japanese herbal medicine, monotherapy in a diagnostically homogenous group of elderly patients without cognitive impairment suffering from very-late-onset schizophrenia. METHODS: Forty patients of mean age 73.1+/-4.8 years, fulfilling both the recent consensus criteria for very late-onset schizophrenia-like psychosis and the DSM-IV-TR criteria for schizophrenia, were assessed by the brief psychiatric rating scale, the clinical global impression scale-severity, and positive and negative syndrome scale at baseline and after 4 weeks administration of TJ-54 (2.5-7.5 g/day). In addition, abnormal movements were evaluated with the Simpson-Angus scale, Barnes Akathisia scale, and abnormal involuntary movement scale. RESULTS: A highly significant (p<0.001) improvement on all measures of psychotic symptomatology was observed in all patients. TJ-54 was very well tolerated by the patients, and no clinically significant adverse effects were observed. Scores on all abnormal movement scales did not differ significantly prior to and after TJ-54 treatment. CONCLUSION: Preliminary results indicate that TJ-54 appears to be an efficacious and safe herbal medicine for treatment of very-late-onset schizophrenia-like psychosis. PMID- 23453831 TI - Induction of apoptosis in human pancreatic MiaPaCa-2 cells through the loss of mitochondrial membrane potential (DeltaPsim) by Gentiana kurroo root extract and LC-ESI-MS analysis of its principal constituents. AB - The objective of the current study was to evaluate the methanolic root extract of Gentiana kurroo for antioxidant and antiproliferative activities as well as to study the effect of the extract on the induction of apoptosis in human pancreatic cancer cell line (MiaPaCa-2). The extract exerted significant antioxidant activity as verified by DPPH, hydroxyl radical, lipid peroxidation and protective oxidative DNA damage assays. The results were comparable to standard antioxidants like alpha-tocopherol, catechin and BHT used in such experiments. Antioxidant potential of G. kurroo may be attributed to the presence of high phenolic and flavonoid content (73+/-1.02 and 46+/-2.05 mg/g extract respectively). The anti proliferative property of Gentiana kurroo root extract was determined by sulphorhodamine B (SRB) assay against Human colon cancer cell line (HCT-116), Lung carcinoma cell line (A-549), Pancreatic cancer cell line (MiaPaCa-2), Lung cancer cell line (HOP-62) and acute monocytic leukaemia cell line (THP-1). G. kurroo root extract inhibited cancer cell growth depending upon the cell line used and in a dose dependent manner. The extract induced potent apoptotic effects in MiaPaCa-2 cells. The population of apoptotic cells increased from 11.4% in case of control to 49.6% at 100 MUg/ml of G. kurroo root extract. The extract also induced a remarkable decrease in mitochondrial membrane potential (DeltaPsim) leading to apoptosis of cancer cells used. The main chemical constituents identified by the liquid chromatography-tandem mass spectrometry (LC ESI-MSMS) were found to be iridoid glucosides (iridoids and secoiridoids), xanthones and flavonoids. Iridoid glucosides are the bitter principles of Gentiana species. Loganic acid, Sweroside, Swertiamarin, Gentiopicroside, Gentisin, Isogentisin, Gentioside, Norswertianolin, Swertianolin, 4"-O-beta-D glucosyl-6'-O-(4-O-beta-D-glucosylcaffeoyl)-linearoside and Swertisin were the principal compounds present in the methanol root extract of G. kurroo. PMID- 23453832 TI - Reprint of "Affective picture processing as a function of preceding picture valence: an ERP analysis". AB - Event-related brain potential (ERP) studies consistently revealed that a relatively early (early posterior negativity; EPN) and a late (late positive potential; LPP) ERP component differentiate between emotional and neutral picture stimuli. Two studies examined the processing of emotional stimuli when preceded either by pleasant, neutral, or unpleasant context images. In both studies, distinct streams of six pictures were shown. In Study 1, hedonic context was alternated randomly across the 180 picture streams. In Study 2, hedonic context sequences were blocked, resulting in 60 preceding sequences of pleasant, neutral, and unpleasant context valence, respectively. The main finding was that the valence of the preceding picture sequence had no significant effect on the emotional modulation of the EPN and LPP components. However, previous results were replicated in that emotional stimulus processing was associated with larger EPN and LPP components as compared to neutral pictures. These findings suggest that the prioritized processing of emotional stimuli is primarily driven by the valence of the current picture. PMID- 23453833 TI - Reprint of "Effortful control, depression, and anxiety correlate with the influence of emotion on executive attentional control". AB - Recent evidence confirms that emotion can trigger executive attentional control. Participants resolve conflict faster when encountering emotionally negative or positive stimuli. This effect is accompanied by an enlarged conflict negativity in event-related brain potentials (ERPs) and activation of the ventral anterior cingulate cortex (ACC) in fMRI. Here, we tested whether temperament (the trait effortful control) and subclinical factors (anxiety, depression) can influence the emotional modulation of executive attention. These factors correlated with conflict processing in six experiments that utilized different conflict tasks (flanker, Simon) and different types of emotional stimuli (visual, auditory). Participants high in effortful control and low in anxiety and depression responded faster to conflict processing in emotional stimuli, showed an enhanced ERP conflict negativity, and additional activation in the ventral ACC. The data show that temperamental effortful control, depression, and anxiety are related to the influence of emotion on executive attention and its underlying neural correlates. PMID- 23453834 TI - Survival after prolonged resuscitation from cardiac arrest due to diabetic ketoacidosis using extracorporeal life support. AB - Management of cardiac arrest due to severe diabetic ketoacidosis (DKA) using bicarbonate therapy and extracorporeal life support (ECLS) remains controversial. We report a case of a 24-year-old man with insulin-dependent type 1 diabetes mellitus who survived without any neurologic complications after prolonged ECLS (including fluid resuscitation and insulin but no aggressive bicarbonate) for cardiac arrest due to severe DKA. In post-DKA cardiac arrest, insulin and fluid resuscitation is the mainstay of treatment, but ECLS should be considered when prolonged cardiac arrest is expected. PMID- 23453835 TI - Optimizing risk-adjusted outcome measures: a moving target. Invited commentary on: Variability of NSQIP assessed surgical quality based on age and disease process. PMID- 23453836 TI - Safety and efficacy of ethylenediaminetetraacetic acid for removing microcapsules. AB - BACKGROUND: Microencapsulated islets are used to prevent immune rejection associated with pancreatic islet transplantation, but cellular overgrowth affects transplantation success, necessitating removal of microcapsules prior to retransplantation. This study aimed to investigate the safety and efficacy of ethylendiaminetetraacetic acid (EDTA) for the removal of microcapsules surrounding islet cells. METHODS: Microcapsule dissolution was investigated after in vitro exposure to EDTA for 72 h. Dissolution, blood biochemical markers, and pathologic changes in abdominal organs were observed after intraperitoneal administration of different concentrations of EDTA to rats with abdominally transplanted empty microcapsules. The extent of overgrowth and time to adhesion development were recorded after implantation of microencapsulated islets into the abdominal cavity of diabetic rats. EDTA (0-240 mmol/L) was injected to observe the transplantation effect and ability to dissolve microcapsules. RESULTS: There was a positive correlation between the rate of microcapsule dissolution and EDTA concentration in vitro. Following administration of 60 mmol/L EDTA, the majority of microcapsules within the abdominal cavity were dissolved and the retrieval rate was 2.6%. No adverse effects, abnormal blood biochemical markers, or organ damage were observed in rats 1 mo following intraperitoneal injection with EDTA at doses up to 60 mmol/L. Microcapsule retrieval and blood glucose were significantly higher in cases of grade II cellular overgrowth than in cases of grade 0-I overgrowth. CONCLUSIONS: EDTA (60 mmol/L) dissolved microcapsules in vivo without affecting islet cell viability or secretion capacity, and without affecting blood biochemical markers. Optimal dissolution was achieved with grade 0-I overgrowth after implantation of microencapsulated islets. PMID- 23453838 TI - Synthesis and anti-acetylcholinesterase properties of novel beta- and gamma substituted alkoxy organophosphonates. AB - Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of beta-substituted ethoxy and gamma substituted propoxy phosphonoesters of the type p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] (R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The beta-fluoroethoxy methylphosphonate analog (R=Me, Z=F, n=2) was the most potent anti-AChE compound comparable (ki ~6 * 10(6)M(-1)min(-1)) to paraoxon against EEAChE. Analogs with Z=Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R=Me) were more potent than the corresponding ethyl phosphonates (R=Et). As expected, analogs with a thionate linkage (PS) were poor inhibitors of the AChEs. PMID- 23453837 TI - Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. AB - The heat shock proteins are essential players in the development of cancer and they are prime therapeutic targets. Targeting multiple hsps in dual therapies decreases the likelihood of drug resistance compared to utilizing mono-therapies. Further, employing an hsp inhibitor in combination with another therapy has proven clinically successful. Examples of efficacious strategies include the inhibition of hsp27, which prevents protein aggregation, controlling hsp40's role as an ATPase modulator, and inhibiting hsp70 from acting as a molecular chaperone. While hsp40 therapies are just in the beginning stages, hsp27 and hsp70 therapies have been successfully used in dual inhibition treatments with hsp90 inhibitors and in combinational therapy with antineoplastic drugs. Both dual and combinatorial therapies show encouraging results when used in treating chemotherapeutically resistant diseases. PMID- 23453839 TI - N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tacaribe virus infections. AB - Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed. A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV. Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity. PMID- 23453840 TI - 2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors. AB - Substitution at the alpha center of the known human arginase inhibitor 2-amino-6 boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases. PMID- 23453841 TI - Deconstruction of sulfonamide inhibitors of the urotensin receptor (UT) and design and synthesis of benzylamine and benzylsulfone antagonists. AB - Potent small molecule antagonists of the urotensin receptor are described. These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor. The series of benzylamine and benzylsulfone antagonists herein reported display a combination of nanomolar molecular and cellular potency as well as acceptable in vitro permeability and metabolic stability. PMID- 23453842 TI - Synthesis and antifungal evaluation of 7-arylamino-5,8-dioxo-5,8 dihydroisoquinoline-4-carboxylates. AB - 7-Arylamino-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Most of tested compounds showed good antifungal activity. The results suggest that those 5,8-dioxo-5,8-dihydroisoquinolines would be potent antifungal agents. PMID- 23453843 TI - Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors. AB - The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthesized compounds were tested on a panel of four kinases in order to evaluate their activity and potential selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cytotoxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and docking calculations were carried out to aid in the interpretation of the results. Taken together, our findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors. PMID- 23453844 TI - [Integration of clinical trial agreement process in Ethics Committee evaluation timelines. Pilot study MINT&R((r))-cec]. PMID- 23453845 TI - Hemodynamic impacts of various types of stenosis in the left coronary artery bifurcation: a patient-specific analysis. AB - This study investigates the hemodynamic changes to various types of coronary stenosis in the left coronary artery bifurcation, based on a patient-specific analysis. Twenty two patients with left coronary artery disease were included in this study. All stenoses involving the left coronary artery bifurcation were classified into four types, according to their locations: A) left circumflex (LCx) and left anterior descending (LAD), B) LCx only, C) left main stem only, and D) LAD only. Computational fluid dynamics (CFD) was performed to analyze the flow and wall shear stress (WSS) changes in all reconstructed left coronary geometries. Our results showed that the flow velocity and WSS were significantly increased at stenotic locations. High WSS was found at >70% lumen stenosis, which ranged from 2.5 Pa to 3.5 Pa. This study demonstrates that in patients with more than 50% stenosis in the left coronary artery bifurcation, WSS plays an important role in providing information about the extent of coronary atherosclerosis in the left coronary artery branch. PMID- 23453846 TI - Serial splintage: Preoperative treatment of upper limb contracture. AB - INTRODUCTION: The present study aimed to study the efficacy of preoperative splints in treatment of upper limb contractures and to evaluate the response of contracture to splints depending on the etiology and the joint involved. METHODS: Ninety joints of 42 patients were studied. Patients age, gender, etiology, duration of contracture, contracture site and joint and type of contracture was noted. The range of motion of the involved joint was recorded. Serial static splints made of thermoplastic material were applied after customizing them for each patient. The range of motion and percentage movement was recorded at weekly interval and the splints were modified as per need. Time taken to reach a plateau stage was noted. To compare the statistical significance between two groups and more than two groups of continuous variable unpaired t-test and one way ANOVA respectively was applied. We considered differences to be statistically significant when the p value was below 0.05. The strength of relationship between the two continuous variables was analyzed by Pearson correlation analysis. RESULTS: Etiological factors were thermal burns (36.7%), electrical burns (13.3%), post traumatic (35.6%) and post cellulitis (14.4%). Age ranged from 2 to 70 years with a mean of 28.9+/-13.4 years. Sixty-two patients treated were males (68.9%) and 28 were female (31.1%). The mean range of motion present across all joints before starting the therapy was 54.7+/-23.6 degrees. The mean improvement in contracture angle obtained by serial splintage was 37.4+/-28.1 degrees. The mean time taken to achieve plateau was 23.6+/-3.2 days. Maximum improvement was seen in thermal burn contractures (41.2+/-30.3 degrees). Least improvement was seen in contractures due to cellulitis (6.5+/-16.2 degrees). This finding was statistically significant [F(3,86)=4.25, p=0.005]. Significant difference was seen in response to therapy based on the joint involved [F(3,86)=3.36, p=0.02]. Highest improvement in the range of motion was seen in the metacarpophalangeal joint (49.61+/-31.3 degrees). CONCLUSIONS: The preoperative use of splints may lead to lesser surgical intervention and in selective cases obviate surgery. Thermal burns which are the most common cause of contractures of the upper limb, show the maximum response to preoperative serial splintage. Patient with minor contracture and supple tissues are fully corrected with splints without surgical intervention. In patients undergoing surgical correction, skin graft decreases due to decreased contracture angle. PMID- 23453847 TI - Associations of ambient hydrogen sulfide exposure with self-reported asthma and asthma symptoms. AB - BACKGROUND: Whether long-term, low-level hydrogen sulfide (H2S) gas is a cause of health effects, including asthma, is uncertain. Rotorua city, New Zealand, has the largest population exposed, from geothermal sources, to relatively high ambient levels of H2S. In a cross-sectional study, the authors investigated associations with asthma in this population. METHODS: A total of 1637 adults, aged 18-65 years, were enrolled during 2008-2010. Residences and workplaces were geocoded. H2S exposures at homes and workplaces were estimated using city-wide networks of passive H2S samplers and kriging to create exposure surfaces. Exposure metrics were based on (1) time-weighted exposures at home and work; and (2) the maximum exposure (home or work). Exposure estimates were entered as quartiles into regression models, with covariate data. RESULTS: Neither exposure metric showed evidence of increased asthma risk from H2S. However, some suggestion of exposure-related reduced risks for diagnosed asthma and asthma symptoms, particularly wheezing during the last 12 months, emerged. With the maximum exposure metric, the prevalence ratio for wheeze in the highest exposure quartile was 0.80 (0.65, 0.99) and, for current asthma treatment, 0.75 (0.52, 1.08). There was no evidence that this was caused by a "survivor effect". CONCLUSIONS: The study provided no evidence that asthma risk increases with H2S exposure. Suggestions of a reduced risk in the higher exposure areas are consistent with recent evidence that H2S has signaling functions in the body, including induction of smooth muscle relaxation and reduction of inflammation. Study limitations, including possible confounding, preclude definitive conclusions. PMID- 23453848 TI - Socioeconomic disparities in indoor air, breath, and blood perchloroethylene level among adult and child residents of buildings with or without a dry cleaner. AB - In many cities, dry cleaners using perchloroethylene are frequently located in multifamily residential buildings and often cause elevated indoor air levels of perchloroethylene throughout the building. To assess individual perchloroethylene exposures associated with co-located dry cleaners, we measured perchloroethylene in residential indoor air, and in blood and breath of adults and children residing in buildings with a dry cleaner as part of the New York City (NYC) Perc Project. We also measured perchloroethylene in indoor air, and in blood and breath of residents of buildings without a dry cleaner for comparison. Here, we evaluate whether an environmental disparity in perchloroethylene exposures is present. Study participants are stratified by residential building type (dry cleaner or reference) and socioeconomic characteristics (race/ethnicity and income); measures of perchloroethylene exposure are examined; and, the influence of stratified variables and other factors on perchloroethylene exposure is assessed using multivariate regression. All measures of perchloroethylene exposure for residents of buildings with a dry cleaner indicated a socioeconomic disparity. Mean indoor air perchloroethylene levels were about five times higher in minority (82.5 ug/m(3)) than in non-minority (16.5 ug/m(3)) households, and about six times higher in low-income (105.5 ug/m(3)) than in high income (17.8 ug/m(3)) households. Mean blood perchloroethylene levels in minority children (0.27 ng/mL) and adults (0.46 ng/mL) were about two and three times higher than in non-minority children (0.12 ng/mL) and adults (0.15 ng/mL), respectively. Mean blood perchloroethylene levels in low income children (0.34 ng/mL) and adults (0.62 ng/mL) were about three and four times higher than in high income children (0.11 ng/mL) and adults (0.14 ng/mL), respectively. A less marked socioeconomic disparity was observed in perchloroethylene breath levels with minority and low income residents having slightly higher levels than non-minority and high income residents. Multivariate regression affirmed that indoor air perchloroethylene level in dry cleaner buildings was the single most important factor determining perchloroethylene in blood and breath. Neither age, gender, nor socioeconomic status significantly influenced perchloroethylene levels in breath or blood. We previously reported that increased indoor air, breath, and blood perchloroethylene levels among NYC Perc Project child participants were associated with an increased risk for slightly altered vision. Thus, the disproportionately elevated perchloroethylene exposures of minority and low income child residents of buildings with a dry cleaner shown here constitutes an environmental exposure disparity with potential public health consequences. Among residents of buildings without a dry cleaner, we observed some small increases in perchloroethylene breath and blood levels among non-minority or high income residents compared to minority or low income residents. These differences were not attributable to differences in indoor air levels of perchloroethylene which did not differ across socioeconomic categories, but appear to be associated with more frequent exposures dry cleaned garments. PMID- 23453849 TI - The relationship between substance use and delinquency among high-school students in Cape Town, South Africa. AB - Research has shown a positive relationship between substance use and delinquent type behaviours among adolescents. The aim of this study is to explore the temporal relationships between these outcomes through secondary data analysis of a longitudinal study of high-school students' risk behaviours. Two regression models were compared and gender, socioeconomic status and repeating a grade were found to be consistent predictors of delinquent-type behaviour. Alcohol (OR: 1.26, CI: 1.02-1.55, p = 0.03) and drug use (OR: 1.10, CI: 1.03-1.16, p = 0.002) in the ordinal regression models were significantly associated with delinquent type behaviours at Time 2 only. A transition model use was then used to measure delinquent-type behaviours as predicted by the previous time period, and results indicated that gender and delinquency were predictive of delinquency. Smoking also significantly interacted with delinquent-type behaviour to increase future risk of this behaviour. The findings point to the need for intervening early with adolescents who show delinquent-type behaviour. PMID- 23453850 TI - The experience and impact of chronic disease peer support interventions: a qualitative synthesis. AB - OBJECTIVE: Our aim was to synthesise qualitative literature about the perceived impact and experience of participating in peer support interventions for individuals with chronic disease. METHODS: We carried out a meta-ethnography to synthesize 25 papers meeting specific inclusion criteria. RESULTS: Thirteen concepts were identified that reflected participants' perceptions of the experience and impact of intervention participation. These were brought together in a conceptual model that highlighted both positive and negative perceptions, while also indicating if specific experiences and impacts had greater pertinence for mentors, mentees, or were mutually experienced. CONCLUSION: Although peer support interventions may establish uneven power relationships between mentors and mentees, there is also potential for initially asymmetrical relationships to become more symmetrical over time. Our synthesis suggests that emotional support is particularly valued when delivered under conditions that do not merely reproduce biomedical hierarchies of power. PRACTICE IMPLICATIONS: This synthesis suggests that those developing and implementing peer support interventions need to be sensitive to their potential negative effects. They will need to manage the tension between the hierarchical and egalitarian aspects of peer support interventions, and consider the impact on both mentors and mentees. PMID- 23453851 TI - Communicating cancer risk within an African context: experiences, disclosure patterns and uptake rates following genetic testing for Lynch syndrome. AB - OBJECTIVE: Data pertaining to Lynch syndrome within a developing country are sparse. This study explored the emotional reaction to a mutation-positive test result among a group of individuals from South Africa. As genetic information is not only limited to the individual but extends to the biological family, communication patterns and uptake of testing among at-risk family members was also investigated. METHODS: Eighty individuals participated in this qualitative interview study. RESULTS: Eight emotional reactions were observed, of which two were of particular concern: (1) secrecy due to disbelief and (2) interpretation of a mutation-positive result as a cancer diagnosis. Disclosure rates of personal genetic test results were high to family members, but low to general healthcare providers. Disclosing the test result was not always followed by a discussion of implications of the genetic information or availability of predictive testing for at-risk family members. The uptake rate of predictive testing among the participants' siblings and children was 97% and 73.6%, respectively. CONCLUSION: Awareness of concerning emotional reactions following the delivery of a genetic test result and insight into disclosure patterns, especially the information that is not communicated, will prove beneficial in improving the effectiveness of counselling and management in Lynch syndrome families. PRACTICE IMPLICATIONS: Implementation of these findings into the PT programme will have a positive effect on the genetic counseling process. PMID- 23453852 TI - Validation of a patient-centered culturally sensitive health care provider inventory using a national sample of adult patients. AB - OBJECTIVE: The Tucker-Culturally Sensitive Health Care Provider Inventory - Patient Form (T-CSHCPI-PF) is an inventory for culturally diverse patients to evaluate provider cultural sensitivity in the health care process. The T-CSHCPI PF is novel in that it assesses provider cultural sensitivity as defined by culturally diverse patients. The purpose of the present study was to determine the factor structure and internal consistency reliability of the T-CSHCPI-PF. METHOD: A sample of 1648 adult patients was recruited by staff at 67 health care sites across the United States. These patients anonymously completed the T-CSHCPI PF, a demographic data questionnaire, and a patient satisfaction questionnaire. RESULTS: Confirmatory factor analyses of the TCSHCPI-PF revealed that it has three factors with high internal consistency and validity. CONCLUSION: It is concluded that the T-CSHCPI-PF is a psychometrically strong and useful inventory for assessing the cultural sensitivity of health care providers. PRACTICAL IMPLICATIONS: The T-CSHCPI-PF may be a useful inventory for obtaining patients' feedback on their providers' cultural sensitivity and for assessing the effectiveness of trainings to promote patient-centered cultural sensitivity among providers. PMID- 23453853 TI - Two arginine residues in the substrate pocket predominantly control the substrate selectivity of thiocyanate hydrolase. AB - Thiocyanate hydrolase (SCNase) of Thiobacillus thioparus THI115 is a cobalt (Co) containing enzyme that catalyzes the hydrolysis of thiocyanate (SCN-), a major component of wastewater from coke oven factories, to carbonyl sulfide and ammonia. Although SCNase exhibits high structural similarities to Co-type nitrile hydratase (NHase), including a unique Co3+ catalytic center with two oxidized Cys ligands, both SCNase and NHase exclusively catalyze only their own substrates. Based on the differences in the substrate-binding pockets of these enzymes, betaArg90 and gammaArg136 of SCNase, with side chains extending toward the pocket, were separately substituted with Phe and Trp, the corresponding residues, respectively, in Co-type NHase. Both SCNase betaArg90 and SCNase gammaArg136 mutants showed no SCN- hydrolysis activity but did catalyze the hydration of nitriles. The estimated kcat values (~2 s-1) corresponded to approximately 0.2% of that of Co-type NHase for nitrile hydration and approximately 3% of that of wild-type SCNase for SCN- hydrolysis. The crystal structure of SCNase gammaR136W is essentially identical to that of the wild-type, including the Co3+ center having Cys oxidations; the size of the substrate pocket was enlarged because of conformational changes on the side chains of the mutated residue. Discussion of the difference in the environments around the substrate-binding pockets among the wild-type and mutant SCNases and Co-type NHase strongly suggests that betaArg90 and gammaArg136, positioned at the top of the Co3+ center, predominantly control the substrate selectivity of SCNase. PMID- 23453854 TI - Expression of food-grade phytase in Lactococcus lactis from optimized conditions in milk broth. AB - The major objective of this study was to engineer lactic acid bacteria to produce the enzyme phytase from a gene native to Bacillus subtilis GYPB04. The phytase gene (phyC) of B. subtilis GYPB04 was cloned into the plasmid pMG36e for expression in Lactococcus lactis. The enzyme activity in L. lactis cultured in GM17 broth was 20.25 U/mL at 36 degrees C. The expressed phytase was characterized as active in a pH range of 2.0-9.0 at a temperature range of 20-80 degrees C, with an optimum pH of 5.5-6.5 and temperature of 60 degrees C. When cultured in food-grade milk broth, the transformed L. lactis grew to an OD(600 nm) value of 1.05 and had a phytase yield of 13.58 U/mL. In same broth under optimized conditions for cell growth and phytase production, the transformant reached an OD(600 nm) value of 1.68 and a phytase yield of 42.12 U/mL, representing approximately 1.6-fold and 3.1-fold increases, respectively, compared to growth in natural milk broth. Fermentation was scaled to 5 L under optimized conditions, and product analysis revealed a final OD(600 nm) value of 1.89 and an extracellular enzyme activity of 24.23 U/mL. The results of this study may be used in the dairy fermentation industry for the development of functional, healthy yogurts and other fermented dairy foods that provide both active phytase and viable probiotics to the consumer. PMID- 23453855 TI - Molecular diagnosis of congenital muscular dystrophies with defective glycosylation of alpha-dystroglycan using next-generation sequencing technology. AB - Targeted resequencing using next-generation sequencing technology is being rapidly applied to the molecular diagnosis of human genetic diseases. The group of muscular dystrophies may be an appropriate candidate for this approach because these diseases exhibit genotype-phenotype heterogeneity. To perform a proof-of concept study, we selected four patients with congenital muscular dystrophies with defective glycosylation of alpha-dystroglycan. A custom-solution-based target enrichment kit was designed to capture whole-genic regions of the 26 muscular-dystrophy-related genes, including six genes implicated in alpha dystroglycanopathies. Although approximately 95% of both coding and noncoding regions were covered with at least 15-read depth, parts of the coding exons of FKRP and POMT2 were insufficiently covered. Homozygous and compound heterozygous POMGnT1 mutations were found in two patients. Two novel noncoding variants of FKTN were identified in one patient who had a retrotransposon insertion mutation of FKTN in only one allele. The current targeted resequencing strategy yielded promising results for the extension of this method to other muscular dystrophies. As suboptimal coverage in a small subset of coding regions may affect the sensitivity of the method, complementary Sanger sequencing may be required. PMID- 23453856 TI - Novel SNP array analysis and exome sequencing detect a homozygous exon 7 deletion of MEGF10 causing early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). AB - Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) is a myopathic disorder associated with mutations in MEGF10. By novel analysis of SNP array hybridization and exome sequence coverage, we diagnosed a 10-years old girl with EMARDD following identification of a novel homozygous deletion of exon 7 in MEGF10. In contrast to previously reported EMARDD patients, her weakness was more prominent proximally than distally, and involved her legs more than her arms. MRI of her pelvis and thighs showed muscle atrophy and fatty replacement. Ultrasound of several muscle groups revealed dense homogenous increases in echogenicity. Cloning and sequencing of the deletion breakpoint identified features suggesting the mutation arose by fork stalling and template switching. These findings constitute the first genomic deletion causing EMARDD, expand the clinical phenotype, and provide new insight into the pattern and histology of its muscular pathology. PMID- 23453857 TI - Spinal muscular atrophy due to a "de novo" 1.3 Mb deletion: implication for genetic counseling. AB - We report a 3-year-old female with type I spinal muscular atrophy (SMA) born to a young and non-consanguineous couple. The child presented at two months of life with intense muscle weakness affecting predominantly proximal portions of the limbs, especially the legs, muscle hypotonia, fasciculation of the tongue, and severe respiratory muscle involvement. She remained in an intensive care unit with an assisted ventilation system from the fourth month of life. She died at 3 years of age from pulmonary infection. Molecular analysis confirmed the diagnosis of SMA but revealed that only the father was an asymptomatic carrier. Because SMN1 is mapped in a complex region containing repetitive elements due to an inverted duplication of approximately 500 kb, we carry out an SNP array and detected a 1.3 Mb deletion including the SMN1 and SMN2 genes that explain the disease. PMID- 23453858 TI - Illuminating CNS and cognitive issues in myotonic dystrophy: Workshop report. PMID- 23453859 TI - Oculopharyngeal muscular dystrophy as a cause of progression of weakness in antibody positive myasthenia gravis. AB - Many neuromuscular conditions cause bulbar and limb weakness, and when several conditions coexist they present additional diagnostic challenges. Here we describe a case of a 45-year-old woman with antibody positive myasthenia gravis since age 16, who then develops treatment-resistant weakness due to genetically proven oculopharyngeal muscular dystrophy. We conclude that the development of treatment-resistant weakness in myasthenia gravis should spur further work up for other neuromuscular disorders including oculopharyngeal muscular dystrophy. PMID- 23453860 TI - The emerging role of MET/HGF inhibitors in oncology. AB - The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in many tumor types, can occur by multiple mechanisms, and promotes cellular proliferation and metastasis via growth factor receptors and other oncogenic receptor pathways. Thus, MET/HGF inhibition has emerged as targeted anticancer therapies. Preclinically, neoplastic and metastatic phenotypes of several tumor cells, including non-small cell lung cancer, hepatocellular carcinoma, and gastric cancer, were abrogated by MET inhibition. Ongoing clinical development with tivantinib, cabozantinib, onartuzumab, crizotinib, rilotumumab, and ficlatuzumab has shown encouraging results. These trials have established a key role for MET in a variety of tumor types. Evidence is emerging for identification of aberrant MET activity biomarkers and selection of patient subpopulations that may benefit from targeted MET and HGF inhibitor treatment. PMID- 23453862 TI - Treat cancers by targeting survivin: just a dream or future reality? AB - Since the discovery of survivin (BIRC5) as a cancer-related molecule by Grazia Ambrosini and Dario C. Altieri at 1997, our knowledge related to the function of this molecule has been extended from simple apoptosis inhibition to complicated, interlinked processes that involve interference of mitosis, apoptosis, autophagy, and even DNA repair recently. However, despite the growing amount of knowledge related to survivin in the last ten years, the development of survivin inhibitors or survivin-related molecular therapies is surprisingly and relatively slow as compared to other therapeutic inhibitors for cancer treatment. Here, the molecular functions of survivin and the progress of development of survivin targeting therapies are discussed in detail. Functional differences between different survivin-specific inhibitors are discussed from both structural and biochemical point of views. This review also reveals different challenges that scientists are currently facing in the development of survivin inhibitors for clinical application. Finally, future directions for the development of survivin targeted therapies are discussed in this review. PMID- 23453863 TI - How much should be paid for specialised treatment? AB - English health policy has moved towards establishing specialist multi disciplinary teams to care for patients suffering rare or particularly complex conditions. But the healthcare resource groups (HRGs), which form the basis of the prospective payment system for hospitals, do not explicitly account for specialist treatment. There is a risk, then, that hospitals in which specialist teams are based might be financially disadvantaged if patients requiring specialised care are more expensive to treat than others allocated to the same HRG. To assess this we estimate the additional costs associated with receipt of specialised care. We analyse costs for 12,154,599 patients treated in 163 English hospitals in fiscal year 2008/09 according to the type of specialised care received, if any. We account for the distributional features of patient cost data, and estimate ordinary least squares and generalised linear regression models with random effects to isolate what influence the hospital itself has on costs. We find that, for nineteen types of specialised care, patients do not have higher costs than others allocated to the same HRG. However, costs are higher if a patient has cancer, spinal, neurosciences, cystic fibrosis, children's, rheumatology, colorectal or orthopaedic specialised services. Hospitals might be paid a surcharge for providing these forms of specialised care. We also find substantial variation in the average cost of treatment across the hospital sector, due neither to the provision of specialised care nor to other characteristics of each hospital's patients. PMID- 23453861 TI - Systematic review of hypofractionated radiation therapy for prostate cancer. AB - Prostate cancer is the second most prevalent solid tumor diagnosed in men in the United States and Western Europe. Conventionally fractionated external beam radiation therapy (1.8-2.0 Gy/fraction) is an established treatment modality for men in all disease risk groups. Emerging evidence from experimental and clinical studies suggests that the alpha/beta ratio for prostate cancer may be as low as 1.5 Gy, which has prompted investigators around the world to explore moderately hypofractionated radiation therapy (2.1-3.5 Gy/fraction). We review the impetus behind moderate hypofractionation and the current clinical evidence supporting moderate hypofractionated radiation therapy for prostate cancer. Although hypofractionated radiation therapy has many theoretical advantages, there is no clear evidence from prospective, randomized, controlled trials showing that hypofractionated schedules have improved outcomes or lower toxicity than conventionally fractionated regimens. Currently, hypofractionated schedules should only be used in the context of clinical trials. High dose rate brachytherapy and stereotactic body radiation therapy (fraction size 3.5 Gy and greater) are alternative approaches to hypofractionation, but are beyond the scope of this report. PMID- 23453864 TI - Type I spinal arteriovenous fistulae exception: a case for reclassification. AB - OBJECTIVE: Type I spinal arteriovenous lesions represent dorsal dural arteriovenous fistulae with no spinal artery involvement. We report an exception to this and propose dividing Type I lesions into dorsal and ventral categories. METHODS: A 51-year-old patient presented with a partial Brown-Sequard syndrome. An angiogram revealed a spinal arteriovenous fistula, most prominently being fed a radicular artery arising from the right vertebral artery with only ventral venous drainage. RESULTS: This feeder was selected and embolized with onyx, however residual fistula persisted and the patient subsequently underwent microsurgical disconnection. At six-month follow-up, patient motor deficits have resolved and difficulty with proprioception is improving. CONCLUSION: Type I dural arteriovenous fistulae are associated with dorsal venous drainage. Our case demonstrates an exception to this. Recognizing this exception was crucial, because it allowed for simple microsurgical disconnection. We propose that type I dural arteriovenous fistulae be subdivided into ventral and dorsal based on their drainage pattern. This differentiation is critical because lesions with ventral drainage have traditionally been classified as type IV. These lesions have a different treatment method given involvement of spinal arteries. PMID- 23453865 TI - Nuclear organisation and RNAi in fission yeast. AB - Over the last decade, the fission yeast Schizosaccharomyces pombe has been used extensively for investigating RNA interference (RNAi)-mediated heterochromatin assembly. However, only recently have studies begun to shed light on the 3D organisation of chromatin and the RNAi machinery in the fission yeast nucleus. These studies indicate association of repressive and active chromatin with different regions of the nuclear periphery, similar to other model organisms, and clustering of functionally related genomic features. Unexpectedly, RNAi factors were shown to associate with nuclear pores and were implicated in the regulation of genomic features outside of the well-studied heterochromatic regions. Nuclear organisation is likely to contribute to substrate specificity of the RNAi pathway. However, further studies are required to elucidate the exact mechanisms and functional importance of this nuclear organisation. PMID- 23453866 TI - Aged garlic extract with supplement is associated with increase in brown adipose, decrease in white adipose tissue and predict lack of progression in coronary atherosclerosis. AB - BACKGROUND: Aged garlic extract with supplement (AGE-S) significantly reduces coronary artery calcium (CAC). We evaluated the effects of AGE-S on change in white (wEAT) and brown (bEAT) epicardial adipose tissue, homocysteine and CAC. METHODS: Sixty subjects, randomized to a daily capsule of placebo vs. AGE-S inclusive of aged garlic-extract (250 mg) plus vitamin-B12 (100 MUg), folic-acid (300 MUg), vitamin-B6 (12.5mg) and L-arginine (100mg) underwent CAC, wEAT and bEAT measurements at baseline and 12 months. The postcuff deflation temperature rebound index of vascular function was assessed using a reactive-hyperemia procedure. Vascular dysfunction was defined according to the tertiles of temperature-rebound at 1 year of follow-up. CAC progression was defined as an annual-increase in CAC>15%. RESULTS: From baseline to 12 months, there was a strong correlation between increase in wEAT and CAC (r(2)=0.54, p=0.0001). At 1 year, the risks of CAC progression and increased wEAT and homocysteine were significantly lower in AGE-S to placebo (p<0.05). Similarly, bEAT and temperature rebound were significantly higher in AGE-S as compared to placebo (p<0.05). Strong association between increase in temperature-rebound and bEAT/wEAT ratio (r(2)=0.80, p=0.001) was noted, which was more robust in AGE-S. Maximum beneficial effect of AGE-S was noted with increase in bEAT/wEAT ratio, temperature-rebound, and lack of progression of homocysteine and CAC. CONCLUSIONS: AGE-S is associated with increase in bEAT/wEAT ratio, reduction of homocysteine and lack of progression of CAC. Increases in bEAT/wEAT ratio correlated strongly with increases in vascular function measured by temperature rebound and predicted a lack of CAC progression and plaque stabilization in response to AGE-S. PMID- 23453867 TI - The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure. AB - INTRODUCTION: Iron Deficiency (ID) is common in heart failure (HF), and is an independent contributor to mortality and morbidity. We examined whether patients with previously known HF who were recently hospitalized, had previous treatment for ID, were investigated for it at the time of hospitalization, and, if ID was found, were prescribed iron on discharge. METHODS: We examined the records of 76 consecutive patients admitted to our hospital medical wards with a primary diagnosis of HF. RESULTS: Anemia (Hb<12 g/dl) was found in 42/76 patients (55.3%). In 55/76 patients (72.4%) there was no iron workup, in 6 (7.9%) an incomplete iron workup with serum iron, transferrin or ferritin lacking and in 15/76 (19.7%) a complete iron workup. If ID was defined as either a serum ferritin of <100 MUg/l or a serum ferritin of 100-299 MUg/l and a %Transferrin Saturation of <20% it was found in 12/15 (80%) of those with a complete workup; in 9 of 10 (90%) of the anemic patients and in 3 of 5 (60%) of those non-anemic patients. At discharge 11/15 (73.3%) of those with a complete iron workup were given iron, 10 orally and 1 IV. In those 6 with an incomplete workup 2 were started on oral iron (33.3%) and in those without any workup, 1 of 55 (1.8%) was given oral iron. IN CONCLUSIONS: ID is common in hospitalized HF patients but is usually not sought after by physicians at the time of admission. However if detected the physicians usually treated it. PMID- 23453868 TI - Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. AB - BACKGROUND AND OBJECTIVES: Sympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond. RESULTS: Average office BP was 170.8 +/- 16.9/89.2 +/ 12.1 mmHg despite the use of 3.8 +/- 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 +/- 16.0 to 148 +/- 11, 150 +/- 14, and 138 +/- 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment. CONCLUSIONS: RDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD. PMID- 23453869 TI - Hypothermia may attenuate ischemia/reperfusion-induced cardiomyocyte death by reducing autophagy. AB - OBJECTIVE: We sought to assess the effect of therapeutic hypothermia on the autophagy that occurred in ischemia-reperfused (IR) H9c2 cardiomyocytes. METHODS: In control studies, the H9c2 cells at a density of 1 * 10(5) per culture dish in six-well plate were exposed to normoxic culture medium at 37 degrees C for 12h. All assays contained appropriate controls and were performed in triplicate and repeated on three separately initiated cultures. In hypothermia-treated group, the ischemic and hypoxic cells were maintained in a 32 degrees C incubation. The trypan blue exclusion method was used to assess the cell viability. Autophagy was evaluated by determining both the microtubule-associated protein 1 light chain 3 [LC3] levels and punctuate distribution of the autophagic vesicle associated form [LC3-II]. RESULTS: The results were mean +/- standard error of mean of triplicates. The viable cell percentage for control group, IR group, and IR group treated with hypothermia at the start of ischemia, or reperfusion were 100% +/- 9%, 20% +/- 1%, 32% +/- 3%, and 41% +/- 3%, respectively. The cell death in I/R H9c2 cells was positively associated with increased LC3 levels and punctuate distribution of (LC3-II). Mild hypothermia adopted at the start of ischemia or reperfusion significantly reduced both the cell death and the autophagy in H9c2 cells. CONCLUSION: Our data indicate that in H9c2, IR stimulates cell autophagy and causes cell death, which can be attenuated by mild hypothermia. Our results, if further confirmed in vivo, may have important clinical implications during IR injury. PMID- 23453870 TI - Review of epidemiology and management of atrial fibrillation in developing countries. AB - BACKGROUND: Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia. In developing countries, AF is a growing public health problem with the epidemiologic transition from communicable to non-communicable diseases. However, relatively little is known about AF in the developing world. The aim of this review is to examine in developing countries the prevalence, associated medical conditions and management of AF. METHODS: A literature search was conducted via MEDLINE and EMBASE (1990-2012). RESULTS: Seventy studies were included in the review. The prevalence of AF in the general population ranged from 0.03% to 1.25%, while the prevalence of AF in hospital-based studies varied from 0.7% to 55.7%. Prevalence of AF in Africa was lower than in other regions. The most common conditions associated with AF were hypertension (10.3%-71.9%) and valvular heart disease (5.6%-66.3%). The prevalence of stroke in patients with AF ranged from 6.7% to 27%. The utilization of anticoagulants was highly variable (2.7%-72.7%). Approximately half of the patients with AF using warfarin had therapeutic International Normalized Ratios (INR). There was a high prevalence of use of rate control therapies (55.3%-87.3%). CONCLUSIONS: The limited studies available suggest that in the developing world there is a significant prevalence of AF, which is predominantly associated with hypertension and valvular heart disease, and carries a risk of stroke. Highly variable use of anticoagulants may be related to different health care and socioeconomic settings. More studies are needed to improve understanding of the epidemiology and management of AF in developing countries. PMID- 23453871 TI - Long term quality-of-life in patients with bradycardia pacemaker implantation. AB - BACKGROUND: Health-related quality of life (HRQoL) values shortly after pacemaker (PM) implantation for bradycardia have been established, however little is known about long-term HRQoL. METHODS: Using the generic SF-36 and the PM specific Aquarel questionnaire, HRQoL was repeatedly measured during a 7.5 year follow-up period in 881 bradycardia PM recipients included in the large scale nationwide Dutch FOLLOWPACE study. HRQoL over time, corrected for age, gender, diabetes, hypertension, heart failure, cardiovascular disease and AV-synchrony, was assessed with a linear mixed model. RESULTS: Increased scores both on overall SF 36 and on all SF-36 subscales were observed shortly after implantation. Although scores on SF-36 gradually declined over time, scores remained improved over the measured pre-implantation values. Also, scores for almost all subscales remained increased throughout the 7.5 year observation period, except for physical functioning which showed a gradual decline several years after the initial rise. Additionally, higher scores on all Aquarel scales were observed after implantation. Scores on the arrhythmias and chest discomfort subscales improved and remained stable throughout follow-up (FU), whereas the dyspnea at exertion subscale showed a gradual decline during FU to reach pre-implantation values at 5 years. CONCLUSIONS: Increased HRQoL is observed not only shortly after PM implantation, but also after long-term FU. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00135174; http://www.clinicaltrials.gov/ct2/show/NCT00135174. PMID- 23453872 TI - Atrial fibrillation followed by torsade de pointes degenerated into ventricular fibrillation spontaneously terminated and restored sinus rhythm. PMID- 23453873 TI - The contribution of stem cell therapy to skeletal muscle remodeling in heart failure. AB - BACKGROUND: The aim of our study was to investigate whether stem cell (SC) therapy with human amniotic fluid stem cells (hAFS, fetal stem cells) and rat adipose tissue stromal vascular fraction cells-GFP positive cells (rSVC-GFP) was able to produce favorable effects on skeletal muscle (SM) remodeling in a well established rat model of right heart failure (RHF). METHODS: RHF was induced by monocrotaline (MCT) in Sprague-Dawley rats. Three weeks later, four millions of hAFS or rSVC-GFP cells were injected via tail vein. SM remodeling was assessed by Soleus muscle fiber cross sectional area (CSA), myocyte apoptosis, myosin heavy chain (MHC) composition, satellite cells pattern, and SC immunohistochemistry. RESULTS: hAFS and rSVC-GFP injection produced significant SC homing in Soleus (0.68 +/- 1.0 and 0.67 +/- 0.75% respectively), with a 50% differentiation toward smooth muscle and endothelial cells. Pro-inflammatory cytokines were down regulated to levels similar to those of controls. SC-treated (SCT) rats showed increased CSA (p<0.004 vs MCT) similarly to controls with a reshift toward the slow MHC1 isoform. Apoptosis was significantly decreased (11.12.+/- 8.8 cells/mm(3) hAFS and 13.1+7.6 rSVC-GFP) (p<0.001 vs MCT) and similar to controls (5.38 +/- 3.0 cells/mm(3)). RHF rats showed a dramatic reduction of satellite cells(MCT 0.2 +/- 0.06% Pax7 native vs controls 2.60 +/- 2.46%, p<0.001), while SCT induced a repopulation of both native and SC derived satellite cells (p<0.005). CONCLUSIONS: SC treatment led to SM remodeling with satellite cell repopulation, decreased atrophy and apoptosis. Modulation of the cytokine milieu might play a crucial pathophysiological role with a possible scenario for autologous transplantation of SC in pts with CHF myopathy. PMID- 23453874 TI - Histopathology of the great vessels in patients with pulmonary arterial hypertension in association with congenital heart disease: large pulmonary arteries matter too. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is considered primarily a disease of the distal pulmonary arteries whereas little is known on the effect of long-standing pulmonary hypertension on the larger proximal pulmonary arteries. This study aims to investigate the structural changes in the great arteries of adults who developed PAH in association with congenital heart disease (CHD), with severe cases termed Eisenmenger syndrome. METHODS: We performed macroscopic and light microscopy analyses on the great arteries of 10 formalin-fixed human hearts from patients with PAH/CHD and compared them to age-matched healthy controls. A detailed histology grading score was used to assess the severity of medial wall abnormalities. RESULTS: Severe atherosclerotic lesions were found macroscopically in the elastic pulmonary arteries of 4 PAH/CHD specimens and organised thrombi in 3; none were present in the controls. Significant medial wall abnormalities were present in the pulmonary trunk (PT), including fibrosis (80%), and atypical elastic pattern (80%). Cyst-like formations were present in less than one third of patients and were severe in a single case leading to wall rupture. The cumulative PT histology grading score was significantly higher in PAH/CHD cases compared to controls (p<0.0001) and correlated positively with larger PT diameters (rho=0.812, p<0.0001) and the degree of medial wall hypertrophy (rho=0.749, p<0.0001). CONCLUSIONS: Chronic PAH in association with CHD results in marked macroscopic and histological abnormalities in the large pulmonary arteries. These abnormalities are likely to affect haemodynamics and contribute to morbidity and mortality in this cohort. PMID- 23453875 TI - A crosstalk between macroangiopathy and microangiopathy in type 2 diabetes. PMID- 23453876 TI - Reduced heart rate variability and baroreflex sensitivity in normotensive children with repaired coarctation of the aorta. PMID- 23453877 TI - Visceral adiposity and risk of coronary heart disease in relatively lean Chinese adults. AB - BACKGROUND: The hypertriglyceridemic waist phenotype (defined using both elevated waist circumference and triglycerides) and visceral adiposity index (VAI, defined using waist circumference, body mass index, triglycerides, and high-density lipoprotein cholesterol) have been suggested to be inexpensive yet effective markers of visceral (intra-abdominal) obesity and related dysmetabolic state. These markers may be particularly useful to Asian populations who generally have a low body weight but are prone to visceral adiposity. METHODS: We examined associations of the hypertriglyceridemic waist phenotype and VAI with risk of coronary heart disease (CHD) in a nested case-control study conducted within two prospective cohort studies of Chinese adults. We identified 355 incident cases of CHD and 697 controls matched for sex, age, and date and time of baseline sample collection. Anthropometric and lipid measurements were performed and used to define the hypertriglyceridemic waist phenotype and VAI according to published methods. Conditional logistic regression was used to evaluate the associations. RESULTS: Cases had a higher prevalence of the hypertriglyceridemic waist phenotype and higher VAI score than controls in both sexes. Adjusted odds ratios of CHD associated with hypertriglyceridemic waist were 5.18 (95% CI, 2.46-10.9) and 4.63 (2.03-10.5) for women and men, respectively. Adjusted odds ratios of CHD comparing the highest vs. lowest quartile of VAI were 4.44 (95% CI, 2.24-8.82) and 4.23 (1.99-9.00) for women and men, respectively. CONCLUSION: Our study demonstrates, for the first time, that the hypertriglyceridemic waist phenotype and high VAI score are associated with substantially elevated risk of CHD in Chinese men and women. PMID- 23453878 TI - Uric acid levels, even in the normal range, are associated with increased cardiovascular risk: the Guangzhou Biobank Cohort Study. AB - OBJECTIVE: To examine the association between serum uric acid (UA) levels and cardiovascular risk factors in subjects without diabetes or hyperuricemia. METHODS: 6172 women and 2662 men aged 50+ years without diabetes from Phase 1 of the Guangzhou Biobank Cohort Study were included. Data on personal history, physical examination and biochemical parameters were collected. Subjects were categorized by serum UA concentration, and the association between UA levels and cardiovascular risk factors was examined using generalized linear models. RESULTS: In both men and women with normouricemia (UA<420 MUmol/l in men and <360 MUmol/l in women), tertiles of UA levels were adversely associated with body mass index, waist circumference, waist-to-hip ratio, total- and HDL-cholesterol, apolipoprotein A1, systolic and diastolic blood pressures, pulse pressure, fasting plasma glucose and white blood cell count (P value for trend ranged from 0.04 to <0.001), and also consistently associated with metabolic disorders including obesity, hypertension, hypertension treatment, dyslipidemia, waist circumference increased since the age of 18 years and the metabolic syndrome (P value for trend ranged from 0.02 to <0.001). CONCLUSION: Increasing UA levels, even in subjects with normouricemia and without diabetes, were associated with increasing prevalence of cardiovascular risk factors, suggesting that clinically dichotomous definition of hyperuricemia may be inadequate and high-normal value of UA may warn of metabolic disorders. PMID- 23453879 TI - Left ventricular diastolic dysfunction and thromboembolic risk in atrial fibrillation: diastolic dysfunction and thromboembolic risk in AF. PMID- 23453880 TI - Reply: To PMID 23151491. PMID- 23453881 TI - Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System. AB - OBJECTIVE: We characterized reports to the Vaccine Adverse Event (AE) Reporting System (VAERS) of pregnant women who received meningococcal polysaccharide protein conjugate vaccine Menactra (MenACWY-D; Sanofi Pasteur Inc., Swiftwater, PA). STUDY DESIGN: We searched VAERS for reports of pregnant women who received MenACWY-D from Jan. 1, 2005 through Dec. 31, 2011. We conducted clinical review of reports and available medical records. RESULTS: Of 103 identified reports, 38 (36.7%) did not describe any AE. No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 17 (16.5%) reports. Urinary tract infections and fever with vomiting were the most frequent nonpregnancy-specific AEs found in 4 (3.9%) and 3 (2.9%) reports, respectively. We identified 1 report with a major congenital anomaly (aqueductal stenosis and severe ventriculomegaly). CONCLUSION: Our comprehensive review of reports to VAERS in pregnant women after MenACWY-D did not identify any concerning patterns in maternal, infant, or fetal outcomes. PMID- 23453882 TI - The influence of BMI on perioperative morbidity following abdominal hysterectomy. AB - OBJECTIVE: The objective of the study was to assess the impact of body mass index (BMI) on 30 day perioperative morbidity following abdominal hysterectomy. STUDY DESIGN: The 2006-2010 National Surgical Quality Improvement Program data registry was retrospectively reviewed for patients undergoing abdominal hysterectomy. Logistic regression was used to investigate the relationship between BMI and postoperative complications. RESULTS: A total of 9917 patients were captured, of which, 2219 were of an ideal BMI, 2765 were overweight, and 4933 were obese. Complications occurred in 11.3% of the procedures, with obese patients experiencing significantly higher rates of morbidity compared with overweight and nonobese patients (13.2%, 9.7%, and 9.0%, respectively; P < .001). Surgical complications were rare; however, a significant step-wise progression was observed with increasing BMI (P < .001). The rate of reoperations and overall medical complication did not differ among cohorts, although the incidence of deep vein thromboses (DVTs) was notably elevated in obese and overweight patients (P = .032). Adjusted odds ratios (ORs) found both overweight and obese patients to be at a significantly higher risk of surgical complications (OR, 1.6 and 3.0, respectively) and wound infections (OR, 1.7 and 3.0, respectively). Overweight patients were also at higher risk for DVTs (OR, 4.6) and obese patients for overall morbidity (OR, 1.4) and wound disruption (OR, 3.6). CONCLUSION: Obese and overweight patients demonstrated an increased risk for periorperative morbidity following abdominal hysterectomies. PMID- 23453883 TI - Planned home birth: the professional response. PMID- 23453884 TI - Qualitative and quantitative measures of various compounded formulations of 17 alpha hydroxyprogesterone caproate. AB - OBJECTIVE: 17-alpha hydroxyprogesterone caproate (17-OHPC) is available both as an Food and Drug Administration (FDA)-approved medication and as a product prepared for individual patients by compounding pharmacies. Compounding pharmacies may omit the preservative that is used in the FDA-approved formulation or use an alternate preservative and may dispense 17-OHPC in containers that differ from the FDA-approved product. The objective of this study was to assess the stability and the microbiologic and pyrogen status of 17-OHPC formulations under various compounding and dispensing conditions. STUDY DESIGN: 17-OHPC was prepared by a local compounding pharmacy. The formulations that were prepared included 1 identical to the FDA-approved product with benzyl alcohol as a preservative, 1 with benzalkonium chloride as a preservative, and 1 without a preservative. These various formulations were dispensed into either single-dose 1 mL plastic syringes or glass vials or 10-mL glass vials. The concentration of 17 OHPC and microbial and pyrogen status were evaluated at various time intervals over the ensuing 19 weeks. RESULTS: The concentration of 17-OHPC did not change over the duration of study, regardless of the dispensing medium that was used or the absence or presence of any preservatives. The preparations remained microbe- and pyrogen-free during the study period, regardless of the dispensing medium that was used or the absence of presence of any preservatives. CONCLUSION: Products that contained 17-OHPC tested in this study were quite stable over the 19-week period of study in different dispensing containers and in the absence or presence of a different preservative. The compounded products remained sterile and pyrogen-free during the period of observation. PMID- 23453886 TI - Shared genetics among major psychiatric disorders. PMID- 23453885 TI - Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. AB - BACKGROUND: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5*10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. INTERPRETATION: Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. FUNDING: National Institute of Mental Health. PMID- 23453888 TI - Illness perceptions in IBD influence psychological status, sexual health and satisfaction, body image and relational functioning: A preliminary exploration using Structural Equation Modeling. AB - BACKGROUND AND AIMS: This study aimed to characterize the relationships between illness perceptions, body image and self-consciousness, sexual health (sexual problems and sexual satisfaction), anxiety and depression, and marital and family functioning in patients with IBD. METHODS: Seventy-four IBD patients (44 CD, 13 males, 61 females, mean age 38 years) completed an online questionnaire. Illness perceptions explored with the Brief Illness Perceptions Questionnaire, and anxiety and depression measured using the Hospital Anxiety and Depression Scale, Sexual Problems Scale, Sexual Satisfaction Scale, Marital Functioning Scale, Family Functioning Scale, and Body Image and Self-Consciousness During Intimacy Scale. RESULTS: Exploratory Structural Equation Modeling (SEM) provided a final model with an excellent fit (chi(2) (25)=27.84, p=.32, chi(2)/N=1.11, CFI>0.99, RMSEA<0.04, SRMR<0.07, GFI>0.93). Illness perceptions had a significant direct influence on depression (beta=0.49, p<0.001), anxiety (beta=0.55, p<0.001), and family functioning (beta=-0.17, p<0.001). Several mediating pathways were also found involving sexual problems, sexual satisfaction, and body image and self consciousness during intimacy. Being female was associated with increased sexual problems but increased sexual satisfaction. CONCLUSIONS: The findings provide further evidence for the adverse impact of patient IBD-related illness perceptions on anxiety and depression. The findings also provide the preliminary evidence for the impact of illness perceptions and psychological comorbidity in relation to sexual health and relationship and family functioning. These aspects of psychological processing provide a framework and direction for further research into the nature of IBD and its influence on the patient and their family. PMID- 23453889 TI - Future seagrass beds: can increased productivity lead to increased carbon storage? AB - While carbon capture and storage (CCS) is increasingly recognised as technologically possible, recent evidence from deep-sea CCS activities suggests that leakage from reservoirs may result in highly CO2 impacted biological communities. In contrast, shallow marine waters have higher primary productivity which may partially mitigate this leakage. We used natural CO2 seeps in shallow marine waters to assess if increased benthic primary productivity could capture and store CO2 leakage in areas targeted for CCS. We found that the productivity of seagrass communities (in situ, using natural CO2 seeps) and two individual species (ex situ, Cymodocea serrulata and Halophila ovalis) increased with CO2 concentration, but only species with dense belowground biomass increased in abundance (e.g. C. serrulata). Importantly, the ratio of below:above ground biomass of seagrass communities increased fivefold, making seagrass good candidates to partially mitigate CO2 leakage from sub-seabed reservoirs, since they form carbon sinks that can be buried for millennia. PMID- 23453887 TI - Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease. AB - The clinical introduction of tumour necrosis factor (TNF) inhibitors has deeply changed the treatment of inflammatory bowel diseases (IBD). It has demonstrated impressive efficacy as compared to alternative treatments, allowing for the chance to achieve near-remission and long-term improvement in function and quality of life and to alter the natural history of Crohn's disease (CD) and ulcerative colitis (UC). As a consequence of longer follow-up periods the number of side effects which may be attributed to treatment with biologics is growing significantly. Cutaneous reactions are among the most common adverse reactions. These complications include injection site reactions, cutaneous infections, immune-mediated complications such as psoriasis and lupus-like syndrome and rarely skin cancers. We review the recent literature and draw attention to dermatological side effects of anti-TNF therapy of inflammatory bowel disease. PMID- 23453890 TI - Effect of deep brain stimulation of the subthalamic nucleus on non-motor fluctuations in Parkinson's disease: two-years' follow-up. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) reduces motor fluctuations in Parkinson's disease (PD) but its effect on non-motor fluctuations (NMF) is not well known. In this study we assess the efficacy of STN DBS on NMF two years after surgery. METHODS: Autonomic, cognitive, psychiatric and sensory NMF in 20 patients were evaluated using a questionnaire designed to assess the frequency and severity of the NMF preoperatively and after two years of follow-up. The UPDRS scale was used for assessing the motor state. RESULTS: Compared with the preoperative situation, STN-DBS at 2 years of follow-up was associated with a significant reduction in the number and severity of autonomic and psychiatric NMF in the "off" state (without medication), and in the severity of sensory NMF, which were not observed in the "on" state (with medication). A cross-sectional analysis at the two-year time-point of the four possible motor conditions (combining medication and stimulation) showed a reduction in the total number of NMF and in the severity of autonomic and sensory NMF after switching on the stimulation in the "on" state. Improvement of the UPDRS-motor score was correlated with a reduction in the severity but not in the frequency of NMF. A worsening of motor function after suppressing stimulation in the "off" state was not paralleled by a worsening of NMF. CONCLUSION: After two years of follow-up, STN-DBS in the "off" medication was associated with a reduction in the frequency and severity of NMF. These results will need to be confirmed in controlled studies. PMID- 23453891 TI - Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery. AB - In advanced Parkinson's disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barre syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high dose oral levodopa. PMID- 23453892 TI - Estimating the costs of tsetse control options: an example for Uganda. AB - Decision-making and financial planning for tsetse control is complex, with a particularly wide range of choices to be made on location, timing, strategy and methods. This paper presents full cost estimates for eliminating or continuously controlling tsetse in a hypothetical area of 10,000km(2) located in south-eastern Uganda. Four tsetse control techniques were analysed: (i) artificial baits (insecticide-treated traps/targets), (ii) insecticide-treated cattle (ITC), (iii) aerial spraying using the sequential aerosol technique (SAT) and (iv) the addition of the sterile insect technique (SIT) to the insecticide-based methods (i-iii). For the creation of fly-free zones and using a 10% discount rate, the field costs per km(2) came to US$283 for traps (4 traps per km(2)), US$30 for ITC (5 treated cattle per km(2) using restricted application), US$380 for SAT and US$758 for adding SIT. The inclusion of entomological and other preliminary studies plus administrative overheads adds substantially to the overall cost, so that the total costs become US$482 for traps, US$220 for ITC, US$552 for SAT and US$993 - 1365 if SIT is added following suppression using another method. These basic costs would apply to trouble-free operations dealing with isolated tsetse populations. Estimates were also made for non-isolated populations, allowing for a barrier covering 10% of the intervention area, maintained for 3 years. Where traps were used as a barrier, the total cost of elimination increased by between 29% and 57% and for ITC barriers the increase was between 12% and 30%. In the case of continuous tsetse control operations, costs were estimated over a 20-year period and discounted at 10%. Total costs per km(2) came to US$368 for ITC, US$2114 for traps, all deployed continuously, and US$2442 for SAT applied at 3 year intervals. The lower costs compared favourably with the regular treatment of cattle with prophylactic trypanocides (US$3862 per km(2) assuming four doses per annum at 45 cattle per km(2)). Throughout the study, sensitivity analyses were conducted to explore the impact on cost estimates of different densities of ITC and traps, costs of baseline studies and discount rates. The present analysis highlights the cost differentials between the different intervention techniques, whilst attesting to the significant progress made over the years in reducing field costs. Results indicate that continuous control activities can be cost effective in reducing tsetse populations, especially where the creation of fly free zones is challenging and reinvasion pressure high. PMID- 23453893 TI - Analysis of climatic and environmental variables associated with the occurrence of West Nile virus in Morocco. AB - West Nile disease (WND) is one of the most widespread mosquito-borne infectious diseases in the World. In Morocco the first WND cases were reported in equines in 1996. After an apparent epidemiological silence, WND re-occurred in 2003 and in 2010, when the disease was reported in equines living in the central and north western part of the country. Eco-climatic variables are known to influence the mosquito presence and abundance and, therefore, the probability of occurrence of mosquito-borne infections. The remote sensed values of Land Surface Temperature (LST), Normalised Difference Vegetation Index (NDVI) and rainfall registered from 2001 to 2010 were evaluated for a possible association with the occurrence of WND cases in 2003 and in 2010. In the zones where WND cases occurred, NDVI values recorded in 2003 and 2010, from June to November, were significantly higher than those registered during the same months in the rest of the decade. Rainfall data showed higher peaks in 2003 and 2010, when the number of days with extreme rainfall was significantly higher during 1-2 months before the occurrence of WND cases. Temperature does not seem to play an important role in Moroccan epidemiological conditions. PMID- 23453894 TI - Bayesian Graphical modelling: applications in veterinary epidemiology. PMID- 23453895 TI - Analysis of a knotless flexor tendon repair using a multifilament stainless steel cable-crimp system. AB - PURPOSE: To compare the biomechanical and technical properties of flexor tendon repairs using a 4-strand cruciate FiberWire (FW) repair and a 2-strand multifilament stainless steel (MFSS) single cross-lock cable-crimp system. METHODS: Eight tests were conducted for each type of repair using cadaver hand flexor digitorum profundus tendons. We measured the required surgical exposure, repair time, and force of flexion (friction) with a custom motor system with an inline load cell and measured ultimate tensile strength (UTS) and 2-mm gap force on a servo-hydraulic testing machine. RESULTS: Repair time averaged less than 7 minutes for the 2-strand MFSS cable crimp repairs and 12 minutes for the FW repairs. The FW repair was performed with 2 cm of exposure and removal of the C-1 and A-3 pulleys. The C-1 and A-3 pulleys were retained in each of the MFSS cable crimp repairs with less than 1 cm of exposure. Following the FW repair, the average increase in friction was 89% compared with an average of 53% for the MFSS repairs. Six of the 8 MFSS specimens achieved the UTS before any gap had occurred, whereas all of the FW repairs had more than 2 mm of gap before the UTS, indicating that the MFSS was a stiffer repair. The average UTS appeared similar for both groups. CONCLUSIONS: We describe a 2-strand multifilament stainless steel single cross-lock cable crimp flexor repair system. In our studies of this cable crimp system, we found that surgical exposure, average repair times, and friction were reduced compared to the traditional 4-strand cruciate FW repair. While demonstrating these benefits, the crimp repair also produced a stiff construct and high UTS and 2-mm gap force. CLINICAL RELEVANCE: A cable crimp flexor tendon repair may offer an attractive alternative to current repair methods. The benefits may be important especially for flexor tendon repair in zone 2 or for the repair of multiple tendons. PMID- 23453896 TI - A comparison of the long-term outcome of partial articular (AO Type B) and complete articular (AO Type C) distal radius fractures. AB - PURPOSE: A short-term comparison of AO type B (shearing) and type C (compression) articular fractures of the distal radius found no significant differences in functional outcome, but long-term studies would provide important information. We tested the null hypothesis that there is no difference in arm-specific disability between patients with type B and C fractures in long-term follow-up. METHODS: We evaluated 46 patients (17 with type B fractures and 29 patients with 31 type C fractures of the distal radius) with a mean age of 39 years at the time of injury at a mean of 20 years after operative treatment. We used the Disabilities of the Arm, Shoulder, and Hand questionnaire and 2 physician-based rating systems, the modified Mayo wrist score and the modified Gartland and Werley score. We performed bivariate and multivariable analyses to identify the factors that contributed most to the variation in these scores. RESULTS: There were no significant differences between patients with type B and C fractures on the Disabilities of the Arm, Shoulder, and Hand, modified Mayo wrist, or Gartland and Werley scores, or with respect to range of motion, grip strength, and arthrosis. The only statistical difference was in volar tilt of the articular surface on lateral radiographs. CONCLUSIONS: On average, patients undergoing operative treatment of type B and type C articular fractures of the distal radius have similar impairment, symptoms, and disability in the long-term. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 23453897 TI - Macrodactyly in the setting of a plexiform schwannoma in neurofibromatosis type 2: case report. AB - Macrodactyly is a rare anomaly. Little is understood about the etiology and underlying mechanisms. To our knowledge, macrodactyly has not previously been associated with neurofibromatosis type 2. We present a case of macrodactyly of the small finger associated with a digital nerve plexiform schwannoma in a patient with neurofibromatosis type 2. PMID- 23453898 TI - Proximal interphalangeal joint injection through a volar approach: anatomic feasibility and cadaveric assessment of success. AB - PURPOSE: The proximal interphalangeal (PIP) joint is a challenging joint to access reliably for corticosteroid injection. Literature has confirmed both a relatively high failure rate for injections performed with the traditional dorsal approach and an improved clinical response rate for confirmed intra-articular injections. We describe a technique for injecting the PIP joint through a volar approach, assess its reliability through cadaveric dissection, and determine its reproducibility by comparing success rates with the dorsal approach in a cadaver model. METHODS: We dissected the PIP joint of 10 cadaveric digits to document necessary anatomic landmarks for this technique. We then used 20 matched pairs of cadaver hands for the remainder of our study. Four PIP joints on each hand (thumb excluded) were injected with a solution of saline and radio-opaque dye using the dorsal approach. We injected each joint on the contralateral matched hand through the volar approach. We obtained standardized fluoroscopic images of each joint immediately after injection, which were reviewed by an independent observer who was blinded to the technique and who rated outcomes as success, failure, or mixed. Success rates were evaluated based on approach used, digit injected, and degree of pre-existing arthritis. RESULTS: We found reproducible anatomic landmarks that justified our injection technique. The rates of absolute failure were similar in the 2 cohorts. The volar approach demonstrated a higher percentage of successful injections with a smaller percentage of mixed results, although results did not reach statistical significance. There was no statistically significant difference in success rates based on digit injected or grade of arthritis in either cohort. CONCLUSIONS: The volar approach to injecting the PIP joint demonstrated success similar to that of the traditional dorsal approach. Reproducible surface landmarks exist to guide practitioners using this technique. Further study is needed to determine the potential complications and clinical outcomes of the volar approach. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23453901 TI - Parental contributions to the transcriptome of early plant embryos. AB - In plants and animals, embryo development becomes ultimately controlled by zygotic genes, but the timing of zygotic genome activation (ZGA) varies greatly between organisms. We recently showed that the transcriptome of young Arabidopsis embryos is dominated by maternal transcripts with a progressive ZGA under the maternal control of epigenetic pathways. In contrast, another study reported that both parental genomes contribute equally to the transcriptome of young embryos, suggesting that ZGA occurs immediately after fertilization. How to explain such dramatic differences? We propose that the discrepancies between these two studies likely reflect genuine biological differences between the two experiments, paving the road towards exciting discoveries on ZGA mechanisms in plants. PMID- 23453899 TI - Adjuvant pegylated liposomal doxorubicin for older women with endocrine nonresponsive breast cancer who are NOT suitable for a "standard chemotherapy regimen": the CASA randomized trial. AB - There is no optimal treatment for breast cancers lacking estrogen (ER) and progesterone (PgR) receptors in elderly women with co-morbidities that prevent use of "standard chemotherapy regimens" such as AC or CMF. The CASA trial studied pegylated liposomal doxorubicin (PLD) and low dose, metronomic cyclophosphamide + methotrexate (CM) for older (>65), vulnerable women with operable, ER and PgR negative breast cancer. After two years the trial closed early, due to slow and inadequate accrual, with 77 patients (38:PLD, 36:CM, 3:nil). Sixty-eight percent completed PLD; 83% completed CM (both 16 weeks). Patients on PLD reported worse quality of life, cognitive and physical functioning than non-PLD regimens (primarily CM). At a median follow-up of 42 months, 81% of randomized patients remained free of any breast cancer recurrence. Based on our limited experience, PLD and CM may be reasonable options for further study for elderly vulnerable patients with endocrine nonresponsive breast cancer. PMID- 23453903 TI - Absence of rapid eye movement sleep with hypnopompic visual hallucinations: a possible harbinger of dementia with Lewy bodies? PMID- 23453900 TI - MicroRNAs in the ionizing radiation response and in radiotherapy. AB - Radiotherapy is a form of cancer treatment that utilizes the ability of ionizing radiation to induce cell inactivation and cell death, generally via inflicting DNA double-strand breaks. However, different tumors and their normal surrounding tissues are not equally sensitive to radiation, posing a major challenge in the field: to seek out factors that influence radiosensitivity. In this review, we summarize the evidence for microRNA (miRNA) involvement in the radioresponse and discuss their potential as radiosensitizers. MicroRNAs are endogenous small, noncoding RNAs that regulate gene expression posttranscriptionally, influencing many processes including, as highlighted here, cellular sensitivity to radiation. Profiling studies demonstrate that miRNA expression levels change in response to radiation, while certain miRNAs, when overexpressed or knocked down, alter radiosensitivity. Finally, we discuss specific miRNA-target pairs that affect response to radiation and DNA damage as good potential targets for modulating radioresponsitivity. PMID- 23453904 TI - Snake: the development and validation of a questionnaire on sleep disturbances in children with severe psychomotor impairment. AB - OBJECTIVE: Sleep disturbance and daytime restlessness are present in 50% to 80% of children with severe psychomotor impairment due to neurologic or other complex diseases. Although these issues severely impair the quality of life of the children and their families, they are not well addressed or managed by professionals. The lack of validated assessment tools prevents further research and the development of adequate therapies. Our aim is to develop and validate a sleep questionnaire for these children that could be used both for clinical management and systematic research. METHODS: The sleep questionnaire for children with severe psychomotor impairment (Schlaffragebogen fur Kinder mit Neurologischen und Anderen Komplexen Erkrankungen, SNAKE) is based on expert opinion and consultation with parents. The psychometric quality of the questionnaire was assessed in a sample of 224 children with severe psychomotor impairment. RESULTS: Confirmative factor analysis showed that SNAKE comprises of five factors (based on ICSD-2). Fit indices, analysis of item characteristics and convergent validity (coherence with measures of sleep [i.e., sleep efficiency]) and correlation with selected subscales of the Sleep Disturbance Scale for Children (SDSC) were good. Re-test analysis (n=62) depicted high stability and good replication of validity. CONCLUSIONS: SNAKE is a reliable and valid tool for the diagnosis of sleep disturbances in children with severe psychomotor impairment. The SNAKE questionnaire is the first tool that addresses the specific relationship between sleep disturbance and severe disability in children. PMID- 23453905 TI - Trilevel adaptive servoventilation for the treatment of central and mixed sleep apnea in chronic heart failure patients. AB - BACKGROUND: Sleep-disordered breathing (SDB) in patients with heart failure (HF) is of major prognostic impact, though treatment of simultaneously occurring central and mixed apnea events is challenging. The objective was to examine long term effects of a new trilevel adaptive servoventilation (ASV) therapy in patients with systolic or diastolic HF. METHODS: A total of 45 consecutive patients with a history of HF, elevated N-terminal prohormone of brain natriuretic peptide levels, objective signs of cardiac dysfunction, and moderate to severe SDB (apnea-hypopnea index [AHI] > or =15/h) with combined central and mixed respiratory events were included in this study and ASV therapy (SOMNOvent CR, Weinmann) was offered. RESULTS: In 38 patients (84%), ASV therapy was successfully initiated, with 23 (51%) patients showing appropriate compliance (device use > or = 4 h/night for > or = 5d/w) after 3.6+/-1.2 months. In these patients ASV therapy and HF status were re-evaluated. A sustained reduction was achieved in AHI (42.8+/-17.5/h vs 8.9+/-5.8/h; p<0.001) and oxygen saturation. Improvements also were recorded in New York Heart Association (NYHA) functional class (2.4+/-0.5-1.9+/-0.4; p<0.001) and oxygen uptake during cardiopulmonary exercise testing (VO2 peak, 13.64+/-3.5-15.8+/-5.8 ml/kg/min; p<0.002). CONCLUSION: In selected HF patients, trilevel ASV therapy is able to treat SDB with combined central and mixed respiratory events. This treatment is associated with an improvement in HF symptoms and objective cardiopulmonary performance. PMID- 23453906 TI - How animal models of leukaemias have already benefited patients. AB - The relative genetic simplicity of leukaemias, the development of which likely relies on a limited number of initiating events has made them ideal for disease modelling, particularly in the mouse. Animal models provide incomparable insights into the mechanisms of leukaemia development and allow exploration of the molecular pillars of disease maintenance, an aspect often biased in cell lines or ex vivo systems. Several of these models, which faithfully recapitulate the characteristics of the human disease, have been used for pre-clinical purposes and have been instrumental in predicting therapy response in patients. We plea for a wider use of genetically defined animal models in the design of clinical trials, with a particular focus on reassessment of existing cancer or non-cancer drugs, alone or in combination. PMID- 23453907 TI - Does postacute care site matter? A longitudinal study assessing functional recovery after a stroke. AB - Patients with stroke may receive postacute rehabilitation services from one or more types of postacute care providers. An article in this issue of Archives of Physical Medicine and Rehabilitation compares the outcomes of patients who received rehabilitation care from an inpatient rehabilitation facility, a skilled nursing facility, a home health agency, or did not receive any postacute care. This commentary discusses challenges in conducting this type of observation study. PMID- 23453909 TI - Purification, cDNA cloning and recombinant protein expression of a phloem lectin like anti-insect defense protein BPLP from the phloem exudate of the wax gourd, Benincasa hispida. AB - Latex and other exudates in plants contain various proteins that are thought to play important defensive roles against herbivorous insects and pathogens. Herein, the defensive effects of phloem exudates against the Eri silkworm, Samia ricini (Saturniidae, Lepidoptera) in several cucurbitaceous plants were investigated. It was found that phloem exudates are responsible for the defensive activities of cucurbitaceous plants, such as the wax gourd Benincasa hispida and Cucumis melo, especially in B. hispida, whose leaves showed the strongest growth-inhibitory activity of all the cucurbitaceous plants tested. A 35 kDa proteinaceous growth inhibitory factor against insects designated BPLP (B. hispida Phloem Lectin-like Protein) was next isolated and purified from the B. hispida exudate, using anion exchange and gel filtration chromatography. A very low concentration (70 MUg/g) of BPLP significantly inhibited growth of S. ricini larvae. The full-length cDNA (1076 bp) encoding BPLP was cloned and its nucleotide sequence was determined. The deduced amino acid sequence of BPLP had 51% identity with a cucurbitaceous phloem lectin (phloem protein 2, PP2), and showed binding specificity to oligomers of N-acetylglucosamine. Some features of BPLP indicated that it does not have a cysteine residue and it is composed of two repeats of similar sequences, suggesting that BPLP is distinct from PP2. Recombinant BPLP, obtained by expressing the cDNA in Escherichia coli, showed both chitin-binding lectin activity and growth-inhibitory activity against S. ricini larvae. The present study thus provides experimental evidence that phloem exudates of Cucurbitaceae plants, analogous to plant latex, play defensive roles against insect herbivores, especially against chewing insects, and contain defensive substances toxic to them. PMID- 23453910 TI - Minor C-geranylated flavanones from Paulownia tomentosa fruits with MRSA antibacterial activity. AB - Exhaustive chromatographic separation of the chloroform portion of the ethanolic extract obtained from Paulownia tomentosa (Thunb). Steud. (Paulowniaceae) fruits has led to isolation of ten C-6 geranylated flavanones tomentodiplacone C-I and mimulone C-E, featured by 3'-methoxy and 4'-hydroxy or 4'-hydroxy substitution of the B-ring of the flavonoid, respectively. The structures of these compounds were determined by using mass spectrometry (including HRMS) and 1D and 2D NMR spectroscopy. The absolute configurations of the compounds at C-2 were determined using circular dichroism. The obtained compounds showed the presence of a geranyl moiety functionalized by a carbonyl, hydroxyl or methoxyl group, or by formation of tetrahydrofuran or fused-pyrane ring, respectively. All of the flavanones described were isolated for the first time from a natural source. The antibacterial activities of selected compounds isolated along with the previously isolated geranylated flavanones were evaluated against a common panel of microbes and MRSA strains. The selected isolated compounds were tested for their ability to affect eukaryotic translation initiation via dual-luciferase reporter assay (firefly and renilla). PMID- 23453908 TI - Cortical plasticity and preserved function in early blindness. AB - The "neural Darwinism" theory predicts that when one sensory modality is lacking, as in congenital blindness, the target structures are taken over by the afferent inputs from other senses that will promote and control their functional maturation (Edelman, 1993). This view receives support from both cross-modal plasticity experiments in animal models and functional imaging studies in man, which are presented here. PMID- 23453911 TI - Leishmanicidal activity of Cecropia pachystachya flavonoids: arginase inhibition and altered mitochondrial DNA arrangement. AB - The plant Cecropia pachystachya Trecul is widely used in Brazilian ethnomedicine to treat hypertension, asthma, and diabetes. Arginase is an enzyme with levels that are elevated in these disorders, and it is central to Leishmania polyamine biosynthesis. The aims of this study were to evaluate antileishmanial activity and inhibition of the arginase enzyme by C. pachystachya extracts, and to study changes in cellular organization using electron microscopy. The ethanol extract of C. pachystachya was tested on Leishmania (Leishmania) amazonensis promastigote survival/proliferation and arginase activity in vitro. Qualitative ultrastructural analysis was also used to observe changes in cell organization. The major bioactive molecules of the ethanol extract were characterized using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). The ethyl acetate fraction of the ethanol extract diminished promastigote axenic growth/survival, inhibited arginase activity, and altered a mitochondrial kinetoplast DNA (K-DNA) array. The bioactive compounds of C. pachystachya were characterized as glucoside flavonoids. Orientin (9) (luteolin-8-C-glucoside) was the main component of the methanol-soluble ethyl acetate fraction obtained from the ethanol extract and is an arginase inhibitor (IC50 15.9 MUM). The ethyl acetate fraction was not cytotoxic to splenocytes at a concentration of 200 MUg/mL. In conclusion, C. pachystachya contains bioactive compounds that reduce the growth of L. (L.) amazonensis promastigotes, altering mitochondrial K-DNA arrangement and inhibiting arginase. PMID- 23453912 TI - Material costs of anterior cruciate ligament reconstruction with hamstring tendons by two different techniques. AB - INTRODUCTION: In France, approximately 36,000 anterior cruciate ligament (ACL) reconstruction surgical procedures are performed every year. Technical progress, in particular arthroscopy, has made surgery more precise, but more expensive. In a context of healthcare cost containment, the increase in the cost of technology must be compared to the improved outcome for the patients. The main aim of this study was to determine all material costs related to ACL reconstruction using hamstring tendons. This study also compared the material costs between the two arthroscopic techniques: standard or "all-inside". MATERIALS AND METHODS: A retrospective study of material costs was performed in 2011. With the standard technique, the tibial tunnel was drilled from outside to inside, while with the all-inside technique two tunnels were drilled from inside to outside. All of the material used from the first swab to the final bandage was reported. It was classified into three categories: reusable arthroscopy material, disposable arthroscopic material, and disposable surgical supplies. The costs were those of our supplier in 2011 (ArthrexTM) and based on Public Hospitals of Paris (AP-HP) public contract tariffs. RESULTS: Standard ligament reconstruction was less expensive than the all-inside technique: 791.59? versus 931.06? excluding taxes (hors taxes [HT]), respectively. The largest percentage of expenses was allocated to disposable material use (81 and 84%). DISCUSSION: Possible avenues of savings are limited: all the material used was necessary. To control costs, correct use and good maintenance of instruments are the most important elements. LEVEL OF EVIDENCE: Level IV. Economic and decision analyses, retrospective study. PMID- 23453913 TI - Outcomes of anterior lumbar interbody fusion in low-grade isthmic spondylolisthesis in adults: a continuous series of 65 cases with an average follow-up of 6.6 years. AB - INTRODUCTION: Surgical treatment of isthmic spondylolisthesis continues to be controversial. The fusion procedure can either be instrumented using a posterior and/or anterior approach or non-instrumented. The role of associated decompression, reduction of the slippage, disc height restoration and lordosis restoration has not definitely been established. The goal of this study was to evaluate the efficacy of anterior approach for interbody fusion (ALIF) without any reduction maneuver. MATERIALS AND METHODS: Sixty-five patients with isthmic spondylolisthesis were operated on, using an ALIF. The average patient age was 40 years. The preoperative maximum walking time was 20 minutes. Ten patients had radiculopathy. The average preoperative Beaujon Hospital disability index was 9/20. Standard static and dynamic X-rays were evaluated in all patients; a CT scan was performed in 33 patients 1 year after the surgery. The olisthetic vertebra had slipped by an average of 12 mm. Thirty-five of the spondylolisthesis cases had abnormal vertebral motion. RESULTS: At an average follow-up of 6.6 years, lumbar pain and radicular pain had been reduced by 4.6 and 5 points on the visual analogue scale, respectively. Twenty-seven patients could walk for an unlimited amount of time. Three patients still had radiculopathy. The Beaujon Hospital disability index had improved by an average of 7.3 points. The fusion rate was 91%. The slippage had decreased by 30%, despite no specific reduction maneuvers at the time of surgery. The disc height had increased by 177%. On the sagittal plane, lordosis had improved by 5 degrees , without any changes in the pelvic parameters. CONCLUSION: In situ ALIF provides results that are comparable to those obtained with other techniques. This study confirms the essential role of fusion in achieving good functional results, given that hypermobility of the olisthetic level contributes to the symptoms generation. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23453914 TI - Treatment of distal humerus fractures with LCP DHPTM locking plates in patients older than 65 years. AB - INTRODUCTION: Fractures of the distal humerus are often complex and therefore challenging to treat. In elderly patients with decreased bone strength due to osteoporosis, strong fixation is crucial to allow resuming early motion that guarantees a good functional outcome as well as minimising mechanical complications. Locked implants meet these requirements. Here, we report outcomes in a uniform series of patients older than 65 years with distal humerus fractures managed with LCP DHP((r)) (Synthes) fixation. Our objective was to evaluate the efficacy and limitations of this technique. HYPOTHESIS: LCP DHP provides strong fixation of osteoporotic bone and leads to good clinical and radiological outcomes. MATERIALS AND METHODS: We retrospectively studied 46 consecutive patients (2004-2010) with a mean age of 80 years including 15 with extra articular and 31 with articular distal humerus fractures. At presentation, 11 complications were noted in nine patients (compound fractures and trauma-related nerve injuries). The transolecranon approach was used in 31 patients. Mean duration of immobilisation was 2.7 weeks in 33 patients. RESULTS: Forty-three patients were re-evaluated after a mean follow-up of 25 months (range, 10-64 months); two patients died and one was lost to follow-up. Flexion was 127 degrees and loss of extension was 23 degrees , producing an average range of motion of 104 degrees . Functional recovery was highly satisfactory with a Mayo Clinic Performance Score of 87 (70-100) and 95% of good and very good results. Postoperative complications consisted of infection (n=3), metaphyseal non-union (n=2), ulnar nerve injury (n=6), transient radial nerve palsy (n=1), and peri articular ossification (n=4). Compound fracture and worse AO fracture type were associated with worse functional outcomes. DISCUSSION: Despite the high complication rate, functional recovery was similar to that reported in previous case series, including after arthroplasty. Furthermore, the rate of mechanical complications was lower. Thus, our working hypothesis was confirmed. LEVEL OF EVIDENCE: Level IV retrospective non-comparative study. PMID- 23453915 TI - Comparison between percutaneous and traditional fixation of lumbar spine fracture: intraoperative radiation exposure levels and outcomes. AB - OBJECTIVE: To compare radiation exposure doses and clinical and radiological outcomes between percutaneous pedicular screwing (closed reduction internal fixation [CRIF]) and classical open reduction internal fixation (ORIF) in lumbar spine fracture without neurologic deficit. MATERIALS AND METHODS: Sixty patients (mean age, 42.5 years) were divided into two treatment groups: (Percutaneous) CRIF versus (traditional) ORIF. Screw position and anatomic vertebral reconstruction were checked on routine control X-ray and postoperative CT scan. Study parameters comprised: surgery time, radiation exposure time, radiation dose level for X-ray (DAP) and for CT (DLP),blood loss, length of hospital stay and postoperative pain (VAS). RESULTS: At a mean 25.5 months' follow-up,there were no significant inter-group differences on the epidemiological parameters: age, gender, fracture level, fracture type on the Magerl classification, preoperative local vertebral kyphosis angle, or fracture-to-surgery interval. Effective radiation dose was 3-fold higher in CRIF than in ORIF, but 6-fold lower than for the postoperative CT scan. Postoperative pain on VAS was significantly lower after CRIF, allowing earlier gait resumption and return to work and daily activity. There were no significant differences in length of hospital stay, patient satisfaction, screw malpositioning or postoperative or end-of-follow-up kyphosis angle. CONCLUSION: Percutaneous surgery provided clinical and radiological outcomes strictly comparable to those of open surgery, but with a higher effective radiation exposure dose, including for the medical team and especially for the surgeon. This higher exposure dose, however, is to be relativized by comparison to that of the postoperative CT scan, which involved a much higher exposure dose for the patient. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23453916 TI - Phytohormones and microRNAs as sensors and regulators of leaf senescence: assigning macro roles to small molecules. AB - Ageing or senescence is an intricate and highly synchronized developmental phase in the life of plant parts including leaf. Senescence not only means death of a plant part, but during this process, different macromolecules undergo degradation and the resulting components are transported to other parts of the plant. During the period from when a leaf is young and green to the stage when it senesces, a multitude of factors such as hormones, environmental factors and senescence associated genes (SAGs) are involved. Plant hormones including salicylic acid, abscisic acid, jasmonic acid and ethylene advance leaf senescence, whereas others like cytokinins, gibberellins, and auxins delay this process. The environmental factors which generally affect plant development and growth, can hasten senescence, the examples being nutrient dearth, water stress, pathogen attack, radiations, high temperature and light intensity, waterlogging, and air, water or soil contamination. Other important influences include carbohydrate accumulation and high carbon/nitrogen level. To date, although several genes involved in this complex process have been identified, still not much information exists in the literature on the signalling mechanism of leaf senescence. Now, the Arabidopsis mutants have paved our way and opened new vistas to elucidate the signalling mechanism of leaf senescence for which various mutants are being utilized. Recent studies demonstrating the role of microRNAs in leaf senescence have reinforced our knowledge of this intricate process. This review provides a comprehensive and critical analysis of the information gained particularly on the roles of several plant growth regulators and microRNAs in regulation of leaf senescence. PMID- 23453917 TI - The important role of lysophosphatidic acid (LPA) induced interleukin-6 and -8 syntheses by human osteoblasts in skeletal biology. PMID- 23453918 TI - [Breech delivery and scarred uterus: a special obstetrical situation?]. AB - AIM: The management of breech delivery in patients with a history of caesarean section is a special situation requiring to anticipate the delivery route if the usual prerequisites for the acceptance of vaginal breech delivery are present. Does a history of caesarean section imply a systematic refusal of vaginal delivery in case of breech presentation or an alternative to an iterative caesarean still exists? MATERIALS AND METHODS: An observational study was undertaken in our level III labour ward from January 1st 1994 to June 30th 2010 on 91 patients with a history of caesarean section and who had breech deliveries of singleton pregnancies at more than 35weeks of amenorrhea. Maternal, obstetrical and neonatal parameters were collected. Patients were divided into three groups: vaginal delivery, caesarean section after an accepted vaginal birth trial, elective caesarean section. RESULTS: The rate of an accepted vaginal birth trial was 24.2% (22 cases) with a 36.4% (eight patients) success rate in this group. There were two (2.9%) unplanned vaginal births. Fourteen patients (15.4%) had caesarian sections after an accepted vaginal birth trial: ten before labour and four during labour for dynamic dystocia or non-reassuring fetal status. Most caesarean sections before labour in case of an accepted vaginal birth trial were justified by an intercurrent factor requiring induction of labour. Neonatal factors did not show any increased morbidity or mortality in the vaginal birth group. No Apgar score was found to be less than or equal to 7 at 5minutes. Umbilical arterial pH and lactate measured as from 2001 were similar between the groups. Indeed, the mean arterial pH after vaginal birth was 7.19 as compared to 7.22 in case of caesarean section after an accepted vaginal birth trial, and 7.26 after elective caesarean section. Likewise, the mean lactate measurement was at 4.71mmol/L after vaginal birth versus 4.54 and 3.07 in the other two groups. Only neonates born after elective caesarean sections were transferred to intensive care (four cases). CONCLUSION: Vaginal breech delivery in case of a scarred uterus is possible, if each obstetrical situation is correctly studied to authorize a vaginal birth trial after a careful selection of patients and a strict management of labour. Vaginal birth does not seem to increase maternal and neonatal morbidity and mortality in this situation. PMID- 23453919 TI - [Fertility preservation among patients with cancer: report of a French regional practical experience]. AB - OBJECTIVE: Improvement in cancer treatments has led to reconsider the importance of quality of life after cancer, especially concerning maintening the potential of fertility since it is often altered after healing. Our objective was to estimate the knowledge and practices of the physicians in the field of Oncology in a French Region (Provence Alpes- Cote d'Azur). PATIENTS AND METHOD: Prospective survey, conducted between January and April 2012, amongst oncologists working in Provence Alpes Cote d'Azur region, through questionnaires distributed during multidisciplinary meetings in oncology. RESULTS: Among 225 replies, 54% of the physicians had sent no patient to any oncofertility consultation during the previous six months (n=120). Besides, 33% of the oncologists (n=68) declared they had difficulties in addressing their patients to oncofertility consultation, and 58% of them (n=39) considered they lacked information on techniques and indications of fertility preservation. CONCLUSION: This study provides an estimation of the current practices in PACA region concerning oncofertility and underlines the physicians' need of information. In this context, the regional oncology network has set up a regional network " cancer and fertility " in order to facilitate the access to fertility preservation prior to any potentially sterilizing treatment for all patients. PMID- 23453920 TI - [Prenatal repair of myelomeningocele: State of the art]. AB - Myelomeningocele is characterized by the extrusion of the spinal cord into a sac filled with cerebrospinal fluid. One part of the postnatal disabilities could be related to the spinal damage and to the cerebral repercussion of the leak of cerebrospinal fluid from the defect. Several experimental studies in animals have demonstrated that a surgical repair of the lesion at middle gestation reduced the postnatal disabilities. These results were confirmed in humans by the Management of Myelomeningocele (MOM) Trial. However, the prenatal surgical repair is associated with maternal and fetal morbidity. PMID- 23453921 TI - [Diagnostic usefulness of pocket echography performed in hypertensive patients by a general practitioner]. AB - BACKGROUND AND OBJECTIVE: Conventional echocardiography is the technique of choice for assessing cardiac involvement in arterial hypertension. Nevertheless, its availability in primary care is very limited. This study aimed to define the diagnostic usefulness of pocket echocardiography performed by a general practitioner (GP) in patients with arterial hypertension. PATIENTS AND METHOD: Cross-sectional study of a random sample of 393 patients with arterial hypertension. A GP appropriately trained in the technique performed an examination with a pocket echocardiograph and semiquantitatively assessed the different findings. The studies were blindly re-assessed by an expert cardiologist and analyzed quantitatively by computer software. Dimensions of the left ventricle, left atrium and ascending aorta were assessed, together with interventricular septum thickness and presence of valve lesions. RESULTS: The study took less than 5min and the quality was good-acceptable in 98%. Analysis showed very good concordance (weighted kappa>0,83) in dimensions of the left ventricle, left atrium and ascending aorta, interventricular septum thickness, aortic regurgitation and aortic valve sclerosis, and good concordance (weighted kappa>0,71) in mitral regurgitation and mitral valve calcification. Only 6 (2.6%) of the significant lesions were diagnosed by the GP. CONCLUSIONS: Pocket echocardiography in primary care performed by a GP, as an extension of the clinical assessment of patients with arterial hypertension, provides an early diagnosis of significant cardiac lesions which may improve therapeutic management. PMID- 23453922 TI - Almanac 2012: Cardiovascular risk scores. PMID- 23453923 TI - Almanac 2012: Adult cardiac surgery. PMID- 23453924 TI - [Bidirectional Glenn: outcomes and risk factor analysis in a 5 years' experience]. AB - OBJECTIVE: Bidirectional Glenn shunt is a palliative surgical procedure in patients with single ventricle. Although morbimortality in this surgery is low, risk factors have been described. The purpose of this study is to report our outcomes in Glenn surgery, identifying mortality risk factors in our population. METHODS: Retrospective study between 2005 and 2009. Age, weight, previous surgery, surgical procedure, and postoperative condition were analyzed. Results are reported as median and rank, or absolute values and percentage. Uni and multivariate analysis was made to identify risk factors of mortality and/or prolonged hospitalization (Stata 9.0). RESULTS: One hundred and one patients were operated; 87 bidirectional Glenn and 14 bilateral Glenn. Median age 15 months (2.5-108), median weight 8.5 kg (4.2-27), and 74% of them with previous surgery. In 54 patients an associated procedure was performed simultaneously, only in 4 additional pulmonary blood flow was left. Median hospitalization was 8 days (2 97). Thirty-five percent of the patients presented complications. No association between age, weight, pulmonary hypertension, cardiopulmonary bypass, cross clamping, associated procedures or Glenn bilateral with mortality or morbidity was found. Overall mortality was 3.9%. CONCLUSION: Mortality was similar to other centers, but morbidity in this group of patients is high. No independent risk factors associated with morbidity or mortality were identified. PMID- 23453925 TI - Drosophila miR-932 modulates hedgehog signaling by targeting its co-receptor Brother of ihog. AB - Hedgehog (Hh) proteins act as morphogens in a variety of developmental contexts to control cell fates and growth in a concentration-dependent manner. Therefore, secretion, distribution, and reception of Hh proteins must be tightly regulated and deregulation of these processes contributes to numerous human diseases. Brother of ihog (Boi) and its close relative Ihog (Interference hedgehog) are cell surface proteins that act as Hh co-receptors required for Hh signaling response and cell-surface maintenance of Hh protein. MicroRNAs (miRNAs) are a group of widely expressed 21-23 nucleotides non-coding RNAs that repress gene function through interactions with target mRNAs. Here, we have identified a novel miRNA, miR-932, as an important regulator for Boi. We show that overexpression of miR-932 in the wing disc can enhance Hh signaling strength, but reduce its signaling range, a phenotype similar to that of boi knockdown. In both in vivo sensor assay and in vitro luciferase assay, miR-932 can suppress Boi by directly binding to its 3'UTR. Meanwhile, down-regulation of miR-932 by sponge elevates the protein level of Boi, confirming that miR-932 is an in vivo regulator of Boi expression. Further, we demonstrate that miR-932 can block Hh signaling when co expressed with ihog-RNAi. Moreover, we find that other predicted miRNAs of Boi fail to suppress it as strong as miR-932. Taken together, our data demonstrate that miR-932 can modulate Hh activity by specifically targeting Boi in Drosophila, illustrating the important roles of miRNAs in fine regulation of the Hh signaling pathway. PMID- 23453927 TI - A dual compartment diffusion chamber for studying axonal chemotaxis in 3D collagen. AB - During nervous system development growing axons are often guided by diffusible chemical gradients. An important contribution to our understanding of the mechanisms involved in this process has been made by in vitro assays. However, an inexpensive and simple assay which allows the establishment of stable and reproducible gradients in a 3D collagen environment has been lacking. Here we present a simple two-compartment diffusion chamber for this purpose. We show that gradient steepnesses of up to 2% are achieved within 1h post setup, and a gradient persists for at least 2 days. We demonstrate the assay by showing robust chemoattraction of dorsal root ganglion neurites by gradients of nerve growth factor (NGF), and chemorepulsion of olfactory bulb neurites by gradients of Slit2. PMID- 23453926 TI - Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. AB - Advanced oxidation protein products (AOPPs) are formed during chronic oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants. Their levels are elevated during various cardiovascular diseases. Because elevated AOPPs serve as independent risk factors for ischemic heart disease, and cardiomyocyte death is a hallmark of ischemic heart disease, we hypothesized that AOPPs will induce cardiomyocyte death. AOPP-modified mouse serum albumin (AOPP MSA) induced significant death of neonatal mouse cardiomyocytes that was attenuated by knockdown of the receptor for advanced glycation end products, but not CD36. Notably, TRAF3-interacting protein 2 (TRAF3IP2; also known as CIKS or Act1) knockdown blunted AOPP-induced apoptosis. AOPP-MSA stimulated Nox2/Rac1 dependent superoxide generation, TRAF3IP2 expression, and TRAF3IP2-dependent JNK activation. The superoxide anion generating xanthine/xanthine oxidase system and hydrogen peroxide both induced TRAF3IP2 expression. Further, AOPP-MSA induced mitochondrial Bax translocation and release of cytochrome c into cytoplasm. Moreover, AOPP-MSA suppressed antiapoptotic Bcl-2 and Bcl-xL expression. These effects were reversed by TRAF3IP2 knockdown or forced expression of mutant JNK. Similar to its effects in neonatal cardiomyocytes, AOPP-MSA induced adult cardiomyocyte death in part via TRAF3IP2. These results demonstrate for the first time that AOPPs induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK activation in vitro and suggest that AOPPs may contribute to myocardial injury in vivo. Thus TRAF3IP2 may represent a potential therapeutic target in ischemic heart disease. PMID- 23453928 TI - [Awake intubation using Pentax Airway Scope as an alternative to awake fiberoptic intubation in management of anticipated difficult tracheal intubation in major burn patients]. AB - Intubating patients with facial burn is difficult to most anesthesiologists. Awake flexible fiberoptic intubation is the gold standard for management of anticipated difficult tracheal intubation. However, serious facial burn and dysmorphic syndrome can make fiberoptic intubation more difficult or impossible. We report the use of awake oral intubation using the Pentax-Airway Scope (AWS) in two major burn patients with facial injury, in whom awake fiberoptic intubation was impossible. As shown in morbidly obese patient and in patients with unstable necks, AWS could be useful to facilitate tracheal intubation in awake, facial burn patients presenting with a potentially difficult airway. Awake AWS intubation seems as a potential alternative to awake fiberoptic intubation. PMID- 23453929 TI - [Difficult airway management: assessment of knowledge and experience in anaesthesiology residents]. AB - OBJECTIVES: Assessment of knowledge and experience in anaesthesiology residents on alternative techniques for difficult airway management. METHOD: Descriptive study using an anonymous electronic questionnaire, with 20 multiple-choice questions of 59 4th- and 5th-year residents in anaesthesiology of Amiens, Rouen and Caen University Hospitals (France). RESULTS: Fourty-three (73%) answered to the questionnaire. Thirteen residents (30%) admitted to know last expert conference of the French Anaesthesiology Society partially, 19 (44%) didn't train on mannequin or simulator. Twelve residents (28%) admitted to be insufficient trained to set up a Fastrach in an emergency context, and 39 (91%) to set up a transtracheal oxygenation technique. The rates of residents reaching the educational objectives on patients were 4% for the Fastrach, 21% for fiberoptic intubation, 12% for cricothyroidotomy. CONCLUSION: Four years after the expert conference of the French Anaesthesiology Society, the educational objectives are not achieved during the resident training, both on mannequins or patients. PMID- 23453930 TI - [Learning ultrasonography: where do the anesthesiology residents of the French north-eastern sector currently stand?]. AB - OBJECTIVE: Ultrasonography is in continuing expansion in anesthesiology and critical care medicine (ACCM). It is an operator-dependent tool whose contribution is partly related to the quality of the user's initial and subsequent training. Within the framework of the ACCM residency, the French north east anesthesiology residents have an initiation to ultrasonography by 24 hours of formal lectures. The evaluation of this teaching has not yet been performed. The objective of this survey is to depict this learning and delineate the expectations of the residents. METHODS: An anonymous computerized self-rated survey, published on a specific internet website, was performed between September 2011 and January 2012, and addressed to the ACCM residents of the French north east anesthesiology residency by the local coordinators. It consisted in several items: current abilities and aims in echography, equipment availability and frequency of use, existence of a potential independent ultrasonography training, desired improvements, evaluation of the teaching and interest of rendering it mandatory, potential interest in creating a form of assessment. RESULTS: In total, 105 questionnaires were analyzed (response rate 44%). The distribution of respondents was homogeneous from the 1st to the 5th year of residency. Thirty percent of residents had good knowledge or mastered echocardiography. Ultrasound guiding during vascular access was the best acquired technique: 73% masterized or had good knowledge of it. The results were more mitigated regarding ultrasound guided regional anesthesia (UGRA) (60%), trans-cranial echography (46%), FAST echo (23%), pleuro-pulmonary echography (38%). At the end of the ACCM residency, 69% wished to master echocardiography and 86% UGRA. The echograph was used more than once a week (76%) and of easy access (93%). The teaching was mainly theoretical; 76% of the residents were unsatisfied and nine out of ten had followed an echography training outside the ACCM residency courses or intended to do so. Moreover, 78% wished a mandatory echography learning, with seminars and a strengthened practical training: 94% considered workshops indispensable, and 62% simulation sessions. An assessment of knowledge was found useful, particularly in practical form. The realization of a training rotation with echographic orientation was desired by 78% of respondents. CONCLUSION: A clear gap exists between the real capability in echocardiography and the intended one. UGRA and echocardiography raise a particular interest. The practical training in ultrasonography using simulation and workshops is to be favored. PMID- 23453931 TI - Proteomic profiles reveal age-related changes in coelomic fluid of sea urchin species with different life spans. AB - Sea urchins have a different life history from humans and traditional model organisms used to study the process of aging. Sea urchins grow indeterminately, reproduce throughout their life span and some species have been shown to exhibit negligible senescence with no increase in mortality rate at advanced ages. Despite these properties, different species of sea urchins are reported to have very different natural life spans providing a unique model to investigate cellular mechanisms underlying life span determination and negligible senescence. To gain insight into the biological changes that accompany aging in these animals, proteomic profiles were examined in coelomic fluid from young and old sea urchins of three species with different life spans: short-lived Lytechinus variegatus, long-lived Strongylocentrotus franciscanus and Strongylocentrotus purpuratus which has an intermediate life span. The proteomic profiles of cell free coelomic fluid were complex with many proteins exhibiting different forms and extensive post-translational modifications. Approximately 20% of the protein spots on 2-D gels showed more than two-fold change with age in each of the species. Changes that are consistent with age in all three species may prove to be useful biomarkers for age-determination for these commercially fished marine invertebrates and also may provide clues to mechanisms of negligible senescence. Among the proteins that change with age, the ectodomain of low-density lipoprotein receptor-related protein 4 (LRP4) was significantly increased in the coelomic fluid of all three sea urchin species suggesting that the Wnt signaling pathway should be further investigated for its role in negligible senescence. PMID- 23453932 TI - The effect of rTMS on auditory processing in adults with chronic, bilateral tinnitus: a placebo-controlled pilot study. AB - BACKGROUND: On the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated the use of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as a potential modulator of this hyperactivity. While these investigations show promise, investigations to date have neglected to consider the possible effect of 1 Hz rTMS on other functions of the auditory cortex of these individuals, such as auditory processing. OBJECTIVE/HYPOTHESIS: This placebo-controlled pilot study aimed to determine whether 1 Hz rTMS applied to the primary auditory cortex (PAC), specifically Brodmann Area 41 (BA41), of adults with chronic, bilateral tinnitus would influence their auditory processing abilities. METHODS: Eight participants with bilateral, chronic tinnitus were randomized to receive a 10-day course of neuronavigationally guided active rTMS (n = 4) or placebo rTMS (n = 4) treatment applied to a focal region of the left PAC (BA41). Participants' auditory processing was measured using Time Compressed Reverberant Speech and three-pair Dichotic Digits (DD). Their tinnitus was measured using the Tinnitus Handicap Inventory (THI) and a psychoacoustic measure of tinnitus perception. All outcome measures were administered at baseline (1 week prior to rTMS), 1 week, 1, 2 and 3 months post-rTMS. RESULTS: All four participants in the active rTMS (A) group, and none of the participants in the sham (placebo) rTMS (S) group, showed improved auditory processing scores at multiple assessment points post stimulation, with the group differences in median normalized gain scores reaching significance at the 5% level from 1 week or 1 month post-stimulation onwards. Three of the four participants in the active rTMS (A) group, and none of the participants in the sham rTMS (S) group, showed improved tinnitus scores at multiple assessment points post-stimulation, with some of the group differences in median normalized gain scores reaching significance at the 5% level. CONCLUSIONS: The results of this preliminary study suggest that 1 Hz rTMS applied to the PAC (BA41) has the capacity to improve both auditory processing and tinnitus perception in some adults with chronic, bilateral tinnitus. PMID- 23453933 TI - Response to "the site of transcranial magnetic stimulation for post-traumatic stress disorder". PMID- 23453934 TI - CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study. AB - BACKGROUND: It has recently been shown that electrical stimulation of sensory afferents within the outer auditory canal may facilitate a transcutaneous form of central nervous system stimulation. Functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) effects in limbic and temporal structures have been detected in two independent studies. In the present study, we investigated BOLD fMRI effects in response to transcutaneous electrical stimulation of two different zones in the left outer auditory canal. It is hypothesized that different central nervous system (CNS) activation patterns might help to localize and specifically stimulate auricular cutaneous vagal afferents. METHODOLOGY: 16 healthy subjects aged between 20 and 37 years were divided into two groups. 8 subjects were stimulated in the anterior wall, the other 8 persons received transcutaneous vagus nervous stimulation (tVNS) at the posterior side of their left outer auditory canal. For sham control, both groups were also stimulated in an alternating manner on their corresponding ear lobe, which is generally known to be free of cutaneous vagal innervation. Functional MR data from the cortex and brain stem level were collected and a group analysis was performed. RESULTS: In most cortical areas, BOLD changes were in the opposite direction when comparing anterior vs. posterior stimulation of the left auditory canal. The only exception was in the insular cortex, where both stimulation types evoked positive BOLD changes. Prominent decreases of the BOLD signals were detected in the parahippocampal gyrus, posterior cingulate cortex and right thalamus (pulvinar) following anterior stimulation. In subcortical areas at brain stem level, a stronger BOLD decrease as compared with sham stimulation was found in the locus coeruleus and the solitary tract only during stimulation of the anterior part of the auditory canal. CONCLUSIONS: The results of the study are in line with previous fMRI studies showing robust BOLD signal decreases in limbic structures and the brain stem during electrical stimulation of the left anterior auditory canal. BOLD signal decreases in the area of the nuclei of the vagus nerve may indicate an effective stimulation of vagal afferences. In contrast, stimulation at the posterior wall seems to lead to unspecific changes of the BOLD signal within the solitary tract, which is a key relay station of vagal neurotransmission. The results of the study show promise for a specific novel method of cranial nerve stimulation and provide a basis for further developments and applications of non-invasive transcutaneous vagus stimulation in psychiatric patients. PMID- 23453935 TI - Evidence of increasing mortality with longer diagnostic intervals for five common cancers: a cohort study in primary care. AB - BACKGROUND: Early diagnosis is considered a key factor in improving the outcomes in cancer therapy; it remains unclear, however, whether long pre-diagnostic patient pathways influence clinical outcomes negatively. The aim of this study was to assess the association between the length of the diagnostic interval and the five-year mortality for the five most common cancers in Denmark while addressing known biases. METHODS: A total of 1128 patients with colorectal, lung, melanoma skin, breast or prostate cancer were included in a prospective, population-based study in a Danish county. The diagnostic interval was defined as the time from the first presentation of symptoms in primary care till the date of diagnosis. Each type of cancer was analysed separately and combined, and all analyses were stratified according to the general practitioner's (GP's) interpretation of the presenting symptoms. We used conditional logistic regression to estimate five-year mortality odds ratios as a function of the diagnostic interval using restricted cubic splines and adjusting for comorbidity, age, sex and type of cancer. RESULTS: We found increasing mortality with longer diagnostic intervals among the approximately 40% of the patients who presented in primary care with symptoms suggestive of cancer or any other serious illness. In the same group, very short diagnostic intervals were also associated with increased mortality. Patients presenting with vague symptoms not directly related to cancer or any other serious illness had longer diagnostic intervals and the same survival probability as those who presented with cancer suspicious/serious symptoms. For the former, we found no statistically significant association between the length of the diagnostic interval and mortality. CONCLUSION: In full coherence with clinical logic, the healthcare system instigates prompt investigation of seriously ill patients. This likely explains the counter intuitive findings of high mortality with short diagnostic intervals; but it does not explain the increasing mortality with longer diagnostic intervals. Thus, the study provides further evidence for the hypothesis that the length of the diagnostic interval affects mortality negatively. PMID- 23453936 TI - Discharge of breast cancer patients to primary care at the end of hospital follow up: a cross-sectional survey. AB - AIM: The present study explored (a) the discharge of breast cancer patients to primary care by specialists, at the end of hospital follow-up and (b) the experiences and views of general practitioners (GPs) regarding transfer of follow up to the primary care setting. METHODS: A cross-sectional survey was performed by sending a self-administered questionnaire to 960 GPs working in the three northern provinces of the Netherlands. Data were analysed using descriptive statistics. RESULTS: Of 949 eligible questionnaires, 502 were returned, providing an adjusted response rate of 53%. In the year before the survey took place, one or more patients aged >60 years, and 5 years after breast-conserving therapy, were discharged to 22% of GPs (n=112) for follow-up. According to 56% of these GPs, transfer of follow-up was communicated by the hospital. The initiative to arrange follow-up visits and mammography appointments was mainly taken by patients. In this survey, 40% of GPs (n=200) were willing to accept exclusive responsibility for follow-up earlier than 5 years after completion of active treatment. Perceived barriers in current and future primary care-based follow-up included: communication with breast cancer specialists, patients' preference for specialist follow-up, GPs' oncology knowledge and skills and the organisation of follow-up in general practice. CONCLUSIONS: Primary care-based follow-up might be improved if breast cancer specialists discharge patients more actively to their GPs. Survivorship care plans are needed to facilitate communication across the primary/secondary interface and with patients. Training of GPs and developing administrative tools may be helpful in arranging follow-up care and using guidelines in general practice. PMID- 23453937 TI - Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. AB - BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers but is responsible for a disproportionate number of deaths. We investigated the relevance, in TNBC, of nano-sized exosomes expelled from cells. Specifically, we compared effects of exosomes derived from the claudin-low TNBC cell line Hs578T and its more invasive Hs578Ts(i)8 variant, as well as exosomes from TNBC patient sera compared to normal sera. METHODS: Exosomes were isolated from conditioned media (CM) of Hs578T and Hs578Ts(i)8 cells and from sera by filtration and ultracentrifugation. Successful isolation was confirmed by transmission electron microscopy and immunoblotting. Subsequent analysis, of secondary/recipient cells in response to exosomes, included proliferation; motility/migration; invasion; anoikis assays and endothelial tubule formation assays. RESULTS: Hs578Ts(i)8-exosomes versus Hs578T-exosomes significantly increased the proliferation, migration and invasion capacity of all three recipient cell lines evaluated i.e. SKBR3, MDA-MB-231 and HCC1954. Exosomes from Hs578Ts(i)8 cells also conferred increased invasiveness to parent Hs578T cells. Hs578Ts(i)8-exosomes increased sensitivity of SKBR3, MDA-MB-231 and HCC1954 to anoikis when compared to the effects of Hs578T-exosomes reflecting the fact that Hs578Ts(i)8 cells are themselves innately more sensitive to anoikis. In relation to vasculogenesis and subsequent angiogenesis, Hs578Ts(i)8-exosomes versus Hs578T exosomes stimulated significantly more endothelial tubules formation. Finally, our pilot translational study showed that exosomes from TNBC patients' sera significantly increased recipient cells' invasion when compared to those derived from age- and gender-matched healthy control sera. CONCLUSION: This study supports the hypothesis that TNBC exosomes may be involved in cancer cell-to-cell communication, conferring phenotypic traits to secondary cells that reflect those of their cells of origin. PMID- 23453938 TI - Engineering and application of P450 monooxygenases in pharmaceutical and metabolite synthesis. AB - Cytochrome P450 monoxygenase (P450s or CYPs) allow access to drug metabolites, necessary for approval of new therapeutics in one step, with increased success being demonstrated using bacterial and fungal P450s. Moreover, 12 of the 13 products of the human metabolism of verapamil can be accessed through engineered and chimeric bacterial P450s. These P450s are also used in the synthesis of pharmaceuticals themselves, including the semi-synthetic production of artemisinin in an engineered cell. The integration of new technologies including ultrasound and polyfluorinated hydrocarbon solvents offers an attractive means by the true synthetic potential of ubiquitous P450s can be fully realised. PMID- 23453939 TI - Antidepressant-like effect of flavonoids extracted from Apocynum venetum leaves on brain monoamine levels and dopaminergic system. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Apocynum venetum L. (Apocynaceae), a traditional medicinal plant, has been used for the improvement of emotions in Asian countries. AIM OF THE STUDY: We explored the antidepressant-like effect and monoaminergic mechanism of a flavonoids extract from Apocynum venetum leaves (AV extract). MATERIALS AND METHODS: Effect of AV-extract (25, 50 and 100 mg/kg, i.g.) on mice's immobility time was assessed in forced swim test (FST) and tail suspension test (TST). The locomotor activity was evaluated in the open-field test (OFT). Additionally, the main monoamine neurotransmitters serotonin (5-HT), noradrenaline (NA) and dopamine (DA) and their metabolites 5-hydroxyindole-3 acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the mouse hippocampus involved in the antidepressant-like effect of AV-extract was also determined by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS). RESULTS: AV-extract (50 and 100 mg/kg, i.g.) administration significantly reduced the immobility time in both the FST and TST without accompanying changes in locomotor activity in the OFT. It was also found that the AV-extract significantly increased the concentrations of the main neurotransmitters NE and DA along with their respective metabolites DOPAC, HVA in the hippocampus. The antidepressant-like effect of the AV-extract (50 mg/kg, i.g.) was prevented by the pretreatment of mice with SCH23390 (0.05 mg/kg, i.g., a dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.g., a dopamine D2 receptor antagonist). CONCLUSION: The AV-extract produced significant antidepressant-like effects, which likely attribute to increased NE and DA along with their respective metabolites DOPAC, HVA in the mouse hippocampus, and dependent on interaction with dopaminergic (D1 and D2 receptor) systems. PMID- 23453940 TI - The status of bovine brucellosis in Ethiopia with special emphasis on exotic and cross bred cattle in dairy and breeding farms. AB - A cross-sectional study was conducted to investigate the seroprevalence of brucellosis and identify risk factors in exotic and cross bred cattle in Ethiopia. A total of 2334 cattle from 273 farms were tested serially for Brucella antibodies using the Rose Bengal Plate Test (RBPT) and the Compliment Fixation Test (CFT). The overall animal level seroprevalence was 1.9% (95% CI: 1.2, 2.6), with urban and peri-urban dairy 2.4% (95% CI: 1.4, 3.4), commercial 1.5% (95% CI: 0.5, 2.5) and breeding farms 1.5% (95% CI: 0.2, 3.2). The overall farm level prevalence was 10.6% (95% CI: 6.9, 14.3), with 8.6% (95% CI: 4.8, 12.4) in urban and peri-urban dairy followed by 16.9% (95% CI: 7.3, 26.6) in commercial and 20.0% (95% CI: 0.0, 59.4) in breeding farms. At individual animal level, purchased cows and adult age groups were observed to associate with Brucella seropositivity while presence of small ruminants on the farm was the only factor associated with increased risk of herd level Brucella infection. The lack of association between reproductive disorders and Brucella seroprevalence suggest that other causes largely outweigh as causes of the aforesaid disorder in studied production systems and demands an investigation. Finally, the need for isolation and characterization of circulating Brucella spp. and institution of regulatory measures to reinforce farm biosecurity was suggested. PMID- 23453941 TI - Expression of the marA, soxS, acrB and ramA genes related to the AcrAB/TolC efflux pump in Salmonella enterica strains with and without quinolone resistance determining regions gyrA gene mutations. AB - Several studies have been conducted in recent years to elucidate the structure, function and significance of AcrB, MarA, SoxS and RamA in Salmonella enterica. In this study, the relative quantification of acrB, soxS, marA and ramA genes expression was evaluated in 14 strains of S. enterica, with or without accompanying mutations in the quinolone resistance-determining regions of the gyrA gene, that were exposed to ciprofloxacin during the exponential growth phase. The presence of ciprofloxacin during the log phase of bacterial growth activated the genes marA, soxS, ramA and acrB in all S. enterica strains analyzed in this study. The highest expression levels for acrB were observed in strains with gyrA mutation, and marA showed the highest expression in the strains without mutation. Considering only the strains with ciprofloxacin minimum inhibitory concentration values<0.125 MUg/mL (sensitive to ciprofloxacin), the most expressed gene in the strains both with and without mutations was acrB. In the strains with ciprofloxacin minimum inhibitory concentration values >= 0.125 MUg/mL (low susceptibility), with and without mutations in gyrA, the most expressed gene was marA. In this study, we observed that strains resistant to nalidixic acid may express genes associated with the efflux pump and the expression of the AcrAB-TolC pump genes seems to occur independently of mutations in gyrA. PMID- 23453942 TI - Obscure gastrointestinal bleeding caused by hookworms. PMID- 23453943 TI - Conventional serological performance in diagnosis of Chagas' disease in southern Brazil. AB - Results of Chagas' disease diagnosis show disagreement. The aim of this study was to compare commercial tests for Chagas' disease serodiagnosis in southern Brazil. A total of 161 samples were evaluated. Three enzyme-linked immunosorbent assays, one indirect hemagglutination and one indirect immunofluorescence were assessed. Trypomastigote excreted-secreted antigen-blot was a confirmatory method. From 161 samples, 65.84% were positive in all tests, while 34.16% presents mismatch result in at least one of the tests. All techniques tested presented false-positive and/or false-negative results as follows: Enzyme-linked immunosorbent assay 1 had more false-positive results (lower specificity), indirect immunofluorescence had the highest rate of false-negative results (lower sensitivity), enzyme-linked immunosorbent assays had fewer false-negative results (higher sensitivity), while indirect hemagglutination showed no false-positive result (higher specificity). Knowing the characteristics of techniques make it possible to combine them and obtain more reliable diagnosis. Therefore, it seems useful to combine techniques for diagnosing this infection. PMID- 23453944 TI - Tuberculosis research meeting in Bahia. PMID- 23453945 TI - Pneumonia severity index compared to CURB-65 in predicting the outcome of community acquired pneumonia among patients referred to an Iranian emergency department: a prospective survey. AB - OBJECTIVE: To compare the prognostic value of the pneumonia severity index and the severity score for community-acquired pneumonia (CURB-65) in predicting mortality and the need for ICU admission of patients with community-acquired pneumonia referred to our emergency department. MATERIALS AND METHODS: This prospective study was performed on patients with community-acquired pneumonia admitted to the emergency department of Imam Hossein Medical Center, Tehran, Iran. A questionnaire with demographic information, clinical signs and symptoms, laboratory and radiographic findings was completed for each patient. The information required for calculating the pneumonia severity index and CURB-65 were extracted from the medical records. The patients' clinical outcome was also recorded within a month after admission. RESULTS: We studied 200 patients with community-acquired pneumonia (122 men, 78 women). The sensitivity and specificity of CURB-65 in predicting mortality were 100% and 82.3%, respectively. As for pneumonia severity index, the rates were 100% and 75%, respectively. The sensitivity and specificity rates of CURB-65 and pneumonia severity index in predicting mortality and need for ICU admission were 96.7% and 89.3%, and 90% and 78.7%, respectively. CONCLUSION: CURB-65 seems to be the preferred method to predict mortality and need for ICU admission in patients with community-acquired pneumonia. Despite their comparable specificity and sensitivity, CURB-65 is much easier to implement. PMID- 23453946 TI - Syphilis and HIV-1 among parturient women in Salvador, Brazil: low prevalence of syphilis and high rate of loss to follow-up in HIV-infected women. AB - BACKGROUND: The occurrence of syphilis and HIV-1 infections during pregnancy are major risks to the fetus due to mother-to-child transmission (MTCT). OBJECTIVES: To determine peripartum seroprevalence and risk factors of syphilis and HIV-1 infection among pregnant women in Salvador, Brazil, and the rate of HIV-1 MTCT. METHODS: Cross-sectional study of pregnant women who were admitted for delivery in a reference maternity hospital between May 2008 and March 2009 was conducted. Women were screened for HIV-1 infection and syphilis, and interviewed regarding demographic, behavioral and obstetric data. Newborns to HIV-infected mothers were tested by b-DNA and DNA-PCR to detect HIV-1. RESULTS: A total 3300/8516 women were evaluated. Mean age was 25.8 +/- 7.3 years. HIV-1 and syphilis seroprevalence rates were 0.84% (28/3300) and 0.51% (17/3300), respectively. HIV 1 infection was associated with: low education (p=0.04), having a partner with known HIV infection (p<0.0001) or with previous sexually transmitted infection (p<0.0001), blood transfusion (p=0.003), or accidental exposure to blood (p=0.003). Syphilis was associated with being Caucasian (p=0.02), having no steady partner (p=0.02), being a housewife (p=0.01), having an intravenous drug user (IVDU) sexual partner (p=0.04) or a sexual partner with previous STI (p<0.001). Higher education (p=0.04) was protective against HIV-infection. Attending a prenatal care program was protective against syphilis (p=0.008) and HIV-1 (p=0.02). No case of HIV-1 MTCT was detected, but 25% of children born to HIV-infected mothers were lost to follow up. CONCLUSIONS: In Salvador, peripartum prevalence of syphilis and HIV-1 infection among pregnant women were low, and associated with classic risk factors for both infections. The great proportion of very late diagnosis of HIV infection, and the high rate of loss of follow-up among positive mothers and their infants are of high concern. PMID- 23453947 TI - An unusual cause of bilateral scrotal abscess in a preterm infant: Candida albicans. AB - Acute scrotal abscess is a rare condition in neonates. Most of these abscesses were reported to be unilateral and caused by Staphylococcus and Salmonella spp. Herein, we report a bilateral scrotal abscess in a preterm infant and Candida albicans was isolated from the scrotal fluid culture. To our knowledge, this is the first bilateral scrotal abscess in a preterm infant caused by C. albicans. Therefore, this organism must be suspected in differential diagnosis of acute scrotal abscess in neonates, especially in preterm infants. PMID- 23453948 TI - Distribution of serotypes and evaluation of antimicrobial susceptibility among human and bovine Streptococcus agalactiae strains isolated in Brazil between 1980 and 2006. AB - Streptococcus agalactiae is a common agent of clinical and subclinical bovine mastitis and an important cause of human infections, mainly among pregnant women, neonates and nonpregnant adults with underlying diseases. The present study describes the genetic and phenotypic diversity among 392 S. agalactiae human and bovine strains isolated between 1980 and 2006 in Brazil. The most prevalent serotypes were Ia, II, III and V and all the strains were susceptible to penicillin, vancomycin and levofloxacin. Resistance to clindamycin, chloramphenicol, erythromycin, rifampicin and tetracycline was observed. Among the erythromycin resistant strains, mefA/E, ermA and, mainly, ermB gene were detected, and a shift of prevalence from the macrolide resistance phenotype to the macrolide-lincosamide-streptogramin B resistance phenotype over the years was observed. The 23 macrolide-resistant strains showed 19 different pulsed-field gel electrophoresis profiles. Regarding macrolide resistance, a major concern in S. agalactiae epidemiology, the present study describes an increase in erythromycin resistance from the 80s to the 90s followed by a decrease in the 2000-2006 period. Also, the genetic heterogeneity described points out that erythromycin resistance in Brazil is rather due to horizontal gene transmission than to spreading of specific macrolide-resistant clones. PMID- 23453949 TI - The onset of Triton X-100 solubilization of sphingomyelin/ceramide bilayers: effects of temperature and composition. AB - The early stages of Triton X-100 solubilization of bilayers consisting of sphingomyelin/ceramide (SM/Cer) mixtures have been studied using a combination of calorimetric and spectroscopic techniques. Compositions based on sphingomyelin, containing up to 30 mol% Cer, at 4, 20 and 50 degrees C have been examined. The presence of Cer does not modify the affinity (in terms of DeltaG of binding per mol total lipid) of the SM-based bilayers for Triton X-100, although it does increase the amount of detergent required for the onset of solubilization. At 50 degrees C more detergent was required to solubilize the SM/Cer bilayers than at 20 degrees C. The data can be rationalized in terms of lipid and detergent geometries and interactions (Lichtenberg et al., 2013). PMID- 23453950 TI - beta-Catenin-driven binary fate specification segregates germ layers in ascidian embryos. AB - beta-catenin is a transcriptional cofactor mediating the "canonical" Wnt signaling pathway, which activates target genes in a complex with TCF (LEF) transcription factors [1]. In many metazoans, embryos are first subdivided during early cleavage stages into nuclear beta-catenin-positive and -negative domains, with beta-catenin specifying endoderm or mesendoderm fate. This process has been demonstrated in a wide range of phyla including cnidarians, nemerteans, and invertebrate deuterostomes (echinoderms, hemichordates, and ascidians), implying that beta-catenin-dependent (mes)endoderm specification is evolutionarily ancient [2-10]. However, the mechanisms leading to the segregation of mesoderm and endoderm fates from a transient mesendodermal state are less well defined. We show that subdivision of the ascidian embryo into the three germ layers involves differential nuclear beta-catenin activity coupled with the first two animal vegetal (A-V)-oriented cell divisions. We reveal that each of these A-V divisions operates as a binary fate choice: the first between ectoderm and mesendoderm and the second between margin (notochord and neural) and endoderm, such that a beta catenin activation sequence of ON-to-ON specifies endoderm, OFF-to-OFF ectoderm, and ON-to-OFF margin. PMID- 23453951 TI - Rheotaxis guides mammalian sperm. AB - BACKGROUND: In sea urchins, spermatozoan motility is altered by chemotactic peptides, giving rise to the assumption that mammalian eggs also emit chemotactic agents that guide spermatozoa through the female reproductive tract to the mature oocyte. Mammalian spermatozoa indeed undergo complex adaptations within the female (the process of capacitation) that are initiated by agents ranging from pH to progesterone, but these factors are not necessarily taxic. Currently, chemotaxis, thermotaxis, and rheotaxis have not been definitively established in mammals. RESULTS: Here, we show that positive rheotaxis, the ability of organisms to orient and swim against the flow of surrounding fluid, is a major taxic factor for mouse and human sperm. This flow is generated within 4 hr of sexual stimulation and coitus in female mice; prolactin-triggered oviductal fluid secretion clears the oviduct of debris, lowers viscosity, and generates the stream that guides sperm migration in the oviduct. Rheotaxic movement is demonstrated in capacitated and uncapacitated spermatozoa in low- and high viscosity media. Finally, we show that a unique sperm motion, which we quantify using the sperm head's rolling rate, reflects sperm rotation that generates essential force for positioning the sperm in the stream. Rotation requires CatSper channels, presumably by enabling Ca(2+) influx. CONCLUSIONS: We propose that rheotaxis is a major determinant of sperm guidance over long distances in the mammalian female reproductive tract. Coitus induces fluid flow to guide sperm in the oviduct. Sperm rheotaxis requires rotational motion during CatSper channel dependent hyperactivated motility. PMID- 23453952 TI - Detection of a temporal error triggers reconsolidation of amygdala-dependent memories. AB - Updating memories is critical for adaptive behaviors, but the rules and mechanisms governing that process are still not well defined. During a limited time window, the reactivation of consolidated aversive memories triggers memory lability and induces a plasticity-dependent reconsolidation process in the lateral nucleus of amygdala (LA) [1-5]. However, whether new information is necessary for initiating reconsolidation is not known. Here we show that changing the temporal relationship between the conditioned stimulus (CS) and unconditioned stimulus (US) during reactivation is sufficient to trigger synaptic plasticity and reconsolidation of an aversive memory in the LA. These findings demonstrate that time is a core part of the CS-US association and that new information must be presented during reactivation in order to trigger LA-dependent reconsolidation processes. In sum, this study provides new basic knowledge about the precise rules governing memory reconsolidation of aversive memories that might be used to treat traumatic memories. PMID- 23453953 TI - Conversion of a signal into forces for axon outgrowth through Pak1-mediated shootin1 phosphorylation. AB - Soluble guidance cues can direct cellular protrusion and migration by modulating adhesion and cytoskeletal dynamics. Actin filaments (F-actins) polymerize at the leading edge of motile cells and depolymerize proximally [1, 2]; this, together with myosin II activity, induces retrograde flow of F-actins [3-5]. It has been proposed that the traction forces underlying cellular motility may be regulated by the modulation of coupling efficiency between F-actin flow and the extracellular substrate via "clutch" molecules [6-10]. However, how cell signaling controls the coupling efficiency remains unknown. Shootin1 functions as a linker molecule that couples F-actin retrograde flow and the substrate at neuronal growth cones to promote axon outgrowth [11]. Here we show that shootin1 is located at a critical interface, transducing a chemical signal into traction forces for axon outgrowth. We found that a chemoattractant, netrin-1, positively regulates traction forces at axonal growth cones via Pak1-mediated shootin1 phosphorylation. This phosphorylation enhanced the interaction between shootin1 and F-actin retrograde flow, thereby promoting F-actin-substrate coupling, force generation, and concomitant filopodium extension and axon outgrowth. These results suggest that dynamic actin-substrate coupling can transduce chemical signals into mechanical forces to control cellular motility and provide a molecular-level description of how this transduction may occur. PMID- 23453954 TI - A Dof transcription factor, SCAP1, is essential for the development of functional stomata in Arabidopsis. AB - Stomata are highly specialized organs that consist of pairs of guard cells and regulate gas and water vapor exchange in plants [1-3]. Although early stages of guard cell differentiation have been described [4-10] and were interpreted in analogy to processes of cell type differentiation in animals [11], the downstream development of functional stomatal guard cells remains poorly understood. We have isolated an Arabidopsis mutant, stomatal carpenter 1 (scap1), that develops irregularly shaped guard cells and lacks the ability to control stomatal aperture, including CO2-induced stomatal closing and light-induced stomatal opening. SCAP1 was identified as a plant-specific Dof-type transcription factor expressed in maturing guard cells, but not in guard mother cells. SCAP1 regulates the expression of genes encoding key elements of stomatal functioning and morphogenesis, such as K(+) channel protein, MYB60 transcription factor, and pectin methylesterase. Consequently, ion homeostasis was disturbed in scap1 guard cells, and esterification of extracellular pectins was impaired so that the cell walls lining the pores did not mature normally. We conclude that SCAP1 regulates essential processes of stomatal guard cell maturation and functions as a key transcription factor regulating the final stages of guard cell differentiation. PMID- 23453955 TI - Evolution of mir-92a underlies natural morphological variation in Drosophila melanogaster. AB - Identifying the genetic mechanisms underlying phenotypic change is essential to understanding how gene regulatory networks and ultimately the genotype-to phenotype map evolve. It is recognized that microRNAs (miRNAs) have the potential to facilitate evolutionary change [1-3]; however, there are no known examples of natural morphological variation caused by evolutionary changes in miRNA expression. Therefore, the contribution of miRNAs to evolutionary change remains unknown [1, 4]. Drosophila melanogaster subgroup species display a portion of trichome-free cuticle on the femur of the second leg called the "naked valley." It was previously shown that Ultrabithorax (Ubx) is involved in naked valley variation between D. melanogaster and D. simulans [5, 6]. However, naked valley size also varies among populations of D. melanogaster, ranging from 1,000 up to 30,000 MUm(2). We investigated the genetic basis of intraspecific differences in the naked valley in D. melanogaster and found that neither Ubx nor shavenbaby (svb) [7, 8] contributes to this morphological difference. Instead, we show that changes in mir-92a expression underlie the evolution of naked valley size in D. melanogaster through repression of shavenoid (sha) [9]. Therefore, our results reveal a novel mechanism for morphological evolution and suggest that modulation of the expression of miRNAs potentially plays a prominent role in generating organismal diversity. PMID- 23453956 TI - Action video games make dyslexic children read better. AB - Learning to read is extremely difficult for about 10% of children; they are affected by a neurodevelopmental disorder called dyslexia [1, 2]. The neurocognitive causes of dyslexia are still hotly debated [3-12]. Dyslexia remediation is far from being fully achieved [13], and the current treatments demand high levels of resources [1]. Here, we demonstrate that only 12 hr of playing action video games-not involving any direct phonological or orthographic training-drastically improve the reading abilities of children with dyslexia. We tested reading, phonological, and attentional skills in two matched groups of children with dyslexia before and after they played action or nonaction video games for nine sessions of 80 min per day. We found that only playing action video games improved children's reading speed, without any cost in accuracy, more so than 1 year of spontaneous reading development and more than or equal to highly demanding traditional reading treatments. Attentional skills also improved during action video game training. It has been demonstrated that action video games efficiently improve attention abilities [14, 15]; our results showed that this attention improvement can directly translate into better reading abilities, providing a new, fast, fun remediation of dyslexia that has theoretical relevance in unveiling the causal role of attention in reading acquisition. PMID- 23453957 TI - A mitochondrial ribosomal and RNA decay pathway blocks cell proliferation. AB - Proliferating cells require coordinated gene expression between the nucleus and mitochondria in order to divide, ensuring sufficient organelle number in daughter cells [1]. However, the machinery and mechanisms whereby proliferating cells monitor mitochondria and coordinate organelle biosynthesis remain poorly understood. Antibiotics inhibiting mitochondrial translation have emerged as therapeutics for human cancers because they block cell proliferation [2, 3]. These proliferative defects were attributable to modest decreases in mitochondrial respiration [3, 4], even though tumors are mainly glycolytic [5] and mitochondrial respiratory chain function appears to play a minor role in cell proliferation in vivo [6]. Here we challenge this interpretation by demonstrating that one class of antiproliferative antibiotic induces stalled mitochondrial ribosomes, which triggers a mitochondrial ribosome and RNA decay pathway. Rescue of the stalled mitochondrial ribosomes initiates a retrograde signaling response to block cell proliferation and occurs prior to any loss of mitochondrial respiration. The loss of respiratory chain function is simply a downstream effect of impaired mitochondrial translation and not the antiproliferative signal. This mitochondrial ribosome quality-control pathway is actively monitored in cells and constitutes an important organelle checkpoint for cell division. PMID- 23453958 TI - Nanostructured and thermoresponsive recombinant biopolymer-based microcapsules for the delivery of active molecules. AB - Multilayer capsules conceived at the nano- and microscales are receiving increasing interest due to their potential role as carriers of biomolecules for drug delivery and tissue engineering. Herein we report the construction of microcapsules by the sequential adsorption of chitosan and a biomimetic elastin like recombinamer into nanostructured layers on inorganic microparticle templates. The release profile of bovine serum albumin, which was studied at 25 and 37 degrees C, shows higher retention and Fickian diffusion at physiological temperature. The self-assembled multilayers act as a barrier and allowed for sustained release over 14 days. The capsules studied are non-cytotoxic towards L929 cells, thereby suggesting multiple applications in the fields of biotechnology and bioengineering, where high control of the delivery of therapeutics and growth/differentiation factors is required. FROM THE CLINICAL EDITOR: In this paper, the construction of microcapsules by sequential adsorption of chitosan and a biomimetic, elastin-like recombinamer into nanostructured layers on inorganic microparticle templates is reported. The layers demonstrated sustained drug release over 14 days. These microcapsules are non-cytotoxic toward L929 cells, suggesting multiple applications where high control of drug or growth factor delivery is required. PMID- 23453960 TI - Use of antibody gene library for the isolation of specific single chain antibodies by ampicillin-antigen conjugates. AB - Isolation of recombinant antibodies from antibody libraries is commonly performed by different molecular display formats including phage display and ribosome display or different cell-surface display formats. We describe a new method which allows the selection of Escherichia coli cells producing the required single chain antibody by cultivation in presence of ampicillin conjugated to the antigen of interest. The method utilizes the neutralization of the conjugate by the produced single chain antibody which is secreted to the periplasm. Therefore, a new expression system based on the pET26b vector was designed and a library was constructed. The method was successfully established first for the selection of E. coli BL21 Star (DE3) cells expressing a model single chain antibody (anti fluorescein) by a simple selection assay on LB-agar plates. Using this selection assay, we could identify a new single chain antibody binding biotin by growing E. coli BL21 Star (DE3) containing the library in presence of a biotin-ampicillin conjugate. In contrast to methods as molecular or cell surface display our selection system applies the soluble single chain antibody molecule and thereby avoids undesired effects, e.g. by the phage particle or the yeast fusion protein. By selecting directly in an expression strain, production and characterization of the selected single chain antibody is possible without any further cloning or transformation steps. PMID- 23453959 TI - PEGylation of cationic, shell-crosslinked-knedel-like nanoparticles modulates inflammation and enhances cellular uptake in the lung. AB - The airway provides a direct route for administration of nanoparticles bearing therapeutic or diagnostic payloads to the lung, however optimization of nanoplatforms for intracellular delivery remains challenging. Poly(ethylene glycol) (PEG) surface modification improves systemic performance but less is known about PEGylated nanoparticles administered to the airway. To test this, we generated a library of cationic, shell crosslinked knedel-like nanoparticles (cSCKs), including PEG (1.5 kDa PEG; 2, 5, 10 molecules/polymer arm) on the outer shell. Delivery of PEGylated cSCK to the mouse airway showed significantly less inflammation in a PEG dose-dependent manner. PEGylation also enhanced the entry of cSCKs in lung alveolar epithelial cells and improved surfactant penetration. The PEGylation effect could be explained by the altered mechanism of endocytosis. While non-PEGylated cSCKs used the clathrin-dependent route for endocytosis, entry of PEGylated cSCK was clathrin-independent. Thus, nanoparticle surface modification with PEG represents an advantageous design for lung delivery. FROM THE CLINICAL EDITOR: In this study, the effects of PEGylation were studied on cross linked knedel-like nanoparticles in drug delivery through the lungs, demonstrating less airway inflammation in the studied model than with non PEGylated nanoparticles, which suggests an overall favorable profile of PEGylated nanoparticles for alveolar delivery. PMID- 23453961 TI - Copious urinary excretion of a male Syrian hamster (Mesocricetus auratus) salivary gland protein after its endocrine-like release upon beta-adrenergic stimulation. AB - Salivary glands, although widely considered as typically exocrine, may also release specific proteins in an endocrine manner. However, endocrine release of salivary gland proteins is not generally acknowledged since the evidences are not easily demonstrable. Submandibular salivary glands (SMG) of male Syrian hamsters express male-specific secretory proteins (MSP; which are lipocalins) visible in SDS-PAGE of SMG extracts, as major bands and also detectable in immunoblots of whole-saliva and urine as low MSP crossreactions. We report here that MSP is localized in acinar cells of SMG and acute treatment with isoproterenol (IPR; non specific beta1/beta2-adrenergic agonist) results in considerable release of MSP in SMG-saliva. Moreover, acute IPR treatment markedly depletes SMG-MSP in a dose- and time-dependent manner. However, MSP depleted from SMG, far exceeds that recovered in SMG-saliva. Blood, submandibular lymph nodes and kidney of IPR treated males showed MSP crossreactions and SDS-PAGE of their urine revealed profuse MSP excretion; this was undetectable in IPR-treated-SMG-ablated males, confirming that a substantial amount of MSP depleted from SMG after IPR treatment enters circulation and is excreted in urine. Treatments with specific beta1- or beta2-adrenergic agonists also reduced SMG-MSP levels and resulted in copious urinary excretion of MSP. Co-treatments with specific beta1/beta2-blockers indicated that above effects of IPR, beta1- and even beta2-agonists are very likely mediated by beta1-adrenoceptors. MSP's detection by SDS-PAGE in urine after beta-agonist treatment is a compelling and easily demonstrable evidence of release into circulation of a salivary gland protein. The possible means (endocrine-like or otherwise) of MSP's release into circulation and significance of its presence in saliva, blood and urine of male hamsters are discussed. PMID- 23453963 TI - Sex peptides and MIPs can activate the same G protein-coupled receptor. AB - In many animal species, copulation elicits a number of physiological and behavioral changes in the female partner. In Drosophila melanogaster, the main molecular effector of these physiological responses has been identified as sex peptide (SP). The sex peptide receptor (SPR) has been characterized and recently, its activation by Drosophila myoinhibiting peptides (MIPs)-in addition to SP-has been demonstrated. The myoinhibiting peptides are members of a conserved peptide family, also known as B-type allatostatins, which generally feature the C terminal motif -WX6Wamide. PMID- 23453962 TI - Photoreceptive oscillators within neurons of the premammillary nucleus (PMM) and seasonal reproduction in temperate zone birds. AB - The pathway for light transmission regulating the reproductive neuroendocrine system in temperate zone birds remains elusive. Based on the evidence provided from our studies with female turkeys, it is suggested that the circadian clock regulating reproductive seasonality is located in putatively photosensitive dopamine-melatonin (DA-MEL) neurons residing in the premammillary nucleus (PMM) of the caudal hypothalamus. Melanopsin is expressed by these neurons; a known photopigment which mediates light information pertaining to the entrainment of the clock. Exposure to a gonad stimulatory photoperiod enhances the activity of the DAergic system within DA-MEL neurons. DAergic activity encoding the light information is transmitted to the pars tuberalis, where thyroid-stimulating hormone, beta (TSHbeta) cells reside, and induces the release of TSH. TSH stimulates tanycytes lining the base of the third ventricle and activates type 2 deiodinase in the ependymal which enhances triiodothyronine (T3) synthesis. T3 facilitates the release of gonadotropin-releasing hormone-I which stimulates luteinizing hormone/follicle stimulating hormone release and gonad recrudescence. These data taken together with the findings that clock genes are rhythmically expressed in the PMM where DA-MEL neurons are localized imply that endogenous oscillators containing photoreceptors within DA-MEL neurons are important in regulating the DA and MEL rhythms that drive the circadian cycle controlling seasonal reproduction. PMID- 23453964 TI - Expression and regulation of miR-17a and miR-430b in zebrafish ovarian follicles. AB - MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression and control many developmental and physiological processes. Oocyte maturation in fish is mainly regulated by luteinizing hormone (LH) and maturation-inducing hormone (MIH). In addition, growth factors, including members of the transforming growth factor beta (TGF-beta) superfamily, have also been shown to play important roles in regulating oocyte maturation. In this study, we determined the expression and regulation of two miRNAs, miR-17a and miR-430b, which potentially target signalling molecules in the TGF-beta pathway, in zebrafish ovarian follicles. Using real-time PCR, we observed that miR-17a and miR-430b levels in follicular cells were significantly lower in late vitellogenic and full grown follicles than in early vitellogenic follicles. Treatment with a LH analog, human chorionic gonadotropin, significantly down-regulated miR-17a and miR-430b expression in follicular cells but had no effect on their expression in oocytes. Forskolin also inhibited follicular cell miR-430b expression; however, no significant changes in miR-17a levels were observed after Forskolin treatment. Finally, MIH did not affect the expression of these miRNAs either in follicular cells or oocytes at the time points tested. These findings suggest that miR-17a and miR-430b may be involved in the regulation of follicle development and oocyte maturation in zebrafish. PMID- 23453965 TI - Origin of chordate peptides by horizontal protozoan gene transfer in early metazoans and protists: evolution of the teneurin C-terminal associated peptides (TCAP). AB - The teneurin C-terminal associated peptides (TCAP) are found at the extracellular face in C-terminal region of the teneurin transmembrane proteins. One of these peptides, TCAP-1 is independently transcribed as a smaller bioactive peptide that possesses a number of stress response-attenuating activities. The teneurin-TCAP system appears to be the result of a horizontal gene transfer from a prokaryotic proteinaceous polymorphic toxin to a choanoflagellate. In a basal metazoan, the TCAP region has been modified from a toxin to a soluble intercellular signaling system. New studies indicate that the teneurin-TCAP system form a complex signaling system associated with adhesion, cytoskeletal regulation and intracellular signaling. TCAP-1 is highly conserved in all vertebrates and in mammals, inhibits corticotropin-releasing factor (CRF)-associated stress. Using the TCAP-teneurin system as a model, it is likely that numerous peptide systems in the Chordata began as a result of horizontal gene transfer from prokaryotes early in metazoan ancestry. PMID- 23453966 TI - Possible involvement of A2A and A3 receptors in modulation of insulin secretion and beta-cell survival in mouse pancreatic islets. AB - Adenosine A1, A2A, A2B and A3 receptor mRNAs were found to be expressed in mouse pancreatic islets and Beta-TC6 cells but their physiological or pharmacological actions are not fully clarified. We showed that adenosine (100 MUM) augmented insulin secretion by islets in the presence of either normal (5.5 mM) or a high concentration of glucose (20 mM). The augmentation of insulin secretion in the presence of high glucose was blocked by an A2A antagonist, but not by A2B and A3 antagonists, while an A1 antagonist potentiated the adenosine effect. An adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA) as well as A1, A2A and A3 receptor agonists also produced stimulation. On the other hand, an A3 agonist markedly reduced Beta-TC6 cell proliferation and the islet cell viability, while adenosine and NECA did not. The effect of A3 agonist was partially blocked by the A3 antagonist. In addition, treatment with the A3 agonist produced a small but significant extent of apoptosis in Beta-TC6 cells as judged by terminal transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. These results combined together suggested that like the A1 receptor, activation of A2A receptors by adenosine results in augmented insulin secretion, while the A3 receptor is involved in modulation of the survival of pancreatic beta-cells. PMID- 23453968 TI - Neuropeptide-gated perception of appetitive olfactory inputs in Drosophila larvae. AB - Understanding how smell or taste translates into behavior remains challenging. We have developed a behavioral paradigm in Drosophila larvae to investigate reception and processing of appetitive olfactory inputs in higher-order olfactory centers. We found that the brief presentation of appetitive odors caused fed larvae to display impulsive feeding of sugar-rich food. Deficiencies in the signaling of neuropeptide F (NPF), the fly counterpart of neuropeptide Y (NPY), blocked appetitive odor-induced feeding by disrupting dopamine (DA)-mediated higher-order olfactory processing. We have identified a small number of appetitive odor-responsive dopaminergic neurons (DL2) whose activation mimics the behavioral effect of appetitive odor stimulation. Both NPF and DL2 neurons project to the secondary olfactory processing center; NPF and its receptor NPFR1 mediate a gating mechanism for reception of olfactory inputs in DL2 neurons. Our findings suggest that eating for reward value is an ancient behavior and that fly larvae are useful for studying neurobiology and the evolution of olfactory reward driven behavior. PMID- 23453967 TI - Mosaic analysis with double markers reveals cell-type-specific paternal growth dominance. AB - Genomic imprinting leads to preferred expression of either the maternal or paternal alleles of a subset of genes. Imprinting is essential for mammalian development, and its deregulation causes many diseases. However, the functional relevance of imprinting at the cellular level is poorly understood for most imprinted genes. We used mosaic analysis with double markers (MADM) in mice to create uniparental disomies (UPDs) and to visualize imprinting effects with single-cell resolution. Although chromosome 12 UPD did not produce detectable phenotypes, chromosome 7 UPD caused highly significant paternal growth dominance in the liver and lung, but not in the brain or heart. A single gene on chromosome 7, encoding the secreted insulin-like growth factor 2 (IGF2), accounts for most of the paternal dominance effect. Mosaic analyses implied additional imprinted loci on chromosome 7 acting cell autonomously to transmit the IGF2 signal. Our study reveals chromosome- and cell-type specificity of genomic imprinting effects. PMID- 23453969 TI - IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex. AB - IkappaB kinase epsilon (IKKepsilon, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-kappaB activation. Here, we show that IKKepsilon is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1beta stimulation induces IKKepsilon K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKepsilon kinase activity, IKKepsilon-mediated NF-kappaB activation, and IKKepsilon-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKepsilon does not affect its overall structure but impairs the recruitment of canonical NF-kappaB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKepsilon. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKepsilon activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene. PMID- 23453970 TI - Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. AB - Mutations in WNK kinases cause the human hypertensive disease pseudohypoaldosteronism type II (PHAII), but the regulatory mechanisms of the WNK kinases are not well understood. Mutations in kelch-like 3 (KLHL3) and Cullin3 were also recently identified as causing PHAII. Therefore, new insights into the mechanisms of human hypertension can be gained by determining how these components interact and how they are involved in the pathogenesis of PHAII. Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. Transgenic mice overexpressing WNK4 showed PHAII phenotypes, and WNK4 protein was indeed increased in Wnk4(D561A/+) PHAII model mice. Thus, WNK4 is a target for KLHL3-mediated ubiquitination, and the impaired ubiquitination of WNK4 is a common mechanism of human hereditary hypertension. PMID- 23453971 TI - Crystal structure and mechanism of activation of TANK-binding kinase 1. AB - Tank-binding kinase I (TBK1) plays a key role in the innate immune system by integrating signals from pattern-recognition receptors. Here, we report the X-ray crystal structures of inhibitor-bound inactive and active TBK1 determined to 2.6 A and 4.0 A resolution, respectively. The structures reveal a compact dimer made up of trimodular subunits containing an N-terminal kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD). Activation rearranges the KD into an active conformation while maintaining the overall dimer conformation. Low-resolution SAXS studies reveal that the missing C-terminal domain (CTD) extends away from the main body of the kinase dimer. Mutants that interfere with TBK1 dimerization show significantly reduced trans-autophosphorylation but retain the ability to bind adaptor proteins through the CTD. Our results provide detailed insights into the architecture of TBK1 and the molecular mechanism of activation. PMID- 23453973 TI - Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1-7) action on these pathways in cultured human myotubes. AB - Glycogen synthase (GS) is activated by glucose/glycogen depletion in skeletal muscle cells, but the contributing signaling pathways, including the chief GS regulator GSK3, have not been fully defined. The MEK/ERK pathway is known to regulate GSK3 and respond to glucose. The aim of this study was to elucidate the GSK3 and MEK/ERK pathway contribution to GS activation by glucose deprivation in cultured human myotubes. Moreover, we tested the glucose-dependence of GSK3 and MEK/ERK effects on GS and angiotensin (1-7) actions on these pathways. We show that glucose deprivation activated GS, but did not change phospho-GS (Ser640/1), GSK3beta activity or activity-activating phosphorylation of ERK1/2. We then treated glucose-replete and -depleted cells with SB415286, U0126, LY294 and rapamycin to inhibit GSK3, MEK1/2, PI3K and mTOR, respectively. SB415286 activated GS and decreased the relative phospho-GS (Ser640/1) level, more in glucose-depleted than -replete cells. U0126 activated GS and reduced the phospho GS (Ser640/1) content significantly in glucose-depleted cells, while GSK3beta activity tended to increase. LY294 inactivated GS in glucose-depleted cells only, without affecting relative phospho-GS (Ser640/1) level. Rapamycin had no effect on GS activation. Angiotensin-(1-7) raised phospho-ERK1/2 but not phospho GSK3beta (Ser9) content, while it inactivated GS and increased GS phosphorylation on Ser640/1, in glucose-replete cells. In glucose-depleted cells, angiotensin-(1 7) effects on ERK1/2 and GS were reverted, while relative phospho-GSK3beta (Ser9) content decreased. In conclusion, activation of GS by glucose deprivation is not due to GS Ser640/1 dephosphorylation, GSK3beta or ERK1/2 regulation in cultured myotubes. However, glucose depletion enhances GS activation/Ser640/1 dephosphorylation due to both GSK3 and MEK/ERK inhibition. Angiotensin-(1-7) inactivates GS in glucose-replete cells in association with ERK1/2 activation, not with GSK3 regulation, and glucose deprivation reverts both hormone effects. Thus, the ERK1/2 pathway negatively regulates GS activity in myotubes, without involving GSK3 regulation, and as a function of the presence of glucose. PMID- 23453972 TI - Structure and ubiquitination-dependent activation of TANK-binding kinase 1. AB - Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) induces type I interferon expression and modulates nuclear factor kappaB (NF-kappaB) signaling. Here, we describe the 2.4 A-resolution crystal structure of nearly full-length TBK1 in complex with specific inhibitors. The structure reveals a dimeric assembly created by an extensive network of interactions among the kinase, ubiquitin-like, and scaffold/dimerization domains. An intact TBK1 dimer undergoes K63-linked polyubiquitination on lysines 30 and 401, and these modifications are required for TBK1 activity. The ubiquitination sites and dimer contacts are conserved in the close homolog inhibitor of kappaB kinase epsilon (IKKepsilon) but not in IKKbeta, a canonical IKK that assembles in an unrelated manner. The multidomain architecture of TBK1 provides a structural platform for integrating ubiquitination with kinase activation and IRF3 phosphorylation. The structure of TBK1 will facilitate studies of the atypical IKKs in normal and disease physiology and further the development of more specific inhibitors that may be useful as anticancer or anti-inflammatory agents. PMID- 23453974 TI - A fluorescent peptide substrate facilitates investigation of ghrelin recognition and acylation by ghrelin O-acyltransferase. AB - Ghrelin is a peptide hormone involved in regulation of appetite, glucose homeostasis, and a range of other physiological processes. Ghrelin requires a unique posttranslational modification, octanoylation of a serine side chain, to bind its cognate receptor to activate signaling. The enzyme that catalyzes this modification, ghrelin O-acyltransferase (GOAT), is receiving increased interest as a potential drug target for the treatment of obesity, diabetes, and other diseases proposed to be linked to ghrelin signaling. In this study, we report the development of a novel fluorescence-based assay for GOAT activity and the use of this assay to investigate GOAT inhibition and interactions underlying human GOAT (hGOAT) substrate selectivity. Using a series of mutations and chemical modifications of our fluorescent peptide substrate, we have identified specific groups on the first two amino acids of ghrelin that potentially contribute to ghrelin recognition by hGOAT. These data provide the first molecular-level information regarding interactions within the ghrelin-hGOAT complex. Defining the interactions used by hGOAT to bind and recognize ghrelin will provide insight into the structure of the hGOAT active site, aid in the design and optimization of targeted hGOAT inhibitors, and help to assess the possibility of novel hGOAT substrates beyond ghrelin. PMID- 23453975 TI - Supporting immunoassay design with biophysical tools. AB - In this article, we demonstrate how the application of biophysical tools facilitates the design of robust immunoassays. The binding characteristics of the reagents used in an immunoassay determine the assay response to the analyte concentrations. We applied several biophysical methods to obtain pertinent equilibrium and kinetic coefficients and used this information in the design of a microparticle-based immunoassay for detection of neutrophil gelatinase-associated lipocalin (NGAL), which is a new diagnostic marker of acute kidney injury (AKI). We characterized the conformational stability of recombinant human NGAL and the solution phase binding properties of six monoclonal antibodies. A preferred antibody pair was selected on the basis of the affinities of the antibodies and their sandwich pairing capabilities. One of the antibodies was coated on magnetic microparticles, and the second antibody was conjugated with a reporter group. The apparent kinetic rates of the immobilized and conjugated antibodies were measured and used to compute the assay calibration plot for the target concentration range of the analyte at specific incubation times. The experimental assay results were found to be in good agreement with the computed data, confirming that applying biophysical tools provides a solid foundation for immunoassay design and optimization. PMID- 23453976 TI - Pumpless steady-flow microfluidic chip for cell culture. AB - The current research engineered a pumpless energy-efficient microfluidic perfusion cell culture chip that works by modifying the basic gravity-driven siphon flow using an intravenous (IV) infusion set as a conventional, inexpensive, and sterile tool. The IV set was modified to control the constant hydrostatic head difference, thereby maintaining the steady flow rate medium perfusion. The micro-bioreactor chip demonstrated flexibility in controlling a wide range of flow rates from 0.1 to 10ml/min, among which 1- and 5-ml/min flow rates were examined as suitable shear flows for long-term dermal fibroblast cell culture, paving the way for artificial skin development. PMID- 23453977 TI - Coping with task demand in aging using neural compensation and neural reserve triggers primarily intra-hemispheric-based neurofunctional reorganization. AB - It has been proposed that cognitive reserve is supported by two neural mechanisms: neural compensation and neural reserve. The purpose of this study was to test how these neural mechanisms are solicited in aging in the context of visual selective attention processing and whether they are inter- or intra hemispheric. Younger and older participants were scanned using fMRI during a visual letter-matching task with two attentional load levels. The results show that in the low-load condition, the older participants activated frontal superior gyri bilaterally; these regions were not activated in the younger participants, in accordance with the compensation mechanism and the Posterior-Anterior Shift in Aging (PASA) phenomenon. However, when task demand increased, the older participants recruited the same regions (parietal) as the younger ones, showing the involvement of a similar neural reserve mechanism. This result suggests that successful cognitive aging relies on the concurrent use of both neural compensation and neural reserve in high-demand tasks, calling on the frontoparietal network. In addition, the finding of intra-hemispheric-based neurofunctional reorganization with a PASA phenomenon for all attentional load levels suggests that the PASA phenomenon is a function more of compensation than of reserve. PMID- 23453978 TI - Thalassic biogas production from sea wrack biomass using different microbial seeds: cow manure, marine sediment and sea wrack-associated microflora. AB - Sea wrack (dislodged sea grasses and seaweeds) was used in biogas production. Fresh water scarcity in island communities where sea wrack could accumulate led to seawater utilization as liquid substrate. Three microbial seeds cow manure (CM), marine sediment (MS), and sea wrack-associated microflora (SWA) were explored for biogas production. The average biogas produced were 2172+/-156 mL (MS), 1223+/-308 mL (SWA) and 551+/-126 mL (CM). Though methane potential (396.9 mL(CH4) g(-1) volatile solid) computed from sea wrack proximate values was comparable to other feedstocks, highest methane yield was low (MS=94.33 mL(CH4) g(-1) VS). Among the microbial seeds, MS proved the best microbial source in utilizing sea wrack biomass and seawater. However, salinity (MS=420/00) observed exceeded average seawater salinity (340/00). Hence, methanogenic activity could have been inhibited. This is the first report on sea wrack biomass utilization for thalassic biogas production. PMID- 23453979 TI - Microbial formation of palladium nanoparticles by Geobacter sulfurreducens for chromate reduction. AB - Geobacter sulfurreducens was studied for the reduction of Pd(II) and production of Pd(0) nanoparticles capable of reducing Cr(VI). Transmission electronic microscopy, energy dispersive X-ray and X-ray diffraction analyses revealed that the nanoscale Pd(0) particles formed were associated with the cell surface and located inside the periplasm. The increase of cell dry weight (CDW):Pd ratio and addition of anthraquinone-2,6-disulfonate (AQDS) not only stimulated Pd(II) reduction, but also resulted in increase of nanoparticle number, decrease of particle diameter and improvement of Cr(VI) reduction efficiency. The relationship between reduction rate and initial Cr(VI) concentration (150-750 MUM) followed Michaelis-Menten kinetics (Vmax=3.6 MUmol h(-1) mg bio-Pd(-1) and Km=891.3 MUM). These findings indicated the potential of using G. sulfurreducens cells for reclamation of palladium, formation of Pd(0) nanoparticles and efficient treatment of Cr(VI) pollution. PMID- 23453980 TI - Isolation of a BTEX-degrading bacterium, Janibacter sp. SB2, from a sea-tidal flat and optimization of biodegradation conditions. AB - An enrichment culture was established using seawater containing BTEX (benzene, toluene, ethylbenzene and xylene) compounds to isolate a BTEX-degrading bacterium from contaminated sea-tidal flat. The enriched microbial communities were characterized by 16S rRNA-based DGGE profiling, which indicated that a Janibacter species was dominant during the enrichment. Strain SB2, corresponding to the major band and able to degrade all BTEX compounds, was isolated and characterized. NH4Cl, NaH2PO4, cell mass and BTEX concentrations were used as independent variables to optimize the degradation of BTEX by strain SB2 in a tidal flat and a statistically significant (R(2)=0.8933, p<0.0001) quadratic polynomial mathematical model was suggested. For the initial concentration of 240 mg/L BTEX in a slurry system containing 3.0*10(7) cells/L, 45.5% BTEX removal was observed under the optimum condition of NH4Cl and NaH2PO4, while 32.2% BTEX removal was observed under the untreated condition of NH4Cl and NaH2PO4. PMID- 23453981 TI - Identification of Monoraphidium contortum as a promising species for liquid biofuel production. AB - In this work, 30 microalgae strains from 17 genera were investigated in regard to biomass productivity in photoautotrophic growth conditions, lipid amount, lipid quality and biomass degradability. Six strains could be identified with robust phototrophic growth properties and high biomass productivities equal or above 300 mg l(-1) day(-1). Anaerobic fermentation of the algal biomass was most efficient for the marine members of the genera Dunaliella and Navicula, while biogas production with the freshwater strains generally resulted in lower methane yields. Monoraphidium contortum was identified as promising candidate for liquid biofuel production, characterized by high biomass productivity during maximum growth (maximum increase of 896 mg dry biomass weight (DW) l(-1) day(-1)) and a promising lipid profile. Neutral lipid production was strongly induced in M. contortum by nitrogen deficient conditions and accumulated to up to 20.4+/-2.2% of DW. PMID- 23453982 TI - Fermentation approach for enhancing 1-butanol production using engineered butanologenic Escherichia coli. AB - In this study, engineered butanologenic Escherichia coli T5 constructed by the OGAB method was used for 1-butanol production. The results showed the feasibility of the artificial butanologenic operon, (Promoter Pr)-thil-crt-bcd-etfB-etfA-hbd adhe1-adhe, where the 1-butanol titer, specific BuOH yield, and BuOH yield were 4.50 mg/L, 4.50 mg-BuOH/g cell, and 0.35 mg-BuOH/g-glucose, respectively. Fermentation conditions of anaerobic, low initial concentrations of carbon sources, low oxidation state of carbon source, pH of 6, addition of glutathione and citrate, had been shown for efficiently improving the 1-butanol production. The premise behind these fermentation approaches can be categorized into two lines of reasoning, either elevated the availability of acetyl-CoA or lowered the intracellular redox state. By comparing the fermentation conditions tested in this study, pH has been shown to be the most efficiency strategies for 1-butanol production while the replacement of glucose with glycerol provides the highest improvement in butanol yield. PMID- 23453983 TI - Performance evaluation and bacterial characterization of membrane bioreactors. AB - A bench-scale conventional membrane bioreactor (C-MBR), a moving bed membrane bioreactor (MB-MBR) and an anoxic/oxic membrane bioreactor (A/O-MBR), operating under similar feed, environmental and operating conditions, were each evaluated for their treatment performance and bacterial diversity. MBRs were compared for the removal of organics (COD) and nutrients (N and P) while pure culture techniques were employed for bacterial isolation and an API 20E kit was used to identify the isolates. Pseudomonas aeruginosa, selected as a representative of denitrifying microorganisms, was isolated only from the A/O-MBR using Citrimide Agar. Using PCR, the nitrifying bacteria Nitrosomonas europaea was detected only in the MB-MBR. On the other hand, Nitrobacter winogradskyi was detected in all three reactors. Addition of media and maintenance of a lesser DO resulted in the highest TN removal in the A/O-MBR as compared to the C-MBR and the MB-MBR, whereas better nitrification was observed in the MB-MBR than in the C-MBR. PMID- 23453984 TI - Continuous mode of carbon dioxide sequestration by C. sorokiniana and subsequent use of its biomass for hydrogen production by E. cloacae IIT-BT 08. AB - The present study investigated to find out the suitability of the CO2 sequestered algal biomass of Chlorella sorokiniana as substrate for the hydrogen production by Enterobacter cloacae IIT-BT 08. The maximum biomass productivity in continuous mode of operation in autotrophic condition was enhanced from 0.05 g L(-1) h(-1) in air to 0.11 g L(-1) h(-1) in 5% air-CO2 (v/v) gas mixture at an optimum dilution rate of 0.05 h(-1). Decrease in steady state biomass and productivity was less sensitive at higher dilution and found fitting with the model proposed by Eppley and Dyer (1965). Pretreated algal biomass of 10 g L(-1) with 2% (v/v) HCl-heat was found most suitable for hydrogen production yielding 9+/-2 mol H2 (kg COD reduced)(-1) and was found fitting with modified Gompertz equation. Further, hydrogen energy recovery in dark fermentation was significantly enhanced compared to earlier report of hydrogen production by biophotolysis of algae. PMID- 23453985 TI - Hypericin-mediated photooxidative damage of alpha-crystallin in human lens epithelial cells. AB - St. John's wort (Hypericum perforatum), a perennial herb native to Europe, is widely used for and seems to be effective in treatment of mild to moderate depression. Hypericin, a singlet oxygen-generating photosensitizer that absorbs in both the visible and the UVA range, is considered to be one of the bioactive ingredients of St. John's wort, and commercial preparations are frequently calibrated to contain a standard concentration. Hypericin can accumulate in ocular tissues, including lenses, and can bind in vitro to alpha-crystallin, a major lens protein. alpha-crystallin is required for lens transparency and also acts as a chaperone to ensure its own integrity and the integrity of all lens proteins. Because there is no crystallin turnover, damage to alpha-crystallin is cumulative over the lifetime of the lens and can lead to cataracts, the principal cause of blindness worldwide. In this work we study hypericin photosensitization of alpha-crystallin and detect extensive polymerization of bovine alpha crystallin exposed in vitro to hypericin and UVA. We use fluorescence confocal microscopy to visualize binding between hypericin and alpha-crystallin in a human lens epithelial (HLE) cell line. Further, we show that UVA irradiation of hypericin-treated HLE cells results in a dramatic decrease in alpha-crystallin detection concurrent with a dramatic accumulation of the tryptophan oxidation product N-formylkynurenine (NFK). Examination of actin in HLE cells indicates that this cytoskeleton protein accumulates NFK resulting from hypericin-mediated photosensitization. This work also shows that filtration of wavelengths <400nm provides incomplete protection against alpha-crystallin modification and NFK accumulation, suggesting that even by wearing UV-blocking sunglasses, routine users of St. John's wort cannot adequately shield their lenses from hypericin mediated photosensitized damage. PMID- 23453986 TI - Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals. AB - The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo regulation, and axis of regulation of other endocrine systems, sexual behaviour and fertility and cardiovascular function. Therefore, concern about TH disruption (THD) has resulted in strategies being developed to identify THD chemicals (THDCs). Information on potential of chemicals causing THD is typically derived from animal studies. For the majority of chemicals, however, this information is either limited or unavailable. It is also unlikely that animal experiments will be performed for all THD relevant chemicals in the near future for ethical, financial and practical reasons. In addition, typical animal experiments often do not provide information on the mechanism of action of THDC, making it harder to extrapolate results across species. Relevant effects may not be identified in animal studies when the effects are delayed, life stage specific, not assessed by the experimental paradigm (e.g., behaviour) or only occur when an organism has to adapt to environmental factors by modulating TH levels. Therefore, in vitro and in silico alternatives to identify THDC and quantify their potency are needed. THDC have many potential mechanisms of action, including altered hormone production, transport, metabolism, receptor activation and disruption of several feed-back mechanisms. In vitro assays are available for many of these endpoints, and the application of modern '-omics' technologies, applicable for in vivo studies can help to reveal relevant and possibly new endpoints for inclusion in a targeted THDC in vitro test battery. Within the framework of the ASAT initiative (Assuring Safety without Animal Testing), an international group consisting of experts in the areas of thyroid endocrinology, toxicology of endocrine disruption, neurotoxicology, high-throughput screening, computational biology, and regulatory affairs has reviewed the state of science for (1) known mechanisms for THD plus examples of THDC; (2) in vitro THD tests currently available or under development related to these mechanisms; and (3) in silico methods for estimating the blood levels of THDC. Based on this scientific review, the panel has recommended a battery of test methods to be able to classify chemicals as of less or high concern for further hazard and risk assessment for THD. In addition, research gaps and needs are identified to be able to optimize and validate the targeted THD in vitro test battery for a mechanism-based strategy for a decision to opt out or to proceed with further testing for THD. PMID- 23453987 TI - Genetic diversity and molecular evolution of the rabies virus matrix protein gene in China. AB - To investigate the diversity of rabies virus (RABV) matrix protein (M) gene in the current Chinese rabies epidemic, we fully examined M gene of 63 street RABVs (Virus isolated from naturally infected animals), and performed phylogenetic and mutational analysis. Our results indicate that the Chinese RABV M gene is well conserved with 90.6% to 100% amino acid similarity. Analysis of the mutations indicates that the sequences can be divided into four groups with each group defined by distinct substitutions. The PPxY motif and residue E58, which are essential for efficient virus production and pathogenicity, were completely conserved. The estimated mean rate of nucleotide substitution was 4.6*10(-4) substitutions per site per year, and the estimated average time of the most recent common ancestor (TMRCA) was 265 years ago based on the M gene of Chinese street RABVs, which are similar to previously reported values for the glycoprotein (G) and nucleoprotein (N) gene. This indicates that the genomic RNA of RABVs circulating worldwide is stable; G, N and M genes are evolving at a similar rate. This study showed that although the Chinese RABV strains could be divided into distinct clades based on the phylogenetic analysis, their functional domains of M proteins were highly conserved. PMID- 23453988 TI - Serum concentrations of DHEA, DHEAS, 17alpha-hydroxyprogesterone, Delta4 androstenedione and testosterone in children determined by TurboFlow-LC-MS/MS. AB - Diagnosis and management of infants and children with sex steroid disorders require fast and simultaneous assessment of several sex steroid metabolites in serum at low concentrations and on small sample volumes. Therefore, we developed a sensitive and selective TurboFlow-LC-MS/MS method for quantification of DHEA, DHEAS, 17alpha-hydroxyprogesterone, Delta4-androstenedione and testosterone in serum from pre-pubertal children. Run time was 10.75 min. Limits of quantification were as follows: DHEA, 0.88 nM; DHEAS, 48 nM; 17alpha hydroxyprogesterone, 0.19 nM; Delta4-androstenedione, 0.18 nM and testosterone, 0.10nM. Intra-day relative standard deviation ranged from 4.6 to 13.8% and inter day relative standard deviation ranged from 5.7 to 15.7%. Steroid concentrations in 38 serum samples from pre-pubertal children were compared with results obtained by immunoassays for DHEAS, Delta4-androstenedione and testosterone. DHEAS gave overall similar results but with several outliers, while levels of Delta4-androstenedione were found to be much lower when analysed by LC-MS/MS. Testosterone was not detected in any of the samples analysed using a sensitive immunoassay, while 30 of 38 samples were quantifiable using the current LC-MS/MS method. The presented method is suitable in a clinical setting for simultaneous quantification of five steroids important for management of children with disorders of sex development and steroid biosynthesis defects. PMID- 23453989 TI - The American Journal of Pathology Centennial Project: the centennial celebration is over, but the science moves forward. PMID- 23453990 TI - Safety and severity of accelerations delivered from whole body vibration exercise devices to standing adults. AB - OBJECTIVES: Whole body vibration devices are used as a means to augment training, and their potential to treat a range of musculoskeletal diseases and injuries is now being considered. The goal of this work is to determine the degree to which acceleration delivered by whole body vibration devices at the plantar surfaces of a standing human is transmitted through the axial and appendicular skeleton, and how this mechanical challenge corresponds to the safety threshold limit values established by the International Standards Organization ISO-2631. DESIGN: Non blinded laboratory assessment of a range of whole body vibration devices as it pertains to acceleration transmission to healthy volunteers. METHODS: Using skin and bite-bar mounted accelerometers, transmissibility to the tibia and cranium was determined in six healthy adults standing on a programmable whole body vibration device as a function of frequency and intensity. Measures of transmissibility were then made from three distinct types of whole body vibration platforms, which delivered a 50-fold range of peak-to-peak acceleration intensities (0.3-15.1 gp-p; where 1g is Earth's gravitational field). RESULTS: For a given frequency, transmissibility was independent of intensity when below 1g. Transmissibility declined non-linearly with increasing frequency. Depending on the whole body vibration device, vibration ranged from levels considered safe by ISO-2631 for up to 8h each day (0.3 gp-p @ 30 Hz), to levels that were seven times higher than what is considered a safe threshold for even 1 min of exposure each day (15.1 gp-p @ 30 Hz). Transmissibility to the cranium was markedly attenuated by the degree of flexion in the knees. CONCLUSIONS: Vibration can have adverse effects on a number of physiologic systems. This work indicates that readily accessible whole body vibration devices markedly exceed ISO guidelines for safety, and extreme caution must be practiced when considering their use. PMID- 23453992 TI - Remembering to attend: the anterior cingulate cortex and remote memory. AB - Damage to the hippocampus, as first demonstrated with patient HM, results in a profound anterograde and temporally-graded retrograde amnesia. The observation that older memories could still be consciously recollected led to the proposal that, over time, information initially processed in the hippocampus is stored in a distributed cortical network. The anterior cingulate cortex (ACC) has recently been implicated in this process. Studies in rodents have demonstrated that the ACC is necessary for recalling behaviors learned a month or more in the past, but not for the same behaviors learned the previous day. Precisely how the ACC contributes to the recall of remote memories is unknown. Is this role distinct from myriad others proposed for the ACC, or has the approach taken in these studies of assessing function at different points after learning provided a new window through which to view established processes? The present review seeks to address this question. First, the data will be presented implicating the ACC in recall of remote memory. This will be followed by a discussion of studies describing two other primary roles of the ACC, mediating attention and premotor planning, with an emphasis on data collected in rodents, as these will be most directly comparable to the memory studies presented. The available evidence supports a connection among these roles, and suggests a possible synthesis for otherwise seemingly disparate functions reported for the ACC. PMID- 23453991 TI - Cell cycle regulation of Golgi membrane dynamics. AB - The Golgi apparatus is a membranous organelle in the cell that plays essential roles in protein and lipid trafficking, sorting, processing, and modification. Its basic structure is a stack of closely aligned flattened cisternae. In mammalian cells, dozens of Golgi stacks are often laterally linked into a ribbon like structure. Biogenesis of the Golgi during cell division occurs through a sophisticated disassembly and reassembly process that can be divided into three distinct but cooperative steps, including the deformation and reformation of the Golgi cisternae, stacks, and ribbon. Here, we review our current understanding of the protein machineries that control these three steps in the cycle of mammalian cell division: GRASP65 and GRASP55 in Golgi stack and ribbon formation; ubiquitin and AAA ATPases in postmitotic Golgi membrane fusion; and golgins and cytoskeleton in Golgi ribbon formation. PMID- 23453993 TI - L23. Renal transplantation in ANCA-associated vasculitis. PMID- 23453994 TI - [Chronic constipation in adults]. AB - Chronic constipation is a very common condition, which is responsible for a major socioeconomic burden. Primary management must rule out secondary constipation before recognizing chronic idiopathic constipation, which is the most common diagnosis. Initial treatment frequently associates simple lifestyle modifications, whose efficacy is limited, with osmotic laxatives or bulking agents. If those measures do not relieve symptoms, a switch of laxatives or a combination must be proposed. Pharmacological treatments of constipation represent a new alternative approach in case of failure of previously mentioned measures. In case of chronic constipation reluctant to all conservative therapies, specific tests are required before considering biofeedback intervention or exceptionally a surgical option. PMID- 23453995 TI - L8. Animal models of ANCA associated vasculitis: the contribution of autoantibodies and autoreactive T cells. PMID- 23453996 TI - L16. The specificities of pediatric vasculitis classification. PMID- 23453997 TI - L20. Memory T-cells in vasculitis. PMID- 23453998 TI - L49. Percutaneous interventions in Takayasu arteritis. PMID- 23453999 TI - [Healing of autoimmune hemolytic anemia only with anti-tuberculosis treatment]. PMID- 23454000 TI - L26. How antigens influence the disease: an immunologist point of view. PMID- 23454001 TI - Winning and losing in public: audiences direct future success in Japanese quail. AB - Among vertebrates, winning a fight enhances the probability of future victories and vice versa and the role of post-conflict testosterone in mediating this 'winner effect' is widely accepted. In a series of staged fights of Japanese quail (Coturnix japonica) we tested both opponents' pre-fight and post-conflict testosterone, behavior and dominance status after returning to their social groups. We found that the presence of a familiar mixed-sex audience during the encounter modulated both the testosterone response and the long-term success after a fighting experience. 'Public losers' but not 'public winners' lacked a post-conflict testosterone response, whereas without an audience both winners and losers increased testosterone metabolite levels. Long-lasting winner and loser effects exclusively occurred when the performance information was perceived by a mixed-sex audience. In further experiments we manipulated the testosterone responsiveness of either the loser or the winner. An artificial post-conflict testosterone surge after having lost a fight effectively reversed the loser effect in Japanese quail. In contrast, the 'winner effect' was not changed by blocking testosterone after the fight. Overall, male Japanese quails' post conflict testosterone was connected to the audiences and thus, own or the observers' perception of the challenge rather than to winning or losing a fight. PMID- 23454002 TI - High rates of pregnancy loss by subordinates leads to high reproductive skew in wild golden lion tamarins (Leontopithecus rosalia). AB - Across taxa, cooperative breeding has been associated with high reproductive skew. Cooperatively breeding golden lion tamarins (Leontopithecus rosalia) were long thought to have a monogynous mating system in which reproduction was limited to a single dominant female. Subordinates with few reproductive opportunities delayed dispersal and remained in the natal group to provide alloparental care to siblings, thus allowing dominant reproductive females to meet the energetic needs associated with high rates of reproduction and successful infant rearing. The goal of this study was to re-assess monogyny in wild golden lion tamarin groups based upon pregnancy diagnoses that used non-invasive enzyme immunoassay for progesterone and cortisol, combined with weekly data on individual weight gain, bi-annual physical examinations noting pregnancy and lactation status and daily behavioral observations. We established quantitative and qualitative criteria to detect and determine the timing of pregnancies that did not result in the birth of infants. Pregnancy polygyny occurred in 83% of golden lion tamarin groups studied. The loss of 64% of subordinate pregnancies compared to only 15% by dominant females limited reproductive success mainly to dominant females, thus maintaining high reproductive skew in female golden lion tamarins. Pregnancy loss by subordinate adults did not appear to result from dominant interference in subordinate hormonal mechanisms, but more likely resulted from subordinate abandonment of newborn infants to mitigate dominant aggression. PMID- 23454003 TI - Ovarian hormones promote recovery from sleep deprivation by increasing sleep intensity in middle-aged ovariectomized rats. AB - Sleep disturbances are commonly associated with menopause. Hormone replacement therapy is often used to treat various menopausal symptoms, but its efficacy for improving sleep is a matter of debate. We addressed this question by using a rodent model of ovarian hormone loss and replacement in midlife. Middle-aged female rats were ovariectomized and implanted with capsules containing estradiol with or without progesterone, or oil. After two weeks, sleep/wake states were recorded polygraphically during a 24-h baseline period, followed by 6h of sleep deprivation in the second half of the light phase, and a 24-h recovery period. During the baseline dark phase, hormone treatments increased wakefulness, and decreased non-rapid eye movement sleep (NREMS) by shortening NREMS episodes; however, NREMS EEG delta power or energy (cumulative power) was unaffected by combined hormones. Following sleep deprivation, all the groups showed NREMS and rapid eye movement sleep (REMS) rebounds, with similar relative increases from respective baseline levels. The increases in NREMS EEG delta power/energy during recovery were enhanced by combined hormones. These results from middle-aged ovariectomized rats indicate that replacement with estrogen with or without progesterone reduces baseline NREMS without affecting sleep intensity, particularly during the dark (active) phase, whereas following sleep deprivation the same hormone treatments do not affect the ability to increase NREMS or REMS, but treatment with both hormones, in particular, enhances the intensity of recovery sleep. These results support the usefulness of ovariectomized middle aged rats as a model system to study the biological effects of hormone replacement on sleep regulation. PMID- 23454004 TI - Discovery of diverse and functional antibodies from large human repertoire antibody libraries. AB - Phage display antibody libraries have a proven track record for the discovery of therapeutic human antibodies, increasing the demand for large and diverse phage antibody libraries for the discovery of new therapeutics. We have constructed naive antibody phage display libraries in both Fab and scFv formats, with each library having more than 250 billion clones that encompass the human antibody repertoire. These libraries show high fidelity in open reading frame and expression percentages, and their V-gene family distribution, VH-CDR3 length and amino acid usage mirror the natural diversity of human antibodies. Both the Fab and scFv libraries show robust sequence diversity in target-specific binders and differential V-gene usage for each target tested, supporting the use of libraries that utilize multiple display formats and V-gene utilization to maximize antibody binding diversity. For each of the targets, clones with picomolar affinities were identified from at least one of the libraries and for the two targets assessed for activity, functional antibodies were identified from both libraries. PMID- 23454005 TI - Optimization of a human IgG B-cell ELISpot assay for the analysis of vaccine induced B-cell responses. AB - B-cell responses after infection or vaccination are often measured as serum titers of antigen-specific antibodies. Since this does not address the aspect of memory B-cell activity, it may not give a complete picture of the B-cell response. Analysis of memory B cells by ELISpot is therefore an important complement to conventional serology. B-cell ELISpot was developed more than 25 years ago and many assay protocols/reagents would benefit from optimization. We therefore aimed at developing an optimized B-cell ELISpot for the analysis of vaccine-induced human IgG-secreting memory B cells. A protocol was developed based on new monoclonal antibodies to human IgG and biotin-avidin amplification to increase the sensitivity. After comparison of various compounds commonly used to in vitro-activate memory B cells for ELISpot analysis, the TLR agonist R848 plus interleukin (IL)-2 was selected as the most efficient activator combination. The new protocol was subsequently compared to an established protocol, previously used in vaccine studies, based on polyclonal antibodies without biotin avidin amplification and activation of memory B-cells using a mix of antigen, CpG, IL-2 and IL-10. The new protocol displayed significantly better detection sensitivity, shortened the incubation time needed for the activation of memory B cells and reduced the amount of antigen required for the assay. The functionality of the new protocol was confirmed by analyzing specific memory B cells to five different antigens, induced in a limited number of subjects vaccinated against tetanus, diphtheria and pertussis. The limited number of subjects did not allow for a direct comparison with other vaccine studies. Optimization of the B-cell ELISpot will facilitate an improved analysis of IgG-secreting B cells in vaccine studies. PMID- 23454006 TI - Association between SNPs in interferon regulatory factor 2 (IRF-2) gene and resistance to Aeromonas hydrophila in freshwater mussel Hyriopsis cumingii. AB - Interferon regulatory factor 2 (IRF-2) is a multi-functional transcription factor in the IRF family exhibiting both transcriptional activating and repressing activities. In this study, an IRF-2 gene (HcIRF-2) from Hyriopsis cumingii was identified and characterized. The cDNA sequence consisted of 2688 bp, encoding a 329 amino acid-protein. The amino acid sequence had a highly conserved N-terminal DBD structure, containing characteristic repeats of six tryptophan residues. The 5'-flanking region contained several transcription regulation elements such as AP1, CdxA, HSF, NIT2 and HNF-3b. Nine SNPs were obtained through direct sequencing of HcIRF-2 from resistant and susceptible stock. Only +2365T/C SNP was significantly associated with resistance/susceptibility of H. cumingii to Aeromonas hydrophila both in genotype (P = 0.021) and allele (P = 0.006) analysis. The SNPs +2248T/C and +2365T/C were in high linkage disequilibrium, and haplotype analysis revealed that haplotype TT frequency in the resistant group was significantly higher than in the susceptible group. The mortality in +2248CC genotype individuals was significantly higher than in CT and TT genotype individuals. These results indicated that haplotype TT and genotype +2248CT and +2248GT individuals were resistant to A. hydrophila, which could make them potential markers in selective breeding of H. cumingii. PMID- 23454007 TI - Time costs of fertility care: the hidden hardship of building a family. AB - OBJECTIVE: To determine the time that infertile couples spend seeking and utilizing fertility care. DESIGN: Prospective cohort. SETTING: Eight community and academic infertility practices. PATIENT(S): A total of 319 couples presenting for a fertility evaluation. INTERVENTION(S): Face-to-face and telephone interviews and questionnaires. MAIN OUTCOME MEASURE(S): Participants recorded diaries of time spent on provider visits, travel, telephone, and miscellaneous activities. Participants also recorded time off from work due to the physical and mental stress related to fertility care. Linear regression was used to assess relationship between fertility characteristics and time spent pursuing care. RESULT(S): Diaries were completed by 319 subjects. Over an 18-month time period, the average time spent on fertility care was 125 hours, equating to 15.6 days, assuming an 8-hour workday. For couples utilizing cycle-based treatments (CBT), overall time spent pursuing care averaged 142 hours, versus 58 hours for couples using other therapies, with the majority of time spent on provider visits (73 hours). After multivariable adjustment for clinical and sociodemographic characteristics, possessing a college degree and intensity of fertility treatment were independently associated with increased time spent pursuing fertility care. Furthermore, couples that spent the most time on care were significantly more likely to experience fertility-related stress. CONCLUSION(S): Over the course of 18 months of observation, couples pursuing fertility treatment dedicated large amounts of time to attaining their family-building goals. This burden on couples adds to the already significant financial and emotional burdens of fertility treatment and provides new insight into the difficulties that these couples face. PMID- 23454008 TI - Residual central nervous system damage due to organoarsenic poisoning. AB - BACKGROUND: Drinking well water contaminated with the organoarsenic compound diphenylarsinic acid (DPAA) causes central nervous system (CNS) disorders that improve within several years after last drinking such water. Subjective symptoms such as lightheadedness and dizziness appear to persist, however, suggesting CNS damage. We evaluated CNS damage due to DPAA by detecting abnormal eye movements. METHODS: Subjects comprised 29 victims of exposure to DPAA in whom this substance had been detected in the nails. Investigations were performed more than 3years following cessation of DPAA exposure. Abnormal eye movements were monitored using electronystagmography. We analysed unpaired t-test between exposure subjects who exhibited upbeat nystagmus and those who did not. Upbeat nystagmus parameters were measured, and mean values were calculated. Associations between the properties of upbeat nystagmus and maximum concentrations of DPAA among DPAA exposure were also investigated. RESULTS: Upbeat nystagmus was common among exposure victims, occurring in 23 of 29 subjects (79.0%). The subjects with upbeat nystagmus had significantly higher ratio than those without upbeat nystagmus in the points of subjective symptoms and DPAA concentration of drinking water (p<0.01). The slow-phase amplitude of upbeat nystagmus enlarged with increasing DPAA concentrations, showing a significant positive correlation (p<0.05). These findings suggest that the level of exposure to DPAA affects the properties of nystagmus. High-frequency pathological square-wave jerks (SWJ) were seen in 14 of 29 patients (48.0%), and mean SWJ frequency was 112.4+/-16.7/min. CONCLUSIONS: Detection of abnormal ocular movements may be useful in evaluating residual/persistent/chronic CNS damage due to organoarsenic poisoning. PMID- 23454009 TI - Glycoprotein C plays a role in the adsorption of duck enteritis virus to chicken embryo fibroblasts cells and in infectivity. AB - Unlike glycoprotein C (gC) of many mammalian herpes viruses, gC of some avian herpes viruses does not play a principle role in the binding of virus to heparin sulfate proteoglycans on the cell surface. The roles of duck enteritis virus (DEV) gC on viral attachment remained unclear. In this study, we showed that gC expressed in vitro could bind to chicken embryo fibroblasts (CEF) cells and inhibit the adsorption of duck enteritis virus (DEV) onto CEF cells effectively and antiserum directed against gC inhibited the infection of DEV. Furthermore, it was confirmed that gC protein expressed in baculovirus system did not bind to heparin-Sepharose beads and virus binding to cells were independent of heparin sulfate proteoglycans on the surface of cells. Therefore, gC contributes to adsorption and infection of DEV. PMID- 23454010 TI - Differential effect of adenosine receptors on growth of human colon cancer HCT 116 and HT-29 cell lines. AB - The study aimed to evaluate the impact of adenosine receptors (ARs) on human colon tumor cells (HCT 116, HT-29) growth and sensitivity to 5-Fluorouracil (5 FU) an anticancer chemotherapeutic drug. The exposure of cancer cells to a selective A(3)-AR agonist (IB-MECA) resulted in an increase in HT-29 cells number, whereas the number of HCT 116 cells decreased significantly. In the presence of IB-MECA (1 MUM) the percentage of apoptotic HT-29 cells significantly decreased, whereas the number of apoptotic and necrotic HCT 116 cells increased by 3- and 2,5-fold, respectively. The application of a selective A(2A)-AR agonist resulted in the increased survival of HCT 116 cells, but not HT-29 cells. The blockade of A(2A)-AR with ZM 241385 (0.1 MUM) significantly increased the cytotoxicity of 5-FU (1 MUM) in HCT 116 cells but not in HT-29 cells. The suppression of A(3)-AR with MRS 1523 (1 MUM) increased the sensitivity of HT-29 cells to 5-FU while response of HCT 116 cells to 5-FU decreased. The growth promoting effect of IB-MECA in HT-29 cells was associated with the decreased intracellular cAMP level, whereas IB-MECA growth inhibitory effect in HCT 116 cells was abolished by okadaic acid (2 nM) indicating the involvement of protein phosphatase PP2A. PMID- 23454011 TI - Impact of co-administration of protonated nanostructured aluminum silicate (cholesterol absorption inhibitor) on the absorption of lipid soluble vitamins D3 and K1: an assessment of pharmacokinetic and in vitro intraluminal processing. AB - Protonated nanostructured aluminum silicate (NSAS) is a protonated montmorillonite clay that was shown to be effective as an inhibitor of intestinal cholesterol absorption. The effect of NSAS on the intestinal absorption of nutrients is unknown. An in vitro lipolysis model was adapted to test the intraluminal processing of vitamin D3 and K1 in the presence of various amounts of NSAS. Additionally, vitamin absorption was assessed in male Sprague-Dawley rats randomized in the following treatment groups: IV administration of 0.1 mg/kg vitamin D3 and 1 mg/kg vitamin K1, and a single-dose gavage of 1 mg/kg vitamin D3 and 5mg/kg of vitamin K1 in peanut oil with various doses of NSAS slurry, 2% NSAS fortified diet, or 50 mg/kg stigmastanol. The solubilized fraction of vitamin D3 in the lipolysis medium was reduced from 70% to 46% upon the addition of 120 mg NSAS. In contrast, the solubilized fractions of vitamin K1 were not significantly affected. Although the NSAS-fortified diet did not significantly affect the absorbed fraction of both vitamins, NSAS slurry decreased the absorption of vitamin D3 as compared to the control. These results indicate that NSAS may be incorporated in diet to treat hypercholesterolemia; however, vitamin D3 monitoring may be required. PMID- 23454012 TI - Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer's disease. AB - The approved treatments for Alzheimer's disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents. A novel approach towards excitotoxicity protection and oxidative stress associated with excess beta amyloid (Abeta) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities. In the present work, GSH (1) or (R)-alpha-lipoic acid (LA) (2) have been covalently linked with the NMDA receptor antagonists memantine (MEM). The new conjugates, proposed as potential antialzheimer drugs, should act both as glutamate receptor antagonists and radical scavenging agents. The physico chemical properties and "in vitro" membrane permeability, the enzymatic and chemical stability, the demonstrated "in vitro" antioxidant activity associated to the capacity to inhibit Abeta(1-42) aggregation makes at least compound 2 a promising candidate for treatment of AD patients. PMID- 23454013 TI - Recent developments in targeting protein misfolding diseases. AB - Protein misfolding is an emerging field that crosses multiple therapeutic areas and causes many serious diseases. As the biological pathways of protein misfolding become more clearly elucidated, small molecule approaches in this arena are gaining increased attention. This manuscript will survey current small molecules from the literature that are known to modulate misfolding, stabilization or proteostasis. Specifically, the following targets and approaches will be discussed: CFTR, glucocerebrosidase, modulation of toxic oligomers, serum amyloid P (SAP) sections and HSF1 activators. PMID- 23454014 TI - Inhibitory effect of 4,4'-dihydroxy-alpha-truxillic acid derivatives on NO production in lipopolysaccharide-induced RAW 264.7 macrophages and exploration of structure-activity relationships. AB - The inhibitory activity of 4,4'-dihydroxy-alpha-truxillic acid and its derivatives (5-1a-5-35a) on nitric oxide (NO) release was evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds 5-3a, 5-4a, 5-5a, 5-10a, 5-24a, 5-26a and 5-30a exhibited significant inhibitory effects on NO production, with IC50 values of 19.8, 21.1, 16.4, 17.5, 20.8, 22.6 and 17.6 MUM, respectively. Their cytotoxicities were also estimated using a CCK-8 assay. Among them, compound 5-10a showed no cytotoxic effect on cells up to a concentration of 50 MUM. The structure-activity relationships of the compounds are also discussed. PMID- 23454015 TI - Triazolopyridazine LRRK2 kinase inhibitors. AB - Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed. PMID- 23454016 TI - Synthesis of novel 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents. AB - As a part of systematic investigation of synthesis and biological activities of indole analogues linked to various heterocyclic systems, we have synthesized new compounds viz., 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H pyran-3-carbonitriles (2a-i), 4,5-diamino-6-(5'-substituted 2'-phenyl-1H-indol-3' yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles (3a i), 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3 d]pyrimidin-2(5H)-ones (4a-i), 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3' yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones (5a-i), 4-(5'-subtituted 2' phenyl-1H-indol-3'-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines (6a-i) and 5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin 4(5H)-ones (7a-i). Antibacterial activity results revealed that, compound 6a showed promising activity versus Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 6d exhibited good activity against S. aureus, K. pneumoniae and Pseudomonas aeruginosa. Antifungal activity results indicated that, compound 4d exhibited maximum zone of inhibition against Aspergillus oryzae and Aspergillus flavus. In case of antioxidant activity, compound 4a showed promising radical scavenging activity, ferric ions (Fe(3+)) reducing antioxidant power (FRAP) and metal chelating activity. PMID- 23454017 TI - Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines. AB - New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4 (trifluoromenthy) benzene moieties exhibited the most potent anticancer activity. PMID- 23454018 TI - Academy of Nutrition and Dietetics: Scope of Practice in Nutrition and Dietetics. AB - The goal of credentialed dietetics practitioners(RDs and DTRs) is to provide safe,culturally competent, quality care. Within the flexible and broad boundaries of the profession of nutrition and dietetics, RDs and DTRs assume accountability and responsibility for safe, ethical, and competent practice that achieves desirable outcomes. RDs and DTRs engage in continuing education and training to maintain currency,demonstrate competence, and advance their careers. The Academy developed this Scope of Practice in Nutrition and Dietetics overview document, as well as other resources, such as the Scope of Practice for the Registered Dietitian and the Scope of Practice for the Dietetic Technician, Registered to aid RDs and DTRs in assessing their individual scope of practice and, if applicable, statutory scope of practice,and to support RDs and DTRs in providing safe, quality food and nutrition services.The Scope of Practice Decision Tool,which is an online, interactive tool, assists RDs and DTRs in examining his or her individual scope of practice activities to meet the needs of quality food and nutrition services. PMID- 23454019 TI - Academy of Nutrition and Dietetics: Revised 2012 Standards of Practice in Nutrition Care and Standards of Professional Performance for Registered Dietitians. AB - RDs face complex situations every day. Competently addressing the unique needs of each situation and applying standards appropriately is essential to providing safe, timely, person-centered quality care and service. All RDs are advised to conduct their practice based on the most recent edition of the Academy's Code of Ethics and the Scope of Practice in Nutrition and Dietetics, the Scope of Practice for the Registered Dietitian, the 2012 Standards of Practice in Nutrition Care and Standards of Professional Performance for RDs, and the applicable focus area SOP and SOPP for RDs. These resources provide minimum standards and tools for demonstrating competence and safe practice, and are used collectively to gauge and guide an RD's performance in nutrition and dietetics practice. The SOP and SOPP for the RD are self-evaluation tools that promote quality assurance and performance improvement. Self-assessment provides opportunities to identify areas for enhancement, new learning, and skill development, and to encourage progression of career growth. All RDs are advised to have in their personal libraries the most recent copy of the Academy's Scope of Practice in Nutrition and Dietetics and its components: The 2012 Academy Standards of Practice in Nutrition Care and Standards of Professional Performance for Registered Dietitians; applicable focus area SOP and SOPP; the Code of Ethics; and the Scope of Practice for the Registered Dietitian. To ensure that credentialed dietetics practitioners always have access to the most current materials, each resource is maintained on the Academy's website. The documents will continue to be reviewed and updated as new trends in the profession of nutrition and dietetics and external influences emerge. PMID- 23454020 TI - Academy of Nutrition and Dietetics: Scope of Practice for the Registered Dietitian. AB - The Scope of Practice for the RD provides standards and tools to guide competence in performing nutrition and dietetics practice. Composed of statutory and individual components, the RD's scope of practice is determined by state statute and the RD's individual scope of practice is based on education, training, credentialing, and demonstrated and documented competence in practice. The Scope of Practice for the RD reflects the Academy's position on the RD's scope of practice and the essential role of the RD in directing and coordinating safe, timely, person-centered care for the delivery of quality food and nutrition services. PMID- 23454021 TI - Academy of Nutrition and Dietetics: Scope of Practice for the Dietetic Technician, Registered. AB - The Scope of Practice for the Dietetic Technician, Registered provides standards and tools to guide competence in performing nutrition and dietetics practice. Composed of statutory and individual components, the DTR's scope of practice is determined by state statute and the DTR's education, training, credentialing, and demonstrated and documented competence in practice. The Scope of Practice for the Dietetic Technician, Registered reflects the Academy's position on the DTR scope of practice and the essential technical assistance role of the DTR in providing safe timely person-centered care for the delivery of quality food and nutrition services. PMID- 23454022 TI - Academy of Nutrition and Dietetics: Revised 2012 Standards of Practice in Nutrition Care and Standards of Professional Performance for Dietetic Technicians, Registered. AB - DTRs face complex situations every day. Competently addressing the unique needs of each situation and applying standards appropriately is essential to providing safe, timely, person-centered quality care and service. All DTRs are advised to conduct their practice based on the most recent edition of the Academy's Code of Ethics and the Scope of Practice in Nutrition and Dietetics, the Scope of Practice for the DTR, the 2012 Standards of Practice in Nutrition Care and Standards of Professional Performance for DTRs. These resources provide minimum standards and tools for demonstrating competence and safe practice, and are used collectively to gauge and guide a DTR's performance in nutrition and dietetics practice. The SOP and SOPP for the DTR are self-evaluation tools that promote quality assurance and performance improvement. Self-assessment provides opportunities to identify areas for enhancement, new learning and skill development, and to encourage progression of career growth. All DTRs are advised to have in their personal libraries the most recent copy of the Academy's Scope of Practice in Nutrition and Dietetics and its components: The 2012 Academy Standards of Practice in Nutrition Care and Standards of Professional Performance for DTRs; the Code of Ethics; and the Scope of Practice for the DTR. To ensure that credentialed dietetics practitioners always have access to the most current materials, each resource is maintained on the Academy's website. The documents will continue to be reviewed and updated as new trends in the profession of nutrition and dietetics and external influences emerge. PMID- 23454024 TI - Cyclosporine and hyperoxia-induced lung damage in neonatal rats. AB - Cyclosporine effects on hyperoxia-induced histopathological and functional changes in the rat adult lung are controversial and the newborn lung has not been studied. Thus, we evaluated the effects of cyclosporine in young rats after 60% hyperoxia exposure postnatally. Experimental categories included: (1) room air for the first 5 postnatal weeks with daily subcutaneous injections of saline from postnatal day (PN)15 to PN35; (2) room air with daily injections of cyclosporine from PN15 to PN35; (3) 60% oxygen from PN0 to PN14 and then daily saline injections during the following three weeks; (4) 60% oxygen from PN0 to PN14 followed by cyclosporine treatment from PN15 to PN35. Hyperoxia significantly reduced the number of secondary crests and microvessel density, and it increased the mean alveolar size and septa thickness. Cyclosporine treatment did not significantly modify the hyperoxia-induced changes. Conversely, in normoxia, cyclosporine reduced microvessel density and the number of secondary crests. In conclusion, cyclosporine did not modify alveolar and microvascular parameters in hyperoxia exposure, although it caused some changes in normoxia. PMID- 23454025 TI - Chemosensory ventilatory responses in the mutant mice with Presbyterian hemoglobinopathy. AB - The working hypothesis of this study was that chronically increased tissue oxygenation would facilitate respiratory endurance to chemical stimuli. We investigated the ventilatory responses to hypoxia and hypercapnia before and after carotid chemodenervation in the anesthetized, spontaneously breathing Presbyterian, which carry a low affinity variant of hemoglobin, and in wild-type mice. We found a dampening of all chemosensory responses in Presbyterian hemoglobinopathy. Particularly, the Presbyterian mouse with intact carotid body innervation was more vulnerable to hypoxia than the wild-type mouse, showing an accelerated decline in breathing frequency which was not counterbalanced by tidal respiration. We further found that chemodenervation in the Presbyterian mouse, performed in normoxia, led to respiratory arrest. The study shows enhanced susceptibility of respiration to hypoxia and indispensability of neural input from the carotid body for upholding the central respiratory controller's function in Presbyterian hemoglobinopathy. The study also suggests a relationship between hemoglobin-oxygen dissociation and respiration, which points to a metabolic, tissue oxygenation-linked component of respiratory regulation. PMID- 23454023 TI - Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats. AB - The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO2 sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO2 sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7% CO2 exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10mg/(kgday)) in adult male BN and SD rats. Fluoxetine had minimal effects on room air breathing in BN and SD rats (p>0.05), although tidal volume (VT) was reduced in BN rats (p<0.05). There were also minimal effects of fluoxetine on CO2 sensitivity in SD rats, but fluoxetine increased minute ventilation, breathing frequency and VT during hypercapnia in BN rats (p<0.05). The augmented CO2 response was reversible upon withdrawal of fluoxetine. Brain levels of biogenic amines were largely unaffected, but 5-HIAA and the ratio of 5-HIAA/5-HT were reduced (p<0.05) consistent with selective and effective 5-HT reuptake inhibition. Thus, fluoxetine increases ventilatory CO2 sensitivity in BN but not SD rats, further suggesting altered 5-HT system function may contribute to the inherently low CO2 sensitivity in the BN rat. PMID- 23454026 TI - Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: implications for peripheral vascular control. AB - Neuronal nitric oxide (NO) synthase (nNOS) inhibition with systemically administered S-methyl-l-thiocitrulline (SMTC) elevates mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle and renal blood flow. We tested the hypothesis that those SMTC-induced cardiovascular effects resulted, in part, from increased sympathetic nerve discharge (SND). MAP, HR, and lumbar and renal SND (direct nerve recordings) were measured in 9 baroreceptor (sino-aortic) denervated rats for 20min each following both saline and SMTC (0.56mg/kg i.v.). SMTC increased MAP (peak DeltaMAP: 50+/-8mmHg, p<0.01) compared to saline. Lumbar and renal SND were not different between saline and SMTC conditions at any time (p>0.05). The DeltaSND between saline and SMTC conditions for the lumbar and renal nerves were not different from zero (peak DeltaSND, lumbar: 2.0+/-6.8%; renal: 9.7+/-9.0%, p>0.05 versus zero for both). These data support that SMTC induced reductions in skeletal muscle and renal blood flow reported previously reflect peripheral nNOS-derived NO vascular control as opposed to increased sympathetic vasoconstriction. PMID- 23454028 TI - Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: The histopathology of nonalcoholic fatty liver disease (NAFLD) is similar to that of alcoholic liver disease. Colonic bacteria are a source of many metabolic products, including ethanol and other volatile organic compounds (VOC) that may have toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. Recent data suggest that the composition of the gut microbiota in obese human beings is different from that of healthy-weight individuals. The aim of this study was to compare the colonic microbiome and VOC metabolome of obese NAFLD patients (n = 30) with healthy controls (n = 30). METHODS: Multitag pyrosequencing was used to characterize the fecal microbiota. Fecal VOC profiles were measured by gas chromatography-mass spectrometry. RESULTS: There were statistically significant differences in liver biochemistry and metabolic parameters in NAFLD. Deep sequencing of the fecal microbiome revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes (Lachnospiraceae; genera, Dorea, Robinsoniella, and Roseburia) in NAFLD patients, which was statistically significant. One member of phylum Firmicutes was under-represented significantly in the fecal microbiome of NAFLD patients (Ruminococcaceae; genus, Oscillibacter). Fecal VOC profiles of the 2 patient groups were different, with a significant increase in fecal ester compounds observed in NAFLD patients. CONCLUSIONS: A significant increase in fecal ester VOC is associated with compositional shifts in the microbiome of obese NAFLD patients. These novel bacterial metabolomic and metagenomic factors are implicated in the etiology and complications of obesity. PMID- 23454029 TI - The other side of the coin: blunted cardiovascular and cortisol reactivity are associated with negative health outcomes. AB - A cornerstone for research into the link between stress and health has been the reactivity hypothesis; cardiovascular reactivity to psychological stressors, if prolonged or exaggerated, can promote the development of cardiovascular disease. However, it has recently been argued that low or blunted reactivity is also associated with negative health outcomes. As such, in this special issue we present further evidence implicating that cardiovascular and stress hormone responses to acute stress at the other end of the response spectrum can also be considered a pathway to ill health. In this introductory article, we explore and review the origins of and potential mechanisms underlying blunted responses to acute stress. In so doing, we aim to highlight: what is currently known regarding this new conceptualization of the reactivity hypothesis; the potential explanations for blunted reactivity; the pathways underlying associations with health outcomes; and where this field is headed in terms of developing our understanding of the link between reactivity and health. PMID- 23454027 TI - Primary sclerosing cholangitis: diagnosis, prognosis, and management. AB - Primary sclerosing cholangitis (PSC) is a chronic immune-mediated disease of the liver of unclear etiology, characterized by chronic inflammation and fibrosis of bile ducts. It primarily affects middle-aged men and is associated with 4-fold increased mortality as compared with an age- and sex-matched population. Progressive biliary and hepatic damage results in portal hypertension and hepatic failure in a significant majority of patients over a 10- to 15-year period from the initial diagnosis. In addition, PSC confers a markedly increased risk of hepatobiliary cancer, including cholangiocarcinoma and gallbladder cancer, as compared with the general population, and cancer is the leading cause of mortality in patients with PSC. It is associated with inflammatory bowel disease in 70% of patients and increases the risk of colorectal cancer almost 10-fold. Despite significant research efforts in this field, the pathogenic mechanisms of PSC are still incompletely understood, although growing evidence supports the role of genetic and immunologic factors. There are no proven medical therapies that alter the natural course of the disease. Thus, liver transplantation is the only available treatment for patients with advanced PSC, with excellent outcomes in this population. PMID- 23454030 TI - Event-related potentials reveal modelling of auditory repetition in the brain. AB - Two auditory event-related potential (ERP) waveforms, mismatch negativity (MMN) and repetition positivity (RP), are sensitive to repetition of auditory stimuli. Increasing repetition of standards produces larger MMN amplitudes to deviant stimuli in an oddball paradigm, known as the memory trace effect, and attributed to increasing strength of the memory trace for standards. RP to standards also increases as a function of repetition in a 'roving' oddball paradigm where the standard changes in pitch following presentation of a deviant tone. As the sensory memory trace representing standard stimuli must be continually updated in the roving paradigm, RP has been proposed to reflect memory trace formation. Given that RP to date has only been observed in roving oddball paradigms, we examined whether RP and the MMN memory trace effect are present in both roving and standard oddball paradigms in 24 young adults (mean age: 22.4+/-5years). Four, 8, or 16 standards preceded a deviant. We observed RP at Fz in standard ERPs in the roving but not constant paradigm. At mastoid sites, RP was observed in both paradigms. A memory trace effect was not observed at Fz in either paradigm. Our findings suggest that different generator sites in the brain model local and global auditory information with generators of mastoid activity primarily sensitive to local or short term stimulus history of auditory regularities while generators of frontal site activity retain more global information regarding stimulus history over a longer time period. PMID- 23454031 TI - Viability of human ovarian tissue confirmed 5 years after freezing with spontaneous ice-formation by autografting and chorio-allantoic membrane culture. AB - To achieve optimal and uniform outcomes, slow cooling protocols for human ovarian tissues generally initiate ice formation at high sub-zero temperatures (-6 to -9 degrees C). The aim of the study was to investigate the function of ovarian tissue that had unintentionally self seeded at -20 degrees C during the freezing step, by examining its development following chicken embryonic chorioallantoic membrane (CAM) grafting and after transplantation back to the patient. Ovarian tissue was frozen in 6% (v/v) dimethyl sulfoxide, 6% (v/v) ethylene glycol and 0.15M sucrose which had self-seeded at -20 degrees C. Five years after cryopreservation, 8 pieces were thawed and transplanted back to the patient. Two small (1 * 2 * 1 mm) pieces of this thawed tissue were cultured in a CAM-system for 5 days to assess the tissue viability. The autografted ovarian tissue re established spontaneous menstrual bleeding within five months and raised serum 17 beta Estradiol from 19 to 330 pg/ml. Ultrasound revealed a dominant follicle at the site of the transplanted tissue in the follicular phase after the menstrual bleed. Analysis of the CAM cultured tissue established that 88% of the primordial follicles are degenerated and there was limited in growth of blood vessels. In conclusion, in spite of the damage caused by the cryopreservation with spontaneous ice-formation the viability could be confirmed by CAM culture and the restoration of ovarian function after auto-transplantation. PMID- 23454032 TI - Evaluation of a policy of selective drug-eluting stent implantation for patients at high risk of restenosis. AB - Drug-eluting stent (DES) deployment during percutaneous coronary intervention (PCI) has reduced target-vessel revascularisation rates (TVR). The selective use of DES in patients at highest risk of restenosis may allay concerns about universal compliance of dual antiplatelet therapy for one year, and potentially reduce costs. If this strategy achieved acceptably low TVR rates, such an approach could be attractive. Late clinical outcomes were examined in 2115 consecutive patients (mean age 63+/-12 years, 75% male, 22% diabetics) who underwent PCI in the first three years from October 2003, after commencing the following selective criteria for DES use: left main stenosis; ostial lesions of major epicardial arteries; proximal LAD lesions; lesions>=20mm in length with vessel diameter<=3.0mm; lesions in vessels<=2.5mm; diabetics with vessel(s)<=3.0mm; and in-stent restenosis. Among patients undergoing PCI, 2075 (98%) patients received stents (29%>=1 DES and 71% bare metal stent [BMS]), and among those who received DES, there was a 92% compliance with these criteria. There were no differences in clinical outcomes between the two stent groups except for definite stent thrombosis, which occurred in 2% after DES, and 0.6% after BMS at one year (p=0.002). With BMS, large coronary arteries (>=3.5mm), intermediate (3-3.49mm) and small arteries (<3mm) in diameter had a TVR rate at one year of 3.6%, 7.2% and 8.2% respectively (p=0.005). It is possible to use selective criteria for DES while maintaining low TVR rates. The TVR rate with BMS was low in those with stent diameters>=3.5mm. The higher DES stent thrombosis rate reflects first generation DES use, though whether routine second generation DES use reduces these rates needs confirmation. PMID- 23454033 TI - Pathogen-free screening of bacteria-specific hybridomas for selecting high quality monoclonal antibodies against pathogen bacteria as illustrated for Legionella pneumophila. AB - Antibodies are potent biological tools increasingly used as detection, diagnostic and therapeutic reagents. Many technological advances have optimized and facilitated production and screening of monoclonal antibodies. We report here an original method to screen for antibodies targeting biosafety level 2 or 3 pathogens without the fastidious handling inherent to pathogen use. A double ELISA screening was performed using as coated antigen transformed Escherichia coli expressing at its surface a protein specific to the pathogenic bacteria versus control untransformed E. coli. This method was applied to Legionella, using the surface-exposed Mip protein (macrophage infectivity potentiator). This screening proved to be an excellent means of selecting mAbs that bind Legionella pneumophila 1 surface-exposed Mip protein. This method also appears more biologically relevant than screening using the recombinant Mip protein alone and less tedious than a test performed directly on Legionella bacteria. We obtained 21 mAbs that bind strongly to L. pneumophila serogroups 1 to 13, and we validated their use in a rapid ELISA (performed in 4.5 h) and an immunochromatographic test (20 min). PMID- 23454034 TI - Surface immobilized hydrogels as versatile reagent reservoirs for microarrays. AB - The accuracy of antibody-based microarrays depends on eliminating or at least minimizing the effect of cross-reactive components. In this work, a method to create a versatile, compartmentalized storage system for antibodies and soluble microarray reagents is described. These containers are made of hydrogel plugs immobilized on a slide facing the corresponding sub-array on a printed surface. The hydrogels were polymerized using a 4% w/v N,N-dimethylacrylamide and 3% w/v bisacrylamide solution, thus generating large pore sizes to allow the facile transfer of intact, functional biomolecules. The hydrogel microenvironments can be desiccated and rehydrated with a desired solution, and they can store reagents in a dry form. These hydrogels were shown to provide limits of detection similar to those obtained by conventional incubation conditions in an assay for HIV p24 antigen. Moreover, they prevent cross-reactivity issues in the detection of Staphylococcus aureus enterotoxins A and B and promote the accurate quantification of interleukin 10 by a microarray-integrated calibration curve. PMID- 23454035 TI - Development of a single-antigen magnetic bead assay (SAMBA) for the sensitive detection of HPA-1a alloantibodies using tag-engineered recombinant soluble beta3 integrin. AB - Timely and accurate testing for human platelet antigen 1a (HPA-1a) alloantibodies is vital for clinical diagnosis of neonatal alloimmune thrombocytopenia (NAIT). Current antigen-specific assays used for the detection of HPA-1 alloantibodies are technically very complex and cumbersome for most diagnostic laboratories. Hence, we designed and applied recombinant soluble (rs) beta3 integrins displaying HPA-1a or HPA-1b epitopes for the development of a single-antigen magnetic bead assay (SAMBA). Soluble HPA-1a and HPA-1b were produced recombinantly in human embryonic kidney 293 (HEK293) cells and differentially tagged. The recombinant soluble proteins were then immobilized onto paramagnetic beads and used for analysis of HPA-1 alloantibodies by enzyme-linked immunosorbent assay (ELISA). HPA-1a serum samples (n=7) from NAIT patients, inert sera and sera containing non-HPA-1a antibodies were used to evaluate the sensitivity and specificity of the SAMBA. Fusion of V5-His or GS-SBP-His tags to the rsbeta3 integrins resulted in high-yield expression. SAMBA was able to detect all HPA-1a and -1b alloantibodies recognized by monoclonal antibody-specific immobilization of platelet antigens assay (MAIPA). No cross-reactions between the sera were observed. Two out of seven of the HPA-1a alloantibody-containing sera demonstrated weak to moderate reactivity in MAIPA but strong signals in SAMBA. SAMBA provides a very reliable method for the detection of HPA-1 antibodies with high specificity and sensitivity. This simple and rapid assay can be adapted for use in any routine laboratory and can be potentially adapted for use on automated systems. PMID- 23454036 TI - Aging leads to prolonged duration of inflammation-induced depression-like behavior caused by Bacillus Calmette-Guerin. AB - Geriatric depression is a costly health issue, but little is known about its physiological underpinnings. Systemic inflammation sensitizes the innate immune system of aged animals and humans, but it is unknown if chronic, low-grade infections affect the duration of depressive-like behaviors. In this report, we infected adult (4-6 months) and aged (20-24 months) Balb/c mice with an attenuated strain of Mycobacterium bovis, Bacillus Calmette-Guerin (BCG), to induce a chronic infection. We then measured depression-like behaviors that have construct, face and predictive validity for human inflammation-associated clinical depression. Exposure to BCG caused acute sickness responses in both adult and aged mice. However, sickness behavior was prolonged in aged mice, as assessed by both locomotor and rearing activity. Two measures of depression-like behavior, which were tests involving sucrose preference and tail suspension, both showed that adult mice displayed depression-like behaviors at one day and seven days after exposure to BCG. However, aged mice continued to express both of these depression-like behaviors at three weeks following infection. Infection with BCG caused an increase in tryptophan catabolism, as evidenced by a significant rise in the plasma kynurenine/tryptophan ratio that peaked at 7 days post-infection. In aged mice, greater tryptophan catabolism persisted longer and remained elevated at 21 days post-infection. This finding is consistent with the prolonged duration of depression-like behaviors in aged mice. These are the first data using a chronic infection model to establish that recovery from inflammation induced depression-like behavior and tryptophan catabolism are prolonged in aged animals. PMID- 23454037 TI - Polymorphisms on chromosome 9p21 confer a risk for acute coronary syndrome in a Chinese Han population. AB - BACKGROUND: Genome-wide association studies have identified 2 single-nucleotide polymorphisms (SNPs) on chromosome arm 9p21, rs10757278, and rs2383207 that confer susceptibility to myocardial infarction. However, these data are mostly from Italian, American Caucasian, South Korean, and Japanese cohorts. This study is the first to investigate whether 6 SNPs (rs10757277, rs10757278, rs10757279, rs1333049, rs1333047, and rs10811656) are associated with acute coronary syndrome (ACS) in a Chinese Han population. METHODS: We performed a case-control analysis in 359 patients with ACS diagnosed by coronary angiography and 398 non-ACS controls of Han background between April 2007 and January 2008 to determine whether these 6 SNPs were associated with ACS. Exon fragments were genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: After we adjusted for clinical parameters, we found the rs10757278 GG genotype to be associated with a significantly elevated risk of ACS (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.35-2.68; P = 0.00035), the rs10811656 T allele to be associated with a higher risk of ACS (OR, 1.67; 95% CI, 1.26-2.23; P = 0.0016) than the CC genotype, and the rs1333047 TT genotype also to be associated with a higher risk of ACS (OR, 1.57; 95% CI, 1.15-2.06; P = 0.0052) than the CC and CT genotypes. After 14.2 +/- 4.5 months of follow-up, the end-point data were obtained: death (cardiac and noncardiac), nonfatal myocardial infarction, and recurrent angina leading to repeated coronary angiography. We found that the rs10757278 GG genotype was significantly associated with recurrent angina compared with the AA and AG genotypes (P = 0.013). CONCLUSIONS: Polymorphisms on 9p21 were associated with ACS in a Chinese Han population. The rs10757278 GG genotype was further associated with adverse cardiac outcomes after ACS. PMID- 23454038 TI - The impact of cardiovascular risk-factor profiles on blood pressure control rates in adults from Canada and the United States. AB - BACKGROUND: It is unclear whether blood pressure control varies across the spectrum of atherosclerotic risk. METHODS: We used data from nonpregnant adults who had fasted laboratory samples drawn for the 2007-2009 cycle of the Canadian Health Measures Survey (CHMS) or the 2005-2008 US National Health and Nutrition Examination Survey (NHANES). RESULTS: The 1692 CHMS subjects and 3541 NHANES participants were demographically similar (aged a mean of 45 years), although NHANES participants exhibited higher obesity rates (33.8% vs. 22.2%, P < 0.001). Over 80% of CHMS and NHANES subjects with hypertension had at least 1 other cardiovascular risk factor. As the number of atherosclerotic risk factors increased, hypertension prevalence increased, but blood pressure control rates improved (from 48% among hypertensives with no other risk factors in CHMS to 77% among those with 3 or more risk factors, and from 35% to 53% in NHANES). However, the converse was not true: The distribution of Framingham risk scores for those subjects with "controlled hypertension" was nearly identical to the distribution among those adults with uncontrolled hypertension in both CHMS and NHANES and substantially higher than scores in normotensive subjects. CONCLUSIONS: Although control of blood pressure was better in patients with multiple atherosclerotic risk factors, hypertensives with controlled blood pressures exhibited risk-factor profiles similar to those of participants with uncontrolled blood pressures. This suggests the need, in educational messaging and therapy decision making, for an increased focus on total atherosclerotic risk rather than just blood pressure control. PMID- 23454039 TI - High blood pressure selected as the theme for World Health Day, April 7, 2013: cup half full or half empty? PMID- 23454040 TI - Should all postmenopausal patients with hormone receptor-positive breast cancer receive initial therapy with aromatase inhibitors? AB - BACKGROUND: In the past few years aromatase inhibitors (AIs) have shown superior efficacy to the previous standard adjuvant endocrine therapy, tamoxifen, and are now recommended as part of current adjuvant endocrine therapy. A range of treatment strategies have been explored. MATERIALS AND METHODS: We assess the role of initial AI therapy for postmenopausal women with hormone receptor positive breast cancer and consider the relative value of initial therapy with an AI compared with switch or extended (>5-yr) adjuvant therapy. RESULTS: Both initial AI therapy and switching/sequential tamoxifen followed by an AI are associated with longer disease- and relapse-free survival versus 5 years of tamoxifen alone. Trials comparing initial therapy with the sequence of tamoxifen followed by an AI have not demonstrated any major efficacy differences between the treatment strategies. Several analyses have been conducted to identify prognostic or predictive markers of treatment benefit to enable selection of the most appropriate adjuvant therapy. CONCLUSIONS: Initial and switching/sequential regimens are equally appropriate adjuvant treatment options for postmenopausal patients with hormone receptor-positive breast cancer. The exact tumour biology which allows for initial AI therapy has not yet been determined with certainty. PMID- 23454042 TI - The effects of aging on the rambling and trembling components of postural sway: effects of motor and sensory challenges. AB - The effects of healthy aging on postural sway and its rambling and trembling components were studied. Young and elderly subjects stood quietly for 1 min in different postures, and with eyes open and closed. We found that age-related changes in postural sway and its components were similar to those observed in young participants in challenging conditions. These changes may therefore be viewed as secondary to the increased subjective perception of the complexity of postural tasks. Contrary to our expectations, stronger effects of age were seen in characteristics of rambling, not trembling. The commonly accepted hypothesis that older persons rely on vision more was not supported by this study: we found no significant interaction effects of age and vision on any of the sway characteristics. It was concluded that the reported higher reliance on vision in older persons may be task-specific. The results are compatible with the ideas that much of the age-related changes in postural sway emerge at the level of exploring the limits of stability and using the drift-and-act strategy. Our results suggest that the dominant view on rambling and trembling as reflecting supraspinal and peripheral mechanisms, respectively, may be too simplistic. PMID- 23454043 TI - Explaining the variability improvements in gait quality as a result of single event multi-level surgery in cerebral palsy. AB - PURPOSE: This is a study of all children with spastic diplegic cerebral palsy (Gross Motor Classification System levels II and III) who had single event multi level surgery (SEMLS) at a single tertiary referral hospital between 1995 and 2008 to identify factors predicting improvement in gait quality as quantified by the gait profile score (GPS). 9 factors (5 dichotomous and 4 continuous, including preoperative GPS) that might be expected to predict outcomes were identified and univariate and multivariable analysis used to explore how these affected outcomes. SCOPE: Data from 121 children were included. The mean improvement in GPS of 4.3 degrees was 2.7 times the minimal clinically important difference. Univariate analysis suggested that preoperative GPS is a very strong predictor of improvement in GPS (p<10(-5)) and when this is considered as a covariate only GMFCS level (p=10(-5)) and having had previous surgery (p=0.026) were found to be statistically significant predictors of GPS improvement (p<0.05). Children of GMFCS level II improved on average by 2 degrees more than those of level III once differences in preoperative GPS had been accounted for. CONCLUSION: Children with the most abnormal gait patterns preoperatively, and hence those with the most potential to improve are those that improve the most and surgery has clearly been beneficial. Over a quarter of children show changes in GPS which were less than the MCID. The majority of these were those with the least abnormal gait patterns preoperatively and further research is required to establish whether and how such children benefit from SEMLS. PMID- 23454041 TI - Ultrasensitivity of an adaptive bacterial motor. AB - The flagellar motor of Escherichia coli adapts to changes in the steady-state level of the chemotaxis response regulator, CheY-P, by adjusting the number of FliM molecules to which CheY-P binds. Previous measurements of motor ultrasensitivity have been made on cells containing different amounts of CheY-P and, thus, different amounts of FliM in flagellar motors. Here, we designed an experiment to measure the sensitivity of motors containing fixed amounts of FliM, finding Hill coefficients about twice as large as those observed before. This ultrasensitivity provides further insights into the motor switching mechanism and plays important roles in chemotaxis signal amplification and coordination of multiple motors. The Hill coefficients observed here appear to be the highest known for allosteric protein complexes, either biological or synthetic. Extreme motor ultrasensitivity broadens our understanding of mechanisms of allostery and serves as an inspiration for future design of synthetic protein switches. PMID- 23454044 TI - Reliability of plantar pressure platforms. AB - Plantar pressure measurement is common practice in many research and clinical protocols. While the accuracy of some plantar pressure measuring devices and methods for ensuring consistency in data collection on plantar pressure measuring devices have been reported, the reliability of different devices when testing the same individuals is not known. This study calculated intra-mat, intra manufacturer, and inter-manufacturer reliability of plantar pressure parameters as well as the number of plantar pressure trials needed to reach a stable estimate of the mean for an individual. Twenty-two healthy adults completed ten walking trials across each of two Novel emed-x((r)) and two Tekscan MatScan((r)) plantar pressure measuring devices in a single visit. Intraclass correlation (ICC) was used to describe the agreement between values measured by different devices. All intra-platform reliability correlations were greater than 0.70. All inter-emed-x((r)) reliability correlations were greater than 0.70. Inter MatScan((r)) reliability correlations were greater than 0.70 in 31 and 52 of 56 parameters when looking at a 10-trial average and a 5-trial average, respectively. Inter-manufacturer reliability including all four devices was greater than 0.70 for 52 and 56 of 56 parameters when looking at a 10-trial average and a 5-trial average, respectively. All parameters reached a value within 90% of an unbiased estimate of the mean within five trials. Overall, reliability results are encouraging for investigators and clinicians who may have plantar pressure data sets that include data collected on different devices. PMID- 23454045 TI - Evaluation of the accuracy of three popular regression equations for hip joint centre estimation using computerised tomography measurements for metal-on-metal hip resurfacing arthroplasty patients. AB - We investigated the accuracy of the regression equations by Bell et al., Davis III et al. and Harrington et al. for hip joint centre (HJC) estimation against the gold standard of computerised tomography (CT) measurements of HJC for 18 patients with metal-on-metal hip resurfacing arthroplasty (MoMHRA). The HJCs were estimated based on the position of the left and right Anterior Superior Iliac Spine (ASIS) and the left and right Posterior Superior Iliac Spine (PSIS) identified from a CT scan. Of the three tested regression equations, only those of Harrington et al. produced results that were not significantly different from the patient's 'true' HJCs as measured from the CT scan in all three directions when analysing left and right hips together for both resurfaced and native hips. When native and resurfaced hips were pooled and analysed for left and right, separately, the Harrington et al. regression equations showed significantly different results in the ML direction. Similar estimation errors were observed for native and resurfaced hips. Since none of the methods tested performed particularly well, we suggest using medical imaging if accurate estimates of HJCs are required. PMID- 23454046 TI - Therapeutic efficacy of plasmonic photothermal nanoparticles in hamster buccal pouch carcinoma. AB - OBJECTIVES: The objective of this study was to assess the short-term effect of plasmonic photothermal therapy (PPTT) on induced hamster buccal pouch (HBP) carcinoma. STUDY DESIGN: Seventy-six Syrian golden male hamsters were used. The induced HBP carcinomas were directly injected with ~30 nm gold nanospheres followed by 15 min laser exposure (PPTT). RESULTS: PPTT caused rapid growth cessation and dramatic decrease in tumor sizes after 4 weeks of treatment (P < .05) compared to controls. Microscopic and immunohistochemical examination of the tumor biopsies revealed significant differences in the cellular apoptotic index (AI) value and proliferating cell nuclear antigen (PCNA) immunoexpression in PPTT treated tumor tissue sections compared to controls (P < .05). Survival probability of the treated animals was increased compared to controls (P < .05). CONCLUSION: PPTT proved to be a successful method for treating superficially located HBP carcinomas. PMID- 23454047 TI - Pathways to seeing music: enhanced structural connectivity in colored-music synesthesia. AB - Synesthesia, a condition in which a stimulus in one sensory modality consistently and automatically triggers concurrent percepts in another modality, provides a window into the neural correlates of cross-modal associations. While research on grapheme-color synesthesia has provided evidence for both hyperconnectivity hyperbinding and disinhibited feedback as potential underlying mechanisms, less research has explored the neuroanatomical basis of other forms of synesthesia. In the current study we investigated the white matter correlates of colored-music synesthesia. As these synesthetes report seeing colors upon hearing musical sounds, we hypothesized that they might show unique patterns of connectivity between visual and auditory association areas. We used diffusion tensor imaging to trace the white matter tracts in temporal and occipital lobe regions in 10 synesthetes and 10 matched non-synesthete controls. Results showed that synesthetes possessed hemispheric patterns of fractional anisotropy, an index of white matter integrity, in the inferior fronto-occipital fasciculus (IFOF), a major white matter pathway that connects visual and auditory association areas to frontal regions. Specifically, white matter integrity within the right IFOF was significantly greater in synesthetes than controls. Furthermore, white matter integrity in synesthetes was correlated with scores on audiovisual tests of the Synesthesia Battery, especially in white matter underlying the right fusiform gyrus. Our findings provide the first evidence of a white matter substrate of colored-music synesthesia, and suggest that enhanced white matter connectivity is involved in enhanced cross-modal associations. PMID- 23454048 TI - Instrument specific brain activation in sensorimotor and auditory representation in musicians. AB - Musicians show a remarkable ability to interconnect motor patterns and sensory processing in the somatosensory and auditory domains. Many of these processes are specific for the instrument used. We were interested in the cerebral and cerebellar representations of these instrument-specific changes and therefore applied functional magnetic resonance imaging (fMRI) in two groups of instrumentalists with different instrumental training for comparable periods (approximately 15 years). The first group (trumpet players) uses tight finger and lip interaction; the second (pianists as control group) uses only the extremities for performance. fMRI tasks were balanced for instructions (piano and trumpet notes), sensory feedback (keypad and trumpet), and hand-lip interaction on the trumpet. During fMRI, both groups switched between different devices (trumpet or keypad) and performance was combined with or without auditory feedback. Playing the trumpet without any tone emission or using the mouthpiece showed an instrument training-specific activation increase in trumpet players. This was evident for the posterior-superior cerebellar hemisphere, the dominant primary sensorimotor cortex, and the left Heschl's gyrus. Additionally, trumpet players showed increased activity in the bilateral Heschl's gyrus during actual trumpet playing, although they showed significantly decreased loudness while playing with the mouthpiece in the scanner compared to pianists. PMID- 23454049 TI - Extraversion is encoded by scale-free dynamics of default mode network. AB - Resting-state functional Magnetic Resonance Imaging (rsfMRI) is a powerful tool to investigate neurological and psychiatric diseases. Recently, the evidences linking the scaling properties of resting-state activity and the personality have been accumulated. However, it remains unknown whether the personality is associated with the scale-free dynamics of default mode network (DMN) - the most widely studied network in the rsfMRI literatures. To investigate this question, we estimated the Hurst exponent, quantifying long memory of a time-series, in DMN of rsfMRI in 20 healthy individuals. The Hurst exponent in DMN, whether extracted by independent component analysis (ICA) or region of interest (ROI), was significantly associated with the extraversion score of the revised Eysenck Personality Questionnaire. Specifically, longer memory in DMN corresponded to lower extraversion. We provide evidences for an association between individual differences in personality and scaling dynamics in DMN, whose alteration has been previously linked with introspective cognition. This association might arise from the efficiency in online information processing. Our results suggest that personality trait may be reflected by the scaling property of resting-state networks. PMID- 23454050 TI - Evidence for a motor gamma-band network governing response interference. AB - The gamma-band response is thought to represent a key neural signature of information processing in the human brain. These brain signals have been associated with a variety of sensory modalities (vision, sensation, and audition) and also following basic motor responses, yet the functional significance of the motor gamma-band response remains unclear. We used the Multi-Source Interference Task (MSIT) to assess the sensitivity of these cortical motor gamma-band rhythms to stimuli producing response interference. We recorded MEG from adult participants (N=24) during MSIT task performance and compared motor gamma-band activity on Control and Interference trials. Reaction time on MSIT Interference trials was significantly longer (~0.2 s) for all subjects. Response interference produced a significant increase in motor gamma-band activity including ~0.5 s sustained increase in gamma-band activity from contralateral primary motor area directly preceding the response. In addition, activation of increased right Inferior Frontal Gyrus (R-IFG) was observed at gamma-band frequencies ~0.2 s prior to the button press response. Post-hoc analysis of R-IFG gamma-band activity was observed to correlate with reaction time increases to response interference. Our study is the first to record MEG during MSIT task performance. We observed novel activity of the motor gamma-band on interference trials which was sustained prior to the response and in novel locations including contralateral (BA6), and R-IFG. Our results support the idea that R-IFG is specialized structure for response control that also functions at gamma-band frequencies. Together, these data provide evidence for a motor gamma-band network for response selection and maintenance of planned behavior. PMID- 23454051 TI - Pharmaceutical feasibility of sub-visible particle analysis in parenterals with reduced volume light obscuration methods. AB - The draft for a new United States Pharmacopoeia (USP) monograph {787} "Sub visible Particulate Matter in Therapeutic Protein Injections" describes the analysis of sub-visible particles by light obscuration at much lower sample volumes as so far required by the European Pharmacopoeia (Ph. Eur.) and the USP for parenterals in general. Our aim was to show the feasibility of minimizing the sample expenditure required for light obscuration similar to the new USP settings for standards and pharmaceutically relevant samples (both proteins and small molecules), without compromising the data quality. The light obscuration method was downscaled from >20 ml volume as so far specified in Ph. Eur./USP to 1 ml total sample volume. Comparable results for the particle concentration in all tested size classes were obtained with both methods for polystyrene standards, stressed BSA solutions, recombinant human IgG1 formulations, and pantoprazol i.v. solution. An additional advantage of the low volume method is the possibility to detect vial-to-vial variations, which are leveled out when pooling several vials to achieve sufficient volume for the Ph. Eur./USP method. This is in particular important for biotech products where not only the general quality aspect, but also aggregate formation of the drug substance is monitored by light obscuration. PMID- 23454052 TI - The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo. AB - The use of nanoparticulate zinc oxide (ZnO-NP) in sunscreens and other cosmetic products has raised public health concerns. The two key issues are the extent of exposure to ZnO-NP and the likely hazard after the application of ZnO-NP in sunscreen and cosmetic products to humans in vivo. Our aims were to assess exposure by the extent of ZnO-NP penetration into the viable epidermis and hazard by changes in the viable epidermal redox state for a number of topical products. Of particular interest is the role of the particle coating, formulation used, and the presence of any enhancers. Multiphoton tomography with fluorescence lifetime imaging microscopy (MPT-FLIM) was used to simultaneously observe ZnO-NP penetration and potential metabolic changes within the viable epidermis of human volunteers after topical application of various ZnO-NP products. Coated and uncoated ZnO-NP remained in the superficial layers of the SC and in the skin furrows. We observed limited penetration of coated ZnO-NP dispersed in a water-in oil emulsion formulation, which was predominantly localized adjacent to the skin furrow. However, the presence of ZnO-NP in the viable epidermis did not alter the metabolic state or morphology of the cells. In summary, our data suggest that some limited penetration of coated and uncoated ZnO-NP may occur into viable stratum granulosum epidermis adjacent to furrows, but that the extent is not sufficient to affect the redox state of those viable cells. PMID- 23454053 TI - Tuning peptide affinity for biofunctionalized surfaces. AB - The control of the interaction between biological systems and surfaces plays a major role in the development of bioactive implants. Random absorbance of different compounds of the body liquids attach at the implant site after surgery. This protein layer triggers the activation of immune cells and is a breeding ground for pathogens, which may induce inflammation processes. Many efforts have been made to block these fouling processes such as PEGylation and unspecific coatings. These systems lead to bioinert implant surfaces that lower the inflammation potential of implanted materials. In contrast, the biomimetic approach attempts the functionalization of implant surfaces with compounds such as peptides, proteins, or sugars that form an artificial layer on the implant that corresponds to the naturally occurring extracellular matrix. This enables the controlled recruitment of cells that improve the healing processes or enhance the osseointegration into the implanted material. An improved connection of implants with cells that enhances the healing processes or tightens the connection of implants with the surrounding tissue is obtained by this approach. However, for bioactive functionalization of implant materials, efficient and robust immobilization techniques are required. Peptides owing to their low toxicity and their multifunctionality are interesting agents that can act as molecular glue to surfaces. Here, an overview is provided of the development of surface binding peptides, the molecular mechanisms of peptide-surface interactions, and the application of surface binding peptides in the development of multifunctional biomaterials that facilitate beneficial characteristics in vitro and in vivo. PMID- 23454054 TI - Characteristics of indomethacin-saccharin (IMC-SAC) co-crystals prepared by an anti-solvent crystallization process. AB - The creation of co-crystals of various insoluble drug substances has been extensively investigated as a promising approach to improve their pharmaceutical performance. In this study, co-crystal powders of indomethacin and saccharin (IMC SAC) were prepared by an anti-solvent (water) addition and compared with co crystals by evaporation method. No successful synthesis of a pharmaceutical co crystal powder via an anti-solvent approach has been reported. Among solvents examined, methanol was practically the only one that resulted in the formation of highly pure IMC-SAC co-crystal powders by anti-solvent approach. The mechanism of a preferential formation of IMC-SAC co-crystal to IMC was explained with two aspects: phase solubility diagram and solution complexation concept. Accordingly, the anti-solvent approach can be considered as a competitive route for producing pharmaceutical co-crystal powders with acceptable properties. PMID- 23454055 TI - Why the dish makes a difference: quantitative comparison of polystyrene culture surfaces. AB - There is wide anecdotal recognition that biological cell viability and behavior can vary significantly as a function of the source of commercial tissue culture polystyrene (TCPS) culture vessels to which those cells adhere. However, this marked material dependency is typically resolved by selecting and then consistently using the same manufacturer's product - following protocol - rather than by investigating the material properties that may be responsible for such experimental variation. Here, we quantified several physical properties of TCPS surfaces obtained from a wide range of commercial sources and processing steps, through the use of atomic force microscopy (AFM)-based imaging and analysis, goniometry and protein adsorption quantification. We identify qualitative differences in surface features, as well as quantitative differences in surface roughness and wettability that cannot be attributed solely to differences in surface chemistry. We also find significant differences in cell morphology and proliferation among cells cultured on different TCPS surfaces, and resolve a correlation between nanoscale surface roughness and cell proliferation rate for both cell types considered. Interestingly, AFM images of living adherent cells on these nanotextured surfaces demonstrate direct interactions between cellular protrusions and topographically distinct features. These results illustrate and quantify the significant differences in material surface properties among these ubiquitous materials, allowing us to better understand why the dish can make a difference in biological experiments. PMID- 23454056 TI - Mechanism of the uptake of cationic and anionic calcium phosphate nanoparticles by cells. AB - The uptake of calcium phosphate nanoparticles (diameter 120nm) with different charge by HeLa cells was studied by flow cytometry. The amount of uptaken nanoparticles increased with increasing concentration of nanoparticles in the cell culture medium. Several inhibitors of endocytosis and macropinocytosis were applied to elucidate the uptake mechanism of nanoparticles into HeLa cells: wortmannin, LY294002, nocodazole, chlorpromazine and nystatin. Wortmannin and LY294002 strongly reduced the uptake of anionic nanoparticles, which indicates macropinocytosis as uptake mechanism. For cationic nanoparticles, the uptake was reduced to a lesser extent, indicating a different uptake mechanism. The localization of nanoparticles inside the cells was investigated by conjugating them with the pH-sensitive dye SNARF-1. The nanoparticles were localized in lysosomes after 3h of incubation. PMID- 23454057 TI - Interactions of U937 macrophage-like cells with decellularized pericardial matrix materials: influence of crosslinking treatment. AB - While macrophages have been implicated in the failure of bioprosthetic heart valves, the macrophage response to crosslinked native pericardial collagen has not been previously investigated. Using decellularized bovine pericardium (DBP) as a model for native collagen, this study investigated the response of macrophage-like cells (U937s) to DBP, either: (i) untreated, or (ii) exogenously crosslinked with glutaraldehyde or 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (EDC). We have previously validated the use of U937 cells as models for the response of human monocyte-derived macrophages to decellularized pericardial materials and, per our previous work, differentiated the U937 cells directly on the three material surfaces. After 72h in culture, the cells and medium were analyzed for DNA content, acid phosphatase activity, and cytokine and matrix metalloproteinase release. As well, cell/substrate samples were fixed for SEM. Fewer cells attached to or survived on the glutaraldehyde-treated substrate, and some showed an abnormal morphology compared to cells cultured on the other surfaces. Further, cells on glutaraldehyde-treated surfaces released more pro inflammatory cytokines, more MMP-1 and less MMP-2 and MMP-9. The poor performance of the U937 macrophage-like cells on the glutaraldehyde-treated surfaces appears to be due to surface characteristics rather than to soluble aldehyde or other components leaching from the crosslinked material. These results provide evidence that crosslinking with glutaraldehyde is cytotoxic to macrophage-like cells, and that crosslinking with a zero-length crosslinker like EDC can be an acceptable alternative crosslinking treatment for biomaterials. PMID- 23454058 TI - Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3. AB - BACKGROUND & AIMS: To examine the antiviral activity of boceprevir, a hepatitis C virus (HCV) protease inhibitor, in HCV genotype (G) 2/3-infected patients. METHODS: We assessed boceprevir and telaprevir activity against an HCV G2 and G3 isolates enzyme panel, in replicon, and in phenotypic cell-based assays. Additionally, a phase I study evaluated the antiviral activity of boceprevir monotherapy (200mg BID, 400mg BID, or 400mg TID) vs. placebo for 14 days in HCV G2/3 treatment-naive patients. RESULTS: Boceprevir and telaprevir similarly inhibited G1 and G2 NS3/4A enzymes and replication in G1 and G2 replicon and cell based assays. However, telaprevir demonstrated lower potency than boceprevir against HCV G3a enzyme (Ki=75 nM vs. 17 nM), in the G3a replicon assay (EC50=953 nM vs. 159 nM), and against HCV G3a NS3 isolates (IC50=3312 nM vs. 803 nM) in the cell-based assay. In HCV G2/3-infected patients, boceprevir (400 mg TID) resulted in a maximum mean decrease in HCV RNA of -1.60 log vs. -0.21 log with placebo. CONCLUSIONS: In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays. In HCV G2/3-infected treatment-naive patients, decreases in HCV RNA levels with boceprevir (400 mg TID) were comparable to those observed with the same dose in HCV treatment-experienced G1-infected patients. PMID- 23454059 TI - On the antiquity of metalloenzymes and their substrates in bioenergetics. AB - Many metalloenzymes that inject and extract reducing equivalents at the beginning and the end of electron transport chains involved in chemiosmosis are suggested, through phylogenetic analysis, to have been present in the Last Universal Common Ancestor (LUCA). Their active centres are affine with the structures of minerals presumed to contribute to precipitate membranes produced on the mixing of hydrothermal solutions with the Hadean Ocean ~4 billion years ago. These mineral precipitates consist of transition element sulphides and oxides such as nickelian mackinawite ([Fe>Ni]2S2), a nickel-bearing greigite (~FeSS[Fe3NiS4]SSFe), violarite (~NiSS[Fe2Ni2S4]SSNi), a molybdenum bearing complex (~Mo(IV/VI)2Fe3S(0/2-)9) and green rust or fougerite (~[Fe(II)Fe(III)(OH)4](+)[OH](-)). They may be respectively compared with the active centres of Ni-Fe hydrogenase, carbon monoxide dehydrogenase (CODH), acetyl coenzyme-A synthase (ACS), the complex iron-sulphur molybdoenzyme (CISM) superfamily and methane monooxygenase (MMO). With the look of good catalysts - a suggestion that gathers some support from prebiotic hydrothermal experimentation and sequestered by short peptides, they could be thought of as the original building blocks of proto-enzyme active centres. This convergence of the makeup of the LUCA-metalloenzymes with mineral structure and composition of hydrothermal precipitates adds credence to the alkaline hydrothermal (chemiosmotic) theory for the emergence of life, specifically to the possibility that the first metabolic pathway - the acetyl CoA pathway - was initially driven from either end, reductively from CO2 to CO and oxidatively and reductively from CH4 through to a methane thiol group, the two entities assembled with the help of a further thiol on a violarite cluster sequestered by peptides. By contrast, the organic coenzymes were entirely a product of the first metabolic pathways. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems. PMID- 23454060 TI - A clinical feasibility study of atrial and ventricular electromechanical wave imaging. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) and atrial ablation procedures currently lack a noninvasive imaging modality for reliable treatment planning and monitoring. Electromechanical wave imaging (EWI) is an ultrasound based method that has previously been shown to be capable of noninvasively and transmurally mapping the activation sequence of the heart in animal studies by estimating and imaging the electromechanical wave, that is, the transient strains occurring in response to the electrical activation, at both high temporal and spatial resolutions. OBJECTIVE: To demonstrate the feasibility of transthoracic EWI for mapping the activation sequence during different cardiac rhythms in humans. METHODS: EWI was perfor'med in patients undergoing CRT and a left bundle branch block (LBBB) during sinus rhythm, left ventricular pacing, and right ventricular pacing, as well as in patients with atrial flutter (AFL) before intervention, EWI findings from patients with AFL were subsequently correlated with results from invasive intracardiac electrical mapping studies during intervention. In addition, the feasibility of single-heartbeat EWI at 2000 frames/s is demonstrated in humans for the first time in a patient with both AFL and right bundle branch block (RBBB). RESULTS: The electromechanical activation maps demonstrated the capability of EWI to localize the pacing sites and characterize the bundle branch block activation sequence transmurally in patients with CRT. In patients with AFL, the EWI propagation patterns obtained with EWI were in excellent agreement with those obtained from invasive intracardiac mapping studies. CONCLUSIONS: Our findings demonstrate the potential capability of EWI to aid in the assessment and follow-up of patients undergoing CRT pacing therapy and atrial ablation, with preliminary validation in vivo. PMID- 23454061 TI - Influence of phosphodiesterases on basal and 5-HT4 receptor facilitated cholinergic contractility in pig descending colon. AB - This study in pig colon descendens circular muscle investigated the possible role of phosphodiesterases (PDEs) (1) in the control of smooth muscle activity and (2) in the signal transduction of the 5-HT4 receptors located on the cholinergic neurons. Submaximal cholinergic contractions were electrically induced in colonic circular muscle strips and the influence of the non-selective PDE inhibitor 3 isobutyl-1-methyl-xanthine (IBMX) and selective inhibitors for the 5 classic PDE families (1-5) vinpocetine (PDE1), EHNA (PDE2), cilostamide (PDE3), rolipram (PDE4) and zaprinast (PDE5) was evaluated. IBMX and cilostamide concentration dependently reduced the amplitude of the cholinergic contractions, as good as abolishing them at 30 and 0.3 MUM respectively. EHNA only reduced the contractions significantly at the highest concentration tested (30 MUM). IBMX and cilostamide also concentration-dependently inhibited submaximal cholinergic contractions induced with the muscarinic receptor agonist carbachol. The 5-HT4 receptor agonist prucalopride (1 MUM) significantly enhanced the electrically induced cholinergic contractions. IBMX, vinpocetine and EHNA did not influence the facilitating effect of prucalopride but rolipram tended to enhance it. When rolipram was added after prucalopride, the facilitating effect of prucalopride was significantly enhanced. These results suggest that PDE3 is the main regulator of circular smooth muscle activity and that the signal transduction of 5-HT4 receptors on the cholinergic nerves towards the circular muscle layer is regulated by PDE4 in pig colon descendens. PMID- 23454062 TI - A histological variant of white spot syndrome virus (WSSV) from the Kingdom of Saudi Arabia. AB - White spot syndrome virus (WSSV) is highly pathogenic to penaeid shrimp. The major targets of WSSV infection are tissues of ectodermal and mesodermal embryonic origin, predominantly the cuticular epithelium and subcuticular connective tissues. Recently, we discovered a WSSV variant in Penaeus indicus that heavily infects the subcuticular connective tissue, with very slight indications in the cuticular epithelium. The variant was also unusual in that WSSV accumulations were found in the interstitial spaces of both the subcuticular connective tissue and the lymphoid organ. This WSSV variant was confirmed through immunohistochemistry with an anti-WSSV VP28 monoclonal antibody, and also by in situ hybridization with a VP28 DNA probe. By in situ hybridization, shrimp with variant and typical histology were shown a deletion in ORF94, which is characteristic of a new type of WSSV found in Saudi Arabia; apparently, the loss of this ORF is not associated with the variant's reduced capability of infecting the cuticular epithelium cells. PMID- 23454063 TI - Structural and functional genomics of plasmid pSinA of Sinorhizobium sp. M14 encoding genes for the arsenite oxidation and arsenic resistance. AB - Plasmid pSinA of Sinorhizobium sp. M14 (Alphaproteobacteria) is the first described, natural, self-transferable plasmid harboring a complete set of genes for oxidation of arsenite. Removal of this plasmid from cells of the host strain caused the loss of resistance to arsenic and heavy metals (Cd, Co, Zn and Hg) and abolished the ability to grow on minimal salt medium supplemented with sodium arsenite as the sole energy source. Plasmid pSinA was introduced into other representatives of Alphaproteobacteria which resulted in acquisition of new abilities concerning arsenic resistance and oxidation, as well as heavy metals resistance. Microcosm experiments revealed that plasmid pSinA can also be transferred via conjugation into other indigenous bacteria from microbial community of As-contaminated soils, including representatives of Alpha- and Gammaproteobacteria. Analysis of "natural" transconjugants showed that pSinA is functional (expresses arsenite oxidase) and is stably maintained in their cells after approximately 60 generations of growth under nonselective conditions. This work clearly demonstrates that pSinA is a self-transferable, broad-host-range plasmid, which plays an important role in horizontal transfer of arsenic metabolism genes. PMID- 23454064 TI - Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice. AB - Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left-ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated proinflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55mg/kg/day for 5 days), to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, the mice were allocated to coenzyme Q10 supplementation (10mg/kg/day), treatment with the angiotensin-converting-enzyme inhibitor (ACE-I) ramipril (3mg/kg/day), treatment with olive oil vehicle, or no treatment for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22(phox), p47(phox) and superoxide production), LV uncoupling protein UCP3 expression, and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q10. Coenzyme Q10 substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure, and LV -dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis), and LV expression of proinflammatory mediators (tumor necrosis factor-alpha, with a similar trend for interleukin IL 1beta). Coenzyme Q10's actions were independent of glycemic control, body mass, and blood pressure. Coenzyme Q10 compared favorably to improvements observed with ramipril. In summary, these data suggest that coenzyme Q10 effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q10 supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients. PMID- 23454066 TI - Nursing students' perceptions of high- and low-fidelity simulation used as learning methods. AB - Due to the increasing focus on simulation used in nursing education, there is a need to examine how the scenarios and different simulation methods used are perceived by students. The aim of this study was to examine nursing students' perceptions of scenarios played out in different simulation methods, and whether their educational level influenced their perception. The study had a quantitative, evaluative and comparative design. The sample consisted of baccalaureate nursing students (n = 86) within various educational levels. The students were randomly divided into groups. They solved a patient case adapted to their educational level by using a high-fidelity patient simulator, a static mannequin or a paper/pencil case study. Data were collected by three instruments developed by the National League for Nursing. The results showed that the nursing students reported satisfaction with the implementation of the scenarios regardless of the simulation methods used. The findings indicated that the students who used the paper/pencil case study were the most satisfied. Moreover, educational level did not seem to influence their perceptions. CONCLUSIONS: Independent of educational level, the findings indicated that simulation with various degrees of fidelity could be used in nursing education. There is a need for further research to examine more closely the rationale behind the students' perception of the simulation methods. PMID- 23454065 TI - Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury. AB - Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2h in mice exposed to a single APAP dose (350mg/kg ip), which caused severe liver necrosis at 24h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3 hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3 nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity. PMID- 23454067 TI - Global gene expression profiling of monocyte-derived macrophages from red deer (Cervus elaphus) genotypically resistant or susceptible to Mycobacterium avium subspecies paratuberculosis infection. AB - Mycobacterium avium subspecies paratuberculosis (MAP) can cause a chronic inflammatory bowel disease, Johne's disease (JD), in ruminant animals. This study has explored the molecular basis of resistance and susceptibility to this disease in red deer breeds previously confirmed to express polarised phenotypes by experimental infection trials and following natural infection. Monocyte-derived macrophage cultures were obtained from uninfected red deer selected for either a resistant or susceptible phenotype. Cells were infected with MAP in vitro and gene expression analysed by RNA-Seq. Transcriptome analysis revealed a more disrupted gene expression profile in macrophages from susceptible animals compared with cells from resistant animals in terms of the number of genes up- or downregulated. Highly upregulated genes were related to chemotaxis (CXCL10, CSF3, and CCL8) and type 1 interferon signalling (RSAD2, IFIT1, IFIT2, ISG12, ISG15, USP18, and HERC6). Upregulation of these genes was observed to be greater in macrophages from susceptible animals compared to cells from resistant animals in response to in vitro MAP infection. These data support the use of transcriptomic approaches to enable the identification of markers associated particularly with susceptibility to MAP infection. PMID- 23454068 TI - [Pre- and post-test probability of obstructive coronary artery disease in two diagnostic strategies: relative contributions of exercise ECG and coronary CT angiography]. AB - INTRODUCTION: The purpose of this study was to assess the change in theoretical probability of coronary artery disease (CAD) in patients with suspected CAD undergoing coronary CT angiography (CCTA) as first line test vs. patients who underwent CCTA after an exercise ECG. METHODS: Pre- and post-test probabilities of CAD were assessed in 158 patients with suspected CAD undergoing dual-source CCTA as the first-line test (Group A) and in 134 in whom CCTA was performed after an exercise ECG (Group B). Pre-test probabilities were calculated based on age, gender and type of chest pain. Post-test probabilities were calculated according to Bayes' theorem. RESULTS: There were no significant differences between the groups regarding pre-test probability (median 23.5% [13.3-37.8] in group A vs. 20.5% [13.4-34.5] in group B; p=0,479). In group A, the percentage of patients with intermediate likelihood of disease (10-90%) was 90% before testing and 15% after CCTA (p<0,001), while in group B, it was 95% before testing, 87% after exercise ECG (p=NS), and 17% after CCTA (p<0,001). CONCLUSION: Unlike exercise testing, CCTA is able to reclassify the risk in the majority of patients with an intermediate probability of obstructive CAD. The use of CCTA as a first-line diagnostic test for CAD may be beneficial in this setting. PMID- 23454069 TI - Understanding cardiac myxoma recurrence: a case report. AB - Recurrence of cardiac myxoma is a rare condition, observed in about 3% of patients in sporadic cases, although it is more frequent in familial ones. Several mechanisms have been proposed to explain such recurrence, and the importance of increased vascularization as a facilitating feature is the subject of debate. The authors report the case of a non-familial right atrial myxoma, unusual for both its histopathology and recurrence. PMID- 23454070 TI - ERP correlates of letter identity and letter position are modulated by lexical frequency. AB - The encoding of letter position is a key aspect in all recently proposed models of visual-word recognition. We analyzed the impact of lexical frequency on letter position assignment by examining the temporal dynamics of lexical activation induced by pseudowords extracted from words of different frequencies. For each word (e.g., BRIDGE), we created two pseudowords: A transposed-letter (TL: BRIGDE) and a replaced-letter pseudoword (RL: BRITGE). ERPs were recorded while participants read words and pseudowords in two tasks: Semantic categorization (experiment 1) and lexical decision (experiment 2). For high-frequency stimuli, similar ERPs were obtained for words and TL-pseudowords, but the N400 component to words was reduced relative to RL-pseudowords, indicating less lexical/semantic activation. In contrast, TL- and RL-pseudowords created from low-frequency stimuli elicited similar ERPs. Behavioral responses in the lexical decision task paralleled this asymmetry. The present findings impose constraints on computational and neural models of visual-word recognition. PMID- 23454071 TI - The role of age of acquisition on past tense generation in Spanish-English bilinguals: an fMRI study. AB - At its most basic sense, the sensorimotor/emergentist (S/E) model suggests that early second language (L2) learning is preferentially reliant upon sensory and motor processes, while later L2 learning is accomplished by greater reliance on executive abilities. To investigate the S/E model using fMRI, neural correlates of L2 age of acquisition were examined by employing a past-tense generation task on 22 L2 proficient bilinguals. Early bilinguals preferentially recruited left hemisphere sensorimotor regions involved in motoric control and articulation. In contrast, later learners, to a greater degree, engaged regions involved in executive cognitive control and lexical access. The data support the notion that early L2 learners devote neural resources to motor control during lexical retrieval. In contrast, later L2 learners recruit executive control mechanisms to generate the past tense. These data are consistent with the S/E model of bilingual language learning, and serve as an extension of cognitive control theories. PMID- 23454072 TI - Brain activation associated with practiced left hand mirror writing. AB - Mirror writing occurs in healthy children, in various pathologies and occasionally in healthy adults. There are only scant experimental data on the underlying brain processes. Eight, right-handed, healthy young adults were scanned (BOLD-fMRI) before and after practicing left-hand mirror-writing (lh-MW) over seven sessions. They wrote dictated words, using either the right hand with regularly oriented writing or lh-MW. An MRI compatible stylus-point recording system was used and online visual feedback was provided. Practice resulted in increased speed and readability of lh-MW but the number of movement segments was unchanged. Post-training signal increases occurred in visual, right lateral and medial premotor areas, and in right anterior and posterior peri-sylvian areas corresponding to language areas. These results suggest that lh-MW may constitute a latent ability that can be reinstated by a relatively brief practice experience. Concurrently, right hemisphere language processing areas may emerge, reflecting perhaps a reduction in trans-hemispheric suppression. PMID- 23454073 TI - Concreteness in word processing: ERP and behavioral effects in a lexical decision task. AB - Relative to abstract words, concrete words typically elicit faster response times and larger N400 and N700 event-related potential (ERP) brain responses. These effects have been interpreted as reflecting the denser links to associated semantic information of concrete words and their recruitment of visual imagery processes. Here, we examined whether there are ERP differences between concrete and abstract stimuli controlled for a large number of factors including context availability (i.e., richness of semantic associations) and imageability. We found that abstract words elicited faster behavioral responses but that concrete words still elicited larger N400 and N700 responses. We propose that once all other factors, including imageability and context availability are controlled, abstract words may trigger a larger number of superficial linguistic associations that can be quickly used for response decisions. The ERP differences, however, would index the greater semantic processing (integration of multimodal information) for concrete than abstract words during meaning activation. PMID- 23454074 TI - Fine tuned modulation of the motor system by adjectives expressing positive and negative properties. AB - Using transcranial magnetic stimulation (TMS), motor evoked potentials (MEPs) were recorded from two antagonistic muscles, the first dorsal interosseus (FDI) of the hand and the extensor communis digitorum (EC) of the forearm. FDI is involved in grasping actions and EC in releasing. TMS pulses were delivered while participants were reading adjectives expressing either negative or positive pragmatic properties, at 150 ms after presentation of language material. Overall findings showed an interaction of adjective type (positive, negative) and muscle (FDI, EC), the effect being driven by a significant difference for negative adjectives. Further analysis aimed at investigating the effectiveness of positive adjectives showed a similar, but opposite, pattern of effects for the positive words in the initial two blocks. The present results indicate that, as for verbs and nouns, adjectives recruit the sensorimotor system, and their processing is best explained by an embodiment rather than an amodal approach to language. PMID- 23454075 TI - Reconciling time, space and function: a new dorsal-ventral stream model of sentence comprehension. AB - We present a new dorsal-ventral stream framework for language comprehension which unifies basic neurobiological assumptions (Rauschecker & Scott, 2009) with a cross-linguistic neurocognitive sentence comprehension model (eADM; Bornkessel & Schlesewsky, 2006). The dissociation between (time-dependent) syntactic structure building and (time-independent) sentence interpretation assumed within the eADM provides a basis for the division of labour between the dorsal and ventral streams in comprehension. We posit that the ventral stream performs time independent unifications of conceptual schemata, serving to create auditory objects of increasing complexity. The dorsal stream engages in the time-dependent combination of elements, subserving both syntactic structuring and a linkage to action. Furthermore, frontal regions accomplish general aspects of cognitive control in the service of action planning and execution rather than linguistic processing. This architecture is supported by a range of existing empirical findings and helps to resolve a number of theoretical and empirical puzzles within the existing dorsal-ventral streams literature. PMID- 23454076 TI - The speakers' accent shapes the listeners' phonological predictions during speech perception. AB - This study investigates the specificity of predictive coding in spoken word comprehension using event-related potentials (ERPs). We measured word-evoked ERPs in Catalan speakers listening to semantically constraining sentences produced in their native regional accent (experiment 1) or in a non-native accent (experiment 2). Semantically anomalous words produced long-lasting negative shift (N400) starting as early as 250 ms, thus reflecting phonological as well as semantic mismatch. Semantically expected but phonologically unexpected (non-native forms embedded in a native context) produced only an early (~250 ms) negative difference. In contrast, this phonological expectancy effect failed for native albeit phonologically unexpected target words embedded in a non-native context. These results suggest phonologically precise expectations when operating over native input, whilst phonologically less specified expectations in a non-native context. Our findings shed light on contextual influence during word recognition, suggesting that word form prediction based on context is sensitive and adaptive to phonological variability. PMID- 23454077 TI - The intestinal microbiota and host immune interactions in the critically ill. AB - The gastrointestinal tract harbors a complex population of microbes that play a fundamental role in the development of the immune system and human health. Besides an important local contribution in the host defense against infections, it has become increasingly clear that intestinal bacteria also modulate immune responses at systemic sites. These new insights can be of profound clinical relevance especially for intensive care medicine where the majority of patients are treated with antibiotics, which have pervasive and long-term effects on the intestinal microbiota. Moreover, considerable progress has been made in defining the role of the intestinal microbiota in both health and disease. In this review, we highlight these aspects and focus on recent key findings addressing the role of intestinal microbiota in antimicrobial defense mechanisms and its impact on intestinal homeostasis in the critically ill. PMID- 23454078 TI - Oxygen, epigenetic signaling, and the evolution of early life. AB - After approximately 3 billion years of unicellular life on Earth, multicellular animals appeared some 600 million years ago, followed by the rapid emergence of most animal phyla during the Cambrian radiation. This evolutionary jump was paralleled by an increase in atmospheric oxygen, which I propose allowed the generation of epigenetic signaling systems that are essential for cellular differentiation in animals. Epigenetic signaling is based on the reversible deposition of chemically stable marks in DNA and histone proteins, with methylation of cytosine and lysine residues, respectively, playing a central role. Recent evidence indicates that the removal of such methyl groups critically depends on oxygenases. Hence, reversible epigenetic systems could only appear after accumulation of oxygen in the atmosphere. PMID- 23454079 TI - Frameshifted prion proteins as pathological agents: quantitative considerations. AB - A quantitatively consistent explanation for the titres of infectivity found in a variety of prion-containing preparations is provided on the basis that the aetiological agents of transmissible spongiform encephalopathy comprise a very small population fraction of prion protein (PrP) variants, which contain frameshifted elements in their N-terminal octapeptide-repeat regions. A mechanism for the replication of frameshifted prions is described and calculations are performed to obtain estimates of the concentration of these PrP variants in normal and infected brain, as well as their enrichment in products of protein misfolding cyclic amplification. These calculations resolve the lack of proper quantitative correlation between measures of infectivity and the presence of conformationally-altered, protease-resistant variants of PrP. Experiments, which could confirm or eventually exclude the role of frameshifted variants in the aetiology of prion disease, are suggested. PMID- 23454080 TI - Kinetic approaches to lactose operon induction and bimodality. AB - The quasi-equilibrium approximation is acceptable when molecular interactions are fast enough compared to circuit dynamics, but is no longer allowed when cellular activities are governed by rare events. A typical example is the lactose operon (lac), one of the most famous paradigms of transcription regulation, for which several theories still coexist to describe its behaviors. The lac system is generally analyzed by using equilibrium constants, contradicting single-event hypotheses long suggested by Novick and Weiner (1957). Enzyme induction as an all or-none phenomenon. Proc. Natl. Acad. Sci. USA 43, 553-566) and recently refined in the study of (Choi et al., 2008. A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 322, 442-446). In the present report, a lac repressor (LacI)-mediated DNA immunoprecipitation experiment reveals that the natural LacI-lac DNA complex built in vivo is extremely tight and long-lived compared to the time scale of lac expression dynamics, which could functionally disconnect the abortive expression bursts and forbid using the standard modes of lac bistability. As alternatives, purely kinetic mechanisms are examined for their capacity to restrict induction through: (i) widely scattered derepression related to the arrival time variance of a predominantly backward asymmetric random walk and (ii) an induction threshold arising in a single window of derepression without recourse to nonlinear multimeric binding and Hill functions. Considering the complete disengagement of the lac repressor from the lac promoter as the probabilistic consequence of a transient stepwise mechanism, is sufficient to explain the sigmoidal lac responses as functions of time and of inducer concentration. This sigmoidal shape can be misleadingly interpreted as a phenomenon of equilibrium cooperativity classically used to explain bistability, but which has been reported to be weak in this system. PMID- 23454081 TI - Task-partitioning in insect societies: Non-random direct material transfers affect both colony efficiency and information flow. AB - Task-partitioning is an important organisational principle in insect colonies and is thought to increase colony efficiency. In task-partitioning, tasks such as the collection of resources are divided into subtasks in which the material is passed from one worker to another. Previous models have assumed that worker-worker interactions are random, but experimental evidence suggests that receivers can have preferences to handle familiar materials. We used an agent-based simulation model to explore how non-random interactions during task-partitioning with direct transfer affect colony work efficiency. Because task-partitioning also allows receivers and donors to acquire foraging related information we analysed the effect of non-random interactions on informative interaction patterns. When receivers non-randomly rejected donors offering certain materials, donors overall experienced increased time delays, hive stay durations and a decreased number of transfer partners. However, the number of transfers was slightly increased, which can improve the acquisition and quality of information for donors. When receivers were non-randomly attracted to donors offering certain materials, donors experienced reduced transfer delays, hive stay durations and an increased number of simultaneous receivers. The number of transfers is slightly decreased. The effects of the two mechanisms "non-random rejection" and "non-random attraction" are biggest if the number of foragers and receivers is balanced. In summary, our results show that colony ergonomics are improved if receivers do not reject donors and if mechanisms exist that help receivers detect potential donors, such as learning the odour of the transferred food. Finally, our simulations suggest that non-random interactions can potentially affect the foraging patterns of colonies in changing environments. PMID- 23454082 TI - Modeling the short time-scale dynamics of beta-amyloid-neuron interactions. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles. The primary protein components of these two histopathological features, beta-amyloid peptide (Abeta) and tau, respectively, have been implicated in neuronal death. Despite extensive research into the disease etiology, its underlying molecular processes remain unknown. Researchers hypothesize that Abeta interacts with the cell surface preceding neuronal dysfunction and cell death; however, there is no consensus about the functional role of Abeta at the cell surface. Utilizing a mathematical model of a neuron, we compared simulation results under voltage-clamp, current clamp and high [K(+)] membrane depolarized conditions of two hypothesized mechanisms of Abeta-neuron interactions: the Abeta blocking of fast-inactivating K(+) (IA) channels and the Abeta-induced increase in membrane conductance. Our model predicts that both mechanisms may lead to changes in ion conductances, cell excitability and Ca(2+) influx under voltage- and current-clamp conditions. Interestingly, membrane depolarization simulations predict very different correlations in Ca(2+) influx between the two mechanisms and may provide data that distinguishes the mechanisms. Our results suggest that our computational modeling methodology may enhance experimental design such that mechanisms of Abeta-induced action on a neuron can be discriminated. PMID- 23454083 TI - Bioethanol production from mixed sugars by Scheffersomyces stipitis free and immobilized cells, and co-cultures with Saccharomyces cerevisiae. AB - Bioethanol can be produced from several biomasses including lignocellulosic materials. Besides 6-carbon sugars that represent the prevalent carbohydrates, some of these feedstocks contain significant amounts of 5-carbon sugars. One common limit of the major part of the xylose-fermenting yeasts is the diauxic shift between the uptake of glucose and xylose during the fermentation of mixed syrups. Thus, optimized fermentation strategies are required. In this paper the ability of Scheffersomyces stipitis strain NRRLY-11544 to ferment mixed syrups with a total sugar concentration in the range 40-80 g/L was investigated by using mono cultures, co-cultures with Saccharomyces cerevisiae strain Bakers Yeast Type II and single cultures immobilized in silica-hydrogel films. The experimental design for the fermentations with immobilized cells included the process analysis in function of two parameters: the fraction of the gel in the broth and the concentration of the cells loaded in the gel. Furthermore, for each total sugars level, the fermentative course of S. stipitis was analyzed at several glucose-to xylose ratios. The results indicated that the use of S. stipitis and S. cerevisiae in free co-cultures ensured faster processes than single cultures of S. stipitis either free or immobilized. However, the rapid production of ethanol by S. cerevisiae inhibited S. stipitis and caused a stuck of the process. Immobilization of S. stipitis in silica-hydrogel increased the relative consumption rate of xylose-to-glucose by 2-6 times depending on the composition of the fermentation medium. Furthermore the films performances appeared stable over three weeks of continuous operations. However, on the whole, the final process yields obtained with the immobilized cells were not meaningfully different from that of the free cells. This was probably due to concurrent fermentations operated by the cells released in the broth. Optimization of the carrier characteristics could improve the performances of the process with immobilized cells. PMID- 23454084 TI - Real-time attack of LL-37 on single Bacillus subtilis cells. AB - Time-lapse fluorescence microscopy of single, growing Bacillus subtilis cells with 2-12s time resolution reveals the mechanisms of antimicrobial peptide (AMP) action on a Gram-positive species with unprecedented detail. For the human cathelicidin LL-37 attacking B. subtilis, the symptoms of antimicrobial stress differ dramatically depending on the bulk AMP concentration. At 2MUM LL-37, the mean single-cell growth rate decreases, but membrane permeabilization does not occur. At 4MUM LL-37, cells abruptly shrink in size at the same time that Sytox Green enters the cytoplasm and stains the nucleoids. We interpret the shrinkage event as loss of turgor pressure (and presumably the membrane potential) due to permeabilization of the membrane. Movies of Sytox Green staining at 0.5frame/s show that nucleoid staining is initially local, more consistent with pore formation than with global permeabilization models. In a novel "growth recovery" assay, cells are incubated with LL-37 for a variable period and then rinsed with fresh growth medium lacking LL-37. The growth rate attenuation observed at 2MUM LL-37 is a recoverable symptom, while the abrupt cell shrinkage observed at 4MUM LL-37 is not. PMID- 23454086 TI - Different roles of cell surface and exogenous glycosaminoglycans in controlling gene delivery by arginine-rich peptides with varied distribution of arginines. AB - The role of cell surface and exogenous glycosaminoglycans (GAGs) in DNA delivery by cationic peptides is controlled to a large extent by the peptide chemistry and the nature of its complex with DNA. We have previously shown that complexes formed by arginine homopeptides with DNA adopt a GAG-independent cellular internalization mechanism and show enhanced gene delivery in presence of exogenous GAGs. In contrast, lysine complexes gain cellular entry primarily by a GAG-dependent pathway and are destabilized by exogenous GAGs. The aim of the current study was to elucidate the factors governing the role of cell surface and soluble glycosaminoglycans in DNA delivery by sequences of arginine-rich peptides with altered arginine distributions (compared to homopeptide). Using peptides with clustered arginines which constitute known heparin-binding motifs and a control peptide with arginines alternating with alanines, we show that complexes formed by these peptides do not require cell surface GAGs for cellular uptake and DNA delivery. However, the charge distribution and the spacing of arginine residues affects DNA delivery efficiency of these peptides in presence of soluble GAGs, since these peptides show only a marginal increase in transfection in presence of exogenous GAGs unlike that observed with arginine homopeptides. Our results indicate that presence of arginine by itself drives these peptides to a cell surface GAG-independent route of entry to efficiently deliver functional DNA into cells in vitro. However, the inherent stability of the complexes differ when the distribution of arginines in the peptides is altered, thereby modulating its interaction with exogenous GAGs. PMID- 23454085 TI - Apolipoprotein A-I binding to anionic vesicles and lipopolysaccharides: role for lysine residues in antimicrobial properties. AB - Human apolipoprotein A-I (apoA-I) is a 28kDa protein and a major component of high-density lipoproteins, mediating several essential metabolic functions related to heart disease. In the present study the potential protective role against bacterial pathogens was explored. ApoA-I suppressed bacterial growth of Escherichia coli and Klebsiella pneumoniae. The protein was able to bind lipopolysaccharides and showed a strong preference for bilayer vesicles made of phosphatidylglycerol over phosphatidylcholine. Lysine side chains of apoA-I were acetylated to evaluate the importance of electrostatic forces in the binding interaction with both membrane components. Electrophoresis properties, dot blot analysis, circular dichroism, and fluorescence spectroscopy to probe for changes in protein structure indicated that the acetylated protein displayed a strongly reduced lipopolysaccharide and phosphatidylglycerol binding. A mutant containing only the N-terminal domain of apoA-I also showed a reduced ability to interact with the membrane components, although to a lesser extent. These results indicate the potential for apoA-I to function as an antimicrobial protein and exerts this function through lysine residues. PMID- 23454087 TI - Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism. AB - Persistent patency of the ductus arteriosus (PDA) is a common problem in preterm infants. The antacid cimetidine is a potent antagonist of the H2 histamine receptor but it also inhibits certain cytochrome P450 enzymes (CYPs), which may affect DA patency. We examined whether cimetidine contributes to PDA and is mediated by CYP inhibition rather than H2 blockade. Analysis of a clinical trial to prevent lung injury in premature infants revealed a significant association between cimetidine treatment and PDA. Cimetidine and ranitidine, both CYP inhibitors as well as H2 blockers, caused relaxation of the term and preterm mouse DA. CYP enzymes that are inhibited by cimetidine were expressed in DA subendothelial smooth muscle. The selective CYP3A inhibitor ketoconazole induced greater DA relaxation than cimetidine, whereas famotidine and other H2 antagonists with less CYP inhibitory effects caused less dilation. Histamine receptors were developmentally regulated and localized in DA smooth muscle. However, cimetidine caused DA relaxation in histamine-deficient mice, consistent with CYP inhibition, not H2 antagonism, as the mechanism for PDA. Oxygen-induced DA constriction was inhibited by both cimetidine and famotidine. These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants. PMID- 23454089 TI - Insulin increases glomerular filtration barrier permeability through dimerization of protein kinase G type Ialpha subunits. AB - The increase in the permeability of the glomerular barrier filtration to albumin is a well-known feature of diabetic microvasculature and a negative prognostic factor for vascular complications. However, the underlying mechanisms are incompletely understood. We demonstrated recently that superoxide anion generation increases dimerization of protein kinase G type Ialpha (PKGIalpha) subunits, leading to podocyte dysfunction. Here we investigated whether high insulin concentration is involved in PKGI-dependent hyperpermeability of the diabetic glomerular filtration barrier. We assessed changes in insulin-induced glomerular permeability by measuring glomerular capillary permeability to albumin in isolated glomeruli from Wistar and obese and lean Zucker rats and transmembrane albumin flux in cultured rat podocytes. Expression of PKGIalpha and upstream proteins was confirmed in the podocytes using Western blotting and immunofluorescence. Insulin (300nM, 5min) increased NAD(P)H-dependent glomerular albumin permeability in Wistar rats and PKGI-dependent transmembrane albumin flux in cultured podocytes. Podocyte exposure to insulin in non-reducing conditions increased PKGIalpha interprotein disulfide bond formation, altered the phosphorylation of the PKG target proteins MYPT1 and MLC, and disrupted the actin cytoskeleton. The role of NADPH oxidase (NOX) in insulin-induced reactive oxygen species (ROS) generation and insulin-evoked increases in albumin permeability in podocytes was confirmed with NOX2 and NOX4 siRNA. Glomerular albumin permeability was increased in hyperinsulinemic Zucker obese rats with isolated glomeruli showing increased expression of PKGIalpha and NOX4. Taken together, these data demonstrate that insulin increases glomerular barrier albumin permeability via a PKGI-dependent mechanism involving NAD(P)H-dependent generation of superoxide anion. These findings reveal a role for insulin in the pathophysiology of diabetic glomerular nephropathy. PMID- 23454088 TI - Biochemical and biophysical changes underlie the mechanisms of basement membrane disruptions in a mouse model of dystroglycanopathy. AB - Mutations in glycosyltransferases, such as protein O-mannose N acetylglucosaminyltransferase 1 (POMGnT1), causes disruptions of basement membranes (BMs) that results in neuronal ectopias and muscular dystrophy. While the mutations diminish dystroglycan-mediated cell-ECM interactions, the cause and mechanism of BM disruptions remain unclear. In this study, we established an in vitro model to measure BM assembly on the surface of neural stem cells. Compared to control cells, the rate of BM assembly on POMGnT1 knockout neural stem cells was significantly reduced. Further, immunofluorescence staining and quantitative proteomic analysis of the inner limiting membrane (ILM), a BM of the retina, revealed that laminin-111 and nidogen-1 were reduced in POMGnT1 knockout mice. Finally, atomic force microscopy showed that the ILM from POMGnT1 knockout mice was thinner with an altered surface topography. The results combined demonstrate that reduced levels of key BM components cause physical changes that weaken the BM in POMGnT1 knockout mice. These changes are caused by a reduced rate of BM assembly during the developmental expansion of the neural tissue. PMID- 23454090 TI - Return flight to the Canary Islands--the key role of peripheral populations of Afrocanarian blue tits (Aves: Cyanistes teneriffae) in multi-gene reconstructions of colonization pathways. AB - Afrocanarian blue tits (Cyanistes teneriffae) have a scattered distribution on the Canary Islands and on the North African continent. To date, the Canary Islands have been considered the species' main Pleistocene evolutionary center, but their colonization pathways remain uncertain. We set out to reconstruct a dated multi-gene phylogeny and ancestral ranges for Cyanistes tit species including the currently unstudied, peripheral Libyan population of C. t. cyrenaicae. In all reconstructions the most easterly and westerly peripheral populations (in Libya and on La Palma) represented basal offshoots of C. teneriffae. These two peripheral populations shared all four major indels and differed in this respect from all other members of the Afrocanarian core group. The basal split of Afrocanarian blue tits from their European relatives was dated to the early Pliocene. The two ancestral area reconstructions were contradictory and suggested either a Canarian or a North African origin of C. teneriffae - but unambiguously ruled out a continental European ancestral range. We conclude that the peripheral populations of C. teneriffae represent relic lineages of a first faunal interchange, presumably downstream colonization from North Africa to the Canary Islands. Subsequent eastward stepping-stone colonization within the Canarian Archipelago culminated in a very recent late (possibly even post-) Pleistocene back-colonization from the Canary Islands to North Africa. PMID- 23454091 TI - Molecular dating of phylogenies by likelihood methods: a comparison of models and a new information criterion. AB - Dating the divergence in a phylogenetic tree is a fundamental step in evolutionary analysis. Some extensions and improvements of the penalised likelihood method originally presented by Sanderson are introduced. The improvements are the introduction of alternative models, including one with non correlated rates of molecular substitution ("relaxed" model), a completely reworked fitting algorithm that considers the high-dimensionality of the optimisation problem, and the development of a new information criterion for model selection in the presence of a penalised term. It is also shown that the strict clock model is a special case of the present approach. An extensive simulation study was conducted to assess the statistical performance of these improvements. Overall, the different estimators studied here appeared as unbiased though their variance varied depending on the fitted and the simulated models and on the number of calibration points. The strict clock model gave good estimates of branch lengths even in the presence of heterogeneous substitution rates. The correlated model gave the best estimates of substitution rates whatever the model used to simulate the data. These results, which are certainly the first from an extensive simulation study of a molecular dating method, call for more comparison with alternative methods, as well as further work on the developments introduced here. PMID- 23454092 TI - Unexpected phylogenetic positions of the genera Rupirana and Crossodactylodes reveal insights into the biogeography and reproductive evolution of leptodactylid frogs. AB - Despite major progress in deciphering the amphibian tree of life by molecular phylogenetics, we identified two questions remaining to be answered regarding relationships within Hyloidea, the clade of South American origin that comprises most extant anuran diversity. A few genera like Rupirana and Crossodactylodes have enigmatic phylogenetic positions, and relationships among major lineages within some families like Leptodactylidae remain ambiguous. To resolve these specific questions we used two approaches (1) a complete matrix approach representing >6.6 kb, including most major Hyloidea lineages (61 terminals) combining different methods of phylogenetic reconstruction and measures of node support; and (2) a supermatrix approach >11.6 kb with a focus on Leptodactylidae. Both Rupirana and Crossodactylodes are unambiguously grouped with Paratelmatobius and Scythrophrys. The clade comprising these four genera is named Crossodactylodinae and embedded within Leptodactylidae. Crossodactylodinae is moderately supported as sister group of Leptodactylinae from (1) and as the sister group of the other Leptodactylidae from (2) with low support. Genera within Crossodactylodinae are scattered along a north-south axis in the Atlantic forest and their origins are very ancient (Paleocene). Such results stress the importance of the northern Atlantic forest in terms of conservation. Moreover, the position of Pseudopaludicola, which is well supported as the sister group to all other Leiuperinae, suggests that foam-nest building may have arisen independently in Leptodactylinae and Leiuperinae. Moreover, in spite of being of similar age, foam-nest builders are more widespread than nonfoam-nest breeders and have higher species diversity. Nevertheless, the bulk of the diversity within foam-nest breeders arose some 20 Myr later than the character itself. PMID- 23454093 TI - Higher level phylogenetic relationships within the bamboos (Poaceae: Bambusoideae) based on five plastid markers. AB - Bamboos are large perennial grasses of temperate and tropical forests worldwide. Two general growth forms exist: the economically and ecologically important woody bamboos (tribes Arundinarieae and Bambuseae), and the understory herbaceous bamboos (tribe Olyreae). Evolutionary relationships among the 1400+described species have been difficult to resolve with confidence. Comparative analysis of bamboo plastid (chloroplast) DNA has revealed three to five major lineages that show distinct biogeographic distributions. Taxon sampling across tribes and subtribes has been incomplete and most published data sets include a relatively small number of nucleotide characters. Branching order among lineages is often poorly supported, and in more than one study herbaceous bamboos form a clade within the woody bamboos. In this paper, the Bamboo Phylogeny Group presents the most complete phylogeny estimation to date of bamboo tribes and subtribes using 6.7 kb of coding and noncoding sequence data and 37 microstructural characters from the chloroplast genome. Quality of data is assessed, as is the possibility of long branch attraction, the degree of character conflict at key nodes in the tree, and the legitimacy of three alternative hypotheses of relationship. Four major plastid lineages are recognized: temperate woody, paleotropical woody, neotropical woody, and herbaceous bamboos. Woody bamboos are resolved as paraphyletic with respect to Olyreae but SH tests cannot reject monophyly of woody species (Arundinarieae+Bambuseae). PMID- 23454094 TI - Complexity of roles and regulation of the PMK1-MAPK pathway in mycelium development, conidiation and appressorium formation in Magnaporthe oryzae. AB - MST50, MST11, MST7, PMK1 and GAS1/GAS2 genes are the important components in the PMK1-MAPK signal transduction pathway in fungi. Mutants with deletion of these five genes of Magnaporthe oryzae, a pathogen of the rice blast, were constructed. A cDNA array containing 4108 unique genes of M. oryzae was developed and used to analyze the gene expression profiles of these mutants against the wild type to dissect the gene expression regulation networks responsible for conidiation and appressorium formation. With this approach, differentially regulated genes by these five components were identified. The vast majority of the regulated genes were mutant-specific, while only a small proportion were in common for all of the mutants, suggesting that each of these genes has its own regulon. Functional groups and expression patterns of the regulated genes showed that (1) gene members in the PMK1-MAPK pathway are associated with multiple signaling pathways; (2) the regulation of PMK1-mediated signaling pathways is very complex and likely involved in other signaling networks; (3) glucose metabolism and signals are required in mycelium development; and (4) appressorium formation likely shares the mechanisms responsible for sexual conjugation and meiosis, which is affected by carbohydrate metabolism. PMID- 23454095 TI - Ligation of porcine Fc gamma receptor I inhibits levels of antiviral cytokine in response to PRRSV infection in vitro. AB - PRRSV infection ADE facilitates the attachment and internalization of the virus onto macrophages through Fc receptor-mediated endocytosis. FcgammaRI is the activating receptor with a tyrosine-based activating motif (ITAM) in its cytoplasmic tail, where up-regulates phagocytosis. However, porcine FcgammaRI's role in the antiviral immune response to PRRSV infection has not been studied. In this study, our results indicated that selective activation of porcine FcgammaRI in PAM cells down-regulated significantly mRNA levels of IFN-alpha and TNF-alpha post-pretreatment, suggesting that porcine FcgammaRI signal can inhibit the innate antiviral response of host cells. PRRSV infection assay mediated by FcgammaRI indicated that selective activation of porcine FcgammaRI in PAM cells inhibited significantly mRNA levels of antiviral cytokine (IFN-alpha and TNF alpha) in response to PRRSV infection, suggesting that FcgammaRI ligation can inhibit the antiviral immune response to PRRSV infection. PMID- 23454096 TI - Sympathetic neuron can promote osteoblast differentiation through BMP signaling pathway. AB - Communication between sympathetic neurons and osteoblasts through the adrenergic receptor pathway has already been reported. To investigate whether the sympathetic neurons have a direct effect on osteoblast differentiation, an in vitro Transwell coculture system was established in which osteoblasts were cocultured with sympathetic neurons with no cell-to-cell contact. The expression of osteogenesis-related genes was upregulated in osteoblasts cocultured with sympathetic neurons. Meanwhile, bone morphogenetic protein (BMP) mRNA and protein expressions were detected in sympathetic neurons, and BMP secretion from sympathetic neurons was also confirmed. However, transfection with BMP-2 and/or BMP-6 siRNA in sympathetic neurons caused a down-regulation of osteogenesis related genes in the cocultured osteoblasts. Sympathetic neurons promoted osteoblast differentiation through BMP signaling pathway, implying that the integrity of sympathetic neurons was important for optimal bone formation and remodeling. PMID- 23454097 TI - Is myopia a failure of homeostasis? AB - This review examines the hypothesis that human myopia is primarily a failure of homeostasis (i.e. regulated growth) and also considers the implications this has for research into refractive errors. There is ample evidence for homeostatic mechanisms in early life. During the first few years of life the eye grows toward emmetropia, a process called emmetropization. The key statistical features of this process are a shift of the mean population refraction toward emmetropia and a reduction in variability. Refractive errors result when either this process fails (primary homeostatic failure) or when an eye that becomes emmetropic fails to remain so during subsequent years (secondary homeostatic failure). A failure of homeostasis should increase variability as well as causing a possible shift in mean refraction. Increased variability is indeed seen in both animal models of myopia such as form deprivation and in human populations from the age of 5 or 6 onwards. Considering ametropia as a homeostatic failure also fits with the growing body of evidence that a wide range of factors and events can influence eye growth and refraction from gestation, through infancy, childhood and into adulthood. It is very important to recognize that the refraction of an eye is not a simple trait like eye colour but the consequence of the complex process of eye growth throughout life. To understand how an eye ends up with a specific refraction it is essential to understand all the factors that may promote the attainment and maintenance of emmetropia. Equally important are the factors that may either disrupt early emmetropization or lead to a loss of emmetropia during later development. Therefore, perhaps the most important single implication of a homeostatic view of myopia is that this condition is likely to have a very wide range of causes. This may allow us to identify subgroups of myopia for which specific environmental influences, genes or treatments can be found, effects that might be lost if all myopes are considered to be equivalent. PMID- 23454098 TI - Aqueous humor levels of vascular endothelial growth factor and adiponectin in patients with type 2 diabetes before and after intravitreal bevacizumab injection. AB - To determine the levels of vascular endothelial growth factor (VEGF) and adiponectin (APN) in the aqueous humor of patients with type 2 diabetes before and after injection of bevacizumab (IVB). Twenty eyes of twenty consecutive patients with type 2 diabetes with PDR and clinically significant macular edema were enrolled in this study. Aqueous samples were collected at baseline and one month after IVB to evaluate VEGF and APN levels. Twenty age-matched patients undergoing cataract surgery were used as control. Best-corrected visual acuity (BCVA) and foveal thickness (FT) changes after IVB were also measured. Safety was assessed by recording the incidence of ocular and non-ocular adverse events. At baseline APN and VEGF levels were significantly lower in controls than in PDR patients (APN: 3.6 +/- 1.1 vs 18.7 +/- 4.5 ng/ml; VEGF: 22.6 +/- 16.1 vs 146.2 +/ 38.71 pg/ml). After IVB, both compounds significantly decreased. FT and BCVA at baseline were significantly different between controls and patients (FT: 215.6 +/ 34.8 vs 532.7 +/- 112.4 MUm; BCVA: 23.6 +/- 4.2 vs 18.4 +/- 7.3 letters). After IVB a significant decrease of FT with a concomitant improvement of BCVA occurred. Neither ocular nor systemic adverse events were reported. Our findings demonstrate that patients with type 2 diabetes, PDR and macular edema show VEGF and APN levels in aqueous humor higher than those found in control subjects. IVB significantly reduced the levels of both compounds, which remained anyway at concentrations higher than those recorded in control subjects. PMID- 23454099 TI - Neuroprotective effects of topical CB1 agonist WIN 55212-2 on retinal ganglion cells after acute rise in intraocular pressure induced ischemia in rat. AB - Neuroprotection in retinal experimental work consists primarily of preventing retinal ganglion cell (RGC) loss after exposure to a hostile event. We have studied the neuroprotective effect on RGCs in an ischemia-reperfusion model by activation of the cannabinoid receptor CB1 using topical application of WIN 55212 2. Intraocular pressure (IOP) was increased by continuous infusion of phosphate buffer saline (PBS) into the anterior chamber of the eye. Mean intraocular pressure was increased up to 88.5 +/- 0.29 mm Hg (control normal IOP 15.1 +/- 0.25 mm Hg), for 35 min. Animals were distributed in 3 groups. Left eyes underwent acute rise in intraocular pressure. First group was treated with topical TocrisolveTM 100 in both eyes. Second group was treated with 1% solution of CB1 agonist WIN 55212-2 in both eyes. Third group was treated with WIN 55212-2 1% and CB1 antagonist AM 251 1% solutions in both eyes. Subsequently, RGCs were immunolabeled with Brn3a and automated quantification of retinal mosaics of RGCs were performed. The ischemic damage led to a mean loss in RGC density of 12.33%. After topic administration of WIN 55212-2, mean loss of RGCs was of 2.45%. Co treatment with CB1 antagonist AM 251 abolished almost completely the neuroprotective effect of WIN 55212-2. Topic 1% WIN 55212-2 showed a neuroprotective effect on RGC degeneration after ischemia-reperfusion without pre activation of CB1 receptors. PMID- 23454100 TI - Rapid determination of growth inhibition of Mycobacterium tuberculosis by GC MS/MS quantitation of tuberculostearic acid. AB - Classical determination of growth inhibition of Mycobacterium tuberculosis in macrophages and mice by new candidate anti-TB drugs utilizes the determination of colony forming units (CFUs) from lung homogenates, a labor-intensive process requiring 2-3 weeks incubation. Qualitative analysis of tuberculostearic acid (TBSA), a cell wall associated biomarker found in M. tuberculosis, has been investigated for clinical diagnosis of tuberculosis (TB) but few reports exist of attempts to quantitate TBSA. Gas chromatography-mass spectroscopy (GC-MS/MS) was used in quantitating the derivatized methyl ester of TBSA during growth of M. tuberculosis in axenic medium, macrophage cultures and in the lungs of gamma interferon knockout (GKO) mice with and without exposure to anti-TB agents. The quantity of TBSA methyl ester (TBSAME) in the absence of and following exposure to anti-TB drugs was positively correlated with CFU in all three models. The stability of TBSA precludes its use as a surrogate for bactericidal activity but its exceptional thermal stability enables lung homogenates to be autoclaved prior to analysis. GC-MS/MS determination of TBSA is a rapid, sensitive and accurate means of detecting growth inhibition of any strain of M. tuberculosis in cell culture and in vivo. PMID- 23454101 TI - Application of Markov chain Monte Carlo analysis to biomathematical modeling of respirable dust in US and UK coal miners. AB - A biomathematical model was previously developed to describe the long-term clearance and retention of particles in the lungs of coal miners. The model structure was evaluated and parameters were estimated in two data sets, one from the United States and one from the United Kingdom. The three-compartment model structure consists of deposition of inhaled particles in the alveolar region, competing processes of either clearance from the alveolar region or translocation to the lung interstitial region, and very slow, irreversible sequestration of interstitialized material in the lung-associated lymph nodes. Point estimates of model parameter values were estimated separately for the two data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. When model parameters were calibrated simultaneously to the two data sets, agreement between the derived parameters for the two groups was very good, and the central tendency values were similar to those derived from the deterministic approach. These findings are relevant to the proposed update of the ICRP human respiratory tract model with revisions to the alveolar-interstitial region based on this long-term particle clearance and retention model. PMID- 23454102 TI - Derivation of a chronic reference concentration for decalin. AB - Decalin is found naturally in crude oil and as a product of combustion. It is used commercially as a solvent due to its ability to solubilize oils and fats. Despite its widespread occurrence in consumer products and the environment that lead to inhalation exposures, an inhalation toxicity value is not currently available for decalin. To derive a reference concentration (RfC) for decalin, inhalation toxicity studies were reviewed using a weight-of-evidence approach. A 2-year mouse inhalation study was chosen as the critical study for the derivation of the chronic RfC. Benchmark dose modeling was utilized to derive a point of departure for hepatic necrosis, syncytial alteration, eosinophilic focus, and erythrophagocytosis. A BMDL10 of 44mg/m(3) was modeled for the most sensitive adverse effect, syncytial alteration. A chronic RfC for decalin of 0.08mg/m(3) was calculated by conversion of the BMDL10 to a human equivalent continuous inhalation dose of 7.9mg/m(3) and application of a total uncertainty factor of 100. Future research is needed to better characterize the toxicity associated with the chronic inhalation of decalin and refine the development of toxicity values. PMID- 23454103 TI - Studies of styrene, styrene oxide and 4-hydroxystyrene toxicity in CYP2F2 knockout and CYP2F1 humanized mice support lack of human relevance for mouse lung tumors. AB - Styrene (S) is lung tumorigenic in mice but not in rats. S and its alkene oxidized metabolite styrene oxide (SO) were not lung toxic in CYP2F2(-/-) [knockout] mice, indicating S-induced mouse lung tumors are mediated through mouse-specific CYP2F2-generated ring-oxidized metabolite(s) in lung bronchioles. The human relevance of the CYP2F MOA was assessed by insertion of a human CYP2F1, 2A13, 2B6 transgene into CYP2F2(-/-) mice; CYP2F1 expression and activity were confirmed in the transgenic (TG) mice. No evidence of cytotoxicity or increased cell proliferation (BrdU labeling) was seen in TG mice treated with either S or SO (200mg/kg/day ip for 5days). In contrast to S and SO, 4HS (105mg/kg/day ip for 5days) increased BrdU labeling 5-10-fold in WT mice, <3-fold increase in KO mice and 2-4-fold in TG mice. The limited response of 4HS in KO and TG mice may result from intrinsic toxicity or from further metabolism; regardless of the MOA, these findings indicate that the CYP2F-mediated tumorigenic MOA in WT mice is not operative for S, SO, or for 4HS putatively derived from metabolism of S by CYP2F1 in humans, and thus S-induced mouse lung tumors are unlikely to be relevant to human risk. PMID- 23454104 TI - Safety evaluation of glucose oxidase from Penicillium chrysogenum. AB - Glucose oxidase (beta-d-glucose:oxygen 1-oxidoreductase; EC 1.1.2.3.4) is used in the food and beverage industry as a preservative and stabilizer and is commonly derived from the fungus Aspergillus niger. Although the safety of glucose oxidase preparations from A. niger is well-established, the use of preparations derived from other fungal species is of interest; however, an assessment of their safety is warranted. Here, we report on the safety of a glucose oxidase preparation derived from the fungus Penicillium chrysogenum (designated as PGO) for commercial use in food processing, as well as an ingredient in food. In a repeated dose 90-day oral toxicity study conducted in rats, PGO was without compound-related adverse effects at doses of up to 15,600U/kg body weight/day, equivalent to 193mg total organic solids/kg body weight/day. In addition, PGO was non-genotoxic in a series of genotoxicity tests, including a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and a combined in vivo mammalian erythrocyte micronucleus test and comet assay. The results of these studies support the safe use of PGO in food for human consumption. PMID- 23454105 TI - Long-term durability of the CLS femoral prosthesis in patients with osteonecrosis of the femoral head. AB - Ninety-five hips with cementless wedge-shaped tapered CLS stem were evaluated with a mean duration of 12.7 years (range, 10.7-17.3 years). All patients were young and diagnosed with osteonecrosis of the femoral head. The Harris hip score was 92 at the latest follow-up. A subsidence greater than 3mm was found in 3 hips (3.2%). Focal femoral osteolysis was found in 12 hips (12.6%). Endosteal bone formation and bony pedestal were observed in 94 hips (98.9%) and in 26 hips (27.4%), respectively. With revision for stem loosening as the end point, the survivorship showed 98.9% (95% CI, range 96.9%-100%) at 13 years. Stem alignment and proximal femur morphology did not influence loosening of the stem (p>0.05). PMID- 23454106 TI - Does the method of component fixation influence clinical outcomes after total knee replacement? A systematic literature review. AB - A systematic literature review was conducted to identify the best available evidence describing the differences in clinical outcome associated with the different methods of total knee replacement (TKR) fixation. Randomized trials published between 1980 and January 2011 comparing differences in clinical outcome scores between groups allocated to either cemented or uncemented fixation for TKR were included. Nine of the 11 studies included in the review reported no significant differences in clinical outcomes between groups with either cemented or uncemented prosthesis components. Critical appraisal of methodological bias revealed consistent shortcomings in study design and execution. It is apparent that more rigorous studies with longer follow-up periods are required to verify which method of fixation may be preferable in enhancing clinical outcomes. PMID- 23454107 TI - Factors in high-flex posterior stabilized fixed-bearing total knee arthroplasty affecting in vivo kinematics and anterior tibial post impingement during gait. AB - One of the most important issues in high-flex posterior stabilized total knee arthroplasty (TKA) is anterior tibial post impingement. We examined 20 knees and 2 TKA designs to evaluate the in vivo kinematics during gait using fluoroscopic image analysis. The AP positions in both stance and swing phases were significantly larger and more anterior in J-curved design TKA compared with Single radius design TKA. Anterior tibial post impingement was observed in five knees implanted with Legacy-flex, and in four of the five knees they were not hyperextended. No impingement was observed with NRG. Less constraint and tibial posterior slope might lead to large AP translations and anterior tibial post impingement. Implant design and operative procedures for high-flexion TKAs affect the in vivo kinematics and the occurrence of anterior tibial post impingement. PMID- 23454108 TI - Polychlorinated biphenyls in human hair at an e-waste site in China: composition profiles and chiral signatures in comparison to dust. AB - We analyzed the polychlorinated biphenyls (PCBs) in human hair collected from an electronic waste (e-waste) recycling area in southern China and compared their composition profiles and chiral signatures to those of workplace and domestic dust. The PCB concentrations showed significant age dependence in dismantling workers' hair but not in residents' hair. Among residents, PCB concentrations decreased in the following order: elderly people>students>pre-school children>adults. The PCB homologue and congener profiles of the workers' hair were similar to those of the workplace dust. However, the PCB homologue profile of the residents' hair was clearly different from that of the domestic dust. The chiral congener CB95 generally exhibited a racemic or near-racemic composition in both hair and dust, with enantiomer fractions (EFs) ranging from 0.485 to 0.525 in hair and from 0.479 to 0.504 in dust. The EFs of CB132 in dust (0.477-0.513) were closer to a racemic chiral signature than those in hair (0.378-0.521), but this difference was not significant. Our results suggest that the chiral signature of PCBs may be a better tool than the PCB composition profile for identifying the external and internal sources of organic contaminants in human hair. Further measurements of chiral PCB signatures in hair and blood from the same individuals are needed to identify the external and internal sources of PCBs in human hair. PMID- 23454109 TI - Baseline blood trihalomethanes, semen parameters and serum total testosterone: a cross-sectional study in China. AB - Toxicological studies showed that trihalomethanes (THMs), the most abundant classes of disinfection by-products (DBPs) in drinking water, impaired male reproductive health, but epidemiological evidence is limited and inconsistent. This study aimed to examine the associations of baseline blood THMs with semen parameters and serum total testosterone in a Chinese population. We recruited 401 men seeking semen examination from the Reproductive Center of Tongji Hospital in Wuhan, China between April 2011 and May 2012. Baseline blood concentrations of THMs, including chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM) were measured using SPME-GC/ECD method. Semen quality and serum total testosterone were analyzed. Multivariable linear regressions were used to assess the associations of baseline blood THM concentrations with semen parameters and serum total testosterone levels. We found that baseline blood THM concentrations were not associated with decrements in sperm motility, sperm straight-line and curvilinear velocity. However, moderate levels of BDCM (beta=-0.13 million; 95% CI: -0.22, -0.03) and DBCM (beta=-4.74%; 95% CI: -8.07, -1.42) were associated with decreased sperm count and declined sperm linearity compared with low levels, respectively. Suggestive dose-response relationships were also observed between elevated blood TCM or ? THMs (sum of TCM, BDCM, DBCM and TBM) concentration and decreased sperm concentration (both p for trend=0.07), and between elevated blood DBCM concentration and decreased serum total testosterone (p for trend=0.07). Our results indicate that elevated THM exposure may lead to decreased sperm concentration and serum total testosterone. However, the effects of THM exposure on male reproductive health still warrant further studies in humans. PMID- 23454110 TI - Prenatal exposure to substance of abuse: a worldwide problem. AB - Substance abuse during pregnancy is an important public health issue affecting the mother and the growing infant. Preterm labor, miscarriage, abruption and postpartum hemorrhage are obstetric complications which have been associated with women who are dependent on abused substances. Moreover, women are also at an increased risk of medical problems such as poor nutrition, anemia, urinary tract infections as well as sexually transmitted infections, hepatitis, HIV and problems related to infection. Intrauterine growth restriction, prematurity, stillbirth, neonatal abstinence syndrome, and Sudden Infant Death Syndrome represent only some of fetal effects. Later on, during childhood, it has been shown that in utero exposure to substances of abuse is associated with increased rates of respiratory infections, asthma, ear and sinus infections. Moreover, these children are more irritable, have difficulty focusing their attention, and have more behavioral problems. Therefore, the assessment of in utero exposure to abused substance is extremely necessary and is relevant for the care of the mother and the offspring. In this sense, several approaches are possible; however, recently the evaluation of in utero exposure to abused drugs has been achieved by testing biological specimens coming from fetus or newborn, pregnant or nursing mother, or from both the fetus and the mother. Maternal and neonatal biological materials reflect exposure in a specific time period and each of them has different advantages and disadvantages in terms of accuracy, time window of exposure and cost/benefit ratio. The methodology for identification and determination of abused substances in biological materials are of great importance. Consequently, sensitive and specific bioanalytical methods are necessary to accurately measure biomarkers. Different immunoassays methods are used as screening methods for drug testing in the above reported specimens, however, the results from immunoassays should be carefully interpreted and confirmed by a more specific and sensitive chromatographic methods such as GC-MS or LC-MS. The interest in the development and optimization of analytical techniques to detect abused substances in different specimens is explained by the several possibilities and information that they can provide. PMID- 23454111 TI - Applications of physiological bases of ageing to forensic sciences. Estimation of age-at-death. AB - Age-at-death estimation is one of the main challenges in forensic sciences since it contributes to the identification of individuals. There are many anthropological techniques to estimate the age at death in children and adults. However, in adults this methodology is less accurate and requires population specific references. For that reason, new methodologies have been developed. Biochemical methods are based on the natural process of ageing, which induces different biochemical changes that lead to alterations in cells and tissues. In this review, we describe different attempts to estimate the age in adults based on these changes. Chemical approaches imply modifications in molecules or accumulation of some products. Molecular biology approaches analyze the modifications in DNA and chromosomes. Although the most accurate technique appears to be aspartic acid racemization, it is important to take into account the other techniques because the forensic context and the human remains available will determine the possibility to apply one or another methodology. PMID- 23454112 TI - Tumor delivery of Photofrin(r) by PLL-g-PEG for photodynamic therapy. AB - Photofrin(r) (porfimer sodium) is a photosensitive reagent used for photodynamic therapy (PDT) of tumors and dysplasias. Because only photo-irradiated sites are damaged, PDT is less invasive than systemic treatments. However, a photosensitive reaction is a major side effect of systemically delivered Photofrin. To enhance localization of Photofrin to tumors, we have formulated Photofrin with the tumor localizing graft copolymer poly(ethylene glycol)-grafted poly(l-lysine), PLL-g PEG. We demonstrate that Photofrin preferentially interacts with PLL-g-PEG through both ionic and hydrophobic interactions. The serum competitive study showed that the highly PEG-grafted PLL is better for preventing serum binding to the Photofrin/PLL-g-PEG complex. In tumor-bearing mice, formulation of Photofrin with PLL-g-PEG enhanced tumor localization of Photofrin as twice as Photofrin alone and concomitantly suppressed the photosensitivity reaction drastically. PMID- 23454113 TI - Examination of the effect of increasing the number of intra-disulfide amino functional groups on the performance of small molecule cyclic polyamine disulfide vectors. AB - Establishing structure-activity relationships is vital if the efficacy of non viral vectors is to match that of their viral counter-parts. Recently, we reported on the ability of a series of small molecule, cyclic polyamine disulfides to condense and cage plasmid DNA (pDNA) by a process of thermodynamically controlled templated polymerization, leading to a series of corresponding pDNA-polyplex nanoparticles able to mediate high levels of transfection with no associated cytotoxicities. The leading cyclic polyamine disulfide was shown to be the spermine tetra-amine disulfide (TetraN-3,4,3). Herein we report on the significantly more challenging syntheses of cyclic disulfides with longer polyamine motifs. Two new cyclic polyamine disulfides, based on hexa- and octa-amine inserts, were prepared and their transfection efficacies and cytotoxicities compared with our previously reported cyclic tri- and tetra-amine disulfides. The new cyclic hexa- and octa-amine disulfides prove more effective at transfection in vitro, especially of lung epithelial A549 cell line. By contrast, our original cyclic tetra-amine disulfide remains the most efficient agent for the transfection of lung epithelial cells in vivo following intra-nasal administration. Hypothetical mechanistic reasons are presented to explain this outcome. Our data in toto support the concept of shorter cyclic polyamine disulfides as preferred agents for polycation-mediated controlled condensation and functional delivery of pDNA to lung epithelial cells in vivo. PMID- 23454114 TI - Yeast and human mitochondrial helicases. AB - Mitochondria are semiautonomous organelles which contain their own genome. Both maintenance and expression of mitochondrial DNA require activity of RNA and DNA helicases. In Saccharomyces cerevisiae the nuclear genome encodes four DExH/D superfamily members (MSS116, SUV3, MRH4, IRC3) that act as helicases and/or RNA chaperones. Their activity is necessary for mitochondrial RNA splicing, degradation, translation and genome maintenance. In humans the ortholog of SUV3 (hSUV3, SUPV3L1) so far is the best described mitochondrial RNA helicase. The enzyme, together with the matrix-localized pool of PNPase (PNPT1), forms an RNA degrading complex called the mitochondrial degradosome, which localizes to distinct structures (D-foci). Global regulation of mitochondrially encoded genes can be achieved by changing mitochondrial DNA copy number. This way the proteins involved in its replication, like the Twinkle helicase (c10orf2), can indirectly regulate gene expression. Here, we describe yeast and human mitochondrial helicases that are directly involved in mitochondrial RNA metabolism, and present other helicases that participate in mitochondrial DNA replication and maintenance. This article is part of a Special Issue entitled: The Biology of RNA helicases - Modulation for life. PMID- 23454115 TI - Progesterone, inflammation and preterm labor. AB - The initiation of human parturition is not fully understood to date. The data from animal experiments demonstrate that the primary impulse for the initiation of physiological labor arises from the fetal hypothalamo-pituitary-adrenal axis (HPA). HPA is responsible for the stimulation of steroid synthesis and prostaglandin production and, in turn, the cervical dilation and the beginning of myometrial contractions. Animal experiments, however, are only partly suitable for understanding the mechanism of human labor due to substantial species specificity. In human, the changing levels of placental CRH control the production of fetal and placental steroids. The fundamental pathogenic manifestation of spontaneous preterm labor is inflammation and similar processes also underlie the full term one. While in full term labor it is not yet precisely known what starts this process, in the preterm one, several factors have been discussed like infection, uteroplacental ischemia, and hormonal abnormalities (progesterone- or CRH-related). Inflammatory processes affect both the mother and the fetus. Fetal inflammatory response (FIRS), which can be expected for children born preterm, is frequently associated with long-term complications, in particular neurological and pulmonary. Research in this field is therefore aimed at predicting preterm labor, and on predicting the fetal inflammatory response. The role of progesterone and its receptors in the pathophysiology of preterm labor are likewise intensively studied. Clinical results on the use of additive doses of progesterone in secondary prevention of preterm labor and current experimental studies point to progesterone and its receptors playing a key role in the pathophysiology of preterm labor. This article is part of a Special Issue entitled 'Pregnancy and Steroids'. PMID- 23454116 TI - Perinatal exposure to diethylstilbestrol alters the functional differentiation of the adult rat uterus. AB - The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation+lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5MUg/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17beta-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by alpha-smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors alpha and beta showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DES-exposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol. PMID- 23454117 TI - Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity. AB - The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro-inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin-angiotensin-aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23454118 TI - NHERF-1 regulation of EGF and neurotensin signalling in HT-29 epithelial cells. AB - Neurotensin receptors (NT-R) and the epidermal growth factor receptors (EGF-R) are commonly overexpressed in many epithelial origin tumours. In addition to their role as mitogenic mediators through specific cell signalling, recent studies indicate that the activity/expression of scaffold proteins responsible for the assembly and coordination of the signalling complexes may also have central roles in epithelial transformation. In particular, the "epithelial" PSD 95/Dlg/Zo-1 (PDZ) scaffold/adapter protein, Na(+)/H(+) exchanger regulatory factor isoform one (NHERF-1), has been identified as a potential regulator of cellular transformation. NHERF-1 is a known regulator of EGF-R function and plays numerous roles in G-protein-coupled receptor signalling. Because of the synergistic signalling between these two potent mitogens, we investigated a potential role for NHERF-1 in the molecular mechanism linking the aberrant proliferative phenotype initiated by some G-Protein-coupled receptor activators in the colon adenocarcinoma HT-29 cell line. Knockdown (80%) of endogenous NHERF 1 leads to significant reduction in proliferation rate; an effect that could not be recovered by exogenous application of either NT or EGF. Inhibition of the EGF R with AG1487 also inhibited proliferation and this effect could not be recovered with NT. Knockdown of NHERF-1 significantly altered the expression of the EGF-R, and almost completely abolished the NT-mediated increases in intracellular free Ca(2+). Knockdown of NHERF-1 also attenuated UTP-mediated purinergic Ca(2+) signalling. Taken together, these data suggest that NHERF-1 plays a more central role in cell proliferation by modulating Gq-mediated signalling pathways. PMID- 23454120 TI - Interaction of RhoD and ZIP kinase modulates actin filament assembly and focal adhesion dynamics. AB - RhoD is a member of the classical Rho GTPases and it has an essential role in the regulation of actin dynamics. Furthermore, RhoD also localizes to early endosomes and recycling endosomes, indicating additional roles in the regulation of endosome trafficking. A yeast two-hybrid screen identified Zipper-Interacting Protein Kinase (ZIPK) as a RhoD target. We found that RhoD interacts with ZIP kinase in a GTP dependent manner and modulates actin and focal adhesion reorganization. Interestingly, while ectopic expression of ZIPK in fibroblasts induces actin reorganization and actomyosin contraction seen as stress fiber bundling and membrane blebbing, the concomitant expression of active RhoD suppressed this phenotype. Previously, RhoD has been associated with focal adhesion regulation, and in line with this notion, we observed that ZIPK resulted in reorganization of focal adhesion and increased adhesion size. Importantly, the RhoD activity suppressed ZIPK-dependent effects on FAK activity, indicating a functional interplay between RhoD and FAK in the focal adhesion dynamics. PMID- 23454119 TI - Translational efficiency of rpoS mRNA from Borrelia burgdorferi: effects of the length and sequence of the mRNA leader region. AB - Regulation of the enzootic cycle in Borrelia burgdorferi requires a shift to the RNA polymerase alternative sigma factor, RpoS. We used in vitro and in vivo assays to assess the relative importance of the putative Shine-Dalgarno sequence and its sequestration for the translational efficiency of rpoS. We created mutant leader regions in which we either removed the Shine-Dalgarno sequence, disrupted the secondary structure or both. Binding assays and toeprint assays demonstrated that both the presence and the availability of the Shine-Dalgarno sequence are important to the efficiency and specificity of ribosome binding. Adding a DsrABb mimic in the form of a single-stranded DNA oligonucleotide increased the level and specificity of binding ribosomes to the transcript with an extended leader, presumably by making the Shine-Dalgarno sequence available for binding. In in vivo assays we confirmed that the Shine-Dalgarno sequence must be both present and un-sequestered in order for translation to proceed efficiently. The longer transcript was significantly better translated in B. burgdorferi at 37 degrees C than at 26 degrees C, lending support to the hypothesis that DsrABb acts as a temperature-dependent stimulator of translation. These studies demonstrate that translational regulation of gene expression in B. burgdorferi may be an important mechanism for responding to environmental signals important in the enzootic cycle. PMID- 23454121 TI - Mechanistic target of rapamycin (mTOR) dependent regulation of thioredoxin interacting protein (TXNIP) transcription in hypoxia. AB - Thioredoxin interacting protein (TXNIP), first identified as an inhibitor of thioredoxin, is also a tumor suppressor as well as an inhibitor of lipogenesis. TXNIP is known to be transcriptionally regulated in response to nutrients such as glucose and stress signals, including endoplasmic reticulum stress and lactic acidosis. In this study, we characterized the transcriptional regulation of TXNIP in response to hypoxia. Using a hepatocellular carcinoma cell line, we have found that TXNIP mRNA expression is regulated in a biphasic manner in hypoxia whereby TXNIP expression showed an initial rapid decrease, followed by an increase under prolonged hypoxia. Interestingly, we have shown that TXNIP induction in prolonged hypoxia is independent of the Hypoxia-Inducible Factor (HIF) transcription factor. The effect of hypoxia on TXNIP expression is mediated via the inhibition of the 4E-BP1/eIF4E axis of mechanistic target of rapamycin (mTORC1). Thus, we found that inhibiting mTORC1-dependent 4E-BP1 phosphorylation mimics the effect of hypoxia on TXNIP expression. Furthermore, overexpressing eIF4E prevents the induction of TXNIP in hypoxia. Our results suggest that mTORC1 may be an important regulator of hypoxia-dependent gene expression. PMID- 23454122 TI - Studying the protein expression in human B lymphoblastoid cells exposed to 1.8 GHz (GSM) radiofrequency radiation (RFR) with protein microarray. AB - In the present study, the protein microarray was used to investigate the protein expression in human B-cell lymphoblastoid cells intermittently exposed to 1.8-GHz GSM radiofrequency radiation (RFR) at the specific absorption rate (SAR) of 2.0 W/kg for 24 h. The differential expression of 27 proteins was found, which were related to DNA damage repair, apoptosis, oncogenesis, cell cycle and proliferation (ratio >1.5-fold, P<0.05). The results validated with Western blot assay indicated that the expression of RPA32 was significantly down-regulated (P<0.05) while the expression of p73 was significantly up-regulated in RFR exposure group (P<0.05). Because of the crucial roles of those proteins in DNA repair and cell apoptosis, the results of present investigation may explain the biological effects of RFR on DNA damage/repair and cell apoptosis. PMID- 23454123 TI - Repression of bone morphogenetic protein 4 by let-7i attenuates mesenchymal migration of head and neck cancer cells. AB - The movement modes of epithelial cancer cells in three-dimensional (3D) environments include the mesenchymal mode, which is associated with local invasion, and the amoeboid mode, which facilitates distant metastasis. The migratory behavior of individual cancer cells is critical for tumor dissemination; however, the mechanism underlying regulation of the switch between movement modes is not clearly understood. For head and neck squamous cell carcinoma (HNSCC), local invasion is the major route of dissemination. We previously demonstrated that, in HNSCC cells, Twist1 represses let-7i expression to elicit mesenchymal-mode movement through activation of Ras-related C3 botulinum toxin substrate 1 (RAC1). In this study, we discover another important target gene of let-7i for regulating HNSCC migration. Using bioinformatic tools, we identified bone morphogenetic protein 4 (BMP4) as a candidate target of let 7i. Further experiments, including 3'-untranslated region (UTR) reporter assays, quantitative RT-PCR and western blotting, confirmed that BMP4 is a bona fide target repressed by let-7i. In the HNSCC cell line OECM-1, knockdown of BMP4 reduced mesenchymal-mode migration and invasion in 3D culture. In clinical HNSCC samples, let-7i expression was inversely correlated with BMP4 expression. Our results revealed that let-7i attenuates mesenchymal-mode migration of HNSCC cells through repression of a novel target, BMP4. PMID- 23454124 TI - Glucose-independent persistence of PAI-1 gene expression and H3K4 tri-methylation in type 1 diabetic mouse endothelium: implication in metabolic memory. AB - Clinical trials with type 1 and type 2 diabetes have identified a phenomenon known as "metabolic memory" in which previous periods of hyperglycemia result in the long-lasting deleterious impact on cardiovascular events. Emerging evidence shows that transient hyperglycemic exposure of human endothelial cells induces histone 3 lysine 4 mono-methylation (H3K4me1) on the promoter and persistent mRNA expression of RelA and IL-8 genes, suggesting that epigenetic histone modification and chromatin structure remodeling is a key event underlying metabolic memory. This burgeoning hypothesis, however, critically remains to be tested for relevance in the disease process of diabetes in vivo, and for broader applicability to an array of genes involved in endothelial dysfunction. To address this, we used type 1 diabetes mouse model induced by streptozocin to be hyperglycemic for 8 weeks, and isolated endothelial cells that were used either freshly after isolation or after 2 to 3-week cell culture in normoglycemic conditions. mRNA expression profiling in diabetic mouse endothelial cells revealed significant and persistent up-regulation of Serpine1 encoding PAI-1, the hypo-fibrinolytic mediator leading to thrombotic diseases in diabetes, along with Rock2, Fn1 and Ccl2, whereas only Serpine 1 was persistently elevated in high glucose-treated mouse endothelial cells. Chromosome immunoprecipitation assay in type 1 diabetic mouse endothelial cells showed predominant enrichment of H3K4 tri methylation on Serpine1 promoter, suggesting a unique epigenetic regulation in diabetic mice as opposed to high glucose-treated human ECs. Our study demonstrates the importance of combining in vivo models of diabetes with high glucose-treated cell culture to better assess the epigenetic mechanisms relevant to disease. PMID- 23454125 TI - CHFR is negatively regulated by SUMOylation-mediated ubiquitylation. AB - CHFR ubiquitin ligase plays an important role in cell cycle progression and tumorigenesis. CHFR tumor suppressor function is highly associated with its protein level. We recently reported that CHFR protein levels are negatively regulated by SUMOylation-mediated proteasomal degradation. In the present study, we uncover a detailed molecular mechanism how SUMOylation promotes CHFR destabilization. We demonstrate that SUMO modification of CHFR promotes its ubiquitylation and subsequent proteasomal degradation. However, SUMOylation of CHFR does not affect its auto-ubiquitylation, which generally serves as a maintenance mechanism for most ubiquitin ligases. Moreover, the E3 ubiquitin ligase activity of CHFR is dispensable for this SUMOylation-mediated ubiquitylation and degradation. Conversely, SENP2 deSUMOylating enzyme reduces SUMOylation-induced ubiquitylation of CHFR, leading to elevated CHFR protein levels. Taken together, our results present a new regulatory mechanism for CHFR that sequential post-translational modifications of CHFR by SUMO and ubiquitin coordinately regulates its stability. PMID- 23454126 TI - Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells. AB - Transcription factor NF-E2 p45-related factor 2 (Nrf2) regulates the expression of a network of genes encoding drug-detoxification, anti-inflammatory, and metabolic enzymes, as well as proteins involved in the regulation of cellular redox homeostasis. Under basal conditions, Kelch-like ECH associated protein 1 (Keap1) targets Nrf2 for ubiquitination and proteasomal degradation via association with Cullin3 (Cul3)-based Rbx1 E3 ubiquitin ligase. Various small molecules (inducers) activate Nrf2 leading to upregulation of cytoprotective gene expression. Inducers chemically modify specific cysteine residues of Keap1 which ultimately loses its ability to target Nrf2 for degradation. Dissociation of the Keap1-Cul3 complex by inducers is one possible mechanism, but evidence in single live cells is lacking. To investigate the diffusion dynamics of the Keap1-Cul3 interaction and the effect of inducers, we developed a quantitative fluorescence recovery after photobleaching (FRAP)-based system using Keap1-EGFP and mCherry Cul3 fusion proteins. We show that Keap1-EGFP and mCherry-Cul3 interact in single live cells. Exposure for 1h to small-molecule inducers of 4 different types, the oleanane triterpenoid CDDO, the isothiocyanate sulforaphane, the sulfoxythiocarbamate STCA, and the oxidant hydrogen peroxide which target distinct cysteine sensors within Keap1 with potencies which differ by nearly 4000 fold, does not dissociate the Keap1-Cul3 complex. As inducers cause conformational changes in Keap1, we conclude that changes in conformation rather than dissociation from Cul3 inactivate the repressor function of Keap1 leading to Nrf2 stabilization. PMID- 23454127 TI - Inhibition of NO-induced beta-cell death by novel NF-kappaB inhibitor (-)-DHMEQ via activation of Nrf2-ARE pathway. AB - Excessive nitric oxide (NO) plays a pivotal role in the progression of beta-cell apoptosis in type 1 diabetes mellitus. We used mouse insulinoma Min6 cells as a model of beta cells in this research. We found that (-)-DHMEQ, an NF-kappaB inhibitor, rescued beta cells from NO-induced apoptosis, and then studied the mechanism of apoptosis inhibition. (-)-DHMEQ activated Nrf2 and induced transcription of Nrf2-target genes following the increase of antioxidant response element (ARE) reporter activity. Similarly, tert-butyl hydroquinone (tBHQ), a known activator of Nrf2, inhibited NO-induced cell death along with the transcriptional activation of ARE. RNAi-mediated knockdown of Nrf2 lowered the cytoprotective effect of (-)-DHMEQ against NO, suggesting that (-)-DHMEQ inhibited NO-induced cell death via Nrf2 activation. Furthermore, overexpression of Nrf2 rendered cells to be more resistant to NO, indicating that Nrf2 activation provides critical defense function against NO in Min6 cells. Taken together, we conclude that (-)-DHMEQ may be a useful therapeutic agent for type 1 diabetes mellitus in the onset of disease by protecting beta cells from apoptosis. PMID- 23454128 TI - Peptide concentration alters intermediate species in amyloid beta fibrillation kinetics. AB - The kinetic mechanism of amyloid aggregation remains to be fully understood. Investigations into the species present in the different kinetic phases can assist our comprehension of amyloid diseases and further our understanding of the mechanism behind amyloid beta (Abeta) (1-40) peptide aggregation. Thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM) have been used in combination to monitor Abeta(1-40) aggregation in vitro at both normal and higher than standard concentrations. The observed fibrillation behaviour deviates, in several respects, from standard concepts of the nucleation-polymerisation models and shows such features as concentration-dependent non-linear effects in the assembly mechanism. Abeta(1-40) fibrillation kinetics do not always follow conventional kinetic mechanisms and, specifically at high concentrations, intermediate structures become populated and secondary processes may further modify the fibrillation mechanism. PMID- 23454129 TI - Serum amyloid A stimulates macrophage foam cell formation via lectin-like oxidized low-density lipoprotein receptor 1 upregulation. AB - Elevated levels of serum amyloid A (SAA) is a risk factor for cardiovascular diseases, however, the role of SAA in the pathophysiology of atherosclerosis remains unclear. Here we show that SAA induced macrophage foam cell formation. SAA-stimulated foam cell formation was mediated by c-jun N-terminal kinase (JNK) signaling. Moreover, both SAA and SAA-conjugated high density lipoprotein stimulated the expression of the important scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) via nuclear factor-kappaB (NF kappaB). A LOX1 antagonist carrageenan significantly blocked SAA-induced foam cell formation, indicating that SAA promotes foam cell formation via LOX1 expression. Our findings therefore suggest that SAA stimulates foam cell formation via LOX1 induction, and thus likely contributes to atherogenesis. PMID- 23454130 TI - Pifithrin-alpha, a pharmacological inhibitor of p53, downregulates lipopolysaccharide-induced nitric oxide production via impairment of the MyD88 independent pathway. AB - The effect of pifithrin (PFT)-alpha, a pharmacological inhibitor of p53, on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. PFT-alpha inhibited the production of NO but not tumor necrosis factor (TNF)-alpha in response to LPS. PFT-alpha inhibited LPS induced NO production via reduced expression of an inducible NO synthase (iNOS). Moreover, PFT-alpha inhibited LPS-induced iNOS expression in p53-silenced cells. PFT-alpha inhibited the production of interferon (IFN)-beta, characteristic of the MyD88-independent pathway of LPS signaling, whereas it did not affect the activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinases in the MyD88-dependent pathway. PFT-alpha inhibited poly I:C-induced NO production whereas it did not inhibit IFN-beta-induced NO production. Further, PFT-alpha reduced the expression of IFN regulatory factor 3 that leads to the IFN-beta production in the MyD88-independent pathway. The most upstream event impaired by PFT-alpha was the reduced expression of TNF receptor-associated factor (TRAF) 3 in the MyD88-independent pathway. PFT-alpha also reduced the in vivo expression of iNOS in the livers of mice injected with LPS. Taken together, PFT-alpha was suggested to inhibit LPS-induced NO production via impairment of the MyD88 independent pathway and attenuated LPS-mediated inflammatory response. PMID- 23454131 TI - Synthesis and evaluation of quinazoline derivatives as phosphodiesterase 7 inhibitors. AB - The latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7. PMID- 23454132 TI - Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole hexahydropyrrolizines as potent cholinesterase inhibitors. AB - Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4 ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 MUM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 MUM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay. PMID- 23454133 TI - Co-encapsulating nanostructured lipid carriers for transdermal application: from experimental design to the molecular detail. AB - Co-encapsulation of drugs directed at commonly associated diseases provides a convenient means for administration, especially if transdermally delivered. In this work, a comprehensive study for the co-encapsulation of drugs with a differential lipophilicity, olanzapine and simvastatin, and their transdermal delivery in a formulation containing nanostructured lipid carriers (NLC) is presented. Focus is given to the evaluation of a strategy in which NLC and chemical permeation enhancers are combined. It comprises in vitro, in silico and cellular viability approaches. The optimization and rationalization of the systems are carried out using a two-step factorial design. It is shown that the external medium in the NLC dispersion strongly influences permeation. It is also seen that the use of NLC determines a synergistic effect with selected permeation enhancers, thus promoting marked flux enhancement ratios (48 and 21, respectively for olanzapine and simvastatin) relative to the drugs in solution. The developed formulations can be considered non-irritant. A correlation between enhancer positioning in a lipid bilayer, partially governed by a H-bonding phenomenon, and enhancement effect is suggested from molecular dynamics studies and experimental observations. PMID- 23454134 TI - DNA delivery via cationic solid lipid nanoparticles (SLNs). AB - In recent years the use of solid lipid nanoparticles (SLNs) as transport systems for the delivery of drugs and biomolecules has become particularly important. The use of cationic SLNs developed by the technique of microemulsion, which are complexed with DNA in order to study their application as non-viral vectors in gene therapy, is reported. The nanoparticles are characterized by scanning electron microscopy and transmission electron microscopy (SEM and TEM), atomic force microscopy (AFM) and differential scanning calorimetry (DSC). Furthermore, the process of lyophilization of the samples and their stability was studied. The nanoparticles obtained presented a particle size of 340 nm with a positive surface charge of 44 mV and the capability of forming lipoplexes with DNA plasmids was stated. PMID- 23454135 TI - Antiproliferative effect of two novel COX-2 inhibitors on human keratinocytes. AB - Selective COX-2 inhibitors (COXib) belonging to the class of diaryl heterocycles (e.g., celecoxib, rofecoxib, etc.), are devoid of the undesirable effects due to their capacity to inhibit selectively inducible (COX-2), responsible for inflammatory effects but not constitutive cyclooxygenase-1 (COX-1)(COX); responsible for cytoprotective effects on gastric mucosa. In addition, several reports have identified an increased risk of cardiovascular events associated with the use of COXib. We have developed a new series of anti-inflammatory agents (1,5-diarylpyrrole-3-alkoxyethyl esters and ethers). To evaluate the effect of two 1,5-diarylpyrrole-3-alkoxyethyl ethers, VA441 and VA428 (up to 100 MUM), respectively, in comparison with two well known COXib, celecoxib and rofecoxib, on HaCaT cell (keratinocytes) proliferation and toxicity. Crucial molecules in cell cycle progression, i.e. NFkappaB and ERK as targets/mediators and cyclin D1 and p21 Cip1/Kip as final effectors were evaluated by Western blot, immunohystochemistry and q-PCR analysis. Both compounds, VA441 and VA428, showed a strong inhibition of cell proliferation, and did not exhibit cytotoxicity. The anti-proliferative effect was accompanied by a strong activation of ERK and induction of the cell cycle inhibitor p21. In addition, there was a clear inhibition of the transcription factor NF-kappaB and downregulation of cyclin D1, with enforced inhibition of the HaCaT cell cycle progression. These data suggest that compounds VA441 and VA428, along with their role in inhibiting COX-2 and inflammation, could have a possible therapeutic (topical and systemic) use against skin proliferative disorders, such as psoriasis. PMID- 23454136 TI - Deactivation of chloroperoxidase by monosaccharides (D-glucose, D-galactose, and D-xylose). AB - In this work, it was found that some monosaccharides normally used to stabilize enzymes at high temperatures, however, actually caused a deactivation of chloroperoxidase (CPO). The red native CPO was converted to a stable pale species that lost enzymatic activity. This deactivation was irreversible and was sensitive to temperature. It was different from the general peroxide-mediated deactivation of CPO. Data from measurement of chlorination activity as well as UV vis, fluorescent, and CD spectral analysis indicated that monosaccharide-induced deactivation can be attributed to precipitation of protein in the presence of monosaccharide and the interaction of the aldehyde group of sugar with amino groups, especially the terminal amino group, on proteins to form Schiff bases which then rearrange to the stable amino ketone. It is further noted that the deactivation efficiency depends on the stereostructure of monosaccharides. D glucose was the most efficient inactivating agents due to its aptitude for both of the interactions mentioned in the above paragraphs. The deactivation was specific to aldose. No deprivation of the heme iron was involved in this deactivation. PMID- 23454137 TI - Synthesis and biological activity of hydroxylated analogues of KRN7000 (alpha galactosylceramide). AB - KRN7000 is one of the alpha-galactosylceramides, which has a 2-hexacosanoylamino 3,4-dihydroxyoctadecyl group. This compound, known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) which release both T helper 1 (Th1) cytokines such as IFNgamma and Th2 cytokines such as IL-4, has been anticipated as an antitumor drug, because of its strong secretion of IFNgamma. This time, we focused on the hydroxylated analogues of KRN7000 which could be thought of as increasing hydrophilicity and showing bias to Th2 cytokine (IL-4) secretion. Therefore, they may become the drugs for autoimmune diseases for the following reasons: (i) compound OCH, one of the alpha-galactosylceramide analogues with a shorter sphingosine chain than KRN7000, increases hydrophilicity relative to KRN7000; and (ii) OCH is known to induce much more Th2 cytokines (IL 4) than Th1 cytokines from iNKT cells compared to KRN7000. Naturally, OCH has become one of the candidate drugs for autoimmune diseases. The more hydroxylated derivatives of KRN7000 are anticipated to induce Th2 bias. Therefore, eight analogues with 1-4 excess hydroxyl groups on the lipid chain of KRN7000 were synthesized to examine if they behave in the same way as OCH. As a result, three out of eight compounds biased largely to IL-4 secretion, and their effectiveness for experimental autoimmune encephalomyelitis (EAE) was examined. It was recognized that two compounds (?)RCAI-147/-160 showed good suppression of EAE symptoms. PMID- 23454138 TI - The structure of an alternative wall teichoic acid produced by a Lactobacillus plantarum WCFS1 mutant contains a 1,5-linked poly(ribitol phosphate) backbone with 2-alpha-D-glucosyl substitutions. AB - A tagF1-tagF2 deletion mutant of Lactobacillus plantarum lacks poly(glycerol phosphate) polymerase activity required for glycerol-type wall teichoic acid (WTA) biosynthesis. The mutant activates an alternative genetic locus, tarIJKL, encoding the enzymes for nucleotide activation and incorporation of ribitol in the WTA backbone polymer. This alternative ribitol-type WTA backbone and its repeating unit were isolated and characterized by HPAEC, UPLC-MS, NMR spectroscopy, and MALDI-TOF MS, using synthetic molecules as references. The structure was established as 1,5-linked poly(ribitol phosphate) which was substituted at the C-2 hydroxyl group of the ribitol residue with alpha-D glucosyl at a frequency of 28%. PMID- 23454139 TI - Isolation and characterization of new minor triterpenoid saponins from the buds of Lonicera macranthoides. AB - Three new minor compounds, 18-oleanene (1), lupine (2), and 12-oleanene (3) type triterpenoid saponins, along with four major known triterpenoid saponins were isolated from the buds of Lonicera macranthoides. Their structures were elucidated by spectroscopic and chemical analyses. 18-oleanene and lupine-type triterpenoid saponins were first isolated from this plant. The isolated compounds were evaluated for their cytotoxic activities against HSC-2 cells. PMID- 23454140 TI - A novel synthesis of ethyl carbonate derivatives of beta-cyclodextrin. AB - The carbonate ester derivatives of beta-cyclodextrin play a very important role in several fields, such as catalytic reaction and enantiomer separation. In this work, a novel synthesis process of the beta-cyclodextrin carbonate ester has been investigated through the reaction between beta-cyclodextrin and diethyl carbonate with anhydrous potassium carbonate as catalyst. The compounds were separated by semi-preparative chromatography and characterized by FT-IR, MS, (1)H NMR, and (13)C NMR spectroscopy. The position of the substituent was confirmed by (13)C NMR and this conclusion coincides with the analyses of MS and (1)H NMR in the main. The yield of the mono-6-O-ethoxycarbonyl beta-CD is 65.8%. PMID- 23454141 TI - Cholestane steroid glycosides from the rhizomes of Dioscorea villosa (wild yam). AB - Phytochemical investigation of the MeOH extract of Dioscorea villosa rhizomes resulted in the isolation of two new bidesmosidic cholestane steroid glycosides, dioscoreavillosides A and B (1 and 2). In addition, the extract yielded 12 previously known furostan and spirostan steroid glycosides (3-14), along with diosgenin (15). Compounds 3-7, 9, 14, and 15 were isolated for the first time from D. villosa. The structures of the isolated compounds were determined using spectroscopic and chemical methods including 1D and 2D NMR. The antimicrobial action of most of these compounds was tested against five fungal and five bacterial strains. PMID- 23454142 TI - Diversity and expression of P450 genes from Dendroctonus valens LeConte (Curculionidae: Scolytinae) in response to different kairomones. AB - Bark beetles (Curculionidae: Scolytinae) are major cause of woody plants death in the world. They colonize the stem and other parts of trees recognizing host produced specific compounds (kairomones) and insect pheromones. Bark beetle's antennae and alimentary canal participate in the host selection identifying chemical compounds produced by trees and insects, and also in the metabolism and detoxification of these compounds. The red turpentine beetle (RTB), Dendroctonus valens LeConte, is an unaggressive species that colonize > 40 pine species (Pinaceae) in North and Central America. Several studies suggest that bark beetle cytochrome P450 enzymes are involved in monoterpene oxidation. In this study we identified by means of PCR, cloning, sequencing, and bioinformatic analysis, eleven full-length genes: five CYP4, four CYP6, and two CYP9 in the antennae and gut region of RTB, after stimulation with vapors of monoterpenes: (+/-)-alpha pinene, (R)-(+)-alpha-pinene, (S)-(-)-beta-pinene, (S)-(-)-alpha-pinene and (+)-3 carene; pine trees volatiles used by RTB as kairomones. The recovered cDNA of these genes vary from 1.5 kb to 1.8 kb and the open frame encodes from 496 to 562 amino acid proteins. The bioinformatic analysis suggests that the majority of P450 proteins encoded by these genes are membrane anchored in the endoplasmic reticulum. RT-qPCR assays showed differential expression of all CYP genes between male and female. The gene expression was dependent of monoterpenes and exposure time, with some of them sex, antennae and gut region specific. Significant differences among monoterpenes, gut region, antennae and exposure time were found. Our results suggest that some of these genes may be involved in the detoxification process of these compounds during tree colonization. PMID- 23454143 TI - Vertebral artery dissection associated with sildenafil abuse. AB - We present a 49-year-old male who suffered a cerebellar infarction due to a vertebral artery dissection. The patient had taken sildenafil daily for at least 2 years for sexual enhancement. There was no sexual intercourse or traumatic event prior to symptom onset. Sildenafil intake has been associated with aortic dissection and, in the light of this report, we suggest that chronic sildenafil intake could be a risk factor for arterial dissection. PMID- 23454144 TI - Role of oxidative stress in chemical allergens induced skin cells activation. AB - Allergic contact dermatitis (ACD) is an important occupational and environmental disease caused by topical exposure to chemical allergens. It describes the adverse effects that may results when exposure to a chemical elicits a T cell mediated inflammatory skin disease. The ability of contact sensitizers to induce the oxidative stress pathway in keratinocytes and dendritic cells has been confirmed by several authors. Reactive oxygen species (ROS) can serve as essential second messengers mediating cellular responses resulting in immune cells activation. Oxidative stress may be the starter point, as it leads to the activation of transcription factors and signaling pathways, including NF-kB and p38 MAPK, which leads to the release of cytokines and chemokines. ROS are also involved in the activation of the NLRP3/NALP3 inflammasome, which is required to direct the proteolytic maturation of inflammatory cytokines such as IL-1beta and IL-18, which are all integral to the process of dendritic cells mobilization, migration and functional maturation. Moreover, emerging evidence correlates ROS to changes in the constitution of the extracellular microenvironment found to facilitate ACD. The purpose of this review is to provide both conceptual and technical frameworks on the role of oxidative stress in chemical allergy. PMID- 23454145 TI - Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. AB - Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1beta, IL-8, IL-10, TNFalpha) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7 ketostigmasterol to have a greater proinflammatory potential than 7 ketocholesterol. In non-pre-treated cells, only efflux transporters were down regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. PMID- 23454146 TI - Neuroprotective effects of neolignans isolated from Magnoliae Cortex against glutamate-induced apoptotic stimuli in HT22 cells. AB - In the course of screening for neuroprotective natural products, Magnoliae Cortex showed potent inhibition of hippocampal neuronal HT22 cell death. Obovatol, honokiol, and magnolol were isolated from the ethanolic extract of Magnoliae Cortex. Isolated compounds obovatol, honokiol, and magnolol were protective against 5mM glutamate-induced cell death. When cells were stressed using glutamate, cell viability decreased to 16.98+/-4.58% over the control (100.00+/ 10.15%). In contrast, 10 MUM obovatol, 10 MUM honokiol, and 50 MUM magnolol increased cell viability to 91.80+/-1.70%, 93.59+/-1.93%, and 85.36+/-7.40%, respectively. The neuroprotective effects of obovatol and honokiol were attributable to the inhibition of intracellular reactive oxygen species production, followed by protection of the mitochondrial membrane potential (DeltaPsim), recovery of Bcl-2 and Bid levels, inhibition of apoptosis-inducing factor expression, and phosphorylation of mitogen-activated protein kinases such as p38 kinases, extracellular signal-regulated kinases, and c-Jun N-terminal kinases. On the contrary, magnolol did not show any significant effect on the DeltaPsim and apoptotic factors. Among three compounds, obovatol most strongly scavenged 2,2-diphenyl-1-picrylhydrazyl radicals and inhibited the elevation of intracellular reactive oxygen species levels in glutamate-stressed HT22 cells. These data suggest that obovatol and honokiol may have clinical applications for preventing neurodegenerative disorders. PMID- 23454147 TI - Cultivated ginseng inhibits 2,4-dinitrochlorobenzene-induced atopic dermatitis like skin lesions in NC/Nga mice and TNF-alpha/IFN-gamma-induced TARC activation in HaCaT cells. AB - Ginseng contains many bioactive constituents, including various ginsenosides that are believed to have anti-allergic, anti-oxidant, and immunostimulatory activities; however, its effects on atopic dermatitis (AD) remain unclear. In the current study, we hypothesized that cultivated ginseng (CG) would inhibit 2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in NC/Nga mice by regulating the T helper (Th)1/Th2 balance. Also, CG inhibits TNF-alpha/IFN-gamma induced thymus- and activation-regulated chemokine (TARC) expression through nuclear factor-kappa B (NF-kappaB)-dependent signaling in HaCaT cells. CG ameliorated DNCB-induced dermatitis severity, serum levels of IgE and TARC, and mRNA expression of TARC, TNF-alpha, IFN-gamma, IL-4, IL-5, and IL-13 in mice. Histopathological examination showed reduced thickness of the epidermis/dermis and dermal infiltration of inflammatory cells in the ears. Furthermore, CG suppressed the TNF-alpha/IFN-gamma-induced mRNA expression of TARC in HaCaT cells. CG inhibited TNF-alpha/IFN-gamma-induced NF-kappaB activation. These results suggest that CG inhibited the development of the AD-like skin symptoms by modulating Th1 and Th2 responses in the skin lesions in mice and TARC expression by suppressing TNF-alpha/IFN-gamma-induced NF-kappaB activation in keratinocytes, and so may be a useful tool in the therapy of AD-like skin symptoms. PMID- 23454148 TI - Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5 fluorouracil and mitomycin C in rat stomach. AB - This study investigated the effect of protein malnutrition on metabolism and toxicity of cisplatin (CP), 5-fluorouracil (FU) and mitomycin C (MMC) in rat stomach. Weanling male Wistar rats received a normal (24%) or low (2.5%) protein diet for 28 days and were allocated into: normally-fed control, protein malnourished control (PM), 3 normally-fed drug-treated groups and 3 protein malnourished drug-treated groups (PM-CP, PM-FU and PM-MMC). Cisplatin and MMC were injected intraperitoneally (8 mg/kg on day 26 and 1 mg/kg/day for 7 days, respectively). 5-Fluorouracil was given orally (50 mg/kg/day for 5 days). Compared with normally-fed counterparts, PM-CP rats exhibited higher glutathione S-transferase, aminopeptidase N and cysteine S-conjugate beta-lyase (CCBL) and lower gamma-glutamyltransferase activities, PM-FU rats exhibited decreased dihydropyrimidine dehydrogenase and cytochrome P450 1A1/2 activities and PM-MMC rats showed higher quinone reductase and depleted xanthine oxidase activities. Protein-malnourished drug-treated groups exhibited exacerbated gastrotoxicity, relative to normally-fed counterparts, manifested by lower mucus levels, higher permeability and histopathological deterioration, along with increased oxidative stress in PM-CP rats and exaggerated prostaglandin E2 production in PM-MMC rats. Conclusively, protein malnutrition alters CP, FU and MMC metabolism in rat stomach by enhancing CCBL pathway for CP activation, delaying FU elimination and activating two-electron reduction of MMC, potentiating their gastrotoxicity. PMID- 23454149 TI - Inhibition of angiogenesis and invasion by DMBT is mediated by downregulation of VEGF and MMP-9 through Akt pathway in MDA-MB-231 breast cancer cells. AB - Invasion, either directly or via metastasis formation, is the main cause of death in cancer patients, development of efficient anti-invasive agents is an important research challenge. In order to obtain more potent inhibitors, a series of brartemicin analogs were synthesized and evaluated for their inhibitory activity against invasion. Among the synthetic analogs tested, DMBT, 6,6'-bis (2,3 dimethoxybenzoyl)-a,a-D-trehalose, was found to be the most potent anti-invasive agent. But the effects of DMBT on breast cancer cells were not known. In this study, the effects of DMBT on invasion and metastasis in MDA-MB-231 cells were investigated. MTT assay showed that no obvious inhibitory or cytotoxic effect of DMBT was found. DMBT could inhibit invasion, migration and tube formation of HUVECs. Gelatin zymography showed that DMBT inhibited secretion and activity of MMP-9. Western blotting demonstrated that DMBT effectively suppressed the expression of VEGF, p-VEGFR-2, p-EGFR, and p-Akt. These results suggested that DMBT could inhibit invasion and angiogenesis by downregulation of VEGF and MMP-9, resulting from the inhibition of Akt pathway. DMBT might be a promising lead molecule for the anti-metastasis and serve as a therapeutic agent to inhibit breast cancer cell invasion and metastasis. PMID- 23454150 TI - Nitrosylation: an adverse factor in Uremic Hemolytic Syndrome. Antitoxin effect of Ziziphus mistol Griseb. AB - Toxins of Escherichia coli (STEC) causing Uremic Hemolytic Syndrome (UHS) generate oxidative stress in human blood with more production of nitric oxide (NO) than reactive oxygen species (ROS). Shiga toxin (Stx) together with the hemolysin (Hly) increased lipid oxidation, as evaluated by malondialdehyde MDA and oxidation of proteins. The addition of Ziziphus mistol Griseb extracts decreased NO, ROS, MDA and simultaneously caused an increase in the degradation of oxidized proteins to advanced oxidation protein products (AOPPs) in controls and samples with toxins. Furthermore, the nitrosylated proteins/AOPP ratio was reduced, due to the increase of AOPP. Z. mistol Griseb extracts exhibited a high proportion of polyphenols and flavonoids, with evident correlation with ferrous reduction antioxidant potential (FRAP). The plasma of eight children with UHS showed oxidative stress and NO stimulus, comparable to the effect of toxins during the assays in vitro. UHS children presented high levels of nitrosylated proteins respect to control children of similar age. Although the degradation of oxidized proteins to AOPP rose in UHS children, the nitrosylated proteins/AOPP rate increased as a consequence of the elevated nitrosative stress observed in these patients. PMID- 23454151 TI - Morbidity and efficacy of ureteroscopic stone treatment in patients with neurogenic bladder. AB - PURPOSE: There is a lack of information on the safety and efficacy of ureteroscopy in the neurogenic bladder population. We hypothesized that ureteroscopy in patients with neurogenic bladder would be associated with an increased risk of complications and a lower stone clearance rate than in patients without neurological impairment. MATERIALS AND METHODS: We reviewed a local registry of patients with ICD-9 codes for urolithiasis between 2004 and 2012. The study cohort was assembled from all eligible patients with neurogenic bladder and a randomly selected control group that had undergone ureteroscopy. Statistical analysis of demographic variables and surgical outcomes was performed. Complications were classified according to the Clavien system. Clearance was defined by computerized tomography, renal/bladder ultrasound or direct ureterorenoscopy. RESULTS: Ureteroscopy was performed a total of 173 times in 127 controls and a total of 45 times in 20 patients with neurogenic bladder. There was no difference between presenting episodes by gender (p = 1.0), race (p = 0.654) or body mass index (p = 0.519). Bacteriuria was associated with the stone episode in 16.4% of controls and 67% of neurogenic bladder cases (p <0.001). Median operative time was significantly longer in those with neurogenic bladder (80.5 minutes, IQR 50-110.5 vs 52, IQR 33-78, p = 0.0003). The proportion of complications was significantly different (p = 0.013). Stones cleared in 86.6% of controls compared to 63% of neurogenic bladder cases (p = 0.004). CONCLUSIONS: Patients with neurogenic bladder have increased morbidity after ureteroscopy for upper tract calculi compared to neurologically unaffected controls. Infection has a role in this morbidity. The clearance rate is lower but the stone burden is more significant in those with neurogenic bladder. PMID- 23454152 TI - Erectile dysfunction precedes other systemic vascular diseases due to incompetent cavernous endothelial cell-cell junctions. AB - PURPOSE: Erectile dysfunction is often a harbinger of cardiovascular disease. We sought to gain mechanistic insight at the cellular and molecular levels into why erectile dysfunction precedes the clinical consequences of cardiovascular disease. MATERIALS AND METHODS: Diabetes was induced by intraperitoneal streptozotocin injection in 8-week-old C57BL/6J mice. At 8 weeks after diabetes induction, we determined the expression of endothelial cell-cell junction proteins and vascular endothelial permeability in the penis, heart and hind limb by systemic injection of various vascular space markers (350 Da to 2,000 kDa) or by immunohistochemical staining with antibody to oxidized low density lipoprotein. We also investigated the effect of recombinant Ang1 protein on cavernous endothelial permeability. RESULTS: Alterations in the integrity of the endothelial cell-cell junction, including a decrease in endothelial cell-cell junction proteins and an increase in vascular permeability to fluorescent tracers or oxidized low density lipoprotein, were prominent in the cavernous tissue of diabetic mice. In contrast, no significant changes in endothelial cell-cell junction proteins or vascular permeability were noted in heart or hind limb tissue according to the diabetic condition. Intracavernous injection of Ang1 protein, an anti-permeability factor, significantly decreased cavernous endothelial permeability to oxidized low density lipoprotein by restoring endothelial cell-cell junction proteins in diabetic mice. CONCLUSIONS: The incompetent cavernous endothelial cell-cell junction in the diabetic condition provides an important clue to why erectile dysfunction is highly prevalent and often precedes other systemic vascular diseases. PMID- 23454153 TI - Genitourinary skin and soft tissue infections: a prospective contemporary evaluation of causative pathogens. AB - PURPOSE: Prior literature identified anaerobes as the predominant causative organisms in genitourinary skin and soft tissue infections. However, the increasing prevalence of community acquired, methicillin resistant Staphylococcus aureus infection has brought about the growing need to reevaluate these infections and their causative organisms. We examined the causative organisms and risk factors in suppurative superficial genitourinary infections, and evaluated the growing role of community acquired, methicillin resistant S. aureus. MATERIALS AND METHODS: We performed a single institution, prospective assessment of 60 adults who presented between August 2008 and July 2010 with genitourinary skin and soft tissue infections requiring incision and drainage. Patients completed a standardized, nonvalidated questionnaire before undergoing debridement of the site. RESULTS: A total of 60 patient specimens were obtained and 92 bacterial pathogens were isolated. Of these pathogens 55% were aerobes. S. aureus was the most predominant cultured organism, representing 25% of all cultured organisms, and 65% of these isolates were community acquired, methicillin resistant S. aureus. The most commonly associated comorbidities included diabetes mellitus, tobacco smoking and heavy alcohol use. HIV/AIDS showed a statistically significant association with community acquired, methicillin resistant S. aureus infection (OR 11.00, 95% CI 1.05-115.51, p = 0.0456), as did the cumulative number of community acquired, methicillin resistant S. aureus risk factors (OR 2.64, 95% CI 1.31-5.33, p = 0.007). CONCLUSIONS: Aerobic organisms now account for most of these infections and community acquired, methicillin resistant S. aureus has emerged as a significant causative organism. Populations that may be at increased risk for these infections include patients with diabetes mellitus, heavy alcohol users and tobacco smokers. In patients with HIV/AIDS or multiple community acquired, methicillin resistant S. aureus risk factors the latter organism is more likely to be the causative organism. PMID- 23454154 TI - Laparoscopic pyelolithotomy compared to percutaneous nephrolithotomy as surgical management for large renal pelvic calculi: a meta-analysis. AB - PURPOSE: We assessed the effectiveness and safety of laparoscopic pyelolithotomy and percutaneous nephrolithotomy as surgical management for solitary renal pelvic calculi larger than 2 cm. MATERIALS AND METHODS: We searched PubMed(r), EMBASE(r), The Cochrane Library and the Web of Knowledge(SM) databases up to November 9, 2012 for relevant published studies. After data extraction and quality assessment, meta-analysis was performed using RevMan 5.1. RESULTS: We identified 7 trials in a total of 176 and 187 patients treated with laparoscopic pyelolithotomy and percutaneous nephrolithotomy, respectively. Operative time and hospital stay were 50.62 minutes and 0.66 days shorter in the nephrolithotomy group (p <0.0001 and 0.04, respectively). Patients in the laparoscopic group benefited from a lesser decrease in hemoglobin (OR -1.00, 95% CI -1.77--0.23), less postoperative fever (OR 0.24, 95% CI 0.08-0.72), a lower incidence of bleeding (OR 0.29, 95% CI 0.10-0.85) and a higher stone-free rate (OR 4.85, 95% CI 1.59-14.82). Sensitivity analysis indicated that all results were stable except the stone-free rate showed no statistically significant difference between the 2 groups (OR 0.33, 95% CI 0.09-1.17). No publication bias was detected. CONCLUSIONS: Current evidence suggests that laparoscopic pyelolithotomy and percutaneous nephrolithotomy are effective and safe for large renal pelvic calculi but laparoscopic pyelolithotomy seems to be more advantageous. However, given the inherent limitations of the included studies, results must be further confirmed in high quality randomized, controlled trials. PMID- 23454155 TI - MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway. AB - PURPOSE: Our microRNA expression signature of renal cell carcinoma revealed that miR-218 expression was significantly decreased in cancer tissues, suggesting that miR-218 is a candidate tumor suppressor. We investigated the functional significance of miR-218 in cancer cells and identified what are to our knowledge novel miR-218 mediated cancer pathways in renal cell carcinoma. MATERIALS AND METHODS: Gain of function studies using mature miR-218 were performed to investigate cell proliferation, migration and invasion in the A498 and 786-O renal cell carcinoma cell lines. To identify miR-218 mediated molecular pathways and responsible genes in renal cell carcinoma, we used gene expression and in silico database analyses. Loss of function assays were performed to investigate the functional significance of miR-218 target genes. RESULTS: Restoration of mature miR-218 significantly inhibited RCC cell proliferation, migration and invasion. Gene expression studies and luciferase reporter assays showed that CAV2 involved in the focal adhesion pathway was directly regulated by miR-218. A silencing study of CAV2 revealed significant inhibition of cell proliferation, migration and invasion. CAV2 mRNA and protein expression was significantly up regulated in renal cell carcinoma clinical specimens. CONCLUSIONS: Loss of tumor suppressive miR-218 enhances cancer cell migration and invasion through dysregulation of the focal adhesion pathway, especially CAV2 as an oncogenic function in renal cell carcinoma. Tumor suppressive microRNA mediated cancer pathways and responsible genes provide new insights into the potential mechanisms of renal cell carcinoma oncogenesis and metastasis. PMID- 23454156 TI - Trends in partial and radical nephrectomy: an analysis of case logs from certifying urologists. AB - PURPOSE: Surgical treatment options for renal masses include radical vs partial nephrectomy and the open vs laparoscopic approach. Using American Board of Urology (ABU) case log data, we investigated contemporary trends in these treatment options, and how surgeon and practice characteristics may influence these trends. MATERIALS AND METHODS: Annualized case log data for nephrectomy were obtained from the ABU for all urologists certifying or recertifying from 2002 to 2010. We evaluated trends in nephrectomy use. Logistic regression was used to evaluate surgeon and practice characteristics as predictors of partial and laparoscopic procedures. RESULTS: From the 3,852 case logs submitted by nonpediatric urologists we analyzed a total of 48,384 nephrectomies. From 2002 to 2010 the proportion of annual nephrectomies performed as open radical nephrectomy gradually decreased from 54% to 29%. During the same period, there was a moderate gradual increase in laparoscopic radical nephrectomies (from 30% to 39%). The proportion of open partial nephrectomies remained stable at 15%, while laparoscopic partial nephrectomy increased from 2% to 17%. On multivariable analysis the use of partial nephrectomy and laparoscopy was predicted by urologist annual nephrectomy volume, initial or recertification status, subspecialty, practice area size and geographic region. CONCLUSIONS: Since 2002, the use of laparoscopic nephrectomy and partial nephrectomy has increased. However, the diffusion of these techniques is not uniform. Initial certification, higher surgical volume, and practicing in areas with more than 1,000,000 population and in the Northeast region were associated with greater use of laparoscopy and partial nephrectomy. Factors that affect the adoption of these techniques require further research. PMID- 23454157 TI - Hydrogen sulfide mediated inhibitory neurotransmission to the pig bladder neck: role of KATP channels, sensory nerves and calcium signaling. AB - PURPOSE: Because neuronal released endogenous H2S has a key role in relaxation of the bladder outflow region, we investigated the mechanisms involved in H2S dependent inhibitory neurotransmission to the pig bladder neck. MATERIALS AND METHODS: Bladder neck strips were mounted in myographs for isometric force recording and simultaneous measurement of intracellular Ca(2+) and tension. RESULTS: On phenylephrine contracted preparations electrical field stimulation and the H2S donor GYY4137 evoked frequency and concentration dependent relaxation, which was reduced by desensitizing capsaicin sensitive primary afferents with capsaicin, and the blockade of adenosine 5'-triphosphate dependent K(+) channels, cyclooxygenase and cyclooxygenase-1 with glibenclamide, indomethacin and SC560, respectively. Inhibition of vanilloid, transient receptor potential A1, transient receptor potential vanilloid 1, vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypeptide and calcitonin gene related peptide receptors with capsazepine, HC030031, AMG9810, PACAP6-38 and CGRP8-37, respectively, also decreased electrical field stimulation and GYY4137 responses. H2S relaxation was not changed by guanylyl cyclase, protein kinase A, or Ca(2+) activated or voltage gated K(+) channel inhibitors. GYY4137 inhibited the contractions induced by phenylephrine and by K(+) enriched (80 mM) physiological saline solution. To a lesser extent it decreased the phenylephrine and K(+) induced increases in intracellular Ca(2+). CONCLUSIONS: H2S produces pig bladder neck relaxation via activation of adenosine 5'-triphosphate dependent K(+) channel and by smooth muscle intracellular Ca(2+) desensitization dependent mechanisms. H2S also promotes the release of sensory neuropeptides and cyclooxygenase-1 pathway derived prostanoids from capsaicin sensitive primary afferents via transient receptor potential A1, transient receptor potential vanilloid 1 and/or related ion channel activation. PMID- 23454158 TI - Renal function after laparoendoscopic single site pyeloplasty. AB - PURPOSE: Outcomes after laparoendoscopic single site pyeloplasty are limited to small cohort studies with short-term followup. We evaluated the clinical and renal function outcomes of what to our knowledge is the largest laparoendoscopic single site pyeloplasty cohort to date with a mean followup of 12 months. MATERIALS AND METHODS: Consecutive patients diagnosed with symptomatic ureteropelvic junction obstruction who underwent robotic or conventional laparoendoscopic single site pyeloplasty were entered into the study. Patient demographics, and preoperative and postoperative renal function outcomes were recorded. Diuretic renogram was performed after stent removal, at 6 months and yearly thereafter. RESULTS: The cohort included 31 conventional and 22 robotic laparoendoscopic single site pyeloplasties. Four laparoendoscopic single site surgeries (7.8%) were converted to another procedure due to failure to progress. Mean +/- SD followup was 12.1 +/- 10.7 months and 22 patients had at least 12 months of followup. No intraoperative complications occurred. Complications developed postoperatively in 11 patients (21%), of which 9 were Clavien grade 3 or greater. Preoperative symptoms resolved in 49 of 51 cases (96%). Severe obstruction (half-time greater than 20 minutes) was seen in 32 of 44 patients (73%) at presentation and obstruction resolved (half-time 20 minutes or less) in 41 (93%). Mean preoperative and postoperative half-time was 24.6 +/- 13.4 and 8.3 +/- 4.1 minutes, respectively, for an improvement of 16.3 +/- 12.3 minutes (p <0.01). CONCLUSIONS: Laparoendoscopic single site pyeloplasty is safe and efficacious. The laparoscopic and robotic techniques provide excellent outcomes in terms of symptomatic relief and radiographic resolution of obstruction. PMID- 23454159 TI - The impact of running versus interrupted anastomosis on ureterointestinal stricture rate after radical cystectomy. AB - PURPOSE: Benign ureterointestinal anastomotic stricture is not uncommon after radical cystectomy and urinary diversion. We studied the impact of the running vs the interrupted technique on the ureterointestinal anastomotic stricture rate. MATERIALS AND METHODS: From July 2007 to December 2008 interrupted end-to-side anastomoses were created and from January 2009 to July 2010 running anastomoses were created. The primary study end point was time to ureterointestinal anastomotic stricture. RESULTS: Of 266 consecutive patients 258 were alive 30 days after radical cystectomy, including 149 and 109 with an interrupted and a running anastomosis, respectively. The groups did not differ in age, gender, body mass index, age adjusted Charlson comorbidity index, receipt of chemotherapy or radiation, blood loss, operative time, diversion type or postoperative pathological findings. The stricture rate per ureter was 8.5% (25 of 293) and 12.7% (27 of 213) in the interrupted and running groups, respectively (p = 0.14). Univariate analysis suggested that postoperative urinary tract infection (HR 2.1, 95% CI 1.1-4.1, p = 0.04) and Clavien grade 3 or greater complications (HR 2.6, 95% CI 1.4-4.9, p <0.01) were associated with ureterointestinal anastomotic stricture. On multivariate analysis postoperative urinary tract infection (HR 2.4, 95% CI 1.2-5.1, p = 0.02) and running technique (HR 1.9, 95% CI 1.0-3.7, p = 0.05) were associated with ureterointestinal anastomotic stricture. Median time to stricture and followup was 289 (IQR 120-352) and 351 days (IQR 132-719) in the running cohort vs 213 (IQR 123-417) and 497 days (IQR 174-1,289) in the interrupted cohort, respectively. Of the 52 strictures 33 (63%) developed within 1 year. Kaplan-Meier analysis controlling for differential followup showed a trend toward higher freedom from stricture for the interrupted ureterointestinal anastomosis (p = 0.06). CONCLUSIONS: A running anastomosis and postoperative urinary tract infection may be associated with ureterointestinal anastomotic stricture. Larger series with multiple surgeons are needed to confirm these findings. PMID- 23454160 TI - Down-regulation of nerve growth factor expression in the bladder by antisense oligonucleotides as new treatment for overactive bladder. AB - PURPOSE: Nerve growth factor over expression in the bladder has a role in overactive bladder symptoms via the mediation of functional changes in bladder afferent pathways. We studied whether blocking nerve growth factor over expression in bladder urothelium by a sequence specific gene silencing mechanism would suppress bladder overactivity and chemokine expression induced by acetic acid. MATERIALS AND METHODS: Female Sprague-Dawley(r) rats anesthetized with isoflurane were instilled with 0.5 ml saline, scrambled or TYETM 563 labeled antisense oligonucleotide targeting nerve growth factor (12 MUM) alone or complexed with cationic liposomes for 30 minutes. The efficacy of nerve growth factor antisense treatments for acetic acid induced bladder overactivity was assessed by cystometry. Bladder nerve growth factor expression levels and cellular distribution were quantified by immunofluorescence staining and enzyme linked immunosorbent assay. Effects on bladder chemokine expression were measured by Luminex(r) xMAP(r) analysis. RESULTS: Liposomes were needed for bladder uptake of oligonucleotide, as seen by the absence of bright red TYE 563 fluorescence in rats instilled with oligonucleotide alone. At 24 hours after liposome oligonucleotide treatment baseline bladder activity during saline infusion was indistinct in the sham and antisense treated groups with a mean +/- SEM intercontraction interval of 348 +/- 55 and 390 +/- 120 seconds, respectively. Acetic acid induced bladder overactivity was shown by a decrease in the intercontraction interval to a mean of 33.2% +/- 4.0% of baseline in sham treated rats. However, the reduction was blunted to a mean of 75.8% +/- 3.4% of baseline in rats treated with liposomal antisense oligonucleotide (p <0.05). Acetic acid induced increased nerve growth factor in the urothelium of sham treated rats, which was decreased by antisense treatment, as shown by enzyme-linked immunosorbent assay and reduced nerve growth factor immunoreactivity in the urothelium. Increased nerve growth factor in bladder tissue was associated with sICAM-1, sE-selectin, CXCL-10 and 1, leptin, MCP-1 and vascular endothelial growth factor over expression, which was significantly decreased by nerve growth factor antisense treatment (p <0.01). CONCLUSIONS: Acetic acid induced bladder overactivity is associated with nerve growth factor over expression in the urothelium and with chemokine up-regulation. Treatment with liposomal antisense suppresses bladder overactivity, and nerve growth factor and chemokine expression. Local suppression of nerve growth factor in the bladder could be an attractive approach for overactive bladder. It would avoid the systemic side effects that may be associated with nonspecific blockade of nerve growth factor expression. PMID- 23454161 TI - Effective humoral immunity against diphtheria and tetanus in patients with systemic lupus erythematosus or myasthenia gravis. AB - INTRODUCTION: Controversy exists about the effectiveness of vaccine-induced immune response in patients with immunoregulatory disorders. Our aim was to determine the antibody titers to diphtheria and tetanus in patients with either of two autoimmune diseases. METHODS: 279 patients with SLE (205 females, aged 45.0 +/- 13.8 years), 158 patients with myasthenia gravis (MG) (101 females, aged 55 +/- 18.7 years) and 208 healthy subjects (122 females, aged 48 +/- 14.6 years) were enrolled. Serum concentrations of diphtheria-antitoxin-IgG (A-DIPHTH) and tetanus-antitoxoid-IgG (A-TET) were determined with ELISA. RESULTS: Equal proportions of healthy subjects, as well as patients with SLE or MG exhibited proper antibody responses and immune protection against diphtheria and tetanus. In all three test groups, serum concentration of A-DIPHTH decreased significantly (p<0.001) with age throughout the study population, while titers of A-TET dropped only in the elderly (>60-years-old) subjects. There were no significant differences among the groups in the age-related changes of A-TET and A-DIPHTH except that in <40-years-old subjects, A-DIPHTH level was significantly (p=0.029) lower in SLE patients than in controls. CONCLUSIONS: Our findings suggest that the level of vaccine-induced immunity against diphtheria and tetanus infections in patients with SLE or MG is comparable to the healthy population. PMID- 23454162 TI - Fine-mapping naturally occurring NY-ESO-1 antibody epitopes in melanoma patients' sera using short overlapping peptides and full-length recombinant protein. AB - The tumor antigen NY-ESO-1 is one of the most antigenic cancer-testis antigens, first identified by serologic analysis of a recombinant cDNA expression library (SEREX). NY-ESO-1 is expressed in different types of cancers including melanoma. NY-ESO-1-specific spontaneous humoral and cellular immune responses are detected in a large proportion of patients with advanced NY-ESO-1-expressing cancers. Therefore NY-ESO-1 is a good candidate antigen for immunotherapy. Although cellular immune responses to NY-ESO-1 are well characterized, much less is known about the humoral immune responses. In this study, we finely mapped linear antibody epitopes using sera from melanoma patients and shorter overlapping peptide sets. We have shown that melanoma patients' humoral immune systems responded to NY-ESO-1 differently in each individual with widely differing antibody specificity, intensity and antibody subtypes. This knowledge will help us further understand anti-tumor immunity and may also help us to monitor cancer progress and cancer vaccine efficacy in the future. PMID- 23454163 TI - Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole genome expression profiling. AB - Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells. PMID- 23454165 TI - Assessment of the RTS,S/AS01 malaria vaccine. PMID- 23454164 TI - Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data. AB - BACKGROUND: The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual participant pooled analysis of phase 2 clinical data. METHODS: We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2-10 years (PrP2-10), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02. FINDINGS: Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0.001). At low transmission (PrP2-10 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP2-10 20%) it was 41% (21 to 57), and at high transmission (PrP2-10 70%) the efficacy was 4% (-10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0.0001)- eg, at low transmission (PrP2-10 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0.038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0.0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% ( 38 to 38) after 3 years. INTERPRETATION: Vaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination. FUNDING: Medical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust. PMID- 23454166 TI - Effect of the Arrabidaea chica extract on collagen fiber organization during healing of partially transected tendon. AB - AIMS: After undergoing lesions, tendons have disorganized collagen fibers compared to undamaged tendons. Arrabidaea chica leaves have the aglycones carajurin and carajurone, components of the antocyanins, with a strong pharmacological potential due to their healing properties. Thus, the aim of this study was to investigate the effect of topical application of A. chica extract during tendon healing. MAIN METHODS: The calcaneal tendon of Wistar rats was partially transected with subsequent treatment with A. chica extract (2.13 g/mL) followed by excision on the 7th, 14th and 21st days. Control rats received only saline treatment. KEY FINDINGS: Transmission electron microscopy analysis showed the presence of a large amount of small segments of collagen fibrils in the transected region of the tendons on the 7th day in both the control and plant treated groups. Considering the organization of the collagen fibers, higher values of birefringence were observed under polarization microscopy in the tendons of the plant-treated group on the 14th day compared to the control group. A larger quantity of dermatan sulfate was also detected after plant treatment in the same period. However, lesser dermatan and chondroitin sulfate were detected in the plant-treated group than in the control group on the 21st day. No differences were found in the values of birefringence between these groups. Intense metachromasy was observed in both transected groups on the 21st day. SIGNIFICANCE: In conclusion, the use of A. chica extract improves collagen organization and increases the quantity of dermatan sulfate on the 14th day of the tendon healing. PMID- 23454167 TI - NAD(+) influx through connexin hemichannels prevents poly(ADP-ribose) polymerase mediated astrocyte death. AB - AIM: Cell death induced by excessive activation of poly(ADP-ribose) polymerase (PARP) is inhibited by administration of NAD(+) extracellularly, but its preventive mechanism remains unclear. Here we investigated the involvement of NAD(+) and/or its metabolites, adenosine and nicotinamide, in the rescue of PARP mediated astrocyte death by NAD(+) and explored the pathway through which intact NAD(+) could enter cells. MAIN METHODS: PARP activation was induced by treatment with N-methyl-N'-nitro-N-nitrosoguanidine, a DNA-alkylating agent. The cellular NAD(+) content was determined by an enzymatic recycling assay, and cell viability was determined by measuring intracellular LDH activity. KEY FINDINGS: NAD(+), but not adenosine and nicotinamide, could restore the cellular NAD(+) levels decreased by PARP activation. Pharmacological inhibition of the uptake of adenosine and nicotinamide had no effect on the prevention of PARP-triggered cell death by NAD(+), suggesting that unmetabolized NAD(+) remaining in the extracellular milieu might prevent PARP-mediated NAD(+) consumption and cell death. The increase in the cellular NAD(+) level caused by NAD(+) administration to PARP-activated cells was significantly inhibited by a connexin hemichannel blocker, carbenoxolone, but not by P2X7 receptor inhibition with selective antagonists and siRNA, or pannexin-selective blockers. Finally, pharmacological blockade of connexin hemichannels with 18beta-glycyrrhetinic acid, octanol and carbenoxolone inhibited the NAD(+)-mediated cell rescue of PARP-triggered cell death. SIGNIFICANCE: These findings suggested that intact NAD(+) could get into astrocytes through connexin hemichannels, and that this process should play a key role in NAD(+)-mediated prevention of PARP-triggered astrocyte death. PMID- 23454169 TI - Phenethyl isothiocyanate regulates inflammation through suppression of the TRIF dependent signaling pathway of Toll-like receptors. AB - AIMS: The aim of this study was to evaluate the therapeutic potential of the phenethyl isothiocyanate (PEITC) in Toll-like receptor (TLR) signaling pathways. MAIN METHODS: To evaluate the cytotoxic nature of PEITC in RAW 264.7 cells, cytotoxicity was determined using the MTS cell viability assay. RAW264.7 cells were transfected with a nuclear factor-kappaB (NF-kappaB), interferon beta (IFNbeta) PRDIII-I, or interferon inducible protein-10 (IP-10) luciferase plasmid and then luciferase enzyme activities were determined by luciferase assay. The expression of inducible nitric oxide synthase (iNOS) and phosphorylation of interferon regulatory factor 3 (IRF3) were determined by Western blotting. The levels of IP-10 were determined with culture medium by using an IP-10 enzyme linked immunosorbent assay (ELISA) kit. KEY FINDINGS: PEITC suppressed the activation of IRF3 and the expression of IP-10 induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly[I:C]). SIGNIFICANCE: TLRs play an important role in the induction of innate immune responses for host defense against invading microbial pathogens. PEITC found in cruciferous vegetables has an effect on treatment of many chronic diseases. Our results suggest that beneficial effects of PEITC on chronic inflammatory diseases are mediated through modulation of Toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent signaling pathway of TLRs. PMID- 23454168 TI - An old method facing a new challenge: re-visiting housekeeping proteins as internal reference control for neuroscience research. AB - The study of specific target protein expression is often performed by western blotting, a commonly used method to measure the protein expression in neuroscience research by specific antibodies. Housekeeping proteins are used as an internal control for protein loading as well as reference in the western blotting analysis. This practice is based on the belief that such housekeeping genes are considered to be ubiquitously and constitutively expressed in every tissue and produce the minimal essential transcripts necessary for normal cellular function. The most commonly used housekeeping proteins are beta-actin, beta-tubulin, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). However, recent studies have shown significant variation in some housekeeping genes both at the mRNA and protein levels in various neuropathological events, such as spinal cord injury and Alzheimer's diseases. Changes of housekeeping genes are also induced by non-neuronal diseases in various tissues. Therefore, these discoveries raise a potential concern regarding whether using a housekeeping protein as an internal standard for target protein analysis is an appropriate practice. This minireview will focus on (I) the effects of neuronal and non neuronal diseases, experimental condition, and tissue-specific roles on alteration of housekeeping genes, and (II) alternative internal standards for gene and protein expression analysis. PMID- 23454170 TI - Antitumour effects of pentapeptide derived from donkey serum albumin both in vitro and in vivo. AB - AIMS: Antitumour effects of pentapeptide (LH) derived from donkey serum albumin hydrolysates were tested against tumour cells both in vitro and in vivo. The mechanism of LH induced tumour cell apoptosis was investigated. MAIN METHODS: Human promyelocytic leukaemia cells (HL 60) were cultured to observe inhibition in vitro. Two animal models, a solid tumour and a non-entity myeloid leukaemia tumour, were used to determine the effect of LH in vivo. The former, fifty BALB/c nude mice were transplanted with HL 60 cells. The tumours were isolated completely and weighed after treatment. The latter, fifty BALB/c mice were injected intravenously with transplantable erythroblastic leukaemia cells (EL9611 cells). The survival time of mice was recorded and organs were used for histological study. The mechanism about tumour cell apoptosis was evaluated using fluorescence-activated cell sorting and transmission electron microscope for morphological assays. KEY FINDINGS: The LH inhibited tumour cell proliferation and the inhibitions were dependent on both the concentration and the dose; the best inhibition rate was up to 70% of the untreated control in vitro. It markedly inhibited the growth of a transplanted tumour with HL 60 cells in an immune deficient nude mouse model. LH was also able to prolong the survival time of leukaemia mice with transplanted EL9611 cells and prevent the infiltration of leukaemia cells to the main internal organs. SIGNIFICANCE: The LH peptide is an excellent inhibitor of tumour cell growth. These data provide the experimental foundation to use the LH peptide as a candidate for antitumour drugs in the future. PMID- 23454171 TI - Expression of NPR-B in neurons of the dorsal root ganglia of the rat. AB - C-type natriuretic peptide (CNP) is an abundant neuropeptide in the central nervous system, which exerts its physiological effects through natriuretic peptide receptor B (NPR-B). Recently, the CNP/NPR-B system has been recognized as an important regulator for the development of sensory axons. The dorsal root ganglion (DRG) contains neurons transmitting several kinds of spinal sensory stimuli to the central nervous system. In this study, we characterized NPR-B receptor expression in the rat DRG, using reverse transcription-polymerase chain reaction, Western blotting and immunohistochemistry. Immunostaining revealed that NPR-B was expressed in neuronal cell bodies and processes of the DRG, with NPR-B immunoreactivity mainly prominent in small and medium-sized DRG neurons. Double immunolabeling showed that NPR-B was expressed in calcitonin gene-related peptide and isolectin B4-positive neurons. Furthermore, NPR-B expression was co localized with calcitonin gene-related peptide in the dorsal horn of the spinal cord. Together, our data suggest that the natriuretic peptides may perform several biological actions on sensory neurons via their binding to NPR-B in the DRG. PMID- 23454172 TI - The ghrelin activating enzyme ghrelin-O-acyltransferase (GOAT) is present in human plasma and expressed dependent on body mass index. AB - Ghrelin is the only known peripherally produced and centrally acting peptide hormone stimulating food intake. The acylation of ghrelin is essential for binding to its receptor. Recently, the ghrelin activating enzyme ghrelin-O acyltransferase (GOAT) was identified in mice, rats and humans. In addition to gastric mucosal expression, GOAT was also detected in the circulation of rodents and its expression was dependent on metabolic status. We investigated whether GOAT is also present in human plasma and whether expression levels are affected under different conditions of body weight. Normal weight, anorexic and obese subjects with body mass index (BMI) 30-40, 40-50 and >50 were recruited (n=9/group). In overnight fasted subjects GOAT protein expression was assessed by Western blot and ghrelin measured by ELISA. GOAT protein was detectable in human plasma. Anorexic patients showed reduced GOAT protein levels (-42%, p<0.01) whereas obese patients with BMI>50 had increased concentrations (+34%) compared to normal weight controls. Ghrelin levels were higher in anorexic patients compared to all other groups (+62-78%, p<0.001). Plasma GOAT protein expression showed a positive correlation with BMI (r=0.71, p<0.001) and a negative correlation with ghrelin (r=-0.60, p<0.001). Summarized, GOAT is also present in human plasma and GOAT protein levels depend on the metabolic environment with decreased levels in anorexic and increased levels in morbidly obese patients. These data may indicate that GOAT counteracts the adaptive changes of ghrelin observed under these conditions and ultimately contributes to the development or maintenance of anorexia and obesity as it is the only enzyme acylating ghrelin. PMID- 23454173 TI - Presence of adropin, nesfatin-1, apelin-12, ghrelins and salusins peptides in the milk, cheese whey and plasma of dairy cows. AB - Biological fluids (milk and serum/plasma) and cheese whey milk-derived fluid contain numerous molecules, especially amino acids and proteins. Therefore, the purpose of this study was to find out whether cheese whey (n:6), cow milk (n:6) and its blood (n=6) have adropin, nesfatin-1, apelin-12, ghrelins and salusin peptides. Adropin, nesfatin-1, apelin-12 concentrations were measured by ELISA, whereas ghrelin and salusin concentrations were measured by EIA methods. It was found that adropin, nesfatin-1, apelin-12, des-acylated ghrelin and salusins in cheese whey were higher than in the corresponding milk peptides and plasma of dairy cows, with the exception of salusin alpha and acylated ghrelin in milk being the same than that of the corresponding cheese whey concentration and plasma of dairy cows. A correlation was also found between milk peptides and cheese whey, as also with plasma of dairy cows. The data suggest that peptides in cow milk might be an important and nutritious food for (neonatal) calves and human diet due to their biological and physiological properties. PMID- 23454174 TI - Deciphering intracellular localization and physiological role of nociceptin and nocistatin. AB - Nociceptin and nocistatin are endogenous ligands of G protein coupled receptor family. Numerous techniques have been used to study the diverse parameters including, localization, distribution and ultrastructure of these peptides. The majority of the study parameters are based on their physiological roles in different organ systems. The present study presents an overview of the different methods used for the study of nociceptin, nocistatin and their receptors. Nociceptin has been implicated in many physiological functions including, nociception, locomotion, stressed-induced analgesia, learning and memory, neurotransmitter and hormone release, renal function, neuronal differentiation, sexual and reproductive behavior, uterine contraction, feeding, anxiety, gastrointestinal motility, cardiovascular function, micturition, cough, hypoxic ischemic brain injury, diuresis and sodium balance, temperature regulation, vestibular function, and mucosal transport. It has been noted that the use of light and electron microscopy was less frequent, though it may be one of the most promising tools to study the intracellular localization of these neuropeptides. In addition, more studies on the level of circulating nociceptin and nocistatin are also necessary for investigating their clinical roles in health and disease. A variety of modern tools including physiological, light and electron microscopy (EM) are needed to decipher the extent of intracellular localization, tissue distribution and function of these peptides. The intracellular localization of nociceptin and nocistatin will require a high resolution transmission EM capable of identifying these peptides and other supporting molecules that co-localize with them. A tracing technique could also elucidate a possible migratory ability of nociceptin and nocistatin from one cellular compartment to the other. PMID- 23454175 TI - Age-dependent reduction of ghrelin- and motilin-induced contractile activity in the chicken gastrointestinal tract. AB - Ghrelin is an endogenous ligand for growth hormone secretagogue-receptor 1a (GHS R1a) and stimulates gastrointestinal (GI) motility in the chicken. Since ghrelin stimulates GH release, which regulates growth, it might be interesting to compare ghrelin-induced responses in GI tract of different-aged chickens. Motilin is a ghrelin-related gut peptide that induces strong contraction in the small intestine. Aim of this study was to clarify age-dependent changes in ghrelin- and motilin-induced contractions of the chicken GI tract and expression of their receptor mRNAs. Chicken ghrelin caused contraction of the crop and proventriculus. Ghrelin-induced contraction in the proventriculus decreased gradually up to 100 days after hatching, but the responses to ghrelin in the crop were the same during the growth period. GHS-R1a mRNA expression in the crop tended to increase, but that in the proventriculus decreased depending on the age. Chicken motilin caused contraction of the chicken GI tract. Atropine decreased the responses to motilin in the proventriculus but not in the ileum. Motilin-induced contraction in the proventriculus but not that in the ileum decreased depending on post-hatching days. On the other hand, motilin receptor mRNA expression in every region of the GI tract decreased with age, but the decrease was more marked in the proventriculus than in the ileum. In conclusion, ghrelin- and motilin-induced GI contractions selectively decreased in the chicken proventriculus depending on post-hatching days, probably due to the age-related decrease in respective receptors expression. The results suggest an age-related contribution of ghrelin and motilin to the regulation of chicken GI motility. PMID- 23454176 TI - Spatio-temporal characterization of the pleiotrophinergic system in mouse cerebellum: evidence for its key role during ontogenesis. AB - The development of the central nervous system requires an appropriate micro environment that is conditioned by a combination of various extracellular components. Most of the known signaling factors, such as neurotransmitters or neuropeptides, are soluble and diffuse into the extracellular matrix. However, other secreted molecules like proteoglycans or glycosaminoglycans anchor in the extracellular matrix to influence cerebral ontogenesis. As such, pleiotrophin (PTN), which binds the proteoglycans syndecan-3 (SDC3) and protein tyrosine phosphatase zeta (PTPzeta), has been described as a pro-migratory and a pro differentiating secreted cytokine on cortical neurons. In rat cerebellum, PTN is highly expressed during the first postnatal week, suggesting that this cytokine could participate to the development of the cerebellar cortex. According to this hypothesis, our spatio-temporal cartography of PTN, PTPzeta and SDC3 indicated that, in mouse, the PTNergic system was present in the cerebellum at least from the first postnatal day (P0). Until P12, PTN was mainly expressed by granule cell precursors and located in the extracellular matrix, while SDC3 was expressed by Purkinje cells, Golgi cells and granule cell precursors, and PTPzeta was present on Purkinje cells and Bergmann fibers. In vitro studies confirmed the presence of SDC3 on immature granule cells and demonstrated that PTN could stimulate directly their velocity in culture. In contrast, subarachnoidal injection of PTN in the cerebellum significantly reduced the rate of migration of granule cells, exacerbated their apoptosis and induced an atrophy of the Purkinje cell dendritic tree. Since differentiated granule cells did not express SDC3 or PTPzeta, the PTN effect observed on migration and apoptosis may be indirectly mediated by Purkinje and/or Bergmann cells. From P21 to adulthood, the distribution of PTN, SDC3 and PTPzeta changed and their expression dramatically decreased even if they were still detectable. PTN and SDC3 immunolabeling was restricted around Purkinje cell bodies and Golgi cells, whereas PTPzeta was located around interneurons. These data suggested that, in the cerebellum of adult mice, PTN participates to the perineuronal nets that control neuronal plasticity. To conclude, the present work represents the first spatio-temporal characterization of the PTNergic system in the mouse cerebellum and indicates that PTN may contribute to cerebellum ontogenesis during the postnatal development as well as to neuronal plasticity at adulthood. PMID- 23454178 TI - Dysphagia as a complication of posterior fossa surgery in adults. PMID- 23454177 TI - Serotonergic mechanisms are necessary for central respiratory chemoresponsiveness in situ. AB - Evidence from in vivo and in vitro experiments conclude that serotonin (5-HT) neurons are involved in and play an important role in central respiratory CO2/H(+) chemosensitivity. This study was designed to assess the importance of 5 HT neurons and 5-HT receptor activation in the frequency and amplitude components of the hypercapnic response of the respiratory network in the unanesthetized perfused in situ juvenile rat brainstem preparation that exhibits patterns of phrenic nerve discharge similar to breathing in vivo. Exposure to a hypercapnic perfusate increased phrenic burst frequency and/or amplitude, the neural correlates of breathing frequency and tidal volume in vivo. Hypercapnic responses were also assessed during exposure to ketanserin (5-HT2 receptor antagonist), and 8-OH-DPAT (inhibiting 5-HT neurons via 5-HT1A autoreceptors). Neither of these drugs substantially altered baseline activity, however, both abolished hypercapnic responses of the respiratory network. These data illustrate that 5-HT neurons and 5-HT receptor activation are not required for respiratory rhythm generation per se, but are critical for CO2 responses in situ, supporting the hypothesis that 5-HT neurons play an important role in central ventilatory chemosensitivity in vivo. PMID- 23454179 TI - Magnification of growth hormone-secreting tumor cells: could electron microscopy be a new paradigm for outcome in acromegaly? PMID- 23454180 TI - Prediction of outcome of endoscopic third ventriculostomy. PMID- 23454181 TI - Myelomeningocele: an overview. PMID- 23454182 TI - Intracranial pressure monitoring as an early predictor of third ventriculostomy outcome. AB - OBJECTIVES: Endoscopic third ventriculostomy (ETV) is a routinely used alternative to ventriculoperitoneal shunt in patients with obstructive hydrocephalus. We attempted to determine the usefulness of the surgeon's intraoperative impression and postoperative period intracranial pressure monitoring that may help guide clinicians in predicting the early functional outcome of ETV. METHODS: Patients who underwent ETV between 2006 and 2011 were retrospectively reviewed. The sample included 63 patients (23 female and 40 male), between the ages of 13 and 69 years. In each case, the surgeon's intraoperative impression, cerebrospinal fluid (CSF) samplings, and postoperative intracranial pressure (ICP) monitoring (via transduced external ventricular drain for up to 72 hours) was recorded and evaluated in light of functional outcome of ETV at discharge and early follow up (1-2 months). RESULTS: ICP monitoring predicted initial function of the ETV in 51 cases (80.9%) and in 12 cases (19%) suggested ETV failure. Monitoring has a positive predictive value (PPV) of 76.3% and a negative predictive value (NPV) of 100% whereas the surgeon's intraoperative impression of future function had a PPV of 76.5% and NPV of 76.9%. CSF sampling has a much poorer predictive quality because the wide confidence interval and a PPV of 63.6% and NPV 38.2%. In our series the evidence of sepsis as a result of external ventricular drain was found to be 11.67%. Subgroup analysis, removing the patients with posterior fossa tumors, results in increased PPV (85.7%) of ICP monitoring. CONCLUSIONS: ETV is a valuable means of treating obstructive hydrocephalus. By considering the surgeon's intraoperative impression and postoperative ICP monitoring course, some of the uncertainty around its functional outcome can be overcome. The surgeon's impression and the ICP monitoring offer approximately the same predictive quality for ETV outcome. PMID- 23454183 TI - Efficient amyloid A clearance in the absence of immunoglobulins and complement factors. AB - Amyloid A amyloidosis is a protein misfolding disease characterized by deposition of extracellular aggregates derived from the acute-phase reactant serum amyloid A protein. If untreated, amyloid A amyloidosis leads to irreversible damage of various organs, including the kidneys, liver, and heart. Amyloid A deposits regress upon reduction of serum amyloid A concentration, indicating that the amyloid can be efficiently cleared by natural mechanisms. Clearance was proposed to be mediated by humoral immune responses to amyloid. Here, we report that amyloid clearance in mice lacking complement factors 3 and 4 (C3C4(-/-)) was equally efficient as in wild-type mice (C57BL/6), and was only slightly delayed in agammaglobulinemic mice (J(H-/-)). Hence, antibodies or complement factors are not necessary for natural amyloid clearance, implying the existence of alternative physiological pathways for amyloid removal. PMID- 23454184 TI - A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma. AB - Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200 mg/m(2). Twenty-five subjects were enrolled into 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225 mg/m(2) + melphalan 200 mg/m(2) was expanded to further evaluate safety. Overall, there was no transplant related mortality and only one grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment were 11 (range, 9 to 14) and 13 (range, 10 to 21), respectively. Disease responses at day +100 posttransplantation were progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with pre-existing high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after autologous stem cell transplant. Bendamustine up to a dose of 225 mg/m(2) added to autologous stem cell transplantation conditioning with high-dose melphalan in patients with multiple myeloma did not exacerbate expected toxicities. PMID- 23454185 TI - Targeted nanoparticles with novel non-peptidic ligands for oral delivery. AB - Orally administered targeted nanoparticles have a large number of potential biomedical applications and display several putative advantages for oral drug delivery, such as the protection of fragile drugs or modification of drug pharmacokinetics. These advantages notwithstanding, oral drug delivery by nanoparticles remains challenging. The optimization of particle size and surface properties and targeting by ligand grafting have been shown to enhance nanoparticle transport across the intestinal epithelium. Here, different grafting strategies for non-peptidic ligands, e.g., peptidomimetics, lectin mimetics, sugars and vitamins, that are stable in the gastrointestinal tract are discussed. We demonstrate that the grafting of these non-peptidic ligands allows nanoparticles to be targeted to M cells, enterocytes, immune cells or L cells. We show that these grafted nanoparticles could be promising vehicles for oral vaccination by targeting M cells or for the delivery of therapeutic proteins. We suggest that targeting L cells could be useful for the treatment of type 2 diabetes or obesity. PMID- 23454186 TI - Recognition and cleavage of a nonstructured CRISPR RNA by its processing endoribonuclease Cas6. AB - Clustered regularly interspaced short palindromic repeats (CRISPRs) confer adaptive immunity to prokaryotes through a small RNA-mediated mechanism. Specific endoribonucleases are required by all CRISPR-bearing organisms to process CRISPR RNAs into small RNA that serve as guides for defensive effector complexes. The molecular mechanism of how the endoribonucleases process the class of CRISPR RNA containing no predicted secondary structural features remains largely elusive. Here, we report cocrystal structures of a processing endoribonuclease bound with a noncleavable RNA substrate and its product-like fragment derived from a nonpalindramic repeat. The enzyme stabilizes a short RNA stem-loop structure near the cleavage site and cleaves the phosphodiester bond using an active site comprised of arginine and lysine residues. The distinct RNA binding and cleavage mechanisms underline the diversity in CRISPR RNA processing. PMID- 23454187 TI - Early folding events protect aggregation-prone regions of a beta-rich protein. AB - Protein folding and aggregation inevitably compete with one another. This competition is even keener for proteins with frustrated landscapes, such as those rich in beta structure. It is interesting that, despite their rugged energy landscapes and high beta sheet content, intracellular lipid-binding proteins (iLBPs) appear to successfully avoid aggregation, as they are not implicated in aggregation diseases. In this study, we used a canonical iLBP, cellular retinoic acid-binding protein 1 (CRABP1), to understand better how folding is favored over aggregation. Analysis of folding kinetics of point mutants reveals that the folding pathway of CRABP1 involves early barrel closure. This folding mechanism protects sequences in CRABP1 that comprise cores of aggregates as identified by nuclear magnetic resonance. The amino acid conservation pattern in other iLBPs suggests that early barrel closure may be a general strategy for successful folding and minimization of aggregation. We suggest that folding mechanisms in general may incorporate steps that disfavor aggregation. PMID- 23454188 TI - Structural insights into the mechanism of GTPase activation in the GIMAP family. AB - GTPases of immunity-associated proteins (GIMAPs) are regulators of lymphocyte survival and homeostasis. We previously determined the structural basis of GTP dependent GIMAP2 scaffold formation on lipid droplets. To understand how its GTP hydrolysis is activated, we screened for other GIMAPs on lipid droplets and identified GIMAP7. In contrast to GIMAP2, GIMAP7 displayed dimerization stimulated GTP hydrolysis. The crystal structure of GTP-bound GIMAP7 showed a homodimer that assembled via the G domains, with the helical extensions protruding in opposite directions. We identified a catalytic arginine that is supplied to the opposing monomer to stimulate GTP hydrolysis. GIMAP7 also stimulated GTP hydrolysis by GIMAP2 via an analogous mechanism. Finally, we found GIMAP2 and GIMAP7 expression differentially regulated in several human T cell lymphoma lines. Our findings suggest that GTPase activity in the GIMAP family is controlled by homo- and heterodimerization. This may have implications for the differential roles of some GIMAPs in lymphocyte survival. PMID- 23454189 TI - PK/PD assessment in CNS drug discovery: Prediction of CSF concentration in rodents for P-glycoprotein substrates and application to in vivo potency estimation. AB - The unbound drug concentration in brain parenchyma is considered to be the relevant driver for interaction with central nervous system (CNS) biological targets. Drug levels in cerebrospinal fluid (C_CSF) are frequently used surrogates for the unbound concentrations in brain. For drugs actively transported across the blood-brain barrier (BBB), C_CSF differs from unbound plasma concentration (Cu_p) to an extent that is commonly unknown. In this study, the relationship between CSF-to-unbound plasma drug partitioning in rats and the mouse Pgp (Mdr1a) efflux ratio (ER) obtained from in vitro transcellular studies has been investigated for a set of 61 CNS compounds exhibiting substantial diversity in chemical structure and physico-chemical properties. In order to understand the in vitro-in vivo extrapolation of Pgp efflux, a mechanistic model was derived relating in vivo CNS distribution kinetics to in vitro active transport. The model was applied to predict C_CSF from Cu_p and ER data for 19 proprietary Roche CNS drug candidates. The calculated CSF concentrations were correlated with CNS pharmacodynamic responses observed in rodent models. The correlation between in vitro and in vivo potency for different pharmacological endpoints indicated that the predicted C_CSF is a valuable surrogate of the concentration at the target site. Overall, C_CSF proved superior description of PK/PD data than unbound plasma or total brain concentration for Mdr1a substrates. Predicted C_CSF can be used as a default approach to understand the PK/PD relationships in CNS efficacy models and can support the extrapolation of efficacious brain exposure for new drug candidates from rodent to man. PMID- 23454190 TI - Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain. AB - Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analyzed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH of IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain. PMID- 23454191 TI - Delayed post-conditioning reduces post-ischemic glutamate level and improves protein synthesis in brain. AB - In the clinic delayed post-conditioning would represent an attractive strategy for the survival of vulnerable neurons after an ischemic event. In this paper we studied the impact of ischemia and delayed post-conditioning on blood and brain tissue concentrations of glutamate and protein synthesis. We designed two groups of animals for analysis of brain tissues and blood after global ischemia and post conditioning, and one for analysis of blood glutamate after transient focal ischemia. Our results showed elevated blood glutamate in two models of transient brain ischemia and decreases in blood glutamate to control in the first 20min of post-conditioning recirculation followed by a consecutive drop of about 20.5% on the first day. Similarly, we recorded reduced protein synthesis in hippocampus and cortex 2 and 3days after ischemia. However, increased glutamate was registered only in the hippocampus. Post-conditioning improves protein synthesis in CA1 and dentate gyrus and, surprisingly, leads to 50% reduction in glutamate in whole hippocampus and cortex. In conclusion, ischemia leads to meaningful elevation of blood and tissue glutamate. Post-conditioning activates mechanisms resulting in rapid elimination of glutamate from brain tissue and/or in the circulatory system that could otherwise impede brain-to-blood glutamate efflux mechanisms. Moreover, post-conditioning induces protein synthesis renewing in ischemia affected tissues that could also contribute to elimination of excitotoxicity. In addition, the potential of glutamate for monitoring the progress of ischemia and efficacy of therapy was shown. PMID- 23454192 TI - Lectin from Canavalia brasiliensis (ConBr) protects hippocampal slices against glutamate neurotoxicity in a manner dependent of PI3K/Akt pathway. AB - The excitotoxicity induced by excessive activation of the glutamatergic neurotransmission pathway is involved in several neuropathologies. In this sense, molecules that prevent the release of glutamate or the excessive activation of its receptors can be useful in preventing the neuronal cell death observed in these diseases. Lectins are proteins capable of reversible binding to the carbohydrates in glycoconjugates, and some have been used in the study and purification of glutamate receptors. ConBr is a mannose/glucose-binding lectin purified from Canavalia brasiliensis seeds. In the present study, we aimed to evaluate the neuroprotective activity of ConBr against glutamate-induced excitotoxicity. Hippocampal slices were isolated from adult male mice and incubated for 6h in Krebs saline/DMEM buffer alone (control), in the presence of glutamate or glutamate plus ConBr. The phosphorylation of Akt and mitogen activated protein kinases (MAPKs) such as ERK1/2, p38(MAPK) and JNK1/2/3 was evaluated with western blotting. The results indicate that glutamate provoked a reduction in the hippocampal slice viability (-25%), diminished the phosphorylation of Akt and augmented p38(MAPK) and ERK1 phosphorylation. No changes were observed in the phosphorylation of JNK1/2/3 or ERK2. Notably, ConBr, through a mechanism dependent on carbohydrate interaction, prevented the reduction of cell viability and Akt phosphorylation induced by glutamate. Furthermore, in the presence of the PI3K inhibitor LY294002, ConBr was unable to reverse glutamate neurotoxicity. Taken together, our data suggest that the neuroprotective effect of ConBr against glutamate neurotoxicity requires oligosaccharide interaction and is dependent on the PI3K/Akt pathway. PMID- 23454193 TI - Increased excitability in tat-transgenic mice: role of tat in HIV-related neurological disorders. AB - HIV-1 associated neurocognitive disorders (HAND) are a major complication of HIV 1 infection. The mechanism(s) underlying HAND are not completely understood but, based on in vitro studies, the HIV-1 Tat protein may play an important role. In this study, the effect of prolonged exposure to endogenously produced Tat in the brain was investigated using a tat-transgenic (TT) mouse model constitutively expressing the HIV-1 tat gene. We found that stimulus-evoked glutamate exocytosis in the hippocampus and cortex was significantly increased in TT as compared with wild-type control (CC) mice, while GABA exocytosis was unchanged in the hippocampus and decreased in the cortex. This suggests that Tat generates a latent hyper-excitability state, which favors the detrimental effects of neurotoxic and/or excitotoxic agents. To challenge this idea, TT mice were tested for susceptibility to kainate-induced seizures and neurodegeneration, and found to exhibit significantly greater responses to the convulsant agent than CC mice. These results support the concept that constitutive expression of tat in the brain generates a latent excitatory state, which may increase the negative effects of damaging insults. These events may play a key role in the development of HAND. PMID- 23454195 TI - Blockage of CR1 prevents activation of rodent microglia. AB - The importance of the complement system in Alzheimer's disease (AD) pathogenesis has been emphasized through recent genome wide association studies. However, the cellular and molecular role of these complement proteins is not fully understood. Microglia express complement receptors and the activation of specific receptors may increase Abeta clearance and reduce neurodegeneration. Here, we investigated the contribution of complement receptor 1 (CR1), the second most significant hit in GWAS studies, on microglia to neuronal damage. We show that microglia displaying an activated phenotype demonstrate an increase in CR1 expression. We also provide evidence that activation of microglial CR1 was detrimental to neurons and this correlated with an increase in microglial intracellular superoxide generation, and tumour necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1beta) secretion. Amyloid-beta 42 (Abeta1-42)-treated microglia displayed an increased ability to phagocytose dextran beads following antibody blockage of CR1 but a decreased capacity to phagocytose fluorescent tagged Abeta1-42. Together, these results indicate that microglial CR1 plays a role in the neuronal death observed in AD and investigating this further may provide a possible strategy to control neurotoxicity in the AD brain. PMID- 23454194 TI - Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury. AB - Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to Alzheimer's disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. PMID- 23454196 TI - A zebrafish model of PINK1 deficiency reveals key pathway dysfunction including HIF signaling. AB - The PTEN induced putative kinase 1 (PINK1) gene is mutated in patients with hereditary early onset Parkinson's disease (PD). The targets of PINK1 and the mechanisms in PD are still not fully understood. Here, we carried out a high throughput and unbiased microarray study to identify novel functions and pathways for PINK1. In larval zebrafish, the function of pink1 was inhibited using splice site morpholino oligonucleotides and the samples were hybridized on a two-color gene expression array. We found 177 significantly altered genes in pink1 morphants compared with the uninjected wildtype controls (log fold change values from -1.6 to +0.9). The five most prominent pathways based on critical biological processes and key toxicological responses were hypoxia-inducible factor (HIF) signaling, TGF-beta signaling, mitochondrial dysfunction, RAR activation, and biogenesis of mitochondria. Furthermore, we verified that potentially important genes such as hif1alpha, catalase, SOD3, and atp1a2a were downregulated in pink1 morphants, whereas genes such as fech, pax2a, and notch1a were upregulated. Some of these genes have been found to play important roles in HIF signaling pathways. The pink1 morphants were found to have heart dysfunction, increased erythropoiesis, increased expression of vascular endothelial growth factors, and increased ROS. Our findings suggest that a lack of pink1 in zebrafish alters many vital and critical pathways in addition to the HIF signaling pathway. PMID- 23454197 TI - Early cortical thickness changes predict beta-amyloid deposition in a mouse model of Alzheimer's disease. AB - Magnetic resonance imaging (MRI) studies have identified aberrant cortical structure in Alzheimer's disease (AD). The association between MRI-derived cortical morphometry measures and beta-amyloid, however, remains poorly understood. In this study, we explored the potential relationship between early alterations in cortical thickness and later stage beta-amyloid deposition, using a novel approach, in a transgenic AD mouse model. We acquired longitudinal anatomical MRI scans from mutant amyloid precursor protein (APP) transgenic mice and age-matched wild-type mice at 1 and 3.5months-of-age, and employed fully automated image processing methods to derive objective, quantitative measures of cortical thickness on a region-of-interest basis. We also generated 3D quantitative immunohistochemistry (qIHC) volumes of deposited beta-amyloid burden from 18month-old transgenic mice using an automated, production-level process. These studies revealed thinner cortex in most regions in the 1month-old transgenic mice relative to age-matched wild-types, with the exception of the frontal, perirhinal/entorhinal, posterior cingulate, and retrosplenial cortical regions. Between 1 and 3.5months-of-age, the transgenic mice demonstrated stable or increasing cortical thickness, while the wild-type mice showed cortical thinning. Based on data from co-registered 3D MRI and qIHC volumes, we identified an association between abnormal, early, regional cortical thickness change over 2.5months and later beta-amyloid deposition. These observations suggest that the spatio-temporal pattern of early (pre-plaque) alterations in cerebral cortical structure is indicative of regional predisposition to later beta-amyloid pathology in a transgenic AD mouse model. PMID- 23454198 TI - The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: evidence for the involvement of astrocytes. AB - Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B1 (B1R) and B2 (B2R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1R mRNA and protein level in the mouse spinal cord 14days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for IL-17, IFN-gamma, IL-6, CXCL 1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up regulation of TNF-alpha and IL-6 release in astrocyte culture. Finally, both B1R and B2R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B1R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS. PMID- 23454199 TI - nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion. AB - It has recently been hypothesized that a sub-lethal ischemic insult induced in one organ is able to protect from a harmful ischemia occurring in a different organ. The objective of this study is to identify new putative mechanisms of neuroprotection elicited by remote ischemic femoral postconditioning. A 50% reduction in the infarct volume was observed when 100min of middle cerebral artery occlusion was followed, 10min later, by the remote postconditioning stimulus represented by 20min of femoral artery occlusion. The use of in vivo silencing strategy allowed to demonstrate that NO production through nNOS mediates part of the neuroprotection. Indeed, whereas CNS nNOS expression was up regulated by remote postconditioning, the pharmacological inhibition of nNOS or its silencing-mediated knocking-down partially prevented this neuroprotective effect. This nNOS overexpression seemed to be p-ERK dependent. In fact, p-ERK expression increased in brain cortex after remote postconditioning, and its pharmacological inhibition prevented both nNOS overexpression and remote postconditioning-mediated neuroprotection. Interestingly, neuroprotection induced by remote postconditioning was partially prevented when ganglion transmission was pharmacologically interrupted by hexamethonium, thus showing that neural factors are involved in this phenomenon. Collectively, the present study demonstrates that p-ERK and nNOS take part to the complex cascade of events triggered by ischemic remote postconditioning. PMID- 23454200 TI - Acetylated methyl 1,2-dideoxyhex-1-enopyranuronates in density functional theory conformational studies. AB - Geometry optimizations at the B3LYP level and single point calculations at the MP2 level are reported for the (4)H(5) and (5)H(4) conformations of methyl 3,4-di O-acetyl-1,2-dideoxy-d-arabino-hex-1-enopyranuronate (methyl 3,4-di-O-acetyl-D glucuronal), and methyl 3,4-di-O-acetyl-1,2-dideoxy-D-lyxo-hex-1-enopyranuronate (methyl 3,4-di-O-acetyl-D-galacturonal). Energy and geometry parameters are presented for the most stable optimized geometries. Conformational analysis of the acetoxy and methoxycarbonyl groups as well as the 1,2-unsaturated pyranoid ring is performed. It is demonstrated that both the acetoxy and methoxycarbonyl groups are planar and prefer cis over trans orientations with respect to the CO-O bond rotations. With regard to the AcO-R bond rotations some of the orientations are forbidden. The (4)H(5)?(5)H(4) conformational equilibrium in both methyl 3,4 di-O-acetyl-D-glucuronal (shifted towards (5)H4) and methyl 3,4-di-O-acetyl-D galacturonal (shifted towards (4)H(5)) is the outcome of the competition between the vinylogous anomeric effect and quasi 1,3-diaxial interactions. It is demonstrated that the orientation of the 4-OAc group influences the strength of the quasi 1,3-diaxial interactions between 3-OAc and 5-COOCH(3) groups. Theoretical results are compared with assignments based on (1)H NMR studies. PMID- 23454201 TI - Preparation of hyaluronan polyaldehyde-a precursor of biopolymer conjugates. AB - Native hyaluronan (HA) has been oxidized to polyaldehyde polymers with a degree of substitution (DS) of up to 50%. Two different procedures enabling the control of the degree of substitution were followed in this study. Selective oxidation of primary hydroxyl groups of N-acetyl-D-glucosamine of hyaluronan was performed either in an aqueous solution containing AcNH-TEMPO/NaBr/NaOCl or in an aprotic solvent containing Dess-Martin periodinane (DMP). It was found that a change of reaction parameters (reaction time and temperature, type of catalyst, oxidant-to HA ratio, presence of nitrogen, buffer type, and concentration) had an influence on the degree of substitution and molecular weight. The derivatives were characterized by MS, NMR spectroscopy, and SEC-MALLS. Degradation of hyaluronic acid by the oxidant was observed and confirmed by SEC. The effect of oxidized derivatives of hyaluronan on cells was studied by means of NIH 3T3 fibroblast viability, which indicates that prepared hyaluronan polyaldehydes are biocompatible and suitable for medical applications and tissue engineering. The function of polyaldehyde as precursor for other modification was illustrated in the reaction with lysine. PMID- 23454202 TI - Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats. AB - SCOPE: To evaluate curcumin loaded solid lipid nanoparticles (C-SLNs) in the experimental paradigm of cerebral ischemia (BCCAO model) in rats. METHODS AND RESULTS: Oral administration of free curcumin and C-SLNs (25 and 50 mg/kg) was started 5 days prior and continued for 3 days after BCCAO. Alleviation in behavioral, oxidative and nitrosative stress, acetylcholinesterase, mitochondrial enzyme complexes, and physiological parameters were assessed. Confirmation of effective brain delivery of C-SLNs (p.o) was done using biodistribution studies in mice and confocal microscopy of rat brain section. There was an improvement of 90% in cognition and 52% inhibition of acetylcholinesterase versus cerebral ischemic group (I/R). Neurological scoring improved by 79%. Levels of superoxide dismutase, catalase, glutathione, and mitochondrial complex enzyme activities were significantly increased, while lipid peroxidation, nitrite, and acetylcholinesterase levels decreased (p<0.05) after C-SLNs administration. It is noteworthy to report the restoration of SOD, GSH, catalase, and mitochondrial complex enzyme levels equivalent to sham control values. Gamma-scintigraphic studies show 16.4 and 30 times improvement in brain bioavailability (AUC) upon oral and i.v administration of C-SLNs versus solubilized curcumin (C-S). CONCLUSIONS: Study indicates protective role of curcumin against cerebral ischemic insult; provided it is packaged suitably for improved brain delivery. PMID- 23454203 TI - Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism. AB - The paullon chalcone derivative KuRei300 is active against Leishmania donovani, the protozoans causing visceral leishmaniasis. The aim of this study was the development of a parenteral formulation of the virtually water insoluble compound in order to enable future studies in mice. Mixed lecithin/bile salt micelles, liposomes, supercooled smectic cholesterol myristate nanoparticles, cubic phase nanoparticles and a triglyceride emulsion were screened for their solubilizing properties. Due to the limited available amount of KuRei300 a passive loading approach with pre-formulated carriers that were incubated with drug substance deposited onto the walls of glass vials was used. The loading capacities of the nanocarriers, the influence of the solid state properties of the drug and its deposits on the loading results and chemical stability aspects of KuRei300 were investigated. Employed methods included HPLC, UV spectroscopy, (1)H NMR, XRPD, and DSC. All nanocarriers substantially improved the solubility of KuRei300; the mixed micelles exhibited the highest drug load. Related to the lipid matrix, however, the smectic nanoparticles solubilized the significantly highest amount of drug. Loading from physically altered drug deposits improved the obtainable concentration to the threefold compared with untreated drug powder. Formulations with KuRei300 must be stored excluded from light under a nitrogen atmosphere as the substance is susceptible to photoisomerization and decomposition. PMID- 23454204 TI - Suppressive chemoprophylaxis invites avoidable risk of serious illness caused by Plasmodium vivax malaria. AB - Despite inadequacy in preventing vivax malaria after travel, suppressive chemoprophylaxis has dominated travel medicine strategy since the advent of chloroquine in 1946. The lethal threat of falciparum malaria versus the perceived benign consequence of vivax malaria underpins this strategic posture. Recent evidence demonstrating vivax malaria as often pernicious should prompt reconsideration of that posture. Causal prophylaxis kills early developing forms of plasmodia in the liver, thus preventing attacks of falciparum and vivax malaria during travel and delayed onset vivax malaria following travel. Primaquine is the only available drug for this application, and has good evidence of safety, tolerability and efficacy in non-pregnant, G6PD-normal travelers. The primaquine label, however, carries no such indication. Risk of pernicious vivax malaria from all across the endemic regions of the globe, including much of sub Saharan Africa, should raise consideration of daily primaquine during travel as the preferred front-line option for chemoprophylaxis against malaria in travelers. PMID- 23454205 TI - The malaria vaccine--status quo 2013. AB - It has been 40 years since David Clyde's landmark induction of sterile immunity against deadly falciparum malaria through immunization by exposure to 1000 irradiated mosquitoes, and the first recombinant Plasmodium falciparum vaccine, RTS,S/AS01, is now in Phase III testing. Interim reports from this largest ever Phase III pediatric trial in Africa show the malaria vaccine decreased clinical and severe disease by 56% and 47% respectively in 5-17 month olds, and by 31% and 26% respectively in infants participating in the Expanded Programme on Immunization. Final data in 2014 will more fully describe the efficacy of RTS,S/AS01 over time against all falciparum malaria cases under a variety of transmission conditions, results essential for decisions on licensure and deployment. Meanwhile, candidate components of a second-generation malaria vaccine are emerging. A field trial of the polymorphic blood stage vaccine AMA 1/AS02 demonstrated no overall efficacy (ve = 17%, P = 0.18), yet a sieve analysis revealed allele-specific efficacy (ve = 64%, P = 0.03) against the vaccine strain, suggesting AMA-1 antigens could be part of a multicomponent vaccine. Initial trials of new antigens include the highly conserved pre erythrocytic candidate PfCelTOS, a synthetic Plasmodium vivax circumsporozoite antigen VMP-001, and sexual stage vaccines containing antigens from both P. falciparum (Pfs25) and P. vivax (Pvs25) intended to interrupt transmission. Targets for a vaccine to protect against placental malaria, the leading remediable cause of low birth weight infants in Africa, have been identified. Lastly, renewed efforts are underway to develop a practical attenuated-sporozoite vaccine to recapture the promise of David Clyde's experiment. PMID- 23454206 TI - Corosolic acid induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro. AB - Corosolic acid (CRA), a triterpenoid from medicinal herbs, has been shown to induce apoptosis in several cell lines, with the exception of A549 cells. In this report, we investigated the apoptotic effect and mechanism of CRA in A549 cells. The present study shows that CRA significantly inhibits cell viability in a concentration- and time-dependent manner. Exposure to CRA induces sub-G1 cell cycle arrest and causes apoptotic death in A549 cells. CRA also triggers the activation of caspases and poly(ADP-ribose) polymerase, an effect antagonized by z-vad-fmk. In addition, exposure to CRA leads to a significant increase in the levels of reactive oxygen species (ROS) in A549 cells. Furthermore, exposure to the ROS scavenger N acetylcysteine (NAC)prevents CRA-induced apoptosis, suggesting a role for ROS in CRA-induced apoptosis. ROS are critical regulators of caspase-mediated apoptosis in A549 cells. These results indicate that CRA induces mitochondria-mediated and caspase-dependent apoptosis in A549 cells by altering anti-apoptotic proteins in a ROS-dependent manner. PMID- 23454207 TI - Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in SD rats. AB - Continuous dopaminergic stimulation (CDS) has been an important strategy of drug development for the treatment of Parkinson's disease (PD). Rotigotine is a non ergoline D3/D2/D1 dopamine agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), a long-acting sustained-release microspheres for injection with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In this study, subchronic toxicity of RoMS in SD rats has been characterized via intramuscular administration with RoMS (0 240 mg/kg/week) on a consecutive weekly dosing schedule for 3 months followed by 1-month recovery period. The No Observed Adverse Effect Level (NOAEL) was 45 mg/kg/week. One male at 240 mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with the dopamine agonist-related pharmacodynamic properties of rotigotine (e.g. hyperactivity and stereotype, enlarged ovary, sporadic gastric mucous membrane lesions, decreased body weight, food consumption and prolactin, and increased mononuclear cell, neutrophil granulocyte, aspartate aminotransferase and alanine aminotransferase) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium. At the end of recovery period, all findings had recovered to a normal level or to a certain degree except foreign body reaction at injection sites. RoMS has exhibited high safety on SD rats. PMID- 23454208 TI - Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells. AB - In this study, we investigated the anti-cancer effects of luteolin, a member of the flavonoid family, in NCI-H460 human lung carcinoma cells. It was shown that luteolin induces apoptotic cell death through modulating both the extrinsic pathway and intrinsic pathways, which are suppressed by z-VAD-fmk, indicating that luteolin triggers caspase-dependant apoptosis. Furthermore, we found that the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha/C/EBP homologous protein pathway, but not the c-Jun N-terminal kinase pathway, played a critical role in induction of apoptosis by luteolin. The data indicated that luteolin also induces autophagy; evidence for this is the accumulation of microtubule-associated protein light chain-3 (LC3) II protein, the increase of LC3 puncta as well as an enhanced autophagy flux. In addition, inhibiting autophagy by bafilomycin A1 reduced apoptotic cell death, suggesting that luteolin-induced autophagy functions as a cell death mechanism. Notably, the activated caspases that appeared with luteolin treatment cleaved Beclin-1, and the expression of LC3II remained the same even after cells were challenged with Beclin-1 siRNA, demonstrating that luteolin induces Beclin-1-independent autophagy. Taken together, our findings showed that luteolin triggers both endoplasmic reticulum stress-related apoptosis and non-canonical autophagy, which function as a cell death mechanism in NCI-H460 human lung cancer cells. PMID- 23454210 TI - The Nap family proteins, CG5017/Hanabi and Nap1, are essential for Drosophila spermiogenesis. AB - Spermiogenesis is a dynamic process leading to alterations in cell morphology. In spermiogenesis, the roles of the histone chaperones are largely unknown. Here, I report the unexpected roles of two Nap family proteins, CG5017/Hanabi and nucleosome assembly protein 1 (Nap1) in Drosophila. Hanabi is mainly localized in the cytoplasm, and the hanabi mutant shows fully scattered nuclei and abnormality of nuclear shaping in spermatid elongation. In contrast, Nap1 is localized at the apical tip of the sperm head, and the nap1 mutant exhibits disruption of the nuclear bundle in the later stage. These findings imply that Nap family proteins might individually sustain cytoskeleton-based morphogenesis, rather than histone biogenesis. PMID- 23454209 TI - Regulated unfolding of proteins in signaling. AB - The transduction of biological signals often involves structural rearrangements of proteins in response to input signals, which leads to functional outputs. This review discusses the role of regulated partial and complete protein unfolding as a mechanism of controlling protein function and the prevalence of this regulatory mechanism in signal transduction pathways. The principles of regulated unfolding, the stimuli that trigger unfolding, and the coupling of unfolding with other well characterized regulatory mechanism are discussed. PMID- 23454211 TI - Disruption of plastid acyl:acyl carrier protein synthetases increases medium chain fatty acid accumulation in seeds of transgenic Arabidopsis. AB - Engineering transgenic plants that accumulate high levels of medium-chain fatty acids (MCFA) has been least successful for shorter chain lengths (e.g., C8). We demonstrate that one limitation is the activity of acyl-ACP synthetase (AAE) that re-activates fatty acids released by acyl-ACP thioesterases. Seed expression of Cuphea pulcherrima FATB acyl-ACP thioesterase in a double mutant lacking AAE15/16 increased 8:0 accumulation almost 2-fold compared to expression in wild type. These results also provide an in planta demonstration that AAE enzymes participate not only in activation of exogenously added MCFA but also in activation of MCFA synthesized in plastids. PMID- 23454212 TI - HIF1-regulated ATRIP expression is required for hypoxia induced ATR activation. AB - The ATR-ATRIP protein kinase complex plays a crucial role in the cellular response to replication stress and DNA damage. Recent studies found that ATR could be activated in response to hypoxia and be involved in hypoxia-induced genetic instability in cancer cells. However, the underlying mechanisms for ATR activation in response to hypoxic stress are still not fully understood. We reported that ATRIP is a direct target of HIF-1. Silencing the expression of HIF 1alpha in cancer cells by RNA interference abolished hypoxia-induced ATRIP expression. Silencing the expression of ATRIP by RNA interference abolished hypoxia induced ATR activation and CHK1 phosphorylation in cancer cells. Taken together, these data shed novel insights on the mechanism of hypoxia-induced activation of the ATR pathway. PMID- 23454213 TI - In vitro bone exposure to strontium improves bone material level properties. AB - In rats treated with strontium ranelate, the ultimate load of intact bone is increased and associated with changes in microstructure and material level properties. Evaluation by micro-computed-tomography-based finite element analysis has shown that these changes independently contribute to the improvement of bone strength induced by strontium ranelate treatment. However, the mechanism by which Sr ion acts on bone material level properties remains unknown. The vertebrae of intact female rats were exposed overnight to 0.5, 1 or 2M chloride salt solutions of Sr, Ca and Ba. The latter two were used to assess the specificity of Sr. Bone material level properties were evaluated by measuring hardness, elastic modulus and working energy in a nanoindentation test. Wavelength dispersive X-ray spectroscopy provided semi-quantitative elemental analysis and mapping. Incubation with Sr rendered bone stiffer, harder and tougher. Among the divalent ions tested, Sr had the greatest effect. Sr affinity was also assessed on in vivo treated bone specimens. After in vitro exposure, the highest improvements were observed in ovariectomized rats. However, anti-osteoporotic treatments did not influence the capacity of Sr to modify bone material level properties. Our findings demonstrated that in vitro incubation with Sr selectively improved bone material level properties, which may contribute to the macroscopic increase of bone properties observed under Sr therapy. PMID- 23454214 TI - Corrosion resistance of a composite polymeric coating applied on biodegradable AZ31 magnesium alloy. AB - The high corrosion rate of magnesium alloys is the main drawback to their widespread use, especially in biomedical applications. There is a need for developing new coatings that provide simultaneously corrosion resistance and enhanced biocompatibility. In this work, a composite coating containing polyether imide, with several diethylene triamine and hydroxyapatite contents, was applied on AZ31 magnesium alloys pre-treated with hydrofluoric acid by dip coating. The coated samples were immersed in Hank's solution and the coating performance was studied by electrochemical impedance spectroscopy and scanning electron microscopy. In addition, the behavior of MG63 osteoblastic cells on coated samples was investigated. The results confirmed that the new coatings not only slow down the corrosion rate of AZ31 magnesium alloys in Hank's solution, but also enhance the adhesion and proliferation of MG63 osteoblastic cells, especially when hydroxyapatite nanoparticles were introduced in the coating formulation. PMID- 23454215 TI - A convenient cellular assay for the identification of the molecular target of ergosterol biosynthesis inhibitors and quantification of their effects on total ergosterol biosynthesis. AB - Increasing resistance of clinically relevant fungi is causing major problems in anti-mycotic therapy. Particularly for immunosuppressed patients fungal infections are of concern and increasing resistance against clinically used antimycotic drugs is hampering successful treatment. In the search for new antifungals ergosterol biosynthesis still is the most prominent target. However, several pitfalls in the bioactivity testing of such substances remain. Two of the major drawbacks certainly are the membrane association of most enzymes participating in ergosterol biosynthesis, and the difficulty to selectively associate growth inhibitory effects with the target pathway (ergosterol biosynthesis). Here we describe a GC-MS based cellular assay for target identification and selective potency determination of test components. In the qualitative part of the assay GC-MS analysis of cell lysates allows target identification by analysis of the changes in the sterol pattern. The quantitative part of the assay makes use of 13C-acetate feeding combined with GC-MS analysis allowing the selective quantification of a compound's effect on total ergosterol biosynthesis. The described cellular assay was analytically and biologically validated and used to characterize the novel ergosterol biosynthesis inhibitor JK 250. PMID- 23454216 TI - Cholesterol suppresses adipocytic differentiation of mouse adipose-derived stromal cells via PPARgamma2 signaling. AB - The effects of cholesterol on cell proliferation and adipocytic differentiation have been evaluated for the first time in mouse adipose-derived stromal cells (mASCs). Cholesterol loading by using cholesterol:methyl- beta-cyclodextrin (Chol:MbetaCD) complexes promoted cellular levels of free cholesterol (FC) and cholesteryl ester (CE), induced high cell proliferation of mASCs dose dependently. Compared with control cells, cholesterol-treated mASCs showed an impaired differentiation process in both dose- and time-dependent manners, based on reduced oil red O-stained lipid droplets, SREBP-1, PPARgamma2 and aP2 expression levels. The involvement of SREBP-1-mediated PPARgamma2 in the effects of cholesterol on mASC adipogenesis was elucidated. These results point to cholesterol as a modulator of adipogenesis, which separate cholesterol itself from other components of modified lipoproteins. PMID- 23454217 TI - Steroids excreted in urine by neonates with 21-hydroxylase deficiency. 4. Characterization, using GC-MS and GC-MS/MS, of 11oxo-pregnanes and 11oxo pregnenes. AB - In 21-hydroxylase deficiency, urinary metabolites of 21-deoxycortisol, mainly derived from its 11oxo form 21-deoxycortisone, are indicators of intra-adrenal overproduction of 17-hydroxyprogesterone. In affected neonates these metabolites are numerous and most have not been previously described. This work forms the concluding part of a comprehensive study of urinary steroids, aiming to enhance the diagnosis of this disorder and to further elucidate steroid metabolism in neonates. Cortisol metabolites found in untreated patients, similarly almost exclusively present in their 11oxo form in neonates, have been included for completeness. Steroids were analyzed, after extraction and enzymatic conjugate hydrolysis, as methyloxime-trimethylsilyl ether derivatives on gas-chromatographs coupled to quadrupole and ion-trap mass-spectrometers. GC-MS and GC-MS/MS spectra were used together to determine the structure of hitherto undescribed 11oxo pregnane(enes). Few GC-MS features were associated with the presence of the non derivatizeable 11oxo group in pregnane(ene)s. GC-MS/MS contributed only to the characterization of structures outside the C-ring, as described in the preceding parts of this study. Parallels were found between the metabolism of 21 deoxycortisone and cortisone. The major metabolic pathway was that of classical 3alpha,5beta-reduction with a prominent further hydroxylation, predominantly at C6. Oxidation of the 6-hydroxyl was also common. We conclude that further oxygenated metabolites of 21-deoxycortisone have potential as more reliable markers of 21-hydroxylase deficiency in the early neonatal period, because their levels are higher during that period of life than for the classical marker 11oxo pregnanetriol. PMID- 23454218 TI - Agaricus bisporus and related Agaricus species on lignocellulose: production of manganese peroxidase and multicopper oxidases. AB - Biotechnological, microbiological, and genetic studies of Agaricus species other than A. bisporus, the white button mushroom, have been limited so far. To expand the knowledge in the genus Agaricus, six novel wild-type isolates of Agaricus spp. were studied on their nutritional demands for enzyme production and mycelial growth. All the selected Agaricus species produced extracellular manganese peroxidase (MnP) and laccase activities in semi-solid rye bran cultures. Moderate MnP activities were measured for A. bisporus, A. bernardii and A. campestris. The highest laccase activities were obtained for A. bisporus and A. campestris. On soy medium, the highest mycelial tyrosinase activity was determined for A. bernardii. For A. bisporus, addition of copper caused no increase in laccase or tyrosinase activities on soy or malt extract media. Hyphal growth rate of the isolates was studied on lignocellulose amended agar plates. Fastest growth was obtained for A. bisporus on wheat bran and birch leaf litter agar. Except for A. bernardii, hyphal growth rates correlated well with MnP and laccase production levels between Agaricus species. Molecular taxonomy of the novel Agaricus spp. positioned them to distinct phylogenetic clusters with species-level identity. In conclusion, our data point to the importance of both MnP and multicopper enzymes in Agaricus spp. while growing on lignocelluloses. PMID- 23454219 TI - The impact of incarceration on juvenile offenders. AB - Increasingly, research points to the negative effects of incarcerating youth offenders, particularly in adult facilities. Literature published since 2000 suggests that incarceration fails to meet the developmental and criminogenic needs of youth offenders and is limited in its ability to provide appropriate rehabilitation. Incarceration often results in negative behavioral and mental health consequences, including ongoing engagement in offending behaviors and contact with the justice system. Although incarceration of youth offenders is often viewed as a necessary means of public protection, research indicates that it is not an effective option in terms of either cost or outcome. The severe behavioral problems of juvenile offenders are a result of complex and interactive individual and environmental factors, which elicit and maintain offending behavior. Therefore, the focus of effective treatment must be on addressing such criminogenic needs and the multiple "systems" in which the young person comes from. Recent research demonstrates that in order to achieve the best outcomes for youth offenders and the general public, community-based, empirically supported intervention practices must be adopted as an alternative to incarceration wherever possible. PMID- 23454220 TI - Specificity of psychological treatments for bulimia nervosa and binge eating disorder? A meta-analysis of direct comparisons. AB - Treatment guidelines state that cognitive-behavioral therapy (CBT) and interpersonal therapy are the best-supported psychotherapies for bulimia nervosa (BN) and that CBT is the preferred psychological treatment for binge eating disorder (BED). However, no meta-analysis which both examined direct comparisons between psychological treatments for BN and BED and considered the role of moderating variables, such as the degree to which psychotherapy was bona fide, has previously been conducted Thus, such an analysis was undertaken. We included 77 comparisons reported in 53 studies. The results indicated that: (a) bona fide therapies outperformed non-bona fide treatments, (b) bona fide CBT outperformed bona fide non-CBT interventions by a statistically significant margin (only approaching statistical significance for BN and BED when examined individually), but many of these trials had confounds which limited their internal validity, (c) full CBT treatments offered no benefit over their components, and (d) the distribution of effect size differences between bona fide CBT treatments was homogeneously distributed around zero. These findings provide little support for treatment specificity in psychotherapy for BN and BED. PMID- 23454221 TI - Life events and treatment outcomes among individuals with substance use disorders: a narrative review. AB - Substance use disorders are characterized by a variable course, in which multiple treatment attempts and relapses are typical. Consistent with conceptualizations of substance use and relapse, life events have been implicated in contributing to poor substance use disorders treatment outcomes. However, inconsistencies in empirical findings regarding the life events-substance use disorders outcome literature have been previously observed. This review provides an updated critique of the literature since the previous review published in 1987 (O'Doherty & Davies, 1987), examining the relationship between life events and substance use disorders treatment outcome among clinical samples of individuals. Review of 18 peer-reviewed articles suggested that data on the life events-outcome relationship continue to be inconclusive. Inconsistencies across studies in the operationalization of life events and substance use treatment outcomes and lack of theoretically driven designs may be contributing to differences in findings. Recommendations for future research that will increase the clinical utility of the life events construct are provided. PMID- 23454222 TI - A systematic review of methods for assessing competence in cognitive-behavioural therapy. AB - Effective assessment of Cognitive Behaviour Therapy (CBT) competence is crucial to the success of the current drive to expand CBT training and service provision, and to the widespread dissemination of CBT into routine practice. However, a lack of consensus about how CBT competence should be assessed has resulted in the use of numerous different methods, many of which have been widely criticised. This review describes and evaluates the various methods of assessing CBT competence. A systematic literature search identified 64 articles pertaining to a method of assessing competence in the provision of standard CBT interventions to adults experiencing mental health problems. Ten methods for assessing CBT therapist competence were identified from these articles and are presented within Miller's (Miller, G. E. [1990]. The assessment of clinical skills/competence/performance. Academic Medicine, 65, 63-67) framework for assessing clinical skill. The advantages and disadvantages of each method are examined in relation to reliability, validity and feasibility. The limitations of the current evidence base are outlined and priorities for future research are highlighted. Tentative recommendations for assessing therapist competence are made within the context of the limited evidence base and need for feasibility in clinical practice settings. PMID- 23454223 TI - Real-time analysis of membrane permeabilizing effects of oleanane saponins. AB - Saponins are a group of plant and marine derived glycosides with numerous biological functions. Two important characteristics of certain plant saponins are their ability to enhance cytotoxicity of type I ribosome inactivating proteins and stimulation of the immune system. The main objective of the present study was to investigate in real-time the permeabilizing effects of saponins on cell membrane. A set of oleanane saponins (glycyrrhizinic acid, Gypsophila, Saponaria and Quillaja saponins) and a steroid saponin (digitonin) were tested. The effects of these saponins on lysosomal membranes and hemolysis, along with their charge were also studied. Real-time monitoring of cell membrane permeabilization facilitated a highly sensitive analysis of the cellular kinetics. Saponins showed variable permeabilizing effects on cellular and lysosomal membranes at concentrations from 6 MUM and hemolysis from 3 MUM. Further, the results suggest that charge of the saponin may be relevant for permeabilizing effects of oleanane saponins. PMID- 23454224 TI - Association between serum zinc concentration and the Plasmodium falciparum antibody titer among rural villagers of Attapeu Province, Lao People's Democratic Republic. AB - Experimental studies have indicated that low serum zinc levels affect immune responses. However, few studies have evaluated the impact of serum zinc levels on antibody responses in the field in developing countries. We investigated an association between the anti-Plasmodium falciparum (Pf) antibody (immunoglobulin G) titer and serum zinc concentration among villagers in rural areas of the Lao People's Democratic Republic. Blood samples were collected to detect Pf infection. An enzyme-linked immunosorbent assay (ELISA) was used to measure the anti-PfIgG antibody titer. Each serum sample was assayed to measure the concentration of zinc. Pearson's correlation coefficient was applied to the association between zinc concentration and anti-PfIgG antibody titers. Multiple linear regression analysis was used to assess the association between zinc concentration and anti-PfIgG antibody titers, controlling for age and albumin level. Of 71 blood samples, 40 were Pf positive and 31 were Pf negative. The median serum zinc concentrations were 56.0 MUg/dl in the Pf-positive group and 62.5 MUg/dl in the Pf-negative group. The median anti-Pf titers were 833.4 in the positive group and 1237.2 in the negative group. Unexpectedly, there was a negative correlation between serum zinc and anti-Pf IgG antibody titers; the correlation coefficient were -0.453 and (p=0.003) in the positive group and 0.461 (p=0.009) in the negative group. The results of this study indicated sustained antibody responses among the villagers, who had likely been exposed to malaria periodically throughout their lives. Further studies are necessary to determine the conditions in which zinc could be effective against malaria. PMID- 23454225 TI - Compatibility of Ugandan Schistosoma mansoni isolates with Biomphalaria snail species from Lake Albert and Lake Victoria. AB - In order to investigate the capacity of being intermediate host for Schistosoma mansoni, the Ugandan F1 generation of Biomphalaria snail species that were laboratory-bred from parent populations originally collected from either Lake Victoria or Lake Albert was challenged with sympatric and non-sympatric S. mansoni isolates. After a prepatent period of 20 days, a daily 10-hourly snail shedding for cercariae was done to determine the infection rate, cercarial production per hour and survival period of infected snails. The study suggests that when parasite strains from a different geographical origin is used for infection, survival of infected snails increase, leading to an increased transmission potential. Although earlier literature had indicated that the Lake Victoria Biomphalaria sudanica is refractory to S. mansoni, we showed that all Ugandan Biomphalaria spp., including B. sudanica from all locations, were highly susceptible to the S. mansoni isolates. Thus if B. choanomphala, which is an efficient intermediate host in Lake Victoria, is given an opportunity to occupy Lake Albert, it will most likely be compatible with the Albertine S. mansoni parasites. Equally, if B. stanleyi, currently restricted to Lake Albert invades Lake Victoria, it is likely to act as an efficient intermediate host. Future work should concentrate on intraspecific population-level differences in compatibility. PMID- 23454226 TI - Biofilm formation on denture liners in a randomised controlled in situ trial. AB - OBJECTIVES: This randomised clinical trial assessed how biofilm development and composition is affected by time and denture material type in denture wearers with and without denture stomatitis. METHODS: Specimens of acrylic resin (control) and denture liners (silicone-based or acrylic resin based, depending on the experimental phase) were inserted into the surface intaglio of 30 denture wearers. Biofilm was formed in two phases of 21 days, and counts of viable micro organisms in the accumulating biofilm were determined after 7, 14 and 21 days of biofilm formation. Data were analysed by three-way ANOVA followed by Tukey test to assess differences among health condition (healthy or with denture stomatitis), materials and time point. RESULTS: Non-albicans Candida species counts were higher in diseased patients with silicone-based denture liners (p=0.01). Denture stomatitis patients showed higher mutans streptococci counts after 7 days (p=0.0041). CONCLUSIONS: Longer biofilm formation time periods did not result in differences on biofilm composition. The denture liners evaluated in this study accumulate greater amount of biofilm, and therefore their use should be carefully planned. CLINICAL SIGNIFICANCE: The silicone-based denture liner tested should be used cautiously in patients with denture stomatitis as it showed increased non-albicans species counts, known to be difficult to treat. PMID- 23454227 TI - The effect on health of switching from cigarettes to snus - a review. AB - Interest in snus (Swedish type moist snuff) as an alternative to smoking is increasing, but the evidence on the health effects of switching from cigarettes to snus has not previously been reviewed. We identified six epidemiological cohort or case-control studies, all from Sweden, which allowed comparison of cancer or cardiovascular disease risk in current snus users who formerly smoked ("switchers") with that of never snus users who continued to smoke ("continuers") or of never snus users who quit smoking ("quitters"). Based on 13 sets of comparisons, one for oral cancer, one for stomach cancer and 11 for various cardiovascular disease endpoints, switchers were consistently found to have a lower risk than continuers, with relative risks varying from 0.35 to 0.61, and a similar risk to quitters. Based on estimates from four studies for ischaemic/coronary heart disease or acute myocardial infarction, meta-analyses gave combined relative risk estimates of 0.55 (95% confidence interval 0.45-0.68) for switchers vs. continuers and 1.02 (95% confidence interval 0.83-1.26) for switchers vs. quitters. Though based on limited evidence with some weaknesses, these results are consistent with a recent review which found no increased risk of cancer or heart disease from snus use. PMID- 23454228 TI - The network level reproduction number for infectious diseases with both vertical and horizontal transmission. AB - A wide range of infectious diseases are both vertically and horizontally transmitted. Such diseases are spatially transmitted via multiple species in heterogeneous environments, typically described by complex meta-population models. The reproduction number, R0, is a critical metric predicting whether the disease can invade the meta-population system. This paper presents the reproduction number for a generic disease vertically and horizontally transmitted among multiple species in heterogeneous networks, where nodes are locations, and links reflect outgoing or incoming movement flows. The metapopulation model for vertically and horizontally transmitted diseases is gradually formulated from two species, two-node network models. We derived an explicit expression of R0, which is the spectral radius of a matrix reduced in size with respect to the original next generation matrix. The reproduction number is shown to be a function of vertical and horizontal transmission parameters, and the lower bound is the reproduction number for horizontal transmission. As an application, the reproduction number and its bounds for the Rift Valley fever zoonosis, where livestock, mosquitoes, and humans are the involved species are derived. By computing the reproduction number for different scenarios through numerical simulations, we found the reproduction number is affected by livestock movement rates only when parameters are heterogeneous across nodes. To summarize, our study contributes the reproduction number for vertically and horizontally transmitted diseases in heterogeneous networks. This explicit expression is easily adaptable to specific infectious diseases, affording insights into disease evolution. PMID- 23454229 TI - Prototype of integrated pseudo-dynamic crosstalk network for cancer molecular mechanism. AB - In this study, we attempted to solve two important challenges in systems biology. First, although the Michaelis-Menten (MM) model provides local kinetic information, it is hard to generalize MM models to model a large system because increasingly large amounts of experimental data are necessary for the parameter identification. In addition, it is not possible to develop an MM model that provides information about the strength of the interactions in the system. Second, although the dynamic simulation of various signal transduction pathways is important in cancer research, it is impossible to theoretically derive a mathematical model to describe the cancer molecular mechanism. Predictive computational approaches can be used to analyze the dynamics of a system and to determine the dysfunction of a regulatory process. In this report, we first propose a pseudo-dynamic pathway to describe protein interactions in an MM system. We then discuss the dynamic behavior of two large-scale systems (antigrowth-signal-induced cell cycle and apoptotic-signal-transduction mechanism). These two systems were constructed through the in-series and organic integration, respectively, of MM modules with Petri net modules; moreover, more than 30% additional reactions were added during this integration step. We then described an extremely large multi-stream system (growth signal transduction); however, the analysis of this system to obtain dynamic predictions is critical but appears impossible. Thus, we introduced a fuzzy concept that can be used to develop a physically realizable model prototype. In the future, through step-by step in vivo modifications, researchers will be able to develop a complete model of cancer metabolism to achieve accurate predictions. PMID- 23454230 TI - Age- and gender-related metabonomic alterations in striatum and cerebellar cortex in rats. AB - In order to identify the neurochemical alterations in motor associated subcortical nuclei, and enhance our understanding of neurophysiology of progressive reduction in fine motor control with aging, the metabolic changes in striatum and cerebellar cortex in SD rats along with aging were investigated using a metabonomic approach based on high resolution "magic angle spinning" 1H NMR spectroscopy and partial least squares-discriminant analysis. It was found that there were increased myo-inositol and lactate, and decreased taurine in these two brain regions of old rats. The above changes may be a marker for alterations of neuronal cells, which reduce fine motor control. Besides, some of the metabolites are gender-related and region-specific. Old female rats had decreased glutamate and increased creatine in striatum, while old male rats had increased choline in striatum, and increased GABA in cerebellar cortex, respectively. However, further analyses showed that most of the metabolites in male rats were not distinctively different with those of female ones except choline, which was in a relative lower level in striatum of male rats. All this results suggest that energy metabolism is an important indication of age-related change, which is not only in male, but also in female rats. PMID- 23454231 TI - L-carnosine inhibits neuronal cell apoptosis through signal transducer and activator of transcription 3 signaling pathway after acute focal cerebral ischemia. AB - Considerable studies have showed that L-carnosine provides anti-oxidative and anti-apoptotic roles in the animal models of global or focal cerebral ischemia. However, the anti-apoptotic mechanisms of L-carnosine in the focal cerebral ischemia model have yet to be elucidated. To investigate the molecular mechanisms, rat models of permanent middle cerebral artery occlusion (pMCAO) and sham operation were first established and then pMCAO and sham-operated rats were treated with L-carnosine or vehicle alone. After this treatment, neurological deficits were evaluated at 12, 24 and 72 h after operation and the infarct volume was measured at 72 h after treatment. In addition, we also detected the mRNA expression of signal transducer and activator of transcription 3 (STAT3) and Pim 1 and the protein expression of phosphorylated STAT3, Pim-1, bcl-2 and cleaved caspase-3 at 12, 24 and 72 h post-pMCAO. Our results showed that the L-carnosine treated rats had milder neurological deficits and smaller infarct volume and showed up-regulated expression in mRNA levels of STAT3 and Pim-1 than vehicle treated rats at 72 h after treatment. Meanwhile, compared with vehicle-treated rats, the L-carnosine-treated rats exhibited higher protein expressions of pSTAT3, Pim-1 and bcl-2 but lower expression of cleaved caspase-3 protein at 72 h following operation. These results indicate that L-carnosine plays an important role in inhibiting neuronal cell apoptosis through STAT3 signaling pathway after acute cerebral ischemia. PMID- 23454232 TI - Regional phenotypes of cellular prion proteins in human brains identified by differential detergent solubility. AB - A hallmark of prion diseases is the accumulation of disease-associated isoforms (PrP(Sc)) which results from the conversion of host-encoded cellular prion proteins (PrP(C)). Using molecular biochemistry, several disease variants of the human Creutzfeldt-Jakob disease have been identified showing several PrP(Sc) variants in individuals and selective accumulation in specific brain regions. As PrP(C) is differentially expressed and post-translationally modified, certain distinct protein compositions may have the ability to convert more efficiently than others. The PrP(C) glycoprotein moiety represents a single yet divers mixture, but little is known about its exact composition. In this study, we separated and characterized PrP(C) derived from six defined human brain regions in regard to their solubility in several detergent solutions and glycoprotein profile formation. We identified four different but regionally distinct protein compositions. PrP(C) found in the neocortex exhibited dominant diglycosylated bands in the high as well as in the low soluble fractions. The proteins in the nucleus lentiformis, thalamus and hippocampus were more soluble with deoxycholic acid as the N-octyl-beta-d-glucopyranoside and the diglycosylated bands displayed strong signals in the supernatants and weaker signals in the sediments. Two different protein profiles were established with PrP(C) derived from the medulla oblongata and the solubility of PrP(C) in the cerebellum clearly differed by the choice of detergent. Our findings indicate the existence of several distinct PrP(C) compositions localized in distinct brain regions. Protein variations may be induced by specific modifications to specific regional biological functions. PMID- 23454233 TI - Role of nicotine on cognitive and behavioral deficits in sepsis-surviving rats. AB - Sepsis and its complications are important causes of mortality in intensive care units and sepsis survivors may present long-term cognitive and emotional impairments, including memory deficits and anxiety symptoms. In the present study, we investigated whether repeated nicotine administration can affect the behavioral changes in sepsis-surviving rats. Male Wistar rats were divided in two groups: sham-operated and experimental sepsis induced by cecal ligation and puncture (CLP). The animals were injected subcutaneously with nicotine (0.1 mg/kg) or vehicle once a day during 1 week before and/or 1 week after sepsis induction. Thirty minutes after the last administration (i.e., 7 days after surgery), the animals were tested in the open field, elevated plus-maze and step down inhibitory avoidance tasks. The repeated nicotine treatment did not affect the survival rate in the sepsis group (50%). Moreover, no significant changes on locomotor activity were observed in the sepsis group while the treatment with nicotine during 1 week after surgery reduced the locomotion of sepsis-surviving rats in the open field. It is important to note that both schedules of nicotine treatment (prior and/or after CLP) improved the sepsis-induced anxiogenic-like responses. Interestingly, nicotine was able to improve short- and long-term inhibitory avoidance memory impairments, observed in sepsis survivors, only when administered during 2 consecutive weeks (i.e., prior and after CLP). Taken together, these results indicate that repeated nicotine administration does not alter the survival rate in rats submitted to CLP and provide new evidence that nicotine can improve long-lasting memory impairments and anxiogenic-like responses in sepsis-surviving animals. PMID- 23454234 TI - Increased susceptibility to pentetrazol-induced seizures in developing rats after cortical photothrombotic ischemic stroke at P7. AB - Perinatal stroke is a common cerebrovascular disorder affecting 1 in every 4000 births; typically associated with epilepsy. We sought to determine seizure susceptibility to pentylentetrazol (PTZ)-induced seizures in developing rats with a history of photothrombotic lesion of sensorimotor cortex induced at postnatal day 7. Lesioned animals were tested at P12 or P25 and compared with sham-operated controls. Three models of epileptic seizures were elicited by PTZ: episodes of spike-and-wave rhythm, minimal clonic seizures and generalized tonic-clonic seizures. PTZ (60 and 100 mg/kg) was administered subcutaneously to assess seizure occurrence, latency and severity. In addition, episodes of rhythmic EEG activity were analyzed at P25 following successive interperitoneal 20 and 40 mg/kg PTZ administration. There was only one significant change in convulsive seizures--decreased latency of generalized seizures in lesioned 12-day-old animals. EEG study demonstrated marked difference between lesioned and control rats. Lesioned rats had longer latencies and longer durations of the first rhythmic episode (following 20 mg/kg PTZ) as compared to controls. After 40 mg/kg of PTZ, 7 in 8 leisioned and 1 in 8 control rats exhibited clonic seizures. Cortical ischemic lesion during early development affected differently the susceptibility of rat's brain to three types of PTZ-induced seizures 5 and 18 days post photothrombotic insults. PMID- 23454235 TI - Multiscale physics of ion-induced radiation damage. AB - This is a review of a multiscale approach to the physics of ion-beam cancer therapy, an approach suggested in order to understand the interplay of a large number of phenomena involved in the radiation damage scenario occurring on a range of temporal, spatial, and energy scales. We describe different effects that take place on different scales and play major roles in the scenario of interaction of ions with tissue. The understanding of these effects allows an assessment of relative biological effectiveness that relates the physical quantities, such as dose, to the biological values, such as the probability of cell survival. PMID- 23454236 TI - Heterochromatinization associated with cell differentiation as a model to study DNA double strand break induction and repair in the context of higher-order chromatin structure. AB - Cell differentiation is associated with extensive gene silencing, heterochromatinization and potentially decreasing need for repairing DNA double strand breaks (DSBs). Differentiation stages of blood cells thus represent an excellent model to study DSB induction, repair and misrepair in the context of changing higher-order chromatin structure. We show that immature granulocytes form gammaH2AX and 53BP1 foci, contrary to the mature cells; however, these foci colocalize only rarely and DSB repair is inefficient. Moreover, specific chromatin structure of granulocytes probably influences DSB induction. PMID- 23454237 TI - The dichotomy of neutrophil granulocytes in cancer. AB - Neutrophil granulocytes are known for decades as central effector cells of the innate immune system. Because of their ability to rapidly recognize, take up and eliminate pathogens, these cells ensure the survival of the host before the onset of adaptive immunity. In tumor immunology neutrophils have long been ignored or at least underestimated, because the field focused on adaptive and antigen specific anti-tumor immunity with tumor antigens, dendritic cells and T cells as the main players. More recently, the role of inflammation during tumor initiation and progression has raised considerable interest in the field. It is not surprising that neutrophils as primary inflammatory cells have also entered the arena of the immunologic tumor host interaction. PMID- 23454238 TI - Nuclear architecture and chromatin structure on the path to cancer. PMID- 23454239 TI - Inhibitory effects of cytoskeleton disrupting drugs and GDP-locked Rab mutants on bradykinin B2 receptor cycling. AB - The bradykinin (BK) B2 receptor (B2R) is G protein coupled and phosphorylated upon agonist stimulation; its endocytosis and recycling are documented. We assessed the effect of drugs that affect the cytoskeleton on B2R cycling. These drugs were targeted to tubulin (paclitaxel, or the novel combretastatin A-4 mimetic 3,4,5-trimethoxyphenyl-4-(2-oxoimidazolidin-1-yl)benzenesulfonate [IMZ 602]) and actin (cytochalasin D). Tubulin ligands did not alter agonist-induced receptor endocytosis, as shown using antibodies reactive with myc-tagged B2Rs (microscopy, cytofluorometry), but rather reduced the progression of the ligand receptor-beta-arrestin complex from the cell periphery to the interior. The 3 fluorescent probes of this complex (B2R-green fluorescent protein [B2R-GFP], the fluorescent agonist fluorescein-5-thiocarbamoyl-D-Arg-[Hyp3, Igl5, Oic7, Igl8]-BK and beta-arrestin2-GFP) were condensed in punctuate structures that remained close to the cell surface in the presence of IMZ-602. Cytochalasin D selectively inhibited the recycling of endocytosed B2R-GFP (B2R-GFP imaging, [3H]BK binding). Dominant negative (GDP-locked)-Rab5 and -Rab11 reproduced the effects of inhibitors of tubulin and actin, respectively, on the cycling of B2R-GFP. GDP locked-Rab4 also inhibited B2R-GFP recycling to the cell surface. Consistent with the displacement of cargo along specific cytoskeletal elements, Rab5-associated progression of the endocytosed BK B2R follows microtubules toward their (-) end, while its recycling progresses along actin fibers to the cell surface. However, tubulin ligands do not suppress the tested desensitization or resensitization mechanisms of the B2R. PMID- 23454240 TI - Semantically predicting protein functions based on protein functional connectivity. AB - BACKGROUND: The current availability of public protein-protein interaction (PPI) databases which are usually modelled as PPI networks has led to the rapid development of protein function prediction approaches. The existing network-based prediction approaches mainly focus on the topological similarities between immediately interacting proteins, neglecting the protein functional connectivity which is the functional tightness between proteins. In this paper, we attempt to predict the functions of unannotated proteins based on PPI networks by incorporating the protein functional connectivity, as well as the similarity of protein functions, into the prediction procedure. RESULTS: An approach named Semantic protein function Prediction based on protein Functional Connectivity (SPFC) is proposed to achieve a higher accuracy in predicting functions of unannotated protein. We define the functional connectivity and function addition for each protein, and incorporate them into the prediction. We evaluated the SPFC on real PPI datasets and the experiment results show that the SPFC method is more effective in function prediction than other network-based approaches. CONCLUSION: Incorporating the functional connectivity of each protein into the function prediction can significantly improve the accuracy of protein prediction. PMID- 23454241 TI - Steroid withdrawal and reduction of cyclosporine A under mycophenolate mofetil after heart transplantation. AB - Survival and quality of life after heart transplantation are limited by a significant incidence of cardiovascular complications. Side effects of immunosuppressives contribute unfavorably. Aim of this study was to determine (1) whether withdrawal of corticosteroids and dose reduction of cyclosporine A can be performed safely under immunosuppressive therapy with mycophenolate mofetil and (2) if this is beneficial for renal function and cardiovascular risk reduction. Long term heart transplant recipients on steroids and cyclosporine A were examined in a monocentric, prospective, single-arm cohort study. Steroids were withdrawn, mycophenolate mofetil introduced and cyclosporine A dose reduced (target level 50-90 ng/ml). Follow up was 24 months. 23 patients were analyzed: Renal parameters (creatinine, urea, uric acid) improved significantly (p<0.01), as did cardiovascular parameters (heart rate [p<0.05], systolic and diastolic blood pressure [p<0.01]), HbA1c (p<0.05) and triglycerides (p<0.05). In contrast, the self-percepted state of health (SF36TM) decreased. Drop outs occurred mostly due to steroid withdrawal syndrome [n=7]. The incidence of adverse events reflected the usual course after heart transplantation. We conclude that CS free immunosuppression comprising reduced cyclosporine levels and addition of MMF in long term heart transplant recipients is safe and improves the cardiovascular risk profile, carbohydrate metabolism and renal function. PMID- 23454243 TI - Gallstone size related to incidence of post cholecystectomy retained common bile duct stones. AB - INTRODUCTION: The morbidity of unexpected retained common bile duct (CBD) stones after cholecystectomy is a significant problem. We hypothesise that smaller size gallstones are associated with a higher incidence of this condition. METHOD: A retrospective analysis of emergency and elective cholecystectomies was performed between Oct 2004-Aug 2009 at our hospital. Gallstone number and size in the histological report for each patient was recorded. Only proven CBD stones found on ERCP performed on patients with unexpected readmissions within a six month period of their surgery were included. RESULTS: In total 1085 cholecystectomies met the inclusion criteria during this period and were considered in the study, 98 emergency, 987 elective. Of the patients, 809 were female, 206 were male, median age 50 (range 19-92). 25 patients, 2.3% as overall incidence, had a subsequent post-operative ERCP confirming retained CBD stones (median gallstone size 5 mm). The remaining 1060 patients did not present with complications relating to a proven retained CBD stone (median gallstone size 14 mm), p = 0.012. DISCUSSION: Patients who had small gallstones were significantly more likely to represent with retained CBD stones. Multiple gallstones within the gallbladder also seemed to be significant risk factor. We were unable to correlate an emergency procedure, patient sex or age as being higher risk groups for retained CBD stones. If gallstone number and size can accurately be determined by pre operative imaging then it is patients with multiple small stones that should be most rigorously targeted for intra operative CBD assessment and action if found. PMID- 23454242 TI - Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. AB - Protein Phosphatase 2A (PP2A) is an important and ubiquitously expressed serine threonine phosphatase and regulates the function by dephosphorylating many critical cellular molecules like Akt, p53, c-Myc and beta-catenin. It plays a critical role in cellular processes, such as cell proliferation, signal transduction and apoptosis. Structurally, it is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. PP2A undergoes post-translational modifications (i.e. phosphorylation and methylation), which in turn, regulates its enzymatic activity. Aberrant expression, mutations and somatic alterations of the PP2A scaffold and regulatory subunits have been observed in various human malignancies, including lung, breast, skin and colon cancer, highlighting its role as a 'tumor suppressor'. This review is focused on the structural complexity of serine/threonine phosphatase PP2A and summarizes its expression pattern in cancer. Additionally, the PP2A interacting and regulatory proteins and substrates are also discussed. Finally, the mouse models developed to understand the biological role of PP2A subunits in an in vivo model system are also reviewed in this article. PMID- 23454244 TI - The management of perforated gastric ulcers. AB - INTRODUCTION: Perforated gastric ulcers are potentially complicated surgical emergencies and appropriate early management is essential in order to avoid subsequent problems including unnecessary gastrectomy. The aim of this study was to examine the management and outcome of patients with gastric ulcer perforation undergoing emergency laparotomy for peritonitis. METHODS: Patients undergoing laparotomy at the Royal Infirmary of Edinburgh for perforated gastric ulcers were identified from the prospectively maintained Lothian Surgical Audit (LSA) database over the five-year period 2007-2011. Additional data were obtained by review of electronic records and review of case notes. RESULTS: Forty-four patients (25 male, 19 female) were identified. Procedures performed were: 41 omental patch repairs (91%), 2 simple closures (4.5%) and 2 distal gastrectomies (4.5%; both for large perforations). Four perforated gastric tumours were identified (8.8%), 2 of which were suspected intra-operatively and confirmed histologically, 1 had unexpected positive histology and 1 had negative intra operative histology, but follow-up endoscopy confirmed the presence of carcinoma (1 positive biopsy in 21 follow-up endoscopies); all 4 were managed without initial resection. Median length of stay was 10 days (range 4-68). Overall 7 patients died in hospital (15.9%) and there were 21 morbidities (54.5%). Registrars performed the majority of the procedures (16 alone, 21 supervised) with no significant difference in post-operative morbidity (P = 0.098) or mortality (P = 0.855), compared to consultants. CONCLUSION: Almost all perforated gastric ulcers can be effectively managed by laparotomy and omental patch repair. Initial biopsy and follow-up endoscopy with repeat biopsy is essential to avoid missing an underlying malignancy. PMID- 23454245 TI - A new flow cytometry method to measure oxidative status: the Peroxidation of Leukocytes Index Ratio (PLIR). AB - BACKGROUND AND AIM: A complex relationship between immune system and metabolic pathway exists and can induce oxidative stress. The objective of this study was to design a new methodology allowing the measurement of oxidative status of leukocytes. METHODS AND RESULTS: We developed a flow cytometry technique, based on C11-BODIPY 581/591 staining, to evaluate peroxidation in leukocytes. We defined the Peroxidation of Leukocytes Index Ratio (PLIR) as the ratio between the damage after AAPH-induced and PMA-induced peroxidation, using Trolox as standard antioxidant. Sensitivity of the method was assessed by correlating results with plasma antioxidant capacity (TRAP and FRAP), levels of endogenous antioxidants (uric acid and sulfhydryls) and markers of metabolic status (cholesterol, triglycerides, glucose and insulin). PLIR measures the ratio between the resistance to exogenous and endogenous ROS injury, independently from baseline level of oxidation, which was directly correlated with plasma cholesterol on lymphocytes (0.738, p=0.029), monocytes (0.691, p=0.047) and neutrophils (0.690, p=0.047). PLIR of lymphocytes was inversely correlated with uric acid (-0.810, p=0.009) and FRAP (-0.738, p=0.029) levels. On the other hand, PLIR of monocytes was directly correlated with the total scavenger antioxidant capacity attributable to nutritional antioxidants (0.738, p=0.029), calculated as the difference between TRAP and the contribution of uric acid and sulfhydryls to its value. CONCLUSIONS: This study reports a feasible and reproducible new flow cytometry assay for assessing the leukocytes redox status. PLIR discriminates between reducing and scavenger activities and is able to appreciate the potentially dangerous effect of uric acid on innate immune response. PMID- 23454246 TI - Evaluation of IgY capture ELISA for sensitive detection of alpha hemolysin of Staphylococcus aureus without staphylococcal protein A interference. AB - Staphylococcal protein A (Spa) secreted by all Staphylococcus aureus strains is the major hindrance in development of specific immunoassays for detecting S. aureus antigens, because of its characteristic feature of binding to Fc region of most mammalian immunoglobulins and also to Fab region of certain classes of mammalian immunoglobulins. Immunoglobulin Y (IgY) is the avian equivalent of mammalian IgG which does not have any affinity to Spa. In the present study we report that using chicken egg yolk IgY over mammalian IgG as capture antibody prevents both soluble and surface bound protein A from causing false positives quantified by chicken anti-protein A antibodies. This was demonstrated by development of sandwich ELISA for detection of alpha hemolysin toxin from culture supernatants of S. aureus strains with anti alpha hemolysin IgY as capture and rabbit anti alpha hemolysin IgG as revealing antibody. This indirect sandwich ELISA was evaluated onto a large number of S. aureus isolates recovered from clinical sources for alpha hemolysin secretion. Results of sandwich ELISA were compared with PCR and Western blot analysis. The immunoassay is highly specific and has high sensitivity of detecting less than 1 ng/ml. This procedure is highly effective in eliminating Spa interference and can be extended to detection of other important superantigen toxins of S. aureus. PMID- 23454247 TI - Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1 expressing carcinomas. AB - INTRODUCTION: Anti-HER1 monoclonal antibody (mAb), panitumumab (Vectibix) is a fully human mAb approved by the FDA for the treatment of epidermal growth factor receptor (EGFR, HER1)-expressing colorectal cancers. By combining the targeted specificity of panitumumab with the quantitative in vivo imaging capabilities of PET, we evaluated the potential of (89)Zr-DFO-panitumumab PET/CT imaging and performed non-invasive, in vivo imaging of HER1 expression and estimated human dosimetry. METHODS: Panitumumab was radiolabeled with (89)Zr using a derivative of desferrioxamine (DFO-Bz-NCS) and with (111)In using CHX-A" DTPA as bifunctional chelators. Comparative biodistribution/dosimetry of both radiotracers was performed in non-tumor bearing athymic nude mice (n=2 females and n=2 males) over 1-week following i.v. injection of either using (89)Zr-DFO panitumumab or (111)In-CHX-A"-DTPA-panitumumab. Micro-PET/CT imaging of female athymic nude mice bearing human breast cancer tumors (n=5 per tumor group) with variable HER1-expression very low (BT-474), moderate (MDA-MB-231), and very high (MDA-MB-468) was performed at over 1 week following i.v. injection of (89)Zr-DFO panitumumab. RESULTS: Radiochemical yield and purity of (89)Zr-Panitumumab was >70% and >98% respectively with specific activity 150 +/- 10 MBq/mg of panitumumab in a ~4 hr synthesis time. Biodistribution of (111)In-CHX-A" DTPA panitumumab and (89)Zr-DFO-panitumumab in athymic non-tumor bearing nude mice displayed similar percent injected dose per gram of tissue with prominent accumulation of both tracers in the lymph nodes, a known clearance mechanism of panitumumab. Also exhibited was prolonged blood pool with no evidence of targeted accumulation in any organ. Human radiation dose estimates showed similar biodistributions with estimated human effective doses of 0.578 and 0.183 mSv/MBq for (89)Zr-DFO-panitumumab and (111)In-CHX-A"-DTPA-panitumumab, respectively. Given the potential quantitative and image quality advantages of PET, imaging of tumor bearing mice was only performed using (89)Zr-DFO-panitumumab. Immuno-PET imaging of (89)Zr-DFO-panitumumab in mice bearing breast cancer xenograft tumors with variable HER1 expression showed high tumor uptake (SUV >7) in the MDA-MB-468 high HER1-expressing mice and a strong correlation between HER1-expression level and tumor uptake (R(2)= 0.857, P < .001). CONCLUSIONS: (89)Zr-DFO-panitumumab can prepared with high radiochemical purity and specific activity. (89)Zr-DFO panitumumab microPET/CT showed uptake corresponding to HER-1 expression. Due to poor clearance, initial dosimetry estimates suggest that only a low dose (89)Zr DFO-panitumumab shows favorable human dosimetry; however due to high tumor uptake, the use of (89)Zr-DFO-panitumumab is expected to be clinically feasible. PMID- 23454248 TI - Antilipolytic drug boosts glucose metabolism in prostate cancer. AB - INTRODUCTION: The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts. METHODS: Subcutaneous tumors were produced in nude mice by injection of PC3 and CWR22Rv1 PCa cells. The mice were divided into two groups (Acipimox vs. controls). Acipimox (50mg/kg) was administered by oral gavage 1h before injection of tracers. 1h after i.v. co-injection of 8.2MBq (222 +/- 6.0 MUCi) (18)F-FDG and~0.0037 MBq (0.1 MUCi) (14)C-acetate, (18)F-FDG imaging was performed using a small-animal PET scanner. Counting rates in reconstructed images were converted to activity concentrations. Quantification was obtained by region-of-interest analysis using dedicated software. The mice were euthanized, and blood samples and organs were harvested. (18)F radioactivity was measured in a calibrated gamma-counter using a dynamic counting window and decay correction. (14)C radioactivity was determined by liquid scintillation counting using external standard quench corrections. Counts were converted into activity, and percentage of the injected dose per gram (%ID/g) tissue was calculated. RESULTS: FDG biodistribution data in mice with PC3 xenografts demonstrated doubled average %ID/g tumor tissue after administration of Acipimox compared to controls (7.21 +/- 1.93 vs. 3.59 +/- 1.35, P=0.02). Tumor-to-organ ratios were generally higher in mice treated with Acipimox. This was supported by PET imaging data, both semi-quantitatively (mean tumor FDG uptake) and visually (tumor-to-background ratios). In mice with CWR22Rv1 xenografts there was no effect of Acipimox on FDG uptake, either in biodistribution or PET imaging. (14)C acetate uptake was unaffected in PC3 and CWR22Rv1 xenografts. CONCLUSIONS: In mice with PC3 PCa xenografts, acute administration of Acipimox increases tumor uptake of (18)F-FDG with general improvements in tumor-to-background ratios. Data indicate that administration of Acipimox prior to (18)F-FDG PET scans has potential to improve sensitivity and specificity in patients with castration resistant advanced PCa. PMID- 23454249 TI - Kinetic analysis of FDG in rat liver: effect of dietary intervention on arterial and portal vein input. AB - INTRODUCTION: Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) input. The purpose of this study was to evaluate kinetic models of [(18)F]FDG metabolism under a wide range of dietary interventions taking into account variations in arterial (HA) and portal vein (PV) input. METHODS: The study consisted of three groups of rats maintained under different diet interventions: 12 h fasted, 24 h fasted and those fed with high fructose diet. [(15)O]H2O PET imaging was used to characterize liver flow contribution from HA and PV to the liver's dual input function (DIF). [(18)F]FDG PET imaging was used to characterize liver metabolism. Differences in [(18)F]FDG kinetics in HA, PV and liver under different diet interventions were investigated. An arterial to PV Transfer Function (TF) was optimized in all three dietary states to noninvasively estimate PV activity. Finally, two compartment 3 parameter (2C3P), two compartment 4-parameter (2C4P), two compartment 5-parameter (2C5P), and three compartment 5-parameter (3C5P) models were evaluated and compared to describe the kinetics of [(18)F]FDG in the liver across diet interventions. Sensitivity of the compartmental models to ratios of HA to PV flow fractions was further investigated. RESULTS: Differences were found in HA and PV [(18)F]FDG kinetics across 12h fasted, 24h fasted and high fructose fed diet interventions. A two exponential TF model was able to estimate portal activity in all the three diet interventions. Statistical analysis suggests that a 2C3P model configuration was adequate to describe the kinetics of [(18)F]FDG in the liver under wide ranging dietary interventions. The net influx of [(18)F]FDG was lowest in the 12h fasted group, followed by 24 h fasted group, and high fructose diet. CONCLUSIONS: A TF was optimized to non-invasively estimate PV time activity curve in different dietary states. Several kinetic models were assessed and a 2C3P model was sufficient to describe [(18)F]FDG liver kinetics despite differences in HA and PV kinetics across wide ranging dietary interventions. The observations have broader implications for the quantification of liver metabolism in metabolic disorders and cancer, among others. PMID- 23454250 TI - Evaluation of the antitumor effects of rilotumumab by PET imaging in a U-87 MG mouse xenograft model. AB - INTRODUCTION: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway has been implicated in various cancers. Rilotumumab is an investigational, fully human monoclonal antibody that binds and neutralizes HGF. The purpose of this study was to evaluate the efficacy of rilotumumab in a U-87 MG mouse xenograft tumor model using (18)F-FDG and (18)F-FLT PET. METHODS: U-87 MG tumor-bearing nude mice received rilotumumab or control IgG2. In the dose response study, increasing doses of rilotumumab (10, 30, 100, 300, or 500 MUg) were administered, and mice were evaluated with (18)F-FDG PET at baseline and 7 days post-treatment. In the time course study, 300 MUg of rilotumumab twice per week was used for the treatment, and mice were evaluated over 7 days using (18)F-FDG and (18)F-FLT PET. RESULTS: In the dose response study, rilotumumab at doses of 300 and 500 MUg was similarly effective against tumor growth. Treatment with 300 and 500 MUg rilotumumab inhibited (18)F-FDG accumulation with significant decreases of -37% and -40% in the percent injected dose per gram of tissue (%ID/g), respectively. In the time course study, treatment with 300 MUg rilotumumab inhibited (18)F-FDG and (18)F-FLT accumulation with a maximum %ID/g of -41% and -64%, respectively. No apparent differences between the use of either tracer to evaluate rilotumumab efficacy were observed. CONCLUSIONS: Rilotumumab inhibited (18)F-FDG and (18)F FLT accumulation as early as 2 and 4 days after treatment, respectively, in a mouse tumor model. Further studies to evaluate (18)F-FDG PET imaging as an early tumor response marker for rilotumumab are warranted. Rilotumumab is currently being tested in patients with MET-positive, advanced gastric and gastroesophageal cancer. PMID- 23454251 TI - Management of intravascular leiomyomatosis: laparoscopic surgery for ordinary uterine fibroids led to an extraordinary finding. AB - An unexpected diagnosis of intravascular leiomyomatosis was made during a laparoscopic procedure. As the extent of the disease was unknown, the initial procedure was limited to laparoscopic hysterectomy and salpingo-oophorectomy. Postoperative computed tomography imaging demonstrated intravascular leiomyomatosis extending into the suprarenal inferior vena cava. The patient underwent exploratory laparotomy to excise residual tumor. PMID- 23454252 TI - Identity crisis: the patient's abdominal discomfort stemmed from a treacherous event. PMID- 23454254 TI - Vascular and ureteral anatomy relative to the midsacral promontory. AB - OBJECTIVE: The objective of the study was to further characterize the vascular and ureteral anatomy relative to the midsacral promontory, a landmark often used during sacrocolpopexy, and suggest strategies to avoid complications. STUDY DESIGN: Distances between the right ureter, aortic bifurcation, and iliac vessels to the midsacral promontory were examined in 25 unembalmed female cadavers and 100 computed tomography (CT) studies. Data were analyzed using Pearson chi(2), unpaired Student t test, and analysis of covariance. RESULTS: The average distance between the midsacral promontory and right ureter was 2.7 cm (range, 1.6 3.8 cm) in cadavers and 2.9 cm (range, 1.7-5.0 cm) on CT (P = .209). The closest cephalad vessel to the promontory was the left common iliac vein, the average distance being 2.7 cm (range, 0.95-4.75 cm) in cadavers and 3.0 cm (range, 1.0 6.1 cm) on CT (P = .289). The closest vessel to the right of the promontory was the internal iliac artery, with the average distance of 2.5 cm (range, 1.4-3.9 cm) in cadavers and 2.2 cm (range, 1.2-3.9 cm) on CT (P = .015). The average distance from the promontory to the aortic bifurcation was 5.3 cm (range, 2.8-9.7 cm) in cadavers and 6.6 cm (range, 3.1-10.1 cm) on CT (P < .001). The average distance from the aortic bifurcation to the inferior margin of the left common iliac vein was 2.3 cm (range, 1.2-3.9 cm) in cadavers and 3.5 cm (range, 1.7-5.6 cm) on CT (P < .001). CONCLUSION: The right ureter, right common iliac artery, and left common iliac vein are found within 3 cm from the midsacral promontory. A thorough understanding of the extensive variability in vascular and ureteral anatomy relative to the midsacral promontory should help avoid serious intraoperative complications during sacrocolpopexy. PMID- 23454253 TI - Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO Study. AB - OBJECTIVE: We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study. STUDY DESIGN: In this prospective matched, exposure cohort design, 495 women aged 18-44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an age- and residence matched population cohort of 131 women (unexposed to surgery, population cohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort. RESULTS: The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3-4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3-4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57-3.76) and population (AOR, 7.91; 95% CI, 1.69-37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28-4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44-5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32-0.75), parity (AOR, 0.42; 95% CI, 0.28-0.64), and body mass index (AOR, 0.95; 95% CI, 0.93-0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor. CONCLUSION: An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized. PMID- 23454255 TI - [Clinical problems in medical mycology: Problem number 47]. AB - A 66 year-old man, who had lived in Paraguay and was a rural worker, was admitted to Infectious Diseases Hospital F. J. Muniz in Buenos Aires. He presented fever, loss of body weight, cough, mucopurulent expectoration, wide perianal ulceration, paresthesia and paresis of both legs as well as vesical and anal sphincter dysfunction. He was a heavy smoker and drinker. Thorax X-ray examination showed bilateral micronodular interstitial lesions. With a NMR of the dorsolumbar spine region a nodular lesion outside the spinal cord (which produced compression of this organ) was shown. The diagnosis of disseminated paracoccidiodomycosis was based on the finding of Paracoccidioides brasiliensis in the skin ulcer in histopathology and mycology studies, and on the positive results of serologic tests with paracoccidioidin antigen. The patient was treated with trimethoprim sulfamethoxazole with good clinical outcome. PMID- 23454256 TI - Interleukin-1 has opposing effects on connective tissue growth factor and tenascin-C expression in human cardiac fibroblasts. AB - Cardiac fibroblasts (CF) play a central role in the repair and remodeling of the heart following injury and are important regulators of inflammation and extracellular matrix (ECM) turnover. ECM-regulatory matricellular proteins are synthesized by several myocardial cell types including CF. We investigated the effects of pro-inflammatory cytokines on matricellular protein expression in cultured human CF. cDNA array analysis of matricellular proteins revealed that interleukin-1alpha (IL-1alpha, 10ng/ml, 6h) down-regulated connective tissue growth factor (CTGF/CCN2) mRNA by 80% and up-regulated tenascin-C (TNC) mRNA levels by 10-fold in human CF, without affecting expression of thrombospondins 1 3, osteonectin or osteopontin. Western blotting confirmed these changes at the protein level. In contrast, tumor necrosis factor alpha (TNFalpha) did not modulate CCN2 expression and had only a modest stimulatory effect on TNC levels. Signaling pathway inhibitor studies suggested an important role for the p38 MAPK pathway in suppressing CCN2 expression in response to IL-1alpha. In contrast, multiple signaling pathways (p38, JNK, PI3K/Akt and NFkappaB) contributed to IL 1alpha-induced TNC expression. In conclusion, IL-1alpha reduced CCN2 expression and increased TNC expression in human CF. These observations are of potential value for understanding how inflammation and ECM regulation are linked at the level of the CF. PMID- 23454258 TI - Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest. AB - BACKGROUND: Arterial carbon dioxide tension (PaCO2) affects neuronal function and cerebral blood flow. However, its association with outcome in patients admitted to intensive care unit (ICU) after cardiac arrest (CA) has not been evaluated. METHODS AND RESULTS: Observational cohort study using data from the Australian New Zealand (ANZ) Intensive Care Society Adult-Patient-Database (ANZICS-APD). Outcomes analyses were adjusted for illness severity, co-morbidities, hypothermia, treatment limitations, age, year of admission, glucose, source of admission, PaO2 and propensity score. We studied 16,542 consecutive patients admitted to 125 ANZ ICUs after CA between 2000 and 2011. Using the APD-PaCO2 (obtained within 24 h of ICU admission), 3010 (18.2%) were classified into the hypo- (PaCO2<35 mmHg), 6705 (40.5%) into the normo- (35-45 mmHg) and 6827 (41.3%) into the hypercapnia (>45 mmHg) group. The hypocapnia group, compared with the normocapnia group, had a trend toward higher in-hospital mortality (OR 1.12 [95% CI 1.00-1.24, p=0.04]), lower rate of discharge home (OR 0.81 [0.70-0.94, p<0.01]) and higher likelihood of fulfilling composite adverse outcome of death and no discharge home (OR 1.23 [1.10-1.37, p<0.001]). In contrast, the hypercapnia group had similar in-hospital mortality (OR 1.06 [0.97-1.15, p=0.19]) but higher rate of discharge home among survivors (OR 1.16 [1.03-1.32, p=0.01]) and similar likelihood of fulfilling the composite outcome (OR 0.97 [0.89-1.06, p=0.52]). Cox-proportional hazards modelling supported these findings. CONCLUSIONS: Hypo- and hypercapnia are common after ICU admission post-CA. Compared with normocapnia, hypocapnia was independently associated with worse clinical outcomes and hypercapnia a greater likelihood of discharge home among survivors. PMID- 23454257 TI - Survival in out-of-hospital cardiac arrests with initial asystole or pulseless electrical activity and subsequent shockable rhythms. AB - BACKGROUND: Non-shockable arrest rhythms (pulseless electrical activity and asystole) represent an increasing proportion of reported cases of out-of-hospital cardiac arrest (OHCA). The prognostic significance of conversion from non shockable to shockable rhythms during the course of resuscitation remains unclear. OBJECTIVE: To evaluate whether out-of-hospital cardiac arrest survival with initially non-shockable arrest rhythms is improved with subsequent conversion to shockable rhythms. METHODS: Secondary analysis of data in Epistry - Cardiac Arrest, an epidemiologic registry maintained by the Resuscitation Outcomes Consortium (ROC). This analysis includes OHCA events from December 1, 2005 through May 31, 2007 contributed by six US and two Canadian sites. For all EMS-treated adult (18 and older) cardiac arrest patients who presented with non shockable cardiac arrest, we compared survival to hospital discharge between patients who did develop a shockable rhythm and those who did not based on receipt of subsequent defibrillation. Missing data were handled using multiple imputation. Multivariable logistic regression was used to adjust for potentially confounding variables. RESULTS: A total of 6556 EMS treated adult cardiac arrest cases presented in non-shockable rhythms. Survival to discharge in patients who converted to a shockable rhythm was 2.77% while survival in those who did not was 2.72% (p=0.92). After adjusting for confounders, conversion to a shockable rhythm was not associated with improved survival (OR 0.88, 95% CI: 0.60-1.30). CONCLUSION: For OHCA patients presenting in PEA/asystole, survival to hospital discharge was not associated with conversion to a shockable rhythm during EMS resuscitation efforts. PMID- 23454259 TI - Prehospital therapeutic hypothermia after cardiac arrest: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Therapeutic hypothermia has been recommended for the treatment of cardiac arrest patients who remain comatose after the return of spontaneous circulation. However, the optimal time to initiate therapeutic hypothermia remains unclear. The objective of the present study is to assess the effectiveness and safety of prehospital therapeutic hypothermia after cardiac arrest. METHODS: Databases such as MEDLINE, Embase, and Cochrane Library were searched from their establishment date to May of 2012 to retrieve randomized control trials on prehospital therapeutic hypothermia after cardiac arrest. Thereafter, the studies retrieved were screened based on predefined inclusion and exclusion criteria. Data were extracted and the quality of the included studies was evaluated. A meta-analysis was performed by using the Cochrane Collaboration Review Manager 5.1.6 software. RESULTS: Five studies involving 633 cases were included, among which 314 cases were assigned to the treatment group and the other 319 cases to the control group. The meta-analysis indicated that prehospital therapeutic hypothermia after cardiac arrest produced significant differences in temperature on hospital admission compared with in-hospital therapeutic hypothermia or normothermia (patient data; mean difference=-0.95; 95% confidence interval -1.15 to -0.75; I(2)=0%). However, no significant differences were observed in the survival to the hospital discharge, favorable neurological outcome at hospital discharge, and rearrest. The risk of bias was low; however, the quality of the evidence was very low. CONCLUSION: This review demonstrates that prehospital therapeutic hypothermia after cardiac arrest can decrease temperature on hospital admission. On the other hand, regarding the survival to hospital discharge, favorable neurological outcome at hospital discharge, and rearrest, our meta-analysis and review produces non-significant results. Using the Grading of Recommendations, Assessment, Development and Evaluation methodology, we conclude that the quality of evidence is very low. PMID- 23454260 TI - The effects of an automatic, low pressure and constant flow ventilation device versus manual ventilation during cardiovascular resuscitation in a porcine model of cardiac arrest. AB - BACKGROUND: Cardiac arrest is an important cause of mortality. Cardiopulmonary resuscitation (CPR) improves survival, however, delivery of effective CPR can be challenging and combining effective chest compressions with ventilation, while avoiding over-ventilation is difficult. We hypothesized that ventilation with a pneumatically powered, automatic ventilator (Oxylator((r))) can provide adequate ventilation in a model of cardiac arrest and improve the consistency of ventilations during CPR. METHODS/RESULTS: Twelve pigs (~40 kg, either sex) underwent 3 episodes each of cardiac arrest and resuscitation consisting of 30s of untreated ventricular fibrillation, followed by 5 min of CPR, defibrillation, and ~30 min of recovery. During CPR in each episode, pigs were ventilated in 1 of 3 ways in random balanced order: manual ventilation using AMBU bag (12 breaths/min), low pressure Oxylator((r)) (maximum airway pressure 15 cm H2O with 20 L/min constant flow in automatic mode [Ox15/20]), or high pressure Oxylator((r)) (maximum airway pressure 20 cm H2O with 30 L/min constant flow in automatic mode [Ox20/30]). During CPR, both Ox15/20 and Ox20/30 resulted in higher levels of positive end expiratory pressure than manual ventilation. Ox15/20 ventilation also resulted in higher arterial pCO2 than manual ventilation. Ox20/30 ventilation yielded higher arterial pO2 and a lower arterial alveolar gradient than manual ventilation. All pigs were successfully defibrillated, and no measured haemodynamic variables were different between the groups. CONCLUSION: Ventilation with an automatic ventilation device during CPR is feasible and provides adequate ventilation and comparable haemodynamics when compared to manual bag ventilation. PMID- 23454261 TI - Loss of dopamine neuron terminals in antipsychotic-treated schizophrenia; relation to tardive dyskinesia. AB - The in vivo labeling and brain imaging of dopamine transporters measure the density of dopamine neuron terminals in the human caudate/putamen. A review of such studies shows that the long-term use of antipsychotics had no major effect on the density of the dopamine terminals in individuals who had no tardive dyskinesia, but had reduced the density in those patients with tardive dyskinesia. In addition, the normal loss of dopamine terminals in healthy individuals was approximately 5% per decade. However, this rate of cell loss was apparently increased by approximately three-fold, to about 15% per decade, in schizophrenia patients using antipsychotics on a long-term basis, as measured by the in vivo imaging of the dopamine transporters in the dopamine neuron terminals. While an apparent reduction in dopamine transporters may result from reduced expression of the transporters secondary to antipsychotic treatment, the seemingly increased loss rate is consistent with the accumulation of antipsychotics in the neuromelanin of the substantia nigra, subsequent injury to the dopamine-containing neurons, and the development of extrapyramidal motor disturbances such as tardive dyskinesia or Parkinson's disease. PMID- 23454262 TI - Visual short-term memory for global motion revealed by directional and speed tuned masking. AB - Neurobehavioral research with non-human primates has shown that different attributes of motion stimuli, such as direction and speed can be stored in visual short-term memory (VSTM) with a high degree of accuracy. We examined VSTM for global motion with a memory masking paradigm to determine which stimulus attributes are important in the storage process. We presented in two visual quadrants global motion random dot kinematograms (RDKs), whereas in the two remaining visual quadrants we presented random-motion RDKs. This pattern of stimulation was displayed in two distinct temporal intervals, i.e., sample and test stimuli (duration: 200 ms), separated in time by a 3.2-s delay period. During the delay period a random- or directional-motion mask was presented briefly (200 ms) either at the beginning, in the middle or at the end of the delay period. The results showed that the mask mainly interferes with performance when displayed 200 ms after the offset of the sample and when it had a coherent direction rather than random directions. Moreover, the mask is significantly more effective when its direction and speed matched that of the remembered sample. These results support the notion that the memory representation of global motion is selective for direction and speed, being compromised by intervening directional stimuli presented immediately after the encoding phase. Moreover, this selectivity suggests that the same neural mechanisms involved in the processing of global motion may be recruited for its storage. PMID- 23454263 TI - The interplay between mood and language comprehension: evidence from P600 to semantic reversal anomalies. AB - Little is known about the relationship between language and emotion. Vissers et al. (2010) investigated the effects of mood on the processing of syntactic violations, as indexed by P600. An interaction was observed between mood and syntactic correctness for which three explanations were offered: one in terms of syntactic processing, one in terms of heuristic processing, and one in terms of more general factors like attention and/or motivation. In this experiment, we further determined the locus of the effects of emotional state on language comprehension by investigating the effects of mood on the processing of semantic reversal anomalies (e.g., "the cat that fled from the mice"), in which heuristics play a key role. The main findings were as follows. The mood induction was effective: participants were happier after watching happy film clips and sadder after watching sad film clips compared to baseline. For P600, a mood by semantic plausibility interaction was obtained reflecting a broadly distributed P600 effect for the happy mood vs. absence of a P600 for the sad mood condition. Correlation analyses confirmed that changes in P600 in happy mood were accompanied by changes in emotional state. Given that semantic reversal anomalies are syntactically unambiguous, the P600 modulation by mood cannot be explained by syntactic factors. The semantic plausibility by mood interaction can be accounted for in terms of (1) heuristic processing (stronger reliance on a good enough representation of the input in happy mood than sad mood), and/or (2) more general factors like attention (e.g., more attention to semantic reversals in happy mood than sad mood). PMID- 23454264 TI - Tessier 30 symphyseal mandibular cleft: early simultaneous soft and hard tissue correction - a case report. AB - A symphyseal mandibular facial cleft (Tessier 30) is a rare congenital abnormality. Nonunion of bone in the symphysis of the mandible, median cleft of the lower lip and tongue adherence in the midline to the floor of the mouth are the principle features of the anomaly. A satisfactory result can be achieved with early surgical correction of both hard and soft tissue defects in the age of 6 months. More than 3 years follow-up shows total bony fusion of the symphysis and normal lower lip function. There were only left deciduous central incisor and the ipsilateral tooth bud of the permanent central incisor missing. PMID- 23454265 TI - Isolated intraosseous lipoma of the ethmoid sinus. AB - Intraosseous lipoma is an extremely rare variant of lipoma. It is most commonly found in the appendicular skeleton and only very rarely in skull base. We present a 38-year-old male patient who was admitted to our clinic with the symptoms of nasal obstruction and headache. Computed tomography (CT) showed a hyperdense area with surrounding calcification was demonstrated in the anteromedial part of ethmoid sinus. Endoscopic left anterior ethmoidectomy was performed and the mass was totally excised. Histopathological examination was consistent with Milgram's stage 1 intraosseous lipoma. To our knowledge, this is the first reported case of isolated intraosseous lipoma of the ethmoid sinuses in the literature. PMID- 23454266 TI - Computer-assisted midface reconstruction in Treacher Collins syndrome part 1: skeletal reconstruction. AB - INTRODUCTION: Treacher Collins syndrome (TCS) is a severe and complex craniofacial malformation affecting the facial skeleton and soft tissues. The palate as well as the external and middle ear are also affected, but his prognosis is mainly related to neonatal airway management. Methods of zygomatico orbital reconstruction are numerous and currently use primarily autologous bone, lyophilized cartilage, alloplastic implants, or even free flaps. This work developed a reliable "customized" method of zygomatico-orbital bony reconstruction using a generic reference model tailored to each patient. METHODS: From a standard computed tomography (CT) acquisition, we studied qualitatively and quantitatively the skeleton of four individuals with TCS whose age was between 6 and 20 years. In parallel, we studied 40 controls at the same age to obtain a morphometric database of reference. Surgical simulation was carried out using validated software used in craniofacial surgery. RESULTS: The zygomatic hypoplasia was very important quantitatively and morphologically in all TCS individuals. Orbital involvement was mainly morphological, with volumes comparable to the controls of the same age. The control database was used to create three-dimensional computer models to be used in the manufacture of cutting guides for autologous cranial bone grafts or alloplastic implants perfectly adapted to each patient's morphology. Presurgical simulation was also used to fabricate custom positioning guides permitting a simple and reliable surgical procedure. CONCLUSIONS: The use of a virtual database allowed us to design a reliable and reproducible skeletal reconstruction method for this rare and complex syndrome. The use of presurgical simulation tools seem essential in this type of craniofacial malformation to increase the reliability of these uncommon and complex surgical procedures, and to ensure stable results over time. PMID- 23454267 TI - Anatomic study to determine a safe surgical reference point for mandibular ramus osteotomy. AB - OBJECTIVE: The purpose of this study was to identify a surgical reference point on the mandibular ramus that can be used during ramus osteotomy to prevent injury to the inferior alveolar nerve. MATERIALS AND METHODS: A total of 125 subjects' mandibles were analyzed and compared on a three-dimensional (3D) model constructed from computed tomography (CT). 25 volunteer subjects with normal class I occlusion (group I, control), 50 consecutive subjects (25 females and 25 males) diagnosed with mandibular retrognathism (group II), and 50 consecutive subjects (25 females and 25 males) with prognathism (group III) were included. This study created a landmark (the midwaist point) at the halfway point on a horizontal plane between the most concave points on the anterior and posterior borders of mandibular ramus, with the vertical plane bisecting the horizontal plane. The midwaist point was compared to other anatomic landmarks including antilingula, lingula, and mandibular foramen for correlation. RESULTS: The distance from the midwaist point to lingula and mandibular foramen along the horizontal plane was not significantly different among three groups. Lingula and mandibular foramen were mostly located within 2 mm posterior of the midwaist point, whereas the locations of lingula and mandibular foramen along the vertical plane to the midwaist point were highly variable. CONCLUSION: The midwaist point is an excellent intraoperative reference point that can help surgeons to identify the position of the lingual and the mandibular foramen, thus preventing inferior alveolar nerve injury. PMID- 23454268 TI - Invited editorial: Homage to Dr. Henry K. Kawamoto, MD, DDS, UCLA, Los Angeles, CA, USA. PMID- 23454270 TI - Familial KANK1 deletion that does not follow expected imprinting pattern. AB - Deletion of the KANK1 gene (also called ANKRD15), located at chromosome position 9p24.3, has been associated with neurodevelopmental disease including congenital cerebral palsy, hypotonia, quadriplegia, and intellectual disability in a four generation family. The inheritance pattern in this family was suggested to be maternal imprinting, as all affected individuals inherited the deletion from their fathers and monoallelic protein expression was observed. We present a family in which the proband's phenotype, including autism spectrum disorder, motor delay, and intellectual disability, is consistent with this previous report of KANK1 deletions. However, a paternally inherited deletion in the proband's unaffected sibling did not support maternal imprinting. This family raises consideration of further complexity of the KANK1 locus, including variable expressivity, incomplete penetrance, and the additive effects of additional genomic variants or the potential benign nature of inherited copy number variations (CNVs). However, when considered with the previous publication, our case also suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. It is also important to consider that KANK1 has two alternately spliced transcripts, A and B. These have differential tissue expression and thus potentially differential clinical significance. Based upon cases in the literature, the present case, and information in the Database of Genomic Variants, it is possible that only aberrations of variant A contribute to neurodevelopmental disease. The familial deletion in this present case does not support maternal imprinting as an inheritance pattern. We suggest that other inheritance patterns and caveats should be considered when evaluating KANK1 deletions, which may become increasingly recognized through whole genome microarray testing, whole genome sequencing, and whole exome sequencing techniques. PMID- 23454269 TI - A cell-penetrating peptide suppresses the hypoxia inducible factor-1 function by binding to the helix-loop-helix domain of the aryl hydrocarbon receptor nuclear translocator. AB - The heterodimeric hypoxia inducible factor-1 (HIF-1) complex is composed of the hypoxia inducible factor-1 alpha (HIF-1alpha) and the aryl hydrocarbon receptor nuclear translocator (ARNT). Activation of the HIF-1 function is essential for tumor growth and metastasis. We previously showed that transfection of a plasmid containing an ARNT-interacting peptide (Ainp1) cDNA suppresses the HIF-1 signaling in Hep3B cells. Here we generated TAT fusion of the Ainp1 peptide (6His TAT-Ainp1) to determine whether and how the Ainp1 peptide suppresses the HIF-1 function. The bacterially expressed 6His-TAT-Ainp1 was purified under denatured condition and then refolded by limited dialysis. The refolded 6His-TAT-Ainp1 interacts with the helix-loop-helix (HLH) domain of ARNT in a similar fashion as the native 6His-Ainp1. 6His-TAT-Ainp1 colocalizes with ARNT in the nucleus of HeLa and Hep3B cells after protein transduction. The transduced protein reaches the maximum intracellular levels within 2 h while remains detectable up to 96 h in HeLa cells. At 2 MUM concentration, 6His-TAT-Ainp1 is not cytotoxic in HeLa cells but suppresses the cobalt chloride-activated, hypoxia responsive enhancer driven luciferase expression in a dose-dependent manner. In addition, it decreases the cobalt chloride-dependent induction of the HIF-1 target genes at both the message (vascular endothelial growth factor and aldolase C) and protein (carbonic anhydrase IX and glucose transporter 1) levels. The protein levels of HIF-1alpha and ARNT are not altered in the presence of 6His-TAT-Ainp1. In summary, we provided evidence to support that the Ainp1 peptide directly suppresses the HIF-1 function by interacting with the ARNT HLH domain, and in turn interfering with the heterodimerization of HIF-1alpha and ARNT. PMID- 23454271 TI - Mosaic 15q13.3 deletion including CHRNA7 gene in monozygotic twins. AB - Deletions in 15q13.3 belong to the most frequently identified recurrent CNVs, and lead to mental retardation, seizures and minor dysmorphism. We report on two monozygotic twin boys with a mosaic 1.5 Mb deletion in 15q13.3, including CHRNA7. The growth parameters were in the normal range for both twins. Both had language delay with hyperactivity, temper tantrums and poor social interaction but attended regular school. The percentage of abnormal cells was 40% on lymphocytes, and 25 and 35% on buccal smear in the first and second twins, respectively. The mosaicism for the 15q13.3 deletion can explain the milder phenotype observed in these two boys. PMID- 23454272 TI - Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. AB - Mutations in the serine palmitoyltransferase subunit 1 (SPTLC1) gene are the most common cause of hereditary sensory neuropathy type 1 (HSN1). Here we report the clinical and molecular consequences of a particular mutation (p.S331Y) in SPTLC1 affecting a patient with severe, diffuse muscle wasting and hypotonia, prominent distal sensory disturbances, joint hypermobility, bilateral cataracts and considerable growth retardation. Normal plasma sphingolipids were unchanged but 1 deoxy-sphingolipids were significantly elevated. In contrast to other HSN patients reported so far, our findings strongly indicate that mutations at amino acid position Ser331 of the SPTLC1 gene lead to a distinct syndrome. PMID- 23454274 TI - Protein kinase C delta is a substrate of tissue transglutaminase and a novel autoantigen in coeliac disease. AB - Post-translational modification of proteins by deamidation or transamidation by tissue transglutaminase (tTG) has been suggested as a possible mechanism for the development of autoimmunity. Sequence analysis of protein kinase C delta (PKCdelta) identified an amino acid motif that suggested the possibility that PKCdelta was a glutamine substrate of tTG and MALDI-TOF analysis of synthesised peptides from PKCdelta proved that this was the case. Polymerisation experiments using recombinant tTG and biotinylated hexapeptide substrate incorporation assays demonstrated that PKCdelta is a substrate for tTG-mediated transamidation. Elevated levels of anti-PKCdelta antibodies were detected in sera from patients with coeliac disease (p<0.0001) but not from patients with other autoimmune disorders. These data suggest that a subset of patients with coeliac disease produce autoantibodies against PKCdelta and that this response may stem from a tTG-PKCdelta substrate interaction. PMID- 23454273 TI - Role for Lhx2 in corticogenesis through regulation of progenitor differentiation. AB - The neocortex represents the brain region that has undergone a major increase in its relative size during the course of mammalian evolution. The larger cortex results from a corresponding increase in progenitor cell number. The progenitors giving rise to neocortex are located in the ventricular zone of the dorsal telencephalon and highly express Lhx2, a LIM-homeodomain transcription factor. The neocortex fails to form in the Lhx2 constitutive knockout, indicating a role for Lhx2 in corticogenesis, but mid-embryonic lethality of the Lhx2 knockout requires the use of conditional strategies for further studies. Therefore, to explore Lhx2 function in neocortical progenitors, we generated mice with Lhx2 conditionally deleted from cortical progenitors at the onset of neurogenesis. We find that Lhx2 is critical for maintaining the proliferative state of neocortical progenitors during corticogenesis. In the conditional knockouts, the neocortex is formed but is significantly smaller than wild type. We find that deletion of Lhx2 leads to significantly decreased numbers of cortical progenitors and premature neuronal differentiation. A likely mechanism is indicated by our findings that Lhx2 is required for the expression of Hes1 in cortical progenitors, a key effector in the Notch signaling pathway that maintains the proliferative progenitor state. We conclude that Lhx2 regulates the balance between proliferation and differentiation in cortical progenitors and through this mechanism Lhx2 controls cortical size. PMID- 23454275 TI - Diarrhea as sole presentation of Good's syndrome mimicking Crohn's disease. PMID- 23454276 TI - Molecular identification and differential expression of sensory neuron membrane proteins in the antennae of the black cutworm moth Agrotis ipsilon. AB - The insect sensory neuron membrane proteins (SNMPs) SNMP1 and SNMP2 are transmembrane domain-containing proteins and are homologs of the vertebrate CD36 transmembrane proteins. It has been suggested that SNMPs play a significant role in insect chemoreception. Previous studies have demonstrated that SNMP1 is expressed in the pheromone-sensitive olfactory receptor neurons (ORNs), whereas SNMP2 is expressed in the supporting cells. In this study, we identified two full length SNMP transcripts, AipsSNMP1 and AipsSNMP2, in the black cutworm moth Agrotis ipsilon (Hufnagel). The qRT-PCR results indicated that the AipsSNMP1 and AipsSNMP2 transcripts were expressed significantly higher in the antennae than in other tissues of both sexes. The expression of AipsSNMP1 and AipsSNMP2 in the antennae from different development stages of both sexes was investigated and was shown to begin to express in the pupae stage from 3days before emergence and then increased dramatically at the day of the emergence, and the high expression levels were maintained during the following 4days after the emergence in both sexes. The mating status had no effect on the expression levels of the AipsSNMP1 and AipsSNMP2 transcripts. Consistent with previous in situ hybridization studies in other Lepidoptera insects, our immunolocalization results at protein level demonstrated that both AipsSNMP1 and AipsSNMP2 were expressed in pheromone sensitive sensilla trichodea but with a completely different expression profile. AipsSNMP1 is more uniformed and highly expressed along the membrane of the ORN dendrites, whereas AipsSNMP2 is widely distributed at the bottom of the sensilla trichodea and highly localized in the sensillum lymph. Our studies provide further detailed evidence for the involvement and general functional role of insect SNMPs in the detection of sex pheromones and general odorant molecules. PMID- 23454277 TI - Electrophysiological correlates of early attentional feature selection and distractor filtering. AB - Using electrophysiology, the attentional functions of target selection and distractor filtering were investigated during visual search. Observers searched for multiple tilted line segments amidst vertical distractors. In different conditions, observers were either looking for a specific line orientation ("feature-based" selection), or for any tilted line ("salience-based"). The search array could contain both left- and rightward tilted lines simultaneously (requiring spatial filtering) or only one line type (no filtering). The amplitude of the P1 event-related potential component was reduced during feature-based selection, compared to salience-based selection. The N1 showed a similar effect, at least when filtering was required. Amplitudes were also somewhat reduced when competing nontarget stimuli required filtering. Interactions between selection and filtering became stronger on the N2a and P3. When both feature-based selection and filtering were required, N2a amplitude was highest, and P3 amplitude was lowest. The results support an early locus of feature-based attentional selection in multi-item search. PMID- 23454278 TI - An environmental wide association study (EWAS) approach to the metabolic syndrome. AB - BACKGROUND: Environmental contaminants have previously been linked to components of the Metabolic Syndrome (MetS). However, exposure to environmental contaminants is in part determined by various lifestyle factors. OBJECTIVE: Using an "Environmental Wide Association Study" (ELWAS) integrating environmental contaminants and lifestyle factors, we aimed to evaluate a possible additive role of both contaminants and lifestyle factors regarding MetS. METHODS: 1016 subjects aged 70years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. 43 environmental contaminants were measured in the circulation. Dietary records were used to evaluate 21 nutrients and the proportions of 13 fatty acids were determined in serum cholesterol esters to further quantify fat quality intake. Adding 5 other important lifestyle factors yielded together 76 environmental and lifestyle factors. MetS was defined by the NCEP/ATPIII-criteria. RESULTS: 23% had MetS. Using cross-validation within the sample, fourteen environmental contaminants or lifestyle factors consistently showed a false discovery rate <0.05. When the major variables entered a multiple model, only p, p'-DDE levels (positive), PCB209 (inverse) and exercise habits (inverse) were together with a fatty acid pattern, with high levels of palmitic acid and oleic acid and low levels of linoleic acid, related to MetS (p<0.002 for all variables). CONCLUSION: Using a cross-sectional EWAS approach, certain environmental contaminants and lifestyle factors were found to be associated with prevalent metabolic syndrome in an additive fashion in an elderly population. PMID- 23454279 TI - Occurrence and removal of antibiotic resistance genes in municipal wastewater and rural domestic sewage treatment systems in eastern China. AB - Antibiotic resistance genes (ARGs) are emerging environmental contaminants and pose a threat to public health. In this study, four tetracycline resistance genes (tetM, tetO, tetQ and tetW) and two sulfonamide resistance genes (sulI and sulII) were evaluated in 4 municipal wastewater and 8 rural domestic sewage treatment systems with different wastewater handling abilities and treatment processes using quantitative polymerase chain reaction (qPCR). In the influents, the relative abundance of different ARGs showed significant variations among the sampling sites. In addition, significant correlations (tetQ: R(2)=0.712, P<0.05; tetO: R(2)=0.394, P<0.05) between the gene copy numbers and wastewater-receiving capacity were observed. Statistical analysis revealed a positive correlation (R(2)=0.756, P<0.05) between the gene copy numbers of sulI and intI1, whereas the gene numbers of tetM and sulI were strongly correlated with 16S rDNA. Significant reductions (1-3 orders of magnitude) in ARGs were observed in municipal wastewater treatment systems, but a smaller reduction was found in the rural domestic sewage treatment systems. These results provide insights into the occurrence and removal of ARGs in wastewater treatment systems in both rural and urban areas in eastern China. PMID- 23454280 TI - Structural, enzymatic and biochemical studies on Helicobacter pylori arginase. AB - Arginase is an enzyme involved in the last step of the urea cycle, where it catalyses the hydrolysis of l-arginine to generate l-ornithine and urea. Compared to the well-characterised arginases from animals, yeast and other bacteria, Helicobacter pylori arginase, or RocF, is unique in at least three aspects. Firstly, it has been identified as an important factor in evasion of the host's immune system and thus contributes to persistent infection by the bacterium. Secondly, the optimal catalytic conditions of RocF are different from those of other arginases. Finally, sequence alignment indicates that RocF possesses considerable differences at its N- and C-terminal from other arginases and harbours an insertion of 13 residues in the middle of the sequence. To better understand these unique biochemical and enzymatic properties, we therefore have embarked on determining the structure of RocF. In this study, the crystal structure of RocF was solved with the molecular replacement method. Based on the structure and systematic mutagenesis studies, we confirmed that the inserted residues form a helix that was not observed in other arginases and was able to raise the arginase activity by 30% probably by change the conformation of the substrate binding pocket. Six residues were involved in Mn(2+) binding, all of which were essential for arginase activity. The C-terminal motif is not sufficient in establishing the oligomeric state of RocF, and no disulphide bonds were observed in RocF. PMID- 23454281 TI - Drosophila type XV/XVIII collagen mutants manifest integrin mediated mitochondrial dysfunction, which is improved by cyclosporin A and losartan. AB - Vertebrate collagen types XV and XVIII are broadly distributed basement membrane components, classified into a structurally distinct subgroup called "multiplexin collagens". Mutations in mammalian multiplexins are identified in some degenerative diseases such as Knobloch syndrome 1 (KNO1) or skeletal/cardiac myopathies, however, these progressive properties have not been elucidated. Here we investigated Drosophila mutants of Multiplexin (Mp), the only orthologue of vertebrate collagen types XV and XVIII, to understand the pathogenesis of multiplexin-related diseases. The mp mutants exhibited morphological changes in cardiomyocytes and progressive dysfunction of the skeletal muscles, reminiscent phenotypes observed in Col15a1-null mice. Ultrastructural analysis revealed morphologically altered mitochondria in mutants' indirect flight muscles (IFMs), resulting in severely attenuated ATP production and enhanced reactive oxygen species (ROS) production. In addition, mutants' IFMs exhibited diminished betaPS integrin clustering and abolished focal adhesion kinase (FAK) phosphorylation. Furthermore, mutants' defective IFMs are improved by the administrations of cyclosporin A, an inhibitor against mitochondrial permeability transition pore (mPTP) opening or losartan, an angiotensin II type 1 receptor (AT1R) blocker. Thus, our results suggest that Mp modulates mPTP opening and AT1R activity through its binding to integrin and that lack of Mp causes unregulated mPTP opening and AT1R activity, leading to mitochondrial dysfunctions. Hence, our results provide new insights towards the roles of multiplexin collagens in mitochondrial homeostasis and may serve as pharmacological evidences for the potential use of cyclosporin A or losartan for the therapeutic strategies. PMID- 23454282 TI - Editorial: Recorded scan times can limit the accuracy of sedimentation coefficients in analytical ultracentrifugation. PMID- 23454284 TI - Deficits of peripheral olfactory inputs reduce cell proliferation in the adult subventricular and subgranular zones. AB - Constitutive adult neurogenesis mainly occurs in the subgranular zone (SGZ) and subventricular zone (SVZ) of the mammalian brain. Intrinsic and extrinsic factors regulate adult neurogenesis processes including cell proliferation, migration, integration and neural survival. The potential contribution of olfactory sensory input to the regulation of adult neurogenesis, especially neurogenesis in the dentate gyrus, however, is not well studied. In the present study, we examined the effects of deficits in the peripheral olfactory inputs on cell proliferation in the adult SGZ and SVZ. With an anosmic model produced by ZnSO4 irrigation of the olfactory epithelium, we found that in the adult SVZ and SGZ the numbers of both BrdU labeled cells and doublecortin labeled cells (immature neurons) were significantly decreased, whereas the number of adult stem cells was not significantly altered. These results suggested that olfactory sensory input may play roles in regulating adult neurogenesis. PMID- 23454283 TI - Low frequency genetic variants in the MU-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine. AB - The MU-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute - Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24-0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. PMID- 23454285 TI - Increased error-related brain activity in youth with obsessive-compulsive disorder and other anxiety disorders. AB - The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response that is thought to reflect activity in the anterior cingulate cortex (ACC) and is often increased in patients with anxiety disorders. This study measured the ERN and correct response negativity (CRN) during an Eriksen flanker task to assess performance monitoring in 26 youth with obsessive-compulsive disorder (OCD), 13 youth with a non-OCD anxiety disorder consisting of either generalized anxiety disorder or separation anxiety disorder, and 27 age-matched healthy controls ranging in age from 8 to 16 years. Compared to healthy controls, ERN amplitude was significantly increased in patients with either OCD or a non-OCD anxiety disorder. There were no significant group differences in CRN amplitude. Treatment with a serotonergic antidepressant or cognitive-behavior therapy had no effect on the ERN in patients. Scores from the Child Behavior Checklist DSM-oriented anxiety problems scale had a significant correlation with ERN amplitude in all subjects. The results provide further evidence that the pathophysiology of OCD and some non-OCD anxiety disorders involves increased ACC activity and that the ERN may serve as a quantitative phenotype in genetic and longitudinal studies of these complex traits. PMID- 23454286 TI - Possible pitfalls investigating cell death responses in genetically engineered mouse models and derived cell lines. AB - Genetically engineered mouse models are frequently used to identify pathophysiological consequences of deregulated cell death. Targeting pro apoptotic or anti-apoptotic proteins of the extrinsic or intrinsic apoptotic signalling cascade is state of the art since more than two decades. Such animal models have been increasingly made use of over the past years to study loss- or gain-of-function consequences of one or more components of the molecular machinery leading to cell death. These studies have helped to separate redundant from non-redundant functions of apoptosis-related proteins in normal physiology and sometimes unravelled unexpected phenotypes. However, correct interpretation of data derived from knockout mice or derived cells and cell lines is often flawed by the comparison of cells originating from different inbred or mixed genetic backgrounds. Here we want to highlight some basic problems associated with genetic background-based modulation of cell death sensitivity and describe some methods that we use to investigate cell death responses in hematopoietic and non-hematopoietic cells. Thereby, we show that hematopoietic cells derived from wild type mice on a C57BL/6:129/SvJ recombinant mixed genetic background are significantly more resistant to spontaneous cell death or DNA-damage induced apoptosis in vitro than cells derived from inbred C57BL/6 mice. Furthermore, we show as an example that C57BL/6 mice are more susceptible to gamma-irradiation induced cell death after whole body irradiation in vivo and subsequent T cell lymphomagenesis. PMID- 23454287 TI - Evaluation of pyroptosis in macrophages using cytosolic delivery of purified flagellin. AB - Pyroptosis is a molecularly controlled form of cell death that exhibits some features of apoptosis as well of necrosis. Pyroptosis is induced by inflammasome activated caspase-1 or caspase-11 (caspase-4 in humans), as a result of distinct pathogenic or damage stimuli. Although pyroptosis displays some morphological and biochemical features of apoptosis, it has an inflammatory outcome due to the loss of plasma membrane integrity and the consequent release of intracellular contents, reminiscent to necrosis. Here, we use cytosolic delivery of purified flagellin as an experimental tool to trigger pyroptosis and describe potential methods to study this form of cell death. Finally, we discuss the advantages and limitations of these methods. PMID- 23454288 TI - In vivo assessment of specific cytotoxic T lymphocyte killing. AB - The direct killing of target cells by cytotoxic T lymphocytes (CTLs) plays a fundamental role in protective immunity to viral, bacterial, protozoan and fungi infections, as well as to tumor cells. In vivo cytotoxic assays take into account the interaction of target and effector cells in the context of the proper microenvironment making the analysis biologically more relevant than in vitro cytotoxic assays. Thus, the development, improvement and validation of in vivo methods are necessary in view of the importance of the results they may provide. We describe and discuss in this manuscript a method to evaluate in vivo specific cytotoxic T lymphocyte killing. We used as model system mice immunized with human recombinant replication-deficient adenovirus 5 (HAd5) containing different transgenes as the trigger of a CTL-mediated immune response. To these mice, we adoptively transferred syngeneic cells labeled with different vital fluorescent dyes. Donor cells were pulsed (target) or not (control non-target) with distinct CD8 T-cell epitopes, mixed in a 1:1 ratio and injected i.v. into immunized or non immunized recipient mice. After 18-24h, spleen cells are collected and analysed by flow cytometry. A deviation from the 1:1 ratio of control and target cell populations indicates antigen specific lysis of target cells. PMID- 23454289 TI - AFM volumetric methods for the characterization of proteins and nucleic acids. AB - The atomic force microscope overestimates lateral dimensions and underestimates heights of nanometer size objects such as proteins and nucleic acids. This has made researchers cautious of AFM measurements, even though there is no other technique capable of measuring topography with sub-nanometer precision. Nevertheless, several approaches for determining the stoichiometry of protein and protein-DNA complexes have been developed which show that, although the absolute values may be incorrect, the AFM volume is essentially proportional to the mass. This has allowed the determination of the mass of protein complexes with the help of a calibration curve. Here we review the main techniques for AFM volume measurements and detail a methodology that significantly reduces the associated errors. This method uses a fragment of DNA as a fiducial marker by which the volume of a protein is normalized. The use of fiducial markers co-adsorbed together with the protein of interest minimizes the contribution of tip-induced artifacts as they affect both the object of interest and the marker. Finally, we apply this method to the measurement of the length of single-stranded DNA. A linear relationship between length and volume was obtained, opening the door to studies of ssDNA intermediates formed during complex DNA transactions such as replication, recombination and repair. PMID- 23454290 TI - Quantification of histone modifications using 15N metabolic labeling. AB - Mass spectrometry has made major contributions to recent discoveries in the field of epigenetics, particularly in the characterization of the myriad post translational modifications (PTMs) of histones which are technically challenging to analyze. These new developments have further aroused great interest in development of robust, new mass spectrometric methods to quantitatively study the dynamics of histone modifications. This review covers quantitative analysis of histone PTMs and discuss an 15N metabolic labeling procedure for quantifying histone PTMs applied to the analysis of methyltransferase knockouts in the model organism, Tetrahymena thermophila. PMID- 23454291 TI - Effects of stressor controllability on diurnal physiological rhythms. AB - Disruptions in circadian and diurnal rhythms are associated with stress-related psychiatric disorders and stressor exposure can disrupt these rhythms. The controllability of the stressor can modulate various behavioral and neurochemical responses to stress. Uncontrollable, but not controllable, stress produces behaviors in rats that resemble symptoms of anxiety and depression. Whether acute stress-induced disruptions in physiological rhythms are sensitive to controllability of the stressor, however, remains unknown. To examine the role of controllability in diurnal rhythm disruption, adult male Sprague-Dawley rats were implanted with Data Sciences International (DSI) biotelemetry devices. Real-time measurements were obtained before, during and after exposure to a controllable or yoked uncontrollable stressor. Controllable and uncontrollable stress equally disrupted diurnal rhythms of locomotor activity and body temperature but not heart rate. The diurnal heart rate the day following stressor exposure was flattened to a greater extent and was significantly higher in rats with control over stress suggesting a relationship between stressor controllability and the heart rate response. Our results are consistent with the conclusion that acute stress-induced disruptions in diurnal physiological rhythms likely contribute little to the behavioral and affective consequences of stress that are sensitive to stressor controllability. PMID- 23454292 TI - Plant growth-promoting bacteria Bacillus amyloliquefaciens NBRISN13 modulates gene expression profile of leaf and rhizosphere community in rice during salt stress. AB - Growth and productivity of rice and soil inhabiting microbial population is negatively affected by soil salinity. However, some salt resistant, rhizosphere competent bacteria improve plant health in saline stress. Present study evaluated the effect of salt tolerant Bacillus amyloliquefaciens NBRISN13 (SN13) inoculation on rice plants in hydroponic and soil conditions exposed to salinity. SN13 increased plant growth and salt tolerance (NaCl 200 mM) and expression of at least 14 genes under hydroponic and soil conditions in rice. Among these 14 genes 4 (NADP-Me2, EREBP, SOSI, BADH and SERK1) were up-regulated and 2 (GIG and SAPK4) repressed under salt stress in hydroponic condition. In greenhouse experiment, salt stress resulted in accumulation of MAPK5 and down-regulation of the remaining 13 transcripts was observed. SN13 treatment, with or without salt gave similar expression for all tested genes as compared to control. Salt stress caused changes in the microbial diversity of the rice rhizosphere and stimulated population of betaine-, sucrose-, trehalose-, and glutamine-utilizing bacteria in salt-treated rice rhizosphere (SN13 + salt). The observations imply that SN13 confers salt tolerance in rice by modulating differential transcription in a set of at least 14 genes. Stimulation of osmoprotectant utilizing microbial population as a mechanism of inducing salt tolerance in rice is reported for the first time in this study to the best of our knowledge. PMID- 23454293 TI - Identification of miRNAs involved in long-term simulated microgravity response in Solanum lycopersicum. AB - To identify the miRNAs associated with the simulated microgravity response in plants and to ascertain the regulation network mediated by miRNAs under simulated microgravity conditions, we constructed a miRNA library by direct cloning method and analyzed the library. Seven miRNAs that are conserved in other plants were cloned for the first time in Solanum lycopersicum under simulated microgravity condition. The expressions of six of the seven miRNAs were up-regulated, especially by long-term simulated microgravity. Gene ontology analysis showed that most of the predicted targeted genes were involved in transcription regulation, signal transduction and stress response, implying a complicated relationship among the external signal, internal transduction and final phenotype. Six of the predicted targets were validated by 5' RACE and reverse transcription real-time quantitative PCR. The results showed that with increasing miRNA expression levels, the corresponding target genes were down-regulated. The target gene of one of miRNAs, miR159e*, was thought to be associated with an increasing of starch amount under microgravity condition. A multi-stresses response network mediated by miRNAs under simulated microgravity condition was proposed. Cis-elements located in the upstream sequences of each miRNA were identified and their roles in gene regulation were investigated. In addition to the seven miRNAs that had homologs in other plants, six conserved S. lycopersicum miRNAs were identified. In the study, miRNAs were identified in S. lycopersicum for the first time under long-term simulated microgravity condition, which will help reveal the regulation mechanism mediated by miRNAs under simulated microgravity condition and adaptation to Earth's gravity. PMID- 23454294 TI - Evaluation of suitable reference genes for normalization of microRNA expression by real-time reverse transcription PCR analysis during longan somatic embryogenesis. AB - Accurate profiling of microRNAs (miRNAs) is an essential step for understanding both developmental and physiological functions of miRNAs. Real-time quantitative PCR (qPCR) is being widely used in miRNA expression studies, but choosing a suitable reference gene is a crucial factor for correct analysis of results. To date, there has been no systematic evaluation of qPCR reference genes for the study of miRNAs during somatic embryogenesis (SE) in the longan tree (Dimocarpus longan). Here, the most stably expressed miRNAs in synchronized longan tree embryogenic cultures at different developmental stages were determined using the geNorm and NormFinder algorithms. Validation qPCR experiments were performed for 24 miRNAs together with a snRNA (U6 snRNA), a rRNA (5S rRNA), and three housekeeping genes. It was found that small RNAs had better expression stability than protein-coding genes, and dlo-miR24 was identified as the most reliable reference gene, followed by dlo-miR168a*, dlo-miR2089*-1 and 5S rRNA. dlo-miR24 was recommended as a normalizer if only a single reference gene was to be used, while the combination of dlo-miR156c, dlo-2089*-1 and 5S rRNA was preferred to normalize miRNA expression data during longan SE. PMID- 23454295 TI - Differential lasting inhibitory effects of oxytocin and food-deprivation on mediobasal hypothalamic polydipsia. AB - This study analyzed the effects of systemic oxytocin (OT) administration and 48-h food deprivation on the polydipsia, hyperphagia, and polyuria produced by electrolytic lesions of the mediobasal hypothalamus (MBH). In a first experiment, food deprivation transiently decreased the polydipsic response, whereas food deprivation plus OT administration reduced the water intake and urine excretion of polydipsic animals but not their subsequent food intake. These results were replicated in a second experiment (20 days), which also showed that OT potentiates sodium excretion, reducing the estimated plasma sodium levels in food deprived MBH-lesioned animals. Administration of OT on day 21 to food-deprived (from day 20 to 22) animals (second period of the experiment 2) blocked the differences in water intake and urine excretion volumes between MBH and control animals on days 21 and 22. Subsequently, this 48-h food deprivation induced an additional and lasting (days 23-40) reduction in the intake of water and food of MBH animals. According to these findings, OT administration and/or food deprivation may potentially exert enduring reducing effects on the polydipsia, polyuria, and hyperphagia of MBH syndrome. PMID- 23454296 TI - Genotoxicity assessment of vaccine adjuvant squalene. AB - The genotoxic potential of the vaccine adjuvant Squalene was assessed by the chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and micronucleus (MNs) tests in human lymphocytes and comet assay in both human and rat lymphocytes. Five different concentrations of squalene (1250-20,000 MUg/ml for human lymphocytes and 0.07-1.12 mg/kg for rat lymphocytes) were studied. Squalene did not affect the CAs and MN frequency, in all treatments in vitro. A significant increase in SCEs was observed in almost all concentrations at 24 h treatment. Squalene did not affect significantly the comet tail length (CTL) (except 2500 MUg/ml) and comet tail intensity (CTI) at all treatments in vitro. In rats, squalene significantly increased and decreased CTL and CTI in some doses. Although there are increasing and reduction in the effect, squalene cannot be regarded as genotoxic in human lymphocytes. However, further in vivo studies are required to be sure on the effect. PMID- 23454297 TI - Caffeic acid treatment alters the extracellular adenine nucleotide hydrolysis in platelets and lymphocytes of adult rats. AB - This study evaluated the effects of caffeic acid on ectonucleotidase activities such as NTPDase (nucleoside triphosphate diphosphohydrolase), Ecto-NPP (nucleotide pyrophosphatase/phosphodiesterase), 5'-nucleotidase and adenosine deaminase (ADA) in platelets and lymphocytes of rats, as well as in the profile of platelet aggregation. Animals were divided into five groups: I (control); II (oil); III (caffeic acid 10 mg/kg); IV (caffeic acid 50 mg/kg); and V (caffeic acid 100 mg/kg). Animals were treated with caffeic acid diluted in oil for 30 days. In platelets, caffeic acid decreased the ATP hydrolysis and increased ADP hydrolysis in groups III, IV and V when compared to control (P<0.05). The 5' nucleotidase activity was decreased, while E-NPP and ADA activities were increased in platelets of rats of groups III, IV and V (P<0.05). Caffeic acid reduced significantly the platelet aggregation in the animals of groups III, IV and V in relation to group I (P<0.05). In lymphocytes, the NTPDase and ADA activities were increased in all groups treated with caffeic acid when compared to control (P<0.05). These findings demonstrated that the enzymes were altered in tissues by caffeic acid and this compound decreased the platelet aggregation suggesting that caffeic acid should be considered a potentially therapeutic agent in disorders related to the purinergic system. PMID- 23454298 TI - An antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery in rats: a 28-day repeated dose test and reproduction/developmental toxicity test. AB - A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N'-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28 days at 0, 100, 300, or 1000 mg/kg bw/day or for a total of 42-46 days at 0, 8, 50, or 300 mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000 mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another female delivered only three live pups at 300 mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8 mg/kg bw/day, respectively. PMID- 23454299 TI - Prediction and characterization of the linear IgE epitopes for the major soybean allergen beta-conglycinin using immunoinformatics tools. AB - The alpha subunit of beta-conglycinin is a major allergen in soybean. The objective of this study was to predict and identify the linear immunoglobulin (Ig)E epitopes of the soybean alpha subunit of beta-conglycinin. Three immunoinformatics tools were used to predict the potential epitopes and were confirmed by dot-blot inhibition using sera from soybean allergic subjects. As a result, 15 peptides were predicted and assembled by solid-phase synthesis. Eleven epitopes were identified by the dot-blot inhibition test. Moreover, peptide 3 had IgE binding capability with all sera(5/5) tested, while peptide 1, 4, 6, 8 and12 could bind to 4/5 of the sera samples. Secondary structure prediction of peptide 3 and circular dichroism test validated that the structure of peptide 3 was a random coil. PMID- 23454300 TI - Phenotypic analysis of ovine antigen presenting cells loaded with nanoparticles migrating from the site of vaccination. AB - Virus-sized particulate adjuvants such as ISCOMs, polystyrene nanoparticles and virus-like particles have been shown to target dendritic cells, resulting in the activation of T and B cells in vivo. Using an ovine pseudo-afferent lymph cannulation model to capture APC that traffic from the site of injection to the local lymph node, we show that 40-50 nm nanoparticles are taken up at the site of injection by dendritic cells (DCs) migrating to the draining lymph node. These DCs can express CD11c, CD1b, CD5, MHC class II and CD8. Nanoparticles transported by DCs migrating from the site of injection to the local lymph node therefore needs to be considered as a new mechanism underlying the immunogenicity of virus sized vaccine delivery systems. PMID- 23454301 TI - Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM), a common cause of heart failure, is characterized by cardiac dilation and reduced left ventricular ejection fraction, but the underlying mechanisms remain unclear. To investigate the mechanistic basis, we performed global metabolomic analysis of myocardial tissues from the left ventricles of J2N-k cardiomyopathic hamsters. This model exhibits symptoms similar to those of human DCM, owing to the deletion of the delta-sarcoglycan gene. Charged and lipid metabolites were measured by capillary electrophoresis mass spectrometry (MS) and liquid chromatography MS(/MS), respectively, and J2N-k hamsters were compared with J2N-n healthy controls at 4 (presymptomatic phase) and 16weeks (symptomatic) of age. Disturbances in membrane phospholipid homeostasis were initiated during the presymptomatic phase. Significantly different levels of charged metabolites, occurring mainly in the symptomatic phase, were mapped to primary metabolic pathways. Reduced levels of metabolites in glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle, together with large decreases in major triacylglycerol levels, suggested that decreased energy production leads to cardiac contractile dysfunction in the symptomatic phase. A mild reduction in glutathione and a compensatory increase in ophthalmate levels suggest increased oxidative stress in diseased tissues, which was confirmed by histochemical staining. Increased levels of 4 eicosanoids, including prostaglandin (PG) E2 and 6-keto-PGF1alpha, in the symptomatic phase suggested activation of the protective response pathways. These results provide mechanistic insights into DCM pathogenesis and may help identify new targets for therapeutic intervention and diagnosis. PMID- 23454302 TI - Studies on the interactions between ginsenosides and liposome by equilibrium dialysis combined with ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - To study the interactions between components of Panax Ginseng and liposome biomembrane, we applied the equilibrium dialysis system combined with ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach to analyze and identify the bioactive components of ginseng. Moreover, the effect of pH value has also been investigated on their interactions between the ginsenosides of ginseng extract and biomembrane. The result shows that seven kinds of ginsenosides have obvious interactions with biomembrane in comparison with the standards in terms of tandem mass spectrometry (MS/MS) data along with retention time, including four panaxadiol ginsenosides (Rb1, Rb2, Rc, Rd) and three panaxatriol ginsenosides (Re, Rf, Rg2). The value of binding degree decreased with the increase of molecular weight. The sugar moieties which are attached to C-20 were the main factor affecting the binding degree of panaxadiol ginsenosides. The interactions between panaxadiol ginsenosides and biomembrane correlate to the type and number of sugar moieties in ginsenosides. The sugar moieties which are at C-6 and C-20 have been shown to influence the value of binding degree for panaxatriol ginsenosides. In addition, the pH value has been shown to have an impact on the interactions. Overall, ginsenoside Rd has a better absorption character among the seven ginsenosides. In the study, we have screened the potential bioactive components of ginseng in vitro using the equilibrium dialysis-UPLC-MS/MS method, and then predicted the potential bioactivities of ginseng, which contribute to the investigation of the efficacy of ginseng. PMID- 23454303 TI - Optimization of on-line solid phase extraction and HPLC conditions using response surface methodology for determination of WM-5 in mouse plasma and its application to pharmacokinetic study. AB - Response surface methodology (RSM) was utilized for rapid and systematic optimization of on-line solid-phase extraction (SPE) parameters to maximize the response and separation of WM-5. The optimization was performed with Box-Behnken designs. Four major parameters were investigated for their contributions to the response and separation of WM-5, with a total of 29 experiments being performed for each instrument, respectively. Quantitative determination of WM-5 in mouse plasma was performed to evaluate the statistical significance of the parameters on chromatographic response. A fully automated on-line SPE and high-performance liquid chromatography (HPLC) with diode array detection (DAD) method was developed for the determination of WM-5 in mouse plasma. Calibration curve with good linearity (r=0.9989) was obtained in the range of 20-4000 ng/mL in mouse plasma. The limit of detection (LOD) and lower limit of quantification (LLOQ) of the assay were 6 ng/mL and 20 ng/mL, respectively. The overall intra-day and the inter-day variations were less than 1.90%. The recovery of the method was in the range of 93.74-96.33% with RSD less than 3.06%. The optimized method demonstrated good performance in terms of specificity, LLOQ, linearity, recovery, precision and accuracy, and was successfully applied to quantify WM-5 in mouse plasma to support the pharmacokinetic study. PMID- 23454304 TI - Deglycosylation systematically improves N-glycoprotein identification in liquid chromatography-tandem mass spectrometry proteomics for analysis of cell wall stress responses in Saccharomyces cerevisiae lacking Alg3p. AB - Post-translational modification of proteins with glycosylation is of key importance in many biological systems in eukaryotes, influencing fundamental biological processes and regulating protein function. Changes in glycosylation are therefore of interest in understanding these processes and are also useful as clinical biomarkers of disease. The presence of glycosylation can also inhibit protease digestion and lower the quality and confidence of protein identification by mass spectrometry. While deglycosylation can improve the efficiency of subsequent protease digest and increase protein coverage, this step is often excluded from proteomic workflows. Here, we performed a systematic analysis that showed that deglycosylation with peptide-N-glycosidase F (PNGase F) prior to protease digestion with AspN or trypsin improved the quality of identification of the yeast cell wall proteome. The improvement in the confidence of identification of glycoproteins following PNGase F deglycosylation correlated with a higher density of glycosylation sites. Optimal identification across the proteome was achieved with PNGase F deglycosylation and complementary proteolysis with either AspN or trypsin. We used this combination of deglycosylation and complementary protease digest to identify changes in the yeast cell wall proteome caused by lack of the Alg3p protein, a key component of the biosynthetic pathway of protein N-glycosylation. The cell wall of yeast lacking Alg3p showed specifically increased levels of Cis3p, a protein important for cell wall integrity. Our results showed that deglycosylation prior to protease digestion improved the quality of proteomic analyses even if protein glycosylation is not of direct relevance to the study at hand. PMID- 23454305 TI - Determination of methylphenidate in plasma and saliva by liquid chromatography/tandem mass spectrometry. AB - Methylphenidate (MPH) is a phenethylamine derivative used in the treatment of attention-deficit hyperactivity disorder (ADHD). In adults, clinical monitoring of MPH therapy is usually performed by measuring plasma MPH concentrations. In children blood sampling is however undesirable. Saliva may be an alternative matrix for monitoring MPH concentrations with the advantage that it can be obtained non-invasively. Therefore, we developed an analytical method for the quantification of MPH in both plasma and saliva. We present the validation of a liquid chromatography-tandem mass spectrometric method using a hydrophilic interaction liquid chromatography column (HILIC). In 100 MUL sample, proteins were precipitated with 750 MUL acetonitrile/methanol 84/16 (v/v) containing d9 methylphenidate as the internal standard. Standard curves were prepared over the MPH concentration range of 0.5-100.0 MUg/L. The total analysis time was 45 s. Accuracy and within- and between-run imprecision were in the range of 98-108% and less than 7.0%, respectively. Matrix effects were greater for plasma than saliva with 46% and 8% ionization suppression. The matrix effects were adequately compensated by the use of deuterated MPH as internal standard. MPH significantly degraded in plasma and saliva at room temperature and 5 degrees C. Samples were stable at -20 degrees C for at least 4 weeks. The method was successfully applied for the determination of MPH concentrations in plasma and saliva samples from an adult healthy volunteer. Using protein precipitation and hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry, this method allows fast, accurate and precise quantification of MPH in both plasma and saliva. PMID- 23454306 TI - Toxic and genotoxic effects of Roundup on tadpoles of the Indian skittering frog (Euflictis cyanophlyctis) in the presence and absence of predator stress. AB - Glyphosate, a post emergent herbicide, has become the backbone of no-till agriculture and is considered safe for animals. However, the impact of glyphosate on non-target organisms, especially on amphibians, is the subject of major concern and debate in recent times. We examined the toxic and genotoxic effects of Roundup, a commercial formulation of glyphosate, in the tadpoles of the Indian skittering frog (Euflictis cyanophlyctis). Roundup at different concentrations (0, 1, 2, 3, 4 and 8mg acid equivalent (ae)/L), tested in a 2*6 factorial design in the presence and absence of predator stress, induced concentration-dependent lethality in tadpoles. The 96-h LC50 for Roundup in the absence and presence of predator stress were 3.76mgae/L and 3.39mgae/L, respectively. The 10-day LC50 value for Roundup was significantly lower, 2.12mgae/L and 1.91mgae/L in the absence and presence of predator stress, respectively. Lower concentrations of Roundup (1, 2 and 3mgae/L) induced the formation of micronuclei (MN) in the erythrocytes of tadpoles at 24-h (F3,56=10.286, p<0.001), 48-h (F3,56=48.255, p<0.001), 72-h (F3,56=118.933, p<0.001) and 96-h (F3,56=85.414, p<0.001) in a concentration-dependent manner. Presence of predator stress apparently increased the toxicity and genotoxicity of Roundup; but these effects were not statistically significant. These findings suggest that Roundup at environmentally relevant concentrations has lethal and genotoxic impact on E. cyanophlyctis; which may have long-term fitness consequence to the species. PMID- 23454307 TI - Inter-site differences of zinc susceptibility of the oyster Crassostrea hongkongensis. AB - Understanding the underlying mechanisms governing metal toxicity is crucial for predicting the risks and effects of metal pollutants. We hypothesized that metal toxicity is related to a threshold concentration of metabolically available metal but not to the total body metal concentration. Following a two-month laboratory Zn exposure, we characterized mortality and Zn bioaccumulation and subcellular partitioning in the oyster Crassostrea hongkongensis sampled from three sites with contrasting histories of Zn exposure and one multiple-metal contaminated site. Large differences in Zn sensitivity, lethal body concentration, and detoxification capability between sites were observed. Specifically, the oysters from the highly Zn-contaminated site were more tolerant to Zn exposure than those from the relatively clean ones, and the former accumulated and detoxified more Zn and had a significantly higher lethal body Zn concentration. The accumulation of Zn in the metabolically available pool (operationally defined as the metal sensitive fraction) in the oysters from the multiple-metal contaminated site was relatively fast, and correspondingly they were highly sensitive to Zn exposure. The lethal threshold concentration of total body Zn varied significantly within the four sites, and thus total body Zn concentration could not serve as a suitable toxicity indicator. Importantly, Zn accumulation within the operationally defined metabolically available pool better explained variances in mortality than Zn accumulation in the whole body. Our results suggested that Zn toxicity is governed by its accumulation in the metabolically available pool, not the total accumulated Zn concentration. PMID- 23454308 TI - Cytotoxicity of aluminium oxide nanoparticles towards fresh water algal isolate at low exposure concentrations. AB - The growing commercial applications had brought aluminium oxide nanoparticles under toxicologists' purview. In the present study, the cytotoxicity of two different sized aluminium oxide nanoparticles (ANP(1), mean hydrodynamic diameter 82.6+/-22nm and ANP(2), mean hydrodynamic diameter 246.9+/-39nm) towards freshwater algal isolate Chlorella ellipsoids at low exposure levels (<=1MUg/mL) using sterile lake water as the test medium was assessed. The dissolution of alumina nanoparticles and consequent contribution towards toxicity remained largely unexplored owing to its presumed insoluble nature. Herein, the leached Al(3+) ion mediated toxicity has been studied along with direct particulate toxicity to bring out the dynamics of toxicity through colloidal stability, biochemical, spectroscopic and microscopic analyses. The mean hydrodynamic diameter increased with time both for ANP(1) [82.6+/-22nm (0h) to 246.3+/-59nm (24h), to 1204+/-140nm (72h)] and ANP(2) [246.9+/-39nm (0h) to 368.28+/-48nm (24h), to 1225.96+/-186nm (72h)] signifying decreased relative abundance of submicron sized particles (<1000nm). The detailed cytotoxicity assays showed a significant reduction in the viability dependent on dose and exposure. A significant increase in ROS and LDH levels were noted for both ANPs at 1MUg/mL concentration. The zeta potential and FT-IR analyses suggested surface chemical interaction between nanoparticles and algal cells. The substantial morphological changes and cell wall damage were confirmed through microscopic analyses (SEM, TEM, and CLSM). At 72h, significant Al(3+) ion release in the test medium [0.092MUg/mL for ANP(1), and 0.19MUg/mL for ANP(2)] was noted, and the resulting suspension containing leached ions caused significant cytotoxicity, revealing a substantial ionic contribution. This study indicates that both the nano-size and ionic dissolution play a significant role in the cytotoxicity of ANPs towards freshwater algae, and the exposure period largely determines the prevalent mode of nano-toxicity. PMID- 23454309 TI - Food web analysis reveals effects of pH on mercury bioaccumulation at multiple trophic levels in streams. AB - Biomagnification processes and the factors that govern them, including those for mercury (Hg), are poorly understood in streams. Total and methyl Hg concentrations and relative trophic position (using delta(15)N) were analyzed in biofilm and invertebrates from 21 streams in New Brunswick, Canada to assess food web biomagnification leading to the common minnow blacknose dace (Rhinichthys atratulus), a species known to have Hg concentrations that are higher in low pH waters. Biomagnification slopes within stream food webs measured using Hg vs. delta(15)N or corresponding trophic levels (TL) differed depending on the chemical species analyzed, with total Hg exhibiting increases of 1.3-2.5 per TL (mean slope of total Hg vs. delta(15)N=0.14+/-0.06 S.D., range=0.06-0.20) and methyl Hg showing a more pronounced increase of 2.8 to 6.0 per TL (mean slope of methyl Hg vs. delta(15)N=0.30+/-0.08 S.D., range=0.22-0.39). While Hg biomagnification slopes through the entire food web (Trophic Magnification Factors, TMFs) were not influenced by water chemistry (pH), dietary concentrations of methyl Hg strongly influenced biomagnification factors (BMFs) for consumer-diet pairs within the food web at lower trophic levels, and BMFs between dace and predatory invertebrates were significantly higher in low pH waters. These analyses, coupled with observations of higher Hg in primary producers in streams with low pH, suggest that pH influences both baseline concentrations and biomagnification of Hg in these systems. Because higher Hg concentrations in the diets of primary consumers and predatory insects in lower pH waters led to lower BMFs, these feeding groups showed insignificant relationships between Hg and pH; thus, altered BMFs associated with dietary concentrations can dampen the effects of environmental conditions on Hg concentrations. PMID- 23454310 TI - Light induced toxicity reduction of silver nanoparticles to Tetrahymena Pyriformis: effect of particle size. AB - As a result of the extensive application of silver nanoparticles (AgNPs), their potential hazards, once they are released into the natural environment, are of great concern to people. Since silver is very sensitive to light, the toxicity of AgNPs released into the natural environment will be inevitably affected by light. The aim of this study was to investigate the relationship between light, toxicity, and particle size of AgNPs and deduce the possible mechanism of any interaction. Our study revealed that there was negative correlation between the particle size and the toxicity: small AgNPs (5-10nm) had higher toxicity than large AgNPs (15-25nm) to Tetrahymena pyriformis (T. pyriformis) under dark condition. Comparing the size dependent AgNPs toxicity under dark and light conditions, the effect of light to size dependent AgNPs toxicity was ascertained. The results indicated that AgNPs toxicity was decreased by light and the most important discovery was that the change of size dependent AgNPs toxicity had significant difference under light irradiation. The decrease of small AgNPs toxicity induced by light was more notable than large AgNPs. The decreased level of cell toxicity for small AgNPs was 32+/-0.7%, whereas it was only 10.6+/-5.2% for large AgNPs kept 24h under light irradiation. The further investigation indicated that the above changes induced by light can be attributed to the decrease of released silver ions, particle growth and aggregation of AgNPs under light irradiation. The obtained results showed that the light irradiation can promote the rapid growth of small AgNPs and result in the obvious increase of particle size and serious aggregation. These phenomena would induce the decrease of silver ions released from small AgNPs, which is responsible for the remarkable decrease of toxicity for small AgNPs. PMID- 23454311 TI - Finding happiness even at work. PMID- 23454312 TI - Azithromycin associated with a small increased risk of cardiovascular death: a review. PMID- 23454313 TI - Pulp capping materials-is there anything better than Dycal? PMID- 23454314 TI - Horizontal root fracture in a maxillary central incisor: a case report. AB - Horizontal root fractures usually are characterized by a fracture line that is perpendicular to the long axis of the tooth's root. Root fractures are diagnosed through clinical and radiographic examination. Treatment depends on the position of the fracture and the extent of root involvement. Successful treatment depends on correct diagnosis, clinical management, and radiographic follow-up. This article describes the successful treatment (with a 3-year follow-up period) of a permanent maxillary central incisor with horizontal root fracture treated with calcium hydroxide, in which the coronal segment was necrotic and the apical segment remained vital. PMID- 23454315 TI - Dental findings in a child with chronic renal failure secondary to cystinosis. AB - Cystinosis is a genetically determined metabolic disorder whose most prominent feature is end-stage renal disease. This case report describes the dental status of a 12-year-old child with a history of chronic renal failure secondary to cystinosis. Observed dental anomalies included enamel hypoplasia and hypocalcification, delayed dental development, and dental agenesis. Oral manifestations of nephropathic cystinosis are not well documented in the literature, so it is very important to highlight the dental characterizations of this complex disease. PMID- 23454316 TI - Healing of apical periodontitis through modern endodontic retreatment techniques. AB - The presence of apical periodontitis in teeth which have undergone initial root canal treatment is largely attributed to bacteria residing in or invading from the apical root canal space. Bacteria-associated apical periodontitis will not heal spontaneously, nor will systemic antibiotics eradicate the infection. Only endodontic retreatment, endodontic surgery, or extraction will control the bacterial etiology. Modern retreatment is an effective means of addressing apical periodontitis. A mandibular premolar with apical periodontitis, apical root resorption, and overfilled gutta percha was retreated with post removal, retrieval of gutta percha from beyond the apex, ultrasonic irrigation and disinfection, and placement of a collagen internal matrix to facilitate a well controlled MTA apical fill. The magnification and illumination imparted by the operating microscope was integral to achievement of treatment objectives. The patient's symptoms were resolved and complete osseous healing occurred. During treatment planning, clinicians should consider the capability of modern endodontic techniques to overcome technical challenges, often allowing the natural dentition to be preserved and restored to function days after retreatment. PMID- 23454317 TI - Effect of endodontic irrigation with 1% sodium hypochlorite and 17% EDTA on primary teeth: a scanning electron microscope analysis. AB - This study evaluated the efficacy of 2 final irrigation solutions for removal of the smear layer (SL) from root canals of primary teeth, using scanning electron microscope (SEM) analysis. Thirty primary molars were selected and a single operator instrumented the canals. The initial irrigation was done with a 1% sodium hypochlorite (NaOCl) solution. After the preparation, the roots were randomly divided into 3 groups for final irrigation: Group 1, 1% NaOCl (n = 10); Group 2, 17% EDTA + 1% NaOCl (n = 10); and Group 3, 17% EDTA + saline solution (n = 10). The roots were prepared for SEM analysis (magnification 1000X). The photomicrographs were independently analyzed by 2 investigators with SEM experience, attributing scores to each root third in terms of SL removal. Kruskal Wallis and Mann-Whitney tests revealed that there was no statistical difference between the groups (P = 0.489). However, a statistical difference was found (P < 0.05) in a comparison of root thirds, with the apical third having the worst results. Comparing the thirds within the same group, all canals showed statistical differences between the cervical and apical thirds (P < 0.05). The authors determined that no substance or association of substances were able to completely remove SL. PMID- 23454318 TI - Tilted implants and prototyping: a security option for improving the anchorage in atrophic maxilla. AB - Rehabilitating atrophic maxilla poses many challenges. Reconstructive techniques that require sinus grafting are viable and acceptable; however, these techniques also are considered to be expensive, invasive, and time-consuming. Tilted implants anchored in distal areas using available bone have been reported as a less invasive and highly predictable treatment option. This article presents a case involving implant anchorage via tilted implants as an alternative technique to bone grafting procedures. PMID- 23454319 TI - Blood contamination of used dental anesthetic cartridges. AB - This study sought to determine the levels of blood contamination found in and/or on used dental anesthetic cartridges and to measure antibacterial effects after exposure to a local anesthetic solution. The study analyzed a total of 1000 used cartridges from an oral surgery clinic, containing 1 of 3 anesthetic types. Blood testing included visual observations (using a dissecting microscope) and chemical analyses. From each cartridge, either 0.5 ml of residual anesthetic solution or a combination of anesthetic solution plus added saline was removed. Using reagent strip dipsticks, the solutions were analyzed for minute amounts of blood. Visual examinations were scored on a positive or negative scale. In addition, 4 types of bacteria were mixed with lidocaine or phosphate buffered saline (PBS) for up to 30 days, and viable cell counts decreases were measured for the 2 solutions. A majority of the cartridges evaluated contained lidocaine, and while only 7 of the 1000 cartridges examined contained visible blood, the reagent strips detected blood in more than 76% of all cartridges. Lidocaine and PBS produced similar bacterial death rates. The authors concluded that blood contamination levels in the absence of pronounced antibacterial activity indicate that dental anesthetic cartridges could be considered a potential type of regulated medical waste. PMID- 23454320 TI - Dental erosion due to abuse of illicit drugs and acidic carbonated beverages. AB - Consumption of illicit drugs and the abusive intake of acidic carbonated beverages (particularly soda) often are associated with similar types of damage to the human dentition, the most common of which is dental erosion. The dentitions of individuals who are addicted to methamphetamines or crack cocaine can be misdiagnosed as dental caries rather than generalized dental erosion, a condition that also is associated with chronic excessive consumption of soda. Failing to identify the causative etiology could lead to a wrongful diagnosis that could in turn adversely affect treatment planning and misdirect a specified prevention protocol. This article seeks to identify the unique clinical features of each one of these conditions, highlight the resemblances between them, and recognize the unambiguous differences in their fundamental characteristics. Three representative cases-involving a methamphetamine user, a crack cocaine addict, and an avid consumer of diet soda-are presented. In each case, the patient has admitted to the cause of their poor oral health. The dental, oral, and paraoral manifestations of each case are documented and differentiated from one another, and the factors that contributed to the associated disease process are discussed. PMID- 23454321 TI - Fracture resistance of weakened teeth restored using accessory glass fiber posts. AB - This study used differential root weakening to evaluate the fracture resistance of bovine teeth restored using glass fiber posts (with or without accessory glass fiber posts). Fifty bovine mandibular incisors were sectioned 14 mm from the apex, fixed in acrylic resin blocks, and divided into 5 groups: healthy roots with a glass fiber post (Group 1), partially weakened teeth with a glass fiber post (Group 2), partially weakened teeth with a glass fiber post and 2 accessory glass fiber posts (Group 3), extensively weakened teeth with a glass fiber post (Group 4), and extensively weakened teeth with a glass fiber post and 5 accessory glass fiber posts (Group 5). Posts were luted with resin cement, cores were prepared using composite resin, and metallic crowns were cemented. The specimens were stored in distilled water at 37 degrees C for more than 72 hours until the fracture resistance test. Specimens were loaded at 135 degrees relative to the long axis of the tooth at a crosshead speed of 0.5 mm/minute in a universal testing machine. All groups predominantly exhibited favorable failure patterns and there were no statistically significant differences between groups (two-way ANOVA, alpha = 0.05). PMID- 23454322 TI - Subepithelial connective tissue graft: an alternative application for treating endoperiodontal lesions. AB - This article presents an endoperiodontal lesion treated with a subepithelial connective tissue graft technique using periosteum. A patient with a right lateral maxillary incisor that had been retracted endodontically had gingival fenestration and recession, as well as an extensive apical lesion. Surgery was performed, and 5 months later a metal-ceramic crown was installed. At 6 years post-treatment, the periodontal tissues were stable and there was satisfactory new apical bone formation. PMID- 23454323 TI - A complete esthetic approach with multiple diastemata in anterior teeth: 1-year follow-up. AB - Anterior diastemata and discolored teeth may interfere with the harmony of a person's smile. This article presents a case involving multidisciplinary intervention for esthetic treatment utilizing integrated microabrasion, dental bleaching, and restorative solutions. The relevant aspects of etiology and treatment planning are discussed. PMID- 23454324 TI - Prevalence and variations of the median maxillary labial frenum in children, adolescents, and adults in a diverse population. AB - The median maxillary labial frenum (MMLF) is a normal anatomic structure with inherent morphologic variations. This study sought to evaluate the prevalence of those variations in a diverse ethnic population and to educate practitioners about the prevalence of MMLF variations to prevent unnecessary biopsies. This study included adult, adolescent, and child patients at the Louisiana State University Health Science Center School of Dentistry. Among the 284 subjects examined, frenum normale was the most common frenum classification, followed by frenum with nodule and frenum with appendix. Most nodules were found in the intermediate third of the MMLF, while appendices were mainly found in the labial third. The prevalence of an appendix was significantly higher (P < 0.001) in Caucasians compared to African-Americans. The prevalence of nodules was marginally higher (P = 0.096) in Caucasians than in African-Americans. No other statistically significant differences were found with regard to ethnicity. Additionally, nodules and appendices on the MMLF were identified in all age groups, and may become more common with increasing age. The authors determined that variations of the MMLF are inherent and do not represent a pathologic condition, nor do they require biopsy for diagnostic purposes. PMID- 23454326 TI - The ethnic custom of tooth adornment in rural Bhutan: report of a case. AB - The practice of tooth modification dates back thousands of years and continues to be performed in some contemporary societies. There is limited information available about the dental customs in Bhutan. A 70-year-old Bhutanese woman presented with a gold disk on her maxillary anterior tooth. Both central incisors had been adorned when she was a teenager and subsequently the gold disk on the right incisor had broken off. They were placed for religious worship, promotion of peace, and to bring good luck. In addition to this case report, a brief literature review of ethnic alterations of the dentition is provided in this article. Recognition of the various practices of tooth modification can enhance cultural sensitivity and add to our general knowledge of social customs. PMID- 23454325 TI - An unusual dentigerous cyst in a young child. AB - A dentigerous cyst is an odontogenic developmental cyst associated with the crown of an unerupted tooth. This article describes the case of a 7-year-old girl with painful swelling in the left facial region, prolonged retention of tooth No. 9d, and a displaced tooth No. 9 in eruption. Radiographic examination revealed an extensive radiolucent lesion of approximately 28 mm and displacement of teeth No. 10 and 11. Marsupialization was performed, teeth No. 8d and 9d were removed, and the swelling reduced immediately. At a 2-year follow-up, radiographs revealed that teeth No. 10 and 11 had erupted but were displaced. Routine radiographic examinations are important for children during the eruption phase to prevent and detect any alterations that could damage the permanent dentition and occlusion. PMID- 23454327 TI - Multiple impacted second molars: a rare radiographic finding. AB - Impaction or cessation of eruption is a relatively common dental finding. The third molars are the teeth usually associated with impaction, followed by canines and premolars. Impaction of second molars has been rarely reported. This report reviews an extremely rare case of multiple impacted second molars, including a discussion of the clinical and radiological features of the case. PMID- 23454328 TI - Episodic facial sweating. Frey Syndrome. PMID- 23454329 TI - Marginal quality of posterior microhybrid resin composite restorations applied using two polymerisation protocols: 5-year randomised split mouth trial. AB - OBJECTIVES: This randomised, split-mouth clinical study evaluated the marginal quality of direct Class I and Class II restorations made of microhybrid composite and applied using two polymerisation protocols, using two margin evaluation criteria. METHODS: A total of 50 patients (mean age: 33 years) received 100 direct Class I or Class II restorations in premolars or molars. Three calibrated operators made the restorations. After conditioning the tooth with 2-step etch and-rinse adhesive, restorations were made incrementally using microhybrid composite (Tetric EvoCeram). Each layer was polymerised using a polymerisation device operated either at regular mode (600-650 mW/cm(2) for 20s) (RM) or high power (1200-1300 mW/cm(2) for 10s) mode (HPM). Two independent calibrated operators evaluated the restorations 1 week after restoration placement (baseline), at 6 months and thereafter annually up to 5 years using modified USPHS and SQUACE criteria. Data were analyzed using Mann-Whitney U-test (alpha=0.05). RESULTS: Alfa scores (USPHS) for marginal adaptation (86% and 88% for RM and HPM, respectively) and marginal discoloration (88% and 88%, for RM and HPM, respectively) did not show significant differences between the two polymerisation protocols (p>0.05). Alfa scores (SQUACE) for marginal adaptation (88% and 88% for RM and HPM, respectively) and marginal discoloration (94% and 94%, for RM and HPM, respectively) were also not significantly different at 5th year (p>0.05). CONCLUSION: Regular and high-power polymerisation protocols had no influence on the marginal quality of the microhybrid composite tested up to 5 years. Both modified USPHS and SQUACE criteria confirmed that regardless of the polymerisation mode, marginal quality of the restorations deteriorated compared to baseline. PMID- 23454330 TI - Do socioeconomic determinants affect the quality of posterior dental restorations? A multilevel approach. AB - OBJECTIVES: This study aimed to evaluate posterior restorations placed in young adults, investigating the association between social determinants experienced during the life course and the quality of tooth fillings. METHODS: A representative sample (n=720) of all 5914 individuals who were born in Pelotas in 1982 was prospectively investigated, and posterior restorations were assessed at 24 years of age. Exploratory variables included demographic and socioeconomic, oral health and dental service payment mode during the life course. Tooth-related variables (type of tooth, material and size of cavity) were also analysed. RESULTS: Multilevel logistic regression models showed that individuals who were always poor from birth to age 23 [odds ratio (OR) 2.35 (1.38-4.00)] and whose mothers had less years of education at their birth (OR 2.60 (1.44-4.68)) were with unsatisfactory restorations in posterior teeth more often. In addition, caries presence at age 15 (high decayed, missing, filled teeth (DMFT) tertile) (OR 1.95 (1.25-3.03)) and cavities with four or more surfaces (OR 18.67 (9.25 37.68)) were associated with the outcome. CONCLUSIONS: These results show that socioeconomic characteristics of the individuals play an important role in restoration failures, reinforcing the need for preventive dental strategies and public policies to reduce inequalities as a major topic of oral health. In addition, the size of cavity appears as the most important determinant for restoration failure. CLINICAL SIGNIFICANCE: Individual socioeconomic characteristics were associated with failure in posterior restorations in detriment of other clinical variables such as restorative material and type of tooth. PMID- 23454331 TI - MMPs activity and bond strength in deciduous dentine-resin bonded interfaces. AB - OBJECTIVES: To determine effect of ageing on deciduous dentine-resin interfaces bond strength and the metalloproteinases (MMPs) activity at the hybrid layer compared to permanent dentine. METHODS: Microtensile bond strength (MTBS) tests were performed in human deciduous and permanent dentine after 24h, 3 and 6 months using an etch and rinse adhesive. C-terminal telopeptide concentrations (ICTP) were calculated, in order to determine MMPs mediated collagen degradation at the hybrid layer. RESULTS: The highest MMPs-mediated collagen degradation values occurred in phosphoric acid demineralized dentine, ICTP values were similar for deciduous and permanent dentine after 1 week. Resin infiltration decreased collagen degradation in both dentins and ICTP values were similar to those attained by for untreated dentine. In resin infiltrated and untreated dentine specimens collagen degradation was always higher for deciduous dentine. At 24h, MTBS was higher in permanent dentine. After ageing MTBS decreased and performed similarly in both dentins. CONCLUSIONS: Higher collagenollytic activity is found in deciduous than in permanent dentine. At 24h, collagen cleavage by MMPs at the hybrid layer is higher in deciduous dentine leading to a lower MTBS. CLINICAL SIGNIFICANCE: The presence of resin monomers reduced collagen degradation when applied on demineralized dentine, but exerted protection was lower in deciduous dentine. PMID- 23454332 TI - Optical effects of different colors of artificial gingiva on ceramic crowns. AB - OBJECTIVES: The interaction between gingival color and the shade of ceramic restorations has never been fully studied. The purpose of this study is to investigate the optical effects of altering artificial gingival color on the ceramic crown shade in the cervical area. METHODS: Thirty-one all-ceramic crowns of different shades were used in this study with six different artificial gingival colors. Using a spectrophotometer (Crystaleye((r)) Olympus, Japan), we measured the shade of crowns in cervical areas with each of six different artificial gingiva. The crown color measured in the presence of pink artificial gingiva (control) was compared with the crown color with five other artificial gingiva. color difference values DeltaE* were calculated and compared between the control group and test groups and the correlation of the artificial gingival color with the crown color was also assessed. RESULTS: Significant differences were found in the mean L* and a* values of all-ceramic crowns at the cervical regions in all six gingival color groups (p<0.001) and significant Pearson correlations were also found for the mean L* (r=0.987, p<0.001) and a* (r=0.856, p=0.03) values between the artificial gingiva and the ceramic crowns. The mean DeltaE* values between the control group and each of the five other gingival groups were all significantly larger than the clinical perceptual threshold of DeltaE* 1.6 (p<0.001). CONCLUSIONS: Different colors of artificial gingiva generated clinically detectable shade differences in the cervical region of ceramic crowns. PMID- 23454333 TI - A new optical detection method to assess the erosion inhibition by in vitro salivary pellicle layer. AB - OBJECTIVES: Application of the recently developed optical method based on the monitoring of the specular reflection intensity to study the protective potential of the salivary pellicle layer against early enamel erosion. METHODS: The erosion progression was compared between two treatment groups: enamel samples coated by the 15 h-in vitro-formed salivary pellicle layer (group P, n=90) and the non coated enamel surfaces (control group C, n=90). Different severity of the erosive impact was modelled by the enamel incubation in 1% citric acid (pH=3.6) for 2, 4, 8, 10 or 15 min. Erosion quantification was performed by the optical method as well as by the microhardness and calcium release analyses. RESULTS: Optical assessment of the erosion progression showed erosion inhibition by the in vitro salivary pellicle in short term acidic treatments (<= 4 min) which was also confirmed by microhardness measurements proving significantly less (p<0.05) enamel softening in the group P at 2 and 4 min of erosion compared to the group C. SEM images demonstrated less etched enamel interfaces in the group P at short erosion durations as well. CONCLUSIONS: Monitoring of the specular reflection intensity can be successfully applied to quantify early erosion progression in comparative studies. In vitro salivary pellicle (2h) provides erosion inhibition but only in short term acidic exposures. CLINICAL SIGNIFICANCE: The proposed optical technique is a promising tool for the fast and non-invasive erosion quantification in clinical studies. PMID- 23454334 TI - The use of the methods of radiolysis to explore the mechanisms of free radical modifications in proteins. AB - The method of radiolysis is based upon the interaction of ionising radiation with the solvent (water). One can form the same free radicals as in conditions of oxidative stress ((*)OH, O2(*)(-), NO2(*)...). Moreover, the quantity of reactive oxygen (ROS) or nitrogen (RNS) species formed in the irradiated medium can be calculated knowing the dose and the radiation chemical yield, G, thus this method is quantitative. The use of the method of radiolysis has provided a wealth of data, especially about the kinetics of the oxidation by various free radicals and their mechanisms, the identification of transients formed, their lifetimes and the possibility to repair them by the so-called antioxidants. In this review we have collected the most recent data about protein oxidation that might be useful to a proteomic approach. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23454335 TI - A simple and general approach to assay protease activity with electrochemical technique. AB - Proteases are involved in a large number of serious disease processes, while the assay of proteolytic activity can be used for clinical diagnostics. In this paper we report a simple electrochemical method to assay protease activity. This method makes use of an unlabeled peptide that comprises the specific substrate domain of a protease, which can be easily operated and generalized for assay of various kinds of proteases. Specifically, the peptide is immobilized onto a gold electrode surface via the chemical adsorption of the C-terminal cysteine residue, forming a positively charged interface derived from the N-terminal cationic residue. Therefore, the positive electrochemical probes [Ru(NH3)5Cl](2+) cannot get across to the electrode to generate signal. Nevertheless, the proteolytic digestion of the peptide will decrease the number of positive charges on the electrode surface and weaken the blocking effect against the positive electrochemical species, resulting in an increased electrochemical signal. Under optimized conditions, the activity of the model protease, trypsin, can be assayed with a detection limit of 0.026 U/mL. The method may also allow the determination of trypsin activity in serum samples. Moreover, since this approach can be used for the assay of other proteases by simply changing the substrate domain of the peptide, it may have great potential in biomedical applications in the future. PMID- 23454336 TI - A CMOS magnetic microbead-based capacitive biosensor array with on-chip electromagnetic manipulation. AB - Magnetic microbeads are widely used in biotechnology and biomedical research for manipulation and detection of cells and biomolecules. Most lab-on-chip systems capable of performing manipulation and detection require external instruments to perform one of the functions, leading to increased size and cost. This work aims at developing an integrated platform to perform these two functions by implementing electromagnetic microcoils and capacitive biosensors on a CMOS (complementary metal oxide semiconductor) chip. Compared to most magnetic-type sensors, our detection method requires no externally applied magnetic fields and the associated fabrication is less complicated. In our experiment, microbeads coated with streptavidin were driven to the sensors in the center of microcoils with functionalized anti-streptavidin antibody. Detection of a single microbead was successfully demonstrated using a capacitance-to-frequency readout. The average capacitance changes for the experimental and control groups were -5.3 fF and -0.2 fF, respectively. PMID- 23454337 TI - A glucose biosensor based on surface active maghemite nanoparticles. AB - A simple carbon paste (CP) electrode, modified with novel maghemite (gamma-Fe2O3) nanoparticles, called SAMNs (surface active maghemite nanoparticles) and characterized by a mean diameter of about 10nm, has been developed. The electrode catalyzes the electro-reduction of hydrogen peroxide at low applied potentials ( 0.1 V vs SCE). In order to improve the electrocatalytic properties of the modified electrode an ionic liquid, namely 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF6), was introduced. At -0.1 V, the sensitivity of the SAMN-BMIM-PF6-CP electrode was 206.51 nA MUM(-1)cm(-2), with a detection limit (S/N=3) of 0.8 MUM, in the 0-1.5mM H2O2 concentration range. Furthermore, glucose oxidase was immobilized on the surface of maghemite nanoparticles as a monomolecular layer, by a bridge constituted of rhodamine B isothiocyanate, leading to a fluorescent, magnetic drivable nanocatalyst, containing 10 +/- 2 enzyme molecules per nanoparticle. The resulting enzyme electrode presents a linear calibration curve toward glucose in solution in the concentration range of 0-1.5mM glucose, characterized by a sensitivity of 45.85 nA MUM(-1)cm(-2) and a detection limit (S/N=3) of 0.9 MUM. The storage stability of the system was evaluated and a half-life of 2 months was calculated, if the electrode is stored at 4 degrees C in buffer. The present work demonstrates the feasibility of these surface active maghemite nanoparticles as efficient hydrogen peroxide electro catalyst, which can be easily coupled to hydrogen peroxide producing enzymes in order to develop oxidase based reagentless biosensor devices. PMID- 23454338 TI - Microbial surface display of glucose dehydrogenase for amperometric glucose biosensor. AB - A genetically engineered Escherichia coli (E. coli) strain displaying glucose dehydrogenase (GDH) with ice-nucleation protein (INP) as the anchoring motif was first constructed. The surface localization and functionality of the fusion protein containing GDH were verified by SDS-PAGE, Western blotting and enzymatic activity assay. The fusion of INP had no effects on the functionality of GDH cofactor binding domain. The activity assay showed that 74.6% of the cell lysate GDH activity was detected in the outer membrane fractions. Compared with the crude enzyme solution from E. coli expressing intracellular GDH, the GDH displaying bacteria (GDH-bacteria) was stable within pH 6-10 below 40 degrees C. Further, a novel electrochemical glucose biosensor was developed by construction of Nafion/GDH-bacteria/multiwalled-carbon-nanotube modified electrode. The as prepared biosensor is linear with the concentration of d-glucose within the range of 50-800 MUM and a low detection limit of 4 MUM D-glucose (S/N=3). Excess saccharides including D-galactose, D-fructose, D-cellbiose, L-arabinose and D sucrose, D-maltose, D-mannose and D-xylose as well as common interfering substances (acetaminophen, ascorbic acid and uric acid) did not affect the detection of D-glucose (0.1mM). The proposed biosensor is stable, specific, reproducible, simple, rapid and cost-effective, which can be used for detection of real samples. It is envisioned that this GDH-bacteria will be found promising applications in biofuel cell, glucose detection and cofactor reproduction system. PMID- 23454339 TI - A novel composite of SiO2-coated graphene oxide and molecularly imprinted polymers for electrochemical sensing dopamine. AB - A novel imprinting route based on graphene oxide (GO) was proposed for preparing a composite of SiO2-coated GO and molecularly imprinted polymers (GO/SiO2-MIPs). In this route, SiO2-coated GO sheets were synthesized in a water-alcohol mixture with sol-gel technique. Prior to polymerization, the vinyl groups were introduced onto the surface of GO/SiO2 through chemical modification with gamma methacryloxypropyl trimethoxysilane (gamma-MAPS), which can direct the selective polymerization on the GO/SiO2 surface. Then a novel composite of GO/SiO2-MIPs was successfully obtained by the copolymerization in presence of vinyl groups functionalized GO/SiO2, dopamine (DA), methacrylic acid and ethylene glycol dimethacrylate. The GO/SiO2-MIPs composite was characterized by FTIR, TGA, Raman spectroscopy, SEM and AFM. The properties such as special binding, adsorption dynamics and selective recognition ability using differential pulse voltammetry (DPV) were evaluated. The DPV current response of GO/SiO2-MIPs sensor was nearly 3.2 times that of the non-imprinted polymers (NIPs). In addition, the GO/SiO2 MIPs sensor could recognize DA from its relatively similar molecules of norepinephrine and epinephrine, while the sensors based on GO/SiO2-NIPs and vinyl groups functionalized GO/SiO2 did not have the ability. The GO/SiO2-MIPs sensor had a wide linear range over DA concentration from 5.0 * 10(-8) to 1.6 * 10(-4)M with a detection limit of 3.0 * 10(-8)M (S/N=3). The sensor based on this novel imprinted composite was applied to the determination of DA in injections and human urine samples with satisfactory results. PMID- 23454340 TI - Electrochemical evaluation of DNA methylation level based on the stoichiometric relationship between purine and pyrimidine bases. AB - An efficient electrochemical approach for the evaluation of DNA methylation level was proposed according to the oxidation signal of DNA bases at an overoxidized polypyrrole (PPyox) directed multiwalled carbon nanotubes (MWNTs) film modified glassy carbon electrode (GCE). The PPyox/MWNTs/GCE exhibited remarkable electrocatalytic activities towards the oxidation of DNA bases due to the advantages of wide potential window, large effective surface area, and excellent antifouling property. As a result, all purine and pyrimidine bases of guanine (G), adenine (A), thymine (T), cytosine (C) and 5-methylcytosine (5-mC) exhibited well identified oxidation peaks at the PPyox/MWNTs/GCE. The direct potential resolution between 5-mC and C was obtained to be 180 mV, which was large enough for their signal recognition and accurate detection in mixture. In particular, the signal interference from T, a great challenge in exploring DNA methylation, was successfully eliminated by an innovative strategy, which was developed based on the stoichiometric relationship between purine and pyrimidine bases in DNA molecular structure. The proposed method was effectively applied to the rapid detection of DNA methylation status in real sample within 45 min with satisfactory results. PMID- 23454341 TI - beta-cyclodextrin-ferrocene host-guest complex multifunctional labeling triple amplification strategy for electrochemical immunoassay of subgroup J of avian leukosis viruses. AB - A novel sandwich-type electrochemical immunosensor was fabricated for ultrasensitive detection of subgroup J of avian leukosis virus (ALVs-J) by employing beta-cyclodextrin-ferrocene (CD-Fc) host-guest complex multifunctional Fe3O4 nanospheres as labels and beta-cyclodextrin functional graphene sheets (CD GS) nanocomposite as sensor platform. The sensitivity was greatly improved based on the triple amplification strategy. Firstly, the CD-GS improved the electron transfer rate as well as increasing the surface area to capture a large amount of primary antibodies (Ab1). Secondly, the CD on the Fe3O4 surface with strong recognition capability could form stable CD-Fc host-guest inclusion complex and provided larger free room for the conjugation of secondary antibodies (Ab2) and glucose oxidase (GOD). Finally, the conjugated GOD exhibited extraordinary electrochemical biocatalysis towards the reduction reaction of Fc(+) by glucose. Under the optimized conditions, the electrochemical immunosensor exhibited a wide working range from 10(2.27)-10(3.50) TCID50/mL (TCID50: 50% tissue culture infective dose) with a low detection limit of 10(2.19) TCID50/mL (S/N=3). The selectivity, reproducibility, and stability are acceptable. The assay was evaluated for real avian serum sample, receiving satisfactory results. This new type of triple amplification strategy may provide potential applications for the clinic application. PMID- 23454342 TI - Highly sensitive detection of alpha-naphthol based on G-DNA modified gold electrode by electrochemical impedance spectroscopy. AB - A highly sensitive, reusable G-rich DNA sensor was reported for the detection of alpha-naphthol by electrochemical impedance spectroscopy (EIS). Specifically, a single-stranded G-rich DNA was self-assembled on the electrode and transformed into K(+)-stabilized G-quadruplex, which could catalyze H2O2-mediated oxidation of alpha-naphthol (with hemin as a cofactor) to 1, 4-naphthoquinone precipitated on the DNA films. Due to the insolubility of 1, 4-naphthoquinone, the charge transfer resistance (RCT) was increased to maximum within 15 min. Depending on the difference in charge transfer resistance change (DeltaRCT), the alpha naphthol could be detected with the detection limit of 0.1 nM in Tris-ClO4 buffer solution (20mM, pH=7.4). Moreover, the sensor demonstrated a high selectivity over other selected phenolic compounds. The performance of the sensor in the real lake water was also explored with the detection limit of 0.8 nM. Finally, the regeneration of the sensor was investigated, which allowed for reuse more than 4 cycles with a mean recovery of 94% of the original signal. PMID- 23454343 TI - DNAzyme-based magneto-controlled electronic switch for picomolar detection of lead (II) coupling with DNA-based hybridization chain reaction. AB - A novel magneto-controlled electrochemical DNA biosensor is designed for the ultrasensitive detection of lead coupling a lead-specific DNAzyme with DNA-based hybridization chain reaction (HCR). To construct such a magnetic lead sensor, DNAzyme-based molecular beacons, selective to cleavage in the presence of Pb(2+), are initially immobilized onto magnetic beads, which were used as the recognition elements. Upon addition of target lead, catalytic cleavage of substrate DNA segments in the double-stranded DNAzymes results in the capture of the initiator strands via the conjugated catalytic strands on magnetic beads. The captured DNA initiator strands trigger the hybridization chain reaction between two alternating hairpin DNA structures labeled with ferrocene to form a nicked double helix on the magnetic beads. Numerous ferrocene molecules are formed on the neighboring probes, each of which produces an electrochemical signal within the applied potential. Under optimal conditions, the electrochemical signal of the magnetic lead sensor increases with the increasing lead level in the sample, and exhibits a linear response over a Pb(2+) concentration range of 0.1-75 nM with a detection limit of 37 pM. Quantitative measurement of Pb(2+) in the complex sample demonstrates the selectivity of the sensor scheme and points favorably to the application of such technologies to the analysis of environmental samples. The unique combination of a DNAzyme with hybridization chain reaction makes it possible to change the DNAzyme to select for other compounds of interest. This work represents the initial steps toward the creation of a robust field sensor for lead in groundwater or drinking water. PMID- 23454344 TI - Designed multiple ligands in metabolic disease research: from concept to platform. AB - Type 2 diabetes mellitus (T2DM) is a multifactorial disease, and drug monotherapy typically results in unsatisfactory treatment outcomes for patients. Even when used in combination, existing therapies lack efficacy in the long term. Designed multiple ligands (DMLs) are compounds developed to modulate multiple targets relevant to a disease. DMLs offer the potential to yield greater efficacy over monotherapies, either by modulating different biological pathways, or by boosting a single one. However, examples of DMLs progressing into clinical trials, or onto the market are rare; DML drug discovery is challenging, and perceived by some to be almost impossible. Nevertheless, with the judicious selection of biological targets, both from a biological and chemical perspective, it is possible to develop drug-like DMLs. PMID- 23454345 TI - Biodiversity of small molecules--a new perspective in screening set selection. AB - How is the 'diversity' of a compound set defined and how is the most appropriate compound subset identified for assay when screening the entire HTS deck is not an option? A common approach has so far been to cover as much of the chemical space as possible by screening a chemically diverse set of compounds. We show that, rather than chemical diversity, the biologic diversity of a compound library is an essential requirement for hit identification. We describe a simple and efficient approach for the design of a HTS library based on compound-target diversity. Biodiverse compound subsets outperform chemically diverse libraries regarding hit rate and the total number of unique chemical scaffolds present among hits. Specifically, by screening ~19% of a HTS collection, we expect to discover ~50-80% of all desired bioactive compounds. PMID- 23454346 TI - Structural and functional consequences of cardiac troponin C L57Q and I61Q Ca(2+) desensitizing variants. AB - Two cTnC variants, L57Q and I61Q, both of which are located on helix C within the N domain of cTnC, were originally reported in the skeletal muscle system [Tikunova, Davis, J. Biol. Chem. 279 (2004) 35341-35352], as the analogous L58Q and I62Q sTnC, and demonstrated a decreased Ca(2+) binding affinity. Here, we provide detailed characterization of structure-function relationships for these two cTnC variants, to determine if they behave differently in the cardiac system and as a framework for determining similarities and differences with other cTnC mutations that have been associated with DCM. We have used an integrative approach to study the structure and function of these cTnC variants both in solution and in silico, to understand how the L57Q and I61Q mutations influence Ca(2+) binding at site II, the subsequent effects on the interaction with cTnI, and the structural changes which are associated with these changes. Steady-state and stopped flow fluorescence spectroscopy confirmed that a decrease in Ca(2+) affinity for recombinant cTnC and cTn complexes containing the L57Q or I61Q variants. The L57Q variant was intermediate between WT and I61Q cTnC and also did not significantly alter cTnC-cTnI interaction in the absence of Ca(2+), but did decrease the interaction in the presence of Ca(2+). In contrast, I61Q decreased the cTnC-cTnI interaction in both the absence and presence of Ca(2+). This difference in the absence of Ca(2+) suggests a greater structural change in cNTnC may occur with the I61Q mutation than the L57Q mutation. MD simulations revealed that the decreased Ca(2+) binding induced by I61Q may result from destabilization of the Ca(2+) binding site through interruption of intra-molecular interactions when residue 61 forms new hydrogen bonds with G70 on the Ca(2+) binding loop. The experimentally observed interruption of the cTnC-cTnI interaction caused by L57Q or I61Q is due to the disruption of key hydrophobic interactions between helices B and C in cNTnC. This study provides a molecular basis of how single mutations in the C helix of cTnC can reduce Ca(2+) binding affinity and cTnC-cTnI interaction, which may provide useful insights for a better understanding of cardiomyopathies and future gene-based therapies. PMID- 23454347 TI - Oxidation and nitration of alpha-synuclein and their implications in neurodegenerative diseases. AB - Synucleinopathies include Parkinson's disease, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease and multiple system atrophy, among the most relevant diseases. All of these diseases are characterized by the presence of amyloid inclusions in neurons, which are rich in the aggregate alpha-synuclein protein. What is the biological mechanism concerned in the gain-of-function that implicates the participation of alpha-synuclein in these diseases? Post translational modifications of alpha-synuclein induced by nitroxidative stress are a relevant hypothesis that may explain many of the experimental data. We will review the biophysical and biochemical properties of alpha-synuclein, methionine residues oxidation, nitration and oxidation of tyrosine residues in alpha synuclein, and modifications of alpha-synuclein mediated by proteins and lipids under nitroxidative stress conditions. The biological consequences of these modifications are analyzed in terms of the properties of alpha-synuclein oligomerization and fibrillation, degradation of alpha-synuclein and the implications in the immunological response. PMID- 23454348 TI - A system for reconstructing B cell antigen receptor signaling in the mouse myeloma J558L cell line. AB - B cell antigen receptor (BCR) signaling is positively and negatively regulated by various cell surface receptors such as CD19 and CD45. Functional analysis of these receptors has been performed using gene targeting technology, which is a valid approach to elucidate their functions. However, this type of analysis is restricted when multiple molecules are evaluated simultaneously. From a different perspective, synthetic biology provides a high degree of freedom for analyzing various molecules. Here we developed a system to reconstruct BCR signaling using the J558L myeloma cell line in combination with the protein-based Ca(2+) indicator YC3.60. BCR-reconstituted J558L cells harboring YC3.60 (J558LMUv11 cells) permitted monitoring of Ca(2+) mobilization. Reconstituting CD19 in J558LMUv11 cells resulted in detectable BCR-induced Ca(2+) mobilization but with kinetics different from that of CD45-expressing cells. Furthermore, we evaluated the validity of the J558L system by proteomic analysis of tyrosine-phosphorylated proteins after antigen stimulation. Identification of more than 100 BCR-induced tyrosine-phosphorylated proteins in J558LMUv11 cells revealed a similarity to that observed in B cells, and a novel member, non-receptor protein tyrosine kinase Fer, was found. Thus, this reconstruction system using J558L cells appeared to be valid for comprehensively investigating BCR signaling. PMID- 23454349 TI - Ligand-dependent cholesterol interactions with the human A(2A) adenosine receptor. AB - We present nearly 10 MUs of all-atom simulation data of a G-protein coupled receptor, the human A2A adenosine receptor, bound to four different ligands. Our focus is on binding of cholesterol to the "cholesterol consensus motif," a cluster of five amino acids on the second and fourth transmembrane helices, which interact with two cholesterols in the intracellular leaflet of the bilayer. We find evidence for a ligand-specific interaction between the CCM and cholesterol, mediated by the rotameric dynamics and configuration of Trp129. Binding of the synthetic agonist UK432097 disrupts hydrogen bonding between Trp129 and Ser47, which activates the rotameric dynamics of Trp129 and disrupts the interaction with one of the two cholesterols. We also investigate the effect of four thermostabilizing mutations, three of which are located on helix two. The conformational stability of helix two has been proposed to be sensitive to interaction with cholesterol in the CCM, suggesting a mechanism for the thermostabilization. However, our data are instead suggestive of a force-field dependent "straightening" of helix two, and therefore offer no basis for rationalizing the effect of the quadruple mutant. PMID- 23454350 TI - Monitoring neural stem cell differentiation using PEDOT-PSS based MEA. AB - BACKGROUND: Transplantation is one potential clinical application of neural stem cells (NSCs). However, it is very difficult to monitor/control NSCs after transplantation and so provide effective treatment. Electrical measurement using a poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) modified microelectrode array (MEA) is a biocompatible, non-invasive, non-destructive approach to understanding cell conditions. This property makes continuous monitoring available for the evaluation/assessment of the development of cells such as NSCs. METHODS: A PEDOT-PSS modified MEA was used to monitor electrical signals during NSC development in a culture derived from rat embryo striatum in order to understand the NSC differentiation conditions. RESULTS: Electrical data indicated that NSCs with nerve growth factor (NGF) generate a cultured cortical neuron-like burst pattern while a random noise pattern was measured with epidermal growth factor (EGF) at 4days in vitro (DIV) and a burst pattern was observed in both cases at 11 DIV indicating the successful monitoring of differentiation differences and developmental changes. CONCLUSIONS: The electrical analysis of cell activity using a PEDOT-PSS modified MEA could indicate neural network formation by differentiated neurons. Changes in NSC differentiation could be monitored. GENERAL SIGNIFICANCE: The method is based on non-invasive continuous measurement and so could prove a useful tool for the primary/preliminary evaluation of a pharmaceutical analysis. This article is part of a Special Issue entitled Organic Bioelectronics-Novel Applications in Biomedicine. PMID- 23454351 TI - Mitochondrial NAD dependent aldehyde dehydrogenase either from yeast or human replaces yeast cytoplasmic NADP dependent aldehyde dehydrogenase for the aerobic growth of yeast on ethanol. AB - BACKGROUND: In a previous study, we deleted three aldehyde dehydrogenase (ALDH) genes, involved in ethanol metabolism, from yeast Saccharomyces cerevisiae and found that the triple deleted yeast strain did not grow on ethanol as sole carbon source. The ALDHs were NADP dependent cytosolic ALDH1, NAD dependent mitochondrial ALDH2 and NAD/NADP dependent mitochondrial ALDH5. Double deleted strain DeltaALDH2+DeltaALDH5 or DeltaALDH1+DeltaALDH5 could grow on ethanol. However, the double deleted strain DeltaALDH1+DeltaALDH2 did not grow in ethanol. METHODS: Triple deleted yeast strain was used. Mitochondrial NAD dependent ALDH from yeast or human was placed in yeast cytosol. RESULTS: In the present study we found that a mutant form of cytoplasmic ALDH1 with very low activity barely supported the growth of the triple deleted strain (DeltaALDH1+DeltaALDH2+DeltaALDH5) on ethanol. Finding the importance of NADP dependent ALDH1 on the growth of the strain on ethanol we examined if NAD dependent mitochondrial ALDH2 either from yeast or human would be able to support the growth of the triple deleted strain on ethanol if the mitochondrial form was placed in cytosol. We found that the NAD dependent mitochondrial ALDH2 from yeast or human was active in cytosol and supported the growth of the triple deleted strain on ethanol. CONCLUSION: This study showed that coenzyme preference of ALDH is not critical in cytosol of yeast for the growth on ethanol. GENERAL SIGNIFICANCE: The present study provides a basis to understand the coenzyme preference of ALDH in ethanol metabolism in yeast. PMID- 23454353 TI - The rate of convergence to early asymptotic behaviour in age-structured epidemic models. AB - Age structure is incorporated in many types of epidemic models. Often it is convenient to assume that such models converge to early asymptotic behaviour quickly, before the susceptible population has been appreciably depleted. We make use of dynamical systems theory to show that for some reasonable parameter values, this convergence can be slow. Such a possibility should therefore be considered when parametrising age-structured epidemic models. PMID- 23454352 TI - P-glycoprotein (Mdr1a/1b) and breast cancer resistance protein (Bcrp) decrease the uptake of hydrophobic alkyl triphenylphosphonium cations by the brain. AB - BACKGROUND: Mitochondrial dysfunction contributes to degenerative neurological disorders, consequently there is a need for mitochondria-targeted therapies that are effective within the brain. One approach to deliver pharmacophores is by conjugation to the lipophilic triphenylphosphonium (TPP) cation that accumulates in mitochondria driven by the membrane potential. While this approach has delivered TPP-conjugated compounds to the brain, the amounts taken up are lower than by other organs. METHODS: To discover why uptake of hydrophobic TPP compounds by the brain is relatively poor, we assessed the role of the P glycoprotein (Mdr1a/b) and breast cancer resistance protein (Bcrp) ATP binding cassette (ABC) transporters, which drive the efflux of lipophilic compounds from the brain thereby restricting the uptake of lipophilic drugs. We used a triple transgenic mouse model lacking two isoforms of P-glycoprotein (Mdr1a/1b) and the Bcrp. RESULTS: There was a significant increase in the uptake into the brain of two hydrophobic TPP compounds, MitoQ and MitoF, in the triple transgenics following intra venous (IV) administration compared to control mice. Greater amounts of the hydrophobic TPP compounds were also retained in the liver of transgenic mice compared to controls. The uptake into the heart, white fat, muscle and kidneys was comparable between the transgenic mice and controls. CONCLUSION: Efflux of hydrophobic TPP compounds by ABC transporters contributes to their lowered uptake into the brain and liver. GENERAL SIGNIFICANCE: These findings suggest that strategies to bypass ABC transporters in the BBB will enhance delivery of mitochondria-targeted antioxidants, probes and pharmacophores to the brain. PMID- 23454354 TI - Exploring the implicit interlayer regulatory mechanism between cells and tissue: stochastic mathematical analyses of the spontaneous ordering in beating synchronization. AB - The present study focused on beating synchronization, and tried to elucidate the interlayer regulatory mechanisms between the cells and clump in beating synchronization with using the stochastic simulations which realize the beating synchronizations in beating cells with low cell-cell conductance. Firstly, the fluctuation in interbeat intervals (IBIs) of beating cells encouraged the process of beating synchronization, which was identified as the stochastic resonance. Secondly, fluctuation in the synchronized IBIs of a clump decreased as the number of beating cells increased. The decrease in IBI fluctuation due to clump formation implied both a decline of the electrophysiological plasticity of each beating cell and an enhancement of the electrophysiological stability of the clump. These findings were identified as the community effects. Because IBI fluctuation and the community effect facilitated the beating stability of the cell and clump, these factors contributed to the spontaneous ordering in beating synchronization. Thirdly, the cellular layouts in clump affected the synchronized beating rhythms. The synchronized beating rhythm in clump was implicitly regulated by a complicated synergistic effect among IBI fluctuation of each beating cell, the community effect and the cellular layout. This finding was indispensable for leading an elucidation of mechanism of emergence. The stochastic simulations showed the necessity of considering the synergistic effect, to elucidate the interlayer regulatory mechanisms in biological system. PMID- 23454355 TI - Developmental fluoride neurotoxicity: Choi et al. Respond. PMID- 23454356 TI - Toxoplasma gondii Alba proteins are involved in translational control of gene expression. AB - Molecular mechanisms controlling gene expression in apicomplexan parasites remain poorly understood. Here, we report the characterization of two Toxoplasma gondii homologs of the ancient archeal Alba proteins named TgAlba1 and TgAlba2. The targeted disruption of TgAlba1 and TgAlba2 genes in both virulent type I and avirulent type II strains of T. gondii reveals that TgAlba proteins may have an important role in regulating stress response. We found that although the steady state level of the Tgalba2 transcript is increased in the DeltaTgalba1 null mutant parasites, the cognate TgAlba2 protein is undetectable, suggesting that TgAlba1 is required for translation of TgAlba2. Using a tandem affinity purification tag strategy combined with proteomic analyses, we provide evidence that many factors known to be involved in the translation machinery are co purified with TgAlba1 and TgAlba2. We further performed RNA pull-down and microarray analyses to show that TgAlba1 and TgAlba2 bind to more than 30 RNAs including their own transcripts. Moreover, we demonstrate that the tight translational regulation of the TgAlba2 endogenous transcript relies on the presence of both its 3' untranslated region and that of the TgAlba1 protein. Thus, our findings on TgAlba1 and TgAlba2 are consistent with a role in gene specific translation. PMID- 23454358 TI - Poor phonemic discrimination does not underlie poor verbal short-term memory in Down syndrome. AB - Individuals with Down syndrome tend to have a marked impairment of verbal short term memory. The chief aim of this study was to investigate whether phonemic discrimination contributes to this deficit. The secondary aim was to investigate whether phonological representations are degraded in verbal short-term memory in people with Down syndrome relative to control participants. To answer these questions, two tasks were used: a discrimination task, in which memory load was as low as possible, and a short-term recognition task that used the same stimulus items. Individuals with Down syndrome were found to perform significantly better than a nonverbal-matched typically developing group on the discrimination task, but they performed significantly more poorly than that group on the recognition task. The Down syndrome group was outperformed by an additional vocabulary matched control group on the discrimination task but was outperformed to a markedly greater extent on the recognition task. Taken together, the results strongly indicate that phonemic discrimination ability is not central to the verbal short-term memory deficit associated with Down syndrome. PMID- 23454359 TI - Infants' sensitivity to the congruence of others' emotions and actions. AB - As humans, we are attuned to the moods and emotions of others. This understanding of emotions enables us to interpret other people's actions on the basis of their emotional displays. However, the development of this capacity is not well understood. Here we show a developmental pattern in 10- and 14-month-old infants' sensitivity to others' emotions and actions. Infants were shown video clips in which happy or angry actors performed a positive action (patting a toy tiger) or a negative action (thumping the toy tiger). Only 14-month-olds, but not 10-month olds, showed selectively greater sympathetic activity (i.e., pupil dilation) both when an angry actor performed the positive action and when a happy actor performed the negative action, in contrast to the actors performing the actions congruent with their displayed emotions. These results suggest that at the beginning of the second year of life, infants become sensitive to the congruence of other people's emotions and actions, indicating an emerging abstract concept of emotions during infancy. The results are discussed in light of previous research on emotion understanding during infancy. PMID- 23454357 TI - Structural and functional studies of gamma-carboxyglutamic acid domains of factor VIIa and activated Protein C: role of magnesium at physiological calcium. AB - Crystal structures of factor (F) VIIa/soluble tissue factor (TF), obtained under high Mg(2+) (50mM Mg(2+)/5mM Ca(2+)), have three of seven Ca(2+) sites in the gamma-carboxyglutamic acid (Gla) domain replaced by Mg(2+) at positions 1, 4, and 7. We now report structures under low Mg(2+) (2.5mM Mg(2+)/5mM Ca(2+)) as well as under high Ca(2+) (5mM Mg(2+)/45 mM Ca(2+)). Under low Mg(2+), four Ca(2+) and three Mg(2+) occupy the same positions as in high-Mg(2+) structures. Conversely, under low Mg(2+), reexamination of the structure of Gla domain of activated Protein C (APC) complexed with soluble endothelial Protein C receptor (sEPCR) has position 4 occupied by Ca(2+) and positions 1 and 7 by Mg(2+). Nonetheless, in direct binding experiments, Mg(2+) replaced three Ca(2+) sites in the unliganded Protein C or APC. Further, the high-Ca(2+) condition was necessary to replace Mg4 in the FVIIa/soluble TF structure. In biological studies, Mg(2+) enhanced phospholipid binding to FVIIa and APC at physiological Ca(2+). Additionally, Mg(2+) potentiated phospholipid-dependent activations of FIX and FX by FVIIa/TF and inactivation of activated factor V by APC. Since APC and FVIIa bind to sEPCR involving similar interactions, we conclude that under the low-Mg(2+) condition, sEPCR binding to APC-Gla (or FVIIa-Gla) replaces Mg4 by Ca4 with an attendant conformational change in the Gla domain omega-loop. Moreover, since phospholipid and sEPCR bind to FVIIa or APC via the omega-loop, we predict that phospholipid binding also induces the functional Ca4 conformation in this loop. Cumulatively, the data illustrate that Mg(2+) and Ca(2+) act in concert to promote coagulation and anticoagulation. PMID- 23454361 TI - Crystal structure analysis of human Sirt2 and its ADP-ribose complex. AB - Sirtuins are NAD(+)-dependent protein deacetylases that regulate metabolism and aging-related processes. Sirt2 is the only cytoplasmic isoform among the seven mamalian Sirtuins (Sirt1-7) and structural information concerning this isoform is limited. We crystallized Sirt2 in complex with a product analog, ADP-ribose, and solved this first crystal structure of a Sirt2 ligand complex at 2.3A resolution. Additionally, we re-refined the structure of the Sirt2 apoform and analyzed the conformational changes associated with ligand binding to derive insights into the dynamics of the enzyme. Our analyses also provide information on Sirt2 peptide substrate binding and structural states of a Sirt2-specific protein region, and our insights and the novel Sirt2 crystal form provide helpful tools for the development of Sirt2 specific inhibitors. PMID- 23454360 TI - Preventive and therapeutic oral administration of the pentacyclic triterpene alpha,beta-amyrin ameliorates dextran sulfate sodium-induced colitis in mice: the relevance of cannabinoid system. AB - The pentacyclic triterpene alpha,beta-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that alpha,beta-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the alpha,beta-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with alpha,beta-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, alpha,beta amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the alpha,beta-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1), beta(2)-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB(1)), but not CB(2), pharmacological blockade significantly reversed the beneficial effects of alpha,beta-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of alpha,beta-amyrin-treated mice. Altogether, these results suggest that the alpha,beta-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms. PMID- 23454362 TI - Overproduction of the N-terminal anticodon-binding domain of the non discriminating aspartyl-tRNA synthetase from Helicobacter pylori for crystallization and NMR measurements. AB - Aminoacyl-tRNA synthetases (aaRSs) covalently attach an amino acid to its cognate tRNA isoacceptors through an ester bond. The standard set of 20 amino acids implies 20 aaRSs for each pair of amino acid/tRNA isoacceptors. However, the genomes of all archaea and some bacteria do not encode for a complete set of 20 aaRSs. For the human pathogenic bacterium Helicobacter pylori, a gene encoding asparaginyl-tRNA synthetase (AsnRS) is absent whilst an aspartyl-tRNA synthetase (AspRS) aminoacylates both tRNA(Asp) and tRNA(Asn) with aspartate. The structural and functional basis for this non-discriminatory behavior is not well understood. Here we report the over-production of the N-terminal anticodon-binding domain of H. pylori ND-AspRS using Escherichia coli BL21(DE3) host cells. Prolonged expression of this protein resulted in a toxic phenotype, limiting the expression period to just 30min. Purified protein was monomeric in solution by gel filtration chromatography and stable up to 42 degrees C as observed in temperature-dependent dynamic light scattering measurements. Circular dichroism indicated a mixture of alpha-helix and beta-sheet secondary structure at 20 degrees C and predominantly beta-sheet at 70 degrees C. Optimized crystallization conditions at pH 5.6 with PEG 4000 as a co-precipitant produced well-formed crystals and (1)H NMR spectrum showed a well dispersed chemical shift envelope characteristic of a folded protein. PMID- 23454363 TI - Synthesis, microstructure and mechanical properties of porous Mg--Zn scaffolds. AB - Magnesium alloys have been intensively studied as biodegradable implant materials, as their mechanical properties render them promising candidates for bone tissue engineering applications. In the present work, porous Mg-4wt% Zn and Mg-6wt% Zn scaffolds were prepared using a powder metallurgy process. The effects of the porosity and Zn content on the microstructure and the mechanical properties of the fabricated scaffolds were studied. The above mentioned fabrication process involved sequential stages of mixing and compression of Mg and Zn powders with carbamide materials as space-holder particles followed by sintering the green compacts at different temperatures below the melting point of Mg. The results indicate that the porous Mg--Zn specimens with a porosity and pore size of approximately 21-36% and 150-400 MUm, respectively, could have enhanced mechanical properties comparable with those of cancellous bone. In addition, an increase in the amount of Zn in the applied alloy gives rise to a significant refinement of magnesium grain size and an improvement in the mechanical properties, such as the compression strength, of the porous Mg--Zn specimens. Furthermore, according to the results, the porous Mg--Zn alloy could be considered one of the most promising scaffold materials for hard tissue regeneration. PMID- 23454364 TI - The relationships between femoral cortex geometry and tissue mechanical properties. AB - Bone tissue and geometry are constantly modified through modeling and remodeling at the periosteal, endosteal and intracortical envelopes. Results from several studies indicate that femoral bone geometry is a predictor of whole bone strength (e.g. femoral neck strength), however, it is not known whether there is a relationship between bone structural and material properties. Bone geometry can be determined from parameters based on plane X-ray radiogrammetry which are used to evaluate femoral bone quality for implant success. If there is a relationship between these parameters and tissue mechanical properties, this would have implications in the interpretation of such parameters for assessment of fracture risk and in further understanding of bone biology. Following measurement of radiogrammetric parameters from antero-posterior and medio-lateral X-rays (cortical thickness, bone diameter, bone area, moment of inertia, cortical index, Singh index), human femurs were machined into standard test specimens for assessment of tensile fracture toughness (GIc) of the tissue. Results indicated that tensile fracture toughness generally increased with increasing bone size. We also found that fracture toughness of the tissue was significantly related to radiogrammetric indices and that some of these indices explained a greater variability in toughness than porosity, age or gender. PMID- 23454365 TI - Effect of high-energy X-ray irradiation on creep mechanisms in bone and dentin. AB - Under long-term loading creep conditions, mineralized biological tissues like bone are expected to behave in a similar manner to synthetic composites where the creeping matrix sheds load to the elastic reinforcement as creep deformation progresses. To study this mechanism in biological composites, creep experiments were performed at 37 degrees C on bovine compact bone and dentin. Static compressive stresses were applied to the samples, while wide- and small-angle scattering patterns from high energy synchrotron X-rays were used to determine, respectively, the elastic strain in the hydroxyapatite (HAP) platelets and the strain in the mineralized collagen fibril, as a function of creep time. In these highly irradiated biological composites, the reinforcing hydroxyapatite platelets progressively transfer some of their stress back to the softer protein matrix during creep. While such behavior can be explained by damage at the interface between the two phases, it is not consistent with measurements of the apparent moduli--the ratio of applied stress to elastic HAP strain measured throughout the creep experiments by elastic unload/load segments--which remained constant throughout the experiment and thus indicated good HAP/protein bonding. A possible explanation is a combination of X-ray and load induced interfacial damage explaining the shedding of load from the HAP during long term creep, coupled with interfacial re-bonding of the load-disrupted reversible bonds upon unloading, explaining the unaffected elastic load partitioning during unload/load segments. This hypothesis is further supported by finite element modeling which shows results mirroring the experimental strain measurements when considering interfacial delamination and a compliant interstitial space at the ends of the HAP platelets. PMID- 23454366 TI - Study of thermomechanical treatment on mechanical-induced phase transformation of NiTi and TiNiCu wires. AB - The nickel-titanium shape memory alloys have been used in orthodontic application due to their unique properties like superelasticity and biocompatibility. The phase transformation behavior of these alloys can be changed by alloying elements and thermomechanical processing conditions. In this study, two types of NiTi and TiNiCu wires of 0.4mm diameter were produced via thermomechanical treatments with final step of 20% cold drawing followed by annealing at different temperatures of 300 and 400 degrees C for varying times of 10, 30 and 60 min. The processed wires were characterized by oral cavity configuration three point bending (OCTPB) test at 37 degrees C to specify the mechanical transformation features. Also, differential scanning calorimetry (DSC) was used to analyze the thermal transformation temperatures of selected wires. The results showed the thermomechanical treatment at 300 degrees C for 30 min was the suitable process in terms of superelasticity and transformation temperatures for orthodontic application. PMID- 23454367 TI - Serotonergic modulation of LTP at excitatory and inhibitory synapses in the developing rat visual cortex. AB - The stability and efficacy of neuronal circuits are achieved through a detailed balance between pyramidal cell and interneuron activities. Interestingly, the neocortical excitatory-inhibitory (E-I) balance is actively maintained at the soma of Layer 5 pyramidal neurons which receive 20% of excitation and 80% of inhibition after dendritic integration, and this is not affected by changes in synaptic strength. To infer the role of serotonergic neuromodulation on the activity-dependent maintenance of the E-I balance, we performed continuous voltage clamp measurements of stimulation-locked conductance dynamics in Layer 5 pyramidal neurons before and after long-term potentiation (LTP) induction, together with chronic or acute manipulation of serotonin function. When a theta burst stimulation was applied in Layer 2/3 of 5-HT depleted cortical slices (after in vivo treatment with the tryptophan hydroxylase inhibitor p chlorophenylalanine (pCPA)), or after in vitro perfusion of the potent 5-HT1A receptor antagonist WAY-100,635, we observed a persistent shift of the ratio between excitation and inhibition toward more inhibition. This was due to a strong LTP of inhibition co-aligned with a weak LTP of excitation, whereas the same protocol caused a similar potentiation of excitatory and inhibitory inputs when applied in control slices. In contrast, neither excitatory nor inhibitory postsynaptic currents were potentiated when LTP protocols were delivered in the presence of either the selective serotonin reuptake inhibitor citalopram or the 5 HT1A receptor agonist 8-OH-DPAT. This is the first demonstration that serotonergic neuromodulation is crucial for the maintenance of the neocortical E I balance during high-frequency regimes. PMID- 23454368 TI - Response times and response accuracy for odor localization and identification. AB - Although significant progress has been made over the last decades, the chemical senses remain less well explored than vision or audition. One method to assess participants' ability to identify or localize odors consists in the application of dichotomous stimuli (e.g., left- and right-sided stimulation). In this study we aimed to explore localization and identification mechanisms by investigating whether response times and response accuracy were correlated, with the aim of establishing the pertinence of response times as an additional measure for assessment of the olfactory function (1). We further examined an advantage of the right nostril which has been reported in several publications (2). We delivered two mixed olfactory/trigeminal odors (benzaldehyde and eucalyptol) to one nostril at a time in a pseudorandomized order to 23 normosmic participants; the other nostril received an odor-free air puff. In half of the trials we asked the participants to detect the stimulated nostril; in the other half, they indicated which odor they had received. We recorded response accuracy and response times. Participants reached higher accuracy in odor identification than in localization, driven by benzaldehyde. For the stimulus eucalyptol exclusively, we observed that participants were faster to respond after stimulation of the right nostril than to the left nostril, in the localization task. Finally, response times were correlated with response accuracy in the identification task, but not in localization. Our findings suggest that odor identification is easier than odor localization. In addition, we find further support for an advantage of the right nostril over the left nostril. Moreover, the measurement of reaction times may supplement other techniques of the assessment of odor identification. PMID- 23454369 TI - Neural transdifferentiation of human bone marrow mesenchymal stem cells on hydrophobic polymer-modified surface and therapeutic effects in an animal model of ischemic stroke. AB - Human bone marrow-derived mesenchymal stem cells (MSCs) have multi-lineage differentiation potential and can become cells of mesodermal and neural lineages. These stem cells thus hold considerable clinical promise for the treatment of neurodegenerative diseases. For successful regeneration of damaged neural tissues, directed differentiation of neural or neuronal precursor cells from MSCs and integration of transplanted cells are pivotal factors. We induced MSCs into neurogenesis using a modified protocol. The therapeutic potency of the resulting neural progenitor cells in a rat model of ischemic stroke was analyzed. Using a highly hydrophobic diphenylamino-s-triazine-bridged p-phenylene (DTOPV)-coated surface and adopting a procedure for propagation of neural stem cells, we efficiently converted MSCs into neurosphere-like cellular aggregates (NS-MSCs). The spherical cells were subsequently induced to differentiate into neural cells expressing neuroectodermal markers. To determine whether these cells had neuronal fates and induced neuro-protective effects in vivo, NS-MSCs were intra-cerebrally administered to rats 48h after permanent middle cerebral artery occlusion (pMCAo). The results showed a remarkable attenuation of ischemic damage with significant functional recovery, although the cells were not fully incorporated into the damaged tissues on post-operative day 26. Improvement in the NS-MSC transplanted rats was faster than in the MSC group and suppression of inflammation was likely the key factor. Thus, our culture system using the hydrophobic surface of a biocompatible DTOPV coating efficiently supported neural cell differentiation from MSCs. Neural-primed MSCs exhibited stronger therapeutic effects than MSCs in rat brains with pMCAo. PMID- 23454370 TI - Functional analysis of platelet-derived growth factor receptor-beta in neural stem/progenitor cells. AB - Activation of neural stem/progenitor cells (NSPCs) is a potential therapeutic strategy of neurological disorders. In this study, NSPCs of subventricular zone were isolated and cultured from platelet-derived growth factor-beta-receptor knockout (PDGFR-beta(-/-)) mice of postnatal day 1 (P1) and P28, and the roles of PDGFR-beta were examined in these cells. In PDGFR-beta-preserving control NSPCs, stem cell activities, such as numbers and diameters of secondary neurospheres, cell proliferation and survival rates, were significantly higher in P1 NSPCs than those in P28 NSPCs. In PDGFR-beta(-/-) NSPCs, most of these parameters were decreased as compared with age-matched controls. Among them, the decrease of secondary neurosphere formation was most striking in P1 and P28 PDGFR-beta(-/-) NSPCs and in P28 control NSPCs as compared with P1 control NSPCs. PCR-array and following quantitative real-time PCR (qRT-PCR) analyses demonstrated that expressions of fibroblast growth factor-2 (FGF2) and exons IV-IX of brain-derived neurotrophic factor (BDNF) were decreased, and noggin was increased in P1 PDGFR beta(-/-) as compared with P1 controls. Addition of BDNF rescued the number and diameter of secondary neurospheres in P1 PDGFR-beta(-/-) NSPCs to similar levels as controls. The expressions of PDGFs and PDGFRs in control NSPCs were increased along with the differentiation-induction, where phosphorylated PDGFR-beta was co localized with neuronal and astrocyte differentiation markers. In controls, the neuronal differentiation was decreased, and the glial differentiation was increased from P1 to P28 NSPCs. Compared with P1 controls, neuronal differentiation was reduced in P1 PDGFR-beta(-/-) NSPCs, whereas glial differentiation was comparable between the two genotypes. These results suggest that PDGFR-beta signaling is important for the self-renewal and multipotency of NSPCs, particularly in neonatal NSPCs. BDNF, FGF2, and noggin may be involved in the effects of PDGFR-beta signaling in these cells. Accordingly, the activation of PDGFR-beta in NSPCs may be a novel therapeutic strategy of neurological diseases. PMID- 23454371 TI - Heavy metal and phenol adsorptive properties of biochars from pyrolyzed switchgrass and woody biomass in correlation with surface properties. AB - In this work, the surface structures of biochars, derived from three types of biomass, switchgrass (SG), hardwood (HW) and softwood (SW) through either fast pyrolysis (FP) in a fluidized-bed reactor (at 500 degrees C) or slow pyrolysis (at 500 degrees and 700 degrees C), were studied in detail, and compared with that of the activated carbons obtained by steam activation of the slow pyrolyzed biochars (at 500 degrees C). The surface acidic functional groups were determined quantitatively by the Boehm Titration method. The adsorptive properties of heavy metals, Zn(2+) and Cu(2+) onto the biochars and the activated carbons were investigated by the adsorption isotherms and SEM images, and correlated with the surface properties. ATR-FTIR and GC techniques were used to analyze the adsorptive behavior of phenol onto the biochars and activated carbons, and the results demonstrated that phenol adsorption capability is directly proportional to the micropore surface area as well as the combined level of the accessible carboxylic and lactonic groups. The relative adsorption capacity with respect to the biomass precursor follows the order: SW > HW > SG. PMID- 23454372 TI - Reuse of solid petroleum waste in the manufacture of porcelain stoneware tile. AB - This study investigates the incorporation of solid petroleum waste as raw material into a porcelain stoneware tile body, in replacement to natural kaolin material by up to 5 wt.%. Tile formulations containing solid petroleum waste were pressed and fired at 1240 degrees C by using a fast-firing cycle. The tile pieces were tested to determine their properties (linear shrinkage, water absorption, apparent density, and flexural strength), sintered microstructure, and leaching toxicity. The results therefore indicated that the growing addition of solid petroleum waste into tile formulations leads to a decrease of linear shrinkage, apparent density, and flexural strength, and to an increase of water absorption of the produced tile materials. It was also found that the replacement of kaolin with solid petroleum waste, in the range up to 2.5 wt.%, allows the production of porcelain stoneware tile (group BIa, ISO 13006 standard). All concentrations of Ag, As, Ba, Cd, Cr (total), Hg, and Pb of the fired porcelain stoneware tile pieces in the leachate comply with the current regulatory limits. These results indicate that the solid petroleum waste could be used for high quality porcelain stoneware tile production, thus giving rise to a new possibility for an environmentally friendly management of this abundant waste. PMID- 23454373 TI - Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: a key to lean phenotype. AB - We are facing a revival of the strategy to counteract obesity and associated metabolic disorders by inducing thermogenesis mediated by mitochondrial uncoupling protein-1 (UCP1). Thus, the main focus is on the adaptive non shivering thermogenesis occurring both in the typical depots of brown adipose tissue (BAT) and in UCP1-containing cells that could be induced in white adipose tissue (WAT). Because contribution of WAT to resting metabolic rate is relatively small, the possibility to reduce adiposity by enhancing energy expenditure in classical white adipocytes is largely neglected. However, several pieces of evidence support a notion that induction of energy expenditure based on oxidation of fatty acids (FA) in WAT may be beneficial for health, namely: (i) studies in both humans and rodents document negative association between oxidative capacity of mitochondria in WAT and obesity; (ii) pharmacological activation of AMPK in rats as well as cold-acclimation of UCP1-ablated mice results in obesity resistance associated with increased oxidative capacity in WAT; and (iii) combined intervention using long-chain n-3 polyunsaturated FA (omega 3) and mild calorie restriction exerted synergism in the prevention of obesity in mice fed a high-fat diet; this was associated with strong hypolipidemic and insulin sensitizing effects, as well as prevention of inflammation, and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) and FA oxidation, specifically in epididymal WAT. Importantly, these changes occurred without induction of UCP1 and suggested the involvement of: (i) futile substrate cycle in white adipocytes, which is based on lipolysis of intracellular triacylglycerols and re-esterification of FA, in association with the induction of mitochondrial OXPHOS capacity, beta-oxidation, and energy expenditure; (ii) endogenous lipid mediators (namely endocannabinoids, eicosanoids, prostanoids, resolvins, and protectins) and their cognate receptors; and (iii) AMP-activated protein kinase in WAT. Quantitatively, the strong induction of FA oxidation in WAT in response to the combined intervention is similar to that observed in the transgenic mice rendered resistant to obesity by ectopic expression of UCP1 in WAT. The induction of UCP1-independent FA oxidation and energy expenditure in WAT in response to the above physiological stimuli could underlie the amelioration of obesity and low grade WAT inflammation, and it could reduce the release of FA from adipose tissue and counteract harmful consequences of lipid accumulation in other tissues. In this respect, new combination treatments may be designed using naturally occurring micronutrients (e.g. omega 3), reduced calorie intake or pharmaceuticals, exerting synergism in the induction of the mitochondrial OXPHOS capacity and stimulation of lipid catabolism in white adipocytes, and improving metabolic flexibility of WAT. The role of mutual interactions between adipocytes and immune cells contained in WAT in tissue metabolism should be better characterised. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease. PMID- 23454374 TI - White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. AB - In all mammals, white adipose tissue (WAT) and brown adipose tissue (BAT) are found together in several fat depots, forming a multi-depot organ. Adrenergic stimulation induces an increase in BAT usually referred to as "browning". This phenomenon is important because of its potential use in curbing obesity and related disorders; thus, understanding its cellular mechanisms in humans may be useful for the development of new therapeutic strategies. Data in rodents have supported the direct transformation of white into brown adipocytes. Biopsies of pure white omental fat were collected from 12 patients affected by the catecholamine-secreting tumor pheochromocytoma (pheo-patients) and compared with biopsies from controls. Half of the omental fat samples from pheo-patients contained uncoupling protein 1 (UCP1)-immunoreactive-(ir) multilocular cells that were often arranged in a BAT-like pattern endowed with noradrenergic fibers and dense capillary network. Many UCP1-ir adipocytes showed the characteristic morphology of paucilocular cells, which we have been described as cytological marker of transdifferentiation. Electron microscopy showed increased mitochondrial density in multi- and paucilocular cells and disclosed the presence of perivascular brown adipocyte precursors. Brown fat genes, such as UCP1, PR domain containing 16 (PRDM16) and beta3-adrenoreceptor, were highly expressed in the omentum of pheo-patients and in those cases without visible morphologic re arrangement. Of note, the brown determinant PRDM16 was detected by immunohistochemistry only in nuclei of multi- and paucilocular adipocytes. Quantitative electron microscopy and immunohistochemistry for Ki67 suggest an unlikely contribution of proliferative events to the phenomenon. The data support the idea that, in adult humans, white adipocytes of pure white fat that are subjected to adrenergic stimulation are able to undergo a process of direct transformation into brown adipocytes. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease. PMID- 23454375 TI - The polar lipids of Clostridium psychrophilum, an anaerobic psychrophile. AB - We have examined the polar lipids of Clostridium psychrophilum, a recently characterized psychrophilic Clostridium isolated from an Antarctic microbial mat. Lipids were extracted from cells grown near the optimal growth temperature (+5 degrees C) and at -5 degrees C, and analyzed by two-dimensional thin layer chromatography and liquid chromatography coupled with mass spectrometry. The major phospholipids of this species are: cardiolipin, phosphatidylethanolamine, and phosphatidylglycerol. Phosphatidylserine and lyso-phosphatidylethanolamine were found as minor components. The most abundant glycolipids are a monoglycosyldiradylglycerol (MGDRG) and a diglycosyldiradylglycerol (DGDRG). The latter was only seen in cells grown at -5 degrees C. An ethanolamine-phosphate derivative of N-acetylglucosaminyldiradylglycerol was seen in cells grown at -5 degrees C and an ethanolamine-phosphate derivative of MGDRG was found in cells grown at +5 degrees C. All lipids were present in both the all acyl and plasmalogen (alk-1'-enyl acyl) forms with the exception of PS and MGDRG, which were predominantly in the diacyl form. The significance of lipid changes at the two growth temperatures is discussed. PMID- 23454376 TI - Resveratrol decreases breast cancer cell viability and glucose metabolism by inhibiting 6-phosphofructo-1-kinase. AB - Cancer cells are highly dependent on glycolysis to supply the energy and intermediates required for cell growth and proliferation. The enzyme 6 phosphofructo-1-kinase (PFK) is critical for glycolysis, and its activity is directly correlated with cellular glucose consumption. Resveratrol is a potential anti-tumoral drug that decreases glucose metabolism and viability in cancer cells. However, the mechanism involved in resveratrol-mediated anti-tumor activity is not entirely clear. In this work, it is demonstrated that resveratrol decreases viability, glucose consumption and ATP content in the human breast cancer cell line MCF-7. These effects are directly correlated with PFK inhibition by resveratrol in these cells. Moreover, resveratrol directly inhibits purified PFK, promoting the dissociation of the enzyme from fully active tetramers into less active dimers. This effect is exacerbated by known negative regulators of the enzyme, such as ATP and citrate. On the other hand, positive modulators that stabilize the tetrameric form of the enzyme, such as fructose-2,6-bisphosphate and ADP, prevent the inhibition of PFK activity by resveratrol, an effect not observed with increased pH. In summary, our results provide evidence that resveratrol directly inhibits PFK activity, therefore disrupting glucose metabolism and reducing viability in cancer cells. PMID- 23454377 TI - Ionic microenvironmental effects on triplex DNA stabilization: cationic counterion effects on poly(dT).poly(dA).poly(dT). AB - The structure and conformation of nucleic acids are influenced by metal ions, polyamines, and the microenvironment. In poly(purine) . poly(pyrimidine) sequences, triplex DNA formation is facilitated by metal ions, polyamines and other ligands. We studied the effects of mono- and di-valent metal ions, and ammonium salts on the stability of triple- and double-stranded structures formed from poly(dA) and poly(dT) by measuring their respective melting temperatures. In the presence of metal ions, the absorbance versus temperature profile showed two transitions: Tm1 for triplex to duplex and single stranded DNA, and Tm2 for duplex DNA melting to single stranded DNA. Monovalent cations (Li(+), Na(+), K(+), Rb(+), Cs(+) and [Formula: see text] ) promoted triplex DNA at concentrations >=150 mM. Tm1 varied from 49.8 degrees C in the presence of 150 mM Li(+) to 30.6 degrees C in the presence of 150 mM K(+). [Formula: see text] was very effective in stabilizing triplex DNA and its efficacy decreased with increasing substitution of the hydrogen atoms with methyl, ethyl, propyl and butyl groups. As in the case of monovalent cations, a concentration-dependent increase in Tm1 was observed with divalent ions and triplex DNA stabilization decreased in the order: Mg(2+) > Ca(2+) > Sr(2+) > Ba(2+). All positively charged cations increased the melting temperature of duplex DNA. Values of Deltan (number of ions released) on triplex DNA melting were 0.46 +/- 0.06 and 0.18 +/- 0.02, respectively, for mono- and di-valent cations, as calculated from 1/Tm1 versus ln[M(+,2+)] plots. The corresponding values for duplex DNA were 0.25 +/- 0.02 and 0.12 +/- 0.02, respectively, for mono- and di-valent cations. Circular dichroism spectroscopic studies showed distinct conformational changes in triplex DNA stabilized by alkali metal and ammonium ions. Our results might be useful in developing triplex forming oligonucleotide based gene silencing techniques. PMID- 23454378 TI - Snail inhibits Notch1 intracellular domain mediated transcriptional activation via competing with MAML1. AB - Notch1 intracellular domain (NICD) is the transcription factor which controls cell fate and differentiation in embryonic and tumor cells. Snail has a critical role which increases invasion and metastasis of cancer cell as a transcription factor and epigenetic regulator. Recently, we discovered NICD induced Snail degradation by direct binding interaction with Snail. In this experiment, we found that Snail suppressed transcriptional activity of the protein complex formed with NICD and RBPJk in nucleus. Moreover, Snail decreased transcription of NICD target genes via competing with MAML1, co-activator, in NICD complex. In conclusion, Snail inhibited NICD-mediated transcriptional activation of target genes by physical interaction with NICD. PMID- 23454379 TI - Non-structural 3 protein expression is associated with T cell protein tyrosine phosphatase and viral RNA levels in chronic hepatitis C patients. AB - The hepatitis C virus (HCV) non-structural 3 (NS3) protein plays key roles in both the viral life cycle and in the modulation of intrahepatic signaling and immunity. We recently showed that NS3 cleaves the T cell protein tyrosine phosphatase (TCPTP). To better understand the inactivation of TCPTP in HCV infected humans, we investigated whether there is an association between TCPTP cleavage, NS3 protein levels and clinical parameters in hepatitis C patients. Liver biopsies were obtained from 69 HCV RNA positive patients with confirmed chronic HCV infection and 16 control patients. Hepatic NS3 and TCPTP protein levels were determined and correlated to viral load or clinical parameters for the severity of liver disease. We found a positive correlation between the viral load and the intrahepatic NS3 protein levels in patients infected with HCV. HCV infected patients had significantly lower intrahepatic TCPTP levels than non infected control patients. In HCV-infected patients both intrahepatic NS3 expression and the viral load were inversely correlated with the intrahepatic TCPTP protein levels. Detection of NS3 did not associate with any other clinical parameters such as liver damage, the grade of liver inflammation or fibrosis stage. This is the first study reporting a detailed analysis of HCV NS3 and TCPTP protein levels in the liver. It demonstrates a clear link between HCV viral load, NS3 expression in the liver and intrahepatic TCPTP levels. Thus, the association between TCPTP cleavage and viral replication may have important consequences for the HCV life cycle and HCV-induced liver diseases. PMID- 23454380 TI - A new anti-tumor strategy based on in vivo tumstatin overexpression after plasmid electrotransfer in muscle. AB - The NC1 domains from the different alpha(IV) collagen chains were found to exert anti-tumorigenic and/or anti-angiogenic activities. A limitation to the therapeutic use of these matrikines is the large amount of purified recombinant proteins, in the milligram range in mice that should be administered daily throughout the experimental procedures. In the current study, we developed a new therapeutic approach based on tumstatin (NC1alpha3(IV)) overexpression in vivo in a mouse melanoma model. Gene electrotransfer of naked plasmid DNA (pDNA) is particularly attractive because of its simplicity, its lack of immune responsiveness and its safety. The pDNA electrotransfer in muscle mediates a substantial gene expression that lasts several months. A pVAX1(c) vector containing the tumstatin cDNA was injected into the legs of C57BL/6 mice and submitted to electrotranfer. Sera were collected at different times and tumstatin was quantified by ELISA. Tumstatin secretion reached a plateau at day 21 with an expression level of 12 MUg/mL. For testing the effects of tumstatin expression on tumor growth in vivo, B16F1 melanoma cells were subcutaneously injected in mice 7 days after empty pVAX1(c) (Mock) or pVAX1(c)-tumstatin electrotransfer. Tumstatin expression triggered a large decrease in tumor growth and an increase in mouse survival. This new therapeutic approach seems promising to inhibit tumor progression in vivo. PMID- 23454381 TI - Alpha1-adrenenoceptor stimulation inhibits cardiac excitation-contraction coupling through tyrosine phosphorylation of beta1-adrenoceptor. AB - Adrenoceptor stimulation is a key determinant of cardiac excitation-contraction coupling mainly through the activation of serine/threonine kinases. However, little is known about the role of protein tyrosine kinases (PTKs) activated by adrenergic signaling on cardiac excitation-contraction coupling. A cytoplasmic tyrosine residue in beta1-adrenoceptor is estimated to regulate Gs-protein binding affinity from crystal structure studies, but the signaling pathway leading to the phosphorylation of these residues is unknown. Here we show alpha1 adrenergic signaling inhibits beta-adrenergically activated Ca(2+) current, Ca(2+) transients and contractile force through phosphorylation of tyrosine residues in beta1-adrenoceptor by PTK. Our results indicate that inhibition of beta-adrenoceptor-mediated Ca(2+) elevation by alpha1-adrenoceptor-PTK signaling serves as an important regulatory feedback mechanism when the catecholamine level increases to protect cardiomyocytes from cytosolic Ca(2+) overload. PMID- 23454382 TI - Functional inhibition of UQCRB suppresses angiogenesis in zebrafish. AB - As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases. PMID- 23454383 TI - The Saccharomyces cerevisiae RhoGAP Rgd1 is phosphorylated by the Aurora B like kinase Ipl1. AB - Polarized growth of the yeast Saccharomyces cerevisiae depends on different biological processes and requires several signaling pathways. Signaling is mediated through a set of proteins, which include Rho3p and Rho4p GTPases. Although these two proteins are involved in the control of distinct aspects of polarized growth in yeast, they have a common regulator: the Rgd1 RhoGAP protein. Here we demonstrate that Rgd1p is phosphorylated by the Aurora B like kinase Ipl1 and we observe that loss of Ipl1 function leads to a new Rgd1p distribution in a small part of the cell population. PMID- 23454384 TI - Salinity impacts photosynthetic pigmentation and cellular morphology changes by distinct mechanisms in Fremyella diplosiphon. AB - Fremyella diplosiphon is a freshwater cyanobacterium that exhibits complementary chromatic adaptation (CCA), which allows the organism to alter its pigmentation and cellular morphology to maximally harvest available green light (GL) and red light (RL) at different depth levels in its aquatic ecosystem. We tested the effect of salinity on CCA-associated pigment and morphological changes in F. diplosiphon. Sodium chloride (NaCl) salt at a concentration of 200mM was found to maximally inhibit growth, chlorophyll levels, and accumulation of phycoerythrin (PE) and phycocyanin (PC) under GL and RL, respectively. NaCl also affected cellular morphology resulting in a larger cell size under both light conditions. Cell length decreased while width increased under GL in the presence of salt, and both cell length and width were increased under RL with salt. The addition of osmoprotectant glycine betaine (GB) to the growth medium in the presence of salt resulted in a reversion of the morphology to that of cells growing in the absence of salt, whereas GB treatment in the presence of salt did not have a major effect on growth or on PE and PC biosynthesis or accumulation. Thus, salt affects cellular morphology due to osmotic stress, while pigmentation is likely affected by ionic toxicity. Understanding the distinct mechanisms of salt-mediated changes on pigmentation and morphology may increase the suitability of strains such as F. diplosiphon, which harbor pigments that allow growth in low light and shaded environments, for adaptation as energy strains. PMID- 23454385 TI - Hydrothermal liquefaction of Chlorella pyrenoidosa in sub- and supercritical ethanol with heterogeneous catalysts. AB - Hydrothermal liquefaction (HTL) of low lipid content microalgae Chlorella pyrenoidosa with heterogeneous catalysts was processed under sub- and supercritical conditions of ethanol (200-300 degrees C, 2.8-9.0 MPa, 30 min). The HTL products were separated into bio-crude, gas, solid residue and volatile components, and then characterized. The highest mass and energy recovery ratios of bio-crude on the dry basis of alga were 71.3% and 101.8% respectively, obtained at 240 degrees C, while the highest higher heating value of bio-crude was 36.19 MJ/kg, obtained at 300 degrees C. Temperature was found to be the most dominant parameter. H2 as a processing gas at an initial pressure of 1.03 MPa slightly improved the bio-crude yield and quality. Raney-Ni and HZSM-5 type zeolite catalysts had no significant effect on the presented HTL process. The results indicated that HTL with ethanol as the solvent was able to produce 50-70 wt.% of bio-crude directly from C. pyrenoidosa. PMID- 23454386 TI - Thermophilic archaeal community succession and function change associated with the leaching rate in bioleaching of chalcopyrite. AB - The community succession and function change of thermophilic archaea Acidianus brierleyi, Metallosphaera sedula, Acidianus manzaensis and Sulfolobus metallicus were studied by denaturing gradient gel electrophoresis (DGGE) analysis of amplifying 16S rRNA genes fragments and real-time qPCR analysis of amplifying sulfur-oxidizing soxB gene associated with chalcopyrite bioleaching rate at different temperatures and initial pH values. The analysis results of the community succession indicated that temperature and initial pH value had a significant effect on the consortium, and S. metallicus was most sensitive to the environmental change, A. brierleyi showed the best adaptability and sulfur oxidation ability and predominated in various leaching systems. Meanwhile, the leaching rate of chalcopyrite closely related to the consortium function embodied by soxB gene, which could prove a desirable way for revealing microbial sulfur oxidation difference and tracking the function change of the consortium, and for optimizing the leaching parameters and improving the recovery of valuable metals. PMID- 23454387 TI - Effect of electron donor source on the treatment of Cr(VI)-containing textile wastewater using sulfate-reducing fluidized bed reactors (FBRs). AB - The treatment of Cr(VI) containing textile wastewater was studied in ethanol and glucose-fed sulfate-reducing fluidized bed reactors at 35 degrees C for around 250 days. The synthetic wastewater contained Cr(VI) (5-45 mg L(-1)), azo dye (Remazol Brilliant Violet 5R) (100-200 mg L(-1)), sulfate (2000 mg L(-1)) and ethanol or glucose (2000 mg L(-1) chemical oxygen demand (COD)). The robustness of two FBRs was assessed under varying Cr(VI) and azo dye loadings. Both reactors performed well in terms of COD, sulfate, color and Cr(VI) removals. However, ethanol-fed FBR performed better than glucose-fed one. The COD, sulfate, chromium and color removals at the highest Cr(VI) concentration (45 mg L(-1)) in ethanol fed FBR were around 75%, 95%, 93%, and 99%, respectively. Further increase in influent Cr(VI) concentration adversely effected reactor performance. The COD, sulfate, chromium and color removals at 45 mg L(-1) Cr(VI) in glucose-fed FBR were around 60%, 50%, 93%, and 76%, respectively. PMID- 23454388 TI - Life cycle analysis of fuel production from fast pyrolysis of biomass. AB - A well-to-wheels (WTW) analysis of pyrolysis-based gasoline was conducted and compared with petroleum gasoline. To address the variation and uncertainty in the pyrolysis pathways, probability distributions for key parameters were developed with data from literature. The impacts of two different hydrogen sources for pyrolysis oil upgrading and of two bio-char co-product applications were investigated. Reforming fuel gas/natural gas for H2 reduces WTW GHG emissions by 60% (range of 55-64%) compared to the mean of petroleum fuels. Reforming pyrolysis oil for H2 increases the WTW GHG emissions reduction up to 112% (range of 97-126%), but reduces petroleum savings per unit of biomass used due to the dramatic decline in the liquid fuel yield. Thus, the hydrogen source causes a trade-off between GHG reduction per unit fuel output and petroleum displacement per unit biomass used. Soil application of biochar could provide significant carbon sequestration with large uncertainty. PMID- 23454389 TI - Transient behavior of devolatilization and char reaction during steam gasification of biomass. AB - Steam gasification of biomass is a promising method for producing high quality syngas for polygeneration. During the steam gasification, devolatilization and char reaction are key steps of syngas production and the contributions of the two reactions are highly related to gasification conditions. In this study, the transient characteristics of devolatilization and char reaction in biomass steam gasification were investigated by monitoring cumulative gas production and composition changes in terms of reaction temperature and S/B ratio. Contribution of each reaction stage on the product gas yield was studied in detail. The results provide important insight for understanding the complex nature of biomass gasification and will guide future improvements to the biomass gasification process. PMID- 23454390 TI - Explicit temperature-based model for anaerobic digestion: application in domestic wastewater treatment in a UASB reactor. AB - Temperature is an important environmental variable that can strongly affect the performance of anaerobic reactors working at ambient temperatures. This study presents a mechanistic mathematical model which depends in an explicit way on the operating temperature. The cardinal temperature model function is proposed to describe the temperature dependence of the kinetic parameters and the experimental data from an UASB-degasification system was used to calibrate and validate the model. The performance of the model is compared with the classic Arrhenius approach. The results showed that the temperature-based model of the anaerobic digestion is able to reproduce a long-term reactor operation in terms of biogas production and the concentration of organic matter at fluctuating ambient temperature. PMID- 23454391 TI - Effect of temperature variation on membrane fouling and microbial community structure in membrane bioreactor. AB - This study aimed to investigate the effect of temperature variation on membrane fouling and microbial community in a membrane bioreactor (MBRs). The results indicated that extracellular polymer substances (EPS) and soluble microbial products (SMPs) increased due to decreasing temperature, which triggered membrane fouling as evidenced by the trans-membrane pressure (TMP) increase rate. Moreover, fluorescent intensity variations in the excitation-emission matrix (EEM) fluorescence spectroscopy of SMPs were closely related to rapid increase in TMP, suggesting that they might be used to monitor SMPs variations and indicate membrane performance. In addition, 16S rRNA clone library and sequence analyses results demonstrated the predominant phyla were always Proteobacteria, Nitrospira and Bacteroidetes. However, at lower temperature, alpha-proteobacteria and some filamentous bacteria such as Actinobacteria, Haliscomenobacteria and Thiothrix were relatively rich. At higher temperature, Zoogloea showed its presence. Detrended correspondence analysis (DCA) and Mantel test results also demonstrated that temperature had strongly influence on microbial community. PMID- 23454392 TI - CEA, AFP and CA 19-9 analysis in peritoneal fluid to differentiate causes of ascites formation. AB - OBJECTIVES: Tumor marker analysis in ascites has been proposed as a measure to aid in the diagnosis of malignancy. The objectives of this study were to establish tumor marker cut-offs and determine the diagnostic performance of measuring CEA, CA 19-9 and AFP in ascites for differentiating between non malignant and malignant etiologies. DESIGN AND METHODS: Ascites from 137 patients (83 non-malignant, 54 malignant) was assayed for CEA, CA 19-9 and AFP concentrations by immunoassay. Diagnostic cut-offs were established via ROC curve analysis. Performance was compared to cytology findings and patient history following medical chart review. Analysis based on cytological findings in combination with tumor marker testing, as well as subset analysis by tumor marker secretion was also performed. RESULTS: Concentrations of CEA, CA 19-9 and AFP were significantly higher in patients with malignant ascites versus non-malignant etiologies. The diagnostic cut-off, sensitivity and specificity for CEA were 3.5 ng/mL, 31% and 95%, respectively; for CA 19-9 were 72 U/mL, 30% and 95%; and for AFP were 5 ng/mL, 17% and 95%. Using cytological findings in conjunction with tumor marker results improved the sensitivity of CEA, CA 19-9 and AFP to 57.4%, 64.8%, and 59.3%, respectively. Improvement in sensitivity was seen when subset analysis by causative malignancy was performed. CONCLUSIONS: Tumor marker analysis in ascites, especially in subset analysis by type of malignancy, demonstrated utility for differentiating non-malignant from malignant etiologies. This analysis should not replace cytology, but offers potential for differentiation in situations where cytology is inconclusive, or in patients with suspected malignancies known to secrete these markers. PMID- 23454393 TI - Comparisons of fully automated syphilis tests with conventional VDRL and FTA-ABS tests. AB - BACKGROUND: Serologic tests are widely used for the diagnosis of syphilis. However, conventional methods require well-trained technicians to produce reliable results. We compared automated nontreponemal and treponemal tests with conventional methods. METHODS: The HiSens Auto Rapid Plasma Reagin (AutoRPR) and Treponema Pallidum particle agglutination (AutoTPPA) tests, which utilize latex turbidimetric immunoassay, were assessed. A total of 504 sera were assayed by AutoRPR, AutoTPPA, conventional VDRL and FTA-ABS. Among them, 250 samples were also tested by conventional TPPA. RESULTS: The concordance rate between the results of VDRL and AutoRPR was 67.5%, and 164 discrepant cases were all VDRL reactive but AutoRPR negative. In the 164 cases, 133 showed FTA-ABS reactivity. Medical records of 106 among the 133 cases were reviewed, and 82 among 106 specimens were found to be collected from patients already treated for syphilis. The concordance rate between the results of AutoTPPA and FTA-ABS was 97.8%. The results of conventional TPPA and AutoTPPA for 250 samples were concordant in 241 cases (96.4%). AutoRPR showed higher specificity than that of VDRL, while VDRL demonstrated higher sensitivity than that of AutoRPR regardless of whether the patients had been already treated for syphilis or not. Both FTA-ABS and AutoTPPA showed high sensitivities and specificities greater than 98.0%. CONCLUSIONS: Automated RPR and TPPA tests could be alternatives to conventional syphilis tests, and AutoRPR would be particularly suitable in treatment monitoring, since results by AutoRPR in cases after treatment became negative more rapidly than by VDRL. PMID- 23454394 TI - Monitoring of tacrolimus concentrations in peripheral blood mononuclear cells: application to cardiac transplant recipients. AB - OBJECTIVES: Despite the intensive therapeutic drug monitoring of tacrolimus (TAC) using trough whole blood concentrations, graft rejections occur in transplant recipient patients. Thus, other ways to monitor closely immunosuppressive treatments are necessary. A promising way of monitoring TAC treatments could be the measure of its concentrations inside of the lymphocyte cell. Whereas the pharmacokinetics of TAC in peripheral blood mononuclear cells (PBMCs) was evaluated in renal and liver transplant recipients, data regarding PBMC concentrations of TAC in cardiac transplant recipients are lacking. This study aimed, in cardiac transplant recipients: to validate a method for determination of TAC in PBMC, to investigate PBMC trough concentrations of TAC, and to evaluate their relationship with trough whole blood concentrations. DESIGN AND METHOD: We developed and validated a High-performance-liquid-chromatography tandem mass spectrometry method of TAC quantitation in PBMC. The method was then evaluated by determining TAC concentrations in PBMC of 24 cardiac transplant recipients. RESULTS: Twenty-four patients were prospectively included in the study. Tacrolimus PBMC concentrations displayed a large inter-individual pharmacokinetic variability (CV=71.4%) in the cohort. A lack of correlation between TAC whole blood trough concentrations and TAC trough concentrations in PBMCs was found (r=0.259; p=0.183). CONCLUSION: Further studies should be implemented to evaluate the correlation between TAC concentrations in PBMC and clinical outcomes in cardiac transplant recipients to allow concluding whether monitoring TAC concentrations in PBMC is a good tool to prevent graft rejection in cardiac recipients. PMID- 23454395 TI - Risus sardonicus: assisted suicide or ritual violent euthanasia? PMID- 23454397 TI - Hemorrhagic vestibular schwannoma: review of the literature. AB - BACKGROUND: Clinically significant intratumoral hemorrhage historically has been reported in only a small fraction of vestibular schwannomas (VS). Patients with hemorrhagic VS are more likely to present with neurologic deficits and have worse outcomes than patients with nonhemorrhagic VS. The purpose of this study is to analyze characteristics that may predispose VS to hemorrhage and that may prove helpful in the management and treatment of VS. METHODS: A literature search was conducted using National Library of Medicine and National Institutes of Health databases to identify articles pertaining to intratumoral hemorrhage in VS. The authors selected 39 cases, described in 18 published articles, to review. RESULTS: Average patient age and tumor size in hemorrhagic cases of VS did not differ significantly from nonhemorrhagic cases of VS. Facial nerve dysfunction at presentation occurred with greater frequency in cases of hemorrhagic VS (33.3%) than in nonhemorrhagic VS (6.0%). Death occurred much more frequently in cases of hemorrhagic VS (10.0%) than in nonhemorrhagic VS (0.2%). Abnormality of tumor associated vasculature was noted histologically in many cases, and a large number of the cases reported prior treatment by stereotactic radiosurgery. CONCLUSIONS: Understanding the origins and clinical implications of intratumoral hemorrhage in VS could potentially assist in clinical decision making and patient counseling. PMID- 23454398 TI - Neurosurgery in India: an overview. AB - This overview of neurosurgery in India during the last six decades gives a holistic perspective of the phenomenal advances made. Neurosurgical education, the change in clinical spectrum of diseases and their presentation, evolution of various subspecialties and societies, the state of research, the issues peculiar to India, including the urban-rural health divide, the increasing role of information and communication technology in neurosurgery, and the gradual but definite global recognition of Indian neurosurgery will be addressed. PMID- 23454399 TI - The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population. AB - INTRODUCTION: Cadmium (Cd) is toxic to the kidney and a major part of the body burden occurs here. Cd in urine (U-Cd) and blood (B-Cd) are widely-used biomarkers for assessing Cd exposure or body burden. However, empirical general population data on the relationship between Cd in kidney (K-Cd), urine, and blood are scarce. Our objectives were to determine the relationship between cadmium in kidney, urine, and blood, and calculate the elimination half-time of Cd from the kidney. METHODS: Kidney cortex biopsies, urine, and blood samples were collected from 109 living kidney donors. Cd concentrations were determined and the relationships between K-Cd, U-Cd, and B-Cd were investigated in regression models. The half-time of K-Cd was estimated from the elimination constant. RESULTS: There was a strong association between K-Cd and U-Cd adjusted for creatinine (rp=0.70, p<0.001), while the association with B-Cd was weaker (rp=0.44, p<0.001). The relationship between K-Cd and U-Cd was nonlinear, with slower elimination of Cd at high K-Cd. Estimates of the K-Cd half-time varied between 18 and 44years. A K-Cd of 25MUg/g corresponds to U-Cd of 0.42MUg/g creatinine in overnight urine (U-Cd/K-Cd ratio: about 1:60). Multivariate models showed Cd in blood and urinary albumin as determinants for U-Cd excretion. DISCUSSION: In healthy individuals with low-level Cd exposure, there was a strong correlation between Cd in kidney and urine, especially after adjustment for creatinine. Urinary Cd was also affected by Cd in blood and urinary albumin. Previous estimates of the U-Cd/K-Cd ratio may underestimate K-Cd at low U-Cd. PMID- 23454400 TI - Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats. AB - Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg.d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 MUM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. PMID- 23454401 TI - Ureteroileal strictures after urinary diversion with an ileal segment-is there a place for endourological treatment at all? AB - PURPOSE: We compared the long-term results of minimally invasive endourological intervention and open surgical revision in patients with a nonmalignant ureteroileal stricture. MATERIALS AND METHODS: We retrospectively evaluated the records of 74 patients (85 renal units) treated for unilateral or bilateral nonmalignant ureteroileal strictures. Overall, 96 endourological and 35 open surgical procedures were performed. Balloon dilatation and Acucise(r) or Ho:YAG laser endoureterotomy were used as minimally invasive endourological interventions. Open surgical revision with stricture resection and open ureteroileal end-to-side-reanastomosis was the alternate therapy. Treatment success was defined as radiological normalization or improvement of upper urinary tract morphology combined with absent flank pain, infection, ureteral stents or percutaneous nephrostomies. RESULTS: Median followup was 29 months (range 2 to 177). The overall success rate was 26% (25 of 96 cases) for endourological intervention vs 91% (32 of 35) for open surgical revision (p <0.001). Subgroup analysis showed a significant difference in the success rate of minimally invasive endourological interventions vs open surgical revision for strictures greater than 1 cm (3 of 52 cases or 6% vs 19 of 22 or 86%, p <0.001). The success rate of endourological and open surgical procedures for strictures 1 cm or less was 50% (22 of 44 cases) and 100% (13 of 13), respectively. After adjusting for multiple preoperative stricture characteristics, only stricture length was strongly and inversely associated with a successful outcome (p <0.001). CONCLUSIONS: Open surgical revision produces better results than minimally invasive endourological intervention for ureteroileal strictures, particularly those greater than 1 cm. The success rate of endourological intervention is acceptable only for ureteroileal strictures 1 cm or less. Therefore, ureteroileal strictures greater than 1 cm should be primarily managed by open surgical revision. PMID- 23454402 TI - Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. AB - PURPOSE: We investigated the efficacy and safety of 50 and 75 MUg desmopressin orally disintegrating tablets in men with nocturia (2 or more nocturnal voids). MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel study 50 and 75 MUg desmopressin were compared with placebo. The co-primary efficacy end points were changes from baseline in mean number of nocturnal voids and proportions of patients achieving at least a 33% reduction from baseline in nocturnal voids (33% responders) during a 3-month treatment period. RESULTS: The full analysis set comprised 385 men (age range 20 to 87 years). The 50 and 75 MUg doses significantly reduced the number of nocturnal voids (-0.37, p <0.0001 and 0.41, p = 0.0003, respectively) and increased the odds of a 33% or greater response (OR 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively) compared with placebo during 3 months. Desmopressin 50 and 75 MUg increased the time to first void from baseline by approximately 40 minutes compared to placebo (p = 0.006 and p = 0.003, respectively). The response to desmopressin was seen by 1 week of treatment and was sustained. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated as only 2 subjects (age 74 and 79 years) on 50 MUg had a serum sodium level of less than 130 mmol/L (vs 9 subjects on 75 MUg). CONCLUSIONS: Desmopressin (orally disintegrating tablet) is an effective and well tolerated treatment for men with nocturia. Treatment with 50 MUg desmopressin, the minimum effective dose, provided sustained improvement of nocturia throughout the study and meaningful benefits to patients with an improved safety profile. PMID- 23454405 TI - Augmentation vs no augmentation for neurogenic bladder incontinence: augmentation. Con. PMID- 23454404 TI - Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. AB - PURPOSE: Previous studies suggest a lower dose of desmopressin orally disintegrating tablet may be effective in females compared to males with nocturia. We confirm the efficacy and safety of 25 MUg desmopressin orally disintegrating tablet compared to placebo in female patients. MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel group study 25 MUg desmopressin once daily was compared to placebo in women with nocturia (2 or more nocturnal voids). The co-primary efficacy end points were change from baseline in mean number of nocturnal voids and proportion of patients achieving at least a 33% reduction from baseline in the mean number of nocturnal voids (33% responders). RESULTS: The full analysis set comprised 261 patients (age range 19 to 87 years). Desmopressin significantly reduced the mean number of nocturnal voids and increased the odds of a 33% or greater response compared to placebo during 3 months, assessed by longitudinal analysis (-0.22, p = 0.028 and OR 1.85, p = 0.006, respectively). Desmopressin increased the mean time to first nocturnal void by 49 minutes compared to placebo at 3 months (p = 0.003). The response to desmopressin was seen by week 1 of treatment and was sustained throughout the trial. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated. Serum sodium levels remained greater than 125 mmol/L throughout the trial and 3 transient decreases to less than 130 mmol/L were recorded. CONCLUSIONS: At a dose of 25 MUg, desmopressin orally disintegrating tablet is an effective and well tolerated treatment for women with nocturia. Treatment provides rapid and sustained improvement in nocturia and quality of life. PMID- 23454406 TI - Animal in vivo models of lower urinary tract dysfunction: translational value. PMID- 23454407 TI - Augmentation vs no augmentation for neurogenic bladder incontinence: no augmentation. Pro. PMID- 23454408 TI - Bilateral mycotic renal artery aneurysms. PMID- 23454409 TI - Urethral mobilization for distal and mid shaft hypospadias with chordee. AB - PURPOSE: Many options are available for repairing mid shaft to distal hypospadias. Reported complications include poor cosmesis, persistent chordee, meatal stenosis and fistula. We hypothesized that advancing the intact native urethra would facilitate chordee correction and minimize complications. MATERIALS AND METHODS: We retrospectively reviewed our records of all 248 hypospadias repairs done from July 2003 to May 2009 and identified patients younger than 18 years with distal or mid shaft hypospadias who underwent repair by urethral mobilization. The outcomes recorded were patient satisfaction, bladder scan volume, and the rate of fistula, meatal stenosis or other complications. RESULTS: Of the patients 83 met study inclusion criteria, including 5 (6%) treated with previous failed hypospadias operations. The hypospadias site was the distal, mid shaft and megameatal intact prepuce variant in 69 (83.1%), 11 (13.3%) and 3 patients (3.6%), respectively. Chordee was present in 80 patients (96.4%). The mean degree of chordee was 61.5 degrees, mean age at operation was 35.7 months and mean followup was 18 months (range 0.25 to 79). Of parental responses 94% were pleased or very pleased. Mean bladder volume on bladder scan was 9.7 ml (range 0 to 81). Fistula developed in 1 patient (1.2%). There were no meatal stenosis cases. CONCLUSIONS: Urethral mobilization results in excellent cosmesis and a low complication rate. This technique is especially well suited to patients with prior operations or deficient preputial skin. Using the native urethra with its blood supply is our preferred method of repairing distal and mid shaft hypospadias with chordee. PMID- 23454410 TI - Aging society and environmental health challenges. PMID- 23454411 TI - A genome-wide association analysis identifies novel susceptibility loci for coronary arterial lesions in patients with Kawasaki disease. PMID- 23454412 TI - Selection of remedial alternatives for mine sites: a multicriteria decision analysis approach. AB - The selection of remedial alternatives for mine sites is a complex task because it involves multiple criteria and often with conflicting objectives. However, an existing framework used to select remedial alternatives lacks multicriteria decision analysis (MCDA) aids and does not consider uncertainty in the selection of alternatives. The objective of this paper is to improve the existing framework by introducing deterministic and probabilistic MCDA methods. The Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE) methods have been implemented in this study. The MCDA analysis involves processing inputs to the PROMETHEE methods that are identifying the alternatives, defining the criteria, defining the criteria weights using analytical hierarchical process (AHP), defining the probability distribution of criteria weights, and conducting Monte Carlo Simulation (MCS); running the PROMETHEE methods using these inputs; and conducting a sensitivity analysis. A case study was presented to demonstrate the improved framework at a mine site. The results showed that the improved framework provides a reliable way of selecting remedial alternatives as well as quantifying the impact of different criteria on selecting alternatives. PMID- 23454413 TI - An inventory of collaborative arrangements between Aboriginal peoples and the Canadian forest sector: linking policies to diversification in forms of engagement. AB - This paper examines collaborative arrangements between Aboriginal peoples and the forest sector across Canada. Using a broad definition of collaboration, we identified 1378 arrangements in 474 Aboriginal communities in all Canadian provinces and territories, except Nunavut. We categorize these collaborative arrangements into five broad types: treaties and other formal agreements; planning and management activities; influence on decision-making; forest tenures; and economic roles and partnerships. Consistent data was available for only the first three types, which showed that close to 60% of Aboriginal communities use each approach. However, this masks significant differences between provinces. For example, economic roles and partnerships are in place in all New Brunswick communities and 74% of communities in British Columbia, but only 12% of Manitoban communities. The proportion of communities that have been involved in participatory processes in forest decision-making (such as advisory committees and consultation processes) is particularly high in Quebec with 88% of communities, but only 32% of communities hold forest tenures. We also find that three-quarters of all communities choose to engage in two or more approaches, despite the demands that this can place upon the time and energy of community members. We finally consider how policy environments in different jurisdictions affect the frequency of certain types of collaboration. This empirical study, and the typology that it demonstrates, can inform policy development for Aboriginal involvement in Canadian forestry and help guide future research into broader issues of collaborative governance of natural resources. PMID- 23454414 TI - Assessing vulnerability of marine bird populations to offshore wind farms. AB - Offshore wind farms may affect bird populations through collision mortality and displacement. Given the pressures to develop offshore wind farms, there is an urgent need to assess population-level impacts on protected marine birds. Here we refine an approach to assess aspects of their ecology that influence population vulnerability to wind farm impacts, also taking into account the conservation importance of each species. Flight height appears to be a key factor influencing collision mortality risk but improved data on flight heights of marine birds are needed. Collision index calculations identify populations of gulls, white-tailed eagles, northern gannets and skuas as of particularly high concern in Scottish waters. Displacement index calculations identify populations of divers and common scoters as most vulnerable to population-level impacts of displacement, but these are likely to be less evident than impacts of collision mortality. The collision and displacement indices developed here for Scottish marine bird populations could be applied to populations elsewhere, and this approach will help in identifying likely impacts of future offshore wind farms on marine birds and prioritising monitoring programmes, at least until data on macro-avoidance rates become available. PMID- 23454415 TI - An integrated model of substrate clogging in vertical flow constructed wetlands. AB - This paper presents an integrated model of substrate clogging in a vertical flow constructed wetland (VFCW). The model simulates the reduction of pore space in the wetland substrate due to combined influences of various physical, biogeochemical and plant-related processes. A series of experiments based on laboratory-scale VFCWs were conducted to examine and measure key parameters related to clogging of the wetland substrate during operation under different conditions. The model was then validated using data collected from the experiments. The results showed that the model was able to replicate the clogging phenomenon as observed in the experiments, in particular, the characteristic clogging time. The model also predicted well individual contributions to clogging by accumulated inert suspended solids, microbial biomass and plant root materials during the wetland operation. Although the validation was based on the laboratory data, the results indicated that the model describes well the processes underlying the clogging and has the potential to become a tool for assessing the performance of prototype CWs in relation to clogging at both the design and operation stages. PMID- 23454416 TI - Water resources management in southern Europe: clues for a research and innovation based regional hypercluster. AB - European countries are facing increasing pressures on their water resources despite stringent regulations and systematic efforts on environmental protection. In this context, research and innovation play a strategic role reinforcing the efficiency of water policies. The present study provides a multilevel assessment of research and innovation practices in the field of water resource management in southern European countries and regions (more specifically; Cyprus, Albania, Poitou-Charentes in France, Andalusia in Spain and the North of Portugal). The analysis was based on a strategic framework aimed at gaining an insight of the current constraints, as well as of the existing and future technological solutions for a better water resource management. The triple helix model proved to be a useful analytical framework for assessing the efforts of different groups towards a common goal. The analysis proved the existence of a significant evolution in the use of technological tools to assist decision-making processes in integrated river basin management in all regions. Nevertheless, the absence of formal channels for knowledge and data exchange between researchers and water resource managers complicates the formers involvement in the decision-making process regarding water allocation. Both researchers and consultants emphasize the low availability of data, together with the need to advance on water resource economics as relevant constraints in the field. The SWOT analysis showed similar concerns among the participating regions and provided a battery of effective projects that resulted in the preparation of a Joint Action Plan. PMID- 23454417 TI - Protein nitration promotes inducible nitric oxide synthase transcription mediated by NF-kappaB in high glucose-stimulated human lens epithelial cells. AB - Although an important event in hyperglycaemia-induced oxidative stress is the nuclear factor-kappa b (NF-kappaB)-activated inducible nitric oxide synthase (iNOS) expression, the underlying mechanism is not fully characterized. Peroxynitrite, formed from NO and superoxide, can induce multiple proteins nitration, even including NF-kappaB and iNOS, to alter their functions. In this study, we found high glucose caused conspicuous nitration of nuclear NF-kappaB p65 and its co-activator p300 in human lens epithelial cells. The nitration of NF kappaB and p300 promoted their co-localization and binding to ensure the activation of the iNOS gene transcription. Moreover, nearly all predicted NF kappaB binding sites in the human iNOS gene promoter were responsive to high glucose stimulation, might for a synergistic role. While, only the NF-kappaB binding site -5212 showed significant alterations by high glucose and peroxynitrite stimulations, indicating it a more important role in the protein nitration promoted iNOS gene transcription. Our results demonstrated that protein nitration can promote the NF-kappaB-activated iNOS gene transcription in human lens epithelial cells by high glucose stimulation. PMID- 23454418 TI - The first Toll receptor from the triangle-shell pearl mussel Hyriopsis cumingii. AB - Toll receptor was first discovered in Drosophila and has an important function in the innate immunity of invertebrates. In this study, the Toll receptor HcToll1 from Hyriopsis cumingii with a full length of 3810 bp consisting of a 3687 bp ORF that encodes a total of 1228 amino acids protein was selected for further study. The HcToll1 protein consisted of a signal peptide, 17 LRR domains, 2 LRRCT domains, 1 LRRNT domain, 1 TM domain, and 1 TIR domain. Phylogenetic analysis results showed that HcToll1 was clustered in one group together with other mollusca tolls. RT-PCR analysis results showed that HcToll1 was expressed in all tested tissues such as hemocytes, hepatopancreas, gills, and mantle. qRT-PCR analysis results showed that HcToll1 expression was increased by the presence of Escherichia coli, Vibrio anguillarum, Staphyloccocus aureus, and White Spot Syndrome Virus (WSSV). Over-expression of HcTIR could up-regulate expression of drosomycin gene in Drosophila S2 cells. The results of our study indicated that HcToll1 is a functional Toll and it has an important function in the generation of innate immune responses of H. cumingii against microbial challenge. PMID- 23454419 TI - Unimanual to bimanual: tracking the development of handedness from 6 to 24 months. AB - Manual skills change dramatically over the first two years of life, creating an interesting challenge for researchers studying the development of handedness. A vast body of work to date has focused on unimanual skills during the period from the onset of reaching to walking. The current study sought to connect such early unimanual hand use to later role-differentiated bimanual manipulation (RDBM), in which one hand stabilizes the object for the other hand's action. We examined hand use in 38 children over 16 monthly visits using a validated measure for assessing hand preference for acquiring objects when children were 6-14 months old. We also developed a new measure for assessing RDBM preference presented when children were 18-24 months old. The new measure reliably elicited RDBM actions in both toddlers and an adult control group (N = 15). Results revealed that some children show preferences for acquiring objects as infants; these preferences are stable and persist into their second year as new skills appear. Moreover, children with no hand preference during infancy shifted to left or right lateralized hand use as toddlers. Despite a higher incidence of left-handedness compared to adult norms, the majority of children were right-handed by 2 years of age. PMID- 23454420 TI - Size matters: how age and reaching experiences shape infants' preferences for different sized objects. AB - Looking and reaching preferences for different-sized objects were examined in 4-5 and 5-6-month-old infants. Infants were presented with pairs of different sized cylinders and preferences were analyzed by age and reaching status. Outcome variables included looking and touching time for each object, first look, and first touch. Significant three-way interactions with age and reaching status were found for both infants' looking and touching duration. Four-5- and 5-6-month-olds with less reaching experience spent more time visually and manually exploring larger objects. In contrast, 5-6-month-olds with more reaching experience spent more time looking at and touching smaller objects, despite a first look and first touch preference for the largest object. Initially, looking and reaching preferences seem to be driven by mechanisms responding to general visual salience independent of an object's potential for manual action. Once reaching skills emerge, infants begin to use visual information to selectively choose smaller, more graspable objects as exploration targets. PMID- 23454421 TI - Gender and discipline in 5-12-month-old infants: a longitudinal study. AB - We examined the effects of infant age and gender on the behaviors of infants and mothers during discipline interactions using longitudinal, naturalistic, home based, taped observations of 16 mother-infant dyads (eight males and eight females). These observations were conducted between the child ages of 5 and 12 months and used a devised Maternal Discipline Coding System to code for the occurrence of discipline events. During discipline interactions, mothers vocalized longer, used harsher tones, and used more explanations with older compared to younger infants. Male infants were more likely than female infants to cry or whine during discipline events. Mothers of male infants used longer vocalizations, more words, and more affectionate terms than mothers of female infants. Male infants were more difficult during discipline interactions than female infants, but it appeared that mothers of males responded to this difficulty by using milder discipline techniques. PMID- 23454422 TI - Stability and antecedents of coparenting quality: the role of parent personality and child temperament. AB - This investigation explored how parent personality and infant temperament were associated with the development and stability of coparenting over the first 3 years of life. We examined the stability of supportive and undermining coparenting from 13 months to 3 years and whether infant difficult temperament moderated the stability of coparenting. We also examined how two dimensions of parent personality, communion and negative emotionality, were directly associated with coparenting quality and how these personality variables interacted with infant difficult temperament in predicting subsequent coparenting quality. Both supportive and undermining coparenting demonstrated moderate stability; however, stability in undermining coparenting was present only for families with less difficult infants. Fathers' communion and negative emotionality were associated with higher and lower coparenting quality, respectively, but only for families with an infant with a more challenging temperament. Mothers' negative emotionality was associated with higher coparenting quality. The results of this study suggest that parents' and children's characteristics are associated in direct and interactive ways with the development of the coparenting relationship across the first few years of a child's life. PMID- 23454423 TI - How infants look at others' manual interactions: the role of experience. AB - Human actions are often embedded in contexts of social interactions. However, just a few studies that have explored the development of infants' understanding of other people's manual actions do take this variable into account. In this study, 10- and 18-month-old infants were shown three interactive manual actions which the infants could or could not perform themselves. The infants' gaze shifts to the action target were recorded with an eye tracker. The results indicated that 18-month-old infants look faster to the target than their younger counterparts when they observe actions that they can perform themselves. The results suggest that the infants' own capacity to perform an action facilitates understanding of the goal of the action in a social interaction. PMID- 23454424 TI - "Be still my beating heart": linkages between mother-infant co-regulation and brief bradycardia at the onset of arm-restraint in 6-month-old infants. AB - This study examined linkages between 6-month-old infants' (n = 101) orienting response, measured physiologically by brief bradycardia or heart deceleration at the onset of a frustration task (maternal arm-restraint) and mother-infant co regulation measured during a 15-min unstructured free play episode. Given the socially disruptive nature of the frustration task, we suspected that infants who experienced more positive co-regulated interactions including symmetrical (both partners actively engaged and attending to each other) or asymmetrical (one partner actively engaged while partner attends to the other) with mothers would be more likely to display an orienting response (bradycardia) during the onset of the arm-restraint procedure than infants who experience unilateral (one partner focused on other but the other focused on self), unengaged (neither partner attending to the other) or disruptive interactions. Findings indicate that dyads that experienced more asymmetrical co-regulation had infants who were more likely to experience bradycardia while unengaged interactions predicted the absence of bradycardia. These findings suggest that mother-infant co-regulation may help establish expectations about social interactions and that when these relational expectancies are violated infants are more likely to exhibit bradycardia at the onset of a socially disruptive task. Alternative explanations are also considered. PMID- 23454425 TI - Six-month-old infants use motion parallax to direct reaching in depth. AB - Recent research shows that young infants are sensitive to motion parallax in visual displays but leaves open the question of whether infants use the information to perceive spatial layout. In this experiment, 6-month-old infants were translated horizontally in front of two objects that were yoked to the infant's movement. One object moved in the same direction as the motion of the infant and the other object moved in the opposite direction. This event provided motion parallax information that the object that moved in the opposite direction was nearer in depth. Infants who viewed the display monocularly reached preferentially to the object that was apparently nearer. A control group of infants who viewed the display binocularly showed no such preference. These results provide the first direct evidence that young infants use the spatial information provided by motion parallax to perceive the relative distance of objects and to direct their actions accordingly. PMID- 23454426 TI - Quality not quantity of television viewing is associated with bilingual toddlers' vocabulary scores. AB - Previous research examining the relationship between television viewing and vocabulary has produced mixed findings that indicate the quality of television exposure may impact language development more than quantity. However, few infant or toddler studies have included both quality and quantity measures and no study has done so with bilinguals. Caregivers of monolingual English, monolingual French, and English-French bilingual infants and toddlers from the same geographical area completed questionnaires regarding television exposure and vocabulary. Factor analysis of the questionnaire data confirmed that quantity and quality of viewing should be assessed separately. Quantity of television viewing was not correlated with language outcomes in any group. Poor quality viewing (television unintended for children, background television, solitary viewing, and earlier age of viewing) was related to lower vocabulary scores overall, but especially the English vocabulary scores of bilingual toddlers. Possible reasons for this finding are discussed. PMID- 23454427 TI - Mothers' vagal regulation during the Still-Face Paradigm: normative reactivity and impact of depression symptoms. AB - This study examined mothers' physiological reactivity in response to infant distress during the Still-Face Paradigm. We aimed to explore normative regulatory profiles and associated physiological and behavioral processes in order to further our understanding of what constitutes regulation in this dyadic context. We examined physiological patterns--vagal tone, indexed by respiratory sinus arrhythmia (RSA)--while mothers maintained a neutral expression over the course of the still face episode, as well as differential reactivity patterns in mothers with depression symptoms compared to non-depressed mothers. Behavioral and physiological data were collected from mothers of 5-month-old infants during the emotion suppression phase of the Still-Face Paradigm. We used Hierarchical Linear Modeling to examine changes in mothers' RSA during infant distress and explored maternal depression as a predictor of physiological profiles. Mothers were generally able to maintain a neutral expression and simultaneously demonstrated a mean-level increase in RSA during the still face episode compared to baseline, indicating an active regulatory response overall. A more detailed time-course examination of RSA trajectories revealed that an initial RSA increase was typically followed by a decrease in response to peak infant distress, suggesting a physiological mobilization response. However, this was not true of mothers with elevated depressive symptoms, who showed no change in RSA during infant distress. These distinct patterns of infant distress-related physiological activation may help to explain differences in maternal sensitivity and adaptive parenting. PMID- 23454428 TI - Asd-based balanced-lethal system in attenuated Edwardsiella tarda to express a heterologous antigen for a multivalent bacterial vaccine. AB - Edwardsiella tarda is an enteric Gram-negative invasive intracellular pathogen, which causes enteric septicemia in fish. It could be potentially used to develop a recombinant attenuated E. tarda vaccine for the aquaculture industry. Because live vaccine strains can potentially be released into the environment upon vaccination, medical and environmental safety issues must be considered. Deletion of the asdB gene in E. tarda resulted in a diaminopimelic acid (DAP)-dependent mutant. The wild type asdB gene was inserted in place of the antibiotic resistance gene in the plasmid, and the resultant non-antibiotic resistant vector was transformed into the attenuated and DAP-dependent E. tarda vaccine strain (WEDDeltaasdB) to obtain a balanced-lethal system for heterologous antigen expression. The balanced-lethal expression system was further optimized by comparing plasmid replicons with different Shine-Dalgarno sequences and start codons for the asdB gene. Utilizing the optimized balanced-lethal expression system, the protective antigen gene gapA34 from the fish pathogen Aeromonas hydrophila LSA34 was expressed in the attenuated E. tarda to generate the multivalent vaccine candidate WEDDeltaasdB/pUTta4DGap. This vaccine was shown to evoke an effective immune response against both E. tarda and A. hydrophila LSA34 by vaccinating turbot via a simple immersion route. This multivalent E. tarda vector vaccine has great potential for broad applications in aquaculture. PMID- 23454429 TI - B cell receptor accessory molecule CD79alpha: characterisation and expression analysis in a cartilaginous fish, the spiny dogfish (Squalus acanthias). AB - CD79alpha (also known as Igalpha) is a component of the B cell antigen receptor complex and plays an important role in B cell signalling. The CD79alpha protein is present on the surface of B cells throughout their life cycle, and is absent on all other healthy cells, making it a highly reliable marker for B cells in mammals. In this study the spiny dogfish (Squalus acanthias) CD79alpha (SaCD79alpha) is described and its expression studied under constitutive and stimulated conditions. The spiny dogfish CD79alpha cDNA contains an open reading frame of 618 bp, encoding a protein of 205 amino acids. Comparison of the SaCD79alpha gene with that of other species shows that the gross structure (number of exons, exon/intron boundaries, etc.) is highly conserved across phylogeny. Additionally, analysis of the 5' flanking region shows SaCD79alpha lacks a TATA box and possesses binding sites for multiple transcription factors implicated in its B cell-specific gene transcription in other species. Spiny dogfish CD79alpha is most highly expressed in immune tissues, such as spleen, epigonal and Leydig organ, and its transcript level significantly correlates with those of spiny dogfish immunoglobulin heavy chains. Additionally, CD79alpha transcription is up-regulated, to a small but significant degree, in peripheral blood cells following stimulation with pokeweed mitogen. These results strongly indicate that, as in mammals, spiny dogfish CD79alpha is expressed by shark B cells where it associates with surface-bound immunoglobulin to form a fully functional BCR, and thus may serve as a pan-B cell marker in future shark immunological studies. PMID- 23454430 TI - Comparative study of beta-glucan induced respiratory burst measured by nitroblue tetrazolium assay and real-time luminol-enhanced chemiluminescence assay in common carp (Cyprinus carpio L.). AB - The respiratory burst is an important feature of the immune system. The increase in cellular oxygen uptake that marks the initiation of the respiratory burst is followed by the production of reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide which plays a role in the clearance of pathogens and tissue regeneration processes. Therefore, the respiratory burst and associated ROS constitute important indicators of fish health status. This paper compares two methods for quantitation of ROS produced during the respiratory burst in common carp: the widely used, single-point measurement based on the intracellular reduction of nitroblue tetrazolium (NBT) and a real-time luminol-enhanced assay based on the detection of native chemiluminescence. Both assays allowed for detection of dose-dependent changes in magnitude of the respiratory burst response induced by beta-glucans in head kidney cells of carp. However, whereas the NBT assay was shown to detect the production of only superoxide anions, the real-time luminol-enhanced assay could detect the production of both superoxide anions and hydrogen peroxide. Only the chemiluminescence assay could reliably record the production of ROS on a real-time scale at frequent and continual time intervals for time course experiments, providing more detailed information on the respiratory burst response. The real-time chemiluminescence assay was used to measure respiratory burst activity in macrophage and neutrophilic granulocyte enriched head kidney cell fractions and total head kidney cell suspensions and proved to be a fast, reliable, automated multiwell microplate assay to quantitate fish health status modulated by beta-glucans. PMID- 23454431 TI - Attention modulates sensory suppression during back movements. AB - Tactile perception is often impaired during movement. The present study investigated whether such sensory suppression also occurs during back movements, and whether this would be modulated by attention. In two tactile detection experiments, participants simultaneously engaged in a movement task, in which they executed a back-bending movement, and a perceptual task, consisting of the detection of subtle tactile stimuli administered to their upper or lower back. The focus of participants' attention was manipulated by raising the probability that one of the back locations would be stimulated. The results revealed that tactile detection was suppressed during the execution of the back movements. Furthermore, the results of Experiment 2 revealed that when the stimulus was always presented to the attended location, tactile suppression was substantially reduced, suggesting that sensory suppression can be modulated by top-down attentional processes. The potential of this paradigm for studying tactile information processing in clinical populations is discussed. PMID- 23454432 TI - Anomalous self-experience in depersonalization and schizophrenia: a comparative investigation. AB - Various forms of anomalous self-experience can be seen as central to schizophrenia and other psychiatric disorders. We examined similarities and differences between anomalous self-experiences common in schizophrenia-spectrum disorders, as listed in the EASE (Examination of Anomalous Self Experiences), and those described in published accounts of severe depersonalization. Our aims were to consider anomalous self-experience in schizophrenia in a comparative context, to refine and enlarge upon existing descriptions of experiential disturbances in depersonalization, and to explore hypotheses concerning a possible core process in schizophrenia (diminished self-affection, an aspect of "ipseity" or minimal self). Numerous affinities between depersonalization and schizophrenia-spectrum experience were found: these demonstrate that rather pure forms of diminished self-affection (depersonalization) can involve many experiences that resemble those of schizophrenia. Important discrepancies also emerged, suggesting that more automatic or deficiency-like factors--probably involving self/world or self/other confusion and erosion of first-person perspective--are more distinctive of schizophrenia-spectrum disorders. PMID- 23454433 TI - Huperzine A promotes hippocampal neurogenesis in vitro and in vivo. AB - Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU(+)/NeuN(+) neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism. PMID- 23454435 TI - Investigating the cryoablative efficacy of a hybrid cryoprobe operating under freeze-thaw cycles. AB - Cryoprobes are minimally invasive tools that apply extremely low temperatures to eradicate undesirable cancerous tissue during cryosurgery. At times, they may generate thermal injury to neighboring good tissue leading to the case of over ablation. The magnitude of this problem becomes significant when tumors are complex, large size and irregular in shape. In this work, we propose a simple yet pragmatic hybrid cryoprobe which can potentially promote better surgical efficacy by improving tumor ablation while reducing undesired thermal injury to the neighboring tissue. To evaluate the performance of the proposed probe operating under cyclic freeze-thaw conditions, a detailed bioheat transfer model incorporating tissue death functions was developed. In-vitro experiments conducted to validate the model yielded a good agreement of 6.7%. We numerically studied the thermal impact of employing the hybrid cryoprobe on tissue temperature distributions. Evaluating the hybrid cryoprobe's control ability, we showed that the proposed device was able to regulate the growth of the ice front while sustaining an excellent coverage of the ablation zone. We also noted the existence of a diminishing temperature effect when alternate freeze-thaw cycles were applied. The performance of the hybrid cryoprobe could potentially lead to a portable and cost-effective device that may prove hugely beneficial for the purposes of surgical planning, rehearsal and control. PMID- 23454434 TI - Autoradiographic evaluation of [3H]CUMI-101, a novel, selective 5-HT1AR ligand in human and baboon brain. AB - [11C]CUMI-101 is the first selective serotonin receptor (5-HT1AR) partial agonist radiotracer for positron emission tomography (PET) tested in vivo in nonhuman primates and humans. We evaluated specific binding of [3H]CUMI-101 by quantitative autoradiography studies in postmortem baboon and human brain sections using the 5-HT1AR antagonist WAY-100635 as a displacer. The regional and laminar distributions of [3H]CUMI-101 binding in baboon and human brain sections matched the known distribution of [3H]8-OH-DPAT and [3H]WAY-100635. Prazosin did not measurably displace [3H]CUMI-101 binding in baboon or human brain sections, thereby ruling out [3H]CUMI-101 binding to alpha1-adrenergic receptors. This study demonstrates that [11C]CUMI-101 is a selective 5-HT1AR ligand for in vivo and in vitro studies in baboon and human brain. PMID- 23454436 TI - Effects of motion on time perception. AB - To investigate the effect of motion on time perception, participants were asked to perform either a temporal discrimination task or a temporal generalization task while running or standing still on a treadmill. In the temporal discrimination (bisection) task, 10 participants were exposed to two anchor stimuli, a 300-ms Short tone and a 700-ms Long tone, and then classified intermediate durations in terms of their similarity to the anchors. In the temporal generalization task, 10 other participants were exposed to a standard duration (500ms) and then judged whether or not a series of comparison-durations, ranging from 300ms to 700ms, had the same duration as the standard. The results showed that in the temporal bisection task the participants produced more "Long" responses under the dual-task condition (temporal judgments+running) than under the single-task condition (temporal judgments only). In the temporal generalization task, accuracy in the temporal judgments was lower in the dual task condition than the single-task condition. These results are discussed in the light of dual-task paradigm and of the Scalar Expectancy Theory (SET). PMID- 23454437 TI - Unexpected good recovery in a comatose post-cardiac arrest patient with poor prognostic features. PMID- 23454438 TI - Post-resuscitation care and outcomes of out-of-hospital cardiac arrest: a nationwide propensity score-matching analysis. AB - OBJECTIVE: This study aimed to determine whether active post-resuscitation care (APRC) was associated with improved out-of-hospital cardiac arrest (OHCA) outcomes on a nationwide level. METHODS AND RESULTS: We used a national OHCA cohort database consisting of hospital and ambulance data. We included all survivors of OHCA, excluding patients with non-cardiac etiology, younger than 15 years, and with unknown outcomes, from (2008 to 2010). The APRC was defined when the OHCA patients received mild therapeutic hypothermia (MTH) or active cardiac care (ACC), such as intravenous thrombolysis, percutaneous coronary intervention, coronary artery bypass surgery, and pacemaker/implantable cardioverter defibrillator insertion, as well as routine intensive care; patients receiving conservative post-resuscitation care (CPRC) served as the other group. The primary and secondary outcomes were survival to discharge and a good neurological outcome (cerebral performance category [CPC] 1-2), respectively. We extracted propensity-matched samples to control for selection bias. A multivariable logistic regression analysis was used to compare the APRC and CPRC groups adjusting for potential risks to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Of total 64,155 patients, 4557 survived to admission and were included in the final analysis. Out of these patients, 1599 (35.1%) cases survived to discharge, and 499 (11.0%) cases were discharged with good neurological recoveries. Overall, 695 cases (15.3%) received any APRC, including MTH (n=377, 8.3%) and ACC (370, 8.1%). The outcomes was better in the APRC group than in the CPRC group for survival to discharge (58.7% vs. 30.8%, p<0.001) and good neurological outcome (27.2% vs. 8.0%, p<0.001), respectively. In the total cohort, the adjusted ORs of the APRC group compared to those the CPRC group were 2.15 (95% CI 1.78-2.59) for survival to discharge and 2.54 (95% CI 1.98-3.27) for a good neurological outcome. In the propensity score-matched cohort, the adjusted ORs for survival to discharge and good neurological outcome of APRC were significantly favorable. CONCLUSIONS: Active post-resuscitation care resulted in significantly improved outcomes in adult OHCA patients with a presumed cardiac etiology in a nationwide, retrospective, observational study. PMID- 23454439 TI - Reply to letter: lateral vs anterior chest thrusts in the generation of airway pressure in anaesthetised pigs. PMID- 23454440 TI - Cardiac arrest in the workplace: pilot study on the ReAC register. PMID- 23454441 TI - Could there ever be evidence to support using lateral chest thrusts in humans with the victim lying on their side to clear upper-airway obstruction? PMID- 23454442 TI - Progesterone restores the female prostate activity in ovariectomized gerbil and may act as competitor of testosterone in intraprostatic environment. AB - AIMS: Little is known about the effect of progesterone on gerbil female prostate. It is known that normal oscillation in the progesterone and estradiol levels during the estrous cycle phases influence the morphophysiology of this gland. The present study aims to evaluate the isolated effect of prolonged administration of progesterone combined or not with testosterone on the prostate of ovariectomized female gerbil. MAIN METHODS: To observe the morphological changes caused by castration in the prostate of different groups stereologic analyses of all prostate compartments, analysis of nuclear area and perimeter, and morphometric measurements of epithelial and smooth muscle cells layers were used. In addition, immunocytochemistry was performed to investigate the distribution of the androgen, estrogen alfa and beta and progesterone receptors in different prostatic compartments. KEY FINDINGS: This study demonstrated that both treatments partially recovered the structure of the gland. In the group treated with progesterone plus testosterone a higher incidence of epithelial and stromal disorders occurred, besides the absence of secretory activity. Thus, treatment only with progesterone showed better results in the restoration of glandular homeostasis mainly seen by the regulation of the secretory activity. SIGNIFICANCE: Collectively, the findings of this study indicate that progesterone may have a significant role on the maintenance of prostate morphophysiology, and showed an interesting evidence of hormonal competition between progesterone and testosterone. PMID- 23454443 TI - Changes in cannabinoid CB(1) receptor functionality in the female rat prefrontal cortex following a high fat diet. AB - AIMS: A high fat diet (HFD) has been found to affect neurotransmission in the prefrontal cortex, but the effects of this dietary regime upon the endocannabinoid system has not been studied in this brain region. In consequence, in the present study, we have investigated the effect of HFD for up to 20 weeks upon the endocannabinoid system in the prefrontal cortex of female rats. MAIN METHODS: CB1 receptor functionality was measured using CP55,940-stimulated [(35)S]GTPgammaS autoradiography. Fatty acid amide hydrolase and monoacylglycerol lipase activities were analysed in brain regions by assessing rates of [(3)H]anandamide and JZL184-sensitive [(3)H]2-oleoylglycerol hydrolysis, respectively. KEY FINDINGS: In the prefrontal cortex, a significantly greater stimulation of [(35)S]GTPgammaS binding by CP55,940 was seen following 4-12, but not 16-20 weeks of HFD. No significant changes were seen for the caudate-putamen, CA1-CA3 region of the hippocampus or the dentate gyrus. The increased response for the 12 week animals was not accompanied by a significant change in the receptor density, measured with [(3)H]CP55,940 autoradiography. No significant changes in the activity of the endocannabinoid hydrolytic enzymes fatty acid amide or monoacylglycerol lipase were seen in the prefrontal cortex, hippocampus, amygdala or hypothalamus following either 12 or 20 weeks of HFD. SIGNIFICANCE: It is concluded that HFD produces an increased CB1 receptor functionality in the prefrontal cortex of female rats. Given that the endocannabinoid system regulates neurotransmission in the prefrontal cortex, the present data would implicate this system in the disturbed prefrontal cortical activity in this region following a high fat diet. PMID- 23454444 TI - Anti-inflammatory properties of potato glycoalkaloids in stimulated Jurkat and Raw 264.7 mouse macrophages. AB - AIMS: The potato glycoalkaloids, alpha-chaconine, alpha-solanine and solanidine, along with potato peel extracts were investigated for potential anti-inflammatory effects in vitro. Their potential to reduce two biomarkers of inflammation, cytokine and nitric oxide (NO) productions, were assessed in the stimulated Jurkat and macrophage models, respectively. MAIN METHODS: Cytokine and nitric oxide productions were stimulated in Jurkat and Raw 264.7 macrophages with Concanavalin A (Con A; 25 MUg/ml) and lipopolysaccaride (LPS; 1 MUg/ml), respectively. Selective concentrations of glycoalkaloids and potato peel extracts were added simultaneously with Con A or LPS for 24h to investigate their potential to reduce inflammatory activity. KEY FINDINGS: alpha-Chaconine and solanidine significantly reduced interleukin-2 (IL-2) and interleukin-8 (IL-8) productions in Con A-induced Jurkat cells. The potato peel extracts did not influence cytokine production. In LPS-stimulated Raw macrophages, alpha-solanine, solanidine and two potato peel extracts significantly reduced induced NO production. SIGNIFICANCE: Our findings suggest that sub-cytotoxic concentrations of potato glycoalkaloids and potato peel extracts possess anti-inflammatory effects in vitro and with further investigation may be useful in the prevention of anti-inflammatory diseases. PMID- 23454445 TI - Imaging of cervical metastases in thyroid cancer. PMID- 23454446 TI - The prevalence of fluid associated with the iliotibial band in asymptomatic recreational runners: an ultrasonographic study. AB - OBJECTIVE: To evaluate the prevalence and distribution of fluid associated with the iliotibial band (ITB) in asymptomatic recreational runners. DESIGN: Prospective cohort study. SETTING: Sports medicine center at a tertiary medical center. PATIENTS: Five male and 15 female asymptomatic recreational runners (10 30 miles per week) ages 18-40 years. METHODS: Participants were examined with the use of ultrasonography to assess for the presence of fluid at the level of the lateral femoral epicondyle and determine its relationship to the ITB at 0 and 30 degrees of knee flexion in both supine (non-weight-bearing) and standing (weight bearing) positions. RESULTS: Fluid was associated with the ITB in 100% of asymptomatic recreational runners and was bilateral in 90%. When examined in full extension with the subject supine, fluid was seen in 67.5% of knees (n = 40) compared with 95% of the knees when standing. When examined in 30 degrees of flexion, the presence of fluid decreased to 30% when supine and 22.5% when standing. With the knee in full extension in a supine/standing position, fluid was located anterior and deep 70%/74% of the time and was anterior only 11%/0% of the time. With the knee flexed to 30 degrees in a supine/standing position, fluid was located anterior and deep 50%/33% of the time and anterior only 33%/67% of the time. CONCLUSION: The prevalence of fluid associated with the ITB varied with body and knee position, was most common in the standing position with the knee extended, and was generally located anterior or anterior and deep to the ITB. The clinical significance of our findings are 2-fold: (1) body position should be considered when searching for fluid in the vicinity of the ITB, and (2) clinicians and imagers should exercise caution when interpreting the clinical significance of fluid associated with the ITB during ultrasonographic evaluation of runners with lateral knee pain. PMID- 23454447 TI - Prognosis for functional deterioration and functional improvement in late life among community-dwelling persons. AB - OBJECTIVE: To examine how health-related, socioeconomic, and environmental factors combine to influence the onset of activity of daily living (ADL) limitations or prognosis for death or further functional deterioration or improvement among elderly people. DESIGN: A national representative sample with 2 year follow-up. SETTING: Community-dwelling people. PARTICIPANTS: Included were 9447 persons (>=70 years of age) in the United States from the Second Longitudinal Study of Aging who were interviewed in 1994, 1995, or 1996. METHODS: Self- or proxy-reported health conditions, ADLs expressed as 5 stages describing severity and pattern of limitations, and other baseline characteristics were obtained. A multinomial logistic regression model was used to predict stage transitions. Because of incomplete follow-up (17.7% of baseline sample), primary analyses were determined by multiple imputation to address potential bias associated with loss to follow-up. MAIN OUTCOME MEASUREMENT: ADL stage transitions in 2 years (death, deteriorated, stable, and improved ADL function). RESULTS: In the imputed-case analysis, the percentages for those who died, deteriorated, were stable, and improved were 12.6%, 32.7%, 48.4%, and 6.2%, respectively. Persons at a mild stage of ADL limitation were most likely to deteriorate further. Persons at advanced stages were most likely to die. Married people and high school graduates had a lower likelihood of deterioration. The risk of mortality and functional deterioration increased with age. Certain conditions, such as diabetes, were associated both with mortality and functional deterioration; other conditions, such as cancer, were associated with mortality only, and arthritis was associated only with functional deterioration. CONCLUSIONS: Although overlap occurs, different clinical traits are associated with mortality, functional deterioration, and functional improvement. ADL stages might aid physical medicine and rehabilitation clinicians and researchers in developing and monitoring disability management strategies targeted to maintaining and enhancing self-care among community-dwelling older people. PMID- 23454448 TI - Morphological diversity of pedicels in phoretic deutonymphs of Uropodina mites (Acari: Mesostigmata). AB - The pedicel is a structure that connects the phoretic deutonymph of Uropodina mites with its carrier and enables dispersal. The shapes, lengths and diameters of pedicels formed by Uropoda orbicularis, Trichouropoda ovalis, Uroobovella pulchella and Uroobovella nova were studied by scanning and light microscopy. Pedicels of U. orbicularis and T. ovalis have the shape of a straight stalk. In U. pulchella, the pedicel is extremely short, irregularly shaped and composed of homogeneous material. The longest pedicel is found in U. nova and it may be helically coiled in this species. The length of the pedicel is positively correlated with deutonymph body size between species, but not within species. Pedicels of U. orbicularis and U. pulchella have the largest diameter. The pedicel diameter in U. orbicularis and T. ovalis is inversely proportional to its length, but not in U. nova and U. pulchella. The constituent of pedicel stems in U. pulchella is homogeneous, whereas in U. orbicularis and T. ovalis it contains a bundle of tightly packed fibres. In U. nova coiled pedicels are comprised of two layered materials of different electron density, one of which is electron lucid and located peripherally. Hypotheses on the origin of the pedicel are proposed. PMID- 23454449 TI - Efficacy of a novel chelator BPCBG for removing uranium and protecting against uranium-induced renal cell damage in rats and HK-2 cells. AB - Chelation therapy is a known effective method to increase the excretion of U(VI) from the body. Until now, no any uranium chelator has been approved for emergency medical use worldwide. The present study aimed to evaluate the efficacy of new ligand BPCBG containing two catechol groups and two aminocarboxylic acid groups in decorporation of U(VI) and protection against acute U(VI) nephrotoxicity in rats, and further explored the detoxification mechanism of BPCBG for U(VI) induced nephrotoxicity in HK-2 cells with comparison to DTPA-CaNa3. Chelating agents were administered at various times before or after injections of U(VI) in rats. The U(VI) levels in urine, kidneys and femurs were measured 24 h after U(VI) injections. Histopathological changes in the kidney and serum urea and creatinine and urine protein were examined. After treatment of U(VI)-exposed HK-2 cells with chelating agent, the intracellular U(VI) contents, formation of micronuclei, lactate dehydrogenase (LDH) activity and production of reactive oxygen species (ROS) were assessed. It was found that prompt, advanced or delayed injections of BPCBG effectively increased 24 h-urinary U(VI) excretion and decreased the levels of U(VI) in kidney and bone. Meanwhile, BPCBG injection obviously reduced the severity of the U(VI)-induced histological alterations in the kidney, which was in parallel with the amelioration noted in serum indicators, urea and creatinine, and urine protein of U(VI) nephrotoxicity. In U(VI)-exposed HK-2 cells, immediate and delayed treatment with BPCBG significantly decreased the formation of micronuclei and LDH release by inhibiting the cellular U(VI) intake, promoting the intracellular U(VI) release and inhibiting the production of intracellular ROS. Our data suggest that BPCBG is a novel bi-functional U(VI) decorporation agent with a better efficacy than DTPA-CaNa3. PMID- 23454452 TI - Sequencing of hippocampal and cerebellar transcriptomes provides new insights into the complexity of gene regulation in the human brain. AB - The hippocampus and cerebellum represent anatomically and functionally distinct parts of the human brain. The RNA-Seq technique makes it possible to investigate the human transcriptome with unprecedented resolution, allowing identification of differential mRNA splicing and promoter usage on a genome-wide scale. We undertook whole-mRNA sequencing of samples from the human hippocampus and cerebellum. A bioinformatic analysis revealed distinct expression patterns of genes related to the molecular physiology of neurons and glial cells. Upregulated genes in hippocampal tissue included serpin peptidase inhibitor, clade A (SERPINA3), lymphocyte antigen 6 complex, locus H (LY6H) and transthyretin (TTR). In cerebellum, the cerebellin 3 precursor (CLBN3) and Zic family member 4 (ZIC4) genes were significantly upregulated. These changes were validated in independent donor samples by qRT-PCR. The hippocampus and the cerebellum showed striking differences in splicing patterns and promoter usage. A notable example of this was the gene for NGFI-A binding protein 2 (NAB2), which displayed tissue-specific isoforms which may affect its function as a transcriptional repressor. PMID- 23454450 TI - Developmental programming: impact of prenatal exposure to bisphenol-A and methoxychlor on steroid feedbacks in sheep. AB - Bisphenol-A (BPA), a polymer used in plastics manufacturing, and methoxychlor (MXC), a pesticide, are endocrine disrupting compounds with estrogenic and anti androgenic properties. Prenatal BPA or MXC treatment induces reproductive defects in sheep with BPA causing prepubertal luteinizing hormone (LH) hypersecretion and dampening of periovulatory LH surges and MXC lengthening follicular phase and delaying the LH surge. In this study, we addressed the underlying neuroendocrine defects by testing the following hypotheses: 1) prenatal BPA, but not MXC reduces sensitivity to estradiol and progesterone negative feedback, 2) prenatal BPA, but not MXC increases pituitary responsiveness to gonadotropin releasing hormone (GnRH), and 3) prenatal BPA dampens LH surge response to estradiol positive feedback challenge while prenatal MXC delays the timing of the LH surge. Pregnant sheep were treated with either 1) 5mg/kg/day BPA (produces approximately twice the level found in human circulation, n=8), 2) 5mg/kg/day MXC (the lowest observed effect level stated in the EPA National Toxicology Program's Report; n=6), or 3) vehicle (cotton seed oil: C: n=6) from days 30 to 90 of gestation. Female offspring of these ewes were ovariectomized at 21months of age and tested for progesterone negative, estradiol negative, estradiol positive feedback sensitivities and pituitary responsiveness to GnRH. Results revealed that sensitivity to all 3 feedbacks as well as pituitary responsiveness to GnRH were not altered by either of the prenatal treatments. These findings suggest that the postpubertal reproductive defects seen in these animals may have stemmed from ovarian defects and the steroidal signals emanating from them. PMID- 23454453 TI - Difficulties in using soil-based methods to assess plant availability of potentially toxic elements in biochars and their feedstocks. AB - The use of biochars in agriculture to improve soil function and carbon sequestration is expected to increase into the future. We aimed to identify the most suitable chemical extractants for the risk assessment of potentially toxic element (PTE) availability in biochars produced from a range of feedstocks, and to investigate the changes in PTE extractability that occur as a result of feedstock pyrolysis using five common extraction methods. We evaluated these methods with regard to their ability to predict PTE phytoavailability in four different biochars against metal uptake by wheat. No single extractant significantly correlated well with >= 4 PTEs from the 10 examined, highlighting that the availability and binding mechanism of individual PTEs differed by biochar type. Commonly used PTE extraction methods need to be reviewed for use with biochars, and that some biochars may be able to stabilise PTEs, reducing risks of contamination upon land application. PMID- 23454454 TI - Evaluation of cytotoxicity of polypyrrole nanoparticles synthesized by oxidative polymerization. AB - Polypyrrole (Ppy) is known as biocompatible material, which is used in some diverse biomedical applications and seeming to be a very promising for advanced biotechnological applications. In order to increase our understanding about biocompatibility of Ppy, in this study pure Ppy nanoparticles (Ppy-NPs) of fixed size and morphology were prepared by one-step oxidative polymerization and their cyto-compatibility was evaluated. The impact of different concentration of Ppy nanoparticles on primary mouse embryonic fibroblasts (MEF), mouse hepatoma cell line (MH-22A), and human T lymphocyte Jurkat cell line was investigated. Cell morphology, viability/proliferation after the treatment by Ppy nanoparticles was evaluated. Obtained results showed that Ppy nanoparticles at low concentrations are biocompatible, while at high concentrations they became cytotoxic for Jurkat, MEF and MH-22A cells, and it was found that cytotoxic effect is dose-dependent. PMID- 23454455 TI - Coupling the dechlorination of aqueous 4-CP with the mechanochemical destruction of solid PCNB using Fe-Ni-SiO2. AB - A novel combined process was developed for mechanochemical destruction of pentachloronitrobenzene (PCNB) in solid waste, coupled with the dechlorination of aqueous 4-chlorophenol (4-CP) using the nonhazardous residue from the solid-phase destruction step. Using the mixture of iron powder, nickel powder and quartz sand as the additives in a planetary ball mill under the room temperature, the mechanochemical reaction was induced and a complete destruction of PCNB was realized. The resulting solid residue was characterized by various measures including X-ray diffraction (XRD), Raman spectroscopy and scanning electron microscopy/energy dispersive X-ray spectrometry (SEM/EDS), which suggested that main components were carbon, chloride besides excess additives. Such nonhazardous residue was then used to effectively dechlorinate aqueous 4-CP. The residue achieving over 93% dechlorination rate was selected as the optimized content. With a series of verification experiments, a possible dechlorination mechanism was proposed, involving the reactions occurred on three interfaces (i.e. Fe/Ni, Fe/C and Fe/C/Ni). PMID- 23454456 TI - Effect of silver or copper middle layer on the performance of palladium modified nickel foam electrodes in the 2-chlorobiphenyl dechlorination. AB - To enhance the activity of chemi-deposited palladium/nickel foam (Pd/Ni) electrodes used for an electrochemical dechlorination process, silver or copper was deposited electrochemically onto the nickel foam substrate (to give Ag/Ni or Cu/Ni) before the chemical deposition of palladium. The physicochemical properties of the resulting materials (Pd/Ni, Pd/Ag/Ni and Pd/Cu/Ni) were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM), and their electrochemical catalytic activities were evaluated by monitoring the electrochemical dechlorination of 2-chlorobiphenyl (2-CB) in strongly alkaline methanol/water solution. The results show that the Pd/Ag/Ni and Pd/Cu/Ni electrodes had consistently higher electrocatalytic activities and current efficiencies (CEs) compared with the untreated Pd/Ni electrode. The Pd/Ag/Ni electrode exhibited the highest activity. The dechlorination was also studied as a function of Pd loading, the Ag or Cu interlayer loadings, and the current density. The Pd loading and the interlayer loadings both had positive effects on the dechlorination reaction. Increasing the current density increased the reaction rate but reduced the CE. The improvement of the electrocatalytic activities of the Pd/Ni electrode by applying the interlayer of Ag or Cu resulted from the enlargement of the effective surface area of the electrode and the adjustment of the metal-H bond energy to the appropriate value, as well as the effective adsorption of 2-CB on Ag. Moreover, the high catalytic activity of the Pd/Ag/Ni electrode was maintained after six successive cyclic experiments, whereas Pd/Cu/Ni electrodes deactivate severely under the same conditions. PMID- 23454457 TI - A comparative study of fungal and bacterial biofiltration treating a VOC mixture. AB - Bacterial biofilters usually exhibit a high microbial diversity and robustness, while fungal biofilters have been claimed to better withstand low moisture contents and pH values, and to be more efficient coping with hydrophobic volatile organic compounds (VOCs). However, there are only few systematic evaluations of both biofiltration technologies. The present study compared fungal and bacterial biofiltration for the treatment of a VOC mixture (propanal, methyl isobutyl ketone-MIBK, toluene and hexanol) under the same operating conditions. Overall, fungal biofiltration supported lower elimination capacities than its bacterial counterpart (27.7 +/- 8.9 vs 40.2 +/- 5.4 gCm(-3) reactor h(-1)), which exhibited a final pressure drop 60% higher than that of the bacterial biofilter due to mycelial growth. The VOC mineralization ratio was also higher in the bacterial bed (~ 63% vs ~ 43%). However, the substrate biodegradation preference order was similar for both biofilters (propanal>hexanol>MIBK>toluene) with propanal partially inhibiting the consumption of the rest of the VOCs. Both systems supported an excellent robustness versus 24h VOC starvation episodes. The implementation of a fungal/bacterial coupled system did not significantly improve the VOC removal performance compared to the individual biofilter performances. PMID- 23454458 TI - Inhibitions on the behavior and growth of the nematode progeny after prenatal exposure to sulfonamides at micromolar concentrations. AB - Sulfonamides are one typical antibiotic which is an emerging hazardous material to the ecological stability due to their continuously application and biological effects to non-target organisms. The parent-progeny transgenerational effects need investigations to indicate their long-term consequences. Currently, we tested the transgenerational effects of sulfadiazine (SD), sulfapyridine (SP) and sulfamethazine (SMZ) on L3 larva of Caenorhabditis elegans. The nematodes were exposed to aqueous sulfonamides at micromolar concentrations for 96 h, and then the effects on the behavior and growth in the exposed parent and unexposed progeny were measured. Results showed that SD, SP and SMZ inhibited three behavior indicators including body bending frequency (BBF), reversal movement (RM) and Omega turn (OT), and the growth indicator (body length, BL). Behavior indicators showed higher sensitivities than the growth indicator, and BBF had the highest sensitivity among the behavior indicators. Moreover, the effects of sulfonamides were also observed in the unexposed progeny with partially rescued or more severe inhibitions on the indicators. The behavior also showed higher sensitivity than the growth in the progeny. The transgenerational effects of sulfonamides indicated that parental exposure can multiply the harmful effects of antibiotic pollution in following generations and their potential ecological risks at environmental concentrations were further raised. PMID- 23454459 TI - miR395 is involved in detoxification of cadmium in Brassica napus. AB - The toxic metal cadmium (Cd) constitutes one of the major inorganic contaminants in environments. microRNAs (miRNAs) are a class of endogenous non-coding small RNAs. miR395 is conserved and regulates sulfate assimilation and distribution in higher plants, but whether it is involved in detoxification of Cd in plants has not been described. In this study, transgenic rapeseed (Brassica napus) over expressing miR395 was identified under Cd stress. miR395-over-expressing plants showed a lower degree of Cd-induced oxidative stress than wild type. By contrast, chlorophyll, glutathione and non-protein thiols contents were higher in the transformants than wild type. Determination of growth response showed that 35S::MIR395 plants accumulated higher levels of biomass and sulfur than wild type under Cd exposure. miR395 transgenic plants had higher levels of Cd in plants, particularly at the high supply of Cd in the medium, but they tended to repress Cd translocation from roots to shoots. Simultaneously, expression of metal tolerance genes such as BnPCS1, BnHO1 and Sultr1;1 was up-regulated under Cd stress, and the expression of the genes was more pronounced in 35S::MIR395 plants than in wild type. These results suggest that miR395 would be involved in detoxification of Cd in B. napus. PMID- 23454460 TI - Electrodialytic removal of Cd from biomass combustion fly ash suspensions. AB - Due to relatively high concentrations of Cd, biomass combustion fly ashes often fail to meet Danish legislative requirements for recycling as fertilizer. In this study, the potential of using electrodialytic remediation for removal of Cd from four different biomass combustion fly ashes was investigated with the aim of enabling reuse of the ashes. The ashes originated from combustion of straw (two ashes), wood chips, and co-firing of wood pellets and fuel oil, respectively. A series of laboratory scale electrodialytic remediation experiments were conducted with each ash. The initial Cd concentration in the ashes varied between 8.8 mg Cd/kg (co-firing ash) and 64 mg Cd/kg (pre-washed straw ash), and pH varied from 3.7 (co-firing ash) to 13.3 (wood ash). In spite of such large variations between the ashes, the electrodialytic method showed to be sufficiently robust to treat the ashes so the final Cd concentration was below 2.0mg Cd/kg DM in at least one experiment done with each ash. This was obtained within 2 weeks of remediation and at liquid to solid (L/S) ratios of L/S 16 for the pre-washed straw ash and L/S 8 for the straw, co-firing and wood ash. PMID- 23454461 TI - Removal of high concentration p-nitrophenol in aqueous solution by zero valent iron with ultrasonic irradiation (US-ZVI). AB - In this study, the US-ZVI system was used to produce the strong reductants including H and nascent Fe(2+) ions to eliminate the toxicity of the high concentration p-nitrophenol (PNP) wastewater. The effect of the reactor structure, initial pH, ZVI dosage, ultrasonic power and initial PNP concentration on the removal efficiency of PNP from water was investigated intensively. The results show that a higher removal rate can be obtained by using a conical structure reactor, and the lower initial pH can aid the acceleration of PNP removal rate by using US-ZVI system. Furthermore, the removal efficiencies of PNP increased obviously with the increase of initial ZVI concentration from 0 to 15 gL(-1). Also, the treatment capacity of ZVI was enhanced remarkably by the ultrasonic irradiation, and the US-ZVI system can maintain high treatment efficiency for the high concentration PNP wastewater (500-10,000 mgL(-1)). Meanwhile, the high removal efficiency of PNP was mainly resulted from the synergistic reaction of ZVI and US. At last, the main degradation product (i.e., p-aminophenol) was detected by gas chromatography-mass spectrum (GC-MS). Thus, the reaction pathway of PNP in the US-ZVI system is proposed as a reducing process by the H and nascent Fe(2+) ions. PMID- 23454462 TI - Synthesis of Ce3+ doped ZnFe2O4 self-assembled clusters and adsorption of chromium(VI). AB - A solvothermal synthetic route was used to prepare Ce(3+) doped Zn ferrites, where sphere-like clusters aggregated by nanosized particles were fabricated. The size of the cluster and the saturation magnetization of the sample are decreasing with the increase of Ce(3+). These samples can be easily separated from aqueous solutions by applying a magnetic field and have a high loading capacity of Cr(VI). The Cr(VI) adsorption experiments indicated that the adsorption was divided into two processes, in which the first one took place about 6h, the second one took place between 6 and 96 h. The maximum adsorption capacity for Cr(VI) was determined to be 57.24 mg/g. Langmuir model was employed to fit the adsorption isotherm, which implied the single layer adsorption. The data of SBET, external area and porous area of the samples can be used to explain these adsorption processes. And the Ce(3+) ions doped in the sample induced the increasing adsorption capacity of Cr(VI). The adsorption process can be described by the pseudo-second-order kinetic model. PMID- 23454463 TI - Optimizing mixed culture of two acidophiles to improve copper recovery from printed circuit boards (PCBs). AB - In the previous research, the effects of different addition time and amount of printed circuit boards (PCBs) on cells growth and metals recovery in separated and mixed culture of Acidithiobacillus thiooxidans and Acidithiobacillus ferrooxidans were investigated. This paper aimed to optimize mixed culture of both acidophiles for maximizing PCBs addition amounts and copper leaching percentage simultaneously. Initially, influences of inoculums ratio between two acidophiles on their cells growth were studied. Then, initial medium pH and concentrations of FeSO4 . 7H2O and elemental sulfur (S(0)) were optimized by response surface methodology (RSM) to improve copper recovery. Finally, multiple point PCBs addition was tested to determine maximal amounts. Results showed that with initial inoculums ratio (Af:At) 1:2, pH 1.56, FeSO4 . 7H2O and S(0) at 16.88 and 5.44 g/L, and PCBs addition 28.8 g/L, copper recovery reached 92.6% after 240 h cultivation. It was indicated that copper could be efficiently leached out from increased PCBs addition amount and FeSO4 . 7H2O was remarkably reduced from 22.1 to 16.88 g/L. PMID- 23454464 TI - Chemical profile identification of fugitive and confined particle emissions from an integrated iron and steelmaking plant. AB - The aim of this study is to obtain the characteristic inorganic chemical profile of important particle sources identified in the integrated iron and steel process: sintering, blast furnace, steelmaking and desulfurization slag processing. A complete chemical and physical characterization program was developed: particle size distribution, chemical analysis, XRD, SEM-EDX and TGA/DTA. The sample collected from the sinter stack showed high levels of K and Cl(-), followed by Fe, NH4(+), Ca, Na and Pb. The profile of the dust samples taken from the sinter cake discharge zone was quite different, showing higher amounts of Fe, Ca and Al, and lower amounts of K, Cl(-), Na and Pb. Dust samples collected from the blast furnace (BF) and steelmaking cast house may be distinguished from each other based on the higher levels of Fe (hematite and magnetite) and lower levels of Ca, Zn and C (graphite) found in BF dust. High levels of Ca and Fe were found in samples taken from the desulfurization slag processing area. Such information can be useful for source apportionment studies at receptor sites that could be influenced by iron and steelmaking plant emissions. PMID- 23454465 TI - Assessment of released heavy metals from electrical and electronic equipment (EEE) existing in shipwrecks through laboratory-scale simulation reactor. AB - In a passenger ship, the existence of EEE is obvious. In time, under shipwreck's conditions, all these materials will undergo an accelerated severe corrosion, due to salt water, releasing, consequently, heavy metals and other hazardous substances in the aquatic environment. In this study, a laboratory-scale reactor was manufactured in order to simulate the conditions under which the "Sea Diamond" shipwreck lies (14 bars of pressure and 16 degrees C of temperature) and remotely observe and assess any heavy metal release that would occur, from part of the EEE present in the ship, into the sea. Ten metals were examined and the results showed that zinc, mercury and copper were abundant in the water samples taken from the reactor and in significantly higher concentrations compared to the US EPA CMC (criterion maximum concentration) criterion. Moreover, nickel and lead were found in concentrations higher than the CCC (criterion constant concentration) criterion set by the US EPA for clean seawater. The rest of the elements were measured in concentrations within the permissible limits. It is therefore of environmental benefit to salvage the wreck and recycle all the WEEE found in it. PMID- 23454466 TI - Phase-dependent phytoavailability of thallium--a synthetic soil experiment. AB - The study deals with the environmental stability of Tl-modified phases (ferrihydrite, goethite, birnessite, calcite and illite) and phytoavailability of Tl in synthetically prepared soils used in a model vegetation experiment. The data presented here clearly demonstrate a strong relationship between the mineralogical position of Tl in the model soil and its uptake by the plant (Sinapis alba L.). The maximum rate of Tl uptake was observed for plants grown on soil containing Tl-modified illite. In contrast, soil enriched in Ksat-birnessite had the lowest potential for Tl release and phytoaccumulation. Root-induced dissolution of synthetic calcite and ferrihydrite in the rhizosphere followed by Tl mobilization was detected. Highly crystalline goethite was more stable in the rhizosphere, compared to ferrihydrite, leading to reduced biological uptake of Tl. Based on the results obtained, the mineralogical aspect must be taken into account prior to general environmental recommendations in areas affected by Tl. PMID- 23454467 TI - Epigenetics in fertilization and preimplantation embryo development. AB - Epigenetic reprogramming of the parental genomes upon fertilization is required for proper embryonic development. It has long been appreciated that asymmetric distribution of histone modifications as well as differences in the level of DNA methylation exist between the parental pronuclei in mammalian zygotes and during preimplantation development. The speed at which the paternal genome is demethylated after entering the oocyte and the fact that rapid demethylation occurs in the absence of DNA replication have led many to hypothesize that a DNA demethylase must exist. However, such an enzyme has not been found. That the genome of mammalian preimplantation embryos undergo a wave of global demethylation was first reported 25 years ago but only in the past three years has data surfaced that can partially explain the elusive nature of this phenomenon. In addition to the global reorganization of the methylation and histone modification patterns, oocyte development prior to germinal vesicle breakdown involves the production of numerous small RNA, including miRNA. Despite their presence, miRNA functional activity is thought to be limited in the mature mouse oocyte. Additionally, molecular signatures in the 3' untranslated region of maternally expressed transcripts may impact mRNA stability during the transcriptionally quiescent period following germinal vesicle breakdown and prior to the maternal to zygote transition. In this review, we reference some of the recent works which attempt to shed light into the importance of the dynamic epigenetic landscape observed during oocyte maturation and preimplantation embryo development in mammals. PMID- 23454468 TI - Searching for the optimal data partitioning strategy in mitochondrial phylogenomics: a phylogeny of Acridoidea (Insecta: Orthoptera: Caelifera) as a case study. AB - One of the main challenges in analyzing multi-locus phylogenomic data is to find an optimal data partitioning strategy to account for variable evolutionary histories of different loci for any given dataset. Although a number of studies have addressed the issue of data partitioning in a Bayesian phylogenetic framework, such studies in a maximum likelihood framework are comparatively lacking. Furthermore, a rigorous statistical exploration of possible data partitioning schemes has not been applied to mitochondrial genome (mtgenome) data, which provide a complex, but manageable platform for addressing various challenges in analyzing phylogenomic data. In this study, we investigate the issue of data partitioning in the maximum likelihood framework in the context of the mitochondrial phylogenomics of an orthopteran superfamily Acridoidea (Orthoptera: Caelifera). The present study analyzes 34 terminals representing all 8 superfamilies within Caelifera, which includes newly sequenced partial or complete mtgenomes for 11 families. Using a new partition-selection method implemented in the software PartitionFinder, we compare a large number of data partitioning schemes in an attempt to identify the most effective method of analyzing the mtgenome data. We find that the best-fit partitioning scheme selected by PartitionFinder is superior to any a priori schemes commonly utilized in mitochondrial phylogenomics. We also show that over-partitioning is often detrimental to phylogenetic reconstruction. A comparative analysis of mtgenome structures finds that the tRNA gene rearrangement between cytochrome c oxidase subunit II and ATP synthase protein 8 does not occur in the most basal caeliferan lineage Tridactyloidea, suggesting that this gene rearrangement must have evolved at least in the common ancestor of Tetrigoidea and Acridomorpha. We find that mtgenome data contain sufficient phylogenetic information to broadly resolve the relationships across Acridomorpha and Acridoidea. PMID- 23454469 TI - Molecular phylogeny of kinorhynchs. AB - We reconstructed kinorhynch phylogeny using maximum-likelihood and Bayesian analyses of nuclear 18S and 28S rRNA gene sequences from 30 species in 13 genera (18S) and 23 species in 12 genera (28S), representing eight families and both orders (Cyclorhagida and Homalorhagida) currently recognized in the phylum. We analyzed the two genes individually (18S and 28S datasets) and in combination (18S+28S dataset). We detected four main clades (I-IV). Clade I consisted of family Echinoderidae. Clade II contained representatives of Zelinkaderidae, Antygomonidae, Semnoderidae, Centroderes, and Condyloderes, the latter two currently classified in Centroderidae; within Clade II, Zelinkaderidae, Antygomonidae, and Semnoderidae comprised a clade with strong nodal support. Clade III contained only two species in Campyloderes, also currently classified in the Centroderidae, indicating polyphyly for this family. Clades I-III, containing all representatives of Cyclorhagida included in the analysis except for Dracoderes abei, formed a clade with high nodal support in the 28S and 18S+28S trees. Clade IV, resolved in the 18S and 18S+28S trees with high nodal support, contained only species in order Homalorhagida, with the exception of the cyclorhagid Dracoderes abei. Order Cyclorhagida as it currently stands is thus polyphyletic, and order Homalorhagida paraphyletic. Our results indicate that Dracoderidae has been misplaced in Cyclorhagida based on homoplasious characters. Our analyses did not resolve the relationships among Clades I-III within Cyclorhagida. Neither gene alone nor the combined dataset resolved all nodes in trees, indicating that additional markers will be needed to reconstruct kinorhynch phylogeny. PMID- 23454470 TI - Inverting adherent cells for visualizing ECM interactions at the basal cell side. AB - Interactions with the extracellular matrix (ECM) govern a wide range of cellular functions, including survival, migration and invasion. However, in adherent cells these interactions occur primarily on the basal cell side, making them inaccessible to high-resolution, surface-scanning imaging techniques such as atomic force microscopy (AFM) or scanning electron microscopy (SEM). Here we describe a fast and reliable method for inverting adherent cells, exposing the basal cell membrane for direct analysis by AFM or SEM in combination with fluorescence microscopy. Cells including their matrix adhesion sites remain intact during the inversion process and are transferred together with the complete array of basally associated ECM proteins. Molecular features of ECM proteins, such as the characteristic 67 nm collagen D-periodicity, are well preserved after inversion. To demonstrate the versatility of the method, we compared basal interactions of fibroblasts with fibrillar collagen I and fibronectin matrices. While fibroblasts remodel the fibronectin layer exclusively from above, they actively invade even thin collagen layers by contacting individual collagen nanofibrils both basally and apically through a network of cellular extensions. Cell-matrix entanglement coincides with enhanced cell spreading and flattening, indicating that nanoscale ECM interactions govern macroscopic changes in cell morphology. The presented cell inversion technique can thus provide novel insight into nanoscale cell-matrix interactions at the basal cell side. PMID- 23454471 TI - Functional MRI to assess alterations of functional networks in response to pharmacological or genetic manipulations of the serotonergic system in mice. AB - Imaging methods that enable the investigation of functional networks both in human and animal brain provide important insights into mechanisms underlying pathologies including psychiatric disorders. Since the serotonergic receptor 1A (5-HT(1A)-R) has been strongly implicated in the pathophysiology of depressive and anxiety disorders, as well as in the action of antidepressant drugs, we investigated brain connectivity related to the 5-HT(1A)-R system by use of pharmacological functional magnetic resonance imaging in mice. We characterized functional connectivity elicited by activation of 5-HT(1A)-R and investigated how pharmacological and genetic manipulations of its function may modulate the evoked connectivity. Functional connectivity elicited by administration of the 5-HT(1A) R agonist 8-OH-DPAT can be described by networks characterized by small-world attributes with nodes displaying highly concerted response patterns. Circuits identified comprised the brain structures known to be involved in stress-related disorders (e.g. prefrontal cortex, amygdala and hippocampus). The results also highlight the dorsomedial thalamus, a structure associated with fear processing, as a hub of the 5-HT(1A)-R functional network. Administration of a specific 5 HT(1A)-R antagonist or use of heterozygous 5-HT(1A)-R knockout mice significantly reduced functional connectivity elicited by 8-OH-DPAT. Whole brain functional connectivity analysis constitutes an attractive tool to characterize impairments in neurotransmission and the efficacy of pharmacological treatment in a comprehensive manner. PMID- 23454472 TI - EEG-fMRI correlation patterns in the presurgical evaluation of focal epilepsy: a comparison with electrocorticographic data and surgical outcome measures. AB - EEG-correlated functional MRI (EEG-fMRI) visualizes brain regions associated with interictal epileptiform discharges (IEDs). This technique images the epileptiform network, including multifocal, superficial and deeply situated cortical areas. To understand the role of EEG-fMRI in presurgical evaluation, its results should be validated relative to a gold standard. For that purpose, EEG-fMRI data were acquired for a heterogeneous group of surgical candidates (n=16) who were later implanted with subdural grids and strips (ECoG). The EEG-fMRI correlation patterns were systematically compared with brain areas involved in IEDs ECoG, using a semi-automatic analysis method, as well as to the seizure onset zone, resected area, and degree of seizure freedom. In each patient at least one of the EEG-fMRI areas was concordant with an interictally active ECoG area, always including the early onset area of IEDs in the ECoG data. This confirms that EEG fMRI reflects a pattern of onset and propagation of epileptic activity. At group level, 76% of the BOLD regions that were covered with subdural grids, were concordant with interictally active ECoG electrodes. Due to limited spatial sampling, 51% of the BOLD regions were not covered with electrodes and could, therefore, not be validated. From an ECoG perspective it appeared that 29% of the interictally active ECoG regions were missed by EEG-fMRI and that 68% of the brain regions were correctly identified as inactive with EEG-fMRI. Furthermore, EEG-fMRI areas included the complete seizure onset zone in 83% and resected area in 93% of the data sets. No clear distinction was found between patients with a good or poor surgical outcome: in both patient groups, EEG-fMRI correlation patterns were found that were either focal or widespread. In conclusion, by comparison of EEG-fMRI with interictal invasive EEG over a relatively large patient population we were able to show that the EEG-fMRI correlation patterns are spatially accurate at the level of neurosurgical units (i.e. anatomical brain regions) and reflect the underlying network of IEDs. Therefore, we expect that EEG-fMRI can play an important role for the determination of the implantation strategy. PMID- 23454473 TI - Carboxy-terminal provasopressin may predict prognosis in nursing home acquired pneumonia. AB - BACKGROUND: This study compares biomarker (including procalcitonin, pro-ANP, and copeptin) levels to pneumonia severity scores to predict 30-day mortality in NHAP (nursing home acquired pneumonia) patients. METHODS: Seventy three patients aged >= 65 y, admitted to general hospitals and who fulfilled the definition of NHAP were included in the study. Data collected at admission included age, gender, nursing home admission, coexisting illness, symptoms and clinical parameters (blood pressure, pulse rate, respiratory rate and status). Additional data collected included laboratory results, radiographic findings and outcome variables. Severity of pneumonia was evaluated using a prediction rule calculated by CURB-65 criteria (confusion, urea nitrogen, respiratory rate, blood pressure, age>65 y). RESULTS: After adjustment for age, sex and CURB-65, copeptin (OR=5.60, 95% confidence interval (CI)=1.20-26.24) was associated with 30-day mortality in NHAP patients, while procalcitonin and pro-ANP were not. The areas under the receiver operating characteristic curves (AUCs) for CURB-65, in predicting mortality were 0.685 [95% CI 0.559-0.811], whereas copeptin showed slightly superior accuracy with an AUC of 0.698 (95% CI 0.568-0.827). CONCLUSIONS: Among 3 biomakers, copeptin was the strongest predictor of 30-day mortality from NHAP. The pathophysiologic and clinical implications of this finding require further investigation. PMID- 23454475 TI - Anti-NMDA-receptor antibody encephalitis: performance evaluation and laboratory experience with the anti-NMDA-receptor IgG assay. AB - BACKGROUND: Antibodies targeting the NR1 subunit of the N-methyl-d-aspartate receptor (NMDAR) are considered diagnostic for a novel form of autoimmune encephalitis. We report the validation of a qualitative indirect immunofluorescence antibody (IFA) test for the detection of anti-NMDAR IgG and describe the attributes of antibody-positive patients. METHODS: The anti-NMDAR IgG assay (Euroimmun Diagnosika, Lubeck, Germany) was validated with serum and cerebrospinal fluid (CSF) specimens from 30 healthy and 50 disease controls as well as 5 anti-NMDAR IgG-positive individuals. Consecutive specimens (n=1671) for anti-NMDAR IgG antibodies were evaluated and positive specimens titrated to end point [starting dilutions: CSF; 1:1 and serum; 1:10]. In a subset of antibody positive patients, we sought clinical information for correlation with diagnostic and treatment outcomes. RESULTS: The assay demonstrated excellent performance characteristics in all groups evaluated. Of the 1671 specimens tested, 1389 were unique cases with a positivity rate of 9.0% (n=123). For the antibody-positive samples, the female to male ratio was 2:1 with a prevalence of 46% in the pediatric population (<=17 years). Antibody titers were titrated to end-point for 106/123 specimens [45 CSF, 41 sera, and 20 CSF and serum pairs] with more than 75% having titers greater than 1:10 (CSF) and 1:20 (serum). Overall, high levels of these antibodies showed correlation to disease severity with variable response to treatment in the subset of patients evaluated. CONCLUSION: Our data suggests a high prevalence for anti-NMDAR antibody encephalitis irrespective of age and gender in our unselected disease cohort with support for measuring antibody titers in the evaluation of these patients. PMID- 23454474 TI - A linear relationship between the ex-vivo sodium mediated expression of two sodium regulatory pathways as a surrogate marker of salt sensitivity of blood pressure in exfoliated human renal proximal tubule cells: the virtual renal biopsy. AB - BACKGROUND: Salt sensitivity (SS) of blood pressure (BP) affects 25% of adults, shares comorbidity with hypertension, and has no convenient diagnostic test. We tested the hypothesis that urine-derived exfoliated renal proximal tubule cells (RPTCs) could diagnose the degree of an individual's SS of BP. METHODS: Subjects were selected who had their SS of BP determined 5 y prior to this study (salt sensitive: >=7 mm Hg increase in mean arterial pressure (MAP) following transition from a random weekly diet of low (10 mmol/day) to high (300 mmol/day) sodium (Na(+)) intake, N=4; inverse salt-sensitive (ISS): >=7 mm Hg increase in MAP transitioning from a high to low Na(+) diet, N=3, and salt-resistant (SR): <7 mm Hg change in MAP transitioned on either diet, N=5). RPTC responses to 2 independent Na(+) transport pathways were measured. RESULTS: There was a negative correlation between the degree of SS and dopamine-1 receptor (D1R) plasma membrane recruitment (y=-0.0107x+0.68 relative fluorescent units (RFU), R(2)=0.88, N=12, P<0.0001) and angiotensin II-stimulated intracellular Ca(++) (y= 0.0016x+0.0336, R(2)=0.7112, P<0.001, N=10) concentration over baseline. CONCLUSIONS: Isolating RPTCs from urine provides a personalized cell-based diagnostic test of SS index that offers advantages over a 2-week controlled diet with respect to cost and patient compliance. Furthermore, the linear relationship between the change in MAP and response to 2 Na(+) regulatory pathways suggests that an individual's RPTC response to intracellular Na(+) is personalized and predictive. PMID- 23454476 TI - Ovarian cancer survivors' experiences of self-advocacy: a focus group study. AB - PURPOSE/OBJECTIVES: To explore ovarian cancer survivors' experiences of self advocacy in symptom management. RESEARCH APPROACH: Descriptive, qualitative. SETTING: A public cafe in an urban setting. PARTICIPANTS: 13 ovarian cancer survivors aged 26-69 years with a mean age of 51.31. METHODOLOGIC APPROACH: Five focus groups were formed. Focus group discussions were audio recorded and transcribed verbatim. The content was analyzed using the constant comparison method with axial coding. In-depth interviews with 5 of the 13 participants occurred via telephone one to five months after each focus group meeting to clarify and expand on identified themes. Preliminary findings were shared with all participants for validation. FINDINGS: Two major themes emerged from the data: (a) knowing who I am and keeping my psyche intact, and (b) knowing what I need and fighting for it. Exemplar quotations illustrate the diverse dimensions of self-advocacy. In addition, a working female-centric definition of self advocacy was attained. CONCLUSIONS: Women have varying experiences with cancer- and treatment-related symptoms, but share a common process for recognizing and meeting their needs. Self-advocacy was defined as a process of learning one's needs and priorities as a cancer survivor and negotiating with healthcare teams, social supports, and other survivors to meet these needs. INTERPRETATION: This phenomenologic process identified key dimensions and a preliminary definition of self-advocacy that nurses can recognize and support when patients seek and receive care consistent with their own needs and preferences. KNOWLEDGE TRANSLATION: Self-advocacy among female cancer survivors is a process of recognizing one's needs and priorities and fighting for them within their cancer care and life. Practitioners can support female cancer survivors through the process of self-advocacy by providing them with skills and resources in making informed choices for themselves. PMID- 23454477 TI - Characterization of the complete mitochondrial genome of Bombyx mori strain H9 (Lepidoptera: Bombycidae). AB - The complete mitochondrial genome (mitogenome) of Bombyx mori strain H9 (Lepidoptera: Bombycidae) is 15,670base pairs (bp) in length, encoding 13 protein coding genes (PCGs), two rRNA genes, 22 tRNA genes and a control region. The nucleotide composition of the genome is highly A+T biased, accounting for 81.31%, with a slightly positive AT skewness (0.059). The arrangement of 13 PCGs is similar to that of other sequenced lepidopterans. All the PCGs are initiated by ATN codons, except for the cytochrome c oxidase subunit 1 (cox1) gene, which is proposed by the TTAG sequence as observed in other lepidopterans. Unlike the other PCGs, the cox1 and cytochrome c oxidase subunit 2 (cox2) genes have incomplete stop codons consisting of just a T. All tRNAs have typical structures of insect mitochondrial tRNAs, which is different from other sequenced lepidopterans. The structure of A+T-rich region is similar to that of other sequenced lepidopterans, including non-repetitive sequences, the ATAGA binding domain, a 18bp poly-T stretch and a poly-A element upstream of transfer RNA M (trnM) gene. Phylogenetic analysis shows that the domesticated silkmoth B. mori originated from the Chinese Bombyx mandarina. PMID- 23454478 TI - Brain-specific-homeobox is required for the specification of neuronal types in the Drosophila optic lobe. AB - The Drosophila optic lobe comprises a wide variety of neurons forming laminar and columnar structures similar to the mammalian brain. The Drosophila optic lobe may provide an excellent model to investigate various processes of brain development. However, it is poorly understood how neuronal specification is regulated in the optic lobe to form a complicated structure. Here we show that the Brain-specific homeobox (Bsh) protein, which is expressed in the lamina and medulla ganglia, is involved in specifying neuronal identity. Bsh is expressed in L4 and L5 lamina neurons and in Mi1 medulla neurons. Analyses of loss-of-function and gain-of function clones suggest that Bsh is required and largely sufficient for Mi1 specification in the medulla and L4 specification in the lamina. Additionally, Bsh is at least required for L5 specification. In the absence of Bsh, L5 is transformed into glial cells. PMID- 23454481 TI - Current status of chemokines in the adult CNS. AB - Chemokines - chemotactic cytokines - are small secreted proteins that attract and activate immune and non-immune cells in vitro and in vivo. It has been suggested that chemokines and their receptors play a role in the central nervous system (CNS), in addition to their well established role in the immune system. We focus here on three chemokines-CXCL12 (C-X-C motif ligand 12), CCL2 (C-C motif ligand 2), and CX3CL1 (C-X-3C motif ligand 1) - and their principal receptors - CXCR4 (C X-C motif receptor 4), CCR2 (C-C motif receptor 2) and CX3CR1 (C-X-3C motif receptor 1), respectively. We first introduce the classification of chemokines and their G-protein coupled receptors and the main signaling pathways triggered by receptor activation. We then discuss the cellular distribution of CXCL12/CXCR4, CCL2/CCR2 and CX3CL1/CX3CR1 in adult brain and the neurotransmission and neuromodulation effects controlled by these chemokines in the adult CNS. Changes in the expression of CXCL12, CCL2 and CX3CL1 and their respective receptors are also increasingly being implicated in the pathogenesis of CNS disorders, such as Alzheimer's disease, Parkinson's disease, HIV associated encephalopathy, stroke and multiple sclerosis, and are therefore plausible targets for future pharmacological intervention. The final section thus discusses the role of these chemokines in these pathophysiological states. In conclusion, the role of these chemokines in cellular communication may make it possible: (i) to identify new pathways of neuron-neuron, glia-glia or neuron-glia communications relevant to both normal brain function and neuroinflammatory and neurodegenerative diseases; (ii) to develop new therapeutic approaches for currently untreatable brain diseases. PMID- 23454479 TI - An autocrine Wnt5a-Ror signaling loop mediates sympathetic target innervation. AB - During nervous system development, axon branching at nerve terminals is an essential step in the formation of functional connections between neurons and target cells. It is known that target tissues exert control of terminal arborization through secretion of trophic factors. However, whether the in growing axons themselves produce diffusible cues to instruct target innervation remains unclear. Here, we use conditional mutant mice to show that Wnt5a derived from sympathetic neurons is required for their target innervation in vivo. Conditional deletion of Wnt5a resulted in specific deficits in the extension and arborization of sympathetic fibers in their final target fields, while no defects were observed in the overall tissue patterning, proliferation, migration or differentiation of neuronal progenitors. Using compartmentalized neuronal cultures, we further demonstrate that the Ror receptor tyrosine kinases are required locally in sympathetic axons to mediate Wnt5a-dependent branching. Thus, our study suggests an autocrine Wnt5a-Ror signaling pathway that directs sympathetic axon branching during target innervation. PMID- 23454480 TI - Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome. AB - Meckel-Gruber syndrome (MKS) is an embryonic lethal ciliopathy resulting from mutations in genes encoding proteins localising to the primary cilium. Mutations in the basal body protein MKS1 account for 7% of cases of MKS. The condition affects the development of multiple organs, including brain, kidney and skeleton. Here we present a novel Mks1(tm1a(EUCOMM)Wtsi) knockout mouse which accurately recapitulates the human condition, consistently developing pre-axial polydactyly, complex posterior fossa defects (including the Dandy-Walker malformation), and renal cystic dysplasia. TOPFlash Wnt reporter assays in mouse embryonic fibroblasts (MEFs) showed general de-regulated high levels of canonical Wnt/beta catenin signalling in Mks1(-/-) cells. In addition to these signalling defects, we also observed ectopic high proliferation in the brain and kidney of mutant animals at mid- to late-gestation. The specific role of Mks1 in regulating cell proliferation was confirmed in Mks1 siRNA knockdown experiments which showed increased levels of proliferation after knockdown, an effect not seen after knockdown of other ciliopathy genes. We suggest that this is a result of the de regulation of multiple signalling pathways (Wnt, mTOR and Hh) in the absence of functional Mks1. This novel model system offers insights into the role of MKS1 in Wnt signalling and proliferation, and the impact of deregulation of these processes on brain and kidney development in MKS, as well as expanding our understanding of the role of Mks1 in multiple signalling pathways. PMID- 23454482 TI - Automatic post-picking using MAPPOS improves particle image detection from cryo EM micrographs. AB - Cryo-electron microscopy (cryo-EM) studies using single particle reconstruction are extensively used to reveal structural information on macromolecular complexes. Aiming at the highest achievable resolution, state of the art electron microscopes automatically acquire thousands of high-quality micrographs. Particles are detected on and boxed out from each micrograph using fully- or semi automated approaches. However, the obtained particles still require laborious manual post-picking classification, which is one major bottleneck for single particle analysis of large datasets. We introduce MAPPOS, a supervised post picking strategy for the classification of boxed particle images, as additional strategy adding to the already efficient automated particle picking routines. MAPPOS employs machine learning techniques to train a robust classifier from a small number of characteristic image features. In order to accurately quantify the performance of MAPPOS we used simulated particle and non-particle images. In addition, we verified our method by applying it to an experimental cryo-EM dataset and comparing the results to the manual classification of the same dataset. Comparisons between MAPPOS and manual post-picking classification by several human experts demonstrated that merely a few hundred sample images are sufficient for MAPPOS to classify an entire dataset with a human-like performance. MAPPOS was shown to greatly accelerate the throughput of large datasets by reducing the manual workload by orders of magnitude while maintaining a reliable identification of non-particle images. PMID- 23454483 TI - Elk1 and AP-1 sites in the TBP promoter mediate alcohol-induced deregulation of Pol III-dependent genes. AB - The major risk factors for hepatocellular carcinoma (HCC) are chronic liver diseases that include hepatitis B, hepatitis C, alcoholic liver disease and non alcoholic steatohepatitis. However, the mechanisms of alcohol-associated HCC remain to be elucidated. The products of RNA Pol III (RNA polymerase III) dependent genes are elevated in both transformation cells and tumor cells. TBP (TATA-box binding protein) is a central transcription factor, which regulates Pol I, Pol II and Pol III gene activity. Our studies have demonstrated that alcohol increases TBP expression and Pol III gene transcription to promote liver tumor formation. We continue to investigate how ethanol mediates TBP expression. Here, we report that ethanol induces TBP promoter activity and the induction is ethanol dose dependent. Blocking the JNK1 pathway by a chemical inhibitor and siRNA reduces this ethanol-induced activity. Furthermore, mutating G>A at a -46 bp Elk1 binding site of the TBP promoter or mutating AP-1 binding site at -37 bp (A>G) and -38 bp (C>T) reduces the TBP promoter activity. Mutation of both Elk1 and AP 1 binding sites dramatically represses this induction. Together, these studies demonstrate that, for the first time, alcohol increases Pol III gene transcription through a response element, which is composed of the overlapping Elk1 and AP-1 binding sites of the TBP promoter and affected by alcohol. It suggests that these binding sites may play a critical role in alcohol-induced deregulation of Pol III genes in liver tumor development. PMID- 23454484 TI - Identification of a SLC19A2 nonsense mutation in Persian families with thiamine responsive megaloblastic anemia. AB - Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive syndrome characterized by early-onset anemia, diabetes, and hearing loss caused by mutations in the SLC19A2 gene. We studied the genetic cause and clinical features of this condition in patients from the Persian population. A clinical and molecular investigation was performed in four patients from three families and their healthy family members. All had the typical diagnostic criteria. The onset of hearing loss in three patients was at birth and one patient also had a stroke and seizure disorder. Thiamine treatment effectively corrected the anemia in all of our patients but did not prevent hearing loss. Diabetes was improved in one patient who presented at the age of 8months with anemia and diabetes after 2months of starting thiamine. The coding regions of SLC19A2 were sequenced in all patients. The identified mutation was tested in all members of the families. Molecular analyses identified a homozygous nonsense mutation c.697C>T (p.Gln233*) as the cause of the disease in all families. This mutation was previously reported in a Turkish patient with TRMA and is likely to be a founder mutation in the Persian population. PMID- 23454485 TI - The effect of alpha-mating factor secretion signal mutations on recombinant protein expression in Pichia pastoris. AB - The methylotrophic yeast, Pichia pastoris, has been genetically engineered to produce many heterologous proteins for industrial and research purposes. In order to secrete proteins for easier purification from the extracellular medium, the coding sequence of recombinant proteins is initially fused to the Saccharomyces cerevisiae alpha-mating factor secretion signal leader. Extensive site-directed mutagenesis of the prepro-region of the alpha-mating factor secretion signal sequence was performed in order to determine the effects of various deletions and substitutions on expression. Though some mutations clearly dampened protein expression, deletion of amino acids 57-70, corresponding to the predicted 3rd alpha helix of alpha-mating factor secretion signal, increased secretion of reporter proteins horseradish peroxidase and lipase at least 50% in small-scale cultures. These findings raise the possibility that the secretory efficiency of the leader can be further enhanced in the future. PMID- 23454486 TI - Molecular cloning, characterization and tissue expression of CD4 in Chinese goose. AB - CD4 protein is a single chain transmembrane glycoprotein belonging to the immunoglobulin superfamily that recognizes the major histocompatibility complex (MHC) class II molecules. It plays an important role in cell-mediated immunity. Here, the full-length cDNA of CD4 in Chinese goose (Anser cygnoides) was cloned and identified. The goose CD4 is 1940bp in length and encodes a single open reading frame of 480 amino acids. The putative amino acid sequence of goose CD4 consisted of a signal peptide, four potential N-glycosylation sites, a transmembrane region and a cytoplasmic tail. The multiple sequence alignment and phylogenetic analysis suggested that goose CD4 shared a higher similarity with avian than other vertebrates. Semi-quantitative RT-PCR analysis showed that the highest level of CD4 mRNA transcripts was presented in the thymus, and relatively lower in the spleen, small intestine, brain and trachea. Low expression was seen in the bursa of fabricius, cecal tonsil, cecum, skin, lung, kidney and liver. In gosling, the CD4 transcript was expressed with high abundance in the thymus, and relatively lower in the spleen, cecal tonsil and small intestine. However, in adult goose, high expression was seen in the thymus, spleen and cecum, and relatively lower in the cecal tonsil and small intestine. During the course of NGVEV infection, the obvious increase in CD4 gene expression was observed in the spleen, bursa of fabricius and harderian gland. Interestingly, a notable decrease in CD4 mRNA expression in the small intestine at 5d PI and followed by an increase of that at 19d PI were shown. PMID- 23454487 TI - Acute regional left atrial ischemia causes acceleration of atrial drivers during atrial fibrillation. AB - BACKGROUND: The mechanisms by which acute left atrial ischemia (LAI) leads to atrial fibrillation (AF) initiation and perpetuation remain unclear. OBJECTIVE: To investigate the electrophysiological mechanisms of AF perpetuation in the presence of regional atrial ischemia. METHODS: LAI (90-minute ischemia) was obtained in isolated sheep hearts by selectively perfusing microspheres into the left anterior atrial artery. Two charge-coupled device cameras and several bipolar electrodes enabled recording from multiple atrial locations: with a dual camera setup (protocol 1, n = 10, and protocol 1', n = 4, for biatrial or atrioventricular camera setups, respectively), in the presence of propranolol/atropine (1 MUM) added to the perfusate after LAI (protocol 2, n = 3) and after a pretreatment with glibenclamide (10 MUM; protocol 3, n = 4). RESULTS: Spontaneous AF occurred in 41.2% (7 of 17) of the hearts that were in sinus rhythm before LAI. LAI caused action potential duration shortening in both the ischemic (IZ) and nonischemic (NIZ) zones by 21% +/- 8% and 34% +/- 13%, respectively (pacing, 5 Hz; P<.05 compared to baseline). Apparent impulse velocity was significantly reduced in the IZ but not in the NIZ (-65% +/- 19% and 9% +/- 18%; P = .001 and NS, respectively). During LAI-related AF, a significant NIZ maximal dominant frequency increase from 7.4 +/- 2.5 to 14.0 +/- 5.5 Hz (P<.05) was observed. Glibenclamide, an ATP-sensitive potassium current (IKATP) channel blocker, averted LAI-related maximal dominant frequency increase (NIZ: LAI vs glibenclamide 14.0 +/- 5.5 Hz vs 5.9 +/- 1.3 Hz; P<.05). An interplay between spontaneous focal discharges and rotors, locating at the IZ-NIZ border zone, maintained LAI-related AF. CONCLUSIONS: LAI leads to an IKATP conductance dependent action potential duration shortening and spontaneous AF maintained by both spontaneous focal discharges and reentrant circuits locating at the IZ border zone. PMID- 23454488 TI - Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia. AB - Hypophosphatasia (HPP) is a heterogeneous rare, inherited disorder of bone and mineral metabolism caused by different mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease. TNAP deficiency, however, may also result in neurological symptoms such as neonatal seizures. The exact biological role of TNAP in the human brain is still not known and the pathophysiology of neurological symptoms due to TNAP deficiency in HPP is not understood in detail. In this report, we describe the clinical features and functional studies of a patient with severe perinatal HPP which presented with rapidly progressive encephalopathy caused by new compound heterozygous mutations in the ALPL gene which result in a functional ALPL "knock out", demonstrated in vitro. In contrast, an in vitro simulation of the genetic status of his currently asymptomatic parents who are both heterozygous for one mutation, showed a residual in vitro AP activity of above 50%. Interestingly, in our patient, the fatal outcome was due to progressive encephalopathy which was refractory to antiepileptic therapy including pyridoxine, rather than hypomineralization and respiratory insufficiency often seen in HPP patients. The patient's cranial MRI showed progressive cystic degradation of the cortex and peripheral white matter with nearly complete destruction of the cerebrum. To our knowledge, this is the first MRI-based report of a deleterious neurological clinical outcome due to a progressive encephalopathy in an infant harboring a functional human ALPL "knock out". This clinical course of disease suggests that TNAP is involved in development and may be responsible for multiple functions of the human brain. According to our data, a certain amount of residual TNAP activity might be mandatory for normal CNS function in newborns and early childhood. PMID- 23454489 TI - An infectious HHV-6B isolate from a healthy adult with chromosomally integrated virus and a reporter based relative viral titer assay. AB - Human herpesvirus 6B (HHV-6B) primary infections occur in early childhood and establish a life-long latency in the most healthy adults. HHV-6B was detectable in the peripheral blood mononuclear cells (PBMC) and granulocytes by serial genomic DNA dilution PCR till 10 pg of template DNA, in a healthy adult. Epstein Barr virus (EBV) mediated transformation of the PBMC resulted in establishment of a B-cell line. Southern hybridization with the PBMC as well as the cell line DNA showed distinct signals for high copy viral genomes and Gardella gel analysis indicated chromosomal integration of the HHV-6B. Integration site analysis in the PBMC and the cell line indicated an atypical viral integration in non-telomeric region of chromosome 12. Cell free culture medium of the cell line could infect different mononuclear cell lines, naive or mitogen stimulated PBMC and was found to impart productive infection in a recipient T cell line. An HIV-1 LTR driven luciferase based reporter cell line was made and a single step assay was developed for estimating HHV-6B relative concentration in the culture supernatants. This study thus reports a new infectious HHV-6B isolate with uncommon integration site, spontaneous production from a cell line and also development of a simple relative HHV-6B titer assay. PMID- 23454490 TI - Protein disulfide isomerase and glutathione are alternative substrates in the one Cys catalytic cycle of glutathione peroxidase 7. AB - BACKGROUND: Mammalian GPx7 is a monomeric glutathione peroxidase of the endoplasmic reticulum (ER), containing a Cys redox center (CysGPx). Although containing a peroxidatic Cys (CP) it lacks the resolving Cys (CR), that confers fast reactivity with thioredoxin (Trx) or related proteins to most other CysGPxs. METHODS: Reducing substrate specificity and mechanism were addressed by steady state kinetic analysis of wild type or mutated mouse GPx7. The enzymes were heterologously expressed as a synuclein fusion to overcome limited expression. Phospholipid hydroperoxide was the oxidizing substrate. Enzyme-substrate and protein-protein interaction were analyzed by molecular docking and surface plasmon resonance analysis. RESULTS: Oxidation of the CP is fast (k+1>10(3)M( 1)s(-1)), however the rate of reduction by GSH is slow (k'+2=12.6M(-1)s(-1)) even though molecular docking indicates a strong GSH-GPx7 interaction. Instead, the oxidized CP can be reduced at a fast rate by human protein disulfide isomerase (HsPDI) (k+1>10(3)M(-1)s(-1)), but not by Trx. By surface plasmon resonance analysis, a KD=5.2MUM was calculated for PDI-GPx7 complex. Participation of an alternative non-canonical CR in the peroxidatic reaction was ruled out. Specific activity measurements in the presence of physiological reducing substrate concentration, suggest substrate competition in vivo. CONCLUSIONS: GPx7 is an unusual CysGPx catalyzing the peroxidatic cycle by a one Cys mechanism in which GSH and PDI are alternative substrates. GENERAL SIGNIFICANCE: In the ER, the emerging physiological role of GPx7 is oxidation of PDI, modulated by the amount of GSH. PMID- 23454491 TI - Apoptosis is signalled early by low doses of ionising radiation in a radiation induced bystander effect. AB - It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05Gy and 0.5Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3, 6 and 7. The data generated consolidated the role of apoptosis following direct IR exposure for all doses and time points as pro apoptotic genes such as Bax and JNK as well as initiator caspase 7 and effector caspase 3 and 9 were up-regulated. However, the gene expression profile for the bystander response was quite different and more complex in comparison to the direct response. The 0.05Gy dose point had a more significant apoptosis gene expression profile compared to the 0.5Gy dose point and genes were not always expressed within 1h but were sometimes expressed 24h later. The bystander data clearly demonstrates initiation of the apoptotic cascade by the up-regulation of TP53, Bax, Bcl-2, initiator caspase 2 and effector caspase 6. The effector caspases 3 and 7 of the bystander samples demonstrated down-regulation in their gene expression levels at 0.05Gy and 0.5Gy at both time points therefore not fully executing the apoptotic pathway. Extensive analysis of the mean-fold gene expression changes of bystander data demonstrated that the apoptosis is initiated in the up-regulation of pro-apoptotic and initiator genes but may not very well be executed to final stages of cell death due to down-regulation of effector genes. PMID- 23454492 TI - New primary standard set for fine particulate matter. PMID- 23454493 TI - Optimized proteomic analysis of rat liver microsomes using dual enzyme digestion with 2D-LC-MS/MS. AB - A systematic approach was developed to optimize the analysis of rat liver microsomes combining ion exchange fractionation with reverse-phase chromatography coupled to high resolution quadrupole-time-of-flight mass spectrometry. A comparison was performed with several conditions to select the most efficient solubilization and proteolysis protocol to achieve highest proteome coverage. Optimal trypsin digestion conditions were achieved with SDS and heat to increase solubilization of microsomal samples, with an increase from 621 to 686 identified proteins when SDS and heat were applied. Pepsin digestion yielded complementary results, especially in terms of hydrophobic environments, thus allowing sequence coverage to be increased substantially. Several dual digestion strategies were tested, with trypsin and pepsin combined in series or in parallel. A parallel tryptic-peptic dual digestion, combining mass spectral data of single enzyme digestions, yielded the best results in terms of number of identified proteins, increasing by 29% from the best single enzyme procedure, and sequence coverage improved by 5% on average for all proteins identified. Using our complete set of data, a total of 1095 proteins were identified with less than 1% FDR, out of which 213 proteins (19.5%) were integral membrane proteins. Proteomics data have been deposited to the ProteomeXchange Consortium with dataset identifier PXD000128. BIOLOGICAL SIGNIFICANCE: A systematic approach to optimize the proteomic analysis of rat liver microsomes by 2D-LC-MS/MS using several different digestion conditions was performed in order to increase our knowledge of the rat liver proteome, especially important to drug metabolism and toxicology. A parallel (combined) tryptic-peptic digestion yielded best overall performance, when mass spectral data were acquired separately and combined prior to database searching. This large-scale data set will be available publicly on the ProteomeXchange server and will therefore be accessible to a large scientific community interested in using this data for their own studies. One of the main goals of this study is to identify a comprehensive list of proteins for follow-up protein covalent binding studies related to drug toxicity. PMID- 23454494 TI - Diversification and reticulation in the circumboreal fern genus Cryptogramma. AB - We investigated the evolutionary complexity that resulted from cryptic diversification and polyploidy in parsley ferns (Cryptogramma). A total of 14 species were included in our data set, with six outgroup species and eight Cryptogramma species. DNA sequence data from six plastid loci (rbcL, rbcL-accD, rbcL-atpB, rps4-trnS, trnG-trnR and trnP-petG) were analyzed using maximum likelihood and Bayesian methods to provide the first rigorous assessment of diversification in the genus, including testing the monophyly of the genus and sections. Cryptogramma and Coniogramme are recovered as reciprocally monophyletic sister genera. We established the monophyly of both sections within Cryptogramma. Furthermore, our sequence data reveal that described species reflect mostly allopatric reciprocally monophyletic lineages that are independent evolutionary trajectories. Using sequence data from the nuclear locus (gapCp) we find that the European C. crispa is an autotetraploid with a partially diploidized genome, while the North American tetraploid Cryptogramma sitchensis is an allopolyploid derived from C. acrostichoides and C. raddeana. Subsequent backcrossing between C. sitchensis and C. acrostichoides has allowed the introgression of C. raddeana alleles into northern populations of C. acrostichoides. PMID- 23454495 TI - Evolution and function of de novo originated genes. AB - De novo origination has recently been appreciated to be an important mechanism contributing to the origin of genes. Evidence indicates that de novo originated genes can evolve important and even essential functions rapidly. We present an "adaptation following neutrality" process to explain the evolution of essential function of new genes. How new de novo originated genes become involved in pathways and interact with other old genes, and the exact functions of these new genes, however, remains largely undocumented. Examinations of the function of de novo origin and the function of noncoding RNA genes should become more frequent and appreciated in the future studies. PMID- 23454496 TI - Proteolytic activity of probiotic strain Lactobacillus helveticus M92. AB - The aim of this research was to investigate the potential of previously defined probiotic strain Lactobacillus helveticus M92 as functional starter culture for fermented dairy products. Therefore, proteolytic activity of L. helveticus M92 was investigated and compared with those of different representatives of probiotic and starter culture strains. Cluster analysis of AFLP fingerprints showed a difference of L. helveticus M92 compared to five other L. helveticus strains, but the percentage of similarity confirmed the identification on species level. Casein hydrolysis by L. helveticus M92 was monitored by agar-well diffusion test, SDS-PAGE and Anson's method. L. helveticus M92 exhibited the highest proteolytic activity among tested probiotic and starter cultures strains with the fastest acidification rate and the highest pH decrease after overnight incubation in skim milk. The presence of prtH2 gene was confirmed by PCR amplification with specific primers, while PCR product was not obtained after amplification with primers specific to prtH. Furthermore, SDS-PAGE LC-MS/MS analysis of insoluble proteome of L. helveticus M92 enabled identification of several proteins involved in proteolytic system of L. helveticus such as protease PrtM as well as proteins involved in Opp peptide transport system and the intracellular peptidases PepE, PepN, and PepQ. PMID- 23454497 TI - Study of the effects of chitosan upon Streptococcus mutans adherence and biofilm formation. AB - The main aim of this work was to access the potential use of high and low molecular weight chitosans as potential oral antimicrobials, particularly as antibiofilm agents. Chitosan's interference with Streptococcus mutans capability to adhere and form biofilms was assessed. Additionally the effect upon mature and polymicrobial biofilms was also evaluated. The results obtained showed that chitosan was capable of interfering with S. mutans adhesion and primary biofilm formation. This action was observed up to a week with little to none decrease in efficiency. In addition chitosan was capable of inhibiting biofilms formed by two microorganisms and was capable of acting upon mature biofilms leading to significant reductions (94%) in biofilm survival. However clear statistical differences (p < 0.05) were registered in all assays with, in most assays, HMw chitosan presenting higher efficiency than LMw chitosan. Considering this results chitosan's potential as a valid alternative to traditional antimicrobials in oral health it's evident. PMID- 23454498 TI - Primary extramammary Paget's disease of the vulva: the clinicopathological features and treatment outcomes in a series of 43 patients. AB - OBJECTIVE: To characterize the clinicopathological features and evaluate the treatment outcomes for cases of primary extramammary Paget's disease of the vulva (EMPDV). METHODS: The medical records and pathology slides were reviewed and analyzed for 43 patients with primary EMPDV. RESULTS: The mean age of the patients was 68.6 years (range, 52-85). Intraepithelial EMPDV, invasive EMPDV and EMPDV with adnexal adenocarcinoma were observed in 33 (76.7%), 7 (16.3%) and 3 (7.0%) cases, respectively. Varied surgical procedures were initially performed in 35 (81.4%) cases. A positive incision margin was observed in 16 cases (47.0%). Definitive radiotherapy at a median dose of 60 Gy was performed in 8 (18.6%) patients. Six patients received postoperative radiotherapy due to a positive margin or lymph node metastasis after surgical excision. During a follow-up period of 6-169 months (median, 54), recurrence was observed in 12 (34.3%) patients. Nine (75.0%) patients underwent repeated surgery and 3 (25.0%) patients received radiotherapy. Long-term overall survival was observed in patients with intraepithelial EMPDV. The median overall survival was 124.5 months in intraepithelial cases, 70.8 months in invasive cases and 21.3 months in cases with adnexal adenocarcinoma (log rank, P=0.032). CONCLUSIONS: Intraepithelial EMPDV accounted for the majority of primary cases and had a better prognosis. Surgical excision was the standard curative treatment for EMPDV. Radiotherapy was an alternative choice for patients with medical contradiction or surgical difficulties. Postoperative radiotherapy could be considered in cases with positive surgical margin or lymph node metastasis. Recurrence was common and repeated excision was often necessary. PMID- 23454499 TI - Robotic surgical staging for endometrial and cervical cancers in medically ill patients. AB - OBJECTIVES: Patients with high anesthesiological risk due to old age, obesity and severe co-morbidities alone or in combination are considered as poor candidates for extensive surgical staging procedures, especially if through minimally invasive approach. We aimed to evaluate the feasibility and safety of robotic surgical staging of endometrial and cervical cancers in the medically ill patient. METHODS: Between 07-2007 and 12-2012, consecutive patients scheduled for staging for endometrial or cervical cancer were directed towards robotic staging and divided into two groups according to their starting score in the American Society for Anaesthesiologists (ASA): Group 1 (ASA 1-2) and Group 2 (ASA >=3). RESULTS: Overall, 169 (71.9%) patients had ASA 1-2 whereas 66 (28.1%) had ASA >=3. ASA >=3 were older (p<0.0001) with a greater proportion of co-morbidities (p<0.0001), as well as of Class II (4.7% vs 19.7%; p=0.0007) and Class III obesity (2.4% vs 31.8%; p<0.0001). No differences were found between groups in terms of operative time, blood loss, intra- and post-operative complications, conversion rate and hospitalization. No differences were recorded either in terms of staging procedures performed or in terms of number of pelvic (p=0.72) and para aortic (p=0.86) lymph nodes retrieved. CONCLUSIONS: Despite theoretical concerns about the performance of robotic surgery in patients with high anesthesiological risk, our experience showed that robotics is a feasible, safe and viable option for the management of endometrial and cervical cancers also in this more vulnerable group of patients. PMID- 23454500 TI - miRNAs: their discovery, biogenesis and mechanism of action. AB - The field of miRNA research is evolving at a very fast pace. Since their discovery almost 20years ago, miRNAs have proven to be of tremendous importance to normal physiological homeostasis as well as to the pathogenesis of major diseases such as cancer. Recent advances describe a key contribution for miRNAs in a wide variety of cellular processes ranging from embryonic development, cell proliferation and apoptosis to prominent roles in disease progression. miRNAs are now of central interest to biomedical research. Here we provide an overview of their discovery, biogenesis and mechanism of action. PMID- 23454501 TI - Apparent color-orientation bindings in the periphery can be influenced by feature binding in central vision. AB - A previous study reported the misbinding illusion in which visual features belonging to overlapping sets of items were erroneously integrated (Wu, Kanai, & Shimojo, 2004, Nature, 429, 262). In this illusion, central and peripheral portions of a transparent motion field combined color and motion in opposite fashions. When observers saw such stimuli, their perceptual color-motion bindings in the periphery were re-arranged in such a way as to accord with the bindings in the central region, resulting in erroneous color-motion pairings (misbinding) in peripheral vision. Here we show that this misbinding illusion is also seen in the binding of color and orientation. When the central field of a stimulus array was composed of objects that had coherent (regular) color-orientation pairings, subjective color-orientation bindings in the peripheral stimuli were automatically altered to match the coherent pairings of the central stimuli. Interestingly, the illusion was induced only when all items in the central field combined color and orientation in an orthogonal fashion (e.g. all red bars were horizontal and all green bars were vertical). If this orthogonality was disrupted (e.g. all red and green bars were horizontal), the central field lost its power to induce the misbinding illusion in the peripheral stimuli. The original misbinding illusion study proposed that the illusion stemmed from a perceptual extrapolation that resolved peripheral ambiguity with clear central vision. However, our present results indicate that visual analyses of the correlational structure between two features (color and orientation) are critical for the illusion to occur, suggesting a rapid integration of multiple featural cues in the human visual system. PMID- 23454503 TI - Ultrasonographic examination of the abdomen of the goat. I. Reticulum, rumen, omasum, abomasum and intestines. AB - This review article summarizes the ultrasonographic findings of the reticulum, rumen, omasum, abomasum and intestines of goats. Ultrasonographic examination is done on both sides with the goat in a standing position using a linear array or convex transducer with a frequency of 5.0 to 7.5 MHz. The shape, contour and motility of the reticulum are assessed; this organ appears as a crescent-shaped structure with a smooth contour immediately adjacent to the diaphragm. There are 0.8 to 2.1 reticular contractions per minute, which may be mono-, bi- and triphasic. The rumen is examined from the 8th to 12th intercostal spaces (ICSs) and flank on the left, and from the 12th ICS and flank on the right. The ruminal wall appears as a thick echoic line. The dorsal and ventral sacs of the rumen are differentiated based on the longitudinal groove, which forms an echoic notch. Differentiation of the dorsal gas cap, fibre mat and fluid layer is not always straightforward and varies among goats. The omasum is examined from the 6th to 11th ICSs on the right. Only the wall closest to the transducer can be imaged and it appears as a crescent-shaped echoic line medial to the liver. The omasal folds and the wall furthest from the transducer cannot be seen. In about two thirds of goats, active omasal motility is apparent as a transient reduction in size of several centimetres, followed by relaxation and return to its original size. There is an average of 1.1 contractions per minute. The abomasum is examined from the ventral midline and the left and right paramedian regions and can always be seen from the ventral midline. In all but a few goats the abomasum is also visible from the left and right paramedian areas. It appears as a heterogeneous, moderately echoic structure with echogenic stippling. The abomasal folds appear as prominent echoic bands in about two thirds of all goats. The small and large intestines are examined on the right from the 8th to the 12th ICSs. Loops of jejunum and ileum are seen mainly in cross-section and have a strong motility. The intestinal content is usually homogeneous and echoic and the diameter of the intestinal loops varies from 0.8 and 2.7 cm. The spiral colon and in many cases also the caecum can be imaged. The former is recognized by its garland-like appearance brought about by the centripetal and centrifugal coils of the intestine. In the spiral colon and the caecum, only the wall closest to the transducer can be imaged because of intraluminal gas. The wall appears as a thick echoic and slightly undulating line 5.6 to 8.0 cm in length. Ultrasonography is an imaging technique that is very well suited for the examination of the gastrointestinal tract of goats. PMID- 23454504 TI - Ultrasonographic examination of the abdomen of the goat. II. Liver, spleen, urinary tract and greater omentum. AB - This review article describes the ultrasonographic findings of the liver, spleen, urinary tract and greater omentum that were previously obtained in studies of healthy female Saanen goats. Real-time B-mode ultrasonography and a linear or convex 5.0 to 7.5 MHz transducer are used to scan standing goats from both sides. The urinary bladder and urethra are also examined transrectally. The liver is scanned from the intercostal spaces (ICSs) on the right from dorsal to ventral. The parenchymal pattern consists of numerous fine echoes that are homogenously distributed across the entire organ. The dorsal visible margin of the liver runs parallel to the lung in a cranioventral to caudodorsal direction. The visible extent of the liver is largest in the 7th and 8th ICSs and the maximum thickness is measured in the 10th ICS. The caudal vena cava has a triangular shape in cross section and is seen only at the 11th or 12th ICS. The portal vein is oval to circular in cross section with stellate ramifications into the liver parenchyma. The gallbladder is pear-shaped and sometimes extends beyond the ventral margin of the liver depending on the amount of bile. In most goats, the gallbladder is only seen from the 9th or 10th ICS. The spleen is scanned from the left where it is almost always seen from the 11th and 12th ICSs. The parenchymal ultrasonographic pattern is similar to that of the liver. The splenic vessels are embedded in the parenchyma and are seen in longitudinal or cross section. The kidneys are best visualized from the flank and last two ICSs on the right. The ultrasonographic appearance varies with the sectional plane. In a sagittal plane through the hilus, the parenchyma is homogenous with fine, evenly distributed echoes. The medullary pyramids are seen near the sinus as oval to circular hypoechoic structures. The hyperechoic sinus is at the centre of the kidney. The urinary bladder is best visualized transrectally but can also be seen in many goats from either inguinal region. The content of the bladder is usually anechoic and the diameter ranges from 1.0 to 4.8 cm. The urethra is seen transrectally as two adjacent parallel echoic lines without an apparent lumen. PMID- 23454505 TI - [Successful treatment of penile prolapse in the dog]. PMID- 23454506 TI - [Methods for the improvement of calf health]. PMID- 23454510 TI - [Maternity compensation and contributions to national insurance]. PMID- 23454511 TI - Annulation of substituted anthracene-9,10-diones yields promising selectively antiproliferative compounds. AB - Anthraquinone derivatives are well-known antiproliferative compounds, and some are currently used in cancer chemotherapy. Some families of annulated anthraquinone analogs have also been examined for antiproliferative activity, but in this regard almost nothing is known of 1-azabenzanthrones (7H dibenzo[de,h]quinolin-7-ones). A series of 1-azabenzanthrone derivatives, their 2,3-dihydro analogs, and congruently substituted 9,10-anthracenediones were tested against normal human fibroblasts and four human cancer cell lines. Most of the heterocyclic compounds proved to be weakly to moderately antiproliferative with IC50 values extending down to 0.86 MUM, and exhibited up to 30-fold selectivity between cancer and normal cells. Both 1-azabenzanthrones and 1-aza 2,3-dihydrobenzanthrones were more potent than their anthraquinone counterparts, and almost without exception, the 2,3-dihydro compounds were more potent than the fully aromatic 1-azabenzanthrones. PMID- 23454512 TI - Synthesis and biological evaluation of a new class of 4-aminoquinoline-rhodanine hybrid as potent anti-infective agents. AB - Synthesis of novel 4-aminoquinoline-rhodanine hybrid using inexpensive starting materials via easy to operate methodology, and their biological activity is reported. All the compounds were screened for their in vitro antimalarial activity against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum, and their cytotoxicity toward VERO cell line. Compounds 9, 19, 21 and 23 exhibited excellent antimalarial activity with IC50 value ranging from 13.2 to 45.5 nM against chloroquine-resistant (K1) strain. Biochemical studies revealed that inhibition of hemozoin formation is the primary mechanism of action of these analogs for their antimalarial activity. Additionally, some derivatives (14, 18 and 26) of this series also exhibited the antimycobacterial activity against H37Rv strain of Mycobacterium tuberculosis with MIC value of 6.25 MUM. PMID- 23454514 TI - Synthesis, evaluation and absolute configuration assignment of novel dihydropyrimidin-2-ones as picomolar sodium iodide symporter inhibitors. AB - A small library of dihydropyrimidin-2-ones (DHPMs) was synthesized and evaluated for their potency to block iodide entrapment in rat thyroid cells. Synthesis was achieved using the multicomponent Biginelli reaction. Twelve compounds were tested for the inhibition of sodium iodide symporter (NIS) in a cell-based assay. One newly synthesized derivative exhibited a remarkably strong activity, with a half-maximum inhibitory concentration value (IC50) of 65 pM. Three DHPMs were further resolved from racemates using chiral HPLC and absolute configurations were assigned using circular dichroism spectroscopy. Biological evaluation showed that most of the activity against NIS resides in one enantiomer. This study provides new insights for the development of anti-thyroid drugs, as well as for the synthesis of novel pharmacological tools designed to investigate iodide transport mechanisms at cellular and molecular levels. PMID- 23454513 TI - Synthesis and biochemical activities of antiproliferative amino acid and phosphate derivatives of microtubule-disrupting beta-lactam combretastatins. AB - The synthesis and biochemical activities of novel water-soluble beta-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, beta-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, beta-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro. This indicates that the beta-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series. Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells. Molecular modelling studies indicated potential binding conformations for the beta-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin. Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents. PMID- 23454515 TI - Chemical synthesis and biological validation of immobilized protein kinase inhibitory Leucettines. AB - Leucettines, a family of marine sponge-derived 2-aminoimidazolone alkaloids, are potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). They constitute promising pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome. In order to investigate the scope of potential targets of Leucettine L41, a representative member of the chemical class, we designed an affinity chromatography strategy based on agarose-immobilized leucettines. A synthesis protocol for the attachment of a polyethylene (3 or 4 units) linker to L41 was first established. The linker attachment site on L41 was selected on the basis of the co-crystal structure of L41 with several kinases. L41 was then covalently bound to agarose beads through the primary amine located at the end of the linker. Control, kinase inactive Leucettine was also immobilized, as well as free linker devoid of ligand. Extracts of several mouse tissues revealed a complex pattern of interacting proteins, some of which probably resulting from non-specific, hydrophobic binding, while others representing bona fide Leucettine interacting proteins. DYRK1A and GSK-3 (glycogen synthase kinase-3) were confirmed as interacting targets by Western blotting in various mouse tissues. The Leucettine affinity chromatography resin constitutes a powerful tool to purify and identify the targets of this new promising therapeutic class of molecules. PMID- 23454516 TI - Synthesis and structure-activity relationships for 1-(4-(piperidin-1 ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3. AB - High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (<100 nM) and isoform selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2 pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells. PMID- 23454517 TI - A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer's disease. AB - A novel series of tacrine-selegiline hybrids was synthesised and evaluated for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B). The results demonstrate that most of the synthesised compounds exhibit high inhibitory activity. Among these compounds, compound 8g provided a good balance of activity towards all targets (with IC50 values of 22.6 nM, 9.37 nM, 0.3724 MUM, and 0.1810 MUM for AChE, BuChE, MAO-A and MAO-B, respectively). These results indicated that 8g has the potential to be a multi-functional candidate for Alzheimer's disease. PMID- 23454518 TI - Systemic heparin delivery by the pulmonary route using chitosan and glycol chitosan nanoparticles. AB - The aim of this study was to evaluate the performance of chitosan (CS) and glycol chitosan (GCS) nanoparticles containing the surfactant Lipoid S100 for the systemic delivery of low molecular weight heparin (LMWH) upon pulmonary administration. These nanoparticles were prepared in acidic and neutral conditions using the ionotropic gelation technique. The size and zeta potential of the NPs were affected by the pH and also the type of polysaccharide (CS or GCS). The size (between 156 and 385 nm) was smaller and the zeta potential (from +11 mV to +30 mV) higher for CS nanoparticles prepared in acidic conditions. The encapsulation efficiency of LMWH varied between 100% and 43% for the nanoparticles obtained in acidic and neutral conditions, respectively. X-ray photoelectron spectroscopy studies indicated that the surfactant Lipoid S100 was localized on the nanoparticle's surface irrespective of the formulation conditions. In vivo studies showed that systems prepared in acidic conditions did not increase coagulation times when administered to mice by the pulmonary route. In contrast, Lipoid S100-LMWH GCS NPs prepared in neutral conditions showed a pharmacological efficacy. Overall, these results illustrate some promising features of CS-based nanocarriers for pulmonary delivery of LMWH. PMID- 23454519 TI - The N-40: an electrophysiological marker of response selection. AB - A frontocentral electrophysiological wave occurring before the response, the N 40, has been reported in response choice situations compared to no-choice situations. This was interpreted as reflecting response selection. The gradual sensitivity of the N-40 to the demands put on response choice was tested by manipulating stimulus-response (S-R) congruence so as to influence response selection processes. After Laplacian transformation, an N-40 clearly emerged and was larger for incongruent (more demanding) than for congruent (less demanding) S R associations. The N-40, which possibly reflects SMA activation, thus provides information about the implementation of response selection in the brain. PMID- 23454520 TI - Error-related brain activity in extraverts: evidence for altered response monitoring in social context. AB - While the personality trait of extraversion has been linked to enhanced reward sensitivity and its putative neural correlates, little is known about whether extraverts' neural circuits are particularly sensitive to social rewards, given their preference for social engagement and social interactions. Using event related potentials (ERPs), this study examined the relationship between the variation on the extraversion spectrum and a feedback-related ERP component (the error-related negativity or ERN) known to be sensitive to the value placed on errors and reward. Participants completed a forced-choice task, in which either rewarding or punitive feedback regarding their performance was provided, through either social (facial expressions) or non-social (verbal written) mode. The ERNs elicited by error trials in the social - but not in non-social - blocks were found to be associated with the extent of one's extraversion. However, the directionality of the effect was in contrast with the original prediction: namely, extraverts exhibited smaller ERNs than introverts during social blocks, whereas all participants produced similar ERNs in the non-social, verbal feedback condition. This finding suggests that extraverts exhibit diminished engagement in response monitoring - or find errors to be less salient - in the context of social feedback, perhaps because they find social contexts more predictable and thus more pleasant and less anxiety provoking. PMID- 23454521 TI - Design and functional evaluation of an optically active MU-opioid receptor. AB - The use of opioids, which achieve therapeutic analgesia through activation of MU opioid receptors, are limited in the management of chronic pain by adverse effects including tolerance and addiction. Optogenetics is an emerging approach of designing molecular targets that can produce cell-specific receptor-mediated analgesia with minimal side effects. Here we report the design and functional characterization of a chimeric MU-opioid receptor that could be photoactivated to trigger intracellular signaling. A prototype optoactive MU-opioid receptor (optoMOR) was designed by replacing the intracellular domains from rhodopsin with those of the native MU-opioid receptor and was transiently expressed in human embryonic kidney (HEK293) cells. Expression and distribution of the protein were confirmed by immunocytochemistry. The signal-transduction mechanisms induced by photoactivation of the optoMOR were evaluated and compared with the native MU opioid receptor stimulation by an agonist, D-Ala(2), N-MePhe(4), Gly-ol enkephalin (DAMGO). Cells were depolarized by extracellular potassium and the depolarization-induced calcium (Ca(2+)) influx was quantified by using Fura-2 imaging. The forskolin-stimulated adenylate cyclase/cAMP cascade was evaluated by ELISA or western blotting of brain-derived neurotrophic factor (BDNF) and the phosphorylation of cAMP response element binding protein (CREB). The optoMOR protein distribution was observed intracellularly and on the plasma membrane similar to the native MU-opioid receptor in HEK293 cells. Photoactivation of optoMOR decreased the Ca(2+) influx and inhibited the forskolin-induced cAMP generation, activation of CREB, and BDNF levels in optoMOR-expressing cells similar to the activation of native MU-opioid receptor by DAMGO. Thus the current study has accomplished the design of a prototype optoMOR and characterized the cellular signaling mechanisms activated by light stimulation of this receptor. PMID- 23454522 TI - Characterization of selective Calcium-Release Activated Calcium channel blockers in mast cells and T-cells from human, rat, mouse and guinea-pig preparations. AB - Loss of function mutations in the two key proteins which constitute Calcium Release Activated Calcium (CRAC) channels demonstrate the critical role of this ion channel in immune cell function. The aim of this study was to demonstrate that inhibition of immune cell activation could be achieved with highly selective inhibitors of CRAC channels in vitro using cell preparations from human, rat, mouse and guinea-pig. Two selective small molecule blockers of CRAC channels; GSK 5498A and GSK-7975A were tested to demonstrate their ability to inhibit mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety of species. Both GSK-5498A and GSK-7975A completely inhibited calcium influx through CRAC channels. This led to inhibition of the release of mast cell mediators and T-cell cytokines from multiple human and rat preparations. Mast cells from guinea-pig and mouse preparations were not inhibited by GSK-5498A or GSK-7975A; however cytokine release was fully blocked from T-cells in a mouse preparation. GSK-5498A and GSK-7975A confirm the critical role of CRAC channels in human mast cell and T-cell function, and that inhibition can be achieved in vitro. The rat displays a similar pharmacology to human, promoting this species for future in vivo research with this series of molecules. Together these observations provide a critical forward step in the identification of CRAC blockers suitable for clinical development in the treatment of inflammatory disorders. PMID- 23454524 TI - Cigarette smoke may increase microbial virulence. PMID- 23454523 TI - Nanoparticle translocation across mouse alveolar epithelial cell monolayers: species-specific mechanisms. AB - Studies of polystyrene nanoparticle (PNP) trafficking across mouse alveolar epithelial cell monolayers (MAECM) show apical-to-basolateral flux of 20 and 120nm amidine-modified PNP is ~65 times faster than that of 20 and 100nm carboxylate-modified PNP, respectively. Calcium chelation with EGTA has little effect on amidine-modified PNP flux, but increases carboxylate-modified PNP flux ~50-fold. PNP flux is unaffected by methyl-beta-cyclodextrin, while ~70% decrease in amidine- (but not carboxylate-) modified PNP flux occurs across chlorpromazine or dynasore-treated MAECM. Confocal microscopy reveals intracellular amidine- and carboxylate-modified PNP and association of amidine- (but not carboxylate-) modified PNP with clathrin heavy chain. These data indicate (1) amidine-modified PNP translocate across MAECM primarily via clathrin-mediated endocytosis and (2) physicochemical properties (e.g., surface charge) determine PNP interactions with mouse alveolar epithelium. Uptake/trafficking of nanoparticles into/across epithelial barriers is dependent on both nanoparticle physicochemical properties and (based on comparison with our prior results) specific epithelial cell type. FROM THE CLINICAL EDITOR: In this study of polystyrene nanoparticle trafficking across mouse alveolar epithelial cell monolayers, the authors determined that uptake/trafficking of nanoparticles into/across epithelial barriers is dependent on both nanoparticle physicochemical properties and the specific type of epithelial cells. PMID- 23454525 TI - In vitro activity of cadazolid against Clostridium difficile strains isolated from primary and recurrent infections in Stockholm, Sweden. AB - One hundred thirty-three Clostridium difficile strains were collected from 71 patients and analyzed for the presence of C. difficile toxin B by the cell cytotoxicity neutralization assay, genes for toxin A, toxin B, binary toxin and TcdC deletion by PCR. All strains were also PCR-ribotyped and analyzed for sporulation frequency. The MICs of the isolates were determined against cadazolid and seven other antimicrobial agents by the agar dilution method. All isolates were positive for toxin B by the cell cytotoxicity neutralization assay. One hundred fourteen isolates were positive for toxin A and B and 16 isolates were positive for toxin A, toxin B and binary toxin by PCR. Three isolates were negative for toxin A but positive for toxin B. Thirty-three different ribotypes were identified. No strain of ribotype 027 was found. No differences in sporulation were noticed between the primary and recurrent isolates. All 133 isolates were sensitive to cadazolid (0.064-0.5 mg/l), fidaxomicin (0.008-0.125 mg/l), metronidazole (0.125-2 mg/l), vancomycin (0.125-1 mg/l) and tigecycline (0.032-0.25 mg/l). Three isolates were resistant to linezolid (8 mg/l), 15 isolates were resistant to moxifloxacin (8-32 mg/l) and 103 isolates were resistant to clindamycin (8-256 mg/l). No association between toxins A, B and binary toxin, ribotypes or the sporulation and the sensitivity to cadazolid could be found. Cadazolid has a potent in vitro activity against C. difficile. PMID- 23454526 TI - Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver. AB - Drug abuse is associated with epigenetic changes, such as histone modifications and DNA methylation. The purpose of the present study was to examine the effect of chronic cocaine and heroin administration on global DNA methylation in brain and liver. Male, 8 week old, C57BL/6J mice received heroin in a chronic 'intermittent' escalating dose paradigm, or cocaine in a chronic escalating dose 'binge' paradigm, which mimic the human pattern of opioid or cocaine abuse respectively. Following sacrifice, livers and brains were removed and DNA was extracted from them. The extracted DNA was hydrolyzed and 2'-deoxycytidine and 5 methyl-2'-deoxycytidine were determined by HPLC-UV. The % 5-methyl-2' deoxycytidine content of DNA was significantly higher in the brain compared to the liver. There were no differences between the control animals and the cocaine or heroin treated animals in neither of the tissues examined, which is surprising since cocaine administration induced gross morphological changes in the liver. Moreover, there was no difference in the % 5-methyl-2'-deoxycytidine content of DNA between the cocaine and the heroin treated animals. The global DNA methylation status in the brain and liver of mice chronically treated with cocaine or heroin remains unaffected, but this finding cannot exclude the existence of anatomical region or gene-specific methylation differences. This is the first time that global DNA methylation in the liver and whole brain has been studied following chronic cocaine or heroin treatment. PMID- 23454527 TI - Effect of serum on diesel exhaust particles (DEP)-induced apoptosis of airway epithelial cells in vitro. AB - Patients with chronic airway diseases may be more susceptible to adverse effects of air pollutants including diesel exhaust particles (DEP). We investigated effects of foetal calf serum (FCS) on DEP-induced changes in airway epithelial cell apoptosis and inflammation. DEP (50-200 MUg/ml) increased A549 cell viability in the absence of FCS. In the presence of 3.3%FCS, DEP (50-400 MUg/ml) decreased A549 cell viability. N-acetylcysteine (NAC, 33 mM) and the c-jun N terminal kinase (JNK) inhibitor (SP600125, 33 MUM) further decreased the viability in the presence of DEP (200 MUg/ml) and 3.3% FCS. Under serum-free (SF) condition, DEP (50 MUg/ml) reduced apoptotic cells; however, when 3.3% FCS added to the culture medium, this effect was abolished. DEP (200 MUg/ml) induced mRNA expression of p21(CIP1/WAF1) both in absence or presence of 3.3% FCS and enhanced JNK2 mRNA expression only in the presence of 3.3% FCS. Under SF condition, DEP (50 MUg/ml) induced mRNA expression for p27 and p53, whereas cyclin E mRNA expression was inhibited by DEP (50 and 200 MUg/ml). Furthermore, DEP (200 MUg/ml) decreased the release of interleukin (IL)-8 in the absence of FCS. In conclusion, FCS modulates effects of DEP on cell death, cell cycle and apoptosis regulating proteins, and IL-8 release by activating oxidant stress pathways, JNK and NF-kappaB. Extravasation of serum, as occurs in the inflamed airways of patients with chronic airway diseases such as asthma and COPD, may render airway epithelial cells more susceptible to the deleterious effects of DEP. PMID- 23454528 TI - Neuropeptide S enhances memory and mitigates memory impairment induced by MK801, scopolamine or Abeta1-42 in mice novel object and object location recognition tasks. AB - Neuropeptide S (NPS), the endogenous ligand of NPSR, has been shown to promote arousal and anxiolytic-like effects. According to the predominant distribution of NPSR in brain tissues associated with learning and memory, NPS has been reported to modulate cognitive function in rodents. Here, we investigated the role of NPS in memory formation, and determined whether NPS could mitigate memory impairment induced by selective N-methyl-D-aspartate receptor antagonist MK801, muscarinic cholinergic receptor antagonist scopolamine or Abeta1-42 in mice, using novel object and object location recognition tasks. Intracerebroventricular (i.c.v.) injection of 1 nmol NPS 5 min after training not only facilitated object recognition memory formation, but also prolonged memory retention in both tasks. The improvement of object recognition memory induced by NPS could be blocked by the selective NPSR antagonist SHA 68, indicating pharmacological specificity. Then, we found that i.c.v. injection of NPS reversed memory disruption induced by MK801, scopolamine or Abeta1-42 in both tasks. In summary, our results indicate that NPS facilitates memory formation and prolongs the retention of memory through activation of the NPSR, and mitigates amnesia induced by blockage of glutamatergic or cholinergic system or by Abeta1-42, suggesting that NPS/NPSR system may be a new target for enhancing memory and treating amnesia. PMID- 23454529 TI - New quinazoline derivatives for telomeric G-quadruplex DNA: effects of an added phenyl group on quadruplex binding ability. AB - To improve the selectivity of indoloquinoline or benzofuroquinoline derivatives, we previously reported several quinazoline derivatives [17]. These compounds could mimic a tetracyclic aromatic system through intramolecular hydrogen bond. Studies showed that these quinazoline derivatives were effective and selective telomeric G-quadruplex ligands. With this encouragement, here we synthesized a series of N-(2-(quinazolin-2-yl)phenyl)benzamide (QPB) compounds as modified quinazoline derivatives. In this modification, a phenyl group was introduced to the aromatic core. The evaluation results showed that part of QPB derivatives had stronger binding ability and better selectivity for telomeric G-quadruplex DNA than LZ-11, the most potential compound of reported quinazoline derivatives. Furthermore, telomerase inhibition of QPB derivatives and their cellular effects were studied. PMID- 23454530 TI - Rational design, synthesis and QSAR study of vasorelaxant active 3 pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function. AB - A variety of 2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles 4a r were prepared via either regioselective reaction of 3-aryl-1-(1H-benzimidazol-2 yl)-2-propen-1-ones 3 with malononitrile or ylidenemalononitriles 6 with 2-acetyl 1H-benzimidazoles 1 in the presence of sodium alkoxide in the corresponding alcohol. All the synthesized compounds showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique. Compounds 4d, 4p, 4l, and 4f exhibited remarkable activity compared with prazosin hydrochloride, which was used as a reference standard in the present study. QSAR studies revealed a good predictive and statistically significant 3 descriptor model (r(2) = 0.913, radjusted(2)=0.8808, rprediction(2)=0.7911). PMID- 23454531 TI - Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3 (1,3,4-oxadiazol-5-yl)methyl-indoles. AB - On the basis of the principle of combination of active structural moieties, a modified and efficient synthetic method for three series of novel indole-based 1,3,4-oxadiazoles is described. Bioassays conducted at Syngenta showed that several of the synthesized compounds exhibit higher antifungal activity than pimprinine, the natural product which inspired this synthesis. Two main structural alterations were found to broaden the spectrum of biological activity in most cases. Compounds 3g, 6c, 6e, 6h, 9d, 9e, 9h and 9m (Fig. 1) were identified as the most active on the biological assays, and will be studied further. PMID- 23454532 TI - Nonclassical antifolates, part 3: synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones. AB - A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3-0.8 MUM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8-41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors. PMID- 23454533 TI - Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy. AB - Clinical use of antineoplastic drugs is associated with the development of numerous adverse effects that many patients find intolerable, including peripheral neuropathy. Cannabinoids have relieved neuropathic pain in different animal models. But their therapeutic activities could be affected by their psychoactive properties. The aim of this work was to determine the effect of cannabinoids in cisplatin-evoked neuropathy. For this purpose, the non-selective agonist WIN 55,212-2 (WIN), the CB1-selective agonist ACEA or the CB2-selective agonist JWH133 (or their vehicle) was either systemically administered at a non psychoactive dose or locally injected in cisplatin-treated rats. Selective CB1 and CB2 cannabinoid antagonists (AM251 and SR144528, respectively) were used to characterize cannabinoid effects. Cisplatin-treated rats showed mechanical allodynia but not thermal hyperalgesia. Cannabinoid agonists alleviated mechanical allodynia. This effect was mediated by both CB1 and CB2 cannabinoid receptors when the cannabinoid was systemically applied. At the dose used, cannabinoid agonists had no psychoactive effect. The local effect of the drug involved the activation of peripheral CB1 receptors whereas involvement of CB2 receptors was less clear. In a rat model of cisplatin-induced neuropathy, cannabinoids have an antinociceptive effect, but the cannabinoid receptors involved could be different depending on the route of administration. Non psychoactive doses of cannabinoid agonists are capable of alleviating the signs of peripheral neuropathy when systemically applied. Interestingly, local administration of selective CB1 agonists or systemic administration of CB2 agonists, which are non-psychoactive, may serve as new therapeutic alternatives for symptom management in painful neuropathy associated with cisplatin treatment. PMID- 23454534 TI - The histone deacetylase inhibitor sodium butyrate modulates acquisition and extinction of cocaine-induced conditioned place preference. AB - Despite decades of research on treatments for cocaine dependence, relapse rates following many behavioral and drug-based therapies remain high. This may be in part because cocaine-associated cues and contexts can invoke powerful drug cravings years after quitting. Recent studies suggest that drugs that promote cognitive function can enhance the formation of memories involving cocaine and other substances. One target of these drugs is facilitating histone acetylation to promote learning by increasing gene transcription that supports memory formation. Here, we investigate the effects of the histone deacetylase (HDAC) inhibitor sodium butyrate (NaBut) on cocaine-induced conditioned place preference (CPP) in C57BL/6 mice. After establishing a graded dose-response curve (2, 5, & 20 mg/kg) for cocaine-induced CPP, we examined the effects of different doses of NaBut (0, 0.3, 0.6, & 1.2 g/kg) on conditioning, extinction, and post-extinction reconditioning of CPP. A high dose of NaBut (1.2 g/kg) enhanced initial acquisition of cocaine CPP, but there were no effects of NaBut on reconditioning of extinguished CPP. Effects of NaBut on extinction were more complex, with a low dose (0.3 g/kg) facilitating extinction and a high dose (1.2 g/kg) weakening extinction evident by preference at a retention test. These findings suggest that HDAC inhibition may have dose dependent effects on different components of cocaine CPP, with implications for (1) involvement of histone acetylation in context-drug learning, (2) interpretation of acute and chronic drug effects, and (3) the targeting of different types of learning in therapeutic application of HDAC inhibitors. PMID- 23454535 TI - Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference. AB - Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self administration and hyperlocomotion paradigms. In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence the induction, extinction or reinstatement of a conditioned cocaine response. We found that the Y5 antagonist L-152,804 causes faster extinction and reduced reinstatement of cocaine-induced CPP but did not reduce the ability of cocaine to induce CPP. Similarly, Y5-KO mice displayed faster extinction, and reinstatement of cocaine-induced CPP was absent. The development of CPP for cocaine was similar between Y5-KO and WT mice. Taken together, the present data show that Y5 antagonism attenuates relapse to cocaine addiction-related behavior. Prevention of relapse is considered to be of pivotal importance for the development of an effective treatment against cocaine addiction and therefore Y5 receptors could be a potential future therapeutic target in cocaine addiction. PMID- 23454536 TI - Suicide prevention program for at-risk groups: pointers from an epidemiological study. AB - OBJECTIVES: The aim of this paper is to identify at-risk groups for a focused suicide prevention program for Malaysia. METHODS: Data from 20,552 persons aged 16 years and above (males 45.9%), was obtained using stratified, random sampling in a national survey of psychiatric morbidity using locally validated General Health Questionnaire (GHQ-28) which included questions on suicidal ideation. RESULTS: The overall prevalence of suicidal ideation (SI) was 6.3%, CI 6.1-6.8 (n=1288). Logistic regression analysis was performed with age, ethnicity, gender, urban/rural residence, age group, marital status, household income, type of household, presence of chronic pain, social dysfunction, somatic, anxiety or depressive symptoms, obesity, and chronic medical illnesses as independent variables. Only Insomnia, Religion, Marital Status, Depression, Social Dysfunction and Anxiety were seen to be significant predictors. Prevalence of SI was significantly higher among Indians (11.0%, CI 9.5-12.5), especially those of the Hindu faith (12.2%, CI 10.5-14.0), Chinese (9.7%, CI 8.8-10.7) and those having depressive symptoms. CONCLUSION: In a developing country with competing priorities, prudent allocation of resources requires focusing suicide prevention efforts on treating depression in vulnerable groups. PMID- 23454537 TI - Community-based dietary and physical activity interventions in low socioeconomic groups in the UK: a mixed methods systematic review. AB - OBJECTIVE: Low socioeconomic status (SES) is a risk factor for type 2 diabetes and changes in diet and physical activity can prevent diabetes. We assessed the effectiveness and acceptability of community-based dietary and physical activity interventions among low-SES groups in the UK. METHOD: We searched relevant databases and web resources from 1990 to November 2009 to identify relevant published and grey literature using an iterative approach, focusing on UK studies. RESULTS: Thirty-five relevant papers (nine quantitative, 23 qualitative and three mixed methods studies) were data extracted, quality assessed and synthesised using narrative synthesis and thematic analysis. The relationship between interventions and barriers and facilitators was also examined. Dietary/nutritional, food retail, physical activity and multi-component interventions demonstrated mixed effectiveness. Qualitative studies indicated a range of barriers and facilitators, which spanned pragmatic, social and psychological issues. The more effective interventions used a range of techniques to address some surface-level psychological and pragmatic concerns, however many deeper-level social, psychological and pragmatic concerns were not addressed. CONCLUSION: Evidence on the effectiveness of community-based dietary and physical activity interventions is inconclusive. A range of barriers and facilitators exist, some of which were addressed by interventions but some of which require consideration in future research. PMID- 23454538 TI - Central PACAP mediates the sympathetic effects of leptin in a tissue-specific manner. AB - We previously demonstrated that the peptidergic neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP) affects the autonomic system and contributes to the control of metabolic and cardiovascular functions. Previous studies have demonstrated the importance of centrally-mediated sympathetic effects of leptin for obesity-related hypertension. Here we tested whether PACAP signaling in the brain is implicated in leptin-induced sympathetic excitation and appetite suppression. In anesthetized mice, intracerebroventricular (ICV) pre treatment with PACAP6-38, an antagonist of the PACAP receptors (PAC1-R and VPAC2), inhibited the increase in white adipose tissue sympathetic nerve activity (WAT-SNA) produced by ICV leptin (2MUg). In contrast, leptin-induced stimulation of renal sympathetic nerve activity (RSNA) was not affected by ICV pre-treatment with PACAP6-38. Moreover, in PACAP-deficient (Adcyap1-/-) mice, ICV leptin induced WAT-SNA increase was impaired, whereas RSNA response was preserved. The reductions in food intake and body weight evoked by ICV leptin were attenuated in Adcyap1-/- mice. Our data suggest that hypothalamic PACAP signaling plays a key role in the control by leptin of feeding behavior and lipocatabolic sympathetic outflow, but spares the renal sympathetic traffic. PMID- 23454540 TI - Modulation of local field potential power of the subthalamic nucleus during isometric force generation in patients with Parkinson's disease. AB - Investigations of local field potentials of the subthalamic nucleus of patients with Parkinson's disease have provided evidence for pathologically exaggerated oscillatory beta-band activity (13-30 Hz) which is amenable to physiological modulation by, e.g., voluntary movement. Previous functional magnetic resonance imaging studies in healthy controls have provided evidence for an increase of subthalamic nucleus blood-oxygenation-level-dependant signal in incremental force generation tasks. However, the modulation of neuronal activity by force generation and its relationship to peripheral feedback remain to be elucidated. We hypothesised that beta-band activity in the subthalamic nucleus is modulated by incremental force generation. Subthalamic nucleus local field potentials were recorded intraoperatively in 13 patients with Parkinson's disease (37 recording sites) during rest and five incremental isometric force generation conditions of the arm with applied loads of 0-400 g (in 100-g increments). Repeated measures analysis of variance (ANOVA) revealed a modulation of local field potential (LFP) power in the upper beta-band (in 24-30 Hz; F(3.042)=4.693, p=0.036) and the gamma band (in 70-76 Hz; F(4)=4.116, p=0.036). Granger-causality was computed with the squared partial directed coherence and showed no significant modulation during incremental isometric force generation. Our findings indicate that the upper beta and gamma-band power of subthalamic nucleus local field potentials are modulated by the physiological task of force generation in patients with Parkinson's disease. This modulation seems to be not an effect of a modulation of peripheral feedback. PMID- 23454539 TI - NADPH-oxidase 2 activation promotes opioid-induced antinociceptive tolerance in mice. AB - The analgesic effectiveness of long-term opioid therapies is compromised by the development of antinociceptive tolerance linked to the overt production of peroxynitrite (ONOO(-), PN), the product of the interaction between superoxide (O2(-), SO) and nitric oxide (NO), and to neuroinflammatory processes. We have recently reported that in addition to post-translational nitration and inactivation of mitochondrial manganese superoxide dismutase (MnSOD), activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase holoenzyme (NOX) in the spinal cord is a major source for the overt production of superoxide derived PN during the development of morphine-induced antinociceptive tolerance. However, the NOX complex involved in these processes is not known. The objective of these studies is to identify a potential role for the NOX2 complex, an enzyme involved in inflammation. Mice lacking the catalytic subunit of NOX2 (Nox2(-/-)) or its regulatory subunit, p47(phox) (p47(phox)(-/-)), developed antinociceptive tolerance similar to wildtype (wt) mice after 3 days of continuous morphine. However, while wt mice continue to develop tolerance by day six, morphine analgesia was restored in both Nox2(-/-) and p47(phox)(-/-) mice. Moreover, the loss of Nox2 or p47 did not affect acute morphine analgesia in naive mice. In wt mice, antinociceptive tolerance was associated with increased activation of NOX, nitration of MnSOD, and proinflammatory cytokines production in the spinal cord. These events were markedly attenuated in Nox2(-/-) and p47(phox)(-/-) mice and instead, there was enhanced formation of antiinflammatory cytokine (IL4 and IL10) production. These results suggest that NOX2 activity provides a significant source of superoxide-derived PN to undertake post-translational modifications of mitochondrial MnSOD and to engage neuroinflammatory signaling in the spinal cord associated with opioid-induced antinociceptive tolerance. Thus, NOX2 may provide a potential target for adjuvant therapy to protect opioid analgesia. PMID- 23454541 TI - Ascending and descending propriospinal pathways between lumbar and cervical segments in the rat: evidence for a substantial ascending excitatory pathway. AB - Precise mechanisms are required to coordinate the locomotor activity of fore- and hind-limbs in quadrupeds and similar mechanisms persist to coordinate movement of arms and legs in humans. Propriospinal neurons (PSNs) are major components of the networks that coordinate these mechanisms. The b subunit of cholera toxin (CTb) was injected unilaterally into either L1 or L3 segments in order to label ascending and descending propriospinal pathways. Labelled cells were examined with light or confocal microscopy. Cells projecting to lumbar segments were evenly distributed, bilaterally throughout all cervical segments. However many more cells were labelled from L1 injections than L3 injections. Roughly 15% of cells in both sides of the C2 segment was found to be immunoreactive for calretinin and a small number (4%) was immunoreactive for calbindin. Axons projecting from L1 to cervical segments formed predominant ipsilateral projections to the cervical intermediate grey matter and ventral horn. Very large numbers of terminals were concentrated within the ventrolateral motor (VLM) nuclei of C7-8 segments but there was sparse innervation of the contralateral nucleus. The vast majority (85%) of these axon terminals in the ipsilateral VML was immunoreactive for the vesicular glutamate transporter 2 (VGLUT2) and the remaining 15% was immunoreactive for the vesicular GABA transporter (VGAT); many of these contained GABA and/or glycine. Inhibitory and excitatory terminals were also found in the contralateral VLM. Most of the terminals in the VLM made contacts with motoneurons. The major finding of this study is the existence of a substantial excitatory propriospinal pathway that projects specifically to the VLM. Motoneurons in the VLM supply muscles of the axilla therefore this pathway is likely to have a profound influence on the activity of the shoulder joint. This pathway may synchronise lumbar and cervical pattern generators and hence the coordination of locomotor activity in the fore- and hind limbs. PMID- 23454542 TI - Perinatal high fat diet alters glucocorticoid signaling and anxiety behavior in adulthood. AB - Maternal obesity carries significant health risks for offspring that manifest later in life, including metabolic syndrome, cardiovascular disease and affective disorders. Programming of the hypothalamic-pituitary-adrenal (HPA) axis during development mediates both metabolic homeostasis and the response to psychosocial stress in offspring. A diet high in fat alters maternal systemic corticosterone levels, but effects in offspring on limbic brain areas regulating the HPA axis and anxiety behavior are poorly understood. In addition to their role in the response to psychosocial stress, corticosteroid receptors form part of the glucocorticoid signaling pathway comprising downstream inflammatory processes. Increased systemic inflammation is a hallmark of high-fat diet exposure, though altered expression of these genes in limbic brain areas has not been examined. We studied the influence of high-fat diet exposure during pre-weaning development in rats on gene expression in the amygdala and hippocampus by quantitative real-time polymerase chain reaction (PCR), anxiety behavior in the Open field, elevated plus maze and light-dark transition tasks, and corticosterone levels in response to stress by radioimmunoassay. As adults, offspring exposed to perinatal high-fat diet show increased expression of corticosterone receptors in the amygdala and altered pro-inflammatory and anti-inflammatory expression in the hippocampus and amygdala in genes known to be regulated by the glucocorticoid receptor. These changes were associated with increased anxiety behavior, decreased basal corticosterone levels and a slower return to baseline levels following a stress challenge. The data indicate that the dietary environment during development programs glucocorticoid signaling pathways in limbic areas relevant for the regulation of HPA function and anxiety behavior. PMID- 23454543 TI - Litter size, age-related memory impairments, and microglial changes in rat dentate gyrus: stereological analysis and three dimensional morphometry. AB - It has been demonstrated that rat litter size affects the immune cell response, but it is not known whether the long-term effects aggravate age-related memory impairments or microglial-associated changes. To that end, we raised sedentary Wistar rats that were first suckled in small or large litters (6 or 12pups/dam, respectively), then separated into groups of 2-3 rats from the 21st post-natal day to study end. At 4months (young adult) or 23months (aged), all individual rats were submitted to spatial memory and object identity recognition tests, and then sacrificed. Brain sections were immunolabeled with anti-IBA-1 antibodies to selectively identify microglia/macrophages. Microglial morphological changes in the molecular layer of the dentate gyrus were estimated based on three dimensional reconstructions. The cell number and laminar distribution in the dentate gyrus was estimated with the stereological optical fractionator method. We found that, compared to young rat groups, aged rats from large litters showed significant increases in the number of microglia in all layers of the dentate gyrus. Compared to the microglia in all other groups, microglia in aged individuals from large litters showed a significantly higher degree of tree volume expansion, branch base diameter thickening, and cell soma enlargement. These morphological changes were correlated with an increase in the number of microglia in the molecular layer. Young adult individuals from small litters exhibited preserved intact object identity recognition memory and all other groups showed reduced performance in both spatial and object identity recognition tasks. We found that, in large litters, brain development was, on average, associated with permanent changes in the innate immune system in the brain, with a significant impact on the microglial homeostasis of aged rats. PMID- 23454544 TI - The Rucker-Markov invariants of complex Bio-Systems: applications in Parasitology and Neuroinformatics. AB - Rucker's walk count (WC) indices are well-known topological indices (TIs) used in Chemoinformatics to quantify the molecular structure of drugs represented by a graph in Quantitative structure-activity/property relationship (QSAR/QSPR) studies. In this work, we introduce for the first time the higher-order (kth order) analogues (WCk) of these indices using Markov chains. In addition, we report new QSPR models for large complex networks of different Bio-Systems useful in Parasitology and Neuroinformatics. The new type of QSPR models can be used for model checking to calculate numerical scores S(Lij) for links Lij (checking or re evaluation of network connectivity) in large networks of all these fields. The method may be summarized as follows: (i) first, the WCk(j) values are calculated for all jth nodes in a complex network already created; (ii) A linear discriminant analysis (LDA) is used to seek a linear equation that discriminates connected or linked (Lij=1) pairs of nodes experimentally confirmed from non linked ones (Lij=0); (iii) The new model is validated with external series of pairs of nodes; (iv) The equation obtained is used to re-evaluate the connectivity quality of the network, connecting/disconnecting nodes based on the quality scores calculated with the new connectivity function. The linear QSPR models obtained yielded the following results in terms of overall test accuracy for re-construction of complex networks of different Bio-Systems: parasite-host networks (93.14%), NW Spain fasciolosis spreading networks (71.42/70.18%) and CoCoMac Brain Cortex co-activation network (86.40%). Thus, this work can contribute to the computational re-evaluation or model checking of connectivity (collation) in complex systems of any science field. PMID- 23454545 TI - Upregulation of galactose metabolic pathway by N-acetylglucosamine induced endogenous synthesis of galactose in Candida albicans. AB - N-Acetylglucosamine (GlcNAc) is an important signaling molecule that plays multiple roles in Candida albicans. Induction of galactose metabolic pathway by GlcNAc is an intriguing aspect of C. albicans biology. In order to investigate the role of galactose metabolic genes (GAL genes) in presence of GlcNAc, we created knockouts of galactokinase (GAL1) and UDP galactose epimerase (GAL10) genes. These mutants failed to grow on galactose and also showed lower growth rate in presence of GlcNAc. Interestingly, expression of GAL genes in presence of GlcNAc was higher in gal1Delta strain relative to that of wild type strain. Moreover, no GlcNAc induced upregulation of GAL genes was observed in the gal10Delta strain suggesting that UDP galactose epimerase is essential for GlcNAc induced activation of GAL genes. GlcNAc induced expression of GAL genes was also investigated in GlcNAc metabolic pathway triple mutant N216 (hxk1Delta nag1Delta dac1Delta). Interestingly, in this mutant the GAL genes are neither induced nor repressed and remain derepressed as found on a neutral carbon source such as glycerol, suggesting that catabolism of GlcNAc play an important role in the expression of GAL genes. GC/MS analysis of derivatized metabolites revealed a significant accumulation of galactose in the gal1Delta strain while no galactose was detected in gal10Delta and N216 strain. Solution-state NMR spectroscopy using N-acetyl-13C1-glucosamine confirmed the flow of 13C label from GlcNAc to galactose. Thus, internal galactose synthesized via UDP galactose pathway from GlcNAc metabolites acts as the inducer of GAL genes in presence of GlcNAc. PMID- 23454546 TI - Relevance of trichothecenes in fungal physiology: disruption of tri5 in Trichoderma arundinaceum. AB - Trichothecenes are sesquiterpenoid mycotoxins produced mainly by Fusarium species. Harzianum A (HA), a non-phytotoxic trichothecene produced by Trichoderma arundinaceum, has recently been found to have antagonistic activity against fungal plant pathogens and to induce plant genes involved in defense responses. In the present work, we have shown that disruption of the T. arundinaceum tri5 gene, which encodes a terpene synthase, stops the production of HA, alters the expression of other tri genes involved in HA biosynthesis, and alters the expression of hmgR, dpp1, erg9, erg1, and erg7, all genes involved in terpene biosynthetic pathways. An increase in the level of ergosterol biosynthesis was also observed in the tri5 disrupted transformant in comparison with the wild type strain. The loss of HA also resulted in a drastic reduction of the biocontrol activity of the transformants against the phytopathogenic fungi Botrytis cinerea and Rhizoctonia solani. Finally, the effect of tri5 gene disruption on the regulation and balance of intermediates in terpene biosynthetic pathways, as well as the hypothetical physiological role of trichothecenes, both inter- and intracellularly, on regulation and biocontrol, are discussed. PMID- 23454547 TI - Expression and phylogenetic analyses of the Gel/Gas proteins of Tuber melanosporum provide insights into the function and evolution of glucan remodeling enzymes in fungi. AB - The beta(1,3)-glucanosyltransferases of the GH72 family are redundant enzymes that are essential for the formation and dynamic remodeling of the fungal wall during different stages of the life cycle. Four putative genes encoding glycosylphosphatidylinositol (GPI)-anchored beta(1,3)-glucanosyltransferases, designated TmelGEL1, TmelGEL2, TmelGEL4 and TmelGAS4, have been annotated in the genome of Tuber melanosporum, an ectomycorrhizal fungus that also produces a hypogeous fruiting body (FB) of great commercial value (black truffle). This work focuses on the characterization and expression of this multigene family by taking advantage of a laser microdissection (LMD) technology that has been used to separate two distinct compartments in the FB, the hyphae and the asci containing the ascospores. Of the four genes, TmelGEL1 was the most up-regulated in the FB compared to the free-living mycelium. Inside the FB, the expression of TmelGEL1 was restricted to the hyphal compartment. A phylogenetic analysis of the Gel/Gas protein family of T. melanosporum was also carried out. A total of 237 GH72 proteins from 51 Ascomycotina and 3 Basidiomycota (outgroup) species were analyzed. The resulting tree provides insight into the evolution of the T. melanosporum proteins and identifies new GH72 paralogs/subfamilies. Moreover, it represents a starting point to formulate new hypotheses on the significance of the striking GH72 gene redundancy in fungal biology. PMID- 23454550 TI - Cognitive Behavioral Therapy for negative symptoms (CBT-n) in psychotic disorders: a pilot study. AB - BACKGROUND AND OBJECTIVES: The treatment of negative symptoms in schizophrenia is a major challenge for mental health care. One randomized controlled trial found that cognitive therapy for low-functioning patients reduced avolition and improved functioning, using an average of 50.5 treatment sessions over the course of 18 months. The aim of our current pilot study was to evaluate whether 20 sessions of Cognitive Behavioral Therapy for negative symptoms (CBT-n) would reduce negative symptoms within 6 months. Also, we wanted to test the cognitive model of negative symptoms by analyzing whether a reduction in dysfunctional beliefs mediated the effects on negative symptoms. METHOD: In an open trial 21 adult outpatients with a schizophrenia spectrum disorder with negative symptoms received an average of 17.5 sessions of CBT-n. At baseline and end-of-treatment, we assessed negative symptoms (PANSS) and dysfunctional beliefs about cognitive abilities, performance, emotional experience, and social exclusion. Bootstrap analysis tested mediation. RESULTS: The dropout rate was 14% (three participants). Intention-to-treat analyses showed a within group effect size of 1.26 on negative symptoms (t = 6.16, | Sig = 0.000). Bootstrap analysis showed that dysfunctional beliefs partially mediated the change. LIMITATIONS: The uncontrolled design induced efficacy biases. Also, the sample was relatively small, and there were no follow-up assessments. CONCLUSIONS: CBT-n may be effective in reducing negative symptoms. Also, patients reported fewer dysfunctional beliefs about their cognitive abilities, performance, emotional experience, and social exclusion, and this reduction partially mediated the change in negative symptoms. The reductions were clinically important. However, larger and controlled trials are needed. PMID- 23454548 TI - Pseudo-constitutivity of nitrate-responsive genes in nitrate reductase mutants. AB - In fungi, transcriptional activation of genes involved in NO3(-) assimilation requires the presence of an inducer (nitrate or nitrite) and low intracellular concentrations of the pathway products ammonium or glutamine. In Aspergillus nidulans, the two transcription factors NirA and AreA act synergistically to mediate nitrate/nitrite induction and nitrogen metabolite derepression, respectively. In all studied fungi and in plants, mutants lacking nitrate reductase (NR) activity express nitrate-metabolizing enzymes constitutively without the addition of inducer molecules. Based on their work in A. nidulans, Cove and Pateman proposed an "autoregulation control" model for the synthesis of nitrate metabolizing enzymes in which the functional nitrate reductase molecule would act as co-repressor in the absence and as co-inducer in the presence of nitrate. However, NR mutants could simply show "pseudo-constitutivity" due to induction by nitrate which accumulates over time in NR-deficient strains. Here we examined this possibility using strains which lack flavohemoglobins (fhbs), and are thus unable to generate nitrate internally, in combination with nitrate transporter mutations (nrtA, nrtB) and a GFP-labeled NirA protein. Using different combinations of genotypes we demonstrate that nitrate transporters are functional also in NR null mutants and show that the constitutive phenotype of NR mutants is not due to nitrate accumulation from intracellular sources but depends on the activity of nitrate transporters. However, these transporters are not required for nitrate signaling because addition of external nitrate (10 mM) leads to standard induction of nitrate assimilatory genes in the nitrate transporter double mutants. We finally show that NR does not regulate NirA localization and activity, and thus the autoregulation model, in which NR would act as a co repressor of NirA in the absence of nitrate, is unlikely to be correct. Results from this study instead suggest that transporter-mediated NO3- accumulation in NR deficient mutants, originating from traces of nitrate in the media, is responsible for the constitutive expression of NirA-regulated genes, and the associated phenotype is thus termed "pseudo-constitutive". PMID- 23454551 TI - The role of CBT in explicit memory bias in bipolar I patients. AB - BACKGROUND AND OBJECTIVES: Cognitive and Behavioural Therapy (CBT) is widely used in bipolar disorder, but recent meta-analyses showed that its impact is either of limited effect or not significant for important aspects such as recurrence rate. A possible benefit of CBT could concern cognitive functions, known to be frequently impaired in patients with bipolar disorder. We analysed if the positive impact of 6 months group-CBT was associated with the improvement of a specific cognitive function, namely explicit memory, trying to disentangle if memory bias (i.e. different capacity according to the emotional valence of words to be recalled) was more improved than memory performance (i.e., total number of recalled words). METHODS: Depressive, manic, anxiety symptoms and explicit memory for emotional words were initially assessed in 68 remitted bipolar I patients. Six months later, with an attrition rate of 16.2%, patients were re-assessed after CBT (N = 42) or as control condition (waiting list, N = 15). The expected impact of CBT was assessed through the improvement in the Dysfunctional Attitudes Scale. RESULTS: After CBT, an increase was observed for the number of neutral, positive and total words recalled, whereas the number of negative words recalled decreased. This increase was still significant when the improvement of dysfunctional attitudes and mood symptoms are taken into account. LIMITATIONS: The small sample of control patients. CONCLUSIONS: CBT was effective, as it improved dysfunctional attitudes and reduced remaining symptoms, but also, and independently, it improved explicit memory performance while reducing memory bias in favour of negative words. PMID- 23454549 TI - alpha-actinin1 and 4 tyrosine phosphorylation is critical for stress fiber establishment, maintenance and focal adhesion maturation. AB - In polarized, migrating cells, stress fibers are a highly dynamic network of contractile acto-myosin structures composed of bundles of actin filaments held together by actin cross-linking proteins such as alpha-actinins. As such, alpha actinins influence actin cytoskeleton organization and dynamics and focal adhesion maturation. In response to environmental signals, alpha-actinins are tyrosine phosphorylated and this affects their binding to actin stress fibers; however, the cellular role of alpha-actinin tyrosine phosphorylation remains largely unknown. We found that non-muscle alpha-actinin1/4 are critical for the establishment of dorsal stress fibers and maintenance of transverse arc stress fibers. Analysis of cells genetically depleted of alpha-actinin1 and 4 reveals two distinct modes for focal adhesion maturation. An alpha-actinin1 or 4 dependent mode that uses dorsal stress fiber precursors as a template for establishing focal adhesions and their maturation, and an alpha-actinin independent manner that uses transverse arc precursors to establish focal adhesions at both ends. Focal adhesions formed in the absence of alpha-actinins are delayed in their maturation, exhibit altered morphology, have decreased amounts of Zyxin and VASP, and reduced adhesiveness to extracellular matrix. Further rescue experiments demonstrate that the tyrosine phosphorylation of alpha actinin1 at Y12 and alpha-actinin4 at Y265 is critical for dorsal stress fiber establishment, transverse arc maintenance and focal adhesion maturation. PMID- 23454552 TI - Reducing analogue trauma symptoms by computerized reappraisal training - considering a cognitive prophylaxis? AB - BACKGROUND AND OBJECTIVES: Distressing intrusions are a hallmark of posttraumatic stress disorder (PTSD). Dysfunctional appraisal of these symptoms may exacerbate the disorder, and conversely may lead to further intrusive memories. This raises the intriguing possibility that learning to 'reappraise' potential symptoms more functionally may protect against such symptoms. Woud, Holmes, Postma, Dalgleish, and Mackintosh (2012) found that 'reappraisal training' when delivered after an analogue stressful event reduced later intrusive memories and other posttraumatic symptoms. The present study aimed to investigate whether reappraisal training administered before a stressful event is also beneficial. METHODS: Participants first received positive or negative reappraisal training (CBM-App training) using a series of scripted vignettes. Subsequently, participants were exposed to a film with traumatic content. Effects of the CBM-App training procedure were assessed via three distinct outcome measures, namely: (a) post-training appraisals of novel ambiguous vignettes, (b) change scores on the Post Traumatic Cognitions Inventory (PTCI), and (c) intrusive symptom diary. RESULTS: CBM-App training successfully induced training-congruent appraisal styles. Moreover, those trained positively reported less distress arising from their intrusive memories of the trauma film during the subsequent week than those trained negatively. However, the induced appraisal bias only partly affected PTCI scores. LIMITATIONS: Participants used their own negative event as a reference for the PTCI assessments. The events may have differed regarding their emotional impact. There was no control group. CONCLUSIONS: CBM-App training has also some beneficial effects when applied before a stressful event and may serve as a cognitive prophylaxis against trauma-related symptomatology. PMID- 23454553 TI - Ribonucleases in bacterial toxin-antitoxin systems. AB - Toxin-antitoxin (TA) systems are widespread in bacteria and archaea and play important roles in a diverse range of cellular activities. TA systems have been broadly classified into 5 types and the targets of the toxins are diverse, but the most frequently used cellular target is mRNA. Toxins that target mRNA to inhibit translation can be classified as ribosome-dependent or ribosome independent RNA interferases. These RNA interferases are sequence-specific endoribonucleases that cleave RNA at specific sequences. Despite limited sequence similarity, ribosome-independent RNA interferases belong to a limited number of structural classes. The MazF structural family includes MazF, Kid, ParE and CcdB toxins. MazF members cleave mRNA at 3-, 5- or 7-base recognition sequences in different bacteria and have been implicated in controlling cell death (programmed) and cell growth, and cellular responses to nutrient starvation, antibiotics, heat and oxidative stress. VapC endoribonucleases belong to the PIN domain family and inhibit translation by either cleaving tRNA(fMet) in the anticodon stem loop, cleaving mRNA at -AUA(U/A)-hairpin-G- sequences or by sequence-specific RNA binding. VapC has been implicated in controlling bacterial growth in the intracellular environment and in microbial adaptation to nutrient limitation (nitrogen, carbon) and heat shock. ToxN shows structural homology to MazF and is also a sequence-specific endoribonuclease. ToxN confers phage resistance by causing cell death upon phage infection by cleaving cellular and phage RNAs, thereby interfering with bacterial and phage growth. Notwithstanding our recent progress in understanding ribonuclease action and function in TA systems, the environmental triggers that cause release of the toxin from its cognate antitoxin and the precise cellular function of these systems in many bacteria remain to be discovered. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23454554 TI - Functions of the DExD/H-box proteins in nuclear pre-mRNA splicing. AB - In eukaryotes, many genes are transcribed as precursor messenger RNAs (pre-mRNAs) that contain exons and introns, the latter of which must be removed and exons ligated to form the mature mRNAs. This process is called pre-mRNA splicing, which occurs in the nucleus. Although the chemistry of pre-mRNA splicing is identical to that of the self-splicing Group II introns, hundreds of proteins and five small nuclear RNAs (snRNAs), U1, U2, U4, U5, and U6, are essential for executing pre-mRNA splicing. Spliceosome, arguably the most complex cellular machine made up of all those proteins and snRNAs, is responsible for carrying out pre-mRNA splicing. In contrast to the transcription and the translation machineries, spliceosome is formed anew onto each pre-mRNA and undergoes a series of highly coordinated reconfigurations to form the catalytic center. This amazing process is orchestrated by a number of DExD/H-proteins that are the focus of this article, which aims to review the field in general and to project the exciting challenges and opportunities ahead. This article is part of a Special Issue entitled: The Biology of RNA helicases - Modulation for life. PMID- 23454555 TI - Comparative efficacy of TACI-Ig with TNF-alpha inhibitor and methotrexate in DBA/1 mice with collagen-induced arthritis. AB - The efficacies of TACI-Ig, rhTNFR:Fc and Methotrexate were compared in collagen induced arthritis (CIA) mice. Sixty animals were divided into six groups: TACI-Ig (9 mg/kg), rhTNFR:Fc (4 mg/kg), Methotrexate (2mg/kg) and IgG-Fc (9 mg/kg) groups and were given medication for six weeks. Meanwhile, normal and CIA mice were given as control. The different efficacies of drugs were evaluated by the analyses of ankle joints and spleens pathology, cytokines, T and B lymphocytes subsets. TACI-Ig and rhTNFR:Fc reduced arthritis scores seven days later than that of Methotrexate. TACI-Ig and Methotrexate were superior to rhTNFR:Fc in reduction synovial hyperplasia and cell infiltration scores. The same result was observed for scores of spleens histopathology. TACI-Ig and Methotrexate presented higher efficacy than rhTNFR:Fc on B lymphocyte stimulator, but TACI-Ig was inferior to rhTNFR:Fc on TNF-alpha. TACI-Ig and Methotrexate could reduce significantly IgA and IgM, but rhTNFR:Fc had no effects on these immunoglobulins. TACI-Ig had more efficacy than rhTNFR:Fc in the decrease of CD4(+)CD154(+) T cell. TACI-Ig and Methotrexate also reduced CD4(+)CD69(+) T cell, rhTNFR:Fc had no effects on the T cell subset. TACI-Ig and Methotrexate were superior to rhTNFR:Fc on CD4(+)CD62L(+)T cells. TACI-Ig and Methotrexate could reduce CD19(+)IgD(+) and CD19(+)CD21(+) B cells, but rhTNFR:Fc had no obvious effect on above B cells subsets. TACI-Ig is as effective as rhTNFR:Fc and Methotrexate on CIA mice by ameliorating joint and spleen pathology, regulating T and B lymphocytes function, although different mechanisms among them. This study would be useful for treatment selection of rheumatoid arthritis in different pathological conditions. PMID- 23454556 TI - Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis. AB - The development of hepatocellular carcinomas from malignant hepatocytes is frequently associated with intra- and peritumoral accumulation of connective tissue arising from activated hepatic stellate cells (HSC). Inhibition of receptor tyrosine kinase (RTK) signaling showed promise in the treatment of hepatocellular carcinoma. However, there is a lack of knowledge about the effects of RTK inhibitors on the tumor supportive cells. We performed in vitro experiments to study whether Sunitinib, a platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) RTKs' inhibitor, could block both activated HSC functions and angiogenesis and thus prevent the progression of cirrhotic liver to hepatocellular carcinoma. In immortalized human activated HSC LX-2, treatment with Sunitinib 100 nM blocked collagen synthesis by 47%, as assessed by Sirius Red staining, attenuated HSC contraction by 65%, and reduced cell migration by 28% as evaluated using a Boyden's chamber, without affecting cell viability, measured by Trypan blue staining, and apoptosis, measured by propidium iodide (PI) incorporation assay. Our data revealed that Sunitinib treatment blocked the transdifferentiation of primary human HSC (hHSC) to activated myofibroblast-like cells by 65% without affecting hHSC apoptosis and migration. In in vitro angiogenic assays, Sunitinib 100 nM reduced endothelial cells (EC) ring formation by 46% and tube formation by 68%, and decreased vascular sprouting in aorta ring assay and angiogenesis in vascular bed of chick embryo. In conclusion, the present study demonstrates that the RTK inhibitor Sunitinib blocks the activation of HSC and angiogenesis suggesting its potential as a drug candidate in pathological conditions like liver fibrosis and hepatocellular carcinoma. PMID- 23454557 TI - (-) Epicatechin prevents alterations in lysosomal glycohydrolases, cathepsins and reduces myocardial infarct size in isoproterenol-induced myocardial infarcted rats. AB - The preventive effects of (-) epicatechin on oxidative stress, cardiac mitochondrial damage, altered membrane bound adenosine triphosphatases and minerals were reported previously in isoproterenol-induced myocardial infarction model. Leakage of lysosomal glycohydrolases and cathepsins play an important role in the pathology of myocardial infarction. This study was aimed to evaluate the preventive effects of (-) epicatechin on alterations in lysosomal glycohydrolases, cathepsins and myocardial infarct size in isoproterenol-induced myocardial infarcted rats. Male albino Wistar rats were pretreated with (-) epicatechin (20mg/kg body weight) daily for a period of 21 days. After the pretreatment period, isoproterenol (100mg/kg body weight) was injected subcutaneously into the rats at an interval of 24h for two days to induce myocardial infarction. The levels of serum cardiac troponin-I and the activities of serum and heart lysosomal enzymes (beta-glucuronidase, beta-N-acetyl glucosaminidase, beta-galactosidase, cathepsin-B and cathepsin-D) were increased significantly (P<0.05) and the activities of beta-glucuronidase and cathepsin-D in the heart lysosomal fractions were significantly (P<0.05) decreased in isoproterenol-induced myocardial infarcted rats. The in vitro study revealed the potent antioxidant action of (-) epicatechin. Pretreatment with (-) epicatechin daily for a period of 21 days prevented the leakage of cardiac marker, lysosomal glycohydrolases, cathepsins, and reduced infarct size, thereby protecting the lysosomal membranes in isoproterenol-induced myocardial infarcted rats, by virtue of its membrane stabilizing property. PMID- 23454559 TI - [Is the spleen a "spleen"?]. PMID- 23454558 TI - The anti-oxidant effects are not the main mechanism for glutamine's protective effects on acute kidney injury in mice. AB - Acute kidney injury (AKI) is a common problem characterized by an inflammatory response in the kidney and oxidative stress. However, there are no interventions to prevent AKI. Glutamine is an important precursor of glutathione and has also been shown to induce heat shock proteins (HSP). Thus, glutamine may affect both oxidative stress and inflammation. This study was to explore the effects of glutamine pretreatment on nephrotoxic AKI and to investigate the underlying mechanisms. First, the effects of alternate doses of glutamine were compared in CD-1 mice with AKI induced with folic acid intra-peritoneal injection. Then the effects of glutamine quercetin (an HSP inhibitor), and quercetin+glutamine, were compared in the same AKI model. AKI were assessed with plasma creatinine, urine neutrophil gelatinase-associated lipocalin, and renal histology. Inflammatory response was monitored with renal tumor necrosis factor (TNF-alpha), chemkines (CXCL1 and CCL2) contents, and neutrophil infiltration. Oxidative injury was detected with reduced glutathione, malondialdehyde, and protein thiol. Glutamine provided dose-dependent renal protection. Pretreatment with quercetin, which was showed to inhibit HSP-70 expression, abolished glutamine's renal-protective effects. Quercetin also abrogated glutamine's beneficial effects on renal TNF alpha, chemokines, and neutrophil infiltration. However, quercetin did not affect glutamine's anti-oxidative effects. These results suggest that glutamine's renal protective effects are mainly related to its activation of HSP-70, which mitigates inflammatory response, renal neutrophil infiltration and subsequent AKI. Regulating neutrophil infiltration might be a potential therapeutic target for AKI. PMID- 23454561 TI - [Hypersplenism]. AB - Hypersplenism is characterized by a significant reduction in one or more of the cellular elements of the blood in the presence of normocellular or hypercellular bone marrow and splenomegaly. The incidence of hypersplenism in patients with cirrhosis and portal hypertension is high. In rare cases the hyperslenism is symptomatic with bleeding disorders or hemolytic anemia. In this situation the splenectomy is the therapy of choice. The arterial partial embolisation is a good alternative procedure in patients with high risk of operation. PMID- 23454560 TI - [What is the spleen needed for?]. AB - Although the spleen is not essential for survival, it has important functions such as immune defence, blood filtration, retention and on demand extramedullary hematopoiesis. The white pulp with its T-lymphocytes in perarteriolar lymphoid sheaths and B-lymphocytes in lymphoid follicules is responsible for the detection and removal of circulating pathogens. After splenectomy, this immune defence is missing, which may lead to overwhelming post- splenectomy sepsis by encapsulated bacteria, which has a high mortality rate. In the red pulp, the blood is filtered through narrow slits in the sinusoidal endothelium, which abnormal and senescent erythrocytes can not pass and are eliminated by macrophages. The spleen is, therefore, not a "spleen" of nature, but a sophisticated organ. PMID- 23454562 TI - [The spleen in non-malignant haematological disorders]. AB - The spleen functions as a filter of the circulating blood, removing aging or abnormal red blood cells, intraerythrocyte inclusions as well as foreign particals. As the spleen is composed of lymphocytic tissue, circulatory elements and mononuclear phagocytic cells it plays an important role in the nonspecific as well as the specific immune response. Additionally, the spleen serves as a reservoir for circulating blood cells, especially platelet sequestration by the spleen is well do cumented. The spleen produces blood cells during fetal development and in certain haematological disorders such as myelofibrosis. The destruction of red blood cells within the splenic cords releases iron in the circulation, which is recycled and used to manufacture new erythrocytes in the bone marrow. In several non-malignant haematological disorders antibody-coated cells are cleared from the circulation by phagocytic cells of the spleen. This involves erythrocytes in autoimmunhaemolytic anaemias, platelets in immunthrombocytopenia and neutrophils in Felty syndrome. In hereditary spherocytosis the spleen destroys the resulting defective, spherical red cells. In pyruvate kinase deficiency impaired production of adenosine triphosphate leads to destruction of red blood cells in the spleen or in the liver. In sickle cell anaemia the defective erythrocytes cause sludging and thrombosis in small vessels with infarcts for instance in the spleen, which over time can result in autosplenectomy. In thalassaemia major abnormal haemoglobin forms protein precipitates in the red cells with development of a severe hypochromic anaemia with haemolysis and intramedullary inef fective erythropoiesis. Therapeutic splenectomy can be an option in all of these mentioned non-malignant haematological disorders. The rationale and the pathophysiology of its role in thrombotic thrombocytopenic purpura is probably at least well understood. The use of new and effective drugs such as the monoclonal antibody rituximab or thrombopoietin agonists in immunthrombocytopenia as well as the option of a laparoscopic rather than an open splenectomy have changed our view on benefits and risks of splenectomy in recent years. To minimize these risks such as overwhelming postsplenectomy infection or abdominal vein thrombosis, prophylactic vaccination, postoperative thromboembolism prophylaxis and patient education is mandatory. PMID- 23454563 TI - [The spleen in hematologic malignancies]. AB - The spleen represents a major lymphatic and hematologic organ and, as such, is frequently involved in hematologic malignancies. Splenomegaly may constitute the first clinical sign leading to the diagnosis of a hematologic malignancy. Vice versa, the presence, or suspicion of a hematologic malignancy requires investigation of the spleen. In case of splenomegaly of unknown origin, directed history, clinical examination, and laboratory testing including a complete blood count with microscopic investigation of a peripheral blood smear, frequently allow to establish a tentative diagnosis. Whenever possible, further specific testing should be based on a thorough primary evaluation to avoid unnecessary diagnostic procedures. In light of the current diagnostic options, diagnostic splenectomy can usually be avoided to establish definitive diagnosis. Indolent lymphomas (chronic lymphocytic leukaemia, hairy cell leukaemia, splenic marginal zone lymphoma) and myeloproliferative neoplasms (chronic myeloid leukaemia, polycythemia vera, essential thrombocythemia, primary and secondary myelofibrosis) are the most prevalent hematologic malignancies associated with splenomegaly. Therapeutic options are highly differentiated depending on the underlying disease. Apart from very rare exceptions, therapeutic splenectomy can usually be avoided. PMID- 23454564 TI - [Elective splenectomy in adults - preparation, operation, and postoperative treatment]. AB - Elective splenectomy in adults is often performed after failure of conservative treatment in patients with hematologic, neoplastic, or autoimmune disorders. The indication to perform a splenectomy should be discussed in an interdisciplinary team and the surgeon should not make the decision on his own. Laparoscopic splenectomy is nowadays established as the gold-standard treatment due to low morbidity and mortality and - compared to open surgery - lower postoperative pain, less intraoperative blood loss and shorter hospital stay. Every patient with planned splenectomy must undergo vaccination against pneumococci and meningococci at least two weeks prior to the operation, which helps reducing the risk of the "overwhelming post-splenectomy infection" (OPSI). Beside re vaccination against pneumococci and meningococci during follow-up, every patient should be informed about the increased risk of infection, receive a personal post splenectomy pass and emergency antibiotics in case of infection. PMID- 23454565 TI - [Traumatic splenic injury]. AB - While the management of penetrating as well as blunt splenic injury with hemodynamic instability is straightforward with immediate operative intervention, the management of blunt splenic injury with stable hemodynamic underwent a paradigm shift over the last 3 decades. Nowadays 80 per cent of hemodynamically stable patients with blunt splenic injury can successfully be treated with a non operative management. Angiographic embolization in selected cases is generally reported to increase the success rates of non-operative management currently approaching 95 per cent. PMID- 23454566 TI - [Current practise in splenectomised patients]. AB - Asplenia is found in a very heterogeneous group of patients with a wide range of age and comorbidities. These patients have an increased risk of overwhelming post splenectomy infections (OPSI) even several decades after splenectomy. The mortality rate associated with OPSI is 30 - 60 %, which is why the immunisation against encapsulated bacteria is mandatory. In addition these patients show an increased risk of thrombosis of the portal venous system. In the present article all the necessary, during daily practice often neglected preventive measures and behavioural rules are discussed. PMID- 23454567 TI - Unfulfilled translation opportunities in industry sponsored clinical trials. AB - Knowledge generated by site representatives through their participation in clinical trials is valuable for testing new products in use and obtaining final market approval. The leverage of this important knowledge is however challenged as the former direct relationships between in-house staff in the industry and site representatives are changing. The process of clinical trials has increased in complexity over the years, resulting in additional management layers. Besides an increase in internal management layers, sponsors often also outsource various tasks related to clinical trials to a CRO (Contract Research Organization) and thereby adding another link in the relationships between site and sponsor. These changes are intended to optimize the time-consuming and costly trial phases; however, there is a need to study whether valuable knowledge and experience is compromised in the process. Limited research exists on the full range of clinical practice insights obtained by investigators during and after clinical trials and how well these insights are transferred to study sponsors. This study explores the important knowledge-transfer processes between sites and sponsors and to what extent sites' knowledge gained in clinical trials is utilized by the industry. Responses from 451 global investigative site representatives are included in the study. The analysis of the extensive dataset reveals that the current processes of collaboration between sites and the industry restrict the leverage of valuable knowledge gained by physicians in the process of clinical trials. These restrictions to knowledge-transfer between site and sponsor are further challenged if CRO partners are integrated in the trial process. PMID- 23454568 TI - Thermal reaction: the spread of bisphenol S via paper products. PMID- 23454569 TI - Picture novelty attenuates semantic interference and modulates concomitant neural activity in the anterior cingulate cortex and the locus coeruleus. AB - Goal-directed behavior requires the ability to focus on information that is relevant to a given task and to ignore information that might interfere with it. In the Stroop task, for example, the influence of an irrelevant word needs to be overcome, which is believed to be difficult because it arises in a fast and automatic fashion, which effectively renders it very salient. Here we address the question of whether this can be counteracted by increasing the saliency of the task-relevant input, for example by modulating its relative novelty, which increases saliency in a fairly implicit and controlled fashion. To test the influence of novelty on interference processing, we employed a picture-word interference task in the fMRI scanner, in which we manipulated the novelty of the task-relevant picture. We found that picture novelty indeed reduced typical behavioral interference from incongruent words. Moreover, familiar incongruent trials were associated with activity increases in the anterior cingulate cortex (ACC), a prime conflict-processing region, as well as in the noradrenergic locus coeruleus (LC), which entertains connections both to and from the ACC. The lack of analogous activations in novel incongruent trials suggests that the reduction of behavioral interference was not related to enhanced conflict-resolution processes, but rather to the automatic prioritization of novel pictures which appears to avert the influence of irrelevant words at the front end. Interestingly, activity in the ACC and LC was slightly stronger in novel congruent trials compared to incongruent ones, which may reflect increased relevance of novel stimuli when encoded in a congruent context. In summary, the present data demonstrate that stimulus novelty clearly reduces semantic interference, and highlights a complex interaction of interference and novelty processing on the neural level, including an involvement of the noradrenergic system in the processing of cognitively and perceptually salient events. PMID- 23454570 TI - Identification of organic xenobiotics in urban aquatic environments using time-of flight mass spectrometry. AB - Qualitative non-target and post-target analysis methods using gas chromatography time-of-flight mass spectrometry were applied for analysing neutral and acidic organic xenobiotics in urban and suburban water samples. Ten water samples representing wastewater, stormwater and surface water matrices were collected and concentrated using solid phase extraction. Compound identification was performed using a spectral deconvolution program, accurate mass measurements and comparisons with library spectra. The non-target and post-target analyses identified 36 and 18 compounds, respectively. The identification of 10 compounds was afterwards confirmed with standard compounds. Organophosphate esters were the most abundant compound group detected. The combination of non-target and post target analyses proved a useful tool in the tentative identification of xenobiotics in water samples. Post-target analysis can complement non-target analysis results at low analyte concentrations. Results showed that several organic xenobiotics originate in urban areas and accumulate in the environment. The wastewater sample produced the highest number of identified compounds, but most of these compounds were also found in stormwater samples from the city centre. Nearly all the compounds present in wastewater were additionally detected in the surface water sample taken 3 km downstream from the wastewater effluent discharge point. Only a few xenobiotics were otherwise detected in the surface water samples. PMID- 23454571 TI - Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area. AB - Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. PMID- 23454572 TI - Identification of hydrocarbon sources in contaminated soils of three industrial areas. AB - The present paper deals with identification of hydrocarbon sources in contaminated soil of three tank farms located in north, central and south Italy. Parent polycyclic aromatic hydrocarbons (naphthalene through benzo(g,h,i)perylene) and n-alkanes (n-C10 through n-C36) were determined. The study of source assignments was carried out by their distribution patterns, their diagnostic ratios, and determination of less-commonly used markers. The data show anthropogenic and biogenic origin of n-alkanes and petrogenic and pyrolytic sources of PAHs. Multiple sources of hydrocarbons, that were not considered in the preliminary environmental assessments, are identified. The application of a multi-criteria approach allows to locate petroleum pollution sources that affect the study sites. The results demonstrate that the application of a multi-criteria approach for source identification is a key point to assess environmental damage and prove that an accurate study of source identification has to be performed. The suggested methodology is a useful tool to manage contaminated sites and to plan appropriate interventions of clean up. PMID- 23454573 TI - Dual asymmetric centrifugation as an alternative preparation method for parenteral fat emulsions in preformulation development. AB - Nanoscaled fat emulsions are well established as a drug delivery system for lipophilic drugs and for the use in parenteral nutrition. Typically, the production of nanoscaled fat emulsions requires several formulation steps, including high pressure homogenization and filtration. The applicability of dual asymmetric centrifugation as an alternative technique to produce submicron fat emulsions in a short and easy way was investigated. The emulsions could be prepared without substance loss in a closed system within 30 min. Formulations with 10% soybean oil and up to 5% emulsifier-mixture were produced. The droplet size distribution was determined by static light scattering. Stability over six months was shown by regular static light scattering measurements and determination of the zeta potential. Furthermore, hemolytic activity of the samples was investigated. With the dual asymmetric centrifugation physiological tolerable emulsions with droplets in the lower micron and submicron range could be prepared. This method could be used as a model for screening active pharmaceutical ingredients. PMID- 23454574 TI - Analytical distance distributions in systems of spherical symmetry with applications to double electron-electron resonance. AB - Based on a simple geometrical approach, we derive analytical expression of the probability density functions (pdfs) of distance of probe molecules distributed homogeneously in spherical aggregates with shell structure. These distance distributions can be utilized in the investigation of double electron-electron resonance (DEER) data of disordered nanometer-sized spin clusters. Structural insights and geometrical parameters of the aggregates can be extracted by modeling the DEER time traces based on the analytical pdfs. This approach is efficient and avoids difficulties of the model-free solution of the inverse problem that are related to multi-spin effects, limited excitation bandwidth, bias introduced by the regularization scheme, or ambiguity resulting from broad distance distributions. The derived pdfs can serve as building blocks, from which the distance distributions in arbitrary spherically symmetric objects can be assembled. The scenario of the pumped species being chemically distinct from the observed species is covered as well as that of a single type of probe molecules. We demonstrate the merits of analytical distance distributions by studying the distribution of three different spin probes in SDS micelles. By simultaneously analyzing DEER data corresponding to different spin probe concentrations, the distribution of the spin probes over the micelle can be determined. Employing Bayesian inference it is found that for all probes studied, a spherical shell model is most appropriate among the studied models and by orders of magnitude more likely than a homogeneous distribution in a ball. This statement also applies to probes that are deemed nonpolar. We envisage that the spin probe distributions in disordered soft and hard matter systems can now be quantified using DEER spectroscopy with greater precision and reduced ambiguity. PMID- 23454575 TI - Broadband CPMG sequence with short composite refocusing pulses. AB - We demonstrate that CPMG sequences with phase-modulated refocusing pulses of the same duration as the standard 180 degrees pulses can generate echo trains with significantly increased amplitudes compared to the standard CPMG sequence in the case when there is a large range of Larmor frequencies across the sample. The best performance is achieved with symmetric phase-alternating (SPA) composite refocusing pulses of the form alpha-ybeta+yalpha-y. In comparison to standard 180 degrees pulses, we show that with SPA refocusing pulses with alpha~27 degrees and beta~126 degrees , it is possible to double the signal-to-noise ratio without increasing the total pulse duration or power consumption of the refocusing pulses. The increased bandwidth of these pulses more than compensates for the decrease in performance in the vicinity of resonance. To achieve the full benefit of the broadband nature of the SPA pulses in a CPMG sequence, it is necessary to combine these refocusing pulses with a broadband excitation pulse. When it is not possible to use a short, high amplitude excitation pulse, we show that phase alternating (PA) excitation pulses are suitable for this purpose. We present a detailed analysis of the underlying spin dynamics of these new pulse sequences and confirm the simulations with experiments. We show that for samples with T1/T2>1, the new sequences in grossly inhomogeneous fields do not only generate echoes with an increased amplitude, but also with an increased decay time. Finally, we analyze the diffusion properties and show quantitatively that the broadband sequences have a substantially higher diffusion sensitivity compared with the standard CPMG sequence. PMID- 23454576 TI - Design of non-selective refocusing pulses with phase-free rotation axis by gradient ascent pulse engineering algorithm in parallel transmission at 7T. AB - At ultra-high magnetic field (>= 7T), B1 and DeltaB0 non-uniformities cause undesired inhomogeneities in image signal and contrast. Tailored radiofrequency pulses exploiting parallel transmission have been shown to mitigate these phenomena. However, the design of large flip angle excitations, a prerequisite for many clinical applications, remains challenging due the non-linearity of the Bloch equation. In this work, we explore the potential of gradient ascent pulse engineering to design non-selective spin-echo refocusing pulses that simultaneously mitigate severe B1 and DeltaB0 non-uniformities. The originality of the method lays in the optimization of the rotation matrices themselves as opposed to magnetization states. Consequently, the commonly used linear class of large tip angle approximation can be eliminated from the optimization procedure. This approach, combined with optimal control, provides additional degrees of freedom by relaxing the phase constraint on the rotation axis, and allows the derivative of the performance criterion to be found analytically. The method was experimentally validated on an 8-channel transmit array at 7T, using a water phantom with B1 and DeltaB0 inhomogeneities similar to those encountered in the human brain. For the first time in MRI, the rotation matrix itself on every voxel was measured by using Quantum Process Tomography. The results are complemented with a series of spin-echo measurements comparing the proposed method against commonly used alternatives. Both experiments confirm very good performance, while simultaneously maintaining a low energy deposition and pulse duration compared to well-known adiabatic solutions. PMID- 23454577 TI - Superconducting microstrip resonator for pulsed ESR of thin films. AB - This article describes a superconducting microstrip resonator operating at 9.5 GHz (X-band) that is specially designed for pulsed ESR on thin films. A novel configuration consisting of an array of half-wave length microstrip transmission lines generates a uniform magnetic field over a 2-D region of 100*1000 MUm(2) with field homogeneity better than 5*10(-2). Using the device, we demonstrate strong coupling of the resonator to an electron spin ensemble and pulsed ESR on Si:P. PMID- 23454578 TI - Matrix-algebra-based calculations of the time evolution of the binary spin-bath model for magnetization transfer. AB - Quantification of magnetization-transfer (MT) experiments are typically based on the assumption of the binary spin-bath model. This model allows for the extraction of up to six parameters (relative pool sizes, relaxation times, and exchange rate constants) for the characterization of macromolecules, which are coupled via exchange processes to the water in tissues. Here, an approach is presented for estimating MT parameters acquired with arbitrary saturation schemes and imaging pulse sequences. It uses matrix algebra to solve the Bloch-McConnell equations without unwarranted simplifications, such as assuming steady-state conditions for pulsed saturation schemes or neglecting imaging pulses. The algorithm achieves sufficient efficiency for voxel-by-voxel MT parameter estimations by using a polynomial interpolation technique. Simulations, as well as experiments in agar gels with continuous-wave and pulsed MT preparation, were performed for validation and for assessing approximations in previous modeling approaches. In vivo experiments in the normal human brain yielded results that were consistent with published data. PMID- 23454579 TI - Direct observation of 17O-185/187Re 1J-coupling in perrhenates by solid-state 17O VT MAS NMR: temperature and self-decoupling effects. AB - (17)O MAS NMR spectra recorded at 14.1T and room temperature (RT) for (17)O enriched samples of the two perrhenates, KReO4 and NH4ReO4, exhibit very similar overall appearances of the manifold of spinning sidebands (ssbs) for the satellite transitions (STs) and the central transition (CT). These overall appearances of the spectra are easily simulated in terms of the usual quadrupole coupling and chemical shift interaction parameters. However, a detailed inspection of the line shapes for the individual ssbs of the STs and, in particular, for the CT in the spectrum of KReO4 reveals line-shape features, which to our knowledge have not before been observed experimentally in 1D MAS NMR spectra for any quadrupolar nucleus, nor emerged from simulations for any combination of second-order quadrupolar interaction and chemical shift anisotropy. In contrast, such line-shape features are not observed for the corresponding ssbs (STs and CT) in the 14.1T RT (17)O MAS NMR spectrum of NH4ReO4. Considering the additional interaction of a combination of residual heteronuclear (17)O-(185/)(187)Re dipolar and scalar J coupling between this spin pair of two quadrupolar nuclei, spectral simulations for KReO4 show that these interactions are able to account for the observed line shapes, although the expected (1)J((17)O-(185/)(187)Re) six-line spin-spin splittings are not resolved. Low-temperature, high-field (21.1T) (17)O VT MAS NMR spectra of both KReO4 and NH4ReO4 show that full resolution into six-line multiplets for the centerbands are achieved at -90 degrees C and -138 degrees C, respectively. This allows determination of (1)J((17)O-(187)Re)=-268Hz and -278Hz for KReO4 and NH4ReO4, respectively, i.e., an isotropic (1)J coupling and its sign between two quadrupolar nuclei, observed for the first time directly from solid-state one pulse 1D MAS NMR spectra, without resort to additional 1D or 2D experiments. Determination of T1((187)Re) spin-lattice relaxation times, observed indirectly through a 2D (17)O EXSY experiment for NH4ReO4 at several low temperatures, show that the dynamics observed for the ReO4(-) anion in the (17)O VT MAS NMR spectra at low temperatures are caused by self-decoupling of (1)J((17)O-(187)Re). The (1)J((17)O-(187)Re) values determined here for ReO4(-) from solid-state (17)O MAS NMR, along with literature (1)J((17)O-M) values for oxoanions (M being a quadrupolar nucleus) obtained from liquid-state NMR, have allowed correlations to be established between the reduced coupling constant (1)K((17)O-M)=2pi(1)J((17)O M)/(gamma17OgammaMh) and the atomic number of M. PMID- 23454580 TI - Multi-Frame SPRITE: a method for resolution enhancement of multiple-point SPRITE data. AB - The Single Point Ramped Imaging with T1 Enhancement (SPRITE) sequence is well suited for the acquisition of magnetic resonance signals from fast relaxing nuclei and from heterogeneous materials. However, it is time inefficient compared to sequences that are based on frequency encoding because only one single point is acquired per excitation. Multiple-point SPRITE (mSPRITE) mitigates this problem with the acquisition of multiple FID points. mSPRITE images reconstructed from early FID samples suffer from reduced spatial resolution due to the limited extent of its corresponding k-space. In this work we present a new reconstruction algorithm for spatial resolution enhancement that solves this problem without changes to the mSPRITE sequence. The method, called Multi-Frame mSPRITE, substitutes high spatial frequencies from late FID points into k-spaces of limited extent constructed from early FID points. In this way, images of high quality and resolution can be obtained despite a large range of zoom factors used to reconstruct images with the same FOV and resolution. PMID- 23454581 TI - Molecular analysis of a conditional hal3 vhs3 yeast mutant links potassium homeostasis with flocculation and invasiveness. AB - Yeast flocculation and invasive growth are processes of great interest in fundamental biology and also relevant in biotechnology and medicine. Hal3 and Vhs3 are moonlighting proteins acting in Saccharomyces cerevisiae both as inhibitors of the Ppz protein phosphatases and as components of a catalytic step in CoA biosynthesis. The double hal3 vhs3 mutant is not viable but, under semi permissive conditions, the tetO:HAL3 vhs3 strain shows a flocculent phenotype, invasive growth and increased expression of the flocculin-encoding FLO11 gene. We show here that all these effects are caused by hyperactivation of Ppz1 as a result of depletion of its natural inhibitors. The evidence indicates that hyperactivation of Ppz1 would impair potassium transport through the Trk1/Trk2 transporters, thus resulting in a decrease in the intracellular pH and a subsequent increase in the levels of cAMP. Mutation of the TPK2 isoform of protein kinase A blocks the increase in FLO11 expression, and eliminates the flocculent and invasive phenotypes produced by depletion of Hal3 and Vhs3. Interestingly, mutation of RIM101 also significantly decreases FLO11 expression under these conditions. Cells lacking Trk1,2 display an invasive phenotype that is abolished by deletion of FLO8 or by increasing the potassium concentration in the medium. Therefore, our results support a model in which hyperactivation of Ppz phosphatases would result in alteration of potassium transport, activation of Tpk2 and signaling to the FLO11 promoter by means of the Flo8 transcription factor, thus modulating flocculation and invasive growth. This model highlights an unsuspected link between potassium homeostasis and these important morphogenetic events. PMID- 23454582 TI - Bacterial lipopolysaccharides stimulate production of XCL1, a calcium-dependent lipopolysaccharide-binding serum lectin, in Xenopus laevis. AB - Xenopus laevis serum lectin XCL1 is a newly identified molecule of the XCGL (or X lectin) family, a unique group of Ca(2+)-dependent lectins that have a fibrinogen like domain. The XCL1 protein was purified from lipopolysaccharide (LPS) stimulated frog sera by sequential affinity chromatography on heparin-acrylic beads and galactose-Sepharose. XCL1 comprises multiple oligomeric proteins consisting of 37-kDa subunit polypeptides, as revealed by sodium dodecyl sulfate polyacrylamide electrophoresis (SDS-PAGE) and Western blot analyses using the monoclonal antibody (mAb) produced against the recombinant XCL1 polypeptide. In the presence of Ca(2+), the protein bound to Escherichia coli, Staphylococcus aureus, LPS and galactose and the bound XCL1 was competitively eluted using ribose and xylose, and the elution was as efficient as that using EDTA, whereas elution using hexoses, GalNAc or GlcNAc was less effective. In reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses, XCL1 expression was ubiquitously detected in frog tissues, with relatively high levels in hematopoietic tissues including the spleen, liver and kidney. Intraperitoneal injection of E. coli, S. aureus or 100-300MUg S-type LPS from various bacteria induced several-fold increases in serum XCL1 concentrations on day 3, and the elevated levels retained up to day 12. It also caused a remarkable increase of the splenic XCL1 expression on day 3, followed by a rapid decline to nearly nonstimulated control levels by day 7. The R-type LPS with shortened polysaccharide chains was less effective in inducing the serum XCL1 response, indicating that the sugar chains of LPS were important, if not essential, for the stimulation of XCL1 production. These results suggest that XCL1 is a pathogen recognition molecule involved in antimicrobial innate immunity in Xenopus. PMID- 23454583 TI - Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas. AB - MicroRNAs (miRNAs) are endogenous, non-coding RNA transcripts that regulate gene expression. Here, we report 175 putative novel miRNAs identified in uterine cancers profiled by Next Generation Sequencing. Our data indicate that one of these putative miRNAs (BCM-173) is conserved across multiple species and is expressed at levels similar to known human miRNAs. Functionally, this miRNA promotes the growth and migration of uterine cancer cell lines by targeting vinculin and altering the distribution of focal adhesions. These results expand our insight into the repertoire of human miRNAs and identify novel pathways by which dysregulated miRNA expression promotes uterine cancer growth. PMID- 23454584 TI - Death of multiple myeloma cells induced by cAMP-signaling involves downregulation of Mcl-1 via the JAK/STAT pathway. AB - There is a continuous search for new therapeutic targets for treatment of multiple myeloma (MM). Here we investigated the mechanisms involved in cAMP induced apoptosis of human MM cells. cAMP-increasing agents rapidly inhibited activation of JAK1 and its substrate STAT3. In line with STAT3 being a regulator of Mcl-1 transcription, the expression of this pro-survival factor was rapidly and selectively reduced. Notably, exogenous interleukin-6 neither prevented the inhibition of JAK1/STAT3 nor the death of MM cells induced by cAMP. Our results suggest that cAMP-mediated killing of MM cells involves inhibition of the JAK/STAT pathway, making the cAMP-pathway a promising target for treatment of MM. PMID- 23454585 TI - Metabolomic changes in follicular fluid induced by soy isoflavones administered to rats from weaning until sexual maturity. AB - Female Wistar rats at 21 days of age were treated with one of three concentrations of soy isoflavones (SIF) (50, 100 or 200mg/kg body weight, orally, once per day) from weaning until sexual maturity (3 months) in order to evaluate the influence of SIF on ovarian follicle development. After treatment, the serum sex hormone levels and enumeration of ovarian follicles of the ovary were measured. The metabolic profile of follicular fluid was determined using HPLC-MS. Principal component analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) was used to identify differences in metabolites and reveal useful toxic biomarkers. The results indicated that modest doses of SIF affect ovarian follicle development, as demonstrated by decreased serum estradiol levels and increases in both ovarian follicle atresia and corpora lutea number in the ovary. SIF treatment-related metabolic alterations in follicular fluid were also found in the PCA and PLS-DA models. The 24 most significantly altered metabolites were identified, including primary sex hormones, amino acids, fatty acids and metabolites involved in energy metabolism. These findings may indicate that soy isoflavones affect ovarian follicle development by inducing metabolomic variations in the follicular fluid. PMID- 23454587 TI - Relating selenium concentrations in a planktivore to selenium speciation in lakewater. AB - We measured selenium (Se) speciation in the waters of 16 lakes located near two major metal smelters and compared it to Se concentrations in a potential biomonitor, the planktivorous insect Chaoborus. We used this sentinel because planktonic algae and crustaceans, which are lower in the trophic chain leading to Chaoborus, are more difficult to separate and identify to species, whereas many fish species are not obligate planktivores. Percentages of selenate and organo-Se were generally higher in acidic lakes, whereas those of selenite were usually greater in alkaline waters. Chaoborus Se concentrations varied widely among lakes and, with the exception of a single high-sulfate lake, were significantly and highly correlated with those of dissolved organo-Se plus selenate (Se(VI)). We suggest that Chaoborus larvae would be highly effective for monitoring the Se exposure of planktonic food webs in lakes. PMID- 23454586 TI - TNF-alpha disrupts morphologic and functional barrier properties of polarized retinal pigment epithelium. AB - Retinal pigment epithelial (RPE) cells form a blood-ocular barrier, and their polarized property is crucial for maintaining the barrier functions. Tumor necrosis factor alpha (TNF-alpha), a major pleotropic inflammatory cytokine that disrupts the barrier function and eventual angiogenesis, is expressed in the choroidal neovascularizations of age-related macular degeneration eyes. Thus, it most likely plays an important role in the progression of the disease. The purpose of this study was to compare the effects of TNF-alpha on the barrier function of polarized RPE cells. Non-polarized RPE cells were used as negative controls. Isolated porcine RPE cells were seeded on TranswellTM membranes. The polarization of the RPE cells was determined by their high transepithelial electrical resistance (TER >150 Omega cm(2)) and by their differential secretion of vascular endothelial growth factor (lower layer/upper layer >2.5X). Polarized RPE cells were incubated with 10 ng/ml of TNF-alpha and the TER was measured. TNF alpha significantly decreased the TER of polarized RPE cells by 17.6 +/- 2.7% (P < 0.001) of the control at 24 h and that of non-polarized RPE cells by 5.4 +/- 6.5% (P = 0.401). The p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked the effects of TNF-alpha of decreasing the TER. Cell junction related molecules, e.g., ZO-1, located between cells in control RPE cells, were disassembled by TNF-alpha, and this breakdown was suppressed by SB203580 in polarized RPEs. These results indicate that the breakdown of the RPE barrier function was caused exclusively by TNF-alpha in polarized RPEs, and TNF-alpha was acting through the p38 MAPK pathways. Investigations of polarized RPE cells should be more suitable for in vitro studies of the pathophysiology of retinochoroidal diseases. PMID- 23454588 TI - Occurrence of zebra mussel parasites: modelling according to contamination in France and the USA. AB - Parasites can be reliable tool in assessing the effects of ecosystem disturbances. However, they can respond in different ways and any changes in assemblages are not easily predictable. Descriptive modelling could be a first step since providing information on the relative importance of a pollutant on parasite occurrence. We chose the zebra mussel, as test organism and twelve sites in France and the United States. Contaminants had not the same impact on microparasite occurrence. Metals enhanced the infection, except zinc associated only with higher prevalence of the commensal ciliate Conchophthirus acuminatus. We should note that Rickettsiales-like organism infection is higher at higher Ni and Cr concentrations. Models indicated also that the most polluted sites were also those with higher rates of co-infections. Therefore, the continuous contamination of freshwater ecosystems implies a significant risk promoting the development of parasites that may affect bivalve populations and other species belonging to their life-cycle. PMID- 23454589 TI - Aluminum sulfate (alum) application interactions with coupled metal and nutrient cycling in a hypereutrophic lake ecosystem. AB - Many lake ecosystems worldwide experience severe eutrophication and associated harmful blooms of cyanobacteria due to high loadings of phosphorus (P). While aluminum sulfate (alum) has been used for decades as chemical treatment of eutrophic waters, the ecological effects of alum on coupled metal and nutrient cycling are not well known. The objective of our study was to investigate the effects of an in-situ alum treatment on aluminum and nutrient (P, N, and S) cycling in a hypereutrophic lake ecosystem. Our results indicate that the addition of alum along with sodium aluminate (as a buffer) increased dissolved aluminum and sulfate in the surface and pore waters, and altered nitrogen cycling by increasing nitrous oxide (N2O) concentrations in the surface water. The increase of aluminum and sulfate may potentially feedback to alter benthic community dynamics. These results enhance our understanding of the unintended ecological consequences of alum treatments in hypereutrophic freshwater ecosystems. PMID- 23454590 TI - Discharge of landfill leachate to streambed sediments impacts the mineralization potential of phenoxy acid herbicides depending on the initial abundance of tfdA gene classes. AB - To understand the role of abundance of tfdA gene classes belonging to beta- and gamma-proteobacteria on phenoxy acid herbicide degradation, streambed sediments were sampled around three seepage meters (SMs) installed in a landfill-impacted groundwater-surface water interface. Highest herbicide mass discharge to SM3, and lower herbicide mass discharges to SM1 and SM2 were determined due to groundwater discharge rates and herbicide concentrations. SM1-sediment with the lowest abundance of tfdA gene classes had the slowest mineralization, whereas SM2- and SM3-sediments with more abundant tfdA genes had faster mineralization. The observed difference in mineralization rates between discharge zones was simulated by a Monod-based kinetic model, which confirmed the role of abundance of tfdA gene classes. This study suggests presence of specific degraders adapted to slow growth rate and high yield strategy due to long-term herbicide exposure; and thus groundwater-surface water interface could act as a natural biological filter and protect stream water quality. PMID- 23454591 TI - Molecular biomarkers for sources of organic matter in lacustrine sediments in a subtropical lake in China. AB - N-alkanes distributions and stable isotopic compositions (delta(13)C and delta(15)N) in the lacustrine sediments of Shijiu lake were measured to assess whether biological source information was recorded in the molecular biomarker. Results showed regular unimodal n-alkanes distribution in range of C16-C33 with strong predominance of odd-numbered n-alkanes, maximizing at C29. The delta(15)N for SON were uniformly low, ranging from -6.70/00 to 3.80/00 and C/N ratios ranged from 6.6 to 10.0, suggesting that most of organic matter was influenced by terrestrial characteristics of the watershed. The delta(13)C for C27 to C31n alkanes and for SOC varied from -32.90/00 to -26.60/00 and -23.40/00 to 21.60/00, respectively, falling within the range of corresponding n-alkanes in leaves mainly from C3 land plants. The values of C/N, CPI, OEP, ACL and C27/C31 exhibit similar temporal changes with the primary production, showing enhanced eutrophication resulted from increased anthropogenic activities in Shijiu lake from 1852 to 2010. PMID- 23454593 TI - Glucosamine inhibits lipopolysaccharide-stimulated inducible nitric oxide synthase induction by inhibiting expression of NF-kappaB/Rel proteins at the mRNA and protein levels. AB - Expression of inducible nitric oxide synthase (iNOS) protein by lipopolysaccharide (LPS) in BV2 microglia cells increased in a biphasic manner. Glucosamine (GlcN) selectively suppressed the late- but not early-stage iNOS response to LPS. Prolonged induction of iNOS expression by LPS was inhibited by cycloheximide, suggesting that de novo protein synthesis was required. Late-phase activation of nuclear factor-kappaB (NF-kappaB) activity required for sustained iNOS induction. Nuclear translocation and DNA binding of NF-kappaB, and Rel proteins expressions were inhibited by GlcN at later time points but not upon immediate early-stage activation by LPS. We show that GlcN selectively inhibits sustained iNOS induction by inhibiting Rel protein expression at both the mRNA and protein levels; such expression is required for prolonged iNOS induction by LPS. Our results provide mechanistic evidence that GlcN regulates inflammation, represented by iNOS. The implication of these results is that GlcN may be a potent transcriptional regulator of iNOS and other genes involved in the general inflammation process. PMID- 23454592 TI - Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: insights regarding where, when and how. AB - Numerous inflammatory disorders are associated with elevated levels of xanthine oxidoreductase (XOR) and allied enhancement of reactive species formation contributory to systemic pathology. Despite a long standing association between increased XOR activity and negative clinical outcomes, recent reports describe a paradigm shift where XOR mediates beneficial actions by catalyzing the reduction of NO2(-) to NO. While provocative, these observations contradict reports of improved outcomes in similar models upon XOR inhibition as well as reports revealing strict anoxia as a requisite for XOR-mediated NO formation. To garner a more clear understanding of conditions necessary for in vivo XOR-catalyzed NO production, this review critically analyzes the impact of O2 tension, pH, substrate concentrations, glycoaminoglycan docking and inhibition strategies on the nitrite reductase activity of XOR and reveals a hypoxic milieu where this process may be operative. As such, information herein serves to link recent reports in which XOR activity has been identified as mediating the beneficial outcomes resulting from nitrite supplementation to a microenvironmental setting where XOR can serve as substantial source of NO. PMID- 23454594 TI - Temporal memory averaging and post-encoding alterations in temporal expectation. AB - Recent work in our lab has demonstrated that rats trained to associate two different reinforcement delays with two different cues will generate a scalar temporal expectation at a time between these delays when presented with the cue compound. This work demonstrates that rats will integrate distinct temporal memories at retrieval, revealing that temporal expectation need not be a veridical representation of experience. Following from this recognition that processes occurring at or after memory retrieval may transform or bias temporal expectations, we suggest that previous pharmacological work that had been interpreted as resulting from sensorial, or clock-speed, changes, may be alternatively interpreted as resulting from mnemonic alterations. We end with a brief review of the impact of post-encoding alterations of memory on behavior other than timing. PMID- 23454595 TI - Is obesity still increasing among pregnant women? Prepregnancy obesity trends in 20 states, 2003-2009. AB - OBJECTIVE: To estimate trends in prepregnancy obesity prevalence among women who delivered live births in the US during 2003-2009, by state, age, and race ethnicity. METHODS: We used Pregnancy Risk Assessment Monitoring System (PRAMS) data from 2003, 2006, and 2009 to measure prepregnancy obesity (body mass index [BMI]>=30kg/m(2)) trends in 20 states. Trend analysis included 90,774 records from 20 US states with data for all 3 study years. We used a chi-square test for trend to determine the significance of actual and standardized trends, standardized to the age and race-ethnicity distribution of the 2003 sample. RESULTS: Prepregnancy obesity prevalence increased by an average of 0.5 percentage points per year, from 17.6% in 2003 to 20.5% in 2009 (P<0.001). Obesity increased among women aged 20-24 (P<0.001), 30-34 (P=0.001) and 35 years or older (P=0.003), and among non-Hispanic white (P<.001), non-Hispanic black (P=0.02), Hispanic (P=0.01), and other women (P=0.03). CONCLUSION: Overall, prepregnancy obesity prevalence continues to increase and varies by race ethnicity and maternal age. These findings highlight the need to address obesity as a key component of preconception care, particularly among high-risk groups. PMID- 23454597 TI - Impact of applied progressive deep muscle relaxation training on the health related quality of life among prostate cancer patients--a quasi experimental trial. AB - PURPOSE: To determine the impact of applied progressive muscle relaxation training on health related quality of life among prostate cancer patients. METHOD: A quasi-experimental study was conducted at the University Malaya Medical Centre (UMMC) and Universiti Kebangsaan Malaysia Medical Centre (UKMMC) over six months. Patients from UMMC received the intervention and patients from UKMMC as a comparison group. The general health related quality of life was measured using Short Form-36 (SF-36). RESULTS: A total of 77 patients from the intervention group and 78 patients from the comparison group participated in the study. At the end of the study, only 90.9% in intervention group and 87.2% in comparison group completed the study. There were significant differences between intervention and comparison groups for mental component summary (MCS) (p=0.032) and overall health related quality of life (p=0.042) scores. However, there was no significant difference between groups for physical component summary (PCS) (p=0.965). CONCLUSION: The improvement in MCS and overall QOL showed the potential of APMRT in the management of prostate cancer patients. Future studies should be carried out over a longer duration to provide stronger evidence for the introduction of relaxation therapy among prostate cancer patients as a coping strategy to improve their QOL. PMID- 23454596 TI - Educational interventions in childhood obesity: a systematic review with meta analysis of randomized clinical trials. AB - OBJECTIVE: To assess the effectiveness of educational interventions including behavioral modification, nutrition and physical activity to prevent or treat childhood obesity through a systematic review and meta-analysis of randomized trials. METHOD: A search of databases (PubMed, EMBASE and Cochrane CENTRAL) and references of published studies (from inception until May 2012) was conducted. Eligible studies were randomized trials enrolling children 6 to 12 years old and assessing the impact of educational interventions during 6 months or longer on waist circumference, body mass index (BMI), blood pressure and lipid profile to prevent or treat childhood obesity. Calculations were performed using a random effects method and pooled-effect estimates were obtained using the final values. RESULTS: Of 22.852 articles retrieved, 26 trials (23.617 participants) were included. There were no differences in outcomes assessed in prevention studies. However, in treatment studies, educational interventions were associated with a significant reduction in waist circumference [-3.21 cm (95%CI -6.34, -0.07)], BMI [-0.86 kg/m(2) (95%CI -1.59, -0.14)] and diastolic blood pressure [-3.68 mmHg (95%CI -5.48, -1.88)]. CONCLUSIONS: Educational interventions are effective in treatment, but not prevention, of childhood obesity and its consequences. PMID- 23454598 TI - Identification of a 14 kDa endocan fragment generated by cathepsin G, a novel circulating biomarker in patients with sepsis. AB - Severe septic syndrome, which is the most prevalent and lethal cause of acute respiratory distress syndrome, remains one of the most frequent causes of admission and death in intensive care units (ICU). Inflammatory phenomenon leading to severe sepsis are multiple and not yet completely understood. The main target damage during severe sepsis is the endothelium. Endocan, specifically secreted by activated-pulmonary vascular endothelial cells, is thought to play a key role in the control of the lung inflammatory reaction. A recent clinical investigation found that a low plasma endocan level was predictive of respiratory failure. In this study, the hypothesis that low levels of endocan may result from proteolysis was tested. We demonstrate that cathepsin G (CG), neutrophil elastase (NE), and to a lesser extent proteinase 3 (PR3), degrade endocan. Interestingly, a novel endocan peptide fragment of 14 kDa, named p14, was identified, resulting from the specific cleavage of endocan by CG, corresponding to the N-terminal 111 116 amino acids of the endocan polypeptide. An immunoassay specific for p14 endocan fragment was then developed, and revealed increased plasma levels of p14 in 20 out of 55 severe septic patients, ranging from 0.52 to 10.40 ng/mL versus undetectable p14 in plasma from 32 control subjects (p=0.0011). No correlations were found between p14 and endocan blood levels in severe septic patients. Taken together, the p14 endocan fragment represents a novel interesting biomarker which could participate to the pathogenesis of sepsis. PMID- 23454599 TI - Using an innovative Quality-by-Design approach for development of a stability indicating UHPLC method for ebastine in the API and pharmaceutical formulations. AB - A stability-indicating ultra high performance liquid chromatographic (UHPLC) method has been developed for purity testing of ebastine and its pharmaceutical formulations. Successful chromatographic separation of the API from impurities was achieved on a Waters Acquity UPLC BEH C18, 50 mm * 2.1 mm, 1.7 MUm particle size column with gradient elution of 10 mM acetate buffer pH 6.2 and a mixture of acetonitrile/2-propanol (1:1) as the mobile phase. Incorporating Quality by Design (QbD) principles to the method development approach by using the chromatography modeling software DryLab4 allows the visualization of a "Design Space", a region in which changes to method parameters will not significantly affect the results as defined in the ICH guideline Q8 (R2). A verification study demonstrated that the established model for Design Space is accurate with a relative error of prediction of only 0.6%. The method was fully validated for specificity, linearity, accuracy and precision, and robustness in compliance to the ICH guideline Q2 (R1). The method was found to be linear in the concentration range from the quantification limit (LOQ) to 125% of the specification limit for ebastine and each of the impurities with correlation coefficients of not less than 0.999. The recovery rate was between 98.15 and 100.30% for each impurity. The repeatability and intermediate precision (RSD) were less than 3.2% for ebastine and each of the impurities. The robustness of the developed method was studied by varying the six parameters: gradient time, temperature, ternary composition of the eluent, flow rate and start and end concentration of the gradient at 3 levels (+1, 0, -1). The resulting 729 experiments were performed in silico from the previously constructed model for Design Space and showed that the required resolution of 2.0 can be reached in all experiments. To prove the stability-indicating performance of the method, forced degradation (acid and base hydrolysis, oxidation, photolytic and thermal stress conditions) of ebastine was carried out. Baseline separation could be achieved for all peaks of the impurities, the degradation products and the API. Total run time was only 4 min, which is an impressive 40-fold increase in productivity in comparison to the method published in the Ph. Eur. monograph and allowed purity testing of more than 360 samples per day. PMID- 23454600 TI - Chemical and physicochemical properties of the high cohesive silicone gel from Poly Implant Prothese (PIP) breast prostheses after explantation: a preliminary, comparative analytical investigation. AB - Aim of this work was to gain a deeper insight into the analytical profile of the macromolecular and LMW fractions of polymeric silicones present in breast implants. The study was conducted on silicone gel samples from (i) breast prostheses (Poly Implant Prothese, PIP) explanted from a patient that needed their therapeutical removal, (ii) from a virgin Mc Ghan 410 MX prosthesis and (iii) from a sample of technical-grade non-cohesive silicone. The gels were analysed using rheological techniques, attenuated total reflectance infrared spectroscopy (ATR-FT-IR), nuclear magnetic resonance ((1)H NMR), gas chromatography coupled to mass spectrometry (GC-MS) and flow injection electrospray mass spectrometry (FI-ESI-MS). Our results demonstrate that, compared to the virgin McGhan gel, the silicone present the PIP prostheses lacks a significant part of the cross-linking sites necessary for the high-cohesive properties of the gel, significant amounts of cholesterol have been absorbed from the breast tissue by the silicone material, demonstrating the lack of impermeability of its elastomer shell. The potential implications and consequences of these analytical results are discussed. PMID- 23454602 TI - A reference transcriptome and inferred proteome for the salamander Notophthalmus viridescens. AB - Salamanders have a remarkable capacity to regenerate complex tissues, such as limbs and brain, and are therefore an important comparative model system for regenerative medicine. Despite these unique properties among adult vertebrates, the genomic information for amphibians in general, and salamanders in particular, is scarce. Here, we used massive parallel sequencing to reconstruct a de novo reference transcriptome of the red spotted newt (Notophthalmus viridescens) containing 118,893 transcripts with a N50 length of 2016 nts. Comparisons to other vertebrates revealed a newt transcriptome that is comparable in size and characteristics to well-annotated vertebrate transcriptomes. Identification of putative open reading frames (ORFs) enabled us to infer a comprehensive proteome, including the annotation of 19,903 newt proteins. We used the identified domain architectures (DAs) to assign ORFs phylogenetic positions, which also revealed putative salamander specific proteins. The reference transcriptome and inferred proteome of the red spotted newt will facilitate the use of systematic genomic technologies for regeneration studies in salamanders and enable evolutionary analyses of vertebrate regeneration at the molecular level. PMID- 23454601 TI - How user characteristics affect use patterns in web-based illness management support for patients with breast and prostate cancer. AB - BACKGROUND: Frequently eHealth applications are not used as intended and they have high attrition rates; therefore, a better understanding of patients' need for support is warranted. Specifically, more research is needed to identify which system components target different patient groups and under what conditions. OBJECTIVE: To explore user characteristics associated with the use of different system components of a Web-based illness management support system for cancer patients (WebChoice). METHODS: For this secondary post hoc analysis of a large randomized controlled trial (RCT), in which WebChoice was tested among 325 breast cancer and prostate cancer patients who were followed with repeated measures for 1 year, usage patterns of 162 cancer patients in the intervention arm with access to WebChoice were extracted from the user log. Logistic regression was performed to identify patterns of associations between system use and patient characteristics. Latent class analyses (LCA) were performed to identify associations among the use of different system components and levels of social support, symptom distress, depression, self-efficacy, and health-related quality of life. RESULTS: Approximately two-thirds (103/162, 63.6%) of the patients logged on to WebChoice more than once, and were defined as users. A high level of computer experience (odds ratio [OR] 3.77, 95% CI 1.20-11.91) and not having other illnesses in addition to cancer (OR 2.10, 95% CI 1.02-4.34) increased the overall probability of using WebChoice. LCA showed that both men with prostate cancer and women with breast cancer who had low scores on social support accompanied with high levels of symptom distress and high levels of depression were more likely to use the e-message component. For men with prostate cancer, these variables were also associated with high use of the self-management advice component. We found important differences between men with prostate cancer and women with breast cancer when associations between WebChoice use and each user characteristic were analyzed separately. High use of all components was associated with low levels of social support among women with breast cancer, but not among men with prostate cancer. High use of e-messages, advice, and the discussion forum were associated with high levels of depression among women with breast cancer, but not among men with prostate cancer. For men with prostate cancer (but not women with breast cancer), high use of symptom assessments, advice, and the discussion forum were associated with high levels of symptom distress. However, it is unclear whether these findings can be attributed to differences related to diagnosis, gender, or both. CONCLUSIONS: This study provides evidence that different user characteristics are associated with different use patterns. Such information is crucial to target Web-based support systems to different patient groups. LCA is a useful technique to identify subgroups of users. In our study, e-messages and self-management advice were highly used components for patients who had low levels of social support and high illness burden, suggesting that patients with these characteristics may find such tools particularly useful. TRIAL REGISTRATION: ClinicalTrials.gov NCT00710658; http://clinicaltrials.gov/ct2/show/NCT00710658 (Archived by WebCite at http://www.webcitation.org/6EmEWZiwz). PMID- 23454603 TI - Transforming growth factor beta family members in regulation of vascular function: in the light of vascular conditional knockouts. AB - Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor beta (TGF-beta) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-beta family in the mouse. PMID- 23454604 TI - Anti-inflammatory effect of O-methylated flavonol 2-(3,4-dihydroxy-phenyl)-3,5 dihydroxy-7-methoxy-chromen-4-one obtained from Cassia sophera Linn in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cassia sophera Linn (Family Caesalpiniaceae), popularly known as kasundi, is used both in the Indian traditional system and folk medicine to treat several inflammatory pathologies such as asthma, arthritis and pains. The aim of the present study was to evaluate the scientific basis of anti-inflammatory activity of Cassia sophera ethanol extracts and of an isolated constituent of Cassia sophera. MATERIALS AND METHODS: The anti-inflammatory activity of Cassia sophera was studied using the carrageenan, dextran induced rat paw edema, and cotton pellet induced granuloma in rats. The ethanol extract was administered at the concentrations of 200 and 400mg/kg body weight whereas rhamnetin (RN) was administered at a dose of 10 and 15 mg/kg, b.w. Indomethacin was used as standard drug. RESULTS: The HPLC analysis revealed that good amounts of rhamnetin (0.18%) was present in Cassia sophera.The ethanol extracts at 400mg/kg, showed maximum inhibition of inflammation induced by carrageenan (44%), dextran (40%), cotton pellets (37.47%). On the other hand rhamnetin (15 mg/kg) exhibited maximum anti-inflammatory effect, that is 79 and 33% at the end of 3h with carrageenin, and dextran-induced rat paw edema, respectively. In a chronic test rhamnetin (15 mg/kg) showed 43.32% reduction in granuloma weight. CONCLUSION: The marked inhibitory effect on paw edema and granuloma showed that Cassia sophera possess remarkable anti-inflammatory activity which may be due to rhamnetin at least in part, supporting the folkloric usage of the plant to treat various inflammatory diseases. PMID- 23454605 TI - Bioprospecting: evolutionary implications from a post-olmec pharmacopoeia and the relevance of widespread taxa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: "Nothing in biology makes sense except in the light of evolution" The historical legacy and relevance of ethnopharmacology in drug discovery is undisputed. Here we connect the parameters influencing the selection of plant derived medicines by human culture with the concept of evolution. AIM OF THE STUDY: In the present contribution we compare global data with local data and try to answer the questions, to what extent are the taxonomic clades included in indigenous pharmacopoeias associated with certain ailment groups, and to what extent can ecology and phylogeny, which we consider a proxy for chemical relatedness and convergence, account for the observed bias? MATERIALS AND METHODS: We use an approximated chi-square test (chi(2)) to check for associations between 12 ethnomedical use-categories and 15 taxonomical clades. With cluster analyses we test for correlations between phylogeny and use categories. We compare the 67 drug-productive families identified by Zhu et al. with the medicinal flora of the Popoluca and the APG database and compare our results with the phylogenetic target classes evidenced by Zhu et al. Furthermore, we compare the medicinal flora of the Popoluca with the world's weeds (cf. Holm et al.) and discuss our results in relation to anthropological rationales for plant selection. RESULTS: The null-hypothesis "species from the 15 taxonomic clades are selected proportionally to their share in the treatment of the twelve organ- and symptom-defined use-categories" is rejected. The cluster dendrogram for the clades shows that the use patterns are to a certain extent associated with Angiosperm phylogeny. With the occurrence of 53 families the 67 drug productive families are overrepresented in the regional flora of the Popoluca. The importance of these families in terms of their share is even more pronounced with the medicinal flora holding around 70% of all individual Popoluca informant responses. CONCLUSIONS: The overall phylogenetic use pattern is influenced by both the inherent pharmacological properties, which depend on phylogeny, biogeography, ecology and ultimately allelopathy, and on culture-specific perception of organoleptic properties. The comparison of the 67 drug-productive Viridiplantae families with the ethnopharmacopoeia of the Popoluca and the APG database, shows that "traditional" pharmacopoeias and plant-derived drugs are obtained from widespread and species-rich taxa. This is not a function of family size alone. We put forward the theory that as a function of evolution, widespread taxa contain a broader range of accumulated ecological information and response encoded in their genes relative to locally occurring taxa. This information is expressed through the synthesis of allelochemicals with a wide ecological radius, showing broad-spectrum biota-specific interactions, including the targeting of proteins of mammals and primates. PMID- 23454606 TI - Khat dependence syndrome: a cross sectional preliminary evaluation amongst UK resident Yemeni khat chewers. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Khat is a natural psychostimulant that has pharmacological effects similar to that of amphetamine. The behaviour of khat chewing is embedded within a cultural context. Meanwhile khat chewing is associated with psychological and physiologically burden, as a 'dependence producing' substance. AIMS OF THE STUDY: To assess the applicability of the construct of substance dependence syndrome (DSM-IV, 1994) to khat chewing and to examine psychosocial and behavioural correlates of this syndrome including tobacco use. MATERIALS AND METHODS: A sample of 204 khat chewers was recruited during random visits to khat sale outlets. A face to face interview that assessed socio-demographic, psychosocial dependence, substance dependence syndrome and behavioural characteristics was conducted. Descriptive, exploratory psychometric and multivariate analyses were employed. RESULTS: Approximately a third (31%) of khat chewers reported symptoms consistent with dependence syndrome including increased khat chewing (13%) and cessation attempts (19%) while 17% reported withdrawal symptoms including depression (61%), increase in appetite (74%) and interrupted sleep (58%). Thirty-eight percent reported continued khat chewing despite impacts on their health. Psychometric assessment of the DSM-IV criteria for khat chewing dependence identified two factors; factor 1 consisted of bio behavioural items and factor 2 withdrawal items, accounting for 67% of the variance and Cronbach's alpha coefficient at 0.78. In multivariate logistic regression modelling, there was an association between intensity of psychological khat dependence (SDS-Khat) and nicotine dependence with the likelihood of exhibiting khat chewing dependence syndrome (p=0.0005, OR=1.51, 95%CI=1.33-1.71; p=0.043, OR=2.87, 95%CI=1.03-7.98, respectively). CONCLUSIONS: The substance dependence syndrome criteria are applicable to khat chewing and associated with increased intensity of nicotine and psychological khat dependence. The applicability of khat dependence syndrome and exploration of its dimensions and associated factors should be extended in future research. Concurrent validation of these findings using specific objective measures for self-report khat chewing is also recommended. PMID- 23454608 TI - Thrombin regulation of synaptic plasticity: implications for physiology and pathology. AB - Thrombin, a serine protease involved in the coagulation cascade has been recently shown to affect neuronal function following blood-brain barrier breakdown. Several lines of evidence have shown that thrombin may exist in the brain parenchyma under normal physiological conditions, yet its role in normal brain functions and synaptic transmission has not been established. In an attempt to shed light on the physiological functions of thrombin and Protease Activated Receptor 1 (PAR1) in the brain, we studied the effects of thrombin and a PAR1 agonist on long term potentiation (LTP) in mice hippocampal slices. Surprisingly, different concentrations of thrombin affect LTP through different molecular routes converging on PAR1. High thrombin concentrations induced an NMDA dependent, slow onset LTP, whereas low concentrations of thrombin promoted a VGCCs, mGluR-5 dependent LTP through activated Protein C (aPC). Remarkably, aPC facilitated LTP by activating PAR1 through an Endothelial Protein C Receptor (EPCR)-mediated mechanism which involves intracellular calcium stores. These findings reveal a novel mechanism by which PAR1 may regulate the threshold for synaptic plasticity in the hippocampus and provide additional insights into the role of this receptor in normal and pathological conditions. PMID- 23454609 TI - Evolution of molluscan hemocyanin structures. AB - Hemocyanin transports oxygen in the hemolymph of many molluscs and arthropods and is therefore a central physiological factor in these animals. Molluscan hemocyanin molecules are oligomers composed of many protein subunits that in turn encompass subsets of distinct functional units. The structure and evolution of molluscan hemocyanin have been studied for decades, but it required the recent progress in DNA sequencing, X-ray crystallography and 3D electron microscopy to produce a detailed view of their structure and evolution. The basic quaternary structure is a cylindrical decamer 35nm in diameter, consisting of wall and collar (typically at one end of the cylinder). Depending on the animal species, decamers, didecamers and multidecamers occur in the hemolymph. Whereas the wall architecture of the decamer seems to be invariant, four different types of collar have been identified in different molluscan taxa. Correspondingly, there exist four subunit types that differ in their collar functional units and range from 350 to 550kDa. Thus, molluscan hemocyanin subunits are among the largest polypeptides in nature. In this report, recent 3D reconstructions are used to explain and visualize the different functional units, subunits and quaternary structures of molluscan hemocyanins. Moreover, on the basis of DNA analyses and structural considerations, their possible evolution is traced. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23454610 TI - A practical guide to the ICPL_ESIQuant software for ICPL-based quantitative proteomics. AB - ICPL_ESIQuant is a proteomics software tool for quantitatively analyzing large mass spectrometric datasets acquired from ICPL based proteomics experiments. It is able to process mass spectrometric data from various vendors and implements results from the Mascot search engine to generate protein and peptide result tables. This protocol briefly introduces ICPL_ESIQuant and presents a detailed step by step tutorial, how to use the software with MS datasets obtained from ICPL duplex, triplex and quadruplex experiments. Requiring MS raw data in .mzXML file format and Mascot search results in .dat format as input, ICPL_ESIQuant reliably quantifies ICPL labeled proteins and provides additional information about all detected, sequenced and identified features in the sample. The software supports both the shotgun and the directed proteomics strategy, enabling the user to apply mass inclusion lists for identifying peptides not fragmented in the first MS cycle. The software together with a test dataset is freely available under http://sourceforge.net/projects/icplquant/. This article is part of a Special Issue entitled: Computational Proteomics in the Post-Identification Era. Guest Editors: Martin Eisenacher and Christian Stephan. PMID- 23454611 TI - Algorithms of GPU-enabled reactive force field (ReaxFF) molecular dynamics. AB - Reactive force field (ReaxFF), a recent and novel bond order potential, allows for reactive molecular dynamics (ReaxFF MD) simulations for modeling larger and more complex molecular systems involving chemical reactions when compared with computation intensive quantum mechanical methods. However, ReaxFF MD can be approximately 10-50 times slower than classical MD due to its explicit modeling of bond forming and breaking, the dynamic charge equilibration at each time-step, and its one order smaller time-step than the classical MD, all of which pose significant computational challenges in simulation capability to reach spatio temporal scales of nanometers and nanoseconds. The very recent advances of graphics processing unit (GPU) provide not only highly favorable performance for GPU enabled MD programs compared with CPU implementations but also an opportunity to manage with the computing power and memory demanding nature imposed on computer hardware by ReaxFF MD. In this paper, we present the algorithms of GMD Reax, the first GPU enabled ReaxFF MD program with significantly improved performance surpassing CPU implementations on desktop workstations. The performance of GMD-Reax has been benchmarked on a PC equipped with a NVIDIA C2050 GPU for coal pyrolysis simulation systems with atoms ranging from 1378 to 27,283. GMD-Reax achieved speedups as high as 12 times faster than Duin et al.'s FORTRAN codes in Lammps on 8 CPU cores and 6 times faster than the Lammps' C codes based on PuReMD in terms of the simulation time per time-step averaged over 100 steps. GMD-Reax could be used as a new and efficient computational tool for exploiting very complex molecular reactions via ReaxFF MD simulation on desktop workstations. PMID- 23454612 TI - Towards the identification of the binding site of benzimidazoles to beta-tubulin of Trichinella spiralis: insights from computational and experimental data. AB - Benzimidazole-2-carbamate derivatives (BzC) are among the most important broad spectrum anthelmintic drugs for the treatment of nematode infections. BzC selectively bind to the beta-tubulin monomer and inhibit microtubule polymerization. However, the crystallographic structure of the nematode tubulin and the mechanism of action are still unknown. Moreover, the relation between the mechanism of action and the binding site of BzC has not yet been explained accurately. By using the amino acid sequence of Trichinella spiralis beta-tubulin as a basis and by applying homology modeling techniques, we were able to build a 3D structure of this protein. In order to identify a binding site for BzC, molecular docking and molecular dynamics calculations were carried out with this model. The results were in good agreement with the most common amino acid mutations associated with drug resistance (F167Y, E198A and F200Y) and with the experimental results of competitive inhibition of colchicine binding to tubulin. Besides, Glu198, Thr165, Cys239 and Gln134 were identified as important amino acids in the binding process since they directly interact with BzC in the formation of hydrogen bonds. The results presented in this paper are a step further towards the understanding, at the molecular level, of the mode of action of anthelmintic drugs. These results constitute valuable information for the design or improvement of more potent and selective molecules. PMID- 23454613 TI - The multifaceted nature of Tourette syndrome: pre-clinical, clinical and therapeutic issues. PMID- 23454614 TI - Scleritis: Immunopathogenesis and molecular basis for therapy. AB - Scleritis is a heterogeneous group of diseases characterized by inflammation of the sclera, which may be due to local or systemic infections or immune mediated diseases. Numerous studies over the last decade have lead to significant progress in understanding the pathogenesis and treatment of this severe and potentially blinding disease. Immunological investigations of non-infectious scleritis and associated diseases have indicated that scleritis is an autoimmune disease and studies on the nature of the local inflammatory response have revealed the prominent role of T and B cells and cytokines, such as TNF-alpha, which in turn has resulted in clinical trials showing the effectiveness of local steroid treatment, anti-TNF and anti-B cell therapy. The widespread use of imaging has led to the realization that posterior scleritis is more common than previously recognized and testing for ANCA antibodies has revealed the prominent role of immune mechanisms in a subset of patients with scleritis and associated systemic vasculitis. PMID- 23454615 TI - Functional aspects of PARylation in induced and programmed DNA repair processes: preserving genome integrity and modulating physiological events. AB - To cope with the devastating insults constantly inflicted to their genome by intrinsic and extrinsic DNA damaging sources, cells have evolved a sophisticated network of interconnected DNA caretaking mechanisms that will detect, signal and repair the lesions. Among the underlying molecular mechanisms that regulate these events, PARylation catalyzed by Poly(ADP-ribose) polymerases (PARPs), appears as one of the earliest post-translational modification at the site of the lesion that is known to elicit recruitment and regulation of many DNA damage response proteins. In this review we discuss how the complex PAR molecule operates in stress-induced DNA damage signaling and genome maintenance but also in various physiological settings initiated by developmentally programmed DNA breakage. To illustrate the latter, particular emphasis will be placed on the emerging contribution of PARPs to B cell receptor assembly and diversification. PMID- 23454617 TI - Motor inhibition of return can affect prepared reaching movements. AB - Inhibition of return (IOR) is a widely studied phenomenon that is thought to affect attention, eye movements, or reaching movements, in order to promote orienting responses toward novel stimuli. Previous research in our laboratory demonstrated that the motor form of saccadic IOR can arise from late-stage response execution processes. In the present study, we were interested in whether the same is true of reaching responses. If IOR can emerge from processes operating at or around the time of response execution, then IOR should be observed even when participants have fully prepared their responses in advance of the movement initiation signal. Similar to the saccadic system, our results reveal that IOR can be implemented as a late-stage execution bias in the reaching control system. PMID- 23454616 TI - Neural time course of emotional conflict control: an ERP study. AB - Previous imaging studies have revealed brain mechanisms associated with emotional conflict control. However, the neural time course remains largely unknown. Therefore, in the present study a face-word Stroop task was used to explore the electrophysiological correlates of emotional conflict control by using event related potentials (ERPs). Behavioral data indicated that response time of congruent condition was faster than incongruent condition, while the accuracy rates of congruent condition was higher than incongruent condition, which showed a robust emotional conflict effect. ERP revealed N350-550 and P700-800 components in the incongruent minus congruent condition. N350-550 might be related to conflict resolution and response selection; P700-800 might be related to post response monitoring. PMID- 23454618 TI - Co-speech gesture production in an animation-narration task by bilinguals: a near infrared spectroscopy study. AB - To examine the neural mechanism of co-speech gesture production, we measured brain activity of bilinguals during an animation-narration task using near infrared spectroscopy. The task of the participants was to watch two stories via an animated cartoon, and then narrate the contents in their first language (Ll) and second language (L2), respectively. The participants showed significantly more gestures in L2 than in L1. The number of gestures lowered at the ending part of the narration in L1, but not in L2. Analyses of concentration changes of oxygenated hemoglobin revealed that activation of the left inferior frontal gyrus (IFG) significantly increased during gesture production, while activation of the left posterior superior temporal sulcus (pSTS) significantly decreased in line with an increase in the left IFG. These brain activation patterns suggest that the left IFG is involved in the gesture production, and the left pSTS is modulated by the speech load. PMID- 23454619 TI - Motion and actions in language: semantic representations in occipito-temporal cortex. AB - Understanding verbs typically activates posterior temporal regions and, in some circumstances, motion perception area V5. However, the nature and role of this activation remains unclear: does language alone indeed activate V5? And are posterior temporal representations modality-specific motion representations, or supra-modal motion-independent event representations? Here, we address these issues by investigating human and object motion sentences compared to corresponding state descriptions. We adopted the blank screen paradigm, which is known to encourage visual imagery, and used a localizer to identify V5 and temporal structures responding to motion. Analyses in each individual brain suggested that language modulated activity in the posterior temporal lobe but not within V5 in most participants. Moreover, posterior temporal structures strongly responded to both motion sentences and human static sentences. These results suggest that descriptive language alone need not recruit V5 and instead engages more schematic event representations in temporal cortex encoding animacy and motion. PMID- 23454620 TI - Influence of photoperiod on expression of DNA (cytosine-5) methyltransferases in Atlantic cod. AB - Photoperiod manipulation during early juvenile stages can influence growth in Atlantic cod. In the present study, one group of cod juveniles were reared under natural photoperiod conditions for Bodo (67 degrees N, 14 degrees E), whereas their counterparts were kept under continuous illumination. The mean weight of juvenile cod reared under continuous illumination was found to be 13% greater than those kept under natural photoperiod after 120days of light treatment. The molecular basis of this phenotypic plasticity is currently unknown but it is likely that DNA (cytosine-5)-methyltransferases (dnmts) are involved, since these genes play a crucial role in epigenetic regulation of gene expression. Phylogenetic analysis of Atlantic cod dnmt1, dnmt2 and dnmt3a revealed that within each group, the phylogeny follows the taxonomic relationship between the various species and comparative mapping of dnmt paralogues showed that these genes lie within regions of conserved synteny amongst teleosts. Of the three dnmt paralogues, dnmt3a had the highest expression in fast muscle of adult cod. In addition, dnmt1 and dnmt2 were differentially expressed between tissues but with prominent expression in gonads. Dnmt1 and dnmt3a transcript levels showed a significant increase in fast muscle of juvenile cod from the continuous light group at several time points. Remarkably, dnmt1 and dnmt3a transcript levels were 2-fold higher at 120days, by which point photoperiod conditions between the two light groups had become identical. Our data revealed that photoperiod can have an extended effect on expression of dnmt genes, which may be involved in the epigenetic regulation of muscle growth by photoperiod in Atlantic cod. PMID- 23454621 TI - The isolation and identification of a light-induced protein in alfalfa sprouts and the cloning of its specific promoter. AB - We used 2D-PAGE to isolate a light-induced protein (AL-A) that is expressed abundantly in light-growth alfalfa sprouts. The seven amino acids of the N terminal region of the protein were identified, and we searched for the protein in GenBank using the BLAST program. The results of the homology analysis showed that the amino acid sequence of the isolated protein is most similar to one from a pea plastocyanin. To identify the protein, we amplified and sequenced the DNA fragment encoding AL-A from genomic alfalfa DNA. We found that the AL-A gene was highly homologous (90%) to the sequences from the pea plastocyanin via multiple alignments, and the deduced protein precursor was predicted to be chloroplast specific via the ChloroP computer program. The protein was named alfalfa plastocyanin (AL-P). It was characterized as being a light-inducible protein, and RT-PCR analysis showed that AL-P mRNA transcription only occurred in the leaves of the alfalfa plant and the alfalfa seedlings growth in lighted conditions. PCR was also used to amplify the DNA fragment encoding the AL-P promoter (AL-Pp) from genomic alfalfa DNA. PlantCARE analysis of the promoter sequence indicated that both a typical TATA box and a CAAT box were located in the promoter sequence, and some of the cis-elements that are responsible for light responsiveness were also identified within this promoter region. The AL-P gene promoter fused to the beta glucuronidase (GUS) reporter gene has been examined for expression in transgenic alfalfa seedlings. Our findings have a potential application in plant genetic engineering; the AL-Pp may be used to drive the expression of heterologous genes in transgenic alfalfa plants. PMID- 23454622 TI - The interleukin-4 -589C/T polymorphism and the risk of asthma: a meta-analysis including 7,345 cases and 7,819 controls. AB - BACKGROUND: A number of studies assessed the association of -589C/T polymorphism in the promoter region of interleukin-4 (IL-4) with asthma in different populations. However, the results were contradictory. A meta-analysis was conducted to investigate the association between polymorphism in the IL-4 and asthma susceptibility. METHODS: Databases including Pubmed, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. RESULTS: Thirty four studies involving 7345 cases and 7819 controls were included. Overall, significant association between -589C/T polymorphism and asthma was observed for TT+CT vs. CC (OR=1.26; 95% CI 1.12-1.42; P=0.0001; I(2)=26%). In the subgroup analysis by ethnicity, significant associations were found among Asians (OR=1.36; 95% CI 1.07-1.73; P=0.01; I(2)=0%) and Caucasians (OR=1.30; 95% CI 1.09-1.54; P=0.004; I(2)=53%) but not among African Americans (OR=1.20; 95% CI 0.72-2.00; P=0.48; I(2)=48%). In the subgroup analysis by atopic status, no significant association was found among atopic asthma patients (OR=1.20; 95% CI 0.92-1.34; P=0.27; I(2)=6%) and non-atopic asthma patients (OR=0.97; 95% CI 0.73-1.28; P=0.81; I(2)=0%). CONCLUSIONS: This meta-analysis suggested that the IL-4 -589C/T polymorphism was a risk factor of asthma. PMID- 23454623 TI - Aspirin insensitive thrombophilia: transcript profiling of blood identifies platelet abnormalities and HLA restriction. AB - Aspirin is the most widely used antiplatelet agent because it is safe, efficient, and inexpensive. However, a significant subset of patients does not exhibit a full inhibition of platelet aggregation, termed 'aspirin resistance' (AR). Several major studies have observed that AR patients have a 4-fold increased risk of myocardial infarction (MI), stroke, and other thrombotic events. Arachidonic acid-stimulated whole blood aggregation was tested in 132 adults at risk for ischemic events, and identified an inadequate response to aspirin therapy in 9 patients (6.8%). Expression profiling of blood RNA by microarray was used to generate new hypotheses about the etiology of AR. Among the differentially expressed genes, there were decreases in several known platelet transcripts, including clusterin (CLU), glycoproteins IIb/IIIa (ITGA2B/3), lipocalin (LCN2), lactoferrin (LTF), and the thrombopoetin receptor (MPL), but with increased mRNA for the T-cell Th1 chemokine CXCL10. There was a strong association of AR with expression of HLA-DRB4 and HLA-DQA1. Similar HLA changes have been linked to autoimmune disorders, particularly antiphospholipid syndrome (APS), in which autoantibodies to phospholipid/protein complexes can trigger platelet activation. Consistent with APS, AR patients exhibited a 30% reduction in platelet counts. Follow-up testing for autoimmune antibodies observed only borderline titers in AR patients. Overall, these results suggest that AR may be related to changes in platelet gene expression creating a hyperreactive platelet, despite antiplatelet therapy. Future studies will focus on determining the protein levels of these differential transcripts in platelets, and the possible involvement of HLA restriction as a contributing factor. PMID- 23454624 TI - Genetic polymorphisms of CYP2E1 and DNA repair genes HOGG1 and XRCC1: association with hepatitis B related advanced liver disease and cancer. AB - A population based case-control study was designed to explore the genetic risk factors for hepatitis B virus (HBV) related liver disease susceptibility. A total of 424 subjects comprising 210 controls, 50 acute HBV (AVH), 84 chronic HBV (CHBV), 25 HBV related cirrhosis and 55 HBV related hepatocellular carcinoma (HCC) cases were included in the study. PCR-RFLP was used for the genotyping of Cyp2E1*5B, hOGG1 codon 326 and XRCC1 codon 399. Compared to controls, Cyp2E1 rsaI variant c2 genotype increased the risk of HBV related liver disease severity by 2.68 fold, the highest for HCC cases (3.981 folds, p=0.106); and was associated with higher histology activity index (HAI) (p<0.001) in CHBV patients. Cyp2E1 and hOGG1 variants were independently associated with a significantly higher fibrosis score in CHBV group. Analysis of gene-gene interaction studies showed an increased risk of HCC, cirrhosis and CHBV in a Cyp2E1 variant+XRCC1 variant combination (p<0.001); and hOGG1 variants+XRCC1 variants. A mutually independent heterozygous hOGG1 and XRCC1 combination resulted in a decreased risk of HBV related liver disease. On the other hand, a wild-type hOGG1 and XRCC1 combination was associated with a significantly higher risk of AVH (p=0.010) but a lower risk of CHBV (p=0.032) and HCC (p=0.006). The gene-gene interactions were also associated with a significant increase in HAI and fibrosis score in CHBV patients. Cyp2E1, hOGG1 and XRCC1 genotypes significantly alter the risk of HBV related liver disease susceptibility and severity, independently or through gene gene interaction. PMID- 23454626 TI - Antivenom for snakebite envenoming in Sri Lanka: the need for geographically specific antivenom and improved efficacy. AB - Sri Lanka is a tropical developing island nation that endures significant economic and medical burden as a result of snakebite envenomation, having not only a high prevalence of envenomations, but also one of the highest incidence rates (200 snakebites/100,000 people/year) of venomous snakebite in the world (Kasturiratne et al., 2005). Ironically, the very snakes responsible for this human morbidity and mortality are a valuable biomedical and ecological national resource, despite the medical and economic consequences of envenomation. Currently, no snake antivenom is produced using venoms from native Sri Lankan snakes as immunogens, and there is a true need for an efficacious Sri Lanka, poly specific snake antivenom. An approach to fulfilling this need via combining the scientific, technological and economical resources from Costa Rica and the United States with the knowledge and talent of Sri Lankan official governmental agencies, legal counsels, environmental, medical and veterinary academic institutions, and religious and cultural leaders has been initiated, coordinated and funded by Animal Venom Research International (AVRI), a nonprofit charity. This bridging of nations and the cooperative pooling of their resources represents a potential avenue for antivenom development in a developing country that suffers the consequences of few specific resources for the medical management of venomous snakebite. The desired final outcome of such an endeavor for Sri Lanka is, most importantly, improved medical outcomes for snakebite patients, with enhanced and expanded science and technology relating to snake venoms and antivenoms, and the collateral benefits of reduced economic cost for the country. PMID- 23454627 TI - The relationship between decision-making and perfectionism in obsessive compulsive disorder and eating disorders. AB - BACKGROUND AND OBJECTIVES: Obsessive-compulsive disorder (OCD) and eating disorders (EDs) show phenotypic similarities and have been independently associated with deficits in decision-making and maladaptive perfectionism. However, research directly comparing the two disorders is sparse and the significance of observed similarities remains in question. Therefore, the present study compared decision-making in OCD and EDs in relationship to perfectionistic personality traits. METHODS: Sixty-one women were enrolled in the study comprising 3 mutually exclusive groups: 19 with OCD, 17 with EDs, and 21 healthy controls. Decision-making performance on the Iowa Gambling Task under two conditions, ambiguity and risk, was examined in relationship to perfectionistic traits. RESULTS: Behavioral results indicated that EDs participants, relative to both OCD and control participants, were impaired in decision-making under conditions of risk. Heightened perfectionism was associated with less risky decision-making in OCD, but more risky decision-making in EDs. LIMITATIONS: Sample size was small and all participants were women, which may limit generalizability. CONCLUSION: Results support decision-making deficits in EDs, which may be related to a dysfunctional determination of risk versus reward. This study is the first to suggest that the relationship between perfectionism and risk taking may manifest differently in these phenotypically similar disorders. PMID- 23454625 TI - Targeting ricin to the ribosome. AB - The plant toxin ricin is highly toxic for mammalian cells and is of concern for bioterrorism. Ricin belongs to a family of functionally related toxins, collectively referred to as ribosome inactivating proteins (RIPs), which disable ribosomes and halt protein synthesis. Currently there are no specific antidotes against ricin or related RIPs. The catalytic subunit of ricin is an N-glycosidase that depurinates a universally conserved adenine residue within the sarcin/ricin loop (SRL) of the 28S rRNA. This depurination activity inhibits translation and its biochemistry has been intensively studied. Yet, recent developments paint a more complex picture of toxicity, with ribosomal proteins and cellular signaling pathways contributing to the potency of ricin. In particular, several studies have now established the importance of the ribosomal stalk structure in facilitating the depurination activity and ribosome specificity of ricin and other RIPs. This review highlights recent developments defining toxin-ribosome interactions and examines the significance of these interactions for toxicity and therapeutic intervention. PMID- 23454628 TI - Thermal stress and cellular signaling processes in hemocytes of native (Mytilus californianus) and invasive (M. galloprovincialis) mussels: cell cycle regulation and DNA repair. AB - In a previous study using hemocytes from native and invasive congeners of Mytilus (Mytilus californianus and Mytilus galloprovincialis, respectively) we showed that DNA damage and cell signaling transduction processes related to the cellular stress response and apoptosis were induced by acute temperature stress. The present study extends this work by examining effects of acute heat- and cold stress on total hemocyte counts (THCs) and expression of key regulatory molecules involved in responding to stress: tumor suppressor factor (p53), cell cycle arrest activator (p21), and a DNA base excision repair enzyme (apurinic/apyrimidinic endonuclease (APE)). Hyperthermia (28 degrees C, 32 degrees C) led to significant decreases of THCs in both species. The extent of decrease in THC was temperature-, time-, and species-dependent; lower THC values were found in M. californianus, the more cold-adapted species. Western blot analyses of hemocyte extracts with antibodies specific for p53 protein, several site-specific phosphorylation states of p53, p21 protein, and APE indicated that heat- and cold (2 degrees C) stress induced a time-dependent activation of stress-related proteins in response to DNA damage; these stress-induced changes could govern cell cycle arrest or DNA damage repair. Our results show that the downstream regulatory response to temperature-induced cell damage may play an important role in deciding cellular fate following heat- and cold stress. Compared to M. californianus, the more warm-adapted M. galloprovincialis appears to have a higher temperature tolerance due to a lesser reduction in THC, faster signaling activation and transduction, and stronger DNA repair ability following heat stress. PMID- 23454629 TI - The effects of body temperature and mass on the postprandial metabolic responses of the African egg-eating snakes Dasypeltis scabra and Dasypeltis inornata. AB - African egg-eating snakes (Dasypeltis) feed only on freshly laid bird eggs which they perforate within their esophagus before swallowing the liquid contents and regurgitating the empty shell. Compared to a snake's typical intact meal, the liquid diet of Dasypeltis would expectedly generate a more moderate postprandial metabolic response and specific dynamic action (SDA). Free-ranging Dasypeltis feed over a range of ambient temperatures and thereby experience predicted temperature-dependent shifts in the duration and magnitude of their postprandial metabolic response. Such shifts would undoubtedly be shared among different species and age classes of Dasypeltis. To examine these expectations, we measured pre- and postprandial metabolic rates of adult Dasypeltis inornata and adult and neonate Dasypeltis scabra in response to liquid egg meals weighing 20% of snake body mass at 20, 25, 27, 30, and 32 degrees C. With an increase in body temperature, postprandial metabolic profiles of neonate and adult snakes became narrower and shorter in duration. Specific dynamic action varied among temperature treatments, increasing from 20 to 32 degrees C. Standard metabolic rate, postprandial peak metabolic rate, and SDA scaled with mass exponents that typically did not differ from 1.0. As expected, Dasypeltis digesting a liquid egg diet experienced a more modest postprandial response and SDA, expending on average only 10.6% of the meal's energy on the breakdown, absorption, and assimilation of the egg meal, whereas other colubrids consuming intact rodent or fish meals expend on average 16.3% of the meal's energy on digestion and assimilation. Actively foraging and feeding throughout the avian egg laying season enable Dasypeltis to survive when eggs are not available. The adaptive suite of traits that enable Dasypeltis to consume eggs of large relative size and ingest only the liquid contents may also be joined by physiological adaptations specific to their liquid diet and extended bouts of fasting. PMID- 23454630 TI - Trypanosoma evansi: detection of Trypanosoma evansi DNA in naturally and experimentally infected animals using TBR(1) & TBR(2) primers. AB - A polymerase chain reaction (PCR-based) assay was evaluated for detection of Trypanosoma evansi DNA in experimentally infected mice and naturally infected camels, sheep and goats using the set of primers TBr(1) & TBr(2) that amplified 164 bp DNA fragment. The results revealed that PCR-based assay was able to detect T. evansi directly from the blood during both acute and chronic phase of infection in all tested animals and in the blood and tissues of intraperitoneally infected mice depending upon the level of infection in the test samples. PCR was more powerful than CATT/T. evansi and mouse inoculation tests, when detected the infection in mice (24 h) post infection. Present results show that sheep & goats probably play a role in transmission of T. evansi to camels and supported that PCR could be used as a diagnostic tool for epidemiological studies on T. evansi in Egypt. PMID- 23454631 TI - A tale of two forests: addressing postnuclear radiation at Chernobyl and Fukushima. PMID- 23454632 TI - Prenatal diagnosis using array-CGH: a French experience. AB - Array-CGH or Chromosomal Microarray Analysis (CMA) is increasingly used in prenatal diagnosis throughout the world. However, routine practices are very different among centers and countries, regarding CMA indications, design and resolution of microarrays, notification and interpretation of Copy Number Alterations (CNA). We present our data and experience from our Fetal Medicine Center on 224 prospective prenatal diagnoses. Our approach is practical, and aims to propose a strategy to offer Chromosomal Microarray Analysis (CMA) to selected fetuses and to help to interpret CNA. We hope that this publication could encourage development of CMA in centers that have not started yet this activity in prenatal routine, and could contribute to edict guidelines in this field. PMID- 23454634 TI - Maintaining good hearing: calorie restriction, Sirt3, and glutathione. AB - Reducing calorie intake extends the lifespan of a variety of experimental models and delays progression of age-related hearing loss (AHL). AHL is a common feature of aging and is characterized by age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. Sirtuins are a family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms and have emerged as broad regulators of cellular fate. Our recent study indicated that mitochondrial Sirt3, a member of the sirtuin family, mediates the anti-aging effects of calorie restriction (CR) on AHL in mice. Interestingly, we also found that weight loss alone may not be sufficient for maintaining normal hearing. How does CR slow the progression of AHL through regulation of Sirt3? Here we review the evidence that during CR, Sirt3 slows the progression of AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system in mice. A significant reduction in food consumption in one's daily life may not be a desirable and realistic option for most people. Therefore, identification/discovery of compounds that induce the activation of SIRT3 or glutathione reductase, or that increase mitochondrial glutathione levels has potential for maintaining good hearing through mimicking the anti-aging effects of CR in human inner ear cells. PMID- 23454633 TI - Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression. AB - Short-term starvation (STS) protects normal cells while simultaneously sensitizing malignant cells to high-dose chemotherapeutic drugs in mice and possibly patients. The fasting-dependent protection of normal cells and sensitization of malignant cells depends, in part, on reduced levels of insulin like growth factor-1 (IGF-1) and glucose. Calorie restricted diets with defined macronutrient (carbohydrate, protein, fat) ratios were evaluated for the effects on stress sensitization markers and protection in mice treated with high-dose chemotherapy. We show that short-term CR significantly reduced both glucose and IGF-1 levels, but when specific macronutrient deficiencies were tested, only the complete lack of proteins reduced IGF-1 levels. Short-term 50% CR combined with either severe protein-deficiency or ketogenic diets improved chemotoxicity resistance similarly to the standard 50% CR, but did not result in the high protection caused by STS. Notably, a high protein diet reversed the beneficial effects of short-term CR. In a subcutaneous mouse model of glioma, feeding a low protein (4% calories from protein) diet for more than 20days did not delay tumor progression once the tumor became palpable. Also, cycles of short-term (3days) 50% CR did not augment the chemotherapy efficacy of cisplatin in a murine breast cancer model. These results indicate that the protection from chemotoxicity and retardation of the progression of certain tumors achieved with fasting is not obtained with short-term calorie and/or macronutrient restriction. PMID- 23454635 TI - Lifespan extension in the spontaneous dwarf rat and enhanced resistance to hyperoxia-induced mortality. AB - Lifespan extension has been demonstrated in dwarfism mouse models relative to their wild-type. The spontaneous dwarf rat (SDR) was isolated from a closed colony of Sprague-Dawley (SD) rats. Growth hormone deficiencies have been indicated to be responsible for dwarfism in SDR. Survival time, the markers of oxidative stress, antioxidant enzymes, and resistance to hyperoxia were compared between SDR and SD rats, to investigate whether SDR, a dwarfism rat model, also extends lifespan and has an enhanced resistance to oxidative stress. SDRs lived 38% longer than SD rats on average. This is the first report to show that dwarf rats exhibit lifespan extensions similar to Ames and Snell mice. Decreased 8-oxo 2'-deoxyguanosine (8-oxodG) content, a marker of oxidative DNA damage, indicated suppressed oxidative stress in the liver, kidney, and lung of SDRs. Increased glutathione peroxidase enzyme activity was consistent with decreased 8-oxodG content in the same tissues. The heart and brain showed a similar tendency, but this was not significant. However, the catalase and superoxide dismutase enzyme activities of SDRs were not different from those of SD rats in any tissue. This was not what the original null hypothesis predicted. SDRs had potent resistance to the toxicity associated with high O2 (85%) exposure. The mean survival time in SDRs was more than 147% that of SD rats with 168h O2 exposure. These results suggest that the enhanced resistance to oxidative stress of SDRs associated with enhanced hydrogen peroxide elimination may support its potential role in lifespan extension. PMID- 23454636 TI - Development of circadian rhythms: role of postnatal light environment. AB - Mammals are born with an immature circadian system, which completes its development postnatally. Evidence suggests that the environment experienced by a newborn will impact and shape its development, which will have future consequences at the levels of circadian system function, circadian behaviour and physiology, and potentially, the animal's long-term health and welfare. Here we review the various stages in postnatal development of the circadian system, and discuss the data available on the long-term effects of early environment, in particular light environment, on the animal's brain, physiology and behaviour. PMID- 23454637 TI - A behavioral neuroenergetics theory of ADHD. AB - Energetic insufficiency in neurons due to inadequate lactate supply is implicated in several neuropathologies, including attention-deficit/hyperactivity disorder (ADHD). By formalizing the mechanism and implications of such constraints on function, the behavioral Neuroenergetics Theory (NeT) predicts the results of many neuropsychological tasks involving individuals with ADHD and kindred dysfunctions, and entails many novel predictions. The associated diffusion model predicts that response times will follow a mixture of Wald distributions from the attentive state, and ex-Wald distributions after attentional lapses. It is inferred from the model that ADHD participants can bring only 75-85% of the neurocognitive energy to bear on tasks, and allocate only about 85% of the cognitive resources of comparison groups. Parameters derived from the model in specific tasks predict performance in other tasks, and in clinical conditions often associated with ADHD. The primary action of therapeutic stimulants is to increase norepinephrine in active regions of the brain. This activates glial adrenoceptors, increasing the release of lactate from astrocytes to fuel depleted neurons. The theory is aligned with other approaches and integrated with more general theories of ADHD. Therapeutic implications are explored. PMID- 23454638 TI - Systematic analysis of genomic organization and structure of long non-coding RNAs in the human genome. AB - The genomic architecture of several functional elements in animals and plants, such as microRNAs and tRNA, has been better characterized. As yet, there is very little known about genomic organization and structure of lncRNA in animals and plants. Here, we conducted a genome-wide systematic computational analysis of genomic architecture of lncRNAs, and further provided a more comprehensive comparative view of genomic organization between lncRNAs and several other functional elements in the human genome. Our study not only provides comprehensive knowledge for further studies into the correlations between the genomic architecture of lncRNAs and their important functional roles in diverse cellular processes and in disease, but also will be valuable for understanding the origin and evolution of lncRNAs. PMID- 23454639 TI - Conformation-specific crosslinking of mitochondrial complex I. AB - Complex I is the only component of the eukaryotic respiratory chain of which no high-resolution structure is yet available. A notable feature of mitochondrial complex I is the so-called active/de-active conformational transition of the idle enzyme from the active (A) to the de-active, (D) form. Using an amine- and sulfhydryl-reactive crosslinker of 6.8A length (SPDP) we found that in the D-form of complex I the ND3 subunit crosslinked to the 39 kDa (NDUFA9) subunit. These proteins could not be crosslinked in the A-form. Most likely, both subunits are closely located in the critical junction region connecting the peripheral hydrophilic domain to the membrane arm of the enzyme where the entrance path for substrate ubiquinone is and where energy transduction takes place. PMID- 23454640 TI - Structural basis for pH gating of plant aquaporins. AB - Plants have evolved to cope with fluctuations in water supply by gating their water channels known as aquaporins. During flooding, a rapid drop of cytosolic pH due to anoxia leads to a simultaneous closure of the aquaporins in the plasma membrane. The closing mechanism has been suggested to involve a conserved histidine on cytosolic loop D. Here we report the crystal structure of a spinach aquaporin at low pH, revealing for the first time the structural basis for how this pH-sensitive histidine helps to keep the aquaporin in a closed state. PMID- 23454641 TI - HIV-1 envelope trimer has similar binding characteristics for carbohydrate binding agents as monomeric gp120. AB - The native HIV-1 Env complex consists of a gp120/gp41 trimer, but surface plasmon resonance (SPR)-directed binding studies for gp120-binding agents were almost exclusively performed on monomeric gp120. SPR-directed binding kinetics of monomeric gp120 and trimeric gp140 were investigated for a broad variety of envelope (Env)-binding agents. Similar kinetics for carbohydrate-binding agents (CBAs), the antibody 2G12 and sCD4 were observed, irrespective of the oligomeric state of gp120 that either contain the native mixture of complex and high-mannose N-glycans or that contain exclusively oligomannose N-glycans. The generally comparable kinetic properties of CBA, 2G12 and sCD4 binding to monomeric gp120 and trimeric gp140 indicate that monomeric gp120 is a good surrogate molecule for native HIV-1 Env trimer to investigate the binding affinities of Env-binding compounds. PMID- 23454642 TI - Overexpression of a key regulator of lipid homeostasis, Scap, promotes respiration in prostate cancer cells. AB - Prostate metabolism is unique, characterised by cholesterol accumulation and reduced respiration. Are these related? We modulated cholesterol levels and despite changes in mitochondrial cholesterol content, we saw no effects on lactate production or respiration. Instead, these features may be related via sterol regulatory element-binding protein 2 (SREBP-2), the master transcriptional regulator of cholesterol synthesis. SREBP-2 diverts acetyl-CoA into cholesterol synthesis and may thus reduce respiration. We examined LNCaP cells overexpressing the SREBP-2 regulator, Scap: although having higher SREBP-2 activity, these cells displayed higher respiration. This striking observation warrants further investigation. Given that SREBP-2 and Scap are regulated by factors driving prostate growth, exploring this observation further could shed light on prostate carcinogenesis. PMID- 23454643 TI - Extracellular matrix components: an intricate network of possible biomarkers for lysosomal storage disorders? AB - Biomarkers are extremely important in the case of multisystemic diseases, such as lysosomal storage disorders (LSDs), which are often difficult to assess in clinical practice. Several studies demonstrated significant alterations in the expression of extracellular matrix (ECM) components in LSD patients, raising important questions in relation to their possible involvement in disease pathogenesis and providing evidence for their possible utility as disease biomarkers. This article provides an overview of the possible pathogenic correlations between LSDs and ECM. Data regarding the expression of these molecules are discussed. Finally, the possible implication of ECM components as therapeutic targets in this group of diseases along with the impact of the differential expression of these components in current LSD treatment will be critically addressed. PMID- 23454644 TI - Preoperative sentinel node mapping with (99m)Tc-nanocolloid SPECT-CT significantly reduces the intraoperative sentinel node retrieval time in robot assisted laparoscopic cervical cancer surgery. AB - OBJECTIVE: To compare preoperative sentinel node (SN) mapping with planar lymphoscintigraphy (LSG) to single photon emission computed tomography with computed tomography (SPECT-CT) for differences in intraoperative SN retrieval time in surgically treated cervical cancer patients. METHODS: In cervical cancer patients planned for radical surgery, one day preoperatively, 220-290 MBq technetium-99m-nanocolloid was injected intracervically in four quadrants. Subsequent SN mapping was performed by either LSG (09.2009-03.2011) or SPECT-CT (03.2011-10.2012). The SN resection, by four armed robot assisted laparoscopy, was based on blue dye and technetium-99m and followed by pelvic lymph node dissection. Timing of perioperative care, including SN procedure times, was prospectively registered. RESULTS: Out of the 62 subjects included, 33 (53.2%) underwent LSG and 29 (46.8%) SPECT-CT. No significant differences in baseline characteristics were observed. Bi- and unilateral SN visualization rates were 75.8% and 15.2% for LSG versus 86.2% and 6.9% for SPECT-CT (p=0.299 and p=0.305, respectively). Intraoperative bi/unilateral SN detection occurred in 84.8% and 9.1% of LSG subjects versus 89.7% and 3.4% for SPECT-CT (p=0.573 and p=0.616). Correlation in SN location between mapping and surgery was low for LSG (Spearman rho=0.098; p=0.449) but high for SPECT-CT (rho=0.798; p<0.001). Bilateral intraoperative SN retrieval times for LSG and SPECT-CT were 75.4+/-33.5 and 50.1+/-15.6 min, resulting in an average difference of 25.4 min (p=0.003). CONCLUSION: SPECT-CT significantly reduces intraoperative SN retrieval with a clinically relevant time compared to LSG. The trend towards better bilateral visualization rates and significantly higher anatomical concordance may partly explain the observed difference in SN retrieval time. PMID- 23454645 TI - A one-step multiplex real-time RT-PCR assay for rapid and simultaneous detection of human norovirus genogroup I, II and IV. AB - A one-step multiplex real-time reverse transcription-PCR (RT-PCR) assay was developed for one-tube and simultaneous detection of three genogroups of human norovirus, genogroup I, II and IV (GI, GII and GIV). The specificity and sensitivity of the assay were evaluated and 50 samples were tested by using this assay. The results showed that the multiplex assay had high sensitivity and specificity. The amplification efficiencies of the assay were 91.3%, 90.1%, 88.9% and the detection limits were up to 16.9, 6.3, 43.0 copies/reaction respectively for norovirus GI, GII and GIV detection. No cross-reaction with the other examined RNA viruses was observed, and the qualitative analysis of samples showed that the multiplex assay had a good consistency with its corresponding monoplex assays for the detection of norovirus GI, GII and GIV (Kappa values were 0.848, 0.876 and 0.812 respectively). PMID- 23454646 TI - Immunodetection of Triticum mosaic virus by DAS- and DAC-ELISA using antibodies produced against coat protein expressed in Escherichia coli: potential for high throughput diagnostic methods. AB - Triticum mosaic virus (TriMV), an economically important virus infecting wheat in the Great Plains region of the USA, is the type species of the Poacevirus genus in the family Potyviridae. Sensitive and high-throughput serology-based detection methods are crucial for the management of TriMV and germplasm screening in wheat breeding programs. In this study, TriMV coat protein (CP) was expressed in Escherichia coli, and polyclonal antibodies were generated against purified soluble native form recombinant CP (rCP) in rabbits. Specificity and sensitivity of resulting antibodies were tested in Western immuno-blot and enzyme-linked immunosorbent assays (ELISA). In direct antigen coating (DAC)-ELISA, antibodies reacted specifically, beyond 1:20,000 dilution with TriMV in crude sap, but not with healthy extracts, and antiserum at a 1:10,000 dilution detected TriMV in crude sap up to 1:4860 dilution. Notably, rabbit anti-TriMV IgG and anti-TriMV IgG-alkaline phosphatase conjugate reacted positively with native virions in crude sap in a double antibody sandwich-ELISA, suggesting that these antibodies can be used as coating antibodies which is crucial for any 'sandwich' type of assays. Finally, the recombinant antibodies reacted positively in ELISA with representative TriMV isolates collected from fields, suggesting that antibodies generated against rCP can be used for sensitive, large-scale, and broad-spectrum detection of TriMV. PMID- 23454647 TI - Combination of allele-specific detection techniques to quantify minority resistance variants in hepatitis B infection: a novel approach. AB - Detection of minor variant viral quasispecies of the rtV173L+rtL180M+rtM204V combination mutation in the hepatitis B virus (HBV) polymerase mediating both lamivudine resistance and vaccine escape is potentially important for tracking the development and evolution of resistance within both individuals and populations. A highly sensitive and specific assay to quantitate HBV genomes was developed with this mutation combination directly from viral DNA in serum using allele-specific quantitative PCR with locked nucleic acid primers and a minor groove binder probe. This combination of primers and probe yields a linear detection range down to 150 copies. This strategy has 100% specificity even in mixtures of predominately wild type genomes. The assay accurately detected 3*102 copies of the triple mutant spiked into 3 * 108 copies of the wild-type genomes (0.0001%), while maintaining 100% specificity. This approach was validated using serum from a subject infected with known lamivudine-resistant HBV. The triple mutant viral population was quantitated at 2.86 * 108 copies/ml within a total viral concentration of 1.03 * 1010 copies/ml of serum (2.8%). This quantitative allele-specific PCR strategy therefore is a useful method for highly sensitive and specific detection of point mutation combinations that are clinically important in the pathogenesis of drug resistance and/or immune escape. PMID- 23454648 TI - Generation of intracellular reactive oxygen species and genotoxicity effect to exposure of nanosized polyamidoamine (PAMAM) dendrimers in PLHC-1 cells in vitro. AB - Polyamidoamine (PAMAM) dendrimers have previously been demonstrated to elicit systematically variable cyto- and eco-toxic responses, promising as the basis for structure-activity relationships governing nanotoxicological responses. In this study, increased production of intracellular reactive oxygen species (ROS), genotoxicity and apoptosis due to in vitro exposure of fish hepatocellular carcinoma cells to dendrimer generations G4, G5 and G6 is demonstrated. A PAMAM dendrimer generation dependent increase in ROS and genotoxicity was observed, consistent with our previous studies. The toxicological responses correlate well with the nanoparticle surface chemistry, specifically, the number of surface amino groups per generation. Although ROS production initially increases approximately linearly, it saturates at higher doses. Notably, normalized to the molar dose of surface amino groups, the dose-dependent ROS production for different generations overlap exactly, indicating that the response is due to these functional units. The genotoxicity response is also well correlated to the number of surface amino groups and therefore generation of PAMAM dendrimers. The observed genotoxicity, related to DNA damage, is related to the generation and dose dependent production of intracellular ROS, at low levels. At the higher ROS levels, increased DNA damage is associated with the onset of necrosis. PMID- 23454650 TI - The Global Sequence Signature algorithm unveils a structural network surrounding heavy chain CDR3 loop in Camelidae variable domains. AB - BACKGROUND: A large fraction of camelid (camels and llamas) antibodies is composed of heavy chain-only homodimers, able to recognise antigens with their variable domain. Events in somatic assembly and maturation of antibodies such as hypermutations and rearrangement of variable loops (CDRs - complementary determining regions) and selection among a wide range of framework variants are generally considered to be random processes. METHODS: An original algorithmic approach (Global Sequence Signature-GSS) was developed, able to take into account multiple functional and/or local sequence properties to detect scattered evolutionary constraints into sequences. RESULTS: Using the GSS approach, we show that the length of the main hypervariable loop (CDR3) is linked to the nature of 19 surrounding residues on the scaffold. Surprisingly, the relation between CDR3 size and scaffold residues strongly depends on the considered species, illustrating either significant differences in selection mechanisms or functional constraints during antibody maturation. CONCLUSIONS: Combined with the statistical coupling analysis (SCA) approach at the level of scaffold residues, this study has unravelled a robust interaction network on antibody structure surrounding the CDR3 loop. GENERAL SIGNIFICANCE: In addition to the general applicability of the GSS algorithm, which can bring together functional and sequence data to locate hot spots of constrained evolution, the relationship between CDR3 and scaffold discussed here should be taken into account in protein engineering when designing antibody libraries. PMID- 23454649 TI - Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury. AB - BACKGROUND: CD11b/CD18 is a key adhesion receptor that mediates leukocyte adhesion, migration and immune functions. We recently identified novel compounds, leukadherins, that allosterically enhance CD11b/CD18-dependent cell adhesion and reduce inflammation in vivo, suggesting integrin activation to be a novel mechanism of action for the development of anti-inflammatory therapeutics. Since a number of well-characterized anti-CD11b/CD18 activating antibodies are currently available, we wondered if such biological agonists could also become therapeutic leads following this mechanism of action. METHODS: We compared the two types of agonists using in vitro cell adhesion and wound-healing assays and using animal model systems. We also studied effects of the two types of agonists on outside-in signaling in treated cells. RESULTS: Both types of agonists similarly enhanced integrin-mediated cell adhesion and decreased cell migration. However, unlike leukadherins, the activating antibodies produced significant CD11b/CD18 macro clustering and induced phosphorylation of key proteins involved in outside-in signaling. Studies using conformation reporter antibodies showed that leukadherins did not induce global conformational changes in CD11b/CD18 explaining the reason behind their lack of ligand-mimetic outside-in signaling. In vivo, leukadherins reduced vascular injury in a dose-dependent fashion, but, surprisingly, the anti-CD11b activating antibody ED7 was ineffective. CONCLUSIONS: Our results suggest that small molecule allosteric agonists of CD11b/CD18 have clear advantages over the biologic activating antibodies and provide a mechanistic basis for the difference. GENERAL SIGNIFICANCE: CD11b/CD18 activation represents a novel strategy for reducing inflammatory injury. Our study establishes small molecule leukadherins as preferred agonists over activating antibodies for future development as novel anti-inflammatory therapeutics. PMID- 23454651 TI - Mass preparation of oligosaccharides by the hydrolysis of chondroitin sulfate polysaccharides with a subcritical water microreaction system. AB - The biological functions of chondroitin sulfate (CS) are executed by the interaction of specific oligosaccharide sequences in the polysaccharide chain with effective proteins. Thus, CS oligosaccharides are expected to have pharmacological applications. Furthermore, the demand for CS in health food supplements and medication is growing. However, the absorbency of CS polysaccharides in the digestive system is very low. Since the activity of orally administered CS is expected to increase by depolymerization, industrial production of CS oligosaccharides is required. In this study, hydrolysis with subcritical and super-critical water was applied to the depolymerization of CS for the first time, and hydrolytic conditions for oligosaccharide production were examined. CS oligosaccharides principally containing an N-acetyl-D-galactosamine residue at their reducing ends were successfully obtained. No significant desulfation was found in CS oligosaccharides prepared under optimized conditions. The production of CS oligosaccharides by this method will have a strong influence on the CS-related materials market. PMID- 23454652 TI - 5,14-HEDGE, a 20-HETE mimetic, reverses hypotension and improves survival in a rodent model of septic shock: contribution of soluble epoxide hydrolase, CYP2C23, MEK1/ERK1/2/IKKbeta/IkappaB-alpha/NF-kappaB pathway, and proinflammatory cytokine formation. AB - We have previously demonstrated that a stable synthetic analog of 20-HETE, N-[20 hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), restores vascular reactivity, blood pressure, and heart rate in endotoxemic rats. The aim of this study was to determine whether decreased renal expression and activity of soluble epoxide hydrolase (sEH), MEK1, ERK1/2, IKKbeta, IkappaB-alpha, and NF-kappaB as well as systemic and renal proinflammatory cytokine production associated with increased expression and activity of CYP2C23 contributes to the effect of 5,14 HEDGE to prevent hypotension, tachycardia, inflammation, and mortality in response to systemic administration of lipopolysaccharide (LPS). Blood pressure fell by 33 mmHg and heart rate rose by 57 beats/min in LPS (10 mg/kg, i.p.) treated rats. Administration of LPS also increased mRNA and protein expression of sEH associated with a decrease in CYP2C23 mRNA and protein expression. Increased activity of sEH and p-MEK1, p-ERK1/2, p-IkappaB-alpha, NF-kappaB, and p-NF-kappaB protein levels as well as TNF-alpha and IL-8 production by LPS were also associated with a decreased activity of AA epoxygenases. These effects of LPS were prevented by 5,14-HEDGE (30 mg/kg, s.c.; 1 h after LPS). Treatment of endotoxemic mice with 5,14-HEDGE also raised the survival rate of animals from 84% to 98%. A competitive antagonist of vasoconstrictor effects of 20-HETE, 20 hydroxyeicosa-6(Z),15(Z)-dienoic acid, 20-HEDE (30 mg/kg, s.c.; 1 h after LPS) prevented the effects of 5,14-HEDGE on blood pressure, heart rate, expression and/or activity of sEH, CYP2C23, and ERK1/2 as well as TNF-alpha and IL-8 levels in rats treated with LPS. These results suggest that decreased expression and/or activity of sEH and MEK1/ERK1/2/IKKbeta/IkappaB-alpha/NF-kappaB pathway as well as proinflammatory cytokine production associated with increased CYP2C23 expression and antiinflammatory mediator formation participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, inflammation, and mortality in the rodent model of septic shock. PMID- 23454653 TI - In chemico evaluation of prohapten skin sensitizers: behavior of 2-methoxy-4 (13C)methylphenol in the peroxidase peptide reactivity assay (PPRA) as an alternative to animal testing. AB - In chemico methods, based on the assessment of a hapten's reactivity toward peptides, have been proposed as alternative methods for the assessment of the skin sensitizing potential of chemicals. However, even with these approaches showing promise, a major drawback is the activation of prohaptens, i.e. molecules needing a metabolic activation to become reactive and therefore sensitizing. Recently, it has been proposed to couple an enzymatic activation step based on horseradish peroxidase (HRP)/hydrogen peroxide to such peptide reactivity assays. To evaluate this approach, the behavior of 2-methoxy-4-methylphenol (2M4MP), reported as a moderate sensitizer according to the Local Lymph Node Assay (LLNA), has been investigated in this assay. To follow the reaction with the peptides and characterize more easily intermediates and adducts, the molecule was first (13)C isotopically substituted at the most probable reactive position. When 2M4MP was incubated with HRP/H2O2 in a mixture PBS (pH 7.4, 0.1M)/acetonitrile 2:1, two main products were formed deriving from the formation of a quinone methide 2M4MQ subsequently trapped by either H2O2 or H2O to form a benzylic hydroperoxide or alcohol, respectively. When nucleophiles such as GSH or a peptide containing a cysteine residue (Pep-Cys) were present in the reaction medium, the quinone methide 2M4MQ was trapped by the more nucleophilic thiol function to form thio adducts. No modifications of 2M4MP were observed when the same reactions were carried out without HRP confirming that the activation of the molecule was enzyme related. Amino nucleophiles were shown to be far less reactive towards the quinone methide 2M4MQ with only tiny formation of adducts with lysine or arginine side chains. In addition we demonstrated that the same enzymatic activation could also take place in a microemulsion based on sodium dodecyl sulfate/tert butanol/chloroform/buffer. PMID- 23454655 TI - Human exposure to mycotoxins and their masked forms through cereal-based foods in Belgium. AB - In the present study, a quantitative dietary exposure assessment of mycotoxins and their masked forms was conducted on a national representative sample of the Belgian population using the contamination data of cereal-based foods. Cereal based food products (n=174) were analysed for the occurrence of deoxynivalenol, 3 acetyldeoxynivalenol, 15-acetyldeoxynivalenol, zearalenone, alpha-zearalenol, beta-zearalenol, T-2-toxin, HT-2-toxin, and their respective masked forms, including, deoxynivalenol-3-glucoside, zearalenone-4-glucoside, alpha-zearalenol 4-glucoside, beta-zearalenol-4-glucoside and zearalenone-4-sulfate. Fibre enriched bread, bran-enriched bread, breakfast cereals, popcorn and oatmeal were collected in Belgian supermarkets according to a structured sampling plan and analysed during the period from April 2010 to October 2011. The habitual intake of these food groups was estimated from a national representative food intake survey. According to a probabilistic exposure analysis, the mean (and P95) mycotoxin intake for the sum of the deoxynivalenol-equivalents, zearalenone equivalents, and the sum of HT-2-and T-2-toxin for all cereal-based foods was 0.1162 (0.4047, P95), 0.0447 (0.1568, P95) and 0.0258 (0.0924, P95) MUg kg( 1)body weight day(-1), respectively. These values were below the tolerable daily intake (TDI) levels for deoxynivalenol, zearalenone and the sum of T-2 and HT-2 toxin (1.0, 0.25 and 0.1 MUg kg(-1)body weight day(-1), respectively). The absolute level exceeding the TDI for all cereal-based foods was calculated, and recorded 0.85%, 2.75% and 4.11% of the Belgian population, respectively. PMID- 23454654 TI - In vitro effects of waterpipe smoke condensate on endothelial cell function: a potential risk factor for vascular disease. AB - AIM: Despite its increasing popularity, little is known about the health effects of waterpipe smoking (WPS), particularly on the cardiovascular system. To investigate the role of WPS as a risk factor for vascular disease, we evaluated its effect on endothelial cell function, which is an early event in vascular disease pathogenesis. We assessed the changes in cell viability, ROS generation, inflammatory and vasodilatory markers and in vitro angiogenesis of human aortic endothelial cells in response to waterpipe smoke condensate exposure. METHODS AND RESULTS: Mainstream waterpipe smoke condensate (WSC) was generated using a standard laboratory machine protocol. Compared to control, WSC induced cell cycle arrest, apoptosis, and oxidative stress in human primary endothelial cells. In addition, we assayed for impaired endothelium-dependent vasodilation and induced inflammation by studying the effect of WPS on the content and activity of AMPK, eNOS proteins and NF-kappaB p65 ser536 phosphorylation, respectively. WSC inhibited AMPK/eNOS phosphorylation and induced phosphorylation of p65. Moreover, we evaluated endothelial cells repair mechanism related properties that include migration/invasion and in vitro tube formation upon treatment with WSC. WSC reduced the motility and inhibited angiogenic potential of HAEC cells. CONCLUSIONS: WPS induced endothelial cell dysfunction as evident by exerting oxidative stress, inflammation, and impaired endothelial vasodilatory function and repair mechanisms. All together these data provide evidence for the potential contribution of WPS to endothelial dysfunction and thus to vascular disease. PMID- 23454656 TI - CACTIN is an essential nuclear protein in Arabidopsis and may be associated with the eukaryotic spliceosome. AB - CACTIN is a conserved eukaryotic protein without known functional domains. Previous research revealed that CACTIN is essential in animals and protists and that it may function in inflammation pathways in animals; however, these pathways are not as broadly conserved as CACTIN. Therefore, the ancestral molecular function of CACTIN remains unknown. Our studies using Arabidopsis show that CACTIN is required for embryogenesis. Fluorescently tagged CACTIN localizes to nuclear speckles and colocalizes with known splicing proteins. In yeast-two hybrid studies, we found that CACTIN binds to a putative component of the spliceosome. These findings support a possible role for CACTIN in splicing. PMID- 23454657 TI - Nonlegacy PCBs: pigment manufacturing by-products get a second look. PMID- 23454658 TI - Phytohemagglutinins augment red kidney bean (Phaseolus vulgaris L.) induced allergic manifestations. AB - Red kidney bean (Phaseolus vulgaris L.), a commonly consumed bean has been reported to induce allergic reactions in susceptible individuals. Phytohemagglutinins (PHAs, mainly PHA-P) contribute a major proportion of red kidney bean seeds. However, their roles in red kidney bean induced allergic reactions are still to be explored. This study was carried out to understand the role of PHAs in allergic manifestations using BALB/c mice and cultures of splenocyte, RBL-2H3 cells as well as bone marrow mast cells (BMMCs). Also, the characterization of allergic components from PHA-P was studied by LC-MS/MS. Enhanced levels of specific IgE and IgG1, clinical scores, cytokines and chemokines, beta-hexosaminidase, histamine, cysteinyl leukotriene, prostaglandin D2 and abrupt histological changes in the intestine, lung and spleen indicated a pivotal role of PHA-P in red kidney bean allergy. Further, LC-MS/MS study revealed two IgE binding components of PHA-P as PHA-L and PHA-E. Enhanced specific IgE/IgG1 and beta-hexosaminidase level elucidated the possible role of PHA-L and PHA-E in allergic manifestations. Furthermore, in the presence of IgE inhibitor piceatannol, reduced beta-hexosaminidase release to some extent was noticed. The up regulated expression of GATA-3 and T-bet expression was observed in PHA-L as well as PHA-E groups. Taken together, this study revealed the fact that allergenicity potential of red kidney bean may get augmented due to the presence of different phytohemagglutinins. BIOLOGICAL SIGNIFICANCE: Although food allergy is an immune provocation induced mainly by dietary allergenic protein components of the food, the role of dietary lectins in the food induced allergic manifestations cannot be ruled out. Here we provide the systematic evidences about the allergenic potential of PHAs and further disclosed the culprit components as PHA-L and PHA-E. It is an important finding that the PHA-L and PHA E can cause allergic manifestations via not only the IgE mediated pathway but also the non-IgE mediated allergic reactions as evident by the Th1/Th2 cytokines and transcription factors. Further, the PHA-L seems to be more allergenic than the PHA-E. This article is part of a Special Issue entitled: Translational plant proteomics. PMID- 23454659 TI - Optimised 'on demand' protein arraying from DNA by cell free expression with the 'DNA to Protein Array' (DAPA) technology. AB - We have previously described a protein arraying process based on cell free expression from DNA template arrays (DNA Array to Protein Array, DAPA). Here, we have investigated the influence of different array support coatings (Ni-NTA, Epoxy, 3D-Epoxy and Polyethylene glycol methacrylate (PEGMA)). Their optimal combination yields an increased amount of detected protein and an optimised spot morphology on the resulting protein array compared to the previously published protocol. The specificity of protein capture was improved using a tag-specific capture antibody on a protein repellent surface coating. The conditions for protein expression were optimised to yield the maximum amount of protein or the best detection results using specific monoclonal antibodies or a scaffold binder against the expressed targets. The optimised DAPA system was able to increase by threefold the expression of a representative model protein while conserving recognition by a specific antibody. The amount of expressed protein in DAPA was comparable to those of classically spotted protein arrays. Reaction conditions can be tailored to suit the application of interest. BIOLOGICAL SIGNIFICANCE: DAPA represents a cost effective, easy and convenient way of producing protein arrays on demand. The reported work is expected to facilitate the application of DAPA for personalized medicine and screening purposes. PMID- 23454660 TI - Reply to drs. John andrew tomenson and clive campbell. PMID- 23454661 TI - Evaluation of microelectrode array data using Bayesian modeling as an approach to screening and prioritization for neurotoxicity testing. AB - The need to assess large numbers of chemicals for their potential toxicities has resulted in increased emphasis on medium- and high-throughput in vitro screening approaches. For such approaches to be useful, efficient and reliable data analysis and hit detection methods are also required. Assessment of chemical effects on neuronal network activity using microelectrode arrays (MEAs) has been proposed as a screening tool for neurotoxicity. The current study examined a Bayesian data analysis approach for assessing effects of a 30 chemical training set on activity of primary cortical neurons grown in multi-well MEA plates. Each well of the MEA plate contained 64 microelectrodes and the data set contains the number of electrical spikes registered by each electrode over the course of each experiment. A Bayesian data analysis approach was developed and then applied to several different parsings of the data set to produce probability determinations for hit selection and ranking. This methodology results in an approach that is approximately 74% sensitive in detecting chemicals in the training set known to alter neuronal function (23 expected positives) while being 100% specific in detecting chemicals expected to have no effect (7 expected negatives). Additionally, this manuscript demonstrates that the Bayesian approach may be combined with a previously published weighted mean firing rate approach in order to produce a more robust hit detection method. In particular, when combined with the weighted mean firing rate approach, the joint analysis produces a sensitivity of approximately 96% and a specificity of 100%. These results demonstrate the utility of a novel approach to analysis of MEA data and support the use of neuronal networks grown on MEAs as a for neurotoxicity screening approach. PMID- 23454663 TI - A systematic review of the influence of community level social factors on alcohol use. AB - PURPOSE: To explore evidence on the influence of community level social factors on alcohol use among adults and adolescents. METHODS AND RESULTS: Major bibliographic databases were searched for quantitative studies meeting inclusion criteria. After screening, narrative synthesis and a quality review were applied. Forty-eight studies met the eligibility criteria. While the findings were inconclusive for associations between alcohol use and deprivation, poverty, income, unemployment, social disorder and crime, there was some indication that social capital characteristics were protective. CONCLUSIONS: Social capital has a potentially important association with reducing alcohol use. Further studies are required to better understand social influences on alcohol use. PMID- 23454662 TI - The zinc-binding region of IL-2 inducible T cell kinase (Itk) is required for interaction with Galpha13 and activation of serum response factor. AB - Tec family kinases play critical roles in the activation of immune cells. In particular, Itk is important for the activation of T cells via the T cell Receptor (TcR), however, molecules that cooperate with Itk to activate downstream targets remain little explored. Here we show that Itk interacts with the heterotrimeric G-protein alpha subunit Galpha13 during TcR triggering. This interaction requires membrane localization of both partners, and is partially dependent on GDP- and GTP-bound states of Galpha13. Furthermore, we find that Itk interacts with Galpha13 via the zinc binding regions within its Tec homology domain. The interaction between Itk and Galpha13 also results in tyrosine phosphorylation of Galpha13, however this is not required for the interaction. Itk enhances Galpha13 mediated activation of serum response factor (SRF) transcriptional activity dependent on its ability to interact with Galpha13, but its kinase activity is not required to enhance SRF activity. These data reveal a new pathway regulated by Itk in cells, and suggest cross talk between Itk and G protein signaling downstream of the TcR. PMID- 23454664 TI - Conceptualization and measurement of environmental exposure in epidemiology: accounting for activity space related to daily mobility. AB - A considerable body of literature has investigated how environmental exposures affect health through various pathways. These studies have generally adopted a common approach to define environmental exposures, focusing on the local residential environment, using census tracts or postcodes to delimit exposures. However, use of such administrative units may not be appropriate to evaluate contextual effets on health because they are generally not a 'true' representation of the environments to which individuals are exposed. Recent work has suggested that advances may be made if an activity-space approach is adopted. The present paper investigates how various disciplines may contribute to the refinement of the concept of activity space for use in health research. In particular we draw on seminal work in time geography, which provides a framework to describe individual behavior in space and time, and can help the conceptualization of activity space. In addition we review work in environmental psychology and social networks research, which provides insights on how people and places interact and offers new theories for improving the spatial definition of contextual exposures. PMID- 23454665 TI - Looking for Mr. PG: masculinities and men's depression in a northern resource based Canadian community. AB - Research has attributed the 'silent suffering' of men with depression to the influences of dominant masculine ideals such as strength and stoicism. Similarly, rural ideals - romanticized notions about rural places - have been shown to mute mental health issues and create barriers to help-seeking. This article examines the experiences of men with depression in Prince George, a northern resource based community in British Columbia, Canada. Findings reveal how depressed men and their female partners enacted strategies to positively reinforce men's gendered sense of self, in a context that otherwise may render them 'out of place'. While favouring men's wellbeing, these strategies can also perpetuate an invisible geography of men's depression. PMID- 23454666 TI - Protocol for an experimental study design to evaluate computer-enabled intervention to prevent and manage metabolic syndrome. AB - INTRODUCTION: The rising prevalence of overweight and obesity has a direct correlation with increasing prevalence of hypertension, dyslipidaemia, type 2 diabetes, metabolic syndrome (MetS) and cardiovascular diseases. Most of the previous studies have been cross-sectional in nature and have looked at the prevalence of metabolic syndrome. Despite the clinical and public health importance of this phenomenon, not enough work has been carried out so far to study and remedy this situation. The objectives of the proposed study is to develop an innovative user-centred informatics platform that will facilitate delivery of a multifactorial intervention after taking into account user sociodemographics, health behaviour, prior disease state and knowledge attitudes and practices. OBJECTIVE: The objective of the proposed study is to develop an innovative user-centred informatics platform that will facilitate delivery of a multifactorial intervention after taking into account users' sociodemographics, health behaviour, prior disease state and knowledge, attitudes and behaviour. METHODS AND ANALYSIS: A randomised two-group repeated-measures clinical trial design will be used, on 750 subjects from urban, rural and slum areas, in an Indian setting. The study participants will be randomly assigned to either the intervention (computer-based MetS Program, CBMP) or control (printed educational material, PEM) group. Both the groups will undergo screening, learning and evaluation assessments at the time of the visit and at follow-up visits 30, 60 and 90 days after the first visit. OUTCOMES: The outcomes expected in the intervention group include improvement in Mets-related knowledge, adherence to self-care practices, better quality of life and increased satisfaction with medical care. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of Asian Institute of Public Health (IRB#621). The proposed study will also help us assess the usefulness and challenges of technology to disseminate health education among diverse users. Findings will be disseminated through peer-reviewed publications and national and international conference presentations to various stakeholders and local community health leaders. The ClinicalTrials.gov Identifier is NCT01713465. PMID- 23454667 TI - Do external stimuli impact the gait of children with idiopathic toe walking? A study protocol for a within-subject randomised control trial. AB - INTRODUCTION: Frequently, toe walking gait is the result of disease processes, trauma or neurogenic influences. Idiopathic toe walking (ITW) is, by definition, the diagnosis of a toe walking gait adopted in the absence of one of these medical conditions. Long-term ITW has been associated with reduced ankle range of motion. Reported treatments have included serial casting, Botulinum toxin type A or surgery to improve the ankle range of motion. Investigating the impact of simple and non-invasive treatment options for ITW is important for future research and clinical outcomes. This study investigates the immediate impact of footwear, footwear with orthotics and whole body vibration on ITW to determine if any one intervention improves heel contact and spatial-temporal gait measures. This determination is important for future clinical trials into treatment effectiveness. METHODS AND ANALYSIS: DESIGN: this protocol describes a within subject randomised controlled trial that measures changes in gait following changes in external stimuli. PARTICIPANTS: 15 children diagnosed with an ITW gait will be recruited from the Victorian Paediatric Rehabilitation Service at Monash Children's Hospital Toe Walking Clinic provided they have ITW and meet the inclusion criteria. PROCEDURE: participants will have their gait recorded walking barefoot, in usual footwear, a custom-made, full-length carbon fibre orthotic in usual footwear and following whole body vibration. Outcome measures will include the presence of bilateral heel contact preintervention and postintervention, stride length (cm), stride width (cm), left and right stride time (s), left and right stance and swing percentage of the gait cycle, gait velocity (m/s), left and right foot toe in/toe out angle ( degrees ) and weight-bearing lunge pre and post each condition. ETHICS AND DISSEMINATION: The results of this study will be published at the conclusion and have been approved by Southern Health HREC:12102B. CLINICAL TRIAL REGISTRY NUMBER: ACTRN12612000975897. PMID- 23454668 TI - The mode of action of juvenile hormone and ecdysone: towards an epi endocrinological paradigm? AB - In some insect species, two sites of juvenile hormone (JH) synthesis have been reported: the very well documented corpora allata that secrete JH for "general use", and the reproductive system, in particular the male accessory glands, in which the function of the sometimes huge amounts of JH (e.g. in Hyalophora cecropia) remains to be clarified. A recent finding in Schistocerca gregaria, namely that suppression of the ecdysteroid peak preceding a molt by RNAi of the Halloween genes spook, phantom and shade does not impede normal molting, challenges the (never experimentally proven) classical concept that such a peak is causally linked to a molt. Recent developments in epigenetic control of gene expression in both the honey bee and in locusts suggest that, in addition to the classical scheme of hormone-receptor (membrane- and/or nuclear) mode of action, there may be a third way. Upon combining these and other orphan data that do not fit in the commonly accepted textbook schemes, we here advance the working hypothesis that both JH and ecdysone might be important but overlooked players in epigenetic control of gene expression, in particular at extreme concentrations (peak values or total absence). In this review, we put forward how epi endocrinology can complement classical arthropod endocrinology. PMID- 23454669 TI - Neuropeptidergic regulation of reproduction in insects. AB - Successful animal reproduction depends on multiple physiological and behavioral processes that take place in a timely and orderly manner in both mating partners. It is not only necessary that all relevant processes are well coordinated, they also need to be adjusted to external factors of abiotic and biotic nature (e.g. population density, mating partner availability). Therefore, it is not surprising that several hormonal factors play a crucial role in the regulation of animal reproductive physiology. In insects (the largest class of animals on planet Earth), lipophilic hormones, such as ecdysteroids and juvenile hormones, as well as several neuropeptides take part in this complex regulation. While some peptides can affect reproduction via an indirect action (e.g. by influencing secretion of juvenile hormone), others exert their regulatory activity by directly targeting the reproductive system. In addition to insect peptides with proven activities, several others were suggested to also play a role in the regulation of reproductive physiology. Because of the long evolutionary history of many insect orders, it is not always clear to what extent functional data obtained in a given species can be extrapolated to other insect taxa. In this paper, we will review the current knowledge concerning the neuropeptidergic regulation of insect reproduction and situate it in a more general physiological context. PMID- 23454670 TI - Reverse genetics tools in zebrafish: a forward dive into endocrinology. AB - The zebrafish is a powerful genetic model organism. In recent years, zebrafish has been increasingly used to model human diseases. Due to a number of recent technological advancements, the genetic tool box is now also stocked with sophisticated transgenic and reverse genetic tools. Here, we focus on both commonly used and recently established reverse genetic and transgenic tools available in zebrafish. These new developments make the zebrafish an even more attractive animal model in comparative endocrinology. PMID- 23454671 TI - Rheumatic fever: a disease still to be kept in mind. PMID- 23454672 TI - Lipophilic components from Fructus Viticis Negundo and their anti-tumor activities. AB - Two new triterpenoids, (24R/S)-24-hydroxy-3alpha 10alpha-epoxy-9-eip-cucurbita-25 ene (1a, b), as well as six known compounds (3-8), were isolated from the extraction of Fructus Viticis Negundo. Their structures were established on the basis of spectral analysis. In addition, all the compounds were tested for inhibitory effect against K-562 and A-549 cell lines. PMID- 23454673 TI - Do robots have goals? How agent cues influence action understanding in non-human primates. AB - The capacity to understand goals and intentions emerges early and universally in humans and is a basic precondition for the interpretation and prediction of others' actions, be it other humans, animals, or even robots. It is unclear, however, how this goal attribution system is acquired, in particular with regard to the role of prior experience with the actor and visual characteristics that are necessary. In four preferential looking time experiments we examined how familiarity, appearance, and movement of different agents influence the capability of marmosets to perceive the behavior of these agents as goal directed. To this end we compared the monkeys' reactions to the same goal directed actions performed by four different agents: a human actor, a conspecific, a monkey-like small robot, and a black box. The results showed that monkeys attributed goals to the human actor, the conspecific, and the robot, but not the box. Thus, the monkeys extended their capacity for goal attribution not only to familiar agents, but also to agents not previously encountered, provided that they had some conspecific-like features. Our results suggest that in non human primates, the system for goal attribution does not require previous experience with a specific agent or agent-category, as long as it exhibits certain visual characteristics like face, body or legs. Furthermore, the results suggest that the capacity to attribute goals emerged very early during evolution and, at least in marmoset monkeys, does not necessarily require pre-learned associations in order to fulfill its function when dealing with unfamiliar agents. PMID- 23454674 TI - Effects of whole body (56)Fe radiation on contextual freezing and Arc-positive cells in the dentate gyrus. AB - The space radiation environment contains high-energy charged particles such as (56)Fe, which could pose a significant hazard to hippocampal function in astronauts during and after the mission(s). The mechanisms underlying impairments in cognition are not clear but might involve alterations in the percentage of neurons in the dentate gyrus expressing the plasticity-related immediate early gene Arc. Previously, we showed effects of cranial (56)Fe irradiation on hippocampus-dependent contextual freezing and on the percentage of Arc-positive cells in the enclosed, but not free, blade. Because it is unclear whether whole body (56)Fe irradiation causes similar effects on these markers of hippocampal function, in the present study we quantified the effects of whole body (56)Fe irradiation (600MeV, 0.5 or 1Gy) on hippocampus-dependent and hippocampus independent cognitive performance and determined whether these effects were associated with changes in Arc expression in the enclosed and free blades of the dentate gyrus. Whole body (56)Fe irradiation impacted contextual but not cued fear freezing and the percentage of Arc-positive cells in the enclosed and free blades. In mice tested for contextual freezing, there was a correlation between Arc-positive cells in the enclosed and free blades. In addition, in mice irradiated with 0.5Gy, contextual freezing in the absence of aversive stimuli correlated with the percentage of Arc-positive cells in the enclosed blade. In mice tested for cued freezing, there was no correlation between Arc-positive cells in the enclosed and free blades. In contrast, cued freezing in the presence or absence of aversive stimuli correlated with Arc-positive cells in the free blade. In addition, in mice irradiated with 1Gy cued freezing in the absence of aversive stimuli correlated with the percentage of Arc-positive neurons in the free blade. These data indicate that while whole body (56)Fe radiation affects contextual freezing and Arc-positive cells in the dentate gyrus, the enclosed blade might be more important for contextual freezing while the free blade might be more important for cued freezing. PMID- 23454675 TI - Effects of lurasidone on executive function in common marmosets. AB - Cognitive impairment is one of the major symptoms of schizophrenia, and is considered largely due to dysfunctions in the prefrontal cortex (PFC). Lurasidone, a novel atypical antipsychotic agent with high binding affinity for dopamine D2, serotonin 5-HT7, 5-HT2A and 5-HT1A receptors has been reported to have superior efficacy in rodents' models of cognitive impairment. However, the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non-human primates. In this study, we investigated the effect of lurasidone on executive function, which is one of the cognitive domains, in common marmosets and compared the results to those of other antipsychotics. The effects of lurasidone, haloperidol, olanzapine, risperidone, quetiapine and clozapine on executive function were evaluated in naive marmosets using the object retrieval with detours (ORD) task. Before drug treatment, marmosets' success rates in the easy trial of the test were almost 90%. However, maximum success in the difficult trial of the task reached only 50% after 8 days of training. Haloperidol, olanzapine and risperidone decreased correct performance even in the easy trial of the task. All drugs, except lurasidone, impaired success rate in the difficult trial. On the other hand, lurasidone dose-dependently increased marmosets' success rates in the difficult trial with significant effect at 10mg/kg. In conclusion, we have shown in this study that lurasidone, unlike conventional antipsychotics, improves cognition associated with executive function in common marmosets. These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics. PMID- 23454676 TI - Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay. AB - This report describes the analytical validation and application of the homogeneous mobility shift assay (HMSA) method for the measurement of adalimumab and human antibodies-to-adalimumab (ATA) in serum samples from patients who have lost response to adalimumab treatment. Validation of the ATA- and the adalimumab HMSA revealed a lower limit of detection to be 0.026 U/mL for ATA and 0.018 MUg/mL for adalimumab in serum samples. Intra-assay and inter-assay precision determination yielded a coefficient of variation of less than 15%, and the accuracy of both assays was within 20%. Adalimumab drug tolerance in the ATA-HMSA was up to 20 MUg/mL in the test serum. Serum samples from 100 drug-naive healthy subjects were tested to set-up the cut point of 0.55 U/mL for ATA and 0.68 MUg/mL for adalimumab. Analysis of 100 serum samples from patients who were losing response to adalimumab showed that 26% had an adalimumab level below the cut point, of these 68% were ATA positive. Overall, 44% of the patients (44/100) were positive for ATA. This study presents evidence that drug and anti-drug antibody levels are important determinants of patient response to therapy. PMID- 23454677 TI - Development and validation of a stability indicating method for seven novel derivatives of lamivudine with anti-HIV and anti-HBV activity in simulated gastric and intestinal fluids. AB - A simple micellar liquid chromatography (MLC) method has been developed and validated for use in stability indicating studies of lamivudine and its carbonate derivatives with proved activity against human immunodeficiency and hepatitis B viruses (HIV and HBV, respectively), in simulated gastric (SGF) and intestinal (SIF) fluids samples. The optimized method involves a C18 column thermostated at 30 degrees C, UV detection at 272 nm, a flow rate of 1.0 mL min(-1) and a micellar mobile phase composed by 0.15M sodium dodecyl sulphate (SDS) - 4% (v/v) 1-butanol - 0.01 M KH2PO4-Na2HPO4 (pH 7), using zidovudine (AZT) as internal standard. Validation under Food and Drug Administration (FDA) guideline of the analytical parameters include: linearity (r(2)>0.9996), LODs (1.6 * 10(-7)-6.9 * 10(-6)M) and LOQ (1 * 10(-5)M), intra (0.02-1.48%) and inter-day precision (0.04 1.66%) expressed as relative standard deviation (R.S.D.), and robustness parameters (less than 1.98%). Using this method, recoveries ranging from 92.9 to 119% were obtained for the eight substances. Thus, this method provides a simple, sensitive, accurate and precise assay for the determination of all compounds that can be readily adaptable to routine use by clinical laboratories with standard equipment. In addition, we evaluated the stability of carbonates of lamivudine in buffer pH 1.2 and 6.8; SGF (pH 1.2) and SIF one (pH 6.8), all as indicated in United States Pharmacopeia (USP) 32. Finally, this chromatographic method was applied to stability studies which resulted in all the compounds following a pseudo-first-order kinetics, and in the determination of its kinetic constant and half-life time. PMID- 23454678 TI - Development and in-line validation of a Process Analytical Technology to facilitate the scale up of coating processes. AB - Incorporation of an active pharmaceutical ingredient (API) into the coating layer of film-coated tablets is a method mainly used to formulate fixed-dose combinations. Uniform and precise spray-coating of an API represents a substantial challenge, which could be overcome by applying Raman spectroscopy as process analytical tool. In pharmaceutical industry, Raman spectroscopy is still mainly used as a bench top laboratory analytical method and usually not implemented in the production process. Concerning the application in the production process, a lot of scientific approaches stop at the level of feasibility studies and do not manage the step to production scale and process applications. The present work puts the scale up of an active coating process into focus, which is a step of highest importance during the pharmaceutical development. Active coating experiments were performed at lab and production scale. Using partial least squares (PLS), a multivariate model was constructed by correlating in-line measured Raman spectral data with the coated amount of API. By transferring this model, being implemented for a lab scale process, to a production scale process, the robustness of this analytical method and thus its applicability as a Process Analytical Technology (PAT) tool for the correct endpoint determination in pharmaceutical manufacturing could be shown. Finally, this method was validated according to the European Medicine Agency (EMA) guideline with respect to the special requirements of the applied in-line model development strategy. PMID- 23454679 TI - A sensitive liquid chromatographic-mass spectrometric method for simultaneous quantification of six iridoid glycosides from Zhi-zi-chi Decoction in rat plasma and its application to a pharmacokinetic study. AB - A sensitive liquid chromatographic-mass spectrometric (LC-MS) method was developed and validated for simultaneous determination of geniposide, geniposidic acid, scandoside methyl ester, gardenoside, deacetyl asperulosidic acid methyl ester and genipin-1-beta-gentiobioside after oral administration of Zhi-zi-chi Decoction in rat plasma. The six iridoid glycosides were extracted from plasma samples by protein precipitation, and then separated on an Apollo C18 column (250 mm * 4.6mm, 5 MUm) through the application of a gradient elution. The analytes were monitored in positive electrospray ionization by selected ion monitoring mode (SIM). The lower limits of quantitation (LLOQ) of the six analytes were all lower than 6 ng/mL. The accuracy (relative error, RE%) was between -7.0% and 9.9%, while the intra- and inter-day precisions (relative standard deviation, RSD%) were less than 6.3% and 9.8% for the six analytes, respectively. The developed method was successfully applied to a comparative pharmacokinetic study of the six iridoids in rat plasma after oral administration of Zhi-zi-chi Decoction and Gardenia jasminoides extract. PMID- 23454680 TI - Role of alpha-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity. AB - Abnormal aggregation of alpha-synuclein (alpha-syn) plays a critical role in the pathogenesis of Parkinson's disease (PD). Iron is also believed to serve as a major contributor by inducing oxidative stress and alpha-syn aggregation. Here, we report that down-regulation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) may contribute to iron-induced alpha-syn aggregation. In this study, we show that ferrous iron down-regulates Nrf2 and HO-1 in a time dependent manner in SK-N-SH neuroblastoma cells. Levels of both Nrf2 and HO-1 are decreased even more by ferrous iron in SK-N-SH cells that overexpress alpha-syn and results in greater cell toxicity. Consistent with these results, knockdown of alpha-syn expression prevents reduction of Nrf2 and HO-1 by ferrous iron, eliminates alpha-syn aggregates, and protects SK-N-SH cells against ferrous iron induced cell damage. Furthermore, increased HO-1 expression exerts a protective role against ferrous iron. These results support a new hypothesis of synergistic alpha-syn/iron cytotoxicity, whereby ferrous iron induces alpha-syn aggregation and neurotoxicity by inhibiting Nrf2/HO-1. Inhibition of Nrf2/HO-1 leads to more alpha-syn aggregation and greater toxicity induced by iron, creating a vicious cycle of iron accumulation, alpha-syn aggregation and HO-1 disruption in PD. PMID- 23454681 TI - Polarization profiles of human M-CSF-generated macrophages and comparison of M1 markers in classically activated macrophages from GM-CSF and M-CSF origin. AB - Monocytes/macrophages (MPhi), considered as plastic cells, can differentiate into either a pro-inflammatory (M1) subtype, also known as a classically activated subtype, or an anti-inflammatory alternatively activated subtype (M2) according to their microenvironment. Phenotypic markers of mouse polarized MPhi have been extensively studied, whereas their human counterparts remain less characterized. The main goal of this study was therefore to carefully characterize phenotypic and genomic markers of primary human MPhi generated from M-CSF-treated blood monocytes and polarized towards M1 or M2 subtype upon the action of lipopolysaccharide and interferon-gamma (for M1) or interleukin (IL)-4 (for M2). Membrane expression of the markers CD80 and CD200R was found to be specific of human M1 and M2 polarized MPhi, respectively, whereas, by contrast, mannose receptor (CD206) expression did not discriminate between M1 and M2. mRNA expression analysis further identified six markers of M1 polarization (IL-12p35, CXCL10, CXCL11, CCL5, CCR7 and IDO1), five markers of M2 polarization (TGF-beta, CCL14, CCL22, SR-B1 and PPARgamma) and transcription factors involved in MPhi polarization. Ability of human M-CSF-generated MPhi to polarize toward M1 or M2 subtype was also associated with enhanced secretion of TNFalpha, IL-1beta, IL 12p40, CXCL10 and IL-10 (for M1) or CCL22 (for M2). Moreover, the comparison of the expression of M1 markers in M-CSF- and GM-CSF-MPhi polarized towards M1 subtype has revealed similarities. In conclusion, we demonstrated that human M CSF MPhi can polarize toward a M1 type after IFNgamma/LPS stimulation. Moreover, the M1 and M2 markers of human polarized MPhi identified in the present study may be useful to better identify human MPhi subtypes, particularly at the tissue level, in order to better understand their respective roles in the development of pathologies. PMID- 23454682 TI - The ratio between dendritic cells and T cells determines whether prostaglandin E2 has a stimulatory or inhibitory effect. AB - Prostaglandin E2 has been shown to enhance the maturation, migration, and antigen presenting capacity of DCs. It is therefore included in many maturation cocktails for the generation of monocyte-derived DCs. Paradoxically, PGE2 is also an important tumor-derived immunosuppressive factor and has inhibitory effects on DC differentiation and function. To further investigate these seemingly contradictory results we studied whether the DC:T cell ratio has an impact on the outcome of the interaction between PGE2-treated DCs and T cells. Surprisingly, at high DC:T cell ratios T cell proliferation was inhibited while at low ratios PGE2 treated DCs displayed enhanced T cell-stimulatory properties. The inhibitory function of PGE2-treated DCs depended primarily on the PGE2-induced induction of indoleamine 2,3-dioxygenase competence. In summary, we show that PGE2-treated DCs can have either an immunogenic or tolerogenic function depending on the DC:T cell ratio. This finding could explain the conflicting results regarding the influence of PGE2 on DC function. PMID- 23454683 TI - The genus Rhododendron: an ethnopharmacological and toxicological review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The vast genus Rhododendron includes species that have been used in traditional medicine for the treatment of inflammatory conditions, pain, gastro-intestinal disorders, common cold, asthma, skin disease, etc. Rhododendrons are also well known for their toxicity and some species have been traditionally used as poison. AIM OF THE REVIEW: The work reviews and analyses the traditional use, biological activities with the corresponding chemical constituents, and toxicological data on Rhododendron species. The review aims at characterizing the ethnopharmacology of the genus in relation to its toxicity in order to identify the therapeutic potential of Rhododendron species and future directions for research. METHODS: Data regarding Rhododendron spp. was collected using electronic databases (SciFinder, PubMed, Google Scholar) and library search for selected peer-reviewed articles. Plant taxonomy was validated by the databases The Plant List, Tropicos, eFloras, Flora Iberica and Flora Europaea (RBGE). Additional information on traditional use and botany was obtained from published books. The review encompasses literature, mainly regarding biological activity and toxicological data, from 1898 to the end of December 2012. RESULTS: Rhododendrons have been used in Asian, North American and European traditional medicine mainly against inflammation, pain, skin ailments, common cold and gastro-intestinal disorders. In vivo and in vitro testing of plant extracts and isolated compounds determined diverse biological activities including anti-inflammatory, analgesic, anti-microbial, anti-diabetic, insecticidal and cytotoxic activity. Rhododendron spp. can cause intoxications in humans following intake of rhododendron honey or medicinal preparations. The toxicity is due to grayanotoxins, diterpenes which activate voltage-gated sodium channels and lead to gastro-intestinal, cardiac and central nervous system symptoms. CONCLUSION: Rhododendron species are useful traditional remedies for the treatment of inflammation, pain, skin ailments, common cold and gastro intestinal disorders. Pharmacological data has validated most indications of rhododendrons in ethnomedicine and toxicology studies have confirmed the toxicity observed by traditional use. Ethnopharmacological data point to the therapeutic potential of the genus Rhododendron for the treatment of inflammatory conditions and pain and, thus, research should focus on identification of active compounds and related mechanistic studies. Prolonged and high dose intake of traditional formulations containing rhododendrons should be avoided until more in depth toxicity studies become available. PMID- 23454684 TI - Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The radices of Glycyrrhiza uralensis Fisch. and herbal preparations containing Glycyrrhiza spp. have been used for thousands of years as an herbal medicine for the treatment of viral induced cough, viral hepatitis, and viral skin diseases like ulcers in China. Glycyrrhizic acid (GA) is considered the principal component in Glycyrrhiza spp. with a wide spectrum of antiviral activity. AIM: The present study attempt to validate the medicinal use of Glycyrrhiza uralensis for hand, foot and mouth disease (HFMD) and further to verify whether GA is an active antiviral component in the water extract of Glycyrrhiza uralensis. MATERIALS AND METHODS: Radices of Glycyrrhiza uralensis Fisch. were extracted with hot water. The chemical contents of the extract were profiled with HPLC analysis. The antiviral activity of the extract and the major components was evaluated against infection of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) on Vero cells. The cytopathic effect caused by the infection was measured with MTT assay. Infectious virion production was determined using secondary infection assays and viral protein expression by immunoblotting analysis. RESULTS: The extract at 1000 MUg/ml suppressed EV71 replication by 1.0 log and CVA16 by 1.5 logs. The antiviral activity was associated with the content of GA in the extract since selective depletion of GA from the extract by acid precipitation resulted in loss of antiviral activity. In contrast, the acid precipitant retained antiviral activity. The precipitant at a concentration of 200 MUg/ml inhibited EV71 and CVA16 replication by 1.7 and 2.2 logs, respectively. Furthermore, GA dose-dependently blocked viral replication of EV71 and CVA16. At 3 mM, GA reduced infectious CVA16 and EV71 production by 3.5 and 2.2 logs, respectively. At 5mM, CVA16 production was reduced by 6.0 logs and EV71 by 4.0 logs. Both EV71 and CVA16 are members of Enterovirus genus, time-of drug addition studies however showed that GA directly inactivated CVA16, while GA anti-EV71 effect was associated with an event(s) post virus cell entry. CONCLUSIONS: This study validated the medicinal usefulness of radices Glycyrrhiza uralensis against the etiological agents of HFMD. In addition to the identification of GA as the antiviral component of Glycyrrhiza uralensis against EV71 and CVA16 infection, this study also reveals that GA inhibits EV71 and CVA16 with distinct mechanisms. PMID- 23454685 TI - Pitfalls and fallacies interfering with correct identification of embryonic stem cells implanted into the brain after experimental traumatic injury. AB - Cell-therapy was proposed to be a promising tool in case of death or impairment of specific cell types. Correct identification of implanted cells became crucial when evaluating the success of transplantation therapy. Various methods of cell labeling have been employed in previously published studies. The use of intrinsic signaling of green fluorescent protein (GFP) has led to a well known controversy in the field of cardiovascular research. We encountered similar methodological pitfalls after transplantation of GFP-transfected embryonic stem cells into rat brains following traumatic brain injury (TBI). As the identification of implanted graft by intrinsic autofluorescence failed, anti-GFP labeling coupled to fluorescent and conventional antibodies was needed to visualize the implanted cells. Furthermore, different cell types with strong intrinsic autofluorescence were found at the sites of injury and transplantation, thus mimicking the implanted stem cells. GFP-positive stem cells were correctly localized, using advanced histological techniques. The activation of microglia/macrophages, accompanying the transplantation post TBI, was shown to be a significant source of artefacts, interfering with correct identification of implanted stem cells. Dependent on the strategy of stem cell tracking, the phagocytosis of implanted cells as observed in this study, might also impede the interpretation of results. Critical appraisal of previously published data as well as a review of different histological techniques provide tools for a more accurate identification of transplanted stem cells. PMID- 23454686 TI - Multimodality treatment of cerebral arteriovenous malformations. AB - BACKGROUND: Many arteriovenous malformations (AVMs) can be treated with one modality, but with increasing complexity a combination of techniques, including surgical excision, embolization, and radiosurgery, may be beneficial. The 2 senior authors' experience in the multimodal management of AVMs from 1980-2008 is reported, including the results in all patients with rehemorrhage while awaiting treatment or after partial initial treatment has begun. The series contains a disproportionately high number of Spetzler-Martin grade IV and V lesions, owing to the nature of the referral practice. METHODS: Data were collected prospectively. Only patients who were managed until treatment options were exhausted were included; this entailed either treatment to the point of AVM obliteration or inability to treat further using any or all modalities. Patients who presented with intracranial hemorrhage (ICH) in extremis in whom the AVM was excised during the first operation were also included. RESULTS: Of the 290 patients, 265 underwent treatment, and 25 were managed conservatively. An unruptured AVM was present in 48% of patients. Cure was achieved in 233 (88%) of treated patients. Cure was achieved in 25 of 37 patients undergoing radiosurgery only, 56 of 57 undergoing surgery, 100 of 101 undergoing embolization and microsurgical excision, 20 of 34 undergoing embolization alone, 12 of 17 undergoing embolization and radiosurgery, 5 of 5 undergoing surgery and radiosurgery, and 14 of 14 patients undergoing all 3 modalities. Spetzler-Martin grade was found to correlate negatively with cure (P < 0.001). There was a good outcome in 210 patients (72%), moderate disability in 40 patients (14%), severe disability in 22 patients (8%), vegetative state in 1 patient, and 17 patients (6%) died. There was a favorable outcome (no or only moderate deficits) in 93% of patients with Spetzler-Martin grade I-III lesions. The outcome was favorable in 13 of 25 patients (52%) having no treatment, 32 of 37 (86%) having radiosurgery only, 30 of 34 (88%) having embolization only, 54 of 57 (95%) having surgery only, 87 of 101 (86%) having embolization and surgery, 16 of 17 (94%) having embolization and radiosurgery, 5 of 5 (100%) having surgery and radiosurgery, and 13 of 14 (93%) having all 3 modalities. These outcomes included morbidity from initial presenting symptoms, from treatment, and from rehemorrhage. Good recovery was more likely in patients who were treated with surgery as one of the treatments (P = .025). Considering only new deficits related to treatment, 9 patients (3%) incurred severe neurologic deficits, 11 patents died after treatment, 2 patients died of postoperative hematomas, and 6 died of rehemorrhage from residual AVM. Increasing age, Spetzler-Martin grade, and rehemorrhage were correlated with a poorer Glasgow Outcome Scale score (P < 0.05). CONCLUSIONS: These data suggest a higher risk of hemorrhage after partial obliteration of AVM. One should ascertain an acceptably high likelihood of complete obliteration before embarking on treatment. Using a multimodality approach, the authors were able to cure 92% of treated Spetzler-Martin grade I-IV lesions but only 53% of treated Spetzler-Martin grade V lesions. A major neurologic deficit, disabling to the patient, was incurred in 3% of cases, and 11 patients died. PMID- 23454687 TI - Treatment of herniated lumbar disk by sequestrectomy or conventional diskectomy. AB - BACKGROUND: The optimal surgical technique to treat disk herniation radiculopathy is uncertain. Advocates of sequestrectomy cite less perioperative pain and preserved disk architecture, whereas advocates of conventional diskectomy cite less frequent recurrent herniation. METHODS: Consecutive patients were evaluated retrospectively from 2 independent practices, one in which sequestrectomy was performed and one in which conventional diskectomy was performed. Demographic, radiographic, and outcomes data were analyzed to assess clinical results and incidence of recurrent herniation requiring further operation. Patients requiring further surgery were identified from a government-run provincial database independent of the surgeon performing the second procedure. RESULTS: Among 172 patients (98 conventional diskectomy procedures, 74 sequestrectomy procedures), there were no significant differences in age, gender, smoking status, or level of disk herniation. Conventional diskectomy was not associated with greater blood loss, longer surgery, or longer length of stay compared with sequestrectomy. At 3 month follow-up, approximately 85% of patients improved clinically regardless of the procedure performed. However, recurrent herniation over 6 years median follow up requiring further surgery was lower among patients receiving conventional diskectomy (10% overall, 6% same-level, 4% adjacent-level) compared with sequestrectomy (19% overall, 15% same-level, 4% adjacent-level). CONCLUSIONS: No clinical advantage was found to performing a limited sequestrectomy instead of conventional microdiskectomy for the treatment of radiculopathy owing to lumbar disk herniation. Conversely, the incidence of recurrent disk herniation requiring revision surgery was lower in patients treated by more aggressive disk removal. PMID- 23454688 TI - Three-dimensional imaging as a teaching method in anterior circulation aneurysm surgery. AB - OBJECTIVE: Our objective is to present and asses the utility of three-dimensional (3D) intraoperative imaging as a teaching method for anterior circulation aneurysm surgery. METHODS: The senior author's experience in anterior circulation aneurysm surgery during a 28-month period was documented and processed as 3D images and compared with two-dimensional (2D) images. Both 2D and 3D sets of images were created, and, along with a specially designed questionnaire, 30 physicians (15 experienced cerebrovascular surgeons and 15 neurosurgical trainees) were asked to answer the query and state the advantages and disadvantages of both methods. RESULTS: All physicians interviewed agreed that 3D imaging was better than 2D imaging, and that depth perception improved understanding of surgical tactics and anatomical landmarks. The resident/young trainee group seemed to receive more benefit from this than the experienced group. A total of 40% of residents and 20% of the experienced surgeons acknowledged a change in clipping strategy when comparing both sets. 3D imaging improved understanding of the ophthalmic segment in 66.6% of residents and 33.3% of the experienced group. CONCLUSION: Real 3D imaging in anterior circulation aneurysm surgery is an excellent tool to enhance vascular training. Inexperienced trainees seem to benefit greatly from it. This technique might be of use in the future development of new technologies. PMID- 23454689 TI - The current role of steroids in acute spinal cord injury. AB - BACKGROUND: Acute spinal cord injury (ASCI) is a catastrophic event that can profoundly affect the trajectory of a patient's life. Debate continues over the pharmacologic management of ASCI, specifically, the widespread but controversial use of the steroid methylprednisolone (MP). Treatment efforts are impeded because of limitations in understanding of the pathobiology of ASCI and the difficulty in proving the efficacy of therapies. METHODS: This review presents the pathophysiology of ASCI and the laboratory and clinical findings on the use of MP. RESULTS: The use of MP remains a contentious issue in part because of the catastrophic nature of ASCI, the paucity of treatment options, and the legal ramifications. Although historical data on the use of MP in ASCI have been challenged, more recent studies have been used both to support and to oppose treatment of ASCI with steroids. CONCLUSIONS: ASCI is a devastating event with a complex aftermath of secondary damaging processes that worsen the initial injury. Although the results of NASCIS (National Acute Spinal Cord Injury Study) II and III trials led to the widespread adoption of a high-dose MP regimen for patients treated within 8 hours of injury, subsequent studies have called into question the validity of NASCIS conclusions. Further evidence of the ineffectiveness of the MP protocol has led to declining confidence in the treatment over the last decade. At the present time, high-dose MP cannot be recommended as a standard of care, but it remains an option until supplanted by future evidence-based therapies. PMID- 23454690 TI - Universal extracranial-intracranial graft bypass for large or giant internal carotid aneurysms: techniques and results in 38 consecutive patients. AB - OBJECTIVE: To present indications, surgical techniques, and outcomes of extracranial-intracranial (EC-IC) graft bypass. METHODS: Between January 1996 and June 2011, 38 patients with large or giant internal carotid artery (ICA) aneurysms were treated using graft bypass, employing the radial artery (RA) or the saphenous vein (SV) as a graft. Preoperative balloon test occlusions were not performed in any of the cases. In 17 patients, the external carotid artery (ECA) RA-M2 segment of the middle cerebral artery bypass was used for treatment, and ECA-SV-M2 bypass was used in 21 patients. RESULTS: All aneurysms were completely trapped, and there were no subarachnoid hemorrhages or recanalizations of aneurysms during the follow-up period (8-170 months). Of the 38 bypasses, 36 (94.7%) remained patent, and there were no permanent neurologic deficits. Hyperperfusion syndrome was not experienced in this series. There were 2 temporary neurologic deficits. In 1 case using the RA, graft vasospasm occurred, and kinking occurred in 1 case using the SV. Another patient with a SV graft had to undergo an emergent revision of the graft 8 hours after the initial operation. One patient with a SV graft underwent a second operation to control an epidural abscess. CONCLUSIONS: Universal EC-IC graft bypass is a safe and effective method for treating large or giant ICA aneurysms. PMID- 23454691 TI - Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. AB - BACKGROUND & AIMS: The Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis. METHODS: We used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice. RESULTS: Contrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice was reduced compared with wild-type mice, largely because of postnatal de differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de differentiation. The phenotype of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice. CONCLUSIONS: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice. PMID- 23454692 TI - Concentration and activity of the soluble form of the interleukin-7 receptor alpha in type 1 diabetes identifies an interplay between hyperglycemia and immune function. AB - Soluble interleukin-7 (IL-7) receptor alpha (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (T1D; n = 390) as compared with concentrations in age-matched islet autoantibody-negative first-degree relatives of patients (n = 392; P = 0.00001). sCD127 concentration in patients was influenced by islet autoantibody status (P = 0.003) and genotype of the rs6897932 single nucleotide polymorphism within the IL-7RA gene (P = 0.006). Release of sCD127 in vitro was strongly upregulated by activation of T lymphocytes and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7-mediated T-cell proliferation, suggesting a regulatory feedback mechanism on T-cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of T1D suggested that physiological regulation of IL-7-mediated T-cell survival and expansion by sCD127 may be compromised in T1D. The findings indicate that genetic, immunologic, and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in T1D and identify a novel hyperglycemia-mediated interference of immune regulatory networks. PMID- 23454693 TI - Central activating transcription factor 4 (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve. AB - Recent studies have revealed that the central nervous system, particularly the hypothalamus, is critical for regulating insulin sensitivity in peripheral tissues. The aim of our current study is to investigate the possible involvement of hypothalamic activating transcription factor 4 (ATF4) in the regulation of insulin sensitivity in the liver. Here, we show that overexpression of ATF4 in the hypothalamus resulting from intracerebroventricular injection of adenovirus expressing ATF4 induces hepatic insulin resistance in mice and that inhibition of hypothalamic ATF4 by intracerebroventricular adenovirus expressing a dominant negative ATF4 variant has the opposite effect. We also show that hypothalamic ATF4-induced insulin resistance is significantly blocked by selective hepatic vagotomy or by inhibiting activity of the mammalian target of rapamycin (mTOR) downstream target S6K1. Finally, we show that inhibition of hypothalamic ATF4 reverses hepatic insulin resistance induced by acute brain endoplasmic reticulum (ER) stress. Taken together, our study describes a novel central pathway regulating hepatic insulin sensitivity that is mediated by hypothalamic ATF4/mTOR/S6K1 signaling and the vagus nerve and demonstrates an important role for hypothalamic ATF4 in brain ER stress-induced hepatic insulin resistance. These results may lead to the identification of novel therapeutic targets for treating insulin resistance and associated metabolic diseases. PMID- 23454695 TI - Non-target effects of three formulated pesticides on microbially-mediated processes in a clay-loam soil. AB - An experiment was performed to study non-target effects of difenoconazole (fungicide), deltamethrin (insecticide) and ethofumesate (herbicide) on microbial parameters in a clay-loam soil. Pesticides were applied as commercial formulations to soil samples at different concentrations (5, 50 and 500 mg kg(-1) DW soil) and then incubated under laboratory conditions for 3 months. Throughout the incubation period, microbial parameters were determined at days 7, 30, 60 and 90. At 5 mg kg(-1) DW soil, none of the three pesticides caused significant changes in soil microbial parameters. In contrast, at 500 mg kg(-1) DW soil, pesticide application decreased overall soil microbial activity, negatively affecting the activity of soil enzymes. Similarly, at 500 mg kg(-1) DW soil, difenoconazole and ethofumesate, but not deltamethrin, caused a pesticide-induced stress on soil microbial communities, as reflected by the respiratory quotient. Besides, deltamethrin and ethofumesate at 50 and 500 mg kg(-1) DW soil resulted in lower values of denitrification potential. It was concluded that, although pesticide concentration had a somewhat inconsistent and erratic effect on soil microbial parameters, pesticide application at 500 mg kg(-1) DW soil did have an impact on many of the microbial parameters studied here. PMID- 23454694 TI - Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans. AB - Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset of insulin resistance upon oral high-fat loading compared with lipid and low-dose endotoxin infusion. Sixteen lean insulin-sensitive volunteers received intravenous fat (iv fat), oral fat (po fat), intravenous endotoxin (lipopolysaccharide [LPS]), and intravenous glycerol as control. After 6 h, whole-body insulin sensitivity was reduced by iv fat, po fat, and LPS to 60, 67, and 48%, respectively (all P < 0.01), which was due to decreased nonoxidative glucose utilization, while hepatic insulin sensitivity was unaffected. Muscle PKCtheta activation increased by 50% after iv and po fat, membrane Di-C18:2 DAG species doubled after iv fat and correlated with PKCtheta activation after po fat, whereas ceramides were unchanged. Only after LPS, circulating inflammatory markers (tumor necrosis factor-alpha, interleukin-6, and interleukin-1 receptor antagonist), their mRNA expression in subcutaneous adipose tissue, and circulating cortisol were elevated. Po fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCtheta activation and a rise in distinct myocellular membrane DAG, while endotoxin-induced insulin resistance is exclusively associated with stimulation of inflammatory pathways. PMID- 23454696 TI - Temperature-mortality relationship in four subtropical Chinese cities: a time series study using a distributed lag non-linear model. AB - BACKGROUND: Numerous studies have reported the association between ambient temperature and mortality. However, few multicity studies have been conducted in subtropical regions in developing countries. The present study assessed the health effects of temperature on mortality in four subtropical cities of China. METHODS: We used "double threshold-natural cubic spline" distributed lag non linear model (DLNM) to investigate the cold and hot effects on mortality at different lags in four subtropical cities. Then we conducted a meta-analysis to estimate the overall cold and hot effects on mortality at different lag days. RESULTS: A U-shaped relationship between temperature and mortality was found in the four cities. Cold effect was delayed and persisted for about 27 days, whereas hot effect was acute and lasted for 3 days. In Changsha, Kunming, Guangzhou and Zhuhai, a 1 degrees C decrease of temperature under the low threshold was associated with a lag0-27 cumulative relative risk (RR) of 1.061 (95% confidence interval (CI): 1.023-1.099), 1.044 (95% CI: 1.033-1.056), 1.096 (95% CI: 1.075 1.117) and 1.111 (95% CI: 1.078-1.145) for total mortality, respectively. And RR for 1 degrees C increase of temperature above the hot threshold at the lag0 was 1.020 (95% CI: 1.003-1.037), 1.017 (95% CI: 1.004-1.030), 1.029 (95% CI: 1.020 1.039) and 1.023 (95% CI: 1.004-1.042), respectively. The cold and hot effects were greater among the elderly in Changsha, Guangzhou and Zhuhai. Meta analysis showed that the hot effect decreased gradually with lag days, with the greatest effect at current day (RR=1.023, 95% CI: 1.015-1.031); while the cumulative cold effect increased gradually with lag days, with the highest effect at lag0-27 (RR=1.076, 95% CI: 1.046-1.107). CONCLUSION: Both low and high temperatures were associated with increased mortality in the four subtropical Chinese cities, and cold effect was more durable and pronounced than hot effect. PMID- 23454697 TI - Contribution of mine wastes to atmospheric metal deposition in the surrounding area of an abandoned heavily polluted mining district (Rio Tinto mines, Spain). AB - The present study seeks to estimate the impact of abandoned mine wastes on the levels and chemical profile of total atmospheric deposition in one of the oldest and largest mining districts in Europe (Rio Tinto mines, Iberian Pyrite Belt), on the basis of a complete geochemical characterization of particulate matter samples periodically collected in five sampling stations located around the mining district between March 2009 and February 2011. The annual levels of total bulk deposition (soluble and insoluble fractions) registered in the Rio Tinto Mining District ranged between 18 and 43 g/m(2) depending on the distance from the sampling station with regard to the mine waste deposits. As a general pattern in the area, high mass levels of Zn and Cu were deposited in a range of 9-62 mg/m(2) not only in the insoluble but also in the soluble fraction. Other potentially toxic trace elements such as As, Sb, Ba, Pb, Sn and Bi showed greater deposition fluxes in the locations closest to the mine waste deposits. A principal component analysis with a Multilinear Regression Analysis certifies the presence of two common sources in the mining area: 1) a mineral factor composed mainly of elements derived from silicate minerals (Al, Ca, Sr, Ti, Li, Mg, Mn, K, Na and Fe), mixed with other anthropogenic species (NH4(+), SO4(2-), NO3(-)) within the village closest to the mine; and 2) a marine factor composed of Na, Cl, Mg, SO4(2-) and Sr. In addition, a mine waste factor made up of toxic elements (Cu, Zn, Ga, As, Sb, Ba, Pb, Sn, Cd and Bi) has been recognized in the sampling sites exposed to dust-bearing winds downwind of the mining area, suggesting that mine wastes are a relevant source of heavy-mineral particles with potentially adverse environmental effects to surrounding soils, plants and humans. PMID- 23454698 TI - Effect of sulfide, selenite and mercuric mercury on the growth and methylation capacity of the sulfate reducing bacterium Desulfovibrio desulfuricans. AB - Cultures of the sulfate reducing bacteria Desulfovibrio desulfuricans were grown under anoxic conditions to study the effect of added sulfide, selenite and mercuric ions. A chemical trap consisting in a CuSO4 solution was used to control the poisoning effect induced by the bacterial production of hydrogen sulfide via the precipitation of CuS. Following the addition of Hg(2+), the formation of methylmercury (MeHg) was correlated to bacterial proliferation with most of MeHg found in the culture medium. A large fraction (50-80%) of added Hg(2+) to a culture ended up in a solid phase (Hg(0) and likely HgS) limiting its bioavailability to cells with elemental Hg representing ~40% of the solid. Following the addition of selenite, a small fraction was converted into Se(0) inside the cells and, even though the conversion to this selenium species increased with the increase of added selenite, it never reached more than 49% of the added amount. The formation of volatile dimethylselenide is suggested as another detoxification mechanism. In cultures containing both added selenite and mercuric ions, elemental forms of the two compounds were still produced and the increase of selenium in the residual fraction of the culture suggests the formation of mercuric selenite limiting the bioavailability of both elements to cells. PMID- 23454699 TI - Study of the uptake of non-steroid anti-inflammatory drugs in wheat and soybean after application of sewage sludge as a fertilizer. AB - Non-steroid anti-inflammatory drugs (NSAIDs) are frequently occurring in sludge and waters from sewage treatment plants (STPs). Sludge obtained from sewage treatment is often applied as a fertilizer in agriculture and not many studies about the uptake of pharmaceuticals into crops can be found. In this paper, we present a greenhouse experiment to study the presence of four NSAIDs (naproxen, ketoprofen, diclofenac and ibuprofen) in two different crops (soybean and wheat) after application of sludge as a fertilizer. Two different amounts of sludge were added to the soil; the recommended amount (with respect to phosphorus content) and the double recommended amount. One treatment without sludge was also included as a blank. The crops were harvested after 60 as well as 110 days. Only diclofenac and ibuprofen were detected in the sludge in concentrations of 22 and 217 ng g(-1) dry weight, respectively. None of the NSAIDs were detected in the crops from any of the treatments. Compared to the amounts applied to the soil, detection limits correspond to an uptake of less than 2% for diclofenac and 0.8% for ibuprofen. PMID- 23454700 TI - Assessing the public health impacts of urban air pollution in 25 European cities: results of the Aphekom project. AB - INTRODUCTION: The Aphekom project aimed to provide new, clear, and meaningful information on the health effects of air pollution in Europe. Among others, it assessed the health and monetary benefits of reducing short and long-term exposure to particulate matter (PM) and ozone in 25 European cities. METHOD: Health impact assessments were performed using routine health and air quality data, and a common methodology. Two scenarios were considered: a decrease of the air pollutant levels by a fixed amount and a decrease to the World Health Organization (WHO) air quality guidelines. Results were economically valued by using a willingness to pay approach for mortality and a cost of illness approach for morbidity. RESULTS: In the 25 cities, the largest health burden was attributable to the impacts of chronic exposure to PM2.5. Complying with the WHO guideline of 10 MUg/m(3) in annual mean would add up to 22 months of life expectancy at age 30, depending on the city, corresponding to a total of 19,000 deaths delayed. The associated monetary gain would total some ?31 billion annually, including savings on health expenditures, absenteeism and intangible costs such as well-being, life expectancy and quality of life. CONCLUSION: European citizens are still exposed to concentrations exceeding the WHO recommendations. Aphekom provided robust estimates confirming that reducing urban air pollution would result in significant health and monetary gains in Europe. This work is particularly relevant now when the current EU legislation is being revised for an update in 2013. PMID- 23454702 TI - Uncertainty analysis of pollutant build-up modelling based on a Bayesian weighted least squares approach. AB - Reliable pollutant build-up prediction plays a critical role in the accuracy of urban stormwater quality modelling outcomes. However, water quality data collection is resource demanding compared to streamflow data monitoring, where a greater quantity of data is generally available. Consequently, available water quality datasets span only relatively short time scales unlike water quantity data. Therefore, the ability to take due consideration of the variability associated with pollutant processes and natural phenomena is constrained. This in turn gives rise to uncertainty in the modelling outcomes as research has shown that pollutant loadings on catchment surfaces and rainfall within an area can vary considerably over space and time scales. Therefore, the assessment of model uncertainty is an essential element of informed decision making in urban stormwater management. This paper presents the application of a range of regression approaches such as ordinary least squares regression, weighted least squares regression and Bayesian weighted least squares regression for the estimation of uncertainty associated with pollutant build-up prediction using limited datasets. The study outcomes confirmed that the use of ordinary least squares regression with fixed model inputs and limited observational data may not provide realistic estimates. The stochastic nature of the dependent and independent variables need to be taken into consideration in pollutant build-up prediction. It was found that the use of the Bayesian approach along with the Monte Carlo simulation technique provides a powerful tool, which attempts to make the best use of the available knowledge in prediction and thereby presents a practical solution to counteract the limitations which are otherwise imposed on water quality modelling. PMID- 23454701 TI - Biomagnification and debromination of polybrominated diphenyl ethers in a coastal ecosystem in Tokyo Bay. AB - By field sampling and laboratory experiments we compared the mechanisms by which polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are biomagnified. We measured PBDEs and PCBs, together with stable carbon and nitrogen isotopes as an index of trophic level, in low-trophic-level organisms collected from a coastal area in Tokyo Bay. PBDEs were biomagnified to a lesser degree than PCBs. The more hydrophobic congeners of each were biomagnified more. However, the depletion of BDE congeners BDE99 and BDE153 from fish was suggested. To study congener-specific biotransformation of halogenated compounds, we conducted an in vitro experiment using hepatic microsomes of two species of fish and five BDE congeners (BDE47, 99, 100, 153, and 154) and five CB congeners with the same substitution positions as the PBDEs. BDE99 and 153 were partially debrominated, but BDE47 and 154 were not debrominated. This congener-specific debromination is consistent with the field results. Both in vitro and field results suggested selective debromination at the meta position. The CB congeners were not transformed in vitro. This result is also consistent with the field results, that PCBs were more biomagnified than PBDEs. We conclude that metabolizability is an important factor in the biomagnification of chemicals, but other factors must be responsible for the lower biomagnification of PBDEs in natural ecosystems. PMID- 23454703 TI - Modeling nanomaterial fate in wastewater treatment: Monte Carlo simulation of silver nanoparticles (nano-Ag). AB - Wastewater effluent and sewage sludge are predicted to be important release pathways for nanomaterials used in many consumer products. The uncertainty and variability of potential nanomaterial inputs, nanomaterial properties, and the operation of the wastewater treatment plant contribute to the difficulty of predicting sludge and effluent nanomaterial concentration. With a model parsimony approach, we developed a mass-balance representation of engineered nanomaterial (ENM) behavior based on a minimal number of input variables to describe release quantities to the environment. Our simulations show that significant differences in the removal of silver nanoparticles (nano-Ag) can be expected based on the type of engineered coatings used to stabilize these materials in suspension. At current production estimates, 95% of the estimated effluent concentrations of the nano-Ag considered to be least well-removed by the average wastewater treatment plant are calculated to fall below 0.12 MUg/L, while 95% of the estimated sludge concentrations of nano-Ag with coatings that increase their likelihood of being present in biosolids, fall below 0.35 MUg/L. PMID- 23454704 TI - Impact of mixed land-use practices on the microbial water quality in a subtropical coastal watershed. AB - Surface runoff water is an important non-point source of fecal pollution to downstream water; however, there is a lack of systematic studies on the microbial quality of surface runoff water from watersheds with mixed land uses. In this study water samples from 12 surface runoff holding water bodies (SRW), which collected runoff from various patterns of land use within the St. Lucie watershed along the southeastern coastline of Florida, were collected monthly for 22 months. The concentration of fecal indicator bacteria (FIB) and frequency of detection of Salmonella and host specific markers (HF183, CF128, CF193, and HS esp) were determined, and their associations with land use, rainfall, and water physico-chemical parameters were investigated. Higher FIB concentrations were observed from urban land and cattle ranch sites. Within the same primary land use pattern, different sub-patterns did not have the same level of FIB: golf communities contributed less to fecal pollution than residential areas, and plant nursery sites contained relative higher FIB concentrations than other agricultural sites. Salmonella, CF128, and CF193 markers were more frequently detected from the cattle ranch sites. In contrast the frequency of detecting human specific markers (HF183 and HS-esp) was much higher in residential sites. Rainfall positively affected the concentration of FIB and occurrence of Salmonella, possibly by providing more inputs or mobilizing the sources from sediments. Water temperature, dissolved organic carbon (DOC), and nutrient levels were positively correlated with FIB concentrations and occurrence in SRW, possibly by promoting their growth and survival. This study indicated the need for site specific mitigation strategies to improve SRW and downstream water quality. PMID- 23454705 TI - Characterization of mercury concentrations in snow and potential sources, Shanghai, China. AB - This work focused on quantifying the total mercury (HgT) and major ion concentrations in snow samples to understand the importance of this pathway and sources of Hg deposited in Shanghai, China. Rare snow event samples were collected at 26 sites within the city of Shanghai on February 18, 2006, January 27, 2008 and January 20, 2011. The sites were distributed among four main functional area types (i.e., industrial impacted, residential impacted, traffic impacted sites and sites in the city center). Concentrations of HgT and major soluble ions, and pH values were determined for each site. Mean HgT concentrations for all sites were 78+/-52 ng L(-1), 277+/-184 ng L(-1), 189+/-123 ng L(-1) in 2006, 2008 and 2011, respectively. Values were higher in Shanghai than observed in other cities including Beijing which has a smaller population and is less industrial. Principle component analysis (PCA) indicated that secondary aerosols (SO4(2-), NO3(-) and NH4(+)), and biomass combustion (K(+), CH3COO(-), and HCOO(-)) were best related to mercury concentrations in the snow in 2008 and 2011. Although HYSPLIT back trajectory modeling indicated air mass transport from areas with significant coal combustion, results indicate that anthropogenic pollution from within Shanghai was the predominant source of Hg in snow. PMID- 23454706 TI - Dechlorination of liquid wastes containing chlorinated hydrocarbons by a binder mixture of cement and slag with Fe(II). AB - Iron-based degradative solidification/stabilization (DS/S-Fe(II)) is a modification of conventional solidification/stabilization (S/S) that incorporates degradative processes for organic contaminant destruction with immobilization. This study investigated the effectiveness of a binder mixture of Portland cement and slag in a DS/S-Fe(II) system to treat trichloroethylene (TCE), 1,1 dichloroethylene (1,1-DCE), vinyl chloride (VC), trichloromethane (CF), and dichloromethane (MC), which are major chlorinated hydrocarbons contained in waste oils and waste organic solvents. For TCE, 1,1-DCE, and VC, degradation experiments were conducted using three different binder combinations with Fe(II) (cement/Fe(II), slag/Fe(II), and cement/slag/Fe(II)). When cement and slag were mixed at a 1:1 ratio (% wt), the TCE and 1,1-DCE dechlorination rate was enhanced compared to that when cement or slag was used alone with Fe(II). Also, batch experiments were conducted in the solid phase consisting of cement, slag, sand, and Fe(II) to treat liquid wastes that contain chlorinated compounds at high concentrations. TCE was completely removed after 5 days in the cement/slag/sand/Fe(II) system, in which the initial TCE concentration was 11.8mM, with Fe(II) concentration of 565 mM. While the CF concentration was decreased by 95% after 5 days when the initial CF and Fe(II) concentration was 0.25 mM and 200 mM, respectively. However, MC was not degraded with the cement/slag/Fe(II) system. PMID- 23454708 TI - Study on photophysical and aggregation induced emission recognition of 1,8 naphthalimide probe for casein by spectroscopic method. AB - A novel water-soluble 1,8-naphthalimide derivative 1, bearing two acetic carboxylic groups, exhibited fluorescent turn-on recognition for casein based on the aggregation induced emission (AIE) character. The photophysical properties of 1 consisting of donor and acceptor units were investigated in different solutions. The fluorescence intensity decreased through taking advantage of twisted intramolecular charge transfer (TICT) and self-association emission with increasing solvent polarity. Moreover, the spectral red-shift and intensity quench in protic solvents were caused by the excited-state hydrogen bond strengthening effect. Density Functional Theory (DFT) calculations revealed that 1 exhibited a strong TICT character. The AIE mechanism of 1 with casein was due to 1 docked in the hydrophobic cavity between sub-micelles and bound with Tyr and Trp residues, resulting in the aggregation of 1 on the casein surface and emission enhancement. Based on this, a novel casein assay method was developed. The proposed exhibited a good linear range from 0.1 to 22 MUg mL(-1), with the detection limit of 2.8 ng mL(-1). Satisfactory reproducibility, reversibility and a short response time were realized. This method was applied to the determination of casein in milk powder samples and the results were in good agreement with the result of Biuret method. PMID- 23454707 TI - Anthropogenic impact and lead pollution throughout the Holocene in Southern Iberia. AB - Present day lead pollution is an environmental hazard of global proportions. A correct determination of natural lead levels is very important in order to evaluate anthropogenic lead contributions. In this paper, the anthropogenic signature of early metallurgy in Southern Iberia during the Holocene, more specifically during the Late Prehistory, was assessed by mean of a multiproxy approach: comparison of atmospheric lead pollution, fire regimes, deforestation, mass sediment transport, and archeological data. Although the onset of metallurgy in Southern Iberia is a matter of controversy, here we show the oldest lead pollution record from Western Europe in a continuous paleoenvironmental sequence, which suggests clear lead pollution caused by metallurgical activities since ~3900 cal BP (Early Bronze Age). This lead pollution was especially important during Late Bronze and Early Iron ages. At the same time, since ~4000 cal BP, an increase in fire activity is observed in this area, which is also coupled with deforestation and increased erosion rates. This study also shows that the lead pollution record locally reached near present-day values many times in the past, suggesting intensive use and manipulation of lead during those periods in this area. PMID- 23454709 TI - Matrix isolation FT-IR and theoretical DFT/B3LYP spectrum of 1-naphthol. AB - The FT-IR spectrum of 1-Naphthol isolated in an argon matrix is performed and compared to the infrared spectra calculated at the DFT (B3LYP)/6-31+G(d) level for cis-1-Naphthol and trans-1-Naphthol rotamers in order to clarify the existence of both rotamers in the standard temperature. Comparison of the computed and the experimental matrix spectra reveals the presence in 1-Naphthol argon matrices in the standard temperature of both cis and trans rotameric forms of 1-Naphthol, the last predominating. The relative stability of the trans-1 Naphthol rotamer has also been supported by a fit comparison between the difference of predicted total energy (ETC) of both rotamers of 0.00195 a.u. corresponding to 5.12 kJ mol(-1) and the variation of the standard free Gibbs energy of rotamerization (DeltaGr degrees ) of 5.06 kJ mol(-1). Almost all 51 active vibrational modes of 1-Naphthol have been assigned. The stretching vibration of the OH group (nuOH) appears to be the unique vibrational mode distinguishing the cis-1-NpOH rotamer from the trans-1-NpOH rotamer in FT-IR spectrum. PMID- 23454710 TI - A rapid method for the simultaneous determination of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet by ultra performance liquid chromatography-tandem mass spectrometry. AB - In present study, a rapid and sensitive method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet. The optimum chromatographic separation was carried out on a reversed phase Waters(r) Acquity UPLC BEH C18 column (1.7 MUm particle size, 100 mm * 2.1 mm ID) with an isocratic elution profile and mobile phase consisting of 0.1% formic acid in water and acetonitrile (75:25, v/v, pH 3.5) at flow rate of 0.5 mL min(-1). The influences of mobile phase composition, flow rate and pH on chromatographic resolution were investigated. The total chromatographic analysis time was as short as 2 min with excellent resolution. Detection and quantification of the target compounds were carried out with a triple quadrupole mass spectrometer using negative electrospray ionization (ESI) and multiple reaction monitoring (MRM) modes. The performance of the method was evaluated and very low limits of detection less than 0.09 MUg g(-1), excellent coefficient correlation (r(2)>0.999) with liner range over a concentration range of 0.1-1.0 MUg g(-1) for both L-ascorbic acid and acetylsalicylic acid, and good intraday and interday precisions (relative standard deviations (R.S.D.) <3%), were obtained. Comparison of system performance with traditional liquid chromatography photo diode array detector (HPLC-PDA) was made with respect to analysis time, sensitivity, linearity and precisions. The proposed UPLC-MS/MS method was found to be reproducible and appropriate for quantitative analysis of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet. PMID- 23454711 TI - Physiochemical characterization and antimicrobial evaluation of phenylthiourea formaldehyde polymer (PTF) based polymeric ligand and its polymer metal complexes. AB - Phenylthiourea-formaldehyde polymer (PTF) has been synthesized via polycondensation of phenylthiourea and formaldehyde in basic medium and its corresponding metal complexes [PTF-M(II)] were prepared with Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) ions. The synthesized polymers have been characterized by elemental analysis, magnetic susceptibility, UV-visible, FT-IR, (1)H NMR, (13)C NMR, ESR spectroscopy and thermogravimetric analysis (TGA). Elemental analysis, electronic spectra and magnetic moment measurement indicate that PTF Mn(II), PTF-Co(II) and PTF-Ni(II) show octahedral geometry, while PTF-Cu(II) and PTF-Zn(II) show square planar and tetrahedral geometry, respectively. The results of TGA ascribed that all the PTF-M(II) showed better heat-resistance properties than PTF resin. In vitro antimicrobial activities were performed against several bacteria and fungi using agar well diffusion method. The results of microbial activity were compared with Kanamycin and Miconazole as standard antibiotics for antibacterial and antifungal activities respectively. PMID- 23454712 TI - Global push: multicontinent project assesses particulate matter and birth weight. PMID- 23454713 TI - Integrating strength tests of amputees within the protocol of conventional clinical gait analysis: a novel approach. AB - Clinical experience tells us that the lower-limb amputees are one of the patient groups who clearly suffer from a strength deficit in their involved side. However, there is no obvious evidence for the relation between the residual limb strength and walking ability in this population. Correlating the results of the conventional clinical gait analysis (CGA) with strength tests could help to find out how deficits in strength impact the amputees' gait. In this contribution, a new device for measuring the isometric muscle strength of the hip and the knee was tested for feasibility. Three groups were tested: one group of 11 healthy subjects (29+/-5 years) to test the repeatability of the device, two unilateral amputees (one transfemoral for 56 years, one transtibial for 65 years), and a reference group of 17 healthy subjects (55+/-10 years). The new method presents an adequate technique to integrate strength testing within a standard protocol of the CGA. Results showed to be repeatable within sessions [i.e., within-day, intraclass correlation coefficient (ICC)>0.972] and between repeated measurements (i.e., day-to-day, ICC>0.765). The tested amputees showed clear deficits in maximum isometric joint moments in their most distal joint. The first results suggest evidence for a relation between the maximum isometric joint moments and gait deviations in amputees. PMID- 23454714 TI - Response to: Transferrin/log(ferritin) ratio: a self-fulfilling prophecy when iron deficiency is defined by serum ferritin concentration. PMID- 23454715 TI - Managing laboratory test ordering through test frequency filtering. AB - BACKGROUND: Modern computer systems allow limits to be set on the periods allowed for repetitive testing. We investigated a computerised system for managing potentially overtly frequent laboratory testing, calculating the financial savings obtained. METHODS: In consultation with hospital physicians, tests were selected for which 'spare periods' (periods during which tests are barred) might be set to control repetitive testing. The tests were selected and spare periods determined based on known analyte variations in health and disease, variety of tissues or cells giving rise to analytes, clinical conditions and rate of change determining analyte levels, frequency with which doctors need information about the analytes and the logistical needs of the clinic. RESULTS: The operation and acceptance of the system was explored with 23 analytes. Frequency filtering was subsequently introduced for 44 tests, each with their own spare periods. The proportion of tests barred was 0.56%, the most frequent of these being for total cholesterol, uric acid and HDL-cholesterol. The financial savings were 0.33% of the costs of all testing, with HbA1c, HDL-cholesterol and vitamin B12 yielding the largest savings. Following the introduction of the system the number of barred tests ultimately decreased, suggesting accommodation by the test requestors. CONCLUSIONS: Managing laboratory testing through computerised limits to prevent overtly frequent testing is feasible. The savings were relatively low, but sustaining the system takes little effort, giving little reason not to apply it. The findings will serve as a basis for improving the system and may guide others in introducing similar systems. PMID- 23454716 TI - Augmentation of blood lipid glycation and lipid oxidation in diabetic patients. AB - Lipid oxidation plays a role in the pathophysiology of several diseases, including diabetes. Patients with type 2 diabetes show abnormally high plasma levels of phosphatidylcholine hydroperoxide (PCOOH). However, little is known about the biochemical processes that increase plasma PCOOH in diabetes. We hypothesized that "glycated lipid moieties" may form in diabetic plasma and cause oxidative stress resulting in PCOOH formation. To evaluate this hypothesis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed to analyze Amadori-glycated phosphatidylethanolamine (Amadori-PE, an early stage Maillard product), as well as the advanced glycation end products (AGE) carboxymethyl-PE (CM-PE) and carboxyethyl-PE (CE-PE). The product ion scan, neutral loss scanning, and multiple reaction monitoring provide useful structural and quantitative information about Amadori-PE, CM-PE, and CE-PE in diabetic plasma and erythrocytes. We found that plasma and erythrocyte Amadori-PE concentrations were significantly higher in diabetic patients (757+/-377 nM plasma, 2793+/-989 nM packed cells) than in normal subjects (165+/-66 nM plasma, 712+/-52 nM packed cells), and that Amadori-PE concentrations were positively correlated with PCOOH. By contrast, no significant differences were observed in blood AGE-PE concentrations between diabetic patients (CM-PE: 7.7+/-3.5 nM plasma, 528+/-83 nM packed cells; CE-PE: 2.5+/-1.1 nM plasma, 82+/-24 nM packed cells) and normal subjects (CM-PE: 6.6+/-3.1 nM plasma, 705+/-533 nM packed cells; CE-PE: 4.2+/-1.5 nM plasma, 68+/-16 nM packed cells). These results suggest that Amadori-PE is more prone to accumulation in the blood with diabetes than CM-PE or CE-PE. This review describes the involvement of blood lipid glycation and lipid oxidation in the development of diabetes. PMID- 23454717 TI - Post-translational modification derived products (PTMDPs): toxins in chronic diseases? AB - In living organisms, proteins are progressively modified by spontaneous non enzymatic reactions generating many post-translational modification derived products (PTMDPs) which exert deleterious effects and may be considered endogenous toxins in diabetes mellitus and chronic renal failure. Non-enzymatic glycation, which refers to the spontaneous binding of reducing sugars to free amino groups, is increased in diabetes mellitus because of hyperglycemia and is amplified by oxidative processes ('glycoxidation'). Glycoxidation leads to the formation of 'advanced glycation end products' (AGEs), together with products of other oxidative pathways. AGEs alter tissue organization and cell-protein interactions, mainly in the case of long-lived extracellular matrix proteins, and interact with membrane receptors, among which RAGE (receptor of AGEs), a multiligand receptor which triggers intracellular signaling pathways stimulating inflammatory functions. Another major protein modification, carbamylation, is increased in chronic renal failure, which may occur during the course of diabetes mellitus. Carbamylation is due to the binding of isocyanic acid on the alpha-NH2 extremity of proteins or amino acids, or on epsilon-NH2 lysine groups, generating homocitrulline, a potential biomarker in atherosclerosis. Isocyanic acid is formed in vivo either by spontaneous dissociation of urea or by myeloperoxidase action on thiocyanate. Carbamylated proteins exhibit altered properties. For example, carbamylated collagen is unable to stimulate oxidative functions of polymorphonuclear neutrophils but increases matrix metalloproteinase-9 production by monocytes. Lipoprotein functions are altered by carbamylation and may contribute to atherogenesis. Thus, the numerous PTMDPs may be considered both hallmarks of protein damage in chronic diseases and endogenous toxins acting at the molecular and cellular levels. PMID- 23454718 TI - Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells. AB - BACKGROUND: Advanced glycation end products (AGEs), the final products of the Maillard reaction, have been shown to impair endothelial proliferation and function, thus contributing to endothelial cell injury present in diabetes, inflammatory and cardiovascular diseases. Endoplasmic reticulum (ER) stress triggered under hyperglycemic, hypoxic and oxidative conditions has been implicated in endothelial dysfunction through activation of the unfolded protein response (UPR). The present study investigates the role of AGEs in ER stress induction in human aortic endothelial cells exposed to variable AGE treatments. METHODS: Human aortic endothelial cells (HAEC) were treated with increasing concentrations (100, 200 MUg/mL) of AGE-bovine serum albumin (AGE-BSA) at different time-points (24, 48, 72 h). The induction of ER stress and the involved UPR components were investigated on mRNA and protein levels. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously. RESULTS: AGEs administration significantly reduced HAEC proliferation in a time- and dose-dependent manner. An immediate induction of the ER chaperones GRP78, GRP94 and the transcriptional activator, XBP-1 was observed at 24 h and 48 h. A later induction of the phospho-elF2alpha and proapoptotic transcription factor CHOP was observed at 48 h and 72 h, being correlated with elevated early apoptotic cell numbers at the same time-points. CONCLUSIONS: The present study demonstrates that AGEs directly induce ER stress in human aortic endothelial cells, playing an important role in endothelial cell apoptosis. Targeting AGEs signaling pathways in order to alleviate ER stress may prove of therapeutic potential to endothelial dysfunction-related disorders. PMID- 23454719 TI - What ethical and legal principles should guide the genotyping of children as part of a personalised screening programme for common cancer? AB - Increased knowledge of the gene-disease associations contributing to common cancer development raises the prospect of population stratification by genotype and other risk factors. Individual risk assessments could be used to target interventions such as screening, treatment and health education. Genotyping neonates, infants or young children as part of a systematic programme would improve coverage and uptake, and facilitate a screening package that maximises potential benefits and minimises harms including overdiagnosis. This paper explores the potential justifications and risks of genotyping children for genetic variants associated with common cancer development within a personalised screening programme. It identifies the ethical and legal principles that might guide population genotyping where the predictive value of the testing is modest and associated risks might arise in the future, and considers the standards required by population screening programme validity measures (such as the Wilson and Jungner criteria including cost-effectiveness and equitable access). These are distinguished from the normative principles underpinning predictive genetic testing of children for adult-onset diseases-namely, to make best-interests judgements and to preserve autonomy. While the case for population-based genotyping of neonates or young children has not yet been made, the justifications for this approach are likely to become increasingly compelling. A modified evaluative and normative framework should be developed, capturing elements from individualistic and population-based approaches. This should emphasise proper communication and genuine parental consent or informed choice, while recognising the challenges associated with making unsolicited approaches to an asymptomatic group. Such a framework would be strengthened by complementary empirical research. PMID- 23454720 TI - The case for a duty to research: not yet proven. AB - In this commentary on 'Why participating in (certain) scientific research is a moral duty', I take issue with a number of Stjernschantz Forsberg et al's claims. Though abiding by the terms of a contract might be obligatory, this won't show that those terms themselves indicate a duty--even allowing that there's a contract to begin with. Meanwhile, though we might have reasons to participate, not all reasons are moral reasons, and the paper does not establish that the reasons here are moral in character. PMID- 23454721 TI - Complementary ensemble clustering of biomedical data. AB - The rapidly growing availability of electronic biomedical data has increased the need for innovative data mining methods. Clustering in particular has been an active area of research in many different application areas, with existing clustering algorithms mostly focusing on one modality or representation of the data. Complementary ensemble clustering (CEC) is a recently introduced framework in which Kmeans is applied to a weighted, linear combination of the coassociation matrices obtained from separate ensemble clustering of different data modalities. The strength of CEC is its extraction of information from multiple aspects of the data when forming the final clusters. This study assesses the utility of CEC in biomedical data, which often have multiple data modalities, e.g., text and images, by applying CEC to two distinct biomedical datasets (PubMed images and radiology reports) that each have two modalities. Referent to five different clustering approaches based on the Kmeans algorithm, CEC exhibited equal or better performance in the metrics of micro-averaged precision and Normalized Mutual Information across both datasets. The reference methods included clustering of single modalities as well as ensemble clustering of separate and merged data modalities. Our experimental results suggest that CEC is equivalent or more efficient than comparable Kmeans based clustering methods using either single or merged data modalities. PMID- 23454722 TI - Developing the "write" skills for publishing. AB - Someone once told me that you (as a writer) are only as good as your worst publication. I think the point of that statement is that you should not submit a paper unless you have put your best effort into writing it. The quality of a paper is often a reflection of the amount of time you spent planning and writing it. As detailed in this Commentary, writing for publication is a not a single step but a process that includes planning, writing, submitting, revising, resubmitting, and proofing. Developing good writing skills involves seeking mentors and opportunities to write. However, if you have the passion or desire to publish, it is possible to develop the "write" skills. PMID- 23454723 TI - Agglutination of intravenously administered phosphatidylcholine-containing lipid emulsions with serum C-reactive protein. AB - BACKGROUND: C-reactive protein (CRP) is able to bind phospholipids in the presence of calcium. We wanted to investigate the reaction of CRP with various commercial fat emulsions and to explore the impact of CRP agglutination on serum CRP levels. MATERIALS AND METHODS: Serum specimens were mixed with Intralipid 20% (soybean oil-based fat emulsion), Structolipid (structured oil-based fat emulsion), Omegaven (fish oil-based fat emulsion), or SMOFlipid (mixed soybean oil-, olive oil-, and fish oil-based emulsion) in Tris-calcium buffer (pH 7.5). After 30 minutes of incubation at 37 degrees C, CRP-phospholipid complexes were turbidimetrically quantified and flow cytometric analysis was performed. Similarly, CRP complexes were monitored in vivo, following administration of fat emulsion. RESULTS: CRP was able to agglutinate phospholipid-containing lipid droplets present in the soybean oil-based fat emulsion and the structured oil based fat emulsion. To a lesser extent, agglutination was observed for fish oil containing fat emulsions, whereas no agglutination was noticed for the mixed soybean oil-, olive oil-, and fish oil-based emulsion. Results for propofol containing emulsions were comparable. Agglutination correlated with phospholipid content of the emulsions. When in vivo agglutination occurred, plasma CRP values dropped due to consumption of CRP by phospholipid-induced agglutination. CONCLUSIONS: In this in vitro experiment, we demonstrated agglutination of CRP with phospholipids in various fat emulsions. Research studies are required in patients to determine which effects occur with various intravenous fat emulsions. PMID- 23454724 TI - Colorectal cancer in a 9-year-old due to combined EPCAM and MSH2 germline mutations: case report of a unique genotype and immunophenotype. PMID- 23454725 TI - Frequent expression of follicular dendritic cell markers in Hodgkin lymphoma and anaplastic large cell lymphoma. AB - AIMS: Although the tumour cells of Hodgkin lymphoma (HL) are derived from mature B-cells, the lineage infidelity of Hodgkin/Reed-Sternberg cells (HRSs) often causes diagnostic problems. Recently introduced HRS markers are also positive for follicular dendritic cells (FDCs). We investigated the expression of several FDC markers in HL and anaplastic large cell lymphoma (ALCL) and evaluated their diagnostic efficacy. METHODS: Eighty-five cases of HL and 52 cases of ALCL were included in this study. Immunohistochemistry was performed for glioma-associated homologue (GLI) 3, class III beta-tubulin (TUBB3), fascin, clusterin, gamma synuclein, podoplanin, syntenin, CD21, CD35 and EGFR. RESULTS: HRSs were diffusely positive for GLI3, fascin and TUBB3; the mean positivity rates per case were 94% for GLI3, 82% for fascin, 69% for TUBB3, 17% for clusterin, 17% for gamma-synuclein and 14% for syntenin. Podoplanin, CD21, CD35 and EGFR were almost negative. However, the frequency of marker expression was not associated with the histologic subtype or the presence of Epstein-Barr virus (EBV). ALCL showed a similar pattern to HL, but the overall frequency of positivity was lower than that observed in HL. The mean positivity rates were 56% for GLI3, 62% for fascin, 58% for TUBB3 and 21% for clusterin. The other markers were nearly negative. Anaplastic large cell lymphoma kinase positivity did not affect the expression rates. CONCLUSIONS: This study confirmed the frequent expression of FDC markers in HL and ALCL. Especially, GLI3, fascin and TUBB3 are the most sensitive markers. Further studies are required to evaluate the association between FDCs, HRSs and ALCL cells. PMID- 23454726 TI - Vitamin D: a negative acute phase reactant. AB - OBJECTIVE: We evaluated the effect of the systemic inflammatory response (SIR), as provoked by elective orthopaedic surgery, on serum vitamin D [25-(OH)D]. METHODS: Serum 25-(OH)D, serum vitamin D binding protein (VDBP) and urinary VDBP were measured in 30 patients before and 48-hours after knee or hip arthroplasty. C-reactive protein (CRP) was measured to assess the SIR. RESULTS: The mean (SD) CRP increased following surgery [5.0 (5.5) vs 116.0 (81.2) mg/L; P<0.0001] as did urine VDBP/Creatinine ratio [8 (9) vs 20 (25) pg/mmol; p=0.0004]. Serum 25-(OH)D [56.2 (30.3) vs 46.0 (27.6) nmol/L; p = 0.0006] and serum VDBP [334 (43) vs 298 (37) mg/L]; P<0.0001] decreased. CONCLUSIONS: Serum 25-(OH)D is a negative acute phase reactant, which has implications for acute and chronic inflammatory diseases. Serum 25-(OH)D is an unreliable biomarker of vitamin D status after acute inflammatory insult. Hypovitaminosis D may be the consequence rather than cause of chronic inflammatory diseases. PMID- 23454727 TI - Who makes uric acid stones and why--observations from a renal stones clinic. AB - AIMS: Excessively acidic urine is the dominant factor in uric acid stone formation. Recent evidence implicating insulin resistance has revived interest in its causation. We reviewed data on uric acid stone formers attending a general stones clinic to find out whether this supports and adds to current concepts. METHODS: A retrospective database study of 1504 stone formers investigated at the Southampton renal stones clinic from 1990 to March 2007. Uric acid stone formers and idiopathic calcium stone formers were compared using non-parametric tests. RESULTS: Fifty-nine patients (3.9%; 43 men) had uric acid stones. In men the commonest associated conditions were diabetes (20%), gout (20%) and an ileostomy (15%); in women, diabetes (33%), urinary infections (27%) and hyperparathyroidism (20%). Most patients with diabetes (85% of men, 75% of women), however, produced calcium stones. Risk factors did not differ significantly between calcium and uric acid stone formers with diabetes, gout or ileostomies. The median urine pH of men with idiopathic calcium stones was 6.20, idiopathic uric acid stones 5.47, diabetes 5.68, gout 6.05, diabetes and gout 5.20 and ileostomy 5.10. Plasma urate was higher with gout and idiopathic uric acid stones. Urate excretion was increased in gout. Oxalate excretion was lower with idiopathic uric acid stones (new finding). Urine volume decreased and oxalate concentration increased with ileostomy. CONCLUSIONS: Uric acid stones are increased in diabetes, but most patients with diabetes make calcium stones. Different mechanisms may explain low pH with diabetes, gout and idiopathic stones. Low oxalate excretion with idiopathic urate stones needs confirmation. PMID- 23454729 TI - Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. AB - Coevolution of microbes and their hosts has resulted in the formation of symbiotic relationships that enable animals to adapt to their environments and protect themselves against pathogens. Recent studies show that contact with tolerogenic microbes is important for the proper functioning of immunoregulatory circuits affecting behavior, emotionality and health. Few studies have examined the potential influence of ambient bacteria, such as Mycobacterium vaccae on the gut-brain-microbiota axis. In this preliminary research, we show that mice fed live M. vaccae prior to and during a maze learning task demonstrated a reduction in anxiety-related behaviors and maze completion time, when tested at three maze difficulty levels over 12 trials for four weeks. Treated mice given M. vaccae in their reward completed the maze twice as fast as controls, and with reduced anxiety-related behaviors. In a consecutive set of 12 maze trials without M. vaccae exposure, treated mice continued to run the maze faster for the first three trials, and with fewer errors overall, suggesting a treatment persistence of about one week. Following a three-week hiatus, a final maze run revealed no differences between the experimentals and controls. Additionally, M. vaccae treated mice showed more exploratory head-dip behavior in a zero maze, and M. vaccae treatment did not appear to affect overall activity levels as measured by activity wheel usage. Collectively, our results suggest a beneficial effect of naturally delivered, live M. vaccae on anxiety-related behaviors and maze performance, supporting a positive role for ambient microbes in the immunomodulation of animal behavior. PMID- 23454730 TI - SQAB 2012: timing. PMID- 23454728 TI - Direct association of the reticulon protein RTN1A with the ryanodine receptor 2 in neurons. AB - RTN1A is a reticulon protein with predominant localization in the endoplasmic reticulum (ER). It was previously shown that RTN1A is expressed in neurons of the mammalian central nervous system but functional information remains sparse. To elucidate the neuronal function of RTN1A, we chose to focus our investigation on identifying possible novel binding partners specifically interacting with the unique N-terminus of RTN1A. Using a nonbiased approach involving GST pull-downs and MS analysis, we identified the intracellular calcium release channel ryanodine receptor 2 (RyR2) as a direct binding partner of RTN1A. The RyR2 binding site was localized to a highly conserved 150-amino acid residue region. RTN1A displays high preference for RyR2 binding in vitro and in vivo and both proteins colocalize in hippocampal neurons and Purkinje cells. Moreover, we demonstrate the precise subcellular localization of RTN1A in Purkinje cells and show that RTN1A inhibits RyR channels in [(3)H]ryanodine binding studies on brain synaptosomes. In a functional assay, RTN1A significantly reduced RyR2-mediated Ca(2+) oscillations. Thus, RTN1A and RyR2 might act as functional partners in the regulation of cytosolic Ca(2+) dynamics the in neurons. PMID- 23454731 TI - Space and power: young mothers' management of smoking in extended families in China. AB - Multigenerational co-residence is a widespread phenomenon in China but there is little knowledge about the impact of power dynamics on smoking behaviors among extended family residents. Using a gender lens, this ethnographic study explored how young mothers in extended families in mainland China managed the smoking of their husbands and other family members. Analysis of data resulted in a model of 'two units-three domains' to reflect gendered relationships between young mothers and other family members, and young mothers' participation in family management. Exploration of the mothers' efforts to deal with household smoking using the model provided an explanation for why the young mothers had limited control over household space and could only impose partial restrictions on home smoking in the extended family. PMID- 23454732 TI - The joint effects of census tract poverty and geographic access on late-stage breast cancer diagnosis in 10 US States. AB - This study evaluated independent and joint effects of census tract (CT) poverty and geographic access to mammography on stage at diagnosis for breast cancer. The study included 161,619 women 40+ years old diagnosed with breast cancer between 2004 -2006 in ten participating US states. Multilevel logistic regression was used to estimate the odds of late-stage breast cancer diagnosis for the entire study population and by state. Poverty was independently associated with late stage in the overall population (poverty rates >20% OR=1.30, 95% CI=1.26- 1.35) and for 9 of the 10 states. Geographic access was not associated with late-stage diagnosis after adjusting for CT poverty. State-specific analysis provided little evidence that geographic access was associated with breast cancer stage at diagnosis, and after adjusting for poverty, geographic access mattered in only 1 state. Overall, compared to women with private insurance, the adjusted odds ratios for late stage at diagnosis among women with either no insurance, Medicaid, or Medicare were 1.80 (95% CI = 1.65, 1.96), 1.75 (95% CI = 1.68, 1.84), and 1.05 (95% CI 1.01, 1.08), respectively. Although geographic access to mammography was not a significant predictor of late-stage breast cancer diagnosis, women in high poverty areas or uninsured are at greatest risk of being diagnosed with late-stage breast cancer regardless of geographic location and may benefit from targeted interventions. PMID- 23454733 TI - Inpatients' and outpatients' satisfaction: the mediating role of perceived quality of physical and social environment. AB - This study analyses the processes through which the physical environment of health care settings impacts on patients' well-being. Specifically, we investigate the mediating role of perceptions of the physical and social environments, and if this process is moderated by patients' status, that is, if the objective physical environment impacts inpatients' and outpatients' satisfaction by different social-psychological processes. Patients (N=206) evaluated the physical and social environments of the care unit where they were receiving treatment, and its objective physical conditions were independently evaluated by two architects. Results showed that the objective environmental quality affects satisfaction through perceptions of environmental quality, and that patients' status moderates this relationship. For inpatients, it is the perception of quality of the social environment that mediates the relationship between objective environmental quality and satisfaction, whereas for outpatients it is the perception of quality of the physical environment. This moderated mediation is discussed in terms of differences on patients' experiences of health care environments. PMID- 23454734 TI - Early life predictors of atrial fibrillation-related mortality: evidence from the health and retirement study. AB - Prior research found that Americans born in 6 southeastern states (the AF-risk zone) had elevated risk of AF-related mortality, but no mechanisms were identified. We hypothesized the association between AF-related mortality and AF risk zone birth is explained by indicators of childhood social disadvantage or adult risk factors. In 24,323 participants in the US Health and Retirement Study, we found that birth in the AF-risk zone was significantly associated with hazard of AF-related mortality. Among whites, the relationship was specific to place of birth, rather than place of adult residence. Neither paternal education nor subjectively assessed childhood SES predicted AF-related mortality. Conventional childhood and adult cardiovascular risk factors did not explain the association between place of birth and AF-related mortality. PMID- 23454735 TI - Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction. AB - Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seems to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) is enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction changes these parameters. In addition, old rats also conserve the capacity to respond to 7weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA. PMID- 23454736 TI - Age >= 60 years was an independent risk factor for diabetes-related complications despite good control of cardiovascular risk factors in patients with type 2 diabetes mellitus. AB - Providing effective medical care for older patients with type 2 diabetes mellitus (T2D) that may contribute to their active aging has always been challenging. We examined the independent effect of age >= 60 years on disease control and its relationship with diabetes-related complications in patients with T2D in Malaysia. This was a cross-sectional study using secondary data from the electronic diabetes registry database Adult Diabetes Control and Management (ADCM). A total of 303 centers participated and contributed a total of 70,889 patients from May 2008 to the end of 2009. Demographic data, details on diabetes, hypertension, dyslipidemia and their treatment modalities, various risk factors and complications were updated annually. Independent associated risk factors were identified using multivariate regression analyses. Fifty-nine percent were female. Malay comprised 61.9%, Chinese 19% and Indian 18%. There were more Chinese, men, longer duration of diabetes and subjects that were leaner or had lower BMI in the older age group. Patients aged >= 60 years achieved glycemic and lipid targets but not the desired blood pressure. After adjusting for duration of diabetes, gender, ethnicity, body mass index, disease control and treatment, a significantly higher proportion of patients >= 60 years suffered from reported diabetes-related complications. Age >= 60 years was an independent risk factor for diabetes-related complications despite good control of cardiovascular risk factors. Our findings caution against the currently recommended control of targets in older T2D patients with more longstanding diseases and complications. PMID- 23454737 TI - Evidence of complement genes in the sea-star Asterias rubens. Comparisons with the sea urchin. AB - The axial organ of the sea star Asterias rubens is a primitive immune organ. The B-like cells, when stimulated by various antigens, produce antibody substances correlating with Ig kappa genes, .On the other hand,component complement genes were found. For each component, one or several contigs were analyzed. It is said that Asterias forbesi, another sea-star, in earlier results, showed complement like activity. A brief comparison with the complement system in sea urchin was performed, especially about the C3 component. PMID- 23454738 TI - High selectivity sensing of cobalt in HepG2 cells based on necklace model microenvironment-modulated carbon dot-improved chemiluminescence in Fenton-like system. AB - In this work, based on electronic spinning resonance and chemiluminescence (CL) measurements, it is found that the reaction kinetics of Co(II)-triggered Fenton like reaction is much faster than those of other transition metal ions, which facilitates the observation of the strong CL signals from Co(II). Utilizing the polymer-surfactant complexes (i.e., necklace model) to act as a novel CL microenvironment, a highly selective CL sensing system for the detection of Co(II) has been successfully fabricated based on the CL resonance energy transfer between the Fenton-like reaction and necklace model microenvironment-modulated carbon dots. Under optimized experimental conditions, this proposed CL system exhibits a stable response to Co(II) over a concentration range from 1.0 to 1000 nM with a detection limit as low as 0.67 nM. Finally, this system has been successfully used for the detection of Co(II) in HepG2 cells, and the results were agreed with those obtained by inductively coupled plasma mass spectrometry (ICP-MS) method. PMID- 23454739 TI - A label-free method for detecting biological thiols based on blocking of Hg2+ quenching of fluorescent gold nanoclusters. AB - A novel, label-free, fluorescent, turn-on sensor for biological thiol detection that uses highly fluorescent gold nanoclusters (AuNCs), prepared by a bovine serum albumin (BSA)-templated green synthetic route, has been developed. The assay relies on blocking Hg(2+)-induced quenching of the fluorescence of AuNCs, caused by metallophilic Hg(2+)-Au(+) interactions, through selective coordination of biological thiols with Hg(2+) ions. Biological thiols entrap added Hg(2+) ions via a robust Hg-S interaction. This phenomenon prevents Hg(2+)-induced quenching and results in fluorescence from AuNCs. By employing this turn-on sensor, biological thiols, such as cysteine (Cys), glutathione (GSH) and homocysteine (Hcy), are successfully detected at concentrations as low as 8.3 nM for Cys, 9.4 nM for GSH, and 14.9 nM for Hcy. The diagnostic capability and potential in practical applications of this method have been demonstrated by detecting biological thiols in human blood serum. PMID- 23454740 TI - pH sensing characteristics and biosensing application of solution-gated reduced graphene oxide field-effect transistors. AB - Solution-gated reduced graphene oxide field-effect transistors (R-GO FETs) were investigated for pH sensing and biochemical sensing applications. A channel of a networked R-GO film formed by self-assembly was incorporated as a sensing layer into a solution-gated FET structure for pH sensing and the detection of acetylcholine (Ach), which is a neurotransmitter in the nerve system, through enzymatic reactions. The fabricated R-GO FET was sensitive to protons (H(+)) with a pH sensitivity of 29 mV/pH in terms of the shift of the charge neutrality point (CNP), which is attributed to changes in the surface potential caused by the interaction of protons with OH surface functional groups present on the R-GO surface. The R-GO FET immobilized with acetylcholinesterase (AchE) was used to detect Ach in the concentration range of 0.1-10mM by sensing protons generated during the enzymatic reactions. The results indicate that R-GO FETs provide the capability to detect protons, demonstrating their applicability as a biosensing device for enzymatic reactions. PMID- 23454741 TI - Molecular determinants of drug-receptor binding kinetics. AB - It is increasingly appreciated that the rates at which drugs associate with and dissociate from receptors--the binding kinetics--directly impact drug efficacy and safety. The molecular determinants of drug-receptor binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug-receptor binding kinetics at the molecular level--molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects- and discuss several possible approaches for the rational design of drugs with desired binding kinetics. PMID- 23454742 TI - Translational medicines research. PMID- 23454743 TI - Hybridization between Cu-O chain and Cu(110) surface states in the O(2*1)/Cu(110) surface from first principles. AB - The O(2*1)/Cu(110) surface reconstruction of the Cu(110) surface is induced by 0.5 ML of oxygen adsorption and is formed by Cu-O chains running along the [001] direction. Here, we show that hybridization between surface states of the Cu(110) substrate and one-dimensional states of the Cu-O chains is crucial in understanding the electronic structure of this surface. Specifically, the interaction between one occupied antibonding band of the Cu-O chain with O(p(y)) character (y-axis taken along the Cu-O chain direction) and the partially occupied surface state at the Y point of the clean Cu(110) surface with Cu(p(y)) character causes major changes in the electronic structure close to the Fermi energy (E(F)). This surface state decays very slowly into the bulk and a thick slab is needed to properly describe it, which might explain why the importance of this hybridization has not been recognized so far. In our calculations we obtain two hybrid bands: (i) a fully occupied band that strongly hybridizes with the bulk Cu sp states nearby E(F), becoming a very broad resonance, thus explaining why it is not observed in photoemission experiments; (ii) an empty band that acquires surface state character, including its dispersion close to the zone boundary at the Y point. This splitting induces a partial population of the p(y) antibonding band that is necessary to reconcile the calculated charge transfer from the Cu(110) substrate to the Cu-O chain (~0.5 electrons/f.u.) with the apparently fully occupied band structure of the adsorbed Cu-O chain (consistent with 1 electron transferred per formula unit). PMID- 23454744 TI - A systems-level approach to studying birth defects: novel method identifies potential key pathway. PMID- 23454745 TI - Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis. AB - Commensal bacteria and their products provide beneficial effects to the mammalian gut by stimulating epithelial cell turnover and enhancing wound healing, without activating overt inflammation. We hypothesized that N-formylpeptide receptors, which bind bacterial N-formylpeptides and are expressed by intestinal epithelial cells, may contribute to these processes. Here we report that formylpeptide receptor-2 (FPR2), which we show is expressed on the apical and lateral membranes of colonic crypt epithelial cells, mediates N-formylpeptide-dependent epithelial cell proliferation and renewal. Colonic epithelial cells in FPR2-deficient mice displayed defects in commensal bacterium-dependent homeostasis as shown by the absence of responses to N-formylpeptide stimulation, shortened colonic crypts, reduced acute inflammatory responses to dextran sulfate sodium (DSS) challenge, delayed mucosal restoration after injury, and increased azoxymethane-induced tumorigenesis. These results indicate that FPR2 is critical in mediating homeostasis, inflammation, and epithelial repair processes in the colon. PMID- 23454747 TI - Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. AB - The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition. PMID- 23454746 TI - IgG4 subclass antibodies impair antitumor immunity in melanoma. AB - Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcgammaRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches. PMID- 23454748 TI - NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. AB - Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gbetagamma/PI3Kgamma/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gbetagamma/PI3Kgamma/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size. PMID- 23454749 TI - BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. AB - BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC-derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC-derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression. PMID- 23454750 TI - Blockade of individual Notch ligands and receptors controls graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These strategies are incompletely effective and decrease the anticancer activity of the allogeneic graft. We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch deprived T cells showed markedly decreased production of inflammatory cytokines, but normal in vivo proliferation, increased accumulation of regulatory T cells, and preserved anticancer effects. Here, we report that gamma-secretase inhibitors can block all Notch signals in alloreactive T cells, but lead to severe on-target intestinal toxicity. Using newly developed humanized antibodies and conditional genetic models, we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during GVHD, with dominant roles for Notch1 and Delta-like4. Notch1 inhibition controlled GVHD, but led to treatment-limiting toxicity. In contrast, Delta-like1/4 inhibition blocked GVHD without limiting adverse effects while preserving substantial anticancer activity. Transient blockade in the peritransplant period provided durable protection. These findings open new perspectives for selective and safe targeting of individual Notch pathway components in GVHD and other T cell-mediated human disorders. PMID- 23454751 TI - STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. AB - Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types of cancer, including head and neck squamous cell carcinoma (HNSCC). In this study, we characterized CD14+HLA-DR(-/lo) cells sorted from the tumors, draining lymph nodes, and peripheral blood of HNSCC patients. CD14+HLA-DR(-/lo) cells were phenotyped as CD11b+, CD33+, CD34+, arginase-I+, and ROS+. In all 3 compartments, they suppressed autologous, antigen-independent T cell proliferation in a differential manner. The abundance of MDSC correlated with stage, but did not correlate with previous treatment with radiation or subsites of HNSCC. Interestingly, MDSC from all 3 compartments showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. Stattic, a STAT3-specific inhibitor, and STAT3-targeted siRNA abrogated MDSC's suppressive function. Inhibition of STAT3 signaling also resulted in decreased arginase-I activity. Analysis of the human arginase-I promoter region showed multiple STAT3-binding elements, and ChIP demonstrated that phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Finally, rescue of arginase-I activity after STAT3 blockade restored MDSC's suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID- 23454754 TI - A conversation with Paul Greengard. Interview by Ushma S. Neill. PMID- 23454752 TI - Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice. AB - The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-gamma-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-gamma and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen presenting cells. PMID- 23454755 TI - Control of inflammation by integration of environmental cues by regulatory T cells. AB - Tregs have been implicated in control of homeostasis in the immune system and beyond. These cells restrain inflammatory responses to self antigens, commensal microorganisms, allergens, and pathogens and adapt their homeostatic and functional capabilities to a particular environment. In this review, we discuss a general model of integration of environmental cues by Tregs in which specialized Treg homeostatic, migratory, and suppression programs are established in dynamically changing inflammatory environments by maintaining an optimal threshold of activation of transcription factors involved in regulation of the corresponding type of effector immune responses. PMID- 23454756 TI - Coming of age: molecular drivers of aging and therapeutic opportunities. AB - Aging is like the weather: everyone talks about it, but no one seems to do anything about it. We believe this may soon change, as an improved understanding of the molecular and genetic pathways underlying aging suggests it is possible to therapeutically target the aging process and increase health span. This Review series focuses on fundamental cellular mechanisms of aging and their relationship to human disease. These pathways include telomere dysfunction in cellular senescence and induction of the senescence-associated secretory phenotype (SASP) in systemic aging, sirtuin family regulation of metabolism and aging-associated diseases, mitochondrial metabolism in aging, the mechanistic target of rapamycin (mTOR) signaling pathway and the use of mTOR inhibitors to increase longevity, the progressive decline of the immune system with age, and aging-associated changes to pancreatic islet beta cells that may contribute to diabetes. Together, these articles explore pathways affecting aging and possible interventional targets to slow or delay the onset of age-related pathologies. PMID- 23454757 TI - The role of mitochondria in aging. AB - Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process. PMID- 23454758 TI - Causes, consequences, and reversal of immune system aging. AB - The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system. PMID- 23454759 TI - Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. AB - Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions. PMID- 23454760 TI - The sirtuin family's role in aging and age-associated pathologies. AB - The 7 mammalian sirtuin proteins compose a protective cavalry of enzymes that can be invoked by cells to aid in the defense against a vast array of stressors. The pathologies associated with aging, such as metabolic syndrome, neurodegeneration, and cancer, are either caused by or exacerbated by a lifetime of chronic stress. As such, the activation of sirtuin proteins could provide a therapeutic approach to buffer against chronic stress and ameliorate age-related decline. Here we review experimental evidence both for and against this proposal, as well as the implications that isoform-specific sirtuin activation may have for healthy aging in humans. PMID- 23454761 TI - Rapalogs and mTOR inhibitors as anti-aging therapeutics. AB - Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling. PMID- 23454762 TI - The role of aging upon beta cell turnover. AB - Preservation and regeneration of beta cell endocrine function is a long-sought goal in diabetes research. Defective insulin secretion from beta cells underlies both type 1 and type 2 diabetes, thus fueling considerable interest in molecules capable of rebuilding beta cell secretion capacity. Though early work in rodents suggested that regeneration might be possible, recent studies have revealed that aging powerfully restricts cell cycle entry of beta cells, which may limit regeneration capacity. Consequently, aging has emerged as an enigmatic challenge that might limit beta cell regeneration therapies. This Review summarizes recent data regarding the role of aging in beta cell regeneration and proposes models explaining these phenomena. PMID- 23454764 TI - Insulin resistance in the vasculature. AB - Insulin resistance is typically defined as a reduced ability of insulin to induce glucose uptake by target tissues such as fat and skeletal muscle cells. It accompanies several disease states, including obesity, type 2 diabetes, hepatitis C, and polycystic ovary syndrome, and is a primary feature of metabolic syndrome. Outside of its effects on blood glucose levels, insulin resistance is also associated with a 2- to 3-fold increased risk of cardiovascular mortality. In 1996, Alain Baron, Helmut Steinberg, and colleagues demonstrated that insulin resistance is associated with endothelial dysfunction. This seminal observation led to significant advances in our understanding of insulin's action in health and disease. PMID- 23454763 TI - Telomeres and age-related disease: how telomere biology informs clinical paradigms. AB - Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies. PMID- 23454765 TI - Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance. AB - T cell surveillance is often effective against virus-associated tumors because of their high immunogenicity. It is not clear why surveillance occasionally fails, particularly against hepatitis B virus- or hepatitis C virus-associated hepatocellular carcinoma (HCC). We established a transgenic murine model of virus induced HCC by hepatocyte-specific adenovirus-induced activation of the oncogenic SV40 large T antigen (TAg). Adenovirus infection induced cytotoxic T lymphocytes (CTLs) targeted against the virus and TAg, leading to clearance of the infected cells. Despite the presence of functional, antigen-specific T cells, a few virus infected cells escaped immune clearance and progressed to HCC. These cells expressed TAg at levels similar to HCC isolated from neonatal TAg-tolerant mice, suggesting that CTL clearance does not select for cells with low immunogenicity. Virus-infected mice revealed significantly greater T cell infiltration in early stage HCC compared with that in late-stage HCC, demonstrating progressive local immune suppression through inefficient T cell infiltration. Programmed cell death protein-1 (PD-1) and its ligand PD-L1 were expressed in all TAg-specific CD8+ T cells and HCC, respectively, which contributed to local tumor-antigen-specific tolerance. Thus, we have developed a model of virus-induced HCC that may allow for a better understanding of human HCC. PMID- 23454766 TI - IQGAP1 suppresses TbetaRII-mediated myofibroblastic activation and metastatic growth in liver. AB - In the tumor microenvironment, TGF-beta induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-beta receptor II (TbetaRII) and suppresses TbetaRII mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-beta1 recruited IQGAP1 to TbetaRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TbetaRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TbetaRII and potentiated TGF-beta1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TbetaRII and TGF-beta dependent myofibroblastic differentiation to constrain tumor growth. PMID- 23454767 TI - MFGE8 inhibits inflammasome-induced IL-1beta production and limits postischemic cerebral injury. AB - Milk fat globule-EGF 8 (MFGE8) plays important, nonredundant roles in several biological processes, including apoptotic cell clearance, angiogenesis, and adaptive immunity. Several recent studies have reported a potential role for MFGE8 in regulation of the innate immune response; however, the precise mechanisms underlying this role are poorly understood. Here, we show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1beta production. MFGE8 inhibited necrotic cell-induced and ATP-dependent IL-1beta production by macrophages through mediation of integrin beta(3) and P2X7 receptor interactions in primed cells. Itgb3 deficiency in macrophages abrogated the inhibitory effect of MFGE8 on ATP-induced IL-1beta production. In a setting of postischemic cerebral injury in mice, MFGE8 deficiency was associated with enhanced IL-1beta production and larger infarct size; the latter was abolished after treatment with IL-1 receptor antagonist. MFGE8 supplementation significantly dampened caspase-1 activation and IL-1beta production and reduced infarct size in wild-type mice, but did not limit cerebral necrosis in Il1b-, Itgb3-, or P2rx7-deficient animals. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1beta production. PMID- 23454768 TI - Transplanted progenitors generate functional enteric neurons in the postnatal colon. AB - Cell therapy has the potential to treat gastrointestinal motility disorders caused by diseases of the enteric nervous system. Many studies have demonstrated that various stem/progenitor cells can give rise to functional neurons in the embryonic gut; however, it is not yet known whether transplanted neural progenitor cells can migrate, proliferate, and generate functional neurons in the postnatal bowel in vivo. We transplanted neurospheres generated from fetal and postnatal intestinal neural crest-derived cells into the colon of postnatal mice. The neurosphere-derived cells migrated, proliferated, and generated neurons and glial cells that formed ganglion-like clusters within the recipient colon. Graft derived neurons exhibited morphological, neurochemical, and electrophysiological characteristics similar to those of enteric neurons; they received synaptic inputs; and their neurites projected to muscle layers and the enteric ganglia of the recipient mice. These findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies. PMID- 23454769 TI - 2-photon imaging of phagocyte-mediated T cell activation in the CNS. AB - Autoreactive T cells can infiltrate the CNS to cause disorders such as multiple sclerosis. In order to visualize T cell activation in the CNS, we introduced a truncated fluorescent derivative of nuclear factor of activated T cells (NFAT) as a real-time T cell activation indicator. In experimental autoimmune encephalomyelitis, a rat model of multiple sclerosis, we tracked T cells interacting with structures of the vascular blood-brain barrier (BBB). 2-photon imaging documented the cytoplasmic-nuclear translocation of fluorescent NFAT, indicative of calcium-dependent activation of the T cells in the perivascular space, but not within the vascular lumen. The activation was related to contacts with the local antigen-presenting phagocytes and was noted only in T cells with a high pathogenic potential. T cell activation implied the presentation of an autoantigen, as the weakly pathogenic T cells, which remained silent in the untreated hosts, were activated upon instillation of exogenous autoantigen. Activation did not cogently signal long-lasting arrest, as individual T cells were able to sequentially contact fresh APCs. We propose that the presentation of local autoantigen by BBB-associated APCs provides stimuli that guide autoimmune T cells to the CNS destination, enabling them to attack the target tissue. PMID- 23454770 TI - p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes. AB - Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensitivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene, but heterozygous carriers, though apparently healthy, are believed to be at increased risk for cancer and more sensitive to ionizing radiation than the general population. Despite progress in functional and sequencing-based assays, no straightforward, rapid, and inexpensive test is available for the identification of A-T homozygotes and heterozygotes, which is essential for diagnosis, genetic counseling, and carrier prediction. The oncosuppressor p53 prevents genomic instability and centrosomal amplification. During mitosis, p53 localizes at the centrosome in an ATM-dependent manner. We capitalized on the latter finding and established a simple, fast, minimally invasive, reliable, and inexpensive test to determine mutant ATM zygosity. The percentage of mitotic lymphoblasts or PBMCs bearing p53 centrosomal localization clearly discriminated among healthy donors (>75%), A-T heterozygotes (40%-56%), and A-T homozygotes (<30%). The test is specific for A-T, independent of the type of ATM mutations, and recognized tumor-associated ATM polymorphisms. In a preliminary study, our test confirmed that ATM is a breast cancer susceptibility gene. These data open the possibility of cost-effective, early diagnosis of A-T homozygotes and large scale screenings for heterozygotes. PMID- 23454774 TI - Asthma and influenza virus infection:focusing on cell death and stress pathways in influenza virus replication. AB - Asthma is one of the fastest growing syndromes in many countries and is adding a huge cost to the health care system. Increasing reports have linked airway infectious diseases to asthma. Influenza is one of the most serious airway infectious diseases and in recent years there have been some serious influenza virus pandemics which caused increased fatality in numerous different populations. Diverse host response pathways during virus infection have been identified, including different cell death and survival pathways. These pathways include 1) programmed cell death I (apoptosis), 2) programmed cell death II (autophagy), and 3) endoplasmic reticulum stress with subsequent unfolded protein response (UPR). There has been extensive research on the regulatory roles of these pathways during the influenza virus life cycle. These studies address the benefits of enhancing or inhibiting these pathways on viral replication. Here we review the most recent and significant knowledge in this area for possible benefits to clinicians and basic scientist researchers in different areas of the respiratory and virology sciences. PMID- 23454772 TI - Adeno-associated virus capsid antigen presentation is dependent on endosomal escape. AB - Adeno-associated virus (AAV) vectors are attractive for gene delivery-based therapeutics, but data from recent clinical trials have indicated that AAV capsids induce a cytotoxic T lymphocyte (CTL) response that eliminates transduced cells. In this study, we used traditional pharmacological agents and AAV mutants to elucidate the pathway of capsid cross-presentation in AAV-permissive cells. Endosomal acidification inhibitors blocked AAV2 antigen presentation by over 90%, while proteasome inhibitors completely abrogated antigen presentation. Using mutant viruses that are defective for nuclear entry, we observed a 90% decrease in capsid antigen presentation. Different antigen presentation efficiencies were achieved by selectively mutating virion nuclear localization signals. Low antigen presentation was demonstrated with basic region 1 (BR1) mutants, despite relatively high transduction efficiency, whereas there was no difference in antigen presentation between BR2 and BR3 mutants defective for transduction, as compared with wild-type AAV2. These results suggest that effective AAV2 capsid antigen presentation is dependent on AAV virion escape from the endosome/lysosome for antigen degradation by proteasomes, but is independent of nuclear uncoating. These results should facilitate the design of effective strategies to evade capsid-specific CTL-mediated elimination of AAV-transduced target cells in future clinical trials. PMID- 23454771 TI - Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. AB - The BRAF mutant, BRAF(V600E), is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF(V600E) metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF(V600E)-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf(V600E)-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf(V600E) mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8(+) T/FoxP3(+)CD4(+) T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy. PMID- 23454775 TI - Differential expression and sequence polymorphism of the olive pollen allergen Ole e 1 in two Iranian cultivars. AB - Molecular evidence on the heterogeneity present in the Ole e 1 allergen of the olive pollen is emerging. Such polymorphism is dependent on the cultivar origin of pollen, which also determines wide differences in the expression of this protein. Determination of biochemical and molecular characteristics of Ole e 1 pollen allergen in two Iranian olive cultivars, namely 'Rowghani' and 'Zard' is necessary to assess their allergenicity potential. SDS-PAGE and immunoblotting analysis of pollen extracts showed that both cultivars present high and low expression of Ole e 1, respectively. These protein levels correlated with similarly different levels of transcripts, as determined by RT-PCR. Two dimensional protein profiles also showed conspicuous differences in the distribution and the level of expression of those spots reacting to an anti-Ole e 1 antibody. Bioinformatic analysis of four Ole e 1 sequences corresponding to 'Rowghani' and two sequences for 'Zard', showed numerous heterogeneities when compared with those Ole e 1 and Ole e 1-like sequences present in databases. Nucleotide substitutions resulted in many cases in changes over the predicted amino acid sequences. A cladistic analysis of the sequences showed Iranian entries in a central position between West-European sequences, and Ole e 1-like sequences from other Oleaceae species. Moreover, amino acid changes affected key epitopes of the protein involved in the recognition of the protein by the human immune system. Putative implications of polymorphism in both the biological role and the allergic reactivity of Ole e 1 are discussed. PMID- 23454776 TI - MCP-1, CCR2 and CCR5 polymorphisms in Tunisian patients with atopic asthma. AB - Chemokines and their receptors play an important role in the late inflammatory stage of asthma. In this study, we aimed to investigate polymorphisms of MCP-1 (CCL2), CCR2 and CCR5 which can affect qualitatively and/or quantitatively their production and thus influence both susceptibility and severity of asthma and its clinical and biological features.MCP-1 (A/G -2518), CCR2 (+/64I), CCR5 (G/A 59029) and CCR5 (?32) polymorphisms were evaluated by PCR in 107 Tunisian patients with asthma and 169 healthy controls.No significant association was found between the four investigated polymorphisms and asthma. Nevertheless the haplotype MCP1*AG/CCR2*+/+ was significantly l ess frequent in patients (20.5%) compared to controls (32.5%) (p=0.03; OR=0.54; 95% CI: 0.29-0.98). Whereas no difference was observed in CCR2/CCR5 haplotypes between patients and controls. Analysis of polymorphisms with clinical and biological features showed that the concomitant presence of MCP-1*G/CCR2*64I alleles was less frequent in severe forms (4.34%) compared to moderate disease (12%) but the difference was not significant (p=0.27). No association was observed between the four polymorphisms and the presence of atopic rhinitis or atopic conjunctivitis and an elevated rate of serum IgE over 200 IU/ml.Additional effects of MCP-1 and its receptor CCR2 polymorphisms seem to be involved in disease susceptibility to asthma in Tunisian patients; nevertheless they could be protective against its severe forms. PMID- 23454777 TI - Immunomodulatory effects of human umbilical cord Wharton's jelly-derived mesenchymal stem cells on differentiation, maturation and endocytosis of monocyte derived dendritic cells. AB - The Wharton's jelly of the umbilical cord is believed to be a source of mesenchymal stem cells (MSCs) which can be therapeutically applied in degenerative diseases.In this study, we investigated the immunomodulatory effect of umbilical cord derived-mesenchymal stem cells (UC-MSCs) and bone marrow derived-mesenchymal stem cells (BM-MSCs) on differentiation, maturation, and endocytosis of monocyte-derived dendritic cells in a transwell culture system under laboratory conditions. Monocytes were differentiated into immature dendritic cells (iDCs) in the presence of GM-CSF and IL-4 for 6 days and then differentiated into mature dendritic cells (mDCs) in the presence of TNF-alpha for 2 days. In every stage of differentiation, immature and mature dendritic cells were separately co-cultured with UC-MSCs and BM-MSCs. The findings showed that UC-MSCs and BM-MSCs inhibited strongly differentiation and maturation of dendritic cells at higher dilution ratios (1:1). The BM-MSCs and UC-MSCs showed more inhibitory effect on CD1a, CD83, CD86 expression, and dendritic cell endocytic activity, respectively. On the other hand, these cells severely up regulated CD14 marker expression. We concluded that UC-MSCs and BM-MSCs could inhibit differentiation, maturation and endocytosis in monocyte-derived DCs through the secreted factors and free of any cell-cell contacts under laboratory conditions. As DCs are believed to be the main antigen presenting cells for naive T cells in triggering immune responses, it would be logical that their inhibitory effect on differentiation, maturation and function can decrease or modulate immune and inflammatory responses. PMID- 23454778 TI - Evaluation of humoral immune function in patients with chronic idiopathic thrombocytopenic purpura. AB - Coincidence of autoimmune diseases such as immune thrombocytopenic purpura (ITP) with immunodeficiencies has been reported previously in patients who suffered from primary antibody deficiency (PAD). But there is no original study on immunological profiles of ITP patients to find out their probable immune deficiency. In this case-control study, ITP patients' humoral immunity was investigated for diagnosis of PAD in comparison with normal population. To evaluate the humoral immune system against polysaccharide antigens, patients' serum immunoglobulin levels were measured and a 23-valent pneumococcal capsular polysaccharide vaccine (PPV23) was administrated to evaluate the antibody response to vaccination. In this study, 14 out of 36 patients (39%) were diagnosed with antibody mediated immune deficiency including 2 patients (5.5%) with immunoglobulin class deficiency and 4 (11%) with IgG subclass deficiency. The remaining patients suffered from specific antibody deficiency. The most frequent deficiency in ITP patients was specific antibody deficiency.Therefore, immunological survey on ITP patients may be important especially for those who have undergone splenectomy. PMID- 23454779 TI - Study of immunomodulatory effects of arteether administrated intratumorally. AB - Recent studies have indicated the profound anti-tumor activity of artemisinin's compounds, among which; arteether is an oil-soluble derivative of artemisinin with an endoperoxide bridge that can induce apoptosis in tumor cells but not in the normal cells. An experiment was carried out on tumor-bearing Balb/c mice to estimate the effects of Arteether on tumor growth and antitumor immune responses. Briefly, 6mg/kg/day of Arteether and diluents were administered to two groups of mice. Tumor sizes were measured using digital verniercallipers. Mice were sacrificed and splenocytes were harvested for lymphocyte proliferation assay, the level of IL-4 and IFN-gamma cytokines, and the percentage of splenic T regulatory cells were measured. According to the findings, there were no statistical differences between the groups with respect to the level of IFN-gamma, IL-4 and proliferation assay; while our results showed that Arteether is effective in the reduction of tumor growth rate. In general, intra-tumoral injection of Arteether as an oil-soluble derivative of artemisinin brings to light some antitumor properties that may aid in development of more effective antitumor agents. PMID- 23454780 TI - The effect of educating the use of spray by visual concept mapping method on the quality of life of children with asthma. AB - One of the most important goals in treating chronic diseases, especially asthma, is the promotion of quality of life (QOL). The present study aimed at identifying the effect of educating method on the QOL of children, who suffered from asthma.In this clinical trial study, 80 children aged 6-12 years with asthma were divided into two groups: control (face-to-face method) and experimental (visual concept mapping method). The QOL of both groups was measured before and after educating by the Juniper's Quality of Life Questionnaire with a one-month interval.The rate of change in the QOL score of the experimental group was 0.3 (+/-0.7) both before and after intervention and 0.1 (+/-0.3) in the control group, which was statistically significant (p<0.05).Educating by the visual concept mapping method with regard to the manner of using sprays is taken into account as an efficient and effective method in improving the QOL of children with asthma. PMID- 23454781 TI - Increased expression of CD69 antigen on human peripheral blood natural killer cells in patients with allergic rhinitis. AB - Allergic rhinitis (AR) is an inflammatory disorder of the nasal mucosa with high morbidity and prevalence. Natural killer (NK) cells might have a role in AR. We aimed to evaluate the changes of the markers and receptors on NK cells in AR patients compared to the non-atopic controls.Flow cytometric analysis was used with double staining of the Peripheral Blood Mononuclear Cells (PBMCs) to examine the expression of CD25 and CD69 markers, and NKG2D and NKG2A receptors on NK cells of 20 patients with AR and 20 non-atopic controls. The serum total IgE level was measured by Enzyme-linked Immunosorbent Assay.The expression of CD69 antigen on NK cells in AR patients was significantly higher than that of healthy group (p=0.03). No significant changes were observed between CD25, NKG2D and NKG2A expression on the surface of NK cells from healthy and AR subjects. Our study also showed that there was no significant correlation between the expression of CD69, CD25, NKG2D and NKG2A and level of serum total IgE in AR patients and normal subjects.These results indicated that the expression of CD69 antigen on NK cells of AR patients was increased. The high expression of CD69 on NK cells in AR patients suggested that these cells were activated, probably due to the cytokines secreted from allergen-stimulated T cells and activated monocytes. PMID- 23454782 TI - Comparison of the levels of tumor necrosis factor-alpha and interleukin-17 in gingival crevicular fluid of patients with peri-implantitis and a control group with healthy implants. AB - Peri-implantitis is a multi-factorial disease involving peri-implant tissues and resulting in therapeutic failure. Inflammatory mediators and cytokines in the Gingival Crevicular Fluid (GCF) have pivotal roles in the disease pathogenesis and could be used for disease monitoring. Therefore, the present study was conducted to compare the GCF levels of TNF-alpha and IL-17 between patients with peri-implantitis and healthy implants.In this case-control study, 24 patients with peri-implantitis and 18 individuals with healthy implants referring to faculty of dentistry in Tehran University of Medical Sciences were selected. GCF was collected by paper cons number 30. Samples were preserved in PBS -70oC. TNF alpha and IL-17 levels in GCF were determined by ELISA method. Data were analyzed by SPSS software version 13, using descriptive indices and independent t tests.Mean probing depth in peri-implantitis and control groups were 6.2 +/- 1.1 and 3.7 +/- 1.6 mm respectively. Mean level of IL-17 in patients with peri implantitis was significantly more than the control group (19.8 +/- 16.0 versus 9.3 +/- 8.4 pg per site in 40 seconds, p=0.016). Also, mean level of TNF-alpha in patients with peri-implantitis was more than control group (39.0 +/- 3.9 versus 14.5 +/- 9.0 pg per site in 40 seconds, p =0.000).The significant higher levels of TNF-alpha and IL-17 in patients with peri-implantitis compared to control group indicated the pivotal role of these cytokines in peri-implantitis and could be suggested as diagnostic markers and in future possibly for immunomodulatory treatments. PMID- 23454783 TI - The effect of Candida albicans systemic infection on matrix metalloproteinases in breast cancer bearing BALB/c mice. AB - Breast cancer patients are susceptible to infections such as candidiasis. Due to the importance and the role of matrix metalloproteinases (MMP) in breast cancer progression and its correlation with tumor metastasis, we analyzed the serum level of MMPs -2, -3, -9 and tissue inhibitor of matrix metalloproteinase-1 (TIMP 1) in breast cancer bearing mice in the presence of systemic Candida albicans infection. Female BALB/c mice were divided into 4 groups: group I had tumor + candidiasis; group II, tumor only; group III, candidiasis only and group IV as negative control. Tumor tissue was separated from stock breast cancer bearing mice and transplanted subcutaneously into the groups I and II mice. Two weeks after tumor transplantation, groups I and III were infected with Candida albicans by intravenous injection. One week after systemic infection, the sera of the experimental groups were prepared and analyzed with ELISA for MMP-2, -3, -9 and TIMP-1 levels. The results showed that the levels of MMP-3, MMP-9 and TIMP-1 were increased in groups I, II and III, as compared to the control group. However, the level of MMP-2 was decreased in mice infected with Candida albicans and in infected mice bearing tumor. These data suggest that candidiasis may have a positive effect on tumor progression and metastasis. PMID- 23454785 TI - Food-dependent exercise-induced anaphylaxis due to wheat in a young woman. AB - Food Dependent Exercise-Induced Allergy is a rare condition. However, the occurrence of anaphylaxis is increasing especially in young people. The diagnosis of anaphylaxis is based on clinical criteria and can be supported by laboratory tests such as serum tryptase and positive skin test results for specific IgE to potential triggering allergens. Anaphylaxis prevention needs strict avoidance of confirmed relevant allergen. Food-exercise challenge test may be an acceptable method for diagnosis of Food Dependent Exercise-Induced Allergy and dietary elimination of food is recommended to manage it. In this study, a 32 year-old woman visited the allergy clinic with a history of several episodes of hives since 11 years ago and 3 life-threatening attacks of anaphylaxis during the previous 6 months. The onsets of majority of these attacks were due to physical activity after breakfast. On Blood RAST test, the panel of common food Allergens was used and she had positive test only to wheat flour. On skin prick tests for common food allergens she showed a 6 millimeter wheal with 14 mm flare to Wheat Extract. The rest of allergens were negative.The patient was diagnosed as wheat dependent exercise-induced, and all foods containing wheat were omitted from her diet. In this report we emphasized on the importance of careful history taking in anaphylaxis diagnosis. PMID- 23454784 TI - Different pattern of gene mutations in Iranian patients with severe congenital neutropenia (including 2 new mutations). AB - Severe congenital neutropenia (SCN) is a rare primary immunodeficiency disease. Different genes are found to be associated with SCN, including ELA2, HAX1, WAS, GFI1, G-CSFR and G6PC3. The aim of this study was to find different gene mutations responsible for SCN in Iranian patients. Twenty-seven patients with SCN referred to Immunology, Asthma and Allergy Research Institute during a five year priod 5 years (May 2007 and May 2012), were included in this study. Neutropenia related exons and flanking regions of ELA2, HAX1, WAS, GFI1, G-CSFR and G6PC3 were amplified by PCR and the sequences were analyzed. The results showed different mutations including 4 ELANE mutations, 11 HAX1 mutations and 2 G6PC3 mutations. None of the patients had GFI1 mutation and also one mutation was found in G-CSFR in a patient with ELANE mutation. Ten patients had unknown genetic diagnosis which was compatible with other studies. According to these results, most of the patients showed HAX1 mutations and this finding which significantly differed from other reports, might be related to differences in Iranian ethnicity and also in high rate of consanguineous marriages in Iran. PMID- 23454786 TI - Organization and establishment of DNA banks in biomedical research centers: a report from immunology, asthma and allergy research institute. PMID- 23454787 TI - Time-to-positivity-based discrimination between Enterobacteriaceae, Pseudomonas aeruginosa and strictly anaerobic Gram-negative bacilli in aerobic and anaerobic blood culture vials. AB - Time-to-positivity (TTP) of first positive blood cultures growing Gram-negative bacilli (GNB) was investigated. When anaerobic vials were positive first, TTP <= 18 h differentiated Enterobacteriaceae from strict anaerobic Gram-negative bacilli (PPV 98.8%). When the aerobic ones were first, TTP <= 13 h differentiated Enterobacteriaceae from Pseudomonas aeruginosa and other GNB (PPV 80.8%). PMID- 23454788 TI - Tissue-specificity and phylogenetics of Pl-MT mRNA during Paracentrotus lividus embryogenesis. AB - Metallothioneins (MTs) constitute a family of cysteine-rich, low molecular weight proteins, which generally provide protection against metal toxicity and oxidative stress counteracting the cell damage caused by essential and non-essential heavy metals. Equally important is the physiological role of MTs in the homeostasis of essential metals, which are involved in a wide variety of cellular processes. The aim of this work was to investigate the expression and the territorial localization of Paracentrotus lividus MT (Pl-MT) mRNA during sea urchin development by Quantitative Polymerase Chain Reaction (QPCR) and Whole Mount In Situ Hybridization (WMISH), as well as the phylogenetic comparison with selected MT homologs present in different phyla. We found that Pl-MT mRNA is accumulated in unfertilized eggs and constitutively expressed during development, with very low levels of maternal mRNA at cleavage stages, followed by a significant rise during gastrulation with a peak at the prism stage. Pl-MT mRNA was expressed in the vegetative plate at mesenchyme blastula, later restricted to the endoderm of gastrula embryos and finally to the gut of plutei. Indirect immunofluorescence (IF) using a specific antibody for the endoderm marker Endo1 demonstrated a co localization with the Pl-MT transcripts in the midgut and hindgut after the intestine differentiation occurs and when larval feeding begins. Our results show for the first time the constitutive temporal and tissue-specific expression of MT in P. lividus embryos, providing new information for studies on the mechanisms controlling basal and induced MT gene expression. The analysis of the phylogenetic relationship of Pl-MT with homologs from different phyla, ranging from yeast to vertebrates, suggests the evolutionary process of these proteins, which could have been selected not only on the basis of their ability to bind metals but also by their tissue-specificity. PMID- 23454789 TI - Degeneration and cell regeneration in the midgut of Podisus nigrispinus (Heteroptera: Pentatomidae) during post-embryonic development. AB - Cell death, proliferation, and differentiation in some developmental stages of insects have been studied in the midgut of ametabolous, which undergo only continuous growth, and holometabolous, which undergo complete metamorphosis. However, in hemimetabolous insects, evolutionarily intermediate between ametabolous and holometabolous, midgut reorganization during the post-embryonic development has been poorly studied. The present study evaluates the post embryonic development of the midgut of a hemimetabolous insect, Podisus nigrispinus, to test the hypothesis that these insects have programmed cell death and proliferation followed by differentiation of regenerative cells during midgut growth from nymphs to adult. The morphometrical data showed a 6-fold increase in midgut length from the first instar nymph to the adult, which did not result from an increase in the size of the midgut cells, suggesting that the growth of the midgut occurs by an increase in cell number. Cell death was rarely found in the midgut, whereas proliferation of regenerative cells occurred quite frequently. The growth of the midgut of P. nigrispinus appears to result from the proliferation of regenerative cells present in the epithelium; unlike ametabolous and holometabolous insects, the midgut of P. nigrispinus does not undergo extensive remodeling, as shown by the low frequency of digestive cell death. PMID- 23454790 TI - Numerical processing efficiency improved in experienced mental abacus children. AB - Experienced mental abacus (MA) users are able to perform mental arithmetic calculations with unusual speed and accuracy. However, it remains unclear whether their extraordinary gains in mental arithmetic ability are accompanied by an improvement in numerical processing efficiency. To address this question, the present study, using a numerical Stroop paradigm, examined the numerical processing efficiency of experienced MA children, MA beginners and their respective peers. The results showed that experienced MA children were less influenced than their peers by physical size information when intentionally processing numerical magnitude information, but they were more influenced than their peers by numerical magnitude information when intentionally processing physical size information. By contrast, MA beginners and peers showed no differences in the reciprocal influences between the two conflicting dimensions. These findings indicate that substantial gains in numerical processing efficiency could be achieved through long-term intensive MA training. Implications for numerical magnitude representations and for training students with mathematical learning disabilities are discussed. PMID- 23454792 TI - Vocal imitation of song and speech. AB - We report four experiments that explored the cognitive bases of vocal imitation. Specifically, we investigated the accuracy with which normal individuals vocally imitated the pitch-time trajectories of spoken sentences and sung melodies, presented in their original form and with phonetic information removed. Overall, participants imitated melodies more accurately than sentences with respect to absolute pitch but not with respect to relative pitch or timing (overall duration). Notably, the presence of phonetic information facilitated imitation of both melodies and speech. Analyses of individual differences across studies suggested that the accuracy of imitating song predicts accuracy of imitating speech. Overall, these results do not accord with accounts of modular pitch processing that emphasize information encapsulation. PMID- 23454791 TI - Bayesian learning and the psychology of rule induction. AB - In recent years, Bayesian learning models have been applied to an increasing variety of domains. While such models have been criticized on theoretical grounds, the underlying assumptions and predictions are rarely made concrete and tested experimentally. Here, I use Frank and Tenenbaum's (2011) Bayesian model of rule-learning as a case study to spell out the underlying assumptions, and to confront them with the empirical results Frank and Tenenbaum (2011) propose to simulate, as well as with novel experiments. While rule-learning is arguably well suited to rational Bayesian approaches, I show that their models are neither psychologically plausible nor ideal observer models. Further, I show that their central assumption is unfounded: humans do not always preferentially learn more specific rules, but, at least in some situations, those rules that happen to be more salient. Even when granting the unsupported assumptions, I show that all of the experiments modeled by Frank and Tenenbaum (2011) either contradict their models, or have a large number of more plausible interpretations. I provide an alternative account of the experimental data based on simple psychological mechanisms, and show that this account both describes the data better, and is easier to falsify. I conclude that, despite the recent surge in Bayesian models of cognitive phenomena, psychological phenomena are best understood by developing and testing psychological theories rather than models that can be fit to virtually any data. PMID- 23454793 TI - Copy me or copy you? The effect of prior experience on social learning. AB - The current study investigated children's solution choice and imitation of causally-irrelevant actions by using a controlled design to mirror naturalistic learning contexts in which children receive social information for tasks about which they have some degree of prior knowledge. Five-year-old children (N=167) were presented with a reward retrieval task and either given a social demonstration of a solution or no information, thus potentially acquiring a solution through personal exploration. Fifty-three children who acquired a solution either socially or asocially were then presented with an alternative solution that included irrelevant actions. Rather than remaining polarised to their initial solution like non-human animals, these children attempted the newly presented solution, incorporating both solutions into their repertoire. Such an adaptive and flexible learning strategy could increase task knowledge, provide generalizable knowledge in our tool-abundant culture and facilitate cumulative culture. Furthermore, children who acquired a solution through personally acquired information omitted subsequently demonstrated irrelevant actions to a greater extent than did children with prior social information. However, as some children with successful personally acquired information did copy the demonstrated irrelevant actions, we suggest that copying irrelevant actions may be influenced by social and causal cognition, resulting in an effective strategy which may facilitate acquisition of cultural norms when used discerningly. PMID- 23454794 TI - Got rhythm...for better and for worse. Cross-modal effects of auditory rhythm on visual word recognition. AB - The present research aimed to investigate whether, as previously observed with pictures, background auditory rhythm would also influence visual word recognition. In a lexical decision task, participants were presented with bisyllabic visual words, segmented into two successive groups of letters, while an irrelevant strongly metric auditory sequence was played in a loop. The first group of letters could either be congruent with the syllabic division of the word (e.g. val in val/se) or not (e.g. va in va/lse). In agreement with the Dynamic Attending Theory (DAT), our results confirmed that the presentation of the correct first syllable on-beat (i.e. in synchrony with a peak of covert attention) facilitated visual word recognition compared to when it was presented off-beat. However, when an incongruent first syllable was displayed on-beat, this led to an aggravation of impaired recognition. Thus, our results suggest that oscillatory attention tapped into cognitive processes rather than perceptual or decisional and motor stages. We like to think of our paradigm, which combines background auditory rhythm with segmented visual stimuli, as a sort of temporal magnifying glass which allows for the enlargement of the reaction time differences between beneficial and detrimental processing conditions in human cognition. PMID- 23454795 TI - Money is essential: ownership intuitions are linked to physical currency. AB - Due to basic processes of psychological essentialism and contagion, one particular token of monetary currency is not always interchangeable with another piece of currency of equal economic value. When money loses its physical form it is perceived as "not quite the same" money (i.e., to have partly lost the original essence that distinguished it from other monetary tokens), diminishing its intuitive link with its original owner. Participants were less likely to recommend stolen or lost money be returned when it had been subsequently deposited in an electronic bank account, as opposed to retaining its original physical form (Studies 1a and 1b). Conversely, an intuitive sense of ownership is enhanced through physical contact with a piece of hard currency. Participants felt the piece of currency a person had originally lost should be returned to him rather than another piece of currency of equivalent value, even when they did not believe he would be able to tell the difference and considered distinguishing it from other money illogical. This effect was reduced when the currency had been sterilized, wiping it clean of all physical traces of its previous owner (Studies 2a, 2b, and 3). PMID- 23454796 TI - Enhanced associative memory for colour (but not shape or location) in synaesthesia. AB - People with grapheme-colour synaesthesia have been shown to have enhanced memory on a range of tasks using both stimuli that induce synaesthesia (e.g. words) and, more surprisingly, stimuli that do not (e.g. certain abstract visual stimuli). This study examines the latter by using multi-featured stimuli consisting of shape, colour and location conjunctions (e.g. shape A+colour A+location A; shape B+colour B+location B) presented in a recognition memory paradigm. This enables distractor items to be created in which one of these features is 'unbound' with respect to the others (e.g. shape A+colour B+location A; shape A+colour A+location C). Synaesthetes had higher recognition rates suggesting an enhanced ability to bind certain visual features together into memory. Importantly, synaesthetes' false alarm rates were lower only when colour was the unbound feature, not shape or location. We suggest that synaesthetes are "colour experts" and that enhanced perception can lead to enhanced memory in very specific ways; but, not for instance, an enhanced ability to form associations per se. The results support contemporary models that propose a continuum between perception and memory. PMID- 23454797 TI - The interaction between central and peripheral processes in handwriting production. AB - Written production studies investigating central processing have ignored research on the peripheral components of movement execution, and vice versa. This study attempts to integrate both approaches and provide evidence that central and peripheral processes interact during word production. French participants wrote regular words (e.g. FORME), irregular words (e.g. FEMME) and pseudo-words (e.g. FARNE) on a digitiser. Pseudo-words yielded longer latencies than regular words. Letter durations were greater for words at earlier letter positions and greater for pseudo-words at the later positions. Letter durations were longer for irregular than regular words. The effect was modulated by the position of the irregularity. These findings indicate that movement production can be affected by lexical and sublexical variables that regulate spelling processes. They suggest that central processing is not completely finished before movement initiation and affects peripheral writing mechanisms in a cascaded manner. Lexical and sublexical processing does not cascade to the same extent. PMID- 23454798 TI - Dual character concepts and the normative dimension of conceptual representation. AB - Five experiments provide evidence for a class of 'dual character concepts.' Dual character concepts characterize their members in terms of both (a) a set of concrete features and (b) the abstract values that these features serve to realize. As such, these concepts provide two bases for evaluating category members and two different criteria for category membership. Experiment 1 provides support for the notion that dual character concepts have two bases for evaluation. Experiments 2-4 explore the claim that dual character concepts have two different criteria for category membership. The results show that when an object possesses the appropriate concrete features, but does not fulfill the appropriate abstract value, it is judged to be a category member in one sense but not in another. Finally, Experiment 5 uses the theory developed here to construct artificial dual character concepts and examines whether participants react to these artificial concepts in the same way as naturally occurring dual character concepts. The present studies serve to define the nature of dual character concepts and distinguish them from other types of concepts (e.g., natural kind concepts), which share some, but not all of the properties of dual character concepts. More broadly, these phenomena suggest a normative dimension in everyday conceptual representation. PMID- 23454799 TI - An improved system for the evaluation of antiviral compounds against herpes simplex virus type 2. AB - Infection with herpes simplex virus type 2 (HSV-2) can result in lesions in reproductive organs, along with long-term latency. In this work, a non-lethal strain of HSV-2 which was isolated clinically was used to infect female mice intravaginally. Body weight, vulval lesions, histological examination of vaginal tissue, and viral load were monitored and used as indices for evaluating antiviral drugs against HSV-2 infection. The results indicated that mice infected with HSV-2 exhibited significant reduction in body weight, serious vulval lesions, massive lymphocyte invasion of vaginal tissue, and approximately 104 copies/MUl of HSV-2 were found in vaginal and uterine tissues. Aciclovir (ACV) treatment inhibited loss in body weight, genital pathology and virus replication (reduced to 100.3 copies/MUl) effectively. The study provides a simple, reproducible and feasible animal model for anti-HSV-2 drugs evaluation and HSV-2 vaccine research. PMID- 23454800 TI - Infectivity enhancement of different HIV-1-based lentiviral pseudotypes in presence of the cationic amphipathic peptide LAH4-L1. AB - Lentiviral vectors (LVs) are promising delivery systems for gene therapy. To enhance the efficiency of target cell transduction by LVs, protocols often include the addition of culture additives. In this study, the cationic amphipathic peptide LAH4-L1 (KKALLAHALHLLALLALHLAHALKKA), a DNA transfection agent, was evaluated for its capacity to improve LV infectivity in cell lines and primary cells. Results show that LAH4-L1 enhances infectivity of all LV pseudotypes tested, particularly GALVTR-LVs. More importantly, LAH4-L1 promotes the transduction of CD34+ hematopoietic stem cells with GALVTR-LVs as efficiently as Retronectin, a culture additive used in ex vivo clinical protocols involving LVs. The action of LAH4-L1 relies both on the GALVTR-LV adhesion and post adhesion steps. LAH4-L1 represents a new and attractive transduction enhancer for hematopoietic gene therapy protocols. PMID- 23454801 TI - Integration of NIRS and PCA techniques for the process monitoring of a sewage sludge anaerobic digester. AB - This study investigates the use of Hotelling's T(2) control charts as the basis of a process monitor for sewage sludge anaerobic digestion. Fourier transform near infrared spectroscopy was used to produce partial least squares regression models of volatile fatty acids, bicarbonate alkalinity and volatile solids. These were utilised in a series of principle component analysis models along with spectral data from digestate and feedstock samples to produce a pseudo steady state model, which was then used with an independent test set to evaluate the system. The system was able to identify disturbances to the digester due to a temporary alteration of the type of feedstock to the digester and separately, halving of the hydraulic retention time of the digester. It could also provide advance warning of disturbances to the digester. This technique could be used to improve the performance of sewage sludge anaerobic digesters by enabling optimisation of the process. PMID- 23454802 TI - Development and optimization of single and combined detoxification processes to improve the fermentability of lignocellulose hydrolyzates. AB - In this work, an enzyme catalyzed detoxification process of lignocellulose hydrolyzates with immobilized laccase from Trametes versicolor was developed and optimized. Further, the immobilized laccase significantly reduced the amount of toxic phenolic compounds in the xylan rich fraction (XRF) by polymerization within 1h. The insoluble products precipitated onto the carrier surface and could be reversible resolubilized by an aqueous ethanol solution. Consequently, an in situ product removal could be realized. The reusability of the immobilized laccase could be additionally shown. The reaction kinetics could be described by a reversible Michaelis Menten equation giving the prerequisite for scaling up the process. In a second step, the organic acids, hydroxymethylfurfural and phenolic acids could be further removed by employing an anion exchanger. Both, the laccase and the laccase+anion exchanger treatment enhanced successfully the fermentability of an organosolv wheat straw fraction. PMID- 23454803 TI - Acid-catalyzed conversion of mono- and poly-sugars into platform chemicals: effects of molecular structure of sugar substrate. AB - Hydrolysis/pyrolysis of lignocellulosic biomass always produces a mixture of sugars with distinct structures as intermediates or products. This study tried to elucidate the effects of molecular structure of sugars on their acid-catalyzed conversions in ethanol/water. Location of carbonyl group in sugars (fructose versus glucose) and steric configuration of hydroxyl groups (glucose versus galactose) significantly affected yields of levulinic acid/ester (fructose>glucose>galactose). The dehydration of fructose to 5 (hydroxymethyl)furfural produces much less soluble polymer than that from glucose and galactose, which results in high yields of levulinic acid/ester from fructose. Anhydrate sugar such as levoglucosan tends to undergo the undesirable decomposition to form less levulinic acid/ester. Catalytic behaviors of the poly sugars (sucrose, maltose, raffinose, beta-cyclodextrins) were determined much by their basic units. However, their big molecular sizes create the steric hindrance that significantly affects their followed conversion over solid acid catalyst. PMID- 23454804 TI - Ecological characteristics of seeding sludge triggering a prompt start-up of anammox. AB - Anammox start-up can be limited by the availability of seeding biomass in some areas. Previous studies have listed suitable alternative seeding sludge for anammox start-up such as anaerobic digestion sludge and conventional activated sludge (CAS), the ecological reasons behind has long been ignored. In this study, the inherent ecological factors that trigger a prompt start-up of anammox were identified, focusing on the initial relative abundance and concentration of anammox bacteria. An external membrane bioreactor was utilized as an enriching tool due to its suitability of retaining cells. Results revealed that a high initial concentration of anammox bacteria benefitted the start-up, meanwhile an even community seeding sludge (Gini coefficient<0.25) gained a more than three time higher anammox activity compared to the uneven one (Gini coefficient>0.5). The discovery reminds to select the seeding sludge that is ecologically appropriate rather than to only care for the type of sludge in general. PMID- 23454805 TI - Mathematical modeling of poly[(R)-3-hydroxyalkanoate] synthesis by Cupriavidus necator DSM 545 on substrates stemming from biodiesel production. AB - Two low structured mathematical models for fed-batch production of polyhydroxybutyrate and poly[hydroxybutyrate-co-hydroxyvalerate] by Cupriavidus necator DSM 545 on renewable substrates (glycerol and fatty acid methyl esters FAME) combined with glucose and valeric acid, were established. The models were used for development/optimization of feeding strategies of carbon and nitrogen sources concerning PHA content and polymer/copolymer composition. Glycerol/glucose fermentation featured a max. specific growth rate of 0.171 h( 1), a max. specific production rate of 0.038 h(-1) and a PHB content of 64.5%, whereas the FAME/valeric acid fermentation resulted in a max. specific growth rate of 0.046 h(-1), a max. specific production rate of 0.07 h(-1) and 63.6% PHBV content with 4.3% of 3-hydroxyvalerate (3HV) in PHBV. A strong inhibition of glycerol consumption by glucose was confirmed (inhibition constant ki,G=4.28*10( 4) g L(-1)). Applied concentration of FAME (10-12 g L(-1)) positively influenced on PHBV synthesis. HV/PHBV ratio depends on applied VA concentration. PMID- 23454806 TI - Objective quality assessment of atrial fibrillation ablation: a novel scoring system. PMID- 23454807 TI - Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. AB - BACKGROUND: Patients with atrial fibrillation (AF) routinely undergo transesophageal echocardiography (TEE) for the evaluation of the left atrial appendage (LAA) to rule out thrombus prior to undergoing pulmonary vein isolation (PVI). Cardiac magnetic resonance (CMR) is now increasingly used for the evaluation of patients with AF to define pulmonary vein (PV) anatomy prior to PVI. OBJECTIVE: To hypothesize that a retrospective comparison of 2-dimensional/3 dimensional (2D/3D) contrast-enhanced CMR sequences with TEE for the evaluation of LAA thrombus in patients with AF selected for PVI will demonstrate equivalence. METHODS: Ninety-seven (N = 97) consecutive patients with AF underwent near-simultaneous TEE and noncontrast and contrast CMR prior to undergoing an initial PVI procedure. The CMR images were analyzed in 2 categories: (1) the 2D noncontrast cine images and early gadolinium enhancement images showing LAA and (2) 3D contrast source images acquired during PV magnetic resonance angiography. CMR variables evaluated were the presence or absence of LAA thrombus and the quality of images, and they were compared with the results of TEE in a blinded fashion. RESULTS: All subjects were analyzed for the presence or absence of LAA thrombus. Thrombus was absent in 98% of the patients on both TEE and CMR and present in 2% on both studies (100% correlation). In 6 subjects, 2D cine CMR images were indeterminate whereas all 2D early gadolinium enhancement images and 3D contrast images were successful in excluding LAA thrombus. There was 100% concordance between CMR and TEE for the final diagnosis of LAA thrombus. CONCLUSIONS: In one single examination, CMR offers a comparable alternative to TEE for the complete noninvasive evaluation of LAA thrombus and PV anatomy in patients with AF referred for PVI without obligate need for TEE. PMID- 23454808 TI - Diagnosis of high-voltage conductor fractures in Sprint Fidelis leads. AB - BACKGROUND: Fractures of pace/sense conductors in implantable cardioverter defibrillator (ICD) leads have been studied extensively, but little is known about fractures of high-voltage (HV) conductors. OBJECTIVE: To characterize the presentation of isolated HV conductor fractures, define the optimal impedance threshold for identifying them, and compare it to the existing nominal impedance threshold (200 Omega) for patient and remote-monitoring alerts. METHODS: This retrospective study analyzed HV fractures in explanted, dual-coil, model 6949 Sprint Fidelis leads (Medtronic, Minneapolis, MN). The study group consisted of 25 leads with structurally and electrically confirmed HV conductor fractures; 41 leads that were structurally and electrically intact served as controls. We analyzed long-term HV impedance trends from stored ICD data files of both groups to determine the optimal impedance threshold that would discriminate fractures from normal leads. RESULTS: In the study group, 14 leads (56%) had fractures of the cable to the right ventricular coil, 9 (36 %) leads had fractures of the cable to the superior vena cava (SVC) coil, and 2 (8%) had both. We found that an impedance threshold of >100 Omega and/or an abrupt 75% increase in chronic HV impedance were diagnostic of HV conductor fractures with 100% sensitivity and specificity. HV fractures proximal to the SVC coil were more likely to be associated with concomitant pace/sense fractures. Large (200 Omega to infinity), abrupt increases in impedance were more common when fractures occurred proximal to the right ventricular coil but distal to the SVC coil. CONCLUSIONS: HV conductor fractures can be diagnosed when HV impedance exceeds 100 Omega or abruptly increases by 75% from baseline. PMID- 23454809 TI - Neutral defects in SrTiO3 studied with screened hybrid density functional theory. AB - The properties of neutral defects in SrTiO3 are calculated using the screened hybrid density functional of Heyd, Scuseria, and Ernzerhof. The formation energies, the crystal field splittings affecting the SrTiO3 band structure, and the relaxation geometries around each defect are discussed. Oxygen vacancies introduced in SrTiO3 are found to cause a small tetragonal elongation of the lattice along the z-axis. The resulting conduction band minimum electron effective masses deviate from the bulk values and support the proposal of enhanced electron mobility along the direction of the compressive strain. The locations of the various defect bands within the SrTiO3 gap are estimated without introducing any post hoc corrections, thus allowing a more reliable comparison with experiment. PMID- 23454810 TI - Survival of Listeria monocytogenes and Salmonella Enteritidis in sea bream (Sparus aurata) fillets packaged under enriched CO2 modified atmospheres. AB - The effect of packaging of fresh sea bream fillets under different modified atmospheres (high levels of CO2 combined with N2) on the behaviour of Listeria monocytogenes and Salmonella Enteritidis was studied. Two different strains of each pathogen were spread over the sea bream fillets stored at either 0 degrees C or 4 degrees C for 16 days under standard supermarket lighting conditions (14 h a day). The atmospheres investigated were 60% CO2/40% N2, 70% CO2/30% N2, 80% CO2/20% N2 and air as control. Mesophilic, psychrotrophic and Enterobacteriaceae microbial counts were also performed in control batches. The results indicate that all the CO2 concentrations used favoured the control of pathogen bacteria inoculated, when compared with air conditions especially, when combined with storage at 0 degrees C. Both storage temperature (0 degrees C and 4 degrees C) resulted in a decrease in Salmonella count. The results were more significant for Listeria strains, because during the storage at 4 degrees C Listeria count increased in all batches, while for samples stored at 0 degrees C a significant reduction in microbial load except in control batch was observed. Sensitivity differences of inoculated strains against temperature and CO2 concentrations were also discussed. PMID- 23454811 TI - Evaluation of potential biocontrol agent for aflatoxin in Argentinean peanuts. AB - Biocontrol by competitive exclusion has been developed as the most promising means of controlling aflatoxins in peanuts. A 2-year study was carried out to determine the efficacy of an Aspergillus flavus strain as biocontrol agent to reduce aflatoxin production in peanuts under field conditions in Argentina. The competitive strain used was a nontoxigenic A. flavus (AFCHG2) naturally occurring in peanut from Cordoba, Argentina. The inoculum was produced through solid-state fermentation on long grain rice and applied at rate of 50kg inoculum/ha. The incidence of the released strain within the A. flavus communities in soil and peanuts was determined using the shift in the ratio toxigenic:nontoxigenic and VCG analysis. During the 2009/2010 growing season, treatments produced significant reductions in the incidence of toxigenic isolates of A. flavus/Aspergillus parasiticus in soil and peanuts. However, no preharvest aflatoxin contamination was observed. In the 2010/2011 growing season, plants were exposed to late season drought conditions that were optimal for aflatoxin contamination. Significant reductions in aflatoxin levels averaging 71% were detected in treated plots with different inoculation treatments. The results suggest that using the strategy of competitive exclusion A. flavus AFCHG2 can be applied to reduce aflatoxin contamination in Argentinean peanuts. PMID- 23454812 TI - Campylobacter contamination and the relative risk of illness from organic broiler meat in comparison with conventional broiler meat. AB - Danish organic broiler meat, represented by carcasses sampled at the end of processing after chilling, was more frequently contaminated with thermotolerant Campylobacter spp. than conventional broiler carcasses; the yearly mean prevalence being 54.2% (CI: 40.9-67.5) for organic and 19.7% (CI: 14.8-24.7) for conventional carcasses. Campylobacter jejuni was the most frequently isolated species. The difference in prevalence was obvious in all quarters of the year. Contamination of organic and conventional broiler carcasses was more likely to occur in the warmer summer months, in this case in the third quarter, as also documented for conventional broiler flocks. When contaminated, the mean concentration of Campylobacter on neck skin samples of organic and conventional carcasses was not significantly different (P=0.428); 2.0+/-0.65 log 10 cfu/g and 2.1+/-0.93 log 10 cfu/g, respectively. Assessing the relative risk of becoming ill following exposure to Campylobacter on conventional or organic broiler meat indicated that the risk per serving from organic carcasses was 1.7 times higher than that of conventional carcasses. The higher risk of illness from organic broiler carcasses compared with conventional broiler carcasses emphasizes the importance of implementing control measures in organic broiler production. PMID- 23454813 TI - Fungal and mycotoxin assessment of dried edible mushroom in Nigeria. AB - In order to determine whether dried mushrooms are a foodstuff that may be less susceptible to infection by toxigenic molds and consequently to mycotoxin contamination, 34 dried market samples were analyzed. Fungal population was determined in the samples by conventional mycological techniques and molecular studies, while the spectrum of microbial metabolites including mycotoxins was analyzed by a liquid chromatography tandem mass spectrometric method covering 320 metabolites. Molds such as Fusarium, Penicillium, Trichoderma and aflatoxigenic species of Aspergillus (Aspergillus flavus and Aspergillus parvisclerotigenus) were recovered from all samples at varying levels. None of the mycotoxins addressed by regulatory limits in the EU was positively identified in the samples. However, 26 other fungal metabolites occurred at sub- to medium MUg/kg levels in the samples, including aflatoxin/sterigmatocystin bio-precursors, bis anthraquinone derivatives from Talaromyces islandicus, emerging toxins (e.g. enniatins) and other Fusarium metabolites, and clavine alkaloids. Although little is known on the toxicology of these substances, the absence of aflatoxins and other primary mycotoxins suggests that dried mushrooms may represent a relatively safe type of food in view of mycotoxin contamination. PMID- 23454814 TI - Molecular characterization, fitness and mycotoxin production of benzimidazole resistant isolates of Penicillium expansum. AB - Penicillium expansum field-strains resistant to benzimidazole fungicides were isolated in high frequency from decayed apple fruit collected from packinghouses and processing industries located in the region of Imathia, N. Greece. In vitro fungitoxicity tests resulted in the identification of two different resistant phenotypes: highly (BEN-HR) and moderately (BEN-MR) carbendazim-resistant. Thirty seven percent of the isolated P. expansum strains belonged to the BEN-HR phenotype, carried no apparent fitness penalties and exhibited resistance levels higher than 60 based on EC50 values. Cross resistance studies with other benzimidazole fungicides showed that all BEN-HR and BEN-MR isolates were also less sensitive to benomyl and thiabendazole. Fungitoxicity tests on the response of BEN-HR isolates to fungicides belonging to other chemical classes revealed no cross-resistance relationships between benzimidazoles and the phenylpyrrole fludioxonil, the dicarboximide iprodione, the anilinopyrimidine cyprodinil, the QoI pyraclostrobin, the imidazole imazalil and the triazole tebuconazole, indicating that a target-site modification is probably responsible for the BEN-HR phenotype observed. Contrary to the above, some BEN-MR isolates exhibited an increased sensitivity to cyprodinil compared to benzimidazole-sensitive ones. BEN MR isolates had fitness parameters similar to the benzimidazole-sensitive isolates except for conidia production which appeared significantly decreased. Analysis of mycotoxin production (patulin and citrinin) showed that all benzimidazole-resistant isolates produced mycotoxins at concentrations significantly higher than sensitive isolates both on culture medium and on artificially inoculated apple fruit. Comparison of the beta-tubulin gene DNA sequence between resistant and sensitive isolates revealed a point mutation resulting from the E198A substitution of the corresponding protein in most but not all HR isolates tested. Molecular analysis of the beta-tubulin gene in moderately resistant isolates did not reveal any amino acid substitution. This is the first report on the existence and distribution of highly mycotoxigenic field isolates of P. expansum resistant to the benzimidazoles indicating a high potential risk of increased mycotoxin contamination of pome fruit and by products. PMID- 23454815 TI - Hyd5 gene based analysis of cereals and malt for gushing-inducing Fusarium spp. by real-time LAMP using fluorescence and turbidity measurements. AB - The surface active class 2 hydrophobin Hyd5p (GenBank accession number DQ449530) has been identified as a causative agent for over foaming (gushing) of beer. In order to estimate the potential of brewing cereals and malt to induce gushing in beer we used a previously described set of primers to amplify a partial sequence of the hyd5 gene in Fusarium culmorum and closely related species in a real-time loop-mediated isothermal amplification assay. Real-time LAMP was optimized and performed on two different platforms using a turbidimeter and a fluorescence reader to monitor the reaction on line. Serial dilutions of purified target DNA were used to set up a calibration curve for quantitative estimation of DNA concentrations. Analysis of model barley samples prepared by mixing infected with non-infected material in different ratios demonstrated a positive correlation between the real-time LAMP results and respective infection levels. In order to investigate the performance of the newly established methods, samples of barley were analyzed for their gushing potential using the Hyd5 real-time LAMP assay and a reference in vitro test for gushing prediction (Modified Carlsberg Test, MCT) in parallel experiments. Results showed that the real-time LAMP assay was in accordance with the reference test in 50% of cases with both platforms used. It predicted a lower number of gushing-positive samples as compared to the current reference test. PMID- 23454816 TI - Biofilms promote survival and virulence of Salmonella enterica sv. Tennessee during prolonged dry storage and after passage through an in vitro digestion system. AB - Salmonella enterica serotypes have been linked to outbreaks associated with low water activity foods. While the biofilm-forming abilities of Salmonella improve its survival during thermal processing and sanitation it is unclear whether biofilms enhance survival to desiccation and gastric stresses. The purpose of this study was to quantify the effect of physiological state (planktonic versus biofilm) and prior exposure to desiccation and storage in dry milk powder on Salmonella survival and gene expression after passage through an in vitro digestion model. Planktonic cells of Salmonella enterica serotype Tennessee were deposited onto membranes while biofilms were formed on glass beads. The cells were subsequently dried at room temperature and stored in dried milk powder (a(w)=0.3) for up to 30 days. Salmonella survival was quantified by serial dilution onto Brilliant Green Agar before desiccation, after desiccation, after 1 day storage and after 30-day storage. At each sampling period both physiological states were tested for survival through a simulated gastrointestinal system. RNA was extracted at the identical time points and Quantitative Real-Time PCR was used to determine relative expression for genes associated with stress response (rpoS, otsB), virulence (hilA, invA, sipC) and a housekeeping gene 16S rRNA. The physiological state and length of storage affected the survival and gene expression of Salmonella within the desiccated milk powder environment and after passage through an in vitro digestion system (p<0.05). Larger numbers of S. Tennessee were recovered by plate counts for biofilms compared to planktonic, however, the numbers of Salmonella genomes detected by qPCR were not significantly different suggesting entry of the planktonic cells of S. Tennessee into a viable but non-culturable state. The increased expression of stress response genes rpoS and otsB correlated with survival, indicating cross protection to low water activity and acid stress. Increased expression of virulence-associated genes was seen in cells exposed to dry storage for short periods, however the largest amount of expression occurred in biofilm cells stored for 30 days at aw 0.3, suggesting increased virulence potential. PMID- 23454817 TI - Incidence of naturally internalized bacteria in lettuce leaves. AB - Lettuce is the fresh leafy vegetable most frequently involved in foodborne disease outbreaks. Human bacterial pathogens may be experimentally internalized into lettuce plants, but the occurrence of natural microflora inside lettuce leaves has not been elucidated. To characterize the endophytic microorganism residing in commercial lettuce leaves, two separate studies were conducted. First, a total of 30 and 25 heads of romaine and red leaf lettuce, respectively, served as the source of individual leaves which were surface sterilized, stomached, enriched in BHI broth for 24h and plated onto BHI agar for non selective isolation of internalized microorganism. In a separate survey, 80 heads of each of the two types of lettuce were similarly processed, except that GN broth and MacConkey agar (MCA) were used for isolation of Gram negative bacteria. Thirty-eight out of 100 leaves were positive for internalized microorganisms, and Bacillus, Pseudomonas and Pantoea were the genera most frequently found in both types of lettuce. Members of the genus Erwinia were isolated from romaine lettuce only. In the second study, 21 and 60% of romaine and red leaf lettuce heads, respectively, had internalized bacteria capable of growing on MCA. Among the Gram negative strains, Pseudomonas and Pantoea genera were most frequently isolated. Enterobacter isolates were obtained from three red leaf samples. In summary, spore-forming bacteria and traditional epiphytic bacterial genera were frequently detected in surface-sterilized commercial lettuce leaves. Despite the common occurrence of internalized bacteria, only Enterobacter was related to Escherichia coli O157:H7 and Salmonella. PMID- 23454818 TI - Characterizing uncertainty when evaluating risk management metrics: risk assessment modeling of Listeria monocytogenes contamination in ready-to-eat deli meats. AB - This report illustrates how the uncertainty about food safety metrics may influence the selection of a performance objective (PO). To accomplish this goal, we developed a model concerning Listeria monocytogenes in ready-to-eat (RTE) deli meats. This application used a second order Monte Carlo model that simulates L. monocytogenes concentrations through a series of steps: the food-processing establishment, transport, retail, the consumer's home and consumption. The model accounted for growth inhibitor use, retail cross contamination, and applied an FAO/WHO dose response model for evaluating the probability of illness. An appropriate level of protection (ALOP) risk metric was selected as the average risk of illness per serving across all consumed servings-per-annum and the model was used to solve for the corresponding performance objective (PO) risk metric as the maximum allowable L. monocytogenes concentration (cfu/g) at the processing establishment where regulatory monitoring would occur. Given uncertainty about model inputs, an uncertainty distribution of the PO was estimated. Additionally, we considered how RTE deli meats contaminated at levels above the PO would be handled by the industry using three alternative approaches. Points on the PO distribution represent the probability that - if the industry complies with a particular PO - the resulting risk-per-serving is less than or equal to the target ALOP. For example, assuming (1) a target ALOP of -6.41 log10 risk of illness per serving, (2) industry concentrations above the PO that are re distributed throughout the remaining concentration distribution and (3) no dose response uncertainty, establishment PO's of -4.98 and -4.39 log10 cfu/g would be required for 90% and 75% confidence that the target ALOP is met, respectively. The PO concentrations from this example scenario are more stringent than the current typical monitoring level of an absence in 25 g (i.e., -1.40 log10 cfu/g) or a stricter criteria of absence in 125 g (i.e., -2.1 log10 cfu/g). This example, and others, demonstrates that a PO for L. monocytogenes would be far below any current monitoring capabilities. Furthermore, this work highlights the demands placed on risk managers and risk assessors when applying uncertain risk models to the current risk metric framework. PMID- 23454819 TI - Effect of steam and lactic acid treatments on the survival of Salmonella Enteritidis and Campylobacter jejuni inoculated on chicken skin. AB - Campylobacteriosis and salmonellosis are the most frequently reported zoonotic infectious diseases. The present work evaluated the effectiveness of steam treatment at 100 degrees C for 8s, a 5% lactic acid treatment for 1 min and their combination for inactivating Salmonella Enteritidis and Campylobacter jejuni inoculated on chicken skin. The impact of each treatment on the total aerobic mesophilic bacteria and the effect of rinsing after contact with lactic acid were also evaluated. Residual bacteria were counted immediately after treatment or after seven days of storage at 4 degrees C. Results demonstrated the immediate efficiency of the steam and the combined treatments with reductions of approximately 6 and 5 log cfu/cm2 respectively for S. Enteritidis and C. jejuni. They also showed significant reductions (equal to or >3.2 log cfu/cm2) in the total aerobic mesophilic plate count. Lactic acid had a persistent effect on pathogen growth during storage which was significantly higher when the skin was not rinsed, reaching reductions of 3.8 log cfu/cm2 for both S. Enteritidis and C. jejuni. Only the combined treatments significantly reduced the recovery of the total aerobic mesophilic bacteria during storage. The significant reductions in both pathogens and total aerobic mesophilic bacteria on treated chicken skins are possible ways to improve the safety and shelf life of the product although high levels of indigenous non-pathogenic bacteria may be beneficial due to their protective effect against potential re-contamination of chicken skin. PMID- 23454820 TI - Potential application of quantitative microbiological risk assessment techniques to an aseptic-UHT process in the food industry. AB - Aseptic ultra-high-temperature (UHT)-type processed food products (e.g., milk or soup) are ready to eat products which are consumed extensively globally due to a combination of their comparative high quality and long shelf life, with no cold chain or other preservation requirements. Due to the inherent microbial vulnerability of aseptic-UHT product formulations, the safety and stability related performance objectives (POs) required at the end of the manufacturing process are the most demanding found in the food industry. The key determinants to achieving sterility, and which also differentiates aseptic-UHT from in-pack sterilised products, are the challenges associated with the processes of aseptic filling and sealing. This is a complex process that has traditionally been run using deterministic or empirical process settings. Quantifying the risk of microbial contamination and recontamination along the aseptic-UHT process, using the scientifically based process quantitative microbial risk assessment (QMRA), offers the possibility to improve on the currently tolerable sterility failure rate (i.e., 1 defect per 10,000 units). In addition, benefits of applying QMRA are (i) to implement process settings in a transparent and scientific manner; (ii) to develop a uniform common structure whatever the production line, leading to a harmonisation of these process settings, and; (iii) to bring elements of a cost-benefit analysis of the management measures. The objective of this article is to explore how QMRA techniques and risk management metrics may be applied to aseptic-UHT-type processed food products. In particular, the aseptic-UHT process should benefit from a number of novel mathematical and statistical concepts that have been developed in the field of QMRA. Probabilistic techniques such as Monte Carlo simulation, Bayesian inference and sensitivity analysis, should help in assessing the compliance with safety and stability-related POs set at the end of the manufacturing process. The understanding of aseptic-UHT process contamination will be extended beyond the current "as-low-as-reasonably-achievable" targets to a risk-based framework, through which current sterility performance and future process designs can be optimised. PMID- 23454821 TI - Implementation of m-health applications in Botswana: telemedicine and education on mobile devices in a low resource setting. AB - Although Botswana has recently been categorised as an upper middle income country, it is burdened by a scarcity of resources, both human and technological. There are barriers to patients' access to specialized care and healthcare providers' access to medical knowledge. Over the past three years, the Botswana University of Pennsylvania Partnership (BUP) has piloted four mobile telemedicine projects in the specialties of women's health (cervical cancer screening utilizing visual inspection with acetic acid), radiology, oral medicine and dermatology. Mobile telemedicine has been used in 11 locations in Botswana, training a total of 24 clinicians and successfully contributing to the management of 643 cases. In addition to mobile telemedicine, BUP has initiated an m-learning programme with the University of Botswana School of Medicine. While successfully providing patients and providers with improved access to healthcare resources, the m-health projects have faced numerous technical and social challenges. These include malfunctioning mobile devices, unreliable IT infrastructure, accidental damage to mobile devices, and cultural misalignment between IT and healthcare providers. BUP has worked with its local partners to develop solutions to these problems. To ensure sustainability, m-health programmes must have strategic goals that are aligned with those of the national health and education system, and the initiatives must be owned and led by local stakeholders. Whenever possible, open source technology and local IT expertise and infrastructure should be employed. PMID- 23454822 TI - Teleconsulting for minor head injury: the Piedmont experience. AB - We evaluated the benefits of teleconsulting for patients hospitalised with minor head injuries in centres without neurosurgery. In the Piedmont region, 1462 consultation requests were received at specialist centres in 2009, relating to 519 patients with a minor head injury diagnosis (ICD 850-854). These were compared with the details of 1895 patients admitted with the same diagnosis during 2009, but for whom no consultations were requested. The mortality risk in the two groups was estimated using logistic regression, after adjusting for the principal confounding factors (sex, age, seriousness of the patient's injury at diagnosis, referral centre). The estimated risk of death for patients for whom no consultation was requested was an odds ratio of 1.32 (95% CI 1.08 to 1.74) compared to those who received a teleconsultation. However, after adjusting for the confounding factors, the risk was not significant (odds ratio = 1.25, 95% CI 0.83 to 1.91). A stratified analysis identified a significant effect for elderly people, aged over 70 years, in whom the odds ratio was 1.14 (95% CI 1.04 to 1.82). The results confirm the benefits of telemedicine, in particular for elderly patients, when teleconsultation is requested in the case of minor head injury. PMID- 23454823 TI - Accumulation of mercury, selenium and PCBs in domestic duck brain, liver and egg from a contaminated area with an investigation of their redox responses. AB - PCBs and methylmercury (MeHg) are two of the most ubiquitous contaminants in the Qingzhen (QZ) area of Guizhou province. The estimated tolerable daily intakes (TDIs) of total mercury (T-Hg), MeHg, PCBs and Se from contaminated rice, eggs and fish by Chinese people in QZ showed that both MeHg and PCBs exceeded the corresponding safety limits. Pearson's correlation analyses of mercury and Se in all duck tissues showed that there were high correlations with T-Hg or MeHg and Se in QZ samples. However, the molar ratio between T-Hg and Se in brain tissues was close to 1, suggesting that Se is antagonistic to mercury toxicity only in brain tissues. Biochemical analyses showed that both superoxide dismutase and glutathione peroxidase increased in the brain, whereas in the liver and egg these enzymes decreased. However, lipid peroxidation and H2O2 generation in liver and egg tissues showed contrary responses, where significant increases in these tissues were seen relative to controls. Mercury and PCBs co-accumulation in liver and egg tissues gave rise to large numbers of free radicals as well as aggravated alkyl free radicals, superoxide radical and nitric oxide, thereby resulting in oxidative stress in these tissues. It can be concluded that an adaptive response of the redox defense system is present in brain tissues, as opposed to a general break down of the redox defense system in liver and egg. The results obtained in this study will provide basic information on exposure and risk assessment in local residents. PMID- 23454824 TI - Protective effect of phlorotannins from Eisenia bicyclis against lipopolysaccharide-stimulated inflammation in HepG2 cells. AB - In this study, four bioactive phloroglucinol derivates including phloroglucinol (1), eckol (2), dioxinodehydroeckol (3), and dieckol (4) were isolated from Eisenia bicyclis and characterized by nuclear magnetic resonance (NMR) spectroscopic methods. Moreover, the anti-inflammatory activity of these compounds was investigated on human hepatoma cell line HepG2 cells stimulated by lipopolysaccharide (LPS). It was demonstrated that LPS can induce the production of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) as well as the expression of inflammatory mediators as cyclooxygenase-2 (COX-2), and inducible nitric oxide synthases (iNOS) from HepG2 cells. Among isolated compounds, compound (1) exhibited significant inhibition on LPS-stimulated inflammatory responses in HepG2 cells without any cytotoxicity. Herein, compound (1) suppresses the production of pro-inflammatory cytokines such as IL-1beta, IL-6, and TNF-alpha and the expression of COX-2 and iNOS. Thus, these results indicated that phlorotannins isolated from E. bicyclis, especially compound (1), can be used as a beneficial source for preventing and treating inflammation response. PMID- 23454825 TI - Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section. AB - BACKGROUND: The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity. METHODS: Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity. RESULTS: The mean [standard deviation (SD)] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) MUg ml(-1). The maximum detected concentration in any patient was 3.76 MUg ml(-1) (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean (SD) peak levels were elevated in these patients, 2.70 (0.46) ug ml(-1). CONCLUSIONS: TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity. PMID- 23454826 TI - Do team processes really have an effect on clinical performance? A systematic literature review. AB - There is a growing literature on the relationship between team processes and clinical performance. The purpose of this review is to summarize these articles and examine the impact of team process behaviours on clinical performance. We conducted a literature search in five major databases. Inclusion criteria were: English peer-reviewed papers published between January 2001 and May 2012, which showed or tried to show (i) a statistical relationship of a team process variable and clinical performance or (ii) an improvement of a performance variable through a team process intervention. Study quality was assessed using predefined quality indicators. For every study, we calculated the relevant effect sizes. We included 28 studies in the review, seven of which were intervention studies. Every study reported at least one significant relationship between team processes or an intervention and performance. Also, some non-significant effects were reported. Most of the reported effect sizes were large or medium. The study quality ranged from medium to high. The studies are highly diverse regarding the specific team process behaviours investigated and also regarding the methods used. However, they suggest that team process behaviours do influence clinical performance and that training results in increased performance. Future research should rely on existing theoretical frameworks, valid, and reliable methods to assess processes such as teamwork or coordination and focus on the development of adequate tools to assess process performance, linking them with outcomes in the clinical setting. PMID- 23454827 TI - An obesogen over time: transgenerational impact of tributyltin. PMID- 23454828 TI - Which metabolites circulate? AB - Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (fm). Our analysis suggests that fm is the major determinant of total drug M/P ratio for amine, alcohol, N- and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with fm due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite. PMID- 23454829 TI - Tissue distribution and identification of radioactivity components at elimination phase after oral administration of [14C]CS-1036, an alpha-amylase inhibitor, to rats. AB - (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-beta-D glucopyranosyl)-alpha-D-glucopyranoside (CS-1036) is a potent inhibitor of pancreatic and salivary alpha-amylase. After oral administration of [14C]CS-1036 to rats, the radioactivity was still detectable up to 7-14 days after administration in various tissues, and its terminal phase in plasma could be explained neither by the exposure of CS-1036 nor its major metabolite M1. The slow elimination of radioactivity in various tissues was hypothesized to be caused by covalent binding to macromolecules or use for biogenic components. To assess the use for biogenic components, amino acid analysis of plasma proteins and lipid analysis of adipose tissue were conducted after repeated oral administration of [14C]CS-1036 by high-performance liquid chromatography and accelerated mass spectrometry and by thin layer chromatography and liquid chromatography/mass spectrometry, respectively. In amino acid analysis, glutamic acid, aspartic acid, alanine, and proline were identified as major radioactive amino acids, and radioactive nonessential amino acids occupied 76.0% of the radioactivity. In lipid analysis, a part of the radioactive lipids were identified as the fatty acids constituting the neutral lipids by lipase hydrolysis. The radioactive fatty acids from neutral lipids were identified as palmitic acid, oleic acid, and 8,11,14-eicosatrienoic acid. Intestinal flora were involved in CS-1036 metabolism and are indicated to be involved in the production of small molecule metabolites, which are the sources for amino acids and fatty acids, from [14C]CS-1036. In conclusion, radioactivity derived from [14C]CS-1036 was incorporated as the constituents of amino acids of plasma proteins and fatty acids of neutral lipids. PMID- 23454831 TI - In vitro nanotoxicity of single-walled carbon nanotube-dendrimer nanocomplexes against murine myoblast cells. AB - Single-wall carbon nanotubes (SWCNTs) and polyamidoamine dendrimers (PAMAM) have been proposed for a variety of biomedical applications. The combination of both molecules makes this new composite nanomaterial highly functionalizable and versatile to theranostic and drug-delivery systems. However, recent toxicological studies have shown that nanomaterials such as SWCNTs and PAMAM may have high toxicity in biological environments. Aiming to elucidate such behavior, in vitro studies with different cultured cells have been conducted in the past few years. This study focuses on the effects of SWCNT-PAMAM nanomaterials and their individual components on the C2C12 murine cell line, which is a mixed population of stem and progenitor cells. The interactions between the cells and the nanomaterials were studied with different techniques usually employed in toxicological analyses. The results showed that SWCNT-PAMAM and PAMAM inhibited the proliferation and caused DNA damage of C2C12 cells. Data from flow cytometry revealed a less toxicity in C2C12 cells exposed to SWCNT compared to the other nanomaterials. The results indicated that the toxicity of SWCNT, SWCNT-PAMAM and PAMAM in C2C12 cells can be strongly correlated with the charge of the nanomaterials. PMID- 23454830 TI - Hydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and mouse CYP27B1. AB - CYP11A1 can hydroxylate vitamin D3 at carbons 17, 20, 22, and 23, producing a range of secosteroids which are biologically active with respect to their ability to inhibit proliferation and stimulate differentiation of various cell types, including cancer cells. As 1alpha-hydroxylation of the primary metabolite of CYP11A1 action, 20S-hydroxyvitamin D3 [20(OH)D3], greatly influences its properties, we examined the ability of both human and mouse CYP27B1 to 1alpha hydroxylate six secosteroids generated by CYP11A1. Based on their kcat/Km values, all CYP11A1-derived metabolites are poor substrates for CYP27B1 from both species compared with 25-hydroxyvitamin D3. No hydroxylation of metabolites with a 17alpha-hydroxyl group was observed. 17alpha,20-Dihydroxyvitamin D3 acted as an inhibitor on human CYP27B1 but not the mouse enzyme. We also tested CYP27B1 activity on 20,24-, 20,25-, and 20,26-dihydroxyvitamin D3, which are products of CYP24A1 or CYP27A1 activity on 20(OH)D3. All three compounds were metabolized with higher catalytic efficiency (kcat/Km) by both mouse and human CYP27B1 than 25-hydroxyvitamin D3. CYP27B1 action on these new dihydroxy derivatives was confirmed to be 1alpha-hydroxylation by mass spectrometry and nuclear magnetic resonance analyses. Both 1,20,25- and 1,20,26- trihydroxyvitamin D3 were tested for their ability to inhibit melanoma (SKMEL-188) colony formation, and were significantly more active than 20(OH)D3. This study shows that CYP11A1-derived secosteroids are 1alpha-hydroxylated by both human and mouse CYP27B1 with low catalytic efficiency, and that the presence of a 17alpha-hydroxyl group completely blocks 1alpha-hydroxylation. In contrast, the secondary metabolites produced by subsequent hydroxylation of 20(OH)D3 at C24, C25, or C26 are very good substrates for CYP27B1. PMID- 23454832 TI - The suppression of hematopoiesis function in Balb/c mice induced by prolonged exposure of microcystin-LR. AB - Microcystins (MCs) cause normocytic anemia in patients in a hemodialysis unit in Caruaru, Brazil in 1996, but the underlying mechanisms are still unclear. In the present study, Balb/c mice were intraperitoneally injected with microcystin-LR (MC-LR) at the doses of 0.5, 2 and 8 MUg/kg body weight (bw) every 48 h for 30 d. After the prolonged exposure of MC-LR, significant decreases of red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) were observed in 2 and 8 MUg/kg bw groups, but erythrocyte mean corpuscular volume (MCV) showed no significant changes. Significantly elevated micronucleus frequency was observed in bone marrow cells (BMCs) in all MC-LR treatments. The proliferation of BMCs significantly declined in both 2 and 8 MUg/kg bw groups. Serum levels of some hematopoietic growth factors significantly changed in 8 MUg/kg bw group, mainly including granulocyte-macrophage (GM-CSF), erythropoietin (EPO), interleukin-3 (IL-3) and TNF-alpha. The transcriptional levels of these 4 genes in BMCs were also significantly changed in 8 MUg/kg bw group. MC-LR exposure significantly increased the apoptosis rates in all MC-LR treatments. The present study indicates prolonged exposure of MC-LR induces normocytic anemia, and the disturbed hematopoietic growth factors and BMCs apoptosis are responsible for this normocytic anemia. PMID- 23454833 TI - Evaluation of the adjuvant effect of silver nanoparticles both in vitro and in vivo. AB - The immunological adjuvant effect of silver nanoparticles (AgNPs) was investigated both in vitro and in vivo. The in vivo adjuvant effect of AgNPs was evaluated with model antigen ovalbumin (OVA) and bovine serum albumin (BSA) in mice by intraperitoneal and subcutaneous immunization. Serum antigen-specific IgG level significantly increased in AgNPs-treated mice comparing to the control group. AgNPs induced the increase of IgG1/IgG2a ratio and antigen-specific IgE, indicating that AgNPs elicited Th2-biased immune responses. By in vitro assay, the mechanism of adjuvant effect was explored. After 48h treatment with AgNPs, both the number of leukocytes and levels of cytokines TNF-alpha and IFN-gamma in abdominal lavage fluid of mice increased. The expression of the major histocompatibility complex class II molecule on the surface of peritoneal macrophages significantly increased. AgNPs can be easily phagocytosed by peritoneal macrophages, while do not affect antigen uptake by the cell. We therefore conclude that AgNPs have significant adjuvant effect and the mechanism of this effect is mainly ascribed to the recruitment and activation of local leukocytes and especially macrophages. For the first time we found the remarkable adjuvant effect of AgNPs, and the result is beneficial for the future applications, especially in biomedicine. PMID- 23454834 TI - Gentamicin caused renal injury deeply related to methylglyoxal and N(E) (carboxyethyl)lysine (CEL). AB - In this study, we investigated the role of carbonyl stress in gentamicin (GM) induced renal injury in rats. Carbonyl stress is represented by methylglyoxal (MGO) and its downstream advanced glycation end products, such as N(E) (carboxyethyl)lysine (CEL). GM (150mg/kg/day, i.p.) administration for 6 days significantly increased blood urea nitrogen (BUN) levels from 24.06+/-0.55 to 85.04+/-21.31mg/dL and decreased creatinine clearance rate (Ccr) from 10.68+/ 0.76 to 2.53+/-1.11ml/min/kg B.W.; biopsy showed tubular injury. The kidney levels of MGO and CEL increased significantly from 9.56+/-1.94 to 79.13+/ 17.96MUg/g of protein and from 0.03+/-0.00 to 0.06+/-0.00MUmol/MUg of protein, respectively. Therefore, MGO and CEL appeared to be associated with GM-induced renal damage. Co-administration of metformin (50 or 100mg/kg/day) and GM for 13 days effectively reversed GM-induced renal damage. The kidney levels of MGO and CEL decreased significantly from 24.95+/-7.74 to 22.98+/-17.74MUg/g of protein and from 0.04+/-0.01 to 0.03+/-0.01MUmol/MUg of protein (both vs. the GM group), respectively. The identification of this new pathway may help prevent GM-induced nephrotoxicity. PMID- 23454835 TI - Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages. AB - The mycotoxin alternariol (AOH), a frequent contaminant in fruit and cereal products, is known to induce DNA damage with subsequent cell cycle arrest. Here we elucidated the effects of AOH on stages of cell cycle progression using the RAW 264.7 macrophage model. AOH resulted in an accumulation of cells in the G2/M phase (4N). Most cells exhibited a large G2 nucleus whereas numbers of true mitotic cells were reduced relative to control. Both cyclin B1 and p-cdc2 levels increased, while cyclin B1 remained in the cytoplasm; suggesting arrest in the G2/M transition point. Remarkably, after exposure to AOH for 24h, most of the cells exhibited abnormally shaped nuclei, as evidenced by partly divided nuclei, nuclear blebs, polyploidy and micronuclei (MN). AOH treatment also induced abnormal Aurora B bridges, suggesting that cytokinesis was interfered within cells undergoing karyokinesis. A minor part of the resultant G1 tetraploid (4N) cells re-entered the S-phase and progressed to 8N cells. PMID- 23454836 TI - Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. AB - Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of thesein vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice. Previous results showed that diet restriction (DR) had minimal or no effect on the lifespan of Rb1+/- mice, suggesting that the beneficial response to DR is dependent on pRb1. Since long-term eRapa treatment may at least partially mimic chronic DR in lifespan extension, we predicted that it would have a minimal effect in Rb1+/- mice. Beginning at 9 weeks of age until death, we fed Rb1+/- mice a diet without or with eRapa at 14 mg/kg food, which results in an approximate dose of 2.24 mg/kg body weight per day, and yielded rapamycin blood levels of about 4 ng/ml. Surprisingly, we found that eRapa dramatically extended life span of both female and male Rb1+/- mice, and slowed the appearance and growth of pituitary and decreased the incidence of thyroid tumors commonly observed in these mice. In this model, eRapa appears to act differently than DR, suggesting diverse mechanisms of action on survival and anti tumor effects. In particular the beneficial effects of rapamycin did not depend on the dose of Rb1. PMID- 23454837 TI - Identification of genes transcribed by Streptococcus equi ssp. zooepidemicus in infected porcine lung. AB - Streptococcus equi ssp. zooepidemicus (SEZ) is a Gram-positive bacterium responsible for respiratory tract infection, septicemia, meningitis, endocarditis and arthritis in swine and humans. However, the expression and regulation of SEZ genes during an infection in vivo are poorly understood. In this study, we focused on the identification of SEZ genes preferentially expressed in vivo during infection in pigs. This study identified 45 SEZ genes that were upregulated in infected porcine lung tissues using the selective capture of transcribed sequences (SCOTS) technique and comparative dot-blot analysis, followed by quantitative RT-PCR validation. The identified genes were characterized into 6 functional categories: metabolism, cell wall-associated, stress response, transporters, regulators and unknown functions. Our study successfully identified multiple genes, which can deepen our understanding about SEZ pathogenesis and infer probable virulence factors. It will promote the development of novel vaccines and therapies about this pathogen for further study. PMID- 23454839 TI - Ionizing radiation induced changes in phenotype, photosynthetic pigments and free polyamine levels in Vigna radiata (L.) Wilczek. AB - Effects of gamma rays on the free polyamine (PA) levels were studied in Vigna radiata (L.) Wilczek. Seeds exposed to different doses of gamma rays were checked for damage on phenotype, germination frequency and alteration in photosynthetic pigments. Free polyamine levels were estimated from seeds irradiated in dry and water imbibed conditions. Polyamine levels of seedlings grown from irradiated seeds, and irradiated seedlings from unexposed seeds were also measured. Damage caused by gamma irradiation resulted in decrease in final germination percentage and seedling height. Photosynthetic pigments decreased in a dose dependent manner as marker of stress. Polyamines decreased in irradiated dry seeds and in seedlings grown from irradiated seeds. Radiation stress induced increase in free polyamines was seen in irradiated imbibed seeds and irradiated seedlings. Response of polyamines towards gamma rays is dependent on the stage of the life cycle of the plant. PMID- 23454840 TI - Response to the changing epidemiology of meningococcal disease in North America 1945-2010. PMID- 23454841 TI - Ab initio calculation of spin-dependent electron-phonon coupling in iron and cobalt. AB - The spin-dependent coupling between electrons and phonons in ferromagnetic Fe and Co is calculated from first principles in a collinear-spin formalism. The added spin polarization is fundamental for the correct representation of the phonons, but also for obtaining good transport properties, and permits decomposition (e.g. of the resistivity) into the contributions of majority and minority spin. In Fe the minority spin coupling is only about 50% more important, but in Co the coupling between phonons and minority spin electrons is an order of magnitude larger than that with the majority spin, and both are strongly anisotropic. PMID- 23454838 TI - Emotion regulation difficulties as a prospective predictor of posttraumatic stress symptoms following a mass shooting. AB - A strong positive association between emotion regulation difficulties (ERD) and posttraumatic stress symptoms (PTSS) has been consistently evidenced in cross sectional research. However, a lack of prospective research has limited hypotheses regarding the temporal relationship between trauma exposure, ERD, and PTSS. The present prospective study investigated the role of pre-trauma difficulties with emotion regulation in the development of PTSS following exposure to a potentially traumatic event. Between Time 1 (T1) and Time 2 (T2), a mass shooting occurred at the participants' (n=691) university campus. ERD and PTSS were assessed prior to the shooting (T1), in the acute aftermath of the shooting (T2), and approximately eight months later (T3). Using a cross-lagged panel design, ERD was found to prospectively predict PTSS from T1 to T2 and T2 to T3. Additionally, PTSS prospectively predicted ERD from T1 to T2. However, T2 PTSS failed to predict T3 PTSS. Results indicate that ERD and PTSS are reciprocally influential from pre- to post-shooting. Further, results suggest that emotion dysregulation in the aftermath of a potentially traumatic event influences one's ability to recover from PTSS over time, even after accounting for the effects of existing symptomatology. To examine the specificity of temporal relations between ERD and PTSS a second cross-lagged panel design, in which a general distress construct was substituted for PTSS, was conducted. Results of this analysis, as well as conceptual and clinical implications, will be discussed. PMID- 23454842 TI - Growth, structural, spectral, optical, and thermal studies on amino acid based new NLO single crystal: L-phenylalanine-4-nitrophenol. AB - A new organic nonlinear optical single crystal, L-phenylalanine-4-nitrophenol (LPAPN) belonging to the amino acid group has been successfully grown by slow evaporation technique. The lattice parameters of the grown crystal have been determined by X-ray diffraction studies. FT-IR spectrum was recorded to identify the presence of functional group and molecular structure was confirmed by NMR spectrum. Thermal strength of the grown crystal has been studied using TG-DTA analyses. The grown crystals were found to be transparent in the entire visible region. The existence of second harmonic generation signals was observed using Nd:YAG laser with fundamental wavelength of 1064 nm. PMID- 23454843 TI - Spectroscopic studies (FTIR, FT-Raman and UV), potential energy surface scan, normal coordinate analysis and NBO analysis of (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2 (hydroxymethyl) piperidine-3,4,5-triol by DFT methods. AB - This work presents the characterization of (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2 (hydroxymethyl)piperidine-3,4,5-triol (abbreviated as HEHMPT) by quantum chemical calculations and spectral techniques. The spectroscopic properties were investigated by FT-IR, FT-Raman and UV-Vis techniques. The FT-IR spectrum (4000 400 cm(-1)) and FT-Raman spectrum (4000-100 cm(-1)) in solid phase was recorded for HEHMPT. The UV-Vis absorption spectrum of the HEHMPT that dissolved in water was recorded in the range of 100-400 nm. The structural and spectroscopic data of the molecule were obtained from B3LYP and M06-2X with 6-31G(d,p) basis set calculations. The theoretical wavenumbers were scaled and compared with experimental FT-IR and FT-Raman spectra. The complete assignments were performed on the basis of the normal co-ordinate analysis (NCA), experimental results and potential energy distribution (PED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method, interpreted in terms of fundamental modes. The stable geometry of the compound has been determined from the potential energy surface scan. The stability of molecule has been analyzed by NBO analysis. The molecule orbital contributions were studied by using the total (TDOS), partial (PDOS), and overlap population (OPDOS) density of states. The electronic properties like UV spectral analysis and HOMO-LUMO energies were reported. The calculated HOMO and LUMO energies shows that charge transfer interactions taking place within the molecule. Mulliken population analysis on atomic charges is also calculated. PMID- 23454844 TI - Spectroscopic investigations on the interactions between isopropanol and trypsin at molecular level. AB - The toxicity of hydroxyl group of isopropanol to trypsin in aqueous solution was investigated by techniques including UV-visible absorption spectroscopy, fluorescence spectroscopy, circular dichroism (CD) spectroscopy, enzyme activity assay and molecular docking technology. The results of UV-visible absorption spectroscopy and CD spectra indicate that isopropanol could change the secondary structure of trypsin by increasing the content of alpha-helix and decreasing the content of beta-sheet. The tertiary structure of trypsin was also changed owing to the loss of environmental asymmetry of amino acid residues. Isopropanol bound into a hydrophobic cavity on the surface of trypsin by a hydrogen bond located between the hydrogen atom on the hydroxyl of isopropanol and the oxygen atoms on SER 214 and hydrophobic interaction, as the molecular docking results showed. In addition, isopropanol could affect the function of trypsin by increasing its catalytic activity. PMID- 23454845 TI - A spectrophotometric and thermodynamic study of the charge-transfer complexes of N-aryl-N'-isopropyloxycarbonylsulfamides with DDQ and TCNE. AB - Molecular charge-transfer complexes of three N-aryl-N' isopropyloxycarbonylsulfamides derivatives with pi-acceptors tetracyanoethylene (TCNE), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), were studied by using zero and second order derivative UV spectrophotometry in different solvents at four different temperatures within the range of 20-35 degrees C. The stoichiometries of the complexes were found to be 1:1 ratio between donors and acceptors using Job's method. The data were analyzed in terms of their stability constant (K), molar extinction coefficient (epsilonCT), thermodynamic standard reaction quantities (DeltaG degrees , DeltaH degrees , DeltaS degrees ), oscillator strength (f), transition dipole moment (MUEN) and ionization potential (ID). The results show that the stability constant (K) for the complexes was found to be dependant upon the nature of electron acceptor, electron donor, and polarity of used solvents. PMID- 23454846 TI - Comparative study of the binding of pepsin to four alkaloids by spectrofluorimetry. AB - The interactions between pepsin and four alkaloids, including caffeine (Caf), aminophylline (Ami), acefylline (Ace), diprophylline (Dip), were investigated by fluorescence, UV-visible absorption, resonance light scattering, synchronous fluorescence spectroscopy and 3D spectroscopy under mimic physiological conditions. The results revealed that Caf (Ami/Ace/Dip) caused the fluorescence quenching of pepsin by the formation of Caf (Ami/Ace/Dip)-pepsin complex. The binding constants and thermodynamic parameters at three different temperatures, the binding locality and the binding power were obtained. The hydrophobic and electrostatic interactions were the predominant intermolecular forces to stabilize the complex. Results showed that aminophylline was the stronger quencher and bound to pepsin with higher affinity than other three alkaloids. PMID- 23454847 TI - Assessing the safety of a replacement chemical: nongenomic activity of bisphenol S. PMID- 23454848 TI - In vitro characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying. AB - Thermal ink-jet spray freeze-drying (TIJ-SFD) was used to produce inhalable particles of terbutaline sulphate, the aerosolisation properties of which were compared to the commercial Bricanyl formulation. Scanning electron micrograph images showed the particles to be spherical, highly porous and suitable for aerosolisation from a simple, capsule-based dry-powder device (Cyclohaler) without the need for additional excipients. Particle size was dependent upon the concentration of solution jetted, as well as the distance between the print head and the surface of the liquid nitrogen. Starting with a 5% (w/v) solution and maintaining this distance at 3cm produced spherical, porous particles of volume median diameter (VMD) 14.1 +/- 0.8 MUm and mass median aerodynamic diameter (MMAD) 4.0 +/- 0.6 MUm. The fine particle fraction (proportion of aerosol with MMAD <= 4.46 MUm) was 22.9 +/- 3.3%, which compared favourably with that of the marketed dry powder inhaler formulation of terbutaline (Bricanyl Turbohaler; 25.7 +/- 3.8%), tested under the same conditions. These findings show that TIJ-SFD is a useful tool to predict the viability of a DPI formulation during preformulation physicochemical characterisation. PMID- 23454849 TI - Optimization of an anti-HER2 monoclonal antibody targeted delivery system using PEGylated human serum albumin nanoparticles. AB - Human serum albumin (HSA) nanoparticles represent an attractive strategy for active targeting of therapeutics into tumor cells due to the presence of superficial functional groups. HER2 is highly expressed in a significant proportion of cancers and monoclonal antibodies (mAbs) directed against HER2 hold great promise for effective therapy. Herein, covalent coupling of a novel mAb (1F2) directed against the extracellular domain of HER2 to the surface of HSA nanoparticles was evaluated to obtain nanoparticles with highest cellular uptake. HER2 reactivity of 1F2-conjugated nanoparticles produced under different conditions was screened by an indirect ELISA and flow cytometry techniques. Monoclonal antibody thiolation with 100-fold molar excess of 2-iminothiolane and the ratio of 10:1 for the thiolated 1F2 (MUg) to PEGylated nanoparticles (mg), were optimum for the attachment process. Under this condition, 23+/-4% of 1F2 was conjugated to nanoparticles. The flow cytometry results show that 1F2-modified nanoparticles interact with nearly all HER2 receptors on the surface of BT474 cells. In addition, no cellular uptake was observed on MCF7 cells. In vitro analyses showed no significant cytotoxicity of produced system against BT474 cells. Therefore, 1F2-attached HSA nanoparticles represent a potential delivery system for targeted transport of therapeutic agents into HER2-positive tumor cells. PMID- 23454850 TI - Needle-free intravaginal DNA vaccination using a stearoyl oligopeptide carrier promotes local gene expression and immune responses. AB - The vaginal mucosa is the most common site of infection for viruses that are transmitted through heterosexual intercourse, including human immunodeficiency virus and papillomavirus. Thus, in order to prevent or respond to these infections, strong vaginal immunity is required as the first line of defense. We previously investigated the use of a needle-free injector as a mucosal vaccination tool in rabbits and demonstrated that this is a promising method for stimulating vaginal gene expression and immune responses. In order to improve gene expression, we have examined local vaginal gene transfection efficiency using a non-needle jet injector combined with an effective peptide carrier in rabbits. The carrier used was a stearoyl (STR) peptide with Cys (C), Arg (R) and His (H) residues that form disulfide cross linkages via Cys (STR-CH2R4H2C) which was developed in our previous study. As a result, vaginal gene expression using the needle-free injector combined with STR-CH2R4H2C carrier was significantly improved compared to that without STR-CH2R4H2C carrier. Moreover, intravaginal pDNA vaccination by the needle-free injector combined with STR-CH2R4H2C carrier and CpG-ODN promoted not only local vaginal IgA and IgG, but also serum IgG secretion, to a degree significantly higher than that of naked pDNA. PMID- 23454851 TI - The effects of pre-test social deprivation on a natural reward incentive test and concomitant 50 kHz ultrasonic vocalization production in adolescent and adult male Sprague-Dawley rats. AB - In rats, ultrasonic vocalizations (USVs) are often used as a measure of affect, with 22 kHz USVs reflecting negative affect and 50 kHz USVs reflecting positive affect. This study used a modified reward approach task to assess behavioral approach and concomitant USV production toward either a food or social stimulus following varied amounts of pre-test social deprivation in both adolescent and adult rats. Adolescents spent significantly more time investigating the social stimulus than adults, although in the presence of the social stimulus isolate housed adults emitted more 50 kHz USVs than isolate housed adolescents. Isolate housed adults emitted more USVs to a social stimulus than adults that received less pre-test social isolation, a social deprivation effect not evident in the social approach data or any measure when animals were tested with a food stimulus. When tested with a food stimulus, adults emitted more 50 kHz USVs than adolescents, although they spent the same (or even less) time investigating that stimulus than did adolescents. Together, these data demonstrate that 50 kHz USV production and time spent investigating a rewarding stimulus are clearly dissociable and hence seemingly measure different states. PMID- 23454852 TI - Transient decline in rats' hippocampal theta power relates to inhibitory stimulus reward association. AB - The hippocampus is important in learning during a discrimination-reversal task. In this task, animals first learn to emit the go response to one stimulus and the no-go response to another stimulus (S1+, S2-) during the discrimination phase, and then they learn to reverse these relationships between stimulus and response during the reversal phase (S1-, S2+). To emit a no-go response for non-reinforced trial during the reversal phase, animals needed to inhibit the previously learned response pattern. This study examined the relationship between the reversal phase of the discrimination-reversal task and hippocampal electric activity in operant conditioning. The results revealed that hippocampal theta power transiently declined during the non-reinforced trial in the reversal phase compared with that during the discrimination phase. This decrease was observed during the 400-600-ms epoch after the onset of stimulus presentation. This study suggested that transient decline in hippocampal theta power is related to negative memory retrieval. PMID- 23454853 TI - Short-term and long-term memory deficits in handedness learning in mice with absent corpus callosum and reduced hippocampal commissure. AB - The corpus callosum (CC) and hippocampal commissure (HC) are major interhemispheric connections whose role in brain function and behaviors is fascinating and contentious. Paw preference of laboratory mice is a genetically regulated, adaptive behavior, continuously shaped by training and learning. We studied variation with training in paw-preference in mice of the 9XCA/WahBid ('9XCA') recombinant inbred strain, selected for complete absence of the CC and severely reduced HC. We measured sequences of paw choices in 9XCA mice in two training sessions in unbiased test chambers, separated by one-week. We compared them with sequences of paw choices in model non-learner mice that have random unbiased paw choices and with those of C57BL/6JBid ('C57BL/6J') mice that have normal interhemispheric connections and learn a paw preference. Positive autocorrelation between successive paw choices during each session and change in paw-preference bias between sessions indicate that 9XCA mice have weak, but not null, learning skills. We tested the effect of the forebrain commissural defect on paw-preference learning with the independent BTBR T+ tf/J ('BTBR') mouse strain that has a genetically identical, non-complementing commissural trait. BTBR has weak short-term and long-term memory skills, identical to 9XCA. The results provide strong evidence that CC and HC contribute in memory function and formation of paw-preference biases. PMID- 23454854 TI - The role of recombinant PTH in human fracture healing: a systematic review. AB - OBJECTIVES: Human parathyroid hormone (PTH) is known to be efficacious in the treatment of osteoporosis and reduction of risk of vertebral and nonvertebral fractures; however, its role in the enhancement of human fracture healing is controversial. Our objective is to conduct a systematic literature review on the use of recombinant PTH in human fracture healing to (1) evaluate the evidence for recombinant PTH in human fracture healing and (2) assess whether there are notable differences between previous case reports and prospective trials. DATA SOURCES: We performed a literature search in PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews for "teriparatide," "PTH (1-84)," "fracture," and "healing." STUDY SELECTION: References of retrieved articles were screened for additional studies, and exclusion criteria were applied. DATA EXTRACTION: Due to the limited publications on the subject, case reports and case series were included in our data analysis. DATA SYNTHESIS: Due to the limited publications on the subject, our data are presented in simple tabular format. CONCLUSIONS: Our literature review yielded 16 publications on the use of recombinant PTH in human fracture healing and 2 randomized controlled trial with 1 retrospective subgroup analysis. There continues to be anecdotal evidence for the use of recombinant PTH to enhance fracture healing. There are discrepancies in study design in the randomized controlled trials and the majority of case reports and, additional prospective studies are warranted. PMID- 23454855 TI - Invited commentary. PMID- 23454856 TI - The effect of acute distal radioulnar joint laxity on outcome after volar plate fixation of distal radius fractures. AB - OBJECTIVES: The objective of this study was to determine whether intraoperative laxity of the distal radioulnar joint (DRUJ) is associated with adverse postoperative outcomes after volar plate fixation of a distal radius fracture (DRF) and 4 weeks of immobilization. DESIGNS: Prospective study with clinical and radiographic assessment. SETTING: Level 1 trauma center. PATIENTS: One hundred consecutive patients were treated by volar locking plate fixation at our institution for an unstable DRF from April 2007 to November 2009. Of these patients, 84 patients with a minimum follow-up of 12 months were enrolled in this study. INTERVENTION: Intraoperative DRUJ laxity was evaluated using a radioulnar stress test after fixation of DRF using volar locking plate and splint immobilization of the forearm for 1 month in patients with intraoperative DRUJ laxity. Patients were allocated to an unstable group or stable group according to the presence of intraoperative DRUJ laxity. MAIN OUTCOME MEASUREMENTS: Our primary outcome measure was disabilities of arm, shoulder, and hand score and the secondary outcome measures were wrist motion, grip strength, modified Mayo wrist score, visual analogue scale for wrist pain, and ongoing pain in the DRUJ. RESULTS: Nineteen of the 84 study subjects were allocated to the unstable group and 65 to the stable group. No significant differences were observed between 2 groups in wrist range of motion, grip strength, modified Mayo wrist score, disabilities of arm, shoulder, and hand score, visual analogue scale score, and ongoing pain in the DRUJ at 1 year postoperatively. CONCLUSIONS: In our series of patients treated with volar locking plate and immobilization of the forearm for 1 month in patients with intraoperative laxity of the DRUJ, laxity did not affect impairment, pain, or disability 1 year after fracture. However, the role of postoperative immobilization of the forearm is debatable and merits additional study. LEVEL OF EVIDENCE: Prognostic level I. PMID- 23454857 TI - Clinical implication of subgrouping in valgus femoral neck fractures: comparison of 31-B1.1 with 31-B1.2 fractures using the OTA/AO classification. AB - OBJECTIVES: This study aimed to identify the clinical implications of valgus impacted femoral neck fractures and compare fractures with >15-degree angle of impaction (31-B1.1) against fractures with <15-degree angle of impaction (31 B1.2). DESIGN: Retrospective study. PATIENTS/PARTICIPANTS: We enrolled 78 patients with 31-B1 femoral neck fractures who were treated by screw osteosynthesis. MAIN OUTCOME MEASUREMENTS: We evaluated the clinical and radiographic outcomes. RESULTS: Thirty-six patients sustained 31-B1.1 fractures, and 42 patients sustained 31-B1.2 fractures. The average follow-up period was 15 months, and bony union occurred in all cases. The mean femur neck shortening was 8.88 mm for B1.1 and 3.70 mm for B1.2 fractures (P < 0.001). The mean sliding distance of the screw was 3.36 mm for B1.1 fractures and 1.38 mm for B1.2 fractures (P < 0.001). The mean Harris hip score was 82.0 for B1.1 and 88.8 for B1.2 fractures (P = 0.029). Avascular necrosis (AVN) of the femoral head occurred in 4 patients with B1.1 fractures, and none with B1.2 fractures (P = 0.041). Eighteen of the 78 patients required a second operation, and 15 of them were included in 31-B1.1 fracture (P = 0.003). Three patients underwent arthroplasty due to AVN, and 15 patients required hardware removal due to pain after bony union. CONCLUSIONS: More femoral neck shortening and less functional recovery should be expected in valgus-impacted femoral neck fracture patients based on the severity of the initial deformity. Even though we obtained bony union in all of the cases, the risk of AVN and second operation after bony union was higher with greater initial deformity. LEVEL OF EVIDENCE: Therapeutic level III. PMID- 23454858 TI - Nonoperative treatment of the medial malleolus in bimalleolar and trimalleolar ankle fractures: a randomized controlled trial. AB - OBJECTIVES: To compare internal fixation with no fixation of the medial malleolus after open reduction and internal fixation of the lateral malleolus and if needed, the posterior malleolus. DESIGN: Randomized prospective trial. SETTING: Level III trauma center in a metropolitan area. PATIENTS: One hundred patients with bimalleolar or trimalleolar Orthopaedic Trauma Association type 44 ankle fractures and displacement of the medial malleolus less than 2 mm after open reduction and internal fixation of the lateral component. INTERVENTION: Internal fixation or nonoperative treatment of the medial malleolus. MAIN OUTCOME MEASUREMENTS: American Orthopaedic Foot and Ankle Society ankle hind foot score (AOFAS), The Olerud Molander Ankle (OMA) score, and visual analogue pain scale (VAS). RESULTS: Median follow-up time was 39 months (range: 24-72). There were no significant differences between the 2 groups with respect to OMA (P = 0.91), AOFAS (P = 0.85), VAS (P = 0.85), or development of osteoarthritis (P = 0.22). Reoperation and complication rates were also comparable, but 4 patients treated nonoperatively developed nonunion of the medial malleolus. These patients reported no functional disabilities and presented OMA, AOFAS, and VAS scores better than average. CONCLUSIONS: Our data indicate that nonoperative treatment of minimally displaced fractures of the medial malleolus after operative fixation of the fibula yields satisfactory results. However, long-term follow-up is needed due to increased risk of nonunion and uncertainty regarding the development of posttraumatic arthritis. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23454859 TI - Radiographic predictors of compartment syndrome in tibial plateau fractures. AB - OBJECTIVES: The purpose of this article was to evaluate the relationship of radiographic features of tibial plateau fractures to the development of compartment syndrome. We hypothesized that the direction and degree of initial displacement of the femur on the tibia, and the amount of tibial widening (TW), were correlated with the development of compartment syndrome. DESIGN: Retrospective case-control study. SETTING: Single level 1 trauma center. PATIENTS: Retrospective evaluation of 158 patients with 162 plateau fractures. INTERVENTION: Grouping with and without compartment syndrome. MAIN OUTCOME MEASURES: The following data were obtained: age, sex, Schatzker and OTA/AO classification, open/closed status, TW, and femoral displacement (FD). A univariate statistical and a logistical regression analysis were performed to determine significance. RESULTS: The overall rate of compartment syndrome was 11%. Univariate analysis found both the TW and FD to be significant with respect to development of compartment syndrome (P < 0.05). Higher Schatzker (IV-VI) and OTA/AO grades were also correlated (P < 0.05) with increased incidence of compartment syndrome. Logistic regression found FD and Schatzker grade to be significant. CONCLUSIONS: Our study is the first to identify easily obtained radiographic parameters that correlate to the occurrence compartment syndrome. There may also be a relationship between TW and FD, as noted by regression result. This study helps to assess which patients with a fracture are at higher risk for developing a compartment syndrome. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23454860 TI - Barefoot stubbing injuries to the great toe in children: a new classification by injury mechanism. AB - OBJECTIVE: This study was conducted to categorize barefoot stubbing injuries to the great toe in children by injury mechanism to differentiate benign stubbing injuries from more complex injuries necessitating surgery. DESIGN: Prospective clinical series of consecutively treated patients. SETTING: Tertiary university hospital setting. PATIENTS: Forty-one children who had sustained an indirect injury to the great toe during barefoot sports activities between January 2001 and December 2009 were included. INTERVENTION: Conservative or surgical treatment was done according to clinical and radiological findings. MAIN OUTCOME MEASUREMENT: Information regarding injury mechanism was collected from patients, parents, and coaches using skeletal models and assessed by a pediatric orthopedic surgeon. Mechanisms of injury were identified and grouped as follows: hyperabduction-flexion, hyperflexion, hyperabduction-extension, hyperextension, and hyperextension-adduction. RESULTS: Hyperabduction-flexion was the most common mechanism (n = 16), in which interphalangeal joint dislocation and skin disruption was noted in most cases. The second most common mechanism was hyperabduction-extension (n = 14) in which avulsion fracture of the lateral volar condyle of the proximal phalanx was noted in most cases. This avulsion fracture had the worst prognosis after conservative care. CONCLUSIONS: Based on these results, we have created a grading system and treatment protocol for indirect hallux sports injuries in children. Avulsion fracture of the lateral condyle of the proximal phalanx, a result of hyperabduction-extension, is a high-risk sign of nonunion and should be aggressively treated, contrary to previous guidelines. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23454861 TI - Regulation of CRAC channels by protein interactions and post-translational modification. AB - Store-operated Ca(2+) entry (SOCE) is a widespread mechanism to elevate the intracellular Ca(2+) concentrations and stimulate downstream signaling pathways affecting proliferation, secretion, differentiation and death in different cell types. In immune cells, immune receptor stimulation induces intracellular Ca(2+) store depletion that subsequently activates Ca(2+)-release-activated-Ca(2+) (CRAC) channels, a prototype of store-operated Ca(2+) (SOC) channels. CRAC channel opening leads to activation of diverse downstream signaling pathways affecting proliferation, differentiation, cytokine production and cell death. Recent identification of STIM1 as the endoplasmic reticulum Ca(2+) sensor and Orai1 as the pore subunit of CRAC channels has provided the much-needed molecular tools to dissect the mechanism of activation and regulation of CRAC channels. In this review, we discuss the recent advances in understanding the associating partners and posttranslational modifications of Orai1 and STIM1 proteins that regulate diverse aspects of CRAC channel function. PMID- 23454862 TI - Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. AB - Microglia mediate multiple facets of neuroinflammation, including cytotoxicity, repair, regeneration, and immunosuppression due to their ability to acquire diverse activation states, or phenotypes. Modulation of microglial phenotype is an appealing neurotherapeutic strategy but a comprehensive study of classical and more novel microglial phenotypic markers in vitro is lacking. The aim of this study was to outline the temporal expression of a battery of phenotype markers from polarised microglia to generate an in vitro tool for screening the immunomodulatory potential of novel compounds. We characterised expression of thirty-one macrophage/microglial phenotype markers in primary microglia over time (4, 12, 36, and 72 h), using RT-qPCR or multiplex protein assay. Firstly, we selected Interleukin-4 (IL-4) and lipopolysaccharide (LPS) as the strongest M1-M2 polarising stimuli, from six stimuli tested. At each time point, markers useful to identify that microglia were M1 included iNOS, Cox-2 and IL-6 and a loss of M2a markers. Markers useful for quantifying M2b-immunomodulatory microglia included, increased IL-1RA and SOCS3 and for M2a-repair and regeneration, included increased arginase-1, and a loss of the M1 and M2b markers were discriminatory. Additional markers were regulated at fewer time points, but are still likely important to monitor when assessing the immunomodulatory potential of novel therapies. Further, to facilitate identification of how novel immunomodulatory treatments alter the functional affects of microglia, we characterised how the soluble products from polarised microglia affected the type and rate of neuronal death; M1/2b induced increasing and M2a-induced decreasing neuronal loss. We also assessed any effects of prior activation state, to provide a way to identify how a novel compound may alter phenotype depending on the stage of injury/insult progression. We identified generally that a prior M1/2b reduced the ability of microglia to switch to M2a. Altogether, we have characterised a profile of phenotype markers and a mechanism of assessing functional outcome that we can use as a reference guide for first-line screening of novel immunomodulatory therapies in vitro in the search for viable neuroprotectants. PMID- 23454863 TI - Curing HIV: lessons from cancer therapy. AB - PURPOSE OF REVIEW: Interest in finding a potential 'cure' for HIV has taken on greater interest and urgency since the report of an individual who underwent allogeneic stem cell transplant from a CCR5 delta 32 homozygote donor after high dose chemotherapy for acute myeloid leukemia. The potential role of cancer chemotherapy and other cancer-directed treatment approaches is discussed in the context of their potential role in helping to eliminate HIV from the infected host. RECENT FINDINGS: Cancer chemotherapy and other cancer-targeted agents have been used successfully in treating a variety of malignancies in both HIV-infected and HIV-uninfected individuals. Lessons learned from these strategies may be of importance in helping to define more effective ways of controlling and eliminating HIV as well. Application of these anticancer strategies to patients with HIV are beginning to be explored and may help determine their potential usefulness in this disease as well. SUMMARY: Although cytotoxic chemotherapy is a crude and not particularly effective way of removing HIV latently infected cells and tissue reservoirs, several new approaches to targeting and controlling cancer proliferation may be of value in HIV cure research and may one day help to end this disease. PMID- 23454866 TI - Dynamical percolation transition in the two-dimensional ANNNI model. AB - The dynamical percolation transition of the two-dimensional axial next nearest neighbor Ising model due to a pulsed magnetic field has been studied by finite size scaling analysis (by Monte Carlo simulation) for various values of frustration parameters, pulse width and temperature (below the corresponding static transition temperature). It has been found that the size of the largest geometrical cluster shows a transition for a critical field amplitude. Although the transition points shift, the critical exponents remain invariant for a wide range of frustration parameters. They are also the same as those obtained for the 2d Ising model. This suggests that although the static phase diagrams of these two models differ significantly in various aspects, the dynamical percolation transitions of these models belong to the same universality class. PMID- 23454864 TI - Immune activation and HIV persistence: considerations for novel therapeutic interventions. AB - PURPOSE OF REVIEW: One of the potential barriers to current HIV cure strategies is the persistence of elevated levels of immune activation despite otherwise effective antiretroviral therapy (ART). The purpose of this review is to examine the relationship between immune activation and HIV persistence, and to review the novel therapeutic interventions that are currently being pursued to target immune activation in treated HIV disease. RECENT FINDINGS: Multiple groups have consistently observed that elevated levels of inflammation, immune activation, and immune dysfunction persist in ART-treated individuals, despite the successful suppression of plasma viremia. Increased immune activation may lead to viral persistence through multiple mechanisms. Several novel interventions aimed at decreasing persistent immune activation are being pursued and include studies aimed at decreasing low-level viral replication, approaches aimed at decreasing microbial translocation, interventions to treat co-infections, and therapies that directly target immune activation. SUMMARY: There appears to be a clear and consistent relationship between immune activation and viral persistence in treated HIV disease. Whether this relationship is causal or mediated through other mechanisms is still unknown. Small-scale, pathogenesis-oriented interventional studies are necessary to further evaluate this relationship and the effect of potential interventions. PMID- 23454865 TI - Overcoming pharmacologic sanctuaries. AB - PURPOSE OF REVIEW: Current antiretroviral treatment regimens represent significant improvements in the management of HIV-1 infection; however, these regimens have not achieved a functional or sterilizing cure. One barrier to achieving a cure may be suboptimal antiretroviral concentrations in sanctuary sites throughout the body, including the central nervous system, gut-associated lymphoid tissue, lymph nodes, and tissue macrophages. This review will focus on the problems associated with achieving effective concentrations in these restricted sanctuary sites, and potential strategies to overcome these barriers. RECENT FINDINGS: Sufficient data exist to conclude that antiretroviral drug distribution is not uniform throughout the body. Low tissue/reservoir concentrations may be associated with viral replication. Multiple means to increase drug concentrations in sanctuary sites are being investigated, including modification of currently utilized drugs, blockade of transporters and enzymes that affect drug metabolism and pharmacokinetics, and local drug administration. Accumulating data suggest these methods increase antiretroviral concentrations in reservoirs of viral replication. No method has yet resulted in the complete clearance of HIV. SUMMARY: New strategies for increasing antiretroviral concentrations in predominant sites of viral replication may provide more effective means for elimination of viral sanctuaries. Additional research is necessary to optimize antiretroviral tissue distribution in order to inhibit virus replication fully, and avoid resistance and replenishment of viral reservoirs that may persist in the face of antiretroviral therapy. PMID- 23454867 TI - Clinical evaluation of therapeutic cancer vaccines. AB - Therapeutic cancer vaccines are an immunotherapy that targets tumor antigens to induce an active immune response. To date, Provenge(r) is the only therapeutic cancer vaccine approved by the United States Food and Drug Administration. Although therapeutic cancer vaccines have not been approved by the European Medicines Agency (EMA), they have been approved in several countries other than the United States (US) and the European Union (EU). Provenge(r) is the only approved cancer vaccine that showed significant primary endpoint efficacy in a phase III study at the time of approval. Retrospective analysis of 23 completed or terminated phase III studies showed that 74% (17/23) failed to demonstrate significant efficacy in the primary endpoint. The reasons for failure were surveyed in 13 of the 17 studies. Despite efforts to minimize tumor burden, including surgery and induction chemotherapy before therapeutic cancer vaccine therapy, 69% (9/13) of the phase III studies failed. These findings indicate that tumor burden may not be the only prognostic factor. Immunological response has often been used as a predictive factor, and a small number of sub-group analyses have succeeded in showing that immunological response is associated with the efficacy of therapeutic cancer vaccines. Being a prognostic factor, inclusion of immunological response in addition to tumor stage in the eligibility criteria or sub-group analysis may minimize study population heterogeneity, a key factor in the success of phase III studies. PMID- 23454868 TI - Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development. AB - FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development. PMID- 23454869 TI - Medical costs of cancer attributable to work in the Basque Country (Spain) in 2008. AB - OBJECTIVES: [corrected] Underreporting of work-related cancer in the Basque Country (Spain) is massive. The aim of our study is to estimate the job-related cancer in the Basque Country in 2008 treated by the Basque Public Health System Osakidetza, as well as the medical costs derived from its treatment in the same year. METHODS: Scientific evidence from industrialised countries is used to estimate the number of processes of cancer attributable to work. Medical costs for specialised care (outpatient and hospital admissions) are derived from the National Health System cost accounts. Costs due to primary health care and pharmaceutical benefits are obtained from Spanish secondary sources. Figures were computed according to disease and sex. RESULTS: We estimate 1,331 work attributable cancers hospitalizations and 229 work-attributable cancers specialized ambulatory cases. Medical costs borne by public health care system exceed 10 million euros. Specialized care accounts for 64.2% of the total cost. Bronchus and lung cancer represents the largest percentage of total expenditure (27%), followed by the bladder cancer (12.6%), mesothelioma (8.6%), the colon cancer (7.3%), and stomach (6.7%). CONCLUSIONS: The magnitude of cancer attributable to work in the Basque Country is much higher than reflected in the official Registry of Occupational Diseases. Underreporting of work-related cancers hampers prevention and shifts funding of medical costs from social security to the tax-financed public health system. PMID- 23454870 TI - Eighth World Congress on Vaccines, Immunisation and Immunotherapy. PMID- 23454871 TI - Letter from the editor. PMID- 23454872 TI - A quantitative high throughput assay for identifying gametocytocidal compounds. AB - Current antimalarial drug treatment does not effectively kill mature Plasmodium falciparum gametocytes, the parasite stage responsible for malaria transmission from human to human via a mosquito. Consequently, following standard therapy malaria can still be transmitted for over a week after the clearance of asexual parasites. A new generation of malaria drugs with gametocytocidal properties, or a gametocytocidal drug that could be used in combinational therapy with currently available antimalarials, is needed to control the spread of the disease and facilitate eradication efforts. We have developed a 1536-well gametocyte viability assay for the high throughput screening of large compound collections to identify novel compounds with gametocytocidal activity. The signal-to-basal ratio and Z'-factor for this assay were 3.2-fold and 0.68, respectively. The IC(50) value of epoxomicin, the positive control compound, was 1.42+/-0.09 nM that is comparable to previously reported values. This miniaturized assay significantly reduces the number of gametocytes required for the AlamarBlue viability assay, and enables high throughput screening for lead discovery efforts. Additionally, the screen does not require a specialized parasite line, gametocytes from any strain, including field isolates, can be tested. A pilot screen utilizing the commercially available LOPAC library, consisting of 1280 known compounds, revealed two selective gametocytocidal compounds having 54- and 7.8-fold gametocytocidal selectivity in comparison to their cell cytotoxicity effect against the mammalian SH-SY5Y cell line. PMID- 23454873 TI - The folate metabolic network of Falciparum malaria. AB - The targeting of key enzymes in the folate pathway continues to be an effective chemotherapeutic approach that has earned antifolate drugs a valuable position in the medical pharmacopoeia. The successful therapeutic use of antifolates as antimalarials has been a catalyst for ongoing research into the biochemistry of folate and pterin biosynthesis in malaria parasites. However, our understanding of the parasites folate metabolism remains partial and patchy, especially in relation to the shikimate pathway, the folate cycle, and folate salvage. A sizeable number of potential folate targets remain to be characterised. Recent reports on the parasite specific transport of folate precursors that would normally be present in the human host awaken previous hypotheses on the salvage of folate precursors or by-products. As the parasite progresses through its life cycle it encounters very contrasting host cell environments that present radically different metabolic milieus and biochemical challenges. It would seem probable that as the parasite encounters differing environments it would need to modify its biochemistry. This would be reflected in the folate homeostasis in Plasmodium. Recent drug screening efforts and insights into folate membrane transport substantiate the argument that folate metabolism may still offer unexplored opportunities for therapeutic attack. PMID- 23454874 TI - Abdominal pain duration impacts the accuracy of ultrasound for diagnosing paediatric appendicitis. PMID- 23454875 TI - Depressive symptoms are a vulnerability factor for heavy episodic drinking: a short-term, four-wave longitudinal study of undergraduate women. AB - Heavy episodic drinking is increasingly common among undergraduate women. Cross sectional research suggests that depressive symptoms and heavy episodic drinking are related. Nonetheless, surprisingly little is known about whether depressive symptoms are an antecedent of heavy episodic drinking, a consequence of heavy episodic drinking, or both. Such knowledge is essential to the accurate conceptualization of heavy episodic drinking, depressive symptoms, and their interrelations. In the present short-term longitudinal study, depressive symptoms and heavy episodic drinking were proposed to reciprocally influence each other over time, with depressive symptoms predicting changes in heavy episodic drinking over 1 week and vice versa. This reciprocal relations model was tested in 200 undergraduate women using a 4-wave, 4-week longitudinal design. Structural equation modeling was used to conduct cross-lagged analyses testing reciprocal relations between depressive symptoms and heavy episodic drinking. Consistent with hypotheses, both depressive symptoms and heavy episodic drinking were temporally stable, and depressive symptoms predicted changes in heavy episodic drinking over 1 week. Contrary to hypotheses, heavy episodic drinking did not predict changes in depressive symptoms over 1 week. Results are consistent with a vulnerability model suggesting depressive symptoms leave undergraduate women vulnerable to heavy episodic drinking. For undergraduate women who are struggling with feelings of sadness, worthlessness, and hopelessness, heavy episodic drinking may provide a temporary yet maladaptive means of avoiding or alleviating depressive symptoms. PMID- 23454876 TI - Comparative effectiveness of the nicotine lozenge and tobacco-free snuff for smokeless tobacco reduction. AB - Long-term smokeless tobacco (ST) use is associated with cardiovascular disease and cancer, but not all ST users want to quit. Previous studies have evaluated the effectiveness of nicotine lozenges and tobacco-free snuff for reducing ST use among ST users not ready to quit, but no comparative effectiveness trials of these two products have been conducted. We conducted a multicenter, randomized clinical pilot study evaluating the comparative effectiveness of the 4-mg nicotine lozenge and tobacco-free snuff for reducing ST use and increasing tobacco abstinence among ST users with no intention of quitting in the next 30 days. Participants received 8 weeks of treatment and behavioral counseling on tobacco reduction strategies with follow-up to 26 weeks. We randomized 81 participants (40 nicotine lozenges, 41 tobacco-free snuff). No significant differences in reduction were observed between the two groups at weeks 8, 12, and 26. No significant differences were observed between groups in nicotine withdrawal or tobacco craving. However, both groups significantly reduced (p<.001) ST use in cans/week and dips/day from baseline which was sustained through the end-of-study. The observed biochemically-confirmed abstinence rates at week 26 were similar between groups (12% vs. 12%, one-tailed p=.615). The 4-mg nicotine lozenge and the tobacco-free snuff both appear to be effective and comparable for reducing ST use among ST users not ready to quit in the next 30 days. PMID- 23454877 TI - Screening instruments for substance use and brief interventions targeting adolescents in primary care: a literature review. AB - BACKGROUND: A review of the literature was conducted to examine substance use screening instruments commonly used with adolescents in medical settings, their comparative usefulness, and SBIRT (Screening, Brief Intervention, and Referral to Treatment). METHODS: We screened two databases (Ovid MEDLINE and PsycINFO) targeting journal articles dealing with screening for alcohol and drug use in adolescence as well as adolescent SBIRT. RESULTS: Adolescents preferred paper forms and computerized questionnaires over interviews with physicians or nurses. The CRAFFT was the best studied instrument for screening for alcohol/drug use and related problems, and is the only tool with data to support its use in medical settings. Other screening instruments require more testing/evaluation in more representative samples of adolescents in primary care settings. Long term follow up data to establish the efficacy of SBIRT in adolescence are not available. Innovative computerized approaches to screening for substance use in this population have recently been proposed. Although promising, they require further evaluation. CONCLUSIONS: The CRAFFT has the most consistent data to support its use in primary care settings. The effects of SBIRT in adolescence have not been adequately evaluated. Adolescents' opinions and preferences for SBIRT should be studied to improve their acceptance. PMID- 23454878 TI - Impulsivity but not sensation seeking is associated with opioid analgesic misuse risk in patients with chronic pain. AB - Impulsivity and sensation seeking have been associated with substance use disorders, including opioid use disorders. This pilot study sought to examine whether impulsivity and sensation seeking, as measured by the Barratt Impulsiveness Scale (BIS) and Sensation Seeking Scale (SSS), were associated with opioid analgesic misuse risk in chronic, low-back pain patients prescribed opioid analgesics. Participants were 42 chronic, low-back pain patients enrolled in a larger study examining problematic opioid analgesic use. Impulsivity was assessed using the BIS, sensation seeking was measured using the SSS, and opioid analgesic misuse risk was assessed using the Current Opioid Misuse Measure (COMM). Significant bivariate associations were found between the COMM and the following predictor variables: age and the three BIS subscales: Attentional Impulsiveness, Non-planning Impulsiveness, and Motor Impulsiveness. Using a multivariate linear regression, after controlling for age, the BIS subscales accounted for 29.0% of the variance in the COMM. Attentional Impulsiveness was the only significant BIS subscale. These results suggest a potential relationship between impulsivity, but not sensation seeking, and risk for opioid analgesic misuse. Impulsivity is not a prominent trait observed in chronic pain patients; however, it may be an important risk factor for opioid analgesic misuse for a subset of individuals with chronic pain. As such, these findings suggest that additional exploration of this potential risk factor is warranted. PMID- 23454879 TI - The uniqueness of negative urgency as a common risk factor for self-harm behaviors, alcohol consumption, and eating problems. AB - Research suggests that self-control, affective lability, and negative urgency are associated with deliberate self-harm, problematic alcohol consumption, and eating problems. Few studies have fully examined how negative urgency might uniquely explain the effects of self-control and affective lability on these outcomes, as compared to other impulsivity-related traits. This was the goal of the current study. Of an initial group of 734 undergraduate students, 29% indicated a history of deliberate self-harm. These 215 individuals were randomly matched with a group of non-self-harmers (total N=430; mean age=22.36, SD=6.59; 76.2% female). Self harmers showed higher rates of alcohol use (F(2, 186)=5.48, p<.001) and eating problems (F(2, 186)=7.74, p<.001). In a structural equation model, negative urgency was significantly associated with self-harming frequency (beta=3.81, p<.001), variety of self-harm methods (beta=5.79, p<.001), the number of years of self-harming (beta=2.75, p<.001), problematic alcohol use (beta=1.80, p<.05), and eating problems (beta=3.99, p<.001). Negative urgency was positively associated with affective lability (beta=7.71, p<.001) and negatively associated with self control (beta=-13.59, p<.001). Negative urgency is the only impulsivity-related trait that is a common risk factor associated with increased self-harm, problematic alcohol use, and eating problems. PMID- 23454880 TI - Implicit drinking identity: Drinker+me associations predict college student drinking consistently. AB - Predicting hazardous drinking in college students continues to be a serious priority. Emerging evidence suggests that implicit measures may offer additional insight in predicting unique variance in alcohol outcomes. Implicit drinking identity, in particular, may be a powerful predictor of alcohol use. The current study examined the predictive validity of three alcohol-related associations (e.g., drinking identity, alcohol approach, and alcohol cope) using adaptations of the Implicit Association Test (IAT) in a sample of 243 undergraduates. Confirming previous findings, drinking identity associations were the most consistent predictor of alcohol consumption and alcohol problems. They were the only associations that were unique predictors of alcohol use after controlling for other implicit associations. In comparison, alcohol cope and alcohol approach associations were weak but consistent predictors of alcohol consumption and alcohol problems. Although positively correlated with all drinking outcomes, neither set of associations predicted unique variance in the drinking outcomes when all implicit associations were included in the same model. Collectively, these results extend previous findings that implicit drinking identity may be a powerful tool for predicting alcohol outcomes and a potential target for clinical intervention and prevention efforts. PMID- 23454881 TI - The role of time and risk preferences in smoking inequalities: a population-based study. AB - Heterogeneity in time and risk preferences has been proposed as one of the mechanisms involved in the educational gradient in smoking, but this mechanism has scarcely been explored empirically. Subjective scales were introduced in the 2008 French National Health, Health Care and Insurance Survey in order to elicit measures of time and risk preferences for a representative sample of 5188 men and 5684 women. Men and women were treated separately. First, logistic regressions were used to test the associations between preferences and education and between preferences and smoking. Second, nested logistic models were built to investigate the mediating role of preferences in the educational gradient in smoking, with an econometric treatment of the rescaling problem. Preference for the present and risk loving were found to be: inversely related to educational level; strongly related to each other, and; strongly associated to current smoking, even after adjustment for educational level. There was a weakening of the educational gradient after the control for preferences, which supports the role of these two preferences as partial mediators in the educational gradient in smoking. Among men, time preference was more strongly associated with smoking than risk aversion, while the reverse was found for women. We provide convincing evidence in favour of the mediating role of time preference and risk aversion in educational inequalities in smoking and highlight the connection between those two dimensions. Gender patterns are discussed and potential implications in terms of designing targeted anti-tobacco programmes are delineated. PMID- 23454882 TI - The Young Adults' Cigarette Dependence (YACD) score: an improved tool for cigarette dependence assessment in university students. AB - BACKGROUND: Cigarette smoking induces dependence in young smokers. PURPOSE: The primary objective of this work was to validate the use of the Fagerstrom Test for Nicotine Dependence (FTND) in young Lebanese university students, and to improve it eventually by adding new items covering DSM-IV and ICD-10 dependence components. METHODS: We used data from a cross-sectional study on university students. A standardized questionnaire was administered, with items related to cigarette dependence: the FTND and the new Young Adults' Cigarette Dependence (YACD) scale. For both tools, factor and reliability analyses were performed. RESULTS: Although the FTND test showed satisfactory psychometric properties, the YACD showed better construct validity and reliability, covered dependence concept better and discriminated better between those who wanted to stop smoking and those who did not. CONCLUSIONS: FTND could be used in university students' population; however, the YACD scale could be more useful. PMID- 23454883 TI - To enforce or engage: the relationship between coercion, treatment motivation and therapeutic alliance within community-based drug and alcohol clients. AB - Three fundamental clinical issues are consistently associated with treatment engagement and outcomes in substance using populations; coercion, motivation and therapeutic alliance. It is accepted that these factors play an integral role in the success of substance use treatment and particularly that higher motivation and therapeutic alliance are advantageous to treatment outcomes. The impact of coercion on engagement and treatment outcome, on the other hand, is less clear, and the relationship between these three issues has not been adequately explored. The current study aimed to address this gap, by examining the presenting characteristics of clients attending a community drug and alcohol counselling service in relation to coercion, motivation, therapeutic alliance and substance use, as well as the effect that these variables had on treatment outcomes 15 weeks later. A total of 77 clients recruited from the Central Coast Drug and Alcohol Service participated in the study, completing a phone assessment upon treatment entry and 15 weeks post-baseline. Results indicated that facets of motivation and therapeutic alliance played a significant role in client's substance use upon presentation for treatment, although coercion did not. Coercion was not associated with substance use outcomes at 15 week follow up. However, due to a relatively small sample completing post-baseline assessments (n=33), further research is needed to examine the predictive effects of these variables in community drug and alcohol clients. PMID- 23454884 TI - Validation of the Drinking Motives Questionnaire (DMQ) in older adults. AB - Drinking motives have been established as an important construct in the prediction of alcohol use and drinking problems among younger adults, but there is little understanding about the drinking motivations of older adults. Although emerging evidence shows the importance of studying older adults' own reasoning for their alcohol consumption, measures that have been used to assess such reasons lack psychometric assessment. This study aims to validate the three dimensional structure of the Drinking Motives Questionnaire (DMQ) in older adults and to investigate the relationships between drinking motives and alcohol use. A sample of community dwelling older adults (N=370) completed self-report measures assessing drinking behavior and motives for drinking. Using confirmatory factor analysis, the results supported a three-factor model of drinking motives. Multi group analysis of invariance showed support for configural and metric invariance, and partial support was met for scalar invariance. Social motivations for drinking were the most frequently endorsed, followed by enhancement, and coping motives. Males reported more frequent drinking for each of the three motives. Social motives were consistently related to drinking behaviors and coping had a direct relationship to drinking problems. Overall, the study shows that the DMQ has promise as a measure for use with older adults. PMID- 23454885 TI - Does the exposure to smoking cues in movies affect adolescents' immediate smoking behavior? AB - INTRODUCTION: Various studies have demonstrated that environmental smoking cues elicit smoking-related responses in smokers. However, cue reactivity studies among adolescent smokers are scarce. Therefore, the aim of this study was to examine the effect of smoking portrayal in movies on immediate smoking behavior in adolescent smokers. METHOD: A total of 65 adolescent daily smokers (between the ages of 16 and 18 years) were exposed to a one-hour movie clip, with or without smoking characters, and were allowed to smoke while watching the movie. RESULTS: The exposure to smoking cues in movies had no effect on immediate smoking behavior. This association was not affected by several smoking- and movie related variables. CONCLUSIONS: No influence of smoking cues in movies on immediate smoking behavior in adolescent daily smokers was found. More experimental research on the effects of environmental cues on adolescent smokers in different stages of addiction is needed. PMID- 23454886 TI - Knowledge of TIA among general practitioners and emergency department physicians. A questionnaire survey in a French semi-rural area. AB - BACKGROUND AND OBJECTIVE: Management of transient ischemic attacks (TIAs) is of vital importance in an attempt to prevent stroke. However, suboptimal management still raise concern among general practitioners (GPs) and emergency department (ED) physicians-the first medical contact of most TIA patients. This may relate to their poorly updated knowledge about TIA. The study was designed to assess knowledge of TIA among these non-neurologists. METHODS: The study was a post mailed questionnaire survey among GPs and ED physicians. The questionnaire related to selective clinical aspects on TIA. RESULTS: There were a total of 85 respondents for analysis, mostly GPs (n=64; 75.3%), out of 177 mailed physicians. Response rate was 52.7%. Many of these respondents were unaware of the newly proposed TIA definition (59%), unfamiliar with TIA mimics and predictors of post TIA early stroke recurrence and therefore with the rationales underlying the need of emergency management of TIA. More than one third (39%) were unaware of the relevant national guidelines. Guidelines-aware respondents performed better in most part of the mailed questionnaire. CONCLUSION: Our results show that poorly updated knowledge about TIA among non-neurologists represents a potential contributing factor to the persisting sub-optimal management of the disorder. Although further studies are needed to confirm this, improved continuous medical education of this group of health care professionals appears warranted. PMID- 23454887 TI - Role of selected genetic variants in lung cancer risk in African Americans. AB - INTRODUCTION: Black/white disparities in lung cancer incidence and mortality mandate an evaluation of underlying biological differences. We have previously shown higher risks of lung cancer associated with prior emphysema in African American compared with white patients with lung cancer. METHODS: We therefore evaluated a panel of 1440 inflammatory gene variants in a two-phase analysis (discovery and replication), added top genome-wide association studies (GWAS) lung cancer hits from white populations, and 28 single-nucleotide polymorphisms (SNPs) from a published gene panel. The discovery set (477 self-designated African Americans cases, 366 controls matched on age, ethnicity, and gender) were from Houston, Texas. The external replication set (330 cases and 342 controls) was from the EXHALE study at Wayne State University. RESULTS: In discovery, 154 inflammation SNPs were significant (p < 0.05) on univariate analysis, as was one of the gene panel SNPs (rs308738 in REV1, p = 0.0013), and three GWAS hits, rs16969968 p = 0.0014 and rs10519203 p = 0.0003 in the 15q locus and rs2736100, in the HTERT locus, p = 0.0002. One inflammation SNP, rs950286, was successfully replicated with a concordant odds ratio of 1.46 (1.14-1.87) in discovery, 1.37 (1.05-1.77) in replication, and a combined odds ratio of 1.40 (1.17-1.68). This SNP is intergenic between IRF4 and EXOC2 genes. We also constructed and validated epidemiologic and extended risk prediction models. The area under the curve (AUC) for the epidemiologic discovery model was 0.77 and 0.80 for the extended model. For the combined datasets, the AUC values were 0.75 and 0.76, respectively. CONCLUSIONS: As has been reported for other cancer sites and populations, incorporating top genetic hits into risk prediction models, provides little improvement in model performance and no clinical relevance. PMID- 23454888 TI - Improving access to dementia services for people from minority ethnic groups. AB - PURPOSE OF REVIEW: Only a minority of people with dementia receive a formal diagnosis despite a growing body of evidence highlighting the benefits of early diagnosis and intervention. People from minority ethnic groups are even more disadvantaged, as they tend to access dementia services later in the illness. Studies exploring the reasons behind underuse of dementia services by minority ethnic groups have highlighted the barriers to help-seeking that seem specific to the cultural groups studied. Understanding the barriers to help-seeking should help to identify the targets for interventions to encourage help-seeking in minority ethnic communities. This review sought to highlight the progress in this field and show what interventions have been developed so far. RECENT FINDINGS: Many countries are carrying out educational campaigns in an effort to increase awareness about dementia and reduce stigma, but none of these have reported any measurable outcomes of their interventions. Studies show that knowledge about dementia has the potential to increase help-seeking, but information should be targeted to the recipient audience. SUMMARY: Not enough has been done to address the inequality in service use for dementia in minority ethnic groups compared with the majority population. The time has come for the development of targeted and evidence-based interventions in order to improve access and affect outcomes. PMID- 23454889 TI - How to measure RNA expression in rare senescent cells expressing any specific protein such as p16Ink4a. AB - Here we describe a carefully optimized method for the preparation of high quality RNA by flow sorting of formaldehyde fixed senescent cells immunostained for any intracellular antigen. Replicative cellular senescence is a phenomenon of irreversible growth arrest triggered by the accumulation of a discrete number of cell divisions. The underlying cause of senescence due to replicative exhaustion is telomere shortening. We document here a spontaneous and apparently stochastic process that continuously generates senescent cells in cultures fully immortalized with telomerase. In the course of studying this phenomenon we developed a preparative fluorescence activated flow sorting method based on immunofluorescent staining of intracellular antigens that can also deliver RNA suitable for quantitative analysis of global gene expression. The protocols were developed using normal human diploid fibroblasts (HDF) and up to 5x107 cells could be conveniently processed in a single experiment. The methodology is based on formaldehyde crosslinking of cells, followed by permeabilization, antibody staining, flow sorting, reversal of the crosslinks, and recovery of the RNA. We explored key parameters such as crosslink reversal that affect the fragmentation of RNA. The recovered RNA is of high quality for downstream molecular applications based on short range sequence analysis, such qPCR, hybridization microarrays, and next generation sequencing. The RNA was analyzed by Affymetrix Gene Chip expression profiling and compared to RNA prepared by the direct lysis of cells. The correlation between the data sets was very high, indicating that the procedure does not introduce systematic changes in the mRNA transcriptome. The methods presented in this communication should be of interest to many investigators working in diverse model systems. PMID- 23454890 TI - Using VARK to assess changes in learning preferences of nursing students at a public university in Jordan: implications for teaching. AB - PURPOSE: The purpose of this study was to describe learning styles of nursing students at a public University in Jordan. SAMPLE: A descriptive research design was used, a purposive sample of 197 nursing students who were enrolled in nursing summer courses. These students were at different academic levels. RESULTS: Almost 55% of students have a multimodal preference, about 60% of multimodal students have the kinesthetic learning preference (K) associated with visual or read write preference. The rest have one dominant learning preference. Of the 45% students who have one dominant preference: 60% had the kinesthetic preference as the dominant preference, and 40% had the auditory preference accompanied with another preference. Analysis of Variance (ANOVA) revealed significant difference between students based on their academic level. CONCLUSIONS: Nursing students have varied learning styles; teachers should accommodate their classes to meet the learning needs and styles of students. Multimodal learners can be more flexible about how they exchange information than those with a single preference. However, multimodal learners need to have at least two, three or four modes involved in learning before they are satisfied. Teachers at nursing program should use more than one teaching modality to be able to make their students satisfied with their learning experience. PMID- 23454891 TI - Beyond the balloon: excimer coronary laser atherectomy used alone or in combination with rotational atherectomy in the treatment of chronic total occlusions, non-crossable and non-expansible coronary lesions. AB - AIMS: To establish success and complication rates of excimer laser coronary atherectomy (ELCA) in a contemporary series of patients with balloon failure during percutaneous coronary intervention (PCI) of both chronic total occlusions (CTO) and lesions with distal TIMI 3 flow. METHODS AND RESULTS: We identified 58 cases of balloon failure treated with ELCA+/-rotational atherectomy (RA) over four years, representing 0.84% of all PCI performed in our centre during this period. Balloon failures were classified according to: (i) mechanism of balloon failure; and (ii) whether this occurred in the context of treating a CTO. ELCA was performed following balloon failure using the CVX-300 Excimer Laser System and a 0.9 mm catheter with saline flush. For the entire cohort, procedure success was achieved in 91% (with ELCA successful: alone in 76.1%, after RA failure in 6.8% and in combination with RA for 8.6%). Only in one case did RA succeed where ELCA had failed. There were four procedure-related complications, including transient no-reflow, side branch occlusion and two coronary perforations, of which one was directly attributable to ELCA and led to subsequent mortality. CONCLUSIONS: ELCA provides safe and effective adjunctive therapy in contemporary PCI to treat lesions associated with balloon failure due to an inability either to cross the lesion or to expand a balloon sufficiently to permit stenting. ELCA was successful in the majority of these selected cases when used independently with further effectiveness achieved when combined with RA or after RA failure. PMID- 23454893 TI - Predictive immunomonitoring -- the COST ENTIRE initiative. PMID- 23454892 TI - Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome. AB - Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p<0.05), with miR-185 expressed at 0.4* normal levels. The 22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance. PMID- 23454894 TI - Reconstruction and analysis of the industrial strain Bacillus megaterium WSH002 genome-scale in silico metabolic model. AB - A genome-scale metabolic model of Bacillus megaterium WSH002, an industrial bacterium widely used in the vitamin C industry, was reconstructed on the basis of the genome annotation and data from the literature and biochemical databases. It comprises 1112 reactions, 993 metabolites, and 1055 genes, including 43 new annotated genes. This model was able to predict qualitatively and quantitatively the growth of B. megaterium on a range of carbon and nitrogen sources, and the results agreed well with experimental data. A gene essentiality analysis predicted a core metabolic essential gene set of 57 genes on three different media. Furthermore, constraint-based analysis revealed that B. megaterium WSH002 is capable of producing and exporting several key metabolites, which could promote the growth of Ketogulonicigenium vulgare and 2-keto-l-gulonic acid (2 KLG) production. Here, the model represents a helpful tool for understanding and exploring this important industrial organism. PMID- 23454895 TI - pH-sensitive nanocargo based on smart polymer functionalized graphene oxide for site-specific drug delivery. AB - Graphene oxide (GO) was functionalized covalently with pH-sensitive poly(2 (diethylamino) ethyl methacrylate) (PDEA) by surface-initiated in situ atom transfer radical polymerization. The structure of the PDEA-grafted GO (GO-PDEA) were examined by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis and atomic force microscopy. The grafted PDEA endowed the GO sheets with good solubility and stability in physiological solutions. Simple physisorption by pi-pi stacking and hydrophobic interactions on GO-PDEA can be used to load camptothecin (CPT), a widely used water-insoluble cancer drug. The loaded CPT was released only at the lower (acidic) pH normally found in a tumor environment but not in basic and neutral pH. GO-PDEA did not show practical toxicity to N2a cancer cells but the GO-PDEA-CPT complex exhibited high potency in killing N2a cancer cells in vitro. These results suggest that the GO-PDEA nanocargo carrier might be a promising material for site-specific anticancer drug delivery and controlled release. PMID- 23454896 TI - Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance. AB - HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC50 near therapeutic drug blood levels (8-14 MUM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 MUM. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal beta1/beta5 active sites, similar to bortezomib/carfilzomib, but in addition the beta2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of beta2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (beta2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro. PMID- 23454897 TI - A prognostic signature of G(2) checkpoint function in melanoma cell lines. AB - As DNA damage checkpoints are barriers to carcinogenesis, G(2) checkpoint function was quantified to test for override of this checkpoint during melanomagenesis. Primary melanocytes displayed an effective G(2) checkpoint response to ionizing radiation (IR)-induced DNA damage. Thirty-seven percent of melanoma cell lines displayed a significant defect in G(2) checkpoint function. Checkpoint function was melanoma subtype-specific with "epithelial-like" melanoma lines, with wild type NRAS and BRAF displaying an effective checkpoint, while lines with mutant NRAS and BRAF displayed defective checkpoint function. Expression of oncogenic B-Raf in a checkpoint-effective melanoma attenuated G(2) checkpoint function significantly but modestly. Other alterations must be needed to produce the severe attenuation of G(2) checkpoint function seen in some BRAF mutant melanoma lines. Quantitative trait analysis tools identified mRNA species whose expression was correlated with G(2) checkpoint function in the melanoma lines. A 165 gene signature was identified with a high correlation with checkpoint function (p < 0.004) and low false discovery rate (<= 0.077). The G(2) checkpoint gene signature predicted G(2) checkpoint function with 77-94% accuracy. The signature was enriched in lysosomal genes and contained numerous genes that are associated with regulation of chromatin structure and cell cycle progression. The core machinery of the cell cycle was not altered in checkpoint defective lines but rather numerous mediators of core machinery function were. When applied to an independent series of primary melanomas, the predictive G(2) checkpoint signature was prognostic of distant metastasis-free survival. These results emphasize the value of expression profiling of primary melanomas for understanding melanoma biology and disease prognosis. PMID- 23454898 TI - Chk1-Mad2 interaction: a crosslink between the DNA damage checkpoint and the mitotic spindle checkpoint. AB - Chk1 is implicated in several checkpoints of the cell cycle acting as a key player in the signal transduction pathway activated in response to DNA damage and crucial for the maintenance of genomic stability. Chk1 also plays a role in the mitotic spindle checkpoint, which ensures the fidelity of mitotic segregation during mitosis, preventing chromosomal instability and aneuploidy. Mad2 is one of the main mitotic checkpoint components and also exerts a role in the cellular response to DNA damage. To investigate a possible crosslink existing between Chk1 and Mad2, we studied Mad2 protein levels after Chk1 inhibition either by specific siRNAs or by a specific and selective Chk1 inhibitor (PF-00477736), and we found that after Chk1 inhibition, Mad2 protein levels decrease only in tumor cells sensitive to Chk1 depletion. We then mapped six Chk1's phosphorylatable sites on Mad2 protein, and found that Chk1 is able to phosphorylate Mad2 in vitro on more than one site, while it is incapable of phoshorylating the Mad2 form mutated on all six phosphorylatable sites. Moreover our studies demonstrate that Chk1 co localizes and physically associates with Mad2 in cells both under unstressed conditions and after DNA damage, thus providing new and interesting evidence on Chk1 and Mad2 crosstalk in the DNA damage checkpoint and in the mitotic spindle checkpoint. PMID- 23454899 TI - Coordinate direct input of both KRAS and IGF1 receptor to activation of PI3 kinase in KRAS-mutant lung cancer. AB - Using a panel of non-small cell lung cancer (NSCLC) lines, we show here that MAP ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS-mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras-induced NSCLC. PI3K pathway activity is dependent on basal IGF1R activity in KRAS-mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS-mutant, but not wild-type, lung cancer cells, whereas acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS mutant lung cancer cells. SIGNIFICANCE: It has not yet been possible to target RAS proteins directly, so combined targeting of effect or pathways acting downstream of RAS, including RAF/MEK and PI3K/AKT, has been the most favored approach to the treatment of RAS -mutant cancers. This work sheds light on the ability of RASto activate PI3K through direct interaction, indicating that input is also required from a receptor tyrosinekinase, IGF1R in the case of KRAS mutant lung cancer. This suggests potential novel combination therapeutic strategies for NSCLC. PMID- 23454901 TI - DNP scholarly projects change practice. PMID- 23454902 TI - Management of patients with complications of cirrhosis. AB - Cirrhosis results from repeated hepatocellular injury over time, leading to portal hypertension and the development of ascites, hepatic encephalopathy, and varices. Despite improvements in medical care for patients with cirrhosis, mortality from infection, renal failure, and hepatocellular carcinoma remain high. PMID- 23454900 TI - Molecular dissection of microsatellite instable colorectal cancer. AB - Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a hereditary and sporadic basis, is linked to a clear clinicopathologic profile, and has prognostic implications. Inconclusive predictive data along with a paucity of targeted drug development have prevented this molecular classification system from being implemented in the clinical setting. New high-throughput genomic data have validated it, thus stressing the fact that it is ready to be applied clinically. SIGNIFICANCE: Application of a molecular classification of colorectal cancer in the clinical arena is an unmet promise. Recent results of large-scale genomic analyses have provided confirmation and further insights into the molecular biology of already known colorectal cancer subgroups. The quintessential example is the microsatellite instability subgroup, which has been well characterized during the past 2 decades. Future drug development and clinical research initiatives in colorectal oncology should consider these and other known cancer subgroups and start targeting these selected patient populations. PMID- 23454903 TI - Multiple sclerosis: managing patients in primary care. AB - In this era of the Patient Centered Medical Home model of care, chronic diseases such as multiple sclerosis (MS) are managed in partnership with specialty care practices. For the patient and family living with MS, assuring that patients get proper care when and where they need it requires that nurse practitioners understand their role in assessing and managing complex chronic diseases. PMID- 23454904 TI - Age and treatment of kidney failure. AB - PURPOSE OF REVIEW: This review discusses issues related to treatment of chronic kidney disease, and kidney failure in particular, among older adults. RECENT FINDINGS: A substantial proportion of older adults have chronic kidney disease and progress to kidney failure. There is considerable variability in treatment practices for advanced kidney disease among older adults, and evidence that treatment decisions such as dialysis initiation may be made without adequate preparation. When initiated, survival among older adults on chronic dialysis remains poor, and is associated with a significant decline in functional status. There is also evidence to suggest that dialysis initiation may not reflect overall treatment goals of elderly patients, but rather a lack of clear communication between patients and health practitioners, and underdeveloped conservative care programs in many centers. SUMMARY: Kidney failure is common among older adults. When considering treatment options for kidney failure, patient priorities, preferences, and symptoms should be taken into account, using a shared decision-making approach. PMID- 23454906 TI - A methodology for elemental and organic carbon emission inventory and results for Lombardy region, Italy. AB - This paper presents a methodology and its application for the compilation of elemental carbon (EC) and organic carbon (OC) emission inventories. The methodology consists of the estimation of EC and OC emissions from available total suspended particulate matter (TSP) emission inventory data using EC and OC abundances in TSP derived from an extensive literature review, by taking into account the local technological context. In particular, the method is applied to the 2008 emissions of Lombardy region, Italy, considering 148 different activities and 30 types of fuels, typical of Western Europe. The abundances estimated in this study may provide a useful basis to assess the emissions also in other emission contexts with similar prevailing sources and technologies. The dominant sources of EC and OC in Lombardy are diesel vehicles for EC and the residential wood combustion (RWC) for OC which together account for about 83% of the total emissions of both pollutants. The EC and OC emissions from industrial processes and other fuel (e.g., gasoline, kerosene and LPG) combustion are significantly lower, while non-combustion sources give an almost negligible contribution. Total EC+OC contribution to regional greenhouse gas emissions is positive for every sector assuming whichever GWP100 value within the range proposed in literature. An uncertainty assessment is performed through a Monte Carlo simulation for RWC, showing a large uncertainty range (280% of the mean value for EC and 70% for OC), whereas for road transport a qualitative analysis identified a narrower range of uncertainty. PMID- 23454907 TI - A really quick easy cheap effective rugged and safe (QuEChERS) extraction procedure for the analysis of particle-bound PAHs in ambient air and emission samples. AB - A quick easy cheap effective rugged and safe (QuEChERS) like extraction procedure is presented for the measurement of polycyclic aromatic hydrocarbons (PAHs) associated to particulate matter from ambient air or combustion process. The procedure is based on a short mechanical agitation (vortex during 90 s) using a small volume of acetonitrile (7 ml) as extraction solvent. Equivalent extraction efficiencies were obtained when comparing the QuEChERS and the traditional pressurized solvent extraction (ASE) procedures for ambient air and emission (wood combustion) filter samples. The developed QuEChERS extraction protocol was validated with the analysis of a standard reference material (NIST SRM 1649a, urban dust). By comparison to other extraction methods including ASE, the simplicity of the QuEChERS protocol allows to minimize experimental errors, to decrease about a factor 5 the cost per extraction and to increase the productivity per working day by a 10-fold factor. This paper constitutes the first report on the applicability of a QuEChERS-like approach for the quantification of PAHs or other organic compounds in atmospheric particulate matter. PMID- 23454908 TI - Dictyostelium discoideum developmental cycle (DDDC) assay: a tool for Hg toxicity assessment and soil health screening. AB - The social amoeba Dictyostelium discoideum has been proposed for assessing stress responses to pollutants in soil and it has already been successfully employed in the aquatic environment. Presently, we developed the DDDC assay (D. discoideum developmental cycle assay) for both soil toxicity assessment and soil health screening. The DDDC assay is primarily aimed at determining the capacity of D. discoideum to undergo its developmental programme forming a fruiting body, measured in terms of fruiting body formation inhibition and fruiting body size factor, which may be considered an indication of its ecological fitness (potential for spore dispersal). A second objective of the solid phase DDDC assay is to identify potential mechanisms of toxic action on the developmental cycle, for which three checkpoints are examined: (a) aggregation arrest, (b) migration arrest, and (c) culmination arrest. Presently, conditions for the DDDC assay such as soil texture, soil water content, soil pH, food availability and incubation time were investigated and optimized. In addition, both solid and liquid phase variants of the DDDC assay were applied to assess the toxicity of Hg, at regulatory concentrations. The developmental cycle and ecological fitness were affected from the exposure to 0.3 mg Hg/kg dry-wt soil onwards. The DDDC assay has been shown to be a high sensitivity test. PMID- 23454909 TI - A polyphasic approach for assessing the suitability of bioremediation for the treatment of hydrocarbon-impacted soil. AB - Bioremediation strategies, though widely used for treating hydrocarbon contaminated soil, suffer from lack of biodegradation endpoint accountability. To address this limitation, molecular approaches of alkB gene analysis and pyrosequencing were combined with chemical approaches of bioaccessibility and nutrient assays to assess contaminant degrading capacity and develop a strategy for endpoint biodegradation predictions. In long-term hydrocarbon-contaminated soil containing 10.3 g C10-C36 hydrocarbons kg(-1), 454 pyrosequencing detected the overrepresentation of potential hydrocarbon degrading genera such as Pseudomonas, Burkholderia, Mycobacterium and Gordonia whilst amplicons for PCR DGGE were detected only with alkB primers targeting Pseudomonas. This indicated the presence of potential microbial hydrocarbon degradation capacity in the soil. Using non-exhaustive extraction methods of 1-propanol and HP-beta-CD for hydrocarbon bioaccessibility assessment combined with biodegradation endpoint predictions with linear regression models, we estimated 33.7% and 46.7% hydrocarbon removal respectively. These predictions were validated in pilot scale studies using an enhanced natural attenuation strategy which resulted in a 46.4% reduction in soil hydrocarbon content after 320 days. When predicted biodegradation endpoints were compared to measured values, there was no significant difference (P=0.80) when hydrocarbon bioaccessibility was assessed with HP-beta-CD. These results indicate that a combination of molecular and chemical techniques that inform microbial diversity, functionality and chemical bioaccessibility can be valuable tools for assessing the suitability of bioremediation strategies for hydrocarbon-contaminated soil. PMID- 23454910 TI - Outcomes of a preoperative "bridging" strategy with glycoprotein IIb/IIIa inhibitors to prevent perioperative stent thrombosis in patients with drug eluting stents who undergo surgery necessitating interruption of thienopyridine administration. AB - AIMS: Surgery after drug-eluting stent (DES) implantation may be associated with increased risk for perioperative stent thrombosis (ST). METHODS AND RESULTS: We evaluated the outcomes of 67 patients who underwent non-cardiac (n=51) or cardiac (n=16) surgery after DES implantation at our institution between 2008 and 2010 and who underwent preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor. Surgery occurred after a mean time of 13.9 +/- 1.7 and 8.7 +/- 2 months post stenting for non-cardiac (NCS) and cardiac surgery, respectively. Glycoprotein IIb/IIIa inhibitors were administered preoperatively for a mean of 7.1 +/- 0.4 and 7.8 +/- 0.7 days, respectively, then discontinued four to six hours before surgery. Most patients received aspirin through the perioperative period (33 NCS patients and 15 cardiac surgery patients). Clopidogrel was restarted as early as possible in the postoperative period. In the non-cardiac surgery group, two patients (3.9%, 95% confidence intervals 0.5% to 13.5%) suffered acute ST in the immediate postoperative period and four patients suffered major bleeding by the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria. One cardiac surgery patient had probable ST one hour postoperatively. CONCLUSIONS: In spite of preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor, postoperative stent thrombosis can still occur in patients with prior DES undergoing surgery requiring antiplatelet medication interruption. PMID- 23454911 TI - Dybowski's sika deer (Cervus nippon hortulorum): genetic divergence between natural primorian and introduced Czech populations. AB - Dybowski's sika deer (Cervus nippon hortulorum) originally inhabited the majority of the Primorsky Krai in Far Eastern Russia, north-eastern China, and Korean Peninsula. At present, only the Russian population seems to be stable, even though this taxon is still classified as endangered by the Russian Federation. Almost 100 years ago, this subspecies, among others, was imported to several European countries including the Czech Republic. We used both mitochondrial (mtDNA; the cytochrome b gene and the control region) and nuclear DNA markers to examine the actual taxonomic status of modern Czech Dybowski's sika population and to compare the genetic diversity between the introduced and the native populations. Altogether, 124 Czech samples and 109 Primorian samples were used in the analyses. Within the samples obtained from individuals that were all morphologically classified as Dybowski's sika, we detected mtDNA haplotypes of Dybowski's sika (84 samples), as well as those belonging to other sika subspecies: northern Japanese sika (25 samples), southern Japanese sika (6 samples), and south-eastern Chinese sika (8 samples). Microsatellite analysis revealed a certain level of heterozygote deficiency and a high level of inbreeding in both populations. The high number of private alleles, factorial correspondence analysis, and Bayesian clustering analysis indicate a high level of divergence between both populations. The large degree of differentiation and the high number of population-specific alleles could be a result of a founder effect, could be a result of a previously suggested bottleneck within the Primorian population, and could also be affected by the crossbreeding of captive individuals with other sika subspecies. PMID- 23454912 TI - Estimating the population mutation rate from a de novo assembled Bactrian camel genome and cross-species comparison with dromedary ESTs. AB - The Bactrian camel (Camelus bactrianus) and the dromedary (Camelus dromedarius) are among the last species that have been domesticated around 3000-6000 years ago. During domestication, strong artificial (anthropogenic) selection has shaped the livestock, creating a huge amount of phenotypes and breeds. Hence, domestic animals represent a unique resource to understand the genetic basis of phenotypic variation and adaptation. Similar to its late domestication history, the Bactrian camel is also among the last livestock animals to have its genome sequenced and deciphered. As no genomic data have been available until recently, we generated a de novo assembly by shotgun sequencing of a single male Bactrian camel. We obtained 1.6 Gb genomic sequences, which correspond to more than half of the Bactrian camel's genome. The aim of this study was to identify heterozygous single-nucleotide polymorphisms (SNPs) and to estimate population parameters and nucleotide diversity based on an individual camel. With an average 6.6-fold coverage, we detected over 116 000 heterozygous SNPs and recorded a genome-wide nucleotide diversity similar to that of other domesticated ungulates. More than 20 000 (85%) dromedary expressed sequence tags successfully aligned to our genomic draft. Our results provide a template for future association studies targeting economically relevant traits and to identify changes underlying the process of camel domestication and environmental adaptation. PMID- 23454913 TI - Tumor-suppressive effects of CDK8 in endometrial cancer cells. AB - CDK8 is either amplified or mutated in a variety of human cancers, and CDK8 functions as an oncoprotein in melanoma and colorectal cancers. Previously, we reported that loss or reduction of CDK8 results in aberrant fat accumulation in Drosophila and mammals, suggesting that CDK8 plays an important role in inhibiting lipogenesis. Epidemiological studies have identified obesity and overweight as the major risk factors of endometrial cancer, thus we examined whether CDK8 regulates endometrial cancer cell growth by using several endometrial cancer cell lines, including KLE, which express low levels of CDK8, as well as AN3 CA and HEC-1A cells, which have high levels of endogenous CDK8. We observed that ectopic expression of CDK8 in KLE cells inhibited cell proliferation and potently blocked tumor growth in an in vivo mouse model. In addition, gain of CDK8 in KLE cells blocked cell migration and invasion in transwell, wound healing and persistence of migratory directionality assays. Conversely, we observed the opposite effects in all of the aforementioned assays when CDK8 was depleted in AN3 CA cells. Similar to AN3 CA cells, depletion of CDK8 in HEC-1A cells strongly enhanced cell migration in transwell assays, while overexpression of CDK8 in HEC-1A cells blocked cell migration. Furthermore, gene profiling of KLE cells overexpressing CDK8 revealed genes whose protein products are involved in lipid metabolism, cell cycle and cell movement pathways. Finally, depletion of CDK8 increased the expression of lipogenic genes in endometrial cancer cells. Taken together, these results show a reverse correlation between CDK8 levels and several key features of the endometrial cancer cells, including cell proliferation, migration and invasion as well as tumor formation in vivo. Therefore, in contrast to the oncogenic effects of CDK8 in melanoma and colorectal cancers, our results suggest that CDK8 plays a tumor-suppressive role in endometrial cancers. PMID- 23454915 TI - Specificity of psychopathology in temporal lobe epilepsy. AB - An investigation into the specificity of psychopathology in temporal lobe epilepsy was conducted using the Minnesota Multiphase Personality Inventory second edition (MMPI-2) profiles. Consecutive series of patients with left temporal lobe epilepsy (n = 49) and those with right temporal lobe epilepsy (n = 45) were compared with patients with other forms of epilepsy (n = 46) and other heterogeneous neurological conditions (n = 69). The investigation focused on the Clinical, Content, and Subscales scales that resembled descriptions of the Interictal Dysphoric Disorder symptoms and Temporal Lobe Epilepsy Personality Traits. Patients with right temporal lobe epilepsy and those with left temporal lobe epilepsy did not have different patterns of scale elevation, nor did they have clinical elevations compared with patients with other types of epilepsy or neurological controls. The MMPI-2 scales that resemble descriptions of the Interictal Dysphoric Disorder or Temporal Lobe Epilepsy Personality Syndrome were not elevated in either group of patients with temporal lobe epilepsy compared with the group of patients with non-temporal lobe epilepsy or heterogeneous neurological controls. This study adds to the mounting body of empirical research that has used standardized measures and matched groups, but failed to detect a special affinity between psychopathology and temporal lobe epilepsy. PMID- 23454914 TI - Peer support groups as an intervention to decrease epilepsy-associated stigma. AB - Eighty percent of people with epilepsy (PWE) reside in low-income countries where stigma contributes substantially to social and medical morbidity. Peer support groups (PSGs) are thought to be beneficial for people with stigmatized conditions, but little data exist regarding PSG effectiveness. We facilitated monthly PSG meetings for men, women, and youth from three Zambian clinics for one year. Pre- and post-intervention assessments measured internalized stigma, psychiatric morbidity, medication adherence, socioeconomic status, and community disclosure. Of 103 participants (39 men, 30 women, and 34 youth), 80 PWE (78%) attended >= 6 meetings. There were no significant demographic differences between PWE who attended >= 6 meetings and those who attended <6 meetings. Among youth attending >= 6 meetings, internalized stigma decreased (p<0.02). Among adults, there was a non-significant stigma decrease. No differences were detected in medication use, medication adherence, or psychiatric morbidity. Peer support groups effectively reduce stigma for youth and may offer a low-cost approach to addressing epilepsy-associated stigma in resource-poor settings. PMID- 23454916 TI - Making Medicare advantage a middle-class program. AB - This paper studies the role of Medicare's premium policy in sorting beneficiaries between traditional Medicare (TM) and managed care plans in the Medicare advantage (MA) program. Beneficiaries vary in their demand for care. TM fully accommodates demand but creates a moral hazard inefficiency. MA rations care but disregards some elements of the demand. We describe an efficient assignment of beneficiaries to these two options, and argue that efficiency requires an MA program oriented to serve the large middle part of the distribution of demand: the "middle class." Current Medicare policy of a "single premium" for MA plans cannot achieve efficient sorting. We characterize the demand-based premium policy that can implement the efficient assignment of enrollees to plans. If only a single premium is feasible, the second-best policy involves too many of the low demand individuals in MA and a too low level of services relative to the first best. We identify approaches to using premium policy to revitalize MA and improve the efficiency of Medicare. PMID- 23454918 TI - Assessing impediments to hydrocarbon biodegradation in weathered contaminated soils. AB - In this study, impediments to hydrocarbon biodegradation in contaminated soils were assessed using chemical and molecular methodologies. Two long-term hydrocarbon contaminated soils were utilised which were similar in physico chemical properties but differed in the extent of hydrocarbon (C10-C40) contamination (S1: 16.5 g kg(-1); S2: 68.9 g kg(-1)). Under enhanced natural attenuation (ENA) conditions, hydrocarbon biodegradation was observed in S1 microcosms (26.4% reduction in C10-C40 hydrocarbons), however, ENA was unable to stimulate degradation in S2. Although eubacterial communities (PCR-DGGE analysis) were similar for both soils, the alkB bacterial community was less diverse in S2 presumably due to impacts associated with elevated hydrocarbons. When hydrocarbon bioaccessibility was assessed using HP-beta-CD extraction, large residual concentrations remained in the soil following the extraction procedure. However, when linear regression models were used to predict the endpoints of hydrocarbon degradation, there was no significant difference (P>0.05) between HP-beta-CD predicted and microcosm measured biodegradation endpoints. This data suggested that the lack of hydrocarbon degradation in S2 resulted primarily from limited hydrocarbon bioavailability. PMID- 23454917 TI - Human CD4(+) effector T lymphocytes generated upon TCR engagement with self peptides respond defectively to IL-7 in their transition to memory cells. AB - The peripheral repertoire of CD4(+) T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4(+) T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4(+) lymphocytes activated by dendritic cells (DCs) presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells (Tmem) from primary effectors activated with mature autologous DCs plus interleukin (IL)-2 (Tmauto), simulating the circumstances of an active immune response, or allogeneic DCs (Tmallo). Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors (demonstrated by CD25 downregulation) particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and Tmallo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tmallo were closely related to conventional memory lymphocytes based on Erk-1/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4(+) T lymphocytes recognizing self peptides in the setting of strong costimulation. PMID- 23454919 TI - Attenuation of porcine circovirus type-2b by replacement with the Rep gene of porcine circovirus type-1. AB - Porcine circovirus type-2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases and has 4 main ORFs, ORF1 (Rep gene), ORF2 (Cap gene), ORF3 within ORF1, and ORF4, which is overlapped with ORF3, and 1 origin (Ori) of replication located between ORF1 and ORF2. The chimeric PCV1-2, containing the PCV2 capsid, PCV1 rep, and Ori genes, is attenuated in pigs. In order to verify the role of the Rep gene or Ori in the virulence of PCV2, 3 chimeric viruses [PCV2b-Ori1 (PCV1 Ori gene cloned into the backbone of PCV2b), PCV2b-rep1 (PCV1 Rep gene cloned into the backbone of PCV2b), and PCV2b-rep1-Ori1 (PCV1 Rep and Ori genes cloned into the backbone of PCV2b)] and 2 wild-type recombinant PCV2b and PCV1 were constructed and identified. The experimental results in piglets showed that clinical symptoms, viremia, viral load, lesions in lymphoid and lung tissues, and IL-10 and TNF-alpha expression levels in PBMCs in the PCV2b-rep1-Ori1 and PCV2b-rep1 groups were significantly decreased, compared to PCV2-infected piglets. Meanwhile, histological lesions of lymphoid and lung tissues, viral loads in lymphoid tissues, viremia, and TNF-alpha expression in PBMCs were not significantly different between groups PCV2b-Ori1 and PCV2b, suggesting that the Rep gene (ORF1) likely contributes to viral pathogenicity in vivo. PMID- 23454920 TI - Intelligence and embodiment: a statistical mechanics approach. AB - Evolutionary neuroscience has been mainly dominated by the principle of phylogenetic conservation, specifically, by the search for similarities in brain organization. This principle states that closely related species tend to be similar because they have a common ancestor. However, explaining, for instance, behavioral differences between humans and chimpanzees, has been revealed to be notoriously difficult. In this paper, the hypothesis of a common information processing principle exploited by the brains evolved through natural evolution is explored. A model combining recent advances in cognitive psychology and evolutionary neuroscience is presented. The macroscopic effects associated with the intelligence-like structures postulated by the model are analyzed from a statistical mechanics point of view. As a result of this analysis, some plausible explanations are put forward concerning the disparities and similarities in cognitive capacities which are observed in nature across species. Furthermore, an interpretation on the efficiency of brain's computations is also provided. These theoretical results and their implications against modern theories of intelligence are shown to be consistent with the formulated hypothesis. PMID- 23454921 TI - Synchronization of two Hindmarsh-Rose neurons with unidirectional coupling. AB - The Hindmarsh-Rose (HR) dynamical system is a well-known model of neuronal activity. It is known that two HR neurons can synchronize when coupled in the action potential variable. Here, I report on exponentially fast synchronization of two HR neurons with novel unidirectional coupling. Explicit proof of global stability is given where the Lyapunov function is found with single parameter bounds as sufficient criteria. Numerical explorations verify such synchronization yet reveal additional single-link unidirectional couplings enabling full or subsystem synchronization where the parameters of two HR neurons might differ. Despite the mathematical prediction, from neuroscience and molecular biology points of view such connectivity between neurons has no simple explanation. The result opens up a fundamental question on the valid interpretation of unidirectional links, their potential use, and if such synchronization is an active principle of biological neurons. PMID- 23454922 TI - Quantitative amplification of weak images by nonlinear propagation. AB - We demonstrate quantitative nonlinear recovery of images that have been hidden by the addition of partially coherent light. The method assumes a simple model for spatial nonlinearity that allows direct Laplacian inversion based on intensity transport. PMID- 23454923 TI - In vivo measurement of the average refractive index of the human crystalline lens using optical coherence tomography. AB - We present a method for measuring the average group refractive index of the human crystalline lens in vivo using an optical coherence tomography (OCT) system which, allows full-length biometry of the eye. A series of OCT images of the eye including the anterior segment and retina were recorded during accommodation. Optical lengths of the anterior chamber, lens, and vitreous were measured dynamically along the central axis on the OCT images. The group refractive index of the crystalline lens along the central axis was determined using linear regression analysis of the intraocular optical length measurements. Measurements were acquired on three subjects of age 21, 24, and 35 years. The average group refractive index for the three subjects was, respectively, n=1.41, 1.43, and 1.39 at 835 nm. PMID- 23454924 TI - Data-resolution based optimal choice of minimum required measurements for image guided diffuse optical tomography. AB - Image-guided diffuse optical tomography has the advantage of reducing the total number of optical parameters being reconstructed to the number of distinct tissue types identified by the traditional imaging modality, converting the optical image-reconstruction problem from underdetermined in nature to overdetermined. In such cases, the minimum required measurements might be far less compared to those of the traditional diffuse optical imaging. An approach to choose these optimally based on a data-resolution matrix is proposed, and it is shown that such a choice does not compromise the reconstruction performance. PMID- 23454925 TI - Random sources generating ring-shaped beams. AB - Two classes of scalar, stochastic sources are introduced, each capable of producing far fields with intensities forming rings. Although the Bessel-Gaussian and the Laguerre-Gaussian Schell-model sources are described by two different math models, the behavior of their degrees of coherence and, hence, the shapes of their far fields are qualitatively similar. The new beams are of importance for optical methods of particle manipulation. PMID- 23454926 TI - Higher-order defect-mode laser in an optically thick photonic crystal slab. AB - The use of an optically thick slab may provide versatile solutions for the realization of a current injection-type laser using photonic crystals. Here, we show that a transversely higher-order defect mode can be designed to be confined by a photonic bandgap in such a thick slab. Using simulations, we show that a high Q of >10(5) is possible from a finely tuned second-order hexapole mode (2h). Experimentally, we achieve optically pumped pulsed lasing at 1347 nm from the 2h with a peak threshold pump power of 88 MUW. PMID- 23454927 TI - 2.4 mJ, 33 W Q-switched Tm-doped fiber laser with near diffraction-limited beam quality. AB - We report on a high pulse energy and high average power Q-switched Tm-doped fiber oscillator. The oscillator produces 2.4 mJ pulses with 33 W average power (at a repetition rate of 13.9 kHz) and nearly diffraction-limited beam quality. This record performance is enabled by a Tm-doped large-pitch fiber, which allows for large core diameters in combination with effective single-mode operation. PMID- 23454928 TI - Fundamental bounds on decay rates in asymmetric single-mode optical resonators. AB - We derive tight upper and lower bounds of the ratio between decay rates to two ports from a single resonance exhibiting Fano interference, based on a general temporal coupled-mode theory formalism. The photon transport between these two ports involves both direct and resonance-assisted contributions, and the bounds depend only on the direct process. The bounds imply that, in a lossless system, full reflection is always achievable at Fano resonance, even for structures lacking mirror symmetries, while full transmission can only be seen in a symmetric configuration where the two decay rates are equal. The analytic predictions are verified against full-field electromagnetic simulations. PMID- 23454929 TI - High contrast, low noise selection and amplification of an individual optical frequency comb line. AB - We present a frequency-selective amplifier for optical frequency combs based on stimulated Brillouin scattering and the effect of a Brillouin dynamic grating. A user defined individual frequency comb line is amplified while the other comb lines are efficiently suppressed, rendering a frequency-stable clean-up oscillator unnecessary. A measured signal to noise ratio of 89 dBc/Hz proves the suitability of the method for phase coherent measurements. The overall noise figure is 6 dB. PMID- 23454930 TI - Femtosecond fiber chirped- and divided-pulse amplification system. AB - We implement both chirped pulse amplification and divided pulse amplification in the same femtosecond fiber amplifier setup. This scheme allows an equivalent stretched pulse duration of 2.4 ns in a compact tabletop system. The generation of 77 W of compressed average power at 4.8 MHz, together with 320 fs and 430 MUJ pulses at a repetition rate of 96 kHz, is demonstrated using a distributed mode filtering, rod-type, ytterbium-doped fiber. Limitations in the temporal recombining efficiency due to gain saturation inside the fiber amplifier are identified. PMID- 23454931 TI - Yb:YAG single crystal fiber power amplifier for femtosecond sources. AB - We demonstrate a versatile femtosecond power amplifier using a Yb:YAG single crystal fiber operating from 10 kHz to 10 MHz. For a total pump power of 75 W, up to 30 W is generated from the double-pass power amplifier. At a repetition rate of 10 kHz, an output energy of 1 mJ is obtained after recompression. In this configuration, the pulse duration is 380 fs, corresponding to a peak power of 2.2 GW. The M2 beam quality factor is better than 1.1 for investigated parameters. PMID- 23454932 TI - Attenuated internal reflection terahertz imaging. AB - We present a terahertz (THz) imaging technique based on attenuated internal reflection, which is ideally suited for the analysis of liquid and biological samples. Inserted in a THz time-domain system, and using a high-resistivity low loss silicon prism to couple the THz wave into the sample, the detection scheme is based on the relative differential spectral phase of two orthogonal polarizations. Biological sample imaging as well as subwavelength (lambda/16) longitudinal resolution are demonstrated. PMID- 23454933 TI - Resolution improvement in spectral-domain optical coherence tomography based on classical intensity correlations. AB - We describe a resolution-improved spectral-domain (SD) optical coherence tomography (OCT) based on classical intensity correlations as a counterpart of the recently proposed intensity-based time-domain OCT. Similarly to quantum OCT, the setup employs the Hong-Ou-Mandel interferometer at the output of the conventional SD-OCT. It is shown theoretically that a factor-of-?2 improvement in axial resolution is obtained with this arrangement. Some unique and useful features of our proposed system are addressed. PMID- 23454934 TI - Optical implementation of a space-time-trellis code for enhancing the tolerance of systems to polarization-dependent loss. AB - We propose a space-time coding scheme designed to increase the tolerance of fiber optic communications systems to polarization-dependent loss (PDL). A notable increase in the tolerable amount of average link PDL is achieved without affecting the complexity of the overall optical communications link. Other advantages include seamless integration with the broadly deployed blind equalization modules relying on the constant modulus algorithm. PMID- 23454935 TI - 1 MUJ, sub-500 fs chirped pulse amplification in a Tm-doped fiber system. AB - We demonstrate a Tm-doped fiber laser system producing ~300 fs pulses with 1 MUJ energy, corresponding to peak powers greater than 3 MW. Pulses of 150 fs with 30 nm spectral bandwidth and 3 nJ pulse energy are generated in a Raman-soliton self frequency shift amplifier, then stretched to ~160 ps using a chirped Bragg grating. The 60 MHz oscillator repetition rate is reduced to 100 kHz using an electro-optic modulator. After a single-mode fiber preamplifier and a large-mode area fiber power amplifier, pulses were compressed using a folded Treacy grating setup to below 500 fs with up to 1 MUJ pulse energy. To the best of our knowledge, this is the highest energy yet demonstrated as well as the first demonstration of peak powers exceeding 1 MW from a Tm:fiber laser system. PMID- 23454936 TI - Probing electronic coherences by combined two- and one-photon excitation in atomic vapors. AB - Wave mixing in a three-level quantum system induced by two-photon resonant pump and one-photon resonant coupling at lower transition has been studied theoretically and experimentally. Resonantly enhanced difference-frequency generation efficiency was observed clearly dependent on the time delay and its sign between the femtosecond pump and probe. The role of the atomic coherences on the amplification without inversion during different sequences of interaction in a closed three-level system has been also stressed. These findings were confirmed experimentally in atomic potassium, where strong parametric amplification, induced by the pump delayed with respect to the probe, has been observed for the first time. PMID- 23454937 TI - Mid-infrared chalcogenide glass Raman fiber laser. AB - We report the first demonstration of a Raman fiber laser (RFL) emitting in the mid-infrared, above 3 MUm. The operation of a single-mode As2S3 chalcogenide glass based RFL at 3.34 MUm is demonstrated by using a low-loss Fabry-Perot cavity formed by a pair of fiber Bragg gratings. A specially designed quasi-cw erbium-doped fluoride fiber laser emitting at 3.005 MUm is used to pump the RFL. A laser output peak power of 0.6 W is obtained with a lasing efficiency of 39% with respect to the launched pump power. PMID- 23454938 TI - Fiber-coupled, 10 kHz simultaneous OH planar laser-induced fluorescence/particle image velocimetry. AB - Planar laser-induced fluorescence (PLIF) and particle-image velocimetry (PIV) techniques that employ free-standing optics face severe challenges when implemented in harsh environments associated with practical combustion facilities because of limited optical access and restrictions on operation of sensitive laser systems. To circumvent this problem, we have developed and implemented a fiber-coupled, high-speed ultraviolet (UV) PLIF/PIV system for measuring hydroxyl radical (OH) concentration and velocity in a realistic 4 MW combustion rig. This system permits delivery of high-power, 10 kHz, nanosecond-duration OH-PLIF excitation pulses (283 nm) and PIV pulses (532 nm) through a common 6 m long, 600 MUm core, deep-UV-enhanced multimode fiber. Simultaneous OH-PLIF and PIV imaging at a data-acquisition rate of 10 kHz is demonstrated in turbulent premixed flames behind a bluff body. The effects of delivering high-repetition-rate, intense UV and visible beams through a long optical fiber are investigated, and potential system improvements are discussed. PMID- 23454939 TI - Two-beam interferometer with optical path difference magnified. AB - A two-beam interferometer is proposed and experimentally demonstrated with OPD magnified. Two cascaded fiber ring resonators with almost the same fiber length are spliced into a fiber loop. An acousto-optic modulator is employed to generate optical pulses and to choose the pulses traveling around one of the resonators for x trips. The interferometer is characterized in displacement in our experiment. Experimental results show the proportional relationship between the sensitivity and x. The high-sensitivity interferometer scheme is useful in some measurement applications that require high sensitivity, such as solid earth tide gauge. PMID- 23454940 TI - Microwave spectrum sensing based on photonic time stretch and compressive sampling. AB - An approach to realizing microwave spectrum sensing based on photonic time stretch and compressive sampling is proposed. The time stretch system is used to slow down the input high-speed signal and the compressive sampling based on random demodulation can further decrease the sampling rate. A spectrally sparse signal in a wide bandwidth can be captured with a sampling rate far lower than the Nyquist rate thanks to both time stretch and compressive sampling. It is demonstrated that a system with a time stretch factor 5 and a compression factor 8 can be used to capture a signal with multiple tones in a 50 GHz bandwidth, which means a sampling rate 40 times lower than the Nyquist rate. In addition, the time stretch of the microwave signal largely decreases the data rate of random data sequence and therefore the speed of the mixer in the random demodulator. PMID- 23454941 TI - Photon number distributions from a diode laser. AB - We use balanced homodyne detection to characterize light from a diode laser as it crosses the threshold. We measure the single-time second-order correlation function g(2), and also extract the photon number distribution. Just above the laser threshold, we find that the measured g(2) exceeds the prediction of the semiclassical single-mode laser model. From the reconstructed photon number distributions, we conclude that this excess is due to emission from nonlasing modes. For higher pumping current, the light noise increases due to a different mechanism, possibly mode competition or mode partition noise. PMID- 23454942 TI - Cascaded Bragg scattering in fiber optics. AB - We report on a theoretical and experimental study of cascaded Bragg scattering in fiber optics. We show that the usual energy-momentum conservation of Bragg scattering can be considerably relaxed via cascade-induced phase-matching. Experimentally we demonstrate frequency translation over six- and 11-fold cascades, in excellent agreement with derived phase-matching conditions. PMID- 23454944 TI - Strongly enhancing photostimulated luminescence by doping Tm3+ in Sr3SiO5: Eu2+. AB - We report a large enhancement of yellow photostimulated luminescence (PSL) by codoping Tm3+ in Sr3SiO5:Eu2+ upon infrared stimulation at 980 nm after pre exposure in Ultraviolet light. The initial PSL intensity and light storage capacity are enhanced by a factor of 33 and 2, respectively, for Tm3+ concentration at 0.0004. The thermoluminescence spectra indicate that codoping Tm3+ generates a trap peaking at 385 K. The trap is much more sensitive to infrared light than the original one, so that the light storage period of the material is beyond tens of days with the minimum detectable infrared power density only 54 MUW/cm2. PMID- 23454943 TI - Multicolor stimulated Raman scattering microscopy with a rapidly tunable optical parametric oscillator. AB - Stimulated Raman scattering (SRS) microscopy allows label-free chemical imaging based on vibrational spectroscopy. Narrowband excitation with picosecond lasers creates the highest signal levels and enables imaging speeds up to video-rate, but it sacrifices chemical specificity in samples with overlapping bands compared to broadband (multiplex) excitation. We develop a rapidly tunable picosecond optical parametric oscillator with an electro-optical tunable Lyot filter, and demonstrate multicolor SRS microscopy with synchronized line-by-line wavelength tuning to avoid spectral artifacts due to sample movement. We show sensitive imaging of three different kinds of polymer beads and live HeLa cells with moving intracellular lipid droplets. PMID- 23454945 TI - Generalized dispersive wave emission in nonlinear fiber optics. AB - We show that the emission of dispersive waves in nonlinear fiber optics is not limited to soliton-like pulses propagating in the anomalous dispersion regime. We demonstrate, both numerically and experimentally, that pulses propagating in the normal dispersion regime can excite resonant dispersive radiation across the zero dispersion wavelength into the anomalous regime. PMID- 23454946 TI - Highly efficient optical filter based on vertically coupled photonic crystal cavity and bus waveguide. AB - We experimentally demonstrate a new optical filter design based on a vertically coupled photonic crystal (PhC) cavity and a bus waveguide monolithically integrated on the silicon-on-insulator platform. The use of a vertically coupled waveguide gives flexibility in the choice of the waveguide material and dimensions, dramatically lowering the insertion loss while achieving very high coupling efficiencies to wavelength scale resonators and thus allows the creation of PhC-based optical filters with very high extinction ratio (>10 dB). PMID- 23454947 TI - Hard x-ray phase contrast imaging using a tabletop Talbot-Lau interferometer with multiline embedded x-ray targets. AB - We demonstrate hard x-ray phase contrast imaging (XPCI) using a tabletop Talbot Lau interferometer in which the x-ray source and source grating are replaced with an x-ray source with multiline metal targets embedded in a diamond substrate. This source realizes an array of linear x-ray sources of a few micrometers width without fabrication difficulty because of the shallow penetration depth of electrons irradiated to the metal targets. This enhances the coherence of x rays from each linear source and allows XPCI within 45 cm source-detector distance under 1.2 W input power for 8 keV x rays. PMID- 23454948 TI - Mode-locking of a high power, 888 nm pumped Nd:YVO4 laser using nonlinear polarization rotation via Type I second harmonic generation. AB - Continuous-wave mode-locking of a laser exploiting the nonlinear polarization rotation (NPR) technique via Type I second harmonic generation is demonstrated for the first time. The NPR is generated by a lithium triborate crystal and transformed into nonlinear cavity losses of a 888 nm pumped Nd:YVO4 laser. Self starting, reliable mode-locking has been achieved at a high average output power of 20.6 W and a pulse duration of 7.3 ps. Furthermore, transform limited pulses down to 2.7 ps have been demonstrated at 9.9 W. PMID- 23454949 TI - Controlling the spectral width in compound waveguide grating structures. AB - Spectral responses in compound waveguide grating structures composed of two ridges with identical widths in each period are presented. For the proposed structures, we show that the spectral width of the guided-mode resonance (GMR) can be tailored in an independent way without modifying the spectral lineshapes and sideband levels. The method described in this Letter offers a very simple and efficient way to control spectral responses in GMR structures. PMID- 23454950 TI - Phase-shift anomaly caused by subwavelength-scale metal slit or aperture diffraction. AB - Terahertz time-domain spectroscopy probes anomalous phase-shift caused by wave diffraction from a subwavelength-scale metal slit or aperture. Carrier frequency phase measurements in the far-field region reveals that nearly 30 degrees phase advance is induced from a subwavelength slit diffraction and that 180 degrees phase-advance from a subwavelength aperture. These results indicate that the conventional 90 degrees phase advance of diffracted waves in the far-field region, known as the Gouy phase shift, is not valid for subwavelength diffraction phenomena. The physical origin of these phase-shift anomalies is attributed to induced electric currents or magnetic dipole radiation, and theoretical analyses based on these factors are in good agreement with the experimental results. PMID- 23454951 TI - Large-visual-angle microstructure inspired from quantitative design of Morpho butterflies' lamellae deviation using the FDTD/PSO method. AB - The wide angular range of the treelike structure in Morpho butterfly scales was investigated by finite-difference time-domain (FDTD)/particle-swarm-optimization (PSO) analysis. Using the FDTD method, different parameters in the Morpho butterflies' treelike structure were studied and their contributions to the angular dependence were analyzed. Then a wide angular range was realized by the PSO method from quantitatively designing the lamellae deviation (Deltay), which was a crucial parameter with angular range. The field map of the wide-range reflection in a large area was given to confirm the wide angular range. The tristimulus values and corresponding color coordinates for various viewing directions were calculated to confirm the blue color in different observation angles. The wide angular range realized by the FDTD/PSO method will assist us in understanding the scientific principles involved and also in designing artificial optical materials. PMID- 23454952 TI - Axicon-based writing of waveguides in BK7 glass. AB - We report on the direct writing of waveguide structures using an axicon lens to focus a 40 fs laser pulse within BK7 glass. The written structures are characterized for waveguiding action: waveguiding action for 635 and 1550 nm light and propagation loss as low as 0.19 dB/cm is measured. Loss values decrease with laser exposure time for incident energy of 300 MUJ, indicating enhancement of index contrast. At higher energies, a reverse trend is obtained: higher loss values are obtained as index contrast degrades with an increase in exposure time. PMID- 23454953 TI - Carbon nanotube electrical-substitution cryogenic radiometer: initial results. AB - A carbon nanotube cryogenic radiometer (CNCR) has been fabricated for electrical substitution optical power measurements. The CNCR employs vertically aligned multiwall carbon nanotube arrays (VANTAs) as the absorber, heater, and thermistor, with a micromachined silicon substrate as the weak thermal link. Compared to conventional cryogenic radiometers, the CNCR is simpler, more easily reproduced and disseminated, orders of magnitude faster, and can operate over a wide range of wavelengths without the need for a receiver cavity. We describe initial characterization results of the radiometer at 3.9 K, comparing electrical measurements and fiber-coupled optical measurements from 50 MUW to 1.5 mW at the wavelength of 1550 nm. We find the response to input electrical and optical power is equivalent to within our measurement uncertainty, which is currently limited by the experimental setup (large temperature fluctuations of the cold stage) rather than the device itself. With improvements in the temperature stability, the performance of the CNCR should be limited only by our ability to measure the reflectance of the optical absorber VANTA. PMID- 23454954 TI - Counterpropagating frequency mixing with terahertz waves in diamond. AB - Frequency conversion by means of Kerr nonlinearity is one of the most common and exploited nonlinear optical processes in the UV, visible, IR, and mid-IR spectral regions. Here we show that wave mixing of an optical field and a terahertz wave can be achieved in diamond, resulting in the frequency conversion of the terahertz radiation either by sum- or difference-frequency generation. In the latter case, we show that this process is phase matched and most efficient in a counterpropagating geometry. PMID- 23454955 TI - Observation of modulationally unstable multi-wave mixing. AB - We demonstrate experimentally that multiple four-wave mixing (FWM) pumped by a dual-frequency input in a single-mode fiber is modulationally unstable. This collective type of instability leads, in the anomalous dispersion regime, to sideband growth around all orders of FWM. This is in contrast with the normal dispersion regime where our measurements show that FWM exhibits no instability. Our conclusions are based on the first systematic mapping of the phenomenon as a function of the dual-pump input frequency separation. PMID- 23454956 TI - Far-field self-focusing and -defocusing radiation behaviors of the electroluminescent light sources due to negative refraction. AB - In recent years, researchers have demonstrated negative refraction theoretically and experimentally by pumping optical power into photonic crystal (PhC) or waveguide structures. The concept of negative refraction can be used to create a perfect lens that focuses an object smaller than the wavelength. By inserting two dimensional PhCs into the peripheral of a semiconductor light emitting structure, this study presents an electroluminescent device with negative refraction in the visible wavelength range. This approach produces polarization dependent collimation behavior in far-field radiation patterns. The modal dispersion of negative refraction results in strong group velocity modulation, and self focusing and -defocusing behaviors are apparent from light extraction. This study further verifies experimental results by using theoretic calculations based on equifrequency contours. PMID- 23454957 TI - Femtosecond laser nanostructuring in porous glass with sub-50 nm feature sizes. AB - We report on controllable production of nanostructures embedded in a porous glass by femtosecond laser direct writing. We show that a hollow nanovoid with a lateral size of ~40 nm and an axial size of ~1500 nm can be achieved by manipulating the peak intensity and polarization of the writing laser beam. Our finding enables applications ranging from direct construction of 3D nanofluidics in glass to clean stealth dicing of transparent plates. PMID- 23454958 TI - Solitons in spiraling Vogel lattices. AB - We address light propagation in Vogel optical lattices and show that such lattices support a variety of stable soliton solutions in both self-focusing and self-defocusing media, whose propagation constants belong to domains resembling gaps in the spectrum of a truly periodic lattice. The azimuthally rich structure of Vogel lattices allows generation of spiraling soliton motion. PMID- 23454959 TI - Rb optical resonance inside a random porous medium. AB - We studied resonant laser interaction with Rb atoms confined to the interstitial cavities of a random porous glass. Due to diffusive light propagation, the effect of atomic absorption on the light scattered by the sample is almost entirely compensated by atomic fluorescence at low atomic densities. For higher densities, radiation trapping increases the probability of nonradiative decay via atom-wall collisions. A simple connection of the fluorescence/absorption yield to the sample porosity is given. PMID- 23454960 TI - Mitigation of photodarkening phenomenon in fiber lasers by 633 nm light exposure. AB - In this work, the influence of photodarkening (PD) and photobleaching (PB) on the lasing features of the ytterbium-doped aluminosilicate fiber lasers is examined. Simultaneous PD and PB with 633 nm irradiation was monitored at the lasing wavelength of 1070 nm and compared with individually caused PD and PB effects. The variation of laser threshold and slope efficiency was reported. By analyzing the laser performances it was found that the ratio of excess loss at 633 and 1070 nm is expected to be less than 20. In addition, considerable mitigation of the PD with 633 nm light irradiation is demonstrated. PMID- 23454961 TI - Study on photoionization in a rubidium diode-pumped alkali laser gain medium with the optogalvanic method. AB - We use the optogalvanic method to calculate the concentration of rubidium ions produced by photoionization in a Rb diode-pumped alkali laser gain medium. With bias voltage added across the electrodes of a rubidium hollow cathode lamp, the measured optogalvanic current is 2.3*10(-7) A. Further study shows that the rubidium ion concentration is proportional to the pump intensity, and the drift velocity of rubidium ions is proportional to the bias voltage. When the photoionization process reaches dynamic equilibrium, the rubidium ion concentration will not increase with growing rubidium atom density. The calculated rubidium ion concentration is 1.5*10(5)-10(6) according to the experiment, and the ionization degree is less than 2.4*10(-7). PMID- 23454962 TI - Enhanced hole transport in InGaN/GaN multiple quantum well light-emitting diodes with a p-type doped quantum barrier. AB - We study hole transport behavior of InGaN/GaN light-emitting diodes with the dual wavelength emission method. It is found that at low injection levels, light emission is mainly from quantum wells near p-GaN, indicating that hole transport depth is limited in the active region. Emission from deeper wells only occurs under high current injection. However, with Mg-doped quantum barriers, holes penetrate deeper within the active region even under low injection, increasing the radiative recombination. Moreover, the improved hole transport leads to reduced forward voltage and enhanced light generation. This is also verified by numerical analysis of hole distribution and energy band structure. PMID- 23454963 TI - High load sensitivity in wideband infrared dual-Vivaldi nanoantennas. AB - Dual-Vivaldi nanoantenna (DVA) arrays were designed, fabricated, and optically characterized in the infrared (IR) and visible regimes. The antenna arrays were characterized by measuring the scattered light at IR (1450-1640 nm) and visible (780 nm) spectral ranges. The radiation efficiency and the spectral response of the antennas were found to be in good agreement with numerical simulations. The results presented here demonstrate the extremely wideband nature of the DVAs and the strong impact of load at the antenna terminals on its scattering response. These properties, as well as their many degrees of freedom for design, render the DVAs excellent candidates for optical sensing applications. PMID- 23454964 TI - Formula for the average bit error rate of free-space optical systems with dual branch equal-gain combining over gamma-gamma turbulence channels. AB - In this Letter we propose a closed-form expression for the average bit error rate of intensity modulation/direct detection free-space optical systems employing dual-branch equal-gain combining and operating over turbulence channels. To offer a realistic error performance of the considered system we assume that both branches undergo independent but not necessarily identically distributed gamma gamma fading. Our newly developed formula is obtained in terms of the bivariate H Fox function, which can be readily evaluated based on its two-fold Mellin-Barnes representation. Numerically evaluated and computer simulation results are presented that verify the accuracy of the proposed mathematical analysis. PMID- 23454965 TI - Probing multifractality in tissue refractive index: prospects for precancer detection. AB - Multiresolution analysis on the spatial refractive index inhomogeneities in the epithelium and connective tissue regions of a human cervix reveals a clear signature of multifractality. Importantly, the derived multifractal parameters, namely, the generalized Hurst exponent and the width of the singularity spectrum, derived via multifractal detrended fluctuation analysis, shows interesting differences between tissues having different grades of precancers. The refractive index fluctuations are found to be more anticorrelated, and the strength of multifractality is observed to be considerably stronger in the higher grades of precancers. These observations on the multifractal nature of tissue refractive index variations may prove to be valuable for developing light-scattering approaches for noninvasive diagnosis of precancer and early-stage cancer. PMID- 23454966 TI - Bend measurement using an etched fiber incorporating a fiber Bragg grating. AB - A fiber Bragg grating (FBG) based bend measurement method using an etched fiber is proposed that utilizes the coupling of the core mode to the cladding and radiation modes at the bending region. An etching region of 99 um diameter that serves as bend sensing head is achieved at 10 mm upstream the FBG through processing in 40% hydrofluoric acid, while the FBG acts as a narrowband reflector to enhance the sensitivity. The power variation curves are obtained for a wide range of bend angles, but the performance is limited due to the presence of the loss peaks. The sensing response is improved by immersing the etching region in a refractive index matching gel. The results are analyzed by using curve fitting formulas and are in good agreement. A large dynamic range of -27 degrees to +27 degrees and sensitivity of 0.43 dBm/deg is achieved, which can be enhanced by reducing the etched diameter. PMID- 23454967 TI - Interferometric switching in coupled resonator optical waveguides-based reconfigurable optical device. AB - Integrated optical devices based on coupled resonator optical waveguides (CROW) for reconfigurable band routing are explored. A reconfiguration principle based on two bus interferometric CROW resonant structures is proposed. This device extends the functionalities of simple add-drop filters, adding more switching features. These new functionalities yield three functional states that comprehend a complete reconfigurability and a 50% splitter mode. PMID- 23454968 TI - Efficient mode converter design using asymmetric graded index photonic structures. AB - Asymmetric graded-index (GRIN) inhomogeneous medium is proposed to enable even-to odd mode conversion. An exponential refractive index profile is implemented to induce an asymmetric refractive index distribution. A two-dimensional photonic crystal structure composed of constant dielectric radii with rectangular unit cells is deployed. Efficient mode transformation in a compact structure may promote the manipulation of light for the creation of other types of higher-order modes in asymmetric GRIN structures. PMID- 23454969 TI - Generation of high-order harmonics with controllable elliptical polarization. AB - We propose and numerically demonstrate a method for obtaining high-harmonic radiation with desirable elliptical polarization. Atoms are shined by a combination of a strong linearly-polarized laser field and an additional weak field, which is elliptically polarized in a plane perpendicular to the polarization direction of the strong field. The strong driver ionizes and recollides electrons with their parent ion, while the weak field perturbatively drives the electrons away from "head-on" collision. Upon recombination, new elliptically polarized harmonics with same ellipticity as the weak driver are emitted at efficiency which linearly depends on the intensity of the weak beam, but is independent of its elilipticity. PMID- 23454970 TI - Nonlinear behavior of vibrating molecules on suspended graphene waveguides. AB - Suspended graphene waveguides over micrometer-scale metal-mesh screens were used as platforms for Raman scattering. Raman signals of B. megaterium spores were found sensitive to in-plane rotations and tilt of the waveguides with respect to the incident linearly polarized pump beam. When at plasmonic resonance for the equivalent long wavelength of the vibration frequency, the Raman signal exhibited an additional quadratic effect. PMID- 23454971 TI - Freeform illumination design: a nonlinear boundary problem for the elliptic Monge Ampere equation. AB - We propose an approach to deal with the problem of freeform surface illumination design without assuming any symmetry based on the concept that this problem is similar to the problem of optimal mass transport. With this approach, the freeform design is converted into a nonlinear boundary problem for the elliptic Monge-Ampere equation. The theory and numerical method are given for solving this boundary problem. Experimental results show the feasibility of this approach in tackling this freeform design problem. PMID- 23454972 TI - Photonic ultrawideband impulse radio shape modulation based on dual-filter tuning. AB - A simple and flexible photonic scheme for the generation of ultrawideband (UWB) pulse shape modulation based on dual-filter tuning is proposed and experimentally demonstrated. By launching a Gaussian signal into a phase modulator, the UWB polarity-switchable monocycle is generated at the output of two optical bandpass filters by adjusting the central wavelengths of the dual-filter appropriately. The doublet pulses with inverted polarities are obtained by combining the pair of UWB monocycle pulses under proper time delay. Meanwhile, with a predefined code pattern and controlling the optical path difference of the two monocycle pulses, the pulse shape modulation can be performed. PMID- 23454973 TI - Figure of merit for task-based assessment of frequency-domain diffusive imaging. AB - A figure of merit (FOM) for frequency-domain diffusive imaging (FDDI) is theoretically developed adapting the concept of Hotelling observer signal-to noise ratio. Different from conventionally used FOMs for FDDI, the newly developed FOM considers diffused intensities, modulation amplitudes, and phases in combination. The FOM applied to Monte Carlo simulations of signal- and background-known-exactly problems shows unique characteristics that are in agreement with findings in the literature. We believe that a task based assessment using the FOM improves the characterization of FDDI systems and allows for complete system optimization. PMID- 23454974 TI - Error-free 320-to-40-Gbit/s optical demultiplexing based on blueshift filtering in a quantum-dot semiconductor optical amplifier. AB - We present an ultrahigh-speed optical demultiplexing concept based on optical blue-shift filtering in a quantum-dot semiconductor optical amplifier (QD-SOA). Using a simple scheme, a QD-SOA and an optical bandpass filter, we have successfully achieved error-free operations at 40 Gbit/s on all the extracted tributaries from an aggregated traffic at 320 Gbit/s. PMID- 23454975 TI - Digital coherent receiver for orbital angular momentum demultiplexing. AB - We put forward a type of receiver for coherent detection of the photon orbital angular momentum (OAM). A coherent array receiver, consisting of multiple subapertures, with each subaperture coupled to a single-mode fiber, maps the complex optical field in the image plane. Using digital samplers connected to each array element, the local electrical signals resulting from the detection process can be measured coherently, moving the complexity of the full OAM measurement from the optical domain to the digital domain. By computer processing the coherent electrical patterns obtained, one can retrieve full information (amplitude and phase) of the different OAM components that constitute any incoming beam. PMID- 23454976 TI - SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. AB - The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between mouse SOCS3, JAK2 (kinase domain) and a fragment of the interleukin-6 receptor beta-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. While the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phosphoindependent manner to a noncanonical surface. The kinase-inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2, and biochemical studies show that it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action. PMID- 23454977 TI - Allosteric signaling and dynamics of the clamshell-like NMDA receptor GluN1 N terminal domain. AB - N-methyl-D-aspartate receptors (NMDARs), neuronal glutamate-gated ion channels, are obligatory heterotetramers composed of GluN1 and GluN2 subunits. Each subunit contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). The GluN2 NTDs form mobile regulatory domains. In contrast, the dynamics of GluN1 NTD and its contribution to NMDAR function remain poorly understood. Here we show that GluN1 NTD is neither static nor functionally silent. Perturbing the conformation of GluN1 NTD affects both receptor gating and pharmacological properties. GluN1 NTD undergoes structural rearrangements that involve hinge bending and large twisting and untwisting motions, allowing for new intra- and intersubunit contacts. GluN1 NTD acts in trans with GluN2 NTD to influence binding of glutamate but, notably, not of GluN1 coagonist glycine. Our work uncovers a dynamic role of GluN1 NTD in controlling NMDAR function through new interdomain allosteric interactions. PMID- 23454978 TI - Friedreich's ataxia-associated GAA repeats induce replication-fork reversal and unusual molecular junctions. AB - Expansion of GAA/TTC repeats is the causative event in Friedreich's ataxia. GAA repeats have been shown to hinder replication in model systems, but the mechanisms of replication interference and expansion in human cells remained elusive. To study in vivo replication structures at GAA repeats, we designed a new plasmid-based system that permits the analysis of human replication intermediates by two-dimensional gel electrophoresis and EM. We found that replication forks transiently pause and reverse at long GAA/TTC tracts in both orientations. Furthermore, we identified replication-associated intramolecular junctions, located between GAA/TTC repeats and other homopurine-homopyrimidine tracts, that were associated with breakage of the plasmid fork not traversing the repeats. Finally, we detected postreplicative, sister-chromatid hemicatenanes on control plasmids, which were replaced by persistent homology-driven junctions at GAA/TTC repeats. These data prove that GAA/TTC tracts interfere with replication in humans and implicate postreplicative mechanisms in trinucleotide repeat expansion. PMID- 23454979 TI - Strategies for handling ethical problems in sudden and unexpected death. AB - How ethical praxis is shaped by different contexts and situations has not been widely studied. We performed a follow-up study on stroke team members' experiences of ethical problems and how the teams managed the situation when caring for patients faced with sudden and unexpected death from stroke. A number of ways for handling ethical problems emerged, which we have now explored further. Data were collected through a three-part form used as base for individual interviews with 15 stroke team members and analyzed using both quantitative and qualitative content analysis. In the analysis, the approaches in the form were condensed into strategies, and the two different ways those strategies were preferred and used by the team members were shown. Hindrances perceived by the team members to impede them from working the preferred way were also revealed and grouped into eight categories. PMID- 23454980 TI - Nurse Activism in the newborn intensive care unit: actions in response to an ethical dilemma. AB - Nurses working in a newborn intensive care unit report that treatment decision disagreements for infants in their care may lead to ethical dilemmas involving all health-care providers. Applying Rest's Four-Component Model of Moral Action as the theoretical framework, this study examined the responses of 224 newborn intensive care unit nurses to the Nurses Ethical Involvement Survey. The three most frequent actions selected were as follows: talking with other nurses, talking with doctors, and requesting a team meeting. The multiple regression analysis indicates that newborn intensive care unit nurses with greater concern for the ethical aspects of clinical practice (p = .001) and an increased perception of their ability to influence ethical decision making (p = .018) were more likely to display Nurse Activism. Future research is necessary to identify other factors leading to and inhibiting Nurse Activism as these findings explained just 8.5% of the variance. PMID- 23454981 TI - Nurses, industrial action and ethics: considerations from the 2010 South African public-sector strike. AB - Several important ethical dilemmas emerge when nurses join a public-sector strike. Such industrial action is commonplace in South Africa and was most notably illustrated by a national wage negotiation in 2010. Media coverage of the proceedings suggested unethical behaviour on the part of nurses, and further exploration is merited. Laws, policies and provisional codes are meant to guide nurses' behaviour during industrial action, while ethical theories can be used to further illuminate the role of nurses in industrial action. There are, however, important aspects to consider before judging whether nurses act unethically when striking. Following Loewy's suggestion that the nature of the work, the proceeding commitment of the nurse to the patient, the prevailing situation when the strike is planned and the person(s) who stand(s) to benefit from the strike be considered, coupled with a consideration of the South African historical socio political context, important aspects of the ethics of nurses' behaviour in industrial action transpire. PMID- 23454982 TI - Ethical controversies in prenatal microarray. AB - PURPOSE OF REVIEW: Chromosome microarray (CMA) analysis enables genome interrogation at a much higher resolution than is possible with conventional karyotyping. CMA is considered 'standard of care' for postnatal genetic testing, yet its introduction into the prenatal setting has been delayed, in part because of ethical concerns about possible psychosocial harm and deficits in informed consent. RECENT FINDINGS: The findings of several large trials have now been reported, allowing preliminary quantification of the relative benefits and harms of CMA in prenatal diagnosis. Qualitative studies have also provided insights into the patient experience particularly in cases in which results of uncertain significance are provided. In an attempt to minimize potential harms, some professional guidelines have suggested limiting access to CMA to patients with fetal abnormality on ultrasound, limiting the diagnostic power of CMA by using targeted platforms or limiting reporting. SUMMARY: We provide an overview of the relative benefits and harms of prenatal CMA, and critically examine the strategies proposed to minimize harms in the context of other important ethical issues such as patient autonomy, justice and equity of access. We advocate for improved patient consent, counselling and support so that patients can fully benefit from the improved diagnostic yield of CMA despite the challenges that are intrinsic to the prenatal setting. PMID- 23454985 TI - From the editor. Managing the costs of care. PMID- 23454986 TI - Guest editorial. What is the value of nursing care? PMID- 23454987 TI - Value-based resource management: a model for best value nursing care. AB - With the health care environment shifting to a value-based payment system, Catholic Health Initiatives nursing leadership spearheaded an initiative with 14 hospitals to establish best nursing care at a lower cost. The implementation of technology-enabled business processes at point of care led to a new model for best value nursing care: Value-Based Resource Management. The new model integrates clinical patient data from the electronic medical record and embeds the new information in care team workflows for actionable real-time decision support and predictive forecasting. The participating hospitals reported increased patient satisfaction and cost savings in the reduction of overtime and improvement in length of stay management. New data generated by the initiative on nursing hours and cost by patient and by population (Medicare severity diagnosis related groups), and patient health status outcomes across the acute care continuum expanded business intelligence for a value-based population health system. PMID- 23454988 TI - The economic value of health care data. AB - The amount of health care data in our world has been exploding, and the ability to store, aggregate, and combine data and then use the results to perform deep analyses have become ever more important. "Big data," large pools of data that can be captured, communicated, aggregated, stored, and analyzed, are now part of every sector and function of the global economy. While most research into big data thus far has focused on the question of their volume, there is evidence that the business and economic possibilities of big data and their wider implications are important for consideration. It is even offering the possibility that health care data could become the most valuable asset over the next 5 years as "secondary use" of electronic health record data takes off. PMID- 23454989 TI - Can and should nurses be aware of patients' expectations for their nursing care? AB - Patients' expectations for their care have long been identified as a critical factor in patient satisfaction that has become a decisive element in hospital reimbursement. But the standard definition of expectations as the level of care patients imagine they would receive in the ideal hospital setting may be off the mark. Most patients do not enter the ideal hospital, so we need to focus on patients' expectations of their real nurses in the actual hospital they are entering. Nurses who are aware of patients' expectations of them may have a distinct advantage in influencing patients' expectations and thus positively affect patients' level of satisfaction with their nursing care. The author discusses what changes may need to occur to shift our focus toward the advantages of nurses becoming aware of patients expectations and reports on her initial efforts to study nurses' awareness of patients' expectations of them. PMID- 23454990 TI - Innovation amidst radical cost containment in health care. AB - The changing health care environment is requiring nurse executives within a hospital setting to design and implement innovative workforce practices that will both improve patient outcomes and lower costs. Since registered nurses comprise the largest percentage of a hospital's workforce, finding ways to incorporate them in these efforts is essential. The Magnet Recognition Program through the American Nurses Credentialing Center is one successful evidence-based strategy that can be adopted to engage nurses in quality improvement processes. This article describes how two community hospitals used the principles of the Magnet Recognition Program to develop and implement new approaches to meet the health care imperative of providing safer, high-quality, cost-effective care. PMID- 23454991 TI - Value, a nursing outcome. AB - This era of health care reform calls for the ability of hospitals to provide quality patient care while managing costs. Nursing practice is a key determinant of patient care quality and associated costs, or simply put, creating value. The value of nursing has been addressed by multiple qualified authors, yet there is no clear, consistent meaning of the term. Researchers and authors have developed some theoretical foundation for the concept of value, which evolved into important research questions that establish value as an important outcome that is sensitive to nursing practice. The opportunity to attend 2 sessions at the Harvard Business School on health care value has prompted the need for nursing to adapt to common thinking on health care value and establish its meaning for the nursing profession. This report summarizes the nursing literature on value, reflects on the executive education, and proposes direction for nursing leaders in education and practice. PMID- 23454992 TI - Creating a transparent and dynamic view of staffing as a foundation for improving quality and efficiency. AB - As the United States moves into health care reform, there will be renewed debate on staffing models and ratios. The state of Massachusetts has developed a dashboard that will prepare them for nursing care models of the future while demonstrating that a variety of staffing templates can result in quality patient care today. Nursing leaders, legislators, and the public have access to information that demonstrates that staffing is complex and cannot be based on precise nursing ratios in all hospital settings. PMID- 23454993 TI - Nursing informatics year in review. AB - Nurses' role in patient care has evolved and so has their role in the use of technology to improve health care delivery. Nursing informatics research seeks to study the science of nursing, computer technology, and information science to enhance the quality of nursing practice. In an effort to increase patient safety and reduce health care-associated costs, nursing administrators have been challenged to incorporate technology and nursing practice. Unfortunately, health care institutions may not benefit from this body of work, as nursing informatics research associated with increased patient safety and cost containment may not be readily accessible for nursing administrators. The purpose of this study was to present the findings of a nursing informatics literature review and highlight those publications seen as most influential in the last year. In addition, we seek identify common topics and emerging themes in nursing informatics published research. PMID- 23454994 TI - Building emotional intelligence: a strategy for emerging nurse leaders to reduce workplace bullying. AB - Bullying is one of the most concerning forms of aggression in health care organizations. Conceptualized as an emotion-based response, bullying is often triggered by today's workplace challenges. Unfortunately, workplace bullying is an escalating problem in nursing. Bullying contributes to unhealthy and toxic environments, which in turn contribute to ineffective patient care, increased stress, and decreased job satisfaction among health care providers. These equate to a poor workforce environment, which in turn increases hospital costs when nurses choose to leave. Nurse managers are in positions of power to recognize and address negative workplace behaviors, such as bullying. However, emerging leaders in particular may not be equipped with the tools to deal with bullying and consequently may choose to overlook it. Substantive evidence from other disciplines supports the contention that individuals with greater emotional intelligence are better equipped to recognize early signs of negative behavior, such as bullying. Therefore, fostering emotional intelligence in emerging nurse leaders may lead to less bullying and more positive workplace environments for nurses in the future. PMID- 23454995 TI - Expectations of millennial nurse graduates transitioning into practice. AB - AIMS: Identified as Millennials, nurses born after 1980 are anticipated to redefine the employer-employee relationship as one based on the employee's wants and needs. The purpose of this study is to portray the expectations of Millennial student nurses immediately before graduation. Understanding these expectations may provide insight for leaders who are responsible for crafting a successful transition experience. Successful transition and decreased turnover are important elements of cost management for the nursing enterprise. METHODS/SUBJECTS: A qualitative descriptive design was used to collect data from 14 students enrolled in a traditional BSN academic nursing program approximately 2 months prior to graduation. Upon completion of private, confidential semistructured interviews, data were transcribed, coded, and analyzed. Demographic data were compiled and interview data summarized according to identified themes. RESULTS/CONCLUSIONS: Three overarching themes emerged: the expectation that transition would be stressful, the expectation that there would be a safety net of support, and the expectation to be valued and respected as a professional. Revealing was the expectation of supportive relationships and a collaborative approach to patient care. Failure to meet those expectations may result in turnover as Millennials seek opportunities that meet their expectations. PMID- 23454996 TI - Defensive medicine in the emergency department: increasing health care costs without increasing quality? AB - Defensive medicine is taxing our health care system more and more each year. Emergency departments are at more risk of malpractice claims due to their quick pace, lack of patient-physician relationship, and patient expectations and demands. It can be assumed that this results in unnecessary, expensive care. There are health risks and monetary and emotional consequences that result from the use of defensive medicine. Eradication of defensive medicine can begin with the use of evidence-based medicine and by ensuring that hospital policies and procedures are followed. PMID- 23454997 TI - Clinical IT in a complex environment. PMID- 23454998 TI - Affordable care act, accountable care, and nurse leaders... PMID- 23454999 TI - New evidence in nursing regulation. PMID- 23455000 TI - Letter to the editor. PMID- 23455001 TI - Contemporary retrograde approach for the recanalisation of coronary chronic total occlusion: on behalf of the Japanese Retrograde Summit Group. AB - AIMS: The retrograde approach to CTO is promising, but questions remain with regard to its wider application and the potential risks. This study evaluated the feasibility and efficacy of retrograde recanalisation of chronic total occlusion (CTO) of the coronary arteries. METHODS AND RESULTS: A total of 378 consecutive patients (previously failed PCI 32.0%) who enrolled in 27 institutions in Japan underwent retrograde recanalisation for CTO. We analysed the data on lesion characteristics, procedural materials, technique used, complications and clinical outcomes. Successful retrograde recanalisation was achieved in 70.4% and the overall procedural success was 83.6%. Collateral crossing was achieved via a septal route in 68.9%, epicardial in 27.2% and bypass grafts in 2.6%, respectively. The retrograde approach was completed with implementation of reverse CART in 42.5%, direct wire crossing in 23.1%, bilateral wiring in 22.7%, and CART in 11.7%. Major and minor collateral injuries and coronary perforations were noted in 1.3%, 10.3% and 2.9% of cases, respectively. Stroke occurred in 0.3%, QWMI and emergency PCI in 0.3% of patients with successful recanalisation. CONCLUSIONS: Wider application of retrograde CTO PCI achieved a high rate of success in recanalisation with an acceptable rate of complications in Japan. PMID- 23455002 TI - Effects of the new wildlife transfer factors on RESRAD-BIOTA's screening Biota Concentration Guides and previous model comparison studies. AB - The RESRAD-BIOTA Level 1 default Biota Concentration Guides (BCGs) are generic screening environmental medium concentrations based on reasonably conservative concentration ratios (CRs). These CRs had been identified from available literature for a variety of biota organisms. The International Atomic Energy Agency (IAEA) Technical Report Series (TRS) handbook on radionuclide transfer to wildlife was recently published with data that can be compared with the RESRAD BIOTA values. In addition, previous IAEA Environmental Modeling for Radiation Safety (EMRAS) II Biota Working Group model comparison results are examined by comparing them with those obtained using the new TRS CR values for wildlife. Since the CR affects only internal doses, the effect on the overall dose depends on the relative contribution from internal and external exposure pathways. PMID- 23455003 TI - Insights into the interplay between molecular structure and diffusional motion in 1-alkyl-3-methylimidazolium ionic liquids: a combined PFG NMR and X-ray scattering study. AB - We report on how the local structure and the diffusional motion change upon increasing the alkyl chain length in 1-alkyl-3-methylimidazolium cation ionic liquids. This study has been performed by combining pulse field gradient (PFG) nuclear magnetic resonance (NMR) spectroscopy and small angle X-ray scattering (SAXS) experiments. The cationic side chain length varies from ethyl (n = 2) to hexadodecyl (n = 16), while the anion is always bis(trifluoromethanesulfonyl)imide (TFSI). We find that the self-diffusivity of the individual ionic species is correlated to the local structure in the corresponding ionic liquid, namely the nano-segregation into polar and non-polar domains. In agreement with previous results, we observe that for relatively short alkyl chains the cations diffuse faster than the anions; however we also note that this difference becomes less evident for longer alkyl chains and a cross over is identified at n ~ 8 with the anions diffusing faster than the cations. Our results indicate that this controversial behavior can be rationalized in terms of different types of cation-cation and anion-anion orderings, as revealed by a detailed analysis of the correlation lengths and their dispersion curves obtained from SAXS data. We also discuss the validity of the Stokes-Einstein relation for these ionic liquids and the evolution of the extrapolated cationic radius that was found to depend non-strictly linearly on n, in agreement with the cation-cation correlation lengths. PMID- 23455004 TI - Risks to Ireland from incidents at Sellafield. PMID- 23455005 TI - Siah: a promising anticancer target. AB - Siah ubiquitin ligases play important roles in a number of signaling pathways involved in the progression and spread of cancer in cell-based models, but their role in tumor progression remains controversial. Siah proteins have been described to be both oncogenic and tumor suppressive in a variety of patient cohort studies and animal cancer models. This review collates the current knowledge of Siah in cancer progression and identifies potential methods of translation of these findings into the clinic. Furthermore, key experiments needed to close the gaps in our understanding of the role Siah proteins play in tumor progression are suggested. PMID- 23455006 TI - Child poisonings are more common in households experiencing psychosocial stressors. PMID- 23455007 TI - Muscle strength during adolescence is associated with longevity. PMID- 23455008 TI - Why couldn't I be nudged to dislike a Big Mac? PMID- 23455009 TI - Doing good by stealth: comments on 'Salvaging the concept of nudge'. PMID- 23455010 TI - Lying and nudging. PMID- 23455011 TI - Should 'nudge' be salvaged? PMID- 23455012 TI - Shifting the concept of nudge. PMID- 23455013 TI - Morphological characteristics of the walls of thrombophlebitic saphenous vein. AB - INTRODUCTION: To investigate the morphological changes in the walls of thrombophlebitic saphenous veins. METHODS: Fifty-four specimens were made into slices for haematoxylin and eosin and Masson trichrome staining; ultrathin slices were also created. Slices were observed under light microscopy and electron microscopy. RESULTS: Under light microscopy, the tunica intima of venous wall in the thrombophlebitic saphenous veins group was obviously thickened and incomplete; intravascular papillary endothelial hyperplasia was observed. Hyperplasia of collagenous fibres in the tunica media was observed. Elastic fibres in the tunica externa became fewer, whereas nourishing vessels were significantly increased in number. Infiltration of many inflammatory cells was observed. Under electron microscopy, Auer bodies with high electron density and round granules could be seen in endothelial cells in the thrombophlebitic saphenous veins group. Smooth muscle cells had an irregular karyotype, with blurred cristae in some mitochondria. Myofilaments basically disappeared. CONCLUSION: Thrombus formation might aggravate re-modelling of the walls of varicose veins. PMID- 23455014 TI - The use of ultrasound in the evaluation of the efficacy of calf muscle pump function in primary chronic venous disease. AB - OBJECTIVES: To evaluate popliteal vein blood flow during calf muscle contraction in chronic venous disease (CVD) patients and healthy controls using ultrasound imaging and to investigate the relationship between venous blood flow and gastrocnemius muscle (GM) morphology. METHODS: Thirty-one subjects participated in this study (mean age: 40.3 [11.8] years), 15 healthy controls and 16 with CVD (clinical classification: C1-4). Popliteal vein cross-sectional area and venous blood flow velocity (FV) were evaluated by Doppler ultrasound at baseline and during three sets of 10 tip-toe movement repetitions. Muscle thickness, muscle fascicle length and pennation angle of both medial and lateral GM were measured by ultrasound. Measures were repeated a week later in 17 participants in order to assess reproducibility with intraclass correlation coefficient (ICC) and Bland Altman analysis. RESULTS: Peak FV was lower in CDV group compared with Control group for both first (40.6 [11.8] versus 62.4 (22.1) cm2/second; P = 0.021) and last (30.4 [9.1] versus 49.5 (22.7) cm2/second; P = 0.024) contraction. In CVD group, peak FV during first contraction increased with GM's muscle fascicle length (r = 0.63; P = 0.041). Popliteal FV also increased with rising range of muscle fascicles pennation change between ankle dorsiflexion and plantar flexion (r = 0.70; P = 0.025). No associations were found between haemodynamics and medial or lateral GM thickness. Calf muscular architecture was similar in both CVD and control participants. Test-retest reliability of FV measured in the same session was high (ICC~0.70) for measures taken in the first contraction of the set but lowered when using the last contraction (ICC<0.50). Reproducibility of ultrasound evaluation of calf pump is acceptable within the same session but is unsatisfactory when testing in separate days. CONCLUSION: Patients with moderate CVD have lower FV during calf muscles contraction but similar muscle anatomical characteristics compared with healthy controls. Changes in calf muscles flexibility and fatigue resistance may be investigated as possible causes of calf pump dysfunction. PMID- 23455015 TI - Thrombus formation using endovenous lasers: an in vitro experiment. AB - OBJECTIVES: The purpose of these experiments was to simulate thrombus formation during endovenous laser closure by measuring coagulum formation of in vitro laser exposures in porcine blood and investigate the role of procedures and equipment in thrombus formation. METHODS: Continuous wave 810, 940, 980, 1310 and 1470 nm lasers and microsecond pulsed wave 1064 nm Nd:YAG (neodymium-doped yttrium aluminium garnet), 1320 nm Nd:YAG and 2100 nm THC:YAG (thulium holmium chromium doped yttrium aluminium garnet) lasers were tested with standard fibres with diameters of 365, 550 and 600 MUm as well as two prototype modified tip fibres. RESULTS: The results show that pulsed lasers with high-peak power densities form less coagulum. Fibre specifications were found not to influence coagulum formation, and prototype modified tip fibres designed to prevent contact between the fibre tip and the vein wall did not eliminate coagulum formation. CONCLUSION: Microsecond-pulsed wave lasers with high-peak power densities may be a better choice to minimize soft thrombus formation during endovenous laser ablation treatments. PMID- 23455016 TI - Frontiers in B-cell immunology. PMID- 23455018 TI - Retraction. RGD-FasL induces apoptosis in hepatocellular carcinoma. PMID- 23455019 TI - Retraction. Induction of tumor cell apoptosis via Fas/DR5. PMID- 23455017 TI - B-cell-targeted therapies in systemic lupus erythematosus. AB - Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of harmful auto-antibodies (auto-Abs), B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator (BLyS) in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells. PMID- 23455020 TI - Serum adiponectin level is not only decreased in metabolic syndrome but also in borderline metabolic abnormalities. AB - OBJECTIVE: Along with the increasing prevalence of obesity and related diseases, particularly atherosclerotic diseases, metabolic syndrome (MetS) is now a common and major public health issue in many countries around the world. Adiponectin, a protein secreted by the adipose tissue, has become recognized as a key player in the development of MetS. These days, not only MetS but also borderline metabolic/physiological abnormalities, such as impaired fasting glucose, high normal blood pressure and high normal plasma cholesterol, have been reported to be risk factors for atherosclerotic disease. Therefore, we undertook this study to determine the relationship between adiponectin and borderline metabolic/physiological abnormalities, as well as MetS. DESIGN: A cross-sectional study performed from April 2007 to November 2009. SUBJECTS: In 16 892 Japanese adults (10 008 men and 6884 women), we examined the relationship between the serum adiponectin concentration and borderline metabolic/physiological abnormalities or MetS by a questionnaire survey about medical treatment, body size measurement and measurement of laboratory parameters including the serum adiponectin concentration. RESULTS: Adiponectin showed a significant negative correlation with the number of MetS components. In subjects without overt diabetes mellitus, hypertension or dyslipidemia, the adiponectin concentration also showed a significant negative correlation with the number of borderline metabolic abnormalities. CONCLUSION: The decrease of circulating adiponectin may start before the development of diabetes mellitus, hypertension, dyslipidemia or MetS. Adiponectin is an important biomarker for reflecting the adverse influence of visceral fat in persons with MetS, and also in these subclinical states. PMID- 23455021 TI - Long-term effect of lifestyle intervention on adiposity, metabolic parameters, inflammation and physical fitness in obese children: a randomized controlled trial. AB - BACKGROUND: Behavioral lifestyle intervention, combined with parental involvement, is preferred over standard care or self-help in childhood obesity. The short-term results of such interventions are promising, but long-term follow up results are equivocal. OBJECTIVE: The objective of the present study was the short (3 months) and long-term (1 and 2 years follow-up) effect evaluation of a family-based multidisciplinary cognitive behavioral lifestyle intervention on markers of adiposity, metabolism, inflammation and physical fitness compared with standard care in children with obesity. Also the association between these outcome variables was determined. METHODS: In this prospective longitudinal clinical trial, obese children were randomly assigned to a 3-month family-based cognitive behavioral multidisciplinary lifestyle treatment (n=40; body mass index standard deviation score (BMI-SDS) 4.2+/-0.7; age; 13.3+/-2.0 years) or to a control group receiving an initial advice on physical activity and nutrition (n=39; BMI-SDS 4.3+/-0.6; age 13.1+/-1.9 years). Anthropometric data, physical fitness, metabolic parameters and inflammatory state were evaluated at baseline, after intervention (at 3 months) and at 1-year follow-up. At 2-year follow-up, anthropometric data and physical fitness were measured in the intervention group. RESULTS: An intervention effect after 1 year was found for adiposity (P=0.02 for BMI-SDS, P=0.03 for waist circumference (WC)-SDS), physical fitness (absolute measured peak value of oxygen uptake (ml min(-1)), standardized for age and gender (VO2peak-SDS), P<0.01) and insulin resistance (HOMA-SDS, P=0.04). No significant intervention effect was found for serum lipid profile, high-sensitive C-reactive protein or for adiponectin. At 2-year follow-up, BMI-SDS in the intervention group (n=31) was 3.8+/-1.2 SDS, significantly less than at baseline (P=0.02). CONCLUSION: A positive 1-year follow-up treatment effect was found for adiposity, physical fitness and glucose homeostasis, but not for inflammatory markers. There was a significant long-term treatment effect on adiposity, although almost all children remained obese. PMID- 23455022 TI - Function of Arabidopsis CPL1 in cadmium responses. AB - Transcriptional and post-transcriptional responses to external iron (Fe) availability are essential for the cellular Fe homeostasis. Fe deficiency strongly induces Fe utilization-related gene expression; however, little is known about the early Fe signaling that regulates expression of a central transcription factor FIT. In Arabidopsis, mutations in RNA polymerase II CTD-phosphatase-like 1 (CPL1) enhance the expression of Fe utilization-related genes including FIT under Fe deficiency. Fe content is significantly increased in the roots and decreased in the shoots of cpl1-2 plants, and root growth of the cpl1-2 mutant shows higher tolerance to Fe deficiency and to toxicity of cadmium (Cd). The cpl1-2 plants accumulate more Cd in the shoots, suggesting that Cd toxicity in the cpl1-2 roots is circumvented by the transport of excess Cd to the shoots. Here we show data suggesting that the root-to-shoot translocation of Cd in cpl1-2 is mediated by yet uncharacterized Cd transport mechanisms. PMID- 23455023 TI - PFT1-controlled ROS balance is critical for multiple stages of root hair development in Arabidopsis. AB - Reactive oxygen species (ROS) have been shown to play key roles in cellular decision making and signal integration in multicellular organisms. In roots, ROS levels are managed by the action of peroxidases and NAPDH oxidases, resulting in a distinct spatial distribution of hydrogen peroxide (H2O2) and superoxide (O2( )) that is critical for the balance between cell proliferation and differentiation. In addition, ROS is required for the determination of the cell shape of root hairs. Mutations in the Mediator subunit MED25/PFT1 result in compromised root hair development, due to altered expression of a suite of H2O2 producing class III peroxidases. pft1-1 mutants form shorter root hairs than wild type plants. Analysis of pft1-1 cross-sections revealed that also root hair initiation is compromised, probably by impeding local cell wall loosening. It is suggested that ROS homeostasis is critical throughout the development of root hairs, controlling various processes via PFT1-regulated transcription of genes encoding redox-active enzymes. PMID- 23455024 TI - Mitochondria-responsive signaling between egg and central cell controls their coordinated maturation. AB - Recent studies suggest a complex regulatory network in female gametophyte of angiosperm. The cell-cell communication between female gametes was confirmed during their maturation and functional specialization. The mitochondria responsive signaling may play a critical role in this process. Here, we briefly summarized the recent discussion on this topic and proposed a two-pathway's mechanism for regulating coordinated development of the female gamete cells. PMID- 23455025 TI - Arsenic and diabetes. PMID- 23455026 TI - Structure-based drug design using GPCR homology modeling: toward the discovery of novel selective CysLT2 antagonists. AB - 3D structure of CysLT2 receptor was constructed by using homology modeling and molecular simulations. The binding pocket of CysLT2 receptor and the proposition of the interaction mode between CysLT2 and HAMI3379 were identified. A series of dicarboxylated chalcones was then virtually evaluated through molecular docking studies. A total of six compounds 13a-f with preferable scores was further synthesized and tested for CysLT2 antagonistic activities by determination of the cytosolic free Ca(2+) levels in HEK293 cells. Compounds 13e and 13f exhibited potent and selective CysLT2 antagonistic activities with IC50 values being 7.5 and 0.25 MUM, respectively. PMID- 23455027 TI - Fungal transformation of cedryl acetate and alpha-glucosidase inhibition assay, quantum mechanical calculations and molecular docking studies of its metabolites. AB - The fungal transformation of cedryl acetate (1) was investigated for the first time by using Cunninghamella elegans. The metabolites obtained include, 10beta hydroxycedryl acetate (3), 2alpha, 10beta-dihydroxycedryl acetate (4), 2alpha hydroxy-10-oxocedryl acetate (5), 3alpha,10beta-dihydroxycedryl acetate (6), 3alpha,10alpha-dihydroxycedryl acetate (7), 10beta,14alpha-dihydroxy cedryl acetate (8), 3beta,10beta-cedr-8(15)-ene-3,10-diol (9), and 3alpha,8beta,10beta dihydroxycedrol (10). Compounds 1, 2, and 4 showed alpha-glucosidase inhibitory activity, whereby 1 was more potent than the standard inhibitor, acarbose, against yeast alpha-glucosidase. Detailed docking studies were performed on all experimentally active compounds to study the molecular interaction and binding mode in the active site of the modeled yeast alpha-glucosidase and human intestinal maltase glucoamylase. All active ligands were found to have greater binding affinity with the yeast alpha-glucosidase as compared to that of human homolog, the intestinal maltase, by an average value of approximately -1.4 kcal/mol, however, no significant difference was observed in the case of pancreatic amylase. PMID- 23455028 TI - Evolving therapeutic targets in renal cell carcinoma. AB - PURPOSE OF REVIEW: Recent developments in the treatment of advanced renal cell carcinoma (RCC) will be discussed, with emphasis on data published over the past year. The genetics and molecular biology of the various histologic subtypes of kidney cancer will be reviewed, as these subtle yet important genomic and metabolic alterations provide the opportunity for rational drug development and personalized treatment regimens. RECENT FINDINGS: Additional targeted agents continue to be added to the uro-oncologist's armamentarium in the fight against metastatic kidney cancer. Targeting the vascular endothelial growth factor and its receptor, or the mammalian target of rapamycin complex, remains the foundation of systemic treatment. In clear cell RCC, increased emphasis is being placed on target selectivity and affinity in a bid to diminish off-target toxicity without compromising efficacy. Combination strategies targeting multiple pathways simultaneously continue to be explored. Histology-specific protocols testing later generation and novel agents in nonclear cell RCC should be made a priority, as there is still not a single drug approved specifically for a nonclear cell indication. SUMMARY: The number of approved treatments for advanced RCC continues to grow, but additional work is needed to further delineate the optimal drug, combination of agents, or sequence best suited to each subtype of RCC. PMID- 23455029 TI - Multidimensional crystal frameworks based on heteropoly blue building block of [SiW10Mo(V)2O40]6-: synthesis, structures and magnetic properties. AB - Four heteropoly blue complexes constructed from Keggin-type heteropoly blue molybdenum-tungsten clusters and Cu(II) ions as linkers, H2[alpha SiW10Mo(V)2O40][Cu(PDA)2.H2O]2 (1), H2[alpha SiW10Mo(V)2O40][Cu(DEF)3.H2O][Cu(DEF)2.2H2O].6H2O (2), H2[alpha SiW10Mo(V)2O40][Cu(DMF)3H2O]2.6H2O (3), and H4[alpha SiW10Mo(V)2O40]2[CuK2(DMF)6][Na0.75K3.25(DMF)6] (4) [PDA = propanediamide, DEF = N,N-diethylformamide and DMF = N,N-dimethylformamide], have been synthesized by conventional reactions and characterized by single-crystal X-ray diffraction, elemental analysis, IR spectroscopy, thermogravimetry, X-ray powder diffraction (XRD) and UV spectra. The amount of Cu(II) and the nature of the ligand (DMF, DEF and PDA) can control both the linkage pattern of Cu(II) ions and the dimensionality of the frameworks; this demonstrates for the first time the possibility to assemble heteropoly blue architectures in different dimensionality ranging from zero-dimensional (0D) to one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D). The magnetic investigation showed that the positive magnetic moment could be observed at room temperature, which should be unusual results in magnetochemistry of the two-electron reduced heteropoly blue. The stability and formation conditions of the four compounds are also discussed. PMID- 23455030 TI - The extended growth of graphene oxide flakes using ethanol CVD. AB - We report the extended growth of Graphene Oxide (GO) flakes using atmospheric pressure ethanol Chemical Vapor Deposition (CVD). GO was used to catalyze the deposition of carbon on a substrate in the ethanol CVD with Ar and H2 as carrier gases. Raman, SEM, XPS and AFM characterized the growth to be a reduced GO (RGO) of <5 layers. This newly grown RGO possesses lower defect density with larger and increased distribution of sp(2) domains than chemically reduced RGO. Furthermore this method without optimization reduces the relative standard deviation of electrical conductivity between chips, from 80.5% to 16.5%, enabling RGO to be used in practical electronic devices. PMID- 23455031 TI - Childbirth fear in expectant fathers: findings from a regional Swedish cohort study. AB - OBJECTIVE: to investigate the prevalence of childbirth related fear in Swedish fathers and associated factors. DESIGN: a regional cohort study. Data was collected by a questionnaire. SETTING: three hospitals in the middle-north part of Sweden PARTICIPANTS: 1047 expectant fathers recruited in mid-pregnancy during one year (2007) who completed the Fear of Birth Scale (FOBS). MEASUREMENTS: prevalence of childbirth fear and associated factors. Crude and adjusted odds ratios were calculated between men who scored 50 and above (childbirth fear) and those that did not (no fear). Logistic regression analysis was used to assess which factors contributed most to childbirth fear in fathers. FINDINGS: the prevalence of childbirth fear in men was 13.6%. Factors associated with childbirth related fear were as follows: Less positive feelings about the approaching birth (OR 3.4; 2.2-5.2), country of birth other than Sweden (OR 2.8; 1.3-6.1), a preference for a caesarean birth (OR 2.1; 1.7-4.1), childbirth thoughts in mid-pregnancy (OR 1.9; 1.1-2.0) and expecting the first baby (OR 1.8; 1.2-2.6). KEY CONCLUSIONS: high levels of fear were associated with first time fathers and being a non-native to Sweden. Men with fear were more likely to experience pregnancy and the coming birth as a negative event. These men were also more likely to identify caesarean section as their preferred mode of birth. IMPLICATIONS FOR PRACTICE: engaging expectant fathers in antenatal conversations about their experiences of pregnancy and feelings about birth provides health care professionals with an opportunity to address childbirth fear, share relevant information and promote birth as a normal but significant life event. PMID- 23455032 TI - A five year follow-up study of the Bristol pregnancy domestic violence programme to promote routine enquiry. AB - OBJECTIVE: a follow-up study to evaluate the degree to which practice changes identified in the 2004/2005 evaluation of the Bristol Pregnancy Domestic Violence Programme (BPDVP) for routine enquiry for domestic abuse have been maintained. METHODS: a multimethod approach was adopted, using a follow-up survey and focus groups. SETTING: an acute Trust within the South West of England. PARTICIPANTS: 58 midwives completed the survey, 73% (n=36) of whom had taken part in the original study in 2004/2005. Eleven of those surveyed also participated in focus group interviews. MEASUREMENTS: participating midwives completed a 54-item questionnaire, where possible the questions were the same as those utilised in the original follow-up questionnaire. Similar to the previous study, the questionnaire was divided into a number of sections, including view of professional education, knowledge of domestic violence and abuse, attitudes and efficacy beliefs, barriers and support. The aim of the focus groups discussion was to obtain the overall views of midwives with the regard to the on-going implementation of routine enquiry. Frequency distributions for midwife responses in 2010 were compared with the corresponding frequency distributions in 2004/2005 and a statistical assessment of differences was performed using the chi(2) test of association. RESULTS: midwives have to feel confident in their abilities to ask about abuse and the findings from this study demonstrate that across the cohort there was a tendency to have an increase in confidence in asking about domestic violence. Midwives have to feel confident in their abilities to ask about abuse. The findings from this study demonstrate that across the cohort there was a statistically significant increase in self-reported confidence in asking women about domestic abuse. In addition, there was a statistically significant increase in the degree of self-reported knowledge of how to deal with a disclosure of domestic violence when comparing the 2010 data with 2005 data. CONCLUSIONS: results suggest that improvements in antenatal enquiry for domestic violence and abuse developed through the 2004/2005 BPDVP have improved over time, with the support of mandatory training. Nevertheless, barriers continue to exist, which include presence of a male partner and lack of face to face interpreting services, both these obstacles need to be addressed if all women and, in particular those who are most at risk of abuse are to be identified and supported. PMID- 23455034 TI - Time-resolved gas-phase kinetic studies of the reaction of dimethylsilylene with triethylsilane-1-d: kinetic isotope effect for the Si-H insertion process. AB - Time-resolved kinetic studies of the reaction of dimethylsilylene, SiMe2, generated by laser flash photolysis of 1,1-dimethyl-1-silacyclopent-3-ene, have been carried out to obtain rate coefficients for its bimolecular reactions with trimethylsilane-1-d, Me3SiD. The reaction was studied in the gas phase at five temperatures in the range 292-605 K. The rate coefficients showed no pressure dependence in the presence of up to 13 kPa of SF6. The second order rate coefficients obtained at 0.7 kPa fitted the Arrhenius equation: log(k/cm(3) molecule(-1) s(-1)) = (-13.53 +/- 0.19) + (11.29 +/- 1.46) kJ mol(-1)/RT ln 10. By comparison with rate coefficients obtained previously for the reaction of SiMe2 with Me3SiH, a set of kinetic isotope effects, kH/kD, of value ca. 1.2 showing very little temperature dependence was obtained. Theoretical support for these values has been obtained by means of quantum chemical calculations used in conjunction with transition state theory. This study provides the first comprehensive set of kinetic isotope effects for the Si-H(D) insertion process of a silylene in the gas phase. PMID- 23455033 TI - One-year outcomes with abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary interventions in patients with non-ST-segment elevation myocardial infarction: updated results from the ISAR-REACT 4 trial. AB - AIMS: Thirty-day results of the double-blind, randomised Intracoronary Stenting and Antithrombotic Regimen -Rapid Early Action for Coronary Treatment (ISAR REACT) 4 trial showed no difference in ischaemic complications and a reduction in bleeding by bivalirudin versus abciximab and heparin in 1,721 patients with non ST-segment elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI). A longer follow-up may be required to assess the whole potential benefit of a periprocedural antithrombotic therapy. METHODS AND RESULTS: The primary outcome for this analysis was the composite of death, myocardial infarction or target vessel revascularisation one year after randomisation. Secondary outcome was the composite of death or myocardial infarction. At one year, the primary outcome occurred in 21.3% of patients assigned to abciximab and heparin versus 21.5% assigned to bivalirudin (hazard ratio [HR] 0.99; 95% confidence interval [CI]: 0.80-1.21; p=0.94). The combined incidence of death or myocardial infarction was 15.7% in the abciximab and heparin group versus 16.0% in the bivalirudin group (HR 0.99; 95% CI: 0.78-1.26; p=0.94). The mortality rates were 4.0% and 4.7%, respectively (HR 0.85; 95% CI: 0.54-1.34; p=0.48). At one year, no significant differences in the primary outcome were observed with abciximab and heparin versus bivalirudin in any of the subgroups analysed. CONCLUSIONS: In patients with NSTEMI undergoing PCI, abciximab with heparin and bivalirudin provide comparable outcomes at one year, although bivalirudin reduced the rate of bleeding at 30 days. CLINICAL TRIAL REGISTRATION INFORMATION: URL www.clinicaltrials.gov; Unique identifier NCT00373451. PMID- 23455035 TI - Retrospective epidemiological survey of diagnostic errors and their implications in the development of human trichinellosis in Brasov County-Romania over a period of 10 years. AB - Trichinellosis is a disease that is difficult to diagnose because its symptoms are polymorphic and can be easily confused for several other diseases (Dupouy Camet et al., 2002). Consuming pork from untested pigs bred in private households elevates risk of contracting trichinellosis. The aims of this paper were to document the frequency and character of misdiagnoses in a ten-year period in an endemic locale (Brasov County, Romania) and to determine whether implementation of an integrated surveillance program significantly reduced the interval between disease and accurate diagnosis and significantly reduced the average length of hospitalization. All 699 cases of trichinellosis in the County were studied from 1983-1992, of which 314 (44.9%) were initially misdiagnosed. The most frequent misdiagnoses (41.7%) attributed disease to digestive disorders, closely followed by respiratory system disorders (32.5%), allergic reactions 4.4%, kidney problems 4.1%, eyes 2.8% and even neurophysical disorders 4.4%. Implementation of a surveillance program substantially shortened the interval prior to accurate diagnosis, and shortened the length of hospitalization. PMID- 23455036 TI - Wrist fractures in adults: getting a grip. PMID- 23455038 TI - International conference on radiation protection in medicine: setting the scene for the next decade. PMID- 23455037 TI - An emerging role for Cullin-3 mediated ubiquitination in sleep and circadian rhythm: insights from Drosophila. AB - Although the neurophysiological correlates of sleep have been thoroughly described, genetic mechanisms that control sleep architecture, long surmised from ethological studies, family histories and clinical observations, have only been investigated during the past decade. Key contributions to the molecular understanding of sleep have come from studies in Drosophila, benefitting from a strong history of circadian rhythm research. For instance, a number of recent papers have highlighted the role of the E3 ubiquitin ligase Cullin-3 in the regulation of circadian rhythm and sleep. We propose that different Cullin-3 substrate adaptors may affect specific molecular pathways and diverse aspects of circadian rhythm and sleep. We have previously shown that mutations in BTBD9, a risk factor for Restless Legs Syndrome (RLS) encoding a Cullin-3 substrate adaptor, lead to reduced dopamine, increased locomotion and sleep fragmentation. Here, we propose that Cullin-3 acts together with BTBD9 to limit the accumulation of iron regulatory proteins in conditions of iron deficiency. Our model is consistent with clinical observations implicating iron homeostasis in the pathophysiology of RLS and predicts that lack of BTBD9 leads to misregulation of cellular iron storage, inactivating the critical biosynthetic enzyme Tyrosine Hydroxylase in dopaminergic neurons, with consequent phenotypic effects on sleep. PMID- 23455039 TI - Revised conformational assignments and conformational evolution of tyrosine by laser desorption supersonic jet laser spectroscopy. AB - The number of conformers and their structures of tyrosine are reassigned on the basis of resonance enhanced multiphoton ionization (REMPI), ultraviolet ultraviolet hole burning (UV-UV HB), infrared (IR) dip spectra, and quantum chemical calculations. From comparison between REMPI and UV-UV HB spectra, it was found that 12 conformers coexist in the supersonic jet. The structures of these conformers are determined by the IR spectra and theoretical calculations. The number of conformers is more than that reported in the previous reports (8 conformers), and is rationalized by the systematic formation of conformers from simpler molecules without substituents, just like evolution. The importance of dipole-dipole interaction between an amino-acid chain and hydroxyl group at the benzene ring was also discussed. PMID- 23455042 TI - gamma-Fe2O3 nanoparticle surface controls PtFe nanoparticle growth and catalytic properties. AB - We report a novel method for synthesis of alloy PtFe nanoparticles (NPs) of different compositions using gamma-Fe2O3 NPs as an iron source. We show here other growth mechanisms than conventional nucleation on a NP surface leading to core-shell NP or seeded NP growth. Depending on reaction conditions, different compositions of PtFe NPs can be obtained. PtFe NPs may coexist with gamma-Fe2O3 NPs in the reaction product. This mixture obtained in situ allows much higher catalytic activity in hydrogenation of methyl-3-buten-2-ol than that of only PtFe nanoparticles or merely mixed PtFe and gamma-Fe2O3 NPs. The presence of both PtFe and gamma-Fe2O3 NPs allows formation of dense and stable NP arrays which hold promise for catalytic applications in microreactors or other reactor designs where a catalytic film is favoured. PMID- 23455041 TI - Eating dark and milk chocolate: a randomized crossover study of effects on appetite and energy intake. AB - OBJECTIVE: To compare the effect of dark and milk chocolate on appetite sensations and energy intake at an ad libitum test meal in healthy, normal-weight men. SUBJECTS/METHODS: A total of 16 young, healthy, normal-weight men participated in a randomized, crossover study. Test meals were 100 g of either milk (2285 kJ) or dark chocolate (2502 kJ). Visual-analogue scales were used to record appetite sensations before and after the test meal was consumed and subsequently every 30 min for 5 h. An ad libitum meal was served 2 h after the test meal had been consumed. RESULTS: The participants felt more satiated, less hungry, and had lower ratings of prospective food consumption after consumption of the dark chocolate than after the milk chocolate. Ratings of the desire to eat something sweet, fatty or savoury were all lower after consumption of the dark chocolate. Energy intake at the ad libitum meal was 17% lower after consumption of the dark chocolate than after the milk chocolate (P=0.002). If the energy provided by the chocolate is included in the calculation, the energy intake after consumption of the dark chocolate was still 8% lower than after the milk chocolate (P=0.01). The dark chocolate load resulted in an overall energy difference of -584 kJ (95% confidence interval (-1027;-141)) during the test period. CONCLUSION: In the present study, dark chocolate promotes satiety, lowers the desire to eat something sweet, and suppresses energy intake compared with milk chocolate. PMID- 23455040 TI - Sexual trauma increases the risk of developing psychosis in an ultra high-risk "prodromal" population. AB - Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large "Ultra High Risk" (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4-14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2-4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals. PMID- 23455043 TI - Toluene biofiltration enhanced by ryegrass. AB - Toluene biofiltration by microorganisms (an unplanted treatment) and by the combination of ryegrass (Lolium perenne L.) and microorganisms (a planted treatment) was investigated in this study. The results showed that toluene was completely removed by the unplanted and the planted biofilters in less than 0.2 g m-3 inlet toluene concentration. Toluene removal capacity for the planted biofilter was significantly higher than that for the unplanted biofilter in the range of 0.2-0.5 g m-3 inlet toluene concentration. This study revealed a significant (p < 0.01) increase in the microbial activity in the planted biofilter in comparison with the unplanted biofilter, indicating that ryegrass growing in a biofilter would significantly (p < 0.05) enhance toluene biodegradation. PMID- 23455044 TI - Arsenic and diabetes: Navas-Acien et al. Respond. PMID- 23455045 TI - Quality assessment of SPR sensor chips; case study on L1 chips. AB - Surface quality of the Surface Plasmon Resonance (SPR) chips is a major limiting issue in most SPR analyses, even more for supported lipid membranes experiments, where both the organization of the lipid matrix and the subsequent incorporation of the target molecule depend on the surface quality. A novel quantitative method to characterize the quality of SPR sensors chips is described for L1 chips subject to formation of lipid films, injection of membrane disrupting compounds, followed by appropriate regeneration procedures. The method consists in analysis of the SPR reflectivity curves for several standard solutions (e.g. PBS, HEPES or deionized water). This analysis reveals the decline of sensor surface as a function of the number of experimental cycles (consisting in biosensing assay and regeneration step) and enables active control of surface regeneration for enhanced reproducibility. We demonstrate that quantitative evaluation of the changes in reflectivity curves (shape of the SPR dip) and of the slope of the calibration curve provides a rapid and effective procedure for surface quality assessment. Whereas the method was tested on L1 SPR sensors chips, we stress on its amenability to assess the quality of other types of SPR chips, as well. PMID- 23455046 TI - Poly(dopamine) coated gold nanocluster functionalized electrochemical immunosensor for brominated flame retardants using multienzyme-labeling carbon hollow nanochains as signal amplifiers. AB - An electrochemical, signal amplified immunosensor was developed to detect 3 bromobiphenyl (BBP) by using a bio-inspired polydopamine (PDOP)/gold nanocluster (AuNc) as the sensor platform and multienzyme-labeled carbon hollow nanochains as the signal amplifier. The self-polymerized dopamine membrane on the AuNc-modified indium tin oxide (ITO) electrode were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle and electrochemical measurements. Such PDOP/AuNc platform featured the mild cross linking reaction with the dense immobilization of BBP-antigens (BBP-Ag). Moreover, by using multiple horseradish peroxidase (HRP) and secondary antibodies (Ab2) modified one-dimensional carbon hollow nanochains (CHNc) as the signal enhancer, it held promise for improving the sensitivity and detection limit of the immunoassay. Based on the competitive immunoassay protocol, this immunosensor showed a linear range from 1 pM to 2 nM for BBP with a detection limit of 0.5 pM. Also, it exhibited high sensitivity, wide linear range, acceptable stability and reproducibility on a promising immobilization platform using a novel signal amplifier, which may extend its application in other environmental monitoring. PMID- 23455047 TI - Graphene-Orange II composite nanosheets with electroactive functions as label free aptasensing platform for "signal-on" detection of protein. AB - The combination of novel nanomaterials and biomolecule recognition units is promising in developing sensitive biosensors. This paper presents a facile approach for the preparation of water-soluble electroactive dye-Orange II functionalized graphene nanosheets (O-GNs). The successful attachment of Orange II on the surface of graphene nanosheets not only prevents the agglomeration of the as-formed graphene nanocomposite in aqueous media, but also endows graphene nanosheets with excellent electroactive property. Integrating the unique properties of the as-prepared O-GNs (high conductivity, high specific surface area and electroactive function) with high affinity and specificity of aptamer, a new label-free electrochemical biosensing concept is demonstrated for the "signal on" detection of targets such as thrombin and lysozyme. The present O-GNs-based aptasensor exhibits good current response to the above proteins. The linear ranges for thrombin and lysozyme are 1.0 * 10(-12)-4.0 * 10(-10)M and 5.0 * 10( 12)-7.0 * 10(-10)M, with the detection limit of 3.5 * 10(-13)M and 1.0 * 10( 12)M, respectively. In contrast to the common laborious and expensive labeling approaches, the present O-GNs based aptasensing process is highly simple, cost efficient and does not need labeling and modification of aptamers or introduce additional electrochemical probes. PMID- 23455048 TI - Supramolecular assembly of enzyme on functionalized graphene for electrochemical biosensing. AB - The self-assembly of cyclodextrin (CD) functionalized graphene (GR) and adamantane-modified horseradish peroxidase (HRP-ADA) by host-guest supramolecular interaction into novel nanostructures in aqueous solution is reported in the present study. Electrochemical impedance spectroscopy and cyclic voltammetry were applied to characterize the self-assembly process and study the electrochemical behaviors of the immobilized proteins. UV-vis spectra indicated that the native structure of HRP was maintained after the assembly, implying good biocompatibility of CD-functionalized GR (CD-GR). Furthermore, the HRP-ADA/CD-GR composites were utilized for the fabrication of enzyme electrodes (HRP-ADA/CD-GR electrodes). The proposed biosensor showed good reproducibility and high sensitivity to H2O2 with the detection limit of 0.1 MUM. In the range of 0.7-35 MUM, the catalytic reduction current of H2O2 was proportional to H2O2 concentration. PMID- 23455049 TI - A novel electrically magnetic-controllable electrochemical biosensor for the ultra sensitive and specific detection of attomolar level oral cancer-related microRNA. AB - Non-invasive early diagnosis of oral cancer is the most effective means to reduce mortality rate from this disease. In this paper, we described a novel magnetic controllable electrochemical RNA biosensor for the ultra sensitive and specific detection of oral cancer-related microRNA (miRNA) based on a home-made electrically magnetic-controllable gold electrode. The electrically magnetic controllable gold electrode combined the merits of heated electrode and magnetic electrode, has notable advantage such as that the strength and direction of the magnetic field and the temperature of the electrode's surface can be easily regulated. The advantage of electrically magnetic-controllable gold electrode, as well as the utilization of "junction-probe" strategy and magnetic beads (MBs) based enzymatic catalysis amplification, make the biosensor has ultra-high sensitivity and discrimination ability even for the detection of similar miRNAs. It can be used to detect as low as 0.22 aM (2.2 * 10(-19)M) of oral cancer related miRNA with a recovery of 93-108% and a RSD<6 (n=5). The high sensitivity and selectivity, as well as the easiness of fabrication, operational convenience, short analysis time, good stability and re-usability, make the biosensor a promising alternative for the early point-of-care diagnosis of oral cancer. The success of the biosensor also leads to a great potential in the development of biosensor for the early diagnosis of other diseases. PMID- 23455050 TI - Multiwalled carbon nanotubes bearing 'terminal monomeric unit' for the fabrication of epinephrine imprinted polymer-based electrochemical sensor. AB - Carbon-nanotubes play a pivotal role in molecularly imprinted polymer technology for inculcating conducting property, high surface to volume ratio, and maximum porosity in the film texture. Contrary to the non-covalent heterogeneous dispersion of pure (unmodified) multiwalled carbon nanotubes in the imprinted polymer film, the homogeneous distribution of their functionalized derivative was found more effective to augment the sensitivity of the measurement. This could be made feasible using multiwalled carbon nanotubes bearing terminal monomeric unit (termed as "CNT-mer") for the polymerization (one CNT-mer in each repeating unit). In this work, the CNT-mer entails a N-hydroxyphenyl maleimide functionality to be utilized in the chain propagation with simultaneous imprinting of epinephrine in the polymeric network. This system, when casted on the tip of a pencil graphite electrode, responded a highly sensitive and selective response for epinephrine, prevalent in aqueous and real samples at ultratrace level (linear range 0.09-5.90 ng mL(-1), limit of detection 0.02 ng mL(-1), S/N=3), without any cross-reactivity and matrix effects. The proposed sensor is advantageous in obtaining enhanced differential pulse anodic stripping voltammetric current vis-a-vis the corresponding imprinted sensor modified with randomly dispersed flocculated multiwalled carbon nanotubes bundles. While the latter might restrict the interlayer diffusion of analyte in the film, the former sensor facilitated high diffusivity with the channelized electron transport to respond higher current. The CNT-mer dispersed sensor was found to be stable and rugged against mechanical stress and can be used, after regeneration, for more than hundred consecutive experiments in clinical settings. PMID- 23455051 TI - Development of a disposable and highly sensitive paper-based immunosensor for early diagnosis of Asian soybean rust. AB - Soybean is one of the most important crops and plays a key role in the whole food chain production. Soybean crops are very susceptible to the fungus Phakopsora Pachyrhizi, the agent responsible by the Asian soybean rust. The spore of the fungus is easily disseminated by wind with adequate environment, leaf wetness, high humidity and temperatures, the crop can be totally lost within few days. A high sensitive, specific and easy test is the key for early diagnosing the soybean rust and therefore save the crop. Here we present a paper-based immunosensor for early stage diagnosis of soybean rust that can be performed by unskilled operators on-site. Nitrocellulose membrane was chosen as the substrate to stick the antigen due to its high binding properties. Polyclonal antibodies labeled with fluorescent nanoparticles were employed as the recognizers. An analytical curve with spiked samples shows a linear response range from 0.0032 to 3.2 MUg/mL. This immunosensor presents a very low detection limit of 2.2 ng/mL, which corresponds approximately to 8-12 spores/mL. The paper-based sensor reachs the detection range of ELISA and PCR based test systems, and outranges the available commercial test kits by two order of magnitude. We believe this immunosensor has a great potential as a point-of-care device for the early diagnosis of Asian soybean rust. PMID- 23455052 TI - Mutiscale substrates based on hydrogel-incorporated silicon nanowires for protein patterning and microarray-based immunoassays. AB - Here, protein micropatterns were prepared on micropatterned nanostructures for potential applications in microarray-based multiplex bioassays with enhanced protein-loading capacity and detection sensitivity. Vertically-aligned silicon nanowires (SiNWs) that were about 8 MUm in height and 150 nm in diameter were prepared using an etching process and were surface-modified with aminopropyltriethoxysilane (APTES) to allow them to covalently immobilize proteins. The SiNW substrate was then overlaid with a micropattern of poly(ethylene glycol) (PEG) hydrogel to create defined arrays of microwells consisting of APTES-modified SiNW on the bottom of the wells, with hydrogel on the walls of the wells. Due to the non-adhesiveness of PEG hydrogels toward proteins, proteins were selectively immobilized on the surface-modified SiNW regions to create protein micropatterns. The increase in surface area increased the protein loading capacity of the SiNWs by more than 10 times the capacity of a planar silicon substrate. Immunobinding assays between IgG and anti-IgG and between IgM and anti-IgM that were performed on micropatterned SiNWs emitted stronger fluorescent signals and showed higher sensitivity than assays performed on planar silicon substrates. Finally, microfluidic channels were successfully integrated into the micropatterned SiNWs to enable the simultaneous performance of multiple immunoassays on a single microarray platform. PMID- 23455053 TI - Detection of target-probe oligonucleotide hybridization using synthetic nanopore resistive pulse sensing. AB - Despite the plethora of DNA sensor platforms available, a portable, sensitive, selective and economic sensor able to rival current fluorescence-based techniques would find use in many applications. In this research, probe oligonucleotide grafted particles are used to detect target DNA in solution through a resistive pulse nanopore detection technique. Using carbodiimide chemistry, functionalized probe DNA strands are attached to carboxylated dextran-based magnetic particles. Subsequent incubation with complementary target DNA yields a change in surface properties as the two DNA strands hybridize. Particle-by-particle analysis with resistive pulse sensing is performed to detect these changes. A variable pressure method allows identification of changes in the surface charge of particles. As proof-of-principle, we demonstrate that target hybridization is selectively detected at micromolar concentrations (nanomoles of target) using resistive pulse sensing, confirmed by fluorescence and phase analysis light scattering as complementary techniques. The advantages, feasibility and limitations of using resistive pulse sensing for sample analysis are discussed. PMID- 23455054 TI - DNAzyme based gap-LCR detection of single-nucleotide polymorphism. AB - Fast and accurate detection of single-nucleotide polymorphism (SNP) is thought more and more important for understanding of human physiology and elucidating the molecular based diseases. A great deal of effort has been devoted to developing accurate, rapid, and cost-effective technologies for SNP analysis. However most of those methods developed to date incorporate complicated probe labeling and depend on advanced equipment. The DNAzyme based Gap-LCR detection method averts any chemical modification on probes and circumvents those problems by incorporating a short functional DNA sequence into one of LCR primers. Two kinds of exonuclease are utilized in our strategy to digest all the unreacted probes and release the DNAzymes embedded in the LCR product. The DNAzyme applied in our method is a versatile tool to report the result of SNP detection in colorimetric or fluorometric ways for different detection purposes. PMID- 23455055 TI - Vitamin D concentration in newborn cord blood is correlated with maternal intake of supplemental vitamin D, and lower levels are associated with increased risk of the infant developing eczema. PMID- 23455056 TI - Novel oleanolic vinyl boronates: synthesis and antitumor activity. AB - A series of novel oleanane-type pentacyclic triterpenoids bearing a boronate ester moiety at C3 have been synthesized by palladium-catalyzed cross-coupling of bis(pinacolato)diboron with vinyl triflates, in the presence of base, and these compounds were fully characterized by 1D and 2D NMR techniques. Evaluation of their antiproliferative effects on a panel of hematological-based and solid tumor cell lines identified three active oleanolic vinyl boronates that inhibited the growth of leukemia (Jurkat, K562), Burkitt's lymphoma (Jijoye), cervix (Hela), colon (SW480), and ovary (SKOV-3) cancer cells without concomitant inhibition of non-tumoral human fibroblasts. Their mechanisms of action were investigated on the leukemia Jurkat cell line. The results show that the incorporation of boron in the oleanolic acid core combined with the presence of amide bonds afforded compounds with desirable biological effects such as apoptosis induction and inhibition of proteasomal activity on tumor cells, which makes them potential templates for further development in the anticancer drug setting. PMID- 23455058 TI - (4-Phenoxyphenyl)tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). AB - Inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principle enzymes involved in the degradation of endogenous cannabinoids like anandamide and 2-arachidonoylglycerol, have potential utility in the treatment of several disorders including pain, inflammation and anxiety. In the present study, the effectivity and selectivity of eight known FAAH and MAGL inhibitors for inhibition of the appropriate enzyme were measured applying in vitro assays, which work under comparable conditions. Because many of the known FAAH and MAGL inhibitors simply consist of a lipophilic scaffold to which a heterocyclic system is bound, furthermore, different heterocyclic structures were evaluated for their contribution to enzyme inhibition by attaching them to the same lipophilic backbone, namely 4-phenoxybenzene. One of the most active compound synthesized during this investigation was N,N-dimethyl-5-(4 phenoxyphenyl)-2H-tetrazole-2-carboxamide (16) (IC50 FAAH: 0.012 MUM; IC50 MAGL: 0.028 MUM). This inhibitor was systematically modified in the lipophilic 4 phenoxyphenyl region. Structure-activity relationship studies revealed that the inhibitory potency against FAAH and MAGL, respectively, could still be increased by replacement of the phenoxy residue of 16 by 3-chlorophenoxy (45) or pyrrol-1 yl groups (49). Finally, the tetrazolecarboxamide 16 and some related compounds were tested for metabolic stability with rat liver S9 fractions showing that these kind of FAAH/MAGL inhibitors are readily inactivated by cleavage of the bond between the tetrazole ring and its carboxamide substituent. PMID- 23455057 TI - Microwave-assisted synthesis of arene ruthenium(II) complexes that induce S-phase arrest in cancer cells by DNA damage-mediated p53 phosphorylation. AB - A series of arene ruthenium(II) complexes coordinated by phenanthroimidazole derivates, [(C6H6)Ru(L)Cl]Cl.2H2O (1b L = IP, 2b L = p-NMe2PIP, 3b L = p-MeOPIP, 4b L = p-HOPIP, 5b L = p-COOHPIP, 6b L = p-CF3PIP, 7b L = p-BrPIP) have been synthesized in yields of 89-92% under microwave irradiation in 30 min, and the crystal structure of 1b by XRD gives a typical "piano stool" conformation. The antitumor activity of these complexes against various tumor cells have been evaluated by MTT assay, and the results show that this type of arene Ru(II) complexes exhibit acceptable inhibitory effect against all of these tumor cells, especially osteosarcoma MG-63 cells, but with low toxicity toward HK-2 human normal cells. Studies on the mechanism revealed that cell cycle arrest at S-phase in MG-63 cells induced by the arene Ru(II) complex 2b, which was confirmed by the increase in the percentage of cells at S-phase and down-regulator of cyclin A. The further studies by Comet assay at single cell level indicated that DNA damage in MG-63 cells was triggered by 2b, following with the up-regulation of phosphorylated p53 and histone. The studies by spectroscopy in vitro also indicate that 2b bind to DNA molecule by intercalative mode to disturb the bio function of tumor cells. In conclusion, the synthetic arene Ru(II) complexes could serve as novel p53 activator with potential application in cancer chemotherapy. PMID- 23455059 TI - Platinum(II) complexes with mono-aminophosphonate ester targeting group that induce apoptosis through G1 cell-cycle arrest: synthesis, crystal structure and antitumour activity. AB - Six new platinum(II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, (1)H NMR, ESI-MS as well as single crystal X-ray diffraction analysis. They are mononuclear structures. In all the crystal structures of complexes 1-6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702. In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest. PMID- 23455060 TI - Labyrinthitis ossificans in a cochlear implant patient with Usher syndrome. PMID- 23455061 TI - How did morality originate? A review of Christopher Boehm, Moral Origins: The Evolution of Virtue, Altruism, and Shame. PMID- 23455063 TI - We are unique when we cry: A review of Michael Trimble, Why Humans Like to Cry: Tragedy, Evolution, and the Brain. PMID- 23455064 TI - A personality for modern living: A review of Kevin Dutton, The Wisdom of Psychpaths: What Saints, Spies, and Serial Killers Can Teach Us About Success. PMID- 23455065 TI - The Right Person, In the Right Place, At the Right Time: A review of Napoleon A. Chagnon, Noble Savages: My Life Among Two Dangerous Tribes-The Yanomamo and the Anthropologists. PMID- 23455072 TI - Development of a subcritical fluid extraction and GC-MS validation method for polychlorinated biphenyls (PCBs) in marine samples. AB - This paper describes a new procedure for extracting polychlorinated biphenyls (PCBs) from marine samples using subcritical 1,1,1,2-tetrafluoroethane (R134a). The extraction procedure was optimized at temperatures varying from 20 to 70 degrees C and pressures ranging from 3 to 15 MPa. The volume of the co-solvent was then optimized using 1,1,1,2-tetrafluoroethane (R134a) as the subcritical phase. PCBs were characterized by GC-MS using the optimized conditions of 3 MPa, 30 degrees C, and a co-solvent volume of 6 mL. The average yields of PCBs from subcritical fluid extraction of spiked oyster samples were measured and found to be greater than 90%, with relative standard deviations (RSD) of less than 10%. Detection limits of this method were in the range of 0.045-0.108 ng/g of dry mass. The method was compared to Soxhlet extraction and then applied for monitoring PCBs in oysters from Qingdao, Shandong, China. PMID- 23455073 TI - Determination of Raddeanin A in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. AB - A simple, rapid and sensitive LC-MS/MS analysis method was developed and validated for the determination of Raddeanin A (RA) in rat plasma. Protein precipitation with three volumes of methanol as the precipitation reagent was used as the sample preparation method. The analysis process was performed on a Thermo Syncronis C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 2.2) (85:15, v/v). RA and glycyrrhetinic acid (internal standard) were monitored under negative electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of RA and IS were 2.1 min and 3.5 min, respectively. The limit of detection was 5 ng/mL and the linear range was 50 50,000 ng/mL. The intra-day and inter-day precision was 1.87-2.94% and 3.25 5.36%, and the intra-day and inter-day accuracy ranged from 5.9% to 10.5% and 5.6% to 11.1%, respectively. The absolute recovery was above 90.3%. The method has been successfully translated to the pharmacokinetic study of RA in rats after intravenous and intraperitoneal administration (0.75 mg/kg). PMID- 23455076 TI - Risk of hematologic toxicities in cancer patients treated with sunitinib: a systematic review and meta-analysis. AB - BACKGROUND: The incidence and risk of unique toxicities associated with a multi targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We performed an up-to-date meta-analysis of trials to evaluate the risk of sunitinib-related hematologic toxicities. METHODS: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to July 2012 for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs of sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 8,526 patients from 60 trials of sunitinib as a single agent revealed that the incidence of sunitinib-associated all-grade and high-grade (Grades 3 and 4) hematologic toxicities were, respectively: neutropenia: 42.1% and 12.8%; thrombocytopenia: 44.7% and 10.7% and anemia: 50.4% and 6.2%. Sunitinib-treated patients (2667 subjects from 10 randomized trials) had a significantly increased risk of all-grade (RR=3.58; 95% CI, 1.71-7.49) and high-grade (RR=3.32; 95% CI, 1.60-6.90) neutropenia, all-grade (RR=4.59; 95% CI, 2.76-7.63) and high-grade (RR=5.84; 95% CI, 2.22-15.41) thrombocytopenia and all-grade anemia (RR=1.15; 95% CI, 1.00-1.31). CONCLUSIONS: Sunitinib is associated with a significant increase in the risk of developing all-grade and high-grade neutropenia and thrombocytopenia and all-grade anemia compared with control. PMID- 23455075 TI - Neurogenic effects of beta-amyloid in the choroid plexus epithelial cells in Alzheimer's disease. AB - beta-amyloid (Abeta) can promote neurogenesis, both in vitro and in vivo, by inducing neural progenitor cells to differentiate into neurons. The choroid plexus in Alzheimer's disease (AD) is burdened with amyloid deposits and hosts neuronal progenitor cells. However, neurogenesis in this brain tissue is not firmly established. To investigate this issue further, we examined the effect of Abeta on the neuronal differentiation of choroid plexus epithelial cells in several experimental models of AD. Here we show that Abeta regulates neurogenesis in vitro in cultured choroid plexus epithelial cells as well as in vivo in the choroid plexus of APP/Ps1 mice. Treatment with oligomeric Abeta increased proliferation and differentiation of neuronal progenitor cells in cultured choroid plexus epithelial cells, but decreased survival of newly born neurons. These Abeta-induced neurogenic effects were also observed in choroid plexus of APP/PS1 mice, and detected also in autopsy tissue from AD patients. Analysis of signaling pathways revealed that pre-treating the choroid plexus epithelial cells with specific inhibitors of TyrK or MAPK diminished Abeta-induced neuronal proliferation. Taken together, our results support a role of Abeta in proliferation and differentiation in the choroid plexus epithelial cells in Alzheimer's disease. PMID- 23455077 TI - Tumor-infiltrating macrophages, cancer stem cells and therapeutic responses. PMID- 23455078 TI - Blind Poissonian images deconvolution with framelet regularization. AB - We propose a maximum a posteriori blind Poissonian images deconvolution approach with framelet regularization for the image and total variation (TV) regularization for the point spread function. Compared with the TV based methods, our algorithm not only suppresses noise effectively but also recovers edges and detailed information. Moreover, the split Bregman method is exploited to solve the resulting minimization problem. Comparative results on both simulated and real images are reported. PMID- 23455079 TI - Directive radiation from a diffuse Luneburg lens. AB - Transformation electromagnetics has opened possibilities for designing antenna structures. Using an analytical approach, we demonstrate here how directive antenna radiation can be achieved from an omnidirectional source behind a diffuse surface. This diffuse surface has been obtained by an optical transformation of a Luneburg lens. Two different transformation approaches have been proposed (polynomial and sinusoidal), and for both cases, the resulting material properties have been simplified to ease the fabrication by using all-dielectric media. Therefore, the proposed design has no upper boundary to the operational frequency. Directive radiation has been achieved from thin diffuse structures, which demonstrates promising future possibilities for this technique. PMID- 23455074 TI - Macro domains as metabolite sensors on chromatin. AB - How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD(+)-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function. PMID- 23455080 TI - Enhanced light trapping in the silicon substrate with plasmonic Ag nanocones. AB - Ag nanocone enhanced light trapping in the silicon substrate is numerically investigated. For a wide range of the dielectric spacer thickness, the normalized scattering cross section of the rear located particles is higher than that of the front located particles, which is contrary to previous reports. This design not only avoids the conflict with the detrimental Fano effect but is also beneficial to the rear located particles. The fraction of the incident light scattered into silicon is calculated. The path length enhancement is assessed. The Ag nanocone shows highly competitive light-trapping potential. PMID- 23455081 TI - Impact excitation of neon atoms by heated seed electrons in filamentary plasma gratings. AB - We demonstrate impact ionization and dissociative recombination of neon (Ne) atoms by means of seeded-electron heating and subsequent electron-atom collisions in an ultraviolet plasma grating, allowing for a substantial fraction of the neutral Ne atomic population to reside in high-lying excited states. A buffer gas with relatively low ionization potential (nitrogen or argon) was used to provide high-density seed electrons. A three-step excitation model is verified by the fluorescence emission from the impact excitation of Ne atoms. PMID- 23455082 TI - Design of broadband metal nanosphere antenna arrays with a hybrid evolutionary algorithm. AB - This Letter presents a method for the design of metal nanosphere antenna arrays with broadband plasmonic field enhancement over the whole visible spectra. In particular, thanks to a customized hybrid genetic algorithm (HGA), the plasmonic near-field enhancement and the sidelobe level are maximized and minimized, respectively, by thinning the nanoarray, optimizing the elements spacing and dimensions. In particular the problem is recast as an optimization one by defining a suitable cost function, which is then minimized with the HGA. The obtained preliminary results demonstrate the potentialities of the proposed approach. PMID- 23455083 TI - Bidirectional phase-modulated hybrid cable television/radio-over-fiber lightwave transport systems. AB - A bidirectional phase-modulated hybrid cable television/radio-over-fiber lightwave transport system employing fiber Bragg grating tilt filter as a phase modulation-to-intensity modulation conversion scheme is proposed and demonstrated. Impressive performances of carrier-to-noise ratio, composite second order, composite triple-beat, and bit-error rate are obtained in our proposed systems over a combination of 40 km single-mode fiber-and 1.43 km photonic crystal fiber transmission. PMID- 23455084 TI - Effective mode selector for tunable terahertz wire lasers. AB - We demonstrate an effective mode selector design that enables a terahertz quantum cascade wire laser to have a robust single-mode operation at frequencies much lower than the gain peak. This is achieved by selectively guiding the undesired modes into a lossy session while keeping the desired lasing mode largely unperturbed. The large mode discrimination obtained by this mode selector is necessary to further extend the tuning range to the lower half of the gain curve. Additionally, the connectors of this mode selector conveniently provide electrical bias to the wire lasers without degrading the lasing performance. PMID- 23455085 TI - Two-dimensional single-shot measurement of angular dispersion for compressor alignment. AB - Misalignment of the stretcher-compressor stages of chirped pulse amplification (CPA) lasers can aggravate the spatiotemporal shape of ultrashort pulses. We demonstrate a simple technique for angular dispersion measurement, which offers real-time single-shot two-dimensional characterization across the entire beam profile. The accuracy of our pilot experiment approaches its current theoretical limit of 0.1 MUrad/nm. Unlike the current one-dimensional techniques working in the near field, the method works in the far field; hence, it is especially appropriate for assisting the most accurate alignment of a CPA laser compressor ensuring the maximum intensity on the target. PMID- 23455086 TI - Nonlinear hyperlens. AB - The performance of an optical hyperlens made of metal-dielectric layers can be improved by incorporating self-focusing nonlinearity in the dielectric layers. Using a modified beam propagation method in cylindrical coordinates, we show increased bandwidth and better propagation length, which can improve the spatial and temporal resolution of the device. PMID- 23455087 TI - Measurement of Raman spectra of single airborne absorbing particles trapped by a single laser beam. AB - We demonstrate a method for optical trapping and Raman spectroscopy of micron sized, airborne absorbing particles using a single focused laser beam. A single Gaussian beam at 532 nm is used to trap and precisely manipulate absorbing airborne particles. The fluctuation of the position of the trapped particles is substantially reduced by controlling the power of the laser beam with a position sensitive detector and a locking circuit. Raman spectra of the position stabilized particles or clusters are then measured with an objective and CCD spectrograph. PMID- 23455088 TI - Pulse lead/lag timing detection for adaptive feedback and control based on optical spike-timing-dependent plasticity. AB - Biological neurons perform information processing using a model called pulse processing, which is both computationally efficient and scalable, adopting the best features of both analog and digital computing. Implementing pulse processing with photonics can result in bandwidths that are billions of times faster than biological neurons and substantially faster than electronics. Neurons have the ability to learn and adapt their processing based on experience through a change in the strength of synaptic connections in response to spiking activity. This mechanism is called spike-timing-dependent plasticity (STDP). Functionally, STDP constitutes a mechanism in which strengths of connections between neurons are based on the timing and order between presynaptic spikes and postsynaptic spikes, essentially forming a pulse lead/lag timing detector that is useful in feedback control and adaptation. Here we report for the first time the demonstration of optical STDP that is useful in pulse lead/lag timing detection and apply it to automatic gain control of a photonic pulse processor. PMID- 23455089 TI - Modeling the population lens effect in thermal lens spectrometry. AB - We report a theoretical model and experimental results for laser-induced lensing in solids. The model distinguishes and quantifies the contributions from population and thermal effects. Laser-induced lensing in ytterbium-doped fluorozirconate glass ZBLAN:Yb(3+) is measured, and the thermal and optical properties obtained from analyzing the data with the proposed model agree well with published values. Photothermal techniques are used extensively for the investigation of laser and laser-cooling materials, and the model developed here enables the interpretation of convoluted laser-induced lensing signals that have contributions from different sources. PMID- 23455090 TI - Metal-dielectric bi-atomic structure for angular-tolerant spectral filtering. AB - We theoretically study metal-dielectric structures made of bi-atomic metallic gratings coupled to a guided-mode dielectric resonator. The bi-atomic pattern grating allows tailoring of the Fourier spectrum of the inverse grating permittivity in order to adapt the frequency gap and obtain a flat dispersion band over a wide angular range. A significant enhancement (two-fold) of the angular tolerance as compared to a simply periodic structure is obtained. PMID- 23455091 TI - Self-similar parabolic plasmonic beams. AB - We demonstrate that an interplay between diffraction and defocusing nonlinearity can support stable self-similar plasmonic waves with a parabolic profile. Simplicity of a parabolic shape combined with the corresponding parabolic spatial phase distribution creates opportunities for controllable manipulation of plasmons through a combined action of diffraction and nonlinearity. PMID- 23455092 TI - Three-dimensional intracellular optical coherence phase imaging. AB - Quantitative phase imaging has many applications for label-free studies of the nanoscale structure and dynamics of cells and tissues. It has been demonstrated that optical coherence phase microscopy (OCPM) can provide quantitative phase information with very high sensitivity. The excellent phase stability of OCPM is obtained by use of a reflection from the microscope cover glass as a local reference field. For detailed intracellular studies a large numerical aperture (N.A.) objective is needed in order to obtain the required resolution. Unfortunately, this also means that the depth of field becomes too small to obtain sufficient power from the cover glass when the beam is focused into the sample. To address this issue, we designed a setup with a dual-beam sample arm. One beam with a large diameter (filling the 1.2 N.A. water immersion objective) enabled high-resolution imaging. A second beam with a small diameter (underfilling the same objective) had a larger depth of field and could detect the cover glass used as a local phase reference. The phase stability of the setup was quantified by monitoring the front and back of a cover glass. The standard deviation of the phase difference was 0.021 rad, corresponding to an optical path displacement of 0.9 nm. The lateral and axial dimensions of the confocal point spread function were 0.42 and 0.84 MUm, respectively. This makes our dual-beam setup ideal for three-dimensional intracellular phase imaging. PMID- 23455093 TI - Miniature fiber-tip photoacoustic spectrometer for trace gas detection. AB - We demonstrate a fiber-tip photoacoustic spectrometric sensor for trace gas detection. The sensor head is a miniature fiber-tip hollow-cavity with a deflectable polymer diaphragm. Periodic light absorption of gas molecules within the cavity generates an acoustic pressure wave, which causes deflection of the diaphragm. The hollow cavity also is a Fabry-Perot interferometer with which the diaphragm deflection is detected with high sensitivity. Experimental test around the P(9) absorption line of C(2)H(2) achieved a minimum detectable gas concentration of 4.3 ppm with an excitation laser power of 8 mW. The miniature sensor head and fiber optic detection system make this type of spectrometers ideally suited for remote and space-limited applications as well as for multipoint detection in a multiplexed fiber optic sensor network. PMID- 23455094 TI - Exploiting breakdown of the similarity relation for diffuse light transport: simultaneous retrieval of scattering anisotropy and diffusion constant. AB - As manifested in the similarity relation of diffuse light transport, it is difficult to assess single scattering characteristics from multiply scattered light. We take advantage of the limited validity of the diffusion approximation of light transport and demonstrate, experimentally and numerically, that even deep into the multiple scattering regime, time-resolved detection of transmitted light allows simultaneous assessment of both single scattering anisotropy and scattering mean free path, and therefore also macroscopic parameters like the diffusion constant and the transport mean free path. This is achieved via careful assessment of early light and matching against Monte Carlo simulations of radiative transfer. PMID- 23455095 TI - Dispersion management in two-photon microscopy by using diffractive optical elements. AB - We demonstrate efficient generation of wide-field fluorescence signals in two photon microscopy exploiting diffractive optical elements and short pulses by using a dispersion-compensated beam delivery optics module. Computer-generated holograms are codified onto a phase-only spatial light modulator, which allows for arbitrary single-shot patterning of the sample. Spatiotemporal shaping of the pulse is mandatory to overcome spatial chirp and pulse-front tilt effects that spread both in space and time the irradiance patterns, thus limiting not only the spatial resolution but also the signal-to-noise ratio in two-photon microscopy. By using a multipass amplifier delivering 30 fs, 0.8 mJ pulses at 1 kHz repetition rate, we experimentally demonstrated arbitrary single-shot fluorescence irradiance patterns in Rhodamine B. PMID- 23455096 TI - Octave-spanning spectrum generation in tapered silica photonic crystal fiber by Yb:fiber ring laser above 500 MHz. AB - We report octave-spanning spectrum generated in a tapered silica photonic crystal fiber by a mode-locked Yb:fiber ring laser at a repetition rate as high as 528 MHz. The output pulses from this laser were compressed to 62 fs. By controlling the hole expansion and core diameter, a silica PCF was tapered to 20 cm with an optimal d/Lambda ratio of 0.6. Pulses with the energy of 280 pJ and the peak power of 4.5 kW were injected into the tapered fiber and the pulse spectrum was expanded from 500 to 1600 nm at the level of -30 dB. PMID- 23455097 TI - Digital broadband linearization of optical links. AB - We present a digital postprocessing linearization technique to efficiently suppress dynamic distortions added to a wideband signal in an analog optical link. Our technique achieves up to 35 dB suppression of intermodulation distortions over multiple octaves of signal bandwidth. In contrast to conventional linearization methods, it does not require excessive analog bandwidth for performing digital correction. This is made possible by regenerating undesired distortions from the captured output, and subtracting it from the distorted digitized signal. Moreover, we experimentally demonstrate a record spurious-free dynamic range of 120 dB.Hz(2/3) over a 6 GHz electrical signal bandwidth. While our digital broadband linearization technique advances state-of-the-art optical links, it can also be applied to other nonlinear dynamic systems. PMID- 23455098 TI - Direction-independent fiber inclinometer based on simplified hollow core photonic crystal fiber. AB - A fiber optical inclinometer based on modal interferometer is demonstrated for bend angle sensing. The device consists of a piece of simplified hollow core photonic crystal fiber sandwiched between single mode fibers with lateral offset. The measurement of bend angles up to 45 degrees is demonstrated, and the spectrum exhibits a blueshift of over 50 nm. The sensitivity is found to increase with the applied bend angles and reaches 2.4 nm/deg at 45 degrees , and the response is independent of the direction of bending. A low temperature sensitivity of 0.5 pm/ degrees C is observed between room temperature and 1000 degrees C. Due to its capacity for withstanding high temperature, the device can work as a direction-independent inclinometer in high-temperature environments. PMID- 23455099 TI - ITO electrode-embedded double-cladding single-crystal LiNbO3 optical fiber. AB - In this Letter, we demonstrate a way to make single-crystal LiNbO(3) optical fibers with silica glass cladding and In(2)O(3)-SnO (ITO) electrodes embedded between core and cladding with a one-step drawing process with the CO(2) laser heated pedestal growth technique. A half-wave voltage (Vpi) of 6.6 V, effective electro-optic coefficient of 23.6 pm/V, and transmission loss of 0.89 dB/cm was achieved in the single-crystal LiNbO(3) optical fiber with core diameter of 9 MUm and electrode distance of 50 MUm. Furthermore, the technique can be applicable to make other single-crystal core optical fibers with ITO-embedded electrodes, which could potentially enable many electrically tunable fiber devices along with the unique property of the single-crystal core. PMID- 23455100 TI - Red and orange Pr3+:LiYF4 planar waveguide laser. AB - In this Letter we report on room temperature continuous wave laser operation in the red (639 nm, (3)P(0)->(3)F(2)) and orange (604 nm, (3)P(0)->(3)H(6)) spectral regions of Pr(3+)-doped LiYF(4) planar waveguides fabricated by liquid phase epitaxy. Output powers of 25 and 12 mW and slope efficiencies of 5% and 6% were achieved at 639 and 604 nm, respectively, by pumping with an optically pumped semiconductor laser operating at 479.2 nm. PMID- 23455102 TI - Polarization beam splitting using a birefringent graded photonic crystal. AB - The use of a birefringent graded photonic crystal (GPhC) is proposed for the realization of an efficient polarization beam splitter. This approach allows decoupling the two functions of efficient light injection for both polarizations and TE/TM beam splitting. A smooth light polarization splitting is naturally achieved due to the different curved trajectories followed within the graded medium by the TE and TM waves. A 160 nm operating bandwidth with insertion loss around 1 dB and interpolarization crosstalk below -15 dB is predicted by a finite difference time domain simulation. The unusually exploited electromagnetic phenomena are experimentally evidenced by scanning near-field optical measurements performed on samples fabricated using the silicon on insulator photonics technology. These experimental works open perspectives for the use of birefringent GPhCs to manage polarization diversity in silicon photonic circuits. PMID- 23455103 TI - Birefringent reflectarray metasurface for beam engineering in infrared. AB - An infrared reflectarray metasurface with engineered birefringent behavior is demonstrated. The array reradiates incoming light into two orthogonal, linearly polarized reflections. The reflectarray is composed of rectangular metallic patch nanoantennas placed on top of a grounded dielectric stand-off layer. The patches are designed to locally manipulate the phase front of the incoming wave. They tailor the reflection phase to transform the phase front on the surface to the one desired for both orthogonal polarizations at the same time. The proposed nanoantenna metasurface can find applications in many optical devices, such as birefringent modulators, waveplates, polarizers, and splitters. PMID- 23455104 TI - Potential for simultaneous strain and temperature sensing based on Brillouin scattering in an all-solid photonic bandgap fiber. AB - We identify the Brillouin scattering spectrum in both the core and the cladding of an all-solid photonic bandgap fiber for the first time to our knowledge. A multipeak Brillouin spectrum with several frequency shifts and particular linewidths is investigated and related to the structural properties accordingly. Because of the different frequency dependences on the surroundings in the core and the cladding, the proposed structure exhibits potential for use as simultaneous temperature and strain sensors. PMID- 23455105 TI - Mode-resolved photon counting via cascaded quantum frequency conversion. AB - Resources for the manipulation and measurement of high-dimensional photonic signals are crucial for implementing qudit-based applications. Here we propose potentially high-performance, chip-compatible devices for such purposes by exploiting quantum frequency conversion in nonlinear optical media. Specifically, by using sum-frequency generation in a chi(2) waveguide, we show how mode resolved photon counting can be accomplished for telecom-band photonic signals subtending multiple temporal modes. Our method is generally applicable to any nonlinear medium with arbitrary dispersion properties. PMID- 23455106 TI - High-performance hybrid Raman/fiber Bragg grating fiber-optic sensor based on simplex cyclic pulse coding. AB - We propose and experimentally demonstrate the use of cyclic pulse coding to improve the performance of hybrid Raman/fiber Bragg grating (FBG) fiber-optic sensors, for simultaneous measurement of distributed static temperature and discrete dynamic strain over the same sensing fiber. Effective noise reduction is achieved in both Raman optical time-domain reflectometry and dynamic interrogation of time-division-multiplexed fiber FBG sensors, enhancing the sensing range resolution and providing real-time point dynamic strain measurement capabilities. The highly integrated sensor scheme employs broadband apodized low reflectivity FBGs, a single narrowband optical source, and a shared receiver block. PMID- 23455107 TI - Distorted Dammann grating. AB - We introduce the Dammann phase-encoding method into original distorted gratings and propose a modified distorted grating, called a distorted Dammann grating (DDG), to realize multiplane imaging of several tens of layers within the object field onto a single image plane. This property implies that the DDG makes it possible to achieve simultaneously high axial resolving power and large axial imaging range without scanning. This DDG should be of high interest for its potential applications in real-time three-dimensional optical imaging and tracking. Multiplane imaging of 7*7 object layers onto a single camera plane is experimentally demonstrated using a 7*7 DDG for an objective of NA=0.127. PMID- 23455108 TI - Phase-coded volume holographic gratings for spatial-spectral imaging filters. AB - We present a design of phase-contrast filters embedded in a three-dimensional pupil to form phase-coded volume holographic gratings (VHGs) for spatial-spectral imaging. The phase-coded VHG improves image contrast and results in strong filtering properties to acquire weak phase structures of an object. In addition, incorporated with in-plane angle multiplexing, the multiplexed phase-coded VHGs enable obtaining weak phase information from multiple depths of an object. We experimentally demonstrate the multiplexed phase-coded VHGs for spatial-spectral imaging to enhance unstained features of spatial-spectral images of human breast cancer cells. PMID- 23455109 TI - Solitons supported by localized parametric gain. AB - We address the existence and properties of one-dimensional solitons maintained by localized parametric gain in focusing and defocusing lossy nonlinear media. Localized parametric gain supports both fundamental and multipole solitons. We found that the family of fundamental solitons is partly stable in focusing nonlinear medium, and completely stable in defocusing medium, while all higher order solitons are unstable. In addition to numerical results, the existence threshold for the solitons and a particular stable exact solution are obtained in an exact analytical form. PMID- 23455110 TI - Dynamically tunable plasmonically induced transparency by planar hybrid metamaterial. AB - We design and numerically analyze a dynamically tunable, plasmonically induced transparency (PIT) planar hybrid metamaterial (MM) in a near-infrared regime, which combines the near-field coupling effect into dynamic MM. The embedded position of tunable material in dynamic MM is optimized. Thermal-tunable VO(2) stripes are filled in the cut-out slots as components of a plasmonic system, which dramatically improve the dynamic modulation depth of the PIT. We also present a four-level plasmonic system to quantitatively analyze the dynamically tunable PIT device. This work may offer a further step in the design of the tunable PIT effect. PMID- 23455111 TI - Generation of tunable sub-45 femtosecond pulses by noncollinear four-wave mixing. AB - Generation of sub-45 fs vacuum UV (VUV) pulses tunable across the spectral range of 146-151 nm at 1 kHz repetition rate is reported. The pulses are produced using noncollinear difference-frequency four-wave mixing between the third-harmonic of an amplified Ti:sapphire laser and the signal wavelength of an infrared optical parametric amplifier (omega(VUV)=2omega(TH)-omega(IR)) in krypton and argon. The generated VUV pulses have energies as high as 90 nJ. Pulse duration measurements are realized by cross correlation between the VUV pulses and the laser fundamental wavelength using pump-probe ionization in xenon. PMID- 23455112 TI - Optimization of two-photon wave function in parametric down conversion by adaptive optics control of the pump radiation. AB - We present an efficient method for optimizing the spatial profile of entangled photon wave function produced in a spontaneous parametric down conversion process. A deformable mirror that modifies a wavefront of a 404 nm CW diode laser pump interacting with a nonlinear beta-barium borate type-I crystal effectively controls the profile of the joint biphoton function. The use of a feedback signal extracted from the biphoton coincidence rate is used to achieve the optimal wavefront shape. The optimization of the two-photon coupling into two, single spatial modes for correlated detection is used for a practical demonstration of this physical principle. PMID- 23455113 TI - Broadband infrared light-emitting patterns in optical glass by laser-induced nanostructuring of NiO-doped alkali-gallium germanosilicates. AB - In this Letter, we show functionalization of NiO-doped 7.5Li(2)O.2.5Na(2)O.20Ga(2)O(3).35SiO(2).35GeO(2) glass by space-selective nanocrystallization via exposure to the focused beam of a pulsed copper vapor laser (510.6 and 578.2 nm) at temperature close to the glass transition point (570 degrees C). Irradiated areas drastically change their color, caused by electronic transitions of Ni(2+) dopant ions, without any alteration of the optical quality. Importantly, irradiated regions acquire broadband infrared luminescence (centered at about 1400 nm and possessing 400 nm effective bandwidth) typical of Ni(2+) ions in crystalline environment, and by positive change of refractive index (more than 10(-3)). Spectroscopic and diffractometric data of the irradiated regions indeed resemble those previously observed in thermally nanocrystallized glass, with Ni(2+) ions embedded in gamma-Ga(2)O(3) nanocrystals. The results demonstrate the possibility of laser writing nanocrystallized multifunction patterns in germanosilicate glasses for the fabrication of active integrated devices. PMID- 23455114 TI - Near-infrared properties of Rh-doped Bi12TiO20 crystals for photonic applications. AB - The effect of Rh doping in Bi(12)TiO(20) (BTO) crystals on the photosensitivity and recording speed at 1064 nm is reported. Response time of 0.1 s is measured during real-time holographic recording without any preliminary treatments. Once the crystal is pre-excited with a green light, the detected response time becomes 0.02 s. A possibility to implement BTO:Rh crystal plate with liquid crystals into a hybrid organic/inorganic device is demonstrated, which opens perspectives for further near-infrared applications. PMID- 23455115 TI - Observation of self-accelerating Bessel-like optical beams along arbitrary trajectories. AB - We experimentally demonstrate self-accelerating Bessel-like optical beams propagating along arbitrary trajectories in free space. With computer-generated holography, such beams are designed to follow different controllable trajectories while their main lobe transverse profiles remain nearly invariant and symmetric. Examples include parabolic, snake-like, hyperbolic, hyperbolic secant, and even three-dimensional spiraling trajectories. The self-healing property of such beams is also demonstrated. This new class of optical beams can be considered as a hybrid between accelerating and nonaccelerating nondiffracting beams that may find a variety of applications. PMID- 23455116 TI - Low noise single-frequency single-polarization ytterbium-doped phosphate fiber laser at 1083 nm. AB - We present a low noise single-frequency and single-polarization distributed Bragg reflector fiber laser at 1083 nm by using a 1.8 cm long newly developed ytterbium doped phosphate single mode glass fiber. The maximum output power is more than 100 mW with a slope efficiency of >29.6%. The signal to noise ratio is higher than 61 dB and the laser linewidth of less than 2 kHz is estimated. The obtained relative intensity noise for frequencies of over 4.0 MHz is less than -150 dB/Hz, which approaches the shot noise limit. The achieved linear polarization extinction ratio is more than 30 dB. PMID- 23455117 TI - In-band pumped Ho3+:KY3F10 2 MUm laser. AB - We report the first observation to our knowledge of room-temperature continuous wave laser operation on the (5)I(7)->(5)I(8) transition of Ho(3+) ions in a KY(3)F(10) single crystal. Using a Tm-doped silica fiber laser operating at 1938 nm as a pump source, a maximum laser power of 1.8 W was obtained at a wavelength of ~2040 nm for 27 W of absorbed pump power with a slope efficiency of 19.1% with respect to absorbed power. At low cavity output coupling, the lasing wavelength shifted to 2060.5 nm. The beam propagation factor (M(2)) was measured to be <1.06 at the maximum output power, confirming fundamental transverse-mode (TEM(00)) operation. Performing a Caird analysis, we determined resonator round-trip losses and intrinsic slope efficiency of 30% and 43.8%, respectively. PMID- 23455118 TI - Infrared microcalorimetric spectroscopy using quantum cascade lasers. AB - We have investigated an IR microcalorimetric spectroscopy technique that can be used to detect the presence of trace amounts of target molecules. The chemical detection is accomplished by obtaining the IR photothermal spectra of molecules adsorbed on the surface of uncooled thermal micromechanical detectors. Although we use a chemical layer to absorb target molecules, IR microcalorimetric spectroscopy requires no chemical specific coatings. The chemical specificity of the presented method is a consequence of the wavelength-specific absorption of IR photons from tunable quantum cascade lasers due to vibrational spectral bands of the analyte. We have obtained IR photothermal spectra for trace concentrations of 1,3,5-Trinitroperhydro-1,3,5-triazine and a monolayer of 2-Sulfanylethan-1-ol (2 mercaptoethanol) over the wavelength region from 6 to 10 MUm. We found that both chemicals exhibit a number of photothermal absorption features that are in good agreement with their respective IR spectra. PMID- 23455119 TI - High-power thermally guiding index-antiguiding-core fibers. AB - We investigate high-power operation of a very-large-mode-area (VLMA) fiber concept based on an index-antiguiding, thermally guiding core in which an ytterbium-doped region is completely surrounded by silica with a slightly higher refractive index. Experimentally, regimes of antiguidance, single-mode operation, and mode instabilities predominantly with radially symmetric higher-order modes are observed. Fundamental limitations for conventional VLMA step-index fibers are discussed. PMID- 23455120 TI - Broadband plasmonic half-wave plates in reflection. AB - We demonstrate, both numerically and experimentally, that metal-insulator-metal configurations in which the top metal layer consists of a periodic arrangement of nanobricks, thus supporting gap-surface plasmon resonances, can be designed to function as reflective broadband half-wave plates. Using gold as the metal, the constructed wave plates in the near-infrared regime show scalability, bandwidth of ~20% of the design wavelength, and theoretical reflectivity above 85%, while a reflectivity of ~50% is experimentally measured. PMID- 23455121 TI - Broadband infrared luminescence in gamma-ray irradiated bismuth borosilicate glasses. AB - The influence of gamma-ray irradiation on the optical properties of Bi(2)O(3) B(2)O(3)-SiO(2) glass has been investigated. Broadband infrared (IR) emission at 1310 nm with a FWHM over 200 nm is observed in the gamma-ray irradiated glass. The IR luminescence depends on the gamma-ray irradiation dose and the concentration of Bi(2)O(3). The thermal stability of the gamma-ray irradiated IR luminescence center is studied, and the origin of the IR luminescence center has been suggested. PMID- 23455122 TI - Efficient high-energy passively Q-switched Nd:YLF/Cr4+:YAG UV laser at 351 nm with pulsed pumping in a nearly hemispherical cavity. AB - We originally utilize a nearly hemispherical cavity to accomplish the energy scale-up for a high-repetition-rate nanosecond pulsed pumped Nd:YLF laser passively Q-switched by the Cr(4+):YAG saturable absorber. This compact laser is able to efficiently generate pulse energy as large as 1.38 mJ and pulse width as short as 5 ns under a pulse repetition rate of 100 Hz. Further employing the developed Nd:YLF laser to perform extracavity harmonic generations, the maximum pulse energies of 490 MUJ at 527 nm and 360 MUJ at 351 nm are achieved with the shortest pulse duration of 4 ns. PMID- 23455123 TI - Self-stabilized quantum optical Fredkin gate. AB - The quantum optical Fredkin gate is an indispensable resource for networkable quantum applications. Its performance in practical implementations, however, is limited fundamentally by the inherent quantum fluctuations of the pump waves. We demonstrate a method to overcome this drawback by exploiting stimulated Raman scattering in fiber-based implementations. Using a Sagnac fiber-loop switch as a specific example, we show that high switching contrast can be maintained even in the presence of significant pump fluctuations. This unique feature of self stabilization, together with high-speed and low-loss performance of such devices, point to a viable technology for practical quantum communications. PMID- 23455124 TI - Chaotic dynamics of frequency combs generated with continuously pumped nonlinear microresonators. AB - We theoretically and experimentally investigate the chaotic regime of optical frequency combs generated in nonlinear ring microresonators pumped with continuous wave light. We show that the chaotic regime reveals itself by a flat top symmetric envelope of the frequency spectrum, when observed by means of an optical spectrum analyzer. The comb, demodulated on a fast photodiode, produces a noisy radio frequency signal with spectral width significantly exceeding the linear bandwidth of the microresonator mode. We discuss practical ways of excitation of a coherent frequency comb and avoiding the chaotic regime. PMID- 23455125 TI - Nondestructive scheme for measuring the attenuation coefficient of polymer optical fiber. AB - Based on the fiber macrobending and the refractive index matching technologies, a measurement scheme is proposed to gauge the attenuation coefficient of polymer optical fibers in this Letter. It is noteworthy that, by realizing both the light injecting into and the light extracting out the fiber core via the fiber cladding, this scheme will not induce any destruction during the whole measurement. Some related experiments and the theoretical verifications are given together with the nondestructive measurement principle. The comparison between the experimental results of this scheme and that of the cut-back scheme indicates a good feasibility of our scheme. As a result, it is promised to have a potential application for achieving the on-line attenuation monitoring that has never been introduced. PMID- 23455126 TI - Polarization-maintaining fiber-optic-grating vector vibroscope. AB - A fiber-optic vector vibroscope based on orthogonal polarization cladding-to-core recoupling is demonstrated. A compact structure in which a short section of polarization-maintained (PM) fiber stub containing a straight fiber Bragg grating (FBG) is spliced to another single-mode fiber. Two well-defined orthogonally polarized cladding modes reflected by the PM-FBG are recoupled at the junction and the coupling intensity shows an extremely high sensitivity to bending in the corresponding orthogonal directions. Both the orientation and amplitude of the vibrations can be determined unambiguously via dual-path power detection of these recoupled orthogonal-polarimetric cladding modes (LP(1,12) and LP(1,13)). Since spectral information is not required, temperature changes do not affect the sensor response, and power fluctuations can be referenced out by monitoring the power in the core mode (LP(0,1)) resonance. PMID- 23455127 TI - Generation of the "perfect" optical vortex using a liquid-crystal spatial light modulator. AB - We introduce the concept of the perfect optical vortex whose dark hollow radius does not depend on the topological charge. It is shown analytically and experimentally that such a vortex can be approximately generated in the Fourier transforming optical system with a computer-controlled liquid-crystal spatial light modulator. PMID- 23455128 TI - Filamentation of arbitrary polarized femtosecond laser pulses in case of high order Kerr effect. AB - We developed a model of femtosecond filamentation which includes high-order Kerr effect and an arbitrary polarization of a laser pulse. We show that a circularly polarized pulse has maximum filament intensity. Also, we show that, independently of the initial pulse polarization, the value of a maximum filament intensity tends to the maximum intensity of either linearly or circularly polarized pulse. PMID- 23455129 TI - Genetic method to optimize binary dithering technique for high-quality fringe generation. AB - The recently proposed dithering techniques could substantially improve measurement quality when fringes are wide, but offer limited improvement when fringes are narrow. This Letter presents a genetic algorithm to optimize the dithering technique for sinusoidal structured pattern representation. We believe both simulation and experimental results show that this proposed algorithm can substantially improve fringe quality for both narrow and wide fringe patterns. PMID- 23455130 TI - Brillouin lasing in integrated liquid-core optical fibers. AB - We report Brillouin lasing in an integrated liquid-core optical fiber filled with neat CS2. This is the first observation of Brillouin lasing in an optical fiber filled with a liquid, to the best of our knowledge. The linewidth of the single frequency liquid-based Brillouin laser was estimated to be <1 kHz by beating two similar but independent lasers against one another. PMID- 23455131 TI - Object authentication in computational ghost imaging with the realizations less than 5% of Nyquist limit. AB - Ghost imaging has attracted much attention, in which the object can be reconstructed by using the correlation of intensity fluctuations. It is well known that a large number of realizations (such as 5000 or even 20,000) are usually required for object reconstructions in ghost imaging. In this Letter, we demonstrate, for the first time to our knowledge, how the reconstructed object can be authenticated using the significantly small number of realizations (i.e., less than 5% of Nyquist limit) in computational ghost imaging. The main objective for our study is to authenticate the object reconstructed by using the small number of realizations rather than to directly extract the high-fidelity object. PMID- 23455132 TI - Spontaneous inelastic Rayleigh scattering in optical fibers. AB - Rayleigh scattering (RS) adds noise to signals that are transmitted over optical fibers and other optical waveguides. This noise can be the dominant noise source in a range between 10 Hz and 100 kHz from the carrier and can seriously degrade the performance of optical systems that require low close-in noise. Using heterodyne techniques, we demonstrate that the backscattered close-in noise spectrum in optical fibers is symmetric about the carrier and grows linearly with both input power and fiber length. These results indicate that the RS is spontaneous and is due to finite-lifetime thermal fluctuations in the glass. PMID- 23455133 TI - Flattened comb generation using only phase modulators driven by fundamental frequency sinusoidal sources with small frequency offset. AB - We propose and experimentally demonstrate a simple scheme to generate flattened optical subcarriers at low insertion loss using only phase modulators driven by fundamental frequency sinusoidal sources. A small frequency offset is introduced in the second stage to obtain phase-insensitive, stable, and flattened subcarriers. Theoretical and numerical analysis with experimental results are carried out on this scheme. Twenty-one stable comb tones with 25 GHz frequency spacing are obtained with power difference less than 3 dB. The good bit-error ratio performance of 160.8 Gb/s polarization-division-multiplexing quadrature phase-shift-keying signal carried by one selected subcarrier clearly demonstrates the feasibility of this comb generation scheme. PMID- 23455134 TI - Robust interferometric frequency lock between cw lasers and optical frequency combs. AB - A transfer interferometer is presented which establishes a versatile and robust optical frequency locking link between a tunable single frequency laser and an optical frequency comb. It enables agile and continuous tuning of the frequency difference between both lasers while fluctuations and drift effects of the transfer interferometer itself are widely eliminated via common mode rejection. Experimental results will be presented for a tunable extended-cavity 1.5 MUm laser diode locked to an Er-fiber based frequency comb. PMID- 23455135 TI - Gain-assisted trapping of light in tapered plasmonic waveguide. AB - We have investigated the slow light and trapping effects in tapered metal insulator-metal plasmonic waveguides. It is found that a significant reduction of group velocity (<0.01c) can be obtained when considering the intrinsic loss of realistic metal. The theoretical analysis shows that the group velocity can be further decreased, even approach zero in the lossless metallic waveguides. The perfect trapping of light is realized when an appropriate gain material is incorporated in the core layer to compensate metallic loss. The proposed ultracompact configuration may find excellent applications on nanoscale optical storages. PMID- 23455136 TI - Passive mode-locking of fiber ring laser at the 337th harmonic using gigahertz acoustic core resonances. AB - We report the experimental demonstration of a passively mode-locked Er-doped fiber ring laser operating at the 337th harmonic (1.80 GHz) of the cavity. The laser makes use of highly efficient Raman-like optoacoustic interactions between the guided light and gigahertz acoustic resonances trapped in the micron-sized solid glass core of a photonic crystal fiber. At sufficient pump power levels the laser output locks to a repetition rate corresponding to the acoustic frequency. A stable optical pulse train with a side-mode suppression ratio higher than 45 dB was obtained at low pump powers (~60 mW). PMID- 23455137 TI - Complex source point theory of paraxial and nonparaxial cosine-Gauss and Bessel Gauss beams. AB - It shown how cosine-Gauss and Bessel-Gauss beams can be generated using the complex source point theory. Paraxial beams are treated first. An analytic expression is derived for the nonparaxial cosine-Gaussian beam, based on the complex source point approach, and numerical results are presented to illustrate its behavior. A way to generate nonparaxial Bessel-Gauss beams is also indicated. PMID- 23455138 TI - Tunable silicon Fabry-Perot comb filters formed by Sagnac loop mirrors. AB - We experimentally demonstrate tunable silicon comb filters based on Fabry-Perot (FP) resonators composed of two Sagnac loop mirrors. The comb filter resolves up to 54 comb lines with a 115 GHz channel spacing over a spectral range from 1510 to 1560 nm. The comb line extinction ratio is ~26.3 dB and the quality factor is ~57,000 around 1550 nm wavelength. Electrical tuning is enabled via periodically interleaved PN junctions embedded inside the FP resonator. The comb lines are blue shifted by ~0.92 nm (one channel spacing) with a 5 mA forward-bias current and red-shifted by ~0.05 nm with a -10 V reverse-bias voltage. PMID- 23455139 TI - Interference-induced peak splitting in extreme ultraviolet superfluorescence. AB - We investigate the laser-induced quantum interference in extreme ultraviolet superfluorescence (SF) occurring in a dense gas of Lambda-type helium atoms coupled by a coherent laser field in the visible region. Due to the constructive interatomic and intraatomic interferences, the SF can split in two pulses conveniently controlled by the gas density and intensity of the driving field, suggesting potential applications for pump-probe experiments. PMID- 23455140 TI - Role of surface plasmon polaritons and photonic modes in light absorption by thin film solar cells patterned with metallic nanogratings. AB - Light absorption by thin-film amorphous Si solar cells patterned with metallic nanogratings is investigated theoretically. Propagative bounded modes that include the surface plasmon polariton (SPP) and the photonic mode (PM) are extracted from the total field to quantitatively evaluate their contribution to the light absorption. Our results show that after removing the propagative bounded modes from the total field, the residual field still contributes to a major part of the total light absorption. This proves, at a quantitative level, that the light absorption of the structure is largely attributed to the residual field that is composed of unbounded or evanescent modes arising from the grating scattering, and the SPP and the PM do not play a dominant role, which is out of the previous intuitive expectations. PMID- 23455141 TI - Nanosecond nonlinear Cerenkov conical beams generation by intracavity sum frequency mixing in KTiOAsO4 crystal. AB - Nanosecond Cerenkov-type conical beam at 628 nm is obtained by intracavity sum frequency mixing (SFM) of 1064 and 1534 nm in KTiOAsO(4) (KTA) crystal. The 1534 nm signal generated by the KTA optical parametric oscillation (OPO), respectively, interacts with the orthogonally polarized 1064 nm radiations by the nonlinear Cerenkov SFM, emitting two red rings with cone angles of 11.4 degrees and 16.0 degrees , respectively. Multidomain structure observed in the KTA crystal can account for the corresponding phenomenon. The KTA crystal simultaneously serves as OPO medium and Cerenkov radiation emitter in this experiment, indicating that it is a promising multifunctional nonlinear crystal material. Furthermore, the naturally grown crystal combined with intracavity Cerenkov-type configuration will provide a simple and compact approach, opening a door for the wide application of nonlinear Cerenkov radiation sources due to its cost-effectiveness. PMID- 23455142 TI - High-speed microwave photonic switch for millimeter-wave ultra-wideband signal generation. AB - We propose a scheme for generating millimeter-wave (MMW) ultra-wideband (UWB) signal that is free from low-frequency components and a residual local oscillator. The system consists of two cascaded polarization modulators and is equivalent to a high-speed microwave photonic switch, which truncates a sinusoidal MMW into short pulses. The polarity switchability of the generated MMW UWB pulse is also demonstrated. PMID- 23455143 TI - Erbium-doped multi-element fiber amplifiers for space-division multiplexing operations. AB - Erbium-doped multi-element fiber (MEF) amplifiers have been fabricated to simultaneously amplify multiple transmission channels. MEF devices comprise of multiple single-core fibers (elements) combined in a common coating, with each element working as a single fiber in isolation. MEFs containing 3-elements and 7 elements have been fabricated and characterized. Each element of the fabricated MEFs provides nearly 32 dB of gain with a noise figure of <5 dB for an input signal level of -23 dBm at 1530 nm. Different permutations of element pairs within the MEFs were checked for crosstalk and none was detected, confirming the simultaneous multi-channel amplification capabilities of MEFs. PMID- 23455144 TI - Rotating point spread function via pupil-phase engineering. AB - A simple approach based on the use of a properly designed pupil-phase profile can yield a 3D point-spread function (PSF) that rotates with changing defocus, while keeping its transverse shape approximately invariant over +/-3-4 waves of defocus. Unlike Gauss-Laguerre mode-based approaches, it generalizes readily for encoding spherical aberration too via PSF rotation. PMID- 23455145 TI - Sidelobe-modulated optical vortices for free-space communication. AB - We propose and experimentally demonstrate a new method for free-space optical (FSO) communication, where the transmitter encodes data into a composite computer generated hologram and the receiver decodes through a retrieved array of sidelobe modulated optical vortices (SMOVs). By employing the SMOV generation and detection technique, the usual stringent alignment and phase-matching requirement of the detection of optical vortices is released. In transmitting a gray-scale picture with 180*180 pixels, a bit error rate as low as 3.01*10(-3) has been achieved. Due to the orbital angular momentum multiplexing and spatial paralleling, this FSO communication method possesses the ability to greatly increase the capacity of data transmission. PMID- 23455146 TI - Demonstration of nondegenerate spectrum reversal in optical-frequency regime. AB - This Letter reports theoretical and experimental studies of spectrum reversal with tunable wavelength offset in the optical-frequency regime-two widely separated spectral sidebands can always behave as mirror images of one another with respect to the center frequency of the controlling pump pulse. We call this interesting physical phenomenon "spectral mirror imaging." PMID- 23455147 TI - Femtosecond-laser-induced highly birefringent Bragg gratings in standard optical fiber. AB - We report highly birefringent fiber Bragg gratings in standard single-mode optical fiber realized with UV femtosecond pulses and line-by-line inscription. By controlling the three-dimensional positioning of the focused laser beam with respect to the fiber core, we achieve very high birefringence at the grating location in a single exposure. A maximum birefringence value of 7.93*10(-4) has been reached for 10th-order gratings when using 2 MUJ pulses, which is to our knowledge the highest birefringence value reported so far. This birefringence results from UV-induced high-densification lines shifted from the center of the core, increasing the asymmetry of the induced-stress lines. With a Bragg wavelength spacing reaching more than 800 pm between polarization modes, such gratings are particularly well suited for selective filtering or, as demonstrated here, for temperature-insensitive transverse-strain measurements. PMID- 23455148 TI - Optical injection locking of a singly resonant continuous-wave optical parametric oscillator. AB - We report on experimental realization of optical injection locking of a singly resonant continuous-wave optical parametric oscillator (OPO) based on a thermally induced waveguide in a magnesium-oxide doped periodically poled lithium niobate. An external cavity diode laser is used to control the frequency of the resonant signal output of the OPO at 795 nm. The key to successful injection locking was the improvement of the OPO spatial modes by a special operating condition with a thermally induced waveguide. The phase coherence of injection locking is confirmed by recording a high-contrast interference fringe between the injection laser and the OPO output. High-resolution measurement of the frequency spectrum of the nonresonant idler output by the delayed self-heterodyne technique shows that the spectral linewidth of the OPO is reduced from 4.5 to 0.4 MHz by injection locking. The full locking range is assumed to be less than 1.7 MHz. PMID- 23455149 TI - High color purity red-emission of NaGdTiO4:Pr3+ via quenching of (3)P(0) emission under low-voltage cathode ray excitation. AB - A high color purity red emission is obtained in Pr(3+) activated NaGdTiO(4) (NGTP) materials. The International Commission on Illumination (CIE) chromaticity coordinates are calculated to be 0.663, 0.337, which are very close to the National Television System Committee (NTSC) red color 0.67, 0.34. The good color coordinates are due to intensive quenching of (3)P(0)-(3)H(4) emissions through the metal-to-metal intervalence charge transfer. Interestingly, the high color purity red emitting is observed not only under UV light excitation but also under low-voltage cathode ray excitation. The results indicate that NGTP may have a potential application in field emission displays. PMID- 23455150 TI - Fine-needle aspiration biopsy in the management of choroidal melanoma. AB - PURPOSE OF REVIEW: Fine-needle aspiration biopsy of choroidal melanoma offers an opportunity to determine the prognosis for metastasis and provide tissue resources for further study to develop molecular-based targeted therapies. Patients increasingly desire as much information as possible about their cancer so that they may plan their lives and investigate new treatments. Physicians who treat choroidal melanoma must become skilled in the technique so that even the smallest tumors, in patients who might benefit most from early treatment, may be safely biopsied. Individualized molecular therapies of the future will be predicated on the results of a patient's fine-needle biopsy. RECENT FINDINGS: Fine-needle aspiration biopsy for metastatic prognostication was first performed in North America at the Jules Stein Eye Institute, the University of California, Los Angeles in 2004. Subsequent reports from the major ophthalmic oncology centers have since evaluated several platforms for prognostication using mainly DNA-based approaches. Monosomy 3 of the primary tumor is the cytogenetic abnormality most strongly associated with the development of metastasis. The longest clinical follow-up of a cohort of patients at the Jules Stein Eye Institute who underwent biopsy for prognostication reported in 2012 revealed no increase in ocular morbidity or metastatic risk. SUMMARY: Fine-needle aspiration biopsy for prognostication in choroidal melanoma is the current standard of care because of new molecular knowledge and a more patient-centered approach to healthcare. Future targeted molecular therapies and metastatic surveillance in patients with choroidal melanoma may be directed by the results of fine-needle aspiration biopsy of the primary tumor. PMID- 23455151 TI - Selective recognition of sulphate in a Cu(II) assisted 1D polymer of a simple pentafluorophenyl substituted pyridyl-urea via second sphere coordination. AB - A pentafluorophenyl (-C6F5) substituted 3-pyridyl urea, L(1), is explored extensively to demonstrate SO4(2-) binding exclusively via second sphere coordination in the cavity of a 1D polymeric self-assembly of L(1), selectively assisted by Cu2+. A single crystal X-ray diffraction study depicts SO4(2-) encapsulation in the C2 symmetric cleft via nine hydrogen bonding interactions contributed by eight urea protons of four L(1) moieties in [CuL(1)4(DMF)2]SO4 (1). To revalidate the importance of Cu2+ selective anion coordination via exclusive second sphere coordination, a complex of L(1) and Cu(NO3)2, i.e. [CuL(1)4(H2O)2](NO3)2 (2), is also isolated and characterized by a single crystal X-ray diffraction study. When SO4(2-) salts of different metal ions such as Co2+/Ni2+ are employed, the first sphere coordination of SO4(2-) is observed in cases of complexes [CoL(1)3(DMF)2SO4] (3) and [NiL(1)3(DMF)2SO4] (4) respectively. These results clearly suggest the importance of Cu2+ towards anion recognition via purely second sphere coordination in the case of complexes 1 and 2. To understand the importance of (-C6F5) substitution in the design of L(1) towards such recognition of SO4(2-) in 1, the phenyl (-C6H5) analogue of L(1), i.e.L(2), is allowed to complex with the SO4(2-) salt of Cu2+. Interestingly, L(2) shows first sphere SO4(2-) coordination in the complex [CuL(2)2(DMF)(H2O)2SO4] (5). Solution state UV-Vis experiments of L(1) with various copper salts such as Cu(ClO4)2, CuSO4, Cu(NO3)2, CuCl2 and CuBr2 in DMF show the formation of a binary complex corresponding to 1. Further, Cu(2+) selective second sphere coordination of SO4(2-) in solution is also demonstrated by UV-Vis studies of complexes isolated from the mixtures of various Cu(2+) salts and/or SO4(2-) salts of different metal ions. PMID- 23455152 TI - Dynactin helps target Polo-like kinase 1 to kinetochores via its left-handed beta helical p27 subunit. AB - Dynactin is a protein complex required for the in vivo function of cytoplasmic dynein, a microtubule (MT)-based motor. Dynactin binds both dynein and MTs via its p150(Glued) subunit, but little is known about the 'pointed-end complex' that includes the protein subunits Arp11, p62 and the p27/p25 heterodimer. Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo-like kinase 1 (Plk1) at kinetochores. Removal of p27/p25 from dynactin results in reduced levels of Plk1 and its phosphorylated substrates at kinetochores in prometaphase, which correlates with aberrant kinetochore-MT interactions, improper chromosome alignment and abbreviated mitosis. To investigate the structural implications of p27 phosphorylation, we determined the structure of human p27. This revealed an unusual left-handed beta-helix domain, with the phosphorylation site located within a disordered, C-terminal segment. We conclude that dynactin plays a previously undescribed regulatory role in the spindle assembly checkpoint by recruiting Plk1 to kinetochores and facilitating phosphorylation of important downstream targets. PMID- 23455153 TI - Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. AB - SMAD6 is a crucial feedback inhibitory regulator of bone morphogenetic protein (BMP)/SMAD signalling. Although little is known regarding the post transcriptional modification of inhibitory SMADs and the mechanism by which their function is regulated. In this study, using a whole proteomic interaction screen for SMAD6, we identified a large putative E2 ubiquitin-conjugating enzyme UBE2O (E2-230K) as a novel interacting protein of SMAD6. We showed that UBE2O functions as an E2-E3 hybrid to monoubiquitinate SMAD6 at lysine 174 and that the cysteine 885 residue of human UBE2O is necessary for SMAD6 monoubiquitination. Inactivation of the SMAD6 monoubiquitination site specially potentiates the inhibitory ability of SMAD6 against BMP7-induced SMAD1 phosphorylation and transcriptional responses. We also found that UBE2O potentiated BMP7 signalling in a SMAD6-dependent manner. Addressing the molecular mechanism by which UBE2O and monoubiquitinated SMAD6 potentiate BMP7 signalling, we demonstrated that monoubiquitinated SMAD6 impairs the binding affinity of non-modified SMAD6 to the BMP type I receptor. Moreover, UBE2O and SMAD6 cooperated in the regulation of BMP7-induced adipogenesis. PMID- 23455154 TI - Interplay between Homeobox proteins and Polycomb repressive complexes in p16INK4a regulation. AB - The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer. PMID- 23455155 TI - Cannabinoid type 1 receptor mediates depot-specific effects on differentiation, inflammation and oxidative metabolism in inguinal and epididymal white adipocytes. AB - OBJECTIVE: The endocannabinoid system is a major component in the control of energy metabolism. Cannabinoid 1 (CB1)-receptor blockade induces weight loss and reduces the risk to develop the metabolic syndrome with its associated cardiovascular complications. These effects are mediated by central and peripheral pathways. Interestingly, weight loss is mainly achieved by a reduction of visceral fat mass. We analyzed fat depot-specific differences on adipocyte differentiation, inflammation and oxidative metabolism in CB1-receptor knockout cells. MATERIALS AND METHODS: We used newly generated epididymal/inguinal adipose cell lines from CB1-receptor knockout mice. Differences in differentiation were measured by fat-specific Oil Red O staining and quantitative analysis of key differentiation markers. Induction of apoptosis was evaluated by cell death detection and investigation of p53 phosphorylation. Inflammation markers were quantified by real-time PCR. For analyzing the process of transdifferentiation we measured oxygen consumption and mitochondrial biogenesis. RESULTS: Differentiation was reduced in visceral adipocytes from CB1-receptor knockout mice as compared with wild-type controls. Moreover, we found an induction of apoptosis in these cells. In contrast, subcutaneous adipocytes from CB1-receptor knockout mice showed an accelerated differentiation and a reduced rate of apoptosis. Inflammation was increased in visceral fat cells, as analyzed by the expression pattern of interleukin-6, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-alpha, whereas in subcutaneous adipocytes these markers were decreased. Furthermore, subcutaneous CB1-receptor knockout cells were more sensitive toward a conversion into a brown fat phenotype. Uncoupling protein-1 as well as PGC-1alpha expression was significantly elevated. This was accompanied by an increase in mitochondrial biogenesis and oxygen consumption. CONCLUSION: In conclusion, we found depot-specific effects on differentiation, apoptosis, inflammation and oxidative metabolism in CB1-receptor knockout cells. Thus, CB1 receptor-mediated pathways differentially target adipose tissue depots to a dual effect that minimizes cardiometabolic risk, on the one hand, by diminishing visceral fat, and that enhances thermogenesis in subcutaneous adipocytes, on the other. PMID- 23455156 TI - Selective formation mechanisms of quantum dots on patterned substrates. AB - We have presented a theoretical model to elucidate the formation mechanisms of quantum dots (QDs) on patterned substrates, which introduced the perspective that the preferred formation site of QDs is determined by the nonuniformity of wetting layer thickness caused by surface potential. Two different preferred formation sites, low surface curvature or high surface curvature, can be switched through controlling growth temperature or selecting appropriate patterns. The model explains some interesting and puzzling experimental observations, which implies that the established approach could be applicable to the physical understanding of the QDs on patterned substrates. PMID- 23455157 TI - Novel method to analyze post-yield mechanical properties at trabecular bone tissue level. AB - Tissue level mechanics is a key factor to be investigated to improve the knowledge of how the overall trabecular structure reacts to loading and overloading. The aim of this study was to develop a new device for measuring the mechanical competence of single trabeculae in the post-yield region for both tensile and bending tests, characterized by high accuracy and precision, and to assess the effect of testing mode, donor age and material composition. A novel approach for measuring the displacement and deformation was developed (accuracy error of 0.3% and a precision of 2.7%). A total of 30 samples from two bovine femora of different ages (from <3-year-old and 14-year-old cows) were tested in tension or bending, while average material properties have been acquired by means of Raman spectroscopy. A group of trabeculae was tested in bending after treatment for collagen degradation. As a result, a complete set of post-yield properties has been reported. The results highlight significant differences between tensile and bending groups, with higher values for the bending test mode for yield strain, ultimate strain and post-yield work and lower for the elastic modulus. Significant higher values were found for the old donor (differences in the range of 30-60%) for elastic modulus, yield stress and ultimate stress as well as for material properties measured by Raman spectroscopy. We quantified that changes in materials properties induced by collagen degradation corresponded to a substantial decrease (up to 120% for post-yield work) of mechanical competence, both in the elastic and inelastic region. PMID- 23455158 TI - The modification of microstructure to improve the biodegradation and mechanical properties of a biodegradable Mg alloy. AB - The effect of microstructural modification on the degradation behavior and mechanical properties of Mg-5wt%Ca alloy was investigated to tailor the load bearing orthopedic biodegradable implant material. The eutectic Mg/Mg2Ca phase precipitated in the as-cast Mg-5wt%Ca alloy generated a well-connected network of Mg2Ca, which caused drastic corrosion due to a micro galvanic cell formed by its low corrosion potential. Breaking the network structure using an extrusion process remarkably retarded the degradation rate of the extruded Mg-5wt%Ca alloy, which demonstrates that the biocompatibility and mechanical properties of Mg alloys can be enhanced through modification of their microstructure. The results from the in vitro and in vivo study suggest that the tailored microstructure by extrusion impede the deterioration in strength that arises due to the dynamic degradation behavior in body solution. PMID- 23455159 TI - Tribological and corrosion behavior of friction stir processed Ti-CaP nanocomposites in simulated body fluid solution. AB - In the present study, friction stir processing was utilized to incorporate nano hydroxyapatite particles into Ti-6Al-4V substrates to fabricate Ti-CaP nanocomposite surface layer. Microstructures of the stir zone and the fabricated Ti-CaP nanocomposite layer were analyzed using optical and scanning electron microscopy, respectively. Microhardness profile and AFM analysis of substrates were then studied. The microhardness of Ti-CaP nanocomposite layer was reached about 386 HV due to the grain refinement and the distribution of nano hydroxyapatite particles. Potentiodynamic polarization studies showed that the Ti CaP nanocomposite layer protected effectively the Ti-6Al-4V substrates from corroding in simulated body fluid solution. The tribological properties of the samples were studied in both dry and simulated biological conditions. The wear rate and friction coefficient decreased by friction stir processing on Ti-6Al-4V substrates. From the analysis of plotted graphs of weight loss versus sliding distance, a correlation between wear coefficient and microhardness through thickness was established. The wear mechanisms were also investigated through scanning electron microscopy. It was shown that the major mechanism was abrasive wear. PMID- 23455160 TI - Effect of air-particle abrasion protocols on the biaxial flexural strength, surface characteristics and phase transformation of zirconia after cyclic loading. AB - This study evaluated the effect of air-particle abrasion protocols on the biaxial flexural strength, surface characteristics and phase transformation of zirconia after cyclic loading. Disc-shaped zirconia specimens (O: 15mm, thickness: 1.2mm) (N=32) were submitted to one of the air-particle abrasion protocols (n=8 per group): (a) 50MUm Al2O3 particles, (b) 110MUm Al2O3 particles coated with silica (Rocatec Plus), (c) 30MUm Al2O3 particles coated with silica (CoJet Sand) for 20s at 2.8bar pressure. Control group received no air-abrasion. All specimens were initially cyclic loaded (*20,000, 50N, 1Hz) in water at 37 degrees C and then subjected to biaxial flexural strength testing where the conditioned surface was under tension. Zirconia surfaces were characterized and roughness was measured with 3D surface profilometer. Phase transformation from tetragonal to monoclinic was determined by Raman spectroscopy. The relative amount of transformed monoclinic zirconia (FM) and transformed zone depth (TZD) were measured using XRD. The data (MPa) were analyzed using ANOVA, Tukey's tests and Weibull modulus (m) were calculated for each group (95% CI). The biaxial flexural strength (MPa) of CoJet treated group (1266.3+/-158(A)) was not significantly different than that of Rocatec Plus group (1179+/-216.4(A,B)) but was significantly higher than the other groups (Control: 942.3+/-74.6(C); 50MUm Al2O3: 915.2+/-185.7(B,C)). Weibull modulus was higher for control (m=13.79) than those of other groups (m=4.95, m=5.64, m=9.13 for group a, b and c, respectively). Surface roughness (Ra) was the highest with 50MUm Al2O3 (0.261MUm) than those of other groups (0.15 0.195MUm). After all air-abrasion protocols, FM increased (15.02%-19.25%) compared to control group (11.12%). TZD also showed increase after air-abrasion protocols (0.83-1.07MUm) compared to control group (0.59MUm). Air-abrasion protocols increased the roughness and monoclinic phase but in turn abrasion with 30MUm Al2O3 particles coated with silica has increased the biaxial flexural strength of the tested zirconia. PMID- 23455161 TI - Superelastic behavior of a beta-type titanium alloy. AB - The superelasticity of a beta Ti alloy, Ti-7.5Nb-4Mo-2Sn (in atom percent) was evaluated by using loading and unloading cyclic tensile tests under different thermomechanical conditions, and the effects of the plastic deformation, temperature, strain rate and cyclic loading on the superelasticity of the alloy were studied. It is found that, with the applied strain increasing, the stress inducing the reverse martensitic transformation sigmaalpha"-beta and the strain recovery rate eta decreases. The increase of deformation temperature promotes sigmabeta-alpha", sigmaalpha"-beta and Deltasigma, and the temperature dependency of the stresses obeys the Clausius-Clapeyron relation. sigmabeta-alpha", sigmaalpha"-beta and Deltasigma are independent on the strain rate when it is lower than 8.35*10(-4)s(-1). However, when the strain rate is higher than 8.35*10(-4)s(-1), sigmabeta-alpha" and Deltasigma increase, but sigmaalpha"-beta decreased with increasing the strain rate. By cyclic loading and unloading to the maximum strain of 6% at 25 degrees C under the strain rate of 1.67*10(-4)s(-1), the alloy exhibits a improved superelasticity after seventh cycles due to the training effect. PMID- 23455162 TI - Strong and tough magnesium wire reinforced phosphate cement composites for load bearing bone replacement. AB - Calcium phosphate cements are brittle biomaterials of low bending strength. One promising approach to improve their mechanical properties is reinforcement with fibers. State of the art degradable reinforced composites contain fibers made of polymers, resorbable glass or whiskers of calcium minerals. We introduce a new class of composite that is reinforced with degradable magnesium alloy wires. Bending strength and ductility of the composites increased with aspect ratio and volume content of the reinforcements up to a maximal bending strength of 139+/ 41MPa. Hybrid reinforcement with metal and polymer fibers (PLA) further improved the qualitative fracture behavior and gave indication of enhanced strength and ductility. Immersion tests of composites in SBF for seven weeks showed high corrosion stability of ZEK100 wires and slow degradation of the magnesium calcium phosphate cement by struvite dissolution. Finally, in vitro tests with the osteoblast-like cell line MG63 demonstrate cytocompatibility of the composite materials. PMID- 23455163 TI - Effects of surface texturing on the performance of biocompatible UHMWPE as a bearing material during in vitro lubricated sliding/rolling motion. AB - The effect of surface texturing on the performance of biocompatible ultra-high molecular weight polyethylene (UHMWPE) as a bearing material has been investigated using the kinematic range of motions reported for a knee-joint replacement. An experimental apparatus consisting of a ball and a disk rotating independently from each other was used to compare the performance of UHMWPE textured versus plain surfaces, under different combinations of sliding and rolling motion, better known as sliding-to-rolling ratio (SRR). Performance was evaluated through the coefficient of traction of a tribosystem comprising a steel ball on a flat UHMWPE disk and distilled water at 36 degrees C, acting as lubricant. A square array of cavities with diameter D=0.397mm and center-to center spacing of 1.5D was machined on UHMWPE disks. The experimental design considered two levels for cavity depth, D and D/2, and two for the applied load, 17 and 25N. The SRR was varied from 1 to 11% and the mean speed range was set from 5 to 55mm/s, covering the kinematics and contact pressure conditions of a sauntering cycle on a knee-joint replacement. Stribeck curves of the plain and textured surfaces were obtained and compared against one another. The results demonstrate that the proposed surface pattern reduces the coefficient of traction of the tribological system for the 17N load in the entire kinematic range explored, while for the 25N load the effects were more noticeable at low mean speed and SRR, corresponding to the beginning of motion. PMID- 23455164 TI - Influence of statistical size effects on the plastic deformation of coronary stents. AB - The dimensions of coronary stent struts are similar to those of the metallic grains of their constituent alloys. This means that statistical size effects (SSEs), which are evident in polycrystals with few grains through their dimensions, can have detrimental effects on the mechanical performance of stent struts undergoing large plastic deformation. Current trends in coronary stent design are towards thinner struts, potentially increasing the influence of SSEs. In order to maintain adequate device performance with decreasing strut thickness, it is therefore important to assess the role of SSEs in the plastic deformation of stents. In this study, finite element modelling and crystal plasticity theory are used to investigate SSEs in the deformation of struts in tension and bending. The relationships between SSEs and microstructure morphology, alloy strain hardening behaviour and secondary phases are also investigated. It is predicted that reducing the number of grains through the strut cross section and increasing the number of grains along the strut length have detrimental effects on mechanical performance. The magnitudes of these effects are predicted to be independent of the uniformity of the studied microstructures, but dependent on alloy strain hardening behaviour. It is believed that model predictions will aid in identifying a lower bound on suitable strut thicknesses in coronary stents for a range of alloys and microstructures. PMID- 23455165 TI - Anisotropic mode-dependent damage of cortical bone using the extended finite element method (XFEM). AB - Anisotropic damage initiation criteria were developed for extended finite element method (XFEM) prediction of crack initiation and propagation in cortical bone. This anisotropic damage model was shown to accurately predict the dependence of crack propagation patterns and fracture toughness on mode mixity and on osteon orientations, as observed experimentally. Four initiation criteria were developed to define crack trajectories relative to osteon orientations and max principal stress for single and mixed mode fracture. Alternate failure strengths for tensile and compressive loading were defined to simulate the asymmetric failure of cortical bone. The dependence of cortical bone elasticity and failure properties on osteon orientation is analogous to the dependence of composite properties on fibre orientation. Hence, three of the criteria developed in the present study were based upon the Hashin damage criteria. The fourth criterion developed was defined in terms of the max principal stress. This criterion initiated off axis crack growth perpendicular to the direction of the max principal stress. The unique set of parameters calibrated accurately predicted; (i) the relationship between fracture energy and osteon alignment, (ii) the alternate crack patterns for both varying osteon orientations and loading angle. Application of the developed anisotropic damage models to cortical bone screw pullout highlights the potential application for orthopaedic device design evaluation. PMID- 23455166 TI - Effect of high-pressure polymerization on mechanical properties of PMMA denture base resin. AB - The aim of this study was to assess the effect of high-pressure polymerization on mechanical properties of denture base resin. A heat-curing denture base resin and an experimental PMMA were polymerized under 500MPa of pressure by means of an isostatic pressurization machine at 70 degrees C for 24h to make rectangular specimens whose dimensions were 30mm*2mm*2mm. Each specimen was deflected on a three-point flexural test until either fracture occurred or the sample was loaded up to 8mm in deflection. The molecular weight of the PMMA without filler was analyzed using the high-speed liquid chromatography system. Increased ductility without fracture was shown in the specimens subjected to high pressure, while most of the control specimens (ambient pressure) fractured. The mean toughness of the PMMA specimens polymerized under the high pressure was significantly higher than the same material polymerized under ambient pressure (p<0.01). The high pressure groups of the denture resin and the PMMA revealed a significantly lower mean 0.2% yield stress, flexural strength, and elastic modulus than control groups (p<0.01). There were certain amounts of higher molecular weight polymers in the high pressure specimens than were present in the controls. The increased toughness shown in the PMMA polymerized under the high pressure was presumably attributed to the higher molecular weight produced by the pressure. The result suggests a potential application of the high-pressure polymerization to the development of PMMA-based denture resin with improved fracture resistance. PMID- 23455167 TI - Liver tissue characterization from uniaxial stress-strain data using probabilistic and inverse finite element methods. AB - Biological soft tissue is highly inhomogeneous with scattered stress-strain curves. Assuming that the instantaneous strain at a specific stress varies according to a normal distribution, a nondeterministic approach is proposed to model the scattered stress-strain relationship of the tissue samples under compression. Material parameters of the liver tissue modeled using Mooney-Rivlin hyperelastic constitutive equation were represented by a statistical function with normal distribution. Mean and standard deviation of the material parameters were determined using inverse finite element method and inverse mean-value first order second-moment (IMVFOSM) method respectively. This method was verified using computer simulation based on direct Monte-Carlo (MC) method. The simulated cumulative distribution function (CDF) corresponded well with that of the experimental stress-strain data. The resultant nondeterministic material parameters were able to model the stress-strain curves from other separately conducted liver tissue compression tests. Stress-strain data from these new tests could be predicted using the nondeterministic material parameters. PMID- 23455168 TI - Wear characteristics of current aesthetic dental restorative CAD/CAM materials: two-body wear, gloss retention, roughness and Martens hardness. AB - OBJECTIVES: This study determined the two-body wear and toothbrushing wear parameters, including gloss and roughness measurements and additionally Martens hardness, of nine aesthetic CAD/CAM materials, one direct resin-based nanocomposite plus that of human enamel as a control group. MATERIALS AND METHODS: Two-body wear was investigated in a computer-controlled chewing simulator (1.2 million loadings, 49N at 1.7Hz; 3000 thermocycles 5/50 degrees C). Each of the 11 groups consisted of 12 specimens and 12 enamel antagonists. Quantitative analysis of wear was carried out with a 3D-surface analyser. Gloss and roughness measurements were evaluated using a glossmeter and an inductive surface profilometer before and after abrasive toothbrushing of machine-polished specimens. Additionally Martens hardness was measured. Statistically significant differences were calculated with one-way ANOVA (analysis of variance). RESULTS: Statistically significant differences were found for two-body wear, gloss, surface roughness and hardness. Zirconium dioxide ceramics showed no material wear and low wear of the enamel antagonist. Two-body wear of CAD/CAM-silicate and -lithium disilicate ceramics, -hybrid ceramics and -nanocomposite as well as direct nanocomposite did not differ significantly from that of human enamel. Temporary polymers showed significantly higher material wear than permanent materials. Abrasive toothbrushing significantly reduced gloss and increased roughness of all materials except zirconium dioxide ceramics. Gloss retention was highest with zirconium dioxide ceramics, silicate ceramics, hybrid ceramics and nanocomposites. Temporary polymers showed least gloss retention. Martens hardness differed significantly among ceramics, between ceramics and composites, and between resin composites and acrylic block materials as well. CONCLUSIONS: All permanent aesthetic CAD/CAM block materials tested behave similarly or better with respect to two-body wear and toothbrushing wear than human enamel, which is not true for temporary polymer CAD/CAM block materials. Ceramics show the best gloss retention compared to hybrid ceramics, composites and acrylic polymers. PMID- 23455169 TI - A quantitative comparison of soft tissue compressive viscoelastic model accuracy. AB - Viscoelastic models are generally considered a good option for modeling biological tissue due to tissue time-dependency. However, although various forms of viscoelastic models have been developed, only a few have shown a good balance between model mathematical simplicity and experimental fit accuracy. Starting from a basic Standard Linear Solid (SLS) model, a systematic modification of the viscoelastic model leading to a more accurate tissue model is presented. A five element model family, with a Double Maxwell-arm Wiechert (DMW) representative model, is selected for its mathematical simplicity and mathematical loading accuracy. This DMW model is then used to fit experimental data collected from stress relaxation indentation tests performed on fresh porcine liver and spleen. The results show that this DMW model provides a closer fit with the experimental liver (SLS R(2)=0.731, DMW R(2)=0.991) and spleen (SLS R(2)=0.720, DMW R(2)=0.981) data, compared to an SLS model, while maintaining appreciable mathematical simplicity by using only five model elements, compared to seven element models. Thus, any model from this five-element model family can be used as a base compressive model for complex soft tissue with an approximate 35% improved model fit over SLS. Finally, model element parameters for in vitro fresh porcine liver and spleen are determined from the associated indentation tests. PMID- 23455170 TI - Influence of the fabrication process and fluoride content on the tribocorrosion behaviour of Ti6Al4V biomedical alloy in artificial saliva. AB - Titanium and its alloys are widely used as dental implants due to their low density, excellent biocompatibility, mechanical properties and corrosion resistance. However, during their lifetime Ti6Al4V biomedical alloys are subjected to different mechanical actions (i.e., sliding or fretting), thus resulting in a tribocorrosion system, which is an irreversible material degradation process due to the combined effect of corrosion and wear. In this study, the tribo-electrochemical behavior of cast and sintered (by powder metallurgy) Ti6Al4V alloy in artificial human saliva solution without and with fluoride additions of 100ppm and 1000ppm and in an average industrial mouth wash solution with a 112ppm fluoride content have been investigated by different electrochemical techniques. The same tribocorrosion mechanisms were found in the cast and sintered titanium alloys, although slightly different wear debris behavior was observed. At low applied passive potentials, wear rates are similar to those obtained under equilibrium conditions (Open Circuit Potential). There exists a critical fluoride concentration above which corrosion and tribocorrosion rates increase. PMID- 23455171 TI - Mechanical behaviour of pressed and sintered CP Ti and Ti-6Al-7Nb alloy obtained from master alloy addition powder. AB - The Ti-6Al-7Nb alloy was obtained using the blending elemental approach with a master alloy and elemental titanium powders. Both the elemental titanium and the Ti-6Al-7Nb powders were characterised using X-ray diffraction, differential thermal analysis and dilatometry. The powders were processed using the conventional powder metallurgy route that includes uniaxial pressing and sintering. The trend of the relative density with the sintering temperature and the microstructural evolution of the materials sintered at different temperatures were analysed using scanning electron microscopy and X-ray diffraction. A minimum sintering temperature of 1200 degrees C has to be used to ensure the homogenisation of the alloying elements and to obtain a pore structure composed of spherical pores. The sintered samples achieve relative density values that are typical for powder metallurgy titanium and no intermetallic phases were detected. Mechanical properties comparable to those specified for wrought Ti-6Al-7Nb medical devices are normally obtained. Therefore, the produced materials are promising candidates for load bearing applications as implant materials. PMID- 23455172 TI - Controlling dynamic mechanical properties and degradation of composites for bone regeneration by means of filler content. AB - Bone tissue is a dynamic composite system that adapts itself, in response to the surrounding daily (cyclic) mechanical stimuli, through an equilibrium between growth and resorption processes. When there is need of synthetic bone grafts, the biggest issue is to support bone regeneration without causing mechanically induced bone resorption. Apart from biological properties, such degradable materials should initially support and later leave room to bone formation. Further, dynamic mechanical properties comparable to those of bone are required. In this study we prepared composites comprising calcium phosphate and L-lactide/D lactide copolymer in various content ratios using the extrusion method. We evaluated the effect of the inorganic filler amount on the polymer phase (i.e. on the post-extrusion intrinsic viscosity). We then studied their in vitro degradation and dynamic mechanical properties (in dry and humid conditions). By increasing the filler content, we observed significant decrease of the intrinsic viscosity of the polymer phase during the extrusion process. Composites containing higher amounts of apatite had faster degradation, and were also mechanically stiffer. But, due to the lower intrinsic viscosity of their polymer phase, they had larger damping properties. Besides this, higher amounts of apatite also rendered the composites more hydrophilic letting them absorb more water and causing them the largest decrease in stiffness. These results show the importance of filler content in controlling the properties of such composites. Further, in this study we observed that the viscoelastic properties of the composite containing 50wt% apatite were comparable to those of dry human cortical bone. PMID- 23455174 TI - An unusual presentation of a small-size synovial sarcoma with an indolent course of over 30 years: a cautionary tale! PMID- 23455173 TI - Biomarkers in nephrology: Core Curriculum 2013. PMID- 23455175 TI - Granular cell tumor of the testicular tunica albuginea: a case report. AB - Granular cell tumor (GCT) is exceedingly rare in the genitourinary tract. We report a case of GCT arising in the tunica albuginea of the testis. A 42-year-old male presented with a painless left testicular mass. Scrotal ultrasound studies showed an intratesticular mass that was suspicious for a testicular malignancy; a left orchiectomy was subsequently performed. Grossly, there was a well circumscribed tumor mass in the periphery of the testis abutting the tunica albuginea. Microscopically, the tumor was poorly delimited and located in the tunica albuginea with minimal infiltration to the underlying testicular parenchyma. The lesion consisted of clusters and sheets of large polygonal cells dissected by fibrous septa. The tumor cells had indistinct cellular borders, abundant granular eosinophilic cytoplasm, and small nuclei with indistinct nucleoli. No cytologic atypia or increased mitotic activity was seen. Immunohistochemically, the tumor cells were positive for S-100, inhibin-alpha, and CD68 and negative for calretinin, Melan-A, and WT-1. Ki-67 showed a low proliferation index (<1%). The morphology, in conjunction with immunohistochemical profile, led to a diagnosis of GCT of the tunica albuginea. Although GCT can occur in almost any location of the body, it has not been described to involve the human testis. PMID- 23455176 TI - Predicting OncoDx recurrence scores with immunohistochemical markers. AB - Recent reports suggest that immunohistochemistry (IHC) markers can be used to give prognostic information in breast cancer that is similar to that contained in the Genomic Health Inc. OncoDx recurrence score (Onco-RS). The goal of this study is to examine the potential prognostic value of a score derived from results of a simple set of IHC tests in the prediction of the Onco-RS. A score (IHC-RS) was derived to predict the Onco-RS using IHC-based quantitative and semiquantitative results from a subset of markers selected from those used in the generation of an Onco-RS score. The patient population consists of a retrospectively identified cohort of 158 women with ER-positive, HER2neu-negative breast cancer who completed OncoDx testing. A predictive model was developed to generate the IHC-RS using stepwise multiple regression incorporating Ki67 percentage and semiquantitative ER and PR scores. Using only these 3 IHC markers, the IHC-RS predicted 62% of the Onco-RS variability (adjusted R=0.624, P=0.004). In addition, analysis of outliers in the correlation between the IHC-RS and the Onco RS reveals the possibility of sampling error as a drawback of the Onco-RS. This is contrasted against potential interlab and intralab variability and preanalytic issues that may negatively impact the implementation of an IHC-RS. PMID- 23455177 TI - Triple-negative breast carcinoma in African American and Caucasian women: clinicopathology, immunomarkers, and outcome. AB - PURPOSE: Breast cancers are often classified on the presence/absence of hormone receptors, and growth factor oncogenes (estrogen receptor, progesterone receptor, HER2). Triple-negative breast cancers, negative for these markers, do not benefit from targeted therapy. We compared clinicopathologic parameters and immunohistochemical markers of prognostic and/or predictive significance, and outcome between African American and Caucasian triple-negative breast cancer patients. METHODS: Invasive triple-negative breast cancers from African American (n=94) and Caucasian (n=68) patients were studied. Clinicopathologic features (age, tumor size, grade, lymph node status, angiolymphatic invasion, visceral metastases) and survival (overall and progression free) were compared. Marker expression (CK5, CK7, CK8, CK14, CK18, CK19, vimentin, CD44, c-Kit, epidermal growth factor receptor, p-cadherin, p53, p63, topoisomerase II, androgen receptor, Ki-67) was assessed in tissue microarrays. RESULTS: Significant differences between African American and Caucasian women were observed for mean age and tumor size. African Americans had a trend toward greater lymph node involvement than Caucasians. The following markers were found in significantly different frequencies between the 2 groups: CK5, CK8, CK19, c-Kit, androgen receptor, and high Ki-67. African Americans show shorter overall and progression free survival. Other clinicopathologic parameters, markers, and outcome were present at similar frequencies. DISCUSSION: African American triple-negative breast cancers were more aggressive, occurring at a younger age, being larger, with higher proliferation, patients more frequently dying of disease, and with a trend toward positive lymph node status. Heterogeneity of marker expression suggests variation in the genetics of breast carcinomas in different races. PMID- 23455178 TI - Evaluation of real-time immunohistochemistry and interaction map as an alternative objective assessment of HER2 expression in human breast cancer tissue. AB - Immunohistochemical study (IHC) is a critical tool in the clinical diagnosis of breast cancer. One common assessment is the expression level of the HER2 receptor in breast cancer tissue samples with the aim of stratifying patients for applicability of the therapeutic antibody Herceptin. In this study, we aimed to investigate whether a novel assay, real-time IHC combined with Interaction Map analysis, offers the possibility of objective assessment of HER2 expression. Interaction Map presents real-time interaction data as a collection of peaks on a surface, and it was performed on 20 patient tissue samples previously scored for HER2 expression. The result shows that the relative weight of the peaks in the maps contains novel information that could discriminate between high and low HER2 expression in an operator-independent manner (P<0.001). We conclude that the real time IHC assay has a promising potential to complement conventional IHC and may improve the precision in the future clinical diagnostics of breast cancer. PMID- 23455179 TI - Differential expression of somatostatin receptors, P44/42 MAPK, and mTOR activation in medulloblastomas and primitive neuroectodermal tumors. AB - Recently, somatostatin receptors (SSR) have been identified on medulloblastomas and proposed as a new target for chemotherapy including inhibitory somatostatin analogs. Activation of SSRs inhibit growth, in part, by activating phosphatases that dephosphorylate/deactivate growth stimulatory signaling of the MEK1-p44/42 MAPK and PI3K-Akt-mTOR pathways. These SSR-inhibited signaling pathways have not been characterized or correlated with SSR expression in medulloblastomas or primitive neuroectodermal tumors (PNETs), yet may represent additional targets for combined chemotherapy. We evaluated the distribution and extent of SSR1 and SSR2 expression and correlated it with activation of downstream MEK1-p44/42 MAPK and PI3K-Akt-mTOR pathways in medulloblastomas and PNETs. Sections from 22 medulloblastomas and 9 PNETs were compared using immunohistochemistry with monoclonal antibodies to SSR1, SSR2, p44/42 MAPK, phosphorylated p44/42 MAPK, and phosphorylated mTOR. SSR1 was detected in 50% of medulloblastomas, extensive in 46%, and similar in classic, desmoplastic, and large cell/anaplastic subtypes. SSR1 was detected in 78% of PNETs and extensive in the majority. SSR2 was found in 18% of medulloblastomas and 33% of PNETs. Activated/phosphorylated pMAPK 44/42 was detected in 82% of medulloblastomas, all subtypes, and in 62.5% of PNETs with coexpression of SSR1 in one third. Activated/phosphorylated mTOR was found in only 18% of medulloblastomas but in 88% of PNETs. SSR1 coexpression with activated/phosphorylated mTOR was identified in 75% of PNETs. These findings suggest that addition of an mTOR inhibitor may potentiate growth inhibitory effects of SSR agonists in the treatment of PNETs. Immunohistochemical identification of mTOR activation/phosphorylation in biopsies of initial and treatment-resistant PNETs may facilitate development of clinical trials and therapeutic decisions. PMID- 23455180 TI - Immunohistochemical study of the Nrf2 pathway in colorectal cancer: Nrf2 expression is closely correlated to Keap1 in the tumor and Bach1 in the normal tissue. AB - Oxidative stress is a contributing factor in the carcinogenesis of colorectal cancer. The Nrf2 [nuclear factor (erythroid-derived 2)-like 2; NFE2L2] pathway is one of the major cellular defense mechanisms against oxidative stress. This study investigated the expression of the Nrf2 pathway in colorectal cancer. Formalin fixed paraffin-embedded tissue arrays consisting of the tumor, adjacent normal, and distant normal tissues from the resected specimens of 83 colorectal cancer patients were subjected to immunohistochemical (IHC) staining with antibodies against Nrf2, kelch-like ECH-associated protein 1 (Keap1), p21, P62, Parkinson protein 7 (Park7), prohibitin, BTB and CNC homology 1 (Bach1), CD34 and 8-hydroxy 2'-deoxyguanosine (8-OHdG). The mean IHC density of each IHC staining was digitally analyzed. The results showed that molecules of the Nrf2 pathway were actively expressed, with different expression profiles among the tumor and normal tissues. The oxidative stress, represented by the mean IHC staining density of 8 OHdG, did not differ but was correlated with the expressions of different Nrf2 pathway molecules to a varied extent in tumor and normal tissues of colorectal cancer. Keap1 [estimate, 0.49; 95% confidence interval (CI), 0.19-0.79] and Bach1 (estimate, 0.24; 95% CI, 0.11-0.38) were significant predictors for the expression of 8-OHdG and had the closest proximity to Nrf2 in the cluster dendrogram of the tumor and distant normal tissues, respectively. Advanced stage (estimate, 14.9; 95% CI, 2.99-26.8) and current smoker (estimate, 15.6; 95% CI, 1.92-29.3) were significant predictors with high estimates for Bach1 in the adjacent and distant normal tissues, respectively. In colorectal cancer, the molecules of the Nrf2 pathway have different expression profiles and a difference in their importance, especially Keap1 and Bach1, related to Nrf2 and oxidative stress among tumor and normal tissues. PMID- 23455181 TI - Immunophenotype of myxopapillary ependymomas. AB - Myxopapillary ependymoma (MPE) is a slow-growing tumor occurring almost exclusively in the region of conus medullaris, cauda equina, and filum terminale. On microscopic examination, some of these tumors show solid sheets of cells with an epithelioid morphology mimicking a metastatic carcinoma. Several immunohistochemical studies addressed this issue with discordant results. We report the immunohistochemical findings of 9 additional cases of MPE. From 2004 to 2011, a total of 9 cases of MPE were recorded in our surgical pathology files. The histologic material and clinical data were reviewed for each case. There were 6 female and 3 male patients. The ages ranged from 15 to 58 years (mean, 31 y). Eight cases were intradural, lumbosacral (L1-S1), and 1 case was located in the sacrum. All tumors expressed CD99 and GFAP (100%). Eight tumors were positive for CD56 (89%). All tumors (100%) expressed focally CKAE1/AE3. One tumor (11%) was focally positive for CK8/18 and CK7. D2-40 was focally positive in 1 case (11%). PLAP and AFP were both negative in all cases. Synaptophysin was focally positive in 1 case. NSE was positive in all cases. All tumors were negative for CK5/6, CK20, E-cadherin, and TTF-1. Our study shows that the vast majority of MPE are positive for CD99, CD56, and GFAP. In selective cases, especially when the material obtained for pathologic evaluation is scanty and the tumor displays epithelioid appearance, the diagnosis may be challenging owing to cytokeratin positivity suggesting metastatic carcinoma. However, the clinical and radiologic features in addition to the positivity for GFAP should prompt pathologists to consider MPE in the differential diagnosis of such cases. Interestingly, we found that MPE are positive for NSE, which suggests a neuroglial differentiation. PMID- 23455182 TI - HER2 in situ hybridization in gastric and gastroesophageal adenocarcinoma: comparison of automated dual ISH to FISH. AB - Patients with gastric and gastroesophageal junction (GEJ) adenocarcinomas that are HER2 positive by immunohistochemistry (IHC) or in situ hybridization show a significant survival benefit with trastuzumab therapy. In situ hybridization is traditionally done by fluorescence in situ hybridization (FISH), despite some limitations. An alternative is the dual in situ hybridization (Dual ISH) technique that is fully automated and uses differentially labeled CEP17 and HER2 probes that can be read by light microscopy on 1 slide. The aim of this study was to assess the utility of Dual ISH in gastric/GEJ cancer and to compare the results with those obtained by IHC and FISH. Cases of gastric/GEJ adenocarcinoma were analyzed by IHC, FISH, and Dual ISH and the correlation between methods calculated. Results for 50 patients were available. There was a 98% (49/50) concordance rate between Dual ISH and FISH. One discrepant case was nonamplified by FISH but showed focal amplification by Dual ISH. Discrepancy was attributed to tumor heterogeneity, which was a frequent finding (78% of HER2-positive cases). There was excellent correlation between Dual ISH and FISH for assessment of HER2 amplification. Dual ISH was rapid, easy to interpret, and maintained cell morphology, which was valuable in identifying tumor heterogeneity. PMID- 23455183 TI - Validation and comparison of anti-alphavbeta3 and anti-alphavbeta5 rabbit monoclonal versus murine monoclonal antibodies in four different tumor entities. AB - Integrins are pivotal in cancer biology and are putative candidates for cancer therapy. The investigation of integrins has been hampered by the lack of antibodies suitable for formalin-fixed and paraffin-embedded (FFPE) tissue specimens. Here, we validated monoclonal rabbit antibodies (RabMAbs) against integrins alphavbeta3 (EM22703) and alphavbeta5 (EM09902) with murine monoclonal antibodies (MuMabs) LM609 (against alphavbeta3) and P1F6 (against alphavbeta5), in immunohistochemistry. Immunostaining was performed on sections of matching unfixed, cryoconserved (CC) and FFPE tissue from 19 colorectal, 20 lung, 17 breast, and 9 ovarian carcinomas. Sections were stained with LM609 and P1F6 and compared with the immunoreactions of the RabMAbs. The degree of concordance was assigned for staining patterns and intensity. Concordance between MuMAbs and RabMAbs ranged from weak, for anti-alphavbeta5 antibodies, to nearly complete for anti-alphavbeta3 antibodies. We confirmed that MuMAbs LM609 and P1F6 bound very weakly in FFPE tissue and no staining was seen. By contrast, RabMAbs EM22703 and EM09902 generally showed a high degree of agreement in staining patterns of CC and FFPE tissue. In summary, the RabMAbs had overlapping staining patterns that were generally more intense for CC when compared with FFPE material. This study suggests that EM22703 and EM09902 staining closely matches the staining of standard MuMAbs and also does so in archival FFPE tissue. PMID- 23455184 TI - Expression of Bcl-2 and the antiapoptotic BAG family proteins in ovarian cancer. AB - In epithelial ovarian cancer (EOC), literature on the prognostic value of B-cell lymphoma 2 (Bcl-2) is limited and inconsistent. Little is known about the expression patterns and the prognostic value of prosurvival proteins of the Bcl-2 associated athanogene (BAG) family proteins interacting with Bcl-2. The major aim of this study was to further define the expression pattern and the prognostic role of Bcl-2 together with BAG-1, BAG-3, and BAG-4 proteins in EOC patients receiving platinum/taxane-based chemotherapy. A tissue array was constructed comprising 63 EOC patients. The expression and the prognostic value of Bcl-2, BAG 1, BAG-3, and BAG-4 in EOC were evaluated by immunohistochemistry and multivariate analysis. A positive cytoplasmic staining for Bcl-2 was observed in 23.8% of EOC samples and in all histologic subtypes. BAG-1, BAG-3, and BAG-4 were detected in tumor cell nuclei and cytoplasm. Interestingly, all patients presenting with a positive Bcl-2 staining showed additional positive nuclear and cytoplasmic BAG-4 expression (P=0.014). Expression of Bcl-2, or the BAG family proteins, independent of nuclear or cytoplasmic localization, had no significant impact on either disease-free or overall survival, both in univariate and multivariate survival analyses with the limitation of a small cohort of cases. In this study, no association between Bcl-2 expression in EOC tumor tissue and prognosis was found. Similarly, nuclear and cytoplasmic expression of the prosurvival proteins of the BAG family had no significant impact on patients' outcome. PMID- 23455185 TI - Molecular analysis of the KIT gene in gastrointestinal stromal tumors with novel mutations. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT gene mutations have great importance for GISTs. This study evaluated the relationship between KIT mutations and GIST clinicopathologic features to define region-specific and population-specific differences. Genomic DNA was extracted from 60 GISTs, and polymerase chain reaction was performed for KIT gene exons 9, 11, 13, and 17. Polymerase chain reaction amplicons were sequenced in both directions. This study represents the first mutation data of the KIT gene in GISTs from a Turkish population and reports novel mutations. The mutation rate in exon 11 (46.7%) was remarkably higher than those of the other exons (8.3% for exon 9; 11.7% for exon 13; 1.7% for exon 17). There was an association between malignancy potential and the presence of KIT mutations (odds ratio=3.18). Cases with mutations in codons W557 K558 in exon 11 had 11-fold greater risk of malignancy when compared with those without a mutation in this exon (odds ratio=11). We report different mutations than those previously reported, which emphasizes the importance of personalized medicine that could be empowered by the use of bioinformatics tools in the diagnostic process and therapeutic approaches. PMID- 23455186 TI - Triple-negative, basal marker-expressing, and high-grade breast carcinomas are characterized by high lymphatic vessel density and the expression of podoplanin in stromal fibroblasts. AB - Podoplanin, expressed in the lymphatic but not in the blood vessel endothelium, is widely used as a specific marker for lymphatic endothelial cells and lymphangiogenesis. The relation between lymphatic vessel density and breast cancer subtype or the expression of basal markers has not yet been investigated. We assessed lymphatic vessel density (LVD), blood vessel density, and the expression of podoplanin in stromal cancer-associated fibroblasts, in 156 invasive ductal breast cancers (T>=1, N>=1, M0). Afterwards, we assessed the relationship between the above-mentioned parameters and (i) breast cancer subtype (luminal vs. HER2 vs. triple negative), (ii) tumor grade (G1 vs. G2 vs. G3), (iii) the expression of cytokeratin (CK) 5/6, (iv) P-cadherin, (v) smooth muscle actin (SMA), and (vi) the pattern/intensity of stromal lymphocytic infiltration. We found a significantly higher LVD and podoplanin expression in stromal fibroblasts in (i) G3 tumors, (ii) triple-negative carcinomas, (iii) tumors expressing CK5/6, SMA, or P-cadherin, and (iv) neoplasms with stroma intensively infiltrated by lymphocytes. Moreover, we observed a significant inverse relationship between the expression of podoplanin in luminal A subtype, P cadherin, CK5/6, and SMA-negative tumors and tumors without strong lymphocytic infiltration. A significantly higher percentage of tumors with strong lymphocytic infiltration was noted among G3 carcinomas. Breast carcinomas of different grades, subtypes, and basal marker expression are characterized by different composition of the stroma, that is different LVD, podoplanin expression in stromal fibroblasts, and the pattern/intensity of lymphocytic infiltration. PMID- 23455187 TI - One-day FISH approach for the high-speed determination of HER2 gene copy status in breast carcinoma. AB - Fluorescence in situ hybridization (FISH) is a commonly used method to detect chromosomal aberrations, for example, to assess human epidermal growth factor receptor 2 (HER2) gene status in breast carcinoma. The classical FISH approach requires overnight incubation for proper hybridization result. Tissue morphologic features are varying because of aggressive pretreatment and application of high temperatures. To eliminate some of the methodological problems, a new 1-day FISH method was recently introduced. The aim of our study was to evaluate the utility of the Instant Quality FISH with the conventional FISH kit from the same provider (Dako pharmDx) for determination of HER2 status. We performed in situ hybridization on the same 40 invasive breast carcinoma samples with both probe kits, and HER2/CEN17 and chromosome 17/cell nucleus ratios were calculated. FISH signal stability was also tested by the reassessment of the slides after 2 months storage. The accordance regarding HER2 gene amplification status between the 2 FISH kits tested was 100%. There was an excellent correlation between HER2/CEN17 ratios with a concordance correlation coefficient of 0.958 and correlation coefficient (R) of 0.959. The 1-day HER2 Instant Quality FISH diagnostic kit points with fast and stable reaction showing the same result in the diagnostic practice when compared with the conventional overnight FISH method. PMID- 23455188 TI - The significance of immunohistochemical expression of merlin, Ki-67, and p53 in meningiomas. AB - Meningiomas are one of the most common CNS tumors whose appearance is closely linked to NF2 gene product merlin. Tumor markers Ki-67 and p53 play established role in tumor progression which should be analyzed in close association with merlin expression. The aim of this study was to investigate the immunohistochemical expression of merlin in meningiomas, correlation with Ki-67 and p53, and to determine the association of these results with histologic grade and subtype. The histologic sections of 170 patients with totally resected meningiomas, between January 2000 and December 2010, were classified according to WHO, immunohistochemically stained for Ki-67, p53, and merlin, and analyzed using light microscope. Ki-67 median was 5.6 times higher in group of patients with negative merlin than in those with positive merlin (P=0.05). Statistically significant correlation of merlin with p53 was found (P<0.001). Merlin expression between 2 combined groups (meningothelial/secretory and fibroblastic/transitional) was statistically significant (P=0.002). By comparing merlin expression and p53 levels, statistically significant difference was found (P=0.017). In the group with positive merlin and negative p53 as well as positive merlin and low p53, meningothelial/secretory subtypes of meningiomas were more common. In combination of negative merlin and negative p53 as well as negative merlin and high p53, there were more meningiomas of fibroblastic/transitional subtype. There was no statistically significant correlation between merlin and tumor grade (P=0.420). There is undeniable influence of merlin on the development and the proliferative ability of meningioma subtypes. Significant role of p53 pathway was confirmed. PMID- 23455189 TI - In vitro tumor cytotoxic activities of extracts from three Liriodendron plants. AB - The extracts prepared from Liriodendron tulipifera Linn., L. chinense (Hemsl.) Sarg., and their hybrid L. chinense x L. tulipifera, were investigated for their cytotoxic abilities in vitro against five human cancer cell lines: MDA-MB-231 and MCF-7 breast cancer cells, SGC-7901 gastric cancer cells, HuH-7 hepatocarcinoma cells, and HCT-15 colon carcinoma cells, and then measured their phenols and alkaloids contents. Of these plant extracts, some of them, especially the lower polar extracts from barks, exhibited potent cytotoxic effects on five tested tumor cell lines. PMID- 23455190 TI - Serum amyloid-A protein and serum rheumatoid factor as serological surrogate markers for smoking risk factor in Saudi population. AB - Tobacco smoking represents major national and international health hazard that interferes with wide range of physiological functions and biomarkers. In the current study we have investigated the influence of tobacco smoking on some biological markers such as serum amyloid protein-A, rheumatoid factor, serum glucose level and lipid profile in Saudi population. The fore mentioned parameters were investigated in a total of 275 cases in 3 different age categories (less than 20 years old, 20-40 years old and older than 40 years old). Long term survey was adopted in all cases; yet, lightly smoking and heavily smoking groups were compared to never smoking healthy population. Results obtained showed significant increase in serum amyloid protein-A and rheumatoid factor in correlation to the degree of smoking nonetheless in the age category older than 40 years old. Serum glucose, triglyceride, and total cholesterol was not affected by smoking in all studied age categories; however serum LDL cholesterol was elevated and serum HDL-cholesterol was depressed in correlation to the degree of smoking in all age categories. In conclusion, tobacco smoking represents major cardiovascular risk factor in Saudi population in all age categories and serum amyloid protein-A and rheumatoid factor might be used as a serological surrogate marker for such risk. PMID- 23455191 TI - Phenolic contents, antioxidant and cytotoxic activities of Elaeocarpus floribundus Blume. AB - Elaeocarpus floribundus is higher plant that has been used as traditional medicine for treating several diseases. There is no previous report on phytochemicals and bioactivity studies of this species. In this investigation, triterpenoids friedelin, epifriedelanol and beta-sitosterol were isolated from its leaves and stem bark. Determination of total phenolic content of methanolic extract of leaves and stem bark was carried out using Folin-Ciocalteu reagent. All extracts and isolated compounds were subjected to screening of antioxidant activity using DPPH free radical scavenging method and cytotoxic activities by MTT assay towards human T4 lymphoblastoid (CEM-SS) and human cervical (HeLa) cancer cells. In the total phenolic content determination, methanolic extract of leaves gave higher value of 503.08+/-16.71 mg GAE/g DW than stem bark with value of 161.5+/-24.81 mg GAE/g DW. Polar extracts of leaves and stem bark possessed promising antioxidant activity with methanol extract of stem bark exhibited strongest activity with IC50 value of 7.36+/-0.01 MUg/ml. In the cytotoxic activity assay, only chloroform extract of leaves showed significant activity with IC50 value of 25.6+/-0.06 MUg/ml against CEM-SS cancer cell, while friedelin and epifriedelanol were found to be active against the two cancer cells with IC50 values ranging from 3.54 to 11.45 MUg/ml. PMID- 23455192 TI - Inhibitory effects of Olea ferruginea crude leaves extract against some bacterial and fungal pathogen. AB - This work aimed to evaluate the inhibitory effects of Olea ferruginea crude leaves extract that are commonly used as remedy to cure infections in the tribal (Khyber Agency) areas of Pakistan against some of bacterial and fungal pathogens. The crude n-hexane fraction was appreciably active against both gram positive and negative microorganisms (MIC ranged from 7.5 to 15 mg/ml) followed by butanol fraction (MIC 15 to 30 mg/ml). Conversely least biological activity was shown by chloroform (30mg/ml) and methanol (15 to 30mg/ml) crude fractions. The MBC observed for all crude fractions was same or 2 times higher when compared with MIC for all crude extract fractions. Likewise all the fractions showed activity against Aspergillus niger and maximum zones of inhibition were shown by the n hexane fraction (14 +/- (0.02), butanol (13 +/- (0.02) followed by methanol (9 +/ (0.05) and chloroform fractions (7 +/- (0.02). These results clearly imitate the antibacterial and antifungal potential of Olea ferruginea and hence we recommend the whole plant for further futuristic studies. PMID- 23455193 TI - Bioequivalence study of montelukast tablets in healthy Pakistani volunteers. AB - Montelukast is a leukotrien receptor antagonist used for asthma treatment. Objective of this study was to evaluate the bioequivalence of two montelukast 10mg tablets, Innovator drug (Singulair) as reference and other locally manufactured drug (Montiget) in 12 healthy volunteers. It was randomized, single dose, two-period crossover study with 1 week washout period. Blood samples (4-5 ml) were collected before and after drug administration and plasma was separated for analysis. Concentrations of montelukast at different time intervals were determined by validated UV-HPLC method at 345nm wavelength. Bioequivalence was assessed by using non compartmental approach and also calculated the 90% confidence interval of the least-squared pharmacokinetic parameters (Cmax, AUC0-t and AUC0-OO). On average, Cmax, AUC0-t, AUC0-inf, was 2.35MUg/mL, 1.28ug.h./ml, 1.67ug.h./ml, for innovator drug and 2.53MUg/mL, 1.53ug.h./ml, 1.96ug.h./ml, for test drug, respectively. Confidence interval (90%) for Cmax, AUC0-t and AUC0-inf was 89-97%, 85-91% and 81-98% respectively. No statistical difference was found between the Cmax and AUC values of test and reference drugs. The confidence intervals for Cmax, AUC0-t and AUC0-OO are fully laid within the acceptable range of FDA (80-125%), thus two formulations are considered to be bioequivalent. PMID- 23455194 TI - Doxofylline and methylprednisolone sodium succinate are stable and compatible under normal injection conditions. AB - To assess the physical compatibility and chemical stability of doxofylline with methylprednisolone sodium succinate in 0.9% sodium chloride or 5% dextrose injection for intravenous infusion. Twenty mL doxofylline solution (0.74 mg/mL) and 1 mL methylprednisolone sodium succinate solution (0.15 mg/mL) were added into 250 mL polyolefin bags containing 5% dextrose injection or 0.9% sodium chloride injection, and stored for 24 h at 20-25( degrees )C. Chemical compatibility was measured with high-performance liquid chromatography (HPLC), and physical compatibility was determined visually. The results showed that samples were clear and colorless when viewed in normal fluorescent room light. The pH value exhibited little change. The particulate content of > 25 MUm was low and within the specification limit. The particulate content of > 10 MUm decreased over time and was similar to the control solution. Analysis of chemical stability revealed that doxofylline is stable with methylprednisolone sodium succinate for up to 24 h, and the degradation of methylprednisolone sodium succinate is unrelated to doxofylline, but is closely related to the pH value of the solution. Doxofylline and methylprednisolone sodium succinate did not affect the stability of each other. PMID- 23455195 TI - Antibacterial activity of some medicinal plants grown in Jordan. AB - In the present study, we evaluated the antimicrobial activity of 16 Jordanian medicinal plant extracts against four reference bacteria; Staphylococcus aureus, Enterobacter faecalis, Escherichia coli, and Salmonella typhi. For that purpose, whole plants were extracted and antimicrobial susceptibility testing and minimum inhibitory concentration (MIC) were determined. Ethanolic extracts of most medicinal plants exerted a dose-dependent cytotoxiciy against different reference bacteria. Origanum syriaca, Varthemia iphionoides, Psidium guajava, Sarcopoterium spinosa plant extracts were most active against S. aureus (MIC; 70 MUg/mL), E. faecalis (MIC; 130 MUg/mL), E. coli (MIC; 153 MUg/mL), and S. typhi (MIC; 110 MUg/mL), respectively. Results indicate that medicinal plants grown in Jordan might be a valuable source of starting materials for the extraction and/or isolation of new antibacterial agents. PMID- 23455196 TI - Oral administration of haloperidol at clinically recommended doses elicits smaller parkinsonian effects but more tardive dyskinesia in rats. AB - The present study was designed to monitor extrapyramidal symptoms (EPS) elicited by the oral administration of haloperidol at clinically recommended doses and to compare it with EPS produced when the drug is injected intraperitoneally at doses used in animal research. Rats injected with haloperidol at a dose of 1 mg/kg daily for 5 weeks exhibited akinesia in an open field and impaired motor coordination. Effects of the drug on motor coordination but not on open field akinesia were attenuated gradually from 2-5 weeks of treatment. Oral administration of haloperidol in drinking water at clinically recommended dose exhibited decreased exploratory activity without producing akinesia. Motor coordination was impaired maximally after 3 weeks and tolerance was developed in the drug induced motor impairment after 5 weeks of treatment. Intensity of vacuous chewing movements (VCMs) and tardive VCMs was greater by oral administration than intraperitoneal injections of haloperidol. The present results showed that oral administration of haloperidol expected to produce sustained effect may result in tolerance in acute parkinsonian like effects but more intensity of tardive dyskinesia. We suggest that drugs which may helpful in alleviating tardive dyskinesia may be more useful if person is on oral drug therapy. PMID- 23455197 TI - Screening of endophytic Streptomycetes isolated from Parthenium hysterophorus L. against nosocomial pathogens. AB - Parthenium hysterophorus L. is an obnoxious weed of the family asteraceae recognized for its detrimental effects and significant economic losses to agriculture. In this study 42 endophytic streptomycetes strains were isolated from its roots and leaves. The isolates were identified by morphological, microscopic, biochemical and physiological characterization as members of genus Streptomyces. In 16S rRNA gene sequencing the selected isolates exhibited maximum similarity with Streptomyces rochei (99%), Streptomyces litmocidini (99%), Streptomyces enissocaesili (99%), Streptomyces djakartensis (99%), Streptomyces olivaceus (99%), Streptomyces spp (99%), Streptomyces plicatus (99%), Streptomyces geysiriensis (99%) and Streptomyces vinaceusdrappus (99%). In biological screening the crude extracts of 12 strains exhibited significant antimicrobial activity against multi drug resistant nosocomial pathogens including Pseudomonas, Enterobacter, Bacillus, Escherichia coli, Staphlococcus aureus and Candida albicans. In chemical screening by thin layer chromatography (TLC) the extracts exhibited an impressive diversity of the bioactive secondary metabolites. Additionally high performance liquid chromatography (HPLC-UV) chromatographs revealed many impressive peaks of unidentified bioactive metabolites. As such this is a first study reporting the isolation, identification and screening of endophytic Streptomyces from the invasive weed. The results provide an insight into an untapped endophytic environment yet to be explored which might be a promising source of lead antimicrobial agents. PMID- 23455198 TI - Calcium activated potassium channel and protein kinase C participate in the cardiac protection of remote post conditioning. AB - The present study was designed to investigate the roles of Ca(2+) activated K(+) channel (KCa) and protein kinase C (PKC) in the protective mechanisms of remote ischemic post conditioning (RPostC) when rat heart was subjected to ischemia/reperfusion (I/R) injury in vivo. Rat heart was subjected to regional ischemia for 45 min and reperfusion for 180 min in vivo to mimic I/R injury. RPostC was induced by 5 min right femoral artery occlusion followed by 5 min reperfusion for 3 cycles (totally 30 min) after 15 min of cardiac ischemia. Delayed remote ischemic post conditioning (delayed RPostC) was induced after 10 min of cardiac reperfusion. The hemodynamic parameters including mean arterial blood pressure and heart rate (HR) were recorded, and lactate dehydrogenase (LDH) release in plasma and infarct size were determined, and arrhythmia scores were calculated. In contrast to I/R, RPostC reduced infarct size and LDH release during reperfusion, the occurrence of arrhythmia was decreased, but no changes in delayed RPostC. The specific inhibitor of KCa iberiotoxin and PKC inhibitor chelerythrine both attenuated the role of RPostC. The findings indicated that RPostC had a protective effect on myocardial ischemia/reperfusion injury. Opening of KCa and activating of PKC may be involved in the mechanisms of RPostC. PMID- 23455199 TI - Phenotypic and molecular characterization of extended-spectrum beta-lactamases and AmpC beta-lactamases in Klebsiella pneumoniae. AB - The incidence of resistance to extended-spectrum cephalosporins (ESC) among Egyptian isolates of Klebsiella pneumoniae has already been increasing and previously reported. This work devotes to investigate the genetic basis of resistance to ESC in K. pneumoniae isolates. Disc diffusion test, minimum inhibitory concentrations (MIC) determination and phenotypic screening for extended spectrum beta-lactamases (ESBLs) and plasmid-mediated AmpC beta lactamases (PABLs) were carried out for 21 K. pneumoniae isolates, collected during 2011 at Sayed Galal Hospital, Cairo. Genes for ESBLs, PABLs and class 1 integrase were sought by PCR and DNA sequencing. Matting out assay was performed to determine the mobility of bla genes. Six (28.57%) of 21 clinical isolates K. pneumoniae were non-sensitive to ESC. ESBL and PABL phenotypes were identified in 5 and one K. pneumoniae isolates, respectively. PABL-producing isolate was found to carry blaCMY-2 and blaSHV-1. All five ESBL-producing isolates carried blaCTX-M 15. CTX-M-15 was associated with SHV-1 and SHV-12 in three isolates and two isolates respectively.TEM-1 was associated with CTX-M-15 and SHV in two isolates. Both CTX-M-15 and CMY-2 genes were located on conjugative plasmids and associated with class 1 integrase. Resistance to ESC was due to CTX-M-15, SHV-12 and CMY-2 in K. pneumoniae. This study represents the first report of CMY-2 and SHV-12 beta lactamase-producing K. pneumoniae isolates in Egypt. PMID- 23455200 TI - Novel indium-111 labeled gastrin peptide analogues (MG-CL1-4): synthesis and quality control. AB - Radiolabeled neuropeptides are widely investigated to diagnose and therapy of tumors. These peptides get internalization after binding with particular receptors at the surface of cells and finally move to lysosome. Internalization into tumor cells helps in mapping the infected site. Minigastrin peptide analogues (MG-CL1-4) were synthesised and labeled with 111-In radioisotope under different sets of conditions for imaging CCk-2 receptor bearing tumors. Different parameters such as temperature (80-100 degrees C), pH (4-12), incubation time (5 30 minutes) and dilution effect were investigated to get the maximum labeling yield and stability. The results indicated that MG-CL1-4 is successfully labeled with indium-111 at pH 4.5 with heating at 98 degrees C for 15 minute. At these conditions i.e. heating, pH and incubation minimum oxidized and maximum labeling yield, more than 94 %, was obtained. The labeling stability was studied by incubating the radiolabeled complex for predefined time points in PBSA and blood serum. Results show that more than 90% radiolabeled MG-CL1-4 remained intact. PMID- 23455201 TI - Medicinal uses of honey (Quranic medicine) and its bee flora from Dera Ismail Khan District, KPK, Pakistan. AB - This study was carried out during 2005-2008 to identify existing plant species visited by workers of honeybees for nectar and pollen collection in Dera Ismail Khan (D.I.Khan) District, Pakistan. The honeybee species investigated in the area were, rock bee (Apis dorsata F.), little bee (A. florea F.) and European honeybee (A. mellifera L.). A detailed list of 86 plant species both wild and cultivated was prepared, out of which 12 species, Phulai (Acacia modesta Wall.), Sarsoon (Brassica campestris L.), Kaghzi nimboo (Citrus aurantifolia L.), Khatta (C. medica L.), Malta (C. sinensis (L.) Osbeck.), Shisham (Dalbergia sissoo Roxb.), Date (Phoenix dactylifera L.), Barseen (Trifolium alexandrianum L.), Shaftal (T. resupinatum L), Makai (Zea mays L.), Ber (Zizyphus mauritiana Lam.) and Jher beri (Z. numularia (Burm. f.) Wight & Arn.,) were found as major sources (table 1) for the production of surplus honey in a year at different localities in the District. Among the minor sources various plant species were included (table 2). These plants fill the flowering gaps between the major sources in various parts of the year and help in continuous supply of food to honey bees. PMID- 23455202 TI - Preparation and in vitro and in vivo evaluation of HupA PLGA microsphere. AB - Acetylcholinesterase inhibitors (AChEIs), including Huperzine A (HupA), have been the mainstay of treatment for Alzheimer's disease (AD). However, AChEIs can cause gastrointestinal side effects, which has been related to the high Cmax and short tmax after oral administration. Clinical trials have verified that extended release formulation with lower Cmax and prolonged tmax, such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended release microspheres formulation of HupA (called as HAM) with poly(lactide-co glycolide) (PLGA) as drug carrier. HAM has showed the loading rate as 1.35% (w/w) and yielded 42% with mean particle size at 72.6 MUm. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the Cmax was lower and the tmax was considerably later in single intramuscular administration of HAM (1,000 MUg/kg) than the counterparts in single intragastric administration of HAT (75 MUg/kg/d). Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in Abeta1-40 i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation. PMID- 23455203 TI - Design and development of insulin emulgel formulation for transdermal drug delivery and its evaluation. AB - The objective of the present study was to formulate an insulin emulgel, selection of an optimize formulation through in vitro drug release kinetics and finally evaluate its hypoglycemic activity in animal model. Insulin emulgel was prepared using emu oil as penetration enhancer with the combination of carbomer or hydroxypropyl methylcellulose (HPMC) as gelling agent and polysorbate 80 as emulsifier. The response of gelling agent type (carbomer or HPMC) and concentration of other two variables penetration enhancer and emulsifier were studied using 2(3)factorial design during in vitro drug release through excised rat skin. Biological activity of emulgel formulation was also investigated using Albino rabbits alone and in combination with iontophoresis. The in vivo efficacy of insulin emulgel was assessed by measuring the blood glucose level at start of the experiment and after every 15 minutes interval for 120 minutes. Total eight formulations were studied. F4 formulation showed maximum insulin permeation flux (4.88 +/- 0.09 MUg/cm(2)/hour) through excised rat skin. Insulin permeation from these formulations was found to follow the Korsmeyer-Peppas model (r(2) =0.975 to 0.998) during 24 hour with non-Fickian mechanism. Formulation F4 was further investigated in Albino rabbits. For the first group (treated with insulin emulgel alone) the blood glucose level decreased from initial value 250+/-10mg/dl to 185+/-7mg/dl at 120 minutes and for the second group (treated with insulin emulgel plus iontophoresis) the blood glucose level decreased to 125+/-5mg/dl in 120 minutes (P<0.05). It was observed that absorption of insulin through transdermal emulgel was greater in combination with iontophoresis to decrease blood glucose level. On the basis of this study, it has been shown that application of insulin emulgel iontophoretically can be used as alternative (acceptable & painless) to injectable insulin subject to further studies on large animals. PMID- 23455204 TI - Development of 99mTc-5-fluorouracil as a potential tumor diagnostic agent. AB - 5-Fluorouracil is a well know drug for chemotherapy of various types of cancer. In the present study, we radiolabeled 5-fluorouracil with (99m)Tc for a diagnostic study of cancer. After successful labeling of the drug we performed an animal study to evaluate the potential of this radiopharmaceutical as a tumor diagnostic agent. The results showed 98.1 +/- 1.2% labeling efficacy of 5 fluorouracil with (99m)Tc. The in vitro stability of the radiolabeled drug at room temperature at 4 hr of post-labeling was >96.5 +/- 0.4%. The binding of the radiolabeled drug with plasma proteins was 66.6 +/- 3%. Partition coefficient results showed that this drug is hydrophilic in nature. Biodistribution study in rabbit models displayed faint uptake in liver. Both kidney and bladder were prominent as excretory route of the labeled drug. Bioevaluation was performed in Swiss Webster mice having naturally developed tumor. Mice were dissected, uptake of drug in various organs was studied and results showed prominent uptake in liver and tumor. Tumor was further investigated by histopathological study. PMID- 23455206 TI - Synthesis, characterization and biological screening of 5-substituted-1,3,4 oxadiazole-2yl-N-(2-methoxy-5-chlorophenyl)-2-sulfanyl acetamide. AB - In the current study, a series of 5-substituted-1,3,4-oxadiazole-2yl-N-(2-methoxy 5-chlorophenyl)-2-sulfanyl acetamide was synthesized by converting variously substituted/unsubstituted aromatic organic acids successively into the corresponding esters, hydrazides and then 5-substituted-1,3,4-oxadiazole-2 thiols. Finally the target compounds were obtained by stirring 5-substituted 1,3,4-oxadiazole-2-thiols with N-(2-methoxy-5-chlorophenyl)-2-bromoacetamide in the presence of N,N-dimethyl formamide (DMF) and sodium hydride (NaH). The structures of the synthesized compounds were confirmed based on (1)H-NMR, IR and mass spectral data. The synthesized compounds were screened against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase enzymes (LOX) and were found to be relatively more active against acetyl cholinesterase. PMID- 23455205 TI - Side effects of antibiotics on the intestinal microflora by PCR-DGGE. AB - Antibiotics are recommended for use in the treatment of infectious diseases, but the side effects have not been thoroughly investigated, especially on the intestinal tract. Fluoroquinolones, macrolides and beta-lactams were tested the side effects on the intestinal microbflora of mice in this study. The similarity and sequence analysis of the dominant bands for different drug administration periods were carried out by denaturing gradient gel electrophoresis (DGGE) profiles. The total amount of 16S rRNA gene increased after drug administration, the bacterial composition and structure could be divided into different clusters for different drug administration periods distinctly. This study revealed a significant change of bacterial composition of microflora from intestinal tract as antibiotics were applied to tested mice. PMID- 23455207 TI - Synthesis, characterization and bioevaluation of technetium-99m labeled N-(2 Hydroxybenzyl)-2-amino-2-deoxy-D-glucose as a tumor imaging agent. AB - N-(2-Hydroxybenzyl)-2-amino-2-deoxy-D-glucose (NHADG) was synthesized by conjugation of salicylaldehyde to glucosamine. The obtained compound was well characterized via different analytical techniques. Labeling of the synthesized compound with technetium-99m ((99m)Tc) in pertechnetate form ((99m)Tc O4-) was carried out via chelation reaction in the presence of stannous chloride dihydrate. Maximum radiochemical yield of (99m)Tc-NHADG complex (99%) was obtained by using 1 mg NHADG, 200 MUg SnCl2.2H2O, at pH 9.5 and reaction time of 15 min. The radiochemical purity of the (99m)Tc-NHADG complex was measured by instant thin layer chromatography (ITLC) and paper chromatography (PC), without any notable decomposition at room temperature over a period of 4h. The biological evaluation results show that the (99m)Tc labeled NHADG conjugate is able to specifically target mammary carcinoma in mice models, thus highlighting its potential as an effective (99m)Tc labeled glucose-derived agent for tumor imaging. PMID- 23455209 TI - In house development of (99m)Tc-Rhenium sulfide colloidal nanoparticles for sentinel lymph node detection. AB - In this study, rhenium sulfide colloidal nanoparticles were developed as radiopharmaceutical for sentinel lymph node detection. We directly used rhenium sulfide as a starting material for the preparation of colloidal nanoparticles. UV visible spectrophotometry was used for characterization of in house developed colloidal particles. The size distribution of radioactive particles was studied by using membrane filtration method. The percentage of radiolabeled colloidal nanoparticles was determined by paper chromatography (PC). The study also includes in vitro stability, protein binding in human blood and bioevaluation in a rabbit model. The results indicate that 77.27 +/- 3.26 % particles of size less than 20nm (suitable for lymphoscintigraphy) were radiolabeled. (99m)Tc labeled rhenium sulfide labeling efficacy with the radiometal is 98.5 +/- 0.5%, which remains considerably stable beyond 5h at room temperature. Furthermore, it was observed that 70.2 +/- 1.3% radiolabeled colloid complex showed binding with the blood protein. Bioevaluation results show the remarkable achievement of our radiopharmaceutical. The in house prepared (99m)Tc labeled rhenium sulfide colloidal nanoparticles reached the sentinel node within 15 min of post injection. These results indicate that (99m)Tc labeled rhenium sulfide colloid nanoparticles kit produced by a novel procedure seems of significant potential as a feasible candidate for further development to be used in clinical practice. PMID- 23455208 TI - Anti-diabetic effect of Murraya koenigii (L) and Olea europaea (L) leaf extracts on streptozotocin induced diabetic rats. AB - Phytotherapy has a promising future in the management of diabetes, considered to be less toxic and free from side effects as compared to the use of synthetic drugs. The aim of the present study was to assess the antidiabetic possible of orally administered aqueous extracts of Murraya koenigii (ML) and Olea europaea (OL) leaves (100 and 200 mg/kg doses), in streptozotocin (70 mg/kg) induced diabetic rats. Metformin was used as a standard drug. Blood glucose, cholesterol, triglycerides, creatinine levels and body weight were estimated. ML and OL administration showed significant decrease (p>0.05) in cholesterol, triglyceride, and serum glucose levels (range 55.6%-64.6%) compared to the metformin (62.7%); however, there was no significant effect on body weight and serum creatinine. Our results suggest that both the ML and OL possess a potent antihyperglycemic and hypolipidemic effect, which may be due to the presence of antioxidants such as carbazole alkaloids and polyphenols. PMID- 23455210 TI - Simultaneous quantification of flavonoids in blood plasma by a high-performance liquid chromatography method after oral administration of Blumea balsamifera leaf extracts in rats. AB - The leaves of Blumea balsamifera are used as a folk medicine in kidney stone diseases in South-East Asia. Phytochemical investigation revealed leaves contained a number of flavonoids. In view of these, the present work was aimed to quantify and preliminary pharmacokinetic investigation of five flavonoids viz. dihydroquercetin-7,4c-dimethyl ether (I), dihydroquercetin-4c-methyl ether (II), 5,7,3c,5c-tetrahydroxyflavanone (III), blumeatin (IV) and quercetin (V) in rat plasma following oral administration (0.5g/Kg) of B. balsamifera leaf extract in rats. Quantification was achieved by using a validated, reproducible high performance liquid chromatographic method. The mean recoveries of I, II, III, IV and V were 90.6, 93.4, 93.5, 91.2 and 90.3% respectively. The limit of quantification was 25 ng/mL for I and IV, 10 ng/mL for II and III and 100 ng/mL for V respectively. The within day and day-to-day precision for all the compounds were < 10%. The validated HPLC method herein was applied for pharmacokinetic studies and the main pharmacokinetic parameters were: t1/2 (hr) 5.8, 4.3, 2.9, 5.7 and 7.3, Cmax (ng/mL) 594.9, 1542.9 1659.9, 208.9 and 3040.4; Tmax (hr) 4.7, 1.0, 1.0, 3.5 and 2.3; AUC0-oo (ng hr/mL) 5040, 5893, 9260, 1064 and 27233 for I, II, III, IV and V respectively. The developed method was suitable for pharmacokinetic studies and this preliminary study also revealed significant absorption after oral dosing in rats. PMID- 23455211 TI - Role of extra-cellular fatty acids in vancomycin induced biofilm formation by vancomycin resistant Staphylococcus aureus. AB - In the present study a vancomycin resistant Staphylococcus aureus (S. aureus) (VRSA) (Labeled as CP2) was isolated from the blood of a post-operative cardiac patient is described. It harbors a plasmid which carry vanA gene and exhibited low-level vancomycin resistance (MIC 16MUg/mL), was sensitive to teicoplanin. It has been observed that sub-lethal dose of vancomycin induced biofilm formation by CP2 on nylon and silicon indwelling. The results divulge new insights into associations between vancomycin induced biofilms and extra-cellular fatty acids. Gas chromatography coupled with mass spectrometry (GC-MS) revealed that biofilm matrix of CP2 contains a variety of saturated and un-saturated fatty acids, especially, diverse species of octadecanoic (C18:0) and octadecenoic acids (C18:1). A large difference in fatty acids composition was noticed in biofilms, isolated from hydrophobic and hydrophilic surfaces. CP2 produced thicker layer of biofilms on hydrophobic silicon and nylon surfaces which contains variety of saturated, un-saturated and cyclic fatty acids. Contrary to this on hydrophilic glass surfaces it produced thinner layer of biofilm which contains only straight chain saturated fatty acids. These fatty acid components seem to play a crucial role in cell-cell communication and in the establishment of biofilms, consequently, advantageous for pathogens to survive in hospital environment under enormous antibiotics pressure. PMID- 23455212 TI - Evaluation of biological activities of Alpinia mutica Roxb. and its chemical constituents. AB - Phytochemicals investigation on rhizomes of Alpinia mutica has afforded five compounds namely 5,6-dehydrokawain (1), flavokawin B (2), pinostrobin (3) and pinocembrin (4) together with beta-sitosterol (5). All crude extracts of the plant demonstrated strong cytotoxicity against CEMss (human T4 lymphoblastoid) cancer cells with IC50 values less than 19 MUg/mL, while flavokawin B (2) was the most cytotoxic isolate with IC50 value 1.86+/-0.37 MUg/mL. Most of the crude extracts and isolated compounds showed weak activity in antimicrobial and diphenylpicrylhydrazyl (DPPH) radical scavenging activity tests. PMID- 23455213 TI - The effect of Persian shallot (Allium hirtifolium Boiss.) extract on blood sugar and serum levels of some hormones in diabetic rats. AB - Diabetes mellitus (DM) is caused by hyperglycemia, resulting from defective insulin secretion or function. It is widely believed that the antioxidant micronutrients obtained from plants afford significant protection against diseases like diabetes mellitus. Present study was aimed to examine the effects of Persian shallot (Allium hirtifolium Boiss) on FBS, HbA1c, insulin, triiodothyronine (T3) and thyroxine (T4) levels in type 1 diabetic rats. Thirty two male Wistar rats were divided into 4 groups of 8. The diabetic groups received 100 and 200 mg/kg Persian shallot extract, diabetic control and normal control received %0.9 saline for 30 days. At the end of treatments, fasting blood specimens were collected. The levels of FBS, HbA1c, insulin, T3 and T4 were measured. Our findings indicated that hydroalcoholic extract of Persian shallot significantly decreased serum levels of FBS and HbA1c in treated groups (in a dose dependent manner) (p<0.05). The serum levels of insulin and T3 slightly increased by Persian shallot but the T4 serum level was declined. These beneficial effects of Persian shallot extracts in diabetic rats could probably be due to the antioxidant capacity of its phenolic and diallyl disulfide content. PMID- 23455214 TI - Anti-inflammatory effects of essential oil in Echinacea purpurea L. AB - Echinacea purpurea L. is a medicinal plant originally from North America. It has become a commonly used herbal medicine worldwide because it contains various biologically active compounds. This study was designed to investigate the anti inflammatory effects of essential oils from E. purpurea in both mice and rats. The extract was obtained from flower of E. purpurea by steam distillation. The anti-inflammatory potential was evaluated in vivo by using different animal models such as xylene-induced mouse ear edema, egg-white-induced rat paw edema, and cotton-induced granuloma tissue proliferating inflammation in mice. The serial dosages were used in vivo: the low dosage, the medium dosage and the high dosage. The low, medium and high dosages of extracts produced inhibitions of 39.24%, 47.22% and 44.79% respectively in the ear edema induced by xylene when compare with the control group. Only the high dosage group showed statistically significant inhibition (48.51%) of paw edema formation induced three hours by egg white compared with the control group (P<0.01). Moreover, the granulation formation was also significantly reduced the most by 28.52% in the high dose groups compared with the control group (P <0.05). The pro-inflammatory cytokines such as IL-2, IL-6 and TNF-alpha in the blood were reduced in the treated groups. The essential oils from extracts of E. purpurea have anti-inflammatory effects. PMID- 23455215 TI - Screening of solvent dependent antibacterial activity of Prunus domestica. AB - Fruit of Prunus domestica was extracted in ethanol. The ethanol extract was further extracted with two solvents ethyl acetate and chloroform. The crude ethanol extract and two fractions (ethyl acetate and chloroform) were screened for their antibacterial activity using the agar well diffusion method .They were tested against nine bacteria; five Gram positive bacteria (Staphylococcus aureus, Streptococcuc intermedius, Bacillus cereus, Bacillus pumilus) and four Gram negative bacteria (Eschrichia coli, Proteus mirabilis Shigella flexneri, Salmonella typhi and Klebsiela pneumoniae). The susceptibility of microorganisms to all three fractions was compared with each other and with standard antibiotic (Ampicillin) Among all fractions ethyl acetate exhibited highest antibacterial activity (average zone of inhibition 34.57mm +/- 1.3) while ethyl alcohol exhibited least antibacterial activity (average zone of inhibition 17.42mm +/- 3.3). Minimum inhibitory concentration of ethanol, ethyl acetate and chloroform fractions was found in the range of 78 MU g/ml to 2500 MU gl/ml against gram positive and gram negative bacteria. PMID- 23455216 TI - Comparative study on resistant pattern of clinical isolates against levofloxacin and cefepime. AB - The aim of this study is to evaluate the susceptibility and resistance pattern of clinical isolates causing different types of infections and to compare the efficacy of antibiotics namely levofloxacin and cefepime. The in-vitro antibacterial activity and resistance patterns of these two well known antibiotics were studied and compared using disk diffusion method. For this, one hundred clinical isolates comprising of Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa were collected from different local pathological laboratories and hospitals. Escherichia coli (17.95% against cefepime and 30.77% against levofloxacin), Staphylococcus aureus (30% against cefepime and 46.66% against levofloxacin) and Pseudomonas aeruginosa (23.53% against cefepime and 35.29% against levofloxacin) were found resistant against the studied antibiotics which show that cefepime is more effective than levofloxacin. In case of Klebsiella pneumoniae, resistance was 42.85% against cefepime and 35.71% against levofloxacin thereby showing that levofloxacin is more effective than cefepime. Concluded that the clinical isolates collected were susceptible to both the antibiotics but the microbial resistance against these antibiotics is increasing in our population which is alarming. Therefore, it is recommended the physicians may prescribe these antibiotics unless no other substitute is available in clinical practice. PMID- 23455217 TI - Study of alteration of adrenergic receptor response by chronic use of lisinopril: an ACE inhibitor. AB - Unpredictable outcomes of life saving drugs have been seen in patients who receive different cardioselective drugs for longer periods. Many studies have been conducted to explore these responses. This study shows the down regulation of adrenergic receptors due to chronic use of lisinopril, an ACE inhibitor as a cause of poor response of adrenaline. Langendroff's technique was used. The data obtained from ten rabbits shows that effective dose of lisinopril (10mg/kg daily orally) reduces the inotropic and chronotropic effects of adrenaline significantly (P<0.05).Therefore it is suggested to use higher doses of adrenaline in cardiac units in patients who have used therapeutic doses of lisinopril for longer periods provided it is supported by clinical studies. PMID- 23455218 TI - PEG-interferon conjugates: effects of length and structure of linker. AB - Di-branched (Y-shaped) polyethylene glycols (PEGs) are considered more effective than linear molecules to enhance the efficacy of the conjugated drug. In the present study interferon alpha-2a was conjugated with three different 40 KDa di branched PEGs. The results of this study show that length and/or the structure of linker between PEG and the protein is also involved in the synthesis, in vitro biological activity and stability of the conjugate. Three conjugates i.e., mPEG2L IFN, mPEG2P-IFN and mPEG(2)M-IFN yielded 25%, 24% and 17%, with bioactivities 2.8 x 10(6) IU/mg, 3.95 x 10(6) IU/mg and 6.7 x 10(6) IU/mg, respectively. The order of bioactivity stability is mPEG2L-IFN > mPEG2P-IFN > mPEG2M-IFN > IFN (native). We report that although lengthy linkers are more reactive in terms of conjugation, they have opposite effect on the in vitro bioactivity of the conjugate. PEGylation as a whole increases the stability of the conjugate, and linkers also add in stability. PMID- 23455219 TI - Comparision of real waste (MSW and MPW) pyrolysis in batch reactor over different catalysts. Part I: product yields, gas and pyrolysis oil properties. AB - Pyrolysis of municipal solid waste (MSW) and municipal plastic waste (MPW) have been investigated in batch reactor at 500, 550 and 600 degrees C both in absence and presence of catalysts (Y-zeolite, beta-zeolite, equilibrium FCC, MoO3, Ni-Mo catalyst, HZSM-5 and Al(OH)3). The effect of the parameters on the product properties was investigated. Products were characterized using gas chromatography, GC/MS, (13)C NMR. Yields of volatile fractions increased, while reaction time necessity for the total cracking decreased in the presence of catalysts. Catalysts have productivity and selectivity in converting aliphatic hydrocarbons to aromatic and cyclic compounds in oil products. Gases from MSW consisted of hydrogen CO, CO2, while exclusively hydrogen and hydrocarbons were detected from MPW. Catalyst efficiency was higher using MPW than MSW. Pyrolysis oils contained aliphatic hydrocarbons, aromatics, cyclic compounds and less ketones, alcohols, acids or esters depending on the raw materials. PMID- 23455220 TI - Kinetics and mechanisms of hydrogen sulfide adsorption by biochars. AB - Three different biochars as cost-effective substitutes for activated carbon (AC) were tested for their hydrogen sulfide (H2S) adsorption ability. The biochars were produced from camphor (SC), bamboo (SB), and rice hull (SR) at 400 degrees C by oxygen-limited pyrolysis. The surface area (SA), pH, and Fourier transform infrared spectras of the biochars and AC were compared. The maximum removal rates and the saturation constants were obtained using the Michaelis-Menten-type equation. The three biochars were found to be alkaline, and the SAs of the biochars were much smaller than that of the AC. The H2S breakthrough capacity was related to the local pH within the pore system of the biochar. The order observed in terms of both biochar and AC adsorption capacity was SR>SB>SC>AC. SR efficiently removed H2S within the inlet concentration range of 10-50 MUL/L. Biochars derived from agricultural/forestry wastes are a promising H2S adsorbent with distinctive properties. PMID- 23455221 TI - Utilization of acetic acid-rich pyrolytic bio-oil by microalga Chlamydomonas reinhardtii: reducing bio-oil toxicity and enhancing algal toxicity tolerance. AB - This work was to utilize acetic acid contained in bio-oil for growth and lipid production of the microalga Chlamydomonas reinhardtii. The acetic acid-rich bio oil fraction derived from fast pyrolysis of softwood contained 26% (w/w) acetic acid, formic acid, methanol, furfural, acetol, and phenolics as identified compounds, and 13% (w/w) unidentified compounds. Among those identified compounds, phenolics were most inhibitory to algal growth, followed by furfural and acetol. To enhance the fermentability of the bio-oil fraction, activated carbon was used to reduce the toxicity of the bio-oil, while metabolic evolution was used to enhance the toxicity tolerance of the microalgae. Combining activated carbon treatment and using evolved algal strain resulted in significant algal growth improvement. The results collectively showed that fast pyrolysis fermentation process was a viable approach for converting biomass into fuels and chemicals. PMID- 23455223 TI - Bicarbonate-based Integrated Carbon Capture and Algae Production System with alkalihalophilic cyanobacterium. AB - An extremely alkalihalophilic cyanobacteria Euhalothece ZM001 was tested in the Bicarbonate-based Integrated Carbon Capture and Algae Production System (BICCAPS), which utilize bicarbonate as carbon source for algae culture and use the regenerated carbonate to absorb CO2. Culture conditions including temperature, inoculation rate, medium composition, pH, and light intensity were investigated. A final biomass concentration of 4.79 g/L was reached in tissue flask culture with 1.0 M NaHCO3/Na2CO3. The biomass productivity of 1.21 g/L/day was achieved under optimal conditions. When pH increased from 9.55 to 10.51, 0.256 M of inorganic carbon was consumed during the culture process. This indicated sufficient carbon can be supplied as bicarbonate to the culture. This study proved that a high biomass production rate can be achieved in a BICCAPS. This strategy can also lead to new design of photobioreactors that provides an alternative supply of CO2 to sparging. PMID- 23455222 TI - The identification of and relief from Fe3+ inhibition for both cellulose and cellulase in cellulose saccharification catalyzed by cellulases from Penicillium decumbens. AB - Lignocellulosic biomass is an underutilized, renewable resource that can be converted to biofuels. The key step in this conversion is cellulose saccharification catalyzed by cellulase. In this work, the effect of metal ions on cellulose hydrolysis by cellulases from Penicillium decumbens was reported for the first time. Fe(3+) and Cu(2+) were shown to be inhibitory. Further studies on Fe(3+) inhibition showed the inhibition takes place on both enzyme and substrate levels. Fe(3+) treatment damages cellulases' capability to degrade cellulose and inhibits all major cellulase activities. Fe(3+) treatment also reduces the digestibility of cellulose, due to its oxidation. Treatment of Fe(3+)-treated cellulose with DTT and supplementation of EDTA to saccharification systems partially relieved Fe(3+) inhibition. It was concluded that Fe(3+) inhibition in cellulose degradation is a complicated process in which multiple inhibition events occur, and that relief from Fe(3+) inhibition can be achieved by the supplementation of reducing or chelating agents. PMID- 23455224 TI - Isolation of structurally distinct lignin-carbohydrate fractions from maize stem by sequential alkaline extractions and endoglucanase treatment. AB - Sequential fractionation of extractive-free maize stems was carried out using two mild alkaline extractions (0.5 and 2 M NaOH, 20 degrees C, 24h) before and after endoglucanase treatment. This procedure provided two lignin-carbohydrate fractions (LC1 and LC2) recovered after each alkali treatment. LC1 and LC2 contained 39% and 8% of the total lignin amount, respectively. These two fractions contained structurally distinct lignin molecules. While the content of resistant interunit bonds in lignin was 77% in LC1, it was increased up to 98% in LC2. Not unexpectedly, both alkali-soluble fractions contained substantial amount of p-coumaric and ferulic acids ether-linked to lignins. These results outline heterogeneity of maize stem lignins related to fractionation of grass materials. PMID- 23455225 TI - Dynamics of nitrobenzene degradation and interactions with nitrogen transformations in laboratory-scale constructed wetlands. AB - Three laboratory-scale CWs (i.e., tidal flow CW as well as planted and unplanted horizontal subsurface flow CWs) were set up to treat artificial nitrobenzene (NB) industry effluents in this study. An inflow NB load equal to or less than 70 mg/L achieved approximately 95% NB removal regardless of wetland type. When NB influent load increased to 160 mg/L, NB removal efficiency decreased to 57%, 46%, and 33% in planted and unplanted horizontal CWs as well as tidal flow CWs, respectively. Higher NB degradation efficiency in planted horizontal CW highlighted the positive effect of wetland plants. Moreover, strong inhibition of nitrogen removal was initiated in CWs with an increase of NB loads to 160 mg/L, which was probably caused by NB toxicity. The investigation indicated not only the potential application of treatment wetlands as a secondary ecological treatment system for NB-containing wastewater, but also the interactions with nitrogen transformations in CWs. PMID- 23455226 TI - Application of crop straw derived biochars to Cu(II) contaminated Ultisol: evaluating role of alkali and organic functional groups in Cu(II) immobilization. AB - When Cu(II) contaminated Ultisol was mixed with biochar derived from straw and incubated for 120 d, acid-soluble Cu(II) decreased by 0.08-0.33 mmol/kg due to the liming effect of biochar; 1.00-1.93 mmol/kg due to organic functional groups of biochar when it was added to the soil at 30 g/kg, and by 1.40-2.43 mmol/kg at 50 g/kg. The total functional groups and volatile matter (VM) were significantly related to Cu(II) immobilization (P<0.01), suggesting that it is functional groups in VM that are essential to Cu(II) immobilization in soil. The percentage of acid soluble Cu(II) decreased from 43.07% for the control, to 18.83-27.45% and 11.03-20.97% for the treatments with 30 and 50 g/kg of crop straw biochars added, respectively. The immobilized Cu(II) was primarily transformed to reducible and oxidizable forms. Biochar could retain Cu(II) for at least 120 d, indicating the long-term stability of biochar in Cu(II) immobilization. PMID- 23455227 TI - Contribution of tertiary amino groups to Re(VII) biosorption on modified corn stalk: competitiveness and regularity. AB - The effects of basic strength and steric hindrance of gels modified by dimethylamine, diethylamine, di-n-octylamine and di-2-ethylhexylamine, respectively, on rhenium (Re(VII)) adsorption capacity and selectivity were discussed. By comparing with the adsorption of other coexisting metals, such as Mo(VI), Cu(II), Pb(II), Fe(III), Zn(II), Mn(VII) and Ni(II), the gel modified by di-n-octylamine (DNOA-OCS) showed a high affinity for Re(VII) at higher hydrochloric acid concentration (C(H)(+)>=1.0 mol L(-1)), and the maximum adsorption capacity was 98.69 mg g(-1). This article not only described the adsorption behavior but also suggested isotherms, kinetics and thermodynamics of Re(VII) onto the DNOA-OCS gel in an aqueous medium using several models. Further study on adsorption of rhenium in a fixed-bed column packed with the DNOA-OCS gel under continuous and recirculating modes could confirm that the corn stalk gel modified by di-n-octylamine could be used as the adsorbent of Re(VII) from Mo containing wastewater. PMID- 23455228 TI - Low pH D-xylonate production with Pichia kudriavzevii. AB - D-xylonic acid is one of the top 30 most desirable chemicals to be derived from biomass sugars identified by the US Department of Energy, being applicable as a non-food substitute for D-gluconic acid and as a platform chemical. We engineered the non-conventional yeast Pichia kudriavzevii VTT C-79090T to express a D-xylose dehydrogenase coding gene from Caulobacter crescentus. With this single modification the recombinant P. kudriavzevii strain produced up to 171 g L(-1) of D-xylonate from 171 g L(-1) D-xylose at a rate of 1.4 g L(-1) h(-1) and yield of 1.0 g [g substrate consumed](-1), which was comparable with D-xylonate production by Gluconobacter oxydans or Pseudomonas sp. The productivity of the strain was also remarkable at low pH, producing 146 g L(-1) D-xylonate at 1.2 g L(-1) h(-1) at pH 3.0. This is the best low pH production reported for D-xylonate. These results encourage further development towards industrial scale production. PMID- 23455229 TI - Capping-agent-free synthesis of substrate-supported porous icosahedral gold nanoparticles. AB - We report a new capping-agent-free strategy for the synthesis of substrate supported porous icosahedral Au nanoparticles (NPs) with rough naked surfaces, based on the crystallization from substrate-supported thin solution layers followed by solid-phase thermolysis. The plasmonic properties of icosahedral Au NPs have been studied using single particle dark-field scattering microscopy and spectroscopy. The two distinct localized surface plasmon resonance (LSPR) bands observed in the single particle dark-field spectra can be ascribed to the quadrupole resonance at ca. 425 nm and the size-dependent dipole resonance in the red region (645-708 nm). The unique rough naked surface, the facile synthesis, together with the ability to control the nanoparticle size and to vary the LSPR frequency in the red region, would make the substrate-supported porous icosahedral Au NPs promising on multiple levels in the applications of catalysis, ultrasensitive biosensors, and in surface-enhanced Raman scattering (SERS). PMID- 23455230 TI - Modeling aeolian transport of soil-bound plutonium: considering infrequent but normal environmental disturbances is critical in estimating future dose. AB - Dose assessments typically consider environmental systems as static through time, but environmental disturbances such as drought and fire are normal, albeit infrequent, events that can impact dose-influential attributes of many environmental systems. These phenomena occur over time frames of decades or longer, and are likely to be exacerbated under projected warmer, drier climate. As with other types of dose assessment, the impacts of environmental disturbances are often overlooked when evaluating dose from aeolian transport of radionuclides and other contaminants. Especially lacking are predictions that account for potential changing vegetation cover effects on radionuclide transport over the long time frames required by regulations. A recently developed dynamic wind transport model that included vegetation succession and environmental disturbance provides more realistic long-term predictability. This study utilized the model to estimate emission rates for aeolian transport, and compare atmospheric dispersion and deposition rates of airborne plutonium-contaminated soil into neighboring areas with and without environmental disturbances. Specifically, the objective of this study was to utilize the model results as input for a widely used dose assessment model (CAP-88). Our case study focused on low levels of residual plutonium found in soils from past operations at Los Alamos National Laboratory (LANL), in Los Alamos, NM, located in the semiarid southwestern USA. Calculations were conducted for different disturbance scenarios based on conditions associated with current climate, and a potential future drier and warmer climate. Known soil and sediment concentrations of plutonium were used to model dispersal and deposition of windblown residual plutonium, as a function of distance and direction. Environmental disturbances that affected vegetation cover included ground fire, crown fire, and drought, with reoccurrence rates for current climate based on site historical patterns. Using site-specific meteorology, accumulation rates of plutonium in soil were modeled in a variety of directions and distances from LANL sources. Model results suggest that without disturbances, areas downwind to the contaminated watershed would accumulate LANL derived plutonium at a relatively slow rate (<0.01 Bq m(-2) yr(-1)). However, model results under more realistic assumptions that include environmental disturbances show accumulation rates more than an order-of-magnitude faster. More generally, this assessment highlights the broader need in radioecology and environmental health physics to consider infrequent but normal environmental disturbances in longer-term dose assessments. PMID- 23455231 TI - Attacking MALT1 for ABC-DLBCL therapy. PMID- 23455232 TI - Evaluation of the axial location of cystoid spaces in retinal vein occlusion using optical coherence tomography. AB - PURPOSE: To analyze the axial distribution of intraretinal cystoid changes in patients with retinal vein occlusion (RVO), incorporating a new hypothesis about the optical coherence tomographic boundary between the outer nuclear layer and the outer plexiform layer. METHODS: Data were collected from patients with RVO who underwent spectral domain coherence tomography imaging. For each image set, certified graders evaluated each retinal layer for cystoid macular edema, defined as hyporeflective intraretinal cystoid spaces. Subretinal fluid, if present, was also noted. RESULTS: Forty-eight eyes were evaluated (24 branch RVO, 18 central RVO, 6 hemiretinal vein occlusion). Cystoid macular edema was present in 30.8% of eyes in outer nuclear layer, 77.9 % in outer plexiform layer, 77.9 % in inner nuclear layer, 36.9 % in inner plexiform layer, 48.8 % in ganglion cell layer, and 4.9% in nerve fiber layer. Subretinal fluid was assessed as present in 23.8% of patients. The presence of subretinal fluid correlated most strongly with cystoid changes in the outer nuclear layer (r = 0.514, P = 0.001) but was not significantly correlated with these changes in the superficial retina. CONCLUSION: Use of spectral domain coherence tomography allows precise characterization of the axial location of cystoid spaces in RVO and highlights the frequency of fluid accumulation in the outer plexiform layer and inner nuclear layer. Using updated definitions, cystoid macular edema seems to occur less frequently in the outer nuclear layer, but when it does so, it is often associated with subretinal fluid. Future longitudinal studies, documenting the axial progression of such changes, and their response to treatment, may be of clinical relevance as pharmacotherapeutic options evolve. PMID- 23455233 TI - Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment. AB - BACKGROUND: Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy affecting vision, with clinical features distinct from neovascular age-related macular degeneration. Currently, no evidence-based guidelines exist for its diagnosis and treatment. METHODS: A panel of experts analyzed a systematic literature search on PCV together with results of the EVEREST trial, the only published randomized controlled clinical trial in PCV. At a subsequent Roundtable meeting, recommendations for the management of PCV were agreed based on this analysis and their own expert opinion. RESULTS: Diagnosis of PCV should be based on early-phase nodular hyperfluorescence from choroidal vasculature visualized using indocyanine green angiography. Recommended initial treatment of juxtafoveal and subfoveal PCV is either indocyanine green angiography-guided verteporfin photodynamic therapy or verteporfin photodynamic therapy plus 3 * 0.5 mg ranibizumab intravitreal injections 1 month apart. If there is incomplete regression of polyps by indocyanine green angiography, eyes should be retreated with verteporfin photodynamic therapy monotherapy or verteporfin photodynamic therapy plus ranibizumab. If there is complete regression of polyps by indocyanine green angiography, but there is leakage on fluorescein angiography and other clinical or anatomical signs of disease activity, eyes should be retreated with ranibizumab. CONCLUSION: Practical guidance on the clinical management of PCV is proposed based on expert evaluation of current evidence. PMID- 23455234 TI - Developmental fluoride neurotoxicity: clinical importance versus statistical significance. PMID- 23455236 TI - Amplification of higher-order modes by stimulated Raman scattering in H2-filled hollow-core photonic crystal fiber. AB - We report a method for amplifying higher-order guided modes, synthesized with a spatial light modulator, in a hydrogen-filled hollow-core photonic crystal fiber. The gain mechanism is intermodal stimulated Raman scattering, a pump laser source in the fundamental mode providing amplification for weak higher-order seed modes at the Stokes frequency. The gain for higher-order modes up to LP31 is calculated and verified experimentally. PMID- 23455237 TI - Imposing narrow spectral bandwidth in a system of passively combined fiber lasers. AB - We investigate intra-cavity coherent beam combining in a system of two fiber lasers when a spectrally selective element is inserted in one of the lasers. We found that narrow spectral content can be imposed on the other laser, resulting in narrowband operation of the system with high combining efficiency. Furthermore, the combining efficiency decreases as the imposed wavelength is farther away from the natural lasing wavelength of the system and depends on the gain imbalance between the lasers. Our results demonstrate, for the first time, the rich dynamics associated with the spectral mode competition in the intra cavity coherently combined system. PMID- 23455238 TI - Gaussian pulse gated InGaAs/InP avalanche photodiode for single photon detection. AB - The capacitive response noise has been problematic for high-speed single photon detection based on gated InGaAs/InP avalanche photodiodes. Traditionally, the noise must be suppressed by complex electronic circuit if low afterpulse probability is desired. In this Letter, we propose a compact and flexible method for noise cancellation, which gates the photodiode with a Gaussian pulse. Because of the differential effect of junction capacitor, the shape of the capacitive response output in our method is the first-order derivative of the Gaussian function that can be matched by the rising edge of a delayed and attenuated version of the gating pulse itself. With matching signal, the avalanche pulse is raised onto a flat platform that can be easily discriminated from the background. For 1550 nm optical signal, the detection efficiency could reach 10.2% with 9.7*10(-6) per gate dark count probability and 3.4% afterpulse probability at 80 MHz gating frequency. Experimental results have shown that the proposed method can decrease the afterpulse probability sharply while maintaining the detection efficiency and dark count performance. PMID- 23455239 TI - Toward endoscopes with no distal optics: video-rate scanning microscopy through a fiber bundle. AB - We report a step toward scanning endomicroscopy without distal optics. The focusing of the beam at the distal end of a fiber bundle is achieved by imposing a parabolic phase profile across the exit face with the aid of a spatial light modulator. We achieve video-rate images by galvanometric scanning of the phase tilt at the proximal end. The approach is made possible by the bundle, designed to have very low coupling between cores. PMID- 23455240 TI - High color purity red-emission of NaGdTiO4:Pr3+ via quenching of 3P0 emission under low-voltage cathode ray excitation. AB - A high color purity red emission is obtained in Pr3+ activated NaGdTiO4 (NGTP) materials. The International Commission on Illumination (CIE) chromaticity coordinates are calculated to be 0.663, 0.337, which are very close to the National Television System Committee (NTSC) red color 0.67, 0.34. The good color coordinates are due to intensive quenching of 3P0-3H4 emissions through the metal to-metal intervalence charge transfer. Interestingly, the high color purity red emitting is observed not only under UV light excitation but also under low voltage cathode ray excitation. The results indicate that NGTP may have a potential application in field emission displays. PMID- 23455242 TI - Probing losses of dielectric multilayers by means of Bloch surface waves. AB - We exploit the excitation of electromagnetic surface waves on high-quality dielectric multilayers to measure the very low extinction coefficient of the structures, with a resolution down to 4.10(-7) and in a simple optical configuration. The effect of exposition to a rhodamine 6G solution in water and ethanol is also reported, including dye adsorption in the layers and bleaching upon resonant excitation. PMID- 23455243 TI - Random resampling masks: a non-Bayesian one-shot strategy for noise reduction in digital holography. AB - Holographic imaging may become severely degraded by a mixture of speckle and incoherent additive noise. Bayesian approaches reduce the incoherent noise, but prior information is needed on the noise statistics. With no prior knowledge, one shot reduction of noise is a highly desirable goal, as the recording process is simplified and made faster. Indeed, neither multiple acquisitions nor a complex setup are needed. So far, this result has been achieved at the cost of a deterministic resolution loss. Here we propose a fast non-Bayesian denoising method that avoids this trade-off by means of a numerical synthesis of a moving diffuser. In this way, only one single hologram is required as multiple uncorrelated reconstructions are provided by random complementary resampling masks. Experiments show a significant incoherent noise reduction, close to the theoretical improvement bound, resulting in image-contrast improvement. At the same time, we preserve the resolution of the unprocessed image. PMID- 23455244 TI - Decoy-state quantum key distribution with nonclassical light generated in a one dimensional waveguide. AB - We investigate a decoy-state quantum key distribution (QKD) scheme with a sub Poissonian single-photon source, which is generated on demand by scattering a coherent state off a two-level system in a one-dimensional waveguide. We show that, compared to coherent state decoy-state QKD, there is a two-fold increase of the key generation rate. Furthermore, the performance is shown to be robust against both parameter variations and loss effects of the system. PMID- 23455245 TI - Single-image far-field subdiffraction limit imaging with axicon. AB - This Letter presents a technique for subdiffraction limit imaging termed Bessel beam microscopy (BBM). By placing a lens in series with an axicon in the optical path of a microscope, the diffraction-limited resolution of the base microscope is improved by one third. This improvement is demonstrated experimentally by resolving individual subdiffraction limit fluorescent beads in a close-pack arrangement. The behavior of the BBM system is explored using angular diffraction simulations, demonstrating the possibility of resolving features spaced as little as 110 nm apart when viewed with a 100*1.4 NA objective. Unique among super resolution techniques, BBM acquires subdiffraction limit information in a single image with broadband unstructured illumination using only static geometric optics placed between the microscope and camera. PMID- 23455246 TI - High-order photonic differentiator employing on-chip cascaded microring resonators. AB - We propose and experimentally demonstrate a high-order photonic differentiator using on-chip complementary metal oxide semiconductor-compatible cascaded microring resonators, including first-, second-, and third-order differentiators. All the microring resonator units have a radius of 150 MUm and a free spectral range of 80 GHz. The microring resonator can implement the first-order derivative of the optical field near its critical coupling region. Hence higher-order differentiation can be obtained by cascading more microring units on a single chip. For the periodical Gaussian optical pulse injection, the average deviations of all differentiators are less than 6.2%. The differentiation of pseudo-random bit sequence signals at 5 Gbit/s is also demonstrated. Our scheme is a compact and low-power-consumption solution since the cascaded microring units are fabricated with compact size on the silicon-on-insulator substrate. PMID- 23455247 TI - Graphene sustained nonlinear modes in dielectric waveguides. AB - We discuss the existence of nonlinear modes sustained by graphene layers in dielectric waveguides. Taking advantage of the almost two dimensional nature of graphene, we introduce the nonlinear effect as a parameter in the continuity equations. We then apply our modeling to a simple slab waveguide to enlighten how graphene can be used to induce huge nonlinear phase shifts at easily accessible power levels. PMID- 23455248 TI - Three-dimensional Cerenkov tomography of energy deposition from ionizing radiation beams. AB - Since its discovery during the 1930s the Cerenkov effect (light emission from charged particles traveling faster than the local speed of light in a dielectric medium) has been paramount in the development of high-energy physics research. The ability of the emitted light to describe a charged particle's trajectory, energy, velocity, and mass has allowed scientists to study subatomic particles, detect neutrinos, and explore the properties of interstellar matter. However, to our knowledge, all applications of the process to date have focused on the identification of particles themselves, rather than their effect upon the surroundings through which they travel. Here we explore a novel application of the Cerenkov effect for the recovery of the spatial distribution of ionizing radiation energy deposition in a medium and apply it to the issue of dose determination in medical physics. By capturing multiple projection images of the Cerenkov light induced by a medical linear accelerator x-ray photon beam, we demonstrate the successful three-dimensional tomographic reconstruction of the imparted dose distribution. PMID- 23455249 TI - Spectroscopy of a narrow-line optical pumping transition in atomic dysprosium. AB - We present measurements of the hyperfine coefficients and isotope shifts of the Dy I 683.731 nm transition, using saturated absorption spectroscopy on an atomic beam. A King Plot is drawn resulting in an updated value for the specific mass shift deltanu(684,sms)(164-162)=-534+/-17 MHz. Using fluorescence spectroscopy, we measure the excited state lifetime tau684=1.68(5) MUs, yielding a linewidth of gamma684=95+/-3 kHz. We give an upper limit to the branching ratio between the two decay channels from the excited state showing that this transition is usable for optical pumping into a dark state and demagnetization cooling. PMID- 23455250 TI - Tunable type II intracavity sum-frequency generation in a two chip collinear vertical external cavity surface emitting laser. AB - We report on the generation and experimental demonstration of intracavity type II sum-frequency generation (SFG) in a two chip InGaAs/GaAs vertical external cavity surface emitting laser cavity. The demonstrated two-chip cavity generates two orthogonally polarized, independently tunable, high-intensity intracavity lasing modes at different colors. Using a lithium triborate nonlinear crystal in the common collinear folded cavity region, high output power in the blue-green band is generated. Wavelength tuning with CW output powers in excess of 750 mW is demonstrated. By independent wavelength tuning of each fundamental color, tunable SFG output around 490 nm is reported. PMID- 23455251 TI - Time reversal of optically carried radiofrequency signals in the microsecond range. AB - The time-reversal (TR) protocol we implement in an erbium-doped YSO crystal is based on photon echoes but avoids the storage of the signal to be processed. Unlike other approaches implying digitizing or highly dispersive optical fibers, the proposed scheme reaches the MUs range and potentially offers high bandwidth, both required for RADAR applications. In this Letter, we demonstrate faithful reversal of arbitrary pulse sequences with 6 MUs duration and 10 MHz bandwidth. To the best of our knowledge, this is the first demonstration of TR via linear filtering in a programmable material. PMID- 23455252 TI - Optimal broadband antireflective taper. AB - We have solved the optimal taper design for minimizing reflection over a broad frequency band for a given tapered length. We believe this work will lead to significant improvement in developing broadband antireflective devices in many areas. PMID- 23455253 TI - Heralded single-photon source in a III-V photonic crystal. AB - In this Letter we demonstrate heralded single-photon generation in a III-V semiconductor photonic crystal platform through spontaneous four-wave mixing. We achieve a high brightness of 3.4*10(7) pairs.s(-1) nm(-1) W(-1) facilitated through dispersion engineering and the suppression of two-photon absorption in the gallium indium phosphide material. Photon pairs are generated with a coincidence-to-accidental ratio over 60 and a low g(2) (0) of 0.06 proving nonclassical operation in the single photon regime. PMID- 23455254 TI - Infrared absorption of n-type tensile-strained Ge-on-Si. AB - We analyze the IR absorption of tensile-strained, n-type Ge for Si-compatible laser applications. A strong intervalley scattering from the indirect L valleys to the direct Gamma valley in n+ Ge-on-Si is reported for the first time to our knowledge. The intervalley absorption edge is in good agreement with the theoretical value. On the other hand, we found that the classical lambda2 dependent Drude model of intravalley free-carrier absorption (FCA) breaks down at lambda<15 MUm. A first-principle model has to be employed to reach a good agreement with the experimental data. The intravalley FCA loss is determined to be <20 cm(-1) for n=4*10(19) cm(-3) at lambda=1.5-1.7 MUm, an order lower than the results from Drude model. The strong L->Gamma intervalley scattering favors electronic occupation of the direct Gamma valley, thereby enhancing optical gain from the direct gap transition of Ge, while the low intravalley free-electron absorption at lasing wavelengths leads to low optical losses. These two factors explain why the first electrically pumped Ge-on-Si laser achieved a higher net gain than the theoretical prediction using lambda2-dependent free-carrier losses of bulk Ge and indicate the great potential for further improvement of Ge-on-Si lasers. PMID- 23455255 TI - Wideband tunable optoelectronic oscillator based on a phase modulator and a tunable optical filter. AB - A widely tunable optoelectronic oscillator (OEO) based on a broadband phase modulator and a tunable optical bandpass filter is proposed and experimentally demonstrated. A tunable range from 4.74 to 38.38 GHz is realized by directly tuning the bandwidth of the optical bandpass filter. To the best of our knowledge, this is the widest fundamental frequency tunable range ever achieved by an OEO. The phase noise performance of the generated signal is also investigated. The single-sideband phase noise is below -120 dBc/Hz at an offset of 10 KHz within the whole tunable range. PMID- 23455256 TI - High-speed stroboscopic imaging with frequency-doubled supercontinuum. AB - We present a supercontinuum (SC) light source designed for stroboscopic white light interferometry. The compact, cost-effective SC source is built from off-the shelf optical components and operates both in the visible and near-IR at arbitrary repetition rates in the 10 kHz-1 MHz frequency range. We estimate that our source allows performing dynamic white-light interferometric characterization of rapidly oscillating objects up to several tens of megahertz. Its current potential is demonstrated by capturing the movement of a microelectromechanical system oscillating at 2.16 MHz with sub-100 nm accuracy. PMID- 23455257 TI - Atom number in magneto-optic traps with millimeter scale laser beams. AB - We measure the number of atoms N trapped in a conventional vapor-cell magneto optic trap (MOT) using beams that have a diameter d in the range 1-5 mm. We show that the N is proportional to d(3.6) scaling law observed for larger MOTs is a robust approximation for optimized MOTs with beam diameters as small as 3 mm. For smaller beams, the description of the scaling depends on how d is defined. The most consistent picture of the scaling is obtained when d is defined as the diameter where the intensity profile of the trapping beams decreases to the saturation intensity. Using this definition, N scales as d(6) for d<2.3 mm but, at larger d, N still scales as d(3.6). PMID- 23455258 TI - Visualization of jet development in laser-induced plasmas. AB - Laser-induced plasmas in gases are known to generate gaseous jets in the postplasma gas plume. The gaseous jet typically develops toward the laser source, and the experiments presented here show, for the first time to our knowledge, that, under certain conditions, these jets can develop in the opposite direction or may not form at all. The data suggest that this is related to the ratio between the energy absorbed in the plasma and the threshold breakdown energy, effectively leading to multiple plasma initiation sites in the focal waist. PMID- 23455259 TI - Transverse mode switchable fiber laser through wavelength tuning. AB - We report a fiber laser design that is capable of producing switchable transverse modes through wavelength tuning. The transverse mode switching is realized by exploiting the particular transverse mode-wavelength association characteristics of the few-mode fiber Bragg grating. Different transverse mode outputs with high spatial mode quality can be obtained by adjusting the oscillating wavelength with a tunable filter within the fiber laser cavity. For each of the spatial mode outputs, the laser operates at the corresponding single wavelength with narrow linewidth. Through adding polarization controllers in the laser cavity, output modes with cylindrical vector polarization are also realized. PMID- 23455260 TI - Slow/fast light using a very short Er3+/Yb3+ co-doped fiber. AB - A slow/fast light device with a sealed size of 130 mm*30 mm*3 mm has been demonstrated. Ultraslow propagation and superluminal propagation with group velocity values from 8.4 to -14.7 m/s are observed in a 3.86 cm long Er3+/Yb3+ co doped single-mode phosphate glass fiber. The dependence of pump power, modulation frequency, and wavelength on the slow/fast light effect in this fiber is investigated in detail. These results suggest that this compact slow/fast device is more suitable for all-fiber applications than those made by traditional methods. PMID- 23455262 TI - In situ FBG inscription during fiber laser operation. AB - We demonstrate the inscription of a 266 nm UV femtosecond pulse-induced fiber Bragg grating (FBG) in an Yb-doped fiber during optical pumping at 976 nm and the initiation of lasing with increasing grating reflectivity. Output spectra show the emission of the pumped fiber changing from the broad-ranged amplified spontaneous emission in the nonlasing case to the narrow-range laser operation due to the enhancement of FBG reflectivity during inscription. The proposed technique enables the direct characterization and control of FBG performance in fiber lasers. After FBG fabrication, we investigate the spectral characteristics of the fiber laser for different laser powers and study the influence of a thermal treatment of the FBG. PMID- 23455261 TI - High-precision, high-accuracy ultralong-range swept-source optical coherence tomography using vertical cavity surface emitting laser light source. AB - We demonstrate ultralong-range swept-source optical coherence tomography (OCT) imaging using vertical cavity surface emitting laser technology. The ability to adjust laser parameters and high-speed acquisition enables imaging ranges from a few centimeters up to meters using the same instrument. We discuss the challenges of long-range OCT imaging. In vivo human-eye imaging and optical component characterization are presented. The precision and accuracy of OCT-based measurements are assessed and are important for ocular biometry and reproducible intraocular distance measurement before cataract surgery. Additionally, meter range measurement of fiber length and multicentimeter-range imaging are reported. 3D visualization supports a class of industrial imaging applications of OCT. PMID- 23455263 TI - Design of ultrathin plasmonic quarter-wave plate based on period coupling. AB - Based on an analysis of the surface admittance of a plasmonic film with a substrate, we propose an ultrathin quarter-wave plate consisting of a periodic plane array of symmetrical L-shaped plasmonic antennas. The period, which determines the coupling among L-shaped antennas, is an important parameter for optimizing the performance of the structure. Numerical simulation results show that an Au quarter-wave plate designed in this Letter can efficiently convert a linearly polarized light at normal incidence into circularly polarized light, whose ellipticity is 0.994 at an operating wavelength of 1550 nm. The thickness is only 30 nm, which is nearly 1/50 of the wavelength of incident light. PMID- 23455264 TI - Sub-Rayleigh imaging via speckle illumination. AB - We demonstrate sub-Rayleigh limit imaging of an object via speckle illumination. Imaging beyond the conventional Rayleigh limit is achieved by illuminating the object with pseudothermal light that exhibits a random speckle pattern. An object image is reconstructed from the second-order correlation measurement and the resolution of the image, which exceeds the Rayleigh limit, is shown to be related to the size of the speckle pattern that is tied to the lateral coherence length of the pseudothermal light. PMID- 23455265 TI - Axial potential mapping of optical tweezers for biopolymer stretching: the bead size matters. AB - Optical tweezers (OT) are widely used for pico (and femto)-Newton range force measurements. The appropriate choice of the bead size is not well understood for biopolymer stretching applications of OT. We have shown, both by theory and experiment, that wrong choice of the bead size could cause errors as large as 295% in the measured force. We provide a simple map for correct choice of the bead size and the direction of pulling for such applications. There is a good agreement between our theoretical and experimental results. PMID- 23455266 TI - Faraday-rotation-based miniature magnetic field sensor using polarimetric heterodyning fiber grating laser. AB - A polarimetric heterodyning fiber grating laser is proposed to sense a magnetic field. When a magnetic field is parallel to the fiber grating laser, a circular birefringence is induced into the laser cavity. An elliptical birefringence results due to the circular birefringence and the intrinsic linear birefringence of the laser cavity. The elliptical birefringence is translated to the beat note frequency between the two orthogonally polarized laser outputs after photodetection. Confirmed by experiment results, it shows that the beat note frequency shift is proportional to the square of the magnetic field magnitude. Because the fiber laser is as short as less than 2 cm, a miniature magnetic field sensor is then demonstrated in principle. PMID- 23455267 TI - Amplification of nanosecond pulses to megawatt peak power levels in Tm3+-doped photonic crystal fiber rod. AB - We report amplification of sub-10-100 ns pulses with repetition rates from 1 to 20 kHz in a rod-type thulium-doped photonic crystal fiber with 80 MUm core diameter. The rod is pumped with a 793 nm laser diode and produces the highest peak power at 1 kHz repetition rate with 6.5 ns pulse duration and more than 7 W average output power. This result exemplifies the potential of this fiber design to scale pulse peak powers and pulse energies to the megawatt and multi millijoule range in the 2 MUm wavelength regime. PMID- 23455268 TI - Robust self-calibration three-dimensional shape measurement in fringe-projection photogrammetry. AB - Commonly, fringe-projection photogrammetry involves two independent stages: system calibration and measurement. The measurement accuracy largely depends on the calibration procedure. However, the results of system calibration may be unstable in different occasions. In this Letter, we propose a robust self calibration 3D shape measurement in fringe-projection photogrammetry by combining control and measurement points. The control points with known 3D coordinates are provided on the checkerboard, and the measurement points are identified by absolute phase information in the deformed fringes. The introduction of control points in the nonlinear collinearity equations can be regarded as invariant in the optimization procedure, which enhances the measurement robustness. Compared to the binocular model in fringe-projection technique, moreover, multiple-view ray intersection is utilized to reflect the advantage of photogrammetry in the fringe-projection 3D measurement. PMID- 23455269 TI - Toward a downconversion source of positively spectrally correlated and decorrelated telecom photon pairs. AB - Frequency correlation (or decorrelation) of photon pairs is of great importance in long-range quantum communications and photonic quantum computing. We experimentally characterize a spontaneous parametric downconversion source, based on a beta-barium borate crystal cut for type-II phase matching at 1550 nm, which has the capability to emit photons with positive or no spectral correlations. Our system employs a carefully designed detection method exploiting two InGaAs detectors. PMID- 23455270 TI - Saliency detection using regional histograms. AB - We propose an efficient regional histogram (RH)-based computation model for saliency detection in natural images. First, the global histogram is constructed by performing an adaptive color quantization on the original image. Then multiple RHs are built on the basis of the region segmentation result, and the color spatial similarity between each pixel and each RH is calculated accordingly. Two efficient measures, distinctiveness and compactness of each RH, are evaluated based on the color difference with the global histogram and the color distribution over the whole image, respectively. Finally, the pixel-level saliency map is generated by integrating the color-spatial similarity measures with the distinctiveness and compactness measures. Experimental results on a dataset containing 1000 test images with ground truths demonstrate that the proposed saliency model consistently outperforms state-of-the-art saliency models. PMID- 23455271 TI - Extreme events in time-delayed nonlinear optics. AB - We report experimentally on extreme events in the pulsating dynamics of an optical time-delayed system, i.e., a diode laser subject to a phase-conjugate feedback. We study the effect of the feedback strength on extreme events' properties. We show a transition to non-Gaussian statistics of the pulse intensity and an increased number of extreme events as the mirror reflectivity increases. The extreme event pulse is anticipated and followed by smaller pulses with time-delay periodicity. PMID- 23455272 TI - High-resolution Fourier-transform spectrometer chip with microphotonic silicon spiral waveguides. AB - We report a stationary Fourier-transform spectrometer chip implemented in silicon microphotonic waveguides. The device comprises an array of 32 Mach-Zehnder interferometers (MZIs) with linearly increasing optical path delays between the MZI arms across the array. The optical delays are achieved by using Si-wire waveguides arranged in tightly coiled spirals with a compact device footprint of 12 mm2. Spectral retrieval is demonstrated in a single measurement of the stationary spatial interferogram formed at the output waveguides of the array, with a wavelength resolution of 40 pm within a free spectral range of 0.75 nm. The phase and amplitude errors arising from fabrication imperfections are compensated using a transformation matrix spectral retrieval algorithm. PMID- 23455273 TI - Wide-field vibrational phase imaging in an extremely folded box-CARS scattering geometry. AB - We present a method that allows one to measure the real and imaginary parts of the third-order susceptibility in a wide-field coherent anti-Stokes Raman scattering setup using a quadriwave lateral shearing interferometer. This permits the retrieval of the undistorted Raman spectrum and the removal of a nonresonant signal from the surrounding solvent, which otherwise may overwhelm weak resonances. PMID- 23455274 TI - Reversible optical memory for twisted photons. AB - We report on an experiment in which orbital angular momentum (OAM) of light is mapped at the single-photon level into and out of a cold atomic ensemble. Based on the dynamic electromagnetically induced transparency protocol, the demonstrated optical memory enables the reversible mapping of Laguerre-Gaussian modes with preserved handedness of the helical phase structure. The demonstrated capability opens the possibility to the storage of qubits encoded as superpositions of OAM states and to multidimensional light matter interfacing. PMID- 23455275 TI - Fano resonance and step-like transmission via guide-mode resonance structure. AB - A two-layer guide-mode resonance structure made of shallow gratings deposited on the Kerr active guiding layer is used to realize high-quality Fano resonance and step-like transmission. The step-like transmission is designed to work between the perfect transmission peak and the dip of the asymmetrical Fano spectrum. It is demonstrated that the steep transition in the transmission should be attributed to the strong field localization in cases of both high and low transmission states. PMID- 23455276 TI - High-intensity, high-contrast laser pulses generated from the fully diode-pumped Yb:glass laser system POLARIS. AB - We report on the first generation of high-contrast, 164 fs duration pulses from the laser system POLARIS reaching focused peak intensities in excess of 2*10(20) W/cm2. To our knowledge, this is the highest peak intensity reported so far that has been achieved with a diode-pumped, solid-state laser. Several passive contrast enhancement techniques have been specially developed and implemented, achieving a relative prepulse intensity smaller than 10(-8) at t=-30 ps before the main pulse. Furthermore a closed-loop adaptive-optics system has been installed. Together with angular chirp compensation, this method has led to a significant reduction of the focal spot size and an increase of the peak intensity. PMID- 23455277 TI - Subwavelength optical trapping with a fiber-based surface plasmonic lens. AB - We demonstrate three-dimensional (3D) optical trapping of subwavelength polystyrene beads and bacteria with a surface plasmonic lens fabricated on the endface of an optical fiber. To the best of our knowledge, this is the first demonstration of 3D trapping of subwavelength particles with single fiber optical tweezers. The optical power for achieving a stable 3D trap is smaller compared with conventional optical tweezers, indicating a stronger trap. Compared with surface plasmon tweezers, the trap enabled by our fiber tweezers is located ~6 wavelengths away from the fiber endface, reducing thermal effects due to the metal absorption and preventing physical contact with the trapped objects. PMID- 23455278 TI - Propagation of few-cycle pulses in nonlinear Kerr media: harmonic generation. AB - We apply our recently developed time-transformation method for studying the propagation of few-cycle optical pulses inside a nonlinear Kerr medium after taking into account that changes in the refractive index vary with the electric field as E2 and not by its average over an optical cycle. Our technique correctly predicts carrier-wave shocking and generation of odd-order harmonics inside a Kerr medium, the two features found earlier with directly solving Maxwell's equations using the finite-difference time-domain (FDTD) methods. We extend our method to study the impact of a finite response of the Kerr nonlinearity on harmonic generation and to include chromatic dispersion that cannot be ignored for ultrashort pulses. We show that nonlinear effects can help in controlling the width of an ultrashort pulse, even though it cannot propagate as a fundamental soliton. Our time-transformation method provides an alternative to the FDTD technique, as it deals with the electric field directly but does not require step size to be a small fraction of the wavelength, resulting in much faster computation speeds. PMID- 23455279 TI - Phase controlled integrated interferometric single-sideband filter based on planar Bragg gratings implementing photonic Hilbert transform. AB - The monolithically integrated all-optical single-sideband (SSB) filter based on photonic Hilbert transform and planar Bragg gratings is proposed and experimentally demonstrated. An SSB suppression of 12 dB at 6 GHz and sideband switching are achieved via thermal tuning. An X-coupler, photonic Hilbert transformer, flat top reflector, and a micro heater are incorporated in a single silicon-on-silica substrate. The device can be thermally tuned by the micro heater on top of the channel waveguide. The device is fabricated using a combination of direct UV grating writing technology and photolithography. PMID- 23455280 TI - Geometrical optics, electrostatics, and nanophotonic resonances in absorbing nanowire arrays. AB - Semiconductor nanowire arrays have shown promise for next-generation photovoltaics and photodetection, but enhanced understanding of the light nanowire interaction is still needed. Here, we study theoretically the absorption of light in an array of vertical InP nanowires by moving continuously, first from the electrostatic limit to the nanophotonic regime and then to the geometrical optics limit. We show how the absorption per volume of semiconductor material in the array can be varied by a factor of 200, ranging from 10 times weaker to 20 times stronger than in a bulk semiconductor sample. PMID- 23455281 TI - Adiabatic thermo-optic Mach-Zehnder switch. AB - In this Letter, we propose and demonstrate a high-speed and power-efficient thermo-optic switch using an adiabatic bend with a directly integrated silicon heater to minimize the heat capacity and therein maximize the performance of the thermo-optic switch. A rapid, tau=2.4 MUs thermal time constant and a low electrical power consumption of P(pi)=12.7 mW/pi-phase shift were demonstrated representing a P(pi)tau product of only 30.5 mW.MUs in a compact device with a phase shifter of only ~10 MUm long. PMID- 23455282 TI - Surface-plasmon-coupled emission microscopy with a polarization converter. AB - Although surface-plasmon-coupled emission-based fluorescence microscopy proves high sensitivity for surface imaging, its donut shape point spread function (PSF) leads to low optical resolution and inefficient signal collection. In this Letter, we experimentally demonstrate the feasibility of solving this problem by the use of a liquid-crystal plate, which could convert the polarization state of surface-plasmon-coupled fluorescence from radial to linear. After being focused by the collection lens, an Airy disk-like PSF of small size can be realized. Experimental results reveal that both the lateral resolution and the signal-to noise ratio can be enhanced simultaneously. PMID- 23455283 TI - Absolute measurement of small-amplitude vibrations by time-averaged heterodyne holography with a dual local oscillator. AB - We report a demonstration of the measurement of the ratio between an optical modulation sideband component and the nonshifted light component by time-averaged heterodyne holography in off-axis and frequency-shifting configuration, through coherent frequency-division multiplexing with a dual optical local oscillator. Experimental results of sinusoidal vibration sensing are reported. This technique enables absolute measurements of subnanometric out-of-plane vibration amplitudes. PMID- 23455284 TI - Investigation of interference in multiple-input multiple-output wireless transmission at W band for an optical wireless integration system. AB - We experimentally investigate the interference in multiple-input multiple-output (MIMO) wireless transmission by adjusting the relative locations of horn antennas (HAs) in a 100 GHz optical wireless integration system, which can deliver a 50 Gb/s polarization-division-multiplexing quadrature-phase-shift-keying signal over 80 km single-mode fiber-28 and a 2*2 MIMO wireless link. For the parallel 2*2 MIMO wireless link, each receiver HA can only get wireless power from the corresponding transmitter HA, while for the crossover ones, the receiver HA can get wireless power from two transmitter HAs. At the wireless receiver, polarization demultiplexing is realized by the constant modulus algorithm (CMA) in the digital-signal-processing part. Compared to the parallel case, wireless interference causes about 2 dB optical signal-to-noise ratio penalty at a bit error ratio (BER) of 3.8*10(-3) for the crossover cases if similar CMA taps are employed. The increase in CMA tap length can reduce wireless interference and improve BER performance. Furthermore, more CMA taps should be adopted to overcome the severe wireless interference when two pairs of transmitter and receiver HAs have different wireless distances. PMID- 23455285 TI - Improving retinal imaging by corneal refractive index matching. AB - Imaging the retina at high resolution requires a dilated pupil, which in turn exposes more corneal irregularities. We diminish the optical errors of the cornea by refractive index matching. Lens-fitted goggles were used for corneal immersion, to reduce its aberrations, while keeping the ocular power. An additional aspheric plate reduced the residual ocular spherical aberration. A comparison of the index-matching-based retinal images with those acquired directly shows resolution improvement for subjects with normal extent of ocular aberrations. A simulation of the point spread function, obtained from an averaged ocular and corneal wavefront error, also reveals substantial improvement when using corneal index matching. The demonstrated improvement using index matching may enable further improvement of current retinal imaging techniques or relaxing requirements for active ocular aberration correction. PMID- 23455286 TI - Angular multiplex recording of data pages by dual-channel polarization holography. AB - Simultaneous recording of two data pages by dual-channel polarization holography is experimentally demonstrated. Two data pages are transferred as two orthogonal scalar wave components of a vector wave. The signal vector wave and reference beam are superposed on a polarization-sensitive medium. The two recorded data pages are simultaneously and independently reconstructed. Furthermore, holographic angular multiplex recording is performed. PMID- 23455287 TI - Statistical characteristics of the tilts of the aero-optical aberration caused by the supersonic turbulent boundary layer. AB - The tilt of the aero-optical aberration caused by the supersonic turbulent boundary layer is obtained by analyzing the center wandering of the far-field optical pattern, and its characteristics are examined from the viewpoint of statistics. When the diameter of the beam propagating through the flow is small compared with the boundary layer thickness, the probability density function (PDF) of the tilt coefficient is centered and can be approximated with a Gaussian distribution. For a larger beam diameter, the PDF of the tilt in the spanwise direction can still be regarded as centered and Gaussian, but the tilt in the streamwise direction clearly deviates from a Gaussian distribution. The correlation of the tilts in the two directions is investigated by computing the correlation coefficient, and the results indicate that the correlation is negative and strong for a small beam diameter and becomes positive and weak for a large beam diameter. These characteristics are explained by the hairpin vortex structures in the boundary layer, which prevail and meander for a very long distance streamwise. PMID- 23455288 TI - Computation of optimal metamers. AB - A fast, accurate model for computing Logvinenko's optimal metamers is introduced. The spectral reflectance of an optimal metamer is uniquely determined from a class of metamers with common tristimulus values. A set of optimal metamers is useful for evaluating the color reproduction and gamut of object colors under different illuminants. In conventional methods, optimal metamers are calculated by interpolating the coordinates of precomputed optimal colors. This model optimizes the spectral reflectance parameters efficiently without switching between bandpass (Type I) and bandstop (Type II) optimal metamers, or requiring any stored optimal-color datasets. Some optimal metamer loci computed using MATLAB are presented. PMID- 23455289 TI - Microfiber in-line Mach-Zehnder interferometer for strain sensing. AB - An elegant way of achieving an ultracompact optical fiber in-line Mach-Zehnder interferometer is to create an inner air cavity in a section of microfiber. The sandwich structure splits the light propagating in the fiber into two beams: one passes through the inner air cavity and the other travels along the silica wall of the cavity before recombining at the cavity end, resulting in an interference fringe pattern. Such a device is applied for strain measurement with a high sensitivity of 6.8 pm/MUepsilon. PMID- 23455290 TI - Revisiting strong coupling between a single molecule and surface plasmons. AB - Strong coupling between a single molecule and surface plasmons is reexamined with a microscopic classical formulation in local and nonlocal responses of metal. In the case of local response, we show that strong single molecule-plasmon coupling can occur in the UV range for a silver particle with a molecule-metal separation of 1 nm or smaller, where the real part of the dielectric function of silver approaches -1. With the nonlocal response consideration, strong coupling happens at shorter molecule-metal distances. The result shows that Rabi splitting can occur even without a resonator. PMID- 23455291 TI - Thermal effects in high average power optical parametric amplifiers. AB - Optical parametric amplifiers (OPAs) have the reputation of being average power scalable due to the instantaneous nature of the parametric process (zero quantum defect). This Letter reveals serious challenges originating from thermal load in the nonlinear crystal caused by absorption. We investigate these thermal effects in high average power OPAs based on beta barium borate. Absorption of both pump and idler waves is identified to contribute significantly to heating of the nonlinear crystal. A temperature increase of up to 148 K with respect to the environment is observed and mechanical tensile stress up to 40 MPa is found, indicating a high risk of crystal fracture under such conditions. By restricting the idler to a wavelength range far from absorption bands and removing the crystal coating we reduce the peak temperature and the resulting temperature gradient significantly. Guidelines for further power scaling of OPAs and other nonlinear devices are given. PMID- 23455292 TI - Generation of phase-coded microwave signals using a polarization-modulator-based photonic microwave phase shifter. AB - A scheme for the generation of phase-coded microwave signals using an electrically tunable photonic microwave phase shifter is proposed and demonstrated. The photonic phase shifter is based on a single-sideband polarization modulator (PolM), and the tuning of the phase shifter is implemented by a second PolM. By introducing an RF signal to the first PolM and an electrical coding signal to the second PolM, a phase-coded microwave signal with binary phase codes or polyphase codes is achieved. An experiment is performed. The simple and flexible operation, high coding rate, large frequency range, excellent transmission performance, and high stability of the system is confirmed. PMID- 23455293 TI - Selective multimode excitation using volume holographic mode multiplexer. AB - We propose a mode multiplexer based on volume holograms to realize a simple and efficient mode-division-multiplexed transmission system that supports a large number of modes. Selective multiexcitation of three spatial modes into a conventional multimode fiber is experimentally demonstrated. This device could potentially multiplex 10 or more modes. Future perspectives of the mode multiplexer for application in mode-division multiplexing are also discussed. PMID- 23455294 TI - Polymer planar Bragg grating sensor for static strain measurements. AB - We report on a new optical strain sensor based on a polymer planar Bragg grating (PPBG). The sensor consists of commercially available bulk Polymethlymethacrylate with a UV-inscribed optical waveguide as well as a Bragg grating, both of which are fabricated simultaneously in a single writing step. Upon axial strain, the Bragg wavelength reveals a quasi-instantaneous spectral red shift that depends linearly on the mechanical load with a sensitivity of 2.95 pm/MUepsilon. The relative reflected intensity of the PPBG remains constant in the investigated load region. PMID- 23455295 TI - Optical model enabling the use of Abbe-type refractometers on turbid suspensions. AB - We derive a simple model for the angular-intensity profiles of diffuse light transmitted from a turbid colloid into a transparent medium of higher refractive index (RI) near the critical angle. Adjusting this model to experimental profiles obtained with an Abbe-type refractometer offers a sensitive and robust way of measuring the complex effective RI of highly scattering media. PMID- 23455296 TI - Fourier transform imaging spectropolarimeter using simultaneous polarization modulation. AB - We introduce a Fourier transform imaging spectropolarimeter composed of a simultaneous polarization modulator and a Fourier transform spectrometer without slit. The spectropolarimeter enables the generation of four sets of fringe patterns with different polarization states of light from an object point. Fourier transform of the fringe patterns provides four equations of Stokes parameters in various wavenumbers. And we can obtain the full-stokes vector from the equations. The most significant advantage of the method is that the four polarized fringe patterns are obtained simultaneously and separated without aliasing. Additionally, the advantages of the Fourier transform spectrometer are maintained, such as high radiative throughput. PMID- 23455297 TI - Resonant coupling in trenched bend-insensitive optical fiber. AB - We report in this Letter the resonant coupling mechanism in bending trenched bend insensitive fiber (BIF). It is found that among the trench parameters, the core trench distance is predominant for optimized BIF design. We reveal that resonant coupling is an intrinsic characteristic of bending trenched BIF, and resonant coupling between the fiber core and the innermost cladding would limit the ultimate bending loss of BIF under tight bend. Resonant coupling is also present in double-trenched BIF, and would impair its bending performance. PMID- 23455298 TI - Single frequency 1645 nm Er:YAG nonplanar ring oscillator resonantly pumped by a 1470 nm laser diode. AB - A 1645 nm Er:YAG nonplanar ring oscillator, resonantly pumped by a 1470 nm laser diode, is reported. By using a 0.5%-doped Er:YAG nonplanar ring resonator, a 0.284 W single-frequency laser output at 1645 nm was obtained with a slope efficiency of 42.1%. The beam quality in x and y directions were 1.064 and 1.039, respectively. PMID- 23455299 TI - Robust depth selectivity in mesoscopic scattering regimes using angle-resolved measurements. AB - We study optical imaging of tissues in the mesoscopic scattering regime in which light multiply scatters in tissues but is not fully diffusive. We use the radiative transport equation to model light propagation and an l1-optimization method to solve the inverse source problem. We show that recovering the location and strength of several point-like sources that are close to each other is not possible when using angle-averaged measurements. The image reliability is limited by a spatial scale that is on the order of the transport mean-free path, even under the most ideal conditions. However, by using just a few angle-resolved measurements, the proposed method is able to overcome this limitation. PMID- 23455300 TI - Two-dimensional dispersive shock waves in dissipative optical media. AB - We study generation of two-dimensional dispersive shock waves and oblique dark solitons upon interaction of tilted plane waves with negative refractive index defects embedded into defocusing material with linear gain and two-photon absorption. Different evolution regimes are encountered, including the formation of well-localized disturbances for input tilts below critical one, generation of extended shock waves containing multiple intensity oscillations in the "upstream" region, and gradually vanishing oblique dark solitons in the "downstream" region for input tilts exceeding critical one. The generation of stable dispersive shock waves is possible only below certain critical defect strength. PMID- 23455301 TI - Size stabilization of surface-supported liquid aerosols using tapered optical fiber coupling. AB - We demonstrate long-term size stabilization of surface-supported liquid aerosols of salt-water. Single tapered optical fibers were used to couple the light from independent heating and probe lasers into individual microdroplets that were kept on a superhydrophobic surface in a high-humidity chamber. Size stabilization of microdroplets resulted from competition between resonant absorption of the infrared heating laser by a microdroplet whispering gallery mode and water condensation in the sample chamber. Microdroplet size was continuously monitored using the tunable red probe laser. Thanks to the narrow linewidth of the heating laser, stabilization of the 110 MUm radius of a microdroplet with a precision down to 0.54 nm was achieved for a period of 410 s. PMID- 23455302 TI - High conversion efficiency, high energy terahertz pulses by optical rectification in cryogenically cooled lithium niobate. AB - We demonstrate highly efficient terahertz (THz) generation by optical rectification (OR) of near-optimum pump pulses centered at 1.03 MUm in cryogenically cooled lithium niobate. Using a close to optimal pulse duration of 680 fs and a pump energy of 1.2 mJ, we report conversion efficiencies above 3.8+/ 0.4%, which is more than an order of magnitude higher than previously reported. The results confirm the advantage of using cryogenic cooling of the lithium niobate crystal that significantly reduces the THz absorption, enabling the scaling of THz pulse energies to the millijoule level via OR. PMID- 23455303 TI - Optical approach to improve the gamma curve in a vertical-alignment liquid crystal cell. AB - In this Letter, we propose an optical configuration of a four-domain vertical alignment (VA) liquid-crystal (LC) cell, which can improve the gamma-curve distortion by using a pair of patterned A plates, without any change in cell structure. In order to find the optimal parameter value of the patterned A film, we calculated the polarization difference between the normal direction and the all-viewing direction as functions of the optical axes and the retardation (Deltand) under the voltage applied state. Based on the calculated results, the proposed LC cell showed an improvement in gamma-curve distortion of more than 80% in each oblique viewing angle compared to a conventional wide-view VA LC cell, without any loss of optical performance in the dark state. PMID- 23455304 TI - Tunable multitap microwave photonic filter with all complex coefficients. AB - Architecture for the implementation of a tunable multitap microwave photonic filter (MPF) with all complex coefficients is proposed and demonstrated. The complex coefficients are realized by 360 degrees tunable photonic microwave phase shifters based on single-sideband polarization modulation. The polarization modulator, wavelength-division multiplexers, polarizer, and photodetector required for achieving the tunable phase shift are shared by all taps. Only a polarization controller is required in each tap to adjust each phase shift independently, making the system simple and compact. A proof-of-concept experiment is performed. A four-tap MPF with full free spectral range tunability and adjustable filter shape is realized. PMID- 23455305 TI - Quantitative transverse flow measurement using optical coherence tomography speckle decorrelation analysis. AB - We propose an inter-Ascan speckle decorrelation based method that can quantitatively assess blood flow normal to the direction of the optical coherence tomography imaging beam. To validate this method, we performed a systematic study using both phantom and in vivo animal models. Results show that our speckle analysis method can accurately extract transverse flow speed with high spatial and temporal resolution. PMID- 23455307 TI - Interactive digital atlas of skeletal surveys for common skeletal dysplasias. AB - BACKGROUND: Skeletal dysplasias are conditions of abnormal bone and cartilage growth resulting in short stature. Developing expertise in the radiographic evaluation of dysplasias can be difficult because more than 250 skeletal dysplasias have been described. Exhaustive description of individual dysplasias can be found in hard copy textbooks, without the ability to compare dysplasias side by side. OBJECTIVE: To provide radiographic images of several common skeletal dysplasias with comparative normal skeletal surveys, thus facilitating understanding of the terminology and differences in imaging appearances commonly encountered in interpreting dysplasias. MATERIALS AND METHODS: Images from skeletal surveys obtained at our institution from 2006 to 2010 were compiled and reviewed for best quality images. Selected surveys were divided into body parts. The software program used for viewing the atlas permits linked scrolling, resizing of images, and simultaneous comparison of cases. RESULTS: Radiographic images for 13 common skeletal dysplasias and 3 comparative normal skeletons (neonate, infant and child) are provided as an interactive digital atlas. CONCLUSION: The placement of images of several common skeletal dysplasias with descriptive text in an interactive and comparative format facilitates understanding of basic radiographic terminology and appearances. We describe the atlas and discuss skeletal survey interpretation. PMID- 23455309 TI - Peripheral inflammatory pseudotumor of the liver and extensive thrombosis of the portal venous system in a child. AB - We report a case of a peripheral inflammatory pseudotumor of the right lobe of the liver with extensive thrombosis of the portal venous system in a 9-year-old boy. Local thrombosis of the portal vein is a known complication of the inflammatory pseudotumor, especially in the hepatic hilum. The extent of the thrombosis in this case was unexpected, considering the peripheral location and the benign nature of the lesion. To our knowledge, thrombosis of this degree has not been described. PMID- 23455308 TI - 18F-FDG PET/CT evaluation of children and young adults with suspected spinal fusion hardware infection. AB - BACKGROUND: Evaluation of the child with spinal fusion hardware and concern for infection is challenging because of hardware artifact with standard imaging (CT and MRI) and difficult physical examination. Studies using (18)F-FDG PET/CT combine the benefit of functional imaging with anatomical localization. OBJECTIVE: To discuss a case series of children and young adults with spinal fusion hardware and clinical concern for hardware infection. These people underwent FDG PET/CT imaging to determine the site of infection. MATERIALS AND METHODS: We performed a retrospective review of whole-body FDG PET/CT scans at a tertiary children's hospital from December 2009 to January 2012 in children and young adults with spinal hardware and suspected hardware infection. The PET/CT scan findings were correlated with pertinent clinical information including laboratory values of inflammatory markers, postoperative notes and pathology results to evaluate the diagnostic accuracy of FDG PET/CT. An exempt status for this retrospective review was approved by the Institution Review Board. RESULTS: Twenty-five FDG PET/CT scans were performed in 20 patients. Spinal fusion hardware infection was confirmed surgically and pathologically in six patients. The most common FDG PET/CT finding in patients with hardware infection was increased FDG uptake in the soft tissue and bone immediately adjacent to the posterior spinal fusion rods at multiple contiguous vertebral levels. Noninfectious hardware complications were diagnosed in ten patients and proved surgically in four. Alternative sources of infection were diagnosed by FDG PET/CT in seven patients (five with pneumonia, one with pyonephrosis and one with superficial wound infections). CONCLUSION: FDG PET/CT is helpful in evaluation of children and young adults with concern for spinal hardware infection. Noninfectious hardware complications and alternative sources of infection, including pneumonia and pyonephrosis, can be diagnosed. FDG PET/CT should be the first-line cross-sectional imaging study in patients with suspected spinal hardware infection. Because pneumonia was diagnosed as often as spinal hardware infection, initial chest radiography should also be performed. PMID- 23455310 TI - Hyperoxia, HMGB1, and ventilator-associated pneumonia: reducing risk by practicing what we teach. PMID- 23455312 TI - Cerebrovascular dilation via selective targeting of the cholane steroid recognition site in the BK channel beta1-subunit by a novel nonsteroidal agent. AB - The Ca(2+)/voltage-gated K(+) large conductance (BK) channel beta1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK beta1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK beta1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate beta1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3 hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + beta1) channels cloned from rat cerebral artery myocytes with a potency (EC50 = 53 MUM) similar to and an efficacy (*2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + beta2, beta3, beta4, or beta1T169A, indicating that this drug selectively targets beta1 containing BK channels via the BK beta1 steroid-sensing site. HENA (3-45 MUM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK beta1's role in HENA action. Finally, carotid artery-infusion of HENA (45 MUM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates beta1-containing BK channels by targeting the steroid sensing site in BK beta1, rendering vasodilation. PMID- 23455313 TI - Activation of both protein kinase A (PKA) type I and PKA type II isozymes is required for retinoid-induced maturation of acute promyelocytic leukemia cells. AB - Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation arrest at the promyelocytic stage. In most cases, this defect can be overcome by treatment with all-trans-retinoic acid (ATRA), leading to complete clinical remission. Cyclic AMP signaling has a key role in retinoid treatment efficacy: it enhances ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some ATRA-resistant cells (including NB4 LR1 cells). We show that the two cell types express identical levels of the Calpha catalytic subunit and comparable global cAMP-dependent protein kinase A (PKA) enzyme activity. However, the maturation-resistant NB4-LR1 cells have a PKA isozyme switch: compared with the NB4 cells, they have decreased content of the juxtanuclearly located PKA regulatory subunit IIalpha and PKA regulatory subunit IIbeta, and a compensatory increase of the generally cytoplasmically distributed PKA-RIalpha. Furthermore, the PKA regulatory subunit II exists mainly in the less cAMP-responsive nonautophosphorylated state in the NB4-LR1 cells. By the use of isozyme-specific cAMP analog pairs, we show that both PKA-I and PKA-II must be activated to achieve maturation in NB4-LR1 as well as NB4 cells. Therefore, special attention should be paid to activating not only PKA-I but also PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting. PMID- 23455314 TI - Contribution of the M1 transmembrane helix and pre-M1 region to positive allosteric modulation and gating of N-methyl-D-aspartate receptors. AB - N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4 dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating. PMID- 23455315 TI - [Prostheses for fractures of the proximal humerus: presentation of current results of anatomical fracture shoulder prosthesis under consideration of alternative concepts]. AB - BACKGROUND: The purpose of this present study was to review the functional and radiological results of patients with complex fractures of the proximal humerus who were treated with an anatomical shoulder prosthesis. PATIENTS AND METHODS: Between 1999 and 2005 a total of 61 patients were treated with an anatomical trauma prosthesis after an acute fracture. RESULTS: Thirty-eight patients (31 women and 7 men) with a mean age of 72 (range, 31-85) years could be followed-up. The absolute Constant score averaged 57.7 of 100 (range, 32-86) points by a mean of 86 (range, 60-129) months. Postoperative active elevation averaged 105 (range, 50-180) degrees and active abduction averaged 96 (50-180) degrees . Tuberosity resorption was found in 52% (20/38) at final follow-up. The outcome was significantly better in patients with healing of the tuberosities (p = 0.02). CONCLUSION: With the use of an anatomical trauma prosthesis the reduction of the pain level is excellent while the gain in function is only slight. The bony union of the tuberosities in an anatomical position is essential to achieve good results. PMID- 23455316 TI - [Biocompatibility of polymer-bioglass cement Cortoss(r): in vitro test with the MG63 cell model]. AB - BACKGROUND: Polymethylmethacrylate (PMMA) cement has been used for fixation of joint replacements for more than 50 years and cement augmentation of vertebrae has become a popular procedure since the first description in 1987. New cements have now been developed which are better suited to the requirements of minimally invasive application techniques for vertebral bodies. The combination of good mechanical properties and biocompatibility is the concern of present research. This study compared the features of a polymer-bioglass cement with a calcium phosphate cement used for vertebral augmentation. METHODS: The human osteoblast like cell culture MG63 was used to study the polymer-glass ceramic cement Cortoss(r) and the hydroxyapatite cement Kyphos(r). Every 24 h for 5-6 days a defined volume of the culture medium was harvested in the presence of the bone cements and added to 16 cell cultures for each time period. The viability of cells was determined photometrically at 550 nm with the MTT assay and cell morphology was studied using light and electron microscopy. RESULTS: In the presence of the calcium phosphate cement an early and small reduction of cell activity was found compared with the controls. At the end of 1 week the viability parameter improved nearly reaching the control level. Electron microscopy showed crystals with a 3-dimensional shape. The cell cultures with Cortoss(r) showed no cellular activity and the microscopic examinations were negative. This effect was not different at days 1-5 after polymerization of the cement. CONCLUSIONS: The calcium phosphate cement studied showed a good biocompatibility and allowed morphological signs of apatite formation. At least within the first 5 days the polymer-glass ceramic cement showed a reasonable cytotoxic effect. There was no sign of recovery of cell function within that period. The biocompatibility of the polymer-glass ceramic cement appeared significantly worse compared with the calcium phosphate cement. An ideal composition of biomechanical properties and biocompatibility has not been achieved so far. PMID- 23455317 TI - [Electromagnetic navigation of transpedicular punctures: more precise than the standard?]. AB - AIM: Before clinical implementation of an approved electromagnetic tracking system (CAPPA IRAD EMT) an experimental trial was performed to investigate the accuracy of the system and its safety in application for transpedicular vertebral punctures in comparison to the classical fluoroscopic method. MATERIAL AND METHODS: A total of 110 transpedicular punctures were performed bilaterally using 11 vertebrae of 5 realistic artificial phantoms and 1 pedicle was punctured with the conventional technique using c-arm fluoroscopy and the other with the electromagnetic tracking system. As a target a radiopaque non-ferromagnetic marker was implanted bilaterally in the anterior wall of the vertebrae. For evaluation of the precision the distance from the end of the puncture to the target and the gradual deviation of the actual channel from the ideal trajectory were assessed in three-dimensional computer tomography. Calculations and statistical analysis were performed according to the Wilcoxon test by means of SPSS 16.0.1 for Windows. RESULTS: The mean distance from the target was 6.6 mm (+/- 3.9 mm standard deviation SD) with electromagnetic navigation compared to 3.2 mm (+/- 2.8 mm SD) with fluoroscopic assistance and the mean aberration from the ideal trajectory was 18.4 degrees (+/- 4.6 degrees SD) compared to 6.5 degrees (+/- 3.5 degrees SD), respectively. The difference of accuracy was highly significant regarding both parameters (p < 0.001). CONCLUSIONS: The minimum requirement for accuracy of transpedicular punctures could not be achieved with electromagnetic navigation. Unless proven otherwise, the lack of accuracy is attributed to unstable referencing. Despite evidence of successful employment for soft tissue punctures the system cannot currently be recommended for osseous applications of the spine. PMID- 23455318 TI - [Guaranteeing an appropriate patient-oriented treatment]. PMID- 23455319 TI - K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. AB - DNA repair is essential for maintaining genomic stability, and defects in this process significantly increase the risk of cancer. Clear-cell renal cell carcinoma (CCRCC) caused by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is characterized by high genomic instability. However, the molecular mechanism underlying the association between the loss of VHL and genomic instability remains unclear. Here, we show that suppressor of cytokine signaling 1 (SOCS1) promotes nuclear redistribution and K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs). Loss of VHL or VHL mutations that compromise its K63-ubiquitylation attenuates the DNA-damage response (DDR), resulting in decreased homologous recombination repair and persistence of DSBs. These results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC. PMID- 23455320 TI - Activation of PDK-1 maintains mouse embryonic stem cell self-renewal in a PKB dependent manner. AB - The phosphatidylinositol 3' kinase (PI3K) pathway is involved in many cellular processes including cell proliferation, survival and glucose transport, and is implicated in various disease states, such as cancer and diabetes. Although there have been numerous studies dissecting the role of PI3K signaling in different cell types and disease models, the mechanism by which PI3K signaling regulates embryonic stem (ES) cell fate remains unclear. It is believed that in addition to proliferation and tumorigenesis, PI3K activity may also be important for ES cell self-renewal. Paling et al. reported that the inhibition of PI3K led to a reduction in the ability of leukemia inhibitory factor to maintain self-renewal, causing cells to differentiate. Studies in our lab have revealed that ES cells completely lacking glycogen synthase kinase-3 (GSK-3) remain undifferentiated compared with wild-type ES cells. GSK-3 is negatively regulated by PI3K, suggesting that PI3K may have a vital role in maintaining pluripotency in ES cells through GSK-3. By using a modified Flp recombinase system, we expressed activated alleles of 3-phosphoinositide-dependent protein kinase-1 and protein kinase B to create stable, isogenic ES cell lines to further study the role of the PI3K signaling pathway in stem cell fate determination. In vitro characterization of the transgenic cell lines revealed a strong tendency toward the maintenance of pluripotency, and this phenotype was found to be independent of canonical Wnt signal transduction. In summary, PI3K signaling is sufficient to maintain the self-renewal and survival of stem cells. As this pathway is frequently mutationally activated in cancers, its effect on suppressing differentiation may contribute to its oncogenicity. PMID- 23455321 TI - Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest-derived cell line. AB - Neuroblastoma arises from sympathoadrenal progenitors of the neural crest and expression of the neurotrophin receptor TrkB and its ligand, brain-derived neurotrophic factor (BDNF), is correlated with poor prognosis. Although activated TrkB signaling promotes a more aggressive phenotype in established neuroblastoma cell lines, whether TrkB signaling is sufficient to transform neural crest derived cells has not been investigated. To address the role of TrkB signaling in malignant transformation, we removed two immunoglobulin-like domains from the extracellular domain of the full-length rat TrkB receptor to create a DeltaIgTrkB that is constitutively active. In the pheochromocytoma-derived cell line PC12, DeltaIgTrkB promotes differentiation by stimulating process outgrowth; however, in the rat neural crest-derived cell line NCM-1, DeltaIgTrkB signaling produces a markedly transformed phenotype characterized by increased proliferation, anchorage-independent cell growth, anoikis resistance and matrix invasion. Furthermore, expression of DeltaIgTrkB leads to the upregulation of many transcripts encoding cancer-associated genes including cyclind1, twist1 and hgf, as well as downregulation of tumor suppressors such as pten and rb1. In addition, DeltaIgTrkB NCM-1 cells show a 21-fold increase in mRNA for MYCN, the most common genetic marker for a poor prognosis in neuroblastoma. When injected into NOD SCID mice, control GFP NCM-1 cells fail to grow whereas DeltaIgTrkB NCM-1 cells form rapidly growing and invasive tumors necessitating euthanasia of all mice by 15 days post injection. In summary, these results indicate that activated TrkB signaling is sufficient to promote the formation of a highly malignant phenotype in neural crest-derived cells. PMID- 23455322 TI - Interaction between PARP-1 and HIF-2alpha in the hypoxic response. AB - Hypoxia-inducible factors (HIFs) mediate the transcriptional adaptation of hypoxic cells. The extensive transcriptional programm regulated by HIFs involves the induction of genes controlling angiogenesis, cellular metabolism, cell growth, metastasis, apoptosis, extracellular matrix remodeling and others. HIF is a heterodimer of HIF-alpha and HIF-beta subunits. In addition to HIF-1alpha, HIF 2alpha has evolved as an isoform that contributes differently to the hypoxic adaptation by performing non-redundant functions. Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein involved in the control of DNA repair and gene transcription by modulating chromatin structure and acting as part of gene specific enhancer/promoter-binding complexes. Previous results have shown that PARP-1 regulates HIF-1 activity. In this study, we focused on the cross-talk between HIF-2alpha and PARP-1. By using different approaches to suppress PARP-1, we show that HIF-2alpha mRNA expression, protein levels and HIF-2-dependent gene expression, such as ANGPTL4 and erythropoietin (EPO), are regulated by PARP-1. This regulation occurs at both the transcriptional and post-trancriptional level. We also show a complex formation between HIF-2alpha with PARP-1. This complex is sensitive to PARP inhibition and seems to protect against the von Hippel-Lindau dependent HIF-2alpha degradation. Finally, we show that parp-1(-/-) mice display a significant reduction in the circulating hypoxia-induced EPO levels, number of red cells and hemoglobin concentration. Altogether, these results reveal a complex functional interaction between PARP-1 and the HIF system and suggest that PARP-1 is involved in the fine tuning of the HIF-mediated hypoxic response in vivo. PMID- 23455323 TI - Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. AB - Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma. PMID- 23455324 TI - Regulation of protein translation and c-Jun expression by prostate tumor overexpressed 1. AB - Prostate tumor overexpressed-1 (PTOV1), a modulator of the Mediator transcriptional regulatory complex, is expressed at high levels in prostate cancer and other neoplasias in association with a more aggressive disease. Here we show that PTOV1 interacts directly with receptor of activated protein C kinase 1 (RACK1), a regulator of protein kinase C and Jun signaling and also a component of the 40S ribosome. Consistent with this interaction, PTOV1 was associated with ribosomes and its overexpression promoted global protein synthesis in prostate cancer cells and COS-7 fibroblasts in a mTORC1-dependent manner. Transfection of ectopic PTOV1 enhanced the expression of c-Jun protein without affecting the levels of c-Jun or RACK1 mRNA. Conversely, knockdown of PTOV1 caused significant declines in global protein synthesis and c-Jun protein levels. High levels of PTOV1 stimulated the motility and invasiveness of prostate cancer cells, which required c-Jun, whereas knockdown of PTOV1 strongly inhibited the tumorigenic and metastatic potentials of PC-3 prostate cancer cells. In human prostate cancer samples, the expression of high levels of PTOV1 in primary and metastatic tumors was significantly associated with increased nuclear localization of active c-Jun. These results unveil new functions of PTOV1 in the regulation of protein translation and in the progression of prostate cancer to an invasive and metastatic disease. PMID- 23455326 TI - Roles of microRNAs during prostatic tumorigenesis and tumor progression. AB - Prostate cancer (PCa) is considered to be a frequently diagnosed cancer in males with high mortality worldwide, but the molecular mechanism responsible for prostate tumorigenesis and progression remains unclear. Increasing evidence has shown that microRNAs (miRNAs) play an important role in PCa. In this review, we focus on the current advances about the role of miRNAs in regulating tumorigenesis and progression of PCa, mainly in suppressing or promoting PCa growth and metastasis, and maintaining the pluripotency of PCa stem cells (PCSC). More studies on miRNAs will provide a better understanding of their regulatory mechanisms in PCa. PMID- 23455327 TI - MicroRNAs regulate both epithelial-to-mesenchymal transition and cancer stem cells. AB - Concepts and experimental models derived from basic research have been successfully applied to the field of molecular oncology, tremendously increasing our knowledge of the nature and the progression of tumors. The process of epithelial-to-mesenchymal transition, the cancer stem cell hypothesis, and their functional association and interdependence represent some of the most significant examples. The molecular determinants underlying the plasticity of cancers are currently the object of extensive research efforts, and a substantial body of evidence suggests that these models can be connected by the regulatory role of microRNAs, small noncoding RNA molecules with a fundamental role in many cellular functions. This review will highlight and discuss this link and its possible implications for the fight against cancer. PMID- 23455325 TI - Aberrant IKKalpha and IKKbeta cooperatively activate NF-kappaB and induce EGFR/AP1 signaling to promote survival and migration of head and neck cancer. AB - The inhibitor-kappaB kinase-nuclear factor-kappaB (IKK-NF-kappaB) and epidermal growth factor receptor-activator protein-1 (EGFR-AP1) pathways are often co activated and promote malignant behavior, but the underlying basis for this relationship is unclear. Resistance to inhibitors of IKKbeta or EGFR is observed in head and neck squamous cell carcinomas (HNSCC). Here, we reveal that both IKKalpha and beta contribute to nuclear activation of canonical and alternate NF kappaB/REL family transcription factors, and overexpression of signal components that enhance co-activation of the EGFR-AP1 pathway. We observed that IKKalpha and IKKbeta exhibit increased protein expression, nuclear localization, and phosphorylation in HNSCC tissues and cell lines. Individually, IKK activity varied among different cell lines, but overexpression of both IKKs induced the strongest NF-kappaB activation. Conversely, siRNA knock down of both IKKs significantly decreased nuclear localization and phosphorylation of canonical RELA and IkappaBalpha and alternative p52 and RELB subunits. Knock down of both IKKs more effectively inhibited NF-kappaB activation, broadly modulated gene expression and suppressed cell proliferation and migration. Global expression profiling revealed that NF-kappaB, cytokine, inflammatory response and growth factor signaling are among the top pathways and networks regulated by IKKs. Importantly, IKKalpha and IKKbeta together promoted the expression and activity of transforming growth factor alpha, EGFR and AP1 transcription factors cJun, JunB and Fra1. Knock down of AP1 subunits individually decreased 8/15 (53%) of IKK-targeted genes sampled and similarly inhibited cell proliferation and migration. Mutations of NF-kappaB and AP1-binding sites abolished or decreased IKK-induced interleukin-8 (IL-8) promoter activity. Compounds such as wedelactone with dual IKK inhibitory activity and geldanomycins that block IKKalpha/beta and EGFR pathways were more active than IKKbeta-specific inhibitors in suppressing NF kappaB activation and proliferation and inducing cell death. We conclude that IKKalpha and IKKbeta cooperatively activate NF-kappaB and EGFR/AP1 networks of signaling pathways and contribute to the malignant phenotype and the intrinsic or acquired therapeutic resistance of HNSCC. PMID- 23455328 TI - End-of-life care attitudes, values, and practices among health care workers. AB - INTRODUCTION: This study aims to ascertain attitudes of health care workers on end-of-life care (EOLC) issues and to highlight the disparity that exists in countries with different backgrounds. METHODS: It is a cross-sectional questionnaire survey across heterogeneous health care providers in India, Chile, the United Kingdom, and the Netherlands using an indigenously prepared questionnaire considering regional variations, covering different areas of EOLC. RESULTS: Of the 109 participants, 68 (62.4%) felt that cardiopulmonary resuscitation should be done selectively, 25 (22.9%) had come in contact with at least 1 patient who had asked them to hasten death, and 36 (33%) felt that training was insufficient to prepare them for skills in issues of EOLC. CONCLUSION: To avoid cumbersome through well-meant interventions, it is important that the caregiving team is aware of the patient's own wishes with respect to EOLC issues. PMID- 23455330 TI - Investigation of magnetic properties induced by group-V element in doped ZnO. AB - For the potential applications in spintronics, we examine systematically the electronic properties of group-V elements (X) doped ZnO to investigate the magnetic properties induced by X based on density functional theory calculations. Our results indicates that X atoms doped in the form of a substitutional X atom at an O anion site (XO) and at a Zn cation site combining with two Zn vacancies (XZn-2VZn complex) under different circumstances can introduce magnetism. The magnetism comes from the p-p and p-d coupling interaction between the dopant X-p orbitals and the host O-2p and Zn-3d orbitals. The stability of the ferromagnetism (FM) phase induced by XO defects decreases with the increase of dopant atomic number due to the lower electronegativity value, which can be interpreted by the phenomenological band-coupling model. The origin of the magnetism induced by XZn-2VZn is similar to that of the Zn vacancy (VZn) in ZnO and comes from the O-2p orbitals dominantly. The FM stability introduced by XZn 2VZn decreases with the order N < Sb < As < P, which is ascribed to the delocalization of the O-2p orbitals. The results mean that 3p/4p/5p dopants could also make ZnO materials into diluted magnetic semiconductors. PMID- 23455329 TI - Periodontal disease and rheumatoid arthritis: the evidence accumulates for complex pathobiologic interactions. AB - PURPOSE OF REVIEW: This review was conducted to focus on the recent clinical and translational research related to the associations between periodontal disease and rheumatoid arthritis. RECENT FINDINGS: There is a growing interest in the associations between oral health and autoimmune and inflammatory diseases. A number of epidemiologic studies have described associations between rheumatoid arthritis and periodontal disease. Recent clinical studies continue to support these reports, and are increasingly linked with biological assessments to better understand the nature of these relationships. A number of recent studies have evaluated the periopathogenic roles of Porphyromonas gingivalis, the oral microbiome, and mechanisms of site-specific and substrate-specific citrullination. These are helping to further elucidate the interactions between these two inflammatory disease processes. SUMMARY: Studies of clinical oral health parameters, the gingival microenvironment, autoantibodies and biomarkers, and rheumatoid arthritis disease activity measures are providing a better understanding of the potential mechanisms responsible for rheumatoid arthritis and periodontal disease associations. The cumulative results and ongoing studies have the promise to identify novel mechanisms and interventional strategies to improve patient outcomes for both conditions. PMID- 23455331 TI - Micromotion and friction evaluation of a novel surface architecture for improved primary fixation of cementless orthopaedic implants. AB - A new surface architecture (OsteoAnchor) for orthopaedic stem components has been developed, which incorporates a multitude of tiny anchor features for embedding into the bone during implantation. It was tested for its ability to provide improved primary fixation compared to existing surface coatings. Friction testing was performed on bovine trabecular bone. It was found that OsteoAnchor provided up to 76% greater resistance to transverse motion under simultaneous normal loading compared to the porous tantalum. Micromotion testing was performed on stem components implanted in cadaver ovine femurs. The micromotion amplitudes for the OsteoAnchor stem were significantly lower than for a corresponding plasma sprayed stem. These results demonstrate that OsteoAnchor has the potential to provide improved primary fixation for stem components in joint replacement operations. PMID- 23455333 TI - Atypical spitz tumors with 6q23 deletions: a clinical, histological, and molecular study. AB - Determining risk assessment for aggressive behavior of atypical Spitz tumors (ASTs) remains a significant challenge for pathologists. Despite the presence of many concerning histological features such as tumor ulceration, expansile growth, dermal mitotic rate, and cytological atypia, the overwhelming majority of these tumors behave in an indolent fashion. Recently, we have noted that using cytogenetics, one can identify ASTs with high likelihood for aggressive behavior allowing for a clinically significant risk assessment. In this retrospective case controlled study, we examined the clinical and histological features of 24 cases of ASTs that were found to have isolated copy number deletions in 6q23 when studied by probes targeting 6p25, 6q23, Cep6, 11q13, 9p21, and Cep9. Although 6 of 11 patients had a positive sentinel node biopsy, none of the patients developed tumor in a nonsentinel node, palpable adenopathy, in transit metastasis, or distant metastasis. Histopathologically, the tumors showed minimal pagetoid spread (P = 0.004) and trended toward a histological presentation with expansile nodular growth (P = 0.08) and focal ulceration (P = 0.19). Furthermore, we also depict and illustrate the challenges that may occur in accurately identifying 6q23 deletions using fluorescence in situ hybridization in ASTs. PMID- 23455334 TI - Apoptosis and in situ and invasive squamous cell carcinoma in sun-exposed sites. AB - In vitro evidence indicates that the E6 protein of human papillomavirus (HPV) targets Bak, a proapoptotic protein, expression of which is enhanced in epidermal keratinocytes in response to ultraviolet B radiation. Given this, our aim was to ascertain Bak expression and prevalence of beta-HPV (beta-HPV) in cutaneous squamous cell carcinoma (SCC) from sun-exposed sites to test our hypothesis that the virus plays a role in the neoplastic process by suppressing UV-induced apoptosis. This retrospective study included 30 cases of cutaneous SCC and 30 cases of SCC in situ (SCCIS) from sun-exposed sites. Immunohistochemical staining for Bak protein was performed on all, and beta-HPV subtyping on 10 randomly selected cases from each group, using a broad-spectrum polymerase chain reaction reverse hybridization assay. A semiquantitative scoring system for immunohistochemical expression of Bak was used based on the percentage positivity of the cells. Of cases studied, 30 of 30 (100%) of SCCIS and SCC (mean score 4.2 and 4.6, respectively, demonstrated immunopositivity, albeit to varying degrees, with Bak. Of the selected cases studied with reverse hybridization assay, 7 of 10 (70%) of SCCIS and 3 of 10 (30%) of SCC had beta-HPV with HPV-5 being the most common subtype detected. Enhanced Bak immunoexpression confirms the presence of UV-induced apoptosis in both in situ as well as invasive epithelial malignancies, although the lack of differences in expression of Bak between both groups studied suggests that its relevance in disease progression is minimal. Expression of Bak in 100% of HPV-containing lesions from sun-exposed sites suggests that the virus does not abrogate UV-induced apoptosis. PMID- 23455335 TI - Comparison of the compositions of the stool microbiotas of infants fed goat milk formula, cow milk-based formula, or breast milk. AB - The aim of the study was to compare the compositions of the fecal microbiotas of infants fed goat milk formula to those of infants fed cow milk formula or breast milk as the gold standard. Pyrosequencing of 16S rRNA gene sequences was used in the analysis of the microbiotas in stool samples collected from 90 Australian babies (30 in each group) at 2 months of age. Beta-diversity analysis of total microbiota sequences and Lachnospiraceae sequences revealed that they were more similar in breast milk/goat milk comparisons than in breast milk/cow milk comparisons. The Lachnospiraceae were mostly restricted to a single species (Ruminococcus gnavus) in breast milk-fed and goat milk-fed babies compared to a more diverse collection in cow milk-fed babies. Bifidobacteriaceae were abundant in the microbiotas of infants in all three groups. Bifidobacterium longum, Bifidobacterium breve, and Bifidobacterium bifidum were the most commonly detected bifidobacterial species. A semiquantitative PCR method was devised to differentiate between B. longum subsp. longum and B. longum subsp. infantis and was used to test stool samples. B. longum subsp. infantis was seldom present in stools, even of breast milk-fed babies. The presence of B. bifidum in the stools of breast milk-fed infants at abundances greater than 10% of the total microbiota was associated with the highest total abundances of Bifidobacteriaceae. When Bifidobacteriaceae abundance was low, Lachnospiraceae abundances were greater. New information about the composition of the fecal microbiota when goat milk formula is used in infant nutrition was thus obtained. PMID- 23455336 TI - Prevalence of extended-spectrum beta-lactamase-producing Escherichia coli on Bavarian dairy and beef cattle farms. AB - Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli strains are believed to be widely distributed among humans and animals; however, to date, there are only few studies that support this assumption on a regional or countrywide scale. Therefore, a study was designed to assess the prevalence of ESBL-producing E. coli in dairy cows and beef cattle in the southern part of Bavaria, Germany. The study population included 30 mixed dairy and beef cattle farms and 15 beef cattle farms. Fecal samples, boot swabs, and dust samples were analyzed for ESBL-producing E. coli using selective media. PCR was performed to screen for CTX-M and ampC resistance genes. A total of 598 samples yielded 196 (32.8%) that contained ESBL-producing E. coli, originating from 39 (86.7%) of 45 farms. Samples obtained from mixed farms were significantly more likely to be ESBL-producing E. coli positive than samples from beef cattle farms (fecal samples, P < 0.001; boot swabs, P = 0.014; and dust samples, P = 0.041). A total of 183 isolates (93.4%) of 196 ESBL-producing E. coli-positive strains harbored CTX-M genes, CTX-M group 1 being the most frequently found group. Forty-six additional isolates contained ampC genes, and 5 of the 46 isolates expressed a blaCMY-2 gene. The study shows that ESBL-producing E. coli strains are commonly found on Bavarian dairy and beef cattle farms. Moreover, to our knowledge, this is the first report of the occurrence of blaCMY-2 in cattle in Germany. PMID- 23455338 TI - Two-plasmid vector system for independently controlled expression of green and red fluorescent fusion proteins in Staphylococcus aureus. AB - We have constructed a system for the regulated coexpression of green fluorescent protein (GFP) and red fluorescent protein (RFP) fusions in Staphylococcus aureus. It was validated by simultaneous localization of cell division proteins FtsZ and Noc and used to detect filament formation by an actin-like ParM plasmid partitioning protein in its native coccoid host. PMID- 23455337 TI - Ruminant rhombencephalitis-associated Listeria monocytogenes strains constitute a genetically homogeneous group related to human outbreak strains. AB - Listeriosis is a disease that causes significant economic losses at the farm level because of high morbidity and mortality in ruminants. This study was performed to investigate the role of ruminants in the epidemiology of listeriosis in northern Italy and the possible association of animal-adapted strains of Listeria monocytogenes with strains associated with human disease. Twenty ruminant rhombencephalitis isolates previously confirmed as L. monocytogenes by bacteriology and PCR were characterized by serotyping, pulsed-field gel electrophoresis, multi-virulence-locus sequence typing (MVLST), and multiplex single nucleotide polymorphism (mSNP) typing for the detection of epidemic clones. Subtyping results were subsequently compared with those obtained from human, food, and environmental isolates of L. monocytogenes, including 311 isolates from the University of Turin, Grugliasco, Italy, and 165 isolates representing major human listeriosis outbreaks worldwide, in addition to other unrelated isolates. Both mSNP typing and MVLST showed that 60% of the isolates analyzed belonged to epidemic clone I (ECI), which has been epidemiologically linked to several human outbreaks of listeriosis. In particular, the 1981 Canada outbreak was linked to the use of sheep manure and the 1985 California outbreak was linked to the use of raw cow's milk. In our study, ECI isolates were collected from different ruminant species on geographically and temporally distinct occasions for the last 13 years. Our results support the hypothesis that ruminants represent possible natural reservoirs of L. monocytogenes strains capable of causing epidemics of listeriosis in humans. PMID- 23455340 TI - Metabolic engineering for L-glutamine overproduction by using DNA gyrase mutations in Escherichia coli. AB - An L-glutamine-overproducing mutant of an Escherichia coli K-12-derived strain was selected from randomly mutagenized cells in the course of L-alanyl-L glutamine strain development. Genome-wide mutation analysis unveiled a novel mechanism for L-glutamine overproduction in this mutant. Three mutations were identified that are related to the L-glutamine overproduction phenotype, namely, an intergenic mutation in the 5'-flanking region of yeiG and two nonsynonymous mutations in gyrA (Gly821Ser and Asp830Asn). Expression of yeiG, which encodes a putative esterase, was enhanced by the intergenic mutation. The nonsynonymous mutations in gyrA, a gene that encodes the DNA gyrase alpha subunit, affected the DNA topology of the cells. Gyrase is a type II topoisomerase that adds negative supercoils to double-stranded DNA. When the opposing DNA-relaxing activity was enhanced by overexpressing topoisomerase I (topA) and topoisomerase IV (parC and parE), an increase in L-glutamine production was observed. These results indicate that a reduction of chromosomal DNA supercoils in the mutant caused an increase in L-glutamine accumulation. The mechanism underlying this finding is discussed in this paper. We also constructed an L-glutamine-hyperproducing strain by attenuating cellular L-glutamine degradation activity. Although the reconstituted mutant (with yeiG together with gyrA) produced 200 mM L-glutamine, metabolic engineering finally enabled construction of a mutant that accumulated more than 500 mM L-glutamine. PMID- 23455339 TI - Characteristics of extended-spectrum beta-lactamase- and carbapenemase-producing Enterobacteriaceae Isolates from rivers and lakes in Switzerland. AB - One of the currently most relevant resistance mechanisms in Enterobacteriaceae is the production of enzymes that lead to modern expanded-spectrum cephalosporin and even carbapenem resistance, mainly extended-spectrum beta-lactamases (ESBLs) and carbapenemases. A worrisome aspect is the spread of ESBL and carbapenemase producers into the environment. The aim of the present study was to assess the occurrence of ESBL- and carbapenemase-producing Enterobacteriaceae and to further characterize ESBL- and carbapenemase-producing Enterobacteriaceae in rivers and lakes in Switzerland. ESBL-producing Enterobacteriaceae were detected in 21 (36.2%) of the 58 bodies of water sampled. One river sample tested positive for a carbapenemase-producing Klebsiella pneumoniae subsp. pneumoniae strain. Seventy four individual strains expressing an ESBL phenotype were isolated. Species identification revealed 60 Escherichia coli strains, seven Klebsiella pneumoniae subsp. pneumoniae strains, five Raoultella planticola strains, one Enterobacter cloacae strain, and one Enterobacter amnigenus strain. Three strains were identified as SHV-12 ESBL producers, and 71 strains carried genes encoding CTX-M ESBLs. Of the 71 strains with CTX-M ESBL genes, 8 isolates expressed CTX-M-1, three produced CTX-M-3, 46 produced CTX-M-15, three produced CTX-M-55, one produced CTX-M-79, six produced CTX-M-14, and four produced CTX-M-27. Three of the four CTX-M-27 producers belonged to the multiresistant pandemic sequence type E. coli B2:ST131 that is strongly associated with potentially severe infections in humans and animals. PMID- 23455341 TI - Prediction of antimicrobial activity of synthetic peptides by a decision tree model. AB - Antimicrobial resistance is a persistent problem in the public health sphere. However, recent attempts to find effective substitutes to combat infections have been directed at identifying natural antimicrobial peptides in order to circumvent resistance to commercial antibiotics. This study describes the development of synthetic peptides with antimicrobial activity, created in silico by site-directed mutation modeling using wild-type peptides as scaffolds for these mutations. Fragments of antimicrobial peptides were used for modeling with molecular modeling computational tools. To analyze these peptides, a decision tree model, which indicated the action range of peptides on the types of microorganisms on which they can exercise biological activity, was created. The decision tree model was processed using physicochemistry properties from known antimicrobial peptides available at the Antimicrobial Peptide Database (APD). The two most promising peptides were synthesized, and antimicrobial assays showed inhibitory activity against Gram-positive and Gram-negative bacteria. Colossomin C and colossomin D were the most inhibitory peptides at 5 MUg/ml against Staphylococcus aureus and Escherichia coli. The methods described in this work and the results obtained are useful for the identification and development of new compounds with antimicrobial activity through the use of computational tools. PMID- 23455342 TI - Autotrophic growth of bacterial and archaeal ammonia oxidizers in freshwater sediment microcosms incubated at different temperatures. AB - Both bacteria and archaea potentially contribute to ammonia oxidation, but their roles in freshwater sediments are still poorly understood. Seasonal differences in the relative activities of these groups might exist, since cultivated archaeal ammonia oxidizers have higher temperature optima than their bacterial counterparts. In this study, sediment collected from eutrophic freshwater Lake Taihu (China) was incubated at different temperatures (4 degrees C, 15 degrees C, 25 degrees C, and 37 degrees C) for up to 8 weeks. We examined the active bacterial and archaeal ammonia oxidizers in these sediment microcosms by using combined stable isotope probing (SIP) and molecular community analysis. The results showed that accumulation of nitrate in microcosms correlated negatively with temperature, although ammonium depletion was the same, which might have been related to enhanced activity of other nitrogen transformation processes. Incubation at different temperatures significantly changed the microbial community composition, as revealed by 454 pyrosequencing targeting bacterial 16S rRNA genes. After 8 weeks of incubation, [(13)C]bicarbonate labeling of bacterial amoA genes, which encode the ammonia monooxygenase subunit A, and an observed increase in copy numbers indicated the activity of ammonia-oxidizing bacteria in all microcosms. Nitrosomonas sp. strain Is79A3 and Nitrosomonas communis lineages dominated the heavy fraction of CsCl gradients at low and high temperatures, respectively, indicating a niche differentiation of active bacterial ammonia oxidizers along the temperature gradient. The (13)C labeling of ammonia-oxidizing archaea in microcosms incubated at 4 to 25 degrees C was minor. In contrast, significant (13)C labeling of Nitrososphaera-like archaea and changes in the abundance and composition of archaeal amoA genes were observed at 37 degrees C, implicating autotrophic growth of ammonia-oxidizing archaea under warmer conditions. PMID- 23455343 TI - Geobacillus thermoglucosidasius endospores function as nuclei for the formation of single calcite crystals. AB - Geobacillus thermoglucosidasius colonies were placed on an agar hydrogel containing acetate, calcium ions, and magnesium ions, resulting in the formation of single calcite crystals (calcites) within and peripheral to the plating area or parent colony. Microscopic observation of purified calcites placed on the surface of soybean casein digest (SCD) nutrient medium revealed interior crevices from which bacterial colonies originated. Calcites formed on the gel contained [1 (13)C]- and [2-(13)C]acetate, demonstrating that G. thermoglucosidasius utilizes carbon derived from acetate for calcite formation. During calcite formation, vegetative cells swam away from the parent colony in the hydrogel. Hard-agar hydrogel inhibited the formation of calcites peripheral to the parent colony. The calcite dissolved completely in 1 M HCl, with production of bubbles, and the remaining endospore-like particles were easily stained with Brilliant green dye. The presence of DNA and protein in calcites was demonstrated by electrophoresis. We propose that endospores initiate the nucleation of calcites. Endospores of G. thermoglucosidasius remain alive and encapsulated in calcites. PMID- 23455344 TI - Fusion of an oligopeptide to the N terminus of an alkaline alpha-amylase from Alkalimonas amylolytica simultaneously improves the enzyme's catalytic efficiency, thermal stability, and resistance to oxidation. AB - In this study, we constructed and expressed six fusion proteins composed of oligopeptides attached to the N terminus of the alkaline alpha-amylase (AmyK) from Alkalimonas amylolytica. The oligopeptides had various effects on the functional and structural characteristics of AmyK. AmyK-p1, the fusion protein containing peptide 1 (AEAEAKAKAEAEAKAK), exhibited improved specific activity, catalytic efficiency, alkaline stability, thermal stability, and oxidative stability compared with AmyK. Compared with AmyK, the specific activity and catalytic constant (kcat) of AmyK-p1 were increased by 4.1-fold and 3.5-fold, respectively. The following properties were also improved in AmyK-p1 compared with AmyK: kcat/Km increased from 1.8 liter/(g.min) to 9.7 liter/(g.min), stable pH range was extended from 7.0 to 11.0 to 7.0 to 12.0, optimal temperature increased from 50 degrees C to 55 degrees C, and the half-life at 60 degrees C increased by ~2-fold. Moreover, AmyK-p1 showed improved resistance to oxidation and retained 54% of its activity after incubation with H2O2, compared with 20% activity retained by AmyK. Finally, AmyK-p1 was more compatible than AmyK with the commercial solid detergents tested. The mechanisms responsible for these changes were analyzed by comparing the three-dimensional (3-D) structural models of AmyK and AmyK-p1. The significantly enhanced catalytic efficiency and stability of AmyK-p1 suggests its potential as a detergent ingredient. In addition, the oligopeptide fusion strategy described here may be useful for improving the catalytic efficiency and stability of other industrial enzymes. PMID- 23455345 TI - Occurrence, genetic diversity, and persistence of enterococci in a Lake Superior watershed. AB - In 2012, the U.S. EPA suggested that coastal and Great Lakes states adopt enterococci as an alternative indicator for the monitoring of recreational water quality. Limited information, however, is available about the presence and persistence of enterococci in Lake Superior. In this study, the density, species composition, and persistence of enterococci in sand, sediment, water, and soil samples were examined at two sites in a Lake Superior watershed from May to September over a 2-year period. The genetic diversity of Enterococcus faecalis isolates collected from environmental samples was also studied by using the horizontal, fluorophore-enhanced repetitive PCR DNA fingerprinting technique. Results obtained by most-probable-number analyses indicated that enterococci were present in 149 (94%) of 159 samples and their densities were generally higher in the summer than in the other months examined. The Enterococcus species composition displayed spatial and temporal changes, with the dominant species being E. hirae, E. faecalis, E. faecium, E. mundtii, and E. casseliflavus. DNA fingerprint analyses indicated that the E. faecalis population in the watershed was genetically diverse and changed spatially and temporally. Moreover, some DNA fingerprints reoccurred over multiple sampling events. Taken together, these results suggest that some enterococci are able to persist and grow in the Lake Superior watershed, especially in soil, for a prolonged time after being introduced. PMID- 23455347 TI - Bioengineering of bacterial polymer inclusions catalyzing the synthesis of N acetylneuraminic acid. AB - N-Acetylneuraminic acid is produced by alkaline epimerization of N acetylglucosamine to N-acetylmannosamine and then subsequent condensation with pyruvate catalyzed by free N-acetylneuraminic acid aldolase. The high-alkaline conditions of this process result in the degradation of reactants and products, while the purification of free enzymes to be used for the synthesis reaction is a costly process. The use of N-acetylglucosamine 2-epimerase has been seen as an alternative to the alkaline epimerization process. In this study, these two enzymes involved in N-acetylneuraminic acid production were immobilized to biopolyester beads in vivo in a one-step, cost-efficient process of production and isolation. Beads with epimerase-only, aldolase-only, and combined epimerase/aldolase activity were recombinantly produced in Escherichia coli. The enzymatic activities were 32 U, 590 U, and 2.2 U/420 U per gram dry bead weight, respectively. Individual beads could convert 18% and 77% of initial GlcNAc and ManNAc, respectively, at high substrate concentrations and near-neutral pH, demonstrating the application of this biobead technology to fine-chemical synthesis. Beads establishing the entire N-acetylneuraminic acid synthesis pathway were able to convert up to 22% of the initial N-acetylglucosamine after a 50-h reaction time into N-acetylneuraminic acid. PMID- 23455346 TI - Searching for genes responsible for patulin degradation in a biocontrol yeast provides insight into the basis for resistance to this mycotoxin. AB - Patulin is a mycotoxin that contaminates pome fruits and derived products worldwide. Basidiomycete yeasts belonging to the subphylum Pucciniomycotina have been identified to have the ability to degrade this molecule efficiently and have been explored through different approaches to understand this degradation process. In this study, Sporobolomyces sp. strain IAM 13481 was found to be able to degrade patulin to form two different breakdown products, desoxypatulinic acid and (Z)-ascladiol. To gain insight into the genetic basis of tolerance and degradation of patulin, more than 3,000 transfer DNA (T-DNA) insertional mutants were generated in strain IAM 13481 and screened for the inability to degrade patulin using a bioassay based on the sensitivity of Escherichia coli to patulin. Thirteen mutants showing reduced growth in the presence of patulin were isolated and further characterized. Genes disrupted in patulin-sensitive mutants included homologs of Saccharomyces cerevisiae YCK2, PAC2, DAL5, and VPS8. The patulin sensitive mutants also exhibited hypersensitivity to reactive oxygen species as well as genotoxic and cell wall-destabilizing agents, suggesting that the inactivated genes are essential for tolerating and overcoming the initial toxicity of patulin. These results support a model whereby patulin degradation occurs through a multistep process that includes an initial tolerance to patulin that utilizes processes common to other external stresses, followed by two separate pathways for degradation. PMID- 23455348 TI - Proline availability regulates proline-4-hydroxylase synthesis and substrate uptake in proline-hydroxylating recombinant Escherichia coli. AB - Microbial physiology plays a crucial role in whole-cell biotransformation, especially for redox reactions that depend on carbon and energy metabolism. In this study, regio- and enantio-selective proline hydroxylation with recombinant Escherichia coli expressing proline-4-hydroxylase (P4H) was investigated with respect to its interconnectivity to microbial physiology and metabolism. P4H production was found to depend on extracellular proline availability and on codon usage. Medium supplementation with proline did not alter p4h mRNA levels, indicating that P4H production depends on the availability of charged prolyl tRNAs. Increasing the intracellular levels of soluble P4H did not result in an increase in resting cell activities above a certain threshold (depending on growth and assay temperature). Activities up to 5-fold higher were reached with permeabilized cells, confirming that host physiology and not the intracellular level of active P4H determines the achievable whole-cell proline hydroxylation activity. Metabolic flux analysis revealed that tricarboxylic acid cycle fluxes in growing biocatalytically active cells were significantly higher than proline hydroxylation rates. Remarkably, a catalysis-induced reduction of substrate uptake was observed, which correlated with reduced transcription of putA and putP, encoding proline dehydrogenase and the major proline transporter, respectively. These results provide evidence for a strong interference of catalytic activity with the regulation of proline uptake and metabolism. In terms of whole-cell biocatalyst efficiency, proline uptake and competition of P4H with proline catabolism are considered the most critical factors. PMID- 23455350 TI - Evaluating the assignment of alkB terminal restriction fragments and sequence types to distinct bacterial taxa. AB - Sequence and terminal restriction fragment length polymorphism (T-RFLP) analyses revealed multiple alkB gene copies/cell in soil bacterial isolates and an apparently high genetic mobility among various phylogenetic groups. Identifying alkane degraders by alkB terminal restriction fragments (T-RFs) and sequences is strongly biased, as the phylogenetic trees based on 16S rRNA and alkB gene sequences were highly inconsistent. PMID- 23455349 TI - Characterization of a regulatory network of peptide antibiotic detoxification modules in Lactobacillus casei BL23. AB - Two-component systems (TCS) are major signal transduction pathways that allow bacteria to detect and respond to environmental and intracellular changes. A group of TCS has been shown to be involved in the response against antimicrobial peptides (AMPs). These TCS are characterized by the possession of intramembrane sensing histidine kinases, and they are usually associated with ABC transporters of the peptide-7 exporter family (Pep7E). Lactobacillus casei BL23 encodes two TCS belonging to this group (TCS09 and TCS12) that are located next to two ABC transporters (ABC09 and ABC12), as well as a third Pep7E ABC transporter not genetically associated with any TCS (orphan ABC). This study addressed the involvement of modules TCS09/ABC09 and TCS12/ABC12 in AMP resistance. Results showed that both systems contribute to L. casei resistance to AMPs, and that each TCS constitutes a functional unit with its corresponding ABC transporter. Analysis of transcriptional levels showed that module 09 is required for the induction of ABC09 expression in response to nisin. In contrast, module 12 controls a wider regulon that encompasses the orphan ABC, the dlt operon (d alanylation of teichoid acids), and the mprF gene (l-lysinylation of phospholipids), thereby controlling properties of the cell envelope. Furthermore, the characterization of a dltA mutant showed that Dlt plays a major role in AMP resistance in L. casei. This is the first report on the regulation of the response of L. casei to AMPs, giving insight into its ability to adapt to the challenging environments that it encounters as a probiotic microorganism. PMID- 23455351 TI - Novel rod-shaped magnetotactic bacteria belonging to the class Alphaproteobacteria. AB - Novel large, rod-shaped magnetotactic bacteria (MTB) were discovered in intertidal sediments of the Yellow Sea, China. They biomineralized more than 300 rectangular magnetite magnetosomes per cell. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that they are affiliated with the Alphaproteobacteria and may represent a new genus of MTB. PMID- 23455352 TI - Self-assembly and photocatalytic property of germanoniobate [H6Ge4Nb16O56]10-: encapsulating four {GeO4} tetrahedra within a {Nb16} cage. AB - An unprecedented organic-inorganic hybrid germanoniobate compound Na4[Cu(en)2(H2O)2]5[Na6Ge8Nb32O108H8(OH)4].41H2O (1) was synthesized under the hydrothermal condition. In compound 1, the {Nb16} cage containing four {GeO4} tetrahedra in its internal cavity results in a heteropolyniobate anion [H4Ge4Nb16O54(OH)2](10-) ({Ge4Nb16}), which is connected by a {Na6} cluster into the first germanoniobate-based sandwich-type structure. Further, the sandwich germanoniobates are connected by [Na2Cu(en)2O6H8] groups into a porous network with one dimensional channels along the a-axis. Photocatalytic study reveals that compound 1 exhibits good photocatalytic activity for the degradation of methylene blue. PMID- 23455353 TI - Lost in the supermarket. PMID- 23455354 TI - Silicon nanowires: electron holography studies of doped p-n junctions and biased Schottky barriers. AB - We report an in situ examination of individual Si p-n junction nanowires (NWs) using off-axis electron holography (EH) during transmission electron microscopy. The SiNWs were synthesized by chemical vapor deposition with an axial dopant profile from n- to p-type, and then placed inside the transmission electron microscope as a cantilever geometry in contact with a movable Pt probe for in situ biasing measurements during simultaneous EH observations. The phase shift from EH indicates the potential shift between the p- and n-segments to be 1.03 +/ 0.17 V due to the built-in voltage. The I-V characteristics of a single SiNW indicate the formation of a Schottky barrier between the NW tip and the movable Pt contact. EH observations show a strong concentration of electric field at this contact, preventing a change in the Si energy bands in the p-n junction region due to the applied bias. PMID- 23455355 TI - A critical study: assessment of the effect of silica particles from 15 to 500 nm on bacterial viability. AB - The current opinion on the toxicity of nanomaterials converges on a size dependent phenomenon showing increasing toxicity with decreasing particle sizes. We demonstrate that SiO2 particles have no or only a mild effect on the viability of five bacterial strains, independently from the particle size. A two-hour exposure to 20 mg L(-1) of 15, 50 and 500 nm sized SiO2 particles neither alters bacterial adenosine triphosphate (ATP) levels nor reduces the number of colony forming units (CFU). Additionally, we tested the effect of Al2O3-coated LUDOX-CL (ACS 20) with a primary particle size of 20 nm. In contrast, these particles caused a significant reduction of ATP levels and CFU. Fluorescence microscopy revealed that ACS 20 induced a pronounced agglomeration of the bacteria, which led to underestimated counts in regard of CFU. Bactericide effects as indicated by decreased ATP levels can be explained by bactericide additives that are present in the ACS 20 suspension. PMID- 23455357 TI - Embedment of anodized p-type Cu2O thin films with CuO nanowires for improvement in photoelectrochemical stability. AB - A highly stable p-type cuprous oxide (Cu2O) photoelectrode has been fabricated by direct anodization of the Cu foil, followed by a thermal treatment to introduce a protective layer of copper oxide (CuO) nanowires penetrating the surface of the Cu2O layer. The anodized Cu2O served as the seeding sites for the growth of CuO nanowires. The embedment of CuO nanowires within the Cu2O matrix enhanced the adhesion of the nanowires onto the Cu substrate. In addition, the presence of CuO nanowires on the outer layer of the composite film, in turn stabilized the Cu2O layer by passivating the redox activities of Cu2O when exposed to the environment. This nanostructured p-type Cu2O photoelectrode generated 360 MUA cm( 2) of photocathodic current density upon visible light illumination and managed to retain its photocathodic current density after being used and kept for one month. The improvement in photoelectrochemical (PEC) stability by introducing a passive layer of CuO nanowires provides useful insights into the development of a Cu2O photoelectrode, as its stability remained as the main challenge. PMID- 23455356 TI - RET gene abnormalities and thyroid disease: who should be screened and when. AB - Mutations in the RET proto-oncogene have been implicated in the pathogenesis of several forms of medullary thyroid cancer (MTC). Multiple endocrine neoplasia type 2 (MEN-2) is an autosomal dominant syndrome caused by germline activating mutations of the RET proto-oncogene and has been categorized into three distinct clinical forms. MEN-2A is associated with MTC, bilateral pheochromocytoma, and primary hyperparathyroidism. MEN-2B is associated with MTC, bilateral pheochromocytoma, and mucosal neuromas. The rarest clinical form of MEN-2 is familial MTC (FMTC), which is also associated with MTC, but other endocrinopathies are characteristically not present. Each clinical form of MEN-2 results from a specific RET gene mutation, with a strong correlation of phenotype expression with regard to the onset and course of MTC and the presence of other endocrine tumors and a corresponding genotype. Recommendations for screening of RET mutations are necessary as their presence or absence will influence interventional strategies such as the timing of a prophylactic thyroidectomy and extent of surgery. Timing of screenings and development of interventional strategies are extremely important in caring for patients with certain RET mutations as evidence of metastatic MTC has been documented as early as 6 years of age. Interventional strategies should consider the risks of complications of these interventions based on certain characteristics of each individual case such as age of the patient, course of disease in affected family members, and the invasiveness of any proposed surgical procedure. PMID- 23455358 TI - Perceptual Adaptation to Room Acoustics and Effects on Speech Intelligibility in Hearing-Impaired Populations. AB - Recent evidence suggests that brief listening exposure to a reverberant room environment can improve closed-set speech intelligibility in that same environment. For normal-hearing populations, this room adaptation effect can result in improvements in intelligibility of as much as 20%, but depends strongly on the reverberation time of the room, and appears to require binaural input. Because poor speech intelligibility in reverberation is a common complaint for hearing-impaired listeners, it is important to determine how room adaptation might impact speech intelligibility for hearing-impaired populations. Here, room adaptation was quantified for a sample of listeners with sensorineural hearing loss that varied in severity and configuration. Speech reception thresholds (SRTs) were measured both with and without prior listening exposure to the room environment. Headphone-based auralization techniques were used to simulate the acoustics of various listening rooms, ranging from anechoic to highly reverberant space (broadband T60 = 3 s). Although SRTs both with and without prior room exposure were found to be generally elevated relative to normal-hearing listeners, the room adaptation effect, as defined by the relative decrease in SRT with room exposure, was comparable on average to that observed for normal-hearing listeners. This result is consistent with the view that room adaptation effects result from central auditory processing mechanisms. PMID- 23455359 TI - Visualizing pericardial inflammation as the cause of acute chest pain in a patient with a congenital pericardial cyst: the incremental diagnostic value of cardiac magnetic resonance. PMID- 23455360 TI - Relation between serum N-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy. AB - AIMS: To determine the relation between serum concentrations of N-terminal pro brain natriuretic peptide (NT-proBNP) and prognosis in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In total, 847 patients (53 +/- 15 years; 67% male) with HCM (28% with left ventricular outflow tract obstruction >= 30 mmHg at rest) were followed for 3.5 years (IQR 2.5-4.5 years). The median NT proBNP concentration was 78 pmol/L (range < 5-1817 pmol/L and IQR 31-183 pmol/L). Sixty-eight patients (8%) reached the primary endpoint of all-cause mortality or cardiac transplantation. NT-proBNP concentration predicted long-term survival from the primary endpoint [area under the receiver operating characteristic curve of 0.78 (95% confidence interval 0.73-0.84)]. A serum concentration of >= 135 pmol/L was associated with an annual event rate of 6.1% (95% CI 4.4-7.7). Three independent predictors of primary outcome were identified in a multivariable Cox model: New York Heart Association class III/IV (HR 2.10, 95% CI 1.21-3.65, P = 0.008), ejection fraction (HR 0.98, 95% CI 0.96-1.00, P = 0.035), log NT-proBNP (HR 2.04, 95% CI 1.56-2.66, P < 0.001). Log NT-proBNP was a significant predictor of heart failure (HF) and transplant-related deaths (n = 23; HR 3.03, 95% CI 1.99 4.60, P < 0.001) but not sudden death or appropriate implantable cardioverter defibrillator shock (n = 11; HR 1.54, 95% CI 0.91-2.60, P = 0.111). In patients with ejection fraction >= 50% (n = 673), log NT-proBNP remained an independent predictor of the primary outcome (HR 2.11, 95% CI 1.54-2.90, P < 0.001). CONCLUSION: In patients with HCM, elevated NT-proBNP concentration is a strong predictor of overall prognosis, particularly HF-related death and transplantation. PMID- 23455361 TI - Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. AB - AIMS: This study compared the clinical, functional, and haemodynamic characteristics and current era survival of subgroups of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD): Eisenmenger syndrome (ES); PAH-CHD associated with systemic-to-pulmonary shunts (SPs); PAH with small defects (SDs); and PAH after defect correction (CDs). METHODS AND RESULTS: Data from consecutive PAH-CHD patients referred to our centre from 1 January 1998 to 31 May 2011 were collected. A contemporary group of idiopathic PAH patients was utilized for comparison. Treatment was per PAH guidelines, including combination therapy, with approved PAH-specific drugs. Survival was assessed with Kaplan-Meier analysis from the first invasive haemodynamic confirmation of PAH and compared across subgroups by log-rank test. Of 192 patients (mean age 41 +/- 17 years; 61% female), 90 had ES (aged 41 +/- 16 years); 48 SP (aged 47 +/- 18 years); 10 SD (aged 25 +/- 21 years); and 44 CD (aged 36 +/- 17 years). Patients with ES had the highest baseline pulmonary vascular resistance and the lowest exercise capacity. Seventy-eight per cent were treated with approved PAH-specific drugs, and 44% were treated with combination therapy. Kaplan-Meier survival estimates (95% confidence interval) at 20 years for ES, SP, and CD were 87% (77-93%), 86% (60-96%), and 36% (12-72%, P = 0.0001 vs. ES; P = 0.004 vs. SP), respectively, and at 15 years for SD was 66% (16-91%, P = 0.015 vs. ES; P = 0.016 vs. SP). The survival of the 278 patients with idiopathic PAH appeared to be worse when compared with the PAH-CHD subgroups. CONCLUSION: Relevant clinical, functional, haemodynamic, and survival differences were observed among subgroups. In particular, patients with CD and SD had the worst survival. These findings should be considered when planning medical or interventional treatment strategies in PAH-CHD patients. PMID- 23455362 TI - Display with 64-detector MDCT angiography of cerebral vascular variations. AB - PURPOSE: The aim of this study was to assess the cerebral variations and observe their frequency in the patients who have undergone angiographies with the state of the art 64-slice multidetector computed tomography (MDCT) angiography technique due to various reasons. METHODS: 500 patients (253 women, 247 men) who had CT scan in the period of April 2008 to March 2010 at Dicle University Medicine Faculty Hospital Radiology Unit were surveyed in this study. Patients who had CT scan with brain CT angio protocol were evaluated using multiplanar, maximum intensity projection (MIP) and volume rendering (VR) images in work station. RESULTS: 773 variations were totally detected among 500 patients. Variations were categorized as Willis polygon, fenestration and other variations. Frequent variations were detected at Willis polygon and posterior communicating artery (PCOA) hypoplasia was detected as the prevalent variation. CONCLUSIONS: In the present study, we have demonstrated that cerebral vascular variations are frequent and that these variations can be detected in a non-invasive manner using the MDCT angiography. The results obtained from our study may serve as preoperative guidelines for the units performing surgical procedures. PMID- 23455363 TI - Rare anatomical variation related to the nasopalatine canal. AB - The nasopalatine canal is a relatively long narrow structure located in the midline of the maxilla that contains the nasopalatine nerve and terminal branch of the descending palatine artery. Anatomical variations related to this structure have been reported. This article aimed to report a case of a complete additional nasopalatine canal on a 53-year-old female patient who underwent an examination by cone beam computed tomography. On sagittal slices, it was possible to observe the presence of an additional canal anterior and superior to the nasopalatine canal, separated by a bony septum. Each canal extended from independent superior openings (located in the nasal cavity) to independent openings located in the remaining alveolar process of the anterior maxilla. Identification of individual anatomical variations, especially involving neurovascular structures, plays an important role in the successful outcomes of surgical procedures involving the anterior maxilla. PMID- 23455364 TI - Anatomical basis of transgluteal approach for pudendal neuralgia and operative technique. AB - BACKGROUND: Pudendal neuralgia is an entrapment syndrome whose both anatomic landmarks and operative technique remain relatively unfamiliar to neurosurgeons. OBJECTIVE: To provide an outline of operative steps that is important to correct application of this approach. METHODS: Surgical illustrations are included. The different figures detail the important steps of the operation. RESULTS: We perform a transmuscular approach leading to the sacrotuberous ligament, which is opened sagittally. The pudendal nerve and internal pudendal artery are found to be enclosed by a fascia sheath. The pudendal nerve swings around the sacrospinous ligament sacrospinous ligament with tension. Both distal branches of the pudendal nerve can be followed, especially the rectal branch running medially. After the section of the sacrospinous ligament, the pudendal nerve can be transposed frontally to the ischial spine within the ischiorectal fat. During this maneuver, significant venous bleeding may be encountered as perineural satellite veins dilatation can accompany or surround the pudendal nerve. It is important to avoid overpacking to limit compression injury to the pudendal nerve using judiciously small pieces of hemostatic device and soft cottonoid with light pressure. Then, the obturator fascia and the membranous falciform process of the sacrotuberous ligament that extend toward the ischioanal fossa must be incised. CONCLUSION: Transgluteal approach is a safe technique and we demonstrate that this approach can be performed safely minimizing pain, size of incision, surgical corridor, and trauma to adjacent muscles of buttock. PMID- 23455365 TI - Cross-sectional study of the neural ossification centers of vertebrae C1-S5 in the human fetus. AB - PURPOSE: An understanding of the normal evolution of the spine is of great relevance in the prenatal detection of spinal abnormalities. This study was carried out to estimate the length, width, cross-sectional area and volume of the neural ossification centers of vertebrae C1-S5 in the human fetus. MATERIALS AND METHODS: Using the methods of CT (Biograph mCT), digital-image analysis (Osirix 3.9) and statistics (the one-way ANOVA test for paired data, the Kolmogorov Smirnov test, Levene's test, Student's t test, the one-way ANOVA test for unpaired data with post hoc RIR Tukey comparisons) the size for the neural ossification centers throughout the spine in 55 spontaneously aborted human fetuses (27 males, 28 females) at ages of 17-30 weeks was studied. RESULTS: The neural ossification centers were visualized in the whole pre-sacral spine, in 74.5 % for S1, in 61.8 % for S2, in 52.7 % for S3, and in 12.7 % for S4. Neither male-female nor right-left significant differences in the size of neural ossification centers were found. The neural ossification centers were the longest within the cervical spine. The maximum values referred to the axis on the right, and to C5 vertebra on the left. There was a gradual decrease in length for the neural ossification centers of T1-S4 vertebrae. The neural ossification centers were the widest within the proximal thoracic spine and narrowed bi-directionally. The growth dynamics for CSA of neural ossification centers were found to parallel that of volume. The largest CSAs and volumes of neural ossification centers were found in the C3 vertebra, and decreased in the distal direction. CONCLUSIONS: The neural ossification centers show neither male-female nor right-left differences. The neural ossification centers are characterized by the maximum length for C2-C6 vertebrae, the maximum width for the proximal thoracic spine, and both the maximum cross-sectional area and volume for C3 vertebra. There is a sharp decrease in size of the neural ossification centers along the sacral spine. A decreasing sequence of values for neural ossification centers along the spine from cervical to sacral appears to parallel the same direction of the timing of ossification. The quantitative growth of the neural ossification centers is of potential relevance in the prenatal diagnosis and monitoring of achondrogenesis, caudal regression syndrome, diastematomyelia and spina bifida. PMID- 23455367 TI - Cardiac papillary fibroelastoma: retrospective clinicopathologic study of 17 tumors with resection at a single institution and literature review. AB - Cardiac papillary fibroelastomas (PFEs), which are mainly found in the valves, are rare benign tumors that can cause embolism. Single-center surgical experience in the treatment of this tumor is uncommon. All patients surgically treated for this neoplasm at our institution from January 1995 to October 2012 (15 patients with 17 lesions) were queried for clinical and pathologic characteristics, and the literature was reviewed. The mean age of detection was 55.8+/-11.48 years. Twenty percent of the patients were male. The tumor was an incidental finding in 60%. Symptoms directly related to PFEs occurred in 40% of patients. The most common clinical presentation in symptomatic cases was embolism (40%), mostly transient ischemic attack or stroke. Cardiac valves were predominantly involved (76.5%); the most commonly valve affected was the aortic valve (29.4%), followed by the mitral valve (17.6%). Concurrent valvular disease was observed in 41.7% of patients. The mean size of tumors was 11.4+/-7.9mm (range 2-25mm). In 86.7% of the patients, the tumor was solitary. The mitral valve was the most common origin of tumor systemic embolism. Fronds core could be the end stage of hypermature elastic fibers, which grows in apposition to young fibers. Simple surgical excision or valvular reconstruction was accomplished in most patients (58.3%). PFE is usually small, appears singly, and can cause potentially serious complications. Symptomatic and left side tumors should undergo surgical excision with valve-spare surgery when possible. Surgical removal of PFE is safe, efficacious, and definitive. PMID- 23455368 TI - Endotrophin - a novel factor linking obesity with aggressive tumor growth. PMID- 23455369 TI - Evaluating the effects of the introduction of off-sale alcohol outlets on violent crime. AB - AIMS: To examine the effects on violence of a policy change that ended prohibition of off-sale alcohol outlets in Lubbock, Texas. METHODS: Time-series analysis of violent crime data from police records comparing the periods before and after the policy change. RESULTS: The effect of the policy change on both total violent crime and aggregated assault was small and did not approach statistical significance. CONCLUSIONS: Increased availability of alcohol through off-sale premises may not influence the type of violence reported to the police in Lubbock, Texas. PMID- 23455371 TI - Ultrasonography as a tool in predicting the severity of dengue fever in children- a useful aid in a developing country. AB - BACKGROUND: Dengue fever accounts for significant mortality in developing countries. Dengue fever serology takes a week at least to be reported positive, thus necessitating the need for other markers of diagnosis and prognosis. OBJECTIVE: The purpose of this study was to investigate the role of ultrasonography as a tool in diagnosing and predicting the severity of dengue fever in children. MATERIALS AND METHODS: This was a prospective study conducted in a tertiary pediatric centre from September 2010 to July 2012. Three hundred twenty-four children with confirmed dengue fever were compared with 422 children of suspected dengue fever. Severity of illness was graded as per WHO criteria and sonography findings were correlated to the grade of illness. RESULTS: Gallbladder wall thickening was seen in 75% of the children with confirmed dengue fever. A significant difference was seen between survivors and non-survivors with respect to pericholecystic fluid collection (P = 0.002), hepatic intraparenchymal fluid (P < 0.001), splenomegaly (P = 0.002), splenic subcapsular fluid (P < 0.001), peripancreatic fluid (P < 0.001), perirenal fluid (P < 0.001) and pericardial fluid (P < 0.001). Other findings included ascites, pleural effusion, hepatomegaly and splenomegaly, which were present irrespective of grade of illness. CONCLUSIONS: Ultrasonography can be used as a useful tool in developing countries to predict the severity of dengue fever in children. PMID- 23455372 TI - Noninvasive imaging in children with hypertension. PMID- 23455373 TI - Properties and self-assembled packing morphology of long alkyl-chained substituted polyhedral oligomeric silsesquioxanes (POSS) cages. AB - Polyhedral oligomeric silsesquioxane (POSS) cubic cage systems (octa-n octadecyloctasilsesquioxane, (T8C18) and octakis(n octadecyldimethylsiloxy)octasilsesquioxane, (Q8C18)) were synthesised with eight long n-alkyl chain (R = C18H37) substituent arms, as model nano-functionalized compounds. The crystalline packing morphology of the cages was studied using time resolved Small- and Wide-angle X-ray scattering (SAXS/WAXS), thermal and optical techniques. From thermal analysis the melting and crystallization temperatures of the Q8 cage were significantly less than those for the T8 cage. X-ray scattering showed that both cage systems have long-range crystalline ordering where the alkyl chains align in a parallel axial disposition from the POSS core giving a 'rod-like' self-assembled packing morphology. The packing length-scale can be directly related to the overall dimensions of the POSS molecules. Compared to the T8 cages, the Q8 cages pack more efficiently allowing the interdigitation of the alkyl chain arms. Different packing modes and thermal behaviour observed for the T8 and Q8 cages is directly attributed to their structural chemistry. For the Q8 cage, the presence of the OSiMe2 spacer groups which tether the alkyl chain arms to the cage (absent in the T8 cages) allows greater flexibility of the arms letting them interdigitate with each other when packing which is not observed for the analogous T8 cages. PMID- 23455374 TI - Growth, structural and optical properties of AlGaN nanowires in the whole composition range. AB - We report on the growth of AlxGa1-xN nanowires by plasma-assisted molecular beam epitaxy for x in the 0.3-0.8 range. Based on a combination of macro- and micro photoluminescence, Raman spectroscopy, x-ray diffraction and scanning electron microscopy experiments, it is shown that the structural and optical properties of AlGaN NWs are governed by the presence of compositional fluctuations associated with strongly localized electronic states. A growth model is proposed, which suggests that, depending on growth temperature and metal adatom density, macroscopic composition fluctuations are mostly of kinetic origin and are directly related to the nucleation of the AlGaN nanowire section on top of the GaN nanowire base which is used as a substrate. PMID- 23455375 TI - Structural vulnerability and access to medical care among migrant street-based male sex workers in Germany. AB - This article discusses health concerns of migrant street-based male sex workers (SMSW) in Germany, a population that remains underexplored by health and social scientists. It is based on five months of ethnographic research in 2011/2012, including 46 semi-structured interviews with physicians, social workers, health department staff, and SMSW from Romania and Bulgaria. This is supplemented with annual reports by organizations providing assistance to this population in eight cities. The article contributes, first, an analysis of the increase in migrant SMSW as a response to economic opportunities (freedom of movement across European Union borders) and constraints (transitional measures restricting access to the labor market). It seeks to move beyond the myopic association between sex work and HIV to contextualize health risks as resultant of macro-level processes associated with migration. Second, the article contributes a summary of primary health concerns for this population. Especially troubling is their lack of access to regular medical services, reflecting a socio-legal position that often resembles that of unauthorized migrants rather than European Union citizens. PMID- 23455376 TI - ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. AB - The aryl hydrocarbon receptor (AhR) plays a suppressive role in cecal carcinogenesis by CUL4B/AhR-mediated ubiquitylation and degradation of beta catenin, which is activated by xenobiotics and natural ligands. AhR-deficient (AhR(-)(/-)) mice develop cecal tumors with severe inflammation. To elucidate whether the tumors develop autonomously in AhR(-/-) mice due to impaired beta catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR(-/-) mice and compound mutant mice lacking genes for AhR and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which plays an essential role in caspase-1 activation in inflammasomes. Both GF AhR(-/-) and AhR(-/-)*ASC(-/-) mice showed considerably reduced tumor development compared with that in AhR(-/-) mice albeit in a 'cancer-prone' state with aberrant beta-catenin accumulation. Blocking of the interleukin (IL)-1beta signaling pathway by treatment with a caspase-1 inhibitor, YVAD, reduced cecal tumorigenesis in AhR(-/-) mice. Signal transducers and activators of transcription 3 (STAT3) activation was detected in the cecal epithelium of the AhR(-/-) mice due to enhanced IL-6 production. An inhibitor of the STAT3 signaling pathway, AG490 suppressed the tumor formation. ASC-mediated inflammation was also found to play a critical role in tumor development in Apc(Min/+) mice, a mouse model of familial adenomatous polyposis. Collectively, these results revealed an important role of the bacteria-triggered or ASC mediated inflammation signaling pathway in the intestinal tumorigenesis of mice and suggest a possible chemical therapeutic intervention, including AhR ligands and inhibitors of the inflammation pathway. PMID- 23455377 TI - Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon. AB - Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signaling. It is unknown whether this changed signaling is caused by cytotoxic stress and/or oxidative stress, as these processes were never studied separately. The aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified, humanized, control diet or the diet supplemented with 0.2 umol heme/g. Oxidative and cytotoxic stress were measured in fecal water. Proliferation was determined by Ki67-immunohistochemistry and mucosal responses by whole-genome transcriptomics. After heme ingestion, there was an acute increase in reactive oxygen species (ROS) leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an acute antioxidant response, but no change in cell turnover. After day 4, cytotoxicity of the colonic contents was increased and this coincided with differential signaling and hyperproliferation, indicating that cytotoxicity was the causal factor. Simultaneously, several oncogenes were activated, whereas the tumor suppressor p53 was inhibited. In conclusion, luminal cytotoxicity, but not ROS, caused differential surface to crypt signaling resulting in mucosal hyperproliferation and the differential expression of oncogenes and tumor suppressor genes. PMID- 23455379 TI - The aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism interacts with alcohol drinking in the risk of stomach cancer. AB - The impact of alcohol on the risk of stomach cancer is controversial. Although aldehyde dehydrogenase 2 (ALDH2) Glu504Lys (rs671) polymorphism has a strong effect on acetaldehyde metabolism, little is known about its impact on stomach cancer risk when combined with alcohol drinking. This case-control study included a total of 697 incident stomach cancer case subjects and 1372 non-cancer control subjects who visited Aichi Cancer Center between 2001 and 2005. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2 genotypes and alcohol consumption using logistic regression models after adjustment for potential confounders, including Helicobacter pylori infection. The ALDH2 504Lys allele was associated with the risk of stomach cancer, with adjusted ORs of 1.40 (95% CI, 1.11-1.76) for Glu/Lys and 1.73 (1.12-2.68) for Lys/Lys compared with Glu/Glu. Heavy drinking was associated with risk (OR 1.72, 1.17-2.52) after adjustment for ALDH2 genotype and other confounders. Moreover, ORs for heavy drinking were 1.28 (0.77-2.12) for those with ALDH2 Glu/Glu and 3.93 (1.99-5.79) for those with the ALDH2 Lys allele relative to non-drinkers with the Glu/Glu genotype (P for interaction = 0.0054). In conclusion, ALDH2 and alcohol drinking showed interaction for risk factors of stomach cancer, indicating that acetaldehyde plays a role in stomach carcinogenesis. PMID- 23455380 TI - Risk of genome-wide association study-identified genetic variants for non-Hodgkin lymphoma in a Chinese population. AB - Recent genome-wide association studies have identified 15 single nucleotide polymorphisms (SNPs) associated with non-Hodgkin lymphoma (NHL) and its subtypes. Because the incidence and subtype portion of NHL between the Chinese population and Caucasian populations are substantially different, we assessed the associations of these SNPs with NHL risk in a case-control study consisting of 792 cases and 1542 controls derived from the Chinese population. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. False positive report probability was also assessed for significant findings. We found that the allele frequencies of the 15 SNPs in our study population significantly differed from those in Caucasian populations, with rs13397985, rs735665 and rs11083846 being extremely rare in Chinese. Only two variants (rs872071 in IRF4 and rs2647012 in HLA class II) were significantly associated with NHL risk in Chinese, with the ORs of 1.20 (95% CI, 1.05-1.38; P = 0.009) and 1.20 (95% CI, 1.03-1.39; P = 0.018) for per allele of rs872071 and rs2647012, respectively, calculated using an additive model. These results indicate a substantial different genetic background for susceptibility to NHL among the different ethnic populations. PMID- 23455381 TI - Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese. AB - Stomach carcinogenesis progresses stepwise from normal mucosa/superficial gastritis, atrophic gastritis (GA) to gastric cancer (GC). Host factors independent of or combined with Helicobacter pylori infection may modulate the carcinogenesis process. In this two-stage study, we selected 24 putative functional tag single-nucleotide polymorphisms (tagSNPs) for six H.pylori-related host genes, MUC1, toll-like receptor 4 (TLR4), protein tyrosine phosphatase, non receptor type 11 (PTPN11), IL-1B, PGC and PGA3-5, and analyzed their influence and interaction with H.pylori on the GA and GC risks. Using high-throughput genotyping, the 24 tagSNPs were preliminarily assessed in a screening population of 552 controls, 254 GA and 236 GC subjects; subsequently, five candidate tagSNPs for gastric diseases risk in the TLR4, PGC and PTPN11 genes were re-evaluated in a larger population of 1276 controls, 907GA and 714 GC subjects. We observed that PGC rs6458238, PGC rs4711690 and PTPN11 rs12229892 were associated with susceptibilities to GA and/or GC. Moreover, rs4711690 and rs12229892 and H.pylori demonstrated significant interaction effects on GA risk. In gastric cancerous specimens, we observed significantly higher messenger RNA level in the subjects carrying the PGC rs6458238 GA genotype than that in subjects with the common GG genotype. These findings indicated that genetic variations of two crucial H.pylori-related host genes, H.pylori's mucosal effecter PGC gene and H.pylori's cellular messenger PTPN11 gene, either dependent or independent of interaction with H.pylori, were associated with the risks of GC and/or GA that precede carcinoma. Functional studies and further independent large-scale studies especially in other ethnic populations are still needed to confirm our results. PMID- 23455378 TI - A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatments. AB - Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested clinically. This analysis supports the contention that understanding modes of resistance to both chemotherapy and molecularly targeted therapies may be very useful in selecting those drugs of each class that will have complementing mechanisms of sensitivity and thereby represent reasonable combination therapies. PMID- 23455382 TI - hnRNP K suppresses apoptosis independent of p53 status by maintaining high levels of endogenous caspase inhibitors. AB - Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related deaths globally. One of the cellular hallmarks of this disease is dysregulation of apoptosis, and a better understanding of this process is important if progress is to be made toward effectively treating HCC. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a RNA-binding protein that is implicated in apoptosis and is upregulated in various cancers, including HCC. In this study, we report new evidence for a crucial role of hnRNP K in suppressing apoptosis in HCC cells. We used the chemotherapeutic agent 5-fluorouracil to induce apoptosis in HCC cell lines and found that hnRNP K was downregulated, independent of both p53 and caspases. Prolonged downregulation of hnRNP K using small interfering RNA (siRNA) significantly decreased cell viability and increased apoptosis in HCC cell lines in a p53-independent manner. Moreover, enhanced tumor necrosis factor related apoptosis-inducing ligand potency, independent of BH3-interacting domain death agonist (BID) cleavage, was also observed in hnRNP K siRNA-treated cells. Examination of the underlying mechanism revealed that hnRNP K suppresses the activity of various caspases through controlling transcription of the caspase inhibitor XIAP. Taken together, this study establishes that hnRNP K plays an antiapoptotic role in HCC cell lines, independent of p53 status, via the maintenance of high levels of endogenous caspase inhibitors, and also identifies hnRNP K as a possible therapeutic marker for cancer treatment. PMID- 23455383 TI - Nutrient reference values for bioactives: new approaches needed? A conference report. AB - Nutrients can be classified as either "essential" or "non-essential," the latter are also termed bioactive substances. Whereas the absence of essential nutrients from the diet results in overt deficiency often times with moderate to severe physiological decrements, the absence of bioactive substances from the diet results in suboptimal health. Nutrient reference values are set by Codex Alimentarius and regulatory bodies in many countries, mostly for essential nutrients with recommended daily intakes. The IOM in the United States has defined a set of four DRIs that, when data are appropriate, include an EAR, a RDA that is derived from the EAR, an AI for nutrients without appropriate data to identify an EAR, and an UL. From the RDA, the United States derives a labeling value called the DV, which applies to older children and most adults. In Codex, the equivalents of the DVs are the NRVs to be used in calculating percentage values on food labels. Nothing in the IOM documents specifies that labeling values can be set only for what have been defined to date as essential nutrients. Indeed, the US Food and Drug Administration sets a labeling value for dietary fiber based on the IOM AI for this ingredient. This conference explores the definitions, concepts, and data on two of the best examples of bioactive substances that, perhaps, should have NRVs: lutein and zeaxanthin, and n-3 long chain polyunsaturated fatty acids. PMID- 23455386 TI - Efficacy of direct arthroscopy-guided suprascapular nerve block after arthroscopic rotator cuff repair: a prospective randomized study. AB - PURPOSE: The purpose of this study was to evaluate the outcomes of arthroscopy guided direct suprascapular nerve block performed after arthroscopic rotator cuff repair. METHODS: In the present prospective, randomized, double-blinded clinical study, 30 patients were divided into two groups: 15 patients (group I) were treated with arthroscopy-guided suprascapular nerve block using 10 mL 0.5 % ropivacaine with 1:200,000 epinephrine, and 15 patients (group II) were treated with placebo using 10 mL 0.9 % saline after arthroscopic rotator cuff repair. Patient pain levels were measured using the visual analog scale (VAS) at 1, 3, 6, 12, 18, and 24 h post-operatively. Additionally, the number of boluses and total amount of fentanyl dispensed by patient-controlled analgesia administration during the 24-h post-operative period were evaluated. RESULTS: VAS scores did not differ significantly between groups I and II during the 24-h post-operative period, but mean fentanyl bolus consumption was significantly less in group I compared with group II (p = 0.015). CONCLUSION: Arthroscopy-guided suprascapular nerve block at the end of a rotator cuff repair was safe and less time-consuming than expected. Although this procedure did not significantly reduce the post operative pain, the post-operative need for fentanyl boluses as analgesia was reduced significantly, and it would be beneficial if this procedure involved a sensory branch of axillary nerve block or was performed at the beginning of the arthroscopic procedure. LEVEL OF EVIDENCE: Prospective, randomized, double blinded clinical trial, Level I. PMID- 23455384 TI - Quantifying the pivot shift test: a systematic review. AB - PURPOSE: This study aims to identify and summarize the evidence on the biomechanical parameters and the corresponding technologies which have been used to quantify the pivot shift test during the clinical and functional assessment of anterior cruciate ligament (ACL) injury and surgical reconstruction. METHODS: Search strategy Internet search of indexed scientific articles on the PubMed database, Web of Science and references on published manuscripts. No year restriction was used. Selection criteria Articles included were written only in English and related to search terms: "pivot shift" AND (OR "ACL"). The reviewers independently selected only those studies that included at least one quantitative parameter for the analysis of the pivot shift test, including both in vitro and in vivo analyses performed on human joint. Those studies that analysed only clinical grading were excluded from the analysis. Analysis After evaluating the methodological quality of the articles, the parameters found were summarized. RESULTS: Six hundred and eight studies met the inclusion criteria, and finally, 68 unique studies were available for the systematic review. Quantitative results were heterogeneous. The pivot shift test has been quantified by means of 25 parameters, but most of the studies focused on anterior-posterior translations, internal-external rotation and acceleration in anterior-posterior direction. CONCLUSION: Several methodologies have been identified and developed to quantify pivot shift test. However, clinical professionals are still lacking a 'gold standard' method for the quantification of knee joint dynamic laxity. A widespread adoption of a standardized pivot shift manoeuvre and measurement method to allow objective comparison of the results of ACL reconstructions is therefore desirable. Further development of measurement methods is indeed required to achieve this goal in a routine clinical scenario. PMID- 23455387 TI - Graft hypertrophy of matrix-based autologous chondrocyte implantation: a two-year follow-up study of NOVOCART 3D implantation in the knee. AB - PURPOSE: Graft hypertrophy is a major complication in the treatment for localized cartilage defects with autologous chondrocyte implantation (ACI) using periosteal flap and its further development, Novocart (a matrix-based ACI procedure). The aim of the present study is to investigate individual criteria for the development of graft hypertrophy by NOVOCART 3D implantation of the knee in the post-operative course of 2 years. METHODS: Forty-one consecutive patients with 44 isolated cartilage defects of the knee were treated with NOVOCART 3D implants. Individual criteria and defect-associated criteria were collected. Follow-up MRIs were performed at 3, 6, 12 and 24 months. The NOVOCART 3D implants were measured and classified. The modified MOCART Score was used to evaluate quality and integration of the NOVOCART 3D implants in MRI. RESULTS: Graft hypertrophy was observed in a total of 11 patients at all post-operative time points. We were able to show that NOVOCART 3D implantation of cartilage defects after acute trauma and osteochondritis dissecans (OCD) led to a significantly increased proportion of graft hypertrophy. No other individual criteria (age, gender, BMI) or defect-associated criteria (concomitant surgery, second-line treatment, defect size, fixation technique) showed any influence on the development of graft hypertrophy. The modified MOCART Score results revealed a significant post operative improvement within 2 years. CONCLUSION: The aetiology of cartilage defects appears to have a relevant influence for the development of graft hypertrophy. Patients, who were treated with NOVOCART 3D implants after an acute event (acute trauma or OCD), are especially at risk for developing a graft hypertrophy in the post-operative course of two years. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 23455388 TI - Less outliers in pinless navigation compared with conventional surgery in total knee arthroplasty. AB - PURPOSE: The aim of this study was to investigate the effectiveness of a new pinless navigation system (BrainLAB((r)) VectorVision((r)) Knee 2.5 Navigation System) as an intra-operative alignment check in total knee arthroplasty using conventional cutting jigs. METHODS: 200 patients who underwent total knee arthroplasty using conventional technique or pinless navigation by a senior surgeon were included in the study and prospectively followed up. Intra-operative readings from the pinless navigation system were recorded, and post-operative long limb radiographic films were taken. The accepted values for normal alignment were 180 +/- 3 degrees for Hip-Knee-Ankle Angle and 90 +/- 3 degrees for Coronal Femoral-Component Angle or Coronal Tibia-Component Angle. RESULTS: There was no difference in the duration of surgery. The mean Coronal Femoral-Component Angle was 89.8 +/- 2.0 degrees and 91.3 +/- 2.3 degrees in the pinless navigation and conventional group, respectively (p < 0.001). For Hip-Knee-Ankle Angle, the proportion of outliers was 10 % in the pinless navigation group compared to 26 % in the conventional group (p = 0.005). For Coronal Femoral Component Angle and Coronal Tibia-Component Angle, the proportion of outliers was 7 and 4 %, respectively, in the pinless navigation group, compared to 22 and 19 % in the conventional group (p = 0.004 and p = 0.001, respectively). The measurements of Coronal Femoral-Component Angle and Coronal Tibia-Component Angle on post-operative radiographic films were similar to intra-operative readings. CONCLUSIONS: This study showed that pinless navigation is an effective tool for reducing the proportion of outliers, without significantly increasing the duration of surgery. The authors recommend its use in total knee arthroplasty using conventional cutting jigs. PMID- 23455389 TI - The dorsal pedis artery as a new distal landmark for extramedullary tibial alignment in total knee arthroplasty. AB - PURPOSE: It is better to use multiple anatomical landmarks to reduce errors in component alignment in total knee arthroplasty. Therefore, it is worthwhile to find a new landmark that can be used as an addition to conventional ones. Herein, we assessed the dorsal pedis artery as a new distal landmark for extramedullary tibial alignment. METHODS: Fifty-two ankles in patients undergoing total knee arthroplasty and 10 ankles in normal controls were included. Color Doppler ultrasonography was used to locate the dorsal pedis artery at the level of the ankle joint. Conventional landmarks, including the tibialis anterior tendon, the extensor hallucis longus tendon, the extensor digitorum longus tendon, and the malleolar centre, were also located on ultrasound images. The distances between the ankle centre and each landmark were measured and compared. RESULTS: The dorsal pedis artery was absent in 2 patients and impalpable but visible with ultrasonography in other 2 patients. The dorsal pedis artery was located anatomically closest to the ankle centre in patients (0.4 +/- 3.4 mm lateral). Statistical analysis showed that the dorsal pedis artery, the extensor hallucis longus tendon, and the malleolar centre were located significantly closer to the ankle centre comparing with the extensor digitorum longus tendon and the tibialis anterior tendon in both patients and controls (p < 0.001). CONCLUSIONS: As long as the dorsal pedis artery exists, it can be used as an addition to the conventional landmarks in total knee arthroplasty. Using this new landmark will help reduce errors in coronal plane alignment of tibial component. LEVEL OF EVIDENCE: II. PMID- 23455390 TI - Avulsion of the anterior medial meniscus root: case report and surgical technique. AB - Injuries of the meniscus roots have become increasingly recognised as a serious pathology of the knee joint. However, the current available literature focuses primarily on posterior meniscus root tears. In this article, a case with an isolated avulsion of the anterior medial meniscus root is presented, and a new arthroscopic technique to treat this type of injury is described. The anterior horn of the medial meniscus was sutured with a double-looped nonabsorbable suture and reattached to the tibial plateau using a knotless suture anchor. This technique may also be useful to treat avulsion injuries of the anterolateral or posteromedial meniscus root, and symptomatic subluxation of the medial meniscus in case of a variant insertion anatomy with an absent attachment of the anterior horn of the medial meniscus to the tibial plateau. Level of evidence V. PMID- 23455391 TI - Silicon nanoparticles encapsulated in hollow graphitized carbon nanofibers for lithium ion battery anodes. AB - Silicon (Si) is a promising material for lithium ion battery (LIB) anodes due to its high specific capacity. To overcome its shortcomings such as insulation property and large volume change during the charge-discharge process, a novel hybrid system, Si nanoparticles encapsulated in hollow graphitized carbon nanofibers, is studied. First, electrospun polyacrylonitrile (PAN)-Si hybrid nanofibers were obtained using water as the collector. The loose nanofiber lumps suspended in water have large inter-fiber distance, allowing in situ coating of a thin layer of polydopamine (PDA), the source for graphitized carbon, uniformly throughout the system. The designed morphology and structure were then realized by etching and calcination, and the morphology and structure were subsequently verified by various analytical techniques. Electrochemical measurements show that the resulting hollow hybrid nanofibers (C-PDA-Si NFs) exhibit much better cycling stability and rate capacity than conventional C/Si nanofibers derived by electrospinning of PAN-Si followed by calcination. For instance, the capacity of C-PDA-Si NFs is as high as 72.6% of the theoretical capacity after 50 cycles, and a high capacity of 500 mA h g(-1) can be delivered at a current density of 5 A g( 1). The significantly improved electrochemical properties of C-PDA-Si NFs are due to the excellent electrical conductivity of the carbonized PDA (C-PDA) shell that compensates for the insulation property of Si, the high electrochemical activity of C-PDA, which has a layered structure and is N-doped, the hollow nature of the nanofibers and small size of Si nanoparticles that ensure smooth insertion extraction of lithium ions and more complete alloying with them, as well as the buffering effect of the remaining PAN-derived carbon around the Si nanoparticles, which stabilizes the structure. PMID- 23455392 TI - Accumulation of mtDNA variations in human single CD34+ cells from maternally related individuals: effects of aging and family genetic background. AB - Marked sequence variation in the mtDNA control region has been observed in human single CD34(+) cells, which persist in vivo and are present also in differentiated hematopoietic cells. In this study, we analyzed 5071 single CD34(+) cells from 49 individuals (including 31 maternally related members from four families and 18 unrelated donors) in order to determine the mutation spectrum within the mtDNA control region in single cells, as related to aging and family genetic background. Many highly mutated sites among family members were hypervariable sites in the mtDNA control region. Further, CD34(+) cells from members of the same family also shared several unique mtDNA variants, suggesting pedigree-specific occurrence of these variants. Overall age-related accumulation of mtDNA mutations in CD34(+) cells varied in different families, suggesting a specific accumulation pattern, which might be modulated by family genetic background. Our current findings have implications for the occurrence of mtDNA mutations in hematopoietic stem cells and progenitors. PMID- 23455393 TI - Fibronectin-induced VEGF receptor and calcium channel transactivation stimulate GLUT-1 synthesis and trafficking through PPARgamma and TC10 in mouse embryonic stem cells. AB - Extracellular matrix (ECM) mediates interactions between integrin and growth factor receptor (GFR) or ion channel. Although this crosstalk promotes integration of the downstream signal pathways and then regulates cellular function, the effect of ECM on glucose transporter (GLUT) in stem cells has not been elucidated. Therefore, we examined the effect of fibronectin on GLUT-1 expression, trafficking, and its related signal pathways in mouse embryonic stem cells (mESCs). Fibronectin increased 2-deoxyglucose (DG) uptake and GLUT-1 protein expression that were blocked by transcription or translation inhibitors. Integrin alpha5beta1-bound fibronectin increased 2-DG uptake through cluster formation with vascular endothelial growth factor receptor (VEGFR) 2, and then activated Ras and PI3K/Akt. In another pathway, integrin alpha5beta1 displayed structural and functional interactions with calcium channels, and stimulated 2-DG uptake through calcium influx and PKC activation. Akt and PKC-induced PPARgamma phosphorylation enhanced the decreased expression of PPARgamma protein, and subsequently increased GLUT-1 protein synthesis and 2-DG uptake. Fibronectin stimulated TC10 activity and cytoskeleton (F-actin) rearrangement, followed by GLUT-1 trafficking. In conclusion, integrin-bound fibronectin stimulates GLUT-1 synthesis through VEGFR2/Ras/PI3K/Akt and calcium channel/Ca(2+)/PKC, which are merged at PPARgamma and GLUT-1 trafficking through TC10 and F-actin. PMID- 23455395 TI - Suppression of Pu.1 function results in expanded myelopoiesis in zebrafish. PMID- 23455394 TI - Notch signaling in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin-Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis. PMID- 23455396 TI - CO2 absorption/emission and aerodynamic effects of trees on the concentrations in a street canyon in Guangzhou, China. AB - In this paper, the effects of trees on CO2 concentrations in a street canyon in Guangzhou, China are examined by Computational Fluid Dynamics (CFD) simulations of the concentration distribution, taking into account both the CO2 absorption/emission and aerodynamic effects of trees. Simulation results show that, under a 2 m/s southerly prevailing wind condition, CO2 absorption by trees will reduce the CO2 concentration by around 2.5% in the daytime and at the same time the trees' resistance will increase the difference of CO2 concentrations in the street and at the inflow by 43%. As the traffic density increases to 50 vehicles/min, the effect of trees on the ambient CO2 concentration will change from positive to negative. At night, trees have a negative effect on the concentration in the street canyon mainly because of their resistance to airflow. When environmental wind changes, the effect of trees will be different. PMID- 23455397 TI - A three-dimensional water quality modeling approach for exploring the eutrophication responses to load reduction scenarios in Lake Yilong (China). AB - Lake Yilong in Southwestern China has been under serious eutrophication threat during the past decades; however, the lake water remained clear until sudden sharp increase in Chlorophyll a (Chl a) and turbidity in 2009 without apparent change in external loading levels. To investigate the causes as well as examining the underlying mechanism, a three-dimensional hydrodynamic and water quality model was developed, simulating the flow circulation, pollutant fate and transport, and the interactions between nutrients, phytoplankton and macrophytes. The calibrated and validated model was used to conduct three sets of scenarios for understanding the water quality responses to various load reduction intensities and ecological restoration measures. The results showed that (a) even if the nutrient loads is reduced by as much as 77%, the Chl a concentration decreased only by 50%; and (b) aquatic vegetation has strong interaction with phytoplankton, therefore requiring combined watershed and in-lake management for lake restoration. PMID- 23455398 TI - Long-range and short-range orderings in K4Fe4P5O20 with a natrolite-like framework. AB - K4Fe4P5O20 shows an interesting natrolite-like structure with a spin-tetrahedron lattice built by mixed valence Fe ions. Single crystals of the title compound are successfully grown by the flux method using KF as flux. Magnetic results combined from magnetic, heat capacity, and (57)Fe Mossbauer spectra measurements show that K4Fe4P5O20 possesses a short-range magnetic ordering at ~13 K and a long-range ordering at ~7 K. Magnetic anisotropy of K4Fe4P5O20 is observed between H||c and H?c, suggesting that the c-axis is the magnetic easy-axis. The spin arrangements in the system are suggested to be ferrimagnetic along the natrolite chains. PMID- 23455399 TI - Asellus aquaticus as a potential carrier of Escherichia coli and other coliform bacteria into drinking water distribution systems. AB - Individuals of the water louse, Asellus aquaticus, enter drinking water distribution systems in temperate parts of the world, where they establish breeding populations. We analysed populations of surface water A. aquaticus from two ponds for associated faecal indicator bacteria and assessed the risk of A. aquaticus transporting bacteria into distribution systems. Concentrations of up to two E. coli and five total coliforms.mL-1 were measured in the water and 200 E. coli and >240 total coliforms.mL-1 in the sediments of the investigated ponds. Concentrations of A. aquaticus associated bacteria never exceeded three E. coli and six total coliforms.A. aquaticus-1. During exposure to high concentrations of coliforms, concentrations reached 350 coliforms.A. aquaticus-1. A. aquaticus associated E. coli were only detected as long as E. coli were present in the water and sediment. The calculated probability of exceeding drinking water guideline values in non-disinfected systems by intrusion of A. aquaticus was low. Only in scenarios with narrow pipes and low flows, did total coliforms exceed guideline values, implying that the probability of detection by routine monitoring is also low. The study expands the knowledge base for evaluating incidents with presence of coliform indicators in drinking water by showing that intruding A. aquaticus were not important carriers of E. coli or other coliform bacteria even when emerging from faecally contaminated waters. PMID- 23455401 TI - Bortezomib for patients with previously untreated multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. AB - Multiple myeloma (MM) is an incurable disease with a poor survival, which has not been affected even by high-dose chemotherapy. This systematic review was performed to assess the efficacy and safety of the novel agent bortezomib for patients with previously untreated MM. We systematically searched biomedical literature databases and identified randomized controlled trials (RCTs) comparing bortezomib with placebo, no bortezomib, or other active agents for patients with previously untreated MM. Overall survival (OS), reported as hazard ratio (HR) with 95% confidence interval (CI), was the primary outcome measure. The secondary outcomes included time to progression (TTP), progression-free survival (PFS), and response rates. Five RCTs involving 2,728 patients were included. Three trials compared bortezomib with no bortezomib, and two compared bortezomib with other active agents (vincristine +/- adriamycin-based chemotherapy). All included RCTs had methodological shortcomings, including no or unclear allocation concealment and blinding. Compared with no bortezomib or vincristine-based chemotherapy, the bortezomib-based regimen significantly improved the OS of patients with previously untreated MM. HR was 0.71 (95% CI 0.55-0.93) and 0.77 (95% CI 0.60 0.99), respectively. However, when compared with the vincristine + adriamycin based regimen, the OS was similar (HR = 0.87, 95% CI 0.57-1.33). TTP, PFS, and response rates were also improved in patients receiving bortezomib-based regimen. However, the risk of peripheral neuropathy was found to be significantly higher. In summary, bortezomib appears to improve survival and response rates of patients with previously untreated MM in spite of higher risk of peripheral neuropathy. PMID- 23455400 TI - Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: a systematic review and meta-analysis. AB - Second-generation azoles may be more effective than first-generation azoles in the prevention of fungal infections in hematology patients. We performed a systematic review with meta-analysis of randomized controlled trials comparing second- with first-generation azoles in hematology patients with respect to proven or probable invasive fungal infections, invasive aspergillosis, receipt of empirical antifungal therapy, overall mortality, and withdrawal from the studies due to the development of adverse effects. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials electronic databases as well as conference proceedings from 2002 to 2012 for randomized controlled trials comparing second generation azoles (voriconazole, posaconazole) versus first-generation azoles (fluconazole, itraconazole). Treatment effect measures for all outcomes were expressed as odds ratio with 95 % confidence interval. Meta-analysis was performed using Review Manager, version 5.1. Data from four randomized clinical trials representing a large population of patients demonstrated that antifungal prophylaxis with second-generation azoles reduces proven or probable invasive fungal infections, invasive aspergillosis, and receipt of empirical antifungal therapy in high-risk hematology patients, while there were no differences between second- and first-generation azoles with regard to overall mortality and patients or withdrawal from the studies due to the development of adverse effects. In conclusion, antifungal prophylaxis with second-generation azoles can significantly reduce the incidence of invasive fungal infections and invasive aspergillosis but with no risk of an increase in adverse events. PMID- 23455402 TI - Thrombosis following acute cytomegalovirus infection: a community prospective study. AB - Infection might be associated with increased risk of venous thromboembolism (VTE) and arterial thrombosis. Specific hypotheses have been raised regarding the procoagulant response induced by acute cytomegalovirus (CMV) infection. Accordingly, we investigated the 6-month incidence of VTE and/or arterial thrombosis in patients that had been tested positive for CMV-IgM antibodies in a large health maintenance organization. Logistic regression analysis was used to identify independent risk factors for VTE and arterial thrombosis. Among 90,515 patients eligible for the VTE analysis and 90,805 patients eligible for the arterial thrombosis analysis, 6,205 (6.9%) and 6,222 (6.9%) patients were tested positive for CMV-IgM antibodies, respectively. During 6 months of follow-up from index date, the incidence rates per 1,000 capita of VTE among CMV-IgM seropositive and CMV-IgM seronegative patients were 3.06 (19 patients) and 1.36 (115 patients), respectively (odds ratio (OR) 2.25; 95% confidence intervals (95% CI) 1.38-3.66; p = 0.003). CMV-IgM seropositivity was independently associated with VTE appearance (OR 2.49; 95% CI 1.53-4.06; p < 0.0001) following adjustment for age, sex, and other confounders. The incidence rates per 1,000 capita of arterial thrombosis among CMV-IgM seropositive and CMV-IgM seronegative patients were 1.12 (7 patients) and 1.06 (90 patients), respectively (OR 1.06; 95% CI 0.49 2.28; p = 0.840). CMV-IgM seropositivity was not associated with arterial thrombosis. We conclude that acute CMV infection might be associated with an increased short-term VTE risk. To the best of our knowledge, this is the largest study ever to confirm this association. PMID- 23455403 TI - Necrotic and ulcerated cutaneous and mucosal leukemia cutis in AML6. PMID- 23455404 TI - Validation of in situ and laboratory gamma spectrometry measurements for determination of 226Ra, 40K and 137Cs in soil. AB - In situ and laboratory gamma spectrometry methods for determination of (226)Ra, (40)K and (137)Cs in soil have been validated and compared. Minimum detectable activity, repeatability, and reproducibility were the main validation parameters. Results have shown that soil humidity lower the in situ measurement results in comparison to laboratory measurements. Measurement uncertainties were also estimated and compared for both techniques. Uncertainty due to soil humidity (55%) using the in situ measurement was the main contributor to the total uncertainty, while the uncertainty due to net counting (71%) using the laboratory measurements was the largest contributor to the total uncertainty value. PMID- 23455405 TI - Effect of thermal treatment on TL response of CaSO4:Dy obtained using a new preparation method. AB - We report the effect of thermal treatment on thermoluminescent (TL) sensitivity property of CaSO4:Dy obtained by a new preparation method at Instituto Nacional de Investigaciones Nucleares (ININ) of Mexico. Samples of phosphor powder were subjected to different thermal treatments respectively at 773, 873, 973 and 1,173K for 1h and then irradiated from 0.1 to 1,000 Gy gamma doses. Low energy dependence was analyzed too by irradiating with X-rays in the range of 16-145 keV. The results were normalized to the energy (1,252 keV) of (60)Co and they were compared with those obtained using the commercial dosimeters TLD-100. Also the kinetic parameters were determined by deconvolution of glow curve. PMID- 23455406 TI - Fluorine-18 labeling by click chemistry: multiple probes in one pot. AB - Click chemistry has been widely applied in drug development including radiopharmaceuticals and has shown great advantages. Here we reported a novel strategy for rapid preparation of multiple (18)F labeled PET probes in one pot using the 'Click Reaction' of Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of terminal alkynes and organic azides (CuAAC). Preliminary results showed its high efficiency and potential for speeding up the preclinical screening of PET probes. PMID- 23455407 TI - Neck pain: combining exercise and manual therapy for your neck and upper back leads to quicker reductions in pain. PMID- 23455408 TI - Autologous blood and platelet-rich plasma injections for enthesopathy of the extensor carpi radialis brevis origin. PMID- 23455409 TI - Functional results following vascularized versus nonvascularized bone grafts for wrist arthrodesis following excision of giant cell tumors. AB - PURPOSE: Wrist arthrodesis after resection of a giant cell tumor of the distal radius can be performed using a vascularized free fibular transfer (VFFT) or a nonvascularized structural iliac crest transfer (NICT). The purpose of this study was to compare the union times, functional outcomes, and complications after these procedures. METHODS: We identified 27 patients at 2 centers: 14 underwent VFFT, and 13 NICT. The 2 groups were comparable for age, sex, and tumor grade. We assessed functional outcomes of the wrist with the Toronto Extremity Salvage Score, Musculoskeletal Tumor Society 1987 and 1993 scores, and Disabilities of the Arm, Shoulder, and Hand scores. RESULTS: Two local recurrences occurred in the VFFT group and 1 in the NICT group. The VFFT group had 3 patients who had already undergone or were planning to undergo surgery for improved appearance, hardware removal, or tendon release. In the NICT group, 2 infections required debridement, one of which went on to free fibular transfer, but there were no reoperations for nonunion or donor site morbidity. The surgical time was significantly shorter for NICT. Functional scores showed no differences between groups on any of the parameters studied for the upper limb. CONCLUSIONS: Both VFFT and NICT were effective surgical techniques for wrist fusion after distal radial resection for giant cell tumor. Vascularized free fibular transfer should be considered when a major skin defect is anticipated, because it allows the inclusion of a vascularized skin paddle, or when the osseous defect is too long (> 10 cm) for NICT. We were unable to demonstrate a difference in upper limb functional scores between VFFT and NICT. Because the surgical time is significantly shorter and the reoperation rate is lower for NICT, we recommend NICT whenever possible. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 23455410 TI - The flexible swan neck deformity in rheumatoid arthritis. PMID- 23455411 TI - Mechanical coupling limits the density and quality of self-organized carbon nanotube growth. AB - Aligned carbon nanotube (CNT) structures are promising for many applications; however, as-grown CNT "forests" synthesized by chemical vapor deposition (CVD) are typically low-density and mostly comprise tortuous defective CNTs. Here, we present evidence that the density and alignment of self-organized CNT growth is limited by mechanical coupling among CNTs in contact, in combination with their diameter-dependent growth rates. This study is enabled by comprehensive X-ray characterization of the spatially and temporally-varying internal morphology of CNT forests. Based on this data, we model the time evolution and diameter dependent scaling of the ensuing mechanical forces on catalyst nanoparticles during CNT growth, which arise from the mismatch between the collective lengthening rate of the forest and the diameter-dependent growth rates of individual CNTs. In addition to enabling self-organization of CNTs into forests, time-varying forces between CNTs in contact dictate the hierarchical tortuous morphology of CNT forests, and may be sufficient to influence the structural quality of CNTs. These forces reach a maximum that is coincident with the maximum density observed in our growth process, and are proportional to CNT diameter. Therefore, we propose that improved manufacturing strategies for self-organized CNTs should consider both chemical and mechanical effects. This may be especially necessary to achieve high density CNT forests with low defect density, such as for improved thermal interfaces and high-permeability membranes. PMID- 23455412 TI - Thin serial step sectioning of sentinel lymph node biopsy specimen may not be necessary to accurately stage the neck in oral squamous cell carcinoma. AB - PURPOSE: The purpose of this study was to assess the predictability of sentinel lymph node biopsy (SNB) for oral squamous cell carcinoma (OSCC) when pathologic processing is performed without serial step sectioning. MATERIALS AND METHODS: We prospectively enrolled 36 patients with T1 or T2 cN0 OSCC into this institutional review board-approved prospective cohort study, and they underwent gamma probe guided SNB in addition to selective neck dissection. The rate of patients with negative SNB results whose neck dissection was also negative for metastasis (negative predictive value) was the primary endpoint. RESULTS: Of the 28 patients whose sentinel lymph nodes were found to be pathologically and clinically node negative by routine hematoxylin-eosin stain and immunohistochemistry, 27 were found to have no other pathologically positive nodes, corresponding to a negative predictive value of 96%. CONCLUSION: The results of this study suggest that SNB performed without the use of thin serial step sectioning may accurately predict neck stage in OSCC. PMID- 23455413 TI - A unique presentation of oral metastases from hepatocellular carcinoma. PMID- 23455414 TI - Lingual nerve repair. PMID- 23455415 TI - Skeletal and dental variables related to the stability of orthognathic surgery in skeletal Class III malocclusion with a surgery-first approach. AB - PURPOSE: The objectives of the study were to identify the parameters related to skeletal stability after orthognathic surgery in skeletal Class III malocclusion using a surgery-first approach and to analyze the factors correlated with surgical relapse. MATERIALS AND METHODS: Forty-five consecutive patients were included. Serial cephalometric radiographs were traced and superimposed to investigate surgical stability at the initial examination, 1 week postoperatively, and after orthodontic debonding (12.22 mo after surgery). Patient grouping was based on the amount of horizontal relapse at the innermost point of the contour of the mandible between the incisor tooth and the bony chin, the B point (less stable group, n = 15; highly stable group, n = 18). Parameters, such as presurgical skeletal and dental variables, the amount of surgical setback, and total treatment duration, were compared between groups and analyzed for correlations with surgical stability. RESULTS: The mean setback at the innermost point of the contour of the mandible between the incisor tooth and the bony chin was 11.19 mm, and the mean relapse rate was 12.46%. The amount of surgical setback, overbite (positive values), overjet, depth of the curve of Spee, and lower anterior facial height showed statistically significant differences between groups. The amount of surgical setback, overbite (positive values), overjet, and depth of the curve of Spee showed statistically significant correlations with the amount of relapse. Skeletal relapse of the mandible increased significantly as the overbite increased. CONCLUSION: The factors for instability in the surgery-first approach include a larger overbite, a deeper curve of Spee, a greater negative overjet, and a greater mandibular setback. The initial overbite may be an indicator to predict possible skeletal relapse of mandibular setback. PMID- 23455416 TI - Gender differences in dentofacial characteristics of adult patients with temporomandibular disc displacement. AB - PURPOSE: The purpose of this study was to assess gender differences in dentofacial characteristics of adult patients according to temporomandibular joint (TMJ) disc displacement (DD) status. MATERIALS AND METHODS: The sample consisted of 293 adult patients (80 male and 213 female). Male and female patients were divided into 3 groups based on magnetic resonance images of bilateral TMJs: bilateral normal disc position (BN), bilateral DD with reduction (DDR), and bilateral DD without reduction (DDNR). Seventeen variables from lateral cephalograms were analyzed by 2-way analysis of variance to identify differences in dentofacial morphologies with respect to gender and TMJ DD status. RESULTS: Patients with TMJ DD had short ramus height, short mandibular body length, and backward positioning of the ramus and mandible. These dentofacial characteristics became more severe as TMJ DD progressed to DDNR. In addition, dentofacial characteristics associated with TMJ DD were not significantly different between men and women except for effective mandibular length (Articulare to pogonion). Effective mandibular length even tended to decrease as TMJ DD progressed, but male patients showed a larger difference in effective mandibular length between BN and DDR than female patients. CONCLUSIONS: This study's findings suggest that dentofacial morphology is strongly associated with TMJ DD status and that skeletal Class II hyperdivergent pattern with a short ramus and mandible may be a potential indicator of TMJ DD regardless of gender. PMID- 23455417 TI - High optical quality single crystal phase wurtzite and zincblende InP nanowires. AB - We report single crystal phase and non-tapered wurtzite (WZ) and zincblende twinning superlattice (ZB TSL) InP nanowires (NWs). The NWs are grown in a metalorganic vapor phase epitaxy (MOVPE) reactor using the vapor-liquid-solid (VLS) mechanism and in situ etching with HCl at a high growth temperature. Our stacking fault-free WZ and ZB TSL NWs allow access to the fundamental properties of both NW crystal structures, whose optical and electronic behaviors are often screened by polytypism or incorporated impurities. The WZ NWs show no acceptor related emission, implying that the VLS-grown NW is almost free of impurities due to sidewall removal by HCl. They only emit light at the free exciton (1.491 eV) and the donor bound exciton transition (1.4855 eV). The ZB NWs exhibit a photoluminescence spectrum being unaffected by the twinning planes. Surprisingly, the acceptor-related emission in the ZB NWs can be almost completely removed by etching away the impurity-contaminated sidewall grown via a vapor-solid mechanism. PMID- 23455419 TI - Lateral meniscus allograft transplantation using a single-incision technique. AB - PURPOSE: The aim of this work is to introduce and evaluate a novel arthroscopically assisted meniscus allograft transplantation (MAT) technique that requires only one small anterior incision for an arthrotomy. METHODS: In the novel technique, the posterior horn of the allograft meniscus was repaired using the modified all-inside suture technique instead of the conventional inside-out technique. By doing this, an additional posterior incision could be avoided. Thirteen consecutive patients with total or subtotal meniscectomy of the lateral meniscus underwent lateral MAT using the novel technique from August 2010 to October 2011. The clinical outcomes were evaluated according to Lysholm scores, International Knee Documentation Committee (IKDC) subjective scores, and Tegner activity level scales. RESULTS: The median follow-up period was 21.0 months (range 13-28 months). The post-operative median Lysholm score improved to 85.0 (range 77-95, P < 0.05). The median IKDC subjective score was 80.0 (range 63-99, P < 0.05) at last follow-up. The median Tegner activity level of 6.0 (range 4-7) was improved compared with the median preoperative level (P < 0.05). None of the patients presented with symptoms requiring a secondary surgical procedure at the time of final follow-up. CONCLUSION: The novel method requires only one small arthrotomy incision except for arthroscopic portals. In addition to the minimal number of incisions, this technique has several advantages over previous techniques. This single-incision technique could be effective and satisfactory option for lateral MAT. LEVEL OF EVIDENCE: Case series with no comparison group, Level IV. PMID- 23455420 TI - Protein-protein interactions in the regulation of WRKY transcription factors. AB - It has been almost 20 years since the first report of a WRKY transcription factor, SPF1, from sweet potato. Great progress has been made since then in establishing the diverse biological roles of WRKY transcription factors in plant growth, development, and responses to biotic and abiotic stress. Despite the functional diversity, almost all analyzed WRKY proteins recognize the TTGACC/T W box sequences and, therefore, mechanisms other than mere recognition of the core W-box promoter elements are necessary to achieve the regulatory specificity of WRKY transcription factors. Research over the past several years has revealed that WRKY transcription factors physically interact with a wide range of proteins with roles in signaling, transcription, and chromatin remodeling. Studies of WRKY interacting proteins have provided important insights into the regulation and mode of action of members of the important family of transcription factors. It has also emerged that the slightly varied WRKY domains and other protein motifs conserved within each of the seven WRKY subfamilies participate in protein protein interactions and mediate complex functional interactions between WRKY proteins and between WRKY and other regulatory proteins in the modulation of important biological processes. In this review, we summarize studies of protein protein interactions for WRKY transcription factors and discuss how the interacting partners contribute, at different levels, to the establishment of the complex regulatory and functional network of WRKY transcription factors. PMID- 23455421 TI - Direct modulation of protein level in Arabidopsis. PMID- 23455422 TI - Crystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state. AB - P-type ATPases are ATP-powered ion pumps that establish ion concentration gradients across biological membranes, and are distinct from other ATPases in that the reaction cycle includes an autophosphorylation step. The best studied is Ca(2+)-ATPase from muscle sarcoplasmic reticulum (SERCA1a), a Ca(2+) pump that relaxes muscle cells after contraction, and crystal structures have been determined for most of the reaction intermediates. An important outstanding structure is that of the E1 intermediate, which has empty high-affinity Ca(2+) binding sites ready to accept new cytosolic Ca(2+). In the absence of Ca(2+) and at pH 7 or higher, the ATPase is predominantly in E1, not in E2 (low affinity for Ca(2+)), and if millimolar Mg(2+) is present, one Mg(2+) is expected to occupy one of the Ca(2+)-binding sites with a millimolar dissociation constant. This Mg(2+) accelerates the reaction cycle, not permitting phosphorylation without Ca(2+) binding. Here we describe the crystal structure of native SERCA1a (from rabbit) in this E1.Mg(2+) state at 3.0 A resolution in addition to crystal structures of SERCA1a in E2 free from exogenous inhibitors, and address the structural basis of the activation signal for phosphoryl transfer. Unexpectedly, sarcolipin, a small regulatory membrane protein of Ca(2+)-ATPase, is bound, stabilizing the E1.Mg(2+) state. Sarcolipin is a close homologue of phospholamban, which is a critical mediator of beta-adrenergic signal in Ca(2+) regulation in heart (for reviews, see, for example, refs 8-10), and seems to play an important role in muscle-based thermogenesis. We also determined the crystal structure of recombinant SERCA1a devoid of sarcolipin, and describe the structural basis of inhibition by sarcolipin/phospholamban. Thus, the crystal structures reported here fill a gap in the structural elucidation of the reaction cycle and provide a solid basis for understanding the physiological regulation of the calcium pump. PMID- 23455423 TI - Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. AB - Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. PMID- 23455424 TI - The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm. AB - The contraction and relaxation of muscle cells is controlled by the successive rise and fall of cytosolic Ca(2+), initiated by the release of Ca(2+) from the sarcoplasmic reticulum and terminated by re-sequestration of Ca(2+) into the sarcoplasmic reticulum as the main mechanism of Ca(2+) removal. Re-sequestration requires active transport and is catalysed by the sarcoplasmic reticulum Ca(2+) ATPase (SERCA), which has a key role in defining the contractile properties of skeletal and heart muscle tissue. The activity of SERCA is regulated by two small, homologous membrane proteins called phospholamban (PLB, also known as PLN) and sarcolipin (SLN). Detailed structural information explaining this regulatory mechanism has been lacking, and the structural features defining the pathway through which cytoplasmic Ca(2+) enters the intramembranous binding sites of SERCA have remained unknown. Here we report the crystal structure of rabbit SERCA1a (also known as ATP2A1) in complex with SLN at 3.1 A resolution. The regulatory SLN traps the Ca(2+)-ATPase in a previously undescribed E1 state, with exposure of the Ca(2+) sites through an open cytoplasmic pathway stabilized by Mg(2+). The structure suggests a mechanism for selective Ca(2+) loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca(2+). These findings may prove useful in studying how autoinhibitory domains of other ion pumps modulate transport across biological membranes. PMID- 23455425 TI - Autophagosomes form at ER-mitochondria contact sites. AB - Autophagy is a tightly regulated intracellular bulk degradation/recycling system that has fundamental roles in cellular homeostasis. Autophagy is initiated by isolation membranes, which form and elongate as they engulf portions of the cytoplasm and organelles. Eventually isolation membranes close to form double membrane-bound autophagosomes and fuse with lysosomes to degrade their contents. The physiological role of autophagy has been determined since its discovery, but the origin of autophagosomal membranes has remained unclear. At present, there is much controversy about the organelle from which the membranes originate--the endoplasmic reticulum (ER), mitochondria and plasma membrane. Here we show that autophagosomes form at the ER-mitochondria contact site in mammalian cells. Imaging data reveal that the pre-autophagosome/autophagosome marker ATG14 (also known as ATG14L) relocalizes to the ER-mitochondria contact site after starvation, and the autophagosome-formation marker ATG5 also localizes at the site until formation is complete. Subcellular fractionation showed that ATG14 co fractionates in the mitochondria-associated ER membrane fraction under starvation conditions. Disruption of the ER-mitochondria contact site prevents the formation of ATG14 puncta. The ER-resident SNARE protein syntaxin 17 (STX17) binds ATG14 and recruits it to the ER-mitochondria contact site. These results provide new insight into organelle biogenesis by demonstrating that the ER-mitochondria contact site is important in autophagosome formation. PMID- 23455426 TI - Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia. AB - The heart's rhythm is initiated and regulated by a group of specialized cells in the sinoatrial node (SAN), the primary pacemaker of the heart. Abnormalities in the development of the SAN can result in irregular heart rates (arrhythmias). Although several of the critical genes important for SAN formation have been identified, our understanding of the transcriptional network controlling SAN development remains at a relatively early stage. The homeodomain transcription factor Shox2 is involved in the specification and patterning of the SAN. While the Shox2 knockout in mice results in embryonic lethality due to severe cardiac defects including improper SAN development, Shox2 knockdown in zebrafish causes a reduced heart rate (bradycardia). In order to gain deeper insight into molecular pathways involving Shox2, we compared gene expression levels in right atria of wildtype and Shox2 (-/-) hearts using microarray experiments and identified the LIM homeodomain transcription factor Islet1 (Isl1) as one of its putative target genes. The downregulation of Isl1 expression in Shox2 (-/-) hearts was confirmed and the affected region narrowed down to the SAN by whole-mount in situ hybridization. Using luciferase reporter assays and EMSA studies, we identified two specific SHOX2 binding sites within intron 2 of the ISL1 locus. We also provide functional evidence for Isl1 as a transcriptional target of Shox2 by rescuing the Shox2-mediated bradycardia phenotype with Isl1 using zebrafish as a model system. Our findings demonstrate a novel epistatic relationship between Shox2 and Isl1 in the heart with important developmental consequences for SAN formation and heart beat. PMID- 23455428 TI - A phase I pharmacokinetic study of PM00104 (Zalypsis) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors. AB - PURPOSE: PM00104 (Zalypsis) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk). METHODS: Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis. RESULTS: DLTs comprised severe neutropenia lasting >5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay >2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m(2). Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease >=3 months. CONCLUSIONS: PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed. PMID- 23455427 TI - mTOR inhibitor efficacy is determined by the eIF4E/4E-BP ratio. PMID- 23455429 TI - Enhanced photoelectric conversion efficiency of dye-sensitized solar cells by the incorporation of dual-mode luminescent NaYF4:Yb3+/Er3+. AB - This work focuses on the design of composite photoanodes with dual-mode luminescent function as well as the effects of luminescent phosphors on the photoelectric properties of dye-sensitized solar cells. Specifically, hexagonal phase NaYF4:Yb(3+)/Er(3+) microcrystals were prepared by a hydrothermal method and added to the TiO2 photoanodes of dye-sensitized solar cells. The results indicated that the TiO2-NaYF4:Yb(3+)/Er(3+) composite photoanodes can emit visible light under 495 or 980 nm excitation, and then the visible light can be absorbed by dye N719 to improve light harvesting and thereby the efficiency of the solar cell. Under simulated solar radiation in the wavelength range of lambda>= 400 nm, the photoelectric conversion efficiency of TiO2 NaYF4:Yb(3+)/Er(3+) cell was increased by 10% compared to pure TiO2 cell. For the electrodes with the same thickness, the amount of dye adsorption of the photoanodes decreased a little after adding NaYF4:Yb(3+)/Er(3+), which was attributed to the decrease of TiO2 in the photoanodes. The electron transport and interfacial recombination kinetics were investigated by the electrochemical impedance spectroscopy and intensity-modulated photocurrent/photovoltage spectroscopy. The TiO2-NaYF4:Yb(3+)/Er(3+) cell has longer electron recombination time as well as electron transport time than pure TiO2 cell. The charge collection efficiency of TiO2-NaYF4:Yb(3+)/Er(3+) cell was little lower than that of pure TiO2 cell. In addition, the interfacial resistance of the TiO2-dye|I3( )/I(-) electrolyte interface of TiO2-NaYF4:Yb(3+)/Er(3+) cell was much bigger than that of pure TiO2 cell. All these results indicated that the charge transport cannot be improved by adding NaYF4:Yb(3+)/Er(3+). And thus, the enhanced photoelectric conversion efficiencies of TiO2-NaYF4:Yb(3+)/Er(3+) cells were closely related to the dual-mode luminescent function of NaYF4:Yb(3+)/Er(3+). PMID- 23455430 TI - Effects of Agaricus lilaceps fairy rings on soil aggregation and microbial community structure in relation to growth stimulation of western wheatgrass (Pascopyrum smithii) in Eastern Montana rangeland. AB - Stimulation of plant productivity caused by Agaricus fairy rings has been reported, but little is known about the effects of these fungi on soil aggregation and the microbial community structure, particularly the communities that can bind soil particles. We studied three concentric zones of Agaricus lilaceps fairy rings in Eastern Montana that stimulate western wheatgrass (Pascopyrum smithii): outside the ring (OUT), inside the ring (IN), and stimulated zone adjacent to the fungal fruiting bodies (SZ) to determine (1) soil aggregate proportion and stability, (2) the microbial community composition and the N-acetyl-beta-D-glucosaminidase activity associated with bulk soil at 0-15 cm depth, (3) the predominant culturable bacterial communities that can bind to soil adhering to wheatgrass roots, and (4) the stimulation of wheatgrass production. In bulk soil, macroaggregates (4.75-2.00 and 2.00-0.25 mm) and aggregate stability increased in SZ compared to IN and OUT. The high ratio of fungal to bacteria (fatty acid methyl ester) and N-acetyl-beta-D-glucosaminidase activity in SZ compared to IN and OUT suggest high fungal biomass. A soil sedimentation assay performed on the predominant isolates from root-adhering soil indicated more soil-binding bacteria in SZ than IN and OUT; Pseudomonas fluorescens and Stenotrophomonas maltophilia isolates predominated in SZ, whereas Bacillus spp. isolates predominated in IN and OUT. This study suggests that growth stimulation of wheatgrass in A. lilaceps fairy rings may be attributed to the activity of the fungus by enhancing soil aggregation of bulk soil at 0-15 cm depth and influencing the amount and functionality of specific predominant microbial communities in the wheatgrass root-adhering soil. PMID- 23455431 TI - Functional profiling and distribution of the forest soil bacterial communities along the soil mycorrhizosphere continuum. AB - An ectomycorrhiza is a multitrophic association between a tree root, an ectomycorrhizal fungus, free-living fungi and the associated bacterial communities. Enzymatic activities of ectomycorrhizal root tips are therefore result of the contribution from different partners of the symbiotic organ. However, the functional potential of the fungus-associated bacterial communities remains unknown. In this study, a collection of 80 bacterial strains randomly selected and isolated from a soil-ectomycorrhiza continuum (oak-Scleroderma citrinum ectomycorrhizas, the ectomycorrhizosphere and the surrounding bulk soil) were characterized. All the bacterial isolates were identified by partial 16S rRNA gene sequences as members of the genera Burkholderia, Collimonas, Dyella, Mesorhizobium, Pseudomonas, Rhizobium and Sphingomonas. The bacterial strains were then assayed for beta-xylosidase, beta-glucosidase, N-acetyl-hexosaminidase, beta-glucuronidase, cellobiohydrolase, phosphomonoesterase, leucine aminopeptidase and laccase activities, chitin solubilization and auxin production. Using these bioassays, we demonstrated significant differences in the functional distribution of the bacterial communities living in the different compartments of the soil-ectomycorrhiza continuum. The surrounding bulk soil was significantly enriched in bacterial isolates capable of hydrolysing cellobiose and N-acetylglucosamine. In contrast, the ectomycorrhizosphere appeared significantly enriched in bacterial isolates capable of hydrolysing glucopyranoside and chitin. Notably, chitinase and laccase activities were found only in bacterial isolates belonging to the Collimonas and Pseudomonas genera. Overall, the results suggest that the ectomycorrhizal fungi favour specific bacterial communities with contrasting functional characteristics from the surrounding soil. PMID- 23455432 TI - Isolation of pandemic Vibrio parahaemolyticus from UK water and shellfish produce. AB - Vibrio parahaemolyticus is a Gram-negative, halophilic bacterium found commonly in temperate and warm estuarine waters worldwide. V. parahaemolyticus is considered an emerging bacterial pathogen in Europe and has been responsible for several recent seafood-associated outbreaks. During ad hoc testing of raw shellfish produce in May 2012, pandemic group (O3:K6) V. parahaemolyticus was isolated from Pacific oysters (Crassostrea gigas), harvested in Southern England. Follow-on testing of water and shellfish, encompassing a small number geographically diverse sites, also retrieved pandemic group isolates. These strains are amongst the most northerly pandemic strains described to date and represent the first instance of pandemic V. parahaemolyticus isolated in the UK, highlighting the expanding geographical distribution of these foodborne pathogens in the environment. PMID- 23455433 TI - Incubation temperature and substrate quality modulate sporulation by aquatic hyphomycetes. AB - Frequency and amplitude of temperature oscillations can profoundly affect structure and function of ecosystems. Unless the rate of a biological process changes linearly within the range of these fluctuations, the cumulative effect of temperature differs from the effect measured at the average temperature (Jensen's inequality). Here, we measured numbers and types of spores released by aquatic hyphomycetes from oak and alder leaves that had been exposed in a Portuguese stream for between 7 and 94 days. Recovered leaves were incubated at four temperatures between 5 and 20 degrees C. Over this range, the sporulation response to temperature was decelerating, with an estimated optimum around 12.5 degrees C. Assuming a linear response, therefore, overestimates spore release from decaying leaves. The calculated discrepancy was more pronounced with recalcitrant oak leaves (greater toughness, phenolics concentration, lower N and P concentration than alder), and reached 26.6 % when temperature was assumed to oscillate between 1 and 9 degrees C, rather than remaining constant at 5 degrees C. The maximum fluctuation of water temperature over 48 h during the field experiment was approximately 3 degrees C, which would result in a discrepancy of up to 6 %. The composition of the fungal community (assessed by species identification of released spores) was significantly influenced by the state of decomposition, but not by leaf species or temperature. When quantifying the potential impact of global change on aquatic fungal communities, the average increase as well as fluctuations of the temperature have to be considered. PMID- 23455434 TI - IMS-3, synthesis, and MR Rescue: no disaster, but down to earth. PMID- 23455435 TI - Adsorption, dissociation, penetration, and diffusion of N2 on and in bcc Fe: first-principles calculations. AB - We report first-principles calculations of adsorption, dissociation, penetration, and diffusion for the complete nitridation mechanism of nitrogen molecules on a pure Fe surface (bcc, ferrite phase). The mechanism of the definite reaction path was calculated by dividing the process into four steps. We investigated various reaction paths for each step including the energy barrier based on the climb image nudged elastic band (CI-NEB) method, and the complete reaction pathway was computed as the minimum energy path (MEP). The adsorption characteristics of nitrogen (N) and molecular nitrogen (N2) indicate that nitrogen atoms and molecules are energetically favorable at the hollow sites on pure Fe(100) and (110). The dissociation of the nitrogen molecule (N2) was theoretically supported by electronic structure calculations. The penetration of nitrogen from the surface to the sub-surface has a large energy barrier compared with the other steps. The activation energy calculated for nitrogen diffusion in pure bcc Fe was in good agreement with the experimental results. Finally, we confirmed the rate determining step for the full nitridation reaction pathway. This study provides fundamental insight into the nitridation mechanism for nitrogen molecules in pure bcc Fe. PMID- 23455436 TI - RNAi suppressor P19 can be broadly exploited for enhanced adenovirus replication and microRNA knockdown experiments. AB - RNA interference (RNAi) is a key regulator of various biological systems including viral infection. Within a virus life cycle gene products can be modulated by the RNA interference (RNAi) pathway which can crucially impact productive virus replication. Herein we explored the RNA interference suppressor protein P19 derived from a plant virus and we found that P19 enhanced adenovirus replication up to 100-fold. Critical factors responsible for this observation were overexpression of adenovirus encoded genes on mRNA and protein levels. To investigate the impact of this phenomenon on recombinant viruses, we exploited its feasibility for therapeutic and genomic applications. We found that P19 significantly increased recombinant adenovirus yields enabling up-scaling for preclinical and clinical studies. Moreover, adenoviruses possessed significantly higher oncolytic activity by expression of P19. Finally, we show that introducing a p19 expression cassette into high-capacity adenovirus provides a strategy to analyze RNAi knockdown in a tissue-specific manner. PMID- 23455437 TI - Effects of attention and laterality on motion and orientation discrimination in deaf signers. AB - Previous studies have asked whether visual sensitivity and attentional processing in deaf signers are enhanced or altered as a result of their different sensory experiences during development, i.e., auditory deprivation and exposure to a visual language. In particular, deaf and hearing signers have been shown to exhibit a right visual field/left hemisphere advantage for motion processing, while hearing nonsigners do not. To examine whether this finding extends to other aspects of visual processing, we compared deaf signers and hearing nonsigners on motion, form, and brightness discrimination tasks. Secondly, to examine whether hemispheric lateralities are affected by attention, we employed a dual-task paradigm to measure form and motion thresholds under "full" vs. "poor" attention conditions. Deaf signers, but not hearing nonsigners, exhibited a right visual field advantage for motion processing. This effect was also seen for form processing and not for the brightness task. Moreover, no group differences were observed in attentional effects, and the motion and form visual field asymmetries were not modulated by attention, suggesting they occur at early levels of sensory processing. In sum, the results show that processing of motion and form, believed to be mediated by dorsal and ventral visual pathways, respectively, are left hemisphere dominant in deaf signers. PMID- 23455438 TI - Systematic identification of allosteric protein-metabolite interactions that control enzyme activity in vivo. AB - Recent data suggest that the majority of proteins bind specific metabolites and that such interactions are relevant to metabolic and gene regulation. However, there are no methods to systematically identify functional allosteric protein metabolite interactions. Here we present an experimental and computational approach for using dynamic metabolite data to discover allosteric regulation that is relevant in vivo. By switching the culture conditions of Escherichia coli every 30 s between medium containing either pyruvate or (13)C-labeled fructose or glucose, we measured the reversal of flux through glycolysis pathways and observed rapid changes in metabolite concentration. We fit these data to a kinetic model of glycolysis and systematically tested the consequences of 126 putative allosteric interactions on metabolite dynamics. We identified allosteric interactions that govern the reversible switch between gluconeogenesis and glycolysis, including one by which pyruvate activates fructose-1,6 bisphosphatase. Thus, from large sets of putative allosteric interactions, our approach can identify the most likely ones and provide hypotheses about their function. PMID- 23455439 TI - A community-driven global reconstruction of human metabolism. AB - Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including ~2* more reactions and ~1.7* more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type-specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/. PMID- 23455440 TI - Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca(2+) signaling in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded trinucleotide CAG repeat in the gene coding for huntingtin. Deregulation of chromatin remodeling is linked to the pathogenesis of HD but the mechanism remains elusive. To identify what genes are deregulated by trimethylated histone H3K9 (H3K9me3)-dependent heterochromatin, we performed H3K9me3-ChIP genome-wide sequencing combined with RNA sequencing followed by platform integration analysis in stable striatal HD cell lines (STHdhQ7/7 and STHdhQ111/111) cells. We found that genes involving neuronal synaptic transmission including cholinergic receptor M1 (CHRM1), cell motility, and neuronal differentiation pathways are downregulated while their promoter regions are highly occupied with H3K9me3 in HD. Moreover, we found that repression of CHRM1 gene expression by H3K9me3 impairs Ca(2+)-dependent neuronal signal transduction in stable cell lines expressing mutant HD protein. Thus, our data indicate that the epigenetic modifications, such as aberrant H3K9me3-dependent heterochromatin plasticity, directly contribute to the pathogenesis of HD. PMID- 23455441 TI - [Hematologic and oncologic emergencies]. AB - The rapid development of novel, targeted drugs in cancer medicine has led to an increase in chronically ill cancer patients and hematology patients, who are being treated aggressively despite significant comorbidities and higher age. This development will lead to an increase in the number of hematologic and oncologic emergencies, and these patients will be seen by various specialties. This review article, therefore, aims at providing clinical management algorithms for the most frequent emergencies. PMID- 23455442 TI - [Daily sedation pauses for mechanically ventilated intensive care patients in addition to protocol-based sedation]. PMID- 23455443 TI - Enteral nutrition is associated with improved outcome in patients with severe sepsis. A secondary analysis of the VISEP trial. AB - INTRODUCTION: The optimal nutritional strategy remains controversial, particularly in severely septic patients. Our aim was to analyze the effect of three nutritional strategies--enteral (EN), parenteral (PN), and combined nutrition (EN+PN)--on the outcome of patients with severe sepsis or septic shock. PATIENTS AND METHODS: This secondary analysis of the prospective, randomized controlled, multicenter "Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis (VISEP)" trial only included patients with a length of stay in the intensive care unit (ICU) of more than 7 days. Besides patient characteristics, data on nutrition therapy were collected daily for up to 21 days. Morbidity as measured by the mean Sequential Organ Failure Assessment (SOFA) score, incidence of secondary infections, renal replacement therapy, ventilator-free days and severe hypoglycemia, length of ICU stay, and mortality at 90 days were compared between the three nutritional strategies. RESULTS: In all, 353 patients were included in the analysis with the majority (68.5 %) receiving EN+PN, 24.4 % receiving EN, and only 7.1 % receiving PN. Median caloric intake was 918 kcal/day (EN), 1,210 kcal/day (PN), and 1,343 kcal/day (EN+PN; p < 0.001). In the latter group, calories were predominantly administered via the parenteral route within the first week. The rate of death at 90 days was lower with EN than with EN+PN (26.7 % vs. 41.3 %, p = 0.048), as was the rate of secondary infections, renal replacement therapy, and duration of mechanical ventilation. In the adjusted Cox regression analysis, the effect on mortality [hazard ratio (HR)= 1.86, 95 % confidence interval (CI): 1.16-2.98, p = 0.010] and the rate of secondary infections (HR= 1.89, 95 % CI: 1.27-2.81, p = 0.002) remained different between EN and EN+PN. CONCLUSION: In patients with severe sepsis or septic shock and prolonged ICU stay, EN alone was associated with improved clinical outcome compared to EN+PN. This hypothesis-generating result has to be confirmed by a randomized-controlled trial in this specific patient population. PMID- 23455444 TI - An energy-harvesting scheme employing CuGaSe2 quantum dot-modified ZnO buffer layers for drastic conversion efficiency enhancement in inorganic-organic hybrid solar cells. AB - We demonstrated a promising route to enhance the performance of inverted organic photovoltaic (OPV) devices by the incorporation of CuGaSe2 (CGS) quantum dots (QDs) into the ZnO buffer layer of P3HT:PCBM-based devices. The modification of QDs provides better band alignment between the organic/cathode interface, improves ZnO crystal quality, and increases photon absorption, leading to more effective carrier transport/collection. By employing this energy-harvesting scheme, short-circuit current density, open-circuit voltage, and fill factor of the OPV device after CGS QD modification are improved by 9.43%, 7.02% and 6.31%, respectively, giving rise to a 23.8% enhancement in the power conversion efficiency. PMID- 23455445 TI - Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. AB - OBJECTIVE: Hereditary pancreatitis is caused by mutations in human cationic trypsinogen (PRSS1) which lead to increased autoactivation by altering chymotrypsin C (CTRC)-dependent trypsinogen activation and degradation. Exceptions are some cysteine mutations which cause misfolding, intracellular retention and endoplasmic reticulum stress. Clinical relevance of many PRSS1 variants found in patients with sporadic chronic pancreatitis is unknown but often assumed by analogy with known disease-causing mutations. Functional comparison of PRSS1 variants found in sporadic and hereditary cases is needed to resolve this dilemma. DESIGN: Here, we investigated the functional phenotype of 13 published PRSS1 variants with respect to autoactivation in the presence of CTRC and cellular secretion. RESULTS: Only mutation p.D100H increased trypsinogen autoactivation, but this gain in function was offset by a marked reduction in secretion. Five mutants (p.P36R, p.G83E, p.I88N, p.V123M, p.S124F) showed decreased autoactivation due to increased degradation by CTRC. Five mutants exhibited strongly (p.D100H, p.C139F) or moderately (p.K92N, p.S124F, p.G208A) reduced secretion, whereas mutant p.K170E showed slightly increased secretion. Mutant p.I88N was also secreted to higher levels but was rapidly degraded by CTRC. Finally, three mutants (p.Q98K, p.T137M, p.S181G) had no phenotypic alterations relative to wild-type trypsinogen. CONCLUSIONS: Rare PRSS1 variants found in sporadic chronic pancreatitis do not stimulate autoactivation but may cause increased degradation, impaired secretion or no functional change. Variants with reduced secretion are likely pathogenic due to mutation-induced misfolding and consequent endoplasmic reticulum stress. PMID- 23455446 TI - The effects of mGlu7 receptor modulation in behavioural models sensitive to antidepressant action in two mouse strains. AB - There is increasing evidence suggesting a role of the neurotransmitter glutamate in depression. The metabotropic glutamate (mGlu) receptors are G-protein coupled receptors, which mediate a slow modulatory response to glutamate signalling. mGlu7 receptor is a presynaptic inhibitory autoreceptor showing great promise as a potential therapeutic target for the treatment of depression. Selective pharmacological modulators of mGlu7 receptor have been developed; the positive allosteric modulator AMN082 and the negative modulator 6-(4-methoxyphenyl)-5 methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). They remain to be extensively characterized in behavioural models sensitive to antidepressant action. Therefore, we assessed the effects of these compounds on behaviour in two different mouse strains using several preclinical tests sensitive to antidepressant pharmacological action. AMN082 (6 mg/kg) reduced immobility in the forced swim test and tail suspension test (TST) in both C57BL/6j and CD1 mice. In CD1 mice, MMPIP (10 and 30 mg/kg) significantly increased the time spent immobile in the TST, whereas this effect was restricted to a dose of 30 mg/kg in C57BL/6j mice. Administration of MMPIP with AMN082 partially attenuated the antidepressant-like effect of AMN082 in C57BL/6j mice in the forced swim test and the TST. However, this effect was absent from the CD1 strain. This further adds to the growing corpus of data promoting the targeting of mGlu7 receptor with the aim of achieving an antidepressant effect. PMID- 23455447 TI - Withania somnifera prevents acquisition and expression of morphine-elicited conditioned place preference. AB - Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor binding assay, the affinity of WSE for u-opioid and gamma-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for gamma aminobutyric acid B than for u-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction. PMID- 23455448 TI - [Correlation between fetal scalp samples and umbilical cord samples]. AB - OBJECTIVE: The objective was to evaluate the correlation between fetal scalp base excess (BE) and umbilical cord BE. Respective value of fetal scalp pH, BE and lactate for the prediction of neonatal metabolic acidosis were also evaluated. METHODS: A retrospective monocentric study was conducted in a French tertiary care academic maternity. All the patients who had a fetal scalp sampling during labor in 2010, less than 90 minutes before delivery were included. Fetal heart rate abnormalities (FHRA) were classified by degree of severity, according to the French guidelines. The differences between fetal scalp samples and umbilical cord samples over time and in relation with the type of FHRA were analyzed for pH and BE. The differences between fetal scalp pH and cord pH over time and in relation with scalp BE were analyzed. The correlation between fetal scalp samples and cord samples for pH, BE and lactate was estimated. Receiver operating characteristics (ROC) curves for fetal scalp pH, lactate and BE to predict umbilical cord pH under 7.20 were calculated. RESULTS: Seventy-one cases were included. The difference between fetal scalp sample and cord sample was lower when the sample was made closest to delivery both for pH and BE. The gravity of FHRA was not predictive of a faster decrease of pH or BE over time. The correlation was significant for pH (r=0.23, p=0.03) between scalp samples and cord samples, as for BE (r=0.49, p=0.001) and lactate (r=0.52, p=0.001). The ROC curves for pH, BE and lactate displayed a similar pattern. CONCLUSION: Fetal scalp and umbilical cord samples, for pH, BE and lactate were significantly correlated but their respective predictive value for cord pH less or equal to 7.20 was poor. PMID- 23455449 TI - Probiotic Bacillus amyloliquefaciens mediate M1 macrophage polarization in mouse bone marrow-derived macrophages. AB - Depending on the microenvironment, macrophages can acquire distinct functional phenotypes, referred to as classically activated M1 and M2. M1 macrophages are considered potent effector cells that kill intracellular pathogens, and M2 macrophages promote the resolution of wound healing. In this study, we are interested to know whether probiotic Bacillus amyloliquefaciens (Ba) can induce macrophages polarization. Real-time fluorescence PCR analysis demonstrated that the expression of IL-1beta, iNOS, TNF-alpha and IL-6 genes for M1 macrophages was significantly increased at 1.5 h after probiotic Ba treatment compared to the probiotic Ba-free treatment (P < 0.01), whereas the expression of M2 macrophage marker genes (Arg1, Fizz1, MR, Ym1) was decreased (P < 0.05). Furthermore, the phagocytic activity was dramatically increased in the Ba-treated BMDMs using a FITC-dextran endocytosis assay. Together, these findings indicated that probiotic Ba facilitated polarization of M1 macrophages and enhanced its phagocytic capacity. The results expanded our knowledge about probiotic function-involved macrophage polarization. PMID- 23455450 TI - Different assembly of acid and salt tolerance response in two dairy Listeria monocytogenes wild strains. AB - A lack on the association between acid tolerance response (ATR) and osmotolerance response (OTR) among Listeria monocytogenes dairy isolates was found. In order to evaluate how wild L. monocytogenes isolates mount tolerance responses under a sub lethal pH and a low sodium chloride concentration (pH 5.5 and 3.5 % [w/v] NaCl), a proteomic approach was used. The ATR and OTR of two L. monocytogenes cheese dairy isolates (strain T8, serotype 4b and A9, serotype 1/2b or 3b) were determined. The proteomes of the adapted and non-adapted cultures were evaluated by 2-DE. One strain displayed an ATR, but not an OTR and the other displayed an OTR, but not an ATR. The ATR positive strain showed the over-production of proteins related with protein synthesis, protein folding, attainment of reduction power, ribose production and cell wall. In contrast, in the OTR-positive-strain proteins related with glycolysis, general stress and detoxification were identified. PMID- 23455451 TI - Physiologically based pharmacokinetic models for everolimus and sorafenib in mice. AB - PURPOSE: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. METHODS: Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate limited, and all data from the diverse studies were fitted simultaneously using a population approach. RESULTS: PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. CONCLUSIONS: The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants. PMID- 23455453 TI - Persistent medial foot pain in an adolescent athlete. AB - The patient was a 15-year-old adolescent male who was referred to a physical therapist for a chief complaint of worsening right medial foot pain. Given the worsening nature of the patient's right medial foot pain, palpatory findings, and a prior recommendation for computed tomography from a radiologist, the patient was referred to his physician. Subsequent computed tomography imaging of the right foot revealed a nondisplaced fracture through the dorsal-medial aspect of the navicular. PMID- 23455452 TI - Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice. AB - PURPOSE: Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth. We investigated whether everolimus, an mTOR inhibitor, and sorafenib, a multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone. METHODS: Tumor volume progression was measured following treatment with both drugs as single agents, in combination, and at multiple doses. Pharmacokinetics in tumors and other tissues was also assessed. Pharmacodynamic interactions were evaluated quantitatively. RESULTS: A 5-week regimen of daily oral doses of 10 mg/kg sorafenib and 0.5 mg/kg everolimus, alone and in combination, did not achieve significant tumor growth inhibition. Higher doses (20 mg/kg of sorafenib and 1 mg/kg of everolimus) inhibited tumor growth significantly when given alone and caused complete inhibition of growth when given in combination. Tumor volume progression was described by a linear growth model, and drug effects were described by Hill-type inhibition. Using population modeling approaches, dual-interaction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugs. CONCLUSIONS: The results indicate that combinations of mTOR and multi kinase inhibitors may offer greater efficacy in pancreatic cancer than either drug alone. Drug effects upon tumor stromal elements may contribute to the enhanced anti-tumor efficacy. PMID- 23455454 TI - Exploring the use of the survivorship consult in providing survivorship care. AB - PURPOSE: Advances in breast cancer treatment have increased survival and contributed to longer periods of survivorship as reported by the Committee CCSsS (Canadian Cancer Statistics) (2011) and Hewitt et al. (2005), increasing the relevance of survivorship care. Survivorship care includes encouraging survivors to acquire the knowledge, skills and confidence to manage their life, as well as engaging survivors through post-diagnosis disease self-management and self-care strategies. The Survivorship Consult (SC) was designed to help survivors reflect on their needs, establish goals and create an action plan. METHODS: Twenty-six breast cancer survivors who participated in the SC at Princess Margaret Cancer Centre took part in semi-structured interviews to assess the survivor experience and effectiveness of the SC. Data from these interviews were coded, and themes were identified using a modified grounded theory approach. RESULTS: Themes that emerged regarding the experience and effectiveness of the SC included (1) the supportive experience of collaborative dialogue with supportive care clinicians (i.e. nurses, social workers, occupational therapists, etc.), (2) the development of personalized goals that motivated individuals to implement recommendations, (3) an enhanced understanding of their health condition, team and options, (4) an improved ability to identify needs and (5) an increased sense of confidence to manage issues related to care. CONCLUSIONS: The assessment of the SC improved the experience of breast cancer patients by providing a supportive environment where they could feel cared about, by increasing understanding of their condition and its treatment, by improving communication with the care team and by motivating patients to manage care issues. Further research is needed on survivors who conduct the SC before the treatment phase of their cancer trajectory. PMID- 23455456 TI - Photoluminescence study of as-grown vertically standing wurtzite InP nanowire ensembles. AB - We demonstrate a method that enables the study of photoluminescence of as-grown nanowires on a native substrate by non-destructively suppressing the contribution of substrate photoluminescence. This is achieved by using polarized photo excitation and photoluminescence and by making an appropriate choice of incident angle of both excitation beam and photoluminescence collection direction. Using TE-polarized excitation at a wavelength of 488 nm at an incident angle of ~70 degrees we suppress the InP substrate photoluminescence relative to that of the InP nanowires by about 80 times. Consequently, the photoluminescence originating from the nanowires becomes comparable to and easily distinguishable from the substrate photoluminescence. The measured photoluminescence, which peaks at photon energies of ~1.35 eV and ~1.49 eV, corresponds to the InP substrate with zinc-blende crystal structure and to the InP nanowires with wurtzite crystal structure, respectively. The photoluminescence quantum yield of the nanowires was found to be ~20 times lower than that of the InP substrate. The nanowires, grown vertically in a random ensemble, neither exhibit substantial emission polarization selectivity to the axis of the nanowires nor follow excitation polarization preferences observed previously for a single nanowire. PMID- 23455455 TI - Distress screening remains important during follow-up after primary breast cancer treatment. AB - BACKGROUND: To improve psychosocial care, the National Comprehensive Cancer Network recommends the use of the Distress Thermometer (DT) to detect distress among cancer patients. OBJECTIVES: The objectives of this study were to describe the prevalence of distress in breast cancer survivors (BCSs) and to investigate demographic, treatment, and psychosocial variables associated with distress and problems most often reported on the problem list. Moreover, we assessed how many BCSs requested referral to a professional for additional support. METHODS: In a cross-sectional study, 258 BCSs identified at an outpatient clinic of a university hospital were asked to complete the following questionnaires: DT, Quality of Life Questionnaire, Hospital Anxiety and Depression Scale, and Illness Cognition Questionnaire. RESULTS: Of the 258 identified BCSs, 129 (50 %) completed all questionnaires. After a mean follow-up period of 5.6 (SD, 10) years, 47 (36 %) of these 129 BCSs experienced distress as assessed by the DT. BCSs experienced significantly more distress in the first 2 years than in the period between 2 and 5 years after surgery. Also, more distress was experienced in BCSs treated with surgery, radiotherapy, and chemotherapy compared to those treated with surgery only. Problems most frequently encountered were fatigue (57 %), decrease in muscle strength (47 %), and lack of physical fitness (42 %). Thirty one (69 %) of the distressed BCSs requested or considered referral to a professional. Regression analysis showed that reduced quality of life, reduced cognitive function, and fatigue were predictors of distress. CONCLUSION: The current study found that more than one third of all BCSs experienced distress. Screening remains an important part of BCSs' care. The professional should be aware of the potential problems and distress patients may experience. PMID- 23455457 TI - PU.1 is a tumor suppressor for B cell malignancies. PMID- 23455458 TI - How does the addition of steric hindrance to a typical N-heterocyclic carbene ligand affect catalytic activity in olefin metathesis? AB - Density functional theory (DFT) calculations were used to predict and rationalize the effect of the modification of the structure of the prototype 1,3-bis(2,6 diisopropylphenyl)imidazol-2-ylidene) N-heterocyclic carbene (NHC) ligand. The modification consists in the substitution of the methyl groups of ortho isopropyl substituent with phenyl groups, and here we plan to describe how such significant changes affect the metal environment and therefore the related catalytic behaviour. Bearing in mind that there is a significant structural difference between both ligands in different olefin metathesis reactions, here by means of DFT we characterize where the NHC ligand plays a more active role and where it is a simple spectator, or at least its modification does not significantly change its catalytic role/performance. PMID- 23455459 TI - Poplars with a PtDDM1-RNAi transgene have reduced DNA methylation and show aberrant post-dormancy morphology. AB - The Arabidopsis thaliana DDM1 (Decreased DNA Methylation) gene is necessary for the maintenance of DNA methylation and heterochromatin assembly. In Arabidopsis, ddm1 mutants exhibit strong but delayed morphological phenotypes. We used RNA interference (RNAi) to suppress transcripts of two orthologous DDM1 paralogs in Populus trichocarpa and examined effects on whole plant phenotypes during perennial growth and seasonal dormancy. The RNAi-PtDDM1 transgenic poplars showed a wide range of DDM1 transcript suppression; the most strongly suppressed line had 37.5 % of the expression of the non-transgenic control. Genomic cytosine methylation (mC %) was 11.1 % in the non-transgenic control, compared with 9.1 % for the transgenic event with lowest mC %, a reduction of 18.1 %. An evaluation of greenhouse growth directly after acclimation of in vitro grown plants showed no developmental or growth rate abnormalities associated with the decrease in PtDDM1 expression. However, after a dormancy cycle and growth outdoors, a mottled leaf phenotype appeared in some of the transgenic insertion events that had strongly reduced PtDDM1 expression and DNA methylation. The phenotypic consequences of reduced DDM1 activity and DNA methylation appears to increase with cumulative plant propagation and growth. PMID- 23455460 TI - Purification and characterization of a soluble beta-1,4-glucan from bean (Phaseolus vulgaris L.)-cultured cells dehabituated to dichlobenil. AB - Bean cells habituated to grow in the presence of dichlobenil exhibited reduced cellulose and hemicellulose content and an increase in pectic polysaccharides. Furthermore, following the extraction of pectins and hemicelluloses, a large amount of neutral sugars was released. These sugars were found to be part of a soluble beta-1,4-glucan in a preliminary characterization, as reported by Encina et al. (Physiol Plant 114:182-191, 2002). When habituated cells were subcultured in the absence of the herbicide (dehabituated cells), the release of neutral sugars after the extraction of pectins and hemicelluloses was maintained. In this study, we have isolated a soluble beta-1,4-glucan from dehabituated cells by sonication of the wall residue (cellulose fraction) remaining after fractionation. Gel filtration chromatography revealed that its average molecular size was 14 kDa. Digestion of the sample with endocellulase revealed the presence of cellobiose, cellotriose, and cellotetraose. Methylation analysis showed that 4 linked glucose was the most abundant sugar residue, but 4,6-linked glucose, terminal arabinose and 4-linked galactose for xyloglucan, and arabinogalactan were also identified. NMR analysis showed that this 1,4-glucan may be composed of various kinds of substitutions along the glucan backbone together with acetyl groups linked to the OH group of sugar residues. Thus, despite its relatively high molecular mass, the beta-glucan remains soluble because of its unique configuration. This is the first time that a glucan with such characteristics has been isolated and described. The discovery of new molecules, as this beta-glucan with unique features, may help understand the composition and arrangement of the polymers within plant cell walls, contributing to a better understanding of this complex structure. PMID- 23455461 TI - Active silver nanoparticles for wound healing. AB - In this preliminary study, the silver nanoparticle (Ag NP)-based dressing, ActicoatTM Flex 3, has been applied to a 3D fibroblast cell culture in vitro and to a real partial thickness burn patient. The in vitro results show that Ag NPs greatly reduce mitochondrial activity, while cellular staining techniques show that nuclear integrity is maintained, with no signs of cell death. For the first time, transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS) analyses were carried out on skin biopsies taken from a single patient during treatment. The results show that Ag NPs are released as aggregates and are localized in the cytoplasm of fibroblasts. No signs of cell death were observed, and the nanoparticles had different distributions within the cells of the upper and lower dermis. Depth profiles of the Ag concentrations were determined along the skin biopsies. In the healed sample, most of the silver remained in the surface layers, whereas in the unhealed sample, the silver penetrated more deeply. The Ag concentrations in the cell cultures were also determined. Clinical observations and experimental data collected here are consistent with previously published articles and support the safety of Ag NP based dressing in wound treatment. PMID- 23455462 TI - Vascular Endothelial Growth Factor Receptor Family in Ascidians, Halocynthia roretzi (Sea Squirt). Its High Expression in Circulatory System-Containing Tissues. AB - The vascular endothelial growth factor (VEGF)-VEGF Receptor (VEGFR) system is an important pathway for regulation of angiogenesis. However, its evolutionary development, particularly the step from invertebrates to vertebrates, is still largely unknown. Here, we molecularly cloned the VEGFR-like gene from Halocynthia roretzi, a species belonging to the Tunicata, the chordate subphylum recently considered the sister group of vertebrates. The cDNA encoded a homolog of human VEGFR, including the transmembrane domain, and the tyrosine kinase domain with a kinase-insert region, which was designated S. sq VEGFR (GenBank AB374180). Similar to Tunicates including ascidians in the phylogenetic tree, the Amphioxus, another chordate, is located close to vertebrates. However, S. sq VEGFR has a higher homology than the Amphioxus VEGFR-like molecule (GenBank AB025557) to human VEGFR in the kinase domain-2 region. The S. sq VEGFR mRNA was expressed at highest levels in circulatory system-containing tissues, suggesting that S. sq VEGFR plays an important role in the formation or maintenance of circulatory system in Tunicates, Halocynthia roretzi. PMID- 23455463 TI - Mitogen-Activated Protein (MAP) Kinase Scaffolding Proteins: A Recount. AB - The mitogen-activated protein kinase (MAPK) pathway is the canonical signaling pathway for many receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor. Downstream of the receptors, this pathway involves the activation of a kinase cascade that culminates in a transcriptional response and affects processes, such as cell migration and adhesion. In addition, the strength and duration of the upstream signal also influence the mode of the cellular response that is switched on. Thus, the same components can in principle coordinate opposite responses, such as proliferation and differentiation. In recent years, it has become evident that MAPK signaling is regulated and fine-tuned by proteins that can bind to several MAPK signaling proteins simultaneously and, thereby, affect their function. These so-called MAPK scaffolding proteins are, thus, important coordinators of the signaling response in cells. In this review, we summarize the recent advances in the research on MAPK/extracellular signal regulated kinase (ERK) pathway scaffolders. We will not only review the well known members of the family, such as kinase suppressor of Ras (KSR), but also put a special focus on the function of the recently identified or less studied scaffolders, such as fibroblast growth factor receptor substrate 2, flotillin-1 and mitogen-activated protein kinase organizer 1. PMID- 23455464 TI - Metabolomics as a tool to investigate abiotic stress tolerance in plants. AB - Metabolites reflect the integration of gene expression, protein interaction and other different regulatory processes and are therefore closer to the phenotype than mRNA transcripts or proteins alone. Amongst all -omics technologies, metabolomics is the most transversal and can be applied to different organisms with little or no modifications. It has been successfully applied to the study of molecular phenotypes of plants in response to abiotic stress in order to find particular patterns associated to stress tolerance. These studies have highlighted the essential involvement of primary metabolites: sugars, amino acids and Krebs cycle intermediates as direct markers of photosynthetic dysfunction as well as effectors of osmotic readjustment. On the contrary, secondary metabolites are more specific of genera and species and respond to particular stress conditions as antioxidants, Reactive Oxygen Species (ROS) scavengers, coenzymes, UV and excess radiation screen and also as regulatory molecules. In addition, the induction of secondary metabolites by several abiotic stress conditions could also be an effective mechanism of cross-protection against biotic threats, providing a link between abiotic and biotic stress responses. Moreover, the presence/absence and relative accumulation of certain metabolites along with gene expression data provides accurate markers (mQTL or MWAS) for tolerant crop selection in breeding programs. PMID- 23455465 TI - Differential Protein Expression in Response to Abiotic Stress in Two Potato Species: Solanum commersonii Dun and Solanum tuberosum L. AB - Better knowledge on responses to dehydration stress could help to improve the existing cryopreservation protocols for potato, since plant tissues processed for cryopreservation are often submitted to similar in vitro stress conditions. Cryopreservation (the best method of conservation for vegetatively propagated plants) of potato still needs to be standardized to make it available and to conserve the wide diversity of this crop. In the present work, the response to osmotic stress and chilling temperature was investigated in two potato species, Solanum tuberosum and its relative, frost-tolerant S. commersonii. After 14 days of exposure, different growth parameters, such as shoot length and number of leaves, were measured. Furthermore, differentially abundant proteins were identified after performing 2-fluorescence difference gel electrophoresis (2 DIGE) experiments, and soluble carbohydrates were analyzed by High Performance Anion Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD). The results show different responses in both species depending on the stress treatment. Focusing on the differences in growth parameters during the treatments, Solanum commersonii seems to be more affected than S. tuberosum cv. Desiree. At the molecular level, there are some differences and similarities between the two potato species studied that are dependent on the type of stressor. PMID- 23455467 TI - Development and antibacterial activity of cashew gum-based silver nanoparticles. AB - The present study describes the development of a green synthesis of silver nanoparticles reduced and stabilized by exuded gum from Anacardium occidentale L. and evaluates in vitro their antibacterial and cytotoxic activities. Characterization of cashew gum-based silver nanoparticles (AgNPs) was carried out based on UV-Vis spectroscopy, transmission electron microscopy and dynamic light scattering analysis which revealed that the synthesized silver nanoparticles were spherical in shape, measuring about 4 nm in size with a uniform dispersal. AgNPs presented antibacterial activity, especially against Gram-negative bacteria, in concentrations where no significant cytotoxicity was observed. PMID- 23455469 TI - Genetic Analysis of HIV-1 Integrase Sequences from Treatment Naive Individuals in Northeastern South Africa. AB - Raltegravir, an integrase inhibitor, is not a component of the current South African antiretroviral treatment guidelines, but it could be introduced in the near future as cases of virological failures from current treatment regimens begin to occur. The aim of this study was to analyze the complete HIV integrase gene obtained from individuals at two treatment sites in northeastern South Africa for the presence of Raltegravir associated drug resistant mutations and viral subtypes based on the integrase gene. Examination for mutations against other integrase inhibitors, such as Elvitegravir and Dolutegravir, was also done. Viruses from 127 treatment naive individuals were analyzed. Genetic drug resistance mutations were determined using the Stanford HIV Drug Resistance Interpretation program and the International AIDS society-USA guidelines. Viral subtyping was done by phylogenetic analysis, and recombinants were determined using the REGA, jpHMM and RIP tools. No major resistance mutations were detected. However, 7% of the sequences had minor mutations and polymorphisms. The majority (99%) of the viruses were HIV-1 C. Recombination analysis showed that the polymerase gene of one virus was likely composed of HIV-1 subtype A1 and C sequences. The present study indicates that Raltegravir, Elvitegravir and Dolutegravir resistant mutations may be absent in the study communities and further indicates the presence of recombinant viruses in northeastern South Africa. PMID- 23455466 TI - Non-Coding RNAs: Functional Aspects and Diagnostic Utility in Oncology. AB - Noncoding RNAs (ncRNAs) have been found to have roles in a large variety of biological processes. Recent studies indicate that ncRNAs are far more abundant and important than initially imagined, holding great promise for use in diagnostic, prognostic, and therapeutic applications. Within ncRNAs, microRNAs (miRNAs) are the most widely studied and characterized. They have been implicated in initiation and progression of a variety of human malignancies, including major pathologies such as cancers, arthritis, neurodegenerative disorders, and cardiovascular diseases. Their surprising stability in serum and other bodily fluids led to their rapid ascent as a novel class of biomarkers. For example, several properties of stable miRNAs, and perhaps other classes of ncRNAs, make them good candidate biomarkers for early cancer detection and for determining which preneoplastic lesions are likely to progress to cancer. Of particular interest is the identification of biomarker signatures, which may include traditional protein-based biomarkers, to improve risk assessment, detection, and prognosis. Here, we offer a comprehensive review of the ncRNA biomarker literature and discuss state-of-the-art technologies for their detection. Furthermore, we address the challenges present in miRNA detection and quantification, and outline future perspectives for development of next generation biodetection assays employing multicolor alternating-laser excitation (ALEX) fluorescence spectroscopy. PMID- 23455468 TI - p53 and Ceramide as Collaborators in the Stress Response. AB - The sphingolipid ceramide mediates various cellular processes in response to several extracellular stimuli. Some genotoxic stresses are able to induce p53 dependent ceramide accumulation leading to cell death. However, in other cases, in the absence of the tumor suppressor protein p53, apoptosis proceeds partly due to the activity of this "tumor suppressor lipid", ceramide. In the current review, we describe ceramide and its roles in signaling pathways such as cell cycle arrest, hypoxia, hyperoxia, cell death, and cancer. In a specific manner, we are elaborating on the role of ceramide in mitochondrial apoptotic cell death signaling. Furthermore, after highlighting the role and mechanism of action of p53 in apoptosis, we review the association of ceramide and p53 with respect to apoptosis. Strikingly, the hypothesis for a direct interaction between ceramide and p53 is less favored. Recent data suggest that ceramide can act either upstream or downstream of p53 protein through posttranscriptional regulation or through many potential mediators, respectively. PMID- 23455470 TI - Isolation and Functional Analysis of ZmLTP3, a Homologue to Arabidopsis LTP3. AB - Plant lipid transfer proteins (LTPs) are encoded by multigene families and play important roles in plant physiology. One full-length cDNA encoding an Arabidopsis LTP3 homologue was isolated from maize by RT-PCR and named as ZmLTP3. RT-PCR analysis indicated that the ZmLTP3 expression is induced by salicylic acid (SA), mannitol and salt. Furthermore, in different tissues the ZmLTP3 displayed different expression patterns, indicating that ZmLTP3 may play multiple roles in stress resistance. Over-expression of ZmLTP3 in wild-type Arabidopsis resulted in the increased salt tolerance. Under salt stress condition, compared to wild-type (WT) plants, transgenic Arabidopsis grew better, had higher seedling fresh (FW), dry weight (DW), seed yields, proline content and lower MDA content and relative electric conductivity level. Our results suggest that maize ZmLTP3 might encode a member of LTPs family and play roles in salt resistance. PMID- 23455472 TI - Wnt secretion and gradient formation. AB - Concentration gradients formed by the lipid-modified morphogens of the Wnt family are known for their pivotal roles during embryogenesis and adult tissue homeostasis. Wnt morphogens are also implicated in a variety of human diseases, especially cancer. Therefore, the signaling cascades triggered by Wnts have received considerable attention during recent decades. However, how Wnts are secreted and how concentration gradients are formed remains poorly understood. The use of model organisms such as Drosophila melanogaster has provided important advances in this area. For instance, we have previously shown that the lipid raft associated reggie/flotillin proteins influence Wnt secretion and spreading in Drosophila. Our work supports the notion that producing cells secrete Wnt molecules in at least two pools: a poorly diffusible one and a reggie/flotillin dependent highly diffusible pool which allows morphogen spreading over long distances away from its source of production. Here we revise the current views of Wnt secretion and spreading, and propose two models for the role of the reggie/flotillin proteins in these processes: (i) reggies/flotillins regulate the basolateral endocytosis of the poorly diffusible, membrane-bound Wnt pool, which is then sorted and secreted to apical compartments for long-range diffusion, and (ii) lipid rafts organized by reggies/flotillins serve as "dating points" where extracellular Wnt transiently interacts with lipoprotein receptors to allow its capture and further spreading via lipoprotein particles. We further discuss these processes in the context of human breast cancer. A better understanding of these phenomena may be relevant for identification of novel drug targets and therapeutic strategies. PMID- 23455473 TI - Secretory Phospholipases A2 in Durum Wheat (Triticum durum Desf.): Gene Expression, Enzymatic Activity, and Relation to Drought Stress Adaptation. AB - Phospholipases A2 (PLA2s) are known to mediate signaling cascades during plant growth and development, as well as biotic and abiotic stress responses. In this context, the present study provides extensive characterization of specific PLA2s in durum wheat, and assesses their involvement in durum wheat response to drought stress. In durum wheat leaves, four full-length expressed sequences encoding putative PLA2s were isolated and characterized as belonging to the class of secretory PLA2s (sPLA2s): TdsPLA2I, TdsPLA2II, TdsPLA2III and TdsPLA2IV. PLA2 activity was also detected, the characteristics of which resemble those of previously characterized plant sPLA2s: strong preference for phospholipids; requirement for millimolar Ca2+ concentrations; optimal activity at basic pH; heat stability; and inhibition by the reducing agent dithiothreitol. With drought stress imposed at both the vegetative and reproductive stages, accumulation of TdsPLA2I and TdsPLA2III transcripts, and to a lesser extent of TdsPLA2IV transcript, paralleled increased PLA2 activity; both transcript levels and enzymatic activity decreased as a consequence of stress recovery. Consistently, free fatty acid analysis of drought-stressed leaves revealed increased linoleate, linolenate and palmitate contents, which were reversed by plant re-watering. Overall, these findings strongly suggest that there are inducible sPLA2 isoforms in durum wheat that have roles in orchestrating the plant response to drought stress. PMID- 23455474 TI - Chicken mannose-binding lectin (MBL) gene variants with influence on MBL serum concentrations. AB - Mannose-binding lectin (MBL) plays a major role in the innate immune defence by activating the lectin complement pathway or by acting as an opsonin. Two forms of MBL have been characterised from several species, but for humans and chickens, only one form of functional MBL has been described. The human MBL2 gene is highly polymorphic, and it causes varying MBL serum levels. Several of the single nucleotide polymorphisms (SNPs) have been associated with the severity of diseases of bacterial, viral or parasitic origin. Association between various diseases and different MBL serum levels has also been identified in chickens. In this study, two inbred chicken lines (L10L and L10H) which have been selected for low and high MBL levels in serum and four other experimental chicken lines were analysed for polymorphism in the MBL gene. The presence of polymorphisms in the MBL gene was revealed by southern blot analyses, and the differences in the serum concentrations of MBL were found to be of transcriptional origin according to real-time quantitative reverse transcription PCR analysis. Several SNPs were discovered in the promoter and the 5' untranslated region of the chicken MBL gene which resulted in the identification of six different alleles. Mapping of regulatory elements in the promoter region was performed, and SNPs that could affect the MBL serum concentration were identified. One SNP that was found to be located in a TATA box was altered in one of the six alleles only. This allele was associated with low MBL serum concentration. PMID- 23455475 TI - Electrochemical dealloying of Al2(Au,X) (X = Pt, Pd, PtPd, Ni, Co and NiCo) alloys in NaCl aqueous solution. AB - The electrochemical dealloying of rapidly solidified Al2(Au,X) (X = Pt, Pd, PtPd, Ni, Co and NiCo) precursors in a 1.0 M NaCl aqueous solution has been systematically investigated using electrochemical measurements including open circuit measurement, potentiodynamic polarization and potentiostatic polarization, and microstructural analysis. The results show that the kind of alloying element(s) has a significant influence on the open-circuit and corrosion potentials of the rapidly solidified Al2(Au,X) precursors. The bulk dealloying of the Al2(Au,X) precursors is affected by the kind of alloying element(s) and also sensitive to the applied potential (or overpotential). The addition of Ni or/and Co easily leads to passivation on the surface of precursors during potentiostatic dealloying. The potentiostatic dealloying of Al2(Au,Pt), Al2(Au,Pd) and Al2(Au,Pt,Pd) results in the formation of ultrafine nanoporous AuPt, AuPd and AuPtPd alloys, owing to the pinning effect of Pt or/and Pd on surface diffusion of Au adatoms. In comparison, the potentiostatic dealloying of Al2(Au,Ni), Al2(Au,Co) and Al2(Au,Ni,Co) leads to the formation of nanoporous Au with a ligament/channel size of ~40 nm due to the simultaneous dissolution of Al and Ni/Co. Moreover, the addition of Pt, Pd or PtPd not only inhibits surface diffusion of Au adatoms (lower diffusivities), but also improves the activation energy for the diffusion process during potentiostatic dealloying. Based upon the present results, nanoporous metals or alloys can be greenly fabricated through electrochemical dealloying in NaCl solutions. PMID- 23455476 TI - RIPSeeker: a statistical package for identifying protein-associated transcripts from RIP-seq experiments. AB - RIP-seq has recently been developed to discover genome-wide RNA transcripts that interact with a protein or protein complex. RIP-seq is similar to both RNA-seq and ChIP-seq, but presents unique properties and challenges. Currently, no statistical tool is dedicated to RIP-seq analysis. We developed RIPSeeker (http://www.bioconductor.org/packages/2.12/bioc/html/RIPSeeker.html), a free open source Bioconductor/R package for de novo RIP peak predictions based on HMM. To demonstrate the utility of the software package, we applied RIPSeeker and six other published programs to three independent RIP-seq datasets and two PAR-CLIP datasets corresponding to six distinct RNA-binding proteins. Based on receiver operating curves, RIPSeeker demonstrates superior sensitivity and specificity in discriminating high-confidence peaks that are consistently agreed on among a majority of the comparison methods, and dominated 9 of the 12 evaluations, averaging 80% area under the curve. The peaks from RIPSeeker are further confirmed based on their significant enrichment for biologically meaningful genomic elements, published sequence motifs and association with canonical transcripts known to interact with the proteins examined. While RIPSeeker is specifically tailored for RIP-seq data analysis, it also provides a suite of bioinformatics tools integrated within a self-contained software package comprehensively addressing issues ranging from post-alignments' processing to visualization and annotation. PMID- 23455477 TI - Utility of flexible bronchoscopy in the evaluation of pulmonary infiltrates in the hematopoietic stem cell transplant population -- a single center fourteen year experience. AB - INTRODUCTION: Pulmonary infiltrates are common within the hematopoietic stem cell transplant (HSCT) population and unfortunately portend an increased mortality. Bronchoscopy is often utilized as an initial diagnostic tool, but the literature supporting its diagnostic utility and effect on clinical management varies significantly. The aim of this study was to investigate the diagnostic ability, complication rate, and clinical impact of flexible bronchoscopy (FB) in evaluating pulmonary infiltrates in a large HSCT population. PATIENTS AND METHOD: Retrospective review of all patients undergoing FB after HSCT in the Bone Marrow Transplant Unit from 1996 to 2009. RESULTS: FB was performed 162times in 144patients with pulmonary infiltrates yielding positive results in 52.5%. The most common positive results were bacterial pneumonia (31%), fungal pneumonia (15%), and alveolar hemorrhage (11%). Treatment changes occurred in 44% of patients after FB. Treatment changes included antibiotic modification (59%), addition of corticosteroids (21%), antifungal modification (12%), and antiviral modification (7%). The overall complication rate associated with FB was 30%, although 84% of these complications were considered minor. CONCLUSIONS: FB in patients with pulmonary infiltrates after HSCT should still be considered a valuable tool in the evaluation and management of pulmonary infiltrates in the HSCT population. Future prospective, multicenter randomized studies are needed to evaluate the overall clinical impact that bronchoscopic results and management changes have in this unique population. PMID- 23455478 TI - Ubiquitylation-dependent localization of PLK1 in mitosis. AB - Polo-like kinase 1 (PLK1) critically regulates mitosis through its dynamic localization to kinetochores, centrosomes and the midzone. The polo-box domain (PBD) and activity of PLK1 mediate its recruitment to mitotic structures, but the mechanisms regulating PLK1 dynamics remain poorly understood. Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors. Expression of a non ubiquitylatable PLK1-K492R mutant phenocopies inactivation of CUL3-KLHL22. KLHL22 associates with the mitotic spindle and its interaction with PLK1 increases on chromosome bi-orientation. Our data suggest that CUL3-KLHL22-mediated ubiquitylation signals degradation-independent removal of PLK1 from kinetochores and SAC satisfaction, which are required for faithful mitosis. PMID- 23455479 TI - F- and G-actin homeostasis regulates mechanosensitive actin nucleation by formins. AB - Physical force evokes rearrangement of the actin cytoskeleton. Signalling pathways such as tyrosine kinases, stretch-activated Ca(2+) channels and Rho GTPases are involved in force sensing. However, how signals are transduced to actin assembly remains obscure. Here we show mechanosensitive actin polymerization by formins (formin homology proteins). Cells overexpressing mDia1 increased the amount of F-actin on release of cell tension. Fluorescence single molecule speckle microscopy revealed rapid induction of processive actin assembly by mDia1 on cell cortex deformation. mDia1 lacking the Rho-binding domain and other formins exhibited mechanosensitive actin nucleation, suggesting Rho independent activation. Mechanosensitive actin nucleation by mDia1 required neither Ca(2+) nor kinase signalling. Overexpressing LIM kinase abrogated the induction of processive mDia1. Furthermore, s-FDAPplus (sequential fluorescence decay after photoactivation) analysis revealed a rapid actin monomer increase on cell cortex deformation. Our direct visualization of the molecular behaviour reveals a mechanosensitive actin filament regeneration mechanism in which G-actin released by actin remodelling plays a pivotal role. PMID- 23455480 TI - New findings on the pollination biology of Mauritia flexuosa (Arecaceae) in Roraima, Brazil: linking dioecy, wind, and habitat. AB - PREMISE OF THE STUDY: Despite the ecological, economic, and cultural importance of the palm Mauritia flexuosa in Amazonia, knowledge of its reproductive biology is scarce. Previous observations of this species suggested beetles as the probable pollinator, but experimental work to confirm this hypothesis was lacking. * METHODS: We investigated the floral biology and pollination of M. flexuosa in undisturbed forest, undisturbed savanna/forest ecotone, and fragmented savanna within plantations of the exotic tree, Acacia mangium, in northern Brazilian Amazonia. In each habitat, we examined floral biology, combined floral visitor observations with laboratory analyses, and performed anemophily and exclusion experiments. * KEY RESULTS: Fruit set was significantly greater in the visitor exclusion treatment than in the wind + visitor exclusion treatment and significantly lower in the wind + visitor exclusion treatment than the open control, but there was no difference in fruit set between the visitor exclusion treatment and the control. We found no significant difference in pollen dispersal among the three habitats. The presence of A. mangium appears to have no immediate effect on pollination of M. flexuosa, although it may indirectly affect other aspects of this native's reproductive ecology. * CONCLUSIONS: Floral visitors of M. flexuosa are not pollinators. This dioecious palm depends on wind as its primary pollen vector. Wind pollination is not necessarily most effective in open habitats. These findings are important because they re-evaluate traditional assumptions of wind pollination and can improve management strategies of this natural resource in the Amazon. PMID- 23455471 TI - Phospholipases of mineralization competent cells and matrix vesicles: roles in physiological and pathological mineralizations. AB - The present review aims to systematically and critically analyze the current knowledge on phospholipases and their role in physiological and pathological mineralization undertaken by mineralization competent cells. Cellular lipid metabolism plays an important role in biological mineralization. The physiological mechanisms of mineralization are likely to take place in tissues other than in bones and teeth under specific pathological conditions. For instance, vascular calcification in arteries of patients with renal failure, diabetes mellitus or atherosclerosis recapitulates the mechanisms of bone formation. Osteoporosis-a bone resorbing disease-and rheumatoid arthritis originating from the inflammation in the synovium are also affected by cellular lipid metabolism. The focus is on the lipid metabolism due to the effects of dietary lipids on bone health. These and other phenomena indicate that phospholipases may participate in bone remodelling as evidenced by their expression in smooth muscle cells, in bone forming osteoblasts, chondrocytes and in bone resorbing osteoclasts. Among various enzymes involved, phospholipases A1 or A2, phospholipase C, phospholipase D, autotaxin and sphingomyelinase are engaged in membrane lipid remodelling during early stages of mineralization and cell maturation in mineralization-competent cells. Numerous experimental evidences suggested that phospholipases exert their action at various stages of mineralization by affecting intracellular signaling and cell differentiation. The lipid metabolites-such as arachidonic acid, lysophospholipids, and sphingosine-1 phosphate are involved in cell signaling and inflammation reactions. Phospholipases are also important members of the cellular machinery engaged in matrix vesicle (MV) biogenesis and exocytosis. They may favour mineral formation inside MVs, may catalyse MV membrane breakdown necessary for the release of mineral deposits into extracellular matrix (ECM), or participate in hydrolysis of ECM. The biological functions of phospholipases are discussed from the perspective of animal and cellular knockout models, as well as disease implications, development of potent inhibitors and therapeutic interventions. PMID- 23455481 TI - Palms do not undergo secondary stem lengthening: a response to Renninger and Phillips (American Journal of Botany 99: 607-613). AB - Woody stems that have completed some maturation of metaxylem elements should not be capable of further axial extension ("secondary stem lengthening"). However, this mechanism has been claimed by Renninger and Phillips (American Journal of Botany 99: 607-613) to be a feature of the palm Iriartea deltoidea. In response, we describe structural features of palm stems based on extensive known features of their anatomy and development. In addition to the inability of metaxylem vessels to extend after they are mature, fully differentiated fibers of the vascular bundle sheath, which would exist at the time of proposed stem elongation would not be capable of belated extension. "Vessel spirals" claimed by these authors to be capable of stretching to accommodate secondary stem lengthening does not refer to well-established features of the course of vascular bundles. The approach adopted by Renninger and Phillips simply measures stems of different sizes as an implied developmental series. Consequently, results do not take into account changes in the development of the palm stem as it ages. The existence of secondary stem lengthening in the palm Iriartea deltoidea, something never before observed in any tree, cannot occur because it would indeed disrupt mature metaxylem vessels and would also require the secondary extension of mature lignified fibers. PMID- 23455482 TI - Secondary stem lengthening in palms: response to commentary by Tomlinson and Quinn. AB - In this response, we address the criticisms put forth by Tomlinson and Quinn (American Journal of Botany 100: 461-464) about our original publication on secondary stem lengthening in Iriartea deltoidea palms (American Journal of Botany 99: 607-613) and find areas on which we may agree. We address our figure of a typical palm vascular bundle; the location, timing, and species where secondary lengthening would likely occur; and our measurement of internodes in various palms as well as our choice of individuals. Our original observations were a novel finding in the field of palm biology, and we invite more research and investigation on this subject. PMID- 23455483 TI - GBM volumetry using the 3D Slicer medical image computing platform. AB - Volumetric change in glioblastoma multiforme (GBM) over time is a critical factor in treatment decisions. Typically, the tumor volume is computed on a slice-by slice basis using MRI scans obtained at regular intervals. (3D)Slicer - a free platform for biomedical research - provides an alternative to this manual slice by-slice segmentation process, which is significantly faster and requires less user interaction. In this study, 4 physicians segmented GBMs in 10 patients, once using the competitive region-growing based GrowCut segmentation module of Slicer, and once purely by drawing boundaries completely manually on a slice-by-slice basis. Furthermore, we provide a variability analysis for three physicians for 12 GBMs. The time required for GrowCut segmentation was on an average 61% of the time required for a pure manual segmentation. A comparison of Slicer-based segmentation with manual slice-by-slice segmentation resulted in a Dice Similarity Coefficient of 88.43 +/- 5.23% and a Hausdorff Distance of 2.32 +/- 5.23 mm. PMID- 23455484 TI - Mechanistic insights into the superoxide-cytochrome c reaction by lysine surface scanning. AB - This study summarizes results which have been obtained by a mutational study of human cytochrome c. The protein can be used as a recognition element in analytical assays and biosensors for superoxide radicals since ferricytochrome c reacts with superoxide to form ferrocytochrome c and oxygen. Here lysine mutagenesis of the distal surface (i.e., of exposed residues around the Met80 axial ligand) of human cytochrome c was pursued to evaluate the effect of the surface charges on the reaction rate with the superoxide anion radical and on the redox properties of the heme protein. The latter feature is particularly relevant when the protein is immobilized on a negatively charged self-assembled monolayer on an electrode to be used as a biosensor. The observed effects of the mutations are rationalized through structural investigations based on solution NMR spectroscopy and computational analysis of the surface electrostatics. The results suggest the presence of a specific path that guides superoxide toward an efficient reaction site. Localized positive charges at the rim of the entry channel are effective in increasing the reaction rate, whereas diffused positive charges or charges far from this area are not effective or are even detrimental, resulting in a misguided approach of the anion to the protein surface. PMID- 23455485 TI - Carrier concentration-dependent electron transfer in Cu2O/ZnO nanorod arrays and their photocatalytic performance. AB - In this paper, we have engineered the interface electronic structure in Cu2O/ZnO nanorod arrays, via adjusting the carrier concentration of Cu2O, and applied them to photocatalysis. The photoinduced charge transfer kinetics at the interface between Cu2O and ZnO were systematically investigated. The Cu2O (pH 11.0)/ZnO nanorod arrays have the largest magnitude of interfacial electric field, and photoinduced charge carriers can be separated rapidly and efficiently, which generates the highest photocatalytic efficiency for the reduction of methylviologen. Heterojunction construction is an exciting direction to pursue for highly active photocatalysts, and also offers opportunities to investigate the relationship between the electronic structure and the photocatalytic performance. PMID- 23455486 TI - Optical coherence tomography imaging of telangiectasias during intense pulsed light treatment: a potential tool for rapid outcome assessment. AB - Vascular malformations commonly occur in the facial region, and can be associated with significant stigma and embarrassment. Studies have shown that even recommended light-based treatments do not always result in complete clearance. This indicates the need for more accurate pre-treatment assessment of vessel morphology to optimize treatment settings and identify possible morphological predictors of the outcome. Fourteen patients (six males, eight females, and aged 37-66 years) with the diagnosis of telangiectasias were enrolled and were all scanned with OCT and digitally photographed before and minutes after IPL treatment. OCT images of the telangiectasias before treatment were displayed as hyporeflective/signal poor bands clearly demarcated from the surrounding tissue. Minutes after treatment, OCT images demonstrated two different reactions. (1) Narrow hyperreflective bands surrounding the vessels, which may indicate edema or insufficient coagulation. (2) Hyperreflective signals within the lumen of the vessels, compatible with the expected irreversible microthrombus formation in the vessels. OCT imaging is capable of real-time assessment of tissue damage during light and laser treatment, including visualization of the perivascular changes. This may offer a more dynamic, more complete understanding of the efficacy and potential outcome of the treatment process. It is hypothesized that these immediate changes may correlate to longer-term treatment outcome. PMID- 23455487 TI - High association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with recurrent aphthous stomatitis. AB - Recurrent aphthous stomatitis (RAS) is a common ulcerative disease of the oral mucosa. Oral ulcers are also the most common feature of Behcet's disease (BD). Association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with BD has been reported in Turkish population. The aim of the present study was to investigate the possible association between ACE gene I/D polymorphism and RAS, and evaluate if there was an association with clinical features in a relatively large cohort of Turkish patients. The study included 198 patients affected by RAS and 214 healthy controls. ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction with I and D allele specific primers. The genotype and allele frequencies of I/D polymorphism showed statistically significant differences between RAS patients and controls (p < 0.0001 and p < 0.0001, respectively). After stratifying RAS patients according to clinical and demographical characteristics, no significant association was observed. In conclusion, the results of this study suggest that I/D polymorphism of the ACE gene was positively associated with predisposition to develop RAS in Turkish population. Further studies with larger populations are recommended. PMID- 23455489 TI - Mesenchymal stem cells as cellular immunotherapeutics in allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option in hematopoietic disorders, immunodeficiencies and leukemia. To date graft-versus-host disease (GvHD) represents a life-threatening complication even if associated with beneficial antileukemic reactivity. GvHD is the clinical manifestation of donor cells reacting against host tissue. Because of their ability to facilitate endogenous repair and to attenuate inflammation, MSC have evolved as a highly attractive cellular therapeutic in allo-HSCT. Here we report on the clinical experience in the use of MSC to enhance engraftment and prevent and treat acute and chronic GvHD. In early clinical trials, MSC have shown considerable benefit in the setting of manifest GvHD. These encouraging results warrant further exploration. PMID- 23455488 TI - Dominance of green sulfur bacteria in the chemocline of the meromictic Lake Suigetsu, Japan, as revealed by dissimilatory sulfite reductase gene analysis. AB - This study investigated the spatiotemporal abundance and diversity of the alpha subunit of the dissimilatory sulfite reductase gene (dsrA) in the meromictic Lake Suigetsu for assessing the sulfur-oxidizing bacterial community. The density of dsrA in the chemocline reached up to 3.1 * 10(6) copies ml(-1) in summer by means of quantitative real-time PCR and it was generally higher than deeper layers. Most of the dsrA clones sequenced were related to green sulfur bacteria such as Chlorobium phaeovibrioides, C. limicola, and C. luteolum. Below the chemocline of the lake, we also detected other dsrA clones related to the purple sulfur bacterium Halochromatium salexigens and some branching lineages of diverse sequences that were related to chemotrophic sulfur bacterial species such as Magnetospirillum gryphiswaldense, Candidatus Ruthia magnifica, and Candidatus Thiobios zoothamnicoli. The abundance and community compositions of sulfur oxidizing bacteria changed depending on the water depth and season. This study indicated that the green sulfur bacteria dominated among sulfur-oxidizing bacterial population in the chemocline of Lake Suigetsu and that certain abiotic environmental variables were important factors that determined sulfur bacterial abundance and community structure. PMID- 23455490 TI - Avulsion fracture of the anterior superior iliac spine. AB - The patient was a 17-year-old adolescent male who was referred to a physical therapist for a chief complaint of anterior right hip pain. The physical therapist reviewed the patient's radiographs, which had been completed and interpreted as normal prior to referral, and determined that there were radiographic signs present that may be concerning for an avulsion fracture. Further evaluation through magnetic resonance imaging confirmed the presence of an avulsion fracture at the right anterior superior iliac spine. PMID- 23455492 TI - The prevalence and severity of fatigue in men with prostate cancer: a systematic review of the literature. AB - BACKGROUND: Cancer-related fatigue is a significant clinical problem and is a symptom commonly experienced by patients with differing cancer types during and following treatment. It is a distressing symptom which interferes with functioning in daily life. However, much less is known about the prevalence and severity of fatigue in prostate cancer when compared to other cancer types, such as breast cancer. METHODS: A systematic review was conducted to appraise the prevalence and severity of cancer-related fatigue in prostate cancer. Systematic searches of published quantitative research relating to the prevalence and severity of fatigue were conducted using databases, including Medline, PsychINFO, CINAHL and ISI Web of Knowledge (January 2012). Included papers measured the prevalence or severity of prostate-cancer-related fatigue and differentiated fatigue outcomes (prevalence, severity) between treatment modalities. RESULTS: Nineteen studies were eligible for the review, of which 17 were cross-sectional and 2 longitudinal. Findings suggest that the prevalence of any fatigue is as high as 74%, whilst chronic fatigue prevalence was highest (39%) when hormone therapy was combined with radiotherapy. Fatigue severity is reported as worse in hormone therapy and treatment combining hormone therapy and radiotherapy. CONCLUSIONS: Fatigue is a common symptom for men with prostate cancer, particularly those prescribed hormone therapy. A wide variety of tools were used to measure fatigue prevalence and severity, which made comparisons across studies difficult. The review is limited by methodological shortcomings in the studies included. PMID- 23455491 TI - NKAIN1-SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent. AB - OBJECTIVE: We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs). METHODS: A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis. RESULTS: A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7*10(-7)<=p<=0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002<=p<=0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4*10(-7)) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence. CONCLUSION: NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways. PMID- 23455494 TI - Chromobacterium violaceum: important insights for virulence and biotechnological potential by exoproteomic studies. AB - Chromobacterium violaceum is a beta-proteobacterium with high biotechnological potential, found in tropical environments. This bacterium causes opportunistic infections in both humans and animals, that can spread throughout several tissues, quickly leading to the death of the host. Genomic studies identified potential mechanisms of pathogenicity but no further studies were done to confirm the expression of these systems. In this study 36 unique protein entries were identified in databank from a two-dimensional profile of C. violaceum secreted proteins. Chromobacterium violaceum exoproteomic preliminary studies confirmed the production of proteins identified as virulence factors (such as a collagenase, flagellum proteins, metallopeptidases, and toxins), allowing us to better understand its pathogenicity mechanisms. Biotechnologically interesting proteins (such as chitinase and chitosanase) were also identified among the secreted proteins, as well as proteins involved in the transport and capture of amino acids, carbohydrates, and oxidative stress protection. Overall, the secreted proteins identified provide us important insights on pathogenicity mechanisms, biotechnological potential, and environment adaptation of C. violaceum. PMID- 23455496 TI - A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. AB - The TLR5 gene encodes an innate immunity receptor. Mice lacking Tlr5 (T5KO) develop insulin resistance and increased adiposity. Owing to the segregation of a dominant nonsense polymorphism (R392X, rs5744168), a portion of humans lack TLR5 function. We investigated whether the nonsense polymorphism influences obesity and susceptibility to type 2 diabetes (T2D). R392X was genotyped in two cohorts from Saudi Arabia, a region where obesity and type 2 diabetes (T2D) are highly prevalent. The nonsense allele was found to protect from obesity (p(combined) = 0.0062; odds ratio, 0.51) and to associate with lower body mass index (BMI) (p(combined) = 0.0061); this allele also correlated with a reduced production of proinflammatory cytokines. A significant interaction was noted between rs5744168 and sex in affecting BMI (p(interaction) = 0.006), and stratification by gender revealed that the association is driven by females (p(combined) = 0.0016 and 0.0006 for obesity and BMI, respectively). The nonsense polymorphism also associated with BMI in nonobese women. After correction for BMI, the 392X allele was found to represent a risk factor for T2D with a sex-specific effect (p(interaction) = 0.023) mediated by females (p = 0.021; odds ratio, 2.60). Fasting plasma glucose levels in nondiabetic individuals were also higher in women carrying the nonsense allele (p = 0.012). Thus, in contrast to T5KO mice, loss of human TLR5 function protects from weight gain, but in analogy to the animal model, the nonsense allele predisposes to T2D. These effects are apparently sex-specific. Data in this study reinforce the hypothesis that metabolic diseases, including T2D, are associated with immune dysregulation. PMID- 23455493 TI - Advances in targeting signal transduction pathways. AB - Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies. PMID- 23455497 TI - Host b7x promotes pulmonary metastasis of breast cancer. AB - B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues, such as the lung epithelium, but is overexpressed in a variety of human cancers with negative clinical associations, including metastasis. However, the function of B7x in the context of cancer, whether expressed on cancer cells or on surrounding "host" tissues, has not been elucidated in vivo. We used the 4T1 metastatic breast cancer model and B7x knockout (B7x (-/-)) mice to investigate the effect of host tissue-expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo, and B7x(-/-) mice had significantly fewer lung 4T1 tumor nodules than did wild-type mice. Furthermore, B7x(-/-) mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor-associated neutrophils, macrophages, and regulatory T cells, into tumor-bearing lungs. Importantly, tumor-associated neutrophils strongly bound B7x protein and inhibited the proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local antitumor immune responses through interactions with the innate and adaptive immune systems. Thus, targeting the B7x pathway holds much promise for improving the efficacy of immunotherapy for metastatic cancer. PMID- 23455499 TI - Galectin-3 negatively regulates dendritic cell production of IL-23/IL-17-axis cytokines in infection by Histoplasma capsulatum. AB - Galectin-3 (gal3) is known for its immunoregulatory functions in infectious, autoimmune, and inflammatory diseases. However, little is known about its regulatory role in the host's IL-17A response to infection. Using a mouse model of histoplasmosis in which both Th1 and Th17 responses contribute to fungal clearance, we investigated how gal3 regulates IL-17A responses. Our study showed that Histoplasma infection induced gal3(-/-) dendritic cells to produce significantly higher levels of IL-23, TGF-beta1, and IL-1beta than did gal3(+/+) cells. Infected by the same inoculum of Histoplasma, gal3(-/-) mice had lower fungal burden and produced higher levels of IL-23/IL-17-axis cytokines and lower levels of IL-12 and IFN-gamma. Additionally, there was an increase in Th17 cells and a reduction in Th1 cells in infected gal3(-/-) mice. In vitro Th1/Th17 skewing experiments excluded the intrinsic effect of gal3 on Th cell differentiation. Although neutrophils from both gal3(+/+) and gal3(-/-) mice produced IL-17A upon IL-23 stimulation, their contribution to IL-17A production was greater in gal3(-/-) mice than in gal3(+/+) mice. Compared with gal3(+/+) dendritic cells, adoptive transfer of gal3(-/-) dendritic cells resulted in production of significantly higher levels of IL-17-axis cytokines and reduced fungal burden. It appears that reduced fungal burden and preferential IL-17A response in gal3(-/-) mice by both Th17 cells and neutrophils were the result of preferential production of IL-23/IL-17-axis cytokines by dendritic cells. Our study showed that gal3 negatively regulates IL-17A responses through inhibition of IL-23/IL-17-axis cytokine production by dendritic cells. PMID- 23455498 TI - NKG2D blockade inhibits poly(I:C)-triggered fetal loss in wild type but not in IL 10-/- mice. AB - Infection and inflammation can disturb immune tolerance at the maternal-fetal interface, resulting in adverse pregnancy outcomes. However, the underlying mechanisms for detrimental immune responses remain ill defined. In this study, we provide evidence for immune programming of fetal loss in response to polyinosinic:polycytidylic acid (polyI:C), a viral mimic and an inducer of inflammatory milieu. IL-10 and uterine NK (uNK) cells expressing the activating receptor NKG2D play a critical role in poly(I:C)-induced fetal demise. In wild type (WT) mice, poly(I:C) treatment induced expansion of NKG2D(+) uNK cells and expression of Rae-1 (an NKG2D ligand) on uterine macrophages and led to fetal resorption. In IL-10(-/-) mice, NKG2D(-) T cells instead became the source of fetal resorption during the same gestation period. Interestingly, both uterine NK and T cells produced TNF-alpha as the key cytotoxic factor contributing to fetal loss. Treatment of WT mice with poly(I:C) resulted in excessive trophoblast migration into the decidua and increased TUNEL-positive signal. IL-10(-/-) mice supplemented with recombinant IL-10 induced fetal loss through NKG2D(+) uNK cells, similar to the response in WT mice. Blockade of NKG2D in poly(I:C)-treated WT mice led to normal pregnancy outcome. Thus, we demonstrate that pregnancy disrupting inflammatory events mimicked by poly(I:C) are regulated by IL-10 and depend on the effector function of uterine NKG2D(+) NK cells in WT mice and NKG2D(-) T cells in IL-10 null mice. PMID- 23455500 TI - Competition for antigen at the level of the APC is a major determinant of immunodominance during memory inflation in murine cytomegalovirus infection. AB - The unique ability of CMV to drive the expansion of virus-specific T cell populations during the course of a lifelong, persistent infection has generated interest in the virus as a potential vaccine strategy. When designing CMV-based vaccine vectors to direct immune responses against HIV or tumor Ags, it becomes important to understand how and why certain CMV-specific populations are chosen to inflate over time. To investigate this, we designed recombinant murine CMVs (MCMVs) encoding a SIINFEKL-enhanced GFP fusion protein under the control of endogenous immediate early promoters. When mice were infected with these viruses, T cells specific for the SIINFEKL epitope inflated and profoundly dominated T cells specific for nonrecombinant (i.e., MCMV-derived) Ags. Moreover, when the virus encoded SIINFEKL, T cells specific for nonrecombinant Ags displayed a phenotype indicative of less frequent exposure to Ag. The immunodominance of SIINFEKL-specific T cells could not be altered by decreasing the number of SIINFEKL-specific cells available to respond, or by increasing the number of cells specific for endogenous MCMV Ags. In contrast, coinfection with viruses expressing and lacking SIINFEKL enabled coinflation of T cells specific for both SIINFEKL and nonrecombinant Ags. Because coinfection allows presentation of SIINFEKL and MCMV-derived Ags by different cells within the same animal, these data reveal that competition for, or availability of, Ag at the level of the APC determines the composition of the inflationary response to MCMV. SIINFEKL's strong affinity for H-2K(b), as well as its early and abundant expression, may provide this epitope's competitive advantage. PMID- 23455501 TI - Reversion of somatic mutations of the respiratory syncytial virus-specific human monoclonal antibody Fab19 reveal a direct relationship between association rate and neutralizing potency. AB - The role of affinity in determining neutralizing potency of mAbs directed against viruses is not well understood. We investigated the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in the Ab H chain V region of Fab19, a well-described neutralizing human mAb directed to respiratory syncytial virus. Comparison of the affinity matured Ab Fab19 with recombinant Fab19 Abs that were variants containing reverted amino acids from the inferred unmutated ancestor sequence revealed the molecular basis for affinity maturation of this Ab. Enhanced binding was achieved through mutations in the third H chain CDR (HCDR3) that conferred a markedly faster on-rate and a desirable increase in antiviral neutralizing activity. In contrast, most somatic mutations in the HCDR1 and HCDR2 regions did not significantly enhance Ag binding or antiviral activity. We observed a direct relationship between the measured association rate (Kon) for F protein and antiviral activity. Modeling studies of the structure of the Ag-Ab complex suggested the HCDR3 loop interacts with the antigenic site A surface loop of the respiratory syncytial virus F protein, previously shown to contain the epitope for this Ab by experimentation. These studies define a direct relationship of affinity and neutralizing activity for a viral glycoprotein-specific human mAb. PMID- 23455502 TI - MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust particles and ambient particulate matter in human bronchial epithelial cells. AB - Air pollution contributes to acute exacerbations of asthma and the development of asthma in children and adults. Airway epithelial cells interface innate and adaptive immune responses, and have been proposed to regulate much of the response to pollutants. Thymic stromal lymphopoietin (TSLP) is a pivotal cytokine linking innate and Th2 adaptive immune disorders, and is upregulated by environmental pollutants, including ambient particulate matter (PM) and diesel exhaust particles (DEP). We show that DEP and ambient fine PM upregulate TSLP mRNA and human microRNA (hsa-miR)-375 in primary human bronchial epithelial cells (pHBEC). Moreover, transfection of pHBEC with anti-hsa-miR-375 reduced TSLP mRNA in DEP but not TNF-alpha-treated cells. In silico pathway evaluation suggested the aryl hydrocarbon receptor (AhR) as one possible target of miR-375. DEP and ambient fine PM (3 MUg/cm(2)) downregulated AhR mRNA. Transfection of mimic-hsa miR-375 resulted in a small downregulation of AhR mRNA compared with resting AhR mRNA. AhR mRNA was increased in pHBEC treated with DEP after transfection with anti-hsa-miR-375. Our data show that two pollutants, DEP and ambient PM, upregulate TSLP in human bronchial epithelial cells by a mechanism that includes hsa-miR-375 with complex regulatory effects on AhR mRNA. The absence of this pathway in TNF-alpha-treated cells suggests multiple regulatory pathways for TSLP expression in these cells. PMID- 23455503 TI - A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) develops in response to elevated TLR4 signaling in the newborn intestinal epithelium and is characterized by TLR4-mediated inhibition of enterocyte migration and reduced mucosal healing. The downstream processes by which TLR4 impairs mucosal healing remain incompletely understood. In other systems, TLR4 induces autophagy, an adaptive response to cellular stress. We now hypothesize that TLR4 induces autophagy in enterocytes and that TLR4-induced autophagy plays a critical role in NEC development. Using mice selectively lacking TLR4 in enterocytes (TLR4(DeltaIEC)) and in TLR4-deficient cultured enterocytes, we now show that TLR4 activation induces autophagy in enterocytes. Immature mouse and human intestine showed increased expression of autophagy genes compared with full-term controls, and NEC development in both mouse and human was associated with increased enterocyte autophagy. Importantly, using mice in which we selectively deleted the autophagy gene ATG7 from the intestinal epithelium (ATG7(DeltaIEC)), the induction of autophagy was determined to be required for and not merely a consequence of NEC, because ATG7(DeltaIEC) mice were protected from NEC development. In defining the mechanisms involved, TLR4-induced autophagy led to impaired enterocyte migration both in vitro and in vivo, which in cultured enterocytes required the induction of RhoA-mediated stress fibers. These findings depart from current dogma in the field by identifying a unique effect of TLR4-induced autophagy within the intestinal epithelium in the pathogenesis of NEC and identify that the negative consequences of autophagy on enterocyte migration play an essential role in its development. PMID- 23455504 TI - Orai1 function is essential for T cell homing to lymph nodes. AB - In T lymphocytes, Ca(2+) release-activated Ca(2+) (CRAC) channels composed of Orai1 subunits trigger Ag-induced gene expression and cell proliferation through the NFAT pathway. We evaluated the requirement of CRAC channel function for lymphocyte homing using expression of a dominant-negative Orai1-E106A mutant to suppress Ca(2+) signaling. To investigate homing and motility of human lymphocytes in immunocompromised mouse hosts, we transferred human lymphocytes either acutely or after stable engraftment after a second transfer from the same blood donor. Human and mouse lymphocyte homing was assessed, and cells were tracked within lymph nodes (LNs) by two-photon microscopy. Our results demonstrate that human T and B lymphocytes home into and migrate within the LNs of immunocompromised NOD.SCID mice similar to murine lymphocytes. Human T and B cells colocalized in atrophied or reconstituted mouse LNs, where T cells migrated in a random walk at velocities of 9-13 MUm/min and B cells at 6 MUm/min. Expression of Orai1-E106A inhibited CRAC channel function in human and mouse T cells, and prevented homing from high endothelial venules into murine LNs. Ca(2+) signals induced by CCL21 were also inhibited in T cells expressing Orai1-E106A. With CRAC channels inhibited, the high-affinity form of LFA-1 failed to become active, and T cells failed to migrate across endothelial cells in a transwell model. These results establish a requirement for CRAC channel-mediated Ca(2+) influx for T cell homing to LNs mediated by high-affinity integrin activation and chemokine-induced transendothelial migration. PMID- 23455505 TI - Differential localization of T-bet and Eomes in CD8 T cell memory populations. AB - In mice, two T-box transcription factors, T-box expressed in T cells (T-bet) and eomesodermin (Eomes), drive the differentiation of CD8 T cell lineages; however, little is known regarding their role in human CD8 T cell differentiation. In this study, we characterized T-bet and Eomes expression and localization within human CD8 memory T cell populations. We find that T-bet and Eomes are broadly expressed in human memory CD8 T cells, with increasing levels of T-bet and Eomes strongly correlating with differentiation from central memory to effector memory and effector subpopulations. In resting T cells, T-bet levels directly correlate to subcellular localization, with a higher propensity for nuclear expression of T bet within T-bet(hi) cells and predominantly cytoplasmic expression in T-bet(lo) cells. In addition, Eomes is also localized to either the nucleus or the cytoplasm. Upon TCR stimulation, the percentage of T cells that express T-bet dramatically increases, whereas the percentage of cells expressing Eomes remains largely unchanged across all memory populations. Of interest, T-bet, but not Eomes, relocalizes to the nucleus in the majority of cells across all populations within 24 h post stimulation. These data indicate that T-bet and Eomes are likely regulated at the level of subcellular localization, potentially via different mechanisms. Together, these findings suggest a novel model for CD8 T cell differentiation in humans that is based on the localization of T-bet and Eomes. PMID- 23455506 TI - Regulation of Foxp3+ inducible regulatory T cell stability by SOCS2. AB - Suppressor of cytokine signaling (SOCS) proteins are key regulators of CD4(+) T cell differentiation, and in particular, we have recently shown that SOCS2 inhibits the development of Th2 cells and allergic immune responses. Interestingly, transcriptome analyses have identified SOCS2 as being preferentially expressed in both natural regulatory T cells (Tregs) and inducible Tregs (iTregs); however, the role of SOCS2 in Foxp3(+) Treg function or development has not been fully elucidated. In this study, we show that despite having no effect on natural Treg development or function, SOCS2 is highly expressed in iTregs and required for the stable expression of Foxp3 in iTregs in vitro and in vivo. Indeed, SOCS2-deficient CD4(+) T cells upregulated Foxp3 following in vitro TGF-beta stimulation, but failed to maintain stable expression of Foxp3. Moreover, in vivo generation of iTregs following OVA feeding was impaired in the absence of SOCS2 and could be rescued in the presence of IL-4 neutralizing Ab. Following IL-4 stimulation, SOCS2-deficient Foxp3(+) iTregs secreted elevated IFN-gamma and IL-13 levels and displayed enhanced STAT6 phosphorylation. Therefore, we propose that SOCS2 regulates iTreg stability by downregulating IL-4 signaling. Moreover, SOCS2 is essential to maintain the anti inflammatory phenotype of iTregs by preventing the secretion of proinflammatory cytokines. Collectively, these results suggest that SOCS2 may prevent IL-4 induced Foxp3(+) iTreg instability. Foxp3(+) iTregs are key regulators of immune responses at mucosal surfaces; therefore, this dual role of SOCS2 in both Th2 and Foxp3(+) iTregs reinforces SOCS2 as a potential therapeutic target for Th2-biased diseases. PMID- 23455507 TI - Primate B-1 cells generate antigen-specific B cell responses to T cell independent type 2 antigens. AB - Ab responses to T cell-independent type 2 (TI-2) Ags, such as bacterial capsular polysaccharides, are critical for host defense. In mice, B-1b cells expressing a CD11b(+)FSC(hi)CD21(lo/-)CD19(hi) phenotype play a key role in producing Abs against TI-2 Ags. In primates, a distinct IgM(+)CD27(+) "memory" B cell population is thought to generate TI-2 Ab responses, and evidence for a B-1b-like cell population participating in these responses is lacking. In this article, we demonstrate that nonhuman primates (NHPs; African green monkeys and cynomolgus macaques) harbor serosal B cells expressing a CD11b(+)FSC(hi)CD21(lo/-)CD80(+/ )CD19(hi) phenotype, constitutively active Stat3, and increased reactivity with phosphorylcholine, similar to murine peritoneal B-1a and B-1b cell populations. Like what is observed for murine B-1b cells, NHP CD11b(+)FSC(hi)CD21(lo/ )CD19(hi) B cells dominate the Ag-specific B cell response and Ab production against the TI-2 Ag trinitrophenyl-Ficoll. Although Ag-specific IgM(+) B cells expressing CD27 were not detected prior to immunization, Ag-specific CD11b(+)CD19(hi) B cells expressed and maintained an IgM(+)IgD(lo)CD27(+)CD80(+) phenotype following immunization. Thus, the murine and NHP B cell populations responding to trinitrophenyl-Ficoll are highly similar, with the main exception being that Ag-specific NHP B-1-like cells express CD27 following TI-2 Ag encounter. Therefore, murine B-1b and primate IgM(+)CD27(+) "memory" B cell subsets proposed to produce TI-2 Ab responses may be highly related, if not identical. Overall, these data not only support that B-1-like cells are present in NHPs but also provide evidence that these cells perform the same functions attributed to murine B-1b cells. PMID- 23455508 TI - Independent and interdependent immunoregulatory effects of IL-27, IFN-beta, and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis. AB - IFN-beta, IL-27, and IL-10 have been shown to exert a range of similar immunoregulatory effects in murine and human experimental systems, particularly in Th1- and Th17-mediated models of autoimmune inflammatory disease. In this study we sought to translate some of our previous findings in murine systems to human in vitro models and delineate the interdependence of these different cytokines in their immunoregulatory effects. We demonstrate that human IL-27 upregulates IL-10 in T cell-activated PBMC cultures and that IFN-beta drives IL 27 production in activated monocytes. IFN-beta-driven IL-27 is responsible for the upregulation of IL-10, but not IL-17 suppression, by IFN-beta in human PBMCs. Surprisingly, IL-10 is not required for the suppression of IL-17 by either IL-27 or IFN-beta in this model or in de novo differentiating Th17 cells, nor is IL-27 signaling required for the suppression of experimental autoimmune encephalomyelitis (EAE) by IFN-beta in vivo. Furthermore, and even more surprisingly, IL-10 is not required for the suppression of Th17-biased EAE by IL 27, in sharp contrast to Th1-biased EAE. In conclusion, IFN-beta and IL-27 both induce human IL-10, both suppress human Th17 responses, and both suppress murine EAE. However, IL-27 signaling is not required for the therapeutic effect of IFN beta in EAE. Suppression of Th17-biased EAE by IL-27 is IL-10-independent, in contrast to its mechanism of action in Th1-biased EAE. Taken together, these findings delineate a complex set of interdependent and independent immunoregulatory mechanisms of IFN-beta, IL-27, and IL-10 in human experimental models and in murine Th1- and Th17-driven autoimmunity. PMID- 23455510 TI - Expression of CXCR3 on specific T cells is essential for homing to the prostate gland in an experimental model of chronic prostatitis/chronic pelvic pain syndrome. AB - Experimental autoimmune prostatitis (EAP) is considered a valid model for the human disease chronic prostatitis/chronic pelvic pain syndrome. In this report, we analyzed phenotypic characteristics of T cells that gain access to the prostate and induce leukocyte recruitment in mice with different susceptibility to EAP. After EAP induction, NOD mice developed a specific cellular response characterized by a mixed Th1/Th17 pattern with specific T cells mainly expressing CXCR3 that infiltrated and damaged the prostate. In contrast, BALB/c mice, as well as NOD-IFN-gamma(-/-), exhibited only Th17 cells mainly expressing CCR6 that were not capable of infiltrating the prostate gland. Adoptive transfer experiments of T cells from NOD or NOD-IFN-gamma(-/-) mice to NOD-SCID recipients showed that only T cells from NOD mice successfully infiltrated the prostate. However, after "in vitro" or "in vivo" treatment with rIFN-gamma, T cells from NOD-IFN-gamma(-/-) mice became capable of homing to the prostate and induced leukocyte recruitment. Chemokine levels in prostate tissue from NOD mice showed increased expression levels of CXCR3 ligands. Additional experiments using adoptive transfer of sorted CXCR3(+)CD3(+) T cells or administrating a CXCR3 antagonist treatment confirmed these previous results. Altogether, our results demonstrate that the expression of CXCR3 on effector T cells is essential for their homing to the prostate gland in EAP. CXCR3 emerges as a potential therapeutic target to control chronic prostatitis/chronic pelvic pain syndrome. PMID- 23455509 TI - Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity. AB - Recently, patients with mutations in DOCK8 have been reported to have a combined immunodeficiency characterized by cutaneous viral infections and allergies. NK cells represent a first-line defense against viral infections, suggesting that DOCK8 might participate in NK cell function. In this study, we demonstrate that DOCK8-suppressed human NK cells showed defects in natural cytotoxicity as well as specific activating receptor-mediated NK cytotoxicity. Additionally, compared with control NK cells, NK cells depleted of DOCK8 showed defective conjugate formation, along with decreased polarization of LFA-1, F-actin, and cytolytic granules toward the cytotoxic synapse. Using a proteomic approach, we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion. Taken together, our results demonstrate an important role for DOCK8 in NK cell effector function and provide important new mechanistic insight into how DOCK8 regulates F-actin and integrin-mediated adhesion in immune cells. PMID- 23455511 TI - Remarkable improvements in the stability and thermal conductivity of graphite/ethylene glycol nanofluids caused by a graphene oxide percolation structure. AB - Versatile efforts have been made to improve the stability of graphite/ethylene glycol (EG) nanofluids. Primitively, non-dispersible graphite nanoparticles were converted to graphite oxide nanoparticles (GONs) by acid treatment. Although GONs could be well dispersed in EG, the GONs/EG nanofluids exhibited limited stability up to less than 1 day. And then, a GO (2 wt%) percolation structure formed in EG was used to anchor and support GONs by common non-covalent interactions including hydrogen bonds, van der Waals forces and pi-pi conjugation. Transmission electron microscopy observations revealed that a GON-GO hybrid forms in the GON-GO (2 wt%)/EG nanofluids with evenly distributed GONs on the GO sheets, which accounted for the high stability of nanofluids up to at least 4 weeks obtained from stability tests, in sharp contrast to that of the GONs/EG nanofluids. In addition, due to the better dispersed state of GONs induced by the GO percolation structure, thermal conductivity (TC) tests demonstrated that the TC enhancements of the GON-GO (2 wt%)/EG nanofluids were also strengthened compared to that of GONs/EG nanofluids. Excitingly, the GONs-GO (2 wt%)/EG nanofluids presented here exhibited anomalous thermal conductivity enhancements up to 123% at 21 wt% GONs content and were highly stable, which might have potential applications in engineering field and energy systems. PMID- 23455512 TI - IL28B SNP screening and distribution in the French Canadian population using a rapid PCR-based test. AB - Single nucleotide polymorphisms (SNPs) in the proximity of the interleukin-28B (IL28B) gene can predict spontaneous resolution of hepatitis C virus (HCV) infection and response to interferon therapy. Screening for this polymorphism has become part of the standard criteria for the management of HCV-infected patients, hence the need for a rapid, cost-effective screening method. Here, we describe a rapid PCR-based test to screen for two IL28B SNPs (rs12979860 and rs8099917). We used this test to investigate IL28B polymorphism and prevalence in a cohort of French Canadian injection drug users who are part of a unique population known to have a strong genetic founder effect. This population had lower linkage disequilibrium between the two tested SNPs as compared to other cohorts (|d'| = 0.68, r = 0.59). The special genetic makeup should be considered in the management of HCV-infected patients within that population. PMID- 23455513 TI - Glycosylation of conotoxins. AB - Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high level of chemical diversity and are of particular interest for scientists as tools employed in neurological studies and for drug development, because they target with exquisite specificity membrane receptors, transporters, and various ion channels in the nervous system. However, these peptides are known to contain a high frequency and variability of post-translational modifications-including sometimes O-glycosylation-which are of importance for biological activity. The potential application of specific conotoxins as neuropharmalogical agents and chemical probes requires a full characterization of the relevant peptides, including the structure of the carbohydrate part. In this review, the currently existing knowledge of O-glycosylation of conotoxins is described. PMID- 23455514 TI - Synthesis and antiproliferative activity of 2,5-bis(3'-indolyl)pyrroles, analogues of the marine alkaloid nortopsentin. AB - 2,5-bis(3'-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54 MUM and 0.67 MUM, respectively. Investigating human tumor xenografts in an ex-vivo clonogenic assay revealed selective antitumor activity, whereas sensitive tumor models were scattered among various tumor histotypes. PMID- 23455515 TI - Effects of multi-layer graphene capping on Cu interconnects. AB - The benefits of multi-layer graphene (MLG) capping on Cu interconnects have been experimentally demonstrated. The resistance of MLG capped Cu wires improved by 2 7% compared to Cu wires. The breakdown current density increased by 18%, suggesting that the MLG can act as an excellent capping material for Cu interconnects, improving the reliability characteristics. With a proper process optimization, MLG capped Cu interconnects could become a promising technology for high density back end-of-line interconnects. PMID- 23455516 TI - Raman enhancement by plasmonic excitation of structurally-characterized metal clusters: Au8, Ag8, and Cu8. AB - The optical responses of metal clusters, M8 (M = Au, Ag and Cu), are investigated by the linear response theory based on the density functional theory. Unlike sodium clusters [Yasuike et al., Phys. Rev. A, 2011, 83, 013201], the plasmonic excitations in the present metal clusters are strongly reduced by the background d-electron excitations, i.e., Landau damping. To avoid the reduction of plasmon intensity, the control of cluster structures is one of the promising strategies. We demonstrate that the plasmonic excitations of the linear clusters are partially decoupled with the background d-electron excitations and their intensities are much stronger than those of the three-dimensional bicapped octahedral isomers. The linear isomer gives a strong enhancement of the Raman vibrational spectrum of a pyrazine molecule. PMID- 23455517 TI - Vertically p-n-junctioned GaN nano-wire array diode fabricated on Si(111) using MOCVD. AB - We demonstrate the fabrication of n-GaN:Si/p-GaN:Mg nanowire arrays on (111) silicon substrate by metal organic chemical vapor deposition (MOCVD) method .The nanowires were grown by a newly developed two-step growth process. The diameter of as-grown nanowires ranges from 300-400 nm with a density of 6-7 * 10(7) cm( 2). The p- and n-type doping of the nanowires is achieved with Mg and Si dopant species. Structural characterization by X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM) indicates that the nanowires are relatively defect-free. The room-temperature photoluminescence emission with a strong peak at 370 nm indicates that the n-GaN:Si/p-GaN:Mg nanowire arrays have potential application in light-emitting nanodevices. The cathodoluminscence (CL) spectrum clearly shows a distinct optical transition of GaN nanodiodes. The nano n-GaN:Si/p-GaN:Mg diodes were further completed using a sputter coating approach to deposit Au/Ni metal contacts. The polysilazane filler has been etched by a wet chemical etching process. The n-GaN:Si/p-GaN:Mg nanowire diode was fabricated for different Mg source flow rates. The current-voltage (I-V) measurements reveal excellent rectifying properties with an obvious turn-on voltage at 1.6 V for a Mg flow rate of 5 sccm (standard cubic centimeters per minute). PMID- 23455518 TI - Cardiac fibroblasts inhibit beta-adrenoceptor-dependent connexin43 expression in neonatal rat cardiomyocytes. AB - Cardiac fibroblasts play an important role in adverse cardiac remodelling. As in many cardiac diseases connexin43 (Cx43) is altered, we wanted to elucidate whether fibroblasts may influence cardiac Cx43 expression. We used four different cell culture systems of neonatal rat cardiomyocytes (CM) and fibroblasts (FB): type 1, pure CM culture; type 2, co-culture of CM/FB; type 3, pure FB culture; type 4, Transwell(r) system: CM/FB co-cultured but separated by a microporous membrane. Stimulation of types 1-3 cell culture models with isoprenaline significantly enhanced Cx43-protein and Cx43-mRNA expression as well as phosphorylation of ERK and translocation of AP1 and CREB only in the CM cultures; whereas, the CM/FB co-cultures and the FB cultures did not respond to isoprenaline. Similarly, if CM and FB were separated by a microporous membrane (Transwell(r) system) the isoprenaline-induced increase in CM Cx43 was completely suppressed, suggesting the existence of a soluble factor responsible for the suppressant effect of FB. Angiotensin II determination in types 1 and 2 cell culture supernatants revealed that the CM/FB co-cultures exhibited a significant higher angiotensin II release than the CM cultures. Furthermore, we aimed to inhibit angiotensin II signal transduction pathway: blockade of AT1 receptors or PKC inhibition restored the responsiveness of CM/FB co-cultures to isoprenaline. Moreover, external addition of angiotensin II to CM cultures also resulted in suppression of isoprenaline-stimulated Cx43 expression in an AT1-receptor- and PKC-dependent manner. Thus, our study indicates that cardiac fibroblasts inhibit beta-adrenoceptor-dependent Cx43 signalling in CM involving angiotensin II. PMID- 23455519 TI - Metastatic mediastinal carcinoid presenting as superior mediastinal syndrome and treated with peptide receptor radionuclide therapy. AB - A 43-year-old man with known superior mediastinal syndrome due to (99m)Tc HYNIC DOTA SPECT/CT and (18)F-FDG PET tracer avid inoperable metastatic carcinoid received peptide receptor based radionuclide therapy (PRRT) with (177)Lu DOTATATE. Repeat evaluation at 3 months post-therapy demonstrated stable disease with alleviation of patient's symptoms and remarkable improvement in the quality of life. PRRT with (177)Lu-DOTATATE may be an option for inoperable mediastinal carcinoids with superior mediastinal syndrome. PMID- 23455520 TI - Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. AB - OBJECTIVE: The aim of this study was to compare 99mTc-MDP bone scanning, 18F NaF PET/CT, 18F FDG PET/CT, and whole-body MRI (WBMRI) for detection of known osseous metastases. PATIENTS AND METHODS: This prospective pilot trial (September 2007 April 2009) enrolled 10 participants (5 men, 5 women, 47-81 years old) diagnosed with cancer and known osseous metastases. 18F NaF PET/CT, 18F FDG PET/CT, and WBMRI were performed within 1 month for each participant. RESULTS: The image quality and evaluation of extent of disease were superior by 18F NaF PET/CT compared to 99mTc-MDP scintigraphy in all patients with skeletal lesions and compared to 18F FDG PET/CT in 3 of the patients with skeletal metastases. 18F NaF PET/CT showed osseous metastases where 18F FDG PET/CT was negative in another 3 participants. Extraskeletal metastases were identified by 18F FDG PET/CT in 6 participants. WBMRI with the combination of iterative decomposition of water and fat with echo asymmetry and least-squares estimation, short tau inversion recovery, and diffusion-weighted imaging pulse sequences showed fewer lesions than 18F NaF PET/CT in 5 patients, same number of lesions in 2 patients, and more lesions in 1 patient. WBMRI showed fewer lesions than 18F FDG in 3 patients and same lesions in 6 patients. CONCLUSIONS: Our pilot phase prospective trial demonstrated superior image quality and evaluation of skeletal disease extent with 18F NaF PET/CT compared to 99mTc-MDP scintigraphy and 18F FDG PET/CT, as well as the feasibility of multisequence WBMRI. In addition, 18F FDG PET/CT provided valuable soft-tissue information that can change disease management. Further evaluation of these findings using the recently introduced PET/MRI scanners is warranted. PMID- 23455521 TI - The value of 18F-FLT PET for detecting second primary cancers and distant metastases in head and neck cancer patients. AB - OBJECTIVE: Diagnostic efficacy of (18)F-FLT PET was compared with that of (18)F FDG PET regarding second primary cancers and distant metastases of head and neck squamous cell cancers (HNSCCs). METHODS: A total of 88 patients with HNSCCs were qualitatively examined with FLT PET and FDG PET for regions of focally increased metabolism. Final diagnoses of second primary cancer and distant metastasis were established on the basis of histological findings or clinical follow-up. RESULTS: FDG PET had 1 false-negative finding with lung metastasis, and FLT PET had 4 false-negative findings with 1 liver metastasis, 1 bone metastasis, and 2 lung metastases. There were no false-positive findings with FLT PET in contrast to 9 with FDG PET (1 in lung, 4 in mediastinum, 1 in rectum, and 3 in stomach). Overall accuracy of FDG PET and FLT PET for pretreatment metastasis staging was 92% and 98%, respectively. Five distant metastases in 3 patients occurred after the initiation of chemoradiotherapy. FLT PET missed 2 metastatic lesions (1 in liver and 1 in lung), whereas FDG PET could not discriminate intracranial metastasis because of FDG uptake in the brain. CONCLUSIONS: FLT PET does not appear to be recommendable to replace FDG PET for pretreatment metastasis staging in HNSCC cases because of its lower sensitivity and higher background activity in the liver and bone marrow. However, it might provide additional diagnostic specificity and biological information. PMID- 23455522 TI - Esophageal metastasis from papillary thyroid cancer: diagnosis by 131I SPECT/CT. AB - We report a case of esophageal metastasis from papillary thyroid cancer diagnosed by I SPECT/CT. A 70-year-old man presented with increasing thyroglobulin levels 13 years after thyroidectomy and ablation with I for thyroid cancer. The whole body radioiodine scan demonstrated marked tracer uptake in the mediastinum, and SPECT/CT could clearly localize the activity to the esophagus. Subsequent surgical resection with histopathologic evaluation revealed an esophageal metastasis from papillary thyroid cancer. I SPECT/CT is a valuable tool for evaluation and precise anatomical localization of the foci of radionuclide activity in thyroid cancer, enabling adequate treatment. PMID- 23455523 TI - Hypermetabolic mesenteric brown adipose tissue on dual-time point FDG PET/CT in a patient with benign retroperitoneal pheochromocytoma. AB - Intense FDG uptake of the mesenteric brown adipose tissue (BAT) is rare. We present a case of benign retroperitoneal pheochromocytoma showing multiple hypermetabolic regions corresponding with common locations of BAT. Furthermore, the mesenteric region showed intense FDG uptake, with SUVmax of 10.6. FDG PET/CT findings of this case supports the previous theories that the incidence of BAT may be higher in patients with pheochromocytoma than in patients without, and the intra-abdominal fat of human adults, including the omental fat, which is brown adipose tissue in infancy, becomes reactivated in the presence of high circulating noradrenaline concentrations. PMID- 23455524 TI - FDG uptake in splenic epidermoid cyst with hemorrhage. AB - Splenic epidermoid cyst is a rare entity and rarely becomes complicated by hemorrhage. We present a case of splenic epidermoid cyst with old hemorrhage showing strong FDG uptake in the cyst wall. Histopathology revealed granulation tissue with abundant inflammatory cells, including many hemosiderin-laden macrophages, in the inner layer of the cyst wall. The abundant inflammatory cells in the granulation tissue may contribute to the strong FDG uptake of the cyst wall. This case highlights that a benign lesion with hemorrhage should be included in the differential diagnosis of abnormal splenic FDG uptake along with tumor and inflammatory processes. PMID- 23455525 TI - Imaging findings and therapy response monitoring in chronic sclerodermatous graft versus-host disease: preliminary data of a simultaneous PET/MRI approach. AB - PURPOSE: Our objective was a multifunctional imaging approach of chronic sclerodermatous graft-versus-host disease (ScGVHD) and its course during therapy using PET/MRI. METHODS: We performed partial-body PET/CT and PET/MRI of the calf in 6 consecutively recruited patients presenting with severe ScGVHD. The patients were treated with different immunosuppressive regimens and supportive therapies. PET/CT scanning started 60.5 +/- 3.3 minutes, PET/MRI imaging 139.5 +/- 16.7 minutes after (18)F-FDG application. MRI acquisition included T1- (precontrast and postcontrast) and T2-weighted sequences. SUV(mean), T1 contrast enhancement, and T2 signal intensity from region-of-interest analysis were calculated for different fascial and muscular compartments. In addition, musculoskeletal MRI findings and the modified Rodnan skin score were assessed. All patients underwent imaging follow-up. RESULTS: At baseline PET/MRI, ScGVHD-related musculoskeletal abnormalities consisted of increased signal and/or thickening of involved anatomical structures on T2-weighted and T1 postcontrast images as well as an increased FDG uptake. At follow-up, ScGVHD-related imaging findings decreased (SUV(mean) n = 4, mean T1 contrast enhancement n = 5, mean T2 signal intensity n = 3) or progressed (SUV(mean) n = 3, mean T1 contrast enhancement n = 2, mean T2 signal intensity n = 4). Clinically modified Rodnan skin score improved for 5 follow-ups and progressed for 2. SUV(mean) values correlated between PET/CT and PET/MRI acquisition (r = 0.660, P = 0.014), T1 contrast enhancement, and T2 signal (r = 0.668, P = 0.012), but not between the SUV(mean) values and the MRI parameters. CONCLUSIONS: PET/MRI as a combined morphological and functional technique seems to assess the inflammatory processes from different points of view and provides therefore in part complementary information. PMID- 23455526 TI - MIBG superscan of metastatic paraganglioma occurring with neurofibromatosis type 1. AB - A Tc MDP bone superscan occurs when osseous activity is extremely intense and genitourinary and soft tissue activity is not identified. A similar phenomenon has been described with metaiodobenzylguanidine (MIBG) in metastatic pheochromocytoma and neuroblastoma. We present a case of metastatic paraganglioma resulting in an MIBG superscan. Neuroendocrine bone metastasis alters the biodistribution of MIBG such that the liver, heart, and urinary bladder are not well visualized. Our case occurred in association with neurofibromatosis type 1 and in the absence of an identified primary tumor. PMID- 23455527 TI - "Shin splint" syndrome and tibial stress fracture in the same patient diagnosed by means of (99m)Tc-HMDP SPECT/CT. AB - We show a patient who presented leg pain triggered by intense exercise. The most likely diagnosis was a possible tibial stress fracture or a "shin splint" syndrome (soleus enthesopathy). We performed a bone scintigraphy including SPECT/CT that revealed the presence of the two concomitant pathologies. SPECT/CT identified the hot spot superimposed with bone lesion in the tibial stress fracture and only remodeling activity without evidence of cortical lesions in the enthesopathy processes. PMID- 23455528 TI - Detection of early onset of hypophysitis by (18)F-FDG PET-CT in a patient with advanced stage melanoma treated with ipilimumab. AB - Ipilimumab is a human monoclonal antibody directed against a receptor expressed on activated T-lymphocytes (CTLA-4). Binding to this receptor induces T-cell activation against tumor cells. A 77-year-old man with a stage IV metastatic melanoma was treated with ipilimumab. F-FDG PET-CT performed for response evaluation revealed intense uptake in the pituitary gland. Two weeks later, biochemical parameters altered confirming hypophysitis. Treatment of the hypophysitis was started, and shortly thereafter, biochemical parameters normalized. Follow-up PET-CT revealed normalization of F-FDG uptake in the pituitary gland. In this case, we present a patient with ipilimumab-induced hypophysitis initially diagnosed on F-FDG PET-CT. PMID- 23455529 TI - Potential pitfall of FDG PET/CT in assessing residual masses postchemotherapy. AB - A 22-year-old man with primary mediastinal choriocarcinoma and bilateral lung metastases underwent an FDG PET/CT scan after completing chemotherapy. Serum beta human chorionic gonadotropin had normalized. PET/CT showed increased FDG uptake in the anterior mediastinal and lung lesions, suspicious for residual disease. After resection of the mediastinal and lung lesions, histopathology revealed necrosis and fibrohistiocytic reaction with no viable tumor. There was discordance between beta-human chorionic gonadotropin (negative) and FDG PET/CT (positive) findings, with PET/CT findings being false positive. Awareness of this potential pitfall of FDG PET/CT is important, and caution should be exercised when using FDG PET/CT to assess residual masses after chemotherapy. PMID- 23455530 TI - Radioguided surgery of thyroid carcinoma recurrences: the role of preoperative (99m)Tc-labeled human serum albumin macroaggregates-SPECT/CT mapping. AB - Reoperative surgery in the neck for recurrent differentiated thyroid cancer (DTC) is associated with increased morbidity compared with primary surgery. Radioguided occult lesion localization was recently proposed in patients with DTC recurrences. Here we report on the combination of radioguided occult lesion localization procedure to preoperative SPECT/CT in 2 patients with DTC recurrences. This combination was proved to be simple and technically feasible. Addition of SPECT/CT to conventional preoperative planar scans provided an accurate 3-dimensional road map for neck exploration. PMID- 23455531 TI - Atypical mycobacteriosis caused by Mycobacterium haemophilum in an immunocompromised patient: diagnosis by (18)F-FDG PET/CT. AB - We report a rare case of atypical mycobacteriosis diagnosed by F-FDG PET/CT. A 28 year-old man with a history of kidney transplantation presented with fever, painful nodular skin lesions, and elevated inflammatory markers. FDG PET/CT demonstrated multiple subcutaneous, cutaneous, and osseous areas of increased tracer uptake. Histopathologic and microbiological evaluation revealed disseminated infection with Mycobacterium haemophilum. FDG PET/CT is a valuable tool for early and correct diagnosis of occult sources of infection in immunocompromised patients. PMID- 23455532 TI - (68)Ga-DOTATATE PET/CT imaging in carotid body tumor. AB - Imaging modalities like Doppler ultrasonography, contrast-enhanced computed tomography and magnetic resonance imaging are routinely used in the diagnosis of carotid body tumors. Ga-DOTATATE PET/CT is another promising noninvasive technique in the diagnosis of carotid body tumors. We present F-FDG PET/CT and Ga DOTATATE PET/CT in a 30-year-old man with carotid body tumor. PMID- 23455533 TI - (18)F-FDG PET/CT in primary right eyelid lymphoma. AB - A 74-year-old man with right upper eyelid swell accepted FDG PET/CT examination, which showed an intensely FDG-avid soft tissue nodular mass within the eyelid. It was suggestive of malignancy. There was no evidence of active neoplastic disease elsewhere. The nodule was excised by surgery. Histopathological findings showed characteristic findings of diffuse large B-cell lymphoma. This case highlights the utility of FDG PET/CT in identifying rare types of lymphoma. PMID- 23455534 TI - Acute neck edema after (131)I ablation of the thyroid. AB - A 36-year-old woman with Graves' disease underwent thyroid ablation with oral I (20 mCi) following poor control of hyperthyroidism with carbimazole. Three days later, she presented to the emergency department with a choking sensation, shortness of breath, dysphagia, neck discomfort, and swelling. The prevertebral soft tissue was grossly thickened on the lateral neck radiograph. An urgent contrast-enhanced CT neck revealed severe neck edema and thyroiditis. TSH and free T4 levels were normal, and the neck swelling gradually resolved with corticosteroids. Acute neck edema is an infrequent complication of I ablation, and cross-sectional imaging is useful to exclude airway compromise or infection. PMID- 23455535 TI - Dynamic FDG PET/CT imaging with diuresis demonstrates an enterovesical fistula in a lymphoma patient with repeated colon diverticulitis. AB - A 43-year-old male patient with follicular B-cell lymphoma was referred for a FDG PET/CT scan due to severe left lower abdominal pain to rule out recurrent cancer. These FDG PET/CT images and previous FDG PET/CT images 5 months ago both revealed an air bubble in the urinary bladder on the CT images. He had a recurrent urinary tract infection history for 6 months. A list-mode dynamic data acquisition with diuresis intravenous injection revealed linear FDG activity extending from the upper-left portion of the bladder to a soft tissue mass in the lower-left pelvic region. An enterovesical fistula was confirmed by surgery. PMID- 23455536 TI - Coronary endothelial dysfunction demonstrated by means of (15)O-labeled water PET/CT in hypothyroid cardiomyopathy. AB - Hypothyroidism is a rare cause of dilated cardiomyopathy. Triiodothyronine was found to target endothelial nitric oxide synthase, which serves to enhance peripheral vascular relaxation by acting on vascular smooth muscle cells. In patients with subclinical hypothyroidism, adenosine-induced coronary flow reserve is significantly reduced. We report the case of a 46-year-old woman with hypothyroid cardiomyopathy manifested as reversible severe left ventricular dysfunction (LVEF = 32%). O-labeled water PET at rest and during cold pressor test showed a severe coronary endothelial dysfunction. In patients with severe hypothyroidism, endothelial function is impaired and may be an important mechanism of heart failure. PMID- 23455537 TI - Parathyroid hyperplasia shown on (99m)Tc-HYNIC-TOC scan. AB - A Tc-HYNIC-TOC scintigraphy was performed on a 68-year-old patient with hypercalcemia and borderline hypophosphatemia to assess the source of suspected tumor-induced osteomalacia. The images revealed increased activity in the upper mediastinum and focal activity in the pancreas. The lesion in the upper mediastinum was subsequently proven pathologically as parathyroid hyperplasia in a patient with multiple endocrine neoplasia type 1 (MEN-1 syndrome). PMID- 23455538 TI - The effect of placental removal method on perioperative hemorrhage at cesarean delivery; a randomized clinical trial. AB - PURPOSE: The aim of this prospective randomized clinical study is to compare whether the removal methods of placenta during cesarean section have an impact on perioperative hemorrhage. METHODS: One hundred women with singleton term pregnancies undergoing elective cesarean section through lower segment transverse incision under general anesthesia were included in this study. They were randomly allocated to two groups according to the type of removal of the placenta from the uterus after childbirth; manually or spontaneously. The main outcome measures were change in hemoglobin levels after cesarean section. The secondary outcomes were operative time, required transfusions and postcesarean endometritis. RESULTS: Fifty patients were randomized to the manual removal group and 50 to the spontaneous group. The demographic characteristics of the two groups were similar. There were no difference in terms of change in hemoglobin levels after cesarean section between two groups (1.6 +/- 1.0 and 1.5 +/- 1.0, respectively; P = 0.711). In addition, none of the patients required blood transfusion and showed postpartum infections. CONCLUSION: There is not an association between the method of removal of the placenta and postpartum blood loss in cesarean section deliveries. PMID- 23455539 TI - Late abortion. Attitudes amongst young physicians in Romania. AB - PURPOSE: The main purpose of this article is to analyze the way in which young physicians analyze and address the issue of therapeutic abortion. METHODS: A multi-institutional survey was conducted using an online questionnaire containing 10 items. RESULTS: Most respondents agreed with therapeutic abortion (1) if the fetus is not yet viable and the mother is put at immediate risk by the continuation of the pregnancy, and (2) when the pregnancy is over 14 weeks and the prenatal screening identifies a very severe malformation. The lowest rate of acceptance was obtained by the option to terminate the pregnancy after 14 weeks for a minor malformation (polydactyly). The vast majority agreed that the OG physician should be permitted to refuse an abortion on moral grounds, even if permitted by law. CONCLUSIONS: Our study reveals that the main reasons for conducting therapeutic abortion (TA) in the 2nd or 3rd trimester are: (1) if the mother is put in immediate risk by the continuation of the pregnancy and (2) if the congenital anomaly is extremely severe. Even though the number of respondents considering Down syndrome to be a congenital malformation severe enough to allow TA, the value much lower compared with other low and middle income countries. The main reasons for refusing TA in the 2nd or 3rd trimester are the presence of a minor congenital anomaly or if it is against the moral principles of the physician. PMID- 23455540 TI - Color Doppler ultrasound (CDU) in the diagnosis of obstructive hydronephrosis in pregnant women. AB - PURPOSE: Color Doppler ultrasound (CDU) accuracy of kidneys and bladder in the diagnosis and treatment of hydronephrosis and/or renal colic in pregnancies was evaluated. METHODS: Between January 2010 and September 2012, 234 pregnant women asymptomatic in 204 cases and with unilateral renal colic in 30 (median 26 years) were evaluated. A CDU of the urinary tract was performed using a sonograph GE Logiq 500 PRO with a multifrequency (3-5 MHz) convex probe. The following parameters were evaluated: resistive index (RI) of the arciform arteries of both kidneys and bilateral ureteric jets. A renal RI > 0.70 and/or a 10 % difference between the kidneys and an asymmetric and/or reduced ureteric jet from the ureteric orifices were considered as diagnostic of obstructive uropathy. RESULTS: Overall incidence of hydronephrosis was equal to 27 % (63 out 234 cases); the incidence of hydronephrosis, RI > 0.70 and abnormal ureteric jet in asymptomatic vs symptomatic pregnant women was equal to 30.9 vs 50 %, 16.1 vs 50 %, 3 vs 60 % (p < 0.05), respectively. In the 63 pregnancies with asymptomatic hydronephrosis RI and ureteric jet evaluation were abnormal in 39 (19.1 %) and 6 cases (3 %), respectively. In the 30 pregnancies with renal colic conventional ultrasound vs CDU, findings were abnormal in 15 (50 %) vs 20 (66.7 %) (p = 0.015) cases, respectively. CONCLUSIONS: Color Doppler ultrasound in pregnancies with hydronephrosis and/or renal colic improves conventional ultrasound accuracy; in fact, CDU adds a functional evaluation of the urinary tract when combined with clinical findings allows performing the appropriate management. PMID- 23455541 TI - Large or persistent lymphocyst increases the risk of lymphedema, lymphangitis, and deep vein thrombosis after retroperitoneal lymphadenectomy for gynecologic malignancy. AB - PURPOSE: This retrospective study examined the incidence of lymphocyst formation after retroperitoneal lymphadenectomy in patients with gynecologic malignancy as well as the relation between lymphocyst formation and such complications as lymphedema, lymphangitis, ileus, and deep vein thrombosis (DVT). METHODS: Three hundred twenty-one patients who underwent primary surgery with pelvic (90 patients) or combined pelvic and paraaortic lymphadenectomy (231 patients) for gynecologic malignancy between January 2001 and December 2009 were enrolled. The incidences of lymphocyst identified by computed tomography at 3 weeks and 1 year after surgery were analyzed in relation to the types of surgery and types of complications. RESULTS: At 3 weeks after surgery, lymphocysts were observed in 282/321 patients (88 %). At 1 year after surgery, lymphocysts persisted in 69 patients (21 %). Lymphedema was observed in 34/321 (11 %) patients, lymphangitis in 36/321 (11 %), ileus in 14/321 (4 %), and DVT in 24/321 (7 %). The incidence of lymphedema was significantly greater in patients with persistent lymphocyst than in those with without (17 vs. 9 %) (p = 0.038); the incidences of lymphangitis (20 vs. 9 %) (p = 0.007) were also greater in this group. Multivariate analysis showed a large lymphocyst (>50 mm) at 3 weeks after surgery to be an independent risk factor for lymphedema (odds ratio 2.76, p = 0.009). CONCLUSIONS: A large lymphocyst at 3 weeks after surgery or persistent lymphocyst increases the risk of lymphedema, lymphangitis, and DVT. PMID- 23455542 TI - Seroprevalence and clinico-epidemiological correlates of hepatitis C viral antibodies at an antenatal booking clinic of a tertiary hospital in Nigeria. AB - PURPOSE: This was to determine the sero-prevalence of hepatitis C viral (HCV) antibodies in pregnant women attending the first antenatal clinic and assess the epidemiologic correlates of women anti-HCV positive. METHODS: This was a prospective observational study which used in vitro diagnostic test kits to detect anti-HCV antibodies. Women attending their first antenatal clinic were recruited at the antenatal clinic of Irrua Specialist Teaching Hospital, Edo State, Nigeria. Seropositive women had liver enzymes assessed, and screening for hepatitis B surface antigen and Human Immuno-deficiency Virus (HIV) was done. RESULTS: Eight out of 205 women were anti-HCV positive. The prevalence of hepatitis C infection was 3.9 %. The mean age of the women was 28.9 +/- 2.1 years. Most (50 %) anti-HCV positive women had tertiary level education. Though health workers made up 3.5 % of the participants, they constituted 25 % women with anti-HCV antibody. Awareness of HCV infection had no impact on the rate of infection. Multiple sexual partners (P = 0.71), blood transfusion (0.64) and female circumcision (P = 1.00) were not significant risks of infection. 2 (1 %) women had hepatitis B co-infection and 1 (12.5 %) woman had both HCV antibody and HIV co-infection. CONCLUSION: Despite the 3.9 % prevalence, routine screening for hepatitis C virus infection in pregnancy is unjustified. Risk-based screening using locally prevailing risk factors with antenatal monitoring and postpartum treatment of women with hepatitis C antibodies is recommended. PMID- 23455543 TI - NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. AB - Nicotinamide N-methyltransferase (NNMT) is overexpressed in a variety of human cancers, where it contributes to tumorigenesis by a mechanism that is still poorly understood. Here we show using metabolomics that NNMT impairs the methylation potential of cancer cells by consuming methyl units from S-adenosyl methionine to create the stable metabolic product 1-methylnicotinamide. As a result, NNMT-expressing cancer cells have an altered epigenetic state that includes hypomethylated histones and other cancer-related proteins combined with heightened expression of protumorigenic gene products. Our findings thus point to a direct mechanistic link between the deregulation of a metabolic enzyme and widespread changes in the methylation landscape of cancer cells. PMID- 23455544 TI - Atomic-resolution monitoring of protein maturation in live human cells by NMR. AB - We use NMR directly in live human cells to describe the complete post translational maturation process of human superoxide dismutase 1 (SOD1). We follow, at atomic resolution, zinc binding, homodimer formation and copper uptake, and discover that copper chaperone for SOD1 oxidizes the SOD1 intrasubunit disulfide bond through both copper-dependent and copper-independent mechanisms. Our approach represents a new strategy for structural investigation of endogenously expressed proteins in a physiological (cellular) environment. PMID- 23455546 TI - ROS regulation of microdomain Ca(2+) signalling at the dyads. AB - Reactive oxygen species (ROS) are emerging as centre-stage players in cardiac functional regulation. ROS and Ca(2+) signals converge at dyads, the structural and functional units of cardiac excitation-contraction coupling. These two prominent signalling systems are intertwined with ROS modulation of the entire Ca(2+)-signalling network, and vice versa. While constitutively generated homoeostatic ROS are important in setting the redox potential of the intracellular milieu, dynamic signalling ROS shape microdomain and global Ca(2+) signals on both the beat-to-beat and greater time scales. However, ROS effects are complex and subtle, characterized by multiphasic and bidirectional Ca(2+) responses; and sustained oxidative stress may lead to compromised contractility and arrhythmogenicity. These new understandings should be leveraged to harness ROS for their beneficial roles while avoiding deleterious effects in the heart. PMID- 23455547 TI - Osteopontin deficiency dampens the pro-atherogenic effect of uraemia. AB - AIMS: Uraemia is a strong risk factor for cardiovascular disease. Osteopontin (OPN) is highly expressed in aortas of uraemic apolipoprotein E knockout (E KO) mice. OPN affects key atherogenic processes, i.e. inflammation and phenotypic modulation of smooth muscle cells (SMCs). We explored the role of OPN on vascular pathology in uraemic mice. METHODS AND RESULTS: Uraemia was induced by 5/6 nephrectomy in E KO and in OPN and E double KO mice (E/OPN KO). In E KO mice, uraemia increased the relative surface plaque area in the aortic arch (from 28 +/ 2% [n = 15], to 37 +/- 3% [n = 20] of the aortic arch area, P < 0.05). A positive correlation was observed between plasma OPN and aortic atherosclerosis in uraemic E KO mice (r(2) = 0.48, P = 0.001). In contrast, aortic atherosclerosis was not increased by uraemia in E/OPN KO mice. OPN deficiency in haematopoietic cells (including macrophages) did not affect development of uraemic atherosclerosis, even though OPN-deficient foam cells had decreased inflammatory capacity. Gene expression analyses indicated that uraemia de differentiates SMCs in the arterial wall. This effect was dampened in whole-body OPN-deficient mice. CONCLUSION: The data suggest that OPN promotes development of uraemic atherosclerosis possibly by changing the phenotype of vascular smooth muscle cells. PMID- 23455550 TI - [The health status of the German workforce and its role in labor market participation]. PMID- 23455548 TI - Over-expression of calpastatin aggravates cardiotoxicity induced by doxorubicin. AB - AIMS: Doxorubicin causes damage to the heart, which may present as cardiomyopathy. However, the mechanisms by which doxorubicin induces cardiotoxicity remain not fully understood and no effective prevention for doxorubicin cardiomyopathy is available. Calpains, a family of calcium-dependent thiol-proteases, have been implicated in cardiovascular diseases. Their activities are tightly controlled by calpastatin. This study employed transgenic mice over-expressing calpastatin to investigate the role of calpain in doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Doxorubicin treatment decreased calpain activities in cultured neonatal mouse cardiomyocytes and in vivo mouse hearts, which correlated with down-regulation of calpain-1 and calpain 2 proteins. Over-expression of calpastatin or incubation with pharmacological calpain inhibitors enhanced apoptosis in neonatal and adult cardiomyocytes induced by doxorubicin. In contrast, over-expression of calpain-2 but not calpain 1 attenuated doxorubicin-induced apoptosis in cardiomyocytes. The pro-apoptotic effects of calpain inhibition were associated with down-regulation of protein kinase B (AKT) protein and mRNA expression, and a concomitant reduction in glycogen synthase kinase-3beta (GSK-3beta) phosphorylation (Ser9) in doxorubicin treated cardiomyocytes. Blocking AKT further increased doxorubicin-induced cardiac injuries, suggesting the effects of calpain inhibition may be mediated by inactivating the AKT signalling. In an in vivo model of doxorubicin-induced cardiotoxicity, over-expression of calpastatin exacerbated myocardial dysfunction as assessed by echocardiography and haemodynamic measurement in transgenic mice 5 days after doxorubicin injection. The 5-day mortality was higher in transgenic mice (29.16%) compared with their wild-type littermates (8%) after doxorubicin treatment. CONCLUSION: Over-expression of calpastatin enhances doxorubicin induced cardiac injuries through calpain inhibition and thus, calpains may protect cardiomyocytes against doxorubicin-induced cardiotoxicity. PMID- 23455549 TI - Multi-channel blockers for treatment of atrial fibrillation: an effective strategy? PMID- 23455551 TI - [Perspectives of work, age, health, and labor market participation in Germany]. AB - The German population is aging and shrinking. This will have a significant impact on the labor market, because labor supply will start to shrink. Consequently, there is a need to develop additional labor market resources. In this setting, a crucial issue is the health and employment of the older working population. This article discusses--on the basis of nine articles in this special issue--the health of the working population in the context of work, age, and labor participation. It shows the diversity of morbidity in the work force in general and particularly in older age, and it identifies older labor force groups with good health and those with bad health. The latter shows that "working while having a bad state of health" is today's reality. Labor market participation is less dependent on health than on the "work ability" and/or the "motivation to work" of older workers. The employment dynamics of an aging population will be a key issue in future political debate. A reliable knowledge base is needed for proper discussion, judgment, and action in the economic, political, and social fields. Current research is often focused on subtopics or on subgroups; however, a network of all the related scientific disciplines and the establishment of new comprehensive research approaches are needed in this area. PMID- 23455552 TI - [Self-rated general health by occupation and age in the working population in Germany]. AB - In occupations, self-rated general health status was examined under special consideration of age. Data from the GEDA 2009 and 2010 surveys (N = 26,303) were analyzed. Professionals had a low prevalence of poor health, whereas unskilled service workers and-among males-unskilled manual workers had a high prevalence. In older workers the prevalence of poor general health was greater than among younger workers. However, the difference in health between young and old was significantly smaller than the general pattern among male managers and women in skilled commercial and administrative occupations. Among male skilled workers and female unskilled manual workers, the difference in health between young and old was greater. The-with increasing age-growing health gap between occupational groups should receive more attention. In order to understand the relationship between work, age and health, targeted longitudinal sectional studies are needed. It might be misleading to adjust associations between work and health by age, because age might moderate this relationship. PMID- 23455553 TI - [Age, job groups, and psychological well-being]. AB - This study examines whether psychological well-being in different job groups is affected by gender and age. Data from the survey 'Gesundheit in Deutschland aktuell' were used, which was carried out during 2009/2010 by the Robert Koch Institute. Information was available for 14,693 employed and unemployed men and women aged 18-64 years. Job groups were differentiated according to the Blossfeld classification. Psychological well-being was measured with the Mental Health Inventory. Men and women in more qualified jobs had better well-being than those in less qualified work. The lowest well-being was found for women in job groups with a high amount of unskilled work. For all job groups, men aged 55-64 years tended to have better well-being than those aged 45-54 years. Among women of older age, there was a tendency for well-being to be lower in the unskilled and semiprofessional groups, but on the same level or better in the more qualified job groups. The reason for this might be the imbalance between the demands of work/personal life and the functional capacity of the individual, which especially applies to women and is further affected by a lack of relief, for example, because of economic pressure. This cumulative strain may be more evident in older working ages. PMID- 23455554 TI - [Age- and occupation-related differences in sick leave due to frequent musculoskeletal disorders. Low back pain and knee osteoarthritis]. AB - Musculoskeletal disorders are the leading cause of sick leave. Because of the importance of back pain and knee osteoarthritis (ICD-10 diagnoses M54 and M17), these conditions are considered in detail. The aim of this study was to clarify whether job-specific differences in the incidence of sick leave events due to these disorders vary depending on age. The study was based on a secondary analysis of data on sick leave from almost all statutory health insurances in 2008. The database contains aggregated data on sick leave of approximately 26.2 million insured employees. The occurrence of sick leave events resulting from the M54 and M17 diagnoses was defined as the outcome variable. The assignment of employees to occupational groups (Blossfeld classification) was considered as the exposure variable. We calculated the morbidity ratios (SMR) of sick leave occurrence stratified by sex and age. The risk of sick leave was increased for both genders and for both diagnoses, particularly in the occupational groups of the production and service industries with low and medium skill level, even after stratification according to age. Sick leave due to these disorders is a significant issue in these occupations regardless of age, and must be considered with regard to social and preventive aspects. PMID- 23455555 TI - [Occupation- and age-related differences in work absence due to frequent cardiovascular diseases using essential hypertension and acute myocardial infarction as examples]. AB - Cardiovascular diseases (CVD) are responsible for a major part of morbidity and mortality. Based on two selected diagnoses (ICD-10) "essential hypertension" (I10) and "acute myocardial infarction" (AMI, I21) the occupational- and age dependent increases in sick leave are described. The secondary data analysis is based on gender-stratified, pooled data (26.2 million legally insured) on sick leave of the German social security workforce in 2008. The number of sick leave cases stratified by sex and age were calculated. Indirectly standardized morbidity ratios (SMR) for the occurrence of sick leave cases stratified by age and occupational groups (according to Blossfeld) with 99.99% confidence intervals are estimated. Age had an influence on the professional group-dependent sick leave. In the youngest age group, a similar risk existed for hypertension and AMI in all occupational groups. In the middle and older age groups, low-skilled service workers and manual occupations had increased risks for both men and women as compared to the occupational group of qualified sales and administrative occupations. Because the workforce is expected to continue to age in the future, primary and secondary prevention of CVD in all age groups is strongly recommended. PMID- 23455556 TI - [Disability retirement risk for different occupations in Germany]. AB - The risk of disability retirement due to long-term illness increases with age and is higher for low-skilled employees. Several studies have shown that low occupational status increases the risk of severe illness. The topic of this analysis is the relative risk of becoming a disability pensioner for different occupational groups (according to the Blossfeld classification) in Germany. The analysis is based on longitudinal data from the German pension office. The hazard risk of invalidity until the age of 59 years is shown for different occupational groups. Survival analysis shows that the highest risk of invalidity exists for low-qualified office clerks or service staff for men and women alike. The already increased disability risk between the ages of 40 and 50 in these occupations can be regarded as an early warning for the higher risk later in life. No such warning signs can be found among professions such as nurses and social workers. However, these groups have the highest risk of disability retirement among women. PMID- 23455557 TI - [Demography and labor shortage. Future challenges of labor market policy]. AB - For demographic reasons, the German labor force will decrease dramatically and it will be much older on average. However, labor demand, especially for qualified workers, is expected to remain high. This paper focuses on the possibilities of expanding the labor force by increasing the participation rates of women and older persons. Herein, the change in the labor force is decomposed with respect to population and labor participation and, moreover, the effects of higher participation rates are simulated. The decomposition and simulation scenarios are based on data published by the Institute for Employment Research. The analysis clearly reveals that the effect of a considerably higher labor participation of women and older workers will disappear over time when the working-age population shrinks more and more. In addition, individuals who are currently unemployed or out of the labor force are not skilled enough. Since it seems difficult to get more qualified workers in the short and even in the medium term, improving the conditions for women and older people to take up jobs should be tackled soon. This includes investments in education and health care. PMID- 23455558 TI - Workers with a chronic disease and work disability. Problems and solutions. AB - The prevalence of chronic diseases in the age group 18-65 years is high. Cardiometabolic conditions and musculoskeletal diseases are the most frequent chronic diseases. Depending on disease and comorbidity, the employment rates are considerably lower than for healthy individuals. Chronically ill workers may have problems in meeting job demands, they may experience physical, cognitive or sensory limitations, have fatigue or pain complaints or other disease symptoms. Psychological distress, depressive feelings, feelings of shame or guilt, lack of coping or communicative skills, and non-supportive colleagues and supervisors may add to work-related problems. The ICF Model (International Classification of Functioning, Disability and Health) of the WHO offers a framework for understanding and considering health-related problems at work and finding solutions. Interventions to prevent problems in functioning, sickness absence and work disability may focus on the worker, the workplace, or health care. Multidisciplinary vocational rehabilitation, exercise therapy, cognitive behavioural interventions, workplace interventions and empowerment are interventions with at least some evidence of effectiveness. Future policy could focus more on promotion of workers' health and future research should include the interests and motivations of employers concerning disability management, skills of line managers, the feasibility of interventions to prevent work disability and the context sensitivity of study outcomes. PMID- 23455559 TI - [Work, age, health, and work participation. A theoretical model]. AB - Research into the associations between work, age, and health and the impact of these associations on employment status has focused on health as a crucial determinant of staying on the job. In our paper, we ask whether concentrating on health is still feasible, particularly when considering the change in demographics and the increasing proportion of older people in the workplace. We introduce a theoretical model describing health as a variable that indirectly influences leaving employment. According to our model, the immediate decision to leave employment is due to work motivation and work ability. These two factors may require intervention activities different from those needed to improve health. Our model explains employment participation as a result of complex associations between work, socioeconomic status, lifestyle, and health especially with work ability and work motivation. The complexity of these processes should be considered in studies by conducting longitudinal investigations like the German lidA study (http://www.lida-studie.de). If the model is verified in scientific studies like lidA, it can be used as a basis for preventive and intervening activities in practice, i.e., in politics, enterprises, and science. PMID- 23455560 TI - [Changes in the nature of work]. AB - "Dynamic", "complexity", and "diversity" are terms that best describe the challenges in the workplace resulting from the changing nature of work. These changes should conform to the criteria of human-related work design. However, the number of pensions for reduced earning capacity and the number of unfit for work days caused by psychic disorders are rising. Affective disorders, including depression, are the largest group. Depression represents a long-term consequence of work demands. Empirical results confirm a significant relationship between depression and the objective existing as well as the subjective perceived workload conditions. Burn-out as a further long-term consequence depends inter alia on the design of the physical work demands, the environmental conditions, the psychosocial conditions, and the transparency of the decision and information processes in a company. Additionally, empirical results show that the short-term consequences of work demands, i.e., fatigue, satiation, and monotony correlate with the burn-out components of exhaustion and alienation from work. Furthermore, using restructuring as an example, it is demonstrated that the changes in work that accompany modifications in the working world also have other health-related consequences. PMID- 23455561 TI - [Calculation of disease-related costs in claims data analyses with the example of attention-deficit hyperactivity disorder. Comparison of methods]. AB - Claims data have proven useful for carrying out cost-of-illness studies. To avoid overestimating disease-related costs, only those costs that are related to a specific disease should be considered. The present study demonstrates two basic approaches for identifying disease-related costs. Using the example of attention deficit hyperactivity disorder (ADHD), the advantages and drawbacks of expert based approaches and those based on control groups are compared. Anonymized data from the "Techniker Krankenkasse" for 2008 were available for the study. The study population encompassed all ADHD patients and a control group that was five times bigger. Additionally, a systematic literature review was carried out on 65 relevant studies. Compared with the control group, disease-related costs were EUR 2,902 per ADHD patient on average. However, using the expert-based approach, costs were established to be EUR 923 lower. This is mainly because a comparison with an appropriate control group incorporates all costs for possible comorbidities and concomitant diseases. Both approaches have specific advantages and drawbacks, and when planning studies the respective limitations need to be considered. PMID- 23455562 TI - [Minimum requirements for the microbiological control of blood components for transfusion. Update of the vote 16]. PMID- 23455563 TI - [Update of the votes and 34 35 "method for tracing (lookback) (in accordance with 19 Transfusion Law)" from 14.06.2006 with regard to hepatitis B infection]. PMID- 23455564 TI - Reproducibility, fidelity, and discriminant validity of linear RNA amplification for microarray-based identification of major human enteric viruses. AB - Human enteric viruses are inherently a group of viruses that confer similar or overlapping clinical symptoms and pose a challenge for correct etiological diagnosis. DNA microarray technology has emerged to be of major interest to detect broad range of viral pathogens including enteric viruses. However, this approach requires a relative large amount of target nucleic acid for hybridization analysis. This feature limits its further applicability. To address this challenge, we evaluated a novel single primer linear isothermal amplification (Ribo-SPIA) procedure for preparation of single-stranded cDNA (sscDNA) from minute amount of starting RNA for microarray-based simultaneous detection and identification of three major human enteric viruses including hepatitis A virus, norovirus, and coxsachievirus B2. We performed a series of tests using different amounts of input RNA ranging from 30 ng to 55 pg to assess amplification yield, reproducibility, analytical sensitivity, and fidelity. We demonstrated that as little as 55 pg of viral RNA could produce adequate material by Ribo-SPIA to enable successful identification by microarray analysis without compromising detection specificity. Pairwise comparison of technical replicates hybridized to the microarrays by regression analysis showed excellent reproducibility in the appropriate sensitivity range. We also showed that the use of sscDNA as labeled targets offered increased microarray detection accuracy over complementary RNA generated by traditional T7 in vitro transcription amplification method. PMID- 23455565 TI - The biotechnological use and potential of plant pathogenic smut fungi. AB - Plant pathogens of the family Ustilaginaceae parasitise mainly on grasses and cause smut disease. Among the best characterised members of this family are the covered smut fungus Ustilago hordei colonising barley and oat as well as the head smut Sporisorium reilianum and the corn smut Ustilago maydis, both infecting maize. Over the past years, U. maydis in particular has matured into a model system for diverse topics like plant-pathogen interaction, cellular transport processes or DNA repair. Consequently, a broad set of genetic, molecular and system biological methods has been established. This set currently serves as a strong foundation to improve existing and establish novel biotechnological applications. Here, we review four promising aspects covering different fields of applied science: (1) synthesis of secondary metabolites produced at fermenter level. (2) Lipases and other hydrolytic enzymes with potential roles in biocatalytic processes. (3) Degradation of ligno-cellulosic plant materials for biomass conversion. (4) Protein expression based on unconventional secretion, a novel approach inspired by basic research on mRNA transport. Thus, plant pathogenic Ustilaginaceae offer a great potential for future biotechnological applications by combining basic research and applied science. PMID- 23455566 TI - Characterization of cry9Da4, cry9Eb2, and cry9Ee1 genes from Bacillus thuringiensis strain T03B001. AB - Three cry9 genes, cry9Da4, cry9Eb2, and cry9Ee1, were cloned from Bacillus thuringiensis strain T03B001 using a high-resolution melting analysis method. All three cry9 genes were overexpressed in Escherichia coli Rosetta (DE3), and the expressed products Cry9Eb2 and Cry9Ee1 were shown to be toxic to Plutella xylostella and Ostrinia furnacalis, but not to Helicoverpa armigera or Colaphellus bowringi. The bioassay of Cry9Eb2 and Cry9Ee1 against Cry1Ac resistant P. xylostella strains indicated that both novel Cry9 toxins exhibited no cross-resistance with Cry1Ac. Cry9Eb2 and Cry9Ee1 can be applied not only for P. xylostella and O. furnacalis control, but also for the Cry1Ac-resistance management of pests. PMID- 23455567 TI - Bridging the gap between qualitative and quantitative colocalization results in fluorescence microscopy studies. AB - Quantitative colocalization studies suffer from the lack of unified approach to interpret obtained results. We developed a tool to characterize the results of colocalization experiments in a way so that they are understandable and comparable both qualitatively and quantitatively. Employing a fuzzy system model and computer simulation, we produced a set of just five linguistic variables tied to the values of popular colocalization coefficients: "Very Weak", "Weak", "Moderate", "Strong", and "Very Strong". The use of the variables ensures that the results of colocalization studies are properly reported, easily shared, and universally understood by all researchers working in the field. When new coefficients are introduced, their values can be readily fitted into the set. PMID- 23455569 TI - Oxime-based carbonates as useful reagents for both N-protection and peptide coupling. AB - We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-protection and peptide coupling. PMID- 23455568 TI - The evolutionary consequences of alternative types of imperfect vaccines. AB - The emergence and spread of mutant pathogens that evade the effects of prophylactic interventions, including vaccines, threatens our ability to control infectious diseases globally. Imperfect vaccines (e.g. those used against influenza), while not providing life-long immunity, confer protection by reducing a range of pathogen life-history characteristics; conversely, mutant pathogens can gain an advantage by restoring the same range of traits in vaccinated hosts. Using an SEIR model motivated by equine influenza, we investigate the evolutionary consequences of alternative types of imperfect vaccination, by comparing the spread rate of three types of mutant pathogens, in response to three types of vaccines. All mutant types spread faster in response to a transmission-blocking vaccine, relative to vaccines that reduce the proportion of exposed vaccinated individuals becoming infectious, and to vaccines that reduce the length of the infectious period; this difference increases with increasing vaccine efficacy. We interpret our results using the first published Price equation formulation for an SEIR model, and find that our main result is explained by the effects of vaccines on the equilibrium host distribution across epidemiological classes. In particular, the proportion of vaccinated infectious individuals among all exposed and infectious hosts, which is relatively higher in the transmission-blocking vaccine scenario, is important in explaining the faster spread of mutant strains in response to that vaccine. Our work illustrates the connection between epidemiological and evolutionary dynamics, and the need to incorporate both in order to explain and interpret findings of complicated infectious disease dynamics. PMID- 23455570 TI - Tetraanionic N2O2-coordinating ligands as potential building blocks for supramolecular magnetic networks. AB - A bisoxamate ligand containing three different types of coordination sites was designed and synthesized. The developed synthetic strategy was adopted to prepare a related 1,2-bis(2-hydroxybenzamido)benzene-derived ligand. Nickel(II) complexes of both the novel ligands were obtained and characterized by X-ray crystallography, NMR, electronic absorption spectroscopy, and theoretical calculations. PMID- 23455571 TI - Alignment of graphene sheets in wax composites for electromagnetic interference shielding improvement. AB - Rapid advancements in carbon-based fillers have enabled a new and more promising platform in the development of electromagnetic attenuation composites. Alignment of fillers in composites with specific structures and morphologies has been widely pursued to achieve high performance based on taking advantage of unique filler characteristics. In this work, few-layer graphene (FLG), obtained from direct exfoliation of graphite, was fabricated into paraffin wax to prepare FLG/wax composites and investigate their electromagnetic interference (EMI) shielding performance. The as-exfoliated FLG/wax samples have shown much improved EMI performance compared to the commercial graphite/wax ones. For further improvement of EMI shielding performance, split-press-merge approaches were applied to align the FLG fillers to achieve anisotropic characteristics in the plane perpendicular to the pressing direction. Much enhanced EMI shielding performance coupled with an improvement in absorption and reflection was observed in the post-alignment FLG/wax composites. An average interparticle distance model associated with improved electrically conducting interconnection and enlarged effective reflection regions with respect to enhanced reflection efficiency were discussed. The results suggest a platform and promising opportunities for preparing high-performance EMI shielding composites. PMID- 23455572 TI - Norrish Type I surface photochemistry for butyrophenone on TiO2(110). AB - The photofragmentation of butyrophenone yields benzoate and a propyl radical on oxidized TiO2(110). Oxygen dissociates in native oxygen vacancies to produce reactive oxygen adatoms which react with butyrophenone to create photoactive butyrophenone-O complexes that are sensitive to hole oxidation created upon UV illumination. The same O adatoms also trap one of the primary photoproducts, phenyl-CO, to produce benzoate. The reaction proceeds via a Norrish Type I like process involving alpha-CC cleavage on the surface, in contrast to the gas phase where a Norrish Type II pathway predominates. The mechanism is probed using mass spectrometry and, for the first time, scanning tunneling microscopy (STM). Our STM experiments show that there is a 1-to-1 correspondence between the immobile butyrophenone-O complex and formation of a benzoate on the surface. We also demonstrate that the benzoate species is in close proximity to the original butyrophenone complex, indicating that benzoate is produced on a time scale more rapid than diffusion of the photoproducts. While the photoproducts of butyrophenone decomposition are similar to ketone oxidation reported previously, butyrophenone reacts via a different starting ground state, based on STM and density functional theory studies. Specifically, butyrophenone does not produce a dioxyalkylene species, which has been proposed to be the photoactive state for other ketones. Based on a combination of STM experiments and density functional theory, we propose that a peroxy-like configuration where the oxygen adatom stabilizes the butyrophenone through its carbonyl oxygen is the surface intermediate that photodecomposes. These results demonstrate the importance of the excited state in determining the photochemistry of ketones on surfaces. PMID- 23455573 TI - Randomization in clinical trials: stratification or minimization? The HERMES free simulation software. AB - OBJECTIVES: Operative clinical trials are often small and open-label. Randomization is therefore very important. Stratification and minimization are two randomization options in such trials. The first aim of this study was to compare stratification and minimization in terms of predictability and balance in order to help investigators choose the most appropriate allocation method. Our second aim was to evaluate the influence of various parameters on the performance of these techniques. MATERIALS AND METHODS: The created software generated patients according to chosen trial parameters (e.g., number of important prognostic factors, number of operators or centers, etc.) and computed predictability and balance indicators for several stratification and minimization methods over a given number of simulations. Block size and proportion of random allocations could be chosen. A reference trial was chosen (50 patients, 1 prognostic factor, and 2 operators) and eight other trials derived from this reference trial were modeled. Predictability and balance indicators were calculated from 10,000 simulations per trial. RESULTS: Minimization performed better with complex trials (e.g., smaller sample size, increasing number of prognostic factors, and operators); stratification imbalance increased when the number of strata increased. An inverse correlation between imbalance and predictability was observed. CONCLUSIONS: A compromise between predictability and imbalance still has to be found by the investigator but our software (HERMES) gives concrete reasons for choosing between stratification and minimization; it can be downloaded free of charge. CLINICAL RELEVANCE: This software will help investigators choose the appropriate randomization method in future two-arm trials. PMID- 23455574 TI - Contact allergies to potential allergens in patients with oral lichen lesions. AB - OBJECTIVE: The aim of the present controlled study was to investigate a possible relationship between contact allergies to potential allergens and oral lichen lesions. METHODS: Eighty-three patients with oral lichen lesions (OLL) and control groups of age- and gender-matched dermatitis patients (DP, n = 83) and patch-tested dermatitis patients randomly selected from files (PSFF, n = 319) were included in the study. OLL and DP groups were patch-tested epicutaneously and examined intraorally. RESULTS: The frequencies of contact allergy to mercury and carvone were statistically higher in the OLL group than in the DP group. Surfaces of amalgam and composite restorations were statistically more frequent in the OLL group compared to the DP group. Contact allergy to nickel and colophony, the latter with a statistically significant difference, was more common in the DP group. The numerical difference found for nickel allergy was, however, not significant comparing the OLL and PSFF groups. CONCLUSION: Contact allergy to mercury was overrepresented in patients with OLL and has been reported in previous studies, but the present finding of an overrepresentation of contact allergy to carvone in patients with oral lichen lesions has not been reported previously. CLINICAL RELEVANCE: Carvone, in addition to mercury and gold, as previously suggested, can be one of the causative or maintenant factors for oral lichen lesions. Carvone-hypersensitive patients with oral lichen lesions should therefore avoid carvone-containing products for oral use. PMID- 23455575 TI - Globulomaxillary cysts--do they really exist? AB - OBJECTIVES: The so-called "globulomaxillary cyst", described as a fissural cyst, caused by entrapped epithelium between the nasal and maxillary process, is no longer considered for its own entity. Nevertheless, cystic lesions, which correspond to the previous image of globulomaxillary cysts, do still occur in daily practice. This raises the question to which entities pathological processes in this particular region actually belong to. MATERIALS AND METHODS: In a retrospective study, 17 cases (12 men and 5 women, 12-59 years old) of primarily diagnosed globulomaxillary cysts are analysed according to clinical, radiological and histological aspects, catamnestic processed and assigned to a new entity. The results are compared with the international literature and draws conclusions on the diagnostic and therapeutic procedure. RESULTS: Seven lateral periodontal cysts, four radicular cysts, two keratocystic odontogenic tumours, one adenomatoid odontogenic tumour, one periapical granuloma, one residual cyst and one undefined jaw cyst were determined. CONCLUSIONS: According to the results of our study and the data from the international literature, the entity globulomaxillary cyst is no longer justified. PMID- 23455576 TI - Amalgam and ART restorations in children: a controlled clinical trial. AB - OBJECTIVES: The aims of this study were to compare 2-year cumulative survival rates of amalgam and atraumatic restorative treatment (ART) restorations in primary molars and to investigate the determinants of the survival rate of restorations. MATERIALS AND METHODS: A controlled clinical trial using a parallel group design was carried out on 258 children aged 6-7 years old, allocated to two treatment groups: conventional restorative treatment using amalgam and ART using high-viscosity glass ionomer. A total of 364 amalgam restorations and 386 ART restorations were placed by three pedodontists in 126 and 158 children, respectively, and were evaluated after 0.5, 1, and 2 years. Restorations were placed in vital primary molars with neither pain nor signs of pulp involvement. The survival analysis was conducted using the proportional hazard rate regression model with frailty correction. RESULTS: The 2-year cumulative survival rates for all amalgam (77.3%) and ART (73.5%) restorations were not statistically significantly different, but there was an effect of "type of surface" (single/multiple) and "cavity filling time" on the survival rates. Both amalgam and ART single-surface restorations had higher survival rates than multiple surface restorations of the same material. Secondary caries was responsible for 36 and 38% of failures in amalgam and ART restorations, respectively. Mean time for restoring all type of cavities with amalgam and ART restorations was 13.6 and 13.7 min, respectively. CONCLUSIONS: Amalgam and ART restorations presented similar survival rates over a 2-year period for all, single-surface, and multiple surface restorations. CLINICAL RELEVANCE: In the cause of finding alternatives to amalgam, ART restorations using high-viscosity glass ionomer might be a suitable option for managing cavitated dentine carious lesions in vital primary molars. PMID- 23455577 TI - Revision nasal surgery after septoplasty: trainees versus trainers. AB - Otolaryngology trainees are expected to be able to successfully perform septoplasty early in their career. An important parameter to assess the success of an operation is to look at the revision surgery rate. This study aimed to investigate the revision nasal surgery rate after septoplasty based on the grade of the primary surgeon. Retrospective review of hospital records of all patients who underwent septoplasty with or without inferior turbinate reduction over 12 years (1998-2010) in a tertiary referral centre in North-East Scotland. Patients were identified from theatre log books and were excluded if they underwent any other simultaneous nasal procedure. Data were collected on demographics, type of primary and revision surgery, grade of surgeon and duration of hospital stay. 2,168 eligible patients (70 % male, 30 % female) with a mean age of 39 years were investigated. Surgeons were divided into four categories: junior trainee (Group A), senior trainee (Group B), staff grade (Group C) and consultant (Group D). There were 753, 644, 298 and 473 patients in Groups A, B, C and D, respectively. The revision rate in Group A was 4.4 % compared to 3.2 % for Group D and this difference was not statistically significant. For their operation, patients in Group A stayed for 1.54 nights compared to 1.47 nights in Group D, the difference being insignificant. Grade of the surgeon does not appear to strongly affect the need for revision nasal surgery and our patients do not appear to be disadvantaged if operated on by trainees. PMID- 23455578 TI - Delayed diagnosis and treatment of benign paroxysmal positional vertigo associated with current practice. AB - The purposes of this study were to demonstrate the current status of benign paroxysmal positional vertigo (BPPV) management and the advantages of repositioning maneuvers as well as to facilitate the accurate and efficient diagnosis and management of BPPV. Of 131 participants with severe dizziness/vertigo who were examined and treated, 31 (23.7%) fulfilled the diagnostic criteria for BPPV. All patients in the study had a diagnosis of BPPV confirmed by their history, typical subjective symptom reports, and characteristic positional nystagmus during the Dix-Hallpike test and/or roll test. All participants were comprehensively interviewed regarding their medical history, characteristics of the first attack of vertigo, associated symptoms, previous financial costs, and number of hospital visits. The average duration from the appearance of the first symptoms until a final diagnostic positional maneuver was >70 months. On average, patients visited hospitals more than eight times before the final diagnosis due to initial visits to inappropriate departments, including neurology, emergency, orthopaedic surgery, and Traditional Chinese Medicine, with a corresponding average financial cost of more than 5,000 RMB. The canalith repositioning procedure (CRP) was effective in 80.65% of patients after the first repositioning maneuver. Our data demonstrated that despite the significant prevalence of BPPV, delays in diagnosis and treatment frequently occur, which have both cost and quality-of-life impacts on both patients and their caregivers. The CRP is very effective for patients with BPPV. It is important for patients to pay more attention to the impact of BPPV on their lives and recognize its nature to ensure compliant follow-up in otolaryngology. PMID- 23455579 TI - Treatment outcomes and compliance according to obesity in patients with obstructive sleep apnea. AB - The objective of this study was to assess treatment outcomes and compliance according to obesity among groups of patients with obstructive sleep apnea (OSA) receiving different treatments. A total of 297 patients with OSA treated between 2006 and 2009 underwent pre- and post-treatment polysomnography. One hundred and fifty-one patients were treated with continuous airway positive pressure (CPAP), 76 with mandible advancement device (MAD), and 70 with oropharyngeal surgery. All patients were classified according to obesity. Treatment success rate and compliance of CPAP were analyzed according to obesity. For each treatment modality, the overall treatment success rate was not significantly different between obese and non-obese patients. However, the oxygen desaturation index was different in patients who were treated with MAD and surgery. Additionally, obese patients with severe OSA showed an unfavorable response to CPAP treatment. For CPAP compliance, obese patients showed a tendency to be highly compliant with CPAP treatment at 12 months than non-obese patients. This study showed that obesity might be a factor in determining the success or failure of treatment. Additionally, obesity may be a predictive factor to determine CPAP compliance. PMID- 23455580 TI - Nasal douches for diseases of the nose and the paranasal sinuses--a comparative in vitro investigation. AB - Nasal douches are applied in great number of diseases of the nose and the paranasal sinuses. For this purpose, many different kinds of nasal douching systems have been introduced into the market. The aim of this study was to examine the irrigation characteristics of the current nasal douching systems. In this context, 26 nasal douching systems were compared regarding irrigation volume, irrigation duration, flow rate and pressure and course of the irrigation stream. The following procedure was applied: First, the spontaneous flow through the nasal douche was measured, then the flow under compression. Finally, these procedures were repeated using a nose model. Furthermore, we asked the manufacturers for information concerning possible cleaning and disinfection techniques. Douching period and flow rate highly depend on physical parameters: distance between liquid column and outlet (hydrostatic pressure) and form and size of the outlet (energy loss because of friction/turbulence). A weak irrigation stream was found in spontaneous release of the douching system when both douching pressure and flow rate offered low values. The douching of the nose model showed that the incompressible nasal douches only reached the lower nasal passage. Only the compressible nasal douching systems led to a diffuse moisturization as well as to a perfusion of the entire nasal cavity. Systematic evaluation of the different recommended cleaning and disinfection methods of the nasal douching systems is still missing. Nasal douches are often recommended in many diseases of the nose and the paranasal sinuses. In this comparative in vitro study, physical parameters and material properties of the nasal douching systems were examined for the first time. For irrigation of the whole nasal cavity and paranasal sinuses, compressible douching systems are recommended which have a minimum output pressure of 120 mbar, a good connection of the outlet to the nostril with a possible insertion into the nasal vestibule and an irrigation stream which is directed upwards (45 degrees ). The material should be transparent, easy to clean and disinfect and should not contain harmful elements. PMID- 23455581 TI - Maxillary sinus surgery in maxillary sinusitis with cystic fibrosis. PMID- 23455582 TI - Association between obstructive sleep apnea and health-related quality of life in individuals affected with Treacher Collins syndrome. AB - Although the relationship between Quality of Life (QoL) and obstructive sleep apnea (OSA) has been reported in several studies, little is known about this relationship among individuals affected with Treacher Collins syndrome (TCS). The aim of this study was to examine the associations between obstructive sleep and QoL in TCS patients. Thirty-six individuals with TCS (8-75 years) were invited to participate in expanded medical examinations, including a sleep study, polysomnography, as well as to respond to questionnaires about health related Health-related quality of life (HRQoL). Twenty-three (64 %) responded to the invitation, but four were later excluded due to additional diagnoses or unconfirmed TCS, and four were below 12 years and excluded due to different scoring rules for sleep and respiratory disturbances in young children and adults. The remaining group comprised 15 adults and adolescents with TCS, 5 male (33 %) and 10 female (66 %). The participants were between 12 and 75 years of age (mean 38.6, SD 18.5). Obstructive sleep was found in 87 % of the patients and several sleep apnea parameters, among these wake time after sleep, subjective snoring and mean saturation, were associated with poorer HRQoL. OSA appears to account for reduced HRQoL in adolescents and adults with TCS. PMID- 23455583 TI - Comparison of the histologic changes in conchae induced by radiofrequency thermal ablation and submucosal diathermy. AB - Objective of study was to determine the histological change induced in the conchae by submucosal diathermy and radiofrequency thermal ablation, two techniques used in the treatment of lower conchal hypertrophy, and to compare the two methods to each other. The study was performed on 15 rabbits. Radiofrequency was applied to the study animals in Group I (n = 5) and submucosal diathermy to Group II (n = 5), while Group III (n = 5) was the untreated control. The animals were decapitated 21 days after treatment and their conchae nasales ventrales excised on both sides. Histology slides were prepared and evaluated by light microscopy for ciliary loss, increase in submucosal vascularity, loss of goblet cells, inflammatory cellular infiltration, fibrosis and epithelial damage. The differences between Groups I and III were not significant regarding ciliary loss, increase in submucosal vascularity, loss of goblet cells and epithelial damage (p > 0.05), while the inflammatory cellular infiltration and fibrosis were significantly different between these groups (p < 0.05). As for the differences between Groups II and III, they were significant for each of the compared parameters (p < 0.05), while among Groups I and II they were significant for ciliary loss (p < 0.05), increase in submucosal vascularity, loss of goblet cells, inflammatory cellular infiltration and epithelial damage but not fibrosis (p > 0.05). Based on these findings, we can state that the use of radiofrequency thermal ablation causes less change in the normal conchal histology than submucosal diathermy application. PMID- 23455584 TI - Comparison between mono-bloc and bi-bloc mandibular advancement devices for obstructive sleep apnea. AB - Although mandibular advancement device (MAD) is widely used, there are a few papers comparing the efficacy and compliance at the same time according to the type of MAD. The aim of this study is to compare the efficacy and compliance between mono-bloc and bi-bloc MAD in the treatment of obstructive sleep apnea (OSA). Ninety-three patients who treated with mono-bloc MAD and 60 patients with bi-bloc MAD from January 2007 through September 2011 were retrospectively enrolled. All the patients underwent full-night polysomnography(PSG) before and 3 months after MAD was applied. The response rate was significantly higher in the patients using mono-bloc than those using bi-bloc MAD (77.4 vs. 58.3 %; P = 0.012). In contrast, the compliance rate of MAD use was significantly higher in the patients using bi-bloc than those using mono-bloc MAD (68.8 vs. 83.3 %; P = 0.044) at 1 year. According to the severity of OSA, the response rate was significantly higher in severe OSA than in mild to moderate OSA (P = 0.033 for mono-bloc MAD and P = 0.048 for bi-bloc MAD). However, there was no difference in the compliance between mild to moderate OSA and severe OSA. Our study showed that mono-bloc MAD was superior to bi-bloc MAD in efficacy while bi-bloc MAD is superior to mono-bloc MAD in compliance. We propose that both the efficacy and compliance should be considered in using MAD for treatment of OSA. PMID- 23455585 TI - 'State-of-the-heart' of cardiac laminopathies. AB - PURPOSE OF REVIEW: LMNA gene encodes the nuclear A-type lamins. LMNA mutations are associated with more than 10 clinical entities and represent one of the first causes of inherited dilated cardiomyopathy. LMNA-dilated cardiomyopathy is associated with conduction disease (DCM-CD) and is a severe and aggressive form of DCM. However, pathogenesis remains largely unknown and no specific treatment is currently available for the patients. In this review, we present recent discoveries that improve the understanding of the cardiac pathophysiological roles of A-type lamins and shed light on potential therapeutic targets. RECENT FINDINGS: In the last decade, many efforts have been made to elucidate how mutations in A-type lamins, ubiquitous proteins, lead to DCM-CD. No clear genotype/phenotype correlations have been found to help in elucidating those mechanisms. Analysis of several mouse models has helped in deciphering critical pathomechanisms. Among those, Mitogen-activated protein kinases (MAPK) and Akt/mTOR appear to be key early-activated signaling pathways in LMNA DCM-CD in both humans and mice. Inhibition of these signaling pathways has shown encouraging beneficial effects upon cardiac evolution of DCM-CD. SUMMARY: These recent findings suggest that targeting MAPK and Akt/mTOR pathways with potent and specific compounds represents a promising intervention for the treatment of LMNA DCM-CD. PMID- 23455586 TI - Erratum to: Purification and characterization of a nitrilase from Aspergillus niger K10. PMID- 23455587 TI - [Acute cholecystitis: primarily conservative or operative approach?]. AB - Acute cholecystitis is one of the most common acute surgical diseases. There is a consensus that laparoscopic cholecystectomy is recommended as the treatment of choice; however, there is a controversy about the best time for surgery. In contrast to delayed cholecystectomy after initial antibiotic treatment, early or immediate cholecystectomy seems to have some advantages. Recent studies and meta analyses have several limitations due to small patient numbers and inhomogeneity in treatment design. Nevertheless, international guidelines tend to recommend early cholecystectomy but the most recent concept of immediate cholecystectomy within 24 h after diagnosis independent of the onset of symptoms is not considered. A current prospective multicenter, randomized controlled trial will shortly bring more clarity to this topic (ACDC trial). PMID- 23455588 TI - [Medicolegal aspects of tumor boards]. AB - The presentation of tumor patients to tumor boards has widely developed into a medical standard. The necessary compliance to the medical standard can lead to obligatory presentation if the complexity of a case dictates that this cannot be comprehensively covered by a single treating physician. The organization of a tumor board must be so that the structure and specialist competence guarantees an adequate consultative function of the represented specialties. Tumor board members are not automatically promoted to become part of the treating team just by participation and therefore do not have a guarantor position but do have the obligation of care of a consulting physician. Tumor board decisions have a recommendation character, are not binding in the legal sense and do not relieve the treating physician from the obligation to critically scrutinize the recommendations before implementation. On the other hand the treating physician must be able to justify not following the recommendations on the basis of the medical obligation to care. The tumor board must fulfil the same requirements for documentation as any other consultative activity. PMID- 23455589 TI - Luteal serum BDNF and HSP70 levels in women with premenstrual dysphoric disorder. AB - Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome characterized by psychological and somatic symptoms commencing in the luteal phase of the menstrual cycle and concludes with menstrual bleeding. PMDD affects 3-8 % of premenopausal women and represents a significant public health problem especially in young women. Decreased brain-derived neurotrophic factor (BDNF) levels are associated with several mental disorders. Heat-shock protein-70 (HSP70) is an important member of the molecular chaperone system, which provides a molecular defense against proteotoxic stress. We hypothesized that there would be changed levels of BDNF and HSP70 in women with PMDD compared with non symptomatic women, reflecting impaired and/or activated stress-related responses involved in the underlying pathogenesis of PMDD. Female medical students were screened, and 24 women without premenstrual symptoms and 25 women with PMDD were enrolled in the study. Psychiatric evaluation and the Daily Record of Severity of Problems-Short Form were used for two consecutive menstrual cycles to diagnose PMDD. Serum BDNF and HSP70 levels were assessed in the third luteal phase. Participants with PMDD had significantly higher serum BDNF and HSP70 levels compared with controls, and there was a significant positive correlation between serum BDNF and HSP70 levels. Increased HSP70 levels may reflect cellular distress in PMDD. Increased serum BDNF levels in the luteal phase in subjects with PMDD may reflect a compensation process, which results in subsequent improvement of PMDD-associated depressive symptoms in the follicular phase. Thus, increased serum BDNF levels may be indicative of a compensating capacity in PMDD. PMID- 23455590 TI - Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. AB - Severe psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms, which often are resistant to current treatment approaches. The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders. A key component is the dysfunction of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood. In schizophrenia, add-on treatments with glycine, D-serine, D-alanine, D cycloserine, D-amino acid oxidase inhibitors, glycine transporter-1 (GlyT-1) inhibitors (e.g., sarcosine, bitopertin) and agonists (e.g., LY2140023) or positive allosteric modulator (e.g., ADX71149) of group II metabotropic glutamate receptors (mGluRs) have been studied. In major depression, the NMDA receptor antagonists (e.g., ketamine, AZD6765), GluN2B subtype antagonists (e.g., traxoprodil, MK-0657), and partial agonists (e.g., D-cycloserine, GLYX-13) at the glycine site of the NMDA receptor have been proven to be effective in animal studies and first clinical trials. In addition, clinical studies of mGluR2/3 antagonist BCI-838 (a prodrug of BCI-632 (MGS0039)), mGluR2/3-negative allosteric modulators (NMAs) (e.g., RO499819, RO4432717), and mGluR5 NAMs (e.g., AZD2066, RO4917523) are in progress. Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs. PMID- 23455591 TI - Long-term (3-year) neurocognitive effectiveness of antipsychotic medications in first-episode non-affective psychosis: a randomized comparison of haloperidol, olanzapine, and risperidone. AB - INTRODUCTION: The initially postulated superior neurocognitive effectiveness of second-generation antipsychotics is currently under debate. METHODS: A prospective, randomized, open-label study was carried out to compare the long term neurocognitive effectiveness of haloperidol, olanzapine, and risperidone in the first episode of schizophrenia spectrum disorders. A final sample of 79 patients randomized to haloperidol (N = 28), olanzapine (N = 23), or risperidone (N = 28) who completed clinical and cognitive evaluations at baseline and 3-year follow-up was included in the final analysis. Forty-one healthy individuals were also included in the final analysis. The main outcome measure was cognitive changes at 3-year follow-up. Due to the fact that some of the patients had switched their initially prescribed antipsychotic medication during the course of the study (6 out of 28 in haloperidol group, 18 out of 23 in olanzapine group, and 24 out of 28 in risperidone group continued with the initial study drug at 3 year assessment), we have also conducted a per protocol analysis. RESULTS: Overall, cognitive changes were similar in the three treatment groups and controls, although a greater improvement in Rey Auditory Verbal Learning Test, Digit Symbol, and Iowa Gambling Test was found in the treatment groups. The better performance observed on Rey Auditory Verbal Learning Test and Digit Symbol in olanzapine treatment group was likely explained by the lower prevalence of use of antimuscarinic drugs. These results were essentially similar to those found in the intention-to-treat analysis. CONCLUSIONS: The major conclusion of this study is that haloperidol, olanzapine, and risperidone have not demonstrated substantial neurocognitive effectiveness, improving cognitive deficits present in the early phases of the illness. The study also underscores the importance of exploring new drugs for the treatment of cognitive impairments and associated functional disabilities in schizophrenia. PMID- 23455592 TI - Caloric restriction increases the sensitivity to the hyperphagic effect of nociceptin/orphanin FQ limiting its ability to reduce binge eating in female rats. AB - RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is a functional antagonist of corticotrophin-releasing factor, the main mediator of the stress response. Stress represents a key determinant of binge eating (BE) for highly palatable food (HPF). OBJECTIVES: In relation to the antistress properties of N/OFQ, we evaluated its effect on BE. After the observation that episodes of food restriction increase the sensitivity to its hyperphagic effects, the function of NOP receptor and N/OFQ was investigated after cycles of food restrictions. MATERIALS AND METHODS: In BE experiments, four groups were used: rats fed normally and not stressed or stressed, rats exposed to cycles of restriction/refeeding and then stressed, or not stressed. In the other experiments, two groups were used: rats exposed or not to food restriction. RESULTS: Only restricted and stressed rats exhibited BE for HPF (containing chocolate cream). Intracerebroventricular injections of N/OFQ of 0.5 nmol/rat significantly reduced BE. N/OFQ 1 nmol/rat did not reduce BE but significantly increased HPF intake following food restrictions. Cycles of food restriction increased animals' sensitivity to the hyperphagic effect of N/OFQ for HPF. In situ hybridization studies following food restrictions showed decreased ppN/OFQ mRNA expression in the bed nucleus of the stria terminalis and increased expression of ppN/OFQ and NOP receptor mRNA in the ventral tegmental area and in the ventromedial hypothalamus, respectively. CONCLUSIONS: These findings indicate that N/OFQ slightly reduces BE at low doses, while higher doses increase HPF intake, due to increased sensitivity to its hyperphagic effect following a history of caloric restrictions. PMID- 23455593 TI - Neural substrates of acupuncture in the modulation of cravings induced by smoking related visual cues: an fMRI study. AB - RATIONALE: Cue reactivity is a key factor in modulating motivational and goal directed behaviors associated with compulsive drug intake and relapse. Smoking associated cues produce smoking urges and cravings and are accompanied by the activation of brain regions involved in attention, motivation, and reward. OBJECTIVES: We investigated whether acupuncture ameliorates cravings induced by smoking-related visual cues, and we explored the neural mechanisms underlying the effects of acupuncture on modulating smoking urges. METHODS: After 36 h of smoking abstinence, 25 right-handed male smokers underwent fMRI, during which smoking-related and neutral visual cues were presented. Twelve subjects were treated with real acupuncture (RA) at HT7 and 13 subjects received sham acupuncture (SA). During the scanning sessions, craving scores to smoking-related visual cues were assessed before and after RA or SA treatment. The differences in brain responses to smoking vs. neutral cues after treatment between the RA and SA groups were detected using three-way ANOVAs (Cue * Session * Group). RESULTS: After treatment, the craving scores were significantly decreased in the RA group, as compared to the SA group. When we explored the neural substrates of acupuncture on the modulation of cravings induced by smoking cues, significant differences were found in the medial prefrontal cortex, the premotor cortex, the amygdala, the hippocampus, and the thalamus. CONCLUSIONS: These findings suggest that acupuncture alleviates cue-induced cravings through the regulation of activity in brain regions involved in attention, motivation, and reward relative to craving scores in the initial abstinence phase. PMID- 23455595 TI - Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. AB - RATIONALE: Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown. OBJECTIVES: As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed. METHODS: The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 * 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days). RESULTS: In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion. CONCLUSIONS: These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response. PMID- 23455594 TI - Insula's functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving. AB - RATIONALE: Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking. OBJECTIVES: We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC). METHODS: Overnight-deprived smokers (n = 24) and nonsmokers (n = 20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC. RESULTS: Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI-vmPFC circuit fully mediated this alexithymia-craving relation. That is, elevated alexithymia predicted decreased aI-vmPFC rsFC and, in turn, decreased aI-vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI-vmPFC mediational effect was not observed following drug administration. CONCLUSIONS: These results suggest that a weakened right aI-vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI-vmPFC functional coupling may be relevant factors for smoking cessation success. PMID- 23455596 TI - Caffeine can decrease subjective energy depending on the vehicle with which it is consumed and when it is measured. AB - RATIONALE: Energy drinks contain glucose and caffeine, although in the longer term both adversely influence blood glucose homeostasis, with the unconsidered potential to have adverse consequences for cognition and mood. OBJECTIVE: The objective of this study was to consider the influence on interstitial glucose levels, mood and cognition of drinks differing in their caffeine content and glycaemic load. METHODS: Ninety minutes after a standard breakfast, a yoghurt-, glucose- or water-based drink, with or without 80 mg of caffeine, was consumed. RESULTS: The consumption of caffeine negatively influenced glucose homeostasis: that is, irrespective of the vehicle, caffeine consumption resulted in elevated levels of blood glucose throughout the study. Thirty minutes after consuming caffeine and water, rather than water alone, greater subjective energy was reported. However, after 90 and 150 min, caffeine administered in water increased tiredness, hostility and confusion. In contrast, combining caffeine with a yoghurt-based drink increased energy, agreeableness and clearheadedness later in the morning. There were no effects of caffeine on ratings of mood when it was taken with glucose. Caffeine, irrespective of vehicle, resulted in better memory, quicker reaction times in the choice reaction time test and the working memory task, and better and quicker responses with the vigilance task. CONCLUSION: Further research should consider how caffeine interacts with macronutrients and the timescale over which such effects occur. PMID- 23455597 TI - Assessment of the abuse liability of ABT-288, a novel histamine H3 receptor antagonist. AB - RATIONALE: Histamine H3 receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H3 antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse. OBJECTIVES: The aim of the present study was to further characterize whether ABT-288 possesses stimulant like properties and whether its pharmacology gives rise to abuse liability. METHODS: The locomotor-stimulant effects of ABT-288 were measured in mice and rats, and potential development of sensitization was addressed. Drug discrimination was used to assess amphetamine-like stimulus properties, and drug self-administration was used to evaluate reinforcing effects of ABT-288. The potential development of physical dependence was also studied. RESULTS: ABT-288 lacked locomotor-stimulant effects in both rats and mice. Repeated administration of ABT-288 did not result in cross-sensitization to the stimulant effects of d amphetamine in mice, suggesting that there is little overlap in circuitries upon which the two drugs interact for motor activity. ABT-288 did not produce amphetamine-like discriminative stimulus effects in drug discrimination studies nor was it self-administered by rats trained to self-administer cocaine. There were no signs of physical dependence upon termination of repeated administration of ABT-288 for 30 days. CONCLUSIONS: The sum of these preclinical data, the first of their kind applied to H3 antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H3 antagonists, as a class, are similar in this regard. PMID- 23455598 TI - The effects of maternal depression and use of antidepressants during pregnancy on risk of a child small for gestational age. AB - RATIONALE: Use of antidepressants during pregnancy has been associated with an increased rate of children small for gestational age (SGA), but it is unclear whether this is due to an effect of the underlying depressive disorder. OBJECTIVES: This study aimed to investigate the effect of antidepressants on SGA in a nationwide sample and to separate the effect of exposure to antidepressants in utero from the effect of maternal depression. METHODS: A register study was conducted on all pregnant women in Denmark from 1996 to 2006 linking nationwide individualized data from the Medical Birth Register, the Psychiatric Central Register, and a prescription database. The rate of SGA (birth weight below the 10 percentile at given gestational week) was investigated for children exposed in utero to antidepressants or to a maternal psychiatric diagnosis of depression compared to children not prenatally exposed to antidepressants or maternal diagnosis. RESULTS: A total of 673,853 pregnancies were included in the study of which 35.737 women had a diagnosis of depression and/or used antidepressants before end of pregnancy. Antidepressant use during pregnancy was weakly associated with SGA (hazard ratios (HR) = 1.19; 95 % confidence interval (CI), 1.11-1.28), whereas a psychiatric diagnosis before or during pregnancy was not (HR = 1.02; 95 % CI, 0.92-1.13). The association for use during pregnancy was found for selective serotonin reuptake inhibitors and newer antidepressants, but not for older antidepressants. CONCLUSIONS: The use of antidepressants during pregnancy slightly increases the rate of SGA. The association seems unrelated to the underlying maternal depressive disorder. PMID- 23455600 TI - New avenues to an old material: controlled nanoscale doping of germanium. AB - We review our recent research into n-type doping of Ge for nanoelectronics and integrated photonics. We demonstrate a doping method in ultra-high vacuum to achieve high electron concentrations in Ge while maintaining atomic-level control of the doping process. We integrated this doping technique with ultra-high vacuum scanning tunneling microscope lithography and femtosecond laser ablation micron scale lithography, and demonstrated basic components of donor-based nanoelectronic circuitry such as wires and tunnel gaps. By repetition of controlled doping cycles we have shown that stacking of multiple Ge:P two dimensional electron gases results in high electron densities in Ge (>10(20) cm( 3)). Because of the strong vertical electron confinement, closely stacked 2D layers - although interacting - maintain their individuality in terms of electron transport. These results bode well towards the realization of nanoscale 3D epitaxial circuits in Ge comprising stacked 2DEGs and/or atomic-scale Ge:P devices with confinement in more dimensions. PMID- 23455599 TI - Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash. AB - RATIONALE: In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioural analysis). Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behaviour during feeding tests have not been thoroughly investigated. OBJECTIVES: This study aimed to assess the behavioural specificity of anorectic responses to bupropion, naltrexone and their combination. METHODS: Video analysis was employed to characterise the behavioural effects of acute systemic treatment with bupropion (10.0-40.0 mg/kg), naltrexone (0.1-3.0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0.1-1.0 mg/kg) in non-deprived male rats exposed for 1 h to palatable mash. Particular attention was paid to the behavioural satiety sequence (BSS). RESULTS: In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS. In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS. In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant. CONCLUSIONS: Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion. PMID- 23455601 TI - Treatment engagement in adolescents with severe psychiatric problems: a latent class analysis. AB - Motivation is considered a pivotal factor in treatment, but a better understanding of this topic is needed. Drieschner et al. (Clin Psychol Rev 23:1115-1137, 2004) proposed to distinguish treatment motivation and treatment engagement. This study aimed to discover whether it is possible to identify classes of adolescents with severe psychiatric problems having comparable profiles of treatment engagement. To this end, professionals filled out the Treatment Engagement Rating Scale 5 times for 49 adolescents (mean age 18.3 years; SD = 1.6) during the first year of case management treatment. Using a longitudinal latent class analysis, the number of profiles of treatment engagement was investigated and described. Results identified three profiles: high (19 clients, 39%), medium (20 clients, 41%) and low (10 clients, 20%). Adolescents with a high engagement profile were at first equally, and later on more engaged in treatment than clients with a medium engagement profile. Adolescents with a low engagement profile made the least effort to engage, except after 30 weeks. Adolescents with a low engagement profile were often substance dependent males with the lowest scores on the Global Assessment of Functioning Scale after a year. Only adolescents with a high engagement profile improved on global functioning. In conclusion, it is possible to identify different treatment engagement profiles by asking one question about level of global treatment engagement. Frequent assessment of engagement of the individual client as well as including a behavioural component into assessment and treatment may help to improve case management treatment for adolescents with medium and low engagement profiles. PMID- 23455603 TI - Targeting lymphomas through MALT1 inhibition. PMID- 23455602 TI - What influences clinicians' decisions about ADHD medication? Initial data from the Influences on Prescribing for ADHD Questionnaire (IPAQ). AB - Despite evidence for its efficacy and effectiveness, the use of medication for the treatment of ADHD remains controversial. Little is known about the factors that influence clinicians' decisions to use medication for ADHD. Here, we present initial data on the attitudes of prescribing clinicians from the Influences on Prescribing for ADHD Questionnaire (IPAQ)-a new clinician-completed, 40-item scale. The eight IPAQ subscales cover attitudes towards (1) treatment outcome optimisation, (2) the use of rule based over more informal approaches, (3) side effects, (4) symptoms control as the primary goal of treatment, (5) the influence of external pressure on medication-related decisions, (6) the value of taking the child's views into account, (7) long-term medication use and (8) the value of psychosocial approaches for the treatment of ADHD. Sixty-eight clinicians from Belgium and the UK took part. All subscales had acceptable levels of internal reliability (Chronbach's alpha = 0.62-0.78). Overall, clinicians reported taking a rule-based approach to prescribing with a focus on treatment optimisation, taking the child's view into account and valuing psycho-social approaches. They focused on treating broader patterns of impairment, but were wary of the potential side effects and long-term treatment. Psychiatrists scored high on their focus on symptom control and preference for long-term medication use, while paediatricians reported using more rule-based approaches. We identified four distinctive response profiles: (1) pro-psychosocial; (2) medication focused; (3) unsystematic; and (4) response optimizers. Future larger scale studies are required to replicate these profiles and to explore their relationship with prescribing behaviour and treatment outcomes. PMID- 23455604 TI - Executive function outcome in preterm adolescents. AB - Preterm birth (PT) and low birthweight (LBW) are risk factors for cognitive, academic, and behavioral difficulties. Executive functioning, which is an umbrella term encompassing higher-order problem-solving and goal-oriented abilities, may help to understand these impairments. This review article examines executive functioning in PT and LBW children, with a specific focus on adolescence and the functional consequences of executive dysfunction in this age group. We have focused on adolescence as it is a critical period for brain, cognitive and social-emotional development, and a period of increased autonomy, independence and reliance on executive functioning. While more longitudinal research is required, there is evidence demonstrating that the PT/LBW population is at increased risk for impairments across all executive domains. Emerging evidence also suggests that executive dysfunction may partly explain poorer academic and social-emotional competence in PT/LBW adolescents. In conclusion, PT/LBW adolescents exhibit poorer executive functioning, and close surveillance is recommended for high-risk individuals. PMID- 23455605 TI - Behavioural outcomes and psychopathology during adolescence. AB - Preterm birth is associated with a high risk of residual neurodevelopmental disability and cognitive impairment. These problems are closely associated with psychiatric disorders and thus it is unsurprising that preterm birth also confers high risk for poor long term mental health. The risk associated with preterm birth is not a general one, but appears to be specific to symptoms and disorders associated with anxiety, inattention and social and communication problems, and manifest in a significantly higher prevalence of emotional disorders, ADHD and Autism. Adolescence is a key period for mental health and studies have shown that problems evident in childhood persist over this time and are more stable amongst preterm individuals than term-born peers. There is also modest evidence for an increased prevalence of psychotic symptoms in preterm adolescents. The high prevalence of psychiatric disorders, present in around 25% of preterm adolescents, requires long term screening and intervention. PMID- 23455606 TI - Micro-optical lens array for fluorescence detection in droplet-based microfluidics. AB - We demonstrate the design and integration of droplet-based microfluidic devices with microoptical element arrays for enhanced detection of fluorescent signals. We show that the integration of microlenses and mirror surfaces in these devices results in an 8-fold increase in the fluorescence signal and in improved spatial resolution. Using an array of microlenses, massively parallel detection of droplets containing fluorescent dyes was achieved, leading to detection throughputs of about 2000 droplets per second and per lens, parallelized over 625 measurement points. PMID- 23455607 TI - Interplay of LRRK2 with chaperone-mediated autophagy. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of alpha-synuclein, another Parkinson's disease-related protein degraded by this pathway. PMID- 23455608 TI - mTORC2 controls actin polymerization required for consolidation of long-term memory. AB - A major goal of biomedical research is the identification of molecular and cellular mechanisms that underlie memory storage. Here we report a previously unknown signaling pathway that is necessary for the conversion from short- to long-term memory. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which contains the regulatory protein Rictor (rapamycin-insensitive companion of mTOR), was discovered only recently and little is known about its function. We found that conditional deletion of Rictor in the postnatal murine forebrain greatly reduced mTORC2 activity and selectively impaired both long-term memory (LTM) and the late phase of hippocampal long-term potentiation (L-LTP). We also found a comparable impairment of LTM in dTORC2-deficient flies, highlighting the evolutionary conservation of this pathway. Actin polymerization was reduced in the hippocampus of mTORC2-deficient mice and its restoration rescued both L-LTP and LTM. Moreover, a compound that promoted mTORC2 activity converted early LTP into late LTP and enhanced LTM. Thus, mTORC2 could be a therapeutic target for the treatment of cognitive dysfunction. PMID- 23455609 TI - Optical control of metabotropic glutamate receptors. AB - G protein-coupled receptors (GPCRs), the largest family of membrane signaling proteins, respond to neurotransmitters, hormones and small environmental molecules. The neuronal function of many GPCRs has been difficult to resolve because of an inability to gate them with subtype specificity, spatial precision, speed and reversibility. To address this, we developed an approach for opto chemical engineering of native GPCRs. We applied this to the metabotropic glutamate receptors (mGluRs) to generate light-agonized and light-antagonized mGluRs (LimGluRs). The light-agonized LimGluR2, on which we focused, was fast, bistable and supported multiple rounds of on/off switching. Light gated two of the primary neuronal functions of mGluR2: suppression of excitability and inhibition of neurotransmitter release. We found that the light-antagonized tool LimGluR2-block was able to manipulate negative feedback of synaptically released glutamate on transmitter release. We generalized the optical control to two additional family members: mGluR3 and mGluR6. This system worked in rodent brain slices and in zebrafish in vivo, where we found that mGluR2 modulated the threshold for escape behavior. These light-gated mGluRs pave the way for determining the roles of mGluRs in synaptic plasticity, memory and disease. PMID- 23455610 TI - Merlin isoform 2 in neurofibromatosis type 2-associated polyneuropathy. AB - The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2-dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2-deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons. PMID- 23455611 TI - Formation of sulfonyl aromatic alcohols by electrolysis of a bisazo reactive dye. AB - Five sulfonyl aromatic alcohols, namely 4-((2-hydroxyethyl)sulfonyl)phenol, 4-((2 (2-((4-hydroxyphenyl)sulfonyl)ethoxy)vinyl)sulfonyl)phenol, 4 (ethylsulfonyl)phenol, 4-(vinylsulfonyl)phenol and 5-((4-aminophenyl)sulfonyl)-2 penten-1-ol were identified by LC-ESI-Qq-TOF-MS as products formed by electrolysis of the bisazo reactive dye Reactive Black 5 (RB5). Since electrolyses were performed in an undivided cell equipped with Ni electrodes in alkaline medium, amines like 4-(2-methoxyethylsulfonyl)benzene-amine (MEBA) with m/z 216 were also suspected to be formed due to the plausible chemical reaction in the bulk or the cathodic reduction of RB5 and its oxidation by-products. Aiming to check this hypothesis, a method was used for the preparation of MEBA with 98% purity, via chemical reduction also of the dye RB5. The logP of the synthesized sulfonyl aromatic compounds was calculated and their logkw values were determined chromatographically. These data were discussed in regard to the relationship between hydrophobicity/lipophilicity and toxicity. PMID- 23455615 TI - Cleavage, incomplete inversion, and cytoplasmic bridges in Gonium pectorale (Volvocales, Chlorophyta). AB - Multicellularity arose several times in evolution of eukaryotes. The volvocine algae have full range of colonial organization from unicellular to colonies, and thus these algae are well-known models for examining the evolution and mechanisms of multicellularity. Gonium pectorale is a multicellular species of Volvocales and is thought to be one of the first small colonial organisms among the volvocine algae. In these algae, a cytoplasmic bridge is one of the key traits that arose during the evolution of multicellularity. Here, we observed the inversion process and the cytoplasmic bridges in G. pectorale using time-lapse, fluorescence, and electron microscopy. The cytoplasmic bridges were located in the middle region of the cell in 2-, 4-, 8-, and 16-celled stages and in inversion stages. However, there were no cytoplasmic bridges in the mature adult stage. Cytoplasmic bridges and cortical microtubules in G. pectorale suggest that a mechanism of kinesin-microtubule machinery similar to that in other volvocine algae is responsible for inversion in this species. PMID- 23455613 TI - Role of glutathione in the oxidative stress response in the fungal pathogen Candida glabrata. AB - Candida glabrata, an opportunistic fungal pathogen, accounts for 18-26 % of all Candida systemic infections in the US. C. glabrata has a robust oxidative stress response (OSR) and in this work we characterized the role of glutathione (GSH), an essential tripeptide-like thiol-containing molecule required to keep the redox homeostasis and in the detoxification of metal ions. GSH is synthesized from glutamate, cysteine, and glycine by the sequential action of Gsh1 (gamma-glutamyl cysteine synthetase) and Gsh2 (glutathione synthetase) enzymes. We first screened for suppressor mutations that would allow growth in the absence of GSH1 (gsh1? background) and found a single point mutation in PRO2 (pro2-4), a gene that encodes a gamma-glutamyl phosphate reductase and catalyzes the second step in the biosynthesis of proline. We demonstrate that GSH is important in the OSR since the gsh1? pro2-4 and gsh2? mutant strains are more sensitive to oxidative stress generated by H2O2 and menadione. GSH is also required for Cadmium tolerance. In the absence of Gsh1 and Gsh2, cells show decreased viability in stationary phase. Furthermore, C. glabrata does not contain Saccharomyces cerevisiae high affinity GSH transporter ortholog, ScOpt1/Hgt1, however, our genetic and biochemical experiments show that the gsh1? pro2-4 and gsh2? mutant strains are able to incorporate GSH from the medium. Finally, GSH and thioredoxin, which is a second redox system in the cell, are not essential for the catalase-independent adaptation response to H2O2. PMID- 23455616 TI - Complete genotyping in conservation genetics, a case study of a critically endangered shrub, Stachyurus macrocarpus var. prunifolius (Stachyuraceae) in the Ogasawara Islands, Japan. AB - More than 3,000 species are listed as critically endangered worldwide, and various conservation measures such as habitat restoration, assisted reproduction and establishment of ex situ populations would be required to prevent their extinction. We determined the genotype of all 15 known wild clumps using nuclear microsatellite markers for Stachyurus macrocarpus var. prunifolius, a critically endangered shrub endemic to the Ogasawara (Bonin) Islands of Japan. In addition, the seedlings propagated from seeds taken from one wild clumps were genotyped. The results of complete genotyping showed that both wild and nursery populations had population-specific alleles. Two alleles were detected only in the nursery population, indicating the existence of undiscovered mature individuals in the wild. Four alleles were found only in the wild and were detected in two geographically isolated clumps, and this finding may propose that re-introduction and transplantation between different sites requires sensitive handling in terms of the conservation of evolutionary significant units. These results show that complete genotyping can provide essential genetic and ecological information for effective management of endangered species. PMID- 23455618 TI - Two novel nonlinear optical carbonates in the deep-ultraviolet region: KBeCO3F and RbAlCO3F2. AB - With the rapid developments of the all-solid-state deep-ultraviolet (deep-UV) lasers, the good nonlinear optical (NLO) crystal applied in this spectral region is currently lacking. Here, we design two novel NLO carbonates KBeCO3F and RbAlCO3F2 from the first-principles theory implemented in the molecular engineering expert system especially for NLO crystals. Both structurally stable crystals possess very large energy band gaps and optical anisotropy, so they would become the very promising deep-UV NLO crystals alternative to KBBF. Recent experimental results on MNCO3F (M = K, Rb, Cs; N = Ca, Sr, Ba) not only confirm our calculations, but also suggest that the synthesis of the KBeCO3F and RbAlCO3F2 crystals is feasible. PMID- 23455617 TI - Changes in the distribution of cell wall polysaccharides in early fruit pericarp and ovule, from fruit set to early fruit development, in tomato (Solanum lycopersicum). AB - During fruit development in tomato (Solanum lycopersicum), cell proliferation and rapid cell expansion occur after pollination. Cell wall synthesis, alteration, and degradation play important roles during early fruit formation, but cell wall composition and the extent of cell wall synthesis/degradation are poorly understood. In this study, we used immunolocalization with a range of specific monoclonal antibodies to examine the changes in cell wall composition during early fruit development in tomato. In exploring early fruit development, the -1 day post-anthesis (DPA) ovary and fruits at 1, 3, and 5 DPA were sampled. Paraffin sections were prepared for staining and immunolabeling. The 5 DPA fruit showed rapid growth in size and an increase in both methyl-esterified pectin and de-methyl-esterified pectin content in the pericarp, suggesting rapid synthesis and de-methyl esterification of pectin during this growth period. Labeling of pectic arabinan with LM6 antibody and galactan with LM5 antibody revealed abundant amounts of both, with unique distribution patterns in the ovule and premature pericarp. These results suggest the presence of rapid pectin metabolism during the early stages of fruit development and indicate a unique distribution of pectic galactan and arabinan within the ovule, where they may be involved in embryogenesis. PMID- 23455619 TI - Enhancement of the Schottky barrier height of Au/ZnO nanocrystal by zinc vacancies using a hydrothermal seed layer. AB - Various seed layers were prepared on a Si substrate using the sol-gel (SG) or hydrothermal (HT) method and then ZnO nanocrystal was grown on the seed layer by an HT process. Au/ZnO nanocrystal Schottky diodes (SDs) were fabricated to study the effects of various seed layers on the electrical properties of Au/ZnO SDs. The observations showed that large numbers of Zn vacancies were present near the interface of Au/ZnO with an HT seed layer. The Zn vacancy plays an acceptor-like role, which raises the barrier height of the Au/ZnO SDs to 0.79 eV with a rectifying ratio of more than 8000. Hence, a non-surface-treated Au/ZnO SD was achieved as compared to those of other reported oxygen-plasma treated surfaces. In contrast, oxygen vacancies appear near the interface of Au/ZnO with an SG seed layer. The O vacancy plays a donor-like role, which reduces the barrier height of Au/ZnO, leading to an Ohmic behavior in the I-V characteristics. Zn out-diffusion is found during Au evaporation by of x-ray photoelectron spectroscopy measurements. PMID- 23455620 TI - Advances in proton-exchange membranes for fuel cells: an overview on proton conductive channels (PCCs). AB - Proton-exchange membranes (PEM) display unique ion-selective transport that has enabled a breakthrough in high-performance proton-exchange membrane fuel cells (PEMFCs). Elemental understanding of the morphology and proton transport mechanisms of the commercially available Nafion(r) has promoted a majority of researchers to tune proton conductive channels (PCCs). Specifically, knowledge of the morphology-property relationship gained from statistical and segmented copolymer PEMs has highlighted the importance of the alignment of PCCs. Furthermore, increasing efforts in fabricating and aligning artificial PCCs in field-aligned copolymer PEMs, nanofiber composite PEMs and mesoporous PEMs have set new paradigms for improvement of membrane performances. This perspective profiles the recent development of the channels, from the self-assembled to the artificial, with a particular emphasis on their formation and alignment. It concludes with an outlook on benefits of highly aligned PCCs for fuel cell operation, and gives further direction to develop new PEMs from a practical point of view. PMID- 23455612 TI - Regulations of sugar transporters: insights from yeast. AB - Transport across the plasma membrane is the first step at which nutrient supply is tightly regulated in response to intracellular needs and often also rapidly changing external environment. In this review, I describe primarily our current understanding of multiple interconnected glucose-sensing systems and signal transduction pathways that ensure fast and optimum expression of genes encoding hexose transporters in three yeast species, Saccharomyces cerevisiae, Kluyveromyces lactis and Candida albicans. In addition, an overview of GAL- and MAL-specific regulatory networks, controlling galactose and maltose utilization, is provided. Finally, pathways generating signals inducing posttranslational degradation of sugar transporters will be highlighted. PMID- 23455622 TI - Sexual health behaviors and sexual orientation in a U.S. national sample of college students. AB - Many studies have examined differences in sexual behavior based on sexual orientation with results often indicating that those with same-sex partners engage in higher risk sexual behavior than people with opposite sex partners. However, few of these studies were large, national sample studies that also include those identifying as unsure. To address that gap, this study examined the relationship of sexual orientation and sexual health outcomes in a national sample of U.S. college students. The Fall 2009 American College Health Association-National College Health Assessment was used to examine sexual health related responses from heterosexual, gay, lesbian, bisexual, and unsure students (N = 25,553). Responses related to sexual behavior, safer sex behaviors, prevention and screening behaviors, and diagnosis of sexual health related conditions were examined. The findings indicated that sexual orientation was significantly associated with engaging in sexual behavior in the last 30 days. Sexual orientation was also significantly associated with the number of sexual partners in the previous 12 months, with unsure men having significantly more partners than gay, bisexual and heterosexual men and heterosexual men having significantly less partners than gay, bisexual and unsure men. Bisexual women had significantly more partners than females reporting other sexual orientations. Results examining the associations between sexual orientation and safer sex, prevention behaviors, and screening behaviors were mixed. Implications for practice, including specific programmatic ideas, were discussed. PMID- 23455621 TI - Community structure and transcript responses of anammox bacteria, AOA, and AOB in mangrove sediment microcosms amended with ammonium and nitrite. AB - The anthropogenic nitrogen (N) input as an important source strongly influences the microbial N cycling in coastal ecosystems. In this study, we investigated the responses of anammox bacteria, ammonia oxidizing archaea (AOA), and ammonia oxidizing bacteria (AOB) to the amendments of ammonium and nitrite into mangrove sediments incubated in laboratory microcosm experiments. The variations of diversity, abundances, and transcription of 16S rRNA and hydrazine oxidoreductase (hzo) genes for anammox bacteria, and amoA genes for AOA and AOB were monitored during the incubation. The T-RFLP analysis demonstrated that both ammonium and nitrite additions significantly altered the community compositions of anammox bacteria, AOA, and AOB, while abundance and transcripts analyzed quantitatively confirmed that the amendment of ammonium (25 mM) stimulated the growth of anammox bacteria, AOA, and AOB, whereas nitrite (0.8 mM) generally inhibited them with some exceptions for specific species of AOA and AOB, showing different responses of anammox bacteria, AOA, and AOB to the nitrite and ammonium amendments. Results further suggest that AOB as the dominant group with higher amoA gene abundances and transcripts might play a more important role on the ammonium oxidization in mangrove sediment of this subtropical site. PMID- 23455623 TI - Sperm competition and the absorption of neuropeptides by the prepuce. PMID- 23455624 TI - [Hypereosinophilic syndrome]. AB - Hypereosinophilic syndrome is a heterogeneous group of diseases characterized by blood hypereosinophilia and eosinophil-related organ damage. A comprehensive diagnostic work-up is necessary to identify underlying conditions and to detect organ involvement, which are important for prognosis. Involvement of the heart is related with a poorer outcome. Some underlying conditions can be treated with targeted therapies, e.g., tyrosine kinase inhibitors. However, glucocorticoids in combination with steroid-sparing drugs are generally used for treatment. Furthermore, the growing understanding of the molecular pathogenesis will lead to new therapies, e.g., the use of anti-cytokine antibodies. PMID- 23455625 TI - [Inflammatory diseases with liver and joint involvement. A differential diagnostic challenge]. AB - Elevated levels of liver enzymes in patients with rheumatic symptoms require a comprehensive differential diagnostic thought process. On the one hand there can be hepatic involvement of primarily rheumatological diseases but this is quite rare. Drug-induced liver injury by antirheumatic medication is more frequent. On the other hand arthralgia can be a sign of primary hepatopathy whereby hemochromatosis and autoimmune hepatitis (AIH) are typical examples. Furthermore, some liver diseases are associated with rheumatological diseases, such as primary biliary cirrhosis (PBC) and chronic hepatitis C infection (HCV). Only an exact diagnosis will lead to specific treatment which will improve the symptoms and course of disease. PMID- 23455626 TI - [Pharmacological treatment of constipation]. AB - Chronic constipation is a frequent condition often requiring pharmacological treatment. A number of laxatives that belong to very different pharmacological groups are available. Most relevant are the older representatives osmotic salts, sugars and sugar alcohols, macrogol, anthraquinones, diphenolic laxatives (bisacodyl and sodium picosulphate), and the newer compounds prucalopride and linaclotide. For all of these laxatives, efficacy has been shown in controlled trials. Electrolyte problems do not occur when laxatives are given in therapeutic doses (rare exceptions with salinic laxatives). The older laxatives are also safe regarding teratogenicity, abortion, and lactation; for the newer compounds no respective data are available as yet. It is questionable whether the newer laxatives offer advantages over the older ones. Unfortunately, comparative trials are lacking. Opiate-induced constipation may also be treated with laxatives or certain opiate antagonists. PMID- 23455627 TI - Antidepressant drug use and off-label prescribing in children and adolescents in Germany: results from a large population-based cohort study. AB - The off-label use of drugs in children and adolescents is widespread. In Germany, the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OADs) is not licensed for the treatment of depressive disorders in children and adolescents except for fluoxetine, which was approved in 2006. Against this background, antidepressant drug (ATD) use with a particular focus on off-label prescribing was characterised in a retrospective cohort study including cross-sectional analyses based on claims data of 2,599,685 patients up to 17 years of age. Prevalence of ATD use was 1.84 (95% CI 1.78-1.90) per 1,000 children in 2004, 1.57 (95% CI 1.52-1.62) in 2005 and 1.66 (95% CI 1.61-1.72) in 2006. More than half of all children treated with ATDs (51.29%) received only one single prescription of an ATD during the study period. Of all prescribed ATDs, 11,172 (42.09%) were tricyclic antidepressants 9,179 (34.58%) were SSRIs, 4,371 (16.47%) were St John's wort preparations and 1,821 (6.86%) were OADs. Around half of all children and adolescents who were treated with ATDs were diagnosed with depressive disorders (56.30%). Overall, 13,035 (49.11%) of all ATDs were prescribed off-label. Off-label use by age (40.18%) was found to be more common than off-label use by indication (16.63%) with 7.70% of off-label use occurring in both categories. Specialist treatment by hospital-based physicians increased the risk (odds ratio: 2.26, 95% CI 2.05-2.48) of receiving an off-label prescription compared to treatment by general practitioners. In summary, off label use of ATDs in children and adolescents was substantial in Germany. PMID- 23455628 TI - The biolabile 2'-O-pivaloyloxymethyl modification in an RNA helix: an NMR solution structure. AB - The pivaloyloxymethyl (PivOM) group is a biolabile 2'-O-ribose protection that is under development in a prodrug-based approach for siRNA applications. Besides an expected cellular uptake, nucleic acid sequences carrying PivOM showed also increased nuclease resistance and, in most cases, an affinity for complementary RNA. The r(CGCU*ACGC)dT:r(GCGUAGCG)dT model duplex containing a single modified residue (U*) was synthesized and its solution structure was determined by NMR. The duplex showed a maintained A-RNA helix. In U*, both 2'-O-acetal ester side chain and ring pucker presented a notable rigid conformation. The PivOM moiety was oriented with the carbonyl group turned outside the minor groove and with trans, -ac and -ac torsion angles around the C2'-O2', O2'-CA and CA-OB1 bonds respectively. Gauche effects and dipolar interactions between the PivOM and the backbone appeared to be the predominant factors influencing the PivOM conformation and the orientation of the two supplementary H acceptors suggested that hydration could also play a role in the duplex stability. PMID- 23455629 TI - A large prospective European cohort study of patients treated with strontium ranelate and followed up over 3 years. AB - Strontium ranelate has been available as an osteoporosis treatment in Europe since 2004. This article describes a large European observational survey of the use of strontium ranelate in clinical daily practice. A retrospective observational registry included 32,446 women consulting for postmenopausal osteoporosis in seven countries. Within the registry, 12,046 women were receiving strontium ranelate and were followed up over 3 years. The baseline characteristics of the follow-up cohort were similar to those of the whole registry cohort (age, 68.9 +/- 10.3 years; body mass index, 25.6 +/- 4.3 kg/m(2); lumbar spine T-score, -2.57 +/- 0.85 SD; femoral neck T-score, -2.11 +/- 0.86 SD). At baseline, 77 % of patients had at least one risk factor for osteoporosis, and 46 % had a previous history of osteoporotic fracture. Mean duration of follow up was 32.0 +/- 9.7 months, and treatment duration was 25.2 +/- 13.7 months (24,956 patient-years of treatment). Persistence with strontium ranelate was 80 % at 1 year, 68 % at 2 years, and 64 % at 32 months; most patients (about 80 %) reported rarely omitting a dose. At least one emergent adverse event was reported in 2,674 (22 %) patients, most frequently gastrointestinal side effects. The crude incidence of venous thromboembolic events was 2.1/1,000 patient-years. No cases of hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), Steven-Johnson syndrome, or toxic epidermal necrolysis, were reported. During follow-up, a fracture occurred in 890 patients (7 %); 429 of the fractures were nonvertebral fractures. Our observational survey over 32 months indicated good rates of adherence with strontium ranelate and confirmed its good safety profile in the management of postmenopausal osteoporosis. PMID- 23455631 TI - Ulnar nerve reference values for cross-sectional area, intranerve cross sectional area variability and side to side difference ratio. PMID- 23455630 TI - Oxidative stress in Mexicans with diffuse cutaneous systemic sclerosis. AB - To compare oxidative stress (OS) biomarkers and antioxidant capacity of plasma (ACP) between dcSSc (diffuse cutaneous systemic sclerosis) and healthy Mexicans and their possible relationship with autoantibodies, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and uric acid (UA). We included 28 dcSSc and 28 healthy individuals. Patients were grouped in early and late dcSSc and were excluded if they had infections, neoplasias, comorbidity, or antioxidant treatment. Lipoperoxidation products (malondialdehyde), protein oxidation products (carbonyls, dityrosines), ACP, CRP, ESR, and UA were investigated. Age was 47.5 +/- 10 in dcSSc versus 48 +/- 7 years in controls. In dcSSc, OS was higher and ACP was decreased versus controls (p < 0.001). OS was similar in early and late dcSSc. Anti-Scl-70 (anti-topoisomerase I) was associated with a higher OS (p < 0.05). Eight dcSSc patients had hyperuricemia (28.5 %). A significant correlation between UA and malondialdehyde, dityrosines and carbonyls levels (r = 0.52, r = 0.78 and r = 0.69, p < 0.01) respectively, was found in dcSSc group. A high level of ESR was present in 71 % and CRP in 40 % of dcSSc patients. Mexican dcSSc patients had elevated lipid/protein OS with respect to healthy controls. These OS biomarkers have direct correlation with UA levels. ESR and CRP were elevated in a great number of dcSSc patients. These biochemical markers suggest that dcSSc patients have a continuous stimulus for endothelial dysfunction and accelerated atherogenesis. PMID- 23455632 TI - Bone density in proton pump inhibitors users: a prospective study. AB - Patients with gastroesophageal reflux disease (GERD) receive long-term therapy with proton pump inhibitor (PPI) agents. Several studies have recently been published suggesting that treatment with PPI may cause bone fractures, although the number of prospective studies in this regard is limited. The aim of this study is to prospectively investigate the effect of PPIs on bone density. Between March 2009 and January 2011, 114 GERD patients (18-56 years) and 110 healthy controls were included in the present study. Bone mineral densitometry (BMD) by using dual-energy X-ray absorptiometry was assessed at lumbar spine and femur neck. BMD measurements were performed on all subjects at the beginning of the study. The patients were divided according to three drugs by their treatment with esomeprazole, lansoprazole, or pantoprazole. The study group was followed for at least 6 months on PPI therapy, and then BMD measurements were repeated. The mean duration of treatment with PPIs was 8.5 +/- 2.3 months. In patients receiving PPIs, the mean reduction in total vertebra T score following treatment compared to pre-treatment values was 00.23 +/- 0.42 units (95 % CI 0.15-0.30) (p < 0.01), while the mean reduction in the femur T score was 0.10 +/- 0.40 units (95 % CI 0.03-0.18) (p = 0.03). Reduction following treatment in L4 and total vertebra T scores of lansoprazole group was significantly higher than of pantoprazole group (p = 0.04). Reduction in femur T score of esomeprazole group was higher than of lansoprazole group and pantroprazole group, but it is not statistically significant. Treatment with a PPI results in a significant reduction in bone density. Close monitoring is beneficial for patients who are to receive long-term treatment with PPI. PMID- 23455633 TI - CIP2A facilitates apoptotic resistance of fibroblast-like synoviocytes in rheumatoid arthritis independent of c-Myc expression. AB - The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days (p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days (p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP (p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt (p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA. PMID- 23455634 TI - Obesity among women may increase the risk of arthritis: observations from the Canadian Community Health Survey, 2007-2008. AB - Cross-sectional data from the 2007 to 2008 Canadian Community Health Survey were used to investigate the joint effect of obesity and female on the prevalence of arthritis. A total of 94,758 subjects (44,282 men and 50,476 women) aged 18 years or over who answered the question concerning arthritis were included, and sampling weights and design effects were taken into account in the analysis. The prevalence of arthritis among obese (body mass index >= 30 kg/m(2)) men was 18.0 % and 29.8 % among obese women. The adjusted prevalence ratio for obesity associated with arthritis was 1.45 (95 % confidence interval 1.39, 1.52) for women and 1.38 (confidence interval 1.29, 1.47) for men. The combined effect of obesity and female sex was more than additivity, with the relative excess risk due to the interaction being 0.21 (95 % confidence interval 0.09, 0.32). Obesity is likely to have a larger effect on women with arthritis than men. PMID- 23455635 TI - Risk genes, metabolic syndrome and eye tracking deficits in psychiatric diseases. PMID- 23455638 TI - Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. AB - We report a new method to estimate the predictive performance of polygenic models for risk prediction and assess predictive performance for ten complex traits or common diseases. Using estimates of effect-size distribution and heritability derived from current studies, we project that although 45% of the variance of height has been attributed to SNPs, a model trained on one million people may only explain 33.4% of variance of the trait. Models based on current studies allow for identification of 3.0%, 1.1% and 7.0% of the populations at twofold or higher than average risk for type 2 diabetes, coronary artery disease and prostate cancer, respectively. Tripling of sample sizes could elevate these percentages to 18.8%, 6.1% and 12.2%, respectively. The utility of polygenic models for risk prediction will depend on achievable sample sizes for the training data set, the underlying genetic architecture and the inclusion of information on other risk factors, including family history. PMID- 23455636 TI - Seven new loci associated with age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 * 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 * 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD. PMID- 23455639 TI - Insect symbiont facilitates vector acquisition, retention, and transmission of plant virus. AB - Tomato yellow leaf curl virus (TYLCV) was first detected in China in 2006, following the introduction of Bemisia tabaci Q into China in 2003. Since then, the incidence of TYLCV in tomato fields in China has greatly increased as has the abundance and distribution of Q whiteflies containing the bacterial symbiont Hamiltonella with high frequency. This suggested that the symbiont Hamiltonella might associate with the transmission efficiency of TYLCV by the whitefly vector. Here we report the first evidence that the Hamiltonella is closely associated with the acquisition, retention, and transmission efficiency of TYLCV by the whitefly vector. Our findings combined with the outbreaks of TYLCV following the introduction of Q, provided an explanation for why Hamiltonella is being maintained at a relatively high level in Chinese B. tabaci Q and also have implications for disease and vector management. PMID- 23455640 TI - Production of volatile compounds in reconstituted milk reduced-fat cheese and the physicochemical properties as affected by exopolysaccharide-producing strain. AB - The application of the exopolysaccharide-producing strains for improving the texture and technical properties of reduced-fat cheese looks very promising. Streptococcus thermophilus TM11 was evaluated for production of reduced-fat cheese using reconstituted milk powder (CRMP). The physicochemical analysis of fresh and stored cheeses showed that this strain slightly increased moisture content resulting in cheese with higher yield and lower protein content compared to the direct acidified cheese. The volatiles of cheese were determined by SPME and GC equipped with a mass spectrometer. The results indicated that the major compounds included aldehydes, ketones and acids, whereas, alcohols and branched chain aldehydes that contribute to exciting and harsh flavors were not found in CRMP. By the textural profile analysis, we found the cheese made with S. thermophilus TM11 had lower cohesiveness, resilience and higher adhesiveness than the direct acidified cheese, and had similar hardness. Further, S. thermophilus TM11 greatly changed the protein matrix with more opened cavities according to observation by scanning electron microscopy. Consequently, use of S. thermophilus TM11 could endow CRMP with the novel and suitable flavor properties and improved texture quality. PMID- 23455641 TI - Published evidence from randomised trials indicates that pain after thoracotomy is more effectively relieved by thoracic epidural analgesia than by paravertebral blocks. PMID- 23455637 TI - A variant in FTO shows association with melanoma risk not due to BMI. AB - We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 * 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity. PMID- 23455642 TI - Engineering a 3D vascular network in hydrogel for mimicking a nephron. AB - Engineering functional vascular networks in vitro is critical for tissue engineering and a variety of applications. There is still a general lack of straightforward approaches for recapitulating specific structures and functions of vasculature. This report describes a microfluidic method that utilizes fibrillogenesis of collagen and a liquid mold to engineer three-dimensional vascular networks in hydrogel. The well-controlled vascular network demonstrates both mechanical stability for perfusing solutions and biocompatibility for cell adhesion and coverage. This technique enables the mimicry of passive diffusion in a nephron one of the main routes transferring soluble organic molecules. This approach could be used for in vitro modelling of mass transfer-involved physiology in vasculature-rich tissues and organs for regeneration and drug screening. PMID- 23455644 TI - Liquid chromatography/time-of-flight mass spectrometry analysis of postmortem blood samples for targeted toxicological screening. AB - A liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS) method for targeted toxicological screening in human postmortem blood samples from forensic autopsy cases has been developed, validated and compared with a previously used method using gas chromatography with nitrogen-phosphorus detection (GC-NPD). Separation was achieved within 12 min by high-resolution gradient chromatography. Ions were generated in positive and negative electrospray ionization mode and were detected in 2-GHz single mass spectrometry mode, m/z range 50-1,000. Before injection, 0.25 g blood was prepared by protein precipitation with 500 MUL of a mixture of acetonitrile and ethanol containing deuterated internal standards. An in-house database comprising 240 drugs and metabolites was built by analysing solutions from certified standards or other documented reference material available. Identification was based on scoring of retention time, accurate mass measurement and isotopic pattern. Validation was performed on spiked blood samples and authentic postmortem blood samples. The thresholds defined as minimum required performance levels were for most compounds in the range from 0.01 to 0.10 MUg/g. Typically, a mass error of less than 2 ppm and a precision of area measurements of less than 5 % coefficient of variation were achieved. Positive identification was confirmed at concentrations up to 500 MUg/g. Most compounds were determined in positive ionization mode, but for a limited number of compounds (fewer than 4 %) negative ionization was needed and a few early-eluted compounds could not be identified owing to substantial influence of interferences from the matrix and were thus not included in the screening. A robust and valid toxicological screening by LC-TOF-MS for postmortem blood samples, covering 50 % more compounds, and with higher precision and sensitivity than the previously used screening by GC-NPD was achieved. PMID- 23455645 TI - Rapid on-site detection of explosives on surfaces by ambient pressure laser desorption and direct inlet single photon ionization or chemical ionization mass spectrometry. AB - Considering current security issues, powerful tools for detection of security relevant substances such as traces of explosives and drugs/drug precursors related to clandestine laboratories are required. Especially in the field of detection of explosives and improvised explosive devices, several relevant compounds exhibit a very low vapor pressure. Ambient pressure laser desorption is proposed to make these substances available in the gas phase for the detection by adapted mass spectrometers or in the future with ion-mobility spectrometry as well. In contrast to the state-of-the-art thermal desorption approach, by which the sample surface is probed for explosive traces by a wipe pad being transferred to a thermal desorber unit, by the ambient pressure laser desorption approach presented here, the sample is directly shockwave ablated from the surface. The laser-dispersed molecules are sampled by a heated sniffing capillary located in the vicinity of the ablation spot into the mass analyzer. This approach has the advantage that the target molecules are dispersed more gently than in a thermal desorber unit where the analyte molecules may be decomposed by the thermal intake. In the technical realization, the sampling capillary as well as the laser desorption optics are integrated in the tip of an endoscopic probe or a handheld sampling module. Laboratory as well as field test scenarios were performed, partially in cooperation with the Federal Criminal Police Office (Bundeskriminalamt, BKA, Wiesbaden, Germany), in order to demonstrate the applicability for various explosives, drugs, and drug precursors. In this work, we concentrate on the detection of explosives. A wide range of samples and matrices have been investigated successfully. PMID- 23455646 TI - Characterising and correcting batch variation in an automated direct infusion mass spectrometry (DIMS) metabolomics workflow. AB - Direct infusion mass spectrometry (DIMS)-based untargeted metabolomics measures many hundreds of metabolites in a single experiment. While every effort is made to reduce within-experiment analytical variation in untargeted metabolomics, unavoidable sources of measurement error are introduced. This is particularly true for large-scale multi-batch experiments, necessitating the development of robust workflows that minimise batch-to-batch variation. Here, we conducted a purpose-designed, eight-batch DIMS metabolomics study using nanoelectrospray (nESI) Fourier transform ion cyclotron resonance mass spectrometric analyses of mammalian heart extracts. First, we characterised the intrinsic analytical variation of this approach to determine whether our existing workflows are fit for purpose when applied to a multi-batch investigation. Batch-to-batch variation was readily observed across the 7-day experiment, both in terms of its absolute measurement using quality control (QC) and biological replicate samples, as well as its adverse impact on our ability to discover significant metabolic information within the data. Subsequently, we developed and implemented a computational workflow that includes total-ion-current filtering, QC-robust spline batch correction and spectral cleaning, and provide conclusive evidence that this workflow reduces analytical variation and increases the proportion of significant peaks. We report an overall analytical precision of 15.9%, measured as the median relative standard deviation (RSD) for the technical replicates of the biological samples, across eight batches and 7 days of measurements. When compared against the FDA guidelines for biomarker studies, which specify an RSD of <20% as an acceptable level of precision, we conclude that our new workflows are fit for purpose for large-scale, high-throughput nESI DIMS metabolomics studies. PMID- 23455647 TI - Semi-automated 3D segmentation of major tracts in the rat brain: comparing DTI with standard histological methods. AB - Researchers working with rodent models of neurological disease often require an accurate map of the anatomical organization of the white matter of the rodent brain. With the increasing popularity of small animal MRI techniques, including diffusion tensor imaging (DTI), there is considerable interest in rapid segmentation methods of neurological structures for quantitative comparisons. DTI derived tractography allows simple and rapid segmentation of major white matter tracts, but the anatomic accuracy of these computer-generated fibers is open to question and has not been rigorously evaluated in the rat brain. In this study, we examine the anatomic accuracy of tractography-based segmentation in the adult rat brain. We analysed 12 major white matter pathways using semi-automated tractography-based segmentation alongside manual segmentation of Gallyas silver stained histology sections. We applied four fiber-tracking algorithms to the DTI data-two integration methods and two deflection methods. In many cases, tractography-based segmentation closely matched histology-based segmentation; however different tractography algorithms produced dramatically different results. Results suggest that certain white matter pathways are more amenable to tractography-based segmentation than others. We believe that these data will help researchers decide whether it is appropriate to use tractography-based segmentation of white matter structures for quantitative DTI-based analysis of neurologic disease models. PMID- 23455650 TI - Activation shift in elderly subjects across functional systems: an fMRI study. AB - The functional specificity of brain areas is diminished with age and accompanied by the recruitment of additional brain regions in healthy older adults. This process has repeatedly been demonstrated within distinct functional domains, in particular the visual system. However, it is yet unclear, whether this phenomenon in healthy aging, i.e., a reduced activation of task-associated areas and increased activation of additional regions, is also present across different functional systems. In the present functional imaging study, comprising 102 healthy subjects, we therefore assessed two distinct tasks engaging the sensory motor system and the visual attention system, respectively. We found a significant interaction between age and task in the parietal operculum bilaterally. This area as a part of the sensory-motor system showed an age related decrease in its BOLD-response to the motor task and an age-related increase of neural activity in response to the visual attention task. The opposite response pattern, i.e., reduced visual attention activation and increased response to the motor task, was observed for regions associated with the visual task: the superior parietal area 7A and the dorsal pre-motor cortex. Importantly, task performance was not correlated with age in either task. This age-by-task interaction indicates that a reduction of functional specificity in the aging brain may be counteracted by the increased recruitment of additional regions not only within, but also across functional domains. Our results thus emphasize the need for comparisons across different functional domains to gain a better understanding of age-related effects on the specificity of functional systems. PMID- 23455648 TI - More insights into early brain development through statistical analyses of eigen structural elements of diffusion tensor imaging using multivariate adaptive regression splines. AB - The aim of this study was to characterize the maturational changes of the three eigenvalues (lambda1 >= lambda2 >= lambda3) of diffusion tensor imaging (DTI) during early postnatal life for more insights into early brain development. In order to overcome the limitations of using presumed growth trajectories for regression analysis, we employed Multivariate Adaptive Regression Splines (MARS) to derive data-driven growth trajectories for the three eigenvalues. We further employed Generalized Estimating Equations (GEE) to carry out statistical inferences on the growth trajectories obtained with MARS. With a total of 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects, we found that the growth velocities of the three eigenvalues were highly correlated, but significantly different from each other. This paradox suggested the existence of mechanisms coordinating the maturations of the three eigenvalues even though different physiological origins may be responsible for their temporal evolutions. Furthermore, our results revealed the limitations of using the average of lambda2 and lambda3 as the radial diffusivity in interpreting DTI findings during early brain development because these two eigenvalues had significantly different growth velocities even in central white matter. In addition, based upon the three eigenvalues, we have documented the growth trajectory differences between central and peripheral white matter, between anterior and posterior limbs of internal capsule, and between inferior and superior longitudinal fasciculus. Taken together, we have demonstrated that more insights into early brain maturation can be gained through analyzing eigen-structural elements of DTI. PMID- 23455651 TI - Revealing surface oxidation on the organic semi-conducting single crystal rubrene with time of flight secondary ion mass spectroscopy. AB - To address the question of surface oxidation in organic electronics the chemical composition at the surface of single crystalline rubrene is spatially profiled and analyzed using Time of Flight - Secondary Ion Mass Spectroscopy (ToF-SIMS). It is seen that a uniform oxide (C42H28O) covers the surface while there is an increased concentration of peroxide (C42H28O2) located at crystallographic defects. By analyzing the effects of different primary ions, temperature and sputtering agents the technique of ToF-SIMS is developed as a valuable tool for the study of chemical composition variance both at and below the surface of organic single crystals. The primary ion beams C60(3+) and Bi3(+) are found to be most appropriate for mass spectroscopy and spatial profiling respectively. Depth profiling of the material is successfully undertaken maintaining the molecular integrity to a depth of ~5 MUm using an Ar cluster ion source as the sputtering agent. PMID- 23455652 TI - Creating accountability in image quality analysis part 1: the technology paradox. PMID- 23455654 TI - Plasmonic photocatalysis. AB - Plasmonic photocatalysis has recently facilitated the rapid progress in enhancing photocatalytic efficiency under visible light irradiation, increasing the prospect of using sunlight for environmental and energy applications such as wastewater treatment, water splitting and carbon dioxide reduction. Plasmonic photocatalysis makes use of noble metal nanoparticles dispersed into semiconductor photocatalysts and possesses two prominent features-a Schottky junction and localized surface plasmonic resonance (LSPR). The former is of benefit to charge separation and transfer whereas the latter contributes to the strong absorption of visible light and the excitation of active charge carriers. This article aims to provide a systematic study of the fundamental physical mechanisms of plasmonic photocatalysis and to rationalize many experimental observations. In particular, we show that LSPR could boost the generation of electrons and holes in semiconductor photocatalysts through two different effects the LSPR sensitization effect and the LSPR-powered bandgap breaking effect. By classifying the plasmonic photocatalytic systems in terms of their contact form and irradiation state, we show that the enhancement effects on different properties of photocatalysis can be well-explained and systematized. Moreover, we identify popular material systems of plasmonic photocatalysis that have shown excellent performance and elucidate their key features in the context of our proposed mechanisms and classifications. PMID- 23455655 TI - Generation of an effective anti-lung cancer vaccine by DTPP-mediated photodynamic therapy and mechanistic studies. AB - The objective of this study was to generate an effective vaccine against lung cancer using photosensitizing drug-mediated photodynamic therapy (PDT) and to study the mechanism. The efficiency of a photosensitizing drug (DTPP) was investigated by singlet oxygen yield determination, killing effect analysis, and cell apoptosis induction effect assessment. DTPP-based PDT tumor cell lysates and cell surface antigens obtained from acid-eluted adherent cells were then used as vaccines to prevent lung cancer using LA795 murine lung cells. The optimal protocol for PDT vaccine preparation was selected based on the tumor growth retardation effect of the vaccines, DTPP concentration, illumination dose, and numbers of DTPP-based PDT cells. To study the mechanism of the anti-tumor effect of vaccines, host anti-tumor immune responses were studied, including CD4(+)/CD8(+) ratios and percentage of NK cells and serum cytokine levels. A comparison of cytokine (IFN-gamma and IL-1) secretion from splenocytes and tumor pathologic features from mice immunized with vaccines were compared with controls and showed that the optimal protocol for PDT vaccine preparation was LA795 cells exposed to 10 MUg/ml DTPP photosensitizer for 24 h, illuminated with 7.2 J/cm(2) at 20 mW/cm(2) (630 nm) and 2 * 10(7) PDT cell lysates injected per mouse. DTPP based PDT cell lysate vaccination had a significant inhibitory effect on tumor growth based on increased CD4(+)/CD8(+) ratios, NK cell percentages, elevated serum IFN-gamma and IL-1 levels, and lymphocyte aggregation at the edge of tumors. Thus, DTPP-based PDT can induce LA795 cell apoptosis that can generate anti-tumor effects without use of an adjuvant. PMID- 23455656 TI - Study of photodynamic therapy in the control of isolated microorganisms from infected wounds--an in vitro study. AB - The effective treatment of infected wounds continues to be a serious challenge, mainly due to the rise of antibiotic-resistant bacteria. Photodynamic therapy (PDT) refers to the topical or systemic administration of a non-toxic, photosensitizing agent (PS), followed by irradiation with visible light of a suitable wavelength. The possibility of applying the PDT locally is what makes it so favorable to the treatment of infected wounds. The goal of this study was to evaluate the action of the PDT in the inactivation in vitro of microorganisms coming from infected wounds, using methylene blue (MB) and photodithazine (PDZ) as the PS and comparing the efficacy of these two compounds for PDT on bacteria. For the application of PDT, isolated microorganisms identified from material collected from wounds were suspended in a saline solution containing 10(6) viable cells/ml. Each isolated microorganism was submitted to PDT with MB and with PDZ in accordance with the following treatment groups: N/T--no treatment; T1--PDT with PDZ; T2--PDT with MB; T3--irradiation without PS; T4--treatment with PDZ without light; and T5--treatment with MB without light. As a light source, an LED based device was used (Biopdi/Irrad-Lead 660), composed of 54 LEDs, each with 70 mW of power in the 660 nm region of the electromagnetic spectrum. Each tray of 96 wells was irradiated with an intensity of 25 mW/cm(2) and a dose of light of 50 J/cm(3) for 33 min. All the tests were made in duplicate. It was then concluded that the PDT with PDZ was capable of inhibiting the growth of gram-positive bacteria samples, however it did not have the same effect on gram-negative bacteria, which showed growth greater than 100,000 CFU; the PDT with MB showed an effectiveness on gram-positive as well as gram-negative bacteria, for it was able to inhibit bacterial growth in both cases. PMID- 23455653 TI - Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes. AB - It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the "hyperfunction theory", which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions. Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age related diseases. As was emphasized by the author of the "hyperfunction model", many (or actually all) of them also play roles in cancer. So these "participants" in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal such as Oncotarget is the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers. PMID- 23455657 TI - The effects of low-level laser irradiation on cellular viability and proliferation of human skin fibroblasts cultured in high glucose mediums. AB - Delayed wound healing is one of the most challenging complications of diabetes mellitus (DM) in clinical medicine. This study has aimed to evaluate the effects of low-level laser therapy (LLLT) on human skin fibroblasts (HSFs) cultured in a high glucose concentration. HSFs were cultured either in a concentration of physiologic glucose (5.5 mM/l) or high glucose media (11.1 and 15 mM/l) for either 1 or 2 weeks after which they were subsequently cultured in either the physiologic glucose or high concentration glucose media during laser irradiation. LLLT was carried out with a helium-neon (He-Ne) laser unit at energy densities of 0.5, 1, and 2 J/cm(2), and power density of 0.66 mW/cm(2) on 3 consecutive days. HSFs' viability and proliferation rate were evaluated with the dimethylthiazol diphenyltetrazolium bromide (MTT) assay. The LLLT at densities of 0.5 and 1 J/cm(2) had stimulatory effects on the viability and proliferation rate of HSFs cultured in physiologic glucose (5.5 mM/l) medium compared to their control cultures (p = 0.002 and p = 0.046, respectively). All three doses of 0.5, 1, and 2 J/cm(2) had stimulatory effects on the proliferation rate of HSFs cultured in high glucose concentrations when compared to their control cultures (p = 0.042, p = 0.000, and p = 0.000, respectively). This study showed that HSFs originally cultured for 2 weeks in high glucose concentration followed by culture in physiologic glucose during laser irradiation showed enhanced cell viability and proliferation. Thus, LLLT had a stimulatory effect on these HSFs. PMID- 23455658 TI - A treatment-oriented typology of self-identified hypersexuality referrals. AB - Men and women have been seeking professional assistance to help control hypersexual urges and behaviors since the nineteenth century. Despite that the literature emphasizes that cases of hypersexuality are highly diverse with regard to clinical presentation and comorbid features, the major models for understanding and treating hypersexuality employ a "one size fits all" approach. That is, rather than identify which problematic behaviors might respond best to which interventions, existing approaches presume or assert without evidence that all cases of hypersexuality (however termed or defined) represent the same underlying problem and merit the same approach to intervention. The present article instead provides a typology of hypersexuality referrals that links individual clinical profiles or symptom clusters to individual treatment suggestions. Case vignettes are provided to illustrate the most common profiles of hypersexuality referral that presented to a large, hospital-based sexual behaviors clinic, including: (1) Paraphilic Hypersexuality, (2) Avoidant Masturbation, (3) Chronic Adultery, (4) Sexual Guilt, (5) the Designated Patient, and (6) better accounted for as a symptom of another condition. PMID- 23455659 TI - [Endoscopic submucosal dissection]. AB - Endoscopic submucosal dissection (ESD) was developed in Japan but has now also become permanently established in various centers in Europe. ESD is an endoscopic en bloc mucosal resection technique for the treatment of early cancers with a diameter >1 cm and also superficial precancerous lesions, which could only be removed unsatisfactorily in several fragments or with uncertain lateral safety margins using previous loop excision procedures. Using ESD a lesion is excised after circular marking and generous submucosal injection with a safety margin of approximately 5 mm and subsequently resected at the level of the submucosa with a 1-3 mm short diathermic knife. ESD requires high technical skills in interventional endoscopy and is more time-consuming than snare resection techniques. However, numerous studies have shown a clear superiority for ESD with respect to the R0 resection rate and the local recurrence rate. The present article gives a current review of the use of ESD in the upper and lower gastrointestinal tract and demonstrates perspectives of the procedure. PMID- 23455663 TI - Effectiveness of sensorimotor training in patients with rheumatoid arthritis: a randomized controlled trial. AB - The objective of this study was to evaluate the effectiveness of a sensorimotor training in patients with rheumatoid arthritis on the improvement of functional skills and quality of life, a double-blinded, prospective, randomized controlled trial. One hundred two participants with rheumatoid arthritis were selected. After the baseline evaluation, the participants were randomized to two different groups: sensorimotor group (2 sessions per week, 30-50 min each session, besides continuing taking the same drugs as the control group) and control group (control group was only submitted to the clinical drug treatment with Methotrexate, Leflunomide and/or Prednisone (5 mg), being then evaluated 4 months later). Functional capacity [Health Assessment Questionnaire (HAQ) and Timed Up & Go Test (TU>)], Balance and Gait (Berg Balance Scale (BBS) and Tinetti Test) and Quality of Life (Short Form Health Survey-SF-36). The study had been concluded with ninety-one participants, and a statistically significant improvement was found in all variables assessed: HAQ (P < .01), TU> (P < .01), BBS (P < .01), Tinetti Test (P < .01) and improvement in the subscales of SF-36 (P < .01) in the sensorimotor group in comparison with the baseline evaluation and control group. No significant difference was found related to the pre- and post-evaluation in the control group. Therefore, the sensorimotor training is effective in the improvement of the functional capacity and quality of life of patients with rheumatoid arthritis. PMID- 23455664 TI - Electric field dependence of excitation spectra in AB-stacked bilayer graphene. AB - The single- and many-particle Coulomb excitation spectra in Bernal bilayer graphene can be modulated by a uniform perpendicular electric field. The field induced oscillatory parabolic bands possess saddle points and local extrema, which, respectively, lead to logarithmically divergent peaks and discontinuous steps in the bare response functions. Such special structures are associated with the plasmon peaks in the screened loss spectra. Their main characteristics, such as their existence, frequency, and strength, vary strongly with the field strength and transferred momentum. The predicted results could be further examined by inelastic light scattering spectroscopy and electron-energy-loss spectroscopy. PMID- 23455665 TI - Cell suspension culture of Eriobotrya japonica regulates the diabetic and hyperlipidemic signs of high-fat-fed mice. AB - The present study investigates the anti-hyperlipidemic and antihyperglycemic effects and mechanism in high-fat (HF)-fed mice of cell suspension culture of Eriobotrya japonica (TA), which contains a great number of pentacyclic terpenoids. Firstly, C57BL/6J mice were randomly divided into two groups: the control (CON) group was fed with a low-fat diet (n = 9), whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was orally given TA or rosiglitazone or not for 4 weeks. Blood and visceral adipose tissue, liver tissue and skeletal muscle were examined. Treatment with TA reduced body weight gain, weights of white adipose tissue (WAT) (including epididymal, perirenal, mesenteric WAT and visceral fat), and hepatic triacylglycerol content significantly without affecting food intake in diet-induced diabetic mice. TA effectively prevented HF diet-induced increases in the levels of blood glucose, insulin, leptin and HOMA-IR index (p < 0.001, p < 0.05, p < 0.05, p < 0.01, respectively) and attenuated insulin resistance. Treatment with TA, adipocytes in the visceral depots showed a reduction in size. TA effectively significantly increased the protein contents of phosphorylation of AMPK-alpha (Thr172) both in liver and adipose tissue. It is shown that TA exhibits hypolipidemic effect in HF fed mice by decreasing gene expressions of fatty acid synthesis, including acyl coenzyme A: diacylglycerol acyltransferase (DGAT) 2, which catalyzes the final step in the synthesis of triglycerides, and antidiabetic properties occurred as a result of decreased hepatic glucose production via phosphenolpyruvate carboxykinase (PEPCK) down- regulation, improved insulin sensitization and TA (at 1.0 g/kg dose) decreased expression of hepatic and adipose 11-beta-hydroxysteroid dehydroxygenase (11beta-HSD1) gene, which contributed in attenuating diabetic state. Futhermore, TA at doses of 0.5 and 1.0 g/kg had serum lipid-lowering action characterized by the inhibition of DGAT 1 expression. Thus, amelioration of diabetic and dyslipidemic state by TA in HF-fed mice occurred by regulation of PEPCK, DGAT2 and AMPK phosphorylation. PMID- 23455666 TI - Insecticidal and feeding deterrent effects of fraxinellone from Dictamnus dasycarpus against four major pests. AB - Fraxinellone, a well-known and significant naturally occurring compound isolated from Meliaceae and Rutaceae spp. has been widely used as a drug for the treatment of tumors. On the other hand, fraxinellone exhibited a variety of insecticidal activities including feeding-deterrent activity, inhibition of growth, and larvicidal activity. The present study focused on the antifeedant and larvicidal activities of fraxinellone against the larvae of Lepidoptera, including Mythimna separata, Agrotis ypsilon, Plutella xylostella, and one kind of sanitary pest, Culux pipiens pallens. Meanwhile, the ovicidal activities and the effects of fraxinellone on the larval development of M. separata were also observed. The LC50 values of fraxinellone against 3rd instar larvae of M. separata, 2nd instar larvae of P. xylostella and 4th instar larvae of C. pipiens pallens were 15.95/6.43/3.60 * 10-2 mg mL-1, and its AFC50 values against 5th instar larvae of M. separata, 2nd instar larvae of P. xylostella and 2nd instar larvae of A. ypsilon were 10.73/7.93/12.58 mg mL-1, respectively. Compared with the control group, fraxinellone obviously inhibited the pupation rate and the growth of M. separata. Once M. separata was treated with fraxinellone at concentrations of 5.0, 10.0, and 20.0 mg mL-1, respectively, the stages from the larvae to adulthood and the egg hatching duration were prolonged to 1/2/3, and 4/3/4 days, respectively. Additionally, fraxinellone strongly inhibited the development rate and the egg hatch proportion of M. separata. PMID- 23455667 TI - Antibacterial activity composition of the fermentation broth of Streptomyces djakartensis NW35. AB - The new compound Z-4-2 was isolated from the fermentation broth of Streptomyces djakartensis NW35, together with the known compound N-acetyltryptamine (Z-9-2) by bioassay-guided fractionation. Its chemical structure was elucidated as (E)-2 methoxy-1,4 naphthoquinone-1-oxime (Z-4-2) mainly by NMR analyses and MS spectral data. Their antibacterial activities against bacteria were evaluated by the filter paper method. The results of indicated that these compounds possess significant antibacterial activities. PMID- 23455668 TI - Secondary metabolites from Sida rhombifolia L. (Malvaceae) and the vasorelaxant activity of cryptolepinone. AB - The phytochemical study of Sida rhombifolia L. (Malvaceae) led to the isolation through chromatographic techniques of eleven secondary metabolites: sitosterol (1a) and stigmasterol (1b), sitosterol-3-O-b-D-glucopyranoside (2a) and stigmasterol-3-O-b-D-glucopyranoside (2b), phaeophytin A (3), 173 ethoxypheophorbide A (4), 132-hydroxy phaeophytin B (5), 173-ethoxypheophorbide B (6), 5,7-dihydroxy-4'-methoxyflavone (7), cryptolepinone (8) and a salt of cryptolepine (9). Their structures were identified by 1H- and 13C-NMR using one- and two-dimensional techniques. In addition, the vasorelaxant activity of cryptolepinone in rat mesenteric artery rings is reported herein for the first time. PMID- 23455669 TI - Lactones 41. Synthesis and microbial hydroxylation of unsaturated terpenoid lactones with p-menthane ring systems. AB - Racemic [(+/-)-4-isopropyl-1-methyl-7-oxa-cis-bicyclo[4.3.0]non-4-en-8-one] and optically active delta,epsilon-unsaturated lactones [(-)-(1R,6R)-4-isopropyl-1 methyl-7-oxabicyclo[4.3.0]non-4-en-8-one and (+)-(1S,6S)-4-isopropyl-1-methyl-7 oxabicyclo[4.3.0] non-4-en-8-one)] with the p-menthane system were obtained and their odoriferous properties were evaluated. Biotransformations of the racemic lactone with three fungal strains: Absidia cylindrospora AM336, Absidia glauca AM177 and Syncephalastrum racemosum AM105, were carried out. Microbial transformations afforded hydroxylactones with the hydroxy group in the allylic position. PMID- 23455670 TI - Synthesis of new BINAP-based aminophosphines and their 31P-NMR spectroscopy. AB - BINAP aminophosphines are prevalent N,P-bidentate, chiral ligands for asymmetric catalysis. While modification via the BINAP-nitrogen linkage is well explored and has provided a diverse body of derivatives, modification of the other substituents of the phosphorous center is another avenue in generating new congeners of this important class of chiral ligands. Herein reported are new BINAP aryl aminophosphines with electron rich or deficient substituents on the aryl rings. This scalable synthesis converted readily available starting material, (S)-BINOL, to a key intermediate (S)-NOBIN, from which the final chiral aminophosphines were prepared via a palladium-catalyzed, phosphonylation reaction. The aryl substituents are able to modify the electronic properties of the phosphorous center as indicated by the range of 31P-NMR shifts of these new ligands. A computational analysis was performed to linearly quantitate contributions to the 31P-NMR shifts from both resonance and field effects of the substituents. This correlation may be useful for designing and preparing other related aminophosphines with varying ligand properties. PMID- 23455671 TI - Characterization of proanthocyanidins from Parkia biglobosa (Jacq.) G. Don. (Fabaceae) by Flow Injection Analysis-Electrospray Ionization Ion Trap Tandem Mass Spectrometry and Liquid Chromatography/Electrospray Ionization Mass Spectrometry. AB - The present study investigates the chemical composition of the African plant Parkia biglobosa (Fabaceae) roots and barks by Liquid Chromatography-Electrospray Ionization and Direct Injection Tandem Mass Spectrometry analysis. Mass spectral data indicated that B-type oligomers are present, namely procyanidins and prodelphinidins, with their gallate and glucuronide derivatives, some of them in different isomeric forms. The analysis evidenced the presence of up to 40 proanthocyanidins, some of which are reported for the first time. In this study, the antiradical activity of extracts of roots and barks from Parkia biglobosa was evaluated using DPPH method and they showed satisfactory activities. PMID- 23455672 TI - Apocynin: chemical and biophysical properties of a NADPH oxidase inhibitor. AB - Apocynin is the most employed inhibitor of NADPH oxidase (NOX), a multienzymatic complex capable of catalyzing the one-electron reduction of molecular oxygen to the superoxide anion. Despite controversies about its selectivity, apocynin has been used as one of the most promising drugs in experimental models of inflammatory and neurodegenerative diseases. Here, we aimed to study the chemical and biophysical properties of apocynin. The oxidation potential was determined by cyclic voltammetry (Epa = 0.76V), the hydrophobicity index was calculated (logP = 0.83) and the molar absorption coefficient was determined (e275nm = 1.1 * 104 M-1 cm-1). Apocynin was a weak free radical scavenger (as measured using the DPPH, peroxyl radical and nitric oxide assays) when compared to protocatechuic acid, used here as a reference antioxidant. On the other hand, apocynin was more effective than protocatechuic acid as scavenger of the non-radical species hypochlorous acid. Apocynin reacted promptly with the non-radical reactive species H2O2 only in the presence of peroxidase. This finding is relevant, since it represents a new pathway for depleting H2O2 in cellular experimental models, besides the direct inhibition of NADPH oxidase. This could be relevant for its application as an inhibitor of NOX4, since this isoform produces H2O2 and not superoxide anion. The binding parameters calculated by fluorescence quenching showed that apocynin binds to human serum albumin (HSA) with a binding affinity of 2.19 * 104 M-1. The association did not alter the secondary and tertiary structure of HSA, as verified by synchronous fluorescence and circular dichroism. The displacement of fluorescent probes suggested that apocynin binds to site I and site II of HSA. Considering the current biomedical applications of this phytochemical, the dissemination of these chemical and biophysical properties can be very helpful for scientists and physicians interested in the use of apocynin. PMID- 23455673 TI - New limonoids and a dihydrobenzofuran norlignan from the roots of Toona sinensis. AB - Two new limonoids, toonins A (1) and B (2), and one new dihydrobenzofuran norlignan, toonin C (3), were isolated from the roots of Toona sinensis together with the ten known compounds 4-methoxy-6-(2',4'-dihydroxy-6'-methylphenyl)-pyran 2-one (4), bourjotinolone A (5), proceranone (6), matairesinol (7), 4-hydroxy-3 methoxybenzene-ethanol (8), syringic acid (9), isoscopoletin (10), lyoniresinol (11), aloeemodin (12), and beta-sitosterol (13). Their structures were elucidated on the basis of one- and two-dimensional spectroscopic analysis. Isolation of compounds 4, 6-13 from this plant is reported here for the first time. PMID- 23455674 TI - Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms. AB - The transcription factor Bcl-6 orchestrates germinal center (GC) reactions through its actions in B cells and T cells and regulates inflammatory signaling in macrophages. Here we found that genetic replacement with mutated Bcl6 encoding Bcl-6 that cannot bind corepressors to its BTB domain resulted in disruption of the formation of GCs and affinity maturation of immunoglobulins due to a defect in the proliferation and survival of B cells. In contrast, loss of function of the BTB domain had no effect on the differentiation and function of follicular helper T cells or that of other helper T cell subsets. Bcl6-null mice had a lethal inflammatory phenotype, whereas mice with a mutant BTB domain had normal healthy lives with no inflammation. The repression of inflammatory responses by Bcl-6 in macrophages was accordingly independent of the repressor function of the BTB domain. Bcl-6 thus mediates its actions through lineage-specific biochemical functions. PMID- 23455675 TI - Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. AB - During pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we found that recognition of intracellular antibodies by TRIM21 activated immune signaling. TRIM21 catalyzed the formation of Lys63 (K63)-linked ubiquitin chains and stimulated the transcription factor pathways of NF-kappaB, AP-1, IRF3, IRF5 and IRF7. Activation resulted in the production of proinflammatory cytokines, modulation of natural killer stress ligands and induction of an antiviral state. Intracellular antibody signaling was abrogated by genetic deletion of TRIM21 and was restored by ectopic expression of TRIM21. The sensing of antibodies by TRIM21 was stimulated after infection by DNA or RNA nonenveloped viruses or intracellular bacteria. Thus, the antibody-TRIM21 detection system provides potent, comprehensive activation of the innate immune system independently of known pattern-recognition receptors. PMID- 23455677 TI - Synergistic effects within a C2-symmetric organocatalyst: the potential formation of a chiral catalytic pocket. AB - This study describes the synthesis of five novel C2-symmetric organocatalysts that facilitate the on-water asymmetric aldol reaction at low catalyst loading (1 mol%) without the use of additives. Each catalyst is composed of two diprolinamide units joined by a symmetric alkyl bridging group allowing for systematic modulation of catalytic site proximity. Typically, catalysts in this manuscript which bear the catalytic units in close proximity gave the best reaction outcomes in terms of conversion (up to >99%), diastereomeric ratio (4/96, syn/anti) and enantiomeric excess (up to 97%). This effect has been attributed to the assembly of a chiral pocket, facilitated by hydrogen bonding at the oil-in-water interface. PMID- 23455676 TI - The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. AB - NKp46+ innate lymphoid cells (ILCs) serve important roles in regulating the intestinal microbiota and defense against pathogens. Whether NKp46+ ILCs arise directly from lymphoid tissue-inducer (LTi) cells or represent a separate lineage remains controversial. We report here that the transcription factor T-bet (encoded by Tbx21) was essential for the development of NKp46+ ILCs but not of LTi cells or nuocytes. Deficiency in interleukin 22 (IL-22)-producing NKp46+ ILCs resulted in greater susceptibility of Tbx21-/- mice to intestinal infection. Haploinsufficient T-bet expression resulted in lower expression of the signaling molecule Notch, and Notch signaling was necessary for the transition of LTi cells into NKp46+ ILCs. Furthermore, NKp46+ ILCs differentiated solely from the CD4- LTi population, not the CD4+ LTi population. Our results pinpoint the regulation of Notch signaling by T-bet as a distinct molecular pathway that guides the development of NKp46+ ILCs. PMID- 23455680 TI - Understanding the experiences of youth living with sickle cell disease: a photovoice pilot. AB - A Photovoice pilot was conducted with youth living with sickle cell disease (SCD), in order to further understand their lived experience and examine the acceptability, feasibility, and utility of this method in this population. SCD is an inherited genetic condition whose primary symptom is severe pain. Youth were able to reflect on their experiences with SCD using Photovoice and the adapted SHOWeD method. Parents and youth found Photovoice to be valuable for children and adolescents with SCD. Emerging themes included the impact of SCD, the importance of everyday activities and interests, and the importance of family and support. PMID- 23455682 TI - The centers for medicare & medicaid services diabetes health disparities reduction program. AB - The Centers for Medicare & Medicaid Services has implemented 3 prevention interventions programs to bring diabetes self-management education to vulnerable populations via Medicare's Quality Improvement Organizations. The programs and the lessons derived from a Federal initiative geared to closing the health disparities gap are described. PMID- 23455681 TI - "The black man's country club": assessing the feasibility of an HIV risk reduction program for young heterosexual African American men in barbershops. AB - Despite increasing HIV/AIDS morbidity and mortality, focus on young heterosexual African American men is limited. Nontraditional community-based prevention programs may be most effective for this demographic. Barbershops are one potential venue; however, barbers' and barbershop owners' views on the concept are less known. This paper describes attitudes and beliefs among barbers and barbershop owners regarding delivering a barber-facilitated, skills-based HIV risk-reduction intervention to their clientele. Participants believed that young heterosexual African American men were at significant risk for HIV and highly regarded the intervention model. This novel work contributes a voice to the literature that is infrequently heard. PMID- 23455683 TI - Hiring a pediatric health care advocate for advisory and support services. AB - In this study, factors that influence a person's likelihood of hiring a pediatric health care advocate (HCA) for support and/or advisory services were examined. Participants were asked to read vignettes in which a child's symptom severity, probability of mortality, and age were manipulated. A significantly higher likelihood of hiring an HCA for advisory services than for support services was found. A significant interaction between level of mortality and type of service indicated that when mortality was depicted as high, participants reported a greater likelihood of hiring an HCA for support services than for advisory services. PMID- 23455684 TI - A community assessment to inform a multilevel intervention to reduce cardiovascular disease risk and risk disparities in a rural community. AB - To complete a formative evaluation to identify community-level assets and barriers to healthy lifestyle choices, we conducted qualitative interviews, community audits, and secondary data analyses. We solicited local leaders' perspectives regarding winnability of obesity prevention policy options. Participants noted that many resources were available, yet a barrier was high cost. There were more parks per capita in low-income areas, but they were of lower quality. The most winnable obesity prevention policy was incentives for use of food from local farms. Results are being used to inform an intervention to reduce cardiovascular disease risk in rural eastern North Carolina. PMID- 23455685 TI - Factors associated with successful completion of the chronic disease self management program by adults with type 2 diabetes. AB - This study examines factors associated with completion (attendance >=4 of 6 sessions) of the Chronic Disease Self-Management Program (CDSMP) by adults with type 2 diabetes. Patients with glycated hemoglobin >= 7.5 within 6 months were enrolled and completed self-report measures on demographics, health status, and self-care (n = 146). Significant differences in completion status were found for several self-care factors including healthful eating plan, spacing carbohydrates, frequent exercise, and general health. Completion was not influenced by race/ethnicity or socioeconomics. Results suggest better attention to exercise and nutrition at the start of CDSMP may be associated with completion, regardless of demographic subgroup. PMID- 23455687 TI - Social determinants of good hand-washing practice (GHP) among adolescents in a rural Indian community. AB - A cross-sectional study was conducted in 5 randomly selected villages to assess prevalence of good hand-washing practice (GHP) among adolescents, and describe the social determinants. The prevalence of adolescent GHP was 32.1% (95% CI = 27.1, 37.1). Logistic regression established 5 significant positive predictors maternal GHP, presence of sanitary latrine, availability of soap at hand-washing locations, in-house water supply, and higher per capita income. Our research provides a scope for better understanding of the socioeconomic determinants of GHP in a rural Indian setting, and may find implications in the Total Sanitation Campaign launched by Government of India. PMID- 23455686 TI - Diabetes prevention, weight loss, and social support: program participants' perceived influence on the health behaviors of their social support system. AB - This study examined participants' perceptions of how their involvement in a well established weight loss and diabetes prevention program influenced their social support persons (SSPs). Utilizing a mixed-methods approach, participants were surveyed to determine their perceived influence on SSPs. Compared to controls, intervention participants reported that SSPs' lifestyle changes were more positively influenced by their study participation, and their amount of weight loss was related to favorability of perceived changes in SSPs' eating habits. Themes of lifestyle changes, knowledge dissemination, and motivation emerged from responses. Future lifestyle change interventions could potentially capitalize on program participants' influence on their social support networks. PMID- 23455688 TI - Study of metabonomic profiles of human esophageal carcinoma by use of high resolution magic-angle spinning 1H NMR spectroscopy and multivariate data analysis. AB - Esophageal carcinoma (EC) is one of the most common malignant tumors. EC survival has remained disappointingly low because of the high malignancy of esophageal cancer and the lack of obvious clinical symptoms at an early stage. Early diagnosis is often difficult because the small tumor nodules are frequently missed. Metabonomics based on high-resolution magic-angle spinning (HRMAS) NMR has been popular for tumor detection because it is highly sensitive, provides rich biochemical information and requires no sample pretreatment. (1)H HRMAS spectra of non-involved adjacent esophageal tissues and of well differentiated and moderately differentiated esophageal carcinoma tumors were recorded and analyzed by use of multivariate and statistical analysis techniques. Moderately differentiated EC tumors were found to have increased total choline, alanine, and glutamate and reduced creatine, myo-inositol, and taurine compared with non involved adjacent tissues. Moreover, clear differences between the metabonomic profiles of EC tissues enabled tumor differentiation. Furthermore, the integral Gly/MI ratio for samples of different tissue types were statistically significantly different; this was sufficient both for distinguishing non-involved tissues from esophageal carcinoma and for classification of well differentiated and moderately differentiated EC tumors. PMID- 23455689 TI - MALDI-Q-TOF mass spectrometric determination of gold and platinum in tissues using their diethyldithiocarbamate chelate complexes. AB - A rapid determination method is presented for gold (Au(3+)) and platinum (Pt(4+)) in tissues using matrix-assisted laser desorption ionization quadrupole time-of flight mass spectrometry (MALDI-Q-TOF-MS). Au and Pt ions in wet-ashed tissue solution were reacted with diethyldithiocarbamate (DDC), and the resulting chelate complex ions Au(DDC)2 (+) and Pt(DDC)3 (+) were detected by MALDI-Q-TOF MS using alpha-cyano-4-hydroxycinnamic acid as a matrix. The limit of detection (LOD) was 0.8 ng/g tissue and the quantification range was 2-400 ng/g for Au, and the LOD was 6 ng/g tissue and the quantification range was 20-4,000 ng/g for Pt. The Pt levels detected by MALDI-Q-TOF-MS in several tissues of a patient overdosed with cisplatin were nearly the same as those detected by flow-injection electrospray ionization mass spectrometry. The LODs of Au and Pt were 0.04 pg per well (sample spot) and 0.3 pg per well, respectively. To our knowledge, this is the first attempt to quantify Au(3+) and Pt(4+) ions in tissues by MALDI-Q-TOF MS. PMID- 23455690 TI - Aeroelasticity-based fluid agitation for lab-on-chips. AB - In this study, we report a robust agitation method for small-volume liquids. It utilizes an elastic diaphragm as the bottom of a liquid chamber, upon which an initial tension is also applied to enhance the aeroelasticity effects at small/micro scales. As a result, spontaneous vibration of the diaphragm can be induced by an external air flow, which further provides fluid agitations. The device structure is simple and can be easily fabricated at low cost. More importantly, the vibration amplitude is controllable and varies widely from several tens to several hundred micrometers depending on the applied air pressure. The resulting agitation is effective and applicable at high viscosities of up to 900 cSt. The influences of air pressure and liquid viscosity on the vibration frequency are discussed. Potential applications of this technique for solid particle agitation, focusing and fluid mixing are also demonstrated. PMID- 23455692 TI - Comparative analysis of DNA methylation polymorphism in drought sensitive (HPKC2) and tolerant (HPK4) genotypes of horse Gram (Macrotyloma uniflorum). AB - DNA methylation is known as an epigenetic modification that affects gene expression in plants. Variation in CpG methylation behavior was studied in two natural horse gram (Macrotyloma uniflorum [Lam.] Verdc.) genotypes, HPKC2 (drought-sensitive) and HPK4 (drought-tolerant). The methylation pattern in both genotypes was studied through methylation-sensitive amplified polymorphism. The results revealed that methylation was higher in HPKC2 (10.1%) than in HPK4 (8.6%). Sequencing demonstrated sequence homology with the DRE binding factor (cbf1), the POZ/BTB protein, and the Ty1-copia retrotransposon among some of the polymorphic fragments showing alteration in methylation behavior. Differences in DNA methylation patterns could explain the differential drought tolerance and the epigenetic signature of these two horse gram genotypes. PMID- 23455693 TI - Gut microbiota as potential therapeutic target for the treatment of cow's milk allergy. AB - Cow's milk allergy (CMA) continues to be a growing health concern for infants living in Western countries. The long-term prognosis for the majority of affected infants is good, with about 80% naturally acquiring tolerance by the age of four years. However, recent studies suggest that the natural history of CMA is changing, with an increasing persistence until later ages. The pathogenesis of CMA, as well as oral tolerance, is complex and not completely known, although numerous studies implicate gut-associated immunity and enteric microflora, and it has been suggested that an altered composition of intestinal microflora results in an unbalanced local and systemic immune response to food allergens. In addition, there are qualitative and quantitative differences in the composition of gut microbiota between patients affected by CMA and healthy infants. These findings prompt the concept that specific beneficial bacteria from the human intestinal microflora, designated probiotics, could restore intestinal homeostasis and prevent or alleviate allergy, at least in part by interacting with the intestinal immune cells. The aim of this paper is to review what is currently known about the use of probiotics as dietary supplements in CMA. PMID- 23455694 TI - High power enzymatic biofuel cell based on naphthoquinone-mediated oxidation of glucose by glucose oxidase in a carbon nanotube 3D matrix. AB - We report the design of a novel glucose/O2 biofuel cell (GBFC) integrating carbon nanotube-based 3D bioelectrodes and using naphthoquinone-mediated oxidation of glucose by glucose oxidase and direct oxygen reduction by laccase. The GBFCs exhibit high open circuit voltages of 0.76 V, high current densities of 4.47 mA cm(-2), and maximum power output of 1.54 mW cm(-2), 1.92 mW mL(-1) and 2.67 mW g( 1). The GBFC is able to constantly deliver 0.56 mW h cm(-2) under discharge at 0.5 V, showing among the best in vitro performances for a GBFC. Using a charge pump, the GBFC finally powered a Light Emitting Diode (LED), demonstrating its ability to amplify micro watts to power mW-demanding electronic devices. PMID- 23455695 TI - Multi-scale simulation of structural heterogeneity of swift-heavy ion tracks in complex oxides. AB - Tracks formed by swift-heavy ion irradiation, 2.2 GeV Au, of isometric Gd2Ti2O7 pyrochlore and orthorhombic Gd2TiO5 were modeled using the thermal-spike model combined with a molecular-dynamics simulation. The thermal-spike model was used to calculate the energy dissipation over time and space. Using the time, space, and energy profile generated from the thermal-spike model, the molecular-dynamics simulations were performed to model the atomic-scale evolution of the tracks. The advantage of the combination of these two methods, which uses the output from the continuum model as an input for the atomistic model, is that it provides a means of simulating the coupling of the electronic and atomic subsystems and provides simultaneously atomic-scale detail of the track structure and morphology. The simulated internal structure of the track consists of an amorphous core and a shell of disordered, but still periodic, domains. For Gd2Ti2O7, the shell region has a disordered pyrochlore with a defect fluorite structure and is relatively thick and heterogeneous with different degrees of disordering. For Gd2TiO5, the disordered region is relatively small as compared with Gd2Ti2O7. In the simulation, 'facets', which are surfaces with definite crystallographic orientations, are apparent around the amorphous core and more evident in Gd2TiO5 along [010] than [001], suggesting an orientational dependence of the radiation response. These results show that track formation is controlled by the coupling of several complex processes, involving different degrees of amorphization, disordering, and dynamic annealing. Each of the processes depends on the mass and energy of the energetic ion, the properties of the material, and its crystallographic orientation with respect to the incident ion beam. PMID- 23455696 TI - High-cell-density culture strategies for polyhydroxyalkanoate production: a review. AB - This article gives an overview of high-cell-density cultures for polyhydroxyalkanoate (PHA) production and their modes of operation for increasing productivity. High cell densities are very important in PHA production mainly because this polymer is an intracellular product accumulated in various microorganisms, so a high cellular content is needed for the polymer production. This review describes relevant results from fed-batch, repeated batch, and continuous modes of operation without and with cell recycle for the production of these polymers by microorganisms. Finally, recombinant microorganisms for PHA production, as well future directions for PHA production, are discussed. PMID- 23455697 TI - Isolation of natural red colorants from fermented broth using ionic liquid-based aqueous two-phase systems. AB - There is a growing demand for natural colorants. This is prompting the search for new alternative and "benign" separation systems allowing higher recoveries, extraction yields, and selectivities. This work investigates the use of aqueous two-phase systems (ATPS) based on ionic liquids as extraction processes for the recovery of red colorants from the fermented broth of Penicillium purpurogenum DPUA 1275. Several ATPS based on quaternary ammonium and imidazolium were studied in this work aiming at separating the red colorants produced from the remaining colorants and contaminant proteins present in the fermented broth. The results suggest that the red colorants can be isolated by an appropriate manipulation of some of the process conditions, such as the use of quaternary ammonium with short alkyl chains, alkaline media, and short tie-line lengths (extraction point systems with lower concentrations of ionic liquid). These conditions allow large partition coefficients for the red colorants (K red = 24.4 +/- 2.3), high protein removal (60.7 +/- 2.8 %) and selectivity parameters (S red/prot = 10.05). PMID- 23455698 TI - Response surface methodology for optimising the culture conditions for eicosapentaenoic acid production by marine bacteria. AB - Polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA), are increasingly attracting scientific attention owing to their significant health promoting role in the human body. However, the human body lacks the ability to produce them in vivo. The limitations associated with the current sources of omega-3 fatty acids from animal and plant sources have led to increased interest in microbial production. Bacterial isolate 717 was identified as a potential high EPA producer. As an important step in the process development of the microbial PUFA production, the culture conditions at the bioreactor scale were optimised for the isolate 717 using a response surface methodology exploring the significant effect of temperature, pH and dissolved oxygen and the interaction between them on the EPA production. This optimisation strategy led to a significant increase in the amount of EPA produced by the isolate under investigation, where the amount of EPA increased from 9 mg/g biomass (33 mg/l representing 7.6 % of the total fatty acids) to 45 mg/g (350 mg/l representing 25 % of the total fatty acids). To avoid additional costs associated with extreme cooling at large scale, a temperature shock experiment was carried out reducing the overall cooling time from the whole cultivation process to 4 h only prior to harvest. The ability of the organism to produce EPA under the complete absence of oxygen was tested revealing that oxygen is not critically required for the biosynthesis of EPA but the production improved in the presence of oxygen. The stability of the produced oil and the complete absence of heavy metals in the bacterial biomass are considered as an additional benefit of bacterial EPA compared to other sources of PUFA. To our knowledge this is the first report of a bacterial isolate producing EPA with such high yields making the large-scale manufacture much more economically viable. PMID- 23455699 TI - Vigilance of hemodynamic changes immediately after transferring patients is crucial. AB - PURPOSE: A decrease in blood pressure is sometimes observed when a postsurgical patient is transferred to another bed after recovering from anesthesia. However, the mechanism behind this hypotension has not been completely elucidated. The purpose of this study was to investigate and compare changes in hemodynamic properties for possible causes of hypotension before and after transfer to another bed of postsurgical patients receiving general anesthesia, combined epidural and general anesthesia, or combined spinal and general anesthesia. METHODS: We studied 69 patients undergoing elective surgery who were randomized to receive anesthesia by one of the three methods. After surgery, the tracheal tube was removed, and each patient was transferred to another bed. Hemodynamic data recorded immediately before and after transfer of the patient to another bed were compared. RESULTS: After transfer of patients receiving general anesthesia or combined epidural and general anesthesia, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and cardiac output (CO) decreased; heart rate (HR) and systemic vascular resistance (SVR) did not change. However, after transfer of patients receiving combined spinal and general anesthesia, SAP, DAP, HR, and CO decreased, but SVR did not change. CONCLUSION: The decrease in blood pressure observed after transfer of a postsurgical patient to another bed after general, combined epidural and general, and combined spinal and general anesthesia was associated with a decrease in CO and no change in SVR, but HR decreased after combined spinal and general anesthesia, whereas it was unchanged after general and combined epidural and general anesthesia. The decrease in blood pressure is assumed to be caused by a decrease in venous return, and several reflexes might participate in this decrease of blood pressure, especially after combined spinal and general anesthesia. PMID- 23455700 TI - Isolated transient diplopia and nystagmus after spinal anesthesia. PMID- 23455701 TI - Retraction note: Notice of formal retraction of articles by Dr. Yoshitaka Fujii. PMID- 23455702 TI - TLR4, IL10RA, and NOD2 mutation in paediatric Crohn's disease patients: an association with Mycobacterium avium subspecies paratuberculosis and TLR4 and IL10RA expression. AB - Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated in the pathogenesis of Crohn's disease (CD). The role of CD susceptibility genes in association with these microbes is not known. Sixty-two early onset paediatric CD patients and 46 controls with known MAP status were analysed for an association with 34 single nucleotide polymorphisms (SNPs) from 18 CD susceptibility genes. Functional studies on peripheral blood mononuclear cells (PBMCs) were conducted on 17 CD patients with known CD mutations to assess IL-6, IL-10, and TNF-alpha expression upon stimulation with MAP precipitated protein derivative (PPD) and lipopolysaccharide (LPS). In addition, surface expression of IL10R and TLR4 on resting B cells, NK cells, T cells, and monocytes was assessed. A mutation in TLR4 (rs4986790) and IL10RA (rs22291130) was significantly associated with MAP positive CD patients compared to MAP-negative CD patients (27.6 vs. 6.1 %, p = 0.021, and 62.1 vs. 33.3 %, p = 0.024, respectively). PPD and LPS significantly increased IL-6, IL-10, and TNF-alpha production in PBMCs. IL-10 and TNF-alpha production were significantly lower in a subgroup of CD patients (5/12) with a known NOD2 mutation. Receptor for IL-10 was significantly higher expressed on NK cells (CD56low) and on NK T cells harbouring a NOD2 mutations compared to wildtype cells (p = 0.031 and 0.005, respectively). TLR4 was significantly higher expressed on NK cells (CD56high) harbouring a NOD2 mutations compared to wildtype cells (p = 0.038). PMID- 23455703 TI - Proximal tibial pain in a child. PMID- 23455704 TI - Computed tomography for the detection of thumb base osteoarthritis: comparison with digital radiography. AB - OBJECTIVE: To compare computed tomography (CT) with digital radiography for the detection of osteoarthritis (OA) of the first carpometacarpal (CMC1) and scaphotrapeziotrapezoid (STT) joint. MATERIALS AND METHODS: We retrospectively identified patients who were assessed for CMC1 OA or STT OA at our hand surgery outpatient clinic between January 2008 and March 2011, and who had both a digital radiograph and a CT scan of the hand within a 3-month period. CT and radiographic images were scored independently by two musculoskeletal radiologists for joint space narrowing (JSN), osteophytes, subchondral sclerosis, bone cysts, and erosions in the CMC1 and STT joints. RESULTS: Thirty patients were identified. The inter-reader reliability of CT for the detection of CMC1 OA (ICC 1.00) and STT OA (ICC 0.80) was higher than radiography (ICC's 0.15 and 0.45). In comparison with their own radiographical scoring, both readers detected with CT 3 more patients with CMC1 OA, and 13 and 5 more patients with STT OA. CONCLUSION: Computed tomography had a higher inter-reader reliability and detection rate for both CMC1 and STT OA, compared with radiography. As surgical treatment selection of thumb base OA depends on the presence of pathology in the CMC1 and STT joints, CT may improve treatment selection and surgical planning. PMID- 23455705 TI - Intra-articular synovial sarcoma. AB - A case of right knee intra-articular synovial sarcoma in a 26-year-old man is reported. The patient had experienced 12 to 18 months of chronic posterior right knee pain with flexion contracture of the leg. Magnetic resonance imaging (MRI) examination demonstrated nonspecific characteristics of a well-circumscribed, homogeneous mass within the posterior lateral compartment of the knee joint. The mass was isointense and hyperintense to muscle on T1- and T2-weighted sequences respectively, and initially clinically diagnosed as a localized tenosynovial giant cell tumor. However, histological examination showed the lesion to be a synovial sarcoma arising from the synovium of the knee joint. Synovial sarcoma may have a nonspecific MR appearance, especially when less than 5 cm in size, often simulating a less aggressive process. Primary intra-articular origin may predispose to earlier presentation, and therefore, radiological evaluation of smaller masses. Nonspecific MR characteristics of small, intra-articular masses provide a diagnostic dilemma. Synovial sarcoma should be considered in the differential diagnosis when distinguishing MR characteristics of other common joint-centered entities are not present. PMID- 23455707 TI - Epithelioid sarcoma presenting as radial mononeuropathy: anatomical, magnetic resonance neurography and diffusion tensor imaging appearances. AB - The authors report an unusual case of radial mononeuropathy caused by epithelioid sarcoma and describe the anatomical 3-Tesla MR neurography and the functional diffusion tensor imaging findings of the case, which were subsequently confirmed on surgical excision and histopathology. PMID- 23455709 TI - Enhanced tolerance to drought and salt stresses in transgenic faba bean (Vicia faba L.) plants by heterologous expression of the PR10a gene from potato. AB - KEY MESSAGE: We report for the first time that expression of potato PR10a gene in faba bean causes enhanced tolerance to drought and salinity. Grain legumes such as soybean (Glycine max L. Merrill), pea (Pisum sativum L.) and faba bean (Vicia faba L.) are staple sources of protein for human and animal nutrition. Among grain legumes, faba bean is particularly sensitive to abiotic stress (in particular osmotic stress due to lack of water or enhanced soil salinity) and often suffers from severe yield losses. Many stress responsive genes have been reported with an effect on improving stress tolerance in model plants. Pathogenesis-related proteins are expressed by all plants in response to pathogen infection and, in many cases, in response to abiotic stresses as well. The PR10a gene isolated from the potato cultivar Desiree was selected for this study due to its role in enhancing salt and/or drought tolerance in potato, and transferred into faba bean cultivar Tattoo by Agrobacterium tumefaciens-mediated transformation system based upon direct shoot regeneration after transformation of meristematic cells derived from embryo axes. The transgene was under the control of the constitutive mannopine synthase promoter (p-MAS) in a dicistronic binary vector, which also contained luciferase (Luc) gene as scorable marker linked by internal ribosome entry site elements. Fertile transgenic faba bean plants were recovered. Inheritance and expression of the foreign genes were demonstrated by PCR, RT-PCR, Southern blot and monitoring of Luciferase activity. Under drought condition, after withholding water for 3 weeks, the leaves of transgenic plants were still green, while non-transgenic plants (WT) wilted and turned brown. Twenty-four hours after re-watering, the leaves of transgenic plants remained green, while WT plants did not recover. Moreover, the transgenic lines displayed higher tolerance to NaCl stress. Our results suggested that introducing a novel PR10a gene into faba bean could be a promising approach to improve its drought and salt tolerance ability, and that MAS promoter is not only constitutive, but also wound-, auxin/cytokinin- as well as stress-inducible. PMID- 23455708 TI - Jasmonate biosynthesis and signaling in monocots: a comparative overview. AB - The plant hormone jasmonate (JA) fulfils essential roles in plant defense and development. While most of our current understanding of the JA pathway comes from the dicotyledonous model plant Arabidopsis thaliana, new studies in monocotyledonous plants are providing additional insights into this important hormone signaling pathway. In this review, we present a comparative overview of the JA biosynthetic and signaling pathways in monocots. We highlight recent studies that have revealed molecular mechanisms (mostly conserved but also diverged) underlying JA signaling and biosynthesis in the economically important plants: maize and rice. A better understanding of the JA pathway in monocots should lead to significant improvements in pest and pathogen resistance in cereal crops, which provide the bulk of the world's food and feed supply. PMID- 23455710 TI - Abnormal body iron distribution and erythropoiesis in a novel mouse model with inducible gain of iron regulatory protein (IRP)-1 function. AB - Disorders of iron metabolism account for some of the most common human diseases. Cellular iron homeostasis is maintained by iron regulatory proteins (IRP)-1 and 2 through their binding to cis-regulatory iron-responsive elements (IREs) in target mRNAs. Mouse models with IRP deficiency have yielded valuable insights into iron biology, but the physiological consequences of gain of IRP function in mammalian organisms have remained unexplored. Here, we report the generation of a mouse line allowing conditional expression of a constitutively active IRP1 mutant (IRP1) using Cre/Lox technology. Systemic activation of the IRP1 transgene from the Rosa26 locus yields viable animals with gain of IRE-binding activity in all the organs analyzed. IRP1 activation alters the expression of IRP target genes and is accompanied by iron loading in the same organs. Furthermore, mice display macrocytic erythropenia with decreased hematocrit and hemoglobin levels as well as impaired erythroid differentiation. Thus, inappropriately high IRP1 activity causes disturbed body iron distribution and erythropoiesis. This new mouse model further highlights the importance of appropriate IRP regulation in central organs of iron metabolism. Moreover, it opens novel avenues to study diseases associated with abnormally high IRP1 activity, such as Parkinson's disease or Friedreich's ataxia. PMID- 23455711 TI - Enhanced detection of myeloperoxidase activity in deep tissues through luminescent excitation of near-infrared nanoparticles. AB - A previous study reported the use of luminol for the detection of myeloperoxidase (MPO) activity using optical imaging in infiltrating neutrophils under inflammatory disease conditions. The detection is based on a photon-emitting reaction between luminol and an MPO metabolite. Because of tissue absorption and scattering, however, luminol-emitted blue light can be efficiently detected from superficial inflammatory foci only. In this study we report a chemiluminescence resonance energy transfer (CRET) methodology in which luminol-generated blue light excites nanoparticles to emit light in the near-infrared spectral range, resulting in remarkable improvement of MPO detectability in vivo. CRET caused a 37-fold increase in luminescence emission over luminol alone in detecting MPO activity in lung tissues after lipopolysaccharide challenge. We demonstrated a dependence of the chemiluminescent signal on MPO activity using MPO-deficient mice. In addition, co-administration of 4-aminobenzoic acid hydrazide (4-ABAH), an irreversible inhibitor of MPO, significantly attenuated luminescent emission from inflamed lungs. Inhibition of nitric oxide synthase with a nonspecific inhibitor, L-NAME, had no effect on luminol-mediated chemiluminescence production. Pretreatment of mice with MLN120B, a selective inhibitor of IKK-2, resulted in suppression of neutrophil infiltration to the lung tissues and reduction of MPO activity. We also demonstrated that CRET can effectively detect MPO activity at deep tissue tumor foci due to tumor development-associated neutrophil infiltration. We developed a sensitive MPO detection methodology that provides a means for visualizing and quantifying oxidative stress in deep tissue. This method is amenable to rapid evaluation of anti-inflammatory agents in animal models. PMID- 23455712 TI - Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. AB - Although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. Here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded RNA viruses. Granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptibility to viral infection ex vivo and in vivo. By transducing cortical neurons with genes that were expressed more highly in granule cell neurons, we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses. Moreover, we found that the epigenetic state and microRNA (miRNA)-mediated regulation of ISGs correlates with enhanced antiviral response in granule cell neurons. Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, which probably contribute to their relative permissiveness to infection. PMID- 23455713 TI - Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. AB - To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8(+) T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-gamma (IFN-gamma)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines. PMID- 23455715 TI - The self-assembly, aggregation and phase transitions of food protein systems in one, two and three dimensions. AB - The aggregation of proteins is of fundamental relevance in a number of daily phenomena, as important and diverse as blood coagulation, medical diseases, or cooking an egg in the kitchen. Colloidal food systems, in particular, are examples that have great significance for protein aggregation, not only for their importance and implications, which touches on everyday life, but also because they allow the limits of the colloidal science analogy to be tested in a much broader window of conditions, such as pH, ionic strength, concentration and temperature. Thus, studying the aggregation and self-assembly of proteins in foods challenges our understanding of these complex systems from both the molecular and statistical physics perspectives. Last but not least, food offers a unique playground to study the aggregation of proteins in three, two and one dimensions, that is to say, in the bulk, at air/water and oil/water interfaces and in protein fibrillation phenomena. In this review we will tackle this very ambitious task in order to discuss the current understanding of protein aggregation in the framework of foods, which is possibly one of the broadest contexts, yet is of tremendous daily relevance. PMID- 23455714 TI - A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. AB - Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding gamma-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors. PMID- 23455716 TI - Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors. AB - BACKGROUND: There is no consensus about the prognostic role of HER2 expression and that of other members of the EGFR family in gastric cancer patients. The aim of this study was to evaluate the prognostic value of the EGFR family in gastric cancer. METHODS: This retrospective study included 201 patients with gastric and esophagogastric junction adenocarcinoma stages 0-IV (AJCC 6th edition) who underwent primary tumor resection. Tissues from primary tumors were analyzed by tissue microarray technology and immunohistochemistry. Correlations between receptor expression and clinicopathological characteristics were performed according to the chi-square test. Survival analysis was calculated according to the Weibull model with a mixture model incorporating long-term survivors. Multivariate analysis of prognostic factors was performed by a regression model incorporating long-term survivors with the Weibull distribution. RESULTS: Membrane expression of HER1, HER2, and HER4 were 9, 17, and 15 %, respectively. No membrane expression of HER3 was observed. Cytoplasmic expression of HER1, HER3, and HER4 were 45, 62, and 24 %, respectively. HER2 and HER3 expression were correlated (p < 0.001) and associated with intestinal-type histology (p = 0.001 and p < 0.001, respectively) and advanced age (p = 0.011 and p = 0.008, respectively). According to a regression model adjusted for age, surgical radicality, surgical modality, Lauren histology, adjuvant therapy, TNM stage, and receptor expressions, only TNM stage showed prognostic influence. CONCLUSIONS: According to analysis by a parametric model, the EGFR family did not have prognostic influence in the gastric cancer population studied. The data presented showed a correlation between HER2 and HER3 expression, which might suggest a potential role for HER2-HER3 heterodimerization inhibitors. PMID- 23455717 TI - Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: a randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). AB - BACKGROUND: Treatment of patients with advanced or metastatic esophagogastric adenocarcinoma should not only prolong life but also provide relief of symptoms and improve quality of life (QOL). Esophagogastric adenocarcinoma mainly occurs in elderly patients, but they are underrepresented in most clinical trials and often do not receive effective combination chemotherapy, most probably for fear of intolerance. Using validated instruments, we prospectively assessed QOL within the randomized FLOT65+ phase II trial. METHODS: Within the FLOT65+ trial, a total of 143 patients aged >=65 years were randomly allocated to receive biweekly oxaliplatin plus 5-fluorouracil (5-FU) continuous infusion and folinic acid (FLO) or the same regimen in combination with docetaxel 50 mg/m(2) (FLOT). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the gastric module STO22 were administered every 8 weeks until progression. Time to definitive deterioration of QOL parameters was analyzed and compared within the treatment arms. RESULTS: The median age of patients was 70 years. Patients receiving FLOT exhibited higher response rates and had improved disease-free and progression-free survival (PFS). The proportions of patients with evaluable baseline EORTC QLQ-C30 and STO22 questionnaires were balanced (83 % in FLOT and 89 % in FLO). Considering evaluable patients with assessable questionnaires (n = 123), neither functioning nor symptom parameters differed significantly in favor of one of the two treatment groups. Particularly, there was no significant difference regarding time to definitive deterioration of global health status/quality of life from baseline (primary endpoint). Notably, patients receiving FLO or FLOT as palliative treatment (n = 98) achieved comparable QOL results. CONCLUSIONS: Although toxicity was higher in patients receiving FLOT, no negative impact of the addition of docetaxel on QOL parameters could be demonstrated. Thus, elderly patients in need of intensified chemotherapy may receive FLOT without compromising patient-reported outcome parameters. PMID- 23455718 TI - Role of committed minorities in times of crisis. AB - The surprising social phenomena of the Arab Spring and the Occupy Wall Street movement posit the question of whether the active role of committed groups may produce political changes of significant importance. Under what conditions are the convictions of a minority going to dominate the future direction of a society? We address this question with the help of a Cooperative Decision Making model (CDMM) which has been shown to generate consensus through a phase transition process. We observe that in a system of a finite size the global consensus state is not permanent and times of crisis occur when there is an ambiguity concerning a given social issue. The correlation function within the cooperative system becomes similarly extended as it is observed at criticality. This combination of independence (free will) and long-range correlation makes it possible for very small but committed minorities to produce substantial changes in social consensus. PMID- 23455719 TI - Coronary optical coherence tomography: minimally invasive virtual histology as part of targeted post-mortem computed tomography angiography. AB - Social, cultural and practical barriers to conventional invasive autopsy have led to considerable interest in the development of minimally invasive radiological techniques as an alternative to the invasive autopsy for determining the cause of death. Critical to accurate diagnosis in this context is detailed examination of coronary anatomy and pathology. Current computed tomography and magnetic resonance imaging approaches have significantly advanced minimally invasive autopsy practice but have limited spatial resolution. This prohibits assessment at a microscopic level, meaning that histological assessment is still required for detailed analysis of, for example, coronary plaque rupture or dissection. Coronary optical coherence tomography (OCT) is used in the living during percutaneous coronary interventions to provide high-resolution coronary imaging, but this technique for obtaining virtual histology has not, to date, been translated into minimally invasive autopsy practice. We present a first description of minimally invasive post-mortem coronary OCT and discuss the potential for this technique to advance current practice. PMID- 23455720 TI - Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis. AB - BACKGROUND: Malignant transformation in ulcerative colitis (UC) is associated with pronounced chromosomal instability, reflected by aneuploidy. Although aneuploidy can precede primary cancer diagnosis in UC for more than a decade, little is known of its cellular consequences. METHODS: Whole-genome gene expression analysis was applied to noninflamed colon mucosa, mucosal biopsies of patients with UC, and UC-associated carcinomas (UCCs). DNA image cytometry was used to stratify samples into ploidy types. Differentially expressed genes (DEGs) were analyzed by Ingenuity Pathway Analysis and validated by real-time quantitative PCR. RESULTS: Gene expression changes were more pronounced between normal mucosa and UC (2587 DEGs) than between UC and UCC (827 DEGs). Cytometry identified colitis patients with euploid or aneuploid mucosa biopsies, whereas all UCCs were aneuploid. However, 1749 DEGs distinguished euploid UC and UCCs, whereas only 15 DEGs differentiated aneuploid UC and UCCs. A total of 16 genes were differentially expressed throughout the whole sequence from normal controls to UCCs. Particularly, genes pivotal for chromosome segregation (e.g., SMC3 and NUF2) were differentially regulated along aneuploidy development. CONCLUSIONS: The high number of DEGs between normal mucosa and colitis is dominated by inflammatory-associated genes. Subsequent acquisition of aneuploidy leads to subtle but distinct transcriptional alterations, revealing novel target genes that drive genomic instability and thus carcinogenesis. The gene expression signature of malignant phenotypes in aneuploid UC suggests that these lesions might need to be considered as severe as high-grade dysplasia. PMID- 23455721 TI - Effects of prefrontal repetitive transcranial magnetic stimulation on the autonomic regulation of cardiovascular function. AB - Several protocols based on repetitive transcranial magnetic stimulation (rTMS) have been proposed for treatment of a variety of neurological disorders. Despite the widespread use, little is known about the effects of rTMS on the autonomic nervous control of the cardiovascular system. Twelve volunteers underwent rTMS sessions consisted in 8-min baseline recording, 8-min 0.7-Hz rTMS stimulation at 100 % of the motor cortex excitability threshold on the prefrontal cortex of one randomly assigned hemisphere. After 8-min recovery, the same procedure was performed on the contra-lateral hemisphere. Non-invasive (Portapres device) beat by-beat blood pressure and heart period time series were recorded and analyzed by spectral and cross-spectral analysis in the low-frequency (LF ~ 0.1 Hz) and in the high-frequency (HF = respiratory frequency) range. Repetitive TMS, particularly after stimulation of the right hemisphere, induced a slight increase in the parasympathetic drive and no effects on the sympathetic activity. There was a significant bradycardia after stimulation on the right hemisphere, not significant bradycardia after left stimulation. LF/HF ratio was 3.8 +/- 2.1 during baseline and changed to 1.9 +/- 0.6 during rTMS on the left and to 1.6 +/- 0.6 during rTMS on the right. No significant changes were observed in blood pressure. Low-frequency rTMS of the prefrontal cortex induces a slight parasympathetic activation and no changes in the sympathetic function. PMID- 23455722 TI - Neurons in the cingulate motor area signal context-based and outcome-based volitional selection of action. AB - Volitional selection of action is subject to continuous adjustment under the influence of information obtained by monitoring behavioral consequences and by exploiting behavioral context based on prior knowledge about the environment. The rostral cingulate motor area (CMAr) is thought to be responsible for adjusting behavior by monitoring its consequences. To investigate whether the CMAr also plays a role in exploitation of behavioral context in action selection, we recorded neuronal activities from the CMAr while monkeys performed a reward-based motor selection task that required them to switch from one action to the other based on the amount of reward. We examined both the behavior of monkeys and the activity of CMA neurons quantitatively by constructing a hybrid reinforcement learning model incorporating context-based and outcome-based action values into a new action value. We found that CMAr neurons encoded the context-based action value by increasing or decreasing their firing rates gradually with the number of repetitions of the same movement (i.e., behavioral context). We also found that CMAr neurons encoded the context-based and outcome-based action values in two distinct time windows at single neuron and population levels. Our findings indicate that the CMAr is involved in behavioral adjustment of action selection by exploiting the behavioral context and not merely by monitoring reward outcome. PMID- 23455723 TI - Visuomotor adaptation and generalization with repeated and varied training. AB - Many studies have shown that reaching movements to visual targets can rapidly adapt to altered visual feedback of hand motion (i.e., visuomotor rotation) and generalize to new target directions. This generalization is thought to reflect the acquisition of a neural representation of the novel visuomotor environment that is localized to the particular trained direction. In these studies, participants perform movements to a small number of target locations repeatedly. However, it is unclear whether adaptation and generalization are comparable when target locations are constantly varied and participants reach to visual targets one time only. Here, we compared performance for reaches to a 30 degrees counter clockwise visuomotor rotation to four targets, spaced 90 degrees apart across four areas of workspace 18 times each (repeated practice (RP)) with one time only reaching movements to 72 targets, spaced 5 degrees apart (varied practice (VP)). For both training groups, participants performed 18 reaches to radial targets (either at the repeated or varied location) in a specific area of the workspace (i.e., one of four quadrants) before reaching in the adjacent workspace. We found that the RP group adapted more completely compared to the VP group. Conversely, the VP group generalized to new target directions more completely when reaching without cursor feedback compared to the RP group. This suggests that RP and VP follow a mainly common pattern of adaptation and generalization represented in the brain, with benefits of faster adaptation with RP and more complete generalization with VP. PMID- 23455724 TI - Durability of classification and action learning: differences revealed using ex Gaussian distribution analysis. AB - It has been shown that in associative learning it is possible to disentangle the effects caused on behaviour by the associations between a stimulus and a classification (S-C) and the associations between a stimulus and the action performed towards it (S-A). Such evidence has been provided using ex-Gaussian distribution analysis to show that different parameters of the reaction time distribution reflect the different processes. Here, using this method, we investigate another difference between these two types of associations: What is the relative durability of these associations across time? Using a task-switching paradigm and by manipulating the lag between the point of the creation of the associations and the test phase, we show that S-A associations have stronger effects on behaviour when the lag between the two repetitions of a stimulus is short. However, classification learning affects behaviour not only in short-term lags but also (and equally so) when the lag between prime and probe is long and the same stimuli are repeatedly presented within a different classification task, demonstrating a remarkable durability of S-C associations. PMID- 23455725 TI - An older view on distance perception: older adults perceive walkable extents as farther. AB - According to the action-specific perception account, spatial perception is affected by the specific energetic costs required to perform an action. In the current experiments, we examined the effect of age on distance perception. Older and younger adults were asked to verbally estimate distance to a target placed in a hallway. Results showed that older adults estimated distances to be farther compared to younger adults. Additionally, older and younger adults estimated distances on a surface that was easier to walk on (carpet) and on a surface that was more difficult to walk on (carpet covered by a plastic tarp). For older adults, distances looked farther on the plastic surface than on the carpet. These differences across surfaces were not found for able, younger adults. These results suggest that the type of floor surface available influences perception of distances. Furthermore, the results suggest that perception is still sensitive to environmental differences that affect ability even as a perceiver ages. PMID- 23455726 TI - Dynamic changes of the neurogenic potential in the rat cochlear nucleus during post-natal development. AB - Neuronal stem cells have been described in the post-natal cochlear nucleus recently. The aim of the study was to analyse the neurogenic potential in the cochlear nucleus from the early post-natal days until adulthood. Cochlear nuclei from Sprague-Dawley rats from post-natal day P3 up to P40 were examined. Neurosphere assays showed persistent neurosphere formation from the early post natal days until adulthood. The numbers of generated neurospheres were fewer in older ages. Neurospheres were smaller, but displayed the same pattern of neuronal stem cell markers. The markers GFAP, MBP and beta-III Tubulin showed differentiation of dissociated cells from the neurospheres in all cells of the neuronal lineage. BrdU incorporation could be detected, in an age-dependent decrease, in whole-mount experiments of the cochlear nucleus on all examined days. BrdU co-labelled with Atoh1 and beta-III Tubulin. In addition, gene expression and cellular distribution studies of the neuronal stem cell markers displayed an age-dependent reduction in both quantity and numbers. The presented results display a possible neurogenic potential until adulthood in the cochlear nucleus by in vitro and in vivo experiments. The fact that this potential is highest at a critical period of development reveals possible functional importance for the development of the cochlear nucleus and the auditory function. The persistent neurogenic potential displayed until adulthood could be a neurogenic niche in the adult cochlear nucleus, which might be used for potential therapeutic strategies. PMID- 23455727 TI - To throw or to place: does onward intention affect how a child reaches for an object? AB - Picking up an object is a seemingly simple and isolated task; however, research has demonstrated that adults plan a reach-to-grasp movement on the basis of forthcoming actions. For example a greater deceleration period is seen in an initial reach movement which precedes a place movement compared to a throw movement. This task-specific or second-order motor planning is also seen in infants and toddlers; however, the developmental progression is unclear. Reach-to grasp movements of 48 children, split into four age groups (4-5, 6-7, 8-9 and 10 11 years) were recorded. These movements preceded a tight place, a loose place or a throw action. All the children showed some degree of tailoring kinematics to the onward action. In the 4-5 year-old group, this was demonstrated by a longer movement duration in the place actions compared to the throw action. In the older children the proportion of time spent decelerating increased as the precision requirements of the task increased. These results demonstrate that all children are able to use second-order planning to integrate onward task demands into their movements. The capacity for this increases with age but is not fully mature at 11 years. These developmental effects may be explained by the relative weighting of costs involved in tailoring a reach action compared to the benefits of producing a more efficient onward action. PMID- 23455728 TI - Moving further moves things further away in visual perception: position-based movement planning affects distance judgments. AB - We examined how different characteristics of planned hand movements affect visual perception of distances in reachable space. Participants planned hand movements of certain amplitude. Before execution of the movement, certain visual distances had to be judged. Distances were judged as larger the larger the amplitude of the concurrently prepared hand movements was. On top of that, with constant movement amplitude, distances were judged as larger, the further away the start point of the planned movement was located from the body. These results indicate that distinct variables specified during motor planning, such as effector's final position, are linked to the visual perception of environmental characteristics. PMID- 23455729 TI - Developmental changes of the biomechanical effect in motor imagery. AB - Motor imagery has been investigated in childhood and early adolescence, but not across adolescence stages; moreover, available evidence did not clarify whether the involvement of motor information in mental rotation of body parts becomes stronger or weaker during development. In the present study, we employed the hand laterality task to assess motor imagery in ninety-seven typically developing adolescents divided into three age groups (i.e., 11-12, 14-15, and 17-18 years); mental rotation of objects and letters were also assessed. As a specific marker of the motor involvement in mental rotation of body parts, we assessed the so called biomechanical effect, that is, the advantage for judging hand pictures showing physically comfortable positions with respect to hand pictures showing physically impossible or awkward positions. Results demonstrated that the biomechanical effect did not significantly affect early adolescents' performance, whereas it became significant in 14- to 15-year-old participants and even more stronger in 17- to 18-year-old participants; this pattern did not depend on an increase in processing speed to mentally rotate both corporeal and non-corporeal (objects and letters) stimuli. The present findings demonstrated that: (1) motor imagery undergoes a continuous and progressive refinement throughout adolescence, and (2) full exploitation of motor information to mentally transform corporeal stimuli can be attained in late adolescence only. PMID- 23455730 TI - Effects of visual information on perceived posture of an experimental phantom foot. AB - Our previous studies showed that a fully extended finger, wrist, and elbow became a flexed phantom hand and arm with ischemic anesthesia, and vice versa (Inui et al. in J Physiol 589:5775-5784, 2011, Exp Brain Res 221:369-375, 2012a, Exp Brain Res 218:487-494, 2012b). It was anticipated that if the ankle and knee were fixed in full extension or flexion before and during ischemic anesthesia, the perceived positions would move in the opposite direction. The present study examined what happened when participants looked at their fixed foot and leg at the end of the anesthesia. Using the left ankle and knee, ten healthy participants demonstrated the perceived postures of the right joints during an ischemic block of the right thigh (40 min) and after they looked at the right joints at the end of the block. When the right ankle and knee were fully extended before and during the block, the final joints were perceived as flexed by all participants, and vice versa. Although there was no significant difference between joints for the magnitude of the perceived changes in flexion, the magnitude in the knee was larger than that in the ankle in extension. At the end of the experiment, when participants were allowed to see their foot, its perceived position reverted to that indicated by them earlier, during the first 25 min of cuff inflation. This new finding suggests that the position of limbs is coded by visual input more dominantly than by proprioceptive input in the brain. PMID- 23455731 TI - Repeated practice of a Go/NoGo visuomotor task induces neuroplastic change in the human posterior parietal cortex: an MEG study. AB - The posterior parietal cortex (PPC) is strongly related to task performance by evaluating sensory cues and visually guided movements. Sensorimotor processing is improved by task repetition as indicated by reduced response time. We investigated practice-induced changes in PPC visuomotor processing during a Go/NoGo task in humans using 306-channel magnetoencephalography. Eleven healthy adult males were instructed to extend the right index finger when presented with the Go stimulus (a red circle), but not to react to the NoGo stimulus (a green circle or a red square). Magnetic fields over the visual, posterior parietal, and sensorimotor cortices were measured before and after 3 days of task practice. The first peak of the visual-evoked field (VEF) occurred at approximately 80 ms after presentation of either the Go or NoGo stimulus, while a PPC response, with latency to a peak of 175.8 +/- 26.7 ms, occurred only after the Go stimulus. No significant change in the first peak of VEF was measured after 3 days of task practice, but there was a significant reduction in the latency to peak PPC activity (160.1 +/- 27.6 ms) and in the time from peak PPC activity to electromyogram onset. In all participants, practice resulted in a significant reduction in reaction time. These results demonstrate that practicing a sensorimotor task induces neuroplastic changes in PPC that accelerate sensorimotor processing and reduce motor response times. PMID- 23455732 TI - Optimized templates for bottom-up growth of high-performance integrated biomolecular detectors. AB - Electrochemical deposition of metals represents an important approach in the bottom-up fabrication of nanostructures and microstructures. We have used this approach to generate high-performance chip-based biosensors using silicon as a platform for the generation of sensor arrays. Here, we explore the applicability of different materials to support the electrodeposition and identify the parameters that are essential for robust sensor growth. We show that inexpensive materials can be used as templates for electrodeposition, and demonstrate that these low-cost sensors exhibit clinically-relevant levels of sensitivity and specificity. In particular, we prove herein that the glass-based sensors successfully detect E. coli in urine, when present at the 100 cfu MUL(-1) levels found typically in samples of patients with urinary tract infections. PMID- 23455733 TI - Higher division of the tibial nerve in the leg: gross anatomical study with clinical implications. AB - BACKGROUND AND OBJECTIVES: Tibial nerve is a branch of the sciatic nerve and it is the main nerve innervating the muscles of the back of the leg. The tibial nerve divides into medial and lateral plantar nerves. The level of division may be important for surgical purpose. The main aim of the present study was to observe the exact level of division of the tibial nerve and discuss its clinical implications. MATERIALS AND METHODS: A total of 20 cadaveric limbs (irrespective of left or right side) were taken randomly. The posterior compartment of the thigh and leg was dissected to trace the tibial nerve and its branches. The specimens were subjected to measurements with respect to an arbitrary horizontal line passing through tip of medial malleolus and the calcaneum. All the specimens were photographed. RESULTS: In 5 cases (25%), the tibial nerve divided deep to the flexor retinaculum. In 15 cases (75%) cases, the tibial nerve divided at a distance of 3.5 cm - 6.5 cm (average 5 cm) above the medial malleolus. CONCLUSION: The tibial nerve and its divisions are important for performing successful nerve blocks and insertion of plates while treating fractures. Variations may account for the various discrepancies between the electromyographic tests and clinical tests. PMID- 23455734 TI - Piper sarmentosum is comparable to glycyrrhizic acid in reducing visceral fat deposition in adrenalectomised rats given dexamethasone. AB - OBJECTIVES: Visceral obesity may be due to the dysregulation of cortisol production or metabolism that lead to metabolic disease. In adipose tissue, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 regulates cortisol metabolism (11beta-HSD1). A previous study showed an increase in the visceral fat deposition in adrenalectomised rats given intramuscular dexamethasone. Glycyrrhizic acid (GCA) has been shown to reduce fat deposition because it is a known potent inhibitor of the 11beta-HSD1 enzyme. Piper sarmentosum (PS) is an edible medicinal plant commonly used in Asia as traditional medicine for treating diabetes, hypertension and joint pains. In this study, we determined the effects of PS extract on the disposition and morphology of perirenal adipocytes of adrenalectomised rats given intramuscular dexamethasone. MATERIALS AND METHODS: A total of 21 male Spraque Dawley rats were adrenalectomised and given intramuscular dexamethasone, 120 MUg/kg/day. These rats were further divided into three groups: adrenalectomised control (ADR+Dexa; n=7), GCA-treated (ADR+Dexa+GCA; dose=240 mg/kg/day; n=7) and PS-treated (ADR+Dexa+PS; dose=125 mg/kg/day; n=7) groups. The various treatments were given via gastric gavage following 2 weeks of adrenalectomy. RESULTS: Treatment with PS extract for 8 weeks showed decreased deposition of perirenal adipocytes which was similar to the GCA-treated group. However, PS-treated rats had thinner adipocyte membrane compared with that of the GCA-treated group. CONCLUSION: In conclusion, PS extract decreased perirenal fat deposition and reduced the diameter of the adipocyte membrane. However, the mechanisms of action needed further study. PMID- 23455735 TI - Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) therapy on the female sexual response cycle of women with major depression. AB - OBJECTIVE: Depression and its treatment may influence all aspects of the female sexual function from desire to sexual satisfaction. This study aimed to examine the components of the female sexual response cycle (SRC) of women with major depression treated with Selective Serotonin Reuptake Inhibitors. MATERIALS AND METHODS: The correlations structure of the items of the SRC's phases (i.e. desire, arousal, orgasm, satisfaction and pain) in a validated Malay version of Female Sexual Function Index (FSFI) was determined using principal component analysis (PCA), with varimax rotation method. The number of factors obtained was decided using Kaiser's criteria. Factor loadings using PCA with varimax rotation divided the sexual domains into three components based on Kaiser's criteria. RESULTS: Sexual desire, sexual arousal, lubrication and orgasm were highly correlated, to form a "sexual drive" construct. Sexual satisfaction and pain made up the second and third components, respectively. SSRIs may affect the components of the SRC causing highly overlapping constructs of sexual drive including orgasm. Recognizing this helps strategizing the treatment approach of female sexual dysfunction in depression particularly in relation to the role of SSRIs. PMID- 23455736 TI - Topographical anatomy of the profunda femoris artery and the femoral nerve: normal and abnormal relationships. AB - BACKGROUND AND OBJECTIVE: Femoral nerve (FN) is the largest branch of lumbar plexus. It lies lateral to femoral artery (FA) and it is located outside the femoral sheath. Profunda femoris artery (PFA) is a branch of the FA. The present study aimed to observe the topographical anatomy and relationship of the PFA and the FN. MATERIALS AND METHODS: A total of 12 embalmed cadaveric lower limbs (7 lefts and 5 rights) were taken and the thighs were dissected in detail. The relationship of PFA and FN were observed. Appropriate measurements were taken and the specimens were photographed. RESULTS: The PFA originated from the FA in all the 12 specimens (100%). In 10 specimens (83.3%), the PFA was found to originate lateral to the FA while in 2 specimens, the origin of PFA was posterior to the FA (16.7%). The PFA originated from the FA at a distance of 6.5 + 1.5 cm with regard to the midinguinal point. All FN were found to lie outside the femoral sheaths. Out of the 12 specimens, only 2 specimens (16.7%) exhibited the FN to lie posterior to the PFA, while in 10 specimens (83.3%), the FN was found to lie anterior to the PFA. CONCLUSION: Prior anatomical knowledge of structures in the anterior compartment of thigh may be helpful for surgeons performing nerve block, cannulation and catheterization. Knowledge of abnormal anatomy of the FN and PFA is important in order to prevent any inadvertent injury to the PFA or FN. PMID- 23455737 TI - [The patient on hemodialysis: psychological and management difficulties]. AB - OBJECTIVES: Chronic renal failure is a public health problem of great relevance for significant mortality and high socio-economic impact. This study purposed to assess the psychological status in patients on hemodialysis; moreover other purpose is to investigate the possible differences among the first 3 months of hemodialysis treatment replacement. MATERIALS AND METHODS: The study was carried out on 12 hemodialysis patients, aged 71.6 years (range: 34-87). Mood was measured by using the Profile of Mood States (POMS) developed in 1971 by Douglas M. McNair. RESULTS: The overall score of mood disorders shows a total negative state in the initial phases of dialysis treatment [F (2,22) = 10.17; p <0.01] and a progressive improvement of the same, with a linear trend [F (1,11) = 12.65; p <0.05]. CONCLUSIONS: The model of hemodialysis patients is particularly interesting for several reasons, but especially for the possibility of crosssectional and longitudinal assessments. The aim of future studies will be to characterize and investigate the complex psycho-social variables in this category of patients, to improve their quality of life. PMID- 23455738 TI - Arterial embolization of a bleeding gastric Dieulafoy lesion: a case report. AB - Dieulafoy's lesion is one of an unusual cause of upper gastrointestinal bleeding (U GIB). Endoscopic intervention has always been a preferred non-surgical method in treating UGIB including bleeding from Dieulafoy's lesion. Owing to recent advances in angiography, arterial embolization has become a popular alternative in non- variceal UGIB especially in cases with failed endoscopic treatment. However, managing bleeding Dieulafoy's with selective arterial embolization as the first line of treatment has not been exclusively practiced. We hereby, report a case of bleeding Dieulafoy lesion which had been primarily treated with arterial embolization. PMID- 23455739 TI - Dumb bell shaped morphology of liver: an autopsy case report. AB - Medicolegal autopsy on the dead body of an elderly female revealed that the liver was having some unusual shape. The left lobe of liver was bifid, having dumb bell type morphology. Also there were some furrows which were observed over the anterior surface of the liver. This type of morphological variant has not been reported hitherto. The clinicians should be aware of developmental morphological anomalies like in this case, as they might cause confusion during the procedures like biopsy, transplantation and lobectomies. We believe that this case report is important for the clinicians who are involved in the diagnosis and management of hepatic diseases. The knowledge is also enlightening for morphologists and embryologists. PMID- 23455740 TI - Unusual architecture of extensor digitorum muscle of hand in conjunction with accessory belly of extensor carpi radialis brevis: a clinico-anatomical insight. AB - The present article highlights an unusual combination of variations of the extensor digitorum and extensor carpi radialis brevis muscles in the dorsum of forearm and hand. The extensor carpi radialis brevis exhibited an accessory musculotendinous belly which inserted into the dorsal digital expansion of index finger. The extensor digitorum showed trifurcation into three distinct parts. Resultant multiple extensor tendon insertion pattern is reported upon highlighting the embryological basis and clinical importance. Knowledge of such anatomical variations adds upon the already existing information in literature and is also of profound interest to the clinician. Anatomical awareness of accessory multiple extensor tendons in the dorsum of hand is essential for successful management of extensor tendon injuries and graft transfer operations. PMID- 23455741 TI - An unusual cause of a penetrating injury to the anterior urethra: a thorny situation. AB - Concurrent penetrating injury to the male external genitalia and the anterior urethra is uncommon. This case illustrates an unusual cause of such an injury, and its subsequent management and outcome. A 69-year-old man had his scrotum and anterior urethra pierced by a long thorn when he fell in his farm. He presented with urine leakage from the scrotal wound each time he micturated. Cystoscopic examination confirmed the cause and extent of the injury, and also facilitated the extraction of the thorn. The injury was allowed time to heal by urinary diversion with a urinary catheter. There were no stricture or fistula formations and the patient remained symptom-free at 3 months follow-up. Careful cystoscopic examination was both diagnostic and therapeutic in this case. A conservative approach is a feasible option in the management of selected cases of penetrating anterior urethral injury. PMID- 23455742 TI - [The selection process in the Faculty of Medicine: the usefulness of a psychological and aptitude assessment]. AB - In almost all the universities worldwide, the admission to the Faculty of Medicine is subject to a specific selection process. In most cases tests are used to assess the cognitive abilities of the candidates. However, a growing number of universities (particularly American and Canadian) is using a set of instruments to evaluate non-cognitive skills in addition to these tests. Among the most commonly used tools are included personal interviews, Multiple Mini Interview (MMI), Personal Quality Assessment (PQA). In Italy in the last decade increasing emphasis was placed on assessing students' attitudes through the use of orientation tests (given in classrooms or online fillable), as part of several projects that involve collaboration between secondary school and university. Nevertheless, the admission to the Faculty of Medicine does not yet provide a psychological and aptitude assessment, but relies exclusively on cognitive features. In a similar way to what is already the case with the selection of personnel in law enforcement agency, we propose a selection model that includes an assessment of psychological features and aptitudes of the candidates, as well as cognitive skills. PMID- 23455743 TI - Treatment of dementia with herbs: a short review. AB - Dementia is a common symptom observed in many psychiatric and neurodegenerative diseases. Alzheimer's disease is the most common form of senile dementia seen in the general population. Multiple factors like oxidative stress, apoptosis, mitochondrial dysfunction and inflammation may be related to the neurodegenerative states. Many drugs like cholinesterase have been used for treatment but the progression of the disease still poses a challenge to the clinician. During recent times, herbs have gained much popularity as supplements because of the cost effectiveness, easy availability and fewer side effects. Early diagnosis and proper treatment may help in the prevention of mortality and morbidity concerned with any neurodegenerative disease. Understanding the cellular and molecular biology of the mode of the action of herbal products may be beneficial for researchers and clinicians. The present review article attempts to look into the potential herbal extracts which may act as an antioxidant in combating dementia. PMID- 23455744 TI - [Ideation of a new operative anoscope in proctology]. AB - BACKGROUND: Rectocele is defined as an erniation of the anterior rectal and vaginal wall in the vaginal lumen due to the loss of recto-vaginal septum. Rectal mucosal prolapse was characterized by the protrusion of the mucosa alone in the rectal lumen. The Authors, herein, reported the results of a new surgical technique defined Sequential Transfixed Stitch Technique (STST) using a new anoscope. MATERIALS AND METHODS; A total of 30 consecutive patients symptomatic III or IV stage rectocele assessed with clinical and instrumental criteria were submitted to STST using the new anoscope. The new anoscope, consisting of non toxic metallic material, designed and realized according to surgery needs and tested by the authors, increases the vision of the anal canal can be fixed according to the operator's needs. RESULTS: STST was correctly performed in all the cases without early and late complications. The mean value was of 17 according to the Agachan-Wexner for patients with rectocele, significantly improved score in comparison to pre-operatory condition (p<0.05). Surgical procedure of rectocele repair was judged satisfactory in 80% of the cases. CONCLUSIONS: The new operative anoscope was useful in III and IV stage rectocele repair with STST, ensuring ease of implementation of the binding repair in the absence of side effects for the patient. PMID- 23455745 TI - [Prosthetic hip revision: relationship between bone stock and quality of life in aseptic loosening of the femoral component]. AB - OBJECTIVES: We evaluated the clinical and radiographic results in the medium and long term in patients undergoing revision surgery for aseptic loosening with different bone quality at the time of the operation. We investigated how different bone quality shapes for a good clinical result. MATERIALS AND METHODS: A total of 33 patients who underwent revision surgery of the hip (for aseptic loosening of the stem) evaluated radiographically and clinically at 1,6,12 and 18 months. The evaluation of clinical status preoperatively and at the end of follow up was be made as questionnaires SF-36, Harris Hip Score and WOMAC; radiographic assessment was made using the scale of Paprosky. The data thus obtained have been related to complications arising and the status of femoral bone-loss before the surgery time. RESULTS: The groups PI and PII (Paprosky) showed a high level of satisfaction with an average value of reference for the postoperative rated as excellent, the absence of complications and good functional recovery at the end of follow-up. The groups PIII and PIV showed increased incidence of complications and difficulties with rehabilitation clinics and SF-36 scores and HHS inferior to other classes. CONCLUSIONS: Our dates confirm that bone quality at the time of surgery affects the therapeutic target. All patients with good bone quality at the time of the revision surgery (groups PI and PII) showed a distinct advantage from surgical treatment. Revision surgery had not much effect in patients with high bone loss. Preservation of bone stock should be considered a good foundation for the success of a prosthetic reimplantation with better functional and radiographic out-come associated with greater satisfaction for the patient. PMID- 23455746 TI - Allergic diseases and climate changes: our experience and an update. AB - AIMS: Recent research has shown that there are many effects of climate change on aeroallergens and thus allergic diseases in humans. It is not easy to evaluate the impact of climate change and air pollution on the prevalence of allergic diseases. The present study is devoted to decipher the possible relationships between climatic changes and allergic diseases, and in particular with atopic dermatitis (AD). MATERIALS AND METHODS: To evaluate the aeroallergens effects on AD, we submitted to an allergological study protocol 59 children patients with AD to study the interaction between aeroallergens-atopy patch test (APT) and skin prick test (SPT). The same tests were performed on to the same patients after 24 months to assess the time trend. RESULTS: We found a high prevalence of house dust mites and grasses pollen APT positivity in AD's and in respiratory patients and we also found an increase in positive results in the same patients after 24 months. However, we observed a variation in the control group, in which in earlier tests all patients had negative results but after 24 months we found some positivity. CONCLUSION: We found a correlation between APT and SPT in AD and we observed a concordance between APT results and the atopy score index, underlying the triggering role of these aereoallergens in the atopic patient's skin reactivity. PMID- 23455747 TI - Doloplus-2 pain assessment: an effective tool in patients over 85 years with advanced dementia and persistent pain. AB - Persistent pain in the elderly with dementia is neglected and effective pain diagnostic tools still lack. The aim of the study was to re-assess pain after 1 year in a group of elderly with dementia, resident in a Nursing Home. Doloplus-2 scale was adopted to detect pain and to evaluate its adequacy to address analgesia. Thirty-six out of 90 residents were affected by moderate-severe dementia and 23 patients with persistent pain were enrolled in the study. The results showed a significant reduction of Doloplus-2 score in the observational period (p <0.001) and of its mean score below the pain threshold (p <0.0001). This case analysis confirmed the clinical utility of Doloplus-2 to detect pain in patients with very advanced age and with severe dementia. The tool also confirmed its handiness and clinical applicability by nurses in order to support a systematic pain assessment in long term care. PMID- 23455748 TI - Self-expandable metal stent placement for treatment of severe sphincterotomy bleeding. AB - One of the most frequent complications of endoscopic sphincterotomy (ES) is bleeding. When post-ES bleeding does not respond to the use of typical endoscopic therapy, the only alternative is angiography or surgery. A 82-year-old female was admitted for jaundice. A RMN-cholangiography revealed multiple stones in the common bile duct (CBD). She underwent endoscopic retrograde cholangiopancreatography (ERCP). The papilla major was located between two large periampullary diverticula. During the ES, a severe bleeding was observed from the upper part of the biliary cut. Several methods of hemostasis (injection of adrenaline, thermal methods and balloon tamponate) were performed without efficacy. A partially covered metallic stent was placed across the biliary orifice, in order to compress mechanically the bleeding site archiving the hemostasis. PMID- 23455749 TI - Persistent vertical diplopia after cataract surgery: a case report. AB - Diplopia is an event that can occur following cataract surgery, although its rate of occurrence is limited and ranges from 0.67% to 0.85%. The authors present a case of vertical diplopia arising after peribulbar anaesthesia for cataract surgery in a 78-year-old woman. Diplopia appeared at distance in primary position, while at near there was binocular single vision. Stereopsis was present at the Lang I - II Test, but the Wirth Test was incomplete. Although in the literature the frequency of these "accidents" is very limited, we think it is relevant to emphasize the need to perform pre-operative routine using a careful orthoptic examination along with a thorough medical, especially strabological, history. PMID- 23455750 TI - Difficulties in the diagnosis of thyroid paraganglioma: a clinical case. AB - Thyroid Paragangliomas are exceptionally rare tumors and only 35 documented cases have been reported in the literature. We report an additional unusual male case of thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma. A 45-year-old man presented with a solitary thyroid nodule. Physical examination revealed a smooth, well-circumscribed, firm, mobile, painless thyroid nodule in the right lobe measuring 3 cm. Ultrasound examination showed a 40 mm hypoechoic, non-homogeneous nodule with peri- and intra-nodular vascular flow. An ultrasound-guided fine needle aspiration biopsy was performed showing the presence of atypical cells (Thy 3). He underwent a total thyroidectomy associated to VI level lymphectomy. Histology showed a thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma measuring 0.3 cm in the greatest dimension. Thyroid Paraganglioma is an elusive tumor. It is difficult to diagnose and should be included in the differential diagnosis of all neuroendocrine tumors of the thyroid, even those arising in men or behaving in a locally aggressive fashion. PMID- 23455751 TI - Lattice Corneal Dystrophy-Variant: a report of three new cases due to p.V631D mutation in the TGFBI gene. AB - PURPOSE: To report clinical findings and molecular defect in three subjects affected by Biber-Haab-Dimmer dystrophy or Lattice Corneal Dystrophy Type I (LCD1), a corneal dystrophy transmitted as an autosomal dominant tract. MATERIALS AND METHODS: Three subjects underwent a complete ophthalmic examination and confocal microscopy study. Following the collection of DNA from the patients, the TGFBI gene was screened for mutations by direct sequencing. RESULTS: Confocal microscopy study revealed that the opacity typical of the disease was assembled in the axial region of the cornea. The causative TGFBI mutation p.Val631Asp was identified in all subjects. CONCLUSIONS: The finding of the p.Val631Asp mutation responsible for this form of LCD-Variant highlights the utility of molecular genetic analysis of the TGFBI gene in order to offer early diagnosis. These results provide more data for molecular diagnosis and prognosis of this clinical and genetic heterogeneous disease. PMID- 23455752 TI - Management of oncologic transplant recipient: the profile of the radiation oncologist. AB - Long-term survival after organ transplantation is increasing. As a result, many physicians may encounter various solid organ cancers during follow up. We review papers who address their attention on those malignancies and their treatment. Aim of this work is to discuss the role of radiotherapy especially when helped by new technologies in the management of brain, skin, head and neck, lung, breast, prostate and anal cancer. In our institution we are used to treat such patients by Helical Tomotherapy in order to avoid graft and to limit high risk toxicity. As example, we include a scalp and pelvic irradiation in which high dose conformality is linked to best organ sparing. PMID- 23455753 TI - Professional exposure to anaesthetic gases in health workers: estimate of some hepatic and renal tests. AB - OBJECTIVES: The aim of this study is to estimate whether the occupational exposure to low dose of anaesthetic gases could cause alterations of haematochemical hepatic and renal parameters in the health workers of a city hospital. MATERIALS AND METHODS: After excluding the main confounding factors, 154 exposed subjects and 98 not exposed controls were included in the study. The exposed subjects were divided in more exposed (group 1: n.54) and less exposed (group 2: n.100). Each worker included in this study underwent the CBC test (Complete Blood Count test). The differences between means were compared using the Student T test for unpaired data and considered significant when the p value was < 0.05. RESULTS: The mean values of serum albumin, alpha 1, alpha 2, beta and gamma globulins were significantly decreased in health workers of both groups compared to controls. The mean values of serum creatinine and gamma-GT were significantly higher in health workers of group 2 compared to controls. CONCLUSIONS: The obtained results suggest that occupational exposure to low dose of anaesthetic gases could influence haematochemical hepatic and renal parameters in exposed health workers. PMID- 23455754 TI - Innovative therapies: general aspects and ethical criteria for evaluating protocols. AB - There are many ways of interpreting the notion of "innovation" with reference to therapeutics. The term is generally given a wide meaning, encompassing anything that brings something new. From the ethical point of view the definition of "innovation" is of key importance, for example when dealing with a major problem such as the evaluation of protocols that propose "innovative" therapies. There is currently debate as to whether this should be accomplished using the same procedures typically applied to experimental research protocols, or by following quite different procedures when "innovation" is involved. The present article offers an overview of the notion of "innovation" in the context of biomedical research, together with some considerations and proposals for evaluating it from the ethical viewpoint. PMID- 23455755 TI - [Scrotal ultrasound: anatomy and pathological findings]. AB - Ultrasonography (US) is the imaging modality of choice for the evaluation of scrotal disease. It provides high anatomical detail and in most cases, it is essential to enable a correct diagnosis and to obtain the right management of the patient. Color Doppler ultrasonography is a non invasive technique that aids important information about testicular perfusion, necessary in reaching a specific diagnosis in many pathologic conditions; moreover contrast-enhanced ultrasonography (CEUS), recently introduced in the clinical practice, may be considered an additional tool in the classification and differentiation of testicular pathology. The purpose of this review, is to provide the state of the art on the role of ultrasonography in the evaluation of different scrotal pathologies including vaginal process' disorders, acute scrotum, varicocele, hydrocele, chronic inflammatory diseases and testicular tumours. PMID- 23455756 TI - Aberrant expression of E-cadherin and integrin beta-1 in trophoblasts is associated with malignant gestational trophoblastic diseases. AB - OBJECTIVE: To investigate the association between malignant gestational trophoblastic diseases and aberrant local expression of E-cadherin and integrin beta-1 in the context of identifying a method to predict and diagnose malignant gestational trophoblastic diseases at an early stage. METHODS: We used immunohistochemistry to assess E-cadherin and integrin beta-1 expression profiles in normal chorionic villus, hydatidiform mole, and invasive mole. RESULTS: E cadherin expression gradually decreased from normal tissue to malignant tissue. Staining for E-cadherin was positive in 90% of normal trophoblastic villus in early pregnancy, 80% in benign hydatidiform mole, and 50% in invasive mole. Notably, invasive mole had significantly lower E-cadherin expression than benign mole (P < 0.05). However, there was no significant difference in staining between benign and malignant moles (15% vs 10%, P > 0.05). Integrin beta-1 expression was identical in benign hydatidiform mole and malignant mole (90% and 90%), but this value was significantly higher than that in normal trophoblastic villus (40%, both P < 0.05). Moreover, malignant mole staining was significantly higher than in the benign mole (30% vs 15%, P < 0.05). CONCLUSIONS: Aberrant expression of E cadherin and integrin beta-1 is closely related to malignant transformation and hydatidiform mole development. Changes in the expression of E-cadherin and integrin beta-1 are informative and may improve the early diagnosis of malignant/invasive moles. PMID- 23455758 TI - Normalization of miRNA qPCR high-throughput data: a comparison of methods. AB - Low-density quantitative real-time PCR (qPCR) arrays are often used to profile expression patterns of microRNAs in various biological milieus. To achieve accurate analysis of expression of miRNAs, non-biological sources of variation in data should be removed through precise normalization of data. We have systematically compared the performance of 19 normalization methods on different subsets of a real miRNA qPCR dataset that covers 40 human tissues. After robustly modeling the mean squared error (MSE) in normalized data, we demonstrate lower variability between replicates is achieved using various methods not applied to high-throughput miRNA qPCR data yet. Normalization methods that use splines or wavelets smoothing to estimate and remove Cq dependent non-linearity between pairs of samples best reduced the MSE of differences in Cq values of replicate samples. These methods also retained between-group variability in different subsets of the dataset. PMID- 23455757 TI - Six-year regression and progression of cervical lesions of different human papillomavirus viral loads in varied histological diagnoses. AB - OBJECTIVE: This study aims to evaluate human papillomavirus (HPV) viral loads as a biomarker for triage into colposcopy and cervical intraepithelial neoplasia grade 2 (CIN2) therapy to reduce the colposcopy referral rate and CIN2 overtreatment in low-resource settings. METHODS: In 1999, 1997 women aged 35 to 45 years in Shanxi, China, received 6 cervical screenings with pathological confirmation. In 2005, 1461 histologically normal women, 99 with CIN grade 1 (CIN1), and 30 with CIN2 or worse (CIN2+) were rescreened in a follow-up study. Human papillomavirus was detected by Hybrid Capture 2. Viral load, estimated by the ratio of relative light units to standard positive control (RLU/PC), was categorized into 4 groups: negative (<1.0), low (>=1.0, <10.0), moderate (>=10.0, <100.0), and high (>=100.0). We estimated the cumulative incidence of CIN2+ by viral load subgroups and calculated adjusted hazard ratios for CIN2+ using Cox proportional hazards regression. RESULTS: Cumulative incidence of CIN2+ increased with baseline HPV viral loads among normal women and women with CIN1 at baseline (P(-trend) < 0.001). Repeat moderate-high viral load was associated with the highest risk for CIN2+ (adjusted hazard ratio, 188.8; 95% confidence interval, 41.2-864.1). Raising the ratio of relative light units to standard positive control cutoff from 1.0 to 10.0 for colposcopy greatly reduced the referral rate from 18.1% to 12.9%. It also increased the specificity (84.8% vs 90.4%), the positive predictive value (22.5% vs 28.9%), and the positive likelihood ratio (6.4 vs 8.9), yet with loss of sensitivity by 12% (97.6% vs 85.7%). Among women with CIN2 at baseline, 56% regressed to normal, 24% regressed to CIN1, 4% remained CIN2, and 16% progressed to CIN grade 3 or worse. CONCLUSIONS: Locales using HPV testing as the primary screening method and lacking high-quality cytology-based screening should consider viral load as an alternative to colposcopy triage for women older than 35 years. Viral loads may also predict CIN2 progression until additional biomarkers become available. PMID- 23455759 TI - Nanomaterials for energy conversion and storage. AB - Nanostructured materials are advantageous in offering huge surface to volume ratios, favorable transport properties, altered physical properties, and confinement effects resulting from the nanoscale dimensions, and have been extensively studied for energy-related applications such as solar cells, catalysts, thermoelectrics, lithium ion batteries, supercapacitors, and hydrogen storage systems. This review focuses on a few select aspects regarding these topics, demonstrating that nanostructured materials benefit these applications by (1) providing a large surface area to boost the electrochemical reaction or molecular adsorption occurring at the solid-liquid or solid-gas interface, (2) generating optical effects to improve optical absorption in solar cells, and (3) giving rise to high crystallinity and/or porous structure to facilitate the electron or ion transport and electrolyte diffusion, so as to ensure the electrochemical process occurs with high efficiency. It is emphasized that, to further enhance the capability of nanostructured materials for energy conversion and storage, new mechanisms and structures are anticipated. In addition to highlighting the obvious advantages of nanostructured materials, the limitations and challenges of nanostructured materials while being used for solar cells, lithium ion batteries, supercapacitors, and hydrogen storage systems have also been addressed in this review. PMID- 23455760 TI - Congenital hypothyroidism caused by a novel homozygous mutation in the thyroglobulin gene. AB - Congenital hypothyroidism (CH) due to thyroglobulin (TG) deficit is an autosomal recessive disease (OMIM #274700) characterized by hypothyroidism, goiter, low serum TG, and a negative perchlorate discharge test. The aim of this study was to perform the genetic analysis of the TG gene in two sisters born from consanguineus parents and affected by CH and low serum TG levels. The index patient and her sister were identified at neonatal screening for CH and treated with L-thyroxine (L-T4). After discontinuation of L-T4 therapy, hypothyroidism was confirmed, serum TG was undetectable, and no organification defect after (123)I scintigraphy and perchlorate test was shown; thyroid ultrasound showed a eutopic gland of normal size. DNA was extracted from peripheral white blood cells of the two sisters and the father. All 48 exons of TG gene were amplified by polymerase chain reaction and subjected to direct sequencing. A novel homozygous point mutation in exon 10 of TG gene was identified in the patient and her sister. The mutation determined a stop codon at position 768 (R768X) resulting in an early truncated protein or in the complete absence of the protein. The father (euthyroid) was heterozygous carrier of the mutation. CONCLUSION: Genetic analysis of TG gene was performed in two sisters affected by CH. A novel point mutation of the TG gene determining a stop codon at position 768 of the protein was identified. The early truncated nonfunctioning protein or the absence of the protein due to the premature degradation of abnormal mRNA may be responsible of the observed phenotype. PMID- 23455761 TI - Bilateral slipped capital femoral epiphysis in a male adolescent with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), chronic renal failure, and severe hyperparathyroidism. AB - Slipped capital femoral epiphysis (SCFE) is the most common orthopedic hip disorder affecting otherwise healthy adolescents. The majority of SCFE cases are classified as idiopathic; rarely, it may be secondary to different endocrinopathies including hyperparathyroidism due to chronic renal failure (CRF). However, over the last decades, the association between SCFE and CRF has almost disappeared, probably due to better management of renal osteodystrophy. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, OMIM no. 248250) is a rare autosomal recessive tubulopathy characterized by renal wasting of calcium and magnesium leading to hypomagnesemia, hypercalciuria, nephrocalcinosis, and CRF. Patients usually show hyperparathyroidism before the onset of advanced CRF caused by FHHNC-related metabolic disturbances. We report on a 15-year-old patient with FHHNC and CRF who developed extreme hyperparathyroidism and high-grade bilateral SCFE after self-discontinuation of supportive treatment of underlying conditions. CONCLUSION: We believe that SCFE was caused not only by untreated CRF but also by metabolic disturbances related to FHHNC. To prevent this complication, careful management of disturbances of calcium, phosphate, and magnesium homeostasis seems to be crucial. PMID- 23455762 TI - Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis. AB - OBJECTIVES: To review the literature on the diagnostic performance of clinical examination and magnetic resonance imaging (MRI) in detecting parametrial invasion and advanced stage disease (FIGO stage >= IIB) in patients with cervical carcinoma. METHODS: Reports of studies were searched using the MEDLINE, EMBASE and Cochrane databases. Two observers reported on data relevant for analysis and methodological quality using the QUADAS scoring system. Publication bias was analysed using Deeks funnel plots. Covariates were added to the model to study the influence on the summary results of the technical and methodological aspects of the clinical examination and MRI. RESULTS: In total, 3,254 patients were included. Partial verification bias was often encountered. Pooled sensitivity was 40 % (95 % CI 25-58) for the evaluation of parametrial invasion with clinical examination and 84 % (95 % CI 76-90) with MRI, 53 % (95 % CI 41-66) for the evaluation of advanced disease with clinical examination, and 79 % (95 % CI 64 89) with MRI. Pooled specificities were comparable between clinical examination and MRI. Different technical aspects of MRI influenced the summary results. CONCLUSIONS: MRI is significantly better than clinical examination in ruling out parametrial invasion and advanced disease in patients with cervical carcinoma. KEY POINTS: * MRI has a higher sensitivity than clinical examination for staging cervical carcinoma. * Clinical examination and MRI have comparably high specificity for staging cervical carcinoma. * Quality of clinical examination studies was lower than that of MRI studies. * The use of newer MRI techniques positively influences the summary results. * Anaesthesia during clinical examination positively influences the summary results. PMID- 23455763 TI - Diffusion-weighted and T2-weighted MR imaging for colorectal liver metastases detection in a rat model at 7 T: a comparative study using histological examination as reference. AB - OBJECTIVES: To compare diffusion-weighted (DW) and T2-weighted MR imaging in detecting colorectal liver metastases in a rat model, using histological examination as a reference method. METHODS: Eighteen rats had four liver injections of colon cancer cells. MR examinations at 7 T included FSE-T2-weighted imaging and SE-DW MR imaging (b = 0, 20 and 150 s/mm(2)) and were analysed by two independent readers. Histological examination was performed on 0.4-mm slices. McNemar's test was used to compare the sensitivities and the Wilcoxon matched pairs test to compare the average number of false-positives per rat. RESULTS: One hundred and sixty-six liver metastases were identified on histological examination. The sensitivity in detecting liver metastases was significantly higher on DW MR than on T2-weighted images (99/166 (60 %) (reader 1) and 92/166 (55 %) (reader 2) versus 77/166 (46 %), P <= 0.001), without an increase in false positives per rat (P = 0.773/P = 0.850). After stratification according to metastasis diameter, DW MR imaging had a significantly higher sensitivity than T2 weighted imaging only for metastases with a diameter (0.6-1.2 mm) similar to that of the spatial resolution of MR imaging in the current study. CONCLUSIONS: This MR study with histological correlations shows the higher sensitivity of DW relative to T2-weighted imaging at 7 T for detecting liver metastases, especially small ones. KEY POINTS: * Diffusion weighted (DW) sequences are increasingly used in magnetic resonance imaging (MRI). * DW has higher sensitivity for liver metastases than T2-weighted imaging at 7 T. * This increase in sensitivity is especially marked for small liver metastasis detection. * This higher sensitivity is confirmed in an animal model with histological correlation. * DW imaging has the potential for earlier diagnosis of small liver metastases. PMID- 23455765 TI - Physiology's impact: discovering life. PMID- 23455764 TI - MRI for response assessment in metastatic bone disease. AB - BACKGROUND: Beyond lesion detection and characterisation, and disease staging, the quantification of the tumour load and assessment of response to treatment are daily expectations in oncology. METHODS: Bone lesions have been considered "non measurable" for years as opposed to lesions involving soft tissues and "solid" organs like the lungs or liver, for which response evaluation criteria are used in every day practice. This is due to the lack of sensitivity, specificity and measurement capabilities of imaging techniques available for bone assessment, i.e. skeletal scintigraphy (SS), radiographs and computed tomography (CT). RESULTS: This paper reviews the possibilities and limitations of these techniques and highlights the possibilities of positron emission tomography (PET), but mainly concentrates on magnetic resonance imaging (MRI). CONCLUSION: Practical morphological and quantitative approaches are proposed to evaluate the treatment response of bone marrow lesions using "anatomical" MRI. Recent developments of MRI, i.e. dynamic contrast-enhanced (DCE) imaging and diffusion-weighted imaging (DWI), are also covered. KEY POINTS: * MRI offers improved evaluation of skeletal metastases and their response to treatment. * This new indication for MRI has wide potential impact on radiological practice. * MRI helps meet the expectations of the oncological community. * We emphasise the practical aspects, with didactic cases and illustrations. PMID- 23455767 TI - Torricelli and the ocean of air: the first measurement of barometric pressure. AB - The recognition of barometric pressure was a critical step in the development of environmental physiology. In 1644, Evangelista Torricelli described the first mercury barometer in a remarkable letter that contained the phrase, "We live submerged at the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight." This extraordinary insight seems to have come right out of the blue. Less than 10 years before, the great Galileo had given an erroneous explanation for the related problem of pumping water from a deep well. Previously, Gasparo Berti had filled a very long lead vertical tube with water and showed that a vacuum formed at the top. However, Torricelli was the first to make a mercury barometer and understand that the mercury was supported by the pressure of the air. Aristotle stated that the air has weight, although this was controversial for some time. Galileo described a method of measuring the weight of the air in detail, but for reasons that are not clear his result was in error by a factor of about two. Torricelli surmised that the pressure of the air might be less on mountains, but the first demonstration of this was by Blaise Pascal. The first air pump was built by Otto von Guericke, and this influenced Robert Boyle to carry out his classical experiments of the physiological effects of reduced barometric pressure. These were turning points in the early history of high-altitude physiology. PMID- 23455768 TI - Modern concepts concerning the origin of the heartbeat. AB - Physiological processes governing the heart beat have been under investigation for several hundred years. Major advances have been made in the recent past. A review of the present paradigm is presented here, including a look back at important steps that led us to where we are today, alongside a glimpse into the exciting future of pacemaker research. PMID- 23455770 TI - Modeling obesity and its associated disorders in Drosophila. AB - In recent years, obesity has been recognized as a major public health problem due to its increased prevalence in both children and adults and its association with numerous life-threatening complications including diabetes, heart disease, hypertension, and cancer. Obesity is a complex disorder that is the result of the interaction between predisposing genetic and environmental factors. However, the precise nature of these gene-gene and gene-environment interactions remains unclear. Here, we will describe recent studies demonstrating how fruit flies can be used to identify and characterize the mechanisms underlying obesity and to establish models of obesity-associated disorders. PMID- 23455769 TI - Proteins and mechanisms regulating gap-junction assembly, internalization, and degradation. AB - Gap junctions (GJs) are the only known cellular structures that allow a direct cell-to-cell transfer of signaling molecules by forming densely packed arrays or "plaques" of hydrophilic channels that bridge the apposing membranes of neighboring cells. The crucial role of GJ-mediated intercellular communication (GJIC) for all aspects of multicellular life, including coordination of development, tissue function, and cell homeostasis, has been well documented. Assembly and degradation of these membrane channels is a complex process that includes biosynthesis of the connexin (Cx) subunit proteins (innexins in invertebrates) on endoplasmic reticulum (ER) membranes, oligomerization of compatible subunits into hexameric hemichannels (connexons), delivery of the connexons to the plasma membrane (PM), head-on docking of compatible connexons in the extracellular space at distinct locations, arrangement of channels into dynamic spatially and temporally organized GJ channel plaques, as well as internalization of GJs into the cytoplasm followed by their degradation. Clearly, precise modulation of GJIC, biosynthesis, and degradation are crucial for accurate function, and much research currently addresses how these fundamental processes are regulated. Here, we review posttranslational protein modifications (e.g., phosphorylation and ubiquitination) and the binding of protein partners (e.g., the scaffolding protein ZO-1) known to regulate GJ biosynthesis, internalization, and degradation. We also look closely at the atomic resolution structure of a GJ channel, since the structure harbors vital cues relevant to GJ biosynthesis and turnover. PMID- 23455772 TI - Corrected right ventricular end-diastolic volume and initial distribution volume of glucose correlate with cardiac output after cardiac surgery. AB - PURPOSE: Appropriate adjustment of cardiac preload is essential to maintain cardiac output (CO), especially in patients after cardiac surgery. This study was intended to determine whether index of right ventricular end-diastolic volume (RVEDVI), corrected RVEDVI using ejection fraction (cRVEDVI), index of initial distribution volume of glucose (IDVGI), or cardiac filling pressures are correlated with cardiac index (CI) following cardiac surgery in the presence or absence of arrhythmias. METHODS: Eighty-six consecutive cardiac surgical patients were studied. Patients were divided into two groups: the non-arrhythmia (NA) group (n = 72) and the arrhythmia (A) group (n = 14). Three sets of measurements were performed: on admission to the ICU and daily on the first 2 postoperative days. The relationship between each cardiac preload variable and cardiac index (CI) was evaluated. A p value less than 0.05 indicated statistically significant differences. RESULTS: Each studied variable was not different between the two groups immediately after admission to the ICU. cRVEDVI had a linear correlation with CI in both group (NA group: r = 0.67, n = 216, p < 0.001; A group: r = 0.77, n = 42, p < 0.001), but RVEDVI had a poor correlation with CI (NA group: r = 0.27, n = 216, p < 0.001; A group: r = 0.19, n = 42, p = 0.036). IDVGI had a linear correlation with CI (NA group: r = 0.49, n = 216, p < 0.001; A group: r = 0.61, n = 42, p < 0.001), Cardiac filling pressures had no correlation with CI. CONCLUSION: Our results demonstrated that cRVEDVI and IDVGI were correlated with CI in the presence or absence of arrhythmias. cRVEDVI and IDVGI have potential as indirect cardiac preload markers following cardiac surgery. PMID- 23455771 TI - Endothelial fatty acid transport: role of vascular endothelial growth factor B. AB - Dietary lipids present in the circulation have to be transported through the vascular endothelium to be utilized by tissue cells, a vital mechanism that is still poorly understood. Vascular endothelial growth factor B (VEGF-B) regulates this process by controlling the expression of endothelial fatty acid transporter proteins (FATPs). Here, we summarize research on the role of the vascular endothelium in nutrient transport, with emphasis on VEGF-B signaling. PMID- 23455774 TI - Peripheral T-cell lymphoma: frequency and distribution in a tertiary referral center in South India. AB - BACKGROUND AND AIM: Peripheral T/NK-cell lymphomas are uncommon types of non Hodgkin's lymphoma (NHL) with a higher frequency in Far East countries as compared to the West. This study was undertaken to ascertain the frequency and distribution pattern of peripheral T-cell lymphomas (PTCLs) diagnosed in a tertiary care center in South India. MATERIALS AND METHODS: This retrospective study was carried out in Department of General Pathology, Christian Medical College, Vellore. The time period was for 2 years from 1 st January 2008 till 31st December 2009. All PTCLs were reviewed and classified according to the World Health Organization (WHO) 2008 classification. RESULTS: Of a total of 1032 cases of NHL, 180 cases were PTCL, which accounted for 17.4% cases of all the NHLs. Of these, PTCL, not otherwise specified (PTCL, NOS) was the most common subtype (48 cases, 26.1%), followed by anaplastic large cell lymphoma (41 cases, 22.8%), mycosis fungoides (21 cases, 11.7%), angioimmunoblastic T-cell lymphoma (16 cases, 8.9%), subcutaneous panniculitis like T-cell lymphoma (15 cases, 8.4%), extranodal NK/T-cell lymphoma, nasal type (12 cases, 6.7%), and hepatosplenic T cell lymphoma (10 cases, 5.6%). The most common primary site of presentation was nodal accounting for 42% followed by cutaneous (34%), upper aerodigestive sites (8.9%), spleen (6.7%), and gastrointestinal tract (GIT; 3.3%). CONCLUSIONS: This is the largest single study on PTCLs in India and we document that its frequency is higher than that reported in Western literature and previous Indian studies and almost similar to that reported in some Far East studies. The frequency of mycosis fungoides, subcutaneous panniculitis like T-cell lymphoma, and hepatosplenic T-cell lymphoma was higher than that reported in the World literature and previous Indian studies. The frequency of extranodal NK/T-cell lymphoma and angioimmunoblastic T-cell lymphoma was much lower than that reported in the Far East literature. PMID- 23455773 TI - Chest anteroposterior diameter affects difficulty of laryngoscopy for non morbidly obese patients. AB - PURPOSE: This prospective, observational study was performed to examine the hypothesis that if conventional 7-cm head elevation is applied, laryngoscopy is more difficult for patients with anteroposterior chest diameter (chest AP diameter) outside the average range (>=17.7 or <=14.7 cm). METHODS: Chest AP diameter at the sternal notch were measured preoperatively. All patients were placed on a surgical bed with an incompressible 7-cm pillow. During laryngoscopy, the laryngeal view was graded by use of the Cormack-Lehane classification. Difficult visualization of the larynx (DVL) was defined as a grade 3 or 4 view. RESULTS: DVL was observed for 49 patients (18.2 %). Differences between measured chest AP diameter for each patient and the calculated median value were used for statistical analysis. In univariate analysis, the difference between chest AP diameter and the median value was significantly related to DVL. Logistic regression analysis confirmed that the difference between chest AP diameter and the median value was an independent predictor of DVL (odds ratio, 3.900; 95 % confidence interval, 2.371-6.415; p < 0.001). Receiver operating characteristic curve analysis showed that this test with a test threshold of 1.5 cm had reasonable diagnostic accuracy (area under the curve of 0.748). CONCLUSION: When using a standard pillow size of 7 cm, chest AP diameter above or below the average range (>=17.7 or <=14.7 cm) was a strong predictor of DVL for apparently normal-sized patients. In such cases, modification of pillow height should be considered. PMID- 23455775 TI - Micronucleus assay of buccal mucosa cells in smokers with the history of smoking less and more than 10 years. AB - INTRODUCTION AND AIM: Cigarette smoking causes severe health problems such as cancer. Micronuclei are structures that present after genomic damages to the cells. The present study is aimed at evaluating the micronucleus assay of buccal mucosa cells in smokers who smoked less or more than 10 years. MATERIALS AND METHODS: The present study has been a historical cohort study. The smokers were divided into two groups: First group include individuals with a smoking history less than 10 years (14 samples) and second group with the smoking history of more than 10 years (26 samples).The control group consisted of nonsmokers (23 samples). The exfoliated buccal mucosa cells were scrapped using spatula and were spread over the glass slide. Feulgen method was used for micronucleus staining. 500 cells per subjects were counted. The presence of micronucleus in all subjects and the mean percentage of micronucleus in nuclei were determined. Data were subjected to statistical analysis using T-test. RESULTS: The mean number of micronucleus of buccal mucosa cells in nonsmokers, first group (smoking history less than 10 years) and second group (smoking history more than 10 years) was 0.94+/-0.94, 1.89+/-0.62 and 2.01+/-0.93 respectively. The difference was statistically significant (P<0.002). Considering the number of micronuclei of the buccal mucosa cells, the difference between groups 1 and 2 was not significant (P<0.6). The mean percentage of micronucleated cells in nonsmokers, group 1 and group 2 was 2.26+/-2.17%, 13.9+/-5.90 and 14.3+/-7.97, respectively. The difference was statistically significant (P<0.001).The difference between the percentage of the cells with micronucleus in smokers with a smoking history of less or more than 10 years was not significant (P<0.6). CONCLUSION: The mean number of micronuclei in buccal mucosa cells of the nonsmokers was significantly lower than that of the smokers. However, the mean number of micronucleus of buccal mucosa cells in smokers who smoked more than 10 years was higher than smokers who smoked less than 10 years. Increasing the smoking duration could heighten the frequency of micronucleus; however, the difference was not significant. PMID- 23455776 TI - Mucinous tubular and spindle cell carcinoma of kidney: a clinicopathologic study of six cases. AB - BACKGROUND: Mucinous tubular and spindle carcinoma (MTSCC) of kidney is a rare, low-grade polymorphic tumor. Recent studies have described a wide morphology spectrum of this tumor. AIM: To report the clinico-pathologic features of six cases of MTSCC of kidney. MATERIALS AND METHODS: Six cases of MTSCC of kidney were studied and literature was reviewed. Immunohistochemistry was done by Envision method. RESULTS: The age of the patients ranged from 44 to 84 years (mean 58.5 years). Four patients were males and two were females. The tumor was located in the left kidney in four cases and in the right kidney in two cases. The tumor size ranged from 4.5 to 15 cm (mean 6.4 cm). All tumors exhibited an admixture of tubules, spindle cells, and mucinous stroma in variable proportions. Tubules were predominant in five cases and spindle cells in one case. Psammomatous calcifications, papillations, and necrosis were seen in two cases. Collections of foamy histiocytes were noted in four cases. Cytoplasmic vacuoles and osseous metaplasia were seen in one case each. All cases were Fuhrman's nuclear grade II. Five cases were of stage pT1, and one was pT3. All cases stained positive for alcian blue at pH 2.5. Immunohistochemical stain CK7 was positive in all cases and CD10 was positive in 1/1 case. All patients were alive and well at follow-up of 12-59 months (mean 33.5 months). No metastases were detected. CONCLUSIONS: We report six cases of MTSCC of kidney, a rare distinct variant of RCC, with a favorable prognosis. A male predominance was seen in our cases. MTSCC shares histologic and immunohistochemical overlap with papillary renal cell carcinoma (PRCC) and cytogenetic analysis should be performed in difficult cases to avoid a misdiagnosis. PMID- 23455777 TI - Epithelial mesenchymal transition in urothelial carcinoma: twist in the tale. AB - CONTEXT: Epithelial to mesenchymal transition (EMT) is a process involving conversion of cells from an epithelial to mesenchymal phenotype. The role of candidate genes promoting EMT and favoring a promigratory phenotype has been demonstrated in epithelial cancer. Existing scientific research has not yielded a clinically relevant biomarker with predictive capacity beyond grade and stage in bladder cancer. AIM: The purpose of this study is to evaluate the immunohistochemical expression pattern of a panel of epithelial and mesenchymal markers in paraffin-embedded archival material of primary urothelial carcinoma as evidence of EMT. MATERIALS AND METHODS: Immunohistochemical expression of transcription factor twist, epithelial (E-cadherin, cytokeratin) and mesenchymal (vimentin, N-cadherin) markers was analyzed on archival paraffin-embedded tissue samples from 48 patients with diagnosis of primary urothelial carcinoma of bladder. STATISTICAL ANALYSIS: Karl Pearson's chi2 test was used to evaluate the association between the expression of immunohistochemical markers and various clinico-pathologic variables. Non-parametric Kendall's tau-b statistics was used to determine the correlation between categorical variables. RESULTS AND CONCLUSION: The study demonstrated statistically significant association of cytokeratin, E-cadherin, vimentin, and twist with stage and grade of bladder cancer. Since these markers form part of the spectrum of changes associated with EMT, the study establishes proof of concept of the existence of this process in vivo. A significant negative correlation was noted between the expression of twist and E-cadherin. Exploiting its role as a transcriptional repressor of E cadherin, twist may prove to be a useful candidate for targeted therapy in urologic oncology. PMID- 23455778 TI - Biochemical evaluation of the supporting structure of pelvic organs in selected numbers of premenopausal and postmenopausal Malaysian women. AB - CONTEXT: Pelvic organ prolapse (POP) is associated with menopause and changes in the proteins of the pelvic supporting system, but there is scant data on the precise alterations in Malaysian women. AIM: The aim of this study is to determine the differences in the extracellular matrices (ECM) of uterosacral ligaments in premenopausal and postmenopausal Malaysian women with or without POP. SETTINGS AND DESIGN: The observational study was conducted for 9 months in three general hospitals involving 30 women who underwent hysterectomies for various indications except for carcinoma of pelvic organs. MATERIALS AND METHODS: Three groups were identified: Premenopausal women (Group 1), postmenopausal women without POP (Group 2), and postmenopausal women with POP (Group 3). Age, duration of menopause, body mass index (BMI), parity, and vaginal deliveries were documented. Only 21 samples of the uterosacral ligaments were stained immunohistochemically for collagen I and III, matrix metalloproteinases (MMPs) 1 and 2, elastin, and tenascin. STATISTICAL ANALYSIS USED: Image J software analysis was utilized for quantification, while non-parametric statistics (Kruskal-Wallis with post-hoc Dunns Multiple Comparison test) was used for result analysis. RESULTS: The profile parameters were not significantly different except for mean age and duration of menopause in Group 3. Samples from Group 2 showed lower expression of almost all proteins except MMP1 and tenascin (higher) as compared to Group 1. The changes appeared to be exaggerated in Group 3, though statistically insignificant. CONCLUSION: A significant difference in the expression of ECM was apparent in postmenopausal subjects as compared to premenopausal (P=0.05), compromising the uterosacral ligament tensile strength. The findings are proven similar as those changes in women from other studies. PMID- 23455779 TI - Relation of CD117 immunoreactivity and microvascular density in invasive breast carcinoma. AB - BACKGROUND AND OBJECTIVE: In breast cancer, the expression of CD117 represents a highly controversial subject but the majority of studies have found decreased c kit expression in malignant breast epithelium. A number of studies have reported that increased intratumoral microvessel density (MVD) is associated with poor prognosis in breast cancer. The aim of the study was to assess the relation of CD117 and MVD with other clinicopathological parameters in invasive breast carcinomas using the tissue microarray technique. MATERIALS AND METHODS: A total of 126 cases of invasive breast carcinoma of different histological types and grades were collected from files of a pathology department during 2010. Clinicopathological and histological parameters were evaluated. Sections from formalin-fixed, paraffin-embedded tumor tissues microarray blocks were immunostained with CD117 and CD34. Statistical analysis of data was done using SPSS, version 16.0. RESULTS: About 29% of invasive breast carcinomas were CD117 positive. There were significant differences between expression of CD117 in the tumor epithelial cells and age of the patient; tumor grade; tumor size, and LN metastasis. Also, there was significant relation between expression of CD117 in the tumor epithelial cells and MVD, expression of estrogen, and progesterone receptors. On multivariate analysis, the most important predictors of negativity of CD117 were tumor size and positive lymph node involvement. CONCLUSION: Lack of CD117 immunoreactivity in invasive breast carcinoma was associated with features of more aggressive tumor behavior as higher microvessel density, larger size, higher tumor grade, more lymph node metastasis, and negative estrogen and progesterone receptors. PMID- 23455780 TI - Spectrum of adrenal lesions on fine needle aspiration cytology. AB - BACKGROUND: Fine needle aspiration (FNA) cytology of adrenal gland is not a commonly performed technique and is limited primarily to tertiary care centers. However, it is a sensitive and specific procedure in the workup of patients with adrenal gland's mass lesions. Though cytomorphological features for various lesions have been described, there are a limited number of studies in cytologic literature. AIMS: We report our 7 years of experience in FNAC of adrenal lesions. We have not only described the cytomorphological details of different lesions, but also tried to discuss the various diagnostic difficulties encountered during reporting of adrenal fine needle aspirations. MATERIALS AND METHODS: All ultrasound-guided percutaneous aspirations of adrenal gland received in the department between the years 2002 and 2009 were reviewed. There were a total of 52 FNA samples of adrenal masses from 35 patients in 7 years. The lesions were categorized as non-neoplastic and neoplastic categories. Neoplastic lesions were further divided into benign and malignant lesions. RESULTS: In our study, FNA proved to be 100% specific for diagnosing malignant lesions. The overall inadequacy rate was 11.4% with no major complications of the procedure. A wide variety of non-neoplastic as well as neoplastic lesions were identified. PMID- 23455781 TI - Usefulness of automated cell counter in detection of malaria in a cancer set up- our experience. AB - BACKGROUND: Malaria diagnosis presents a challenge to all laboratories. In malaria-endemic areas, there is a need for rapid, sensitive and cost-effective method to effectively screen all samples, especially when the workload is very high. Various hematology analyzers have been investigated for detection of malaria in the past. Here, we present our experience of malaria detection in a cancer hospital where a large number of complete blood count requests are received either before or during chemotherapy. Fever, being a very common symptom in cancer patients, causes a suspicion of malaria. AIM: This study was conducted to assess the usefulness of hematology cell counter, viz. WBC-DIFF and WBC/BASO scatter plots and the flaggings generated in malaria-positive cases. The occurrence of pseudoeosinophilia as reported by previous studies was also assessed. The parasitic index was determined and its correlation with the abnormalities found on the Hematology analyzer was also studied. MATERIALS AND METHODS: Blood samples were collected from 80 out-patient department and inpatients with various solid as well as hematological malignancies, who presented with acute febrile illness during September 2010 and January 2012, and for whom complete blood cell analysis and peripheral smear for malaria parasite had been requested. RESULTS: Of the 80 patients who presented with fever and suspicion of malaria, 29 patients were positive for malaria and 10 cases were diagnosed incidentally by the findings on the cell counter and were confirmed by Giemsa-stained blood smears. The sensitivity and specificity of the abnormalities detected in the WBC-Diff channel in detecting malaria is 82% and 100% respectively. Using WBC-BASO channel abnormality for initial diagnosis the sensitivity and specificity is 50% and 92.5% respectively. The sensitivity and specificity with respect to pseudoeosinophilia is 18% and 100% respectively. The most common WBC and PLT flags were leukopenia, atypical lymphocytes, lymphopenia, WBC abnormal scattergram, platelet clumps, thrombocytopenia, platelet abnormal distribution flag. CONCLUSION: The instrument provides significantly valuable diagnostic parameters in detecting acute Plasmodium vivax malaria; however, it is not very useful for acute falciparum malaria infection. It is suggested that the laboratories using the hematology analyzers should be aware of such specific parameters, even in the absence of a clinical request. PMID- 23455782 TI - Significant increases in monocyte counts and serum creatine kinase in acute myocardial infarction versus general infections. AB - BACKGROUND: Biomarkers specificity is an important factor for their reliable utilization. Known markers for acute myocardial infarction (AMI), including creatine kinase (CK), C-reactive protein (CRP), and blood cell counts are thought to be altered in other pathologic conditions, such as infections. AIM: To compare the level of these biomarkers in AMI patients and infected controls with respect to normal subjects. MATERIALS AND METHODS: We recruited 15 AMI patients, 15 patients with bacterial infections (infected control group) and 35 normal subjects. Peripheral blood samples were obtained for blood cell counts and biochemical analyses. RESULTS: Only monocytes were significantly increased in AMI patients (0.793*10(9)/L) than normal controls (0.497*10(9)/L). Infected controls showed a significant increase in total white blood cell (11.50*10(9)/L versus 6.149*10(9)/L) and neutrophil (9.360 versus 3.223*10(9)/L) counts and a significant decrease in red blood cell (3.750 versus 5.105*10(12)/L) counts as compared with normal controls. Serum CK was significantly increased in AMI patients (313.20+/-94.84 U/L) and decreased in infected controls (48.40+/-10.35 U/L) as compared with normal controls (100.82+/-8.86 U/L). The levels of CRP were significantly higher in infected controls (136.93+/-34.83 mg/L) and nonsignificantly higher in AMI patients (38.53+/-12.76 mg/L) than normal controls (3.48+/-0.59 mg/L). Monocytes were significantly correlated with both CK and CRP; however, there was no correlation between CK and CRP. CONCLUSION: Differential trends of monocytes and CK in AMI and infective controls point toward their possible application in prognosis of AMI patients. PMID- 23455783 TI - Molecular detection of TT virus and SEN virus infections in hemodialysed patients and blood donors in south of Iran. AB - BACKGROUND: SEN virus (SEN-V) and TT virus (TTV) have been classified in the circoviridae family. Both are single-stranded, non-enveloped DNA viruses of about 3800 nucleotides. Patients on maintenance hemodialysis (HD) have a high risk of blood-borne viral infections. SEN-V and TTV has been reported from a number of HD units from various countries throughout the world. MATERIALS AND METHODS: A total of 377 blood samples obtained from 150 healthy donors and 227 HD patients were collected at the HD center. SEN-V and TTV DNA was determined by polymerase chain reaction (PCR) in all samples. RESULTS: TTV was detected in 109 (48.01%) of 227 hemodialysed patients and 14 (9.33%) of 150 voluntary blood donors (significant, P<0.05). The PCR results for SEN-V-D/H DNA showed that 65 (28.63%) were positive for SEN-V-D and 33 (14.53%) were positive for SEN-V-H. 9.69% of 227 patients were positive for SEN-V-D/H co-infection. In the control group, SEN-V-D was detected in 14 (9.33%) and SEN-V-H was detected in 15 (10%) of the 150 (100%) blood donors. CONCLUSION: These findings show that the prevalence of SEN-V-D/H and TTV is higher than healthy blood donors. Also, these results indicate that the prevalence of SEN-V and TTV infections in our region is similar with that in other countries. PMID- 23455784 TI - Correlation between HER2 gene amplification and protein overexpression through fluorescence in situ hybridization and immunohistochemistry in breast carcinoma patients. AB - BACKGROUND: In India, the incidence of breast cancer has increased in the urban population, with 1 in every 22 women diagnosed with breast cancer. It is important to know the HER2/neu gene status for a better prognostication of these patients. AIM: The aim of this study was to compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for determining HER2/neu alteration in breast carcinoma. MATERIALS AND METHODS: A total of 188 histologically proven breast carcinoma cases between the years 2007 and 2011 were retrospectively analyzed on the paraffin tissue sections by both IHC and FISH techniques. FISH for HER2/neu gene amplification was performed on cases where the IHC status was already known and the results were compared. RESULTS: A total of 64 (30%) patients were found to be amplified and the remaining 124 (65.9%) cases were found to be unamplified through FISH. Patients observed with 3+ reading on IHC were later confirmed as unamplified in 29.5% cases through FISH. CONCLUSION: It has been confirmed with the present study that IHC is a prudent first-step technique to screen tissue samples for HER2/neu gene status, but should be supplemented with the FISH technique especially in equivocal cases. PMID- 23455785 TI - Adherent Escherichia coli in colorectal mucosal biopsies: a histological and ultrastructural evaluation. AB - BACKGROUND: Colorectal mucosal biopsies occasionally demonstrate the presence of bacteria adherent to the epithelium. This study evaluated the histological and ultrastructural correlates of such bacterial adherence. MATERIALS AND METHODS: Rectal mucosal biopsies from eight patients in whom histopathological examination of biopsies had earlier demonstrated adherent bacteria were examined by electron microscopy and by bacterial culture. Colorectal biopsies of 69 patients with adherent bacteria detected histologically were retrospectively evaluated for histological changes at sites proximal and distant to adherent bacteria. RESULTS: Escherichia coli of different serogroups were isolated from 7 of 8 rectal biopsies demonstrating bacterial adherence. All isolates showed diffuse or focal adherence to HEp-2 cell monolayers. Ultrastructural changes noted included microvillus damage, pedestal formation, actin web condensation, and protrusions of the apical cytoplasm of epithelial cells into the lumen towards the bacteria. Histological changes noted at light microscopy included reduction in epithelial cell height, focal epithelial cell degeneration, cryptitis and neutrophil infiltration at sites of bacterial adherence whereas these were usually absent at sites distant to adherent bacteria. Bacterial adherence was noted more often in biopsies from Crohn's disease patients than in patients without this diagnosis (P<0.001). CONCLUSION: Adherent Escherichia coli in colorectal biopsies were associated with focal epithelial damage and showed an association with Crohn's disease. PMID- 23455786 TI - Application of fnbA gene as new target for the species-specific and quantitative detection of Staphylococcus aureus directly from lower respiratory tract specimens by real time PCR. AB - Staphylococcus aureus is a significant cause of hospital-acquired pneumonia (HAP), particularly in mechanically ventilated patients. We used the fibronectin binding protein A gene (fnbA) for the species-specific and quantitative detection of S. aureus directly from lower respiratory tract (LRT) specimens by a Taq Man real time PCR. For this reason, a total of 269 lower respiratory tract (LRT) specimens collected from patients with hospital-acquired pneumonia were assayed. Amplification of fnbA in serial dilutions ranged from 10(9) CFU/ ml to 10(2) CFU/ml. Standard curve of triplicate every dilution had slope 3.34+/-0.1 and R2>0.99 with SD 0.1. Based on these data, the sensitivity and specificity of the newly developed real time PCR targeting the fnbA gene were both 100%. The Cohen's Kappa test showed the Kappa value of 1.0. The fnbA gene is a potential marker for the species-specific detection of S. aureus and can be used to detect this bacterium in any clinical specimens by real time PCR. Moreover, this method reduces the time needed for quantitative detection of Staphylococcus aureus from LRT specimens to nearly 2 hours compared to 1 to 4 days for culture and provided sensitivity equal to or greater than culture. PMID- 23455787 TI - Tumefactive demyelinating lesions: a clinicopathological correlative study. AB - Tumefactive demyelinating (TDL) lesions are focal zones of demyelination in the central nervous system and they often mimic the neuroimaging features of an intraxial neoplasm. In this report we describe the clinical, neuroimaging and neuropathological features of six cases of TDL. Only in two patients the neuroimaging features in MRI (magnetic resonance imaging) scans were suggestive of TDL while in the other four cases a diagnosis of glioma was suggested. In order to establish a confirmatory diagnosis neuronavigation/stereotactic biopsy was undertaken and the diagnosis of TDL was established in all six cases at histopathology. Two out of six patients did not respond to the conventional corticosteroid therapy and they were treated with plasma exchange. It is being concluded that neuronavigation biopsy, though provide only a small amount of tissue, and is extremely useful in making the diagnosis of TDL. PMID- 23455788 TI - Cri du chat syndrome: a series of five cases. AB - The cri du chat syndrome (CdCS) is a chromosomal deletion syndrome associated with a partial deletion of the short (p) arm of chromosome 5. We describe five children who were diagnosed to have CdCS by conventional cytogenetic analysis. The deletion was at 5p15 in four patients, whereas the fifth had a larger, more proximal deletion at 5p14. Fluorescence in situ hybridization (FISH) analysis confirmed the deletion of the CdCS critical region at 5p15.2. All five children had global developmental delay and dysmorphism with microcephaly. The other clinical features were variable. Since the clinical diagnosis of CdCS may not always be evident because of the phenotypic heterogeneity, cytogenetic analysis is necessary to establish the diagnosis and confirm that the deletion involves the CdCS critical region. This will enable early intervention which plays an important role in improving the outcome. PMID- 23455789 TI - Mycophenolate mofetil-induced colitis with graft versus host disease-like features in a liver transplant recipient. AB - Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug in the management of transplant recipients. Gastrointestinal (GI) toxicity (diarrhea) is the most frequently reported adverse event in MMF-treated transplant patients. MMF-induced Graft versus Host Disease has rarely been reported in literature. We report a case of MMF-induced colitis with Graft versus Host Disease-like features, to highlight the importance of high clinical suspicion for its diagnosis, and that appropriate management in such a setting can reduce morbidity and mortality. We also review the relevant literature. PMID- 23455790 TI - Ovarian hemangioma with stromal luteinization and HCG-producing mononucleate and multinucleate cells of uncertain histogenesis: a rare co-existence with therapeutic dilemma. AB - A 21 year old female presented with amenorrhea, hirsutism and change in voice along with an elevated serum beta-HCG (human chorionic gonadotrophin) level and normal CA-125 level. Laparotomy revealed an enlarged right ovary measuring 6*5*1 cms with presence of an ovarian hemangioma along with stromal luteinization and HCG producing mononucleate as well as multinucleate cells of uncertain histogenesis on histopathological examination. Immunohistochemistry for inhibin and calretinin were positive in the luteinized component whereas beta-HCG and Ki 67 were positive in the multinucleate cell component. The diagnostic rarity and therapeutic dilemma of such a rare mixed tumor within a single ovary has proven to be an exceptional case and an excellent investigative opportunity. PMID- 23455791 TI - Malignant pleural mesothelioma forming a huge mediastinal mass and causing atrial fibrillation. AB - A patient with malignant pleural mesothelioma was admitted with atrial fibrillation. Chest computed tomography showed a huge mediastinal tumor adjacent to the heart. Autopsy revealed a 12*9.5-cm mediastinal mass involving the right lung, which distorted and stretched the myocardial sleeve surrounding the right inferior pulmonary vein. This case demonstrates that advanced malignant pleural mesothelioma can cause atrial fibrillation, possibly by stimulating myocardium around a pulmonary vein. PMID- 23455792 TI - Low grade follicular lymphoma with high proliferation index; diagnostic and management issues. AB - Follicular Lymphoma (FL) is the second most common B-Non Hodgkin Lymphoma after diffuse large B cell lymphoma (DLBCL). Low grade FL is known for its indolent behavior; however, one subset of FL behave aggressively and may require intensive therapy. One of the diagnostic issues in FL is to identify this subgroup of cases. Proliferation index can have prognostic importance in this subset of cases. We discuss one case of low grade FL with a paradoxically high proliferative index. A 63 year male presented with generalized lymphadenopathy of one year duration, which was gradually increasing in size. On examination, patient had bilateral cervical, axillary and inguinal nodes. Biopsy of the left cervical lymph node was reported as FL-Grade 2, with high proliferative Index (60%). The patient was put on CHOP regimen targeted for high grade lymphomas, and had complete remission. High proliferative index in FL is a poor prognostic factor irrespective of the histologic grade. So, proliferative index should be assessed in all cases of FL as an adjunct to histologic grading. PMID- 23455793 TI - Ectomesenchymal chondromyxoid tumor of tongue. AB - Ectomesenchymal chondromyxoid tumor (ECMT) is a rare entity of the dorsal tongue first described in 1995. Herein, we report a rare case of lingual ECMT in a 41 year-old man. Patient presented with an asymptomatic, small nodule (0.5 cm in diameter) in the anterior tongue. The pathological findings showed uni-lobular proliferation of fusiform cells, arranged in net-like sheets or swirls, in a chondromyxoid background. The tumor cells were immunoreactive for S-100 and glial fibrillary acidic protein (GFAP), but negative for epithelial markers. Familiarity with this entity helps pathologists make a correct diagnosis. PMID- 23455794 TI - Pediatric gliosarcoma with fibrosarcomatous differentiation: report of a rare case. AB - Gliosarcoma is a rare variant of glioblastoma with a biphasic pattern showing glial and mesenchymal differentiation. It is seen in adults during their fifth to sixth decades of life and is extremely rare in children. We report a case of primary gliosarcoma with fibrosarcomatous differentiation in an 11-year-old boy presenting with headache and vomiting. Imaging showed a contrast-enhancing isodense space-occupying lesion with areas of calcification in the right temporoparietal cortex. A total excision was done and, on histopathologic examination, a differential diagnostic consideration of gliosarcoma and teratoma with malignant transformation was made. After immunohistochemical analysis, a final diagnosis of gliosarcoma with fibrosarcomatous differentiation was then made. Primary gliosarcoma is a very rare tumor in children with a poor prognosis. PMID- 23455795 TI - Renal cell carcinoma metastasizing to adenocarcinoma of esophagogastric junction: a rare case of tumor-to-tumor metastasis. AB - The simultaneous occurrence of two primary tumors in one patient is not uncommon, but one tumor metastasizing to another malignancy is a rare phenomenon. Tumor-to tumor metastasis was first described by Berent in 1902. Since then fewer than 200 cases have been reported in the literature. In most of these cases renal cell carcinoma acted as a recipient tumor. In tumor-to-tumor metastasis renal cell carcinoma acting as a donor is exceedingly rare and there are no reported cases of adenocarcinoma of the esophagogastric junction acting as a recipient. We present a case of renal cell carcinoma metastasizing to an adenocarcinoma of esophagogastric junction. To our knowledge, this is the first reported case of such a combination. PMID- 23455796 TI - Pigmented hepatocellular adenoma with complete CD34 immunostaining pattern: a diagnostic dilemma. AB - WHO defines hepatocellular adenoma (HCA) as a benign tumor composed of cells closely resembling normal hepatocytes, which are arranged in plates separated by sinusoids. It is more common in women. The present concerns a 41 years female who was found to have a mass lesion in liver on ultrasound while undergoing routine evaluation for dyspepsia. Computed tomography scan of abdomen showed 10*8 cm lesion in liver. Extended left hepatectomy was performed. Grossly hepatic cut surface showed circumscribed tumor with dark gray or black color. Microscopy revealed hepatocellular adenoma with abundant Dubin Johnson like pigment deposition. CD34 immunostaining showed complete sinusoidal pattern. We labeled the tumor as pigmented hepatic adenoma with complete CD34 staining pattern. To the best of author's knowledge only eight cases of pigmented hepatocellular adenoma are described in world literature. PMID- 23455797 TI - Postchemotherapy-related changes in mediastinal mixed germ cell tumor masquerading as a vascular neoplasm. AB - Florid vascular proliferation in teratoma is rare morphological presentation. We present a case of mediastinal germ cell tumor masquerading as a vascular neoplasm in a 14-year-old male who presented with right hemithoracic mass. The initial histopathology of resected mass was suggestive of vascular neoplasm. Fine needle aspiration cytology (FNAC) of right axillary mass with immunohistochemistry on cell block was consistent with metastatic mixed germ cell tumor. Repeat extensive sectioning of the resected mediastinal mass showed focal viable tumor with mainly teratomatous component. Further enquiry into the history revealed patient having received prior chemotherapy; this he received in another hospital before being admitted to our hospital for surgical resection of the mass. The florid vascular proliferation may represent postchemotherapy change or a rare component of germ cell tumor possibly resistant to preoperative chemotherapy. PMID- 23455798 TI - Primary intraspinal ganglioneuroblastoma of the thoracic spine: a rare case report. AB - Cerebral ganglioneuroblastoma is an embryonal tumor of the central nervous system, which has been rarely encountered into the spinal cord. The standard treatment for ganglioneuroblastoma is complete surgical excision. A 15-year old boy was presented with cord compression. Magnetic resonance imaging revealed an intradural and intramedullar enhancing lesion over T2 spine. A histomorphological diagnosis was made in the presence of immature small round cells admixed with a good number of ganglion cells. The morphological diagnosis was verified by immunohistochemistry. This is the first reported case of compressive myelopathy in the thoracic region of the spine. PMID- 23455799 TI - A case of collision tumor or transdifferentiation between malignant melanoma and leiomyosarcoma. AB - A 73-year-old woman was referred to the hospital due to a pigmented, asymptomatic nevus on her right arm that had changed in size and color. The histopathological examination showed a superficial spreading malignant melanoma, Clark level III, 2.26 mm in thickness. Two years later, the patient presented a 10 cm rapidly growing mass in her right axilla. The mass in the axilla measured 12.5?9?cm. It revealed a lymph node metastases with a tumor growth composed of two different contiguous morphological and immunohistochemical components, respectively, melanosomes and leiomyosarcoma. The combination of a melanocytic nevus with other tumor of epidermal or adnexal origin has been described before, but still the co existence of two different neoplasms within a lesion is still uncommon. The most common combination is basal cell carcinoma and melanocytic nevus or one of them together with a seborrheic keratosis. There have also been occasional reports of rhabdomyosarcomatous differentiation. However, mesenchymal differentiation, and in this case leiomysarcoma, with formation of heterologous elements in melanocytic tumor is very rare. Another plausible explanation may be that malignant melanoma cells could have transdifferentiated into a leiomyosarcomatoid phenotype with resulting metastases of either type. Malignant melanomas have shown a wide variety of cytological changes and can mimic carcinomas, lymphomas, and sarcomas. Spindle cell melanomas commonly simulate spindle cell carcinomas. It has also been documented that desmoplastic melanomas can change into fibroblastic, Schwannian, and myofibroblastic differentiation. PMID- 23455800 TI - Congenital pulmonary airway malformation with mucoepidermoid carcinoma: a case report and review of literature. AB - Congenital cystic adenomatoid malformations (CCAM) are rare developmental anomalies of the lung characterized by cysts of varying sizes and/or adenomatoid proliferation. Type I CCAM, the most frequent subtype, is associated with an increased incidence of malignant transformation, principally bronchioloalveolar carcinoma, with a reported incidence of around 1%. We report the first case of mucoepidermoid carcinoma arising in a type 1 CCAM. PMID- 23455801 TI - An unusual case of invasive papillary carcinoma of the breast. AB - Invasive papillary carcinoma is a rare variant of breast cancer. We report an unusual case of invasive papillary carcinoma of the breast with high nuclear grade, brisk mitosis, necrosis, extensive apocrine differentiation, and intense lymphoplasmacytic infiltrate; additionally triple-negativity for estrogen and progesterone receptors and Her2 neu. The patient underwent modified radical mastectomy and adjuvant chemotherapy. But, it was a node negative breast carcinoma. Increasing the awareness of this clinicopathologic entity would be helpful in avoiding overtreatment of patients with this cancer even if the tumor has negative morphological and immunohistochemical prognosticators. PMID- 23455802 TI - A unique case of well differentiated papillary mesothelioma involving an inguinal hernia. AB - Well Differentiated Papillary Mesothelioma (WDPM) is an uncommon tumor occurring predominantly in the peritoneum of young women with no history of asbestos exposure. In this report, we present a case of 48 year old male patient presenting with indirect inguinal hernia and incidental finding of a WDPM in the hernial sac during surgery. The unusual site of presentation and the relative rarity of this neoplasm in males evoke much clinico-pathological interest. PMID- 23455803 TI - Primary intravascular large B-cell lymphoma of pituitary. AB - A 68-year-old retired nurse, who was a known hypertensive on medication, presented with prolonged fever of 2-month duration without any clinical evidence of infection. On examination she had altered mental status. She also had other nonspecific complaints such as sleep disturbances, loss of weight, etc. On investigation, she was found to have anemia, thrombocytopenia, raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and lactate dehydrogenase (LDH) values. She also had electrolyte imbalance. Radiological evaluation of brain showed mass lesion in the sella turcica, suggestive of pituitary adenoma. Biochemical evaluation showed hypopituitarism. Trans-sphenoidal biopsy was done. Based on histopathological and immunohistochemical findings a diagnosis of intravascular large B-cell lymphoma (IVLBCL) of pituitary was made. Our patient's condition deteriorated rapidly and she succumbed to her illness before therapy could be initiated. We are reporting this case because of the rare subtype of large B-cell lymphoma presenting at an extremely unusual primary site. PMID- 23455804 TI - Histological identification of muscular sarcocystis: a report of two cases. AB - Sarcocystis is an apicomplexan protozoan belonging to same phylum as toxoplasma. The parasite encysts inside striated muscles of its intermediate host. Humans are accidental host infected by eating food or water contaminated with oocysts or sporocysts of an infected definitive host. The infection is increasing in Southeast Asia and may be overlooked in histological sections if one is not aware of the histomorphological features. The size and shape of the bradyzoites and the appearance of the cyst wall are the reliable features to distinguish this parasite from other parasites of the same phylum. The incidence of human infection is rising in Southeast Asia and histopathology is an important method for the diagnosis of muscular infection. It is important to recognize the histomorphology of this parasite and its differentiation from similar parasites. PMID- 23455805 TI - Fibro-osteochondroma of the uterus. AB - A case of a uterine fibro-osteochondroma in a 61-year-old woman with postmenopausal bleeding was presented. Ultrasound revealed a calcified lesion in the posterior wall of the uterus and a hysterectomy was performed. Histopathologic examination showed a well-circumscribed triphasic tumor composed of peripheral lobules of mature hyaline cartilage and foci of trabecular bone with a core of loosely arranged fibroblast-like, spindle cells. This is the second reported case of fibro-osteochondroma, which has been described only in the uterus. Diagnosis requires thorough histopathologic examination to exclude metaplasia within a leiomyoma or uterine sarcoma. It is histologically benign and complete excision should be curative. PMID- 23455806 TI - Testicular capillary hemangioma--a case report of a rare tumor. AB - Testicular hemangioma is a very rare benign vascular neoplasm, mostly occurring in children and young adults. We present a case of capillary hemangioma of the testis in a twenty three years old male who presented with painless mass in the right scrotum of 2 months duration. He was diagnosed with a right testicular tumor based on the physical examination, ultrasonography and magnetic resonance imaging studies. Serum tumor markers were normal. Right radical orchiectomy was performed. On histology, the tumor was diagnosed as capillary hemangioma of the testis. Immunohistochemical staining for CD31 and factor VIII confirmed the vascular nature of the tumor. To our knowledge, there are only twenty two cases of testicular hemangiomas reported in the literature. Although it is a rare tumor, surgeons and pathologists should be aware of it especially with the negative tumor marker findings. Intra-operative frozen section examination may be requested as tumor enucleation with testicular sparing surgery is considered adequate. PMID- 23455807 TI - Cervical metastasis of esophagogastric junction cancer. AB - As cervical metastases in esophagogastric junction cancer are extremely rare, the authors herein report a case. A 63-year-old woman presented with dysphagia since 6 months. Diagnostic endoscopy showed that the tumor was located at the esophagogastric junction and histopathological diagnosis of adenocarcinoma was offered. A subtotal gastrectomy was performed. Histopathological diagnosis was moderately differentiated adenocarcinoma, invading upto the serosa with metastases to perigastric nodes. The patient received chemotherapy of cisplatin and fluorouracil for one cycle and oral capecitabine for two cycles. Two years later, the patient presented with vaginal bleeding and magnetic resonance imaging of pelvis revealed a tumor of the cervix. Histopathological impression of the tumor was metastatic cervical adenocarcinoma and immunohistochemistry showed the tumor was cytokeratin, villin, and CDX2 were positive and cytokeratin 20, CA125, and CA199 were negative. The immunohistochemical profile was the same as that of primary. PMID- 23455808 TI - Follicular hybrid cyst on the cheek: a combination of infundibular, isthmic, and pilomatrical differentiation. AB - A hybrid cyst is a rare condition which includes any type of cyst arising from the various parts of the pilosebaceous unit. We report a case of hybrid cyst with infundibular, isthmic, and pilomatrical differentiation. A 12-year-old boy presented with a mass on the right cheek. The physical examination revealed an oval-shaped, dark-gray protruding mass with dimensions of 0.9 cm*0.6 cm that was non-tender to palpation. The mass was totally excised. The diagnosis of a hybrid cyst was confirmed by histological evaluation. It was a well-encapsulated mass and showed combined histologic features of infundibular, isthmus, and pilomatrical differentiation. The hybrid cyst is a follicular cyst that includes two or more components of a cystic lesion arising from the pilosebaceous unit. Occasionally, there have been reports of hybrid cysts consisting of two components in differentiation, but those showing more than two components of differentiation have been extremely rare. The pathogenesis of this unusual disease is not yet known. PMID- 23455809 TI - A 60-year-old lady with leonine facies: a rare diagnosis. AB - Systemic mastocytosis is a rare clonal disorder characterized by mast cell infiltration of one or more organs, with or without skin involvement. Leonine facies is a rare presentation and corresponds to the morphologic manifestation of diffuse dermal infiltration of the face as a result of long standing disease. Bone marrow aspiration and biopsy findings in a 60-year-old woman, who had extensive cutaneous infiltration due to systemic mastocytosis, resulting in 'leonine facies,' are described, and causes of leonine facies are discussed. PMID- 23455810 TI - Cytokeratin-positive primitive neuroectodermal tumor of the prostate: case report and review of literature. AB - Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) of the prostate is extremely rare. Here, we report a case of ES/PNET of prostate in a 24-year-old man presenting with dysuria and pelvic discomfort. Computed tomography scan revealed a heterogeneous mass involving the prostate without evidence of distant metastases. Histologically, the tumor was composed of small round blue cells strongly and diffusely positive for CD99 and epithelial markers. Fluorescence in situ hybridization confirmed rearrangement of the Ewing's sarcoma region on chromosome 22. PMID- 23455811 TI - A fatal case of bone marrow embolism of unknown cause masquerading clinically as dengue shock syndrome. AB - Bone marrow fat embolism usually occurs following multiple bone fractures, intraosseous surgical procedures, following vigorous cardiac resuscitation, ecclampsia, sickle cell anemia, malignancies, etc. We present a case of 70-year old male who presented with fever, cough with expectoration, respiratory distress, altered sensorium, hypotension and thrombocytopenia, and diagnosed to have dengue shock syndrome and expired within 1 day of admission. Postmortem lung biopsy revealed bone marrow fat embolism. PMID- 23455812 TI - CD34 positive-microgranular variant of acute promyelocytic leukemia in a child. AB - Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) in which abnormal promyelocytes predominate. APL is rare in children (approximately 10% of childhood AML) and is characterized by a higher incidence of hyperleukocytosis, an increased incidence of microgranular morphology, the presence of balanced t(15;17)(q22;q11.2-12) translocation, and more frequent occurrence of the PML-RARalpha isoforms bcr 2 and bcr 3 compared to adults. The cytomorphology of microgranular variant blasts is obviously different from AML M3 blasts; these cells have a nongranular or hypogranular cytoplasm or contain fine dust-like cytoplasmic azurophil granules that may not be apparent by light microscopy. This case report emphasizes the importance of a high index of suspicion for the diagnosis of APL, the hypogranular variant in particular. They are responsive to differentiation therapy with all trans-retinoic acid and complete remission in seen in >80% cases. PMID- 23455813 TI - Burkholderia pseudomallei infection in a healthy adult from a rural area of South India. AB - Melioidosis is an emerging disease producing protean manifestations, and is more common in alcoholics and diabetics. The disease can be a trivial localized lesion or a fatal septicemia. Early diagnosis and appropriate antimicrobial treatment greatly reduces the mortality rate. We report a case of localized form of the disease in an elderly male with no known predisposing medical disease who responded well to oral amoxycillin-clavulanic acid and cotrimoxazole treatment. PMID- 23455814 TI - Progression of hepatic aspergillosis following second renal transplantation in a patient with recurrent glomerulonephritis. AB - Invasive aspergillosis is a serious complication in renal transplant recipients. Hepatic involvement, although seen in liver transplant recipients, has not been reported following renal transplantation. We describe here an interesting occurrence of hepatic Aspergillus infection in a renal transplant recipient. The infection responded to anti-fungal therapy, but there was re-activation following a second renal transplant. In addition, the patient had recurrence of the underlying membrano-proliferative glomerulonephritis following both transplants. The relevant existing literature relating to these problems has been reviewed. PMID- 23455815 TI - Vulvar basal cell carcinoma. AB - Although the basal cell carcinoma (BCC) is the most common malignancy of skin, it is rarely seen in vulva and constitutes 2% to 4% of all vulvar cancers. The cause is unknown but, chronic vulvar irritation is the most important underlying factor. The patients over 60 years are affected more frequently than younger ones. PMID- 23455816 TI - Diffuse leiomyomatosis of the uterus diagnosed during pregnancy with successful vaginal delivery. PMID- 23455817 TI - A case of primitive neuroectodermal tumor of the kidney and review of the literature. PMID- 23455818 TI - Pulmonary aspergilloma with prominent oxalate deposition. PMID- 23455819 TI - Preoperative cytological diagnosis of ameloblastoma involving the maxilla. PMID- 23455820 TI - Psoas and thyroid abscess in a renal allograft recipient. PMID- 23455821 TI - High-risk HPV-16 DNA testing after treatment for carcinoma cervix. PMID- 23455822 TI - Calcaneal osteosarcoma. PMID- 23455823 TI - Multiple vessels in the umbilical cord: a report of four cases. PMID- 23455824 TI - Perineurial soft tissue tumors: a tale of three cases exemplifying underdiagnoses of these "uncommon" tumors. PMID- 23455825 TI - Diaphyseal giant cell-rich osteosarcoma: unusual histological variant in an unusual site. PMID- 23455826 TI - Multilocular epithelial cyst of spleen: a rare occurrence. PMID- 23455827 TI - Icteric donor plasma: to transfuse or to discard? PMID- 23455828 TI - A rare but diagnostic fungal microorganism in cervical Pap smears. PMID- 23455829 TI - Multidrug-resistant Shigella flexneri bacteremia in an immunocompetent adult. PMID- 23455830 TI - Salmonella enterica serovar Typhi in breast abscess: a case report. PMID- 23455831 TI - Granulicatella adiacens--an unusual causative agent for carbuncle. PMID- 23455832 TI - Juvenile hyaline fibromatosis or hyaline fibromatosis syndrome? PMID- 23455833 TI - Evaluation of immunochromatographic test in early serological diagnosis of dengue fever. PMID- 23455834 TI - Cytomegalovirus pneumonia in a neonate presenting as a space occupying lesion mimicking a tumor. PMID- 23455835 TI - Back to the scanner: expected and unexpected imaging findings following spinal puncture and access. AB - Spinal canal procedures to withdraw fluid or introduce drugs are common minimally invasive techniques after which patients may experience new symptoms causing presentation to the emergency department. CT or MR imaging as part of the diagnostic workup may reveal expected or unexpected findings which may explain these symptoms. Small foci of gas within the spinal canal or intracranial compartment are common but are usually self-limited. Postlumbar puncture headache, presumed to be due to intracranial hypotension, may manifest on brain MR as dural thickening and low-lying cerebellar tonsils. Treatment with a blood patch is sometimes required for persistent symptoms. Spinal subarachnoid hemorrhage may be a devastating complication of dural puncture and may result in pain and paraplegia. In this review, technical details of these procedures are described and examples of common and uncommon postprocedure appearances on imaging are presented. PMID- 23455836 TI - The pliant and ag(g)reeable erythrocyte. PMID- 23455837 TI - Hyperviscosity in plasma cell dyscrasias. AB - Plasma cell dyscrasias are characterized by a malignant clonal proliferation of plasma cells. Due to the excessive production of abnormal clonal gammaglobulins, or paraproteins, there are major hemorheologic changes in the circulation. As a result, clinical manifestations of the hyperviscosity syndrome become a major cause of morbidity and mortality. Pathogenic factors for the hyperviscosity are due both to increased plasma viscosity and to increased erythrocyte aggregation, leading to increased whole blood viscosity. These changes are dependent on the plasma concentration as well as the molecular size of the paraprotein with the threshold for onset of hyperviscosity for IgG >15 g/dl, for polymerized IgG3 >4-5 g/dl, for IgA >10-11 g/dl; for polymerized IgA >6-7 g/dl and for IgM >3 g/dl. Correspondingly, the incidence of symptomatic hyperviscosity in Waldenstrom's macroglobulinemia is 10-30%, while that in IgG myeloma is 2-6%. Clinically, the syndrome has neurologic features of headache and dizziness, visual changes, renal failure, and cardiac failure from increased plasma volume. Thrombotic complications are frequent. Paradoxically, there can be bleeding complications due to impairment of platelet function. Removal of the paraprotein by plasma exchange (plasmapheresis) can effectively reduce the hyperviscosity. Long-term control of paraprotein production can be achieved by chemotherapy. The early recognition of the symptoms of hyperviscosity, confirmed by laboratory findings of increased paraproteins and of increased blood viscosity, is essential for the proper management of this group of disorders. PMID- 23455838 TI - Obesity-related increase in whole blood viscosity includes different profiles according to fat localization. AB - In a precedent study we observed that overall adiposity evaluated with the body mass index (BMI) was correlated with plasma viscosity and red blood cells (RBC) aggregation while abdominal obesity as assessed with the waist to hip ratio (WHR) was correlated with hematocrit. We investigated this issue in 129 women (age 15 65 years, BMI: 15 to 44 kg/m(2), WHR: 0.65 to 1.13, fatness: 12-58%) who were divided into fatness groups: 17 underweight women (BMI <18.5), 75 normal weigh (BMI 18.5-24.9), 11 overweight (BMI 25-29.9), and 26 obese (BMI >30) divided according to WHR into 13 lower body and 13 upper body obese women. Whole blood viscosity significantly increases across obesity classes, and is higher in upper body than in lower body obesity (2.84 +/- 0.08 vs 3.29 +/- 0.09 mPa.s, p < 0.05). The correlations between whole blood viscosity and BMI (r = 0.383 p < 0.01) and WHR (r = 0.364 p < 0.01) are found again. The former is explained by correlations of BMI with plasma viscosity (r = 0.303 p < 0.01) and red cell rigidity (r = 0.356 p < 0.01) and the latter is only explained by a correlation between WHR and hematocrit (r = 0.524 p < 0.01). BMI is also correlated with RBC aggregation parameters. Actually, when total fatness is evaluated with the percentage of fat (%fat) given by bioimpedance analysis (BIA), the picture is slightly different, since %fat is correlated with whole blood viscosity and RBC aggregation parameters but not with hematocrit, plasma viscosity and red cell rigidity. Fat free mass is also correlated with whole blood viscosity (r = 0.227 p < 0.02) due to a correlation with hematocrit (r = 0.483 p < 0.01) but neither RBC rheology nor plasma viscosity. This study shows that fatness by its own is associated with increased red cell aggregation, that abdominal fat increases blood viscosity due to a rise in hematocrit, and that overall body size as assessed with the BMI is associated with increased plasma viscosity and red cell rigidity. PMID- 23455839 TI - Classification of endoleaks in the follow-up after EVAR using the time-to-peak of the contrast agent in CEUS examinations. AB - PURPOSE: To evaluate the feasibility of the classification of endoleaks following endovascular aortic aneurysm repair using the time-to-peak of the contrast agent in CEUS examinations. MATERIAL AND METHODS: In this retrospective study, a cohort of 171 patients with a total of 489 CEUS follow-up examinations after EVAR were included. In 254 of the 489 examinations, an endoleak was seen and the time-to peak was measured in seconds. Existence of an endoleak was confirmed by CT as the gold standard. RESULTS: We evaluated 254 CEUS video sequences showing an endoleak out of a total of 489 examinations. Kruskal-Wallis test revealed with p = 0.001 differences between the single endoleak types based on the time to peak. Correction after Bonferroni showed significant differences between type Ia compared to Ib and to IIa over inferior mesenteric artery (IMA) and IIa over lumbar artery (LA). There are also disparities between type Ib and type IIa IMA and type III, furthermore between type IIa IMA compared to IIa LA and type III as well as type IIa LA matched to type III. CONCLUSION: CEUS is an important method for the follow-up after EVAR. The time-to-peak does not seem to be a useful additional feature in classifying endoleaks, although there are differences between the time-to-peak of the single endoleak types and it is possible to make an order of the different endoleak types referring to the mean values. PMID- 23455840 TI - Anatomical remodelling of the anterior abdominal wall arteries in obesity. AB - Obesity is associated with structural alterations in subcutaneous small resistance arteries. The aim of the present work is to study modifications of perforators vessels of abdominal wall and subcutaneous tissue characteristics in obese patients after massive weight loss. An anatomo-radiologic study was carried out on 15 patients (5M, 10F, mean age 54.9 y), who underwent abdominoplasty after massive weight loss. Their pre-operative Computed Tomographic (CT) results of the anterior abdominal wall were compared with CT of 15 normal weighted controls. Anatomo-microscopic and morphometric examinations were conducted on full thickness specimens of panniculectomy samples. 10 right panniculectomy were sampled from donor cadavers. All the measurements were taken on transverse sections. In patients, at CT the mean luminal diameter (LD) and standard deviation of perforator branches of the deep inferior epigastric artery (DIEA) was 3.7 +/- 0.4 mm (control 2.2 +/- 0.1 mm; p < 0.05). At microscopic examination, the wall thickness of perforator arteries was 212.7 MU +/- 83.9 versus 143.9 +/- 32.8 (p < 0.05) deep to the superficial fascia and 120.4 MU +/- 74.8 versus 72.3 +/- 23.5 (p < 0.05) superficial to it. A thickening of the muscular layer was observable and the tunica media represented 71.4% +/- 5.6 of the whole area of the wall (controls 37.1% +/- 3.5, p < 0.0001). Our data demonstrate that the major LD of the perforators in patients matches with hypertrophy of the tunica media and we think that the major thickness of perforator walls can facilitate the microsurgical technique in free microsurgical flap reconstruction. PMID- 23455842 TI - The influence of polystyrene and poly(ether imide) inserts with different roughness, on the activation of dendritic cells. AB - Dendritic cells (DC) have a pivotal role during inflammation. DC efficiently present antigens to T cells and shape the subsequent immune response by the secretion of pro- or anti-inflammatory cytokines and by the expression of co stimulatory molecules. They respond to "danger signals" such as microbial products or fragments from necrotic cells or tissues, but were also described to be reactive towards biomaterials. However, how mechanical and physical properties of the subjacent substrate influences the DC activation is currently poorly understood. In this study micro patterned inserts prepared from polystyrene (PS) as well as from poly (ether imide) (PEI) with three different roughness levels of i) Rq = 0.29 MUm (PS) and 0.23 MUm (PEI); ii) Rq = 3.47 MUm (PS) and 3.92 MUm (PEI); and iii) Rq = 22.16 MUm (PS) and 22.65 MUm (PEI) were analyzed for their capacity to influence the activation of human monocytes derived DC. Since the DC were directly cultured in the inserts, the effects of the testing material alone could be investigated and influences from additional culture dish material could be excluded. The viability, the expression of the DC activation markers, and their cytokine/chemokine secretion were determined after the incubation with the different inserts in vitro. Both the PS and the PEI inserts did not influence the survival of the DC and their expression of co-stimulatory molecules. The expression of inflammatory cytokines was not altered by the PEI and PS inserts. However, the secretion of chemokines such as CCL2, CCL3, and CCL4 was influenced by the different roughness levels, indicating that material roughness has the capacity to modulate the DC phenotype. The data presented here will help to understand the interaction of DC with structured polymer surfaces. Biomaterial induced immuno-modulatory effects mediated by DC may promote tissue regeneration or could potentially reduce inflammation caused by the implant material. PMID- 23455843 TI - Comparison of plasma viscosity as a marker of endothelial dysfunction with nitric oxide and asymmetric dimethylarginine in subjects with dyslipidemia. AB - OBJECTIVE: In this study, we aimed to investigate the alterations in plasma viscosity and whether there was a relationship between plasma viscosity and endothelial dysfunction markers such as nitric oxide (NOx), asymmetric dimethylarginine (ADMA) and oxidized Low Density Lipoprotein (oxLDL) in dyslipidemic subjects. MATERIAL AND METHOD: 35 subjects with normolipidemia and 30 subjects with hyperlipidemia were involved in this study. Dyslipidemia was defined as total cholesterol levels >=200 mg/dL and/or triglyceride level >=150 mg/dL. Plasma total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, total protein, albumin levels and NOx were determined by enzymatic methods using commercial kits. Plasma ADMA concentrations and serum levels of total oxLDL were determined by ELISA. Plasma viscosity was measured by Harkness capillary viscometer. RESULT: Plasma viscosity, ADMA and oxLDL values were significantly higher in subjects with dyslipidemia than in subjects with normolipidemia. Plasma NOx concentration was decreased in dyslipidemic subjects compared to the normo-lipidemic subjects. We found that fibrinogen had no effect upon plasma viscosity in selected patients with dyslipidemia. CONCLUSION: Our results demonstrated that the rheological impairment of dyslipidemic patients was related with endothelial dysfunction and this was a possible cause of both micro and macrovascular complications. Therefore, as plasma viscosity is also a sensitive parameter, it can add useful information about the diagnosis and treatment of various disorders, and it should be utilized more frequently in clinical medicine. PMID- 23455845 TI - Age- and sex-dependent contact call usage in Japanese macaques. AB - The question of the flexibility of nonhuman primate vocal communication remains open today, especially due to early evidence of innately guided vocal production. However, socially determined flexibility can be found when the debate is moved from vocal structure to vocal usage. While increasing evidence shows that the audience quality influences the vocal behaviour of nonhuman primates, the impact of the caller's characteristics has been far less studied. Here, we tested the influence of an individual's sex and age on the usage style of contact calls. We recorded contact calls of male and female Japanese macaques and compared the vocal usage styles of approximately 1-year-old juveniles with those of adults at various ages. We found, first, important differences in call usage style between juveniles and adults, the latter forming temporally ruled vocal exchanges respecting an interindividual turntaking principle. Moreover, sex differences were substantial in adults but nonexistent in juveniles. Finally, age continued to influence female vocal behaviour during adulthood, whereas dominance rank explained differences between adult males. Two nonexclusive mechanisms can explain this phenomenon, that is, a socially guided development of the appropriate form of calling versus an emotional maturation to control call emission, opening new lines of research on nonhuman primate vocal development of appropriate usages. PMID- 23455846 TI - [Pelvic girdle and acetabulum]. PMID- 23455847 TI - [Hindfoot arthrodesis for post-infectious ankle destruction using an intramedullary retrograde hindfoot nail]. AB - BACKGROUND: Limb salvage after operations with deep infections of the ankle is often successful using arthrodesis of the hindfoot. The aim of this study was to evaluate the results of arthrodesis using a retrograde intramedullary nail following post-infectious ankle destruction. PATIENTS AND METHODS: Between 2007 and 2010 a total of 44 patients were treated with tibiotalocalcaneal (TTC) arthrodesis and 14 patients with tibiocalcaneal (TC) arthrodesis using a retrograde hindfoot nail after quieting of infection. Evaluation included the American Orthopaedic Foot and Ankle Society (AOFAS) and the short-form 12-item (SF-12) scores. RESULTS: Of the 58 patients 49 (35 male and 14 female) could be followed-up. The average time of follow-up was 18 months and the mean age was 58 years. In 85.7 % bony union could be achieved and 10.2 % suffered from reinfections. The mean results achieved in the different scores were AOFAS 56 and SF-12 39.1 (physical health summary scale) and 46.1 (mental health summary scale). Statistical analysis showed a significantly higher rate of bony fusion for TTC arthrodesis. Bony non-union showed a significant correlation to patients with reinfection and to diabetic patients. CONCLUSIONS: Hindfoot arthrodesis for treatment of septic arthritis after infections is possible by using an intramedullary nail. The results show a high rate of fusion with an acceptable reinfection rate and good patient acceptance. PMID- 23455848 TI - Medical malpractice and legal medicine. PMID- 23455849 TI - Phase diagram for magnon condensate in Yttrium Iron Garnet film. AB - Recently, magnons, which are quasiparticles describing the collective motion of spins, were found to undergo Bose-Einstein condensation (BEC) at room temperature in films of Yttrium Iron Garnet (YIG). Unlike other quasiparticle BEC systems, this system has a spectrum with two degenerate minima, which makes it possible for the system to have two condensates in momentum space. Recent Brillouin Light Scattering studies for a microwave-pumped YIG film of thickness d = 5 MUm and field H = 1 kOe find a low-contrast interference pattern at the characteristic wavevector Q of the magnon energy minimum. In this report, we show that this modulation pattern can be quantitatively explained as due to unequal but coherent Bose-Einstein condensation of magnons into the two energy minima. Our theory predicts a transition from a high-contrast symmetric state to a low-contrast non symmetric state on varying the d and H, and a new type of collective oscillation. PMID- 23455850 TI - Artificially engineered superlattices of pnictide superconductors. AB - Significant progress has been achieved in fabricating high-quality bulk and thin film iron-based superconductors. In particular, artificial layered pnictide superlattices offer the possibility of tailoring the superconducting properties and understanding the mechanism of the superconductivity itself. For high-field applications, large critical current densities (J(c)) and irreversibility fields (H(irr)) are indispensable along all crystal directions. On the other hand, the development of superconducting devices such as tunnel junctions requires multilayered heterostructures. Here we show that artificially engineered undoped Ba-122/Co-doped Ba-122 compositionally modulated superlattices produce ab-aligned nanoparticle arrays. These layer and self-assemble along c-axis-aligned defects, and combine to produce very large J(c) and H(irr) enhancements over a wide angular range. We also demonstrate a structurally modulated SrTiO3(STO)/Co-doped Ba-122 superlattice with sharp interfaces. Success in superlattice fabrication involving pnictides will aid the progress of heterostructured systems exhibiting new interfacial phenomena and device applications. PMID- 23455851 TI - Transferred wrinkled Al2O3 for highly stretchable and transparent graphene-carbon nanotube transistors. AB - Despite recent progress in producing transparent and bendable thin-film transistors using graphene and carbon nanotubes, the development of stretchable devices remains limited either by fragile inorganic oxides or polymer dielectrics with high leakage current. Here we report the fabrication of highly stretchable and transparent field-effect transistors combining graphene/single-walled carbon nanotube (SWCNT) electrodes and a SWCNT-network channel with a geometrically wrinkled inorganic dielectric layer. The wrinkled Al2O3 layer contained effective built-in air gaps with a small gate leakage current of 10(-13) A. The resulting devices exhibited an excellent on/off ratio of ~10(5), a high mobility of ~40 cm(2) V(-1) s(-1) and a low operating voltage of less than 1 V. Importantly, because of the wrinkled dielectric layer, the transistors retained performance under strains as high as 20% without appreciable leakage current increases or physical degradation. No significant performance loss was observed after stretching and releasing the devices for over 1,000 times. The sustainability and performance advances demonstrated here are promising for the adoption of stretchable electronics in a wide variety of future applications. PMID- 23455853 TI - Modelling the growth of ZnO thin films by PVD methods and the effects of post annealing. AB - Results are presented for modelling of the evaporation and magnetron sputter deposition of Zn(x)O(y) onto an O-terminated ZnO (0001-) wurtzite surface. Growth was simulated through a combination of molecular dynamics (MD) and an on-the-fly kinetic Monte Carlo (otf-KMC) method, which finds diffusion pathways and barriers without prior knowledge of transitions. We examine the effects of varying experimental parameters, such as substrate bias, distribution of the deposition species and annealing temperature. It was found when comparing evaporation and sputtering growth that the latter process results in a denser and more crystalline structure, due to the higher deposition energy of the arriving species. The evaporation growth also exhibits more stacking faults than the sputtered growth. Post-annealing at 770 K did not allow complete recrystallization, resulting in films which still had stacking faults where monolayers formed in the zinc blende phase, whereas annealing at 920 K enabled the complete recrystallization of some films to the wurtzite structure. At the latter temperature atoms could also sometimes be locked in the zinc blende phase after annealing. When full recrystallization did not take place, both wurtzite and zinc blende phases were seen in the same layer, resulting in a phase boundary. Investigation of the various distributions of deposition species showed that, during evaporation, the best quality film resulted from a stoichiometric distribution where only ZnO clusters were deposited. During sputtering, however, the best quality film resulted from a slightly O rich distribution. Two stoichiometric distributions, one involving mainly ZnO clusters and the other involving mainly single species, showed that the distribution of deposition species makes a huge impact on the grown film. The deposition of predominantly single species causes many more O atoms at the surface to be sputtered or reflected, resulting in an O deficiency of up to 18% in the deposited film and therefore resulting in more stacking faults and phase boundaries. The methods used allow analysis of key mechanisms that occur during the growth process and give hints as to the optimum conditions under which complete crystalline layers can form. PMID- 23455852 TI - Crossmodal influences on early somatosensory processing: interaction of vision, touch, and task-relevance. AB - Previous research suggests that somatosensory cortex is subject to modulation based on the relevancy of incoming somatosensory stimuli to behavioural goals. Recent fMRI findings provide evidence for modulation of primary somatosensory cortex when simultaneous visual and tactile stimuli were relevant to the performance of a motor task. The present study aimed to (1) determine the temporal characteristics of this modulation using event-related potentials (ERPs) and (2) investigate the role of task-relevance in mediating such a modulation. Electroencephalography was collected from healthy subjects during visual, vibrotactile or bimodal stimulation as they performed a sensory-guided motor task. Experiment 1 tested the hypothesis that simultaneous bimodal stimuli would be associated with modulation of somatosensory ERPs, and Experiment 2 tested the hypothesis that such effects would only be seen when both modalities are relevant. ERPs were time-locked to stimulus onset, and mean ERP amplitudes and latencies were extracted for the P50, P100, and N140. The bimodal condition in the first experiment was associated with larger amplitudes at both early and mid latency components. The manipulation of task-relevance under bimodal conditions produced more complex results for the mid-latency components. For the P50, this enhancement was observed only when both stimuli were relevant, whereas the P100 was smallest when the tactile stimuli were not relevant to the response. These results provide evidence that crossmodal stimuli can modulate early somatosensory event-related potentials and that these effects are mediated by stimulus relevance. PMID- 23455854 TI - A year in cardiology: 2012: the latest developments were discussed at The British Cardiovascular Society annual symposium. PMID- 23455855 TI - How much care is too much care? PMID- 23455856 TI - Finding a practical model for determining staff to patient ratios. PMID- 23455858 TI - CNE article: safety culture in Australian intensive care units: establishing a baseline for quality improvement. AB - BACKGROUND: Workplace safety culture is a crucial ingredient in patients' outcomes and is increasingly being explored as a guide for quality improvement efforts. OBJECTIVES: To establish a baseline understanding of the safety culture in Australian intensive care units. METHODS: In a nationwide study of physicians and nurses in 10 Australian intensive care units, the Safety Attitudes Questionnaire intensive care unit version was used to measure safety culture. Descriptive statistics were used to summarize the mean scores for the 6 subscales of the questionnaire, and generalized-estimation-equations models were used to test the hypotheses that safety culture differed between physicians and nurses and between nurse leaders and bedside nurses. RESULTS: A total of 672 responses (50.6% response rate) were received: 513 (76.3%) from nurses, 89 (13.2%) from physicians, and 70 (10.4%) from respondents who did not specify their professional group. Ratings were highest for teamwork climate and lowest for perceptions of hospital management and working conditions. Four subscales, job satisfaction, teamwork climate, safety climate, and working conditions, were rated significantly higher by physicians than by nurses. Two subscales, working conditions and perceptions of hospital management, were rated significantly lower by nurse leaders than by bedside nurses. CONCLUSIONS: Measuring the baseline safety culture of an intensive care unit allows leaders to implement targeted strategies to improve specific dimensions of safety culture. These strategies ultimately may improve the working conditions of staff and the care that patients receive. PMID- 23455859 TI - Establishing a culture of safety. PMID- 23455860 TI - Using a criteria-based reminder to reduce use of indwelling urinary catheters and decrease urinary tract infections. AB - BACKGROUND: Duration of indwelling urinary catheterization is an important risk factor for urinary tract infection. OBJECTIVES: To determine whether a reminder approach reduces the use of urinary catheters and the incidence of catheter associated urinary tract infections. METHODS: A randomized control trial was performed in 2 respiratory intensive care units in a 2990-bed tertiary referral medical center. Patients who had urinary catheters in place for more than 2 days from April through November 2008 were randomly assigned to either the intervention group (use of a criteria-based reminder to remove the catheter) or the control group (no reminder). RESULTS: A total of 278 patients were recruited. Utilization rate of indwelling urinary catheters was decreased by 22% in the intervention group compared with the control group (relative risk, 0.78; 95% CI, 0.76-0.80; P < .001). The intervention significantly shortened the median duration of catheterization (7 days vs 11 days for the control group; P < .001). The success rate for removing the catheters in the intervention group by day 7 was 88%. The reminder intervention reduced the incidence of catheter-associated infections by 48% (relative risk, 0.52; 95% CI, 0.32-0.86; P = .009) in the intervention group compared with the control group. CONCLUSIONS: Use of a criteria-based reminder to remove indwelling urinary catheters can diminish the use of urinary catheterization and reduce the likelihood of catheter-associated urinary infections. This reminder approach can prevent catheter-associated urinary infections, and its use should be strongly considered as a way to enhance the safety of patients. PMID- 23455861 TI - CNE article: pain after lung transplant: high-frequency chest wall oscillation vs chest physiotherapy. AB - Background Chest physiotherapy and high-frequency chest wall oscillation (HFCWO) are routinely used after lung transplant to facilitate removal of secretions. To date, no studies have been done to investigate which therapy is more comfortable and preferred by lung transplant recipients. Patients who have less pain may mobilize secretions, heal, and recover faster. Objectives To compare effects of HFCWO versus chest physiotherapy on pain and preference in lung transplant recipients. Methods In a 2-group experimental, repeated-measures design, 45 lung transplant recipients (27 single lung, 18 bilateral) were randomized to chest physiotherapy (10 AM, 2 PM) followed by HFCWO (6 PM, 10 PM; group 1, n=22) or vice versa (group 2, n=23) on postoperative day 3. A verbal numeric rating scale was used to measure pain before and after treatment. At the end of the treatment sequence, a 4-item patient survey was administered to assess treatment preference, pain, and effectiveness. Data were analyzed with chi(2) and t tests and repeated-measures analysis of variance. Results A significant interaction was found between mean difference in pain scores from before to after treatment and treatment method; pain scores decreased more when HFCWO was done at 10 AM and 6 PM (P =.04). Bilateral transplant recipients showed a significant preference for HFCWO over chest physiotherapy (11 [85%] vs 2 [15%], P=.01). However, single lung recipients showed no significant difference in preference between the 2 treatments (11 [42%] vs 14 [54%]). Conclusions HFCWO seems to provide greater decreases in pain scores than does chest physiotherapy. Bilateral lung transplant recipients preferred HFCWO to chest physiotherapy. HFCWO may be an effective, feasible alternative to chest physiotherapy. (American Journal of Critical Care. 2013;22:115-125). PMID- 23455862 TI - Enteral nutritional intake in adult korean intensive care patients. AB - BACKGROUND: Nutritional support is important for maximizing clinical outcomes in critically ill patients, but enteral nutritional intake is often inadequate. OBJECTIVE: To assess the nutritional intake of energy and protein during the first 4 days after initiation of enteral feeding and to examine the relationship between intake and interruptions of enteral feeding in Korean patients in intensive care. METHODS: A cohort of 34 critically ill adults who had a primary medical diagnosis and received bolus enteral feeding were studied prospectively. Energy and protein requirements were determined by using the Harris-Benedict equation and the American Dietetic Association equation. Energy and protein intake prescribed and received and the reasons for and lengths of feeding interruptions were recorded for 4 consecutive days immediately after enteral feeding began. RESULTS: Although the differences between requirements and intakes of energy and protein decreased significantly, patients did not receive required energy and protein intake during the 4 days of the study. Energy intake prescribed was consistently less than required on each of the 4 days. Enteral nutrition was withheld for a mean of 6 hours per patient for the 4 days. Prolonged feeding interruptions due to gastrointestinal intolerance (r= -0.874; P < .001) and procedures (r= -0.839; P = .005) were negatively associated with the percentage of prescribed energy received. CONCLUSIONS: Enteral nutritional intake was insufficient in bolus-fed Korean intensive care patients because of prolonged feeding interruptions and underprescription of enteral nutrition. Feeding interruptions due to gastrointestinal intolerance and procedures were the main contributors to inadequate energy intake. PMID- 23455864 TI - CNE article: moral distress and psychological empowerment in critical care nurses caring for adults at end of life. AB - BACKGROUND: Critical care nurses providing care for adults at the end of life may encounter moral distress when they cannot do what they believe is ethically correct. Psychological empowerment can decrease moral distress among critical care nurses. OBJECTIVES: To describe the relationships between moral distress, psychological empowerment, and demographics in critical care nurses caring for patients at the end of life. METHOD: A total of 277 critical care nurses were surveyed via the Moral Distress Scale and the Psychological Empowerment Instrument. Responses were scored on a Likert scale of 1 to 7. RESULTS: Moral distress intensity was high (mean 5.34, SD 1.32) and positively correlated with age (r = 0.179, P = .01). Moral distress frequency was moderate (mean 2.51, SD 0.87) and negatively correlated with nurses' collaboration in end-of-life patient care conferences (r = -0.191, P = .007). Psychological empowerment scores (mean 5.31, SD 1.00) were high and positively correlated with age (r = 0.139, P = .03), years of experience (r = 0.165, P = .01), collaboration in end-of-life-care conferences (r = 0.163, P = .01), and end-of-life-care education (r = 0.221, P = .001) and were negatively correlated with moral distress frequency (r = -0.194, P = .01). Multiple regression analysis revealed that empowerment was a significant predictor of moral distress frequency (a = .222, P < .01). CONCLUSION: The significant negative correlation between psychological empowerment and frequency of moral distress in these nurses indicated that nurses with higher perceived empowerment experience moral distress less often. This finding is of particular interest as interventions to decrease moral distress are sought. PMID- 23455863 TI - Outcomes of nasal bridling to secure enteral tubes in burn patients. AB - BACKGROUND: Reliable securement of nasally inserted enteral tubes is a problem in patients with facial burns that make use of traditional adhesive tape ineffective. OBJECTIVE: To implement the nasal bridle as a way to decrease inadvertent removal of nasally inserted enteral tubes and improve subsequent patient outcomes. METHODS: The nasal bridle was implemented in the burn unit of the University of Kansas Hospital, Kansas City, Kansas, as a quality improvement project. Outcomes for the calendar year 2010 were measured in patients treated before use of the bridle (prebridle control group) and in patients for whom the bridle was used. The groups were compared on measures of tube insertions per tube day, abdominal radiographs per tube day, and a number of complications. RESULTS: A total of 50 patients were studied: 33 in the control group and 17 in the bridle group. Baseline characteristics of age and sex did not differ between the groups. The bridle group had significantly fewer tube insertions and abdominal radiographs per tube day than the control group. Although complications were generally less common in the bridle group, the differences were not statistically significant. CONCLUSIONS: In burn patients, use of a nasal bridle to secure nasally inserted tubes had clinical advantages over securement with traditional adhesive tape. PMID- 23455865 TI - The new practice guidelines for pain, agitation, and delirium. PMID- 23455866 TI - Nursing handoffs: ensuring safe passage for patients. PMID- 23455867 TI - Implantable electrical devices. PMID- 23455868 TI - Dabigatran etexilate: management in acute ischemic stroke. AB - A 54-year-old man treated with dabigatran experienced new onset of a stroke with a score of 9 on the National Institutes of Health Stroke Scale. Administration of recombinant tissue plasminogen activator (rtPA) was not recommended because of the dabigatran therapy. Angiography showed occlusion of the left middle cerebral artery by an embolic thrombus. Suction thrombectomy achieved flow through the inferior division of the artery. Computed tomography of the head showed possible intracranial hemorrhage, and dabigatran reversal was attempted with prothrombin complex concentrate and recombinant factor VIIa. Coagulation studies before administration of the reversal blood products showed a partial thromboplastin time of 30.3 seconds; 1 hour after administration, the partial thromboplastin time was 28.5 seconds. No evidence of intracranial hemorrhage was apparent on repeated computed tomography scans of the brain. He was discharged with aspirin and warfarin and a stroke score of 8. (American Journal of Critical Care. 2013;22:169-176) The use of long-term oral anticoagulation is indicated for prevention of cardiac thromboembolism in selected patients with nonvalvular atrial fibrillation. With the emergence of new potent oral agents- including the selective direct thrombin inhibitor dabigatran-clinicians must become familiar with the management of such patients. In this case report, we present a man who had an acute ischemic stroke while taking dabigatran and discuss the medical decision making regarding management issues. PMID- 23455869 TI - Prediction of human genes and diseases targeted by xenobiotics using predictive toxicogenomic-derived models (PTDMs). AB - New technologies for systems-level determinants of human exposure to drugs, industrial chemicals, pesticides, and other environmental agents provide an invaluable opportunity to extend the understanding of human health and potential environmental hazards. We report here the development of a new computational systems toxicology framework, called predictive toxicogenomics-derived models (PTDMs). PTDMs integrate three networks of chemical-gene interactions (CGIs), chemical-disease associations (CDAs) and gene-disease associations (GDAs) to infer chemical hazard profiles, identify exposure data gaps and to incorporate genes and disease networks into chemical safety evaluations. Three comprehensive networks addressing CGI, CDA and GDA extracted from the comparative toxicogenomics database (CTD) were constructed. The areas under the receiver operating characteristics curve ranged from 0.85 to 0.97 and were yielded using our methodology using a 10-fold cross validation by a simulation carried out 100 times. As the illustrated examples show, we predicted new potential target genes and diseases for bisphenol A and aspirin. The molecular hypothesis and experimental evidence from published literature for these predictions were provided. The results demonstrated that our method has potential applications for chemical profiling in human health exposure and environmental hazard assessment. PMID- 23455870 TI - Familial clustering of HBV in families with children who are diagnosed as chronic hepatitis B or inactive carriers of HBV. AB - The aim of this study was to assess and compare the spread of HBV infection in families with children who are diagnosed as chronic hepatitis B or are inactive carriers of HBV. A total of 570 patients aged 2-16 years and 2358 family members were included in the study. Patients were classified as inactive carriers (Group 1, 350 patients) or patients diagnosed as chronic active hepatitis B (Group 2, 220 patients). Demographic features of the families, HBV serological markers and routes of transmission were evaluated. Parental transmission was lower compared to nonparental transmission (34.8% and 65.1%, respectively). HBsAg positivity rate was found to be highest among mothers in both of the groups. HBeAg positivity and anti-HBs positivity were significantly higher in family members of Group 2. Transmission rates were significantly higher in families consisting of five or more members compared to families consisting of less than five members. HBsAg positivity of siblings was lowest when both parents were HbsAg negative and highest when both parents were HBsAg positive in both groups. A high risk of HBV transmission among mothers of HBsAg carriers and patients with chronic hepatitis B was demonstrated. PMID- 23455871 TI - Nurses' knowledge of and attitudes towards fever and fever management in one Irish children's hospital. AB - This study aims to describe nurses' knowledge of and attitudes towards the management of fever in one children's hospital in Ireland. A descriptive, quantitative research design was employed. One hundred and nineteen nurses working in one children's hospital completed a self-report questionnaire. Nurses' mean knowledge score about the physiology of fever, fever management and antipyretics was 51 per cent (n = 119), which was lower than expected. Nurses had both appropriate and inappropriate attitudes towards fever and fever management. Inconsistent attitudes between nurses were identified. Nurses who participated in this study are not expert managers of fever. Their lack of knowledge and inconsistent attitudes are affecting the care of febrile children, and may be fuelling parents' fever phobia. Further education is required to improve nurses' knowledge of fever and fever management. Inappropriate attitudes need to be challenged and addressed in an effort to promote evidence-based care for febrile children. PMID- 23455872 TI - Contextual and cultural risks and their association with family asthma management in urban children. AB - This study examines the association between caregivers' perceptions of home and neighborhood safety on family asthma management in the context of cultural risk factors (e.g., discrimination and acculturative stress) in a sample of urban and ethnic minority families. Participants included 147 children (ages 6-13) and their primary caregiver from Latino, African American and Non-Latino White (NLW) backgrounds. When controlling for poverty, caregivers' perceptions of home and neighborhood safety predicted family asthma management for the overall sample and for the NLW families. Additionally, for caregivers who endorsed higher levels of perceived discrimination, home and neighborhood safety predicted family asthma management. This study demonstrates the utility of considering caregivers' perceptions of home and neighborhood safety when examining urban families' day-to day engagement with asthma management tasks. PMID- 23455873 TI - Children's social/emotional characteristics at entry to school: implications for school nurses. AB - Children entering school need to build healthy peer relationships; school, however, is the central place for bullying. School nurses have a growing focus on providing care for students with social, emotional and behavioural problems. We examined the relational development of children at school entry in regard to aggression and empathy, showing that teacher-reported aggression decreased between Pre-primary and Year One, while empathy increased between Year One and Year Two classes. No gender difference was found in teacher-reported total, or covert aggression. Understanding how development of empathy can be supported in children at school entry is important, thereby supporting development of pro social behaviour and decreasing bullying. School nurses must understand the importance of surrounding children with safety in relationships as they begin school. PMID- 23455874 TI - Parental concerns' prevalence and socio-demographic variables in general parenting. AB - The aim of this study was to evaluate parental concerns in general parenting. The participants were 3842 parents of children between 3 and 10 years old, attending public preschools and primary schools, from a stratified random sample of Portuguese parents. Parents completed a parental concerns' scale that comprises five subscales: family and school problems; eating, sleep and physical complaints; preparation; fears; and negative behaviours. The results reported that 93.4 per cent of parents expressed some concern about the issues presented in the scale. Comparative analysis reported significant differences between mothers and fathers; child's gender; child's schooling level; mothers' and fathers' level of education, age at childbirth, marital status, and employment status. These results may indicate that parental concerns are an expected aspect of parenting, and that they should be addressed in family practice. Moreover, the reported differences between groups pointed to the need to develop specific intervention strategies. PMID- 23455875 TI - Adolescents' perceptions and experiences of family meals. AB - Benefits of family meals include diet quality, social interaction and wellbeing, yet previous research indicates only one in four adolescents eats a meal with their family every day. This study identified factors relating to the frequency and importance of family meals. A focus group conducted with seven adolescents was analysed thematically. The themes and findings of past research were used to develop a Family Meals Questionnaire (FMQ), completed by 76 adolescents. Regular engagement in healthy family meals eaten around the table was reported, with the majority of participants reporting that their meals included a variety of foods and portions of vegetables. Frequency of family meals was associated with increased family togetherness for both males and females. The nutritional value of meals was found to be most important to females, whereas the impact of family meals on mood was more salient for males. Findings suggest that the views and behaviour of other family members may influence adolescents' enjoyment and perceptions of the importance of family meals, and therefore impact on their frequency. These findings may inform the development of future interventions aimed at increasing adolescent engagement in family meals by adopting a family systems approach to improve the frequency and experience of family meals. PMID- 23455876 TI - Algorithm for automated selection of application-specific fiber-optic reflectance probes. AB - Several optical techniques and fiber-optic probe systems have been designed to measure the optical properties of tissue. While a wide range of options is often beneficial, it poses a problem to investigators selecting which method to use for their biomedical application of interest. We present a methodology to optimally select a probe that matches the application requirements. Our method is based both on matching a probe's mean sampling depth with the optimal diagnostic depth of the clinical application and on choosing a probe whose interrogation depth and path length is the least sensitive to alterations in the target medium's optical properties. Satisfying these requirements ensures that the selected probe consistently assesses the relevant tissue volume with minimum variability. To aid in probe selection, we have developed a publicly available graphical user interface that takes the desired sampling depth and optical properties of the medium as its inputs and automatically ranks different techniques in their ability to robustly target the desired depth. Techniques investigated include single fiber spectroscopy, differential path length spectroscopy, polarization gating, elastic light scattering spectroscopy, and diffuse reflectance. The software has been applied to biological case studies. PMID- 23455878 TI - A simplified approach to derive Cleland model for enzymatic reactions. AB - Metabolic modeling can suggest which is the key enzyme activity that needs to be controlled or its activity enhanced for the required production of a metabolite in a pathway. It also helps to find possible drug targets (enzymes to be inhibited). In metabolic modeling, knowing the kinetics of the enzymes involved in a pathway is mandatory. Most enzymatic reactions involve multi-substrates and follow an ordered sequential or ping-pong mechanism. The kinetic parameters involved in the model are obtained by fitting experimental data using a model based on the mechanism. The Cleland model has been used for some years. The grouping of parameters, such as dissociation constant and Michaelis-Menten constant, makes the strategy meaningful and hence the Cleland model is still in use. Although other alternate methods, e.g., the King-Altman method, are available, derivation by determinants can be used to derive a rate expression for the sequential or ping-pong mechanism, they are tedious. Hence, a meaningful modification is suggested in this communication for deriving the enzyme mechanism which is based on Thilakavathi et al. (Biotech Lett 28:1889-1894, 2006) to obtain the Cleland model in an easier way. PMID- 23455877 TI - Improvements in outcomes in methadone patients on probation/parole regardless of counseling early in treatment. AB - OBJECTIVE: This secondary data analysis examined the association between criminal justice (CJ) status and outcomes over 12 months of methadone maintenance treatment. METHODS: In the parent study, 230 newly admitted patients were randomly assigned to methadone either with or without counseling for 4 months followed by standard methadone with counseling. Participants completed the ASI and urine drug testing at baseline and 4- and 12-month follow-up and the Treatment Readiness (TR) scale at baseline. The relationship between baseline CJ status (whether participants were on probation or parole), CJ status by study counseling condition, and CJ status by TR with heroin and cocaine use, illegal activity, days in treatment and treatment retention, arrests, and the number of days incarcerated or hospitalized during follow-up was examined. RESULTS: Compared with participants not on probation/parole, probationers/parolees showed significant reductions in cocaine-positive tests from baseline to 12 months (P < 0.001). Probationers/parolees additionally reported significantly fewer days of illegal activity than nonprobationers/parolees at 12 months (P = 0.02). There was no relationship between CJ status and counseling condition for any outcomes. The relationship between CJ status and TR was significant only for cocaine-positive tests assessed over time (P = 0.017). CONCLUSIONS: Findings suggest that methadone participants on probation/parole showed improvements in outcomes in comparison with participants not on probation/parole, regardless of whether they received counseling during the first 4 months of treatment. PMID- 23455879 TI - The eleventh Korea-Japan-Germany joint symposium on cancer and ageing research. PMID- 23455880 TI - KRAS allel-specific activity of sunitinib in an isogenic disease model of colorectal cancer. AB - PURPOSE: To investigate the impact of different KRAS mutations on treatment with the tyrosine kinase inhibitor sunitinib in SW48 colorectal cancer cell line variants. MATERIALS AND METHODS: Isogenic SW48 KRAS wt, G12A, G12C, G12D, G12R, G12S, G12 V, and G13D cells were evaluated for ERK phosphorylation with and without EGF stimulation. In addition, the respective cell lines were tested for the effect of sunitinib on ERK/ELK phosphorylation, cell cycle, and cytotoxicity. RESULTS: Compared to KRAS wt cells, all KRAS mutant variants were associated with resistance to sunitinib treatment. In the MTT chemosensitivity assay, the grade of resistance was less pronounced in G13D and highest in G12A, G12C, and G12S mutant cells. The reduction in ERK phosphorylation due to treatment with sunitinib was highest in G12V (89 %) mutant cells and lowest in G12A (24 %) mutant cells. ELK phosphorylation was less decreased in all KRAS mutant variants compared to KRAS wt cells following sunitinib treatment. The grade of resistance appears to correlate with the individual KRAS-dependent intrinsic activation of ERK. CONCLUSION: Our isogenic cell culture model suggests that KRAS mutations in SW48 colorectal cancer cells are linked to resistance to the multityrosine kinase inhibitor sunitinib. KRAS G13D mutant SW48 cells represented the KRAS subspecies with the lowest grade of resistance. Future studies will have to clarify whether KRAS can be used to guide sunitinib treatment or-in general-a treatment with a multityrosine kinase inhibitor in mCRC. PMID- 23455882 TI - Discovery of stable icosahedral quasicrystals: progress in understanding structure and properties. AB - The geometrical concept and structural framework of quasicrystals (QCs) were established shortly after the discovery of QCs. Specifically, the static and dynamic properties of the atoms and the electronic structures of quasiperiodic lattices were theoretically developed. Experimental studies lagged behind theoretical progress due to the lack of suitable samples. This situation changed with the discovery of several highly ordered stable QCs. Studies of these new QCs have provided new insights into the structure and properties of QCs. This article chronologically reviews the discoveries of various stable icosahedral QCs and subsequent studies that determined their structures, properties, and stabilization mechanisms. PMID- 23455881 TI - Factors related to biopsy willingness in patients with advanced cancer in a phase 1 clinic for molecularly targeted therapy. AB - PURPOSE: Tumor biopsies are critical for delineating pharmacodynamic effects of drugs and for optimal patient selection during oncology clinical trials of molecular targeted therapies. The purpose of this study was to identify factors related to patients' willingness to provide study-related tumor biopsies in phase 1 clinical trials of molecularly targeted therapy. METHODS: An investigator designed survey, that assessed biopsy willingness, demographic and clinical factors, was completed anonymously by patients with advanced cancer in a phase 1 clinic for targeted therapy. Data were analyzed using multivariate logistic regression models with odds ratios (OR) and 95 % confidence intervals (CI). RESULTS: Three hundred and sixty-two patients with advanced cancer (50 % male, 56 % aged <= 60 years) participated. In univariate analyses, willingness to provide study-related biopsy was associated with male gender, white race, higher income, using the Internet for cancer-related information, and having had a biopsy previously (p < 0.05). In multivariate analyses, male gender (OR 2.41, 95 % CI 1.54, 3.78) and having had a biopsy (OR 3.71, 95 % CI 1.68, 8.15) were associated with willingness to have one biopsy; male gender (OR 1.97, 95 % CI 1.30, 3.00) and relying on the Internet as a source of information (OR 1.87, 95 % CI 1.21, 2.89) were associated with willingness to have more than one biopsy. CONCLUSIONS: The results suggest that male gender is associated with greater stated willingness to undergo biopsy. Also, the Internet is an important source of information for patients with cancer and may strongly influence their decisions about whether to consent to biopsies in early clinical trials. PMID- 23455883 TI - Cryopreservation of ectomycorrhizal fungi has minor effects on root colonization of Pinus sylvestris plantlets and their subsequent nutrient uptake capacity. AB - The use of ectomycorrhizal (ECM) fungi for afforestation, bioremediation, and timber production requires their maintenance over long periods under conditions that preserve their genetic, phenotypic, and physiological stability. Cryopreservation is nowadays considered as the most suitable method to maintain the phenotypic and genetic stability of a large number of filamentous fungi including the ECM fungi. Here, we compared the ability of eight ECM fungal isolates to colonize Pinus sylvestris roots and to transport inorganic phosphate (Pi) and NH4 (+) from the substrate to the plant after cryopreservation for 6 months at -130 degrees C or after storage at 4 degrees C. Overall, the mode of preservation had no significant effect on the colonization rates of P. sylvestris, the concentrations of ergosterol in the roots and substrate, and the uptake of Pi and NH4 (+). Comparing the isolates, differences were sometimes observed with one or the other method of preservation. Suillus bovinus exhibited a reduced ability to form mycorrhizas and to take up Pi following cryopreservation, while one Suillus luteus isolate exhibited a decreased ability to take up NH4 (+). Conversely, Hebeloma crustuliniforme, Laccaria bicolor, Paxillus involutus, and Pisolithus tinctorius exhibited a reduced ability to form mycorrhizas after storage at 4 degrees C, although this did not result in a reduced uptake of Pi and NH4 (+). Cryopreservation appeared as a reliable method to maintain important phenotypic characteristics (i.e., root colonization and nutrient acquisition) of most of the ECM fungal isolates studied. For 50 % of the ECM fungal isolates, the colonization rate was even higher with the cultures cryopreserved at -130 degrees C as compared to those stored at 4 degrees C. PMID- 23455884 TI - Comparative proteomic study between human normal motility sperm and idiopathic asthenozoospermia. AB - PURPOSE: Idiopathic asthenozoospermia is considered as one of the causes of male infertility and characterized by reduced sperm motility. For a better determination of pathogenic mechanism of asthenozoospermia, the exploration of differentially expressed proteins in normal sperm motility and idiopathic asthenozoospermia was conducted in our study. METHODS: Sperm proteins were extracted and isolated by two-dimensional electrophoresis. All significantly changed protein spots were picked up from 2D gels and identified by tandem mass spectrometry. Sixteen of the thirty-three total differentially expressed protein spots were successfully identified by matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. RESULTS: Sixteen proteins identified belonged to 15 unique protein groups. GRP78, lactoferrin, SPANXB, PGK2, flagellin, DJ-1, XPA binding protein 2, CAB2, GPX4, and GAPDH were the first to be identified as differentially expressed proteins in idiopathic asthenospermia patients. Meanwhile, the analysis of quantitative RT-PCR was carried out to compare the protein levels, and the results indicated that the expression levels of the gene and protein were not entirely consistent. CONCLUSIONS: These experimental results expand the scope of the protein database, generating targets for further investigation of the pathogenic mechanism of idiopathic asthenozoospermia. PMID- 23455885 TI - The risk factors for the presence of pelvic lymph node metastasis in penile squamous cell carcinoma patients with inguinal lymph node dissection. AB - OBJECTIVE: To evaluate factors in penile squamous cell carcinoma predictive of pelvic lymph node metastasis and survival. MATERIALS AND METHODS: Data were collected and analyzed retrospectively in 146 patients with squamous cell carcinoma of penis who underwent bilateral inguinal lymph node dissection in our center between January 1998 and April 2011. Variables recorded included serum squamous cell carcinoma antigen, primary tumor p53 immunoreactivity, histological grade, pathological tumor stage, lymphatic or vascular invasion, absent/unilateral or bilateral inguinal lymph node involvement, number of metastatic inguinal lymph nodes, presence of extracapsular growth and lymph node density. RESULTS: Seventy patients had inguinal lymph node metastasis (LNM). Of these, 33 (47.1%) had pelvic LNM. Primary tumor strong p53 expression, lymphatic or vascular invasion, involvement of more than two inguinal lymph nodes and 30% or greater lymph node density were significant predictors of pelvic LNM. Primary tumor strong p53 expression (odds ratio [OR] 5.997, 95% confidence intervals [CI] 1.615-22.275), presence of extracapsular growth (OR 2.209, 95% CI 1.166-4.184), involvement of more than two inguinal lymph nodes (OR 2.494, 95% CI 1.086-5.728) and pelvic lymph node involvement (OR 18.206, 95% CI 6.807-48.696) were independent prognostic factors for overall survival. CONCLUSIONS: Primary tumor expression of p53, lymphatic or vascular invasion, number of metastatic inguinal lymph nodes and lymph node density were all predictors of pathologic pelvic lymph node involvement. Patients with pelvic LNM had an adverse prognosis, with a 3 year overall survival rate of approximately 12.1%. Pelvic lymph node dissection should be considered in these cases. PMID- 23455889 TI - Tear nitric oxide levels in Behcet's disease. AB - The aim of this study was to evaluate the tear nitric oxide (NO) level in patients with Behcet's disease and to compare it with that in healthy subjects. MATERIAL AND METHODS. The subjects were divided into 3 groups: the active disease, inactive disease, and control groups. NO concentrations were determined by a nitrate/nitrite colorimetric assay kit and measured spectrophotometrically at 540 nm. RESULTS. The tear nitrate/nitrite levels were 0.06 nmol/MUL (SD, 0.05) in the active disease group, 0.05 nmol/MUL (SD, 0.05) in the inactive disease group, and 0.02 nmol/MUL (SD, 0.01) in the control group. The tear nitrate/nitrite levels of both active and inactive groups were higher than those of the control group (P=0.001 and P=0.047, respectively), but there was no significant difference between the active and inactive groups. CONCLUSION. Our results demonstrated that the tear NO levels were elevated in the patients with Behcet's disease. We imply that a better understanding of NO function in the pathogenesis of Behcet uveitis is necessary to develop new therapies based on the inhibitors of NO synthases. PMID- 23455886 TI - Impact of the length of time between diagnosis and surgical removal of urologic neoplasms on survival. AB - OBJECTIVE: Our aim was to assess the effect of surgical wait time on the survival of patients with urological neoplasms, including prostate, bladder, penile, and testicular cancers and upper tract tumours (UTUC). MATERIALS AND METHODS: Current, relevant studies were identified from the literature. Keywords used for article retrieval were as follows: delay; surgery; prostate cancer; urothelial carcinoma; renal cell carcinoma; testicular cancer; bladder; renal pelvis; ureter; and survival. RESULTS: Regarding the length of surgical wait time, it does not matter in cases of incidental T1a renal cell carcinomas. In other cases of renal cell carcinomas, surgery should be considered within <1 month; it is of crucial importance in bladder cancer and should be <1 month for a TURBT in cases of non-muscle-invasive bladder cancer and <1 month for a radical cystectomy in cases of muscle-invasive bladder cancer; it is important in invasive UTUC and should be <1 month for a radical nephroureterectomy; it is not crucial in cases of low-risk prostate cancer. In any other case, radical prostatectomy should be considered within <2 months; it is important in testicular cancer and should be fewer than 10 days for an orchiectomy. CONCLUSION: Prolonged surgical wait times have an impact on the overall quality of life and anxiety of the patient. Extending the wait time beyond a given threshold can also have a negative impact on the patient's clinical outcomes, but this threshold differs between urological neoplasms. PMID- 23455891 TI - Assessment of the effect of anthropometric data on the alterations of cardiovascular parameters in Lithuanian elite male basketball players during physical load. AB - OBJECTIVES. The aim of the study was to assess the effect of the anthropometric data of basketball players on the alterations of cardiovascular parameters during the physical load applying the model of integrated evaluation. MATERIAL AND METHODS. The research sample consisted of 113 healthy Caucasian male basketball players, candidates of the Lithuanian National men's basketball teams. Basketball players were divided into 2 groups: 69 taller and heavier male basketball players (with a higher percentage of body fat) (TMB) and 44 shorter and less heavy male basketball players (with a lower percentage of body fat) (SMB). The amount of fat, expressed in percentage, was measured using the body composition analyzer TBF-300. "Kaunas-Load," a computerized ECG analysis system, was used to evaluate the functional condition of the cardiovascular system during the load. RESULTS. The TMB group had a lower heart rate during the warming-up phase and the steady state of the load as compared with the SMB group (P<0.05). The JT interval in the TMB group was greater during the warming-up and the steady state as compared with the SMB group (P<0.05). The JT/RR ratio index in the TMB group was found to be lower in the warming-up phase and in the steady state compared with the respective parameter in the SMB group (P<0.05). CONCLUSIONS. The cardiovascular system of taller and heavier male basketball players with a greater relative amount of body fat functioned more economically. PMID- 23455890 TI - Tuberculosis complications after BCG treatment for urinary bladder cancer. AB - Bacillus Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that has been effectively used in the treatment of non-muscle invasive bladder carcinoma. The complications of this treatment are uncommon, and the causes of dissemination are still discussed. We report a case of disseminated tuberculosis in a 66-year-old smoking man without a history of pulmonary diseases, who underwent immunotherapy with BCG after the initial surgical treatment of bladder cancer. After the last BCG instillation, he developed a fever. The diagnosis of sepsis was not confirmed, and miliary pulmonary tuberculosis was suspected. The diagnosis was confirmed by clinical manifestation, computed tomography of the lungs, and histological examination. PMID- 23455892 TI - Potential candidate genes for alveolar hypoxia identified by transcriptome network analysis. AB - BACKGROUND. Alveolar hypoxia is an important condition related to many disorders such as chronic pulmonary hypertension, pulmonary vasoconstriction, and pulmonary vascular remodeling. The aim of present study was to disclose the biological response and the potential transcriptome networks regulating the hypoxia response in the lungs. MATERIALS AND METHODS. In this study, the microarray dataset GSE11341 was used to construct a regulatory network and identify the potential genes related to alveolar hypoxia. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term enrichment analyses were also performed. RESULTS. Hypoxia inducible factor 1 alpha (HIF-1alpha), peroxisome proliferator-activated receptor gamma (PPARgamma), and nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kB) were to be the hub nodes in the transcriptome network. HIF-1alpha may regulate potassium voltage-gated channel, shaker-related subfamily, member (5KCNA5), solute carrier family 2 (facilitated glucose transporter), member (1SLC2A1), and heme oxygenase (decycling) 1 (HMOX1) expression through the regulation of membrane potential, glucose metabolism, and anti-inflammation pathways. HMOX-1 mediates signaling pathways that relate to NF-kB. CCND1 (cyclin D1) expression could be regulated by PPARgamma and HIF-1alpha via the cell cycle pathway. In addition, new transcriptional factors and target genes, such as phosphofructokinase (PFKL, liver), aldolase A (ALDOA, fructose-bisphosphate), and trefoil factor 3 (intestinal) (TFF3), were also identified. CONCLUSIONS. Transcriptome network analysis is a helpful method for the identification of the candidate genes in alveolar hypoxia. The KEGG pathway and GO term analysis are beneficial in the prediction of the underlying molecular mechanism of these identified genes in alveolar hypoxia. PMID- 23455893 TI - Evaluation of leadership competencies of executives in Lithuanian public health institutions. AB - BACKGROUND AND OBJECTIVE. Lithuanian and international public health experts emphasize the importance of leadership in public health. The aim of this study was to explore the self-assessed level of leadership competencies of executives in Lithuanian public health institutions. MATERIAL AND METHODS. Data were collected in a cross-sectional survey of executives of Lithuanian public health institutions in 2010. The total number of returned questionnaires was 55 (response rate, 58.5%). Respondents were asked about their competencies in leadership, teamwork, communication, and conflict management. The evaluation was carried out by analyzing the answers provided in the survey, which used a 5-point rating scale. In addition, the Belbin Team-Role Self-Perception Inventory and the Thomas-Kilmann Conflict Mode Instrument were used. RESULTS. The results showed that respondents were reserved or limited in their individual capacities through this evaluation of their leadership competencies. The mean score was 3.47 (SD, 0.71). Skills in competency areas of communication, teamwork, and conflict management were scored higher (3.73 [SD, 0.67], 3.73 [SD, 0.62], and 3.53 [SD, 0.63], respectively). Most of executives preferred to choose action-oriented roles (76.2%). The most common role was "implementer" (69.1%). "Avoiding" (52.7%) was the most common conflict solving strategy. The results showed that 89.1% of executives wanted to improve teamwork; 83.6%, leadership competencies; 81.8%, communication; and 80.0%, conflict management. CONCLUSIONS. The study results suggest that the executives of Lithuanian public health institutions evaluate their leadership competencies moderately. These results indicate the value of leadership training for public health executives. PMID- 23455894 TI - Evaluation of health-related quality of life in Lithuanian brain tumor patients using the EORTC brain cancer module. AB - BACKGROUND AND OBJECTIVE. Health-related quality of life (HRQoL) is considered an important outcome measure in neuro-oncology. The aim of this study was to evaluate the psychometric properties of the brain cancer-specific Quality of Life Questionnaire (QLQ-BN20) of the European Organization for Research and Treatment of Cancer (EORTC) in Lithuanian brain tumor patients. MATERIAL AND METHODS. One hundred consecutive patients (71% of women; mean age, 58 +/- 14 years) admitted for elective brain tumor surgery were evaluated for HRQoL using the QLQ-BN20, QLQ C30 (a core EORTC questionnaire for cancer patients), and SF-36 scale; for motor dysfunction (clinical examination); for cognitive dysfunction (Mini-Mental State Examination); and for disability (Barthel Index). RESULTS. The QLQ-BN20 subscales had an adequate internal consistency (Cronbach alpha, 0.75-0.90). Motor dysfunction on neurological examination was associated with greater motor dysfunction on the QLQ-BN20; greater disability, with greater future uncertainty, motor dysfunction, communication deficits, headaches, seizures, drowsiness, itchy skin, weakness of legs, and poor bladder control on the QLQ-BN20; and cognitive dysfunction, with greater future uncertainty, visual deficits, motor dysfunction, communication deficits, headaches, drowsiness, and weakness of legs symptoms on the QLQ-BN20, suggesting an adequate clinical validity of the QLQ-BN20. A score for motor dysfunction on the QLQ-BN20 correlated with a score for motor dysfunction on the QLQ-C30 and SF-36 scales; a score for headache on the QLQ BN20, with a score for pain on the QLQ-C30 and SF-36 scales; and a score for drowsiness symptoms on the QLQ-BN20, with a score for fatigue on the QLQ-C30. CONCLUSIONS. The Lithuanian version of the EORTC-QLQ-BN20 scale has acceptable psychometric properties and can be reliably used for the assessment of HRQoL in brain tumor patients. PMID- 23455895 TI - Social determinants of smoking, alcohol and drug use among Lithuanian School-aged children: results from 5 consecutive HBSC surveys, 1994-2010. AB - The aim of this study was to analyze the changes in the prevalence of smoking, alcohol and drug use among Lithuanian school-aged children in relation to the place of residence, family affluence, and family structure. MATERIAL AND METHODS. National surveys (26 556 anonymous questionnaires analyzed) of schoolchildren aged 11, 13, and 15 years were conducted in 1994, 1998, 2002, 2006, and 2010 in the framework of the international Health Behaviour in School-aged Children (HBSC) study. RESULTS. In 1994-2010, a significant increase in smoking prevalence was observed both among boys (11.3% to 21.5%, P<0.05) and girls (3.6% to 14.8%, P<0.05). Weekly alcohol consumption increased from 9.6% to 12.9% (P<0.05) among boys and from 4.3% to 7.9% (P<0.05) among girls. The prevalence of "ever use" of any psychoactive substance (data for 15-year-old group only) increased both in boys (14.6% to 33.5%) and girls (6.7% to 18.4%). Urban girls smoked more often than their rural peers. For both genders, such a residential gradient was observed in the use of alcohol and drugs. The respondents from intact families used drugs less frequently than the adolescents from not intact families. The adolescents from affluent families smoked less often, while the prevalence of alcohol and drug use was higher (except weekly alcohol use in girls). CONCLUSIONS. The study has demonstrated a significant increase in the prevalence of smoking, drinking, and drug use among Lithuanian school-aged children during the period of transition to market economy. This study provides some insight that should be addressed in equity-oriented control policies of substance use. PMID- 23455896 TI - Pharmacovigilance and principle of nonmaleficence in sex reassignment. AB - Physicians are obliged to provide treatment that is consistent with their commitment to avoid or minimize harm (nonmaleficence) and their commitment to do good (beneficence). Therefore, if patient's desires were contradictory to the primary aim of medicine, the doctor's calling would require him/her to thoroughly analyze the cause of the disease and provide an adequate as well as ethical treatment rather than obediently follow patient's requests. Yet, chemical and surgical sex reassignment is one of the areas where some physicians surrender to the desire of their patients instead of finding out what their real condition is and trying to manage it in a way the essence of medicine would require. The objective of this article was to provide specific pharmacovigilance search details for the evaluation of the current situation and the scientific background of the treatment of gender dysphoria and to analyze its conformity with one of the two main ethical principles of medicine - nonmaleficence. Literature retrieval was accessed through Medline (1979-2011) using the terms "gender dysphoria," "replacement hormonal therapy," and "pharmacovigilance." The article concludes that hormonal and surgical interventions have not proven to be medically justified and could be harmful, not treating the cause, but resulting in irreversible disability. Thus, these interventions contradict the principle of nonmaleficence and goals of basic therapeutics and pharmacovigilance. They are not based on clinical trials and are lacking a thorough follow-up assessment. PMID- 23455897 TI - No facultative worker policing in the honey bee (Apis mellifera L.). AB - Kin selection theory predicts that in colonies of social Hymenoptera with multiply mated queens, workers should mutually inhibit ("police") worker reproduction, but that in colonies with singly mated queens, workers should favor rearing workers' sons instead of queens' sons. In line with these predictions, Mattila et al. (Curr Biol 22:2027-2031, 2012) documented increased ovary development among workers in colonies of honey bees with singly mated queens, suggesting that workers can detect and respond adaptively to queen mating frequency and raising the possibility that they facultative police. In a follow up experiment, we test and reject the hypothesis that workers in single-patriline colonies prefer worker-derived males and are able to reproduce directly; we show that their eggs are policed as strongly as those of workers in colonies with multiply mated queens. Evidently, workers do not respond facultatively to a kin structure that favors relaxed policing and increased direct reproduction. These workers may instead be responding to a poor queen or preparing for possible queen loss. PMID- 23455899 TI - Optimization of an analog intersatellite microwave photonics link with an optical preamplifier. AB - An exact analytical expression of the signal-to-noise ratio (SNR) for an intersatellite microwave photonics link with an optical preamplifier is derived considering the signal fade caused by the pointing errors of the transceiver, and an optimized model for laser output power and direct current (DC) bias phase shift of the Mach-Zehnder modulator is established. It is shown that, given the desired SNR and the root mean square (rms) random pointing jitter, an optimal DC bias phase shift exists that minimizes laser output power. The effects of the optical preamplifier parameters on the minimum laser output power and optimal DC bias phase shift are also examined. Numerical results show that the preamplifier noise figure determines the minimum laser output power needed to achieve the desired SNR but affects the optimal DC bias phase shift little. For a SNR of 20 dB, doubling the preamplifier noise figure results in a 6.36 dB increase in minimum laser output power for rms pointing jitter of 0.4 MUrad. PMID- 23455898 TI - Effects of vegetative-periodic-induced rhizosphere variation on the uptake and translocation of metals in Phragmites australis (Cav.) Trin ex. Steudel growing in the Sun Island Wetland. AB - To evaluate the vegetative periodic effect of rhizosphere on the patterns of metal bioaccumulation, the concentrations of Mg, K, Ca, Mn, Zn, Fe, Cu, Cr, Ni, Cd and Pb in the corresponding rhizosphere soil and tissues of Phragmites australis growing in the Sun Island wetland (Harbin, China) were compared. The concentrations of Zn, Fe, Cu, Cr, Ni, Cd and Pb in roots were higher than in shoots, suggesting that roots are the primary accumulation organs for these metals and there exists an exclusion strategy for metal tolerance. In contrast, the rest of the metals showed an opposite trend, suggesting that they were not restricted in roots. Harvesting would particularly be an effective method to remove Mn from the environment. The concentrations of metals in shoots were generally higher in autumn than in summer, suggesting that Ph. australis possesses an efficient root-to-shoot translocation system, which is activated at the end of the growing season and allows more metals into the senescent tissues. Furthermore, metal bioaccumulation of Ph. australis was affected by vegetative periodic variation through the changing of physicochemical and microbial conditions. The rhizospheric microbial characteristics were significantly related to the concentrations of Mg, K, Zn, Fe and Cu, suggesting that microbial influence on metal accumulation is specific and selective, not eurytopic. PMID- 23455900 TI - Cherenkov radiation versus X-shaped localized waves: comment. AB - In this communication, certain comments are made on the X-shaped field generated by a really superluminal (point) charge treated in Subsection 2.D in the paper by Zamboni-Rached et al., "Cherenkov radiation versus X-shaped localized waves," [J. Opt. Soc. Am. A27, 928 (2010)]. PMID- 23455902 TI - Interdependence between the temporal and spatial longitudinal and transverse degrees of partial coherence and a generalization of the van Cittert-Zernike theorem. AB - The interdependence between the temporal and the longitudinal and transverse spatial coherence is analyzed. The analysis concerns both the derivation of the exact analytical propagation equation of the mutual coherence in free space from a planar and spherical boundary surface and the numerical analysis of a specific model. This model assumes the mutual coherence function to be spatially incoherent at a planar surface. The temporal coherence of the mutual coherence function on the planar or spherical boundary surface is not quasi-monochromatic but much more general and given by Eq. (41). Two theorems are derived that are a generalization of the van Cittert-Zernike theorem. PMID- 23455903 TI - Fiber-optic interferometer fringe projection using integrating bucket modulation. AB - A new fiber-optic interferometer fringe projection with the integrating bucket method is presented. This method is based on the sinusoidal phase-modulating technique and makes use of Mach-Zehnder interferometer structure and Young's double pinhole interference principle to achieve interference fringe projection. Here, we consider the modulated signal with the modulation intensity of laser (companion amplitude modulation) m in the calculation directly, adjust the optimal value of z to accommodate different m, and calculate the initial phase with phase generated carrier technology at the same time. Preliminary results from the optimum phase modulation z and initial phase phi(0) are discussed. PMID- 23455904 TI - Entropy, color, and color rendering. AB - The Shannon entropy [Bell Syst. Tech J.27, 379 (1948)] of spectral distributions is applied to the problem of color rendering. With this novel approach, calculations for visual white entropy, spectral entropy, and color rendering are proposed, indices that are unreliant on the subjectivity inherent in reference spectra and color samples. The indices are tested against real lamp spectra, showing a simple and robust system for color rendering assessment. The discussion considers potential roles for white entropy in several areas of color theory and psychophysics and nonextensive entropy generalizations of the entropy indices in mathematical color spaces. PMID- 23455905 TI - Number of colors generated by smooth nonfluorescent reflectance spectra. AB - In this study, we have analyzed statistical properties of the values of the first and second-order derivatives of spectral reflectance curves. We show that values of all four tested spectral data sets have very similar statistical properties. We set outer limits that bound the clear majority of the values of the first- and second-order derivatives. These limits define smoothness of all nonfluorescent reflectance curves, and they can be used to form a new object color solid inside classical MacAdam limits, including all possible colors generated by smooth nonfluorescent reflectance spectra. We have used the CIELAB color space and filled the new object color solid with a hexagonal closest packing-point lattice to estimate that there exist about 2.5 million different colors, when viewed under the D65 standard illumination. PMID- 23455906 TI - Light scattering from a moving atom. AB - In this work, scattering of an incident electric field from a moving atom is reexamined classically in two steps: the time-dependent current density created by the field inside the atom is first calculated under the electric-dipole approximation, and is then used to calculate the field scattered from the atom. Unlike the conventional frame-hopping method, the present method does not need to treat the Doppler effect as an effect separated from the scattering process, and it derives instead of simply uses the Doppler effect. PMID- 23455907 TI - Theory of diffraction effects in spatial frequency-modulated imaging. AB - An analytic theory describing the effects of diffraction and aberrations on single-pixel imaging performed by temporally modulating illumination light is presented. This method encodes spatial information using sinusoidal temporal modulations that are chirped in frequency across the extent of an illumination line focus. With some approximations, a point spread function relationship as a function of defocus or other aberrations is found for both spatially coherent and incoherent cases. The theory is validated through experiments and simulations, including measurement of the transverse and longitudinal optical transfer function, and confirmation of insensitivity to aberrations and significant optical scattering after encoding of spatial information through temporal modulation. PMID- 23455908 TI - Two models for partially coherent imaging. AB - This paper discusses the physical difference between two image formation approaches for partially coherent imaging. In one approach, the pupil function is shifted according to illumination condition as in the transmission cross coefficient (TCC) approach, whereas in the other approach, the object spectrum is shifted. Although the two approaches result in identical images, they are built on distinct physical models. Eigenfunction analysis reveals that the TCC approach is built on an artificial optical model only for image calculation. Therefore, the two approaches are not interchangeable except for image calculation. Such an example is found in calculating the entropy in an imaging system. PMID- 23455909 TI - Multimodal adaptive optics retinal imager: design and performance. AB - Optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) are complementary imaging modalities, the combination of which can provide clinicians with a wealth of information to detect retinal diseases, monitor disease progression, or assess new therapies. Adaptive optics (AO) is a tool that enables correction of wavefront distortions from ocular aberrations. We have developed a multimodal adaptive optics system (MAOS) for high-resolution multifunctional use in a variety of research and clinical applications. The system integrates both OCT and SLO imaging channels into an AO beam path. The optics and hardware were designed with specific features for simultaneous SLO/OCT output, for high fidelity AO correction, for use in humans, primates, and small animals, and for efficient location and orientation of retinal regions of interest. The MAOS system was tested on human subjects and rodents. The design, performance characterization, and initial representative results from the human and animal studies are presented and discussed. PMID- 23455910 TI - Theoretical evaluation of scattering effect on retroreflective free-space optical communication. AB - Retroreflective free-space optical (RFSO) communication is a new concept of optical communication; it consists of an optical transceiver and a retromodulator and has advantages such as light weight, small volume, and low power consumption. The power captured by the receiver consists of two parts: retroreflective and scattering. The retroreflective characteristics are obtained using an analytical formula, the scattering characteristics using a Monte Carlo model. Results show that the scattering power plays an important role in a RFSO communication link, especially when the communication range is long or the meteorological range is short. Some rules are also obtained for the sake of system design, which include increasing the range from the transmitter and the receiver properly, increasing the area of the retromodulator, limiting the field of view of the receiver, and limiting the beam divergence of the transmitter. PMID- 23455911 TI - Spectral reflectivity recovery from the tristimulus values using a hybrid method. AB - This study proposes an effective and accurate mechanism for spectral reflectivity recovery based on a hybrid technique. Adaptive non-negative matrix transformation, three-dimensional interpolation, and two-dimensional interpolation were reconstructed to an integrative hybrid recovery method. The existing spectral reflectivity data of 1269 Munsell matte color chips were used as reference data. Under the standard condition of a D65 illuminant and a 10 degrees observer of 1964 CIE, the spectral reflectivity of the 1269 Munsell colors was reconstructed successfully using the optimized hybrid recovery method. The root mean square error and goodness of fitting were used to determine the quality of the presented method. Using the hybrid method, the strategy for fast and reliable spectral reflectivity recovery of given images were also presented and demonstrated. PMID- 23455912 TI - Analytical expressions for the log-amplitude correlation function for plane wave propagation in anisotropic non-Kolmogorov refractive turbulence. AB - An analytical expression for the log-amplitude correlation function for plane wave propagation through anisotropic non-Kolmogorov turbulent atmosphere is derived. The closed-form analytic results are based on the Rytov approximation. These results agree well with wave optics simulation based on the more general Fresnel approximation as well as with numerical evaluations, for low-to-moderate strengths of turbulence. The new expression reduces correctly to the previously published analytic expressions for the cases of plane wave propagation through both nonisotropic Kolmogorov turbulence and isotropic non-Kolmogorov turbulence cases. These results are useful for understanding the potential impact of deviations from the standard isotropic Kolmogorov spectrum. PMID- 23455913 TI - Optical transfer function of the supersonic mixing layer. AB - The optical path difference (OPD) of the supersonic mixing layer with convective Mach number 0.5 is measured using the nanoparticle-based planar laser scattering technique, and its short-exposure optical transfer function (OTF) is computed with the proper orthogonal decomposition (POD). The OPD is analyzed from the viewpoint of structure function, and remarkable power law behavior is found. The power exponent is computed and analyzed. Taking the advantage of POD in capturing the energy of a signal, we present a model for the temporal evolution of OPD, which combines the deterministic and random factors together. With this model, the short-exposure OTF of the mixing layer is computed and analyzed. The amplitude modulation is evident at low frequencies, and it is almost negligible at high frequencies. The imaginary part of OTF for the mixing layer with developed vortex structures is of considerable amplitude, and the phase modulation becomes important for image degradation. We compare this phenomenon with the early result in aero-optics and explain it with the non-Gaussian statistics of OPD. PMID- 23455914 TI - Effect of optical transformation order on design of arbitrary polygonal invisible cloak. AB - The design of an arbitrary polygonal invisible cloak is introduced in this paper by considering the different transformation orders. The transformation order is considered as a design variable to achieve the allowable constitutive parameters for a practical cloak with the optimum performance. In the proposed method, a thin layer is removed from the inner cloak boundary to avoid the inevitable singularity at this boundary. Then the transformation order is optimized to achieve the best performance in this truncated cloak. Also, the effect of transformation order in choosing the cloak shield thickness is investigated to design a truncated cloak with better performance. PMID- 23455915 TI - Elimination of speckle and target orientation requirements in millimeter-wave active imaging by modulated multimode mixing illumination. AB - Active imaging can provide significantly larger signal margins in the millimeter wave spectral region than passive imaging, especially indoors-an important application for which there is no cold sky illumination. However, coherent effects, such as speckle, negate much of this advantage by destroying image clarity and target recognition. Moreover, active imaging demonstrations often use strategically chosen target orientations to optimally reflect power from the active illuminator back to the imaging receiver. In this paper we will discuss and show experimental results for a new active imaging approach that largely eliminates coherent effects and the need for optimized target orientation. The work described uses a synthesized harmonic multiplier chain to drive a 5 W extended interaction klystron at 218.4 GHz, a mechanical mode mixer to illuminate and modulate many modes, and a heterodyne receiver coupled into a 60 cm scanning mirror. Large signal margins were obtained in this ~50 m range work, showing paths to imaging at ~1 km, imaging with considerably less powerful illuminators, and the use of focal plane arrays. PMID- 23455916 TI - Systematic design of loss-engineered slow-light waveguides. AB - This paper employs topology optimization to systematically design free-topology loss-engineered slow-light waveguides with enlarged group index bandwidth product (GBP). The propagation losses of guided modes are evaluated by the imaginary part of eigenvalues in complex band structure calculations, where the scattering losses due to manufacturing imperfections are represented by an edge-related effective dissipation. The loss engineering of slow-light waveguides is realized by minimizing the propagation losses of design modes. Numerical examples illustrate that the propagation losses of free-topology dispersion-engineered waveguides can be significantly suppressed by loss engineering. Comparisons between fixed- and free-topology loss-engineered waveguides demonstrate that the GBP can be enhanced significantly by the free-topology loss-engineered waveguides with a small increase of the propagation losses. PMID- 23455917 TI - Comparison of two single-image phase-retrieval algorithms for in-line x-ray phase contrast imaging. AB - The attenuation of x-rays in a material forms the basis of x-ray radiography and tomography. By measuring the transmission of the x-rays over a large amount of raypaths, the three-dimensional (3D) distribution of the x-ray linear attenuation coefficient can be reconstructed in a 3D volume. In x-ray microtomography (MUCT), however, the x-ray refraction yields a significant signal in the transmission image and the 3D distribution of the refractive index can be reconstructed in a 3D volume. To do so, several methods exist, on both a hardware and software level. In this paper, we compare two similar software methods, the modified Bronnikov algorithm and the simultaneous phase-and-amplitude retrieval. The first method assumes a pure phase object, whereas the latter assumes a homogeneous object. Although these assumptions seem very restrictive, both methods have proven to yield good results on experimental data. PMID- 23455918 TI - Beam shaping using genetically optimized two-dimensional photonic crystals. AB - We propose the use of two-dimensional (2D) photonic crystals (PhCs) with engineered defects for the generation of an arbitrary-profile beam from a focused input beam. The cylindrical harmonics expansion of complex-source beams is derived and used to compute the scattered wave function of a 2D PhC via the multiple scattering method. The beam shaping problem is then solved using a genetic algorithm. We illustrate our procedure by generating different orders of Hermite-Gauss profiles, while maintaining reasonable losses and tolerance to variations in the input beam and the slab refractive index. PMID- 23455919 TI - Exact ray tracing formulas based on a nontrigonometric alternative to Snell's law. AB - In this work, Fermat's principle is applied to derive a simple exact formula for refraction (reflection) in terms of the lengths of the incident and refracted rays. This formula is a nontrigonometric alternative to Snell's law and is general for all optical surfaces. It is used to derive the paraxial optics equations in a more simple and direct way than that often used in the literature. It's also applied to derive a new single, exact ray tracing formula for the nonparaxial refraction (reflection) at a single optical surface. The obtained formulas are used to develop a simple ray tracing procedure for meridional refraction through systems of spherical surfaces without the need to use any form of Snell's law. Numerical examples are provided and discussed. PMID- 23455920 TI - Interval estimate with probabilistic background constraints in deconvolution. AB - We present in this article the use of probabilistic background constraints in astronomical image deconvolution to approach a solution as an interval estimate. We elaborate our objective-the interval estimate of the unknown object from observed data and our approach-Monte Carlo experiment and analysis of marginal distributions of image values. One-dimensional observation and deconvolution using the proposed approach are simulated. Confidence intervals revealing the uncertainties due to the background constraint are calculated and significance levels for sources retrieved from restored images are provided. PMID- 23455921 TI - Computational modeling of optical projection tomographic microscopy using the finite difference time domain method. AB - We present a method for modeling image formation in optical projection tomographic microscopy (OPTM) using high numerical aperture (NA) condensers and objectives. Similar to techniques used in computed tomography, OPTM produces three-dimensional, reconstructed images of single cells from two-dimensional projections. The model is capable of simulating axial scanning of a microscope objective to produce projections, which are reconstructed using filtered backprojection. Simulation of optical scattering in transmission optical microscopy is designed to analyze all aspects of OPTM image formation, such as degree of specimen staining, refractive-index matching, and objective scanning. In this preliminary work, a set of simulations is performed to examine the effect of changing the condenser NA, objective scan range, and complex refractive index on the final reconstruction of a microshell with an outer radius of 1.5 MUm and an inner radius of 0.9 MUm. The model lays the groundwork for optimizing OPTM imaging parameters and triaging efforts to further improve the overall system design. As the model is expanded in the future, it will be used to simulate a more realistic cell, which could lead to even greater impact. PMID- 23455922 TI - Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS. AB - The characterization of all protein complexes of human cells under defined physiological conditions using affinity purification-mass spectrometry (AP-MS) is a highly desirable step in the quest to understand the phenotypic effects of genomic information. However, such a challenging goal has not yet been achieved, as it requires reproducibility of the experimental workflow and high data consistency across different studies and laboratories. We systematically investigated the reproducibility of a standardized AP-MS workflow by performing a rigorous interlaboratory comparative analysis of the interactomes of 32 human kinases. We show that it is possible to achieve high interlaboratory reproducibility of this standardized workflow despite differences in mass spectrometry configurations and subtle sample preparation-related variations and that combination of independent data sets improves the approach sensitivity, resulting in even more-detailed networks. Our analysis demonstrates the feasibility of obtaining a high-quality map of the human protein interactome with a multilaboratory project. PMID- 23455923 TI - Ultrahigh accuracy imaging modality for super-localization microscopy. AB - Super-localization microscopy encompasses techniques that depend on the accurate localization of individual molecules from generally low-light images. The obtainable localization accuracies, however, are ultimately limited by the image detector's pixelation and noise. We present the ultrahigh accuracy imaging modality (UAIM), which allows users to obtain accuracies approaching the accuracy that is achievable only in the absence of detector pixelation and noise, and which we found can experimentally provide a >200% accuracy improvement over conventional low-light imaging. PMID- 23455924 TI - A Y2H-seq approach defines the human protein methyltransferase interactome. AB - To accelerate high-density interactome mapping, we developed a yeast two-hybrid interaction screening approach involving short-read second-generation sequencing (Y2H-seq) with improved sensitivity and a quantitative scoring readout allowing rapid interaction validation. We applied Y2H-seq to investigate enzymes involved in protein methylation, a largely unexplored post-translational modification. The reported network of 523 interactions involving 22 methyltransferases or demethylases is comprehensively annotated and validated through coimmunoprecipitation experiments and defines previously undiscovered cellular roles of nonhistone protein methylation. PMID- 23455925 TI - Theoretical study of the kinetics of chlorine atom abstraction from chloromethanes by atomic chlorine. AB - Ab initio calculations at the G3 level were used in a theoretical description of the kinetics and mechanism of the chlorine abstraction reactions from mono-, di-, tri- and tetra-chloromethane by chlorine atoms. The calculated profiles of the potential energy surface of the reaction systems show that the mechanism of the studied reactions is complex and the Cl-abstraction proceeds via the formation of intermediate complexes. The multi-step reaction mechanism consists of two elementary steps in the case of CCl4 + Cl, and three for the other reactions. Rate constants were calculated using the theoretical method based on the RRKM theory and the simplified version of the statistical adiabatic channel model. The temperature dependencies of the calculated rate constants can be expressed, in temperature range of 200-3,000 K as [Formula: see text]. The rate constants for the reverse reactions CH3/CH2Cl/CHCl2/CCl3 + Cl2 were calculated via the equilibrium constants derived theoretically. The kinetic equations [Formula: see text] allow a very good description of the reaction kinetics. The derived expressions are a substantial supplement to the kinetic data necessary to describe and model the complex gas-phase reactions of importance in combustion and atmospheric chemistry. PMID- 23455926 TI - A DFT study of tautomers of 3-amino-1-nitroso-4-nitrotriazol-5-one-2-oxide. AB - We report herein the structure and explosive properties of the possible isomers of 3-amino-1-nitroso-4-nitrotriazol-5-one-2-oxide computed from the B3LYP/aug-cc pVDZ level. The optimized structures, vibrational frequencies and thermodynamic values for triazol-5-one-N-oxides were obtained in the ground state. Several designed compounds have densities varying from 2.103 to 2.177 g/cm(3). The detonation properties were evaluated by the Kamlet-Jacob equations based on the predicted density and the calculated heat of explosion. The detonation properties of triazol-5-one-N-oxides (D 9.87 to 10.11 km s(-1) and P 48.95 to 50.61 GPa) appear to be promising compared with those of 2,4,6,8,10,12-hexanitro 2,4,6,8,10,12-hexaazaisowurtzitane (D 9.20 km s(-1), P 42.0 Gpa) and octanitrocubane (D 9.90 km s(-1), P 48.45 GPa). The substitution of secondary amino hydrogen of the triazole ring by amino group shows better impact sensitivity/or stability however the model compounds seem to be highly sensitive. PMID- 23455927 TI - Why tazobactam and sulbactam have different intermediates population with SHV-1 beta-lactamase: a molecular dynamics study. AB - The imine intermediates of tazobactam and sulbactam bound to SHV-1 beta-lactamase were investigated by molecular dynamics (MD) simulation respectively. Hydrogen bond networks around active site were found different between tazobactam and sulbactam acyl-enzymes. In tazobactam imine intermediate, it was observed that the triazolyl ring formed stable hydrogen bonds with Asn170 and Thr167. The results suggest that conformation of imine determined the population of intermediates. In imine intermediate of tazobactam, the triazolyl ring is trapped in Thr_Asn pocket, and it restricts the rotation of C5-C6 bond so that tazobactam can only generate trans enamine intermediate. Further, conformational cluster analyses are performed to substantiate the results. These findings provide an explanation for the corresponding experimental results, and will be potentially useful in the development of new inhibitors. PMID- 23455928 TI - Insights into the strength and nature of carbene...halogen bond interactions: a theoretical perspective. AB - Halogen-bonding, a noncovalent interaction between a halogen atom X in one molecule and a negative site in another, plays critical roles in fields as diverse as molecular biology, drug design and material engineering. In this work, we have examined the strength and origin of halogen bonds between carbene CH2 and XCCY molecules, where X = Cl, Br, I, and Y = H, F, COF, COOH, CF3, NO2, CN, NH2, CH3, OH. These calculations have been carried out using M06-2X, MP2 and CCSD(T) methods, through analyses of surface electrostatic potentials V S(r) and intermolecular interaction energies. Not surprisingly, the strength of the halogen bonds in the CH2...XCCY complexes depend on the polarizability of the halogen X and the electron-withdrawing power of the Y group. It is revealed that for a given carbene...X interaction, the electrostatic term is slightly larger (i.e., more negative) than the dispersion term. Comparing the data for the chlorine, bromine and iodine substituted CH2...XCCY systems, it can be seen that both the polarization and dispersion components of the interaction energy increase with increasing halogen size. One can see that increasing the size and positive nature of a halogen's sigma-hole markedly enhances the electrostatic contribution of the halogen-bonding interaction. PMID- 23455929 TI - Natural bond orbital, nuclear magnetic resonance analysis and hybrid-density functional theory study of sigma-aromaticity in Al2F6, Al2Cl6, Al2Br6 and Al2I6. AB - Natural bond orbital (NBO), nuclear magnetic resonance (NMR) analysis and hybrid density functional theory based method (B3LYP/Def2-TZVPP) were used to investigate the correlation between the nucleus-independent chemical shifts [NICS, as an aromaticity criterion], sigma Al(1)-X2(b) -> sigma*Al(3)-X4(b) electron delocalizations and the dissociation energies of Al2F6, Al2Cl6, Al2Br6 and Al2I6 to 2AlX3 (X = F, Cl, Br, I). The results obtained showed that the dissociation energies of Al2F6, Al2Cl6, Al2Br6 and Al2I6 decrease from Al2F6 to Al2I6. Like aromatic molecules, these compounds have relatively significant negative NICSiso(0) values. Clearly, based on magnetic criteria, they exhibit aromatic character and make it possible to consider them as sigma-delocalized aromatic species, such as Mobius sigma-aromatic species. The sigma-aromatic character which is demonstrated by their NICSiso(0) values decreases from Al2F6 to Al2I6. The NICSiso values are dominated by the in-plane sigma22 (i.e., sigmayy, the plane containing halogen atoms bridged) chemical shift components. The increase of the NICSiso values explains significantly the decrease of the corresponding dissociation energies of Al2F6, Al2Cl6, Al2Br6 and Al2I6. Importantly, the NBO results suggest that in these compounds the dissociation energies are controlled by the stabilization energies associated with sigma Al(1) X2(b) ->sigma*Al(3)-X4(b) electron delocalizations. The decrease of the stabilization energies associated with sigma Al(1)-X2(b) ->sigma*Al(3)-X4(b) electron delocalizations is in accordance with the variation of the calculated NICSiso values. The correlations between the dissociation energies of Al2F6, Al2Cl6, Al2Br6 and Al2I6, sigma Al(1)-X2(b) ->sigma*Al(3)-X4(b) electron delocalizations, natural atomic orbitals (NAOs) and NICSiso values have been investigated. PMID- 23455930 TI - Effects of water content on the tetrahedral intermediate of chymotrypsin - trifluoromethylketone in polar and non-polar media: observations from molecular dynamics simulation. AB - The work uses MD simulation to study effects of five water contents (3 %, 10 %, 20 %, 50 %, 100 % v/v) on the tetrahedral intermediate of chymotrypsin - trifluoromethyl ketone in polar acetonitrile and non-polar hexane media. The water content induced changes in the structure of the intermediate, solvent distribution and H-bonding are analyzed in the two organic media. Our results show that the changes in overall structure of the protein almost display a clear correlation with the water content in hexane media while to some extent U shaped/bell-shaped dependence on the water content is observed in acetonitrile media with a minimum/maximum at 10-20 % water content. In contrast, the water content change in the two organic solvents does not play an observable role in the stability of catalytic hydrogen-bond network, which still exhibits high stability in all hydration levels, different from observations on the free enzyme system [Zhu L, Yang W, Meng YY, Xiao X, Guo Y, Pu X, Li M (2012) J Phys Chem B 116(10):3292-3304]. In low hydration levels, most water molecules mainly distribute near the protein surface and an increase in the water content could not fully exclude the organic solvent from the protein surface. However, the acetonitrile solvent displays a stronger ability to strip off water molecules from the protein than the hexane. In a summary, the difference in the calculated properties between the two organic solvents is almost significant in low water content (<10 %) and become to be small with increasing water content. In addition, some structural properties at 10 ~ 20 % v/v hydration zone, to large extent, approach to those in aqueous solution. PMID- 23455931 TI - Pure adult-onset spastic paraplegia caused by a novel mutation in the KIAA0196 (SPG8) gene. AB - SPG8 is a rare autosomal dominant hereditary spastic paraplegia (AD-HSP), with only six SPG8 families described so far. Our purpose was to screen for KIAA0196 (SPG8) mutations in AD-HSP patients and to investigate their phenotype. Extensive family investigation was performed after positive KIAA0196 mutation analysis, which was part of an on-going mutation screening effort in AD-HSP patients. A novel pathogenic KIAA0196 mutation p.(Gly696Ala) was identified in two AD-HSP patients, who subsequently were shown to belong to a single large Dutch pedigree with more than 10 affected family members. The phenotype consisted of a pure HSP with ages at onset between 20 and 60 years, distally reduced vibration sense in the legs in all, and urinary urgency in seven out of 10 patients. Frequent features were exercise- or emotion-induced increase of spasticity and gait problems and chronic nonspecific lower back and joint pains. We have identified a fourth pathogenic KIAA0196 mutation in a Dutch HSP-family, the seventh family worldwide, with a less severe clinical course than described before. PMID- 23455932 TI - Association of smoking with risk of multiple sclerosis: a population-based study. AB - Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have shown an association between smoking and MS risk. Here, in a population-based Canadian cohort, we investigate the relationship between personal and maternal smoking exposure and the risk of MS. Using the longitudinal Canadian database, 3,157 MS cases and 756 spouse controls were administered questionnaires on active and passive smoking history. Mothers of cases and controls were also asked about their smoking exposure during pregnancy. The MS cases were more likely to have smoked than spouse controls (odds ratio 1.32, 95 % confidence interval 1.10-1.60, p = 0.003). This association was driven by an excess of ever-smokers in male MS cases. No association was seen with maternal active or passive smoking exposure during pregnancy. Ever-smoking is associated with increased MS risk in males. Further work is needed to understand the mechanism underlying this association. PMID- 23455933 TI - Nicotianamine synthase gene family as central components in heavy metal and phytohormone response in maize. AB - Nicotianamine (NA) is an important divalent metal chelator and the main precursor of phytosiderophores. NA is synthesized from S-adenosylmethionine in a process catalyzed by nicotianamine synthase (NAS). In this study, a set of structural and phylogenetic analyses have been applied to identify the maize NAS genes based on the maize genome sequence release. Ten maize NAS genes have been mapped; seven of them have not been reported to date. Phylogenetic analysis and expression pattern from microarray data led to their classification into two different orthologous groups. C-terminal fusion of ZmNAS3 with GFP was found in the cytoplasm of Arabidopsis leaf protoplast. Expression analysis by reverse transcription polymerase chain reaction revealed ZmNAS genes are responsive to heavy metal ions (Ni, Fe, Cu, Mn, Zn, and Cd), and all 10 ZmNAS genes were only observed in the root tissue except of ZmNAS6. The promoter of ZmNAS genes was analyzed for the presence of different cis-element response to all kinds of phytohormones and environment stresses. We found that the ZmNAS gene expression of maize seedlings was regulated by jasmonic acid, abscisic acid, and salicylic acid. Microarray data demonstrated that the ZmNAS genes show differential, organ-specific expression patterns in the maize developmental steps. The integrated comparative analysis can improve our current view of ZmNAS genes and facilitate the functional characterization of individual members. PMID- 23455934 TI - In vitro efficacy of triclabendazole and clorsulon against the larval stage of Echinococcus multilocularis. AB - Alveolar echinococcosis (AE) caused by the cestode Echinococcus multilocularis (E. multilocularis) is endemic in wide areas of the Northern hemisphere. Untreated AE progresses and leads to death in more than 90% of cases. Until the advent of benzimidazoles, no antihelminthic drugs were available to cure AE. Benzimidazoles have greatly improved the prognosis of patients with AE. However, benzimidazoles have only a parasitostatic effect on E. multilocularis. Albendazole (ABZ) must sometimes be withdrawn because of adverse events. Alternative drugs are urgently needed. The antihelminthic triclabendazole (TCZ) and clorsulon (CLS) are more effective than ABZ to cure infections by the liver flukes Fasciola spp. The efficacy of TCZ and CLS was investigated on an in vitro culture of E. multilocularis larval tissue. E. multilocularis vesicles were evaluated for their morphology before and after adding TCZ, TCZ sulfoxide (TCZSX) and CLS to the larval tissue culture. TCZ at the concentrations of 20 MUg/ml culture solution led to maximum vesicle damage within 12 days and of 25 MUg/ml within 13 days, and TCZSX at the concentrations of 20 MUg/ml within 20 days and of 25 MUg/ml within 14 days. Contrary, CLS added at 5, 10 and 15 MUg/ml to culture solution did not lead to any vesicle damage. TCZ is a promising further candidate drug for the treatment of AE. PMID- 23455935 TI - Identification and biochemical characterization of adenylate kinase 1 from Clonorchis sinensis. AB - Adenylate kinase 1 is responsible for the conversion of AMP into ADP involved in purine metabolism. In the present study, adenylate kinase 1 gene (CsADK1) was isolated from an adult cDNA library of Clonorchis sinensis, and the recombinant protein was expressed in Escherichia coli. Bioinformatics analysis implied that the putative protein contained 197 amino acids, and some residues in conservative binding sites of CsADK1 were substituted. The structure modeling analysis showed that CsADK1 was composed of a core domain, an NMP-binding domain, and a LID domain, which was just a small loop. It demonstrated that CsADK1 was a short isoform of ADKs. Moreover, CsADK1 was identified as an excretory/secretory product by western blot analysis. Real-time quantitative PCR showed that expression level of CsADK1 at the stage of excysted metacercaria was higher than those of adult worm (18.8-folds, P<0.01), metacercariae (1.5-folds, P<0.01), and eggs (5.6-folds, P<0.01). In addition, histochemistry analysis showed that CsADK1 was extensively distributed in metacercariae and in the vitellaria and eggs of adult worms. The Km and Vmax value for substrate ADP were 2.2 mM and 0.9 mM/min, respectively. The optimal temperature and pH value were 37 degrees C and from 7.5 to 8.0, respectively. The enzyme activity was highly dependent on Mg2+, and the optimal concentration of Mg2+ was 2 mM. However, the enzyme activity was slightly activated by Ca2+, and Mn2+ has no effect on activity. For monovalent ions, activity was highly activated by K+ and NH4+, but slightly by Li+. Taken together, CsADK1 was a metal ion-dependent enzyme involved in purine metabolism, which was important for development and reproduction, and might be a potential candidate for drug target for clonorchiasis. PMID- 23455937 TI - Laccase2 is required for sclerotization and pigmentation of Aedes albopictus eggshell. AB - Laccase (EC 1.10.3.2) is a member of multicopper oxidases that have been found in higher plants, fungus, bacterium, and insects. Two types of laccase genes have been detected in many species of insects: laccase1 and laccase2. It has been identified that laccase2 enzyme may play a key role in sclerotization and pigmentation of insect cuticle. But few attentions were given to the biological role of laccase2 in the synthesizing of similar structures, such as oothecae, eggshell, or silk cocoons. We cloned laccase2 gene from Aedes albopictus, one main mosquito vector of dengue virus in China. An upregulation of laccase2 gene was observed after a blood meal in female adult mosquitoes, suggesting that laccase2 gene may have an involvement in the development of ovary. RNA interference experiment was performed by using adult female mosquitoes. Female mosquitoes were injected with 20 ng of double-strain RNA into the thorax. Pigmentation of mosquito eggshell was blocked that these eggs never became dark. And the incomplete sclerotization of eggshell weakened the stability and flexibility of the eggs. These eggs without enough protection were deformed and died in water. These results demonstrate that laccase2 plays a critical role in the development of eggs of A. albopictus. Laccase2 may provide a novel target for mosquito control and management. PMID- 23455936 TI - Fight against dengue in India: progresses and challenges. AB - At the end of the last century, India has faced resurgence of many infectious diseases, of which dengue is one of the most important in terms of morbidity and mortality. The National Vector Borne Disease Control Program data show that dengue is established in India and is becoming endemic to many areas (dengue cases have increased steadily from ~450 to ~50,000 from 2000 to 2012). Despite extensive efforts being made in developing the effective dengue control measures, the number of dengue cases, their severity, and geographical boundaries are expanding alarmingly and posing dengue as one of the deadly disease. Recently, the increasing burden of dengue in the country has attracted the scientific as well as Indian Government's administrative attention; however, a lot remain to be achieved for managing the disease under threshold level. Like other vector-borne diseases, better management of the dengue needs balanced approach involving various aspects like disease prevention, cure/treatment, and the vector control, simultaneously. We have briefly discussed here the situation of dengue in India and have tried to highlight the worrying facets of dengue control and its implementation in Indian perspective. The review on various aspects of dengue control has revealed an urgent need for permanent surveillance programs, coupled with improvised disease diagnostics, effective anti-dengue treatment measures, and controlling the disease transmission by following an effective implementation of vector control programs. PMID- 23455938 TI - The specific, reversible JNK inhibitor SP600125 improves survivability and attenuates neuronal cell death in experimental cerebral malaria (ECM). AB - Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum in humans and major cause of death. SP600125 is a specific, small molecule inhibitor of JNK that prevents the phosphorylation of c-Jun and blocks the expression of proinflammatory cytokines and attenuates neuronal apoptosis in several neurodegenerative disorders. We evaluated the effect of SP600125 treatment on the survival of Plasmodium berghei ANKA (PbA)-infected C57BL/6J mice. Administration of SP600125 improved survival in PbA-infected C57BL6J mice but has no effect on parasitemia. Further, SP600125 administration resulted in attenuation of neuronal cell death along with inhibition of proinflammatory mediators TNF-alpha and COX-2 and proapoptotic mediators p-c-Jun and active caspase 3 in PbA-infected mice. The promising findings of this study make SP600125 a potential agent for supportive therapy to alleviate inflammation and neuronal cell death associated with CM. PMID- 23455939 TI - In Romania, exposure to Toxoplasma gondii occurs twice as often in swine raised for familial consumption as in hunted wild boar, but occurs rarely, if ever, among fattening pigs raised in confinement. AB - A wide range of swine husbandry practices prevail in Romania: pork for human consumption is derived from hunting wild boar, from household rearing of small numbers of backyard pigs, and from indoor, industrial production of swine raised in confinement indoors. Romania thus represents an instructive place for evaluating the influence of animal management on the exposure risk of the zoonotic parasite, Toxoplasma gondii. The fact that many Romanians eat uncooked or undercooked pork, especially when raised for household consumption, elevates the public health imperative to understand these risks. The aim of the study, therefore, was to evaluate the seroprevalence of T. gondii in pigs and wild boars from Romania. During 2008-2010, we collected 3,595 serum samples from pigs (fattening pigs, sows, backyard pigs) and 150 serum samples from wild boars. The sera were assayed by immunofluorescence antibody test (cutoff, 1:32) for antibodies against T. gondii. The overall seroprevalence of T. gondii infection was 23.1 % (829/3,595) in pigs and 16 % (24/150) in wild boars. The seroprevalence was significantly higher (p < 0.001) in backyard pigs (30.5 %; 783/2,564) than in sows (12.4 %; 46/371) or fattening pigs (none of the sera was positive). The management system (indoor pigs versus backyard pigs) represented the most important factor in the epidemiology of T. gondii infection. The proximity of backyard pigs to the definitive host of this parasite (cats), as well as their access to contaminated meat products, elevated their exposure risk well above that of pigs raised in confinement, and even above that of wild boars inhabiting sylvatic environments. PMID- 23455940 TI - Ultrastructural characterization of male and female Physaloptera rara (Spirurida: Physalopteridae): feline stomach worms. AB - Physaloptera rara (Spirurida: Physalopteridae) has been found in dogs, coyotes, raccoons, wolves, foxes, cats, and bobcats in North America. The parasites' developmental cycles involve insects, including beetles, cockroaches, and crickets, as intermediate hosts. The nematodes firmly attach to the wall of the stomach and duodenum, where they feed on the mucosa and suck blood. Frequent movement of these nematodes results in erosions and ulcers in the gastrointestinal tract. The present study reports the morphological features of adult P. rara using scanning electron microscopy. Adult worms were removed from the stomach of an infected domestic cat. Male and female worms measured 25-29 and 27-41 mm, respectively. The worms were stout and the cuticle was reflected over the lips to form a large cephalic collarette with fine transverse striations. The worms possessed two large, simple triangular lateral pseudolabia, each armed with one external tooth, three internal teeth, two submedian cephalic papillae, an amphid, and three porous-like circumscribed regions. The internal margins of the lips had a pair of cuticular folds. At the anterior end of both male and female worms, an excretory pore was located on the ventral side and a pair of lateral ciliated cervical papillae was seen. The vulva was anterior to the middle of the body of female worms. The tail ends of the female worms were stumpy, with two large phasmids near their extremities. The males' tails bore large lateral alae. Ventral ornamentation, in male worms, was composed of three different cuticular patterns; coblestone-like formations, longitudinal cuticular ridges, and rows of bead-like structures. The spicules were unequal and dissimilar; the right spicule had a thick end and the left spicule had a sharp tip. At the posterior end of the males, four pairs of stalked precloacal papillae, three pairs of postcloacal papillae, and two phasmids were present. Three and four sessile papillae were seen directly anterior and posterior to the cloaca, respectively. The middle papilla of the three sessile papillae, directly anterior to cloaca was different in shape and size. PMID- 23455941 TI - Characterization of the ribosomal RNA gene of Kudoa neothunni (Myxosporea: Multivalvulida) in tunas (Thunnus spp.) and Kudoa scomberi n. sp. in a chub mackerel (Scomber japonicus). AB - Kudoa neothunni is the first described Kudoa species having six shell valves and polar capsules, previously assigned to the genus Hexacapsula Arai and Matsumoto, 1953. Since its genetic analyses remain to be conducted, the present study characterizes the ribosomal RNA gene (rDNA) using two isolates from a yellowfin tuna (Thunnus albacares) with post-harvest myoliquefaction and a northern bluefin tuna (Thunnus thynnus) without tissue degradation. Spores of the two isolates localized in the myofiber of trunk muscles, forming pseudocysts, and showed typical morphology of K. neothunni with six equal-sized shell valves radially arranged in apical view: spores (n = 15) measuring 9.5-11.4 MUm in width, 7.3-8.6 MUm in suture width, 8.9-10.9 MUm in thickness, and 7.3-7.7 MUm in length; and polar capsules measuring 3.6-4.1 MUm by 1.8-2.3 MUm. In lateral view, the spores were pyramidal in shape without apical protrusions. Their 18S and 5.8S rDNA sequences were essentially identical, but variations in the ITS1 (62.4 % similarity across 757-bp length), ITS2 (66.9 % similarity across 599-bp length), and 28S (99.0 % similarity across 2,245-bp length) rDNA regions existed between the two isolates. On phylogenetic trees based on the 18S or 28S rDNA sequence, K. neothunni formed a clade with Kudoa spp. with more than four shell valves and polar capsules, particularly K. grammatorcyni and K. scomberomori. Semiquadrate spores of a kudoid species with four shell valves and polar capsules were detected from minute cysts (0.30-0.75 mm by 0.20-0.40 mm) embedded in the trunk muscle of a chub mackerel (Scomber japonicus) fished in the Sea of Japan. Morphologically, it resembled K. caudata described from a chub mackerel fished in the southeastern Pacific Ocean off Peru; however, it lacked filamentous projections on the shell valves of spores. Additionally, it morphologically resembled K. thunni described from a yellowfin tuna also fished in the Pacific Ocean; spores (n = 30) measuring 8.2-10.5 MUm in width, 7.0-8.8 MUm in thickness, and 6.1-6.8 MUm in length; and polar capsule measuring 2.5-3.4 MUm by 1.3-2.0 MUm. The similarities of the 18S and 28S rDNA sequences between these two species were 98.5 % and 96.3 %, respectively. Simultaneously, the dimensions of cysts in the trunk muscle formed by K. thunni are clearly larger than those of the present species from a chub mackerel: 1.3-2.0 mm by 1.1-1.4 mm (n = 14) vs. 0.30-0.75 mm by 0.20-0.40 mm (n = 7), respectively. Thus, Kudoa scomberi n. sp. is proposed for this multivalvulid species found in the chub mackerel. PMID- 23455942 TI - Haemin enhances the in vivo efficacy of artemether against juvenile and adult Schistosoma mansoni in mice. AB - Among the potential alternatives to praziquantel, interestingly, the antimalarial artemether (Art) also exhibits antischistosomal properties. Previous in vitro studies suggested that Art interacts with haemin and together produce a lethal agent against schistosomes. This study investigates the in vivo effect of Art plus haemin on juvenile and adult Schistosoma mansoni worms and on their antioxidant enzymes. Infected mice were allocated into two batches each in four groups (I-IV): (I) untreated control; (II) injected with haemin (ip, 100 mg/kg/day) on days 26, 27, and 28 post-infection (PI) for juvenile stage and on days 47, 48, and 49 PI for adult stage; (III) treated with a single oral dose of Art (300 mg/kg) either after 28 or 49 days PI, respectively; and (IV) received both haemin, as group (II) and Art as group (III). Half of mice for each batch were killed 72 h; meanwhile, the remaining half was killed 3 weeks after Art administration. Parasitological criteria of cure and worms' antioxidant enzymes were assessed. Glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD) activities were lower in juvenile worms than adult ones and in females than males. Haemin plus Art at the juvenile and adult stages produced significant inhibition in worms' GST, GPx, and SOD activities 72 h after Art treatment, compared with Art-treated group, with enhanced killing of females (96.98 and 91.47 % versus 87.04 and 72.97 %, respectively) and total worms (91 and 83.39 % versus 75 and 59.01 %, respectively) 3 weeks posttreatment. In conclusion, Art plus haemin has a higher harmful effect on juvenile and adult schistosomes and antioxidant capacity than Art alone. This gives new insights into the importance of haemin in the antischistosomal properties of artemether. PMID- 23455943 TI - Description and relationships of two novel species of Ceratomyxa Thelohan, 1892 infecting the gallbladders of Aulopiformes: Atlantic lizardfish Synodus saurus Linnaeus, 1758 and royal flagfin Aulopus filamentosus Bloch, 1792 from Cretan Sea, Greece. AB - Two members of Aulopiformes (grinners) were examined for myxosporean parasites in their gallbladders. Synodus saurus and Aulopus filamentosus from Cretan Sea, Greece were infected by Ceratomyxa parasites which are described in this paper. Both species of Ceratomyxa are new and referred for the first time as Ceratomyxa cretensis n.sp. and Ceratomyxa filamentosi n.sp. The new species are described morphologically by light and scanning electron microscopy analysis, and characterized genetically by sequencing the small subunit (SSU) rDNA. The SSU rDNA sequences obtained from the two novel Ceratomyxa species were used for the construction of a phylogenetic tree with all the available Ceratomyxa SSU rDNA sequences. PMID- 23455944 TI - Comparison of in vitro activity of metronidazole and garlic-based product (Tomex(r)) on Trichomonas vaginalis. AB - Trichomonas vaginalis is a common sexually transmitted parasite in humans. Metronidazole has been the gold standard for treatment of trichomoniasis. The prevalence of metronidazole resistance and its unpleasant adverse effects drew the attention to the investigation of other lines of treatment, as that of herbal medicine. Garlic has been proven to have antibacterial, antiprotozoal, and antihelminthic activity. The current study was carried out to evaluate the efficacy of commercially available garlic (Tomex(r)) on T. vaginalis in vitro. The effect of different concentrations of garlic (12.5, 25, 50, and 100 MUg/ml) was determined on multiplication and motility of trophozoites at different time points (after 24, 48, 72, and 96 h) in comparison to the same concentrations of metronidazole at the same different time points. The results showed that parasite multiplication inhibition was noticed in proportion of concentration of Tomex and incubation time. The minimal lethal concentration of Tomex was 100 MUg/ml after 24 h, 50 MUg/ml after 48 h, 25 MUg/ml after 72 h, and 12.5 MUg/ml after 96 h. These results were similar to that of metronidazole as its minimal lethal concentration was 50 MUg/ml after 24 and 48 h and 12.5 MUg/ml after 72 and 96 h. Garlic had completely inhibited the motility of trophozoites with concentration of 100 MUg/ml after 24 h, 50 MUg/ml after 48 h, 25 MUg/ml after 72 h, and 12.5 MUg/ml after 96 h while metronidazole had completely inhibited the motility of trophozoites with concentration of 50 MUg/ml after 24 h, 25 MUg/ml after 48 h, and 12.5 MUg/ml after 72 and 96 h. This suggests that commercially available garlic (Tomex(r)) may be a promising phytotherapeutic agent for trichomoniasis. PMID- 23455945 TI - Attentional blink and impulsiveness: evidence for higher functional impulsivity in non-blinkers compared to blinkers. AB - The attentional blink (AB) represents a fundamental limit of information processing. About 5-10 % of all subjects, however, do not show the AB. Because of the low base rate of these so-called non-blinkers, studies on mechanisms underlying non-blinkers' absent AB are extremely scant. The few existent studies found non-blinkers to be faster and more efficient in information processing compared to blinkers. A personality trait that has been linked previously to speed and efficiency of information processing as well as to the magnitude of the AB is impulsivity. Therefore, the present study investigated whether 15 non blinkers and 15 blinkers differed from each other in functional and/or dysfunctional impulsivity. To obtain a better understanding of the underlying processing mechanisms, the P300 component in the event-related potential was recorded during performance on the AB task. Our results indicated higher functional impulsivity in non-blinkers compared to blinkers but no differences between the two groups in dysfunctional impulsivity. As indicated by shorter P300 latency, non-blinkers processed information faster than blinkers after the AB period but slower during the AB period. These speed effects, however, were not associated with functional impulsivity. Thus, impulsivity and speed of information processing appear to represent two rather independent sources for non blinkers' absent AB. PMID- 23455946 TI - A cross-sectional survey of blood pressure of a coastal city's resident victims of the 2011 Tohoku tsunami. AB - BACKGROUND: Blood pressure (BP) increase as a reaction to major disasters has been well documented; however, the impact has been underdocumented for tsunamis. This study aimed to confirm whether different levels of flooding/inundation and other damage caused by the 2011 Tohoku (northeast Japan) tsunami were associated with BP among resident victims in Higashi-Matsushima, Miyagi. METHODS: Cross sectional household screening was conducted 7-19 weeks after the disaster in administrative areas totally or partially flooded by the tsunami. Systolic and diastolic BP (SBP/DBP) were measured in 4,311 residents. RESULTS: There was a degree-dependent association between SBP/DBP and flooding height above sea level among victims not on antihypertensive medication (P < 0.01 for both). Disruption of the gas supply was also significantly associated with SBP/DBP (P < 0.01 for both). Among individuals on antihypertensive medication, the discontinuation of medication was associated with SBP/DBP (P < 0.01 for both). After adjusting for confounding and multiplicity, a matched case-control analysis did not identify any significant associations between the tsunami or lifeline indicators and high BP (SBP >=160mm Hg or DBP >=100mm Hg). CONCLUSIONS: This study suggests that after a major tsunami, resident victims in areas highly inundated by flood waters and those with disrupted gas supply are more likely to have higher BP and thus might warrant getting BP screening earlier than other residents. Those with hypertension should be given assistance to resume or commence antihypertensive medication as soon as possible to reduce the risk of cardiovascular morbidity and mortality. PMID- 23455947 TI - Tumor-bowel fistula: what radiologists should know. AB - Tumor-bowel fistula is an under reported complication of abdomino-pelvic malignancies which may occur spontaneously due to tumor growth or can be associated with cancer treatment. Chemotherapy and radiotherapy are commonly responsible for tumor-bowel fistulas. Molecular targeted therapies are a new class of drugs that can cause tumor fistulization due to their antiangiogenic properties. Clinically, the fistula can be asymptomatic or can result in devastating complications. Imaging helps in the prompt detection of these fistulas and the complications associated with them. Management of tumor-bowel fistula is individualized but often involves discontinuation of the associated treatment. Radiologists should promptly alert the oncology team about the presence of tumor-bowel fistula and any risk factors for its occurrence like pneumatosis or large metastatic deposits close to bowel loops. PMID- 23455948 TI - A qualitative study exploring patients' and carers' experiences of Early Supported Discharge services after stroke. AB - OBJECTIVE: To investigate patients' and carers' experiences of Early Supported Discharge services and inform future Early Supported Discharge service development and provision. DESIGN AND SUBJECTS: Semi-structured interviews were completed with 27 stroke patients and 15 carers in the Nottinghamshire region who met evidence-based Early Supported Discharge service eligibility criteria. Participants were either receiving Early Supported Discharge or conventional services. SETTING: Community stroke services in Nottinghamshire, UK. RESULTS: A thematic analysis process was applied to identify similarities and differences across datasets. Themes specific to participants receiving Early Supported Discharge services were: the home-based form of rehabilitation; speed of response; intensity and duration of therapy; respite time for the carer; rehabilitation exercises and provision of technical equipment; disjointed transition between Early Supported Discharge and ongoing rehabilitation services. Participants receiving Early Supported Discharge or conventional community services experienced difficulties related to: limited support in dealing with carer strain; lack of education and training of carers; inadequate provision and delivery of stroke-related information; disjointed transition between Early Supported Discharge and ongoing rehabilitation services. CONCLUSIONS: Accelerated hospital discharge and home-based rehabilitation was perceived positively by service users. The study findings highlight the need for Early Supported Discharge teams to address information and support needs of patients and carers and to monitor their impact on carers in addition to patients, using robust outcome measures. PMID- 23455949 TI - Sciatica-like symptoms and the sacroiliac joint: clinical features and differential diagnosis. AB - PURPOSE: To compare the clinical features of patients with sacroiliac joint (SIJ) related sciatica-like symptoms to those with sciatica from nerve root compression and to investigate the necessity to perform radiological imaging in patients with sciatica-like symptoms derived from the SIJ. METHODS: Patients with pain radiating below the buttocks with a duration of 4 weeks to 1 year were included. After physical and radiological examinations, a diagnosis of SI joint-related pain, pain due to disk herniation, or a combination of these two causes was made. RESULTS: Patients with SIJ-related leg pain (n = 77/186) were significantly more often female, had shorter statue, a shorter duration of symptoms, and had more often pain radiating to the groin and a history of a fall on the buttocks. Muscle weakness, corkscrew phenomenon, finger-floor distance >=25 cm, lumbar scoliosis, positive Bragard or Kemp sign, and positive leg raising test were more often present when radiologic nerve root compression was present. Although these investigations may help, MRI of the spine is necessary to discriminate between the groups. CONCLUSIONS: Sciatica-like symptoms derived from the SIJ can clinically mimic a radiculopathy. We suggest to perform a thorough physical examination of the spine, SI joints, and hips with additional radiological tests to exclude other causes. PMID- 23455950 TI - Analysis of factors that affect shoulder balance after correction surgery in scoliosis: a global analysis of all the curvature types. AB - PURPOSE: To identify factors that can affect postoperative shoulder balance in AIS. METHOD: 89 adolescent idiopathic scoliosis patients with six types of curvatures who underwent surgery were included in this study. Whole spine antero posterior and lateral radiographs were obtained pre- and postoperatively. In radiograms, shape and changes in curvatures were analyzed. In addition, four shoulder parameters and coronal balance were analyzed in an effort to identify factors significantly related to postoperative shoulder balance. RESULT: In general, all the four shoulder parameters (CHD, CA, CRID, RSH) were slightly increased at final follow up (t test, P < 0.05), although there was a decrease in Lenke type II and IV curvatures. However, pre- and postoperative shoulder parameters were not significantly different between each curvature types (ANOVA, P > 0.05). Moreover, no significant differences of pre- and postoperative shoulder level between different level of proximal fusion groups (ANOVA, P > 0.05) existed. In the analysis of coronal curvature changes, no difference was observed in every individual coronal curvatures between improved shoulder balance and aggravated groups (P > 0.05). However, the middle to distal curve change ratio was significantly lower in patients with aggravated shoulder balance (P < 0.05). In addition, patients with smaller preoperative shoulder imbalance showed the higher chance of aggravation after surgery with similar postoperative changes (P < 0.05). CONCLUSIONS: Significant relations were found between correction rate of middle, and distal curvature, and postoperative shoulder balance. In addition, preoperative shoulder level difference can be a determinant of postoperative shoulder balance. PMID- 23455951 TI - Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts. AB - INTRODUCTION: Aneurysmal bone cysts (ABCs) are expansive and destructive lesions positive for osteoclast markers, resembling benign giant cell tumors (GCTs). Treatment options include surgical resection, curettage and cavity filling, embolization, injection of fibrosing agents, or radiotherapy. Particularly in children and adolescents with spinal ABCs, these options may be unsatisfactory, and innovative forms of treatment are needed. Denosumab is a human monoclonal antibody that inhibits osteoclast function by blocking the cytokine receptor activator of the nuclear factor-kappa B ligand. Satisfactory results with denosumab in treating GCTs and immunohistochemical similarities suggest that it may also have positive effects on ABCs. METHODS AND RESULTS: This report is the first description of the therapeutic use of denosumab in two patients with spinal ABCs. Two boys (aged 8 and 11) had recurrent ABCs at C5 after surgery with intralesional tumor resection. Treatment options were discussed by the interdisciplinary tumor board. Arterial embolization was attempted, but failed due to an absence of appropriate afferent arteries. After the families had received extensive information and provided written consent, denosumab therapy was initiated as an individualized treatment, despite the absence as yet of scientific evidence. After the start of denosumab therapy, both patients recovered from pain and neurologic symptoms significantly and are now in a healthy condition with no severe side effects. Magnetic resonance imaging check ups after 2 or 4 months of denosumab treatment, respectively, showed tumor regression in both patients. DISCUSSION: Longer follow-up and clinical studies are warranted to establish the value of denosumab in the treatment of ABCs. PMID- 23455952 TI - Calcium pyrophosphate dihydrate deposition disease of the filum terminale. AB - INTRODUCTION: Calcium pyrophosphate dihydrate crystal deposition disease (CPPDD) is a rare benign inflammatory joint disorder characterized by the presence of calcium pyrophosphate dihydrate crystal in the interarticular and periarticular tissue. It has been rarely described with spinal localization. METHODS: A 50-year old woman, affected by CPPDD, presented a progressive weakness of both lower limbs associated with neurogenic claudication. Neuroradiological examinations revealed the presence of two intradural calcified lesions at level L3-L4, with no post-contrast enhancement. RESULTS: Surgery was performed and the histopathological exams documented the presence of rod-shaped crystals embedded in a fibrocartilaginous stroma. The postoperative course was uneventful and the patient experienced complete symptoms relief with a 5-year follow-up. CONCLUSION: Intradural CPPD localization at the filum terminale is an extremely rare occurrence. Total removal should be preferably attempted with a long-term focal control of the disease as we observed in our case. PMID- 23455953 TI - Metabolic disturbances identified by SPECT-CT in patients with a clinical diagnosis of sacroiliac joint incompetence. AB - PURPOSE: To establish the sensitivity and specificity of cross-sectional scintigraphy [single photon emission computed tomography (SPECT)] combined with computed X-ray tomography (CT) in the detection of sacroiliac joint (SIJ) mechanical dysfunction and evaluate reproducibility of reporting. METHODS: Patients with pelvic girdle pain either on the basis of peri-partum SIJ dysfunction or trauma were included. These patients were imaged with bone scintigraphy with hybrid imaging with SPECT/CT. RESULTS: The study group comprised 100 patients (72 females, 28 males). Trauma accounted for 52% and the remainder were patients with peri-partum pain. Average age was 43 years and average length of history was >2 years. The major finding was increased uptake in the upper SIJ and posterior soft-tissues/ligaments. Hybrid imaging had a sensitivity of 95% and specificity of 99%. Positive predictive value was 99% and negative predictive value 94%. Power of the test was 1.0. Reproducibility of the test was good with kappa values of 0.85. CONCLUSION: Hybrid imaging with SPECT/CT reproducibly demonstrates metabolic alterations around the SIJ in patients with SIJ dysfunction, which we have termed SIJ incompetence. The condition is more common than previously recognised and frequently occurs after trauma, which has not been reported previously. PMID- 23455954 TI - Risk factors for survival of 106 surgically treated patients with symptomatic spinal epidural metastases. AB - PURPOSE: Evaluation of risk factors for survival in patients surgically treated for symptomatic spinal epidural metastases (SEM). METHODS: One hundred and six patients who were surgically treated for symptomatic SEM in a 10-year period in two cooperatively working hospitals were retrospectively studied for nine risk factors: age, gender, site of the primary tumor, location of the symptomatic spinal metastasis, functional and neurologic status, the presence of visceral metastases and the presence of other spinal and extraspinal bone metastases. Analysis was performed using the Kaplan-Meier method, univariate log-rank tests and Cox-regression models. RESULTS: Overall median survival was 10.7 months (0.2 107.5 months). Overall 30-day complication rate was 33 %. Multivariate Cox regression analysis showed that fast growing primary tumors (HR 3.1, 95 % CI 1.6 6.2, p = 0.001), the presence of visceral metastases (HR 1.7, 95 % CI 1.0-2.9, p = 0.033) and a low performance status (HR 2.7, 95 % CI 1.1-6.6, p = 0.025) negatively influenced the survival. CONCLUSION: Primary tumor type, presence of visceral metastases and performance status are significant predictors for survival after surgery for symptomatic SEM and should be evaluated before deciding on the extent of treatment. More accurate prediction models are needed to select the best treatment option for the individual patient. PMID- 23455955 TI - Comparison of global responses to mild deficiency and excess copper levels in Arabidopsis seedlings. AB - Copper is an essential micronutrient in higher plants, but it is toxic in excess. The fine adjustments required to fit copper nutritional demands for optimal growth are illustrated by the diverse, severe symptoms resulting from copper deficiency and excess. Here, a differential transcriptomic analysis was done between Arabidopsis thaliana plants suffering from mild copper deficiency and those with a slight copper excess. The effects on the genes encoding cuproproteins or copper homeostasis factors were included in a CuAt database, which was organised to collect additional information and connections to other databases. The categories overrepresented under copper deficiency and copper excess conditions are discussed. Different members of the categories overrepresented under copper deficiency conditions were both dependent and independent of the general copper deficiency transcriptional regulator SPL7. The putative regulatory elements in the promoter of the copper deficiency overrepresented genes, particularly of the iron superoxide dismutase gene FSD1, were also analysed. A 65 base pair promoter fragment, with at least three GTAC sequences, was found to be not only characteristic of them all, but was responsible for most of the FSD1 copper-dependent regulations. Moreover, a new molecular marker for the slight excess copper nutritional status is proposed. Taken together, these data further contribute to characterise copper nutritional responses in higher plants. PMID- 23455956 TI - Cultivation and characterization of bacterial isolates capable of degrading pharmaceutical and personal care products for improved removal in activated sludge wastewater treatment. AB - Pharmaceutical and personal care products (PPCPs) discharged with wastewater treatment plant (WWTP) effluents are an emerging surface water quality concern. Biological transformation has been identified as an important removal mechanism during wastewater treatment. The aim of this research was the identification of bacteria with characteristics for potential bioaugmentation to enhance PPCP removal. We report here the cultivation and characterization of bacteria capable of degrading PPCPs to ng/L concentrations. An isolation approach was developed using serial enrichment in mineral medium containing 1 mg/L of an individual PPCP as the sole organic carbon source available to heterotrophs until the original activated sludge inocula was diluted to ~10(-8) of its initial concentration, followed by colony growth on solid R2A agar. Eleven bacteria were isolated, eight that could remove triclosan, bisphenol A, ibuprofen, or 17beta-estradiol to below 10 ng/L, one that could remove gemfibrozil to below 60 ng/L, and two that could remove triclosan or E2, but not to ng/L concentrations. Most bacterial isolates degraded contaminants during early growth when grown utilizing rich carbon sources and were only able to degrade the PPCPs on which they were isolated. Seven of the bacterial isolates were sphingomonads, including all the triclosan and bisphenol A degraders and the ibuprofen degrader. The study results indicate that the isolated bacteria may have a positive influence on removal in WWTPs if present at sufficient concentrations and may be useful for bioaugmentation. PMID- 23455957 TI - Nanoparticle assemblies: dimensional transformation of nanomaterials and scalability. AB - Integration of nanoparticles (NPs) and other nanomaterials with existing technologies must take place in order to substantially widen the spectrum of their applications. This task can be simplified by taking advantage of NP assemblies provided that they retain the unique properties of nanomaterials in organized systems of larger dimensions. There is a large variety of methods of assembling NPs into superstructures containing 10-10(10) particles that include field-, bio-, and interface-directed techniques as well as self-organization. Some of them can traverse the scales from typical lengths of 10(-9) m (nano) to 10(-5) m (micro) and 10(1) m (macro) conducive to other technologies. Such dimensional transformation of nanomaterials makes possible utilization of well established processing techniques, and hardware tools operating at these scales. Therefore, answering the question "What types of the assembly techniques are suitable for such a task?" is vital for the future application of nanoscale materials in any field of use. These techniques must result in organized structures of at least 5 * 10(-7) m in size, offer relative simplicity and fault tolerance. This review focuses on the recent development of NP assembly techniques that have the possibility of satisfying these requirements. The expected applications and future developments are also discussed. PMID- 23455958 TI - Time-lapse ultrashort pulse microscopy of infection in three-dimensional versus two-dimensional culture environments reveals enhanced extra-chromosomal virus replication compartment formation. AB - The mechanisms that enable viruses to harness cellular machinery for their own survival are primarily studied in cell lines cultured in two-dimensional (2-D) environments. However, there are increasing reports of biological differences between cells cultured in 2-D versus three-dimensional (3-D) environments. Here we report differences in host-virus interactions based on differences in culture environment. Using ultrashort pulse microscopy (UPM), a form of two-photon microscopy that utilizes sub-10-fs pulses to efficiently excite fluorophores, we have shown that de novo development of extra-chromosomal virus replication compartments (VRCs) upon murine cytomegalovirus (mCMV) infection is markedly enhanced when host cells are cultured in 3-D collagen gels versus 2-D monolayers. In addition, time-lapse imaging revealed that mCMV-induced VRCs have the capacity to grow by coalescence. This work supports the future potential of 3-D culture as a useful bridge between traditional monolayer cultures and animal models to study host-virus interactions in a more physiologically relevant environment for the development of effective anti-viral therapeutics. These advances will require broader adoption of modalities, such as UPM, to image deep within scattering tissues. PMID- 23455959 TI - Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia. AB - We explore diagnostic utility of a multicolor excitation multimodal nonlinear optical (NLO) microscopy for noninvasive detection of squamous epithelial precancer in vivo. The 7,12-dimenthylbenz(a)anthracene treated hamster cheek pouch was used as an animal model of carcinogenesis. The NLO microscope system employed was equipped with the ability to collect multiple tissue endogenous NLO signals such as two-photon excited fluorescence of keratin, nicotinamide adenine dinucleotide, collagen, and tryptophan, and second harmonic generation of collagen in spectral and time domains simultaneously. A total of 34 (11 controlled and 23 treated) Golden Syrian hamsters with 62 in vivo spatially distinct measurement sites were assessed in this study. High-resolution label free NLO images were acquired from stratum corneum, stratum granulosum-stratum basale, and stroma for all tissue measurement sites. A total of nine and eight features from 745 and 600 nm excitation wavelengths, respectively, involving tissue structural and intrinsic biochemical properties were found to contain significant diagnostic information for precancers detection (p<0.05). Particularly, 600 nm excited tryptophan fluorescence signals emanating from stratum corneum was revealed to provide remarkable diagnostic utility. Multivariate statistical techniques confirmed the integration of diagnostically significant features from multicolor excitation wavelengths yielded improved diagnostic accuracy as compared to using the individual wavelength alone. PMID- 23455960 TI - Staining-free malaria diagnostics by multispectral and multimodality light emitting-diode microscopy. AB - We report an accurate optical differentiation technique between healthy and malaria-infected erythrocytes by quasi-simultaneous measurements of transmittance, reflectance, and scattering properties of unstained blood smears using a multispectral and multimode light-emitting diode microscope. We propose a technique for automated imaging, identification, and counting of malaria-infected erythrocytes for real-time and cost-effective parasitaemia diagnosis as an effective alternative to the manual screening of stained blood smears, now considered to be the gold standard in malaria diagnosis. We evaluate the performance of our algorithm against manual estimations of an expert and show a spectrally resolved increased scattering from malaria-infected blood cells. PMID- 23455961 TI - Depth-resolved dual-beamlet vibrometry based on Fourier domain low coherence interferometry. AB - We present an optical vibrometer based on delay-encoded, dual-beamlet phase sensitive Fourier domain interferometric system to provide depth-resolved subnanometer scale vibration information from scattering biological specimens. System characterization, calibration, and preliminary vibrometry with biological specimens were performed. The proposed system has the potential to provide both amplitude and direction of vibration of tissue microstructures on a single two dimensional plane. PMID- 23455962 TI - Rapid radial optical coherence tomography image acquisition. AB - We demonstrate how compressive sampling can be used to expedite volumetric optical coherence tomography (OCT) image acquisition. We propose a novel method to interpolate OCT volumetric images from data acquired by radial B-scans in the Cartesian coordinate system. Due to the inherent polar symmetry in the human eye, the (r, theta, z) coordinate system provides a natural domain to perform the interpolation. We demonstrate that the method has minimal effect on image quality even when up to 88% of the data is not acquired. The potential outcome of this work could lead to significant reductions in OCT volume acquisition time in clinical practice. PMID- 23455963 TI - Using optical fibers with different modes to improve the signal-to-noise ratio of diffuse correlation spectroscopy flow-oximeter measurements. AB - The dual-wavelength diffuse correlation spectroscopy (DCS) flow-oximeter is an emerging technique enabling simultaneous measurements of blood flow and blood oxygenation changes in deep tissues. High signal-to-noise ratio (SNR) is crucial when applying DCS technologies in the study of human tissues where the detected signals are usually very weak. In this study, single-mode, few-mode, and multimode fibers are compared to explore the possibility of improving the SNR of DCS flow-oximeter measurements. Experiments on liquid phantom solutions and in vivo muscle tissues show only slight improvements in flow measurements when using the few-mode fiber compared with using the single-mode fiber. However, light intensities detected by the few-mode and multimode fibers are increased, leading to significant SNR improvements in detections of phantom optical property and tissue blood oxygenation. The outcomes from this study provide useful guidance for the selection of optical fibers to improve DCS flow-oximeter measurements. PMID- 23455966 TI - Detachable fiber optic tips for use in thulium fiber laser lithotripsy. AB - The thulium fiber laser (TFL) has recently been proposed as an alternative to the Holmium:YAG (Ho:YAG) laser for lithotripsy. The TFL's Gaussian spatial beam profile provides higher power transmission through smaller optical fibers with reduced proximal fiber tip damage, and improved saline irrigation and flexibility through the ureteroscope. However, distal fiber tip damage may still occur during stone fragmentation, resulting in disposal of the entire fiber after the procedure. A novel design for a short, detachable, distal fiber tip that can fit into an ureteroscope's working channel is proposed. A prototype, twist-lock, spring-loaded mechanism was constructed using micromachining methods, mating a 150-MUm-core trunk fiber to 300-MUm-core fiber tip. Optical transmission measuring 80% was observed using a 30-mJ pulse energy and 500-MUs pulse duration. Ex vivo human calcium oxalate monohydrate urinary stones were vaporized at an average rate of 187 MUg/s using 20-Hz modulated, 50% duty cycle 5 pulse packets. The highest stone ablation rates corresponded to the highest fiber tip degradation, thus providing motivation for use of detachable and disposable distal fiber tips during lithotripsy. The 1-mm outer-diameter prototype also functioned comparable to previously tested tapered fiber tips. PMID- 23455964 TI - Application of the critical angle method to refractive index measurement of human skin in vivo under partial contact. AB - We adapted the critical angle method for measuring rough surfaces under partial contact to acquire an in vivo skin refractive index (RI). Assuming that the total reflection is the simple sum of reflection from areas that are in contact and reflection from those that are not in contact, the RI can be estimated even for partial contact with a rough surface. We found that cheek skin is sufficiently soft that a sufficiently large area can be in contact and that the critical angle was detectable. The RIs of the cheeks of adult females were measured. The RI range was about 1.51 to 1.53, at a wavelength of 550 nm, without considering systematic errors. The RIs of cheeks are significantly correlated with their conductance, which corresponds to their water content. We determined the relationship between the RI and conductance within the variation of skin under normal conditions; this relationship was theoretically obtained in previous studies. In the present study, a direct in vivo measurement method was developed that enabled us to measure the RI in daily life, although this method contains errors for several reasons, including disregarding absorption. PMID- 23455968 TI - Organization and activity of the Replantation Service for amputated hands in Poland. AB - A permanent on-call service for hand amputations (Replantation Service) was established in 2010 of the initiative of the Council of Polish Society for Surgery of the Hand. It is run by three qualified hand centres in Trzebnica, Poznan and Szczecin. Organization of this system, rules of activity and spectrum of cases admitted to replantation units was presented. A scheme of referral of amputations was shown and the main problems that appeared during almost three year activity of the Service were discussed. Medico-legal and ethical implications arising from these problems were shown and organization of replantation service in other European countries was outlined. Establishing of the Replantation Service constituted a significant progress in the organization of the management of upper limb amputations. Thanks to that, over the period of three years, more than 200 patients were saved from severe disability, receiving a chance to regain an amputated limb. PMID- 23455969 TI - Connect the dots: patient safety and health information technology. PMID- 23455965 TI - Monte Carlo lookup table-based inverse model for extracting optical properties from tissue-simulating phantoms using diffuse reflectance spectroscopy. AB - We present a Monte Carlo lookup table (MCLUT)-based inverse model for extracting optical properties from tissue-simulating phantoms. This model is valid for close source-detector separation and highly absorbing tissues. The MCLUT is based entirely on Monte Carlo simulation, which was implemented using a graphics processing unit. We used tissue-simulating phantoms to determine the accuracy of the MCLUT inverse model. Our results show strong agreement between extracted and expected optical properties, with errors rate of 1.74% for extracted reduced scattering values, 0.74% for extracted absorption values, and 2.42% for extracted hemoglobin concentration values. PMID- 23455970 TI - Determining optimal waste volume from an intravenous catheter. AB - Waste is blood drawn from an intravenous (IV) catheter to remove saline or heparin before obtaining a blood sample. This study examines the minimum waste volume resulting in an undiluted sample. A repeated-measures design was used. Investigators placed an IV catheter in 60 healthy adults and obtained samples at baseline and following waste volumes ranging from 0.5 to 3 mL. A random effects mixed model was used to determine the stabilizing point, which was 1 mL of waste. Knowing that only 1 mL of waste is needed will prevent clinicians from obtaining extra waste and discarding blood needlessly. PMID- 23455971 TI - Emerging therapies in pediatric pain management. AB - Infants and children are typically undertreated for pain. Many treatment options are available to prevent and diminish the pain experienced by children during venipuncture. Infusion nurses must employ pharmacologic and nonpharmacologic treatment options to make the experience more positive for the child, the family, and the nurse. These treatment options are explored in this article. PMID- 23455972 TI - Providing culturally competent care in home infusion nursing. AB - All health care providers, and particularly nurses who are on the front lines of patient care, must be skilled in providing culturally appropriate and competent care. Cultural competence needs to be guided by a philosophical framework. This article was written to describe cultural care in the context of home infusion nursing using the Process of Cultural Competence in the Delivery of Healthcare Services model. The model is used to provide structural reference in order to offer nursing care to members of diverse cultures. The 5-part model gives an overarching conceptual orientation to assist the nurse in providing quality care that is culturally sensitive. PMID- 23455973 TI - Critically ill and septic patient: is red blood cell transfusion adding to the Domino Effect? AB - Sepsis is a major cause of patient morbidity and mortality. Many critically ill patients are septic, and red blood cell transfusion is often part of their treatment plan. Studies have shown that red blood cell transfusion is associated with a dose-dependent increase in patient morbidity and mortality. Although red blood cells are transfused to increase the recipient's oxygen-carrying capacity, there are new and emerging data to support that red blood cell transfusion may potentially decrease perfusion and oxygen delivery to the microcirculation, particularly when older red blood cells are transfused. In addition, there are similar effects in the pathophysiology of sepsis that may overlap with the changes that occur with storage of red blood cells. This article will discuss recent literature addressing red cell transfusion in critically ill and septic patients and discuss general guidelines for red cell transfusion in this patient population. This article will also discuss the epidemiology and pathophysiology of sepsis and relate how storage and transfusion of red cells may potentially contribute to changes observed in a septic patient. PMID- 23455974 TI - Principles in the selection of intravenous solutions replacement: sodium and water balance. AB - Inappropriate intravenous fluid therapy results in increased patient morbidity and mortality. By far the most common fluid and electrolyte problems that confront both chronically and critically ill patients are disturbances in sodium and water balance. Thus, it is important for the infusion therapy nurse to understand the basic pathophysiology of sodium imbalances as well as therapeutic approaches for their correction. Adding to this need is the recognition that, in hospital settings, disorders of sodium and water balance are often iatrogenic. PMID- 23455976 TI - Insulin resistance as a predictor of cardiovascular disease in patients on peritoneal dialysis. AB - BACKGROUND: Insulin resistance is associated with multiple risk factors for cardiovascular (CV) disease in the general population. Patients on peritoneal dialysis (PD) are more likely to develop insulin resistance. However, no evaluation of the impact of insulin resistance on CV disease morbidity or mortality in patients on PD has been performed. METHODS: Our prospective cohort study included all non-diabetic patients on PD at our center (n = 66). Insulin resistance was evaluated at baseline by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels. The cohort was followed for up to 58 months (median: 41.3 months; interquartile range: 34.3 months). A multivariate Cox model was used to analyze the impact of insulin resistance on CV disease mortality. RESULTS: Fourteen CV events occurred in the higher HOMA-IR group [IR-H (HOMA-IR values in the range 2.85 - 19.5), n = 33], but only one event occurred in the lower HOMA-IR group (IR-L (HOMA-IR values in the range 0.83 - 2.71), n = 33) during the follow-up period. Level of HOMA-IR was a significant predictor of CV events [risk ratio: 17.7; 95% confidence interval (CI): 2.10 to 149.5; p = 0.008]. In the IR-H group, 10 patients died (8 CV events), but in the IR-L group, only 4 patients died (1 CV event). Patients in the IR-H group experienced significantly higher CV mortality (hazard ratio: 9.02; 95% CI: 1.13 to 72.2; p = 0.04). Even after adjustments for age, systolic blood pressure, body mass index, C-reactive protein, triglycerides, resistin, and leptin, HOMA-IR remained an independent predictor of CV mortality (hazard ratio: 14.8; 95% CI: 1.22 to 179.1; p = 0.03). CONCLUSIONS: Insulin resistance assessed using HOMA-IR was an independent predictor of CV morbidity and mortality in a cohort of nondiabetic patients on PD. Insulin resistance is a modifiable risk factor; the reduction of insulin resistance may reduce CV risk and improve survival in this group of patients. PMID- 23455978 TI - Evaluation of inorganic particles of composite resins with nanofiller content. AB - The purposes of this study were evaluate by energy dispersed X-ray (EDS) and scanning electron microscopy (SEM) the inorganic particles of three nanofilled composite resins, comparing particles sizes, shape and composition, and the filler weight content by thermogravimetric analyzes (TGA). Three composite resins classified as nanofilled were selected to this study: Esthet-X; Grandio; Filtek Supreme XT. The shade was standardized (A2) for enamel (E) or dentin (D). Ten samples with 20 mg (+/-10 mg) of each composite resin were submitted to thermogravimetric analyzes (TGA) in order to record the filler weight content (wt%). The amount of inorganic phase ranged from 75.75 to 87 wt%, to Esthet-X (D) and Grandio (D), respectively. The filler composition was analyzed by energy dispersed X-ray (EDS), and the size and shape were evaluated by scanning electron microscopy (SEM). The filler average size (um) obtained by SEM were: Esthet-X (E) 1.16; Esthet-X (D) 1.39; Filtek Supreme XT (E) 0.6 (nanocluster); Filtek Supreme XT (D) 1.14 (nanocluster); Grandio (E) 2.05 and Grandio (D) 3.1. Silica (SiO2), Ba and Al were observed through EDS. The shape of Esthet-X and Grandio fillers showed similar characteristics with high quantity of irregular inorganic particles and heterogeneous filler. However, Filtek Supreme XT showed spherical and regular particles with homogeneous distribution and sizes. Based in the analysis of nanofilled composites inorganic phase, inconsistencies of weight content, composition, shape and size can be stated between the literature and manufacturer's instructions. PMID- 23455977 TI - Cost analysis of hemodialysis and peritoneal dialysis access in incident dialysis patients. AB - BACKGROUND: Although several studies have demonstrated the economic advantages of peritoneal dialysis (PD) over hemodialysis (HD), few reports in the literature have compared the costs of HD and PD access. The aim of the present study was to compare the resources required to establish and maintain the dialysis access in patients who initiated HD with a tunneled cuffed catheter (TCC) or an arteriovenous fistula (AVF) and in patients who initiated PD. METHODS: We retrospectively analyzed the 152 chronic kidney disease patients who consecutively initiated dialysis treatment at our institution in 2008 (HD-AVF, n = 65; HD-CVC, n = 45; PD, n = 42). Detailed clinical and demographic information and data on access type were collected for all patients. A comprehensive measure of total dialysis access costs, including surgery, radiology, hospitalization for access complications, physician costs, and transportation costs was obtained at year 1 using an intention-to-treat approach. All resources used were valued using 2010 prices, and costs are reported in 2010 euros. RESULTS: Compared with the HD AVF and HD-TCC modalities, PD was associated with a significantly lower risk of access-related interventions (adjusted rate ratios: 1.572 and 1.433 respectively; 95% confidence intervals: 1.253 to 1.891 and 1.069 to 1.797). The mean dialysis access-related costs per patient-year at risk were ?1171.6 [median: ?608.8; interquartile range (IQR): ?563.1 - ?936.7] for PD, ?1555.2 (median: ?783.9; IQR: ?371.4 - ?1571.7) for HD-AVF, and ?4208.2 (median: ?1252.4; IQR: ?947.9 - ?2983.5) for HD-TCC (p < 0.001). In multivariate analysis, total dialysis access costs were significantly higher for the HD-TCC modality than for either PD or HD AVF (beta = -0.53; 95% CI: -1.03 to -0.02; and beta = -0.50; 95% CI: -0.96 to 0.04). CONCLUSIONS: Compared with patients initiating HD, those initiating PD required fewer resources to establish and maintain a dialysis access during the first year of treatment. PMID- 23455979 TI - Adaptation and validation of the early childhood oral health impact scale in Lithuania. AB - BACKGROUND: The Early Childhood Oral Health Impact Scale (ECOHIS) is a parent- assessed oral health related quality of life measure developed to assess the impact of oral health problems on preschool children. AIM: The aim of this study was to develop a Lithuanian version of the ECOHIS and evaluate its validity and reliability among preschool children in Lithuania. DESIGN: A lithuanian version of ECOHIS (L-ECOHIS) was developed through a forward-backword translation. A cross-sectional study was performed to assess discriminant and convergent validity and internal consistency. Data was collected from 130 parents of 0-5 year-old children visiting the dental department. A subsample of parents filled the questionnaire again to assess the test-retest reliability. RESULTS: Cronbach's alpha for the instrument was 0.869. Item-total correlation coefficients ranged from 0.389 to 0.797. Scores of the child and family sections were significantly correlated (P<0.001). The scale scores indicating worse quality of life were significantly associated with poor parental ratings of their child's oral health and problem-based dental attendance. The intra-class correlation coefficient was 0.98. CONCLUSION: The L-ECOHIS is a valid and reliable measure to assess OHRQoL of 0-5 year-old children with Lithuanian speaking parents. PMID- 23455980 TI - Influence of the temperature on the cement disintegration in cement-retained implant restorations. AB - The aim of this study was to estimate the average disintegration temperature of three dental cements used for the cementation of the implant-supported prostheses. One hundred and twenty metal frameworks were fabricated and cemented on the prosthetic abutments with different dental cements. After heat treatment in the dental furnace, the samples were set for the separation to test the integration of the cement. Results have shown that resin-modified glass-ionomer cement (RGIC) exhibited the lowest disintegration temperature (p<0.05), but there was no difference between zinc phosphate cement (ZPC) and dual cure resin cement (RC) (p>0.05). Average separation temperatures: RGIC - 306 +/- 23 degrees C, RC 363 +/- 71 degrees C, it could not be calculated for the ZPC due to the eight unseparated specimens. Within the limitations of the study, it could be concluded that RGIC cement disintegrates at the lowest temperature and ZPC is not prone to break down after exposure to temperature. PMID- 23455981 TI - Pain and discomfort perception among patients undergoing orthodontic treatment: results from one month follow-up study. AB - OBJECTIVE: To explore pain and discomfort experience among patients undergoing orthodontic treatment with different appliances during one month after the appliance insertion, and to elucidate predicting role of patients' motivation for treatment and awareness of discomfort to the intensity of pain. MATERIAL AND METHODS: The study group consisted of 93 orthodontic patients treated with braces (48.4%), braces and head gear (9.7%), removable appliances (34.4%) and functional appliances (7.5%). The patients were asked about pain and discomfort (increased salivation, soft tissues lesion, etc.) they had experienced during one month after the appliance insertion and about motivation for treatment as well as awareness of probable discomfort. RESULTS: 72.0% of patients reported that they complained of pain after one day the appliance had been inserted, but the percentage of such respondents significantly decreased during one month. Patients experienced the highest scores of discomfort from 12 hours to 2 days after the appliance insertion. The change of pain intensity and scores of other discomforts depended on treatment method showing favourable trends for patients treated with braces and head gear, and functional appliances. Patients who were positively motivated for the treatment or were aware of possible pain and discomfort reported significantly decreasing pain during treatment. CONCLUSIONS: The perception of pain and discomfort among orthodontic patients was variable during the first month after the appliance insertion regarding the type of appliance, patients' motivation for treatment and their awareness of probable discomfort. PMID- 23455982 TI - Evaluation of mechanical properties on three nanofilled composites. AB - The purpose of this study was to evaluate the mechanical behavior of three composites with nanoparticles Filtek Z350 XT (3M ESPE), Esthet X (Dentsply), Grandio (Voco) in enamel and body shades (A2) trough nanohardness, elastic modulus, compressive strength test, flexural strength test, diametral tensile strength, flexural modulus, weight filler content and Knoop microhardness. One sample of each material was submitted to nanohardness and elastic modulus. Five values of ten indentations were considered valids inside confidence intereval. Ten samples of each material were submitted to compressive strength, flexural strength and diametral tensile strength test at universal testing machine. The flexural modulus test was calculated based on flexural strength results. Ten samples of each group were submitted to knoop microhardness test. The results were submitted to ANOVA and Tukey statistical tests. The highest inorganic weight filler content for Grandio was registered after the organic mould decomposition. After statistical analysis Grandio showed the highest averages for nanohardness, elastic modulus, flexural modulus and knoop microhardness. For diametral tensile strength Grandio and Filtek Z350 XT obtained the highest averages. The tested composite resins ranged similar medias statistically for compressive strength. For flexural strength Filtek Z350 XT and Esthet X showed the highest averages. The results suggest that the weight filler content, the filler size and shape and the contact surface between nanofillers and organic phase has direct relation with composite resins with nanoparticles mechanical properties. Further studies should be carried out to improve the knowledge of composites with nanoparticles mechanical behavior. PMID- 23455983 TI - [Correlation of mental activity with cognitive functions in mild cognitive impairment and early stage dementia]. AB - INTRODUCTION: Mental activities have been suggested to influence the risk and course of dementia. This study was performed in order to assess the association of various mental activities with diagnosis and cognitive functions in an elderly population. METHODS: A total of 191 memory clinic patients (mean age 71.7 +/- 10.7 years) were included in this study. Participants completed a standardized neuropsychological test battery, a clinical interview, and a semistructured interview to assess mental activities. RESULTS: Of the 191 patients, 39 were diagnosed as cognitively intact, 72 had mild cognitive impairment, and 80 mild Alzheimer's disease. Group comparisons of mental activity scores revealed differences for the variables art, culture, media consumption, travelling, and cognitive activities. Correlation analysis showed a significant association of culture, media consumption, travelling, and cognitive activities with cognitive functions. CONCLUSION: Our results suggest that mental activities may influence the extent of cognitive impairment and possibly the risk for Alzheimer's disease. PMID- 23455984 TI - Orientation of luminescent excitons in layered nanomaterials. AB - In nanomaterials, optical anisotropies reveal a fundamental relationship between structural and optical properties. Directional optical properties can be exploited to enhance the performance of optoelectronic devices, optomechanical actuators and metamaterials. In layered materials, optical anisotropies may result from in-plane and out-of-plane dipoles associated with intra- and interlayer excitations, respectively. Here, we resolve the orientation of luminescent excitons and isolate photoluminescence signatures arising from distinct intra- and interlayer optical transitions. Combining analytical calculations with energy- and momentum-resolved spectroscopy, we distinguish between in-plane and out-of-plane oriented excitons in materials with weak or strong interlayer coupling-MoS2 and 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA), respectively. We demonstrate that photoluminescence from MoS2 mono-, bi- and trilayers originates solely from in-plane excitons, whereas PTCDA supports distinct in-plane and out-of-plane exciton species with different spectra, dipole strengths and temporal dynamics. The insights provided by this work are important for understanding fundamental excitonic properties in nanomaterials and designing optical systems that efficiently excite and collect light from exciton species with different orientations. PMID- 23455985 TI - Subcellular control of Rac-GTPase signalling by magnetogenetic manipulation inside living cells. AB - Many cell functions rely on the coordinated activity of signalling pathways at a subcellular scale. However, there are few tools capable of probing and perturbing signalling networks with a spatial resolution matching the intracellular dimensions of their activity patterns. Here we present a generic magnetogenetic approach based on the self-assembly of signalling complexes on the surface of functionalized magnetic nanoparticles inside living cells. The nanoparticles act as nanoscopic hot spots that can be displaced by magnetic forces and trigger signal transduction pathways that bring about a cell response. We applied this strategy to Rho-GTPases, a set of molecular switches known to regulate cell morphology via complex spatiotemporal patterns of activity. We demonstrate that the nanoparticle-mediated activation of signalling pathways leads to local remodelling of the actin cytoskeleton and to morphological changes. PMID- 23455986 TI - Epidemiology, co-morbidities, and medication use of patients with Alzheimer's disease or vascular dementia in the UK. AB - Epidemiologic studies on age-specific incidence rates (IRs) separating Alzheimer's disease (AD) and vascular dementia (VaD) in the UK are scarce. We sought to assess IRs of AD and VaD in the UK and to compare co-morbidities and medication use between patients with AD, VaD, or without dementia. We identified cases aged >=65 years with an incident diagnosis of AD or VaD between 1998 and 2008 using the General Practice Research Database (GPRD). We assessed IRs, stratified by age and gender, matched one dementia-free control patient to each demented patient, and analyzed co-morbidities and medication use. We identified 7,086 AD and 4,438 VaD cases. Overall, the IR of AD was 1.59/1,000 person-years (py) (95% CI 1.55-1.62) and the IR of VaD 0.99/1,000 py (95% CI 0.96-1.02). For AD, IRs were higher for women than for men, but not for VaD. Except for orthostatic hypotension, the prevalence of all cardiovascular (CV) co-morbidities and exposure to CV drugs was lower in patients with AD than in corresponding controls, whereas the opposite was true for VaD. The lower prevalence of CV diseases in patients with AD may be a true finding or the result of a channeling effect, i.e., the possibility that demented patients with CV diseases may be more likely diagnosed with VaD than AD. PMID- 23455987 TI - Effects of aging and mild cognitive impairment on electrophysiological correlates of performance monitoring. AB - Performance monitoring tasks are suitable for investigating aging-related decline in executive functions. However, little is known about performance monitoring in premature pathological aging and mild cognitive impairment (MCI). This study recorded the error-related negativity (ERN) and the correct-related negativity (CRN) as indices of performance monitoring and compared these responses in older adults with MCI to the ones of younger and older adult controls. No differences in either ERN or CRN were found between younger and older adult controls. Compared to both control groups, we observed a more negatively pronounced CRN in MCI subjects. Only in this group did the amplitude of the CRN not differ from the one of the ERN. In general, larger differences between both components (i.e., ERN > CRN) were associated with better performances in cognitive tests requiring inhibition and executive control. These results indicate that electrophysiological correlates of performance monitoring (ERN and CRN) are differentially affected by aging and MCI. PMID- 23455989 TI - Ibuprofen inhibits the synaptic failure induced by the amyloid-beta peptide in hippocampal neurons. AB - Epidemiological studies have reported a decrease in the prevalence of Alzheimer's disease in individuals who chronically use non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trials, on the other hand, have been less positive. Nevertheless, it has been proposed that NSAIDs exert part of their effects by reducing long-term cerebral neuroinflammation, although this mechanism has not been proven. In this study, we report that ibuprofen, one of the more widely used non-steroidal anti-inflammatory drugs, was able to alter the ultrastructure of amyloid-beta peptide (Abeta) and significantly decrease its association to neuronal membranes, and consequently, its synaptotoxic effect in rat primary hippocampal and cortical cultures at 24 h incubation. In agreement with these results, we found that the decrease in the frequency of calcium transients with Abeta was partly recovered by addition of ibuprofen (8.0 * 10-2 Hz in control; 3.4 * 10-2 Hz in 5 MUM Abeta, and 5.9 * 10-2 Hz in the presence of Abeta and 200 MUM ibuprofen). Additionally, this effect correlated well with the increment and recovery of miniature spontaneous currents (47 +/- 5% of control in 1 MUM Abeta alone and 104 +/- 14% in the presence of Abeta and ibuprofen). Our results suggest that ibuprofen could be exerting its neuroprotective effect by directly interacting with Abeta and altering its toxic aggregated forms. We postulate that other ibuprofen analogs with better pharmacological properties might have a higher efficacy in AD. PMID- 23455990 TI - Increased apolipoprotein D dimer formation in Alzheimer's disease hippocampus is associated with lipid conjugated diene levels. AB - Previous studies indicate that apolipoprotein D (apoD) may have a lipid antioxidant function in the brain. We have shown that apoD can reduce free radical-generating lipid hydroperoxides to inert lipid hydroxides in a reaction that involves conversion of surface exposed apoD methione-93 (Met93) residue to Met93-sulfoxide (Met93-SO). One consequence of this reaction is the formation of a stable dimerized form of apoD. As cerebral lipid peroxidation is associated with Alzheimer's disease (AD), in the present study we aimed to assess the possible presence of apoD dimers in postmortem hippocampal and cerebellar tissues derived from a cohort of pathologically defined cases ranging from control to late stage AD. Both soluble and insoluble (requiring guanidine HCl extraction) fractions of tissue homogenates were analyzed for apoD and its dimerized form. We also assessed amyloid-beta levels by ELISA and levels of lipid peroxidation by lipid conjugated diene and F2-isoprostane analysis. Our studies reveal a significant association between soluble apoD levels and AD Braak stage whereas apoD dimer formation appears to increase predominantly in the advanced stages of disease. The formation of apoD dimers is closely correlated to lipid conjugated diene levels and occurs in the hippocampus but not in the cerebellum. These results are consistent with the hypothesis that apoD acts as a lipid antioxidant in the brain. PMID- 23455988 TI - The transcriptomic response of mixed neuron-glial cell cultures to 1,25 dihydroxyvitamin d3 includes genes limiting the progression of neurodegenerative diseases. AB - Seasonal or chronic vitamin D deficiency and/or insufficiency is highly prevalent in the human population. Receptors for 1,25-dihydroxyvitamin D3, the hormonal metabolite of vitamin D, are found throughout the brain. To provide further information on the role of this hormone on brain function, we analyzed the transcriptomic profiles of mixed neuron-glial cell cultures in response to 1,25 dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 treatment increases the mRNA levels of 27 genes by at least 1.9 fold. Among them, 17 genes were related to neurodegenerative and psychiatric diseases, or brain morphogenesis. Notably, 10 of these genes encode proteins potentially limiting the progression of Alzheimer's disease. These data provide support for a role of 1,25 dihydroxyvitamin D3 in brain disease prevention. The possible consequences of circannual or chronic vitamin D insufficiencies on a tissue with a low regenerative potential such as the brain should be considered. PMID- 23455991 TI - Disease state fingerprint in frontotemporal degeneration with reference to Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND: Disease state index and disease state fingerprint represent a novel tool which collates data information from different sources, helping the clinician in the diagnosis and follow-up of dementia diseases. It has been demonstrated that it is applicable in the diagnosis of Alzheimer's disease (AD). OBJECTIVE: We applied this novel tool to classify frontotemporal dementia (FTD) cases in comparison with controls, AD, and mild cognitive impairment (MCI) subjects. METHODS: Thirty seven patients with FTD, 35 patients with AD, 26 control subjects, and 64 subjects with MCI were included in the study. The disease state index encompassed data from cognitive performance assessed by Mini Mental State Examination, cerebrospinal fluid biomarkers, MRI volumetric and morphometric parameters as well as APOE genotype. RESULTS: We applied the Disease State Index for comparisons at the group level. The data showed that FTD patients could be differentiated with a high accuracy, sensitivity, and specificity from controls (0.84, 0.84, 0.83) and from MCI (0.79, 0.78, 0.80). However, the correct accuracy was lower in the FTD versus AD comparison (0.69, 0.70, 0.71). In addition, we demonstrated the use of Disease State Fingerprint by comparing one particular FTD case with control, AD, and MCI population data. CONCLUSION: The results suggest that the Disease State Fingerprint and the underlying Disease State Index are particularly useful in differentiating between normal status and disease in patients with dementia, but it may also help to distinguish between the two dementia diseases, FTD and AD. PMID- 23455992 TI - Highly selective and fast diagnosis of Alzheimer's disease hallmark lesions using Congo Red in isopropyl alcoholic solution. AB - A highly selective, rapid, inexpensive, simple, and immunocytochemical compatible fluorescence staining method for Alzheimer's disease hallmark lesions applicable to sections of human specimens embedded in paraffin is described. Human necropsy material was fixed in buffered formalin, sectioned at 10 MUm, mounted on slides, deparaffinized, and partially hydrated (70% ethanol). After partial hydration, sections were stained for 10 min in a solution of 0.2% Congo red in 70% isopropanol. After washing in 70% isopropanol and rehydration, auto-fluorescence of sections were quenched (optional) and processed for immunocytochemistry (optional). Finally, sections were mounted in an adequate mounting medium. Amyloid deposits appear pink at light microscopy and all Alzheimer's disease hallmark lesions appear orange or red under fluorescence microscopy using blue or green exciting light, respectively. The present method can be used in combination with all pre- or post-immunocytochemical techniques. PMID- 23455993 TI - SORL1 is genetically associated with neuropathologically characterized late-onset Alzheimer's disease. AB - SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE epsilon4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD. PMID- 23455994 TI - Alzheimer's disease: neuroprogesterone, epoxycholesterol, and ABC transporters as determinants of neurodesmosterol tissue levels and its role in amyloid protein processing. AB - Evidence is emerging that during the development of Alzheimer's disease (AD), changes in the synthesis and metabolism of cholesterol and progesterone are occurring that may or may not affect the progression of the disease. The concept arose from the recognition that dehydrocholesterol 24-reductase (DHCR24/Seladin 1), one of the nine enzymes in the endoplasmic reticulum that determines the transformation of lanosterol to cholesterol, is selectively reduced in late AD. As a consequence, the tissue level of desmosterol increases, affecting the expression of ABC transporters and the structure of lipid rafts, both determinants of amyloid-beta processing. However, the former effect is considered beneficial and the latter detrimental to processing. Other determinants of desmosterol tissue levels are 24,25 epoxycholesterol and the ABCG1 and ABCG4 transporters. Progesterone and its metabolites are determinants of tissue levels of desmosterol and several other sterol intermediates in cholesterol synthesis. Animal models indicate marked elevations in the tissue levels of these sterols at early time frames in the progression of neurodegenerative diseases. The low level of neuroprogesterone and metabolites in AD are consonant with the low level of desmosterol and may have a role in amyloid-beta processing. The sparse data that has accumulated appears to be a sufficient basis for proposing a systematic evaluation of the biologic roles of sterol intermediates in the slowly progressive neurodegeneration characteristic of AD. PMID- 23455995 TI - Impacts of spinosad and lambda-cyhalothrin on spider communities in cabbage fields in south Texas. AB - Spiders are a principal arthropod group that preys on numerous pests of vegetables and other crops. In this study, we determined the effects of the two most commonly used insecticides, spinosad and lambda-cyhalothrin, on diversity of spiders on cabbage in south Texas. In two seasons (fall 2008 and spring 2009), we collected a total of 588 spiders belonging to 53 species in 11 families from spinosad and lambda-cyhalothrin-treated cabbages and the untreated control plants. A great majority of spiders were collected from the pitfall traps (554) where only a few (34) were collected from the blower/vacuum sampling. In the insecticide-treated plots, there were significantly fewer spider individuals, species and families than in untreated fields. Spinosad had significantly less effect on spiders in total individuals, number of species and families than lambda-cyhalothrin. The effects of the two insecticides were further demonstrated by the Shannon-Weiner index (H') and the hierarchical richness index (HRI). Spider diversity in the spinosad-treated plots were not significantly different from that in the untreated fields but were greater than those in lambda cyhalothrin-treated plots in both seasons when measured by H' values. In contrast, the H' values of spider's diversity in the lambda-cyhalothrin-treated plots were significantly lower than spinosad-treated and untreated plots. High values of HRI for spider richness in the spinosad-treated plots suggested that spinosad had less effect on spiders than lambda-cyhalothrin. We concluded that spinosad was more compatible with spiders on cabbage compared to lambda cyhalothrin and that this information should be used when developing insecticide resistance management strategies. PMID- 23455996 TI - Modeling highly focused laser beam in optical tweezers with the vector Gaussian beam in the T-matrix method. AB - The vector Gaussian beam with high-order corrections is used to describe accurately the laser beam up to numerical aperture NA=1.20 in the optical tweezers for trapping nanoparticles. The beam is then expanded in the T-matrix method into the vector spherical wave function (VSWF) series using the point matching method with a new selection of the matching points. The errors in the beam description and in the VSWF expansion are much lower than those that occur in the paraxial Gaussian beam model. PMID- 23455997 TI - Conformal cubical 3D transformation-based metamaterial invisibility cloak. AB - A conformal cubical transformation-based metamaterial invisibility cloak is presented and verified, in the near and the far field, by a rigorous full-wave numerical technique based on a higher-order, large-domain finite element method, employing large anisotropic, continuously inhomogeneous generalized hexahedral finite elements, with no need for discretization of the permittivity and permeability profiles of the cloak. The analysis requires about 30 times fewer unknowns than with commercial software. To our knowledge, this is the first conformal cubical cloak and the first full-wave computational characterization of such a structure with sharp edges. The presented methodology can also be used in development of conformal, transformation-based perfectly matched layers. PMID- 23455998 TI - Fast and automatic algorithm for optic disc extraction in retinal images using principle-component-analysis-based preprocessing and curvelet transform. AB - Optic disc or optic nerve (ON) head extraction in retinal images has widespread applications in retinal disease diagnosis and human identification in biometric systems. This paper introduces a fast and automatic algorithm for detecting and extracting the ON region accurately from the retinal images without the use of the blood-vessel information. In this algorithm, to compensate for the destructive changes of the illumination and also enhance the contrast of the retinal images, we estimate the illumination of background and apply an adaptive correction function on the curvelet transform coefficients of retinal images. In other words, we eliminate the fault factors and pave the way to extract the ON region exactly. Then, we detect the ON region from retinal images using the morphology operators based on geodesic conversions, by applying a proper adaptive correction function on the reconstructed image's curvelet transform coefficients and a novel powerful criterion. Finally, using a local thresholding on the detected area of the retinal images, we extract the ON region. The proposed algorithm is evaluated on available images of DRIVE and STARE databases. The experimental results indicate that the proposed algorithm obtains an accuracy rate of 100% and 97.53% for the ON extractions on DRIVE and STARE databases, respectively. PMID- 23455999 TI - Full speckle suppression in laser projectors using two Barker code-type diffractive optical elements. AB - The mathematical model of a speckle-suppression method based on two Barker code type diffractive optical elements (DOEs) moving in orthogonal directions is developed. The analytic formulae for speckle suppression efficiency are obtained. The model indicates that the one pair of DOEs can be used for laser beams of different colors. The speckle contrast is not dependent on the distance from the viewer to the screen until the distance decreases below the distance where the spatial resolution of the eye on the screen is less than the length of the image of the DOE structure period on the screen. The analysis of the simulated results demonstrates that the method can decrease the speckle contrast to less than 5%, which is below human eye sensitivity, with an optical efficiency greater than 90%. PMID- 23456000 TI - Serial-parallel decompositions of Mueller matrices. AB - The algebraic methods for serial and parallel decompositions of Mueller matrices are combined in order to obtain a general framework for a suitable analysis of polarimetric measurements based on equivalent systems constituted by simple components. A general procedure for the parallel decomposition of a Mueller matrix into a convex sum of pure elements is presented and applied to the two canonical forms of depolarizing Mueller matrices [Ossikovski, J. Opt. Soc. Am. A 27, 123 (2010).], leading to the serial-parallel decomposition of any Mueller matrix. The resultant model is consistent with the mathematical structure and the reciprocity properties of Mueller matrices. PMID- 23456002 TI - Optimization of an autodyne laser interferometer for high-speed confocal imaging. AB - In autodyne interferometry, the beating between the reference beam and the signal beam takes place inside the laser cavity and therefore the laser fulfills simultaneously the roles of the emitter and the detector of photons. In these conditions, the laser relaxation oscillations play a leading role, both in the laser quantum noise that determines the signal-to-noise ratio (SNR) and also in the laser dynamics that determine the response time of the interferometer. In the present study, we have theoretically analyzed the SNR and the response time of a laser optical feedback imaging (LOFI) setup based on an autodyne interferometer. More precisely, we have compared the image quality of two lasers having the same output power and the same relaxation frequency, but having two different values of the LOFI gain induced by two different values of the laser response time. From this study, we have finally determined the best laser dynamical parameters and the best experimental conditions for high-speed imaging at the shot-noise limit. Finally, we conclude that a laser diode with a very short response time (in the nanosecond range) seems to be an interesting candidate compared to solid-state microchip laser with a response time of several tens of microseconds. Analytical predictions are confirmed by numerical simulations. PMID- 23456001 TI - Robust spectral-domain optical coherence tomography speckle model and its cross correlation coefficient analysis. AB - In this study, we propose a generic speckle simulation for optical coherence tomography (OCT) signal, by convolving the point-spread function (PSF) of the OCT system with the numerically synthesized random sample field. We validate our model and use the simulation method to study the statistical properties of cross correlation coefficients between A-scans, which have been recently applied in transverse motion analysis by our group. The results of simulation show that oversampling is essential for accurate motion tracking; exponential decay of OCT signal leads to an underestimate of motion that can be corrected; lateral heterogeneity of sample leads to an overestimate of motion for a few pixels corresponding to the structural boundary. PMID- 23456003 TI - Partial polarization theory of pulsed optical beams. AB - We introduce a consistent matrix formalism for the characterization of partial polarization and coherence of random, nonstationary electromagnetic beams in time and frequency domains. We derive the temporal and spectral degrees of polarization and the Stokes parameters in terms of the time-domain and frequency domain polarization matrices. The connections between temporal polarization and spectral coherence on the one hand and spectral polarization and temporal coherence on the other hand are discussed. Additionally, we establish equivalence theorems for fields with different temporal coherence properties to have the same spectral polarization states and for fields with different spectral coherence properties to possess identical temporal polarization. The theory is illustrated by analyzing specific examples of time-domain and frequency-domain electromagnetic Gaussian Schell-model pulsed beams. PMID- 23456004 TI - Wavefront reconstruction in adaptive optics systems using nonlinear multivariate splines. AB - This paper presents a new method for zonal wavefront reconstruction (WFR) with application to adaptive optics systems. This new method, indicated as Spline based ABerration REconstruction (SABRE), uses bivariate simplex B-spline basis functions to reconstruct the wavefront using local wavefront slope measurements. The SABRE enables WFR on nonrectangular and partly obscured sensor grids and is not subject to the waffle mode. The performance of SABRE is compared to that of the finite difference (FD) method in numerical experiments using data from a simulated Shack-Hartmann lenslet array. The results show that SABRE offers superior reconstruction accuracy and noise rejection capabilities compared to the FD method. PMID- 23456005 TI - Coupled-mode formulation of two-parallel photonic-crystal waveguides. AB - A self-contained coupled-mode formulation for coupled two-dimensional photonic crystal waveguides (PCWs) is discussed. Using a perturbation theory, the first order coupled-mode equations are systematically derived, which govern the evolution of the modal amplitude of individual PCWs in isolation. The coupled mode equations are used to analyze the coupled symmetric PCWs consisting of a square lattice of circular dielectric rods or air holes. It is shown that the results are in good agreement with those obtained by the rigorous direct analysis of the coupled waveguide system. PMID- 23456006 TI - Efficient method for the determination of image correspondence in airborne applications using inertial sensors. AB - This paper presents a computationally efficient method for the measurement of a dense image correspondence vector field using supplementary data from an inertial navigation sensor (INS). The application is suited to airborne imaging systems, such as an unmanned air vehicle, where size, weight, and power restrictions limit the amount of onboard processing available. The limited processing will typically exclude the use of traditional, but computationally expensive, optical flow and block matching algorithms, such as Lucas-Kanade, Horn-Schunck, or the adaptive rood pattern search. Alternatively, the measurements obtained from an INS, on board the platform, lead to a closed-form solution to the correspondence field. Airborne platforms are well suited to this application because they already possess INSs and global positioning systems as part of their existing avionics package. We derive the closed-form solution for the image correspondence vector field based on the INS data. We then show, through both simulations and real flight data, that the closed-form inertial sensor solution outperforms traditional optical flow and block matching methods. PMID- 23456007 TI - Pixelated source and mask optimization for immersion lithography. AB - Immersion lithography systems with hyper-numerical aperture (hyper-NA) (NA>1) have become indispensable in nanolithography for technology nodes of 45 nm and beyond. Source and mask optimization (SMO) has emerged as a key technique used to further improve the imaging performance of immersion lithography. Recently, a set of pixelated gradient-based SMO approaches were proposed under the scalar imaging models, which are inaccurate for hyper-NA settings. This paper focuses on developing pixelated gradient-based SMO algorithms based on a vector imaging model that is accurate for current immersion lithography. To achieve this goal, an integrative and analytic vector imaging model is first used to formulate the simultaneous SMO (SISMO) and sequential SMO (SESMO) frameworks. A gradient-based algorithm is then exploited to jointly optimize the source and mask. Subsequently, this paper studies and compares the performance of individual source optimization (SO), individual mask optimization (MO), SISMO, and SESMO. Finally, a hybrid SMO (HSMO) approach is proposed to take full advantage of SO, SISMO, and MO, consequently achieving superior performance. PMID- 23456008 TI - True random number generator based on discretized encoding of the time interval between photons. AB - We propose an approach to generate true random number sequences based on the discretized encoding of the time interval between photons. The method is simple and efficient, and can produce a highly random sequence several times longer than that of other methods based on threshold or parity selection, without the need for hashing. A proof-of-principle experiment has been performed, showing that the system could be easily integrated and applied to quantum cryptography and other fields. PMID- 23456009 TI - Kalman filtering techniques for focal plane electric field estimation. AB - For a coronagraph to detect faint exoplanets, it will require focal plane wavefront control techniques to continue reaching smaller angular separations and higher contrast levels. These correction algorithms are iterative and the control methods need an estimate of the electric field at the science camera, which requires nearly all of the images taken for the correction. The best way to make such algorithms the least disruptive to science exposures is to reduce the number required to estimate the field. We demonstrate a Kalman filter estimator that uses prior knowledge to create the estimate of the electric field, dramatically reducing the number of exposures required to estimate the image plane electric field while stabilizing the suppression against poor signal-to-noise. In addition to a significant reduction in exposures, we discuss the relative merit of this algorithm to estimation schemes that do not incorporate prior state estimate history, particularly in regard to estimate error and covariance. Ultimately the filter will lead to an adaptive algorithm which can estimate physical parameters in the laboratory for robustness to variance in the optical train. PMID- 23456010 TI - Axial resonance of periodic patterns by using a Fresnel biprism. AB - This paper proposes a method for the generation of high-contrast localized sinusoidal fringes with spatially noncoherent illumination and relatively high light throughput. The method, somehow similar to the classical Lau effect, is based on the use of a Fresnel biprism. It has some advantages over previous methods for the noncoherent production of interference fringes. One is the flexibility of the method, which allows the control of the fringe period by means of a simple axial shift of the biprism. Second is the rapid axial fall-off in visibility around the high-contrast fringe planes. And third is the possibility of creating fringes with increasing or with constant period as the light beam propagates. Experimental verifications of the theoretical statements are also provided. PMID- 23456011 TI - Broadband Faraday isolator. AB - Driving on an analogy with the technique of composite pulses in quantum physics, we theoretically propose a broadband Faraday rotator and thus a broadband optical isolator, which is composed of sequences of ordinary Faraday rotators and achromatic quarter-wave plates rotated at the predetermined angles. PMID- 23456012 TI - How to remove subannular pannus formation beneath the prosthetic valve. PMID- 23456013 TI - Thyrotoxicosis-facilitated bridge to recovery with a continuous-flow left ventricular assist device. AB - The HeartMate II is a continuous-flow left ventricular assist device that can be explanted from patients after cardiac recovery. We implanted a HeartMate II in a 21-year-old man who had idiopathic cardiomyopathy. A year later, he developed thyrotoxicosis, presumably secondary to amiodarone administered for ventricular fibrillation. Four months after the diagnosis of thyrotoxicosis, thyroid hormone levels had returned to normal, and native cardiac function had improved remarkably. After a support period of 24 months, the HeartMate II was explanted. Six years later, the patient continues to be in New York Heart Association functional Class I. Amiodarone-induced thyrotoxicosis may have contributed to myocardial recovery. PMID- 23456014 TI - Phrenic nerve injury after paediatric heart surgery: is aggressive plication of the diaphragm beneficial? AB - OBJECTIVES: Phrenic nerve injury after paediatric heart surgery is associated with significant morbidity. Surgical plication of the diaphragm is believed to be beneficial to the patient, with difficult weaning from ventilation; however, the optimal timing remains unclear. We aimed to compare the outcome after two different strategies for treating hemidiaphragmatic paresis. METHODS: A retrospective analysis of all patients with paresis of the diaphragm between 2000 and 2010 was performed, with special attention to the rate of reintubations, ventilation and intensive care unit (ICU) stay and the rate of plication. In 2005, the strategy for treating diaphragmatic paresis in our institution changed from conservative treatment with plication after multiple extubation efforts towards an aggressive one with plication after a single unsuccessful extubation. We compared the outcome of all patients and that of the newborns separately from the two periods. RESULTS: During the study period, 148 patients with diaphragmatic paresis were diagnosed and included. Median age at the cardiac operation was 7 months (1 day-18 years), ventilation time ranged from 4 h to 41 days (median 7 days), 42 (28.4%) of the patients required at least one reintubation and ICU stay ranged from 2 to 63 days (median 11 days). A total of 63 plications were performed-5 (9%) before 2004 and 58 (62%) after 2005, P < 0.001. There were no significant differences in the ventilation time-6 (1-40) vs 8 (0-41) days, P = 0.36, reintubation rate-28 vs 29%, P = 0.85 and ICU stay-10 (3 63) vs 12 (2-55) days, P = 0.41 between both groups. The newborn patients, treated with the different strategies, also did not differ significantly in their outcome: ventilation time-12 (2-40) vs 11.5 (3-34) days, P = 0.38; reintubation rate-43 vs 41%, P = 0.62; ICU stay-16 (6-63) vs 15 (7-55) days, P = 0.55. CONCLUSIONS: Changing the strategy for phrenic nerve injury after paediatric heart surgery towards a more aggressive one with early plication of the diaphragm was not associated with the better outcome. Prospective randomized studies are needed to determine the optimal management of this complication. PMID- 23456015 TI - Prognostic and predictive value of serum vascular endothelial growth factor (VEGF) in squamous cell carcinoma of the head and neck. AB - INTRODUCTION: This study aimed to investigate the prognostic and predictive value of serum vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinoma (HNSCC). METHOD: Preoperative and 6-month postoperative serum VEGF levels were measured using a quantitative sandwich enzyme immunoassay technique in 55 consecutive patients with HNSCC and two control groups. The first control group included normal, healthy, age- and sex-matched individuals (n = 20), while the second control group included the patients who had history of HNSCC and were free of disease for at least 5 years (n = 25). RESULTS: The mean baseline serum VEGF concentrations of the 55 patients with HNSCC and the first and the second control groups were 437.86, 42.56, and 48.03 pg/ml, respectively (P < 0.001). After a median follow-up of 75 months, 15 patients of the study group developed recurrent disease and 40 patients remained free of disease. The mean preoperative and 6-month postoperative serum VEGF levels for the 40 patients who did not have recurrent disease were respectively 327.69 and 153.50 pg/ml compared to 731.72 and 692.96 pg/ml for the 15 patients with recurrent disease (P < 0.001). High (>=540 pg/ml) serum VEGF level was associated with poor overall survival (P < 0.001). Moreover, multivariate analysis showed node stage (P < 0.001) and preoperative serum VEGF level (P = 0.020) as significant, independent prognostic factors for overall survival. CONCLUSION: Preoperative or postoperative elevated serum levels of VEGF are highly predictive for disease recurrence and are associated with poor disease-free and overall survival of patients with HNSCC. PMID- 23456016 TI - Can patients return to high-impact physical activities after hip resurfacing? A prospective study. AB - PURPOSE: Although the resumption of low-impact sports activities is compatible with total hip arthroplasty (THA), participation in high-impact sports seems problematic, and there is no consensus as to whether it is advisable. The purpose of this article is to evaluate the quality and possibility of resuming high impact physical activities after hip resurfacing. MATERIALS: The study was performed in an on-going, single-surgeon, prospective series of 215 resurfacing arthroplasties (RSA). Mean follow-up was 44.1 months (range, 39.1-54.5). Clinical evaluation included the Postel-Merle d'Aubigne (PMA) score, the Oxford hip score, the Harris hip score (HHS), Devane score, and UCLA activity score. A specific questionnaire analysing sports activities was administered to each patient to assess the number and level of physical activities performed (both before the operation and at final follow-up). RESULTS: In the series of 202 consecutive patients (215 RSA), 50 patients (55 RSA) engaged regularly in at least one high impact activity before their operation and the onset of pain, 102 patients practised at least one intermediate-impact activity, and the 50 remaining patients undertook only low-impact activities. Harris hip score increased from 44.8 (range, 23-68) before the operation to 97.8 (range, 85-100) at the last follow-up. Mean time to sports resumption after surgery was 14.6 weeks (range, 7 29). The resumption rate was 98 % for sports of any impact level and 82 % for high-impact activities. No osteolysis or implant loosening was observed at follow up. No revision was performed. CONCLUSION: In 2012, no consensus recommendations yet exist for the resumption of sports activities after RSA. Existing recommendations concern only conventional THA. We believe that RSA allows younger and more active patients to resume physical and sports activities without restriction. The rate of return to sports after RSA appears to be excellent and unequalled by conventional hip prostheses. High-impact sports seem to be compatible with hip resurfacing, although no long-term studies have analysed the impact of these activities on wear and/or aseptic loosening. PMID- 23456017 TI - Biomechanical comparison of different fixation techniques for reconstruction of tibial avulsion fractures of the anterior cruciate ligament. AB - PURPOSE: The most common fixation techniques for tibial avulsion fractures of the anterior cruciate ligament (ACL) described in the literature are screw and suture fixation. The fixation of these fractures with the TightRope(r) device might be an alternative. Up to now it has been commonly used in other injuries, such as acromioclavicular joint or syndesmosis ruptures. The purpose of this study was to evaluate the biomechanical properties of different fixation techniques for the reconstruction of tibial avulsion fractures. METHODS: Type III tibial avulsion fractures were simulated in 40 porcine knees. Each specimen was randomly assigned to one of four groups: (1) anterograde screw fixation, (2) suture fixation, (3) TightRope(r) fixation or (4) control group. The initial displacement, strength to failure and the failure mode were documented. RESULTS: The maximum load to failure was 1,345 +/- 155.5 N for the control group, 402.5 +/- 117.6 N for the TightRope(r) group, 367 +/- 115.8 N for the suture group and 311.7 +/- 120.3 N for the screw group. The maximum load to failure of the control group was significantly larger compared to all other groups. The initial dislocation was 0.28 +/- 0.09 mm for the control group, 0.55 +/- 0.26 mm for the TightRope(r) group, 0.84 +/- 0.15 mm for the screw group and 1.14 +/- 0.9 mm for the suture group. The initial dislocation was significantly larger for the suture group compared to the TightRope(r) and control groups. CONCLUSIONS: The TightRope(r) fixation shows significantly lower initial displacement compared to the suture group. The TightRope(r) fixation might be an alternative for the repair of ACL tibial avulsion fractures that can be used arthroscopically. PMID- 23456018 TI - Use of patient-specific templates in hip resurfacing arthroplasty: experience from sixteen cases. AB - PURPOSE: Hip resurfacing arthroplasty (HRA) is a technically demanding operation, requiring both accuracy and precision in placement of the acetabular and femoral components. Malalignment of the component can lead to notching and possible femoral neck fractures. We used specific templates created using a rapid prototyping machine based on the patients' anatomy, to aid in accurate intraoperative pin placement. METHODS: A 3D model of the hip was reconstructed using spiral computed tomography (CT) data by Amira 3.1 software in 16 patients in whom HRA was planned for hip osteoarthritis (OA). All of the patients in the study had normal contralateral hips. The rotational centre of femoral head on the normal side was superimposed using Imageware12.0 software to determine the centre of the femoral head on the contralateral side. The data was then used to produce patient-specific templates using a rapid prototyping technique. These templates were designed according to the anatomical features of femoral head surface, the rotation centre and the planned prosthesis shaft angle. The orientation of the prosthesis was determined by matching the model to the femoral head surface during the operation. In addition, a control group of 18 patients with OA was operated upon by the conventional method. RESULTS: The mean prosthesis stem shaft angle (SSA), as determined from postoperative imaging, was 138.68 +/- 8.85 degrees for the locating template group, and (118.9 +/- 12.8) for the conventional group. CONCLUSIONS: The locating template designed and constructed preoperatively can provide precise and dependable location for hip resurfacing femoral components during arthroplasty and ensure the valgus stem placement necessary for optimal outcomes. PMID- 23456019 TI - Evaluation of Cam-type femoroacetabular impingement by ultrasound. AB - PURPOSE: In the diagnosis of femoroacetabular impingement (FAI), magnetic resonance imaging (MRI) and X-ray are widely accepted methods for detection. When evaluating the hip head-neck junction using MRI, oblique axial sequences are required. However, the construction and analysis of these images are restricted to specialist radiologists and surgeons in the field of hip joint MRI. This study sought to investigate whether ultrasound, a simple and inexpensive method, can be used as a reliable tool for diagnosing Cam-type FAI. METHODS: Forty patients, with a mean age of 39 years (range, 18-61 years), were consecutively included in this prospective study, following a diagnosis of Cam-type FAI on an oblique axial MRI. All patients underwent ultrasound examination in the ventral longitudinal section at 20 degrees external rotation, neutral position and 20 degrees internal rotation. The alpha angle, anterior offset, offset-ratio, and anterior femoral distance (AFD) were measured using MRI and ultrasound. RESULTS: No significant differences were detected between the alpha angle on MRI and that using ultrasound in the neutral position or in 20 degrees internal rotation, with strong correlations observed between these parameters (r = 0.67 for neutral position, r = 0.77 for 20 degrees internal rotation). The Pearson's correlation coefficient for the alpha angle on MRI and the ratio of AFD/anterior offset on ultrasound in internal rotation was 0.76 (p < 0.0001). CONCLUSIONS: The results show strong correlations between MRI and ultrasound measurements in patients with Cam-type FAI. Consequently, ultrasound may provide a useful tool for the early diagnosis of Cam-type FAI in daily practice. PMID- 23456020 TI - The damages of high intensity focused ultrasound to transplanted hydatid cysts in abdominal cavities of rabbits with aids of ultrasound contrast agent and superabsorbent polymer. AB - The present study investigates the damages of high intensity focused ultrasound (HIFU) to transplanted hydatid cysts in abdominal cavities of rabbits with aids of ultrasound contrast agent (UCA) and superabsorbent polymer (SAP) alone or in combination. A rabbit model with transplanted hydatid cyst was established by implanting hydatid cyst isolated from infected sheep liver, and HIFU was used to ablate the transplanted cysts with the aid of UCA and SAP alone or in combination. The hydatid cyst with thin wall, good elasticity, approximately spherical, and a diameter of approximately 30 mm was selected for the following experiments. According to our previous studies, a mixture of 0.1 g SAP and 0.5 ml anhydrous ethanol, and the solution of 0.1 ml UCA SonoVue, or both materials were injected into different cyst before HIFU ablation, respectively. The cyst inoculated with the SAP and UCA alone or in combination was immediately implanted into the abdominal cavity of rabbit for HIFU ablation at a dosage of 100 W acoustic powers. The ablation mode was spot scanning at the speed of 3 mm/s. Every target point was scanned three times; every ablating time lasted 3 s. The distance of each ablated layer was 5 mm. The total ablation time depended on the volume of cyst. The comparison of ultrasound image for each layer of hydatid cyst was made before and after HIFU ablation. The protoscolices in ablated cysts were stained by trypan blue exclusion assay, and their structures were observed by light microscopy. To estimate ablation effects of HIFU to the walls of hydatid cysts, the ultrastructure changes of cyst walls were examined by electron microscopy. The pathological changes of rabbits' skins through which ultrasound penetrated were observed to investigate the side effects of HIFU ablation. The results demonstrated that HIFU had some lethal effects to hydatid cysts in vivo, namely, echo enhancements of ultrasound images of cysts, increases in mortality rate of protoscolices from 15.19 % (HIFU alone) to 48.66 % (HIFU + SAP), 38.67 % (HIFU + UCA), and 67.75 % (HIFU + SAP + UCA), respectively, serious structural damages of protoscolices, and destructions or even disappearance of laminated layers and germinal layers in the walls of hydatid cysts ablated by HIFU aided with UCA and SAP alone or in combination. This study demonstrated that destructive effects of HIFU to transplanted hydatid cyst could be enhanced by UCA and SAP alone, but the destruction of HIFU aided with a combination of UCA and SAP to hydatid cysts was more effective than those aided with UCA or SAP alone. The enhanced thermal and cavitation effects of HIFU induced by UCA and SAP might be involved in the enhanced destructive effects of HIFU on hydatid cysts. There were no evidences of pathological changes on rabbits' skins overlying the hydatid cysts after HIFU ablation. The results suggested that the rabbit model with transplanted hydatid cyst may serve as an optional animal model for the experiments of HIFU ablation to hydatid cyst in vivo, and the materials of UCA and SAP were proved as enhancing agents of HIFU ablation to hydatid cysts, and HIFU at a dosage of 100 W acoustic powers was a safe and feasible parameter to ablate the hydatid cysts in this special animal model. These results laid a theoretical foundation for improving HIFU therapy for cystic echinococcosis by inoculation of UCA and SAP into hydatid cysts. PMID- 23456021 TI - Hidden haemosporidian infections in Ruffs (Philomachus pugnax) staging in Northwest Europe en route from Africa to Arctic Europe. AB - In their African freshwater wintering habitats, shorebirds show a high prevalence of blood parasites, whereas no parasites are detected elsewhere along the migration route. We looked at two genera of haemosporidian parasites, Haemoproteus and Plasmodium, in the long-distance migrating Ruff (Philomachus pugnax) along a geographical/seasonal gradient to verify the infection pattern and examine possible hidden organ infections at European staging areas. We amplified parasite DNA from blood of 53 healthy birds wintering in Mali, 53 samples of seven organ tissues (spleen, liver, kidneys, heart, lungs, brain, and pectoral muscle) from healthy individuals caught during spring migration, and 18 weak birds found sick in summer in The Netherlands. We confirm that Ruffs wintering in Africa carried blood infections and that some infections developed into hidden organ infections during spring migration. Moreover, sick birds either had new infections (in one juvenile) or relapses (in an adult harboring an African lineage). Our results suggest that some parasites develop latency. This strategy may be beneficial for the parasite as it may take control over reappearance in the blood to help further transmission. PMID- 23456022 TI - A redescription of Haemogregarina damiettae Ramadan et al. 1996 naturally infecting the Acanthodactylus boskianus from Egypt, with new merognic data. AB - Haemogregarina damiettae was previously described form Acanthodactylus boskianus in Egypt, and the description was base only on the blood stages with no data on the tissue stages. In the present study, both blood and tissue stages were encountered. The prevalence of infection was found to be 60 % (30/50). The blood stages were found to be confined to the erythrocytes and none in the leucocytes. The erythrocytic stages could be differentiated into small and large forms. The small form, trophozoite, measured 10 * 3 MUm, while the large form, mature gamontocyte, measured 18 * 5 MUm. The cytoplasm of the mature gamontocyte was finely granular and faintly stained with Giemsa, while the nucleus was relatively large and occupied about one third of the body length and was formed of a network of chromatin filaments. Infected erythrocytes were hypertrophied and their nuclei either longitudinally stretched or split into two fragments. The tissue stages were observed in the lungs and hearts of the infected lizards. The merogonic stages were evident as multinucleated ovoid to subspherical bodies enclosed by parasitophorous vacuoles. Mature meronts measured 16 * 12 MUm and estimated to produce 15-25 merozoites. PMID- 23456023 TI - Resistance to new chemical insecticides in the house fly, Musca domestica L., from dairies in Punjab, Pakistan. AB - The house fly, Musca domestica L., is one of the major pests in dairy operations that has developed resistance to a number of insecticides with different modes of action. Adult house fly populations from six dairies in Punjab, Pakistan were evaluated for resistance to insecticides with novel modes of action (abamectin, emamectin benzoate, fipronil, imidacloprid, indoxacarb, and spinosad). Significant levels of resistance to most of the insecticides tested were observed in the present study. For avermectins at LC50 level, the resistance ratios were in the range of 38.40 to 94.44-fold for abamectin and 13.16 to 36.30-fold for emamectin benzoate. Fipronil LC50 resistance ratios exceeded 10-fold in three house fly populations, while all the populations had >10-fold resistance ratios for imidacloprid. Indoxacarb and spinosad had the lowest resistance ratios that ranged from 3.02 to 7.12-fold for indoxacarb and 2.91 to 9.0-fold for spinosad. As the resistance to fipronil, indoxacarb, and spinosad are emerging, therefore these chemicals should be used cautiously in management programs to retain the efficacy for longer times. PMID- 23456024 TI - Norman Geschwind (1926-1984). PMID- 23456025 TI - An algorithm for candidate sequencing in non-dystrophic skeletal muscle channelopathies. AB - Human skeletal muscle channelopathies (HSMCs) are a group of heritable conditions with ion channel-related etiology and similar presentation. To create a comprehensive picture of the phenotypic spectrum for each condition and to devise a strategy that facilitates the differential diagnosis, we collected the genotype and phenotype information from more than 500 previously published HSMC studies. Using these records, we were able to identify clear correlations between particular clinical features and the underlying alteration(s) in the genes SCN4A, CACNA1S, KCNJ2, and CLCN1. This allowed us to develop a clinical, symptom-based, binary decision flow algorithm that predicts the proper genetic origin with high accuracy (0.88-0.93). The algorithm was implemented in a stand-alone online tool ("CGPS"- http://cgps.ddd.co.kr ) to assist with HSCM diagnosis in the clinical practice. The CGPS provides simple, symptom-oriented navigation that guides the user to the most likely molecular basis of the presentation, which permits highly targeted genetic screens and, upon confirmation, tailored pharmacotherapy based on the molecular origin. PMID- 23456026 TI - Electrical neurocoagulation may be effective for intractable trigeminal neuralgia caused by vertebrobasilar dolichoectasia. PMID- 23456028 TI - Identifying scoliosis in population-based cohorts: development and validation of a novel method based on total-body dual-energy x-ray absorptiometric scans. AB - The purpose of this study was to develop and validate a novel method of identifying scoliosis on total-body dual energy X-ray absorptiometric (DXA) scans. Scoliosis was identified on total-body DXA scans by triaging to distinguish true curves from positioning errors, followed by a modified Ferguson method to measure angles. Precision was assessed on 174 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), who underwent repeat DXA scans at age 15, 2-6 weeks apart. In addition, precision of angle estimation was evaluated on 20 scans measured five times. To evaluate accuracy, angle size was compared to spinal radiographs in 13 individuals with known scoliosis. Subsequently, this method was applied to estimate scoliosis prevalence rates and curve patterns from DXA scans previously obtained in 7,298 ALSPAC participants at age 9 and 5,122 at age 15. There was substantial agreement in identifying those with scoliosis on repeat DXA scans taken 2-6 weeks apart (kappa 0.74, 95 % CI 0.59-0.89). Of repeat angle measures, 95 % were within 5 degrees . Angle size was underestimated by approximately 40 %. Prevalence of scoliosis >=10 degrees in the ALSPAC was 0.3 % at age 9 and 3.5 % at age 15 and was higher in girls at both time points. The mean +/- SD curve size was 12 +/- 4 degrees at age 9 years and 15 +/- 7 degrees at age 15. We have developed and validated a novel method for identifying scoliosis from DXA scans. Comparison with prevalence data using more established techniques suggests our method provides valid estimates of scoliosis prevalence in population-based cohorts. PMID- 23456027 TI - Vascular calcification: an update on mechanisms and challenges in treatment. AB - Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high-risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a nonocclusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification are also reviewed. PMID- 23456030 TI - An alternative position for the BIS-Vista montage in frontal approach neurosurgical cases. AB - BACKGROUND: Appropriate placement of the bispectral index (BIS)-vista montage for frontal approach neurosurgical procedures is a neuromonitoring challenge. The standard bifrontal application interferes with the operative field; yet to date, no other placements have demonstrated good agreement. The purpose of our study was to compare the standard BIS montage with an alternate BIS montage across the nasal dorsum for neuromonitoring. MATERIALS AND METHODS: The authors performed a prospective study, enrolling patients and performing neuromonitoring using both the standard and the alternative montage on each patient. Data from the 2 placements were compared and analyzed using a Bland-Altman analysis, a Scatter plot analysis, and a matched-pair analysis. RESULTS: Overall, 2567 minutes of data from each montage was collected on 28 subjects. Comparing the overall difference in score, the alternate BIS montage score was, on average, 2.0 (6.2) greater than the standard BIS montage score (P<0.0001). The Bland-Altman analysis revealed a difference in score of -2.0 (95% confidence interval, -14.1, 10.1), with 108/2567 (4.2%) of the values lying outside of the limit of agreement. The scatter plot analysis overall produced a trend line with the equation y=0.94x+0.82, with an R coefficient of 0.82. CONCLUSIONS: We determined that the nasal montage produces values that have slightly more variability compared with that ideally desired, but the variability is not clinically significant. In cases where the standard BIS-vista montage would interfere with the operative field, an alternative positioning of the BIS montage across the nasal bridge and under the eye can be used. PMID- 23456031 TI - Postischemic sevoflurane offers no additional neuroprotective benefit to preischemic dexmedetomidine. AB - BACKGROUND: We designed this study to determine whether a combination of dexmedetomidine and sevoflurane postconditioning provides additive neuroprotection in a rat model of transient global cerebral ischemia. METHODS: Forty rats were randomly allocated to 4 groups. Control group (group C, n=10) received no treatment. Dexmedetomidine group (group D, n=10) received dexmedetomidine of 100 MUg/kg intraperitoneally 30 minutes before ischemia. Sevoflurane postconditioning group (group P, n=10) underwent 2 sevoflurane inhalations after ischemia. Each inhalation consisted of 5 minutes of 2.5% sevoflurane and a subsequent washout time of 10 minutes. Sevoflurane postconditioning plus dexmedetomidine group (group PD, n=10) received received dexmedetomidine and 2 sevoflurane inhalations 30 minutes before ischemia and after ischemia, respectively. In all the groups, ischemia was induced by a bilateral common carotid artery occlusion plus hemorrhagic hypotension and was maintained for 8 minutes. Histologic outcomes and apoptosis-related proteins were measured 7 days after ischemia in the CA1 area of the rat hippocampus. RESULTS: Groups D, P, and PD contained more viable cells and less apoptotic cells in the hippocampal CA1 area than group C (P<0.01). There was a significant difference in the Bax and Bcl-2 expression between group C and other groups (P<0.05). But the number of viable and apoptotic cells, and the Bax and Bcl-2 expression were not statistically different between group D or P and group PD. CONCLUSIONS: A combination of preischemic dexmedetomidine and sevoflurane postconditioning provides no additional neuroprotective benefit over preischemic dexmedetomidine or sevoflurane postconditioning alone. PMID- 23456032 TI - Isolated bradycardia due to skull pin fixation: raised ICP or TCR? PMID- 23456033 TI - In reply. PMID- 23456034 TI - Cervical spinal cord AVM rupture in parturient. PMID- 23456035 TI - Report on SNACC's 40th anniversary meeting. PMID- 23456036 TI - Elevated amyloid-beta plaque deposition in dietary selenium-deficient Tg2576 transgenic mice. AB - Selenium-containing proteins (e.g., glutathione peroxidases) are important antioxidants in neuronal defense against oxidative stress. In this study, the production of amyloid-beta (Abeta) plaques in the brain of the Tg2576 transgenic mice was investigated under dietary selenium-deficient conditions. The 16-week old mice were fed a selenium-deficient diet (0.004 MUg-selenium g(-1)-diet) or a selenium-adequate diet (0.386 MUg-selenium g(-1) diet) for 76 weeks. The selenium concentrations of the organs/tissues in the selenium-deficient diet-fed mice were significantly decreased in comparison to those in the selenium-adequate diet-fed mice; 1.7% of that in the selenium-adequate diet-fed mice in the liver and 43% of that in the selenium-adequate diet-fed mice in the brain. The Abeta plaques formed in the brain were fluorescently stained with thioflavin T, and then the obtained images of the brain slices were qualitatively analyzed. The feeding of the selenium-deficient diet to the Tg2576 transgenic mice resulted in more than a two-fold increase in the total area of the Abeta plaques in comparison to that of the selenium-adequate diet. The elevated Abeta plaque deposition in the selenium deficient mice can be explained as a consequence of decrease in the selenium concentration, which suggests that the selenium status is associated with the production and/or the clearance of the Abeta peptide. The selenium-deficiency could possibly promote the onset and/or progression of Alzheimer's disease (AD) dementia, if the Abeta peptides initiate a sequence of events that lead to AD dementia. Consequently, the results shown here suggest that AD has an important relation with the selenium status in vivo. PMID- 23456037 TI - Recent advances in isocyanide insertion chemistry. AB - As valuable C1 building blocks, isocyanides represent an important class of reactive species and synthons. During the past decades, exhaustive efforts have been devoted to the discovery of highly efficient reactions involving isocyanide on the basis of the development of the Passerini and Ugi reactions. Several types of reactions involving isocyanides have been reported, such as nucleophilic attack, electrophilic addition, imidoylation reactions, and oxidation etc. In this review, recent progress in isocyanide insertion chemistry is presented. Among all isocyanide insertions, two catalytic systems have been developed, that is, Lewis (Bronsted) acid-catalyzed isocyanide insertions and transition-metal enabled isocyanide insertions, respectively. This review is hence written in the sequence of Lewis (Bronsted) acid-catalyzed isocyanide insertion and transitional metal-enabled isocyanide insertion, where isocyanide insertion into heteroatom hydrogen bonds, carbon-halogen bonds, carbon-hydrogen bonds, and metal carbenes are summarized. PMID- 23456038 TI - Unraveling a phosphorylation event in a folded protein by NMR spectroscopy: phosphorylation of the Pin1 WW domain by PKA. AB - The Pin1 protein plays a critical role in the functional regulation of the hyperphosphorylated neuronal Tau protein in Alzheimer's disease and is by itself regulated by phosphorylation. We have used Nuclear Magnetic Resonance (NMR) spectroscopy to both identify the PKA phosphorylation site in the Pin1 WW domain and investigate the functional consequences of this phosphorylation. Detection and identification of phosphorylation on serine/threonine residues in a globular protein, while mostly occurring in solvent-exposed flexible loops, does not lead to chemical shift changes as obvious as in disordered proteins and hence does not necessarily shift the resonances outside the spectrum of the folded protein. Other complications were encountered to characterize the extent of the phosphorylation, as part of the (1)H,(15)N amide resonances around the phosphorylation site are specifically broadened in the unphosphorylated state. Despite these obstacles, NMR spectroscopy was an efficient tool to confirm phosphorylation on S16 of the WW domain and to quantify the level of phosphorylation. Based on this analytical characterization, we show that WW phosphorylation on S16 abolishes its binding capacity to a phosphorylated Tau peptide. A reduced conformational heterogeneity and flexibility of the phospho binding loop upon S16 phosphorylation could account for part of the decreased affinity for its phosphorylated partner. Additionally, a structural model of the phospho-WW obtained by molecular dynamics simulation and energy minimization suggests that the phosphate moiety of phospho-S16 could compete with the phospho substrate. PMID- 23456039 TI - Nmrglue: an open source Python package for the analysis of multidimensional NMR data. AB - Nmrglue, an open source Python package for working with multidimensional NMR data, is described. When used in combination with other Python scientific libraries, nmrglue provides a highly flexible and robust environment for spectral processing, analysis and visualization and includes a number of common utilities such as linear prediction, peak picking and lineshape fitting. The package also enables existing NMR software programs to be readily tied together, currently facilitating the reading, writing and conversion of data stored in Bruker, Agilent/Varian, NMRPipe, Sparky, SIMPSON, and Rowland NMR Toolkit file formats. In addition to standard applications, the versatility offered by nmrglue makes the package particularly suitable for tasks that include manipulating raw spectrometer data files, automated quantitative analysis of multidimensional NMR spectra with irregular lineshapes such as those frequently encountered in the context of biomacromolecular solid-state NMR, and rapid implementation and development of unconventional data processing methods such as covariance NMR and other non-Fourier approaches. Detailed documentation, install files and source code for nmrglue are freely available at http://nmrglue.com. The source code can be redistributed and modified under the New BSD license. PMID- 23456040 TI - Evidence of a heterogeneous tissue oxygenation: renal ischemia/reperfusion injury in a large animal model. AB - Renal ischemia that occurs intraoperatively during procedures requiring clamping of the renal artery (such as renal procurement for transplantation and partial nephrectomy for renal cancer) is known to have a significant impact on the viability of that kidney. To better understand the dynamics of intraoperative renal ischemia and recovery of renal oxygenation during reperfusion, a visible reflectance imaging system (VRIS) was developed to measure renal oxygenation during renal artery clamping in both cooled and warm porcine kidneys. For all kidneys, normothermic and hypothermic, visible reflectance imaging demonstrated a spatially distinct decrease in the relative oxy-hemoglobin concentration (%HbO2) of the superior pole of the kidney compared to the middle or inferior pole. Mean relative oxy-hemoglobin concentrations decrease more significantly during ischemia for normothermic kidneys compared to hypothermic kidneys. VRIS may be broadly applicable to provide an indicator of organ ischemia during open and laparoscopic procedures. PMID- 23456041 TI - [MR-guided focused ultrasound. Current and future applications]. AB - STANDARD RADIOLOGICAL METHODS: High-intensity focused ultrasound (synonyms FUS and HIFU) under magnetic resonance imaging (MRI) guidance (synonyms MRgFUS and MR HIFU) is a completely non-invasive technology for accurate thermal ablation of a target tissue while neighboring tissues and organs are preserved. METHODICAL INNOVATIONS: The combination of FUS with MRI for planning, (near) real-time monitoring and outcome assessment of treatment markedly enhances the safety of the procedure. ACHIEVEMENTS: The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier. PMID- 23456042 TI - [Arterial closure devices. What device for which clinical situation?]. AB - CLINICAL/METHODICAL ISSUE: Access site complications after endovascular catheterization sometimes require open surgery and negatively impair safety, patient comfort and reimbursement. Increasing numbers of procedures and patients with multiple anticoagulants as well as cost pressure explain the demand for an immediate and stable access site closure. STANDARD RADIOLOGICAL METHODS: Manual compression followed by compression bandage and bed rest for 4-24 h is still the gold standard but is unable to prevent access site complications in all cases. METHODICAL INNOVATIONS: Arterial vascular closure devices allow immediate and stable closure of the puncture channel either by suture or by implantation of occluding foreign bodies or gluing fluids. PERFORMANCE: The safety has been proven in several clinical trials. The main advantage lies in closing large lumen access sites without surgery and in patients treated with multiple anticoagulants as well as in outpatient procedures. ACHIEVEMENTS: They have become a valuable supplement to the interventional arsenal. PRACTICAL RECOMMENDATIONS: The physician, however, has to decide between different systems and mechanisms with respect to patient constitution, selected access vessel and level of calcification and diameter. Furthermore, all systems require a defined training prior the first use. PMID- 23456043 TI - [Irreversible image compression in radiology. Current status]. AB - Due to increasing amounts of data in radiology methods for image compression appear both economically and technically interesting. Irreversible image compression allows markedly higher reduction of data volume in comparison with reversible compression algorithms but is, however, accompanied by a certain amount of mathematical and visual loss of information. Various national and international radiological societies have published recommendations for the use of irreversible image compression. The degree of acceptable compression varies across modalities and regions of interest.The DICOM standard supports JPEG, which achieves compression through tiling, DCT/DWT and quantization. Although mathematical loss due to rounding up errors and reduction of high frequency information occurs this results in relatively low visual degradation.It is still unclear where to implement irreversible compression in the radiological workflow as only few studies analyzed the impact of irreversible compression on specialized image postprocessing. As long as this is within the limits recommended by the German Radiological Society irreversible image compression could be implemented directly at the imaging modality as it would comply with S 28 of the roentgen act (RoV). PMID- 23456044 TI - Bacterial toxins: Exposing the exporter. PMID- 23456046 TI - Microbial physiology: Optimal codons break the clock's rhythm. PMID- 23456045 TI - Competition sensing: the social side of bacterial stress responses. AB - The field of ecology has long recognized two types of competition: exploitative competition, which occurs indirectly through resource consumption, and interference competition, whereby one individual directly harms another. Here, we argue that these two forms of competition have played a dominant role in the evolution of bacterial regulatory networks. In particular, we argue that several of the major bacterial stress responses detect ecological competition by sensing nutrient limitation (exploitative competition) or direct cell damage (interference competition). We call this competition sensing: a physiological response that detects harm caused by other cells and that evolved, at least in part, for that purpose. A key prediction of our hypothesis is that bacteria will counter-attack when they sense ecological competition but not when they sense abiotic stress. In support of this hypothesis, we show that bacteriocins and antibiotics are frequently upregulated by stress responses to nutrient limitation and cell damage but very rarely upregulated by stress responses to heat or osmotic stress, which typically are not competition related. We argue that stress responses, in combination with the various mechanisms that sense secretions, enable bacteria to infer the presence of ecological competition and navigate the 'microbe-kill-microbe' world in which they live. PMID- 23456047 TI - Bacterial virulence: HopU1 puts a stop to immune signalling. PMID- 23456048 TI - Burns, hypertrophic scar and galactorrhea. AB - An 18-year-old woman was admitted to Motahari Burn Center suffering from 30% burns. Treatment modalities were carried out for the patient and she was discharged after 20 days. Three to four months later she developed hypertrophic scar on her chest and upper limbs. At the same time she developed galactorrhea in both breasts and had a disturbed menstrual cycle four months post-burn. On investigation, we found hyperprolactinemia and no other reasons for the high level of prolactin were detected.She received treatment for both the hypertrophic scar and the severe itching she was experiencing. After seven months, her prolactin level had decreased but had not returned to the normal level. It seems that refractory hypertrophic scar is related to the high level of prolactin in burns patients. PMID- 23456050 TI - Exploiting spatial sparsity for multiwavelength imaging in optical interferometry. AB - Optical interferometers provide multiple wavelength measurements. In order to fully exploit the spectral and spatial resolution of these instruments, new algorithms for image reconstruction have to be developed. Early attempts to deal with multichromatic interferometric data have consisted in recovering a gray image of the object or independent monochromatic images in some spectral bandwidths. The main challenge is now to recover the full three-dimensional (spatiospectral) brightness distribution of the astronomical target given all the available data. We describe an approach to implement multiwavelength image reconstruction in the case where the observed scene is a collection of point-like sources. We show the gain in image quality (both spatially and spectrally) achieved by globally taking into account all the data instead of dealing with independent spectral slices. This is achieved thanks to a regularization that favors spatial sparsity and spectral grouping of the sources. Since the objective function is not differentiable, we had to develop a specialized optimization algorithm that also accounts for non-negativity of the brightness distribution. PMID- 23456049 TI - 1/lambda4 scattering of light during the drying process in porous Vycor glass with nano-sized pores. AB - Porous Vycor glass with nano-sized pores is transparent in the visible region and is often used in colorimetric chemical sensing, when it is impregnated with selectively reacting reagents. However, it has some disadvantages in its use, since changes in the humidity of ambient air strongly affect the transmission. In this work, we analyzed the transparency change during the drying process to correlate the turbidity of the glass with the amount of water in it. The transparency change in the visible region takes place for the duration of the drying and is found to be dependent on the inverse 4th power of the wavelength (1/lambda(4)), which implies that Rayleigh-type scattering takes place during the drying process. Based on the above observation, it is shown that the transitory white turbidity of nanoporous glasses during the drying process can be interpreted consistently and quantitatively analyzed by a simple Rayleigh scattering mechanism. PMID- 23456051 TI - Experimental determination of the radius of curvature of an isotropic Gaussian Schell-model beam. AB - We propose a method to determine the radius of curvature of an isotropic Gaussian Schell-model (GSM) beam by measuring the transverse beam widths and the transverse coherence widths at two different planes. Furthermore, we carry out experimental determination of the radius of curvature of a GSM beam. Using the measured beam parameters, we carry out a comparative study of the propagation properties of a GSM beam both theoretically and experimentally. Our experimental results agree well with theoretical predictions. PMID- 23456052 TI - Wavefronts, caustics, and ronchigrams of a spherical wave reflected by a spherical mirror. AB - The aim of the present work is twofold: first we obtain analytical expressions for both the wavefronts and the caustic associated with the light rays reflected by a spherical mirror after being emitted by a point light source located at an arbitrary position in free space, and second, we describe, in detail, the structure of the ronchigrams when the grating or Ronchi ruling is placed at different relative positions to the caustic region and the point light source is located on and off the optical axis. We find that, in general, the caustic has two branches: one is a segment of a line, and the other is a two-dimensional surface. The wavefronts, at the caustic region, have self intersections and singularities. The ronchigrams exhibit closed-loop fringes when the grating is placed at the caustic region. PMID- 23456053 TI - Toraldo filters with concentric unequal annuli of fixed phase by evolutionary programming. AB - The resolving power of an optical imaging system is limited by residual aberrations and diffraction effects. The Rayleigh-Abbe diffraction limit of resolution corresponds to radius of the central lobe of the point spread function of an aberration free diffraction limited system. An attempt to circumvent this limitation was proposed by Toraldo di Francia, who showed that suitable pupil plane filtering can overcome this resolution limit, albeit over a restricted field. This paper reports results of our investigations on the use of evolutionary programming to obtain globally or quasi-globally optimum solutions in synthesis of lossless Toraldo filters consisting of concentric unequal area zones of fixed phase. PMID- 23456054 TI - Oblique electromagnetic scattering from lossless or lossy composite elliptical dielectric cylinders. AB - The oblique electromagnetic scattering by a dielectric elliptical cylinder which is coated eccentrically by a nonconfocal dielectric elliptical cylinder is examined in this work. The problem is solved using the separation of variables in terms of Mathieu functions, in combination with the addition theorem for Mathieu functions, a complicated procedure due to the following three factors: the nonexistence of the orthogonality relations for Mathieu functions due to the different constitutive parameters between the two cylinders and the background medium, the complex expressions due to the oblique incidence that leads to hybrid waves for both the scattered and induced fields, and the use of the addition theorem, which introduces a cross relation between even and odd terms. The method described here is exact, its solution is validated compared with other published results from the literature, and the high accuracy is revealed. Both polarizations are examined and numerical results are given for the scattering cross sections, including lossless and lossy materials. PMID- 23456055 TI - Spectral BRDF-based determination of proper measurement geometries to characterize color shift of special effect coatings. AB - A reduced set of measurement geometries allows the spectral reflectance of special effect coatings to be predicted for any other geometry. A physical model based on flake-related parameters has been used to determine nonredundant measurement geometries for the complete description of the spectral bidirectional reflectance distribution function (BRDF). The analysis of experimental spectral BRDF was carried out by means of principal component analysis. From this analysis, a set of nine measurement geometries was proposed to characterize special effect coatings. It was shown that, for two different special effect coatings, these geometries provide a good prediction of their complete color shift. PMID- 23456056 TI - Diffraction of an optical pulse as an expansion in ultrashort orthogonal Gaussian beam modes. AB - The Laguerre-Gaussian (LG) beam expansion is described as a numerical and physical model of paraxial ultrashort pulse diffraction in the time domain. An overview of the dynamics of higher-order ultrashort planar LG modes is given through numerical simulations, and the finite width of these beams is shown to induce a dispersive-like axial broadening of the fields, which creates related variations in the on-axis amplitude of such pulses. The propagation of a pulsed plane wave scattered at an aperture is then illustrated as a finite weighted sum of individual planar LG pulses, which allows for intuitive illustration of the convergence of this expansion technique. By applying such an expansion to diffraction at a hard aperture, the planar pulsed LG beams are described as the paraxial analogs of the Bessel boundary waves typically observed in such situations, with both exhibiting superluminal group velocities along the optical axis. Numerical results of pulse diffraction at an aperture highlight the suitability of the LG expansion method for efficient and practical simulation of ultrashort fields in the paraxial regime. PMID- 23456057 TI - Optimal speckle suppression in laser projectors using a single two-dimensional Barker code diffractive optical element. AB - An effective method of speckle suppression using one 2D diffractive optical element (DOE) moving with constant velocity based on the periodic Barker code sequence is developed. We prove that this method has the same optical parameters as the method based on two 1D Barker code DOEs stretched and moving in orthogonal directions. We also show that DOE movement in a special direction allows the full numerical aperture of the objective lens to be used for speckle averaging by angle diversity. It is found that the 2D DOE based on a Barker code of length of 13 allows the speckle contrast to be decreased below the sensitivity of the human eye with optical losses of less than 10%. PMID- 23456058 TI - Fractional spiral zone plates. AB - In this paper, we generalize the concept of classical spiral zone plates (SZPs) to fractional spiral zone plates (FSZPs). By using an SZP with a fractional topological charge and controlling the starting orientation, we can break down the symmetry of the focusing process to give orientation-selective anisotropic vortex foci. Numerical results show that its binary structure gives additional high-order foci on the optical axis and the intensities in the foci can be controlled by properly choosing the fractional topological charge. Our study reveals the feasibility to control the intensity in the foci by means of FSZPs. PMID- 23456059 TI - How complicated must an optical component be? AB - We analyze how complicated a linear optical component has to be if it is to perform one of a range of functions. Specifically, we devise an approach to evaluating the number of real parameters that must be specified in the device design or fabrication, based on the singular value decomposition of the linear operator that describes the device. This approach can be used for essentially any linear device, including space-, frequency-, or time-dependent systems, in optics, or in other linear wave problems. We analyze examples including spatial mode converters and various classes of wavelength demultiplexers. We consider limits on the functions that can be performed by simple optical devices, such as thin lenses, mirrors, gratings, modulators, and fixed optical filters, and discuss the potential for greater functionalities using modern nanophotonics. PMID- 23456060 TI - Patterned cholesteric liquid crystal polymer film. AB - Herein, the ability to create arbitrarily patterned circular polarized optical devices is demonstrated by using cholesteric liquid crystal polymer. Photoalignment with polarized ultraviolet light is utilized to create aligned cholesteric liquid crystal films. Two different methods, thermal annealing and solvent rinse, are utilized for patterning cholesteric liquid crystal films over large areas. The patterned cholesteric liquid crystal films are measured using a Mueller matrix imaging polarimeter, and the polarization properties, including depolarization index, circular diattenuation (CD), and circular retardance are derived. Patterned nonlinearly polarized optical devices can be fabricated with feature sizes as small as 20 MUm with a CD of 0.812+/-0.015. Circular polarizing filters based on polymer cholesteric liquid crystal films have applications in three-dimensional displays, medical imaging, polarimetry, and interferometry. PMID- 23456061 TI - Adaptive boundaryless finite-difference method. AB - The boundaryless beam propagation method uses a mapping function to transform the infinite real space into a finite-size computational domain [Opt. Lett.21, 4 (1996)]. This leads to a bounded field that avoids the artificial reflections produced by the computational window. However, the method suffers from frequency aliasing problems, limiting the physical region to be sampled. We propose an adaptive boundaryless method that concentrates the higher density of sampling points in the region of interest. The method is implemented in Cartesian and cylindrical coordinate systems. It keeps the same advantages of the original method but increases accuracy and is not affected by frequency aliasing. PMID- 23456062 TI - Number of discernible object colors is a conundrum. AB - Widely varying estimates of the number of discernible object colors have been made by using various methods over the past 100 years. To clarify the source of the discrepancies in the previous, inconsistent estimates, the number of discernible object colors is estimated over a wide range of color temperatures and illuminance levels using several chromatic adaptation models, color spaces, and color difference limens. Efficient and accurate models are used to compute optimal-color solids and count the number of discernible colors. A comprehensive simulation reveals limitations in the ability of current color appearance models to estimate the number of discernible colors even if the color solid is smaller than the optimal-color solid. The estimates depend on the color appearance model, color space, and color difference limen used. The fundamental problem lies in the von Kries-type chromatic adaptation transforms, which have an unknown effect on the ranking of the number of discernible colors at different color temperatures. PMID- 23456063 TI - From the Board of Editors: on plagiarism. PMID- 23456064 TI - [Construction of special reporter to detect DNA methylation regulatory activity in FCER1G gene promoter through patch-methylation]. AB - OBJECTIVE: To construct a special luciferase reporter to detect DNA methylation regulatory activity in FCER1G gene promoter regulatory element. METHODS: We constructed special full and mock methylated FCER1G gene promoter regulatory luciferase reporters by patch-methylation, and detected DNA methylation regulatory activity by comparing the luciferase activity of full-methylated luciferase reporters with mock-methylated reporters. RESULTS: We successfully constructed the full and mock methylated FCER1G gene promoter regulatory luciferase reporters. The ratio of luciferase activity between the full methylated and the mock methylated was (0.36+/-0.07):1 (P<0.001). CONCLUSION: FCER1G promoter activity is methylation-sensitive and is regulated by DNA methylation. PMID- 23456065 TI - [Differential protein expressions in breast cancer between drug sensitive tissues and drug resistant tissues]. AB - OBJECTIVE: To investigate the differential expression of the sensitive and resistant relative proteins in human breast cancer tissue. METHODS: A drug sensitive group and a drug resistant group for chemotherapy in patients with breast cancer were selected through neoadjuvant. The differential protein expression in 2 groups was detected by proteomics techniques, and parts of differential proteins were identified by Western blot. RESULTS: There were 13 differential proteins in the 2 groups, in which the expression of 3 proteins was up-regulated and 10 down-regulated. Seven proteins were identified by Western blot. The expression of keratin type I cytoskeletal 19 (KIC19), thymidine phosphorylase (TYPH) was upregulated, and the expression of heat shock protein 27 (HSP27), keratin type I cytoskeletal 9 (KIC9), collagen alpha-2(VI) (CO6A2), vimentin (VIME), and actin cytoplasmic 1 (ACTB) was down-regulated in the drug resistant group. There was significant difference between the 2 groups (P<0.01). CONCLUSION: The expression of KIC19 and TYPH may be correlated with drug resistance in patients with breast cancer, and HSP27, KIC9, CO6A2, VIME, and ACTB may be correlated with drug sensitivity. PMID- 23456066 TI - [Effect of cryopreservation method on islets specific T cell responses in type 1 diabetic patient]. AB - OBJECTIVE: To explore the better freezing protocol to preserve peripheral blood monuclear cells (PBMCs), islets antigen-specific T cells responses compared with freshly isolated samples in type 1 diabetic (T1D) patients. METHODS: The T cell Workshop Committee of the Immunology of Diabetes Society (IDS-TCW) organized the Freezing Study I and we were one of the 9 centers in the world to participate in the study. According to the two standardized T cell freezing protocols (warm and cold) to freshly isolated PBMCs in terms of recovery, viability, cell subset composition (FACS) and performance in Enzyme-linked immunospot (ELISPOT) assays, we chose 5 newly onset T1D patients and 5 age and sex matched healthy controls. Besides the protocols, all the freezing reagents and antigens were also centralized. The antigens used in ELISPOT were labeled blindedly. RESULTS: 1) Although warm frozen-thawed (W) samples had a slightly higher recovery rate (61.2% vs 60.1%, P>0.05) and viability (77.5% vs 74.9%, P>0.05) as compared with the cold frozen ones (C), the difference was not significant. 2) Both protocols led to a relative loss in monocytes as compared with the fresh samples (F) [3.2+/ 1.1% (C) and 3.0+/-0.9% (W) vs 7.0+/-1.1% (F), both P<0.05], while other subsets including CD4+T, CD8+T, B cells, NK cells and NKT cells didn't. 3) Freezing and fresh samples showed similar IFN-gamma secretion responses to polystimuli in ELISPOT. Irrespective of the freezing protocol, recall antigen Pediacel and islet antigen-reactive responses were both lower in the frozen cells compared with fresh PBMCs. The stimuli index (SI) of GADspecific T cell response in the fresh samples from T1D patients was 5.1, higher than that of frozen samples with either cold protocol (1.3) or warm one (1.4) (both P<0.05). Only fresh samples from T1D showed significantly higher GAD-specific T cell responses than the healthy controls no matter in SI (5.1 vs 0.9, P<0.05) or spot forming cells (8.1 vs 0.1, P<0.05), whereas the frozen samples did not show such difference. CONCLUSION: More studies are needed to verify a freezing method to bring comparable islets antigen specific T cell responses in T1D patients to fresh PBMCs. PMID- 23456067 TI - [Clinical study of invasive fungal infection secondary to systemic lupus erythematosus]. AB - OBJECTIVE: To study the clinical characteristics of invasive fungal infection secondary to systemic lupus erythematosus (SLE). METHODS: We observed the clinical features and experimental examination in 91 patients treated in Xiangya Hospital in recent years, of which 48 patients with invasive fungal infection and 41 patients without invasive fungal infection. RESULTS: The invasive fungal infection secondary to SLE mainly occurred in the lungs, nervous system, and urinary system. The fungi were mainly Candida albins and Aspergillus. The rate of invasive fungal infection in SLE patients and the level of CRP and TNF-alpha in these patients were significantly increased. The occurrence of invasive fungal infection was positively correlated with the prolonged course of disease, long term use of immunosuppressants and antibiotics, and occurrence of complications, such as hypoproteinemia, leukocytopenia, and so on. The levels of C-reactive protein (CRP) and tumor necrosis factor-alpha(TNF-alpha) were increased in SLE patients with invasive fungal infection. CONCLUSION: The clinical features of SLE patients with invasive fungal infections are long course of disease, long-time use of immunosuppressants or antibiotics, and occurrence of complications, such as hypoproteinemia or leukopenia. The level of CRP and TNF-alpha can be used as an important reference index for diagnosing invasive fungal infections. PMID- 23456068 TI - [A novel improved TOPSIS method and its application in medical science]. AB - The TOPSIS method is a static comprehensive evaluation method for wide range applications. However, it encounters the reverse order problem in practical applications. Moreover, its evaluation value Ci only reflects the relative proximity of each evaluation object inside but not to the degree of closeness to the ideal optimal solution. The evaluation value is also limited to distinguish between the ranges of merit ranking. Since TOPSIS method has the wide range of applications, it is necessary to overcome the drawbacks of TOPSIS method. This article proposes a new improved TOPSIS method, which shows strict isotonicity and is more sensitive than the traditional TOPSIS method. The medical application based on this improved TOPSIS method is introduced. PMID- 23456069 TI - Effect of Naoling decoction on the expression of microglia and IL-6 in hippocampal CA3 region of rats with synthetic Alzheimer's disease. AB - OBJECTIVE: To observe the effect of Naoling decoction on the learning and memory behaviors and the expression of microglia and IL-6 in hippocampal CA3 region of rats with Alzheimer's disease (AD), and to elucidate the potential mechanism. METHODS: Thirty SD rats were randomly divided into 5 groups: a normal group, a sham-operation group, an AD group, a Naoling decoction group and a Naofukang group. The spatial learning and memory behaviors of the rats were investigated by water maze and Y-maze. The Alzheimer's disease model was established by injecting Abeta1-42 into the hippocamal of the rats. Expression of OX-42 (one of the microglia specific markers) and IL-6 in the CA3 region of hippocamal was measured by immunohistochemical stain. RESULTS: Morris water maze experiment showed that the escape latency of hidden platform in the AD group was significantly delayed (P<0.05) and the average times of passing was decreased (P<0.05). Y-maze test showed that the times needed to the learn how to evade the electrical stimulation in the AD group was most than in other groups (P<0.05). Compared with the AD group, the Morris water maze test and Y-maze test of the Naoling decoction group were significantly different (P<0.05). The expression of OX-42 and IL-6 in the CA3 region of hippocamal in the Naoling decoction group was decreased (P<0.05). CONCLUSION: Naoling decoction can improve learning and memory, and weaken the expression of OX-42 and IL-6 in hippocampal CA3 of AD rats, which may partly be the therapeutic mechanism of Naoling decoction for AD. PMID- 23456070 TI - [Expression of SH2B1 adaptor protein in oesophageal cancer and its clinical significance]. AB - OBJECTIVE: To explore the expression of SH2B1 adaptor protein in oesophageal cancer and its clinical significance. METHODS: SH2B1 expression in tissue specimens of 120 primary oesophageal cancers, tissues of 120 paired adjacent non cancer and another 120 normal tissues was analyzed by immunohistochemical SABC staining and Western blot. SH2B1 expression in the oesophageal cancer tissues was analyzed with clinicopathological parameters. SH2B1 expression of normal human esophageal epithelial cells (HEEC) and 2 oesophageal cancer cell lines, TE-1 and Eca109, were evaluated by RT-PCR and Western blot. RESULTS: SH2B1 expression in the normal oesophageal tissues, adjacent non-cancer tissues and cancer tissues was gradually increased (P<0.05), and significantly associated with the depth of invasion, clinical TNM stage, lymph node metastasis (P<0.05), but it did not have significant association with gender, age, drinking, type and grade of tumor (P>0.05). SH2B1 expression was detectable in all cell lines by RT-PCR and Western blot, but the expression in the two oesophageal cancer cell lines was significantly higher than that in the normal HEEC. CONCLUSIONS: Over-expression of SH2B1 might play an important role in the occurrence and development of human oesophageal cancer and closely correlate with malignant progression of invasion and metastasis of oesophageal cancer. PMID- 23456071 TI - [Scope and method of image registration and clinical target volume margin for central-type non-small cell lung cancer in image-guided radiotherapy]. AB - OBJECTIVE: To determine the influence of different registration scopes and methods on kilo-voltage cone beam CT (kVCBCT) image and CT image and to estimate the appropriate clinical target volume (CTV)-to-planned target volume (PTV) margin for central-type non-small cell lung cancer in image-guided radiation therapy (IGRT). METHODS: Twenty-six patients with central-type non-small cell lung cancer (NSCLC) who received IGRT were enrolled in this study and totally 104 flames of kVCBCT scanning acquired before radiotherapy were analyzed. First, registrations were performed by gray plus manual match and were compared among different registration scopes of tumor and tumor plus vertebra. Then, the results of registration as well as time cost using tumor plus vertebra as registration scope were compared among different registration methods of gray plus manual match and bone plus manual match. At last, 200 registrations using tumor plus vertebra as the registration scope performed by bone plus manual match were recorded and the CTV-to-PTV margin was calculated. RESULTS: There was no significant difference in X, Y and Z translational and rotational movements between the registration scopes of tumor and tumor plus vertebra when gray plus manual match was used as the registration method (P>0.05). The registration results of gray plus manual match and bone plus manual match were equal when tumor plus vertebra was used as the registration scope (P>0.05), but the time cost of bone plus manual match [(1.9+/-0.3) min] was shorter than that of gray plus manual match [(3.1+/-0.2) min]. The CTV-to-PTV margins were 5.3, 4.9 and 5.7 mm in X, Y, and Z directions respectively. CONCLUSION: For central-type NSCLC, tumor and vertebra can be used as registration scope and the bone plus manual match is suggested in IGRT. To avoid errors, we suggest a CTV-to-PTV margin of 6 mm. PMID- 23456072 TI - [Impact of diabetes mellitus on clinicopathological factors and relation with radiation pneumonitis in 332 patients with lung cancer]. AB - OBJECTIVE: To explore the relation between diabetes mellitus and clinicopathological factors and the incidence of radiation pneumonitis in patients with non-small cell lung cancer. METHODS: The data of 332 patients with non-small cell lung cancer, who were admitted to the Department of Oncology of Third Xiangya Hospital of Central South University between January 2007 and August 2009, were collected retrospectively. The patients were divided into a diabetes mellitus (DM) group (n=45) and a non-diabetes mellitus (NDM) group (n=287). The clinicopathological factors were compared between the two groups. The patients who received radiotherapy were further divided into a diabetes mellitus (DMR) group (n=33) and a non-diabetes mellitus group (NDMR) group(n=287), and the incidence of radiation pneumonitis was compared. RESULTS: A total of 45 patients (13.55%)developed diabetes mellitus. There was significant difference in the body-weight, age and hypertension (P<0.05), while no significant difference in the pathologic factors, such as tumor pathological type, degree of differentiation, and classification of malignant tumors (TNM) stage between the two groups(P>0.05). No significant difference in the irradiation area was found between the DM group and the NDM group(P>0.05). The incidence of radiation pneumonitis in the DMR group was 42.42%(14 out of 33), while 21.31%(39 out of 183) in the NDMR group, with significant difference in the incidence of radiation pneumonitis between the DMR group and the NDMR group(P<0.05). The risk value in the DMR group was 2.721 folds (95%CI, 1.253 5.910) that in the NDMR group in patients with non-small cell lung cancer companied with diabetes mellitus. CONCLUSION: Diabetes mellitus is the risk factor of radiation pneumonitis for patients with nonsmall cell lung cancer who receive radiotherapy. PMID- 23456073 TI - [TGF-alpha increases neuroendocrine differentiation and strengthens chemoresistance in prostate cancer DU145 cells]. AB - OBJECTIVE: To study whether TGF-alpha possesses similar EGF effect of enforcing neuroendocrine differentiation (NED) in prostate cancer cell line DU145 and determine the influence of NED induced by TGF-alpha on chemoresistance. METHODS: DU145 cells were divided into 3 groups: a group with 2% FBS, a group with 2%FBS+TGF-alpha 5 ng/mL and a group with 2%FBS+TGF-alpha 10 ng/mL. Morphological change in DU145 cells was observed after TGF-alpha treatment. Expression levels of NSE mRNA were detected with real time RT-PCR. Western blot was used to detect the expression levels of protein NSE, P-gp, MRP1 and Bcl-2. Cell cycles of DU145 cells in the 3 groups were examined with flow cytometry. MTT assay was used to evaluate the influence of TGF-alpha in chemoresistance. RESULTS: Compared with DU145 cells cultured with 2% FBS, cells treated with 2% FBS+TGF-alpha were pleomorphic and pseudopodia extended. The expression level of NSE mRNA upregulated to (3.6+/-0.5) folds (P<0.05) and (10.1+/-0.1) folds (P<0.01). Western blot showed that the expression levels of protein NSE, Bcl-2, and MRP1 increased after treatment with different concentrations of TGF-alpha; P-gp was not detected. The proportion of DU145 cells in phase G1 decreased; proportions of cells in phase S and phase G2/M were increased after TGF-alpha treatment (5 MUg/mL). At the same time, chemoresistance of DU145 cells to cisplatin increased. CONCLUSION: TGF-alpha can increase NED in DU145 cells and enforce the chemoresistance to cisplatin. PMID- 23456074 TI - [Effect of corticotrophin-releasing hormone on connexin-43 phosphorylation and gap junction intercellular communication in human myometrial smooth muscle cells]. AB - OBJECTIVE: To determine the effect of human corticotrophin-releasing hormone (CRH) on the expression of connexin-43 phosphate (P-Cx43) in human myometrial smooth muscle cells (SMCs) and the function of cell gap junction intercellular communication in SMCs. METHODS: Human non-conceive myometial SMCs were cultured with different concentrations of CRH (0, 5.85, 58.5, 585 and 5850 pmol/L). Western blot was used to test P-Cx43 and Cx43 non-phosphate (NP-Cx43) of protein expression. Cell scratch was used to test cell gap junction intercellular communication opening status in human myometrial SMCs. RESULTS: Compared with the control group, the expression of P-Cx43 was higher in the CRH groups (P<0.01), and was concentration-dependent. There was no significant difference in NPCx43 between the control group and the CRH groups (P>0.05). The transmission of cell layers in the CRH groups was higher than that in the control group (P<0.01), and as the concentration of CRH increased, the time was concentration-dependent (P<0.01). CONCLUSION: CRH can enhance the expression of P-Cx43 and the function of gap junction intercellular communication in the primary cultured myometrial SMCs. PMID- 23456075 TI - [Correlation between self-management and knowledge of and attitude to diabetes in type 2 diabetic patients in Changsha]. AB - OBJECTIVE: To assess the level of diabetes knowledge, attitude and self management activities of the patients with type 2 diabetes mellitus (T2DM), and explore the correlation between diabetes knowledge, attitude and self-care. METHODS: Totally 200 T2DM patients finished the questionnaires, including the demographic information questionnaire, the Audit of Diabetes Knowledge (ADKnowl), the third version of Diabetes Attitude scale (DAS-3) and the Summary of Diabetes Self-Care Activities (SDSCA). RESULTS: The ADKnowl score was 68.06+/-10.07. The DAS-3 score was 122.60+/-5.66. The SDSCA score was 57.98+/-15.30. Education level, duration of diabetes, complications and periodic review were the influential factors for self-care behaviors. The score of self-care behaviors was positively related to diabetes knowledge (r=0.176, P<0.05) and attitude (r=0.256, P<0.01). CONCLUSION: Diabetes knowledge and self-care behaviors in the vast majority of T2DM patients are at a low level. Medical staff should not only emphasize the diabetes knowledge, but also pay enough attention to the attitude of T2DM patients and improve their self-care behaviors. PMID- 23456076 TI - [Expression of survivin in rheumatoid arthritis]. AB - OBJECTIVE: To detect the correlation between survivin and rheumatoid arthritis (RA) to determine the possible mechanism of RA and multidrug resistance in refractory rheumatoid arthritis (RRA). METHODS: We collected 15 normal controls, 35 early untreated RA patients, 20 effectively treated RA patients and 25 RRA patients according to selection standard. The expression of survivin in the peripheral blood lymphocytes was detected by immunocytochemical method. RESULTS: There was significant difference in the survivin expression in the peripheral blood lymphocytes between the early untreated and normal control group (chi(2)=29.59, P<0.01). The survivin expression in the peripheral blood lymphocytes of effectively treated RA group slightly elevated, but had no significant difference with the normal control group (chi(2)=1.591, P>0.05). The survivin expression in the peripheral blood lymphocytes of the RRA group was significantly stronger than in the effectively treated RA group (chi(2)=24.35, P<0.01), and normal control group (chi(2)=26.53, P<0.01), with no significant difference compared with early untreated group (chi(2)=0.014,P>0.05). CONCLUSION: Survivin has an influential role in the occurrence and development of rheumatism arthritis. Survivin might be involved in refractory multidrug resistance of RA and be one of the multidrug resistance mechanism of RRA. PMID- 23456077 TI - [Treatment of external fixator in young patients with valgus deformity of the knee companied with leg shortening]. AB - OBJECTIVE: To explore the efficacy and experience of callus distraction technique with the external fixator for valgus deformity of the knee companied with leg shortening in young patients and to provide evidence for selecting reasonable therapy. METHODS: From January 2002 to January 2009, the clinical data of 28 young patients (17 males and 11 females, aged 8 to 14, mean age 11.9 years) treated with callus distraction, who had valgus deformity of the knee, companied with leg shortening, were analyzed retrospectively. Three had bilateral total valgus deformity of the knee, with a total of 31 knees. Before the operation, the abnormal limbs shortened from 3 to 7 cm (average 4.1 cm) companied with the normal one. The tibiofemoral angle ranged from 138 degrees to 160 degrees (mean angle 148 degrees ) and the Condyle interval from 5 to 33 cm (mean interval 15.2 cm). RESULTS: The 28 patients were followed up for 35 to 84 ( mean 62 ) months. The extent length ranged from 4.5 to 10.1 cm (average 6.8 cm). The tibiofemoral angle ranged from 169 degrees to 175 degrees (mean 173 degrees ) after the union. The patients resumed the normal length of limbs, and the severe valgus deformity of the knee was corrected. CONCLUSION: Callus distraction with external fixator is effective for serious valgus deformity of the knee companied with leg shortening. PMID- 23456078 TI - [Family function among the bereaved in hard-hit areas 1 year after Wenchuan earthquake]. AB - OBJECTIVE: To investigate the family function among the bereaved in hard-hit areas 1 year after Wenchuan earthquake and to provide basic information for family reconstruction. METHODS: A cross-sectional study was used to survey 264 bereaved who were selected according to the criteria in hard-hit areas after Wenchuan earthquake. RESULTS: The scores of family care function of the bereaved in hard-hit areas after Wenchuan earthquake were 6.52+/-2.65. Fifty percent of the participants' family kept in good state. The scores of the bereaved family cohesion ranged from 28 to 83 (64.22+/-9.18), and the scores of family adaptability ranged from 21 to 62 (41.84+/-6.62). There was no significant difference in the score of family cohesion between the bereaved family and the non-bereaved family (P>0.05). But the score of the family adaptability of the bereaved family was significantly lower than that of the non-bereaved family (P<0.05). The bereaved family types were as follows: 22.0% balanced type, 53.8% middle type and 24.2% extreme type. In the 16 family types, the "intimate-rigid" (24.6%), "intimate-regular" (19.7%) and "disengaged-rigid" (19.3%) type ranked the top three. CONCLUSION: The family care function of the bereaved in hard-hit areas after Wenchuan earthquake is damaged to different degrees. The main type of family is the middle type. The loss of relatives reduces the participant family adaptability. In the late intervention, we should help the bereaved improve and enhance family function, and promote family reconstruction of the bereaved. PMID- 23456079 TI - [Description and intervention of the ability of military men to treat burns]. AB - OBJECTIVE: To survey and promote the ability of military men to treat burns. METHODS: A total of 2200 military men were recruited to survey and examine their acknowledge and technique to treat burns, and then acknowledge and technique were taught to treat burns through multimedia and demonstration. One year later, the same subjects were surveyed again. RESULTS: Before the intervention, their ability was deficient (the mean score was 51). Their scores were significantly promoted after the intervention (the mean score was 75, P<0.01). Before and after the intervention, the service age, education and position had no effect on the score, but before the intervention, the navy's score was significantly better than the army's or the air force's (P>0.01). CONCLUSION: The ability of military men to treat burns needs to be improved for the potential hightech warfare. PMID- 23456080 TI - [8.5 year-follow-up of combined heart-lung transplantation in a patient]. AB - To summarize the case of combined heart-lung transplantation for a patient who survived for 8.5 years. On September 20, 2003, at Second Xiangya Hospital of Central South University, homologous heartlung transplantation was performed on a male patient who was diagnosed with cardiopulmonary failure secondary to congenital ventricular septal defect with severe pulmonary hypertension. Heart lung allograft was preserved with 1500 mL modified St.Thomas solution and 3000 mL modified LPD solution. Postoperative immunosuppressive therapies included: methylprednisolone and human anti-lymphocyte globulin protein in the induction period; and combination of ciclosporin A, CellCept and prednisolone in the stable period. In 2007, the treatment was changed to CellCept mg, twice a day+FK506 4 mg, twice a day. The patient lived 8.5 years of normal life with cardiac function of NYHA I-II. Echocardiogram showed left ventricular ejection fraction of 61% to 74%. Heart-lung transplantation proved reliable therapy modality for terminal cardiopulmonary failure. Excellent donor organ preservation and proper perioperative treatment are key factors for long-term survival after heart-lung transplantation. PMID- 23456081 TI - [Modulation of non-ion channel proteins by membrane potential]. AB - The different concentration of specific ion species and the electrodiffusion of the ions down their electrochemical gradient generate transmembrane potential. The regulation of membrane potential for the function of numerous membrane proteins such as ion channels, transporters, pumps and enzymes plays primary role in the conversion of extracellular electric stimulation into a sequence of intracellular biochemical signals. Some ion channels regulated by membrane potential are well known, and the membrane non-ion channels protein is also modulated physiologically by membrane potential. PMID- 23456082 TI - [Influence of LPS and Toll-like receptor 4 antagonist on progesterone receptor, interleukin-1beta, and cyclooxygenase-2 in decidual cells]. AB - OBJECTIVE: To observe the expression of progesterone receptor (PR), interleukin 1beta (IL-1beta), and cyclooxygenase-2 (COX-2) induced by lipopolysaccharide (LPS) or Toll-like receptor 4 antagonist (TLR4 mAb) in decidual cells in vitro, and then to explore the effect of LPS and its antagonist on PR of decidual cells and the relation between PR and inflammatory cytokines. METHODS: We isolated and cultured human decidua of early abortion in the sterile state. When the cells passaged to the 4th generation, the cells were randomly divided into 6 pore plates: A control group was added the culture medium alone; experimental group I was added 100 ng/mL of LPS; experimental group II was add 1 MUg/mL of TLR4 mAb; experimental group III was added 3 MUg/ mL of TLR4 mAb; experimental group IV was added 1 MUg/mL of TLR4 mAb pretreatment for 24 h, and then 100 ng/mL LPS; and experimental group V was added 3 MUg/mL of TLR4 mAb pretreatment for 24 h, and then 100 ng/mL LPS for 24 h culture. Subsequently, HE staining and immunofluorescence were used to observe the morphology and identify the purity of decidual cells in the 6 groups. The levels of mRNA expression of PR, IL-1beta, and COX-2 were detected by reverse transcription PCR (RT-PCR). RESULTS: LPS reduced the mRNA expression of PR (P<0.05), increased the mRNA expression of IL 1beta and COX-2 (P<0.05). TLR4 mAb increased the mRNA expression of PR (P<0.05) and reduced the mRNA expression of IL-1beta (P<0.05) after LPS-stimulated decidual cells. High concentrations of TLR4 mAb reduced the mRNA expression of COX-2 (P<0.05) after LPS stimulated decidual cells. CONCLUSION: The mRNA expression of PR is reduced, and the mRNA expressions of IL-1beta and COX-2 are increased after LPS-stimulated decidual cells in vitro. TLR4 mAb antagonize the role of LPS on PR, IL-1beta, and COX-2. PMID- 23456083 TI - Fixation strength of anteriorly inserted headless screws for talar neck fractures. AB - BACKGROUND: For noncomminuted talar neck fractures, traditional fixation is with small fragment screws or cannulated screws. Newer screw systems on the market allow placement of cannulated headless screws, which provide compression by virtue of a variable-pitch thread. The headless construct has an inherent advantage, particularly for the talus, when the screws must be countersunk to prevent wear of the joint articular surfaces. This study tested the biomechanical fixation strength of cannulated headless variable-pitch screws compared with conventional cannulated screws, both placed in an anterior to posterior direction. METHODS: A reproducible talar neck fracture was created in nine paired, preserved, cadaver talar necks using a materials testing machine. Talar head fixation was then performed with two cannulated headless variable-pitch 4/5 screws or two 4.0-mm conventional cannulated screws. The specimens were tested to failure and the fixations were normalized to their intact pairs and compared. RESULTS: The headless variable-pitch screw fixation had significantly lower failure displacement than the conventional screw fixation. No significant differences were found between the two fixations for failure stiffness, load at failure or energy absorbed. CONCLUSIONS: Cannulated headless variable-pitch screws significantly improved failure displacement when compared to conventional cannulated screws in a cadaveric model, and may be a viable option for talus fracture fixation. CLINICAL RELEVANCE: Headless, fully threaded, variable-pitch screws have inherent advantages over conventional screws in that they may be less damaging to the articular surface and can compress the fracture for improved reduction. This study demonstrates these screws are also biomechanically similar to conventional screws. PMID- 23456084 TI - Comparative analysis of inter- and intraligamentous distribution of sensory nerve endings in ankle ligaments: a cadaver study. AB - BACKGROUND: The aim of this study was to analyze the inter-, intraligamentous, and side-related patterns of sensory nerve endings in ankle ligaments. METHODS: A total of 140 ligaments from 10 cadaver feet were harvested. Lateral: calcaneofibular, anterior-, posterior talofibular; sinus tarsi: lateral- (IERL), intermediate-, medial-roots inferior extensor retinaculum, talocalcaneal oblique and canalis tarsi (CTL); medial: tibionavicular (TNL), tibiocalcaneal (TCL), superficial tibiotalar, anterior/posterior tibiotalar portions; syndesmosis: anterior tibiofibular. Following immunohistochemical staining, the innervation and vascularity was analyzed between ligaments of each anatomical complex, left/right feet, and within the 5 levels of each ligament. RESULTS: Significantly more free nerve endings were seen in all ligaments as compared to Ruffini, Pacini, Golgi-like, and unclassifiable corpuscles (P <= .005). The IERL had significantly more free nerve endings and blood vessels than the CTL (P <= .001). No significant differences were seen in the side-related distribution, except for Ruffini endings in right TCL (P = .016) and unclassifiable corpuscles in left TNL (P = .008). The intraligamentous analysis in general revealed no significant differences in mechanoreceptor distribution. CONCLUSIONS: The IERL at the entrance of the sinus tarsi contained more free nerve endings and blood vessels, as compared to the deeper situated CTL. Despite different biomechanical functions in the medial and lateral ligaments, the interligamentous distribution of sensory nerve endings was equal. CLINICAL RELEVANCE: The intrinsic innervation patterns of the ankle ligaments provides an understanding of their innate healing capacities following injury as well as the proprioception properties in postoperative rehabilitation. PMID- 23456085 TI - Integrated care pathways in lower-limb arthroplasty: are they effective in reducing length of hospital stay? AB - PURPOSE: The aim of this study was to examine the effect of an integrated care pathway (ICP) for total hip and knee arthroplasty (THA/TKA) on length of stay (LOS), day of surgery admission rate (DOSA) and postoperative length of stay (POLOS). METHODS: Three hundred and eight THAs and 299 TKAs were assessed in a retrospective before-after trial design. LOS, POLOS and DOSA were recorded for patients before and after introduction of the ICP. The ICP encompassed a patient education programme, specific daily management goals, variance mapping, daily facilitated meetings and a DOSA policy. Subgroup analysis according to age and gender was also performed. RESULTS: Mean LOS was significantly reduced by 1.4 (from 6.9 to 5.5) days for THA and 0.8 (from 6.4 to 5.6) days for TKA. Elderly patients and men achieved greater LOS reductions than their counterparts for both operations. Younger patients undergoing THA achieved a significantly higher DOSA rate than older patients (89 % vs 71 %, p = 0.010); however, this difference was not observed in the TKA population. Mean POLOS for THA was reduced by 0.6 (from 5.9 to 5.3) days, again with the greatest benefit seen in elderly and male patients. POLOS for TKA patients was not significantly affected by the ICP. CONCLUSIONS: The introduction of an ICP reduced LOS by 1.4 days for THA and 0.8 days for TKA. Elderly and male patients benefitted most. PMID- 23456086 TI - Complications with reverse total shoulder arthroplasty and recent evolutions. AB - Since its description by Paul Grammont from Dijon, France, several tens of thousands of reverse total shoulder arthroplasties (RTSA) have been performed for diverse conditions. The purpose of this analysis is to identify the complications of this procedure in the literature and in clinical practice. A total of 240 papers concerning RTSA published between 1996 and 2012 have been identified. Over 80 papers describe complications associated with this type of implant. A list of prostheses satisfying European and US standards, CE and FDA approved, has been produced on the basis of information provided by the manufacturers. Data from the literature do not support a meta-analysis. The inventory of best practices shows excellent results in the short and medium term in specific indications, while the number of complications varies between 10 and 65 % in long-term series. Complications can be classified into (A) non-specific including infections (superficial and deep), phlebitis, haematoma, neurological complications of the suprascapular, radial and axillary nerves and (B) specific complications associated with RTSA including (1) on the glenoid side: intraoperative fracture of the glenoid and acromion, late fracture of the scapula, impingement at the scapular neck (notching), glenoid loosening, dissociation of the glenoid component (snatching of the glenosphere) and fractures of the glenoid baseplate; (2) on the humeral side: metaphyseal deterioration, humeral loosening, instability of the shoulder, stiffness with limitation of external and/or internal rotation; and (3) muscular complications with fatty degeneration of the deltoid. Additionally we have identified specific situations related to the type of implant such as the disassembly of the humeral or the glenoid component, dissociation of the polyethylene humeral plate, dissociation of the metaphysis and osteolysis of the tuberosities. The integration of results from different clinical series is difficult because of the lack of a database and the multitude of implants used. PMID- 23456087 TI - Meningeal osteochondroma simulating meningioma with metaplastic change: a rare golf-ball-like lesion of non-meningothelial mesenchymal origin. AB - Non-meningothelial mesenchymal tumors of the central nervous system (CNS), including those originating from the meninges, histologically correspond to tumors of soft tissue or bone. These individual entities arising from the meninges are rare, and probably have their origin in the multipotent primitive mesenchymal stem cells of the dura. Though it is a common bone tumor, the meningeal origin of osteochondroma has only very rarely been reported. We describe a case of a 35-year-old female with a well-demarcated, golf-ball-like osteochondroma of meningeal origin which was enucleated en bloc on craniotomy. Such a lesion can resemble a meningioma that exhibits metaplastic (osseous) change on imaging. However, provided that there is clinico-radiological awareness of such tumors, magnetic resonance imaging (MRI) can guide the way to this rare differential diagnosis, as it reflects the pathologic appearance of osteochondroma and allows the thickness of the cartilage cap to be estimated in order to check for rare malignant change. Complete excision along with the cartilage cap usually offers a favorable prognosis without recurrence. PMID- 23456088 TI - Minimum 10-year follow-up results of ALPINA cementless hydroxyapatite-coated anatomic unicompartmental knee arthroplasty. AB - One hundred and one unicompartmental knee arthroplasties (UKA) were done between 1996 and 2000 with ALPINA((r)) UNI, a cementless hydroxyapatite-coated anatomic prosthesis. Sixty-five knees were available for the long-term follow-up at a mean of 11 years. The mean IKS improved from 119.3 +/- 16.8 points preoperatively to 171.4 +/- 25.3 at the latest follow-up (p < 0.0001). Eighty-nine percentage of the knees were rated good and excellent. The mean knee flexion has significantly improved from 120 degrees 5 preoperatively to 127 degrees 3 at the latest follow up (p < 0.01). Eleven revision procedures were done: 1 for early knee degeneration on rheumatoid arthritis, 1 for degeneration of osteoarthritis in the opposite compartment of the knee, 1 for unexplained pain and 1 for late ACL rupture, all these 4 cases were replaced by total knee arthroplasties; 3 revisions by another UKA were done due to polyethylene insert fracture; and 4 partial revision were done for bearing exchange due to severe polyethylene wear. When revision for any reason was defined as the end point, the 13-year Kaplan Meier survival rate was 88 % (95 % CI 81-95 %) and when revision due to implant mechanical failure (excluding degeneration of osteoarthritis in the opposite compartment of the knee and bearing exchange only) was defined as the end point, the 13-year survival rate was 94 % (95 % CI 89.1-99.1 %). PMID- 23456089 TI - The chemistry of functional nanomaterials. AB - Nanostructured materials are the core components of nanotechnology, providing basic building blocks for fabricating complex devices with desired functions. Thanks to their inherent quantum size and shape effects, nanomaterials have many important applications in electronics, optoelectronics, information processing, catalysis, biomedical science, environmental science, energy conversion and storage, advanced defense technologies, and many other fields. Chemistry plays a central role in the development of novel nanostructured materials. This themed issue on the chemistry of functional nanomaterials gives a broad overview of the synthesis, structural manipulation, characterization, surface modification, self assembly, processing and integration of nanoscale materials into functional devices. PMID- 23456090 TI - Calcium responses of circadian pacemaker neurons of the cockroach Rhyparobia maderae to acetylcholine and histamine. AB - The accessory medulla (aMe) is the pacemaker that controls circadian activity rhythms in the cockroach Rhyparobia maderae. Not much is known about the classical neurotransmitters of input pathways to the cockroach circadian system. The circadian pacemaker center receives photic input from the compound eye, via unknown excitatory and GABAergic inhibitory entrainment pathways. In addition, neuropeptidergic inputs couple both pacemaker centers. A histamine-immunoreactive centrifugal neuron connects the ventral aMe with projection areas in the lateral protocerebrum and may provide non-photic inputs. To identify neurotransmitters of input pathways to the circadian clock with Fura-2-dependent Ca(2+) imaging, primary cell cultures of the adult aMe were stimulated with acetylcholine (ACh), as the most prominent excitatory, and histamine, as common inhibitory neurotransmitter. In most of aMe neurons, ACh application caused dose-dependent increases in intracellular Ca(2+) levels via ionotropic nicotinic ACh receptors. These ACh-dependent rises in Ca(2+) were mediated by mibefradil-sensitive voltage activated Ca(2+) channels. In contrast, histamine application decreased intracellular Ca(2+) levels in only a subpopulation of aMe cells via H2-type histamine receptor chloride channels. Thus, our data suggest that ACh is part of the light entrainment pathway while histamine is involved in a non-photic input pathway to the ventral circadian clock of the Madeira cockroach. PMID- 23456091 TI - Combined analysis of genome-wide-linked susceptibility loci to Kawasaki disease in Han Chinese. AB - Kawasaki disease (KD) is a dominant cause of acquired heart disease in children due to frequent complicating coronary artery lesions (CALs). Genome-wide association study and linkage analysis have recently identified 6 susceptibility loci at genome-wide significance of P < 5.0 * 10(-8) in subjects of Japanese, Taiwanese and European. In present study, we analysed the variants of 6 single nucleotide polymorphisms (SNPs) in the genetic loci to investigate their potential effect on KD susceptibility and outcomes in Han Chinese population. As a result, the risk alleles of rs1801274 and rs2254546 were observed significant effect on KD with higher frequencies in 358 patients than those in 815 controls. The significant role of rs1801274, rs2857151 and rs2254546 in KD was found in the multi-variable logistic regression analysis of the SNPs. Two 2-locus and one 3 locus combinations of the SNPs showed significant effect on KD with stronger association with KD relative to comparable single SNP or 2-locus combinations. Significant susceptibility to CALs was found in KD patients with high-risk genotypes at both rs1801274 and rs2857151. The meta-analyses first revealed significant risk for CALs in KD patients carrying risk allele of rs11340705, and the association of rs28493229 with KD was not observed in the Han Chinese. In conclusion, the findings demonstrated that 5 of the 6 genetic loci influence the risk for KD and 3 of them may be involved in secondary CALs formation in Han Chinese. The additive effects of 3 multi-locus combinations on KD/CALs imply that some loci may participate together in certain unknown gene networks related to KD/CALs. Further function studies of the genetic loci are helpful for better understanding the pathophysiology of KD. PMID- 23456092 TI - Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication. AB - Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case-control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 * 10(-21), OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD. PMID- 23456093 TI - Vanadium compounds modulate PPARgamma activity primarily by increasing PPARgamma protein levels in mouse insulinoma NIT-1 cells. AB - Vanadium compounds are promising agents in the therapeutic treatment of diabetes; however, their mechanism of action has not been clearly elucidated. The current study investigated the effects of vanadium compounds, vanadyl acetylacetonate [V(IV)O(acac)2] and sodium metavanadate (NaV(V)O3), on peroxisome proliferator activated receptors (PPARs), especially PPARgamma, which are important targets of anti-diabetic drugs. Our experimental results revealed that treatment of NIT-1 beta-pancreas cells with vanadium compounds resulted in PPARgamma activation and elevation of PPARgamma protein levels. Vanadium compounds did not increase PPARgamma transcription but ameliorated PPARgamma degradation induced by inflammatory stimulators TNF-alpha/IL-6. Vanadium compounds induced binding of PPARgamma to heat shock protein (Hsp60). This PPARgamma-Hsp60 interaction might cause inhibition of PPARgamma degradation, thus elevating the PPARgamma level. In addition, modulation of PPARgamma phosphorylation was also observed upon vanadium treatment. The present work demonstrated for the first time that vanadium compounds are novel PPARgamma modulators. The results may provide new insights for the mechanism of anti-diabetic action of vanadium compounds. PMID- 23456094 TI - Role of radiolabelled leucocyte scintigraphy in patients with a suspicion of prosthetic valve endocarditis and inconclusive echocardiography. AB - AIMS: In patients with a suspicion of prosthetic valve endocarditis (PVE), detection of perivalvular infection can be difficult based only on echocardiography. The aim of this retrospective study was to test the interest of radiolabelled leucocyte scintigraphy (LS) for the detection of perivalvular infection in patients with a suspicion of PVE and inconclusive transoesophageal echocardiography (TEE). METHODS AND RESULTS: LS was performed in 42 patients. The results of LS were classified as positive in the cardiac area (intense or mild), or negative. Macroscopical aspects and bacteriology were obtained from patients who underwent cardiac surgery (n = 10). Clinical outcome was collected in patients treated medically (n = 32). Among patients with intense signal with LS who underwent surgery (n = 6), five had an abscess confirmed during intervention and one, post-operatively. Patients with intense accumulation of radiolabelled leucocytes with scintigraphy and treated medically (n = 3) had a poor outcome: death (n = 1); prosthetic valve dehiscence (n = 1); and recurrent endocarditis (n = 1). Among patients with mild activity with LS (n = 5), one patient developed a large prosthetic valve dehiscence during the follow-up. The remaining four patients were treated medically and did not present any recurrent endocarditis after a median follow-up of 14 months. No abscess was detected in patients with negative LS who underwent surgery (n = 4). Among the patients with negative LS treated medically (n = 24), none presented recurrent endocarditis after a mean follow-up of 15 +/- 16 months. Patient management was influenced by the results of LS in 12 out of 42 patients (29%). CONCLUSION: This study suggests that LS is useful for the identification of perivalvular infection in patients with a suspicion of PVE and inconclusive TEE. PMID- 23456095 TI - Left common pulmonary venous ostium mimicking aneurysmal left atrial appendage on transthoracic echocardiography. PMID- 23456096 TI - Inhibitory zinc sites in enzymes. AB - Several pathways increase the concentrations of cellular free zinc(II) ions. Such fluctuations suggest that zinc(II) ions are signalling ions used for the regulation of proteins. One function is the inhibition of enzymes. It is quite common that enzymes bind zinc(II) ions with micro- or nanomolar affinities in their active sites that contain catalytic dyads or triads with a combination of glutamate (aspartate), histidine and cysteine residues, which are all typical zinc-binding ligands. However, for such binding to be physiologically significant, the binding constants must be compatible with the cellular availability of zinc(II) ions. The affinity of inhibitory zinc(II) ions for receptor protein tyrosine phosphatase beta is particularly high (K i = 21 pM, pH 7.4), indicating that some enzymes bind zinc almost as strongly as zinc metalloenzymes. The competitive pattern of zinc inhibition for this phosphatase implicates its active site cysteine and nearby residues in the coordination of zinc. Quantitative biophysical data on both affinities of proteins for zinc and cellular zinc(II) ion concentrations provide the basis for examining the physiological significance of inhibitory zinc-binding sites in proteins and the role of zinc(II) ions in cellular signalling. Regulatory functions of zinc(II) ions add a significant level of complexity to biological control of metabolism and signal transduction and embody a new paradigm for the role of transition metal ions in cell biology. PMID- 23456097 TI - Combining NMR and small angle X-ray and neutron scattering in the structural analysis of a ternary protein-RNA complex. AB - Many processes in the regulation of gene expression and signaling involve the formation of protein complexes involving multi-domain proteins. Individual domains that mediate protein-protein and protein-nucleic acid interactions are typically connected by flexible linkers, which contribute to conformational dynamics and enable the formation of complexes with distinct binding partners. Solution techniques are therefore required for structural analysis and to characterize potential conformational dynamics. Nuclear magnetic resonance spectroscopy (NMR) provides such information but often only sparse data are obtained with increasing molecular weight of the complexes. It is therefore beneficial to combine NMR data with additional structural restraints from complementary solution techniques. Small angle X-ray/neutron scattering (SAXS/SANS) data can be efficiently combined with NMR-derived information, either for validation or by providing additional restraints for structural analysis. Here, we show that the combination of SAXS and SANS data can help to refine structural models obtained from data-driven docking using HADDOCK based on sparse NMR data. The approach is demonstrated with the ternary protein-protein-RNA complex involving two RNA recognition motif (RRM) domains of Sex-lethal, the N terminal cold shock domain of Upstream-to-N-Ras, and msl-2 mRNA. Based on chemical shift perturbations we have mapped protein-protein and protein-RNA interfaces and complemented this NMR-derived information with SAXS data, as well as SANS measurements on subunit-selectively deuterated samples of the ternary complex. Our results show that, while the use of SAXS data is beneficial, the additional combination with contrast variation in SANS data resolves remaining ambiguities and improves the docking based on chemical shift perturbations of the ternary protein-RNA complex. PMID- 23456098 TI - Insights into drug precipitation kinetics during in vitro digestion of a lipid based drug delivery system using in-line raman spectroscopy and mathematical modeling. AB - PURPOSE: To determine drug precipitation during in vitro lipolysis of a lipid based drug delivery system (LBDDS) using Raman spectroscopy as a real-time monitoring technique. A second aim was to describe the kinetics of lipolysis triggered drug precipitation using a theoretical nucleation and growth model. METHODS: A model LBDDS containing different concentration of fenofibrate was digested in vitro and drug precipitation was determined after ultracentrifugation and nanofiltration (off-line methods), as well as by Raman spectroscopy (in-line method). Subsequently, a theoretical nucleation and growth model was fitted to the obtained drug crystallization profiles by considering the lipolysis-triggered change in drug solubility. RESULTS: Compared with standard off-line measurements, Raman spectroscopy enabled a more robust and highly time-resolved analysis of lipolysis-triggered drug precipitation. Although the formulation was rapidly digested, fenofibrate remained in a supersaturated state for several minutes before beginning to crystallize. The in vitro digestion results were in excellent agreement with the theoretical model (R (2) > 0.976). CONCLUSIONS: The combination of real-time Raman spectroscopy and mathematical modeling provided insights into the kinetics of lipolysis-triggered drug crystallization. This knowledge allows a better biopharmaceutical understanding and will, ultimately, lead to the improved development of lipid-based drug formulations. PMID- 23456100 TI - Astigmatism in patients with idiopathic congenital nystagmus. AB - PURPOSE: To evaluate the association between astigmatism and idiopathic congenital nystagmus (ICN) in infantile nystagmus syndrome (INS). MATERIALS AND METHODS: We analysed refractive errors in a cohort of 488 consecutive patients with ICN (group A) and further compared the results obtained with those of 488 age-matched controls with no nystagmus (group B). Only the worst eye was considered for statistical analysis. All patients were stratified into the following age groups: 1 to 4 years (age group 1); 5 to 12 years (age group 2); and 13 years to 57 years (age group 3) (mean age: 29). RESULTS: Three hundred and seventy patients (69.7 %) in group A and 269 patients (55,12 %) in group B had refractive errors. The types of refractive errors observed were: myopia, hyperopia (>0.50 dioptres) and astigmatism (>1.25 dioptres). Results in group A were as follows: 319 patients (65.37 %) were astigmatic, 34 (6.97 %) were hyperopic, and 17 (3.48 %) were myopic. Mean right-eye astigmatism was 2.72 dioptres, and mean left-eye astigmatism was 2.69 dioptres. Results in group B were as follows: 56 (11.47 %) were astigmatic, 165 (33.81) were hyperopic, and 48 (9.84) were myopic. Mean right-eye astigmatism was 2.05 dioptres, and mean left eye astigmatism was 2.37 dioptres. The prevalence of astigmatism is greater, in the entire sample, for subjects from age groups 2 and 3 (p<0.005). It shows a tendency to increase with age for patients of group A and in age group 3 (p=0.009). CONCLUSIONS: Astigmatism is more common in patients with ICN than in the general population (65.37 % vs 11.47 %) (p<0.001). Astigmatism increases with age, with a very high statistical significance in patients 13 years old and above (age group 3) when nystagmus is also present. Thus, nystagmus appears to be a predisposing factor for both the presence of astigmatism and the development with the age of high values of this refractive error. This findings should be taken into due account when considering visual dysfunctions in nystagmic patients. PMID- 23456099 TI - One-year results of reduced fluence photodynamic therapy for central serous chorioretinopathy: the outer nuclear layer thickness is associated with visual prognosis. AB - PURPOSE: To evaluate the efficacy of reduced-fluence photodynamic therapy (RFPDT) for central serous chorioretinopathy (CSC). METHODS: This retrospective medical record review of consecutive CSC patients treated with RFPDT (full-dose verteporfin and laser fluence of 25 J/cm(2)) examined 22 eyes of 21 patients (20 males and one female). All patients were followed-up for 1 year. Best-corrected visual acuity (BCVA), complete resolution of subretinal fluid (CR of SRF), central retinal thickness (CRT), the outer nuclear layer (ONL) thickness, and the photoreceptor inner and outer segments (IS/OS) line determined by optical coherence tomography imaging were evaluated at baseline, 1, 3, 6, 9, and 12 months after initial RFPDT. RESULTS: A single RFPDT session was performed in all cases during a 12-month period. CR of SRF was identified in all patients. BCVA significantly improved between 3 and 12 months (P < 0.05). The CRT significantly decreased between 1 and 12 months. A significantly thicker ONL was observed at 1 month, and 17 eyes (77.2 %) showed recovery of the continuous foveal IS/OS line. ONL thickness was correlated with BCVA at 12 months (P < 0.01). Stepwise analysis indicated that pre-treatment BCVA (P < 0.01) and ONL thickness (P < 0.01) were significant predictive factors for BCVA at 12 months. Neither ocular nor systemic adverse effects were observed during the follow-up period. CONCLUSION: RFPDT appears to be an effective treatment method for CSC. ONL thickness is an important visual predictive factor of RFPDT for CSC. PMID- 23456101 TI - Development of a placebo effect model combined with a dropout model for bipolar disorder. AB - The aim of this study was to develop a placebo model for bipolar disorder to help optimize clinical trial designs for studies targeting manic episodes in bipolar disorder. A bipolar disease database was built based on individual longitudinal data collected from over 3,000 patients in 11 clinical trials for 5 approved bipolar drugs. An empirical placebo effect model with an exponential decay process plus a linear progression process was developed to quantify the time course of the Young Mania Rating Scale total score based on only placebo data from the database. In order to describe the dropout pattern during the trials, a parametric survival model was developed and the Weibull distribution was identified to be the best distribution to describe the data. Based on the likelihood ratio test, it was found that patients with higher baseline score, slower disease improvement and more rapid disease progression tended to dropout earlier, and the trial features such as trial starting year and trial site were also significant covariates for dropout. A combination of the placebo effect model and the dropout model was applied to simulate new clinical trials through Monte-Carlo simulation. Both the placebo effect model and dropout model described the observed data reasonably well based on various diagnostic plots. The joint placebo response and dropout models can serve as a tool to simulate the most likely level of placebo response with the expected dropout pattern to help design a new clinical trial. PMID- 23456103 TI - In vivo measurement of skin microrelief using photometric stereo in the presence of interreflections. AB - This paper proposes and describes an implementation of a photometric stereo-based technique for in vivo assessment of three-dimensional (3D) skin topography in the presence of interreflections. The proposed method illuminates skin with red, green, and blue colored lights and uses the resulting variation in surface gradients to mitigate the effects of interreflections. Experiments were carried out on Caucasian, Asian, and African American subjects to demonstrate the accuracy of our method and to validate the measurements produced by our system. Our method produced significant improvement in 3D surface reconstruction for all Caucasian, Asian, and African American skin types. The results also illustrate the differences in recovered skin topography due to the nondiffuse bidirectional reflectance distribution function (BRDF) for each color illumination used, which also concur with the existing multispectral BRDF data available for skin. PMID- 23456102 TI - Molecular phylogeny and evolution of the proteins encoded by coleoid (cuttlefish, octopus, and squid) posterior venom glands. AB - In this study, we report for the first time a detailed evaluation of the phylogenetic history and molecular evolution of the major coleoid toxins: CAP, carboxypeptidase, chitinase, metalloprotease GON-domain, hyaluronidase, pacifastin, PLA2, SE-cephalotoxin and serine proteases, with the carboxypeptidase and GON-domain documented for the first time in the coleoid venom arsenal. We show that although a majority of sites in these coleoid venom-encoding genes have evolved under the regime of negative selection, a very small proportion of sites are influenced by the transient selection pressures. Moreover, nearly 70 % of these episodically adapted sites are confined to the molecular surface, highlighting the importance of variation of the toxin surface chemistry. Coleoid venoms were revealed to be as complex as other venoms that have traditionally been the recipient of the bulk of research efforts. The presence of multiple peptide/protein types in coleoids similar to those present in other animal venoms identifies a convergent strategy, revealing new information as to what characteristics make a peptide/protein type amenable for recruitment into chemical arsenals. Coleoid venoms have significant potential not only for understanding fundamental aspects of venom evolution but also as an untapped source of novel toxins for use in drug design and discovery. PMID- 23456104 TI - Efficient camera self-calibration method based on the absolute dual quadric. AB - Visual measurement technology has been widely used in fields such as industrial production or measurement and monitoring. Camera calibration is a very important link of visual measurement, because it directly determines the accuracy and precision of visual measurement. It often does not need extremely high-precision measurement but simple, rapid, effective measurement in many engineering surveys. Therefore, the camera self-calibration technique is really needed. The advantages of camera self-calibration are that it does not need any calibration target or complex mechanical structure that is used to control the camera's motion. In this paper, we propose an efficient camera self-calibration method based on the abstract quadric that is simple for calculation and has good robustness. PMID- 23456105 TI - Numerical solution of an inverse diffraction grating problem from phaseless data. AB - This paper is concerned with the numerical solution of an inverse diffraction grating problem, which is to reconstruct a periodic grating profile from measurements of the phaseless diffracted field at a constant height above the grating structure. An efficient continuation method is developed to recover the Fourier coefficients of the periodic grating profile. The continuation proceeds along the wavenumber and updates are obtained from the Landweber iteration at each step. Numerical results are presented to show that the method can effectively reconstruct the shape of the grating profile. PMID- 23456106 TI - Probability summation--a critique. AB - This Discussion Paper seeks to kill off probability summation, specifically the high-threshold assumption, as an explanatory idea in visual science. In combination with a Weibull function of a parameter of about 4, probability summation can accommodate, to within the limits of experimental error, the shape of the detectability function for contrast, the reduction in threshold that results from the combination of widely separated grating components, summation with respect to duration at threshold, and some instances, but not all, of spatial summation. But it has repeated difficulty with stimuli below threshold, because it denies the availability of input from such stimuli. All the phenomena listed above, and many more, can be accommodated equally accurately by signal detection theory combined with an accelerated nonlinear transform of small, near threshold, contrasts. This is illustrated with a transform that is the fourth power for the smallest contrasts, but tends to linear above threshold. Moreover, this particular transform can be derived from elementary properties of sensory neurons. Probability summation cannot be regarded as a special case of a more general theory, because it depends essentially on the 19th-century notion of a high fixed threshold. It is simply an obstruction to further progress. PMID- 23456107 TI - Absorption and scattering of light from ensembles of randomly oriented aggregates. AB - This paper presents one approach to the absorption and scattering of light from aggregates of primary particles. The primary particles are sphere-like and small compared to the wavelength, whereas the aggregate can be large compared to the wavelength. This situation applies to when soot particles formed in flames are measured using methods based on laser light. The method presented in this work, called generalized Rayleigh-Debye-Gans, leads to closed-form expressions for the scattered intensity and the absorbed power of an ensemble of aggregates with random positions and orientations. The expressions ensure a fast and accurate numerical evaluation of the scattering and absorption from ensembles of aggregates. The numerical results are compared with the ones obtained from the T matrix method and the discrete dipole approximation method. PMID- 23456108 TI - Electromagnetic wave scattering from a rough interface above a chiral medium: generalized field transforms. AB - In order to derive full-wave solutions for electromagnetic wave scattering from rough interfaces between achiral media (free space for instance) and chiral media that satisfy generalized constitutive relations, it is necessary to employ complete modal expansions for the electromagnetic fields above and below the interface. To this end, the familiar Fourier transforms of the fields are expressed as generalized field transforms consisting of the radiation term, the lateral waves, and the surface waves. Maxwell's equations are converted into generalized telegraphists' equations [in the companion paper (this issue), J. Opt. Soc. Am. A 30, 335 (2013)] upon the imposition of exact boundary conditions. These telegraphists' equations are coupled first-order differential equations for the forward- and backward-traveling wave amplitudes associated with all the different species of waves (radiation, lateral, and surface waves) excited at the surface of the chiral medium. The analysis presented here includes the completeness and orthogonal relations of the basis functions associated with the modal expansions. This work is used to distinguish between depolarization due to the chiral properties of the medium and depolarization due to surface irregularities. It has applications in remote sensing and identification of biological and chemical materials based on their optical activity. PMID- 23456109 TI - Electromagnetic wave scattering from a rough interface above a chiral medium: generalized telegraphists' equations. AB - Using complete modal expansions for the electromagnetic fields above and below a rough interface between free space and chiral media and on imposing exact boundary conditions at the interface, Maxwell's equations are converted into generalized telegraphists' equations for the wave amplitudes of different species of waves (radiation far fields, lateral, and surface waves). The local basis functions, used in the complete modal expansions, are functions of the fluctuating surface height and medium parameters. The generalized telegraphists' equations are coupled first-order differential equations for the forward- and backward-traveling wave amplitudes. The coupling between the different species of waves is due to the fluctuations of the rough surface height and medium parameters. A Taylor series expansion of the surface element scattering matrix in terms of the chiral parameter is used to distinguish between depolarization due to surface roughness and the chiral properties of the medium. The analysis has applications in remote sensing and identification of biological and chemical materials through their optical activity. PMID- 23456110 TI - Transparency perception: the key to understanding simultaneous color contrast. AB - The well-known simultaneous color contrast effect is traditionally explained in terms of visual color constancy mechanisms correcting for the confounding influence of ambient illumination on the retinal color signal. Recent research, however, suggests that the traditional gross quantitative laws of simultaneous color contrast, which are readily compatible with this functional explanation, should be revised and replaced by others, which are not readily understandable in terms of this perspective. Here, we show that the revised laws of simultaneous color contrast are well accounted for by an alternative theory explaining the simultaneous contrast effect in terms of mechanisms subserving the perception of transparent media. PMID- 23456111 TI - Hierarchy of nonlocal means for preferred automatic sharpness enhancement and tone mapping. AB - Existing hierarchical techniques that decompose an image into a smooth image and high frequency components based on Gaussian filter and bilateral filter suffer from halo effects, whereas techniques based on weighted least squares extract low contrast features as details. Other techniques require multiple images and are not tolerant to noise. We use a single image to enhance sharpness based on a hierarchical framework using a modified Laplacian pyramid. In order to ensure robustness, we remove noise by using an extra level in the hierarchical framework. We use an edge-preserving nonlocal means filter and modify it to remove potential halo effects and gradient reversals. However, these effects are only reduced but not removed completely after similar modifications are made to the bilateral filter. We compare our results with existing techniques and show better decomposition and enhancement. Based on validation by human observers, we introduce a new measure to quantify sharpness quality, which allows us to automatically set parameters in order to achieve preferred sharpness enhancement. This causes blurry images to be sharpened more and sufficiently sharp images not to be sharpened. Finally, we demonstrate applications in the context of robust high dynamic range tone mapping that is better than state-of-the-art approaches and enhancement of archaeological artifacts. PMID- 23456112 TI - Sparse ptychographical coherent diffractive imaging from noisy measurements. AB - Ptychography is a lensless coherent diffractive imaging that uses intensity measurements of multiple diffraction patterns collected with a localized illumination probe from overlapping regions of an object. An iterative algorithm is proposed that is targeted on optimal processing noisy measurements. The noise suppression is enabled by two instruments: first, the maximum-likelihood technique formulated for Poissonian (photon-counting) measurements, and, second, sparse approximation of the phase and magnitude of the object and probe. It is shown that the maximum-likelihood estimate of the wavefield at the sensor plane for noisy measurements is essentially different from the famous Gerchberg-Saxton Fienup solution, where the magnitude of the estimate is replaced by the square root of the intensity measurement. The simulation experiments demonstrate the state-of-the-art performance of the proposed algorithm both numerically and visually. PMID- 23456113 TI - PMD correlation properties in the hinge model. AB - We demonstrate that within the framework of the hinge model, the polarization mode dispersion (PMD) vector correlation function averaged over time and wavelength is only appreciably affected by the position of the last hinge. Further, the correlation function width is found within the context of a standard hinge model to decrease nearly monotonically with the number of hinges. We finally derive, through a theoretical analysis, an upper bound for the mean squared differential group delay of the last fiber section in the link in terms of the correlation function. PMID- 23456114 TI - Uniaxial absorbing media: conditions for refraction in the direction of the optical axis. AB - When a plane wave is incident from an isotropic medium into a uniaxial transparent medium so that the ordinary wave propagates in the direction of the optical axis, the extraordinary wave will also propagate in the same direction and with the same refractive index. We will show that this is not the case when the second medium is a uniaxial absorbing material. In this work, we will state a clear and precise interpretation of the meaning of propagation in the direction of the optical axis in the case of uniaxial absorbing media. Assuming that the ordinary wave is refracted in the direction of the optical axis we will analyze the refraction of the extraordinary wave and we will compare it with the case of transparent media. The necessary conditions to have both ordinary and extraordinary waves refracted in the direction of the optical axis will be obtained. PMID- 23456115 TI - Performance of visual search tasks from various types of contour information. AB - A recently proposed visual aid for patients with a restricted visual field (tunnel vision) combines a see-through head-mounted display and a simultaneous minified contour view of the wide-field image of the environment. Such a widening of the effective visual field is helpful for tasks, such as visual search, mobility, and orientation. The sufficiency of image contours for performing everyday visual tasks is of major importance for this application, as well as for other applications, and for basic understanding of human vision. This research aims is to examine and compare the use of different types of automatically created contours, and contour representations, for practical everyday visual operations using commonly observed images. The visual operations include visual searching for items, such as cutlery, housewares, etc. Considering different recognition levels, identification of an object is distinguished from mere detection (when the object is not necessarily identified). Some nonconventional visual-based contour representations were developed for this purpose. Experiments were performed with normal-vision subjects by superposing contours of the wide field of the scene over a narrow field (see-through) background. From the results, it appears that about 85% success is obtained for searched object identification when the best contour versions are employed. Pilot experiments with video simulations are reported at the end of the paper. PMID- 23456116 TI - Structured-light-based highly dense and robust 3D reconstruction. AB - In this paper, a structured-light-based highly dense and robust 3D reconstruction method is proposed by combining a Gray code and region-shifting pattern. The region-shifting pattern is transformed to the trapezoidal and triangle wave shifting pattern by combining all frames of the region-shifting pattern, and then the boundary of the trapezoidal wave shifting pattern and the peak and phase of the triangle wave shifting pattern are estimated. Through this technique, the spatial resolution is increased about three times. Consequently, the 3D points are reconstructed with a resolution much higher than a camera image resolution. Moreover, as the proposed method measures the boundary and the peak with all frames, it increases the signal-to-noise ratio and is more robust than the conventional methods that use only one or two frames to detect them. PMID- 23456117 TI - A reinterpretation of transparency perception in terms of gamut relativity. AB - Classical approaches to transparency perception assume that transparency constitutes a perceptual dimension corresponding to the physical dimension of transmittance. Here I present an alternative theory, termed gamut relativity, that naturally explains key aspects of transparency perception. Rather than being computed as values along a perceptual dimension corresponding to transmittance, gamut relativity postulates that transparency is built directly into the fabric of the visual system's representation of surface color. The theory, originally developed to explain properties of brightness and lightness perception, proposes how the relativity of the achromatic color gamut in a perceptual blackness whiteness space underlies the representation of foreground and background surface layers. Whereas brightness and lightness perception were previously reanalyzed in terms of the relativity of the achromatic color gamut with respect to illumination level, transparency perception is here reinterpreted in terms of relativity with respect to physical transmittance. The relativity of the achromatic color gamut thus emerges as a fundamental computational principle underlying surface perception. A duality theorem relates the definition of transparency provided in gamut relativity with the classical definition underlying the physical blending models of computer graphics. PMID- 23456118 TI - Time-and-frequency domains approach to data processing in multiwavelength optical scatterometry of dielectric gratings. AB - This paper focuses on scatterometry problems arising in lithography production of periodic gratings. Namely, the paper introduces a theoretical and numerical modeling-oriented approach to scatterometry problems and discusses its capabilities. The approach allows for reliable detection of deviations in gratings' critical dimensions (CDs) during the manufacturing process. The core of the approach is the one-to-one correspondence between the electromagnetic (EM) characteristics and the geometric/material properties of gratings. The approach is based on highly accurate solutions of initial boundary-value problems describing EM waves' interaction on periodic gratings. The advantage of the approach is the ability to perform simultaneously and interactively both in frequency and time domains under conditions of possible resonant scattering of EM waves by infinite or finite gratings. This allows a detection of CDs for a wide range of gratings, and, thus is beneficial for the applied scatterometry. PMID- 23456119 TI - Greedy reconstruction algorithm for fluorescence molecular tomography by means of truncated singular value decomposition conversion. AB - Fluorescence molecular tomography (FMT) is a promising imaging modality that enables three-dimensional visualization of fluorescent targets in vivo in small animals. L2-norm regularization methods are usually used for severely ill-posed FMT problems. However, the smoothing effects caused by these methods result in continuous distribution that lacks high-frequency edge-type features and hence limits the resolution of FMT. In this paper, the sparsity in FMT reconstruction results is exploited via compressed sensing (CS). First, in order to ensure the feasibility of CS for the FMT inverse problem, truncated singular value decomposition (TSVD) conversion is implemented for the measurement matrix of the FMT problem. Then, as one kind of greedy algorithm, an ameliorated stagewise orthogonal matching pursuit with gradually shrunk thresholds and a specific halting condition is developed for the FMT inverse problem. To evaluate the proposed algorithm, we compared it with a TSVD method based on L2-norm regularization in numerical simulation and phantom experiments. The results show that the proposed algorithm can obtain higher spatial resolution and higher signal-to-noise ratio compared with the TSVD method. PMID- 23456120 TI - Vector Monte Carlo simulations on atmospheric scattering of polarization qubits. AB - In this paper, a vector Monte Carlo (MC) method is proposed to study the influence of atmospheric scattering on polarization qubits for satellite-based quantum communication. The vector MC method utilizes a transmittance method to solve the photon free path for an inhomogeneous atmosphere and random number sampling to determine whether the type of scattering is aerosol scattering or molecule scattering. Simulations are performed for downlink and uplink. The degrees and the rotations of polarization are qualitatively and quantitatively obtained, which agree well with the measured results in the previous experiments. The results show that polarization qubits are well preserved in the downlink and uplink, while the number of received single photons is less than half of the total transmitted single photons for both links. Moreover, our vector MC method can be applied for the scattering of polarized light in other inhomogeneous random media. PMID- 23456121 TI - Postprocessing method for reducing phase effects in reconstructed microcomputed tomography data. AB - With increased resolution in x-ray computed tomography, refraction adds increasingly to the attenuation signal. Though potentially beneficial, the artifacts caused by refraction often need to be removed from the image. In this paper, we propose a postprocessing method, based on deconvolution, that is able to remove these artifacts after conventional reconstruction. This method poses two advantages over existing projection-based (preprocessing) phase-retrieval or phase-removal algorithms. First, evaluation of the parameters can be done very quickly, improving the overall speed of the method. Second, postprocessing methods can be applied when projection data is not available, which occurs in several commercial systems with closed software or when projection data has been deleted. It is shown that the proposed method performs comparably to state-of-the art methods in terms of image quality. PMID- 23456122 TI - In-plane displacement measurement in vortex metrology by synthetic network correlation fringes. AB - Recently we proposed an alternative method of displacement analysis in vortex metrology, based on the application of the Fourier optics techniques, that is suitable for an intermediate range of displacement measurements ranging below the resolution of speckle photography and above that of the conventional vortex metrology. However, for smaller displacements, we introduce an approach to perform the Fourier analysis from vortex networks. In this work, we present an enhanced method for measuring uniform in-plane displacements, taking advantage of the capability of determining the subpixel locations of vortices and having the ability to track the homologous vortices onto a plane. It is shown that high quality fringe systems can be synthesized and analyzed to accurately measure in an extended range of displacements and for highly decorrelated speckle patterns. Experimental results supporting the validity of the method are presented and discussed. PMID- 23456123 TI - Truncated Fourier-series approximation of the time-domain radiative transfer equation using finite elements. AB - The radiative transfer equation (RTE) is widely accepted to accurately describe light transport in a medium with scattering particles, and it has been successfully applied as a light-transport model, for example, in diffuse optical tomography. Due to the computationally expensive nature of the RTE, most of these applications have been in the frequency domain. In this paper, an efficient solution method for the time-domain RTE is proposed. The method is based on solving the frequency-domain RTE at multiple modulation frequencies and using the Fourier-series representation of the radiance to obtain approximation of the time domain solution. The approach is tested with simulations. The results show that the method can be used to obtain the solution of the time-domain RTE with good accuracy and with significantly fewer computational resources than are needed in the direct time-domain solution. PMID- 23456124 TI - Sparse spectrum model for a turbulent phase. AB - Monte Carlo (MC) simulation of phase front perturbations by atmospheric turbulence finds numerous applications for design and modeling of the adaptive optics systems, laser beam propagation simulations, and evaluating the performance of the various optical systems operating in the open air environment. Accurate generation of two-dimensional random fields of turbulent phase is complicated by the enormous diversity of scales that can reach five orders of magnitude in each coordinate. In addition there is a need for generation of the long "ribbons" of turbulent phase that are used to represent the time evolution of the wave front. This makes it unfeasible to use the standard discrete Fourier transform-based technique as a basis for the MC simulation algorithm. We propose a new model for turbulent phase: the sparse spectrum (SS) random field. The principal assumption of the SS model is that each realization of the random field has a discrete random spectral support. Statistics of the random amplitudes and wave vectors of the SS model are arranged to provide the required spectral and correlation properties of the random field. The SS-based MC model offers substantial reduction of computer costs for simulation of the wide-band random fields and processes, and is capable of generating long aperiodic phase "ribbons." We report the results of model trials that determine the number of sparse components, and the range of wavenumbers that is necessary to accurately reproduce the random field with a power-law spectrum. PMID- 23456125 TI - Angular spectrum and localized model of Davis-type beam. AB - The angular spectrum of the Davis fifth-order linearly polarized, dual, and symmetrized fields of a focused Gaussian laser beam is obtained. Since the original Davis fields are not an exact solution of the vector wave equation and Maxwell's equations, a beam remodeling procedure within the angular spectrum is described that produces an exact solution. The spherical multipole beam shape coefficients of the remodeled beam are then obtained, and it is shown that in the weak focusing limit they simplify to the localized model Gaussian beam shape coefficients for both on-axis and off-axis beams. The angular spectrum method is then applied to a transversely confined electromagnetic beam with arbitrary profile in the focal plane, and to a general zero-order Bessel beam. PMID- 23456126 TI - Caustics in a meridional plane produced by plano-convex aspheric lenses. AB - We study the formation of caustic surfaces formed in both convex-plano and plano convex aspheric lenses by considering a plane wave incident on the lens along the optical axis. Using the caustic formulas and a paraxial approximation we derive expressions to evaluate the spherical aberration at third-order and also provide a formula to reduce it, where the first-order aspheric term is given in a simply analytic equation. Furthermore, we redefine the method to evaluate the circle of least confusion for a positive lens as a function of all parameters involved in the process of refraction through the aspheric lenses. PMID- 23456127 TI - Fast and accurate analysis of large-scale composite structures with the parallel multilevel fast multipole algorithm. AB - Accurate electromagnetic modeling of complicated optical structures poses several challenges. Optical metamaterial and plasmonic structures are composed of multiple coexisting dielectric and/or conducting parts. Such composite structures may possess diverse values of conductivities and dielectric constants, including negative permittivity and permeability. Further challenges are the large sizes of the structures with respect to wavelength and the complexities of the geometries. In order to overcome these challenges and to achieve rigorous and efficient electromagnetic modeling of three-dimensional optical composite structures, we have developed a parallel implementation of the multilevel fast multipole algorithm (MLFMA). Precise formulation of composite structures is achieved with the so-called "electric and magnetic current combined-field integral equation." Surface integral equations are carefully discretized with piecewise linear basis functions, and the ensuing dense matrix equations are solved iteratively with parallel MLFMA. The hierarchical strategy is used for the efficient parallelization of MLFMA on distributed-memory architectures. In this paper, fast and accurate solutions of large-scale canonical and complicated real-life problems, such as optical metamaterials, discretized with tens of millions of unknowns are presented in order to demonstrate the capabilities of the proposed electromagnetic solver. PMID- 23456128 TI - Accurate image quantization adapted to multisource photometric reconstruction for rough textured surface analysis. AB - In classical photometric stereo (PS), a Lambertian surface is illuminated from three distant light sources to recover one normal direction per pixel of the input image. In continuous noiseless cases, PS allows us to reconstruct the textured surfaces in three-dimensions with a high degree of accuracy and a high resolution. In the real world, an image is a digital quantization, a limited and noisy representation of a surface. In this paper, we present an accurate 3D recovery approach for real textured surfaces based on an acquisition PS method. The proposed method uses a sequence of images for each light source to recover an accurate and unlimited representation of a surface. To evaluate the performances of the proposed method, we compare it to other traditional PS methods on real textured surfaces. PMID- 23456129 TI - Calculation of the scalar diffraction field from curved surfaces by decomposing the three-dimensional field into a sum of Gaussian beams. AB - We present a local Gaussian beam decomposition method for calculating the scalar diffraction field due to a two-dimensional field specified on a curved surface. We write the three-dimensional field as a sum of Gaussian beams that propagate toward different directions and whose waist positions are taken at discrete points on the curved surface. The discrete positions of the beam waists are obtained by sampling the curved surface such that transversal components of the positions form a regular grid. The modulated Gaussian window functions corresponding to Gaussian beams are placed on the transversal planes that pass through the discrete beam-waist position. The coefficients of the Gaussian beams are found by solving the linear system of equations where the columns of the system matrix represent the field patterns that the Gaussian beams produce on the given curved surface. As a result of using local beams in the expansion, we end up with sparse system matrices. The sparsity of the system matrices provides important advantages in terms of computational complexity and memory allocation while solving the system of linear equations. PMID- 23456130 TI - Analytical solutions for diffuse fluorescence spectroscopy/imaging in biological tissues. Part I: zero and extrapolated boundary conditions. AB - The mathematical model for diffuse fluorescence spectroscopy/imaging is represented by coupled partial differential equations (PDEs), which describe the excitation and emission light propagation in soft biological tissues. The generic closed-form solutions for these coupled PDEs are derived in this work for the case of regular geometries using the Green's function approach using both zero and extrapolated boundary conditions. The specific solutions along with the typical data types, such as integrated intensity and the mean time of flight, for various regular geometries were also derived for both time- and frequency-domain cases. PMID- 23456131 TI - Analytical solutions for diffuse fluorescence spectroscopy/imaging in biological tissues. Part II: comparison and validation. AB - The analytical solutions for the coupled diffusion equations that are encountered in diffuse fluorescence spectroscopy/imaging for regular geometries were compared with the well-established numerical models, which are based on the finite element method. Comparison among the analytical solutions obtained using zero boundary conditions and extrapolated boundary conditions (EBCs) was also performed. The results reveal that the analytical solutions are in close agreement with the numerical solutions, and solutions obtained using EBCs are more accurate in obtaining the mean time of flight data compared to their counterpart. The analytical solutions were also shown to be capable of providing bulk optical properties through a numerical experiment using a realistic breast model. PMID- 23456132 TI - Medical complications and outcomes at an onsite rehabilitation unit for older people. AB - BACKGROUND: The rehabilitation of older patients in Ireland after an acute medical event occurs at dedicated onsite hospital units or at offsite centres. Information on medical complications and outcomes is inadequate. AIMS: Enumeration of medical complications of patients admitted to a dedicated onsite rehabilitation unit for older people, and the extent of co-morbidity in the population with the effects that this had on the evolution of medical complications. METHODS: A retrospective analysis of patients admitted to a 58-bed onsite unit over a 1-year period was performed. Information collating co morbidities, medical complications and functional outcomes was recorded. RESULTS: Medical complications occurred in almost 95% of patients, where full data were available. Over one-third required intravenous therapy. CONCLUSION: Twenty-four hour medical cover is required for older patients managed at onsite rehabilitation units. Further studies on offsite medical rehabilitation facilities for older patients are required. PMID- 23456133 TI - Evaluation of the effects of ozone therapy on Escherichia coli-induced cytitis in rat. AB - OBJECTIVES: The aim of the study was to investigate the effect of ozone on oxidative/nitrosative stress and bladder injury caused by Escherichia coli in rat bladder. METHODS: Twenty-one Wistar-Albino-type female rats included in the study were divided into three groups of equal number: (1) sham operation (control), (2) E. coli-only (EC), (3) EC + ozone. After ozone therapy for 3 days, urine and tissue samples were obtained for biochemical, microbiological, and histopathological analysis. RESULTS: Tissue malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) level were increased, whereas superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity was decreased in the EC group. MDA, MPO, and NO levels were decreased, whereas SOD, GPx activity was increased in the ozone-treated group. Also, there was no bacterial translocation in this group. CONCLUSION: The results of the present study suggest that ozone may be used as an agent to protect the bladder from oxidative/nitrosative stress occurring in cystitis. PMID- 23456134 TI - Peripheral blood CD40-CD40L expression in human breast cancer. AB - BACKGROUND: Breast cancer is the most common cancer in women. T cell-based immunotherapy for cancer has attracted much attention recently. CD40 and CD40L occupy an important position of specific immune response. In this paper, we want to study the role of co-stimulatory molecules CD40/CD40L and their clinical significance in peripheral blood of patients with breast cancer. METHODS: Thirty breast cancer patients served as observation group, who were diagnosed as having infiltrating ductal breast cancer histopathologically, and 30 healthy as control group. Flow cytometric analysis was conducted to detect the expression of CD40 and CD40L on B and T lymphocytes in peripheral blood. The relationship between the CD40/CD40L expression levels and pathological grades was analyzed. RESULTS: The expression levels of CD40/CD40L on B cells and T cells in breast cancer patients were significantly higher than those in the controls (all P < 0.001), and CD40/CD40L levels had a significant positive relationship with pathological grades (all P < 0.001). CONCLUSIONS: The upregulated levels of co-stimulators CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. PMID- 23456135 TI - Genomics-based high-resolution mapping of the BaMMV/BaYMV resistance gene rym11 in barley (Hordeum vulgare L.). AB - Soil-borne barley yellow mosaic virus disease, caused by different strains of Barley yellow mosaic virus (BaYMV) and Barley mild mosaic virus (BaMMV), is one of the most important diseases of winter barley (Hordeum vulgare L.) in Europe and East Asia. The recessive resistance gene rym11 located in the centromeric region of chromosome 4HL is effective against all so far known strains of BaMMV and BaYMV in Germany. In order to isolate this gene, a high-resolution mapping population (10,204 meiotic events) has been constructed. F2 plants were screened with co-dominant flanking markers and segmental recombinant inbred lines (RILs) were tested for resistance to BaMMV under growth chamber and field conditions. Tightly linked markers were developed by exploiting (1) publicly available barley EST sequences, (2) employing barley synteny to rice, Brachypodium distachyon and sorghum and (3) using next-generation sequencing data of barley. Using this approach, the genetic interval was efficiently narrowed down from the initial 10.72 % recombination to 0.074 % recombination. A marker co-segregating with rym11 was developed providing the basis for gene isolation and efficient marker assisted selection. PMID- 23456136 TI - Association between ultrasound measurements of muscle thickness, pennation angle, echogenicity and skeletal muscle strength in the elderly. AB - The increase of elderly in our society requires simple tools for quantification of sarcopenia in inpatient and outpatient settings. The aim of this study was to compare parameters determined with musculoskeletal ultrasound (M-US) with muscle strength in young and elderly patients. In this prospective, randomised and observer blind study, 26 young (24.2 +/- 3.7 years) and 26 old (age 67.8 +/- 4.8 years) patients were included. Muscle thickness, pennation angle and echogenicity of all muscles of musculus quadriceps were measured by M-US and correlated with isometric maximum voluntary contraction force (MVC) of musculus quadriceps. Reproducibility of M-US measurements as well as simple and multiple regression models were calculated. Of all measured M-US variables the highest reproducibility was found for measurements of thickness (intraclass correlation coefficients, 85-97%). Simple regression analysis showed a highly significant correlation of thickness measurements of all muscles of musculus quadriceps with MVC in the elderly and in the young. Multiple regression analysis revealed that thickness of musculus vastus medialis had the best correlation with MVC in the elderly. This study showed that measurement of muscle thickness, especially of musculus vastus medialis, by M-US is a reliable, bedside method for monitoring the extent of sarcopenia. PMID- 23456137 TI - Cohort studies with low baseline response may not be generalisable to populations with different exposure distributions. AB - Several advocates of mega-cohorts in epidemiology recently stated that high baseline response needs not be a driving scientific factor. We illustrate how cohort studies with low baseline response can become less generalisable than cohort studies with reasonable high baseline response. Assuming exposure prevalences of 32%, and 39% for former, and current smoking in the general population, we postulate that 10% in each group have a specific genotype G that makes them susceptible for the effect of smoking on the outcome (synergism between genotype and smoking). The existence and the mechanism of this synergism is unknown to the investigator. The parameter of interest is the average effect of smoking on the outcome expressed as relative risk (RR). We consider three different scenarios. In scenario 1, the RR for former and present smokers is 50 and 100 for subjects with G, translating into RR of 5.9 and 10.9 at population level. In scenario 2, the according figures are 10 and 20 for subjects with G and 1.9 and 2.9 at the population level, while in scenario 3, the according numbers are 2 and 5, and 1.1 and 1.4, respectively. We assume a differential baseline response by genotype G with overall baseline responses of 10% (low) and 50% (high). In all scenarios, we observe generalisability for a high baseline response. In contrast, for low baseline response the RRs for former and current smokers lack generalisability with loss of dose response relationship leading to 2.58 and 2.09 in scenario 1, to 1.29 and 1.21 in scenario 2, and in scenario 3 with RRs very close to unity (1.03 and 1.04 respectively). RR estimates may lack generalisability and dose response relationships even may be inverted if baseline response is low. Thus, even mega-cohorts should strive for a reasonable high baseline response. PMID- 23456139 TI - Gout and the risk of Parkinson's disease in Denmark. PMID- 23456138 TI - Vitamin D and risk of future hypertension: meta-analysis of 283,537 participants. AB - The evidence on the association between baseline vitamin D status and risk of incident hypertension in general populations is limited and has not been reliably quantified. We conducted a systematic review and meta-analysis of published prospective studies evaluating the associations of baseline vitamin D status (circulating 25-hydroxyvitamin D [25(OH)D] levels and dietary vitamin D intake) with risk of hypertension. Eligible studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to November 2012. Pooled relative risks (RRs) with 95% confidence intervals were calculated using random effects models. Generalized least-squares trend estimation was used to assess dose-response relationships. Of the 2,432 articles reviewed for eligibility, eight unique prospective cohorts with aggregate data on 283,537 non-overlapping participants and 55,816 incident hypertension cases were included. The RRs (95% CIs) for hypertension in a comparison of extreme thirds of baseline levels of vitamin D were 0.70 (0.58, 0.86) for seven studies that measured blood 25(OH) D levels and 1.00 (0.95, 1.05) for four studies that assessed dietary vitamin D intake. The pooled RR of incident hypertension per 10 ng/mL increment in baseline 25(OH)D levels was 0.88 (0.81, 0.97) in dose-response analysis. Evidence was lacking of heterogeneity among studies that measured blood 25(OH) D levels and those that assessed dietary vitamin D status. Studies are needed to determine whether the association of vitamin D with hypertension represents a causal association and also to determine whether vitamin D therapy may be beneficial in the prevention or the treatment of hypertension. PMID- 23456140 TI - Weekly, low-dose docetaxel combined with estramustine for Japanese castration resistant prostate cancer: its efficacy and safety profile compared with tri weekly standard-dose treatment. AB - BACKGROUND: We retrospectively investigated the efficacy and safety profile of weekly low-dose docetaxel (DTX) with estramustine in comparison with triweekly standard-dose DTX treatment for Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Between April 2002 and January 2011, 75 CRPC patients were treated with triweekly DTX (60-75 mg/m(2) every 3 weeks) (standard dose group), and 76 CRPC patients were treated with weekly low-dose DTX (20-30 mg/m(2) on days 2 and 9 with estramustine 560 mg on days 1-3 and 8-10) every 3 weeks (low-dose group). Prostate-specific antigen (PSA) response and progression free and overall survival were analyzed in each group. RESULTS: Median serum PSA level of the standard-dose group and low-dose group was 25.0 and 35.5 ng/ml, respectively. In the standard-dose and low-dose groups, 57.8 and 65.2 % of patients, respectively, achieved a PSA decline >= 50 %. There was no significant difference in either median time to progression between the standard-dose group (10.0 months) and low-dose group (7.1 months) or in median duration of survival between the standard-dose group (24.2 months) and low-dose group (30.6 months). Multivariate analysis with a Cox proportional hazards regression model showed that DTX treatment protocol did not influence the risk of death. Incidences of grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia were significantly higher in the standard-dose versus low-dose group (58.7 vs. 7.9 %, 16.0 vs. 3.9 %, and 8.0 vs. 0 %, respectively). CONCLUSION: For Japanese CRPC patients, weekly low-dose DTX combined with estramustine has similar efficacy to standard-dose DTX but with fewer adverse events. PMID- 23456141 TI - Clinicopathological correlation for the role of fluorodeoxyglucose positron emission tomography computed tomography in detection of choroidal malignant melanoma. AB - BACKGROUND: The purpose of this study was to redefine the role of whole-body 2 [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography fused with computed tomography (PET/CT) in the clinical diagnosis of choroidal malignant melanoma. METHODS: The study design was a retrospective case series involving 7 consecutive patients with choroidal malignant melanoma who underwent enucleation to reach the final pathological diagnosis. FDG-PET/CT was performed together with magnetic resonance imaging and ophthalmological examinations before the surgery. The area, thickness, longest diameter, and circumference of the tumor mass were measured on pathological sections, and were correlated with maximum standardized uptake values (SUVmax) of the tumors on FDG-PET/CT. RESULTS: Abnormally high uptake of FDG was noted in the affected eyes of 5 patients, but not in the eyes of 2 patients. The 5 patients with high uptake showed nodular tumors extruding into the vitreous cavity while the 2 patients with absence of uptake showed diffusely infiltrating tumors in the wide area of the choroid with or without a small mushroom-like protrusion. One patient with diffuse infiltration showed concurrent liver metastases with high uptake on PET/CT while another patient with a nodular tumor developed liver metastases a year later. The tumors with higher SUVmax had a tendency to have a wider area and greater thickness on pathological sections (rho = 0.775, P = 0.0557, Spearman rank correlation test). CONCLUSIONS: FDG-PET/CT showed correlation of the uptake with tumor sizes but was limited in detecting diffusely infiltrating tumors in the choroid without nodular formation. PMID- 23456142 TI - Publication ethics in biomedical journals from countries in Central and Eastern Europe. AB - Publication ethics is an important aspect of both the research and publication enterprises. It is particularly important in the field of biomedical science because published data may directly affect human health. In this article, we examine publication ethics policies in biomedical journals published in Central and Eastern Europe. We were interested in possible differences between East European countries that are members of the European Union (Eastern EU) and South East European countries (South-East Europe) that are not members of the European Union. The most common ethical issues addressed by all journals in the region were redundant publication, peer review process, and copyright or licensing details. Image manipulation, editors' conflicts of interest and registration of clinical trials were the least common ethical policies. Three aspects were significantly more common in journals published outside the EU: statements on the endorsement of international editorial standards, contributorship policy, and image manipulation. On the other hand, copyright or licensing information were more prevalent in journals published in the Eastern EU. The existence of significant differences among biomedical journals' ethical policies calls for further research and active measures to harmonize policies across journals. PMID- 23456143 TI - Becoming men: Gender, disability, and transitioning to adulthood. AB - Children and youth with progressive conditions are living longer, and there is increased interest in designing programs that will assist them with "transitioning" to adulthood. Almost none of the transitions research to date, however, has attended to the experiences of disabled boys in "becoming men," nor has there been critical conceptual work problematizing notions of "normal" adulthood or theorizing the complex, diverse, and gendered experiences of transitioning. In this Canadian study, we investigated the intersectionality of gender, disability, and emerging adulthood with 15 young men with Duchenne muscular dystrophy. Participants created audio diaries and photographs that were explored in in-depth interviews. Using a Bourdieusian lens and Arthur Frank's notion of the narrative habitus, we examined how participants re/negotiated identities in everyday practices. Our analysis suggested that disability, masculinities, and generational (life stage) identities intersected through "narratives of nondifference," wherein participants worked to establish identities as typical "guys." Within limited fields of school and work, participants distanced themselves from the label of "disabled" and discussed their successes and challenges in terms of normative developmental trajectories. We suggest that the pursuit of "normal" is reproduced and reinforced in health and social programs and closes off other narratives and possibilities. PMID- 23456144 TI - In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph. AB - The standard diagnostic procedure for basal cell carcinoma (BCC) is invasive tissue biopsy with time-consuming histological examination. To reduce the number of biopsies, noninvasive optical methods have been developed providing high resolution skin examination. We present direct comparison of a reflectance confocal microscope (RLSM) and a multiphoton tomograph (MPT) for BCC diagnosis. Both systems are applied to nine patients prior to surgery, and the results are analyzed, including histological results. Both systems prove suitable for detecting typical characteristics of BCC in various stages. The RLSM allows large horizontal overview images to be obtained, enabling the investigator to find the regions of interest quickly, e.g., BCC nests. Elongated cells and palisading structures are easily recognized using both methods. Due to the higher resolution, changes in nucleus diameter or cytoplasm could be visualized with the MPT. Therefore, the nucleus diameter, nucleus/cytoplasm ratio, and cell density are estimated for normal and BCC cells using the MPT. The nucleus of elongated BCC cells is significantly longer than other measured normal skin cells, whereas the cell density and nucleus/cytoplasm ratio of BCC cannot be significantly distinguished from granular cells. PMID- 23456145 TI - Management of severe rhinophyma with sculpting surgical decortication. AB - Rhinophyma, a progressive, disfiguring disease of the nose, is considered the final stage of acne rosacea. In its early stages, rhinophyma can be managed with medical treatment using isotretinoin or oral antibiotics (metronidazole). However, severe cases usually are refractory to medical approaches. Surgical therapies to treat these severe refractory cases have been described. This report describes a simple, safe, efficient, and cost-effective approach to the treatment of severe rhinophyma using a scalpel and the electroscalpel, instruments readily available in every operating room. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23456146 TI - Prevention of capsular contracture with Guardix-SG((r)) after silicone implant insertion. AB - BACKGROUND: Capsular contracture is the most common side effect of breast implant insertion and the problem that breast surgeons seek to avoid the most. Previous animal studies have proved that an antiadhesive barrier solution (AABS) prevents peri-implant capsule formation. In this study, the authors sought to explore the effect that Guardix-SG((r)), an AABS that can encapsulate implants in the form of a gel, can have on capsular contracture. METHOD: This study used 12 female New Zealand white rabbits weighing 2.5-3 kg. Implants were inserted into the subpanniculus carnosus plane through an incision in the bilateral midback area. Once the implant was inserted, 3 g of Guardix-SG((r)) and normal saline were instilled into the left and right sides, respectively. The rabbits were killed 6 months after the procedure. The intracapsular pressure was measured using tonometry with a 38.2-g circular glass piece, and capsular thickness was measured by dyeing the biopsy specimen with hematoxylin and eosin and Masson's trichrome stain. The myofibroblasts were quantitatively analyzed through monoclonal anti alpha smooth muscle actin antibody immunohistochemistry staining. RESULTS: The intracapsular pressure in the control group (4.51 +/- 0.98 mmHg) was significantly higher (p = 0.002) than in the study group (3.51 +/- 0.4 mmHg). The average capsular thickness was significantly greater in the control group (0.33 +/- 0.15 mm; p = 0.015). In the analysis, the interrelation between capsular thickness and intracapsular pressure was insignificant in both groups, as was the number of myofibroblasts in both groups (p = 0.582). CONCLUSION: Through this study, the authors were able to demonstrate that capsular contracture can be suppressed in the rabbit model by instilling Guardix-SG((r)) after insertion of cohesive gel implants in the subpanniculus carnosus plane. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23456147 TI - Impact of the defect size, the mesh overlap and the fixation depth on ventral hernia repairs: a combined experimental and numerical approach. AB - BACKGROUND: Ventral hernia repairs (VHRs) still exhibit clinical complications in terms of recurrence, pain, and discomfort. Factors such as surgical technique or mesh features are thought to be highly influent. The aim was to evaluate the impact of the defect size, the mesh overlap and the fixation depth on VHR using both physical and numerical models. METHODS: The physical model was developed to mimic a passive abdominal wall. Healthy, damaged, and repaired configurations were evaluated using a spherical plunger. The associated numerical (Finite Elements) model was first loaded by a plunger for validation. A parametric study was then conducted with the numerical model loaded by a uniform pressure. Two defect sizes (3.5 * 5 cm and 8.25 * 12 cm elliptic shape), two overlaps (2 and 5 cm), and two fixation depths (peritoneum or muscle) were investigated for both passive and active abdominal walls. RESULTS: With the physical model, the repaired configuration was 22 % stiffer than the damaged configuration. The statistical analysis of the parametric study showed that the defect size was the most influential parameter regarding the stress in the mesh, the bulging and the pull-out force at the fixation points. The overlap was influential in terms of stress in the mesh. The fixation depth was not influential. These trends increased with the abdominal wall activity. CONCLUSION: Increase of the defect size and decrease of the overlap affected significantly the VHR mechanical performances. Such numerical models could help to better understand the behavior of the repaired abdominal wall and finally to reduce the clinical complications. PMID- 23456148 TI - Kugel patch repair of superior lumbar hernias. PMID- 23456149 TI - Incisional hernia rate after open abdomen treatment with negative pressure and delayed primary fascia closure. AB - PURPOSE: Various techniques for delayed primary fascia closure have been published in patients treated with open abdomen (OA) and application of negative pressure, but to date, no data are available on incisional hernia (IH) rate. The aim of this retrospective analysis was to investigate the long-term outcome of this patient population with special interest in IH development. METHODS: Two hundred and nine consecutive patients, 90(43 %) female, were treated at our institution for various abdominal emergencies involving OA from June 2006 to June 2011. Mean age was 63(16-92) years. The indication was abdominal sepsis in 155(74 %) patients, ischemia in 24(12 %) and other reasons in 30(14 %). Hospital mortality was 21 %(n = 44); and planned ventral hernia was 7 %(n = 15); and mortality until follow-up was 16 %(n = 25), and 9 %(n = 13) patients were lost to follow-up, leaving 112 patients for evaluation of IH development. RESULTS: The rate of IH for patients with OA and delayed primary fascia closure was overall 35 % at a median (range) follow-up time of 26(12-81) months. Mean time for development of a ventral hernia was 11 months; 21(57 %) patients underwent surgery for symptomatic hernia (2 emergency operations for incarceration). Kaplan Meier estimate for 5 years gave a 66 % IH rate. BMI, small bowel as source of infection and rapid adsorbable interrupted suture were identified risk factors. CONCLUSION: The rate of IH after open abdomen treatment with delayed primary fascia closure is high with a running suture with slow absorbable suture material showing the best results. PMID- 23456150 TI - Comment to: the use of sterilized mosquito nets for hernioplasty: a systematic review. Sorensen CG, Rosenberg J. Hernia 2012; 16: 621-625. PMID- 23456151 TI - Surgical treatment for giant incisional hernia: a qualitative systematic review. AB - INTRODUCTION: Repair for giant incisional hernias is a challenge due to unacceptable high morbidity and recurrence rates. Several surgical techniques are available, but all are poorly documented. This systematic review was undertaken to evaluate the existing literature on repair for giant incisional hernia. METHODS: Literature was identified through a systematic search on PubMed, EMBASE, and CINAHL. We only included studies with clearly defined surgical techniques and defect size of at least 15 cm. The heterogeneity of the studies precluded a meta analysis. The analysis was based on the premises of a systematic review of the literature. RESULTS: We identified 14 studies (1,198 patients) including one randomised trial. Studies were mainly small and retrospective and highly heterogenic regarding design, outcome, inclusion, and exclusion criteria. The overall morbidity rate was median 32 % with a wide range between studies of 4-100 %. The mortality ranged from 0 to 5 % (median 0 %) and recurrence rate ranged from 0 to 53 % (median 5 %). Study follow-up ranged from 15 to 97 months (median 36 months). Mesh repair should always be used for patients undergoing repair for a giant hernia, and the sublay position may have advantages over onlay positioning. To avoid tension, it may be advisable to use a mesh in combination with a component separation technique. Inlay positioning of the mesh and repair without a mesh should be avoided. CONCLUSIONS: Evidence to optimise repair for giant hernias is weak due to the heterogeneity and the poor quality of studies. However, sublay positioning of the mesh perhaps in combination with a component separation technique may be advantageous compared with other surgical techniques for giant hernia repair. Giant hernia repair is a challenging surgical procedure and severely lack evidence-based research from high-quality, large-scaled randomised studies. PMID- 23456152 TI - Room temperature C-N bond cleavage of anionic guanidinate ligand in rare-earth metal complexes. AB - The dissociation of the anionic guanidinate ligand N=C(NMe2)2 promoted by rare earth metal complexes at room temperature is described. Treatment of CpLnCl2(THF)3 with two equiv. of Li[N=C(NMe2)2] in THF at room temperature affords [Cp2Ln(MU-eta(1):eta(2)-L2)]2 (Ln = Y; L = N=C(NMe2)N=C(NMe2)2) and CpLn[N=C(NMe2)2](MU-eta(1):eta(2)-L)2LnCp2 (Ln = Dy) in moderated yields, respectively. YCl3 reacts with three equiv. of Li[N=C(NMe2)2] under the same conditions to give a trinuclear yttrium guanidinate [(Me2N)2C=N]5Y3[MU N=C(NMe2)2]2(MU-eta(1):eta(2)-L)2 in 63% yield. These reactions show that rare earth metals can promote a C-N bond cleavage of the guanidine anion [N=C(NMe2)2]( ) at room temperature. All new complexes were characterized by elemental analysis and spectroscopic properties, and their solid-state structures were determined through single-crystal X-ray diffraction analysis. PMID- 23456153 TI - Novel technique for relieving anastomotic tension using halo-vest immobilization after tracheal sleeve resection. AB - We describe a novel technique of using halo-vest-enforced immobilization to relieve anastomotic tension after tracheal sleeve resection. Immediately after the tracheal sleeve resection, four halo titanium pins were inserted in the skulls of the patients to secure the halo-vest. All patients fitted with halo vests were able to eat and drink and their clinical course was good. Bronchoscopy confirmed the absence of anastomotic leaks and stenoses, and there were no complications associated with the halo-vest. We believe that ensuring neck flexion using a halo-vest after tracheal sleeve resection is an excellent way of relieving anastomotic tension that would predispose the wound to dehiscence. PMID- 23456154 TI - A hidden giant: Wallenberg syndrome and aortal wall thickening as an atypical presentation of a giant cell arteritis. AB - We report a case of a 73-year-old woman with a brainstem stroke presenting as Wallenberg syndrome. By transoesophageal echocardiography and combined 18F fluordeoxyglucose positron emission and CT (18F-FDG PET/CT), the diagnosis of large artery vasculitis owing to giant cell arteritis was confirmed. In the absence of classical clinical signs, the examination of the large extracranial vessels by ultrasound and 18F-FDG PET/CT played the key role in detecting a widespread vasculitis. PMID- 23456155 TI - Tuberculous myopericarditis: a rare presentation in an immunocompetent host. AB - Tuberculosis is a common cause of pericardial disease in India. Myocardial involvement, although well described in the literature, is a rare manifestation of tuberculosis. We report a patient with disseminated tuberculosis and myopericarditis manifesting as cardiogenic shock. The patient gradually improved on antituberculosis drug therapy, steroids and an evidence-based guideline driven therapy for heart failure. Follow-up imaging showed calcification of the pericardium and improvement of his left ventricular systolic function. PMID- 23456156 TI - Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: a question of prophylaxis. AB - A man in his late 50s with a history of membranoproliferative glomerulonephritis presented with fever and mild dyspnoea. He was HIV-negative and had been on corticosteroids as immunosuppression for 6 months prior to tapering them off 1 week before presentation. He was not taking prophylaxis for Pneumocystis jirovecii pneumonia. After unsuccessful treatment for community-acquired pneumonia, his condition worsened and he required intubation and mechanical ventilation. Full respiratory workup including bronchoscopy revealed P jirovecii as a source for the patient's infection. He was treated successfully with a 21 day course of trimethoprim-sulfamethoxazole and eventually weaned off the ventilator. He has had no complications to date. In our review of this case and the existing literature, we believe that proper utilisation of prophylaxis for pneumocystis pneumonia may have prevented our patient's transfer to intensive care unit. In our article, we discuss this issue and explore current evidence for prophylaxis. PMID- 23456157 TI - Acute kidney injury requiring haemodialysis following ingestion of mephedrone. AB - A 25-year-old man was found to have acute kidney injury (AKI) following ingestion of mephedrone. He presented to this local emergency department with worsening bilateral loin pain. He became oligoanuric, serum creatine peaked at 1214 umol/l and he required several sessions of haemodialysis before kidney function began to improve. The mechanism of AKI and legal aspects of the use of mephedrone are discussed. PMID- 23456158 TI - An unusual cause of cyanosis in a patient with COPD. AB - We present a case of acquired methaemoglobinaemia related to the prolonged use of dapsone in a patient with chronic hypoxia. The patient was initially successfully treated for infective exacerbation of chronic obstructive pulmonary disease (COPD). However, he remained persistently hypoxic on pulse oximetry despite a normal PaO2 on arterial blood gas sampling. His fraction of methaemoglobin (FMetHb) was found to be elevated at 13%. After cessation of dapsone, his clinical cyanosis recuperated, his exercise tolerance and functional capacity improved and his FMetHb normalised to 1%. PMID- 23456159 TI - A dangerous cough. AB - Patient X is a 48-year-old retired potteries worker who presented to his general practitioner (GP) with a non-productive cough, which had lasted over 1 month, and it was a television advert that he had seen that prompted him to visit his doctor. A cough is the most common presenting complaint for patients when they visit their GP and when considering differential diagnoses it is important to look at a patient's medical, drug and social history. It would have been easy for the GP to dismiss the cough as an exacerbation of the patient's asthma based on his medical history, but on further questioning into the patient's social history an emergency chest x-ray was ordered, which later revealed a bronchial carcinoma. This case highlights the importance of the media in healthcare advertising and describes how a fairly innocent presentation can later turn out to be a more sinister pathology. PMID- 23456160 TI - How far you can trust c-ANCA? AB - The suspicion of a serious condition arises if a smoker is coughing and losing weight constantly. Serology and imaging are great options for diagnosis, but what is their specificity? A 62-year-old man presented with persistent cough, weight loss and hypoxia. A chest x-ray revealed bilateral interstitial infiltrates. Treatment with several antibiotics failed. Serological results showed antineutrophil cytoplasmic antibodies (c-ANCA) positivity. However, biopsy result indicated cryptogenic organising pneumonia. This case report discloses the differential diagnosis of c-ANCA positive interstitial lung disease in detail. PMID- 23456161 TI - Bilateral bisphosphonate-related osteonecrosis of the jaw with left chronic infection in an 82-year-old woman. PMID- 23456162 TI - 'Nevi of Ota: the unusual birthmarks': a case review. AB - Nevi of Ota are usually characterised by unilateral, mottled, slate blue or dark brown macules on the forehead and face around the eye area. These are unusual skin discolorations in which melanocytes are found deeper than normal. Ota's nevus is usually congenital but may appear in early childhood or in puberty. We summarise a case report along with histological and management aspects of this cosmetically unappealing condition. PMID- 23456163 TI - Haemophagocytic syndrome with disseminated intravascular coagulation associated with tuberculosis. AB - Haemophagocytic syndrome (HPS) is a clinical entity that combines non-specific clinical and biological features. The diagnosis is usually confirmed by a bone marrow examination. HPS may be primary or secondary to a malignancy or to an infectious or autoimmune disease. Early aggressive survey of the aetiology and optimal treatment of the underlying disease improve the outcome of life threatening HPS. Infection-associated HPS occurs predominantly in immunocompromised patients and is usually fatal. Leading trigger agents are viruses, especially the Epstein-Barr virus and cytomegalovirus. Mycobacterial infections associated with HPS are rare but should be considered in those patients where there is associated fever of unknown origin. We present a case of disseminated tuberculosis-associated HPS. PMID- 23456164 TI - Synchronous sclerosing haemangiomas of the lung: an unusual presentation of a rare tumour. AB - Pulmonary sclerosing haemangioma is a rare lung tumour with a preponderance for Asian oriental women. Typically a well-circumscribed, solitary lesion with benign characteristics, there are concerns of malignant potential including regional lymph node metastases. Four histological subtypes exist. Diagnosis can be challenging as patients are usually asymptomatic and radiological findings are non-specific. Surgical resection alone is diagnostic and therapeutic. We present a case of this rare tumour with an uncommon presentation as two synchronous tumours initially misdiagnosed as a pulmonary adenocarcinoma. PMID- 23456165 TI - Feeling blue with metformin-associated lactic acidosis. AB - An active 66-year-old diabetic woman presented with a 5-day history of vomiting and abdominal pain, refractory shock and acute kidney injury (AKI). There was concomitant ACE inhibitor (ACEi) use and metformin toxicity with severe lactic acidosis. She suffered a pulseless electrical activity (PEA) cardiac arrest within 30 min of arrival to the Medical Admissions Unit. Despite a serum pH of 6.57 she was successfully resuscitated. She remained haemodynamically unstable even with fluid resuscitation, inotropic support and haemodiafiltration, yet made a full and rapid recovery following the introduction of a methylene blue infusion. PMID- 23456166 TI - Thyroid cancer in Plummer's disease. AB - Thyroid cancer with concomitant hyperthyroidism is rare. Most foci of malignancy are small and seen postoperatively as incidental findings after surgery for hyperthyroidism. Thyroid masses with clinical features of malignancy and concomitant hyperthyroidism are less-commonly reported. We report two cases of multinodular toxic goitre or Plummer's disease with clinical features of malignancy. Both patients had large multinodular goitres with evidence of metastasis to the manubrium for the first patient and to the lymph node and lungs for the second patient. Both were clinically euthyroid but with free hormone excess and suppressed thyroid stimulating hormone (TSH) on laboratory testing. Both patients received methimazole prior to thyroidectomy. Histopathology revealed follicular variant of papillary cancer with metastasis to the manubrium for the first patient and follicular thyroid cancer with lymph node metastasis for the second. While rare, thyrotoxicosis can occur with malignancy, Plummer's disease may harbour cancer and behave aggressively. PMID- 23456167 TI - Does low daily energy expenditure drive low metabolic capacity in the tropical robin, Turdus grayi? AB - Temperate and tropical birds possess divergent life history strategies. Physiological parameters including energy metabolism correlate with the life history such that tropical species with a slower 'pace of life' have lower resting and maximal metabolic rates than temperate congeners. To better understand the physiological mechanisms underlying these differences, we investigated the relationship of metabolic capacity, muscle oxidative capacity and activity patterns to variation in life history patterns in American robins (Turdus migratorius), while resident in central North America and Clay-colored robins (Turdus grayi) resident in Panama. We measured summit metabolism [Formula: see text] in birds from both tropical and temperate habitats and found that the temperate robins have a 60 % higher metabolic capacity. We also measured the field metabolic rate (FMR) of free-living birds using heart rate (HR) telemetry and found that temperate robins' daily energy expenditure was also 60 % higher. Thus, [Formula: see text] and FMR both reflect life history differences between the species. Further, both species operate at a nearly identical ~50 % of their thermogenic capacity throughout a given day. As a potential mechanism to explain differences in activity and metabolic capacity, we ask whether oxidative properties of flight muscle are altered in accordance with life history variation and found minimal differences in oxidative capacity of skeletal muscle. These data demonstrate a close relationship between thermogenic capacity and daily activity in free-living birds. Further, they suggest that the slow pace of life in tropical birds may be related to the maintenance of low activity rather than functional capacity of the muscle tissue. PMID- 23456168 TI - Genome-wide association study in Han Chinese identifies three novel loci for human height. AB - Human height is a complex genetic trait with high heritability but discovery efforts in Asian populations are limited. We carried out a meta-analysis of genome-wide association studies (GWAS) for height in 6,534 subjects with in silico replication of 1,881 subjects in Han Chinese. We identified three novel loci reaching the genome-wide significance threshold (P < 5 * 10(-8)), which mapped in or near ZNF638 (rs12612930, P = 2.02 * 10(-10)), MAML2 (rs11021504, P = 7.81 * 10(-9)), and C18orf12 (rs11082671, P = 1.87 * 10(-8)). We also confirmed two loci previously reported in European populations including CS (rs3816804, P = 2.63 * 10(-9)) and CYP19A1 (rs3751599, P = 4.80 * 10(-10)). In addition, we provided evidence supporting 35 SNPs identified by previous GWAS (P < 0.05). Our study provides new insights into the genetic determination of biological regulation of human height. PMID- 23456169 TI - Association of polymorphisms in the Chr18q11.2 locus with tuberculosis in Chinese population. AB - A GWAS study has reported that two single nucleotide polymorphisms (SNPs) were associated with predisposition to tuberculosis (TB) in African populations. These two loci represented the long-waited GWAS hits for TB susceptibility. To determine whether these two SNPs are associated with TB in Chinese population, we attempted an replication in a cohort of over one thousand Chinese TB patients and 1,280 healthy controls using melting temperature shift allele-specific genotyping analysis. We found that only SNP rs4331426 was significantly associated with TB in Chinese population (p = 0.011). However, the effect was opposite. The G allele of the SNP in Chinese population is a protective allele (OR = 0.62, 95 % CI 0.44 0.87), while it was the risk allele for African population (OR = 1.19, 95 % CI 1.12-1.26). No significance was found for SNP rs2335704. The results provided an independent support for a role in susceptibility to TB for SNP rs4331426. However, it also indicated that direct predisposition element to TB and the association effects may vary across ethnic groups. PMID- 23456171 TI - Spontaneous lens extrusion: an unusual late complication of Acanthamoeba keratitis. PMID- 23456170 TI - Mussel and mammalian ATP synthase share the same bioenergetic cost of ATP. AB - The molecular mechanism by which the membrane-embedded FO sector of the mitochondrial ATP synthase translocates protons, thus dissipating the transmembrane protonmotive force and leading to ATP synthesis, involves the neutralization of the carboxylate residues of the c-ring. Carboxylates are thought to constitute the binding sites for ion translocation. In order to cast light on this mechanism, we exploited N,N'-dicyclohexylcarbodiimide, which covalently binds to FO c-ring carboxylates, and ionophores which selectively modulate the transmembrane electric (Deltaphi) and chemical (DeltapH) gradients such as valinomycin, nigericin and dinitrophenol. ATP hydrolysis was evaluated in mitochondrial preparations and/or inside-out submitochondrial particles from mussel and mammalian tissues under different experimental conditions. The experiments pointed out striking similarities between mussel and mammalian mitochondrial ATP synthase. Our results support the hypothesis that the ATP synthase of Mytilus galloprovincialis induces intersubunit torque generation and translocates H(+) by coordinating the hydronium ion (H3O(+)) in the ion binding site of FO. Our results are consistent with the hypothesis that in mussel mitochondria the main component of the electrochemical gradient driving proton flux and ATP synthesis is Deltaphi. Therefore, mussel FO probably contains a small c-ring, which implies a low bioenergetic cost of making ATP as in mammals. These features which make mussel mitochondria as efficient in ATP production as mammalian ones may be especially advantageous in facultative aerobic species which intermittently exploit mitochondrial respiration to generate ATP. PMID- 23456172 TI - Searching for viral antibodies and genome in intraocular fluids of patients with Fuchs uveitis and non-infectious uveitis. AB - BACKGROUND: To characterise the polyspecific intraocular antibody synthesis in aqueous humor of patients with Fuchs uveitis and other types of non-infectious uveitis. METHODS: Aqueous and serum samples collected from 24 patients with Fuchs uveitis, 21 patients with non-infectious uveitis, and 27 healthy subjects undergoing elective cataract surgery (control group) were analysed. In addition, vitreous samples, collected from seven uveitis patients (five Fuchs and two panuveitis) during retinal surgery, were examined. Specific immunoglobulin G antibodies against cytomegalovirus (CMV), rubella virus, herpes simplex virus (HSV), and varicella zoster virus (VZV) were investigated, and Goldmann-Witmer coefficients (GWCs) were calculated. Real-time PCR was performed to detect viral genome for HSV, VZV, and CMV, while nested PCR was conducted to detect rubella RNA. RESULTS: None of the control samples tested positive for any of the viral antibodies investigated. Intraocular antibody production was found in eight samples of patients affected by Fuchs uveitis (6/8 positive for rubella virus and 2/8 positive for herpes virus). Among patients with non-infectious uveitis, three tested positive for intraocular antibody production (one RV, one HSV and one for VZV). PCR was positive for RV in two patients with Fuchs uveitis, in three patients with non-infectious uveitis (one for RV and two for HSV), and in three control subjects (one for CMV and one for HSV). CONCLUSIONS: Our series confirmed the presence of specific viral antibodies, especially against rubella virus, in the subgroup of patients affected by Fuchs uveitis, suggesting that this virus may be responsible for this chronic inflammatory condition. Rubella virus is probably the main causative agent of Fuchs uveitis, but other viruses may also be involved in the pathogenesis of this disease. PMID- 23456173 TI - Characterisation of novel uveal melanoma cell lines under serum-free conditions. AB - BACKGROUND: The establishment of long-term uveal melanoma (UM) cell lines is difficult. However, studying living cells and their behaviour in the presence of other cells and the extracellular matrix is important in terms of understanding tumour biology and malignant behaviour. We have established three UM cell lines and report a first characterisation of these cell lines. METHODS: Three established UM cell lines (UMT2, UMT26 and UMT33) were analysed according to their morphologic characteristics, melanocytic differentiation, adhesion on different extracellular matrices and proliferative activity. Copy number changes of chromosomes 1, 3, 6 and 8 were studied by multiplex ligation-dependent probe amplification (MLPA). Oncogenic mutations in UM involving exons 4 and 5 of GNAQ and GNA11, respectively, were analysed by sequencing. RESULTS: All cell lines grew in suspension. UMT2 cells were homogeneous, UMT26 and UMT33 cells heterogeneous with regard to cell size and pigmentation. All UM cell lines revealed a melanocytic differentiation. UMT2 and 33 adhered on various extracellular matrices, while UMT26 only adhered to basal membrane extract (BME). This difference corresponded to the different expression of various integrins. Ki67 was expressed by 89% of UMT2 and 95% of UMT33 cells, which thus were in a proliferative stage, while only 2% of UMT26 cells revealed immunostaining for this proliferation marker. The doubling time of UMT2 was 3 days, 12 days for UMT33, and circa 3-4 months for UMT26. MLPA revealed disomy 3 in UMT2 and monosomy 3 in UMT33. The same point mutation was found in UMT2, 26 and 33, in exon 5 of GNA11 at codon 209 (p.Q209L). CONCLUSIONS: The establishment of UM cell lines under serum-free conditions is possible. Characterisation of UMT2, 26, and 33 revealed obvious differences in cytomorphology, melanocytic differentiation, adhesion on extracellular matrices, and proliferative activity. UMT2, 26 and 33 showed the same oncogenic mutation in exon 5 of GNA11. PMID- 23456174 TI - Weight management in community pharmacy: what do the experts think? AB - BACKGROUND: The increasing prevalence of obesity and overweight adults creates a significant public health burden and there is great potential for pharmacists to be involved in the provision of weight management services, other than the mundane supply of commercial products. In order to provide optimal services that can be integrated into the healthcare system, a best practice model for weight management services in community pharmacy should be in place. We sought experts' and key stakeholders' opinions on this matter. OBJECTIVES: (1) To identify components of a best practice model of a weight management service feasible in Australian community pharmacy. (2) To identify the role of pharmacists and the training requirements to up-skill pharmacists to competently provide weight management services. (3) To elicit any practical suggestions that would contribute to successful implementation of weight management services in pharmacy. SETTING: Australian primary care sector. METHOD: Semi-structured interviews were conducted with a purposive sample of 12 participants including Australian experts in obesity and representatives of main Australian professional organisations in pharmacy. Interviews were digitally recorded, transcribed verbatim and thematically analysed using the framework approach. MAIN OUTCOME MEASURE: Recommended components of pharmacy-based weight management services and training requirements. RESULTS: Participants perceived two potential roles for pharmacists involved in weight management: health promotion and individualised service. Multi-component interventions targeting all three areas: diet, physical activity and behaviour change were emphasised. Physical assessment (e.g. weight, waist circumference measurements), goal setting, referral to allied healthcare professionals and on-going support for weight maintenance were also proposed. Participants suggested pharmacists should undergo formal training and identified various training topics to improve pharmacists' knowledge, attributes and skills to acquire competencies necessary for delivery of this service. Some physical and financial barriers in providing these services were also identified including infrastructure, pharmacists' time and cost-effectiveness. CONCLUSION: Pharmacists are well-positioned to promote healthy weight and/or implement weight management interventions. Furthering pharmacists' role would involve training and up skilling; and addressing key practice change facilitators such as pharmacy layout and remuneration. This study provides some insight into the design and implementation of a best practice model for pharmacy-based weight management services in Australia. PMID- 23456175 TI - Current self-complianced and self-rectifying resistive switching in Ag-electroded single Na-doped ZnO nanowires. AB - We demonstrate current self-complianced and self-rectifying bipolar resistive switching in an Ag-electroded Na-doped ZnO nanowire device. The resistive switching is controlled by the formation and rupture of an Ag nanoisland chain on the surface along the Na-doped ZnO nanowire. Na-doping plays important roles in both the self-compliance and self-rectifying properties. PMID- 23456176 TI - DUF538 protein super family is predicted to be the potential homologue of bactericidal/permeability-increasing protein in plant system. AB - DUF538 protein super family includes a number of plant proteins that their role is not yet clear. These proteins have been frequently reported to be expressed in plants under various stressful stimuli such as bacteria and elicitors. In order to further understand about this protein family we utilized bioinformatics tools to analyze its structure in details. As a result, plants DUF538 was predicted to be the partial structural homologue of BPI (bactericidal/permeability increasing) proteins in mammalian innate immune system that provides the first line of defense against different pathogens including bacteria, fungi, viruses and parasites. Moreover, on the base of the experimental data, it was identified that exogenously applied purified fused product of Celosia DUF538 affects the bacterial growth more possibly similar to BPI through the binding to the bacterial membranes. In conclusion, as the first ever time report, we nominated DUF538 protein family as the potential structural and functional homologue of BPI protein in plants, providing a basis to study the novel functions of this protein family in the biological systems in the future. PMID- 23456177 TI - The possible role of nuclear imaging in assessment of the cardiac resynchronization therapy effectiveness in patients with moderate heart failure. AB - BACKGROUND: The aim of the study was to elucidate the role of nuclear medicine imaging in the selection of candidates for cardiac resynchronization therapy (CRT) and in the evaluation of CRT effectiveness METHODS: We studied 28 patients (19 male and 9 female) with dilated cardiomyopathy (DCM) and heart failure (HF). Before implantation of CRT device, all patients underwent SPECT with (99m)Tc-MIBI at rest to evaluate the myocardial perfusion, (123)I-BMIPP to evaluate the myocardial metabolism, and gated cardiac blood-pool SPECT (GBPS) to assess the myocardial contractile function. Following CRT, all patients were examined with 99mTc-MIBI SPECT and GBPS 12 +/- 3 months after the intervention. RESULTS: All patients after CRT were divided into three groups. The first group included 10 patients with LVEF increased by more than 10 % (hyperresponders), the 2nd group included 11 patients with an increase in EF of more than 5 % but less than 10 % (responders) and third group consisted of 7 males whose LVEF remained unchanged or worsened compared with pre-operative values (nonresponders). Prior to CRT, no statistically significant differences were found between groups in hemodynamic parameters (EF, EDV, ESV, SV), intra- and interventricular dyssynchrony, as well as in the midsize of perfusion defects. Following long-term CRT, we found increase in LVEF and decrease in average size of perfusion defects in groups of hyperresponders and responders (p < 0.05). Results of SPECT with (123)I-BMIPP, performed prior to CRT, showed that nonresponders had more pronounced disturbance of myocardial metabolism compared with the group of hyperresponders (20 vs. 14.7 %, p < 0.05). CONCLUSION: The radionuclide methods can be used as possible indicators in the evaluation effectiveness and selection of candidates on the CRT. PMID- 23456178 TI - Metastasis of femoral osteosarcoma to the abdominal wall detected on 99m Tc-MDP skeletal scintigraphy. AB - Osteosarcoma is the most frequent primary malignancy of bone, and usually metastasizes to the lung and bones, while other sites are rare. In most reported cases, soft tissue metastasis of osteosarcoma is unusual, and only develops in the advanced stages of the disease, especially following multiple recurrences. We present a patient with recently diagnosed osteosarcoma of the right femur, showing abdominal wall metastasis diagnosed by technetium-99m-methylene diphosphonate (99m Tc-MDP) whole body bone scintigraphy and confirmed histologically. The present case highlights the importance of whole body imaging of patients with osteosarcoma for detecting unusual sites of metastasis, especially in soft tissue organs. PMID- 23456179 TI - Genetic mapping of two genes conferring resistance to powdery mildew in common bean (Phaseolus vulgaris L.). AB - Powdery mildew (PM) is a serious disease in many legume species, including the common bean (Phaseolus vulgaris L.). This study investigated the genetic control behind resistance reaction to PM in the bean genotype, Cornell 49242. The results revealed evidence supporting a qualitative mode of inheritance for resistance and the involvement of two independent genes in the resistance reaction. The location of these resistance genes was investigated in a linkage genetic map developed for the XC RIL population. Contingency tests revealed significant associations for 28 loci out of a total of 329 mapped loci. Fifteen were isolated or formed groups with less than two loci. The thirteen remaining loci were located at three regions in linkage groups Pv04, Pv09, and Pv11. The involvement of Pv09 was discarded due to the observed segregation in the subpopulation obtained from the Xana genotype for the loci located in this region. In contrast, the two subpopulations obtained from the Xana genotype for the BM161 locus, linked to the Co-3/9 anthracnose resistance gene (Pv04), and from the Xana genotype for the SCAReoli locus, linked to the Co-2 anthracnose resistance gene (Pv11), exhibited monogenic segregations, suggesting that both regions were involved in the genetic control of resistance. A genetic dissection was carried out to verify the involvement of both regions in the reaction to PM. Two resistant recombinant lines were selected, according to their genotypes, for the block of loci included in the Co-2 and Co-3/9 regions, and they were crossed with the susceptible parent, Xana. Linkage analysis in the respective F2 populations supported the hypothesis that a dominant gene (Pm1) was located in the linkage group Pv11 and another gene (Pm2) was located in the linkage group Pv04. This is the first report showing the localization of resistance genes against powdery mildew in Phaseolus vulgaris and the results offer the opportunity to increase the efficiency of breeding programs by means of marker-assisted selection. PMID- 23456180 TI - TVRAM flap: a modified rectus abdominis musculocutaneous flap for anal cancer salvage surgery. PMID- 23456181 TI - The special finding of three-dimension high-resolution manometry in the diagnosis of presacral epidermoid cyst. PMID- 23456182 TI - A Medicaid and commercial insured claims-based study to estimate improved antipsychotic medication adherence among patients with schizophrenia. AB - Compliance with antipsychotic medication is clinically important but challenging for schizophrenia patients. Clinical trials and epidemiological studies strongly suggest that improved compliance results in reduced hospitalizations and other adverse outcomes. Examination of Medicaid and commercial claim data suggests that a significant portion of schizophrenia patients have a regular pattern of visits with one outpatient professional, yet are noncompliant with their medication. For many of these patients, results show that the administration of once-monthly verifiable therapy would improve compliance. PMID- 23456183 TI - Initial results from the newborn hearing screening programme in Ireland. AB - INTRODUCTION: Hearing screening programmes aim to detect hearing loss in the neonate. The Health Service Executive (HSE) South was the first phase of a national roll-out of a neonatal hearing screening programme in Ireland, going live on 28 April 2011. RESULTS: Over 11,738 babies have been screened for permanent childhood hearing impairment (PCHI) during the first 12 months. The percentage of eligible babies offered hearing screening was 99.2 %. Only 0.2 % (n = 25) of those offered screening declined. 493 (4 %) were referred for immediate diagnostic audiological assessment. The average time between screen and diagnostic audiology appointment was 2 weeks. 15 (1.3/1,000) babies have been identified with a PCHI over the 12-month period. 946 (4 %) babies screened were admitted to the neonatal intensive care unit (NICU) for >48 h. The prevalance of PCHI is 7.3/1,000 in the NICU population compared to 0.6/1000 in the well baby population. 214 (1.8 % of total babies screened) had a clear response in the screening programmes, but were deemed to be at risk of an acquired childhood hearing impairment. These babies will be reassessed with a diagnostic audiology appointment at 8-9 months of age. To date, there is one case of acquired hearing impairment through this targeted follow-up screen. Of the 15 cases of PCHI identified, 8 (53 %) of these had one or more risk factors for hearing loss and 7 (37 %) were admitted to the NICU for >48 h. Four babies were referred for assessment at the National Cochlear Implant Centre. PMID- 23456184 TI - Decreased physical effort, fatigue, and mental distress in patients with coronary artery disease: importance of personality-related differences. AB - BACKGROUND: Identification of cardio-toxic psychological symptoms in coronary artery disease (CAD) patients is important. PURPOSE: We examined the association of negative affectivity (NA), social inhibition (SI), and their combination in the distressed (Type D) personality with functional status, fatigue, and mental distress in CAD patients. METHOD: Following acute coronary syndrome, 690 consecutive CAD patients agreed to participate in this cross-sectional study and were evaluated for clinical characteristics, including left ventricular ejection fraction (LVEF), and for NA, SI, and Type D personality (i.e., NA and SI; DS14 scale) when they entered a cardiac rehabilitation program in Lithuania. Patient centered outcomes included functional status (bicycle ergometer), symptoms of fatigue (Multidimensional Fatigue Inventory-20), and mental distress (Beck Depression Inventory-II and Hospital Anxiety and Depression Scale). RESULTS: The reference subgroup (neither NA nor SI) included 34 % of patients; 13 % had NA only, 19 % had SI only, and 34 % had Type D profile. Type D patients had worse functional status, and Type D patients and NA-only patients had higher symptom levels of fatigue and mental distress. In multivariate regression models that included LVEF, clinical characteristics, and depressive symptoms, Type D personality was an independent predictor of decreased exercise capacity (OR = 1.77, 95 % CI 1.06-2.95, p = .03) and decreased motivation for activity (OR = 3.14, 95 % CI 1.73-5.73, p < .001). Type D, NA, and SI were also independent predictors of mental distress. CONCLUSIONS: Type D personality traits independently predicted poor functional status and worse patient-centered outcomes independently from LVEF and depression. Further studies exploring personality-related differences in cardiovascular outcomes are needed. PMID- 23456185 TI - Maze learning in patients with intracranial arachnoid cysts. AB - BACKGROUND: The temporal lobe is of importance for visuospatial orientation. Intracranial arachnoid cysts have a predilection for the temporal fossa, and might therefore affect visuospatial orientation. The aim was to find out whether temporal cysts affect maze learning and if surgical cyst decompression improves maze performance. METHODS: Forty-five patients with a temporal arachnoid cyst and 17 control patients with cervical disc disease were tested in a labyrinth route in the hospital corridors the day before surgery and at least 3 months postoperatively. RESULTS: Thirty-five cyst patients (78 %) experienced postoperative improvement of their preoperative complaints. The cyst patients spent significantly longer time than the controls navigating through the maze in the preoperative test, 161 s and 127 s, respectively, but there was no difference in number of errors between the two groups. However, the cyst patients improved significantly in the postoperative test, both with regards to number of errors they made and time spent, contrary to the control patients, whose postoperative performance equalled that of the preoperative test. For the cyst patients, postoperative improvement in the labyrinth test correlated with the clinical outcome-but not the neuroradiological outcome-after the operation. CONCLUSIONS: Thus, temporal arachnoid cysts may affect visuospatial orientation and learning in a reversible manner. PMID- 23456186 TI - Do professional athletes perform better than recreational athletes after arthroscopy for femoroacetabular impingement? AB - BACKGROUND: Although a large number of athletes' returns to sports after hip arthroscopic surgery for femoroacetabular impingement (FAI), it is not clear if they do so to the preinjury level and whether professional athletes (PA) are more likely to return to the preinjury level compared with recreational athletes (RA). QUESTIONS/PURPOSES: We therefore compared (1) the time taken to return to the preinjury level of sport between professional and recreational athletes; (2) the degree of improvement in time spent in training and competitive activities after arthroscopic surgery for FAI; and (3) the difference in trend of improvement in hip scores. METHODS: We prospectively followed 80 athletes (PA = 40, RA = 40; mean age, 35.7 years; males = 50, females = 30; mean followup, 1.4 years; range, 1-1.8 years) who underwent hip arthroscopy for FAI. We measured the time to return to sports; training time and time in competition; and the modified Harris hip score and the nonarthritic hip score. RESULTS: There was a 2.6-fold improvement in the training time (from 7.8 to 20 hours per week) and a 3.2-fold increase in time in competition (from 2.5 to 7.9 hours per week) 1 year after surgery. The mean time to return to sporting activities was 5.4 months, which was lower for PA (4.2) as compared with RA (6.8). Eighty-two percent (66) (PA = 88% [35] versus RA = 73% [29]) returned to their preinjury level of sport within 1 year of surgery. CONCLUSIONS: The data suggest PA may show quicker return to sports than RA but the hip scores and rate of return to sports are similar. PMID- 23456187 TI - What are the factors influencing outcome among patients admitted to a hospital with a proximal humeral fracture? AB - BACKGROUND: Fracture of the proximal humerus is common in older patients during the decline of their physical health. QUESTIONS/PURPOSES: Our purpose was to evaluate the association between specific risk factors in patients with fractures of the proximal humerus and any inpatient adverse events, mortality, and discharge to a short-term or long-term care facility. METHODS: The National Hospital Discharge Survey (NHDS) provided estimates of all adult patients who were admitted to hospitals after fractures of the proximal humerus in the United States between 1990 and 2007. The influences of sex, age, days of care, diagnosis and procedures (based on ICD-9 codes) on inpatient adverse events and death, and discharge to a short-term or long-term care facility, were studied in bivariate and multivariable analyses. RESULTS: Among an estimated 867,282 patients admitted for proximal humerus fractures, 20% experienced adverse events, and 2.3% died in the hospital. Older age, concomitant femur and femoral neck fractures or head trauma, operative fracture care, congestive heart failure, and chronic alcoholism were associated with inpatient adverse events. Intubation, acute myocardial infarctions, malignancies, and skull fractures were associated with inpatient deaths. Older age, lower limb fractures, specific comorbidities (obesity, congestive heart failure, dementia), and inpatient adverse events (pneumonia, anemia treated with transfusion) were associated with discharges to short-term or long-term care facilities. CONCLUSIONS: Knowledge of risk factors for inpatient adverse events, mortality, and discharge to facilities can help make treatment decisions, improve overall care, discharge planning, and resource utilization for patients with proximal humeral fractures. PMID- 23456188 TI - Trapeziometacarpal joint stability: the evolving importance of the dorsal ligaments. AB - BACKGROUND: Trapeziometacarpal (TMC) arthritis of the thumb is a common source of hand pain and disability. TMC ligamentous instability may play a role in TMC degeneration. However, the relative importance of the TMC ligaments in the etiology of degeneration and the use of surgery to treat instability in early stage arthritis are unclear. QUESTIONS/PURPOSES: In this review, we addressed several questions: (1) What are the primary ligamentous stabilizers of the thumb TMC joint? (2) What is the evidence for ligament reconstruction or ligament imbrication in the treatment of thumb TMC joint osteoarthritis? And (3) what is the evidence for thumb metacarpal osteotomy in the treatment of thumb TMC joint osteoarthritis? METHODS: We performed a systematic review of the literature using PubMed (MEDLINE((r))) and Scopus((r)) (EMBASE((r))) for peer-reviewed articles published until November 2012. Fifty-two studies fit the inclusion criteria. Twenty-four studies were anatomic, biomechanical, or histopathologic studies on TMC joint ligamentous anatomy, 16 studies were clinical studies concerning ligament reconstruction, and 12 studies were clinical studies on thumb metacarpal osteotomy. RESULTS: Over the past two decades, increasing evidence suggests the dorsoradial ligament is the most important stabilizer of the TMC joint. Other ligaments consistently identified are the superficial anterior oblique, deep anterior oblique, intermetacarpal, ulnar collateral, and posterior oblique ligaments. Ligament reconstruction and metacarpal osteotomy relieve pain and improve grip strength based on Level IV studies. CONCLUSIONS: The dorsal ligaments are the primary stabilizers of the TMC joint. Ligament reconstruction and metacarpal osteotomy ameliorate ligamentous laxity and relieve pain based on Level IV studies. PMID- 23456189 TI - Oxford hip scores at 6 months and 5 years are associated with total hip revision within the subsequent 2 years. AB - BACKGROUND: The Oxford hip score (OHS) is commonly reported in research studies as a reflection of pain and function but it is unclear whether it predicts subsequent prosthesis failure. QUESTIONS/PURPOSES: We determined whether OHS obtained at 6 months and 5 years after surgery predicts risk of revision within the subsequent 2 years. METHODS: We reviewed data from the New Zealand Joint Registry between January 1999 and December 2010. OHS at 6 months was available for 17,831 total hip patients. Patients were separated into four categories based on their OHS: 10,458 (59%) scored 42-48, 4726 (26%) scored 34-41, 1592 (9%) scored 27-33, and 1028 (6%) scored 0-26. Five-year OHSs were available for 3665 patients. Of these patients, 2619 (72%) scored 42-48, 657 (18%) scored 34-41, 225 (6%) scored 27-33, and 164 (4%) scored 0-26. RESULTS: For patients with a 6-month OHS, revision risk within 2 years was 0.4% in the 42-48 group, 1.0% in the 34-41 group, 1.7% in the 27-33 group, and 6.2% in the 0-27 group. For patients with 5 year OHS, revision risk within 2 years was 0.3%, 1.1%, 3.6%, and 6.1%, respectively. Increase in revision risk for the 0-27 versus the 42-48 OHS group was 15-fold at 6 months and 18-fold at 5 years. CONCLUSIONS: Our data suggest patients with an OHS of 42-48 at 6 months need a 5-year postoperative appointment. Those patients with a 5-year OHS of 42-48 need not be followed up for a further 5 years. PMID- 23456190 TI - Clinical faceoff: One- versus two-stage exchange arthroplasty for prosthetic joint infections. PMID- 23456191 TI - Special considerations for TKA in Asian patients: editorial comment. PMID- 23456192 TI - CORR InsightsTM: Risk of thromboembolism in shoulder arthroplasty: effect of implant type and traumatic indication. PMID- 23456193 TI - Multi-angle indicators system of non-point pollution source assessment in rural areas: a case study near Taihu Lake. AB - This study aims to identify key environmental risk sources contributing to water eutrophication and to suggest certain risk management strategies for rural areas. The multi-angle indicators included in the risk source assessment system were non point source pollution, deficient waste treatment, and public awareness of environmental risk, which combined psychometric paradigm methods, the contingent valuation method, and personal interviews to describe the environmental sensitivity of local residents. Total risk values of different villages near Taihu Lake were calculated in the case study, which resulted in a geographic risk map showing which village was the critical risk source of Taihu eutrophication. The increased application of phosphorus (P) and nitrogen (N), loss vulnerability of pollutant, and a lack of environmental risk awareness led to more serious non point pollution, especially in rural China. Interesting results revealed by the quotient between the scores of objective risk sources and subjective risk sources showed what should be improved for each study village. More environmental investments, control of agricultural activities, and promotion of environmental education are critical considerations for rural environmental management. These findings are helpful for developing targeted and effective risk management strategies in rural areas. PMID- 23456194 TI - Plasma IGF-1 and IGFBP-3 may be imprecise surrogates for breast concentrations: an analysis of healthy women. AB - We investigated insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 concentrations in histologically normal breast tissues and assessed their association with plasma concentrations, and breast cancer risk factors. IGF 1 and IGFBP-3 were assessed in plasma and breast tissues of 90 women with no history of any cancer and undergoing reduction mammoplasty. Pearson correlations and ANOVAs were used to describe plasma-breast associations and biomarker differences by breast cancer risk factors, respectively. Multivariable regression models were used to determine associations between risk factors, and breast IGF-1 and IGFBP-3. The mean age of the study sample was 37.3 years, 58 % were white, and generally these women were obese (mean BMI = 30.8 kg/m(2)). We observed no plasma-breast correlation for IGF-1, IGFBP-3, or IGF-1/IGFBP-3 (r = -0.08, r = 0.14, and r = 0.03, respectively; p-values >0.05). Through age- and BMI-adjusted analysis, BMI and years of oral contraceptive (OC) use were inversely associated with breast IGF-1 (p-values = 0.02 and 0.003, respectively) and age was associated with breast IGFBP-3 (p = 0.01), while breast IGF-1/IGFBP-3 was higher in blacks than whites (1.08 vs. 0.68, p = 0.04) and associated with age and BMI (p-values = 0.03 and 0.002, respectively). In multivariable-adjusted models, some breast cancer risk factors studied herein explained 24, 10, and 15 % of the variation in breast IGF-1, IGFBP-3, and IGF-1/IGFBP-3, respectively. While reasons for the lack of plasma-breast hormone correlations in these cancer-free women are unknown, several factors were shown to be associated with breast concentrations. The lack of correlation between blood and tissue IGF-1 and IGFBP 3 suggests that studies of breast cancer risk assessing blood IGF-1 and IGFBP-3 may have important limitations in understanding their role in breast carcinogenesis. PMID- 23456195 TI - Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up. AB - Tamoxifen is associated with a reduced risk of coronary heart disease (CHD). However, there are few reports on long-term effects. Using data from a large Swedish randomized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer, we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment. A total of 4,150 patients were breast cancer recurrence-free after 2 years. Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease. Hazard ratios were estimated using Cox regression. Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [hazard ratio (HR), 0.83; 95 % CI 0.70-1.00], especially apparent during the active treatment period (HR 0.65; 95 % CI 0.43-1.00). The mortality from CHD was significantly reduced (HR 0.72; 95 % CI 0.53-0.97). During the active treatment, the morbidity of other heart diseases was also significantly reduced (HR 0.40; 95 % CI 0.25-0.64) but not after treatment stopped (HR 1.06; 95 % CI 0.87-1.30). Similar results were seen for both heart failure and atrial fibrillation/flutter. As compared to 2 years of therapy, 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases. The risk reduction is most apparent during the active treatment period, and later tends to diminish. PMID- 23456196 TI - A rare case of myocardial infarction related to diagnostic intravascular ultrasound. AB - A 71-year-old man underwent intracoronary stent implantation for acute inferior myocardial infarction (MI). Immediately after diagnostic intravascular ultrasound (IVUS) at 8 months' follow-up, an acute occlusion of the sinus node (SN) artery appeared, which developed sinus arrest with junctional escape rhythm. The serum level of high-sensitivity troponin T (TpT) was markedly elevated on the day after the procedure (2.1-32.5 ng/l), which was indicative of MI related to IVUS. Under continuous intravenous infusion of unfractionated heparin, the escape rhythm changed to lower atrial rhythm on the 4th day, and recovered to sinus rhythm on the 14th day. Coronary angiography (CAG) on 15th day showed a recanalization of the SN artery, but optical coherence tomography identified that disrupted plaque and white thrombus still existed in the ostium of the SN artery. The patient was discharged on maintenance anticoagulation therapy. We hypothesized from this case that IVUS-related myocardial injury may exist without clinical problems. Our retrospective investigation showed that the median levels of high-sensitivity TpT in 20 patients who underwent CAG and subsequent diagnostic IVUS significantly increased from 0.6 (interquartile range 0.3-1.1) to 1.6 (0.7-3.6) ng/l (P < 0.05), suggesting that IVUS may induce very low levels of myocardial injury. In conclusion, we experienced a rare case of IVUS-related MI caused by an acute occlusion of the SN artery. This case reaffirms that we should pay more attention to manipulation of IVUS catheters. PMID- 23456197 TI - Journal of Artificial Organs 2012: the year in review. PMID- 23456199 TI - Effects of two contrasting hemiparasitic plant species on biomass production and nitrogen availability. AB - Hemiparasitic plants can substantially change plant community structure; the drainage of host resources has a direct negative effect on host biomass and, as a consequence, promotes non-host biomass production (parasitism pathway); on the other hand, hemiparasitic litter inputs can enhance nutrient cycling which may have an indirect positive effect on both host and non-host biomass production (litter pathway). We evaluated the net effect of both pathways on total shoot biomass (with and without the hemiparasite) and shoot biomass of graminoids, forbs and ericaceous shrubs using a removal experiment in three sites infested with the annual Rhinanthus angustifolius, and three sites infested with the biennial Pedicularis sylvatica. We addressed the potential importance of litter effects by determination of litter quantity and quality, as well as modeling N release during decomposition. In the second year after removing the hemiparasites, total plant biomass at Rhinanthus sites was 24 % higher in weeded plots than in control plots, while weeding had no significant effect at Pedicularis sites. The increase in total biomass following Rhinanthus removal was mainly due to a higher biomass of graminoids. The amount of litter produced by Rhinanthus was only half of that produced by Pedicularis; N contents were similar. The amount of N in the litter was 9 and 30 % of the amount removed by mowing for Rhinanthus and Pedicularis sites, respectively. Within 2 months, about 45 % of the N in both hemiparasitic litter types was released by decomposition. Our results suggest that in addition to the suppression of host biomass due to parasitism, positive litter feedbacks on host and non-host biomass-via an increase in nutrient availability-also affect plant community structure. We propose that, depending on the particular hemiparasite and/or site conditions, these positive litter feedbacks on shoot biomass can compensate for the negative effect of parasitism. PMID- 23456198 TI - Extra-matrix Mg2+ limits Ca2+ uptake and modulates Ca2+ uptake-independent respiration and redox state in cardiac isolated mitochondria. AB - Cardiac mitochondrial matrix (m) free Ca(2+) ([Ca(2+)]m) increases primarily by Ca(2+) uptake through the Ca(2+) uniporter (CU). Ca(2+) uptake via the CU is attenuated by extra-matrix (e) Mg(2+) ([Mg(2+)]e). How [Ca(2+)]m is dynamically modulated by interacting physiological levels of [Ca(2+)]e and [Mg(2+)]e and how this interaction alters bioenergetics are not well understood. We postulated that as [Mg(2+)]e modulates Ca(2+) uptake via the CU, it also alters bioenergetics in a matrix Ca(2+)-induced and matrix Ca(2+)-independent manner. To test this, we measured changes in [Ca(2+)]e, [Ca(2+)]m, [Mg(2+)]e and [Mg(2+)]m spectrofluorometrically in guinea pig cardiac mitochondria in response to added CaCl2 (0-0.6 mM; 1 mM EGTA buffer) with/without added MgCl2 (0-2 mM). In parallel, we assessed effects of added CaCl2 and MgCl2 on NADH, membrane potential (DeltaPsim), and respiration. We found that >=0.125 mM MgCl2 significantly attenuated CU-mediated Ca(2+) uptake and [Ca(2+)]m. Incremental [Mg(2+)]e did not reduce initial Ca(2+)uptake but attenuated the subsequent slower Ca(2+) uptake, so that [Ca(2+)]m remained unaltered over time. Adding CaCl2 without MgCl2 to attain a [Ca(2+)]m from 46 to 221 nM enhanced state 3 NADH oxidation and increased respiration by 15 %; up to 868 nM [Ca(2+)]m did not additionally enhance NADH oxidation or respiration. Adding MgCl2 did not increase [Mg(2+)]m but it altered bioenergetics by its direct effect to decrease Ca(2+) uptake. However, at a given [Ca(2+)]m, state 3 respiration was incrementally attenuated, and state 4 respiration enhanced, by higher [Mg(2+)]e. Thus, [Mg(2+)]e without a change in [Mg(2+)]m can modulate bioenergetics independently of CU-mediated Ca(2+) transport. PMID- 23456200 TI - Temporal variation of juvenile survival in a long-lived species: the role of parasites and body condition. AB - Studies of population dynamics of long-lived species have generally focused on adult survival because population growth should be most sensitive to this parameter. However, actual variations in population size can often be driven by other demographic parameters, such as juvenile survival, when they show high temporal variability. We used capture-recapture data from a long-term study of a hunted, migratory species, the greater snow goose (Chen caerulescens atlantica), to assess temporal variability in first-year survival and the relative importance of natural and hunting mortality. We also conducted a parasite-removal experiment to determine the effect of internal parasites and body condition on temporal variation in juvenile survival. We found that juvenile survival showed a higher temporal variability than adult survival and that natural mortality was more important than hunting mortality, unlike in adults. Parasite removal increased first-year survival and reduced its annual variability in females only. Body condition at fledging was also positively correlated with first-year survival in treated females. With reduced parasite load, females, which are thought to invest more in their immune system than males according to Bateman's principle, could probably reallocate more energy to growth than males, leading to a higher survival. Treated birds also had a higher survival than control ones during their second year, suggesting a developmental effect that manifested later in life. Our study shows that natural factors such as internal parasites may be a major source of variation in juvenile survival of a long-lived, migratory bird, which has implications for its population dynamics. PMID- 23456202 TI - Chemiluminescence of carbon dots under strong alkaline solutions: a novel insight into carbon dot optical properties. AB - We report the surprising chemiluminescence (CL) behavior of fluorescent carbon dots in the presence of a strong alkaline solution, such as NaOH or KOH. The CL intensity was dependent on the concentration of the base and carbon dots in a certain range. A possible CL mechanism was studied by UV-Vis, fluorescence, CL, FTIR, XPS and EPR spectroscopy. Radiative recombination of the injected electrons by "chemical reduction" of carbon dots with thermally excited generated holes was proposed, which sheds new light on the characteristics of carbon dots. PMID- 23456201 TI - Zooming in on plant interactions. PMID- 23456203 TI - Ritualistic, theistic, and existential spirituality: initial psychometric qualities of the RiTE measure of spirituality. AB - An expanded model to conceptualize sacred human experiences is discussed wherein the term Spirituality is broadened to include: (1) Ritualistic Spirituality, (2) Theistic Spirituality, and (3) Existential Spirituality. However, a measure incorporating this expanded model does not yet exist. A 67-item self-report questionnaire was developed and data were collected from 1,301 undergraduate students. A series of factor analytic procedures yielded a three-factor structure consistent with the guiding theoretical model and refinement produced three 10 item subscales. Evidence for construct validity and sound psychometric properties was indicative of a reliable, valid, and unique tool to assess the multidimensional nature of spirituality. PMID- 23456204 TI - Disseminated Mycobacterium avium complex infection in a patient carrying autoantibody to interferon-gamma. AB - A 66-year-old man was admitted to our hospital on suspicion of lung cancer with bone metastasis. He suffered multiple joint and muscle pain. 18F-Fluorodeoxy glucose positron emission tomography (FDG-PET) showed multiple accumulations in the lung, bones including the vertebrae, and mediastinal lymph nodes. Anti-human immunodeficiency virus (HIV) antibody was negative. Because Mycobacterium avium complex (MAC) was isolated from bronchial lavage fluid, bronchial wall, peripheral blood, and muscle abscess, he was diagnosed as having disseminated MAC infection. Although multidrug chemotherapy was initiated, his condition rapidly deteriorated at first. After surgical curettage of the musculoskeletal abscess, his condition gradually improved. As for etiology, we suspected that neutralizing factors against interferon-gamma (IFN-gamma) might be present in his serum because a whole blood IFN-gamma release assay detected low IFN-gamma level even with mitogen stimulation. By further investigation, autoantibodies to IFN-gamma were detected, suggesting the cause of severe MAC infection. We should consider the presence of autoantibodies to IFN-gamma when a patient with disseminated NTM infection does not indicate the presence of HIV infection or other immunosuppressive condition. PMID- 23456205 TI - Nasopharyngeal tuberculosis. AB - Today, the opportunity to see tuberculosis is decreasing. Nasopharyngeal tuberculosis is a rare entity, even in endemic tuberculosis areas. A case of nasopharyngeal tuberculosis is described. A 28-year-old woman presented with a sore throat. Irregular mucosal thickening was seen in the nasopharynx. Staining for acid-fast bacilli was positive (Gaffky 1), and the PCR test was positive for Mycobacterium tuberculosis from pharyngeal mucus. Computed tomography showed mucosal thickening in the pharynx and old pulmonary tuberculosis in the right upper lobe. Multiple anti-tuberculosis drug therapy was performed for 6 months. A few days after the initiation of therapy, the pharyngeal pain subsided. The irregular mucosal thickening was quite thin after 1 month of multidrug therapy and was no longer observed after 2 months. A case of nasopharyngeal tuberculosis is reported. A good result was obtained with multiple anti-tuberculous drug therapy for 6 months. Nasopharyngeal tuberculosis should be considered in the differential diagnosis of a white nasopharyngeal coating, especially in a patient with a history of pulmonary tuberculosis. PMID- 23456206 TI - GSL-enriched membrane microdomains in innate immune responses. AB - Many pathogens target glycosphingolipids (GSLs), which, together with cholesterol, GPI-anchored proteins, and various signaling molecules, cluster on host cell membranes to form GSL-enriched membrane microdomains (lipid rafts). These GSL-enriched membrane microdomains may therefore be involved in host pathogen interactions. Innate immune responses are triggered by the association of pathogens with phagocytes, such as neutrophils, macrophages and dendritic cells. Phagocytes express a diverse array of pattern-recognition receptors (PRRs), which sense invading microorganisms and trigger pathogen-specific signaling. PRRs can recognize highly conserved pathogen-associated molecular patterns expressed on microorganisms. The GSL lactosylceramide (LacCer, CDw17), which binds to various microorganisms, including Candida albicans, is expressed predominantly on the plasma membranes of human mature neutrophils and forms membrane microdomains together with the Src family tyrosine kinase Lyn. These LacCer-enriched membrane microdomains can mediate superoxide generation, migration, and phagocytosis, indicating that LacCer functions as a PRR in innate immunity. Moreover, the interactions of GSL-enriched membrane microdomains with membrane proteins, such as growth factor receptors, are important in mediating the physiological properties of these proteins. Similarly, we recently found that interactions between LacCer-enriched membrane microdomains and CD11b/CD18 (Mac-1, CR3, or alphaMbeta2-integrin) are significant for neutrophil phagocytosis of non opsonized microorganisms. This review describes the functional role of LacCer enriched membrane microdomains and their interactions with CD11b/CD18. PMID- 23456207 TI - The dysfunction of NK cells in patients with type 2 diabetes and colon cancer. AB - Glucose metabolism disorders influence anticarcinogenic function of natural killer (NK) cells. The aim of this study was to evaluate the number and cytotoxic activity of NK cells in type 2 diabetic (T2D) patients with negative family history of cancer, type 2 diabetic subjects with newly diagnosed untreated colon cancer (T2DCC) and patients without type 2 diabetes with newly diagnosed, untreated colon cancer (CC). Incubation tests were performed in 18 T2D patients, treated with diet and oral antidiabetic agents, 16 T2DCC; cT1-4N0M0 (c-clinical diagnosis based on computed tomography, colonoscopy and histopathology) treated with diet and oral antidiabetic agents and 16 normoglycemic CC; cT1-4N0M0. Control group included 18 metabolically healthy (with normal fasting glucose and normal glucose tolerance) subjects (HS) with negative family history of cancer, matched by age, BMI and waist circumference. Peripheral blood mononuclear cells were isolated by means of gradient centrifugation. The K562 human erythroleukemia cell line served as the standard target for human NK cytotoxicity assay. The T2D revealed an increased number of NK cells (13.56 +/- 5.9 vs 9.50 +/- 4.8 %; p < 0.05) when compared with HS, yet these cells had a decreased activity (3.3 +/- 2.5 vs 9.4 +/- 3.6 %; p < 0.01). The CC demonstrated a decreased activity (2.9 +/ 1.8 %; p < 0.01) but a similar number (8.82 +/- 3.7 %; not significant) of NK cells when compared to HS. The T2DCC NK cells were characterized by trace cytotoxic activity (1.1 +/- 0.7 %; p < 0.01) and nearly three times greater amount (21.24 +/- 7.5 %; p < 0.01) when compared to T2D. Type 2 diabetes and CC are associated with disadvantageous alterations of NK cells, leading to impairment in their cytotoxic activity. The impaired activity of NK cells in T2D can be involved in the increased carcinogenic risk and can promote a higher incidence of CC. PMID- 23456208 TI - Anti-CCL25 antibody prolongs skin allograft survival by blocking CCR9 expression and impairing splenic T-cell function. AB - Chemokines, by virtue of their ability to recruit immune cells into allografts, play critical roles in acute transplantation rejection. CCR9 and its ligand, CCL25, is one of the key regulators of thymocyte migration and maturation in normal and inflammatory conditions. Moreover, several studies have revealed that high expression of CCR9 and CCL25 participated in many kinds of diseases. However, the role of CCR9 in allograft rejection is still unclear. In this study, we established a murine skin transplantation model of acute rejection. Our findings showed that the proportion of CCR9-expressing T cells was significantly increased in the spleen of allotransplanted mice compared with syngeneic transplantation. Furthermore, expression of CCL25 in allograft was similarly increased. Neutralization of CCL25 by intravenous injection of anti-CCL25 monoclonal antibody significantly prolonged skin allograft survival, decreased the number of infiltrating cells, and simultaneously suppressed the chemotactic ability and the proliferation of the splenic T cells in response to allogeneic antigens. Finally, blockade of CCL25 also diminished the secretion of IFN-gamma by splenic T cells. These studies indicated that CCR9/CCL25 was involved in acute transplantation rejection and anti-CCL25 strategies might be useful in preventing acute rejection. PMID- 23456210 TI - Efficacy of the lithotripsy in treating lower pole renal stones. AB - Use of extracorporeal lithotripsy is declining in North America and many European countries despite international guidelines advocating it as a first-line therapy. Traditionally, lithotripsy is thought to have poor efficacy at treating lower pole renal stones. We evaluated the success rates of lithotripsy for lower pole renal stones in our unit. 50 patients with lower pole kidney stones <=15 mm treated between 3/5/11 and 19/4/12 were included in the study. Patients received lithotripsy on a fixed-site Storz Modulith SLX F2 lithotripter according to a standard protocol. Clinical success was defined as stone-free status or asymptomatic clinically insignificant residual fragments (CIRFs) <=3 mm at radiological follow-up. The mean stone size was 7.8 mm. The majority of stones (66 %) were between 5 and 10 mm. 28 % of stones were between 10 and 15 mm. For solitary lower pole stones complete stone clearance was achieved in 63 %. Total stone clearance including those with CIRFs was achieved in 81 % of patients. As expected, for those with multiple lower pole stones the success rates were lower: complete clearance was observed in 39 % and combined clearance including those with CIRFs was 56 %. Overall, complete stone clearance was observed in 54 % of patients and clearance with CIRFs was achieved in 72 % of patients. Success rate could not be attributed to age, stone size or gender. Our outcome data for the treatment of lower pole renal stones (<=15 mm) compare favourably with the literature. With this level of stone clearance, a non-invasive, outpatient-based treatment like lithotripsy should remain the first-line treatment option for lower pole stones. Ureteroscopy must prove that it is significantly better either in terms of clinical outcome or patient satisfaction to justify replacing lithotripsy. PMID- 23456211 TI - Acute cyst rupture, hemorrhage and septic shock after a shockwave lithotripsy in a patient with autosomal dominant polycystic kidney disease. AB - The incidence of urinary calculi in autosomal dominant polycystic kidney disease (ADPKD) ranges from 10 to 36 %. Shockwave lithotripsy (SWL) for urinary calculi in ADPKD was reported to be a safe and effective treatment option. However, there is a potential risk of cyst rupture and traumatic hemorrhage because of shockwaves. A 39-year-old female with polycystic kidneys and upper ureter stone was treated with SWL and developed life-threatening complications of cyst rupture, traumatic hemorrhage and septic shock. She was initially treated with supportive care in the intensive care unit, but in the end nephrectomy was performed. PMID- 23456209 TI - Associations of objectively measured sedentary behaviour and physical activity with markers of cardiometabolic health. AB - AIMS/HYPOTHESIS: The study aimed to examine the associations between objectively measured sedentary time, breaks in sedentary time, moderate-to-vigorous physical activity (MVPA) and total physical activity with markers of cardiometabolic health in a population with known risk factors for type 2 diabetes mellitus. METHODS: This study reports data from two ongoing diabetes prevention programmes. Participants with known risk factors were recruited from primary care practices located within the East Midlands, UK, over the period 2010-2011. ActiGraph GT3X accelerometers (15 s epochs) were used to assess sedentary time (<25 counts per 15 s), MVPA (>= 488 counts per 15 s) and total physical activity (total counts). A break was considered as any interruption in sedentary time (>= 25 counts per 15 s). Linear regression examined the independent association of sedentary time, breaks in sedentary time, MVPA and total physical activity with markers of cardiometabolic health. RESULTS: The sample comprised 878 participants; 153 from Project STAND (Sedentary Time And Diabetes) (age 32.9 +/- 5.6 years, 28.8% male) and 725 from Walking Away from Diabetes (age 63.7 +/- 7.8 years, 64.8% male). Following adjustment for various covariates, including MVPA and BMI, there were detrimental linear associations of sedentary time with 2 h plasma glucose (standardised beta coefficient) (beta = 0.220, p < 0.001), triacylglycerol (beta = 0.206, p = 0.001) and HDL-cholesterol (beta = -0.123, p = 0.029). Breaks in sedentary time, total physical activity and MVPA were significantly inversely associated with measures of adiposity, but not with any other cardiometabolic variables after adjustment for sedentary time and BMI. CONCLUSIONS/INTERPRETATION: In adults at high risk of type 2 diabetes mellitus, time spent sedentary is strongly and adversely associated with cardiometabolic health and may be a more important indicator of poor health than MVPA. PMID- 23456212 TI - Hypopituitarism in patients with vasculotoxic snake bite envenomation related acute kidney injury: a prospective study on the prevalence and outcomes of this complication. AB - Acute kidney injury (AKI) is common in patients with vasculotoxic snake bite (SB) envenomation but hypopituitarism (HP) is an uncommonly reported complication. We conducted a prospective observational study on survivors of SB-AKI who were evaluated and followed up from September 2010 till September 2012. Pituitary function tests were done if they developed any symptoms of HP. MRI of the hypothalamo-pituitary axis was done in those with documented HP. Response to therapy in the form of improvement in the quality of life (QoL) was evaluated by asking patients to mark on a visual analogue scale marked over 0-100 mm which was reported as percentage improvement. 126 patients were included for this study (30 were lost to follow up and were excluded). 25 cases were clinically suspected to have pituitary dysfunction and underwent evaluation with 9 (9.37%, n = 96) found to have evidence of HP. One child had partial empty sella on MRI with anterior as well as posterior pituitary abnormality and stunting; imaging was normal in others. Higher number of patients with HP had hypotension (p = 0.005, n = 7), coagulation abnormalities (p = 0.005, n = 9), severe clinical snake bite envenomation (p = 0.024, n = 9) and progression to chronic kidney disease (CKD) (p = 0.001, n = 5) as compared to those who did not. Dialysis dependence at presentation was not significantly different (p = 0.348, n = 9). Only development of CKD on follow up predicted the development of HP. Patients had an improvement in the QoL after treatment with mean score on the visual analogue scale of 66.67 +/- 14.14%. HP is not very uncommon in patients with severe vasculotoxic SB-AKI. Threshold of clinical suspicion and evaluation should be low as it causes significant morbidity. PMID- 23456213 TI - Characteristics of breast cancer survivors that predict partners' participation in research. AB - BACKGROUND: Psycho-oncology couples' research frequently includes fewer than 50 % of those eligible. PURPOSE: This research examined individual and relationship characteristics associated with recruitment and retention of breast cancer survivors' partners. METHODS: Investigators asked survivors from the Moving Beyond Cancer trial for permission to invite their partners to a parallel, longitudinal study. RESULTS: Of 384 survivors with male partners, 280 survivors provided consent to contact partners, and 164 partners completed both assessments. Backward stepwise regression indicated that greater family income and support from a partner and helpful other increased the likelihood of survivor consent to contact her partner. Greater family income, better survivor physical and emotional quality of life, and white ethnicity increased the likelihood of partner participation. CONCLUSIONS: Breast cancer patients who are ethnic minorities, have lower socioeconomic status, or have poorer physical and mental quality of life appear less likely to participate in psycho-oncology couples' research, whereas women with supportive partners might be overrepresented. PMID- 23456214 TI - The best laid plans: planning skill determines the effectiveness of action plans and implementation intentions. AB - BACKGROUND: Theories of action control emphasise the importance of planning, but plans are not universally beneficial. PURPOSE: The present study investigates whether the effectiveness of plans depends upon the skill of the planner. METHODS: Study 1 prospectively predicted changes in unhealthy snacking behaviour over 1 week from intentions, action planning and performance on a standardised cognitive test of planning skill (n = 72). Study 2 experimentally randomised skilled and poor planners to receive (or not) a planning intervention before completing an online food diary (n = 144) RESULTS: Spontaneously generated action plans about snacking explained significantly more variance in subsequent snacking if produced by a skilled rather than a poor planner. The planning intervention (implementation intention) significantly improved goal attainment but only in poor planners. CONCLUSIONS: Plans are only as good as the people who make them. Poor planners' plans do not help achieve goals. Planning interventions can compensate for a lack of planning skill. PMID- 23456215 TI - Parental anxiety and stress before pediatric anesthesia: a pilot study on the effectiveness of preoperative clown intervention. AB - As induction of pediatric anesthesia can elicit anxiety in children and parents alike, this study was aimed at evaluating the effectiveness of clown intervention in decreasing maternal anxiety and stress in the preoperative phase. Before anesthesia induction, 25 children were randomly assigned to clown intervention and 25 to a control group with a routine procedure. In the waiting room and after separation from the child, maternal anxiety and stress were measured. The results showed that after separation, only in the clown group, maternal state anxiety significantly decreased and the tendency to somatization did not increase. Moreover, after clown intervention, older children's mothers significantly reduced the level of perceived stress. As clown intervention can positively influence maternal anxiety and stress in the preoperative period, its promotion in clinical-hospital environments is recommended. PMID- 23456216 TI - Health insurance status, psychological processes, and older African Americans' use of preventive care. AB - The current study examined the influence of health insurance, psychological processes (i.e. psychological competency and vulnerability), and the interaction of these two constructs on older African Americans' utilization of five preventive care services (e.g. cholesterol screening and mammogram/prostate examination) using data from 211 older African Americans (median age = 60). In addition to direct effects, the influence of health insurance sometimes varied depending on respondents' psychological competency and/or vulnerability. Policies and interventions to increase older African Americans' use of preventive health services should consider structural (e.g. health insurance) and psychological (e.g. psychological competency and vulnerability) factors along with the interaction between these factors. PMID- 23456217 TI - MAGPI hypospadias repair: factors that determine outcome. AB - BACKGROUND: This is a review of our experience with the meatal advancement and glanuloplasty incorporated (MAGPI) hypospadias repair, and we point to some of the factors that determine outcome. METHODS: We identified all patients who underwent MAGPI repair by a single surgeon over an 8-year period. We performed a retrospective chart review followed by telephone interview to assess parent satisfaction and also functional and cosmetic outcome. Decision to undergo this type of repair was intra-operative, depending on position and mobility of the meatus and the quality of peri-urethral tissue. RESULTS: We identified 48 patients, with a median age of 19 months (8 months-13 years). Position of meatus was glanular (40) or coronal (eight cases). Chordee required correction in 40 % (12/30). Urethral stenting was required in one case. There was no case of fistula, meatal regression, stenosis, or second procedure. A single case of mucosal prolapse was encountered. The majority (47/48) were performed as a day case. Forty parents agreed to telephone interview. Cosmetic outcome was deemed satisfactory in 95 % (38/40). With regard to unsatisfactory cosmetic outcome, one had a megameatus and the other was aged 13 years and developed a mucosal prolapse. CONCLUSION: In selected cases, the MAGPI hypospadias repair provide excellent functional and cosmetic outcomes with minimal complications, and it can safely be performed as a day-case procedure. PMID- 23456218 TI - Delivering general paediatric surgery in Ireland: how to avert a crisis? PMID- 23456219 TI - The effectiveness of health interventions in cardiovascular risk reduction among emergency service personnel. AB - PURPOSE: The physical demands and hazards associated with emergency service work place particular stress on responders' cardiovascular systems. Indeed, cardiovascular disease (CVD) is a significant problem for emergency service personnel. Although it may be difficult to alter the cardiovascular health hazards associated with the work environment, it is possible for personnel to control their modifiable CVD risk factors, cardiovascular fitness levels and subsequently, reduce their CVD risk. This review aimed to determine the effectiveness and methodological quality of health interventions designed to mitigate CVD risk in emergency service personnel. METHODS: A literature search of electronic journal databases was performed. Sixteen relevant studies were assessed for methodological quality using a standardised assessment tool. Data regarding the effectiveness of each intervention were extracted and synthesised in a narrative format. RESULTS: Fifteen studies were rated 'Weak' and one study was rated 'Strong'. Interventions which combined behavioural counselling, exercise and nutrition were more effective in improving cardiovascular health than nutrition, exercise or CVD risk factor assessment-based interventions alone. Further, CVD risk factor assessment in isolation proved to be an ineffective intervention type to reduce CVD risk. CONCLUSION: Combined interventions appear most effective in improving the cardiovascular health of emergency service personnel. Accordingly, fire and emergency service agencies should consider trialling multifaceted interventions to improve the cardiovascular health of personnel and avoid interventions focused only on one of nutrition, exercise or CVD risk factor assessment. However, as most studies were methodologically weak, further studies of a higher methodological quality are needed. PMID- 23456221 TI - River pollution remediation monitored by optical and infrared high-resolution satellite images. AB - The Bormida River Basin, located in the northwestern region of Italy, has been strongly contaminated by the ACNA chemical factory. This factory was in operation from 1892 to 1998, and contamination from the factory has had deleterious consequences on the water quality, agriculture, natural ecosystems and human health. Attempts have been made to remediate the site. The aims of this study were to use high-resolution satellite images combined with a classical remote sensing methodology to monitor vegetation conditions along the Bormida River, both upstream and downstream of the ACNA chemical factory site, and to compare the results obtained at different times before and after the remediation process. The trends of the Normalised Difference Vegetation Index (NDVI) and the Enhanced Vegetation Index (EVI) along the riverbanks are used to assess the effect of water pollution on vegetation. NDVI and EVI values show that the contamination produced by the ACNA factory had less severe effects in the year 2007, when most of the remediation activities were concluded, than in 2006 and 2003. In 2007, the contamination effects were noticeable up to 6 km downstream of the factory, whereas in 2003 and 2006 the influence range was up to about 12 km downstream of the factory. The results of this study show the effectiveness of remediation activities that have been taking place in this area. In addition, the comparison between NDVI and EVI shows that the EVI is more suitable to characterise the vegetation health and can be considered an additional tool to assess vegetation health and to monitor restoration activities. PMID- 23456220 TI - Validating abbreviated measures of effort-reward imbalance at work in European cohort studies: the IPD-Work consortium. AB - BACKGROUND: Effort-reward imbalance (ERI) is an established conceptualisation of work stress. Although a validated effort-reward questionnaire is available for public use, many epidemiological studies adopt shortened scales and proxy measures. To examine the agreement between different abbreviated measures and the original instrument, we compared different versions of the effort-reward scales available in 15 European cohort studies participating in the IPD-Work (Individual participant-data meta-analysis in working populations) consortium. METHODS: Five of the 15 studies provide information on the original ('complete') scales measuring 'effort' and 'reward', whereas the 10 remaining studies used 'partial' scales. To compare different versions of the ERI scales, we analyse individual level data from 31,790 participants from the five studies with complete scales. RESULTS: Pearson's correlation between partial and complete scales was very high in case of 'effort' (where 2 out of 3 items were used) and very high or high in case of 'reward', if at least 4 items (out of 7) were included. Reward scales composed of 3 items revealed good to satisfactory agreement, and in one case, a reward scale consisting of 2 items only demonstrated a modest, but still acceptable degree of agreement. Sensitivity and specificity of a composite measure, the ratio of effort and reward, comparing partial versus complete scales ranged between 59-93 and 85-99 %, respectively. Complete and partial scales were strongly associated with poor self-rated health. CONCLUSION: Our results support the notion that short proxy measures or partial versions of the original scales can be used to assess effort-reward imbalance. PMID- 23456222 TI - Assessment of six Indian cultivars of mung bean against ozone by using foliar injury index and changes in carbon assimilation, gas exchange, chlorophyll fluorescence and photosynthetic pigments. AB - Six Indian cultivars of Vigna radiata L. (HUM-1, HUM-2, HUM-6, HUM-23, HUM-24 and HUM-26) were exposed with ambient and elevated (ambient + 10 ppb ozone (O3) for 6 h day(-1)) level of O3 in open top chambers. Ozone sensitivity was assessed by recording the magnitude of foliar visible injury and changes in various physiological parameters. All the six cultivars showed visible foliar symptoms due to O3, ranging 7.4 to 55.7 % injured leaf area. O3 significantly depressed total chlorophyll, photosynthetic rate (Ps), quantum yield (F(v)/F(m)) and total biomass although the extent of variation was cultivar specific. Cultivar HUM-1 showed maximum reduction in Ps and stomatal conductance. The fluorescence parameters also indicated maximum damage to PSII reaction centres of HUM-1. Injury percentage, chlorophyll loss, Ps, F(v)/F(m) and total biomass reduced least in HUM-23 depicting highest O3 resistance (R%). PMID- 23456223 TI - Decision support methods for the environmental assessment of contamination at mining sites. AB - Polluting mine accidents and widespread environmental contamination associated with historic mining in Europe and elsewhere has triggered the improvement of related environmental legislation and of the environmental assessment and management methods for the mining industry. Mining has some unique features such as natural background pollution associated with natural mineral deposits, industrial activities and contamination located in the three-dimensional sub surface space, the problem of long-term remediation after mine closure, problem of secondary contaminated areas around mine sites and abandoned mines in historic regions like Europe. These mining-specific problems require special tools to address the complexity of the environmental problems of mining-related contamination. The objective of this paper is to review and evaluate some of the decision support methods that have been developed and applied to mining contamination. In this paper, only those methods that are both efficient decision support tools and provide a 'holistic' approach to the complex problem as well are considered. These tools are (1) landscape ecology, (2) industrial ecology, (3) landscape geochemistry, (4) geo-environmental models, (5) environmental impact assessment, (6) environmental risk assessment, (7) material flow analysis and (8) life cycle assessment. This unique inter-disciplinary study should enable both the researcher and the practitioner to obtain broad view on the state-of-the art of decision support methods for the environmental assessment of contamination at mine sites. Documented examples and abundant references are also provided. PMID- 23456224 TI - Short- and long-term mortality after appendectomy in Sweden 1987-2006: influence of appendectomy diagnosis, sex, age, co-morbidity, surgical method, hospital volume, and time period--a national population based cohort study. PMID- 23456225 TI - Lymph node ratio may be supplementary to TNM nodal classification in node positive breast carcinoma based on the results of 2,151 patients. AB - BACKGROUND: The aim of the present study was to determine how lymph node ratio (LNR; the ratio of the number of metastatic lymph nodes to the number of removed lymph nodes) can supplement the TNM nodal classification in breast carcinoma. METHODS: We retrospectively reviewed the file records of 2,151 patients. RESULTS: Lymph node ratio-based low- (LNR <= 0.20), intermediate- (LNR 0.21-0.65), and high-risk (LNR > 0.65) patient groups had significantly different disease-free survival (DFS) (P < 0.001). The DFS of patients with N1, N2, and N3 disease was significantly different (P < 0.001). When LNR and TNM nodal groupings were included together in the Cox analysis, both groupings had independent prognostic significance (P < 0.001 and P < 0.001, respectively). The most significant LNR threshold value separating patients in low-risk and high-risk groups in terms of disease recurrence was 0.20 for N1 disease (P < 0.001), 0.35 for N2 disease (P < 0.001), and 0.90 for N3 disease (P < 0.001). CONCLUSIONS: Lymph node ratio and TNM nodal groupings show no superiority over each other in categorizing patients with node-positive breast carcinoma into prognostic groups of low-, intermediate , and high-risk. However, LNR grouping may supplement TNM nodal classification by categorizing patients within each TNM nodal group into low-risk and high-risk groups with significantly different survival. PMID- 23456226 TI - Robotically assisted revision of bariatric surgeries is safe and effective to achieve further weight loss. AB - BACKGROUND: As more bariatric operations are being performed in the USA every year, the number of revisions has increased. These operations are challenging and have a higher morbidity than the initial operation. We have reviewed our series of robotically assisted revisions. METHODS: At the University of Texas Medical School at Houston, we reviewed robotic revision cases from 2004 through 2011 and found 99 bariatric revisions using robotic assistance. Selected endpoints included body mass index (BMI) at follow-up, percent excess weight loss (%EWL), complications, intubation time, operative time, and length of hospital stay. RESULTS: The average BMI at the time of revision was 44.8 kg/m(2) and fell to 29 kg/m(2) after 3 years. BMI was significantly lower at all time intervals (3, 12, 24, and 36 months) compared to initial BMI (p < 0.001). The %EWL was also significant at 1, 3, 12, 24, and 36 months post-revision (p < 0.001). There was a 24 % (13/55) 90-day readmission rate. The overall complication rate was 17 %, with each individual complication rate between 2 and 4 %. There were no deaths. The average operative time was 204 min, and the average length of hospital stay was 2.3 days. CONCLUSIONS: Revising previous bariatric operations to gastric bypass is difficult and time consuming. Although robotically assisted revision can be done safely and can result in effective further weight loss, the high postoperative complication rate is an issue that warrants further attention. PMID- 23456227 TI - Surgical resection versus conformal radiotherapy combined with TACE for resectable hepatocellular carcinoma with portal vein tumor thrombus: a comparative study. AB - BACKGROUND: The aim of this study was to compare the results of surgical resection with three-dimensional conformal radiotherapy (3D-CRT) in the treatment of resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Transarterial chemoembolization (TACE) was given to both groups of patients when possible. METHODS: A retrospective study of 371 patients with resectable HCC with PVTT was conducted in two tertiary referral centers. The treatment of choice for these patients in one center was surgical resection. In the other center it was 3D-CRT. In the radiotherapy group (RG, n = 185), patients received 3D-CRT to the tumor and PVTT for a total radiation dose of 30-52 Gy (median 40 Gy). In the surgical group (SG, n = 186), patients underwent surgical resection. TACE was applied after surgery or 3D-CRT and then was repeated every 4 6 weeks if the patient tolerated the treatment. RESULTS: The median survival was 12.3 months for RG and 10.0 months for SG. The 1-, 2-, and 3-year overall survivals were 51.6, 28.4, and 19.9 %, respectively, for RG and 40.1, 17.0, and 13.6 %, respectively, for SG (p = 0.029). Stepwise multivariate analysis showed that the extent of PVTT and mode of treatment were independent risk factors of overall survival. The most common cause of death after treatment was liver failure as a consequence of progressive intrahepatic disease. CONCLUSIONS: 3D-CRT gave better survival than surgical resection for HCC with PVTT. PMID- 23456228 TI - Epidural blood patch in a patient with multiple sclerosis: is it safe? AB - PURPOSE: Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system resulting in demyelination and axonal injury. Epidural blood patch (EBP) to treat postdural puncture headache (PDPH) in an MS patient may be of concern because of the potential for this to interfere with axonal conduction. Even with normal axons, pressure can interfere with impulse conduction, and it is unknown whether affected axons of the MS patient are particularly vulnerable to the increase in epidural pressure that occurs as a consequence of the EBP. We describe our experience with EBP in an MS patient. While peridural pressure changes were not measured, we attempted to quantify any pressure-induced interference with axonal conduction by measuring changes in somatosensory evoked responses. CLINICAL FEATURES: A 50-yr-old female MS patient required an EBP for a PDPH after a diagnostic lumbar puncture. The first EBP (20 mL autologous blood, L3-4 interspace) was followed by a transient improvement in PDPH and then a worsening with increased lower-extremity weakness. A second EBP was performed (12 mL autologous blood, L3-L4 interspace) with concomitant evoked potential recordings (stimulating electrodes over the left posterior tibial nerve and recording electrodes at CZ-FZ coordinates). Postdural puncture headache symptoms were permanently relieved, and the effects of the EBP on evoked P40 latency responses (39.7 msec and 44.3 msec pre- and post-EBP, respectively) were considered to be physiologically insignificant. CONCLUSION: A report of EBP to treat PDPH in an MS patient is presented. We postulate that this type of patient may be at risk for impaired conduction of impulses in affected axons due to the increase in pressure produced by epidural injection of blood. Literature review indicates that pressure increases may be reduced by injecting the blood slowly. When EBP is considered in patients with axon conduction deficits, consideration should be given to concomitant monitoring of somatosensory evoked responses to help quantify interference with axonal conduction as a consequence of injection of blood into the epidural space. PMID- 23456230 TI - Disseminated tumour cells in the bone marrow in early breast cancer: morphological categories of immunocytochemically positive cells have different impact on clinical outcome. AB - Detection of disseminated tumour cells (DTCs) in bone marrow by immunocytochemistry (ICC) includes morphological evaluation of cytokeratin immunopositive cells. The aim of this study was to disclose the prognostic significance of different morphological categories of ICC-positive cells according to treatment status and tumour subtype. Bone marrow samples (at surgery) were analysed for the presence of cytokeratin-positive DTCs by a standard immunocytochemical method. The immunopositive cells were classified into the following categories, prior to any analysis of the association between DTCs and clinical outcome: tumour cells (TC), uninterpretable cells (UIC), hematopoietic cells (HC), and questionable HC (QHC). The analysis included 747 early breast cancer patients. Median follow-up was 84 months for relapse, and 99 months for death. The categorisation of the ICC positive cells revealed TC in 13.3 % of the patients, whereas 13.1, 17.8, and 21.4 % of the cases were positive for UIC, QHC, and HC, respectively. Analysing all patients, only TC and UIC predicted systemic relapse. Separate analysis of all patients not receiving adjuvant systemic treatment (No-Adj; n = 389) showed that only QHC were associated with reduced survival (DDFS: p = 0.008; BCSS: p = 0.004, log rank) and the presence of QHC also remained significant in multivariate analysis. Primary tumour subgroup analysis (of all patients) by hormone receptors (HR) and HER2, demonstrated that only TC/UIC had prognostic impact in the HR+/HER2- patients, whereas presence of QHC was associated with unfavourable outcome only in triple negative patients (DDFS: p = 0.004; BCSS: p = 0.024). Patients with >=3HC had improved outcome compared to those with fewer/no HC (DDFS: p = 0.005; BCSS: p = 0.009). Hence, morphological DTC subgroups may differ in clinical significance according to primary tumour subtype and treatment status. This emphasises the importance of DTC characterisation, and separate analyses of DTC categories according to tumour subtype. Hematopoietic ("false positive") cells might predict an immune-related favorable clinical outcome. PMID- 23456229 TI - Dysregulation of FHL1 spliceforms due to an indel mutation produces an Emery Dreifuss muscular dystrophy plus phenotype. AB - Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early-onset joint contractures, progressive muscular weakness and wasting and late-onset cardiac disease. The more common X-linked recessive form of EDMD is caused by mutations in either EMD (encoding emerin) or FHL1 (encoding four and a half LIM domains 1), while mutations in LMNA (encoding lamin A/C), SYNE1 (encoding nesprin-1) and SYNE2 (encoding nesprin-2) lead to autosomal dominant forms of the condition. Here, we identify a three-generation family with an extended EDMD phenotype due to a novel indel mutation in FHL1 that differentially affects the relative expression of the three known transcript isoforms produced from this locus. The additional phenotypic manifestations in this family-proportionate short stature, facial dysmorphism, pulmonary valvular stenosis, thoracic scoliosis, brachydactyly, pectus deformities and genital abnormalities-are reminiscent of phenotypes seen with dysregulated Ras-mitogen-activated protein kinase (RAS-MAPK) signalling [Noonan syndrome (NS) and related disorders]. The misexpression of FHL1 transcripts precipitated by this mutation, together with the role of FHL1 in the regulation of RAS-MAPK signalling, suggests that this mutation confers a complex phenotype through both gain- and loss-of-function mechanisms. This indel mutation in FHL1 broadens the spectrum of FHL1-related disorders and implicates it in the pathogenesis of NS spectrum disorders. PMID- 23456231 TI - Can we select individuals with low risk ductal carcinoma in situ (DCIS)? A population-based outcomes analysis. AB - Ductal carcinoma in situ (DCIS), a non-invasive breast cancer, is usually treated by breast-conserving surgery (BCS). Randomized trials prove that the addition of radiotherapy (XRT) leads to lower rates of recurrence. Despite the evidence, half of women do not receive XRT after BCS. It is unknown how well clinicians identify women with low risk DCIS for treatment by BCS alone or to what extent women with DCIS develop recurrent cancer due to the omission of radiotherapy. We report the outcomes of a population of women with DCIS treated with BCS, alone or with radiotherapy, and evaluate the effectiveness of each therapeutic approach. All women diagnosed with DCIS and treated with BCS, alone or with radiotherapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were validated by chart review. Survival analyses were used to study the development of local recurrence (LR) in relation to patient and tumor characteristics and the use of radiotherapy. The cohort included 3,762 women treated with breast-conserving therapy; 1,895 of whom (50 %) also received radiation. At 10 years median follow up, LR developed in 233 (12 %) women who received radiotherapy and in 363 (19 %) of women who did not (p < 0.0001). The 10-year actuarial LR rate for women who did and did not receive radiotherapy was 12.7 and 20.0 % (p < 0.0001). Differences were significant for both for invasive LR (7.0 vs. 10.0 %, p < 0.0001) and for DCIS recurrence (6.1 vs. 10.8 %, p < 0.0001). We estimate that 22 % of recurrences diagnosed in Ontario women treated for DCIS between 1994 and 2003 would have been prevented if all patients had received radiotherapy. The omission of radiotherapy after BCS for DCIS resulted in substantive recurrences that might have been avoided with treatment. Additional markers are needed to identify a low risk group in whom radiation can be safely omitted. PMID- 23456232 TI - Impact of local surgical treatment on survival in young women with T1 breast cancer: long-term results of a population-based cohort. AB - The aim of this study was to analyze the effect of the type of local surgical treatment on survival in young women aged less than 40 years with T1 breast cancer. We analyzed data from 3,512 patients aged <=40 years old who were diagnosed with T1 breast cancer from the Korean Breast Cancer Registry database between January 1988 and December 2006 and underwent either breast-conserving therapy (BCT) or mastectomy. The overall survival (OS) and breast-cancer-specific survival (BCSS) were compared between BCT and mastectomy. Of the 3,512 patients analyzed, 1,951 (55.6 %) underwent BCT, and 1,561 (44.4 %) underwent mastectomy. The median follow-up period was 111.0 (79.0-131.5) months. Overall, the 10-year OS rates for BCT and mastectomy were 95 and 92.1 %, respectively (p = 00004), and the 10-year BCSS rates for BCT and mastectomy patients were 96.9 and 94.9 %, respectively (p = 0.12). In node-negative patients, no significant difference was observed in either the OS (adjusted hazard ratio [HR] 1.072; 95 % CI, 0.750 1.5332, p = 0.704) or BCSS (adjusted HR 0.988; 95 % CI, 0.620-1.574, p = 0.960) rate between the BCT and mastectomy groups. In node-positive patients, no significant difference was observed in the OS (adjusted HR 1.634; 95 % CI, 0.982 2.272, p = 0.59) and BCSS (adjusted HR 1.410; 95 % CI, 0.755-2.633, p = 0.281) rates between the BCT and mastectomy groups. In this large, population-based analysis of young women with T1 breast cancer, the OS and BCSS were not different between BCT and mastectomy. PMID- 23456233 TI - The intercalated cells of the mouse kidney OMCD(is) are the target of the vasopressin V1a receptor axis for urinary acidification. AB - BACKGROUND: Vasopressin V1a receptor (V1aR) null mice have insufficient acid-base balance, but the target cell for V1aR signaling which results in the urinary acidification has not been identified. METHODS: By using a quantitative in situ hybridization technique and a double-staining technique with an anti-AQP3 antibody in mice, we investigated the axial distribution and acidosis-induced expression of V1aR mRNA along the nephron. We also investigated the acidosis induced morphological change in the tubule cells from wild-type and V1aR-null (V1aR(-/-)) mice. RESULTS: In the normal condition, V1aR mRNA was moderately expressed in the medullary thick ascending limb (MTAL) and highly expressed in the intercalated cell (IC) throughout the collecting duct (CD). However, no expression was observed in the proximal tubule, thin limbs of Henle's loop, and the principal cell of the CD. Importantly, V1aR mRNA was upregulated significantly both in the TAL and the IC of the CD in the inner stripe of the outer medulla (MTALis and IC of OMCDis, respectively) when mice were treated with NH4Cl (0.28 mol/L) for 6 days. Acidosis-induced hypertrophy, which was completely attenuated in V1aR(-/-) mice, was observed only in the IC of OMCDis (P < 0.005). In addition, urinary excretion of ammonia (NH3/NH4 (+)) was significantly decreased on day 3 (P < 0.05) and day 6 (P < 0.005) in the V1aR(-/-) mice treated with NH4Cl. CONCLUSION: In conclusion, the IC of OMCDis may be the target cell stimulated by the vasopressin V1aR axis and contribute to urinary acidification, at least during metabolic acidosis. PMID- 23456235 TI - Polythiophene-gold nanoparticle hybrid systems: Langmuir-Blodgett assembly of nanostructured films. AB - In this work, we demonstrate a simple method of synthesizing nanoscale polythiophene-gold nanoparticle (AuNP) hybrid systems assembled by the Langmuir Blodgett (LB) method. Regio-regular poly(3-(2 methoxyethoxy)ethoxymethyl)thiophene-2,5-diyl (PMEEMT) and poly(3 dodecylthiophene) (PDDT) were employed as the polymeric constituents. The presence of PDDT improved the amphiphilicity of PMEEMT by addressing the phase separation that occurred due to convective hydrodynamic instability on the substrate. 4 layer stacks of 90% and 99% PMEEMT films exhibited uniform film structure with a significant reduction in phase separation. A detailed mechanism for minimization of the surface effect has been proposed based on the interaction of polythiophenes with the substrate. For the first time, an ex situ approach has been adopted to incorporate AuNPs into LB films without affecting the film morphology and uniformity. The incorporation of AuNPs into the polythiophene matrix, aided by the affinity of sulphur for gold, was strongly dependent on the molecular arrangement of the matrix, which in turn depended on the composition of the matrix. The hybrid polythiophene films exhibited enhanced conductivity and can be applied in sensors, photovoltaics and memory devices. PMID- 23456234 TI - Structures of acylated sucroses and an acylated flavonol glycoside and inhibitory effects of constituents on aldose reductase from the flower buds of Prunus mume. AB - Five new acylated sucroses, mumeoses K-O, and a new acylated flavonol glycoside, mumeflavonoside A, were isolated from the flower buds of Prunus mume, cultivated in Zhejiang province, China. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects of the isolated acylated sucroses and flavonol glycosides on aldose reductase were also investigated. Several flavonol glycosides including mumeflavonoside A were shown to inhibit aldose reductase. PMID- 23456236 TI - The intracranial bridging veins: a comprehensive review of their history, anatomy, histology, pathology, and neurosurgical implications. AB - INTRODUCTION: The intracranial bridging veins are pathways crucial for venous drainage of the brain. They are not only involved in pathological conditions but also serve as important landmarks within neurological surgery. METHODS: The medical literature on bridging veins was reviewed in regard to their historical aspects, embryology, histology, anatomy, and surgery. CONCLUSION: Knowledge on the intracranial bridging veins and their dynamics has evolved over time and is of great significance to the neurosurgeon. PMID- 23456237 TI - Patellofemoral pain: an update on diagnostic and treatment options. AB - Patellofemoral pain is a frequent and often challenging clinical problem. It affects females more than males and includes many different pathologic entities that result in pain in the anterior aspect of the knee. Diagnosis of the specific cause of pain can be difficult and requires assessment of lower extremity strength, alignment, and range of motion, as well as specific patella alignment, tracking, and mobility. The treatment for patellofemoral pain is usually conservative with anti-inflammatory medications, activity modification, and a specific physical therapy program focusing on strengthening and flexibility. Infrequently, surgical treatment may be indicated after a non-operative program fails. The outcomes of surgical management may include debridement, lateral release, and realignment of the extensor mechanism to unload the patellofemoral articulation are favorable. PMID- 23456238 TI - Surgical approach to the posteromedial corner: indications, technique, outcomes. AB - Injuries to the medial side of the knee can occur in isolation or in conjunction with multiple other ligaments about the knee. In addition, medial knee injuries can involve isolated injury to the medial collateral ligament or include the posteromedial structures of the knee. Treatment strategies differ greatly depending on injury pattern. In order to select an appropriate treatment strategy, one must accurately diagnose the injury pattern based on clinical examination and the use of appropriate imaging studies. The fundamental basis for diagnosis of a medial sided knee injury stems from understanding the static and dynamic stabilizing structures that compose the medial side of the knee. It is our aim to define the anatomic roles of medial sided structures, their importance in protecting the biomechanical stability of the knee, as well as provide indications and our preferred procedures for surgical management of these complex injuries. PMID- 23456239 TI - Is endoscopic third ventriculostomy superior to shunts in patients with non communicating hydrocephalus? A systematic review and meta-analysis of the evidence. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) and shunts are both utilized in the treatment of non-communicating hydrocephalus. The objective of this study was to review the evidence comparing the effectiveness of these two techniques. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL) and Medline databases were searched between 1990 and August 2012. We included all studies comparing the failure rate of patients with non-communicating hydrocephalus treated with ETV and shunts. Two authors (HJM and FTR) appraised quality and extracted data independently. RESULTS: Of 313 articles identified, 12 were selected for further review. Of these, 6 were included for qualitative analysis, and 5 for quantitative analysis (n = 504). ETV was associated with a non statistically significant reduction in failure using the random-effects model (OR 0.58, 95 % CI 0.29-1.13). CONCLUSIONS: Both ETV and shunts are associated with a relatively high failure rate. At present there is insufficient proof to unequivocally recommend one mode of treatment above the other. However, there is some evidence that ETV may confer long-term survival advantage over shunts in the treatment of non-communicating hydrocephalus, particularly in patients with certain aetiologies such as aqueductal stenosis. Prospective randomized controlled trials are currently underway and may provide more robust evidence to answer this important question and better guide future management. PMID- 23456240 TI - Enhanced neuroregenerative effects by scaffold for the treatment of a rat spinal cord injury with Wnt3a-secreting fibroblasts. AB - BACKGROUND: Wnt proteins are bifunctional axon guidance molecules, several of which appear to mediate guidance of corticospinal tract axons along the spinal cord. Here, we studied increasing effect on regeneration by Wnt-containing alginate scaffolds on spinal cord injury (SCI). METHODS: A total of 32 rats were injured at the T7-8 level with an NYU impactor. According to transplantation materials, rats were classified into four groups: a Wnt3a-secreting fibroblast transplantation group (Wnt group, n = 8), a Wnt3a-secreting fibroblast with alginate transplantation group (Wnt + alginate group, n = 8), an alginate transplantation group (alginate group, n = 8), and a contusion-only group (sham group, n = 8). Behavioral tests were performed on the first, second, and third days after injury, and then weekly for 8 weeks. Five of the eight rats from each group were selected for manganese-enhanced magnetic resonance imaging (ME-MRI). Two rats from each group were examined for GAP43 and MAP2 expression using monoclonal and polyclonal primary antibodies, respectively. RESULTS: Seven weeks after transplantation (8 weeks after SCI), Wnt + alginate group rats achieved an average Basso-Beattie-Bresnahan locomotor score of 19.0, which was significantly higher than that of other groups. ME-MRI at 8 weeks after SCI revealed significantly higher relative signal intensities in the Wnt + alginate group. Gap43 and Map2 immunostaining, showed strong positive in the Wnt + alginate group. CONCLUSION: The Wnt + alginate complex exerted significantly enhanced recovery in a rat SCI model compared to alginate or Wnt3a alone. These results suggest that alginate scaffolds facilitate the regeneration of axon working with Wnt3a protein that promotes regeneration of the injured spinal cord. PMID- 23456241 TI - Winter weather versus group thermoregulation: what determines survival in hibernating mammals? AB - For socially hibernating mammals, the effectiveness of huddling as a means of energy conservation should increase with group size. However, group size has only been linked to increased survival in a few hibernating species, and the relative importance of social structure versus winter conditions during hibernation remains uncertain. We studied the influence of winter weather conditions, social group composition, age-structure, and other environmental factors and individual attributes on the overwinter survival of hoary marmots (Marmota caligata) in the Yukon Territory, Canada. Juvenile hoary marmot survival was negatively correlated with the mean winter (November to May) Pacific Decadal Oscillation (PDO) index. Survival in older age-classes was negatively correlated with PDO lagged by 1 year. Social group size and structure were weakly correlated with survival in comparison to PDO. The relationship between winter PDO and survival was most likely due to the importance of snowpack as insulation during hibernation. The apparent response of hoary marmots to changing winter conditions contrasted sharply with those of other marmot species and other mammalian alpine herbivores. In conclusion, the severity of winter weather may constrain the effectiveness of group thermoregulation in socially hibernating mammals. PMID- 23456242 TI - Intraspecific variation overrides origin effects in impacts of litter-derived secondary compounds on larval amphibians. AB - Secondary compounds leached from plant litter can negatively affect aquatic amphibian larvae. Non-native plants and their potentially distinct secondary compounds may constitute cryptic threats to native amphibians. We used the availability of both native and introduced Phragmites australis (common reed) populations in North America to assess the importance of origin, intraspecific variation, and two purified classes of compounds (tannins and saponins; gradients 0-25 mg L(-1)) on two common and widespread amphibians (Ambystoma maculatum, spotted salamander, and Lithobates palustris, pickerel frog). In experiments with purified compounds, high tannin concentrations reduced A. maculatum survival and developmental rate while high saponin concentrations reduced survival, developmental rate, and size of L. palustris and reduced A. maculatum developmental rate. In experiments using leaf litter extracts of 14 different P. australis populations, A. maculatum larval survival varied among populations but plant origin (native or introduced) did not explain this variation. In contrast to the lack of effects of purified saponins, increases in saponin concentrations in P. australis leachates significantly decreased A. maculatum survival. Our results suggest: (1) secondary compounds can impact larval amphibian survival and development in species-specific ways; (2) impacts of P. australis on A. maculatum vary among P. australis populations, reflecting intraspecific variation in secondary chemistry; and (3) origin (whether the plant is native or introduced) is a poor predictor of P. australis effects on A. maculatum. Scientists and managers may need to move beyond considering origin as a predictive variable when managing plant communities to benefit amphibians. PMID- 23456243 TI - Attracting pollinators and avoiding herbivores: insects influence plant traits within and across years. AB - Perennial plants interact with herbivores and pollinators across multiple growing seasons, and thus may respond to herbivores and pollinators both within and across years. Joint effects of herbivores and pollinators influence plant traits, but while some of the potential interactions among herbivory, pollination, plant size, and plant reproductive traits have been well studied, others are poorly understood. This is particularly true for perennial plants where effects of herbivores and pollinators may manifest across years. Here, we describe two experiments addressing the reciprocal interactions of plant traits with herbivore damage and pollination across 2 years using the perennial plant Chamerion angustifolium. We measured (1) plant responses to manipulation of damage and pollination in the year of treatment and the subsequent season, (2) damage and pollination responses to manipulation of plant size and flowering traits in the year of treatment, and (3) plant-mediated indirect interactions between herbivores and pollinators. We found that plant traits had little effect on damage and pollination, but damage and pollination affected plant traits in both the treatment year and the subsequent year. We found evidence of indirect effects between leaf herbivores and pollinators in both directions; indirect effects of pollinators on leaf herbivores have not been previously demonstrated. Our results indicate that pollen receipt results in shorter plants with fewer stems but does not change flower number, while leaf herbivory results in taller plants with fewer flowers. Together, herbivory and pollination may contribute to intermediate plant height and plants with fewer stems and flowers in our system. PMID- 23456244 TI - Parental monitoring, parental warmth, and minority youths' academic outcomes: exploring the integrative model of parenting. AB - Guided by the integrative model of parenting, the present study investigated the relationship between parental monitoring and racial/ethnic minority adolescents' school engagement and academic motivation as a function of parental warmth, and explored whether these associations varied for boys and girls. Participants (60 % female) were 208 sixth through eighth grade students (63 % African American, 19 % Latino, 18 % Multiracial) from an urban middle school in the Midwestern United States. Youth completed an in-school survey with items on parenting (parental monitoring, mothers'/fathers' warmth), cognitive engagement (school self-esteem), behavioral engagement (school trouble), and academic motivation (intrinsic motivation). As hypothesized, mothers' warmth enhanced the association between parental monitoring and youths' engagement and motivation. No gender differences in these associations emerged. Fathers' warmth strengthened the negative association between parental monitoring and school trouble, and this association was stronger for boys. Implications regarding the importance of sustaining a high level of monitoring within the context of warm parent-adolescent relationships to best support academic outcomes among minority youth are discussed. PMID- 23456246 TI - Downstream effectors of light- and phytochrome-dependent regulation of hypocotyl elongation in Arabidopsis thaliana. AB - Arabidopsis, like most plants, exhibits tissue-specific, light-dependent growth responses. Cotyledon and leaf growth and the accumulation of photosynthetic pigments are promoted by light, whereas hypocotyl growth is inhibited. The identification and characterization of distinct phytochrome-dependent molecular effectors that are associated with these divergent tissue-specific, light dependent growth responses are limited. To identify phytochrome-dependent factors that impact the photoregulation of hypocotyl length, we conducted comparative gene expression studies using Arabidopsis lines exhibiting distinct patterns of phytochrome chromophore inactivation and associated disparate hypocotyl elongation responses under far-red (FR) light. A large number of genes was misregulated in plants lacking mesophyll-specific phytochromes relative to constitutively-deficient phytochrome lines. We identified and characterized genes whose expression is impacted by light and by phyA and phyB that have roles in the photoregulation of hypocotyl length. We characterized the functions of several identified target genes by phenotyping of T-DNA mutants. Among these genes is a previously uncharacterized LHE (LIGHT-INDUCED HYPOCOTYL ELONGATION) gene, which we show impacts light- and phytochrome-mediated regulation of hypocotyl elongation under red (R) and FR illumination. We describe a new approach for identifying genes involved in light- and phytochrome-dependent, tissue-specific growth regulation and confirmed the roles of three such genes in the phytochrome dependent photoregulation of hypocotyl length. PMID- 23456247 TI - A DESD-box helicase functions in salinity stress tolerance by improving photosynthesis and antioxidant machinery in rice (Oryza sativa L. cv. PB1). AB - The exact mechanism of helicase-mediated salinity tolerance is not yet understood. We have isolated a DESD-box containing cDNA from Pisum sativum (Pea) and named it as PDH45. It is a unique member of DEAD-box helicase family; containing DESD instead of DEAD/H. PDH45 overexpression driven by constitutive cauliflower mosaic virus-35S promoter in rice transgenic [Oryza sativa L. cv. Pusa Basmati 1 (PB1)] plants confers salinity tolerance by improving the photosynthesis and antioxidant machinery. The Na(+) ion concentration and oxidative stress parameters in leaves of the NaCl (0, 100 or 200 mM) treated PDH45 overexpressing T1 transgenic lines were lower as compared to wild type (WT) rice plants under similar conditions. The 200 mM NaCl significantly reduced the leaf area, plant dry mass, net photosynthetic rate (PN), stomatal conductance (gs), intercellular CO2 (Ci), chlorophyll (Chl) content in WT plants as compared to the transgenics. The T1 transgenics exhibited higher glutathione (GSH) and ascorbate (AsA) contents under salinity stress. The activities of antioxidant enzymes viz. superoxide dismutase (SOD), ascorbate peroxidase (APX), guaiacol peroxidase (GPX) and glutathione reductase (GR) were significantly higher in transgenics; suggesting the existence of an efficient antioxidant defence system to cope with salinity induced-oxidative damage. Yeast two-hybrid assay indicated that the PDH45 protein interacts with Cu/Zn SOD, adenosine-5'-phosphosulfate kinase, cysteine proteinase and eIF(4G), thus confirming the involvement of ROS scavenging machinery in the transgenic plants to provide salt tolerance. Furthermore, the T2 transgenics were also able to grow, flower, and set viable seeds under continuous salinity stress of 200 mM NaCl. This study provides insights into the mechanism of PDH45 mediated salinity stress tolerance by controlling the generation of stress induced reactive oxygen species (ROS) and also by protecting the photosynthetic machinery through a strengthened antioxidant system. PMID- 23456248 TI - OsSNDP1, a Sec14-nodulin domain-containing protein, plays a critical role in root hair elongation in rice. AB - Rice is cultivated in water-logged paddy lands. Thus, rice root hairs on the epidermal layers are exposed to a different redox status of nitrogen species, organic acids, and metal ions than root hairs growing in drained soil. To identify genes that play an important role in root hair growth, a forward genetics approach was used to screen for short-root-hair mutants. A short-root hair mutant was identified and isolated by using map-based cloning and sequencing. The mutation arose from a single amino acid substitution of OsSNDP1 (Oryza sativa Sec14-nodulin domain protein), which shows high sequence homology with Arabidopsis COW1/AtSFH1 and encodes a phosphatidylinositol transfer protein (PITP). By performing complementation assays with Atsfh1 mutants, we demonstrated that OsSNDP1 is involved in growth of root hairs. Cryo-scanning electron microscopy was utilized to further characterize the effect of the Ossndp1 mutation on root hair morphology. Aberrant morphogenesis was detected in root hair elongation and maturation zones. Many root hairs were branched and showed irregular shapes due to bulged nodes. Many epidermal cells also produced dome shaped root hairs, which indicated that root hair elongation ceased at an early stage. These studies showed that PITP-mediated phospholipid signaling and metabolism is critical for root hair elongation in rice. PMID- 23456249 TI - Relationships between discrimination in health care and health care outcomes among four race/ethnic groups. AB - Discrimination has been found to be detrimental to health, but less is known about the influence of discrimination in health care. To address this, the current study (1) compared levels of racial/ethnic discrimination in health care among four race/ethnic groups; (2) determined associations between this type of discrimination and health care outcomes; and (3) assessed potential mediators and moderators as suggested by previous studies. Multivariate logistic regression models were used within a population-based sample of 1,699 White, African American, Mexican, and Puerto Rican respondents. Overall, 23% of the sample reported discrimination in health care, with levels varying substantially by race/ethnicity. In adjusted models, this type of discrimination was associated with an increased likelihood of having unmet health care needs (OR = 2.48, CI = 1.57-3.90) and lower odds of perceiving excellent quality of care (OR = 0.43, CI = 0.28-0.66), but not with the use of a physician when not sick or use of alternative medicine. The mediating role of mental health factors was inconsistently observed and the relationships were not moderated by race/ethnicity. These findings expand the literature and provide preliminary evidence that can eventually inform the development of interventions and the training of health care providers. PMID- 23456251 TI - Liver tumors and loco-regional therapy. PMID- 23456250 TI - The relationship between acculturative stress and eating disorder symptoms: is it unique from general life stress? AB - The purpose of the current study was to expand upon the literature examining the relationship between acculturative stress and eating disorder symptoms among different ethnic groups. Specifically, acculturative stress was explored as a moderator of the relationship between body dissatisfaction and eating disorder symptoms among ethnic minority women. Additionally, the distinction between acculturative stress and general life stress in predicting eating disorder symptoms was assessed. Participants consisted of 247 undergraduate women, all of whom were members of an ethnic minority group including African Americans, Asian Americans, and Latinas. Acculturative stress was found to moderate the relationship between body dissatisfaction and eating disorder symptoms, but only among African American women. Acculturative stress was also found to significantly predict bulimic symptoms above and beyond general life stress among African American, Asian American, and Latina women. PMID- 23456252 TI - Comparative analysis of solid-state bioprocessing and enzymatic treatment of finger millet for mobilization of bound phenolics. AB - The present work investigates the probable bioprocessing technique to mobilize the bound phenolics naturally found in finger millet cell wall for enriching it with dietary antioxidants. Comparative study was performed between the exogenous enzymatic treatment and solid-state fermentation of grain (SSF) with a food grade organism Rhizopus oryzae. SSF results indicated that at the 6th day of incubation, total phenolic content (18.64 mg gallic acid equivalent/gds) and antioxidant property (DPPH radical scavenging activity of 39.03 %, metal chelating ability of 54 % and better reducing power) of finger millet were drastically enhanced when fermented with GRAS filamentous fungi. During the enzymatic bioprocessing, most of the phenolics released during the hydrolysis, leached out into the liquid portion rather than retaining them within the millet grain, resulting in overall loss of dietary antioxidant. The present study establishes the most effective strategy to enrich the finger millet with phenolic antioxidants. PMID- 23456253 TI - Enzyme-based glucose delivery: a possible tool for biosorbent preparation for heavy metal removal from polluted environments. AB - This study was performed to examine the influence of the controlled glucose supply technology, EnBase((r)) Flo, on growth and heavy metals uptake capacity of two Bacillus strains isolated from food industry wastewater. Bacillus sp. growth on EnBase Flo (mineral salt complex medium containing starch-derived polymer as substrate) was examined in 24 deep well plates, controlling the glucose amount release by adding two amyloglucosidase concentrations (3 and 6 UL(-1)). Adsorption of the heavy metals Zn(2+), Cd(2+) and Pb(2+) was assessed in a single component system using synthetic metal solutions and as a function of the initial concentration of adsorbate, equilibrium time and removal efficiency. The Langmuir and Freundlich adsorption models were used for the mathematical description of the biosorption equilibrium and isotherm constants. A pseudo second-order model was applied to describe the uptake rate for two isolates. The EnBase((r)) Flo technology improved the cells growth over ten times after 24 h of fed-batch cultivation. The EnBase((r)) Flo technology improved the Cd(2+) and Pb(2+) uptake capacity of the bacterial strains by approximately 55 and 44 %, respectively. The biosorption of each metal was fairly rapid (within 30 min), which could be an advantage for large scale treatment of contaminated sites. This initial study may be a basis for future developments to apply EnBase Flo for the biomass production used further as biosorbent for heavy metal removal from aqueous solutions. PMID- 23456254 TI - Assessment of the phytotoxicity of seaport sediments in the framework of a quarry deposit scenario: germination tests of sediments aged artificially by column leaching. AB - The aim of the Sustainable Management of Sediments Dredged in Seaports (SEDIGEST) project is to assess the risks of treated port sediments for terrestrial ecosystems when deposited in quarries. We simulated the "ageing" of these sediments up to the "moment" when plants can germinate. Sediments were leached by water percolating through a laboratory column. Sediments 1 and 2, taken from the port of Toulon (France), were dried and aired. Sediment 3, taken from the port of Guilvinec (France), was stabilised with lime. Phytotoxicity was evaluated on the three artificially aged sediments using germination and early development tests (48 h to 7 days) by Phytotoxkit F(TM) bioassays. The three dilutions tested were performed with the reference "ISO substrate" and with Lolium perenne sp. (rye grass), Sinapis alba (white mustard), and Lepidium sativum (watercress). The tests performed with sediments 1 and 2 showed (1) a decrease of their toxicity to the germination of the species selected following leaching and (2) that L. perenne was the most sensitive species. The tests performed with sediment 3 showed that it was improper for colonisation even after leaching simulating 16 months of ageing. These germination tests on aged sediments identified the effects of leaching and made it possible to appreciate the capacity of the sediments to allow colonisation by plants. PMID- 23456255 TI - Bioavailability of IgG administered by the subcutaneous route. AB - PURPOSE: US licensing studies of subcutaneous IgG (SCIG) calculate dose adjustments necessary to achieve area under the curve (AUC) of serum IgG vs. time on SCIG that is non-inferior to that on intravenous IgG (IVIG), within the FDA set limit of +/-20%. The results are interpreted as showing that different SCIGs differ in bioavailability. We used three approaches to determine if the bioavailabilities were actually different. METHODS: Dose adjustments and AUCs from published licensing studies were used to calculate bioavailabilities using the formula: Bioavailability (% of IVIG) = AUC(SCIG) / AUC(IVIG) x 1/Dose Adjustment. We also compared the increment in serum IgG concentration achieved with varying doses of SCIG in recent meta-analyses with the increment with different doses of IVIG, and determined the serum IgG concentrations when patients switched SCIG products at the same dose. RESULTS: The actual bioavailabilities were: Gamunex(r) 65.0%, Hizentra(r) 65.5%, Gammagard(r) 67.2%, Vivaglobin(r) 69.0%. Regression analyses of serum IgG vs. dose showed that the mean increase in serum IgG resulting from a 100 mg/kg/month increment in SCIG dosing was 69.4% of the increase with the same increment in IVIG dosing (84 mg/dL vs. 121 mg/dL). Patients switching SCIG preparations at the same dose had no change in serum IgG levels, confirming that bioavailabilities of the SCIG preparations did not differ. CONCLUSIONS: Decreased bioavailability appears to be a basic property of SCIG and not a result of any manufacturing process or concentration. Because serum IgG levels do not vary with different SCIG products at the same dose, adjustments are not necessary when switching products. PMID- 23456259 TI - Early and late presentations of graft arterial pseudoaneurysm following pancreatic transplantation. AB - BACKGROUND: Graft pseudoaneurysm (PSA) following pancreatic transplantation (PT) is a rarely reported complication that has significant morbidity and mortality. Few case reports and small series of this complication exist. METHODS: Retrospective review of files of 106 patients who underwent PT at the Tel-Aviv Sourasky Medical center between 1995 and 2010. Accessible asymptomatic patients (n = 35) were referred for graft PSA screening using ultrasound-Doppler. RESULTS: Eight patients developed graft PSA (8 %). All had early posttransplant sepsis. PSA incidence among patients who had perioperative sepsis is 13 %. Three patients developed early postoperative PSA, presenting as massive abdominal bleeding requiring urgent laparotomy and graft resection. Five patients were diagnosed with late-onset graft PSA between 3 months and 11 years posttransplant: clinical presentations were massive gastrointestinal bleeding (n = 2), acute renal failure (n = 1), and asymptomatic finding on screening ultrasound-Doppler (n = 2, 6 % of screened patients). CONCLUSIONS: PSA following PT occurs in 8 % of patients. Perioperative infection is a risk factor. Early PSAs present as massive intra abdominal bleeding. PSA may develop years posttransplant, may be asymptomatic, but late rupture is possible and presents as gastrointestinal bleeding. We recommend screening of patients at risk with ultrasound Doppler for early detection and treatment of asymptomatic PSAs. PMID- 23456258 TI - Association of suicide rates, gun ownership, conservatism and individual suicide risk. AB - OBJECTIVES: The purpose of the study was to examine the association of suicide rates, firearm ownership, political conservatism, religious integration at the state level, and individual suicide risk. Social structural and social learning and social integration theories were theoretical frameworks employed. It was hypothesized that higher suicide rates, higher state firearm availability, and state conservatism elevate individual suicide risk. METHOD: Data were pooled from the Multiple Cause of Death Files. Multilevel logistic regression models were fitted to all deaths occurring in 2000 through 2004 by suicide. RESULTS: The state suicide rate significantly elevated individual suicide risk (AOR = 1.042, CI = 1.037, 1.046). Firearm availability at the state level was associated with significantly higher odds of individual suicide (AOR = 1.004, CI = 1.003, 1.006). State political conservatism elevated the odds of individual suicides (AOR = 1.005, CI = 1.003, 1.007), while church membership at the state level reduced individual odds of suicide (AOR = 0.995, CI = 0.993, 0.996). The results held even after controlling for socioeconomic and demographic variables at the individual level. CONCLUSION: It was concluded that the observed association between individual suicide odds and national suicide rates, and firearm ownership cannot be discounted. Future research ought to focus on integrating individual level data and contextual variables when testing for the impact of firearm ownership. Support was found for social learning and social integration theories. PMID- 23456256 TI - Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration? AB - The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have been proposed as a possible therapeutic tool for CNS disorders. In addition to their differentiation potential, it is well accepted nowadays that their beneficial actions can also be mediated by their secretome. Indeed, it was already demonstrated, both in vitro and in vivo, that MSCs are able to secrete a broad range of neuroregulatory factors that promote an increase in neurogenesis, inhibition of apoptosis and glial scar formation, immunomodulation, angiogenesis, neuronal and glial cell survival, as well as relevant neuroprotective actions on different pathophysiological contexts. Considering their protective action in lesioned sites, MSCs' secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Thus, in this review we analyze the current understanding of MSCs secretome as a new paradigm for the treatment of CNS neurodegenerative diseases. PMID- 23456260 TI - Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland. AB - We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics. PMID- 23456257 TI - Epigenetic methylations and their connections with metabolism. AB - Metabolic pathways play fundamental roles in several processes that regulate cell physiology and adaptation to environmental changes. Altered metabolic pathways predispose to several different pathologies ranging from diabetes to cancer. Specific transcriptional programs tightly regulate the enzymes involved in cell metabolism and dictate cell fate regulating the differentiation into specialized cell types that contribute to metabolic adaptation in higher organisms. For these reasons, it is of extreme importance to identify signaling pathways and transcription factors that positively and negatively regulate metabolism. Genomic organization allows a plethora of different strategies to regulate transcription. Importantly, large evidence suggests that the quality of diet and the caloric regimen can influence the epigenetic state of our genome and that certain metabolic pathways are also epigenetically controlled reveling a tight crosstalk between metabolism and epigenomes. Here we focus our attention on methylation based epigenetic reactions, on how different metabolic pathways control these activities, and how these can influence metabolism. Altogether, the recent discoveries linking these apparent distant areas reveal that an exciting field of research is emerging. PMID- 23456261 TI - Primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) comprises approximately 5 % of all primary brain tumors. During the past two decades the incidence of PCNSL has increased, and as a result clinical research to determine the optimal treatment for PCNSL patients also has increased. Diagnosis is based on histopathologic findings traditionally established by biopsy only. More recent data raise controversy and challenges this biopsy-only paradigm, showing a potential advantage for surgical resection with progression-free survival (PFS) and overall survival (OS). Using high-dose intravenous (IV) methotrexate-based chemotherapy alone or as part of a regimen can lead to disease cure. The role of whole brain radiotherapy (WBRT) remains controversial and more frequently is omitted to avoid potential delayed neurocognitive effects, especially in patients older than age 60 years. Newer data from Memorial Sloan Kettering Cancer Center (MSKCC) using five cycles of Rituximab, Methotrexate, Vincristine, and Procarbazine (R-MVP) followed by low-dose WBRT (2,340 cgy), and then two cycles of Ara-C had excellent disease control with low neuro-toxicity and is now the basis of an ongoing RTOG (Radiation Treatment Oncology Group) trial comparing early versus delayed WBRT. Other chemotherapeutics and novel treatments, such as autologous stem cell transplantation, are being studied for potential use in PCNSL. Unlike many other primary brain tumors seen in adults, PCNSL is potentially curable; therefore, balancing treatment decisions with long-term neurocognitive effects and toxicities is crucial. PMID- 23456263 TI - Successful salvage therapy using lenalidomide in a patient with relapsed multiple myeloma after allogeneic hematopoietic stem cell transplantation. PMID- 23456262 TI - Molecular pathogenesis of multiple myeloma: basic and clinical updates. AB - Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p. PMID- 23456264 TI - Successful anticoagulant therapy for two pregnant PNH patients, and prospects for the eculizumab era. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by intravascular hemolysis and thrombosis. The most serious complication is thrombosis, the risk of which is augmented by the hyper coagulable state that occurs during pregnancy; despite this risk, however, young female PNH patients often desire to have a baby. We recently experienced two successful deliveries in PNH patients, who were treated with anticoagulant therapy during their pregnancies. Meanwhile, given the potential benefit of eculizumab (Soliris), a humanized monoclonal antibody against C5, in reducing thrombosis and hemolysis, it represents a promising therapeutic option for the treatment of pregnant PNH patients in combination with, or in replacement of, anticoagulant therapy. PMID- 23456265 TI - The involvement of magnoflorine in the sedative and anxiolytic effects of Sinomeni Caulis et Rhizoma in mice. AB - The present study seeks to evaluate the sedative and anxiolytic effects of the 70% ethanol extract of Sinomeni Caulis et Rhizoma (SR). The extract was orally administered to mice at dosages of 25, 50, 100, 200 or 400 mg/kg. The mice were then subjected to an array of behavioral tests to assess the sedative (open field, rota-rod, and thiopental sodium-induced sleeping test) and anxiolytic (elevated plus maze test) effects of the substance. SR (100, 200 mg/kg) significantly reduced locomotor activity, decreased rota-rod performance, and potentiated thiopental sodium-induced sleeping in mice, all indicative of its sedative effects. SR (50, 100 mg/kg) also produced anxiolytic effects, as shown by an increase in entries and staying time on the open arm of the plus maze. SR's sedative and anxiolytic effects were comparable to that of the benzodiazepine, diazepam. Moreover, to identify SR's probable mechanism of action, intracellular Cl- ion influx was observed in cultured human neuroblastoma cells. SR dose dependently increased Cl- influx, which was blocked by co-administration of the GABAA receptor competitive antagonist, bicuculline. Among the major constituents of SR, only magnoflorine showed a similar increment in Cl- influx, which was also blocked by bicuculline. Altogether, the present results suggest that SR has sedative and anxiolytic effects, probably mediated by magnoflorine through a GABAergic mechanism of action. PMID- 23456266 TI - Foreign accent strength and listener familiarity with an accent codetermine speed of perceptual adaptation. AB - We investigated how the strength of a foreign accent and varying types of experience with foreign-accented speech influence the recognition of accented words. In Experiment 1, native Dutch listeners with limited or extensive prior experience with German-accented Dutch completed a cross-modal priming experiment with strongly, medium, and weakly accented words. Participants with limited experience were primed by the medium and weakly accented words, but not by the strongly accented words. Participants with extensive experience were primed by all accent types. In Experiments 2 and 3, Dutch listeners with limited experience listened to a short story before doing the cross-modal priming task. In Experiment 2, the story was spoken by the priming task speaker and either contained strongly accented words or did not. Strongly accented exposure led to immediate priming by novel strongly accented words, while exposure to the speaker without strongly accented tokens led to priming only in the experiment's second half. In Experiment 3, listeners listened to the story with strongly accented words spoken by a different German-accented speaker. Listeners were primed by the strongly accented words, but again only in the experiment's second half. Together, these results show that adaptation to foreign-accented speech is rapid but depends on accent strength and on listener familiarity with those strongly accented words. PMID- 23456267 TI - Expression of a highly active catalase VktA in the cyanobacterium Synechococcus elongatus PCC 7942 alleviates the photoinhibition of photosystem II. AB - The repair of photosystem II (PSII) after photodamage is particularly sensitive to reactive oxygen species-such as H2O2, which is abundantly produced during the photoinhibition of PSII. In the present study, we generated a transformant of the cyanobacterium Synechococcus elongatus PCC 7942 that expressed a highly active catalase, VktA, which is derived from a facultatively psychrophilic bacterium Vibrio rumoiensis, and examined the effect of expression of VktA on the photoinhibition of PSII. The activity of PSII in transformed cells declined much more slowly than in wild-type cells when cells were exposed to strong light in the presence of H2O2. However, the rate of photodamage to PSII, as monitored in the presence of chloramphenicol, was the same in the two lines of cells, suggesting that the repair of PSII was protected by the expression of VktA. The de novo synthesis of the D1 protein, which is required for the repair of PSII, was activated in transformed cells under the same stress conditions. Similar protection of the repair of PSII in transformed cells was also observed under strong light at a relatively low temperature. Thus, the expression of the highly active catalase mitigates photoinhibition of PSII by protecting protein synthesis against damage by H2O2 with subsequent enhancement of the repair of PSII. PMID- 23456268 TI - Chlorophyll a fluorescence: beyond the limits of the Q(A) model. AB - Chlorophyll a fluorescence is a non-invasive tool widely used in photosynthesis research. According to the dominant interpretation, based on the model proposed by Duysens and Sweers (1963, Special Issue of Plant and Cell Physiology, pp 353 372), the fluorescence changes reflect primarily changes in the redox state of Q(A), the primary quinone electron acceptor of photosystem II (PSII). While it is clearly successful in monitoring the photochemical activity of PSII, a number of important observations cannot be explained within the framework of this simple model. Alternative interpretations have been proposed but were not supported satisfactorily by experimental data. In this review we concentrate on the processes determining the fluorescence rise on a dark-to-light transition and critically analyze the experimental data and the existing models. Recent experiments have provided additional evidence for the involvement of a second process influencing the fluorescence rise once Q(A) is reduced. These observations are best explained by a light-induced conformational change, the focal point of our review. We also want to emphasize that-based on the presently available experimental findings-conclusions on alpha/beta-centers, PSII connectivity, and the assignment of FV/FM to the maximum PSII quantum yield may require critical re-evaluations. At the same time, it has to be emphasized that for a deeper understanding of the underlying physical mechanism(s) systematic studies on light-induced changes in the structure and reaction kinetics of the PSII reaction center are required. PMID- 23456269 TI - On the role of plant mitochondrial metabolism and its impact on photosynthesis in both optimal and sub-optimal growth conditions. AB - Given that the pathways of photosynthesis and respiration catalyze partially opposing processes, it follows that their relative activities must be carefully regulated within plant cells. Recent evidence has shown that the components of the mitochondrial electron transport chain are essential for the proper maintenance of intracellular redox gradients, to allow considerable rates of photorespiration and in turn efficient photosynthesis. Thus considerable advances have been made in understanding the interaction between respiration and photosynthesis during the last decades and the potential mechanisms linking mitochondrial function and photosynthetic efficiency will be reviewed. Despite the fact that manipulation of various steps of mitochondrial metabolism has been demonstrated to alter photosynthesis under optimal growth conditions, it is likely that these changes will, by and large, not be maintained under sub-optimal situations. Therefore producing plants to meet this aim remains a critical challenge. It is clear, however, that although there have been a range of studies analysing changes in respiratory and photosynthetic rates in response to light, temperature and CO2, our knowledge of the environmental impact on these processes and its linkage still remains fragmented. We will also discuss the metabolic changes associated to plant respiration and photosynthesis as important components of the survival strategy as they considerably extend the period that a plant can withstand to a stress situation. PMID- 23456271 TI - Prospective cohort studies of bowel movement frequency and laxative use and colorectal cancer incidence in US women and men. AB - PURPOSE: The associations between bowel movement frequency, laxative use, and colorectal cancer incidence remain uncertain. No published studies have accounted for potential latency between these factors and colorectal cancer onset. METHODS: We prospectively examined these associations among 88,173 women in the Nurses' Health Study (NHS, 1982-2010) and 23,722 men in the Health Professionals Follow up Study (HPFS, 2000-2010). Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs, 95 % CIs). We conducted time lagged analyses to evaluate the potential latency in the NHS. RESULTS: We documented 2,012 incident colorectal cancer cases. The HRs (95 % CIs) for infrequent bowel movement relative to daily were 0.86 (95 % CI 0.71-1.04) in women and 0.81 (95 % CI 0.48-1.37) in men. The HRs for weekly to daily relative to never laxative use were 0.98 (95 % CI 0.81-1.20) in women and 1.41 (95 % CI 0.96-2.06) in men. In women, the HRs for every 3 days or less bowel movement relative to daily were 0.87 (95 % CI 0.59-1.27) for colorectal cancers that developed within 10 years of assessment, 1.03 (95 % CI 0.85-1.26) for 11-18 years after assessment, and 0.73 (95 % CI 0.54-1.01) for 19-28 years after assessment. The corresponding HRs for weekly to daily relative to never laxative use were 0.93 (95 % CI 0.63-1.37), 1.03 (95 % CI 0.74-1.44), and 0.98 (95 % CI 0.71-1.35), respectively. CONCLUSION: Bowel movement frequency and laxative use appear not to be associated with colorectal cancer risk in this study. PMID- 23456272 TI - Physiological adaptations during endurance training below anaerobic threshold in rats. AB - To assess the effects of continuous exercise training at intensities corresponding to 80 and 90 % of the lactate minimum test (LM), we evaluated antioxidant activity, hormone concentration, biochemical analyses and aerobic and anaerobic performance, as well as glycogen stores, during 12 weeks of swimming training in rats. One-hundred rats were separated into three groups: control (CG, n = 40), exercise at 80 (EG80, n = 30) and 90% (EG90, n = 30) of LM. The training lasted 12 weeks, with sessions of 60 min/day, 6 days/week. The intensity was based at 80 and 90% of the LM. The volume did not differ between training groups (X of EG80 = 52 +/- 4 min; X of EG90 = 56 +/- 2 min). The glycogen concentration (mg/100 mg) in the gastrocnemius increased after the training in EG80 (0.788 +/- 0.118) and EG90 (0.795 +/- 0.157) in comparison to the control (0.390 +/- 0.132). The glycogen stores in the soleus enhanced after the training in EG90 (0.677 +/- 0.230) in comparison to the control (0.343 +/- 0.142). The aerobic performance increased by 43 and 34% for EG80 and EG90, respectively, in relation to baseline. The antioxidant enzymes remain unchanged during the training. Creatine kinase (U/L) increased after 8 weeks in both groups (EG80 = 427.2 +/- 97.4; EG90 = 641.1 +/- 90.2) in relation to the control (246.9 +/- 66.8), and corticosterone (ng/mL) increased after 12 weeks in EG90 (539 +/- 54) in comparison to the control (362 +/- 44). The continuous exercise at 80 and 90% of the LM has a marked aerobic impact on endurance performance without significantly biomarkers changes compared to control. PMID- 23456270 TI - Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case control studies. AB - PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease. PMID- 23456273 TI - Distribution of radionuclides in surface soils, Singhbhum Shear Zone, India and associated dose. AB - Gamma emitters were estimated in surface soils from a mineralized zone in Eastern India using high purity Germanium detector-based high resolution gamma spectrometry system. Activities of (238)U, (226)Ra, (232)Th, (235)U, (227)Th, (234 m)Pa, (210)Pb, (40)K, and (137)Cs were 79 +/- 50, 81 +/- 53, 65 +/- 23, 4 +/ 2, 5 +/- 4, 92 +/- 50, 97 +/- 45, 517 +/- 201, and 4 +/- 2 Bq/kg, respectively. Most radionuclides were observed to follow log-normal distribution. The correlation between physicochemical properties of the samples, like pH, organic matter content, particle size, and moisture content were also studied. Activity ratios of (226)Ra/(238)U, (210)Pb/(226)Ra, and (227)Th/(235)U indicated deviation from secular equilibrium in some samples. The associated annual effective dose ranged from 0.07 to 0.24 mSv and the mean was calculated to be 0.12 +/- 0.04 mSv for this region, indicating it to be one of normal natural background radiation. PMID- 23456274 TI - Persistence of thiacloprid residues on brinjal (Solanum melongena L.). AB - Thiacloprid, a neonicotinoid insecticide with novel mode of action, is found to be effective against several lepidopteran as well as hemipteran pests. The present studies were carried out to observe the persistence pattern of thiacloprid on brinjal and to suggest suitable waiting period for the safety of consumers. Persistence of thiacloprid in brinjal was studied following three applications of thiacloprid (Alanto 240 SC) at 180 and 360 g a.i. ha(-1) at 7 days interval. Residues of thiacloprid in brinjal were estimated by high performance liquid chromatography and were confirmed by liquid chromatography mass spectrometry. The average initial deposits of thiacloprid were observed to be 0.48 and 1.05 mg kg(-1) on the brinjal fruit following third application of thiacloprid at recommended and double the recommended dosages, respectively. Half life periods for thiacloprid were found to be 0.47 and 0.50 days at single and double the application rates, respectively. Residues of thiacloprid declined below its limit of quantification of 0.05 mg kg(-1) after 3 and 5 days, respectively, at recommended and double the recommended application rates. Therefore, the use of thiacloprid does not seem to pose any risk hazard and a waiting period of 1 day is suggested for safe consumption of brinjal fruits. PMID- 23456275 TI - Gene cloning, expression, and characterization of a cyclic nucleotide phosphodiesterase from Arthrobacter sp. CGMCC 3584. AB - Based on thermal asymmetric interlaced polymerase chain reaction, the arpde gene encoding a cyclic nucleotide-specific phosphodiesterase was cloned from Arthrobacter sp. CGMCC 3584 for the first time. The 930-bp region encoded a 309 amino-acid protein with a molecular weight of 33.6 kDa. The recombinant ArPDE was able to hydrolyze 3',5'-cAMP, 3',5'-cGMP, and 2',3'-cAMP. The K m values of ArPDE for 3',5'-cAMP and 3',5'-cGMP were 6.82 and 12.82 mM, respectively. ArPDE was thermostable and displayed optimal activity at 45 degrees C and pH 7.5. The enzyme did not require any metal cofactors, although its activity was stimulated by 2 mM Co(2+) and inhibited by Zn(2+). Nucleotides, reducing agents, and sulfhydryl reagents had different inhibitory effects on the activity of ArPDE. NaF, the actual compound used to improve the industrial yield of cAMP, exhibited 62 % inhibitions at concentrations of 10 mM. PMID- 23456276 TI - Sodium dodecyl sulphate, a strong inducer of thermostable glucanhydrolase secretion from a derepressed mutant strain of Bacillus alcalophilus GCBNA-4. AB - In the present study, we report the optimisation of batch conditions for improved alpha-1,4-glucan-glucanohydrolase (GGH) secretion by a nitrous acid (NA)-treated Bacillus alcalophilus. The wild (isolate GCB-18) and NA-derivative (mutant GCBNA 4) were grown in a medium containing 10 g/L nutrient broth, 10 g/L starch, 5 g/L lactose, 2 g/L ammonium sulphate, 2 g/L CaCl2 and phosphate buffer (pH 7.6). Sodium dodecyl sulphate (SDS) was used as an enzyme inducer while batch fermentations were carried out at 40 degrees C. The mutant produced GGH in 40 h which was 15-fold higher than the wild in presence of SDS. Thermodynamic studies revealed that the mutant culture exhibited the capability for improved enzyme activity over a broad range of temperature (35-70 degrees C). The enzyme was purified by cation-exchange column chromatography with ~80 % recovery. The performance of fuzzy-logic system control was found to be highly promising for the improved substrate conversion rate. The correlation (1.045E + 0025) among variables demonstrated the model terms as highly significant indicating commercial utility of the culture used (P < 0.05). PMID- 23456277 TI - Effect of subchronic hypobaric hypoxia on oxidative stress in rat heart. AB - We examined the effect of subchronic hypobaric hypoxia in rat heart. Adult male Sprague-Dawley rats were exposed at 25,000 ft for different time periods (2 and 5 days). Susceptibility of their hearts to oxidative stress as well as modulation in gene expression was evaluated. The results showed a crosstalk between reactive oxygen species (ROS) and nitric oxide (NO), initial response was accompanied by increase in ROS generation and development of oxidative stress as confirmed by increased lipid peroxidation, protein oxidation and accumulation of 2, 4 dinitrophenyl hydrazine and 4-hydroxy-2-nonenal adducts. At the same time, glutathione activity decreased; however, antioxidant enzymatic activities of superoxide dismutases, glutathione-S-transferase, and glutathione peroxidase rose in response to 5-days hypoxia. Interestingly, NO level increased till 5 days, however ROS decreased after 5 days; this observation suggests that ROS/NO balance plays an important role in cardioprotection. This observation is further supported by upregulation of antioxidant genes hemeoxygenase (HO-1) and metallothionein (MT). In addition, hypoxia also induces gradual upregulation of hypoxia-inducible transcription factor (HIF-1alpha), which in turn induces the expression of adaptive genes erythropoiesis, vascular endothelial growth factor, glucose transporter-1, nitric oxide synthase. Collectively, our data suggests a reciprocal regulation of ROS and NO and this effect is mediated by the increase in antioxidant proteins HO-1 and MT. Along with this HIF-1-mediated induction of various cardioprotective genes also plays an important role in acclimatization. PMID- 23456278 TI - Application of pigeon pea (Cajanus cajan) stalks as raw material for xylooligosaccharides production. AB - Pigeon pea (Cajanus cajan) is a perennial plant widely cultivated in tropical and subtropical regions of many countries. The present studies aimed to produce xylooligosaccharides (XOS) from pigeon pea stalks in order to do value addition. The chemical analysis of stalks revealed 18.33 +/- 1.40 % hemicelluloses in addition to cellulose, protein, and lignin. Sodium hydroxide coupled with steam application enabled almost 96 % recovery of original xylan, present in the pigeon pea stalks. Enzymatic hydrolysis of xylan led to production of XOS namely, xylobiose and xylotriose. Response surface model indicated a maximum yield of xylobiose (0.502 mg/ml) under the hydrolysis conditions of pH 4.91, temperature at 48.11 degrees C, enzyme dose at 11.01 U, and incubation time at 15.65 h. The ideal conditions for higher xylotriose yield (0.204 mg/ml) were pH 5.44, temperature at 39.29 degrees C, enzyme dose at 3.23 U, and incubation time at 15.26 h. The present investigation was successful in assessing the prospect of using pigeon pea stalks as a raw material for xylan extraction vis-a-vis XOS production. PMID- 23456279 TI - Anaerobic digestion of cassava wastewater pre-treated by fungi. AB - Cassava wastewater (cww) contains high concentrations of easily acidifying compounds, requiring a buffered system to allow a stable operation during anaerobic digestion (AD). The possibility to include a preliminary one-step fungi treatment aimed at raising the pH and buffering the cww prior to AD was studied. Preliminary tests were performed with a naturally grown fungal mixed culture, under aerated (AE), non-aerated (NAE) and initially oxygen-deprived (IOD) conditions. The cww was pre-treated by the NAE condition, until reaching a soluble chemical oxygen demand (COD) of 10 g L(-1) and pH 6.4 (batch A) and pH 5.7 (batch B). The fungal mixed culture showed ability to biodegrade the cww with initial pH of 4.4 and 14,500 mg COD L(-1), raising the pH over 8.5, with only 13 % of COD remaining within 27 days for both AE and NAE condition. The fungal pre treated-cww (FPTcww) was subjected to anaerobic digestion under different buffered (CaCO3 and NaHCO3) and non-buffered conditions. The FPTcww with initial pH at 6.4 provided stability during the anaerobic biodegradability tests, showing the possibility of system operation without buffer addition, with final pH around 7. The application of a fungal pre-treatment can be a promising strategy to permit the anaerobic digestion of carbohydrate-rich wastewaters. PMID- 23456280 TI - Maximum production of fermentable sugars from barley straw using optimized soaking in aqueous ammonia (SAA) pretreatment. AB - Soaking in aqueous ammonia (SAA) pretreatment was investigated to improve enzymatic digestibility and consequently to increase total fermentable sugar production from barley straw. Various effects of pretreatment process parameters, such as reaction temperature, reaction time, solid:liquid ratio, and ammonia concentration, were evaluated, and the optimum conditions for two of the most important factors, reaction temperature and time were determined using response surface methodology. Optimized reaction conditions were 77.6 degrees C treatment temperature, 12.1 h. treatment time, 15 wt.% ammonia concentration, and 1:8 solid to-liquid ratio, which gave a sugar recovery yield of 71.5 % (percent of theoretical sugar recovered from the untreated barley straw) with enzyme loading of 15 FPU/g-glucan. In the optimization of the SAA pretreatment process, ammonia concentration, reaction temperature, and reaction time were determined to be the most significant factors correlated to subsequent enzyme digestibility. Based on tested conditions exhibiting high sugar recovery yields of >60 %, it appeared that reaction temperature affected total fermentable sugar production more significantly than reaction time. PMID- 23456281 TI - The oxidation of phenylhydrazine by tyrosinase. AB - Tyrosinase was found to catalyze the oxidation of phenylhydrazine to phenol in a reaction that did not resemble those typically performed by tyrosinase. The kinetics of this reaction was investigated by measuring the initial velocity of the formation of phenol (25 degrees C). The values of k cat and K M for the oxidation of phenylhydrazine were obtained as 11.0 s(-1) and 0.30 mM, respectively. The generation of superoxides during the oxidation of phenylhydrazine by tyrosinase was monitored by nitroblue tetrazolium (NBT) assay. In the phenylhydrazine-tyrosinase reaction, 1 mol O2 was required for the production of 1 mol phenol and 1/6 mol superoxide. The decomposition of superoxide by superoxide dismutase enhanced the rate constant of the oxidation of phenylhydrazine. Phenol formed in the oxidation of phenylhydrazine by tyrosinase was further oxidized by tyrosinase to an o-quinone, after the oxidation of phenylhydrazine by tyrosinase was almost completed. PMID- 23456282 TI - Neyman, Markov processes and survival analysis. AB - J. Neyman used stochastic processes extensively in his applied work. One example is the Fix and Neyman (F-N) competing risks model (1951) that uses finite homogeneous Markov processes to analyse clinical trials with breast cancer patients. We revisit the F-N model, and compare it with the Kaplan-Meier (K-M) formulation for right censored data. The comparison offers a way to generalize the K-M formulation to include risks of recovery and relapses in the calculation of a patient's survival probability. The generalization is to extend the F-N model to a nonhomogeneous Markov process. Closed-form solutions of the survival probability are available in special cases of the nonhomogeneous processes, like the popular multiple decrement model (including the K-M model) and Chiang's staging model, but these models do not consider recovery and relapses while the F N model does. An analysis of sero-epidemiology current status data with recurrent events is illustrated. Fix and Neyman used Neyman's RBAN (regular best asymptotic normal) estimates for the risks, and provided a numerical example showing the importance of considering both the survival probability and the length of time of a patient living a normal life in the evaluation of clinical trials. The said extension would result in a complicated model and it is unlikely to find analytical closed-form solutions for survival analysis. With ever increasing computing power, numerical methods offer a viable way of investigating the problem. PMID- 23456283 TI - Extra-hepatic bile duct hamartoma in a 10-month-old with a morgagni hernia and multiple anatomical anomalies: a rare and incidental finding. AB - Von Meyenburg complexes (VMCs), also known as bile duct hamartomas, are a part of a group of ductal plate malformations. They are typically present intrahepatically. In this case, we present to our knowledge the first report of an extra-hepatic VMC in the pediatric population. The patient presented as a 10 month-old infant with a weeklong history of progressive breathing difficulty. A chest radiograph was obtained, showing intestinal loops in the thoracic cavity consistent with a Morgagni's hernia, unrelated to his breathing difficulty. The patient then underwent an elective repair of his congenital diaphragmatic defect. During the operation, the bile duct hamartoma was found adherent to the accessory lobe of the liver, present to the left of the ligamentum teres. PMID- 23456284 TI - Splanchnic-cerebral oxygenation ratio (SCOR) values in healthy term infants as measured by near-infrared spectroscopy (NIRS). AB - PURPOSE: The splanchnic-cerebral oxygenation ratio (SCOR) is a measurement comparing regional tissue oxygen saturation of splanchnic organs and brain tissue. SCOR has been previously proposed as a marker of clinical conditions associated with gut ischemia. Our goal was to determine SCOR values in healthy neonates in their first and second days of life. METHODS: Prospective observational study measuring SCOR in term neonates in the nursery using near infrared spectroscopy (NIRS). RESULTS: Forty-five subjects with a mean gestational age of 39.4 +/- 1.3 weeks were included. Mean SCOR on the first day was 0.90 +/- 0.16 and 0.97 +/- 0.16 on the second day, p = 0.02 (n = 45). No correlation was found between SCOR and gestational age; however, we did find a positive correlation between hour of life and SCOR values (r = 0.28, r(2) = 0.08, p < 0.01, two tails); SCOR appears to stabilize by 36 h. CONCLUSIONS: Our findings demonstrate SCOR values in healthy neonates consistent with those previously theorized and help to validate it as a diagnostic measure. In addition, we have demonstrated that SCOR values may normally be lower in infants during their first days of life, and this information may be helpful to clinicians using NIRS as a diagnostic tool. PMID- 23456285 TI - Segmental aganglionosis (zonal aganglionosis or "skip" lesions) in Hirschsprungs disease: a report of 2 unusual cases. AB - INTRODUCTION: There is accumulating evidence that "skip" lesions or zonal aganglionosis do occur in HSCR disease, albeit rarely. They are of interest because it may cause confusion in interpreting surgical margins as well as understanding the pathophysiology of HSCR disease. Normally described as "a skip area" of normally ganglionated bowel, surrounded proximally and distally by aganglionosis with variations may occur. CASE REPORTS: We report two cases of infants with unusual types of "skip lesions", identified within the last 5 years. RESULTS: One patient had an area of zonal aganglionosis in the transverse colon and recto-sigmoid, bordered by areas of normally enervated bowel in the right and descending colon. In the second patient, the terminal ileum, transverse, descending and sigmoid colons and rectum were histologically aganglionic, but focal patches of ganglion cells were identified in 21 cm of the right ascending colon and the appendix, suggesting some ENS plasticity and possible incomplete apoptosis. CONCLUSION: These cases illustrate the point that the presence of ganglion cells at the resection line is not sufficient to guarantee postoperative function and "skip" lesions may uncommonly confuse the picture. In addition, they raise questions as to its pathophysiology and favor an alternate hypothesis of local changes promoting neuroblast apoptosis as the possible cause. PMID- 23456286 TI - Bilateral Wilms' tumour in a developing country: a descriptive study. AB - PURPOSE: To present our experience of 20 children with bilateral Wilms' tumour seen in a resource-challenged environment over a 10-year period. METHOD: All patients with a diagnosis of bilateral synchronous Wilms' tumour were identified and recruited. RESULTS: Study patients represented 11 % of a cohort of 177 new patients with Wilms' tumour seen over the same period. Three patients had a syndromic predisposition to Wilms' tumour. Metastatic disease was seen at presentation in four patients (20 %) and three children presented with unilateral tumour rupture. One patient presented with paraplegia and one with obstruction of the duodenum. All children received neoadjuvant chemotherapy. One HIV-infected child died of IRIS after neoadjuvant treatment, but before surgery. One child died of progressive disease after unilateral nephrectomy. Nephron-sparing surgery was performed in 22 kidneys and 15 kidneys were removed in toto. Following enucleation of tumours, three children had positive margins. Discordant histopathology was seen in 53 % of patients. Overall survival at 2 years is 85 %. CONCLUSION: Despite significant co-morbidity and advanced disease, bilateral Wilms' tumour is a treatable disease in a resource-constrained environment. PMID- 23456287 TI - Appendicitis in children: an ongoing debate. PMID- 23456288 TI - Cephalopod neurobiology: an introduction for biologists working in other model systems. AB - This paper concisely summarizes major aspects of cephalopod biology, behavior, and ecology providing a backdrop against which neurobiology of these animals can be interpreted. Reproduction, camouflage, motor control, memory, learning, and behavioral ecology are introduced, and thorough literature reviews of these subjects are cited for further reading. The aim of this paper is to provide a general introduction to cephalopods for use by workers currently focused on other model systems. PMID- 23456289 TI - Dengue: the continual re-emergence of a centuries-old disease. PMID- 23456291 TI - Centenary of Lewy bodies (1912-2012). AB - During the years from 1908 until 1923, Lewy was the first to detail the pathological anatomy of Parkinson's disease, leading to his seminal contribution in 1912 describing the neuronal eosinophilic cytoplasmatic concentric inclusion bodies in the brainstem, later accomplished by more systematic investigations in 1923 (Lewy in Lewandowsky's Handbuch der Neurologie, 3. Band: Spez. Neurologie II. Springer, Berlin, pp 920-933, 1912). With the exception of a minority of cases and those that displayed postencephalitic Parkinsonism, Lewy was not able to confirm the significance of the substantia nigra. The findings of Tretiakoff in 1919 (significance of the substantia nigra in PD and coining of the term 'Corps de Lewy') have been underestimated or ignored for a long time. In a historical review on basal ganglia diseases from 1942, Lewy stressed the histological abnormalities of the basal ganglia and their diffuse distribution but not expressly the inclusion bodies, which in his former studies were unique in PD. For Lewy this finding was not a characteristic of the disease. Subsequent to his expulsion from Nazi-Germany in 1933, Lewy never resumed his research on PD. At the time of Lewy's death in 1950, the era of the Lewy bodies, Lewy-body disease and the identification of atypical Parkinson syndrome cases had not even begun and followed much later. PMID- 23456290 TI - Motor and nonmotor complications in Parkinson's disease: an argument for continuous drug delivery? AB - The complications of long-term levodopa therapy for Parkinson's disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations-at least equally common, but less well appreciated-in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)-or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated. PMID- 23456292 TI - Evaluation of subvalvular aortic stenosis in children: a 16-year single-center experience. AB - Subvalvular aortic stenosis accounts for 1-2 % of all congenital heart disease and for 8-20 % of cases of left-ventricular outflow tract (LVOT) obstruction in children. Recurrence of subaortic stenosis (SAS) is not uncommon after surgical management. This study was performed to investigate the clinical and surgical outcomes and to estimate the predictability of recurrences of SAS. Seventy-nine patients age 3-21 years with SAS between 1994 and 2010 were reviewed. Fifty-one patients had discrete SAS, whereas the remaining 15 patients had fibromuscular ridge-type SAS. Mean follow-up time without surgery was 22 months (range of 1 94). Forty-one patients with a diagnosis of SAS underwent surgery. Recurrence rates were 22.7 % (15 patients), and these patients developed SAS at a mean of 4.7 years follow-up. We performed second surgical membrane resection in only 1 patient. The risk of recurrence of SAS was only linked to higher preoperative LVOT gradient. Twenty-three patients had no aortic regurgitation (AR) at preoperative echocardiography. Of these, 39.1 % had trivial, 8.7 % had mild, and 8.7 % had moderate AR after surgery; there was no significant AR. We conclude that surgical intervention was required most of the time in patients with SAS, and surgical outcomes was excellent even if there were associated cardiac defects. The risk of recurrences was higher, especially in patients with higher initial LVOT gradients, although a second surgery was rarely necessary in these patients. PMID- 23456293 TI - Connecting the dots: rule-based decision support systems in the modern EMR era. AB - The intensive care unit (ICU) environment is rich in both medical device and electronic medical record (EMR) data. The ICU patient population is particularly vulnerable to medical error or delayed medical intervention both of which are associated with excess morbidity, mortality and cost. The development and deployment of smart alarms, computerized decision support systems (DSS) and "sniffers" within ICU clinical information systems has the potential to improve the safety and outcomes of critically ill hospitalized patients. However, the current generations of alerts, run largely through bedside monitors, are far from ideal and rarely support the clinician in the early recognition of complex physiologic syndromes or deviations from expected care pathways. False alerts and alert fatigue remain prevalent. In the coming era of widespread EMR implementation novel medical informatics methods may be adaptable to the development of next generation, rule-based DSS. PMID- 23456294 TI - Live image profiling of neural crest lineages in zebrafish transgenic lines. AB - Zebrafish transgenic lines are important experimental tools for lineage tracing and imaging studies. It is crucial to precisely characterize the cell lineages labeled in transgenic lines to understand their limitations and thus properly interpret the data obtained from their use; only then can we confidently select a line appropriate for our particular research objectives. Here we profiled the cell lineages labeled in the closely related neural crest transgenic lines Tg(foxd3:GFP), Tg(sox10:eGFP) and Tg(sox10:mRFP). These fish were crossed to generate embryos, in which foxd3 and sox10 transgenic neural crest labeling could be directly compared at the cellular level using live confocal imaging. We have identified key differences in the cell lineages labeled in each line during early neural crest development and demonstrated that the most anterior cranial neural crest cells initially migrating out of neural tube at the level of forebrain and anterior midbrain express sox10:eGFP and sox10:mRFP, but not foxd3:GFP. This differential profile was robustly maintained in the differentiating progeny of the neural crest lineages until 3.5dpf. Our data will enable researchers to make an informed choice in selecting transgenic lines for future neural crest research. PMID- 23456295 TI - Rice small C2-domain proteins are phosphorylated by calcium-dependent protein kinase. AB - We previously reported that OsERG1 and OsERG3 encode rice small C2-domain proteins with different biochemical properties in Ca(2+)- and phospholipid binding assays. Os-ERG1 exhibited Ca(2+)-dependent phospholipid binding, which was not observed with OsERG3. In the present study, we show that both OsERG1 and OsERG3 proteins exhibit oligomerization properties as determined by native polyacrylamide gel electrophoresis (PAGE) and glutaraldehyde cross-linking experiments. Furthermore, in vitro phosphorylation assays reveal the phosphorylation of OsERG1 and OsERG3 by a rice calcium-dependent protein kinase, OsCDPK5. Our mutation analysis on putative serine phosphorylation sites shows that the first serine (Ser) at position 41 of OsERG1 may be an essential residue for phosphorylation by OsCDPK5. Mutation of Ser41 to alanine (OsERG1S41A) and aspartate (OsERG1S41D) abolishes the ability of OsERG1 to bind phospholipids regardless of the presence or absence of Ca(2+) ions. In addition, unlike the OsERG1 wild-type form, the mutant OsERG1 (S41A)::smGFP construct lost the ability to translocate from the cytosol to the plasma membrane in response to calcium ions or fungal elicitor. These results indicate that Ser41 may be essential for the function of OsERG1. PMID- 23456296 TI - RNA-dependent RNA polymerase 6 is required for efficient hpRNA-induced gene silencing in plants. AB - In plants, transgenes with inverted repeats are used to induce efficient RNA silencing, which is also frequently induced by highly transcribed sense transgenes. RNA silencing induced by sense transgenes is dependent on RNA dependent RNA polymerase 6 (RDR6), which converts single-stranded (ss) RNA into double-stranded (ds) RNA. By contrast, it has been proposed that RNA silencing induced by self-complementary hairpin RNA (hpRNA) does not require RDR6, because the hpRNA can directly fold back on itself to form dsRNA. However, it is unclear whether RDR6 plays a role in hpRNA-induced RNA silencing by amplifying dsRNA to spread RNA silencing within the plant. To address the efficiency of hpRNA-induced RNA silencing in the presence or absence of RDR6, Wild type (WT, Col-0) and rdr6 11 Arabidopsis thaliana lines expressing green fluorescent protein (GFP) were generated and transformed with a GFP-RNA interference (RNAi) construct. Whereas most GFP-RNAi-transformed WT lines exhibited almost complete silencing of GFP expression in the T1 generation, various levels of GFP expression remained among the GFP-RNAi-transformed rdr6-11 lines. Homozygous expression of GFP-RNAi in the T3 generation was not sufficient to induce complete GFP silencing in several rdr6 11 lines. Our results indicate that RDR6 is required for efficient hpRNA-induced RNA silencing in plants. PMID- 23456297 TI - Regulatory effects of resveratrol on antioxidant enzymes: a mechanism of growth inhibition and apoptosis induction in cancer cells. AB - Resveratrol (RSV) is a natural polyphenol that is known as a powerful chemopreventive and chemotherapeutic anticancer molecule. This study focused on the effects of RSV on the activities and expression levels of antioxidant enzymes in the cancer cells. Prostate cancer PC-3 cells, hepatic cancer HepG2 cells, breast cancer MCF-7 cells and the non-cancerous HEK293T kidney epithelial cells were treated with a wide range of RSV concentrations (10-100 MUM) for 24-72 h. Cell growth was estimated by trypan blue staining, activities of the antioxidant enzymes were measured spectrophotometrically, expression levels of the antioxidant enzymes were quantified by digitalizing the protein band intensities on Western blots, and the percentage of apoptotic cells was determined by flow cytometry. Treatment with a low concentration of RSV (25 MUM) significantly increased superoxide dismutase (SOD) activity in PC-3, HepG2 and MCF-7 cells, but not in HEK293T cells. Catalase (CAT) activity was increased in HepG2 cells, but no effect was found on glutathione peroxidase (GPX) upon RSV treatment. RSV induced SOD2 expression was observed in cancer cells, although the expression of SOD1, CAT and GPX1 was unaffected. Apoptosis increased upon RSV treatment of cancer cells, especially in PC-3 and HepG2 cells. Together, our data demonstrated that RSV inhibits cancer cell growth with minimal effects on non-cancerous cells. We postulate that the disproportional up-regulation of SOD, CAT and GPX expression and enzymatic activity in cancer cells results in the mitochondrial accumulation of H2O2, which in turn induces cancer cell apoptosis. PMID- 23456298 TI - S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-kappaB activation in gastric cancer cells. AB - S100A8 and S100A9 (S100A8/A9) are low-molecular weight members of the S100 family of calcium-binding proteins. Recent studies have reported S100A8/A9 promote tumorigenesis. We have previously reported that S100A8/A9 is mostly expressed in stromal cells and inflammatory cells between gastric tumor cells. However, the role of environmental S100A8/A9 in gastric cancer has not been defined. We observed in the present study the effect of S100A8/A9 on migration and invasion of gastric cancer cells. S100A8/ A9 treatment increased migration and invasionat lower concentrations that did not affect cell proliferation and cell viability. S100A8/A9 caused activation of p38 mitogenactivated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB). The phosphorylation of p38 MAPK was not affected by the NF-kappaB inhibitor Bay whereas activation of NF-kappaB was blocked by p38 MAPK inhibitor SB203580, indicating that S100A8/A9-induced NF kappaB activation is mediated by phosphorylation of p38 MAPK. S100A8/A9-induced cell migration and invasion was inhibited by SB203580 and Bay, suggesting that activation of p38 MAPK and NF-kappaB is involved in the S100A8/A9 induced cell migration and invasion. S100A8/A9 caused an increase in matrix metalloproteinase 2 (MMP2) and MMP12 expression, which were inhibited by SB203580 and Bay. S100A8/A9-induced cell migration and invasion was inhibited by MMP2 siRNA and MMP12 siRNA, indicating that MMP2 and MMP12 is related to the S100A8/A9 induced cell migration and invasion. Taken together, these results suggest that S100A8/A9 promotes cell migration and invasion through p38 MAPKdependent NF-kappaB activation leading to an increase of MMP2 and MMP12 in gastric cancer. PMID- 23456299 TI - Hypermethylation of EBF3 and IRX1 genes in synovial fibroblasts of patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease of unknown origin, which exhibits a complex heterogeneity in its pathophysiological background, resulting in differential responses to a range of therapies and poor long-term prognosis. RA synovial fibroblasts (RASFs) are key player cells in RA pathogenesis. Identification of DNA methylation biomarkers is a field that provides potential for improving the process of diagnosis and prognosis of various human diseases. We utilized a genome-wide technique, methylated DNA isolation assay (MeDIA), in combination with a high resolution CpG microarray for discovery of novel hypermethylated genes in RASFs. Thirteen genes (APEX1, EBF3, EGR2, EN1, IRX1, IRX6, KIF12, LHX2, MIPOL1, SGTA, SIN3A, TOLLIP, and ZHX2) with three consecutive hypermethylated probes were isolated as candidate genes through two CpG microarrays. Pyrosequencing assay was performed to validate the methylation status of TGF-beta signaling components, EBF3 and IRX1 genes in RASFs and osteoarthritis (OA) SFs. Hypermethylation at CpG sites in the EBF3 and IRX1 genes was observed with a high methylation index (MI) in RASFs (52.5% and 41.4%, respectively), while a lower MI was observ ed in OASFs and h ealthy SFs (13.2% for EBF3 and 4.3% for IRX1). In addition, RT-PCR analysis showed a remarkable decrease in their mRNA expression in the RA group, compared with the OA or healthy control, and their reduction levels correlated with MI. The current findings suggest that methylation-associated down-regulation of EBF3 and IRX1 genes may play an important role in a pathogenic effect of TGF-beta on RASFs. However, further clinical validation with large numbers of patients is needed in order to confirm our findings. PMID- 23456300 TI - Hemi-levator excision to provide greater sphincter preservation in low rectal cancer. PMID- 23456301 TI - Association of PTPN22 gene (rs2488457) polymorphism with ulcerative colitis and high levels of PTPN22 mRNA in ulcerative colitis. AB - PURPOSE: Our aims were to evaluate protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms in ulcerative colitis (UC) and explore PTPN22 mRNA levels in colonic biopsies of UC patients in central China. METHODS: A total of 165 Chinese UC patients and 300 healthy controls were enrolled in this study. PTPN22 -1123G/C, +1858C/T, and +788G/A polymorphisms were genotyped by PCR restriction fragment length polymorphism method. PTPN22 mRNA expressions in colonic biopsies and serum C-reactive protein (CRP) levels were determined by quantitative PCR and immunonephelometry, respectively. RESULTS: The frequency of C carrier was higher in UC patients than in healthy controls (66.7 vs. 53.3%, P = 0.005, odds ratios = 1.75, 95% CI 1.18-2.60) and associated with extensive colitis (P = 0.029). PTPN22 mRNA levels were elevated in UC patients than in healthy controls (P < 0.001). Among UC patients, PTPN22 mRNA expression levels were higher in biopsies of inflamed colonic tissue compared with noninflamed tissue (P < 0.001) and were correlated with CRP levels (r = 0.578, P < 0.001). PTPN22 mRNA expression levels were elevated in extensive colitis compared to proctitis (P = 0.008) and to left-sided colitis (P = 0.029) and were higher in moderate and severe disease than in mild disease (P = 0.005). CONCLUSIONS: Our study showed the potential association between PTPN22 -1123G/C polymorphism and UC in central China. PTPN22 mRNA levels were highly expressed in UC, especially in active disease, and were correlated with CRP levels, disease location, and disease severity in UC patients. PMID- 23456302 TI - Study of polycyclic aromatic hydrocarbon contamination of major rivers in the Czech Republic using biliary metabolite in chub, Leuciscus cephalus L. AB - The aim of the present study was to evaluate polycyclic aromatic hydrocarbon (PAH) contamination of the major rivers in the Czech Republic using 1 hydroxypyrene (1-OHP) content in chub bile as a biomarker. The highest concentration of 1-OHP was found in the Otava River at Topelec (80.5 ng mg protein(-1)); the lowest content of 1-OHP was found in the Vltava at Zelcin (9.6 ng mg protein(-1)). At all sites, bottom sediment samples were collected and analyzed for PAH content. The PAH content ranged between 1.2 and 15.2 mg kg dry mass(-1) at all sites. Statistically significant positive correlations (p < 0.05) between biliary 1-OHP and sediment PAH content were found. Correlation coefficients for total and individual priority PAHs ranged from 0.63 to 0.77. PMID- 23456303 TI - A test of the survival processing advantage in implicit and explicit memory tests. AB - The present study was designed to investigate the survival processing effect (Nairne, Thompson, & Pandeirada, Journal of Experimental Psychology: Learning, Memory, and Cognition, 33, 263-273, 2007) in cued implicit and explicit memory tests. The survival effect has been well established in explicit free recall and recognition tests, but has not been evident in implicit memory tests or in cued explicit tests. In Experiment 1 of the present study, we tested implicit and explicit memory for words studied in survival, moving, or pleasantness contexts in stem completion tests. In Experiment 2, we further tested these effects in implicit and explicit category production tests. Across the two experiments, with four separate memory tasks that included a total of 525 subjects, no survival processing advantage was found, replicating the results from implicit tests reported by Tse and Altarriba (Memory & Cognition, 38, 1110-1121, 2010). Thus, although the survival effect appears to be quite robust in free recall and recognition tests, it has not been replicated in cued implicit and explicit memory tests. The similar results found for the implicit and explicit tests in the present study do not support encoding elaboration explanations of the survival processing effect. PMID- 23456304 TI - The effect of vocabulary knowledge on novel word identification. AB - The study investigated the relationship between vocabulary knowledge and novel word reading. Fourth-grade students were assessed on standardized measures of word identification, decoding, and receptive vocabulary, as well as on an experimental word identification measure using words that students in the fourth grade are unlikely to have seen before in print. In the experimental measure, pairs of words were matched on printed frequency and orthographic pattern (with a variety of spelling patterns represented), but differed in terms of the frequency of expected oral exposure for children (i.e., higher vs. lower). Results showed that students' receptive vocabulary knowledge was significantly related to performance on both the standardized and experimental measures of word identification, even after accounting for the substantial amount of variance explained by decoding ability. Students performed better reading the words with higher expected oral frequencies on the experimental task than on those items with lower expected oral frequencies. The results point to the benefits, albeit modest, of oral word familiarity for reading words when they are first encountered in print and suggest that this top-down effect is not limited to exception words, as has been suggested, but has a wider scope. PMID- 23456306 TI - Orientation enhancement in early visual processing can explain time course of brightness contrast and White's illusion. AB - Dynamics of orientation tuning in V1 indicates that computational model of V1 should not only comprise of bank of static spatially oriented filters but also include the contribution for dynamical response facilitation or suppression along orientation. Time evolution of orientation response in V1 can emerge due to time- dependent excitation and lateral inhibition in the orientation domain. Lateral inhibition in the orientation domain suggests that Ernst Mach's proposition can be applied for the enhancement of initial orientation distribution that is generated due to interaction of visual stimulus with spatially oriented filters and subcortical temporal filter. Oriented spatial filtering that appears much early (<70 ms) in the sequence of visual information processing can account for many of the brightness illusions observed at steady state. It is therefore expected that time evolution of orientation response might be reflecting in the brightness percept over time. Our numerical study suggests that only spatio temporal filtering at early phase can explain experimentally observed temporal dynamics of brightness contrast illusion. But, enhancement of orientation response at early phase of visual processing is the key mechanism that can guide visual system to predict the brightness by "Max-rule" or "Winner Takes All" (WTA) estimation and thus producing White's illusions at any exposure. PMID- 23456307 TI - Reductive decolourisation of sulphonated mono and diazo dyes in one- and two stage anaerobic systems. AB - This work assessed the application of one- and two-stage mesophilic anaerobic systems to colour removal of sulphonated mono and diazo dyes with ethanol as electron donor. The dyes Congo Red (CR), Reactive Black 5 (RB5) and Reactive Red 2 (RR2) were selected as model compounds and tested separately in seven different periods. The one-stage system (R(1)) consisted of a single up-flow anaerobic sludge blanket (UASB) reactor, whereas the two-stage system (R(2)) consisted of an acidogenic UASB reactor (R(A)), a settler and a methanogenic UASB reactor (R(M)). For CR and RB5, no remarkable difference was observed between the colour removal performance of both anaerobic systems R(1) and R(2). The experiments with RR2 revealed that R(2) was more efficient on colour removal than R(1), showing efficiencies almost 2-fold (period VI) and 2.5-fold (period VII) higher than those found by R(1). Additionally, R(2) showed a higher stability, giving a good prospect for application to textile wastewaters. Finally, the acidogenic reactor (R(A)) had an important role in the overall decolourisation achieved by R(2) during the experiments with CR and RB5 (>78 %), whereas for RR2, a more recalcitrant dye, R(A) was responsible for up to 38 % of the total colour removal. PMID- 23456308 TI - Persistence of anti-HLA antibody after cord blood transplantation engraftment in acute myelogenous leukemia: a potential marker of minimal residual disease, but not a significant factor in secondary humoral engraftment failure. AB - The presence of pre-transplant anti-HLA antibodies in recipients of cord blood transplantation (CBT) is associated with failed engraftment. However, only a small number of studies have reported that recipient-derived anti-HLA antibodies persist after CBT and have potential impact on the outcome. Of 61 patients who underwent HLA-mismatched CBT at Saiseikai Maebashi Hospital, three patients were identified as having anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB. All patients achieved successful engraftment. However, the three patients with the pre-transplant anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB continued to produce these antibodies even after engraftment; the persistence of these antibodies served as a sensitive minimal residual disease (MRD) marker. In contrast, donor HLA-specific and newly produced third party antibodies were not detectable even after relapse. The persistence of anti-HLA antibodies even after engraftment may be a potential marker for MRD, but is not a significant factor in secondary humoral engraftment failure. PMID- 23456305 TI - Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND. AB - Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID- 23456309 TI - Midterm results after uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for symptomatic uterine fibroids. AB - PURPOSE: To compare the rate of reintervention and midterm changes in symptom severity (SS) and Total health-related quality of life (HRQoL) scores after uterine artery embolization (UAE) and magnetic resonance-guided high-intensity focused ultrasound (MR-g HIFU) for symptomatic uterine fibroids. METHODS: Eighty women (median age 38.3 years), equally eligible for MR-g HIFU and UAE who underwent one of both treatments between 2002 and 2009 at our institution, were included. The primary end point of the study was defined as the rate of reintervention after both therapies. The secondary outcome was defined as changes in SS and Total HRQoL scores after treatment. SS and Total HRQoL scores before treatment and at midterm follow-up (median 13.3 months) were assessed by the uterine fibroid symptom and quality-of-life questionnaire (UFS-QoL) and compared. RESULTS: The rate of reintervention was significantly lower after UAE than after MR-g HIFU (p = 0.002). After both treatments, SS and Total HRQoL scores improved significantly from baseline to follow-up (UAE: p < 0.001, p < 0.001; MR-g HIFU: p = 0.002, p < 0.001). Total HRQoL scores were significantly higher after UAE than after MR-g HIFU (p = 0.032). Changes in the SS scores did not differ significantly for both treatments (p = 0.061). CONCLUSION: UAE and MR-g HIFU significantly improved the health-related quality of life of women with symptomatic uterine fibroids. After UAE, the change in Total HRQoL score improvement was significantly better, and a significantly lower rate of reintervention was observed. PMID- 23456310 TI - An assessment of radiologically inserted transoral and transgastric gastroduodenal stents to treat malignant gastric outlet obstruction. AB - INTRODUCTION: Self-expanding metallic stents (SEMS) are used to palliate malignant gastric outlet obstruction (GOO) and are useful in patients with limited life expectancy or severe medical comorbidity, which would preclude surgery. Stenting can be performed transorally or by a percutaneous transgastric technique. Our goal was to review the outcome of patients who underwent radiological SEMS insertion performed by a single consultant interventional radiologist. METHODS: Patients were identified from a prospectively collected database held by one consultant radiologist. Data were retrieved from radiological reports, multidisciplinary team meetings, and the patients' case notes. Univariate survival analysis was performed. RESULTS: Between December 2000 and January 2011, 100 patients (63 males, 37 females) had 110 gastroduodenal stenting procedures. Median age was 73 (range 39-89) years. SEMS were inserted transorally (n = 66) or transgastrically (n = 44). Site of obstruction was the stomach (n = 37), duodenum (n = 50), gastric pull-up (n = 10), or gastroenterostomy (n = 13). Seven patients required biliary stents. Technical success was 86.4 %: 83.3 % for transoral insertion, 90.9 % for transgastric insertion. Eleven patients developed complications. Median GOO severity score: 1 pre-stenting, 2 post-stenting (p = 0.0001). Median survival was 54 (range 1-624) days. Post-stenting GOO severity score was predictive of survival (p = 0.0001). CONCLUSIONS: The technical success rate for insertion of palliative SEMS is high. Insertional technique can be tailored to the individual depending on the location of the tumor and whether it is possible to access the stomach percutaneously. Patients who have successful stenting and return to eating a soft/normal diet have a statistically significant increase in survival. PMID- 23456311 TI - Engagement matters: lessons from assessing classroom implementation of steps to respect: a bullying prevention program over a one-year period. AB - Steps to Respect: A Bullying Prevention Program (STR) relies on a social ecological model of prevention to increase school staff awareness and responsiveness, foster socially responsible beliefs among students, and teach social-emotional skills to students to reduce bullying behavior. As part of a school-randomized controlled trial of STR, we examined predictors and outcomes associated with classroom curriculum implementation in intervention schools. Data on classroom implementation (adherence and engagement) were collected from a sample of teachers using a weekly on-line Teacher Implementation Checklist system. Pre-post data related to school bullying-related outcomes were collected from 1,424 students and archival school demographic data were obtained from the National Center for Education Statistics. Results of multilevel analyses indicated that higher levels of program engagement were influenced by school level percentage of students receiving free/reduced lunch, as well as classroom level climate indicators. Results also suggest that higher levels of program engagement were related to lower levels of school bullying problems, enhanced school climate and attitudes less supportive of bullying. Predictors and outcomes related to program fidelity (i.e., adherence) were largely nonsignificant. Results suggest that student engagement is a key element of program impact, though implementation is influenced by both school-level demographics and classroom contexts. PMID- 23456312 TI - Estimation in a competing risks proportional hazards model under length-biased sampling with censoring. AB - What population does the sample represent? The answer to this question is of crucial importance when estimating a survivor function in duration studies. As is well-known, in a stationary population, survival data obtained from a cross sectional sample taken from the population at time t(0) represents not the target density f (t) but its length-biased version proportional to t f (t), for t > 0. The problem of estimating survivor function from such length-biased samples becomes more complex, and interesting, in presence of competing risks and censoring. This paper lays out a sampling scheme related to a mixed Poisson process and develops nonparametric estimators of the survivor function of the target population assuming that the two independent competing risks have proportional hazards. Two cases are considered: with and without independent censoring before length biased sampling. In each case, the weak convergence of the process generated by the proposed estimator is proved. A well-known study of the duration in power for political leaders is used to illustrate our results. Finally, a simulation study is carried out in order to assess the finite sample behaviour of our estimators. PMID- 23456313 TI - Anthropometric factors in relation to risk of glioma. AB - INTRODUCTION: Increased height and greater adiposity have been linked to an increased risk of many cancer types, though few large studies have examined these associations in glioma. We examined body weight and height as potential risk factors for glioma in a large US-based case-control study. METHODS: The analysis included 1,111 glioma cases and 1,096 community controls. In a structured interview, participants reported their height and weight at 21 years of age, lowest and highest weight in adulthood, and weight 1-5 years in the past. RESULTS: Being underweight at age 21 (BMI < 18.5 kg/m(2)) was inversely associated with the risk of glioma development. This protective association was observed in both men and women, but reached statistical significance in women only (multivariate OR 0.68; 95 % CI 0.48, 0.96). When BMI at age 21 was assessed as a continuous variate, a small but significant increase in risk was observed per unit increase in kg/m(2) (OR 1.04; 95 % CI 1.02, 1.07). Adult height, recent body weight, and weight change in adulthood were not associated with glioma risk. All results were similar among never smokers and were consistent after stratifying by glioma subtype. CONCLUSION: The present data suggest that a low body weight in early adulthood is associated with a reduced risk of glioma later in life. Results are consistent with previous studies in showing no material association of glioma risk with usual adult body weight. The present study does not support any association of adult stature with glioma risk. PMID- 23456314 TI - Influence of treatment modality in outcomes for different stages of resectable esophageal adenocarcinomas. AB - BACKGROUND: There is no consensus on the most effective modality for the treatment of resectable esophageal adenocarcinomas (EAC). We theorized that treatment modality may influence survival differently depending on the stage of disease. METHODS: A single-institution, retrospective examination of resectable EAC between 2000 and 2008 was performed. Resectable EAC were stratified into early disease (stage 2a or less) and late disease (stage 2b or more) based on pretreatment endoscopic ultrasound (EUS). Patients with T4, >N2, and/or distant disease were excluded. RESULTS: A total of 156 patients were included in this study. Most patients were white (97 %), male (83 %), and over 60 years of age (51 %). Patients with early disease on pretreatment EUS exhibited improved overall survival compared to patients with late disease (P < 0.001). Irrespective of treatment modality, there were no significant differences in overall 5-year survival for patients with early or late disease. Early and late disease patients whose disease responded to neoadjuvant chemotherapy (NAC) had significantly improved overall survival compared to nonresponsive disease (P < 0.05). The only negative independent predictors of overall 5-year survival were late stage disease on pretreatment EUS (hazard ratio 2.402, 95 % confidence interval 1.24 4.67, P = 0.01) and late stage disease on final pathological stage (hazard ratio 2.29, 95 % confidence interval 1.22-4.31, P = 0.01). CONCLUSIONS: Our data lack statistical power but reveal no difference in survival with the addition of neoadjuvant therapies to surgery for early or late resectable EAC. However, patients with disease that responded to NAC had improved outcomes at 5 years for both groups. Therefore, the prognosis for patients undergoing NAC may be optimized by immediate surgical resection if neoadjuvant therapies do not result in a dramatic clinical response. PMID- 23456315 TI - Staging of adenocarcinoma of the esophagogastric junction: comparison of AJCC 6th and 7th gastric and 7th esophageal staging systems. AB - BACKGROUND: Adenocarcinoma of esophagogastric junction (EGJ) is currently staged by the esophageal staging criteria according to the American Joint Committee on Cancer (AJCC) staging system, 7th edition. We compared the performance of 6th gastric (G6), 7th gastric (G7), and 7th esophageal (E7) staging systems. METHODS: A total of 202 curatively resected adenocarcinomas of EGJ were analyzed. Patient outcomes were assessed according to G6, G7, and E7 staging. Tumor invasion to the subserosal or serosa layer was regarded as invasion to the adventitia for E7 staging. Performance was measured based on monotonicity (decreasing survival with increasing stage), distinctiveness (survival difference between different stages), and homogeneity (homogenous survival in the same stage). RESULTS: Each staging system was monotonous except for T1-2N0 lesions of E7. This was related to the introduction of histologic grade in E7 staging. Distinctiveness in each staging system was variable. As for the homogeneity, patients whose disease was staged as Ib (E7) exhibited different survival when reassessed by G6 and G7; again, this was related to histologic grading. Patients with IIIb (G7) and IIIc (E7) disease had different survival when reassessed by G6 staging, reflecting the poorer survival of patients with more than 15 lymph node metastases. CONCLUSIONS: Staging of EGJ cancer based on the current AJCC, 7th edition, criteria of esophageal cancer staging has several limitations. We recommend considering modifications of the following in future updates of the staging system: accurate anatomical definition of tumor depth, removal of histologic grade from staging parameters, and classification of more than 15 lymph node metastases as a highly advanced stage. PMID- 23456316 TI - Early assessment of axillary response with 18F-FDG PET/CT during neoadjuvant chemotherapy in stage II-III breast cancer: implications for surgical management of the axilla. AB - BACKGROUND: If all initially node-positive patients undergo axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC), overtreatment may occur in patients with complete response. Positron emission tomography-computed tomography (PET/CT) during NAC may predict axillary response and select patients appropriate for less invasive treatment after NAC. We evaluated the value of sequential (18)F fluorodeoxyglucose (FDG) PET/CTs during NAC for axillary response monitoring in stage II-III breast cancer. METHODS: A total of 219 PET/CTs were performed in 80 patients with cytology-proven, node-positive disease at baseline (PET/CT1, n = 80) and twice during NAC (PET/CT2 n = 62, PET/CT3, n = 77). The relative changes in maximum standardized uptake value (SUVmax) of axillary nodes were examined for their ability to assess pathological response. All patients underwent ALND after chemotherapy, and complete axillary response (pCR), defined as absence of isolated tumor cells and of micro- and macrometastases, served as the reference standard. RESULTS: A total of 32 (40 %) patients experienced axillary pCR. The relative decrease in SUVmax was significantly higher in patients with pCR than in those without, both on PET/CT2 (p < 0.001) and PET/CT3 (p = 0.025). The area under the receiver operating characteristic curve values for PET/CT2 and PET/CT3 were 0.80 (95 % confidence interval 0.68-0.92) and 0.65 (95 % confidence interval 0.52-0.79), respectively. A relative decrease of >=60 % on PET/CT2 had an excellent specificity (35 of 37, 95 %), a high positive predictive value (12 of 14, 86 %), and a sensitivity of 48 %-that is, it accurately identified histologic pCR in 12 of 25 patients with disease that responded to therapy. CONCLUSIONS: (18)F-FDG PET/CT early during NAC is useful for axillary response monitoring in cytology-proven node-positive breast cancer because it identifies pathological response, thus permitting ALND to be spared. PMID- 23456317 TI - Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis. AB - BACKGROUND: We performed a systematic review and meta-analysis to investigate the prognostic value of tumor cells in blood (circulating tumor cells [CTCs]) or bone marrow (BM) (disseminated tumor cells) of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer (CRC). MATERIALS AND METHODS: The following databases were searched in May 2011: MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cochrane Library. Studies that investigated the association between tumor cells in blood or BM and long-term outcome in patients with metastatic CRC were included. We extracted hazard ratios (HRs) and confidence intervals (CIs) from the included studies and performed random-effects meta-analyses for survival outcomes. RESULTS: The literature search yielded 16 studies representing 1,491 patients. The results of 12 studies representing 1,329 patients were suitable for pooled analysis. The overall survival (HR, 2.47; 95 % CI 1.74-3.51) and progression-free survival (PFS) (HR, 2.07; 95 % CI 1.44-2.98) were worse in patients with CTCs. The subgroup of studies with more than 35 % CTC positive patients was the only subgroup with a statistically significant worse PFS. All eight studies that performed multivariable analysis identified the detection of CTCs as an independent prognostic factor for survival. CONCLUSION: The detection of CTCs in peripheral blood of patients with resectable colorectal liver metastases or widespread metastatic CRC is associated with disease progression and poor survival. PMID- 23456318 TI - Rare breast cancer: 933 adenoid cystic carcinomas from the National Cancer Data Base. AB - BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare subtype of breast malignancy. METHODS: Patients with ACC and infiltrating ductal carcinoma (IDC) reported to the National Cancer Data Base from 1998 to 2008 were reviewed for patient age, ethnicity, tumor size, nodal status, American Joint Committee on Cancer TNM Stage, tumor grade, initial treatment, hormone receptor status (for patients from 2004 to 2008), and survival (for patients from 1998 to 2003). RESULTS: A total of 933 patients with ACC and 729,938 with IDC were identified. No differences were found for incidence by race/ethnicity (p = 0.97). The group with ACC was older (median 60 vs. 58 years), had larger tumors (median 18 vs. 16 mm), had more grade 1 tumors (46 vs. 18 %), was less likely to undergo axillary lymph node evaluation (75.9 vs. 96.3 %), had fewer node-positive patients (5.1 vs. 35.5 %), had fewer estrogen receptor-positive tumors (15.4 vs. 75.6 %), had fewer progesterone receptor-positive tumors (13.3 vs. 65.2 %), and underwent breast-conserving surgery more often (69.8 vs. 59.8 %). Chemotherapy was provided less often for ACC (11.3 vs. 46.4 %), as was hormone therapy (9.1 vs. 42.3 %). All of these differences were statistically significant (p < 0.0001). With a median follow-up of 65.7 months (ACC) and 64.9 months (IDC), 5-year overall survival (OS) was 88 % for ACC vs. 84 % for IDC (p = 0.02). Grade 1 OS (ACC, 91 % vs. IDC, 92 %; p = 0.50) and stage I OS (ACC, 90 % vs. IDC, 91 %; p = 0.93) were equal. CONCLUSIONS: Compared with IDC, ACC has different characteristics (lower grade, hormone receptor negative, node negative), is treated differently (less axillary surgery, fewer mastectomies, less chemotherapy, less hormone therapy), and has an improved prognosis, with 88 % 5-year survival. PMID- 23456319 TI - Expression of Brachyury gene is a significant prognostic factor for primary lung carcinoma. AB - BACKGROUND: The clinical significance of Brachyury expression and its relationship to epithelial-mesenchymal transition in primary lung carcinoma is unclear. METHODS: Expression of Brachyury mRNA was investigated in 104 surgically resected primary lung carcinoma tissues. Immunohistochemical analysis of Brachyury transcription factor, Slug, E-cadherin, IL-8, N-cadherin, and Ki67 was performed in 67 of 104 cases, and their expression was correlated to prognoses and clinicopathological factors. RESULTS: Brachyury mRNA expression in primary lung carcinoma tissues was a significant predictor of poor prognosis for 5-year disease-free survival and overall survival rates and was significantly correlated to vascular invasion, lymphatic permeation, histological grade, pathologic T stage, and pathologic N stage (P < 0.05). Brachyury mRNA expression was significantly inversely correlated to E-cadherin expression (P = 0.0252) and positively correlated to IL-8 protein (P = 0.0241) and to Slug protein (P = 0.0243) in adenocarcinoma tissues. CONCLUSIONS: A positive association between Brachyury and Slug and IL-8, and a negative association with E-cadherin may lead to invasiveness and metastasis in primary lung carcinoma. Brachyury mRNA expression is a significant predictor of poor prognosis in primary lung carcinoma. PMID- 23456320 TI - Fine-scale genetic structure of Nothofagus pumilio (lenga) at contrasting elevations of the altitudinal gradient. AB - Montane forests provide the natural framework to test for various ecological settings at distinct elevations as they may affect population demography, which in turn will affect the spatial genetic structure (SGS). We analyzed the fine scale SGS of Nothofagus pumilio, which dominates mountain areas of Patagonia, in three pairs of sites at contrasting elevations (low- vs. high-elevation). Within a total area of 1 ha fresh leaf tissue from 90 individuals was collected at each of the six studied stands following a spatially explicit sampling design. Population genetic diversity parameters were analyzed for all sampled individuals using five polymorphic isozyme loci, and a subset of 50 individuals per stand were also screened for five microsatellite loci. The SGS was assessed on 50 individuals/stand, using the combined datasets of isozymes and microsatellites. Most low-elevation stands consisted of older individuals with complex age structures and genetically diverse plots. In contrast, high-elevation stands and one post-fire low-elevation population yielded even-aged structures with evidence of growth suppression, and were genetically homogeneous. All stands yielded significant SGS. Similarly to mature stands of the non-sprouter congener Nothofagus dombeyi, multi-age low-altitude N. pumilio yielded significant SGS weakened by competing species of the understory and the formation of seedling banks. Alike the sprouter Nothofagus antarctica, high-altitude stands produced significant SGS as a consequence of occasional seedling establishment reinforced by vegetative spread. PMID- 23456321 TI - Disability is the major negative predictor for achievement of Boolean-based remission in patients with rheumatoid arthritis treated with tocilizumab. AB - OBJECTIVE: To analyze the efficacy of tocilizumab (TCZ) and the factors that influence achievement of Boolean-based remission in patients with rheumatoid arthritis (RA) treated with TCZ in daily clinical practice. METHODS: The efficacy of TCZ at 24 weeks after initiation of TCZ in 80 patients with RA was analyzed by comparing achievement of "DAS28 remission" with that of "Boolean-based remission". The predictive factors that influence achievement of Boolean-based remission were determined using multiple logistic regression analysis using a step-wise method. RESULTS: DAS28 remission and Boolean-based remission were achieved in 50.0 and 12.5% of patients, respectively. Significant differences in achieving Boolean-based remission were observed when patients were stratified by disease duration in tertiles (p < 0.05) and by physical function in tertiles (p < 0.05); no such differences were observed for achieving DAS28 remission. The least achievable component among the Boolean-based remission criteria was patient's global assessment. The predictive factor for not achieving Boolean-based remission at 24 weeks was having a worse baseline physical function (odds ratio, 3.66; 95 % confidence interval, 1.17-14.48). CONCLUSIONS: This study suggests that baseline disability predicts a lack of achievement of Boolean-based remission. Thus, better responses to TCZ may be obtained when TCZ is initiated in RA patients before disability develops. PMID- 23456325 TI - Timing differences between cued and noncued swallows in healthy young adults. AB - Temporal parameters such as stage transition duration, bolus location at swallow onset, and pharyngeal transit time are often measured during videofluoroscopy, but these parameters may vary depending on assessment instructions. Specifically, "command" (cued) swallows have been observed to alter timing compared to spontaneous (noncued) situations in healthy older adults. The aim of our study was to confirm whether healthy young people show timing differences for thin liquid swallows between cued and noncued conditions. Twenty healthy young adults swallowed 10-cc boluses of ultrathin barium in videofluoroscopy. The cued condition was to hold the bolus in the mouth for 5 s before swallowing. Three noncued swallows were also recorded. In the cued condition, bolus advancement to the pyriform sinuses prior to swallow initiation was seen significantly less frequently. Stage transition durations showed a nonsignificant trend toward being shorter. Pharyngeal transit times and pharyngeal response time (a measure capturing the interval between hyoid movement onset and bolus clearance through the upper esophageal sphincter) were both significantly longer in the cued condition. Our study in healthy young adults confirms findings previously observed in older adults, namely, that swallow onset patterns and timing differ between cued and noncued conditions. In particular, bolus advancement to more distal locations in the pharynx at the time of swallow onset is seen more frequently in noncued conditions. This pattern should not be mistaken for impairment in swallow onset timing during swallowing assessment. PMID- 23456326 TI - Analysis of hyoid bone using 3D geometric morphometrics: an anatomical study and discussion of potential clinical implications. AB - The aim of this study was to obtain a quantitative anatomical description of the hyoid bone using modern 3D reconstruction tools and to discuss potential applications of the knowledge in clinical practice. The study was conducted on 88 intact hyoid bones taken from cadavers during forensic autopsies (group 1) and on 92 bones from CT scan images of living adult subjects (group 2). Three dimensional reconstructions were created from CT scan images using Amira 5.3.3(r) software. An anatomical and anthropological study of hyoid bones was carried out using metric and morphological analyses. Groups 1 and 2 were compared to evaluate the influence of muscle traction on hyoid bone shape. Characteristics of the hyoid bone were highly heterogeneous and were closely linked with the sex, height, and weight of the individuals. Length and width were significantly greater in men than in women (39.08 vs. 32.50 mm, p = 0.033 and 42.29 vs. 38.61 mm, p = 0.003), whereas the angle between the greater horns was larger in females (44.09 vs. 38.78, p = 0.007). There was a significant positive correlation between the height (Pearson coefficient correlation r = 0.533, p = 0.01) and weight (r = 0.497, p = 0.01) of subjects and the length of the hyoid bone. Significant metric differences were shown between group 1 and group 2. This very reproducible methodology is important because it may lead to clinical studies in, e.g., head and neck cancer or sleep apnea. Such studies are ongoing in our research program. PMID- 23456327 TI - Generalization to unfamiliar talkers in artificial language learning. AB - While there is evidence that talker-specific details are encoded in the phonetics of the lexicon (Kraljic, Samuel, & Brennan, Psychological Science 19(4):332-228, 2008; Logan, Lively, & Pisoni, Journal of the Acoustical Society of America, 89(2):874-886, 1991) and in sentence processing (Nygaard & Pisoni, Perception & Psychophysics, 60(3):355-376, 1998), it is unclear whether categorical linguistic patterns are also represented in terms of talker-specific details. The present study provides evidence that adult learners form talker-independent representations for productive linguistic patterns. Participants were able to generalize a novel linguistic pattern to unfamiliar talkers. Learners were exposed to spoken words that conformed to a pattern in which vowels of a word agreed in place of articulation, referred to as vowel harmony. All items were presented in the voice of one single talker. Participants were tested on items that included both the familiar talker and an unfamiliar talker. Participants generalized the pattern to novel talkers when the talkers spoke with a familiar accent (Experiment 1), as well as with an unfamiliar accent (Experiment 2). Learners showed a small advantage for talker familiarity when the words were familiar, but not when the words were novel. These results are consistent with a theory of language processing in which the lexicon stores fine-grained, talker specific phonetic details, but productive linguistic processes are subject to abstract, talker-independent representations. PMID- 23456328 TI - Reconsidering the role of temporal order in spoken word recognition. AB - Models of spoken word recognition assume that words are represented as sequences of phonemes. We evaluated this assumption by examining phonemic anadromes, words that share the same phonemes but differ in their order (e.g., sub and bus). Using the visual-world paradigm, we found that listeners show more fixations to anadromes (e.g., sub when bus is the target) than to unrelated words (well) and to words that share the same vowel but not the same set of phonemes (sun). This contrasts with the predictions of existing models and suggests that words are not defined as strict sequences of phonemes. PMID- 23456329 TI - Olfactory carbon dioxide detection by insects and other animals. AB - Carbon dioxide is a small, relatively inert, but highly volatile gas that not only gives beer its bubbles, but that also acts as one of the primary driving forces of anthropogenic climate change. While beer brewers experiment with the effects of CO2 on flavor and climate scientists are concerned with global changes to ambient CO2 levels that take place over the course of decades, many animal species are keenly aware of changes in CO2 concentration that occur much more rapidly and on a much more local scale. Although imperceptible to us, these small changes in CO2 concentration can indicate imminent danger, signal overcrowding, and point the way to food. Here I review several of these CO2-evoked behaviors and compare the systems insects, nematodes, and vertebrates use to detect environmental CO2. PMID- 23456330 TI - Reactive oxygen species and tumor metastasis. AB - The migration and invasion of cancer cells are the first steps in metastasis. Through a series of cellular responses, including cytoskeletal reorganization and degradation of the extracellular matrix, cancer cells are able to separate from the primary tumor and metastasize to distant locations in the body. In cancer cells, reactive oxygen species (ROS) play important roles in the migration and invasion of cells. Stimulation of cell surface receptors with growth factors and integrin assembly generates ROS, which relay signals from the cell surface to important signaling proteins. ROS then act within cells to promote migration and invasion. In this review, we collect recent evidence pointing towards the involvement of ROS in tumor metastasis and discuss the roles of ROS at different stages during the process of cancer cell migration, invasion and epithelial mesenchymal transition. PMID- 23456331 TI - Identification and promoter analysis of PERV LTR subtypes in NIH-miniature pig. AB - Porcine endogenous retroviruses (PERVs) are integrated into the genomes of all pigs. Since some PERVs can also infect human cells, they represent a potential risk for xenotransplantation involving pig cells or organs. The long terminal repeat (LTR) elements of PERVs show promoter activity that can affect human functional genes; therefore, we examined these elements in this study. We detected several expressed LTRs in the NIH-miniature pig liver, among which we identified 9 different subtypes. When these LTRs were compared, distinct structures that contained several insertion and deletion (INDEL) events and tandem repeats were identified in the U3 region. The transcriptional activity of the 9 LTR subtypes was analyzed in the PK15 porcine cell line and in the HepG2 and Hep3B human liver cell lines, and transcriptional regulation was found to be different in the 3 cell lines. The D LTR subtype was found to have stronger promoter activity than all other types in 4 different human cell lines (HepG2, Hep3B, U251, and 293). Using computational approaches, the D type was shown to contain 4 transcription factor-binding sites distinct from those in the U3 regions of the other subtypes. Therefore, deletion mutants were constructed and examined by a transient transfection luciferase assay. The results of this analysis indicated that the binding site for the Hand1:E47 transcription factor might play a positive role in the transcriptional regulation of PERV LTR subtype D in human liver cell lines. PMID- 23456332 TI - Broad activity against porcine bacterial pathogens displayed by two insect antimicrobial peptides moricin and cecropin B. AB - In response to infection, insects produce a variety of antimicrobial peptides (AMPs) to kill the invading pathogens. To study their physicochemical properties and bioactivities for clinical and commercial use in the porcine industry, we chemically synthesized the mature peptides Bombyx mori moricin and Hyalophora cecropia cecropin B. In this paper, we described the antimicrobial activity of the two AMPs. Moricin exhibited antimicrobial activity on eight strains tested with minimal inhibitory concentration values (MICs) ranging between 8 and 128 MUg/ml, while cecropin B mainly showed antimicrobial activity against the Gramnegative strains with MICs ranging from 0.5 to 16 MUg/ml. Compared to the potent antimicrobial activity these two AMPs displayed against most of the bacterial pathogens tested, they exhibited limited hemolytic activity against porcine red blood cells. The activities of moricin and cecropin B against Haemophilus parasuis SH 0165 were studied in further detail. Transmission electron microscopy (TEM) of moricin and cecropin B treated H. parasuis SH 0165 indicated extensive damage to the membranes of the bacteria. Insights into the probable mechanism utilized by moricin and cecropin B to eliminate pathogens are also presented. The observations from this study are important for the future application of AMPs in the porcine industry. PMID- 23456333 TI - Lipoteichoic acid isolated from Lactobacillus plantarum suppresses LPS-mediated atherosclerotic plaque inflammation. AB - Chronic inflammation plays an important role in atherogenesis. Experimental studies have demonstrated the accumulation of monocytes/macrophages in atherosclerotic plaques caused by inflammation. Here, we report the inhibitory effects of lipoteichoic acid (LTA) from Lactobacillus plantarum (pLTA) on atherosclerotic inflammation. pLTA inhibited the production of proinflammatory cytokines and nitric oxide in lipopolysaccharide (LPS)-stimulated cells and alleviated THP-1 cell adhesion to HUVEC by down-regulation of adhesion molecules such as intracellular adhesion molecule-1 (ICAM-I), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. The inhibitory effect of pLTA was mediated by inhibition of NF-kappaB and activation of MAP kinases. Inhibition of monocyte/macrophage infiltration to the arterial lumen was shown in pLTA-injected ApoE(-/-) mice, which was concurrent with inhibition of MMP-9 and preservation of CD31 production. The antiinflammatory effect mediated by pLTA decreased expression of atherosclerotic markers such as COX-2, Bax, and HSP27 and also cell surface receptors such as TLR4 and CCR7. Together, these results underscore the role of pLTA in suppressing atherosclerotic plaque inflammation and will help in identifying targets with therapeutic potential against pathogen-mediated atherogenesis. PMID- 23456334 TI - ATHB17 is a positive regulator of abscisic acid response during early seedling growth. AB - We performed activation tagging screen to isolate abscisic acid (ABA) response mutants. One of the mutants, designated ahs10 (ABA-hypersensitive 10), exhibited ABA-hypersensitive phenotypes. TAIL-PCR analysis of the mutant revealed that T DNA was inserted in the promoter region of the Arabidopsis gene, At2g01430, which encodes a homeodomain-leucine zipper protein ATHB17. Subsequent expression analysis indicated that ATHB17 was activated in ahs10. To recapitulate the mutant phenotypes, we prepared ATHB17 OX lines and investigated their phenotypes. The results showed that ATHB17 confers ABA-hypersensitivity and drought tolerance. On the contrary, ATHB17 knockout lines were ABA-insensitive and drought-sensitive, further demonstrating that ATHB17 is involved in ABA and water-stress responses. Interestingly, the ATHB17 effect on seedling growth in the presence of ABA was observed only during the postgermination seedling establishment stage, suggesting that it functions during a narrow developmental window of early seedling growth. PMID- 23456335 TI - Mitochondrial oxidative phosphorylation reserve is required for hormone- and PPARgamma agonist-induced adipogenesis. AB - Adipocyte differentiation requires the coordinated activities of several nuclear transcription factors. Recently, mitochondria biogenesis was reported to occur during adipocyte differentiation and following treatment with thiazolidinediones in vitro and in vivo. Crif1 is a translational factor for mitochondrial DNA (mtDNA) and is important for transcription of the mitochondrial oxidative phosphorylation (OXPHOS) complex. To investigate the role of OXPHOS in adipogenesis, we analyzed adipocyte differentiation following disruption of Crif1 in vitro and in vivo. The adipose-specific Crif1 knockout mouse had a lower body weight and less fat mass than wild-type mice. Furthermore, adipocytes were smaller and had a dysplastic morphology in the adipose-specific Crif1 knockout mouse. 3T3-L1 adipocytes or adipose-derived stem cells (ADSCs) that lacked Crif1 expressed lower levels of mtDNA-encoded OXPHOS subunits, and adipocyte differentiation was disrupted. Rosiglitazone treatment did not induce adipogenesis or mitochondria biogenesis in Crif1 knockout ADSCs. These results show that mitochondrial OXPHOS and Crif1 are required for rosiglitazone- and hormone-induced adipogenesis. PMID- 23456336 TI - Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, potentiates ATP-gated P2X1 receptor channel currents. AB - Ginseng, the root of Panax ginseng C.A. Meyer, is used as a general tonic. Recently, we isolated a novel ginsengderived lysophosphatidic acid (LPA) receptor ligand, gintonin. Gintonin activates G protein-coupled LPA receptors with high affinity in cells endogenously expressing LPA receptors, e.g., Xenopus oocytes. P2X receptors are ligandgated ion channels activated by extracellular ATP, and 7 receptor subtypes (P2X1-P2X7) have been identified. Most of the P2X1 receptors are expressed in the smooth muscles of genitourinary organs involved in reproduction. A main characteristic of the P2X1 receptor is rapid desensitization after repeated ATP treatment of cells or tissues expressing P2X1 receptors. In the present study, we examined the effect of gintonin on P2X1 receptor channel activity. P2X1 receptors were heterologously expressed in Xenopus oocytes. ATP treatment of oocytes expressing P2X1 receptors induced large inward currents (I ATP ), but repetitive ATP treatments induced a rapid desensitization of I ATP . Gintonin treatment after P2X1 receptor desensitization potentiated I ATP in a concentration-dependent manner. We further examined the signaling transduction pathways involved in gintonin-mediated potentiation of I ATP . Gintoninmediated I ATP potentiation was blocked by Ki16425, an LPA1/3 receptor antagonist, a PKC inhibitor, a PLC inhibitor, and a PI4-Kinase inhibitor but not by a calcium chelator. In addition, mutations of the phosphoinositide binding site of the P2X1 receptor greatly attenuated the gintonin-mediated I ATP potentiation. These results indicate that G protein-coupled LPA receptor activation by gintonin is coupled to the potentiation of the desensitized P2X1 receptor through a phosphoinositide-dependent pathway. PMID- 23456337 TI - Backbone dynamics of an atypical orphan response regulator protein, Helicobacter pylori 1043. AB - An atypical orphan response regulator protein, HP1043 (HP-RR) in Helicobacter pylori, is proven to be essential for cell growth and does not require the well known phosphorelay scheme. HP-RR was identified as a symmetric dimer with two functional domains, an N-terminal regulatory domain (HP-RR(r)) and a C-terminal effector domain (HP-RR(e)). HP-RR is a new class of response regulator, as a phosphorylation-independent regulator. Previously, we have presented a detailed three-dimensional structure of HP-RR using NMR spectroscopy and X-ray crystallography. In this study, in order to understand the functional importance of flexibilities in HP-RR(r) and HP-RR(e), T1, T2, heteronuclear NOE experiments have been performed and backbone dynamics of HP-RR(r) and HP-RR(e) were investigated. HP-RR(r) is a symmetric dimer and the interface region, alpha4 beta5-alpha5 of dimer, showed high rigidity (high S (2) values). Site of rearrangements associated with phosphorylation of HP-RR(r) (Ser(75): R ex = 3.382, Ile(95): R ex = 5.228) showed slow chemical exchanges. HP-RR(e) is composed of three alpha-helices flanked on two sides by anti-parallel beta sheets. Low order parameters as well as conformational exchanges in the centers of loop regions known as the DNA binding site and transcription site of HP-RR(e) suggested that flexibility of HP-RR(e) is essential for interaction with DNA. In conclusion, backbone dynamics information for HP-RR implies that structural flexibilities in HP-RR(r) are necessary for the phosphorylation site and the dynamic nature of HP-RR(e) is essential for the regulation of interaction between protein and DNA. PMID- 23456339 TI - Retraction note: A hot pepper cDNA encoding a pathogenesis-related protein 4 is induced during the resistance response to tobacco mosaic virus. Mol. Cells 11 (2001) 122-7. PMID- 23456338 TI - Mutant-specific gene expression profiling identifies SRY-related HMG box 11b (SOX11b) as a novel regulator of vascular development in zebrafish. AB - Previous studies have identified two zebrafish mutants, cloche and groom of cloche, which lack the majority of the endothelial lineage at early developmental stages. However, at later stages, these avascular mutant embryos generate rudimentary vessels, indicating that they retain the ability to generate endothelial cells despite this initial lack of endothelial progenitors. To further investigate molecular mechanisms that allow the emergence of the endothelial lineage in these avascular mutant embryos, we analyzed the gene expression profile using microarray analysis on isolated endothelial cells. We find that the expression of the genes characteristic of the mesodermal lineages are substantially elevated in the kdrl (+) cells isolated from avascular mutant embryos. Subsequent validation and analyses of the microarray data identifies Sox11b, a zebrafish ortholog of SRY-related HMG box 11 (SOX11), which have not previously implicated in vascular development. We further define the function sox11b during vascular development, and find that Sox11b function is essential for developmental angiogenesis in zebrafish embryos, specifically regulating sprouting angiogenesis. Taken together, our analyses illustrate a complex regulation of endothelial specification and differentiation during vertebrate development. PMID- 23456340 TI - Retraction note: Induction of a pepper cDNA encoding SAR8.2 protein during the resistance response to tobacco mosaic virus. Mol. Cells 12 (2001) 250-6. PMID- 23456341 TI - Retraction note: A hot pepper cDNA encoding ascorbate peroxidase is induced during the incompatible interaction with virus and bacteria. Mol. Cells 14 (2002) 75-84. PMID- 23456342 TI - Retraction note: Nicotiana tabacum Tsip1-interacting ferredoxin 1 affects biotic and abiotic stress resistance. Mol. Cells 34 (2012) 43-52. PMID- 23456343 TI - Soil consumed by chacma baboons is low in bioavailable iron and high in clay. AB - Despite widespread consumption of soil among animals, the role of geophagy in health maintenance remains an enigma. It has been hypothesized that animals consume soil for supplementation of minerals and protection against toxins. Most studies determine only the total elemental composition of soil, which may not reflect the amount of minerals available to the consumer. Our aim was to test these hypotheses by evaluating the bioavailability of iron in soil consumed by chacma baboons, using a technique that simulates digestion and adsorption. Our results indicate that, despite variation in absolute iron concentration of soil samples, actual iron bioavailability was low while clay content was quite high. This suggests that iron supplementation is unlikely to be the primary motivation for geophagy in this population, and that detoxification is a plausible explanation. This study demonstrates that more research on bioavailability and clay composition is needed to determine the role geophagy plays in health maintenance. PMID- 23456344 TI - Pheromonal divergence between two strains of Spodoptera frugiperda. AB - Spodoptera frugiperda consists of two genetically and behaviorally different strains, the corn- and the rice-strain, which seem to be in the process of sympatric speciation. We investigated the role of strain-specific sexual communication as a prezygotic mating barrier between both strains by analyzing strain-specific variation in female pheromone composition of laboratory and field strains, and also male attraction in wind tunnel and field experiments. Laboratory-reared and field-collected females from Florida exhibited strain specific differences in their relative amount of (Z)-7-dodecenyl acetate (Z7 12:OAc) and (Z)-9-dodecenyl acetate (Z9-12:OAc). In wind tunnel assays, we did not find strain-specific attraction of males to females. However, in field experiments in Florida, we observed some differential attraction to synthetic pheromone blends. In a corn field, the corn-strain blend attracted more males of both strains than the rice-strain blend, but both blends were equally attractive in a grass field. Thus, habitat-specific volatiles seemed to influence male attraction to pheromones. In dose-response experiments, corn-strain males were more attracted to 2 % Z7-12:OAc than other doses tested, while rice-strain males were attracted to a broader range of Z7-12:OAc (2-10 %). The attraction of corn strain males to the lowest dose of Z7-12:OAc corresponds to the production of this compound by females; corn-strain females produced significantly smaller amounts of Z7-12:OAc than rice-strain females. Although corn-strain individuals are more restricted in their production of and response to pheromones than rice strain individuals, it seems that differences in sexual communication between corn- and rice-strain individuals are not strong enough to cause assortative mating. PMID- 23456345 TI - Performance of an herbivorous leaf beetle (Phratora vulgatissima) on Salix F2 hybrids: the importance of phenolics. AB - The genotype of the plant determines, through the expression of the phenotype, how well it is suited as food for herbivores. Since hybridization often results in profound genomic alterations with subsequent changes in phenotypic traits, it has the potential to significantly affect plant-herbivore interactions. In this study, we used a population of F2 hybrids that originated from a cross between a Salix viminalis and a Salix dasyclados genotype, which differed in both phenolic content and resistance to the herbivorous leaf beetle Phratora vulgatissima. We screened for plants that showed a great variability in leaf beetle performance (i.e., oviposition and survival). By correlating leaf phenolics to the response of the herbivores, we evaluated the importance of different phenolic compounds for Salix resistance to the targeted insect species. The performance of P. vulgatissima varied among the F2 hybrids, and two patterns of resistance emerged: leaf beetle oviposition was intermediate on the F2 hybrids compared to the parental genotypes, whereas leaf beetle survival demonstrated similarities to one of the parents. The findings indicate that these life history traits are controlled by different resistance mechanisms that are inherited differently in the hybrids. Salicylates and a methylated luteolin derivative seem to play major roles in hybrid resistance to Phratora vulgatissima. Synergistic effects of these compounds, as well as potential threshold concentrations, are plausible. In addition, we found considerable variation in both distributions and concentrations of different phenolics in the F2 hybrids. The phenolic profiles of parental genotypes and F2 hybrids differed significantly (e.g., novel compounds appeared in the hybrids) suggesting genomic alterations with subsequent changes in biosynthetic pathways in the hybrids. PMID- 23456346 TI - Maternal education and excessive gestational weight gain in New York city, 1999 2001: the effect of race/ethnicity and neighborhood socioeconomic status. AB - To examine the association between maternal education and excessive gestational weight gain (EGWG) and whether this association differs by maternal race/ethnicity and neighborhood socio-economic status (SES). A sample of 56,911 New York City births between 1999 and 2001 was used. Self-reported EGWG was defined as gaining >40 pounds. Maternal education and race/ethnicity were obtained from birth record data. Neighborhood SES was determined from 2000 US Census data. Women with a high school [prevalence ratio (PR) = 1.21; 95 % CI 1.10 1.32] and some college (PR = 1.33; 95 % CI 1.21-1.47) education were more likely to gain excessive weight during pregnancy than their counterparts with less than a high school education. Having a college or more education was associated with a decreased EGWG for non-Hispanic white women (PR = 0.81; 95 % CI 0.67-0.96) but an increased EGWG for Hispanic women (PR = 1.25; 95 % CI 1.12-1.44). EGWG increased for women with a college or more education in medium and low SES neighborhoods (1.26; 95 % CI 1.04-1.53 and 1.20; 95 % CI 1.10-1.30, respectively); whereas a college or more education was not significant in the high SES neighborhoods. Our findings suggest that maternal education is associated with EGWG. However, this association depends on race/ethnicity and SES of the neighborhood of residence. PMID- 23456347 TI - Gestational weight gain among Hispanic women. AB - To describe gestational weight gain among Hispanic women and to examine psychological, social, and cultural contexts affecting weight gain. A total of 282 Hispanic women were surveyed post-partum before leaving the hospital. Women were queried about their prepregnancy weight and weight gained during pregnancy. Adequacy of gestational weight gain was based on guidelines set by the Institute of Medicine in 2009. Independent risk factors for excessive or insufficient weight gain were examined by logistic regression. Most women were unmarried (59 %), with a mean age of 28.4 +/- 6.6 years and an average weight gain of 27.9 +/- 13.3 lbs. Approximately 45 % of women had gained too much, 32 % too little, and only 24 % had an adequate amount of weight gain. The mean birth weight was 7.3, 7.9, and 6.8 lbs among the adequate, excessive, and insufficient weight gain groups. Among women who exercised before pregnancy, two-thirds continued to do so during pregnancy; the mean gestational weight gain of those who continued was lower than those who stopped (26.8 vs. 31.4 lbs, p = 0.04). Independent risk factors for excessive weight gain were being unmarried, U.S. born, higher prepregnancy body mass index, and having indifferent or negative views about weight gain. Independent risk factors for insufficient weight gain were low levels of support and late initiation of prenatal care. Depression, stress, and a woman's or her partner's happiness regarding pregnancy were unrelated to weight gain. The results of this study can be used by prenatal programs to identify Hispanic women at risk for excessive or insufficient gestational weight gain. PMID- 23456348 TI - Proposed changes to the American Psychiatric Association diagnostic criteria for autism spectrum disorder: implications for young children and their families. AB - The American Psychiatric Association has revised the diagnostic criteria for their DSM-5 manual. Important changes have been made to the diagnosis of the current (DSM-IV) category of Pervasive Developmental Disorders. This category includes Autistic Disorder (autism), Asperger's Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). The DSM-5 deletes Asperger's Disorder and PDD-NOS as diagnostic entities. This change may have unintended consequences, including the possibility that the new diagnostic framework will adversely affect access to developmental interventions under Individuals with Disabilities Education Act (IDEA) programs, Early Intervention (for birth to 2 years olds) and preschool special education (for 3 and 4 years olds). Changing the current diagnosis of PDD-NOS to a "Social Communication Disorder" focused on language pragmatics in the DSM-5 may restrict eligibility for IDEA programs and limit the scope of services for affected children. Young children who meet current criteria for PDD-NOS require more intensive and multi disciplinary services than would be available with a communication domain diagnosis and possible service authorization limited to speech-language therapy. Intensive behavioral interventions, inclusive group setting placements, and family support services are typically more available for children with an autism spectrum disorder than with diagnoses reflecting speech-language delay. The diagnostic distinction reflective of the higher language and social functioning between Asperger's Disorder and autism is also undermined by eliminating the former as a categorical diagnosis and subsuming it under autism. This change may adversely affect treatment planning and misinform parents about prognosis for children who meet current criteria for Asperger's Disorder. PMID- 23456349 TI - Characterization of the chitinase gene in Bacillus thuringiensis Mexican isolates. AB - The chitinase gene was molecularly characterized in five Bacillus thuringiensis Mexican isolates, MR10, MR11, MR21, MR33, and RN52. The proteins derived from these genes were tested for their chitinase activity using fluorogenic chitin derivatives. In order to verify if chitinase genes were functional, they were cloned, and enzymatic activity of recombinant chitinases was also tested. Results indicated that enzymes exhibited endochitinase activity. The highest hydrolytic activity shown against the chitin tetrameric derivative occurred at pH value of 6.5, and the optimum activity temperature was around 60 degrees C. The recombinant endochitinases showed a molecular mass of ~77 kDa with isoelectric points from 6.5 to 7.0. Analysis of the nucleotide sequences showed highly conserved sequences among all isolates (97-99 %). Gene sequence analysis revealed a putative promoter (-35 TTGAGA and -10 TTAATA) and a Shine-Dalgarno sequence (5' AGGAGA-3') upstream from the open reading frame. The deduced amino acid sequence revealed that the proteins are modular enzymes composed by a family 18 glycosyl hydrolase domain located between amino acids 134 and 549, a fibronectin-binding domain (580 through 656), and a chitin-binding domain (664 through 771). The deduced amino acid sequences of our isolates showed a similarity close to 100 % respect to the sequences reported in the GenBank database. PMID- 23456350 TI - Infective endocarditis due to Bartonella quintana: a severe disease and underdiagnosed etiology. PMID- 23456351 TI - Effect of TiO2 nanoparticles on chickpea response to cold stress. AB - Nanoparticles (NPs) in agricultural systems can potentially be used as appropriate candidate for change in growth, development, productivity, and quality of plants. In the present study, we assessed the effect of TiO2 NP concentrations (0, 2, 5, and 10 ppm) on changes of membrane damage indexes like electrolyte leakage index (ELI) and malondialdehyde (MDA) during cold stress (CS) 4 degrees C in sensitive (ILC 533) and tolerant (Sel 11439) chickpea (Cicer arietinum L.) genotypes. Aggregation of NPs within the vacuole and chloroplast indicated absorbed NPs in seedlings. Bioaccumulation of NPs showed that, under thermal treatments, the sensitive genotype had more permeability to NPs compared to the tolerant one, and TiO2 content was higher during CS compared to optimum temperature. Physiological indexes were positively affected by NP treatments during thermal treatments. TiO2 NP treatments (especially 5 ppm) caused a decrease in ELI during thermal treatments, whereas ELI content under CS treatment increased at 0 ppm TiO2 in both genotypes. Under thermal treatments, although the genotype 11439 showed lower accumulation of MDA than ILC 533 genotype, a significant decrease was observed in MDA content at 5 ppm TiO2. Results showed that TiO2 treatments not only did not induce oxidative damage in sensitive and tolerant chickpea genotypes but also alleviated membrane damage indexes under CS treatment. It was suggested for the first time that TiO2 NPs improved redox status of the genotypes under thermal treatments. New findings possibly would reveal the use of NPs generally or TiO2 NPs especially for increase of cold tolerance in crops. PMID- 23456352 TI - Endoscopy-guided empiric arterial embolization for angiographically negative upper gastrointestinal bleeding: use it without fear! PMID- 23456353 TI - Endovascular treatment of pelvic congestion syndrome: visual analog scale (VAS) long-term follow-up clinical evaluation in 202 patients. AB - PURPOSE: This study was designed to evaluate the clinical outcome and patients' satisfaction after a 5 year follow-up period for pelvic congestion syndrome (PCS) coil embolization in patients who suffered from chronic pelvic pain that initially consulted for lower limb venous insufficiency. METHODS: A total of 202 patients suffering from chronic pelvic pain were recruited prospectively in a single center (mean age 43.5 years; range 27-57) where they were being treated for lower limb varices. Inclusion criteria were: lower limb varices and chronic pelvic pain (>6 months), >6 mm pelvic venous caliber in ultrasonography, and venous reflux or presence of communicating veins. Both ovarian and hypogastric veins were targeted for embolization. Pain level was assessed before and after embolotherapy and during follow-up using a visual analog scale (VAS). Technical and clinical success and recurrence of leg varices were studied. Patients completed a quality questionnaire. Clinical follow-up was performed at 1, 3, and 6 months and every year for 5 years. RESULTS: Technical success was 100%. Clinical success was achieved in 168 patients (93.85%), with complete disappearance of symptoms in 60 patients (33.52%). Pain score (VAS) was 7.34 +/- 0.7 preprocedural versus 0.78 +/- 1.2 at the end of follow-up (P < 0.0001). Complications were: groin hematoma (n = 6), coil migration (n = 4), and reaction to contrast media (n = 1). Twenty-three cases presented abdominal pain after procedure. In 24 patients (12.5%), there was recurrence of their leg varices within the follow-up. The mean degree of patients' satisfaction was 7.4/9. CONCLUSIONS: Coil embolization of PCS is an effective and safe procedure, with high clinical success rate and degree of satisfaction. PMID- 23456354 TI - Letter reply re: "endoscopy-guided empiric arterial embolization for angiographically negative upper gastrointestinal bleeding: use it without fear!". PMID- 23456355 TI - Risk factors for recurrence following complete cytoreductive surgery and HIPEC in colorectal cancer-derived peritoneal surface malignancies. AB - PURPOSE: Recurrent disease following complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a relevant clinical scenario. We aimed to determine risk factors for recurrence. METHODS: Prospectively collected data of patients enrolled in the Peritoneal Surface Malignancy Program at the University of Tubingen between 2005 and 2011 were retrospectively analyzed. All patients were treated by standardized CRS and HIPEC. Recurrence was defined either radiographically by CT, PET-CT scan, or reoperation. RESULTS: Fifty-two patients received complete CRS (CC-0/CC-1) and HIPEC. Median time to recurrence was 229 days (103-1,028). Overall recurrence rate within follow-up was 48 %. Of patients with recurrent disease, 44 % experienced extraperitoneal systemic tumor spread. In multivariate analysis, grading of >= 3 was shown as an independent risk factor for recurrent disease, while a trend was observed for maximal tumor load in the upper abdominal region. Clinical parameters did not show an impact on recurrence. CONCLUSIONS: Primary tumor grading seems to be an independent risk factor for recurrence following complete CRS and HIPEC in colorectal cancer-derived peritoneal surface malignancies. PMID- 23456356 TI - Don't give up on wound protectors yet. PMID- 23456357 TI - Long-term results of transvaginal/transumbilical versus classical laparoscopic cholecystectomy--an analysis of 88 patients. AB - INTRODUCTION: Transvaginal/transumbilical cholecystectomy using rigid instruments (TVC) is an alternative to the traditional laparoscopic technique (LC). Due to a lack of long-term data, the transvaginal approach is still controversial. METHODS: Our first 50 TVC patients and 50 LC patients from the same time period with the same limits according to age, BMI and ASA classification were asked 48 questions 2 years postoperatively (mean) about resuming sexual intercourse, the domains "satisfaction" and "pain" of the German Female Sexual Function Index, resuming everyday life, postoperative abdominal pain, subjective impairment, incisional hernias, satisfaction with the aesthetic result, the overall postoperative result, and others. Postoperative sexual satisfaction and pain were defined as main outcome. Forty-six TVC patients and 42 LC patients answered the questions (36 TVC patients and 25 LC patients could answer the questions about sexual function). RESULTS: No significant differences were found for postoperative sexual function, change in menorrhea, vaginal discharge and postoperative abdominal pain. TVC patients felt significantly less impaired postoperatively (p = 0.034). Two patients in the LC group developed a trocar hernia (p = 0.225). TVC patients could resume everyday life significantly earlier (p < 0.001) and were significantly more satisfied with the aesthetic (p < 0.001) and the overall postoperative result (p = 0.001). Significantly more TVC patients would recommend the applied surgical technique to friends and family (p < 0.001). CONCLUSIONS: This long-time prospective data acquisition from 88 or, for some data, 61 patients accounts for the safety of TVC, particularly with regard to sexual function. Additionally, it found less postoperative impairment, quicker recovery and improved satisfaction for TVC as compared to LC. PMID- 23456358 TI - Very long-term follow-up of strut apposition and tissue coverage with Biolimus A9 stents analyzed by optical coherence tomography. AB - First generation drug-eluting stents (DES) are associated with reduced in-stent restenosis but significant increased risk of very late stent thrombosis (VLST). The absence of polymer in DES systems may reduce the occurrence of VLST. Optic coherence tomography (OCT) has been used for stent analysis as a surrogate safety endpoint. This study aimed to assess the long-term follow up of strut apposition and tissue coverage of BioMatrix DES by OCT. 20 patients undergoing BioMatrix DES (n = 15) or S-Stent BMS (n = 5) implantation were followed for at least 5 years and evaluated by quantitative coronary angiography, intravascular ultrasound, and OCT. The difference between the stent types was evaluated by nonparametric Mann Whitney U test while categorical variables were evaluated by Fisher exact test. Rates of in-stent late loss were similar between groups [0.40 (0.21;0.77) vs. 0.68 (0.66; 0.82) mm, p = 0.205, for BioMatrix and S-Stent, respectively]. The vessel, stent and lumen volumes did not differ between groups. Patients treated with BioMatrix had significantly less stent obstruction [5.6 (4.4;9.7) vs. 28.6 (24.7;29.0) %, p = 0.001]. OCT analysis of 12 stents (Biomatrix = 9 and S-Stent = 3) demonstrated 126 (8.7 %) uncovered struts in the BioMatrix group compared to 23 (4.0 %) in the S-Stent group (p = 0.297), being the majority of them well apposed (117/126 and 21/23, respectively, p = 0.292). Only 9 (0.6 %) struts in the DES and 2 (0.4 %) struts in the BMS groups were simultaneously uncovered and malapposed (p = 0.924). BioMatrix DES was associated with lower rates of in-stent obstruction, and similar percentage of neointimal coverage on struts and of complete strut apposition. PMID- 23456359 TI - Comparison of neointimal hyperplasia and peri-stent vascular remodeling after implantation of everolimus-eluting versus sirolimus-eluting stents: intravascular ultrasound results from the EXCELLENT study. AB - This study was designed to compare neointimal hyperplasia and peri-stent arterial remodeling after implantation of everolimus-eluting stent (EES) versus sirolimus eluting stent (SES) using intravascular ultrasound (IVUS). The study population was a subgroup of 278 patients from the EXCELLENT trial, a randomized study comparing EES to SES in de novo coronary artery lesions (total n = 1,443, 3:1 randomization) who underwent post-PCI and 9-month follow-up IVUS evaluation. There were 209 patients in the EES group and 69 in the SES group. Baseline clinical and angiographic characteristics were similar between the two groups except for age and target lesion locations. At 9 months, percent neointimal volume obstruction did not differ between EES and SES (2.6 +/- 4.0 % vs. 2.5 +/- 4.8 %, p = 0.814). However, the relative change in the vessel (4.3 +/- 13.7 % vs. 8.8 +/- 18.6 %, p = 0.030) and plaque volume index (4.2 +/- 17.4 % vs. 10.5 +/- 22.3 %, p = 0.016) of the stented segment from post-intervention to follow-up was significantly less with EES than with SES. In addition, positive peri-stent vascular remodeling defined as an increase in vessel volume index >10 % (27.8 vs. 42.0 %, p = 0.027) and late acquired stent malapposition (LASM, 1.9 vs. 15.9 %, p < 0.001) were observed less frequently with EES than SES. EES and SES were similarly effective in reducing neointimal hyperplasia. However, positive peri stent vascular remodeling and LASM occurred less frequently with EES than SES. PMID- 23456360 TI - Impact of StentBoost subtract imaging on patient radiation exposure during percutaneous coronary intervention. AB - The purpose of this study was to assess the impact of StentBoost Subtract (SBS) imaging on patient radiation dose during percutaneous coronary intervention. Data were prospectively collected between February 2010 and November 2012 at a tertiary cardiac catheterization. All patients who had scheduled for coronary stent implantation performed by one expert interventional cardiologist with sufficient experience in SBS imaging and radiation protection, were included. The patients were divided into groups with or without SBS. A multiple linear regression analysis was used to determine the impact of SBS imaging on patient radiation dose. Of 712 patients screened, 414 patients were enrolled in the study (with SBS: n = 177, without SBS: n = 237). Although the DAP, fluoroscopy time and cine frames used in the group with SBS were significantly increased when compared with those used in the group without SBS (P < 0.05), multiple linear regression shows SBS imaging has no significant impact on patient radiation dose (P > 0.05). Multivariate predictors of patient radiation dose were the patients' BMI, B2/C lesions, number of stents placed and bifurcation stenting (P < 0.05). In selected patients, SBS imaging can be performed with comparable patient radiation dose, compared with plain fluoroscopic imaging. This may attribute to the operator's sufficient experience in SBS imaging and radiation protection. PMID- 23456361 TI - Dwarfism and increased adiposity in the gh1 mutant zebrafish vizzini. AB - Somatic growth and adipogenesis are closely associated with the development of obesity in humans. In this study, we identify a zebrafish mutant, vizzini, that exhibits both a severe defect in somatic growth and increased accumulation of adipose tissue. Positional cloning of vizzini revealed a premature stop codon in gh1. Although the effects of GH are largely through igfs in mammals, we found no decrease in the expression of igf transcripts in gh1 mutants during larval development. As development progressed, however, we found overall growth to be progressively retarded and the attainment of specific developmental stages to occur at abnormally small body sizes relative to wild type. Moreover, both subcutaneous (sc) and visceral adipose tissues underwent precocious development in vizzini mutants, and at maturity, the sizes of different fat deposits were greatly expanded relative to wild type. In vivo confocal imaging of sc adipose tissue (SAT) expansion revealed that vizzini mutants exhibit extreme enlargement of adipocyte lipid droplets without a corresponding increase in lipid droplet number. These findings suggest that GH1 signaling restricts SAT hypertrophy in zebrafish. Finally, nutrient deprivation of vizzini mutants revealed that SAT mobilization was greatly diminished during caloric restriction, further implicating GH1 signaling in adipose tissue homeostasis. Overall, the zebrafish gh1 mutant, vizzini, exhibits decreased somatic growth, increased adipose tissue accumulation, and disrupted adipose plasticity after nutrient deprivation and represents a novel model to investigate the in vivo dynamics of vertebrate obesity. PMID- 23456362 TI - Insulin-mediated oxidative stress and DNA damage in LLC-PK1 pig kidney cell line, female rat primary kidney cells, and male ZDF rat kidneys in vivo. AB - Hyperinsulinemia, a condition with excessively high insulin blood levels, is related to an increased cancer incidence. Diabetes mellitus is the most common of several diseases accompanied by hyperinsulinemia. Because an elevated kidney cancer risk was reported for diabetic patients, we investigated the induction of genomic damage by insulin in LLC-PK1 pig kidney cells, rat primary kidney cells, and ZDF rat kidneys. Insulin at a concentration of 5nM caused a significant increase in DNA damage in vitro. This was associated with the formation of reactive oxygen species (ROS). In the presence of antioxidants, blockers of the insulin, and IGF-I receptors, and a phosphatidylinositol 3-kinase inhibitor, the insulin-mediated DNA damage was reduced. Phosphorylation of protein kinase B (PKB or AKT) was increased and p53 accumulated. Inhibition of the mitochondrial and nicotinamide adenine dinucleotide phosphatase oxidase-related ROS production reduced the insulin-mediated damage. In primary rat cells, insulin also induced genomic damage. In kidneys from healthy, lean ZDF rats, which were infused with insulin to yield normal or high blood insulin levels, while keeping blood glucose levels constant, the amounts of ROS and the tumor protein (p53) were elevated in the high-insulin group compared with the control level group. ROS and p53 were also elevated in diabetic obese ZDF rats. Overall, insulin-induced oxidative stress resulted in genomic damage. If the same mechanisms are active in patients, hyperinsulinemia might cause genomic damage through the induction of ROS contributing to the increased cancer risk, against which the use of antioxidants and/or ROS production inhibitors might exert protective effects. PMID- 23456363 TI - Hypoxia-inducible factor and vascular endothelial growth factor are targets of dietary soy during acute stroke in female rats. AB - Dietary soy and soy isoflavones are neuroprotective in experimental cerebral ischemia. Because these isoflavones have estrogenic properties, we hypothesized that, like estrogens, they would inhibit acute vascular injury and the detrimental acute increase in hypoxia-induced vascular endothelial growth factor (VEGF) that leads to cerebral edema after stroke. Mature ovariectomized female Sprague Dawley rats were fed soy-free or soy-containing diets for 4 weeks followed by 90 minutes of transient middle cerebral artery occlusion. Similar to estrogens, dietary soy significantly reduced cerebral edema and vascular apoptosis 24 hours after stroke. Soy also inhibited the ischemia-induced increase in cortical VEGF and VEGF receptor (VEGFR)-2 protein expression observed 4 and 24 hours after stroke, although mRNA levels increased. The reduction in VEGF/VEGFR-2 was associated both with decreases in receptor phosphorylation and signaling to AKT and endothelial nitric oxide synthase. Furthermore degradation of the VEGFR-2 was increased with dietary soy. The primary ischemic stimulus for VEGF, hypoxia inducible factor 1alpha (HIF1alpha), was similarly reduced by dietary soy 4 hours after transient middle cerebral artery occlusion in both the cortex and striatum. The inhibition of HIF1alpha activity was further confirmed by a significant decrease in the HIF1alpha-activated apoptotic mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Nip3-like protein X). These data suggest that soy isoflavones target events early in the ischemic cascade as part of their neuroprotective actions and counterbalance some of the detrimental effects of the endogenous response to cerebral injury. PMID- 23456364 TI - A positive regulatory domain in CCAAT/enhancer binding protein beta (C/EBPBeta) is required for the glucocorticoid-mediated displacement of histone deacetylase 1 (HDAC1) from the C/ebpalpha promoter and maximum adipogenesis. AB - Glucocorticoids promote adipogenesis and contribute to the metabolic syndrome through a number of mechanisms. One of the effectors of glucocorticoid action is the CCAAT/enhancer binding protein beta (C/EBPbeta). C/EBPbeta is a basic leucine zipper transcription factor involved in diverse processes including differentiation, cellular proliferation, and inflammation. C/EBPbeta transcriptional activity is regulated, in part, by its acetylation profile resulting from its dynamic interaction with either acetylases general control nonrepressed protein 5/p300/CBP associated factor (GCN5/PCAF) or deacetylase complexes (mSin3A/histone deacetylase 1 [HDAC1]). Glucocorticoid treatment of preadipocytes promotes C/EBPbeta acetylation, leading to mSin3A/HDAC1 dissociation from C/EBPbeta and resulting in C/ebpalpha promoter activation at the onset of adipogenesis, thus increasing the differentiation rate. We recently showed that the regulatory domain 1 (RD1) of C/EBPbeta contains four residues (153-156) required for its interaction with HDAC1, therefore supporting RD1 proposed inhibitory role. In an attempt to further elucidate the intrinsic regulatory property of RD1, we sought to characterize the regulatory potential of the N terminus region of RD1 (residues 141-149). In this study, we show that C/EBPbetaDelta141-149 transcriptional activity was compromised on the C/ebpalpha, but not on the Ppargamma, promoter. Additionally, the ability of C/EBPbetaDelta141-149 to induce adipogenesis in NIH 3T3 cells was compromised when compared with C/EBPbetawt owing to a delayed expression of C/ebpalpha at the onset of differentiation. Furthermore, the data suggest that the reduced expression of C/ebpalpha in cells expressing C/EBPbetaDelta141-149 was due to a persistent recruitment of HDAC1 to the C/ebpalpha promoter after glucocorticoid treatment. Together, these results suggest that amino acids 141-149 of C/EBPbeta act as a positive regulatory domain required for maximum transcriptional activity. PMID- 23456365 TI - [Biologics register JuMBO. Long-term safety of biologic therapy of juvenile idiopathic arthritis]. AB - In recent years the treatment of juvenile idiopathic arthritis (JIA) has changed dramatically. Nowadays one out of three children with polyarticular JIA is treated with a biologic drug; however, knowledge about the long-term safety of biologics is still limited. Information on drug safety is collected in the JIA biologic register (BiKeR) and the follow-up register juvenile arthritis methotrexate/biologics long-term observation (JuMBO). The latter currently includes information on more than 700 young adults most of whom were treated with etanercept and prospectively followed for more than 5 years. Preliminary data on the long-term safety of etanercept for JIA are therefore available. Over an observation period of 1,800 etanercept exposure-years, events of particular interest, such as malignancies, serious infections and new onset immune-mediated diseases have been recorded which occurred at rates of 0.1, 1.1 and 0.9/100 patient-years, respectively. Overall, new safety risks were not detected during long-term etanercept exposure. Moreover, JuMBO has also provided information on the long-term outcome of JIA and initial evidence suggests that JIA outcome, especially in functional aspects has improved in the biologic era. Data from BiKeR and JuMBO contribute to the risk-benefit assessment of biologic drugs which have been implemented in the routine treatment of JIA. PMID- 23456366 TI - [Ultrasound in rheumatology. What's new?]. AB - Ultrasound has become an established imaging modality in rheumatology and is now indispensible in the clinical routine. In the last few years the technology has remarkably improved and new areas of application have been introduced. This review provides an overview of the innovations that are relevant in rheumatologic practice. PMID- 23456367 TI - [Therapy of myositis]. AB - Idiopathic inflammatory myopathy consists of dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). At all stages of myositis, physiotherapy is effective in improving muscle strength, endurance and in maintaining joint motion. In DM and PM the therapy is initiated with glucocorticosteroids. Steroid-sparing agents (azathioprine, methotrexate and cyclosporin A) are added to prevent Cushing's syndrome or an unsatisfactory response. Therapy can also be escalated with intravenous immunoglobulins. Tacrolimus and mycophenolate mofetil (MMF) were effective in small case series. Cyclophosphamide is restricted to patients not responding to previous agents. For treatment intensification immunoglobulins can also be combined with MMF. There is not enough evidence to routinely recommend rituximab. The results with TNF-alpha inhibitors and plasmapheresis were negative or inconsistent. In DM skin involvement responds to sun blockers, antimalarials, topical corticosteroids or calcineurin inhibitors. In NAM statins should be discontinued and treatment with prednisone and immunosuppressants initiated. In IBM a therapeutic trial with prednisone, methotrexate or azathioprine may be warranted, especially in cases in which the serum creatine kinase (CK) is elevated or an inflammatory infiltrate is present in the muscle biopsy. PMID- 23456368 TI - [Dual energy computed tomography. Can the diagnostics of gout be improved with this method?]. PMID- 23456369 TI - Restless legs syndrome in patients with systemic sclerosis. Prevalence and possible causes. AB - This study aims to assess the prevalence and possible causes of restless legs syndrome (RLS) in patients with systemic sclerosis (SSc). The prevalence of RLS was assessed in 27 patients with SSc and 60 healthy controls. We evaluated the impact of age, disease duration, disease form, antibodies, and metoclopramide on the development of RLS in SSc patients. In order to reveal peripheral neuropathy or iron deficiency as possible causes of the syndrome, patients with RLS underwent electromyoneurography (EMNG) and ferritin level testing. RLS was diagnosed in 40.7% of SSc patients (11 out of 27), compared to 4.9% of healthy controls (p< 0.001). Eight out of 18 patients (44.4%) with diffuse SSc and 3 out of 9 patients (33.3%) with limited SSc exhibited RLS (p = 0.28). Mean age and mean disease duration did not differ significantly between patients with or without RLS. RLS was observed in 47.1% of patients with anticentromere antibodies and 30% of patients with anti-topoisomerase I antibodies (p = 0.22). RLS was diagnosed more frequently (p = 0.02) in patients taking metoclopramide (75%) than in patients who were not being treated with this drug (26.3%). EMNG revealed sensitive polyneuropathy in four, and lumbosacral radiculopathy in two out of 11 patients with RLS. Two patients with SSc and RLS had low levels of ferritin. Three patients had normal EMNG findings and ferritin levels. In conclusion, RLS is a common disorder in patients with SSc. Possible causes include sensitive polyneuropathy, lumbosacral radiculopathy, and iron deficiency. A strong relationship was observed between RLS and metoclopramide, which is sometimes used to treat SSc-related gastrointestinal motility disturbances. PMID- 23456370 TI - Affective temperaments in alcohol and opiate addictions. AB - Temperament is considered as a biological disposition reflected by relatively stable features related to mood and reactivity to external and internal stimuli, including variability in emotional reactions. The aim of the present study is to test the hypothesis that affective temperaments might differ according to co occurring mood disorders among patients with alcohol and/or opiate dependence; to explore the relationship between temperaments and dual substance use disorders (SUDs, alcohol and other drugs). Ninety-two patients attending an alcohol addiction treatment facility and 47 patients in an opiate addiction treatment facility were assessed for SUDs, mood disorders and affective temperaments using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego 39-item auto questionnaire. Comparison of patients with bipolar disorder, depressive unipolar disorder and no (or substance-induced) mood disorder revealed significant differences for the cyclothymic subscale, with highest scores among patients with bipolar disorder. No difference was observed for the depressive, irritable, hyperthymic and anxious subscales. After adjustment for age, gender and bipolar disorder, irritable temperament was a significant risk factor for past or present history of drug use disorders in patients treated for alcohol addiction (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.05-1.93). Anxious temperament was a significant risk factor for history of alcohol use disorders in patients treated for opiate addiction (OR 3.30, 95% CI 1.36-7.99), whereas the hyperthymic subscale appeared as a significant protective factor (OR 0.65, 95% CI 0.42-0.99). The results highlight the need to consider temperamental aspects in further research to improve the long-term outcome of patient with addictive disorders, who often present complex comorbidity patterns. PMID- 23456371 TI - Analyzing the nursing organizational structure and process from a scheduling perspective. AB - The efficient and effective management of nursing personnel is of critical importance in a hospital's environment comprising approximately 25 % of the hospital's operational costs. The nurse organizational structure and the organizational processes highly affect the nurses' working conditions and the provided quality of care. In this paper, we investigate the impact of different nurse organization structures and different organizational processes for a real life situation in a Belgian university hospital. In order to make accurate nurse staffing decisions, the employed solution methodology incorporates shift scheduling characteristics in order to overcome the deficiencies of the many phase-specific methodologies that are proposed in the academic literature. PMID- 23456372 TI - Characteristics of the mean radiant temperature in high latitude cities- implications for sensitive climate planning applications. AB - Knowledge of how the mean radiant temperature (T mrt ) is affected by factors such as location, climate and urban setting contributes to the practice of climate sensitive planning. This paper examines how T mrt varies within an urban setting and how it is influenced by cloudiness. In addition, variations of T mrt in three high latitude cities are investigated in order to analyse the impact of geographical context and climate conditions. Results showed large spatial variations between sunlit and shaded areas during clear weather conditions, with the highest values of T mrt close to sunlit walls and the lowest values in the areas shaded by buildings and vegetation. As cloudiness increases, the spatial pattern is altered and the differences are reduced. The highest T mrt under cloudy conditions is instead found in open areas where the proportion of shortwave diffuse radiation from the sky vault is high. A regional comparison between three Swedish coastal cities showed that T mrt during summer is similar regardless of latitudinal location. On the other hand, large differences in T mrt during winter were found. Shadows, both from buildings and vegetation are the most effective measure to reduce extreme values of T mrt. However, extensive areas of shadow are usually not desired within outdoor urban environments at high latitude cities. One solution is to create diverse outdoor urban spaces in terms of shadow and also ventilation. This would provide individuals with access to a choice of thermal environments which they can use to assist their thermal regulation, based on personal needs and desires. PMID- 23456373 TI - Phantosmia as a meteorological forecaster. AB - In normosmics, olfactory ability has been found to vary with ambient humidity, barometric pressure, and season. While hallucinated sensations of phantom pain associated with changes in weather have been described, a linkage to chemosensory hallucinations has heretofore not been reported. A 64-year-old white male with Parkinson's disease presents with 5 years of phantosmia of a smoky burnt wood which changed to onion-gas and then to a noxious skunk-onion excrement odor. Absent upon waking it increases over the day and persists for hours. When severe, there appears a phantom taste with the same qualities as the odor. It is exacerbated by factors that manipulate intranasal pressure, such as coughing. When eating or sniffing, the actual flavors replace the phantosmia. Since onset, he noted the intensity and frequency of the phantosmia forecasted the weather. Two to 3 h before a storm, the phantosmia intensifies from a level 0 to a 7-10, which persists through the entire thunderstorm. Twenty years prior, he reported the ability to forecast the weather, based on pain in a torn meniscus, which vanished after surgical repair. Extensive olfactory testing demonstrates underlying hyposmia. Possible mechanisms for such chemosensory-meteorological linkage includes: air pressure induced synesthesia, disinhibition of spontaneous olfactory discharge, exacerbation of ectopic discharge, affect mediated somatic sensory amplification, and misattribution error with expectation and recall bias. This is the first reported case of weather-induced exacerbation of phantosmia. Further investigation of the connection between chemosensory complaints and ambient weather is warranted. PMID- 23456374 TI - Extended season for northern butterflies. AB - Butterflies are like all insects in that they are temperature sensitive and a changing climate with higher temperatures might effect their phenology. Several studies have found support for earlier flight dates among the investigated species. A comparative study with data from a citizen science project, including 66 species of butterflies in Sweden, was undertaken, and the result confirms that most butterfly species now fly earlier during the season. This is especially evident for butterflies overwintering as adults or as pupae. However, the advancement in phenology is correlated with flight date, and some late season species show no advancement or have even postponed their flight dates and are now flying later in the season. The results also showed that latitude had a strong effect on the adult flight date, and most of the investigated species showed significantly later flights towards the north. Only some late flying species showed an opposite trend, flying earlier in the north. A majority of the investigated species in this study showed a general response to temperature and advanced their flight dates with warmer temperatures (on average they advanced their flight dates by 3.8 days/ degrees C), although not all species showed this response. In essence, a climate with earlier springs and longer growing seasons seems not to change the appearance patterns in a one-way direction. We now see butterflies on the wings both earlier and later in the season and some consequences of these patterns are discussed. So far, studies have concentrated mostly on early season butterfly-plant interactions but also late season studies are needed for a better understanding of long-term population consequences. PMID- 23456375 TI - Models for the beginning of sour cherry blossom. AB - Seven different model approaches to calculate the onset of sour cherry blossom for the main growing regions in Rhineland-Palatinate (Germany) were compared. Three of the approaches were pure forcing models (M1, M2, M2DL) and the remaining four models were combined sequential chilling-forcing (CF) models. Model M1 was the commonly used growing degree day (GDD) model in which the starting date of temperature accumulation (t1), the base temperature (TBF) and the forcing requirement F* were optimized on the basis of observed data. Because of a relatively late optimal starting date (t1=1 March), the model can be applied only to calculate the onset of cherry blossom for present climate conditions. In order to develop forcing models that could possibly be used to estimate possible shifts in the timing of cherry blossom due to climate change, the starting date t 1 of the models was intentionally set to 1 January (M2, M2DL). Unfortunately, model M2 failed in both the optimization and validation period. The introduction of a daylength term (DL) in model M2DL improved model performance. In order to project possible shifts in the timing of plant phenological events, combined CF-models are preferred over pure GDD-models. For this reason four CF-models were developed with (M3DL, M4DL) and without (M3, M4) consideration of daylength in the GDD approach. The chilling requirement was calculated using chilling hours (M3, M3DL) and chill portions (M4, M4DL). Both models without daylength estimated implausible model parameters and failed model validation. However, models M3DL and M4DL showed meaningful model parameter estimations and the error between modelled and observed data was markedly reduced. Moreover, the models optimized and validated (internal validation) for one sour cherry growing region in Germany, were applied successfully to calculate the beginning of the blossom period in other regions in Europe and even at one station in North America (external validation). PMID- 23456376 TI - Isolated limb infusion in a series of over 100 infusions: a single-center experience. AB - BACKGROUND: Isolated limb infusion (ILI) is a therapeutic option for patients with recurrent, unresectable extremity malignancies. METHODS: A prospectively collected single-institution database of patients undergoing ILI was analyzed for preoperative, intraoperative, and postoperative parameters and outcomes. RESULTS: From May 2007 to January 2012, a total of 76 patients successfully underwent initial ILI, and 28 after either previous hyperthermic isolated limb perfusion or ILI. Seventy-nine patients (74 %) had melanoma, 24 (22 %) sarcoma, 3 (3 %) Merkel cell, and 1 (1 %) squamous cell carcinoma. There were 55 (72 %) initial and 22 (79 %) repeat lower extremity (LE) ILIs, and 21 (78 %) initial and 6 (22 %) repeat upper extremity (UE) ILIs. Serologic toxicity, measured by serum creatine kinase (CK), peaked higher and later in LE ILIs, median 620 versus 124 IU/L, and postoperative day 4 versus 2, respectively (P < 0.05). LE ILIs had a longer hospital length of stay (LOS), median 6 versus 5 days (P < 0.0001). A median grade II Wieberdink regional toxicity was observed. Three-month follow-up was available in 94 (90 %). A response (overall response rate, ORR) was seen in 72 % of ILIs performed for melanoma and 58 % for sarcoma. No difference in response was observed between UE versus LE or between initial versus repeat ILIs. Repeat UE ILIs, however, appeared to have an improved ORR than repeat LE ILIs, 83 versus 64 %. CONCLUSIONS: ILI may be successfully performed for cutaneous and soft tissue malignancies. LE ILIs have higher CK levels and slightly longer LOS. Repeat ILIs are not associated with increased toxicity and similar ORR. UE ILIs may have better ORR. PMID- 23456377 TI - Right hemicolectomy for mucinous adenocarcinoma of the appendix: just right or too much? AB - BACKGROUND: The surgical management of mucinous adenocarcinoma of the appendix (MA) is controversial, given its infrequent nodal metastases and its propensity for peritoneal dissemination compared to nonmucinous adenocarcinoma. We sought to identify the appropriateness of a right hemicolectomy (RH) for MA in staging and treatment of these tumors. METHODS: We queried all patients with MA captured in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2007. Demographics, and tumor and therapy characteristics were extracted. Overall and disease-specific survival was compared by Cox regression analyses. RESULTS: Of 2,101 patients with MA, the median age was 59 (range 49-72) years; 55 % were women (n = 1,151). Tumor, node, metastasis staging revealed that tumors were frequently T3 (33 %) or T4 (46 %), N0 (80 %), and M1 (46 %). Fifty-one percent (n = 666) of patients underwent an appendectomy. In patients with complete staging information who underwent RH, nodal metastases were less frequent than the nonmucinous adenocarcinoma group (odds ratio 0.63, p = 0.003). Well differentiated tumors had a low likelihood of nodal metastases (6 % T1, 0 % T2, 7 % T3, 22 % T4). Adjusted survival for patients undergoing appendectomy was similar to those undergoing a RH (hazard ratio 0.93, p = 0.52). Median survival for both groups was similar with positive nodes (28 [appendectomy] vs. 26 months [RH], p = 0.26) or metastatic disease (52 [appendectomy] vs. 43 months [RH], p = 0.28). CONCLUSIONS: There does not appear to be a therapeutic benefit to a RH in the setting of known node-positive or metastatic disease. Benefits of a staging operation can be individualized on the basis of the probability of nodal metastases, which is lower than nonmucinous tumors. PMID- 23456378 TI - Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of hyperthermia. AB - BACKGROUND: In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model. METHODS: Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells. RESULTS: Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor cells in vivo. CONCLUSIONS: Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies. PMID- 23456379 TI - Plasma cytokine analysis in patients with advanced extremity melanoma undergoing isolated limb infusion. AB - BACKGROUND: Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in transit extremity melanoma. METHODS: Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1alpha, IL-1Ralpha, IP-10, IL-1beta, IL-1alpha, MCP-1, IL-6, IL-17, EGF, IL 12p40, VEGF, GM-CSF, and MIP-1beta) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated. RESULTS: Of 180 ILIs performed, 28 % (95 % confidence interval 22-35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1alpha, IL-1Ralpha, IL-1beta, IL-1alpha, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1beta were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients. CONCLUSIONS: Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune targeted therapies and immune monitoring in patients with regionally advanced melanoma. PMID- 23456380 TI - Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma. AB - BACKGROUND: Transarterial chemoembolization (TACE) is often utilized for patients with inoperable neuroendocrine carcinoma liver metastases. Often, metastatic disease is not limited to the liver. The impact of extrahepatic disease (EHD) on outcomes and response after TACE has not been described. METHODS: We reviewed 192 patients who underwent TACE for large hepatic tumor burden, progression of liver metastases, or poorly controlled carcinoid syndrome due to neuroendocrine carcinoma. Demographics, clinicopathologic characteristics, response to TACE, complications, and survival were compared between patients with (n = 123) and without (n = 69) EHD. RESULTS: Demographics, histopathologic characteristics, and complications were similar between groups. As well, those with and without EHD had similar biochemical (85 vs. 88 %) and radiographic response (76 vs. 79 %) to TACE (all p = NS); however, symptomatic responses were improved in those with EHD (79 vs. 60 %, p = 0.01). The group without EHD had better overall survival compared to those with EHD disease at the time of TACE (median 62 vs. 28 months, p = 0.001). DISCUSSION: Although patients with EHD from neuroendocrine carcinoma experience shorter overall survival after TACE compared to those without EHD, they had similar symptomatic, biochemical, and radiographic response to TACE. Meaningful response to TACE is still possible in the presence of EHD and should be considered, particularly in those with carcinoid syndrome. PMID- 23456381 TI - Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from rectal cancer. AB - BACKGROUND: Cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is the treatment most likely to achieve prolonged survival in peritoneal carcinomatosis (PC). Yet the efficacy of HIPEC in rectal patients is controversial because of the retroperitoneal location of the primary tumor. Therefore, we reviewed our experience in patients with PC from a rectal primary tumor. METHODS: A retrospective analysis of a prospective database of 950 HIPEC procedures was performed. Performance status, age, albumin level, prior surgical score, resection status, morbidity, mortality, and survival were reviewed. RESULTS: A total of 13 and 204 patients with PC from rectal and colon cancer, respectively, were identified. Median follow-up was 40.1 and 88.1 months, respectively. Eastern Cooperative Oncology Group (ECOG) score was zero or one for 92 % of patients with rectal cancer and 83 % for colon, while R1 resection was achieved in 54 and 51 %. The 30-day mortality was 5 % for colon cancer. There were no deaths in the rectal group. The morbidity for the colon and rectal groups was 57 and 46 %, respectively, with a 23 % 30-day readmission rate. In univariate analysis, age, ECOG, prior surgical score, albumin level, and node and resection status were not statistically significant in predicting survival for the rectal cancer patients. Median survival for the rectal and colon groups was 14.6 versus 17.3 months, while the 3-year survival was 28.2 versus 25.1 %. CONCLUSIONS: Our data demonstrate similar 3-year survival for patients with rectal and colon cancer PC treated with CS/HIPEC. This can be attributed to patient selection bias. Selected rectal cancer PC patients should not be excluded from an attempted cytoreduction and HIPEC. PMID- 23456382 TI - Surveillance MR imaging is superior to serum tumor markers for detecting early tumor recurrence in patients with appendiceal cancer treated with surgical cytoreduction and HIPEC. AB - BACKGROUND: The purpose of this study was to determine if MRI surveillance is better than serum tumor makers in detecting early recurrence in patients with mucinous appendiceal neoplasm. MATERIALS AND METHODS: A total of 50 patients with appendiceal neoplasm (DPAM 11, PMCA 39) underwent abdominal and pelvic MRI prior to surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients then entered follow-up surveillance with serial MRI every 6 months and serial laboratory studies including CA 125, CEA, and CA19-9. Written reports for surveillance MRI exams were reviewed for tumor recurrence and compared with results of serial laboratory tests. Proof of tumor recurrence was by a consensus of surgery and histopathology, as well as clinical and imaging findings on serial examinations. RESULTS: During surveillance tumor recurrence was documented in 30 patients (60 %) with median time to recurrence of 13 months (range 3-56 months). MRI detected recurrent tumor in 28 patients, including 11 patients with normal laboratory values (sensitivity 0.93, specificity 0.95, accuracy 0.94, PPV 0.97, and NPV 0.90). Serial laboratory values showed tumor recurrence in 14 patients (sensitivity 0.48, specificity 1.00, accuracy 0.69, PPV 1.0, and NPV 0.57). Median survival was 50 months for 11 patients with earlier MRI detection of recurrence vs 33 months for the other 19 patients with recurrence. CONCLUSIONS: Following cytoreductive surgery and HIPEC MRI detects tumor recurrence earlier and with greater accuracy than serial tumor markers alone. PMID- 23456383 TI - Assessment of neoadjuvant chemotherapy on operative parameters and outcome in patients with peritoneal dissemination from high-grade appendiceal cancer. AB - BACKGROUND: High-grade appendiceal adenocarcinoma is a rare malignancy with propensity for peritoneal metastases (PM). The impact of neoadjuvant chemotherapy on operative cytoreduction (CRS) and intraperitoneal chemotherapy (HIPEC) and patient survival was reviewed. METHODS: A total of 45 patients with PM from high grade appendiceal adenocarcinoma were identified from a prospective database. All patients had laparotomy with intent to undergo CRS and HIPEC. Operative parameters, complications, and survival outcomes were analyzed. RESULTS: Of the 45 patients (male: 27, female: 18; median age: 55 years), 26 received neoadjuvant chemotherapy +/- bevacizumab. Of the 26, 15 (58 %) had a response based on improvement in imaging, biomarkers, or both and 9 (34 %) had stable disease. The median peritoneal cancer index (PCI) was 27. Also, 30 (67 %) had a completeness of cytoreduction score (CCR) of <=1 and 37 (82 %) received HIPEC. There were no differences in PCI, CCR score, operative blood loss, or major organ resection between those who received or did not receive neoadjuvant chemotherapy. Operative time was significantly shorter in those who did not receive neoadjuvant chemotherapy. Major complications and length of hospital stay were similar between the groups. The median actuarial overall survival calculated from the date of initial therapeutic intervention was not different in those treated with or without neoadjuvant therapy. CONCLUSIONS: Neoadjuvant chemotherapy has marked clinical activity in patients with PM from high-grade appendiceal adenocarcinoma and does not adversely affect operative outcomes. These data support conducting a prospective clinical trial to define the role of neoadjuvant chemotherapy in this clinical setting. PMID- 23456384 TI - Body surface area predicts plasma oxaliplatin and pharmacokinetic advantage in hyperthermic intraoperative intraperitoneal chemotherapy. AB - BACKGROUND: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface-spreading malignancies to maximize local drug concentrations while minimizing systemic effects. The pharmacokinetic advantage of HIPEC is defined as the intraperitoneal to intravascular ratio of drug concentrations. We hypothesized that body surface area (BSA) would correlate with the pharmacokinetic advantage of HIPEC. Because oxaliplatin is administered in 5 % dextrose, we hypothesized that BSA would correlate with glycemia. METHODS: We collected blood and peritoneal perfusate samples from ten patients undergoing HIPEC with a BSA-based dose of 250 mg/m(2) oxaliplatin, and measured drug concentrations by inductively coupled plasma mass spectrophotometry. We monitored blood glucose for 24 h postoperatively. Areas under concentration-time curves (AUC) were calculated by trapezoidal rule. Pharmacokinetic advantage was calculated by (AUC[peritoneal fluid]/AUC[plasma]). We used linear regression to test for statistical significance. RESULTS: Higher BSA was associated with lower plasma oxaliplatin AUC (p = 0.0075) and with a greater pharmacokinetic advantage (p = 0.0198) over the 60-minute duration of HIPEC. No statistically significant relationships were found between BSA and blood glucose AUC or peak blood glucose levels. CONCLUSIONS: Higher BSA is correlated with lower plasma drug levels and greater pharmacokinetic advantage in HIPEC, likely because of increased circulating blood volume with inadequate time for equilibration. Plasma glucose levels after oxaliplatin HIPEC were not clearly related to BSA. PMID- 23456385 TI - Extensive cytoreductive surgery for appendiceal carcinomatosis: morbidity, mortality, and survival. AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) are frequently used to treat appendiceal carcinomatosis. Some patients require multivisceral resection because of the volume of disease. It is unclear whether extent of CRS impacts survival in appendiceal carcinomatosis. METHODS: We analyzed 282 patients undergoing attempted CRS/HIPEC for appendiceal carcinomatosis. Patients were defined as having undergone Extensive CRS (n = 60) if they had >3 organ resections or >2 anastomoses; a subgroup of Extreme CRS patients (n = 10) had >=5 organ resections and >=3 anastomoses. Kaplan-Meier survival curves and multivariate Cox-regression models were used to identify prognostic factors affecting outcomes. RESULTS: Relative to the comparison group, patients undergoing Extensive CRS had a higher median peritoneal carcinomatosis index, operative duration, blood loss, and length of stay. No difference in completeness of cytoreduction, severe morbidity, or 60-day mortality was evident. Subgroup analysis of 10 patients undergoing extreme CRS likewise revealed no increase in severe morbidity or mortality. Median progression-free (PFS) and overall survival (OS) were 23.5 and 74 months in the comparison group; 18.5 (p = 0.086) and 51 (p = 0.85) months in the Extensive CRS group; and 40 months and not reached in the Extreme CRS subgroup. In a multivariable analysis, extent of CRS was not independently associated with PFS or OS. CONCLUSIONS: Extensive CRS is associated with greater OR time, blood loss, and length of stay, but is not associated with higher morbidity, mortality, or inferior oncologic outcomes in patients with appendiceal carcinomatosis. PMID- 23456386 TI - The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: The aim of this study was to evaluate the effects of perioperative systemic chemotherapy (CT) on short-term surgical and long-term oncologic results in diffuse malignant peritoneal mesothelioma (DMPM) patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS: We retrospectively analyzed data obtained from an institutional prospective database at NCI of Milan. The study group comprised 116 DMPM patients treated with CRS + HIPEC from August 1995 to October 2011. A total of 60 cases underwent preoperative CT (PRECT), 30 underwent postoperative CT (POSTCT), and 26 did not undergo any CT (NOCT). Also, 55 cases used the perioperative combination of platinum and pemetrexed. We tested whether covariates related to clinical, histologic, PRECT, and surgical treatment were correlated with completeness of cytoreduction (CC), postoperative G3-5 morbidity, and progression-free survival and overall survival (OS). Univariate and multivariate analyses were performed. RESULTS: Factors independently associated with CC were ECOG performance status (PF) of 0, and PCI <20. Factors independently associated with postoperative G3-5 morbidity were ECOG >1, bowel anastomosis, and number of peritonectomy procedures. Preoperative platelet count >400 * 103/mm(3), histological subtype (biphasic and sarcomatoid vs epithelial), CC, and G3-5 morbidity were independent prognostic factors. PRECT was not associated with CC or G3-5 morbidity. There was no significant difference in terms of survival between the PRECT, POSTCT, and NOCT groups. CONCLUSIONS: The CC, G3-5, and OS were not influenced by aspects related to perioperative CT. The present data warrants confirmation reconducting the comparative analysis in a larger multi-institutional series preferably using matching control techniques. PMID- 23456387 TI - Complications and toxicities after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - INTRODUCTION: The purpose of our study was to evaluate the perioperative complications, toxicity, mortality rates after cytoreductive surgery (CRS), and effects of hyperthermic intraperitoneal chemotherapy (HIPEC) used in the treatment of peritoneal surface malignancies. METHODS: Between September 2007 and March 2012, we performed 118 CRS and HIPEC with the closed abdominal technique on 115 patients with peritoneal carcinomatosis (PC). Systemic toxicities were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria and were analyzed from a prospectively collected database. RESULTS: The mean age of patients was 53.4 (range, 20-82) years; 76.3 % were female. PC was synchronous to primary cancer in 53.4 % of patients, metachronous in 41.5 %, and recurrent in 5.1 % of the patients. PCI was >=15 in 53.4 % of the patients, and CC-0 cytoreduction was achieved in 68.5 % of the patients. Perioperative mortality was observed in 9 (7.6 %) patients. A total of 98 complications were observed in 46 (39.0 %) patients, and 4 patients underwent 6 reoperations for perioperative surgical complications. We observed toxicity in 25.4 % of the patients, nephrotoxicity in 18.6 %, and hematological toxicity in 13.6 % of patients. No significant difference was observed among age, gender, PCI and CC scores, origin of the primary tumor, and occurrence of toxicity and surgical complications. Prolonged operation times resulted in higher complication and/or toxicity rates (P < 0.01). CONCLUSIONS: Cytoreductive surgery and HIPEC is a combined treatment strategy for peritoneal surface malignancies with acceptable complication and toxicity rates. PMID- 23456388 TI - Regional therapies for cancer. PMID- 23456389 TI - Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. AB - BACKGROUND: Mutations in KRAS and TP53 are common in colorectal carcinogenesis and are associated with resistance to therapy. Rectal cancers carrying both mutations are less likely to respond to neoadjuvant chemoradiation therapy (CRT) compared with wild-type tumors. Codon-specific KRAS mutations are associated with variable resistance to targeted therapies, but their association with rectal cancer response to CRT remains unclear. Our objective was to establish a correlation between specific KRAS mutations and rectal cancer response to CRT and to investigate if the correlation was related to a different association between KRAS and TP53 mutations. METHODS: A total of 148 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery. DNA was extracted from pretreatment tumor biopsies and paired normal surgical tissues and KRAS and TP53 genotyping was performed. Specific KRAS mutations were then correlated with tumor response and with concurrent TP53 mutation. RESULTS: A total of 60 patients had KRAS mutation, 12 in codon 13 and 48 in other locations. Also, 80 patients had TP53 mutation; 27 had concurrent KRAS/TP53 mutations. Tumors with any KRAS mutation were less likely to have a pCR compared with wild-type KRAS (p = 0.006). Specifically, no tumors with KRAS codon 13 mutations had a pCR (p = 0.03). Tumors with KRAS codon 13 mutations also had a higher incidence of concurrent TP53 mutation compared with tumors with other KRAS mutations (p = 0.02). CONCLUSIONS: Mutations in different KRAS codons may have different effects on rectal cancer resistance to CRT. This variable resistance may be related to a different frequency of TP53 mutations in KRAS mutant tumors. PMID- 23456390 TI - Response of human pancreatic cancer cell xenografts to tetraiodothyroacetic acid nanoparticles. AB - Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC 1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (*P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caused accumulation of pro-apoptotic protein BcLx-s. Tetrac NP was more effective than tetrac in increasing cellular abundance of mRNAs of pro-apoptotic p53 and p21 and anti-angiogenesis thrombospondin 1 protein in PANC-1 and MPanc96 cancer cell lines. Tetrac NP noticeably decreased expression of EGFR and of anti-apoptosis gene XIAP; tetrac did not affect EGFR and increased XIAP mRNA in both MPanc96 and PANC-1. In conclusion, tetrac or Tetrac NP effectively inhibited human pancreatic xenograft growth and tumor angiogenesis via a plasma membrane receptor that downstream modulated cellular abundance of proteins or mRNAs relevant to apoptosis and angiogenesis. PMID- 23456394 TI - Pomalidomide approved for multiple myeloma. PMID- 23456393 TI - Pharmacokinetics of intravenous conivaptan in subjects with hepatic or renal impairment. AB - BACKGROUND: Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment. OBJECTIVE: The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function. STUDY DESIGN: These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US. PATIENTS: Men and non pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups. INTERVENTION: Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered. MAIN OUTCOME MEASURE: Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUCinfinity), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48). RESULTS: For each of C LD, C 48, and AUCinfinity, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUCinfinity compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event. CONCLUSION: Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment. PMID- 23456391 TI - Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: correlation with polymorphisms in the vitamin D genes. AB - Cholecalciferol (D(3)) supplementation results in variable increases in serum 25(OH)D(3) levels, however, the influence of genetic polymorphisms on these variable responses is unclear. We measured serum 25(OH)D(3), 24,25(OH)(2)D(3), 1,25(OH)2D(3) and VDBP levels in 50 colorectal cancer (CRC) patients before and during 2,000 IU daily oral D(3) supplementation for six months and in 263 archived CRC serum samples. Serum PTH levels and PBMC 24-OHase activity were also measured during D(3) supplementation. TagSNPs in CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR, and GC genes were genotyped in all patients, and the association between these SNPs and serum vitamin D(3) metabolites levels before and after D(3) supplementation was analyzed. The mean baseline serum 25(OH)D(3) level was less than 32 ng/mL in 65 % of the 313 CRC patients. In the 50 patients receiving D(3) supplementation, serum levels of 25(OH)D(3) increased (p = 0.008), PTH decreased (p = 0.036) and 24,25(OH)(2)D(3), 1,25(OH)(2)D(3), VDBP levels and PBMC 24-OHase activity were unchanged. GC SNP rs222016 was associated with high 25(OH)D(3) and 1,25(OH)(2)D(3) levels at baseline while rs4588 and rs2282679 were associated with lower 25(OH)D(3) and 1,25(OH)(2)D(3) levels both before and after D(3) supplementation. CYP2R1 rs12794714 and rs10500804 SNPs were significantly associated with low 25(OH)D(3) levels after supplementation but not with baseline 25(OH)D(3). Our results show that D(3) supplementation increased 25(OH)D(3) levels in all patients. GC rs4588 and rs2283679 SNPs were associated with increased risk of vitamin D(3) insufficiency and suboptimal increase in 25(OH)D(3) levels after D(3) supplementation. Individuals with these genotypes may require higher D(3) supplementation doses to achieve vitamin D(3) sufficiency. PMID- 23456396 TI - Stroke guideline supports expanded alteplase use. PMID- 23456398 TI - Promotion of off-label use not always a crime. PMID- 23456399 TI - Effect on institutional revenue of clinical pharmacy services in an ambulatory care clinic. PMID- 23456400 TI - Institutional collaboration on a residency research project. PMID- 23456401 TI - Making the transition from student to teacher. PMID- 23456402 TI - Management of advanced colorectal cancer, Part 2. AB - PURPOSE: Important developments in chemotherapy for advanced colorectal cancer over the past 15 years are reviewed, with an emphasis on the most recently published data from clinical trials of newer multidrug regimens, administration techniques, and dosing schedules. SUMMARY: Eight agents are approved by the Food and Drug Administration (FDA) for use in treating patients with advanced colorectal cancer. Fluorouracil and leucovorin still constitute the foundation of most chemotherapy regimens for this population; combination fluorouracil leucovorin therapy plus either irinotecan (the FOLFIRI regimen) or oxaliplatin (the FOLFOX regimen) are two firmly established first-line treatments shown to produce similar outcomes. In Phase III trials conducted over the past six to seven years, regimens of capecitabine plus oxaliplatin (CapeOx) were demonstrated to have clinical effectiveness comparable to that of FOLFOX therapy. Response rates of 35-55% and median overall survival of >=20 months have been documented with some of the newer regimens. Research to define the optimal role of the three monoclonal antibody agents approved by FDA for use in managing advanced colorectal cancer is ongoing; bevacizumab has been shown to confer significant survival benefits when added to certain chemotherapy regimens, and other monoclonal antibodies (cetuximab and panitumumab) also appear to offer significant benefits in select patients as first- or second-line therapies. CONCLUSION: Over the past 15 years, a shift toward multiagent treatment strategies including a variety of chemotherapy agents and monoclonal antibodies has yielded improved rates of response and prolonged survival among patients with advanced colorectal cancer. The CapeOx, FOLFOX, and FOLFIRI regimens are currently among the most widely used first-line treatments. PMID- 23456403 TI - Drug rash with eosinophilia and systemic symptoms syndrome associated with use of phenytoin, divalproex sodium, and phenobarbital. AB - PURPOSE: A probable case of drug reaction with eosinophilia and systemic symptoms (DRESS) associated with consecutive use of three medications for seizure control is reported. SUMMARY: A 36-year-old woman was treated at a community hospital for a mild fever (37.9 degrees C) and diffuse raised maculopapular rash with erythema. Three weeks previously, she had been diagnosed with a seizure disorder and initiated on phenytoin (dose unknown) at that time; about two weeks later, she developed a rash, prompting a switch from phenytoin to extended-release divalproex sodium 250 mg orally twice daily. During the week after discontinuation of phenytoin, the rash was improving, but about five days after the initiation of divalproex therapy, she had worsening rash and pruritus requiring urgent treatment; the divalproex was discontinued, and phenobarbital 30 mg three times daily was initiated for continued seizure control. Despite the discontinuation of phenytoin and divalproex, the patient's hepatic function worsened over five days, and phenobarbital therapy was discontinued. With continued deterioration of the patient's condition to fulminant hepatic failure, a transfer to a liver transplant facility was arranged. The use of the adverse reaction probability scale of Naranjo et al. in this case yielded a score of 8, indicating a probable relationship between DRESS and the serial use of phenytoin, divalproex, and phenobarbital. CONCLUSION: After receiving phenytoin for treatment of seizure disorder, a 36-year-old woman developed a fever and maculopapular rash with erythema. This reaction continued even after drug therapy was switched to extended-release divalproex and then phenobarbital. The patient's liver function deteriorated despite discontinuation of all seizure medications. PMID- 23456404 TI - Prasugrel use in a patient allergic to clopidogrel: effect of a drug shortage on selection of dual antiplatelet therapy. AB - PURPOSE: A case illustrating multiple considerations in choosing safe and effective dual antiplatelet therapy for a patient with a history of clopidogrel allergy-including concerns relating to a national drug shortage-is described. SUMMARY: A 75-year-old woman required dual antiplatelet therapy (aspirin plus a thienopyridine) after a cardiac catheterization procedure; during a prior emergency department visit for acute coronary syndrome, she had experienced an allergic reaction within 24 hours of receiving dual therapy including clopidogrel. A team of pharmacy and allergy staff determined that challenging the patient with prasugrel was the best treatment option. Key considerations in the decision-making process included (1) concerns that an alternative thienopyridine, ticlopidine, might be unavailable for long-term outpatient use due to an ongoing national drug shortage, (2) the patient's concomitant use of metoprolol (cessation of beta-blocker use is recommended for four days before attempted clopidogrel desensitization), and (3) recent reports of the safe use of prasugrel in three patients with a history of clopidogrel allergy. In the case described here, prasugrel administration was effective and did not result in adverse effects; however, the risk of cross-reactivity of clopidogrel and ticlopidine or prasugrel remains largely unknown. The case highlights the importance of careful consideration of a number of patient- and drug-specific factors in the selection of the most appropriate antiplatelet dual therapy for patients with a history of allergic reactions to clopidogrel. CONCLUSION: A shortage of ticlopidine prompted the use of prasugrel in a clopidogrel-allergic patient requiring dual antiplatelet therapy. Prasugrel therapy was well tolerated, with no evidence of allergic reaction. PMID- 23456405 TI - Compatibility of butorphanol and droperidol in 0.9% sodium chloride injection. AB - PURPOSE: The compatibility and stability of butorphanol tartrate and droperidol in polyvinyl chloride (PVC) bags and glass bottles stored at 4 degrees C and 25 degrees C for up to 15 days were studied. METHODS: Admixtures were assessed initially and for 15 days after preparation in PVC bags and glass bottles using 0.9% sodium chloride injection as a diluent and stored at 4 degrees C and 25 degrees C. The initial drug concentrations were 0.08 mg/mL for butorphanol tartrate and 0.05 mg/mL for droperidol. Samples were withdrawn from each container immediately after preparation and at predetermined intervals (2, 4, 8, 24, 48, 72, 120, 168, 240, and 360 hours after preparation). The solutions were visually inspected for precipitation, cloudiness, and discoloration at each sampling interval. Drug concentrations were determined using a validated high pressure liquid chromatography method. RESULTS: After 15 days of storage, all formulations tested retained >98% of the initial concentrations of both drugs. The drug mixtures were clear in appearance, and no color change or precipitation was observed. Throughout this period, pH values remained stable. CONCLUSION: Admixtures of butorphanol tartrate 0.08 mg/mL and droperidol 0.05 mg/mL in 0.9% sodium chloride injection were stable for at least 360 hours when stored in PVC bags or glass bottles at 4 degrees C and 25 degrees C and protected from light. PMID- 23456407 TI - Projecting future drug expenditures in U.S. nonfederal hospitals and clinics- 2013. AB - PURPOSE: Factors likely to influence drug expenditures, drug expenditure trends in 2012, and projected drug expenditures for U.S. nonfederal hospitals and clinics in 2013 are discussed. METHODS: Prescription drug expenditure data for 2011 through September 2012 were obtained from the IMS Health National Sales Perspectives database. Expenditure projections were based on a combination of quantitative and qualitative analyses, combined with expert opinion. RESULTS: Total prescription sales in the United States for the 12-month period ending September 2012 were $326.0 billion, a 0.8% increase from the previous 12 months. This rate of growth was the lowest in recent history and can be attributed to modest increases in expenditures for new products (3.3%) and the prices of existing products (5.9%), coupled with a marked decline in overall volume and mix (-8.4%). For the 9 months ending in September 2012, total prescription expenditures grew 2.7% when compared with the same period in 2011. Oncology products remained important expenditures for hospitals and clinics. Antineoplastic agents were the top medication class for expenditures in nonfederal hospitals, and oncology products accounted for 32.2% of drug expenditures in the clinic setting in the first 9 months of 2012. CONCLUSION: For 2013, we project a 1-3% increase in total drug expenditures across all settings, a 2-4% increase in expenditures for clinic-administered drugs, and a 0.5% decline to 1.5% increase in hospital drug expenditures. Health-system pharmacy leaders should carefully examine their own local drug-utilization patterns to determine their own organization's drug expenditure forecast. PMID- 23456406 TI - Physical compatibility of various drugs with neonatal total parenteral nutrient solution during simulated Y-site administration. AB - PURPOSE: The physical compatibility of various drugs with neonatal total parenteral nutrient (TPN) solution during simulated Y-site administration was evaluated. METHODS: Study drugs were selected based on the lack of compatibility data with them and neonatal TPN solution and the frequency of use in a local neonatal unit. These drugs included amiodarone, caffeine citrate, clindamycin, enalaprilat, epinephrine, fluconazole, fosphenytoin sodium, hydrocortisone, metoclopramide, midazolam, pentobarbital, phenobarbital, and rifampin. Equal volumes of neonatal TPN solution or sterile water for injection were combined with study drugs or sterile water for injection at concentrations used clinically in neonates. Each test was performed in triplicate. The samples were examined via turbidimetric analysis and visually against light and dark backgrounds immediately after mixing and at 0.25, 0.5, 1, 2, and 3 hours after mixing. Analysis of variance was used to determine statistically significant differences between the test and control solutions. RESULTS: Many of the drugs studied exhibited no visual or turbidimetric evidence of incompatibility when combined with neonatal TPN solution for up to three hours in a simulated Y-site injection. Pentobarbital, phenobarbital, and rifampin formed visible precipitation immediately after mixing with the neonatal TPN solution. CONCLUSION: Caffeine citrate, clindamycin, enalaprilat, epinephrine, fluconazole, fosphenytoin sodium, hydrocortisone, metoclopramide, and midazolam exhibited no visual or turbidimetric evidence of incompatibility when combined with a neonatal TPN solution for up to three hours in a simulated Y-site injection. Amiodarone, pentobarbital, phenobarbital, and rifampin were not compatible with the neonatal TPN solution and should not be coadministered via Y-site injection. PMID- 23456408 TI - Implementing standardized intravenous antibiotic desensitizations among hospital inpatients. AB - PURPOSE: Patient safety improvements and increased efficiencies achieved through the establishment of standardized protocols and order sets for selected antibiotic desensitization procedures are described. SUMMARY: Errors in the ordering and administration of antimicrobial desensitization regimens can result in life-threatening complications. To enhance patient safety, the University of Colorado Hospital pharmacy department worked with allergy and immunology physicians (AIPs) to implement standardized desensitization protocols to reduce the potential for confusion surrounding the prescribing and administration of these complex regimens to acutely ill populations such as patients with cystic fibrosis, as many as 30% of whom develop one or more antimicrobial allergies. Nine i.v. antibiotics were identified as suitable for the standardization initiative; based on AIP experience and published guidelines, therapeutic doses of each targeted medication were determined. For each of the nine drugs, the interdisciplinary team developed an instruction sheet on preparing stock concentrations and compounding sequential doses for desensitization, with a corresponding preprinted order set detailing infusion procedures, monitoring requirements, guidance on the use of rescue medications and other steps for managing adverse reactions, and patient safeguards. Initial experience with the standardized protocols indicated that relative to previous practices (i.e., physician submission of handwritten patient-specific orders, with pharmacist calculation of required dilutions case by case), the standardization initiative (1) reduced the potential for errors, (2) sharply reduced order-entry and product preparation times, and (3) helped achieve antimicrobial stewardship goals. CONCLUSION: Standardized antimicrobial desensitization protocols helped to optimize patient care and antimicrobial stewardship while enabling more efficient use of pharmacy and AIP resources and fostering enhanced pharmacist-physician collaboration. PMID- 23456409 TI - Acute coronary syndromes: advances in antithrombotics. AB - Contemporary management of acute coronary syndromes (ACS) has evolved to include rapid revascularization, potent antithrombotic, and antiplatelets, all of which reduce the risk of ischemic complications. Despite these advances, recurrent ischemic and bleeding event rates are still substantial. This increased risk post percutaneous coronary intervention (PCI) has been the seminal event leading to recent clinical trials evaluating more potent antiplatelet drugs (prasugrel, ticagrelor, and protease-activated receptor-1 [PAR-1] inhibitors) and novel oral anticoagulants (NOAC). Ideally, an effective anticoagulation regimen adequately reduces the incidence of recurrent ischemia and limits iatrogenic bleeding. In this review, we will discuss the advances in ACS pharmacotherapy, review the recent trials evaluating these drugs, and discuss the major dilemmas in interpreting and implementing their findings. PMID- 23456410 TI - Fragile visual short-term memory is an object-based and location-specific store. AB - Fragile visual short-term memory (FM) is a recently discovered form of visual short-term memory. Evidence suggests that it provides rich and high-capacity storage, like iconic memory, yet it exists, without interference, almost as long as visual working memory. In the present study, we sought to unveil the functional underpinnings of this memory storage. We found that FM is only completely erased when the new visual scene appears at the same location and consists of the same objects as the to-be-recalled information. This result has two important implications: First, it shows that FM is an object- and location specific store, and second, it suggests that FM might be used in everyday life when the presentation of visual information is appropriately designed. PMID- 23456411 TI - Is handedness just response bias? AB - Although most people prefer to use the right hand for unimanual tasks, it is unknown whether handedness arises from response bias. Whether it does is a question inspired by signal detection theory. We drew on the framework of signal detection theory to assess bias and sensitivity in hand choice by asking right handers to choose between two tasks-one performed with the left hand, and one performed with the right. For some participants, the left-hand task stayed constant while the right-hand task was varied. For other participants, the right hand stayed constant while the left-hand task was varied. We reasoned that if hand preference only reflected bias, participants would choose the generally preferred hand to the same degree, regardless of whether its task was constant or varied. Our participants followed this strategy only to some extent, suggesting that bias and sensitivity both contribute to hand preference. PMID- 23456413 TI - Integrating the life course into MCH service delivery: from theory to practice. AB - To describe the efforts of a community-based maternal and child health coalition to integrate the life course into its planning and programs, as well as implementation challenges and results of these activities. Jacksonville-Duval County has historically had infant mortality rates that are significantly higher than state and national rates, particularly among its African American population. In an effort to address this disparity, the Northeast Florida Healthy Start Coalition embraced the life course approach as a model. This model was adopted as a framework for (1) community needs assessment and planning; (2) delivery of direct services, including case management, education and support in the Magnolia Project, its federal Healthy Start program; (3) development of community collaborations, education and awareness; and, (4) advocacy and grass roots leadership development. Implementation experience as well as challenges in transforming traditional approaches to delivering maternal and child health services are described. Operationalizing the life course approach required the Coalition to think differently about risks, levels of intervention and the way services are organized and delivered. The organization set the stage by using the life course as a framework for its required local planning and needs assessments. Based on these assessments, the content of case management and other key services provided by our federal Healthy Start program was modified to address not only health behaviors but also underlying social determinants and community factors. Individual interventions were augmented with group activities to build interdependence among participants, increasing social capital. More meaningful inter-agency collaboration that moved beyond the usual referral relationships were developed to better address participants' needs. And finally, strategies to cultivate participant advocacy and community leadership skills, were implemented to promote social change at the neighborhood-level. Transforming traditional approaches to delivering maternal and child health services and sustaining change is a long and laborious process. The Coalition has taken the first steps; but its efforts are far from complete. Based on the agency's initial implementation experience, three areas presented particular challenges: staff, resources and evaluation. The life course is an important addition to the MCH toolbox. Community-based MCH programs should assess how a life course approach can be incorporated into existing programs to broaden their focus, and, potentially, their impact on health disparities and birth outcomes. Some areas to consider include planning and needs assessment, direct service delivery, inter-agency collaboration, and community leadership development. Continued disparities for people of color, despite medical advances, demand new interventions that purposefully address social inequities and promote advocacy among groups that bear a disproportionate burden of infant mortality. Successful transformation of current approaches requires investment in staff training to garner buy-in, flexible resources and the development of new metrics to measure the impact of the life course approach on individual and programmatic outcomes. PMID- 23456412 TI - 25 years of research on the use of geometry in spatial reorientation: a current theoretical perspective. AB - The purpose of this article is to review and evaluate the range of theories proposed to explain findings on the use of geometry in reorientation. We consider five key approaches and models associated with them and, in the course of reviewing each approach, five key issues. First, we take up modularity theory itself, as recently revised by Lee and Spelke (Cognitive Psychology, 61, 152-176, 2010a; Experimental Brain Research, 206, 179-188, 2010b). In this context, we discuss issues concerning the basic distinction between geometry and features. Second, we review the view-matching approach (Sturzl, Cheung, Cheng, & Zeil, Journal of Experimental Psychology: Animal Behavior Processes, 34, 1-14, 2008). In this context, we highlight the possibility of cross-species differences, as well as commonalities. Third, we review an associative theory (Miller & Shettleworth, Journal of Experimental Psychology: Animal Behavior Processes, 33, 191-212, 2007; Journal of Experimental Psychology: Animal Behavior Processes, 34, 419-422, 2008). In this context, we focus on phenomena of cue competition. Fourth, we take up adaptive combination theory (Newcombe & Huttenlocher, 2006). In this context, we focus on discussing development and the effects of experience. Fifth, we examine various neurally based approaches, including frameworks proposed by Doeller and Burgess (Proceedings of the National Academy of Sciences of the United States of America, 105, 5909-5914, 2008; Doeller, King, & Burgess, Proceedings of the National Academy of Sciences of the United States of America, 105, 5915-5920, 2008) and by Sheynikhovich, Chavarriaga, Strosslin, Arleo, and Gerstner (Psychological Review, 116, 540-566, 2009). In this context, we examine the issue of the neural substrates of spatial navigation. We conclude that none of these approaches can account for all of the known phenomena concerning the use of geometry in reorientation and clarify what the challenges are for each approach. PMID- 23456414 TI - Analysis of the prevalence of cataracts and glaucoma in systemic lupus erythematosus and evaluation of the rheumatologists' practice for the monitoring of glucocorticoid eye toxicity. AB - Chronic glucocorticoid (GC) therapy is associated with an increased risk of developing cataracts and glaucoma, and recommendations have been developed for monitoring these side effects in patients with rheumatic diseases. The aim of this study was to assess the prevalence of cataracts and glaucoma and the adherence to the existing recommendations for monitoring eye toxicity of chronic GC therapy among systemic lupus erythematosus (SLE) patients in routine clinical practice. Clinical charts of 170 patients were examined, and 34 (20%) of them never underwent an eye assessment. The remaining 136 underwent an eye assessment with an interval of 75 +/- 61.7 months. Only 45 (33%) had received an evaluation during the previous 12 months. All these 170 patients were taking chronic CG therapy at a mean daily dose of 5.4 +/- 2.4 mg prednisone and a mean cumulative dose of 27.6 +/- 20.5 g. Out of the 136 patients with at least one eye assessment, cataracts were observed in 39 patients (29%) and glaucoma in 4 patients (3%). Cataracts were diagnosed at a mean age of 46.5 +/- 10 years; the development of cataracts was associated with age, disease duration, and cumulative GC dose. Glaucoma was diagnosed at a mean age of 40.5 +/- 16 years; due to the small number of patients, no correlations were made. The prevalence of cataracts and glaucoma is higher than in the general population, and these conditions occur early in the life of SLE patients. An association between GC and cataracts is confirmed. The adherence to recommendations is suboptimal as only 33% of patients underwent an eye assessment over the previous 12 months. These data reinforce the need to improve adherence to recommendations for eye monitoring among SLE patients under chronic therapy with GC. PMID- 23456415 TI - Systemic lupus erythematosus (SLE) at the Kenyatta National Hospital. AB - Systemic lupus erythematosus (SLE) is a complex disease with varied clinical presentation and autoantibody production. It has previously been reported as rare in Black Africans. We established a Rheumatology clinic at the Kenyatta National Hospital in April 2010, and a 1 year audit of this clinic was carried out in September 2011. This is a report of this audit of patients who met the American College of Rheumatology (ACR) criteria for SLE. Thirteen patients met the ACR criteria; their mean age was 34 years, and they were all female. The commonest manifestations were malar rash and arthritis in 69.2 %. Antinuclear antibody was present in 79.6 %, and anti-dsDNA was present in 38.5 %. None of them had human immunodeficiency virus infection; 30 % had other comorbidities (hypertension, diabetes, and renal failure). Thirty percent also had an infection during this period. All these 13 were on prednisolone and 92 % of them were on hydroxychloroquine. There was no reported death during the study period. This confirms the presence of SLE in patients in Kenya who meet the ACR criteria. PMID- 23456416 TI - Spectroscopic and computational study of a naphthalene derivative as colorimetric and fluorescent sensor for bioactive anions. AB - The anion recognition property of a naphthalene based receptor (L) was investigated by naked-eye, UV-Vis, fluorescence, (1)H NMR and computational methods. The receptor L showed fluoride selective naked-eye detectable colorimetric and UV-Vis spectral changes over other tested anions due to the formation of hydrogen bonding complex in 1:1 stoichiometry and/or deprotonation between fluoride and the receptor. Interestingly, the fluorescence of L was quenched by fluoride but enhanced by acetate. PMID- 23456417 TI - Study on the fluorescence quenching reaction of amitriptyline and clomipramine hydrochlorides with eosin Y and its analytical application. AB - Amitriptyline.HCl (AMI) and clomipramine.HCl (CMI) react with eosin Y (EY) in pH 3.8 NaAc-AcH buffer solution to form ion association complex which results in quenching of fluorescence of EY and appearance of a new resonance Rayleigh scattering (RSS) spectrum at 620 nm. The spectral characteristics of absorption, fluorescence and RSS spectra have been investigated. The factors influencing the reaction were studied and optimum conditions for the reaction have been determined. Based on fluorescence quenching, a simple and sensitive spectrofluorimetric method for determination of AMI and CMI has been developed. The fluorescence quenching intensity was measured at 550 nm using an excitation wavelength of 310 nm. The calibration graph was found to be rectilinear in the range 0.08-2.0 MUg mL(-1) with detection limit of 0.017 MUg mL(-1) for AMI and 0.06-2.0 MUg mL(-1) with detection limit of 0.015 MUg mL(-1) for CMI. The method can be satisfactorily applied to the determination of AMI and CMI in tablets without interference from commonly occurring exicipients. The recovery and RSD values obtained indicate good accuracy and precision of the method. The mechanism of the reaction and fluorescence quenching has also been discussed. PMID- 23456418 TI - Study of fluorescence quenching in aluminum-doped ceria nanoparticles: potential molecular probe for dissolved oxygen. AB - This work investigates a novel usage of aluminum-doped ceria nanoparticles (ADC NPs), as the molecular probe in optical fluorescence quenching for sensing the dissolved oxygen (DO). Cerium oxide (ceria) nanoparticles can be considered one of the most unique nanomaterials that are being studied today due to the diffusion and reactivity of oxygen vacancies in ceria, which contributes to its high oxygen storage capability. Aluminum can be considered a promising dopant to increase the oxygen ionic conductivity in ceria nanoparticles which can improve the sensitivity of ceria nanoparticles to DO. The fluorescence intensity of ADC NPs, synthesized via chemical precipitation, is found to have a strong inverse relationship with the DO concentration in aqueous solutions. Stern-Volmer constant of ADC-NPs at room temperature is determined to be 454.6 M(-1), which indicates that ADC-NPs have a promising sensitivity to dissolved oxygen, compared to many presently used fluorophores. In addition, Stern-Volmer constant is found to have a relatively small dependence on temperature between 25 degrees C to 50 degrees C, which shows excellent thermal stability of ADC-NPs sensitivity. Our work suggests that ADC-NPs, at 6 nm, are the smallest diameter DO molecular probes between the currently used optical DO sensors composed of different nanostructures. This investigation can improve the performance of fluorescence quenching DO sensors for industrial and environmental applications. PMID- 23456419 TI - A feasible add-on upgrade on a commercial two-photon FLIM microscope for optimal FLIM-FRET imaging of CFP-YFP pairs. AB - Fluorescence lifetime imaging microscopy (FLIM) based on time-correlated single photon counting (TCSPC) is a widely used method for fluorescence resonance energy transfer (FRET). Here we report a feasible add-on approach to upgrade a commercial two-photon FLIM microscope into a single-photon FLIM microscope which provides optimal FLIM-FRET imaging of FRET pairs consisting of cyan fluorescent proteins (CFPs) as the donor and yellow fluorescent proteins (YFPs) as the acceptor. The capability of the upgraded system is evaluated and discussed, and the imaging performance of the system is demonstrated using FLIM-FRET experiments with a representative CFP-YFP FRET pair (mCerulean-mCitrine). PMID- 23456420 TI - The challenges of assessing osteoarthritis and postoperative pain in dogs. AB - The challenge of measuring pain in veterinary medicine is compounded by the lack of fully validated, reliable methods to measure and assess pain in nonverbal patients. In human medicine, there are numerous, validated pain assessment tools (PATs) for assessing various, specific types of pain. The advances in human medicine pain management and numerous validated pain scales should serve as incentives and templates to facilitate similar advances in the development of validated PATs for use in dogs (and other species). The limited number of canine PATs constrains our ability to adequately and reliably assess pain. Improving the ability to quantify osteoarthritis and postoperative pain in dogs would enhance the development of analgesics for animals, advance the management of animal pain, facilitate the use of animal pain models in preclinical trials for human analgesics, and provide insight into the quantification of pain responses in humans who lack the ability to adequately communicate. This review describes the need for practical, valid, and reliable PATs for use in veterinary patients and discusses some currently available PATs commonly used to evaluate acute and chronic pain in dogs. PMID- 23456421 TI - Prevalence and molecular characterization of porcine enteric caliciviruses and first detection of porcine kobuviruses in US swine. AB - The prevalence of porcine sapoviruses (SaVs) and noroviruses (NoVs) in nursing piglets on three pig farms in Ohio was studied. Fecal samples (n = 139) were collected from individual pigs and screened for caliciviruses by RT-PCR. Phylogenetic analysis was conducted using partial sequences of the RNA polymerase region. Three different SaV genogroups, including a newly emerging one (DO19 Korea-like) were detected. No NoVs were detected. Kobuviruses, emerging members of the family Picornaviridae, were detected by primers designed for SaV. To our knowledge, this is the first report of porcine DO19 Korea-like SaV and kobuvirus in the United States. PMID- 23456422 TI - A consensus envelope protein domain III can induce neutralizing antibody responses against serotype 2 of dengue virus in non-human primates. AB - We have previously demonstrated that vaccination with a subunit dengue vaccine containing a consensus envelope domain III with aluminum phosphate elicits neutralizing antibodies against all four serotypes of dengue virus in mice. In this study, we evaluated the immunogenicity of the subunit dengue vaccine in non human primates. After vaccination, monkeys that received the subunit vaccine with aluminum phosphate developed a significantly strong and long-lasting antibody response. A specific T cell response with cytokine production was also induced, and this correlated with the antibody response. Additionally, neutralizing antibodies against serotype 2 were detected in two of three monkeys. The increase in serotype-2-specific antibody titers and avidity observed in these two monkeys suggested that a serotype-2-biased antibody response occurs. These data provide evidence that a protective neutralizing antibody response was successfully elicited in non-human primates by the dengue subunit vaccine with aluminum phosphate adjuvant. PMID- 23456423 TI - Molecular characterization of HetRV8-ir1, a partitivirus of the invasive conifer pathogenic fungus Heterobasidion irregulare. AB - The Heterobasidion annosum (Fr.) Bref. complex includes some of the most destructive conifer pathogenic fungi in the Boreal forest region. H. irregulare, formerly known as the North American pine type of H. annosum, was introduced from North America into Italy during the Second World War and occurs as an invasive pathogen in Pinus pinea stands together with the native European species H. annosum sensu stricto. We describe the complete nucleotide sequence of a new putative partitivirus from an Italian strain of H. irregulare. The bisegmented genome of HetRV8-ir1 encodes an RNA-dependent RNA polymerase of 704 aa and a capsid protein of 638 aa. The polymerase and capsid aa sequences are relatively similar (59-78 %) to those of Fusarium poae virus 1, Pleurotus ostreatus virus 1, and grapevine-associated partitivirus 1. HetRV8-ir1 is the first virus described from H. irregulare, and it is distantly related to previously known partitiviruses of Heterobasidion species. PMID- 23456426 TI - The availability of allograft skin for large scale medical emergencies in the United States. AB - Mass injury events present a unique medical challenge. Effective communications and coordination of resources including trained personnel as well as supplies and equipment are critical in these emergent situations. In the U.S., the availability of allograft skin plays a lifesaving role in treatment of burn injuries. Maintaining an adequate and readily available supply of this precious resource is critical for treatment of multiple injuries in the event of a national emergency. Allograft skin has historically been a local resource but contraction and consolidation of tissue banks has given rise to a small number of more nationally focused skin suppliers. While distinctly separate and essentially competing entities, these organizations come together in times of crisis to serve patients in need. Emergency preparations must include the ability to monitor and coordinate the capabilities of these organizations to supply lifesaving tissue grafts in times of national and global disasters. PMID- 23456425 TI - CD73+ adipose-derived mesenchymal stem cells possess higher potential to differentiate into cardiomyocytes in vitro. AB - Adipose-derived mesenchymal stem cells (ADMSCs) are an attractive adult-derived stem cell population for cardiovascular repair. ADMSCs are heterogeneous cell populations with pluripotent capacity to differentiate into different types of cells. In the present study, we investigated the biological characteristics and differentiation potential of CD73-positive (CD73(+)) and CD73-negative (CD73(-)) ADMSCs. Our results show that in terms of morphological shape, CD73(+)-ADMSCs are mainly small-sized cells, whereas CD73(-)-ADMSCs are big-sized cells; both subpopulations can equally differentiate into adipocytes and osteoblasts in vitro. However, the CD73(+)-ADMSCs possess a higher potential to differentiate into cardiomyocytes than the CD73(-)-ADMSCs. The expression of the cardiac specific genes, cTnT, Gata4, and Nkx2.5, is much higher in the CD73(+)-ADMSCs than in the CD73(-)-ADMSCs. Furthermore, Nanog expression at both the mRNA and protein levels is significantly higher in CD73(+)-ADMSCs than in CD73(-)-ADMSCs, suggesting that CD73(+)-ADMSCs are an undifferentiated subpopulation that can differentiate into cardiomyocytes in vitro more efficiently. Therefore, this study facilitates a better understanding of the differentiation of the ADMSCs subgroups and attempts to identify if CD73 is a useful marker for sorting and purifying the subpopulation of ADMSCs with a higher capacity for differentiation into cardiomyocytes. PMID- 23456427 TI - Effect of fluoride and low versus high levels of dietary calcium on mRNA expression of osteoprotegerin and osteoprotegerin ligand in the bone of rats. AB - The ratio of osteoprotegerin ligand (OPGL) to osteoprotegerin (OPG) determines the delicate balance between bone resorption and synthesis. The main objective of the present study is to investigate the possible role of OPGL and OPG in the bone metabolism of rats exposed to fluoride and the protective or aggravating effect of calcium (Ca). In a 6-month study, 270 weanling male Sprague-Dawley rats weighing between 70 and 90 g were divided randomly into six groups of 45 rats in each group. Three groups (groups I, III, and V)served as controls and drank deionized water and were fed purified rodent diets containing either 1,000 mg Ca/kg (low Ca), 5,000 mg Ca/kg (normal Ca), or 20,000 mg Ca/kg (high Ca). The three experimental groups (groups II, IV, and VI) were given the same diets but they drank water containing 100 mg F ion/L (from NaF). Every 2 months 15 rats were randomly selected from each group and sacrificed for the study. The ratio of OPGL mRNA to OPG mRNA was significantly increased by the sixth month in the distal femur joints of the F-exposed rats. Serum tartrate-resistant acid phosphatase activity and serum calcitonin activity in the F-exposed groups was increased, although changes were not apparent in the serum alkaline phosphatase or Gla-containing proteins, especially in the low calcium and high calcium diet F exposed groups. The results indicated that OPG and OPGL may play important roles in skeletal fluorosis, and that fluoride may enhance osteoclast formation and induce osteoclastic bone destruction. A high Ca diet did not play a protective role, but rather may aggravate the damage of fluoride. PMID- 23456428 TI - Successful percutaneous coronary intervention for chronic total occlusion of right coronary artery in patient with dextrocardia. AB - Situs inversus with dextrocardia is rare congenital anomaly. Coronary artery disease in such patients is quite rare. We reported a 52-year-old man with dextrocardia and chronic total occlusion at the proximal right coronary artery just after conus branch and severe stenosis at the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with stenting of total occluded right coronary artery and simultaneously stenting of the proximal left anterior descending artery. PMID- 23456429 TI - Percutaneous coronary intervention of all three coronary arteries originating from single coronary artery arising from the right sinus. AB - Anomalous origin of left coronary artery from right sinus of Valsalva (RSV) is extremely rare when not associated with other cardiac anomalies. We describe a case of single coronary artery arising from the RSV in a 75-year-old male patient with coronary heart disease. Angiography revealed significant atherosclerotic stenosis in all the three coronary arteries. This report highlights the feasibility and safety of multivessel percutaneous coronary intervention (PCI) in this rare anomaly and discusses the important technical considerations to be kept in mind while attempting such a case. This is the first report in the literature describing PCI in all the vessels of a single coronary trunk arising from RSV. PMID- 23456430 TI - Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. AB - The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and resistance to therapy in prostate cancer and other solid tumors. Given the significance of the PI3K/Akt/mTOR pathway in integrating cell survival signals and the high prevalence of activating PI3K/Akt/mTOR pathway alterations in prostate cancer, inhibitors of this pathway have great potential for clinical benefit. Here, we review the role of the PI3K/Akt/mTOR pathway in prostate cancer and discuss the potential use of pathway inhibitors as single agents or in combination in the evolving treatment landscape of castration-resistant prostate cancer. PMID- 23456424 TI - German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors. AB - INTRODUCTION: Over the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable ("low risk") papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages. METHODS: The present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization. RESULTS: The practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases. CONCLUSION: These evidence-based recommendations for surgical therapy reflect various "treatment corridors" that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk. PMID- 23456431 TI - Impact of opioid pharmacotherapy on arterial stiffness and vascular ageing: cross sectional and longitudinal studies. AB - Whilst there is a small literature on the cardiovascular toxicity of opiates, there is no detailed antemortem data on non-cardiovascular patient populations. A cross-sectional and longitudinal naturalistic observational study was performed comparing methadone (N = 71)-, buprenorphine (N = 593)-, naltrexone (N = 23) treated patients with controls (N = 576) on indices of arterial stiffness and vascular age by Pulse Wave Analysis in primary care, 2006-2011. Controls were younger 29.96 +/- 0.45 (mean +/- SEM) vs. 34.00 +/- 0.34-39.22 +/- 1.11 years (all P < 0.005) and had fewer smokers (15.9 % vs. 86.9 %-92.96 %, all P < 0.0001). The sex ratio was similar (69.6 vs. 67.7 % male, P = 0.46). These baseline differences were controlled for by multiple regression. Linear regression of vascular age, central augmentation pressure, central augmentation index and other measures against chronologic age showed significant protective effects by treatment group against the treatment standard of methadone, in both sexes in additive and interactive models (all P < 0.02). Interactive terms in treatment type remained significant including all conventional risk factors accounting for differing opiate exposures. The principal findings from multiple regression were confirmed in the time series analysis up to 5 years by repeated measures nonlinear regression. These studies show that the deleterious impact of chronic opiate pharmacotherapy on vascular age and arterial stiffness varies significantly by treatment type. PMID- 23456432 TI - The exportability of the ACOSOG Z0011 criteria for omitting axillary lymph node dissection after positive sentinel lymph node biopsy findings: a multicenter study. AB - PURPOSE: To determine the exportability of the criteria defined by the American College of Surgeons Oncology Group Z0011 trial for selecting patients who are eligible for omitting completion axillary lymph node dissection (cALND) after a positive sentinel lymph node (SLN) biopsy result and to investigate whether not following the Z0011 criteria might affect patient outcomes. METHODS: From a multicenter database, we selected 188 patients with positive SLNs and then excluded patients with positive SLNs on immunohistochemistry only. We retrospectively applied the Z0011 criteria and grouped the patients as eligible or ineligible for omitting cALND. The eligible group was compared with the cohort included in the Z0011 trial and with the ineligible group. Kaplan-Meier survival curves were calculated for each group, and univariate analyses assessed associations between the groups and clinicopathological variables. RESULTS: The final analysis involved 125 patients with positive SLNs. Eighty-seven patients (69.6 %) were potentially eligible for omitting cALND. The estrogen receptor status, T stage, grade, and number of positive non-SLNs were not statistically different between the eligible group and the Z0011 cohort. The ineligible group had significantly more positive non-SLNs (P = 0.01) and a lower 5-year overall survival rate than the eligible group (P < 0.001). CONCLUSIONS: The similarity of clinical characteristics between the Z0011 trial cohort and our eligible group confirms the exportability of these criteria to another population. The worse prognosis of patients who did not meet the Z0011 criteria suggests prudence before disregarding or enlarging broadening the indications for omitting cALND. PMID- 23456433 TI - Probing the micromechanics of a multi-contact interface at the onset of frictional sliding. AB - Digital Image Correlation is used to study the micromechanics of a multi-contact interface formed between a rough elastomer and a smooth glass surface. The in plane elastomer deformation is monitored during the incipient sliding regime, i.e. the transition between static and sliding contact. As the shear load is increased, an annular slip region, in coexistence with a central stick region, is found to progressively invade the contact. From the interfacial displacement field, the tangential stress field can be further computed using a numerical inversion procedure. These local mechanical measurements are found to be correctly captured by Cattaneo and Mindlin (CM)'s model. However, close comparison reveals significant discrepancies in both the displacement and stress fields that reflect the oversimplifying hypothesis underlying CM's scenario. In particular, our optical measurements allow us to exhibit an elasto-plastic-like friction constitutive equation that differs from the rigid-plastic behavior assumed in CM's model. This local constitutive law, which involves a roughness related length scale, is consistent with the model of Bureau et al. (Proc. R. Soc. London, Ser. A 459, 2787 (2003)) derived for homogeneously loaded macroscopic multi-contact interfaces, thus extending its validity to mesoscopic scales. PMID- 23456434 TI - Surface instability of a gel disc in swelling. AB - The swelling of a soft disc made of polymeric gel and attached to a fixed substrate is modeled using a variational method in nonlinear elasticity. A linear stability analysis is performed to detect the onset of a surface instability. An exact solution of the perturbed disc is found, and both the threshold values of the growth rates and the surface morphology are derived analytically. PMID- 23456435 TI - Altered calsequestrin glycan processing is common to diverse models of canine heart failure. AB - Calsequestrin-2 (CSQ2) is a resident glycoprotein of junctional sarcoplasmic reticulum that functions in the regulation of SR Ca(2+) release. CSQ2 is biosynthesized in rough ER around cardiomyocyte nuclei and then traffics transversely across SR subcompartments. During biosynthesis, CSQ2 undergoes N linked glycosylation and phosphorylation by protein kinase CK2. In mammalian heart, CSQ2 molecules subsequently undergo extensive mannose trimming by ER mannosidase(s), a posttranslational process that often regulates protein breakdown. We analyzed the intact purified CSQ2 from mongrel canine heart tissue by electrospray mass spectrometry. The average molecular mass of CSQ2 in normal mongrel dogs was 46,306 +/- 41 Da, corresponding to glycan trimming of 3-5 mannoses, depending upon the phosphate content. We tested whether CSQ2 glycan structures would be altered in heart tissue from mongrel dogs induced into heart failure (HF) by two very different experimental treatments, rapid ventricular pacing or repeated coronary microembolizations. Similarly dramatic changes in mannose trimming were found in both types of induced HF, despite the different cardiomyopathies producing the failure. Unique to all samples analyzed from HF dog hearts, 20-40 % of all CSQ2 contained glycans that had minimal mannose trimming (Man9,8). Analyses of tissue samples showed decreases in CSQ2 protein levels per unit levels of mRNA for tachypaced heart tissue, also indicative of altered turnover. Quantitative immunofluorescence microscopy of frozen tissue sections suggested that no changes in CSQ2 levels occurred across the width of the cell. We conclude that altered processing of CSQ2 may be an adaptive response to the myocardium under stresses that are capable of inducing heart failure. PMID- 23456436 TI - In vitro and in vivo evaluation of amorphous solid dispersions generated by different bench-scale processes, using griseofulvin as a model compound. AB - Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical industry to improve bioavailability for poorly water-soluble compounds. Spray-drying is the most common process involved in the manufacturing of ASD material. However, spray-drying involves a high investment of material quantity and time. Lower investment manufacturing processes such as fast evaporation and freeze-drying (lyophilization) have been developed to manufacture ASD at the bench level. The general belief is that the overall performance of ASD material is thermodynamically driven and should be independent of the manufacturing process. However, no formal comparison has been made to assess the in vivo performance of material generated by different processes. This study compares the in vitro and in vivo properties of ASD material generated by fast evaporation, lyophilization, and spray-drying methods using griseofulvin as a model compound and hydroxypropyl methylcellulose acetate succinate as the polymer matrix. Our data suggest that despite minor differences in the formulation release properties and stability of the ASD materials, the overall exposure is comparable between the three manufacturing processes under the conditions examined. These results suggest that fast evaporation and lyophilization may be suitable to generate ASD material for oral evaluation. However, caution should be exercised since the general applicability of the present findings will need to be further evaluated. PMID- 23456437 TI - Do statins cause diabetes? AB - A wealth of evidence has established that cholesterol-lowering statin drugs, widely used for the prevention of cardiovascular disease, do increase the risk of new-onset diabetes, possibly by impairing pancreatic beta cell function and decreasing peripheral insulin sensitivity. Groups at particular risk include the elderly, women, and Asians. The diabetogenic effect of statins appear directly related to statin dose and the degree of attained cholesterol lowering. Statins can cause hyperinsulinemia even in the absence of hyperglycemia and the potential mitogenic effects and implications of prolonged hyperinsulinemia are discussed. Suggestions are made as to how physicians might avert the hyperinsulinemic and diabetogenic effects of statin therapy in clinical practice, and modulate the detrimental effects of these drugs on exercise performance. Finally, long-term studies are needed to determine if the deleterious hyperinsulinemic and diabetogenic effects of statin therapy undermine the beneficial cardiovascular disease risk outcomes in various segments of the population. PMID- 23456438 TI - Comparison of the effects between animal-derived trypsin and recombinant trypsin on human skin cells proliferation, gene and protein expression. AB - Animal-derivative free reagents are preferred in skin cell culture for clinical applications. The aim of this study was to compare the performance and effects between animal-derived trypsin and recombinant trypsin for skin cells culture and expansion. Full thickness human skin was digested in 0.6 % collagenase for 6 h to liberate the fibroblasts, followed by treatment with either animal-derived trypsin; Trypsin EDTA (TE) or recombinant trypsin; TrypLE Select (TS) to liberate the keratinocytes. Both keratinocytes and fibroblasts were then culture-expanded until passage 2. Trypsinization for both cell types during culture-expansion was performed using either TE or TS. Total cells yield was determined using a haemocytometer. Expression of collagen type I, collagen type III (Col-III), cytokeratin 10, and cytokeratin 14 genes were quantified via RT-PCR and further confirmed with immunocytochemical staining. The results of our study showed that the total cell yield for both keratinocytes and fibroblasts treated with TE or TS were comparable. RT-PCR showed that expression of skin-specific genes except Col III was higher in the TS treated group compared to that in the TE group. Expression of proteins specific to the two cell types were confirmed by immunocytochemical staining in both TE and TS groups. In conclusion, the performance of the recombinant trypsin is comparable with the well-established animal-derived trypsin for human skin cell culture expansion in terms of cell yield and expression of specific cellular markers. PMID- 23456440 TI - Warfarin for prevention of thrombosis among long-term care residents with atrial fibrillation: evidence of continuing low use despite consideration of stroke and bleeding risk. AB - OBJECTIVES: The aims of the study were to evaluate usage rates of warfarin in stroke prophylaxis and the association with assessed stages of stroke and bleeding risk in long-term care (LTC) residents with atrial fibrillation (AFib). METHODS: A cross-sectional analysis of two LTC databases (the National Nursing Home Survey [NNHS] 2004 and an integrated LTC database: AnalytiCare) was conducted. The study involved LTC facilities across the USA (NNHS) and within 19 states (AnalytiCare). It included LTC residents diagnosed with AFib (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnostic code 427.3X). Consensus guideline algorithms were used to classify residents by stroke risk categories: low (none or 1+ weak stroke risk factors), moderate (1 moderate), high (2+ moderate or 1+ high). Residents were also classified by number of risk factors for bleeding (0-1, 2, 3, 4+). Current use of warfarin was assessed. A logistic regression model predicted odds of warfarin use associated with the stroke and bleeding risk categories. RESULTS: The NNHS and AnalytiCare databases had 1,454 and 3,757 residents with AFib, respectively. In all, 34 % and 45 % of residents with AFib in each respective database were receiving warfarin. Only 36 % and 45 % of high-stroke-risk residents were receiving warfarin, respectively. In the logistic regression model for the NNHS data, when compared with those residents having none or 1+ weak stroke risk and 0-1 bleeding risk factors, the odds of receiving warfarin increased with stroke risk (odds ratio [OR] = 1.93, p = 0.118 [1 moderate risk factor]; OR = 3.19, p = 0.005 [2+ moderate risk factors]; and OR = 8.18, p <= 0.001 [1+ high risk factors]) and decreased with bleeding risk (OR = 0.83, p = 0.366 [2 risk factors]; OR = 0.47, p <= 0.001 [3 risk factors]; OR = 0.17, p <= 0.001 [4+ risk factors]). A similar directional but more constrained trend was noted for the AnalytiCare data: only 3 and 4+ bleeding risk factors were significant. CONCLUSIONS: The results from two LTC databases suggest that residents with AFib have a high risk of stroke. Warfarin use increased with greater stroke risk and declined with greater bleeding risk; however, only half of those classified as appropriate warfarin candidates were receiving guideline recommended anticoagulant prophylaxis. PMID- 23456441 TI - A case of simultaneous neuromyelitis optica spectrum disorder and subacute combined degeneration. PMID- 23456439 TI - Follistatin as potential therapeutic target in prostate cancer. AB - Follistatin is a single-chain glycosylated protein whose primary function consists in binding and neutralizing some members of the transforming growth factor-beta superfamily such as activin and bone morphogenic proteins. Emerging evidence indicates that this molecule may also play a role in the malignant progression of several human tumors including prostate cancer. In particular, recent findings suggest that, in this tumor, follistatin may also contribute to the formation of bone metastasis through multiple mechanisms, some of which are not related to its specific activin or bone morphogenic proteins' inhibitory activity. This review provides insight into the most recent advances in understanding the role of follistatin in the prostate cancer progression and discusses the clinical and therapeutic implications related to these findings. PMID- 23456442 TI - Neuroprotective effect of TAT PTD-Ngb fusion protein on primary cortical neurons against hypoxia-induced apoptosis. AB - Hypoxic-ischemic injury increases neuroglobin (Ngb) expression in the brain. In our previous study, we have generated a transactivator-of-transcription protein transduction domain-neuroglobin fusion protein (TAT PTD-Ngb) that successfully mediated exogenous Ngb expression in the primary neurons. In this study, we further investigated the role of TAT PTD-Ngb in protecting neurons against hypoxia-induced apoptosis and explored the possible mechanism. The primary cultured neurons were divided into four groups: (1) the normal group (no hypoxic injury); (2) the vehicle group (vehicle treatment and hypoxia injury); (3) the TAT PTD-Ngb group (TAT PTD-Ngb treatment and hypoxia injury); and (4) the Ngb group (Ngb treatment and hypoxia injury). Translocation of TAT PTD-Ngb into neurons was detected using fluorescent immunostaining against His-tag as early as 30 min after incubation. MTT assay showed that the TAT PTD-Ngb group had significantly increased cell viability compared to the vehicle or Ngb group after hypoxia. The result of transmission electron microscopy (TEM) also displayed rescued ultrastructure in TAT PTD-Ngb neurons compared to that of apoptotic neurons. In addition, TAT PTD-Ngb neurons showed significantly increased expression of anti-apoptotic Bcl-2 protein and decreased activities of caspase-3 and caspase-9 in response to hypoxia. These results suggest that TAT PTD-Ngb fusion protein protects primary cortical neurons against hypoxia-induced injury possibly through suppressing mitochondria apoptotic pathway. PMID- 23456443 TI - Superficial siderosis of central nervous system in patients with brachial plexus injury. PMID- 23456444 TI - Brain metastases in colorectal cancer patients: less rare than before. PMID- 23456445 TI - Association of thromboxane A2 receptor gene polymorphisms with cerebral infarction in a Chinese population. AB - Platelet aggregation is crucial for the development of cerebral infarction (CI) and it is markedly increased due to the binding of thromboxane A2 (TXA2) to its receptor (TXA2R). Therefore, TXA2R plays a central role in the pathogenesis of atherosclerosis and thrombosis. This study aimed to investigate the relationship between human TXA2R gene single nucleotide polymorphisms (SNPs) and non cardiogenic CI in a Chinese cohort. Two SNPs, rs768963 and rs4523, located in the regulatory and coding regions of TXA2R gene, respectively, were examined in DNA samples from 407 Chinese patients with CI and 270 controls. 407 CI was categorized into subtypes using Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. There was no significant association between rs4523 variants and CI. However, there was a significant difference in the overall distribution of genotypes and dominant/recessive models of rs768963 between CI and control groups. In addition, multiple logistic regression analysis revealed that the C allele of rs768963 was significantly associated with total CI (P = 0.023), large artery atherosclerosis subtype (P = 0.009), small artery occlusion subtype (P = 0.044) after adjusting for confounding factors (odds ratio = 1.533, 1.918 and 1.573, respectively). We conclude that TXA2R rs768963 polymorphism is associated with CI in a Chinese population. PMID- 23456446 TI - Role of microangiopathy in diabetic cardiomyopathy. AB - Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in altering cardiac structure and function. Three major defects, such as endothelial dysfunction, alteration in the production/release of hormones, and shift in metabolism of smooth muscle cells, have been suggested to produce damage to the small arteries and capillaries (microangiopathy) due to hyperglycemia, and promote the development of diabetic cardiomyopathy. These factors may either act alone or in combination to produce oxidative stress as well as changes in cellular signaling and gene transcription, which in turn cause vasoconstriction and structural remodeling of the coronary vessels. Such alterations in microvasculature produce hypoperfusion of the myocardium and thereby lower the energy status resulting in changes in Ca(2+)-handling, apoptosis, and decreased cardiac contractile force. This article discusses diabetes-induced mechanisms of microvascular damage leading to cardiac dysfunction that is characterized by myocardial dilatation, cardiac hypertrophy as well as early diastolic and late systolic defects. Metabolic defects and changes in neurohumoral system due to diabetes, which promote disturbances in vascular homeostasis, are highlighted. In addition, increase in the vulnerability of the diabetic heart to the development of heart failure and the signaling pathways integrating nuclear factor kappaB and protein kinase C in diabetic cardiomyopathy are also described for comparison. PMID- 23456448 TI - Weather factors in the short-term forecasting of daily ambulance calls. AB - The daily ambulance demand for Hong Kong is rising, and it has been shown that weather factors (temperature and humidity) play a role in the demand for ambulance services. This study aimed at developing short-term forecasting models of daily ambulance calls using the 7-day weather forecast data as predictors. We employed the autoregressive integrated moving average (ARIMA) method to analyze over 1.3 million cases of emergency attendance in May 2006 through April 2009 and the 7-day weather forecast data for the same period. Our results showed that the ARIMA model could offer reasonably accurate forecasts of daily ambulance calls at 1-7 days ahead of time and with improved accuracy by including weather factors. Specifically, the inclusion of average temperature alone in our ARIMA model improved the predictability of the 1-day forecast when compared to that of a simple ARIMA model (8.8% decrease in the root mean square error, RMSE=53 vs 58). The improvement in the 7-day forecast with average temperature as a predictor was more pronounced, with a 10% drop in prediction error (RMSE=62 vs 69). These findings suggested that weather forecast data can improve the 1- to 7-day forecasts of daily ambulance demand. As weather forecast data are readily accessible from Hong Kong Observatory's official website, there is virtually no cost to including them in the ARIMA models, which yield better prediction for forward planning and deployment of ambulance manpower. PMID- 23456447 TI - Animal models of insulin resistance and heart failure. AB - The incidence of heart failure (HF) and diabetes mellitus is rapidly increasing and is associated with poor prognosis. In spite of the advances in therapy, HF remains a major health problem with high morbidity and mortality. When HF and diabetes coexist, clinical outcomes are significantly worse. The relationship between these two conditions has been studied in various experimental models. However, the mechanisms for this interrelationship are complex, incompletely understood, and have become a matter of considerable clinical and research interest. There are only few animal models that manifest both HF and diabetes. However, the translation of results from these models to human disease is limited, and new models are needed to expand our current understanding of this clinical interaction. In this review, we discuss mechanisms of insulin signaling and insulin resistance, the clinical association between insulin resistance and HF, and its proposed pathophysiologic mechanisms. Finally, we discuss available animal models of insulin resistance and HF and propose requirements for future new models. PMID- 23456449 TI - Psychiatric presentations/manifestations of medical illnesses. AB - Psychiatry is clearly an integral part of medicine. With a history and physical exam (called the mental status exam in psychiatry), appropriate laboratory or imaging studies, a differential diagnosis is made. If a specific DSM-IV-TR diagnosis is made, then the treatment will naturally follow. The diagnoses are scientifically established with good validity, specificity, sensitivity and inter rater reliability. Similarly the treatments are established through scientific research. However, sometimes medical illnesses may present with symptoms seemingly pointing to a psychiatric origin. Making a misdiagnosis can be quite problematic and dangerous for the patient. The opposite is also true, that psychiatric illnesses may present with symptoms implying a medical diagnostic origin. Finally, psychiatric patients may have more than one psychiatric diagnosis and in addition, a medical diagnosis too. A high degree of suspicion should always be entertained by the diagnosing physician, psychiatric or non psychiatric. This paper reviews the literature regarding these situations and then presents several clinical cases where this conundrum was present. Making the correct diagnosis was critical in the successful treatment outcome of each of the clinical cases. When asked to consult on a patient by non-psychiatric physicians, the psychiatrist must be careful to also look for non-psychiatric origins for the referring symptoms. It is important for psychiatrists to build on their medical knowledge from medical school and internship and continue to be kept abreast of confounding symptomatology. PMID- 23456450 TI - Exercise capacity and quality of life in patients with schizophrenia. AB - The aim of this study was to resolve the relationship between physical capacity (PC) and quality of life (Qol) in schizophrenic patients and healthy controls. 31 patients (PG: 18 male, 13 female) and a control group (CG) of 50 healthy subjects (15 male, 35 female) were involved. PC was assessed as peak oxygen uptake [VO2peak, (ml (min kgKG)(-1))] and power output expressed as watts per kilogram (W kg(-1)). Qol was assessed using the SF-36 questionnaire. Patients with schizophrenia showed reduced VO2peak (male: PG 29 +/- 5 vs. CG 44 +/- 10; female: PG 21 +/- 4 vs. CG 30 +/- 8) and power output (male: PG 2.04 +/- 0.47 vs. CG 3.43 +/- 0.70; female PG 1.40 +/- 0.28 vs. CG 2.43 +/- 0.52). Scales of the SF-36 questionnaire were lower in the PG. While in the CG correlations were found between PC and several subscales of Qol, this was not the case in the PG. The restricted PC seen in the PG showed no relation to their subjectively assessed worsened Qol, which would indicate that schizophrenic patients evaluate limitations arising from this differently than healthy control subjects. PMID- 23456451 TI - Effect of selenium and grape seed extract on indomethacin-induced gastric ulcers in rats. AB - Indomethacin (IND) is a non-steroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the protective effect of selenium (SEL), grape seed extract (GSE), and both on IND induced gastric mucosal ulcers in rats. Sprague-Dawley rats (200-250 g) were given SEL, GSE, and both by oral gavage for 28 days, and then gastric ulcers were induced by oral administration of 25 mg/kg IND. Malondialdehyde (MDA), non enzymatic (reduced glutathione, GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants, prostaglandin E2 (PGE2) in gastric mucosa, and serum tumor necrosis factor alpha (TNF-alpha) were measured. Moreover, gastric ulcer index and preventive index were determined. Indomethacin increased the gastric ulcer index, MDA, TNF-alpha, and decreased PGE2 and non enzymatic (GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants. Pretreatment with SEL, GSE, and both significantly decreased the gastric ulcer index, MDA, and TNF and increased antioxidants and PGE2. Histopathological observations confirm the gastric ulcer index and biochemical parameters. Selenium and GSE have a protective effect against IND induced gastric ulcers through prevention of lipid peroxidation, increase of GSH, activation of radical scavenging enzymes, PGE2 generation, and anti-inflammatory activity. Co-administration of GSE and SEL is more effective than GSE or SEL alone. PMID- 23456452 TI - Polymicrobial endocarditis involving Veillonella parvula in an intravenous drug user: case report and literature review of Veillonella endocarditis. PMID- 23456453 TI - The preparation and performance of a new polyurethane vascular prosthesis. AB - We investigated the performance of small-caliber polyurethane (PU) small-diameter vascular prosthesis generated using the electrospinning technique. PU was electrospun into small-diameter, small-caliber tubular scaffolds for potential application as vascular grafts. We investigated the effects of electrospinning conditions (solution concentration, mandrel rotation speed) on the microstructure and porosity of the scaffolds for the purpose of preparing scaffolds with optimum microstructures and properties. We evaluated the mechanical properties of the scaffolds by tensile tests and the cytotoxicity of the PU small-diameter, small caliber PU synthetic vascular graft by the MTT assay. The adhesion of endothelial cells to the PU scaffold was characterized by Hoechst staining and fluorescence microscopy, and we measured endothelial cell proliferation on the PU scaffold by the CCK-8 assay. We analyzed the prosthesis microstructure and endothelial cell morphology using scanning electron microscopy. With increasing PU concentration in the electrospinning solution, the fiber diameter of the vascular graft increased and the porosity decreased. In addition, with increasing electrospinning time, the wall thickness increased and the porosity decreased. We found that regular fiber orientation can be obtained by adjusting the rotation speed of the mandrel. Cell proliferation was not inhibited as the small-caliber PU synthetic vascular grafts showed little cytotoxicity. The endothelial cells had faster adherence to the PU scaffolds than to the PTFE surface during the initial contact. After prolonged cell culture, significantly higher endothelial cell proliferation rate was observed in the PU scaffold groups than the PTFE group. We obtained small-caliber PU vascular grafts with optimal fiber arrangement, excellent mechanical properties, and optimal biocompatibility by optimizing the electrospinning conditions. This study provides in vitro biocompatibility data that is helpful for the clinical application of the PU small-diameter, small-caliber PU vascular grafts. PMID- 23456454 TI - GABAergic pharmacological activity of propofol related compounds as possible enhancers of general anesthetics and interaction with membranes. AB - Phenol compounds, such as propofol and thymol, have been shown to act on the GABAA receptor through interaction with specific sites of this receptor. In addition, considering the high lipophilicity of phenols, it is possible that their pharmacological activity may also be the result of the interaction of phenol molecules with the surrounding lipid molecules, modulating the supramolecular organization of the receptor environment. Thus, in the present study, we study the pharmacological activity of some propofol- and thymol-related phenols on the native GABAA receptor using primary cultures of cortical neurons and investigate the effects of these compounds on the micro viscosity of artificial membranes by means of fluorescence anisotropy. The phenol compounds analyzed in this article are carvacrol, chlorothymol, and eugenol. All compounds were able to enhance the binding of [(3)H]flunitrazepam with EC50 values in the micromolar range and to increase the GABA-evoked Cl(-) influx in a concentration dependent manner, both effects being inhibited by the competitive GABAA antagonist bicuculline. These results strongly suggest that the phenols studied are positive allosteric modulators of this receptor. Chlorothymol showed a bell type effect, reducing its positive effect at concentrations >100 MUM. The concentrations necessary to induce positive allosteric modulation of GABAA receptor were not cytotoxic. Although all compounds were able to decrease the micro viscosity of artificial membranes, chlorothymol displayed a larger effect which could explain its effects on [(3)H]flunitrazepam binding and on cell viability at high concentrations. Finally, it is suggested that these compounds may exert depressant activity on the central nervous system and potentiate the effects of general anesthetics. PMID- 23456455 TI - Antibiotic resistance and molecular epidemiology of methicillin-resistant Staphylococcus aureus from lower respiratory tract: multi-resistance and high prevalence of SCCmec III type. AB - We sought to study antibiotic resistance and molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) from lower respiratory tracts of patients in Shanghai Pulmonary Hospital. Hundred and seven strains of MRSA were isolated from the patients of nine wards. The tests for antibiotic resistance (Kirby-Bauer paper dispersion method), the Panton-Valentine Leukocidin (PVL) and Staphyloccoccal Cassette Chromosome mec (SCCmec) genes (PCR), and homology analysis (32 randomly selected MRSA strains; pulsed-field gel electrophoresis) were carried out. All 107 strains were susceptible to vancomycin, teicoplanin, and linezolid, but highly or completely resistant to tetracycline, gentamicin, clindamycin, levofloxacin, azithromycin, erythromycin, trimethoprim/sulphamethoxazole, and ciprofloxacin. All 107 strains were negative for PVL gene. Most of the strains (81.3%) were SCCmec III type, while the SCCmec II and IV types were less frequent (15.9 and 2.8%, respectively). No SCCmec I or V types were detected. The homology analysis test showed that 32 MRSA strains could be divided into 4 groups: type A (25 strains), type B (5 strains), type C (1 strain), and type D (1 strain). The type A included 3 subtypes: A1 (17 strains), A2 (1 strain), and A3 (7 strains). Further, most of the strains were isolated from the same wards or units (e.g., intensive care unit or tuberculosis wards) within a short period of time, indicating an outbreak status. In conclusion, the observed MRSA from low respiratory tracts from patients at Shanghai Pulmonary Hospital were multiple-resistant, with the SCCmec III being the main documented genotype. PMID- 23456456 TI - Accumulation of noncrystalline cellulose in Physarum microplasmodia. AB - Physarum plasmodium lives as a slimy mass of protoplast in the dark fragments into small multinucleated microplasmodia (mPL) in a liquid medium. When mPL are exposed to several unfavorable environments, they transform into "spherules" with a cell wall. Using a synchronous spherule-induction system for mPL, we examined the effect of 2,6-dichlorobenzonitrile on the synthesis of cellulose in mPL, by observing mPL under a fluorescence microscope, and isolated cellulose from mPL to identify them morphologically under scanning electron microscopy. Moreover, we examined in vivo labeling to determine when cellulose synthesis is activated in step 2. We found that the nourishment medium in step 2 was essential for mPL prior to spherulation and that the conversion starts at 48 h in step 2 of our system. From the experiments using Updegraff reagent for the sedimentation of cellulose in the cell wall fraction from mPL, we propose that cellulose produced in mPL is likely noncrystalline cellulose. We conclude that mPL of multinucleated protoplasts without the cell wall structure synthesize cellulose under constitutive condition and accumulate abundantly noncrystalline cellulose, in preparation for unfavorable environments that may occur in the future in which mPL must initiate the program to form the cell wall of spherules. PMID- 23456458 TI - Analysis of cytotoxicity of melittin on adherent culture of human endothelial cells reveals advantage of fluorescence microscopy over flow cytometry and haemocytometer assay. AB - Melittin, from the honeybee venom, is a membrane active protein, whose cytotoxicity to human endothelial cells has not been described yet. In this work, we studied its time-dependent cytotoxicity on human umbilical vein endothelial cells (HUVECs). Since HUVECs grow in culture as adherent cells, suspension of cells is required before measuring cytotoxicity with a haemocytometer or flow cytometry. Therefore, we also tried to discover whether the result of cytotoxicity tests of melittin is influenced by the preparation of the cell suspension. For this purpose, we compared the results of haemocytometer-based trypan blue assay and flow cytometry using 7-aminoactinomycin D (7-AAD) with results of fluorescence microscopy using 7-AAD and 4', 6-diamidino-2-phenylindole (DAPI). Melittin over 60 min exposure evoked a rapid decline in the survival of HUVEC. After 60 min exposure to melittin, the phase contrast microscopy demonstrated massive necrosis in the remaining attached cells. Fluorescence microscopy detected both viable and non-viable cells in adequate proportions at all exposure times, whereas haemocytometer-based assay and flow cytometry highly underestimated the percentage of non-viable cells or even failed to detect any dead cells. Our data clearly indicate that the induction of large-scale damage to adherent endothelial cells by melittin results in a loss of the majority of necrotic cells during sample preparation for flow cytometry or a haemocytometer based assay. In the case of adherent cell culture, therefore, fluorescence microscopy was shown to be a more appropriate method for quantitative analysis of cell death caused by a fast-acting cytolytic toxin such as melittin. PMID- 23456459 TI - Living is information processing: from molecules to global systems. AB - We extend the concept that life is an informational phenomenon, at every level of organisation, from molecules to the global ecological system. According to this thesis: (a) living is information processing, in which memory is maintained by both molecular states and ecological states as well as the more obvious nucleic acid coding; (b) this information processing has one overall function-to perpetuate itself; and (c) the processing method is filtration (cognition) of, and synthesis of, information at lower levels to appear at higher levels in complex systems (emergence). We show how information patterns, are united by the creation of mutual context, generating persistent consequences, to result in 'functional information'. This constructive process forms arbitrarily large complexes of information, the combined effects of which include the functions of life. Molecules and simple organisms have already been measured in terms of functional information content; we show how quantification may be extended to each level of organisation up to the ecological. In terms of a computer analogy, life is both the data and the program and its biochemical structure is the way the information is embodied. This idea supports the seamless integration of life at all scales with the physical universe. The innovation reported here is essentially to integrate these ideas, basing information on the 'general definition' of information, rather than simply the statistics of information, thereby explaining how functional information operates throughout life. PMID- 23456457 TI - CEP proteins: the knights of centrosome dynasty. AB - Centrosome forms the backbone of cell cycle progression mechanism. Recent debates have occurred regarding the essentiality of centrosome in cell cycle regulation. CEP family protein is the active component of centrosome and plays a vital role in centriole biogenesis and cell cycle progression control. A total of 31 proteins have been categorized into CEP family protein category and many more are under candidate evaluation. Furthermore, by the recent advancements in genomics and proteomics researches, several new CEP proteins have also been characterized. Here we have summarized the importance of CEP family proteins and their regulation mechanism involved in proper cell cycle progression. Further, we have reviewed the detailed molecular mechanism behind the associated pathological phenotypes and the possible therapeutic approaches. Proteins such as CEP57, CEP63, CEP152, CEP164, and CEP215 have been extensively studied with a detailed description of their molecular mechanisms, which are among the primary targets for drug discovery. Moreover, CEP27, CEP55, CEP70, CEP110, CEP120, CEP135, CEP192, CEP250, CEP290, and CEP350 also seem promising for future drug discovery approaches. Since the overview implicates that the overall researches on CEP proteins are not yet able to present significant details required for effective therapeutics development, thus, it is timely to discuss the importance of future investigations in this field. PMID- 23456462 TI - Giant inverted T waves. PMID- 23456460 TI - The molecular mechanism and potential role of heat shock-induced p53 protein accumulation. AB - Workers who are exposed to extreme heat or work in hot environments may be at risk of heat stress. Exposure to extreme heat can result in occupational illnesses and injuries. On the other hand, local and regional heat therapy has been used for the treatment of some cancers, such as liver cancer, lung cancer, and kidney cancer. Although heat stress has been shown to induce the accumulation of p53 protein, a key regulator of cell cycle, apoptosis, DNA repair, and autophagy, how it regulates p53 protein accumulation and what the p53 targets are remain unclear. Here, we show that, among various genotoxic stresses, including ionizing radiation (IR) and ultraviolet (UV) radiation, heat stress contributes significantly to increase p53 protein levels in normal liver cells and liver cancer cells. Heat stress did not increase p53 mRNA expression as well as p53 promoter activity. However, heat stress enhanced the half-life of p53 protein. Moreover, heat stress increased the expression of puma and light chain 3 (LC-3), which are associated with the apoptotic and autophagic function of p53, respectively, whereas it did not change the expression of the cell cycle regulators p21, 14-3-3delta, and GADD45alpha, suggesting that heat-triggered alteration of p53 selectively modulates the downstream targets of p53. Our study provides a novel mechanism by which heat shock stimulates p53 protein accumulation, which is different from common DNA damages, such as IR and UV, and also provides new molecular basis for heat injuries or heat therapy. PMID- 23456463 TI - Sore throat, odynophagia, hoarseness, and a muffled, high-pitched voice. PMID- 23456465 TI - Cervical cancer screening: what's new and what's coming? AB - In their 2012 guidelines for cervical cancer screening, several organizations call for less-frequent but more-effective screening that incorporates testing for human papillomavirus (HPV). We review these recommendations and the possible future direction of screening. PMID- 23456466 TI - A 67-year old man with an abdominal aortic aneurysm. PMID- 23456467 TI - Frailty in older adults: implications for end-of-life care. AB - Frailty has important implications for the care needs of older adults and how those needs are met. By recognizing frailty and measuring it objectively, clinicians can better engage patients and their loved ones in difficult discussions about treatment plans and prognosis, and ultimately deliver better palliative care. PMID- 23456468 TI - Septic shock: the initial moments and beyond. AB - Our understanding of the pathophysiology and treatment of sepsis has advanced over the last decade, and evidence-based protocols have improved its outcomes. Here, we review its management in the first hours and afterward, including topics of ongoing study and debate. PMID- 23456469 TI - Emergency contraception. PMID- 23456470 TI - Bilateral adrenal masses. PMID- 23456471 TI - Sex, statins, and diabetes. PMID- 23456473 TI - Anatomical and neuropsychological effects of cluster munitions. AB - The aim of this article is to investigate the effects of cluster munitions on the different environmental, anatomical and neuropsychological levels. We conducted a study to explore the effects of sub-munitions on Lebanese victims. The study included a total of 407 cases that have been subjected to the detonation of unexploded sub-munitions in Lebanon, between 2006 and 2011. In our series, 356 casualties were injured and 51 were dead. 382 were males and 25 were females. We recorded 83 cases of amputations, and injuries involving cranio-facial regions, thorax, abdomen, and upper and lower extremities. These injuries lead to loss of function, body disfiguration, and chronic pain caused by the injuries or the amputations, as well as post-traumatic stress disorder. The peripheral nervous system was mostly affected and patients suffered from significant psychosocial tribulations. Cluster munitions harm human beings and decrease biodiversity. Survivors suffer from physical and psychological impairments. Laws should be passed and enforced to ban the use of these detrimental weapons that have negative effects on ecosystem and societal levels. PMID- 23456474 TI - Co-evolution of breast-to-brain metastasis and neural progenitor cells. AB - Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-beta superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain metastatic) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling. PMID- 23456475 TI - The influence of recrystallized caffeine on water-swellable polymethacrylate mucoadhesive buccal films. AB - The aim of this work was to investigate the influence of particles on the properties of polymethacrylate films intended for buccal delivery. A solvent casting method was used with Eudragit RS and RL (ERS and ERL, respectively) as film-forming rate-controlling polymers, with caffeine as a water-soluble model drug. The physicochemical properties of the model films for a series of formulations with increasing concentrations of caffeine were determined in terms of morphology, mechanical and mucoadhesive properties, drug content uniformity, and drug release and associated kinetics. Typically regarded as non-mucoadhesive polymers, ERS and mainly ERL, were found to be good mucoadhesives, with ERL01 exhibiting a work of mucoadhesion (WoA) of 118.9 MUJ, which was about five to six times higher than that observed for commonly used mucoadhesives such as Carbopol((r)) 974P (C974P, 23.9 MUJ) and polycarbophil (PCP, 17.4 MUJ). The mucoadhesive force for ERL01 was found to be significantly lower yet comparable to C974P and PCP films (211.1 vs. 329.7 and 301.1 mN, respectively). Inspection of cross-sections of the films indicated that increasing the concentration of caffeine was correlated with the appearance of recrystallized agglomerates. In conclusion, caffeine agglomerates had detrimental effects in terms of mucoadhesion, mechanical properties, uniformity, and drug release at large particle sizes. ERL series of films exhibited very rapid release of caffeine while ERS series showed controlled release. Analysis of release profiles revealed that kinetics changed from a diffusion controlled to a first-order release mechanism. PMID- 23456476 TI - The critical roles of information and nonequilibrium thermodynamics in evolution of living systems. AB - Living cells are spatially bounded, low entropy systems that, although far from thermodynamic equilibrium, have persisted for billions of years. Schrodinger, Prigogine, and others explored the physical principles of living systems primarily in terms of the thermodynamics of order, energy, and entropy. This provided valuable insights, but not a comprehensive model. We propose the first principles of living systems must include: (1) Information dynamics, which permits conversion of energy to order through synthesis of specific and reproducible, structurally-ordered components; and (2) Nonequilibrium thermodynamics, which generate Darwinian forces that optimize the system.Living systems are fundamentally unstable because they exist far from thermodynamic equilibrium, but this apparently precarious state allows critical response that includes: (1) Feedback so that loss of order due to environmental perturbations generate information that initiates a corresponding response to restore baseline state. (2) Death due to a return to thermodynamic equilibrium to rapidly eliminate systems that cannot maintain order in local conditions. (3) Mitosis that rewards very successful systems, even when they attain order that is too high to be sustainable by environmental energy, by dividing so that each daughter cell has a much smaller energy requirement. Thus, nonequilibrium thermodynamics are ultimately responsible for Darwinian forces that optimize system dynamics, conferring robustness sufficient to allow continuous existence of living systems over billions of years. PMID- 23456477 TI - The first case report of non-nosocomial healthcare-associated infective endocarditis due to methicillin-resistant Staphylococcus aureus USA400 in Rio de Janeiro, Brazil. AB - Staphylococcus aureus is the main causal pathogen of infective endocarditis (IE), which may have distinct origins, namely, community, nosocomial, or non-nosocomial healthcare-associated (NNHCA). We report the first case of NNHCA-IE caused by methicillin-resistant S. aureus strain USA400/SCCmec IV in which the combination therapy of rifampin and vancomycin had a favorable outcome for the patient. PMID- 23456478 TI - Apolipoprotein A-I Helsinki promotes intracellular acyl-CoA cholesterol acyltransferase (ACAT) protein accumulation. AB - Reverse cholesterol transport is a process of high antiatherogenic relevance in which apolipoprotein AI (apoA-I) plays an important role. The interaction of apoA I with peripheral cells produces through mechanisms that are still poorly understood the mobilization of intracellular cholesterol depots toward plasma membrane. In macrophages, these mechanisms seem to be related to the modulation of the activity of acyl-CoA cholesterol acyltransferase (ACAT), the enzyme responsible for the intracellular cholesterol ester biosynthesis that is stored in lipid droplets. The activation of ACAT and the accumulation of lipid droplets play a key role in the transformation of macrophages into foam cells, leading to the formation of atheroma or atherosclerotic plaque. ApoA-I Helsinki (or ?K107) is a natural apoA-I variant with a lysine deletion in the central protein region, carriers of which have increased atherosclerosis risk. We herein show that treatment of cultured RAW macrophages or CHOK1 cells with ?K107, but not with wild-type apoA-I or a variant containing a similar deletion at the C-terminal region (?K226), lead to a marked increase (more than 10 times) in the intracellular ACAT1 protein level as detected by western blot analysis. However, we could only detect a slight increase in cholesteryl ester produced by ?K107 mainly when Chol loading was supplied by low-density lipoprotein (LDL). Although a similar choline-phospholipid efflux is evoked by these apoA-I variants, the change in phosphatidylcholine/sphyngomyelin distribution produced by wild-type apoA-I is not observed with either ?K107 or ?K226. PMID- 23456479 TI - Differential effects of mesenchymal stem cells on a heterogeneous cell population within lung cancer cell lines. AB - Although mesenchymal stem cells (MSCs) promote lung cancer growth in vivo, in vitro studies indicate that they inhibit the proliferation of lung cancer cells. Because malignant tumors contain a heterogeneous cell population with variable capacity for self-renewal, the aim of this study was to determine whether the inconsistencies between in vitro and in vivo studies are a result of differential effects of MSCs on the heterogeneous cell population within lung cancer cell lines. Human MSCs were isolated from the bone marrow, and their cell surface antigen expression and multi-lineage differentiation capacity was examined at passage 10. CD133+ cells were isolated from A549 and H446 cell lines using immunomagnetic separation. The effects of MSCs on the growth and microsphere formation of heterogeneous cell populations within two lung cancer cell lines (A549 and H446) were compared. MSCs inhibited the in vitro proliferation of both cell lines, but significantly accelerated tumor formation and stimulated tumor growth in vivo (P < 0.05). In CD133+ cells isolated from both A549 and H446 cells, co-culture with MSCs for 1-3 days significantly increased their proliferation (P < 0.05). MSCs also significantly increased microsphere formation in both cell lines (P < 0.05). Selective stimulation of CD133+ cell growth may account for the discrepant effects of MSCs on lung cancer progression. PMID- 23456480 TI - Nitric oxide attenuates matrix metalloproteinase-9 production by endothelial cells independent of cGMP- or NFkappaB-mediated mechanisms. AB - Cardiovascular diseases involve critical mechanisms including impaired nitric oxide (NO) levels and abnormal matrix metalloproteinase (MMP) activity. While NO downregulates MMP expression in some cell types, no previous study has examined whether NO downregulates MMP levels in endothelial cells. We hypothesized that NO donors could attenuate MMP-9 production by human umbilical vein endothelial cells (HUVECs) as a result of less NFkappaB activation or cyclic GMP (cGMP)-mediated mechanisms. We studied the effects of DetaNONOate (10-400 MUM) or SNAP (50-400 MUM) on phorbol 12-myristate 13-acetate (PMA; 10 nM)-induced increases in MMP-9 activity (by gel zymography) or concentrations (by ELISA) as well as on a tissue inhibitor of MMPs' (TIMP)-1 concentrations (by ELISA) in the conditioned medium of HUVECs incubated for 24 h with these drugs. We also examined whether the irreversible inhibitor of soluble guanylyl cyclase ODQ modified the effects of SNAP or whether 8-bromo-cGMP (a cell-permeable analog of cGMP) influenced PMA induced effects on MMP-9 expression. Total and phospho-NFkappaB p65 concentrations were measured in HUVEC lysates to assess NFkappaB activation. Both NO donors attenuated PMA-induced increases in MMP-9 activity and concentrations without significantly affecting TIMP-1 concentrations. This effect was not modified by ODQ, and 8-bromo-cGMP did not affect MMP-9 concentrations. While PMA increased phospho-NFkappaB p65 concentrations, SNAP had no influence on this effect. In conclusion, this study shows that NO donors may attenuate imbalanced MMP expression and activity in endothelial cells independent of cGMP- or NFkappaB mediated mechanisms. Our results may offer an important pharmacological strategy to approach cardiovascular diseases. PMID- 23456481 TI - Role of CC-chemokine receptor 5 on myocardial ischemia-reperfusion injury in rats. AB - The expression level of CC-chemokine receptor 5 (CCR5) is enhanced post inflammatory stimulations and might play a crucial role on inflammatory cells infiltration post myocardial ischemia. The purpose of this study was to evaluate the role of CCR5 on myocardial ischemia-reperfusion (I/R) injury in rats. Adult male rats were randomized to sham group, I/R group (I/R, 30 min coronary artery occlusion followed by 2-h reperfusion), ischemic preconditioning (I/R + Pre), CCR5 antibody group [I/R + CCR5Ab (0.2 mg/kg)], and CCR5 agonist group [I/R + CCR5Ago, RNATES (0.1 mg/kg)], n = 12 each group. The serum level of creatine kinase (CK) and tumor necrosis factor alpha (TNF-alpha) were measured by ELISA. Myocardial infarction size and myeloperoxidase (MPO) activity were determined. Myocardial protein expression of CCR5 and intercellular adhesion molecule-1 (ICAM 1) were evaluated by Western blotting and immunohistochemistry staining, respectively. Myocardial nuclear factor-kappa B (NF-kappaB) activity was assayed by electrophoretic mobility shift assay. Myocardial CCR5 protein expression was significantly reduced in I/R + Pre group (P < 0.05 vs. I/R) and further reduced in I/R + CCR5Ab group (P < 0.05 vs. I/R + Pre). LVSP and +/-dP/dt(max) were significantly lower while serum CK and TNF-alpha as well as myocardial MPO activity, ICAM-1 expression, and NF-kappaB activity were significantly higher in I/R group than in sham group (all P < 0.05), which were significantly reversed by I/R + Pre (all P < 0.05 vs. I/R) and I/R + CCR5Ab (all P < 0.05 vs. I/R + Pre) while aggravated by I/R + CCR5Ago (all P < 0.05 vs. I/R). Our results suggest that blocking CCR5 attenuates while enhancing CCR5 aggravates myocardial I/R injury through modulating inflammatory responses in rat heart. PMID- 23456482 TI - Hyperglycemia and vascular metabolic memory: truth or fiction? AB - Prevention of long-term complications remains the main challenge in the treatment of diabetes. A strong relationship between glucose control and development of complications is apparent in all epidemiologic studies. Yet, intervention trials have yielded questionable results, particularly when intensive treatment was introduced in patients with long-standing diabetes. It has been postulated that in these subjects, prior exposure to chronic hyperglycemia may have generated a negative "metabolic memory," preventing full exertion of the beneficial effects of any subsequent improvement of glucose control. This phenomenon has been replicated in animal models and it recognizes a molecular basis in the role of oxidative stress, advanced glycation processes, and epigenetic mechanisms accounting for self-perpetuating modifications of gene expression. Conversely, early intervention in both type 1 and type 2 diabetes has proven that good glycemic control reduces the risk of development and progression of complications with a beneficial effect that extends well beyond the duration of near normoglycemia. This has brought up the concept of "metabolic legacy," an advantage handed down by early and effective implementation of treatments designed to reduce blood glucose levels as safely as possible along with multifactorial intervention of all cardiovascular risk factors. The evidence, nature, and clinical implication of these concepts are reviewed. PMID- 23456483 TI - Preliminary clinical experience with hyaluronan anti-adhesion gel in arthroscopic arthrolysis for posttraumatic elbow stiffness. AB - BACKGROUND: Loss of motion of the elbow joint is a common finding after elbow trauma. It has been shown that arthroscopic treatment leads to excellent restoration of elbow motion, although it is still a demanding procedure. The aim of our cohort study was to assess clinical outcomes following treatment of posttraumatic elbow stiffness using arthroscopic arthrolysis with or without the associated use of a hyaluronan anti-adhesion gel. MATERIALS AND METHODS: A cohort of 36 consecutive patients undergoing elbow arthroscopic arthrolysis were enrolled: 17 patients in the hyaluronan gel group and 19 in the control group. The patients underwent prospective control visits 30 and 75 days after surgery. Functional outcome was measured by the range of motion and the Liverpool elbow score (LES), whereas pain and quality of life were evaluated using the visual analogue scale and the SF-36 questionnaire, respectively. RESULTS: The range of motion and the overall LES score increased over time in both groups. The mean increase over time was statistically significant (p < 0.001) in both groups and there was no difference between the groups. There was also no interaction between time and treatment. The percentage of patients who reported pain decreased significantly over time (p = 0.0419) in the hyaluronan-treated group (suggesting limited contractions and better comfort during rehabilitation), but not in the control group. The intensity of pain decreased significantly over time in both groups (p < 0.0001) without any significant difference between the groups. All the changes in patient quality of life as measured by the SF-36 questionnaire were similar for the two groups of patients. No adverse event or complication related to the application of hyaluronan gel occurred. CONCLUSIONS: Our preliminary clinical experience showed promising results upon the use of hyaluronan gel, considering that it significantly reduced pain in the short term, facilitating a more comfortable rehabilitation. These findings should be confirmed by larger studies. PMID- 23456484 TI - Multi-allergen challenge stimulates steriod-resistant airway inflammation via NF kappaB-mediated IL-8 expression. AB - Neutrophilic airway inflammation associated with multiple allergens has been related to steroid-resistant asthma. However, most animal models use only one allergen, which cannot simulate asthma closely as seen in patients. To determine the mechanism of inflammatory process involved in this severe condition, BALB/c mice were repetitively challenged with the pooled extract of dust mite, ragweed, and Aspergillus species (DRA). We found that DRA increased interleukin (IL)-10 and TGF-beta levels and neutrophil recruitment in bronchial alveolar lavage fluid. We also found that although dexamethasone suppressed the release of these two cytokines, mast cells recruitment, and mucus hypersecretion, it actually increased neutrophil infiltration and the level of keratinocyte-derived chemokine (mKC), a functional homolog of human IL-8. Treatment of human lung alveolar A549 cells with Der p1, an extract of house dust mite Dermatophagoides pteronyssinus, increased the expression of IL-8 and activity of NF-kappaB. The elevated IL-8 level was suppressed by BAY11-7082, a selective NF-kappaB inhibitor, but not by dexamethasone. These results suggest that increased IL-8 (mKC) levels may be involved in steroid-resistant neutrophilic airway inflammation through an NF kappaB-dependent pathway. PMID- 23456485 TI - [About a note published in 1926 on a BCG vaccine trial in leprosy treatment]. AB - By 1926, two French physicians working in Indochina, R. Pons and L. Chastel, have suggested to treat leprosy by subcutaneous injections of bacillus Calmette Guerin. This treatment appeared efficient since the lepromatous lesions quickly regressed and the Hansen bacillus disappeared from the nasal mucus. These results were quickly confirmed by other authors. They were all more appreciated than, at this time, the Chaulmoogra oil and its products, the only available drugs, were poorly efficient against the disease. Nevertheless, although not a panacea, the BCG therapy allowed to relieve these unfortunate patients until the beginning of the 1950's when an effective treatment by sulfones was at length available. PMID- 23456486 TI - (99m)Tc-labeled monomeric and dimeric NGR peptides for SPECT imaging of CD13 receptor in tumor-bearing mice. AB - CD13 receptor plays a critical role in tumor angiogenesis and metastasis. We therefore aimed to develop (99m)Tc-labeled monomeric and dimeric NGR-containing peptides, namely, NGR1 and NGR2, for SPECT imaging of CD13 expression in HepG2 hepatoma xenografts. Both NGR-containing monomer and dimer were synthesized and labeled with (99m)Tc. In vivo receptor specificity was demonstrated by successful blocking of tumor uptake of (99m)Tc-NGR dimer in the presence of 20 mg/kg NGR2 peptide. Western blot and immunofluorescence staining confirmed the CD13 expression in HepG2 cells. The NGR dimer showed higher binding affinity and cell uptake in vitro than the NGR-containing monomer, presumably due to a multivalency effect. (99m)Tc-Labeled monomeric and dimeric NGR-containing peptides were subjected to SPECT imaging and biodistribution studies. SPECT scans were performed in HepG2 tumor-bearing mice at 1, 4, 12, and 24 h post-injection of ~7.4 MBq tracers. The metabolism of tracers was determined in major organs at different time points after injection which demonstrated rapid, significant tumor uptake and slow tumor washout for both traces. Predominant clearance from renal and hepatic system was also observed in (99m)Tc-NGR1 and (99m)Tc-NGR2. In conclusion, monomeric and dimeric NGR peptide were developed and labeled with (99m)Tc successfully, while the high integrin avidity and long retention in tumor make (99m)Tc-NGR dimer a promising agent for tumor angiogenesis imaging. PMID- 23456487 TI - Learning protein multi-view features in complex space. AB - Protein attribute prediction from primary sequences is an important task and how to extract discriminative features is one of the most crucial aspects. Because single-view feature cannot reflect all the information of a protein, fusing multi view features is considered as a promising route to improve prediction accuracy. In this paper, we propose a novel framework for protein multi-view feature fusion: first, features from different views are parallely combined to form complex feature vectors; Then, we extend the classic principal component analysis to the generalized principle component analysis for further feature extraction from the parallely combined complex features, which lie in a complex space. Finally, the extracted features are used for prediction. Experimental results on different benchmark datasets and machine learning algorithms demonstrate that parallel strategy outperforms the traditional serial approach and is particularly helpful for extracting the core information buried among multi-view feature sets. A web server for protein structural class prediction based on the proposed method (COMSPA) is freely available for academic use at: http://www.csbio.sjtu.edu.cn/bioinf/COMSPA/ . PMID- 23456488 TI - Chemical synthesis and orexigenic activity of rat/mouse relaxin-3. AB - The insulin-like peptide, relaxin-3 was first identified just a decade ago via a genomic database search and is now recognized to be a key neuropeptide with several roles including the regulation of arousal, stress responses and neuroendocrine homeostasis. It also has significant potential as a drug to treat stress and obesity. Its actions are mediated via its cognate G protein-coupled receptor, RXFP3, which is found in abundant numbers in the brain. However, much remains to be determined with respect to the mechanism of neurological action of this peptide. Consequently, the chemical synthesis of the rat and mouse (which share identical primary structures) two-chain, three disulfide peptide was undertaken and the resulting peptide subjected to detailed in vitro and in vivo assay. Use of efficient solid-phase synthesis methods provided the two regioselectively S-protected A- and B-chains which were readily combined via sequential disulfide bond formation. The synthetic rat/mouse relaxin-3 was obtained in high purity and good overall yield. It demonstrated potent orexigenic activity in rats in that central intracerebroventricular infusion led to significantly increased food intake and water drinking. PMID- 23456489 TI - Souvenir from South Africa. PMID- 23456490 TI - Corticospinal responses to sustained locomotor exercises: moving beyond single joint studies of central fatigue. AB - There is substantial evidence that fatiguing exercise is accompanied by changes within the central nervous system that reduce the force that can be produced by working muscles. Here we review studies that used non-invasive neurophysiological techniques to show that sustained single-joint contractions have the capacity to increase corticospinal responsiveness and reduce motoneuronal responsiveness. We contrast these findings with new evidence from our laboratory regarding corticospinal responsiveness during sustained cycling exercise. There seems to be a similar increase in responsiveness of the intracortical inhibitory interneurons during sustained locomotor and single-joint exercise which might be due to acute exercise responses that are common to fatiguing exercise of any nature, such as local accumulation of fatigue metabolites. In contrast, the pattern of changes in corticospinal responsiveness is fundamentally different between the two modes of exercise which might be due to greater systemic fatigue responses to locomotor exercises. PMID- 23456491 TI - Skin conditions of baseball, cricket, and softball players. AB - Each year in the United States over 80 million people participate in bat-and-ball sports, for example baseball and softball. Cricket, the world's second most popular sport, is enjoyed by hundreds of millions of participants in such countries as India, Pakistan, Australia, New Zealand, Bangladesh, South Africa, West Indies, Sri Lanka, United Kingdom, and Zimbabwe. Although any player can develop skin disease as a result of participation in these bat-and-ball sports, competitive team athletes are especially prone to skin problems related to infection, trauma, allergy, solar exposure, and other causes. These diseases can produce symptoms that hinder individual athletic performance and participation. In this review, we discuss the diagnosis and best-practice management of skin diseases that can develop as a result of participation in baseball, softball, and cricket. PMID- 23456493 TI - Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing. AB - Fatigue during prolonged exercise is often described as an acute impairment of exercise performance that leads to an inability to produce or maintain a desired power output. In the past few decades, interest in how athletes experience fatigue during competition has grown enormously. Research has evolved from a dominant focus on peripheral causes of fatigue towards a complex interplay between peripheral and central limitations of performance. Apparently, both feedforward and feedback mechanisms, based on the principle of teleoanticipation, regulate power output (e.g., speed) during a performance. This concept is called 'pacing' and represents the use of energetic resources during exercise, in a way such that all energy stores are used before finishing a race, but not so far from the end of a race that a meaningful slowdown can occur.It is believed that the pacing selected by athletes is largely dependent on the anticipated exercise duration and on the presence of an experientially developed performance template. Most studies investigating pacing during prolonged exercise in ambient temperatures, have observed a fast start, followed by an even pace strategy in the middle of the event with an end sprint in the final minutes of the race. A reduction in pace observed at commencement of the event is often more evident during exercise in hot environmental conditions. Further, reductions in power output and muscle activation occur before critical core temperatures are reached, indicating that subjects can anticipate the exercise intensity and heat stress they will be exposed to, resulting in a tactical adjustment of the power output. Recent research has shown that not only climatic stress but also pharmacological manipulation of the central nervous system has the ability to cause changes in endurance performance. Subjects seem to adapt their strategy specifically in the early phases of an exercise task. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. Manipulations of serotonin and, especially, noradrenaline, have the opposite effect and force subjects to decrease power output early in the time trial. Interestingly, after manipulation of brain serotonin, subjects are often unable to perform an end sprint, indicating an absence of a reserve capacity or motivation to increase power output. Taken together, it appears that many factors, such as ambient conditions and manipulation of brain neurotransmitters, have the potential to influence power output during exercise, and might thus be involved as regulatory mechanisms in the complex skill of pacing. PMID- 23456492 TI - Neural correlates of motor vigour and motor urgency during exercise. AB - This article reviews the brain structures and neural circuitry underlying the motor system as it pertains to endurance exercise. Some obvious phenomena that occur during endurance racing events that need to be explained neurophysiologically are variable pacing strategies, the end spurt, motivation and the rating of perceived exertion. Understanding the above phenomena physiologically is problematic due to the sheer complexity of obtaining real-time brain measurements during exercise. In those rare instances where brain measurements have been made during exercise, the measurements have usually been limited to the sensory and motor cortices; or the exercise itself was limited to small muscle groups. Without discounting the crucial importance of the primary motor cortex in the execution of voluntary movement, it is surprising that very few exercise studies pay any attention to the complex and dynamic organization of motor action in relation to the subcortical nuclei, given that they are essential for the execution of normal movement patterns. In addition, the findings from laboratory-based exercise performance trials are hampered by the absence of objective measures of the motivational state of subjects. In this review we propose that some of the above phenomena may be explained by distinguishing between voluntary, vigorous and urgent motor behaviours during exercise, given that different CNS structures and neurotransmitters are involved in the execution of these different motor behaviours. PMID- 23456494 TI - Can the adenoma detection rate reliably identify low-performing endoscopists? Results of a modeling study. AB - BACKGROUND: Experts have stated that adenoma detection rates (ADR) of individual endoscopists should be measured to assess colonoscopy quality. AIM: The purpose of this study was to quantify the reliability of the ADR as a quality marker. METHODS: We simulated a population of endoscopists and patients using published data on adenoma prevalence and adenoma miss rates. For each endoscopist, the ADR was calculated. The proportion of ADR variance attributable to endoscopist and the area under the ROC (AUROC) curve for low-performing endoscopists (lowest quartile or decile) were also calculated. RESULTS: In the base-case analysis (200 patients per endoscopist, miss rate 22 %, adenoma prevalence 24 %), only 13 % of ADR variance was attributable to endoscopist performance (AUROC up to 0.73). An ADR cutoff of <16.5 % identified approximately half of endoscopists in the lowest performance decile (test sensitivity = 53 %), but most (79 %) of the endoscopists identified by this cutoff were NOT low performers (i.e., false positives). In sensitivity analysis, increasing the number of patients per endoscopist, reducing the variance of adenoma prevalence between endoscopists (i.e., performing case mix adjustment), and increasing the variance in performance between endoscopists all improved ADR test characteristics (AUROC up to 0.88). However, regardless of assumptions, a substantial proportion of endoscopists would be misclassified if a simple ADR cutoff were utilized. CONCLUSIONS: The ADR has limited reliability as a quality marker under real-world assumptions. Simple cutoffs are likely to either be insufficiently sensitive or have high false positive rates. Future studies should identify alternative means for assessing endoscopist performance. PMID- 23456495 TI - Management for CBD stone-related mild to moderate acute cholangitis: urgent versus elective ERCP. AB - BACKGROUND: There is no doubt that urgent biliary decompression needs to be done in case of severe acute cholangitis. However, it remains to be determined how early biliary decompression should be performed and elective intervention would be comparable to urgent intervention, in case of mild to moderate choledocholithiasis associated cholangitis. METHODS: One hundred ninety-five patients were enrolled who were diagnosed with mild to moderate cholangitis with common bile duct (CBD) stones between January 2006 and August 2010. They were divided into two groups according to door to intervention time, and urgent (<=24 h, n = 130) versus elective (>24 h, n = 82). Primary outcomes of this study were technical success rate (CBD stones removal) and clinical success rate (improvement of cholangitis) between the two groups. Hospital stay and intervention-related complications were also evaluated. RESULTS: There was no statistically significant difference in technical, clinical success rate and intervention-related complications between the urgent and elective groups (P = 0.737, 0.285, 0.398, respectively). Patients in the urgent group had significantly shorter hospitalization than in the elective group (6.8 vs. 9.2 days, P < 0.001), and furthermore, intervention to discharge time was also significantly shorter by 1.1 days in the urgent group (P = 0.035). In terms of laboratory parameters, initial CRP level was the only factor correlated with hospital stay and intervention to discharge time. CONCLUSIONS: This study demonstrates that urgent ERCP would be recommended in the management of patients with CBD stone-related mild to moderate acute cholangitis because of the advantage of short hospital stay and intervention to discharge time. PMID- 23456496 TI - Cholecystectomy and clinical presentations of gastroparesis. AB - BACKGROUND: Many patients with gastroparesis have had their gallbladders removed. AIM: To determine if clinical presentations of patients with gastroparesis differ in those with prior cholecystectomy compared to patients who have not had their gallbladder removed. METHODS: Gastroparetic patients were prospectively enrolled in the NIDDK Gastroparesis Registry. Detailed history and physical examinations were performed; patients filled out questionnaires including patient assessment of GI symptoms. RESULTS: Of 391 subjects with diabetic or idiopathic gastroparesis (IG), 142 (36 %) had a prior cholecystectomy at the time of enrollment. Patients with prior cholecystectomy were more often female, older, married, and overweight or obese. Cholecystectomy had been performed in 27/59 (46 %) of T2DM compared to 19/78 (24 %) T1DM and 96/254 IG (38 %) (p = 0.03). Patients with cholecystectomy had more comorbidities, particularly chronic fatigue syndrome, fibromyalgia, depression, and anxiety. Postcholecystectomy gastroparesis patients had increased health care utilization, and had a worse quality of life. Independent characteristics associated with prior cholecystectomy included insidious onset (OR = 2.06; p = 0.01), more comorbidities (OR = 1.26; p < 0.001), less severe gastric retention (OR(severe) = 0.68; overall p = 0.03) and more severe symptoms of retching (OR = 1.19; p = 0.02) and upper abdominal pain (OR = 1.21; p = 0.02), less severe constipation symptoms (OR = 0.84; p = 0.02), and not classified as having irritable bowel syndrome (OR = 0.51; p = 0.02). Etiology was not independently associated with a prior cholecystectomy. CONCLUSIONS: Symptom profiles in patients with and without cholecystectomy differ: postcholecystectomy gastroparesis patients had more severe upper abdominal pain and retching and less severe constipation. These data suggest that prior cholecystectomy is associated with selected manifestations of gastroparesis. PMID- 23456497 TI - Low expression of cyclinH and cyclin-dependent kinase 7 can decrease the proliferation of human esophageal squamous cell carcinoma. AB - BACKGROUND: Increased expression of cyclinH (CCNH) and cyclin-dependent kinase 7 (CDK7) has a relationship with poor prognosis in most human cancers. AIM: Investigate the expression of CCNH and CDK7 in human esophageal squamous cell carcinoma (ESCC) and the effect of chemotherapy on their expression. METHODS: Western blotting and immunohistochemistry were used to measure the expression of CCNH and CDK7 proteins in ESCC and adjacent normal tissue in 98 patients. We use Cell Counting Kit-8 and cell flow to analyze the effects of cisplatin and interference of CCNH and CDK7 in cell cycle process. RESULTS: Immunohistochemical analysis showed that CCNH and CDK7 expression were significantly associated with unfavorable clinicopathologic variables. CCNH and CDK7 protein levels were elevated in ESCC tissues in comparison with adjacent normal tissues. Survival analysis revealed that CCNH and CDK7 overexpression were significantly associated with overall survival (P < 0.001). Cisplatin or interference of CCNH or CDK7 led cells to grow slowly. Overexpression of CCNH and CDK7 in TE1 cells can lead to resistance to cisplatin. CONCLUSIONS: We can conclude that CCNH and CDK7 may play an important role in the tumorigenesis and development of ESCC. CCNH and CDK7 expression affected the chemotherapy of tumor. PMID- 23456498 TI - Rapid colonoscopy preparation using bolus lukewarm saline combined with sequential posture changes: a randomized controlled trial. AB - OBJECTIVE: In this randomized clinical trial, we have compared the ShudhTM colon cleanse (SCC) with HalfLytely((r)) colon prep (HCP) to evaluate the efficacy, bowel preparation time (BPT), adverse events, electrolyte abnormalities and patient acceptability. METHODS: Patients were randomized to receive either SCC (n = 65) or HCP (n = 68). All colonoscopies were performed by a single, blinded endoscopist. Colon prep was evaluated on a 5 point grading scale. Statistical non inferiority was pre-defined as a difference of <15 % in the lower limit of the 95.5 % confidence interval for the treatment difference. Data that were collected include bowel prep score, BPT, adverse events, electrolyte abnormalities and patient acceptability. RESULTS: Bowel preparation efficacy was rated as "successful" for 59/65 (90.7 %) in SCC versus 66/68 (97.1 %) in HCP. This gave a success difference of -6.4 % with a 1-sided 95 % lower confidence limit (LCI) for the difference = -13.3 % (non-inferiority p = 0.25). This difference fell within the predefined limit for non-inferiority. The average BPT for SCC was 1.9 h versus 10.9 in HCP (p < 0.001). No serious adverse events were reported in either group. None of the patients in either group had any clinically significant electrolyte imbalance. Patient ratings for palatability and willingness to repeat were significantly better for SCC (p < 0.05). CONCLUSION: SCC was found to not be inferior to PEG with regards to the quality of bowel preparation. It is worth highlighting that a major advantage of SCC is shorter BPT. PMID- 23456499 TI - T cell co-stimulatory molecules: a co-conspirator in the pathogenesis of eosinophilic esophagitis? AB - Eosinophilic esophagitis (EoE) has become a common gastrointestinal disease. It is characterized by severe eosinophil infiltration in the esophagus. EoE is strongly associated with food allergy, asthma, atopic dermatitis, and other allergic diseases. T lymphocytes, especially Th2 cells, play an instrumental role in the development of allergic inflammation. Recent studies have shown that the ligation of co-stimulatory molecules contributes to the activation, differentiation, and proliferation of T cells. In this review, we will discuss the growing evidence of co-stimulatory molecules including OX40, Light, and HVEM in the pathogenesis of Th2-driven EoE. Our goal is to provide the rationale for the development of novel therapy therapies that target co-stimulatory molecules. PMID- 23456500 TI - MYO5B is epigenetically silenced and associated with MET signaling in human gastric cancer. AB - BACKGROUND: Our previous study has shown that MYO5B is downregulated in gastric cancer. However, the mechanism by which the expression of MYO5B was inhibited remains unknown. METHODS: Inspection of the human MYO5B locus uncovered a large and dense CpG island within the 5' region of this gene. Methylation-specific PCR (MSP) and bisulfite sequencing (BSP) were used for determination of MYO5B promoter methylation in gastric cancer cell lines and gastric cancer samples. Involvement of histone H3 methylation in those cell lines were examined by ChIP assay. RESULTS: The densely methylated MYO5B promoter region was confirmed by MSP and BSP. Enhanced gene expression was detected when the cells were treated with the DNA-demethylating agent 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA), a histone deacetylase inhibitor. Knockdown of MYO5B expression in gastric cancer cells expressing endogenous MYO5B inhibits HGF-stimulated MET degradation, concomitant with sustained c-MET levels and signaling. CONCLUSION: The results of our study showed for the first time that MYO5B is epigenetically silenced in gastric cancer cells by aberrant DNA methylation and histone modification. Inactivation of MYO5B expression in gastric cancer cells expressing endogenous MYO5B inhibits HGF-stimulated MET degradation, concomitant with sustained c-MET levels and signaling. PMID- 23456501 TI - Safely stretching our options for removing large CBD stones. PMID- 23456502 TI - Small bowel motility from videocapsule endoscopy: beware of false prophets! PMID- 23456503 TI - Impact of an incomplete colonoscopy referral program on recommendations after incomplete colonoscopy. AB - BACKGROUND: There are limited data on recommendations and adherence to complete colon evaluation (CCE) after incomplete colonoscopy (IC). AIMS: Our objectives were to (1) identify recommendations and adherence to recommendations after IC, (2) determine the diagnostic yield of CCE after IC, and (3) determine the effect of an IC referral program on recommendations for CCE. METHODS: We conducted a retrospective review of IC procedures at a teaching hospital over two time periods (January 1 to May 1 2004 and July 1 to November 1 2010). A referral process for repeat colonoscopy after IC was instituted in April 2009. Outcomes included (1) recommendations (2) adherence, and (3) yield of CCE after IC. RESULTS: A total of 222 patients underwent at least one IC (overall rate of 2.5 %). In 120 patients (54.1 %), CCE was recommended within 1 year; the rate did not change from 2004 to 2010. Patients with IC due to poor preparation were more likely to have specific CCE recommendations (85.5 vs. 72.2 %, P = 0.03) and recommendations of endoscopic follow-up (76.3 vs. 10.4 %, P < 0.0001) than those with IC due to difficult anatomy. When IC was due to difficult colonoscopy, there was increase in endoscopic follow-up recommended (16.3 vs. 2.8 %, P = 0.01) in 2010 compared to 2004. Adherence to recommendations was similar regardless of modality recommended, inpatient/outpatient status, polyps on initial exam, or extent of initial exam. Polyp detection rate was greater utilizing colonoscopy than barium enema (34.3 vs. 3.6 %, P < 0.0001). CONCLUSIONS: There is a lack of consensus in management strategies for patients after IC. Implementation of a referral program has had minimal impact on provider recommendations. PMID- 23456504 TI - Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis. AB - BACKGROUND: Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been perplexing most clinicians and users of NSAIDs. Rebamipide is increasingly advocated as a candidate option for the prevention of NSAIDs induced gastrointestinal mucosal injury. AIMS: To assess the efficacy and the safety of rebamipide for the prevention and treatment of NSAID-induced gastroenteropathy. METHODS: PubMed, Embase, Web of Science, Google Scholar, the Cochrane Library, Japan Science and Technology Information Aggregator, and China Biology Medicine Disc were searched up to December 2011. Randomized controlled trials (RCTs) recruiting subjects with co-prescriptions of NSAIDs and rebamipide were eligible. Efficacy and safety of rebamipide were reevaluated, and dichotomous data were pooled to obtain relative risk (RR) with a 95 % confidence interval. Heterogeneity and publication bias were assessed by the inconsistency index statistic and funnel plot analysis, respectively. RESULTS: The search identified 338 citations, and 15 RCTs including 965 individuals were eligible. In general, rebamipide acted better than placebo against short-term NSAID-induced gastroduodenal injury. Separate studies showed rebamipide was equal to or not superior to traditional strategies (including PPIs, H2RA and misoprostol treatment). Especially, rebamipide showed a beneficial effect against the small bowel damage (total RR = 2.70, 95 % confidence interval = 1.02-7.16, P = 0.045) when compared with placebo group. The average incidence of adverse events was about 36.1 % (0-70.0 %) but no serious event was recorded. CONCLUSIONS: Current evidences show rebamipide is effective and safe for defending against NSAID induced gastroduodenal and lower-gastrointestinal injuries. However, more well designed trials should be conducted to fully confirm the practical value of rebamipide. PMID- 23456505 TI - Biliary stenting in patients with malignant biliary obstruction: comparison of double layer, plastic and metal stents. AB - BACKGROUND AND AIM: The double layer stent (DLS) has a unique design and has been used for palliation of malignant biliary obstruction, but literature on this stent is limited. Our aim was to compare plastic (PS), DLS and metal stents (MS) in terms of complication rates, time to occlusion, and patency rate in patients with malignant biliary obstruction (MBO). METHODS: A retrospective review of stents placed for MBO at our institution in the period between January 2009 and April 2011 was conducted. A total of 114 stents were identified, of which 44 were MS (39 %), 37 DLS (32 %), and 33 PS (29 %). A stent was considered occluded when an unplanned stent removal or intervention occurred due to clinical suspicion of biliary obstruction. RESULTS: Stents remained patent for 95 days (range 7-359 days) in the DLS group and 59 days (range 7-228 days) in the PS group (P = 0.014) and 128.7 days (range 4-602 days) in the metal stent group. Twenty-seven percent (n = 9) of PS occluded after a mean of 60 days while 16 % (n = 7) of MS occluded after a mean of 87 days and 5 % (n = 2) of DLS occluded after a mean of 85 days (DLS vs. PS P = 0.012, DLS vs. MS P = 0.13, MS vs. PS P = 0.22). CONCLUSIONS: DLS are superior to PS in patients with MBO and appear to be comparable to MS. MS had a longer patency rate but were comparable to DLS in early and late complications. We speculate that the less expensive DLS may be a cost effective alternative in the palliation of MBO. PMID- 23456506 TI - Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma. AB - BACKGROUND: Fibroblast growth factor 19 (FGF19)-mediated activation of mitogen activated protein kinase and the beta-catenin pathway may be involved in the development and progression of hepatocellular carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients. METHODS: By immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6 months. RESULTS: FGF19 protein expression was observed in 135 (48.0 %) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size (P < 0.001), and higher BCLC stage (P = 0.001). FGF19 expression was correlated with the early recurrence (P < 0.001), but not with the late recurrence (P = 0.582). FGF19 expression (P = 0.002), viral etiology (P = 0.028), and intrahepatic metastasis (P < 0.001) were independent predictors of early recurrence. Multivariate analyses of survival revealed that FGF19 expression (P < 0.001), intrahepatic metastasis (P < 0.001), and liver cirrhosis (P = 0.019) were independent predictors of shorter disease-free survival. FGF19 expression (P = 0.005), larger tumor size (P = 0.038), major portal vein invasion (P = 0.048), intrahepatic metastasis (P < 0.001), lower albumin level (P = 0.024), and liver cirrhosis (P = 0.031) were independent predictors of shorter disease-specific survival. CONCLUSIONS: FGF19 protein expression might be an effective predictor of early recurrence and a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy, indicating that FGF19 might be a potential preventive target in hepatocellular carcinoma patients. PMID- 23456507 TI - Can an engineer fix an immune system?--Rethinking theoretical biology. AB - In an instant classic paper (Lazebnik, in Cancer Cell 2(3); 2002: 179-182) biologist Yuri Lazebnik deplores the poor effectiveness of the approach adopted by biologists to understand and "fix" biological systems. Lazebnik suggests that to remedy this state of things biologist should take inspiration from the approach used by engineers to design, understand, and troubleshoot technological systems. In the present paper I substantiate Lazebnik's analysis by concretely showing how to apply the engineering approach to biological problems. I use an actual example of electronic circuit troubleshooting to ground the thesis that, in engineering, the crucial phases of any non-trivial troubleshooting process are aimed at generating a mechanistic explanation of the functioning of the system, which makes extensive recourse to problem-driven qualitative reasoning possibly based on cognitive artifacts applied to systems that are known to have been designed for function. To show how to translate these findings into biological practice I consider a concrete example of biological model building and "troubleshooting", aimed at the identification of a "fix" for the human immune system in presence of progressing cancer, autoimmune disease, and transplant rejection. The result is a novel immune system model--the danger model with regulatory cells--and new, original hypotheses concerning the development, prophylaxis, and therapy of these unwanted biological processes. Based on the manifest efficacy of the proposed approach, I suggest a refocusing of the activity of theoretical biologists along the engineering-inspired lines illustrated in the paper. PMID- 23456509 TI - Evaluation of choroidal and retinal thickness measurements using optical coherence tomography in non-diabetic haemodialysis patients. AB - The aim of this study is to evaluate the effects of haemodialysis with a high ultrafiltration rate on the choroidal and retinal thickness of non-diabetic end stage chronic renal failure (CRF) patients using optical coherence tomography (OCT). Twenty-one eyes of 21 male CRF patients aged between 46 and 80 years were included in this prospective study. Retinal and choroidal thicknesses of the patients were measured using high-resolution OCT line scans with the activated enhanced depth imaging mode before and shortly after haemodialysis. Retinal and choroidal thickness measurements were taken at the fovea and at two points that were 1,500 MUm nasal and temporal to the fovea. The relationships between the haemodynamic changes, intraocular pressure (IOP) and central corneal thickness (CCT) were also evaluated. The mean choroidal thicknesses before haemodialysis at the subfoveal, temporal and nasal locations were 232.81 +/- 71.92, 212.43 +/- 70.50 and 182.14 +/- 68.88 MUm, respectively. The mean choroidal thicknesses after haemodialysis at the subfoveal, temporal and nasal locations were 210.90 +/ 65.53, 195.38 +/- 66.48 and 165.19 +/- 66.73 MUm, respectively. There were significant differences between the choroidal thicknesses before and after haemodialysis (p < 0.001 for all). The mean retinal thicknesses before haemodialysis at the foveal, temporal and nasal locations were 215.86 +/- 41.06, 308.86 +/- 37.73 and 338.00 +/- 33.32 MUm, respectively. The mean retinal thicknesses after haemodialysis at the foveal, temporal and nasal locations were 216.90 +/- 39.70, 313.86 +/- 32.89 and 335.29 +/- 36.85 MUm, respectively. There was no significant difference between the retinal thicknesses before and after haemodialysis (p > 0.05 for all). The mean CCT decreased insignificantly from 550.48 +/- 17.46 to 548.10 +/- 21.12 MUm (p = 0.411). The mean IOP decreased significantly from 14.09 +/- 2.58 to 12.54 +/- 2.23 mmHg (p = 0.003), which did not correlate with the CCT [r = (-)0.134, p = 0.562]. Haemodialysis with a high ultrafiltration volume did not alter the retinal thickness but caused a significant choroidal thinning and an IOP decrease in non-diabetic end-stage CRF patients. PMID- 23456510 TI - The black lacrimal sac: a clinicopathological correlation of a malignant melanoma with anterior lacrimal crest infiltration. AB - Primary lacrimal sac melanoma is an extremely rare clinical entity with fewer than 25 cases reported in the literature. We present a well-documented case of lacrimal sac melanoma with anterior lacrimal crest infiltration and discuss the clinical, radiological and histopathological features along with surgical challenges and treatment. PMID- 23456511 TI - Pupil occlusion due to a large dislocated Soemmering ring in an aphakic eye. AB - We report an 84-year-old female patient who presented to our clinic with a complaint of low vision in her right eye. She described an occasional foreign body-like object around the pupil area. She had a history of extracapsular cataract surgery without an intraocular lens implantation 20 years ago. The patient underwent surgery to remove the foreign body-like object after conducting necessary investigations before surgery. The histopathological features of the specimen were consistent with a Soemmering ring. However, a Soemmering ring does not usually reduce vision unless it is dislocated, as in this case. We report this unusual case to show that ophthalmologists can encounter unexpected cases that present with complications as a result of previous cataract surgery after a lengthy period of time. PMID- 23456512 TI - Shifting bubble-guided sutureless technique for performing descemetorhexis for retained Descemet's membrane after penetrating keratoplasty. AB - We describe the use of anterior segment optical coherence tomography in the diagnosis of inadvertent retention of Descemet's membrane (DM) after penetrating keratoplasty, and a novel technique for its removal in a case of congenital hereditary endothelial dystrophy. In this technique, we use a modification of the shifting bubble technique, commonly used in deep anterior lamellar keratoplasty where a viscocohesive ophthalmic viscosurgical device is injected into the false anterior chamber which causes migration of the central air bubble placed in the anterior chamber peripherally and helps in confirming the correct space. The DM is then peeled in a circular fashion with the help of 23-G vitreoretinal micro forceps. PMID- 23456513 TI - Anterior segment parameters in Indian young adults using the Pentacam. AB - To evaluate Pentacam-Scheimpflug imaging of anterior segment parameters in young Indian adults. In this prospective study 120 eyes of 60 normal Indian subjects with a mean age of 25.93 +/- 6.58 years (range 17-39 years) were assessed by Pentacam. Main outcome measures were central corneal thickness (CCT), thinnest corneal thickness (TCT), apex corneal thickness (apex CT), peripheral corneal thickness at 2, 4, 6 and 8 mm from the thinnest point, location of the thinnest pachymetry, corneal volume (CV), anterior chamber depth (ACD), anterior chamber volume (ACV) and anterior chamber angle (ACA). Independent samples t test, dependent samples t test, ANOVA and Pearson correlation test were used for statistical analysis. The mean CCT, TCT, Apex CT and CV were 544.95 +/- 35.42, 542 +/- 35.19, 545.43 +/- 35.45 and 61.64 +/- 4.17 MUm, respectively. There was a gradual increase in CT from the thinnest point to the periphery. The mean ACD was 3.14 +/- 0.33 mm, mean ACV was 177.77 +/- 29.02 mm(3), and mean ACA was 39.36 degrees +/- 5.42 degrees . There was no significant difference between CCT, TCT and Apex CT. A significant positive correlation was found between CCT and peripheral CT and also between anterior chamber parameters. TCT was mainly located in the inferotemporal and superotemporal zone. No significant difference was found in parameters between the right and left eyes and also between genders. This study provided information about a wide range of parameters in the anterior segment of healthy Indian eyes. These results could be helpful in assessment of patients with corneal diseases, glaucoma and screening for refractive surgeries. PMID- 23456514 TI - Chloroquine and hydroxychloroquine retinopathy-related risk factors in a Turkish cohort. AB - To evaluate the role of previously reported risk factors on developing retinopathy in patients treated with chloroquine (CQ) and hydroxychloroquine (HCQ). Ophthalmologic examination, visual field testing, and spectral domain optical coherence tomography were performed in 31 patients treated with CQ and HCQ. Toxicity diagnosis was proven by electrophysiological assessment. The risk factors reported by the American Academy of the Ophthalmology (AAO) were compared between patients with (n = 5) and without toxicity (n = 26) findings. Risk score was calculated for each patient. CQ daily overdose per actual body weight was significantly higher in affected patients. There was no statistically significant difference between groups concerning risk score, estimated cumulative dose of CQ, daily dose of HCQ and CQ per lean body weight, daily overdose of CQ per lean body weight and actual body weight (>3 mg/kg). The cumulative dose of HCQ was significantly higher in non-affected patients. The risk factors reported by the AAO might not be applicable to all CQ- and HCQ-treated patients. Different risk factors not yet reported may play a role in the development of CQ and HCQ retinopathy. PMID- 23456515 TI - The significance of non correlation between interleukin-8 serum levels with bone marrow microvascular density in patients with myeloma multiple. AB - In multiple myeloma (MM), angiogenesis plays a substantial role in disease progression. Interleukin-8 (IL-8), a pro-inflammatory chemokine with potent pro angiogenic properties, has been implicated in the pathophysiology of MM. The aim of the study is to measure serum levels of IL-8 in MM patients and to correlate them with markers of angiogenesis, such as circulating levels of platelet derived growth factor-AB (PDGF-AB) and angiogenin (Ang), and bone marrow microvascular density (MVD). Fifty-three newly diagnosed MM patients, 23 of them, who reached plateau phase after effective treatment and 20 healthy controls, were studied. Serum levels of PDGF-AB, Ang and IL-8 were measured by ELISA, whereas bone marrow MVD was estimated by immunohistochemical staining of vessels with anti-CD31. All measured parameters were higher in MM patients compared to controls and in increased disease stages. They all also significantly decreased in plateau phase. IL-8 correlated positively with Ang and PDGF-AB, but not with MVD. The circulating levels of IL-8, PDGF-AB and Ang are elevated in patients with MM. The lack of correlation between IL-8 with MVD suggests that its levels represent the inflammatory element of MM disease and the participation in angiogenesis process is rather complex with multifactorial mechanisms. PMID- 23456516 TI - Ornithine phenylacetate revisited. AB - In patients with liver failure hyperammonemia is associated with the development of hepatic encephalopathy (HE) and immune impairment. Treatment of hyperammonemia is an unmet clinical need. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. This review describes the mechanism of action of OP and its effect on plasma ammonia levels, brain function and inflammation of OP in both acute and chronic liver failure. Ammonia levels could shown to be reduced for up to 24 h in animal models until 120 h in patients with repeated dosing of the drug. Reduction of plasma ammonia levels is due to the stimulation of ammonia removal in the form of glutamine (through glutamine synthetase), the direct excretion of ammonia in the form phenylacetylglutamine and to a normalisation of glutaminase activity in the gut. Administration of OP is associated with a reduction of brain oedema in rats with chronic bile duct ligation and diminution of intracranial hypertension in a pig model of ALF. Studies to date have indicated that it is safe in humans and trials in overt HE are underway to establish OP as a treatment for this major complication of liver disease. PMID- 23456517 TI - Disaccharides in the treatment of hepatic encephalopathy. AB - Management of hepatic encephalopathy (HE) primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as nonabsorbable disaccharides and antimicrobial agents like rifaximin. The nonabsorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and minimal hepatic encephalopathy (MHE). Lactulose significantly improves cognitive function and health-related quality of life in patients with MHE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Lactulose has also shown to be effective in primary and secondary prophylaxis of HE. Disaccharides were found to be comparable to rifaximin in recent systemic reviews in the treatment of HE however conclusion was based on inclusion of some poor quality trials. Combination therapy of disaccharides either with rifaximin, L-ornithine L aspartate,probiotics for the treatment of HE needs further validation in large studies. PMID- 23456518 TI - Strategies to reduce relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia. AB - The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant. PMID- 23456519 TI - 17beta-Estradiol enhances the efficacy of adipose-derived mesenchymal stem cells on remyelination in mouse model of multiple sclerosis. AB - Previous studies have demonstrated the potential of monotherapy with either mesenchymal stem cells (MSCs) or estrogen in autoimmune and cuprizone models of multiple sclerosis (MS). The aim of this study was to examine the effects of co administration of 17beta-estradiol (E2) and adipose-derived mesenchymal stem cells (ADSCs) on remyelination of corpus callosum axons in a cuprizone model of MS. Forty eight male C57BL/6 mice were fed cuprizone (0.2%) for 6 weeks. At day 0 after cuprizone removal, animals were randomly divided into four groups. The E2 monotherapy, ADSCs monotherapy, E2/ADSCs combined therapy and vehicle control. Some mice of the same age were fed with their normal diet to serve as healthy control group. E2 pellets, designed to release 5.0 mg E2 over 10 days, were implanted subcutaneously. 10(6) PKH26 labeled ADSCs were transplanted into lateral tail. The extent of demyelination, remyelination, and cell type's composition of host brain were examined at 10 days post-transplantation in the body of the corpus callosum. Transplanted cells migrated to the corpus callosum injury. Histological examination revealed efficacy of intravenous ADSCs transplantation in remyelination of mouse cuprizone model of MS can be significantly enhanced by E2 administration. Flow cytometry showed that the mean percentages of expression of Iba-1, Olig2 and O4 were significantly increased in E2/ADSCs combined therapy in comparison with ADSCs monotherapy. In conclusion, the findings of this study revealed that E2 administration enhanced efficacy of intravenous ADSCs transplantation in remyelination of corpus callosum axons in mouse cuprizone model of MS. PMID- 23456520 TI - In vitro susceptibility of aflatoxigenic and non-aflatoxigenic Aspergillus flavus strains to conventional antifungal agents. AB - Presently appearance of resistance to antifungal agents among Aspergillus species is dramatically increasing. The objective of this study was to look at the in vitro activities of antifungal drugs against Iranian clinical (from nail, bronchoalveolar lavage, paranasal sinus) isolated A. flavus strains. The susceptibility of 45 aflatoxigenic and non-aflatoxigenic Aspergillus flavus strains were evaluated to six antifungal agents (caspofungin, itraconazole, amphotericin B, ketoconazole, fluconazole, nystatin) using CLSI M38-A2 broth microdilution method. The results indicated that 57.1%, 28.6% of aflatoxigenic and 25.8%, 6.5% of non-aflatoxigenic isolates were susceptible to caspofungin, amphotericin B respectively. All isolates but one aflatoxigenic strain were sensitive to ketoconazole. All 45 strains showed to be resistant to nystatin. Also 64.28%, 92.9% of aflatoxigenic and 64.51%, 100% of non-aflatoxigenic isolates were resistant to fluconazole and itraconazole in ranking order. There was no statistically significant difference between the susceptibilities of aflatoxigenic and non-aflatoxigenic strains of A. flavus to tested antifungal agents. PMID- 23456522 TI - Radiation exposure to critical organs in panoramic dental examination. AB - Nowadays, radiography is a necessary procedure in diagnosis and treatment of patients with dental problems. According to the ALARA (as low as reasonably achievable) principle, dentists must take radiographs of sufficient quality at the lowest possible radiation dose to the patients. The assessment of patient dose on panoramic radiography is difficult because of dynamic nature of the imaging process and the narrow width of the x-ray beam. The present work describes an experiment undertaken using thermoluminescence dosimeters (TLD-100) to obtain the absorbed dose in organs and sensitive tissues in head and neck region during panoramic radiography, based on patient measurement. The overall mean entrance surface dose on thyroid, right and left lens of eyes, parotid glands (right and left) and occipital region in panoramic were 38, negligible, negligible, 367, 319 and 262 MUGy, respectively. The results show that there are differences between patient doses examined by different panoramic systems. There is a tendency for lower organ doses for digital compared with analogue panoramic units. PMID- 23456521 TI - Evaluation of group B Streptococci colonization rate in pregnant women and their newborn. AB - Group B Streptococcus (GBS) is one of the most important bacteria in the majority of maternal and neonatal infections, such as chorioamnionitis, endometritis, bacteremia, sepsis and meningitis. During pregnancy, GBS screening is one of the recommended strategies that are recommended by center of disease control (CDC). This study was aimed to determine the rectovaginal colonization prevalence among pregnant women, and also the rate of transmission to their offspring. Between June 2008 and April 2009, two hundred pregnant women admitted in department of Obstetrics and Gynecology (Ghaem Hospital, Mashhad, Iran) were enrolled in present study. Samples from maternal rectum and vagina as well as neonate ear and umbilical cord were taken for culture. The colonization rate for GBS in pregnant women and their neonates was around 6% and 5% respectively. All the carrier mothers were cases with premature rupture of membranes (at least 18 hours before delivery). In terms of colonization, there was a significant correlation between mothers and newborns, and more than 80% of neonates from GBS carrier mothers were colonized by GBS. PMID- 23456523 TI - Biochemical risk factors for stone formation in healthy school children. AB - Prevalence of urolithiasis in childhood is increasing. The wide geographic variation in the incidence of lithiasis in childhood is related to climatic, dietary, and socioeconomic factors. Many children with stone disease have a metabolic abnormality. In Southeast Asia, urinary calculi are endemic and are related to dietary factors. The main aim of this study was to determine the prevalence of renal stone, urine metabolic abnormality, control of blood pressure and demographic character in elementary school children of Qom. A cross sectional study was performed on 110 primary school children (56 girls and 54 boys) aged 7 to 11 years old. Demographic data such as age, height, weight were gathered, and systolic and diastolic blood pressure, Urine analysis and culture, urinary levels of calcium, creatinine, phosphorus, magnesium, sodium, potassium, uric acid, cystine, citrate, oxalate, protein and sonographic findings were evaluated. The mean (+/-SD) of age was 8.85+/-1.51 years. Only one child had renal stone (1%), but the prevalence of abnormal renal sonography was 7%. The most prevalent urine metabolic abnormalities were hypercalciuria (23%) and hypocitraturia (100%). 11.2% of children had positive urine culture that all were female. The prevalence of high blood pressure was 7.1% for girls and 11.1% for boys. The prevalence of renal stone in children in this study was 1%, which means the accurate judgment about the prevalence of renal stone in Qom city needs more comprehensive studies. Similar to other studies in Iran this study shows that the prevalence of hypercalciuria is significantly higher comparing to other countries, it may be associated with excessive intake of sodium. PMID- 23456524 TI - Depression in parents of children with cerebral palsy in Bosnia and Herzegovina. AB - The aim of the research is to examine depression in parents of children with cerebral palsy, with hypothesis to have more depressive symptom among mothers of children with cerebral palsy. The sample of examinees (between 23 and 62 age) was used in this research. The first subsample of examinees (N=23) was made of mothers (average 33+/-5.83) of children with cerebral palsy. The second subsample of examinees (N=12) was made of fathers of children with cerebral palsy (average 38+/-9.8). The third subsample of examinees (N=16) represented the control group, and it was made of mothers of children without disorders (average 38+/-6.57). For the purpose of quantitative measurement of depression, the Zung self-evaluated method for depression was applied. All data research were processed by parametric and nonparametric statistics. The frequencies and percents were also calculated, and Kruskal-Valis single-factor analysis of variants was applied for checking the hypothesis. According to the results of this research, it was concluded that there was no statistically significant difference in the evaluation of depression between mothers and fathers of children with cerebral palsy, as well as there is no statistically significant difference in relation to mothers of children without disorders. PMID- 23456525 TI - The prevalence of iodine deficiency disorder in two different populations in northern province of Iran: a comparison using different indicators recommended by WHO. AB - Comparison of the prevalence of iodine deficiency disorder (IDD) in neonates and school children using two different WHO indicators. From 2006 to 2010, 119701 newborns were screened by measurement of serum TSH level by heel prick. Neonates who had blood TSH >= 5 mIU/l were recalled for more evaluation. In the same period of time, urine iodine was measured in 1200 school-aged children. The severity of IDD was classified using WHO, UNICEF, ICCIDD criteria. Between 2006 and 2010 a total of 138832 neonates were screened in Guilan province and the total recall rate (neonates with TSH level >= 5 mIU/l) was 1.8 %. The incidence rate of Congenital Hypothyroidism (CH) was 1/625. The median urine iodine level in school-aged children was 200-299 MUg/l. Considering the WHO, UNICEF, ICCIDD criteria, Guilan province would be classified as a none-IDD endemic area. However, health care systems should pay attention to the iodine excess and the risk of iodine induced hyperthyroidism in this population. PMID- 23456526 TI - A rare cytogenetic presentation of acute myeloid leukemia (AML-M2). AB - Acute myeloid leukemia (AML) with t(8;21)(q22;q22) generating the AML1/ETO fusion gene on 8q22 is a distinct type of AML t(8;21) category (WHO)/AML-M2 (FAB), generally associated with a favourable prognosis. Variant additional chromosomal abnormalities are frequently reported. We report three adult cases of this category with unusual karyotype. Bone marrow cytogenetics of case no. 1: 45,X,-Y, t(8;21)(q13;q22) with a novel breakpoint of chromosome 8 at (q13). Case no. 2: 46,X,t(X;2)(q22;q37),t(3;7)(q21;q36),t(5;14)(p15;q11),del(8)(q22) a complex rearrangement without the involvement of chromosome 21. Case no. 3: 49,XX,+5, t(8;21)(q22;q22), +16, +der(21)t(8;21)(q22;q22) with additional der(21). Endometrial in this case which was positive for myeloperoxidase (MPO) and CD117 conforming the AML infiltration. All are morphologically AML with t(8;21). Relevant literature in cytogenetic of AML-M2 is reviewed. The molecular mechanism involved in unusual rearrangements and clinical significance of them are subjected for further studies. PMID- 23456527 TI - Brachydactylia as a phenotypic feature of mitochondrial disorder. AB - Mitochondrial disorders (MIDs) may occasionaly go along with dysmorphism but hand deformities, as in the following case, have been only rarely reported. A 72 year old female with ptosis, hypoacusis, tremor, myopathy, diabetes mellitus, arterial hypertension, severe cardiac disease, pulmonary hypertension, gastric carcinoid, hepatopathy, generalised atherosclerosis, anemia, polyarthrosis, and hyperlipidemia, additionally presented with brachydactylia. Upon neurological work-up a MID was suspected. The family history was positive for diabetes but negative for brachydactylia or other features of a MID. MIDs may be associated with brachydactylia. Skeletal deformities may be a phenotypic manifestation of MIDs. PMID- 23456528 TI - Transient neonatal diabetes as a presentation of Fanconi- Bickel Syndrome. AB - Fanconi- Bickel Syndrome (FBS) is a rare type of glycogen storage disease (GSD) Characterized by hepatomegaly, proximal renal tubular acidosis (RTA) and marked growth retardation. We report a case of FBS presenting with diabetic ketoacidosis and transient neonatal diabetes. A female infant, product of consanguineous marriage presented with diabetic ketoacidosis at age 33 days, and was treated as neonatal diabetes with insulin. At age 14 months, insulin was discontinued. She presented with short stature, hepatomegaly, RTA and hypophosphatemic rickets at age 4 and (FBS) was diagnosed. Diagnosis was confirmed by mutation analysis, showing mutation in SLC2 A2 gene. In conclusion,: neonatal diabetes or diabetic ketoacidosis may be the first presentation of infants with FBS. PMID- 23456529 TI - Primary ovarian and pararectal hydatid cysts mimicking pelvic endometriosis. AB - We report a case of 48-year-old woman with multiple hydatid cysts in pararectal region and right paraovarian localization with an unusual sonographic and computed tomographic presentation mimicking a pelvic endometriosis. During laparotomy, multiple pararectal and right ovarian cysts resembling endometriosis were resected. Pathologic examination gives the diagnosis of hydatid cysts. Retrospectively, we investigate the primary infection but the patient had no history of hepatic and liver involvement, it is a case of primary infection. PMID- 23456530 TI - Recurrent bacterial meningitis in a child with hearing impairment, mondini dysplasia: a case report. AB - Recurrent bacterial meningitis is not a common disease and makes physicians seek underlying predisposing factors which can result from anatomic anomalies or immunodeficiency. In this paper we present a boy with recurrent bacterial meningitis with the history of trauma and sensorineural hearing loss. Mondini dysplasia was demonstrated with computed homographic scans (CT-Scan) of temporal bones. PMID- 23456531 TI - Multi organ failure following intravenous gasoline for suicide: a case report. AB - Hydrocarbons are ubiquitous in daily life and include plant and animal fats, alcohols, solvents, natural gas, petroleum derivates. Majority of intoxication reports of hydrocarbons are due to inhalation or ingestion, but there is few reports about intravenous injection of gasoline. We report a 58 year-old man who injected gasoline intravenously for suicide. He developed soft tissue necrosis of forearm and bilateral pulmonary infiltration. He underwent fasciotomy and extensive debridement of necrotic tissues, at the operation room. He was intubated and mechanically ventilated because of acute lung injury. He developed acute kidney injury after 2 days. These symptoms seem to be due to extravasation of gasoline from vessels which lead to inflammation, cell damage and organ failure. The patient developed multi organ failure which unfortunately did not respond to our treatment and he died at day 21. Management of gasoline intoxication depends on the rout of exposure. Like other types of toxications, intravenous toxication has pulmonary involvement, however in this case we had multiple organ involvement. It seems that in such cases we should consider early end organ targeted therapy to stop the future organ failure. PMID- 23456532 TI - Non parasitic splenic cyst: a case report. AB - Primary splenic cyst is a rare entity and majority of the cases are classified as epithelial cysts. They are uncommon, comprising only about 10% of benign non parasitic cysts. Most of the cysts are asymptomatic, and they are incidental findings during abdominal ultrasonography. We report a case of 20 years old male who presented with 1 year history of mild abdominal pain and left upper quadrant fullness. Ultrasound and computed tomography (CT) both were suggestive of splenic cyst. Serological tests were negative for parasitic infection. Splenectomy was done. Histopathological findings are consistent with splenic epithelial cyst. PMID- 23456533 TI - Opsoclonus associated with salmonellosis in a 6-week-old infant. AB - A 6-week-old male infant presented with 2 days of fever, emesis, and diarrhea, associated with episodic and chaotic rapid eye movements, determined to be opsoclonus. An electroencephalogram (EEG) obtained during the events was normal. He was treated empirically for meningitis, and an initial workup for neuroblastoma including urine homovanillic acid and vanillylmandelic acid levels, abdominal ultrasonography, and computed tomography (CT) of the chest, abdomen, and pelvis was negative. Stool and blood cultures were positive for Salmonella, and antibiotic regimen was adjusted appropriately. Over the next few days, his fever, emesis, and diarrhea subsided, and the opsoclonus resolved by hospital day 6. He was back to baseline by hospital day 9. Although there have been cases of parainfectious opsoclonus associated with Lyme disease, enterovirus, Streptococcus, and West Nile virus, this represents the first reported pediatric case of opsoclonus associated with salmonellosis. Only 2 such cases in adults have been reported in the literature. PMID- 23456534 TI - A unique phenotype of 2q24.3-2q32.1 duplication: early infantile epileptic encephalopathy without mesomelic dysplasia. AB - The voltage-gated sodium channel genes and HOXD genes are clustered on chromosome 2q, and duplication of this region is associated with 2 clinical phenotypes: early-onset epilepsy and mesomelic dysplasia Kantaputra type, respectively. We report a case involving 2q24.3-2q32.1 duplication encompassing both the voltage gated sodium channel and HOXD gene clusters, which were detected by a comparative genomic hybridization array. The associated clinical features were early infantile-onset epilepsy, hypoplastic left heart syndrome, and global developmental delay. However, no features of mesomelic dysplasia were found. A fluorescent in situ hybridization study showed that the noncontiguous insertion of the duplicated chromosome 2q segment into chromosome 6q was inherited from the father, who has a balanced insertional translocation. The unique genotype phenotype correlation in the present case suggests that dosage-sensitive effects might apply only to the voltage-gated sodium channel genes. PMID- 23456535 TI - Unilateral foot drop as an initial presentation of a brain tumor in a child. AB - Foot drop is commonly caused by compromise of the peripheral nervous system. Unilateral foot drop as the first sign of a parasagittal brain tumor has been reported in the adult literature but never previously in the pediatric population. We report a child with a right parietal rhabdomyosarcoma in which foot drop was the only abnormal neurologic finding at initial presentation. Localization to the central nervous system should be included in children presenting with foot drop. PMID- 23456536 TI - Can global positioning systems quantify participation in cerebral palsy? AB - This study examined whether motor-related participation could be assessed by global positioning systems in individuals with cerebral palsy. Global positioning systems monitoring devices were given to 2 adolescent girls (14-year-old with diplegic cerebral palsy and her 15-year-old healthy sister). Outcome measures were traveling distances, time spent outdoors, and Children's Assessment of Participation and Enjoyment questionnaires. Global positioning systems documented that the girl with cerebral palsy did not visit nearby friends, spent less time outdoors and traveled shorter distances than her sister (P = .02). Participation questionnaire corroborated that the girl with cerebral palsy performed most activities at home alone. Lower outdoor activity of the girl with cerebral palsy measured by a global positioning system was 29% to 53% of that of her sibling similar to participation questionnaires (44%). Global positioning devices objectively documented low outdoor activity in an adolescent with cerebral palsy compared to her sibling reflecting participation reported by validated questionnaires. Global positioning systems can potentially quantify certain aspects of participation. PMID- 23456537 TI - Cation modulation of hemoglobin interaction with sodium n-dodecyl sulfate (SDS). III: Calcium interaction with R- and mixed spin states of hemoglobin S at pH 5.0: the musical chair paradox. AB - We investigate the interaction of Ca(2+) (0-500 uM) and a membrane mimic (0.60 mM SDS) with both the R- and mixed spin states hemoglobin S (HbS) as a function of time. These interactions were carried out at pH 5.0. We aim at ascertaining if there is or are differences in the UV-Visible spectra of such interactions to account for the dynamics of calcium ion concentrations [Ca(2+)] in initiating structures which may ultimately suggest HbS polymerization and or resistance to Plasmodium attack. From our results, we conclude that (a) simultaneous interaction of 40 uM Ca(2+) and 0.60 mM SDS with the R state protein would promote structural formations that can "lock up" the protein for nucleation on the membranes and or become cytotoxic to the parasite; (b) simultaneous R state HbS-SDS or R state HbS-Ca(2+) would lead to enhanced hemin formation and less deoxyHb species. This condition is unlikely to precipitate polymerization in the HbS but the resulting hemin would poison the parasite; (c) the mixed spin state HbS-SDS and 40 uM Ca(2+) interaction yields more toxic products to that of the interaction of the mixed spin HbS-SDS with 500 uM Ca(2+) thus suggesting why the 40 uM Ca(2+) is important in parasite Hb proteolysis; and (d) pronounced structural changes on interaction with SDS and Ca(2+) are more in the R state to the mixed spin state. PMID- 23456538 TI - Inhibition of connective tissue growth factor suppresses hepatic stellate cell activation in vitro and prevents liver fibrosis in vivo. AB - Activation of hepatic stellate cells (HSC) represents a critical event in fibrosis, and connective tissue growth factor (CTGF) plays a profibrotic activity and a key factor in the pathogenesis of tissue fibrosis. The current study aimed to determine whether lentivirus-mediated short hairpin RNA (shRNA)-targeted CTGF downregulates the CTGF expression and furthermore whether it suppresses the activation and proliferation of HSC in vitro and prevents liver fibrosis in vivo. HSC-T6 cells were treated with recombinant lentivirus carrying CTGF siRNA. Real time PCR, Western blotting, MTT, and flow cytometry were performed to investigate the activation and proliferation of HSC-T6 cells in response to CTGF silence. CCl4-induced rats were received lentivirus containing CTGF siRNA by intraportal vein injection. Levels of liver fibrosis were assessed by biochemical and histopathologic examinations. Recombinant lentivirus containing CTGF siRNA could effectively and specifically downregulate the expression of CTGF in both HSC-T6 cells and CCl4-induced rats with liver fibrosis. Blockade of CTGF resulted in significant inhibition of HSC activation and proliferation with decrease in TIMPs, MMP2, MMP9, and collagen I, as well as increase in cells in S phase. Silencing CTGF expression with siRNA prevented liver fibrosis in CCl4-induced rat model. These findings indicated that CTGF plays a key role in the pathogenesis of liver fibrosis and lentiviral-mediated CTGF siRNA has the potential to be an effective treatment for liver fibrosis. PMID- 23456539 TI - Cancer-related coagulopathy (Trousseau's syndrome): review of the literature and experience of a single center of internal medicine. AB - Venous thromboembolism (VTE) occurs roughly in one out of five cancer patients and is the second cause of death in this population. When all cancer patients are considered together, a sevenfold increased risk for VTE has been calculated. Over the last 20 years, a number of risk factors have been recognized. These have been used in several risk assessment models aimed at identifying high-risk patients who are therefore candidates for thromboprophylaxis. An easily applicable and reliable risk score is based on the cancer site, hemoglobin levels, pre chemotherapy platelet and leukocyte counts as well as body mass index. The additional measurement of two biomarkers, namely D-dimer and soluble P-selectin, may improve estimates of the cumulative VTE probability. A variable incidence of VTE has been determined in patients with specific types of malignancy, with the highest odds in those with pancreatic cancer followed by head and neck tumors. In terms of histotype, the risk of VTE is significantly higher in patients with adenocarcinoma than in those with squamous cell carcinoma and in patients with high-grade versus low-grade tumors. Cancer therapy may also be responsible for VTE; specifically, the presence of an indwelling central venous catheter, immunomodulatory drugs such as thalidomide and lenalidomide, monoclonal antibodies, such as bevacizumab, erythropoiesis-stimulating agents and hormonal therapy with tamoxifen place patients at higher risk. The pathogenesis of cancer related VTE is poorly understood but is likely to be multifactorial. "Virchow's triad," comprising stasis consequent to a decreased blood flow rate, an enhanced blood clotting tendency such as accompanies inflammation and growth factor expression, and structural modifications in blood vessel walls, is thought to play a central role in the induction of VTE. The prophylaxis and treatment of VTE are based on well-established drugs such as vitamin K antagonists and unfractionated and low-molecular-weight heparins as well as on an expanding group of new oral anticoagulants, including fondaparinux, rivaroxaban, apixaban and dabigatran. Furthermore, aspirin has been shown to prevent arterial thrombosis and to reduce the rate of major vascular events. Guidelines for the general management of VTE in cancer patients and in those with an indwelling central venous catheter have been recently developed with the aim of selecting the most rational therapeutic approach for each clinical situation. The main features of VTE based on our own observations of 92 cancer patients and 159 patients with non neoplastic disease are briefly described herein. PMID- 23456540 TI - Impact of a preventive intervention for perinatal depression on mood regulation, social support, and coping. AB - Perinatal depression prevention trials have rarely examined proximal outcomes that may be relevant for understanding long-term risk for depression. The Mothers and Babies (MB) Course is a cognitive-behavioral depression prevention intervention, which has been shown to prevent depressive symptoms among at-risk perinatal women of color. This study examined intervention impact on three proximal outcomes that are theoretically linked with the intervention's model of change and have been empirically linked with risk for depression: mood regulation expectancies, perceived social support, and coping. The study used data from a randomized intervention trial of the MB Course with 78 low-income, predominantly African-American perinatal women enrolled at one of four home visitation programs in Baltimore City. Mood regulation expectancies, perceived social support, and coping were assessed with self-report instruments at baseline, post-intervention, and 3- and 6-month follow-ups. The intervention group experienced 16 % greater growth in mood regulation from baseline to 6-month follow-up compared to the usual care group, suggesting a prevention effect. The pattern of findings was similar, although not statistically significant, for social support. Contrary to prediction, the control group experienced less growth in avoidant coping than the intervention group. Findings indicate the MB Course enhances mood regulation, which may facilitate prevention of depression over time. Assessment of intervention effects on proximal outcomes is beneficial for understanding how interventions may enhance protective factors relevant to successful long-term outcomes. PMID- 23456541 TI - Validity of somatic symptoms as indicators of depression in pregnancy. AB - Somatic symptoms (e.g., fatigue, appetite changes, and sleep disruption) are common to both pregnancy and depression. The goal of the present study was to examine the validity of somatic symptoms as indicators of depression during pregnancy. The Inventory of Depression and Anxiety Symptoms (IDAS) was administered to a cross-sectional sample of 255 pregnant women as well as 820 women from five community-based samples, who served as a control group. Confirmatory factor analysis (CFA) was used to evaluate the fit of a single factor model of depression in pregnant and community samples. Multigroup CFA was used to test the invariance of the factor loadings of eight depression-related symptom scales. The fit for a one-factor model was adequate for both the pregnant and community samples. All eight IDAS scales were valuable indicators of depression in the community group; however, Appetite Loss and Appetite Gain were poor indicators of depression among the pregnant women. The factor loadings for Lassitude and Appetite Gain were significantly weaker amongst the pregnant women than community women. The magnitude of the factor loadings for Insomnia and Well Being were significantly greater for the pregnant group. With the exception of appetite disturbance, somatic symptoms, though a common occurrence during pregnancy, are valid indicators of depression during pregnancy. When assessing for prenatal depression, somatic symptoms should not necessarily be dismissed as normative pregnancy experiences. PMID- 23456543 TI - Spectral domain optical coherence tomography findings in bilateral peripheral cone dystrophy. AB - INTRODUCTION: To report spectral domain optical coherence (OCT) tomography findings in a case of bilateral peripheral cone dystrophy. CASE REPORT: A 21-year old man complained of blurred visual fields on the lateral sides of both eyes. The patient's best-corrected visual acuity was 20/20 in both eyes. Fundus examination revealed mild temporal pallor, while fluorescein angiography did not show any abnormalities. Humphrey's visual field revealed a C-shaped scotoma. Photopic electroretinogram (ERG) and 30-Hz flicker revealed decreased cone function; however, scotopic ERG noted a normal response. Multifocal ERG revealed a relatively well-preserved macular area but with reduced amplitude in the peripheral areas of both eyes. On OCT, the photoreceptor inner and outer segment junction and retinal pigment epithelium (RPE) layers were well preserved in both eyes, except for a slight decrease in outer layer thickness. Moreover, on the macular thickness map obtained from Cirrus HD-OCT, a reduction in internal limiting membrane-RPE thickness that correlated well with visual field defects was revealed in both eyes. On the retinal nerve fiber layer (RNFL) thickness map obtained from Cirrus HD-OCT, the superior quadrant showed decreased RNFL thickness; however, thickness in the temporal quadrant corresponded with thickness in the macular area and was normal in both eyes. DISCUSSION: The OCT of a patient with peripheral cone dystrophy revealed decreased thickness of the macula with well-preserved retinal structures, which may be one of the distinctive features of this condition. PMID- 23456542 TI - In the Zzz zone: the effects of Z-drugs on human performance and driving. AB - Despite their improved pharmacokinetic profile, the Z-drugs, zolpidem, zopiclone, and zaleplon, have a spectrum of adverse effects comparable to benzodiazepines. This review focuses on the impairment from Z-drugs on cognition, behavior, psychomotor performance, and driving ability. Z-drugs are short-acting GABA agonists that reduce sleep latency without disturbing sleep architecture. Bizarre behavioral effects have prompted warnings on the prescription, dispensation, and use of Z-drugs. Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives, that are taken at higher-than recommended doses and when mixed with other psychoactive substances including alcohol. Zopiclone and higher doses of zolpidem are more likely to cause anterograde amnesia than zaleplon. Z-drugs, especially zolpidem, are associated with complex behaviors such as sleepwalking, sleep-driving, and hallucinations. Patients taking zopiclone and zolpidem have an increased risk of motor vehicle collisions, over double that of unexposed drivers. Driving impairment occurs with zopiclone and higher doses of zolpidem but is unlikely to occur after 4 h post zaleplon administration. The residual effect of Z-drugs on next-day cognitive and psychomotor performance has significant impact on lifestyle, safety, and occupational considerations, including motor vehicle and machine operation. The risk-benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions. Prescribers should warn patients taking Z-drugs of minimum time thresholds before they operate machinery or drive motor vehicles. PMID- 23456544 TI - Frontal sinusitis caused by first and second secondary middle turbinates co existing with an accessory middle turbinate. AB - The anatomy of the nasal cavity and the paranasal sinuses is complex. After widespread use of endoscopes and computed tomography, many variations have been described. Secondary and accessory middle turbinates (AMTs) can mimic the real middle turbinate. These variations may arise during embryological development. I believe that detailed knowledge of anomalies of the sinonasal tract is critical for successful management, and important in enabling the surgeon to perform safe surgery. Failure to recognize the variants could lead to inadvertent damage to the orbital lamina papyracea during surgery. Knowledge and correct description of anatomical variations of the turbinates by use of computed tomography images will aid achievement of correct diagnosis and surgical management and avoidance of potential complications during endoscopic procedures. To the best of my knowledge, this is the first report in the world literature of sinusitis caused by first and second secondary middle turbinates co-existing with an AMT. PMID- 23456545 TI - F-18 FDG-PET/CT in evaluation of patients with fever of unknown origin. AB - OBJECTIVES: This study was carried out to evaluate the diagnostic utility of FDG PET/CT in patients with fever of unknown origin (FUO). METHODS: Medical records of 103 patients who underwent FDG-PET/CT and anatomic imaging as a part of FUO workup were analyzed. Final diagnosis of the cause of FUO was reached based on serologic assays, cultures, biopsy, surgery or 6 months of clinical follow-up. RESULTS: The definite cause of fever was established in 69/103 patients. Abnormal FDG uptake was found in 63/103 patients and contributed to the final diagnosis (TP) in 62 patients (98.48 %). Of the remaining 40 patients with negative PET/CT, the final definite cause of fever (FN) could be determined only in seven patients (17.5 %). PET/CT had a sensitivity, specificity, positive predictive value and negative predictive value of 90, 97, 98.4 and 82.5 % compared to 43.5, 67.6, 73.2 and 37.1 %, respectively, for anatomic imaging. FDG-PET/CT had a higher accuracy (92.2 vs. 51.5 %; p = 0.003) compared to anatomic imaging for suggesting a cause of FUO. CONCLUSIONS: PET/CT showed high sensitivity and specificity in suggesting a definite diagnosis in the evaluation of FUO. PMID- 23456546 TI - IgG4-related inflammatory pseudotumors mimicking multiple meningiomas. AB - IgG4-related disease is an emerging clinicopathologic entity. Hypophysitis, diffuse thickening of dura, and enlargement of the trigeminal nerve are well known intracranial involvements of IgG4-related disease. This report of a case of systemic IgG4-related disease is the first to present neuroimaging of apparent supratentorial meningioma-like lesions and thickening and contrast enhancement of the walls of the intracranial internal carotid arteries. It is important to recognize IgG4-related intracranial pseudotumors so that patients do not undergo unnecessary surgical procedures. PMID- 23456547 TI - 18F-FDG-PET/CT findings of retroperitoneal tumors: a pictorial essay. AB - A variety of different tumors can arise from any of the tissues present in the retroperitoneum, and they exhibit a wide range of pathologic types. Although computed tomography (CT) and magnetic resonance imaging (MRI) can demonstrate important characteristics of these tumors, diagnosis is often challenging for radiologists. The purpose of this pictorial essay is to review (18)F fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) features of different kinds of benign and malignant retroperitoneal tumors in comparison with CT or MRI findings alone and to become familiar with the wide variety of imaging characteristics. PMID- 23456548 TI - Measurement consistency of MR elastography at 3.0 T: comparison among three different region-of-interest placement methods. AB - PURPOSE: To test inter- and intraobserver consistency of liver stiffness measurement on MR elastography (MRE) at 3.0 T. MATERIALS AND METHODS: Two abdominal radiologists independently measured stiffness of the liver on MRE in three volunteers and seven patients with chronic liver diseases using three different region-of-interest (ROI) placement methods. Methods 1 and 2 involved placing circular and free-hand-drawn ROIs, respectively, visually referring to anatomical (three-dimensional T1-weighted) and wave images. Method 3 involved placing ROIs on the fused images of MRE and anatomical images developed on a work station, visually referring to wave images. The inter- and intraobserver consistency was assessed with regression and Bland-Altman analysis. RESULTS: Thirty-eight images were available for measurement in total. As for interobserver consistency, method 3 showed the best regression coefficient, correlation coefficient, and y intercept. The absolute values of the interobserver differences for method 3 were significantly smaller than those of method 1 or method 2 (p < 0.05, each). Intraobserver consistency of method 3 was excellent for both observers. CONCLUSION: Stiffness measurement of the liver on MRE performed with the fusion method at 3.0 T provides the highest inter- and intraobserver consistency. PMID- 23456549 TI - MicroRNA-335 acts as a candidate tumor suppressor in prostate cancer. AB - MicroRNA-335 (miR-335) acts as a tumor suppressor or a tumor promoter in different human malignancies. However, the involvement of miR-335 in prostate cancer (PCa) is still unclear. The purpose of this study was to investigate the functional and clinical significance of miR-335 in PCa. miR-335 expression in 3 PCa cell lines (LNCaP/DU145/PC3) and in 20 clinical PCa tissues were detected by real-time quantitative reverse transcriptase-PCR compared with corresponding controls. The function of miR-335 was investigated for cell proliferation, invasion and migration in PCa cells transfected with agents containing EGFP-miR 335 expression vector. Additionally, miR-335 expression in 104 clinical PCa tissues was detected by in situ hybridization. Its assocaitions with clinicopathological features and prognosis in patients with PCa were also determined. miR-335 was significantly down-regulated in PCa cell lines than in the normal prostate cell line (P < 0.01). With the similar results in vitro, the reduced expression of miR-335 was also found in human PCa tissues comparing with paired adjacent benign prostate tissues (P < 0.05). Moreover, the increased expression of miR-335 suppressed cell proliferation, invasion and migration of PCa cell lines in vitro. Turning to its clinical significance, the low expression of miR-335 was significantly associated with high Gleason Score (P = 0.04), advanced clinical stage (P = 0.04), and positive metastasis (P = 0.02), but not with prognosis in PCa patients. Our data demonstrated for the first time the inhibitory effect of miR-335 on cell proliferation and invasion for PCa cells. The loss of this microRNA might be associated with clinical progression of PCa patients. PMID- 23456550 TI - Management of infantile hemangiomas : current and potential pharmacotherapeutic approaches. AB - Infantile hemangiomas (IH), benign vascular neoplasms, are the most common tumors of infancy and childhood. Most IH are medically insignificant; however, a proportion will require treatment because of interference with vital structures, threat of significant disfigurement, ulceration, or bleeding. This article reviews current and potential pharmacotherapeutic approaches to the treatment of IH. While corticosteroids have long been considered the mainstay of medical therapy for IH, several new treatments have recently emerged, the most promising of which is oral propranolol. Topical timolol and imiquimod are additional new therapies that may also prove to be effective, particularly for the treatment of superficial IH. PMID- 23456551 TI - TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis. AB - TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10-100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR-644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2(Tyr15). Moreover TR-644 inhibited VEGF-induced phosphorylation of VE cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1-1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg). PMID- 23456552 TI - Pros and cons of screening for sudden cardiac death in sports. PMID- 23456553 TI - A firm foundation. PMID- 23456554 TI - Arthroscopic classification of acetabular rim labrochondral disease. PMID- 23456556 TI - Gastric parietal cell antibodies, Helicobacter pylori infection, and chronic atrophic gastritis: evidence from a large population-based study in Germany. AB - BACKGROUND: Striking similarities between autoimmune gastritis and Helicobacter Pylori (H. pylori)-associated gastritis have suggested a potential link between these two pathologic conditions in the progression of chronic atrophic gastritis (CAG); however, evidence has remained conflicting. METHODS: Serum pepsinogen I and II, and antibodies against H. pylori in general, the cytotoxin-associated gene A protein (CagA) and parietal cells were measured by ELISA in 9,684 subjects aged 50 to 74 years. Antigastric parietal cell antibody (APCA) prevalence was examined in the overall population and according to sex, age, and H. pylori serostatus. The association between APCA prevalence and CAG was assessed by logistic regression, overall and according to H. pylori status, controlling for potential confounding factors. RESULTS: Overall APCA prevalence was 19.5%. APCA prevalence was strongly associated with CAG, and the association was increasing with increasing severity of CAG. Furthermore, the association between APCA and CAG was even stronger among H. pylori-negative subjects [odds ratio (OR) = 11.3; 95% confidence interval (CI): 7.5-17.1)] than among H. pylori-positive subjects (OR = 2.6; 95% CI: 2.1-3.3). CONCLUSIONS: APCA may play a role on the development of gastric atrophy, irrespective of H. pylori infection. IMPACT: Assessment of APCA might be a useful complement to established markers (such as pepsinogens and H. pylori antibodies) in screening for CAG. PMID- 23456555 TI - Risk of pancreatic cancer in breast cancer families from the breast cancer family registry. AB - BACKGROUND: Increased risk of pancreatic cancer has been reported in breast cancer families carrying BRCA1and BRCA2 mutations; however, pancreatic cancer risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate pancreatic cancer risk in high-risk breast cancer families according to the BRCA mutation status. METHODS: A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for pancreatic cancer. A total of 5,799 families with >=1 breast cancer case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with >=2 breast cancer diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4). RESULTS: BRCA1 mutation carriers were at increased risk of pancreatic cancer [SIR = 4.11; 95% confidence interval (CI), 2.94-5.76] as were BRCA2 mutation carriers (SIR = 5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased pancreatic cancer risk, which did not appear to vary by number of members with early-onset breast cancer (SIR = 1.31; 95% CI, 1.06-1.63 for class 3 and SIR = 1.30; 95% CI, 1.13-1.49 for class 4). CONCLUSIONS: Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of pancreatic cancer. Members of BRCAX families are also at increased risk of pancreatic cancer, pointing to the existence of other genetic factors that increase the risk of both pancreatic cancer and breast cancer. IMPACT: This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, pancreatic cancer should be included in risk assessment in familial breast cancer counseling. PMID- 23456557 TI - Physical activity and fatigue in breast cancer survivors: a panel model examining the role of self-efficacy and depression. AB - BACKGROUND: Physical activity is associated with reductions in fatigue in breast cancer survivors. However, mechanisms underlying this relationship are not well understood. The purpose of this study was to longitudinally test a model examining the role of self-efficacy and depression as potential mediators of the relationship between physical activity and fatigue in a sample of breast cancer survivors using both self-report and objective measures of physical activity. METHODS: All participants (N = 1,527) completed self-report measures of physical activity, self-efficacy, depression, and fatigue at baseline and 6 months. A subsample was randomly selected to wear an accelerometer at both time points. It was hypothesized that physical activity indirectly influences fatigue via self efficacy and depression. Relationships among model constructs were examined over the 6-month period using panel analysis within a covariance modeling framework. RESULTS: The hypothesized model provided a good model-data fit (chi(2) = 599.66, df = 105, P <= 0.001; CFI = 0.96; SRMR = 0.02) in the full sample when controlling for covariates. At baseline, physical activity indirectly influenced fatigue via self-efficacy and depression. These relationships were also supported across time. In addition, the majority of the hypothesized relationships were supported in the subsample with accelerometer data (chi(2) = 387.48, df = 147, P <= 0.001, CFI = 0.94, SRMR = 0.04). CONCLUSIONS: This study provides evidence to suggest the relationship between physical activity and fatigue in breast cancer survivors may be mediated by more proximal, modifiable outcomes of physical activity participation. IMPACT: Recommendations are made relative to future applications and research concerning these relationships. PMID- 23456558 TI - It's in the way that you use it: attachment and the dyadic nature of humor during conflict negotiation in romantic couples. AB - In a behavioral observation study with dating couples, we examined (a) how attachment orientations predict humor use and (b) how people respond to their partners' use of humor. Couples were videotaped while trying to resolve a relationship conflict. Each discussion was rated on several theoretically relevant dimensions. Highly avoidant individuals used more aggressive humor and less affiliative humor during their discussions, whereas highly anxious individuals used more self-defeating humor. Individuals also tailored their humor use to partners who were highly anxious and distressed. Aggressive humor was received more negatively by partners who sought more care. Affiliative humor was favorably received, especially when partners were more distressed, whereas self defeating humor elicited negative responses from highly distressed partners. Both highly anxious and avoidant individuals reacted unfavorably when they were the recipients of the humor styles they used most often. The implications of these results for our understanding of relationships and humor are discussed. PMID- 23456559 TI - Collective futures: how projections about the future of society are related to actions and attitudes supporting social change. AB - We identified the active ingredients in people's visions of society's future ("collective futures") that could drive political behavior in the present. In eight studies (N = 595), people imagined society in 2050 where climate change was mitigated (Study 1), abortion laws relaxed (Study 2), marijuana legalized (Study 3), or the power of different religious groups had increased (Studies 4-8). Participants rated how this future society would differ from today in terms of societal-level dysfunction and development (e.g., crime, inequality, education, technology), people's character (warmth, competence, morality), and their values (e.g., conservation, self-transcendence). These measures were related to present day attitudes/intentions that would promote/prevent this future (e.g., act on climate change, vote for a Muslim politician). A projection about benevolence in society (i.e., warmth/morality of people's character) was the only dimension consistently and uniquely associated with present-day attitudes and intentions across contexts. Implications for social change theories, political communication, and policy design are discussed. PMID- 23456561 TI - Optimism following a tornado disaster. AB - Effects of exposure to a severe weather disaster on perceived future vulnerability were assessed in college students, local residents contacted through random-digit dialing, and community residents of affected versus unaffected neighborhoods. Students and community residents reported being less vulnerable than their peers at 1 month, 6 months, and 1 year after the disaster. In Studies 1 and 2, absolute risk estimates were more optimistic with time, whereas comparative vulnerability was stable. Residents of affected neighborhoods (Study 3), surprisingly, reported less comparative vulnerability and lower "gut level" numerical likelihood estimates at 6 months, but later their estimates resembled the unaffected residents. Likelihood estimates (10%-12%), however, exceeded the 1% risk calculated by storm experts, and gut-level versus statistical-level estimates were more optimistic. Although people believed they had approximately a 1-in-10 chance of injury from future tornadoes (i.e., an overestimate), they thought their risk was lower than peers. PMID- 23456560 TI - Responses to endorsement of commonality by ingroup and outgroup members: the roles of group representation and threat. AB - Two experiments integrated research on the roles of common identity and social norms in intergroup orientations. Experiment 1 demonstrated that learning that ingroup members categorized the ingroup (Spaniards) and outgroup (Eastern European immigrants) within a common identity (European) produced more positive intergroup orientations toward immigrants. By contrast, learning that outgroup members held the same position elicited less positive orientations compared with a condition in which the information came from a neutral source. The effects were mediated by one-group representations. Experiment 2 also found that endorsement of a common identity generated more positive intergroup orientations when it was expressed by ingroup than outgroup members and revealed how this effect may be sequentially mediated by personal one-group representations and symbolic threat. PMID- 23456562 TI - Brief report: regression timing and associated features in MECP2 duplication syndrome. AB - The aim of this study was to determine the frequency, timing, and associated features of developmental regression in MECP2 duplication syndrome. We also examined whether duplication size was associated with regression. Comprehensive psychological evaluations were used to assess 17 boys with MECP2 duplication syndrome. Information about regression was gathered via parent report. Eight of 17 boys exhibited regression in language skills, while seven of 17 exhibited regression in other skill areas. Regression in "other skill" areas coincided with seizure onset and with a prior autism diagnosis in six of seven participants. Regression was not associated with duplication size. Questions remain as to why some boys regress, and future work is necessary to understand the underlying mechanism(s) that causes regression. PMID- 23456563 TI - An open-label study of the safety and tolerability of pazopanib in combination with FOLFOX6 or CapeOx in patients with colorectal cancer. AB - BACKGROUND: Although combining targeted agents with conventional, first-line cytotoxic therapy has improved survival outcomes in patients with advanced colorectal cancer, further improvements in outcomes and tolerability are needed. METHODS: This phase I study evaluated the feasibility of combining oral pazopanib, an agent that targets multiple proangiogenic factors, with FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) or CapeOx (oxaliplatin and capecitabine). This phase I study evaluated the optimally tolerated regimen of daily pazopanib (dose-escalated) plus standard FOLFOX6 or CapeOx in patients with advanced colorectal cancer. At the optimally tolerated regimen, each cohort was expanded to further evaluate safety and clinical response. RESULTS: The optimally tolerated regimens were pazopanib 800 mg plus FOLFOX6 and pazopanib 800 mg plus reduced CapeOx (capecitabine 850 mg/m(2)). The most commonly reported adverse events in the FOLFOX6 cohorts included decreased appetite, neutropenia, diarrhea, peripheral neuropathy, and vomiting. Similarly, the most commonly reported adverse events in the CapeOx cohorts included fatigue, vomiting, and decreased appetite. The overall response rate was 40 % (8/20 patients) in the pazopanib plus FOLFOX6 cohorts and 38 % (8/21 patients) in the pazopanib plus CapeOx cohorts. CONCLUSION: Pazopanib combined with FOLFOX6 or reduced CapeOx was adequately tolerated in this patient population. PMID- 23456564 TI - Predictors of adherence to inhaled medications. PMID- 23456565 TI - Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury. AB - Premature birth is a significant economic and public health burden, and its incidence is rising. Periventricular leukomalacia (PVL) is the predominant form of brain injury in premature infants and the leading cause of cerebral palsy. PVL is characterized by selective white-matter damage with prominent oligodendroglial injury. The maturation-dependent vulnerability of developing and premyelinating oligodendrocytes to excitotoxic, oxidative, and inflammatory forms of injury is a major factor in the pathogenesis of PVL. Recent studies using mouse models of PVL reveal that synapses between axons and developing oligodendrocytes are quickly and profoundly damaged in immature white matter. Axon-glia synapses are highly vulnerable to white-matter injury in the developing brain, and the loss of synapses between axons and premyelinating oligodendrocytes occurs before any cellular loss in the immature white matter. Microglial activation and astrogliosis play important roles in triggering white-matter injury. Impairment of white-matter development and function in the neonatal period contributes critically to functional and behavioral deficits. Preservation of the integrity of the white matter is likely key in the treatment of PVL and subsequent neurological consequences and disabilities. PMID- 23456566 TI - Regulation of the timing of oligodendrocyte differentiation: mechanisms and perspectives. AB - Axonal myelination is an essential process for normal functioning of the vertebrate central nervous system. Proper formation of myelin sheaths around axons depends on the timely differentiation of oligodendrocytes. This differentiation occurs on a predictable schedule both in culture and during development. However, the timing mechanisms for oligodendrocyte differentiation during normal development have not been fully uncovered. Recent studies have identified a large number of regulatory factors, including cell-intrinsic factors and extracellular signals, that could control the timing of oligodendrocyte differentiation. Here we provide a mechanistic and critical review of the timing control of oligodendrocyte differentiation. PMID- 23456568 TI - Quantification of sesquiterpene lactones in Parthenium hyterophorous by normal phase HPLC. AB - This paper describes the development of a normal-phase liquid chromatography ultraviolet-diode array detection method for the simultaneous quantification of parthenin and coronopilin in the leaves and flowers of Parthenium hysterophorous. The compounds were analyzed on a Merck Si60 silica column (5 um, 250 * 4 mm) using an isocratic 15:85 mixture of isopropyl alcohol and hexane. The calibration curves resulting from the reference compounds in the concentration range of 200 2,000 ng exhibited acceptable linearity (r > 0.999). The method was developed to study the levels of parthenin and coronopilin in the leaves and flowers of P. hysterophorous collected during different seasons, and the method was validated by analyzing the spiked samples. PMID- 23456567 TI - Medication, reperfusion therapy and survival in a community-based setting of hospitalised myocardial infarction. AB - OBJECTIVE: To examine the survival benefit of multiple medical therapies in a large, community-based population of validated myocardial infarction (MI) events. DESIGN: Retrospective observational cohort study. SETTING: Population-based sample of 30 986 definite or probable MIs in residents of four US communities aged 35-74 years randomly sampled between 1987 and 2008 as part of the Atherosclerosis Risk in Communities Surveillance Study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: All-cause mortality 30, 90 and 365 days after discharge. RESULTS: We used unadjusted and propensity score (PS) adjusted models to examine the relationship between medical therapy use and mortality. In unadjusted models, each medication and procedure was inversely associated with 30-day mortality. After PS adjustment, the crude survival benefits were attenuated for all therapies except for intravenous tissue plasminogen activator therapy (IV-tPA) and stent use. After inclusion of other therapies received during the event in regression models, risk ratio effect estimates (RR; (95% CI)) were attenuated for aspirin (0.66; (0.58 to 0.76) to 0.91 (0.80 to 1.03)), non-aspirin antiplatelets (0.74; (0.59 to 0.92) to 0.92 (0.72 to 1.18)), IV-tPA (0.50; (0.41 to 0.62) to 0.65 (0.52 to 0.80)) and stents (0.53 (0.40 to 0.69) to 0.68 (0.49 to 0.94)). Effect estimates remained stable for all other therapies and were similar for 90- and 365-day mortality endpoints. CONCLUSIONS: We observed inverse associations between receipt of six medications and procedures for MI and all-cause mortality at 30, 90 and 365 days after adjustment for PS. The mortality benefits observed in this population-based setting are consistent with those reported in clinical trials. PMID- 23456569 TI - Beneficial cardiac effects of caloric restriction are lost with age in a murine model of obesity. AB - Obesity is associated with increased diastolic stiffness and myocardial steatosis and dysfunction. The impact of aging on the protective effects of caloric restriction (CR) is not clear. We studied 2-month (younger) and 6-7-month (older) old ob/ob mice and age-matched C57BL/6J controls (WT). Ob/ob mice were assigned to diet ad libitum or CR for 4 weeks. We performed echocardiograms, myocardial triglyceride assays, Oil Red O staining, and measured free fatty acids, superoxide, NOS activity, ceramide levels, and Western blots. In younger mice, CR restored diastolic function, reversed myocardial steatosis, and upregulated Akt phosphorylation. None of these changes was observed in the older mice; however, CR decreased oxidative stress and normalized NOS activity in these animals. Interestingly, myocardial steatosis was not associated with increased ceramide, but CR altered the composition of ceramides. In this model of obesity, aging attenuates the benefits of CR on myocardial structure and function. PMID- 23456570 TI - Inhibitory effects of simvastatin on staphylococcus aureus lipoteichoic acid induced inflammation in human alveolar macrophages. AB - Staphylococcus aureus (S. aureus) is the most common bacterium in sepsis and pneumonia involving gram-positive bacteria. Lipoteichoic acid (LTA) is a cell wall component of gram-positive bacteria. It is a potent inducer of inflammatory mediators in human dendritic cells, human pulmonary epithelial cells, and murine macrophages. However, the effect of LTA on human alveolar macrophages (AMs) which are the major effector cells in host defense against respiratory tract infections has hardly been studied. Statins have anti-inflammatory, immunomodulatory, antioxidative, anticoagulant, and antibacterial activities. These effects may be contributed to reduce the markers of systemic inflammation. Emerging retrospective studies have demonstrated that statin use decreased the mortality of pneumonia. However, the precise mechanisms responsible for these effects are unclear. The purpose of this study is to define the role of S. aureus LTA in human AMs and the effects of simvastatin (SV) on LTA-stimulated human AMs. The results showed that LTA induced tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8 mRNA expression, and suppressed IL-10 mRNA expression in human AMs. Simultaneously, LTA induced human AMs apoptosis. These effects were parallel with the up-regulation of the expression of NF-kappaB-P65 protein in the LTA-stimulated human AMs. The above effects of LTA on human AMs were inhibited significantly by SV. These data indicate that S. aureus LTA induces potent pro-inflammatory and pro-apoptotic effects on human AMs and statins exert anti-inflammatory effects by mediating inhibition of NF-kappaB activation and cytokine mRNA expression in human AMs. These results may explain, in part, the mechanisms responsible for favorable effects of statins on pneumonia. PMID- 23456571 TI - CA19-9 and CA242 as tumor markers for the diagnosis of pancreatic cancer: a meta analysis. AB - Pancreatic cancer has the worst prognosis of any gastrointestinal cancer, with the mortality approaching the incidence. Early detection is crucial for improving patient prognosis. We therefore performed a meta-analysis to evaluate and compare the sensitivity and specificity of CA19-9 and CA242 in pancreatic cancer. We searched PubMed, EMBASE, and the Cochrane Library for studies that evaluated the diagnostic validity of CA19-9 and CA242 between January 1966 and March 2011. Meta analysis methods were used to pool sensitivity and specificity and to construct a summary receiver-operating characteristic (SROC) curve. A total of 11 studies that included 2,316 patients who fulfilled all of the inclusion criteria were considered for analysis. The pooled sensitivities for CA242 and CA19-9 were 0.719 (95 % confidence interval [CI] 0.690-0.746) and 0.803 (95 % CI 0.777-0.826), respectively. The pooled specificities of CA242 and CA19-9 were 0.868 (95 % CI 0.849-0.885) and 0.802 (95 % CI 0.780-0.823), respectively. The diagnostic odds ratio (DOR) estimate was significantly higher for CA242 (16.261) than for CA19-9 (15.637). Our meta-analysis showed that CA242 and CA19-9 could play different roles in the diagnosis of pancreatic cancer. Although the sensitivity of CA242 is lower than that of CA19-9, its specificity is greater. PMID- 23456572 TI - Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement. AB - Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed. PMID- 23456573 TI - A novel dynamic layer-by-layer assembled nano-scale biointerface: functionality tests with platelet adhesion and aggregate morphology influenced by adenosine diphosphate. AB - An improved biointerface was developed, dynamic layer-by-layer self-assembly surface (d-LbL), and utilized as a biologically-active substrate for platelet adhesion and aggregation. Possible clinical applications for this research include improved anti-coagulation surfaces. This work demonstrated the functionality of d-LbL biointerfaces in the presence of platelet-rich-plasma (PRP) with the addition of 20 MUM adenosine diphosphate (ADP), a thrombus activator. The surface morphology of the experimental control, plain PRP, was compared to PRP containing additional ADP (PRP + ADP) and resulted in an expected increase of platelet adhesions along the fibrinogen d-LbL substrate. The d-LbL process was used to coat glass slides with fibrinogen, Poly (sodium 4-styrene sulfonate), and Poly (diallydimethlyammonium chloride). Slides were exposed to PRP under flow and static conditions with and without 20 MUM of ADP. Fluorescence microscopy (FM), phase contrast microscopy (PCM), atomic force microscopy (AFM), and field emission-scanning electron microscopy (FE-SEM) were used to evaluate platelet adhesions under the influence of varied shear conditions. PCM images illustrated differences between the standard LbL and d-LbL substrates. FM images provided percent surface coverage values. For high-shear conditions, percent surface coverage values increased when using ADP whereas plain PRP exposure displayed no significant increase. AFM scans also displayed higher mean peak height values and unique surface characteristics for PRP + ADP as opposed to plain PRP. FE-SEM images revealed platelet adhesions along the biointerface and unique characteristics of the d-LbL surface. In conclusion, PRP + ADP was more effective at increasing platelet aggregation, especially under high shear conditions, providing further validation of the improved biointerface. PMID- 23456574 TI - From bench to bedside: review of gene and cell-based therapies and the slow advancement into phase 3 clinical trials, with a focus on Aastrom's Ixmyelocel-T. AB - There is a large body of preclinical research demonstrating the efficacy of gene and cellular therapy for the potential treatment of severe (limb-threatening) peripheral arterial disease (PAD), including evidence for growth and transcription factors, monocytes, and mesenchymal stem cells. While preclinical research has advanced into early phase clinical trials in patients, few late phase clinical trials have been conducted. The reasons for the slow progression of these therapies from bench to bedside are as complicated as the fields of gene and cellular therapies. The variety of tissue sources of stem cells (embryonic, adult bone marrow, umbilical cord, placenta, adipose tissue, etc.); autologous versus allogeneic donation; types of cells (hematopoietic, mesenchymal stromal, progenitor, and mixed populations); confusion and stigmatism by the public and patients regarding gene, protein, and stem cell therapy; scaling of manufacturing; and the changing regulatory environment all contribute to the small number of late phase (Phase 3) clinical trials and the lack of Food and Drug Administration (FDA) approvals. This review article provides an overview of the progression of research from gene therapy to the cellular therapy field as it applies to peripheral arterial disease, as well as the position of Aastrom's cellular therapy, ixmyelocel-T, within this field. PMID- 23456575 TI - Polymer peel-off mask for high-resolution surface derivatization, neuron placement and guidance. AB - We present a dry lift-off method using a chemically resistant spin-on plastic, polyimide, to pattern surfaces with high accuracy and resolution. Using well known lithographic and reactive ion etching techniques, the spin-on polymer is patterned over a silicon dioxide surface. The plastic efficiently adheres to the silicon dioxide surface during the chemical modification and is readily lifted off following the derivatization process, permitting highly reliable surface derivatization. The verticality of the reactive ion etch enables sub-micrometer features to be patterned, down to 0.8 um. The technique is used to pattern neurons on silicon dioxide surfaces: efficient neuron placement over a 4 mm area is shown for patterns larger than 50 um while process guidance is shown for 10 um patterns. PMID- 23456577 TI - HIV transmission in the United States: considerations of viral load, risk behavior, and health disparities. AB - Ongoing HIV transmission is related to prevalence, risk behavior and viral load among persons with HIV. We assessed the contribution of these factors to HIV transmission with transmission rate models and data reported to National HIV Surveillance and published rates of risk behavior. We also estimated numbers of persons with risk behaviors and unsuppressed viral load among sexual risk groups. The transmission rate is higher considering risk behavior (18.5 infections per 100 people with HIV) than that attributed to unsuppressed viral load (4.6). Since persons without risk behavior or suppressed viral load presumably transmit HIV at very low rates, transmission can be attributed to a combination of these factors (28.9). Service needs are greatest for MSM; their number with unsuppressed viral load engaging in unprotected discordant sex was 8 times the number of male heterosexuals and more than twice the number of female heterosexuals with high risk transmission potential. While all persons with HIV need optimal care, treatment as prevention is most relevant when risk behavior is present among persons with unsuppressed HIV viral load. PMID- 23456578 TI - Co-culture of spermatogonial stem cells with sertoli cells in the presence of testosterone and FSH improved differentiation via up-regulation of post meiotic genes. AB - Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout life in the male. Maintenance of SSCs and induction of spermiogenesis in vitro may provide a therapeutic strategy to treat male infertility. This study investigated in vitro differentiation of mouse SSCs in presence or absence of Sertoli cells, hormones and vitamins. Spermatogonial populations were enriched from testes of 4-6 week old males by magnetic activated cell sorting and anti-Thy-1 antibody. Sertoli cells isolated from 6-8 week old testes were enriched using lectin-DSA-coated plates. Isolated SSCs were cultured in the presence of Leukemia inhibitory factor (LIF) for 7 days in gelatin-coated dishes, then dissociated and cultured for 7 days in media lacking LIF in the presence or absence of Sertoli cells, with or without FSH, testosterone and vitamins. After one week, the effects of Sertoli cells +/- supplementary media on SSC differentiation was evaluated by microscopy and expression of meiotic and postmeiotic transcripts using RT-PCR. SSC colonies had limited development after LIF removal alone, exhibiting low expression of meiotic (Scp3, Th2b) but not postmeiotic transcript, and loss of Stra8 and Dazl expression. SSCs co-cultured with Sertoli cells, hormones and vitamins developed spermatid-like cells expressing postmeiotic markers (TP1, TP2, Prm1) at levels over 2-fold higher than Sertoli cells or hormone/vitamins alone. Our present SSC Sertoli co-culture provides conditions that may allow efficient in vitro differentiation of SSCs for the treatment of male infertility. PMID- 23456576 TI - Management of alcohol dependence in patients with liver disease. AB - Alcohol dependence represents a chronic and relapsing disease affecting nearly 10 % of the general population both in the USA and in Europe, with a widespread burden of morbidity and mortality. Alcohol dependence represents the most common cause of liver damage in the Western world. Although alcoholic liver disease is associated primarily with heavy drinking, continued alcohol consumption, even in low doses after the onset of liver disease, increases the risk of severe consequences, including mortality. Consequently, the ideal treatment of patients affected by alcohol dependence and alcoholic liver disease should aim at achieving long-term total alcohol abstinence and preventing relapse. The aim of the present review is to provide an update on the management of alcohol dependence in patients with alcoholic liver disease. Increasing evidence suggests the usefulness of psychosocial interventions and medications combined in order to reduce alcohol intake, promote abstinence and prevent relapse in alcohol dependent patients. Disulfiram, naltrexone and acamprosate have been approved for this indication; gamma-hydroxybutyric acid (GHB) is approved in Italy and Austria. However, these drugs have not been tested in patients with advanced liver disease. Amongst other emerging pharmacotherapies for alcoholism, topiramate, ondansetron, and baclofen seem the most promising ones. Both topiramate and ondansetron have a safe profile in alcoholic patients; however, none of them has been tested in alcoholic patients with advanced liver disease. To date, baclofen represents the only anti-craving medication formally tested in a randomized clinical trial in alcoholic patients affected by liver cirrhosis, although additional confirmatory studies are warranted. PMID- 23456579 TI - Effects of coenzyme Q(10) on LDL oxidation in vitro. AB - Coenzyme Q(10), a lipid soluble benzoquinone, has excellent antioxidant and membrane stabilizing properties in the cardiac tissue. The present study quantitatively investigated the effects of coenzyme Q(10) on in vitro LDL oxidation. The formation of conjugated dienes, malondialdehyde (MDA) and electrophoretic mobility were monitored as markers of the oxidation of LDL, respectively. Coenzyme Q(10) showed a decrease the formation of conjugated dienes and MDA, respectively, against oxidation in vitro. Coenzyme Q(10) also reduced electrophoretic mobility of the oxidized human LDL. Thus, results showed that the coenzyme Q(10) exhibits strong antioxidant activity in CuSO(4)-mediated oxidation of LDL (P<0.05) in vitro. The inhibitory effects of the coenzyme Q(10) on LDL oxidation were dose-dependent at concentrations ranging from 20 nM to 300 nM. Moreover, the effects of coenzyme Q(10) on LDL oxidation were compared with vitamin E and vitamin C. This study showed that coenzyme Q(10) is a potent antioxidant to protect LDL against oxidation in vitro and may be a good alternative to reduce the risk of atherosclerosis and coronary heart disease and other free radical associated health problems. PMID- 23456580 TI - Cutaneous leiomyoma: novel histologic findings for classification and diagnosis. AB - Smooth muscle tumors rather benign or malignant can arise wherever the muscular tissue presents but cutaneous leiomyoma is one of the rare benign tumors of the which even the diagnostic criteria from the malignant type of the tumor is still in doubt. This study was aimed to compare the subtypes of cutaneous leiomyoma from different histologic aspects in order to find unique criteria for better classification and diagnosis. The six year data base of our center was reviewed and 25 patients with cutaneous leiomyoma were included in this study. Of 25 patients, 5 were female and 20 were male. 5 patients had angioleiomyoma (ALM) and 20 had pilar leiomyoma (PLM). ALM had following characteristics: dilated vascular canals intermingled with compact smooth muscle bundles; well circumscribe counter and myxoid and hyaline changes through the tumor. In contrast, PLMs had following histologic features: poor defined outline, entrapped hair follicles and eccrine glands, acanthosis and elongated rete ridges with hyperpigmentation and smooth muscle bundles which are interdigitated with elongated rete ridges. Here we introduced some distinct histological features for each subtype of the cutaneous leiomyoma which can lead to create novel criteria for classification and diagnosis of the lesion. PMID- 23456581 TI - Thyroid function and prevalence of anti-thyroperoxidase (TPO) and anti thyroglobulin (Tg) antibodies in outpatients hospital setting in an area with sufficient iodine intake: influences of age and sex. AB - In order to examine the prevalence of thyroid disease in a hospital outpatient setting, in an area of sufficient iodine intake, serum levels of TSH, T4, T3, anti-Tg and anti-TPO antibodies were examined in 909 individuals with an age range of 12.4 to 88.5 years, participating in a checkup outpatient setting. The study was conducted in Henry Dynant Hospital located in the metropolitan area of Athens, Greece, during a 2 year period. Hormonal parameters were determined by chemiluminescence immunoassay. Overt thyrotoxicosis was found in 4.95% of the total population and subclinical thyrotoxicosis in 5.5%. Overt hypothyroidism was found in 1.43% and subclinical hypothyroidism in 4.51%. In male population, overt thyrotoxicosis was found in 4.4 % and subclinical thyrotoxicosis was also found in 4.4%. On the other hand, overt hypothyroidism was found in 1.4% and subclinical hypothyroidism was found in 3.7% in males. In female population, overt thyrotoxicosis was found in 5.2% whereas subclinical thyrotoxicosis was found in 6.0%. Overt hypothyroidism was found in 1.5% and subclinical hypothyroidism was found in 4,9% in females. Positive anti-TPO antibodies were detected more often (30.4%) than anti-Tg (15.4%) in the tested population. The positivity in both anti-TPO and anti-Tg antibodies was correlated with abnormally high TSH concentrations after the age of 50 years, especially in female population. In conclusion distinct profile of thyroid hormonal parameters was observed in inhabitants in the metropolitan area of Athens, with overt thyrotoxicosis strikingly overcome overt hypothyroidism while subclinical forms of each dysfunction also exhibit analogous results. PMID- 23456582 TI - The prevalence of anticardiolipin antibody in patients with systemic lupus erythematosus and its association with clinical manifestations. AB - The central immunological disturbance in systemic lupus erythematosus (SLE) is autoantibody production. Some of these antibodies affecting components of the cell nucleus are the major characteristics of SLE. The present study was aimed to assess importance of anticardiolipin (ACL) antibody and its association with clinical state in SLE patients. A cross sectional study was performed on 100 patients with SLE referred to rheumatology outpatient clinic in Ekbatan hospital in Hamadan (Iran) between 2007 and 2008. Serum samples were extracted and screened for IgG and IgM using an ACL enzyme-linked immunosorbent assay. Up to 36% of patients were positive for ACL antibody that was more frequent in women than men (39.8% versus 8.3%). No association was revealed between ACL antibody and age. Clinical manifestations of antiphospholipid antibody syndrome were observed in 23.0% of patients that was more prevalent in ACL positive group compared with ACL negative group (41.7% versus 125%). The prevalence of other manifestations including pregnancy-related disorders (recurrent abortion), central nervous system defects, and deep vein thrombosis was 33.3%, 25.0%, and 30.6% in ACL positive group and was 9.4%, 7.8%, and 7.8% in ACL negative group that all were more frequent in the former group. The prevalence of thrombocytopenia was also higher in ACL positive group than another group (22.2% versus 15.6%). Among ACL positive patients with clinical manifestations of antiphospholipid antibody syndrome, 86.6% had medium to high titer of ACL. Our study emphasized value of (ACL) antibody to assess clinical status in SLE patients. PMID- 23456583 TI - The side effects of gonadotropin releasing hormone analog (diphereline) in treatment of idiopathic central precocious puberty. AB - Treatment of central precocious puberty (CPP) is the administration of GnRH analogs. Metabolic syndrome comprised metabolic disturbances that confer increased risk of (CVD) diabetes mellitus (DM) and cardiovascular disease. This study is a longitudinal prospective study in pediatric endocrinology clinic. 30 non-obese children with idiopathic CPP were involved. Total body weight, height, blood pressure, BMI and waist circumference of the patients along with their triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), fasting plasma sugar (FPS) were evaluated at the beginning and during 3 and 6 months GnRH analog therapy. All of the patients involved in this study were female with age 9.5+/-1.02 years. Waist circumference, weight and BMI were 69.3 cm, 37.21 kg, and 19.13 kg/cm(2) before therapy and 72.25 cm, 40.11 kg, and 19.54 kg/m(2) 6 months after therapy respectively. Mean systolic and diastolic blood pressure of the patients before therapy was 96.83 mmHg, 66mmHg and after 6 months therapy was 98.66 mmHg, 89.63 mmHg respectively. Mean TG, LDL, HDL and FPS were 90.06 mg/dl, 91.6 mg/dl, 43.7 mg/dl and 89.6 mg/dl before therapy and 96.4 mg/dl, 93.1 mg/dl, 44.7 mg/dl and 91.36 after 6 months therapy respectively. GnRH analog therapy doesn't cause metabolic syndrome after 3 and 6 month therapy but it may cause hyperlipidemia and central obesity. PMID- 23456584 TI - Normative life events and PTSD in children: how easy stress can affect children's brain. AB - Exposure to traumatic events is common in children and adolescent. Post traumatic stress disorder (PTSD) is an emotional reaction to traumatic events, which is increasingly recognized to be a prevalent and disabling disorder. The aim of this study is to determine the distribution of normative life events which predicts PTSD in youth who referred to an outpatient clinic in Rasht, Iran. This study is a cross-sectional descriptive study. The samples of children and adolescents ranging from 1-18 yr old who were diagnosed PTSD based on DSM-IV criteria in psychiatric interview and K-SADS (Kiddie-schedule for affective disorder and schizophrenia for school age children) semi-structured diagnostic interview, from 2005 until 2008.The information consist of: age, sex, comorbidity with PTSD, events accompanying with PTSD, and time interval between events and visit. Eighty four youth who met the diagnosis of PTSD and their parents participated in the survey. Half of PTSD youth were 6-11 years old and admitted to clinic in the first 3 months after events. The most common events were witnessing violent or fearful scenes on TV followed by witnessing someone's death or funeral ceremony. The most comorbidity with PTSD included: attention deficit hyperactivity disorder, depression and anxiety. Our results indicate that youth exposure to violent or fearful scenes on TV could be very traumatic for them. Informing parents about the potential effect of low-magnitude stressors such as violent or fearful scenes on TV and funeral ceremony can decrease the prevalence of PTSD in youth. PMID- 23456585 TI - Application of the health belief model in promotion of self-care in heart failure patients. AB - Heart failure (HF) is a condition due to a problem with the structure or function of the heart impairs its ability to supply sufficient blood flow to meet the body's needs. In developing countries, around 2% of adults suffer from heart failure, but in people over the age of 65, this rate increases to 6-10%. In Iran, around 3.3% of adults suffer from heart failure. The Health Belief Model (HBM) is one of the most widely used models in public health theoretical framework. This was a cohort experimental study, in which education as intervention factor was presented to case group. 180 Heart failure patients were randomly selected from patients who were referred to the Shahid Rajaee center of Heart Research in Tehran and allocated to two groups (90 patients in the case group and 90 in the control group). HBM was used to compare health behaviors. The questionnaire included 69 questions. All data were collected before and 2 months after intervention. About 38% of participants don't know what, the heart failure is and 43% don't know that using the salt is not suitable for them. More than 40% of participants didn't weigh any time their selves. There was significant differences between the mean grades score of variables (perceived susceptibility, perceived threat, knowledge, Perceived benefits, Perceived severity, self efficacy Perceived barriers, cues to action, self- behavior) in the case and control groups after intervention that was not significant before it. Based on our study and also many other studies, HBM has the potential to be used as a tool to establish educational programs for individuals and communities. Therefore, this model can be used effectively to prevent different diseases and their complications including heart failure. PMID- 23456586 TI - Medical podcasting in Iran; pilot, implementation and attitude evaluation. AB - Podcasting has become a popular means of transferring knowledge in higher education through making lecture contents available to students at their convenience. Accessing courses on media players provides students with enhanced learning opportunities. Development of teaching methods able to cope with ever changing nature of medicine is crucial to train the millennium students. Pharmacology education in Tehran University of Medical Sciences has been based on lectures so far; our aim was to implement a pilot study to evaluate the advantages and disadvantages of offering the course contents as podcasts as well as evaluating whether such program can be feasible in our educational program. 46% of students downloaded the podcast according to our download center. 48% favored usage of both internet and DVD-ROM concurrently. Overall 96% of students perceived that podcasting had a positive impact on their learning in pharmacology course. Our results indicate that most of attendants proposed the positive yields of podcasting despite low usage of it, mainly as a pre-class preparing tool. PMID- 23456587 TI - Clinical learning environment at Shiraz Medical School. AB - Clinical learning occurs in the context of a dynamic environment. Learning environment found to be one of the most important factors in determining the success of an effective teaching program. To investigate, from the attending and resident's perspective, factors that may affect student leaning in the educational hospital setting at Shiraz University of Medical Sciences (SUMS). This study combined qualitative and quantitative methods to determine factors affecting effective learning in clinical setting. Residents evaluated the perceived effectiveness of the university hospital learning environment. Fifty two faculty members and 132 residents participated in this study. Key determinants that contribute to an effective clinical teaching were autonomy, supervision, social support, workload, role clarity, learning opportunity, work diversity and physical facilities. In a good clinical setting, residents should be appreciated and given appropriate opportunities to study in order to meet their objectives. They require a supportive environment to consolidate their knowledge, skills and judgment. PMID- 23456588 TI - Agenesis of the lung--a rare congenital anomaly of the lung. AB - Pulmonary agenesis is a very rare condition and many of them are associated with a variety of cardiac and non-cardiac malformations. We report an eight-month old girl with chronic lung infection due to right sided pulmonary agenesis without any associated major cardiac or non-cardiac abnormalities. The case brings in forth the importance of investigating any infant presenting with features of chronic lung infection for any congenital abnormality of the lung including aplasia of the lung. This case also emphasizes that mildness of the attack does not exclude right sided aplasia of the lung. PMID- 23456589 TI - Thyroid synovial sarcoma: a case report. AB - Sarcomas are rare tumors account for about 1% of cancers in adult. Soft tissue sarcomas are the most common one. Synovial sarcoma's incident is about 10% of all sarcomas and most commonly rise from para-articular regions in young adults. Based on our knowledge there have been only two reports of thyroid synovial sarcoma in medical literature. We report a 44-year old woman presented with a rapid growing neck mass. The pathology report revealed sarcoma and the immunohistochemistry (IHC) was compatible with synovial sarcoma. It could be understood that synovial sarcoma can be found in various tissues even if there is no synovial cells. PMID- 23456590 TI - Genetics of neonatal diabetes mellitus. PMID- 23456591 TI - A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1. AB - New Delhi metallo-beta-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known beta-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing beta-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the beta-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem beta-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies. PMID- 23456592 TI - Vital staining of blood vessels and bile ducts with carboxyfluorescein diacetate succinimidyl ester: a novel tool for isolation of cholangiocytes. AB - BACKGROUND AND AIM: Current methods for visualization of the blood vasculature, biliary tree and for isolation of vital cholangiocytes are afflicted with a plethora of technical difficulties, especially in mice. In this project, we propose a novel, reliable and straightforward alternative technique for histological demonstration of blood- and biliary systems and derivation of vital cholangiocytes. METHODS: Intravital retrograde perfusion of bile ducts was performed in twenty wild type mice. Liver and gallbladder were exposed by median laparotomy. Using a venous catheter, the gallbladder was cannulated, a few millimeters of the liver edge were cropped to allow free outflow of the perfusate, and carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) solution was retrogradely infused. Thereafter, formaldehyde solution was either injected through the same catheter, or the liver was immediately dissociated into a single cell suspension for FACS-analysis. Intravital perfusion of the vascular system was performed in ten Lewis rats by direct intra-arterial injection of CFDA-SE into the abdominal aorta. The specificity and sensitivity of CFDA-SE labeling was controlled using Indian ink or cytokeratin 19 immunohistochemistry respectively. RESULTS: Upon histomorphological analysis of cryo- and paraffin sections, strong fluorescence was noted in large and small bile ducts throughout the entire liver and in the vascular system after infusion of the CFDA-SE solution. In preliminary FACS-experiments, we succeeded in separating cholangiocytes based on combined CFDA-SE-staining and cell size. CONCLUSIONS: Visualization of liver architecture and the isolation of cholangiocytes is feasible using a fast and cost-effective method of retrograde perfusion and vital fluorescent labeling of mouse bile duct epithelium and vascular endothelium with CFDA-SE. PMID- 23456594 TI - HIV stigma mechanisms and well-being among PLWH: a test of the HIV stigma framework. AB - The current work evaluates the HIV Stigma Framework in a sample of 95 people living with HIV recruited from an inner-city clinic in the Bronx, NY. To determine the contributions of each HIV stigma mechanism (internalized, enacted, and anticipated) on indicators of health and well-being, we conducted an interviewer-delivered survey and abstracted data from medical records. Results suggest that internalized stigma associates significantly with indicators of affective (i.e., helplessness regarding, acceptance of, and perceived benefits of HIV) and behavioral (i.e., days in medical care gaps and ARV non-adherence) health and well-being. Enacted and anticipated stigma associate with indicators of physical health and well-being (i.e., CD4 count less than 200 and chronic illness comorbidity respectively). By differentiating between HIV stigma mechanisms, researchers may gain a more nuanced understanding of how HIV stigma impacts health and well-being and better inform targeted interventions to improve specific outcomes among people living with HIV. PMID- 23456595 TI - Phase response properties of half-center oscillators. AB - We examine the phase response properties of half-center oscillators (HCOs) that are modeled by a pair of Morris-Lecar-type neurons connected by strong fast inhibitory synapses. We find that the two basic mechanisms for half-center oscillations, "release" and "escape", give rise to strikingly different phase response curves (PRCs). Release-type HCOs are most sensitive to perturbations delivered to cells at times when they are about to transition from the active to the suppressed state, and PRCs are dominated by a large negative peak (phase delays) at corresponding phases. On the other hand, escape-type HCOs are most sensitive to perturbations delivered to cells at times when they are about to transition from the suppressed to the active state, and PRCs are dominated by a large positive peak (phase advances) at corresponding phases. By analyzing the phase space structure of Morris-Lecar-type HCO models with fast synaptic dynamics, we identify the dynamical mechanisms underlying the shapes of the PRCs. To demonstrate the significance of the different shapes of the PRCs for the release-type and escape-type HCOs, we link the shapes of the PRCs to the different frequency modulation properties of release-type and escape-type HCOs, and we show that the different shapes of the PRCs for the release-type and escape type HCOs can lead to fundamentally different phase-locking dynamics. PMID- 23456593 TI - Interventions to promote linkage to and utilization of HIV medical care among HIV diagnosed persons: a qualitative systematic review, 1996-2011. AB - This qualitative systematic review examined interventions that promote linkage to or utilization of HIV care among HIV-diagnosed persons in the United States. We conducted automated searches of electronic databases (i.e., MEDLINE, EMBASE, PsycINFO, CINAHL) and manual searches of journals, reference lists, and listservs. Fourteen studies from 19 published reports between 1996 and 2011 met our inclusion criteria. We developed a three-tier approach, based on strength of study design, to evaluate 6 findings on linkage to care and 18 findings on HIV care utilization. Our review identified similar strategies for the two outcomes, including active coordinator's role in helping with linking to or utilizing HIV care; offering information and education about HIV care; providing motivational or strengths-based counseling; accompanying clients to medical appointments and helping with appointment coordination. The interventions focused almost exclusively on individual-level factors. More research is recommended to examine interventions that address system and structural barriers. PMID- 23456596 TI - Management of herpes zoster and post-herpetic neuralgia. AB - Herpes zoster and its sequela post-herpetic neuralgia (PHN) are conditions with significant morbidity. PHN is a chronic, debilitating neuropathic pain that can persist long beyond resolution of visible cutaneous manifestations. This paper provides practical guidelines for management of herpes zoster and PHN. For herpes zoster, antivirals should be started, preferably within 72 h of onset, to reduce the severity and duration of the eruptive phase and to reduce the intensity of acute pain. PHN can be treated with either topical or systemic agents. Topical lidocaine and capsaicin are effective. For patients with more severe pain, the following systemic agents can be considered (in decreasing order of recommendation): the anticonvulsants gabapentin and pregabalin, the tricyclic antidepressants amitriptyline, nortriptyline, and desipramine, and, lastly, the opioid analgesics tramadol, morphine, oxycodone, and methadone. For patients at high risk of developing PHN, early initiation of gabapentin or amitriptyline after the onset of herpes zoster is suggested. The new zoster vaccine has been shown to be effective in reducing the incidence of herpes zoster and PHN. PMID- 23456598 TI - Evaluating the impact of California's full service partnership program using a multidimensional measure of outcomes. AB - This study evaluates the impact of California's full-service partnership (FSP) program using a multidimensional measure of outcomes. The FSP program is a key part of California's 2005 Mental Health Services Act. Secondary data were collected from the Consumer Perception Survey, the Client and Service Information System, and the Data Collection and Reporting System, all data systems which are maintained by the California Department of Mental Health. The analytic sample contained 39,681 observations of which 588 were FSP participants (seven repeated cross-sections from May 2005 to May 2008). We performed instrumental variables (IV) limited information maximum likelihood and IV Tobit analyses. The marginal monthly improvement in outcomes of services for FSP participants was approximately 3.5 % higher than those receiving usual care with the outcomes of the average individual in the program improving by 33.4 %. This shows that the FSP program is causally effective in improving outcomes among the seriously mentally ill. PMID- 23456599 TI - Synthesis of a novel tertiary amine containing urethane dimethacrylate monomer (UDMTA) and its application in dental resin. AB - A novel tertiary amine containing urethane dimethacrylate monomer UDMTA was synthesized with the aim of replacing Bis-GMA as one component of dental restorative materials. The structure of UDMTA was confirmed by FT-IR and (1)H-NMR spectra. UDMTA was incorporated into Bis-GMA/TEGDMA (50 wt%/50 wt%) resin system to replace Bis-GMA partly and totally. Double bond conversion, polymerization volumetric shrinkage, water sorption and solubility, flexural strength and modulus of UDMTA containing resin formulations were studied with neat Bis GMA/TEGDMA resin formulation as a reference. Results showed that UDMTA could be used as a coinitiator in photocurable dental resin, UDMTA containing resin had higher double bond conversion and lower polymerization shrinkage than that of Bis GMA/TEGDMA resin, and the UDMTA containing copolymer had higher flexural strength and flexural modulus than Bis-GMA/TEGDMA copolymer. When UDMTA was used to replace more than 25 wt% of Bis-GMA, the obtained copolymer had higher water sorption and solubility. The optimized resin composition is by replacing 25 wt% of Bis-GMA in Bis-GMA/TEGDMA (50/50 by wt%), for the prepared resin had the best comprehensive properties. PMID- 23456597 TI - Exploring the multifactorial nature of autism through computational systems biology: calcium and the Rho GTPase RAC1 under the spotlight. AB - Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene-environment interactions (GENVI model) where calcium (Ca(2+)) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism. PMID- 23456601 TI - Chromatin immunoprecipitation of adult murine cardiomyocytes. AB - This unit describes a streamlined two-step protocol for the isolation of adult murine cardiomyocytes with subsequent Chromatin ImmunoPrecipitation (ChIP). Isolation and culturing of cardiomyocytes is a delicate process and the protocol presented here optimizes the combination of cardiomyocyte isolation with ChIP. ChIP is an invaluable method for analyzing molecular interactions occurring between a specific protein (or its post-translationally modified form) and a region of genomic DNA. ChIP has become a widely used technique in the last decade since several groundbreaking studies have focused attention on epigenetics and have identified many epigenetic regulatory mechanisms. However, epigenetics within cardiovascular biology is a new area of focus for many investigators, and we have optimized a method for performing ChIP in adult murine cardiomyocytes, as we feel this will be an important aid to both the cardiovascular field and for the development of cell- and tissue-specific ChIP. PMID- 23456600 TI - Alcohol congener analysis and the source of alcohol: a review. AB - For many decades traditional alcohol congener analysis has provided the concentrations of fermentation by-product congeners found in blood, to ascertain if the claims of an individual regarding the alcoholic beverage(s) they have consumed were feasible, assisting in cases where after-drinking is involved. However, this technique does not provide information on the exact alcoholic beverage(s) consumed. More recently, ingredient biomarker congeners specific to certain alcoholic beverages have been detected in blood, making it possible to identify the particular alcoholic beverage consumed and therefore the source of alcohol (albeit only for a limited number of beverages). This novel approach may reduce current limitations that exist with traditional methods of detecting fermentation by-product congeners, which restrict the use of alcohol congener analysis internationally and for other medico-legal scenarios. This review examines the forensic application of alcohol congener analysis in determining the source of alcohol and other techniques. PMID- 23456602 TI - Imaging tumor cell movement in vivo. AB - This unit describes the methods that we have been developing for analyzing tumor cell motility in mouse and rat models of breast cancer metastasis. Rodents are commonly used both to provide a mammalian system for studying human tumor cells (as xenografts in immunocompromised mice) as well as for following the development of tumors from a specific tissue type in transgenic lines. The Basic Protocol in this unit describes the standard methods used for generation of mammary tumors and imaging them. Additional protocols for labeling macrophages, blood vessel imaging, and image analysis are also included. PMID- 23456603 TI - Photoactivated Localization Microscopy (PALM) of adhesion complexes. AB - Key to understanding a protein's biological function is the accurate determination of its spatial distribution inside a cell. Although fluorescent protein markers allow the targeting of specific proteins with molecular precision, much of this information is lost when the resultant fusion proteins are imaged with conventional, diffraction-limited optics. In response, several imaging modalities that are capable of resolution below the diffraction limit (~200 nm) have emerged. Here, both single- and dual-color superresolution imaging of biological structures using photoactivated localization microscopy (PALM) are described. The examples discussed focus on adhesion complexes: dense, protein filled assemblies that form at the interface between cells and their substrata. A particular emphasis is placed on the instrumentation and photoactivatable fluorescent protein (PA-FP) tags necessary to achieve PALM images at ~20 nm resolution in 5 to 30 min in fixed cells. PMID- 23456604 TI - Susceptibility and physiological responses of Jatropha curcas accessions to broad mite infestation. AB - The broad mite Polyphagotarsonemus latus is a key pest of physic nut (Jatropha curcas L.). The purpose of this study was to identify physic nut accessions that are less susceptible to P. latus, in support of the breeding program of J. curcas. We first evaluated population growth rate and injury symptoms of P. latus on different J. curcas accessions and then carried out physiological analyses on P. latus-infested and uninfested accessions. From the germplasm bank of the Federal University of Vicosa, 15 physic nut accessions with high seed oil content, with different genetic background, were tested. The following traits were evaluated: instantaneous population growth rate of P. latus (r i ), injury symptoms, relative leaf water content, specific leaf area, gas exchange, photosynthetic pigments, nitrogen and biomass of the aerial part. Significant differences were observed for P. latus population growth rate and injury symptoms among accessions. A positive correlation between P. latus growth rate and injury was found. The UFVJC72 accession stood out as the more resistant, considering P. latus growth rate and injury symptoms, compared with most accessions. Physiological responses did not vary among accessions, but did between infested and uninfested plants. In P. latus-infested plants, net photosynthesis was on average 50.5 % lower than in uninfested plants, whereas stomatal conductance and transpiration decreased by 46.2 and 51.6 %, respectively. PMID- 23456605 TI - Life cycle of Ornithodoros rostratus (Acari: Argasidae) under experimental conditions and comments on the host-parasite relationship in the Pantanal wetland region, Brazil. AB - The genus Ornithodoros is represented by 15 species in Brazil, on which no detailed life cycle studies have been published, except for O. talaje and O. mimon. The aim of the present study was to evaluate life cycle parameters of O. rostratus based on ticks collected in the Pantanal wetland region of the state of Mato Grosso do Sul, Brazil, using domestic rabbits as experimental hosts. The periods of pre-attachment and feeding of the larvae lasted an average of 39 min (range 15-76 min). Five or six nymphal instars were found. The emergence of adults started with N3 in the following sequence: N3-two males; N4-13 males; N5 three males and 16 females; and N6-two females. Mean weight of N4 that molted to males was 31.7 +/- 13.6 mg, whereas mean weight of N5 that molted to females was 100.1 +/- 36.2 mg. The overall sex ratio was 1:1. Oviposition lasted 14 days, with a sharp decline beginning with the 7th day. The overall duration of the life cycle of O. rostratus ranged from approximately 66 to 136 days. Comments on the tick-host relationship in the Pantanal region are offered. PMID- 23456606 TI - Detection of lumpy skin disease virus in saliva of ticks fed on lumpy skin disease virus-infected cattle. AB - Lumpy skin disease is an economically important disease of cattle that is caused by the lumpy skin disease virus (LSDV), which belongs to the genus Capripoxvirus. It is endemic in Africa and outbreaks have also been reported in the Middle-East. Transmission has mostly been associated with blood-feeding insects but recently, the authors have demonstrated mechanical transmission by Rhipicephalus appendiculatus as well as mechanical/intrastadial and transstadial transmission by Amblyomma hebraeum. Saliva is the medium of transmission of pathogens transmitted by biting arthropods and, simultaneously, it potentiates infection in the vertebrate host. This study aimed to detect LSDV in saliva of A. hebraeum and R. appendiculatus adult ticks fed, as nymphs or as adults, on LSDV-infected animals, thereby also demonstrating transstadial or mechanical/intrastadial passage of the virus in these ticks. Saliva samples were tested for LSDV by real time PCR and virus isolation. Supernatants obtained from virus isolation were further tested by real-time PCR to confirm that the cytopathic effects observed were due to LSDV. Lumpy skin disease virus was detected, for the first time, in saliva samples of both A. hebraeum and R. appendiculatus ticks. At the same time, mechanical/intrastadial and transstadial passage of the virus was demonstrated and confirmed in R. appendiculatus and A. hebraeum. PMID- 23456607 TI - Resistance to fresh and salt water in intertidal mites (Acari: Oribatida): implications for ecology and hydrochorous dispersal. AB - The resistance to fresh water and seawater in three intertidal oribatid mite species from Bermuda, Alismobates inexpectatus, Fortuynia atlantica and Carinozetes bermudensis, was tested in laboratory experiments. Larvae are more sensitive to fresh and salt water, nymphs and adults showed equal tolerances. Fortuynia atlantica and A. inexpectatus were more resistant to salt water whereas C. bermudensis survived longer in fresh water. Differences in the resistance to fresh and salt water among the three species may be related to their different vertical occurrences in the eulittoral zone but also to the ability of single species to dwell in periodically brackish waters. In all three species half of the specimens survived at least 10 days in fresh water and more than 18 days in salt water. Maximal submersion time in fresh and salt water ranged from 40 to 143 days. Based on median lethal times it could be estimated that each species would be able to survive transport in seawater along the Gulf Stream over a distance of 3,000 km, from Central America to Bermuda. Thus hydrochorous dispersal should be assumed as the most likely mode of dispersal in intertidal fortuyniid and selenoribatid mites. PMID- 23456608 TI - Improved polyhydroxybutyrate production by Saccharomyces cerevisiae through the use of the phosphoketolase pathway. AB - The metabolic pathways of the central carbon metabolism in Saccharomyces cerevisiae are well studied and consequently S. cerevisiae has been widely evaluated as a cell factory for many industrial biological products. In this study, we investigated the effect of engineering the supply of precursor, acetyl CoA, and cofactor, NADPH, on the biosynthesis of the bacterial biopolymer polyhydroxybutyrate (PHB), in S. cerevisiae. Supply of acetyl-CoA was engineered by over-expression of genes from the ethanol degradation pathway or by heterologous expression of the phophoketolase pathway from Aspergillus nidulans. Both strategies improved the production of PHB. Integration of gapN encoding NADP(+) -dependent glyceraldehyde-3-phosphate dehydrogenase from Streptococcus mutans into the genome enabled an increased supply of NADPH resulting in a decrease in glycerol production and increased production of PHB. The strategy that resulted in the highest PHB production after 100 h was with a strain harboring the phosphoketolase pathway to supply acetyl-CoA without the need of increased NADPH production by gapN integration. The results from this study imply that during the exponential growth on glucose, the biosynthesis of PHB in S. cerevisiae is likely to be limited by the supply of NADPH whereas supply of acetyl-CoA as precursor plays a more important role in the improvement of PHB production during growth on ethanol. PMID- 23456609 TI - Route of infection and hematological effect of Metarhizium anisopliae (Metsch.) Sorokin on Dysdercus cingulatus (Fab.) adult. AB - The primary objective of this work was to identify, under laboratory conditions, the route of infection and hemogram of Dysdercus cingulatus (Fab.) adults by Metarhizium anisopliae. The infection process in D. cingulatus by M. anisopliae involved the conidia adherence to the host cuticle and germination after 24 h post-infection, accompanied by falling of bristles. The subsequent step, within 24-48 h post-infection, comprised penetration of fungus through spiracles, root of bristles, hemolymph, and the three dorsal sacs. Subsequently, within 72-96 h post-infection, the fungus penetrated into trachea and sacs, then emerged on cuticular surface and was found to be maximum in hemolymph. A great decrease in hemocytes count was observed within 96 h from infection. The hemosomic index (HSI) decreased gradually as the incubation period increased. As far as we know, this is the first study to know the mechanism of action of M. anisopliae to D. cingulatus. PMID- 23456610 TI - SOX10 rs139883 polymorphism is associated with the age of onset in schizophrenia. AB - Schizophrenia is a common psychiatric disorder with high heritability. The age of onset is an important phenotype of schizophrenia and may be under considerable genetic control. Our previous study showed that a single nucleotide polymorphism (SNP) rs139887 in sex-determining region Y-box 10 (SOX10) gene was associated with the age of onset in schizophrenia. The aim of this study was to evaluate the effect of another SNP rs139883 in the exon 4 of SOX10 on schizophrenia using an early-onset samples in the Han Chinese population. A total of 309 schizophrenic patients with onset before age 18 and 390 healthy controls were recruited for association study. No significant differences of allele or genotype frequencies were identified between the schizophrenic patients and controls. However, the C allele was significantly associated with an earlier age of onset in total patients and male patients (Kaplan-Meier log rank test P = 0.026; Kaplan-Meier log rank test P = 0.047, respectively), but not in females. In conclusion, the SOX10 rs139883 polymorphism influenced the age of onset of schizophrenia in a gender-specific manner and this may represent a vital genetic clue for the etiology of schizophrenia. PMID- 23456611 TI - Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine. AB - Research models that replicate the diverse genetic and molecular landscape of breast cancer are critical for developing the next-generation therapeutic entities that can target specific cancer subtypes. Patient-derived tumorgrafts, generated by transplanting primary human tumor samples into immune-compromised mice, are a valuable method to model the clinical diversity of breast cancer in mice, and are a potential resource in personalized medicine. Primary tumorgrafts also enable in vivo testing of therapeutics and make possible the use of patient cancer tissue for in vitro screens. Described in this unit are a variety of protocols including tissue collection, biospecimen tracking, tissue processing, transplantation, and three-dimensional culturing of xenografted tissue, which enable use of bona fide uncultured human tissue in designing and validating cancer therapies. PMID- 23456612 TI - Discovery of biologically active oncologic and immunologic small molecule therapies using zebrafish: overview and example of modulation of T cell activation. AB - Zebrafish models continue to gain popularity as in vivo models for drug discovery. Described in this overview are advantages and challenges of zebrafish drug screening, as well as a novel in vivo screen for immunomodulatory compounds using transgenic, T cell reporting zebrafish larvae designed for discovery of compounds targeting T cell leukemia. This assay system allows rapid screening of large numbers of compounds while avoiding the pitfalls of assays based on cell cultures, which lack biologic context and are afflicted by genomic instability. The rationale for this approach is based on similarities of immature normal T cells and developmentally arrested, malignant lymphoblasts in mammalian species. The screening algorithm has been used to identify a nontoxic compound with activity in both acute leukemia models and models of multiple sclerosis, demonstrating the utility of this screening procedure. PMID- 23456614 TI - Cigarette smoke exposure as a model of inflammation associated with COPD. AB - Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation resulting from inflammation-driven pathologies in the lungs that are a consequence of smoking over many years. Given that the disease is increasing globally, understanding the mechanism by which cigarette smoke (CS) causes lung inflammation and exploiting that knowledge to develop effective treatments is urgently required. Animal models of CS exposure are commonly used to examine the inflammatory processes that may be involved in the development of COPD. The protocols described in this unit detail the development of preclinical models of CS-driven lung inflammation. These systems can be utilized to investigate the role of various biological pathways in CS-mediated inflammation and to assess the efficacy of new therapeutic strategies for treating COPD. PMID- 23456613 TI - The human kinome and kinase inhibition. AB - Protein and lipid kinases play key regulatory roles in a number of biological processes. Unsurprisingly, activating mutations in kinases have been linked to a number of disorders and diseases, most notably cancers. Thus, kinases have emerged as promising clinical targets. There are more than 500 human protein kinases and about 20 lipid kinases. Most protein kinases share a highly conserved domain, the eukaryotic protein kinase (ePK) domain, which contains the ATP and substrate-binding sites. Many inhibitors in clinical use bind to the highly conserved ATP binding site. For this reason, many kinase inhibitors are not exclusively selective for their intended targets. Furthermore, despite the current interest in kinase inhibitors, very few kinases implicated in disease have validated inhibitors. This unit describes the human kinome, ePK structure, and types of kinase inhibitors, focusing on methods to identify potent and selective kinase inhibitors. PMID- 23456615 TI - Overview of determination of biopharmaceutical properties for development candidate selection. AB - The physicochemical and biopharmaceutical properties of putative drug molecules impact their performance in both in vitro and in vivo studies. The design and selection of molecules with drug-like properties assists in the selection of drug candidates with a higher probability of success in the development process. Described in this overview are commonly used approaches for measuring compound solubility, permeability, and partitioning in drug discovery and development. The utility of these methods in the drug discovery process and product development is discussed. The evaluation of crystallinity and physicochemical stability in relation to biopharmaceutical properties and in assessing the potential for successful development are also discussed. PMID- 23456616 TI - Laser exposure of gold nanorods can increase neuronal cell outgrowth. AB - The usage of gold nanoparticles (Au NPs) in biological applications has risen significantly over the last 10 years. With the wide variety of chemical and biological functionalization available and their distinctive optical properties, Au NPs are currently used in a range of biological applications including sensing, labeling, drug delivery, and imaging applications. Among the available particles, gold nanorods (Au NRs) are particularly useful because their optical absorption can be tuned across the visible to near infrared region. Here, we present a novel application of Au NRs associated with low power laser exposure of NG108-15 neuronal cells. When cells were irradiated with a 780 nm laser, the average number of neurons with neurites increased. A similar stimulatory effect was observed for cells that were cultured with poly-(4-styrenesulfonic acid) coated and silica-coated Au NRs. Furthermore, when the NG108-15 cells were cultured with both bare and coated Au NRs and then irradiated with 1.2-7.5 W/cm(2) at 780 nm, they showed a neurite length increase of up to 25 um versus control. To the best of our knowledge, this effect has never been reported before. While the pathways of the stimulation is not yet clear, the data presented here demonstrates that it is linked to the absorption of light by the Au NRs. These initial results open up new opportunities for peripheral nerve regeneration treatments and for novel approaches to addressing central nervous system axons following spinal cord injury. PMID- 23456617 TI - Expression of cry3A gene and its toxicity against Asian Gray Weevil Myllocerus undecimpustulatus undatus Marshall (Coleoptera: Curculionidae). AB - Coleopterans are the most damaging pests of many agricultural and forestry crops; there is an urgent need to develop effective biopesticides against these insects. Enhancers of Bt toxicity typify an opportunity to improve currently available commercial products into more effective control agents against diverse pests. A 1.9 kb DNA fragment, PCR amplified from native isolates of Bt using cry3A gene specific primers was cloned in expression vector pQE-80L and then used for transformation of Escherichia coli M15 cells. The sequence of the cloned crystal protein gene showed almost complete homology with a Coleopteran active Cry3A toxin gene with 117 mutations scattered in different domain regions encoding a protein of 645 amino acid residues in length, with a predicted molecular mass of 77.4 kDa. Phylogenetic analysis could be compulsive for new/novel Bacillus thuringiensis strains, allowing them to be grouped with related Cry proteins. The toxicity of Bt protein was determined against Myllocerus undecimpustulatus undatus Marshall (Coleoptera: Curculionidae) LC50 152 ng cm(-2). Genes coding for Coleopteran active Cry3A proteins have been isolated and their efficient expression will provide the tools necessary to increase the efficacy of Cry-based biopesticide against economically important beetles. PMID- 23456618 TI - DNA polymerase zeta as a potential biomarker of chemoradiation resistance and poor prognosis for cervical cancer. AB - DNA Polymerase zeta (Polzeta), an error-prone DNA polymerase involved in translesion DNA synthesis, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of several cancers. To evaluate the association of Polzeta with chemoradiation resistance and prognosis in cervical cancer, we enrolled 123 patients with squamous cell carcinoma of cervical cancer, who had adjuvant concurrent chemoradiation therapy after radical surgery treated at Fudan University Shanghai Cancer Center between 2008 and 2009, and tested their in vitro tumor inhibition rates using the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide method and Polzeta protein expression in paraffin-embedded tissues using immunohistochemistry. We found that the Polzeta-positive expression was detected in 22 % of the cases. The median in vitro inhibition rate of tumor cell growth by cisplatin, carboplatin, nedaplatin, and oxaliplatin was 80, 37, 78, and 51 %, respectively. Among the tumor-related variables, FIGO stage, tumor grade, and Polzeta protein expression (adjusted HR 6.7, 4.2 and 6.7; 95 % CI 1.7 26.3, 1.0-17.3 and 1.8-25.4; P = 0.007, 0.046 and 0.005, respectively) were found to be significant predictors for recurrence. Kaplan-Meier survival estimates showed that the patients with more advanced stage (IIB) or Polzeta-positive expression had a significantly shorter progression-free survival. Polzeta positive expression was significantly associated with depth of cervical stromal invasion (P = 0.012). However, the association between Polzeta expression and in vitro tumor inhibition rates was not significant. Taken together, Polzeta expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the cervical cancer patients. The mechanism deserves further exploration. PMID- 23456619 TI - Clinical benefit of trabectedin in uterine adenosarcoma. AB - Uterine adenosarcoma is an extremely rare uterine malignancy, and the utility of chemotherapy in this disease is not well defined. This study assessed the safety and efficacy of trabectedin in patients with recurrent/metastatic uterine adenosarcoma with sarcomatous overgrowth. A retrospective search of a prospectively maintained database was performed to identify patients with adenosarcoma treated with trabectedin between 2010 and 2012, within a compassionate use trial. Three patients with recurrent/metastatic uterine adenosarcoma treated with trabectedin were identified. All three patients tolerated the drug well. Two patients obtained prolonged clinical benefit from treatment, one having received 17 cycles and another 11 cycles of therapy. Trabectedin is well tolerated and has clinical activity in recurrent/metastatic uterine adenosarcoma. PMID- 23456620 TI - Central nervous system prophylaxis in patients with aggressive diffuse large B cell lymphoma: an analysis of 3,258 patients in a single center. AB - Central nervous system (CNS) relapse continues to be a frequent and usually fatal complication in patients with diffuse large B cell lymphoma (DLBCL). Multiple factors identify the possibility of relapse and justify neurological prophylaxis; however, most of these have not been confirmed. Thus, the use of prophylaxis has not been defined. From 1988 to 2008, 3,258 patients with DLBCL with higher clinical risks and multiple extranodal involvement that have been treated with standard anthracycline-based chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-R (CHOP plus rituximab) and that achieve complete response were retrospectively analyzed to assess the efficacy of CNS prophylaxis. One thousand five patients received different schedules for CNS prophylaxis, and 2,253 patients did not receive CNS prophylaxis. CNS relapse was similar in patients who receive prophylaxis (6 %) compared to patients who did not receive prophylaxis (5.9 %). Overall survival of patients who either receive or did not receive prophylaxis was not statistically significant: 49 % versus 53 % (p = 0.802). Thus, it seems that CNS prophylaxis did not improve outcome in this special setting of patients, and no prognostic factors to predict the presence of CNS relapse were identified. It is evident that multicentric studies are necessary to define the role of prophylaxis in order to prevent CNS relapse and that the therapeutic procedure will be carefully revised. PMID- 23456621 TI - Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors. AB - The aim of this study was to investigate the associations between secondary mutations of c-KIT/PDGFRalpha and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRalpha (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing. A total of 50 samples before imatinib and 52 samples after imatinib were collected. Among 52 samples after imatinib, 38 samples were imatinib resistant and 14 samples were imatinib sensitive. All patients before imatinib treatment had primary mutations of c-KIT exon 11 (n = 45) or exon 9 (n = 5), and no PDGFRalpha mutations were found in these patients. After imatinib treatment, 25 of 38 (65.8 %) resistant tumors had secondary mutations in c-KIT exon 13 (n = 10), exon 14 (n = 1), exon 17 (n = 12) and exon 18 (n = 2), while no secondary mutations of c-KIT were found in 14 sensitive tumors (P < 0.001), indicating the close association of c-KIT secondary mutations with imatinib-acquired resistance. In our study, 19 patients received sunitinib treatment after the failure of imatinib, and it seemed that the median progression-free survival (7 vs. 19 months, P = 0.244) in patients with secondary mutations (n = 13) was lower than that in patients without secondary mutations (n = 6). Secondary mutations of c-KIT were significantly associated with acquired resistance to imatinib in Chinese GIST patients, and whether secondary mutations of c-KIT could influence the efficacy of sunitinib needed to be further investigated. PMID- 23456622 TI - Proteasomal regulation of caspase-8 in cancer cell apoptosis. AB - Previous studies demonstrated that proteasome inhibition sensitizes TRAIL resistant prostate cancer cells to TRAIL-mediated apoptosis via stabilization of the active p18 subunit of caspase-8. The present study investigated the impact of proteasome inhibition on caspase-8 stability, ubiquitination, trafficking, and activation in cancer cells. Using caspase-8 deficient neuroblastoma (NB7) cells for reconstituting non-cleavable mutant forms of caspase-8, we demonstrated that the non-cleavable forms of caspase-8 are capable of inducing apoptosis comparably to wild-type caspase-8, in response to proteasome inhibitor and GST-TRAIL. Moreover in the LNCaP human prostate cancer cells, caspase-8 polyubiquitination occurs after TRAIL stimulation and caspase-8 processing. Subcellular fractionation analysis revealed caspase-8 activity in both cytosol and plasma membrane fractions in both NB7 reconstituted caspase-8 cell lines, as well the LNCaP prostate cancer cells. The present results suggest that caspase-8 stabilization through proteasome inhibition leads to reactivation of the extrinsic pathway of apoptosis and identify E3 ligase mediating caspase-8 polyubiquitination, as a novel molecular target. Inhibition of this E3 ligase in combination with TRAIL towards restoring apoptosis signaling activation may have potential therapeutic significance in resistant tumors. PMID- 23456623 TI - The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms. AB - TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT 29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL based, anti-cancer combination therapy. PMID- 23456624 TI - Hepatic apoptosis can modulate liver fibrosis through TIMP1 pathway. AB - Apoptotic injury participates in hepatic fibrosis, but the molecular mechanisms are not well understood. The present study aimed to investigate the role of inducible TIMP1 in the pathogenesis of hepatic apoptosis-fibrosis. Apoptosis was induced with GCDC, LPS, and alcohol in precision-cut liver slices or bile duct ligation (BDL) in rats, as reflected by caspase-3 activity, TUNEL assay, and apoptosis-related gene profiles. The hepatic fibrosis was detected with Picrosirius staining, hydroxyproline determination, and expression profiling of fibrosis-related genes. Levels of TIMP1 were upregulated by the hepatic apoptosis, but downregulated by caspase inhibitor. The inducible TIMP1 was apoptosis-dependent. Once TIMP1 was inhibited with treatment of TIMP1-siRNA, the fibrotic response was reduced as demonstrated by hydroxyproline assay. In addition, the expression of fibrosis-related genes aSMA, CTGF, and TGFb2r were down-regulated subsequent to the treatment of TIMP1-siRNA. TIMP1 could mediate the expression of fibrosis-related genes. TIMP1 was transcriptionally regulated by nuclear factor c-Jun as demonstrated by EMSA and ChIP assay. The treatment of c-Jun siRNA could significantly decrease the expression of TIMP1 induced by alcohol, GCDC, or LPS treatment. Hepatic apoptosis induces the expression of TIMP1. Inducible TIMP1 can modulate the expression of fibrosis-related genes in liver. TIMP1 pathway is a potential target for therapeutic intervention of fibrotic liver diseases. PMID- 23456625 TI - MAPK p38 and JNK have opposing activities on TRAIL-induced apoptosis activation in NSCLC H460 cells that involves RIP1 and caspase-8 and is mediated by Mcl-1. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce both caspase-dependent apoptosis and kinase activation in tumor cells. Here, we examined the consequences and mechanisms of TRAIL-induced MAPKs p38 and JNK in non-small cell lung cancer (NSCLC) cells. In apoptosis sensitive H460 cells, these kinases were phosphorylated, but not in resistant A549 cells. Time course experiments in H460 cells showed that induction of p38 phosphorylation preceded that of JNK. To explore the function of these kinases in apoptosis activation by TRAIL, chemical inhibitors or siRNAs were employed to impair JNK or p38 functioning. JNK activation counteracted TRAIL-induced apoptosis whereas activation of p38 stimulated apoptosis. Notably, the serine/threonine kinase RIP1 was cleaved following TRAIL treatment, concomitant with detectable JNK phosphorylation. Further examination of the role of RIP1 by short hairpin (sh)RNA dependent knockdown or inhibition by necrostatin-1 showed that p38 can be phosphorylated in both RIP1-dependent and -independent manner, whereas JNK phosphorylation occurred independent of RIP1. On the other hand JNK appeared to suppress RIP1 cleavage via an unknown mechanism. In addition, only the activation of JNK by TRAIL was caspase-8-dependent. Finally, we identified Mcl-1, a known substrate for p38 and JNK, as a downstream modulator of JNK or p38 activity. Collectively, our data suggest in a subset of NSCLC cells a model in which TRAIL induced activation of p38 and JNK have counteracting effects on Mcl-1 expression leading to pro- or anti-apoptotic effects, respectively. Strategies aiming to stimulate p38 and inhibit JNK may have benefit for TRAIL-based therapies in NSCLC. PMID- 23456626 TI - Standards for the use of animals in surgical research. PMID- 23456630 TI - Prospective study on loss of signal on the first side during neuromonitoring of the recurrent laryngeal nerve in total thyroidectomy (Br J Surg 2013; 100: 662 666). PMID- 23456627 TI - Radioactive seed localization for non-palpable breast cancer. AB - BACKGROUND: Radioactive seed localization (RSL) is an alternative to wire localization for guiding surgical excision of non-palpable breast cancer. This review provides an overview of the available evidence on the accuracy of RSL in patients undergoing breast-conserving surgery. METHODS: PubMed, Embase and the Cochrane Library were searched systematically in January 2012 for studies that addressed localization of non-palpable breast cancer using an iodine-125-labelled seed. Studies were deemed eligible if they reported on the proportion of patients with tumour-positive margins after RSL, the proportion of patients needing re excision after RSL, and procedural complications. RESULTS: Six studies reported data on RSL in 1611 patients with non-palpable breast lesions. Overall complete resection rates ranged from 73 to 96.7 per cent. Three studies included over 300 patients, and complete resection rates in these studies varied between 89.5 and 96.7 per cent. The risk of seed migration and failure of seed placement ranged from 0 to 0.6 per cent and 0 to 7.2 per cent respectively. CONCLUSION: Available scientific evidence suggests that RSL is a safe and accurate technique for localization of non-palpable breast lesions. PMID- 23456631 TI - Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids. AB - BACKGROUND: Omega-3 fatty acids (FAs) have been shown to reduce experimental hepatic steatosis and protect the liver from ischaemia-reperfusion injury. The aim of this study was to examine the effects of omega-3 FAs on regeneration of steatotic liver. METHODS: Steatosis was induced in rats by a 3-week methionine/choline-deficient diet, which was continued for an additional 2 weeks in conjunction with oral administration of omega-3 FAs or saline solution. Steatosis was graded histologically and quantified by proton magnetic resonance spectroscopy ((1) H-MRS) before and after the diet/treatment. Liver function was determined by (99m) Tc-labelled mebrofenin hepatobiliary scintigraphy (HBS). In separate experiments, the hepatic regenerative capacity and functional recovery of omega-3 FA-treated, saline-treated or non-steatotic (control) rats were investigated 1, 2, 3 and 5 days after partial (70 per cent) liver resection by measurement of liver weight change and hepatocyte proliferation (Ki-67) and HBS. RESULTS: Severe steatosis (over 66 per cent) in the saline group was reduced by omega-3 FAs to mild steatosis (less than 33 per cent), and hepatic fat content as assessed by (1) H-MRS decreased 2.2-fold. (99m) Tc-mebrofenin uptake in the saline group was more than 50 per cent lower than in the control group, confirming the functional effects of steatosis. (99m) Tc-mebrofenin uptake and regenerated liver mass were significantly greater in the omega-3 group compared with the saline group on days 1 and 3. The posthepatectomy proliferation peak response was delayed until day 2 in saline-treated rats, compared with day 1 in the omega-3 and control groups. CONCLUSION: Omega-3 FAs effectively reduced severe hepatic steatosis, which was associated with improved liver regeneration and functional recovery following partial hepatectomy. PMID- 23456634 TI - Impact of legal measures prevent transplant tourism: the interrelated experience of The Philippines and Israel. AB - We describe the parallel changes that have taken place in recent years in two countries, Israel and The Philippines, the former once an "exporter" of transplant tourists and the latter once an "importer" of transplant tourists. These changes were in response to progressive legislation in both countries under the influence of the Declaration of Istanbul. The annual number of Israeli patients who underwent kidney transplantation abroad decreased from a peak of 155 in 2006 to an all-time low of 35 in 2011 while in the Philippines the annual number of foreign transplant recipients fell from 531 in 2007 to two in 2011. The experience of these two countries provides a "natural experiment" on the potential impact of legal measures to prevent transplant tourism. PMID- 23456635 TI - Galleria mellonella hemocytes destruction after infection with Pseudomonas aeruginosa. AB - The influence of infection with an entomopathogenic strain of Pseudomonas aeruginosa on Galleria mellonella hemocytes was investigated. Extensive bacteriaemia developed 18 h after infection. This was correlated with significant changes in morphology, viability and the spreading ability of immunocompetent hemocytes, namely granulocytes and plasmatocytes. Since bacteriaemia developed, membrane blebbing, cytoplasm vacuolization, cell and organelle swelling, and chromatin condensation were observed among others. These features are typical for apoptotic and autophagal cell death. A gradually increasing level of procaspase and its activation as well as lack of DNA degradation were also detected. Propidium iodide and acridine orange staining indicated that hemocytes become dead ultimately. Infection of G. mellonella larvae with P. aeruginosa also caused significant changes in the arrangement of the actin cytoskeleton in the hemocytes, which might be correlated with their restricted spreading ability. PMID- 23456638 TI - Paenibacillus marinum sp. nov., a thermophilic xylanolytic bacterium isolated from a marine hot spring in Tunisia. AB - Among a large collection of Tunisian hot springs bacterial isolates a bacterial strain, THE22(T) , with xylanolytic properties was identified. The bacterium was isolated from a natural hot spring "Ain Echefa" at Mediteranean sea (Korbous, North-Eastern Tunisia). The novel strain was Gram positive, spore-forming, rod shaped, facultatively anaerobic and grew optimally under conditions of 55 degrees C, 1% (w/v) NaCl and pH 7-8. The 16S rRNA gene sequence analysis showed that strain THE22(T) fell within the radiation of the cluster comprising Paenibacillus species with Paenibacillus phyllosphaerae PALXIL04(T) as the closest phylogenetic neighbour (95.8%). The predominant components in the fatty methyl ester profile were iso-C16:0 (34.46%), C16:0 (19.64%), anteiso-C15:0 (19.18%) and anteiso-C17:0 (18.11%). The major respiratory quinone was menaquinone-7 (MK-7). The diamino acid found in the cell-wall peptidoglycan was meso-diaminopimelic acid. The base composition of DNA was 56 mol%. Based on the polyphasic taxonomic data, strain THE-22(T) (=DSM 18499(T) = LMG 23758(T) ) was recognized as a novel species within the genus Paenibacillus. The name Paenibacillus marinum sp. nov. is proposed. PMID- 23456637 TI - Association of PYGO2 and EGFR in esophageal squamous cell carcinoma. AB - Wnt signaling is an important evolutionary conserved pathway that is not only involved in determination of cellular development, self-renewal, and fate, but also has significant roles in tumor development and progression. Deregulation of the Wnt/beta-catenin signaling pathway and aberrant expression of its components is commonly observed in solid tumors. Such aberrant regulation of Wnt signaling is commonly related to either malfunction of its components or crosstalk with other cellular processes such as the epidermal growth factor receptor (EGFR) signaling cascade. Therefore, identification of the roles of major involved components may be useful to identify new therapeutic targets for cancer treatment. In this study, we assessed EGFR and PYGO2 mRNA expression in tumors and margin normal tissues from 55 esophageal squamous cell carcinoma (ESCC) patients using real-time qRT-PCR, and evaluated clinicopathology relative to the two genes' expression levels. Significant PYGO2 and EGFR overexpression was observed in 30.9 % (P = 0.017) and 38.2 % (P = 0.006) of tumors, respectively. PYGO2 and EGFR expression were significantly associated not only with each other (P < 0.001), but also with tumor staging and depth (P < 0.001). Furthermore, PYGO2 expression was significantly correlated with the tumor grade (P = 0.043) and size (P = 0.023). We identify PYGO2 as a new molecular marker of invasive tumors, introducing its probable oncogenic role in ESCC progression and aggressiveness. In line with other reports, we also illustrate the oncogenic function of EGFR in the development of ESCC through advance stages. We also observed a significant correlation between PYGO2 and EGFR in ESCC tumors, which reveals a mutual convergent influence of these factors in tumor progression and development. Considering aberrant expression, mutual positive feedback, and the significant clinical relevance of these genes in ESCC, we introduce them as appropriate therapeutic targets in adjuvant therapy of ESCC. PMID- 23456639 TI - A simple route for the synthesis of novel N-alkyl-2-(alkylthio)-1H-imidazole derivatives. AB - Novel N-alkyl-2-(alkylthio)-1H-imidazole derivatives were synthesized in a single step by an efficient and simple method in high yields. Readily available starting materials, mild reaction conditions, operational simplicity and novelty are the key advantages of this method. Besides their novel structures, these compounds may have important biological activities and industrial applications. PMID- 23456640 TI - Isolation of genes related to abscisic acid production in Botrytis cinerea TB-3 H8 by cDNA-AFLP. AB - Abscisic acid (ABA) plays important roles in many aspects of plant growth and development. Botrytis cinerea TB-3-H8, a high-yield strain of ABA, was used to elucidate the molecular mechanisms of ABA production in the present work. cDNA amplified fragment length polymorphism (cDNA-AFLP) technique was applied to isolate genes differentially expressed between ABA high and low-yield conditions. This resulted in the identification of 856 differentially expressed transcript derived fragments (TDFs). Forty-five TDFs that displayed obvious up-regulated expression profiles in the ABA high-yield condition were sequenced. Based on BlastX in NCBI, 31 TDFs were assumed to have homology with genes encoding proteins with known functions. According to molecular function of gene ontology (GO) analysis, the 31 TDFs were categorized to proteins with enzyme catalytic activities, transcription factor activities, transporter activities, and kinds of binding activities. Further confirmation of the differential expression of these sequences was carried out by performing semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) on 10 randomly selected TDFs. Five up regulated genes were selected to analyze the expression profiles using real-time PCR. This study enriches our knowledge of the molecular basis for ABA biosynthesis in B. cinerea TB-3-H8. PMID- 23456641 TI - Habitat-specific foraging and sex determine mercury concentrations in sympatric benthic and limnetic ecotypes of threespine stickleback. AB - Mercury (Hg) is a widespread environmental contaminant known for the neurotoxicity of its methylated forms, especially monomethylmercury, which bioaccumulates and biomagnifies in aquatic food webs. Mercury bioaccumulation and biomagnification rates are known to vary among species utilizing different food webs (benthic vs limnetic) within and between systems. The authors assessed whether carbon and nitrogen stable isotope values and total Hg (THg) concentrations differed between sympatric benthic and limnetic ecotypes and sexes of threespine stickleback fish (Gasterosteus aculeatus) from Benka Lake, Alaska, USA. The mean THg concentration in the limnetic ecotype was significantly higher (difference between benthic and limnetic means equals 26 mg/kg dry wt or 16.1%) than that of the benthic ecotype. Trophic position and benthic carbon percentage utilized were both important determinants of THg concentration; however, the 2 variables were of approximately equal importance in females, whereas trophic position clearly explained more of the variance than benthic carbon percentage in males. Additionally, strong sex effects (mean difference between females and males equals 45 mg/kg dry wt or 29.4%) were observed in both ecotypes, with female fish having lower THg concentrations than males. These results indicate that trophic ecology and sex are both important determinants of Hg contamination even within a single species and lake and likely play a role in governing Hg concentrations in higher trophic levels. PMID- 23456642 TI - Immune responses induced in HHD mice by multiepitope HIV vaccine based on cryptic epitope modification. AB - CD8+ T cells play an important role in early HIV infection. However, HIV has the capacity to avoid specific CTL responses due to a high rate of mutation under selection pressure. Although the HIV proteins, gag and pol, are relatively conserved, these sequences generate low-affinity MHC-associated epitopes that are poorly immunogenic. Here, we applied an approach that enhanced the immunogenicity of low-affinity HLA-A2.1-binding peptides. The first position with tyrosine (P1Y) substitution enhanced the affinity of HLA-A2.1-associated peptides without altering their antigenic specificity. More importantly, P1Y variants efficiently stimulated in vivo native peptide-specific CTL that also recognized the corresponding naturally processed epitope. The potential to generate CTL against any low-affinity HLA-A2.1-associated peptide provides us with the necessary technique for identification of virus cryptic epitopes for development of peptide based immunotherapy. Therefore, identification and modification of the cryptic epitopes of gal and pol provides promising candidates for HIV immunotherapy dependent upon efficient presentation by virus cells. Furthermore, this may be a breakthrough that overcomes the obstacle of immune escape caused by high rates of mutation. In this study, bioinformatics analysis was used to predict six low affinity cryptic HIV gag and pol epitopes presented by HLA-A*0201. A HIV compound multi-CTL epitope gene was constructed comprising the gene encoding the modified cryptic epitope and the HIV p24 antigen, which induced a strong CD8+ T cell immune response regardless of the mutation. This approach represents a novel strategy for the development of safe and effective HIV prophylactic and therapeutic vaccines. PMID- 23456643 TI - Microarray gene expression profiling analysis combined with bioinformatics in multiple sclerosis. AB - Multiple sclerosis (MS) is the most prevalent demyelinating disease and the principal cause of neurological disability in young adults. Recent microarray gene expression profiling studies have identified several genetic variants contributing to the complex pathogenesis of MS, however, expressional and functional studies are still required to further understand its molecular mechanism. The present study aimed to analyze the molecular mechanism of MS using microarray analysis combined with bioinformatics techniques. We downloaded the gene expression profile of MS from Gene Expression Omnibus (GEO) and analysed the microarray data using the differentially coexpressed genes (DCGs) and links package in R and Database for Annotation, Visualization and Integrated Discovery. The regulatory impact factor (RIF) algorithm was used to measure the impact factor of transcription factor. A total of 1,297 DCGs between MS patients and healthy controls were identified. Functional annotation indicated that these DCGs were associated with immune and neurological functions. Furthermore, the RIF result suggested that IKZF1, BACH1, CEBPB, EGR1, FOS may play central regulatory roles in controlling gene expression in the pathogenesis of MS. Our findings confirm the presence of multiple molecular alterations in MS and indicate the possibility for identifying prognostic factors associated with MS pathogenesis. PMID- 23456644 TI - Emergency management of acute abdomen in children. AB - Acute abdomen can be defined as a medical emergency in which there is sudden and severe pain in abdomen with accompanying signs and symptoms that focus on an abdominal involvement. It accounts for about 8 % of all children attending the emergency department. The goal of emergency management is to identify and treat any life-threatening medical or surgical disease condition and relief from pain. In mild cases often the cause is gastritis or gastroenteritis, colic, constipation, pharyngo-tonsilitis, viral syndromes or acute febrile illnesses. The common surgical causes are malrotation and Volvulus (in early infancy), intussusception, acute appendicitis, and typhoid and ischemic enteritis with perforation. Lower lobe pneumonia, diabetic ketoacidosis and acute porphyria should be considered in patients with moderate-severe pain with little localizing findings in abdomen. The approach to management in ED should include, in order of priority, a rapid cardiopulmonary assessment to ensure hemodynamic stability, focused history and examination, surgical consult and radiologic examination to exclude life threatening surgical conditions, pain relief and specific diagnosis. In a sick patient the initial steps include rapid IV access and normal saline 20 ml/kg (in the presence of shock/hypovolemia), adequate analgesia, nothing per oral/IV fluids, Ryle's tube aspiration and surgical consultation. An ultrasound abdomen is the first investigation in almost all cases with moderate and severe pain with localizing abdominal findings. In patients with significant abdominal trauma or features of pancreatitis, a Contrast enhanced computerized tomography (CECT) abdomen will be a better initial modality. Continuous monitoring and repeated physical examinations should be done in all cases. Specific management varies according to the specific etiology. PMID- 23456645 TI - Toxic behavior of silver and zinc oxide nanoparticles on environmental microorganisms. AB - Silver and zinc oxide nanoparticles (Ag and ZnO NPs) are widely used as antimicrobial agents. However, their potential toxicological impact on environmental microorganisms is largely unexplored. The aim of this work was to investigate the sensitivity and adaptability of five bacterial species isolated from sewage towards Ag and ZnO NPs. The bacterial species were exposed to increasing concentration of nanoparticles and the growth inhibitory effect, exopolysaccharides (EPSs) and extracellular proteins (ECPs) productions were determined. The involvement of surface charge in nanoparticles toxicity was also determined. The bacterial species were constantly exposed to nanoparticles to determine the adaptation behavior toward nanoparticles. The nanoparticles exhibited remarkable growth inhibitory effect on tested bacterial species. The toxicity of nanoparticles was found to be strongly dependent on surface charge effects. Though, these organisms are highly sensitive to Ag and ZnO NPs, the continuous exposure to these nanoparticles leads to moderate adaptation of bacterial species and the adapted bacterial species convert the highly toxic nano form to less toxic microform. Finally we predict that the continuing applications of nanoparticles in consumer products may lead to the development of nanoparticles resistant bacterial strains in future. PMID- 23456646 TI - Complexes of the antimicrobial ciprofloxacin with soil, peat, and aquatic humic substances. AB - Natural organic matter (NOM) is implicated in the binding of antibiotics by particles in soils and waters. The authors' previous computational study revealed structural rearrangement of both hydrophilic and hydrophobic moieties of NOM to favor H-bonding and other intermolecular interactions, as well as both competition with ion-exchange reactions and bridging interactions by NOM-bound divalent cations. The importance of these interactions was investigated using fluorescence-quenching spectroscopy to study the adsorption of ciprofloxacin (Cipro), a fluoroquinolone antibiotic, on 4 reference humic substances (HSs): Elliott soil humic acid (HA), Pahokee peat HA, and Suwannee river HA and fulvic acid. A simple affinity spectrum HS model was developed to characterize the cation-exchange capacity and the amount of H-bond donor moieties as a function of pH. The adsorption results stress the influence of both pH conditions and the type of HS: both soil HA and peat HA exhibited up to 3 times higher sorption capacity than the aquatic HS at pH >= 6, normalizing to the aromatic C content accounted for the differences among the terrestrial HS, and increasing the concentration of divalent cations led to a decrease in adsorption on aquatic HA but not on soil HA. In addition, the pH-dependent speciation models of the Cipro HS complexes illustrate an increase in complexation due to an increase in deprotonation of HS ligands with increasing pH and, at circumneutral and alkaline pH, enhanced complexation of zwitterionic Cipro only in the presence of soil HA and peat HA. The findings of the present study imply that, in addition to electrostatic interactions, van der Waals interactions as facilitated by aromatic structures and H-bond donating moieties in terrestrial HS may facilitate a favorable binding environment. Environ Toxicol Chem 2013;32:1467-1478. (c) 2013 SETAC. PMID- 23456647 TI - Model performance evaluation (validation and calibration) in model-based studies of therapeutic interventions for cardiovascular diseases : a review and suggested reporting framework. AB - Decision analytic models play an increasingly important role in the economic evaluation of health technologies. Given uncertainties around the assumptions used to develop such models, several guidelines have been published to identify and assess 'best practice' in the model development process, including general modelling approach (e.g., time horizon), model structure, input data and model performance evaluation. This paper focuses on model performance evaluation. In the absence of a sufficient level of detail around model performance evaluation, concerns regarding the accuracy of model outputs, and hence the credibility of such models, are frequently raised. Following presentation of its components, a review of the application and reporting of model performance evaluation is presented. Taking cardiovascular disease as an illustrative example, the review investigates the use of face validity, internal validity, external validity, and cross model validity. As a part of the performance evaluation process, model calibration is also discussed and its use in applied studies investigated. The review found that the application and reporting of model performance evaluation across 81 studies of treatment for cardiovascular disease was variable. Cross model validation was reported in 55 % of the reviewed studies, though the level of detail provided varied considerably. We found that very few studies documented other types of validity, and only 6 % of the reviewed articles reported a calibration process. Considering the above findings, we propose a comprehensive model performance evaluation framework (checklist), informed by a review of best practice guidelines. This framework provides a basis for more accurate and consistent documentation of model performance evaluation. This will improve the peer review process and the comparability of modelling studies. Recognising the fundamental role of decision analytic models in informing public funding decisions, the proposed framework should usefully inform guidelines for preparing submissions to reimbursement bodies. PMID- 23456648 TI - Quantification of serum HBXAP DNA in lung cancer patients by quantitative fluorescent polymerase chain reaction. AB - Hepatitis B virus x associated protein (HBXAP), as a subunit of chromatin remodeling and spacing factor, plays a critical role in cancer development through gene amplification. In this study, we aimed to quantify the levels of serum HBXAP DNA, to analyze and compare its diagnostic value with existing clinical parameters in lung cancer, and to potentially provide a novel tumor marker for lung cancer. Serum HBXAP DNA from 65 lung cancer patients and 20 healthy controls was quantified using real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) analysis. The data were analyzed by statistical software SPSS 13.0. We found that serum HBXAP DNA levels in lung cancer patients were higher compared to healthy controls (u = 219.0, p = 0.001) and were closely associated with TNM stage and lymph node metastasis (p = 0.015 and p = 0.016, respectively). However, serum HBXAP DNA levels were not associated with patient age, gender, smoking status, histological type, or tumor size (p > 0.05). We identified a sensitivity of 61.9 % and a specificity of 93.7 % for the ability of HBXAP DNA levels to detect lung cancer at a cutoff value of 1,557.6 copies/MUl. The sensitivity for existing lung-tumor markers, such as squamous cell carcinoma antigen, cytokeratin fragment 21-1, and neuron specific enolase, was increased from 35.7 %, 53.5 %, and 56.0 % to 75.0 %, 86.0 %, and 80.0 %, respectively, by inclusion of serum HBXAP DNA. Taken together, quantification of serum HBXAP DNA by FQ-PCR could potentially serve as a novel complementary tool for the clinical screening and detection of lung cancer. PMID- 23456649 TI - Moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the parotid gland: report of three cases with contemporary review of salivary neuroendocrine carcinomas. AB - Primary neuroendocrine carcinomas (NECs) of the salivary glands are rare. Most reported NECs in that region are small cell carcinomas with few cases of large cell undifferentiated carcinoma and typical carcinoid tumors. Only two moderately differentiated NECs (atypical carcinoid tumors) have been previously reported. In the current series, the authors report three additional moderately differentiated NECs (atypical carcinoid tumors) of the parotid gland; two occurred in women and one in a man. All patients were initially treated with parotidectomy, with selective lymph node excision in one, and radiation therapy in another. Follow-up was available for two cases (18 and 79 months). One patient had two local recurrences, developing lymph node and liver metastases requiring further surgery and chemotherapy. Currently, she is alive with disease, on supportive care. The second patient is alive with no signs of recurrence. Patients' work-up excluded the possibility of metastatic NECs to the salivary glands in all cases. Histologically, the tumors demonstrated infiltrating nests, cords and trabeculae of round, oval to spindle shaped cells with moderate to focally abundant eosinophilic cytoplasm, small to prominent nucleoli and chromatin stippling. Scattered rosette-like structures were prominent in one tumor. The highest mitotic counts for the three tumors ranged from 5 to 8 mitotic figures/10 hpfs. Necrosis, focal but distinct, was noted in two tumors, vascular invasion in two tumors and perineural invasion in one tumor. Immunohistochemical staining was diagnostic of neuroendocrine carcinoma, showing uniform positive labeling with broad-spectrum cytokeratin (with a paranuclear punctuate pattern in one case), chromogranin and synaptophysin antibodies. CK20 was negative in two tumors and stained rare cells (<1%) in the third. PMID- 23456650 TI - Protective roles of methionine-R-sulfoxide reductase against stresses in Schizosaccharomyces pombe. AB - The Schizosaccharomyces pombe msrB(+) gene encoding methionine-R-sulfoxide reductase (MsrB) was cloned into the shuttle vector pRS316 to generate the recombinant plasmid pFMetSO. The msrB(+) mRNA level was significantly increased in the S. pombe cells harboring pFMetSO, indicating that the cloned msrB(+) gene is functioning. In the presence of 0.1 mM L-methionine-(R,S)-sulfoxide, the S. pombe cells harboring pFMetSO could grow normally but the growth of the vector control cells was almost arrested. The S. pombe cells harboring pFMetSO exhibited the enhanced growth on the minimal medium plates with stress-inducing agents, such as hydrogen peroxide, superoxide radical-generating menadione (MD), nitric oxide (NO)-generating sodium nitroprusside (SNP), and cadmium (Cd), when compared with the vector control cells. They also gave rise to the enhanced growth at the high incubation temperature of 37 degrees C than the vector control cells. The S. pombe cells harboring pFMetSO contained lower reactive oxygen species (ROS) and higher total glutathione (GSH) levels than the vector control cells. In brief, the S. pombe MsrB plays a protective role against oxidative, nitrosative, and thermal stresses, and is involved in diminishing intracellular ROS level. PMID- 23456651 TI - Toxicokinetics of polybrominated diphenyl ethers across life stages in the northern leopard frog (Lithobates pipiens). AB - Polybrominated diphenyl ethers (PBDEs), a class of flame retardants, are bioaccumulative toxins that can biomagnify in food webs. However, little is known about the toxicokinetics of total and congener-specific BDEs in lower vertebrates. The authors exposed northern leopard frog (Lithobates (Rana) pipiens) tadpoles to diets containing DE-71 (a pentabromodiphenyl ether mixture (0 ng/g as control, 71.4 ng/g, and 634 DE-71 ng/g wet mass)) for 50 d, followed by a period of depuration during which they were fed only undosed (control) food. After 28 d, tadpoles eliminated over 94% of the SigmaPBDEs from their tissues (t1/2 = 5.9 +/- 1.9 d) with no significant differences in elimination rates for the predominant congeners. Elimination of BDE-99 was independent of dose, indicating first-order kinetics. It did not fit a biexponential model significantly better than a monoexponential model, indicating single-compartment elimination. To compare developmental life-stage kinetics following larval exposure, the authors collected individuals at the beginning and end of metamorphosis and at 70 d postmetamorphosis. During metamorphosis, total-body residues per individual did not significantly change, implying little to no elimination. After 70 d, juvenile frogs eliminated 89.7% of the SigmaPBDEs from their tissues, and BDE-47 was eliminated at a faster rate (t1/2 = 17.3 d) than BDE-99 and BDE-100 (t1/2 = 63.0 d and 69.3 d, respectively). Because the kinetics of PBDEs in L. pipiens differed among life stages, developmental life stage-especially for species that undergo metamorphosis-should be considered when determining the toxicity of persistent organic pollutants. PMID- 23456652 TI - A novel approach to improve the function of FGF21. AB - BACKGROUND AND OBJECTIVE: Fibroblast growth factor 21 (FGF21) has potent effects on normalizing glucose, lipid, and energy homeostasis, and represents an attractive novel therapy for type 2 diabetes mellitus and obesity. Approaches to improve the pharmacokinetic properties of FGF21, such as conjugation with polyethylene glycol, have been explored for therapeutic development. However, not only is there room for further pharmacokinetic improvements, additional re engineering approaches to improve the potency and stability of FGF21 have not been reported. Here, we describe a novel approach to modify and improve the function of FGF21 by altering its C-terminal betaKlotho interaction domain. METHODS: We first identified Avimer proteins that are capable of binding betaKlotho. Then we explored replacing the C-terminal betaKlotho interaction domain of FGF21 with a betaKlotho-binding Avimer protein. RESULTS: Such a betaKlotho-binding Avimer protein was able to fully complement the C-terminal domain function of FGF21. The resulting FGF21-Avimer fusion is functionally indistinguishable from wild type FGF21, and more tolerant of C-terminal modification. CONCLUSION: These results demonstrate a viable strategy to modulate the affinity, potency, and engineering of FGF21, paving the way for further improvements of FGF21 as a therapeutic. PMID- 23456653 TI - B-cell targeted therapies in systemic lupus erythematosus: successes and challenges. AB - Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the formation of autoantibodies that target a variety of self antigens. B cells are fundamental to the development of these antibodies and are a target for intervention in the disease. This review discusses four therapies that target B cells by inducing B-cell depletion, reduction in B-cell proliferation and differentiation, or modulation of B-cell function. Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes B cells but not plasma cells. Systematic reviews of open label studies, particularly in lupus patients refractory to conventional therapy, have suggested that rituximab can be an effective treatment for non-renal lupus and lupus nephritis. However, randomized, double-blind, controlled trials comparing rituximab with placebo in addition to standard of care therapy for non-renal lupus and lupus nephritis over 12 months failed to demonstrate efficacy using the planned primary endpoints, although there were some post-hoc analyses suggesting that rituximab may have beneficial effects that would be worthy of further study as no significant toxicity has been demonstrated. Treatment with belimumab, a humanized monoclonal antibody targeted against B lymphocyte stimulator (BLys), was more efficacious than placebo and had no significant increase in adverse events in two non-renal, phase III lupus trials when given in addition to standard of care therapy for 52 weeks. Belimumab is licensed for the management of lupus in the US and in Europe. Atacicept is a humanized fusion protein that binds BLys and APRIL (a proliferation-inducing ligand) that might be more effective than belimumab in the management of lupus. Unfortunately a phase II/III trial of atacicept in lupus nephritis had to be stopped due to the development of low immunoglobulin levels and pneumonias in some patients. However, in retrospect these complications may have been due to concomitant treatment with mycophenolate mofetil and results of a 52-week, non renal, phase III trial with atacicept are awaited. Epratuzumab is a humanized monoclonal antibody that targets CD22 on B cells and results in modulation of B cell function and migration, as CD22 regulates adhesion and inhibits B-cell receptor (BCR) signalling. Epratuzumab at a cumulative dose of 2,400 mg over 4 weeks has been shown to improve lupus disease activity compared with placebo 12 weeks after initiation of therapy in a phase II study, and a 12-month phase III study is on-going. B-cell targeted therapies are an attractive prospect for treating lupus disease and the results of current phase III trials are eagerly awaited. Finding the most appropriate trial design to demonstrate efficacy in lupus trials has been a challenge. The SRI (SLE response index) used in the belimumab studies and the BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) used in the epratuzumab studies are currently the promising trial designs for non-renal studies. For lupus nephritis it is important that trials are of adequate duration to be able to demonstrate benefit of new therapies over conventional therapy. PMID- 23456654 TI - Treatment of primary CNS lymphoma (PCNSL) following successful treatment of systemic non-Hodgkin's lymphoma (NHL): a case series. AB - Management of PCNSL occurring after successful treatment of systemic non Hodgkin's lymphoma (NHL) is poorly defined. Illustrate a treatment approach for PCNSL following prior treatment of a systemic NHL. A retrospective case series of 6 patients (mean age 60 years; range 46-65) diagnosed with a diffuse large B cell lymphoma of the CNS following prior successful treatment of a systemic NHL (low grade in 2; high-grade in 4). Mean interval to diagnosis of PCNSL after diagnosis of systemic NHL was 12 months (range 7-18). In 4/6 patients in whom genetic analysis could be performed, the PCNSL and NHL differed. Treatment utilized high dose methotrexate and rituximab (immunochemotherapy) followed in patients with a radiographic complete response by autologous peripheral stem cell transplant (ASCT) with total body irradiation (TBI) and multi-agent conditioning chemotherapy (BEAM: carmustine, etoposide, cytarabine, melphalan). 5/6 patients had a radiographic complete response to immunochemotherapy and were treated with ASCT. 4/5 patients were free of disease following ASCT with a mean follow-up of 3 years (range 0.5-4 years). There were no toxic deaths and all patients transplanted successfully engrafted within 28 days (mean 18). Using a treatment paradigm similar to that utilized for recurrent systemic NHL (induction chemotherapy followed by ASCT) for PCNSL occurring metachronously after successful treatment of systemic NHL appears safe and effective. PMID- 23456656 TI - A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer. AB - Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM. PMID- 23456655 TI - GC/MS-based metabolomic analysis of cerebrospinal fluid (CSF) from glioma patients. AB - Metabolomics has recently undergone rapid development; however, metabolomic analysis in cerebrospinal fluid (CSF) is not a common practice. We analyzed the metabolite profiles of preoperative CSF samples from 32 patients with histologically confirmed glioma using gas chromatography/mass spectrometry (GC/MS). We assessed how alterations in the metabolite levels were related to the World Health Organization (WHO) tumor grades, tumor location, gadolinium enhancement on magnetic resonance imaging (MRI), and the isocitrate dehydrogenase (IDH) mutation status. Sixty-one metabolites were identified in the CSF from glioma patients using targeted, quantitative and non-targeted, semi-quantitative analysis. The citric and isocitric acid levels were significantly higher in the glioblastoma (GBM) samples than in the grades I-II and grade III glioma samples. In addition, the lactic and 2-aminopimelic acid levels were relatively higher in the GBM samples than in the grades I-II glioma samples. The CSF levels of the citric, isocitric, and lactic acids were significantly higher in grade I-III gliomas with mutant IDH than in those with wild-type IDH. The tumor location and enhancement obtained using MRI did not significantly affect the metabolite profiles. Higher CSF levels of lactic acid were statistically associated with a poorer prognosis in grades III-IV malignant gliomas. Our study suggests that the metabolomic analysis of CSF from glioma patients may be useful for predicting the glioma grade, metabolic state, and prognosis of gliomas. PMID- 23456658 TI - Diversity of Streptococcus mutans strains in bacterial interspecies interactions. AB - Biofilms are matrix-enclosed microbial population adhere to each other and to surfaces. Compared to planktonic bacterial cells, biofilm cells show much higher levels of antimicrobial resistance. We aimed to investigate Streptococcus mutans strain diversity in biofilm formation and chlorhexidine (CHX) resistance of single S. mutans and dual S. mutans-Enterococcus faecalis biofilms. Four clinical S. mutans strains (C180-2, C67-1, HG723 and UA159) formed 24-h biofilms with or without an E. faecalis strain. These biofilms were treated for 10 min with 0.025% CHX. Biofilm formation, CHX resistance and S.mutans-E. faecalis interactions were evaluated by biomass staining, resazurin metabolism, viable count and competition agar assays. The main finding is that the presence of E. faecalis generally reduced all dual-species biofilm formation, but the proportions of S. mutans in the dual-species biofilms as well as CHX resistance displayed a clear S. mutans strain dependence. In particular, decreased resistance against CHX was observed in dual S. mutans C67-1 biofilms, while increased resistance was found in dual S. mutans UA159 biofilms. In conclusion, the interaction of S. mutans with E. faecalis in biofilms varies between strains, which underlines the importance of studying strain diversity in inter-species virulence modulation and biofilm antimicrobial resistance. PMID- 23456657 TI - Participation in productive activities and depression among older Europeans: survey of Health, Ageing and Retirement in Europe (SHARE). AB - OBJECTIVE: Although engagement in productive activities is associated with favourable outcomes with respect to the health and well-being of older individuals, the association between such activities and depression in older populations remains relatively unexplored. The purpose of this study was to evaluate the association among five productive activities (paid work, formal volunteering, caregiving, informal helping and caring for grandchildren) with depression in older adults in 14 European countries. METHODS: This cross sectional study used the first two waves of data collected by the Survey of Health, Ageing and Retirement in Europe and analysed a total sample of 7238 relatively healthy community residents aged 60 years and older from 14 European countries. The Survey of Health, Ageing and Retirement in Europe excluded potential participants with a past history of depression, cognitive impairment and physical limitations. Depression was categorised using the EURO-D instrument, and associations with participating in productive activities were investigated. RESULTS: Depression was less prevalent among those individuals who were employed or self-employed and those who participated in formal volunteering or informal helping, whereas caregiving was associated with a higher risk of depression. Caring for grandchildren was not associated positively or negatively with depression. Formal volunteering and caregiving remained associated with depression after adjustment for age, sex, marital status, education, economic status, country and presence of long-term illness. CONCLUSIONS: Availability of formal volunteering may be important in reducing depression risk, whereas caregiving is associated with a higher risk of depression in older European adults. Further research is required to clarify the direction of causation and evaluate interventions. PMID- 23456659 TI - Organ culture stability of the intervertebral disc: rat versus rabbit. AB - There is a need to develop mechanically active culture systems to better understand the role of mechanical stresses in intervertebral disc (IVD) degeneration. Motion segment cultures that preserve the native IVD structure and adjacent vertebral bodies are preferred as model systems, but rapid ex vivo tissue degeneration limits their usefulness. The stability of rat and rabbit IVDs is of particular interest, as their small size makes them otherwise suitable for motion segment culture. The goal of this study was to determine if there are substantial differences in the susceptibility of rat and rabbit IVDs to culture induced degeneration. Lumbar IVD motion segments were harvested from young adult male Sprague-Dawley rats and New Zealand White rabbits and cultured under standard conditions for 14 days. Biochemical assays and safranin-O histology showed that while glycosaminoglycan (GAG) loss was minimal in rabbit IVDs, it was progressive and severe in rat IVDs. In the rat IVD, GAG loss was concomitant with the loss of notochordal cells and the migration of endplate (EP) cells into the nucleus pulposus (NP). None of these changes were evident in the rabbit IVDs. Compared to rabbit IVDs, rat IVDs also showed increased matrix metalloproteinase 3 (MMP-3) and sharply decreased collagen type I and II collagen expression. Together these data indicated that the rabbit IVD was dramatically more stable than the rat IVD, which showed culture-related degenerative changes. Based on these findings we conclude that the rabbit motion segments are a superior model for mechanobiologic studies. PMID- 23456660 TI - Suicidal ideation in family carers of people with dementia: a pilot study. AB - OBJECTIVE: The objective of this pilot study was to gather preliminary evidence on suicidal ideation in family carers of people with dementia. METHODS: An online, cross-sectional survey was conducted with 120 family carers, the majority of whom were located in Australia and USA. The survey included measures of suicidality, self-efficacy, physical health, depression, hopelessness, anxiety, optimism, caregiver burden, coping strategies and social support. RESULTS: Twenty six percent of carers had contemplated suicide more than once in the previous year. Only half of these had ever told someone they might commit suicide and almost 30% said they were likely to attempt suicide in the future. Carers who had contemplated suicide had poorer mental health, lower self-efficacy for community support service use and greater use of dysfunctional coping strategies than those who had not. In a logistic regression, only depression predicted the presence of suicidal thoughts. CONCLUSIONS: A significant number of people might contemplate suicide while caring for a family member with dementia. Although more research is required to confirm this finding, there are clear implications for policy and clinical practice in terms of identifying and supporting carers who are already contemplating suicide. PMID- 23456662 TI - Gcse, a novel germ-cell-specific gene, is differentially expressed during meiosis and gametogenesis. AB - Gametogenesis is a complex process wherein germ cells develop from primordial diploid cells into haploid gametes. To understand the mechanisms controlling gametogenesis, we identified a novel germ-cell-specific gene, Gcse. Gcse produces two major transcripts that are 1589 bp (Gcse-l) and 906 bp (Gcse-s) in length. Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) analyses of multiple tissues reveal that Gcse-l is expressed in both adult testes and ovaries, but Gcse-s is expressed only in adult testes. During female gonad development, Gcse-l is expressed from embryonic day 13.5 to adulthood, specifically in oocytes, and maintained in ovulated and fertilized eggs. However, Gcse-s signals were detected only in ovulated oocytes and fertilized eggs but not in adult ovary. During male gonad development, strong Gcse-l signals were detected in late pachytene spermatocytes and round spermatids. However, Gcse-s transcripts exist only in round spermatids. Furthermore, the expression of GCSE-L proteins and their subcellular localizations within cells are stage specific. GCSE-L is detected in the nucleus of late pachytene spermatocytes. During meiosis, GCSE-L is translocated to acrosome regions in spermatids and maintained in the acrosome of spermatozoa. GCSE-L colocalizes with acrosin and lectin peanut agglutinin in the Golgi apparatus. However, GCSE-S proteins are expressed only in the nucleus of spermatids. From these results, we suggest that GCSE proteins play roles in meiosis and may be involved in acrosome biogenesis during spermiogenesis. PMID- 23456661 TI - Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus like vesicles, and apoptotic bodies. AB - Recent studies suggest both normal and cancerous cells secrete vesicles into the extracellular space. These extracellular vesicles (EVs) contain materials that mirror the genetic and proteomic content of the secreting cell. The identification of cancer-specific material in EVs isolated from the biofluids (e.g., serum, cerebrospinal fluid, urine) of cancer patients suggests EVs as an attractive platform for biomarker development. It is important to recognize that the EVs derived from clinical samples are likely highly heterogeneous in make-up and arose from diverse sets of biologic processes. This article aims to review the biologic processes that give rise to various types of EVs, including exosomes, microvesicles, retrovirus like particles, and apoptotic bodies. Clinical pertinence of these EVs to neuro-oncology will also be discussed. PMID- 23456663 TI - Metabolic pathways involved in 2-methoxyestradiol synthesis and their role in preeclampsia. AB - Preeclampsia (PE) remains a major cause of maternal/fetal morbidity-mortality worldwide. The first stage of PE is characterized by placental hypoxia due to a relative reduction in uteroplacental blood flow, resulting from restricted trophoblast invasion. However, hypoxia is also an essential element for the success of invasion. Under hypoxic conditions, 2-methoxyestradiol (2-ME) could induce the differentiation of cytotrophoblast cells into an invasive phenotype in culture. 2-Methoxyestradiol is generated by catechol-O-methyltransferase, an enzyme involved in the metabolic pathway of estrogens. During pregnancy, circulating 2-ME levels increase significantly when compared to the menstrual cycle. Interestingly, plasma levels of 2-ME are lower in women with PE than in controls, and these differences are apparent weeks or even months before the clinical manifestations of the disease. This article reviews the metabolic pathways involved in 2-ME synthesis and discusses the roles of these pathways in normal and abnormal pregnancies, with particular emphasis on PE. PMID- 23456664 TI - Blood transcriptomics: applications in toxicology. AB - The number of new chemicals that are being synthesized each year has been steadily increasing. While chemicals are of immense benefit to mankind, many of them have a significant negative impact, primarily owing to their inherent chemistry and toxicity, on the environment as well as human health. In addition to chemical exposures, human exposures to numerous non-chemical toxic agents take place in the environment and workplace. Given that human exposure to toxic agents is often unavoidable and many of these agents are found to have detrimental human health effects, it is important to develop strategies to prevent the adverse health effects associated with toxic exposures. Early detection of adverse health effects as well as a clear understanding of the mechanisms, especially at the molecular level, underlying these effects are key elements in preventing the adverse health effects associated with human exposure to toxic agents. Recent developments in genomics, especially transcriptomics, have prompted investigations into this important area of toxicology. Previous studies conducted in our laboratory and elsewhere have demonstrated the potential application of blood gene expression profiling as a sensitive, mechanistically relevant and practical surrogate approach for the early detection of adverse health effects associated with exposure to toxic agents. The advantages of blood gene expression profiling as a surrogate approach to detect early target organ toxicity and the molecular mechanisms underlying the toxicity are illustrated and discussed using recent studies on hepatotoxicity and pulmonary toxicity. Furthermore, the important challenges this emerging field in toxicology faces are presented in this review article. PMID- 23456665 TI - The antinociceptive effect of SNAP5114, a gamma-aminobutyric acid transporter-3 inhibitor, in rat experimental pain models. AB - BACKGROUND: Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian central nervous system. GABAergic transmission has an important role in regulating nociception at the spinal dorsal horn. It is terminated by rapid uptake of the neurotransmitter from the synaptic cleft into neurons and glial cells, via specific GABA transporters (GATs). Among the 4 GATs, GAT-3 has the greatest expression in central nervous system regions closely associated with nociceptive transmission, including the spinal cord. In this study, we examined the antinociceptive effect of intrathecal administration of a selective GAT-3 inhibitor, SNAP5114, on acute, inflammatory, and neuropathic pain in experimental models. METHODS: Male Sprague-Dawley rats were used to assess thermal, mechanical, and chemical nociception in the tail flick and hotplate tests, the paw pressure test, and the formalin test. A rotarod test was performed to assess motor function. Chronic constriction injury to the sciatic nerve was induced in the rats. The electronic von Frey test and the plantar test were then performed to assess mechanical allodynia and thermal hyperalgesia. SNAP5114 (10, 50, 100, or 200 MUg) was administered intrathecally to examine antinociceptive activity. To confirm whether the action of SNAP5114 was mediated by GABAergic transmission, the GABAA receptor antagonist bicuculline (0.3 MUg) or the GABAB receptor antagonist CGP35348 (30 MUg) was administered intrathecally before 200 MUg of SNAP5114 in the tail flick test, the formalin test, and the electronic von Frey test. RESULTS: Spinally applied SNAP5114 in normal rats dose-dependently prolonged withdrawal latencies in the tail flick test and suppressed the late phase response in the formalin test. SNAP5114 did not affect motor performance. In the chronic constriction injury rats, SNAP5114 inhibited mechanical allodynia dose-dependently. The antinociceptive action of SNAP5114 was partially reversed by bicuculline or CGP35348 at doses at which the antagonist alone did not affect baseline behavioral responses. CONCLUSIONS: These results suggest that SNAP5114 exerts antinociceptive effects by activating GABAA and GABAB receptors in the spinal cord. The GAT-3 inhibitor may prove useful in treatment of various painful conditions. PMID- 23456666 TI - Simulation of the kinetics of neuromuscular block: implications for speed of onset. AB - BACKGROUND: The onset time for paralysis varies 3-fold among nondepolarizing muscle relaxants. Possible explanations include: (a) pharmacokinetic differences among drugs and (b) buffering of drug molecules by acetylcholine receptors as they diffuse into the neuromuscular junction. Although some pharmacokinetic models consider buffered diffusion, these models do not account for either the high density of receptors or synapse geometry. Here, I used computer simulations to calculate the kinetics of buffered diffusion. The goal was to determine the conditions under which buffered diffusion could account for differences in onset time among nondepolarizing muscle relaxants. METHODS: Monte Carlo simulation was used along with a realistic 3-dimensional model of the rat neuromuscular junction. Simulations determined the time dependence of the number of drug-bound receptors. A 1000-fold range of drug potency was examined. In some simulations, the drug concentration outside the junction was changed instantaneously. In other simulations, the concentration changed according to predictions of pharmacokinetic models assuming time-dependent changes in plasma drug concentration. The rate constant for equilibration of drug between plasma and muscle, keo, was varied between 0.15 and 0.6 min(-1). Twitch amplitude was calculated from receptor occupancy assuming a high safety margin for neuromuscular transmission. Some simulations used a synaptic model with an increased nerve-muscle contact width. RESULTS: Simulations with instantaneous changes in drug concentration at the synapse, indicated that the time to 50% twitch depression (onset time) was 0.1 to 30 seconds and was proportional to drug potency. This corresponds to iontophoretic application of drug to isolated neuromuscular junctions, but is too fast to explain onset times in humans. When pharmacokinetic models were used to calculate the drug concentration outside the synapse, buffered diffusion increased onset times of potent drugs (drugs for which the effective concentration at 50% twitch height is <600 nM). Simulations using keo = 0.6 min(-1) and a model with a 2- to 3-fold wider nerve-muscle contact width indicated that buffered diffusion could account for the differences in clinical onset times among the nondepolarizing muscle relaxants. CONCLUSION: Monte Carlo simulation provides a biophysically appropriate way to incorporate buffered diffusion into pharmacokinetic modeling. The simulations indicated that buffered diffusion could account for differences in onset time among drugs. However, a better understanding of the geometry of the human neuromuscular junction is needed before the magnitude of the effect of buffered diffusion can be quantified. PMID- 23456667 TI - Statistical grand rounds: a review of analysis and sample size calculation considerations for Wilcoxon tests. AB - When a study uses an ordinal outcome measure with unknown differences in the anchors and a small range such as 4 or 7, use of the Wilcoxon rank sum test or the Wilcoxon signed rank test may be most appropriate. However, because nonparametric methods are at best indirect functions of standard measures of location such as means or medians, the choice of the most appropriate summary measure can be difficult. The issues underlying use of these tests are discussed. The Wilcoxon-Mann-Whitney odds directly reflects the quantity that the rank sum procedure actually tests, and thus it can be a superior summary measure. Unlike the means and medians, its value will have a one-to-one correspondence with the Wilcoxon rank sum test result. The companion article appearing in this issue of Anesthesia & Analgesia ("Aromatherapy as Treatment for Postoperative Nausea: A Randomized Trial") illustrates these issues and provides an example of a situation for which the medians imply no difference between 2 groups, even though the groups are, in fact, quite different. The trial cited also provides an example of a single sample that has a median of zero, yet there is a substantial shift for much of the nonzero data, and the Wilcoxon signed rank test is quite significant. These examples highlight the potential discordance between medians and Wilcoxon test results. Along with the issues surrounding the choice of a summary measure, there are considerations for the computation of sample size and power, confidence intervals, and multiple comparison adjustment. In addition, despite the increased robustness of the Wilcoxon procedures relative to parametric tests, some circumstances in which the Wilcoxon tests may perform poorly are noted, along with alternative versions of the procedures that correct for such limitations. PMID- 23456668 TI - Anti-fibrosis effect of BMP-7 peptide functionalization on cobalt chromium alloy. AB - Orthopedic metallic prosthetic implants are commonly made of cobalt chromium (CoCr) alloys. However, such metal-based implants are susceptible to fibrous capsule formation on the implant surface after implantation. At the bone-implant interface, this capsule can prevent implant integration, resulting in loosening and failure. Minimizing the development of such a capsule on the CoCr surface would improve direct bone-implant bonding leading to long-term implant functionality. We evaluated the anti-fibrosis effect of bone morphogenic protein 7 (BMP-7) peptide covalently bonded to CoCr alloy. This peptide, a biomimetic derivation of the knuckle epitope of BMP-7, was conjugated at the N-terminus with a cysteine amino acid. X-ray photoelectron spectroscopy (XPS) and probe binding assay were used to evaluate different stages of grafting and surface functionalization using polydopamine coating. Cellular functions were studied using fibroblast attachment, cell proliferation, and MTT assays. Fibroblasts were grown on functionalized and pristine CoCr substrates, and the efficacy of BMP-7 peptide on anti-fibrosis was analyzed via gene expression and protein expression of fibrosis markers ACTA2, Collagen 1A1, and fibronectin. The peptide functionalized substrates showed significant reduction of fibrosis markers expression after 1 week of incubation compared to controls. BMP-7 signaling pathway activation was shown by the presence of phosphorylation of Smad1/5/8. These findings may contribute to the improvement of CoCr implants in orthopedic surgery applications. PMID- 23456672 TI - Improved efficacy of intramuscular weekly administration of clodronate 200 mg (100 mg twice weekly) compared with 100 mg (once weekly) for increasing bone mineral density in postmenopausal osteoporosis. AB - BACKGROUND: Clodronate is a bisphosphonate used for the treatment of postmenopausal osteoporosis and all conditions characterized by excess bone resorption. We have previously reported that intramuscular (IM) therapy with clodronate at a dose of 100 mg/week displays significant effects on bone mineral density (BMD) although a plateau effect is observed after 1 year of treatment. Previous reports indicate that the densitometric effects of bisphosphonates directly correlate with the drug dosage and suggest that using IM clodronate at doses higher than 100 mg/week may result in improved efficacy. However, to the best of our knowledge, this has never been proved. OBJECTIVE: The primary endpoint of the study was the effect on BMD of IM clodronate 100 mg once weekly or 100 mg twice weekly in patients with postmenopausal osteoporosis. The incidence of non-traumatic vertebral fractures and adverse events was also reported. METHODS: The present study was a randomized, open-label, parallel-group trial conducted between January 2007 and December 2009 in the Osteoporosis and Osteoarticular Instrumental Diagnosis Centre (University of Siena, Siena, Italy). The study involved 60 women, aged 57-78 years, with a history of postmenopausal osteoporosis for more than 5 years. Patients were randomized to receive IM clodronate 100 mg once weekly (Group A, 30 patients) or 100 mg twice weekly (Group B, 30 patients), for 2 years. RESULTS: Significant increases compared with baseline in BMD were observed for both groups at 1 and 2 years, with significantly higher increases for Group B compared with Group A. Group B displayed a BMD increase (+/- SD) at the lumbar spine of +4.0 % (+/- 2.1) and +5.9 % (+/- 2.0) at 1 and 2 year(s), respectively, compared with +2.8 % (+/- 1.7) and +3.5 % (+/- 2.2), respectively, observed for Group A. Similarly, Group B showed better performance compared with Group A for BMD increase at the femoral neck, with an observed increase of +3.5 % (+/- 1.7) and +5.4 % (+/- 1.8) at 1 and 2 year(s), respectively, compared with a change of +2.3 % (+/- 1.9) and +2.5 % (+/- 1.9), respectively, registered in Group A. Consistently, the BMD increase measured at the total femur was significantly higher for Group B [+3.4 % (+/- 1.9) and +4.9 % (+/- 2.1) at years 1 and 2, respectively] compared with Group A [+1.6 % (+/- 0.9) and +2.4 % (+/- 1.9) at years 1 and 2, respectively]. When the change in BMD from year 1 to year 2 was compared, a significant increase of BMD was seen in Group B in all the analysed regions, contrary to that observed for Group A where a plateau effect resulted in no significant change from year 1 to year 2. Three non-traumatic vertebral fractures occurred during the study: two in Group A and one in Group B. CONCLUSION: The present study indicates the superior performance of IM clodronate 200 mg weekly (100 mg twice weekly) compared with 100 mg once weekly in BMD in women with postmenopausal osteoporosis. This work demonstrated that administration of twice the drug dosage in a week significantly improved the efficacy of the treatment without inducing serious adverse events. Therefore, IM clodronate 200 mg weekly may be considered a valid therapeutic choice for the treatment of postmenopausal osteoporosis. PMID- 23456673 TI - Tazarotene foam versus tazarotene gel: a randomized relative bioavailability study in acne vulgaris. AB - BACKGROUND AND OBJECTIVE: Tazarotene, a retinoid pro-drug, is available in gel, cream and foam for the topical treatment of acne vulgaris. This single-centre, randomized, open-label study assessed relative bioavailability of its active metabolite tazarotenic acid after dosing of tazarotene foam or gel. STUDY DESIGN AND METHODS: Subjects with moderate-to-severe acne received a mean, once-daily dose of 3.7 g tazarotene foam or gel applied to face, chest, upper back and shoulders. Blood samples were collected pre-dose on multiple days and multiple time points over a 72-h period to measure plasma tazarotenic acid and tazarotene. RESULTS: Mean tazarotenic acid area under the plasma concentration-time curve (AUC) and maximum measured plasma concentration (Cmax) values were significantly higher for gel versus foam. Cmax occurred within 5-6 h after dosing, with an apparent terminal elimination half-life (t1/2) of 18-22 h. Accumulation was observed upon repeated dosing with steady-state conditions achieved at day 20. Mean tazarotene concentrations were also higher following gel application versus foam. Both foam and gel demonstrated an acceptable safety profile. CONCLUSION: Tazarotene foam, 0.1 % is an alternative to gel with less systemic exposure. PMID- 23456674 TI - Clinical relevance of serum aquaporin-4 antibody levels in neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory disease that selectively affects the optic nerves and spinal cord. The discovery of NMO-IgG targeting aquaporin-4 (AQP4) in NMO patients suggested that NMO is a distinct entity, with a fundamentally different etiology from that of multiple sclerosis (MS). Although NMO usually leads to grave disability because of the more severe tissue destruction compared with classical MS, there have been several reports describing a benign form of NMO over a long disease term. NMO-IgG/AQP4 antibodies show high specificity but medium sensitivity for NMO, while the clinical relevance of AQP4 antibody titers remains to be determined. We aimed to clarify the clinical relevance of AQP4 antibody levels determined by a bridging enzyme linked immunosorbent assay in 38 patients with NMO or NMO spectrum disorder. The AQP4 antibody levels were higher in patients with optic neuritis (ON) than in those without ON (p = 0.0164). Among the 12 patients examined in a longitudinal study, four showed an increase in the ELISA values during some relapses, and eight showed no clear correlation between the ELISA values and relapse. Of the four patients who demonstrated a steady rise in the antibody levels over time, two patients had no concomitant relapses, despite elevation of the AQP4 antibody levels. We conclude that high AQP4 antibody levels are associated with the occurrence of ON, but that the antibody levels themselves are not closely correlated with the onset of relapse. PMID- 23456675 TI - Chemokine fractalkine attenuates overactivation and apoptosis of BV-2 microglial cells induced by extracellular ATP. AB - Microglia, the resident macrophages of the central nervous system (CNS), are activated by a myriad of signaling molecules including ATP, an excitatory neurotransmitter and neuron-glial signal with both neuroprotective and neurotoxic effects. The "microglial dysfunction hypothesis" of neurodegeneration posits that overactivated microglia have a reduced neuroprotective capacity and instead promote neurotoxicity. The chemokine fractalkine (FKN), one of only two chemokines constitutively expressed in the CNS, is neuroprotective in several in vivo and in vitro models of CNS pathology. It is possible, but not yet demonstrated, that high ATP concentrations induce microglial overactivation and apoptosis while FKN reduces ATP-mediated microglial overactivation and cytotoxicity. In the current study, we examined the effects of FKN on ATP-induced microglial apoptosis and the underlying mechanisms in the BV-2 microglial cell line. Exposure to ATP induced a dose-dependent reduction in BV-2 cell viability. Prolonged exposure to a high ATP concentration (3 mM for 2 h) transformed ramified (quiescent) BV-2 cells to the amoebic state, induced apoptosis, and reduced Akt phosphorylation. Pretreatment with FKN significantly inhibited ATP induced microglial apoptosis and transformed amoebic microglia to ramified quiescent cells. These protective effects were blocked by chemical inhibition of PI3 K, strongly implicating the PI3 K/Akt signaling pathway in FKN-mediated protection of BV-2 cells from cytotoxic ATP concentrations. Prevention of ATP induced microglial overactivation and apoptosis may enhance the neuroprotective capacity of these cells against both acute insults and chronic CNS diseases. PMID- 23456677 TI - beta1 integrin is a long-sought sensor for tauroursodeoxycholic acid. PMID- 23456676 TI - Targeting interleukin-6 in rheumatoid arthritis. AB - Interleukin (IL)-6 is a potent pro-inflammatory agent that plays a crucial role in the pathogenesis of systemic inflammatory disease. Targeting this pathway in rheumatoid arthritis (RA) seems an attractive option as IL-6 is important for both joint destruction and systemic manifestations. Currently, tocilizumab, which binds the IL-6 receptor, is licensed for treatment in active, moderate to severe disease in RA and systemic juvenile idiopathic arthritis (JIA). Several other promising IL-6 blocking agents as well as a subcutaneous form of tocilizumab are currently undergoing phase III clinical trials. The aim of this article is to provide an up-to-date analysis of clinical efficacy and tolerability data concerning the use of IL-6 inhibitors. Data from clinical trials demonstrated that clinical efficacy for tocilizumab, which included improvement in physical function and halting radiographic progression, were comparable to other biologics licensed for use in RA. Patients who should gain most are RA patients with systemic features such as high inflammatory markers and anaemia. Perhaps, the strongest selling point lies in its effectiveness as a monotherapy. This is particularly useful in those who are not tolerating combination treatment with methotrexate. Tocilizumab is one of a few biologics that have been shown to be superior to methotrexate in head-to-head studies. The safety profile of tocilizumab also is comparable to other currently available biologics. There is a small but significant increase in adverse events including infections in patients treated with tocilizumab compared to placebo, particularly in patients who are elderly and those with multiple comorbidities. Elevated lipid profiles are frequent but have not been associated with major cardiovascular events. IL-6 blockade is a major advancement in the treatment of RA as it targets a unique molecule. Over the next few years, evidence will be available on the long-term cardiovascular safety and efficacy of subcutaneous IL-6 blocking agents. PMID- 23456678 TI - LiverTox: a website on drug-induced liver injury. PMID- 23456679 TI - The FDA, bridging data, and hepatitis C. PMID- 23456680 TI - Finnish female prisoners - heavy consumers of health services. AB - AIMS: Previous prison studies show that female prisoners often have more health problems than male prisoners do and that they have many chronic health conditions. Few studies have been made among offenders concerning the use of health services, and even fewer concerning physical diseases. We studied the self reported lifetime somatic diseases, the use of health services and the current use of prescription medicines among Finnish female prisoners and compared them with males. METHODS: The sample consisted of 101 females and 309 male prisoners as controls. The study included several questionnaires and interviews conducted by experienced prison nurses. RESULTS: The women had more commonly genitourinary, virus hepatitis/HIV infections and group "other diseases" than the men. Over 80% of the women and men have had accidents/injuries. Four out of five women, and half of the men, used some medicine regularly. Of the females, 92% (80% of the males) reported lifetime hospital care and 65% (61%) treatment in surgery department, respectively; 70% of the females (53% of the males) reported lifetime use of any psychiatric service; 66% of the women (46% of the men) had received psychiatric out-patient services, and 43% (31%) psychiatric in-patient hospital care and 38% (30%) substance abuse services, respectively. CONCLUSIONS: The heavy use of health services among female prisoners resulted mainly from the use of services for substance use and other mental disorders and treatment in surgery department. Compared to men, the difference in using health services was associated with psychiatric services. PMID- 23456681 TI - Hierarchical porous surface for efficiently controlling microdroplets' self removal. PMID- 23456682 TI - Comparative molecular field analysis and comparative molecular similarity index analysis studies on 1H NMR chemical shift of NH group of diaryl triazene derivatives. AB - Comparative molecular field analysis (CoMFA), comparative molecular field analysis region focusing (CoMFA-RF) for optimizing the region for the final partial least square analysis, and comparative molecular similarity indices analysis (CoMSIA) methods were employed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models of (1)H NMR chemical shift of NH proton of diaryl triazene derivatives. The best orientation was searched by all orientation search (AOS) strategy to minimize the effect of the initial orientation of the structures. The predictive abilities of CoMFA-RF and CoMSIA models were determined using a test set of ten compounds affording predictive correlation coefficients of 0.721 and 0.754, respectively, indicating good predictive power. For further model validation, cross validation (leave one out), progressive scrambling, and bootstrapping were also applied. The accuracy and speed of obtained 3D-QSAR models for the prediction of (1)H NMR chemical shifts of NH group of diaryl triazene derivatives were greater compared to some computational well-known procedures. PMID- 23456683 TI - How to build your own coronary anastomosis simulator from scratch. AB - OBJECTIVES: Gaining cardiac surgical competence is a complex, multifactorial process that may take years of experience and on-the-job training. It is critical to provide suitable educational opportunities to gain the necessary knowledge, judgment and skills. In response to the multitude of factors (e.g. European Working Time Directive) currently influencing cardiac surgical training, there have been concerted efforts to reform training practices. Simulation plays an increasingly important role in the educational process and serves to fill the most important gap in the current training model, i.e. operative exposure. Therefore, a contest has been written out for cardiac surgical trainees to construct their own coronary anastomosis simulator using everyday materials. METHODS: Cardiac surgical trainees were invited to construct their own coronary anastomosis simulator. An international jury of cardiac surgeons assessed the simulator and its presentation according to preset developmental criteria (low fidelity concept, innovative character, general presentation and description, general attractiveness to the scholar, ergonomical issues, perceived haptics, number of applicable components, transportability, ease of construction, repeatability and overall costs of the simulator). RESULTS: Six prototypes of simulators built by cardiac surgical trainees were generated. A general evaluation of each simulator prototype is provided according to the preset developmental criteria. CONCLUSIONS: All simulator prototypes have provided a considerable contribution to the field of surgical simulation. By designing simulator prototypes, the trainees have demonstrated their 'out of the box' thinking capability, which is of paramount importance for the development of future innovative surgical techniques and procedures. The Valladolid cardiac team coronary anastomosis simulator box was selected for the EACTS Ethicon Simulation Award 2011. This project will be mass produced and distributed to the participants of structured simulation sessions for coronary anastomoses. PMID- 23456684 TI - Liberal use of axillary artery cannulation for aortic and complex cardiac surgery. AB - OBJECTIVES: Axillary artery cannulation for cardiopulmonary bypass has been described previously as a safe and reliable technique, with a low risk of atheroemboli, avoidance of malperfusion in aortic dissection and facilitation of selective antegrade cerebral perfusion during hypothermic circulatory arrest. The aim of this study was to document the broad applicability of axillary cannulation and its associated morbidity and identify where it was not possible to use planned axillary cannulation. METHODS: A retrospective review of a single surgeon's 10-year experience of axillary cannulation using the side-graft technique in 184 consecutive patients (age 22-92 years) in aortic and complex cardiac surgery from July 2002 to June 2012. RESULTS: There were no intraoperative deaths and no major complications related to axillary artery use. There were six postoperative deaths unrelated to axillary artery cannulation. Six patients (3.3%) had minor complications as a direct result of axillary cannulation including seroma, haematoma, chronic pain and pectoralis major muscle atrophy. There were 10 cases where planned axillary cannulation was abandoned, due to inadequate size of the axillary artery in 8 patients and axillary artery dissection and morbid obesity in 1 patient each. CONCLUSIONS: Axillary artery cannulation is an ideal arterial inflow site in cases where the ascending aorta is unsuitable as it is safe, reliable and reduces the risks of atheroembolization and malperfusion. Major complications are rare with this meticulous technique and it is our standard practice in complex cardiac and aortic surgery. PMID- 23456686 TI - Cardiovascular health status among Caribbean Hispanics living in Northern Manhattan and Ecuadorian natives/mestizos in rural coastal Ecuador: a comparative study. AB - Knowledge of cardiovascular health (CVH) status of a given population is mandatory to reduce the burden of vascular diseases in the region. We compared CVH of two distinct populations having similar ethnic backgrounds to understand the role of lifestyle and environment on their CVH, and to provide insights in the planning of cost-effective health strategies. CVH status was compared in two Hispanic populations living in Northern Manhattan and Atahualpa (rural coastal Ecuador) using the health metrics proposed by the American Heart Association. Both studies used similar definitions of CVH and similar inclusion criteria for participating subjects (age >=40 years, cardiovascular disease-free status, and living at their respective localities for >=3 months). The studied populations consisted of 1,617 Caribbean Hispanics living in Northern Manhattan (mean age 66 +/- 9 years), and 616 Atahualpa residents (mean age 59 +/- 13 years). Atahualpa residents had significantly better metrics than Caribbean Hispanics, with the exception of fasting glucose levels. Likewise, the odds for having 5-7 ideal metrics were also better in Atahualpa residents, irrespective of age. CVH is better in Atahualpa residents than in Caribbean Hispanics living in Northern Manhattan. These differences are likely related to a healthier lifestyle in a rural setting and provide insights for setting cardiovascular prevention priorities. PMID- 23456687 TI - Childhood lead poisoning in a Somali refugee resettlement community in New Hampshire. AB - Despite the gradual decrease in childhood lead poisoning in the United States, the risk for lead poisoning among African refugee children who resettle in the United States remains elevated. Communication methods implemented by resettlement agencies in the public health system for preventing childhood lead poisoning in this at-risk population warrant further investigation. We utilized structured interviews with key stakeholders (resettlement agencies, social service agencies developed by African refugees and resettled Somali refugees) involved in the refugee resettlement process to (1) describe the agency's role in the refugee resettlement process; (2) examine communication methods utilized and barriers experienced by the public health system in reference to childhood lead poisoning; (3) describe the refugee population's perception of childhood lead poisoning; (4) examine general challenges experienced by the public health system and the refugee population during the resettlement process; and (5) describe stakeholders' recommendations to improve health communication efforts. Based on our findings, we propose that communities are important determinants in health related problems for refugee populations. Each community has its own environment and public health system that interacts with each other to influence health risks and risk perceptions of its populations. We advocate that understanding a community's ecology and implementing a culture-centered approach is essential for the public health system to help educate and prevent communication inequalities and health disparities among an at-risk African refugee population. This action can reduce a population's resistance to communication and help build a community's capacity to address a persistent public health problem, such as childhood lead poisoning. PMID- 23456688 TI - Morphological and molecular identification to secure cultivar maintenance and management of self-sterile Rubus arcticus. AB - BACKGROUND AND AIMS: Preservation of cultivar purity creates a particular challenge for plants that are self-incompatible, require insects for cross pollination, and have easily germinating seeds and vigorously spreading rhizomes. As the fields must be planted with mixed populations, and a balance must be maintained between the cultivars to achieve effective pollination, methods for field monitoring of the relative density of different cultivars must be practical. Furthermore, a DNA-based method is needed for cultivar verification in the collections and outside of the growing season. The aim of this study was to develop both types of methods for Rubus arcticus (arctic bramble). METHODS: Morphological parameters were measured from six cultivars grown on three farms. Observations from the flowers and fruits included: petal and sepal number, flower diameter, arrangement of petals, size of calyx in relation to corolla, fruit weight, yield and soluble sugars. Observations from the leaves included: width and height of middle leaflet, shape of the base of terminal leaflet, shape of terminal leaflet, leaf margin serration and fingertip touch. The applicability of simple sequence repeat (SSR) or microsatellite DNA markers developed for red raspberry was tested on eight arctic bramble cultivars. KEY RESULTS AND CONCLUSIONS: Morphological and molecular identification methods were developed for R. arcticus. The best morphological characteristics were the length-to-width ratio of the middle leaflet and leaf margin serration. A particular characteristic, fingertip touch, was shown by electron microscopy to be related to the density and quality of the leaf hairs. Red raspberry SSR marker no. 126 proved to be applicable for differentiation of the eight arctic bramble cultivars tested. These identification methods are critical to secure the maintenance and management of R. arcticus. However, the challenges faced and approaches taken are equally applicable to other species with similar biology. PMID- 23456689 TI - Viminaria juncea does not vary its shoot phosphorus concentration and only marginally decreases its mycorrhizal colonization and cluster-root dry weight under a wide range of phosphorus supplies. AB - BACKGROUND AND AIMS: The Australian legume species Viminaria juncea forms both cluster roots and mycorrhizal associations. The aim of this study was to identify if these root specializations are expressed at differential supplies of phosphorus (P) and at different shoot P concentrations [P]. METHODS: Seedlings were planted in sand and provided with a mycorrhizal inoculum and basal nutrients plus one of 21 P treatments, ranging from 0 to 50 mg P kg(-1) dry soil. Plants were harvested after 12 weeks, and roots, shoots and cluster roots were measured for length and fresh and dry weight. The number of cluster roots, the percentage of mycorrhizal colonization, and shoot [P] were determined. KEY RESULTS: Shoot biomass accumulation increased with increasing P supply until a shoot dry weight of 3 g was reached at a P supply of approx. 27.5 mg P kg(-1) dry soil. Neither cluster-root formation nor mycorrhizal colonization was fully suppressed at the highest P supply. Most intriguingly, shoot [P] did not differ across treatments, with an average of 1.4 mg P kg(-1) shoot dry weight. CONCLUSIONS: The almost constant shoot [P] in V. juncea over the very wide range of P supplies is, to our knowledge, unprecedented. To maintain these stable values, this species down regulates its growth rate when no P is supplied; conversely, it down-regulates its P-uptake capacity very tightly at the highest P supplies, when its maximum growth rate has been reached. It is proposed that the persistence of cluster roots and mycorrhizal colonization up to the highest P treatments is a consequence of its tightly controlled shoot [P]. This unusual P physiology of V. juncea is surmised to be related to the habitat of this N2-fixing species. Water and nutrients are available at a low but steady supply for most of the year, negating the need for storage of P which would be metabolically costly and be at the expense of metabolic energy and P available for symbiotic N2 fixation. PMID- 23456691 TI - Determination of plasma dibasic amino acids following trimethylsilyl trifluoroacyl derivatization using gas chromatography-mass spectrometry. AB - A rapid analytical method was developed to quantify dibasic amino acids (ornithine, lysine and arginine) after two-step derivatization procedure with good sensitivity and specificity on human plasma. If early diagnosis has not been made, patients with inborn metabolic disorders such as HHH syndrome, Hyperornithinemia and dibasic aminoaciduria rapidly progress to sudden death, physical defect or mental retardation resulting in storage of the toxic material into the brain. Therefore, it is necessary to develop the analytical method for rapid screening and/or correct confirmation diagnosis. The formation of trimethylsilyl derivative of the carboxylic (COO-) functional group was performed by adding MSTFA. Five MUL of methyl orange was added to the residue until the color changed into yellow. Consecutively, the trifluoroacyl derivative of the amino (-NH2) functional group was produced by adding MBTFA. Specific ions was chosen for quantification with following ions; m/z 166 and m/z 212 for ornithine, m/z 180 and m/z 395 for lysine, and m/z 292 and, m/z 519 for arginine. A calibration curve showed a linear relationship for the dibasic amino acids spiked to pooled normal plasma showing R(2) of 0.9955-0.9979 in the range of 0.1-600 ng investigated. The utility of the method for screening and diagnosis was demonstrated by recovery 80-125 % and reproducibility with RSD (9-17 %) at low, medium and high concentration fortified to pooled plasma. Collectively, the present study suggest that this method could be useful for diagnosis, screening, therapeutic monitoring of metabolic disorders on dietary therapy with excellent sensitivity and rapidity. PMID- 23456690 TI - Lateral root development in the maize (Zea mays) lateral rootless1 mutant. AB - BACKGROUND AND AIMS: The maize lrt1 (lateral rootless1) mutant is impaired in its development of lateral roots during early post-embryonic development. The aim of this study was to characterize, in detail, the influences that the mutation exerts on lateral root initiation and the subsequent developments, as well as to describe the behaviour of the entire plant under variable environmental conditions. METHODS: Mutant lrt1 plants were cultivated under different conditions of hydroponics, and in between sheets of moist paper. Cleared whole mounts and anatomical sections were used in combination with both selected staining procedures and histochemical tests to follow root development. Root surface permeability tests and the biochemical quantification of lignin were performed to complement the structural data. KEY RESULTS: The data presented suggest a redefinition of lrt1 function in lateral roots as a promoter of later development; however, neither the complete absence of lateral roots nor the frequency of their initiation is linked to lrt1 function. The developmental effects of lrt1 are under strong environmental influences. Mutant primordia are affected in structure, growth and emergence; and the majority of primordia terminate their growth during this last step, or shortly thereafter. The lateral roots are impaired in the maintenance of the root apical meristem. The primary root shows disturbances in the organization of both epidermal and subepidermal layers. The lrt1-related cell-wall modifications include: lignification in peripheral layers, the deposition of polyphenolic substances and a higher activity of peroxidase. CONCLUSIONS: The present study provides novel insights into the function of the lrt1 gene in root system development. The lrt1 gene participates in the spatial distribution of initiation, but not in its frequency. Later, the development of lateral roots is strongly affected. The effect of the lrt1 mutation is not as obvious in the primary root, with no influences observed on the root apical meristem structure and maintenance; however, development of the epidermis and cortex are impaired. PMID- 23456692 TI - Oleanane-type triterpenoid saponins from the roots of Pulsatilla koreana and their apoptosis-inducing effects on HL-60 human promyelocytic leukemia cells. AB - Twenty-four oleanane-type triterpenoid saponins were isolated from a methanol extract of the Pulsatilla koreana roots. Their structures were elucidated by comparing spectroscopic data to published values. Among them, compounds 8-12 and 20-24 significantly diminished the proliferation of HL-60 human promyelocytic leukemia cells with IC50 values from 0.3 to 4.2 MUM, whereas compounds 7 and 19 showed moderate cytotoxic activity. Furthermore, apoptotic characteristics such as chromatin condensation and increase in the population of sub-G1 hypodiploid cells were observed after the HL-60 cells were treated with these compounds. PMID- 23456693 TI - The surmountable effect of FSCPX, an irreversible A(1) adenosine receptor antagonist, on the negative inotropic action of A(1) adenosine receptor full agonists in isolated guinea pig left atria. AB - A1 adenosine receptors (A1 receptors) are widely expressed in mammalian tissues; therefore attaining proper tissue selectivity is a cornerstone of drug development. The fact that partial agonists chiefly act on tissues with great receptor reserve can be exploited to achieve an appropriate degree of tissue selectivity. To the best of our knowledge, the A1 receptor reserve has not been yet quantified for the atrial contractility. A1 receptor reserve was determined for the direct negative inotropic effect of three A1 receptor full agonists (NECA, CPA and CHA) in isolated, paced guinea pig left atria, with the use of FSCPX, an irreversible A1 receptor antagonist. FSCPX caused an apparently pure dextral displacement of the concentration-response curves of A1 receptor agonists. Accordingly, the atrial A1 receptor function converging to inotropy showed a considerably great, approximately 80-92 % of receptor reserve for a near maximal (about 91-96 %) effect, which is greater than historical atrial A1 receptor reserve data for any effects other than inotropy. Consequently, the guinea pig atrial contractility is very sensitive to A1 receptor stimulation. Thus, it is worthwhile considering that even partial A1 receptor agonists, given in any indication, might decrease the atrial contractile force, as an undesirable side effect, in humans. PMID- 23456694 TI - Premicellar interaction of PEO-PPO-PEO triblock copolymers with partially hydrophobic alcohols: NMR study. AB - The interactions of three alcohols, namely, 2-butanol (BuOH), 3-methyl-2-butanol (MeBuOH), and 3,3-dimethyl-2-butanol (Me2BuOH) with propylene oxide octamer (PO8) and the copolymers (EO)8(PO)13(EO)8(L35) and (EO)13(PO)30(EO)13(L64) in D2O were studied using (13)C NMR spectra and relaxations and (1)H PFG NMR diffusion measurements. For L64, it was shown that the temperature at which the PO chain starts to change its conformation under dehydration decreases by 6 K for each additional methyl group in the alcohol molecule (i.e. with increasing its hydrophobicity), and the analogous conformation states are attained at temperatures approximately 10 K lower compared using ketonic analogs of the alcohols under the same conditions. Also, the first signs of L64 aggregation, according to the normalized diffusion coefficients, are at temperatures 7, 10, and 13 K lower for BuOH, MeBuOH, and Me2BuOH, respectively. These effects are much weaker for (PO)13 in L35 or nonexistent for (PO)8 in PO8, thus showing the role of cooperativity in dehydration and aggregation processes. According to diffusion measurements, the molar fraction of the alcohol hydrogen bonded to L64 increases with its hydrophobicity and, in an apparent conflict with thermodynamics, with increasing temperature at which also higher NOE can be observed. Strong hydrogen bond interaction, which is in cooperation with hydrophobic interaction, does not preclude the exchange between bound and free states of the alcohol, however. Using (13)C transverse relaxation, its correlation time is shown to be of the order of 10 ms. PMID- 23456695 TI - Rhythm of carbon and nitrogen fixation in unicellular cyanobacteria under turbulent and highly aerobic conditions. AB - Nitrogen fixing cyanobacteria are being increasingly explored for nitrogenase dependent hydrogen production. Commercial success however will depend on the ability to grow these cultures at high cell densities. Photo-limitation at high cell densities leads to hindered photoautotrophic growth while turbulent conditions, which simulate flashing light effect, can lead to oxygen toxicity to the nitrogenase enzyme. Cyanothece sp. strain ATCC 51142, a known hydrogen producer, is reported to grow and fix nitrogen under moderately oxic conditions in shake flasks. In this study, we explore the growth and nitrogen fixing potential of this organism under turbulent conditions with volumetric oxygen mass transfer coefficient (KL a) values that are up to 20-times greater than in shake flasks. In a stirred vessel, the organism grows well in turbulent regime possibly due to a simulated flashing light effect with optimal growth at Reynolds number of approximately 35,000. A respiratory burst lasting for about 4 h creates anoxic conditions intracellularly with near saturating levels of dissolved oxygen in the extracellular medium. This is concomitant with complete exhaustion of intracellular glycogen storage and upregulation of nifH and nifX, the genes encoding proteins of the nitrogenase complex. Further, the rhythmic oscillations in exhaust gas CO2 and O2 profiles synchronize faithfully with those in biochemical parameters and gene expression thereby serving as an effective online monitoring tool. These results will have important implications in potential commercial success of nitrogenase-dependent hydrogen production by cyanobacteria. PMID- 23456696 TI - Perfusion deficits in patients with mild traumatic brain injury characterized by dynamic susceptibility contrast MRI. AB - Perfusion deficits in patients with mild traumatic brain injury (TBI) from a military population were characterized by dynamic susceptibility contrast perfusion imaging. Relative cerebral blood flow (rCBF) was calculated by a model independent deconvolution approach from the tracer concentration curves following a bolus injection of gadolinium diethylenetriaminepentaacetate (Gd-DTPA) using both manually and automatically selected arterial input functions (AIFs). Linear regression analysis of the mean values of rCBF from selected regions of interest showed a very good agreement between the two approaches, with a regression coefficient of R = 0.88 and a slope of 0.88. The Bland-Altman plot also illustrated the good agreement between the two approaches, with a mean difference of 0.6 +/- 12.4 mL/100 g/min. Voxelwise analysis of rCBF maps from both approaches demonstrated multiple clusters of decreased perfusion (p < 0.01) in the cerebellum, cuneus, cingulate and temporal gyrus in the group with mild TBI relative to the controls. MRI perfusion deficits in the cerebellum and anterior cingulate also correlated (p < 0.01) with neurocognitive results, including the mean reaction time in the Automated Neuropsychological Assessment Metrics and commission error and detection T-scores in the Continuous Performance Test, as well as neurobehavioral scores in the Post-traumatic Stress Disorder Checklist Civilian Version. In conclusion, rCBF calculated using AIFs selected from an automated approach demonstrated a good agreement with the corresponding results using manually selected AIFs. Group analysis of patients with mild TBI from a military population demonstrated scattered perfusion deficits, which showed significant correlations with measures of verbal memory, speed of reaction time and self-report of stress symptoms. PMID- 23456697 TI - Quality and efficiency in small practices transitioning to patient centered medical homes: a randomized trial. AB - BACKGROUND: There is growing evidence that even small and solo primary care practices can successfully transition to full Patient Centered Medical Home (PCMH) status when provided with support, including practice redesign, care managers, and a revised payment plan. Less is known about the quality and efficiency outcomes associated with this transition. OBJECTIVE: Test quality and efficiency outcomes associated with 2-year transition to PCMH status among physicians in intervention versus control practices. DESIGN: Randomized Controlled Trial. PARTICIPANTS: Eighteen intervention practices with 43 physicians and 14 control practices with 24 physicians; all from adult primary care practices. INTERVENTIONS: Modeled on 2008 NCQA PPC(r)-PCMHTM, intervention practices received 18 months of tailored practice redesign support; 2 years of revised payment, including up to $2.50 per member per month (PMPM) for achieving quality targets and up to $2.50 PMPM for PPC-PCMH recognition; and 18 months of embedded care management support. Controls received yearly participation payments. MAIN MEASURES: Eleven clinical quality indicators from the 2009 HEDIS process and health outcomes measures derived from patient claims data; Ten efficiency indicators based on Thomson Reuter efficiency indexes and Emergency Department (ED) Visit Ratios; and a panel of costs of care measures. KEY RESULTS: Compared to control physicians, intervention physicians significantly improved TWO of 11 quality indicators: hypertensive blood pressure control over 2 years (intervention +23 percentage points, control -2 percentage points, p =0.02) and breast cancer screening over 3 years (intervention +3.5 percentage points, control -0.4 percentage points, p =0.03). Compared to control physicians, intervention physicians significantly improved ONE of ten efficiency indicators: number of care episodes resulting in ED visits was reduced (intervention -0.7 percentage points, control + 0.5 percentage points, p = 0.002), with 3.8 fewer ED visits per year, saving approximately $1,900 in ED costs per physician, per year. There were no significant cost-savings on any of the pre-specified costs of care measures. CONCLUSIONS: In a randomized trial, we observed that some indicators of quality and efficiency of care in general adult primary care practices transitioning to PCMH status can be significantly, but modestly, improved over 2 years, although most indicators did not improve and there were no cost-savings compared with control practices. For the most part, quality and efficiency of care provided in unsupported control practices remained unchanged or worsened during the trial. PMID- 23456698 TI - Fecal occult blood test (FOBT) overuse. PMID- 23456699 TI - Comment on "Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function". PMID- 23456700 TI - The mechanism of tissue-restricted antigen gene expression by AIRE. AB - The autoimmune regulator is a critical transcription factor for generating central tolerance in the thymus. Recent studies have revealed how the autoimmune regulator targets many otherwise tissue-restricted Ag genes to enable negative selection of autoreactive T cells. PMID- 23456701 TI - Retraction: Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dependent signal transduction, Ca2+ signals, enzyme release, cytokine production, and chemotaxis. PMID- 23456702 TI - Retraction: Phospholipase D1 plays a key role in TNF-alpha signaling. PMID- 23456703 TI - Retraction: VAMP8 is essential in anaphylatoxin-induced degranulation, TNF-alpha secretion, peritonitis, and systemic inflammation. PMID- 23456704 TI - Effects of fluoridated drinking water on dental caries in Australian adults. AB - Systematic reviews produce conflicting conclusions regarding dental caries preventive effects of water fluoridation in adults. The authors investigated the relationship using data from the nationally representative 2004-2006 Australian National Survey of Adult Oral Health. Effects were compared between the pre fluoridation cohort born before 1960 (n = 2,270) and the cohort born between 1960 and 1990 (n = 1,509), when widespread implementation of fluoridation increased population coverage from < 1% to 67%. Residential history questionnaires determined the percentage of each person's lifetime exposed to fluoridated water. Examiners recorded decayed, missing, and filled teeth (DMF-Teeth) and decayed and filled tooth surfaces (DF-Surfaces). Socio-demographic and preventive dental behaviors were included in multivariable least-squares regression models adjusted for potential confounding. In fully adjusted models, > 75% of lifetime exposure to fluoridation relative to < 25% of lifetime exposure was associated with 11% and 10% fewer DMF-Teeth in the pre-1960 (p < .0001) and 1960-1990 cohorts (p = .018), respectively. Corresponding reductions in DF-Surfaces were 30% (p < .001) and 21% (p < .001). Findings for intermediate fluoridation exposure suggested a dose-response relationship. Results were consistent in sensitivity analyses accounting for missing data. In this nationally representative sample of Australian adults, caries-preventive effects of water fluoridation were at least as great in adults born before widespread implementation of fluoridation as after widespread implementation of fluoridation. PMID- 23456705 TI - Toxin-producing cyanobacteria in freshwater: a review of the problems, impact on drinking water safety, and efforts for protecting public health. AB - Cyanobacteria have adapted to survive in a variety of environments and have been found globally. Toxin-producing cyanobacterial harmful algal blooms (CHABs) have been increasing in frequency worldwide and pose a threat to drinking and recreational water. In this study, the prevalence, impact of CHABs and mitigation efforts were reviewed, focusing on the Lake Erie region and Ohio's inland lakes that have been impacted heavily as an example so that the findings can be transferrable to other parts of the world that face the similar problems due to the CHABs in their freshwater environments. This paper provides a basic introduction to CHABs and their toxins as well as an overview of public health implications including exposure routes, health effects, and drinking water issues, algal bloom advisory practices in Ohio, toxin measurements results in Ohio public water supplies, and mitigation efforts. PMID- 23456706 TI - Role of heavy metal resistant Ochrobactrum sp. and Bacillus spp. strains in bioremediation of a rice cultivar and their PGPR like activities. AB - The present study demonstrates the metal toxicity ameliorating and growth promoting abilities of three different bacterial isolates when applied to rice as host plant. The three bacterial strains included a cadmium resistant Ochrobactrum sp., a lead resistant Bacillus sp. and an arsenic resistant Bacillus sp. designated as CdSP9, PbSP6, and AsSP9, respectively. When these isolates were used as inocula applied to metal-treated rice plants of variety Satabdi, the germination percentage, relative root elongation (RRE), amylase and protease activities were increased. The toxic effect of metal was reduced in presence of these bacteria. The overall biomass and root/shoot ratio were also enhanced by bacterial inoculation. Hydroponic studies showed that the superoxide dismutase (SOD) activity and malondialdehyde (MDA) level, which had been increased in the presence of metal stress in rice roots, were lowered by the bacterial inoculation. In addition, all three strains were 1-aminocyclopropane-1 carboxylate (ACC) deaminase and catalase positive, whereas siderophore producing ability was lacking in PbSP6. However, both PbSP6 and AsSP9 were protease positive and could hydrolyse starch. The data indicate that these bacteria have promise for bioremediation as well as for plant growth promotion. PMID- 23456707 TI - Quantification of toxigenic Microcystis spp. in freshwaters by quantitative real time PCR based on the microcystin synthetase A gene. AB - A method to estimate the abundance of toxigenic Microcystis in environmental samples by using quantitative real-time PCR was developed and optimized. The basis of this method is the amplification of a highly conserved region of the mcyA gene within the microcystin synthetase gene cluster. Using this method, the average copy number of mcyA gene per cell in toxigenic Microcystis strains was estimated. The molecular markers and method developed in this study can be used to monitor toxigenic strains of Microcystis in Korean freshwaters, in which harmful cyanobacterial blooms are routinely found. PMID- 23456708 TI - Pedobacter namyangjuensis sp. nov. isolated from soil and reclassification of Nubsella zeaxanthinifaciens Asker et al. 2008 as Pedobacter zeaxanthinifaciens comb. nov. AB - A Gram-stain-negative, non-motile, strictly aerobic, yellow-pigmented bacterium, designated strain 5G38(T), was isolated from a field cultivated with Chinese cabbage in Korea. The strain grew at 5-40 degrees C and at pH 6.0-8.0. 16S rRNA gene sequence analysis revealed that strain 5G38(T) represented a distinct lineage within the family Sphingobacteriaceae and showed the highest 16S rRNA gene sequence similarity of 95.2% with Pedobacter koreensis WPCB189(T), followed by Pedobacter agri PB92(T) (94.6%), Pedobacter suwonensis 15-52(T) (94.4%), Pedobacter rhizosphaerae 01-96(T) (94.4%), Pedobacter sandarakinus DS-27(T) (94.4%), and Nubsella zeaxanthinifaciens TDMA-5(T) (94.3%). Strain 5G38(T) formed monophyletic clade with Nubsella zeaxanthinifaciens in the cluster comprised of species of the genus Pedobacter. Chemotaxonomic characteristics of the novel strains, including DNA G+C content of genomic DNA (37.0 mol%), the predominant respiratory quinine (MK-7), and the major fatty acids which were iso-C15:0, summed feature 3 (comprising C16:1 omega7c and/or iso-C15:0 2-OH) and iso-C17:0 3 OH, are similar to those of the genus Pedobacter. However, the novel strains can be distinguished from the other species of Pedobacter by physiological properties. The name Pedobacter namyangjuensis sp. nov. is therefore proposed for strain 5G38(T) (KACC 13938(T) =NBRC 107692(T)) as the type strain. Furthermore, the reclassification of Nubsella zeaxanthinifaciens as Pedobacter zeaxanthinifaciens comb. nov. is proposed. PMID- 23456709 TI - Development of SCAR primers based on a repetitive DNA fingerprint for Escherichia coli detection. AB - The present study aimed to use enterobacterial repetitive intergenic consensus (ERIC) fingerprints to design SCAR primers for the detection of Escherichia coli. The E. coli strains were isolated from various water sources. The primary presumptive identification of E. coli was achieved using MacConkey agar. Nineteen isolates were selected and confirmed to be E. coli strains based on seven biochemical characteristics. ERIC-PCR with ERIC 1R and ERIC 2 primers were used to generate DNA fingerprints. ERIC-PCR DNA profiles showed variant DNA profiles among the tested E. coli strains and distinguished all E. coli strains from the other tested bacterial strains. A 350 bp band that predominated in five E. coli strains was used for the development of the species-specific SCAR primers EC-F1 and EC-R1. The primers showed good specificity for E. coli, with the exception of a single false positive reaction with Sh. flexneri DMST 4423. The primers were able to detect 50 pg and 10(0) CFU/ml of genomic DNA and cells of E. coli, respectively. PMID- 23456710 TI - Bhargavaea indica sp. nov., a member of the phylum Firmicutes, isolated from Arabian Sea sediment. AB - A Gram-positive, aerobic, coccoid-rod shaped, non-motile, catalase- and oxidase positive bacterium, designated strain KJW98(T), was isolated from the marine sediment of Karwar jetty, west coast of India. The strain was beta-haemolytic, non-endospore-forming and grew with 0-8.5% (w/v) NaCl, at 15-48 degrees C and at pH 6.5-9.0, with optimum growth with 0.5% (w/v) NaCl, at 42 degrees C and at pH 7.0-8.0. Phylogenetic analyses based on 16S rRNA and gyrB gene sequences showed that strain KJW98(T) forms a lineage within the genus Bhargavaea. The G+C content of the genomic DNA was 55 mol%. The DNA-DNA relatedness values of strain KJW98(T) with B. beijingensis DSM 19037(T), B. cecembensis LMG 24411(T) and B. ginsengi DSM 19038(T) were 43.2, 39 and 26.5%, respectively. The major fatty acids were anteiso-C15:0 (37.7%), iso-C15:0 (19.7%), anteiso-C17:0 (17.0%) and iso-C16:0 (11.1%). The predominant menaquinone was MK-8 and the cell-wall peptidoglycan was of A4alpha type with L-lysine as the diagnostic diamino acid. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The phenotypic, genotypic and DNA-DNA relatedness data indicate that strain KJW98(T) should be distinguished from the members of the genus Bhargavaea, for which the name Bhargavaea indica sp. nov. is proposed with the type strain KJW98(T) (=KCTC 13583(T) =LMG 25219(T)). PMID- 23456711 TI - Phylogenetic relationships of Korean Sparassis latifolia based on morphological and ITS rDNA characteristics. AB - Recent studies based on morphological characteristics and molecular analyses have revealed that the characteristics of Sparassis crispa from Asia are not concordant with those of collections from Europe and North America. Consequently, the Asian isolate was redefined as Sparassis latifolia. This study is the first report of Sparassis latifolia collected in Korea. The taxonomic relationships and replacement of Sparassis species were inferred from a comparison of the morphological characteristics and by molecular sequence analysis of the internal transcribed spacer (ITS) rDNA regions. In particular, this study focused on the phylogenetic relationships inferred from the biogeographical distribution of isolates within the genus Sparassis. PMID- 23456712 TI - Interrelationship of Bradyrhizobium sp. and plant growth-promoting bacteria in cowpea: survival and symbiotic performance. AB - The objective of this study was to evaluate the survival of cowpea during bacterial colonization and evaluate the interrelationship of the Bradyrhizobium sp. and plant growth-promoting bacteria (PGPB) as a potential method for optimizing symbiotic performance and cowpea development. Two experiments using the model legume cowpea cv. "IPA 206" were conducted. In the first experiment, cowpea seeds were disinfected, germinated and transferred to sterilized Gibson tubes containing a nitrogen-free nutritive solution. The experimental design was randomized blocks with 24 treatments [Bradyrhizobium sp. (BR 3267); 22 PGPB; absolute control (AC)] with three replicates. In the second experiment, seeds were disinfected, inoculated according to their specific treatment and grown in Leonard jars containing washed and autoclaved sand. The experimental design was randomized blocks with 24 treatments [BR 3267; 22 BR 3267 + PGPB; AC] with three replicates. Scanning electron microscopy demonstrated satisfactory colonization of the roots of inoculated plants. Additionally, synergism between BR 3267 and PGPB in cowpeas was observed, particularly in the BR 3267 + Paenibacillus graminis (MC 04.21) and BR 3267 + P. durus (C 04.50), which showed greater symbiotic performance and promotion of cowpea development. PMID- 23456713 TI - Novel and highly diverse fungal endophytes in soybean revealed by the consortium of two different techniques. AB - Fungal endophytes were isolated from the leaves of soybean cultivars in Brazil using two different isolation techniques - fragment plating and the innovative dilution-to-extinction culturing - to increase the species richness, frequency of isolates and diversity. A total of 241 morphospecies were obtained corresponding to 62 taxa that were identified by analysis of the internal transcribed spacer (ITS) of the ribosomal DNA (rDNA). The Phylum Ascomycota predominated, representing 99% and 95.2% of isolates in the Monsoy and Conquista cultivars, respectively, whereas the Phylum Basidiomycota represented 1% and 4.8% of isolates, respectively. The genera Ampelomyces, Annulohypoxylon, Guignardia, Leptospora, Magnaporthe, Ophiognomonia, Paraconiothyrium, Phaeosphaeriopsis, Rhodotorula, Sporobolomyces, and Xylaria for the first time were isolated from soybean; this suggests that soybean harbours novel and highly diverse fungi. The yeasts genera Rhodotorula and Sporobolomyces (subphylum Pucciniomycotina) represent the Phylum Basidiomycota. The species richness was greater when both isolation techniques were used. The diversity of fungal endophytes was similar in both cultivars when the same isolation technique was used except for Hill's index, N1. The use of ITS region sequences allowed the isolates to be grouped according to Order, Class and Phylum. Ampelomyces, Chaetomium, and Phoma glomerata are endophytic species that may play potential roles in the biological control of soybean pathogens. This study is one of the first to apply extinction culturing to isolate fungal endophytes in plant leaves, thus contributing to the development and improvement of this technique for future studies. PMID- 23456714 TI - Beginning to understand the role of sugar carriers in Colletotrichum lindemuthianum: the function of the gene mfs1. AB - Fungi of the Colletotrichum genus are among the most prominent phytopathogens that cause diseases with a considerable economic impact, such as anthracnose. The hemibiotrophic fungus Colletotrichum lindemuthianum (teleomorph Glomerella cingulata f. sp. phaseoli) is the causal agent of the anthracnose of the common bean; and similarly to other phytopathogens, it uses multiple strategies to gain access to different carbon sources from its host. In this study, we examine mfs1, a newly identified C. lindemuthianum hexose transporter. The mfs1 gene is expressed only during the necrotrophic phase of the fungus' interaction within the plant and allows it to utilize the available sugars during this phase. The deletion of mfs1 gene resulted in differential growth of the fungus in a medium that contained glucose, mannose or fructose as the only carbon source. This study is the first to describe a hexose transporter in the hemibiotrophic pathogen C. lindemuthianum and to demonstrate the central role of this protein in capturing carbon sources during the necrotrophic development of the plant/pathogen interaction. PMID- 23456715 TI - Identification of Petriella setifera LH and characterization of its crude carboxymethyl cellulase for application in denim biostoning. AB - The phylogenetic tree of the partial elongation factor-1 alpha gene fits better than the partial 18S rDNA for generic classification. From the results of the molecular tree and analysis of morphological characters, Petriella setifera LH was identified. It can be induced to produce carboxymethyl cellulase (CMCase). The crude CMCase only shows a 44.1-kDa band by activity staining after SDS-PAGE. It is optimally active at 55 degrees C and pH 6.0, and is stable from pH 5.0-8.0 and at 45 degrees C or below. The crude CMCase, which is not affected by Co(2+), is strongly activated in the presence of 10 mM Na(+), K(+), Ca(2+), Mg(2+), EDTA, and Mn(2+). It is strongly inhibited by 10 mM Fe(2+), Pb(2+), Al(3+), Zn(2+), Ag(+), Fe(3+), and Cu(2+). When compared with denim treatment by Novoprime A800 (a commercial neutral cellulase), crude CMCase exhibits a similar fabric weight loss and indigo dye removal. These results indicate that crude CMCase has potential application in denim biostoning. PMID- 23456716 TI - Clades of gamma-glutamyltransferases (GGTs) in the ascomycota and heterologous expression of Colletotrichum graminicola CgGGT1, a member of the pezizomycotina only GGT clade. AB - Gamma-glutamyltransferase (GGT, EC 2.3.2.2) cleaves the gamma-glutamyl linkage in glutathione (GSH). Ascomycetes in either the Saccharomycotina or the Taphrinomycotina have one to three GGTs, whereas members of the Pezizomycotina have two to four GGTs. A Bayesian analysis indicates there are three well supported main clades of GGTs in the Ascomycota. 1) A Saccharomycotina and a Taphrinomycotina-specific GGT sub-clade form a yeast main clade. This clade has the three relatively well-characterized fungal GGTs: (Saccharomyces cerevisiae CIS2 and Schizosaccharomyces pombe Ggt1 and Ggt2) and most of its members have all 14 of the highly conserved and critical amino acids that are found in GGTs in the other kingdoms. 2) In contrast, a main clade (GGT3) differs in 11 of the 14 highly conserved amino acids that are found in GGTs in the other kingdoms. All of the 44 Pezizomycotina analyzed have either one or two GGT3s. 3) There is a Pezizomycotina-only GGT clade that has two well-supported sub-clades (GGT1 and GGT2); this clade differs in only two of the 14 highly conserved amino acids found in GGTs in the other kingdoms. Because the Pezizomycotina GGTs differ in apparently critical amino acids from the cross-kingdom consensus, a putative GGT from Colletotrichum graminicola, a member of the Pezizomycotina, was cloned and the protein product was expressed as a secreted protein in Pichia pastoris. A GGT enzyme assay of the P. pastoris supernatant showed that the recombinant protein was active, thereby demonstrating that CgGGT1 is a bona fide GGT. PMID- 23456717 TI - Expression analysis of LeNHX1 gene in mycorrhizal tomato under salt stress. AB - The plant growth, stem sap flow, Na(+) and Cl(-) content, and the expression of vacuolar Na(+)/H(+) antiporter gene (LeNHX1) in the leaves and roots of tomato under different NaCl stresses (0.5% and 1%) were studied to analyze the effect of arbuscular mycorrhizal fungi (AMF) on Na(+) and Cl(-) accumulation and ion exchange. The results showed that arbuscular mycorrhizal (AM) plant growth and stem sap flow increased and salt tolerance improved, whereas Na(+) and Cl(-) accumulated. Na(+) significantly decreased, and no significant decline was detected in Cl(-) content after AMF inoculation compared with the non-AM plants. The LeNHX1 gene expression was induced in the AM and non-AM plants by NaCl stress. However, AMF did not improve the LeNHX1 level, and low expression was observed in the AM tomato. Hence, the mechanism that reduced the Na(+) damage to tomato induced by AMF has little relation to LeNHX1, which can export Na(+) from the cytosol to the vacuole across the tonoplast. PMID- 23456718 TI - Hrq1 functions independently of Sgs1 to preserve genome integrity in Saccharomyces cerevisiae. AB - Maintenance of genome stability in eukaryotes involves a number of conserved proteins, including RecQ helicases, which play multiple roles at various steps in homologous recombination and DNA repair pathways. Sgs1 has been described as the only RecQ helicase in lower eukaryotes. However, recent studies revealed the presence of a second RecQ helicase, Hrq1, which is most homologous to human RECQL4. Here we show that hrq1Delta mutation resulted in increased mitotic recombination and spontaneous mutation in Saccharomyces cerevisiae, and sgs1Delta mutation had additive effects on the phenotypes of hrq1Delta. We also observed that the hrq1Delta mutant was sensitive to 4-nitroquinoline 1-oxide and cisplatin, which was not complemented by overexpression of Sgs1. In addition, the hrq1Delta sgs1Delta double mutant displayed synthetic growth defect as well as a shortened chronological life span compared with the respective single mutants. Analysis of the type of age-dependent Can(r) mutations revealed that only point mutations were found in hrq1Delta, whereas significant numbers of gross deletion mutations were found in sgs1Delta. Our results suggest that Hrq1 is involved in recombination and DNA repair pathways in S. cerevisiae independent of Sgs1. PMID- 23456719 TI - Clonal spread of carbapenem resistant Acinetobacter baumannii ST92 in a Chinese Hospital during a 6-year period. AB - The carbapenem resistance rate of Acinetobacter baumannii in our hospital has increased steadily since 2004. The molecular epidemiology of carbapenem resistant A. baumannii (CRAB) clinical isolates was characterized by multilocus sequence typing (MLST) and rep-PCR in parallel, with pan-drug susceptible A. baumannii (PSAB) used as control. MLST was performed to determine the sequence types (STs), and eBURST algorithm was used to analyze their relatedness. Carbapenem resistance related genes (oxa-23, oxa-24, oxa-51, oxa-58, imp, vim, and adeB) were screened using Polymerase Chain Reaction (PCR) method. 23 STs were identified in the 65 included isolates, with ST92 being the predominant clone. PSAB clustered into more singletons than CRAB. The positivity of oxa-23 and adeB correlated with high level carbapenem resistance (MICIPM>32 mg/L, MICMEM >32 mg/L) of CRAB ST92 isolates in 2009, which was different from the resistance pattern (MICIPM<=4 mg/L, 8 mg/L <=MICMEM<=16 mg/L) of CRAB ST92 isolates in 2004. These observations suggest that clonal spread of CRAB ST92 isolates longitudinally is the possible reason for carbapenem resistance rate increase and correlate with high level carbapenem resistance in our hospital. PMID- 23456720 TI - Isolation and characterization of a mycovirus in Lentinula edodes. AB - A mycovirus was isolated from an edible mushroom, Lentinula edodes, that was suffering from a severe epidemic. Fractionation of the diseased cell extract by isopycnic centrifugation with 50% CsCl revealed that the diseased mushroom was infected by Lentinula edodes spherical virus (LeSV), a new spherical virus with a diameter of 55 nm. The particle of LeSV encapsidated the 12 kb RNA genome by a 120 kDa coat protein. BLAST analysis of the partially sequenced LeSV genome showed 95% sequence identity with a putative RNA-dependent RNA polymerase (RdRp) gene of the mycovirus HKB, which was previously reported as being a double stranded RNA (dsRNA) element. In contrast to HKB, the RNA genome in LeSV is encapsidated by the 120 kDa coat protein. To confirm that the LeSV coat protein is encoded by the viral genome, the N-terminal amino acid sequence of the coat protein was determined. The resulting N-terminal amino acid sequence, N SALDVAPVVPELYFXXLEV-C, was found to be located in the middle of the HKB ORF1, suggesting that the LeSV coat protein was indeed encoded by the virus. To detect LeSV in L. edodes, a primer set targeting the RdRp gene was designed based on the partial sequence of the LeSV genome. RT-PCR analysis showed that 56 of the 84 commercially available dikaryotic cultivars carry LeSV. The transmission pattern of the virus was determined by analysing basidiospores from LeSV-infected and LeSV-free fruiting bodies. Nine out of 10 basidiospores from the LeSV-infected cultivars contained the virus while the spores from the LeSV-free parent were free of LeSV, suggesting that vertical transmission is the primary mode of LeSV propagation. PMID- 23456721 TI - Full sequence analysis and characterization of a human astrovirus type 1 isolate from South Korea. AB - Human astroviruses are recognized as an important cause of infantile gastroenteritis around the world. In South Korea, sporadic cases of HAstV infection have been reported since 2002. However, hitherto, there have been no studies reporting the whole genome sequence of an HAstV isolate from South Korea. Hence, we sequenced and analyzed the entire genome of an HAstV-1 strain (lhar) that was isolated in Seoul, South Korea. The whole-genome sequence analysis revealed 3 open reading frames comprising the whole genome: ORF1a (2,763 bp), ORF1b (1,548 bp), and ORF2 (2,364 bp). The lhar strain showed amino acid identities with 8 other reference strains of 87.6-98.7%, 94.2-98.8%, and 62.6 99.0% in the ORF1a, ORF1b, and ORF2 regions, respectively. The amino acid sequence of the capsid region encoded by ORF2 was compared with a total of 19 HAstV-1 strains and 8 HAstVs reference strains isolated in various countries. This revealed 1 amino acid substitution, at aa412 (Pro -> Arg) in ORF2. This study, the first to report the full-length sequence of an HAstV isolated in South Korea, is meaningful in that it can be used as a full-length HAstV sequence standard for future comparison studies. It may also prove useful to the field of public health field by facilitating the diagnosis and the prediction of new emerging variants. PMID- 23456722 TI - Sublingual administration of bacteria-expressed influenza virus hemagglutinin 1 (HA1) induces protection against infection with 2009 pandemic H1N1 influenza virus. AB - Influenza viruses are respiratory pathogens that continue to pose a significantly high risk of morbidity and mortality of humans worldwide. Vaccination is one of the most effective strategies for minimizing damages by influenza outbreaks. In addition, rapid development and production of efficient vaccine with convenient administration is required in case of influenza pandemic. In this study, we generated recombinant influenza virus hemagglutinin protein 1 (sHA1) of 2009 pandemic influenza virus as a vaccine candidate using a well-established bacterial expression system and administered it into mice via sublingual (s.l.) route. We found that s.l. immunization with the recombinant sHA1 plus cholera toxin (CT) induced mucosal antibodies as well as systemic antibodies including neutralizing Abs and provided complete protection against infection with pandemic influenza virus A/CA/04/09 (H1N1) in mice. Indeed, the protection efficacy was comparable with that induced by intramuscular (i.m.) immunization route utilized as general administration route of influenza vaccine. These results suggest that s.l. vaccination with the recombinant non-glycosylated HA1 protein offers an alternative strategy to control influenza outbreaks including pandemics. PMID- 23456723 TI - Quantification of toxic effects of the herbicide metolachlor on marine microalgae Ditylum brightwellii (Bacillariophyceae), Prorocentrum minimum (Dinophyceae), and Tetraselmis suecica (Chlorophyceae). AB - Toxic effects of the herbicide metolachlor (MC) were evaluated for three marine microalgae, Tetraselmis suecica (chlorophyte), Ditylum brightwellii (diatom), and Prorocentrum minimum (dinoflagellate). MC showed a significant reduction in cell counts and chlorophyll a levels. Median effective concentration (EC50) was calculated based on chlorophyll a levels after a 72-h MC exposure. EC50 values for T. suecica, D. brightwellii, and P. minimum were 21.3, 0.423, and 0.07 mg/L, respectively. These values showed that the dinoflagellate was most sensitive when exposed to the herbicide, at a concentration comparable to freshwater algae, suggesting its potential as an appropriate model organism for ecotoxicity assessments in marine environments. PMID- 23456724 TI - Mutations upregulating the flhDC operon of Escherichia coli K-12. AB - Bacterial motility is governed by the flhDC master operon that is under the control of factors like OmpR, LrhA, HdfR, and H-NS. Previously, derivatives of the wild-type MG1655 strain of E. coli K-12 with enhanced motility were found to contain insertion sequences (ISs) in the regulatory region of the flhDC operon. Here, we report that not only integrations of IS insertion sequences into the regulatory region of the flhDC operon, but also a missense mutation in the lrhA gene enhances motility by relieving transcriptional repression of the flhDC operon. Two novel IS insertions were found upstream of flhDC. So far, the relationships between the trans- acting factors and the cis-acting regulatory sequences associated with the flhDC operon have not been clearly established. In this study, it was found that effects of the cis- and trans-acting mutations were acting in parallel, suggesting their apparently independent regulation of flagellar expression. PMID- 23456725 TI - Heavy metal tolerance in the psychrotolerant Cryptococcus sp. isolated from deep sea sediments of the Central Indian Basin. AB - A deep-sea isolate of the psychrotolerant yeast Cryptococcus sp. (NIOCC#PY13) obtained from polymetallic nodule-bearing sediments of the Central Indian Basin was examined for its capacity to grow in the presence of various concentrations of the heavy metal salts i.e., ZnSO4 , CuSO4 , Pb(CH3 COO)2 and CdCl2 . It demonstrated considerable growth in the presence of 100 mg/l concentrations of the above-mentioned four heavy metal salts both at 30 degrees C and 15 degrees C. This strain tolerated comparatively higher levels of these four metal salts than other deep-sea and terrestrial yeast isolates belonging to Cryptococcus, Rhodotorula, Rhodosporidium and Sporidiobolus spp. Optimum pH for growth of this isolate was in the range of 6-8 in the presence of heavy metal salts at these two temperatures. Scanning electron microscopic (SEM) studies exhibited altered cell surface morphology of the cells under the influence of heavy metals compared to that with control. The adsorption of heavy metals to the cells was demonstrated by FTIR and EDAX analysis. As evidenced by atomic absorption spectrophotometric (AAS) analysis, about 30-90% of the heavy metals were removed from the culture supernatant after 4 days of growth at 30 degrees C. This deep-sea yeast isolate appears to be a potential candidate for bioremediation of metal-contaminated sites. Moreover, its metal tolerance properties provide a significant insight into its ecological role and adaptations to growth in such extreme conditions. PMID- 23456726 TI - Noninfectious disease among the Bhutanese refugee population at a United States urban clinic. AB - A large number of Bhutanese are currently being resettled to the United States. A high prevalence of noninfectious diseases has been noted in some refugee groups, but data on the Bhutanese refugee population are lacking. A retrospective, chart review study was conducted to determine proportion of noninfectious disease among ethnically Nepali Bhutanese refugees (n = 66) seen at the Grady Refugee Clinic (GRC). GRC disease proportions included the following: 52 % of the patients were overweight/obese (n = 34), 23 % were hypertensive (n = 15), 12 % had vitamin B(12) deficiency (n = 8), 15 % had depression (n = 10), and 14 % had diabetes (n = 9). Nine (90 %) patients with depression had chronic disease compared to 30 (54 %) of the patients without depression. The study found a substantial burden of chronic disease, micronutrient deficiency, and depression in the GRC. Further research is needed to accurately describe the disease burden in refugee populations and to evaluate pre-resettlement disease prevention strategies to provide a framework for future public health interventions. PMID- 23456727 TI - Contrast aortography and the aortic annulus. PMID- 23456728 TI - Quantitative analysis of the thermal requirements for stepwise physical dormancy break in seeds of the winter annual Geranium carolinianum (Geraniaceae). AB - BACKGROUND AND AIMS: Physical dormancy (PY)-break in some annual plant species is a two-step process controlled by two different temperature and/or moisture regimes. The thermal time model has been used to quantify PY-break in several species of Fabaceae, but not to describe stepwise PY-break. The primary aims of this study were to quantify the thermal requirement for sensitivity induction by developing a thermal time model and to propose a mechanism for stepwise PY breaking in the winter annual Geranium carolinianum. METHODS: Seeds of G. carolinianum were stored under dry conditions at different constant and alternating temperatures to induce sensitivity (step I). Sensitivity induction was analysed based on the thermal time approach using the Gompertz function. The effect of temperature on step II was studied by incubating sensitive seeds at low temperatures. Scanning electron microscopy, penetrometer techniques, and different humidity levels and temperatures were used to explain the mechanism of stepwise PY-break. KEY RESULTS: The base temperature (Tb) for sensitivity induction was 17.2 degrees C and constant for all seed fractions of the population. Thermal time for sensitivity induction during step I in the PY breaking process agreed with the three-parameter Gompertz model. Step II (PY break) did not agree with the thermal time concept. Q10 values for the rate of sensitivity induction and PY-break were between 2.0 and 3.5 and between 0.02 and 0.1, respectively. The force required to separate the water gap palisade layer from the sub-palisade layer was significantly reduced after sensitivity induction. CONCLUSIONS: Step I and step II in PY-breaking of G. carolinianum are controlled by chemical and physical processes, respectively. This study indicates the feasibility of applying the developed thermal time model to predict or manipulate sensitivity induction in seeds with two-step PY-breaking processes. The model is the first and most detailed one yet developed for sensitivity induction in PY-break. PMID- 23456729 TI - Enzyme production by the mixed fungal culture with nano-shear pretreated biomass and lignocellulose hydrolysis. AB - Cellulase, xylanase, and beta-glucosidase production was studied on novel nano shear pretreated corn stover by the mixed fungi culture. The high shear force from a modified Tayor-Couette nano-shear mixing reactor efficiently disintegrated corn stover, resulting in a homogeneous watery mash with particles in much reduced size. Scanning electron microscope study showed visible mini-pores on the fiber cell wall surface, which could improve the accessibility of the pretreated corn stover to microorganisms. Mixed fungal culture of Trichoderma reesei RUT-C30 and Aspergillus niger produced enzymes with higher cellulolytic and xylanolytic activities on corn stover pretreated with nano-shear mixing reactor, in comparison with other pretreatment methods, including acid and ammonia fiber explosion (AFEX) pretreatment. The hydrolytic potential of the whole fermentation broth from the mixed fungi was studied, and the possibility of applying the whole cell saccharification concept was also investigated to further reduce the cost of lignocellulose hydrolysis. PMID- 23456731 TI - Efficacy and safety of herbal medicine yun-cai tea in the treatment of hyperlipidemia: A double-blind placebo-controlled clinical trial. AB - OBJECTIVE: Animal studies have demonstrated a lipid-modulating effect of yun-cai tea. However, little is known about the lipid-lowering effect in humans.The aim of this study was to evaluate the lipid lowering effects and safety of yun-cai tea in patients with elevated lipid levels in a human clinical trial. METHODS: This was a 12-week, randomly assigned, parallel-group, double-blind, and placebo controlled pilot clinical study. Sixty primary hyperlipidemia patients were included and randomly assigned to the yun-cai tea group (30 patients) and the placebo group (30 patients), for 8 weeks of treatment and 4 weeks of follow-up. The primary endpoint was changes in plasma low-density lipoprotein-cholesterol (LDL-C) at 8 weeks. The secondary endpoints included total cholesterol (TC) and triglycerides (TG). RESULTS: Our results revealed no statistically signifificant differences in LDL-C and TC between the two groups. Despite the lack of a statistically signifificant difference in the level of TG between the two groups, a declining trend was noted. A signifificant reduction of TG was observed in the yun-cai tea group at week 8, compared to baseline (P=0.048). The incidence of stomach discomfort, gastroesophageal reflfl ux, diarrhea, and constipation was slightly higher in the yun-cai tea group. No other signifificant adverse events were found. CONCLUSION: It is unlikely that yun-cai tea used had a blood lipid reduction effect. Further larger scale clinical trials with a longer duration and larger dose are necessary. PMID- 23456732 TI - Pharmacokinetics and pharmacodynamics of atazanavir-containing antiretroviral regimens, with or without ritonavir, in patients who are HIV-positive and treatment-naive. AB - STUDY OBJECTIVE: To investigate the pharmacokinetic and pharmacodynamic relationships of the human immunodeficiency virus (HIV)-protease inhibitor atazanavir (ATV) in the presence and absence of the pharmacokinetic booster ritonavir, utilizing ATV plasma trough concentrations (Ctrough ) and clinical biomarkers of antiviral efficacy and safety over 48 weeks. DESIGN: Randomized, open-label, multicenter, study designed to compare the efficacy and safety of ATV 300 mg plus ritonavir 100 mg (ATV300/r) with that of ATV 400 mg (ATV400). SETTING: Thirty clinic sites across 10 countries in Africa, Europe, North America, and South America. PATIENTS: Patients who were HIV-positive and treatment-naive. INTERVENTIONS: Randomized to once-daily ATV400 (105 patients) or ATV300/r (95 patients) plus lamivudine and extended-release stavudine. MEASUREMENTS AND MAIN RESULTS: The Ctrough approximately 24 hours after the prior unobserved dose was measured through week 48. Composite Ctrough (i.e., the geometric mean of all trough concentrations over the 48 weeks), population inhibitory quotient ([IQ], i.e., Ctrough divided population estimated protein binding adjusted effective concentration at 90% [EC90 , 14 ng/ml]), composite population IQ (i.e., ATV composite trough divided by population estimated protein binding adjusted EC90 ), HIV RNA, CD4 cell counts, and metabolic and safety parameters were also assessed. For ATV400 and ATV300/r, respectively, geometric mean composite Ctrough (CV%) were 127 (106) ng/ml and 670 (63) ng/ml, geometric mean composite population IQ were 9 and 48, and composite Ctrough values of HIV EC90 or more were achieved in 98% and 100% of patients. High ATV Ctrough was associated with low HIV RNA at week 48; however, 88% of patients had HIV RNA less than 400 copies/ml in the lowest composite Ctrough quartile. There was no clear relationship between ATV Ctrough and changes in CD4 cell count. Increases in total bilirubin or jaundice were associated with higher Ctrough . Modest increases in triglycerides and cholesterol were associated with the addition of ritonavir. CONCLUSION: ATV-containing regimens with or without ritonavir achieved ATV exposures that provide robust antiretroviral efficacy and acceptable tolerability in treatment-naive patients. PMID- 23456733 TI - Comparative evaluation of single fixed dosing and weight-based dosing of rasburicase for tumor lysis syndrome. AB - STUDY OBJECTIVE: To evaluate single fixed dosing versus weight-based dosing strategies for rasburicase to determine the minimum dose required to mitigate hyperuricemia in the treatment or prevention of tumor lysis syndrome. DESIGN: Retrospective medical record review SETTING: Academic medical center PATIENTS: A total of 373 patients with a diagnosis of a hematologic malignancy or solid tumor and who received at least one dose of rasburicase over a 6-year period between January 1, 2005, and February 18, 2011; 180 patients received single doses of 3 mg (38 patients), 6 mg (99 patients), or 7.5 mg (43 patients), and 193 patients received weight-based dosing. MEASUREMENTS AND MAIN RESULTS: Tumor lysis syndrome laboratory data were recorded at baseline and monitored up to 72 hours after initial rasburicase administration. Median baseline plasma uric acid levels were 6.85 mg/dl, 8.80 mg/dl, 8.00 mg/dl, and 9.20 mg/dl, respectively, in the 3-mg, 6 mg, 7.5-mg, and weight-based dosing groups. Treatment success was defined as a normalized plasma uric acid level (< 7.5 mg/dl) within 24 hours after receiving rasburicase. The mean weight-based dose was 0.16 mg/kg. Six rasburicase treatment failures occurred; two were in the 3-mg group, one was in the 6-mg group, and three were in the weight-based dosing group. At 24 hours after rasburicase administration, no statistically significant differences in treatment success were noted among groups (92.9% vs 97.6% vs 100.0% vs 98.0% in the 3-mg, 6-mg, 7.5 mg, and weight-based dosing groups, respectively, p=0.1238). CONCLUSION: The efficacy of all single fixed doses and weight-based dosing strategies evaluated in this study appear to be comparable in normalizing plasma uric acid levels within 24 hours of rasburicase administration. Although use of a 3-mg rasburicase dose may be the most cost-effective treatment strategy in managing hyperuricemia secondary to tumor lysis syndrome, the 6-mg dose resulted in lower sustained uric acid levels after rasburicase administration. Further analysis of patient specific factors contributing to the need for repeat rasburicase administration should be conducted in larger, prospective clinical trials. PMID- 23456734 TI - Augmentation with atypical antipsychotics for depression: a review of evidence based support from the medical literature. AB - Major depressive disorder (MDD) is a chronic mental illness that affects an estimated 5-26% of adults at some time in their lives. Treatment is often started as pharmacotherapy using a single drug such as a selective serotonin reuptake inhibitor. If a patient fails to respond adequately to the initial antidepressant, typically three pharmacotherapy options are available to the practitioner. The dose of the current therapy can be maximized, a change can be made to a different drug, or the current regimen can be augmented with another drug. Atypical antipsychotics have recently become a major focus for augmentation of traditional antidepressant therapy. This review summarizes the evidence for efficacy and safety of augmenting treatment-refractory or treatment-resistant depression with atypical antipsychotics. The National Library of Medicine's MEDLINE database was searched for all English-language articles published from January 1966-December 2011 describing the use of atypical antipsychotics in treatment-resistant depression. The literature retrieved was limited to case series, open-label trials, and randomized controlled trials (RCT). Studies of bipolar depression, psychotic depression, or studies conducted in children and adolescents were excluded. Thirty-five studies using atypical antipsychotics for augmentation treatment of depression were included in this analysis. Trials were identified for aripiprazole (six open-label; three RCT), clozapine (one case series), olanzapine (three open-label, including two case series; four RCT), quetiapine (four open-label; five RCT), risperidone (two open-label; five RCT), and ziprasidone (two open-label). The atypical antipsychotics may be effective as adjunctive therapy in MDD; however, their adverse effect profile may be unfavorable to some patients. Trying at least one alternative treatment strategy after an initial antidepressant is indicated before augmentation is implemented with these agents. If atypical antipsychotics are used, safety and efficacy should be frequently reassessed and dosage should be individualized. PMID- 23456735 TI - Life-threatening hypoglycemia associated with intentional insulin ingestion. AB - There are reports of insulin overdose by injection, yet little is known regarding the potential harms of intentional oral ingestion of insulin. In this report, we describe a case of massive insulin ingestion and ensuing hypoglycemia. To our knowledge, there are no previously published cases of hypoglycemia caused by intentional insulin ingestion. A 51-year-old man intentionally ingested three 10 ml vials (total of 3000 units) of various insulins: one vial each of insulin aspart, lispro, and glargine. Four symptomatic hypoglycemic episodes, with blood glucose levels of 48, 25, 34, and 40 mg/dl, occurred approximately 1, 3, 4, and 5 hours, respectively, after ingestion. The hypoglycemia could not be explained other than the ingestion of the insulins. The patient was admitted for observation, and euglycemia occurred within 24 hours without any additional hypoglycemic episodes. Hypoglycemia treatment is reviewed in this case report, and factors that may affect systemic response of orally ingested insulin, including gastrointestinal absorption and insulin sensitivity, are discussed. In addition, the findings of our case report may provide useful insight into the development of novel oral insulin products that are currently in research. Despite poor bioavailability (1%) when taken orally, insulin may produce symptomatic hypoglycemia with a massive ingestion. Vigilant blood glucose monitoring, supportive care with glucose replacement therapy, and admission to the hospital for observation may be required. PMID- 23456730 TI - Combination prevention: new hope for stopping the epidemic. AB - HIV research has identified approaches that can be combined to be more effective in transmission reduction than any 1 modality alone: delayed adolescent sexual debut, mutual monogamy or sexual partner reduction, correct and consistent condom use, pre-exposure prophylaxis with oral antiretroviral drugs or vaginal microbicides, voluntary medical male circumcision, antiretroviral therapy (ART) for prevention (including prevention of mother to child HIV transmission [PMTCT]), treatment of sexually transmitted infections, use of clean needles for all injections, blood screening prior to donation, a future HIV prime/boost vaccine, and the female condom. The extent to which evidence-based modalities can be combined to prevent substantial HIV transmission is largely unknown, but combination approaches that are truly implementable in field conditions are likely to be far more effective than single interventions alone. Analogous to PMTCT, "treatment as prevention" for adult-to-adult transmission reduction includes expanded HIV testing, linkage to care, antiretroviral coverage, retention in care, adherence to therapy, and management of key co-morbidities such as depression and substance use. With successful viral suppression, persons with HIV are far less infectious to others, as we see in the fields of sexually transmitted infection control and mycobacterial disease control (tuberculosis and leprosy). Combination approaches are complex, may involve high program costs, and require substantial global commitments. We present a rationale for such investments and cite an ongoing research agenda that seeks to determine how feasible and cost-effective a combination prevention approach would be in a variety of epidemic contexts, notably that in a sub-Saharan Africa. PMID- 23456736 TI - Evidence produced in Japan: tegafur-based preparations for postoperative chemotherapy in breast cancer. AB - Oral fluoropyrimidine anticancer agents (oral 5-fluorouracil [5-FU]) able to be used as chemotherapy for breast cancer include tegafur-uracil (UFT), tegafur gimeracil-oteracil potassium (S-1), doxifluridine, and capecitabine. Since the 1980s, UFT has been most widely used for postoperative chemotherapy in breast cancer. UFT is an oral preparation that was designed to achieve and maintain high concentrations of 5-FU in plasma by combining tegafur, a prodrug of 5-FU, with uracil. UFT is characterized by mild adverse events, allowing long-term treatment. The prolonged maintenance of high plasma 5-FU concentrations has been suggested to inhibit micrometastases after surgery. Recently, large clinical trials conducted in Japan have shown that UFT-based postoperative chemotherapy is therapeutically useful in patients with node-negative (n0), high-risk breast cancer. We review the results of clinical trials of postoperative chemotherapy with UFT in Japan and discuss its roles and future prospects. PMID- 23456737 TI - Identification of a novel inhibitor of triple-negative breast cancer cell growth by screening of a small-molecule library. AB - BACKGROUND: Triple-negative breast cancers (TNBC) are defined as not having amplification of the estrogen receptor, progesterone receptor, or epidermal growth factor receptor 2. Recovery of patients is, currently, severely limited after diagnosis of metastatic TNBC, with fewer than 30 % of patients surviving more than 5 years. The most effective therapy to date is chemotherapy, which has been unsuccessful because of lack of therapeutic targets for these aggressive cancers. To identify new molecular targets for TNBC, we have developed a novel method for drug discovery using active compounds for identification of pharmacodynamic biomarkers. METHODS: We used chemical informatics to design a small-molecule library with structural diversity. This library was used to screen for compounds that selectively inhibit proliferation of TNBC cell lines. Different gene-expression profiles in cell lines before and after the addition of selected compounds were analyzed and compared with those of control cells. RESULTS: We identified (E)-3-(3,4-dihydroxybenzylidene)benzofuran-2(3H)-one (DBBF) which specifically inhibited proliferation of a TNBC cell line, MDA-MB 468, with an IC50 of 2.4 MUM. Microarray analysis identified several signaling pathways, including the irinotecan pathway, which changed specifically in the TNBC cell lines on addition of DBBF. CONCLUSION: We have developed a novel research strategy that involves screening of selective inhibitors of TNBC cell line proliferation that can be used for identification of pharmacodynamic biomarkers for TNBC. The discovery of new pathways by this technique should lead to the identification of new therapeutic targets for this aggressive cancer. PMID- 23456738 TI - The emerging role of breast tomosynthesis. AB - Digital breast tomosynthesis (DBT) is a new modality that aids in breast cancer detection. It is a pseudo-three-dimensional digital mammography imaging system that produces a series of 1-mm-slice images with multiple very low-dose X-ray projections to reveal the inner architecture of the breast after eliminating interference from overlapping breast tissue. This review article provides an overview of the current and potential use of DBT. The illustrations and discussion are based on our experience with the Selenia Dimensions (Hologic, USA) DBT system approved by the US Food and Drug Administration. PMID- 23456739 TI - Chiral discrimination and interaction mechanism between enantiomers and serum albumins. AB - The chiral discrimination studies of biological system are theoretically and practically significant for the development of chiral drugs and life science. Our work has embarked upon the interaction between serum albumin (SA) (including human SA and bovine SA), R,S-1-(4-methoxyphenyl)ethylamine, and R,S-1-(3 methoxyphenyl)ethylamine. The formation of intermediate transition state, binding sites, and chiral discrimination ability can be investigated by ultraviolet visible spectra and fluorescence spectra. Moreover, both the changes of hydrophobic microenvironment and energy transfer can be detected by synchronous fluorescence spectra and fluorescence lifetime. PMID- 23456740 TI - Importance of the interaction protein-protein of the CaM-PDE1A and CaM-MLCK complexes in the development of new anti-CaM drugs. AB - Protein-protein interactions play central roles in physiological and pathological processes. The bases of the mechanisms of drug action are relevant to the discovery of new therapeutic targets. This work focuses on understanding the interactions in protein-protein-ligands complexes, using proteins calmodulin (CaM), human calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A active human (PDE1A), and myosin light chain kinase (MLCK) and ligands alphaII-spectrin peptide (alphaII-spec), and two inhibitors of CaM (chlorpromazine (CPZ) and malbrancheamide (MBC)). The interaction was monitored with a fluorescent biosensor of CaM (hCaM M124C-mBBr). The results showed changes in the affinity of CPZ and MBC depending on the CaM-protein complex under analysis. For the Ca(2+) -CaM, Ca(2+) -CaM-PDE1A, and Ca(2+) -CaM-MLCK complexes, CPZ apparent dissociation constants (Kds ) were 1.11, 0.28, and 0.55 MUM, respectively; and for MBC Kds were 1.43, 1.10, and 0.61 MUM, respectively. In competition experiments the addition of calmodulin binding peptide 1 (alphaII spec) to Ca(2+) -hCaM M124C-mBBr quenched the fluorescence (Kd = 2.55 +/- 1.75 pM) and the later addition of MBC (up to 16 MUM) did not affect the fluorescent signal. Instead, the additions of alphaII-spec to a preformed Ca(2+) -hCaM M124C mBBr-MBC complex modified the fluorescent signal. However, MBC was able to displace the PDE1A and MLCK from its complex with Ca(2+) -CaM. In addition, docking studies were performed for all complexes with both ligands showing an excellent correlation with experimental data. These experiments may help to explain why in vivo many CaM drugs target prefer only a subset of the Ca(2+) -CaM regulated proteins and adds to the understanding of molecular interactions between protein complexes and small ligands. PMID- 23456741 TI - Opening dynamics of 8-oxoguanine in DNA. AB - 8-oxoguanine is a major lesion of genomic DNA that results from oxidation of guanine by reactive oxygen species. The repair of this lesion is initiated by 8 oxoguanine glycosylases, which excise the damaged base by "flipping" it outside the DNA double helix. The molecular mechanisms involved in the specific recognition of the damaged base by the enzyme are not yet fully understood. Several models have proposed that, in DNA, the base pair between 8-oxoguanine and cytosine may possess altered dynamic properties that could help the enzyme locate the lesion and could favor the selective extra-helical flipping of the damaged base. To test this proposal, we have characterized the spontaneous opening of the base pair between 8-oxoguanine and cytosine in a DNA double helix using NMR spectroscopy and proton exchange. The results show that the rate of spontaneous opening of 8-oxoguanine and the lifetime of the base in the extra-helical state are the same as those of a canonical guanine-cytosine base pair, in the same base sequence context. This finding suggests that the opening dynamics of 8 oxoguanine, when paired with cytosine in DNA, does not play a significant role in the recognition of the lesion by glycosylases. PMID- 23456742 TI - The promiscuous protein binding ability of erythrosine B studied by metachromasy (metachromasia). AB - The present study aims to elucidate aspects of the protein binding ability of erythrosine B (ErB), a poly-iodinated xanthene dye and an FDA-approved food colorant (FD&C Red No. 3), which we have identified recently as a promiscuous inhibitor of protein-protein interactions (PPIs) with a remarkably consistent median inhibitory concentration (IC50 ) in the 5- to 30-MUM range. Because ErB exhibits metachromasy, that is, color change upon binding to several proteins, we exploited this property to quantify its binding to proteins such as bovine serum albumin (BSA) and CD40L (CD154) and to determine the corresponding binding constants (Kd ) and stoichiometry (nb ) using spectrophotometric methods. Binding was reversible, and the estimated affinities for both protein targets obtained here (Kd values of 14 and 20 MUM for BSA and CD40L, respectively) were in good agreement with that expected from the PPI inhibitory activity of ErB. A stoichiometry greater than one was observed both for CD40L and BSA binding (nb of 5-6 and 8-9 for BSA and CD40L, respectively), indicating the possibility of nonspecific binding of the flat and rigid ErB molecule at multiple sites, which could explain the promiscuous PPI inhibitory activity if some of these overlap with the binding site of the protein partner and interfere with the binding. PMID- 23456743 TI - A biomimetic Protein G affinity adsorbent: an Ugi ligand for immunoglobulins and Fab fragments based on the third IgG-binding domain of Protein G. AB - This work reports the development of a synthetic affinity adsorbent for immunoglobulins based on the Fab-binding domain of Streptococcal Protein G (SpG domain III). The ligand (A2C7I1) was synthesized by the four-component Ugi reaction to generate a substituted peptoidal scaffold mimicking key amino acid residues of SpG. Computer-aided analysis suggests a putative binding site on the CH 1 domain of the Fab molecule. In silico studies, supported by affinity chromatography in comparison with immobilized SpG, as well as analytical characterization by liquid chromatography/electrospray ionization-mass spectrometry and (1) H nuclear magnetic resonance of the ligand synthesized in solution, indicated the authenticity and suitability of the designed ligand for the purification of immunoglobulins. The immobilized ligand displayed an apparent static binding capacity of ~17 mg IgG ml(-1) and a dissociation constant of 5.34 * 10(-5) M. Preparative chromatography demonstrated the ability of the immobilized ligand to purify IgG and Fab fragments from crude mammalian and yeast cell cultures, under near physiological ionic strength and pH, to yield proteins of 99% and 93% purity, respectively. PMID- 23456746 TI - 'A healthier and more hopeful person': illegitimacy, mental disorder and the improved prognosis of the adolescent mother. AB - This paper aims to contribute to the exploration of the shift from a problematisation of 'unwed motherhood' to 'teenage motherhood' in late twentieth century Britain. It does so by exploring the dominant social scientific understanding of 'unwed mothers' during the 1950s and 1960s which suggested that these women suffered from a psychological disorder. I then analyse the conceptualisation of 'adolescent unwed mothers' exploring why professionals deemed them to be less disturbed than older women in their predicament. This finding is discussed in light of contemporary social scientific concern with adolescent motherhood. PMID- 23456745 TI - Phase I study of ofatumumab, a human anti-CD20 antibody, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. AB - OBJECTIVES: Ofatumumab is a human IgG1kappa monoclonal antibody that targets a membrane proximal epitope encompassing the small and large loops of CD20. This Phase I study evaluated the safety, tolerability, efficacy and pharmacokinetics of ofatumumab monotherapy in Japanese patients with relapsed/refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma. METHODS: Ofatumumab was administered intravenously weekly for a total of eight doses (dose escalation: 500 and 1000 mg). Six patients (two chronic lymphocytic leukemia and four small lymphocytic lymphoma) were enrolled into two dose cohorts (500 mg, three patients; 1000 mg, three patients). All six patients received 300 mg ofatumumab at the first infusion and either 500 or 1000 mg at seven subsequent weekly infusions. RESULTS: No dose-limiting toxicities or serious adverse events were observed. Grade 3-4 adverse events observed were grade 3 lymphocytopenia (n = 1) and neutropenia (n = 1). Grade 1-2 infusion-related adverse events leading to temporary interruption of ofatumumab infusion were observed in all six patients on the first infusion day, and all patients completed the planned eight infusions. The overall response rate was 50% (3/6). CONCLUSIONS: Ofatumumab was well tolerated at doses up to 1000 mg and showed preliminary evidence of activity in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, warranting further investigations. PMID- 23456747 TI - Foreword--as per verse: the queer in the clinic in the poem. AB - This essay introduces a series of poems by six authors: Rafael Campo, Susan Holbrook, Katie Price, Trish Salah, Qwo-Li Driskill, and Brian Teare. I argue that the poems demonstrate that a queer bioethics, whether literary or medical, must dispense with commonplace assumptions about the ways in which selves, especially queer selves, are represented in language. Instead, poetry's sound sense and avoidance of language-as-usual can serve as an analogy for modes of approach, analysis, and even recognition that do not receive official sanction; the non-linear modes of reading required by contemporary poetry can serve as methodological models for a queer bioethics. PMID- 23456748 TI - Forward--the visual culture of the queer in the clinic. AB - This short essay provides an overview of the Visual Studies section of the special issue "Queer in the Clinic." Addressing the impact of visual culture on queer experiences in the clinic, the author offers thoughts on the graphic artwork of Edie Fake and Brain Cremins's essay included in this issue. Arguing that contemporary and historical visual assessments of the LGBTQ clinical subject are vital contributors to queer bioethical debates, she explains relevant concepts such as "radical somatic transformation," "the nature of bodily possibility," and Walter Benjamin's "world of secret affinities." PMID- 23456749 TI - Magnetic resonance imaging in the prenatal diagnosis of neural tube defects. AB - OBJECTIVE: To assess the role of magnetic resonance imaging (MRI) in the prenatal diagnosis of neural tube defects (NTDs). BACKGROUND: NTDs comprise a heterogeneous group of congenital anomalies that derive from the failure of the neural tube to close. Advances in ultrasonography and MRI have considerably improved the diagnosis and treatment of NTDs both before and after birth. Ultrasonography is the first technique in the morphological study of the fetus, and it often makes it possible to detect or suspect NTDs. Fetal MRI is a complementary technique that makes it possible to clear up uncertain ultrasonographic findings and to detect associated anomalies that might go undetected at ultrasonography. The progressive incorporation of intrauterine treatments makes an accurate diagnosis of NTDs essential to ensure optimal perinatal management. The ability of fetal MRI to detect complex anomalies that affect different organs has been widely reported, and it can be undertaken whenever NTDs are suspected. CONCLUSION: We describe the normal appearance of fetal neural tube on MRI, and we discuss the most common anomalies involving the structures and the role of fetal MRI in their assessment. KEY POINTS: * To learn about the normal anatomy of the neural tube on MRI * To recognise the MR appearance of neural tube defects * To understand the value of MRI in assessing NTDs. PMID- 23456750 TI - Extra-spinal incidental findings at lumbar spine MRI in the general population: a large cohort study. AB - OBJECTIVE: To determine the prevalence of clinically and non-clinically relevant extra-spinal incidental findings (IF) in patients undergoing magnetic resonance imaging (MRI) of the lumbar spine and to evaluate the rate of undetected findings in archived radiological reports. METHODS: A retrospective search of patients undergoing lumbar spine MRI from January 2006 to December 2010 was conducted. By means of randomisation, we retrospectively reviewed 3,000 lumbar spine MRI examinations. Extra-spinal abnormalities were classified according to a modified CT Colonography Reporting and Data System (C-RADS). We retrospectively compared our structured approach with the archived MRI reports as it regarded the detection of extra-spinal IF to estimate non-detection rates. RESULTS: By means of the structured approach used, extra-spinal findings were detected in 2,060 (68.6 %) of the 3,000 lumbar spine MRI examinations; 362 (17.6 %) patients had indeterminate or clinically important findings (E3 and E4) requiring clinical correlation or further evaluation. After review of the original archived radiological reports, potentially important C-RADS E3 and E4 extra-spinal IF were respectively reported in 47 of the 265 (17.7 %) and in 8 of 74 (10.8 %) patients. CONCLUSIONS: Our study shows that incidental extra-spinal findings at conventional lumbar spine MRI are common but underestimated in radiological reports. PMID- 23456751 TI - Vascular remodeling at both branch ostia in bifurcation disease assessed by intravascular ultrasound. AB - BACKGROUND: The aim of this study was to assess vascular remodeling at both mainbranch (MB) and sidebranch (SB) ostia in left main (LM), and non-LM coronary artery disease. METHODS: Using both pullback intravascular ultrasound, MB and SB ostia were evaluated in 169 bifurcation lesions with angiographic stenosis >50% before procedure. Remodeling index (RI) was the ratio of external elastic membrane (EEM) area at the minimal lumen area (MLA) site within the ostium to EEM area of distal reference. RESULTS: In 81 LM bifurcation lesions, constrictive remodeling (RI < 1) was frequent at MB and SB ostia (91% and 90%). In 88 non-LM bifurcation lesions, constrictive remodeling was also frequent at the MB and SB ostia (76% and 92%). RI was the lowest at the SB ostium in non-LM bifurcation (0.80 +/- 0.13). RI was related to neither large plaque burden nor extensive calcification. The non-LM bifurcation lesions with RI <1 at the SB ostium showed smaller distal carina angle (51 +/- 25 degrees vs. 64 +/- 14 degrees , P = 0.044) compared with those with RI >1. At all ostial sites of bifurcation lesions, plaque burden and RI at the ostium and EEM area of distal reference were the independent factors affecting the MLA within the corresponding ostium as a continuous variable. CONCLUSIONS: At both MB and SB ostia, constrictive remodeling was frequent even in the lesions with small amount of plaque and minimal calcification, which contribute further luminal narrowing. (c) 2012 Wiley Periodicals, Inc. PMID- 23456752 TI - Solid versus liquid-satiety study in well-adjusted lap-band patients. AB - BACKGROUND: Patients following laparoscopic adjustable gastric banding (LAGB) are generally advised to avoid liquid calories, opt for solids and refrain from drinking with meals as this is believed to prolong satiety. The role of food consistency and satiety following LAGB is largely uninvestigated. The purpose of the study was to: (1) determine if food consistency impacts on post meal satiety in participants with well-adjusted LAGB and (2) compare the level of satiety achieved after consuming a solid versus a liquid meal between groups. METHODS: Twenty intervention (well-adjusted LAGB) and 20 control participants were recruited. All participants consumed three iso-caloric breakfasts that were randomised for nine mornings. Participants were asked to rate their satiety on visual analogue scales (VAS) at set times after the test meal. Areas under the curve (AUC) VAS scores were compared within and between groups. RESULTS: Solids (bars) with or without water provided greater satiety than the liquids (shakes) for both groups. Drinking water with the bar did influence satiety in the intervention group. For the intervention group (LAGB), AUC VAS values for the bar with water were 77.4 +/- 11.2* and 72.4 +/- 16.7* for the controls. CONCLUSION: Solid meals are more satisfying in both LAGB and non-LAGB individuals. However, a solid meal with accompanying water did not alter meal satiety. PMID- 23456753 TI - Does self-rated health predict dementia? AB - OBJECTIVES: 1. To determine if Self-Rated Health (SRH) predicts dementia over a five period in cognitively intact older adults, and in older adults with Cognitive Impairment, No Dementia (CIND); and 2. To determine if different methods of eliciting SRH (age-referenced (AR) versus unreferenced) yield similar results. DESIGN: Prospective cohort. POPULATION: 1468 cognitively intact adults and 94 older adults with CIND aged 65+ living in the community, followed over five years. MEASURES: Age, gender, education, subjective memory loss, depressive symptoms, functional status, cognition, SRH and AR-SRH were all measured; dementia was diagnosed on clinical examination. Those with abnormal cognition not meeting criteria for dementia were diagnosed with CIND. RESULTS: In those who were cognitively intact at time 1, and had good SRH: 69.4% were intact; 6.0% had CIND; 6.9% had dementia, and 17.7% had died at time 2, while in those with poor SRH: 44.9% were intact, 11.1% had CIND, 9.1% had dementia, and 34.8% had died (p<0.001, chi-square test). In multinomial regression models SRH predicted dementia and death. In those with CIND at time 1 and good SRH: 2.3% were intact: 18.6% had CIND; 34.9% had dementia and 44.2% had died at time 2, while in those with poor SRH: 4.8% were intact, 31.0% had CIND, 19.0% had dementia, and 43.6% had died (p=0.30, chi-square test). In multinomial regression models, this was not significant. AR-SRH analyses were similar. CONCLUSIONS: In cognitively intact older adults SRH predicts dementia. In older adults with CIND, SRH does not predict dementia. PMID- 23456754 TI - Between-within models for survival analysis. AB - A popular way to control for confounding in observational studies is to identify clusters of individuals (e.g., twin pairs), such that a large set of potential confounders are constant (shared) within each cluster. By studying the exposure outcome association within clusters, we are in effect controlling for the whole set of shared confounders. An increasingly popular analysis tool is the between within (BW) model, which decomposes the exposure-outcome association into a 'within-cluster effect' and a 'between-cluster effect'. BW models are relatively common for nonsurvival outcomes and have been studied in the theoretical literature. Although it is straightforward to use BW models for survival outcomes, this has rarely been carried out in practice, and such models have not been studied in the theoretical literature. In this paper, we propose a gamma BW model for survival outcomes. We compare the properties of this model with the more standard stratified Cox regression model and use the proposed model to analyze data from a twin study of obesity and mortality. We find the following: (i) the gamma BW model often produces a more powerful test of the 'within-cluster effect' than stratified Cox regression; and (ii) the gamma BW model is robust against model misspecification, although there are situations where it could give biased estimates. PMID- 23456755 TI - Visualizing cellulase activity. AB - Commercial exploitation of lignocellulose for biotechnological production of fuels and commodity chemicals requires efficient-usually enzymatic saccharification of the highly recalcitrant insoluble substrate. A key characteristic of cellulose conversion is that the actual hydrolysis of the polysaccharide chains is intrinsically entangled with physical disruption of substrate morphology and structure. This "substrate deconstruction" by cellulase activity is a slow, yet markedly dynamic process that occurs at different length scales from and above the nanometer range. Little is currently known about the role of progressive substrate deconstruction on hydrolysis efficiency. Application of advanced visualization techniques to the characterization of enzymatic degradation of different celluloses has provided important new insights, at the requisite nano-scale resolution and down to the level of single enzyme molecules, into cellulase activity on the cellulose surface. Using true in situ imaging, dynamic features of enzyme action and substrate deconstruction were portrayed at different morphological levels of the cellulose, thus providing new suggestions and interpretations of rate-determining factors. Here, we review the milestones achieved through visualization, the methods which significantly promoted the field, compare suitable (model) substrates, and identify limiting factors, challenges and future tasks. PMID- 23456756 TI - Editorial : wide coverage of topics and countries. PMID- 23456759 TI - Acceptability and efficacy of an emollient containing ceramide-precursor lipids and moisturizing factors for atopic dermatitis in pediatric patients. AB - BACKGROUND: Atopic eczema or dermatitis (AD) is associated with atopy and is characterized by reduced skin hydration and an impaired skin barrier in the epidermis. We investigated the patient acceptability and efficacy of an emollient containing ceramide-precursor lipids and moisturizing factors (LMF) in AD. METHODS: Consecutive AD patients were recruited. Swabs and cultures were obtained from the right antecubital fossa and the worst-affected eczematous area, and disease severity [according to the SCORing Atopic Dermatitis (SCORAD) Index], skin hydration, and transepidermal water loss (TEWL) were measured prior to and after 2 weeks' use of the LMF moisturizer. The general acceptability of treatment was documented as being 'very good', 'good', 'fair', or 'poor'. RESULTS: Twenty four AD patients [mean age 13.8 (standard deviation 5.7) years] were recruited. Two thirds of the patients reported very good or good acceptability of the LMF moisturizer, whereas one third reported fair or poor acceptability. There were no inter-group differences in the pre-use clinical parameters of age, objective SCORAD score, pruritus score, sleep disturbance score, skin hydration, TEWL, topical corticosteroid use, oral antihistamine use, or acceptability of previously used proprietary emollients. However, patients in the fair/poor acceptability group were more likely to have Staphylococcus aureus colonization and to be female (odds ratio 13, 95 % confidence interval 1.7-99.4; p = 0.021). Following use of the LMF moisturizer, the objective SCORAD score, pruritus score, and sleep disturbance score were lower in the very good/good acceptability group than in the fair/poor acceptability group. The mean objective SCORAD score improved (from 31.5 to 25.7; p = 0.039) and skin hydration improved [from 30.7 arbitrary units (a.u.) to 36.0 a.u.; p = 0.021] in the very good/good acceptability group. When the data were analyzed for the strength of the agreement of the rating of acceptability, the kappa values were 0.338 (fair) for use of body wash and 0.118 (poor) for use of emollients before and after the trial. CONCLUSION: The LMF moisturizer was considered acceptable by two thirds of the patients with AD. It seems that patients who found the moisturizer acceptable were less likely to be female or to be colonized by S. aureus before switching to the product, and they had less severe eczema, less pruritus, and less sleep disturbance after its use than patients who did not find the product acceptable. Gender and S. aureus colonization may have influenced the patient acceptability and clinical efficacy of the LMF moisturizer. The lack of agreement with regard to the acceptability of the moisturizer implies that there is room for parent/patient education to improve compliance. PMID- 23456758 TI - Periconceptional maternal alcohol consumption and neural tube defects. AB - BACKGROUND: Neural tube defects (NTD)s, which occur when the neural tube fails to close during early gestation, are some of the most common birth defects worldwide. Alcohol is a known teratogen and has been shown to induce NTDs in animal studies, although most human studies have failed to corroborate these results. Using data from the National Birth Defects Prevention Study, associations between maternal reports of periconceptional (1 month prior through 2 months postconception) alcohol consumption and NTDs were examined. METHODS: NTD cases and unaffected live born control infants, delivered from 1997 through 2005, were included. Interview reports of alcohol consumption (quantity, frequency, variability, and type) were obtained from 1223 case mothers and 6807 control mothers. Adjusted odds ratios (aOR)s and 95% confidence intervals were estimated using multivariable logistic regression analysis. RESULTS: For all NTDs combined, most aORs for any alcohol consumption, one or more binge episodes, and different type(s) of alcohol consumed were near unity or modestly reduced (>= 0.7 < aOR <= 1.1) and were not statistically significant. Findings were similar for individual NTD subtypes. CONCLUSIONS: These findings suggest no elevated association between maternal periconceptional alcohol consumption and NTDs. Underreporting of alcohol consumption, due to negative social stigma associated with alcohol consumption during pregnancy, and limited reports for mothers with early pregnancy loss of a fetus with an NTD may have affected the estimated odds ratios. Future studies should aim to increase sample sizes for less prevalent subtypes, reduce exposure misclassification, and improve ascertainment of fetal deaths and elective terminations. PMID- 23456760 TI - The symmetric-range accuracy under a one-way random model with balanced or unbalanced data. AB - The symmetric-range accuracy A of a sampler is defined as the fractional range, symmetric about the true concentration, that includes a specified proportion of sampler measurements. In this article, we give an explicit expression for A assuming that the sampler measurements follow a one-way random model so as to capture different components of variability, for example, variabilities among and within different laboratories or variabilities among and within exposed workers. We derive an upper confidence limit for A based on the concept of a 'generalized confidence interval'. A convenient approximation is also provided for computing the upper confidence limit. Both balanced and unbalanced data situations are investigated. Monte Carlo evaluation indicates that the proposed upper confidence limit is satisfactory even for small samples. The statistical procedures are illustrated using an example. PMID- 23456762 TI - External validation of a prognostic nomogram for overall survival in women with uterine leiomyosarcoma. AB - BACKGROUND: There is no validated system to identify prognostically distinct cohorts of women with uterine leiomyosarcoma (ULMS). By using an independent, pooled, multi-institutional, international patient cohort, the authors validated a recently proposed ULMS nomogram. METHODS: The ULMS nomogram incorporated 7 clinical characteristics (age, tumor size, tumor grade, cervical involvement, locoregional metastases, distant metastases, and mitotic index (per 10 high-power fields) to predict overall survival (OS) after primary surgery. Independent cohorts from 2 sarcoma centers were included. Eligible women, at minimum, underwent a hysterectomy for primary, locally advanced, or metastatic ULMS and received part of their care at 1 of the centers between 1994 and 2010. RESULTS: In total, 187 women with ULMS were identified who met the above criteria described above (median age, 51 years; median tumor size, 9 cm; median mitotic index, 20 per 10 high-power fields). Tumors generally were high grade (88%), FIGO stage I or II (61%) without cervical involvement (93%) and without locoregional metastases (77%) or distant metastases (83%). The median OS and the 5-year OS rate were 4.5 years (95% confidence interval, 3.2-5.3 years) and 46%, respectively; and 65 women (35%) remained alive at last follow-up. The nomogram concordance index was 0.67(standard error, 0.02), which was as high as the concordance index from the initial cohort used for nomogram development. The concordance between actual OS and nomogram predictions suggests excellent calibration because predictions were within 1% of actual 5-year OS rates for patients with a predicted 5-year OS of less than 0.68. CONCLUSIONS: The ULMS nomogram was externally validated using independent cohorts. These findings support the international use of the ULMS nomogram prognostic of OS in ULMS. PMID- 23456763 TI - An automated diagnosis system of liver disease using artificial immune and genetic algorithms. AB - The rise of health care cost is one of the world's most important problems. Disease prediction is also a vibrant research area. Researchers have approached this problem using various techniques such as support vector machine, artificial neural network, etc. This study typically exploits the immune system's characteristics of learning and memory to solve the problem of liver disease diagnosis. The proposed system applies a combination of two methods of artificial immune and genetic algorithm to diagnose the liver disease. The system architecture is based on artificial immune system. The learning procedure of system adopts genetic algorithm to interfere the evolution of antibody population. The experiments use two benchmark datasets in our study, which are acquired from the famous UCI machine learning repository. The obtained diagnosis accuracies are very promising with regard to the other diagnosis system in the literatures. These results suggest that this system may be a useful automatic diagnosis tool for liver disease. PMID- 23456764 TI - The effects of Hsp90 expression alteration on spinal metastases of breast carcinoma. AB - Previous studies have demonstrated that Hsp90 is closely associated with tumor metastases, and inhibition of Hsp90 expression can result in reduced tumor invasiveness and migration capability. However, its role in spinal metastases of breast carcinoma remains unknown. The paper aimed to further detect Hsp90 expression in a mouse model of spinal metastases of breast carcinoma which was established by left ventricular injection of breast cancer cell lines TM40D to nude mice. The BALB/c nude mice were divided into four groups at random: blank control group (n=10), model group (n=30), negative control group (n=10), and experimental group (n=30). Mice in the experimental group were given intraperitoneal injection of 12 mg/kg 17-allylamino-demethoxy geldanamycin (17 AAG), an inhibitor for Hsp90. The protein and mRNA expressions of Hsp90 were respectively determined using immunohistochemistry and real-time PCR. Bioluminescence imaging, dissection, and hematoxylin and eosin staining were performed to observe tumor formation and bone damage. Our results suggested that Hsp90 expression in mice with breast cancer metastasis in the spine was significantly higher than that in normal mice. Furthermore, Hsp90 expression was decreased and the spinal metastasis from breast cancer was inhibited by 17-AAG application. Hsp90 could be considered as an indicator to forecast tumor metastasis and provide a target for the treatment of spinal metastasis of breast cancer. PMID- 23456765 TI - Improved efficacy of therapeutic vaccination with viable human umbilical vein endothelial cells against murine melanoma by introduction of OK432 as adjuvant. AB - Vaccination with xenogeneic or syngeneic endothelial cells targeting tumor angiogenesis is effective for inhibiting tumor growth. OK432, an effective adjuvant, was mixed with viable human umbilical vein endothelial cells (HUVECs) to prepare a novel HUVECs-OK432 vaccine, which could have an improved therapeutic efficacy. In this study, HUVECs-OK432 was administrated in mice by subcutaneous injection in a therapeutic procedure. The results showed that a stronger HUVEC specific Abs and cytotoxic T lymphocyte immune response were elicited, which resulted in significant inhibition on the growth of B16F10 melanoma and remarkably prolonged survival of B16F10 melanoma-bearing mice compared with HUVECs. Besides, parallel results were obtained in vitro showing a stronger inhibition of HUVEC proliferation by immune sera of HUVECs-OK432 than that of HUVECs. Moreover, histochemistry and immunohistochemistry analysis showed that HUVECs-OK432 induced large areas of continuous necrosis within tumors and significantly reduced the vessel density, correlating well with the extent of tumor inhibition. Our present results suggest that OK432 could be employed as an effective adjuvant for HUVEC vaccines and therefore should be useful for adjuvant immunotherapy of cancer. PMID- 23456766 TI - Association of GSTT1 gene polymorphisms with the risk of prostate cancer: an updating meta-analysis. AB - It has been demonstrated that the glutathione S-transferase (GST) superfamily helps remove carcinogens from the body and thus might be associated with prostate cancer risk. In recent years, GSTT1 polymorphism has been extensively studied as a potential prostate cancer risk factor; however, the results are inconsistent. To investigate the association between GSTT1 and prostate cancer, we conducted a meta-analysis of 33 studies with 6,697 prostate patients and 7,643 controls. For GSTM1 null versus present genotype, the random effects odds ratio was 0.98 (95 % confidence interval (CI) 0.83-1.16) based on a wide population. Subgroup analyses in the different ethnic groups and different controls were performed. The OR was 1.01 (95 % CI 0.86-1.19) in Caucasians, 1.01 (95 % CI 0.70-1.47) in Asians, and 0.77 (95 % CI 0.42-1.42) in Africans. The OR was 0.98 (95 % CI 0.82-1.16) in non benign prostate hyperplasia (BPH) controls and 1.09 (95 % CI 0.66-1.79) in BPH controls. In conclusion, our present meta-analysis demonstrates that there is no association between GSTT1 polymorphism and prostate cancer, even in the sub analysis concerning different races and control sources. The direction of further research should focus not only on the simple relationship of GSTT1 and prostate cancer but also on gene-environment interaction and distinctions of different GSTs. PMID- 23456767 TI - Effect of NS-398, a cyclooxygenase-2 selective inhibitor, on the cytotoxicity of cytotoxic T lymphocytes to ovarian carcinoma cells. AB - Cyclooxygenase-2 (COX-2) is a key limited enzyme of prostaglandin (PG) synthesis and has been demonstrated to be overexpressed in cancer. N-[2-(cyclohexyloxy)-4 nitropheny]-methane sulfonamide (NS-398) is a special inhibitor of COX-2 and may suppress PGE2 release and promote immune response mechanism of cytotoxic T lymphocytes (CTLs). We aimed to investigate the effect of NS-398 on the PGE2 release, proliferation of ovarian carcinoma cell line CAOV3, and immune cytotoxicity of CTLs. CAOV3 cells were incubated with 0, 50, and 100 MUmol/L NS 398 for 24, 48, and 72 h. Cell viability was determined by trypan blue staining. PGE2 was measured using radioimmunoassay. CTLs were generated from peripheral blood mononuclear cells after stimulated by CAOV3 cells or CAOV3 cells treated with NS-398 when IL-2 existed. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay was used to evaluate the cytotoxicity of CTLs. As expected, the amount, cell density, cellular volume, and growth speed of CAOV3 cells incubated with NS-398 were significantly decreased compared with control group. This difference became more obvious with an increase in the NS-398 concentration and incubation time. Similarly, PGE2 released from CAOV3 cells treated with 50 and 100 MUmol/L NS-398 was significantly decreased compared with control group (P<0.05). There was also significance in PGE2 between the two groups treated with 50 and 100 MUmol/L NS-398 (P<0.05). Compared with control group, the killing rates of CTLs to CAOV3 treated with 50 and 100 MUmol/L NS-398 were significantly increased (P<0.05). However, there is no significant difference between them. Together, our results suggest that NS-398 could be useful in prevention and therapy of ovarian carcinoma. PMID- 23456768 TI - Glutathione S-transferase P1 Ile105Val polymorphism contributes to increased risk of gastric cancer in East Asians. AB - Glutathione S-transferase P1 (GSTP1) is an important enzyme playing critical roles in the phase II detoxification pathway. There were many studies investigating the association between GSTP1 gene Ile105Val polymorphism and gastric cancer risk, but studies from East Asians reported inconsistent findings. We performed a meta-analysis to investigate the association in East Asians. Published literature from PubMed and Chinese Biomedical Literature databases were searched for eligible publications. Pooled odds ratios (ORs) with 95 % confidence intervals (95 %CIs) were calculated using random or fixed-effect model according the between-study heterogeneity. A total of 12 studies with 2,552 cases and 5,474 controls were finally included into the meta-analysis. Meta-analysis of those 12 studies showed that there was an obvious association between GSTP1 Ile105Val polymorphism and gastric cancer risk in East Asians under three genetic models (for valine vs. isoleucine, OR=1.32, 95 %CI 1.05-1.66, P=0.015; for ValVal vs. IleIle, OR=2.00, 95 %CI 1.34-2.98, P=0.001; for the recessive model, OR=1.96, 95 %CI 1.35-2.83, P<0.001). Sensitivity analysis by removing one study at a time suggested the pooled results were stable under the three genetic models above. There was no risk of publication bias. In conclusion, the meta-analysis suggests that there is a strong evidence for the association between GSTP1 Ile105Val polymorphism and increased risk of gastric cancer in East Asians and contributes to increased risk of gastric cancer in East Asians. PMID- 23456769 TI - Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial. AB - SCOPE: By increasing blood folate concentrations, folic acid supplementation reduces risk for neural tube defect-affected pregnancies, and lowers homocysteine concentrations. We assessed response of red blood cell (RBC) and serum folate to folic acid supplementation, and examined association of response with the genetic polymorphism C677T of the methylenetetrahydrofolate NAD(P)H (MTHFR) gene. METHODS AND RESULTS: Randomized, controlled, crossover trial with two folic acid supplement treatment periods and a 30-week washout period. The primary outcome is blood folate (serum and RBC) concentrations. Volunteers (n = 142) aged 18-69 were randomized to two of three doses (0, 200, and 400 MUg) of folic acid for 12 weeks. Serum folate response depended on treatment period with significant responses to 200 MUg seen only in the second treatment periods (4.4 ng/mL or 3.4 ng/mL). Additionally, serum folate increased as folic acid dose increased to 400 MUg (p < 0.01) and response was greater after the washout period (8.7 ng/mL), than after a 6-week run-in (2.3 ng/mL). The differential change attributable to a daily supplement of 400 MUg compared to 200 MUg was 96.8 ng/mL; while the change attributable to 400 MUg compared to 0 MUg was 121.4. Increases in RBC folate concentrations with 400 MUg occurred within MTHFR gene mutation (C677T); and in the African American group. CONCLUSION: Serum folate concentration is responsive to modest increases in folic acid intake. RBC folate increases only with higher additional doses of folic acid supplementation, and this is true for each MTHFR C677T genotype. PMID- 23456770 TI - Pharmacokinetics, pharmacodynamics and toxicities of methotrexate in healthy and collagen-induced arthritic rats. AB - Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPG(n)) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen-induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post-induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPG(n) in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple-doses, RBC MTX reached steady-state (82.4 nm) within 4 days. The MTXPG(2) and MTXPG(3) in RBC kept increasing until the end of the study, attaining 12.5 and 17.7 nm. Significant weight loss was observed after dosing with 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing with 0.3 mg/kg/2 days. A pharmacokinetic/pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX and RBC MTXPG(n) concentrations, and paw size was developed using naive data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. Methotrexate showed modest (I(maxd) = 0.16) but sensitive (IC(50d) = 0.712 nm) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of the effects of methotrexate on rheumatoid arthritis. PMID- 23456772 TI - Effect of passive ultrassonic instrumentation as a final irrigation protocol on debris and smear layer removal--a SEM analysis. AB - This study sought to evaluate the efficacy of passive ultrasonic irrigation (PUI) on removing the smear layer and debris from root dentin using scanning electron microscopy (SEM). Twenty-five bovine incisors were manually prepared and divided into three groups according to the final irrigation protocol: EDTA, final irrigation with 12 mL of 17% EDTA for 3 minutes followed by 5 mL of 2.5% NaOCl; EDTA/PUI, final flush with 4 mL of 17% EDTA and PUI for 30 seconds. These procedures were repeated three times to standardize the volume of the irrigant. Control group, after preparation, the specimens were irrigated only with 17 mL of 2.5% NaOCl. The roots were fractured and analyzed using SEM. The intragroup analysis revealed that the EDTA/PUI protocol removed a higher amount of debris at the cervical third (P = 0.03). The intergroup analysis revealed that EDTA/PUI presented the lowest amount of debris at the cervical third (P = 0.007). Smear layer scores were higher in the control group compared with the EDTA and EDTA/PUI groups, but only at the cervical third (P = 0.02). None of the final irrigant protocols completely removed the smear layer and debris. EDTA/PUI only improved the removal of debris at the cervical third. PMID- 23456771 TI - Chronopharmacology of anti-convulsive therapy. AB - Approximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatile drug delivery or in the form of 'zeitgebers' that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacology in the treatment of epilepsy as well as future treatment avenues. PMID- 23456774 TI - Top practice-changing articles over the last two years. AB - The field of thromboembolic disease and anticoagulation has had critical advances since the Anticoagulation Forum last met (May of 2011). We summarize our "top ten list" of papers that are likely to change the care of the anticoagulated population and improve their outcomes: (1) Patient self-management of their vitamin K antagonist and self monitoring can decrease thromboembolic events; (2) restarting warfarin after gastrointestinal bleeding may decrease mortality; (3) rivaroxaban is effective in the treatment of pulmonary embolism; either (4) apixaban or (5) low-dose aspirin prevented recurrent venous thromboembolic disease after a standard course of therapy; (6) warfarin prevents thrombotic complications up to at least 90 days after bioprosthetic aortic valve replacement; (7) the relative risk reduction of apixaban compared to warfarin is similar across CHADS2 scores, but the absolute risk reduction is higher in high risk patients; (8) adherence to a warfarin dose-adjustment algorithm improved time in the therapeutic range and thromboembolic outcomes in the RE-LY trial; (9) warfarin had little benefit (if any) over aspirin in patients with decreased ejection fraction and sinus rhythm; (10) adding clopidogrel to aspirin in patients with lacunar infarcts did not reduce the risk of recurrent stroke and increased bleeding. PMID- 23456775 TI - Determination of haloperidol in biological samples with the aid of ultrasound assisted emulsification microextraction followed by HPLC-DAD. AB - A rapid and simple quantitative method for preconcentration and determination of haloperidol in biological samples was developed using ultrasound-assisted emulsification microextraction, based on the solidification of floating organic droplet combined with HPLC-DAD. The effects of several factors were investigated. A total of 30 MUL of 1-undecanol as an extraction solvent was injected slowly into a glass-centrifuge tube containing 4 mL alkaline sample solution that was located inside the ultrasonic water bath. The formed emulsion was centrifuged and the fine droplets of solvent were floated at the top of the test tube, then it was cooled in an ice bath and the solidified solvent was transferred into a conical vial, after melt, the analysis of the extract was carried out by HPLC. Under the optimal conditions, the extraction efficiencies were more than 90% and the preconcentration factors were obtained between 119-122. The LOQs were obtained between 4-8 MUg/L and the calibration curves were linear within the range of 4-1000 MUg/L. Finally this method was applied to the determination of haloperidol in plasma and urine samples in the range of MUg/L and satisfactory results were achieved (RSDs <7%). PMID- 23456773 TI - Pannexin1 hemichannels are critical for HIV infection of human primary CD4+ T lymphocytes. AB - HIV is a major public health issue, and infection of CD4(+) T lymphocytes is one of its key features. Whereas several cellular proteins have been identified that facilitate viral infection and replication, the role of hemichannels in these processes has not been fully characterized. We now show that the HIV isolates, R5 and X4, induced a transient-early (5-30 min) and a later, persistent (48-120 h) opening of Panx1 hemichannels, which was dependent on the binding of HIV to CD4 and CCR5/CXCR4 receptors. Blocking Panx1 hemichannels by reducing their opening or protein expression inhibited HIV replication in CD4(+) T lymphocytes. Thus, our findings demonstrate that Panx1 hemichannels play an essential role in HIV infection. PMID- 23456777 TI - Critical analysis of contemporary clinical research in muscle-invasive and metastatic urothelial cancer: a report from the Bladder Cancer Advocacy Network Clinical Trials Working Group. AB - BACKGROUND: There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities. METHODS: These authors performed a search for clinical trials exploring interventions in muscle-invasive and metastatic urothelial cancer, using the ClinicalTrials.gov registry. Data extracted from the registry included title, recruitment status, interventions, sponsor, phase, enrollment, study design, and study sites. RESULTS: Among 120 eligible trials exploring interventions in muscle-invasive and metastatic urothelial cancer, 73% were phase 2 and 73% were nonrandomized. The majority (63%) involved treatment in the metastatic disease state. The median planned enrollment size per trial was 45 patients (interquartile range, 47 patients). The majority of trials (55%) involved <= 3 study sites. Trials most commonly explored interventions in the first-line metastatic (30%) or second-line metastatic (37%) settings. Targeted therapeutics were studied in 58% of the trials. Among 56 trials that completed enrollment, the median time to complete accrual was 50 months (range, 10-109 months), and these trials enrolled a median of 40 patients per trial (interquartile range, 44 patients). CONCLUSIONS: The majority of contemporary clinical trials in muscle-invasive and metastatic urothelial cancer are small, nonrandomized, phase 2 trials involving 1 to 3 study sites. Enhanced communication and collaboration among the urothelial cancer community, and other stakeholders, is needed to facilitate the design and conduct of trials capable of expediting progress in this disease. PMID- 23456778 TI - Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). AB - BACKGROUND: The OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes the quality of life (QoL) and updated PFS analyses from this study. PATIENTS AND METHODS: Chinese patients >= 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/day; n = 82) or gemcitabine carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS). RESULTS: Patients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105-0.256; P < 0.0001), which was similar to the previously reported primary analysis. CONCLUSION: Erlotinib improves QoL compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC. PMID- 23456780 TI - Homegardens as a multi-functional land-use strategy in Sri Lanka with focus on carbon sequestration. AB - This paper explores the concept of homegardens and their potential functions as strategic elements in land-use planning, and adaptation and mitigation to climate change in Sri Lanka. The ancient and locally adapted agroforestry system of homegardens is presently estimated to occupy nearly 15 % of the land area in Sri Lanka and is described in the scientific literature to offer several ecosystem services to its users; such as climate regulation, protection against natural hazards, enhanced land productivity and biological diversity, increased crop diversity and food security for rural poor and hence reduced vulnerability to climate change. Our results, based on a limited sample size, indicate that the homegardens also store significant amount of carbon, with above ground biomass carbon stocks in dry zone homegardens (n = 8) ranging from 10 to 55 megagrams of carbon per hectare (Mg C ha(-1)) with a mean value of 35 Mg C ha(-1), whereas carbon stocks in wet zone homegardens (n = 4) range from 48 to 145 Mg C ha(-1) with a mean value of 87 Mg C ha(-1). This implies that homegardens may contain a significant fraction of the total above ground biomass carbon stock in the terrestrial system in Sri Lanka, and from our estimates its share has increased from almost one-sixth in 1992 to nearly one-fifth in 2010. In the light of current discussions on reducing emissions from deforestation and forest degradation (REDD+), the concept of homegardens in Sri Lanka provides interesting aspects to the debate and future research in terms of forest definitions, setting reference levels, and general sustainability. PMID- 23456779 TI - Novel organisms: comparing invasive species, GMOs, and emerging pathogens. AB - Invasive species, range-expanding species, genetically modified organisms (GMOs), synthetic organisms, and emerging pathogens increasingly affect the human environment. We propose a framework that allows comparison of consecutive stages that such novel organisms go through. The framework provides a common terminology for novel organisms, facilitating knowledge exchange among researchers, managers, and policy makers that work on, or have to make effective decisions about, novel organisms. The framework also indicates that knowledge about the causes and consequences of stage transitions for the better studied novel organisms, such as invasive species, can be transferred to more poorly studied ones, such as GMOs and emerging pathogens. Finally, the framework advances understanding of how climate change can affect the establishment, spread, and impacts of novel organisms, and how biodiversity affects, and is affected by, novel organisms. PMID- 23456781 TI - Cocoa flavonoids improve insulin signalling and modulate glucose production via AKT and AMPK in HepG2 cells. AB - SCOPE: Cocoa and (-)-epicatechin (EC), a main cocoa flavanol, have been suggested to exert beneficial effects in diabetes, but the mechanism for their insulin-like effects remains unknown. In this study, the modulation of insulin signalling by EC and a cocoa phenolic extract (CPE) on hepatic HepG2 cells was investigated by analysing key proteins of the insulin pathways, namely insulin receptor, insulin receptor substrate (IRS) 1 and 2, PI3K/AKT and 5'-AMP-activated protein kinase (AMPK), as well as the levels of the glucose transporter GLUT-2 and the hepatic glucose production. METHODS AND RESULTS: EC and CPE enhanced the tyrosine phosphorylation and total insulin receptor, IRS-1 and IRS-2 levels and activated the PI3K/AKT pathway and AMPK in HepG2 cells. CPE also enhanced the levels of GLUT-2. Interestingly, EC and CPE modulated the expression of phosphoenolpyruvate carboxykinase, a key protein involved in the gluconeogenesis, leading to a diminished glucose production. In addition, EC- and CPE-regulated hepatic gluconeogenesis was prevented by the blockage of AKT and AMPK. CONCLUSION: Our data suggest that EC and CPE strengthen the insulin signalling by activating key proteins of that pathway and regulating glucose production through AKT and AMPK modulation in HepG2 cells. PMID- 23456782 TI - Anterior tibialis CMAP amplitude correlations with impairment in CMT1A. AB - INTRODUCTION: CMT1A is the most common form of Charcot-Marie-Tooth disease (CMT), a slowly progressive neuropathy in which impairment is length dependent. Fibular nerve conduction studies to the anterior tibialis muscle (AT) may serve as a physiological marker of disease progression in patients with CMT1A. The objective of this study is to determine whether the AT compound muscle action potential (CMAP) amplitude correlates with impairment in patients with CMT1A. METHODS: We correlated AT CMAP amplitudes and impairment measured by the CMT Neuropathy Score (CMTNS) in a cross-section of 121 patients with CMT1A and a subset of 27 patients with longitudinal data. RESULTS: AT CMAP amplitudes correlated with impairment as measured by the CMTNS in cross sectional analysis. Longitudinal changes in the AT CMAP showed a strong inverse correlation with leg strength but not other components of the CMTNS. CONCLUSIONS: AT CMAP amplitude may serve as a useful outcome measure for physiological changes in natural history studies and clinical trials for patients with CMT1A. PMID- 23456783 TI - Insulin at a unicellular eukaryote level. AB - The unicellular ciliate, Tetrahymena, has been the main model for studying the hormonal system of unicellular animals. Tetrahymena produce, store, secrete and take up insulin, the hormone being similar to that of mammals, both immunocytochemically and functionally. The plasma membrane and nuclear envelope of Tetrahymena have insulin receptors, which are structurally similar to the mammalian receptor, as it their binding capacity. The cell has also second messengers and signal pathways for insulin. Insulin influences the synthesis of other hormones. The first short encounter between the cell and insulin provokes the hormonal imprinting that alters the function of the cells and is transmitted to the progeny, and can persist for over 1,000 generations, in hormone binding, hormone content, phagocytosis, cell growth and movement. Insulin has a survival function in Tetrahymena and during stress insulin production and binding are elevated. Other protozoa also react to insulin, and the evolutionary aspects are discussed in this review since it is still not appreciated that the hormones are of great antiquity in the animal kingdom. PMID- 23456784 TI - A review of the evidence regarding associations between attachment theory and experimentally induced pain. AB - Theoretical and empirical evidence suggests that adult attachment and pain related variables are predictably and consistently linked, and that understanding these links may guide pain intervention and prevention efforts. In general, insecure attachment has been portrayed as a risk factor, and secure attachment as a protective factor, for people with chronic pain conditions. In an effort to better understand the relationships among attachment and pain variables, these links have been investigated in pain-free samples using induced-pain techniques. The present paper reviews the available research linking adult attachment and laboratory-induced pain. While the diverse nature of the studies precludes definitive conclusions, together these papers offer support for associations between insecure attachment and a more negative pain experience. The evidence presented in this review highlights areas for further empirical attention, as well as providing some guidance for clinicians who may wish to employ preventive approaches and other interventions informed by attachment theory. PMID- 23456785 TI - Efficacy of Strychnos spinosa (Lam.) and Solanum incanum L. aqueous fruit extracts against cattle ticks. AB - The efficacy of Solanum incanum and Strychnos spinosa aqueous fruit extracts was evaluated against cattle ticks in on-station experiments and laboratory tick bioassays. In the on-station experiment using cattle, fruit extracts were applied at three concentrations 5, 10, and 20 % (w/v) and compared with a commercial acaricide, Tickbuster (amitraz) spray (positive control) and no treatment (negative control). The treatments were applied at weekly intervals for 6 weeks as surface sprays on 32 Mashona cattle in a completely randomized design experiment. Ticks on individual cattle were identified, counted, and recorded daily. Peripheral blood samples were collected for parasite screening. In the laboratory, tick bioassays were conducted at four concentrations, 5, 10, 20, and 40% (w/v) fruit extracts compared to Tickbuster (amitraz) spray (positive control) and distilled water (negative control). The extracts were incubated with Rhipicephalus (Boophilus) decoloratus tick larvae and mortalities for each treatment level recorded after 24 and 48 h. The 5% Solanum incanum treatment had higher efficacy ratio (P < 0.05) than the other fruit extract concentrations of the same plant species. Efficacy ratio was higher (P < 0.05) in the 5% S. spinosa treated cattle than in the untreated control but lower (P < 0.05) than that for the amitraz treatment. The bioassays indicated that there was a high efficacy ratio for the lowest fruit extract concentrations when ticks were exposed to acaricidal treatments for 48 h compared to 24 h. Overall, the results indicate that Solanum incanum and Strychnos spinosa individually have some acaricidal effect. PMID- 23456786 TI - Multivariate analysis of heat tolerance characteristics in Santa Ines and crossbred lambs in the Federal District of Brazil. AB - Heat tolerance is an important trait for deciding on which genetic resource to use on farms in tropical regions. Three genetic groups of lambs were evaluated by physical and physiological parameters related to adaptation and multivariate analyses used to test if these traits were efficient in separating the genetic groups and which traits were more important in this separation. Crossbred lambs were more similar to each other than to Santa Ines, in general; but individually there was an overlap between Ile de France and Santa Ines lambs. Size traits had higher canonical correlation with physiological variables, while rectal temperature, heart rate, and hemoglobin were more highly correlated with physical traits. Error rates using only physiological traits were high, suggesting that these are inefficient in separating groups of lambs for heat tolerance, while separation with physical traits was more efficient. PMID- 23456787 TI - Effects of high dietary sodium chloride content on performance and sodium and potassium balance in growing pigs. AB - Thirty castrated male Moo Lath pigs (6-8 weeks of age) were used in a 15-week growth trial to study the effect of high dietary sodium chloride (NaCl) content on feed and water intake, performance, sodium (Na) and potassium (K) balance, and plasma aldosterone concentration. The pigs were randomly allocated (ten per treatment) to diets containing 0.24 % Na (Na0.24), 0.28 % Na (Na0.28), and 0.32 % Na (Na0.32) per kg diet. Feed and water was provided ad libitum, and water consumption, feed offered, and feed residues were recorded daily. Every third week, the pigs were weighed, blood samples were collected, and a 3-day total collection of urine and feces was performed. Water intake was higher (P = 0.001) in pigs fed with diets Na0.28 (3.7 L/day) and Na0.32 (3.9 L/day) than in pigs fed with diet Na0.24 (3.4 L/day), and dry matter (DM) intake was higher on diet Na0.32 (P = 0.041) than on the other diets. The average daily body weight (BW) gain was higher on diet Na0.32 than on the other diets (P = 0.031). The feed conversion ratio (in kilogram feed DM to kilogram BW gain) was 4.6, 4.6, and 4.1 on treatments Na0.24, Na0.28, and Na0.32, respectively (P = 0.14). The highest Na balance was observed on diet Na0.32 followed by diets Na0.28 and Na0.24 (P < 0.001), while there was no treatment-related pattern for the K balance. The Na/K ratio in feces and urine increased (P < 0.001), and the K/Na ratio in feces (P < 0.001) decreased with increasing Na content in the diet. Plasma aldosterone concentration decreased (P < 0.001) with increasing dietary content of Na. These results indicate that high NaCl intake and free access to water will increase Na balance but do not negatively influence feed intake and performance of growing local pigs. PMID- 23456788 TI - Determination of organic pollutants in coking wastewater by dispersive liquid liquid microextraction/GC/MS. AB - A method based on dispersive liquid-liquid microextraction coupled with GC/MS was developed for quantitative analysis of the major organic pollutants listed in the United States Environmental Protection Agency method 8270 and the 15 European priority polycyclic aromatic hydrocarbons in coking wastewater. The major parameters such as extraction solvent, dispersive solvent, solution pH, and extraction time were systematically optimized. The optimum extraction conditions were found to be: 15 MUL mixture of 2:1 v/v carbon tetrachloride and chlorobenzene as the extraction solvent, 0.75 mL ACN as the dispersive solvent, solution pH of 8, and extraction time of 2 min. For the major pollutants listed in the United States Environmental Protection Agency 8270, the linear ranges were 0.1 to 100 mg/L, the enrichment factors ranged from 452 to 685, and the relative recoveries ranged from 67.5 to 103.5% with RSDs of 4.0-9.1% (n = 5) at the concentrations of 10 mg/L under the optimum extraction conditions. For the 15 polycyclic aromatic hydrocarbons, the linear ranges were 0.1 to 100 MUg/L, the enrichment factors ranged from 645 to 723, and the relative recoveries ranged from 94.5 to 107.6% with RSDs of 4.6-9.0% (n = 5) at the concentrations of 10 MUg/L. The usefulness of the developed method was demonstrated by applying it in the analysis of real-world coking wastewater samples. PMID- 23456789 TI - Hospital volume is associated with survival but not multimodality therapy in Medicare patients with advanced head and neck cancer. AB - BACKGROUND: Given the complexity of management of advanced head and neck squamous cell carcinoma (HNSCC), this study hypothesized that high hospital volume would be associated with receiving National Comprehensive Cancer Network (NCCN) guideline therapy and improved survival in patients with advanced HNSCC. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify patients with advanced HNSCC. Treatment modalities and survival were determined using Medicare data. Hospital volume was determined by the number of patients with HNSCC treated at each hospital. RESULTS: There were 1195 patients with advanced HNSCC who met inclusion criteria. In multivariable analyses, high hospital volume was not associated with receiving multimodality therapy per NCCN guidelines (odds ratio = 1.02, 95% confidence interval = 0.66-1.60), but showed a nearly significant inverse association with survival in a model adjusted for National Cancer Institute-designated cancer center status, age, sex, race, socioeconomic status, marital status, comorbidity, year of diagnosis, tumor site, and tumor stage (hazard ratio = 0.85, 95% confidence interval = 0.69-1.04). CONCLUSIONS: Medicare patients with advanced HNSCC treated at high-volume hospitals were not more likely to receive NCCN guideline therapy, but had nearly statistically significant better survival, when compared with patients treated at low-volume hospitals. These results suggest that features of high-volume hospitals other than delivery of NCCN guideline therapy influence survival. Cancer 2013. (c) 2013 American Cancer Society. PMID- 23456790 TI - Factors affecting visualization of postmenopausal ovaries: descriptive study from the multicenter United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). AB - OBJECTIVE: Transvaginal sonography (TVS) is core to any ovarian cancer screening strategy. General-population screening involves older postmenopausal women in whom ovarian visualization is difficult because of decreasing ovarian size and lack of follicular activity. We report on factors affecting the visualization of postmenopausal ovaries in the multicenter United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). METHODS: The UKCTOCS is a randomized controlled trial of 202 638 postmenopausal women with 50 639 women in the ultrasound scan arm. TVS is the primary screening modality in the ultrasound scan arm. Age, education, ethnicity, body mass index (BMI), previous pelvic surgery, lifestyle and reproductive factors, and a personal/family history of cancer were assessed for their effects on ovarian visualization at the initial TVS. RESULTS: Between 11 June 2001 and 18 August 2007, 43 867 women underwent TVS. The median age and BMI of the women were 60.6 (interquartile range (IQR), 9.9) years and 25.7 (IQR, 5.8), respectively. The right ovary was visualized in 29 297 (66.8%) and the left ovary was visualized in 28 726 (65.5%). Visualization of ovaries decreased with previous hysterectomy (odds ratio (OR) = 0.534; 95% CI, 0.504 0.567), previous tubal ligation (OR = 0.895; 95% CI, 0.852-0.940), increasing age (OR = 0.953; 95% CI, 0.950-0.956), unilateral oophorectomy (OR = 0.224; 95% CI, 0.186-0.269) and being overweight (OR = 0.918; 95% CI, 0.876-0.962) or obese (OR = 0.715; 95% CI, 0.677-0.755). Increased visualization was observed with a history of infertility (OR = 1.134; 95% CI, 1.005-1.279) and increasing age (in years) at menopause (OR = 1.005; 95% CI, 1.001-1.009). CONCLUSIONS: Several factors affect the visualization of postmenopausal ovaries. Their impact needs to be taken into consideration when developing quality assurance for ovarian ultrasound scanning or comparing study results as their prevalence may differ between populations. PMID- 23456791 TI - Thermo-active elastomer composite for optical heating in microfluidic systems. AB - Single-walled carbon nanotubes are used as doping agents to form thermo-active composites with an elastomeric block-copolymer. Thermal imaging reveals that the temperature response upon irradiation with NIR laser light is dependent (among other things) on the mass fraction of the nanotubes in the polymer matrix. PMID- 23456793 TI - Reply: To PMID 22907223. PMID- 23456794 TI - Pharmacokinetics following intravenous administration and pharmacodynamics of cefquinome in buffalo calves. AB - Disposition following single intravenous injection (2 mg/kg) and pharmacodynamics of cefquinome were investigated in buffalo calves 6-8 months of age. Drug levels in plasma were estimated by high-performance liquid chromatography. The plasma concentration-time profile following intravenous administration was best described by a two-compartment open model. Rapid distribution of cefquinome was evident from the short distribution half-life (t 1/2 alpha = 0.36 +/- 0.01 h), and small apparent volume of distribution (Vd area = 0.31 +/- 0.008 L/kg) indicated limited drug distribution in buffalo calves. The values of area under plasma concentration-time curve, elimination half-life (t 1/2 beta ), total body clearance (ClB), and mean residence time were 32.9 +/- 0.56 MUg . h/mL, 3.56 +/- 0.05 h, 60.9 +/- 1.09 mL/h/kg, and 4.24 +/- 0.09 h, respectively. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration of cefquinome were 0.035-0.07 and 0.05-0.09 MUg/mL, respectively. A single intravenous injection of 2 mg/kg may be effective to maintain the MIC up to 12 h in buffalo calves against the pathogens for which cefquinome is indicated. PMID- 23456795 TI - Computational prediction and characterisation of ubiquitously expressed new splice variant of Prkaca gene in mouse. AB - Prkaca gene of mouse encodes for a cAMP dependent protein kinase catalytic alpha subunit. PKA occurs naturally as a 4-membered structure having two regulatory (R) and two catalytic (C) subunits each encoded by separate gene. Alternatively spliced two transcript variants are known for the Prkaca gene, which encode for two isoforms of PKA C-subunits, namely Calpha1 and Calpha2. These isoforms arise as a result of alternative splicing of the first coding exon with the internal exons. We have identified a new transcript variant using combinatorial approach of bioinformatics and molecular biology techniques involving RT-PCR, semi-nested PCR and sequencing. The new transcript variant encoding Calpha3 isoform has N terminus that differs from Calpha1 and Calpha2 isoforms. Calpha3 isoform also arise as a result of alternative splicing of first coding exon with the internal exon. Newly identified transcript is expressed ubiquitously in different tissues examined. PMID- 23456796 TI - Cancer pain management: what's new? AB - Decades after the publication of the World Health Organization's analgesic ladder, cancer pain is still a major cause of suffering for patients with cancer and affects millions of people worldwide. Owing to the increasing incidence of cancer, cancer-related pain is a major public health problem worldwide. Unfortunately, current research revealed that available options for the successful treatment of cancer pain is still massively underutilized by physicians, and many patients suffer from insufficiently controlled pain despite available treatment options. This review aims to present a concise update about new data or treatment recommendations from the field of cancer pain management. Therefore, information from guidelines, systematic reviews, and original articles that were published in the year 2012 are presented. Specifically, the publication covers information on tapentadol, fixed oxycodone/naloxone combinations, rapid onset fentanyl, nabiximols, ketamine, denusomab, and specialized psychosocial interventions including early palliative care. PMID- 23456797 TI - Severe left heart obstruction with retrograde arch flow influences fetal cerebral and placental blood flow. AB - OBJECTIVE: Decreased middle cerebral artery (MCA) pulsatility index (PI) is a marker of fetal brain-sparing in placental insufficiency and it is also found in fetuses with severe congenital heart disease. This study sought to explore the impact of anatomical subtypes in fetal heart disease on MCA-PI and head growth. METHODS: We retrospectively reviewed fetal echocardiograms of pregnancies complicated by fetal hypoplastic left heart syndrome (HLHS; n = 42) with and without anatomic coarctation (n = 28 and n = 10, respectively), isolated severe aortic coarctation (n = 21), D-transposition of the great arteries (TGA; n = 11) and pulmonary outflow tract obstruction without forward flow across the pulmonary valve (POTO; n = 15), comparing observations with gestational age-matched controls (n = 89). No fetus had major extracardiac pathology or aneuploidy. MCA and umbilical artery (UA) PI, the cerebral placental ratio (CPR = MCA-PI/ UA PI) and neonatal head circumference were obtained and expressed as Z-scores. RESULTS: Lower MCA-PI, higher UA-PI and lower CPR were observed in fetal HLHS and isolated coarctation with reversed arch flow (n = 6) (P < 0.001) but not TGA, POTO or isolated coarctation with antegrade arch flow (n = 15) compared with controls. No difference was found between HLHS with anatomical coarctation and those without; however, MCA-PI correlated positively with neonatal head circumference in HLHS with reversed distal arch flow (r = 0.33, P < 0.05). CONCLUSIONS: Severe left heart obstruction with reversed aortic arch flow is associated with altered fetal cerebral blood flow, and in these conditions, MCA PI positively correlates with head growth. Anatomical arch obstruction itself may not be a contributing factor to altered MCA flow in fetal HLHS. PMID- 23456798 TI - Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) play critical roles in tumor development and progression. The finding that a single miRNA can regulate hundreds of genes places miRNAs at critical hubs of signaling pathways. For the current study, the authors investigated the miRNA expression profile of gastric adenocarcinomas and compared it with esophageal adenocarcinomas to better identify a unique miRNA signature of gastric adenocarcinoma. METHODS: miRNA expression profiles were obtained using 2 different proprietary microarray platforms on primary gastric adenocarcinoma tissue samples. The cross comparison of results identified 17 up regulated miRNAs and 12 down-regulated miRNAs that overlapped in both platforms. Quantitative real-time polymerase chain reaction was performed for independent validation of a representative set of 8 miRNAs in gastric and esophageal adenocarcinomas compared with normal gastric mucosa or esophageal mucosa, respectively. RESULTS: The deregulation of miR-146b-5p, miR-375, miR-148a, miR 31, and miR-451 was associated significantly with gastric adenocarcinomas. Conversely, deregulation of miR-21 (up-regulation) and miR-133b (down-regulation) was detectable in both gastric and esophageal adenocarcinomas. It was noteworthy that miR-200a was significantly down-regulated in gastric adenocarcinoma samples (P = .04) but was up-regulated in esophageal adenocarcinoma samples (P = .001). In addition, the expression level of miR-146b-5p displayed a strong correlation with the tumor stage of gastric cancer. CONCLUSIONS: Gastric adenocarcinoma displayed a unique miRNA signature that distinguished it from esophageal adenocarcinoma. This specific signature may reflect differences in the etiology and/or molecular signaling in these 2 closely related cancers. The current findings suggest important miRNA candidates that can be investigated for their biological functions and for their possible diagnostic, prognostic, and therapeutic role in gastric adenocarcinoma. PMID- 23456799 TI - Gastric bypass surgery elevates NT-ProBNP levels. AB - BACKGROUND: Brain natriuretic peptide (BNP) is produced in the heart in response to stretching of the myocardium. BNP levels are negatively correlated to obesity, and in obese subjects, a reduced BNP responsiveness has been described. Diet induced weight loss has been found to lower or to have no effect on BNP levels, whereas gastric banding and gastric bypass have reported divergent results. We studied obese patients undergoing gastric bypass (GBP) surgery during follow-up of 1 year. METHODS: Twenty patients, 18 women, mean 41 (SD 9.5) years old, with a mean preoperative BMI of 44.6 (SD 5.5) kg/m(2) were examined. N-terminal pro brain natriuretic peptide (NT-ProBNP), glucose and insulin were measured preoperatively, at day 6 and months 1, 6 and 12. In 14 of the patients, samples were also taken at days 1, 2 and 4. RESULTS: The NT-ProBNP levels showed a marked increase during the postoperative week (from 54 pg/mL preop to 359 pg/mL on day 2 and fell to 155 on day 6). At 1 year, NT-ProBNP was 122 pg/mL (125 % increase, p = 0.01). Glucose, insulin and HOMA indices decreased shortly after surgery without correlation to NT-ProBNP change. Mean BMI was reduced from 44.6 to 30.5 kg/m(2) at 1 year and was not related to NT-ProBNP change. CONCLUSIONS: The data indicate that GBP surgery rapidly alters the tone of BNP release, by a mechanism not related to weight loss or to changes in glucometabolic parameters. The GBP induced conversion of obese subjects, from low to high NT-ProBNP responders, is likely to influence the evaluation of cardiac function in GBP operated individuals. PMID- 23456801 TI - Is amyotrophic lateral sclerosis (ALS) a multi system disorder? PMID- 23456800 TI - A distal forearm fracture in childhood is associated with an increased risk for future fragility fractures in adult men, but not women. AB - Distal forearm fractures are among the most common fractures during childhood, but it remains unclear whether they predict an increased fracture risk later in life. We studied a population-based cohort of 1776 children <=18 years of age, from Olmsted County, MN, USA, who had a distal forearm fracture in 1935-1992. Incident fractures occurring at age >=35 years were identified through review of complete medical records using the linkage system of the Rochester Epidemiology Project. Observed nonpathologic fractures resulting from no more than moderate trauma (fragility fractures) were compared with expected numbers estimated from fracture site-specific incidence rates, based on age, sex, and calendar year, for Olmsted County (standardized incidence ratios [SIR]). In 1086 boys (mean +/- SD age; 11 +/- 4 years) and 690 girls (10 +/- 4 years) followed for 27,292 person years after the age of 35 years, subsequent fragility fractures were observed in 144 (13%) men and 74 (11%) women. There was an increased risk for future fragility fractures in boys who had a distal forearm fracture (SIR, 1.9; 95% CI, 1.6-2.3) but not girls (SIR, 1.0; 95% CI, 0.8-1.2). Fragility fractures at both major osteoporotic (hip, spine, wrist, and shoulder) sites (SIR, 2.6; 95% CI, 2.1 3.3) and remaining sites (SIR, 1.7; 95% CI, 1.3-2.0) were increased in men, irrespective of age at distal forearm fracture as boys. A distal forearm fracture in boys, but not girls, is associated with an increased risk for fragility fractures as older adults. It is necessary to determine whether the increased fractures observed in men is due to persistent deficits of bone strength, continued high fracture risk activity, or both. Until then, men should be asked about a childhood distal forearm fracture and, if so, warrant further screening and counseling on measures to optimize bone health and prevent fractures. PMID- 23456803 TI - Kaistia hirudinis sp. nov., isolated from the skin of Hirudo verbana. AB - A Gram-negative, rod-shaped bacterium was isolated from the skin of the medical leech Hirudo verbana and studied for its taxonomic allocation. 16S rRNA gene sequence similarities to other strains showed that the strain was closely related to species of the genus Kaistia. Kaistia geumhonensis was shown to be the most closely related species (96.8%), followed by Kaistia soli (96.6%) and Kaistia dalseonensis (96.2%). All other species of the genus Kaistia showed 16S rRNA gene sequence similarities <96%. Chemotaxonomic data for strain E94(T) (major ubiquinone: Q-10; major polar lipids: diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, hydroxyphosphatidylethanolamine, phosphatidylserine, unknown phospholipids, aminolipids and aminophospholipids; and major fatty acids: C(18:1)omega7c, C(19:0)omega8c cylco, C(16:0) and C(18:0)) supported the affiliation of the isolate to the genus Kaistia. Phenotypic differentiation of strain E94(T) from all species of the genus Kaistia was possible using different physiological characters. Strain E94(T) represents a novel species of the genus Kaistia, for which the name Kaistia hirudinis sp. nov. is proposed, with the type strain E94(T) ( = LMG 26925(T) =CIP 110381(T) =CCM 8401(T)). PMID- 23456802 TI - Herbaspirillum psychrotolerans sp. nov., a member of the family Oxalobacteraceae from a glacier forefield. AB - A novel psychrotolerant, Gram-negative, shiny white, curved-rod-shaped, facultatively anaerobic bacterium PB1(T) was isolated from a soil sample collected from a glacier forefield of the Larsemann Hills, East Antarctica. Isolate PB1(T) has catalase and low urease activity and hydrolyses gelatin and starch. Strain PB1(T) is able to grow between -5 degrees C and 30 degrees C with optimum growth at 14-20 degrees C. Glycerol, dl-arabinose, d-xylose, d galactose, d-fructose, d-lyxose, d-fucose and potassium gluconate are used as sole carbon sources. The major quinone is ubiquinone Q-8. The major fatty acids (>10%) for PB1(T) are C(16:0) (19.1%), C(16:1)omega7cis (44.6%) and C(18:1)omega7cis (16.2%). The major polyamines are putrescine [54.9 umol (g dry weight)(-1)] and 2-hydroxy putrescine [18.5 umol (g dry weight)(-1)]. DNA G+C content is 62.5 mol%. Strain PB1(T) is phylogenetically related to species of the genus Herbaspirillum, with highest 16S rRNA gene sequence similarities to Herbaspirillum canariense (97.3%), Herbaspirillum aurantiacum (97.2%), Herbaspirillum soli (97.2%) and Herbaspirillum frisingense (97.0%). The DNA-DNA relatedness values were below 30% between PB1(T) and the type strains of Herbaspirillum canariense, Herbaspirillum aurantiacum and Herbaspirillum soli. The different geographical origin of strain PB1(T) from its closest phylogenetic relatives resulted in different phenotypic and genotypic specifications, whereby strain PB(T) represents a novel species of the genus Herbaspirillum, for which the name Herbaspirillum psychrotolerans is proposed. The type strain is PB1(T) (DSM 26001(T) =LMG 27282(T)). PMID- 23456804 TI - Streptomyces aidingensis sp. nov., an actinomycete isolated from lake sediment. AB - A novel actinomycete strain, designated TRM 46012(T), was isolated from sediment of Aiding Lake in Tulufan Basin (42 degrees 64' N 89 degrees 26' E), north-west China. The strain was aerobic and Gram-staining-positive with an optimum NaCl concentration for growth of 0-5% (w/v). The isolate had sparse aerial mycelium and produced bud-shaped spores at the end of the aerial mycelium on ISP medium 4. The isolate contained ll-diaminopimelic acid as the diagnostic diamino acid and ribose as the major whole-cell sugar. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylinositol mannoside, one unidentified phospholipid and three unidentified glycolipids. The predominant menaquinones were MK-9(H6), MK-9(H8) and MK-9(H4). The major fatty acids were iso C(16:0), anteiso-C(17:0) and anteiso-C(15:0). The G+C content of the DNA was 74.4 mol%. Phylogenetic analysis showed that strain TRM 46012(T) had 16S rRNA gene sequence similarity of 95.7% with the most closely related species with a validly published name, Streptomyces cheonanensis, and it could be distinguished from all species in the genus Streptomyces by using the data from this polyphasic taxonomic study. On the basis of these data, strain TRM 46012(T) should be designated as a representative of a novel species of the genus Streptomyces, for which the name Streptomyces aidingensis sp. nov. is proposed. The type strain is TRM 46012(T) ( =CGMCC 4.5739(T) =NBRC 108211(T)). PMID- 23456805 TI - Halopenitus malekzadehii sp. nov., an extremely halophilic archaeon isolated from a salt lake. AB - Strain CC65(T), a novel extremely halophilic archaeon, was isolated from a brine sample of a salt lake in Iran. The novel strain was light yellow-pigmented, non motile, pleomorphic and required at least 1.7 M NaCl and 0.02 M MgCl2 for growth. Optimal growth was achieved at 3.5 M NaCl and 0.4 M MgCl2. The optimum pH and temperature for growth were pH 7.5 and 40 degrees C, respectively, while it was able to grow over a pH and a temperature range of pH 6.5-9.0 and 30-50 degrees C, respectively. Analysis of 16S rRNA gene sequence revealed that strain CC65(T) clustered with the sole member of the genus Halopenitus, Halopenitus persicus DC30(T) with a sequence similarity of 98.0%. The polar lipid profile of strain CC65(T) consisted of phosphatidylglycerol and phosphatidylglycerol phosphate methyl ester. An unidentified glycolipid and two minor phospholipids were also observed. The only quinone present was MK-8(II-H2). The DNA G+C content of strain CC65(T) was 63.8 mol%. On the basis of the biochemical and physiological characteristics, as well as DNA-DNA hybridization (44% with Halopenitus persicus IBRC 10041(T)), strain CC65(T) is classified as a novel species of the genus Halopenitus, for which the name Halopenitus malekzadehii sp. nov. is proposed. The type strain is CC65(T) ( = IBRC-M 10418(T) =KCTC 4045(T)). PMID- 23456806 TI - Prosthecate sphingomonads: proposal of Sphingomonas canadensis sp. nov. AB - Two stalked, aerobic, catalase- and oxidase-positive rod-shaped isolates, VKM B 1508 ( = CB 258) and FWC47(T), were analysed using a polyphasic approach. While the morphology and the 16S rRNA gene sequence of strain VKM B-1508 were 100% identical to the ones of Sphingomonas leidyi DSM 4733(T), the morphology of FWC47(T) was different, and the closest recognized species were Sphingomonas oligophenolica S213(T) ( = DSM 17107(T)) and Sphingomonas leidyi DSM 4733(T) with 97.2% and 97.0% 16S rRNA gene sequence similarity, respectively. DNA-DNA hybridization studies supported the differentiation of strain FWC47(T) from S. oligophenolica and S. leidyi. Strain FWC47(T) grew optimally at 28-30 degrees C, and pH 6.0-8.0. The major respiratory quinone was Q10 and the major polyamine was sym-homospermidine. The major fatty acids were C(17:1)omega6c and C(18:1)omega7c and C(15:0) 2-OH was the major 2-hydroxy fatty acid. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidyldimethylethylamine and unidentified sphingoglycolipids. The G+C content of the genomic DNA of strain FWC47(T) was 67.1 mol%. Strain FWC47(T) differed from S. leidyi by its ability to assimilate l-alanine, maltose and sucrose, by the presence of beta-galactosidase and alpha-chymotrypsin, and the lack of valine arylamidase and beta-glucosidase activities. Contrary to S. leidyi, FWC47(T) did not reduce nitrate and could not use fructose, acetate and N-acetyl-glusosamine. In the genus Sphingomonas, the dimorphic life cycle involving a prosthecate sessile and a flagellated swarmer cell was hitherto only known from Sphingomonas leidyi. Therefore, strain FWC47(T) represents an additional distinct prosthecate species in this genus for which the name Sphingomonas canadensis is proposed. The type strain is FWC47(T) ( =LMG 27141(T) =CCUG 62982(T)). PMID- 23456807 TI - Description of Xenorhabdus khoisanae sp. nov., the symbiont of the entomopathogenic nematode Steinernema khoisanae. AB - Bacterial strain SF87(T), and additional strains SF80, SF362 and 106-C, isolated from the nematode Steinernema khoisanae, are non-bioluminescent Gram-reaction negative bacteria that share many of the carbohydrate fermentation reactions recorded for the type strains of recognized Xenorhabdus species. Based on 16S rRNA gene sequence data, strain SF87(T) is shown to be closely related (98% similarity) to Xenorhabdus hominickii DSM 17903(T). Nucleotide sequences of strain SF87 obtained from the recA, dnaN, gltX, gyrB and infB genes showed 96-97% similarity with Xenorhabdus miraniensis DSM 17902(T). However, strain SF87 shares only 52.7% DNA-DNA relatedness with the type strain of X. miraniensis, confirming that it belongs to a different species. Strains SF87(T), SF80, SF362 and 106-C are phenotypically similar to X. miraniensis and X. beddingii, except that they do not produce acid from aesculin. These strains are thus considered to represent a novel species of the genus Xenorhabdus, for which the name Xenorhabdus khoisanae sp. nov. is proposed. The type strain is SF87(T) ( =DSM 25463(T) =ATCC BAA-2406(T)). PMID- 23456808 TI - Morphology and morphogenesis of a soil ciliate, Rigidohymena candens (Kahl, 1932) Berger, 2011 (Ciliophora, Hypotricha, Oxytrichidae), with notes on its molecular phylogeny based on small-subunit rDNA sequence data. AB - The morphology and morphogenesis of the stylonychine hypotrich Rigidohymena candens (Kahl, 1932) Berger, 2011, isolated from garden soil in Qingdao, China, were investigated using live observation and protargol impregnation methods. The Qingdao isolate possesses all diagnostic morphological characters of R. candens. The main events during binary fission are as follows: (i) the proter retains the parental adoral zone of membranelles entirely, whereas the old undulating membranes dedifferentiate into an anlage that gives rise to the leftmost frontal cirrus and the new undulating membranes of the proter; (ii) five streaks of fronto-ventral-transverse cirral anlagen are segmented in the pattern 3 : 3 : 3 : 4 : 4 from left to right, which form two frontal, four frontoventral, one buccal, five ventral and five transverse cirri, respectively; (iii) dorsal morphogenesis is in the typical Oxytricha pattern; (iv) three caudal cirri are formed, one at the posterior end of each of dorsal kineties 1, 2 and 4; and (v) the postoral ventral cirrus V/3 is not involved in primordia formation. The morphological and morphogenetic observations and phylogenetic analyses based on the small-subunit rDNA sequence data support the validity of Rigidohymena Berger, 2011 and its systematic position in the subfamily Stylonychinae. PMID- 23456809 TI - Flavobacterium hauense sp. nov., isolated from soil and emended descriptions of Flavobacterium subsaxonicum, Flavobacterium beibuense and Flavobacterium rivuli. AB - A strictly aerobic, Gram-staining-negative, rod-shaped, non-motile, yellow pigmented bacterial strain, designated BX12(T), was isolated from soil collected from the peak area of Wudang Mountain in the city of Shiyan, Hubei province, China. Phylogenetic analysis of the 16S rRNA gene sequences showed that strain BX12(T) was most closely related to Flavobacterium subsaxonicum WB 4.1-42(T) (95.9% 16S rRNA gene sequence similarity), followed by Flavobacterium beibuense F44-8(T) (95.6%) and Flavobacterium rivuli WB 3.3-2(T) (94.1%). The major fatty acids (>=5%) of strain BX12(T) were summed feature 3 (comprising C(16:1)omega7c and/or C(16:1)omega6c), iso-C(15:0), C(16:0), iso-C(17:0) 3-OH, and C(16:0) 3-OH. The major polar lipid was phosphatidylethanolamine, and the major respiratory quinone was menaquinone-6. The genomic DNA G+C content was 43.9 mol%. On the basis of a high number of phenotypic differentiating properties and phylogenetic uniqueness, strain BX12(T) represents a novel species of the genus Flavobacterium for which the name Flavobacterium hauense sp. nov. is proposed. The type strain is BX12(T) ( =CCTCC AB 2012197(T) =KCTC 32147(T)). Emended descriptions of Flavobacterium subsaxonicum, Flavobacterium beibuense and Flavobacterium rivuli are also proposed. PMID- 23456810 TI - Chryseobacterium carnipullorum sp. nov., isolated from raw chicken. AB - Three Gram-staining-negative, rod-shaped, non-spore-forming, non-motile, oxidase positive, yellow pigmented and aerobic bacterial isolates designated 8_R23573, 9_R23581(T) and 10_R23577 were isolated from raw chicken at a broiler processing plant in Bloemfontein, South Africa. A polyphasic taxonomic approach was used to determine their exact taxonomic identities. Phylogenetic analysis of the 16S rRNA gene sequences showed that the three strains belonged to the genus Chryseobacterium, exhibiting the highest similarities to Chryseobacterium shigense DSM 17126(T) (98.6-99.2%) and Chryseobacterium luteum DSM 18605(T) (98.3 98.7%). The most abundant quinone was menaquinone MK-6 and the predominant cellular fatty acids were iso-15:0, iso-17:1omega9c, iso-17:0 3-OH and summed feature 3 (iso-16:1omega7c and/or iso-15:0 2-OH), which supported the affiliation of the strains to the genus Chryseobacterium. The DNA G+C contents of the strains were 36.9, 36.7 and 36.6 mol% respectively. The DNA-DNA hybridization results gave relatedness values ranging from 78.8 to 87.2% among the three strains and 23.4 to 56.1% to the two nearest phylogenetic neighbours C. shigense DSM 17126(T) and C. luteum LMG 23785(T). On the basis of the data from this polyphasic study, the three strains are concluded to represent a novel species of the genus Chryseobacterium for which the name Chryseobacterium carnipullorum sp. nov. is proposed. The type strain is 9_R23581(T) ( = LMG 26732(T) =DSM 25581(T)). PMID- 23456811 TI - Staphylococcus jettensis sp. nov., a coagulase-negative staphylococcal species isolated from human clinical specimens. AB - Eight coagulase-negative, novobiocin-susceptible staphylococcal strains were isolated from human clinical specimens at two different Belgian medical facilities. All strains were non-motile, Gram-stain-positive, catalase-positive cocci. DNA G+C content, peptidoglycan type, menaquinone pattern, the presence of teichoic acid and cellular fatty acid composition were in agreement with the characteristics of species of the genus Staphylococcus. Sequencing of the 16S rRNA gene and four housekeeping genes (dnaJ, tuf, gap and rpoB) demonstrated that these strains constitute a separate taxon within the genus Staphylococcus. Less than 41% DNA-DNA hybridization with the most closely related species of the genus Staphylococcus (Staphylococcus haemolyticus, Staphylococcus hominis and Staphlococcus lugdunensis) was observed. Key biochemical characteristics that allowed these bacteria to be distinguished from their nearest phylogenetic neighbours are arginine dihydrolase positivity, ornithine decarboxylase negativity and inability to produce acid aerobically from D-mannose, alpha lactose and turanose. Acid is produced aerobically from trehalose. Based on these results, a novel species of the genus Staphylococcus is described and named Staphylococcus jettensis sp. nov. The type strain is SEQ110(T) ( =LMG 26879(T) =CCUG 62657(T) =DSM 26618(T)). PMID- 23456812 TI - Role of apoptosis in mediating diclofenac-induced teratogenesis: An in vitro approach. AB - Diclofenac (DCF) is among the most commonly used nonsteroidal anti-inflammatory drugs worldwide for the treatment of various conditions in postpubertal women. However, very limited information is available regarding its safety during pregnancy and teratogenecity. The present study was designed to elucidate the effects of DCF on the developing rat embryos during the major organogenesis period and investigate the critical role of apoptosis in bringing about these congenital anomalies. Embryos were exposed in vitro to various concentrations of DCF, that is, 0, 3.75, 7.5 and 15 ug/ml for 24 h, respectively, and examined for the growth and differentiation at the end of the culture period for the presence of any specific malformations. Growth and developmental parameters such as weight of embryos, crown-rump length and number of somites were found to be lower in the embryos exposed to high concentrations of DCF (7.5 and 15.0 MUg/ml) when compared with the untreated control. However, no significant difference in growth parameters was found between embryos exposed to 3.75 ug/ml and the control group. In parallel to this, flow cytometric analysis and DNA quantitation of cultured rat embryos were performed to verify the involvement of apoptosis in mediating DCF-induced teratogenesis. A concentration-dependent increase in apoptosis in embryos suggests a possible engagement of apoptosis in the role of DCF as a teratogenic agent. A detailed analysis of the actual effect of DCF on cellular apoptotic machinery necessitates further evaluation. PMID- 23456813 TI - The hazardous effects of three natural food dyes on developmental stages and longevity of Drosophila melanogaster. AB - Nowadays, food dyes obtained from herbal, animal, microbial and mineral sources are widely used as food additives. In this study, the toxic effects of three different natural food dyes (carmine, turmeric and annatto) on 72 +/- 4 h larvae of Oregon-R wild type of Drosophila melanogaster were investigated. For this purpose, four different application doses (50, 75, 100, 125 mg mL(-1)) were chosen by means of preliminary studies. It was determined that larval mortality increased with increasing concentration in the application groups and the toxicity order was carmine > turmeric > annatto. It was observed that the survival rate was highest in the control with 98% and lowest in 125 mg mL(-1) carmine with 16%. In addition, the average lifespan of the adult individuals obtained from third instar larvae was also studied. While the average lifespan was 40.88 +/- 1.44 days in the control group, these values were 10.81 +/- 0.55 23.90 +/- 1.27 days in the carmine group, 15.00 +/- 0.80-22.42 +/- 1.43 days in the turmeric group and 10.33 +/- 1.03-35.68 +/- 1.54 days in the annatto group, respectively. According to the obtained results, when both the developmental period from larvae into adults and the lifespan of the developing adults were compared with the control group, the food dyes were found to be toxic and the toxicity order of carmine > turmeric > annatto was identified. PMID- 23456814 TI - Effects of Urtica dioica on oxidative stress, proliferation and apoptosis after partial hepatectomy in rats. AB - The present study was performed to investigate the effect of Urtica dioica (UD) on liver regeneration after partial hepatectomy (PH) in rats. A total of 24 male Sprague Dawley rats were divided into three groups: sham-operated, PH and PH + UD; each group contains eight animals. The rats in UD-treated groups were given UD oils (2 ml/kg/day) once a day orally for 7 days starting 3 days prior to hepatectomy operation. At day 7 after resection, liver samples were collected. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were estimated in liver homogenates. Moreover, histopathological examination, mitotic index (MI), proliferating cell nuclear antigen labeling, proliferation index (PI), transferase-mediated deoxyuridine triphosphate nick end labeling assay, apoptotic index (AI) were evaluated at day 7 after hepatectomy. As a result, UD significantly increased MI and PI, significantly decreased AI and also attenuated hepatic vacuolar degeneration and sinusoidal congestion in PH rats. UD treatment significantly decreased the elevated tissue MDA level and increased the reduced SOD activity and GSH level in the tissues. These results suggest that UD pretreatment was beneficial for rat liver regeneration after partial hepatectomy. PMID- 23456815 TI - Genotoxic, antigenotoxic and antioxidant properties of methanol extracts obtained from Peltigera horizontalis and Peltigera praetextata. AB - Now-a-days, there is a big need to reduce genotoxic effects of mutagenic and carcinogenic agents in environment, which are increased by the technological development. Lichens produce a wide variety of unique metabolites due to being in various extreme areas and being symbiotic organisms of fungi and algae. Therefore, this study was planned to search new sources having antimutagenic activity by researching two different lichen species and to determine whether their usage is safe. With this respect, the mutagenic and antimutagenic properties of methanol extracts of the lichens were determined by the bacterial reverse mutation and sister chromatid exchange assays. Furthermore, the malondialdehyde level, superoxide dismutase, glutathione and glutathione peroxidase activities against aflatoxin B1 were determined for understanding the ways in which the lichens showed their genotoxic properties. PMID- 23456816 TI - A novel model approach for esophageal burns in rats: A comparison of three methods. AB - BACKGROUND: Corrosive esophageal injury causes serious clinical problems. We aimed to create a new experimental esophageal burn model using a single catheter without a surgical procedure. MATERIALS AND METHODS: We conducted the study with two groups of 12 male rats that fasted for 12 h before application. A modified Foley balloon catheter was inserted into the esophageal lumen. The control group was given 0.9% sodium chloride, while the experimental group was given 37.5% sodium hydroxide with the other part of the catheter. After 60s, esophagus was washed with distilled water. The killed rats were examined using histopathological methods after 28 days. RESULTS: In comparison with the histopathological changes experienced by the study groups, the control groups were observed to have no pathological changes. Basal cell degeneration, dermal edema, and a slight increase in the keratin layer and collagen density of submucosa due to stenosis were all observed in the group subjected to esophageal corrosion. CONCLUSION: A new burn model can thus, we believe, be created without the involvement of invasive laparoscopic surgery and general anesthesia. The burn in our experiment was formed in both the distal and proximal esophagus, as in other models; it can also be formed optionally in the entire esophagus. PMID- 23456817 TI - Epidemiologic data of adult native biopsy-proven renal diseases in Croatia. AB - PURPOSE: There is a paucity of epidemiological data on biopsy-proven renal disease in Croatia. The purpose of this report is a review of clinical and histological data, over a period of 15 years, from the single biggest adult native renal biopsy center in Croatia. METHODS: This report includes data from 922 adult native renal biopsies in patients referred from the whole country and performed in our center from 1996 till February 2012. Data on age, gender, serum creatinine, urine sediment, 24-h proteinuria, clinical syndrome and histological diagnosis were collected and analyzed retrospectively. In all patients, light, immunofluorescence and electron microscopic analysis was performed. RESULTS: The median age of the patients was 48 years (interquartile range 36-59 years), and the majority of patients were men (57.8 %). The most common indication for renal biopsy was nephrotic syndrome (40.3 %) followed by asymptomatic urinary abnormalities (31.7 %). The most common biopsy-proven renal disease in total was IgA glomerulonephritis (19.3 %), followed by focal segmental glomerulosclerosis (FSGS) (15.8 %) and membranous glomerulonephritis (9.2 %). In men, similar results were found, while in women, the most common were hereditary nephritis (13.4 %), FSGS (12.9 %) and connective tissue disease-related glomerular disorders (11.6 %). CONCLUSION: The presented data are an important contribution to the better understanding of the epidemiology of biopsy-proven renal disease in Croatia and Europe throughout comparison with other registry data. This data should be the basis for the formation of Croatian Registry of Renal Biopsies. PMID- 23456819 TI - Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK-dependent pathways. AB - TMEM67 mutations are associated with severe autosomal recessive polycystic kidney disease (ARPKD) in both humans and animals. However, the molecular mechanisms underlying the pathogenesis of PKD caused by TMEM67 mutations remain to be determined. We have investigated the possible signalling pathways involved in the pathogenesis of PKD. Overexpression of TMEM67 in human embryonic kidney (HEK293) cells triggered the activation of overall tyrosine phosphorylated proteins, extracellular signal-regulated kinase (ERK) and c-jun N-terminal KINASE (JNK). Activation was suppressed by pharmacological inhibitors of ERK or JNK. Activation of the mammalian target of rapamycin (mTOR) or p70s kinase (S6K) did not occur, although elevated phosphorylation of eIF4E-binding protein 1 (4E-BP1), a target of S6K, was seen. In animal studies, activation of a variety of signalling molecules was linked to ERK, JNK and 4E-BP1. Significant induction of phosphorylation of tyrosine phosphorylated proteins, ERK and 4E-BP1, at different postnatal ages was detected in mutant kidneys of B6C3Fe a/a-bpck mice, a cystic renal disease mouse model caused by TMEM67 loss of function mutation. Based on these in vitro and in vivo observations, we propose that TMEM67 mutations cause PKD through ERK- and JNK-dependent signalling pathways, which may provide novel insight into the therapy of polycystic kidney diseases. PMID- 23456818 TI - Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. AB - BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes. PMID- 23456820 TI - A mass weighted chemical elastic network model elucidates closed form domain motions in proteins. AB - An elastic network model (ENM), usually Calpha coarse-grained one, has been widely used to study protein dynamics as an alternative to classical molecular dynamics simulation. This simple approach dramatically saves the computational cost, but sometimes fails to describe a feasible conformational change due to unrealistically excessive spring connections. To overcome this limitation, we propose a mass-weighted chemical elastic network model (MWCENM) in which the total mass of each residue is assumed to be concentrated on the representative alpha carbon atom and various stiffness values are precisely assigned according to the types of chemical interactions. We test MWCENM on several well-known proteins of which both closed and open conformations are available as well as three alpha-helix rich proteins. Their normal mode analysis reveals that MWCENM not only generates more plausible conformational changes, especially for closed forms of proteins, but also preserves protein secondary structures thus distinguishing MWCENM from traditional ENMs. In addition, MWCENM also reduces computational burden by using a more sparse stiffness matrix. PMID- 23456821 TI - In vitro ischemia suppresses hypoxic induction of hypoxia-inducible factor-1alpha by inhibition of synthesis and not enhanced degradation. AB - Hypoxia-inducible factor (HIF) mediates a broad, conserved adaptive response to hypoxia, and the HIF pathway is a potential therapeutic target in cerebral ischemia. This study investigated the mechanism by which in vitro ischemia (oxygen-glucose deprivation; OGD) affects canonical hypoxic HIF-1alpha stabilization. We validated the use of a reporter containing the oxygen-dependent degradation domain of HIF-1alpha fused to firefly luciferase (ODD-luc) to monitor quantitatively distinct biochemical events leading to hypoxic HIF-1alpha expression or stabilization in a human neuroblastoma cell line (SH-SY5Y). When OGD was imposed following a 2-hr hypoxic stabilization of ODD-luc, the levels of the reporter were reduced, consistent with prior models proposing that OGD enhances HIF prolylhydroxylase (PHD) activity. Surprisingly, PHD inhibitors and proteasome inhibitors do not stabilize ODD-luc in OGD. Furthermore, OGD does not affect the half-life of ODD-luc protein following hypoxia, suggesting that OGD abrogates hypoxic HIF-1alpha induction by reducing HIF-1alpha synthesis rather than by enhancing its degradation. We observed ATP depletion under OGD vs. hypoxia and propose that ATP depletion enhances translational suppression, overcoming the selective synthesis of HIF concurrent with global decreases in protein synthesis in hypoxia. Taken together, these findings biochemically characterize a practical reporter for monitoring HIF-1alpha levels and support a novel model for HIF regulation in an in vitro model of human ischemia. PMID- 23456823 TI - Glycans-by-design: engineering bacteria for the biosynthesis of complex glycans and glycoconjugates. AB - There is an urgent need for new tools that enable better understanding of the structure, recognition, metabolism, and biosynthesis of glycans as well as the production of biologically important glycans and glycoconjugates. With the discovery of glycoprotein synthesis in bacteria and functional transfer of glycosylation pathways between species, Escherichia coli cells have become a tractable host for both understanding glycosylation and the underlying glycan code of living cells as well as for expressing glycoprotein therapeutics and vaccines. Here, we review recent efforts to harness natural biological pathways and engineer synthetic designer pathways in bacteria for making complex glycans and conjugating these to lipids and proteins. The result of these efforts has been a veritable transformation of bacteria into living factories for scalable, bottom-up production of complex glycoconjugates by design. PMID- 23456822 TI - C-reactive protein, bone strength, and nine-year fracture risk: data from the Study of Women's Health Across the Nation (SWAN). AB - Higher levels of C-reactive protein (CRP), an inflammatory marker, are associated with increased fracture risk, although previous studies on CRP and bone mineral density (BMD) have yielded conflicting results. We aimed to test the hypotheses that composite indices of femoral neck strength relative to load, which are inversely associated with fracture risk, would also be inversely associated with CRP, and would explain part of the association between CRP and fracture risk. We analyzed data from a multisite, multiethnic prospective cohort of 1872 community dwelling women, premenopausal or early perimenopausal at baseline. Femoral neck composite strength indices in three failure modes were calculated using dual energy X-ray absorptiometry (DXA)-derived femoral neck width (FNW), femoral neck axis length (FNAL), femoral neck BMD and body size at baseline, as BMD*FNW/weight for compression strength, BMD*(FNW)(2) /(FNAL*weight) for bending strength, and BMD*FNW*FNAL/(height*weight) for impact strength. Incident nondigital, noncraniofacial fractures were ascertained annually over a median follow-up of 9 years. In analyses adjusted for age, race/ethnicity, diabetes, menopause transition stage, body mass index, smoking, alcohol use, physical activity, medications, prior fracture, and study site, CRP was associated inversely with each composite strength index (0.035-0.041 SD decrement per doubling of CRP, all p < 0.001), but not associated with femoral neck or lumbar spine BMD. During the follow-up, 194 women (10.4%) had fractures. In Cox proportional hazards analyses, fracture hazard increased linearly with loge (CRP), only for CRP levels >= 3 mg/L. Addition of femoral neck or lumbar spine BMD to the model did not attenuate the CRP-fracture association. However, addition of any of the composite strength indices attenuated the CRP-fracture association and made it statistically nonsignificant. We conclude that fracture risk increases with increasing CRP, only above the threshold of 3 mg/L. Unlike BMD, composite strength indices are inversely related to CRP levels, and partially explain the increased fracture risk associated with inflammation. PMID- 23456824 TI - Losartan affects glomerular AKT and mTOR phosphorylation in an experimental model of type 1 diabetic nephropathy. AB - The AKT-mTOR pathway is activated in diabetic nephropathy. Renin-angiotensin system modulators exert beneficial effects on the diabetic kidney. We explored the action of losartan on AKT-mTOR phosphorylation in glomeruli and podocytes. Diabetes mellitus was induced to Sprague-Dawley rats by streptozotocin. Five months later, the rats were commenced on losartan and euthanized 2 months later. Kidneys were processed for immunofluorescence studies. Glomeruli were isolated for Western blot analysis. Diabetes increased activated forms of AKT and mTOR both in glomeruli and podocytes. In diabetic rats, losartan decreased phosphorylated/activated forms of AKT (Thr308) and mTOR (Ser2448) in glomeruli but decreased only activated mTOR in podocytes. However, in both glomeruli and podocytes of healthy animals, an inverse pattern was evident. In conclusion, a new body of evidence indicates the differential activation of AKT-mTOR in glomeruli and podocytes of healthy and diabetic animals in response to losartan. PMID- 23456825 TI - Quantitative histological assessment of xenobiotic-induced liver enzyme induction and pituitary-thyroid axis stimulation in rats using whole-slide automated image analysis. AB - Preclinical evaluation of a new compound, RO2910, identified a hypertrophic response in liver, thyroid gland, and pituitary gland (pars distalis). We aimed to develop and validate automated image analysis methods to quantify and refine the interpretation of semi-quantitative histology. Wistar-Han rats were administered RO2910 for 14 days. Liver, thyroid, and pituitary gland tissues were processed for routine histology and immunolabeled with anti-thyroid stimulating hormone (TSH) antibody (pituitary) and anti-topoisomerase II antibody (thyroid). Glass slides were scanned, image analysis methods were developed and applied to whole-slide images, and numerical results were compared with histopathology, circulating hormone levels, and liver enzyme mRNA expression for validation. Quantitative analysis of slides had strong individual correlation with semi quantitative histological evaluation of all tissues studied. Hepatocellular hypertrophy quantification also correlated strongly with liver enzyme mRNA expression. In the pars distalis, measurement of TSH weak-staining areas correlated with both hypertrophy scores and circulating TSH levels. Whole-slide image analysis enabled automated quantification of semi-quantitative histopathology findings and a more refined interpretation of these data. The analysis also enabled a direct correlation with non-histological parameters using straightforward statistical analysis to provide a more refined dose- and sex response relationship and integration among affected parameters. These findings demonstrate the utility of our image analysis to support preclinical safety evaluations. PMID- 23456826 TI - Rho kinase pathway is likely responsible for the profibrotic actions of aldosterone in renal epithelial cells via inducing epithelial-mesenchymal transition and extracellular matrix excretion. AB - It has been demonstrated that aldosterone (ALD) plays a direct profibrotic role in the kidney but the underlying mechanism remains unclear. We examined the role of Rho kinase signal pathway in epithelial-mesenchymal transition (EMT) process and extracellular matirx (ECM) synthesis induced by ALD in human renal proximal tubular epithelial (HK-2) cells in vitro. Rho kinase and collagen I, III protein expressions were detected by ELISA. E-cadherin, alpha-smooth muscle actin (SMA), collagen_I and collagen III mRNA expressions were detected by real time PCR. E cadherin, and alpha-SMA protein expressions were measured by Western blot. Our results showed that ALD could significantly activate the Rho kinase in HK-2 cells, while in the presence of mineralocorticoid receptor (MR) antagonist eplerenone and Rho kinase inhibitor Y27632, the Rho kinase protein expression were almost completely prevented. Exposure of HK-2 cells to ALD for 48 h induced EMT as evidenced by loss of E-cadherin, and de novo expression of alpha-SMA. The EMT was completely blocked by eplerenone and Y27632. Meanwhile, ALD could significantly increase the mRNA and protein expressions of collagen I, III in HK 2 cells when compared with the control group, while eplerenone and Y27632 could almost reverse these effects. These observations suggest that ALD can activate Rho kinase pathway and Rho kinase pathway is likely responsible for the profibrotic actions of ALD in renal proximal tubular epithelial cells via inducing EMT and ECM excretion. PMID- 23456828 TI - Granulocyte macrophage colony-stimulating factor promotes regeneration of retinal ganglion cells in vitro through a mammalian target of rapamycin-dependent mechanism. AB - Lack of regeneration in the adult central nervous system (CNS) is a major hurdle that limits recovery from neurological ailments. Although accumulating research suggests the possibility of axon regeneration by targeting intrinsic signaling mechanisms, it remains a matter of controversy whether functional recovery can be achieved by manipulating aspects of molecular signaling. Recent studies have shown that granulocyte macrophage colony-stimulating factor (GM-CSF) may be an effective means of targeting repair following CNS injury; how this molecule is able to produce this effect is not known. Indeed, GM-CSF has been shown to promote neuronal survival, potentially through activation of as yet unknown cytokine-dependent signals and potentially through regulation of antiapoptotic mechanisms. It is well established that the loss of intrinsic regenerative ability is highly correlated with development of CNS neurons. We therefore designed experiments, using a well-established in vitro retinal ganglion cell (RGC) culture system, to evaluate the effect of GM-CSF on axon growth and cell survival and define possible mechanisms involved in GM-CSF-mediated effects in vitro. Several developmental stages were evaluated, with particular focus placed on stages at which axon growth is known to be significantly diminished. Our results reveal that GM-CSF not only promotes axon growth in postnatal RGCs but also enhances cell survival through a mammalian target of rapamycin (mTOR) dependent mechanism. PMID- 23456827 TI - A novel norovirus recombinant strain GII.4/GII.21 in Bangladesh, 2011. AB - We identified a novel inter-genotype recombinant norovirus strain, Dhaka85/2011/BGD, collected from a stool specimen of a nine-month-old infant who was hospitalized with diarrhea. Molecular investigation and phylogenetic analysis classified its RNA polymerase gene as GII.4-like, which commonly circulates in humans. The capsid gene was classified as GII.21-like, most likely originated from water. The discovery of this novel strain is an illustration of the enormous diversity among the norovirus strains, especially in developing countries and has important implications for future vaccine strategies. PMID- 23456829 TI - Regadenoson and exercise myocardial perfusion imaging: the courtship continues. PMID- 23456831 TI - Description of a novel c.374 G>A mutation in Becker disease. PMID- 23456830 TI - Prognosis in patients with suspected or known ischemic heart disease and normal myocardial perfusion: long-term outcome and temporal risk variations. AB - BACKGROUND: The prognostic value of a normal myocardial perfusion scintigraphy (MPS) may be well described, but long-term follow-up data are sparse, and temporal variations in risk are insufficiently elucidated. METHODS AND RESULTS: During long-term follow-up (mean 6.2 years) of 1,327 consecutive Danish patients with normal MPS, the rate of all-cause death (ACD) was 1.9%/year (differing by gender) and of cardiac death (CD)/myocardial infarction (MI) 0.8%/year (differing by coronary artery disease, CAD). Female gender (HR: 0.60), age (HR: 1.07 per year increment), and known CAD without prior revascularization (HR: 2.17) were statistically significant factors for ACD, whereas diabetes and previous MI per se were not. Known CAD with previous revascularization carried a low risk of ACD when adjusted for gender and age (HR: 0.56). For CD/MI, risk increased with age and threefold with known CAD, previous MI, and previous percutaneous coronary intervention. Judged from smoothed hazard functions, mortality risk increased further with time for men, elderly, and diabetics and markedly further with known CAD without prior revascularization. CONCLUSIONS: Following a normal MPS, rates of death and hard cardiac events were low. Risk varied with age, gender, and disease history. Novel aspects of temporal risk variation suggested a general warranty period of 5 years, but less in risk groups. PMID- 23456832 TI - Vita-PAMPs: signatures of microbial viability. AB - Can the innate immune system detect and respond to microbial viability? Using bacteria as a model, we found that indeed the very essence of microbial infectivity, viability itself, can be detected, and notably, in the absence of the activity of virulence factors. The microbial molecule that serves as the signature of viability is bacterial messenger RNA (mRNA), common to all bacteria, and without which bacteria cannot survive. Prokaryotic mRNAs also differ from eukaryotic mRNAs in several ways, and as such, these features all fulfill the criteria, and more, for a pathogen-associated molecular pattern (PAMP) as originally proposed by Charles Janeway. Because these mRNAs are lost from dead bacteria, they belong to a special class of PAMPs, which we call vita-PAMPs. Here we discuss the possible receptors and pathways involved in the detection of bacterial mRNAs, and thus microbial viability. We also consider examples of vita PAMPs other than bacterial mRNA. PMID- 23456833 TI - Innate lymphoid cells in immunity and disease. AB - The family of innate lymphoid cells (ILCs) comprises of natural killer (NK) cells, Rorgammat-dependent ILCs (lymphoid tissue inducer (LTi) cells, ILC22, and ILC17), and type 2 ILCs. Apart from a common requirement for inhibitor of DNA binding 2 (Id2) expression and common gamma-chain (gammac) signaling, the differentiation of ILC populations is regulated by distinct transcription factors. ILCs play fundamental roles in processes such as cytotoxicity, lymphoid organogenesis, intestinal homeostasis, immunity against infections, and wound healing. However, the dysregulation of ILCs has been implicated in autoimmune and inflammatory diseases. Here, we will review the recent advances in ILC development and their roles in immunity and disease, with a primary focus on type 2 ILCs. PMID- 23456834 TI - Tuning cross-presentation of apoptotic T cells in immunopathology. AB - Cross-presentation of several long-lived antigens associated with apoptotic T cells requires caspase-dependent cleavage to efficiently deliver antigenic fragments to the processing machinery of antigen-presenting cells. The resulting emergence of a large population of autoreactive CD8(+) T effector cells specific for apoptotic T cell-associated self-epitopes plays a key role in improving immunopathology in several infections and autoimmune diseases. Importantly, they endow mixed polyfunctional type-1, type-2, and type-17 responses and correlate with the chronic progression of various pathological conditions. This evolution is related to the selection of autoreactive CD8(+) T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients undergoing disease resolution. The development of mixed responses with divergent differentiation requirements is consistent with distinct sites or kinetics of CD8(+) T cell priming in vivo. Therefore, we propose a strict link among cross-presentation of apoptotic T cells, the generation of high frequencies of mixed autoreactive CD8(+) T cells producing a broad array of cytokines (IFN gamma, IL-17, IL-4, IL-2, etc.), and the progression towards chronic inflammatory diseases. PMID- 23456835 TI - Regulation of type 2 immunity by basophils. AB - The immune response against helminths and allergens is generally characterized by high levels of IgE and increased numbers of Th2 cells, eosinophils, and basophils. Basophils represent a relatively rare population of effector cells and their in vivo functions are incompletely understood. Recent studies with basophil depleting antibodies revealed that these cells might play an important role during the early and late stages of type 2 immune responses. To further characterize the relevance of basophils for protective immunity and orchestration of allergic inflammation, we generated constitutively basophil-deficient mice. We observed a normal Th2 response induced by helminth infections or immunization with alum/OVA or papain/OVA. However, basophils contributed to worm expulsion during secondary helminth infection and mediated an IgE-dependent inflammatory response of the skin. These results argue against a critical role of basophils as antigen-presenting cells for induction of Th2 polarization and highlight their effector cell potential during later stages of a type 2 immune response. PMID- 23456836 TI - Crosstalk between adaptive and innate immune cells leads to high quality immune protection at the mucosal borders. AB - Mucosal effector memory CD8 T cells are located at the epithelium and have a heightened and immediate effector function. By contrast, central memory T cells reside within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of effector memory T cells at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of memory cell subsets are poorly understood. We recently showed that CD8alphaalpha, induced selectively on the most highly activated primary CD8alphabeta T cells, together with its ligand, the thymic leukemia (TL) antigen, induced on mucosal antigen presenting cells and constitutively expressed on intestinal epithelial cells (IEC), serve as key components to mediate the selective accumulation of the fittest effector cells to form mucosal effector memory T cells. Therefore, the generation of mucosal effector memory is controlled by an innate-adaptive crosstalk that provides for host defense at the body's largest interface. PMID- 23456837 TI - The interaction between filarial parasites and human monocyte/macrophage populations. AB - Lymphatic filariasis is a mafor tropical disease affecting approximately 120 million people worldwide. Patent infection, by and large, is clinically asymptomatic but is associated with the inability of T cells to proliferate or produce IFN-gamma in response to parasite antigen. Monocyte dysfunction is one hypothesis felt to explain the lack of an antigen-specific T cell response. In fact, monocytes from filaria-infected individuals have been shown to be studded with internalized filarial antigens. Understanding how the phenotype and the function of these monocytes are altered through the internalization of these parasite antigens is one of the areas our laboratory has focused on. In fact, the existence and/or function of alternatively activated macrophages in murine models of filarial infections have been extensively studied. Whether this population of macrophages can be induced in human filarial infections is the main focus of this review. PMID- 23456838 TI - Innate-like B cells and their rules of engagement. AB - Antibodies are an integral part of the immune system. They are produced in response to an infection or insult but are also present prior to any encounter with antigen as so-called natural antibodies. This review focuses on the tissues and cellular origins of natural antibodies. It summarizes recent data showing that B-1 cells, an innate-like B cell population distinct in development, repertoire, and tissue location from the majority conventional or B-2 cells, are the main contributors of natural antibodies in mice in steady state. Furthermore, they show that natural IgM production appears largely confined to B-1 cell populations in the spleen and bone marrow. In contrast, B-1 cells in the body cavities, sites of predominance of this population, harbor B-1 cells that do not constitutively produce antibodies. Instead, these cells act as rapid immune responders that relocate to secondary lymphoid tissues and differentiate to cytokine and antibody-secreting cells shortly after an infection. Thus, the process of B-1 cell response participation is distinct from that of B-2 cell activation as the accumulation of effector B-1 cells does not rely on extensive clonal expansion, but instead on their rapid migration and redistribution, a process that appears under the control of infection-induced innate signals. PMID- 23456839 TI - The CD28/B7 pathway: a novel regulator of plasma cell function. AB - The CD28/B7 pathway is pivotal for the activation, optimal function, and regulation of T cell function. While the CD28 receptor and its ligands B7.1/B7.2 are also expressed on plasma cells, little is known of the role of the CD28/B7 pathway in plasma cell function. In this chapter we discuss the recent studies that have examined the role of CD28 expression on plasma cell function. Both stimulatory and inhibitory effects of CD28 on plasma cells have been reported. Based on our findings we propose that under homeostatic conditions the CD28/B7 interaction mediates regulation of plasma cell function whereas during inflammation this pathway can be perturbed to ramp up Ab production from existing plasma cells. PMID- 23456840 TI - Memory CD8+ T cell protection. AB - Memory CD8+ T cells play an essential role in controlling pathogenic infections. Therefore generating protective memory CD8+ T cells by vaccination is an attractive strategy for preventing and treating a variety of human diseases. Understanding what comprises a protective memory CD8+ T cell response will help optimize vaccine-induced CD8+ T cell immunity. Here we discuss essential antiviral effector functions and highlight how recall expansion of memory CD8+ T cells may affect the primary response. PMID- 23456841 TI - Human T follicular helper cells: development and subsets. AB - Antibody response constitutes one of the key immune protection mechanisms. T follicular helper (Tfh) cells represent the major CD4+ T cell subset that provides help to B cells to induce antibody response. How Tfh cells develop and how Tfh cells or their associated subsets regulate antibody response in humans remains largely unknown. In this review, we will summarize the recent discoveries on the biology of Tfh cells, with a particular focus on human Tfh cells. PMID- 23456842 TI - Differentiation and activation of gammadelta T Lymphocytes: Focus on CD27 and CD28 costimulatory receptors. AB - gammadelta T lymphocytes are major providers of the pro-inflammatory cytokines interferon-gamma (IFN-gamma) and interleukin-17 (IL-17) at early stages of (auto)immune responses. We and others have recently described the phenotype and differentiation requirements of two distinct murine gammadelta T cell subsets producing either IFN-gamma or IL-17. Here we summarize our current understanding of the molecular mechanisms that control gammadelta T cell differentiation, which is programmed in the thymus, and peripheral activation upon infection. We focus on the costimulatory receptors CD27 and CD28, which play independent and non redundant roles in the physiology of gammadelta T cells in mice and in humans. PMID- 23456843 TI - Decisions on the road to memory. AB - A fundamental property of the adaptive immune system is the ability to generate antigen-specific memory, which protects against repeated infections with the same pathogens and determines the success of vaccination. Immune memory is built up alongside a response providing direct protection during the course of a primary immune response. For CD8 T cells, this involves the generation of two distinct types of effector cells. Short lived effector cells (SLECs) confer immediate protection, but contribute little to the memory repertoire. Memory precursor effector cells (MPECs) have the ability to respond to survival signals and develop into memory cells. These two types of cells can be distinguished on the basis of surface markers and express distinct genetic programs. A single naive CD8 T cell can give rise to both MPEC and SLEC daughter cells. This may involve an initial asymmetric division or depend on later instructive signals acting on equipotent daughter cells. Strong inflammatory signals favor the generation of SLECs and weaker inflammation favors the generation of MPECs. A distinguishing feature of MPECs is their ability to persist when most effector cells die. This survival depends on signals from the IL-7 receptor, which induce expression of anti-apoptotic factors. MPECs are therefore characterized by expression of the IL 7 receptor as well as the CCR7 chemokine receptor, which allows homing to areas in lymphoid organs where IL-7 is produced. Critical for persistence of MPECs is further their responsiveness to myeloid cell derived IL-15, which instructs these cells to switch their metabolic programs from glycolysis associated with rapid proliferation to fatty acid oxidation required during a more resting state. As the mechanisms determining generation of immunological memory are unraveled, opportunities will emerge for the improvement of vaccination strategies. PMID- 23456844 TI - Targeting the skin for microneedle delivery of influenza vaccine. AB - Influenza infection represents a major socioeconomic burden worldwide. Skin represents a new target that has gained much attention in recent years for delivery of influenza vaccine as an alternative to the conventional intramuscular route of immunization. In this review we describe different microneedle vaccination approaches used in vivo, including metal and dissolving microneedle patches that have demonstrated promising results. Additionally we analyze the immunological basis for microneedle skin immunization and targeting of the skin's dense population of antigen presenting cells, their role, characterization, and function. Additionally we analyze the importance of inflammatory signaling in the skin after microneedle delivery. PMID- 23456845 TI - Cloning, expression, and evolutionary analysis of alpha-gliadin genes from Triticum and Aegilops genomes. AB - Fifteen novel alpha-gliadin genes were cloned and sequenced from Triticum and related Aegilops genomes by allele-specific polymerase chain reaction (AS-PCR). Sequence comparison displayed high diversities in the alpha-gliadin gene family. Four toxic epitopes and glutamine residues in the two polyglutamine domains facilitated these alpha-gliadins to be assigned to specific chromosomes. Five representative alpha-gliadin genes were successfully expressed in Escherichia coli, and their amount reached a maximum after 4 h induced by isopropyl-beta-D thiogalactoside (IPTG), indicating a high level of expression under the control of T7 promoter. The transcriptional expression of alpha-gliadin genes during grain development detected by quantitative real-time polymerase chain reaction (qRT-PCR) showed a similar up-down regulation pattern in different genotypes. A neighbor-joining tree constructed with both full-open reading frame (ORF) alpha gliadin genes and pseudogenes further revealed the origin and phylogenetic relationships among Triticum and related Aegilops genomes. The evolutionary analysis demonstrated that alpha-gliadin genes evolved mainly by synonymous substitutions under strong purifying selection during the evolutionary process. PMID- 23456846 TI - MicroRNAs-1614-3p gene seed region polymorphisms and association analysis with chicken production traits. AB - In the present study, a total of 860 chickens from a Gushi-Anka F2 resource population were used to evaluate the genetic effect of the gga-miR-1614-3p gene. A novel, silent, single nucleotide polymorphism (SNP, +5 C>T) was detected in the gga-miR-1614-3p gene seed region through AvaII polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and PCR products sequencing methods. Associations between the SNP and chicken growth, meat quality and carcass traits were performed by association analysis. The results showed that the SNP was significantly associated with breast muscle shear force and leg muscle water loss rate, wing weight, liver weight and heart weight (p<0.05), and highly significantly associated with the weight of the abdominal fat (p<0.01). The secondary structure of gga-miR-1614 and the free energy were altered due to the variation predicted by the M-fold program. PMID- 23456847 TI - First evidence of autotriploidization in sterlet (Acipenser ruthenus). AB - Polyploidization has played an important role in vertebrate evolution. Acipenseridae bring clear examples of polyploidy ancestry and, also, polyploidization seems to be an ongoing process in these fishes. In the present study, the genetic origin of six triploid specimens morphologically determined as Acipenser ruthenus from commercial aquaculture was analyzed using a combination of mitochondrial and nuclear markers. A further five successive statistical analyses including median joining of mitochondrial DNA control region sequences, principal coordinate analysis (PCA), factorial correspondence analysis (FCA), STRUCTURE assignation, and NewHybrids status determination for microsatellite data were applied for the clarification of the origin of one extra chromosome set added in these triploids genomes. Although interspecific hybridization had been suggested as a source of these triploids, the statistical analyses showed that the investigated triploids originate from autotriploidization rather than from interspecific hybridization. Therefore, we conclude that a combination of molecular markers with suitable statistical analyses should be used to verify the origin of unusual ploidy level. Evidently, such an approach is critically essential in aquaculture, where interspecific hybridization is very common and usually detected by changes in ploidy levels only. PMID- 23456848 TI - Can we extend thrombolysis indications for acute ischaemic stroke? The IST-3 study. PMID- 23456849 TI - Prognostic impact of absolute lymphocyte counts at the end of remission induction in childhood acute lymphoblastic leukemia. AB - BACKGROUND: Absolute lymphocyte counts (ALC) during treatment have been associated with outcome in children and adults with hematologic malignancies. However, the impact of ALC relative to that of other prognostic factors on the outcome of children with acute lymphoblastic leukemia (ALL) treated in recent trials is unknown. METHODS: Outcomes of 399 patients aged <=18 years with newly diagnosed ALL who were enrolled in the Total Therapy XV study at St. Jude Children's Research Hospital were analyzed according to ALC at the end of remission induction therapy. RESULTS: An ALC >=500 cells/MUL was significantly more prevalent among patients with B-lineage ALL, in those with favorable presenting features, and in those who achieved negative minimal residual disease (MRD) status on day 43 of treatment. Both overall survival (OS) and event-free survival (EFS) were superior among patients with higher ALC, but only the association with OS was statistically significant in a univariate analysis. In multivariable analyses, ALC was not a significant predictor of outcome after controlling for age, leukocyte count, lineage, risk group, and MRD status at the end of induction (P > .1 for all comparisons). However, among MRD-negative patients, those with low ALC had a 5-year OS rate of 84.2% +/- 8.9% versus 97.3% +/- 1.0% for patients with higher ALC (P = .036). CONCLUSIONS: ALC at the end of induction is related to favorable presenting features and good initial treatment response but does not independently predict outcome in the context of contemporary, MRD-guided therapy. PMID- 23456851 TI - Enhanced algal growth rate in a Taylor vortex reactor. AB - The rate of production of algal biomass in optically dense photobioreactors depends crucially on the temporal light exposure of microorganisms, which in turn is determined by fluid flow patterns and the quantity and spatial distribution of photosynthetically active radiation. In this report it is demonstrated that highly organized and robust toroidal flow structures known as Taylor vortices cause significant increases in the rate of biomass production, efficiency of light utilization, and CO2 uptake, and these effects become more pronounced at higher Reynolds numbers. In light of these findings and previously reported experiments using Taylor vortex flow to culture algae, it is argued that the flashing light effect, rather than mass transport effects, is responsible for the observed increases in the rate of photosynthesis. PMID- 23456850 TI - Rapid cortical bone loss in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) patients may have high rates of bone loss and fractures, but microarchitectural and biochemical mechanisms of bone loss in CKD patients have not been fully described. In this longitudinal study of 53 patients with CKD Stages 2 to 5D, we used dual-energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT), and biochemical markers of bone metabolism to elucidate effects of CKD on the skeleton. Median follow-up was 1.5 years (range 0.9 to 4.3 years); bone changes were annualized and compared with baseline. By DXA, there were significant declines in areal bone mineral density (BMD) of the total hip and ultradistal radius: -1.3% (95% confidence interval [CI] -2.1 to -0.6) and -2.4% (95% CI -4.0 to -0.9), respectively. By HRpQCT at the distal radius, there were significant declines in cortical area, density, and thickness and increases in porosity: -2.9% (95% CI 3.7 to -2.2), -1.3% (95% CI -1.6 to -0.6), -2.8% (95% CI -3.6 to -1.9), and +4.2% (95% CI 2.0 to 6.4), respectively. Radius trabecular area increased significantly: +0.4% (95% CI 0.2 to 0.6), without significant changes in trabecular density or microarchitecture. Elevated time-averaged levels of parathyroid hormone (PTH) and bone turnover markers predicted cortical deterioration. Higher levels of serum 25-hydroxyvitamin D predicted decreases in trabecular network heterogeneity. These data suggest that significant cortical loss occurs with CKD, which is mediated by hyperparathyroidism and elevated turnover. Future investigations are required to determine whether these cortical losses can be attenuated by treatments that reduce PTH levels and remodeling rates. PMID- 23456852 TI - Valvular heart disease in antiphospholipid syndrome. AB - Heart valve disease (HVD) is the most frequent cardiac manifestation in patients with antiphospholipid syndrome (APS), with prevalence of 30 %. The definition is based on the presence of thickening or vegetation of the valves (mainly mitral and aortic) as described by Libman and Sacks for patients with systemic lupus erythematosus (SLE). Transthoracic and/or transoesophageal echocardiography (TTE and TEE, respectively) enable early and accurate diagnosis and help avoid misdiagnosis as rheumatic valve disease. The presence of antiphospholipid antibodies (aPL) in SLE patients is associated with a threefold greater risk of HVD, confirming the crucial importance of these antibodies in the pathogenic process, leading to thrombotic manifestations on valves because of hypercoagulability. Natural history is characterized by worsening of HVD over time with an increased risk for stroke. APS patients undergoing valve-replacement surgery are at high risk of thrombotic and bleeding complications. Thus aPL associated HVD has affects clinical management of APS patients. PMID- 23456853 TI - Psychometric evaluation of the eating disorder examination adapted for children. AB - The Eating Disorder Examination adapted for children (ChEDE) is the child version of the semi-structured gold standard eating disorder interview for adults. This study was a comprehensive test statistic evaluation of the German ChEDE in a large sample of children and adolescents with anorexia nervosa, binge eating disorder, loss of control eating, overweight and obesity, as well as non-eating disordered and chronically ill control probands (n = 352). Excellent inter-rater reliability, adequate internal consistency and satisfactory stability of ChEDE indicators were demonstrated. ChEDE indicators discriminated between diverse forms of eating and weight disturbances and normative eating and were significantly correlated with conceptually related measures. Factorial validity was not convincing; a brief eight-item scale showed the best fit. Item statistics were mostly acceptable. Overall, the ChEDE's German translation reliably and validly assesses psychopathology across the eating and weight disorder spectrum and facilitates international comparison of eating disorder research. PMID- 23456854 TI - Oligomeric states of the Shigella translocator protein IpaB provide structural insights into formation of the type III secretion translocon. AB - The Shigella flexneri Type III secretion system (T3SS) senses contact with human intestinal cells and injects effector proteins that promote pathogen entry as the first step in causing life threatening bacillary dysentery (shigellosis). The Shigella Type III secretion apparatus (T3SA) consists of an anchoring basal body, an exposed needle, and a temporally assembled tip complex. Exposure to environmental small molecules recruits IpaB, the first hydrophobic translocator protein, to the maturing tip complex. IpaB then senses contact with a host cell membrane, forming the translocon pore through which effectors are delivered to the host cytoplasm. Within the bacterium, IpaB exists as a heterodimer with its chaperone IpgC; however, IpaB's structural state following secretion is unknown due to difficulties isolating stable protein. We have overcome this by coexpressing the IpaB/IpgC heterodimer and isolating IpaB by incubating the complex in mild detergents. Interestingly, preparation of IpaB with n-octyl-oligo oxyethylene (OPOE) results in the assembly of discrete oligomers while purification in N,N-dimethyldodecylamine N-oxide (LDAO) maintains IpaB as a monomer. In this study, we demonstrate that IpaB tetramers penetrate phospholipid membranes to allow a size-dependent release of small molecules, suggesting the formation of discrete pores. Monomeric IpaB also interacts with liposomes but fails to disrupt them. From these and additional findings, we propose that IpaB can exist as a tetramer having inherent flexibility, which allows it to cooperatively interact with and insert into host cell membranes. This event may then lay the foundation for formation of the Shigella T3SS translocon pore. PMID- 23456855 TI - Modeling the impact of the indigenous microbial population on the maximum population density of Salmonella on alfalfa. AB - Within a microbial risk assessment framework, modeling the maximum population density (MPD) of a pathogenic microorganism is important but often not considered. This paper describes a model predicting the MPD of Salmonella on alfalfa as a function of the initial contamination level, the total count of the indigenous microbial population, the maximum pathogen growth rate and the maximum population density of the indigenous microbial population. The model is parameterized by experimental data describing growth of Salmonella on sprouting alfalfa seeds at inoculum size, native microbial load and Pseudomonas fluorescens 2-79. The obtained model fits well to the experimental data, with standard errors less than ten percent of the fitted average values. The results show that the MPD of Salmonella is not only dictated by performance characteristics of Salmonella but depends on the characteristics of the indigenous microbial population like total number of cells and its growth rate. The model can improve the predictions of microbiological growth in quantitative microbial risk assessments. Using this model, the effects of preventive measures to reduce pathogenic load and a concurrent effect on the background population can be better evaluated. If competing microorganisms are more sensitive to a particular decontamination method, a pathogenic microorganism may grow faster and reach a higher level. More knowledge regarding the effect of the indigenous microbial population (size, diversity, composition) of food products on pathogen dynamics is needed in order to make adequate predictions of pathogen dynamics on various food products. PMID- 23456856 TI - Characters of compost teas from different sources and their suppressive effect on fungal phytopathogens. AB - Compost teas (CT) are fermented watery extracts of composted materials that are used to control plant diseases and on crop fertilization. In this work, aerated (ACT) and non-aerated compost teas (NCT) were obtained from four different composts: spent mushroom substrate compost, grape marc compost, greenhouse horticultural crop residues compost, and vermicompost. Physico-chemical and microbiological analysis were carried out to determine their properties. In vitro assays were performed to assess their suppressive effect on the mycelial growth of eight fungal phytopathogens. In vivo trials aimed to assess their effect on gummy stem blight (Didymella bryonae) and powdery mildew (Podosphaera fusca) in melon plants. Results showed that ACT and NCT filtrates inhibited the in vitro growth of all tested pathogens while autoclaved CT did not completely lose their inhibitory effect, and CT sterilized by microfiltration had no effect on the pathogen growth. The severity of powdery mildew was highly reduced by ACT and NCT from all sources, though in gummy stem blight assay only a delay in disease development was observed. In general, all compost teas showed a high level of microbial populations and nutrients. Results suggest that the efficacy of ACT and NCT firstly depend on the microbiota present in them. We consider compost teas from the four tested sources as a viable way to manage plant diseases and crop fertilization, throughout its integration in pest management programs and fertirrigation systems under different dilution rates. PMID- 23456857 TI - Screening of high alpha-arbutin producing strains and production of alpha-arbutin by fermentation. AB - A mutant Xanthomonas maltophilia BT-112 with high alpha-anomer-selective glycosylation activity was screened by a series of mutation methods including UV light, N-methyl-N-nitro-N-nitroso-guanidine treatment and quick neutron mutation. The alpha-arbutin titer increased 15-folds compared with the parent strain. The optimal conditions for culture medium and the operational conditions for lab scale fermenter were investigated. Under optimized conditions, the maximal hydroquinone (HQ) tolerance of cells and yield of alpha-arbutin were 120 mM and 30.6 g/l, respectively. The molar conversion yield of alpha-arbutin based on the amount of HQ supplied reached 93.6 %. The product was identified as alpha-arbutin by (13)C NMR and (1)H NMR analysis. In conclusion, the results in this work provide a one-step and cost-effective method for the large-scale production of alpha-arbutin. PMID- 23456859 TI - Erythropoietin and engineered innate repair activators. AB - Erythropoietin (EPO) is a pleiotropic type I cytokine that has been identified as a major endogenous tissue protective molecule. In response to injury, EPO and a distinct receptor are expressed with a characteristic temporal and spatial expression pattern. Together, these serve to limit injury and to initiate repair. Administration of EPO in the setting of injury has been shown to be beneficial in a multitude of preclinical models. However, translation into the clinic has been hampered by EPO's adverse effects, including promotion of thrombosis. Recently, engineered molecules based on EPO's structure-activity relationships have been developed that are devoid of hematopoietic effects. These compounds are promising candidates for treatment of a wide variety of acute and chronic diseases. PMID- 23456858 TI - Stability of puroindoline peptides and effects on wheat rust. AB - Peptides modelled on the tryptophan rich domain of puroindolines and the related grain softness protein-1 have a broad range of antibacterial and antifungal activities. With the aims of further investigating the activities of these antimicrobial peptides we studied their activity against wheat rust diseases and environmental stability. PINA-based peptides were found to have high pH and thermal stability in addition to being stable over long periods at room temperature. These properties could make them excellent candidates as preservatives in food. PuroA, Pina-R39G and PuroB peptides adversely affected the morphology of the stripe rust spores (Puccinia striiformis f. sp. tritici), while PuroA and PuroB showed moderate inhibition of their germination. Additionally, GSP-5D reduced the germination of leaf rust spores (P. triticina). PuroA and PuroB sprayed onto stripe rust infected plants effected a moderate reduction in the number of stripe rust uredinia on wheat seedlings, as did PuroB sprayed onto the seedlings and allowed to coat the leaves for 5 day prior to spore infection. The results suggest that the presence of the PIN-based peptides may lower frequency of initial infection foci. PMID- 23456860 TI - Epo and non-hematopoietic cells: what do we know? AB - The hematopoietic growth factor erythropoietin (Epo) circulates in plasma and controls the oxygen carrying capacity of the blood (Fisher. Exp Biol Med (Maywood) 228:1-14, 2003). Epo is produced primarily in the adult kidney and fetal liver and was originally believed to play a role restricted to stimulation of early erythroid precursor proliferation, inhibition of apoptosis, and differentiation of the erythroid lineage. Early studies showed that mice with targeted deletion of Epo or the Epo receptor (EpoR) show impaired erythropoiesis, lack mature erythrocytes, and die in utero around embryonic day 13.5 (Wu et al. Cell 83:59-67, 1995; Lin et al. Genes Dev. 10:154-164, 1996). These animals also exhibited heart defects, abnormal vascular development as well as increased apoptosis in the brain suggesting additional functions for Epo signaling in normal development of the central nervous system and heart. Now, in addition to its well-known role in erythropoiesis, a diverse array of cells have been identified that produce Epo and/or express the Epo-R including endothelial cells, smooth muscle cells, and cells of the central nervous system (Masuda et al. J Biol Chem. 269:19488-19493, 1994; Marti et al. Eur J Neurosci. 8:666-676, 1996; Bernaudin et al. J Cereb Blood Flow Metab. 19:643-651, 1999; Li et al. Neurochem Res. 32:2132-2141, 2007). Endogenously produced Epo and/or expression of the EpoR gives rise to autocrine and paracrine signaling in different organs particularly during hypoxia, toxicity, and injury conditions. Epo has been shown to regulate a variety of cell functions such as calcium flux (Korbel et al. J Comp Physiol B. 174:121-128, 2004) neurotransmitter synthesis and cell survival (Velly et al. Pharmacol Ther. 128:445-459, 2010; Vogel et al. Blood. 102:2278-2284, 2003). Furthermore Epo has neurotrophic effects (Grimm et al. Nat Med. 8:718-724, 2002; Junk et al. Proc Natl Acad Sci U S A. 99:10659-10664, 2002), can induce an angiogenic phenotype in cultured endothelial cells and is a potent angiogenic factor in vivo (Ribatti et al. Eur J Clin Invest. 33:891-896, 2003) and might enhance ventilation in hypoxic conditions (Soliz et al. J Physiol. 568:559-571, 2005; Soliz et al. J Physiol. 583, 329-336, 2007). Thus multiple functions have been identified breathing new life and exciting possibilities into what is really an old growth factor.This review will address the function of Epo in non hematopoietic tissues with significant emphasis on the brain and heart. PMID- 23456861 TI - Tissue-protective cytokines: structure and evolution. AB - Cytokines are important mediators of host defense and immunity, and were first identified for their role in immunity to infections. It was then found that some of them are pathogenic mediators in inflammatory diseases and much of the emphasis is now on pro-inflammatory cytokines, also in consideration of the fact that TNF inhibitors became effective drugs in chronic inflammatory diseases. The recent studies on the tissue-protective activities of erythropoietin (EPO) led to the term "tissue-protective cytokine." We discuss here how tissue-protective actions might be common to other cytokines, particularly those of the 4-alpha helical structural superfamily. PMID- 23456862 TI - The regenerative activity of interleukin-6. AB - Interleukin-6 (IL-6) is a cytokine which is involved in many inflammatory processes and in the development of cancer. In addition, IL-6 has been shown to be important for the induction of hepatic acute-phase proteins, for the regeneration of the liver and for the stimulation of B-cells. IL-6 binds to a transmembrane IL-6 receptor (IL-6R), which is present on hepatocytes and some leukocytes. The complex of IL-6 and IL-6R associates with a second protein, gp130, which is expressed on all cells of the body. Since neither IL-6 nor IL-6R has a measurable affinity for gp130, cells, which do not express IL-6R, are not responsive to the cytokine IL-6. It could be shown, however, that a naturally occurring soluble IL-6R (sIL-6R) in complex with IL-6 can bind to gp130 on cells with no IL-6R expression. Therefore, cells shedding the sIL-6R render cells, which only express gp130, responsive to the cytokine. This process has been called trans-signaling. In the present chapter, we summarize the known activities of IL-6 with a special emphasis on regenerative activities, which often depend on the sIL-6R. A designer cytokine called Hyper-IL-6, which is a fusion protein of IL-6 and the sIL-6R, can mimic IL-6 trans-signaling responses in vitro and in vivo with considerably higher efficacy than the combination of the natural proteins IL-6 and sIL-6R. We present recent examples from animal models in which the therapeutic potential of Hyper-IL-6 has been evaluated. We propose that Hyper IL-6 can be used to induce potent regeneration responses in liver, kidney, and other tissues and therefore will be a novel therapeutic approach in regenerative medicine. PMID- 23456863 TI - Brain ischemic injury in rodents: the protective effect of EPO. AB - Animal models constitute an indispensable tool to investigate human pathology. Here we describe the procedure to induce permanent and transient cerebral ischemia in the mouse and the rat. The model of transient occlusion of the middle cerebral artery (MCA) is performed by the insertion of an occlusive filament until the origin of the MCA while the permanent occlusion described in the mice is performed by a distal electrocoagulation of the MCA. Those models allow evaluating the efficiency of therapeutic strategy of ischemia from tissular aspect to behavioral and cognitive impairment assessment. They were widely used in the literature to evaluate the efficiency of different drugs including the cytokines and especially erythropoietin (EPO) or its derivatives. PMID- 23456864 TI - Experimental traumatic spinal cord injury. AB - Animal models are important to develop therapies for individuals suffering from spinal cord injuries. For this purpose, rats are commonly preferred. In sharp injury models, spinal cord is completely or incompletely cut to assess axonal regeneration. On the other hand, spinal cord is compressed or contused to mimic the human injury in blunt injury models for understanding as well as managing the secondary pathophysiologic processes following injury. Especially, contusions are thought to be biomechanically similar to vertebral fractures and/or dislocations and thus provide the most realistic experimental setting in which to test potential neuroprotective and regenerative strategies. PMID- 23456866 TI - Evaluating effects of EPO in rodent behavioral assays related to depression. AB - The cytokine erythropoietin (EPO) is an important regulator of hematopoesis and has well-known tissue protective properties. Neurotrophic action is implicated as mechanistically important in the treatment of depression, and neurotrophic actions of EPO suggest potential therapeutic utility of an EPO-like mechanism in depressive disorder. Rodent behavioral models that are responsive to clinically used antidepressants as well as to neurotrophic compounds can be used to assess potential antidepressant properties of EPO and EPO-like compounds. Rodent models described here are the forced-swim test (FST), a hyponeophagia test and the novel object recognition test. Each of these models provides different information and relevance to depression and each can be tested with EPO and similar compounds. PMID- 23456865 TI - Erythropoietin as a neuroprotectant for neonatal brain injury: animal models. AB - Prematurity and perinatal hypoxia-ischemia are common problems that result in significant neurodevelopmental morbidity and high mortality worldwide. The Vannucci model of unilateral brain injury was developed to model perinatal brain injury due to hypoxia-ischemia. Because the rodent brain is altricial, i.e., it develops postnatally, investigators can model either preterm or term brain injury by varying the age at which injury is induced. This model has allowed investigators to better understand developmental changes that occur in susceptibility of the brain to injury, evolution of brain injury over time, and response to potential neuroprotective treatments. The Vannucci model combines unilateral common carotid artery ligation with a hypoxic insult. This produces injury of the cerebral cortex, basal ganglia, hippocampus, and periventricular white matter ipsilateral to the ligated artery. Varying degrees of injury can be obtained by varying the depth and duration of the hypoxic insult. This chapter details one approach to the Vannucci model and also reviews the neuroprotective effects of erythropoietin (Epo), a neuroprotective treatment that has been extensively investigated using this model and others. PMID- 23456867 TI - Erythropoietin and cytoprotective cytokines in experimental traumatic brain injury. AB - The various biochemical cascades that follow primary brain injury result in secondary brain injury which can adversely affect the clinical outcome. Over the last few years it has been well established that molecules like erythropoietin (Epo) have a neuroprotective role in experimental traumatic brain injury (TBI). Epo is shown to produce this effect by modulating multiple cellular processes, including apoptosis, inflammation, and regulation of cerebral blood flow. Derivatives of Epo, including asialo Epo and carbamylated Epo, have been developed to separate the neuroprotective properties from the erythropoiesis stimulating activities of Epo which may have adverse effects in clinical situations. Peptides that mimic a portion of the Epo molecule, including Helix B surface peptide and Epotris, have also been developed to isolate the neuroprotective activities. The TBI model in rodents most commonly used to study the effect of Epo and these derivatives in TBI is controlled cortical impact injury, which is a model of focal contusion following a high velocity impact to the parietal cortex. Following TBI, rodents are given Epo or an Epo derivative vs. placebo and the outcome is evaluated in terms of physiological parameters (cerebral blood flow, intracranial pressure, cerebral perfusion pressure), behavioral parameters (motor and memory), and histological parameters (contusion volumes, hippocampus cell counts). PMID- 23456868 TI - Therapeutic efficacy of erythropoietin in experimental autoimmune encephalomyelitis in mice, a model of multiple sclerosis. AB - Erythropoietin (EPO) has neuroprotective effects in many models of damage and disease of the nervous system where neuroinflammation plays a substantial role, including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Since the first pioneering studies, in which EPO was shown to protect rats with acute EAE mainly by inhibiting inflammation, many other studies have pointed out other mechanisms of protection, including oligodendrogenesis and inhibition of axonal damage.Here we review the preclinical studies in which EPO has shown therapeutic efficacy in several models of EAE in mice and rats. Moreover, we report in detail the protocol to administer EPO to mice with myelin oligodendrocyte glycoprotein (MOG)-induced chronic progressive EAE, and a representative result. In this model, EPO inihibits the clinical score of the disease when administered according to a preventive but also to a therapeutic schedule, and therefore at disease onset, suggesting that it might not only inhibit inflammation but also actively stimulate repair. PMID- 23456869 TI - Deciphering the intracellular signaling of erythropoietin in neuronal cells. AB - The search for potential drugs to treat neurodegenerative diseases has been intense in the last two decades. Among many candidates, erythropoietin (EPO) was identified as a potent protectant of neurons suffering from various adverse conditions. A wide array of literature indicates that endogenous or exogenous recombinant human erythropoietin and its variants activate cell signaling that initiates survival-promoting events in neurons and neuronal cells. This chapter gives an overview of the pro-survival signaling induced by endogenous and exogenous erythropoietin in vitro and in vivo and provides methods to further investigate the intracellular signaling. It is important to know that EPO is neuroprotective, but it will greatly enhance our chances to establish EPO as a new drug candidate if we know how EPO protects neurons.The descriptions below summarize our current knowledge in non-neuronal and neuronal signaling pathways induced by EPO. The signaling pathways involved in EPO are multiple; some are well known whereas others are still under intense investigation and few are observed in very specific cell types. It is important to note that neuronal signaling events triggered by EPO are still incomplete and require further research. Therefore, excellent review articles that explore specific EPO signaling events are referenced. PMID- 23456870 TI - Assessment of allodynia relief by tissue-protective molecules in a rat model of nerve injury-induced neuropathic pain. AB - Neuropathic pain following nerve injury is a chronic disease characterized by allodynia and hyperalgesia of either mechanical or thermal origin. The mechanism underlying this disease is poorly understood leading to pharmacologic and physiotherapeutic control that is often insufficient. In this chapter, we describe a method to induce nerve injury in rats to create a robust animal model for studying neuropathic pain. Additionally we describe a method to follow up on animals in the process of testing treatments for efficacy in alleviating allodynia by testing for both mechanical and thermal allodynia with reproducible results. PMID- 23456871 TI - Intra-epidermal nerve fibers density and nociception in EPO-treated type 1 diabetic rats with peripheral neuropathy. AB - Small-diameter nerve fibers, which subserve nociception, can be affected early in peripheral neuropathies, although their injury may not be detectable by routine neurophysiologic tests. On the other hand, skin biopsy has proved to be a reliable tool to examine nonmyelinated nerve fibers, as assessed by the quantification of intra-epidermal nerve fiber (IENF) density not only along with the degenerative process but, noteworthy, IENF density could be very helpful in evaluating drug efficacy such as erythropoietin (EPO) treatment. PMID- 23456872 TI - ARA290 in a rat model of inflammatory pain. AB - Chronic pain affects as many as one in five people. A proportion of patients with symptoms of neuropathic -pain do not have clinical signs of any obvious tissue or nerve injury. Such patients include those with diffuse limb pain, back pain, and complex regional pain syndrome type 1. These patients remain a clinical enigma. However, through the development of the neuritis model, it has become apparent that local nerve inflammation in the absence of gross pathology (i.e., axonal degeneration and demyelination) may underlie part of the mechanisms of pain. In this chapter, we describe a method to induce the neuritis model. We also describe in detail a reliable method to test for mechanical allodynia and heat hyperalgesia. Data that demonstrates the potential benefits of the neuroprotective agent ARA290 in reducing pain behavior in the neuritis model are presented. PMID- 23456873 TI - In vivo angiogenic activity of erythropoietin. AB - The role of erythropoietin (Epo) has been demonstrated in tissues outside the hematopoietic system, including the cardiovascular system, where Epo promotes various effects in endothelial cells. Here, we have demonstrated the angiogenic capacity of recombinant human Epo (rhuEpo) in vivo, by means of the chick embryo chorioallantoic membrane (CAM) assay, a well-established in vivo assay to study angiogenesis and antiangiogenesis. PMID- 23456874 TI - Photoreceptor degeneration in mice: adeno-associated viral vector-mediated delivery of erythropoietin. AB - The exogenous delivery of erythropoietin (EPO) and EPO derivatives (EPO-Ds) represents a valuable strategy to protect the retina from degeneration. In this chapter we describe a method to deliver EPO and the EPO derivative S100E in the light-damage model of induced retinal degeneration using adeno--associated viral (AAV) vectors and to evaluate the functional and morphological protection of the retina from light damage. PMID- 23456876 TI - Using plethysmography to determine erythropoietin's impact on neural control of ventilation. AB - The evaluation of respiratory parameters often requires the use of anesthetics (that depress the neural -network controlling respiration), and/or ways to restrain the animal's mobility (that produces a stress-dependent increase of respiration). Consequently, the establishment of plethysmography represented an invaluable technique in respiratory physiology. Plethysmography, indeed, allows the assessment of ventilatory parameters on living, unanesthetized, and unrestrained animals. The conception of the barometric plethysmography relies on the fact that an animal placed inside a hermetically closed chamber generates through its breathing a fluctuation of pressure in the chamber than can be recorded. Thus, the respiratory frequency and the tidal volume can be directly measured, while the animal's ventilation is calculated indirectly by the multiplication of these two parameters. In our hands, plethysmography was a key tool to investigate the impact of erythropoietin (Epo) on the neural control of hypoxic ventilation in mice. PMID- 23456875 TI - Myocardial infarction: cardioprotection by erythropoietin. AB - Extensive research during the last decade demonstrated that a single systemic administration of -erythropoietin (EPO) lead to significant attenuation of myocardial infarction (MI) induced in animals, mostly small rodents, either by a myocardial ischemia followed by reperfusion or by a permanent ligation of a coronary artery. Both methods are critically reviewed with the aim of helping the reader in appreciating key issues in the translation of experimental results to the clinic. Results of several clinical trials in patients with acute MI completed to date failed to demonstrate beneficial effects of EPO, and thus put into question the validity of results obtained in animal models. Comprehensive review of design and results of animal experiments and clinical trials presented here allowed authors to postulate that therapeutic window for EPO during developing MI is very narrow and was possibly missed in negative clinical trials. This point was illustrated by the negative outcome of experiment in the rat model of MI in which timing of EPO administration was similar to that in clinical trials. The design of future clinical trials should allow for a narrow therapeutic window of EPO. Given current standards for onset-to-door and door-to balloon time the optimal time for EPO administration should be just prior to PCI. PMID- 23456877 TI - Cerebral malaria: protection by erythropoietin. AB - Cerebral malaria (CM) is still responsible for unacceptable death rate, while new antimalarial drugs were recently developed. CM pathophysiology shares essential biological features with cerebral ischemia. Because erythropoietin (Epo) was demonstrated to reduce mortality rate during experimental cerebral ischemia, in the early 2000, we wondered whether Epo could help to reduce the burden of CM. There is now evidence that Epo high doses could prevent early mortality during cerebral malaria. This evidence was obtained first using mice model of cerebral malaria, and later confirmed by prospective clinical trial in endemic area. High doses of Epo are needed to cross the blood-brain barrier and to favor the cytoprotective versus hematopoietic effect of this pleiotropic cytokine. PMID- 23456878 TI - Connexin 43 channels protect osteocytes against oxidative stress-induced cell death. AB - The increased osteocyte death by oxidative stress (OS) during aging is a major cause contributing to the impairment of bone quality and bone loss. However, the underlying molecular mechanism is largely unknown. Here, we show that H2O2 induced cell death of primary osteocytes and osteocytic MLO-Y4 cells, and also caused dose-dependent decreased expression of gap junction and hemichannel forming connexin 43 (Cx43). The decrease of Cx43 expression was also demonstrated with the treatment of other oxidants, rotenone and menadione. Antioxidant reversed the effects of oxidants on Cx43 expression and osteocyte cell death. Cx43 protein was also much lower in the osteocytes from 20-month-old as opposed to the 5-week-old or 20-week old mice. Dye transfer assay showed that H2O2 reduced the gap junction intercellular communication (GJIC). In contrast to the effect on GJIC, there was a dose-dependent increase of hemichannel function by H2O2, which was correlated with the increased cell surface expression of Cx43. Cx43(E2) antibody, an antibody that specifically blocks Cx43 hemichannel activity but not gap junctions, completely blocked dye uptake induced by H2O2 and further exacerbated H2O2-induced osteocytic cell death. In addition, knockdown of Cx43 expression by small interfering RNA (siRNA) increased the susceptibility of the cells to OS-induced death. Together, our study provides a novel cell protective mechanism mediated by osteocytic Cx43 channels against OS. PMID- 23456879 TI - Preparation and application of trimethylamine amination polychloromethyl styrene nanolatex coated capillary column for the determination of bromate by field amplified sample stacking open-tubular capillary electrochromatography. AB - A new trimethylamine amination polychloromethyl styrene nanolatex (TMAPL) and TMAPL coated capillary column (ccc-TMAPL) were successfully prepared. The TMAPL coating was characterized with reversed steady EOF values of ca. -16.8 * 10(-5) cm(2) V(-1) s(-1) . It was applied to establish open-tubular (OT) CEC and field amplified sample stacking (FASS) OT-CEC methods for the determination of bromate in tap water. Compared to OT-CEC, the LOD with FASS-OT-CEC was improved from 80 to 8 ng/mL. The developed FASS-OT-CEC method was practically used for the analysis of bromate in tap water samples with recoveries ranging from 93.6 to 103.5%. PMID- 23456880 TI - Virgil Leroy Woods, Jr. (1948-2012). PMID- 23456881 TI - Formaldehyde: catalytic oxidation as a promising soft way of elimination. AB - Compared to other molecules such as benzene, toluene, xylene, and chlorinated compounds, the catalytic oxidation of formaldehyde has been studied rarely. However, standards for the emission level of this pollutant will become more restrictive because of its extreme toxicity even at very low concentrations in air. As a consequence, the development of a highly efficient process for its selective elimination is needed. Complete catalytic oxidation of formaldehyde into CO2 and H2 O using noble-metal-based catalysts is a promising method to convert this pollutant at room temperature, making this process energetically attractive from an industrial point of view. However, the development of a less expensive active phase is required for a large-scale industrial development. Nanomaterials based on oxides of manganese are described as the most promising catalysts. The objective of this Minireview is to present promising recent studies on the removal of formaldehyde through heterogeneous catalysis to stimulate future research in this topic. PMID- 23456882 TI - Aromatic interactions with naphthylalanine in a beta-hairpin peptide. AB - Stable peptides have been explored as epitope mimics for protein-protein and protein-nucleic acid interactions; however, presentation of a regular structure is critical. Aromatic interactions are ubiquitous and are competent at stabilizing a beta-hairpin fold. The greatest stabilization has been reported from pairs of tryptophan side chains. Naphthylalanine residues are often used as tryptophan replacements, but it is not clear if 1-naphthylalanine or 2 naphthylalanine is adequate at replicating the geometry and stability observed with tryptophan aromatic interactions. Herein, a 12-residue peptide has been constructed with laterally disposed aromatic amino acids. A direct comparison is made between tryptophan and other bicyclic, unnatural amino acids. Significant stabilization is gained from all bicyclic amino acids; however, geometric analysis shows that only 1-naphthylalanine adopts a similar edge to face geometry as tryptophan, whereas the 2-naphthylalanine appears most similar to a substituted phenylalanine. PMID- 23456883 TI - Chronic degeneration of dorsal raphe serotonergic neurons modulates cortical spreading depression: a possible pathophysiology of migraine. AB - The vascular serotonergic system in the brain has been implicated in the pathophysiology of migraine, however, involvement of the serotonergic nervous system of the brain parenchyma in the pathophysiology remains unclear. To investigate whether the brain parenchymal serotonergic nervous system is involved in the etiology of migraine, we prepared an experimental model of migraine by generation of cortical spreading depression (SD), characterized by spreading of neuronal/glial membrane depolarization accompanied by temporal elevation of the cerebral blood flow (CBF) throughout the cerebral cortical hemisphere in rats, which underwent pharmacological treatment for degeneration of serotonergic neurons in the dorsal raphe nucleus. We show here that (1) significant degeneration of serotonergic neurons in the dorsal raphe nucleus and serotonergic fibers in the cerebral cortex was observed in treated rats, (2) spreading velocity of the CBF changes was significantly increased in these rats, and (3) calculated width of the depolarization wave was significantly extended in these rats. These results indicate that the dorsal raphe serotonergic neurons modulate cortical spreading depression and might be involved in migraine pathology via a similar mechanism. PMID- 23456884 TI - Treatment costs of acute myocardial infarction in the Netherlands. AB - BACKGROUND: This study aimed to calculate the treatment costs of acute myocardial infarction (AMI) in the Netherlands for 2012. Also, the degree of association between treatment costs of AMI and some patient and hospital characteristics was examined. METHODS: For this retrospective cost analysis, patients were drawn from the database of the Diagnosis Treatment Combination (Diagnose Behandeling Combinatie, DBC) casemix system, which contains data on the resource use of all hospitalisations in the Netherlands. All costs were based on Euro 2012 cost data. RESULTS: The analysis was based on data of 25,657 patients. Mean treatment costs were estimated at 5021, with significant cost increases for patients with percutaneous coronary intervention (PCI) treatment. ST-segment elevation myocardial infarction (STEMI) patients receiving thrombolysis incurred the lowest ( 4286), while non-STEMI patients receiving PCI the highest costs ( 6060). Length of stay and hospital type were strong predictors of treatment costs. CONCLUSIONS: This study is the most extensive cost assessment of the treatment costs of AMI in the Netherlands thus far. Our results may be used as input for health-economic models and economic evaluations to support the decision making of registration, reimbursement and pricing of interventions in healthcare. PMID- 23456885 TI - Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. AB - PURPOSE: While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. PROCEDURES: Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. RESULT: Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. CONCLUSION: [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage. PMID- 23456886 TI - Bacterial microcompartment shells of diverse functional types possess pentameric vertex proteins. AB - Bacterial microcompartments (MCPs) are large proteinaceous structures comprised of a roughly icosahedral shell and a series of encapsulated enzymes. MCPs carrying out three different metabolic functions have been characterized in some detail, while gene expression and bioinformatics studies have implicated other types, including one believed to perform glycyl radical-based metabolism of 1,2 propanediol (Grp). Here we report the crystal structure of a protein (GrpN), which is presumed to be part of the shell of a Grp-type MCP in Rhodospirillum rubrum F11. GrpN is homologous to a family of proteins (EutN/PduN/CcmL/CsoS4) whose members have been implicated in forming the vertices of MCP shells. Consistent with that notion, the crystal structure of GrpN revealed a pentameric assembly. That observation revived an outstanding question about the oligomeric state of this protein family: pentameric forms (for CcmL and CsoS4A) and a hexameric form (for EutN) had both been observed in previous crystal structures. To clarify these confounding observations, we revisited the case of EutN. We developed a molecular biology-based method for accurately determining the number of subunits in homo-oligomeric proteins, and found unequivocally that EutN is a pentamer in solution. Based on these convergent findings, we propose the name bacterial microcompartment vertex for this special family of MCP shell proteins. PMID- 23456887 TI - Lipase-catalyzed (trans)esterification of 5-hydroxy- methylfurfural and separation from HMF esters using deep-eutectic solvents. AB - 5-Hydroxymethylfurfural (HMF) is a valuable biomass-derived building block. Among possible HMF valorization products, a broad range of HMF esters can be synthesized. These HMF esters have found some promising applications, such as monomers, fuels, additives, surfactants, and fungicides, and thus several catalytic approaches for HMF (trans)esterifications have been reported. The intrinsic reactivity of HMF is challenging, forcing the use of mild reaction conditions to avoid by-product formation. This paper explores the lipase catalyzed (trans)esterification of HMF with different acyl donors (carboxylic acids and methyl- and ethyl esters) mostly in solvent-free conditions. The results demonstrate that lipases may be promising alternatives for the synthesis of HMF esters-with high productivities and reactions at high substrate loadings provided that robust systems for lipase immobilization are applied to assure an adequate reusability of the enzymes. Once (trans)esterifications have been conducted, the separation of unreacted HMF and HMF esters is performed by using deep-eutectic solvents (DES) as separation agents. DES are able to dissolve hydrogen-bond donors (e.g., HMF), whereas non-hydrogen-bond donors (in this case HMF esters) form a second phase. By using this approach, high ester purities (>99 %) and efficiencies (up to >90 % HMF ester recovery) in separations were obtained by using choline chloride-based DES. PMID- 23456888 TI - Meta-analytic approaches to determine gender differences in the age-incidence characteristics of schizophrenia and related psychoses. AB - A recent systematic review and meta-analysis of the incidence and prevalence of schizophrenia and other psychoses in England investigated the variation in the rates of psychotic disorders. However, some of the questions of interest, and the data collected to answer these, could not be adequately addressed using established meta-analysis techniques. We developed a novel statistical method, which makes combined use of fractional polynomials and meta-regression. This was used to quantify the evidence of gender differences and a secondary peak onset in women, where the outcome of interest is the incidence of schizophrenia. Statistically significant and epidemiologically important effects were obtained using our methods. Our analysis is based on data from four studies that provide 50 incidence rates, stratified by age and gender. We describe several variations of our method, in particular those that might be used where more data is available, and provide guidance for assessing the model fit. PMID- 23456889 TI - Monte Carlo simulation of ion trajectories of reacting chemical systems: mobility of small water clusters in ion mobility spectrometry. AB - For the comprehensive simulation of ion trajectories including reactive collisions at elevated pressure conditions, a chemical reaction simulation (RS) extension to the popular SIMION software package was developed, which is based on the Monte Carlo statistical approach. The RS extension is of particular interest to SIMION users who wish to simulate ion trajectories in collision dominated environments such as atmospheric pressure ion sources, ion guides (e.g., funnels, transfer multi poles), chemical reaction chambers (e.g., proton transfer tubes), and/or ion mobility analyzers. It is well known that ion molecule reaction rate constants frequently reach or exceed the collision limit obtained from kinetic gas theory. Thus with a typical dwell time of ions within the above mentioned devices in the ms range, chemical transformation reactions are likely to occur. In other words, individual ions change critical parameters such as mass, mobility, and chemical reactivity en passage to the analyzer, which naturally strongly affects their trajectories. The RS method simulates elementary reaction events of individual ions reflecting the behavior of a large ensemble by a representative set of simulated reacting particles. The simulation of the proton bound water cluster reactant ion peak (RIP) in ion mobility spectrometry (IMS) was chosen as a benchmark problem. For this purpose, the RIP was experimentally determined as a function of the background water concentration present in the IMS drift tube. It is shown that simulation and experimental data are in very good agreement, demonstrating the validity of the method. PMID- 23456890 TI - para-Nitroaniline is a promising matrix for MALDI-MS imaging on intermediate pressure MS systems. AB - para-Nitroaniline (PNA) is presented as a promising matrix for matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) on an intermediate-pressure ion source (~1 Torr) QqTOF instrument using an Nd:YVO4 laser operated at 5 kHz. An imaging study was carried out to determine the utility of PNA at this pressure by analyzing 14 tissue sections. We demonstrate acquisition of high-quality imaging data over a 6-h period in the ion source. In this study, comparisons were made between PNA and alpha-cyano-4-hydroxycinnamic acid (CHCA) in positive ion mode to demonstrate the utility of PNA in these circumstances. PNA performed as well as or better than CHCA in terms of lipid ion intensities, resulting in lower levels of ion fragmentation and in lower incidences of analyte migration at the edges of the tissue sections when using airspray matrix deposition. PMID- 23456892 TI - The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate. AB - Rosiglitazone (RSG) is an antidiabetic drug that has been associated with increased peripheral fractures, primarily in postmenopausal women. In this report, we investigated the underlying mechanisms of RSG-associated bone loss in ovariectomized (OVX) rats and determined whether changes in bone parameters associated with RSG administration are reversible on treatment cessation or preventable by coadministration with an antiresorptive agent. Nine-month-old Sprague-Dawley rats underwent OVX or sham operation. Sham-operated rats received oral vehicle only; OVX animals were randomized to receive vehicle, RSG, alendronate (ALN), or RSG plus ALN for 12 weeks. All treatment started the day after ovariectomy. After the 12-week treatment period, the OVX and RSG groups also underwent an 8-week treatment-free recovery period. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Microcomputed tomography was also used to investigate changes in microarchitecture. RSG significantly increased deoxypyridinoline levels compared with OVX. Significant exacerbation of OVX-induced loss of bone mass, strength, and microarchitectural deterioration was observed in RSG-treated OVX animals compared with OVX controls. These effects were observed predominantly at sites rich in trabecular bone, with less pronounced effects in cortical bone. Coadministration of RSG and ALN prevented the bone loss associated with RSG treatment. Following cessation of RSG treatment, effects on bone mass and strength showed evidence of reversal. Thus, treatment of OVX rats with RSG results in loss of bone mass and strength, primarily at sites rich in trabecular bone, mainly due to increased bone resorption. These effects can be prevented by concomitant treatment with ALN and may be reversed following discontinuation of RSG. PMID- 23456893 TI - Conduction disorders in the setting of transcatheter aortic valve implantation: a clinical perspective. AB - The presence of periprocedural conduction disorders (CDs) and the need for permanent pacemaker (PPM) after transcatheter aortic valve implantation (TAVI) are frequent findings in clinical practice. Notwithstanding, robust information on the prognostic and therapeutic implications of these complications are lacking. The newly occurrence of CD after TAVI seems related to the trauma of the conduction system during procedure. On the contrary, major predictors for PPM implantation after TAVI seem to be the use of CoreValve prosthesis (Medtronic, Minneapolis, MN) and the presence of CD before TAVI. An accurate pre-TAVI screening, careful valve implantation, as well as post-TAVI monitoring must be pursued to prevent avoidable PPM implantation. The aim of this report is to analyze the available data on this field and to propose some practical clinical tips to prevent or to manage these complications. PMID- 23456899 TI - Local Hartree-Fock orbitals using a three-level optimization strategy for the energy. AB - Using the three-level energy optimization procedure combined with a refined version of the least-change strategy for the orbitals--where an explicit localization is performed at the valence basis level--it is shown how to more efficiently determine a set of local Hartree-Fock orbitals. Further, a core valence separation of the least-change occupied orbital space is introduced. Numerical results comparing valence basis localized orbitals and canonical molecular orbitals as starting guesses for the full basis localization are presented. The results show that the localization of the occupied orbitals may be performed at a small computational cost if valence basis localized orbitals are used as a starting guess. For the unoccupied space, about half the number of iterations are required if valence localized orbitals are used as a starting guess compared to a canonical set of unoccupied Hartree-Fock orbitals. Different local minima may be obtained when different starting guesses are used. However, the different minima all correspond to orbitals with approximately the same locality. PMID- 23456891 TI - Cross-species analysis of nicotine-induced proteomic alterations in pancreatic cells. AB - Toxic compounds in tobacco, such as nicotine, may adversely affect pancreatic function. We aim to determine nicotine-induced protein alterations in pancreatic cells, thereby revealing links between nicotine exposure and pancreatic disease. We compared the proteomic alterations induced by nicotine treatment in cultured pancreatic cells (mouse, rat, and human stellate cells and human duct cells) using MS-based techniques, specifically SDS-PAGE (gel) coupled with LC-MS/MS and spectral counting. We identified thousands of proteins in pancreatic cells, hundreds of which were identified exclusively or in higher abundance in either nicotine-treated or untreated cells. Interspecies comparisons of stellate cell proteins revealed several differentially abundant proteins (in nicotine treated versus untreated cells) common among the three species. Proteins appearing in all nicotine-treated stellate cells include amyloid beta (A4), procollagen type VI alpha 1, integral membrane protein 2B, and toll-interacting protein. Proteins that were differentially expressed upon nicotine treatment across cell lines were enriched in certain pathways, including nicotinic acetylcholine receptor, cytokine, and integrin signaling. At this analytical depth, we conclude that similar pathways are affected by nicotine, but alterations at the protein level among stellate cells of different species vary. Further interrogation of such pathways will lead to insights into the potential effect of nicotine on pancreatic cells at the biomolecular level and the extension of this concept to the effect of nicotine on pancreatic disease. PMID- 23456900 TI - Accuracy of clinically estimated fetal weight in pregnancies complicated by diabetes mellitus and obesity. AB - OBJECTIVE: To determine the accuracy of clinically estimated fetal weight (CEFW) in patients with gestational diabetes (GDM), pregestational diabetes (DM), and obesity. STUDY DESIGN: This is a retrospective analysis of Consortium of Safe Labor data. Subjects were classified into six groups: DM, DM and obese, GDM, GDM and obese, nondiabetic obese, and controls. The mean difference between birth weight (BW) and CEFW, the percent of accurate CEFW (defined as < 10% difference), and the sensitivity for identifying BW > 4,000 g and > 4,500 g were calculated for each group. RESULTS: The accuracy of CEFW in our population was 54.3 to 64.4% and was significantly lower in patients with DM and obesity and patients with obesity but not diabetes. When CEFW was analyzed in the >4,000-g and > 4,500-g groups, its accuracy was 20 to 51% and 14 to 40%, respectively. CEFW overestimated BW more commonly in GDM, obese GDM, and obese groups. The sensitivity of CEFW for diagnosing BW > 4,000 g or > 4,500 g was 19.6% and 9.6%, respectively, and it improved in pregnancies complicated by diabetes. CONCLUSION: CEFW is a poor predictor of macrosomia in pregnancies complicated by obesity and diabetes. PMID- 23456901 TI - Perceptions and practices of therapeutic hypothermia in American neonatal intensive care units. AB - OBJECTIVE: In 2005, therapeutic hypothermia (TH) was used in few American neonatal intensive care units (NICUs) with great variability in practices. We hypothesized that TH would be used with greater frequency and uniformity today. STUDY DESIGN: We surveyed directors of 797 NICUs queried in our prior study to determine attitudes toward and practices of TH. RESULTS: Of the 781 participants with valid addresses, we received completed surveys from 330 (42.3%). There was an increase in the number of respondents who believed that TH is effective (85% versus 31%, p < 0.0001). More NICUs used TH (50% versus 6%, p < 0.0001) and nearly all not offering TH transferred eligible neonates to centers that did (97% versus 29%, p < 0.0001). There has been increased standardization of TH practices with regard to enrollment criteria, duration, and methods of monitoring. CONCLUSION: TH has become standard of care for the treatment of HIE in the United States. Most NICUs that use TH adhere to protocols, but variation still exists in TH practices. PMID- 23456902 TI - Physical activity, maternal metabolic measures, and the incidence of gallbladder sludge or stones during pregnancy: a randomized trial. AB - OBJECTIVE: To evaluate the effect of a physical activity intervention upon the incidence of gallbladder sludge or stones during pregnancy. STUDY DESIGN: Pregnant women without gallstones were randomized to an intervention to increase moderate to vigorous physical activity or control. Intervention group women received motivational materials and small-group instruction to increase physical activity. Gallbladder ultrasound and blood draws were obtained at entry, 18 weeks' gestation, and 36 weeks' gestation. RESULTS: In all, 591 were randomized to the intervention and 605 women to control groups. Women in the intervention group reported modestly higher levels of physical activity compared with control women, and fewer women in the intervention group reported no physical activity during pregnancy. The incidence of gallbladder sludge or stones was similar in intervention and control groups at 18 weeks (4.8% versus 5.4%; relative risk 0.89; 95% confidence interval 0.53, 1.47) and 36 weeks (4.3% versus 3.3%; relative risk 1.31; 95% confidence interval 0.70, 2.54). Fasting glucose, lipid, insulin, leptin, and adiponectin levels were similar in the two groups, as was insulin sensitivity and the incidence of gestational diabetes. CONCLUSION: An intervention to increase moderate to vigorous physical activity did not decrease the incidence of gallbladder sludge or stones during pregnancy and did not result in improvement in maternal metabolic measures. PMID- 23456903 TI - Prophylactic indomethacin worsens short-term respiratory outcomes in extremely low-birth-weight infants. AB - OBJECTIVE: To compare the effects of prophylactic indomethacin versus expectant management on short-term respiratory outcomes in extremely low-birth-weight (ELBW) infants. METHODS: This was a retrospective cohort study of ELBW infants with gestational age less than 28 weeks, born at a level III neonatal intensive care unit from 2004 to 2009. Patients were grouped based on whether they received prophylactic indomethacin or expectant treatment. The key outcome was the cumulative number of days of mechanical ventilation. Other outcomes were cumulative number of days supplemental oxygen and continuous positive airway pressure (CPAP) were required; duration of hospital stay; mortality; and other morbidities such as necrotizing enterocolitis and intraventricular hemorrhage. Multivariable linear regression was performed with treatment group and seven covariates, defined a priori, as predictor variables and cumulative number of days of mechanical ventilation as the outcome. RESULTS: There were 144 infants in the prophylaxis group and 221 infants in the expectant treatment group. At baseline, the Score for Neonatal Acute Physiology-Perinatal Extension, incidence of respiratory distress syndrome, and usage of antenatal corticosteroids were significantly higher in the prophylaxis group. The cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP were significantly higher in the prophylaxis group. On multivariable linear regression, after adjusting for confounders, use of prophylactic indomethacin (unstandardized beta coefficient = 12.4; 95% confidence interval [CI]: 6.6, 18.1; p < 0.001), birth weight (beta = 0.025; 95% CI: -0.05, -0.001; p = 0.043), and gestation (beta = -4.5; 95% CI: 7.24, -1.8; p = 0.001) were the independent predictors of cumulative number of days of mechanical ventilation. CONCLUSION: ELBW infants who received prophylactic indomethacin had significantly longer cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP. Prophylactic indomethacin is an independent predictor of cumulative number of days of mechanical ventilation. PMID- 23456904 TI - Subsequent pregnancy outcomes in women previously diagnosed with subclinical hypothyroidism. AB - OBJECTIVE: To evaluate subsequent pregnancy outcomes in women previously identified during an index pregnancy to have subclinical hypothyroidism (SCH). STUDY DESIGN: From 2000 to 2003, thyroid analytes were measured in 17,298 women. Using their index pregnancy thyroid-analyte classification, pregnancy outcomes were compared between the returning cohorts. RESULTS: There were 6,985 women previously screened and subsequently delivered at our hospital though 2011 with 230 (3.3%) designated to have SCH and 6,645 (95.1%) euthyroid. Significant differences between the two cohorts included risk for diabetes (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.2 to 2.7, p = 0.005), gestational diabetes (OR 1.74, 95% CI 1.13 to 2.69, p = 0.015), and stillbirth (OR 3.5, 95% CI 1.05 to 11.68, p = 0.042). After adjustment, the increased likelihood of diabetes (adjusted OR 1.58, 95% CI 1.04 to 2.40, p = 0.032) and stillbirth (adjusted OR 3.41, 95% CI 1.01 to 11.49, p = 0.048) persisted. CONCLUSIONS: Women identified during a previous pregnancy with SCH are at increased risk for some adverse perinatal outcomes during a subsequent pregnancy. PMID- 23456905 TI - Predictive factors of abdominal compartment syndrome in neonatal age. AB - In the pediatric population, abdominal compartment syndrome (ACS) is a known complication of abdominal wall defect repair. However, there are only few reports on ACS in newborns and only a proposal of critical intra-abdominal pressure value (IAP) in term newborns, absent in preterm newborns. Although the prevalent clinical sign is tense abdominal distension, it may be difficult to distinguish ACS from pathologies that will not require decompression. The purpose of this study was to identify predictors for ACS and therefore morbidity or mortality indicators. We reviewed newborns presenting with tense abdominal distension and end organ failure. Anamnestic, clinical, laboratory, and instrumental investigations were analyzed to extrapolate predictors. Outcomes were compared with a control group. The incidence of ACS in our neonatal intensive care unit was 5% in the overall population of babies, 16% in tracheal-ventilated newborns, and 57% in infants with abdominal wall defects. We found that, with onset of acidosis or high gastric residuals, the lactate values will be predictive for mortality. We can also suggest paying particular attention to high lactate values just at the onset of distension, in infants with more advanced gestational age, with previously surgical repair, to determine early surgical intervention independently of a specific IAP measurement. PMID- 23456906 TI - Neutrophil CD64 with hematologic criteria for diagnosis of neonatal sepsis. AB - OBJECTIVE: To assess the sensitivity and specificity of neutrophil CD64 as a diagnostic marker for clinical sepsis (based on a hematologic score) and as an additional marker with hematologic parameters for culture-proven sepsis in neonates. STUDY DESIGN: Prospective observational cohort over 18 months in a single-center neonatal intensive care unit. RESULTS: Hematologic and CD64 data were available on 1,156 sepsis evaluations done in 684 infants, of which 411 (36%) instances of positive clinical sepsis were identified. The CD64 index for clinical sepsis had an overall area under the receiver operating characteristic curve of 0.71. An optimum CD64 cut point value of 2.19 for late-onset clinical sepsis was calculated with a sensitivity of 78%, a specificity of 59%, and a negative predictive value of 81%. The birth weight-specific CD64 cut point for early onset clinical sepsis was 3.13, 2.34, and 2.05 for very low, low, and normal birth weight, respectively. Neutrophil CD64, in combination with the absolute neutrophil count or the absolute band count, had the highest sensitivity (91%) and specificity (93%), respectively, to diagnose culture-proven sepsis. CONCLUSION: We conclude that neutrophil CD64 index can be incorporated with specific hematologic criteria as an additional marker for diagnosis of neonatal sepsis. PMID- 23456908 TI - Spontaneous preterm birth in African-American and Caucasian women receiving 17alpha-hydroxyprogesterone caproate. AB - OBJECTIVE: To determine if the rates of recurrent spontaneous preterm birth in women receiving 17alpha-hydroxyprogesterone caproate (17P) differ according to maternal race. STUDY DESIGN: Retrospective analysis of a cohort of women enrolled in outpatient 17P administration at < 27 weeks. Maternal characteristics, obstetric history, and rates of recurrent preterm birth were determined using chi square and multivariable Cox proportional hazards regression at two-tailed alpha = 0.05. Primary study outcome was defined as having a spontaneous preterm birth < 34 weeks. RESULTS: African-American women initiated 17P injections later (19.6 versus 18.9 weeks, p < 0.001) and discontinued injections earlier (33.2 versus 34.1 weeks, p < 0.001) than Caucasian women. Spontaneous recurrent preterm birth < 34 weeks was higher in African-Americans versus Caucasians receiving 17P (odds ratio 2.1; 95% confidence interval 1.7, 2.4). After adjusting for other significant factors, African-American race retained the strongest association with recurrent spontaneous preterm birth < 34 weeks. Within each racial group, short cervical length < 25 mm before 27 weeks' gestation had the highest hazard of recurrent spontaneous preterm delivery. CONCLUSION: Despite treatment with 17P, African-American women have higher rates of recurrent preterm birth. PMID- 23456907 TI - Maternal genotype and gestational diabetes. AB - OBJECTIVE: To determine whether genetic variants associated with glucose homeostasis are associated with gestational diabetes (GDM). STUDY DESIGN: We genotyped 899 self-identified Caucasian women and 386 self-identified African American women in the Pregnancy, Infection and Nutrition (PIN) Studies cohorts for 38 single-nucleotide polymorphisms (SNPs) associated with type II diabetes (T2DM) and/or glucose homeostasis in European populations. RESULTS: GDM was diagnosed in 56 of 899 (6.2%) Caucasian and 24 of 386 (6.2%) African-American women. Among Caucasian women, GDM was associated with carriage of TCF7L2 rs7901695, MTNR1B rs10830963 and GCKR rs780094 alleles that are associated with T2DM and fasting glucose in nonpregnant populations. Among African-American participants, we found an increased risk among TSPAN8 rs7961581 C allele homozygotes and reduced risk among carriers of the JAZF1 rs864745 T allele. CONCLUSION: We found several SNPs that are associated with GDM risk in the PIN cohorts. Maternal genotyping may identify women at risk for impaired gestational glucose tolerance. PMID- 23456909 TI - Physical exercise, body mass index and risk of chronic arm pain: longitudinal data on an adult population in Norway. AB - AIM: The aim of this study was to prospectively investigate the association between leisure time physical exercise, body mass index (BMI) and risk of chronic arm pain. METHODS: The study population comprises 14,041 women and 13,674 men in the Norwegian HUNT Study without musculoskeletal pain or physical impairment at baseline in 1984-86. Chronic arm pain was assessed at follow-up in 1995-97. A generalized linear model was used to calculate adjusted relative risks (RRs). RESULTS: At follow-up, 2205 women and 1458 men reported chronic arm pain. Level of physical exercise was inversely associated with risk of chronic arm pain (P trend, <=0.03 for both sexes). Compared with inactive persons, women and men who exercised >= 2 h/week had adjusted RRs of 0.84 [95% confidence interval (CI), 0.73-0.96] and 0.74 (95% CI, 0.63-0.87), respectively. BMI was positively associated with risk of chronic arm pain (P-trend, <=0.002 for both sexes). Compared with normal-weight persons, women and men classified as obese (BMI >= 30 kg/m2) had adjusted RRs of 1.26 (95% CI, 1.11-1.44) and 1.29 (95% CI, 1.07-1.57), respectively. Combined analysis showed that obese women and men who exercised >= 1 h/week had a RR of 1.20 (95% CI 0.97-1.48) compared with normal-weight women and men with a similar activity level, whereas the RR was 1.41 (95% CI 1.21-1.65) for obese women and men who were physically inactive. CONCLUSION: Regular physical exercise reduces risk of chronic arm pain while high BMI increases the risk. Exercise can to some extent compensate for the adverse effect of obesity on risk of chronic arm pain. PMID- 23456910 TI - Ethnic group differences in cardiometabolic disease risk factors independent of body mass index among American youth. AB - OBJECTIVE: The purpose of this analysis was to identify any ethnic group differences in the prevalence of cardiometabolic disease risk factors independent of BMI in United States youth. DESIGN AND METHODS: Data on 3,510 boys and girls aged 8-11 years from the 1999-2008 National Health and Nutrition Examination Surveys were analyzed to determine the prevalence of 1 or >=3 cardiometabolic disease risk factors: abnormal waist circumference and systolic (SBP) and diastolic blood pressure (DBP), increased concentrations of fasting triglyceride, and decreased concentrations of high-density lipoprotein (HDL) cholesterol before and after adjusting for BMI. RESULTS: Abnormal waist circumference and HDL cholesterol significantly differed by ethnic group before and after adjusting for BMI (P < 0.01). Non-Hispanic blacks were significantly less likely to have abnormal HDL-cholesterol concentrations than were Hispanics and non-Hispanic whites, but non-Hispanic whites were significantly more likely to have elevated triglycerides and three or more abnormal cardiometabolic risk factors than non Hispanic blacks. CONCLUSION: These findings point to ethnic group disparities not related to BMI alone, even in children as young as 8-11 years. Programs to prevent and treat eventual cardiometabolic disease in children could be tailored for specific ethnic backgrounds as a result. PMID- 23456911 TI - A plasma microRNA panel for early detection of colorectal cancer. AB - Colonoscopy remains the standard screening method for detecting colorectal cancer (CRC) at an early stage. However, many people avoid having a colonoscopy because of the fear for its potential complications. Our study aimed to identify plasma microRNAs for preliminarily screening CRC in general population, so that some unnecessary colonoscopies can be avoided. We investigated plasma microRNA expression in three independent cohorts including the discovery (n = 80), training (n = 112), and validation (n = 49) phases recruited at two medical centers. Microarrays were used for screening 723 microRNAs in 80 plasma samples to identify candidate microRNAs. Quantitative reverse-transcriptase PCR was performed on the 161 training and validation plasma samples to evaluate the candidate microRNAs discovered from microarrays. A logistic regression model was constructed based on the training cohort and then verified by using the validation dataset. Area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified a panel of miR-409 3p, miR-7, and miR-93 that yielded high diagnostic accuracy in discriminating CRC from healthy group (AUC: 0.866 and 0.897 for training and validation dataset, respectively). Moreover, the diagnostic performance of the microRNA panel persisted in nonmetastasis CRC stages (Dukes' A-B, AUC: 0.809 and 0.892 for training and validation dataset, respectively) and in metastasis CRC stages (Dukes' C-D, AUC: 0.917 and 0.865 for training and validation dataset, respectively). In conclusion, our study reveals a plasma microRNA panel that has potential clinical value in early CRC detection and would play a critical role on preliminarily screening CRC in general population. PMID- 23456912 TI - Broken heart syndrome, neurogenic stunned myocardium and stroke. AB - OPINION STATEMENT: The diagnosis of stress cardiomyopathy is often made during coronary angiography. At this point hemodynamic parameters should be assessed; a right heart catheterization with measurement of cardiac output by Fick and thermodilution methods is helpful. Patients with acute neurologic pathology who develop left ventricular dysfunction (neurogenic stunned myocardium) may not be candidates for coronary angiography and in such cases real-time myocardial contrast echocardiography or nuclear perfusion scan can be used to exclude obstructive coronary disease. Hypotension and shock can be due to low output state or left ventricular outflow tract obstruction. Low output state can be managed with diuretics and vasopressor support. Refractory shock and/or severe mitral regurgitation may require an intra-aortic balloon pump for temporary support. In patients with intraventricular gradient intravenous beta-blockers have been used safely. Hemodynamically unstable patients should be managed in a critical care unit and stable patients should be monitored on a telemetry unit as arrhythmias may occur. An echocardiogram should be performed to look for intraventricular gradient, mitral regurgitation, or left ventricular thrombus. If left ventricular thrombus is seen or suspected anticoagulation with warfarin or low molecular weight heparin is generally advised until recovery of myocardial function and resolution of thrombus occurs. In patients with subarachnoid hemorrhage the use of vasopressors to reduce cerebral vasospasm may worsen left ventricular outflow tract gradient. In hemodynamically stable patients, a beta blocker or combined alpha/beta blocker should be initiated. Myocardial function generally recovers within days to weeks with supportive treatment in most patients. The use of a standard heart failure regimen including an angiotensin converting enzyme inhibitor or aldosterone receptor antagonist, beta-blocker titrated to maximal dose, diuretics, and aspirin is common until complete recovery of myocardial function occurs. Chronic therapy with a beta-blocker may be advisable. The underlying diagnosis that precipitated stress cardiomyopathy such as critical illness, neurologic injury, or medication exposure should be identified and treated. PMID- 23456913 TI - Therapeutic Options to Reduce Lp-PLA2 Levels and the Potential Impact on Vascular Risk Reduction. AB - OPINION STATEMENT: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in the metabolism of Low-density lipoprotein (LDL) to pro-inflammatory mediators. Lp-PLA2 is highly expressed in the necrotic core of atherosclerotic plaques and has been associated with atherosclerotic plaque instability. Multiple studies have shown an association between elevated Lp-PLA2 levels and risk of both stroke and myocardial infarction, even after adjustment for standard vascular risk factors, and several professional organizations have recommended Lp PLA2 as a potentially usefully tool to improve risk stratification for individual patients. Therapies directed at lowering Lp-PLA2 levels may represent a novel approach to reducing vascular risk, though direct clinical benefit from targeting treatment to Lp-PLA2 levels remains unproven. Statins appear to significantly lower Lp-PLA2 levels; fibrates and niacin may also lower Lp-PLA2 levels, though this is less well established. Darapladib, a potent, selective Lp-PLA2 inhibitor, is currently in phase III trials for prevention of recurrent vascular events in patients with coronary artery disease. PMID- 23456914 TI - Attract-and-kill as a new strategy for the management of the potato tuber moths Phthorimaea operculella (Zeller) and Symmetrischema tangolias (Gyen) in potato: evaluation of its efficacy under potato field and storage conditions. AB - BACKGROUND: Attract-and-kill composed of pure sex pheromones of the potato tuber moths Phthorimaea operculella (Zeller) and Symmetrischema tangolias (Gyen) and the insecticide cyfluthrin resulted in 100% mortality of males under controlled laboratory conditions. The aim of the present study was to investigate the efficacy of this strategy in different potato agroecologies as well as under simulated potato storage conditions. RESULTS: Attract-and-kill was highly effective at reducing male flight activity and significantly reduced daily moth catches in pheromone-baited water traps (by 51.8-99.9%) in comparison with untreated plots. This largely depended on the field size, the attract-and-kill droplet size and the density applied per hectare. Highest efficacy, which was independent of pest density, was achieved when attract-and-kill was applied on larger potato fields using a droplet density of 2500 source points ha(-1) at a droplet size of 100 uL. Consequently, pest infestation on vegetative plant parts as well as on tubers was significantly reduced (by up to 90%) in comparison with untreated controls. Under simulated storage conditions with a high number of females and males released periodically, an efficacy of 84.1 and 87.2% was achieved in reducing tuber infestation by P. operculella and S. tangolias respectively. CONCLUSIONS: Attract-and-kill is very effective in controlling the two potato tuber moth species under both field and storage conditions; it is a new, attractive and (for storage conditions) low-cost method that can be easily integrated in potato pest management programmes, especially in small-scale agricultural systems of the tropics and subtropics. PMID- 23456919 TI - Micronuclei-associated MYC amplification in the form of double minute chromosomes in acute myeloid leukemia. PMID- 23456920 TI - A modular design of low-background bioassays based on a high-affinity molecular pair barstar:barnase. AB - High-affinity molecular pairs provide a convenient and flexible modular base for the design of molecular probes and protein/antigen assays. Specificity and sensitivity performance indicators of a bioassay critically depend on the dissociation constant (K(D)) of the molecular pair, with avidin:biotin being the state-of-the-art molecular pair (K(D) ~ 1 fM) used almost universally for applications in the fields of nanotechnology and proteomics. In this paper, we present an alternative high-affinity protein pair, barstar:barnase (K(D) ~ 10 fM), which addresses several shortfalls of the avidin:biotin system, including non-negligible background due to the non-specific binding. A quantitative assessment of the non-specific binding carried out using a model assay revealed inherent irreproducibility of the [strept]avidin:biotin-based assays, attributed to the avidin binding to solid phases, endogenous biotin molecules and serum proteins. On the other hand, the model assays assembled via a barstar:barnase protein linker proved to be immune to such non-specific binding, showing good prospects for high-sensitivity rare biomolecular event nanoproteomic assays. PMID- 23456921 TI - Which density functional is close to CCSD accuracy to describe geometry and interaction energy of small non-covalent dimers? A benchmark study using Gaussian09. AB - A benchmark study on all possible density functional theory (DFT) methods in Gaussian09 is done to locate functionals that agree well with CCSD/aug-cc-pVTZ geometry and Ave-CCSD(T)/(Q-T) interaction energy (Eint) for small non-covalently interacting molecular dimers in "dispersion-dominated" (class 1), "dipole-induced dipole" (class 2), and "dipole-dipole" (class 3) classes. A DFT method is recommended acceptable if the geometry showed close agreement to CCSD result (RMSD < 0.045) and Eint was within 80-120% accuracy. Among 382 tested functionals, 1-46% gave good geometry, 13-44% gave good Eint , while 1-33% satisfied geometry and energy criteria. Further screening to locate the best performing functionals for all the three classes was made by counting the acceptable values of energy and geometry given by each functionals. The meta generalized gradient approximation (GGA) functional M06L was the best performer with total 14 hits; seven acceptable energies and seven acceptable geometries. This was the only functional "recommended" for at least two dimers in each class. The functionals M05, B2PLYPD, B971, mPW2PLYPD, PBEB95, and CAM-B3LYP gave 11 hits while PBEhB95, PW91B95, Wb97x, BRxVP86, BRxP86, HSE2PBE, HSEh1PBE, PBE1PBE, PBEh1PBE, and PW91TPSS gave 10 hits. Among these, M05, B971, mPW2PLYPD, Wb97x, and PW91TPSS were among the "recommended" list of at least one dimer from each class. Long-range correction (LC) of Hirao and coworkers to exchange-correlation functionals showed massive improvement in geometry and Eint . The best performing LC-functionals were LC-G96KCIS and LC-PKZBPKZB. Our results predict that M06L is the most trustworthy DFT method in Gaussian09 to study small non-covalently interacting systems. PMID- 23456923 TI - Spectroscopic and theoretical study on electronically modified chromophores in LOV domains: 8-bromo- and 8-trifluoromethyl-substituted flavins. AB - Two chemically synthesized flavin derivatives, 8-trifluoromethyl- and 8 bromoriboflavin (8-CF(3)RF and 8-BrRF), were photochemically characterized in H(2)O and studied spectroscopically after incorporation into the LOV domain of the blue light photoreceptor YtvA from Bacillus subtilis. The spectroscopic studies were paralleled by high-level quantum chemical calculations. In solution, 8-BrRF showed a remarkably high triplet quantum yield (0.97, parent compound riboflavin, RF: 0.6) and a small fluorescence quantum yield (0.07, RF: 0.27). For 8-CF(3)RF, the triplet yield was 0.12, and the fluorescence quantum yield was 0.7. The high triplet yield of 8-BrRF is due to the bromine heavy atom effect causing a stronger spin-orbit coupling. Theoretical calculations reveal that the decreased triplet yield of 8-CF(3)RF is due to a smaller charge transfer and a less favorable energetic position of T(2), required for intersystem crossing from S(1) to T(1), as an effect of the electron-withdrawing CF(3) group. The reconstitution of the LOV domain with the new flavins resulted in the typical LOV photochemistry, consisting of triplet state formation and covalent binding of the chromophore, followed by a thermal recovery of the parent state, albeit with different kinetics and photophysical properties. PMID- 23456922 TI - Fast trabecular bone strength predictions of HR-pQCT and individual trabeculae segmentation-based plate and rod finite element model discriminate postmenopausal vertebral fractures. AB - Although high-resolution peripheral quantitative computed tomography (HR-pQCT) has advanced clinical assessment of trabecular bone microstructure, nonlinear microstructural finite element (uFE) prediction of yield strength using a HR-pQCT voxel model is impractical for clinical use due to its prohibitively high computational costs. The goal of this study was to develop an efficient HR-pQCT based plate and rod (PR) modeling technique to fill the unmet clinical need for fast bone strength estimation. By using an individual trabecula segmentation (ITS) technique to segment the trabecular structure into individual plates and rods, a patient-specific PR model was implemented by modeling each trabecular plate with multiple shell elements and each rod with a beam element. To validate this modeling technique, predictions by HR-pQCT PR model were compared with those of the registered high-resolution micro-computed tomography (HR-uCT) voxel model of 19 trabecular subvolumes from human cadaveric tibia samples. Both the Young's modulus and yield strength of HR-pQCT PR models strongly correlated with those of uCT voxel models (r2 = 0.91 and 0.86). Notably, the HR-pQCT PR models achieved major reductions in element number (>40-fold) and computer central processing unit (CPU) time (>1200-fold). Then, we applied PR model uFE analysis to HR-pQCT images of 60 postmenopausal women with (n = 30) and without (n = 30) a history of vertebral fracture. HR-pQCT PR model revealed significantly lower Young's modulus and yield strength at the radius and tibia in fracture subjects compared to controls. Moreover, these mechanical measurements remained significantly lower in fracture subjects at both sites after adjustment for areal bone mineral density (aBMD) T-score at the ultradistal radius or total hip. In conclusion, we validated a novel HR-pQCT PR model of human trabecular bone against uCT voxel models and demonstrated its ability to discriminate vertebral fracture status in postmenopausal women. This accurate nonlinear uFE prediction of the HR-pQCT PR model, which requires only seconds of desktop computer time, has tremendous promise for clinical assessment of bone strength. PMID- 23456925 TI - The correlation of neurophysiological findings with clinical and functional status in patients following traumatic nerve injury. AB - In this study, we aimed to determine whether there is a correlation between the electrodiagnostic findings and the functional status, muscle strength and sensibility in patients with traumatic nerve injury to the wrists. We assessed 50 patients at a mean of 11.6 months (SD 5.85) (range 6-25) after nerve injury. Sensibility was assessed by monofilament testing. Motor function was evaluated by assessing the manual muscle grade of the abductor pollicis brevis and abductor digiti minimi muscles. Function was evaluated by the Sollerman Hand Function Test. The amplitudes of the compound muscle action potential and the sensory nerve action potential were determined by electroneuromyography. While the compound muscle action potential and sensory nerve action potential amplitudes had significant correlation with muscle grade and Semmes Weinstein Monofilament tests, there was no correlation with the functional scores. PMID- 23456926 TI - The diaphysial axis-metacarpal head angle in the management of fractures of the base of the proximal phalanx in children. AB - The diaphysial axis-metacarpal head angle (DHA) is the angle formed between the longitudinal axis of the diaphysis of the proximal phalanx and central point of the metacarpal head. The normal DHA ranges from 177.1 degrees and 180.0 degrees . There were no significant differences between DHA measurements when taken by the same observer at two separate occasions (P = 0.986) or when taken by two different observers (P = 0.948). We have put an algorithm of management of paediatric phalangeal base fractures incorporating the DHA in the decision making. A prospective study of 92 children (5-14 years) with phalangeal base fractures was conducted. Closed reduction was possible in all but one case in which open reduction and K-wire fixation was required. Closed reduction of the remaining 91 fractures yielded a 'good' reduction in 80 cases (no finger deformity on clinical examination with a post-reduction DHA greater than 177 degrees ). After a mean follow-up of 4.2 months, all these 80 cases qualified for an excellent outcome as per Al-Qattan's criteria. The remaining 11 children were considered to have an 'acceptable' reduction (no scissoring, but there was a mild residual lateral deviation of the finger with a DHA angle of 169.4 degrees to 176.2 degrees ). At a mean follow-up of 28 months, all these 11 mal-united fractures remodelled with normalization of the DHA; and all 11 children qualified for an excellent outcome as per Al-Qattan's criteria. The current series stresses on the advantages of using DHA in the objective assessment of paediatric phalangeal base fractures and demonstrates the remodelling of fractures with about 10 degrees of lateral deviation. PMID- 23456927 TI - TNF antagonists and shingles: is vaccination advisable? PMID- 23456928 TI - Supporting TB clinicians managing difficult cases: the ERS/WHO Consilium. PMID- 23456929 TI - Who can pay for innovative medicines? PMID- 23456930 TI - Rebuilding a diseased lung: repair and regeneration. PMID- 23456931 TI - Consensus statement on inert gas washout measurement: at the threshold of clinical use. PMID- 23456932 TI - A BOLD statement on how to case-find moderate/severe COPD. PMID- 23456933 TI - Sleep apnoea and hypertension: time for recommendations. PMID- 23456934 TI - Small airways in asthma: their independent contribution to the severity of hyperresponsiveness. PMID- 23456935 TI - Sarcoid-like lesion is a frequent benign cause of lymphadenopathy in neoplastic patients. PMID- 23456936 TI - HHIP, HDAC4, NCR3 and RARB polymorphisms affect fetal, childhood and adult lung function. PMID- 23456937 TI - Contact screening in tuberculosis: can we identify those with higher risk? PMID- 23456938 TI - Evidence of respiratory system remodelling in a competitive freediver. PMID- 23456939 TI - Alveolar macrophages carbon load: a marker of exposure? PMID- 23456940 TI - Inspiratory pressure during noninvasive ventilation in stable COPD: help the lungs, but do not forget the heart. PMID- 23456941 TI - Inspiratory pressure during noninvasive ventilation in stable COPD: help the lungs, but do not forget the heart. PMID- 23456943 TI - A mechanism for the synergism of FGF- and Wnt-signaling during lens fiber cell differentiation. PMID- 23456944 TI - The internal circadian clock increases hunger and appetite in the evening independent of food intake and other behaviors. AB - OBJECTIVE: Despite the extended overnight fast, paradoxically, people are typically not ravenous in the morning and breakfast is typically the smallest meal of the day. We assessed whether this paradox could be explained by an endogenous circadian influence on appetite with a morning trough, while controlling for sleep/wake and fasting/feeding effects. DESIGN AND METHODS: Twelve healthy non-obese adults (six males; age, 20-42 years) were studied throughout a 13-day laboratory protocol that balanced all behaviors, including eucaloric meals and sleep periods, evenly across the endogenous circadian cycle. Participants rated their appetite and food preferences by visual analog scales. RESULTS: There was a large endogenous circadian rhythm in hunger, with the trough in the biological morning (8 AM) and peak in the biological evening (8 PM; peak to-trough amplitude = 17%; P = 0.004). Similarly-phased significant endogenous circadian rhythms were present in appetites for sweet, salty and starchy foods, fruits, meats/poultry, food overall, and for estimates of how much food participants could eat (amplitudes 14-25%; all P < 0.05). CONCLUSIONS: In people who sleep at night, the intrinsic circadian evening peak in appetite may promote larger meals before the fasting period necessitated by sleep, whereas the circadian morning trough would theoretically facilitate the extended overnight fast. Furthermore, the circadian decline in hunger across the night would theoretically counteract the fasting-induced hunger increase that could otherwise disrupt sleep. PMID- 23456945 TI - Cadmium adsorption by willow root: the role of cell walls and their subfractions. AB - Plant cell walls may play an important role in the uptake and accumulation of heavy metals. This study was undertaken to obtain a better understanding of the role of the root cell walls (RCW) and their subfractions on adsorption of cadmium (Cd) in a promising woody phytoremediation species, Salix jiangsuensis J172. In order to examine how Cd binding was affected by pectin and hemicellulose, RCW were isolated and sequentially fractioned by removing pectin (RCW1), partial removal of hemicellulose (RCW2), and complete removal of hemicellulose (RCW3). The RCW and fractions were characterized by Fourier transform infrared spectroscopy, which suggested decomposition of hemicellulose and a decline in nitrogen content following cell wall isolation and fractionation. The adsorption affinity of Cd increased gradually following the sequential extraction of root cells, suggesting that hemicellulose negatively impacted Cd adsorption, while pectin and cellulose enhanced Cd adsorption. Cd adsorption dynamics and isotherms could be best described by the pseudo-second-order (R>0.99) and Freundlich (R>0.97) models, respectively. Thermodynamic properties (?G, ?H, and ?S), determined using the van't Hoff equation, indicated that while Cd adsorption was endothermic, and spontaneous for RCW2 and RCW3, adsorption was not spontaneous for the root, RCW, and RCW1. The results provide evidence for the importance of the root cell walls in the adsorption of Cd by willow roots. PMID- 23456946 TI - Contamination of the River Ganga and its toxic implication in the blood parameters of the major carp Labeo rohita (Ham). AB - A field study was conducted to examine different physicochemical properties of water and various haematological and biochemical parametres of the fish Labeo rohita collected from the Ganga River (National river of India) at Varanasi district, India. The water was found to be greatly contaminated with a number of dissolved metals (Fe, Cr, Zn, Cu, Mn, Ni and Pb) whose concentrations were above the safe limits suggested by Bureau of Indian Standard (BIS 1991) for drinking water (Fe, 1,353.33 %; Cr, 456 %; Mn, 553.33 %; Ni, 4,490 % and Pb, 1,410 %). The metal accumulation in the fish blood was very high (Fe, 2,408 %; Cr, 956.57 %; Zn, 464.90 %; Cu, 310.57 %; Mn, 1,115.48 %) in comparison to the control fish maintained under strict quality control. Lower values of the various haematological parameters (total erythrocytes count, haemoglobin, haematocrit, mean corpuscular volume and O2-carrying capacity) in the river fish in comparison to the control indicate toxic manifestation exerted by the contaminated river water on the fish. The higher level of total leucocytes count further illustrates stressed condition of the river fish. The toxic impact of the Ganga water is also expressed in the fish by the presence of higher levels of cholesterol, glucose, elevated activities of the enzymes aspartate amino transferase and alanine amino transferase, and lowered protein concentration. PMID- 23456947 TI - Investigation of preparation conditions and photocatalytic efficiency of nano ZnO using different polysaccharides. AB - The development of a complete set of extensive studies combining both the preparation factors of catalysts and photocatalytic experimental factors for the photodegradation of methylene blue, crystal violet, and Congo red using effective nano zinc oxide (ZnO) obtained from polysaccharides (chitosans, corn starch, and sodium alginate) as chelating agents was the main objective of this study. The influence of nature of polysaccharides, ratio of reactants, calcination temperatures during preparation process, and effects of photocatalytic experimental conditions on photodegradation was investigated. Corn starch and sodium alginate were found to be effective chelating agents and optimum preparation parameters were set as 3:3 % ratio of reactants and 450 degrees C calcination temperature to prepare nano ZnO with good photocatalytic activity. The order of organic dyes based on their photodegradation rates was arranged as crystal violet > methylene blue > Congo red. Our findings shed light on the optimization of both preparation conditions of photocatalysts and photocatalytic experimental conditions. PMID- 23456948 TI - New trends in the analytical determination of emerging contaminants and their transformation products in environmental waters. AB - Since the so-called emerging contaminants were established as a new group of pollutants of environmental concern, a great effort has been devoted to the knowledge of their distribution, fate and effects in the environment. After more than 20 years of work, a significant improvement in knowledge about these contaminants has been achieved, but there is still a large gap of information on the growing number of new potential contaminants that are appearing and especially of their unpredictable transformation products. Although the environmental problem arising from emerging contaminants must be addressed from an interdisciplinary point of view, it is obvious that analytical chemistry plays an important role as the first step of the study, as it allows establishing the presence of chemicals in the environment, estimate their concentration levels, identify sources and determine their degradation pathways. These tasks involve serious difficulties requiring different analytical solutions adjusted to purpose. Thus, the complexity of the matrices requires highly selective analytical methods; the large number and variety of compounds potentially present in the samples demands the application of wide scope methods; the low concentrations at which these contaminants are present in the samples require a high detection sensitivity, and high demands on the confirmation and high structural information are needed for the characterisation of unknowns. New developments on analytical instrumentation have been applied to solve these difficulties. Furthermore and not less important has been the development of new specific software packages intended for data acquisition and, in particular, for post-run analysis. Thus, the use of sophisticated software tools has allowed successful screening analysis, determining several hundreds of analytes, and assisted in the structural elucidation of unknown compounds in a timely manner. PMID- 23456949 TI - Consumption of Ruditapes philippinarum and Ruditapes decussatus: comparison of element accumulation and health risk. AB - Ruditapes philippinarum, a species native from the Indo-Pacific region, was introduced in Europe at the beginning of the 1970s for culture purposes, leading to a massive decrease of the native species Ruditapes decussatus and a high increase of R. philippinarum yields in Europe. Bivalves can accumulate high amounts of metals and thus easily reach concentrations that are toxic not only to themselves but also to consumers. Since differences in the accumulation of pollutants may exist between bivalve species, different health risks may be overcome. For this reason, the level of metals in seafood raises public health concerns, and international organisations like European Food Safety Authority, United States Food and Drug Administration, and Food Standards Australia and New Zealand (FSANZ) set maximum levels (MLs), above which edible seafood cannot be marketed. In order to evaluate the risk associated with the consumption of R. philippinarum and R. decussatus, both clam species were collected in the same site in Ria de Aveiro and the concentration of eight elements determined in organisms before and after a 48-h depuration period. Results evidence that even at low contaminated areas, the MLs for some elements can easily be achieved. The concentrations of As were above the reference values for FSANZ, and the provisional tolerable weekly intake (PTWI) is exceeded for As when more than 0.5 kg of R. decussatus and 0.9 kg of R. philippinarum clam flesh is consumed, in 1 week, by an adult (70 kg). When comparing with other systems worldwide, consumers of depurated clams from this coastal system have a similar or lower risk of exceeding the PTWI for Cd, As, Pb, and Hg. The recently introduced clam, R. philippinarum, accumulates lower amounts of the most health-threatening elements (less than 71 % of Cd, 40 % of As, and 20 % of Hg) than the native R. decussatus, except for Pb. R. philippinarum also reduces more the element burden when subjected to depuration than R. decussatus. Moreover, R. philippinarum allocates a lower proportion of the accumulated elements in the soluble fraction, where they are readily available. Thus, it is safer to consume R. philippinarum than R. decussatus, except when clams come from areas heavily polluted by Pb. PMID- 23456950 TI - Occurrence and larval movement of Diatraea saccharalis (Lepidoptera: Crambidae) in seed mixes of non-Bt and Bt pyramid corn. AB - BACKGROUND: Larval movement of target pest populations among Bt and non-Bt plants is a major concern in the use of a seed mixture refuge strategy for Bt resistance management. In this study, occurrence and larval movement of the sugarcane borer, Diatraea saccharalis (F.), were evaluated in four planting patterns of non-Bt and Bt plants containing Genuity(r) SmartStax(TM) traits in 2009-2011. The four planting patterns were: (1) a pure stand of 27 Bt plants; (2) one non-Bt plant in the center, surrounded by 26 Bt plants; (3) a pure stand of 27 non-Bt plants; (4) one Bt plant in the center, surrounded by 26 non-Bt plants. Studies were conducted under four conditions: (1) open field with natural infestation; (2) greenhouse with artificial infestations; open field with artificial infestations (3) on the center plants only and (4) on every plant. The major objective of this study was to determine whether refuge plants in a seed mixture strategy could provide a comparable refuge population of D. saccharalis to a 'structured refuge' planting. RESULTS: Larvae of D. saccharalis showed the ability to move from infested plants to at least four plants away, as well as to adjacent rows, but the majority remained within the infested row. However, the number of larvae found on the non-Bt plants in the mixture plantings was not significantly reduced compared with the pure stand of non-Bt corn. CONCLUSION: The results of this study show that refuge plants in a seed mixture may be able to provide a comparable refuge population of D. saccharalis to a structured refuge planting. PMID- 23456951 TI - National Institute on Drug Abuse symposium report: drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. AB - The National Institute on Drug Abuse organized a symposium on drugs of abuse, dopamine, and HIV-associated neurocognitive disorders (HAND)/HIV-associated dementia (HAD) in Rockville, Maryland, October 4, 2011. The purpose of this symposium was to evaluate the potential role of dopamine in the potentiation of HAND/HAD by drugs of abuse. A summary of the symposium has been presented in this report. PMID- 23456952 TI - Acquisition and long-term retention of spatial learning in the human immunodeficiency virus-1 transgenic rat: effects of repeated nicotine treatment. AB - The HIV-1 transgenic (HIV-1Tg) rat shows a deficit in learning to locate a submerged platform in a multiple-trial water maze task compared to transgenic littermate and F344 control rats (Vigorito et al., J.Neuroimmune Pharmacol 2:319 328, 2007; Lashomb et al., J.Neurovirol 15:14-24, 2009). Nicotine is known to have neuroprotective effects possibly by minimizing cytotoxic effects of glutamate or by modulating a cholinergic anti-inflammatory pathway. Nicotine also improves performance in a variety of learning tasks by enhancing attention and short-term memory (STM). The purpose of this study was to determine if the learning deficit in HIV-1Tg is ameliorated by repeated nicotine treatment independent of its effects on STM. HIV-1Tg and F344 rats were treated (subcutaneous) with nicotine (0.25 mg/kg/injection) or saline twice daily and tested in a single-trial-per-day procedure which precludes the impact of STM on the acquisition of the spatial learning task. HIV-1Tg rats showed a deficit in the acquisition of the task and in the long-term retention for the platform location in a probe test. Nicotine did not ameliorate the deficit in HIV-1Tg rats and slightly worsened performance during acquisition. Analysis of individual differences in performance during the probe test suggested that nicotine improved performance in some F344 rats but not in HIV-1Tg rats. These results indicate that a deficit in the consolidation of long-term memory contributes to the acquisition deficit of HIV1-Tg rats. The results, however, do not provide any evidence of the amelioration of the learning deficit observed in this behavioral model at least with the nicotine dose tested. PMID- 23456953 TI - Search for varicella zoster virus and herpes simplex virus-1 in normal human cerebral arteries. AB - Virological confirmation of varicella zoster virus (VZV) vasculopathy is provided by presence of virus in the cerebral arteries, frequently associated with inflammation. Yet, cerebral arteries from normal subjects have never been studied for VZV DNA or antigen. We analyzed 63 human cerebral arteries from 45 subjects for VZV DNA and antigen, control herpes simplex virus (HSV)-1 DNA and antigen, and leukocyte-specific CD45 antigen. No cerebral arteries contained VZV or HSV-1 DNA or antigen; eight arteries from seven subjects contained leukocytes expressing CD45. Thus, the presence of VZV antigen in cerebral arteries of patients with stroke is likely to be clinically significant. PMID- 23456954 TI - Epithelioid hemangioendothelioma involving bone marrow presenting with persistent anemia. PMID- 23456955 TI - Structure and biosynthesis of fimsbactins A-F, siderophores from Acinetobacter baumannii and Acinetobacter baylyi. AB - Novel chatechol/hydroxamate siderophores (named "fimsbactins") were identified in Acinetobacter baumannii ATCC 17978 and Acinetobacter baylyi ADP1. The major compound, fimsbactin A, was isolated from low-iron cultures of A. baylyi ADP1, and its chemical structure was elucidated by mass spectrometry, and detailed (1)H, (13)C and (15)N NMR spectroscopy. From inverse feeding experiments following HPLC-MS analysis, the structures of five additional derivatives were elucidated. The gene cluster encoding the fimsbactin synthetase (fbs) was identified in both genomes, and mutants in fbs genes in A. baylyi were analyzed, thus allowing prediction of the fimsbactin biosynthesis pathway. PMID- 23456956 TI - Comparative safety of selective serotonin reuptake inhibitors among pediatric users with respect to adverse cardiac events. AB - PURPOSE: This study aims to perform a comparative safety study assessing the risk of ventricular arrhythmia, cardiac arrest, or sudden death among pediatric selective serotonin reuptake inhibitor (SSRI) users. METHODS: Using US claims data from 1997 to 2009, new pediatric (age < 18 years) users of SSRI monotherapy were identified. Adverse cardiac outcomes occurring within 12 months of SSRI initiation were identified using a previously validated International Classification of Disease, ninth edition algorithm. Cox proportional hazard analysis was used to estimate the risk for each SSRI, using fluoxetine as the referent group, adjusting for the propensity to receive an individual SSRI, demographics, and exposure covariates. RESULTS: Over the study period, 113,714 subjects met the inclusion criteria and contributed 40,639 person-years of SSRI exposure time. Sertraline (33%) and fluoxetine (29%) were the most commonly prescribed SSRIs. Forty events occurred within 12 months of SSRI initiation. The crude incidence rate was highest for escitalopram (19.5/10,000 person-years) and lowest for fluoxetine (4.2/10,000 person-years). The median time to event ranged from 45 to 86 days. The adjusted risk of adverse event, relative to fluoxetine, was highest for citalopram Hazard Ratio (HR) = 3.53, 95% confidence interval [CI] = 1.09-11.46) and escitalopram (HR = 3.30, 95%CI = 1.08-10.14) and lowest for paroxetine (HR = 1.34, 95%CI = 0.30-5.99) and sertraline (HR = 2.14, 95%CI = 0.75 6.16). CONCLUSIONS: The incidence of adverse cardiac events among pediatric SSRI users was low. However, the risk of an adverse outcome was higher for citalopram and escitalopram users as compared with fluoxetine users. Future studies should focus on confirming these findings and identifying modifying risk factors to optimize medication selection for this population. PMID- 23456958 TI - The unfolded protein response regulator GRP78 is a novel predictive biomarker in colorectal cancer. AB - Adjuvant fluoropyrimidine-based (5-FU) chemotherapy is a mainstay of treatment for colorectal cancer (CRC), but only provides benefit for a subset of patients. To improve stratification we examined (for the first time in CRC), whether analysis of GRP78 expression provides a predictive biomarker and performed functional studies to examine the role of GRP78 in sensitivity to 5-FU. 396 CRC patient samples were collected in a prospective uniform manner and GRP78 expression was determined by immunohistochemistry on tissue microarrays using a well-validated antibody. Expression was correlated with clinicopathological parameters and survival. The role of GRP78 in 5-FU sensitivity was examined in CRC cells using siRNA, drug inhibition and flow cytometry. GRP78 expression was significantly elevated in cancer tissue (p < 0.0001), and correlated with depth of invasion (p = 0.029) and stage (p = 0.032). Increased overall 5-year survival was associated with high GRP78 expression (p = 0.036). Patients with stage II cancers treated by surgery alone, with high GRP78 also had improved survival (71% v 50%; p = 0.032). Stage III patients with high GRP78 showed significant benefit from adjuvant chemotherapy (52% vs. 28%; p = 0.026), whereas patients with low GRP78 failed to benefit (28% vs. 32%; p = 0.805). Low GRP78 was an independent prognostic indicator of reduced overall 5-year survival (p = 0.004; HR = 1.551; 95%CI 1.155-2.082). In vitro, inhibition of GRP78 reduces apoptosis in response to 5-FU in p53 wild-type cells. GRP78 expression may provide a simple additional risk stratification to inform the adjuvant treatment of CRC and future studies should combine analysis with determination of p53 status. PMID- 23456957 TI - Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor. AB - States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF 1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF 1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth. PMID- 23456959 TI - [Social and economic consequences of night-time aircraft noise in the vicinity of Frankfurt/Main airport]. AB - A prospective calculation of disease-related social and economic costs due to night-time aircraft noise in the vicinity of Frankfurt/Main airport was performed for the calendar years 2012-2021. It was based on risk estimates for a variety of diagnostic entities (cardiovascular disease, depression, psychosis, diabetes mellitus, dementia and Alzheimer's disease, all cancers except malignancies of the respiratory system) from a previous case-control study on more than 1 million persons enrolled in compulsory sickness funds in the vicinity of the Cologne-Bonn airport, on disease-related cost estimates performed by the German Federal Statistical Office for the calender years 2002-2008, and calculations of the population exposed to night-time aircraft noise in the vicinity of Frankfurt/Main airport (2005 aircraft routes and flight frequencies). Total estimated costs came to more than 1.5 billion ? with an excess of 23 400 cases of diseases treated in hospitals and of 3 400 subsequent deaths. PMID- 23456960 TI - An automated in-gel digestion/iTRAQ-labeling workflow for robust quantification of gel-separated proteins. AB - Simple protein separation by 1DE is a widely used method to reduce sample complexity and to prepare proteins for mass spectrometric identification via in gel digestion. While several automated solutions are available for in-gel digestion particularly of small cylindric gel plugs derived from 2D gels, the processing of larger 1D gel-derived gel bands with liquid handling work stations is less well established in the field. Here, we introduce a digestion device tailored to this purpose and validate its performance in comparison to manual in gel digestion. For relative quantification purposes, we extend the in-gel digestion procedure by iTRAQ labeling of the tryptic peptides and show that automation of the entire workflow results in robust quantification of proteins from samples of different complexity and dynamic range. We conclude that automation improves accuracy and reproducibility of our iTRAQ workflow as it minimizes the variability in both, digestion and labeling efficiency, the two major causes of irreproducible results in chemical labeling approaches. PMID- 23456961 TI - Developing the discipline and practice of comprehensive men's health. AB - Men of all ages in the United States experience disproportionately higher rates of morbidity and premature death than females. The reasons for this are complex and include biological, sociological, and health system-related issues, but this is also in part due to the fact that men and boys tend to lead more risky lifestyles and generally avoid preventive care when compared with women and girls. These disparities not only affect males but also their loved ones and can adversely affect their participation in the workforce and in their communities. Better understanding of the drivers of men's health disparities is needed to enable health professionals to more effectively address this problem. One of the fundamental building blocks for changing health care delivery to males is to provide a core curricular framework for education and training of health professionals related to the specific health issues of men and boys. This article will present a study assessing what men's health courses are available in the United States and identifying the content within such courses that will prepare health care professionals to deliver programs and care to this demographic. The study identified that as of 2012, there were only 21 courses in 18 institutions that address gender-appropriate health care for boys and men. The authors conclude that developing and incorporating an expert, consensus-based men's health core curriculum in universities and colleges, particularly in health professional programs, is an extremely important cornerstone in advancing the science and practice of true and balanced gender-based care delivery. PMID- 23456962 TI - Comparative assessment of computational methods for the determination of solvation free energies in alcohol-based molecules. AB - The determination of differences in solvation free energies between related drug molecules remains an important challenge in computational drug optimization, when fast and accurate calculation of differences in binding free energy are required. In this study, we have evaluated the performance of five commonly used polarized continuum model (PCM) methodologies in the determination of solvation free energies for 53 typical alcohol and alkane small molecules. In addition, the performance of these PCM methods, of a thermodynamic integration (TI) protocol and of the Poisson-Boltzmann (PB) and generalized Born (GB) methods, were tested in the determination of solvation free energies changes for 28 common alkane alcohol transformations, by the substitution of an hydrogen atom for a hydroxyl substituent. The results show that the solvation model D (SMD) performs better among the PCM-based approaches in estimating solvation free energies for alcohol molecules, and solvation free energy changes for alkane-alcohol transformations, with an average error below 1 kcal/mol for both quantities. However, for the determination of solvation free energy changes on alkane-alcohol transformation, PB and TI yielded better results. TI was particularly accurate in the treatment of hydroxyl groups additions to aromatic rings (0.53 kcal/mol), a common transformation when optimizing drug-binding in computer-aided drug design. PMID- 23456963 TI - Coexistence of granulomatous enteric inflammation and neoplasia in an adult sheep. AB - A 7-year-old dairy sheep suffering from chronic loss of weight without diarrhea or anorexia was euthanized after failing to respond to any treatment (antibiotic and antiparasitic). The main findings at the necropsy of this animal were multifocal miliary nodules in several organs, mainly in the Peyer's patches of the small intestine, and a segmental thickening of the jejunal wall. Histologic examination of the samples taken at the necropsy showed a multifocal chronic granulomatous inflammation, with mineralization and caseous necrosis at the core of the larger granulomas and scarce intrahistiocytic acid-fast bacilli consistent with a disseminated digestive tuberculosis. Polymerase chain reaction and bacteriological culture from these samples confirmed Mycobacterium avium subsp avium to be the etiologic agent of this infection. Histologically, the cause of the segmental thickening of the jejunal wall was found to be a small intestine adenocarcinoma, which in some areas coexisted with the granulomatous lesion. PMID- 23456964 TI - From bipeds to an honorary member of the American College of Veterinary Pathologists. PMID- 23456965 TI - Tumoral calcinosis form of hydroxyapatite deposition disease in related red bellied short-necked turtles, Emydura subglobosa. AB - Ten of 12 red-bellied short-necked turtles from a single clutch presented at 9 months of age with multiple white to tan nodules on their feet. Histologically, the nodules were composed of large periarticular deposits of mineralized crystalline material that extended into the joint spaces of interphalangeal joints and was surrounded by granulomatous inflammation and fibrosis. Crystallographic analysis determined the material to be apatite (calcium phosphate hydroxide) consistent with the tumoral calcinosis form of hydroxyapatite deposition disease (HADD). HADD has previously been described in aquatic turtles and rarely lizards and must be differentiated from gout in reptiles. A cause for the tumoral calcinosis lesions in these turtles could not be determined; however, based on previous reports in this species, a species specific predilection, in conjunction with unknown environmental factors, is suspected. The use of the terms HADD, pseudogout (calcium pyrophosphate crystal deposition disease), and calcinosis circumscripta has been inconsistent, creating confusion in the literature. PMID- 23456966 TI - Use of computed tomography and histopathologic review for lung lesions produced by the interaction between Mycoplasma hyopneumoniae and fumonisin mycotoxins in pigs. AB - Mycoplasma hyopneumoniae has a primary role in the porcine respiratory disease complex (PRDC). The objective of this study was to determine whether fumonisin mycotoxins influence the character and/or the severity of pathological processes induced in the lungs of pigs by Mycoplasma hyopneumoniae. Four groups of pigs (n = 7/group) were used, one fed 20 ppm fumonisin B1 (FB1) from 16 days of age (group F), one only infected with M. hyopneumoniae on study day 30 (group M), and a group fed FB1 and infected with M. hyopneumoniae (group MF), along with an untreated control group (group C). Computed tomography (CT) scans of infected pigs (M and MF) on study day 44 demonstrated lesions extending to the cranial and middle or in the cranial third of the caudal lobe of the lungs. The CT images obtained on study day 58 showed similar but milder lesions in 5 animals from group M, whereas lungs from 2 pigs in group MF appeared progressively worse. The evolution of average pulmonary density calculated from combined pixel frequency values, as measured by quantitative CT, was significantly influenced by the treatment and the age of the animals. The most characteristic histopathologic lesion in FB1-treated pigs was pulmonary edema, whereas the pathomorphological changes in Mycoplasma-infected pigs were consistent with catarrhal bronchointerstitial pneumonia. FB1 aggravated the progression of infection, as demonstrated by severe illness requiring euthanasia observed in 1 pig and evidence of progressive pathology in 2 pigs (group MF) between study days 44 and 58. PMID- 23456967 TI - Histological characterization of dilated cardiomyopathy in the juvenile toy Manchester terrier. AB - Dilated cardiomyopathy (DCM), the most common form of cardiomyopathy in the dog, most often occurs in certain breeds. The objective of this study was to describe a rapidly progressive form of DCM that has been recently recognized in juvenile Toy Manchester Terrier dogs (TMTs). The clinical history and gross findings were reviewed in a group of 14 TMTs, and histologic sections of heart were examined in 12 of those 14 TMTs with DCM. Histochemical and histomorphometric analyses were employed to compare the heart in TMTs affected by DCM with that of control dogs. TMTs ranged in age from 10 to 58.3 weeks, with males and females being equally affected. Affected TMT hearts contained foci of degeneration and loss of myofibers with fibrosis and mild lymphoplasmacytic infiltrates. Less prominent features included foci of acute myofiber degeneration and necrosis with or without intralesional mineralization and mild to moderate suppurative and lymphoplasmacytic infiltrates. Morphometric quantification demonstrated that the right ventricle was more severely affected (P <= .05) than the left ventricle with variable involvement of the interventricular septum. Immunohistochemistry for canine parvovirus was negative in all heart samples. However, the absence of parvoviral antigen does not rule out a possible viral or autoimmune cause. The presence of these myocardial lesions among closely related dogs suggests a genetic contribution to this disease process in the TMT. PMID- 23456968 TI - Sudden behavior change in a cat. AB - A 5-year-old, spayed female, domestic short-haired cat had a 10-day history of sudden behavioral changes followed by seizures. Blood parameters were in the reference ranges, and radiographs failed to detect a mass lesion in the brain. Euthanasia was followed by rabies testing, which was negative. Gross lesions were absent. Histologic changes were present only in the brain and consisted of foci of hippocampal pyramidal cell loss, mild gliosis, pallor of the associated neuropil, and neovascularization. PMID- 23456969 TI - Classification of canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas based on microscopic, immunohistochemical, and molecular characteristics. AB - Canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas have been previously diagnosed as gastrointestinal stromal tumors (GIST), leiomyosarcomas, or nonspecified spindle cell sarcomas, but diagnostic criteria for each entity are poorly defined. We propose a classification for canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas based on microscopic, immunohistochemical, and molecular characteristics. Applying the classification to 40 canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas documented its diagnostic and prognostic value. Eighteen (45%) sarcomas were classified as GIST based on positive KIT immunoreactivity. All GISTs were positive for vimentin, 14 (78%) were positive for S-100, and 6 (33%) were positive for smooth muscle actin (SMA). In contrast to their human counterparts, canine GISTs occurred mainly in the small intestine (67%) but commonly metastasized (5/18) to liver, lymph nodes, and omentum. Six GISTs had an activated KIT mutation in exon 11 of c-Kit, but no mutations were detected in exons 8, 9, 13, and 17. Twelve (30%) sarcomas were classified as leiomyosarcomas based on positive labeling for SMA and negative labeling for KIT. Four of these neoplasms were well differentiated leiomyosarcomas characterized by weak to no labeling for vimentin, and 8 were poorly differentiated leiomyosarcomas characterized by strong labeling for vimentin. None of the leiomyosarcomas metastasized, but poorly differentiated leiomyosarcomas had a higher risk of local invasion. Ten (25%) sarcomas were classified as non-GIST/nonleiomyosarcomas that were negative for KIT and SMA but positive for vimentin and either S-100 and/or PGP 9.5. These neoplasms most likely represent sarcomas of neurogenic differentiation resembling Schwann cells or perineurial or endoneurial fibroblasts, respectively. PMID- 23456970 TI - Pathology of tumors in fish associated with retroviruses: a review. AB - Thirteen proliferative diseases in fish have been associated in the literature with 1 or more retroviruses. Typically, these occur as seasonal epizootics affecting farmed and wild fish, and most lesions resolve spontaneously. Spontaneous resolution and lifelong resistance to reinfection are 2 features of some piscine retrovirus-induced tumors that have stimulated research interest in this field. The purpose of this review is to present the reader with the epidemiological and morphological features of proliferative diseases in fish that have been associated with retroviruses by 1 or more of the following methods: detection of C-type retrovirus-like particles or reverse transcriptase activity in tumor tissues; successful tumor transmission trials using well-characterized, tumor-derived, cell-free inocula; or molecular characterization of the virus from spontaneous and experimentally induced tumors. Two of the diseases included in this review, European smelt spawning papillomatosis and bicolor damselfish neurofibromatosis, at one time were attributed to a retroviral etiology, but both are now believed to involve additional viral agents based on more recent investigations. We include the latter 2 entities to update the reader about these developments. PMID- 23456971 TI - The speed and accuracy of material recognition in natural images. AB - We studied the time course of material categorization in natural images relative to superordinate and basic-level object categorization, using a backward-masking paradigm. We manipulated several low-level features of the images-including luminance, contrast, and color-to assess their potential contributions. The results showed that the speed of material categorization was roughly comparable to the speed of basic-level object categorization, but slower than that of superordinate object categorization. The performance seemed to be crucially mediated by low-level factors, with color leading to a solid increase in performance for material categorization. At longer presentation durations, material categorization was less accurate than both types of object categorization. Taken together, our results show that material categorization can be as fast as basic-level object categorization, but is less accurate. PMID- 23456972 TI - A further examination of the lexical-processing stages hypothesized by the E-Z Reader model. AB - Participants' eye movements were monitored while they read sentences in which high- and low-frequency target words were presented normally (i.e., the normal condition) or with either reduced stimulus quality (i.e., the faint condition) or alternating lower- and uppercase letters (i.e., the case-alternated condition). Both the stimulus quality and case alternation manipulations interacted with word frequency for the gaze duration measure, such that the magnitude of word frequency effects was increased relative to the normal condition. However, stimulus quality (but not case alternation) interacted with word frequency for the early fixation time measures (i.e., first fixation, single fixation), whereas case alternation (but not stimulus quality) interacted with word frequency for the later fixation time measures (i.e., total time, go-past time). We interpret this pattern of results as evidence that stimulus quality influences an earlier stage of lexical processing than does case alternation, and we discuss the implications of our results for models of eye movement control during reading. PMID- 23456973 TI - Music can elicit a visual motion aftereffect. AB - Motion aftereffects (MAEs) are thought to result from the adaptation of both subcortical and cortical systems involved in the processing of visual motion. Recently, it has been reported that the implied motion of static images in combination with linguistic descriptions of motion is sufficient to elicit an MAE, although neither factor alone is thought to directly activate visual motion areas in the brain. Given that the monotonic change of musical pitch is widely recognized in music as a metaphor for vertical motion, we investigated whether prolonged exposure to ascending or descending musical scales can also produce a visual motion aftereffect. After listening to ascending or descending musical scales, participants made decisions about the direction of visual motion in random-dot kinematogram stimuli. Metaphoric motion in the musical stimuli did affect the visual direction judgments, in that repeated exposure to rising or falling musical scales shifted participants' sensitivity to visual motion in the opposite direction. The finding that music can induce an MAE suggests that the subjective interpretation of monotonic pitch change as motion may have a perceptual foundation. PMID- 23456974 TI - Hypnotherapy: first line treatment for children with irritable bowel syndrome? PMID- 23456975 TI - Amaranth oil increased fecal excretion of bile Acid but had no effect in reducing plasma cholesterol in hamsters. AB - Hamsters were fed for 4 weeks on four different diets: control (C) (balanced diet containing 20 % corn oil as the lipid source), hypercholesterolemic (H) (identical to C but containing 12 % coconut oil, 8 % corn oil and 0.1 % cholesterol as the lipid source), amaranth oil (A) (identical to H without corn oil but with amaranth oil), and squalene (S) (identical to H but admixed with squalene in the ratio found in amaranth oil). There were no significant differences in lipid profile, and in the cholesterol excreted in the animals' feces from amaranth oil (A) and squalene (S) groups. Fecal excretion of bile acids was greater in the amaranth oil (A) and squalene groups (S) as compared to the other groups. The scores of steatosis and parenchymal inflammation observed in the amaranth oil (A) and squalene groups (S) were superior to the ones observed in the other groups. Our findings demonstrated that amaranth oil, and its component squalene, increased the excretion of bile acids but did not have a hypocholesterolemic effect in hamsters fed on a diet containing high amounts of saturated fat and cholesterol. PMID- 23456976 TI - N-3 polyunsaturated fatty acids: relationship to inflammation in healthy adults and adults exhibiting features of metabolic syndrome. AB - Individuals with metabolic syndrome (MetS) have a higher risk of type 2 diabetes and cardiovascular disease, therefore, research has been directed at reducing various components that contribute to MetS and associated metabolic impairments, including chronic low-grade inflammation. Epidemiological, human, animal and cell culture studies provide evidence that dietary n-3 polyunsaturated fatty acids (n 3 PUFA), including alpha-linolenic acid (18:3n-3, ALA), eicosapentaenoic acid (20:5n-3, EPA) and/or docosahexaenoic acid (22:6n-3, DHA) may improve some of the components associated with MetS. The current review will discuss recent evidence from human observational and intervention studies that focused on the effects of ALA, EPA or DHA on inflammatory markers in healthy adults and those with one or more features of MetS. Observational studies in healthy adults support the recommendation that a diet rich in n-3 fatty acids may play a role in preventing and reducing inflammation, whereas intervention studies in healthy adults have yielded inconsistent results. The majority of intervention studies in adults with features of MetS have reported a benefit for some inflammatory measures; however, other studies using high n-3 fatty acid doses and long supplementation periods have reported no effect. Overall, the data reviewed herein support recommendations for regular fatty fish consumption and point toward health benefits in terms of lowering inflammation in adults with one or more features of MetS. PMID- 23456978 TI - Plasminogen plays a crucial role in bone repair. AB - The further development in research of bone regeneration is necessary to meet the clinical demand for bone reconstruction. Plasminogen is a critical factor of the tissue fibrinolytic system, which mediates tissue repair in the skin and liver. However, the role of the fibrinolytic system in bone regeneration remains unknown. Herein, we investigated bone repair and ectopic bone formation using plasminogen-deficient (Plg-/-) mice. Bone repair of the femur is delayed in Plg-/ mice, unlike that in the wild-type (Plg+/+) mice. The deposition of cartilage matrix and osteoblast formation were both decreased in Plg-/- mice. Vessel formation, macrophage accumulation, and the levels of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-beta) were decreased at the site of bone damage in Plg-/- mice. Conversely, heterotopic ossification was not significantly different between Plg+/+ and Plg-/- mice. Moreover, angiogenesis, macrophage accumulation, and the levels of VEGF and TGF-beta were comparable between Plg+/+ and Plg-/- mice in heterotopic ossification. Our data provide novel evidence that plasminogen is essential for bone repair. The present study indicates that plasminogen contributes to angiogenesis related to macrophage accumulation, TGF-beta, and VEGF, thereby leading to the enhancement of bone repair. PMID- 23456977 TI - Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease. AB - Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)-6- or stroma-dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease. Am. J. Hematol. 88:463-471, 2013. (c) 2013 Wiley Periodicals, Inc. PMID- 23456979 TI - Physicochemical characterization of Acidiphilium sp. biofilms. AB - The biofilm formation of a strain of the extremophile bacterium Acidiphilium sp., capable of donating electrons directly to electrodes, was studied by different surface characterization techniques. We develop a method that allows the simultaneous study of bacterial biofilms by means of fluorescence microscopy and atomic force microscopy (AFM), in which transparent graphitic flakes deposited on a glass substrate are used as a support for the biofilm. The majority of the cells present on the surface were viable, and the growth of the biofilms over time showed a critical increase of the extracellular polymeric substances (EPS) as well as the formation of nanosized particles inside the biofilm. Also, the presence of Fe in Acidiphilium biofilms was determined by X-ray photoelectron spectroscopy (XPS), whereas surface-enhanced infrared absorption spectroscopy indicated the presence of redox-active proteins. PMID- 23456980 TI - Modeling of phytochrome absorption spectra. AB - Phytochromes constitute one of the six well-characterized families of photosensory proteins in Nature. From the viewpoint of computational modeling, however, phytochromes have been the subject of much fewer studies than most other families of photosensory proteins, which is likely a consequence of relevant high resolution structural data becoming available only in recent years. In this work, hybrid quantum mechanics/molecular mechanics (QM/MM) methods are used to calculate UV-vis absorption spectra of Deinococcus radiodurans bacteriophytochrome. We investigate how the choice of QM/MM methodology affects the resulting spectra and demonstrate that QM/MM methods can reproduce the experimental absorption maxima of both the Q and Soret bands with an accuracy of about 0.15 eV. Furthermore, we assess how the protein environment influences the intrinsic absorption of the bilin chromophore, with particular focus on the Q band underlying the primary photochemistry of phytochromes. PMID- 23456981 TI - Tissue proteomics of the low-molecular weight proteome using an integrated cLC ESI-QTOFMS approach. AB - Analysis of the protein/peptide composition of tissue has provided meaningful insights into tissue biology and even disease mechanisms. However, little has been published regarding top down methods to investigate lower molecular weight (MW) (500-5000 Da) species in tissue. Here, we evaluate a tissue proteomics approach involving tissue homogenization followed by depletion of large proteins and then cLC-MS (where c stands for capillary) analysis to interrogate the low MW/low abundance tissue proteome. In the development of this method, sheep heart, lung, liver, kidney, and spleen were surveyed to test our ability to observe tissue differences. After categorical tissue differences were demonstrated, a detailed study of this method's reproducibility was undertaken to determine whether or not it is suitable for analyzing more subtle differences in the abundance of small proteins and peptides. Our results suggest that this method should be useful in exploring the low MW proteome of tissues. PMID- 23456982 TI - Carcinoid of the ovary: diagnostic challenge on fine-needle aspiration cytology. AB - Carcinoid of the ovary is an uncommon tumor. In the present article we have described the cytological features of carcinoid of the ovary in a 53-year old post-menopausal female. The patient presented with abdominal discomfort and loose stools. Ultrasound-guided fine-needle aspiration cytology (FNAC) of the left adnexal mass showed clusters and also scattered, relatively monomorphic population of tumor cells with vague rosette-like structures. Cytological diagnosis of malignant ovarian tumor possibly sex cord stromal tumor or carcinoid of ovary was offered and subsequent histopathology and immunohistochemistry confirmed the diagnosis of carcinoid. PMID- 23456983 TI - The Adult Reading History Questionnaire (ARHQ) in Icelandic: Psychometric Properties and Factor Structure. AB - This article describes psychometric testing of an Icelandic adaptation of the Adult Reading History Questionnaire (ARHQ), designed to detect a history of reading difficulties indicative of dyslexia. Tested in a large and diverse sample of 2,187 adults, the Icelandic adaptation demonstrated internal consistency reliability (Cronbach's alpha = .92) and test-retest reliability (r = .93). Validity was established by comparing scores of adults who as children received ICD-10 diagnoses of specific reading disorder (F81.0; n = 419) to those of adults defined as nondyslexics (n = 679). ROC curve analysis resulted in an area under the curve of .92 (95% CI = .90, .93, p < .001) and a cutoff score of .43 with sensitivity of 84.5% and specificity of 83.7%. An exploratory factor analysis (n = 2,187) suggested three subscales, Dyslexia Symptoms, Current Reading, and Memory, the mean scores of which differed significantly among diagnosed dyslexics, relatives of dyslexics, and population controls. Our results support the applicability of the ARHQ in Icelandic as a self-report screening tool for adult dyslexia in Iceland. PMID- 23456984 TI - Pesticide-laden dust emission and drift from treated seeds during seed drilling: a review. AB - Dressing seeds with pesticides to control pests is a widespread practice with important advantages. Recent incidents of bee losses, however, have directed attention to the emission of abraded pesticide-coated seed particles to the environment during sowing. This phenomenon of drift of pesticide dust can lead to pesticide contamination of air, water and other natural resources in crop-growing areas. This review article presents the state of the art of the phenomenon of dust emission and drift from pesticide seed dressing during sowing and its consequences. Firstly, pesticide seed treatment is defined and its pros and cons are set out, with the focus on dust, dust emission and dust drift from pesticide coated seed. The factors affecting emission of pesticide dust (e.g. seed treatment quality, seed drilling technology and environmental conditions) are considered, along with its possible effects. The measuring techniques and protocols and models currently in use for calculating the behaviour of dust are reviewed, together with their features and limitations. Finally, possible mitigation measures are discussed, such as improving the seed quality and the use of modified seed drilling technology, and an overview of regulations and stewardship activities is given. PMID- 23456985 TI - Kikuchi-Fujimoto disease masquerading as tuberculosis. AB - Kikuchi-Fujimoto disease (KFD) is a benign, self-limiting subacute necrotizing lymphadenitis with unknown aetiology that has a predilection for young Far East Asian women. It presents with fever, fatigue and lymphadenomegaly and is often misdiagnosed. We report an unusual presentation in a South Asian woman with isolated mediastinal lymphadenopathy masquerading as tuberculosis. There is only one other reported case in the literature presenting with isolated mediastinal lymphadenopathy. PMID- 23456986 TI - Cadaveric donor lobar lung transplantation for patients on extracorporeal membrane oxygenation as bridge-to-transplant. AB - The total number of lung transplants reported to the International Society of Heart and Lung Transplantation registry continues to increase steadily. In the US, the lung transplant volume has increased from 1172 in 2004 to 1822 in 2011 since lung allocation score system was implemented in 2005 while the overall 1 year survival after transplantation has not changed significantly. One of the most common reasons why lung offers are declined is size-mismatch. Size-reduced lung transplantation including non-anatomical lung volume reduction and lobar lung transplantation is an advanced surgical technique to alleviate donor organ shortage. Living-related donor lung transplantation almost disappeared in the US, but alternatively, we perform lobar transplantation using cadaveric donor lungs. With recent advances in extracorporeal membrane oxygenation (ECMO) technology and surgical experience, ECMO has been used before, during and after lung transplant surgery successfully. PMID- 23456987 TI - Thoracoscopic lobectomy: is a training program feasible with low postoperative morbidity? AB - OBJECTIVE: To evaluate the feasibility of training program in video assisted thoracic surgery (VATS) lobectomy comparing intraoperative and postoperative data of patients operated on by an established consultant and trainees. METHODS: Retrospective analysis of 100 consecutive patients who underwent VATS lobectomies between May 2008 and May 2012. 66 patients were operated on by an established consultant (Group A) and 34 by trainees (Group B). RESULTS: The groups were comparable for clinical characteristics and pathological staging. The mean operating time in Group A was 125 +/- 30 min and in Group B was 133 +/- 26 min (p = 0.18). The rate of conversion was similar in both groups: 9.1% in Group A and 8.8% in Group B (p = 0.6). The complication rate was comparable (p = 0.4): 36.3% in Group A and 32.3% in Group B. Median time to drain removal and median length of hospital stay was 3 and 5.5 days in Group A and 3 and 5 days in Group B, showing no statistical differences between the two groups (p = 0.3 and 0.5). There were no differences in term of long-term complications between the two groups. CONCLUSION: Our study showed that a training program in VATS lobectomy is feasible, without increasing the operative time, conversion rate, postoperative complication, time to drain removal, and length of hospital stay. PMID- 23456988 TI - CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease. AB - Combined detection of cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation-associated protein (MAL) promoter methylation in cervical scrapes is a promising triage strategy for high-risk human papillomavirus (hrHPV)-positive women. Here, CADM1 and MAL DNA methylation levels were analysed in cervical scrapes of hrHPV-positive women with no underlying high-grade disease, high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer. CADM1 and MAL methylation levels in scrapes were first related to CIN-grade of the corresponding biopsy and second to CIN-grade stratified by the presence of 'normal' or 'abnormal' cytology as present in the accompanying scrape preceding the cervical biopsy. The scrapes included 167 women with <= CIN1, 54 with CIN2/3 and 44 with carcinoma. In a separate series of hrHPV-positive scrapes of women with CIN2/3 (n = 48), methylation levels were related to duration of preceding hrHPV infection (PHI; <5 and >= 5 years). Methylation levels were determined by quantitative methylation-specific PCR and normal cytology scrapes of hrHPV positive women with histologically <= CIN1 served as reference. CADM1 and MAL methylation levels increased proportional to severity of the underlying lesion, showing an increase of 5.3- and 6.2-fold in CIN2/3, respectively, and 143.5- and 454.9-fold in carcinomas, respectively, compared to the reference. Methylation levels were also elevated in CIN2/3 with a longer duration of PHI (i.e. 11.5- and 13.6-fold, respectively). Moreover, per histological category, methylation levels were higher in accompanying scrapes with abnormal cytology than in scrapes with normal cytology. Concluding, CADM1 and MAL promoter methylation levels in hrHPV positive cervical scrapes are related to the degree and duration of underlying cervical disease and markedly increased in cervical cancer. PMID- 23456990 TI - Child protection and adult depression: evaluating the long-term consequences of evacuating children to foster care during World War II. AB - This paper combined data collected from war time government records with survey data including background characteristics, such as factors that affected eligibility, to examine the adult depression outcomes of individuals who were evacuated from Finland to temporary foster care in Sweden during World War II. Using war time government records and survey data for a random sample of 723 exposed individuals and 1321 matched unexposed individuals, the authors conducted least squares adjusted means comparison to examine the association between evacuation and adult depression (Beck Depression Inventory). The random sample was representative for the whole population of evacuees who returned to their biological families after World War II. The authors found no statistically significant difference in depressive symptoms during late adulthood between the two groups; for example, the exposed group had a 0.41 percentage points lower average Beck Depression Inventory score than the unexposed group (p = 0.907). This study provides no support for family disruption during early childhood because of the onset of sudden shocks elevating depressive symptoms during late adulthood. PMID- 23456989 TI - Mycobacterium tuberculosis-specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease. AB - Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8(+) T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8(+) T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb specific CD8(+) T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8(+) T cells in LTBI subjects were mostly T EMRA cells (CD45RA(+) CCR7(-)), coexpressing 2B4 and CD160, and in TB patients were mostly TEM cells (CD45RA(-) CCR7(-)), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8(+) T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8(+) T cells expressed perforin and granulysin. Finally, Mtb-specific CD8(+) T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8(+) T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8(+) T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response. PMID- 23456991 TI - 2D DIGE proteomic analysis of early post mortem muscle exudate highlights the importance of the stress response for improved water-holding capacity of fresh pork meat. AB - Variation in water-holding capacity (WHC), which presents a major economic burden to the swine industry, is considered to be underpinned by variation at a molecular and biochemical level. High-resolution 2D DIGE followed by MS analysis and Western blot were used to unravel the proteome of muscle exudate, collected following centrifugation, in the pH 4-7 range. A first 2DE-based protein map of this substrate was produced where 89 spots were successfully characterised. Two phenotypes divergent for WHC plus one intermediate were compared with a view to deciphering the biochemical processes impacting on variation in WHC. Twenty spots were observed to be altered across the phenotypes. Of these, 14 represented sixteen proteins including metabolic enzymes, stress response proteins and structural proteins. Triosephosphate isomerase and transferrin showed a major difference between the two extreme phenotypes, and may have potential as biological markers for WHC prediction. Several members of the HSPs family were highlighted. This proteomic study makes an important contribution towards a more detailed molecular view of the processes behind WHC and will provide a valuable resource for future investigations. PMID- 23456992 TI - Seizures induced by desloratadine, a second-generation antihistamine: clinical observations. AB - Some clinical experiences indicate that H1-antihistamines, especially first generation H1-antagonists, occasionally provoke convulsions in healthy children as well as epileptic patients. Desloratadine is a frequently used second generation antihistamine considered to be effective and safe for the treatment of allergic diseases. We describe four children who experienced epilepsy associated with the nonsedating H(1)-antagonist desloratadine and discuss the neurophysiologic role of the central histaminergic system in seizure susceptibility. In conclusion, we recommend caution in treating epileptic patients with the histamine H(1)-antagonists, including second- and third generation drugs that are frequently referred because they are considered to be nonsedating antihistamines. PMID- 23456993 TI - Fine-needle aspiration biopsy for the diagnosis of metastatic type B thymoma to lymph nodes: a case report. PMID- 23456994 TI - Cooperative behaviour of Pt microelectrodes during CO bulk electrooxidation. AB - Cooperative behaviour of an array of microelectrodes: The interplay of bistable reaction kinetics with global coupling results in a spontaneous sequential activation of electrodes when the applied current is increased. PMID- 23456995 TI - PRRT2 gene mutations in familial and sporadic paroxysmal kinesigenic dyskinesia cases. PMID- 23456996 TI - Comment on "Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome". PMID- 23456997 TI - Author's reply regarding "Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome". PMID- 23456998 TI - Fetal surveillance, chronic disease costs, and reasonable social policy. PMID- 23456999 TI - Influence of soil environments on nematicidal activity of fluensulfone against Meloidogyne javanica. AB - BACKGROUND: Fluensulfone, a fluoroalkenyl group nematicide, has proved to be very effective in controlling root-knot nematodes, Meloidogyne spp. The authors evaluated some soil environmental factors that might affect its nematicidal activity. RESULTS: Meloidogyne javanica juveniles exposed to fluensulfone lost their infectivity, even though they were rinsed in water when they were still active. Exposure of juveniles to fluensulfone at >1 mg L(-1) for 48 h was very effective in reducing root galls. Peat as organic matter added to soil reduced nematicidal efficacy against M. javanica in pot experiments. Peat added to a soil column inhibited the downward movement of fluensulfone. The movement of fluensulfone was faster in sandy vs loess soil. Repeated soil application of fluensulfone did not reduce the nematicidal activity of fenamiphos or cadusafos, and repeated applications of these nematicides did not lower the nematicidal activity of a subsequent application of fluensulfone. CONCLUSION: Fluensulfone nematicidal activity and movement were affected by organic matter and clay content, probably via adsorption. Enhanced biodegradation or cross-biodegradation of fluensulfone by other compounds was not observed. Soil environment should be considered to obtain effective nematode control efficacy with a given compound. PMID- 23457000 TI - The management of complex periprosthetic humeral fractures: a case series of strut allograft augmentation, and a review of the literature. AB - There is little published discussion on the management of postoperative periprosthetic humeral fractures where rotator cuff function is poor, the bone stock is dwindling or both. This is a phenomenon increasingly seen in the older, more osteoporotic population and presents an interesting challenge especially in when faced with these patients with poor bone quality. We present the treatment of three fractures with the use of long-stem reverse geometry arthroplasty and other surgical techniques more commonly reserved for periprosthetic fractures of the proximal femur such as cortical strut allograft augmentation. We believe revision to reverse geometry long-stem implant with cortical strut allograft augmentation to be safe and appropriate in the management of these complex injuries, although technically challenging, and has excellent initial and medium term results. PMID- 23457001 TI - Compliance in early-phase cancer clinical trials research. AB - Regulations and ethical principles require that investigators seek consent and that patients participate in experimental studies only under circumstances that minimize the possibility of undue pressure and/or enticements. In recent years, there has been a rapid rise in the monitoring requirements of early-phase trials accompanied by an increasing emphasis on assuring "investigator" compliance with the protocol. It is actually, however, the patient who must comply with the requirements of the study. If there is divergence from the protocol, investigators may be reported to regulatory bodies or agencies. Whereas the investigative community is expected to be vigilant about ensuring that patients participate in studies voluntarily and that their consent is procured without duress, it is also required to guarantee that complex protocols, which entail multiple procedures, be followed exactly by participants who suffer from the complications of advanced cancer. We explore the issue of compliance in a research environment in which investigators are subject to disciplinary action if they fail to ensure that patients adhere precisely to the intense monitoring mandates of a clinical trial. PMID- 23457003 TI - Upholding the principles of autonomy, beneficence, and justice in phase I clinical trials. PMID- 23457002 TI - Analysis of dermatologic events in vemurafenib-treated patients with melanoma. AB - BACKGROUND: Vemurafenib has been approved for the treatment of patients with advanced BRAF(V600E)-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). METHODS: Dermatologic AEs were assessed from three ongoing trials of BRAF(V600E) mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. RESULTS: A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%-95% of patients. Rash was the most common AE (64%-75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%-63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%-10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%-26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. CONCLUSIONS: Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients. PMID- 23457004 TI - AMXT-1501, a novel polyamine transport inhibitor, synergizes with DFMO in inhibiting neuroblastoma cell proliferation by targeting both ornithine decarboxylase and polyamine transport. AB - Neuroblastoma (NB) is associated with MYCN oncogene amplification occurring in approximately 30% of NBs and is associated with poor prognosis. MYCN is linked to a number of genes including ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. ODC expression is elevated in many forms of cancer including NB. Alpha-difluoromethylornithine (DFMO), an ODC inhibitor, is currently being used in a Phase I clinical trial for treatment of NB. However, cancer cells treated with DFMO may overcome their polyamine depletion by the uptake of polyamines from extracellular sources. A novel polyamine transport inhibitor, AMXT-1501, has not yet been tested in NB. We propose that inhibiting ODC with DFMO, coupled with polyamine transport inhibition by AMXT-1501 will result in enhanced NB growth inhibition. Single and combination drug treatments were conducted on three NB cell lines. DFMO IC50 values ranged from 20.76 to 33.3 mM, and AMXT-1501 IC50 values ranged from 14.13 to 17.72 uM in NB. The combination treatment resulted in hypophosphorylation of retinoblastoma protein (Rb), suggesting growth inhibition via G1 cell cycle arrest. Increased expression of cleaved PARP and cleaved caspase 3 in combination-treated cells starting at 48 hr suggested apoptosis. The combination treatment depleted intracellular polyamine pools and decreased intracellular ATP, further verifying growth inhibition. Given the current lack of effective therapies for patients with relapsed/refractory NB and the preclinical effectiveness of DFMO with AMXT-1501, this combination treatment provides promising preclinical results. DFMO and AMXT 1501 may be a potential new therapy for children with NB. PMID- 23457005 TI - A case of anaplastic lymphoma kinase-positive large B-cell lymphoma: aspiration cytology findings. AB - Anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma (LBCL) is a rare subtype of non-Hodgkin B-cell lymphoma that exhibits a more aggressive clinical course and poorer prognosis than the typical diffuse large B-cell lymphoma. In this study, we report the case of a 67-year-old man with left cervical lymph node swelling. Aspiration cytology revealed many clusters of cohesive, large, and solitary cells. The tumor cells had abundant cytoplasm and large round-to-oval nuclei with prominent nucleoli. The Giemsa staining specimens exhibited amorphous global bodies adjacent to some clusters. Histologically, large tumor cells occupied the lymph nodes in a sinusoidal pattern, and immunohistochemically, these cells were cytokeratin-, CD19(-), CD20(-), CD79a(-), CD3(-), CD30(-), CD138(+), IgG(-), IgA(+), and ALK(+). Chromogenic in situ hybridization revealed restricted immunoglobulin light-chain expression. Fluorescent in situ hybridization demonstrated translocation of the ALK gene. The tumor cells were negative for Epstein-Barr virus and human herpesvirus 8. It is important to differentiate ALK+LBCL from metastatic carcinoma and other lymphoma subtypes with similar histological features to ensure a proper treatment strategy and prediction of prognosis. PMID- 23457007 TI - A two-dimensional proteome map of the aflatoxigenic fungus Aspergillus flavus. AB - The filamentous fungus Aspergillus flavus is an opportunistic soil-borne pathogen that produces aflatoxins, the most potent naturally occurring carcinogenic compounds known. This work represents the first gel-based profiling analysis of A. flavus proteome and establishes a 2D proteome map. Using 2DE and MALDI-TOF MS/MS, we identified 538 mycelial proteins of the aflatoxigenic strain NRRL 3357, the majority of which were functionally annotated as related to various cellular metabolic and biosynthetic processes. Additionally, a few enzymes from the aflatoxin synthesis pathway were also identified. PMID- 23457008 TI - A morphometric study of the human fetal heart on post-mortem 3-tesla magnetic resonance imaging. AB - OBJECTIVE: To report on the feasibility of assessing cardiac structures on post mortem 3-tesla MRI (pmMRI) and to provide morphometric data in fetuses without cardiac abnormalities. METHODS: Retrospective single center study on 3T pmMRI of 39 consecutive fetuses without cardiac abnormalities (13-38 weeks of gestation). Fetal cardiac anatomy was assessed and measurements of cardiac structures were performed on T2-weighted 3D multiplanar reconstructed images. Linear regression analysis was performed to examine changes of cardiac dimensions during gestation. RESULTS: The four-chamber view of the fetal heart could be obtained and the measurements of cardiac chambers and ventricular walls could be performed in all 39 cases. The aorta and the pulmonary artery were visualized and their diameters were measured in 38 (97.4%) fetuses, ductus arteriosus in 32 (82%). All measurements showed strong linear correlation with gestational age. The relationship of the diameters of the pulmonary artery, aorta, and ductus arteriosus remained constant over pregnancy. All these observations are consistent with what is known from prenatal ultrasound. CONCLUSIONS: The present study proves the feasibility of visualizing normal cardiac structures on 3-tesla pmMRI in fetuses beyond 14 weeks. We provide morphometric data that may enable diagnostic evaluation of cardiac abnormalities on pmMRI. PMID- 23457006 TI - A novel Lyn-protein kinase Cdelta/epsilon-protein kinase D axis is activated in B cells by signalosome-independent alternate pathway BCR signaling. AB - BCR signaling initiates multiple activities critical for B-cell function. Recently, we identified an alternate BCR signaling pathway, induced by IL-4, that is signalosome-independent, unlike the classical signalosome-dependent pathway, and that leads to activation of the MAP kinase, ERK. Here we questioned whether alternate pathway signaling extends to other key downstream events, especially protein kinase D (PKD) activation. We found that in murine spleen-derived B cells the IL-4-induced alternate pathway for BCR signaling results in PKD and PKD substrate phosphorylation, and that alternate pathway phosphorylation of HDAC5/7 and other key substrates requires PKD. Furthermore, we found that tyrosine phosphorylation of PKCdelta/epsilon occurs as a result of alternate but not classical pathway signaling and is required for phosphorylation of PKD and PKD substrates. This result identifies PKCdelta/epsilon tyrosine phosphorylation as a unique outcome of the alternate pathway. The alternate pathway is mediated by Lyn that is not required for classical pathway signaling and we found that Lyn associates directly with PKCdelta/epsilon and is required for phosphorylation of PKCdelta/epsilon and of PKD. These findings indicate that IL-4 influences B-cell activation by inducing a novel signaling pathway from BCR to Lyn to PKCdelta/epsilon to PKD. PMID- 23457010 TI - Implementing the NICE osteoarthritis guidelines in primary care: a role for practice nurses. PMID- 23457011 TI - Nebivolol prevents desensitization of beta-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond beta1-adrenoceptor blockage. AB - The importance of chronic stimulation of beta-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of beta-blockers in the treatment of heart failure. Nebivolol is a third-generation beta-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or beta3-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on beta-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective beta1-adrenoceptor blocker. Rats infused by isoprenaline (100 MUg.kg(-1).day(-1), 14 days) were randomized into three groups according to the treatment with metoprolol (30 mg.kg(-1).day(-1)), nebivolol (10 mg.kg(-1).day(-1)), or placebo for 13 days starting on day 1 after implantation of minipump. Both metoprolol and nebivolol caused a similar reduction on heart rate. Nebivolol mediated a significant improvement on cardiac mass, coronary flow, mRNA expression levels of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) and atrial natriuretic peptide and phospholamban (PLN)/SERCA2a and phospho-PLN/PLN ratio compared with metoprolol and placebo. Nebivolol prevented the detrimental effects of isoprenaline infusion on isoprenaline (68% of control at 30 MUM), BRL37344 (63% of control at 0.1 MUM), and forskolin (64% of control at 1 MUM) responses compared with metoprolol (isoprenaline, 34% of control; BRL37344, no response; forskolin, 26% of control) and placebo (isoprenaline, 33% of control; BRL37344, 28% of control; forskolin, 12% of control). Both beta-blockers improved the changes in mRNA expressions of beta1- and beta3-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of beta-adrenoceptor signaling and the development of cardiac hypertrophy independent of its beta1-adrenoceptor blocking effect. PMID- 23457012 TI - Assessment of cardiac proteome dynamics with heavy water: slower protein synthesis rates in interfibrillar than subsarcolemmal mitochondria. AB - Traditional proteomics provides static assessment of protein content, but not synthetic rates. Recently, proteome dynamics with heavy water ((2)H2O) was introduced, where (2)H labels amino acids that are incorporated into proteins, and the synthesis rate of individual proteins is calculated using mass isotopomer distribution analysis. We refine this approach with a novel algorithm and rigorous selection criteria that improve the accuracy and precision of the calculation of synthesis rates and use it to measure protein kinetics in spatially distinct cardiac mitochondrial subpopulations. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated from adult rats, which were given (2)H2O in the drinking water for up to 60 days. Plasma (2)H2O and myocardial (2)H-enrichment of amino acids were stable throughout the experimental protocol. Multiple tryptic peptides were identified from 28 proteins in both SSM and IFM and showed a time-dependent increase in heavy mass isotopomers that was consistent within a given protein. Mitochondrial protein synthesis was relatively slow (average half-life of 30 days, 2.4% per day). Although the synthesis rates for individual proteins were correlated between IFM and SSM (R(2) = 0.84; P < 0.0001), values in IFM were 15% less than SSM (P < 0.001). In conclusion, administration of (2)H2O results in stable enrichment of the cardiac precursor amino acid pool, with the use of refined analytical and computational methods coupled with cell fractionation one can measure synthesis rates for cardiac proteins in subcellular compartments in vivo, and protein synthesis is slower in mitochondria located among the myofibrils than in the subsarcolemmal region. PMID- 23457013 TI - Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning. AB - Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC). Cardiac UCP3 knockout (UCP3(-/-)) and wild-type (WT) mice hearts were subjected to ex vivo and in vivo models of I/R injury and IPC. Isolated UCP3(-/-) mouse hearts were retrogradely perfused and found to have poorer recovery of left ventricular function compared with WT hearts under I/R conditions. In vivo occlusion of the left coronary artery resulted in twofold larger infarcts in UCP3(-/-) mice compared with WT mice. Moreover, the incidence of in vivo I/R arrhythmias was higher in UCP3(-/-) mice. Myocardial energetics were significantly impaired with I/R, as reflected by a decreased ATP content and an increase in the AMP-to-ATP ratio. UCP3(-/-) hearts generated more reactive oxygen species (ROS) than WT hearts during I/R. Pretreatment of UCP3(-/-) hearts with the pharmacological uncoupling agent carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone improved postischemic functional recovery. Also the protective efficacy of IPC was abolished in UCP3(-/ ) mice. We conclude that UCP3 plays a critical role in cardioprotection against I/R injury and the IPC phenomenon. There is increased myocardial vulnerability to I/R injury in hearts lacking UCP3. The mechanisms of UCP3-mediated cardioprotection include regulation of myocardial energetics and ROS generation by UCP3 during I/R. PMID- 23457015 TI - Update on innovative initiatives for the American Journal of Physiology-Heart and Circulatory Physiology. PMID- 23457019 TI - Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. AB - BACKGROUND: Alpha-synuclein plays a central role in the pathophysiology of Parkinson's disease. Three missense mutations in SNCA, the gene encoding alpha synuclein, as well as genomic multiplications have been identified as causes for autosomal-dominantly inherited Parkinsonism. METHODS: Here, we describe a novel missense mutation in exon 4 of SNCA encoding a H50Q substitution in a patient with dopa-responsive Parkinson's disease with a family history of parkinsonism and dementia. RESULTS: The variant was not observed in public databases or identified in unrelated subjects. CONCLUSIONS: The substitution's evolutionary conservation and protein modeling provide additional support for pathogenicity as the amino acid perturbs the same amphipathic alpha helical structure as the previously described pathogenic mutations. PMID- 23457020 TI - Unusual amino acids and monofluoroacetate from Dichapetalum michelsonii (Umutambasha), a toxic plant from Rwanda. AB - In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly identified as Dichapetalum michelsonii Hauman. Conclusive evidence for a monofluoroacetate presence came from its isolation from the freeze-dried extract of stem bark. Three free unusual amino acids, named N-methyl-alpha-alanine, N-methyl-beta-alanine, and 2,7 diaminooctan-1,8-dioic acid, described for the first time in a plant, and known trigonelline were also isolated from the stem bark of D. michelsonii. Structure elucidations were mainly achieved by spectroscopic methods (1H-NMR, 2D-NMR, MS) and by comparison with authentic references. These unusual amino acids were detected by a fast, reliable TLC analysis in all our batches of Umutambasha, suggesting that they could be used for identification purposes in case of human or livestock intoxications. Finally, EEG recordings and behavioural observations performed in mice suggested that the convulsive patterns produced by Umutambasha are the consequence of monofluoroacetate presence in D. michelsonii. PMID- 23457014 TI - Cardiac optogenetics. AB - Optogenetics is an emerging technology for optical interrogation and control of biological function with high specificity and high spatiotemporal resolution. Mammalian cells and tissues can be sensitized to respond to light by a relatively simple and well-tolerated genetic modification using microbial opsins (light gated ion channels and pumps). These can achieve fast and specific excitatory or inhibitory response, offering distinct advantages over traditional pharmacological or electrical means of perturbation. Since the first demonstrations of utility in mammalian cells (neurons) in 2005, optogenetics has spurred immense research activity and has inspired numerous applications for dissection of neural circuitry and understanding of brain function in health and disease, applications ranging from in vitro to work in behaving animals. Only recently (since 2010), the field has extended to cardiac applications with less than a dozen publications to date. In consideration of the early phase of work on cardiac optogenetics and the impact of the technique in understanding another excitable tissue, the brain, this review is largely a perspective of possibilities in the heart. It covers the basic principles of operation of light sensitive ion channels and pumps, the available tools and ongoing efforts in optimizing them, overview of neuroscience use, as well as cardiac-specific questions of implementation and ideas for best use of this emerging technology in the heart. PMID- 23457021 TI - Antileishmanial activity of 5-methyl-2,2' : 5',2"-terthiophene isolated from Porophyllum ruderale is related to mitochondrial dysfunction in Leishmania amazonensis. AB - Recently, our group isolated and reported the antiproliferative activity in promastigotes and axenic amastigote forms of Leishmania amazonensis treated with 5-methyl-2,2':5',2"-terthiophene (compound A) and 5'-methyl-[5-(4-acetoxy-1 butynyl)]-2,2'-bi-thiophene (compound B) isolated from the aerial parts of Porophyllum ruderale. Here, we demonstrated that both compounds exhibited activity against intracellular amastigotes showing IC50 values of 37 and 51 ug/mL for compounds A and B, respectively. Both compounds showed low levels of toxicity for human cells, even at the highest concentrations (hemolytic index < 10 % at 500 ug/mL). Promastigotes treated with compound A showed an alteration in the mitochondrial membrane when observed by flow cytometry through labeling with rhodamine 123 and this was confirmed by transmission electron microscopy. Alterations on morphology (rounded cells) were observed by scanning electron microscopy in parasites treated with the compounds. Further studies should be performed employing compounds A and B for the development of new drugs for chemotherapy of leishmaniasis. PMID- 23457022 TI - New flavonol and diterpenoids from the endophytic fungus Aspergillus sp. YXf3. AB - One new flavonol, chlorflavonin A (1), four new diterpenoids, aspergiloids E-H (3, 5-7), together with eight known compounds (2, 4, 8-13) were isolated from solid fermentation of Aspergillus sp. (strain no. YXf3), an endophytic fungus from Ginkgo biloba. Their structures were determined through detailed spectroscopic analysis combined with comparison of NMR spectra data with reported ones. All of them were screened on cytotoxicity against KB, SGC-7901, SW1116, and A549 cell lines; compounds 4, 9-11 exhibited moderate activities with IC50 values ranging from 6.74 to 46.64 uM. PMID- 23457023 TI - Importance of wine-treated Angelica Sinensis Radix in Si Wu Tang, a traditional herbal formula for treating women's ailments. AB - Si Wu Tang (Four Agents Decoction), a traditional Chinese decoction composed of Angelica Sinensis Radix, Chuanxiong Rhizoma, Paeoniae Radix Alba, and Rehmanniae Radix Praeparata in a ratio of 1 : 1 : 1 : 1, has been used to treat women's diseases for more than a thousand years. According to the original description of Si Wu Tang, Angelica Sinensis Radix should be treated with wine. However, the importance of this wine-treated Angelica Sinensis Radix in Si Wu Tang's function has not been identified. In this article, the chemical and biological properties of two decoctions processed in different ways (Si Wu Tang with crude Angelica Sinensis Radix and Si Wu Tang with wine-treated Angelica Sinensis Radix) were compared for examination. The herbal decoction Si Wu Tang prepared from wine treated Angelica Sinensis Radix contained much different amounts of its active compounds. Compared with Si Wu Tang using crude Angelica Sinensis Radix, Si Wu Tang prepared from wine-treated Angelica Sinensis Radix had better biological responses. Therefore, these findings accentuate the functional importance of herbs treated with wine in the Chinese decoction. PMID- 23457024 TI - A note on the expected biases in conventional iterative health state valuation protocols. AB - BACKGROUND: Typical health state valuation exercises use tradeoff methods, such as the time tradeoff or the standard gamble, involving a series of iterated questions so that a value for each health state by each individual respondent is elicited. This iterative process is a source of potential biases, but this has not received much attention in the health state valuation literature. The issue has been researched widely in the contingent valuation (CV) literature, which elicits the monetary value of hypothetical outcomes. METHODS: The lessons learned in the CV literature are revisited in the context of the design and administration of health state valuations. The article introduces the main known biases in the CV literature and then examines how each might affect conventional iterative health state valuations. RESULTS: Of the 8 main types of biases, starting point bias, range bias, and incentive incompatibility bias are found to be potentially relevant. Furthermore, the magnitude and direction of the bases are unlikely to be uniform and depend on the range of the value (e.g., between 0 and 0.5). Limitation. This is an overview article, and the conclusions drawn need to be tested empirically. CONCLUSIONS: Health state valuation studies, like CV studies, are susceptible to a number of possible biases that affect the resulting values. Their magnitude and direction are unlikely to be uniform, and thus empirical studies are needed to diagnose the problem and, if necessary, to address it. PMID- 23457025 TI - The "hazards" of extrapolating survival curves. AB - BACKGROUND: It is widely recommended that health technology appraisals adopt a lifetime horizon to assess the relative costs and benefits of an intervention. However, most trials or clinical studies have relatively short follow-up periods, with the event of interest not occurring before the end of the study for many subjects. In such cases, survival analysis using parametric models can be used to extrapolate into the future. OBJECTIVE: To assess the accuracy of survival analysis in projecting future events beyond the sample estimation period. DESIGN: Using a previously published comparison of 2 alternative hip replacement prostheses based on 8 years of data as a case study, we extend the data set to include 8 years more data. Using the new data, the parametric assumptions of the previous study and its success in predicting the outcomes are assessed. RESULTS: The extended data set casts doubt on the previous study's findings. The failure curves of the 2 prostheses now cross, and the proportional hazards assumption no longer holds. Extrapolations from the original data set yielded very good predictions for one prosthesis for the full 16 years but were much poorer for the other, even when the proportionality assumption was relaxed. CONCLUSIONS: Care should be taken when extrapolating treatment benefits for new technologies early in their life cycle based on observational or randomized controlled trial data sources. This case study reveals that predictions of prosthesis failure based on a short follow-up period were inaccurate compared with those after a longer period of follow-up. PMID- 23457026 TI - Pleiotropic effects of herbicide-resistance genes on crop yield: a review. AB - The rapid adoption of genetically engineered herbicide-resistant crop varieties (HRCVs)-encompassing 83% of all GM crops and nearly 8% of the worldwide arable area-is due to technical efficiency and higher returns. Other herbicide-resistant varieties obtained from genetic resources and mutagenesis have also been successfully released. Although the benefit for weed control is the main criteria for choosing HRCVs, the pleiotropic costs of genes endowing resistance have rarely been investigated in crops. Here the available data of comparisons between isogenic resistant and susceptible varieties are reviewed. Pleiotropic harmful effects on yield are reported in half of the cases, mostly with resistance mechanisms that originate from genetic resources and mutagenesis (atrazine in oilseed rape and millet, trifluralin in millet, imazamox in cotton) rather than genetic engineering (chlorsulfuron and glufosinate in some oilseed rape varieties, glyphosate in soybean). No effect was found for sethoxydim and bromoxynil resistance. Variable minor effects were found for imazamox, chlorsulfuron, glufosinate and glyphosate resistance. The importance of the breeding plan and the genetic background on the emergence of these effects is pointed out. Breeders' efforts to produce better varieties could compensate for the yield loss, which eliminates any possibility of formulating generic conclusions on pleiotropic effects that can be applied to all resistant crops. PMID- 23457027 TI - Label-free quantitative analysis of the membrane proteome of Bace1 protease knock out zebrafish brains. AB - The aspartyl protease BACE1 cleaves neuregulin 1 and is involved in myelination and is a candidate drug target for Alzheimer's disease, where it acts as the beta secretase cleaving the amyloid precursor protein. However, little is known about other substrates in vivo. Here, we provide a proteomic workflow for BACE1 substrate identification from whole brains, combining filter-aided sample preparation, strong-anion exchange fractionation, and label-free quantification. We used bace1-deficient zebrafish and quantified differences in protein levels between wild-type and bace1 -/- zebrafish brains. Over 4500 proteins were identified with at least two unique peptides and quantified in both wild-type and bace1 -/- zebrafish brains. The majority of zebrafish membrane proteins did not show altered protein levels, indicating that Bace1 has a restricted substrate specificity. Twenty-four membrane proteins accumulated in the bace1 -/- brains and thus represent candidate Bace1 substrates. They include several known BACE1 substrates, such as the zebrafish homologs of amyloid precursor protein and the cell adhesion protein L1, which validate the proteomic workflow. Additionally, several candidate substrates with a function in neurite outgrowth and axon guidance, such as plexin A3 and glypican-1 were identified, pointing to a function of Bace1 in neurodevelopment. Taken together, our study provides the first proteomic analysis of knock-out zebrafish tissue and demonstrates that combining gene knock-out models in zebrafish with quantitative proteomics is a powerful approach to address biomedical questions. PMID- 23457029 TI - Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion. AB - Metastasis-associated in colon cancer-1 (MACC1) is a newly identified oncogene, and little is known about its role in gastric cancer (GC). Our study was performed to investigate whether MACC1 influences the prognosis of GC patients and to explore the potential mechanisms involved. MACC1 expression was verified to be higher in GC tissues than in adjacent nontumorous tissues by Western blotting. A retrospective analysis of 361 GC patients (Stages I-IV) revealed that higher MACC1 expression was associated with more advanced disease, more frequent postoperative recurrence, more metastases and a higher mortality rate. The disease-free survival of Stage I-III patients and overall survival of Stage-IV patients were significantly worse when their tumors showed high MACC1 expression. To investigate the underlying mechanisms, MACC1 overexpression and downregulation were established in two GC cell lines (BGC-823 and MKN-28 cells). MACC1 overexpression significantly accelerated tumor growth and facilitated metastasis in athymic mice. MACC1 also promoted the proliferation, migration and invasion of both GC cell lines. Moreover, gastric MACC1 mRNA expression levels were significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT) in patients with GC. MACC1 overexpression upregulated mesenchymal epithelial transition factor and induced changes to markers of EMT, whereas silencing of MACC1 reversed all these changes. These findings provide some novel insights into the role of MACC1, a gene that contributes to a poor prognosis of GC by promoting tumor cell proliferation and invasion as well as the EMT. PMID- 23457030 TI - MR1B, a natural spliced isoform of the MHC-related 1 protein, is expressed as homodimers at the cell surface and activates MAIT cells. AB - The MHC-related 1 (MR1) protein is a monomorphic, evolutionarily conserved MHC class I-like molecule, which is necessary for the development and functions of mucosal-associated invariant T (MAIT) cells, a new subset of innate-like lymphocytes. Multiple isoforms of the MR1 gene are naturally transcribed, but only the full-length MR1A has been analyzed so far. Using transfected cell lines expressing an alternative spliced transcript, MR1B, characterized by the absence of the alpha3 extracellular domain, we show that MR1B is transcribed and glycosylated but remains in an immature (endoglycosidase H-sensitive) state. MR1B mostly accumulates in the ER, without interacting with proteins of the peptide loading complex such as tapasin. Interestingly, it is nevertheless found expressed at the cell surface, independently of beta2-microglobulin, in a homodimeric form. MR1B is functional as its overexpression induces MAIT cell activation in vitro in the presence of bacteria. Altogether, these data show that MR1B displays several remarkable features, and probably plays a physiological role complementary to MR1A with respect to MAIT cell development and/or function. PMID- 23457031 TI - Acceptability of a minimally invasive perinatal/paediatric autopsy: healthcare professionals' views and implications for practice. AB - BACKGROUND: Perinatal autopsy provides essential clinical information, including cause of death; yet, autopsy rates have steadily declined because of parental refusal. Technology now enables less invasive alternatives to traditional autopsy and may increase the acceptability of post-mortem examination. OBJECTIVE: This study aimed to examine the relative acceptability among healthcare professionals of a minimally invasive autopsy (MIA; magnetic resonance imaging and laparoscopic guided tissue sampling), compared with standard autopsy. METHODS: This study was questionnaire-based survey of healthcare professionals working in clinical settings where paediatric and perinatal deaths occur. RESULTS: Of 250 questionnaires distributed, 224 were returned (90% response rate). Autopsy was generally perceived as acceptable. Demographic factors affecting acceptability included ethnicity and religion but not professional role. MIA compared favourably with traditional autopsy, 50% of respondents reporting both equally acceptable, 40% reporting MIA more acceptable and 10% less acceptable. Healthcare professionals agreed that having a MIA option would make it easier to discuss autopsy with parents (P < 0.001). CONCLUSION: Less invasive autopsy appears an acceptable alternative to traditional autopsy for most respondents. Healthcare professionals should be aware that ethnic and religious opinions influence their own views on autopsy decisions and should be mindful of this when discussing autopsy with parents. Further research is needed to determine parental opinions. PMID- 23457028 TI - Association of pre-operative brain pathology with post-operative delirium in a cohort of non-small cell lung cancer patients undergoing surgical resection. AB - OBJECTIVE: Post-operative delirium is associated with pre-operative cognitive difficulties and diminished functional independence, both of which suggest that brain pathology may be present in affected individuals prior to surgery. Currently, there are few studies that have examined imaging correlates of post operative delirium. To our knowledge, none have examined the association of delirium with existing structural pathology in pre-operative cancer patients. Here, we present a novel, retrospective strategy to assess pre-operative structural brain pathology and its association with post-operative delirium. Standard of care structural magnetic resonance imaging (MRIs) from a cohort of surgical candidates prior to surgery were analyzed for white matter hyperintensities and cerebral atrophy. METHODS: We identified 23 non-small cell lung cancer patients with no evidence of metastases in the brain pre-operatively, through retrospective chart review, who met criteria for post-operative delirium within 4 days of surgery. 24 age- and gender-matched control subjects were identified for comparison to the delirium sample. T1 and fluid-attenuated inversion recovery sequences were collected from standard of care pre-operative MRI screening and assessed for white matter pathology and atrophy. RESULTS: We found significant differences in white matter pathology between groups with the delirium group exhibiting significantly greater white matter pathology than the non-delirium group. Measure of cerebral atrophy demonstrated no significant difference between the delirium and non-delirium group. CONCLUSIONS: In this preliminary study utilizing standard of care pre-operative brain MRIs for assessment of structural risk factors to delirium, we found white matter pathology to be a significant risk factor in post-operative delirium. Limitations and implications for further investigation are discussed. PMID- 23457032 TI - The neurobiology of tetrahydrobiopterin biosynthesis: a model for regulation of GTP cyclohydrolase I gene transcription within nigrostriatal dopamine neurons. AB - Within the brain, the reduced pteridine cofactor 6R-L-erythro-5,6,7,8 tetrahydrobiopterin (BH4) is absolutely required for the synthesis of the monoamine (MA) neurotransmitters dopamine (DA), norepinephrine, epinephrine (E), and serotonin (5-HT), the novel gaseous neurotransmitter nitric oxide and the production of yet to be identified 1-O-alkylglycerol-derived lipids. GTP cyclohydrolase I (GTPCH) catalyzes the first and limiting step in the BH4 biosynthetic pathway, which is now thought to involve up to eight different proteins supporting six alternate de novo and two alternate salvage pathways. Gene expression analysis across different regions of the human brain shows the abundance of transcripts coding for all eight of these proteins to be highly correlated with each other and to be enriched within human MA neurons. The potential for multiple routes for BH4 synthesis therefore exists within the human brain. GTPCH expression is particularly heterogeneous across different populations of human and rodent MA-containing neurons, with low expression levels and therefore BH4 being a characteristic of nigrostriatal DA (NSDA) neurons. Basic knowledge of how GCH1 gene transcription is controlled within NSDA neurons may explain the distinctive susceptibility of these neurons to human genetic mutations that result in BH4 deficiency. A model for cyclic adenosine monophosphate-dependent GCH1 transcription is described that involves a unique combination of DNA regulatory sequences and transcription factors. This model proposes that low levels of GCH1 transcription within NSDA neurons are driven by their distinctive physiology, suggesting that pharmacological manipulation of GCH1 gene transcription can be used to modify BH4 levels and therefore DA synthesis in the basal ganglia. PMID- 23457034 TI - Enhancing clinical outcomes in hepatocellular carcinoma. PMID- 23457033 TI - Fine-needle aspiration cytology of orbital and eyelid lesions. AB - Fine-needle aspiration cytology (FNAC) of orbital lesions is now increasingly popular. Because of its unique location and the occurrence of varieties of lesions, diagnosis of orbital lesion is a challenge to the cytopathologists. FNAC of orbital and eyelid tumors is a suitable diagnostic technique that necessitates close co-operation between the ophthalmologist and pathologist. No radical procedure should be planned on the basis of FNAC, but it allows the diagnosis of a new primary lesion or the recurrence or metastasis of a tumor and can be done to identify lesions that require either specific medical therapy, as in nonresectable, inflammatory, and lymphoid tumors, or limited surgery for benign resectable neoplasms. With the help of various ancillary techniques a definitive diagnosis is possible on orbital and adnexal lesions. It is essential to have a detailed knowledge on the FNAC of these lesions and their potential pitfalls. In this present review, we have discussed various orbital lesions, their clinical presentations, cytomorphology, and ancillary techniques to confirm the diagnosis. PMID- 23457035 TI - Emerging targeted strategies in advanced hepatocellular carcinoma. AB - Treatment of advanced-stage hepatocellular carcinoma (HCC) remains a challenge because of the complex nature of the disease and the lack of available therapies. The antiangiogenic multikinase inhibitor sorafenib is the first therapy to demonstrate a significant overall survival benefit in advanced HCC. However, new agents for both first- and second-line treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation, and survival provide many opportunities for the development of molecularly targeted therapies. Many novel agents are under investigation in phase III trials in advanced HCC, including antiangiogenic multikinase inhibitors (e.g., brivanib, sunitinib, linifanib) and inhibitors of the mammalian target of rapamycin (mTOR) pathway (e.g., everolimus). Although these therapies have demonstrated some utility as single agents in advanced HCC, rational combinations of therapies are likely to provide greater success. Current research efforts are directed at combining agents targeting different molecular pathways (e.g., sorafenib in combination with erlotinib) and combining molecularly targeted agents with systemic chemotherapy or transarterial chemoembolization (TACE). Therapies targeting other molecular pathways in HCC are in early development; future research will focus on discovering additional targets for therapy and identifying biomarkers that predict the success of current therapies. PMID- 23457036 TI - Shaping the future management of hepatocellular carcinoma. AB - Several advances in recent years have led to improved surveillance, diagnostic, and treatment options for hepatocellular carcinoma (HCC). Despite these advances, care for this malignancy remains suboptimal, in part because of poor adherence to established guidelines. When diagnosed at an early stage, outcomes for HCC are positive; however, use of appropriate screening techniques and surveillance of at risk patients is still not widely employed. Although a multidisciplinary care team is considered an essential part of successful HCC treatment, fewer than half of the patients with HCC in the United States receive multidisciplinary care. The current suboptimal utilization of potentially curative treatments, including those recommended by treatment guidelines, can be linked to the absence of multidisciplinary care. Additionally, the lack of prognostic and predictive biomarkers for HCC remains challenging, particularly as therapeutic approaches in advanced disease evolve to the use of molecularly targeted agents. Much research is currently focused on the identification of biomarkers for HCC, but improvements in adherence to guidelines for surveillance and appropriate use of available therapies is necessary before care for patients with HCC will improve. PMID- 23457037 TI - Multidisciplinary management of hepatocellular carcinoma: where are we today? AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, and the incidence of HCC continues to rise. Improved understanding of risk factors for HCC has allowed the development of more effective prevention and surveillance strategies to reduce the global burden of this malignancy. Because of the complex nature of HCC, arising in a background of chronic liver dysfunction and often associated with viral infection, appropriate treatment requires a multidisciplinary approach designed to control the cancer and treat the underlying liver disease. Treatment approaches vary based on disease stage and severity, making accurate diagnosis and staging of disease critical. This has been aided by the development of new staging criteria, such as the Barcelona Clinic Liver Cancer Staging System. For earlier-stage disease, resection, radiofrequency ablation, transplantation, and transarterial chemoembolization (TACE) are preferred treatment modalities that provide optimal outcome. Until recently, few treatment options existed for patients with more advanced disease. Improved understanding of the underlying biology of the disease and the development of molecularly targeted therapies, including the multitargeted angiokinase inhibitor sorafenib, has improved outcomes in this patient population. Research into therapeutic targets and novel agents continues for more advanced disease. PMID- 23457038 TI - Antagonism of chemokine receptor CCR8 is ineffective in a primate model of asthma. AB - BACKGROUND: Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data. OBJECTIVE: To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma. METHODS: ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine. RESULTS: ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086. CONCLUSIONS: These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma. PMID- 23457039 TI - Sub-lethal effects of four neonicotinoid seed treatments on the demography and feeding behaviour of the wheat aphid Sitobion avenae. AB - BACKGROUND: Neonicotinoids are widely used as seed treatments in wheat fields against the grain aphid (Sitobion avenae F.) in China. Due to the degradation of neonicotinoids in wheat plants, wheat aphids are more likely to be exposed to low concentrations of neonicotinoids over long periods. It is therefore expected that neonicotinoids, aside from acute (lethal) effects, may also cause a range of sub lethal effects on this pest. RESULTS: The growth and fertility of S. avenae feeding on wheat plants treated with a sub-lethal concentration (LC10 ) of imidacloprid, dinotefuran, thiacloprid and thiamethoxam were not greatly affected. However, the population growth parameters of S. avenae were significantly reduced at median lethal concentration (LC50 ). Electronic penetration graph recordings showed a higher percentage of no probing phase and shorter phloem sap ingestion phase on the wheat plants treated with LC10 and LC50 concentrations. CONCLUSION: The results indicate that even low concentrations of neonicotinoid treatments on wheat seeds have long-term, adverse effects on wheat aphid. As such, neonicotinoid seed treatments have far greater effects on wheat aphids than estimated by acute toxicity tests. These results benefit our understanding on the subtle effects of the four tested neonicotinoids when applied as seed treatments. PMID- 23457040 TI - EBARDenovo: highly accurate de novo assembly of RNA-Seq with efficient chimera detection. AB - MOTIVATION: High-accuracy de novo assembly of the short sequencing reads from RNA Seq technology is very challenging. We introduce a de novo assembly algorithm, EBARDenovo, which stands for Extension, Bridging And Repeat-sensing Denovo. This algorithm uses an efficient chimera-detection function to abrogate the effect of aberrant chimeric reads in RNA-Seq data. RESULTS: EBARDenovo resolves the complications of RNA-Seq assembly arising from sequencing errors, repetitive sequences and aberrant chimeric amplicons. In a series of assembly experiments, our algorithm is the most accurate among the examined programs, including de Bruijn graph assemblers, Trinity and Oases. AVAILABILITY AND IMPLEMENTATION: EBARDenovo is available at http://ebardenovo.sourceforge.net/. This software package (with patent pending) is free of charge for academic use only. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23457042 TI - RCPedia: a database of retrocopied genes. AB - MOTIVATION: Retrocopies are copies of mature RNAs that are usually devoid of regulatory sequences and introns. They have routinely been classified as processed pseudo-genes with little or no biological relevance. However, recent findings have revealed functional roles for retrocopies, as well as their high frequency in some organisms, such as primates. Despite their increasing importance, there is no user-friendly and publicly available resource for the study of retrocopies. RESULTS: Here, we present RCPedia, an integrative and user friendly database designed for the study of retrocopied genes. RCPedia contains a complete catalogue of the retrocopies that are known to be present in human and five other primate genomes, their genomic context, inter-species conservation and gene expression data. RCPedia also offers a streamlined data representation and an efficient query system. AVAILABILITY AND IMPLEMENTATION: RCPedia is available at http://www.bioinfo.mochsl.org.br/rcpedia. PMID- 23457041 TI - ChIP-PED enhances the analysis of ChIP-seq and ChIP-chip data. AB - MOTIVATION: Although chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) or tiling array hybridization (ChIP-chip) is increasingly used to map genome-wide-binding sites of transcription factors (TFs), it still remains difficult to generate a quality ChIPx (i.e. ChIP-seq or ChIP-chip) dataset because of the tremendous amount of effort required to develop effective antibodies and efficient protocols. Moreover, most laboratories are unable to easily obtain ChIPx data for one or more TF(s) in more than a handful of biological contexts. Thus, standard ChIPx analyses primarily focus on analyzing data from one experiment, and the discoveries are restricted to a specific biological context. RESULTS: We propose to enrich this existing data analysis paradigm by developing a novel approach, ChIP-PED, which superimposes ChIPx data on large amounts of publicly available human and mouse gene expression data containing a diverse collection of cell types, tissues and disease conditions to discover new biological contexts with potential TF regulatory activities. We demonstrate ChIP-PED using a number of examples, including a novel discovery that MYC, a human TF, plays an important functional role in pediatric Ewing sarcoma cell lines. These examples show that ChIP-PED increases the value of ChIPx data by allowing one to expand the scope of possible discoveries made from a ChIPx experiment. AVAILABILITY: http://www.biostat.jhsph.edu/~gewu/ChIPPED/ PMID- 23457043 TI - MicroRNA-146a targets PRKCE to modulate papillary thyroid tumor development. AB - MicroRNAs are single-stranded noncoding RNAs composed of approximately 22 nucleotides that suppress gene expression by selectively binding via base-pairing to the complementary 3'-untranslated region (3'-UTR) of messenger RNA transcripts. Protein kinase C epsilon (PKCepsilon) is an important modulating member of the transducing Ras/Raf-1 signal pathway; a computational search revealed miR-146a putatively binds to the 3'-UTR of the PRKCE gene, and thus decreasing PKCepsilon expression. Moreover, PKCepsilon inhibits mitochondrial apoptosis and is associated with the Bcl family. However, it has been previously reported that miR-146a expression in papillary thyroid carcinoma (PTC) is slightly elevated. Thus, we hypothesized that because miR-146a expression depends on nuclear factor kappaB (NF-kappaB) activation and NF-kappaB expression is elevated in PTC, miR-146a is potentially upregulated in PTC via negative feedback of NF-kappaB, and thus suppressing PKCepsilon expression. In our study, we investigated whether overexpression of miR-146a, a tumor-suppressing-miR, in PTC cells decreases cell survival and induces apoptosis. Luciferase reporter assay analysis confirmed the direct binding of miR-146a and PRKCE 3'-UTR. Specific overexpression of exogenous miR-146a significantly decreased PKCepsilon levels in PTC cell line NPA-187 and increased apoptosis. Additionally, using stably expressing miR-146a thyroid carcinoma cells to establish subcutaneous tumors, the tumor growth exhibited significant inhibition. Our study confirmed the tumor suppressing role of miR-146a in thyroid carcinoma cells and contributes to the knowledge regarding modulation of Ras/Raf-1 signal transduction and apoptosis via PKCepsilon targeted by miR-146a in PTC; moreover, our findings confirmed that miR 146a is involved in the feedback system of the classical NF-kappaB signal pathway in PTC. PMID- 23457045 TI - Pigmented paget's disease: a diagnostic pitfall. PMID- 23457044 TI - Phenylalanine hydroxylase: function, structure, and regulation. AB - Mammalian phenylalanine hydroxylase (PAH) catalyzes the rate-limiting step in the phenylalanine catabolism, consuming about 75% of the phenylalanine input from the diet and protein catabolism under physiological conditions. In humans, mutations in the PAH gene lead to phenylketonuria (PKU), and most mutations are mainly associated with PAH misfolding and instability. The established treatment for PKU is a phenylalanine-restricted diet and, recently, supplementation with preparations of the natural tetrahydrobiopterin cofactor also shows effectiveness for some patients. Since 1997 there has been a significant increase in the understanding of the structure, catalytic mechanism, and regulation of PAH by its substrate and cofactor, in addition to improved correlations between genotype and phenotype in PKU. Importantly, there has also been an increased number of studies on the structure and function of PAH from bacteria and lower eukaryote organisms, revealing an additional anabolic role of the enzyme in the synthesis of melanin like pigments. In this review, we discuss these recent studies, which contribute to define the evolutionary adaptation of the PAH structure and function leading to sophisticated regulation for effective catabolic processing of phenylalanine in mammalian organisms. PMID- 23457046 TI - Induction of heat shock gene expression in RAT1 primary fibroblast cells by ELF electric fields. AB - Recent studies have demonstrated that the Ku70 gene fragment can be placed in the anti-sense orientation under the control of a heat-inducible heat shock protein 70 (HSP70) promoter and activated through heat shock exposure. This results in attenuation of the Ku70 protein expression, inhibiting cellular repair processes, and sensitizing the transfected cells to exposures such as the ionizing radiation exposures used clinically. However, achieving the tissue temperatures necessary to thermally induce the HSP70 response presents significant limitations to the clinical application of this strategy. Previous findings suggest an alternative approach to inducing a heat shock response, specifically through the use of extremely low frequency (ELF) electrical field stimulation. To further pursue this approach, we investigated HSP70 responses in transfected rat primary fibroblast (RAT1) cells exposed to 10 Hz electric fields at intensities of 20-500 V/m. We confirmed that low frequency electric fields can induce HSP70 heat shock expression, with peak responses obtained at 8 h following a 2 h field exposure. However, the approximate threefold increase in expression is substantially lower than that obtained using thermal stimulation, raising questions of the clinical utility of the response. PMID- 23457048 TI - Mixing tests: diagnostic aides in the investigation of prolonged prothrombin times and activated partial thromboplastin times. AB - Mixing tests are a relatively simple procedure used in the hemostasis laboratory as a first-line investigation into the cause of an abnormal screening test, typically a prolonged activated partial thromboplastin time and/or a prolonged prothrombin time. The mixing test involves combining the test plasma with normal plasma, then repeating the screening test on the mixture to assess whether the clotting time becomes normal or remains prolonged. The primary purpose of a mixing test is to guide further investigations. When mixing test results "normalize," this suggests the test plasma is deficient in clotting factor(s) and thus specific factor assays can be performed to determine which are reduced. When the mixing test result does not "normalize," this suggests the presence of an inhibitor or other type of interference (e.g., the presence of an anticoagulant such as high-dose heparinoids), and so the laboratory needs to determine if this is a lupus anticoagulant or a specific coagulation factor inhibitor, or another type of inhibitor. Because these follow-up investigations are more costly and time-consuming than the basic screening tests, the appropriate performance and interpretation of mixing tests is advantageous for the laboratory. Moreover, the correct laboratory approach is also clinically relevant, as patient management is ultimately affected, and an incorrect interpretation may lead to inappropriate therapies being established. Components of a mixing test that can influence result interpretation include the sensitivity of the used screening reagents to various factor deficiencies and inhibitors, the source or composition of the normal plasma, and the setting of cutoffs for the formula used in expressing mixing test results. Numerous and differing criteria for mixing test interpretation have been suggested historically, which can lead to confusion as to which approach is the most appropriate. The use of differing criteria will also lead to differing interpretations regarding "normalization." For this pivotal reason, standardized mixing test procedures and a consistent set of validated interpretive criteria represent the most favorable approach to maximizing the utility of a mixing test, and ensure the most accurate diagnosis for investigated patients. PMID- 23457049 TI - Thrombin activatable fibrinolysis inhibitor: a putative target to enhance fibrinolysis. AB - Thrombin activatable fibrinolysis inhibitor (TAFI) was discovered two decades ago consequent to the identification of an unstable carboxypeptidase (CPU) formed upon thrombin activation of its proenzyme. The antifibrinolytic effects of the activated form (TAFIa, CPU) are linked with its capacity to remove C-terminal lysines from the surface of the fibrin clot. A distinctive characteristic of TAFIa is its temperature-dependent conformational instability: TAFIa activity spontaneously decays with an apparent half-life of 8 to 15 minutes at 37 degrees C. A variety of studies has demonstrated a role for TAFI/TAFIa in venous and arterial diseases. In addition, a role for TAFI/TAFIa in inflammation and cell migration has also been shown. Because TAFI/TAFIa is a potential risk factor for thrombotic disorders, many inhibitors, both at the level of activation or at the level of activity, have been developed and were proven to exhibit a profibrinolytic effect in animal models. Pharmacologically active inhibitors of the TAFI/TAFIa system may open new ways for the prevention of thrombotic diseases or for the establishment of adjunctive treatments during thrombolytic therapy. PMID- 23457047 TI - High-throughput cloning and expression library creation for functional proteomics. AB - The study of protein function usually requires the use of a cloned version of the gene for protein expression and functional assays. This strategy is particularly important when the information available regarding function is limited. The functional characterization of the thousands of newly identified proteins revealed by genomics requires faster methods than traditional single-gene experiments, creating the need for fast, flexible, and reliable cloning systems. These collections of ORF clones can be coupled with high-throughput proteomics platforms, such as protein microarrays and cell-based assays, to answer biological questions. In this tutorial, we provide the background for DNA cloning, discuss the major high-throughput cloning systems (Gateway(r) Technology, Flexi(r) Vector Systems, and Creator(TM) DNA Cloning System) and compare them side-by-side. We also report an example of high-throughput cloning study and its application in functional proteomics. This tutorial is part of the International Proteomics Tutorial Programme (IPTP12). PMID- 23457050 TI - A resistance mechanism dependent upon the inhibition of ethylene biosynthesis. AB - BACKGROUND: The highly selective auxin-type herbicide quinclorac is widely used to control important dicotyledon and monocotyledon weeds in rice fields. Echinochloa crusgalli var. zelayensis is one of the most troublesome weeds in China, and is very difficult to control in east China due to misuse of herbicides. RESULTS: The JZD -R, JTJ -R, JCW -R and SSX -R biotypes of E. crusgalli var. zelayensis had resistance to quinclorac with resistance levels ranked as JZD -R < JTJ -R < JCW -R < SSX -R. Growth reduction in different biotypes was positively correlated with ethylene production. Stimulated levels of ethylene and 1-aminocyclopropane-1-carboxylic acid (ACC) and activities of ACC synthase and ACC oxidase in resistant biotypes were less than the susceptible biotype, and were negatively correlated with quinclorac resistance levels, suggesting that inhibition of ethylene biosynthesis was positively correlated with resistance levels. CONCLUSION: Considering the resistance-dependent inhibition in the ethylene biosynthetic pathway, the mechanisms of resistance to quinclorac in E. crusgalli var. zelayensis involved alteration(s) in the ethylene response pathway, consisting of at least alteration in induction of the enzymes activity of ACC synthase and ACC oxidase. PMID- 23457052 TI - Inhomogeneous background magnetic field in biological incubators is a potential confounder for experimental variability and reproducibility. AB - This report shows that the background magnetic field in biological incubators can vary by orders of magnitude within and between incubators. These variations can be observed within the same incubator in locations that are centimeters apart from each other as well as between incubators that are identical and located in the same laboratory. Additionally, the values measured were frequently outside the range of magnitudes found naturally on the Earth's surface or ordinary habitation spaces. Exposure to such altered magnetic field environments has been experimentally shown to be sufficient to cause numerous effects in cell cultures. Examples of the effects reported span from differential generation of free radicals and heat shock proteins to differences in cellular proliferation, differentiation, and death. Although the effects are not well established and the molecular mechanism of action is currently under debate, these observations alone support the notion that the inhomogeneity of the background magnetic field in incubators is a potential confounding source of the variability and reproducibility for studies performed on cell cultures. In this regard, it is recommended that special measures be adopted to control the background magnetic fields in incubators when investigating the biological effects of exposure to magnetic fields of comparable characteristics as the ones measured in this study, or when studying small biological effects in general. PMID- 23457053 TI - On-target ultrasonic digestion of proteins. AB - In the present work, we report a novel on-target protein cleavage method. The method utilizes ultrasonic energy and allows up to 20 samples to be cleaved in 5 min for protein identification and one sample in 30 s for on-tissue digestion. The standard proteins were spotted on a conductive glass slide in a volume of 0.5 MUL followed by 5 min of ultrasonication after trypsin addition. Controls (5 min, 37 degrees C no ultrasonication) were also assayed. After trypsin addition, digestion of the tissues was enhanced by 30 s of ultrasonication. The samples were analyzed and compared to those obtained by using conventional 3 h heating proteolysis. The low sample volume needed for the digestion and reduction in sample-handling steps and time are the features that make this method appealing to the many laboratories working with high-throughput sample treatment. PMID- 23457054 TI - Structures and reaction mechanisms of GTP cyclohydrolases. AB - GTP cyclohydrolases generate the first committed intermediates for the biosynthesis of certain vitamins/cofactors (folic acid, riboflavin, deazaflavin, and tetrahydrobiopterin), deazapurine antibiotics, some t-RNA bases (queuosine, archaeosine), and the phytotoxin, toxoflavin. They depend on divalent cations for hydrolytic opening of the imidazole ring of the substrate, guanosine triphosphate (GTP). Surprisingly, the ring opening reaction is not the rate-limiting step for GTP cyclohydrolases I and II whose mechanism have been studied in some detail. GTP cyclohydrolase I, Ib, and II are potential targets for novel anti-infectives. Genetic factors modulating the activity of human GTP cyclohydrolase are highly pleiotropic, since the signal transponders whose biosyntheses require their participation (nitric oxide, catecholamines) impact a very wide range of physiological phenomena. Recent studies suggest that human GTP cyclohydrolase may become an oncology target. PMID- 23457055 TI - Identification of oropharyngeal squamous cell carcinomas with active HPV16 involvement by immunohistochemical analysis of the retinoblastoma protein pathway. AB - Viral oncogene RNA expression is regarded as reliable biomarker to identify oropharyngeal squamous cell carcinomas (OPSCC) with active HPV16 involvement. This study addressed whether the expression profile of the cellular proteins p16(INK4a), pRb, Cyclin D1 and p53 provide surrogate marker combinations that identify OPSCC with active HPV16 in situations where only formalin-fixed biopsies are available. Protein expression was analyzed by immunohistochemistry on tissue microarrays created from 188 OPSCC of which the HPV16 DNA and RNA status had been established previously from snap-frozen biopsies. Associations of single markers and of marker combinations with HPV16 DNA, viral RNA expression patterns and overall survival as primary end point were evaluated by statistical analysis. Most tumors with active HPV16 involvement (RNA(+) group; n = 40) showed a specific protein pattern, that is, high p16(INK4a) (80%), low pRb (85%), low Cyclin D1 (95%) and normal p53 (73%). This pattern was significantly different from the pattern observed in HPV DNA-negative tumors (HPV(-) group) and in HPV16 DNA-positive tumors lacking viral RNA expression patterns (RNA(-) group). The combination of high p16(INK4a) and low pRb levels was distinctly superior to p16(INK4a) alone; it was strongly associated with RNA(+) tumors (OR 41.4, 95%CI 10.7-162.5), with improved survival (HR 0.37, 95%CI 0.2-0.8) and had best predictive values (78% sensitivity, 93% specificity, 78% PPV, 93% NPV). In conclusion, if only formalin-fixed biopsy material is available, the marker combination high p16(INK4a) /low pRb is well suited to identify OPSCC with biologically active HPV16 which represent a distinct OPSCC entity with improved prognosis. PMID- 23457056 TI - Real-time PCR to study the effect of timing and persistence of fungicide application and wheat varietal resistance on Mycosphaerella graminicola and its sterol 14alpha-demethylation-inhibitor-resistant genotypes. AB - BACKGROUND: Sterol 14alpha-demethylase inhibitors (DMIs) have been widely used for more than 20 years against wheat Septoria leaf blotch. However, resistance towards DMIs has increased in recent years. The objective of this study was to evaluate the effect of fungicide timing and persistence and wheat resistance varietal on Mycosphaerella graminicola and its DMI-resistant genotypes. RESULTS: Using qPCR, M. graminicola was detected 2 weeks later in the resistant cultivar than in the susceptible cultivar. A high proportion of DMI-moderate resistant genotypes (>=94%) was found in all samples, with an average of 74.2, 0.1 and 19.7% for R6, R7- and R7+ genotypes, respectively. Distribution of DMI-resistant genotypes was neither affected by different wheat cultivars nor by analysis dates. Electron microscopy coupled with qPCR analysis showed that the DMI fungicide prothioconazole had a significant inhibitive effect against spore germination and post-germination. However, the preventive treatment was the most effective, but it was affected strongly by fungicide persistence. CONCLUSION: Preventive fungicide applications are more effective against Septoria leaf blotch than the curative treatments, so persistence and wheat varietal resistance should be taken into account in the management of this disease. It would seem that none of the studied factors affect the frequency of DMI-resistant genotypes. PMID- 23457057 TI - Isolation and characterization of Gibberella intermedia CA3-1, a novel and versatile nitrilase-producing fungus. AB - Nitrilase-mediated biocatalysis has attracted substantial attention for its application in carboxylic acid production in recent years. In the present study, the fungus CA3-1 was isolated and identified as Gibberella intermedia based on its morphology, its 18S ribosomal DNA (rDNA), and internal transcribed spacer (ITS) sequences. The enzymatic properties of G. intermedia resting cells were determined, and the optimum activity was achieved at 40 degrees C with pH 7.6. The half-lives of the nitrilase at 30, 40, and 50 degrees C were 231.1, 72.9, and 6.4 h, respectively. This Gibberella nitrilase showed a wide substrate spectrum with high specificity for heterocyclic and aliphatic nitriles. It remained extremely active in 5% propanol. The presence of Ag(+), Hg(2+), and excess substrate inhibited the nitrilase activity, whereas Fe(2+), Mn(2+), and Li(+) improved enzyme activity. 3-Cyanopyridine (50 mM) was hydrolyzed into nicotinic acid within 30 min, whereas only <5% of nicotinamide was detected. The results show that this fungal nitrilase is a promising candidate for commercial application in nicotinic acid production. PMID- 23457058 TI - Unique role of self-assembled monolayers in carbon nanomaterial-based field effect transistors. AB - Molecular self-assembly is a promising technology for creating reliable functional films in optoelectronic devices with full control of thickness and even spatial resolution. In particular, rationally designed self-assembled monolayers (SAMs) play an important role in modifying the electrode/semiconductor and semiconductor/dielectric interfaces in field-effect transistors. Carbon nanomaterials, especially single-walled carbon nanotubes and graphene, have attracted intense interest in recent years due to their remarkable physicochemical properties. The combination of the advantages of both SAMs and carbon nanomaterials has been opening up a thriving research field. In this Review article, the unique role of SAMs acting as either active or auxiliary layers in carbon nanomaterials-based field-effect transistors is highlighted for tuning the substrate effect, controlling the carrier type and density in the conducting channel, and even installing new functionalities. The combination of molecular self-assembly and molecular engineering with materials fabrication could incorporate diverse molecular functionalities into electrical nanocircuits, thus speeding the development of nanometer/molecular electronics in the future. PMID- 23457059 TI - Library dependent LC-MS/MS acquisition via mzAPI/Live. AB - The use of MS for characterization of small molecules, nucleotides, and proteins in model organisms as well as primary tissues and clinical samples continues to proliferate at a rapid pace. The complexity and dynamic range of target analytes in biological systems hinders comprehensive analysis and simultaneously drives improvements in instrument hardware and software. As a result, state-of-the-art commercial mass spectrometers are equipped with sophisticated embedded control systems that provide robust acquisition methods accessed through intuitive graphical interfaces. Although optimized for speed, these preconfigured scan functions are otherwise closed to end-user customization beyond simple, analytical-centric parameters supplied by the manufacturer. Here, we present an open-source framework (mzAPI/Live) that enables users to generate arbitrarily complex LC-MS(n) acquisition methods via simple Python scripting. As a powerful proof-of-concept, we demonstrate real-time assignment of tandem mass spectra through rapid query of NIST peptide libraries. This represents an unprecedented capability to make acquisition decisions based on knowledge of analyte structures determined during the run itself, thus providing a path toward biology-driven MS data acquisition for the broader community. PMID- 23457060 TI - Chlorothiazide is a substrate for the human uptake transporters OAT1 and OAT3. AB - The thiazide diuretic chlorothiazide is poorly metabolized, and is predominantly excreted via the kidneys. We have previously shown that chlorothiazide is transported by ATP-binding cassette transporter G2, suggesting a potential role for this transporter in apical efflux of chlorothiazide in the kidney. However, because of the poor passive permeability of the drug, it is likely that uptake transporters on the basolateral membrane are also involved to facilitate vectorial transport in the renal proximal tubule. Two suggested candidate transporters for this role are the human organic anion transporters, OAT1 and OAT3. By using mammalian cells stably expressing these transporters, we have demonstrated OAT1- and OAT3-dependent uptake of chlorothiazide with Michaelis constant values of 14.5 and 37.6 uM, respectively. Furthermore, we have found that probenecid, furosemide, and diclofenac inhibit chlorothiazide transport by OAT1 and OAT3, of which the probenecide-mediated inhibition may be of clinical importance. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1683-1687, 2013. PMID- 23457061 TI - A comparison of bootstrap approaches for estimating uncertainty of parameters in linear mixed-effects models. AB - A version of the nonparametric bootstrap, which resamples the entire subjects from original data, called the case bootstrap, has been increasingly used for estimating uncertainty of parameters in mixed-effects models. It is usually applied to obtain more robust estimates of the parameters and more realistic confidence intervals (CIs). Alternative bootstrap methods, such as residual bootstrap and parametric bootstrap that resample both random effects and residuals, have been proposed to better take into account the hierarchical structure of multi-level and longitudinal data. However, few studies have been performed to compare these different approaches. In this study, we used simulation to evaluate bootstrap methods proposed for linear mixed-effect models. We also compared the results obtained by maximum likelihood (ML) and restricted maximum likelihood (REML). Our simulation studies evidenced the good performance of the case bootstrap as well as the bootstraps of both random effects and residuals. On the other hand, the bootstrap methods that resample only the residuals and the bootstraps combining case and residuals performed poorly. REML and ML provided similar bootstrap estimates of uncertainty, but there was slightly more bias and poorer coverage rate for variance parameters with ML in the sparse design. We applied the proposed methods to a real dataset from a study investigating the natural evolution of Parkinson's disease and were able to confirm that the methods provide plausible estimates of uncertainty. Given that most real-life datasets tend to exhibit heterogeneity in sampling schedules, the residual bootstraps would be expected to perform better than the case bootstrap. PMID- 23457063 TI - Acetabular bone loss in revision total hip arthroplasty: evaluation and management. AB - As the number of primary total hip arthroplasty (THA) procedures performed continues to rise, the burden of revision THA procedures is also expected to increase. Proper evaluation and management of acetabular bone loss at the time of revision surgery will be an increasing challenge facing orthopaedic surgeons. Proper preoperative patient assessment and detailed preoperative planning are essential in obtaining a good clinical result. Appropriate radiographs are critical in assessing acetabular bone loss, and specific classification schemes can identify bone loss patterns and guide available treatment options. Treatment options include impaction grafting and cementation of the acetabulum, noncemented hemispheric acetabular reconstruction, structural allograft reconstruction, noncemented reconstruction with modular porous metal augments, ring and cage reconstruction, oblong cup reconstruction, cup-cage reconstruction, and triflange reconstruction. PMID- 23457064 TI - Total wrist arthroplasty. AB - Over the past 40 years, total wrist arthroplasty (TWA) has emerged as a cost effective treatment option for wrist arthritis. First-generation implant designs have changed tremendously; current devices are designed to enhance wrist stability, provide greater implant longevity, and minimize surgical and postoperative complications. Although arthrodesis remains the standard for surgical management, TWA outcomes demonstrate that the procedure has excellent clinical promise. Additional prospective studies are needed to compare outcomes of wrist arthrodesis with those of TWA with current implants. PMID- 23457065 TI - Management of fractures of the proximal ulna. AB - Proximal ulna fractures can be difficult to manage because of the elbow's complex anatomy. Advances in understanding elbow anatomy and biomechanics, however, have led to new insights. Careful preoperative evaluation is critical because failure to restore normal anatomy of the proximal ulna could have a detrimental effect on postoperative elbow function. Management options include anatomic plates, intramedullary devices, and strong tension band materials. Determining the most appropriate option for an individual fracture is based on analysis of radiographs and CT scans, including three-dimensional reconstruction. Coronoid fractures, olecranon fractures, and associated elbow instability influence the indications for any given fixation device. Appreciating the subtleties of proximal ulna anatomy and biomechanics can lead to improved clinical outcomes. Recent concepts affecting fracture management include proximal ulna dorsal angulation, the importance of the anteromedial facet of the coronoid, and intermediate fragments of the olecranon. PMID- 23457066 TI - Obesity and osteoarthritis: more than just wear and tear. AB - A link has been established between obesity and osteoarthritis (OA), but the precise relationship has yet to be defined. OA has a multifactorial etiology, and obesity is consistently identified as an independent and modifiable risk factor. The biomechanical relationship is intuitive: increased loads on articular cartilage cause subsequent wear and cartilage breakdown. Less intuitive, and possibly more important, are the systemic effects of obesity on OA. Promising investigations into relationships between lipid metabolism and OA have been rarely reported in the orthopaedic literature. These reports argue that, in obese patients, weight loss may not only help prevent OA but also may be an effective treatment strategy. Orthopaedic surgeons should be aware of the biomechanical and systemic implications of obesity with respect to OA so that patients may be counseled accordingly. PMID- 23457067 TI - The pediatric polytrauma patient: current concepts. AB - Understanding the pediatric response to polytrauma is essential for the orthopaedic surgeon. The physiologic effects of multisystem injury that manifest in a child have important implications for coordination of treatment, particularly in relation to the timing and incidence of organ failure. The orthopaedic surgeon plays an important role in managing hemodynamic instability, vascular insult, and neurologic damage in the child with multiple injuries. Indications for surgery and postoperative immobilization in the pediatric polytrauma patient differ from those in the patient with an isolated injury. Further research is needed to determine the most appropriate method of management for extremity fractures in the pediatric polytrauma patient, particularly regarding the timing of fixation and management of open fractures. PMID- 23457069 TI - Shared decision making tool: should I take antibiotics before my dental procedure? PMID- 23457068 TI - Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures. AB - The Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures evidence-based clinical practice guideline was codeveloped by the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association. This guideline replaces the previous AAOS Information Statement, "Antibiotic Prophylaxis in Bacteremia in Patients With Joint Replacement," published in 2009. Based on the best current evidence and a systematic review of published studies, three recommendations have been created to guide clinical practice in the prevention of orthopaedic implant infections in patients undergoing dental procedures. The first recommendation is graded as Limited; this recommendation proposes that the practitioner consider changing the long-standing practice of routinely prescribing prophylactic antibiotic for patients with orthopaedic implants who undergo dental procedures. The second, graded as Inconclusive, addresses the use of oral topical antimicrobials in the prevention of periprosthetic joint infections. The third recommendation, a Consensus statement, addresses the maintenance of good oral hygiene. PMID- 23457070 TI - The antibiotic prophylaxis guideline for prosthetic joints: trying to do the right thing. PMID- 23457071 TI - The new AAOS-ADA clinical practice guideline on Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures. PMID- 23457073 TI - Interaction of miltefosine with the lipid and protein components of the erythrocyte membrane. AB - Miltefosine (MT) is an alkylphospholipid that has been approved for the treatment of breast cancer metastasis and visceral leishmaniasis, although its mechanism of action remains poorly understood. Electron paramagnetic resonance spectroscopy of a spin-labeled lipid and a thiol-specific spin label showed that MT causes an increase in the molecular dynamics of erythrocyte ghost membranes and detergent resistant membranes (DRMs) prepared from erythrocyte ghosts. In the vesicles of lipid raft constituents, it was shown that 20 mol % sphingomyelin could be replaced by 20 mol % MT with no change in the molecular dynamics. The effect of MT in DRMs was more pronounced than in erythrocyte ghosts, supporting the hypothesis that MT is a lipid raft modulator. At the reported MT-plasma concentrations found during the treatment of leishmaniasis (31-90 ug/mL), our measurements in the blood plasma indicated a hemolytic level of 2%-5%. The experiments indicated that MT acts predominantly on the protein component of the membrane. MT aggregates may wrap around the hydrophobic polypeptide chains, forming micelle-like structures that stabilize protein conformations more exposed to the solvent. Proteins with higher hydrophobicity may induce the penetration of the hydrophilic groups of MT into the membrane and cause it to rupture. PMID- 23457074 TI - Biodegradation of petroleum hydrocarbons in the presence of nickel and cobalt. AB - Bioremediation of environments co-contaminated with hydrocarbons and heavy metals often pose a challenge as heavy metals exert toxicity to existing communities of hydrocarbon degraders. Multi-resistant bacterial strains were studied for ability to degrade hydrocarbons in chemically defined media amended with 5.0 mM Ni(2+), and Co(2+). The bacteria, Pseudomonas aeruginosa CA207Ni, Burkholderia cepacia AL96Co, and Corynebacterium kutscheri FL108Hg, utilized crude oil and anthracene without lag phase at specific growth rate spanning 0.3848-0.8259 per day. The bacterial populations grew in hydrocarbon media amended with nickel (Ni) and cobalt (Co) at 0.8393-1.801 days generation time (period of exponential growth, t = 15 days). The bacteria degraded 96.24-98.97, and 92.94-96.24% of crude oil, and anthracene, respectively, within 30 days without any impedance due to metal toxicity (at 5.0 mM). Rather, there was reduction of Ni and Co concentrations in the axenic culture 30 days post-inoculation to 0.08-0.12 and 0.11-0.15 mM, respectively. The metabolic functions of the bacteria are active in the presence of toxic metals (Ni and Co) while utilizing petroleum hydrocarbons for increase in biomass. These findings are useful to other baseline studies on decommissioning of sites co-contaminated with hydrocarbons and toxic metals. PMID- 23457075 TI - Addressing disparities in HIV mortality: antiretroviral therapy is necessary but not sufficient. PMID- 23457076 TI - Cellulitis, by any other name. PMID- 23457077 TI - Influence of geographical origin and ethnicity on mortality in patients on antiretroviral therapy in Canada, Europe, and the United States. AB - BACKGROUND: Our objective was to assess differences in all-cause mortality, as well as AIDS and non-AIDS death rates, among patients started on antiretroviral therapy (ART) according to their geographical origin and ethnicity/race in Europe, Canada, and the United States. METHODS: This was a collaboration of 19 cohort studies of human immunodeficiency virus-positive subjects who have initiated ART (ART Cohort Collaboration) between 1998 and 2009. Adjusted mortality hazard ratios (AHRs) were estimated using Cox regression. A competing risk framework was used to estimate adjusted subdistribution hazard ratios for AIDS and non-AIDS mortality. RESULTS: Of 46 648 European patients, 16.3% were from sub-Saharan Africa (SSA), 5.1% Caribbean and Latin America, 1.6% North Africa and Middle East, and 1.7% Asia/West; of 1371 patients from Canada, 14.9% were First Nations and 22.4% migrants, and of 7742 patients from North America, 55.5% were African American and 6.6% Hispanic. Migrants from SSA (AHR, 0.79; 95% confidence interval [CI], .68-.92) and Asia/West (AHR, 0.62; 95% CI, .41-.92) had lower mortality than Europeans; these differences appeared mainly attributable to lower non-AIDS mortality. Compared with white Canadians, mortality in Canadian First Nations people (AHR, 1.48; 95% CI, .96-2.29) was higher, both for AIDS and non-AIDS mortality rates. Among US patients, when compared with whites, African Americans had higher AIDS and non-AIDS mortality, and hazard ratios for all-cause mortality increased with time on ART. CONCLUSIONS: The lower mortality observed in migrants suggests "healthy migrant" effects, whereas the higher mortality in First Nations people and African Americans in North America suggests social inequality gaps. PMID- 23457078 TI - Debridement, antibiotic therapy, and implant retention in Staphylococcus aureus prosthetic joint infections. PMID- 23457079 TI - Reply to Krause et al. PMID- 23457080 TI - Clinical trial: comparative effectiveness of cephalexin plus trimethoprim sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial. AB - BACKGROUND: Community-associated methicillin-resistant S. aureus (CA-MRSA) is the most common organism isolated from purulent skin infections. Antibiotics are usually not beneficial for skin abscess, and national guidelines do not recommend CA-MRSA coverage for cellulitis, except purulent cellulitis, which is uncommon. Despite this, antibiotics targeting CA-MRSA are prescribed commonly and increasingly for skin infections, perhaps due, in part, to lack of experimental evidence among cellulitis patients. We test the hypothesis that antibiotics targeting CA-MRSA are beneficial in the treatment of cellulitis. METHODS: We performed a randomized, multicenter, double-blind, placebo-controlled trial from 2007 to 2011. We enrolled patients with cellulitis, no abscesses, symptoms for <1 week, and no diabetes, immunosuppression, peripheral vascular disease, or hospitalization (clinicaltrials.gov NCT00676130). All participants received cephalexin. Additionally, each was randomized to trimethoprim-sulfamethoxazole or placebo. We provided 14 days of antibiotics and instructed participants to continue therapy for >=1 week, then stop 3 days after they felt the infection to be cured. Our main outcome measure was the risk difference for treatment success, determined in person at 2 weeks, with telephone and medical record confirmation at 1 month. RESULTS: We enrolled 153 participants, and 146 had outcome data for intent-to-treat analysis. Median age was 29, range 3-74. Of intervention participants, 62/73 (85%) were cured versus 60/73 controls (82%), a risk difference of 2.7% (95% confidence interval, -9.3% to 15%; P = .66). No covariates predicted treatment response, including nasal MRSA colonization and purulence at enrollment. CONCLUSIONS: Among patients diagnosed with cellulitis without abscess, the addition of trimethoprim-sulfamethoxazole to cephalexin did not improve outcomes overall or by subgroup. CLINICAL TRIALS REGISTRATION: NCT00676130. PMID- 23457081 TI - Enhanced mechanical properties of epoxy nanocomposites by mixing noncovalently functionalized boron nitride nanoflakes. AB - The influence of surface modifications on the mechanical properties of epoxy hexagonal boron nitride nanoflake (BNNF) nanocomposites is investigated. Homogeneous distributions of boron nitride nanoflakes in a polymer matrix, preserving intrinsic material properties of boron nitride nanoflakes, is the key to successful composite applications. Here, a method is suggested to obtain noncovalently functionalized BNNFs with 1-pyrenebutyric acid (PBA) molecules and to synthesize epoxy-BNNF nanocomposites with enhanced mechanical properties. The incorporation of noncovalently functionalized BNNFs into epoxy resin yields an elastic modulus of 3.34 GPa, and 71.9 MPa ultimate tensile strength at 0.3 wt%. The toughening enhancement is as high as 107% compared to the value of neat epoxy. The creep strain and the creep compliance of the noncovalently functionalized BNNF nanocomposite is significantly less than the neat epoxy and the nonfunctionalized BNNF nanocomposite. Noncovalent functionalization of BNNFs is effective to increase mechanical properties by strong affinity between the fillers and the matrix. PMID- 23457082 TI - Carbimazole embryopathy in a Chinese population: case series and literature review. AB - BACKGROUND: The data in the literature suggests that Methimazole (MMI)/Carbimazole (CMZ) embryopathy is rare. This study examined the incidence of CMZ embryopathy in the Hong Kong Chinese population and the factors associated with its development. METHODS: Of the 145 pregnant women with hyperthyroidism managed from 2008 to 2010, 29 (20%) had taken CMZ during pregnancy. The presence and details of birth defects, the dosage of CMZ, and the period of exposure during pregnancy were examined in these 29 pregnancies. All cases of CMZ embryopathy in the English literature were reviewed in the same way. RESULTS: Of the 27 babies (93.1%) with known outcome, 3 had aplasia cutis and 1 had an omphalocele in addition, and 1 affected baby had a sibling with aplasia cutis and patent vitellointestinal duct. The incidence of CMZ embryopathy in our study group is 11.1%. Amongst the 21 cases of CMZ embryopathy in the literature, 85% were exposed to a CMZ dosage of >=20 mg/day, and the minimum duration of exposure being 7 weeks from last menstrual period. The most common abnormality is ectodermal anomaly (62%), followed by oro-nasal anomaly (48%), facial dysmorphism (38%), gastrointestinal anomaly (33%) and abdominal wall defect (19%). There was no relationship between the type of abnormality and the dosage or duration of exposure to CMZ. CONCLUSIONS: The incidence of CMZ embryopathy in our study group is 11.1%. Critical factors for its development are exposure to a CMZ dosage of >=20 mg/day before 7 weeks of gestation. Genetic susceptibility may also play a role. PMID- 23457083 TI - Christopher Peterson: "other people matter". PMID- 23457085 TI - Burnout and vigor as predictors of the incidence of hyperlipidemia among healthy employees. AB - We examined the effects of burnout and vigor on the incidence of hyperlipidemia. Based on the bivariate theoretical approach to negative and positive affects and on past studies on the prediction of blood lipids by burnout and vigor, we expected increases from Time 1 (T1) to Time 2 (T2) in burnout levels to be associated with an increase in the risk for hyperlipidemia and T1-T2 increases in vigor levels to be associated with a decrease in the risk of hyperlipidemia. Our sample consisted of 3,337 healthy employees (2,214 men and 1,123 women) who were followed up for about 27 months on average. Burnout and vigor were assessed by well-validated multiple-item instruments. We used logistic regressions and controlled for variables associated with blood lipids as well as with vigor and burnout. We cross-validated all self-reported hyperlipidemia by their T2 lipids levels. As expected, we found that T1-T2 increases in vigor levels were associated with a decreased risk of hyperlipidemia. However, the T1-T2 change in burnout levels was marginally significant (p = .06) in predicting hyperlipidemia. We consider our finding that vigor and burnout are independently associated with the risk of hyperlipidemia as providing support for the bivariate approach to affective states. In addition, our major finding suggests a possible mechanism via which vigor influences physical health outcomes. PMID- 23457084 TI - Restoring psychology's role in peptic ulcer. AB - This paper reviews the history of the transition from the belief that gastrointestinal ulcers are caused primarily by psychological factors to the current state of belief that they are caused primarily by infection and argues that neither is fully accurate. We argue that psychological factors play a significant role as predisposing to vulnerability, modulating of precipitation, and sustaining of gastric ulceration. We review data that challenge the assumption of a simple infectious disease model and adduce recent preclinical data that confirm the predisposing, modulatory, and sustaining roles for psychological factors. We note that others, too, are now challenging the adequacy of the contemporary simple bacterial infection model. We hope to replace the competition between psychology and medicine with cooperation in understanding and treating patients suffering gastric ulceration and ulcer. PMID- 23457087 TI - Toward identifying a broader range of social cognitive determinants of dietary intentions and behaviors. AB - BACKGROUND: Measurement of social cognitive variables is often restricted to long term and health-related outcomes. A more comprehensive measurement of cognitive determinants would enable evidence-based design of health behavior interventions with a focus on the most relevant targets. The purpose of this study was to examine the relative impact of different social cognitive determinants on fruit and vegetable (FV) and fast food consumption. METHODS: Finnish male conscripts (N = 855, age M = 20) filled in questionnaires on social cognitive factors when entering the military service, and on food consumption frequency after two months. The data were analysed using structural equation modeling. RESULTS: Physical well-being expectation and bad taste expectation were most strongly related to both FV and fat avoidance intentions. Perceived weight gain risk predicted fat avoidance intention, whereas perceived risk for other health problems predicted FV intention. Social self-efficacy was associated with FV intention only. Consumption of both FV and fast food was predicted by action planning and intention. CONCLUSIONS: A more careful evaluation of subtypes of social cognitions sheds light on the specific content behind motivation. Such understanding might help in designing more effective intervention messages. PMID- 23457086 TI - Testing phase-specific self-efficacy beliefs in the context of dietary behaviour change. AB - BACKGROUND: Self-efficacy is an important predictor of health behaviour change. Within the health action process approach (HAPA; Schwarzer, 2008), motivational and volitional self-efficacy can be distinguished. Motivational self-efficacy is assumed to serve as predictor of intention formation whereas volitional self efficacy should be relevant for behaviour change. This study examined these assumptions in a sample with overweight and obese individuals. Moreover, we tested whether behavioural intentions moderate the association between volitional self-efficacy and behaviour. METHODS: Overall, 373 overweight and obese individuals completed a baseline and six months later a follow-up questionnaire on HAPA variables and dietary behaviour. RESULTS: A factor analysis confirmed the phase-specific separation of self-efficacy. Motivational self-efficacy emerged as predictor for behavioural intentions over and above other HAPA variables after six months, whereas volitional self-efficacy did not. Volitional self-efficacy interacted with intention in the prediction of behaviour, indicating that volitional self-efficacy is only beneficial for individuals with high levels of intentions. CONCLUSIONS: The results provide evidence for the phase-specific distinction of self-efficacy in the context of dietary change in an overweight or obese sample. Thus, differentiating between motivational and volitional self efficacy beliefs should be considered when developing future interventions of dietary change. PMID- 23457088 TI - Preparing for physical activity: pedometer acquisition as a self-regulatory strategy. AB - When people intend and plan to perform higher levels of physical activity, they do not start on impulse without preparing. Thus, preparation is a behavioral construct positioned between planning and target behavior. This may be reflected by the acquisition of sports equipment as well as monitoring devices such as pedometers. The research questions are who takes such preparatory action, whether picking up a complimentary pedometer can be predicted by self-efficacy and outcome expectancies, and whether this kind of preparatory action facilitates subsequent physical activity. A longitudinal physical activity survey was conducted with 143 university students who were offered a complimentary pedometer. Collecting this free gift served as indicator of preparatory behavior. Outcome expectancies and self-efficacy beliefs were specified as predictors of this behavior. Two weeks later, physical activity differences between the groups were determined. Collecting the pedometer was associated with higher levels of physical activity at follow-up. Outcome expectancies failed to predict the pedometer collection, but self-efficacy did. An interaction between these two factors indicated that self-efficacy compensated for low outcome expectancies. Pedometer acquisition signifies a preparatory action that is facilitated by self efficacy. Positioned between planning and target behavior, they constitute a proximal self-regulatory step towards health behavior change. PMID- 23457089 TI - Comparative molecular analysis of the prokaryotic diversity of two salt mine soils in southwest China. AB - While much is known about the microbial diversity in some hypersaline environments, little is known about those of salt mine tunnel soils. The objective of this study was to conduct a comprehensive phylogenetic comparison of the archaeal and bacterial communities present in Yipinglang salt mine (YPL) and Qiaohou salt mine (QH) tunnels differing in salinity and salt composition using 16S rRNA gene clone libraries. Two hundred twenty-eight sequences for QH and 182 sequences for YPL were analyzed by amplified ribosomal DNA-restriction analysis. Libraries revealed 44 bacterial and 57 archaeal different operational taxonomic units belonging to at least 8 bacterial and 3 archaeal divisions, but not all divisions were observed in both salt mines. The bacterial community affiliated with the Bacteroidetes was the most abundant (60% of clones) in QH, while the community in YPL was dominated by delta-Proteobacteria (45% of clones). All archaeal clones from QH were affiliated with Halobacteriaceae. In contrast, in the YPL library, 49% of clones belonged to Halobacteriaceae, 31% of clones related to unclassified archaea, and 21% of clones belonged to Crenarchaeota. Bioinformatic analysis and comparisons showed that the clone libraries were significantly different between two salt mines. PMID- 23457090 TI - Robust synthesis of gold cubic nanoframes through a combination of galvanic replacement, gold deposition, and silver dealloying. AB - A facile, robust approach to the synthesis of Au cubic nanoframes is described. The synthesis involves three major steps: 1) preparation of Au-Ag alloyed nanocages using a galvanic replacement reaction between Ag nanocubes and HAuCl4 ; 2) deposition of thin layers of pure Au onto the surfaces of the nanocages by reducing HAuCl4 with ascorbic acid, and; 3) formation of Au cubic nanoframes through a dealloying process with HAuCl4 . The key to the formation of Au cubic nanoframes is to coat the surfaces of the Au-Ag nanocages with sufficiently thick layers of Au before they are dealloyed. The Au layer could prevent the skeleton of a nanocage from being fragmented during the dealloying step. The as-prepared Au cubic nanoframes exhibit tunable localized surface plasmon resonance peaks in the near-infrared region, but with much lower Ag content as compared with the initial Au-Ag nanocages. PMID- 23457095 TI - Roy Schafer: a beginning. AB - The author provides a biographical overview of Schafer's life, culled from his published work and focused primarily on his professional development. This biography is used to demonstrate some of Schafer's central theoretical insights on narrativity and language, and reveals the consistency of his thinking over his long career. A brief discussion of his writing on King Lear provides a bridge between theoretical and biographical material. PMID- 23457096 TI - Roy Schafer's contributions to psychological testing: from clinical sensibility to the analytic attitude. AB - The author reviews Schafer's contributions to psychological testing, emphasizing his development of the test battery, his significant contributions to psychoanalytically oriented Rorschach interpretation, and his understanding of the complex interpersonal dynamics involved in psychological test interpretation. The author also discusses his use of Schafer's writing in his own teaching and academic work, noting that Schafer's contributions have not only provided innovative methods for examining test data, but have also promoted a respectful, humanistic, and individualized approach to the patient in testing and treatment. The author asserts that Schafer's later seminal contributions to psychoanalysis had their origins in his early career as a psychologist applying psychoanalytic ideas to testing. PMID- 23457097 TI - Appreciating difference: Roy Schafer on psychoanalysis and women. AB - The author describes and appreciates Roy Schafer's critique of Freud's view of female psychology and his other contributions to the psychoanalytic literature on women, noting his then-novel emphasis that took into account social and cultural factors in analytic treatment. She relates the influence on Schafer's work of his ambiance in that era: the Yale University Student Health Services during the social turmoil of the 1970s (where she was his supervisee), with the university becoming coed, as well as the theoretical plurality even in the early days of the Western New England Psychoanalytic Institute. PMID- 23457098 TI - The second sphere and the story of no story. AB - The author discusses Roy Schafer's ideas of the second self and second reality, as well as his consistent theme of storyteller and story. The latter theme is also explored in the context of more recent psychoanalytic influences, such as Bionian thought, trauma theory, the French approach, and the interpersonal perspective. To illustrate the idea of the nonstory in today's clinical encounters, the author presents two clinical vignettes. PMID- 23457099 TI - The value of uncertainty. AB - The author discusses some of the characteristics of Roy Schafer's contributions to psychoanalysis that he finds most valuable, such as his openness to uncertainty, his anti-reductive view of analytic constructions, his unique formulation of the analyst's role, and his close attention to how the patient engenders particular emotional reactions in the analyst. The author also presents a clinical vignette illustrating the value of the analyst's tolerance of uncertainty in the face of the patient's push for interpretations, explanations, and reassurance. PMID- 23457100 TI - Action, agency, and empathy: Schafer on the analyst's dilemma. AB - Throughout his career, a central feature of Roy Schafer's theorizing has been to highlight the role of activity and personal agency in every facet of human experience. This theme has remained at the forefront of Schafer's work, despite being embedded within different frames of reference. In this paper, the author highlights Schafer's focus on activity, notes some clinical problems to which it can give rise, and suggests the way that Schafer has attempted to deal with these difficulties. PMID- 23457101 TI - Roy Schafer: a narrative. AB - The author provides a brief overview of the papers given at the Schafer Symposium in October 2012 by the following six presenters: Henry Schwartz, Richard Fritsch, Rosemary Balsam, Lucy LaFarge, Michael Feldman, and Jay Greenberg. He also highlights some important ongoing themes in Schafer's writing, including theory about which Schafer takes a unique position-history, and ideas from other disciplines. Schafer prefers continuing explorations over arriving at conclusions, the author notes, and believes that students should remain faithful to their mentors' thinking-until it is time for them to move beyond it. PMID- 23457102 TI - Final word. PMID- 23457103 TI - Editor's introduction. PMID- 23457104 TI - The analyst's hatred of analysis. AB - Analytic work is loved and hated. Both attitudes deserve scrutiny, but the analyst's hatred of analysis, which transcends countertransference responses to individual patients, represents an impediment to gratifying analytic work whose recognition and conceptualization has been resisted. The author suggests that antipathy among analysts toward analysis and the analytic situation is normative and expectable, yet commonly experienced as shameful. He speculates that it is sometimes disavowed and projected. Training institutes might inadvertently foster this sense of shame rather than promote its working through. The recognition that analytic identity functions as both a loving and a persecutory internal object has implications for psychoanalytic education and practice. PMID- 23457105 TI - Discussion of "the analyst's hatred of analysis". PMID- 23457106 TI - An addendum to Kravis: an appreciative note on hating one's work. PMID- 23457107 TI - Negation of awe: shame in the burgeoning psychoanalyst. PMID- 23457108 TI - "Pull down thy vanity": a discussion of "the analyst's hatred of analysis". PMID- 23457110 TI - Chemistry and containing: the analyst's use of unavoidable failures. AB - Certain patients overwhelm the analyst's capacity to contain both the patient and the analyst's own unbearable feelings. Though some such failures of containing may lead fairly quickly to self-correction and others to clinical impasse, our focus is on an in-between state in which the analyst's ability to tolerate his inevitable failures and gradually to (re)establish his containing capacities through difficult self-analytic work can lead to significant change that might not otherwise be possible. The authors argue that this internal psychological work on the analyst's part, which may require considerable time, effort, and suffering, is an important aspect of "good enough" containing. The unique chemistry generated between patient and analyst plays an important role in both establishing and maintaining this kind of productive analytic process. PMID- 23457112 TI - Genomic comparisons between paired bacterial strains with strong and weak GC skews. AB - A majority of known eubacterial genomes are characteristic of GC skew, i.e., the leading strand has exceeding number of G over C. The cause of this compositional bias is still not very clear. In this study, we chose five pairs of genomes from distantly related bacterial genera, i.e., Buchnera, Haemophilus, Mycoplasma, Mycobacterium, and Synechococcus, each containing one with strong GC skew and the other with weak GC skew. Through comparison of the orthologous genes in these genera, we found that neither chromosomal rearrangement nor CDS skew has direct relationship with GC skew. PMID- 23457113 TI - Atrial premature beats during decrementally conducting antidromic tachycardia. AB - BACKGROUND: Advancement of ventricular activation by an atrial premature beat (APB) given during His bundle refractoriness followed by resetting of an antidromic tachycardia (AT) in patients with decrementally conducting accessory pathway (DAP) is a helpful maneuver to prove pathway existence and participation in the circuit. We aim to assess in a large cohort the role of APB during AT in patients with a DAP. METHODS AND RESULTS: Thirty-three patients with a DAP having 34 AT were included in the study: 29 patients had an atriofascicular pathway, 1 had a long atrioventricular DAP, and 4 had a short atrioventricular fiber. APBs were delivered initially from the lateral right atrium, scanning diastole with a 10-ms decrement until AT termination or refractoriness. We observed 4 patterns of response after APB during AT: advancement of activation (29 cases), delay (2), advancement followed by delay (3), and termination (7). Eight patients required an earlier APB to advance or delay ventricular activation. These 8 patients had a shorter AT cycle length (median of 273 versus 315 ms; P=0.003) and had a shorter resetting zone (median coupling interval of 30 versus 50 ms; P=0.01). CONCLUSIONS: APB delivered during AT in patients with a DAP advanced and/or delayed ventricular activation in all patients. In 1 of 5 of cases the AT was terminated by a single APB. In approximately a quarter of the patients an earlier coupled APB was needed to reset AT. The high RA was an adequate stimulation site in all right-sided DAP. PMID- 23457114 TI - Synthesis of isoidide through epimerization of isosorbide using ruthenium on carbon. AB - A highly efficient procedure for obtaining resin-grade isoidide through catalytic epimerization of isosorbide using a ruthenium-on-carbon (Ru/C) catalyst is reported. A comprehensive reaction-parameter variation study involving substrate concentration, catalyst (type of metal, support, and loading), initial pH value, hydrogen pressure, solvent, and reaction temperature demonstrates that superior performance and high selectivity can be achieved. Epimerization of isosorbide in water (pH 8) at 220 degrees C, under 40 bar of hydrogen, and using a Ru/C catalyst (5 % Ru) for 2 h results in a thermodynamic equilibrium mixture containing 55 % isoidide, 40 % isosorbide, and 5 % isomannide. In comparison with previously reported nickel-based catalysts, the Ru/C catalyst is advantageous because it is highly active (as low as 360 ppm Ru) and recyclable. High purity isoidide is obtained by high-vacuum distillation of an equilibrium mixture on a 200 g scale. The high substrate loading (50 wt % in water), high selectivity, and the possibility for substrate reuse makes this procedure highly atom efficient and therefore, highly attractive for industrial use. PMID- 23457115 TI - Low-density extraction solvent based solvent-terminated dispersive liquid-liquid microextraction for quantitative determination of ionizable pesticides in environmental waters. AB - A rapid, efficient, and new solvent terminated dispersive liquid-liquid microextraction technique coupled with HPLC was developed for selective extraction and analysis of s-triazine herbicides from environmental water samples. Important parameters influencing the extraction process including type and volume of extraction and disperser solvent, extraction time, sample pH, ionic strength, and extraction temperature were successfully optimized. Under the optimal conditions, there are excellent linear relationships between the analytical results and concentration in the range of 10-400 mg/L for atrazine, propazine, prometryn, and terbutryn. LOD and LOQ ranged from 0.60 to 2.33 MUg/L and 2.0 to 7.7 MUg/L, respectively. Performance of the analytical technique was evaluated by carrying out the repeatability and reproducibility analyses that were ranged from 2.86 to 5.66% and 4.64 to 5.89% for 100 MUg/L of each target analyte, respectively. The proposed method has been successfully applied to the analysis of real water samples and acceptable relative recoveries over the range of 65.93-101.46%, with RSDs <= 8.80%, were obtained. The overall results have been compared with the literature values. Thus, the method developed could efficiently be used for selective extraction of the target analytes from complex matrices, particularly environmental waters. PMID- 23457117 TI - Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. PMID- 23457116 TI - Electricity storage in biofuels: selective electrocatalytic reduction of levulinic acid to valeric acid or gamma-valerolactone. AB - Herein, we report an effective approach to electricity storage in biofuels by selective electrocatalytic reduction of levulinic acid (LA) to high-energy density valeric acid (VA) or gamma-valerolactone (gVL) on a non-precious Pb electrode in a single-polymer electrolyte membrane electrocatalytic (flow) cell reactor with a very high yield of VA (>90 %), a high Faradaic efficiency (>86 %), promising electricity storage efficiency (70.8 %), and a low electricity consumption (1.5 kWhL(VA)(-1) ). The applied potential and electrolyte pH can be used to accurately control the reduction products: lower overpotentials favor the production of gVL, whereas higher overpotentials facilitate the formation of VA. A selectivity of 95 % to VA in acidic electrolyte (pH 0) and 100 % selectivity to gVL in neutral electrolyte (pH 7.5) are obtained. The effect of the molecular structure on the electrocatalytic reduction of ketone and aldehyde groups of biomass compounds was investigated. Whereas LA can be fully electroreduced to VA though a four-electron transfer, the C-O groups are only electroreduced to -OH by a two-electron-transfer process when glyoxylic acid and pyruvic acid serve as feedstocks. PMID- 23457118 TI - High-resolution separation of homogeneous chitooligomers series from 2-mers to 7 mers by ion-exchange chromatography. AB - Highly purified chitooligomers with single degree of polymerization are of significance for studying bioactivity of chitooligomers. However, there are few reports on high-resolution preparative separation of chitooligomers, especially for those oligomers with degree of polymerization higher than 4. This study developed a high-resolution chromatography for the preparative separation of a pure fully deacetylated chitooligomer series. A glucosamine oligomer mixture with low degree of polymerization was prepared by acid hydrolysis of a highly deacetylated chitosan. Then, six fractions were separated from the prepared oligomer mixture by ion-exchange chromatography and analyzed by HPLC and ESI/MS, which primarily contained glucosamine dimers, trimers, tetramers, pentamers, hexamers, and heptamers, respectively, with chromatographic purities over 98% for dimers to hexamers and a purity of 93% for heptamers. The yields of a single round of separation were 75, 60, 60, 55, 35, and 20 mg for glucosamine dimers, trimers, tetramers, pentamers, hexamers, and heptamers, respectively. Furthermore, a chromatographic separation model for GlcN homomers was established. The capacity factor (k) of glucosamine oligomers and their degrees of polymerization (DPs) exhibited a good correlation, lnk = 0.786 + 0.846 lnDP, (R(2) = 0.997). Based on this equation, glucosamine octamers are expected to be separated by this system. PMID- 23457119 TI - [18F]FDG-PET as an imaging biomarker to NMDA receptor antagonist-induced neurotoxicity. AB - Positron emission tomography (PET) is an effective tool for noninvasive examination of the body and provides a range of functional information. PET imaging with [(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) has been used to image alterations in glucose metabolism in brain or cancer tissue in the field of clinical diagnosis but not in the field of toxicology. A single dose of N-methyl d-aspartate (NMDA) receptor antagonist induces neuronal cell degeneration/death in the rat retrosplenial/posterior cingulate (RS/PC) cortex region. These antagonists also increase local cerebral glucose utilization. Here, we examined the potential of [(18)F]FDG-PET as an imaging biomarker of neurotoxicity induced by an NMDA receptor antagonist, MK-801. Using [(18)F]FDG-PET, we determined that increased glucose utilization involved the neurotoxicity induced by MK-801. The accumulation of [(18)F]FDG was increased in the rat RS/PC cortex region showing neuronal cell degeneration/death and detected before the onset of neuronal cell death. This effect increased at a dose level at which neuronal cell degeneration recovered 24h after MK-801 administration. Scopolamine prevented the neurotoxicity and [(18)F]FDG accumulation induced by MK-801. Furthermore, in cynomolgus monkeys that showed no neuronal cell degeneration/death when treated with MK-801, we noted no differences in [(18)F]FDG accumulation between test and control subjects in any region of the brain. These findings suggest that [(18)F]FDG-PET, which is available for clinical trials, may be useful in generating a predictive imaging biomarker for detecting neurotoxicity against NMDA receptor antagonists with the same pharmacological activity as MK-801. PMID- 23457120 TI - Peptide YY3-36 and 5-hydroxytryptamine mediate emesis induction by trichothecene deoxynivalenol (vomitoxin). AB - Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3-36 (PYY3-36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15 30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3-36 (30-60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON's emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3-36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3-36 and 5-HT play contributory roles in DON-induced emesis. PMID- 23457121 TI - Biological and tumor-promoting effects of dioxin-like and non-dioxin-like polychlorinated biphenyls in mouse liver after single or combined treatment. AB - To assess the impact of a mixture containing dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs), male mice were initiated with N-nitroso diethylamine and subsequently treated with PCB126, an Ah-Receptor agonist, and PCB153, acting via activation of the constitutive androstane receptor. The two congeners were given at two dose levels: the low dose was adjusted to induce ~150 fold increases in cytochrome P450 (Cyp)1a1 (PCB126) and Cyp2b10 mRNAs (PCB153), and the high dose was chosen as twice the low dose. To keep the liver PCB levels constant, mice were given initial loading doses followed by weekly maintenance doses calculated on the basis of the PCBs' half-lives. Mice were treated with the individual congeners (low and high dose) or with a mixture consisting of the low doses of the 2 PCBs. The following results were obtained: (1) the 2 PCBs produced dose-dependent increases in Cyp1a1 and Cyp2b10 mRNA, protein, and activity when given individually; (2) combined treatment caused more than additive effects on Cyp1a1 mRNA expression, protein level, and ethoxyresurofin activity; (3) changes in the levels of several proteins were detected by proteome analysis in livers of PCB-treated mice; (4) besides these biological responses, the individual PCBs caused no significant increase in the number of glucose-6-phospatase (G6Pase) deficient neoplastic lesions in liver, whereas a moderate significant effect occurred in the combination group. These results suggest weak but significant response-additive effects of the 2 PCBs when given in combination. They also suggest that the Cyp biomarkers tend to overestimate the carcinogenic response produced by the PCBs in mouse liver. PMID- 23457123 TI - Delay and impairment in brain development and function in rat offspring after maternal exposure to methylmercury. AB - Maternal exposure to the neurotoxin methylmercury (MeHg) has been shown to have adverse effects on neural development of the offspring in man. Little is known about the underlying mechanisms by which MeHg affects the developing brain. To explore the neurodevelopmental defects and the underlying mechanism associated with MeHg exposure, the cerebellum and cerebrum of Wistar rat pups were analyzed by [(18)F]FDG PET functional imaging, field potential analysis, and microarray gene expression profiling. Female rat pups were exposed to MeHg via maternal diet during intrauterinal and lactational period (from gestational day 6 to postnatal day (PND)10), and their brain tissues were sampled for the analysis at weaning (PND18-21) and adulthood (PND61-70). The [(18)F]FDG PET imaging and field potential analysis suggested a delay in brain activity and impaired neural function by MeHg. Genome-wide transcriptome analysis substantiated these findings by showing (1) a delay in the onset of gene expression related to neural development, and (2) alterations in pathways related to both structural and functional aspects of nervous system development. The latter included changes in gene expression of developmental regulators, developmental phase-associated genes, small GTPase signaling molecules, and representatives of all processes required for synaptic transmission. These findings were observed at dose levels at which only marginal changes in conventional developmental toxicity endpoints were detected. Therefore, the approaches applied in this study are promising in terms of yielding increased sensitivity compared with classical developmental toxicity tests. PMID- 23457124 TI - Persistent neurological damage associated with spontaneous recurrent seizures and atypical aggressive behavior of domoic acid epileptic disease. AB - The harmful alga Pseudo-nitzschia sp. is the cause of human amnesic shellfish poisoning and the stranding of thousands of sea lions with seizures as a hallmark symptom. A human case study and epidemiological report of hundreds of stranded sea lions found individuals presenting months after recovery with a neurological disease similar to temporal lobe epilepsy. A rat model developed to establish and better predict how epileptic disease results from domoic acid poisoning demonstrated that a single episode of status epilepticus (SE), after a latent period, leads to a progressive state of spontaneous recurrent seizure (SRS) and expression of atypical aggressive behaviors. Structural damage associated with domoic acid-induced SE is prominent in olfactory pathways. Here, we examine structural damage in seven rats that progressed to epileptic disease. Diseased animals show progressive neuronal loss in the piriform cortex and degeneration of terminal fields in these layers and the posteromedial cortical amygdaloid nucleus. Animals that display aggressive behavior had additional neuronal damage to the anterior olfactory cortex. This study provides insight into the structural basis for the progression of domoic acid epileptic disease and relates to the California sea lion, where poisoned animals progress to a disease characterized by SRS and aggressive behaviors. PMID- 23457122 TI - Prenatal bisphenol A exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala. AB - Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERalpha) and ESR2 (ERbeta) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6-21 with vehicle, 2.5 or 25 MUg/kg bw/day BPA, or 5 or 10 MUg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naive control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naive control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure. PMID- 23457126 TI - Cerebral regulation of insulin secretion and the development of insulin resistance in type 2 diabetes. AB - Type 2 diabetes (T2DM) is a metabolic disorder that still constitutes a significant clinical problem due to its numerous micro- and macroangiopathic complications. Although many pathogenic factors for T2DM have been established to date, along with many methods of control and compensation, diabetes is still a subject of intense research aimed at finding new therapeutic regimens. Established protocols of management are based on the modification of risk factors and the administration of hypoglycemic agents, which act at the level of the pancreas or in target tissues for insulin. However, in recent years research has more and more frequently been centered upon the superior role of the central nervous system in the maintenance of the widely understood energy balance of the body, including carbohydrate metabolism. In this review the authors present current evidence confirming an association between the central nervous system (CNS) and insulin release, and discuss the potential risk of developing insulin resistance, obesity and diabetes in states of impaired CNS function. The key point of this review is to provide an analysis of a system of selected neuropeptides of central origin that act both at the level of the brain and in the periphery, playing an important role in the control of energy balance. The conclusions derived from the experimental studies and clinical trials discussed in this review undoubtedly suggest that impairment of the hereby presented system of central regulators can result in metabolic disorders. PMID- 23457125 TI - Lipophilicity of oils and fats estimated by TLC. AB - A representative series of natural toxins belonging to alkaloids and mycotoxins classes was investigated by TLC on classical chemically bonded plates and also on oils- and fats-impregnated plates. Their lipophilicity indices are employed in the characterization and comparison of oils and fats. The retention results allowed an accurate indirect estimation of oils and fats lipophilicity. The investigated fats and oils near classical chemically bonded phases are classified and compared by means of multivariate exploratory techniques, such as cluster analysis, principal component analysis, or fuzzy-principal component analysis. Additionally, a concrete hierarchy of oils and fats derived from the observed lipophilic character is suggested. Human fat seems to be very similar to animal fats, but also possess RP-18, RP-18W, and RP-8. PMID- 23457127 TI - Effect of garlic extract on blood glucose level and lipid profile in normal and alloxan diabetic rabbits. AB - OBJECTIVES: Comparative hypoglycemic and hypolipidaemic activity of garlic (ethanol) extract and metformin was the aim of the study in 24 normal and diabetic rabbits. MATERIAL AND METHODS: In group A of 12 rabbits, the influence of different doses (250, 300 and 350 mg/kg body weight) of garlic extract was evaluated, six of them were kept normal, while six were caused to be diabetic with alloxan (150 mg/kg body weight). In another group B of 12 rabbits, the influence of various doses of metformin (250, 375 and 500 mg/kg body weight) was also assessed in the similar grouping of six normal and six diabetic rabbits. RESULTS: The maximum hypoglycemic response was observed with highest doses of garlic extract (350 mg/kg body weight) in normal rabbits 4 h after garlic extract administration, while in diabetic rabbits, blood glucose level (270.3 +/- 0.8 mg/dl) was significantly (p < 0.05) lowered as compared to the control level (303.8 +/- 1.8 mg/dl). The levels of triglycerides (44.0 +/- 0.9 mg/dl) and cholesterol (32.8 +/- 0.7 mg/dl) also significantly (p < 0.05) decreased in normal rabbits after 4 h of extract administration as compared to that of 0 h samples (triglycerides 66.0 +/- 1.5 mg/dl and cholesterol 47.5 +/- 0.5 mg/dl). In diabetic rabbits, 0 h level of triglyceride and cholesterol was found to be 86.5 +/- 1.1 mg/dl and 93.8 +/- 0.9 mg/dl, respectively and levels seen in 4 h sample were 61.3 +/- 1.2 mg/dl and 57.0 +/- 1.8 mg/dl, respectively. CONCLUSIONS: In normal as well as diabetic rabbits, garlic extract produced hypoglycemia as well as hypolipidaemia like metformin, but the hypoglycemic effect was more pronounced with metformin, whereas garlic extract was more effective in causing hypolipidaemia as compared to metformin. PMID- 23457128 TI - Sodium nitrite and cardioprotective effect in pig regional myocardial ischemia reperfusion injury model. AB - OBJECTIVES: The present study was designed to investigate the cardioprotective effect of sodium nitrite (NaNO2) and sodium nitrate (NaNO3) against myocardial ischemia-reperfusion (I/R) injury in a pig regional ischemia model. MATERIAL AND METHODS: Eighteen pigs were randomly divided into three groups as control (Group 1), sodium nitrite (Group 2) and sodium nitrate (Group 3) groups. Before the exploration of the heart, blood samplings were taken for alanine aminotranspherase (ALT), aspartate aminotranspherase (AST), lactate dehydrogenase (LDH), creatinine kinase-muscle band (CK-MB), troponin-t, glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nitrite/nitrate (NO2-/NO3-) in all groups (T0). Following sternotomy and stabilization, blood and tissue samples were repeated (T1). Then, intracoronary sodium nitrite and sodium nitrate were given (0.5ug/kg) in Groups 2 and 3. Five minutes later, the left anterior descending (LAD) artery was ligated for I/R experiments. Blood and tissue samplings were repeated after 60 minutes of ischemia (T2) and 180 minutes of reperfusion period (T3). Light and electron microscopic investigations were performed. RESULTS: There were statistically significant results in favor of Group 2 in all studied parameters. Hemodynamic parameters showed a decrease in mean arterial pressure (MAP), cardiac output (CO), cardiac index (CI) and an increase in heart rate, mean pulmonary artery pressure (MPAP), left ventricle end-diastolic pressure (LVEDP), pulmonary capillary wedge pressure (PCWP) during ischemia. Following the ischemia these parameters returned to their near normal levels. This was prominent in group 2. Oxidative parameters showed protective increases in GPx, SOD, CAT and NO2-/NO3- levels and a decrease at MDA both in tissue and blood samples in group 2. There were statistical differences only in T3 for AST, troponin-t and CK-MB levels in favor of Group 2. Histological and electron microscopy examinations were also in favor of NO2- group. CONCLUSIONS: The results of the present study indicate that NaNO2 provides protection against myocardial I/R injury when compared to control and NaNO3 groups. PMID- 23457129 TI - Estimating the postmortem interval by the difference between oxidant/antioxidant parameters in liver tissue. AB - BACKGROUND: So far the authors could not find any published paper that shows the presence of a possibly significant relationship between oxidant/antioxidant parameters and time of death. OBJECTIVES: This study sought to investigate whether the differences between the levels of endogenous parameters like Superoxide dismutase (SOD), Malondialdehyde (MDA), Glutathione peroxidase (GPx), Glutathione S-transferases (GST), Total glutathione (tGSH), Catalase (CAT) and Nitric oxide (NO) have a relationship with the early postmortem interval (EPI). MATERIAL AND METHODS: A total of 60 Albino Wistar male rats weighing between 220 230 grams were obtained. The rats were divided into six subgroups (n = 10), fed at room temperature (220C) and then decapitated. The livers of the dead rats were extracted at intervals of one hour and biochemical examinations were performed and biochemical results obtained from the animal groups had been evaluated. RESULTS: The authors performed linear regression analysis in order to search for factors predicting the time of death. The time of death was taken as a dependent variable with SOD, MDA, GPx, GST, GSH, CAT, and NO as independent variables. This model resulted with a high predictive value (adjusted R square = 94.0%). SOD, GST and NO were found to be significant factors independently affecting the prediction of the death time. CONCLUSIONS: In conclusion, the results obtained from the experiment showed that the oxidant and antioxidant parameters are important for estimating the EPI. PMID- 23457130 TI - Comparison of two doses of tranexamic acid on bleeding and surgery site quality during sinus endoscopy surgery. AB - BACKGROUND: One of the main concerns in sinus surgery is blood loss due to the high vasculature of the mucosa. Tranexamic acid (TA) is an antifibrinolytic agent which reduces bleeding following certain surgical procedures. MATERIAL AND METHODS: This randomized double-blinded clinical trial was performed on 70 patients with class I and II ASA (American Society of Anesthesiologists) who were scheduled for endoscopic sinus surgery under general anesthesia. The average ages of the patients were 18 to 50 years old. Thirty-five patients (group A) received 5 mg/Kg of TA, and another 35 patients (group B) received 15 mg/Kg of TA. The mean arterial pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) were documented. Also, the amount of blood loss and satisfaction scores were obtained from the surgeon in 30th, 60th, 90th, 120th and 180th minutes. All the data was analyzed by SPSS-15 software with T test. RESULTS: A total of 52 males and 18 females participated in the study. There were no significant differences between the mean age, MAP, DBP, SBP and HR during surgery between groups. Blood loss was 272.74 +/- 25.77 mL 242.89 +/- 51.77 mL in the group A and B respectively (P < 0.003). The surgeon was more satisfied with the surgical field of the group B than the group A (mean scores 4 (3-5) vs. 3 (1-5) respectively, P < 0.005). Surgery period and need for supplement drug to control bleeding in group B was significantly less than in group A (P < 0.05). But there was no significant difference between the two groups in terms of side effects. CONCLUSIONS: Administration of 15 mg/Kg TA intravenously is more effective than 5 mg TA to achieve hemostasis and improving the quality of surgical field, surgeon satisfaction, less surgery period and bleeding volume during endoscopic sinus surgery without any significant side effects. PMID- 23457131 TI - Anatomical variability of median nerve formation in human foetuses in clinical aspect. AB - BACKGROUND: The median nerve is an important nerve leaving the brachial plexus. Median nerve damages may result from tunnel syndromes or injuries. The nerve anatomical variants are of great clinical importance in hand surgery. OBJECTIVES: Clinical evaluation of median nerve divergence from brachial plexus morphological variability in foetal period. MATERIAL AND METHODS: The material consisted of 220 brachial plexus sections derived from 110 foetuses aged 14-32 weeks of foetal life (50 females and 60 males, in CRL: 80-233 mm). The survey incorporated the following methods: dissection, anthropological, image digital acquisition, Image J computer transformation system, GIMP programme and statistical methods. Typology assessment was based on 0/1 system. Sexual dimorphism and symmetry were examined. RESULTS: Median nerve left directly lateral cord in 5 cases. In 59 (26.81%) plexuses, anterior division of middle trunk co-created median nerves anomalies. The total of 9 types of anterior division of middle trunk as well as of median nerve were distinguished. Median nerve double root leaving lateral cord was observed in 10 (9.09%) cases, whereas triple lateral root was seen in one case. In 1/3 of the examined plexuses, median nerve roots combined to form the nerve beneath humeral bone head and even in 1/2 of the bone distal length (type II and III). Type II prevailed more often on the left side. CONCLUSIONS: Median nerve roots as well as the median nerve itself are characteristic for significant morphological variability. Nerve roots low junction into median nerve is clinically favourable as it can prevent nerve damage during injuries. PMID- 23457132 TI - The influence of natural head position on the assessment of facial morphology. AB - BACKGROUND: Skeletal relationships play a major part in determining occlusal relationships, and that is why they also affect orthodontic treatment. Facial morphology can be assessed by clinical or radiological methods. Soft tissue analysis of the face is accepted as an integral part of orthodontic diagnosis and treatment planning. OBJECTIVES: The aim of the study was to determine the impact of the inclination between the Frankfort horizontal(FH) and the extracranial horizontal (HOR) lines with the head in the natural position (NHP) on the assessment of facial morphology. MATERIAL AND METHODS: Lateral facial photographs of 200 young adult males and females were taken with the head in the natural head position and then analyzed. Each image was rotated in order to position the Frankfort line parallel to the extracranial horizontal line. Twelve landmarks on each of the 400 profile photographs (200 originals,200 processed) were identified, and nine linear measurements and three angular measurements were assessed. RESULTS: The inclination angle between the extracranial horizontal line and the Frankfort horizontal line in the NHP varied from -7.1 degrees to 5.6 degrees (mean -1.20 degrees ). Significant correlations were found between the inclination angle FH/HOR and both sagittal and vertical morphology predictors such as the sections N-Sn (r = 0.3737, p = 0.0001), Sn-Gn(r = 0.3231, p = 0.0000), and both facial angles (r = 0.9774, p = 0.0000) and proflle angles (r = 0.9654, p = 0.0000). CONCLUSIONS: A comparison of soft tissue measurements determined with reference to the Frankfort horizontal and extracranial horizontal lines with the head in the natural position reveals significant differences PMID- 23457133 TI - A high-carbohydrate diet effects on the A allele of hepatic lipase polymorphism on the apoB100/apoAI ratio in young Chinese males. AB - BACKGROUND: Diet induces changes in plasma lipid profiles, and the plasma lipid profiles vary among different genetic backgrounds. OBJECTIVES: The aim of this study was to investigate how a high-carbohydrate (high-CHO) diet interacts with hepatic lipase G-250A promoter polymorphism to affect the ratios of plasma lipids and apolipoproteins (apo) in a young Chinese population. MATERIAL AND METHODS: Experiments were conducted on 56 university students. A stabilization diet was given for 7 days and a high-CHO diet was followed for 6 days. The diets used in this study were described by Song et al. and the following parameters were evaluated: total plasma triglyceride (TG), total plasma cholesterol (TC), plasma high-density lipoprotein cholesterol (HDL-C), plasma low-density lipoprotein cholesterol (LDL-C), apoB100 and apoAI. The plasma lipids and apoB100/apoAI ratios were also calculated and hepatic lipase G-250A polymorphism was analyzed. RESULTS: At baseline, no significant difference was detected for subjects with different genotypes and genders. All the parameters showed significant differences before and after the high-CHO diet, and these differences are gender specific: after the high-CHO diet, the TG/HDL-C ratios significantly increased in females (GG genotype: P = 0.004; A carriers: P = 0.005). The TC/HDL-C ratios significantly decreased in GG genotype males (P = 0.007), A carrier males (P < 0.0001) and A carrier females (P = 0.016) and the LDL-C/HDL-C ratios significantly decreased in the GG genotype males (P = 0.011), A carrier males (P < 0.0001) and A carrier females (P = 0.001). However, comparing the apoB100/apoAI ratio before and after the high-CHO diet, a significant difference only existed in male A carriers (P = 0.009). CONCLUSIONS: The results of this study show that the high-CHO diet induces the positive effects on the lipid ratios in general, only except the TG/HDL-C ratio in females. Noticeably, the decreased apoB100/apoAI ratio is associated with the A allele of hepatic lipase G-250A polymorphism only in young Chinese males. PMID- 23457134 TI - The application of human papilloma virus genotyping for the identification of neoplasm lesions in the cervix of women with abnormal cytology smears. AB - BACKGROUND: A connection between infections with a highly oncogenic type of human papilloma virus and the development of cervical intraepithelial neoplasia and preinvasive cervical cancer has been proven both experimentally and clinically. The period after which persistent virus infection will lead to the development of precancerous and invasive lesions is dependent on, among others, the HPV genotype. The oncogenic types of human papilloma virus destabilize the genome of an infected cell and thus initiate the carcinogenesis process. OBJECTIVES: The aim of this work was to analyze the frequency of occurrence of different oncogenic HPV genotypes among women with abnormal cytological smears and the correlation of this data with the degree of cervical intraepithelial neoplasia exacerbation. MATERIAL AND METHODS: The sample consisted of 75 women of child bearing age (16-43 years old) with an abnormal cytological smear and positive test identifying an infection with an oncogenic type of human papilloma virus. In every case histopathological verification, aimed at excluding pathologies in the endocervix, was conducted using a colposcopy with guided biopsy and cervix abrasion. RESULTS: The authors found that the frequency of occurrence of different HPV genotypes of the groups of cytological diagnoses ASC-US, LSIL and HSIL do not differ statistically (p = 0.57). However, what is noteworthy is the more common occurrence of HPV 16 in type LSIL lesions (45.45%) and HPV 18 of a more advanced type HSIL (37.50%) pathology. Through the verification of the cytology results with histopathological diagnosis of the above groups the authors obtained statistically significant differences (p < 0.001) of individual pathological states. When regarding cytological HSIL diagnosis, CIN 1 was never diagnosed, while in other cytological groups cervical intraepithelial neoplasia of a low degree constituted over 40%. Analogically about 40% of HSIL diagnoses after histopathological verification turned out to be cancer of a pre-invasive state (CIS/AIS), the presence of which was not revealed by ASC-US and LSIL. What is more, CIN2/3 diagnosis was less frequent in the ASC-US cytological group than in the other two groups. While analyzing a share of other than HPV 16 and HPV 18 oncogenic types of human papilloma virus, the authors found that the most common were HPV 31, 45 and 33. In CIN 1 and CIN 2 their share was over 60%. In CIS/AIS type pathologies, no other types of human papilloma virus than HPV 16 and HPV 18 were shown. CONCLUSIONS: Positive results of DNA HR HPV testing of women with abnormal cytology results identified a risk group for the development of cervical cancer. No statistically significant differences of the frequency of HPV 16 and HPV 18 type occurrences were found in analyzed groups with cytological and histopathological diagnoses. PMID- 23457135 TI - The decrease in prolidase activity in myeloproliferative neoplasms. AB - BACKGROUND: The development of bone marrow fibrosis is a severe complication in hematological diseases. The progress of bone marrow myelofibrosis is evaluated by a trephine examination and may be characterized by the biochemical markers of collagen turnover determination. OBJECTIVES: Investigation of serum prolidase activity and biochemical markers of collagen metabolism in order to establish its role in the development of bone marrow fibrosis. MATERIAL AND METHODS: The group of 37 patients with myeloproliferative neoplasms (MPN) before treatment, consisted of 16 patients with chronic myeloid leukemia (CML), 7 with primary myelofibrosis (PMF), 8 with essential thrombocythopenia (ET), and 6 with polycythemia vera (PV). RESULTS: It was found that the plasma activity of prolidase (Pro) was reduced to almost half together with the serum level of osteocalcin (BGL), and hydroxyproline (H-PRO) in the serum and urine of patients with MPN in comparison to the control group. In the MPN group of patients, the levels of N-terminal procollagen III peptide (PIIINP), type I procollagen (PICP) and the C-terminal telopeptide of type I collagen (ICTP) were significantly higher. CONCLUSIONS: The alteration of collagen turnover markers in the MPN patient group (the elevation of synthesis and inhibition of collagen catabolism rate) has suggested that a diminished prolidase activity may contribute to such alteration of collagen metabolism and should be consider a biomarker of MPN progress. PMID- 23457136 TI - The psychometric properties of the Portuguese version of the Stroke Quality of Life Scale. AB - BACKGROUND: Quality of life (QoL) is currently of particular importance to health services and is regarded a key dimension for the assessment of stroke outcomes. However there are few instruments available for the Portuguese population. OBJECTIVES: The aim of the present work is to determine the psychometric properties of the Portuguese version of the Stroke Quality of Life Scale (ECVI 38), including acceptability, construct and criterion validity. MATERIAL AND METHODS: The sample comprised 51 patients with a clinical history of stroke (2 to 24 months prior) from the outpatient clinic of two Portuguese hospitals.. Patients with neuropsychiatric pathologies or other health conditions that might affect QoL were excluded. Parallel to the application of the ECVI-38, several other tests were used in order to determine the discriminative and concurrent validity of the scale. RESULTS: The ECVI-38 showed good acceptability, with missing data below 10%, and ceiling and floor effects below 80%. Cronbach's alpha for the total scale was 0.94 and ranged between 0.7 and 0.9 in each domain. ECVI 38 results were able to differentiate patients according to the severity of neurological impairment. Every domain of the scale correlated significantly with instruments of similar content. CONCLUSIONS: The Portuguese version of the ECVI 38 showed good psychometric characteristics. PMID- 23457137 TI - Effectiveness of cardiac simulator on the acquirement of cardiac auscultatory skills of medical students. AB - BACKGROUND: Cardiac simulators have been developed as an alternative training model in order to improve the cardiac auscultation skills of medical students. The effectiveness of the cardiac simulator's use in cardiac auscultatory training is presently not yet well established. OBJECTIVES: The authors aimed to investigate whether the use of a cardiac simulator can improve the auscultation skills of medical students. MATERIAL AND METHODS: The students taking the auscultation training on the cardiac simulator were grouped as Group A and the students not taking the auscultation training on the cardiac simulator were grouped as Group B (before). The students in Group B (before) were grouped as Group B (after) after receiving the auscultation training on the cardiac simulator. The percentages of accurate diagnoses for the tested heart murmurs were compared between Group A and Group B (before), and between Group B (before) and Group B (after). RESULTS: The rate of making correct diagnoses of normal heart sounds was similar in all the groups (Group A, Group B (before), and Group B (after)). By contrast, the percentage of accurate diagnoses for the tested heart murmurs was notably improved among the students in Group A with respect to Group B (before) (p < 0.01). Similarly, the rate of correct diagnoses for the tested heart murmurs was markedly higher among the students in Group B (after) than in Group B (before) (p < 0.01). CONCLUSIONS: The use of a cardiac simulator as a training tool can improve the auscultation skills of medical students quickly and efficiently. PMID- 23457138 TI - Characteristics of the Chlamydia trachomatis species - immunopathology and infections. AB - Chlamydiae are microorganisms exhibiting characteristics intermediate between bacteria and viruses. Chlamydia is widespread in the natural world, intracellular parasites of people and animals. They are capable of independent reproduction, because they do not synthesize ATP, in its development cycle using the host cell metabolic pathways. The life cycle of these microorganisms is original, unique among bacteria and lasts from 24 to 48 hours. Chlamydia antigens consist of 4 groups: group-specific, species-specific, type-specific and subspecies-specific. The group of species-specific antigens consists of MOMP and heat shock proteins. C. trachomatis is a potent immunogen, stimulating the immune processes of microorganisms. In the course of C. trachomatis infection, the response mechanisms involved are: non-specific, specific, humoral and cellular. Chronic infection is characterized by maintenance of microorganisms in the host cell. Inflammation is formed in less time and with increased intensity and has a rapid immune response on the part of previously sensitized lymphocytes. C. trachomatis infections are the most common bacterial sexually-transmitted infections. It represents an important clinical problem for doctors in many areas of medicine such as dermatology, venereology, ophthalmology, gynecology and obstetrics, rheumatology and others. Chlamydial infections are important pathogens in medical practice, not only because they cause disease in various fields of medicine, but also because of the large proportion of the population suffering and exposed to these microbial infections. Chlamydial infections are characterized by multifocality and polymorphism changes. Chlamydia causes inflammation in the adult urethra and cervix with the possibility of serious complications, and can cause perinatal infections in infants. PMID- 23457139 TI - Genetic aspects of pheochromocytoma. AB - Pheochromocytomas are derived from chromaffin cells of the adrenal medulla which synthesize and secrete catecholamines, thus affecting the cardiovascular system and metabolic processes. Pheochromocytoma is a tumor of the following multicarcinoma hereditary syndromes: type 2 multiple endocrine neoplasia, von Hippel-Lindau disease, type 1 neurofibromatosis and the pheochromocytomas/paragangliomas syndrome. Pheochromocytomas are relatively rare, and because of non-specific manifestation of these tumors and the possible lack of signs and symptoms for extended periods of time, the diagnosis may be delayed, which may, in turn, lead to death. Pheochromocytomas may occur sporadically. However, due to the frequent incidence of hereditary forms of these cancers, the presymptomatic genetic testing of family members with a positive family history is indicated, thus allowing for selecting people with higher risk of cancer. Early detection of the syndrome and the coexisting tumors (which may be malignant) may lead to a correct diagnosis, regular surveillance, preventive examinations and implementation of appropriate early treatment. Recent examinations have shown significant involvement of RET, VHL, NF1, SDHB and SDHD as well as the newly discovered KIF1Bbeta, TMEM127 and MAX genes in pathogenesis of these tumors. The microarray-gene expression studies, based on the analysis of cellular pathways, have revealed two distinct clusters indicating two different routes of tumorgenesis. The genotype-phenotype correlations are still being studied and future research can give us clearer information about the function of these genes, which may prove crucial from the clinical point of view. PMID- 23457140 TI - Novel clinical applications of dual energy computed tomography. AB - Dual energy CT (DECT) was conceived at the very beginning of the computed tomography era. However the first DECT scanner was developed in 2006. Nowadays there are three different types of DECT available: dual-source CT with 80(100) kVp and 140 kVp tubes (Siemens Medical Solution); dual-layer multi-detector scanner with acquisition 120 or 140kVp (Philips Healthcare); CT unit with one rapid kVp switching source and new detector based on gemstone scintillator materials (GE Healthcare). This article describes the physical background and principles of DECT imaging as well as applications of this innovative method in routine clinical practice (renal stone differentiation, pulmonary perfusion, neuroradiology and metallic implant imaging). The particular applications are illustrated by cases from author's material. PMID- 23457141 TI - Advances and changes in the treatment of children with nephroblastoma. AB - Wilms' tumor or nephroblastoma is the most common malignant tumor stemming from kidney cells and second only to neuroblastoma when it comes to extracranial solid tumors in children. The results of nephroblastoma treatment are a perfect example of therapeutic success resulting from an interdisciplinary approach to the problem and the cooperation of pediatric surgeons, pediatric oncologists, pathologists, radiologists and radiotherapists leading to precise diagnoses and the selection of the optimal treatment. At the end of the sixties, international research teams began studying the best treatment for this tumor in children. In Europe, it was the International Society of Paediatric Oncology (SIOP), which has used the working name SIOP- RTSG (Renal Tumor Study Group - Group for the Study of Kidney tumors) since 2008 and in North America NWTS (National Wilms' Tumor Study - The National Committee for Research on Wilms' tumor). Summarizing the experience and knowledge on the treatment of nephroblastoma, it should be noted that, despite years of research and information exchange, uniform guidelines have not yet been developed, and there are still differences in treatment of this tumor. The biggest differences are between the "American" treatment recommended by the NWTS and the "European" by SIOP. In the first it is recommended to start treatment from the surgical removal of the tumor, even in the case of disseminated disease with the presence of metastases in the lungs. The treatment method is chosen by the institution managing the patient; for this reason on the American continent in Brazil, Wilms' tumor is treated according to the recommendations of "European" protocols (SIOP) and some institutions in Europe, for example in Italy, treat patients with nephroblastoma according to the "American" protocols recommended by the NWTS; until recently, focal disease was treated with primary nephrectomy in the UK. PMID- 23457142 TI - Mycoplasma species isolated from intramammary infection of Japanese dairy cows. PMID- 23457143 TI - High-resolution peptide separations using nano-LC at ultra-high pressure. AB - We report on the optimization of nano-LC gradient separations of proteomic samples that vary in complexity. The gradient performance limits were visualized by kinetic plots depicting the gradient time needed to achieve a certain peak capacity, while using the maximum system pressure of 80 MPa. The selection of the optimal particle size/column length combination and corresponding gradient steepness was based on scouting the performance of 75 MUm id capillary columns packed with 2, 3, and 5 MUm fully porous silica C18 particles. At optimal gradient conditions, peak capacities up to 500 can be obtained within a 120 min gradient using 2 MUm particle-packed capillary columns. Separations of proteomic samples including a cytochrome c tryptic digest, a bovine serum albumin tryptic digest, a six protein mix digest, and an Escherichia coli digest are demonstrated while operating at the kinetic-performance limit, i.e. using 2-MUm packed columns, adjusting the column length and scaling the gradient steepness according to sample complexity. Finally, good run-to-run retention time stability (RSD values below 0.18%) was demonstrated applying ultra-high pressure conditions. PMID- 23457144 TI - Moving the discourse on quality in pediatrics: recent contributions of Robert Wood Johnson Foundation clinical scholars. PMID- 23457145 TI - Management of bronchiolitis in the emergency department: impact of evidence-based guidelines? AB - OBJECTIVE: Recent practice guidelines from the American Academy of Pediatrics recommend limiting use of bronchodilators, corticosteroids, antibiotics, and diagnostic testing for patients with bronchiolitis. We sought to determine the association of the evidence-based guidelines with bronchiolitis care in the emergency department (ED). METHODS: We analyzed data from the National Hospital Ambulatory Medical Care Survey, a nationally representative sample of ED visits. We compared utilization for patient visits before and after the publication of the guidelines. We used logistic regression to determine the association of the availability of the guidelines with resource utilization. RESULTS: Bronchodilators were used in 53.8% of patient visits with no differences noted after the introduction of the guidelines (53.6% vs 54.2%, P = .91). Systemic steroids were used in 20.4% of patient visits, and antibiotics were given in 33.2% of visits. There were no changes in the frequency of corticosteroid (21.9% vs 17.8%, P = .31) or antibiotic (33.6% vs 29.7%, P = .51) use. There was an associated decrease in use of chest x-rays (65.3% vs 48.6%, P = .005). This association remained significant after adjusting for patient and hospital characteristics with an adjusted odds ratio of 0.41 (95% confidence interval 0.26 0.67). CONCLUSIONS: For patients seen in the ED with bronchiolitis, utilization of diagnostic imaging has decreased with the availability of the American Academy of Pediatrics practice guidelines. However, there has not been an associated decrease in use of nonrecommended therapies. Targeted efforts will likely be required to change practice significantly. PMID- 23457146 TI - Assessing quality improvement in health care: theory for practice. AB - OBJECTIVES: To review the role of theory as a means to enhance the practice of quality improvement (QI) research and to propose a novel conceptual model focused on the operations of health care. METHODS: Conceptual model, informed by literature review. RESULTS: To optimize learning across QI studies requires the integration of small-scale theories (middle-range theories, theories of change) within the context of larger unifying theories. We propose that health care QI research would benefit from a theory that describes the operations of health care delivery, including the multiplicity of roles that interpersonal interactions play. The broadest constructs of the model are entry into the system, and assessment and management of the patient, with the subordinate operations of access; recognition, assessment, and diagnosis; and medical decision-making (developing a plan), coordination of care, execution of care, referral and reassessment, respectively. Interpersonal aspects of care recognize the patient/caregiver as a source of information, an individual in a cultural context, a complex human being, and a partner in their care. Impacts to any and all of these roles may impact the quality of care. CONCLUSIONS: Such a theory can promote opportunities for moving the field forward and organizing the planning and interpretation of comparable studies. The articulation of such a theory may simultaneously provide guidance for the QI researcher and an opportunity for refinement and improvement. PMID- 23457147 TI - Reducing quality-of-care disparities in childhood asthma: La Red de Asma Infantil intervention in San Juan, Puerto Rico. AB - BACKGROUND AND OBJECTIVE: Although children living in Puerto Rico have the highest asthma prevalence of all US children, little is known regarding the quality-of-care disparities they experience nor the adaptability of existing asthma evidence-based interventions to reduce these disparities. The objective of this study was to describe our experience in reducing quality-of-care disparities among Puerto Rican children with asthma by adapting 2 existing evidence-based asthma interventions. METHODS: We describe our experience in adapting and implementing 2 previously tested asthma evidence-based interventions: the Yes We Can program and the Inner-City Asthma Study intervention. We assessed the feasibility of combining key components of the 2 interventions to reduce asthma symptoms and estimated the potential cost savings associated with reductions in asthma-related hospitalizations and emergency department visits. A total of 117 children with moderate and severe asthma participated in the 12-month intervention in 2 housing projects in San Juan, Puerto Rico. A community-academic team with the necessary technical and cultural competences adapted and implemented the intervention. RESULTS: Our case study revealed the feasibility of implementing the combined intervention, henceforth referred to as La Red intervention, in the selected Puerto Rican communities experiencing a disproportionately high level of asthma burden. After 1-year follow-up, La Red intervention significantly reduced asthma symptoms and exceeded reductions of the original interventions. Asthma-related hospitalizations and emergency department use, and their associated high costs, were also significantly reduced. CONCLUSIONS: Asthma evidence-based interventions can be adapted to improve quality of care for children with asthma in a different cultural community setting. PMID- 23457148 TI - National quality measures for child mental health care: background, progress, and next steps. AB - OBJECTIVE: To review recent health policies related to measuring child health care quality, the selection processes of national child health quality measures, the nationally recommended quality measures for child mental health care and their evidence strength, the progress made toward developing new measures, and early lessons learned from these national efforts. METHODS: Methods used included description of the selection process of child health care quality measures from 2 independent national initiatives, the recommended quality measures for child mental health care, and the strength of scientific evidence supporting them. RESULTS: Of the child health quality measures recommended or endorsed during these national initiatives, only 9 unique measures were related to child mental health. CONCLUSIONS: The development of new child mental health quality measures poses methodologic challenges that will require a paradigm shift to align research with its accelerated pace. PMID- 23457150 TI - Do parent perceptions predict continuity of publicly funded care for attention deficit/hyperactivity disorder? AB - OBJECTIVE: To examine whether parent perceptions about care (barriers, disorder knowledge, treatment willingness) vary among children who drop out of or stay in publicly funded care for attention-deficit/hyperactivity disorder (ADHD) and to explore whether parent perceptions are predictive of staying in care over time. METHODS: A longitudinal cohort study of 529 children ages 5 to 11 years receiving care for ADHD in primary care or specialty mental health clinics in a large, countrywide, managed-care Medicaid program. Multiple logistic regression analyses were performed to identify parent perceptions associated with the likelihood of staying in care across three 6-month time intervals, controlling for child and parent demographic characteristics, parental distress, clinical need, and recent special education use. RESULTS: At least three-fourths of children had at least 1 contact for any mental health care during a 6-month time interval (75%, 85%, 76%). Parent-perceived barriers, ADHD knowledge, and counseling willingness did not predict staying in care, whereas willingness for medication treatment was predictive at baseline. Minority status, nonmarried parent, parental distress, clinical need, and special education use were predictive of staying in care, but mostly during only one 6-month time interval, and their influence varied over time. CONCLUSIONS: Parent willingness for medication treatment along with several demographic and need factors predicted staying in care but not consistently over time. Future research is needed to develop practical tools for clinicians to elicit parent priorities about ADHD treatment and to integrate them into quality improvement interventions targeted to improving shared decision-making for longer term ADHD care. PMID- 23457151 TI - Systematic update of computerized physician order entry order sets to improve quality of care: a case study. AB - BACKGROUND AND OBJECTIVES: Seattle Children's Hospital was one of the early adopters of computerized physician order entry. As part of our 2003 go-live, order sets were created opportunistically by using an ad hoc development process. A pilot study revealed that this ad hoc development process resulted in order sets that were neither internally nor externally consistent. We sought to update order sets by using software development techniques, to try and improve consistency and also to review clinical content so that they could be updated to current evidence and consensus-based best practice. We also sought to identify and categorize errors found in the original order sets. METHODS: This is a case study of a new order set development process that: (1) assigned order set ownership; (2) created and applied standards for how orders should appear and be organized within order sets; (3) supported multidisciplinary review and update; and (4) enforced submitting completed specifications before order set build. We extracted order sets into Microsoft Word specifications, updated content by using the Track Changes function, and then updated our Clinical Information System. Changes were reviewed and organized according to themes. RESULTS: We created standard order formats for 98 orders; 191 order sets were standardized. Multidisciplinary review identified medication issues in 37% of order sets (used in 47.6% of inpatient admissions). CONCLUSIONS: This case study demonstrates that it is not sufficient to simply implement computerized physician order entry. Clinical decision supports should be subject to rigorous development processes to ensure both clinical appropriateness and correctness. PMID- 23457152 TI - Methods of mortality risk adjustment in the NICU: a 20-year review. AB - BACKGROUND AND OBJECTIVES: Improving the quality of care delivered in NICUs relies on the ability to partition variation associated with patient characteristics from those attributed to processes of care delivery through risk adjustment. Multiple methods of mortality risk adjustment have been proposed for NICU populations. We review existing literature pertaining to mortality risk adjustment in the NICU. METHODS: PubMed and Scopus were searched to identify unique methods of mortality risk adjustment in the NICU and their trends in citation since original publication. Additional online searches were performed to identify organizational and government agency means of mortality risk adjustment for patients in the NICU. RESULTS: Among 10 unique neonatal mortality risk adjustment scores identified by this review, there are >3 dozen different measurement components. No score includes >28 components; no score contains <6. Scores differ substantively in their intended purposes, component parameters and intensity of data collection. The Clinical Risk Index for Babies (CRIB) has been referenced most frequently in other research articles (447 citations), while the National Institutes of Child Health and Human Development "calculator" has the greatest rate of citations per year since initial publication (37). The scores are notably inconsistent in their approaches to timing of data collection and inclusion of comorbidity indicators. CONCLUSIONS: Rigorous means of risk adjustment in the NICU are essential to enhancing the quality of care delivered to neonates, by facilitating more meaningful comparisons in quality improvement. Building on the first 20 years of neonatal mortality risk adjustment will ultimately allow researchers and quality improvement teams to apply measures that facilitate cross-institutional comparisons thoroughly and fairly. PMID- 23457149 TI - Well-child care clinical practice redesign for young children: a systematic review of strategies and tools. AB - BACKGROUND AND OBJECTIVE: Various proposals have been made to redesign well-child care (WCC) for young children, yet no peer-reviewed publication has examined the evidence for these. The objective of this study was to conduct a systematic review on WCC clinical practice redesign for children aged 0 to 5 years. METHODS: PubMed was searched using criteria to identify relevant English-language articles published from January 1981 through February 2012. Observational studies, controlled trials, and systematic reviews evaluating efficiency and effectiveness of WCC for children aged 0 to 5 were selected. Interventions were organized into 3 categories: providers, formats (how care is provided; eg, non-face-to-face formats), and locations for care. Data were extracted by independent article review, including study quality, of 3 investigators with consensus resolution of discrepancies. RESULTS: Of 275 articles screened, 33 met inclusion criteria. Seventeen articles focused on providers, 13 on formats, 2 on locations, and 1 miscellaneous. We found evidence that WCC provided in groups is at least as effective in providing WCC as 1-on-1 visits. There was limited evidence regarding other formats, although evidence suggested that non-face-to-face formats, particularly web-based tools, could enhance anticipatory guidance and possibly reduce parents' need for clinical contacts for minor concerns between well-child visits. The addition of a non-medical professional trained as a developmental specialist may improve receipt of WCC services and enhance parenting practices. There was insufficient evidence on nonclinical locations for WCC. CONCLUSIONS: Evidence suggests that there are promising WCC redesign tools and strategies that may be ready for larger-scale testing and may have important implications for preventive care delivery to young children in the United States. PMID- 23457153 TI - Accuracy of hospital administrative data in reporting central line-associated bloodstream infections in newborns. AB - OBJECTIVES: Central line-associated bloodstream infections (CLABSIs) are a significant source of morbidity and mortality in the NICU. In 2010, Medicaid was mandated not to pay hospitals for treatment of CLABSI; however, the source of CLABSI data for this policy was not specified. Our objective was to evaluate the accuracy of hospital administrative data compared with CLABSI confirmed by an infection control service. METHODS: We evaluated hospital administrative and infection control data for newborns admitted consecutively from January 1, 2008, to December 31, 2010. Clinical and demographic data were collected through chart review. We compared cases of CLABSI identified by administrative data (International Classification of Diseases, Ninth Revision, Clinical Modification 999.31) with infection control data that use national criteria from the Centers for Disease Control and Prevention as the gold standard. To ascertain the nature possible deficiencies in the administrative data, each patient's medical record was searched to determine if clinical phrases that commonly refer to CLABSI appeared. RESULTS: Of 2920 infants admitted to the NICU during our study period, 52 were identified as having a CLABSI: 42 by infection control data only, 7 through hospital administrative data only, and 3 appearing in both. Against the gold standard, hospital administrative data were 6.7% sensitive and 99.7% specific, with a positive predictive value of 30.0% and a negative predictive value of 98.6%. Only 48% of medical records indicated a CLABSI. CONCLUSIONS: Our findings from a major children's hospital NICU indicate that International Classification of Diseases, Ninth Revision, Clinical Modification code 993.31 is presently not accurate and cannot be used reliably to compare CLABSI rates in NICUs. PMID- 23457154 TI - Variation in surgical outcomes for adolescents and young adults with inflammatory bowel disease. AB - OBJECTIVE: To examine whether hospital type (children's hospital or generalist hospital) and surgeon specialty are associated with variations in surgical outcomes for hospitalized adolescents and young adults with inflammatory bowel disease (IBD) requiring surgery. METHODS: The 2007-2009 Perspective Data Warehouse was used to identify a retrospective cohort study of all inpatients 16 to 25 years old who received surgery for IBD. Multivariate regression, clustered at the hospital level, examined the association of hospital type and surgical specialty with surgical complications and 30-day readmissions. RESULTS: Surgery was performed in 917 hospitalizations of 598 patients across 20 children's hospitals and 198 general hospitals by 566 general surgeons, 46 pediatric surgeons, and 305 colorectal surgeons. After adjustment, children's hospitals had higher predicted probabilities of surgical complication (predicted probability [PP]: 35% [95% confidence interval (CI): 28-42]) compared with general hospitals (PP: 26% [95% CI: 23-29]). Despite higher complications among children's hospitals, pediatric surgeons had lowest predicated probabilities of surgical complication or 30-day readmission (PP: 24% [95% CI: 10-39]) compared with general surgeons (PP: 39% [95% CI: 35-43]) and colorectal surgeons (PP: 35% [95% CI: 28-42]). CONCLUSIONS: Disparate outcomes for adolescents and young adults receiving care in children's versus generalist hospitals and from different types of surgeons reveal the need to better understand how practice setting and surgical specialty may modify outcomes for a population that traverses a variety of health care settings. PMID- 23457155 TI - The factors associated with high-quality communication for critically ill children. AB - OBJECTIVE: Timely, high quality communication with families is essential to family-centered decision-making. Quality communication is represented by widespread documentation of prognostic, goals-of-care conversations (PGOCC) in the pediatric intensive care unit (PICU) and should occur without variation by patient characteristics. METHODS: Cohort included 645 PICU admissions in the top decile of risk of mortality on admission over six years. Electronic medical records were used to determine PGOCC, diagnosis on admission and complex chronic condition (CCC) status. Multivariate logistic regression and time-to-event analyses were used. RESULTS: Overall, 31% had a documented PGOCC. 51% had CCC status. 11% had an oncologic, 13% had a cardiovascular diagnosis on admission. 94% of patients who died in the PICU had PGOCC documented, but among the 200 patients with documented PGOCC, 78% did not die in the PICU. Oncologic diagnosis on admission was associated with a higher likelihood of PGOCC compared to non-CCC patients (ARR=1.86; SE=0.26) whereas no other diagnosis category reached the level of statistical significance. Median time from admission to PGOCC was 2 days. Age, gender and CCC status were not associated with whether a PGOCC was documented or with time from admission to PGOCC documentation. 45% of PGOCC in the cohort and 50% of conversations in patients with CCC were documented by PICU physicians. CONCLUSIONS: This study reveals the opportunity for improvement in documentation of PGOCC for critically ill children. It raises the questions of why there is variation of PGOCC across disease categories and whether PGOCC should be considered a quality measure for family-centered care. PMID- 23457156 TI - Rapid adoption of Lactobacillus rhamnosus GG for acute gastroenteritis. AB - BACKGROUND AND OBJECTIVES: A 2007 meta-analysis showed probiotics, specifically Lactobacillus rhamnosus GG (LGG), shorten diarrhea from acute gastroenteritis (AGE) by 24 hours and decrease risk of progression beyond 7 days. In 2005, our institution published a guideline recommending consideration of probiotics for patients with AGE, but only 1% of inpatients with AGE were prescribed LGG. The objective of this study was to increase inpatient prescribing of LGG at admission to >90%, for children hospitalized with AGE, within 120 days. METHODS: This quality improvement study included patients aged 2 months to 18 years admitted to general pediatrics with AGE with diarrhea. Diarrhea was defined as looser or >= 3 stools in the preceding 24 hours. Patients with complex medical conditions or with presumed bacterial gastroenteritis were excluded. Admitting and supervising clinicians were educated on the evidence. We ensured LGG was adequately stocked in our pharmacies and updated an AGE-specific computerized order set to include a default LGG order. Failure identification and mitigation were conducted via daily electronic chart review and e-mail communication. Primary outcome was the percentage of included patients prescribed LGG within 18 hours of admission. Intervention impact was assessed with run charts tracking our primary outcome over time. RESULTS: The prescribing rate increased to 100% within 6 weeks and has been sustained for 7 months. CONCLUSIONS: Keys to success were pharmacy collaboration, use of an electronic medical record for a standardized order set, and rapid identification and mitigation of failures. Rapid implementation of evidence-based practices is possible using improvement science methods. PMID- 23457157 TI - The European Respiratory Review: mature, expanding and targeting new challenges. PMID- 23457158 TI - Personalised medicine for cystic fibrosis: treating the basic defect. PMID- 23457160 TI - Pulmonary hypertension. AB - 2011 to 2012 has seen an explosion in published research in the field of pulmonary vascular disease, especially pulmonary hypertension. In conjunction with this research has been an explosion in clinical interest in treating pulmonary hypertension. This is possible because we now have three different generic classes of drug therapy: endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclins. Clearly, however, we need to be careful that we are treating the correct disease with the correct drug and measuring the correct response. Herein, I will review the papers published over the last year that offer the most insight into the pathobiology, but also those that give us the clinical information we need in epidemiology, treatment and end points so that we can treat this devastating group of disease. PMID- 23457161 TI - Interstitial lung disease. AB - This article reviews the most important articles published in interstitial lung disease, as reviewed during the Clinical Year in Review session at the 2012 annual European Respiratory Society Congress in Vienna, Austria. Since the recent international guidelines for the management of idiopathic pulmonary fibrosis (IPF), important new evidence is available. The anti-fibrotic drug pirfenidone has been recently approved in Europe. Other pharmacological agents, especially nintedanib, are still being tested. The so-called triple combination therapy, anticoagulation therapy and endothelin receptor antagonists, especially ambrisentan, are either harmful or ineffective in IPF and are not recommended as treatment. Although the clinical course of IPF is highly variable, novel tools have been developed for individual prediction of prognosis. Acute exacerbations of IPF are associated with increased mortality and may occur with higher frequency in IPF patients with associated pulmonary hypertension. Interstitial lung disease associated with connective tissue disease has been definitely established to have a better long-term survival than IPF. A subset of patients present with symptoms and/or biological autoimmune features, but do not fulfil diagnostic criteria for a given autoimmune disease; this condition is associated with a higher prevalence of nonspecific interstitial pneumonia pattern, female sex and younger age, although survival relevance is unclear. PMID- 23457162 TI - Nonsmall cell lung cancer. AB - The objective of this review is to report the Clinical Year in Review proceedings in the field of nonsmall cell lung cancer that were presented at the 2012 European Respiratory Society Congress in Vienna, Austria. Various topics were reviewed, including epidemiology, screening, diagnosis, treatment, prognosis, and palliative and end of life care. PMID- 23457159 TI - Scleroderma lung disease. PMID- 23457163 TI - Smoking cessation and COPD. AB - The mainstay in smoking cessation is counselling in combination with varenicline, nicotine replacement therapy (NRT) or bupropion SR. Varenicline and combination of two NRTs is equally effective, while varenicline alone is more effective than either NRT or bupropion SR. NRT is extremely safe but cardiovascular and psychiatric adverse events with varenicline have been reported. These treatments have also been shown to be effective in patients with chronic obstructive pulmonary disease (COPD). A model study is the Lung Health Study from the USA. Findings from this study of 5,587 patients with mild COPD showed that repeated smoking cessation for a period of 5 yrs resulted in a quit rate of 37%. After 14.5 yrs the quitters had a higher lung function and a higher survival rate. A study with a new nicotine formulation, a mouth spray, showed high relative efficacy. As 5-10% of quitters use long-term NRT, we report the results of a study where varenicline compared with placebo increased the quit rate in long term users of NRT. Smoking cessation is the most effective intervention in stopping the progression of COPD, as well as increasing survival and reducing morbidity. This is why smoking cessation should be the top priority in the treatment of COPD. PMID- 23457164 TI - Adult-onset asthma: is it really different? AB - Asthma that starts in adulthood differs from childhood-onset asthma in that it is often non-atopic, more severe and associated with a faster decline in lung function. Understanding of the underlying mechanism of adult-onset asthma and identification of specific phenotypes may further our understanding of pathophysiology and treatment response, leading to better targeting of both existing and new approaches for personalised management. Pivotal studies in past years have led to sustained progress in many areas, ranging from risk factors for development, identification of different phenotypes, and introduction of new therapies. This review highlights and discusses literature on adult-onset asthma, with special focus on the differences from childhood-onset asthma, risk factors for development, phenotypes of adult-onset asthma and new approaches for personalised management. PMID- 23457165 TI - Stratified medicine: drugs meet genetics. AB - It is well recognised that genetic factors play a major role in the development of respiratory diseases such as asthma and chronic obstructive pulmonary disease. However, whilst extensive data exist on diseases caused primarily by single gene defects, such as alpha1-antitrypsin deficiency, the genetic factors responsible for the development of complex disease are only now being defined. Once the gene(s) responsible for the heritable element of disease risk are known, the next step is to identify the mechanisms underlying the pathophysiological effects of the causal mutations in these genes. This process can be time consuming, but allows a full understanding of the mechanisms underlying disease development to be obtained. This knowledge can then potentially be used to stratify patient groups within (or even across) disease boundaries and then to target therapy more effectively. PMID- 23457166 TI - Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. AB - Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine. PMID- 23457167 TI - Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation. AB - Cystic fibrosis (CF) is an autosomal recessive lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for CFTR, an epithelial cell-surface expressed protein responsible for the transport of chloride (Cl(-)). Gating mutations associated with defective conductance can be modulated by CFTR potentiators. Ivacaftor is a CFTR potentiator approved for the treatment of CF patients >6 yrs of age with at least one copy of the G551D-CFTR mutation. Herein, the clinical trial development programme for ivacaftor will be reviewed, including two pivotal studies in adolescents/adults and in children. These studies report sustained improvements in lung function and sweat chloride concentrations, and a reduction in pulmonary exacerbations over a 48-week treatment period. In the era of personalised medicine, ivacaftor offers an effective and well-tolerated treatment for the clinical management of CF patients with the G551D mutation. A long-term, open label study will report the effects of ivacaftor over a further 48 weeks. PMID- 23457168 TI - The impact of personalised therapies on respiratory medicine. AB - Stratified approaches to treating disease are very attractive, as efficacy is maximised by identifying responders using a companion diagnostic or by careful phenotyping. This approach will spare non-responders form potential side-effects. This has been pioneered in oncology where single genes or gene signatures indicate tumours that will respond to specific chemotherapies. Stratified approaches to the treatment of asthma with biological therapies are currently being extensively studied. In cystic fibrosis (CF), therapies have been developed that are targeted at specific functional classes of mutations. Ivacaftor, the first of such therapies, potentiates dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein Class III mutations and is now available in the USA and some European countries. Pivotal studies in patients with a G551D mutation, the most common Class III mutation, have demonstrated significant improvements in clinically important outcomes such as spirometry and exacerbations. Sweat chloride was significantly reduced demonstrating a functional effect on the dysfunctional CFTR protein produced by the G551D mutation. Symptom scores are also greatly improved to a level that indicates that this is a transformational treatment for many patients. This stratified approach to the development of therapies based on the functional class of the mutations in CF is likely to lead to new drugs or combinations that will correct the basic defect in many patients with CF. PMID- 23457169 TI - Thymic epithelial tumours: from basic principles to individualised treatment strategies. AB - Thymic epithelial tumours represent a wide range of anatomical, clinical, histological and molecular malignant entities that may be aggressive and difficult to treat. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas may be associated with autoimmune disorders. The management of thymic epithelial tumours is a paradigm of co-operation between clinicians, surgeons and pathologists, from establishing the diagnosis to organising the multimodal therapeutic strategy. Surgery is the mainstay of the curative-intent treatment, as complete resection represents the most significantly favourable prognostic factor on overall survival. In case of invasion of intra-thoracic structures and/or dissemination to the pleura and the pericardium, precluding complete resection to be achieved, primary chemotherapy has been used to reduce the tumour burden, possibly allowing subsequent surgery and/or radiotherapy. Novel strategies are needed, especially for refractory, recurrent tumours and thymic carcinomas, which carry a poor prognosis. Personalised approaches are currently being developed, as potentially "druggable" molecular targets are emerging from recent integrated genomic analyses. Along with the large variety of questions relative to the treatment strategy, thymic epithelial tumours represent a model of therapeutic implementation and achievement in orphan thoracic oncology, showing how the advent of new results induces new questions, as well as diversifies further clinical research directions and international collaborative initiatives. PMID- 23457170 TI - Hot tub lung: an occupational hazard. PMID- 23457171 TI - Solitary cystic mediastinal lymphangioma. PMID- 23457172 TI - Pulmonary toxicity after long-term treatment with lenalidomide in two myeloma patients. PMID- 23457173 TI - What are the benefits of medical screening and surveillance? PMID- 23457174 TI - What are the benefits of medical screening and surveillance? PMID- 23457175 TI - Progressive metastatic pulmonary calcification after successful renal transplantation. PMID- 23457176 TI - Recruitment into psychiatry: quantitative myths and qualitative challenges. AB - Recruitment into psychiatry is perceived as problematic in the UK but the paper by Goldacre and colleagues in this issue of the Journal shows that recruitment of new UK graduates has altered little over 35 years. Sources of psychiatry's malaise should be sought in its changing focus and the quality, rather than quantity, of its recruits. PMID- 23457177 TI - Biological psychiatry: time for new paradigms. AB - Biological psychiatry has not yet produced clinically viable biomarkers for any of the major psychiatric diseases, and the past 25 years have not brought any fundamentally new biological treatment principles. I discuss reasons for this slow progress and suggest avenues for the development of biomarkers and the discovery of new treatment targets. PMID- 23457178 TI - Early intervention for psychosis in low- and middle-income countries needs a public health approach. AB - Early intervention in psychosis has significantly improved outcomes compared with standard treatment but it is considered as a luxury for low- and middle-income (LAMI) countries. However, a public health approach that is based on the principles of supplying all essential medication free of charge for at least the first 2 years of illness, medication being taken under supervision of a caregiver and treatment following a standardised treatment algorithm can prove a cost effective early intervention model for LAMI countries. PMID- 23457179 TI - Pros and cons of specialised care in bipolar disorder: an international perspective. AB - Highly specialised care may have both pros and cons. Centralised expert treatment may be more effective than standard community care for bipolar disorder. Rather than trying to solve the false dichotomy between specialised v. community care, the rational integration of both approaches may enhance quality of care and cost effectiveness. PMID- 23457180 TI - Bipolar disorder and substance misuse: pathological and therapeutic implications of their comorbidity and cross-sensitisation. AB - BACKGROUND: Bipolar disorder has a high co-occurrence with substance use disorders, but the pathophysiological mechanisms have not been adequately explored. AIMS: To review the role of stress in the onset and recurrence of affective episodes and substance misuse. METHOD: We review the mechanisms involved in sensitisation (increased responsivity) to recurrence of stressors, mood episodes and cocaine use. RESULTS: Evidence suggests that intermittent stressors, mood episodes and bouts of cocaine use not only show sensitisation to themselves, but cross-sensitisation to the others contributing to illness progression. Converseley, an understanding of the common mechanisms of sensitisation (such as regionally selective alterations in brain derived neurotrophic factor (BDNF) and hyperactivity of striatally based habit memories), could also result in single therapies (such as N-acetylcysteine) having positive effects in all three domains. CONCLUSIONS: These interacting sensitisation processes suggest the importance of early intervention in attempting to prevent increasingly severe manifestations of bipolar illness and substance misuse progression. PMID- 23457181 TI - Affective disorders and risk of developing dementia: systematic review. AB - BACKGROUND: Affective disorders are associated with cognitive disturbances but their role as risk factors for dementia is still not fully investigated. AIMS: To evaluate the risk of developing dementia in individuals with a history of affective disorder. METHOD: We conducted a systematic review of case-control and cohort studies addressing the risk of developing dementia in people with affective disorders. To the best of our knowledge, this is the first systematic review that has included studies evaluating this risk specifically in people with bipolar disorder. RESULTS: Fifty-one studies were included. Most of the studies found an increased risk for developing dementia in individuals with depression. Greater frequency and severity of depressive episodes seem to increase this risk. The evidence is contradictory regarding whether there is a difference in risk in people with early- or late-onset depression. The few available risk estimates for dementia in people with bipolar disorder suggest an even higher risk than for those with depression. CONCLUSIONS: Affective disorders appear to be associated with an increased risk of developing dementia, and one that is dependent on clinical and demographic variables. Depression may be both a prodrome and a risk factor for dementia. Future research should aim to elucidate the mechanisms that mediate these links. PMID- 23457183 TI - Ethnic effects--a view from West London. PMID- 23457182 TI - Transitional interventions to reduce early psychiatric readmissions in adults: systematic review. AB - BACKGROUND: Up to 13% of psychiatric patients are readmitted shortly after discharge. Interventions that ensure successful transitions to community care may play a key role in preventing early readmission. AIMS: To describe and evaluate interventions applied during the transition from in-patient to out-patient care in preventing early psychiatric readmission. METHOD: Systematic review of transitional interventions among adults admitted to hospital with mental illness where the study outcome was psychiatric readmission. RESULTS: The review included 15 studies with 15 non-overlapping intervention components. Absolute risk reductions of 13.6 to 37.0% were observed in statistically significant studies. Effective intervention components were: pre- and post-discharge patient psychoeducation, structured needs assessments, medication reconciliation/education, transition managers and in-patient/out-patient provider communication. Key limitations were small sample size and risk of bias. CONCLUSIONS: Many effective transitional intervention components are feasible and likely to be cost-effective. Future research can provide direction about the specific components necessary and/or sufficient for preventing early psychiatric readmission. PMID- 23457184 TI - Identifying treatment-resistant schizophrenia. PMID- 23457185 TI - Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension. AB - Mineralocorticoid receptor (MR) activation stimulates systemic vascular and left ventricular remodeling. We hypothesized that MR contributes to pulmonary vascular and right ventricular (RV) remodeling of pulmonary hypertension (PH). We evaluated the efficacy of MR antagonism by spironolactone in two experimental PH models; mouse chronic hypoxia-induced PH (prevention model) and rat monocrotaline induced PH (prevention and treatment models). Last, the biological function of the MR was analyzed in cultured distal pulmonary artery smooth muscle cells (PASMCs). In hypoxic PH mice, spironolactone attenuated the increase in RV systolic pressure, pulmonary arterial muscularization, and RV fibrosis. In rat monocrotaline-induced PH (prevention arm), spironolactone attenuated pulmonary vascular resistance and pulmonary vascular remodeling. In the established disease (treatment arm), spironolactone decreased RV systolic pressure and pulmonary vascular resistance with no significant effect on histological measures of pulmonary vascular remodeling, or RV fibrosis. Spironolactone decreased RV cardiomyocyte size modestly with no significant effect on RV mass, systemic blood pressure, cardiac output, or body weight, suggesting a predominantly local pulmonary vascular effect. In distal PASMCs, MR was expressed and localized diffusely. Treatment with the MR agonist aldosterone, hypoxia, or platelet derived growth factor promoted MR translocation to the nucleus, activated MR transcriptional function, and stimulated PASMC proliferation, while spironolactone blocked these effects. In summary, MR is active in distal PASMCs, and its antagonism prevents PASMC proliferation and attenuates experimental PH. These data suggest that MR is involved in the pathogenesis of PH via effects on PASMCs and that MR antagonism may represent a novel therapeutic target for this disease. PMID- 23457186 TI - Household air pollution: a call for studies into biomarkers of exposure and predictors of respiratory disease. AB - Household air pollution (HAP) from indoor burning of biomass or coal is a leading global cause of morbidity and mortality, mostly due to its association with acute respiratory infection in children and chronic respiratory and cardiovascular diseases in adults. Interventions that have significantly reduced exposure to HAP improve health outcomes and may reduce mortality. However, we lack robust, specific, and field-ready biomarkers to identify populations at greatest risk and to monitor the effectiveness of interventions. New scientific approaches are urgently needed to develop biomarkers of human exposure that accurately reflect exposure or effect. In this Perspective, we describe the global need for such biomarkers, the aims of biomarker development, and the state of development of tests that have the potential for rapid transition from laboratory bench to field use. PMID- 23457187 TI - Influenza matrix protein 2 alters CFTR expression and function through its ion channel activity. AB - The human cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-activated chloride (Cl(-)) channel in the lung epithelium that helps regulate the thickness and composition of the lung epithelial lining fluid. We investigated whether influenza M2 protein, a pH-activated proton (H(+)) channel that traffics to the plasma membrane of infected cells, altered CFTR expression and function. M2 decreased CFTR activity in 1) Xenopus oocytes injected with human CFTR, 2) epithelial cells (HEK-293) stably transfected with CFTR, and 3) human bronchial epithelial cells (16HBE14o-) expressing native CFTR. This inhibition was partially reversed by an inhibitor of the ubiquitin-activating enzyme E1. Next we investigated whether the M2 inhibition of CFTR activity was due to an increase of secretory organelle pH by M2. Incubation of Xenopus oocytes expressing CFTR with ammonium chloride or concanamycin A, two agents that alkalinize the secretory pathway, inhibited CFTR activity in a dose-dependent manner. Treatment of M2- and CFTR-expressing oocytes with the M2 ion channel inhibitor amantadine prevented the loss in CFTR expression and activity; in addition, M2 mutants, lacking the ability to transport H(+), did not alter CFTR activity in Xenopus oocytes and HEK cells. Expression of an M2 mutant retained in the endoplasmic reticulum also failed to alter CFTR activity. In summary, our data show that M2 decreases CFTR activity by increasing secretory organelle pH, which targets CFTR for destruction by the ubiquitin system. Alteration of CFTR activity has important consequences for fluid regulation and may potentially modify the immune response to viral infection. PMID- 23457188 TI - Gene expression profiles reveal molecular mechanisms involved in the progression and resolution of bleomycin-induced lung fibrosis. AB - Lung fibrosis is the final result of a large number of disorders and is usually considered an irreversible process. However, some evidence suggests that fibrosis could eventually be reversible. In this study we aimed to document the time related reversibility of bleomycin-induced lung fibrosis and to examine the gene expression profile associated with its initial progression and subsequent resolution. C57BL/6 mice were instilled with a single dose of bleomycin and euthanized at 1, 4, 8, 12, and 16 wk. Control animals received an equal volume of saline. Lung fibrosis was examined by morphology and hydroxyproline content and the transcriptional signature by gene microarray analysis. Our results showed that bleomycin-injured mice developed prominent inflammation at 1 wk, followed by fibrosis that peaked at 2 mo. Then fibrosis resolved until lungs displayed almost normal architecture at 4 mo. Genomewide transcriptional profiling revealed 533 significantly changed genes. Self-organizing maps analysis of these genes identified four clusters based on the temporal pattern of gene expression. Clusters 1 and 2 contained genes upregulated during the inflammatory and fibrotic response and were enriched for extracellular matrix-related genes including several collagens, matrix metalloproteinases, and TIMP-1. Cluster 3 identified upregulated genes during the fibrotic response, and cluster 4 contained genes decreased during inflammation and fibrosis that increased during resolution. Most enriched pathways included genes involved in cell cycle and in regulation of transcription. Our findings corroborate the reversibility of bleomycin-induced lung fibrosis and reveal transcriptional signatures that characterize the progression and resolution. PMID- 23457189 TI - The IGF-I/IGF-R1 pathway regulates postnatal lung growth and is a nonspecific regulator of alveologenesis in the neonatal rat. AB - IGF-I, IGF-II, and the IGF-I receptor are widely distributed throughout the neonatal rat lung on days 4, 7, 10, and 14 of life, with a similar abundance at each of these time points. Injection of 20 MUg/g of a truncated soluble IGF-I receptor on days 2 and 5 of life, to decoy ligand away from the endogenous IGF-I receptor, reduced lung weight and lung-to-body weight ratio, reduced lung tissue fraction, and impaired alveolar formation, as assessed by secondary crest formation and mean linear intercepts on day 7 of life. Lung procollagen I content and elastin fiber density were also reduced. Injection of 100 MUg/day of neutralizing anti-IGF-I, to prevent IGF-I from binding to the IGF-I receptor, on days 3, 4, and 5 of life reduced tissue fraction and elastin fiber density and impaired alveolar formation on day 6 of life. Both interventions reduced total lung cell and secondary crest cell DNA synthesis and small vessel counts per unit area, but these effects were lost after normalization to the reduced tissue fraction. These findings are consistent with a role for IGF-I binding to the IGF I receptor in postnatal lung growth and on alveologenesis through a nonspecific positive effect on DNA synthesis. Injection of 100 MUg/day of neutralizing anti IGF-II, to prevent IGF-II from binding to the IGF-I receptor, on days 3, 4, and 5 of life had no effect on total lung cell DNA synthesis per unit area on day 6 of life, and a role for IGF-II in postnatal alveologenesis was not further pursued. PMID- 23457190 TI - Secretion of quinolinic acid, an intermediate in the kynurenine pathway, for utilization in NAD+ biosynthesis in the yeast Saccharomyces cerevisiae. AB - NAD(+) is synthesized from tryptophan either via the kynurenine (de novo) pathway or via the salvage pathway by reutilizing intermediates such as nicotinic acid or nicotinamide ribose. Quinolinic acid is an intermediate in the kynurenine pathway. We have discovered that the budding yeast Saccharomyces cerevisiae secretes quinolinic acid into the medium and also utilizes extracellular quinolinic acid as a novel NAD(+) precursor. We provide evidence that extracellular quinolinic acid enters the cell via Tna1, a high-affinity nicotinic acid permease, and thereby helps to increase the intracellular concentration of NAD(+). Transcription of genes involved in the kynurenine pathway and Tna1 was increased, responding to a low intracellular NAD(+) concentration, in cells bearing mutations of these genes; this transcriptional induction was suppressed by supplementation with quinolinic acid or nicotinic acid. Our data thus shed new light on the significance of quinolinic acid, which had previously been recognized only as an intermediate in the kynurenine pathway. PMID- 23457191 TI - The response of Nannochloropsis gaditana to nitrogen starvation includes de novo biosynthesis of triacylglycerols, a decrease of chloroplast galactolipids, and reorganization of the photosynthetic apparatus. AB - Microalgae of the genus Nannochloropsis are capable of accumulating triacylglycerols (TAGs) when exposed to nutrient limitation (in particular, nitrogen [N]) and are therefore considered promising organisms for biodiesel production. Here, after nitrogen removal from the medium, Nannochloropsis gaditana cells showed extensive triacylglycerol accumulation (38% TAG on a dry weight basis). Triacylglycerols accumulated during N deprivation harbored signatures, indicating that they mainly stemmed from freshly synthesized fatty acids, with a small proportion originating from a recycling of membrane glycerolipids. The amount of chloroplast galactoglycerolipids, which are essential for the integrity of thylakoids, decreased, while their fatty acid composition appeared to be unaltered. In starved cells, galactolipids were kept at a level sufficient to maintain chloroplast integrity, as confirmed by electron microscopy. Consistently, N-starved Nannochloropsis cells contained less photosynthetic membranes but were still efficiently performing photosynthesis. N starvation led to a modification of the photosynthetic apparatus with a change in pigment composition and a decrease in the content of all the major electron flow complexes, including photosystem II, photosystem I, and the cytochrome b(6)f complex. The photosystem II content was particularly affected, leading to the inhibition of linear electron flow from water to CO(2). Such a reduction, however, was partially compensated for by activation of alternative electron pathways, such as cyclic electron transport. Overall, these changes allowed cells to modify their energetic metabolism in order to maintain photosynthetic growth. PMID- 23457192 TI - Detection of fungal DNA in human body fluids and tissues during a multistate outbreak of fungal meningitis and other infections. AB - Exserohilum rostratum was the major cause of an outbreak of fungal infections linked to injections of contaminated methylprednisolone acetate. Because almost 14,000 persons were exposed to product that was possibly contaminated with multiple fungal pathogens, there was unprecedented need for a rapid throughput diagnostic test that could detect both E. rostratum and other unusual agents of fungal infection. Here we report development of a novel PCR test that allowed for rapid and specific detection of fungal DNA in cerebrospinal fluid (CSF), other body fluids and tissues of infected individuals. The test relied on direct purification of free-circulating fungal DNA from fluids and subsequent PCR amplification and sequencing. Using this method, we detected Exserohilum rostratum DNA in 123 samples from 114 case-patients (28% of 413 case-patients for whom 627 samples were available), and Cladosporium DNA in one sample from one case-patient. PCR with novel Exserohilum-specific ITS-2 region primers detected 25 case-patients with samples that were negative using broad-range ITS primers. Compared to fungal culture, this molecular test was more sensitive: of 139 case patients with an identical specimen tested by culture and PCR, E. rostratum was recovered in culture from 19 (14%), but detected by PCR in 41 (29%), showing a diagnostic sensitivity of 29% for PCR compared to 14% for culture in this patient group. The ability to rapidly confirm the etiologic role of E. rostratum in these infections provided an important contribution in the public health response to this outbreak. PMID- 23457194 TI - MR cholangiopancreatography at 3.0 T in children: diagnostic quality and ability in assessment of common paediatric pancreatobiliary pathology. AB - OBJECTIVE: To assess the diagnostic quality of MR cholangiopancreatography (MRCP) at 3.0 T in children and to assess its diagnostic ability in answering the clinical query. Also, to determine the frequency of artefacts and anatomic variations in ductal anatomy. METHODS: Consecutive MRCPs performed in children using a 3-T scanner were retrospectively reviewed to note indications, findings, imaging diagnosis, normal variants, quality and artefacts. Analysis was performed based on the final diagnosis assigned by pathology or the combination of clinical, laboratory, imaging features and follow-up to determine whether it was possible to answer the clinical query by MRCP findings. RESULTS: There were 82 MRCPs performed at 3.0 T on 77 children. 42/82 (51%) MRCPs were of good quality, 35/82 (43%) MRCPs were suboptimal but diagnostic and the remaining 5/82 (6%) MRCPs were non-diagnostic. MRCP answered the clinical query in 61/82 (74%) cases; however, it did not answer the clinical query in 11/82 (14%) cases and was equivocal in 10/82 (12%) cases. There was significant association between the quality of MRCP and the ability of MRCP to answer the clinical query (p<0.0001). 64/82 (78%) MRCP examinations had at least 1 artefact. Variation in the bile duct anatomy was seen in 27/77 (35%) children. CONCLUSION: MRCP performed at 3.0 T is of diagnostic quality in most cases and is able to provide an answer to the clinical query in the majority of cases. ADVANCES IN KNOWLEDGE: 3-T MRCP is feasible and useful in the assessment of pancreatobiliary abnormalities in children. PMID- 23457193 TI - The carboxyl terminus of Rtt109 functions in chaperone control of histone acetylation. AB - Rtt109 is a fungal histone acetyltransferase (HAT) that catalyzes histone H3 acetylation functionally associated with chromatin assembly. Rtt109-mediated H3 acetylation involves two histone chaperones, Asf1 and Vps75. In vivo, Rtt109 requires both chaperones for histone H3 lysine 9 acetylation (H3K9ac) but only Asf1 for full H3K56ac. In vitro, Rtt109-Vps75 catalyzes both H3K9ac and H3K56ac, whereas Rtt109-Asf1 catalyzes only H3K56ac. In this study, we extend the in vitro chaperone-associated substrate specificity of Rtt109 by showing that it acetylates vertebrate linker histone in the presence of Vps75 but not Asf1. In addition, we demonstrate that in Saccharomyces cerevisiae a short basic sequence at the carboxyl terminus of Rtt109 (Rtt109C) is required for H3K9ac in vivo. Furthermore, through in vitro and in vivo studies, we demonstrate that Rtt109C is required for optimal H3K56ac by the HAT in the presence of full-length Asf1. When Rtt109C is absent, Vps75 becomes important for H3K56ac by Rtt109 in vivo. In addition, we show that lysine 290 (K290) in Rtt109 is required in vivo for Vps75 to enhance the activity of the HAT. This is the first in vivo evidence for a role for Vps75 in H3K56ac. Taken together, our results contribute to a better understanding of chaperone control of Rtt109-mediated H3 acetylation. PMID- 23457196 TI - Circulating microRNAs: what is their relevance? PMID- 23457195 TI - Primary mediastinal large B-cell lymphoma segregating in a family: exome sequencing identifies MLL as a candidate predisposition gene. AB - Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B cell lymphoma (DLBCL) accounting for 2% to 4% of all non-Hodgkin lymphomas. We report a family of 3 siblings with PMBCL and their cousin with extranodal DLBCL. The histopathological characteristics of lymphomas of all 4 patients are similar, implying post-germinal center differentiation and growth deregulation by other mechanisms than BCL2-mediated inhibition of apoptosis and suggesting a shared biological background. We aimed to identify the genetic defect underlying lymphoma susceptibility in this family using exome sequencing and linkage analysis. The only variant segregating in all 4 patients and not reported in genetic databases was 5533C>A (His1845Asn) in the MLL gene. To our knowledge, this is the first time when familial clustering of PMBCL is reported. Although we propose MLL as a candidate predisposition gene for this condition, this finding needs to be validated in additional cases. PMID- 23457197 TI - Alcohol use disorders in adolescents. PMID- 23457198 TI - Pediatric neck masses. PMID- 23457199 TI - Pediatric vision screening. PMID- 23457200 TI - Fever and bacteremia. PMID- 23457201 TI - Index of suspicion. Case 1: Daily fevers, rash, myalgia, arthralgia, and hepatomegaly in a teen-age girl. Case 2: Subcutaneous nodules and arthritis in an 11-year-old boy. Case 3: Fever, fatigue, cervical lymphadenopathy, and hepatosplenomegaly in a 3-year-old boy. PMID- 23457202 TI - Otitis externa. PMID- 23457203 TI - International adoption. PMID- 23457204 TI - Visual diagnosis: 2-week-old has a red, peeling rash. PMID- 23457205 TI - Scaffolds for partial meniscal replacement: an updated systematic review. AB - INTRODUCTION: Meniscectomy, a most common orthopaedic procedure, results in increased contact area of the articular surfaces of tibia and femur leading to early osteoarthritis. We systematically review the literature on clinical outcomes following partial meniscal replacement using different scaffolds. SOURCES OF DATA: We performed a comprehensive search of Medline, CINAHL, Embase and the Cochrane Central Registry of Controlled Trials. The reference lists of the selected articles were then examined by hand. Only studies focusing on investigation of clinical outcomes on patients undergoing a partial meniscal replacement using a scaffold were selected. We then evaluated the methodological quality of each article using the Coleman methodology score (CMS), a 10 criteria scoring list assessing the methodological quality of the selected studies (CMS). AREAS OF AGREEMENT: Fifteen studies were included, all prospective studies, but only 2 were randomized controlled trials. Biological scaffolds were involved in 12 studies, 2 studies investigated synthetic scaffolds, whereas 1 remaining article presented data from the use of both classes of device. The mean modified CMS was 64.6. AREAS OF CONTROVERSY: Several demographic and biomechanical factors could influence the outcomes of this treatment modality. GROWING POINTS: Partial replacement using both classes of scaffolds achieves significant and encouraging improved clinical results when compared with baseline values or with controls when present, without no adverse reaction related to the device. RESEARCH: There is a need for more and better designed randomized trials, to confirm with a stronger level of evidence the promising preliminary results achieved by the current research. PMID- 23457206 TI - Nuclear receptors and their selective pharmacologic modulators. AB - Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators. PMID- 23457207 TI - A new diagnostic tool with the potential to predict tumor metastasis. PMID- 23457209 TI - Palliative care programs still face obstacles in mainstream cancer care. PMID- 23457210 TI - Will prescriptions for cultural change improve the NHS? PMID- 23457211 TI - WHO is urged to exclude alcohol industry from talks on reducing harms. PMID- 23457212 TI - Consultants' contract of 2003 is my biggest regret, Milburn says. PMID- 23457213 TI - Promotion of physical activity and fitness in sedentary patients with Parkinson's disease: randomised controlled trial. AB - OBJECTIVE: To evaluate whether a multifaceted behavioural change programme increases physical activities in patients with Parkinson's disease. DESIGN: Multicentre randomised controlled trial. SETTING: 32 community hospitals in the Netherlands, collaborating in a nationwide network (ParkinsonNet). PARTICIPANTS: 586 sedentary patients with idiopathic Parkinson's disease aged between 40 and 75 years with mild to moderate disease severity (Hoehn and Yahr stage <= 3). INTERVENTION: Patients were randomly assigned to the ParkFit programme or a matched general physiotherapy intervention. ParkFit is a multifaceted behavioural change programme, designed specifically to achieve an enduring increase in the level of physical activity (coaches using motivational strategies; ambulatory feedback). MAIN OUTCOME MEASURES: The primary endpoint was the level of physical activity, measured every six months with a standardised seven day recall (LASA physical activity questionnaire-LAPAQ). Secondary endpoints included two other measures of physical activity (activity diary and ambulatory activity monitor), quality of life (Parkinson's disease questionnaire-PDQ-39), and fitness (six minute walk test). RESULTS: 540 (92.2%) patients completed the primary outcome. During follow-up, overall time spent on physical activities (LAPAQ) was comparable between the groups (adjusted group difference 7%, 95% confidence interval -3 to 17%; P=0.19). Analyses of three secondary outcomes indicated increased physical activity in ParkFit patients, as suggested by the activity diary (difference 30%; P<0.001), the activity monitor (difference 12%; P<0.001), and the six minute walk test (difference 4.8 m; P=0.05). PDQ-39 did not differ between ParkFit patients and controls (difference -0.9 points; P=0.14). The number of fallers was comparable between ParkFit patients (184/299; 62%) and controls (191/287; 67%). CONCLUSIONS: The ParkFit behavioural change programme did not increase overall physical activity, as measured with the LAPAQ. The analysis of the secondary endpoints justifies further work into the possible merits of behavioural change programmes to increase physical activities in daily life in Parkinson's disease. TRIAL REGISTRATION: Clinical trials NCT00748488. PMID- 23457214 TI - Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress. AB - Proteasome is central to proteostasis maintenance, as it degrades both normal and damaged proteins. Herein, we undertook a detailed analysis of proteasome regulation in the in vivo setting of Drosophila melanogaster. We report that a major hallmark of somatic tissues of aging flies is the gradual accumulation of ubiquitinated and carbonylated proteins; these effects correlated with a ~50% reduction of proteasome expression and catalytic activities. In contrast, gonads of aging flies were relatively free of proteome oxidative damage and maintained substantial proteasome expression levels and highly active proteasomes. Moreover, gonads of young flies were found to possess more abundant and more active proteasomes than somatic tissues. Exposure of flies to oxidants induced higher proteasome activities specifically in the gonads, which were, independently of age, more resistant than soma to oxidative challenge and, as analyses in reporter transgenic flies showed, retained functional antioxidant responses. Finally, inducible Nrf2 activation in transgenic flies promoted youthful proteasome expression levels in the aged soma, suggesting that age-dependent Nrf2 dysfunction is causative of decreasing somatic proteasome expression during aging. The higher investment in proteostasis maintenance in the gonads plausibly facilitates proteome stability across generations; it also provides evidence in support of the trade-off theories of aging. PMID- 23457215 TI - Spaceflight-induced alterations in cerebral artery vasoconstrictor, mechanical, and structural properties: implications for elevated cerebral perfusion and intracranial pressure. AB - Evidence indicates that cerebral blood flow is both increased and diminished in astronauts on return to Earth. Data from ground-based animal models simulating the effects of microgravity have shown that decrements in cerebral perfusion are associated with enhanced vasoconstriction and structural remodeling of cerebral arteries. Based on these results, the purpose of this study was to test the hypothesis that 13 d of spaceflight [Space Transportation System (STS)-135 shuttle mission] enhances myogenic vasoconstriction, increases medial wall thickness, and elicits no change in the mechanical properties of mouse cerebral arteries. Basilar and posterior communicating arteries (PCAs) were isolated from 9-wk-old female C57BL/6 mice for in vitro vascular and mechanical testing. Contrary to that hypothesized, myogenic vasoconstrictor responses were lower and vascular distensibility greater in arteries from spaceflight group (SF) mice (n=7) relative to ground-based control group (GC) mice (n=12). Basilar artery maximal diameter was greater in SF mice (SF: 236+/-9 MUm and GC: 215+/-5 MUm) with no difference in medial wall thickness (SF: 12.4+/-1.6 MUm; GC: 12.2+/-1.2 MUm). Stiffness of the PCA, as characterized via nanoindentation, was lower in SF mice (SF: 3.4+/-0.3 N/m; GC: 5.4+/-0.8 N/m). Collectively, spaceflight-induced reductions in myogenic vasoconstriction and stiffness and increases in maximal diameter of cerebral arteries signify that elevations in brain blood flow may occur during spaceflight. Such changes in cerebral vascular control of perfusion could contribute to increases in intracranial pressure and an associated impairment of visual acuity in astronauts during spaceflight. PMID- 23457216 TI - HSulf sulfatases catalyze processive and oriented 6-O-desulfation of heparan sulfate that differentially regulates fibroblast growth factor activity. AB - Sulfs are extracellular sulfatases that have emerged recently as critical regulators of heparan sulfate (HS) activities through their ability to catalyze specific 6-O-desulfation of the polysaccharide. Consequently, Sulfs have been involved in many physiological and pathological processes, and notably for Sulf 2, in the development of cancers with poor prognosis. Despite growing interest, little is known about the structure and activity of these enzymes and the way they induce dynamic remodeling of HS 6-O-sulfation status. Here, we have combined an array of analytical approaches, including mass spectrometry, NMR, HS oligosaccharide sequencing, and FACS, to dissect HSulf-2 sulfatase activity, either on a purified octasaccharide used as a mimic of HS functional domains, or on intact cell-surface HS chains. In parallel, we have studied the functional consequences of HSulf-2 activity on fibroblast growth factor (FGF)-induced mitogenesis and found that the enzyme could differentially regulate FGF1 and FGF2 activities. Notably, these data supported the existence of precise 6-O-sulfation patterns for FGF activation and provided new insights into the saccharide structures involved. Altogether, our data bring to light an original processive enzymatic mechanism, by which HSulfs catalyze oriented alteration of HS 6-O desulfation patterns and direct fine and differential regulation of HS functions. PMID- 23457217 TI - miR-145 regulates myofibroblast differentiation and lung fibrosis. AB - The expression of smooth muscle actin-alpha (SMA-alpha) by fibroblasts defines phenotypic transition to myofibroblasts and is a primary contributor to contractile force generation by these differentiated cells. Although the regulation of SMA-alpha expression has been the focus of many studies, there is presently only limited information concerning miRNA regulation of lung myofibroblast differentiation and the involvement of these miRNAs in pulmonary fibrosis. To determine the role of miR-145 in regulating lung myofibroblast differentiation and pulmonary fibrosis. Wild-type and miR-145(-/-) mice were studied. Lung fibrosis models and cell culture systems were employed. miR-145 mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic and contractile activities of lung fibroblasts were determined. We found that miR-145 expression is upregulated in TGF-beta1-treated lung fibroblasts. miR-145 expression is also increased in the lungs of patients with idiopathic pulmonary fibrosis as compared to in normal human lungs. Overexpression of miR-145 in lung fibroblasts increased SMA-alpha expression, enhanced contractility, and promoted formation of focal and fibrillar adhesions. In contrast, miR-145 deficiency diminished TGF-beta1 induced SMA-alpha expression. miR-145 did not affect the activity of TGF-beta1, but promoted the activation of latent TGF-beta1. miR-145 targets KLF4, a known negative regulator of SMA-alpha expression. Finally, we found that miR-145(-/-) mice are protected from bleomycin-induced pulmonary fibrosis. miR-145 plays an important role in the differentiation of lung myofibroblasts. miR-145 deficiency is protective against bleomycin-induced lung fibrosis, suggesting that miR-145 may be a potential target in the development of novel therapies to treat pathological fibrotic disorders. PMID- 23457218 TI - Platelet neuropeptide Y is critical for ischemic revascularization in mice. AB - We previously reported that the sympathetic neurotransmitter neuropeptide Y (NPY) is potently angiogenic, primarily through its Y2 receptor, and that endogenous NPY is crucial for capillary angiogenesis in rodent hindlimb ischemia. Here we sought to identify the source of NPY responsible for revascularization and its mechanisms of action. At d 3, NPY(-/-) mice demonstrated delayed recovery of blood flow and limb function, consistent with impaired collateral conductance, while ischemic capillary angiogenesis was reduced (~70%) at d 14. This biphasic temporal response was confirmed by 2 peaks of NPY activation in rats: a transient early increase in neuronally derived plasma NPY and increase in platelet NPY during late-phase recovery. Compared to NPY-null platelets, collagen-activated NPY-rich platelets were more mitogenic (~2-fold vs. ~1.6-fold increase) for human microvascular endothelial cells, and Y2/Y5 receptor antagonists ablated this difference in proliferation. In NPY(+/+) mice, ischemic angiogenesis was prevented by platelet depletion and then restored by transfusion of platelets from NPY(+/+) mice, but not NPY(-/-) mice. In thrombocytopenic NPY(-/-) mice, transfusion of wild-type platelets fully restored ischemia-induced angiogenesis. These findings suggest that neuronally derived NPY accelerates the early response to femoral artery ligation by promoting collateral conductance, while platelet derived NPY is critical for sustained capillary angiogenesis. PMID- 23457220 TI - Cerebral desaturations in preterm infants: a crossover trial on influence of oxygen saturation target range. AB - OBJECTIVE: To test the hypothesis that a higher pulsoximetric arterial oxygen saturation (SpO2) target range is associated with reduced cerebral tissue oxygen desaturations from baseline during events of hypoxaemia or bradycardia. DESIGN: Randomised crossover trial. SETTING: Single tertiary care neonatal intensive care unit. PATIENTS: Sixteen preterm infants with severe intermittent hypoxaemia or bradycardia. INTERVENTIONS: SpO2 target was set to 80-92% and 85-96% for 4 h each in random sequence. On a subsequent day, the target sequence was reversed and the study was repeated. MAIN OUTCOME MEASURES: We simultaneously recorded cerebral tissue oxygen saturation (cerebral StO2), SpO2 and heart rate. Cerebral StO2 was measured by near infrared spectroscopy. The primary outcome was the cumulative cerebral StO2 desaturation score representing the area below a cerebral StO2 baseline value before onset of each hypoxaemic or bradycardic event. RESULTS: During low SpO2 target range the median (IQR) cumulative cerebral StO2 desaturation score was higher (27384 (15825-37396) vs 18103 (6964-32946), p=0.011) and the mean (+/-SD) number of events was higher (29.1 (+/-15.3) vs 21.1 (+/-11.4), p=0.001). More time was spent with SpO2 below 80% (57.2 (+/-24.8) min vs 34.0 (+/-29.6) min, p=0.006). Total time of hyperoxaemia (defined as SpO2 >=97% and >=99%, respectively) and total time with cerebral StO2 <60% and <55% were similar. CONCLUSIONS: A lower SpO2 target range was associated with a greater cumulative cerebral StO2 desaturation score, caused by more frequent SpO2 desaturations. However, time at very low cerebral StO2 was not affected. Episodes of hyperoxaemia were not reduced. PMID- 23457219 TI - A copper sulfate and hydroxylysine treatment regimen for enhancing collagen cross linking and biomechanical properties in engineered neocartilage. AB - The objective of this study was to improve the biomechanical properties of engineered neotissues through promoting the development of collagen cross-links. It was hypothesized that supplementing medium with copper sulfate and the amino acid hydroxylysine would enhance the activity of lysyl oxidase enzyme to form collagen cross-links, increasing the strength and integrity of the neotissue. Neocartilage constructs were generated using a scaffoldless, self-assembling process and treated with copper sulfate and hydroxylysine, either alone or in combination, following a 2-factor, full-factorial study design. Following a 6-wk culture period, the biomechanical and biochemical properties of the constructs were measured. Results found copper sulfate to significantly increase pyridinoline (PYR) cross-links in all copper sulfate-containing groups over controls. When copper sulfate and hydroxylysine were combined, the result was synergistic, with a 10-fold increase in PYR content over controls. This increase in PYR cross-links manifested in a 3.3-fold significant increase in the tensile properties of the copper sulfate + hydroxylysine group. In addition, an 123% increase over control values was detected in the copper sulfate group in terms of the aggregate modulus. These data elucidate the role of copper sulfate and hydroxylysine toward improving the biomechanical properties of neotissues through collagen cross-linking enhancement. PMID- 23457221 TI - Fasciculation potentials: a diagnostic biomarker of early ALS? PMID- 23457222 TI - Safety and efficacy of gravitational shunt valves in patients with idiopathic normal pressure hydrocephalus: a pragmatic, randomised, open label, multicentre trial (SVASONA). AB - OBJECTIVES: To investigate whether gravitational valves reduce the risk of overdrainage complications compared with programmable valves in ventriculoperitoneal (VP) shunt surgery for idiopathic normal pressure hydrocephalus (iNPH). BACKGROUND: Patients with iNPH may benefit from VP shunting but are prone to overdrainage complications during posture changes. Gravitational valves with tantalum balls are considered to reduce the risk of overdrainage but their clinical effectiveness is unclear. METHODS: We conducted a pragmatic, randomised, multicentre trial comparing gravitational with non-gravitational programmable valves in patients with iNPH eligible for VP shunting. The primary endpoint was any clinical or radiological sign (headache, nausea, vomiting, subdural effusion or slit ventricle) of overdrainage 6 months after randomisation. We also assessed disease specific instruments (Black and Kiefer Scale) and Physical and Mental Component Scores of the Short Form 12 (SF-12) generic health questionnaire. RESULTS: We enrolled 145 patients (mean (SD) age 71.9 (6.9) years), 137 of whom were available for endpoint analysis. After 6 months, 29 patients in the standard and five patients in the gravitational shunt group developed overdrainage (risk difference -36%, 95% CI -49% to -23%; p<0.001). This difference exceeded predetermined stopping rules and resulted in premature discontinuation of patient recruitment. Disease specific outcome scales did not differ between the groups although there was a significant advantage of the gravitational device in the SF-12 Mental Component Scores at the 6 and 12 month visits. CONCLUSIONS: Implanting a gravitational rather than another type of valve will avoid one additional overdrainage complication in about every third patient undergoing VP shunting for iNPH. PMID- 23457224 TI - The strange sensation of deja vu: not so strange in temporal lobe epilepsy. PMID- 23457223 TI - Ion channel disorders: still a fascinating topic--news on episodic ataxia type 1. PMID- 23457225 TI - Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes. AB - BACKGROUND: Cognitive impairment and dementia are common after stroke. It is unclear if risk differs between ischaemic stroke subtypes. Lacunar strokes might be less likely to affect cognition than more severe, larger cortical strokes, except that lacunar strokes are associated with cerebral small vessel disease (SVD), which is the commonest vascular cause of dementia. METHODS: We searched MEDLINE and PsychINFO for studies of mild cognitive impairment (MCI) or dementia after lacunar or cortical ischaemic stroke. We calculated the OR for cognitive impairment/dementia in lacunar versus non-lacunar stroke, and their incidence and prevalence in lacunar stroke as a pooled proportion. FINDINGS: We identified 24 relevant studies of 7575 patients, including 2860 with lacunar stroke; 24% had MCI or dementia post stroke. Similar proportions of patients with lacunar and non lacunar stroke (16 studies, n=6478) had MCI or dementia up to 4 years after stroke (OR 0.72 (95% CI 0.43 to 1.20)). The prevalence of dementia after lacunar stroke (six studies, n=1421) was 20% (95% CI 9 to 33) and the incidence of MCI or dementia (four studies, n=275) was 37% (95% CI 23 to 53). Data were limited by short follow-up, subtype classification methods and confounding. INTERPRETATION: Cognitive impairment appears to be common after lacunar strokes despite their small size, suggesting that associated SVD may increase their impact. New prospective studies are required with accurate stroke subtyping to assess long term outcomes while accounting for confounders. PMID- 23457226 TI - Autophagy contributes to nighttime energy availability for growth in Arabidopsis. AB - Autophagy is an intracellular process leading to the vacuolar degradation of cytoplasmic components. Autophagic degradation of chloroplasts is particularly activated in leaves under conditions of low sugar availability. Here, we investigated the importance of autophagy in the energy availability and growth of Arabidopsis (Arabidopsis thaliana). autophagy-deficient (atg) mutants showed reduced growth under short-day conditions. This growth inhibition was largely relieved under continuous light or under short-day conditions combined with feeding of exogenous sucrose, suggesting that autophagy is involved in energy production at night for growth. Arabidopsis accumulates starch during the day and degrades it for respiration at night. Nighttime energy availability is perturbed in starchless mutants, in which a lack of starch accumulation causes a transient sugar deficit at night. We generated starchless and atg double mutants and grew them under different photoperiods. The double mutants showed more severe phenotypes than did atg or starchless single mutants: reduced growth and early cell death in leaves were observed when plants were grown under 10-h photoperiods. Transcript analysis of dark-inducible genes revealed that the sugar starvation symptoms observed in starchless mutants became more severe in starchless atg double mutants. The contents of free amino acids (AAs) increased, and transcript levels of several genes involved in AA catabolism were elevated in starchless mutant leaves. The increases in branched-chain AA and aromatic AA contents were partially compromised in starchless atg double mutants. We conclude that autophagy can contribute to energy availability at night by providing a supply of alternative energy sources such as AAs. PMID- 23457227 TI - Protein-coding cis-natural antisense transcripts have high and broad expression in Arabidopsis. AB - Pairs of genes within eukaryotic genomes are often located on opposite DNA strands such that transcription generates cis-natural sense antisense transcripts (cis-NATs). This orientation of genes has been associated with the biogenesis of splice variants and natural antisense small RNAs. Here, in an analysis of currently available data, we report that within Arabidopsis (Arabidopsis thaliana), protein-coding cis-NATs are also characterized by high abundance, high coexpression, and broad expression. Our results suggest that a permissive chromatin environment may have led to the proximity of these genes. Compared with other genes, cis-NAT-encoding genes have enriched low-nucleosome-density regions, high levels of histone H3 lysine-9 acetylation, and low levels of H3 lysine-27 trimethylation. Promoters associated with broadly expressed genes are preferentially found in the 5' regulatory sequences of cis-NAT-encoding genes. Our results further suggest that natural antisense small RNA production from cis NATs is limited. Small RNAs sequenced from natural antisense small RNA biogenesis mutants including dcl1, dcl2, dcl3, and rdr6 map to cis-NATs as frequently as small RNAs sequenced from wild-type plants. Future work will investigate if the positive transcriptional regulation of overlapping protein-coding genes contributes to the prevalence of these genes within other eukaryotic genomes. PMID- 23457228 TI - Correlative imaging of fluorescent proteins in resin-embedded plant material. AB - Fluorescent proteins (FPs) were developed for live-cell imaging and have revolutionized cell biology. However, not all plant tissues are accessible to live imaging using confocal microscopy, necessitating alternative approaches for protein localization. An example is the phloem, a tissue embedded deep within plant organs and sensitive to damage. To facilitate accurate localization of FPs within recalcitrant tissues, we developed a simple method for retaining FPs after resin embedding. This method is based on low-temperature fixation and dehydration, followed by embedding in London Resin White, and avoids the need for cryosections. We show that a palette of FPs can be localized in plant tissues while retaining good structural cell preservation, and that the polymerized block face can be counterstained with cell wall probes. Using this method we have been able to image green fluorescent protein-labeled plasmodesmata to a depth of more than 40 MUm beneath the resin surface. Using correlative light and electron microscopy of the phloem, we were able to locate the same FP-labeled sieve elements in semithin and ultrathin sections. Sections were amenable to antibody labeling, and allowed a combination of confocal and superresolution imaging (three-dimensional-structured illumination microscopy) on the same cells. These correlative imaging methods should find several uses in plant cell biology. PMID- 23457230 TI - Glycosylation defects as an emerging novel cause leading to a limb-girdle type of congenital myasthenic syndromes. PMID- 23457229 TI - AGAMOUS-Like15 promotes somatic embryogenesis in Arabidopsis and soybean in part by the control of ethylene biosynthesis and response. AB - Many of the regulatory processes occurring during plant embryogenesis are still unknown. Relatively few cells are involved, and they are embedded within maternal tissues, making this developmental phase difficult to study. Somatic embryogenesis is a more accessible system, and many important regulatory genes appear to function similar to zygotic development, making somatic embryogenesis a valuable model for the study of zygotic processes. To better understand the role of the Arabidopsis (Arabidopsis thaliana) MADS factor AGAMOUS-Like15 (AGL15) in the promotion of somatic embryogenesis, direct target genes were identified by chromatin immunoprecipitation-tiling arrays and expression arrays. One potential directly up-regulated target was At5g61590, which encodes a member of the ethylene response factor subfamily B-3 of APETALA2/ethylene response factor transcription factors and is related to Medicago truncatula somatic embryo related factor1 (MtSERF1), which has been shown to be required for somatic embryogenesis in M. truncatula. Here, we report confirmation that At5g61590 is a directly expressed target of AGL15 and that At5g61590 is essential for AGL15's promotion of somatic embryogenesis. Because At5g61590 is a member of the ethylene response factor family, effects of ethylene on somatic embryogenesis were investigated. Precursors to ethylene stimulate somatic embryogenesis, whereas inhibitors of ethylene synthesis or perception reduce somatic embryogenesis. To extend findings to a crop plant, we investigated the effects of ethylene on somatic embryogenesis in soybean (Glycine max). Furthermore, we found that a potential ortholog of AGL15 in soybean (GmAGL15) up-regulates ethylene biosynthesis and response, including direct regulation of soybean orthologs of At5g61590/MtSERF1 named here GmSERF1 and GmSERF2, in concordance with the M. truncatula nomenclature. PMID- 23457231 TI - Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis. METHODS: We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias. RESULTS: 58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE epsilon4 with CAA (epsilon4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE epsilon2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor beta1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (~200 participants) of APOE and hereditary CAA or familial Alzheimer's disease. CONCLUSIONS: There is convincing evidence for a dose dependent association between APOE epsilon4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA. PMID- 23457232 TI - Identifying loci under selection against gene flow in isolation-with-migration models. AB - When divergence occurs in the presence of gene flow, there can arise an interesting dynamic in which selection against gene flow, at sites associated with population-specific adaptations or genetic incompatibilities, can cause net gene flow to vary across the genome. Loci linked to sites under selection may experience reduced gene flow and may experience genetic bottlenecks by the action of nearby selective sweeps. Data from histories such as these may be poorly fitted by conventional neutral model approaches to demographic inference, which treat all loci as equally subject to forces of genetic drift and gene flow. To allow for demographic inference in the face of such histories, as well as the identification of loci affected by selection, we developed an isolation-with migration model that explicitly provides for variation among genomic regions in migration rates and/or rates of genetic drift. The method allows for loci to fall into any of multiple groups, each characterized by a different set of parameters, thus relaxing the assumption that all loci share the same demography. By grouping loci, the method can be applied to data with multiple loci and still have tractable dimensionality and statistical power. We studied the performance of the method using simulated data, and we applied the method to study the divergence of two subspecies of European rabbits (Oryctolagus cuniculus). PMID- 23457233 TI - Intragenomic conflict between the two major knob repeats of maize. AB - Examples of meiotic drive, the non-Mendelian segregation of a specific genomic region, have been identified in several eukaryotic species. Maize contains the abnormal chromosome 10 (Ab10) drive system that transforms typically inert heterochromatic knobs into centromere-like domains (neocentromeres) that move rapidly poleward along the spindle during meiosis. Knobs can be made of two different tandem repeat sequences (TR-1 and 180-bp repeat), and both repeats have become widespread in Zea species. Here we describe detailed studies of a large knob on chromosome 10 called K10L2. We show that the knob is composed entirely of the TR-1 repeat and is linked to a strong activator of TR-1 neocentromere activity. K10L2 shows weak meiotic drive when paired with N10 but significantly reduces the meiotic drive exhibited by Ab10 (types I or II) in Ab10/K10L2 heterozygotes. These and other data confirm that (1) there are two separate and independent neocentromere activities in maize, (2) that both the TR-1 and knob 180 repeats exhibit meiotic drive (in the presence of other drive genes), and (3) that the two repeats can operate in competition with each other. Our results support the general concept that tandem repeat arrays can engage in arms-race like struggles and proliferate as an outcome. PMID- 23457234 TI - The SWI/SNF chromatin remodeling complex selectively affects multiple aspects of serotonergic neuron differentiation. AB - Regulatory programs that control the specification of serotonergic neurons have been investigated by genetic mutant screens in the nematode Caenorhabditis elegans. Loss of a previously uncloned gene, ham-3, affects migration and serotonin antibody staining of the hermaphrodite-specific neuron (HSN) pair. We characterize these defects here in more detail, showing that the defects in serotonin antibody staining are paralleled by a loss of the transcription of all genes involved in serotonin synthesis and transport. This loss is specific to the HSN class as other serotonergic neurons appear to differentiate normally in ham-3 null mutants. Besides failing to migrate appropriately, the HSNs also display axon pathfinding defects in ham-3 mutants. However, the HSNs are still generated and express a subset of their terminal differentiation features in ham-3 null mutants, demonstrating that ham-3 is a specific regulator of select features of the HSNs. We show that ham-3 codes for the C. elegans ortholog of human BAF60, Drosophila Bap60, and yeast Swp73/Rsc6, which are subunits of the yeast SWI/SNF and vertebrate BAF chromatin remodeling complex. We show that the effect of ham-3 on serotonergic fate can be explained by ham-3 regulating the expression of the Spalt/SALL-type Zn finger transcription factor sem-4, a previously identified regulator of serotonin expression in HSNs and of the ham-2 Zn transcription factor, a previously identified regulator of HSN migration and axon outgrowth. Our findings provide the first evidence for the involvement of the BAF complex in the acquisition of terminal neuronal identity and constitute genetic proof by germline knockout that a BAF complex component can have cell-type-specific roles during development. PMID- 23457235 TI - Effects of genetic drift and gene flow on the selective maintenance of genetic variation. AB - Explanations for the genetic variation ubiquitous in natural populations are often classified by the population-genetic processes they emphasize: natural selection or mutation and genetic drift. Here we investigate models that incorporate all three processes in a spatially structured population, using what we call a construction approach, simulating finite populations under selection that are bombarded with a steady stream of novel mutations. As expected, the amount of genetic variation compared to previous models that ignored the stochastic effects of drift was reduced, especially for smaller populations and when spatial structure was most profound. By contrast, however, for higher levels of gene flow and larger population sizes, the amount of genetic variation found after many generations was greater than that in simulations without drift. This increased amount of genetic variation is due to the introduction of slightly deleterious alleles by genetic drift and this process is more efficient when migration load is higher. The incorporation of genetic drift also selects for fitness sets that exhibit allele-frequency equilibria with larger domains of attraction: they are "more stable." Moreover, the finiteness of populations strongly influences levels of local adaptation, selection strength, and the proportion of allele-frequency vectors that can be distinguished from the neutral expectation. PMID- 23457237 TI - Global cancer risk from Fukushima is low, says WHO. PMID- 23457238 TI - UK regulator is to take lighter approach to drug advertisements. PMID- 23457236 TI - The nuclear argonaute NRDE-3 contributes to transitive RNAi in Caenorhabditis elegans. AB - The Caenorhabditis elegans nuclear RNA interference defective (Nrde) mutants were identified by their inability to silence polycistronic transcripts in enhanced RNAi (Eri) mutant backgrounds. Here, we report additional nrde-3-dependent RNAi phenomena that extend the mechanisms, roles, and functions of nuclear RNAi. We show that nrde-3 mutants are broadly RNAi deficient and that overexpressing NRDE 3 enhances RNAi. Consistent with NRDE-3 being a dose-dependent limiting resource for effective RNAi, we find that NRDE-3 is required for eri-dependent enhanced RNAi phenotypes, although only for a subset of target genes. We then identify pgl 1 as an additional limiting RNAi resource important for eri-dependent silencing of a nonoverlapping subset of target genes, so that an nrde-3; pgl-1; eri-1 triple mutant fails to show enhanced RNAi for any tested gene. These results suggest that nrde-3 and pgl-1 define separate and independent limiting RNAi resource pathways. Limiting RNAi resources are proposed to primarily act via endogenous RNA silencing pathways. Consistent with this, we find that nrde-3 mutants misexpress genes regulated by endogenous siRNAs and incompletely silence repetitive transgene arrays. Finally, we find that nrde-3 contributes to transitive RNAi, whereby amplified silencing triggers act in trans to silence sequence-similar genes. Because nrde-dependent silencing is thought to act in cis to limit the production of primary transcripts, this result reveals an unexpected role for nuclear processes in RNAi silencing. PMID- 23457239 TI - Regulator is set to call in administrators to rescue Mid Staffordshire trust. PMID- 23457240 TI - Israeli doctors are given conflicting advice on treating hunger strikers. PMID- 23457241 TI - Survival from breast cancer is lower in UK than in other developed countries. PMID- 23457242 TI - Russia to restrict smoking in public places from June. PMID- 23457243 TI - Francis won't be drawn on resignation of NHS head in wake of Mid Staffordshire inquiry. PMID- 23457244 TI - S1 and KH domains of polynucleotide phosphorylase determine the efficiency of RNA binding and autoregulation. AB - To better understand the roles of the KH and S1 domains in RNA binding and polynucleotide phosphorylase (PNPase) autoregulation, we have identified and investigated key residues in these domains. A convenient pnp::lacZ fusion reporter strain was used to assess autoregulation by mutant PNPase proteins lacking the KH and/or S1 domains or containing point mutations in those domains. Mutant enzymes were purified and studied by using in vitro band shift and phosphorolysis assays to gauge binding and enzymatic activity. We show that reductions in substrate affinity accompany impairment of PNPase autoregulation. A remarkably strong correlation was observed between beta-galactosidase levels reflecting autoregulation and apparent KD values for the binding of a model RNA substrate. These data show that both the KH and S1 domains of PNPase play critical roles in substrate binding and autoregulation. The findings are discussed in the context of the structure, binding sites, and function of PNPase. PMID- 23457245 TI - The tRNA thiolation pathway modulates the intracellular redox state in Escherichia coli. AB - We have performed a screening of hydroxyurea (HU)-sensitive mutants using a single-gene-deletion mutant collection in Escherichia coli K-12. HU inhibits ribonucleotide reductase (RNR), an enzyme that catalyzes the formation of deoxyribonucleotides. Unexpectedly, seven of the mutants lacked genes that are required for the incorporation of sulfur into a specific tRNA modification base, 5-methylaminomethyl-2-thiouridine (mnm(5)s(2)U), via persulfide relay. We found that the expression of RNR in the mutants was reduced to about one-third both in the absence and presence of HU, while sufficient deoxynucleoside triphosphate (dNTP) was maintained in the mutants in the absence of HU but a shortage occurred in the presence of HU. Trans-supply of an RNR R2 subunit rescued the HU sensitivity of these mutants. The mutants showed high intracellular ATP/ADP ratios, and overexpression of Hda, which catalyzes the conversion of DnaA-ATP to DnaA-ADP, rescued the HU sensitivity of the mutants, suggesting that DnaA-ATP represses RNR expression. The high intracellular ATP/ADP ratios were due to high respiration activity in the mutants. Our data suggested that intracellular redox was inclined toward the reduced state in these mutants, which may explain a change in RNR activity by reduction of the catalytically formed disulfide bond and high respiration activity by the NADH reducing potential. The relation between persulfide relay and intracellular redox is discussed. PMID- 23457246 TI - Structural analysis of succinoglycan oligosaccharides from Sinorhizobium meliloti strains with different host compatibility phenotypes. AB - Sinorhizobium meliloti NRG247 has a Fix(+) phenotype on Medicago truncatula A20 and is Fix(-) on M. truncatula A17, and the phenotype is reversed with S. meliloti NRG185. As the succinoglycan was shown to impact host specificity, an analysis of the succinoglycan oligosaccharides produced by each strain was conducted. The symbiotically active succinoglycan trimeric oligosaccharides (STOs) from the two S. meliloti strains were compared by chromatography and mass spectrometry, and the analysis of the S. meliloti NRG247 oligosaccharides showed that this strain produces an abundance of STO trimer 1 (T1), containing no succinate (i.e., three nonsuccinylated repeats), yet the low-molecular-weight pool contained no nonsuccinylated monomers (potential repeats). This showed that STO T1 is likely to be the active signal on M. truncatula A20 and that the biosynthesis of the STOs is not a random polymerization of the monomer population. The results also suggest that the fully succinylated STO T7 is required for the infection of M. truncatula A17. PMID- 23457247 TI - FtsZ ring stability: of bundles, tubules, crosslinks, and curves. AB - The first step in bacterial cytokinesis is the assembly of a stable but dynamic cytokinetic ring made up of the essential tubulin homolog FtsZ at the future site of division. Although FtsZ and its role in cytokinesis have been studied extensively, the precise architecture of the in vivo medial FtsZ ring (Z ring) is not well understood. Recent advances in superresolution imaging suggest that the Z ring comprises short, discontinuous, and loosely bundled FtsZ polymers, some of which are tethered to the membrane. A diverse array of regulatory proteins modulate the assembly, stability, and disassembly of the Z ring via direct interactions with FtsZ. Negative regulators of FtsZ play a critical role in ensuring the accurate positioning of FtsZ at the future site of division and in maintaining Z ring dynamics by controlling FtsZ polymer assembly/disassembly processes. Positive regulators of FtsZ are essential for tethering FtsZ polymers to the membrane and promoting the formation of stabilizing lateral interactions, permitting assembly of a mature Z ring. The past decade has seen the identification of several factors that promote FtsZ assembly, presumably through a variety of distinct molecular mechanisms. While a few of these proteins are broadly conserved, many positive regulators of FtsZ assembly are limited to small groups of closely related organisms, suggesting that FtsZ assembly is differentially modulated across bacterial species. In this review, we focus on the roles of positive regulators in Z ring assembly and in maintaining the integrity of the cytokinetic ring during the early stages of division. PMID- 23457249 TI - Differential detergent extraction of mycobacterium marinum cell envelope proteins identifies an extensively modified threonine-rich outer membrane protein with channel activity. AB - A striking characteristic of mycobacteria is the presence of an unusual outer membrane which forms a thick permeability barrier and provides resistance to many antibiotics. Although specialized proteins must reside in this layer, only few mycolate outer membrane (MOM) proteins have been identified to date. Their discovery is complicated by difficulties in obtaining good separation of mycobacterial inner and outer membranes. During our efforts to identify novel mycobacterial outer membrane proteins (MOMPs), we discovered that we can enrich for MOMPs using differential solubilization of mycobacterial cell envelopes. Subsequently, these different fractions were analyzed by nano liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). This proteomic analysis confirmed that our marker proteins for inner membrane and MOM were found in their expected fractions and revealed a few interesting candidate MOMPs. A number of these putative MOMPs were further analyzed for their expression and localization in the cell envelope. One identified MOMP, MMAR_0617 of Mycobacterium marinum, was purified and demonstrated to form a large oligomeric complex. Importantly, this protein showed a clear single-channel conductance of 0.8 +/- 0.1 ns upon reconstitution into artificial planar lipid bilayers. The most surprising feature of MMAR_0617 is a long C-terminal threonine-rich domain with extensive modifications. In summary, we have identified a novel mycobacterial outer membrane porin with unusual properties. PMID- 23457248 TI - The stringent response controls catalases in Pseudomonas aeruginosa and is required for hydrogen peroxide and antibiotic tolerance. AB - Pseudomonas aeruginosa, a human opportunistic pathogen, possesses a number of antioxidant defense enzymes under the control of multiple regulatory systems. We recently reported that inactivation of the P. aeruginosa stringent response (SR), a starvation stress response controlled by the alarmone (p)ppGpp, caused impaired antioxidant defenses and antibiotic tolerance. Since catalases are key antioxidant enzymes in P. aeruginosa, we compared the levels of H2O2 susceptibility and catalase activity in P. aeruginosa wild-type and DeltarelA DeltaspoT (DeltaSR) mutant cells. We found that the SR was required for optimal catalase activity and mediated H2O2 tolerance during both planktonic and biofilm growth. Upon amino acid starvation, induction of the SR upregulated catalase activity. Full expression of katA and katB also required the SR, and this regulation occurred through both RpoS-independent and RpoS-dependent mechanisms. Furthermore, overexpression of katA was sufficient to restore H2O2 tolerance and to partially rescue the antibiotic tolerance of DeltaSR cells. All together, these results suggest that the SR regulates catalases and that this is an important mechanism in protecting nutrient-starved and biofilm bacteria from H2O2 and antibiotic-mediated killing. PMID- 23457250 TI - PilMNOPQ from the Pseudomonas aeruginosa type IV pilus system form a transenvelope protein interaction network that interacts with PilA. AB - Pseudomonas aeruginosa type IV pili (T4P) are virulence factors that promote infection of cystic fibrosis and immunosuppressed patients. As the absence of T4P impairs colonization, they are attractive targets for the development of novel therapeutics. Genes in the pilMNOPQ operon are important for both T4P assembly and a form of bacterial movement, called twitching motility, that is required for pathogenicity. The type II membrane proteins, PilN and PilO, dimerize via their periplasmic domains and anchor this complex in the inner membrane. Our earlier work showed that PilNO binds PilP, a periplasmic lipoprotein (S. Tammam, L. M. Sampaleanu, J. Koo, P. Sundaram, M. Ayers, P. A. Chong, J. D. Forman-Kay, L. L. Burrows, and P. L. Howell, Mol. Microbiol. 82:1496-1514, 2011). Here, we show that PilP interacts with the N0 segment of the outer membrane secretin PilQ via its C-terminal domain, and that the N-terminal cytoplasmic tail of PilN binds to the actin-like protein PilM, thereby connecting all cellular compartments via the PilMNOPQ protein interaction network. We show that PilA, the major pilin subunit, interacts with PilNOPQ. The results allow us to propose a model whereby PilA makes extensive contacts with the transenvelope complex, possibly to increase local concentrations of PilA monomers for polymerization. The PilNOP complex could provide a stable anchor in the inner membrane, while the PilMNOPQ transenvelope complex facilitates transit of the pilus through the periplasm and clamps the pilus in the cell envelope. The PilMN interaction is proposed to be responsible for communicating signals from the cytoplasmic to periplasmic components of this complex macromolecular machine. PMID- 23457251 TI - The major outer sheath protein (Msp) of Treponema denticola has a bipartite domain architecture and exists as periplasmic and outer membrane-spanning conformers. AB - The major outer sheath protein (Msp) is a primary virulence determinant in Treponema denticola, as well as the parental ortholog for the Treponema pallidum repeat (Tpr) family in the syphilis spirochete. The Conserved Domain Database (CDD) server revealed that Msp contains two conserved domains, major outer sheath protein(N) (MOSP(N)) and MOSP(C), spanning residues 77 to 286 and 332 to 543, respectively, within the N- and C-terminal regions of the protein. Circular dichroism (CD) spectroscopy, Triton X-114 (TX-114) phase partitioning, and liposome incorporation demonstrated that full-length, recombinant Msp (Msp(Fl)) and a recombinant protein containing MOSP(C), but not MOSP(N), form amphiphilic, beta-sheet-rich structures with channel-forming activity. Immunofluorescence analysis of intact T. denticola revealed that only MOSP(C) contains surface exposed epitopes. Data obtained using proteinase K accessibility, TX-114 phase partitioning, and cell fractionation revealed that Msp exists as distinct OM integrated and periplasmic trimers. Msp(Fl) folded in Tris buffer contained slightly less beta-sheet structure than detergent-folded Msp(Fl); both forms, however, partitioned into the TX-114 detergent-enriched phase. CDD analysis of the nine Tpr paralogs predicted to be outer membrane proteins (OMPs) revealed that seven have an Msp-like bipartite structure; phylogenetic analysis revealed that the MOSP(N) and MOSP(C) domains of Msp are most closely related to those of TprK. Based upon our collective results, we propose a model whereby a newly exported, partially folded intermediate can be either processed for OM insertion by the beta-barrel assembly machinery (BAM) or remain periplasmic, ultimately forming a stable, water-soluble trimer. Extrapolated to T. pallidum, our model enables us to explain how individual Tprs can localize to either the periplasmic (e.g., TprK) or OM (e.g., TprC) compartments. PMID- 23457252 TI - Positive feedback regulation of stgR expression for secondary metabolism in Streptomyces coelicolor. AB - LysR-type transcriptional regulators (LTTRs) compose a large family and are responsible for various physiological functions in bacteria, while little is understood about their regulatory mechanism on secondary metabolism in Streptomyces. Here we reported that StgR, a typical LTTR in Streptomyces coelicolor, was a negative regulator of undecylprodigiosin (Red) and gamma actinorhodin (Act) production in the early developmental phase of secondary metabolism by suppressing the expression of two pathway-specific regulator genes, redD and actII-orf4, respectively. Meanwhile, stgR expression was downregulated during secondary metabolism to remove its repressive effects on antibiotic production. Moreover, stgR expression was positively autoregulated by direct binding of StgR to its own promoter (stgRp), and the binding site adjacent to translation start codon was determined by a DNase I footprinting assay. Furthermore, the StgR-stgRp interaction could be destroyed by the antibiotic gamma-actinorhodin produced from S. coelicolor. Thus, our results suggested a positive feedback regulatory mechanism of stgR expression and antibiotic production for the rapid and irreversible development of secondary metabolism in Streptomyces. PMID- 23457253 TI - 6S-1 RNA function leads to a delay in sporulation in Bacillus subtilis. AB - We have discovered that 6S-1 RNA (encoded by bsrA) is important for appropriate timing of sporulation in Bacillus subtilis in that cells lacking 6S-1 RNA sporulate earlier than wild-type cells. The time to generate a mature spore once the decision to sporulate has been made is unaffected by 6S-1 RNA, and, therefore, we propose that it is the timing of onset of sporulation that is altered. Interestingly, the presence of cells lacking 6S-1 RNA in coculture leads to all cell types exhibiting an early-sporulation phenotype. We propose that cells lacking 6S-1 RNA modify their environment in a manner that promotes early sporulation. In support of this model, resuspension of wild-type cells in conditioned medium from DeltabsrA cultures also resulted in early sporulation. Use of Escherichia coli growth as a reporter of the nutritional status of conditioned media suggested that B. subtilis cells lacking 6S-1 RNA reduce the nutrient content of their environment earlier than wild-type cells. Several pathways known to impact the timing of sporulation, such as the skf- and sdp dependent cannibalism pathways, were eliminated as potential targets of 6S-1 RNA mediated changes, suggesting that 6S-1 RNA activity defines a novel mechanism for altering the timing of onset of sporulation. In addition, 6S-2 RNA does not influence the timing of sporulation, providing further evidence of the independent influences of these two related RNAs on cell physiology. PMID- 23457254 TI - Gene PA2449 is essential for glycine metabolism and pyocyanin biosynthesis in Pseudomonas aeruginosa PAO1. AB - Many pseudomonads produce redox active compounds called phenazines that function in a variety of biological processes. Phenazines are well known for their toxicity against non-phenazine-producing organisms, which allows them to serve as crucial biocontrol agents and virulence factors during infection. As for other secondary metabolites, conditions of nutritional stress or limitation stimulate the production of phenazines, but little is known of the molecular details underlying this phenomenon. Using a combination of microarray and metabolite analyses, we demonstrate that the assimilation of glycine as a carbon source and the biosynthesis of pyocyanin in Pseudomonas aeruginosa PAO1 are both dependent on the PA2449 gene. The inactivation of the PA2449 gene was found to influence the transcription of a core set of genes encoding a glycine cleavage system, serine hydroxymethyltransferase, and serine dehydratase. PA2449 also affected the transcription of several genes that are integral in cell signaling and pyocyanin biosynthesis in P. aeruginosa PAO1. This study sheds light on the unexpected relationship between the utilization of an unfavorable carbon source and the production of pyocyanin. PA2449 is conserved among pseudomonads and might be universally involved in the assimilation of glycine among this metabolically diverse group of bacteria. PMID- 23457255 TI - Microbiota and autoimmunity. AB - The commensal microbiota affects many aspects of mammalian health including control of the immune system to such a extent that a "commensalocentric" view of the maintenance of overall health could be suggested. Autoimmunity is a case of mistaken identity: The immune system reacts to self-tissues and cells as if they were pathogens. Autoimmune reactions can be both advanced or blocked by the commensal microbiota, which can affect innate and adaptive arms of immune responses as well as the mechanisms of "innate-adaptive connection." Whether specific microbial lineages affect immunity and autoimmunity (the "specific lineage hypothesis") or multiple lineages can tip the homeostatic balance that regulates host/microbiota homeostasis toward reduced or enhanced host reactivity (the "balanced signal hypothesis") is yet unknown. The complexity of host/microbiota interactions needs to be fully appreciated in order to find the means for prophylaxis and treatment of autoimmune disorders. PMID- 23457256 TI - Signaling and transcriptional networks in heart development and regeneration. AB - The mammalian heart is the first functional organ, the first indicator of life. Its normal formation and function are essential for fetal life. Defects in heart formation lead to congenital heart defects, underscoring the finesse with which the heart is assembled. Understanding the regulatory networks controlling heart development have led to significant insights into its lineage origins and morphogenesis and illuminated important aspects of mammalian embryology, while providing insights into human congenital heart disease. The mammalian heart has very little regenerative potential, and thus, any damage to the heart is life threatening and permanent. Knowledge of the developing heart is important for effective strategies of cardiac regeneration, providing new hope for future treatments for heart disease. Although we still have an incomplete picture of the mechanisms controlling development of the mammalian heart, our current knowledge has important implications for embryology and better understanding of human heart disease. PMID- 23457257 TI - Evolution of the animal apoptosis network. AB - The number of available eukaryotic genomes has expanded to the point where we can evaluate the complete evolutionary history of many cellular processes. Such analyses for the apoptosis regulatory networks suggest that this network already existed in the ancestor of the entire animal kingdom (Metazoa) in a form more complex than in some popular animal model organisms. This supports the growing realization that regulatory networks do not necessarily evolve from simple to complex and that the relative simplicity of these networks in nematodes and insects does not represent an ancestral state, but is the result of secondary simplifications. Network evolution is not a process of monotonous increase in complexity, but a dynamic process that includes lineage-specific gene losses and expansions, protein domain reshuffling, and emergence/reemergence of similar protein architectures by parallel evolution. Studying the evolution of such networks is a challenging yet interesting subject for research and investigation, and such studies on the apoptosis networks provide us with interesting hints of how these networks, critical in so many human diseases, have developed. PMID- 23457258 TI - Signaling pathways that control cell proliferation. AB - Cells decide to proliferate or remain quiescent using signaling pathways that link information about the cellular environment to the G1 phase of the cell cycle. Progression through G1 phase is controlled by pRB proteins, which function to repress the activity of E2F transcription factors in cells exiting mitosis and in quiescent cells. Phosphorylation of pRB proteins by the G1 cyclin-dependent kinases (CDKs) releases E2F factors, promoting the transition to S phase. CDK activity is primarily regulated by the binding of CDK catalytic subunits to cyclin partners and CDK inhibitors. Consequently, both mitogenic and antiproliferative signals exert their effects on cell proliferation through the transcriptional regulation and ubiquitin-dependent degradation of cyclins and CDK inhibitors. PMID- 23457259 TI - The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. AB - Unlike prototypical receptor tyrosine kinases (RTKs), which are single-chain polypeptides, the insulin receptor (InsR) is a preformed, covalently linked tetramer with two extracellular alpha subunits and two membrane-spanning, tyrosine kinase-containing beta subunits. A single molecule of insulin binds asymmetrically to the ectodomain, triggering a conformational change that is transmitted to the cytoplasmic kinase domains, which facilitates their trans phosphorylation. As in prototypical RTKs, tyrosine phosphorylation in the juxtamembrane region of InsR creates recruitment sites for downstream signaling proteins (IRS [InsR substrate] proteins, Shc) containing a phosphotyrosine binding (PTB) domain, and tyrosine phosphorylation in the kinase activation loop stimulates InsR's catalytic activity. For InsR, phosphorylation of the activation loop, which contains three tyrosine residues, also creates docking sites for adaptor proteins (Grb10/14, SH2B2) that possess specialized Src homology-2 (SH2) domains, which are dimeric and engage two phosphotyrosines in the activation loop. PMID- 23457262 TI - Signaling by nuclear receptors. PMID- 23457260 TI - Prokaryotic nucleotide excision repair. AB - Nucleotide excision repair (NER) has allowed bacteria to flourish in many different niches around the globe that inflict harsh environmental damage to their genetic material. NER is remarkable because of its diverse substrate repertoire, which differs greatly in chemical composition and structure. Recent advances in structural biology and single-molecule studies have given great insight into the structure and function of NER components. This ensemble of proteins orchestrates faithful removal of toxic DNA lesions through a multistep process. The damaged nucleotide is recognized by dynamic probing of the DNA structure that is then verified and marked for dual incisions followed by excision of the damage and surrounding nucleotides. The opposite DNA strand serves as a template for repair, which is completed after resynthesis and ligation. PMID- 23457263 TI - Strain-alleviation model of ADP-ribosylation. PMID- 23457261 TI - Translesion DNA synthesis and mutagenesis in eukaryotes. AB - The structural features that enable replicative DNA polymerases to synthesize DNA rapidly and accurately also limit their ability to copy damaged DNA. Direct replication of DNA damage is termed translesion synthesis (TLS), a mechanism conserved from bacteria to mammals and executed by an array of specialized DNA polymerases. This chapter examines how these translesion polymerases replicate damaged DNA and how they are regulated to balance their ability to replicate DNA lesions with the risk of undesirable mutagenesis. It also discusses how TLS is co opted to increase the diversity of the immunoglobulin gene hypermutation and the contribution it makes to the mutations that sculpt the genome of cancer cells. PMID- 23457264 TI - Quasiresonant amplification of planetary waves and recent Northern Hemisphere weather extremes. AB - In recent years, the Northern Hemisphere has suffered several devastating regional summer weather extremes, such as the European heat wave in 2003, the Russian heat wave and the Indus river flood in Pakistan in 2010, and the heat wave in the United States in 2011. Here, we propose a common mechanism for the generation of persistent longitudinal planetary-scale high-amplitude patterns of the atmospheric circulation in the Northern Hemisphere midlatitudes. Those patterns--with zonal wave numbers m = 6, 7, or 8--are characteristic of the above extremes. We show that these patterns might result from trapping within midlatitude waveguides of free synoptic waves with zonal wave numbers k ~ m. Usually, the quasistationary dynamical response with the above wave numbers m to climatological mean thermal and orographic forcing is weak. Such midlatitude waveguides, however, may favor a strong magnification of that response through quasiresonance. PMID- 23457266 TI - A study examining rates of medical staff recognition of pressure ulceration in hospital inpatients. AB - BACKGROUND: The incidence of pressure ulceration among UK hospital inpatients has been estimated at 10.2-10.3%. These patients are at increased risk of developing osteomyelitis and subsequent sepsis. This study sought to test whether medical staff recognition rates of hospital inpatients with pressure ulceration were low and to consider underlying causes and potential solutions. METHODS: Interviews were conducted with nursing staff on multiple wards in July 2012 to obtain a definitive list of patients with pressure ulcers, with their corresponding location and grade. Junior members of medical teams with responsibility for the same group of patients were independently interviewed and asked to identify all patients who they knew to have pressure ulcers. The number correctly identified by the medical teams was compared with the total number of known pressure ulcers to produce a recognition rate. Patients with clinical evidence of sepsis were highlighted. RESULTS: Twenty-seven patients on five wards were identified by nursing staff as having pressure ulceration areas. Nine patients were stated to have multiple pressure ulceration areas, giving a total of 38 pressure ulcers. Medical teams correctly identified eight of 27 (29.6%) of these patients. The correct site and grade was identified in four of 38 (10.5%) and two of 38 (5.3%) cases, respectively. Of these patients 14/27 (51.8%) had evidence of infection. In this subgroup five of 14 (35.7%) were correctly identified as having pressure ulceration areas. CONCLUSIONS: The lack of medical awareness could lead to delayed recognition of deep-seated infection or osteomyelitis. Reasons for this are likely to be multifactorial and require a combination of cultural change, improved education and improved information sharing. PMID- 23457268 TI - BVA calls for a single national equine database. PMID- 23457265 TI - Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. AB - Mutations in the Tar DNA binding protein of 43 kDa (TDP-43; TARDBP) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43(+) inclusions (FTLD-TDP). To determine the physiological function of TDP-43, we knocked out zebrafish Tardbp and its paralogue Tardbp (TAR DNA binding protein-like), which lacks the glycine-rich domain where ALS- and FTLD-TDP-associated mutations cluster. tardbp mutants show no phenotype, a result of compensation by a unique splice variant of tardbpl that additionally contains a C-terminal elongation highly homologous to the glycine-rich domain of tardbp. Double-homozygous mutants of tardbp and tardbpl show muscle degeneration, strongly reduced blood circulation, mispatterning of vessels, impaired spinal motor neuron axon outgrowth, and early death. In double mutants the muscle specific actin binding protein Filamin Ca is up-regulated. Strikingly, Filamin C is similarly increased in the frontal cortex of FTLD-TDP patients, suggesting aberrant expression in smooth muscle cells and TDP-43 loss-of-function as one underlying disease mechanism. PMID- 23457269 TI - Joint guidance on ethical review processes for practice-based research. PMID- 23457270 TI - VMD reports on progress of SBV vaccine application. PMID- 23457271 TI - New dog breeding rules to come into force in Northern Ireland. PMID- 23457272 TI - VN Council discusses disclosure of convictions and compliance with CPD. PMID- 23457273 TI - Equine vet joins hall of fame. PMID- 23457275 TI - Veterinary medicines: product update. PMID- 23457276 TI - Reclassification of anthelmintics would require significant policy shift, says VMD. PMID- 23457277 TI - Diagnoses of fasciolosis show a rise in Scotland. PMID- 23457278 TI - Time to talk about behavioural problems. PMID- 23457279 TI - Canine behaviour problems: discussions between veterinarians and dog owners during annual booster consultations. AB - The veterinary profession recently acknowledged its responsibility to provide behaviour support, following criticism for focussing on the physiological aspects of welfare and overlooking the psychological. To further understand the practising of behavioural medicine, a 'fly-on-the-wall' approach was used to investigate welfare discussions during dog booster vaccinations. Seventeen consultations involving six veterinarians in two UK small-animal practices were videoed. Qualitative methods were used to analyse themes discussed and questionnaires completed to obtain participant information and perceptions. Five main topics of discussion were identified: navigation, medical, husbandry, behaviour and cost. Veterinarians led the discussion of all topics except behaviour which was instigated approximately equally by veterinarian and client. All clients reported one or more behaviours that were a concern to them, totalling 58 across the sample. Disconcertingly, only 10 were discussed during consultations and none fully explored nor managed beyond the consultation. Behaviour discussion varies between veterinarians; this may reflect their experience, confidence or clients' requests. Owners access welfare information from a variety of sources, not always from veterinarians. Where sources are not knowledgeable, both human and animal welfare can be seriously compromised. Veterinarians need to ensure that clients are enabled to discuss behaviour issues and are provided with appropriate support, be that in-house or via referral. PMID- 23457280 TI - Babesia vogeli in a quarantined dog. PMID- 23457281 TI - Horsemeat and the food chain. PMID- 23457283 TI - Characteristics of electronic training collars for dogs. PMID- 23457284 TI - Characteristics of electronic training collars for dogs. J. A. Lines, K. van Driel and J. J. Cooper comment. PMID- 23457285 TI - Assessment of canine emotion through behaviour. PMID- 23457291 TI - Pituitary macroadenoma due to hypothyroidism. PMID- 23457293 TI - The cystic fibrosis airway microbiome. AB - Repeated pulmonary exacerbation and progressive lung function decline characterize cystic fibrosis (CF) disease, and represents one of the leading causes of mortality in this patient population. Recent studies have shown, using culture-independent assays, that multiple microbial species can be detected in airway samples from CF patients. Moreover, specific groups of bacteria within these bacterial communities or microbiota, are highly associated with disease associated factors such as antibiotic administration. This raises the possibility that, as in other human niches, pathogenic processes in the CF airways represent polymicrobial activities and that microbiome composition and perturbations to these communities define patient pulmonary health status. Airway samples are typically collected through the mouth, and are thus susceptible to contamination by upper airway secretions; hence, caution must be exercised in interpreting these data. Nonetheless, given the continuum of the upper and lower respiratory tract, understanding the contribution of these mixed-species assemblages to airway health is essential to improving CF patient care. This article aims to discuss recent advances in the field of CF airway microbiome research and interpret these findings in the context of CF pulmonary disease. PMID- 23457292 TI - Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) requires dynamic fluctuations between states in its gating cycle for proper channel function, including changes in the interactions between the nucleotide-binding domains (NBDs) and between the intracellular domain (ICD) coupling helices and NBDs. Such motions are also linked with fluctuating phosphorylation-dependent binding of CFTR's disordered regulatory (R) region to the NBDs and partners. Folding of CFTR is highly inefficient, with the marginally stable NBD1 sampling excited states or folding intermediates that are aggregation-prone. The severe CF-causing F508del mutation exacerbates the folding inefficiency of CFTR and leads to impaired channel regulation and function, partly as a result of perturbed NBD1-ICD interactions and enhanced sampling of these NBD1 excited states. Increased knowledge of the dynamics within CFTR will expand our understanding of the regulated channel gating of the protein as well as of the F508del defects in folding and function. PMID- 23457294 TI - In vitro and in vivo model systems for studying enteropathogenic Escherichia coli infections. AB - Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) belong to a group of bacteria known as attaching and effacing (A/E) pathogens that cause disease by adhering to the lumenal surfaces of their host's intestinal epithelium. EPEC and EHEC are major causes of infectious diarrhea that result in significant childhood morbidity and mortality worldwide. Recent advances in in vitro and in vivo modeling of these pathogens have contributed to our knowledge of how EPEC and EHEC attach to host cells and subvert host-cell signaling pathways to promote infection and cause disease. A more detailed understanding of how these pathogenic microbes infect their hosts and how the host responds to infection could ultimately lead to new therapeutic strategies to help control these significant enteric pathogens. PMID- 23457295 TI - Probiotics: properties, examples, and specific applications. AB - Probiotics are beneficial components of the microbiota that have been used for centuries because of the health benefits they confer to the host. Only recently, however, has the contribution of probiotics to modulation of immunological, respiratory, and gastrointestinal functions started to be fully appreciated and scientifically evaluated. Probiotics such as Escherichia coli Nissle 1917 and lactic acid bacteria are currently used to, or have been evaluated for use to, prevent or treat a range of intestinal maladies including inflammatory bowel disease, constipation, and colon cancer. Engineering these natural probiotics to produce immunomodulatory molecules may help to further increase the benefit to the host. In this article, we will discuss some of the mechanisms of action of probiotics as well as advances in the rational design of probiotics. PMID- 23457297 TI - Specific activation of the G protein-coupled receptor BNGR-A21 by the neuropeptide corazonin from the silkworm, Bombyx mori, dually couples to the G(q) and G(s) signaling cascades. AB - Corazonin, an undecapeptide neurohormone sharing a highly conserved amino acid sequence across Insecta, plays different physiological roles in the regulation of heart contraction rates, silk spinning rates, the induction of dark color and morphometric phase changes, and ecdysis. Corazonin receptors have been identified in Drosophila melanogaster, Manduca sexta, and Musca domestica. However, detailed information on the signaling and major physiological functions of corazonin and its receptor is largely unknown. In the current study, using both the mammalian cell line HEK293 and insect cell lines BmN and Sf21, we paired the Bombyx corazonin neuropeptide as a specific endogenous ligand for the Bombyx neuropeptide G protein-coupled receptor A21 (BNGR-A21), and we therefore designated this receptor as BmCrzR. Further characterization indicated that synthetic BmCrz demonstrated a high affinity for and activated BmCrzR, resulting in intracellular cAMP accumulation, Ca(2+) mobilization, and ERK1/2 phosphorylation via the Gq- and Gs-coupled signaling pathways. The direct interaction of BmCrzR with BmCrz was confirmed by a rhodamine-labeled BmCrz peptide. Moreover, experiments with double-stranded RNA and synthetic peptide injection suggested a possible role of BmCrz/BmCrzR in the regulation of larval growth and spinning rate. Our present results provide the first in-depth information on BmCrzR-mediated signaling for further elucidation of the BmCrz/BmCrzR system in the regulation of fundamental physiological processes. PMID- 23457296 TI - Erythropoietin. AB - During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment. PMID- 23457298 TI - Respective contribution of mitochondrial superoxide and pH to mitochondria targeted circularly permuted yellow fluorescent protein (mt-cpYFP) flash activity. AB - Superoxide flashes are transient bursts of superoxide production within the mitochondrial matrix that are detected using the superoxide-sensitive biosensor, mitochondria-targeted circularly permuted YFP (mt-cpYFP). However, due to the pH sensitivity of mt-cpYFP, flashes were suggested to reflect transient events of mitochondrial alkalinization. Here, we simultaneously monitored flashes with mt cpYFP and mitochondrial pH with carboxy-SNARF-1. In intact cardiac myocytes and purified skeletal muscle mitochondria, robust mt-cpYFP flashes were accompanied by only a modest increase in SNARF-1 ratio (corresponding to a pH increase of <0.1), indicating that matrix alkalinization is minimal during an mt-cpYFP flash. Individual flashes were also accompanied by stepwise increases of MitoSOX signal and decreases of NADH autofluorescence, supporting the superoxide origin of mt cpYFP flashes. Transient matrix alkalinization induced by NH4Cl only minimally influenced flash frequency and failed to alter flash amplitude. However, matrix acidification modulated superoxide flash frequency in a bimodal manner. Low concentrations of nigericin (< 100 nM) that resulted in a mild dissipation of the mitochondrial pH gradient increased flash frequency, whereas a maximal concentration of nigericin (5 MUm) collapsed the pH gradient and abolished flash activity. These results indicate that mt-cpYFP flash events reflect a burst in electron transport chain-dependent superoxide production that is coincident with a modest increase in matrix pH. Furthermore, flash activity depends strongly on a combination of mitochondrial oxidation and pH gradient. PMID- 23457299 TI - The Legionella pneumophila Dot/Icm-secreted effector PlcC/CegC1 together with PlcA and PlcB promotes virulence and belongs to a novel zinc metallophospholipase C family present in bacteria and fungi. AB - Legionella pneumophila is a water-borne bacterium that causes pneumonia in humans. PlcA and PlcB are two previously defined L. pneumophila proteins with homology to the phosphatidylcholine-specific phospholipase C (PC-PLC) of Pseudomonas fluorescens. Additionally, we found that Lpg0012 shows similarity to PLCs and has been shown to be a Dot/Icm-injected effector, CegC1, which is designated here as PlcC. It remained unclear, however, whether these L. pneumophila proteins exhibit PLC activity. PlcC expressed in Escherichia coli hydrolyzed a broad phospholipid spectrum, including PC, phosphatidylglycerol (PG), and phosphatidylinositol. The addition of Zn(2+) ions activated, whereas EDTA inhibited, PlcC-derived PLC activity. Protein homology search revealed that the three Legionella enzymes and P. fluorescens PC-PLC share conserved domains also present in uncharacterized fungal proteins. Fifteen conserved amino acids were essential for enzyme activity as identified via PlcC mutagenesis. Analysis of defined L. pneumophila knock-out mutants indicated Lsp-dependent export of PG hydrolyzing PLC activity. PlcA and PlcB exhibited PG-specific activity and contain a predicted Sec signal sequence. In line with the reported requirement of host cell contact for Dot/Icm-dependent effector translocation, PlcC showed cell associated PC-specific PLC activity after bacterial growth in broth. A PLC triple mutant, but not single or double mutants, exhibited reduced host killing in a Galleria mellonella infection model, highlighting the importance of the three PLCs in pathogenesis. In summary, we describe here a novel Zn(2+)-dependent PLC family present in Legionella, Pseudomonas, and fungi with broad substrate preference and function in virulence. PMID- 23457300 TI - Loss of vacuolar H+-ATPase (V-ATPase) activity in yeast generates an iron deprivation signal that is moderated by induction of the peroxiredoxin TSA2. AB - Vacuolar H(+)-ATPases (V-ATPases) acidify intracellular organelles and help to regulate overall cellular pH. Yeast vma mutants lack V-ATPase activity and allow exploration of connections between cellular pH, iron, and redox homeostasis common to all eukaryotes. A previous microarray study in a vma mutant demonstrated up-regulation of multiple iron uptake genes under control of Aft1p (the iron regulon) and only one antioxidant gene, the peroxiredoxin TSA2 (Milgrom, E., Diab, H., Middleton, F., and Kane, P. M. (2007) Loss of vacuolar proton-translocating ATPase activity in yeast results in chronic oxidative stress. J. Biol. Chem. 282, 7125-7136). Fluorescent biosensors placing GFP under transcriptional control of either an Aft1-dependent promoter (P(FIT2)-GFP) or the TSA2 promoter (P(TSA2)-GFP) were constructed to monitor transcriptional signaling. Both biosensors were up-regulated in the vma2Delta mutant, and acute V ATPase inhibition with concanamycin A induced coordinate up-regulation from both promoters. PTSA2-GFP induction was Yap1p-dependent, indicating an oxidative stress signal. Total cell iron measurements indicate that the vma2Delta mutant is iron-replete, despite up-regulation of the iron regulon. Acetic acid up-regulated P(FIT2)-GFP expression in wild-type cells, suggesting that loss of pH control contributes to an iron deficiency signal in the mutant. Iron supplementation significantly decreased P(FIT2)-GFP expression and, surprisingly, restored P(TSA2)-GFP to wild-type levels. A tsa2Delta mutation induced both nuclear localization of Aft1p and P(FIT2)-GFP expression. The data suggest a novel function for Tsa2p as a negative regulator of Aft1p-driven transcription, which is induced in V-ATPase mutants to limit transcription of the iron regulon. This represents a new mechanism bridging the antioxidant and iron-regulatory pathways that is intimately linked to pH homeostasis. PMID- 23457302 TI - Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. AB - SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan syndromes, two of several autosomal-dominant conditions characterized by gain-of-function mutations in the Ras pathway. Interestingly, Noonan syndrome SHP2 mutants are constitutively active, whereas LEOPARD syndrome SHP2 mutants exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD syndrome mutants engender gain-of-function phenotypes? Our study reveals that LEOPARD syndrome mutations weaken the intramolecular interaction between the N SH2 and phosphatase domains, leading to a change in SHP2 molecular switching mechanism. Consequently, LEOPARD syndrome SHP2 mutants bind upstream activators preferentially and are hypersensitive to growth factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates for the reduced phosphatase activity. The study provides a solid framework for understanding how individual SHP2 mutations cause diseases. PMID- 23457301 TI - Human genetic disorders caused by mutations in genes encoding biosynthetic enzymes for sulfated glycosaminoglycans. AB - A number of genetic disorders are caused by mutations in the genes encoding glycosyltransferases and sulfotransferases, enzymes responsible for the synthesis of sulfated glycosaminoglycan (GAG) side chains of proteoglycans, including chondroitin sulfate, dermatan sulfate, and heparan sulfate. The phenotypes of these genetic disorders reflect disturbances in crucial biological functions of GAGs in human. Recent studies have revealed that mutations in genes encoding chondroitin sulfate and dermatan sulfate biosynthetic enzymes cause various disorders of connective tissues. This minireview focuses on growing glycobiological studies of recently described genetic diseases caused by disturbances in biosynthetic enzymes for sulfated GAGs. PMID- 23457303 TI - Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. AB - Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1(f/f) mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet. PMID- 23457304 TI - Platelet-derived growth factor-BB activates calcium/calmodulin-dependent and independent mechanisms that mediate Akt phosphorylation in the neurofibromin deficient human Schwann cell line ST88-14. AB - Neurofibromatosis type 1-derived Schwann cells isolated from malignant peripheral nerve sheath tumors (MPNSTs) overexpress PDGF receptor-beta and generate an aberrant intracellular calcium increase in response to PDGF-BB. Using the human MPNST Schwann cell line ST88-14, we demonstrate that, in addition to a transient phosphorylation of Akt, PDGF-BB stimulation produces an atypical sustained phosphorylation of Akt that is dependent on calcium and calmodulin (CaM). The sustained Akt phosphorylation did not occur in PDGF-BB-stimulated normal human Schwann cells or ST88-14 cells stimulated with stem cell factor, whose receptor is also overexpressed in ST88-14 cells. The sustained Akt phosphorylation induced by PDGF-BB was inhibited by pretreatment of the cells with either the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid tetrakis(acetoxymethyl) ester (BAPTA-AM) or the CaM antagonist W7, whereas the transient portion was not inhibited. Akt also co immunoprecipitated with CaM in a PDGF-BB-dependent manner, suggesting that direct interaction between Akt and CaM is involved in the sustained phosphorylation of Akt. Furthermore, we provide evidence that anti-apoptotic effects of PDGF-BB on serum-deprived ST88-14 cells can be inhibited by W7, implicating the PDGF-BB induced activation of calcium/CaM in promoting cell survival, presumably through sustained Akt activation. We conclude that the activation of the calcium/CaM/Akt pathway resulting from stimulation of overexpressed PDGF receptor-beta may contribute to the survival and tumorigenicity of MPNST cells. PMID- 23457307 TI - Pentoxifylline treatment for protecting diabetic retinopaty in children with type 1 diabetes. AB - OBJECTIVE: The purpose of this study was to determine whether oral pentoxifylline (PTX) would improve retinal microvascular hemodynamics in children with type 1 diabetes mellitus (DM). PATIENTS AND METHODS: Non-invasive ultrasonographic measurements were made in 56 type 1 diabetic patients. The diabetic patients were matched first in terms of age, diabetes duration, then one individual within each pair was randomized into a pentoxifylline group and a control group. Pentoxifylline was administered for 6 months. We investigated the change of peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), and resistivity index (RI) of central retinal artery (CRA) at 6 months after pentoxifylline. We investigated the relationship between PI, RI and carotide cross-sectional compliance (C-CSC). RESULTS: In comparison to changes in CRA measurements between the two groups, the pentoxifylline treatment group had significantly lower PI values (p=0.01). The RI, PSV and EDV were lower in pentoxifylline group but not statistically different. There was a positive correlation between CRA PSV and carotid Vmax (cm/s) (r=0.29, p=0.02) and also C CSC (r=0.27, p=0.03). In addition, there was a positive correlation between PI and C-CSC (r=0.3, p=0.02). In the pentoxifylline group there was a significant reduction in systolic blood pressure, diastolic blood pressure, microalbuminuria and an increase in HDL level. CONCLUSION: Our results suggest that pentoxifylline may have a protective action for diabetic retinopathy and might modulate risk factors for atherosclerosis in type 1 diabetes. PMID- 23457306 TI - Self-catalytic DNA depurination underlies human beta-globin gene mutations at codon 6 that cause anemias and thalassemias. AB - The human beta-globin gene contains an 18-nucleotide coding strand sequence centered at codon 6 and capable of forming a stem-loop structure that can self catalyze depurination of the 5'G residue of that codon. The resultant apurinic lesion is subject to error-prone repair, consistent with the occurrence about this codon of mutations responsible for 6 anemias and beta-thalassemias and additional substitutions without clinical consequences. The 4-residue loop of this stem-loop-forming sequence shows the highest incidence of mutation across the gene. The loop and first stem base pair-forming residues appeared early in the mammalian clade. The other stem-forming segments evolved more recently among primates, thereby conferring self-depurination capacity at codon 6. These observations indicate a conserved molecular mechanism leading to beta-globin variants underlying phenotypic diversity and disease. PMID- 23457305 TI - Chaperone-mediated autophagy targets hypoxia-inducible factor-1alpha (HIF-1alpha) for lysosomal degradation. AB - Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that mediates adaptive responses to hypoxia. We demonstrate that lysosomal degradation of the HIF-1alpha subunit by chaperone-mediated autophagy (CMA) is a major regulator of HIF-1 activity. Pharmacological inhibitors of lysosomal degradation, such as bafilomycin and chloroquine, increased HIF-1alpha levels and HIF-1 activity, whereas activators of chaperone-mediated autophagy, including 6 aminonicotinamide and nutrient starvation, decreased HIF-1alpha levels and HIF-1 activity. In contrast, macroautophagy inhibitors did not increase HIF-1 activity. Transcription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity. HIF-1alpha interacts with HSC70 and LAMP2A, which are core components of the CMA machinery. Overexpression of HSC70 or LAMP2A decreased HIF-1alpha protein levels, whereas knockdown had the opposite effect. Finally, hypoxia increased the transcription of genes involved in CMA and lysosomal biogenesis in cancer cells. Thus, pharmacological and genetic approaches identify CMA as a major regulator of HIF-1 activity and identify interplay between autophagy and the response to hypoxia. PMID- 23457308 TI - Ceramide mediates inhibition of the Akt/eNOS pathway by high levels of glucose in human vascular endothelial cells. AB - OBJECTIVE: To investigate how ceramide mediates the effects of high-glucose induced inhibition of the Akt/endothelial nitric oxide synthase (eNOS) signalling pathway in human vascular endothelial cells (HUVECs). MATERIALS AND METHODS: NO levels were determined by ELISA. Endogenous ceramide levels were determined using a liquid chromatography-mass spectrometry assay. Akt and eNOS protein expressions were determined by Western blotting. RESULTS: High-glucose levels induce ceramide accumulation in a dose- and time-dependent manner (p<0.05). We also show that exposure of HUVECs to high-glucose conditions inhibits the insulin-mediated activation of Akt/eNOS signalling and the subsequent NO generation in a dose dependent manner (p<0.05). Preventing de novo ceramide synthesis attenuated the antagonistic effects of high-glucose levels on the Akt/eNOS signalling pathway (p<0.05); conversely, inducing ceramide build-up augmented the inhibitory effects of high-glucose levels on the Akt/eNOS signalling pathway (p<0.05). CONCLUSION: Ceramide is both necessary and sufficient for mediating the inhibition of the Akt/eNOS signalling pathway by high-glucose levels in endothelial cells. PMID- 23457309 TI - Congenital hypothyroidism caused by a novel mutation of the dual oxidase 2 (DUOX2) gene. AB - The dual oxidase 2 (DUOX2) mutation results in an impairment of the hydrogen peroxidase-generating system and is identified as a dyshormonogenic cause of congenital hypothyroidism (CH). Here, we describe two unrelated Japanese girls with CH due to a novel DUOX2 mutation. They had high serum thyrotropin levels and low free thyroxine/thyroxine concentrations during the neonatal period. A novel missense mutation with a transversion of G to A at position 1462 in exon 12 of the DUOX2 gene that caused a replacement of glycine (G) with arginine (R) at codon 488 of the protein (c.1462G>A, p.[G488R]) was identified. One patient was a compound heterozygote for p.[L479SfsX3]+[G488R]. The other was homozygous for p.[G488R]. This p.G488R substitution occurred in a highly conserved glycine residue of the mammalian DUOX2 protein. The two patients had different haplotypes, suggesting that the p.G488R alleles were the result of independent, recurrent mutations. Later in life, both patients were still euthyroid even after discontinuing thyroid hormone therapy. We conclude that this p.G488R missense mutation in the DUOX2 gene of the patients is associated with thyroid dysfunction that presents during the neonatal period. PMID- 23457311 TI - The effect of different nutritional states on puberty onset and the expression of hypothalamic Kiss1/kisspepetin. AB - The possibility of an alteration in the age at which pubertal onset occurs has shown that we still lack knowledge on the molecular and physiological mechanisms of normal female puberty. In this study, the adjustment effects of different suckling and prepuberty nutrition on puberty onset and the expression of hypothalamic Kiss1/kisspeptin and gonadotrophin-releasing hormone (GnRH) were examined in 1-day-old female Sprague-Dawley rats. Animals were randomly assigned according to different suckling nutritional challenges (different milk intake before weaning) and prepuberty nutritional challenges (different food supply after weaning) into four groups: overnutrition group 1, overnutrition group 2 (O2), normal group (N, control group), and malnutrition group (M). In situ hybridization, Western blot analysis, and immunohistochemistry were used to analyze the expression of hypothalamic Kiss1/kisspeptin and GnRH. In the O1 group, GnRH and Kiss1/kisspeptin levels in the hypothalamus peaked at an early age, while malnutrition resulted in a delay in the GnRH and Kiss1/kisspeptin peaks. This study indicated that nutrition greatly affected the sexual development of female rats and that the effects of suckling nutrition were much greater than those of prepuberty nutrition. PMID- 23457310 TI - Arginine-guanidinoacetate-creatine pathway in preterm newborns: creatine biosynthesis in newborns. AB - The phosphocreatine/creatine system is fundamental for the proper development of the embryonic brain. Being born prematurely might alter the creatine biosynthesis pathway, in turn affecting creatine supply to the developing brain. We enrolled 53 preterm and very preterm infants and 55 full-term newborns. The levels of urinary guanidinoacetate, creatine, creatinine and amino acids were measured in the preterm and very preterm groups, 48 h and 9 days after birth and at discharge, and 48 h after birth in the full-term group. Guanidinoacetate concentrations of both preterm and very preterm newborns were significantly higher at discharge than the values for the full-term group at 48 h, while very preterm infants showed urinary creatine values significantly lower than those measured in the full-term group. Our results suggest an impairment of the creatine biosynthesis pathway in preterm and very preterm newborns, which could lead to creatine depletion affecting the neurological outcome in prematurely born infants. PMID- 23457312 TI - Trends in hospitalizations among children with type 1 diabetes in Spain, 2001 2009. AB - AIM: To examine the trends in the incidence of hospital discharges among children between 0 and 14 years with type 1 diabetes in Spain (2001-2009). METHODS: We identified all hospital discharges with a diagnosis of type 1 diabetes, using national hospital discharge data. RESULTS: A total of 22,955 type 1 diabetes discharges to Spanish hospitals were recorded. The discharge incidence per year increased from 39.6 in 2001 to 40.02 per 100,000 inhabitants in 2009. There was no significant change in hospital discharge rates for children 0-14 years old. In the 0-4 years group, the incidence increased significantly over the study period (incidence rate ratio, 1.031; 95% confidence interval, 1.017-1.045). CONCLUSION: Hospitalization trends in children 0-4 years old with type 1 diabetes has increased over the study period, consistent with an increase in the incidence of diabetes in Spain. The stable rate for those aged 10-14 years may indicate that the control of these patients in specialized outpatient settings is preventing the expected increase in hospitalizations. PMID- 23457313 TI - A clinically euthyroid child with a large goiter due to a thyroglobulin gene defect: clinical features and genetic studies. AB - A 10-year old child born to consanguineous parents presented with an extremely large goiter, a low free T4 level and free T4 index, and normal TSH concentration. The findings of undetectable thyroglobulin (TG) and low free T4, and an elevated free T3/free T4 ratio suggested the possibility of a defect in TG synthesis. Noteworthy aspects of this case were the extremely elevated thyroidal radioiodide uptake despite a normal TSH concentration and the fact that the reduction in the size of her goiter only occurred when her TSH was suppressed below the normal range. Gene sequencing revealed that the patient was homozygous for a donor splice site mutation in intron 30 (IVS30+1G>C). Isolation of RNA obtained from the thyroid gland by fine needle aspiration and sequencing of the TG cDNA confirmed the prediction that exon 30 was skipped, resulting in an in frame loss of 46 amino acids. PMID- 23457314 TI - Attempted suicide with levothyroxine in an adolescent girl. AB - Attempted suicide with levothyroxine is very rare and has been described only in a few case reports. Although acute accidental or intentional overdoses of thyroid hormones can lead to marked elevations in serum T4 levels, many children who take as much as 5-10 mg of levothyroxine as a single dose have few or no symptoms of thyrotoxicosis. We report an adolescent girl who attempted suicide by ingesting levothyroxine. She responded well to beta-adrenergic blockade. PMID- 23457315 TI - Differentiated thyroid carcinoma in a girl with resistance to thyroid hormone management with triiodothyroacetic acid. AB - Thyroid hormone resistance syndrome is characterized by a reduced target tissue response to the action of thyroid hormone, which leads to high levels of free thyroxine and free triiodothyronine with non-suppressed levels of thyrotropin (TSH). Recently, three cases of papillary thyroid carcinoma associated with thyroid hormone resistance syndrome were published. The main challenge in this situation is the difficulty of maintaining the suppression of TSH levels without producing symptoms of hyperthyroidism. We present another case of an association of thyroid hormone resistance syndrome and papillary thyroid carcinoma, and we share our experience with 3,5,3'-triiodothyroacetic acid, which made possible an easier management of the carcinoma after surgery, maintaining the TSH levels suppressed despite the resistance to thyroid hormones. PMID- 23457316 TI - Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation. AB - 3-M syndrome is an underdiagnosed autosomal recessive disorder characterized by severe pre- and postnatal growth retardation with minimal dysmorphic features and distinguishing radiological findings. We report a patient who was first admitted at 7.5 years of age. He was born to consanguineous parents with a birth weight of 2250 g. Physical examination revealed a severe short stature (height, 95 cm; SD score -5.64) and minimal dysmorphic features. Biochemistry, endocrine work-up, and karyotype were normal. Reevaluation at 16.5 years of age revealed a height of 128.5 cm (SD score -5.27), prominent forehead, anteverted nasal openings, fleshy nasal tip, full lips, malar hypoplasia, hyperlordosis, prominent heels, testicular volumes 8-10 mL, and pubic hair consistent with Tanner stage II. Growth hormone trial for a year resulted in inadequate height gain (3 cm). The diagnosis of 3-M syndrome was made upon typical findings (thin long bones with diaphyseal narrowing and tall lumbar vertebrae) in a recent skeletal survey. Genetic analysis disclosed a homozygote frame shift mutation in exon 2: c.457_458delinsT resulting in p.Gly153fs. PMID- 23457317 TI - Conn syndrome and Crohn disease in a pediatric case: an interesting parallel. AB - Conn syndrome is characterized by surreptitious secretion of aldosterone in which patients are found to have hypertension, hypokalemia, and metabolic alkalosis. Although rare, the most common presentation in the pediatric population is bilateral hyperplasia of the adrenal glands as opposed to an adenoma. Crohn disease is part of the spectrum of inflammatory bowel disease, which manifests in children as flare-ups of bloody diarrhea and abdominal pain. The association of concurrent Conn syndrome and Crohn disease has been previously presented in two cases in adults. This is the first pediatric case to be reported in the literature. PMID- 23457318 TI - Severe hypothalamopituitary dysfunction accompanied by influenza-associated encephalopathy: report of two pediatric cases. AB - Severe influenza infection may lead to neurological damage, such as encephalopathy. This may, in turn, cause acquired hypothalamopituitary dysfunction, which can result in severe morbidity and even death. We herein report two pediatric patients who developed influenza-associated hypopituitarism and were subsequently diagnosed with encephalopathy. They were diagnosed with acute necrotizing encephalopathy and postresuscitation encephalopathy, respectively. Both showed evidence of endocrine dysfunction, and hormone replacement therapy of adrenal, thyroid, and antidiuretic hormones are resulting in continued cardiac activity and resulted in prolonged survival. Screening for endocrine function is important in patients with severe central nervous system dysfunction. PMID- 23457319 TI - Duplication of SOX9 is not a common cause of 46,XX testicular or 46,XX ovotesticular DSD. PMID- 23457320 TI - Does childhood adversity account for poorer mental and physical health in second generation Irish people living in Britain? Birth cohort study from Britain (NCDS). AB - OBJECTIVES: Worldwide, the Irish diaspora experience elevated mortality and morbidity across generations, not accounted for through socioeconomic position. The main objective of the present study was to assess if childhood disadvantage accounts for poorer mental and physical health in adulthood, in second-generation Irish people. DESIGN: Analysis of prospectively collected birth cohort data, with participants followed to midlife. SETTING: England, Scotland and Wales. PARTICIPANTS: Approximately 17 000 babies born in a single week in 1958. Six per cent of the cohort were of second-generation Irish descent. OUTCOMES: Primary outcomes were common mental disorders assessed at age 44/45 and self-rated health at age 42. Secondary outcomes were those assessed at ages 23 and 33. RESULTS: Relative to the rest of the cohort, second-generation Irish children grew up in marked material and social disadvantage, which tracked into early adulthood. By midlife, parity was reached between second-generation Irish cohort members and the rest of the sample on most disadvantage indicators. At age 23, Irish cohort members were more likely to screen positive for common mental disorders (OR 1.44; 95% CI 1.06 to 1.94). This had reduced slightly by midlife (OR 1.27; 95% CI 0.96 to 1.69). Although at age 23 second-generation cohort members were just as likely to report poorer self-rated health (OR 1.06; 95% CI 0.79 to 1.43), by midlife this difference had increased (OR 1.25; 95% CI 0.98 to 1.60). Adjustment for childhood and early adulthood adversity fully attenuated differences in adult health disadvantages. CONCLUSIONS: Social and material disadvantage experienced in childhood continues to have long-range adverse effects on physical and mental health at midlife, in second-generation Irish cohort members. This suggests important mechanisms over the life-course, which may have important policy implications in the settlement of migrant families. PMID- 23457321 TI - Sympathetic skin response and heart rate variability as diagnostic tools for the differential diagnosis of Lewy body dementia and Alzheimer's disease: a diagnostic test study. AB - OBJECTIVE: The purpose of this study is to investigate the usefulness of sympathetic skin response (SSR) and heart rate variability (HRV) for the differential diagnosis of patients with dementia with Lewy bodies (DLB). DESIGN: A diagnostic test study. SETTING: Single centre in Japan. PARTICIPANTS: We examined 20 patients with probable Alzheimer's disease (AD) diagnosed with NINCDS ADRDA criteria and 20 with probable DLB diagnosed with the criteria of the third international DLB workshop. METHODS: For the SSR measurement, surface electrodes were used: the active recording electrode was placed on the palm of the hand and the reference electrode was placed on the dorsum of the same hand. SSR was induced by a median nerve electrical stimulation at an amplitude of 20 mA. For the HRV measurement, the A-A intervals were measured twice for 2 min with an interval of 5 min in a sitting position after a rest of 5 min. From the low frequency power (LF; 0.02-0.15 Hz) and high-frequency power (HF; 0.15-0.50 Hz), the ratio of LF to HF power (LF/HF) was calculated using the maximal entropy method. RESULTS: SSR and HRV could detect the abnormality of autonomic function in patients with DLB at sensitivities of 85% and 90%, respectively. On the other hand, SSR and HRV detected an abnormality of autonomic function in patients with AD at sensitivities of 15% and 25% (p<0.05). The combination of the SSR and the HRV (double-positive) indicated abnormal autonomic function was recorded in only 1 of 20 patients (5%) with AD. In contrast, this combination indicated autonomic abnormality in 15 of 20 patients with DLB by our criteria (75%). CONCLUSIONS: SSR and HRV can be applied to differentiate DLB from AD. PMID- 23457322 TI - The interactions of ethical notions and moral values of immediate stakeholders of immunisation services in two Indian states: a qualitative study. AB - OBJECTIVES: This study examines the existing norms regarding immunisation within the communities and the ethical notions that govern the actions of different health professionals and their collective synergistic or conflicting effects on the governance of the programme. DESIGN: We used descriptive and analytical qualitative methods as it suited the research question. SETTING: The data were collected from areas under 16 primary health centres in Kerala and Tamil Nadu identified through a three-step sampling process. PARTICIPANTS: This involved in depth interviews with stakeholders including providers, beneficiaries and other stakeholders, focus group discussions with mothers of under-five children and participant and non-participant observations of vaccination-related activities. RESULTS: Unlike most other ethical analyses that look at the ethics of vaccination policies, the interactions of normative principles and notions are analysed in this article. Moral obligation of parents towards their children, beneficence of healthcare providers and the utilitarian aspirations of the state are the key normative principles involved. Our analysis points to the interplay of both synergy and conflict in ethical notions and moral values in the context of immunisation services. Paternalistic interventions like special immunisation campaigns against polio and Japanese encephalitis are a case in point: they generate conflict at the normative level and create mistrust. CONCLUSIONS: Analysis of vaccination policies and programmes needs to go beyond factors that assess monetary benefits or herd immunity. Understanding the interactions of normative notions that shape the social organisation of the providers and the users of vaccination is important in creating a sustainable environment for the programme. PMID- 23457323 TI - Semen quality and reproductive hormones in Faroese men: a cross-sectional population-based study of 481 men. AB - OBJECTIVES: To determine semen quality and reproductive hormone levels in young Faroese men. DESIGN: Descriptive cross-sectional study of Faroese men compared with Danish men. SETTING: Faroese one-centre study. PARTICIPANTS: 481 men born from 1981 to 1987 and investigated from 2007 to 2010. OUTCOME MEASURES: Sperm concentration, semen volume, total sperm count, sperm motility, sperm morphology and reproductive hormone levels. RESULTS: Sperm concentrations for the Faroese men were lower than for the Danish men (crude median 40 vs 48 mill/ml, p<0.0005). Semen volume was higher, and thus the total sperm counts did not differ (159 vs 151 mill, p=0.2). Motility and morphology did not differ between the Faroese and Danes. The inhibin B/follicle-stimulating hormone ratios for the Faroese men were lower than for the Danes (64 vs 76, p=0.001). Similarly, lower total testosterone/luteinising hormone (LH) ratio (4.6 vs 6.0, p<0.0005) and lower calculated free-testosterone/LH ratio (94 vs 134, p<0.0005) were detected for the Faroese men. CONCLUSIONS: Semen quality among the Faroese men is at the same low level as reported for Danish men, and the reproductive hormone levels furthermore indicated a lower Leydig cell capacity for testosterone production. The influence of environmental exposure and genetic factors on semen quality has to be studied further. PMID- 23457324 TI - Initiation rites at menarche and self-reported dysmenorrhoea among indigenous women of the Colombian Amazon: a cross-sectional study. AB - OBJECTIVES: To investigate the association between self-reported dysmenorrhoea and patterns of female initiation rites at menarche among Amazonian indigenous peoples of Vaupes in Colombia. DESIGN: A cross-sectional study of all women in seven indigenous communities. Questionnaire administered in local language documented female initiation rites and experience of dysmenorrhoea. Analysis examined 10 initiation components separately, then together, comparing women who underwent all rites, some rites and no rites. SETTINGS: Seven indigenous communities belonging to the Tukano language group in the Great Eastern Reservation of Vaupes (Colombia) in 2008. PARTICIPANTS: All women over the age of 13 years living in the seven communities in Vaupes, who had experienced at least two menstruations (n=185), aged 13-88 years (mean 32.5; SD 15.6). PRIMARY AND SECONDARY OUTCOME MEASURES: The analysis rested on pelvic pain to define dysmenorrhoea as the main outcome. Women were also asked about other disorders present during menstruation or the precedent days, and about the interval between two menstruations and duration of each one. RESULTS: Only 17.3% (32/185) completed all initiation rites and 52.4% (97/185) reported dysmenorrhoea. Women not completing the rites were more likely to report dysmenorrhoea than those who did so (p=0.01 Fisher exact), taking into account age, education, community, parity and use of family planning. Women who completed less than the full complement of rites had higher risk than those who completed all rites. Those who did not complete all rites reported increased severity of dysmenorrhoea (p=0.00014). CONCLUSIONS: Our results are compatible with an association between traditional practices and women's health. We could exclude indirect associations with age, education, parity and use of family planning as explanations for the association. The study indicates feasibility, possible utility and limits of intercultural epidemiology in small groups. PMID- 23457325 TI - Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in Parkinson's disease: a cross-sectional and 3-year longitudinal cohort study. AB - OBJECTIVE: Dysphagia is one of the cardinal symptoms of Parkinson's disease (PD). It is closely related to the quality of life and longevity of PD patients. The aim of the study is to clarify the pathophysiological mechanisms responsible for dysphagia in PD. DESIGN: A cross-sectional and longitudinal comparative study. SETTING: Tohoku University Hospital. PARTICIPANTS: Eight patients with dysphagia, 15 patients without dysphagia and 10 normal control subjects. MAIN OUTCOME MEASURES: The time needed for swallowing initiation and changes in brain glucose metabolism at baseline and after a 3-year follow-up period. RESULTS: The time needed for swallowing initiation was significantly longer in the patients with dysphagia compared with the patients without dysphagia at baseline and after the 3-year follow-up period (p<0.05). The patients with dysphagia exhibited hypometabolism in the supplementary motor area (SMA) and the anterior cingulate cortex (ACC) compared with the 10 normal control subjects at baseline (uncorrected p<0.001). After the 3-year follow-up period, the number of brain areas showing hypometabolism increased, involving not only the SMA and the ACC but also the bilateral medial frontal lobes, middle cingulate cortex, thalamus and right superior, middle, inferior and orbital frontal gyri (uncorrected p<0.001). In contrast, the patients without dysphagia showed virtually no regional hypometabolism at baseline (uncorrected p<0.001) and only a small degree of hypometabolism in the SMA and ACC after the 3-year follow-up period (uncorrected p<0.001). CONCLUSIONS: These results suggest that dysphagia in PD patients is mainly related to a difficulty in swallowing initiation that is based on a combination of poor movement planning due to SMA dysfunction and impaired cognitive processing due to ACC dysfunction. PMID- 23457326 TI - Peer-to-peer mentoring for individuals with early inflammatory arthritis: feasibility pilot. AB - OBJECTIVES: To examine the feasibility and potential benefits of early peer support to improve the health and quality of life of individuals with early inflammatory arthritis (EIA). DESIGN: Feasibility study using the 2008 Medical Research Council framework as a theoretical basis. A literature review, environmental scan, and interviews with patients, families and healthcare providers guided the development of peer mentor training sessions and a peer-to peer mentoring programme. Peer mentors were trained and paired with a mentee to receive (face-to-face or telephone) support over 12 weeks. SETTING: Two academic teaching hospitals in Toronto, Ontario, Canada. PARTICIPANTS: Nine pairs consisting of one peer mentor and one mentee were matched based on factors such as age and work status. PRIMARY OUTCOME MEASURE: Mentee outcomes of disease modifying antirheumatic drugs (DMARDs)/biological treatment use, self-efficacy, self-management, health-related quality of life, anxiety, coping efficacy, social support and disease activity were measured using validated tools. Descriptive statistics and effect sizes were calculated to determine clinically important (>0.3) changes. Peer mentor self-efficacy was assessed using a self-efficacy scale. Interviews conducted with participants examined acceptability and feasibility of procedures and outcome measures, as well as perspectives on the value of peer support for individuals with EIA. Themes were identified through constant comparison. RESULTS: Mentees experienced improvements in the overall arthritis impact on life, coping efficacy and social support (effect size >0.3). Mentees also perceived emotional, informational, appraisal and instrumental support. Mentors also reported benefits and learnt from mentees' fortitude and self-management skills. The training was well received by mentors. Their self efficacy increased significantly after training completion. Participants' experience of peer support was informed by the unique relationship with their peer. All participants were unequivocal about the need for peer support for individuals with EIA. CONCLUSIONS: The intervention was well received. Training, peer support programme and outcome measures were demonstrated to be feasible with modifications. Early peer support may augment current rheumatological care. TRIAL REGISTRATION NUMBER: NCT01054963, NCT01054131. PMID- 23457328 TI - Predictors of non-response in a UK-wide cohort study of children's accelerometer determined physical activity using postal methods. AB - OBJECTIVES: To investigate the biological, social, behavioural and environmental factors associated with non-consent, and non-return of reliable accelerometer data (>=2 days lasting >=10 h/day), in a UK-wide postal study of children's activity. DESIGN: Nationally representative prospective cohort study. SETTING: Children born across the UK, between 2000 and 2002. PARTICIPANTS: 13 681 7 to 8 year-old singleton children who were invited to wear an accelerometer on their right hip for 7 consecutive days. Consenting families were posted an Actigraph GT1M accelerometer and asked to return it by post. PRIMARY OUTCOME MEASURES: Study consent and reliable accelerometer data acquisition. RESULTS: Consent was obtained for 12 872 (94.5%) interviewed singletons, of whom 6497 (50.5%) returned reliable accelerometer data. Consent was less likely for children with a limiting illness or disability, children who did not have people smoking near them, children who had access to a garden, and those who lived in Northern Ireland. From those who consented, reliable accelerometer data were less likely to be acquired from children who: were boys; overweight/obese; of white, mixed or 'other' ethnicity; had an illness or disability limiting daily activity; whose mothers did not have a degree; who lived in rented accommodation; who exercised once a week or less; who had been breastfed; were from disadvantaged wards; had younger mothers or lone mothers; or were from households with just one, or more than three children. CONCLUSIONS: Studies need to encourage consent and reliable data return in the wide range of groups we have identified to improve response and reduce non-response bias. Additional efforts targeted at such children should increase study consent and data acquisition while also reducing non-response bias. Adjustment must be made for missing data that account for missing data as a non-random event. PMID- 23457327 TI - Current treatments in diabetic macular oedema: systematic review and meta analysis. AB - OBJECTIVES: The aim of this systematic review is to appraise the evidence for the use of anti-VEGF drugs and steroids in diabetic macular oedema (DMO) as assessed by change in best corrected visual acuity (BCVA), central macular thickness and adverse events DATA SOURCE: MEDLINE, EMBASE, Web of Science with Conference Proceedings and the Cochrane Library (inception to July 2012). Certain conference abstracts and drug regulatory web sites were also searched. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Randomised controlled trials were used to assess clinical effectiveness and observational trials were used for safety. Trials which assessed triamcinolone, dexamethasone, fluocinolone, bevacizumab, ranibizumab, pegaptanib or aflibercept in patients with DMO were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias was assessed using the Cochrane risk of bias tool. Study results are narratively described and, where appropriate, data were pooled using random effects meta-analysis. RESULTS: Anti VEGF drugs are effective compared to both laser and placebo and seem to be more effective than steroids in improving BCVA. They have been shown to be safe in the short term but require frequent injections. Studies assessing steroids (triamcinolone, dexamethasone and fluocinolone) have reported mixed results when compared with laser or placebo. Steroids have been associated with increased incidence of cataracts and intraocular pressure rise but require fewer injections, especially when steroid implants are used. LIMITATIONS: The quality of included studies varied considerably. Five of 14 meta-analyses had moderate or high statistical heterogeneity. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The anti-VEGFs ranibizumab and bevacizumab have consistently shown good clinical effectiveness without major unwanted side effects. Steroid results have been mixed and are usually associated with cataract formation and intraocular pressure increase. Despite the current wider spectrum of treatments for DMO, only a small proportion of patients recover good vision (>=20/40), and thus the search for new therapies needs to continue. PMID- 23457329 TI - The incidence and impact of recurrent workplace injury and disease: a cohort study of WorkSafe Victoria, Australia compensation claims. AB - OBJECTIVE: To determine the incidence and impact of recurrent workplace injury and disease over the period 1995-2008. DESIGN: Population-based cohort study using data from the state workers' compensation system database. SETTING: State of Victoria, Australia. PARTICIPANTS: A total of 448 868 workers with an accepted workers' compensation claim between 1 January 1995 and 31 December 2008 were included into this study. Of them, 135 349 had at least one subsequent claim accepted for a recurrent injury or disease during this period. MAIN OUTCOME MEASURES: Incidence of initial and recurrent injury and disease claims and time lost from work for initial and recurrent injury and disease. RESULTS: Over the study period, 448 868 workers lodged 972 281 claims for discrete occurrences of work-related injury or disease. 53.4% of these claims were for recurrent injury or disease. On average, the rates of initial claims dropped by 5.6%, 95% CI ( 5.8% to -5.7%) per annum, while the rates of recurrent injuries decreased by 4.1%, 95% CI (-4.2% to -0.4%). In total, workplace injury and disease resulted in 188 978 years of loss in full-time work, with 104 556 of them being for the recurrent injury. CONCLUSIONS: Recurrent work-related injury and disease is associated with a substantial social and economic impact. There is an opportunity to reduce the social, health and economic burden of workplace injury by enacting secondary prevention programmes targeted at workers who have incurred an initial occupational injury or disease. PMID- 23457330 TI - Poststroke fatigue and depression are related to mortality in young adults: a cohort study. AB - OBJECTIVES: To investigate the relationship between poststroke fatigue and depression and subsequent mortality in young ischaemic stroke patients in a population-based study. DESIGN: A prospective cohort study. SETTING: All surviving young ischaemic stroke patients living in Hordaland County. PARTICIPANTS: Young ischaemic stroke patients aged 15-50 years at the time of the stroke were invited to a follow-up on an average 6 years after the index stroke. Psychosocial factors and risk factors were registered. Fatigue was self-assessed by the Fatigue Severity Scale (FSS). Depression was measured by Montgomery-Asberg Depression Rating Scale (MADRS). INTERVENTION: No intervention was performed. PRIMARY AND SECONDARY OUTCOME MEASURE: Mortality on follow-up. RESULTS: In total, 190 patients were included. The mean age on follow-up was 48 years and subsequent follow-up period was 12 years. Cox regression analysis showed that mortality was associated with FSS score (p=0.005) after adjusting for age (p=0.06) and sex (p=0.19). Cox regression analysis showed that mortality was associated with MADRS score (p=0.006) after adjusting for age (p=0.10) and sex (p=0.11). CONCLUSIONS: Both fatigue and depression are associated with long-term mortality in young adults with ischaemic stroke. Depression may be linked to higher mortality because of psychosocial factors and unhealthy lifestyles whereas the link between fatigue and mortality is broader including connection to diabetes mellitus, myocardial infarction and psychosocial factors. PMID- 23457331 TI - A cluster-randomised, parallel group, controlled intervention study of genetic prostate cancer risk assessment and use of PSA tests in general practice--the ProCaRis study: study protocol. AB - INTRODUCTION: Unsystematic screening for prostate cancer (PCa) is common, causing a high number of false-positive results. Valid instruments for assessment of individual risk of PCa have been called for. A DNA-based genetic test has been tested retrospectively. The clinical use of this test needs further investigation. The primary objective is to evaluate the impact on the use of prostate-specific antigen (PSA) tests of introducing genetic PCa risk assessment in general practice. The secondary objectives are to evaluate PCa-related patient experiences, and to explore sociocultural aspects of genetic risk assessment in patients at high PCa risk. METHODS AND ANALYSIS: The study is a cluster randomised, controlled intervention study with practice as the unit of randomisation. We expect 140 practices to accept participation and include a total of 1244 patients in 4 months. Patients requesting a PSA test in the intervention group practices will be offered a genetic PCa risk assessment. Patients requesting a PSA test in the control group practices will be handled according to current guidelines. Data will be collected from registers, patient questionnaires and interviews. Quantitative data will be analysed according to intention-to-treat principles. Baseline characteristics will be compared between groups. Longitudinal analyses will include time in risk, and multivariable analysis will be conducted to evaluate the influence of general practitioner and patient-specific variables on future PSA testing. Interview data will be transcribed verbatim and analysed from a social-constructivist perspective. ETHICS AND DISSEMINATION: Consent will be obtained from patients who can withdraw from the study at any time. The study provides data to the ongoing conceptual and ethical discussions about genetic risk assessment and classification of low-risk and high-risk individuals. The intervention model might be applicable to other screening areas regarding risk of cancer with identified genetic components, for example, colon cancer. The study is registered at the ClinicalTrials.gov (Identifier: NCT01739062). PMID- 23457332 TI - The association of patient characteristics and surgical variables on symptoms of pain and function over 5 years following primary hip-replacement surgery: a prospective cohort study. AB - OBJECTIVES: To identify patient characteristics and surgical factors associated with patient-reported outcomes over 5 years following primary total hip replacement (THR). DESIGN: Prospective cohort study. SETTING: Seven hospitals across England and Scotland. PARTICIPANTS: 1431 primary hip replacements for osteoarthritis. MAIN OUTCOME MEASURES: The Oxford Hip Score (OHS) was collected preoperatively and each year up to 5 years postoperatively. Repeated measures such as linear regression modelling are used to identify patient and surgical predictors of outcome and describe trends over time. RESULTS: The majority of patients demonstrated substantial improvement in pain/function in the first year after surgery-between 1 and 5 years follow-up, there was neither further improvement nor decline. The strongest determinant of attained postoperative OHS was the preoperative OHS-those with worse preoperative pain/function had worse postoperative pain/function. Other predictors with small but significant effects included: femoral component offset-women with an offset of 44 or more had better outcomes; age-compared to those aged 50-60, younger (age <50) and older patients (age >60) had worse outcome, increasing body mass index (BMI), more coexisting diseases and worse Short Form 36 mental health (MH) was related to worse postoperative pain/function. Assessment of change in OHS between preoperative and postoperative assessments revealed that patients achieved substantial and clinically relevant symptomatic improvement (change), regardless of variation in these patient and surgical factors. CONCLUSIONS: Patients received substantial benefit from surgery, regardless of their preoperative assessments and surgical characteristics (baseline pain/function, age, BMI, comorbidities, MH and femoral component offset). Further research is needed to identify other factors that can improve our ability to identify patients at risk of poor outcomes from THR surgery. PMID- 23457333 TI - Use of record-linkage to handle non-response and improve alcohol consumption estimates in health survey data: a study protocol. AB - INTRODUCTION: Reliable estimates of health-related behaviours, such as levels of alcohol consumption in the population, are required to formulate and evaluate policies. National surveys provide such data; validity depends on generalisability, but this is threatened by declining response levels. Attempts to address bias arising from non-response are typically limited to survey weights based on sociodemographic characteristics, which do not capture differential health and related behaviours within categories. This project aims to explore and address non-response bias in health surveys with a focus on alcohol consumption. METHODS AND ANALYSIS: The Scottish Health Surveys (SHeS) aim to provide estimates representative of the Scottish population living in private households. Survey data of consenting participants (92% of the achieved sample) have been record linked to routine hospital admission (Scottish Morbidity Records (SMR)) and mortality (from National Records of Scotland (NRS)) data for surveys conducted in 1995, 1998, 2003, 2008, 2009 and 2010 (total adult sample size around 40 000), with maximum follow-up of 16 years. Also available are census information and SMR/NRS data for the general population. Comparisons of alcohol-related mortality and hospital admission rates in the linked SHeS-SMR/NRS with those in the general population will be made. Survey data will be augmented by quantification of differences to refine alcohol consumption estimates through the application of multiple imputation or inverse probability weighting. The resulting corrected estimates of population alcohol consumption will enable superior policy evaluation. An advanced weighting procedure will be developed for wider use. ETHICS AND DISSEMINATION: Ethics approval for SHeS has been given by the National Health Service (NHS) Multi-Centre Research Ethics Committee and use of linked data has been approved by the Privacy Advisory Committee to the Board of NHS National Services Scotland and Registrar General. Funding has been granted by the MRC. The outputs will include four or five public health and statistical methodological international journal and conference papers. PRIMARY SUBJECT HEADING: Public health. SECONDARY SUBJECT HEADING: Addiction: health policy; mental health. PMID- 23457334 TI - Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase (PFKFB2) isoenzyme by amino acids. AB - Reciprocal regulation of metabolism and signaling allows cells to modulate their activity in accordance with their metabolic resources. Thus, amino acids could activate signal transduction pathways that control cell metabolism. To test this hypothesis, we analyzed the effect of amino acids on fructose-2,6-bisphosphate (Fru-2,6-P2) metabolism. We demonstrate that amino acids increase Fru-2,6-P2 concentration in HeLa and in MCF7 human cells. In conjunction with this, 6 phosphofructo-2-kinase activity, glucose uptake, and lactate concentration were increased. These data correlate with the specific phosphorylation of heart 6 phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2) isoenzyme at Ser-483. This activation was mediated by the PI3K and p38 signaling pathways. Furthermore, Akt inactivation blocked PFKFB2 phosphorylation and Fru-2,6-P2 production, thereby suggesting that the above signaling pathways converge at Akt kinase. In accordance with these results, kinase assays showed that amino acid-activated Akt phosphorylated PFKFB2 at Ser-483 and that knockdown experiments confirmed that the increase in Fru-2,6-P2 concentration induced by amino acids was due to PFKFB2. In addition, similar effects on Fru-2,6-P2 metabolism were observed in freshly isolated rat cardiomyocytes treated with amino acids, which indicates that these effects are not restricted to human cancer cells. In these cardiomyocytes, the glucose consumption and the production of lactate and ATP suggest an increase of glycolytic flux. Taken together, these results demonstrate that amino acids stimulate Fru-2,6-P2 synthesis by Akt-dependent PFKFB2 phosphorylation and activation and show how signaling and metabolism are inextricably linked. PMID- 23457335 TI - A TRPV4 channel C-terminal folding recognition domain critical for trafficking and function. AB - The Ca(2+)-permeable transient receptor potential vanilloid subtype 4 (TRPV4) channel mediates crucial physiological functions, such as calcium signaling, temperature sensing, and maintaining cell volume and energy homeostasis. Noticeably, most disease-causing genetic mutations are concentrated in the cytoplasmic domains. In the present study, we focused on the role of the TRPV4 C terminus in modulating protein folding, trafficking, and activity. By examining a series of C-terminal deletions, we identified a 20-amino acid distal region covering residues 838-857 that is critical for channel folding, maturation, and trafficking. Surface biotinylation, confocal imaging, and fluorescence-based calcium influx assay demonstrated that mutant proteins missing this region were trapped in the endoplasmic reticulum and unglycosylated, leading to accelerated degradation and loss of channel activity. Rosetta de novo structural modeling indicated that residues 838-857 assume a defined conformation, with Gly(849) and Pro(851) located at critical positions. Patch clamp recordings confirmed that lowering the temperature from 37 to 30 degrees C rescued channel activity of folding-defective mutants. Moreover, biochemical tests demonstrated that, in addition to participating in C-C interaction, the C terminus also interacts with the N terminus. Taken together, our findings indicate that the C-terminal region of TRPV4 is critical for channel protein folding and maturation, and the short distal segment plays an essential role in this process. Therefore, selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as pain and skeletal dysplasias. PMID- 23457337 TI - Odor-taste learning assays in Drosophila larvae. AB - The Drosophila larva is an emerging model for studies in behavioral neurogenetics because of its simplicity in terms of cell number. Despite this simplicity, basic features of neuronal organization and key behavior faculties are shared with adult flies and with mammals. Here, we describe a pavlovian-type learning assay in fruit fly larvae. A group of larvae is sequentially exposed to specific odors in the presence or the absence of sugar, and then tested to determine whether they prefer the odor previously experienced with the reward. The protocol uses a two-group, reciprocal training design: One group of Drosophila larvae is exposed to n-amyl acetate (AM) with a sugar reward (+), then subsequently exposed to 1 octanol (OCT) with no reward (denoted AM+/OCT). The other group receives the reciprocal training (AM/OCT+). The two groups of larvae are then tested for their choices between AM and OCT. Relatively higher preferences for AM after AM+/OCT training than after AM/OCT+ training reflect associative learning and are quantified by the learning index (LI). This method offers a robust, simple, cheap, and reasonably quick test for learning ability (an aversive version is available as well, using either high-concentration salt or quinine as punishment). With the concerted efforts of the Drosophila research community, we anticipate it will allow us to unravel the full circuitry underlying odor-taste learning on a single-cell level. PMID- 23457338 TI - Tissue shrinkage and stereological studies. AB - Shrinkage often takes place in biological tissues during the different phases of preparation for microscopy. This can have detrimental effects on the stereological estimates, even when unbiased procedures are used. There are different types of shrinkage, and an awareness of them is essential when designing stereological studies. Some forms of shrinkage can be taken into account to ensure the unbiasedness of an estimator, but some cannot and should be avoided. Dimensional changes that take place during fixation, embedding, sectioning, mounting, and staining can seriously compromise one's ability to make assumption-free estimates of length and surface, but there are steps that can be taken to reduce the impact of these changes on estimates of object number and size. This article describes types of shrinkage and the effects of shrinkage on estimators of object number. It gives an example of how to make a number-weighted correction of section thickness and also discusses the consequences of shrinkage for the validity of estimates of object size. PMID- 23457336 TI - The Xenopus oocyte: a single-cell model for studying Ca2+ signaling. AB - In the four decades since the Xenopus oocyte was first demonstrated to have the capacity to translate exogenous mRNAs, this system has been exploited for many different experimental purposes. Typically, the oocyte is used either as a "biological test tube" for heterologous expression of proteins without any particular cell biological insight or, alternatively, it is used for applications where cell biology is paramount, such as investigations of the cellular adaptations that power early development. In this article, we discuss the utility of the Xenopus oocyte for studying Ca(2+) signaling in both these contexts. PMID- 23457339 TI - The RNase protection assay. AB - The RNase protection assay is a sensitive method for transcription start-site localization. It begins with an RNA probe that is uniformly labeled by incorporation of one [alpha-(32)P]NTP, usually [alpha-(32)P]UTP. The RNA probe is synthesized by bacteriophage RNA polymerase (SP6, T7, or T3), which initiates transcription from specific phage promoters that have been engineered into a number of common plasmid vectors. The plasmid template contains a genomic DNA fragment spanning the region thought to contain the transcription start site for the gene of interest. This genomic fragment is subcloned into the plasmid downstream of the phage promoter in the antisense orientation, so that a portion of the 5' end of the resulting RNA probe will be complementary to the mRNA of interest. The radiolabeled probe is annealed to cytoplasmic or total cellular mRNA purified from the cells of interest, with the hybridization reaction proceeding for several hours or overnight. RNase A and/or RNase T1 is then added to the hybridization reactions. These nucleases digest the single-stranded overhang regions of RNA molecules, but RNA-RNA hybrids are resistant to cleavage. This resistance forms the conceptual basis for the procedure; the region of the probe that anneals to the specific mRNA will be resistant to digestion. The length of the resistant region of the probe will correspond to the distance from the 5' end of the probe to the transcription start site. The size of the resistant fragment can be determined by electrophoresis on a high-resolution, denaturing polyacrylamide gel. PMID- 23457341 TI - A rapid Western blotting protocol for the Xenopus oocyte. AB - Often experimentalists require a quantitative assessment of the levels of heterologously expressed proteins to best interpret changed Ca(2+) signaling patterns. Here, we detail a rapid and convenient western blotting method for individual Xenopus oocytes. The method exploits recently introduced rapid blotting systems, commercially available from Invitrogen (iBlot) or Bio-Rad (Trans-Blot Turbo). The key advantage is speed: from live cell to transferred membrane in <1 h. Therefore, oocytes can be conveniently processed for western blotting to assess relative expression levels, even after a long day of Ca(2+) imaging experiments. PMID- 23457340 TI - Nuclear microinjection to assess how heterologously expressed proteins impact Ca2+ signals in Xenopus oocytes. AB - The Xenopus oocyte is frequently used for heterologous expression and for studying the spatiotemporal patterning of Ca(2+) signals. Here, we outline a protocol for nuclear microinjection of the Xenopus oocyte for the purpose of studying how subsequently expressed proteins impact intracellular Ca(2+) signals evoked by inositol trisphosphate (InsP3). Injected oocytes can easily be identified by reporter technologies and the impact of heterologously expressed proteins on the generation and properties of InsP3-evoked Ca(2+) signals can be resolved using caged InsP3 and fluorescent Ca(2+) indicators. PMID- 23457342 TI - Site-specific labeling of RNA. AB - In this protocol, RNAs containing a specific internally labeled phosphate are generated. The entire transcript of interest is synthesized using in vitro transcription. It is then digested with RNase H in the presence of a complementary chimeric oligonucleotide of the sequence 5'-NNNddddNNNNNNN-3', where N is a 2'-O-methyl (2' OMe) ribonucleotide and d is a de-oxy-nu-cle-o-tide. RNase H specifically cleaves the RNA in the oligonucleotide-RNA hybrid at the phosphodiester bond opposite the 5'-most deoxynucleotide, creating 3'-hydroxyl and 5'-phosphate termini. After dephosphorylation of the 5' end of the 3' fragment with phosphatase, this terminus is labeled to high specific activity with [gamma-(32)P]ATP. The fragments of the original RNA are then resealed with T4 DNA ligase in the presence of a splint (or bridge) oligonucleotide. These labeled RNAs can be used in subsequent procedures to probe RNA-protein or RNA-RNA interactions. PMID- 23457343 TI - Two-photon imaging of immune cells in neural tissue. AB - To develop new therapeutic strategies for many central nervous system (CNS) diseases, it is essential to observe the motility and function of immune cells within neural tissue. Two-photon laser-scanning microscopy is an outstanding technique for imaging these phenomena under in vivo-like conditions. To gain deeper insight into the pathological phenomena that occur during chronic neuroinflammation of the CNS, we use it to view acute murine hippocampal slices cocultured with different subpopulations of immune cells and to view in vivo the brain stem of anesthetized transgenic mice affected by experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. This protocol describes the preparation of cocultures of acute hippocampal slices with antigen specific T helper 17 (Th17) cells migrating into the parenchyma, and the preparation of anesthetized mice for imaging the brain stem. We also discuss technical aspects of dual-color, two-photon laser-scanning microscopy that is used to image these samples and that allows for greater flexibility in the choice of fluorophores. PMID- 23457344 TI - Preparation of transgenic zebrafish embryos for imaging the developing retina. AB - The zebrafish retina is an ideal model system for addressing neural fate specification in vivo. As in all vertebrate species studied, the retina is composed of seven major cell types distributed in a laminated histogenetic arrangement. The major connections and final positioning of cell types are well known, allowing lineage tracing and identification of final cell outcome by location, morphology, and subsequent immunostaining. The retina is conveniently located on the outside of the fish, allowing the embryos to be mounted such that the eye is close to the coverslip. This enables the entire structure to be imaged in four dimensions (4D) within the given focusing depth constraints. When preparing cells for lineage tracing, it is very important to label isolated cells mosaically, so that they stand out in a mostly unlabeled background. This can be achieved by transplanting cells from transgenic or injected embryos into uninjected embryos, as is described in this protocol. Transgenic (wild-type or mutant) embryos expressing stable green or red fluorescent protein (GFP or RFP) are used as donors, and non-transgenics or transgenics expressing a different fluorescent label are used as hosts. Mosaic labeling can also be achieved by DNA injection. PMID- 23457345 TI - Imaging retinal progenitor lineages in developing zebrafish embryos. AB - In this protocol, we describe how to make and analyze four dimensional (4D) movies of retinal lineage in the zebrafish embryo in vivo. 4D consists of three spatial dimensions (3D) reconstructed from stacks of confocal planes plus one time dimension. Our imaging is performed on transgenic cells that express fluorescent proteins under the control of cell-specific promoters or on cells that transiently express such reporters in specific retinal cell progenitors. An important aspect of lineage tracing is the ability to follow individual cells as they undergo multiple cell divisions, final migration, and differentiation. This may mean many hours of 4D imaging, requiring that cells be kept healthy and maintained under conditions suitable for normal development. The longest movies we have made are ~50 h. By analyzing these movies, we can see when a specific cell was born and who its sister was, allowing us to reconstruct its retinal lineages in vivo. PMID- 23457346 TI - Lasers for nonlinear microscopy. AB - Various versions of nonlinear microscopy are revolutionizing the life sciences, almost all of which are made possible because of the development of ultrafast lasers. In this article, the main properties and technical features of short pulse lasers used in nonlinear microscopy are summarized. Recent research results on fiber lasers that will impact future instruments are also discussed. PMID- 23457347 TI - Detecting RNA-protein interactions by photocross-linking using RNA molecules containing uridine analogs. AB - Various cross-linking techniques form covalent attachments between proteins and RNAs. Straight ultraviolet (UV) cross-linking using short-wavelength UV light is inherently very inefficient. Therefore, it is often desirable to increase the efficiency of cross-linking. The uridine analogs 4-thiouridine and halogenated uridine (5-bromouridine or 5-iodouridine) are much more photoreactive than uridine. Accordingly, RNAs substituted with these bases are quite effective for cross-linking applications. This protocol describes the detection of RNA-protein interactions by photocross-linking using RNA molecules containing 4-thiouridine, but identical procedures apply to using 5-bromouridine or 5-iodouridine. Fully substituted RNAs are useful in determining whether any proteins interact with the RNA of interest. However, it may be preferable to use site-specifically substituted RNA if one has foreknowledge of critical regions in the RNA of interest. For any cross-linking application using substituted RNA, it is essential to remember that the uridine analogs are activated at a wavelength >304 nm (312 nm) than is used for short-wavelength (254 nm) cross-linking. PMID- 23457348 TI - Brain tumor imaging: live imaging of glioma by two-photon microscopy. AB - Glioblastoma is a highly invasive and aggressive brain tumor that is very difficult to treat. The rat glioma cell line CNS-1 is a widely used, well characterized model of infiltrative glioma. We have used CNS-1 to study tumors that initiate within the brain parenchyma. The CNS-1 cells were stably transfected with the yellow fluorescent protein (YFP) variant Venus to enable standard one-photon and two-photon imaging. In this protocol, we describe how to prepare a cranial window and how to inject the tumor cells into the cerebral cortex at a depth suitable for two-photon imaging. Imaging can begin 24 h after implantation of the cells. Two-photon imaging uses a long excitation wavelength (920 nm); the emission spectrum is the same for the fluorophore as for standard one-photon imaging (emission maximum = 528 nm). Two-photon microscopy permits tissue imaging to depths of 500 MUm with three-dimensional (3D) high resolution and minimal photodamage to surrounding tissues. Multiple imaging sessions can be conducted over weeks in the same animal, depending on how long the cranial window remains clear and how quickly the tumor grows. Using this technique, the kinetics of tumor growth and invasion into the surrounding brain parenchyma can be measured in the same animal. This model can be used for determining the molecular and cellular players in brain tumor growth and invasion and for testing potential drug therapies to prevent brain metastasis. PMID- 23457349 TI - Brain tumor imaging: imaging brain metastasis using a brain-metastasizing breast adenocarcinoma. AB - Brain metastases from primary or secondary breast tumors are difficult to model in the mouse. When metastatic breast cancer cell lines are injected directly into the arterial circulation, only a small fraction of cells enter the brain to form metastatic foci. To study the molecular and cellular mechanisms of brain metastasis, we have transfected MB-231BR, a brain-homing derivative of a human breast adenocarcinoma line MDA-MB-231, with the yellow fluorescent protein (YFP) variant Venus. MB-231BR selectively enters the brain after intracardiac injection into the arterial circulation, resulting in accumulation of fluorescent foci of cells in the brain that can be viewed by standard fluorescence imaging procedures. We describe how to perform the intracardiac injection and the parameters used to quantify brain metastasis in brain sections by standard one photon fluorescence imaging. The disadvantage of this model is that the kinetics of growth over time cannot be determined in the same animal. In addition, the injection technique does not permit precise placement of tumor cells within the brain. This model is useful for determining the molecular determinants of brain tumor metastasis. PMID- 23457350 TI - BAC transgenic mice and the GENSAT database of engineered mouse strains. AB - The brain is a complex tissue comprising hundreds of distinct cell types, each of which has unique circuitry and plays a discrete role in nervous system function. Large-scale studies mapping gene-expression patterns throughout the nervous system have revealed that many genes are exclusively expressed in specific cell populations. The GENSAT (Gene Expression Nervous System Atlas) Project created a library of engineered mice utilizing bacterial artificial chromosomes (BACs) to drive the expression of enhanced green fluorescent protein (eGFP) in genetically defined cell populations. BACs contain large segments of genomic DNA and retain most of the transcriptional regulatory elements directing the expression of a given gene, resulting in more faithful reproduction of endogenous expression patterns. BAC transgenic mice offer a robust solution to the challenging task of stably and reproducibly accessing specific cell types from a heterogeneous tissue such as the brain. A significant advantage of utilizing eGFP as a reporter is the fact that it can fill entire cells, including neuronal dendrites and axons as well as glial processes, making GENSAT reporter mice a powerful tool for neuroimaging studies. This article provides a primer on the generation of BAC transgenic mice and advantages for their use in labeling genetically defined cell types. It also provides an overview of searching the GENSAT database and ordering engineered mouse lines. PMID- 23457351 TI - Guidelines for brain amyloid imaging published. PMID- 23457354 TI - A focus on football injury. PMID- 23457355 TI - Choosing wisely in nuclear medicine and molecular imaging. PMID- 23457356 TI - Learning: The JNM editorial process. PMID- 23457357 TI - Eye movements while viewing narrated, captioned, and silent videos. AB - Videos are often accompanied by narration delivered either by an audio stream or by captions, yet little is known about saccadic patterns while viewing narrated video displays. Eye movements were recorded while viewing video clips with (a) audio narration, (b) captions, (c) no narration, or (d) concurrent captions and audio. A surprisingly large proportion of time (>40%) was spent reading captions even in the presence of a redundant audio stream. Redundant audio did not affect the saccadic reading patterns but did lead to skipping of some portions of the captions and to delays of saccades made into the caption region. In the absence of captions, fixations were drawn to regions with a high density of information, such as the central region of the display, and to regions with high levels of temporal change (actions and events), regardless of the presence of narration. The strong attraction to captions, with or without redundant audio, raises the question of what determines how time is apportioned between captions and video regions so as to minimize information loss. The strategies of apportioning time may be based on several factors, including the inherent attraction of the line of sight to any available text, the moment by moment impressions of the relative importance of the information in the caption and the video, and the drive to integrate visual text accompanied by audio into a single narrative stream. PMID- 23457358 TI - The temporal characteristics of the early and late stages of the L- and M-cone pathways that signal color. AB - Flickering long-wavelength light appears more yellow than steady light of the same average intensity. The hue change is consistent with distortion of the visual signal at some nonlinear site (or sites) that produces temporal components not present in the original stimulus (known as distortion products). We extracted the temporal attenuation characteristics of the early (prenonlinearity) and late (post-nonlinearity) filter stages in the L- and M-cone chromatic pathway by varying the input stimulus to manipulate the distortion products and the measuring of the observers' sensitivity to them. The early, linear, filter stage acts like a band-pass filter peaking at 10-15 Hz with substantial sensitivity losses at both lower and higher frequencies. Its characteristics are consistent with nonlinearity being early in the visual pathway but following surround inhibition. The late stage, in contrast, acts like a low-pass filter with a cutoff frequency around 3 Hz. The response of the early stage speeds up with radiance, but the late stage does not. A plausible site for the nonlinearity, which modelling suggests may be smoothly compressive but with a hard limit at high input levels, is after surround inhibition from the horizontal cells. PMID- 23457359 TI - On higher ground: ethical reasoning and its relationship with error disclosure. AB - BACKGROUND: There is broad consensus that disclosure of harmful medical errors is vital to improve safety and is ethically required. Although most physicians-in training are taught ethics, there have been no empirical studies on whether ethical reasoning is related to disclosure. We examined whether scores on a test of ethical reasoning were associated with greater willingness to disclose errors. METHODS: We conducted a cross-sectional survey of house officers in internal medicine at Johns Hopkins Hospital. Ethical reasoning was assessed using the Defining Issues Test, V.2 (DIT-2). Higher DIT-2 scores are associated with more sophisticated ethical reasoning, and scores tend to improve after formal ethical training. Respondents were then given a medical error scenario with multiple scripted disclosure options. Ethical reasoning scores were compared for different levels of disclosure. RESULTS: A total of 29 out of 127 medicine residents completed the survey (response rate=22.8%). The 41% of residents who would explicitly tell a patient that, 'an error happened' had significantly higher DIT 2 scores than those who would not (51.1 vs 31.6, p<0.01). Higher DIT-2 scores were found in the 62% of residents who would give the most detail about the error (44.8 vs 31.2, p=0.04) and in the 71% of residents who would take personal responsibility (43.5 vs 27.9, p=0.03). CONCLUSIONS: Ethical reasoning scores were associated with acknowledging an error, providing more detailed explanations and taking personal responsibility. The low response rate may limit generalisability. Nevertheless, taken together with prior studies showing that ethical reasoning can be taught and measured, our findings suggest that ethical training may help to improve disclosure of medical errors. PMID- 23457360 TI - To what extent are inpatient deaths preventable? The author's reply. PMID- 23457361 TI - High-reliability emergency response teams in the hospital: improving quality and safety using in situ simulation training. AB - INTRODUCTION: In situ simulation training is a team-based training technique conducted on actual patient care units using equipment and resources from that unit, and involving actual members of the healthcare team. We describe our experience with in situ simulation training in a major children's medical centre. MATERIALS AND METHODS: In situ simulations were conducted using standardised scenarios approximately twice per month on inpatient hospital units on a rotating basis. Simulations were scheduled so that each unit participated in at least two in situ simulations per year. Simulations were conducted on a revolving schedule alternating on the day and night shifts and were unannounced. Scenarios were preselected to maximise the educational experience, and frequently involved clinical deterioration to cardiopulmonary arrest. RESULTS: We performed 64 of the scheduled 112 (57%) in situ simulations on all shifts and all units over 21 months. We identified 134 latent safety threats and knowledge gaps during these in situ simulations, which we categorised as medication, equipment, and/or resource/system threats. Identification of these errors resulted in modification of systems to reduce the risk of error. In situ simulations also provided a method to reinforce teamwork behaviours, such as the use of assertive statements, role clarity, performance of frequent updating, development of a shared mental model, performance of independent double checks of high-risk medicines, and overcoming authority gradients between team members. Participants stated that the training programme was effective and did not disrupt patient care. CONCLUSIONS: In situ simulations can identify latent safety threats, identify knowledge gaps, and reinforce teamwork behaviours when used as part of an organisation-wide safety programme. PMID- 23457362 TI - Platelets coming of age: implications for our understanding of allergic inflammation. PMID- 23457363 TI - A rare glimpse behind the mask of sepsis-induced organ failures provides hope for an eventual cure. PMID- 23457364 TI - Why does the transplanted lung sometimes fail to work? PMID- 23457365 TI - Willing suspension of disbelief: new roles for Violetta and Mimi. PMID- 23457366 TI - Lung volume reexpansion surgery: a surgical secret. PMID- 23457367 TI - Issues applying a math model to estimate continuous positive airway pressure response in Cheyne-Stokes respiration. PMID- 23457368 TI - Drug concentration monitoring in Mycobacterium avium lung disease: problems with methods and conclusions. PMID- 23457369 TI - Biliary sarcoidosis: early diagnosis minimizes the need for surgery. PMID- 23457370 TI - Aortoatrial fistula. PMID- 23457371 TI - The effect of failure mode and effect analysis on reducing percutaneous coronary intervention hospital door-to-balloon time and mortality in ST segment elevation myocardial infarction. AB - BACKGROUND: Door-to-balloon (D2B) time is an important factor in the outcome of ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. We aimed to use failure mode and effect analysis to reduce the D2B time for patients with STEMI and to improve clinical outcomes. METHODS: There were three stages in this study. In Stage 0, data collected from 2005-2006 was used to identify failures in the process, and during Stage 2 (2007) and Stage 3 (2008) the efficacy of intrahospital and interhospital strategies to reduce the D2B time were evaluated. This study enrolled 385 patients; 86 from 2005-2006; 80 in 2007; and 219 in 2008. RESULTS: By making improvements in these steps, the median D2B time was reduced from 146 min to 32 min for all patients. The proportion of patients with a D2B time of <90 min significantly increased from Stage 0 to Stage 1 and from Stage 1 to Stage 2, for all patients as well as for the non-transferred and transferred subgroups of patients (all p values <0.0001). For non-transferred patients, only reinfarction free survival showed significant difference among the three stages (p=0.0225), and for transferred patients, only overall survival showed significant difference among the three stages (p=0.0322). Cox's proportional hazards regression analysis showed Stage 2 was associated with a lower risk of reinfarction and mortality compared with Stage 0. CONCLUSIONS: This study found that failure mode and effect analysis is a powerful method for identifying weaknesses in D2B processes and evaluating strategies to reduce the D2B time. PMID- 23457372 TI - Development of a specific method to evaluate 8-hydroxy, 2-deoxyguanosine in sperm nuclei: relationship with semen quality in a cohort of 94 subjects. AB - Oxidative stress (OS) is involved in many disoders including male infertility. Human spermatozoa are very sensitive targets of reactive oxygen species (ROS) and most sperm functions are impaired in the case of OS. In addition unbalanced production of ROS is considered one of the most important causes of sperm DNA fragmentation, a semen trait of infertile men. The relationship between oxidative damage and semen quality is partially controversial, probably due to the different methods and/or targets used to reveal the OS. In this study, by fluorescence microscopy and flow cytometry, we compared two methods to reveal 8 hydroxy,2-deoxyguanosine (8-OHdG), the hallmark of oxidative DNA damage: an immunofluorescence method and the commercial OxyDNA kit. We found that although both methods localized the labelling in sperm nuclei they yielded different measures, and only with the immunofluorescence method was the labelling specific for sperm 8-OHdG. The immunofluorescence method, coupled to flow cytometry, was thus selected to analyse the 8-OHdG content in semen samples from 94 subfertile patients and to investigate the relationship with semen quality. We found that the percentages of spermatozoa with 8-OHdG (mean+/-s.d., 11.4+/-6.9%) were related to sperm count (Pearson's correlation coefficient (r)=-0.27, P=0.04 (ANOVA and student's t-test)), motility (progressive: r=-0.22, P=0.04; non progressive: r=0.25, P=0.01), and normal morphology (r=-0.27, P=0.01). In conclusion, we demonstrate that immunofluorescence/flow cytometry is a reliable and specific method to detect 8-OHdG at single-cell level and show that oxidative damage only partially overlaps poor semen quality, suggesting that it could provide additional information on male fertility with respect to routine semen analysis. PMID- 23457373 TI - CrossTalk proposal: Forward and backward pressure waves in the arterial system do represent reality. PMID- 23457374 TI - CrossTalk opposing view: Forward and backward pressure waves in the arterial system do not represent reality. PMID- 23457377 TI - Agreement between the DAS28-CRP assessed with 3 and 4 variables in patients with rheumatoid arthritis treated with biological agents in the daily clinic. AB - OBJECTIVE: The Disease Activity Score-28-C-reactive Protein 4 [DAS28-CRP(4)] composite measure for rheumatoid arthritis (RA) is based on 4 variables: tender and swollen joint counts, CRP, and patient global assessment. DAS28-CRP(3) includes only 3 variables, because patient global assessment has been omitted. Thresholds for low and high disease activity are the same for the 2 scores. The objective of our study was to compare the 2 DAS scores and their responses on the individual patient level. METHODS: Baseline and 12-week disease activity data from 239 patients with RA treated with a biological agent were extracted from the Danish registry for biological treatment (DANBIO). Cohen's effect sizes (ES) and disease activity levels according to the DAS thresholds were assessed. The Bland Altman method was used to examine the bias between the DAS scores and the 95% limits of agreement (LoA). RESULTS: Baseline values for DAS28-CRP(4) and DAS28 CRP(3) were 4.8 +/- 1.2 and 4.6 +/- 1.1, respectively. At 12 weeks, DAS28-CRP(4) had improved by -1.39 +/- 1.34 (p < 0.0001). At that timepoint the bias of DAS28 CRP(3) was -0.07 (LoA -0.69, 0.55) (p < 0.0001). The bias of the DAS28-CRP(3) response was +0.21 (LoA -0.49, 0.91) (p < 0.0001). ES for DAS28-CRP(4) was 1.2 +/ 1.1 versus 1.1 +/- 1.1 for DAS28-CRP(3) (p < 0.0001). Compared to DAS28-CRP(4), DAS28-CRP(3) categorized 33% fewer patients as having a high level of disease activity, 8% fewer patients as good responders, and 12% more patients as nonresponders. CONCLUSION: Mean values of DAS28-CRP(4) and DAS28-CRP(3) agreed well, but in the individual patient the difference between the scores and their responses may be substantial. PMID- 23457378 TI - Mycophenolate mofetil improves lung function in connective tissue disease associated interstitial lung disease. AB - OBJECTIVE: Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF. METHODS: We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF. RESULTS: We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% +/- 1.9%, p = 0.01; 6.1% +/- 1.8%, p = 0.0008; and 7.3% +/- 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% +/- 2.8%, p = 0.02; 7.1% +/- 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%. CONCLUSION: In a large diverse cohort of CTD ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD. PMID- 23457379 TI - Progression of nailfold microvascular damage and antinuclear antibody pattern in systemic sclerosis. AB - OBJECTIVE: This study evaluates possible correlations between the pattern of antinuclear antibodies (ANA) on indirect immunofluorescence (IIF) testing and nailfold microangiopathy stage (early, active, and late stage) in systemic sclerosis (SSc). Patients with SSc were followed prospectively to monitor progression of microvascular damage. METHODS: The ANA pattern on IIF was searched in 42 patients with SSc showing an early pattern of nailfold microangiopathy at baseline, and was followed using nailfold videocapillaroscopy (NVC) for a median time of 91 months. RESULTS: Among patients whose microangiopathy showed a rapid progression from early to late pattern on NVC, the IIF pattern was fine-speckled + nucleolar (Scl-70+) in 44%, centromeric in 33%, nucleolar in 11%, and homogeneous in 11% of patients with SSc. Antitopoisomerase I antibodies were significantly more frequent (57%) in patients with late pattern of microangiopathy on NVC. The median time of progression from early to active disease was significantly lower in patients with both fine-speckled + nucleolar and nucleolar ANA positivity. The severity of microangiopathy was higher in patients with the nucleolar pattern on IIF. Patients already showing a slight reduction of capillary number at baseline were likely to have either the nucleolar or the fine-speckled + nucleolar pattern on IIF. Of note, 37% of patients still showing the early microangiopathy pattern on NVC at the end of the followup were ANA-negative. CONCLUSION: ANA-negative patients with SSc display a slower progression of nailfold microangiopathy characterized by the early pattern on NVC. Progression to the late NVC pattern (more advanced stage of microvascular damage) seems to be associated with a different autoantibody pattern on IIF (fine speckled + nucleolar pattern being the most prevalent). PMID- 23457380 TI - Efficacy and tolerability of probenecid as urate-lowering therapy in gout; clinical experience in high-prevalence population. AB - OBJECTIVE: Probenecid is recommended as urate-lowering therapy (ULT) in patients with gout where xanthine oxidase inhibitors are ineffective, not tolerated, or contraindicated. The aim of our study was to determine the efficacy of probenecid to achieve serum urate (SU) targets (< 0.36 mmol/l) in clinical practice. METHODS: We identified 57 patients prescribed with probenecid from a database of 521 rheumatology clinic attenders with gout. Demographic characteristics, indications for probenecid, probenecid doses, side effects, and laboratory data including estimated glomerular filtration rate (eGFR) and SU were recorded. RESULTS: There were 30/57 (53%) patients treated with probenecid as monotherapy and 27/57 (47%) patients treated with probenecid in combination with allopurinol. Target SU concentrations (< 0.36 mmol/l) were achieved in 10/30 (33%) of the probenecid monotherapy group and 10/27 (37%) of the combination treatment group. Baseline SU concentrations, but not eGFR or probenecid dose, independently predicted achievement of target SU. Target SU was achieved in 5/15 (33%) patients with eGFR < 50 ml/min/1.73 m(2). There was no difference in the percentage of patients achieving SU target in those with eGFR < 50 ml/min/1.73 m(2) compared with those with eGFR >= 50 ml/min/1.73 m(2). Adverse events attributed to probenecid were observed in 8/42 (19%) patients with eGFR >= 50 ml/min/1.73 m(2) and in 2/15 (13%) patients with eGFR < 50 ml/min/1.73 m(2). CONCLUSION: Probenecid has moderate efficacy as ULT in clinical management of patients with complex gout who have a lack of efficacy or intolerance to allopurinol. Patients with chronic kidney disease may respond to probenecid with similar rates of adverse events. PMID- 23457381 TI - Periarticular bone gain at proximal interphalangeal joints and changes in bone turnover markers in response to tumor necrosis factor inhibitors in rheumatoid and psoriatic arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are characterized by periarticular bone erosion; periarticular bone formation is a feature in PsA. The effect of anti-tumor necrosis factor-alpha (TNF-alpha) on periarticular bone remodeling is unclear in both diseases. Our aim was to assess the response of bone turnover markers (BTM) and hand bone mineral density (BMD) to anti-TNF over 3 years in RA and PsA. METHODS: We measured serum bone-specific alkaline phosphatase (bone ALP), procollagen type-I N-propeptide (PINP), intact osteocalcin, C-terminal cross-linking telopeptides (CTX-I), urinary N-terminal cross-linking telopeptide of type-I collagen (NTX-I), and free deoxypyridinoline crosslinks (fDPD) at baseline, 1, 12, and 36 months. BMD measurements (hands/spine/hip) were obtained at 3 timepoints. RESULTS: We recruited 62 patients (RA 35; PsA 27). BTM correlated significantly with hand BMD but not with central BMD. Low hand BMD was associated with RA and increased BTM. Following anti-TNF therapy, hip BMD declined while spine and hand BMD were unchanged. Periarticular BMD at proximal interphalangeal (PIP) joints increased while it decreased at metacarpophalangeal joints. Bone ALP increased steadily and was always higher in PsA. PINP and intact osteocalcin increased to a lesser extent, but resorption markers did not change. CONCLUSION: At baseline, hand BMD was inversely associated with BTM. Bone formation rather than resorption markers better showed the bone response to anti-TNF. Despite a lack of effect on central BMD, the modest effect of anti-TNF on PIP BMD may provide evidence that BTM reflect specifically bone remodeling activity at periarticular sites of inflammation in RA and PsA. PMID- 23457382 TI - Effect of all-transretinoic acid on Th17 and T regulatory cell subsets in patients with ankylosing spondylitis. AB - OBJECTIVE: We compared Th17 and T regulatory cells in patients with ankylosing spondylitis (AS) and in healthy controls. The effect of all-transretinoic acid (ATRA) was studied on cultured CD4+ T cells of patients with AS compared to controls. METHODS: Eighteen patients with AS and 18 age- and sex-matched healthy controls were included. CD4+ T cells were separated and cultured in conditions of anti-CD3 and anti-CD28 stimulation with and without ATRA. Intracellular and secreted cytokines, transcription factors, and gene expression were evaluated after 72 h. RESULTS: The frequency of CD4+IL-17+ T cells was significantly higher in patients with AS compared to controls, and ATRA could significantly decrease it. The frequency of forkhead box protein 3 (FOXP3)+ retinoic acid-related orphan receptor gammat (RORgammat) negative T-bet negative CD4+ cells was significantly lower in cases compared to controls. Intracellular and secreted interferon-gamma (IFN-gamma) was not significantly different between cases and controls. ATRA significantly increased intracellular IFN-gamma in cases but not in controls. Tumor necrosis factor-alpha (TNF-alpha) secretion was significantly higher and interleukin 10 secretion was significantly lower in culture supernatant of cases compared to controls. ATRA could significantly decrease TNF-alpha secretion in cases. CONCLUSION: Our findings favor a pathogenic role for Th17 cells in AS. Th1 cells did not seem to contribute in the pathogenesis of this disease. The effect of ATRA as an immunomodulator on deviated immune cells was associated with decreased inflammatory markers. This association could be a reason for a clinical trial of ATRA in patients with AS. PMID- 23457383 TI - Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. AB - OBJECTIVE: To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patient data were from 5 randomized controlled TCZ trials (n = 4211), their open-label extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis. RESULTS: Total duration of observation was 12,293 patient years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216. CONCLUSION: TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program. PMID- 23457384 TI - Longterm outcomes and damage accrual in patients with childhood systemic lupus erythematosus with psychosis and severe cognitive dysfunction. AB - OBJECTIVE: (1) To describe the clinical course and response to treatment; and (2) to evaluate and compare damage accrual of distinct phenotypic subgroups of patients with clinically important psychiatric illness of pediatric systemic lupus erythematosus (pSLE). METHODS: A single-center cohort study of patients with pSLE followed at a pediatric lupus clinic from 1985 to July 2009. Clinical course and response to treatment were studied. Remission was defined by absence of psychiatric/cognitive symptoms while receiving minimal doses of prednisone. Disease activity and damage were measured using SLE Disease Activity Index and SLE Damage Index. RESULTS: Fifty-three children were included: 40 with psychosis and cognitive dysfunction (PSYC group) and 13 with isolated cognitive dysfunction (COG group). All received immunosuppressive treatment. Eighteen of 32 treated with azathioprine required a change to cyclophosphamide for poor response but none on cyclophosphamide required a change. The median times to remission were 72 weeks (PSYC) and 70 weeks (COG). Eight patients (7 PSYC, 1 COG) experienced flare following response/remission. New damage was noted in 50% of children at a median of 11 months: 57% of PSYC group, 31% of COG group. Persistent cognitive dysfunction was seen in 16% of PSYC patients and 15% of COG patients. CONCLUSION: Most patients responded to immunosuppressive treatment, although median time to remission was > 1 year. Roughly half the patients acquired a new damage item, most of which did not interfere with functional abilities. Fewer than 20% of patients developed neuropsychiatric damage. Both phenotypes of psychiatric pSLE responded equally well to current treatment. PMID- 23457385 TI - Recommendations for frequency of visits to monitor systemic lupus erythematosus in asymptomatic patients: data from an observational cohort study. AB - OBJECTIVE: The aim of our study was to determine the optimal frequency of followup visits in patients with systemic lupus erythematosus (SLE). METHODS: Patients followed in the lupus clinic over a 2-year period who had at least 3 visits and at least 18 months of followup were included. At each visit patients undergo a complete history, physical examination, and laboratory evaluation. The following variables that would not have been recognized by the patient were identified: proteinuria, hematuria, pyuria, casts, low hemoglobin, leukopenia, thrombocytopenia, elevated serum creatinine, positive anti-DNA antibodies, and low complement. When one of these variables was detected, it was determined whether it was new, and whether other features of activity were present. Thus isolated new variables of interest were identified. Descriptive statistics were used. RESULTS: A total of 515 patients (89% female, 61% white) met the inclusion criteria, with an average of 6.1 +/- 1.5 for a total of 3126 visits. The average length of time between visits was 3.8 +/- 1.0 months. In the 515 patients, the variables of interest were the sole manifestation of SLE in 126 (24.5%) patients (in a total of 175 visits). The commonest manifestations were renal, low complement, and DNA antibodies followed by thrombocytopenia, low hemoglobin, and elevated creatinine. CONCLUSION: One in 4 patients with SLE seen over a 2-year period will have a solitary silent variable of interest that could be detected only by routine laboratory followup. Patients with mild or inactive disease should be followed with clinical and laboratory measures at 3-4 month intervals. PMID- 23457386 TI - RANKL/OPG ratio and DKK-1 expression in primary osteoblastic cultures from osteoarthritic and osteoporotic subjects. AB - OBJECTIVE: To evaluate the expression of Dickkopf-1 protein factor (DKK-1), DKK 2, and beta-catenin, components of the Wnt pathway, in human osteoarthritic (OA) and osteoporotic (OP) osteoblasts and to correlate it to cell metabolic activity, proliferation, and receptor activator of nuclear factor-kappaB ligand/osteoprotegerin (RANKL/OPG) expression. METHODS: Primary human osteoblast cultures were obtained from healthy, OA, and OP donors. In each cell population we evaluated DKK-1, DKK-2, nonphosphorylated beta-catenin and RANKL/OPG expression, osteocalcin and alkaline phosphatase (ALP) synthesis, and cell proliferation, both in basal condition and after vitamin D3 stimulation. RESULTS: DKK-1 and DKK-2 showed opposite patterns of expression in OA and OP osteoblasts. The RANKL/OPG ratio was significantly higher in the OP group because of a greater expression of RANKL, whereas it was significantly lower in the OA group because of a higher expression of OPG. Treatment with vitamin D3 increased the RANKL/OPG ratio and DKK-2 expression and reduced DKK-1 expression in each cell population, but did not affect beta-catenin levels. Both osteocalcin and ALP production and cell proliferation were enhanced in OA cells and reduced in the OP ones. CONCLUSION: These data confirm that OA and OP are characterized by opposite bone changes, consisting of reduced bone remodeling processes with increased osteoblast activity in OA, and enhanced bone resorptive activity with reduction of osteoblast metabolism in OP, and suggest that the Wnt pathway is involved in the pathogenesis of both diseases. PMID- 23457388 TI - Retraction: Myristic acid stimulates endothelial nitric-oxide synthase in a CD36- and an AMP kinase-dependent manner. PMID- 23457387 TI - Evaluation of serum biomarkers associated with radiographic progression in methotrexate-naive rheumatoid arthritis patients treated with methotrexate or golimumab. AB - OBJECTIVE: To evaluate associations between biomarkers and radiographic progression in methotrexate (MTX)-naive patients with rheumatoid arthritis (RA) treated with MTX or golimumab, a tumor necrosis factor inhibitor (with or without MTX). METHODS: Serum samples from 152 MTX-naive adults with active RA who received placebo + MTX (n = 37) or golimumab (combined 50 mg + MTX or 100 mg +/- MTX; n = 115) were analyzed for selected markers of inflammation and bone/cartilage turnover. One hundred patients were randomly selected for additional protein profiling using multianalyte profiles (HumanMap v1.6, Rules Based Medicine). Radiographs at baseline, Week 28, and Week 52 were scored using van der Heijde-Sharp (vdH-S) methodology. Correlations were assessed between biomarker levels (baseline and change at Week 4) and joint space narrowing, erosion, and total vdH-S scores (changes at Weeks 28 and 52). Statistical significance was defined as a correlation coefficient with an absolute value >= 0.3 and p < 0.05. RESULTS: Biomarker correlations with changes in vdH-S scores at Week 28 and/or 52 were observed predominantly in the placebo + MTX group and rarely in the combined golimumab treatment group. Changes in epidermal growth factor (EGF) and CD40 ligand (CD40L) at Week 4 were positively correlated with changes in total vdH-S scores at Weeks 28 and 52 in the placebo + MTX group. CONCLUSION: These preliminary findings indicate that EGF and CD40L may have utility in monitoring MTX-treated patients with RA who are more likely to have radiographic progression as measured by increases in vdH-S scores. PMID- 23457390 TI - Retraction: Palmitoylation of caveolin-1 is required for cholesterol binding, chaperone complex formation, and rapid transport of cholesterol to caveolae. PMID- 23457389 TI - Retraction: Hypercholesterolemia promotes a CD36-dependent and endothelial nitric oxide synthase-mediated vascular dysfunction. PMID- 23457391 TI - Retraction: Cholesteryl ester is transported from caveolae to internal membranes as part of a caveolin-annexin II lipid-protein complex. PMID- 23457392 TI - Retraction: Characterization of a cytosolic heat-shock protein-caveolin chaperone complex.: involvement in cholesterol trafficking. PMID- 23457396 TI - In memoriam - Duncan A. Gordon, 1930-2012. PMID- 23457397 TI - Lighting up the genetic understanding of fibromyalgia. PMID- 23457398 TI - Workers' compensation, fibromyalgia, and kafka. PMID- 23457399 TI - No enthesis should be overlooked when psoriatic arthritis is suspected: enthesitis of the extensor digitorum tendons. PMID- 23457400 TI - Raynaud's phenomenon of the tongue. PMID- 23457401 TI - Prognosis factors for cardiovascular events in patients with rheumatoid arthritis: multivariate analysis is indispensable. PMID- 23457402 TI - Biologic drug access and juvenile idiopathic arthritis in Canada: improving collaboration between clinician experts and funders. PMID- 23457403 TI - Chronic nonbacterial osteomyelitis in a child with previous juvenile dermatomyositis. PMID- 23457404 TI - Fluorescence imaging of GFP-fused periplasmic components of Na+-driven flagellar motor using Tat pathway in Vibrio alginolyticus. AB - The twin-arginine translocation (Tat) system works to export folded proteins across the cytoplasmic membrane via specific signal peptides harbouring a twin arginine motif. In Escherichia coli, a functional GFP is exported to the periplasm through the Tat pathway by fusion of the signal peptide of TorA, which is one of the periplasmic proteins exported by the Tat pathway. In this study, we fused the signal peptide of Vibrio alginolyticus TorA (TorASP) to GFP and demonstrate the export of functional GFP to the periplasm of V. alginolyticus. We also made fusions of TorASP-GFP with MotX, MotY and FlgT, which are periplasmic components of the Na(+)-driven flagellar motor. Those fusion proteins were localized to the flagellar motor independent of the Na(+) concentration in the environment. PMID- 23457405 TI - Trypanosoma brucei 14-3-3I and II proteins predominantly form a heterodimer structure that acts as a potent cell cycle regulator in vivo. AB - Hetero- and homodimerization of 14-3-3 proteins demonstrate distinctive functions in mammals and plants. Trypanosoma brucei 14-3-3I and II (Tb14-3-3I and II) play pivotal roles in motility, cytokinesis and the cell cycle; however, the significance and the mechanism of Tb14-3-3 dimerization are remained to be elucidated. We found that ectopically expressed epitope-tagged Tb14-3-3I and II proteins formed hetero- and homodimers with endogenous Tb14-3-3I and II proteins. However, we also found the ability to form hetero- or homodimers between Tb14-3 3I and II proteins was clearly affected by the sequence and location of the epitope tag used. We found a blue native polyacrylamide gel electrophoresis system followed by western blotting may distinguish monomer from dimer structure, and stable from unstable conformation of Tb14-3-3. Combined with co immunoprecipitation results, we revealed that Tb14-3-3 proteins mainly existed as heterodimeric form. Furthermore, co-overexpression of Tb14-3-3I and II proteins in T. brucei induced aberrant numbers of organelles in cells, but overexpression of either isoform alone rarely produced such morphology. These results suggest that heterodimers play more significant roles than homodimers not only in the maintenance of steady-state levels of the 14-3-3 proteins but also in the regulation of cytokinesis. PMID- 23457406 TI - Cross-sectional study of vitamin D levels, immunologic and virologic outcomes in HIV-infected adults. AB - CONTEXT: Vitamin D is increasingly recognized as an important immunomodulator. Lower levels of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) are observed in persons living with HIV. OBJECTIVE: The purpose of this study was to evaluate the relationship of 25(OH)D, and 1,25(OH)2D to HIV viral load, and CD4+ T cells in HIV-infected adults. DESIGN: This was a cross sectional study completed between January 2010 and April 2011. SETTING: This study was conducted with volunteers who received HIV care in Wisconsin at either a University-based HIV clinic or an urban community HIV clinic. PATIENTS: One hundred twelve adults with HIV infection participated in this study. MAIN OUTCOME MEASURES: The primary outcome for this study was the relationship between 1,25(OH)2D and HIV viral load. Secondary outcomes included relationships between 25(OH)D and HIV viral load, 25(OH)D and 1,25(OH)2D to CD4+ T cells, and predictors of vitamin D deficiency. RESULTS: The 112 volunteers included 24 women and 3 transgender individuals; 68% were from the university clinic, and 32% were from the urban clinic. Mean age was 44.2 years. The mean 25(OH)D level was 22.5 ng/mL; mean 1,25(OH)2D level was 23.5 pg/mL. Twenty-two percent had 25(OH)D <=10 ng/mL; 53% had values <20 ng/mL, and 73% were <=30 ng/mL. There was no association between vitamin D and CD4. A nonlinear relationship between viral load and 1,25(OH)2D was found. For 1,25(OH)2D below 32 pg/mL, for each 10 pg/mL decrease in 1,25(OH)2D, (log10) viral load increased by 0.84 (95% CI: 0.16-1.51, P = .015). For 1,25(OH)2D above 32 pg/mL, for each 10 pg/mL increase in 1,25(OH)2D, (log10) viral load increased by 0.36 (95% CI: 0.15-0.57, P = .0009). CONCLUSION: Vitamin D deficiency was common in this HIV population, as seen in other HIV cohorts. A novel, U-shaped relationship between 1,25(OH)2D and viral load, with the lowest and highest 1,25(OH)2D levels seen with high viral loads, was found and deserves further study. PMID- 23457408 TI - Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased beta cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort. AB - CONTEXT: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. OBJECTIVE: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. DESIGN AND PARTICIPANTS: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. RESULTS: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 with T2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14 rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. CONCLUSIONS: BCAR1 rs7202877 may mediate its diabetogenic impact through impaired beta-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance. PMID- 23457407 TI - Comparison of detection of normal puberty in girls by a hormonal sleep test and a gonadotropin-releasing hormone agonist test. AB - CONTEXT: The magnitude of sleep-related gonadotropin rise required to activate pubertal feminization is not established. OBJECTIVE: The objective of the study was to determine the normal relationship of pubertal hormone responses to sleep and to GnRH agonist (GnRHag) challenge across the female pubertal transition. DESIGN/SETTING: This was a prospective study in a General Clinical Research Center. PARTICIPANTS: Sixty-two healthy 6- to 13-year-old volunteer girls participated in the study. INTERVENTIONS: Interventions included overnight blood sampling followed by GnRHag (leuprolide acetate) injection. PRIMARY OUTCOME VARIABLES: The primary outcome variables included LH, FSH, and estradiol. RESULTS: LH levels rose steadily during sleep and after GnRHag throughout the prepubertal years. The LH response to sleep and GnRHag correlated well across groups (eg, r = 0.807, peak vs 4 h post-GnRHag value); however, this correlation was less robust than in boys (r = 0.964, P < .01). Sleep peak LH of 1.3 U/L or greater had 85% sensitivity and 2.1 U/L or greater 96% specificity for detecting puberty (thelarche). The LH 1-hour post-GnRHag value of 3.2 U/L or greater had 95% sensitivity and 5.5 U/L or greater 96% specificity for detecting puberty. Girls entered puberty at lower LH levels than boys. FSH levels rose day and night during the prepubertal years to reach 1.0 U/L or greater during puberty but discriminated puberty poorly. Estradiol of 34 pg/mL or greater at 20-24 hours after GnRHag was 95% sensitive and 60 pg/mL or greater was 95% specific for puberty. Thirty-six percent of overweight early pubertal girls had meager hormonal evidence of puberty. CONCLUSIONS: These data suggest that sleep-related pubertal hormone levels critical for puberty are normally reflected in the responses to GnRHag testing across the normal female pubertal transition. Inconsistencies between clinical and hormonal staging may arise from peripubertal cyclicity of neuroendocrine function and from excess adiposity. PMID- 23457409 TI - Influence of vitamin D status on vertebral fractures, bone mineral density, and bone turnover markers in normocalcemic postmenopausal women with high parathyroid hormone levels. AB - OBJECTIVE: The aims of the study were to analyze whether there is an association between serum PTH and the prevalence of vertebral fractures and its possible dependence on vitamin D status, and to assess the influence of serum 25 hydroxyvitamin D (25OHD) in the relationship between PTH and bone mineral density (BMD) or bone turnover markers (BTMs). DESIGN, PARTICIPANTS, AND SETTING: A total of 820 postmenopausal women were recruited after excluding those with any known condition that could influence serum PTH levels, except for a possible low serum 25OHD. Serum PTH and 25OHD concentrations, as well as vertebral fracture prevalence, BMD, and BTM (CTX and PINP) values were recorded. Serum PTH levels were divided into tertiles, and women were grouped into those in the highest tertile (>58 pg/ml) and those below. Serum 25OHD levels were stratified in 3 categories (<20, 20-30, and >30 ng/ml). RESULTS: Vertebral fracture prevalence was greater in women with PTH above 58 pg/ml (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.04-2.84). After stratifying by 25OHD, this difference was only significant in women below 20 ng/ml (OR, 2.00; 95% CI, 1.02-3.87), those with 25OHD between 20 and 30 ng/ml showing a trend toward this (OR, 1.99; 95% CI, 0.92-4.36). Differences in BMD or BTM between women above and below 58 pg/ml of PTH were also observed only in those below 20 ng/ml. CONCLUSION: Elevated PTH levels are associated with increased prevalence of vertebral fractures, low bone mass, or higher BTM only in the presence of hypovitaminosis D. An adequate nutritional status in the vitamin appears to protect the bone from the deleterious effect of a high PTH. PMID- 23457410 TI - Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. AB - CONTEXT: It has been hypothesized that increased plasma bile acids (BAs) contribute to metabolic improvements after Roux-en-Y gastric bypass (RYGB) surgery by the G protein-coupled receptor TGR5-mediated effects on glucagon-like peptide-1 secretion and thyroid hormones. OBJECTIVE: The objective of this study was to evaluate the importance of bariatric surgery-induced alterations in BA physiology on factors that regulate glucose homeostasis (insulin secretion and sensitivity) and energy metabolism (resting energy expenditure and thyroid hormone axis). DESIGN, PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURE: Eighteen extremely obese subjects were studied before and after 20% weight loss, induced by either laparoscopic adjustable gastric banding (LAGB) (n = 10) or RYGB surgery (n = 8). RESULTS: Plasma BAs more than doubled after RYGB [fasting: 1.08 (0.26-1.42) to 2.28 (1.59-3.28) MUmol/L, P = .03; postprandial: 2.46 +/- 1.59 to 6.00 +/- 2.75 MUmol/L, P = .01] but were either lower or did not change after LAGB [fasting: 1.80 (1.49-2.19) to 0.92 (0.73-1.15) MUmol/L, P = .02; postprandial: 3.71 +/- 2.61 to 2.82 +/- 1.75 MUmol/L, P = .14]. Skeletal muscle expression of TGR5 targets, Kir6.2 and cyclooxygenase IV, increased after RYGB but not LAGB. Surgery-induced changes in BAs were associated with increased peak postprandial plasma glucagon-like peptide-1 (r(2) = 0.509, P = .001) and decreased serum TSH (r(2) = 0.562, P < .001) but did not correlate with the change in insulin response to a meal (r(2) = 0.013, P = .658), insulin sensitivity (assessed as insulin stimulated glucose disposal during a hyperinsulinemic-euglycemic clamp procedure) (r(2) = 0.001, P = .995), or resting energy expenditure (r(2) = 0.004, P = .807). CONCLUSIONS: Compared with LAGB, RYGB increases circulating BAs and TGR5 signaling, but this increase in BAs is not a significant predictor of changes in glucose homeostasis or energy metabolism. PMID- 23457411 TI - Elevated endothelin-1 (ET-1) levels may contribute to hypoadiponectinemia in childhood obesity. AB - CONTEXT: Pediatric obesity is associated with endothelial dysfunction and hypoadiponectinemia, but the relationship between these two conditions remains to be fully clarified. Whether enhanced release of endothelin-1 (ET-1) may directly impair adiponectin (Ad) production in obese children is not known. OBJECTIVE: The aim of the study was to explore whether and how high circulating levels of ET-1 may contribute to impair Ad production, release, and vascular activity. DESIGN AND PARTICIPANTS: Sixty children were included into obese (Ob; n = 30), overweight (OW; n = 11), and lean (n = 19) groups. Total and high-molecular weight Ad, ET-1, vascular cell adhesion molecule-1, and von Willebrand factor levels were measured in serum samples. Adipocytes were stimulated with exogenous ET-1 or with sera from lean, OW, and Ob, and Ad production and release measured in the absence or in the presence of ETA (BQ-123) and ETB (BQ-788) receptor blockers, p42/44 MAPK inhibitor PD-98059, or c-Jun NH2-terminal protein kinase inhibitor SP-600125. Vasodilation to Ad was evaluated in rat isolated arteries in the absence or in the presence of BQ-123/788. RESULTS: Total and high-molecular weight Ad was significantly decreased and ET-1 levels significantly increased in OW (P < .01) and Ob (P < .001) children. A statistically significant linear regression (P < .01) was found between Ad and ET-1. Exposure of adipocytes to exogenous ET-1 or serum from OW and Ob significantly decreased Ad mRNA and protein levels (P < 0.001). The inhibitory effect of ET-1 on Ad was reverted by BQ-123/788 or PD-98059 but not SP-600125. Ad-mediated vasodilation was further increased in arteries pretreated with BQ-123/788. CONCLUSIONS: ET-1-mediated inhibition of Ad synthesis via p42/44 MAPK signaling may provide a possible explanation for hypoadiponectinemia in pediatric obesity and contribute to the development of cardiovascular complications. PMID- 23457412 TI - Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. AB - CONTEXT: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS: All-cause and cause specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease. PMID- 23457414 TI - Vocal communication between male Xenopus laevis. AB - This study focuses on the role of male-male vocal communication in the reproductive repertoire of the South African clawed frog, Xenopus laevis. Six male and two female call types were recorded from native ponds in the environs of Cape Town, South Africa. These include all call types previously recorded in the laboratory as well as one previously unidentified male call: chirping. The amount of calling and the number of call types increased as the breeding season progressed. Laboratory recordings indicated that all six male call types were directed to males; three of these were directed to both sexes and three were directed exclusively to males. Both female call types were directed exclusively to males. The predominant call type, in both field and laboratory recordings, was the male advertisement call. Sexual state affected male vocal behaviour. Male pairs in which at least one male was sexually active (gonadotropin injected) produced all call types, whereas pairs of uninjected males rarely called. Some call types were strongly associated with a specific behaviour and others were not. Clasped males always growled and clasping males typically produced amplectant calls or chirps; males not engaged in clasping most frequently advertised. The amount of advertising produced by one male was profoundly affected by the presence of another male. Pairing two sexually active males resulted in suppression of advertisement calling in one; suppression was released when males were isolated after pairing. Vocal dominance was achieved even in the absence of physical contact (clasping). We suggest that X. laevis males gain a reproductive advantage by competing for advertisement privileges and by vocally suppressing neighbouring males. PMID- 23457413 TI - Selected reaction monitoring to differentiate and relatively quantitate isomers of sulfated and unsulfated core 1 O-glycans from salivary MUC7 protein in rheumatoid arthritis. AB - Rheumatoid arthritis is a common and debilitating systemic inflammatory condition affecting up to 1% of the world's population. This study aimed to investigate the immunological significance of O-glycans in chronic arthritis at a local and systemic level. O-Glycans released from synovial glycoproteins during acute and chronic arthritic conditions were compared and immune-reactive glycans identified. The sulfated core 1 O-glycan (Galbeta1-3GalNAcol) was immune reactive, showing a different isomeric profile in the two conditions. From acute reactive arthritis, three isomers could be sequenced, but in patients with chronic rheumatoid arthritis, only a single 3-Gal sulfate-linked isomer could be identified. The systemic significance of this glycan epitope was investigated using the salivary mucin MUC7 in patients with rheumatoid arthritis and normal controls. To analyze this low abundance glycan, a selected reaction monitoring (SRM) method was developed to differentiate and relatively quantitate the core 1 O-glycan and the sulfated core 1 O-glycan Gal- and GalNAc-linked isomers. The acquisition of highly sensitive full scan linear ion trap MS/MS spectra in addition to quantitative SRM data allowed the 3- and 6-linked Gal isomers to be differentiated. The method was used to relatively quantitate the core 1 glycans from MUC7 to identify any systemic changes in this carbohydrate epitope. A statistically significant increase in sulfation was identified in salivary MUC7 from rheumatoid arthritis patients. This suggests a potential role for this epitope in chronic inflammation. This study was able to develop an SRM approach to specifically identify and relatively quantitate sulfated core 1 isomers and the unsulfated structure. The expansion of this method may afford an avenue for the high throughput investigation of O-glycans. PMID- 23457415 TI - Hydrogen Peroxide as a Sustainable Energy Carrier: Electrocatalytic Production of Hydrogen Peroxide and the Fuel Cell. AB - This review describes homogeneous and heterogeneous catalytic reduction of dioxygen with metal complexes focusing on the catalytic two-electron reduction of dioxygen to produce hydrogen peroxide. Whether two-electron reduction of dioxygen to produce hydrogen peroxide or four-electron O2-reduction to produce water occurs depends on the types of metals and ligands that are utilized. Those factors controlling the two processes are discussed in terms of metal-oxygen intermediates involved in the catalysis. Metal complexes acting as catalysts for selective two-electron reduction of oxygen can be utilized as metal complex modified electrodes in the electrocatalytic reduction to produce hydrogen peroxide. Hydrogen peroxide thus produced can be used as a fuel in a hydrogen peroxide fuel cell. A hydrogen peroxide fuel cell can be operated with a one compartment structure without a membrane, which is certainly more promising for the development of low-cost fuel cells as compared with two compartment hydrogen fuel cells that require membranes. Hydrogen peroxide is regarded as an environmentally benign energy carrier because it can be produced by the electrocatalytic two-electron reduction of O2, which is abundant in air, using solar cells; the hydrogen peroxide thus produced could then be readily stored and then used as needed to generate electricity through the use of hydrogen peroxide fuel cells. PMID- 23457417 TI - Estimating Latent Variable Interactions With Non-Normal Observed Data: A Comparison of Four Approaches. AB - A Monte Carlo simulation was conducted to investigate the robustness of four latent variable interaction modeling approaches (Constrained Product Indicator [CPI], Generalized Appended Product Indicator [GAPI], Unconstrained Product Indicator [UPI], and Latent Moderated Structural Equations [LMS]) under high degrees of non-normality of the observed exogenous variables. Results showed that the CPI and LMS approaches yielded biased estimates of the interaction effect when the exogenous variables were highly non-normal. When the violation of non normality was not severe (normal; symmetric with excess kurtosis < 1), the LMS approach yielded the most efficient estimates of the latent interaction effect with the highest statistical power. In highly non-normal conditions, the GAPI and UPI approaches with ML estimation yielded unbiased latent interaction effect estimates, with acceptable actual Type-I error rates for both the Wald and likelihood ratio tests of interaction effect at N >= 500. An empirical example illustrated the use of the four approaches in testing a latent variable interaction between academic self-efficacy and positive family role models in the prediction of academic performance. PMID- 23457416 TI - Stromal interactions as regulators of tumor growth and therapeutic response: A potential target for photodynamic therapy? AB - It has become increasingly widely recognized that the stroma plays several vital roles in tumor growth and development and that tumor-stroma interactions can in many cases account poor therapeutic response. Inspired by an emerging body of literature, we consider the potential role of photodynamic therapy (PDT) for targeting interactions with stromal fibroblasts and mechano-sensitive signaling with the extracellular matrix as a means to drive tumors toward a more therapeutically responsive state and synergize with other treatments. This concept is particularly relevant for cancer of the pancreas, which is characterized by tumors with a profoundly dense, rigid fibrous stroma. Here we introduce new in vitro systems to model interactions between pancreatic tumors and their mechanical microenvironment and restore signaling with stromal fibroblasts. Using one such model as a test bed it is shown here that PDT treatment is able to destroy fibroblasts in an in vitro 3D pancreatic tumor fibroblast co-culture. These results and the literature suggest the further development of PDT as a potential modality for stromal depletion. PMID- 23457418 TI - What Explains Divorced Women's Poorer Health?: The Mediating Role of Health Insurance and Access to Health Care in a Rural Iowan Sample* AB - The economic restructuring in rural areas in recent decades has been accompanied by rising marital instability. To examine the implications of the increase in divorce for the health of rural women, we examine how marital status predicts adequacy of health insurance coverage and health care access, and whether these factors help to account for the documented association between divorce and later illness. Analyzing longitudinal data from a cohort of over 400 married and recently divorced rural Iowan women, we decompose the total effect of divorce on physical illness a decade later using structural equation modeling. Divorced women are less likely to report adequate health insurance in the years following divorce, inhibiting their access to medical care and threatening their physical health. Full-time employment acts as a buffer against insurance loss for divorced women. The growth of marital instability in rural areas has had significant ramifications for women's health; the decline of adequate health insurance coverage following divorce explains a component of the association between divorced status and poorer long-term health outcomes. PMID- 23457419 TI - Strain-release mechanisms in bimetallic core-shell nanoparticles as revealed by Cs-corrected STEM. AB - Lattice mismatch in a bimetallic core-shell nanoparticle will cause strain in the epitaxial shell layer, and if it reaches the critical layer thickness misfit dislocations will appear in order to release the increasing strain. These defects are relevant since they will directly impact the atomic and electronic structures thereby changing the physical and chemical properties of the nanoparticles. Here we report the direct observation and evolution through aberration-corrected scanning transmission electron microscopy of dislocations in AuPd core-shell nanoparticles. Our results show that first Shockley partial dislocations (SPD) combined with stacking faults (SF) appear at the last Pd layer; then, as the shell grows the SPDs and SFs appear at the interface and combine with misfit dislocations, which finally diffuse to the free surfaces due to the alloying of Au into the Pd shell. The critical layer thickness was found to be at least 50% greater than in thin films, confirming that shells growth on nanoparticles can sustain more strain due to the tridimensional nature of the nanoparticles. PMID- 23457420 TI - Scalpel-free surgery could reduce surgeons' risk of HIV and hepatitis. AB - The risk of intraoperative Human Immunodeficiency Virus(HIV) infection poses a challenge to practicing surgeons worldwide, particularly in sub-Saharan Africa with its high HIV prevalence. The risk of acquiring HIV infection from one infected percutaneous exposure is 0.3-0.4%. Prior to extensive screening, blood transfusions were responsible for an estimated 5-10% of new HIV infections in sub Saharan Africa. In this paper we describe the experience of minimally invasive techniques as alternatives to surgery in urology patients. Trans-urethral ethanol ablation of the prostate (TEAP) for prostatic enlargement, phenol sclerotherapy for hydroceles, and percutaneous aspiration and sclerotherapy for symptomatic renal cysts may result in reduced blood loss, and diminished contact with the patients' exposed tissues or body fluids compared with more invasive surgical options. PMID- 23457421 TI - Biferrocene-Based Diphosphine Ligands: Synthesis and Application of Walphos Analogues in Asymmetric Hydrogenations. AB - A total of four biferrocene-based Walphos-type ligands have been synthesized, structurally characterized, and tested in the rhodium-, ruthenium- and iridium catalyzed hydrogenation of alkenes and ketones. Negishi coupling conditions allowed the biferrocene backbone of these diphosphine ligands to be built up diastereoselectively from the two nonidentical and nonracemic ferrocene fragments (R)-1-(N,N-dimethylamino)ethylferrocene and (SFc)-2-bromoiodoferrocene. The molecular structures of (SFc)-2-bromoiodoferrocene, the coupling product, two ligands, and the two complexes ([PdCl2(L)] and [RuCl(p-cymene)(L)]PF6) were determined by X-ray diffraction. The structural features of complexes and the catalysis results obtained with the newly synthesized biferrocene-based ligands were compared with those of the corresponding Walphos ligands. PMID- 23457422 TI - Remarks on " Two new species of Tornidae (Caenogastropoda, Rissooidea) from Espirito Santo, Brazil," by Luiz Ricardo Simone ( ZooKeys 238: 77-85, 2012) and a plea for improvement in ZooKeys editorial policy. PMID- 23457424 TI - Longitudinal evaluation of the psychosocial wellbeing of recent orphans compared with non-orphans in a school-attending cohort in KwaZulu-Natal, South Africa. AB - To assess differences in psychosocial wellbeing between recent orphans and non orphans, we followed a cohort of 157 school-going orphans and 480 non-orphans ages 9-15 in a context of high HIV/AIDS mortality in South Africa from 2004 to 2007. Several findings were contrary to published evidence to date, as we found no difference between orphans and non-orphans in anxiety/depression symptoms, oppositional behavior, self-esteem, or resilience. Female gender, self-reported poor health, and food insecurity were the most important predictors of children's psychosocial wellbeing. Notably, girls had greater odds of reporting anxiety/depression symptoms than boys, and scored lower on self-esteem and resilience scales. Food insecurity predicted greater anxiety/depression symptoms and lower resilience. Perceived social support was a protective factor, as it was associated with lower odds of anxiety/depression symptoms, lower oppositional scores, and greater self-esteem and resilience. Our findings suggest a need to identify and strengthen psychosocial supports for girls, and for all children in contexts of AIDS-affected and economic adversity. PMID- 23457423 TI - Self-Assembly for the Synthesis of Functional Biomaterials. AB - The use of self-assembly for the construction of functional biomaterials is a highly promising and exciting area of research, with great potential for the treatment of injury or disease. By using multiple noncovalent interactions, coded into the molecular design of the constituent components, self-assembly allows for the construction of complex, adaptable, and highly tunable materials with potent biological effects. This review describes some of the seminal advances in the use of self-assembly to make novel systems for regenerative medicine and biology. Materials based on peptides, proteins, DNA, or hybrids thereof have found application in the treatment of a wide range of injuries and diseases, and this review outlines the design principles and practical applications of these systems. Most of the examples covered focus on the synthesis of hydrogels for the scaffolding or transplantation of cells, with an emphasis on the biological, mechanical, and structural properties of the resulting materials. In addition, we will discuss the distinct advantages conferred by self-assembly (compared with traditional covalent materials), and present some of the challenges and opportunities for the next generation of self-assembled biomaterials. PMID- 23457425 TI - COMMUNITY COLLEGE RE-ENROLLMENT AFTER HURRICANE KATRINA. AB - In this study, we explored predictors of community college re-enrollment after Hurricane Katrina among a sample of low-income women (N = 221). It was predicted that participants' pre-hurricane educational optimism would predict community college re-enrollment a year after the hurricane. The influence of various demographic and additional resources (e.g., social support, childcare, hours of employment, psychological well-being) was also explored. High levels of pre- and post-hurricane educational optimism were significant predictors of re-enrollment, as were lower post-hurricane psychological distress and fewer post-hurricane hours employed. In addition, experiencing a greater number of moves since the hurricane was a marginally significant predictor of post-hurricane re-enrollment. PMID- 23457426 TI - Concurrent Treatment of Substance Abuse, Child Neglect, Bipolar Disorder, Post Traumatic Stress Disorder, and Domestic Violence: A Case Examination Involving Family Behavior Therapy. AB - High rates of co-occurrence between substance abuse and child neglect have been well documented and especially difficult to treat. As a first step in developing a comprehensive evidence-based treatment for use in this population, the present case examination underscores Family Behavior Therapy (FBT) in the treatment of a mother who evidenced Substance Dependence, child neglect, Post-Traumatic Stress Disorder, Bipolar I Disorder, and domestic violence. Utilizing psychometrically validated self-report inventories and objective urinalysis, treatment was found to result in the cessation of substance use, lower risk of child maltreatment, improved parenting attitudes and practices, and reduced instances of violence in the home. The importance of utilizing validity scales in the assessment of referrals from child welfare settings is discussed, and future directions are reported in light of the results. PMID- 23457427 TI - A New Maximum Likelihood Approach for Free Energy Profile Construction from Molecular Simulations. AB - A novel variational method for construction of free energy profiles from molecular simulation data is presented. The variational free energy profile (VFEP) method uses the maximum likelihood principle applied to the global free energy profile based on the entire set of simulation data (e.g from multiple biased simulations) that spans the free energy surface. The new method addresses common obstacles in two major problems usually observed in traditional methods for estimating free energy surfaces: the need for overlap in the re-weighting procedure and the problem of data representation. Test cases demonstrate that VFEP outperforms other methods in terms of the amount and sparsity of the data needed to construct the overall free energy profiles. For typical chemical reactions, only ~5 windows and ~20-35 independent data points per window are sufficient to obtain an overall qualitatively correct free energy profile with sampling errors an order of magnitude smaller than the free energy barrier. The proposed approach thus provides a feasible mechanism to quickly construct the global free energy profile and identify free energy barriers and basins in free energy simulations via a robust, variational procedure that determines an analytic representation of the free energy profile without the requirement of numerically unstable histograms or binning procedures. It can serve as a new framework for biased simulations and is suitable to be used together with other methods to tackle with the free energy estimation problem. PMID- 23457428 TI - A roadmap to the human virome. PMID- 23457431 TI - Special issue on precision risk stratification-based screening in colorectal cancer. PMID- 23457432 TI - HISPANICS IN HIGHER EDUCATION AND THE TEXAS TOP TEN PERCENT LAW. AB - This paper examines the consequences of changes in Hispanic college enrollment after affirmative action was banned and replaced by an admission guarantee for students who graduate in the top 10% of their high school class. We use administrative data on applicants, admittees and enrollees from the two most selective public institutions and TEA data about high schools to evaluate whether and how application, admission and enrollment rates changed under the three admission regimes. Despite popular claims that the top 10% law has restored diversity to Texas's public flagships, our analyses that account for secular changes in the size of graduation cohorts show that Hispanics are more disadvantaged relative to whites under the top 10% admission regime at both UT and TAMU. Simulations of Hispanics' gains and losses at each stage of the college pipeline reveal that affirmative action is the most efficient policy to diversify college campuses, even in highly segregated states like Texas. PMID- 23457430 TI - Gaseous VOCs rapidly modify particulate matter and its biological effects - Part 1: Simple VOCs and model PM. AB - This is the first of a three-part study designed to demonstrate dynamic entanglements among gaseous organic compounds (VOC), particulate matter (PM), and their subsequent potential biological effects. We study these entanglements in increasingly complex VOC and PM mixtures in urban-like conditions in a large outdoor chamber. To the traditional chemical and physical characterizations of gas and PM, we added new measurements of gas-only- and PM-only-biological effects, using cultured human lung cells as model indicators. These biological effects are assessed here as increases in cellular damage or expressed irritation (i.e., cellular toxic effects) from cells exposed to chamber air relative to cells exposed to clean air. The exposure systems permit gas-only- or PM-only exposures from the same air stream containing both gases and PM in equilibria, i.e., there are no extractive operations prior to cell exposure.Our simple experiments in this part of the study were designed to eliminate many competing atmospheric processes to reduce ambiguity in our results. Simple volatile and semi-volatile organic gases that have inherent cellular toxic properties were tested individually for biological effect in the dark (at constant humidity). Airborne mixtures were then created with each compound and PM that has no inherent cellular toxic properties for another cellular exposure. Acrolein and p tolualdehyde were used as model VOCs and mineral oil aerosol (MOA) was selected as a surrogate for organic-containing PM. MOA is appropriately complex in composition to represent ambient PM, and it exhibits no inherent cellular toxic effects and thus did not contribute any biological detrimental effects on its own.Chemical measurements, combined with the responses of our biological exposures, clearly demonstrate that gas-phase pollutants can modify the composition of PM (and its resulting detrimental effects on lung cells) - even if the gas-phase pollutants are not considered likely to partition to the condensed phase: the VOC-modified-PM showed significantly more damage and inflammation to lung cells than did the original PM. Because gases and PM are transported and deposited differently within the atmosphere and the lungs, these results have significant consequences. For example, current US policies for research and regulation of PM do not recognize this "effect modification" phenomena (NAS, 2004).These results present an unambiguous demonstration that - even in these simple mixtures - physical and thermal interactions alone can cause a modification of the distribution of species among the phases of airborne pollution mixtures and can result in a non-toxic phase becoming toxic due to atmospheric thermal processes only. Subsequent work extends the simple results reported here to systems with photochemical transformations of complex urban mixtures and to systems with diesel exhaust produced by different fuels. PMID- 23457439 TI - Searching remote homology with spectral clustering with symmetry in neighborhood cluster kernels. AB - Remote homology detection among proteins utilizing only the unlabelled sequences is a central problem in comparative genomics. The existing cluster kernel methods based on neighborhoods and profiles and the Markov clustering algorithms are currently the most popular methods for protein family recognition. The deviation from random walks with inflation or dependency on hard threshold in similarity measure in those methods requires an enhancement for homology detection among multi-domain proteins. We propose to combine spectral clustering with neighborhood kernels in Markov similarity for enhancing sensitivity in detecting homology independent of "recent" paralogs. The spectral clustering approach with new combined local alignment kernels more effectively exploits the unsupervised protein sequences globally reducing inter-cluster walks. When combined with the corrections based on modified symmetry based proximity norm deemphasizing outliers, the technique proposed in this article outperforms other state-of-the art cluster kernels among all twelve implemented kernels. The comparison with the state-of-the-art string and mismatch kernels also show the superior performance scores provided by the proposed kernels. Similar performance improvement also is found over an existing large dataset. Therefore the proposed spectral clustering framework over combined local alignment kernels with modified symmetry based correction achieves superior performance for unsupervised remote homolog detection even in multi-domain and promiscuous domain proteins from Genolevures database families with better biological relevance. Source code available upon request. CONTACT: sarkar@labri.fr. PMID- 23457440 TI - Kinetic energy of Throughfall in subtropical forests of SE China - effects of tree canopy structure, functional traits, and biodiversity. AB - Throughfall kinetic energy (TKE) plays an important role in soil erosion in forests. We studied TKE as a function of biodiversity, functional diversity as well as structural stand variables in a secondary subtropical broad-leaved forest in the Gutianshan National Nature Reserve (GNNR) in south-east China, a biodiversity hotspot in the northern hemisphere with more than 250 woody species present. Using a mixed model approach we could identify significant effects of all these variables on TKE: TKE increased with rarefied tree species richness and decreased with increasing proportion of needle-leaved species and increasing leaf area index (LAI). Furthermore, for average rainfall amounts TKE was decreasing with tree canopy height whereas for high rainfall amounts this was not the case. The spatial pattern of throughfall was stable across several rain events. The temporal variation of TKE decreased with rainfall intensity and increased with tree diversity. Our results show that more diverse forest stands over the season have to cope with higher cumulative raindrop energy than less diverse stands. However, the kinetic energy (KE) of one single raindrop is less predictable in diverse stands since the variability in KE is higher. This paper is the first to contribute to the understanding of the ecosystem function of soil erosion prevention in diverse subtropical forests. PMID- 23457441 TI - CD133: enhancement of bone healing by local transplantation of peripheral blood cells in a biologically delayed rat osteotomy model. AB - Sufficient angiogenesis is crucial during tissue regeneration and therefore also pivotal in bone defect healing. Recently, peripheral blood derived progenitor cells have been identified to have in addition to their angiogenic potential also osteogenic characteristics, leading to the hypothesis that bone regeneration could be stimulated by local administration of these cells. The aim of this study was to evaluate the angiogenic potential of locally administered progenitor cells to improve bone defect healing. Cells were separated from the peripheral blood of donor animals using the markers CD34 and CD133. Results of the in vitro experiments confirmed high angiogenic potential in the CD133(+) cell group. CD34(+) and CD133(+) cells were tested in an in vivo rat femoral defect model of delayed healing for their positive effect on the healing outcome. An increased callus formation and higher bone mineral density of callus tissue was found after the CD133(+) cell treatment compared to the group treated with CD34(+) cells and the control group without cells. Histological findings confirmed an increase in vessel formation and mineralization at day 42 in the osteotomy gap after CD133(+) cell transplantation. The higher angiogenic potential of CD133(+) cells from the in vitro experients therefore correlates with the in vivo data. This study demonstrates the suitability of angiogenic precursors to further bone healing and gives an indication that peripheral blood is a promising source for progenitor cells circumventing the problems associated with bone marrow extraction. PMID- 23457442 TI - Imaging trans-cellular neurexin-neuroligin interactions by enzymatic probe ligation. AB - Neurexin and neuroligin are transmembrane adhesion proteins that play an important role in organizing the neuronal synaptic cleft. Our lab previously reported a method for imaging the trans-synaptic binding of neurexin and neuroligin called BLINC (Biotin Labeling of INtercellular Contacts). In BLINC, biotin ligase (BirA) is fused to one protein while its 15-amino acid acceptor peptide substrate (AP) is fused to the binding partner. When the two fusion proteins interact across cellular junctions, BirA catalyzes the site-specific biotinylation of AP, which can be read out by staining with streptavidin fluorophore conjugates. Here, we report that BLINC in neurons cannot be reproduced using the reporter constructs and labeling protocol previously described. We uncover the technical reasons for the lack of reproducibilty and then re-design the BLINC reporters and labeling protocol to achieve neurexin neuroligin BLINC imaging in neuron cultures. In addition, we introduce a new method, based on lipoic acid ligase instead of biotin ligase, to image trans cellular neurexin-neuroligin interactions in human embryonic kidney cells and in neuron cultures. This method, called ID-PRIME for Interaction-Dependent PRobe Incorporation Mediated by Enzymes, is more robust than BLINC due to higher surface expression of lipoic acid ligase fusion constructs, gives stronger and more localized labeling, and is more versatile than BLINC in terms of signal readout. ID-PRIME expands the toolkit of methods available to study trans cellular protein-protein interactions in living systems. PMID- 23457443 TI - Impaired lung function is associated with increased carotid intima-media thickness in middle-aged and elderly Chinese. AB - BACKGROUND: Impairment of lung function was reported to be associated with cardiovascular disease (CVD). The aim of the present study is to evaluate the relationship between lung function and carotid intima-media thickness (cIMT) in participants without chronic pulmonary disease. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 6,423 participants aged 40 years and above were recruited from Jiading District, Shanghai, China. Lung function, evaluated by forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) was measured with standard spirometry. CIMT was measured with high-resolution ultrasonography by trained physicians. Mean values of FVC (% pred) and FEV1 (% pred) in participants with elevated cIMT were significantly lower than in those without (0.92+/-0.20 vs. 0.99+/-0.19, 0.83+/-0.24 vs. 0.90+/-0.22; both p-values < 0.0001). The levels of cIMT in the lowest quartile of FVC (% pred) and FEV1 (% pred) were markedly higher than in the second, third and fourth quartile, respectively (p < 0.0001 for all). The lowest quartile of FVC (% pred) and FEV1 (% pred) was associated with increased odds of elevated cIMT, with the fully adjusted odds ratio of 1.34 and 1.41 (95% confidence interval (CI) 1.09-1.65, p = 0.006, 95% CI 1.15-1.72, p = 0.0008), respectively. CONCLUSIONS AND SIGNIFICANCE: Impaired lung function is associated with elevated cIMT in middle aged and elderly Chinese. These findings suggest the need to screen impairment of lung function in people without respiratory disease for the presence of subclinical atherosclerosis in CVD prevention. PMID- 23457444 TI - Prediction of auditory and visual p300 brain-computer interface aptitude. AB - OBJECTIVE: Brain-computer interfaces (BCIs) provide a non-muscular communication channel for patients with late-stage motoneuron disease (e.g., amyotrophic lateral sclerosis (ALS)) or otherwise motor impaired people and are also used for motor rehabilitation in chronic stroke. Differences in the ability to use a BCI vary from person to person and from session to session. A reliable predictor of aptitude would allow for the selection of suitable BCI paradigms. For this reason, we investigated whether P300 BCI aptitude could be predicted from a short experiment with a standard auditory oddball. METHODS: Forty healthy participants performed an electroencephalography (EEG) based visual and auditory P300-BCI spelling task in a single session. In addition, prior to each session an auditory oddball was presented. Features extracted from the auditory oddball were analyzed with respect to predictive power for BCI aptitude. RESULTS: Correlation between auditory oddball response and P300 BCI accuracy revealed a strong relationship between accuracy and N2 amplitude and the amplitude of a late ERP component between 400 and 600 ms. Interestingly, the P3 amplitude of the auditory oddball response was not correlated with accuracy. CONCLUSIONS: Event-related potentials recorded during a standard auditory oddball session moderately predict aptitude in an audiory and highly in a visual P300 BCI. The predictor will allow for faster paradigm selection. SIGNIFICANCE: Our method will reduce strain on patients because unsuccessful training may be avoided, provided the results can be generalized to the patient population. PMID- 23457446 TI - OpenCFU, a new free and open-source software to count cell colonies and other circular objects. AB - Counting circular objects such as cell colonies is an important source of information for biologists. Although this task is often time-consuming and subjective, it is still predominantly performed manually. The aim of the present work is to provide a new tool to enumerate circular objects from digital pictures and video streams. Here, I demonstrate that the created program, OpenCFU, is very robust, accurate and fast. In addition, it provides control over the processing parameters and is implemented in an intuitive and modern interface. OpenCFU is a cross-platform and open-source software freely available at http://opencfu.sourceforge.net. PMID- 23457445 TI - Molecular analysis of the prostacyclin receptor's interaction with the PDZ1 domain of its adaptor protein PDZK1. AB - The prostanoid prostacyclin, or prostaglandin I2, plays an essential role in many aspects of cardiovascular disease. The actions of prostacyclin are mainly mediated through its activation of the prostacyclin receptor or, in short, the IP. In recent studies, the cytoplasmic carboxy-terminal domain of the IP was shown to bind several PDZ domains of the multi-PDZ adaptor PDZK1. The interaction between the two proteins was found to enhance cell surface expression of the IP and to be functionally important in promoting prostacyclin-induced endothelial cell migration and angiogenesis. To investigate the interaction of the IP with the first PDZ domain (PDZ1) of PDZK1, we generated a nine residue peptide (KK(411)IAACSLC(417)) containing the seven carboxy-terminal amino acids of the IP and measured its binding affinity to a recombinant protein corresponding to PDZ1 by isothermal titration calorimetry. We determined that the IP interacts with PDZ1 with a binding affinity of 8.2 uM. Using the same technique, we also determined that the farnesylated form of carboxy-terminus of the IP does not bind to PDZ1. To understand the molecular basis of these findings, we solved the high resolution crystal structure of PDZ1 bound to a 7-residue peptide derived from the carboxy-terminus of the non-farnesylated form of IP ((411)IAACSLC(417)). Analysis of the structure demonstrates a critical role for the three carboxy terminal amino acids in establishing a strong interaction with PDZ1 and explains the inability of the farnesylated form of IP to interact with the PDZ1 domain of PDZK1 at least in vitro. PMID- 23457447 TI - Filament-filament switching can be regulated by separation between filaments together with cargo motor number. AB - How intracellular transport controls the probability that cargos switch at intersections between filaments is not well understood. In one hypothesis some motors on the cargo attach to one filament while others attach to the intersecting filament, and the ensuing tug-of-war determines which filament is chosen. We investigate this hypothesis using 3D computer simulations, and discover that switching at intersections increases with the number of motors on the cargo, but is not strongly dependent on motor number when the filaments touch. Thus, simply controlling the number of active motors on the cargo cannot account for in vivo observations that found reduced switching with increasing motor number, suggesting additional mechanisms of regulation. We use simulations to show that one possible way to regulate switching is by simultaneously adjusting the separation between planes containing the crossing filaments and the total number of active motors on the cargo. Heretofore, the effect of filament filament separation on switching has been unexplored. We find that the switching probability decreases with increasing filament separation. This effect is particularly strong for cargos with only a modest number of motors. As the filament separation increases past the maximum head-to-head distance of the motor, individual motors walking along a filament will be unable to reach the intersecting filament. Thus, any switching requires that other motors on the cargo attach to the intersecting filament and haul the cargo along it, while motor(s) engaged on the original filament detach. Further, if the filament separation is large enough, the cargo can have difficulty proceeding along the initial filament because the engaged motors can walk underneath the intersecting filament, but the cargo itself cannot fit between the filaments. Thus, the cargo either detaches entirely from the original filament, or must dip to the side of the initial filament and then pass below the crossing filament. PMID- 23457448 TI - Fear learning increases the number of polyribosomes associated with excitatory and inhibitory synapses in the barrel cortex. AB - Associative fear learning, resulting from whisker stimulation paired with application of a mild electric shock to the tail in a classical conditioning paradigm, changes the motor behavior of mice and modifies the cortical functional representation of sensory receptors involved in the conditioning. It also induces the formation of new inhibitory synapses on double-synapse spines of the cognate barrel hollows. We studied density and distribution of polyribosomes, the putative structural markers of enhanced synaptic activation, following conditioning. By analyzing serial sections of the barrel cortex by electron microscopy and stereology, we found that the density of polyribosomes was significantly increased in dendrites of the barrel activated during conditioning. The results revealed fear learning-induced increase in the density of polyribosomes associated with both excitatory and inhibitory synapses located on dendritic spines (in both single- and double-synapse spines) and only with the inhibitory synapses located on dendritic shafts. This effect was accompanied by a significant increase in the postsynaptic density area of the excitatory synapses on single-synapse spines and of the inhibitory synapses on double-synapse spines containing polyribosomes. The present results show that associative fear learning not only induces inhibitory synaptogenesis, as demonstrated in the previous studies, but also stimulates local protein synthesis and produces modifications of the synapses that indicate their potentiation. PMID- 23457449 TI - Increasing sequence search sensitivity with transitive alignments. AB - Sequence alignment is an important bioinformatics tool for identifying homology, but searching against the full set of available sequences is likely to result in many hits to poorly annotated sequences providing very little information. Consequently, we often want alignments against a specific subset of sequences: for instance, we are looking for sequences from a particular species, sequences that have known 3d-structures, sequences that have a reliable (curated) function annotation, and so on. Although such subset databases are readily available, they only represent a small fraction of all sequences. Thus, the likelihood of finding close homologs for query sequences is smaller, and the alignments will in general have lower scores. This makes it difficult to distinguish hits to homologous sequences from random hits to unrelated sequences. Here, we propose a method that addresses this problem by first aligning query sequences against a large database representing the corpus of known sequences, and then constructing indirect (or transitive) alignments by combining the results with alignments from the large database against the desired target database. We compare the results to direct pairwise alignments, and show that our method gives us higher sensitivity alignments against the target database. PMID- 23457450 TI - The potential cost and benefits of raltegravir in simplified second-line therapy among HIV infected patients in Nigeria and South Africa. AB - BACKGROUND: There is an urgent need to improve the evidence base for provision of second-line antiretroviral therapy (ART) following first-line virological failure. This is particularly the case in Sub-Saharan Africa where 70% of all people living with HIV/AIDS (PHA) reside. The aim of this study was to simulate the potential risks and benefits of treatment simplification in second-line therapy compared to the current standard of care (SOC) in a lower-middle income and an upper-middle income country in Sub-Saharan Africa. METHODS: We developed a microsimulation model to compare outcomes associated with reducing treatment discontinuations between current SOC for second-line therapy in South Africa and Nigeria and an alternative regimen: ritonavir-boosted lopinavir (LPV/r) combined with raltegravir (RAL). We used published studies and collaborating sites to estimate efficacy, adverse effect and cost. Model outcomes were reported as incremental cost effectiveness ratios (ICERs) in 2011 USD per quality adjusted life year ($/QALY) gained. RESULTS: Reducing treatment discontinuations with LPV/r+RAL resulted in an additional 0.4 discounted QALYs and increased the undiscounted life expectancy by 0.8 years per person compared to the current SOC. The average incremental cost was $6,525 per treated patient in Nigeria and $4,409 per treated patient in South Africa. The cost-effectiveness ratios were $16,302/QALY gained and $11,085/QALY gained for Nigeria and South Africa, respectively. Our results were sensitive to the probability of ART discontinuation and the unit cost for RAL. CONCLUSIONS: The combination of raltegravir and ritonavir-boosted lopinavir was projected to be cost-effective in South Africa. However, at its current price, it is unlikely to be cost-effective in Nigeria. PMID- 23457451 TI - Latitudinal variations in seasonal activity of influenza and respiratory syncytial virus (RSV): a global comparative review. AB - BACKGROUND: There is limited information on influenza and respiratory syncytial virus (RSV) seasonal patterns in tropical areas, although there is renewed interest in understanding the seasonal drivers of respiratory viruses. METHODS: We review geographic variations in seasonality of laboratory-confirmed influenza and RSV epidemics in 137 global locations based on literature review and electronic sources. We assessed peak timing and epidemic duration and explored their association with geography and study settings. We fitted time series model to weekly national data available from the WHO influenza surveillance system (FluNet) to further characterize seasonal parameters. RESULTS: Influenza and RSV activity consistently peaked during winter months in temperate locales, while there was greater diversity in the tropics. Several temperate locations experienced semi-annual influenza activity with peaks occurring in winter and summer. Semi-annual activity was relatively common in tropical areas of Southeast Asia for both viruses. Biennial cycles of RSV activity were identified in Northern Europe. Both viruses exhibited weak latitudinal gradients in the timing of epidemics by hemisphere, with peak timing occurring later in the calendar year with increasing latitude (P<0.03). Time series model applied to influenza data from 85 countries confirmed the presence of latitudinal gradients in timing, duration, seasonal amplitude, and between-year variability of epidemics. Overall, 80% of tropical locations experienced distinct RSV seasons lasting 6 months or less, while the percentage was 50% for influenza. CONCLUSION: Our review combining literature and electronic data sources suggests that a large fraction of tropical locations experience focused seasons of respiratory virus activity in individual years. Information on seasonal patterns remains limited in large undersampled regions, included Africa and Central America. Future studies should attempt to link the observed latitudinal gradients in seasonality of viral epidemics with climatic and population factors, and explore regional differences in disease transmission dynamics and attack rates. PMID- 23457453 TI - Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E. AB - The HOXB13 missense mutation G84E (rs138213197) is associated with increased risk of prostate cancer, but the current estimate of increased risk has a wide confidence interval (width of 95% confidence interval (CI) >200-fold) so the point estimate of 20-fold increased risk could be misleading. Population-based family studies can be more informative for estimating risks for rare variants, therefore, we screened for mutations in an Australian population-based series of early-onset prostate cancer cases (probands). We found that 19 of 1,384 (1.4%) probands carried the missense mutation, and of these, six (32%) had a family history of prostate cancer. We tested the 22 relatives of carriers diagnosed from 1998 to 2008 for whom we had a DNA sample, and found seven more carriers and one obligate carrier. The age-specific incidence for carriers was estimated to be, on average, 16.4 (95% CI 2.5-107.2) times that for the population over the time frame when the relatives were at risk prior to baseline. We then estimated the age and birth year- specific cumulative risk of prostate cancer (penetrance) for carriers. For example, the penetrance for an unaffected male carrier born in 1950 was 19% (95% CI 5-46%) at age 60 years, 44% (95% CI 18-74%) at age 70 years and 60% (95% CI 30-85%) at age 80 years. Our study has provided a population-based estimate of the average risk of prostate cancer for HOXB13 missense mutation G84E carriers that can be used to guide clinical practice and research. This study has also shown that the majority of hereditary prostate cancers due to the HOXB13 missense mutation are 'sporadic' in the sense that unselected cases with the missense mutation do not typically report having a family history of prostate cancer. PMID- 23457452 TI - Altered transfer of momentary mental states (ATOMS) as the basic unit of psychosis liability in interaction with environment and emotions. AB - Psychotic disorders are thought to represent altered neural function. However, research has failed to map diagnostic categories to alterations in neural networks. It is proposed that the basic unit of psychotic psychopathology is the moment-to-moment expression of subtle anomalous experiences of subclinical psychosis, and particularly its tendency to persist from moment-to-moment in daily life, under the influence of familial, environmental, emotional and cognitive factors.In a general population twin sample (n = 579) and in a study of patients with psychotic disorder (n = 57), their non-psychotic siblings (n = 59) and unrelated controls (n = 75), the experience sampling paradigm (ESM; repetitive, random sampling of momentary mental states and context) was applied. We analysed, in a within-person prospective design, (i) transfer of momentary anomalous experience at time point (t-1) to time point (t) in daily life, and (ii) moderating effects of negative affect, positive affect, daily stressors, IQ and childhood trauma. Additionally, (iii) familial associations between persistence of momentary anomalous experience and psychotic symptomatology were investigated. Higher level of schizotypy in the twins (but not higher level of psychotic symptoms in patients) predicted more persistence of momentary anomalous experience in daily life, both within subjects and across relatives. Persistence of momentary anomalous experience was highest in patients, intermediate in their siblings and lowest in controls. In both studies, persistence of momentary anomalous experience was moderated by higher levels of negative affect, daily stressors and childhood trauma (only in twins), and by lower levels of positive affect. The study of alterations in the moment-to-moment transfer of subtle anomalous experience of psychosis, resulting in their persistence, helps to explain why psychotic and emotional dysregulation tend to cluster in a single phenotype such as schizophrenia, and how familial and environmental risks increase the risk of expression of psychosis from, first, subtle momentary anomalous experience to, second, observable clinical symptoms. PMID- 23457454 TI - The secret ingredient for social success of young males: a functional polymorphism in the 5HT2A serotonin receptor gene. AB - In adolescence, being socially successful depends to a large extent on being popular with peers. Even though some youths have what it takes to be popular, they are not, whereas others seem to have a secret ingredient that just makes the difference. In this study the G-allele of a functional polymorphism in the promotor region of the 5HT2A serotonin receptor gene (-G1438A) was identified as a secret ingredient for popularity among peers. These findings build on and extend previous work by Burt (2008, 2009). Tackling limitations from previous research, the role of the 5HT2A serotonin receptor gene was examined in adolescent males (N = 285; average age 13) using a unique sample of the TRAILS study. Carrying the G-allele enhanced the relation between aggression and popularity, particularly for those boys who have many female friends. This seems to be an "enhancer" effect of the G-allele whereby popularity relevant characteristics are made more noticeable. There is no "popularity gene", as the G allele by itself had no effect on popularity. PMID- 23457455 TI - Ssk1p-independent activation of Ssk2p plays an important role in the osmotic stress response in Saccharomyces cerevisiae: alternative activation of Ssk2p in osmotic stress. AB - In Saccharomyces cerevisiae, external high osmolarity activates the HOG MAPK pathway, which controls various aspects of osmoregulation. MAPKKK Ssk2 is activated by Ssk1 in the SLN1 branch of the osmoregulatory HOG MAPK pathway under hyperosmotic stress. We observed that Ssk2 can be activated independent of Ssk1 upon osmotic shock by an unidentified mechanism. The domain for the Ssk1p independent activation was identified to be located between the amino acids 177~240. This region might be involved in the binding of an unknown regulator to Ssk2 which in turn activates Ssk2p without Ssk1p under hyperosmotic stress. The osmotic stress response through the Ssk1p-independent Ssk2p activation is strong, although its duration is short compared with the Ssk1p-dependent activation. The alternative Ssk2p activation is also important for the salt resistance. PMID- 23457456 TI - Kruppel-like factor 2 is required for normal mouse cardiac development. AB - Kruppel-like factor 2 (KLF2) is expressed in endothelial cells in the developing heart, particularly in areas of high shear stress, such as the atrioventricular (AV) canal. KLF2 ablation leads to myocardial thinning, high output cardiac failure and death by mouse embryonic day 14.5 (E14.5) in a mixed genetic background. This work identifies an earlier and more fundamental role for KLF2 in mouse cardiac development in FVB/N mice. FVB/N KLF2-/- embryos die earlier, by E11.5. E9.5 FVB/N KLF2-/- hearts have multiple, disorganized cell layers lining the AV cushions, the primordia of the AV valves, rather than the normal single layer. By E10.5, traditional and endothelial-specific FVB/N KLF2-/- AV cushions are hypocellular, suggesting that the cells accumulating at the AV canal have a defect in endothelial to mesenchymal transformation (EMT). E10.5 FVB/N KLF2-/- hearts have reduced glycosaminoglycans in the cardiac jelly, correlating with the reduced EMT. However, the number of mesenchymal cells migrating from FVB/N KLF2-/ AV explants into a collagen matrix is reduced considerably compared to wild type, suggesting that the EMT defect is not due solely to abnormal cardiac jelly. Echocardiography of E10.5 FVB/N KLF2-/- embryos indicates that they have abnormal heart function compared to wild-type. E10.5 C57BL/6 KLF2-/- hearts have largely normal AV cushions. However, E10.5 FVB/N and C57BL/6 KLF2-/- embryos have a delay in the formation of the atrial septum that is not observed in a defined mixed background. KLF2 ablation results in reduced Sox9, UDP-glucose dehydrogenase (Ugdh), Gata4 and Tbx5 mRNA in FVB/N AV canals. KLF2 binds to the Gata4, Tbx5 and Ugdh promoters in chromatin immunoprecipitation assays, indicating that KLF2 could directly regulate these genes. In conclusion, KLF2-/- heart phenotypes are genetic background-dependent. KLF2 plays a role in EMT through its regulation of important cardiovascular genes. PMID- 23457457 TI - Cardiovascular pathology in males and females with 45,X/46,XY mosaicism. AB - CONTEXT: The phenotype of 45,X/46,XY mosaicism is heterogeneous ranging from females with Turner syndrome (TS) to apparently normal males. Males with 45,X/46,XY frequently show stigmata typically associated with TS. We hypothesised that males with 45,X/46,XY have similar cardiovascular pathology as females with 45,X/46,XY. OBJECTIVE: To investigate cardiovascular abnormalities in 45,X/46,XY males and to compare them with 45,X/46,XY females. DESIGN: Patients with 45,X/46,XY mosaicism were selected from the Belgian Registry for Growth and Puberty problems and via the multidisciplinary clinic for disorders of sexual development. PATIENTS: EIGHTEEN PATIENTS WERE INCLUDED: 8 raised as females (F) and 10 as males (M). INTERVENTION: Complete cardiac examination with blood pressure measurement, ECG, echocardiography and MRI. MAIN OUTCOME MEASUREMENT: Cardiac parameters were registered for both groups. In a second phase, clinical features and external masculinisation score (EMS) were retrospectively collected from the medical files. RESULTS: A structural heart defect was diagnosed before inclusion in 1 F with coarctation and 1 M with spontaneously closed VSD. A bicuspid aortic valve was found in 8 (3 F, 5 M). Dilation of the ascending aorta was present in 4 M and was severe in 2 young boys. QTc was prolonged in 3 F and 2 M. CONCLUSION: Males with 45,X/46,XY mosaicism have similar cardiovascular pathology as 45,X/46,XY females. Dilation of the ascending aorta can be important, also in males. We advise cardiac screening and life-long monitoring in all males with 45,X/46,XY mosaicism according to the existing guidelines for Turner syndrome. PMID- 23457458 TI - Dopamine-mediated oxidation of methionine 127 in alpha-synuclein causes cytotoxicity and oligomerization of alpha-synuclein. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. Many recent studies focused on the interaction between alpha-synuclein (alpha-syn) and dopamine in the pathogenesis of PD, and fluorescent anisotropy suggested that the C-terminal region of alpha-syn may be a target for modification by dopamine. However, it is not well understood why PD-related pathogenesis occurs selectively in dopaminergic neurons. We investigated the interaction between dopamine and alpha-syn with regard to cytotoxicity. A soluble oligomer was formed by co incubating alpha-syn and dopamine in vitro. To clarify the effect of dopamine on alpha-syn in cells, we generated PC12 cells expressing human alpha-syn, as well as the alpha-syn mutants, M116A, Y125D, M127A, S129A, and M116A/M127A, in a tetracycline-inducible manner (PC12-TetOFF-alpha-syn). Overexpression of wildtype alpha-syn in catecholaminergic PC12 cells decreased cell viability in long-term cultures, while a competitive inhibitor of tyrosine hydroxylase blocked this vulnerability, suggesting that alpha-syn-related cytotoxicity is associated with dopamine metabolism. The vulnerabilities of all mutant cell lines were lower than that of wildtype alpha-syn-expressing cells. Moreover, alpha-syn containing dopamine-mediated oxidized methionine (Met(O)) was detected in PC12-TetOFF-alpha syn. Met(O) was lower in methionine mutant cells, especially in the M127A or M116A/M127A mutants, but also in the Y125D and S129A mutants. Co-incubation of dopamine and the 125YEMPS129 peptide enhanced the production of H2O2, which may oxidize methionine residues and convert them to Met(O). Y125- or S129-lacking peptides did not enhance the dopamine-related production of H2O2. Our results suggest that M127 is the major target for oxidative modification by dopamine, and that Y125 and S129 may act as enhancers of this modification. These results may describe a mechanism of dopaminergic neuron-specific toxicity of alpha-syn in the pathogenesis of PD. PMID- 23457459 TI - Novel isoforms of the transport regulator klar. AB - Klar is a regulator of microtubule-motor dependent transport processes in Drosophila, including nuclear migration, vesicle motility, and lipid-droplet transport. The single klar locus gives rise to multiple isoforms that presumably have unique functions. Up to now, three Klar isoforms (alpha, beta, gamma) were known. Here we describe two novel isoforms, delta and epsilon, whose expression depends on a previously uncharacterized promoter. Klar delta and/or epsilon are widely expressed during development, including in the embryonic and larval nervous system as well as in ovaries. When we specifically ablate Klar delta and epsilon expression genetically, no gross organismal phenotypes are apparent. However, ectopic expression of these isoforms causes nuclear mispositioning in developing photoreceptors and in oocytes, demonstrating their biological activity. Our analysis identifies novel forms of the Klar protein and provides new tools for functionally dissecting the complex klar locus. PMID- 23457460 TI - The anti-migratory effects of FKBPL and its peptide derivative, AD-01: regulation of CD44 and the cytoskeletal pathway. AB - FK506 binding protein-like (FKBPL) and its peptide derivatives exert potent anti angiogenic activity in vitro and in vivo and control tumour growth in xenograft models, when administered exogenously. However, the role of endogenous FKBPL in angiogenesis is not well characterised. Here we investigated the molecular effects of the endogenous protein and its peptide derivative, AD-01, leading to their anti-migratory activity. Inhibition of secreted FKBPL using a blocking antibody or siRNA-mediated knockdown of FKBPL accelerated the migration of human microvascular endothelial cells (HMEC-1). Furthermore, MDA-MB-231 tumour cells stably overexpressing FKBPL inhibited tumour vascular development in vivo suggesting that FKBPL secreted from tumour cells could inhibit angiogenesis. Whilst FKBPL and AD-01 target CD44, the nature of this interaction is not known and here we have further interrogated this aspect. We have demonstrated that FKBPL and AD-01 bind to the CD44 receptor and inhibit tumour cell migration in a CD44 dependant manner; CD44 knockdown abrogated AD-01 binding as well as its anti migratory activity. Interestingly, FKBPL overexpression and knockdown or treatment with AD-01, regulated CD44 expression, suggesting a co-regulatory pathway for these two proteins. Downstream of CD44, alterations in the actin cytoskeleton, indicated by intense cortical actin staining and a lack of cell spreading and communication were observed following treatment with AD-01, explaining the anti-migratory phenotype. Concomitantly, AD-01 inhibited Rac-1 activity, up-regulated RhoA and the actin binding proteins, profilin and vinculin. Thus the anti-angiogenic protein, FKBPL, and AD-01, offer a promising and alternative approach for targeting both CD44 positive tumours and vasculature networks. PMID- 23457462 TI - The effects of sampling bias and model complexity on the predictive performance of MaxEnt species distribution models. AB - Species distribution models (SDMs) trained on presence-only data are frequently used in ecological research and conservation planning. However, users of SDM software are faced with a variety of options, and it is not always obvious how selecting one option over another will affect model performance. Working with MaxEnt software and with tree fern presence data from New Zealand, we assessed whether (a) choosing to correct for geographical sampling bias and (b) using complex environmental response curves have strong effects on goodness of fit. SDMs were trained on tree fern data, obtained from an online biodiversity data portal, with two sources that differed in size and geographical sampling bias: a small, widely-distributed set of herbarium specimens and a large, spatially clustered set of ecological survey records. We attempted to correct for geographical sampling bias by incorporating sampling bias grids in the SDMs, created from all georeferenced vascular plants in the datasets, and explored model complexity issues by fitting a wide variety of environmental response curves (known as "feature types" in MaxEnt). In each case, goodness of fit was assessed by comparing predicted range maps with tree fern presences and absences using an independent national dataset to validate the SDMs. We found that correcting for geographical sampling bias led to major improvements in goodness of fit, but did not entirely resolve the problem: predictions made with clustered ecological data were inferior to those made with the herbarium dataset, even after sampling bias correction. We also found that the choice of feature type had negligible effects on predictive performance, indicating that simple feature types may be sufficient once sampling bias is accounted for. Our study emphasizes the importance of reducing geographical sampling bias, where possible, in datasets used to train SDMs, and the effectiveness and essentialness of sampling bias correction within MaxEnt. PMID- 23457461 TI - Association of RNAs with Bacillus subtilis Hfq. AB - The prevalence and characteristics of small regulatory RNAs (sRNAs) have not been well characterized for Bacillus subtilis, an important model system for Gram positive bacteria. However, B. subtilis was recently found to synthesize many candidate sRNAs during stationary phase. In the current study, we performed deep sequencing on Hfq-associated RNAs and found that a small subset of sRNAs associates with Hfq, an enigmatic RNA-binding protein that stabilizes sRNAs in Gram-negatives, but whose role is largely unknown in Gram-positive bacteria. We also found that Hfq associated with antisense RNAs, antitoxin transcripts, and many mRNA leaders. Several new candidate sRNAs and mRNA leader regions were also discovered by this analysis. Additionally, mRNA fragments overlapping with start or stop codons associated with Hfq, while, in contrast, relatively few full length mRNAs were recovered. Deletion of hfq reduced the intracellular abundance of several representative sRNAs, suggesting that B. subtilis Hfq-sRNA interactions may be functionally significant in vivo. In general, we anticipate this catalog of Hfq-associated RNAs to serve as a resource in the functional characterization of Hfq in B. subtilis. PMID- 23457463 TI - Examining the role of effective population size on mitochondrial and multilocus divergence time discordance in a songbird. AB - Estimates of speciation times are subject to a number of potential errors. One source of bias is that effective population size (Ne) has been shown to influence substitution rates. This issue is of particular interest for phylogeographic studies because population sizes can vary dramatically among genetically structured populations across species' ranges. In this study, we used multilocus data to examine temporal phylogeographic patterns in a widespread North American songbird, the Northern Cardinal (Cardinalis cardinalis). Species tree estimation indicated that the phylogeographic structure of C. cardinalis was comprised of four well-supported mainland lineages with large population sizes (large Ne) and two island lineages comprised of much smaller populations (small Ne). We inferred speciation times from mtDNA and multilocus data and found there was discordance between events that represented island-mainland divergences, whereas both estimates were similar for divergences among mainland lineages. We performed coalescent simulations and found that the difference in speciation times could be attributed to stochasticity for a recently diverged island lineage. However, the magnitude of the change between speciation times estimated from mtDNA and multilocus data of an older island lineage was substantially greater than predicted by coalescent simulations. For this divergence, we found the discordance in time estimates was due to a substantial increase in the mtDNA substitution rate in the small island population. These findings indicate that in phylogeographic studies the relative tempo of evolution between mtDNA and nuclear DNA can become highly discordant in small populations. PMID- 23457464 TI - Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci. AB - The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system. PMID- 23457465 TI - Determinants of microdamage in elderly human vertebral trabecular bone. AB - Previous studies have shown that microdamage accumulates in bone as a result of physiological loading and occurs naturally in human trabecular bone. The purpose of this study was to determine the factors associated with pre-existing microdamage in human vertebral trabecular bone, namely age, architecture, hardness, mineral and organic matrix. Trabecular bone cores were collected from human L2 vertebrae (n = 53) from donors 54-95 years of age (22 men and 30 women, 1 unknown) and previous cited parameters were evaluated. Collagen cross-link content (PYD, DPD, PEN and % of collagen) was measured on surrounding trabecular bone. We found that determinants of microdamage were mostly the age of donors, architecture, mineral characteristics and mature enzymatic cross-links. Moreover, linear microcracks were mostly associated with the bone matrix characteristics whereas diffuse damage was associated with architecture. We conclude that linear and diffuse types of microdamage seemed to have different determinants, with age being critical for both types. PMID- 23457466 TI - Dissociating memory networks in early Alzheimer's disease and frontotemporal lobar degeneration - a combined study of hypometabolism and atrophy. AB - INTRODUCTION: We aimed at dissociating the neural correlates of memory disorders in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: We included patients with AD (n = 19, 11 female, mean age 61 years) and FTLD (n = 11, 5 female, mean age 61 years) in early stages of their diseases. Memory performance was assessed by means of verbal and visual memory subtests from the Wechsler Memory Scale (WMS-R), including forgetting rates. Brain glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and brain atrophy by voxel-based morphometry (VBM) of T1-weighted magnetic resonance imaging (MRI) scans. Using a whole brain approach, correlations between test performance and imaging data were computed separately in each dementia group, including a group of control subjects (n = 13, 6 female, mean age 54 years) in both analyses. The three groups did not differ with respect to education and gender. RESULTS: Patients in both dementia groups generally performed worse than controls, but AD and FTLD patients did not differ from each other in any of the test parameters. However, memory performance was associated with different brain regions in the patient groups, with respect to both hypometabolism and atrophy: Whereas in AD patients test performance was mainly correlated with changes in the parieto-mesial cortex, performance in FTLD patients was correlated with changes in frontal cortical as well as subcortical regions. There were practically no overlapping regions associated with memory disorders in AD and FTLD as revealed by a conjunction analysis. CONCLUSION: Memory test performance may not distinguish between both dementia syndromes. In clinical practice, this may lead to misdiagnosis of FTLD patients with poor memory performance. Nevertheless, memory problems are associated with almost completely different neural correlates in both dementia syndromes. Obviously, memory functions are carried out by distributed networks which break down in brain degeneration. PMID- 23457467 TI - Increased HIV incidence in men who have sex with men despite high levels of ART induced viral suppression: analysis of an extensively documented epidemic. AB - BACKGROUND: There is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ARTcoverage has increased for reasons which remain unclear. METHODS: We analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour. RESULTS: HIV incidence has increased (estimated mean incidence 0.30/100 person-years 1990 1997, 0.45/100 py 1998-2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006-2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections. CONCLUSION: A rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections. PMID- 23457468 TI - Post-breeding season migrations of a top predator, the harbor seal (Phoca vitulina richardii), from a marine protected area in Alaska. AB - Marine protected areas (MPAs) are increasingly being used as a conservation tool for highly mobile marine vertebrates and the focus is typically on protecting breeding areas where individuals are aggregated seasonally. Yet movements during the non-breeding season can overlap with threats that may be equally as important to population dynamics. Thus understanding habitat use and movements of species during the non-breeding periods is critical for conservation. Glacier Bay National Park, Alaska, is one of the largest marine mammal protected areas in the world and has the only enforceable protection measures for reducing disturbance to harbor seals in the United States. Yet harbor seals have declined by up to 11.5%/year from 1992 to 2009. We used satellite-linked transmitters that were attached to 37 female harbor seals to quantify the post-breeding season migrations of seals and the amount of time that seals spent inside vs. outside of the MPA of Glacier Bay. Harbor seals traveled extensively beyond the boundaries of the MPA of Glacier Bay during the post-breeding season, encompassing an area (25,325 km(2)) significantly larger than that used by seals during the breeding season (8,125 km(2)). These movements included the longest migration yet recorded for a harbor seal (3,411 km) and extended use (up to 23 days) of pelagic areas by some seals. Although the collective utilization distribution of harbor seals during the post-breeding season was quite expansive, there was a substantial degree of individual variability in the percentage of days that seals spent in the MPA. Nevertheless, harbor seals demonstrated a high degree of inter-annual site fidelity (93%) to Glacier Bay the following breeding season. Our results highlight the importance of understanding the threats that seals may interact with outside of the boundaries of the MPA of Glacier Bay for understanding population dynamics of seals in Glacier Bay. PMID- 23457469 TI - Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket. AB - HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucidated. Although allostery has been found in some of its homologs, it has not been characterized in HtrA2 so far. Here, with an in silico and biochemical approach we have shown that allostery does regulate HtrA2 activity. Our studies identified a novel non-canonical selective binding pocket in HtrA2 which initiates signal propagation to the distal active site through a complex allosteric mechanism. This non-classical binding pocket is unique among HtrA family proteins and thus unfolds a novel mechanism of regulation of HtrA2 activity and hence apoptosis. PMID- 23457470 TI - Increased HIV testing will modestly reduce HIV incidence among gay men in NSW and would be acceptable if HIV testing becomes convenient. AB - OBJECTIVE: Determine the acceptability and epidemiological impact of increases in HIV testing in gay men in New South Wales (NSW), Australia- particularly pertinent when considering treatment as prevention and the need to reduce undiagnosed infections. METHODS: We conducted an online survey and focus groups to assess whether increases in HIV testing would be acceptable to gay men in NSW. In parallel, we assessed the potential impact of increases in testing coverage and/or frequency using an individual-based model of HIV transmission. RESULTS: If sexual practices and the rate of initiating HIV treatment are unchanged then increasing HIV testing reduces infections. Increasing testing frequency has the largest impact, with a 13.8% reduction in HIV infections over 10 years if the ~55 75% of men who test at least once per year increased their testing frequency to four times per year. If testing levels decrease from current levels then we expect an increase in HIV infections with a sharply rising trend over time. Increasing HIV testing would be acceptable if testing was more convenient. However, only ~25% of men surveyed were 'very likely' to increase their level of HIV testing. Men delayed or avoided testing due to the slowness in obtaining results and if they believed they had not put themselves at risk. CONCLUSIONS: An increase in HIV testing alone is unlikely to reduce HIV incidence substantially in NSW gay men- however, the relatively high testing levels need to continue to prevent an increase in HIV infections. In jurisdictions with lower levels of HIV testing, increases in testing coverage and frequency are likely to have a larger impact. Successful treatment as prevention interventions will require increases in testing rates; such increases would be acceptable to gay men in NSW but only if more convenient testing and rapid communication of results were available. PMID- 23457471 TI - Seroprevalence of bactericidal, specific IgG antibodies and incidence of meningitis due to group A Neisseria meningitidis by age in Burkina Faso 2008. AB - BACKGROUND: We investigated serological correlates of protection against Neisseria meningitidis serogroup A (NmA) in Burkina Faso before the introduction of NmA conjugate vaccine. METHODOLOGY/PRINCIPAL FINDINGS: We collected blood from a representative sample (N = 1022) of Bobo-Dioulasso residents. Sera were evaluated for serum bactericidal antibody (SBA) activity against NmA strains of immunotype L11 (F8238) and L10 (3125) and NmA-specific IgG. Seroprevalence was compared to the age-specific NmA meningitis incidence in Bobo-Dioulasso during March 2007-February 2008. Meningococcal carriage was evaluated in a subset (N = 538). Geometric mean titres (GMT)/concentrations (GMC) of SBA and NmA-specific IgG increased with age, peaking around age 20 years. Overall, 70% of our sample had NmA-specific IgG >=2 ug/mL. Meningitis incidence was highest in those aged <6 months and 5-19 years. No NmA carriers were found. Compared to the reference strain SBA, GMTs were higher against a locally isolated strain and around 40-fold lower against Dutch strain 3125. CONCLUSIONS/SIGNIFICANCE: This study provides estimates of natural immunity to NmA, according to a variety of antibody measures, which will be helpful in ascertaining antibody persistence after MenAfriVacTM introduction. Age-specific seroprevalence of reference strain SBA titres most likely reflects exposure to meningococci and consecutive reactive immunity. We could not define any serological correlate of protection. PMID- 23457472 TI - Impact on bacterial community in midguts of the Asian corn borer larvae by transgenic Trichoderma strain overexpressing a heterologous chit42 gene with chitin-binding domain. AB - This paper is the first report of the impact on the bacterial community in the midgut of the Asian corn borer (Ostrinia furnacalis) by the chitinase from the transgenic Trichoderma strain. In this study, we detected a change of the bacterial community in the midgut of the fourth instar larvae by using a culture independent method. Results suggested that Proteobacteria and Firmicutes were the most highly represented phyla, being present in all the midgut bacterial communities. The observed species richness was simple, ranging from four to five of all the 16S rRNA clone libraries. When using Trichoderma fermentation liquids as additives, the percentages of the dominant flora in the total bacterial community in larval midgut changed significantly. The community of the genus Ochrobactrum in the midgut decreased significantly when the larvae were fed with the fermentation liquids of the transgenic Trichoderma strain Mc4. However, the Enterococcus community increased and then occupied the vacated niche of the Ochrobactrum members. Furthermore, the Shannon-Wiener (H) and the Simpson (1-D) indexes of the larval midgut bacterial library treated by feeding fermentation liquids of the transgenic Trichoderma strain Mc4 was the lowest compared with the culture medium, fermentation liquids of the wild type strain T30, and the sterile artificial diet. The Enterococcus sp. strain was isolated and characterized from the healthy larvae midgut of the Asian corn borer. An infection study of the Asian corn borer larvae using Enterococcus sp. ACB-1 revealed that a correlation existed between the increased Enterococcus community in the larval midgut and larval mortality. These results demonstrated that the transgenic Trichoderma strain could affect the composition of the midgut bacterial community. The change of the midgut bacterial community might be viewed as one of the factors resulting in the increased mortality of the Asian corn borer larvae. PMID- 23457474 TI - Evaluating the impact of flexible alcohol trading hours on violence: an interrupted time series analysis. AB - BACKGROUND: On November 24(th) 2005, the Government of England and Wales removed regulatory restrictions on the times at which licensed premises could sell alcohol. This study tests availability theory by treating the implementation of Licensing Act (2003) as a natural experiment in alcohol policy. METHODS: An interrupted time series design was employed to estimate the Act's immediate and delayed impact on violence in the City of Manchester (Population 464,200). We collected police recorded rates of violence, robbery, and total crime between the 1st of February 2004 and the 31st of December 2007. Events were aggregated by week, yielding a total of 204 observations (95 pre-, and 109 post-intervention). Secondary analysis examined changes in daily patterns of violence. Pre- and post intervention events were separated into four three-hour segments 18?00-20?59, 21?00-23.59, 00?00-02?59, 03?00-05?59. RESULTS: Analysis found no evidence that the Licensing Act (2003) affected the overall volume of violence. However, analyses of night-time violence found a gradual and permanent shift of weekend violence into later parts of the night. The results estimated an initial increase of 27.5% between 03?00 to 06?00 (omega = 0.2433, 95% CI = 0.06, 0.42), which increased to 36% by the end of the study period (delta = -0.897, 95% CI = -1.02, 0.77). CONCLUSIONS: This study found no evidence that a national policy increasing the physical availability of alcohol affected the overall volume of violence. There was, however, evidence suggesting that the policy may be associated with changes to patterns of violence in the early morning (3 a.m. to 6 a.m.). PMID- 23457473 TI - DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity. AB - BACKGROUND: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. METHODOLOGY/PRINCIPAL FINDINGS: The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44-817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5-102) and were not associated with protection. Ex vivo IFN-gamma ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13-408; AMA1 348, range 88-1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-gamma mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. SIGNIFICANCE: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection. TRIAL REGISTRATION: ClinicalTrials.govNCT00870987. PMID- 23457475 TI - In silico analysis of putative paralytic shellfish poisoning toxins export proteins in cyanobacteria. AB - Paralytic shellfish poisoning toxins (PSTs) are a family of more than 30 natural alkaloids synthesized by dinoflagellates and cyanobacteria whose toxicity in animals is mediated by voltage-gated Na(+) channel blocking. The export of PST analogues may be through SxtF and SxtM, two putative MATE (multidrug and toxic compound extrusion) family transporters encoded in PSTs biosynthetic gene cluster (sxt). sxtM is present in every sxt cluster analyzed; however, sxtF is only present in the Cylindrospermopsis-Raphidiopsis clade. These transporters are energetically coupled with an electrochemical gradient of proton (H(+)) or sodium (Na(+)) ions across membranes. Because the functional role of PSTs remains unknown and methods for genetic manipulation in PST-producing organisms have not yet been developed, protein structure analyses will allow us to understand their function. By analyzing the sxt cluster of eight PST-producing cyanobacteria, we found no correlation between the presence of sxtF or sxtM and a specific PSTs profile. Phylogenetic analyses of SxtF/M showed a high conservation of SxtF in the Cylindrospermopsis-Raphidiopsis clade, suggesting conserved substrate affinity. Two domains involved in Na(+) and drug recognition from NorM proteins (MATE family) of Vibrio parahaemolyticus and V. cholerae are present in SxtF/M. The Na(+) recognition domain was conserved in both SxtF/M, indicating that Na(+) can maintain the role as a cation anti-transporter. Consensus motifs for toxin binding differed between SxtF and SxtM implying differential substrate binding. Through protein modeling and docking analysis, we found that there is no marked affinity between the recognition domain and a specific PST analogue. This agrees with our previous results of PST export in R. brookii D9, where we observed that the response to Na(+) incubation was similar to different analogues. These results reassert the hypothesis regarding the involvement of Na(+) in toxin export, as well as the motifs L(398)XGLQD(403) (SxtM) and L(390)VGLRD(395) (SxtF) in toxin recognition. PMID- 23457476 TI - Bacillus megaterium has both a functional BluB protein required for DMB synthesis and a related flavoprotein that forms a stable radical species. AB - Despite the extensive study of the biosynthesis of the complex molecule B12 (cobalamin), the mechanism by which the lower ligand 5,6-dimethylbenzimidazole (DMB) is formed has remained something of a mystery. However, recent work has identified and characterized a DMB-synthase (BluB) responsible for the oxygen dependent, single enzyme conversion of FMN to DMB. In this work, we have identified BluB homologs from the aerobic purple, nonsulfur, photosynthetic bacterium Rhodobacter capsulatus and the aerobic soil bacterium Bacillus megaterium and have demonstrated DMB synthesis by the use of a novel complementation assay in which a B12 deficient strain, substituted with the precursor cobinamide is recovered either by the addition of DMB or by the recombinant expression of a bluB gene. The DMB-synthetic activity of the purified recombinant BluB enzymes was further confirmed in vitro by providing the enzyme with FMNH2 and oxygen and observing the formation of DMB by HPLC. The formation of a 4a-peroxyflavin intermediate, the first step in the oxygen dependent mechanism of DMB biosynthesis, is reported here and is the first intermediate in the enzyme catalysed reaction to be demonstrated experimentally to date. The identification and characterization of an FMN-binding protein found on the cobI operon of B. megaterium, CbiY, is also detailed, revealing an FMN-containing enzyme which is able to stabilize a blue flavin semiquinone upon reduction with a 1-electron donor. PMID- 23457477 TI - Outcomes of antiretroviral therapy in Vietnam: results from a national evaluation. AB - OBJECTIVES: Vietnam has significantly scaled up its national antiretroviral therapy (ART) program since 2005. With the aim of improving Vietnam's national ART program, we conducted an outcome evaluation of the first five years of the program in this concentrated HIV epidemic where the majority of persons enrolled in HIV care and treatment services are people who inject drugs (PWID). The results of this evaluation may have relevance for other national ART programs with significant PWID populations. DESIGN: Retrospective cohort analysis of patients at 30 clinics randomly selected with probability proportional to size among 120 clinics with at least 50 patients on ART. METHODS: Charts of patients whose ART initiation was at least 6 months prior to the study date were abstracted. Depending on clinic size, either all charts or a random sample of 300 charts were selected. Analyses were limited to treatment-naive patients. Multiple imputations were used for missing data. RESULTS: Of 7,587 patient charts sampled, 6,875 were those of treatment-naive patients (74.4% male, 95% confidence interval [CI]: 72.4-76.5, median age 30, interquartile range [IQR]: 26-34, 62.0% reported a history of intravenous drug use, CI: 58.6-65.3). Median baseline CD4 cell count was 78 cells/mm(3) (IQR: 30-162) and 30.4% (CI: 25.8-35.1) of patients were at WHO stage IV. The majority of patients started d4T/3TC/NVP (74.3%) or d4T/3TC/EFV (18.6%). Retention rates after 6, 12, 24, and 36 months were 88.4% (CI: 86.8 89.9), 84.0% (CI: 81.8-86.0), 78.8% (CI: 75.7-81.6), and 74.6% (CI: 69.6-79.0). Median CD4 cell count gains after 6, 12, 24, and 36 months were 94 (IQR: 45-153), 142 (IQR: 78-217), 213 (IQR: 120-329), and 254 (IQR: 135-391) cells/mm(3). Patients who were PWID showed significantly poorer retention. CONCLUSIONS: The study showed good retention and immunological response to ART among a predominantly PWID group of patients despite advanced HIV infections at baseline. PMID- 23457478 TI - Phosphorescent imaging of living cells using a cyclometalated iridium (III) complex. AB - A cell permeable cyclometalated iridium(III) complex has been developed as a phosphorescent probe for cell imaging. The iridium(III) solvato complex [Ir(phq)2(H2O]2)] preferentially stains the cytoplasm of both live and dead cells with a bright luminescence. PMID- 23457479 TI - Homologization of the flight musculature of zygoptera (insecta: odonata) and neoptera (insecta). AB - Among the winged insects (Pterygota) the Dragonflies and Damselflies (Odonata) are unique for several reasons. Behaviourally they are aerial predators that hunt and catch their prey in flight, only. Morphologically the flight apparatus of Odonata is significantly different from what is found in the remaining Pterygota. However, to understand the phylogenetic relationships of winged insects and the origin and evolution of insect flight in general, it is essential to know how the elements of the odonatan flight apparatus relate to those of the other Pterygota. Here we present a comprehensive, comparative morphological investigation of the thoracic flight musculature of damselflies (Zygoptera). Based on our new data we propose a homologization scheme for the thoracic musculature throughout Pterygota. The new homology hypotheses will allow for future comparative work and especially for phylogenetic analyses using characters of the thoracic musculature throughout all winged insects. This will contribute to understand the early evolution of pterygote insects and their basal phylogenetic relationship. PMID- 23457480 TI - Emergence of cowpox: study of the virulence of clinical strains and evaluation of antivirals. AB - The last years, cowpox infections are being increasingly reported through Eurasia. Cowpox viruses (CPXVs) have been reported to have different genotypes and may be subdivided in at least five genetically distinct monophyletic clusters. However, little is known about their in vitro and in vivo features. In this report, five genetically diverse CPXVs, including one reference strain (CPXV strain Brighton) and four clinical isolates from human and animal cases, were compared with regard to growth in cells, pathogenicity in mice and inhibition by antivirals. While all CPXVs replicated similarly in vitro and showed comparable antiviral susceptibility, marked discrepancies were seen in vivo, including differences in virulence with recorded mortality rates of 0%, 20% and 100%. The four CPXV clinical isolates appeared less pathogenic than two reference strains, CPXV Brighton and vaccinia virus Western-Reserve. Disease severity seemed to correlate with high viral DNA loads in several organs, virus titers in lung tissues and levels of IL-6 cytokine in the sera. Our study highlighted that the species CPXV consists of viruses that not only differ considerably in their genotypes but also in their in vivo phenotypes, indicating that CPXVs should not be longer classified as a single species. Lung virus titers and IL-6 cytokine level in mice may be used as biomarkers for predicting disease severity. We further demonstrated the potential benefit of cidofovir, CMX001 and ST-246 use as antiviral therapy. PMID- 23457481 TI - Recent history and geography of virtual water trade. AB - The global trade of goods is associated with a virtual transfer of the water required for their production. The way changes in trade affect the virtual redistribution of freshwater resources has been recently documented through the analysis of the virtual water network. It is, however, unclear how these changes are contributed by different types of products and regions of the world. Here we show how the global patterns of virtual water transport are contributed by the trade of different commodity types, including plant, animal, luxury (e.g., coffee, tea, and alcohol), and other products. Major contributors to the virtual water network exhibit different trade patterns with regard to these commodity types. The net importers rely on the supply of virtual water from a small percentage of the global population. However, discrepancies exist among the different commodity networks. While the total virtual water flux through the network has increased between 1986 and 2010, the proportions associated with the four commodity groups have remained relatively stable. However, some of the major players have shown significant changes in the virtual water imports and exports associated with those commodity groups. For instance, China has switched from being a net exporter of virtual water associated with other products (non-edible plant and animal products typically used for manufacturing) to being the largest importer, accounting for 31% of the total water virtually transported with these products. Conversely, in the case of The United states of America, the commodity proportions have remained overall unchanged throughout the study period: the virtual water exports from The United States of America are dominated by plant products, whereas the imports are comprised mainly of animal and luxury products. PMID- 23457482 TI - Spatiotemporal expression of repulsive guidance molecules (RGMs) and their receptor neogenin in the mouse brain. AB - Neogenin has been implicated in a variety of developmental processes such as neurogenesis, neuronal differentiation, apoptosis, migration and axon guidance. Binding of repulsive guidance molecules (RGMs) to Neogenin inhibits axon outgrowth of different neuronal populations. This effect requires Neogenin to interact with co-receptors of the uncoordinated locomotion-5 (Unc5) family to activate downstream Rho signaling. Although previous studies have reported RGM, Neogenin, and/or Unc5 expression, a systematic comparison of RGM and Neogenin expression in the developing nervous system is lacking, especially at later developmental stages. Furthermore, information on RGM and Neogenin expression at the protein level is limited. To fill this void and to gain further insight into the role of RGM-Neogenin signaling during mouse neural development, we studied the expression of RGMa, RGMb, Neogenin and Unc5A-D using in situ hybridization, immunohistochemistry and RGMa section binding. Expression patterns in the primary olfactory system, cortex, hippocampus, habenula, and cerebellum were studied in more detail. Characteristic cell layer-specific expression patterns were detected for RGMa, RGMb, Neogenin and Unc5A-D. Furthermore, strong expression of RGMa, RGMb and Neogenin protein was found on several major axon tracts such as the primary olfactory projections, anterior commissure and fasciculus retroflexus. These data not only hint at a role for RGM-Neogenin signaling during the development of different neuronal systems, but also suggest that Neogenin partners with different Unc5 family members in different systems. Overall, the results presented here will serve as a framework for further dissection of the role of RGM-Neogenin signaling during neural development. PMID- 23457483 TI - Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx. AB - Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S(35) and (3)H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress. PMID- 23457484 TI - Depth structure from asymmetric shading supports face discrimination. AB - To examine the effect of illumination direction on the ability of observers to discriminate between faces, we manipulated the direction of illumination on scanned 3D face models. In order to dissociate the surface reflectance and illumination components of front-view face images, we introduce a symmetry algorithm that can separate the symmetric and asymmetric components of the face in both low and high spatial frequency bands. Based on this approach, hybrid faces stimuli were constructed with different combinations of symmetric and asymmetric spatial content. Discrimination results with these images showed that asymmetric illumination information biased face perception toward the structure of the shading component, while the symmetric illumination information had little, if any, effect. Measures of perceived depth showed that this property increased systematically with the asymmetric but not the symmetric low spatial frequency component. Together, these results suggest that (1) the asymmetric 3D shading information dramatically affects both the perceived facial information and the perceived depth of the facial structure; and (2) these effects both increase as the illumination direction is shifted to the side. Thus, our results support the hypothesis that face processing has a strong 3D component. PMID- 23457485 TI - Acute kidney injury in patients with newly diagnosed high-grade hematological malignancies: impact on remission and survival. AB - BACKGROUND: Optimal chemotherapy with minimal toxicity is the main determinant of complete remission in patients with newly diagnosed hematological malignancies. Acute organ dysfunctions may impair the patient's ability to receive optimal chemotherapy. DESIGN AND METHODS: To compare 6-month complete remission rates in patients with and without acute kidney injury (AKI), we collected prospective data on 200 patients with newly diagnosed high-grade malignancies (non-Hodgkin lymphoma, 53.5%; acute myeloid leukemia, 29%; acute lymphoblastic leukemia, 11.5%; and Hodgkin disease, 6%). RESULTS: According to RIFLE criteria, 137 (68.5%) patients had AKI. Five causes of AKI accounted for 91.4% of cases: hypoperfusion, tumor lysis syndrome, tubular necrosis, nephrotoxic agents, and hemophagocytic lymphohistiocytosis. Half of the AKI patients received renal replacement therapy and 14.6% received suboptimal chemotherapy. AKI was associated with a lower 6-month complete remission rate (39.4% vs. 68.3%, P<0.01) and a higher mortality rate (47.4% vs. 30.2%, P<0.01) than patients without AKI. By multivariate analysis, independent determinants of 6-month complete remission were older age, poor performance status, number of organ dysfunctions, and AKI. CONCLUSION: AKI is common in patients with newly diagnosed high-grade malignancies and is associated with lower complete remission rates and higher mortality. PMID- 23457486 TI - Photodynamic and antibiotic therapy impair the pathogenesis of Enterococcus faecium in a whole animal insect model. AB - Enterococcus faecium has emerged as one of the most important pathogens in healthcare-associated infections worldwide due to its intrinsic and acquired resistance to many antibiotics, including vancomycin. Antimicrobial photodynamic therapy (aPDT) is an alternative therapeutic platform that is currently under investigation for the control and treatment of infections. PDT is based on the use of photoactive dye molecules, widely known as photosensitizer (PS). PS, upon irradiation with visible light, produces reactive oxygen species that can destroy lipids and proteins causing cell death. We employed Galleria mellonella (the greater wax moth) caterpillar fatally infected with E. faecium to develop an invertebrate host model system that can be used to study the antimicrobial PDT (alone or combined with antibiotics). In the establishment of infection by E. faecium in G. mellonella, we found that the G. mellonella death rate was dependent on the number of bacterial cells injected into the insect hemocoel and all E. faecium strains tested were capable of infecting and killing G. mellonella. Antibiotic treatment with ampicillin, gentamicin or the combination of ampicillin and gentamicin prolonged caterpillar survival infected by E. faecium (P = 0.0003, P = 0.0001 and P = 0.0001, respectively). In the study of antimicrobial PDT, we verified that methylene blue (MB) injected into the insect followed by whole body illumination prolonged the caterpillar survival (P = 0.0192). Interestingly, combination therapy of larvae infected with vancomycin resistant E. faecium, with antimicrobial PDT followed by vancomycin, significantly prolonged the survival of the caterpillars when compared to either antimicrobial PDT (P = 0.0095) or vancomycin treatment alone (P = 0.0025), suggesting that the aPDT made the vancomycin resistant E. faecium strain more susceptible to vancomycin action. In summary, G. mellonella provides an invertebrate model host to study the antimicrobial PDT and to explore combinatorial aPDT-based treatments. PMID- 23457487 TI - Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia. AB - Bioactive components from dietary supplements such as curcumin may represent attractive agents for cancer prevention or treatment. DNA methylation plays a critical role in acute myeloid leukemia (AML) development, and presents an excellent target for treatment of this disease. However, it remains largely unknown how curcumin, a component of the popular Indian spice turmeric, plays a role in DNA hypomethylation to reactivate silenced tumor suppressor genes and to present a potential treatment option for AML. Here we show that curcumin down regulates DNMT1 expression in AML cell lines, both in vitro and in vivo, and in primary AML cells ex vivo. Mechanistically, curcumin reduced the expression of positive regulators of DNMT1, p65 and Sp1, which correlated with a reduction in binding of these transcription factors to the DNMT1 promoter in AML cell lines. This curcumin-mediated down-regulation of DNMT1 expression was concomitant with p15(INK4B) tumor suppressor gene reactivation, hypomethylation of the p15(INK4B) promoter, G1 cell cycle arrest, and induction of tumor cell apoptosis in vitro. In mice implanted with the human AML MV4-11 cell line, administration of curcumin resulted in remarkable suppression of AML tumor growth. Collectively, our data indicate that curcumin shows promise as a potential treatment for AML, and our findings provide a basis for future studies to test the clinical efficacy of curcumin - whether used as a single agent or as an adjuvant - for AML treatment. PMID- 23457488 TI - Effects of exposure, diet, and thermoregulation on fecal glucocorticoid measures in wild bears. AB - We examined fecal glucocorticoid (fGC) measures of nutrition and thermoregulatory demands on wild bears in Glacier National Park, Montana, and assessed how these measures changed in samples left in the field. Both ambient temperature and exposure can impact thermoregulation and sample degradation. Bear diets vary markedly with season, affecting body condition and thus fGC. We collected fecal samples during September and October, 2001, when ambient temperatures ranged from 30 degrees C to -5 degrees C. We collected half of each sample immediately and left the other half in its original location for 1-28 days. We used generalized linear models (GLM) to first predict fGC concentrations in fresh samples based on proxies of nutrition, ambient temperature, thermal exposure, and precipitation. These same covariates were then used to predict degradation-based differences in fGC concentrations between the paired sample halves. Variation in fGC was predicted by diet, Julian date, aspect, and the interaction between Julian date and aspect in both fresh and exposed samples. Cumulative precipitation was also a significant predictor of fGC concentrations in the exposed samples, independent of time, indicating that precipitation contributes to sample degradation but not enough to mask effects of other environmental factors on fGC concentrations. Differences between sample halves were only predicted by cumulative precipitation and exposure time; cumulative precipitation decreased, whereas exposure time increased, fGC concentrations in the exposed sample halves. Results indicate that fGC can provide reliable indices of nutrition and thermoregulatory demands in bears and that sample degradation impacts on these relations are minimal and can be virtually eliminated by controlling for cumulative precipitation over the estimated exposure times. PMID- 23457489 TI - Clusterin protects hepatocellular carcinoma cells from endoplasmic reticulum stress induced apoptosis through GRP78. AB - Clusterin (CLU) is a stress-activated chaperone, which plays an important role in cancer development and progression through promoting cell survival. However, the exact mechanism of how CLU exerts its cell protective role under ER stress condition is still unclear. Therefore, in order to explore the molecular mechanisms by which CLU inhibited ER stress-induced apoptosis, HCC cell lines were treated with tunicamycin (TN), an ER stress inducer. We found that the expressions of both CLU and GRP78 were increased after TN treatment. Knockdown of CLU expression in SMMC7721 and HCCLM3 cells inhibited GRP78 expression after TN treatment and enhanced ER stress-induced apoptosis, whereas over-expression of CLU in HepG2 cells increased GRP78 expression after TN induction and abolished the effect of TN on cell apoptosis. Furthermore, knockdown of GRP78 expression in CLU-HepG2 cells abrogated the protective role of CLU under ER stress condition. Co-immunoprecipitation (co-IP) and confocal microscopy experiments confirmed the direct interaction between CLU and GRP78 under ER stress condition. The effect of CLU knockdown on GRP78 expression and cell apoptosis in HCC tumors were further determined in orthotopic xenograft tumor model. Knockdown of CLU expression in HCCLM3 cells inhibited GRP78 expression in tumor tissues, accompanied with increased number of apoptotic cancer cells. Moreover, the correlation between CLU and GRP78 expression was further determined in clinical HCC specimens. Taken together, these findings reveal that CLU protects HCC cells from ER stress induced apoptosis at least partially through interacting with GRP78. PMID- 23457490 TI - Changing the name of schizophrenia: patient perspectives and implications for DSM V. AB - INTRODUCTION: The diagnosis of schizophrenia is increasingly contested by researchers, clinicians, patients and family members. Preeminent researchers proposed its replacement with the salience syndrome concept, arguing for increased validity and less stigmatizing potential. This is the first study exploring the effects on stigma of this nosological proposal. METHODS: TWO STUDIES WERE CONDUCTED: one with 161 undergraduate students regarding their stigmatizing attitudes linked to the label of schizophrenia or salience syndrome, the other involved in-depth qualitative interviews with 19 participants treated in a first episode psychosis program. The interviews explored the subjective validity, acceptability and effects on stigma of a diagnosis of schizophrenia or salience syndrome. RESULTS: Overall, no significant differences were found between labels in study 1. For study 2, the majority of participants preferred a diagnosis of salience syndrome, considering it less stigmatizing mostly because of its novelty and the concealing potential of the new diagnostic entity, though many found it hard to relate to and somewhat difficult to understand. DISCUSSION: Our results suggest that the label change does not impact the stigmatizing potential for individuals who are not familiar with mental illness - they appear to base their attitudes on descriptions rather than the label alone. For those suffering from mental illness, a name change for schizophrenia to "salience syndrome" might offer only a temporary relief from stigma. Claims of de stigmatizing effects should be grounded in sound scientific models of stigma and ideally in empirical data. PMID- 23457491 TI - The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization. AB - In this study, we examined anti-fungal and anti-inflammatory effects of the synthetic melanocortin peptide (Ac-Cys-Lys-Pro-Val-NH2)2 or (CKPV)2 against Candida albicans vaginitis. Our in vitro results showed that (CKPV)2 dose dependently inhibited Candida albicans colonies formation. In a rat Candida albicans vaginitis model, (CKPV)2 significantly inhibited vaginal Candida albicans survival and macrophages sub-epithelial mucosa infiltration. For mechanisms study, we observed that (CKPV)2 inhibited macrophages phagocytosis of Candida albicans. Meanwhile, (CKPV)2 administration inhibited macrophage pro inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) release, while increasing the arginase activity and anti-inflammatory cytokine IL-10 production, suggesting macrophages M1 to M2 polarization. Cyclic AMP (cAMP) production was also induced by (CKPV)2 administration in macrophages. These above effects on macrophages by (CKPV)2 were almost reversed by melanocortin receptor-1(MC1R) siRNA knockdown, indicating the requirement of MC1R in the process. Altogether, our results suggest that (CKPV)2 exerted anti-fungal and anti-inflammatory activities against Candida albicans vaginitis probably through inducing macrophages M1 to M2 polarization and MC1R activation. PMID- 23457492 TI - VCP Is an integral component of a novel feedback mechanism that controls intracellular localization of catalase and H2O2 Levels. AB - Catalase is a key antioxidant enzyme that catalyzes the decomposition of hydrogen peroxide (H2O2) to water and oxygen, and it appears to shuttle between the cytoplasm and peroxisome via unknown mechanisms. Valosin-containing protein (VCP) belongs to the AAA class of ATPases and is involved in diverse cellular functions, e.g. cell cycle and protein degradation, etc. Here we show that VCP and PEX19, a protein essential for peroxisome biogenesis, interact with each other. Knockdown of either VCP or PEX19 resulted in a predominantly cytoplasmic redistribution of catalase, and loss of VCP ATPase activity also increased its cytoplasmic redistribution. Moreover, VCP knockdown decreased intracellular ROS levels in normal and H2O2-treated cells, and an oxidation-resistant VCP impaired the ROS-induced cytoplasmic redistribution of catalase. These observations reveal a novel feedback mechanism, in which VCP can sense H2O2 levels, and regulates them by controlling the localization of catalase. PMID- 23457493 TI - The role of IgE-receptors in IgE-dependent airway smooth muscle cell remodelling. AB - BACKGROUND: In allergic asthma, IgE increases airway remodelling but the mechanism is incompletely understood. Airway remodelling consists of two independent events increased cell numbers and enhanced extracellular matrix deposition, and the mechanism by which IgE up-regulates cell proliferation and extracellular matrix deposition by human airway smooth muscle cells in asthma is unclear. OBJECTIVE: Characterise the role of the two IgE receptors and associated signalling cascades in airway smooth muscle cell remodelling. METHODS: Primary human airway smooth muscle cells (8 asthmatics, 8 non-asthmatics) were stimulated with human purified antibody-activated IgE. Proliferation was determined by direct cell counts. Total collagen deposition was determined by Sircol; collagen species deposition by ELISA. IgE receptors were silenced by siRNA and mitogen activated protein kinase (MAPK) signalling was blocked by chemical inhibitors. RESULTS: IgE dose-dependently increased extracellular matrix and collagen deposition by airway smooth muscle cells as well as their proliferation. Specifically in cells of asthma patients IgE increased the deposition of collagen type-I, -III, -VII and fibronectin, but did not affect the deposition of collagens type-IV. IgE stimulated collagen type-I and type-VII deposition through IgE receptor-I and Erk1/2 MAPK. Proliferation and deposition of collagens type III and fibronectin involved both IgE receptors as well as Erk1/2 and p38 MAPK. Pre-incubation (30 minutes) with Omalizumab prevented all remodelling effects completely. We observed no changes in gelatinase activity or their inhibitors. CONCLUSION CLINCAL RELEVANCE: Our study provides the molecular biological mechanism by which IgE increases airway remodelling in asthma through increased airway smooth muscle cell proliferation and deposition of pro-inflammatory collagens and fibronectin. Blocking IgE action prevents several aspects of airway smooth muscle cell remodelling. Our findings may explain the recently described reduction of airway wall thickness in severe asthma patients treated with humanised anti-IgE antibodies. PMID- 23457494 TI - Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. AB - BACKGROUND: Colon carcinogenesis is a multistep process and it emanates from a series of molecular and histopathological alterations. Glycyrrhizic acid (GA) is a natural and major pentacyclic triterpenoid glycoside of licorice roots extracts. It has several pharmacological and biological properties such as anti inflammatory, anti-viral, and anti-cancer. In the present study, we investigated the chemopreventive potential of GA against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions i.e., aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. METHODS: Animals were divided into 5 groups. In group III, IV and V, GA was administered at the dose of 15 mg/kg b. wt. orally while in group II, III and IV, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b.wt once a week for first 5 weeks and animals were euthanized after 9 weeks. RESULTS: GA supplementation suppressed the development of precancerous lesions and it also reduced the infiltration of mast cells, suppressed the immunostaining of Ki-67, NF-kB-p65, COX-2, iNOS and VEGF while enhanced the immunostaining of p53, connexin-43, caspase-9 and cleaved caspase-3. GA treatment significantly attenuated the level of TNF-alpha and it also reduced the depletion of the mucous layer as well as attenuated the shifting of sialomucin to sulphomucin. CONCLUSION: Our findings suggest that GA has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of GA. PMID- 23457495 TI - Selection of appropriate reference genes for RT-qPCR analysis in a streptozotocin induced Alzheimer's disease model of cynomolgus monkeys (Macaca fascicularis). AB - Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) has been widely used to quantify relative gene expression because of the specificity, sensitivity, and accuracy of this technique. In order to obtain reliable gene expression data from RT-qPCR experiments, it is important to utilize optimal reference genes for the normalization of target gene expression under varied experimental conditions. Previously, we developed and validated a novel icv-STZ cynomolgus monkey model for Alzheimer's disease (AD) research. However, in order to enhance the reliability of this disease model, appropriate reference genes must be selected to allow meaningful analysis of the gene expression levels in the icv-STZ cynomolgus monkey brain. In this study, we assessed the expression stability of 9 candidate reference genes in 2 matched pair brain samples (5 regions) of control cynomolgus monkeys and those who had received intracerebroventricular injection of streptozotocin (icv-STZ). Three well-known analytical programs geNorm, NormFinder, and BestKeeper were used to choose the suitable reference genes from the total sample group, control group, and icv-STZ group. Combination analysis of the 3 different programs clearly indicated that the ideal reference genes are RPS19 and YWHAZ in the total sample group, GAPDH and RPS19 in the control group, and ACTB and GAPDH in the icv-STZ group. Additionally, we validated the normalization accuracy of the most appropriate reference genes (RPS19 and YWHAZ) by comparison with the least stable gene (TBP) using quantification of the APP and MAPT genes in the total sample group. To the best of our knowledge, this research is the first study to identify and validate the appropriate reference genes in cynomolgus monkey brains. These findings provide useful information for future studies involving the expression of target genes in the cynomolgus monkey. PMID- 23457496 TI - Insomnia, daytime sleepiness and cardio-cerebrovascular diseases in the elderly: a 6-year prospective study. AB - OBJECTIVE: To examine 1) the associations between history of cardio cerebrovascular diseases (CVD) and insomnia complaints and excessive daytime sleepiness (EDS), and 2) the relationships between sleep complaints and future CVD in persons over 65. METHODS: CVD was assessed at baseline and during two, four, and six-year follow-up in 5494 non-demented subjects. Self-reported insomnia complaints (poor sleep quality, difficulty in initiating sleep, difficulty in maintening sleep, and early morning awakening), EDS and sleep medication use were evaluated at baseline. Logistic regression models and Cox proportional hazard models, with delayed entry and age of participants as the time scale, were adjusted for socio-demographic, lifestyle and clinical variables. RESULTS: At baseline, 748 participants had a past-history of CVD. A past-history of CVD was associated with EDS (OR = 1.28 95%CI = [1.05-1.57]) and the number of insomnia complaints (OR = 1.26 95%CI = [1.03-1.55] for 1-2 insomnia complaints; OR = 1.32 95%CI = [1.03-1.71] for >=3 complaints). In longitudinal analyses, neither the four components of insomnia nor the number of insomnia complaints were significantly associated with first or recurrent CVD events (n = 391 events). EDS was independently associated with future CVD events even after adjusting for prescribed sleep medication and past-history of CVD (HR = 1.35 95%CI = [1.06-1.71]). CONCLUSION: Our results suggest that the relationships between sleep complaints and CVD could be complex. Insomnia complaints are more likely a consequence of CVD, whereas EDS appears to be a determinant of CVD independently of past-history of CVD. EDS screening may thus constitute a means of detecting persons at high risk of CVD. PMID- 23457497 TI - Characterising the mechanism of airway smooth muscle beta2 adrenoceptor desensitization by rhinovirus infected bronchial epithelial cells. AB - Rhinovirus (RV) infections account for approximately two thirds of all virus induced asthma exacerbations and often result in an impaired response to beta2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlying RV-induced beta2 adrenoceptor desensitization in primary human airway smooth muscle cells (ASMC). RV infection of primary human bronchial epithelial cells (HBEC) for 24 hours produced conditioned medium that caused beta2 adrenoceptor desensitization on ASMCs without an effect on ASMCs viability. Less than 3 kDa size fractionation together with trypsin digestion of RV-induced conditioned medium did not prevent beta2 adrenoceptor desensitization, suggesting it could potentially be mediated by a small peptide or lipid. RV infection of BECs, ASMCs and fibroblasts produced prostaglandins, of which PGE2, PGF2alpha and PGI2 had the ability to cause beta2 adrenoceptor desensitization on ASMCs. RV induced conditioned medium from HBECs depleted of PGE2 did not prevent ASMC beta2 adrenoceptor desensitization; however this medium induced PGE2 from ASMCs, suggesting that autocrine prostaglandin production may be responsible. Using inhibitors of cyclooxygenase and prostaglandin receptor antagonists, we found that beta2 adrenoceptor desensitization was mediated through ASMC derived COX-2 induced prostaglandins. Since ASMC prostaglandin production is unlikely to be caused by RV-induced epithelial derived proteins or lipids we next investigated activation of toll-like receptors (TLR) by viral RNA. The combination of TLR agonists poly I:C and imiquimod induced PGE2 and beta2 adrenoceptor desensitization on ASMC as did the RNA extracted from RV-induced conditioned medium. Viral RNA but not epithelial RNA caused beta2 adrenoceptor desensitization confirming that viral RNA and not endogenous human RNA was responsible. It was deduced that the mechanism by which beta2 adrenoceptor desensitization occurs was by pattern recognition receptor activation of COX-2 induced prostaglandins. PMID- 23457498 TI - Antigenicity and immunogenicity of Plasmodium vivax merozoite surface protein-3. AB - A recent clinical trial in African children demonstrated the potential utility of merozoite surface protein (MSP)-3 as a vaccine against Plasmodium falciparum malaria. The present study evaluated the use of Plasmodium vivax MSP-3 (PvMSP-3) as a target antigen in vaccine formulations against malaria caused by P. vivax. Recombinant proteins representing MSP-3alpha and MSP-3beta of P. vivax were expressed as soluble histidine-tagged bacterial fusions. Antigenicity during natural infection was evaluated by detecting specific antibodies using sera from individuals living in endemic areas of Brazil. A large proportion of infected individuals presented IgG antibodies to PvMSP-3alpha (68.2%) and at least 1 recombinant protein representing PvMSP-3beta (79.1%). In spite of the large responder frequency, reactivity to both antigens was significantly lower than was observed for the immunodominant epitope present on the 19-kDa C-terminal region of PvMSP-1. Immunogenicity of the recombinant proteins was studied in mice in the absence or presence of different adjuvant formulations. PvMSP-3beta, but not PvMSP-3alpha, induced a TLR4-independent humoral immune response in the absence of any adjuvant formulation. The immunogenicity of the recombinant antigens were also tested in formulations containing different adjuvants (Alum, Salmonella enterica flagellin, CpG, Quil A,TiterMax(r) and incomplete Freunds adjuvant) and combinations of two adjuvants (Alum plus flagellin, and CpG plus flagellin). Recombinant PvMSP-3alpha and PvMSP-3beta elicited higher antibody titers capable of recognizing P. vivax-infected erythrocytes harvested from malaria patients. Our results confirm that P. vivax MSP-3 antigens are immunogenic during natural infection, and the corresponding recombinant proteins may be useful in elucidating their vaccine potential. PMID- 23457499 TI - The genetic polymorphisms and colonization process of olive fly populations in Turkey. AB - The olive fruit fly, Bactrocera oleae, is the most important pest of olives in olive growing regions worldwide, especially in the Mediterranean basin and North America. Despite the economic importance of the olive fly, the colonization route of this species is unclear. We used nuclear microsatellite markers and mitochondrial DNA to provide information about the population structure and invasion route of olive fly populations in Turkey, as representative of the Eastern Mediterranean region. Adult fly samples were collected from 38 sublocations covering all olive growing regions in Turkey. The simple sequence variability data revealed a significant genetic variability in olive fly populations and a certain degree of differentiation between Mediterranean and Aegean populations. Mediterranean populations harbor higher levels of microsatellite variation than Aegean populations, which points to the eastern part of the Mediterranean as the putative source of invasion. mtDNA results suggest olive flies from the western part of Turkey are closely related to Italo Aegean flies of the Mediterranean basin and the olive fly populations have invaded the northern part of the Mediterranean basin through western Turkey. In addition, finding specific American haplotypes in high frequencies might indicate that Turkey is the possible source of American olive fly populations. In order to more precisely characterize the population structure and invasion routes of this organism, more DNA-based sequence analysis should be carried out worldwide. PMID- 23457500 TI - Trends in the prevalence of diarrheagenic Escherichia coli among hospitalized diarrheal patients in Kolkata, India. AB - BACKGROUND: To analyse the trends in the prevalence of different pathogroups of diarrheagenic Escherichia coli (DEC) among hospitalized acute diarrheal patients. METHODOLOGY/PRINCIPAL FINDINGS: From the active surveillance of diarrheal disease at the Infectious Diseases Hospital, Kolkata, 3826 stool specimens collected during 2008-2011 were screened for DEC and other enteric pathogens. PCR was used in the detection of enterotoxigenic, enteropathogenic and enteroaggregative E. coli and 10 major colonization factor antigens (CFs) of enterotoxigenic E. coli. The relationship between DEC infected patient's age group and clinical symptoms were also investigated. Multiplex PCR assay showed that the prevalence of EAEC was most common (5.7%) followed by ETEC (4.2%) and EPEC (1.8%). In diarrheal children >2 year of age, EAEC and EPEC were detected significantly (p = 0.000 and 0.007, respectively). In children >2 to 5 and >5 to 14 years, ETEC was significantly associated with diarrhea (p = 0.000 each). EAEC was significantly associated with diarrheal patients with age groups >14 to 30 and >30 to 50 years (p = 0.001, and p = 0.009, respectively). Clinical symptoms such as vomiting, abdominal pain, watery diarrhea, were recorded in patients infected with ETEC. Dehydration status was severe among patients infected by ST-ETEC (19%) and EPEC (15%). CS6 was frequently detected (37%) among ETEC. CONCLUSIONS/SIGNIFICANCE: Hospital based surveillance reviled that specific pathogroups of DEC are important to certain age groups and among ETEC, CS6 was predominant. PMID- 23457501 TI - The association between MTHFR gene polymorphisms and hepatocellular carcinoma risk: a meta-analysis. AB - BACKGROUND: The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and hepatocellular carcinoma (HCC) risk was inconsistent and underpowered. To clarify the effects of MTHFR gene polymorphisms on the risk of HCC, a meta-analysis of all available studies relating C677T and/or A1298C polymorphisms of MTHFR gene to the risk of HCC was conducted. METHODS: The authors searched PubMed, EMBASE, Cochrane Library, Web of Science, and Chinese Biomedical Literature database (CBM) for the period up to July 2012. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS: Finally, 12 studies with 2,351 cases and 4,091 controls were included for C677T polymorphism and 6 studies with 1,333 cases and 1,878 controls were included for A1298C polymorphism. With respect to A1298C polymorphism, significantly decreased HCC risk was found in the overall population (CC vs. AA: OR = 0.660, 95%CI 0.460 0.946, P = 0.024; recessive model: OR = 0.667, 95%CI = 0.470-0.948, P = 0.024). In subgroup analyses, significantly decreased HCC risk was found in Asian population (CC vs. AA: OR = 0.647, 95%CI = 0.435-0.963; P = 0.032) and population based studies (CC vs. AA: OR = 0.519, 95%CI = 0.327-0.823; P = 0.005). With respect to C677T polymorphism, no significant association with HCC risk was demonstrated in overall and stratified analyses. CONCLUSIONS: We concluded that MTHFR A1298C polymorphism may play a protective role in the carcinogenesis of HCC. Further large and well-designed studies are needed to confirm this association. PMID- 23457502 TI - A systematic review of reported cost for smear and culture tests during multidrug resistant tuberculosis treatment. AB - BACKGROUND: In 2011, World Health Organization revised its recommendation for microbiological monitoring during treatment for multidrug-resistant tuberculosis (MDR-TB) by increasing the frequency of culture examination from quarterly to monthly after culture conversion. Implementing the recommendation requires substantial additional investment in laboratory infrastructure. The objective of this review is to provide cost evidence that is needed for national TB programs to budget for optimal monitoring strategies. METHODS AND FINDINGS: WE CONDUCTED THE FIRST SYSTEMATIC LITERATURE REVIEW ON UNIT COST ESTIMATES OF THREE MONITORING STRATEGIES: 1) smear only; 2) culture only; 3) combined smear and culture. 26 peer-reviewed studies were selected by searching 10 databases in English and Chinese for literature published between 1995 and 2012. Cost estimates were converted into 2010 constant USD and international dollars. We assessed the quality of the estimates using a matrix with five essential elements and provided a cost projection for the combined smear and culture tests where the data were available. The 26 studies reported the cost estimates in 16 predominantly high- or middle-income countries from 1993 to 2009. The estimated unit cost for smear, culture, and combined tests ranges from $0.26 to $10.50, $1.63 to $62.01, and $26.73 to $39.57, respectively. The ratio of culture to smear costs varies from 1.35 to 11.98. The wide range of estimates is likely attributable to using different laboratory methods in different regions and years and differing practices in collecting and reporting cost data. Most studies did not report information critical for generalizing their conclusions. CONCLUSION: The paucity and low quality of unit cost estimates for TB monitoring in resource-poor settings impose technical challenges in predicting the resources needed for strengthening microbiological monitoring. To improve the validity and comparability of the cost data, we strongly advocate the data collection, estimation, and reporting follow protocols proposed by WHO. PMID- 23457503 TI - Involvement of Rab28 in NF-kappaB nuclear transport in endothelial cells. AB - Our previous proteomic analysis revealed the expression of Rab28 in arteries of rats. However, the function of Rab28 in mammalian cells, and its role in vessels are still unknown. Coarctation of abdominal aorta above left kidney artery in rat was used as hypertensive animal model. FX-4000 cyclic strain loading system was used to mimic the mechanical condition on vascular cells during hypertension in vitro. Immunofluorescence and co-immunoprecipitation (Co-IP) were used to identify distribution and interaction of Rab28 and nuclear factor kappa B (NF kappaB). Rab28 expression was significantly increased in carotid arteries of hypertensive rats. High cyclic strain induced Rab28 expression of endothelial cells (ECs) through a paracrine control of vascular smooth muscles cells (VSMCs), which at least partly via angiotensin II (Ang II). Rab28 knockdown decreased proliferation of ECs, while increased apoptosis and migration. Immunofluorescence revealed that Ang II stimulated the co-translocation of Rab28 and NF-kappaB from cytoplasm into nucleus. Knockdown of Rab28 attenuated NF-kappaB activation. Co-IP of NF-kappaB p65 and Rab28 indicated their interaction. Our results revealed that Rab28, as a novel regulator of NF-kappaB nuclear transport, might participate in the disturbance of EC homeostasis. PMID- 23457504 TI - Pneumococcal transmission and disease in silico: a microsimulation model of the indirect effects of vaccination. AB - BACKGROUND: The degree and time frame of indirect effects of vaccination (serotype replacement and herd immunity) are key determinants in assessing the net effectiveness of vaccination with pneumococcal conjugate vaccines (PCV) in control of pneumococcal disease. Using modelling, we aimed to quantify these effects and their dependence on coverage of vaccination and the vaccine's efficacy against susceptibility to pneumococcal carriage. METHODS AND FINDINGS: We constructed an individual-based simulation model that explores the effects of large-scale PCV programmes and applied it in a developed country setting (Finland). A population structure with transmission of carriage taking place within relevant mixing groups (families, day care groups, schools and neighbourhoods) was considered in order to properly assess the dependency of herd immunity on coverage of vaccination and vaccine efficacy against carriage. Issues regarding potential serotype replacement were addressed by employing a novel competition structure between multiple pneumococcal serotypes. Model parameters were calibrated from pre-vaccination data about the age-specific carriage prevalence and serotype distribution. The model predicts that elimination of vaccine-type carriage and disease among those vaccinated and, due to a substantial herd effect, also among the general population takes place within 5 10 years since the onset of a PCV programme with high (90%) coverage of vaccination and moderate (50%) vaccine efficacy against acquisition of carriage. A near-complete replacement of vaccine-type carriage by non-vaccine-type carriage occurs within the same time frame. CONCLUSIONS: The changed patterns in pneumococcal carriage after PCV vaccination predicted by the model are unequivocal. The overall effect on disease incidence depends crucially on the magnitude of age- and serotype-specific case-to-carrier ratios of the remaining serotypes relative to those of the vaccine types. Thus the availability of reliable data on the incidence of both pneumococcal carriage and disease is essential in assessing the net effectiveness of PCV vaccination in a given epidemiological setting. PMID- 23457505 TI - Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma. AB - Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma. PMID- 23457506 TI - IL-33 attenuates anoxia/reoxygenation-induced cardiomyocyte apoptosis by inhibition of PKCbeta/JNK pathway. AB - BACKGROUND: Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family. The objectives of present study are to assess whether IL-33 can protect cardiomyocytes from anoxia/reoxygenation (A/R)-induced injury and the mechanism involved in the protection. METHODS: Cardiomyocytes derived from either wild type or JNK1(-/-) mice were challenged with an A/R with or without IL-33. Myocyte apoptosis was assessed by measuring caspase 3 activity, fragmented DNA and TUNEL staining. In addition, cardiomyocyte oxidative stress was assessed by measuring DHR123 oxidation; PKCbetaII and JNK phosphorylation were assessed with Western blot. RESULTS: Challenge of cardiomyocytes with an A/R resulted in cardiomyocyte oxidative stress, PKCbetaII and JNK phosphorylation, and myocyte apoptosis. Treatment of the cardiomyocytes with IL-33 attenuated the A/R-induced myocyte oxidative stress, prevented PKCbetaII and JNK phosphorylation and attenuated the A/R-induced myocyte apoptosis. The protective effect of the IL-33 did not show in cardiac myocytes with siRNA specific to PKCbetaII or myocytes deficient in JNK1. Inhibition of PKCbetaII prevented the A/R-induced JNK phosphorylation, but inhibition of JNK1 showed no effect on A/R-induced PKCbetaII phosphorylation. CONCLUSIONS: Our results indicate that IL-33 prevents the A/R-induced myocyte apoptosis through inhibition of PKCbeta/JNK pathway. PMID- 23457507 TI - Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: a comparative metabolomic study. AB - Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA) and spinal-cord homogenate (SC-H), whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group). Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE) or extra-cerebral (AA) inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and/or due to the presence of systemic proinflammatory molecules. Regardless of the nature of these mechanisms, our findings may be of interest for future clinical studies, e.g. by in-vivo magnetic resonance spectroscopy. PMID- 23457508 TI - Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice. AB - Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM). Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of T2DM and complications, and that removal of the metabolic overload with dietary interventions may be more efficacious. We explored the efficacy and systems effects of pharmaceutical interventions versus dietary lifestyle intervention (DLI) in developing T2DM and complications. To mimic the situation in humans, high fat diet (HFD)-fed LDLr-/- mice with already established disease phenotype were treated with ten different drugs mixed into HFD or subjected to DLI (switch to low-fat chow), for 7 weeks. Interventions were compared to untreated reference mice kept on HFD or chow only. Although most of the drugs improved HFD-induced hyperglycemia, drugs only partially affected other risk factors and also had limited effect on disease progression towards microalbuminuria, hepatosteatosis and atherosclerosis. By contrast, DLI normalized T2DM risk factors, fully reversed hepatosteatosis and microalbuminuria, and tended to attenuate atherogenesis. The comprehensive beneficial effect of DLI was reflected by normalized metabolite profiles in plasma and liver. Analysis of disease pathways in liver confirmed reversion of the metabolic distortions with DLI. This study demonstrates that the pathogenesis of T2DM towards complications is reversible with DLI and highlights the differential effects of current pharmacotherapies and their limitation to resolve the disease. PMID- 23457509 TI - Suppression of XBP1S mediates high glucose-induced oxidative stress and extracellular matrix synthesis in renal mesangial cell and kidney of diabetic rats. AB - Recent evidences suggest that endoplasmic reticulum (ER) stress was involved in multi pathological conditions, including diabetic nephropathy (DN). X-box binding protein 1(XBP1), as a key mediator of ER stress, has been proved having the capability of preventing oxidative stress. In this study, we investigated the effects of spliced XBP1 (XBP1S), the dominant active form of XBP1, on high glucose (HG)-induced reactive oxygen species (ROS) production and extracellular matrix (ECM) synthesis in cultured renal mesangial cells (MCs) and renal cortex of STZ-induced diabetic rats. Real time PCR and Western blot were used to evaluate the mRNA and protein levels respectively. Transfection of recombinant adenovirus vector carrying XBP1S gene (Ad-XBP1S) was used to upregulate XBP1S expression. XBP1S siRNA was used to knockdown XBP1S expression. ROS level was detected by dihydroethidium (DHE) fluorescent probe assay. The results showed that HG treatment significantly reduced XBP1S protein and mRNA level in the cultured MCs while no obvious change was observed in unspliced XBP1 (XBP1U). In the mean time, the ROS production, collagen IV and fibronectin expressions were increased. Diphenylene-chloride iodonium (DPI), a NADPH oxidase inhibtor, prevented HG-induced increases in ROS as well as collagen IV and fibronectin expressions. Transfection of Ad-XBP1S reversed HG-induced ROS production and ECM expressions. Knockdown intrinsic XBP1S expression induced increases in ROS production and ECM expressions. Supplementation of supreoxide reversed the inhibitory effect of Ad-XBP1S transfection on ECM synthesis. P47phox was increased in HG-treated MCs. Ad-XBP1S transfection reversed HG-induced p47phox increase while XBP1S knockdown upregulated p47phox expression. In the renal cortex of diabetic rats, the expression of XBP1S was reduced while p47phox, collagen IV and fibronectin expression were elevated. These results suggested that XBP1S pathway of ER stress was involved in HG-induced oxidative stress and ECM synthesis. A downstream target of XBP1S in regulating ROS formation might be NADPH oxidase. PMID- 23457510 TI - The Muller-Lyer Illusion in a computational model of biological object recognition. AB - Studying illusions provides insight into the way the brain processes information. The Muller-Lyer Illusion (MLI) is a classical geometrical illusion of size, in which perceived line length is decreased by arrowheads and increased by arrowtails. Many theories have been put forward to explain the MLI, such as misapplied size constancy scaling, the statistics of image-source relationships and the filtering properties of signal processing in primary visual areas. Artificial models of the ventral visual processing stream allow us to isolate factors hypothesised to cause the illusion and test how these affect classification performance. We trained a feed-forward feature hierarchical model, HMAX, to perform a dual category line length judgment task (short versus long) with over 90% accuracy. We then tested the system in its ability to judge relative line lengths for images in a control set versus images that induce the MLI in humans. Results from the computational model show an overall illusory effect similar to that experienced by human subjects. No natural images were used for training, implying that misapplied size constancy and image-source statistics are not necessary factors for generating the illusion. A post-hoc analysis of response weights within a representative trained network ruled out the possibility that the illusion is caused by a reliance on information at low spatial frequencies. Our results suggest that the MLI can be produced using only feed-forward, neurophysiological connections. PMID- 23457511 TI - Developing genetic epidemiological models to predict risk for nasopharyngeal carcinoma in high-risk population of China. AB - To date, the only established model for assessing risk for nasopharyngeal carcinoma (NPC) relies on the sero-status of the Epstein-Barr virus (EBV). By contrast, the risk assessment models proposed here include environmental risk factors, family history of NPC, and information on genetic variants. The models were developed using epidemiological and genetic data from a large case-control study, which included 1,387 subjects with NPC and 1,459 controls of Cantonese origin. The predictive accuracy of the models were then assessed by calculating the area under the receiver-operating characteristic curves (AUC). To compare the discriminatory improvement of models with and without genetic information, we estimated the net reclassification improvement (NRI) and integrated discrimination index (IDI). Well-established environmental risk factors for NPC include consumption of salted fish and preserved vegetables and cigarette smoking (in pack years). The environmental model alone shows modest discriminatory ability (AUC = 0.68; 95% CI: 0.66, 0.70), which is only slightly increased by the addition of data on family history of NPC (AUC = 0.70; 95% CI: 0.68, 0.72). With the addition of data on genetic variants, however, our model's discriminatory ability rises to 0.74 (95% CI: 0.72, 0.76). The improvements in NRI and IDI also suggest the potential usefulness of considering genetic variants when screening for NPC in endemic areas. If these findings are confirmed in larger cohort and population-based case-control studies, use of the new models to analyse data from NPC-endemic areas could well lead to earlier detection of NPC. PMID- 23457512 TI - Effects of NFKB1 and NFKBIA gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathological features. AB - BACKGROUND: Constitutive activation of nuclear factor (NF)-kappaB is frequently observed in hepatocellular carcinoma (HCC). The current study examined associations of polymorphisms within promoter regions of NFKB1 encoding NF kappaB1 and NFKBIA encoding IkappaBalpha with the susceptibility of developing HCC and clinicopathological characteristics of the tumors. METHODOLOGY AND PRINCIPAL FINDINGS: Genetic polymorphisms of NFKB1 and NFKBIA were analyzed by a real-time polymerase chain reaction (PCR) in 135 HCC patients and 520 healthy controls. The genotypic frequency of the NFKB1 -94 Ins polymorphism in HCC patients was significantly higher than that of the controls (adjusted odds ratio (AOR) = 2.23; 95% confidence interval (CI) 1.32~3.77). No statistical significance was observed for the distribution frequency of the NFKBIA --519 C/T, -826 C/T, or -881 A/G genotype and haplotype polymorphisms between HCC patients and controls. Furthermore, female HCC patients carrying the NFKB1 -94 Ins polymorphism were associated with lower clinical stages and smaller tumor sizes. CONCLUSIONS: Our results indicate that the NFKB1 -94 Ins promoter polymorphism increased the risk of HCC, and may be applied as a predictive factor for the clinical stage and tumor size in female HCC patients. PMID- 23457513 TI - Crystal structure of an uncommon cellulosome-related protein module from Ruminococcus flavefaciens that resembles papain-like cysteine peptidases. AB - BACKGROUND: Ruminococcus flavefaciens is one of the predominant fiber-degrading bacteria found in the rumen of herbivores. Bioinformatic analysis of the recently sequenced genome indicated that this bacterium produces one of the most intricate cellulosome systems known to date. A distinct ORF, encoding for a multi-modular protein, RflaF_05439, was discovered during mining of the genome sequence. It is composed of two tandem modules of currently undefined function that share 45% identity and a C-terminal X-dockerin modular dyad. Gaining insight into the diversity, architecture and organization of different types of proteins in the cellulosome system is essential for broadening our understanding of a multi enzyme complex, considered to be one of the most efficient systems for plant cell wall polysaccharide degradation in nature. METHODOLOGY/PRINCIPAL FINDINGS: Following bioinformatic analysis, the second tandem module of RflaF_05439 was cloned and its selenium-labeled derivative was expressed and crystallized. The crystals belong to space group P21 with unit-cell parameters of a = 65.81, b = 60.61, c = 66.13 A, beta = 107.66 degrees and contain two protein molecules in the asymmetric unit. The crystal structure was determined at 1.38-A resolution by X-ray diffraction using the single-wavelength anomalous dispersion (SAD) method and was refined to Rfactor and Rfree of 0.127 and 0.152 respectively. The protein molecule mainly comprises a beta-sheet flanked by short alpha-helixes, and a globular alpha-helical domain. The structure was found to be structurally similar to members of the NlpC/P60 superfamily of cysteine peptidases. CONCLUSIONS/SIGNIFICANCE: The 3D structure of the second repeat of the RflaF_05439 enabled us to propose a role for the currently undefined function of this protein. Its putative function as a cysteine peptidase is inferred from in silico structural homology studies. It is therefore apparent that cellulosomes integrate proteins with other functions in addition to the classic well-defined carbohydrate active enzymes. PMID- 23457514 TI - MALDI-TOF MS distinctly differentiates nontypable Haemophilus influenzae from Haemophilus haemolyticus. AB - Nontypable Haemophilus influenzae (NTHi) and Haemophilus haemolyticus exhibit different pathogenicities, but to date, there remains no definitive and reliable strategy for differentiating these strains. In this study, we evaluated matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as a potential method for differentiating NTHi and H. haemolyticus. The phylogenetic analysis of concatenated 16S rRNA and recombinase A (recA) gene sequences, outer membrane protein P6 gene sequencing and single-gene PCR were used as reference methods. The original reference database (ORD, provided with the Biotyper software) and new reference database (NRD, extended with Chinese strains) were compared for the evaluation of MALDI-TOF MS. Through a search of the ORD, 76.9% of the NTHi (40/52) and none of the H. haemolyticus (0/20) strains were identified at the species level. However, all NTHi and H. haemolyticus strains used for identification were accurately recognized at the species level when searching the NRD. From the dendrogram clustering of the main spectra projections, the Chinese and foreign H. influenzae reference strains were categorized into two distinct groups, and H. influenzae and H. haemolyticus were also separated into two categories. Compared to the existing methods, MALDI-TOF MS has the advantage of integrating high throughput, accuracy and speed. In conclusion, MALDI-TOF MS is an excellent method for differentiating NTHi and H. haemolyticus. This method can be recommended for use in appropriately equipped laboratories. PMID- 23457516 TI - Population specific and up to date cardiovascular risk charts can be efficiently obtained with record linkage of routine and observational data. AB - BACKGROUND: Only few countries have cohorts enabling specific and up-to-date cardiovascular disease (CVD) risk estimation. Individual risk assessment based on study samples that differ too much from the target population could jeopardize the benefit of risk charts in general practice. Our aim was to provide up-to-date and valid CVD risk estimation for a Swiss population using a novel record linkage approach. METHODS: Anonymous record linkage was used to follow-up (for mortality, until 2008) 9,853 men and women aged 25-74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CVD) study of 1983-92. The linkage success was 97.8%, loss to follow-up 1990-2000 was 4.7%. Based on the ESC SCORE methodology (Weibull regression), we used age, sex, blood pressure, smoking, and cholesterol to generate three models. We compared the 1) original SCORE model with a 2) recalibrated and a 3) new model using the Brier score (BS) and cross-validation. RESULTS: Based on the cross-validated BS, the new model (BS = 14107*10(-6)) was somewhat more appropriate for risk estimation than the original (BS = 14190*10(-6)) and the recalibrated (BS = 14172*10(-6)) model. Particularly at younger age, derived absolute risks were consistently lower than those from the original and the recalibrated model which was mainly due to a smaller impact of total cholesterol. CONCLUSION: Using record linkage of observational and routine data is an efficient procedure to obtain valid and up to-date CVD risk estimates for a specific population. PMID- 23457515 TI - Reduced syncytin-1 expression levels in placental syndromes correlates with epigenetic hypermethylation of the ERVW-1 promoter region. AB - Terminal differentiation of villous cytotrophoblasts (CT) ends in formation of the multinucleated syncytiotrophoblast representing the fetal-maternal interface. Aberrations during this cell-fusion process are associated with Intrauterine Growth Restriction (IUGR), Preeclampsia (PE) and High Elevated Liver and Low Platelets (HELLP) Syndrome. Syncytin-1, the envelope gene of the human Endogenous Retrovirus ERVW-1, is one of the most important genes involved in cell-fusion and showed decreased gene expression during these pathological pregnancies. The aim of this study was to determine the methylation pattern of the entire promoter of ERVW-1 and to correlate these findings with the expression profile of Syncytin-1 in the placental syndromes. 14 isolated villous cytotrophoblasts from control (n = 3), IUGR (n = 3), PE (n = 3), PE/IUGR (n = 3) and HELLP/IUGR (n = 2) placentae were used to determine the mean methylation level (ML) for the ERVW-1 promoter region. ML rose significantly from 29% in control CTs to 49% in IUGR, 53% in PE, 47% in PE/IUGR and 64% in HELLP/IUGR indicating an epigenetic down-regulation of Syncytin-1 by promoter hypermethylation. DNA demethylation of the trophoblast like cell lines BeWo, JEG-3 and JAR with 5-AZA-2'desoxycytidine (AZA) showed an increased Syncytin-1 expression and fusion ability in all cell lines. Promoter activity of the 5'LTR could be inhibited by hypermethylation 42-fold using a luciferase based reporter-gene assay. Finally overexpression of the methyltransferases DNMT3a and LSH could be responsible for a decreased Syncytin-1 expression by promoter hypermethylation of ERVW-1. Our study linked decreased Syncytin-1 expression to an epigenetic hypermethylation of the entire promoter of ERVW-1. Based on our findings we are predicting a broad aberrant epigenetic DNA methylation pattern in pathological placentae affecting placentogenesis, but also the development of the fetus and the mother during pregnancy. PMID- 23457517 TI - Sleeping patterns of Afghan unaccompanied asylum-seeking adolescents: a large observational study. AB - Unaccompanied asylum-seeking children (UASC) have experienced multiple traumas and are a high-risk group for posttraumatic stress disorder (PTSD). The effects of trauma are known to be associated with sleep problems; indeed sleeping problems are core features of PTSD. However, there has been no systematic research examining the sleep of this high risk group of children. This study presents the first evidence on the sleeping patterns of Afghan UASC living in the UK. A total of 222 male Afghan children, aged 13-18, were interviewed using validated self-report questionnaires measuring sleeping patterns and PTSD. Overall, UASC patterns for bed time and rise time appear acculturated to the country of asylum. Mean UASC sleep onset latency scores were approximately 20 minutes greater compared with normative scores, which may be a reflection of UASC pre-migration and post-migration experiences. As expected, UASC who screened above the clinical cut-off for PTSD reported significantly greater sleep onset latency, increased nightmares, and less total sleep time compared to the non-PTSD group. The results may be of particular interest to clinicians given that, compared to screening for PTSD, screening for sleep problems may be a less culturally disputed form of initial assessment indicating distress in UASC. Similarly, the field of UASC and refugee child interventions is largely focused on trauma, yet sleep may provide a novel avenue for equally or more effective treatment. PMID- 23457518 TI - In vitro maturation of cumulus-oocyte complexes for efficient isolation of oocytes from outbred deer mice. AB - BACKGROUND: The outbred (as with humans) deer mice have been a useful animal model of research on human behavior and biology including that of the reproductive system. One of the major challenges in using this species is that the yield of oocyte isolation via superovulation is dismal according to the literature to date less than ~5 oocytes per animal can be obtained so far. OBJECTIVE: The goal of this study is to improve the yield of oocyte isolation from outbred deer mice close to that of most laboratory mice by in vitro maturation (IVM) of cumulus-oocyte complexes (COCs). METHODS: Oocytes were isolated by both superovulation and IVM. For the latter, COCs were obtained by follicular puncture of antral follicles in both the surface and inner cortical layers of ovaries. Immature oocytes in the COCs were then cultured in vitro under optimized conditions to obtain metaphase II (MII) oocytes. Quality of the oocytes from IVM and superovulation was tested by in vitro fertilization (IVF) and embryo development. RESULTS: Less than ~5 oocytes per animal could be isolated by superovulation only. However, we successfully obtained 20.3+/-2.9 oocytes per animal by IVM (16.0+/-2.5) and superovulation (4.3+/-1.3) in this study. Moreover, IVF and embryo development studies suggest that IVM oocytes have even better quality than that from superovulation The latter never developed to beyond 2-cell stage as usual while 9% of the former developed to 4-cells. SIGNIFICANCE: We have successfully established the protocol for isolating oocytes from deer mice with high yield by IVM. Moreover, this is the first ever success to develop in vitro fertilized deer mice oocytes beyond the 2-cell stage in vitro. Therefore, this study is of significance to the use of deer mice for reproductive biology research. PMID- 23457519 TI - Genomic profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization. AB - We designed a study to investigate genetic relationships between primary tumors of oral squamous cell carcinoma (OSCC) and their lymph node metastases, and to identify genomic copy number aberrations (CNAs) related to lymph node metastasis. For this purpose, we collected a total of 42 tumor samples from 25 patients and analyzed their genomic profiles by array-based comparative genomic hybridization. We then compared the genetic profiles of metastatic primary tumors (MPTs) with their paired lymph node metastases (LNMs), and also those of LNMs with non metastatic primary tumors (NMPTs). Firstly, we found that although there were some distinctive differences in the patterns of genomic profiles between MPTs and their paired LNMs, the paired samples shared similar genomic aberration patterns in each case. Unsupervised hierarchical clustering analysis grouped together 12 of the 15 MPT-LNM pairs. Furthermore, similarity scores between paired samples were significantly higher than those between non-paired samples. These results suggested that MPTs and their paired LNMs are composed predominantly of genetically clonal tumor cells, while minor populations with different CNAs may also exist in metastatic OSCCs. Secondly, to identify CNAs related to lymph node metastasis, we compared CNAs between grouped samples of MPTs and LNMs, but were unable to find any CNAs that were more common in LNMs. Finally, we hypothesized that subpopulations carrying metastasis-related CNAs might be present in both the MPT and LNM. Accordingly, we compared CNAs between NMPTs and LNMs, and found that gains of 7p, 8q and 17q were more common in the latter than in the former, suggesting that these CNAs may be involved in lymph node metastasis of OSCC. In conclusion, our data suggest that in OSCCs showing metastasis, the primary and metastatic tumors share similar genomic profiles, and that cells in the primary tumor may tend to metastasize after acquiring metastasis-associated CNAs. PMID- 23457520 TI - Influenza forecasting with Google Flu Trends. AB - BACKGROUND: We developed a practical influenza forecast model based on real-time, geographically focused, and easy to access data, designed to provide individual medical centers with advanced warning of the expected number of influenza cases, thus allowing for sufficient time to implement interventions. Secondly, we evaluated the effects of incorporating a real-time influenza surveillance system, Google Flu Trends, and meteorological and temporal information on forecast accuracy. METHODS: Forecast models designed to predict one week in advance were developed from weekly counts of confirmed influenza cases over seven seasons (2004-2011) divided into seven training and out-of-sample verification sets. Forecasting procedures using classical Box-Jenkins, generalized linear models (GLM), and generalized linear autoregressive moving average (GARMA) methods were employed to develop the final model and assess the relative contribution of external variables such as, Google Flu Trends, meteorological data, and temporal information. RESULTS: A GARMA(3,0) forecast model with Negative Binomial distribution integrating Google Flu Trends information provided the most accurate influenza case predictions. The model, on the average, predicts weekly influenza cases during 7 out-of-sample outbreaks within 7 cases for 83% of estimates. Google Flu Trend data was the only source of external information to provide statistically significant forecast improvements over the base model in four of the seven out-of-sample verification sets. Overall, the p-value of adding this external information to the model is 0.0005. The other exogenous variables did not yield a statistically significant improvement in any of the verification sets. CONCLUSIONS: Integer-valued autoregression of influenza cases provides a strong base forecast model, which is enhanced by the addition of Google Flu Trends confirming the predictive capabilities of search query based syndromic surveillance. This accessible and flexible forecast model can be used by individual medical centers to provide advanced warning of future influenza cases. PMID- 23457521 TI - Divergent profile of emerging cutaneous leishmaniasis in subtropical Brazil: new endemic areas in the southern frontier. AB - BACKGROUND: Although known to be highly endemic in the Amazon regions of Brazil, the presence of cutaneous leishmaniasis (CL) in the subtropical southern part of the country has largely been ignored. This study was conducted to demonstrate CL is emerging in the Brazilian state of Santa Catarina, as well as to characterize the epidemiological profile and Leishmania species involved. METHODOLOGY/PRINCIPAL FINDINGS: For this cross-sectional study, data from all CL cases from Santa Catarina, Brazil, reported to the Brazilian National Notifiable Diseases Information System from 2001 to 2009 were investigated. Amplification of the kDNA minicircle conserved region followed by restriction fragment length polymorphism (PCR-RFLP) was conducted to screen for Leishmania species present in patient biopsy. Overall, 542 CL cases were reported, with majority resulting from autochthonous transmission (n = 401, 73.99%) and occurring in urban zones (n = 422, 77.86%). Age, gender, zone of residence, origin of case, clinical form and case outcome were found to differ significantly by region. Imported cases were over seven times more likely to relapse (95% CI 2.56-21.09). Mapping of cases revealed new endemic areas in northeastern Santa Catarina with two species present. With the exception of three L. (Leishmania) amazonensis cases (1.20%), majority of PCR positive samples were found to be L. (Viannia) braziliensis (n = 248, 98.80%). CONCLUSIONS/SIGNIFICANCE: CL is now endemic in the state of Santa Catarina, Brazil, with case profiles varying significantly by region. L. (V.) braziliensis has been identified as the predominant species in the region. PMID- 23457523 TI - Dysregulation of multiple facets of glycogen metabolism in a murine model of Pompe disease. AB - Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1 to 2 years of age to a slower progressive course that causes significant morbidity and early mortality in children and adults. The aim of this study is to better understand the biochemical consequences of glycogen accumulation in the Pompe mouse. We evaluated glycogen metabolism in heart, triceps, quadriceps, and liver from wild type and several strains of GAA(-/-) mice. Unexpectedly, we observed that lysosomal glycogen storage correlated with a robust increase in factors that normally promote glycogen biosynthesis. The GAA(-/-) mouse strains were found to have elevated glycogen synthase (GS), glycogenin, hexokinase, and glucose-6 phosphate (G-6-P, the allosteric activator of GS). Treating GAA(-/-) mice with recombinant human GAA (rhGAA) led to a dramatic reduction in the levels of glycogen, GS, glycogenin, and G-6-P. Lysosomal glycogen storage also correlated with a dysregulation of phosphorylase, which normally breaks down cytoplasmic glycogen. Analysis of phosphorylase activity confirmed a previous report that, although phosphorylase protein levels are identical in muscle lysates from wild type and GAA(-/-) mice, phosphorylase activity is suppressed in the GAA(-/-) mice in the absence of AMP. This reduction in phosphorylase activity likely exacerbates lysosomal glycogen accumulation. If the dysregulation in glycogen metabolism observed in the mouse model of Pompe disease also occurs in Pompe patients, it may contribute to the observed broad spectrum of disease severity. PMID- 23457522 TI - Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene. AB - Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data. PMID- 23457524 TI - Immunoproteasome deficiency modifies the alternative pathway of NFkappaB signaling. AB - Immunoproteasome is a protease abundant in immune cells and also present, albeit at lower concentrations, in cells outside the immune system. Recent evidence supports a novel role for the immunoproteasome in the cellular stress response potentially through regulation of NFkappaB signaling, which is the primary response to multiple stressors. The current study tests whether the Classical or Alternative Pathways are regulated by immunoproteasome following chronic TNFalpha exposure in cultured retinal pigment epithelial cells isolated from wild-type mice and mice deficient in one (LMP2, L2) or two (LMP7 and MECL-1, L7M1) immunoproteasome subunits. Assays were performed to assess the expression of NFkappaB responsive genes, the content and activity of NFkappaB transcription factors (p65, p50, p52, cRel, RelB), and expression and content of regulatory proteins (IkappaBalpha, A20, RPS3). Major findings include distinct differences in expression of NFkappaB responsive genes in both KO cells. The mechanism responsible for the altered gene expression could not be established for L7M1 since no major differences in NFkappaB transcription factor content or activation were observed. However, L2 cells exhibited substantially higher content and diminished activation of NFkappaB transcription factors associated with the Alternative Pathway and delayed termination of the Classical Pathway. These results provide strong experimental evidence supporting a role for immunoproteasome in modulating NFkappaB signaling. PMID- 23457525 TI - Does the number of oocytes retrieved influence pregnancy after fresh embryo transfer? AB - BACKGROUND: The nature of the association between the number of oocytes retrieved and in vitro fertilization (IVF) outcomes after fresh embryo transfer remains unclear because of conflicting results reported in the studies on this subject. In addition, the influence of the quality of the embryos transferred is usually neglected. The objective of this study is to assess the relationships of the number of oocytes retrieved, the number and quality of embryos transferred, and the prospects of pregnancy after fresh embryo transfer. METHODS: The data on 3131 infertile women undergoing their first IVF treatment cycle between January 2009 and December 2010 were collected retrospectively. Restricted cubic splines and stratified analyses were used to explore the relationships between the number of oocytes retrieved, the number and quality of embryos transferred, and the IVF outcomes. RESULTS: When stratified by the number and quality of transferred embryos, no significant differences in the chances for clinical pregnancy and live birth were found in three groups of oocytes yielded (<=6, 7-14, or >=15). The relationship between the number of oocytes retrieved and pregnancy is nearly a reflection of the pattern of the relationship between the number of oocytes retrieved and the probability of having two good-quality embryos transferred. The patients with the "optimal" number of oocytes were not only younger but also had the highest probability of having two good-quality embryos replaced. CONCLUSIONS: Similarly aged patients have similar pregnancy prospects after fresh embryo transfer when the same number and quality of embryos are replaced, irrespective of their number of oocytes. Selecting the desired number of good-quality embryos for transfer is the key to IVF success. Thus, aiming at retrieving an optimal number of oocytes to maximize IVF outcomes in a fresh cycle could place undue stress on the patients and may not be the best medical decision. PMID- 23457526 TI - Folate catabolites in spot urine as non-invasive biomarkers of folate status during habitual intake and folic acid supplementation. AB - BACKGROUND: Folate status, as reflected by red blood cell (RCF) and plasma folates (PF), is related to health and disease risk. Folate degradation products para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (apABG) in 24 hour urine have recently been shown to correlate with blood folate. AIM: Since blood sampling and collection of 24 hour urine are cumbersome, we investigated whether the determination of urinary folate catabolites in fasted spot urine is a suitable non-invasive biomarker for folate status in subjects before and during folic acid supplementation. STUDY DESIGN AND METHODS: Immediate effects of oral folic acid bolus intake on urinary folate catabolites were assessed in a short term pre-study. In the main study we included 53 healthy men. Of these, 29 were selected for a 12 week folic acid supplementation (400 ug). Blood, 24 hour and spot urine were collected at baseline and after 6 and 12 weeks and PF, RCF, urinary apABG and pABG were determined. RESULTS: Intake of a 400 ug folic acid bolus resulted in immediate increase of urinary catabolites. In the main study pABG and apABG concentrations in spot urine correlated well with their excretion in 24 hour urine. In healthy men consuming habitual diet, pABG showed closer correlation with PF (rs = 0.676) and RCF (rs = 0.649) than apABG (rs = 0.264, ns and 0.543). Supplementation led to significantly increased folate in plasma and red cells as well as elevated urinary folate catabolites, while only pABG correlated significantly with PF (rs = 0.574) after 12 weeks. CONCLUSION: Quantification of folate catabolites in fasted spot urine seems suitable as a non invasive alternative to blood or 24 hour urine analysis for evaluation of folate status in populations consuming habitual diet. In non-steady-state conditions (folic acid supplementation) correlations between folate marker (RCF, PF, urinary catabolites) decrease due to differing kinetics. PMID- 23457527 TI - Identification of the genes chemosensitizing hepatocellular carcinoma cells to interferon-alpha/5-fluorouracil and their clinical significance. AB - The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. Interferon-alpha (IFN-alpha)/5-fluorouracil (5-FU) therapy is reportedly effective in some HCC patients. In the present study, to improve HCC prognosis, we identified the genes that are sensitizing to these agents. The screening strategy was dependent on the concentration of ribozymes that rendered HepG2 cells resistant to 5-FU by the repeated transfection of ribozymes into the cells. After 10 cycles of transfection, which was initiated by 5,902,875 sequences of a ribozyme library, three genes including protein kinase, adenosine monophosphate (AMP)-activated, gamma 2 non-catalytic subunit (PRKAG2); transforming growth factor-beta receptor II (TGFBR2); and exostosin 1 (EXT1) were identified as 5-FU-sensitizing genes. Adenovirus-mediated transfer of TGFBR2 and EXT1 enhanced IFN-alpha/5-FU-induced cytotoxicity as well as 5-FU, although the overexpression of these genes in the absence of IFN-alpha/5 FU did not induce cell death. This effect was also observed in a tumor xenograft model. The mechanisms of TGFBR2 and EXT1 include activation of the TGF-beta signal and induction of endoplasmic reticulum stress, resulting in apoptosis. In HCC patients treated with IFN-alpha/5-FU therapy, the PRKAG2 mRNA level in HCC tissues was positively correlated with survival period, suggesting that PRKAG2 enhances the effect of IFN-alpha/5-FU and serves as a prognostic marker for IFN alpha/5-FU therapy. In conclusion, we identified three genes that chemosensitize the effects of 5-FU and IFN-alpha/5-FU on HCC cells and demonstrated that PRKAG2 mRNA can serve as a prognostic marker for IFN-alpha/5-FU therapy. PMID- 23457528 TI - Genetic variation and exchange in Trypanosoma cruzi isolates from the United States. AB - Trypanosoma cruzi, the causative agent of Chagas disease, is a multiclonal parasite with high levels of genetic diversity and broad host and geographic ranges. Molecular characterization of South American isolates of T. cruzi has demonstrated homologous recombination and nuclear hybridization, as well as the presence of 6 main genetic clusters or "discrete typing units" (DTUs). Few studies have extensively investigated such exchange events and genetic diversity in North American isolates. In the current study, we genetically characterized over 50 US isolates from wildlife reservoirs (e.g., raccoons, opossums, armadillos, skunks), domestic dogs, humans, nonhuman primates, and reduviid vectors from nine states (TX, CA, OK, SC, FL, GA, MD, LA, TN) using a multilocus sequencing method. Single nucleotide polymorphisms were identified in sequences of the mismatch-repair class 2 (MSH2) and Tc52 genes. Typing based on the two genes often paralleled genotyping by classic methodologies using mini-exon and 18S and 24Salpha rRNA genes. Evidence for genetic exchange was obtained by comparing sequence phylogenies of nuclear and mitochondrial gene targets, dihydrofolate reductase-thymidylate synthase (DHFR-TS) and the cytochrome oxidase subunit II- NADH dehydrogenase subunit I region (COII-ND1), respectively. We observed genetic exchange in several US isolates as demonstrated by incongruent mitochondrial and nuclear genes phylogenies, which confirms a previous finding of a single genetic exchange event in a Florida isolate. The presence of SNPs and evidence of genetic exchange illustrates that strains from the US are genetically diverse, even though only two phylogenetic lineages have been identified in this region. PMID- 23457530 TI - Health-related hot topic detection in online communities using text clustering. AB - Recently, health-related social media services, especially online health communities, have rapidly emerged. Patients with various health conditions participate in online health communities to share their experiences and exchange healthcare knowledge. Exploring hot topics in online health communities helps us better understand patients' needs and interest in health-related knowledge. However, the statistical topic analysis employed in previous studies is becoming impractical for processing the rapidly increasing amount of online data. Automatic topic detection based on document clustering is an alternative approach for extracting health-related hot topics in online communities. In addition to the keyword-based features used in traditional text clustering, we integrate medical domain-specific features to represent the messages posted in online health communities. Three disease discussion boards, including boards devoted to lung cancer, breast cancer and diabetes, from an online health community are used to test the effectiveness of topic detection. Experiment results demonstrate that health-related hot topics primarily include symptoms, examinations, drugs, procedures and complications. Further analysis reveals that there also exist some significant differences among the hot topics discussed on different types of disease discussion boards. PMID- 23457529 TI - Altered prostanoid signaling contributes to increased skin tumorigenesis in Tpl2 knockout mice. AB - Squamous cell carcinoma is the second most common form of skin cancer with the incidence expected to double over the next 20 years. Inflammation is believed to be a critical component in skin cancer progression. Therefore, understanding genes involved in the regulation of inflammatory pathways is vital to the design of targeted therapies. Numerous studies show cyclooxygenases (COXs) play an essential role in inflammation-associated cancers. Tpl2 (MAP3K8) is a protein kinase in the MAP Kinase signal transduction cascade. Previous research using a two-stage skin carcinogenesis model revealed that Tpl2(-/-) mice have significantly higher tumor incidence and inflammatory response than wild-type (WT) controls. The current study investigates whether cyclooxygenase-2 (COX-2) and COX-2- regulated prostaglandins and prostaglandin receptors drive the highly tumorigenic state of Tpl2(-/-) mice by investigating the relationship between Tpl2 and COX-2. Keratinocytes from newborn WT or Tpl2(-/-) mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for various times over 24 hours. Western analysis revealed significant differences in COX-2 and COX-2 dependent prostanoids and prostanoid receptors. Additionally, in vivo experiments confirmed that COX-2 and COX-2 downstream factors were elevated in TPA-treated Tpl2(-/-) skin, as well as in papillomas from Tpl2(-/-) mice. Use of the selective COX-2 inhibitor Celecoxib showed the increased tumorigenesis in the Tpl2(-/-) mice to primarily be mediated through COX-2. These experiments illustrate COX-2 induction in the absence of Tpl2 may be responsible for the increased tumorigenesis found in Tpl2(-/-) mice. Defining the relationship between Tpl2 and COX-2 may lead to new ways to downregulate COX-2 through the modulation of Tpl2. PMID- 23457531 TI - Increasing lysine content of waxy maize through introgression of opaque-2 and opaque-16 genes using molecular assisted and biochemical development. AB - The low lysine content of waxy maize cannot meet the nutritional requirements of humans, livestock, or poultry. In the present study, the high-lysine genes o2 and o16 were backcrossed into wx lines using the maize high-lysine inbreds TAIXI19 (o2o2) and QCL3021 (o16o16) as donors and the waxy maize inbred line QCL5019 (wxwx) as a receptor. In the triple-cross F1, backcross, and inbred generations, the SSR markers phi027 and phi112 within the wx and o2 genes and the SSR marker umc1121 linked to the o16 gene were used for foreground selection. Background selection of the whole-genome SSR markers was performed for the selected individuals. The grain lysine content was determined using the dye-binding lysine method. The waxiness of the grain was determined with the I2-KI staining and dual wavelength spectrophotometric analysis. The BC2F2 generation included 7 plants of genotype wxwxo2o2O16_, 19 plants of genotype wxwxo16o16O2_, and 3 plants of genotype wxwxo2o2o16o16. In these seeds, the average amylopectin content was 96.67%, 96.87%, and 96.62%, respectively, which is similar to that of QCL5019. The average lysine content was 0.555%, 0.380%, and 0.616%, respectively, representing increases of 75.1%, 19.9%, 94.3%, respectively, over QCL5019. The average genetic background recovery rate of the BC2F3 families was 95.3%, 94.3%, 94.2%, respectively. Among these 3 wxwxo2o2O16O16 families, 4 wxwxo2o2O16o16 families, and 3 wxwxo2o2o16o16 families, the longest imported parent donor fragment was 113.35 cM and the shortest fragment was 11.75 cM. No significant differences in lysine content were found between the BC2F4 seeds and the BC2F3 seeds in these 10 families. This allowed us to increase the lysine content of waxy corn and produce seeds with excellent nutritional characteristics suitable for human consumption, animal feed, and food processing. This may be of significance in the breeding of high-quality corn and in improvement of the nutrition of humans, livestock, and poultry. PMID- 23457532 TI - RUNX3 suppresses migration, invasion and angiogenesis of human renal cell carcinoma. AB - RUNX3 (runt-related transcription factor-3) is a known tumor suppressor gene which exhibits potent antitumor activity in several carcinomas. However, little is known about the role of RUNX3 in human renal cell carcinoma (RCC). To investigate the clinical relevance of RUNX3 in RCC patients, immunohistochemistry was performed to detect the clinical relevance of RUNX3 in 75 RCC tissues and paired non-cancerous tissues by using tissue microarray (TMA). We also investigated the role of RUNX3 in RCC cell migration, invasion and angiogenesis. The RUNX3 expression was decreased dramatically in human RCC tissue. The RUNX3 expression was significantly correlated with tumor size (P<0.001), depth of invasion (P<0.001), and of TNM stage (P<0.001). Restoration of RUNX3 significantly decreased renal carcinoma cell migration and invasion capacity compared with controls. In addition, we found that overexpression of RUNX3 reduced the proliferation and tube formation of human umbilical vascular endothelial cells (HUVECs). Gelatin zymography and Western blot showed that RUNX3 expression suppressed matrix metalloproteinase-9 (MMP-9) protein level and enzyme activity. Western blot and ELISA showed that RUNX3 restoration inhibited the expression and secretion of vascular endothelial growth factor (VEGF). Taken together, our studies indicate that decreased expression of RUNX3 in human RCC tissue is significantly correlated with RCC progression. Restoration of RUNX3 expression significantly inhibits RCC cells migration, invasion and angiogenesis. These findings provide new insights into the significance of RUNX3 in migration, invasion and angiogenesis of RCC. PMID- 23457533 TI - Habitat availability and heterogeneity and the indo-pacific warm pool as predictors of marine species richness in the tropical Indo-Pacific. AB - Range overlap patterns were observed in a dataset of 10,446 expert-derived marine species distribution maps, including 8,295 coastal fishes, 1,212 invertebrates (crustaceans and molluscs), 820 reef-building corals, 50 seagrasses, and 69 mangroves. Distributions of tropical Indo-Pacific shore fishes revealed a concentration of species richness in the northern apex and central region of the Coral Triangle epicenter of marine biodiversity. This pattern was supported by distributions of invertebrates and habitat-forming primary producers. Habitat availability, heterogeneity, and sea surface temperatures were highly correlated with species richness across spatial grains ranging from 23,000 to 5,100,000 km(2) with and without correction for autocorrelation. The consistent retention of habitat variables in our predictive models supports the area of refuge hypothesis which posits reduced extinction rates in the Coral Triangle. This does not preclude support for a center of origin hypothesis that suggests increased speciation in the region may contribute to species richness. In addition, consistent retention of sea surface temperatures in models suggests that available kinetic energy may also be an important factor in shaping patterns of marine species richness. Kinetic energy may hasten rates of both extinction and speciation. The position of the Indo-Pacific Warm Pool to the east of the Coral Triangle in central Oceania and a pattern of increasing species richness from this region into the central and northern parts of the Coral Triangle suggests peripheral speciation with enhanced survival in the cooler parts of the Coral Triangle that also have highly concentrated available habitat. These results indicate that conservation of habitat availability and heterogeneity is important to reduce extinction of marine species and that changes in sea surface temperatures may influence the evolutionary potential of the region. PMID- 23457534 TI - Comparison of treatment outcomes of new smear-positive pulmonary tuberculosis patients by HIV and antiretroviral status in a TB/HIV clinic, Malawi. AB - BACKGROUND: Smear-positive pulmonary TB is the most infectious form of TB. Previous studies on the effect of HIV and antiretroviral therapy on TB treatment outcomes among these highly infectious patients demonstrated conflicting results, reducing understanding of important issues. METHODS: All adult smear-positive pulmonary TB patients diagnosed between 2008 and 2010 in Malawi's largest public, integrated TB/HIV clinic were included in the study to assess treatment outcomes by HIV and antiretroviral therapy status using logistic regression. RESULTS: Of 2,361 new smear-positive pulmonary TB patients, 86% had successful treatment outcome (were cured or completed treatment), 5% died, 6% were lost to follow-up, 1% failed treatment, and 2% transferred-out. Overall HIV prevalence was 56%. After adjusting for gender, age and TB registration year, treatment success was higher among HIV-negative than HIV-positive patients (adjusted odds ratio 1.49; 95% CI: 1.14-1.94). Of 1,275 HIV-infected pulmonary TB patients, 492 (38%) received antiretroviral therapy during the study. Pulmonary TB patients on antiretroviral therapy were more likely to have successful treatment outcomes than those not on ART (adjusted odds ratio : 1.83; 95% CI: 1.29-2.60). CONCLUSION: HIV co-infection was associated with poor TB treatment outcomes. Despite high HIV prevalence and the integrated TB/HIV setting, only a minority of patients started antiretroviral therapy. Intensified patient education and provider training on the benefits of antiretroviral therapy could increase antiretroviral therapy uptake and improve TB treatment success among these most infectious patients. PMID- 23457536 TI - Reciprocal influence of protein domains in the cold-adapted acyl aminoacyl peptidase from Sporosarcina psychrophila. AB - Acyl aminoacyl peptidases are two-domain proteins composed by a C-terminal catalytic alpha/beta-hydrolase domain and by an N-terminal beta-propeller domain connected through a structural element that is at the N-terminus in sequence but participates in the 3D structure of the C-domain. We investigated about the structural and functional interplay between the two domains and the bridge structure (in this case a single helix named alpha1-helix) in the cold-adapted enzyme from Sporosarcina psychrophila (SpAAP) using both protein variants in which entire domains were deleted and proteins carrying substitutions in the alpha1-helix. We found that in this enzyme the inter-domain connection dramatically affects the stability of both the whole enzyme and the beta propeller. The alpha1-helix is required for the stability of the intact protein, as in other enzymes of the same family; however in this psychrophilic enzyme only, it destabilizes the isolated beta-propeller. A single charged residue (E10) in the alpha1-helix plays a major role for the stability of the whole structure. Overall, a strict interaction of the SpAAP domains seems to be mandatory for the preservation of their reciprocal structural integrity and may witness their co evolution. PMID- 23457537 TI - The impact of global warming and anoxia on marine benthic community dynamics: an example from the Toarcian (Early Jurassic). AB - The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of "dead zones" in modern oceans. PMID- 23457538 TI - Genetic deficiency of GABA differentially regulates respiratory and non respiratory motor neuron development. AB - Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E) day 13 and birth (postnatal day 0). Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study). For respiratory-based motor neurons (hypoglossal and phrenic motor pools), we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic) and muscle innervations (55% decrease). By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase) and muscle innervations (99% increase); however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar) regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to that of glycine. PMID- 23457539 TI - Pregnancy associated plasma protein A2 (PAPP-A2) affects bone size and shape and contributes to natural variation in postnatal growth in mice. AB - Pregnancy associated plasma protein A2 (PAPP-A2) is a protease of insulin-like growth factor binding protein 5 and is receiving increasing attention for its roles in pregnancy and postnatal growth. The goals of the present study were to characterize the effects of PAPP-A2 deletion on bone size and shape in mice at 10 weeks of age, and to determine whether Pappa2 is the gene responsible for a previously-identified quantitative trait locus (QTL) contributing to natural variation in postnatal growth in mice. Mice homozygous for constitutive PAPP-A2 deletion were lighter than wild-type littermates, and had smaller mandible dimensions and shorter skull, humerus, femur, tibia, pelvic girdle, and tail bone. Furthermore, PAPP-A2 deletion reduced mandible dimensions and the lengths of the skull, femur, pelvic girdle, and tail bone more than would be expected due to the effect on body mass. In addition to its effects on bone size, PAPP-A2 deficiency also altered the shape of the mandible and pelvic girdle, as assessed by geometric morphometrics. Mice homozygous for the PAPP-A2 deletion had less deep mandibles, and pelvic girdles with a more feminine shape. Using a quantitative complementation test, we confirmed that Pappa2 is responsible for the effects of the previously-identified QTL, demonstrating that natural variation in the Pappa2 gene contributes to variation in postnatal growth in mice. If similar functional variation in the Pappa2 gene exists in other species, effects of this variation on the shape of the pelvic girdle might explain the previously-reported associations between Pappa2 SNPs and developmental dysplasia of the hip in humans, and birthing in cattle. PMID- 23457540 TI - Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data. AB - PURPOSE: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events. METHODS: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis. RESULTS: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed. CONCLUSION: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts. PMID- 23457541 TI - The pancreas is altered by in utero androgen exposure: implications for clinical conditions such as polycystic ovary syndrome (PCOS). AB - Using an ovine model of polycystic ovary syndrome (PCOS), (pregnant ewes injected with testosterone propionate (TP) (100 mg twice weekly) from day (d)62 to d102 of d147 gestation (maternal injection - MI-TP)), we previously reported female offspring with normal glucose tolerance but hyperinsulinemia. We therefore examined insulin signalling and pancreatic morphology in these offspring using quantitative (Q) RT-PCR and western blotting. In addition the fetal pancreatic responses to MI-TP, and androgenic and estrogenic contributions to such responses (direct fetal injection (FI) of TP (20 mg) or diethylstilbestrol (DES) (20 mg) at d62 and d82 gestation) were assessed at d90 gestation. Fetal plasma was assayed for insulin, testosterone and estradiol, pancreatic tissue was cultured, and expression of key beta-cell developmental genes was assessed by QRT-PCR. In female d62MI-TP offspring insulin signalling was unaltered but there was a pancreatic phenotype with increased numbers of beta-cells (P<0.05). The fetal pancreas expressed androgen receptors in islets and genes involved in beta-cell development and function (PDX1, IGF1R, INSR and INS) were up-regulated in female fetuses after d62MI-TP treatment (P<0.05-0.01). In addition the d62MI-TP pancreas showed increased insulin secretion under euglycaemic conditions (P<0.05) in vitro. The same effects were not seen in the male fetal pancreas or when MI-TP was started at d30, before the male programming window. As d62MI-TP increased both fetal plasma testosterone (P<0.05) and estradiol concentrations (P<0.05) we assessed the relative contribution of androgens and estrogens. FI-TP (commencing d62) (not FI-DES treatment) caused elevated basal insulin secretion in vitro and the genes altered by d62MI-TP treatment were similarly altered by FI-TP but not FI-DES. In conclusion, androgen over-exposure alters fetal pancreatic development and beta-cell numbers in offspring. These data suggest that that there may be a primary pancreatic phenotype in models of PCOS, and that there may be a distinct male and female pancreas. PMID- 23457542 TI - Intracranial somatosensory responses with direct spinal cord stimulation in anesthetized sheep. AB - The efficacy of spinal cord stimulators is dependent on the ability of the device to functionally activate targeted structures within the spinal cord, while avoiding activation of near-by non-targeted structures. In theory, these objectives can best be achieved by delivering electrical stimuli directly to the surface of the spinal cord. The current experiments were performed to study the influence of different stimulating electrode positions on patterns of spinal cord electrophysiological activation. A custom-designed spinal cord neurostimulator was used to investigate the effects of lead position and stimulus amplitude on cortical electrophysiological responses to spinal cord stimulation. Brain recordings were obtained from subdural grids placed in four adult sheep. We systematically varied the position of the stimulating lead relative to the spinal cord and the voltage delivered by the device at each position, and then examined how these variables influenced cortical responses. A clear relationship was observed between voltage and electrode position, and the magnitude of high gamma band oscillations. Direct stimulation of the dorsal column contralateral to the grid required the lowest voltage to evoke brain responses to spinal cord stimulation. Given the lower voltage thresholds associated with direct stimulation of the dorsal column, and its possible impact on the therapeutic window, this intradural modality may have particular clinical advantages over standard epidural techniques now in routine use. PMID- 23457543 TI - Epidemiology of cryptococcal meningitis in the US: 1997-2009. AB - Cryptococcal meningitis (CM) causes significant morbidity and mortality globally; however, recent national trends have not been described. Incidence and trends for CM-associated hospitalizations in 18 states were estimated using the Agency for Healthcare and Research Quality (AHRQ) State Inpatient Databases (SID) datasets for 1997 through 2009. We identified 30,840 hospitalizations coded for CM, of which 21.6% were among HIV-uninfected patients. CM in-hospital mortality was significant (12.4% for women and 10.8% for men) with a total of 3,440 deaths over the study period. Co-morbidities of CM coded at increased frequency in HIV uninfected CM hospitalized populations included hydrocephalus and acute/chronic renal failure as well as possible predispositions including transplantation, combined T and B cell defects, Cushing's syndrome, liver disease and hypogammaglobulinemia. Median hospitalization costs were significant for CM and higher for HIV-uninfected patients (16,803.01 vs. 15,708.07; p<0.0001). Cryptococcal meningitis remains a disease with significant morbidity and mortality in the U.S. and the relative burden among persons without HIV infection is increasing. PMID- 23457544 TI - Headbobber: a combined morphogenetic and cochleosaccular mouse model to study 10qter deletions in human deafness. AB - The recessive mouse mutant headbobber (hb) displays the characteristic behavioural traits associated with vestibular defects including headbobbing, circling and deafness. This mutation was caused by the insertion of a transgene into distal chromosome 7 affecting expression of native genes. We show that the inner ear of hb/hb mutants lacks semicircular canals and cristae, and the saccule and utricle are fused together in a single utriculosaccular sac. Moreover, we detect severe abnormalities of the cochlear sensory hair cells, the stria vascularis looks severely disorganised, Reissner's membrane is collapsed and no endocochlear potential is detected. Myo7a and Kcnj10 expression analysis show a lack of the melanocyte-like intermediate cells in hb/hb stria vascularis, which can explain the absence of endocochlear potential. We use Trp2 as a marker of melanoblasts migrating from the neural crest at E12.5 and show that they do not interdigitate into the developing strial epithelium, associated with abnormal persistence of the basal lamina in the hb/hb cochlea. We perform array CGH, deep sequencing as well as an extensive expression analysis of candidate genes in the headbobber region of hb/hb and littermate controls, and conclude that the headbobber phenotype is caused by: 1) effect of a 648 kb deletion on distal Chr7, resulting in the loss of three protein coding genes (Gpr26, Cpmx2 and Chst15) with expression in the inner ear but unknown function; and 2) indirect, long range effect of the deletion on the expression of neighboring genes on Chr7, associated with downregulation of Hmx3, Hmx2 and Nkx1.2 homeobox transcription factors. Interestingly, deletions of the orthologous region in humans, affecting the same genes, have been reported in nineteen patients with common features including sensorineural hearing loss and vestibular problems. Therefore, we propose that headbobber is a useful model to gain insight into the mechanisms underlying deafness in human 10qter deletion syndrome. PMID- 23457545 TI - Phylogenetic analysis of glucosyltransferases and implications for the coevolution of mutans streptococci with their mammalian hosts. AB - Glucosyltransferases (Gtfs) catalyze the synthesis of glucans from sucrose and are produced by several species of lactic-acid bacteria. The oral bacterium Streptococcus mutans produces large amounts of glucans through the action of three Gtfs. GtfD produces water-soluble glucan (WSG), GtfB synthesizes water insoluble glucans (WIG) and GtfC produces mainly WIG but also WSG. These enzymes, especially those synthesizing WIG, are of particular interest because of their role in the formation of dental plaque, an environment where S. mutans can thrive and produce lactic acid, promoting the formation of dental caries. We sequenced the gtfB, gtfC and gtfD genes from several mutans streptococcal strains isolated from the oral cavity of humans and searched for their homologues in strains isolated from chimpanzees and macaque monkeys. The sequence data were analyzed in conjunction with the available Gtf sequences from other bacteria in the genera Streptococcus, Lactobacillus and Leuconostoc to gain insights into the evolutionary history of this family of enzymes, with a particular emphasis on S. mutans Gtfs. Our analyses indicate that streptococcal Gtfs arose from a common ancestral progenitor gene, and that they expanded to form two clades according to the type of glucan they synthesize. We also show that the clade of streptococcal Gtfs synthesizing WIG appeared shortly after the divergence of viviparous, dentate mammals, which potentially contributed to the formation of dental plaque and the establishment of several streptococci in the oral cavity. The two S. mutans Gtfs capable of WIG synthesis, GtfB and GtfC, are likely the product of a gene duplication event. We dated this event to coincide with the divergence of the genomes of ancestral early primates. Thus, the acquisition and diversification of S. mutans Gtfs predates modern humans and is unrelated to the increase in dietary sucrose consumption. PMID- 23457546 TI - EVI1 inhibits apoptosis induced by antileukemic drugs via upregulation of CDKN1A/p21/WAF in human myeloid cells. AB - Overexpression of ecotropic viral integration site 1 (EVI1) is associated with aggressive disease in acute myeloid leukemia (AML). Despite of its clinical importance, little is known about the mechanism through which EVI1 confers resistance to antileukemic drugs. Here, we show that a human myeloid cell line constitutively overexpressing EVI1 after infection with a retroviral vector (U937_EVI1) was partially resistant to etoposide and daunorubicin as compared to empty vector infected control cells (U937_vec). Similarly, inducible expression of EVI1 in HL-60 cells decreased their sensitivity to daunorubicin. Gene expression microarray analyses of U937_EVI1 and U937_vec cells cultured in the absence or presence of etoposide showed that 77 and 419 genes were regulated by EVI1 and etoposide, respectively. Notably, mRNA levels of 26 of these genes were altered by both stimuli, indicating that EVI1 regulated genes were strongly enriched among etoposide regulated genes and vice versa. One of the genes that were induced by both EVI1 and etoposide was CDKN1A/p21/WAF, which in addition to its function as a cell cycle regulator plays an important role in conferring chemotherapy resistance in various tumor types. Indeed, overexpression of CDKN1A in U937 cells mimicked the phenotype of EVI1 overexpression, similarly conferring partial resistance to antileukemic drugs. PMID- 23457547 TI - Synaptic competition sculpts the development of GABAergic axo-dendritic but not perisomatic synapses. AB - The neurotransmitter GABA regulates many aspects of inhibitory synapse development. We tested the hypothesis that GABAA receptors (GABAARs) work together with the synaptic adhesion molecule neuroligin 2 (NL2) to regulate synapse formation in different subcellular compartments. We investigated mice ("gamma2 knockdown mice") with an engineered allele of the GABAAR gamma2 subunit gene which produced a mosaic expression of synaptic GABAARs in neighboring neurons, causing a strong imbalance in synaptic inhibition. Deletion of the gamma2 subunit did not abolish synapse formation or the targeting of NL2 to distinct types of perisomatic and axo-dendritic contacts. Thus synaptic localization of NL2 does not require synaptic GABAARs. However, loss of the gamma2 subunit caused a selective decrease in the number of axo-dendritic synapses on cerebellar Purkinje cells and cortical pyramidal neurons, whereas perisomatic synapses were not significantly affected. Notably, gamma2-positive cells had increased axo-dendritic innervation compared with both gamma2-negative and wild-type counterparts. Moreover heterologous synapses on spines, that are found after total deletion of GABAARs from all Purkinje cells, were rare in cerebella of gamma2 knockdown mice. These findings reveal a selective role of gamma2 subunit-containing GABAARs in regulating synapse development in distinct subcellular compartments, and support the hypothesis that the refinement of axo dendritic synapses is regulated by activity-dependent competition between neighboring neurons. PMID- 23457548 TI - Cotton fiber cell walls of Gossypium hirsutum and Gossypium barbadense have differences related to loosely-bound xyloglucan. AB - Cotton fiber is an important natural textile fiber due to its exceptional length and thickness. These properties arise largely through primary and secondary cell wall synthesis. The cotton fiber of commerce is a cellulosic secondary wall surrounded by a thin cuticulated primary wall, but there were only sparse details available about the polysaccharides in the fiber cell wall of any cotton species. In addition, Gossypium hirsutum (Gh) fiber was known to have an adhesive cotton fiber middle lamella (CFML) that joins adjacent fibers into tissue-like bundles, but it was unknown whether a CFML existed in other commercially important cotton fibers. We compared the cell wall chemistry over the time course of fiber development in Gh and Gossypium barbadense (Gb), the two most important commercial cotton species, when plants were grown in parallel in a highly controlled greenhouse. Under these growing conditions, the rate of early fiber elongation and the time of onset of secondary wall deposition were similar in fibers of the two species, but as expected the Gb fiber had a prolonged elongation period and developed higher quality compared to Gh fiber. The Gb fibers had a CFML, but it was not directly required for fiber elongation because Gb fiber continued to elongate rapidly after CFML hydrolysis. For both species, fiber at seven ages was extracted with four increasingly strong solvents, followed by analysis of cell wall matrix polysaccharide epitopes using antibody based Glycome Profiling. Together with immunohistochemistry of fiber cross sections, the data show that the CFML of Gb fiber contained lower levels of xyloglucan compared to Gh fiber. Xyloglucan endo-hydrolase activity was also higher in Gb fiber. In general, the data provide a rich picture of the similarities and differences in the cell wall structure of the two most important commercial cotton species. PMID- 23457549 TI - Mutational analysis of the terminal protein Tpg of Streptomyces chromosomes: identification of the deoxynucleotidylation site. AB - The linear chromosomes and linear plasmids of Streptomyces are capped by terminal proteins (TPs) covalently bound to the 5' ends of the DNA. The TPs serve as primers for DNA synthesis that patches in the single-stranded gaps at the telomeres resulting from the bi-directional replication ('end patching'). Typical Streptomyces TPs, designated Tpgs, are conserved in sequence and size (about 185 amino acids), and contain a predicted helix-turn-helix domain and a functional nuclear localization signal. The Tpg-encoding gene (tpg) is often accompanied by an upstream gene tap that encodes an essential telomere-associating protein. Five lone tpg variants (not accompanied by tap) from various Streptomyces species were tested, and three were found to be pseudogenes. The lone tpg variant on the SLP2 plasmid, although functional, still requires the presence of tap on the chromosome for end patching. Using a combination of in vitro deoxynucleotidylation, physical localization, and genetic analysis, we identified the threonine at position 114 (T114) in Tpg of Streptomyces lividans chromosome as the deoxynucleotidylated site. Interestingly, T114 could be substituted by a serine without destroying the priming activity of Tpg in vitro and in vivo. Such T114S substitution is seen in and a number of pseudogenes as well as functional Tpgs. T114 lies in a predicted coil flanked by two short helixes in a highly hydrophilic region. The location and structural arrangement of the deoxynucleotidylated site in Tpg is similar to those in the TPs of phage o 29 and adenoviruses. However, these TPs are distinct in their sequences and sizes, indicating that they have evolved independently during evolution. Using naturally occurring and artificially created tpg variants, we further identified several amino acid residues in the N-terminus and the helix-turn-helix domain that were important for functionality. PMID- 23457535 TI - Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a case-control study. AB - BACKGROUND: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV infected patients do not currently exist. METHODS: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1?1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. RESULTS: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 ug/mL in cases vs. 1.93 ug/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). CONCLUSIONS: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP D, were not associated with bacterial pneumonia risk. PMID- 23457550 TI - The epitope of monoclonal antibodies blocking erythrocyte invasion by Plasmodium falciparum map to the dimerization and receptor glycan binding sites of EBA-175. AB - The malaria parasite, Plasmodium falciparum, and related parasites use a variety of proteins with Duffy-Binding Like (DBL) domains to bind glycoproteins on the surface of host cells. Among these proteins, the 175 kDa erythrocyte binding antigen, EBA-175, specifically binds to glycophorin A on the surface of human erythrocytes during the process of merozoite invasion. The domain responsible for glycophorin A binding was identified as region II (RII) which contains two DBL domains, F1 and F2. The crystal structure of this region revealed a dimer that is presumed to represent the glycophorin A binding conformation as sialic acid binding sites and large cavities are observed at the dimer interface. The dimer interface is largely composed of two loops from within each monomer, identified as the F1 and F2 beta-fingers that contact depressions in the opposing monomers in a similar manner. Previous studies have identified a panel of five monoclonal antibodies (mAbs) termed R215 to R218 and R256 that bind to RII and inhibit invasion of erythrocytes to varying extents. In this study, we predict the F2 beta-finger region as the conformational epitope for mAbs, R215, R217, and R256, and confirm binding for the most effective blocking mAb R217 and R215 to a synthetic peptide mimic of the F2 beta-finger. Localization of the epitope to the dimerization and glycan binding sites of EBA-175 RII and site-directed mutagenesis within the predicted epitope are consistent with R215 and R217 blocking erythrocyte invasion by Plasmodium falciparum by preventing formation of the EBA-175- glycophorin A complex. PMID- 23457551 TI - Bacterial communities associated with the leaves and the roots of Arabidopsis thaliana. AB - Diverse communities of bacteria inhabit plant leaves and roots and those bacteria play a crucial role for plant health and growth. Arabidopsis thaliana is an important model to study plant pathogen interactions, but little is known about its associated bacterial community under natural conditions. We used 454 pyrosequencing to characterize the bacterial communities associated with the roots and the leaves of wild A. thaliana collected at 4 sites; we further compared communities on the outside of the plants with communities in the endophytic compartments. We found that the most heavily sequenced bacteria in A. thaliana associated community are related to culturable species. Proteobacteria, Actinobacteria, and Bacteroidetes are the most abundant phyla in both leaf and root samples. At the genus level, sequences of Massilia and Flavobacterium are prevalent in both samples. Organ (leaf vs root) and habitat (epiphytes vs endophytes) structure the community. In the roots, richness is higher in the epiphytic communities compared to the endophytic compartment (P = 0.024), while the reverse is true for the leaves (P = 0.032). Interestingly, leaf and root endophytic compartments do not differ in richness, diversity and evenness, while they differ in community composition (P = 0.001). The results show that although the communities associated with leaves and roots share many bacterial species, the associated communities differ in structure. PMID- 23457552 TI - RhoA/Rho-kinase and nitric oxide in vascular reactivity in rats with endotoxaemia. AB - RhoA/Rho-kinase (RhoA/ROK) pathway promotes vasoconstriction by calcium sensitivity mechanism. LPS causes nitric oxide (NO) overproduction to induce vascular hyporeactivity. Thus, we tried to examine the role of RhoA/ROK and NO in the regulation of vascular reactivity in different time-point of endotoxaemia. Male Wistar rats were intravenously infused for 10 min with saline or E. coli endotoxin (lipopolysaccharide, LPS, 10 mg/kg) and divided to five groups (n = 8 in each group): (i) Control, sacrificed at 6 h after saline infusion; (ii) LPS1h, sacrificed at 1 h after LPS infusion; (iii) LPS2h, sacrificed at 2 h after LPS infusion; (iv) LPS4h, sacrificed at 4 h after LPS infusion; and (v) LPS6h, sacrificed at 6 h after LPS infusion. LPS1h and LPS2h were regarded as early endotoxaemia, whereas LPS4h and LPS6h were regarded as late endotoxaemia. Indeed, our results showed that LPS reproduced a biphasic hypotension and sustained vascular hyporeactivity to noradrenaline (NA) in vivo. Interestingly, this hyporeactivity did not occur in ex vivo during early endotoxaemia. This could be due to increases of aortic RhoA activity (n = 5, P<0.05) and myosin phosphatase targeting subunit 1 phosphorylation (n = 3, P<0.05). In addition, pressor response to NA and vascular reactivity in early endotoxaemia were inhibited by ROK inhibitor, Y27632. Furthermore, plasma bradykinin was increased at 10 min (24.6+/-13.7 ng/mL, n = 5, P<0.05) and aortic endothelial NO synthase expression was increased at 1 h (+200%. n = 3, P<0.05) after LPS. In late endotoxaemia, the vascular hyporeactivity was associated with aortic inducible NO synthase expression (n = 3, P<0.05) and an increased serum NO level (n = 8, P<0.05). Thus, an increased RhoA activity could compensate vascular hyporeactivity in early endotoxaemia, and the large NO production inhibiting RhoA activity would lead to vascular hyporeactivity eventually. PMID- 23457554 TI - Laparoscopic versus open peritoneal dialysis catheter insertion: a meta-analysis. AB - BACKGROUND: Peritoneal dialysis is an effective treatment for end-stage renal disease. Key to successful peritoneal dialysis is a well-functioning catheter. The different insertion techniques may be of great importance. Mostly, the standard operative approach is the open technique; however, laparoscopic insertion is increasingly popular. Catheter malfunction is reported up to 35% for the open technique and up to 13% for the laparoscopic technique. However, evidence is lacking to definitely conclude that the laparoscopic approach is to be preferred. This review and meta-analysis was carried out to investigate if one of the techniques is superior to the other. METHODS: Comprehensive searches were conducted in MEDLINE, Embase and CENTRAL (the Cochrane Library 2012, issue 10). Reference lists were searched manually. The methodology was in accordance with the Cochrane Handbook for interventional systematic reviews, and written based on the PRISMA-statement. RESULTS: Three randomized controlled trials and eight cohort studies were identified. Nine postoperative outcome measures were meta analyzed; of these, seven were not different between operation techniques. Based on the meta-analysis, the proportion of migrating catheters was lower (odds ratio (OR) 0.21, confidence interval (CI) 0.07 to 0.63; P = 0.006), and the one-year catheter survival was higher in the laparoscopic group (OR 3.93, CI 1.80 to 8.57; P = 0.0006). CONCLUSIONS: Based on these results there is some evidence in favour of the laparoscopic insertion technique for having a higher one-year catheter survival and less migration, which would be clinically relevant. PMID- 23457553 TI - Diminished vision in healthy aging is associated with increased retinal L-type voltage gated calcium channel ion influx. AB - Extensive evidence implicates an increase in hippocampal L-type voltage-gated calcium channel (L-VGCC) expression, and ion influx through these channels, in age-related cognitive declines. Here, we ask if this "calcium hypothesis" applies to the neuroretina: Is increased influx via L-VGCCs related to the well documented but poorly-understood vision declines in healthy aging? In Long-Evans rats we find a significant age-related increase in ion flux through retinal L VGCCs in vivo (manganese-enhanced MRI (MEMRI)) that are longitudinally linked with progressive vision declines (optokinetic tracking). Importantly, the degree of retinal Mn(2+) uptake early in adulthood significantly predicted later visual contrast sensitivity declines. Furthermore, as in the aging hippocampus, retinal expression of a drug-insensitive L-VGCC isoform (alpha1D) increased - a pattern confirmed in vivo by an age-related decline in sensitivity to L-VGCC blockade. These data highlight mechanistic similarities between retinal and hippocampal aging, and raise the possibility of new treatment targets for minimizing vision loss during healthy aging. PMID- 23457555 TI - Displacement behaviour is associated with reduced stress levels among men but not women. AB - Sex differences in the ability to cope with stress may contribute to the higher prevalence of stress-related disorders among women compared to men. We recently provided evidence that displacement behaviour--activities such as scratching and face touching--represents an important strategy for coping with stressful situations: in a healthy population of men, displacement behaviour during a social stress test attenuated the relationship between anxiety experienced prior to this test, and the subsequent self-reported experience of stress. Here, we extend this work to look at physiological and cognitive (in addition to self reported) measures of stress, and study both men and women in order to investigate whether sex moderates the link between displacement behaviour and the response to stress. In a healthy study population, we quantified displacement behaviour, heart rate and cognitive performance during the Trier Social Stress Test, and used self-report questionnaires to assess the experience of stress afterwards. Men engaged in displacement behaviour about twice as often as women, and subsequently reported lower levels of stress. Bivariate correlations revealed that for men, higher rates of displacement behaviour were associated with decreased self-reported stress, fewer mistakes in the cognitive task and a trend towards lower heart rate; no relationships between displacement behaviour and stress measures were found for women. Moreover, moderation analyses revealed that high rates of displacement behaviour were associated with lower stress levels in men but not in women, and that high displacement behaviour rates were associated with poorer cognitive performance in women, but not men. These results point to an important sex difference in coping strategies, and highlight new avenues for research into sex biases in stress-related disorders. PMID- 23457556 TI - NMR spectroscopy of macrophages loaded with native, oxidized or enzymatically degraded lipoproteins. AB - Oxidized and enzymatically modified low-density lipoproteins (oxLDL and eLDL) play a key role in early stages of atherogenesis. Their uptake by recruited macrophages leads to endolysosomal phospholipidosis or foam cell formation, respectively, each of which is preceded by highly differential lipid restructuring processes. We applied (1)H-NMR spectroscopy (NMRS) to elucidate these structural rearrangements both in consequence of lipoprotein modifications and following phagocytosis. Being specifically sensitive to the mobile lipid subset, NMRS of oxLDL and eLDL revealed a partial and total immobilization of lipids, respectively. NMRS of intact macrophages showed a sixfold increase in mobile lipids in case of loading with eLDL but no significant changes for oxLDL or native LDL. This finding reflected the disparate lipid storage in lipid droplets and in multilamellar endolysosomal clusters when loaded with either eLDL or oxLDL, respectively. Moreover, a significant shift of the degree of saturation towards mainly polyunsaturated fatty acid chains was found for the mobile lipid pool in eLDL-loaded macrophages. Additional analyses of lipid extracts by NMRS and mass spectrometry (MS) reflected these changes in lipid content and in fatty acid composition only partially. In summary, in-cell NMRS represents a unique lipidomics tool to investigate structural changes within the mobile lipid pool following atherogenic triggers that can be not detected by the analysis of lipid extracts by MS or NMRS. PMID- 23457557 TI - Interactions of carbon dioxide and food odours in Drosophila: olfactory hedonics and sensory neuron properties. AB - Behavioural responses of animals to volatiles in their environment are generally dependent on context. Most natural odours are mixtures of components that can each induce different behaviours when presented on their own. We have investigated how a complex of two olfactory stimuli is evaluated by Drosophila flies in a free-flying two-trap choice assay and how these stimuli are encoded in olfactory receptor neurons. We first observed that volatiles from apple cider vinegar attracted flies while carbon dioxide (CO2) was avoided, confirming their inherent positive and negative values. In contradiction with previous results obtained from walking flies in a four-field olfactometer, in the present assay the addition of CO2 to vinegar increased rather than decreased the attractiveness of vinegar. This effect was female-specific even though males and females responded similarly to CO2 and vinegar on their own. To test whether the female specific behavioural response to the mixture correlated with a sexual dimorphism at the peripheral level we recorded from olfactory receptor neurons stimulated with vinegar, CO2 and their combination. Responses to vinegar were obtained from three neuron classes, two of them housed with the CO2-responsive neuron in ab1 sensilla. Sensitivity of these neurons to both CO2 and vinegar per se did not differ between males and females and responses from female neurons did not change when CO2 and vinegar were presented simultaneously. We also found that CO2 sensitive neurons are particularly well adapted to respond rapidly to small concentration changes irrespective of background CO2 levels. The ability to encode temporal properties of stimulations differs considerably between CO2- and vinegar-sensitive neurons. These properties may have important implications for in-flight navigation when rapid responses to fragmented odour plumes are crucial to locate odour sources. However, the flies' sex-specific response to the CO2 vinegar combination and the context-dependent hedonics most likely originate from central rather than peripheral processing. PMID- 23457558 TI - Using Haloarcula marismortui bacteriorhodopsin as a fusion tag for enhancing and visible expression of integral membrane proteins in Escherichia coli. AB - Membrane proteins are key targets for pharmacological intervention because of their vital functions. Structural and functional studies of membrane proteins have been severely hampered because of the difficulties in producing sufficient quantities of properly folded and biologically active proteins. Here we generate a high-level expression system of integral membrane proteins in Escherichia coli by using a mutated bacteriorhodopsin (BR) from Haloarcula marismortui (HmBRI/D94N) as a fusion partner. A purification strategy was designed by incorporating a His-tag on the target membrane protein for affinity purification and an appropriate protease cleavage site to generate the final products. The fusion system can be used to detect the intended target membrane proteins during overexpression and purification either with the naked eye or by directly monitoring their characteristic optical absorption. In this study, we applied this approach to produce two functional integral membrane proteins, undecaprenyl pyrophosphate phosphatase and carnitine/butyrobetaine antiporter with significant yield enhancement. This technology could facilitate the development of a high throughput strategy to screen for conditions that improve the yield of correctly folded target membrane proteins. Other robust BRs can also be incorporated in this system. PMID- 23457559 TI - Molecular epidemiology and complete genome characterization of H1N1pdm virus from India. AB - BACKGROUND: Influenza A virus is one of world's major uncontrolled pathogen, causing seasonal epidemic as well as global pandemic. This was evidenced by recent emergence and continued prevalent 2009 swine origin pandemic H1N1 Influenza A virus, provoking first true pandemic in the past 40 years. In the course of its evolution, the virus acquired many mutations and multiple unidentified molecular determinants are likely responsible for the ability of the 2009 H1N1 virus to cause increased disease severity in humans. Availability of limited data on complete genome hampers the continuous monitoring of this type of events. Outbreaks with considerable morbidity and mortality have been reported from all parts of the country. METHODS/RESULTS: Considering a large number of clinical cases of infection complete genome based sequence characterization of Indian H1N1pdm virus and their phylogenetic analysis with respect to circulating global viruses was undertaken, to reveal the phylodynamic pattern of H1N1pdm virus in India from 2009-2011. The Clade VII was observed as a major circulating clade in phylogenetic analysis. Selection pressure analysis revealed 18 positively selected sites in major surface proteins of H1N1pdm virus. CONCLUSIONS: This study clearly revealed that clade VII has been identified as recent circulating clade in India as well globally. Few clade VII specific well identified markers undergone positive selection during virus evolution. Continuous monitoring of the H1N1pdm virus is warranted to track of the virus evolution and further transmission. This study will serve as a baseline data for future surveillance and also for development of suitable therapeutics. PMID- 23457560 TI - Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma. AB - BACKGROUND: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001). CONCLUSIONS/SIGNIFICANCE: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients. PMID- 23457561 TI - AHP6 inhibits cytokinin signaling to regulate the orientation of pericycle cell division during lateral root initiation. AB - In Arabidopsis thaliana, lateral roots (LRs) initiate from anticlinal cell divisions of pericycle founder cells. The formation of LR primordia is regulated antagonistically by the phytohormones cytokinin and auxin. It has previously been shown that cytokinin has an inhibitory effect on the patterning events occurring during LR formation. However, the molecular players involved in cytokinin repression are still unknown. In a similar manner to protoxylem formation in Arabidopsis roots, in which AHP6 (ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 6) acts as a cytokinin inhibitor, we reveal that AHP6 also functions as a cytokinin repressor during early stages of LR development. We show that AHP6 is expressed at different developmental stages during LR formation and is required for the correct orientation of cell divisions at the onset of LR development. Moreover, we demonstrate that AHP6 influences the localization of the auxin efflux carrier PIN1, which is necessary for patterning the LR primordia. In summary, we show that the inhibition of cytokinin signaling through AHP6 is required to establish the correct pattern during LR initiation. PMID- 23457562 TI - Cost-effectiveness of lifestyle counselling as primary prevention of gestational diabetes mellitus: findings from a cluster-randomised trial. AB - AIMS: The aim was to evaluate the cost-effectiveness of primary prevention of gestational diabetes mellitus (GDM) through intensified counselling on physical activity, diet, and appropriate weight gain among the risk group. MATERIALS AND METHODS: The cost-effectiveness analysis was based on data from a cluster randomised controlled GDM prevention trial carried out in primary health-care maternity clinics in Finland. Women (n = 399) with at least one risk factor for GDM were included. The incremental cost-effectiveness ratio (ICER) was calculated in terms of birth weight, 15D, and perceived health as measured with a visual analogue scale (VAS). A bootstrap technique for cluster-randomised samples was used to estimate uncertainty around a cost-effectiveness acceptability curve. RESULTS: The mean total cost in the intervention group was ?7,763 (standard deviation (SD): ?4,511) and in the usual-care group was ?6,994 (SD: ?4,326, p = 0.14). The mean intervention cost was ?141. The difference for costs in the birth weight group was ?753 (95% CI: -250 to 1,818) and in effects for birth weight was 115 g (95% CI: 15 to 222). The ICER for birth weight was almost ?7, with 86.7% of bootstrap pairs located in the north-east quadrant, indicating that the intervention was more effective and more expensive in birth weight terms than the usual care was. The data show an 86.7% probability that each gram of birth weight avoided requires an additional cost of ?7. CONCLUSIONS: Intervention was effective for birth weight but was not cost-effective for birth weight, 15D, or VAS when compared to the usual care. TRIAL REGISTRATION: ISRCTN 33885819. PMID- 23457563 TI - Rapid inverse planning for pressure-driven drug infusions in the brain. AB - Infusing drugs directly into the brain is advantageous to oral or intravenous delivery for large molecules or drugs requiring high local concentrations with low off-target exposure. However, surgeons manually planning the cannula position for drug delivery in the brain face a challenging three-dimensional visualization task. This study presents an intuitive inverse-planning technique to identify the optimal placement that maximizes coverage of the target structure while minimizing the potential for leakage outside the target. The technique was retrospectively validated using intraoperative magnetic resonance imaging of infusions into the striatum of non-human primates and into a tumor in a canine model and applied prospectively to upcoming human clinical trials. PMID- 23457564 TI - DNA methylation analysis of allotetraploid hybrids of red crucian carp (Carassius auratus red var.) and common carp (Cyprinus carpio L.). AB - Hybridization and polyploidization may lead to divergence in adaptation and boost speciation in angiosperms and some lower animals. Epigenetic change plays a significant role in the formation and adaptation of polyploidy. Studies of the effects of methylation on genomic recombination and gene expression in allopolyploid plants have achieved good progress. However, relevant advances in polyploid animals have been relatively slower. In the present study, we used the bisexual, fertile, genetically stable allotetraploid generated by hybridization of Carassius auratus red var. and Cyprinus carpio L. to investigate cytosine methylation level using methylation-sensitive amplification polymorphism (MSAP) analysis. We observed 38.31% of the methylation changes in the allotetraploid compared with the parents at 355 randomly selected CCGG sites. In terms of methylation status, these results indicate that the level of methylation modification in the allotetraploid may have increased relative to that in the parents. We also found that the major methylation changes were hypermethylation on some genomic fragments and genes related to metabolism or cell cycle regulation. These results provide circumstantial evidence that DNA methylation might be related to the gene expression and phenotype variation in allotetraploid hybrids. Our study partly fulfils the need for epigenetic research in polyploid animals, and provides evidence for the epigenetic regulation of allopolyploids. PMID- 23457565 TI - Biophysical characterization of the feline immunodeficiency virus p24 capsid protein conformation and in vitro capsid assembly. AB - The Feline Immunodeficiency Virus (FIV) capsid protein p24 oligomerizes to form a closed capsid that protects the viral genome. Because of its crucial role in the virion, FIV p24 is an interesting target for the development of therapeutic strategies, although little is known about its structure and assembly. We defined and optimized a protocol to overexpress recombinant FIV capsid protein in a bacterial system. Circular dichroism and isothermal titration calorimetry experiments showed that the structure of the purified FIV p24 protein was comprised mainly of alpha-helices. Dynamic light scattering (DLS) and cross linking experiments demonstrated that p24 was monomeric at low concentration and dimeric at high concentration. We developed a protocol for the in vitro assembly of the FIV capsid. As with HIV, an increased ionic strength resulted in FIV p24 assembly in vitro. Assembly appeared to be dependent on temperature, salt concentration, and protein concentration. The FIV p24 assembly kinetics was monitored by DLS. A limit end-point diameter suggested assembly into objects of definite shapes. This was confirmed by electron microscopy, where FIV p24 assembled into spherical particles. Comparison of FIV p24 with other retroviral capsid proteins showed that FIV assembly is particular and requires further specific study. PMID- 23457566 TI - Month of birth and mortality in Sweden: a nation-wide population-based cohort study. AB - BACKGROUND: Month of birth--an indicator for a variety of prenatal and early postnatal exposures--has been associated with life expectancy in adulthood. On the northern hemisphere, people born in the autumn live longer than those born during the spring. Only one study has followed a population longitudinally and no study has investigated the relation between month of birth and mortality risk below 50 years. METHODS AND RESULTS: In this nation-wide Swedish study, we included 6,194,745 subjects, using data from population-based health and administrative registries. The relation between month of birth (January-December) and mortality risk was assessed by fitting Cox proportional hazard regression models using attained age as the underlying time scale. Analyses were made for ages >30, >30 to 50, >50 to 80 and >80 years. Month of birth was a significant predictor of mortality in the age-spans >30, >50 to 80, and >80 years. In models adjusted for gender and education for ages >30 and >50 to 80 years, the lowest mortality was seen for people born in November and the highest mortality in those born in the spring/summer, peaking in May for mortality >30 years (250/00 excess hazard ratio compared to November, [95% confidence interval = 16-34 ]) and in April for mortality >50 to 80 years (420/00 excess hazard ratio compared to November, [95% confidence interval = 30-55]). In the ages >80 years the pattern was similar but the differences in mortality between birth months were smaller. For mortality within the age-span >30 to 50 years, results were inconclusive. CONCLUSION: Month of birth is associated to risk of mortality in ages above 50 years in Sweden. Further studies should aim at clarifying the mechanisms behind this association. PMID- 23457567 TI - The dynamics of attention during free looking. AB - Simple methods to study attention dynamics in challenging research and practical applications are limited. We explored the utility of examining attention dynamics during free looking with steady-state visual evoked potentials (SSVEPs), which reflect the effects of attention on early sensory processing. This method can be used with participants who cannot follow verbal instructions and patients without voluntary motor control. In our healthy participants, there were robust fluctuations in the strength of SSVEPs driven by the fixated and non-fixated stimuli (rapidly changing pictures of faces) in the seconds leading up to the moment they chose to shift their gaze to the next stimulus sequence. Furthermore, the amplitude of SSVEPs driven by the fixated stimuli predicted subsequent recognition of individual stimuli. The results illustrate how information about the temporal course of attention during free looking can be obtained with simple methods based on the attentional modulation of SSVEPs. PMID- 23457568 TI - Modulation of functional EEG networks by the NMDA antagonist nitrous oxide. AB - Parietal networks are hypothesised to play a central role in the cortical information synthesis that supports conscious experience and behavior. Significant reductions in parietal level functional connectivity have been shown to occur during general anesthesia with propofol and a range of other GABAergic general anesthetic agents. Using two analysis approaches (1) a graph theoretic analysis based on surrogate-corrected zero-lag correlations of scalp EEG, and (2) a global coherence analysis based on the EEG cross-spectrum, we reveal that sedation with the NMDA receptor antagonist nitrous oxide (N2O), an agent that has quite different electroencephalographic effects compared to the inductive general anesthetics, also causes significant alterations in parietal level functional networks, as well as changes in full brain and frontal level networks. A total of 20 subjects underwent N2O inhalation at either 20%, 40% or 60% peak N2O/O2 gas concentration levels. N2O-induced reductions in parietal network level functional connectivity (on the order of 50%) were exclusively detected by utilising a surface Laplacian derivation, suggesting that superficial, smaller spatial scale, cortical networks were most affected. In contrast reductions in frontal network functional connectivity were optimally discriminated using a common-reference derivation (reductions on the order of 10%), indicating that the NMDA antagonist N2O induces spatially coherent and widespread perturbations in frontal activity. Our findings not only give important weight to the idea of agent invariant final network changes underlying drug-induced reductions in consciousness, but also provide significant impetus for the application and development of multiscale functional analyses to systematically characterise the network level cortical effects of NMDA receptor related hypofunction. Future work at the source space level will be needed to verify the consistency between cortical network changes seen at the source level and those presented here at the EEG sensor space level. PMID- 23457569 TI - Social interactions through the eyes of macaques and humans. AB - Group-living primates frequently interact with each other to maintain social bonds as well as to compete for valuable resources. Observing such social interactions between group members provides individuals with essential information (e.g. on the fighting ability or altruistic attitude of group companions) to guide their social tactics and choice of social partners. This process requires individuals to selectively attend to the most informative content within a social scene. It is unclear how non-human primates allocate attention to social interactions in different contexts, and whether they share similar patterns of social attention to humans. Here we compared the gaze behaviour of rhesus macaques and humans when free-viewing the same set of naturalistic images. The images contained positive or negative social interactions between two conspecifics of different phylogenetic distance from the observer; i.e. affiliation or aggression exchanged by two humans, rhesus macaques, Barbary macaques, baboons or lions. Monkeys directed a variable amount of gaze at the two conspecific individuals in the images according to their roles in the interaction (i.e. giver or receiver of affiliation/aggression). Their gaze distribution to non-conspecific individuals was systematically varied according to the viewed species and the nature of interactions, suggesting a contribution of both prior experience and innate bias in guiding social attention. Furthermore, the monkeys' gaze behavior was qualitatively similar to that of humans, especially when viewing negative interactions. Detailed analysis revealed that both species directed more gaze at the face than the body region when inspecting individuals, and attended more to the body region in negative than in positive social interactions. Our study suggests that monkeys and humans share a similar pattern of role-sensitive, species- and context-dependent social attention, implying a homologous cognitive mechanism of social attention between rhesus macaques and humans. PMID- 23457570 TI - Characterization of Osterix protein stability and physiological role in osteoblast differentiation. AB - Osterix (Osx/SP7) is a C2H2 zinc finger-containing transcription factor of the SP gene family. Osx knockout mice indicate that the gene plays an essential role in osteoblast differentiation and bone formation. However, the mechanisms involved in the regulation of Osx are still poorly understood. Here, we report a novel post-translational mechanism for the regulation of Osx in mammalian cells. We found that the stability of endogenous and exogenous Osx reduced after cycloheximide treatment. In cells treated with the proteasome inhibitors MG-132 or lactacystin, both endogenous and exogenous Osx protein expression increased in a time-dependent manner. Co-immunoprecipitation (Co-IP) assays showed that both endogenous and exogenous Osx were ubiquitinated. Six lysine residues of Osx were identified as candidate ubiquitination sites by construction of point mutant plasmids and luciferase reporter assays. Furthermore, we confirmed that K58 and K230 are the ubiquitination sites of Osx by Co-IP assays and protein stability assays. Moreover, the Osx K58R and K230R mutations promoted the expression of osteoblast differentiation markers (alkaline phosphatase, collagen I and osteocalcin) and enhanced osteogenic differentiation in C2C12 cells. Taken together, our data indicate that Osx is an unstable protein, and that the ubiquitin-proteasome pathway is involved in the regulation of Osx and thereby regulates osteoblast differentiation. PMID- 23457571 TI - Amide proton solvent protection in amylin fibrils probed by quenched hydrogen exchange NMR. AB - Amylin is an endocrine hormone that accumulates in amyloid plaques in patients with advanced type 2 diabetes. The amyloid plaques have been implicated in the destruction of pancreatic beta-cells, which synthesize amylin and insulin. To better characterize the secondary structure of amylin in amyloid fibrils we assigned the NMR spectrum of the unfolded state in 95% DMSO and used a quenched hydrogen-deuterium exchange technique to look at amide proton solvent protection in the fibrils. In this technique, partially exchanged fibrils are dissolved in 95% DMSO and information about amide proton occupancy in the fibrils is determined from DMSO-denatured monomers. Hydrogen exchange lifetimes at pH 7.6 and 37 degrees C vary between ~5 h for the unstructured N-terminus to 600 h for amide protons in the two beta-strands that form inter-molecular hydrogen bonds between amylin monomers along the length of the fibril. Based on the protection data we conclude that residues A8-H18 and I26-Y37 comprise the two beta-strands in amylin fibrils. There is variation in protection within the beta-strands, particularly for strand beta1 where only residues F15-H18 are strongly protected. Differences in protection appear to be due to restrictions on backbone dynamics imposed by the packing of two-layers of C2-symmetry-related beta-hairpins in the protofilament structure, with strand beta1 positioned on the surface and beta2 in the interior. PMID- 23457572 TI - Projected near-future levels of temperature and pCO2 reduce coral fertilization success. AB - Increases in atmospheric carbon dioxide (pCO2) are projected to contribute to a 1.1-6.4 degrees C rise in global average surface temperatures and a 0.14-0.35 reduction in the average pH of the global surface ocean by 2100. If realized, these changes are expected to have negative consequences for reef-building corals including increased frequency and severity of coral bleaching and reduced rates of calcification and reef accretion. Much less is known regarding the independent and combined effects of temperature and pCO2 on critical early life history processes such as fertilization. Here we show that increases in temperature (+3 degrees C) and pCO2 (+400 uatm) projected for this century negatively impact fertilization success of a common Indo-Pacific coral species, Acropora tenuis. While maximum fertilization did not differ among treatments, the sperm concentration required to obtain 50% of maximum fertilization increased 6- to 8- fold with the addition of a single factor (temperature or CO2) and nearly 50- fold when both factors interact. Our results indicate that near-future changes in temperature and pCO2 narrow the range of sperm concentrations that are capable of yielding high fertilization success in A. tenuis. Increased sperm limitation, in conjunction with adult population decline, may have severe consequences for coral reproductive success. Impaired sexual reproduction will further challenge corals by inhibiting population recovery and adaptation potential. PMID- 23457573 TI - Cysteine-rich protein 61 plays a proinflammatory role in obstructive kidney fibrosis. AB - Cysteine-rich protein 61 (Cyr61) is a secreted matrix-associated protein that regulates a broad spectrum of biological and cellular activities. This study aimed to investigate the role of Cyr61 in progressive kidney fibrosis induced by unilateral ureteral obstruction (UUO) surgery in mice. The expression of Cyr61 transcripts and proteins in the obstructed kidneys were increased from day 1 and remained high until day 10 after surgery. Immunohistochemistry indicated that Cyr61 was expressed mainly in renal tubular epithelial cells. The upregulated Cyr61 in UUO kidneys was reduced in mice treated with pan-transforming growth factor-beta (TGF-beta) antibody. The role of TGF-beta in tubular Cyr61 upregulation after obstructive kidney injury was further supported by experiments showing that TGF-beta1 stimulated Cyr61 expression in cultured tubular epithelial cells. Notably, the upregulation of Cyr61 in UUO kidneys was followed by a marked increase in monocyte chemoattractant protein 1 (MCP-1) transcripts and macrophage infiltration, which were attenuated in mice treated with anti-Cyr61 antibodies. This proinflammatory property of Cyr61 in inducing MCP-1 expression was further confirmed in tubular epithelial cells cultured with Cyr61 protein. The anti-Cyr61 antibody in UUO mice also reduced the levels of collagen type 1-alpha1 transcripts, collagen fibril accumulation evaluated by picrosirius red staining, and the levels of alpha-smooth muscle actin (alpha-SMA) transcripts and proteins on day 4 after surgery; however, the antifibrotic effect was not sustained. In conclusion, the TGF-beta-mediated increase in tubular Cyr61 expression involved renal inflammatory cell infiltration through MCP-1 induction during obstructive kidney injury. The Cyr61 blockade attenuated kidney fibrosis in the early phase, but the antifibrotic effect could not be sustained. PMID- 23457574 TI - Acclimation of foliar respiration and photosynthesis in response to experimental warming in a temperate steppe in northern China. AB - BACKGROUND: Thermal acclimation of foliar respiration and photosynthesis is critical for projection of changes in carbon exchange of terrestrial ecosystems under global warming. METHODOLOGY/PRINCIPAL FINDINGS: A field manipulative experiment was conducted to elevate foliar temperature (Tleaf) by 2.07 degrees C in a temperate steppe in northern China. Rd/Tleaf curves (responses of dark respiration to Tleaf), An/Tleaf curves (responses of light-saturated net CO2 assimilation rates to Tleaf), responses of biochemical limitations and diffusion limitations in gross CO2 assimilation rates (Ag) to Tleaf, and foliar nitrogen (N) concentration in Stipa krylovii Roshev. were measured in 2010 (a dry year) and 2011 (a wet year). Significant thermal acclimation of Rd to 6-year experimental warming was found. However, An had a limited ability to acclimate to a warmer climate regime. Thermal acclimation of Rd was associated with not only the direct effects of warming, but also the changes in foliar N concentration induced by warming. CONCLUSIONS/SIGNIFICANCE: Warming decreased the temperature sensitivity (Q10) of the response of Rd/Ag ratio to Tleaf. Our findings may have important implications for improving ecosystem models in simulating carbon cycles and advancing understanding on the interactions between climate change and ecosystem functions. PMID- 23457575 TI - Association of an MHC class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs. AB - A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 "graded" controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis. PMID- 23457576 TI - Incidence and predictors of maternal cardiovascular mortality and severe morbidity in The Netherlands: a prospective cohort study. AB - OBJECTIVE: To assess incidence and possible risk factors of severe maternal morbidity and mortality from cardiovascular disease in The Netherlands. DESIGN: A prospective population based cohort study. SETTING: All 98 maternity units in The Netherlands. POPULATION: All women delivering in The Netherlands between August 2004 and August 2006 (n = 371,021). METHODS: Cases of severe maternal morbidity and mortality from cardiovascular disease were prospectively collected during a two-year period in The Netherlands. Women with cardiovascular complications during pregnancy or postpartum who were admitted to the ward, intensive care or coronary care unit were included. Cardiovascular morbidity was defined as cardiomyopathy, valvular disease, ischaemic heart disease, arrhythmias or aortic dissection. All women delivering in the same period served as a reference cohort. MAIN OUTCOME MEASURES: Incidence, case fatality rates and possible risk factors. RESULTS: Incidence of severe maternal morbidity due to cardiovascular disease was 2.3 per 10,000 deliveries (84/358,874). Maternal mortality rate from cardiovascular disease was 3.0 per 100,000 deliveries (11/358,874). Case fatality rate in women with severe maternal morbidity due to cardiovascular disease was 13% (11/84). Case fatality rate was highest in aortic dissection (83%). Pre existing acquired or congenital heart disease was identified in 34% of women. Thirty-one percent of women were of advanced maternal age (>35 years of age) and 5 percent above 40 years of age. Possible risk factors for cardiovascular morbidity were caesarean section (either resulting in or as a result of cardiovascular disease), multiple pregnancy, prior caesarean section, non-Western ethnicity and obesity. CONCLUSIONS: In The Netherlands cardiovascular disease is a rare cause of severe maternal morbidity with an incidence of 2.3 per 10,000 deliveries and a high case fatality rate of 13%. Cardiovascular complications develop mostly in women not known with cardiac disease pre-pregnancy. PMID- 23457577 TI - Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. AB - Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion. To explore the mechanism(s) of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon bevacizumab treatment, we also tested the effect of dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion.We show that 1) activation of Src family kinases (SFKs) is common in GBM, 2) the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and 3) SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that dasatinib treatment effectively blocked the increased invasion induced by bevacizumab.Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic. PMID- 23457578 TI - Predicting chemical toxicity effects based on chemical-chemical interactions. AB - Toxicity is a major contributor to high attrition rates of new chemical entities in drug discoveries. In this study, an order-classifier was built to predict a series of toxic effects based on data concerning chemical-chemical interactions under the assumption that interactive compounds are more likely to share similar toxicity profiles. According to their interaction confidence scores, the order from the most likely toxicity to the least was obtained for each compound. Ten test groups, each of them containing one training dataset and one test dataset, were constructed from a benchmark dataset consisting of 17,233 compounds. By a Jackknife test on each of these test groups, the 1(st) order prediction accuracies of the training dataset and the test dataset were all approximately 79.50%, substantially higher than the rate of 25.43% achieved by random guesses. Encouraged by the promising results, we expect that our method will become a useful tool in screening out drugs with high toxicity. PMID- 23457579 TI - Cobalt protoporphyrin accelerates TFEB activation and lysosome reformation during LPS-induced septic insults in the rat heart. AB - Lipopolysaccharide (LPS)-induced myocardial dysfunction is caused, at least in part, by mitochondrial dysfunction. Mitochondrial dysfunction and the oxidative damage associated with it are scavenged through various cellular defense systems such as autophagy to prevent harmful effects. Our recent study has demonstrated that cobalt protoporphyrin IX (CoPPIX), a potent inducer of heme oxygenase-1 (HO 1), ameliorates septic liver injuries by enhancing mitochondrial autophagy in rats. In our current study, we show that CoPPIX (5 mg/kg s.c.) not only accelerates the autophagic response but also promotes lysosome reformation in the rat heart treated with LPS (15 mg/kg i.p.). Lysosomal membrane-associated protein 2 (LAMP2), which is essential to the maintenance of lysosomal functions in the heart, is depleted transiently but restored rapidly during LPS administration in the rat. Activation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, was also observed, indicating a hyper consumption and subsequent reformation of the lysosome to meet the increased demand for autophagosome cleaning. CoPPIX was found to promote these processes and tended to restore the LPS-induced suppression of cardiac performances whilst chloroquine (CQ; 20 mg/kg i.p.), an inhibitor of lysosomes and autophagic protein degradation, abrogates these beneficial effects. The cardioprotective effect of CoPPIX against LPS toxicity was also observed via decreased levels of cardiac releasing enzymes in the plasma. Taken together, our current data indicate that lysosome reformation mediated by TFEB may be involved in cardioprotection against LPS-induced septic insults, and serve as a novel mechanism by which CoPPIX protects the heart against oxidative stress. PMID- 23457580 TI - Love is blind: indiscriminate female mating responses to male courtship pheromones in newts (Salamandridae). AB - Internal fertilization without copulation or prolonged physical contact is a rare reproductive mode among vertebrates. In many newts (Salamandridae), the male deposits a spermatophore on the substrate in the water, which the female subsequently takes up with her cloaca. Because such an insemination requires intense coordination of both sexes, male newts have evolved a courtship display, essentially consisting of sending pheromones under water by tail-fanning towards their potential partner. Behavioral experiments until now mostly focused on an attractant function, i.e. showing that olfactory cues are able to bring both sexes together. However, since males start their display only after an initial contact phase, courtship pheromones are expected to have an alternative function. Here we developed a series of intraspecific and interspecific two-female experiments with alpine newt (Ichthyosaura alpestris) and palmate newt (Lissotriton helveticus) females, comparing behavior in male courtship water and control water. We show that male olfactory cues emitted during tail-fanning are pheromones that can induce all typical features of natural female mating behavior. Interestingly, females exposed to male pheromones of their own species show indiscriminate mating responses to conspecific and heterospecific females, indicating that visual cues are subordinate to olfactory cues during courtship. PMID- 23457583 TI - Carbon stocks of tropical coastal wetlands within the karstic landscape of the Mexican Caribbean. AB - Coastal wetlands can have exceptionally large carbon (C) stocks and their protection and restoration would constitute an effective mitigation strategy to climate change. Inclusion of coastal ecosystems in mitigation strategies requires quantification of carbon stocks in order to calculate emissions or sequestration through time. In this study, we quantified the ecosystem C stocks of coastal wetlands of the Sian Ka'an Biosphere Reserve (SKBR) in the Yucatan Peninsula, Mexico. We stratified the SKBR into different vegetation types (tall, medium and dwarf mangroves, and marshes), and examined relationships of environmental variables with C stocks. At nine sites within SKBR, we quantified ecosystem C stocks through measurement of above and belowground biomass, downed wood, and soil C. Additionally, we measured nitrogen (N) and phosphorus (P) from the soil and interstitial salinity. Tall mangroves had the highest C stocks (987+/-338 Mg ha(-1)) followed by medium mangroves (623+/-41 Mg ha(-1)), dwarf mangroves (381+/ 52 Mg ha(-1)) and marshes (177+/-73 Mg ha(-1)). At all sites, soil C comprised the majority of the ecosystem C stocks (78-99%). Highest C stocks were measured in soils that were relatively low in salinity, high in P and low in N?P, suggesting that P limits C sequestration and accumulation potential. In this karstic area, coastal wetlands, especially mangroves, are important C stocks. At the landscape scale, the coastal wetlands of Sian Ka'an covering ~172,176 ha may store 43.2 to 58.0 million Mg of C. PMID- 23457581 TI - Interplay of protein and DNA structure revealed in simulations of the lac operon. AB - The E. coli Lac repressor is the classic textbook example of a protein that attaches to widely spaced sites along a genome and forces the intervening DNA into a loop. The short loops implicated in the regulation of the lac operon suggest the involvement of factors other than DNA and repressor in gene control. The molecular simulations presented here examine two likely structural contributions to the in-vivo looping of bacterial DNA: the distortions of the double helix introduced upon association of the highly abundant, nonspecific nucleoid protein HU and the large-scale deformations of the repressor detected in low-resolution experiments. The computations take account of the three dimensional arrangements of nucleotides and amino acids found in crystal structures of DNA with the two proteins, the natural rest state and deformational properties of protein-free DNA, and the constraints on looping imposed by the conformation of the repressor and the orientation of bound DNA. The predicted looping propensities capture the complex, chain-length-dependent variation in repression efficacy extracted from gene expression studies and in vitro experiments and reveal unexpected chain-length-dependent variations in the uptake of HU, the deformation of repressor, and the folding of DNA. Both the opening of repressor and the presence of HU, at levels approximating those found in vivo, enhance the probability of loop formation. HU affects the global organization of the repressor and the opening of repressor influences the levels of HU binding to DNA. The length of the loop determines whether the DNA adopts antiparallel or parallel orientations on the repressor, whether the repressor is opened or closed, and how many HU molecules bind to the loop. The collective behavior of proteins and DNA is greater than the sum of the parts and hints of ways in which multiple proteins may coordinate the packaging and processing of genetic information. PMID- 23457582 TI - Metagenomic analysis of the pygmy loris fecal microbiome reveals unique functional capacity related to metabolism of aromatic compounds. AB - The animal gastrointestinal tract contains a complex community of microbes, whose composition ultimately reflects the co-evolution of microorganisms with their animal host. An analysis of 78,619 pyrosequencing reads generated from pygmy loris fecal DNA extracts was performed to help better understand the microbial diversity and functional capacity of the pygmy loris gut microbiome. The taxonomic analysis of the metagenomic reads indicated that pygmy loris fecal microbiomes were dominated by Bacteroidetes and Proteobacteria phyla. The hierarchical clustering of several gastrointestinal metagenomes demonstrated the similarities of the microbial community structures of pygmy loris and mouse gut systems despite their differences in functional capacity. The comparative analysis of function classification revealed that the metagenome of the pygmy loris was characterized by an overrepresentation of those sequences involved in aromatic compound metabolism compared with humans and other animals. The key enzymes related to the benzoate degradation pathway were identified based on the Kyoto Encyclopedia of Genes and Genomes pathway assignment. These results would contribute to the limited body of primate metagenome studies and provide a framework for comparative metagenomic analysis between human and non-human primates, as well as a comparative understanding of the evolution of humans and their microbiome. However, future studies on the metagenome sequencing of pygmy loris and other prosimians regarding the effects of age, genetics, and environment on the composition and activity of the metagenomes are required. PMID- 23457584 TI - Epithelial cells as active player in fibrosis: findings from an in vitro model. AB - Kidney fibrosis, a scarring of the tubulo-interstitial space, is due to activation of interstitial myofibroblasts recruited locally or systemically with consecutive extracellular matrix deposition. Newly published clinical studies correlating acute kidney injury (AKI) to chronic kidney disease (CKD) challenge this pathological concept putting tubular epithelial cells into the spotlight. In this work we investigated the role of epithelial cells in fibrosis using a simple controlled in vitro system. An epithelial/mesenchymal 3D cell culture model composed of human proximal renal tubular cells and fibroblasts was challenged with toxic doses of Cisplatin, thus injuring epithelial cells. RT-PCR for classical fibrotic markers was performed on fibroblasts to assess their modulation toward an activated myofibroblast phenotype in presence or absence of that stimulus. Epithelial cell lesion triggered a phenotypical modulation of fibroblasts toward activated myofibroblasts as assessed by main fibrotic marker analysis. Uninjured 3D cell culture as well as fibroblasts alone treated with toxic stimulus in the absence of epithelial cells were used as control. Our results, with the caveats due to the limited, but highly controllable and reproducible in vitro approach, suggest that epithelial cells can control and regulate fibroblast phenotype. Therefore they emerge as relevant target cells for the development of new preventive anti-fibrotic therapeutic approaches. PMID- 23457585 TI - A lectin-based glycomic approach to identify characteristic features of Xenopus embryogenesis. AB - Cell surface glycans show dynamic changes during cell differentiation. Several glycans are useful biomarkers of tumors, stem cells, and embryogenesis. Glycomic studies have been performed using liquid chromatography and mass spectrometry, which are powerful tools for glycan structural analysis but are difficult to use for small sample sizes. Recently, a lectin microarray system was developed for profiling cell surface glycome changes to terminal carbohydrate chains and branch types, using sample sizes of a few micrograms. In this study, we used the lectin microarray system for the first time to investigate stage-specific glycomes in Xenopus laevis embryos. Unsupervised cluster analysis of lectin microarray data indicated that glycan profiles changed sequentially during development. Nine lectin probes showed significantly different signals between early and the late stage embryos: 4 showed higher signals in the early stages, and 5 exhibited higher signals in the late stages. The gene expression profiles of relevant glycosyltransferase genes support the lectin microarray data. Therefore, we have shown that lectin microarray is an effective tool for high-throughput glycan analysis in Xenopus embryogenesis, allowing glycan profiling of early embryos and small biopsy specimens. PMID- 23457586 TI - Is transcranial alternating current stimulation effective in modulating brain oscillations? AB - Transcranial alternating current stimulation (tACS) is a promising tool for modulating brain oscillations, as well as a possible therapeutic intervention. However, the lack of conclusive evidence on whether tACS is able to effectively affect cortical activity continues to limit its application. The present study aims to address this issue by exploiting the well-known inhibitory alpha rhythm in the posterior parietal cortex during visual perception and attention orientation. Four groups of healthy volunteers were tested with a Gabor patch detection and discrimination task. All participants were tested at the baseline and selective frequencies of tACS, including Sham, 6 Hz, 10 Hz, and 25 Hz. Stimulation at 6 Hz and 10 Hz over the occipito-parietal area impaired performance in the detection task compared to the baseline. The lack of a retinotopically organised effect and marginal frequency-specificity modulation in the detection task force us to be cautious about the effectiveness of tACS in modulating brain oscillations. Therefore, the present study does not provide significant evidence for tACS reliably inducing direct modulations of brain oscillations that can influence performance in a visual task. PMID- 23457587 TI - Characterization of spontaneous and TGF-beta-induced cell motility of primary human normal and neoplastic mammary cells in vitro using novel real-time technology. AB - The clinical complications derived from metastatic disease are responsible for the majority of all breast cancer related deaths. Since cell migration and invasion are a prerequisite for metastasis their assessment in patient cancer cells in vitro may have prognostic value for the tumor's metastatic capacity. We employed real-time cell analysis (RTCA) on the xCELLigence DP system to determine in vitro motility of patient-derived primary human breast cancer epithelial cells (HBCEC). Initially, the RTCA assay was validated using established human breast cancer cell lines with either an invasive (MDA-MB-231, MDA-MB-435s) or a non invasive phenotype (MCF-7, MDA-MB-468), and primary NSCLC cells (Tu459). Previous standard assays of cell migration/invasion revealed that only MDA-MB-231, -435s, and Tu459 cells exhibited spontaneous and TGF-beta1-stimulated migration and invasion through a Matrigel barrier. In the present study, the TGF-beta1 stimulated activities could be blocked by SB431542, a potent kinase inhibitor of the TGF-beta type I receptor ALK5. Application of the RTCA assay to patient derived tumor cells showed that 4/4 primary HBCEC and primary NSCLC cells, but not normal human mammary epithelial cells (HMEC), displayed high spontaneous migratory and invasive activity which correlated with higher MMP-2 expression and uPA protein levels in HBCEC compared to HMEC. Upon treatment with TGF-beta1, HBCEC exhibited morphologic and gene regulatory alterations indicative of epithelial-to-mesenchymal transition. However, exclusively the invasive but not the migratory activity of HBCEC was further enhanced by TGF-beta1. This indicates the requirement for molecular, e.g. integrin interactions with Matrigel components in HBCEC in order to become responsive to pro-invasive TGF-beta effects. Together, these results show for the first time that tumorigenic HBCEC but not normal HMEC possess a strong basal migratory as well as a basal and TGF beta1-inducible invasive potential. These findings qualify the RTCA assay as an in vitro migration/invasion testing system for patient-specific primary breast cancer cells. PMID- 23457588 TI - Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood. AB - AIMS: The antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice. METHODS: Metformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig 1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR. RESULTS: Metformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig 1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice. CONCLUSIONS: The present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy. PMID- 23457589 TI - Enhanced T cell lymphoma in NOD.Stat5b transgenic mice is caused by hyperactivation of Stat5b in CD8+ thymocytes. AB - Activation of signal transducers and activators of transcription (STAT) proteins may be critical to their oncogenic functions as demonstrated by the development of B-cell lymphoma/leukemia in transgenic (TG) mice overexpressing a constitutively activated form of Stat5b. However, low incidence of CD8(+) T cell lymphoma was observed in B6 transgenic mice overexpressing a wild-type Stat5b (B6.Stat5b(Tg)) despite of undetectable Stat5b phosphorylation and the rate of lymphomagenesis was markedly enhanced by immunization or the introduction of TCR transgenes [1]. Here, we report that the wild-type Stat5b transgene leads to the acceleration and high incidence (74%) of CD8(+) T cell lymphoblastic lymphomas in the non-obese-diabetic (NOD) background. In contrast to the B6.Stat5b(Tg) mice, Stat5b in transgenic NOD (NOD.Stat5b(Tg)) mice is selectively and progressively phosphorylated in CD8(+) thymocytes. Stat5 phosphorylation also leads to up regulation of many genes putatively relevant to tumorigenesis. Treatment of NOD.Stat5b(Tg) mice with cancer chemopreventive agents Apigenin and Xanthohumol efficiently blocked lymphomagenesis through reduction of Stat5 phosphorylation and genes up-regulated in the NOD.Stat5b(Tg) mice. These results suggest that NOD genetic background is critical to the Stat5b-mediated lymphomagenesis through regulation of Stat5 hyperactivation. NOD.Stat5b(Tg) mouse is an excellent model for studying the molecular mechanisms underlying lymphomagenesis and testing novel chemoprevention strategies. PMID- 23457590 TI - Endoplasmic reticulum membrane reorganization is regulated by ionic homeostasis. AB - Recently we described a new, evolutionarily conserved cellular stress response characterized by a reversible reorganization of endoplasmic reticulum (ER) membranes that is distinct from canonical ER stress and the unfolded protein response (UPR). Apogossypol, a putative broad spectrum BCL-2 family antagonist, was the prototype compound used to induce this ER membrane reorganization. Following microarray analysis of cells treated with apogossypol, we used connectivity mapping to identify a wide range of structurally diverse chemicals from different pharmacological classes and established their ability to induce ER membrane reorganization. Such structural diversity suggests that the mechanisms initiating ER membrane reorganization are also diverse and a major objective of the present study was to identify potentially common features of these mechanisms. In order to explore this, we used hierarchical clustering of transcription profiles for a number of chemicals that induce membrane reorganization and discovered two distinct clusters. One cluster contained chemicals with known effects on Ca(2+) homeostasis. Support for this was provided by the findings that ER membrane reorganization was induced by agents that either deplete ER Ca(2+) (thapsigargin) or cause an alteration in cellular Ca(2+) handling (calmodulin antagonists). Furthermore, overexpression of the ER luminal Ca(2+) sensor, STIM1, also evoked ER membrane reorganization. Although perturbation of Ca(2+) homeostasis was clearly one mechanism by which some agents induced ER membrane reorganization, influx of extracellular Na(+) but not Ca(2+) was required for ER membrane reorganization induced by apogossypol and the related BCL-2 family antagonist, TW37, in both human and yeast cells. Not only is this novel, non-canonical ER stress response evolutionary conserved but so also are aspects of the mechanism of formation of ER membrane aggregates. Thus perturbation of ionic homeostasis is important in the regulation of ER membrane reorganization. PMID- 23457591 TI - Genomic insights into the glutathione S-transferase gene family of two rice planthoppers, Nilaparvata lugens (Stal) and Sogatella furcifera (Horvath) (Hemiptera: Delphacidae). AB - BACKGROUND: Glutathione S-transferase (GST) genes control crucial traits for the metabolism of various toxins encountered by insects in host plants and the wider environment, including insecticides. The planthoppers Nilaparvata lugens and Sogatella furcifera are serious specialist pests of rice throughout eastern Asia. Their capacity to rapidly adapt to resistant rice varieties and to develop resistance to various insecticides has led to severe outbreaks over the last decade. METHODOLOGY/PRINCIPAL FINDINGS: Using the genome sequence of N. lugens, we identified for the first time the complete GST gene family of a delphacid insect whilst nine GST gene orthologs were identified from the closely related species S. furcifera. Nilaparvata lugens has 11 GST genes belonging to six cytosolic subclasses and a microsomal class, many fewer than seen in other insects with known genomes. Sigma is the largest GST subclass, and the intron exon pattern deviates significantly from that of other species. Higher GST gene expression in the N. lugens adult migratory form reflects the higher risk of this life stage in encountering the toxins of non-host plants. After exposure to a sub lethal dose of four insecticides, chlorpyrifos, imidacloprid, buprofezin or beta cypermethrin, more GST genes were upregulated in S. furcifera than in N. lugens. RNA interference targeting two N. lugens GST genes, NlGSTe1 and NlGSTm2, significantly increased the sensitivity of fourth instar nymphs to chlorpyrifos but not to beta-cypermethrin. CONCLUSIONS/SIGNIFICANCE: This study provides the first elucidation of the nature of the GST gene family in a delphacid species, offering new insights into the evolution of metabolic enzyme genes in insects. Further, the use of RNA interference to identify the GST genes induced by insecticides illustrates likely mechanisms for the tolerance of these insects. PMID- 23457592 TI - Compensatory effort parallels midbrain deactivation during mental fatigue: an fMRI study. AB - Fatigue reflects the functioning of our physiological negative feedback system, which prevents us from overworking. When fatigued, however, we often try to suppress this system in an effort to compensate for the resulting deterioration in performance. Previous studies have suggested that the effect of fatigue on neurovascular demand may be influenced by this compensatory effort. The primary goal of the present study was to isolate the effect of compensatory effort on neurovascular demand. Healthy male volunteers participated in a series of visual and auditory divided attention tasks that steadily increased fatigue levels for 2 hours. Functional magnetic resonance imaging scans were performed during the first and last quarter of the study (Pre and Post sessions, respectively). Tasks with low and high attentional load (Low and High conditions, respectively) were administrated in alternating blocks. We assumed that compensatory effort would be greater under the High-attentional-load condition compared with the Low-load condition. The difference was assessed during the two sessions. The effect of compensatory effort on neurovascular demand was evaluated by examining the interaction between load (High vs. Low) and time (Pre vs. Post). Significant fatigue-induced deactivation (i.e., Pre>Post) was observed in the frontal, temporal, occipital, and parietal cortices, in the cerebellum, and in the midbrain in both the High and Low conditions. The interaction was significantly greater in the High than in the Low condition in the midbrain. Neither significant fatigue-induced activation (i.e., Pre[PreE- PostE]) may reflect suppression of the negative feedback system that normally triggers recuperative rest to maintain homeostasis. PMID- 23457593 TI - Norovirus diversity in diarrheic children from an African-descendant settlement in Belem, Northern Brazil. AB - Norovirus (NoV), sapovirus (SaV) and human astrovirus (HAstV) are viral pathogens that are associated with outbreaks and sporadic cases of gastroenteritis. However, little is known about the occurrence of these pathogens in relatively isolated communities, such as the remnants of African-descendant villages ("Quilombola"). The objective of this study was the frequency determination of these viruses in children under 10 years, with and without gastroenteritis, from a "Quilombola" Community, Northern Brazil. A total of 159 stool samples were obtained from April/2008 to July/2010 and tested by an enzyme immunoassay (EIA) and reverse transcription-polymerase chain reaction (RT-PCR) to detect NoV, SaV and HAstV, and further molecular characterization was performed. These viruses were detected only in the diarrheic group. NoV was the most frequent viral agent detected (19.7%-16/81), followed by SaV (2.5%-2/81) and HAstV (1.2%-1/81). Of the 16 NoV-positive samples, 14 were sequenced with primers targeting the B region of the polymerase (ORF1) and the D region of the capsid (ORF2). The results showed a broad genetic diversity of NoV, with 12 strains being classified as GII-4 (5 41.7%), GII-6 (3-25%), GII-7 (2-16.7%), GII-17 (1-8.3%) and GI-2 (1-8.3%), as based on the polymerase region; 12 samples were classified, based on the capsid region, as GII-4 (6-50%, being 3-2006b variant and 3-2010 variant), GII-6 (3 25%), GII-17 (2-16.7%) and GII-20 (1-8.3%). One NoV-strain showed dual genotype specificity, based on the polymerase and capsid region (GII-7/GII-20). This study provides, for the first time, epidemiological and molecular information on the circulation of NoV, SaV and HAstV in African-descendant communities in Northern Brazil and identifies NoV genotypes that were different from those detected previously in studies conducted in the urban area of Belem. It remains to be determined why a broader NoV diversity was observed in such a semi-isolated community. PMID- 23457594 TI - Influence of hemianopic visual field loss on visual motor control. AB - BACKGROUND: Homonymous hemianopia (HH) is an anisotropic visual impairment characterized by the binocular inability to see one side of the visual field. Patients with HH often misperceive visual space. Here we investigated how HH affects visual motor control. METHODS AND FINDINGS: Seven patients with complete HH and no neglect or cognitive decline and seven gender- and age-matched controls viewed displays in which a target moved randomly along the horizontal or the vertical axis. They used a joystick to control the target movement to keep it at the center of the screen. We found that the mean deviation of the target position from the center of the screen along the horizontal axis was biased toward the blind side for five out of seven HH patients. More importantly, while the normal vision controls showed more precise control and larger response amplitudes when the target moved along the horizontal rather than the vertical axis, the control performance of the HH patients was not different between these two target motion experimental conditions. CONCLUSIONS: Compared with normal vision controls, HH affected patients' control performance when the target moved horizontally (i.e., along the axis of their visual impairment) rather than vertically. We conclude that hemianopia affects the use of visual information for online control of a moving target specific to the axis of visual impairment. The implications of the findings for driving in hemianopic patients are discussed. PMID- 23457595 TI - An exploration of the serotonin system in antisocial boys with high levels of callous-unemotional traits. AB - BACKGROUND: The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations - those with psychopathic (callous-unemotional) personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour. METHOD: Participants were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66) and/or serotonin-system single nucleotide polymorphisms (N = 157) were assayed. RESULTS: Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B) and 2a receptor gene (HTR2A) were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits. CONCLUSION: Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required. PMID- 23457596 TI - MicroRNA variants increase the risk of HPV-associated squamous cell carcinoma of the oropharynx in never smokers. AB - BACKGROUND: Both microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). In addition, microRNAs affect all facets of the immune/inflammation responses to infection, which may control HPV clearance. We thus hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk. METHODS: Four single-nucleotide polymorphisms in microRNAs were genotyped and HPV16 serology was determined in 325 cases and 335 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariable logistic regression models. RESULTS: Overall, each polymorphism had no significant main effect on OSCC risk. Compared with the risk among individuals with both miR146 rs2910164 GG genotype and HPV16 seronegativity, risk of OSCC was increased among those with CG or CC genotype and HPV16 seronegativity (OR, 1.2; 95% CI, 0.9-1.8), GG genotype and HPV16 seropositivity (OR, 3.0; 95% CI, 1.8-5.0), and CG or CC genotype and HPV16 seropositivity (OR, 4.7; 95% CI, 2.3-9.4). Similar results were found for miR149 rs2292832, miR196 rs11614913, and miR499 rs3746444. Analyses stratified by tumor sites and smoking status showed that each polymorphism significantly increased the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly prominent in never smokers. CONCLUSIONS: Our results indicate that microRNA polymorphisms modify the risk of OSCC associated with HPV16 seropositivity, particularly in patients with SCCOP and never smokers. Larger studies are needed to verify our findings. PMID- 23457597 TI - Bioactivity-guided identification and cell signaling technology to delineate the lactate dehydrogenase A inhibition effects of Spatholobus suberectus on breast cancer. AB - Aerobic glycolysis is an important feature of cancer cells. In recent years, lactate dehydrogenase A (LDH-A) is emerging as a novel therapeutic target for cancer treatment. Seeking LDH-A inhibitors from natural resources has been paid much attention for drug discovery. Spatholobus suberectus (SS) is a common herbal medicine used in China for treating blood-stasis related diseases such as cancer. This study aims to explore the potential medicinal application of SS for LDH-A inhibition on breast cancer and to determine its bioactive compounds. We found that SS manifested apoptosis-inducing, cell cycle arresting and anti-LDH-A activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cell. Oral herbal extracts (1 g/kg/d) administration attenuated tumor growth and LDH-A expression in both breast cancer xenografts. Bioactivity-guided fractionation finally identified epigallocatechin as a key compound in SS inhibiting LDH-A activity. Further studies revealed that LDH-A plays a critical role in mediating the apoptosis-induction effects of epigallocatechin. The inhibited LDH-A activities by epigallocatechin is attributed to disassociation of Hsp90 from HIF-1alpha and subsequent accelerated HIF-1alpha proteasome degradation. In vivo study also demonstrated that epigallocatechin could significantly inhibit breast cancer growth, HIF-1alpha/LDH-A expression and trigger apoptosis without bringing toxic effects. The preclinical study thus suggests that the potential medicinal application of SS for inhibiting cancer LDH A activity and the possibility to consider epigallocatechin as a lead compound to develop LDH-A inhibitors. Future studies of SS for chemoprevention or chemosensitization against breast cancer are thus warranted. PMID- 23457598 TI - Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. AB - Heterotopic ossification (HO) is defined as the formation of ectopic bone in soft tissue outside the skeletal tissue. HO is thought to result from aberrant differentiation of osteogenic progenitors within skeletal muscle. However, the precise origin of HO is still unclear. Skeletal muscle contains two kinds of progenitor cells, myogenic progenitors and mesenchymal progenitors. Myogenic and mesenchymal progenitors in human skeletal muscle can be identified as CD56(+) and PDGFRalpha(+) cells, respectively. The purpose of this study was to investigate the osteogenic differentiation potential of human skeletal muscle-derived progenitors. Both CD56(+) cells and PDGFRalpha(+) cells showed comparable osteogenic differentiation potential in vitro. However, in an in vivo ectopic bone formation model, PDGFRalpha(+) cells formed bone-like tissue and showed successful engraftment, while CD56(+) cells did not form bone-like tissue and did not adapt to an osteogenic environment. Immunohistological analysis of human HO sample revealed that many PDGFRalpha(+) cells were localized in proximity to ectopic bone formed in skeletal muscle. MicroRNAs (miRNAs) are known to regulate many biological processes including osteogenic differentiation. We investigated the participation of miRNAs in the osteogenic differentiation of PDGFRalpha(+) cells by using microarray. We identified miRNAs that had not been known to be involved in osteogenesis but showed dramatic changes during osteogenic differentiation of PDGFRalpha(+) cells. Upregulation of miR-146b-5p and -424 and downregulation of miR-7 during osteogenic differentiation of PDGFRalpha(+) cells were confirmed by quantitative real-time RT-PCR. Inhibition of upregulated miRNAs, miR-146b-5p and -424, resulted in the suppression of osteocyte maturation, suggesting that these two miRNAs have the positive role in the osteogenesis of PDGFRalpha(+) cells. Our results suggest that PDGFRalpha(+) cells may be the major source of HO and that the newly identified miRNAs may regulate osteogenic differentiation process of PDGFRalpha(+) cells. PMID- 23457599 TI - Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis. AB - Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation. PMID- 23457600 TI - Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells. AB - Berberine, an isoquinoline alkaloid, is an active component of Ranunculaceae and Papaveraceae plant families. Berberine has been found to suppress growth of several tumor cell lines in vitro through the cell-type-dependent mechanism. Expression and activation of epidermal growth factor receptor (EGFR) is increased in colonic precancerous lesions and tumours, thus EGFR is considered a tumour promoter. The aim of this study was to investigate the effects and mechanisms of berberine on regulation of EGFR activity and proliferation in colonic tumor cell lines and in vivo. We reported that berberine significantly inhibited basal level and EGF-stimulated EGFR activation and proliferation in the immorto Min mouse colonic epithelial (IMCE) cells carrying the APC(min) mutation and human colonic carcinoma cell line, HT-29 cells. Berberine acted to inhibit proliferation through inducing G1/S and G2/M cell cycle arrest, which correlated with regulation of the checkpoint protein expression. In this study, we also showed that berberine stimulated ubiquitin ligase Cbl activation and Cbl's interaction with EGFR, and EGFR ubiquitinylation and down-regulation in these two cell lines in the presence or absence of EGF treatment. Knock-down Cbl expression blocked the effects of berberine on down-regulation of EGFR and inhibition of proliferation. Furthermore, berberine suppressed tumor growth in the HT-29 cell xenograft model. Cell proliferation and EGFR expression level was decreased by berberine treatment in this xenograft model and in colon epithelial cells of APC(min/+) mice. Taken together, these data indicate that berberine enhances Cbl activity, resulting in down-regulation of EGFR expression and inhibition of proliferation in colon tumor cells. PMID- 23457601 TI - Inverted expression profiles of sex-biased genes in response to toxicant perturbations and diseases. AB - The influence of sex factor is widely recognized in various diseases, but its molecular basis, particularly how sex-biased genes, those with sexually dimorphic expression, behave in response to toxico-pathological changes is poorly understood. In this study, zebrafish toxicogenomic data and transcriptomic data from human pathological studies were analysed for the responses of male- and female-biased genes. Our analyses revealed obvious inverted expression profiles of sex-biased genes, where affected males tended to up-regulate genes of female biased expression and down-regulate genes of male-biased expression, and vice versa in affected females, in a broad range of toxico-pathological conditions. Intriguingly, the extent of these inverted profiles correlated well to the susceptibility or severity of a given toxico-pathological state, suggesting that inverted expression profiles of sex-biased genes observed in this study can be used as important indicators to assess biological disorders. PMID- 23457602 TI - Succession influences wild bees in a temperate forest landscape: the value of early successional stages in naturally regenerated and planted forests. AB - In many temperate terrestrial forest ecosystems, both natural human disturbances drive the reestablishment of forests. Succession in plant communities, in addition to reforestation following the creation of open sites through harvesting or natural disturbances, can affect forest faunal assemblages. Wild bees perform an important ecosystem function in human-altered and natural or seminatural ecosystems, as they are essential pollinators for both crops and wild flowering plants. To maintain high abundance and species richness for pollination services, it is important to conserve and create seminatural and natural land cover with optimal successional stages for wild bees. We examined the effects of forest succession on wild bees. In particular, we evaluated the importance of early successional stages for bees, which has been suspected but not previously demonstrated. A range of successional stages, between 1 and 178 years old, were examined in naturally regenerated and planted forests. In total 4465 wild bee individuals, representing 113 species, were captured. Results for total bees, solitary bees, and cleptoparasitic bees in both naturally regenerated and planted conifer forests indicated a higher abundance and species richness in the early successional stages. However, higher abundance and species richness of social bees in naturally regenerated forest were observed as the successional stages progressed, whereas the abundance of social bees in conifer planted forest showed a concave-shaped relationship when plotted. The results suggest that early successional stages of both naturally regenerated and conifer planted forest maintain a high abundance and species richness of solitary bees and their cleptoparasitic bees, although social bees respond differently in the early successional stages. This may imply that, in some cases, active forest stand management policies, such as the clear-cutting of planted forests for timber production, would create early successional habitats, leading to significant positive effects for bees in general. PMID- 23457603 TI - Neighbourhood environment and stroke: a follow-up study in Sweden. AB - BACKGROUND: In recent years, research on the association between physical environments and cardiovascular disease outcomes has gained momentum with growing attention being paid to Geographic Information Systems (GIS). This nationwide study is the first to examine the effect of neighbourhood physical environments on individual-level stroke, using GIS-based measures of neighbourhood availability of potentially health-damaging (fast food restaurants and pubs/bars) and health-promoting (physical activity and healthcare) resources. METHODS: The study population comprised a nationwide sample of 2,115,974 men and 2,193,700 women aged 35-80 years who were followed between 1 December 2005 and 31 December 2007 in Sweden. Totally 42,270 first-ever strokes (both morbidity and mortality) were identified. Multilevel logistic regression models were used to estimate the association between neighbourhood availability of four different resources (fast food restaurants, pubs/bars, physical activity and healthcare) and individual level stroke. PRINCIPAL FINDINGS: There were significant associations between neighbourhood availability of the four types of neighbourhood resources and individual-level stroke. The significant odds ratios varied between 1.06 and 1.12 for men and 1.07 and 1.24 for women. After adjustment for age, income, and neighbourhood-level deprivation, the increased odds remained statistically significant for neighbourhood availability of fast food restaurants in both men and women. CONCLUSIONS: Specific neighbourhood availability of resources were associated with individual-level stroke but most of these associations were explained by individual-level sociodemographic factors and neighbourhood-level deprivation. PMID- 23457604 TI - Prevalence and associated risk factors of dyslexic children in a middle-sized city of China: a cross-sectional study. AB - BACKGROUND: There are many discussions about dyslexia based on studies conducted in western countries, and some risk factors to dyslexia, such as gender and home literacy environment, have been widely accepted based on these studies. However, to our knowledge, there are few studies focusing on the risk factors of dyslexia in China. Therefore, the aim of our study was to investigate the prevalence of dyslexia and its potential risk factors. METHODS: A cross-sectional study was conducted in Qianjiang, a city in Hubei province, China. Two stages sampling strategy was applied to randomly selected 5 districts and 9 primary schools in Qianjiang. In total, 6,350 students participated in this study and there were 5,063 valid student questionnaires obtained for the final analyses. Additional questionnaires (such as Dyslexia Checklist for Chinese Children and Pupil Rating Scale) were used to identify dyslexic children. The chi-square test and multivariate logistic regression were employed to reveal the potential risk factors to dyslexia. RESULTS: Our study revealed that the prevalence of dyslexia was 3.9% in Qianjiang city, which is a middle-sized city in China. Among dyslexic children, the gender ratio (boys to girls) was nearly 3?1. According to the P value in the multivariate logistic regression, the gender (P<0.01), mother's education level (P<0.01), and learning habits (P<0.01) (active learning, scheduled reading time) were associated with dyslexia. CONCLUSION: The prevalence rate of dyslexic children in middle-sized cities is 3.9%. The potential risk factors of dyslexic children revealed in this study will have a great impact on detecting and treating dyslexic children in China as early as possible, although more studies are still needed to further investigate the risk factors of dyslexic children in China. PMID- 23457605 TI - Possible natural hybridization of two morphologically distinct species of Acropora (Cnidaria, Scleractinia) in the Pacific: fertilization and larval survival rates. AB - Natural hybridization of corals in the Indo-Pacific has been considered rather rare. However, field studies have observed many corals with intermediate interspecific or unusual morphologies. Given that the existence of F1 hybrids with intermediate interspecific morphologies has been proven in the Caribbean, hybrids may also inhabit the Indo-Pacific and occur more frequently than expected. In this study, we focused on two morphologically different species, Acropora florida and A. intermedia, and performed crossing experiments at Akajima Island, Japan. Results showed that these species could hybridize in both directions via eggs and sperm, but that fertilization rates significantly differed according to which species provided eggs. These results are similar to those reported from the Caribbean. Although all embryos developed normally to the planular larval stage, the developmental processes of some hybrid embryos were delayed by approximately 1 h compared with conspecific embryos, suggesting that fertilization occurred 1 h later in interspecific crosses than in intraspecific crosses. More successful hybridization could occur under conditions with low numbers of conspecific colonies. Additionally, a comparison of survival rates between hybrid and intraspecific larvae revealed that intra- and interspecific larvae produced from eggs of A. florida survived for significantly longer than those produced from eggs of A. intermedia. Considering these data, under specific conditions, hybrids can be expected to be produced and survive in nature in the Pacific. Furthermore, we identified one colony with intermediate morphology between A. florida and A. intermedia in the field. This colony was fertilized only by eggs of A. florida, with high fertilization rates, suggesting that this colony would be a hybrid of these two species and might be backcrossed. PMID- 23457606 TI - Barcode server: a visualization-based genome analysis system. AB - We have previously developed a computational method for representing a genome as a barcode image, which makes various genomic features visually apparent. We have demonstrated that this visual capability has made some challenging genome analysis problems relatively easy to solve. We have applied this capability to a number of challenging problems, including (a) identification of horizontally transferred genes, (b) identification of genomic islands with special properties and (c) binning of metagenomic sequences, and achieved highly encouraging results. These application results inspired us to develop this barcode-based genome analysis server for public service, which supports the following capabilities: (a) calculation of the k-mer based barcode image for a provided DNA sequence; (b) detection of sequence fragments in a given genome with distinct barcodes from those of the majority of the genome, (c) clustering of provided DNA sequences into groups having similar barcodes; and (d) homology-based search using Blast against a genome database for any selected genomic regions deemed to have interesting barcodes. The barcode server provides a job management capability, allowing processing of a large number of analysis jobs for barcode based comparative genome analyses. The barcode server is accessible at http://csbl1.bmb.uga.edu/Barcode. PMID- 23457607 TI - Levels of aqueous humor trace elements in patients with non-exsudative age related macular degeneration: a case-control study. AB - Trace elements might play a role in the complex multifactorial pathogenesis of age-related macular degeneration (AMD). The aim of this study was to measure alterations of trace elements levels in aqueous humor of patients with non exsudative (dry) AMD. For this pilot study, aqueous humor samples were collected from patients undergoing cataract surgery. 12 patients with dry AMD (age 77.9+/ 6.62, female 8, male 4) and 11 patients without AMD (age 66.6+/-16.7, female 7, male 4) were included. Aqueous levels of cadmium, cobalt, copper, iron, manganese, selenium, and zinc were measured by use of Flow-Injection-Inductively Coupled-Plasma-Mass-Spectrometry (FI-ICP-MS), quality controlled with certified standards. Patients with AMD had significantly higher aqueous humor levels of cadmium (median: 0.70 umol/L, IQR: 0.40-0.84 vs. 0.06 umol/L; IQR: 0.01-.018; p = 0.002), cobalt (median: 3.1 umol/L, IQR: 2.62-3.15 vs. 1.17 umol/L; IQR: 0.95 1.27; p<0.001), iron (median: 311 umol/L, IQR: 289-329 vs. 129 umol/L; IQR: 111 145; p<0.001) and zinc (median: 23.1 umol/L, IQR: 12.9-32.6 vs. 5.1 umol/L; IQR: 4.4-9.4; p = 0.020) when compared with patients without AMD. Copper levels were significantly reduced in patients with AMD (median: 16.2 umol/L, IQR: 11.4-31.3 vs. 49.9 umol/L; IQR: 32.0-.142.0; p = 0.022) when compared to those without. No significant differences were observed in aqueous humor levels of manganese and selenium between patients with and without AMD. After an adjustment for multiple testing, cadmium, cobalt, copper and iron remained a significant factor in GLM models (adjusted for age and gender of the patients) for AMD. Alterations of trace element levels support the hypothesis that cadmium, cobalt, iron, and copper are involved in the pathogenesis of AMD. PMID- 23457608 TI - Air-stimulated ATP release from keratinocytes occurs through connexin hemichannels. AB - Cutaneous ATP release plays an important role in both epidermal stratification and chronic pain, but little is known about ATP release mechanisms in keratinocytes that comprise the epidermis. In this study, we analyzed ATP release from cultured human neonatal keratinocytes briefly exposed to air, a process previously demonstrated to trigger ATP release from these cells. We show that exposing keratinocytes to air by removing media for 15 seconds causes a robust, long-lasting ATP release. This air-stimulated ATP release was increased in calcium differentiated cultures which showed a corresponding increase in connexin 43 mRNA, a major component of keratinocyte hemichannels. The known connexin hemichannel inhibitors 1-octanol and carbenoxolone both significantly reduced air stimulated ATP release, as did two drugs traditionally used as ABC transporter inhibitors (glibenclamide and verapamil). These same 4 inhibitors also prevented an increase in the uptake of a connexin permeable dye induced by air exposure, confirming that connexin hemichannels are open during air-stimulated ATP release. In contrast, activity of the MDR1 ABC transporter was reduced by air exposure and the drugs that inhibited air-stimulated ATP release had differential effects on this transporter. These results indicate that air exposure elicits non-vesicular release of ATP from keratinocytes through connexin hemichannels and that drugs used to target connexin hemichannels and ABC transporters may cross-inhibit. Connexins represent a novel, peripheral target for the treatment of chronic pain and dermatological disease. PMID- 23457609 TI - Neutrophil-to-lymphocyte ratio and its association with critical limb ischemia in PAOD patients. AB - BACKGROUND: The Neutrophil-to-Lymphocyte ratio (NLR) is an easy to perform test from the white blood cell count. An increase in NLR has been associated with vascular endpoints reflecting inflammation in atherosclerotic lesions. Atherosclerosis is a global threat and vascular endpoints, like myocardial infarction or critical limb ischemia (CLI), are a leading cause of death in industrialized countries. We therefore investigated NLR and its association with CLI and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. METHODS AND FINDINGS: We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. NLR was calculated and the cohort was divided into tertiles according to the NLR. An optimal cut-off value for the continuous NLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in NLR. As an optimal cut-off a NLR of 3.95 was identified. Two groups were categorized, one containing 1441 patients (NLR<=3.95) and a second group with 680 patients (NLR>3.95). CLI was more frequent in NLR>3.95 patients (330(48.5%)) compared to NLR<=3.95 patients (350(24.3%)) (p<0.001), as were prior myocardial infarction (48(7.0%) vs. 47(3.3%), p<0.001) and stroke (73(10.7) vs. 98(6.8%), p<0.001). Regarding other inflammatory parameters, C-reactive protein (median 5.6 mg/l (2.3-19.1) vs. median 3 mg/l (1.5-5.5)) and fibrinogen (median 412 mg/dl (345.5-507.5) vs. 344 mg/dl (308-403.5)) also significantly differed in the two patient groups (both p<0.001). A NLR>3.95 was associated with an OR of 2.5 (95%CI 2.3-2.7) for CLI even after adjustment for other vascular risk factors. CONCLUSIONS: An increased NLR is significantly associated with patients at high risk for CLI and other vascular endpoints. The NLR is an easy to perform test, which could be used to highlight patients at high risk for vascular endpoints. PMID- 23457610 TI - Use of a molecular decoy to segregate transport from antigenicity in the FrpB iron transporter from Neisseria meningitidis. AB - FrpB is an outer membrane transporter from Neisseria meningitidis, the causative agent of meningococcal meningitis. It is a member of the TonB-dependent transporter (TBDT) family and is responsible for iron uptake into the periplasm. FrpB is subject to a high degree of antigenic variation, principally through a region of hypervariable sequence exposed at the cell surface. From the crystal structures of two FrpB antigenic variants, we identify a bound ferric ion within the structure which induces structural changes on binding which are consistent with it being the transported substrate. Binding experiments, followed by elemental analysis, verified that FrpB binds Fe(3+) with high affinity. EPR spectra of the bound Fe(3+) ion confirmed that its chemical environment was consistent with that observed in the crystal structure. Fe(3+) binding was reduced or abolished on mutation of the Fe(3+)-chelating residues. FrpB orthologs were identified in other Gram-negative bacteria which showed absolute conservation of the coordinating residues, suggesting the existence of a specific TBDT sub-family dedicated to the transport of Fe(3+). The region of antigenic hypervariability lies in a separate, external sub-domain, whose structure is conserved in both the F3-3 and F5-1 variants, despite their sequence divergence. We conclude that the antigenic sub-domain has arisen separately as a result of immune selection pressure to distract the immune response from the primary transport function. This would enable FrpB to function as a transporter independently of antibody binding, by using the antigenic sub-domain as a 'molecular decoy' to distract immune surveillance. PMID- 23457611 TI - Optimal sleep duration in the subarctic with respect to obesity risk is 8-9 hours. AB - INTRODUCTION: Sleep duration, chronotype and social jetlag have been associated with body mass index (BMI) and abdominal obesity. The optimal sleep duration regarding BMI has previously been found to be 7-8 hours, but these studies have not been carried out in the subarctic or have lacked some central variables. The aims of our study were to examine the associations between sleep variables and body composition for people living in the subarctic, taking a range of variables into consideration, including lifestyle variables, health variables and biological factors. METHODS: The cross sectional population Tromso Study was conducted in northern Norway, above the Arctic Circle. 6413 persons aged 30-65 years completed questionnaires including self-reported sleep times, lifestyle and health. They also measured height, weight, waist and hip circumference, and biological factors (non-fasting serum level of cholesterol, HDL-cholesterol, LDL cholesterol, triglycerides and glucose). The study period was from 1 October 2007 to 19 December 2008. RESULTS: The optimal sleep length regarding BMI and waist circumference was found to be 8-9 hours. Short sleepers (<6 h) had about 80% increased risk of being in the BMI>=25 kg/m2 group and male short sleepers had doubled risk of having waist circumference >=102 cm compared to 8-9 hours sleepers. We found no impact of chronotype or social jetlag on BMI or abdominal obesity after controlling for health, lifestyle, and biological parameters. CONCLUSIONS: In our subarctic population, the optimal sleep duration time regarding risk of overweight and abdominal obesity was 8-9 hours, which is one hour longer compared to findings from other studies. Short sleepers had 80% increased risk of being overweight, and men had a doubled risk of having abdominal obesity. We found no associations between chronotype or social jetlag and BMI or abdominal obesity, when we took a range of life-style, health and biological variables into consideration. PMID- 23457612 TI - Dynamic light scattering study of inhibition of nucleation and growth of hydroxyapatite crystals by osteopontin. AB - We study the effect of isoforms of osteopontin (OPN) on the nucleation and growth of crystals from a supersaturated solution of calcium and phosphate ions. Dynamic light scattering is used to monitor the size of the precipitating particles and to provide information about their concentration. At the ion concentrations studied, immediate precipitation was observed in control experiments with no osteopontin in the solution, and the size of the precipitating particles increased steadily with time. The precipitate was identified as hydroxyapatite by X-ray diffraction. Addition of native osteopontin (nOPN) extracted from rat bone caused a delay in the onset of precipitation and reduced the number of particles that formed, but the few particles that did form grew to a larger size than in the absence of the protein. Recombinant osteopontin (rOPN), which lacks phosphorylation, caused no delay in initial calcium phosphate precipitation but severely slowed crystal growth, suggesting that rOPN inhibits growth but not nucleation. rOPN treated with protein kinase CK2 to phosphorylate the molecule (p rOPN) produced an effect similar to that of nOPN, but at higher protein concentrations and to a lesser extent. These results suggest that phosphorylations are critical to OPN's ability to inhibit nucleation, whereas the growth of the hydroxyapatite crystals is effectively controlled by the highly acidic OPN polypeptide. This work also demonstrates that dynamic light scattering can be a powerful tool for delineating the mechanism of protein modulation of mineral formation. PMID- 23457613 TI - The course of apparent diffusion coefficient values following perinatal arterial ischemic stroke. AB - BACKGROUND: Diffusion weighted MR imaging (DWI) plays an important role in the diagnosis of perinatal arterial ischemic stroke (PAIS) during the acute phase. Its derived apparent diffusion coefficient (ADC) can be used to quantify the diffusion restriction. Aim of the current study was to identify the changes in ADC values in the acute phase following PAIS. METHODS: A cohort of 36 infants with a confirmed PAIS who were examined once during the first ten days of life was studied. ADC values in the core of the ischemic tissue (iADC) were determined and correlated with postnatal age. ADC ratios (rADC) were calculated by dividing the iADC value by the ADC value of the corresponding area in the contralateral 'healthy' hemisphere. RESULTS: Infants were scanned between days two and ten. A non-linear increase in iADC and rADC values was observed over time and large middle cerebral artery strokes resulted in lower iADC and rADC values. Normalisation of rADC values was observed after day seven. rADC values were lower when compared to previously published rADC values of infants with hypoxic ischemic encephalopathy, suggesting more severe injury. CONCLUSIONS: Following PAIS, DWI showed decreased ADC values with a non-linear increase during the first week, and pseudonormalization after day 7, which limits the use of DWI to assess PAIS to the first week. Compared to previous studies, ADC values were lower when compared to infants with hypoxic ischemic encephalopathy, most likely due to more severe injury. PMID- 23457614 TI - Cell-free fetal DNA and cell-free total DNA levels in spontaneous abortion with fetal chromosomal aneuploidy. AB - BACKGROUND: Cell-free fetal DNA and cell-free total DNA in maternal circulation have been proposed as potential markers for noninvasive monitoring of the placental condition during the pregnancy. However, the correlation of and change in cell-free fetal DNA and cell-free total DNA in spontaneous abortion (SA) with fetal chromosomal aneuploidy have not yet been reported. Therefore, we investigated cell-free fetal DNA and cell-free total DNA levels in SA women with fetal chromosomal aneuploidy. METHODOLOGY/PRINCIPAL FINDINGS: A nested case control study was conducted with maternal plasma collected from 268 women in their first trimester of pregnancy. Subjects included 41 SA with normal fetal karyotype, 26 SA with fetal chromosomal aneuploidy, and 201 normal controls. The unmethylated PDE9A gene was used to measure the maternal plasma levels of cell free fetal DNA. The GAPDH gene was used to measure the maternal plasma levels of cell-free total DNA. The diagnostic accuracy was measured using receiver operating characteristic (ROC) curves. Levels of cell-free fetal DNA and cell free total DNA were significantly higher in both SA women with normal fetal karyotype and SA women with fetal chromosomal aneuploidy in comparison with the normal controls (P<0.001 in both). The correlation between cell-free fetal DNA and cell-free total DNA levels was stronger in the normal controls (r = 0.843, P<0.001) than in SA women with normal karyotype (r = 0.465, P = 0.002) and SA women with fetal chromosomal aneuploidy (r = 0.412, P = 0.037). The area under the ROC curve for cell-free fetal DNA and cell-free total DNA was 0.898 (95% CI, 0.852-0.945) and 0.939 (95% CI, 0.903-0.975), respectively. CONCLUSIONS: Significantly high levels of cell-free fetal DNA and cell-free total DNA were found in SA women with fetal chromosomal aneuploidy. Our findings suggest that cell-free fetal DNA and cell-free total DNA may be useful biomarkers for the prediction of SA with fetal chromosomal aneuploidy, regardless of fetal gender. PMID- 23457615 TI - The effect of heparan sulfate application on bone formation during distraction osteogenesis. AB - Bone morphogenetic proteins (BMPs) are recognized for their ability to induce bone formation in vivo and in vitro. Their osteogenic and osteoinductive properties are tightly regulated by the secretion of specific BMP antagonists, which have been shown to physically bind and sometimes be blocked by the extracellular proteoglycan heparan sulphate side chains (from hereon referred to as HS). The purpose of this study was to investigate if local application of 5 ug of HS proteoglycan to a bone regenerate site in a mouse model of distraction osteogenesis (DO) can accelerate bone healing and affect the expression of key members of the BMP signaling pathway. DO was performed on the right tibia of 115 adult male wild-type mice. At mid-distraction (day 11), half the group was injected locally with 5 ug of HS, while the other half was injected with saline. The mice were sacrificed at 2 time-points: mid-consolidation (34 days) and full consolidation (51 days). The distracted tibial zone was then collected for analysis by MUCT, radiology, biomechanical testing, immunohistochemistry, and histology. While MUCT data showed no statistically significant difference in bone formation, the results of biomechanical testing in stiffness and ultimate force were significantly lower in the HS-injected bones at 51 days, compared to controls. Immunohistochemistry results also suggested a decrease in expression of several key members of the BMP signaling pathway at 34 days. Furthermore, wound dehiscence and infection rates were significantly elevated in the HS group compared to the controls, which resulted in a higher rate of euthanasia in the treatment group. Our findings demonstrate that exogenous application of 5 ug of HS in the distracted gap of a murine model had a negative impact on bone and wound healing. PMID- 23457616 TI - Assessment of long-term effects of nanoparticles in a microcarrier cell culture system. AB - Nano-sized materials could find multiple applications in medical diagnosis and therapy. One main concern is that engineered nanoparticles, similar to combustion derived nanoparticles, may cause adverse effects on human health by accumulation of entire particles or their degradation products. Chronic cytotoxicity must therefore be evaluated. In order to perform chronic cytotoxicity testing of plain polystyrene nanoparticles on the endothelial cell line EAhy 926, we established a microcarrier cell culture system for anchorage-dependent cells (BioLevitator(TM)). Cells were cultured for four weeks and exposed to doses, which were not cytotoxic upon 24 hours of exposure. For comparison, these particles were also studied in regularly sub-cultured cells, a method that has traditionally been used to assess chronic cellular effects. Culturing on basal membrane coated microcarriers produced very high cell densities. Fluorescent particles were mainly localized in the lysosomes of the exposed cells. After four weeks of exposure, the number of cells exposed to 20 nm polystyrene particles decreased by 60% as compared to untreated controls. When tested in sub-cultured cells, the same particles decreased cell numbers to 80% of the untreated controls. Dose-dependent decreases in cell numbers were also noted after exposure of microcarrier cultured cells to 50 nm short multi-walled carbon nanotubes. Our findings support that necrosis, but not apoptosis, contributed to cell death of the exposed cells in the microcarrier culture system. In conclusion, the established microcarrier model appears to be more sensitive for the identification of cellular effects upon prolonged and repeated exposure to nanoparticles than traditional sub-culturing. PMID- 23457618 TI - Molecular phylogeny of echiuran worms (Phylum: Annelida) reveals evolutionary pattern of feeding mode and sexual dimorphism. AB - The Echiura, or spoon worms, are a group of marine worms, most of which live in burrows in soft sediments. This annelid-like animal group was once considered as a separate phylum because of the absence of segmentation, although recent molecular analyses have placed it within the annelids. In this study, we elucidate the interfamily relationships of echiuran worms and their evolutionary pattern of feeding mode and sexual dimorphism, by performing molecular phylogenetic analyses using four genes (18S, 28S, H3, and COI) of representatives of all extant echiuran families. Our results suggest that Echiura is monophyletic and comprises two unexpected groups: [Echiuridae+Urechidae+Thalassematidae] and [Bonelliidae+Ikedidae]. This grouping agrees with the presence/absence of marked sexual dimorphism involving dwarf males and the paired/non-paired configuration of the gonoducts (genital sacs). Furthermore, the data supports the sister group relationship of Echiuridae and Urechidae. These two families share the character of having anal chaetae rings around the posterior trunk as a synapomorphy. The analyses also suggest that deposit feeding is a basal feeding mode in echiurans and that filter feeding originated once in the common ancestor of Urechidae. Overall, our results contradict the currently accepted order-level classification, especially in that Echiuroinea is polyphyletic, and provide novel insights into the evolution of echiuran worms. PMID- 23457617 TI - Haploinsufficiency of the Sec7 guanine nucleotide exchange factor gea1 impairs septation in fission yeast. AB - Membrane trafficking is essential to eukaryotic life and is controlled by a complex network of proteins that regulate movement of proteins and lipids between organelles. The GBF1/GEA family of Guanine nucleotide Exchange Factors (GEFs) regulates trafficking between the endoplasmic reticulum and Golgi by catalyzing the exchange of GDP for GTP on ADP Ribosylation Factors (Arfs). Activated Arfs recruit coat protein complex 1 (COP-I) to form vesicles that ferry cargo between these organelles. To further explore the function of the GBF1/GEA family, we have characterized a fission yeast mutant lacking one copy of the essential gene gea1 (gea1+/-), the Schizosaccharomyces pombe ortholog of GBF1. The haploinsufficient gea1+/- strain was shown to be sensitive to the GBF1 inhibitor brefeldin A (BFA) and was rescued from BFA sensitivity by gea1p overexpression. No overt defects in localization of arf1p or arf6p were observed in gea1+/- cells, but the fission yeast homolog of the COP-I cargo sac1 was mislocalized, consistent with impaired COP-I trafficking. Although Golgi morphology appeared normal, a slight increase in vacuolar size was observed in the gea1+/- mutant strain. Importantly, gea1+/- cells exhibited dramatic cytokinesis-related defects, including disorganized contractile rings, an increased septation index, and alterations in septum morphology. Septation defects appear to result from altered secretion of enzymes required for septum dynamics, as decreased secretion of eng1p, a beta-glucanase required for septum breakdown, was observed in gea1+/- cells, and overexpression of eng1p suppressed the increased septation phenotype. These observations implicate gea1 in regulation of septum breakdown and establish S. pombe as a model system to explore GBF1/GEA function in cytokinesis. PMID- 23457619 TI - MADD knock-down enhances doxorubicin and TRAIL induced apoptosis in breast cancer cells. AB - The Map kinase Activating Death Domain containing protein (MADD) isoform of the IG20 gene is over-expressed in different types of cancer tissues and cell lines and it functions as a negative regulator of apoptosis. Therefore, we speculated that MADD might be over-expressed in human breast cancer tissues and that MADD knock-down might synergize with chemotherapeutic or TRAIL-induced apoptosis of breast cancer cells. Analyses of breast tissue microarrays revealed over expression of MADD in ductal and invasive carcinomas relative to benign tissues. MADD knockdown resulted in enhanced spontaneous apoptosis in human breast cancer cell lines. Moreover, MADD knockdown followed by treatment with TRAIL or doxorubicin resulted in increased cell death compared to either treatment alone. Enhanced cell death was found to be secondary to increased caspase-8 activation. These data indicate that strategies to decrease MADD expression or function in breast cancer may be utilized to increase tumor cell sensitivity to TRAIL and doxorubicin induced apoptosis. PMID- 23457621 TI - A nonsense mutation in the acid alpha-glucosidase gene causes Pompe disease in Finnish and Swedish Lapphunds. AB - Pompe disease is a recessively inherited and often fatal disorder caused by the deficiency of acid alpha-glucosidase, an enzyme encoded by the GAA gene and needed to break down glycogen in lysosomes. This glycogen storage disease type II has been reported also in Swedish Lapphund dogs. Here we describe the genetic defect in canine Pompe disease and show that three related breeds from Scandinavia carry the same mutation. The affected dogs are homozygous for the GAA c.2237G>A mutation leading to a premature stop codon at amino acid position 746. The corresponding mutation has previously been reported in humans and causes infantile Pompe disease in combination with a second fully deleterious mutation. The affected dogs from both the Finnish as well as the Swedish breed mimic infantile-onset Pompe disease genetically, but also clinico-pathologically. Therefore this canine model provides a valuable tool for preclinical studies aimed at the development of gene therapy in Pompe disease. PMID- 23457620 TI - Inhibitory effects of resveratrol on PDGF-BB-induced retinal pigment epithelial cell migration via PDGFRbeta, PI3K/Akt and MAPK pathways. AB - PURPOSE: In diseases such as proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy, and age-related macular degeneration, retinal pigment epithelial (RPE) cells proliferate and migrate. Moreover, platelet-derived growth factor (PDGF) has been shown to enhance proliferation and migration of RPE cells in PVR. Even resveratrol can suppress the migration and adhesion of many cell types, its effects on RPE cell migration and adhesion remain unknown. In this study, we investigated the inhibitory effects of resveratrol on RPE cell migration induced by PDGF-BB, an isoform of PDGF, and adhesion to fibronectin, a major ECM component of PVR tissue. METHODS: The migration of RPE cells was assessed by an electric cell-substrate impedance sensing migration assay and a Transwell migration assay. A cell viability assay was used to determine the viability of resveratrol treated-cells. The cell adhesion to fibronectin was examined by an adhesion assay. The interactions of resveratrol with PDGF-BB were analyzed by a dot binding assay. The PDGF-BB-induced signaling pathways were determined by western blotting and scratch wound healing assay. RESULTS: Resveratrol inhibited PDGF-BB-induced RPE cell migration in a dose-dependent manner, but showed no effects on ARPE19 cell adhesion to fibronectin. The cell viability assay showed no cytotoxicity of resveratrol on RPE cells and the dot binding assay revealed no direct interactions of resveratrol with PDGF-BB. Inhibitory effects of resveratrol on PDGF-BB-induced platelet-derived growth factor receptor beta (PDGFRbeta) and tyrosine phosphorylation and the underlying pathways of PI3K/Akt, ERK and p38 activation were found; however, resveratrol and PDGF-BB showed no effects on PDGFRalpha and JNK activation. Scratch wound healing assay demonstrated resveratrol and the specific inhibitors of PDGFR, PI3K, MEK or p38 suppressed PDGF-BB-induced cell migration. CONCLUSIONS: These results indicate that resveratrol is an effective inhibitor of PDGF-BB-induced RPE cell migration via PDGFRbeta, PI3K/Akt and MAPK pathways, but has no effects on the RPE cell adhesion to fibronectin. PMID- 23457622 TI - Right ventricular morphology and the onset of dyspnea: the MESA-right ventricle study. AB - BACKGROUND: The association of right ventricular (RV) structure and function with symptoms in individuals without cardiopulmonary disease is unknown. We hypothesized that greater RV mass and RV end-diastolic volume (RVEDV), smaller RV stroke volume (RVSV), and lower RV ejection fraction (RVEF) measured by cardiac magnetic resonance imaging (MRI) in participants free of clinical cardiovascular disease at baseline would be associated with a greater risk of self-reported dyspnea. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRIs on participants without clinical cardiovascular disease between 2000 and 2002. We excluded subjects who reported "prevalent" dyspnea at the first assessment (24 months). The presence of dyspnea was assessed at 24 months, 42 months, and 60 months from baseline. Cox proportional hazards models were used to examine the relationship between RV measures and incident dyspnea. RESULTS: In the final study sample (N = 2763), there were significant interactions between RV measures and sex in terms of the risk of dyspnea (p<0.05). Among men (N = 1453), lower RV mass (p = 0.003), smaller RVEDV (p<0.001), smaller RV end-systolic volume (RVESV) (p = 0.03) and decreased RVSV (p<0.001) were associated with an increased risk of developing dyspnea after adjusting for covariates. Associations remained after adjusting for left ventricular function and lung function. However, there were no significant associations between RV measures and the risk of dyspnea in women. CONCLUSIONS: Lower RV mass and smaller RV volumes were associated with an increased risk of dyspnea in men, but not in women. PMID- 23457624 TI - Using consensus bayesian network to model the reactive oxygen species regulatory pathway. AB - Bayesian network is one of the most successful graph models for representing the reactive oxygen species regulatory pathway. With the increasing number of microarray measurements, it is possible to construct the bayesian network from microarray data directly. Although large numbers of bayesian network learning algorithms have been developed, when applying them to learn bayesian networks from microarray data, the accuracies are low due to that the databases they used to learn bayesian networks contain too few microarray data. In this paper, we propose a consensus bayesian network which is constructed by combining bayesian networks from relevant literatures and bayesian networks learned from microarray data. It would have a higher accuracy than the bayesian networks learned from one database. In the experiment, we validated the bayesian network combination algorithm on several classic machine learning databases and used the consensus bayesian network to model the Escherichia coli's ROS pathway. PMID- 23457623 TI - TWEAK enhances E-selectin and ICAM-1 expression, and may contribute to the development of cutaneous vasculitis. AB - Our previous work indicated that TWEAK is associated with various types of cutaneous vasculitis (CV). Herein, we investigate the effects of TWEAK on vascular injury and adhesion molecule expression in CV mice. We showed that TWEAK priming in mice induced a local CV. Furthermore, TWEAK priming also increased the extravasation of FITC-BSA, myeloperoxidase activity and the expression of E selectin and ICAM-1. Conversely, TWEAK blockade ameliorated the LPS-induced vascular damage, leukocyte infiltrates and adhesion molecules expression in LPS induced CV. In addition, TWEAK treatment of HDMECs up-regulated E-selectin and ICAM-1 expression at both mRNA and protein levels. TWEAK also enhanced the adhesion of PMNs to HDMECs. Finally, western blot data revealed that TWEAK can induce phosphorylation of p38, JNK and ERK in HDMECs. These data suggest that TWEAK acted as an inducer of E-selectin and ICAM-1 expression in CV mice and HDMECs, may contribute to the development of CV. PMID- 23457625 TI - Type A Francisella tularensis acid phosphatases contribute to pathogenesis. AB - Different Francisella spp. produce five or six predicted acid phosphatases (AcpA, AcpB, AcpC, AcpD, HapA and HapB). The genes encoding the histidine acid phosphatases (hapA, hapB) and acpD of F. tularensis subsp. Schu S4 strain are truncated or disrupted. However, deletion of HapA (FTT1064) in F. tularensis Schu S4 resulted in a 33% reduction in acid phosphatase activity and loss of the four functional acid phosphatases in F. tularensis Schu S4 (DeltaABCH) resulted in a>99% reduction in acid phosphatase activity compared to the wild type strain. All single, double and triple mutants tested, demonstrated a moderate decrease in mouse virulence and survival and growth within human and murine phagocytes, whereas the DeltaABCH mutant showed >3.5-fold decrease in intramacrophage survival and 100% attenuation of virulence in mouse. While the Schu S4 DeltaABCH strain was attenuated in the mouse model, it showed only limited protection against wild type challenge. F. tularensis Schu S4 failed to stimulate reactive oxygen species production in phagocytes, whereas infection by the DeltaABCH strain stimulated 5- and 56-fold increase in reactive oxygen species production in neutrophils and human monocyte-derived macrophages, respectively. The DeltaABCH mutant but not the wild type strain strongly co-localized with p47 (phox) and replicated in macrophages isolated from p47 (phox) knockout mice. Thus, F. tularensis Schu S4 acid phosphatases, including the truncated HapA, play a major role in intramacrophage survival and virulence of this human pathogen. PMID- 23457626 TI - Combined inhibition of ErbB1/2 and Notch receptors effectively targets breast ductal carcinoma in situ (DCIS) stem/progenitor cell activity regardless of ErbB2 status. AB - Pathways involved in DCIS stem and progenitor signalling are poorly understood yet are critical to understand DCIS biology and to develop new therapies. Notch and ErbB1/2 receptor signalling cross talk has been demonstrated in invasive breast cancer, but their role in DCIS stem and progenitor cells has not been investigated. We have utilised 2 DCIS cell lines, MCF10DCIS.com (ErbB2-normal) and SUM225 (ErbB2-overexpressing) and 7 human primary DCIS samples were cultured in 3D matrigel and as mammospheres in the presence, absence or combination of the Notch inhibitor, DAPT, and ErbB1/2 inhibitors, lapatinib or gefitinib. Western blotting was applied to assess downstream signalling. In this study we demonstrate that DAPT reduced acini size and mammosphere formation in MCF10DCIS.com whereas there was no effect in SUM225. Lapatinb reduced acini size and mammosphere formation in SUM225, whereas mammosphere formation and Notch1 activity were increased in MCF10DCIS.com. Combined DAPT/lapatinib treatment was more effective at reducing acini size in both DCIS cell lines. Mammosphere formation in cell lines and human primary DCIS was reduced further by DAPT/lapatinib or DAPT/gefitinib regardless of ErbB2 receptor status. Our pre clinical human models of DCIS demonstrate that Notch and ErbB1/2 both play a role in DCIS acini growth and stem cell activity. We report for the first time that cross talk between the two pathways in DCIS occurs regardless of ErbB2 receptor status and inhibition of Notch and ErbB1/2 was more efficacious than either alone. These data provide further understanding of DCIS biology and suggest treatment strategies combining Notch and ErbB1/2 inhibitors should be investigated regardless of ErbB2 receptor status. PMID- 23457627 TI - Role of bacterial surface structures on the interaction of Klebsiella pneumoniae with phagocytes. AB - Phagocytosis is a key process of the immune system. The human pathogen Klebsiella pneumoniae is a well known example of a pathogen highly resistant to phagocytosis. A wealth of evidence demonstrates that the capsule polysaccharide (CPS) plays a crucial role in resistance to phagocytosis. The amoeba Dictyostelium discoideum shares with mammalian macrophages the ability to phagocytose and kill bacteria. The fact that K. pneumoniae is ubiquitous in nature and, therefore, should avoid predation by amoebae, poses the question whether K. pneumoniae employs similar means to counteract amoebae and mammalian phagocytes. Here we developed an assay to evaluate K. pneumoniae-D. discoideum interaction. The richness of the growth medium affected the threshold at which the cps mutant was permissive for Dictyostelium and only at lower nutrient concentrations the cps mutant was susceptible to predation by amoebae. Given the critical role of bacterial surface elements on host-pathogen interactions, we explored the possible contribution of the lipopolysaccharide (LPS) and outer membrane proteins (OMPs) to combat phagoyctosis by D. discoideum. We uncover that, in addition to the CPS, the LPS O-polysaccharide and the first core sugar participate in Klebsiella resistance to predation by D. discoideum. K. pneumoniae LPS lipid A decorations are also necessary to avoid predation by amoebae although PagP-dependent palmitoylation plays a more important role than the lipid A modification with aminoarabinose. Mutants lacking OMPs OmpA or OmpK36 were also permissive for D. discoideium growth. Except the LPS O-polysaccharide mutants, all mutants were more susceptible to phagocytosis by mouse alveolar macrophages. Finally, we found a correlation between virulence, using the pneumonia mouse model, and resistance to phagocytosis. Altogether, this work reveals novel K. pneumoniae determinants involved in resistance to phagocytosis and supports the notion that Dictyostelium amoebae might be useful as host model to measure K. pneumoniae virulence and not only phagocytosis. PMID- 23457629 TI - Deficiency in p38beta MAPK fails to inhibit cytokine production or protect neurons against inflammatory insult in in vitro and in vivo mouse models. AB - The p38 MAPK pathway plays a key role in regulating the production of proinflammatory cytokines, such as TNFalpha and IL-1beta, in peripheral inflammatory disorders. There are four major isoforms of p38 MAPK (p38alpha, beta, delta, gamma), with p38alpha and p38beta the targets of most p38 MAPK inhibitor drugs. Our previous studies demonstrated that the p38alpha MAPK isoform is an important contributor to stressor-induced proinflammatory cytokine up regulation and neurotoxicity in the brain. However, the potential role of the p38beta MAPK isoform in CNS proinflammatory cytokine overproduction and neurotoxicity is poorly understood. In the current studies, we used primary microglia from wild type (WT) and p38beta knockout (KO) mice in co-culture with WT neurons, and measured proinflammatory cytokines and neuron death after LPS insult. We also measured neuroinflammatory responses in vivo in WT and p38beta KO mice after administration of LPS by intraperitoneal or intracerebroventricular injection. WT and p38beta KO microglia/neuron co-cultures showed similar levels of TNFalpha and IL-1beta production in response to LPS treatment, and no differences in LPS-induced neurotoxicity. The in vitro results were confirmed in vivo, where levels of TNFalpha and IL-1beta in the CNS were not significantly different between WT or p38beta KO mice after LPS insult. Our results suggest that, similar to peripheral inflammation, p38alpha is critical but p38beta MAPK is dispensable in the brain in regards to proinflammatory cytokine production and neurotoxicity induced by LPS inflammatory insult. PMID- 23457628 TI - Choline catabolism to glycine betaine contributes to Pseudomonas aeruginosa survival during murine lung infection. AB - Pseudomonas aeruginosa can acquire and metabolize a variety of molecules including choline, an abundant host-derived molecule. In P. aeruginosa, choline is oxidized to glycine betaine which can be used as an osmoprotectant, a sole source of carbon and nitrogen, and as an inducer of the virulence factor, hemolytic phospholipase C (PlcH) via the transcriptional regulator GbdR. The primary objective was to determine the contribution of choline conversion to glycine betaine to P. aeruginosa survival during mouse lung infection. A secondary objective was to gain insight into the relative contributions of the different roles of glycine betaine to P. aeruginosa survival during infection. Using a model of acute murine pneumonia, we determined that deletion of the choline oxidase system (encoded by betBA) decreased P. aeruginosa survival in the mouse lung. Deletion of the glycine betaine demethylase genes (gbcA-B), required for glycine betaine catabolism, did not impact P. aeruginosa survival in the lung. Thus, the defect of the betBA mutant was not due to a requirement for glycine betaine catabolism or dependence on a downstream metabolite. Deletion of betBA decreased the abundance of plcH transcript during infection, which suggested a role for PlcH in the betBA survival defect. To test the contribution of plcH to the betBA mutant phenotype a betBAplcHR double deletion mutant was generated. The betBA and betBAplcHR double mutant had a small but significant survival defect compared to the plcHR single mutant, suggesting that regulation of plcH expression is not the only role for glycine betaine during infection. The conclusion was that choline acquisition and its oxidation to glycine betaine contribute to P. aeruginosa survival in the mouse lung. While defective plcH induction can explain a portion of the betBA mutant phenotype, the exact mechanisms driving the betBA mutant survival defect remain unknown. PMID- 23457630 TI - TRIF is required for TLR4 mediated adjuvant effects on T cell clonal expansion. AB - Toll like receptor 4 (TLR4) is an important pattern recognition receptor with the ability to drive potent innate immune responses and also to modulate adaptive immune responses needed for long term protection. Activation of TLR4 by its ligands is mediated by engagement of the adapter proteins MyD88 (myeloid differentiation factor 88) and TRIF (Toll-interleukin 1 receptor domain containing adapter inducing interferon-beta). Previously, we showed that TRIF, but not MyD88, plays an important role in allowing TLR4 agonists to adjuvant early T cell responses. In this study, we investigated the T cell priming events that are regulated specifically by the TRIF signaling branch of TLR4. We found that TRIF deficiency prevented the TLR4 agonist lipid A from enhancing T cell proliferation and survival in an adoptive transfer model of T cell priming. TRIF deficient DC showed defective maturation as evidenced by their failure to upregulate co-stimulatory molecules in response to lipid A stimulation. Importantly, TRIF alone caused CD86 and CD40 upregulation on splenic DC, but both TRIF and MyD88 were required for CD80 upregulation. The impairment of T cell adjuvant effects and defective DC maturation in TRIF (lps/lps) mice after TLR4 stimulation was mainly due to loss of type I IFN production, indicating that type I interferons are central to TLR4's adjuvant effects. These results are useful for the continued development of TLR4 based vaccine adjuvants that avoid inflammatory risks while retaining beneficial immune response. PMID- 23457631 TI - Systematic biases in human heading estimation. AB - Heading estimation is vital to everyday navigation and locomotion. Despite extensive behavioral and physiological research on both visual and vestibular heading estimation over more than two decades, the accuracy of heading estimation has not yet been systematically evaluated. Therefore human visual and vestibular heading estimation was assessed in the horizontal plane using a motion platform and stereo visual display. Heading angle was overestimated during forward movements and underestimated during backward movements in response to both visual and vestibular stimuli, indicating an overall multimodal bias toward lateral directions. Lateral biases are consistent with the overrepresentation of lateral preferred directions observed in neural populations that carry visual and vestibular heading information, including MSTd and otolith afferent populations. Due to this overrepresentation, population vector decoding yields patterns of bias remarkably similar to those observed behaviorally. Lateral biases are inconsistent with standard bayesian accounts which predict that estimates should be biased toward the most common straight forward heading direction. Nevertheless, lateral biases may be functionally relevant. They effectively constitute a perceptual scale expansion around straight ahead which could allow for more precise estimation and provide a high gain feedback signal to facilitate maintenance of straight-forward heading during everyday navigation and locomotion. PMID- 23457632 TI - Multiple breath nitrogen washout: a feasible alternative to mass spectrometry. AB - BACKGROUND: The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early cystic fibrosis (CF) lung disease. Current evidence is based on a customized mass spectrometry system that uses sulfur hexafluoride (SF6) as a tracer gas, which is not widely available. Nitrogen (N2) washout may be better suited for clinical use and multi-center trials. OBJECTIVE: To compare the results obtained from a N2 washout system to those generated by the SF6 based system in healthy children and children with CF. METHODS: Children with CF were recruited from outpatient clinics; healthy children were recruited from the Research4Kids online portal. Participants performed MBWSF6 (Amis 2000, Innovision, Denmark) and MBWN2 (ExhalyzerD, EcoMedics, Switzerland) in triplicate, in random order on the same day. Agreement between systems was assessed by Bland-Altman plot. RESULTS: Sixty-two healthy and 61 children with CF completed measurements on both systems. In health there was good agreement between systems (limits of agreement -0.7 to 1.9); on average N2 produced higher values of LCI (mean difference 0.58 (95% CI 0.42 to 0.74)). In CF the difference between systems was double that in health with a clear bias towards disproportionately higher LCIN2 compared to LCISF6 at higher mean values of LCI. CONCLUSION: LCIN2 and LCISF6 have similar discriminative power and intra-session repeatability but are not interchangeable. MBWN2 offers a valid new tool to investigate early obstructive lung disease in CF, but requires independent normative values. PMID- 23457633 TI - Visualization of SNPs with t-SNE. AB - BACKGROUND: Single Nucleotide Polymorphisms (SNPs) are one of the largest sources of new data in biology. In most papers, SNPs between individuals are visualized with Principal Component Analysis (PCA), an older method for this purpose. PRINCIPAL FINDINGS: We compare PCA, an aging method for this purpose, with a newer method, t-Distributed Stochastic Neighbor Embedding (t-SNE) for the visualization of large SNP datasets. We also propose a set of key figures for evaluating these visualizations; in all of these t-SNE performs better. SIGNIFICANCE: To transform data PCA remains a reasonably good method, but for visualization it should be replaced by a method from the subfield of dimension reduction. To evaluate the performance of visualization, we propose key figures of cross-validation with machine learning methods, as well as indices of cluster validity. PMID- 23457634 TI - Carbon availability affects diurnally controlled processes and cell morphology of Cyanothece 51142. AB - Cyanobacteria are oxygenic photoautotrophs notable for their ability to utilize atmospheric CO2 as the major source of carbon. The prospect of using cyanobacteria to convert solar energy and high concentrations of CO2 efficiently into biomass and renewable energy sources has sparked substantial interest in using flue gas from coal-burning power plants as a source of inorganic carbon. However, in order to guide further advances in this area, a better understanding of the metabolic changes that occur under conditions of high CO2 is needed. To determine the effect of high CO2 on cell physiology and growth, we analyzed the global transcriptional changes in the unicellular diazotrophic cyanobacterium Cyanothece 51142 grown in 8% CO2-enriched air. We found a concerted response of genes related to photosynthesis, carbon metabolism, respiration, nitrogen fixation, ribosome biosynthesis, and the synthesis of nucleotides and structural cell wall polysaccharides. The overall response to 8% CO2 in Cyanothece 51142 involves different strategies, to compensate for the high C/N ratio during both phases of the diurnal cycle. Our analyses show that high CO2 conditions trigger the production of carbon-rich compounds and stimulate processes such as respiration and nitrogen fixation. In addition, we observed that high levels of CO2 affect fundamental cellular processes such as cell growth and dramatically alter the intracellular morphology. This study provides novel insights on how diurnal and developmental rhythms are integrated to facilitate adaptation to high CO2 in Cyanothece 51142. PMID- 23457635 TI - Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1beta-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. AB - Astrocytes are essential for proper central nervous system (CNS) function and are intricately involved in neuroinflammation. Despite evidence that immune-activated astrocytes contribute to many CNS pathologies, little is known about the inflammatory pathways controlling gene expression. Our laboratory identified altered levels of tissue inhibitor of metalloproteinase (TIMP)-1 in brain lysates from human immunodeficiency virus (HIV)-1 infected patients, compared to age matched controls, and interleukin (IL)-1beta as a key regulator of astrocyte TIMP 1. Additionally, CCAAT enhancer binding protein (C/EBP)beta levels are elevated in brain specimens from HIV-1 patients and the transcription factor contributes to astrocyte TIMP-1 expression. In this report we sought to identify key signaling pathways necessary for IL-1beta-mediated astrocyte TIMP-1 expression and their interaction with C/EBPbeta. Primary human astrocytes were cultured and treated with mitogen activated protein kinase-selective small molecule inhibitors, and IL-1beta. TIMP-1 and C/EBPbeta mRNA and protein expression were evaluated at 12 and 24 h post-treatment, respectively. TIMP-1 promoter-driven luciferase plasmids were used to evaluate TIMP-1 promoter activity in inhibitor treated astrocytes. These data show that extracellular regulated kinase (ERK) 1/2 selective inhibitors block IL-1beta-induced astrocyte TIMP-1 expression, but did not decrease C/EBPbeta expression in parallel. The p38 kinase (p38K) inhibitors partially blocked both IL-1beta-induced astrocyte TIMP-1 expression and C/EBPbeta expression. The ERK1/2-selective inhibitor abrogated IL-1beta-mediated increases in TIMP-1 promoter activity. Our data demonstrate that ERK1/2 activation is critical for IL-1beta-mediated astrocyte TIMP-1 expression. ERK1/2-selective inhibition may elicit a compensatory response in the form of enhanced IL-1beta mediated astrocyte C/EBPbeta expression, or, alternatively, ERK1/2 signaling may function to moderate IL-1beta-mediated astrocyte C/EBPbeta expression. Furthermore, p38K activation contributes to IL-1beta-induced astrocyte TIMP-1 and C/EBPbeta expression. These data suggest that ERK1/2 signals downstream of C/EBPbeta to facilitate IL-1beta-induced astrocyte TIMP-1 expression. Astrocyte ERK1/2 and p38K signaling may serve as therapeutic targets for manipulating CNS TIMP-1 and C/EBPbeta levels, respectively. PMID- 23457636 TI - STELLA facilitates differentiation of germ cell and endodermal lineages of human embryonic stem cells. AB - Stella is a developmentally regulated gene highly expressed in mouse embryonic stem (ES) cells and in primordial germ cells (PGCs). In human, the gene encoding the STELLA homologue lies on chromosome 12p, which is frequently amplified in long-term cultured human ES cells. However, the role played by STELLA in human ES cells has not been reported. In the present study, we show that during retinoic acid (RA)-induced differentiation of human ES cells, expression of STELLA follows that of VASA, a marker of germline differentiation. By contrast, human embryonal carcinoma cells express STELLA at a higher level compared with both karyotypically normal and abnormal human ES cell lines. We found that over expression of STELLA does not interfere with maintenance of the stem cell state of human ES cells, but following retinoic acid induction it leads to up regulation of germline- and endodermal-associated genes, whereas neural markers PAX6 and NEUROD1 are down-regulated. Further, STELLA over-expression facilitates the differentiation of human ES cells into BE12-positive cells, in which the expression of germline- and endodermal-associated genes is enriched, and suppresses differentiation of the neural lineage. Taken together, this finding suggests a role for STELLA in facilitating germline and endodermal differentiation of human ES cells. PMID- 23457637 TI - The Sclerotinia sclerotiorum mating type locus (MAT) contains a 3.6-kb region that is inverted in every meiotic generation. AB - Sclerotinia sclerotiorum is a fungal plant pathogen and the causal agent of lettuce drop, an economically important disease of California lettuce. The structure of the S. sclerotiorum mating type locus MAT has previously been reported and consists of two idiomorphs that are fused end-to-end as in other homothallics. We investigated the diversity of S. sclerotiorum MAT using a total of 283 isolates from multiple hosts and locations, and identified a novel MAT allele that differed by a 3.6-kb inversion and was designated Inv+, as opposed to the previously known S. sclerotiorum MAT that lacked the inversion and was Inv-. The inversion affected three of the four MAT genes: MAT1-2-1 and MAT1-2-4 were inverted and MAT1-1-1 was truncated at the 3'-end. Expression of MAT genes differed between Inv+ and Inv- isolates. In Inv+ isolates, only one of the three MAT1-2-1 transcript variants of Inv- isolates was detected, and the alpha1 domain of Inv+ MAT1-1-1 transcripts was truncated. Both Inv- and Inv+ isolates were self fertile, and the inversion segregated in a 1?1 ratio regardless of whether the parent was Inv- or Inv+. This suggested the involvement of a highly regulated process in maintaining equal proportions of Inv- and Inv+, likely associated with the sexual state. The MAT inversion region, defined as the 3.6-kb MAT inversion in Inv+ isolates and the homologous region of Inv- isolates, was flanked by a 250 bp inverted repeat on either side. The 250-bp inverted repeat was a partial MAT1 1-1 that through mediation of loop formation and crossing over, may be involved in the inversion process. Inv+ isolates were widespread, and in California and Nebraska constituted half of the isolates examined. We speculate that a similar inversion region may be involved in mating type switching in the filamentous ascomycetes Chromocrea spinulosa, Sclerotinia trifoliorum and in certain Ceratocystis species. PMID- 23457638 TI - A new family of intrinsically disordered proteins: structural characterization of the major phasin PhaF from Pseudomonas putida KT2440. AB - Phasins are intracellular polyhydroxyalkanoat4e (PHA)-associated proteins involved in the stabilization of these bacterial carbon storage granules. Despite its importance in PHA metabolism and regulation, only few reports have focused so far on the structure of these proteins. In this work we have investigated the structure and stability of the PhaF phasin from Pseudomonas putida KT2440, a protein that is involved in PHA granule stabilization and distribution to daughter cells upon cell division. A structural, three-dimensional model of the protein was built from homology modeling procedures and consensus secondary structure predictions. The model predicts that PhaF is an elongated protein, with a long, amphipathic N-terminal helix with PHA binding capacity, followed by a short leucine zipper involved in protein oligomerization and a superhelical C terminal domain wrapped around the chromosomal DNA. Hydrodynamic, spectroscopical and thermodynamic experiments validated the model and confirmed both that free PhaF is a tetramer in solution and that most part of the protein is intrinsically disordered in the absence of its ligands. The results lay a molecular basis for the explanation of the biological role of PhaF and, along with an exhaustive analysis of phasin sequence databases, suggest that intrinsic disorder and oligomerization through coiled-coils may be a widespread mechanism among these proteins. PMID- 23457639 TI - Association of plasminogen activator inhibitor-type 1 (-675 4G/5G) polymorphism with pre-eclampsia: systematic review. AB - BACKGROUND AND AIMS: Excessive generation of plasminogen activator inhibitor-type 1 (PAI-1) is implicated in the pathogenesis of pre-eclampsia and related conditions. The PAI-1 (-675 4G/5G) promoter polymorphism (rs1799889) affects transcriptional activity and is a putative genetic risk factor for pre-eclampsia. The aim of this study was identify, appraise and synthesise the available evidence for the association of the PAI-1 (-675 4G/5G) polymorphism with pre eclampsia. METHODS: Systematic review and random effects meta-analysis of genetic association studies. RESULTS: We found 12 eligible genetic association studies in which a total of 1511 women with pre-eclampsia, eclampsia or HELLP syndrome and 3492 controls participated. The studies were generally small (median number of cases 102, range 24 to 403) and underpowered to detect plausible association sizes. Meta-analysis of all of the studies detected statistically significant gene-disease associations in the recessive [pooled odds ratio 1.28 (95% confidence interval 1.09, 1.50); population attributable risk 7.7%] and dominant [pooled odds ratio 1.21 (95% confidence interval 1.01, 1.44); population attributable risk 13.7%] models. We did not find evidence of statistical heterogeneity, funnel plot asymmetry or small study bias. CONCLUSIONS: These data suggest that the fibrinolytic pathway regulated by the PAI-1 gene may contribute to the pathogenesis of pre-eclampsia and related conditions. This association, if confirmed in larger genetic association studies, may inform research efforts to develop novel interventions or help to prioritise therapeutic targets that merit evaluation in randomised clinical trials. PMID- 23457640 TI - Xenogeneic human p53 DNA vaccination by electroporation breaks immune tolerance to control murine tumors expressing mouse p53. AB - The pivotal role of p53 as a tumor suppressor protein is illustrated by the fact that this protein is found mutated in more than 50% of human cancers. In most cases, mutations in p53 greatly increase the otherwise short half-life of this protein in normal tissue and cause it to accumulate in the cytoplasm of tumors. The overexpression of mutated p53 in tumor cells makes p53 a potentially desirable target for the development of cancer immunotherapy. However, p53 protein represents an endogenous tumor-associated antigen (TAA). Immunization against a self-antigen is challenging because an antigen-specific immune response likely generates only low affinity antigen-specific CD8(+) T-cells. This represents a bottleneck of tumor immunotherapy when targeting endogenous TAAs expressed by tumors. The objective of the current study is to develop a safe cancer immunotherapy using a naked DNA vaccine. The vaccine employs a xenogeneic p53 gene to break immune tolerance resulting in a potent therapeutic antitumor effect against tumors expressing mutated p53. Our study assessed the therapeutic antitumor effect after immunization with DNA encoding human p53 (hp53) or mouse p53 (mp53). Mice immunized with xenogeneic full length hp53 DNA plasmid intramuscularly followed by electroporation were protected against challenge with murine colon cancer MC38 while those immunized with mp53 DNA were not. In a therapeutic model, established MC38 tumors were also well controlled by treatment with hp53 DNA therapy in tumor bearing mice compared to mp53 DNA. Mice vaccinated with hp53 DNA plasmid also exhibited an increase in mp53-specific CD8(+) T-cell precursors compared to vaccination with mp53 DNA. Antibody depletion experiments also demonstrated that CD8(+) T-cells play crucial roles in the antitumor effects. This study showed intramuscular vaccination with xenogeneic p53 DNA vaccine followed by electroporation is capable of inducing potent antitumor effects against tumors expressing mutated p53 through CD8(+) T cells. PMID- 23457641 TI - Cardiomyocyte imaging using real-time spatial light interference microscopy (SLIM). AB - Spatial light interference microscopy (SLIM) is a highly sensitive quantitative phase imaging method, which is capable of unprecedented structure studies in biology and beyond. In addition to the pi/2 shift introduced in phase contrast between the scattered and unscattered light from the sample, 4 phase shifts are generated in SLIM, by increments of pi/2 using a reflective liquid crystal phase modulator (LCPM). As 4 phase shifted images are required to produce a quantitative phase image, the switching speed of the LCPM and the acquisition rate of the camera limit the acquisition rate and, thus, SLIM's applicability to highly dynamic samples. In this paper we present a fast SLIM setup which can image at a maximum rate of 50 frames per second and provide in real-time quantitative phase images at 50/4 = 12.5 frames per second. We use a fast LCPM for phase shifting and a fast scientific-grade complementary metal oxide semiconductor (sCMOS) camera (Andor) for imaging. We present the dispersion relation, i.e. decay rate vs. spatial mode, associated with dynamic beating cardiomyocyte cells from the quantitative phase images obtained with the real time SLIM system. PMID- 23457642 TI - Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death--a Danish nationwide cohort study. AB - PURPOSE: Chronic inflammatory diseases have been linked to increased risk of atherothrombotic events, but the risk associated with inflammatory bowel disease (IBD) is unclear. We therefore examined the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with IBD. METHODS: In a nationwide Danish population-based setting, a cohort of patients with incident IBD between 1996 and 2009 were identified in national registers. Hospitalizations with IBD as primary diagnosis, initiation of biological treatment and dispensed prescriptions of corticosteroids were all used as surrogate markers for disease activity, with flares classified as the first 120 days after diagnosis of IBD, and 120 days after a new corticosteroid prescription, biological treatment or IBD hospitalization, respectively. Continued corticosteroid prescriptions or IBD hospitalizations were defined as persistent activity, and periods free of such events were defined as remissions. Poisson regression was used to examine risk of MI, stroke, and cardiovascular death using a matched population-based comparison cohort as reference. RESULTS: We identified 20,795 IBD patients with a mean age of 40.3 years that were matched according to age and sex with 199,978 controls. During the study period, there were 365 patients with MI, 454 with stroke, and 778 with cardiovascular death. Patients with IBD had an overall increased risk of MI (rate ratio [RR] 1.17 [95% confidence interval 1.05-1.31]), stroke (RR 1.15 [1.04-1.27], and cardiovascular death (RR 1.35 [1.25-1.45]). During flares and persistent IBD activity the RRs of MI increased to 1.49 (1.16-1.93) and 2.05 (1.58-2.65), the RRs of stroke to 1.53 (1.22-1.92) and 1.55 (1.18-2.04) and for cardiovascular death 2.32 (2.01-2.68) and 2.50 (2.14-2.92). In remission periods, the risk of MI, stroke and cardiovascular death was similar to controls. CONCLUSION: Inflammatory bowel disease is associated with increased risk of MI, stroke, and cardiovascular death during periods with active disease. PMID- 23457643 TI - Regulation of the membrane insertion and conductance activity of the metamorphic chloride intracellular channel protein CLIC1 by cholesterol. AB - The Chloride Intracellular ion channel protein CLIC1 has the ability to spontaneously insert into lipid membranes from a soluble, globular state. The precise mechanism of how this occurs and what regulates this insertion is still largely unknown, although factors such as pH and redox environment are known contributors. In the current study, we demonstrate that the presence and concentration of cholesterol in the membrane regulates the spontaneous insertion of CLIC1 into the membrane as well as its ion channel activity. The study employed pressure versus area change measurements of Langmuir lipid monolayer films; and impedance spectroscopy measurements using tethered bilayer membranes to monitor membrane conductance during and following the addition of CLIC1 protein. The observed cholesterol dependent behaviour of CLIC1 is highly reminiscent of the cholesterol-dependent-cytolysin family of bacterial pore forming proteins, suggesting common regulatory mechanisms for spontaneous protein insertion into the membrane bilayer. PMID- 23457644 TI - High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer. AB - Some Escherichia coli strains produce toxins designated cyclomodulins (CMs) which interfere with the eukaryotic cell cycle of host cells, suggesting a possible link between these bacteria and cancers. There are relatively few data available concerning the colonization of colon tumors by cyclomodulin- and genotoxic producing E. coli. We did a qualitative and phylogenetic analysis of mucosa associated E. coli harboring cyclomodulin-encoding genes from 38 patients with colorectal cancer (CRC) and 31 with diverticulosis. The functionality of these genes was investigated on cell cultures and the genotoxic activity of strains devoid of known CM-encoding gene was investigated. Results showed a higher prevalence of B2 phylogroup E. coli harboring the colibatin-producing genes in biopsies of patients with CRC (55.3%) than in those of patients with diverticulosis (19.3%), (p<0.01). Likewise, a higher prevalence of B2 E. coli harboring the CNF1-encoding genes in biopsies of patients with CRC (39.5%) than in those of patients with diverticulosis (12.9%), (p = 0.01). Functional analysis revealed that the majority of these genes were functional. Analysis of the ability of E. coli to adhere to intestinal epithelial cells Int-407 indicated that highly adherent E. coli strains mostly belonged to A and D phylogroups, whatever the origin of the strains (CRC or diverticulosis), and that most E. coli strains belonging to B2 phylogroup displayed very low levels of adhesion. In addition, 27.6% (n = 21/76) E. coli strains devoid of known cyclomodulin-encoding genes induced DNA damage in vitro, as assessed by the comet assay. In contrast to cyclomodulin-producing E. coli, these strains mainly belonged to A or D E. coli phylogroups, and exhibited a non significant difference in the distribution of CRC and diverticulosis specimens (22% versus 32.5%, p = 0.91). In conclusion, cyclomodulin-producing E. coli belonging mostly to B2 phylogroup colonize the colonic mucosa of patients with CRC. PMID- 23457645 TI - Spatial distribution of cerebral white matter lesions predicts progression to mild cognitive impairment and dementia. AB - CONTEXT: White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years. METHODS: In 426 healthy subjects from a cohort of community dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia. RESULTS: Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia. CONCLUSIONS: Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia. PMID- 23457646 TI - Adaptation of endothelial cells to physiologically-modeled, variable shear stress. AB - Endothelial cell (EC) function is mediated by variable hemodynamic shear stress patterns at the vascular wall, where complex shear stress profiles directly correlate with blood flow conditions that vary temporally based on metabolic demand. The interactions of these more complex and variable shear fields with EC have not been represented in hemodynamic flow models. We hypothesized that EC exposed to pulsatile shear stress that changes in magnitude and duration, modeled directly from real-time physiological variations in heart rate, would elicit phenotypic changes as relevant to their critical roles in thrombosis, hemostasis, and inflammation. Here we designed a physiological flow (PF) model based on short term temporal changes in blood flow observed in vivo and compared it to static culture and steady flow (SF) at a fixed pulse frequency of 1.3 Hz. Results show significant changes in gene regulation as a function of temporally variable flow, indicating a reduced wound phenotype more representative of quiescence. EC cultured under PF exhibited significantly higher endothelial nitric oxide synthase (eNOS) activity (PF: 176.0+/-11.9 nmol/10(5) EC; SF: 115.0+/-12.5 nmol/10(5) EC, p = 0.002) and lower TNF-a-induced HL-60 leukocyte adhesion (PF: 37+/-6 HL-60 cells/mm(2); SF: 111+/-18 HL-60/mm(2), p = 0.003) than cells cultured under SF which is consistent with a more quiescent anti-inflammatory and anti-thrombotic phenotype. In vitro models have become increasingly adept at mimicking natural physiology and in doing so have clarified the importance of both chemical and physical cues that drive cell function. These data illustrate that the variability in metabolic demand and subsequent changes in perfusion resulting in constantly variable shear stress plays a key role in EC function that has not previously been described. PMID- 23457648 TI - Sequential soil transport and its influence on the spatial organisation of collective digging in leaf-cutting ants. AB - The Chaco leaf-cutting ant Atta vollenweideri (Forel) inhabits large and deep subterranean nests composed of a large number of fungus and refuse chambers. The ants dispose of the excavated soil by forming small pellets that are carried to the surface. For ants in general, the organisation of underground soil transport during nest building remains completely unknown. In the laboratory, we investigated how soil pellets are formed and transported, and whether their occurrence influences the spatial organisation of collective digging. Similar to leaf transport, we discovered size matching between soil pellet mass and carrier mass. Workers observed while digging excavated pellets at a rate of 26 per hour. Each excavator deposited its pellets in an individual cluster, independently of the preferred deposition sites of other excavators. Soil pellets were transported sequentially over 2 m, and the transport involved up to 12 workers belonging to three functionally distinct groups: excavators, several short-distance carriers that dropped the collected pellets after a few centimetres, and long-distance, last carriers that reached the final deposition site. When initiating a new excavation, the proportion of long-distance carriers increased from 18% to 45% within the first five hours, and remained unchanged over more than 20 hours. Accumulated, freshly-excavated pellets significantly influenced the workers' decision where to start digging in a choice experiment. Thus, pellets temporarily accumulated as a result of their sequential transport provide cues that spatially organise collective nest excavation. PMID- 23457647 TI - The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. AB - Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg(2+) re-absorption in the distal convoluted tubule via the Mg(2+) channel TRPM6. This study investigates the role of TRPM Mg(2+) channels, claudines, and EGF in the Mg(2+) homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg(2+). Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR) and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg(2+) loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg(2+) loss in medication-induced nephropathy. PMID- 23457649 TI - The epidemiological relevance of family study in Chagas disease. PMID- 23457651 TI - CASE REPORT Laser-Assisted Indocyanine Green Evaluation of Paramedian Forehead Flap Perfusion Prior to Pedicle Division. AB - OBJECTIVE: To present the use of indocyanine green and the LifeCell SpyElite System to confirm perfusion and viability of a forehead flap prior to division and inset, thereby eliminating the question of flap survival based on clinical judgment alone. METHODS: A case report of a 67-year-old man with a forehead flap reconstruction following an acquired nasal defect due to resection of an adenoid cystic carcinoma is presented. LifeCell SpyElite System was used to confirm perfusion prior to pedicle division. RESULTS: The LifeCell SpyElite System was used to confirm perfusion to the forehead flap prior to pedicle division during the second stage of the procedure. After confirming perfusion, the pedicle was divided and the flap was inset. The remainder of the patient's operative and postoperative course was uneventful, and he healed without incident. CONCLUSIONS: Indocyanine green and the LifeCell SpyElite System is a reliable method to confirm perfusion and viability of staged reconstructive procedures prior to division and inset, thereby eliminating the question of flap survival based on clinical judgment alone. This is a practical application of this technology that has not been previously described in the plastic surgery literature. PMID- 23457652 TI - Subungual melanoma of the thumb. PMID- 23457653 TI - The rheumatoid hand. PMID- 23457650 TI - Trachoma: protective and pathogenic ocular immune responses to Chlamydia trachomatis. AB - Trachoma, caused by Chlamydia trachomatis (Ct), is the leading infectious blinding disease worldwide. Chronic conjunctival inflammation develops in childhood and leads to eyelid scarring and blindness in adulthood. The immune response to Ct provides only partial protection against re-infection, which can be frequent. Moreover, the immune response is central to the development of scarring pathology, leading to loss of vision. Here we review the current literature on both protective and pathological immune responses in trachoma. The resolution of Ct infection in animal models is IFNgamma-dependent, involving Th1 cells, but whether this is the case in human ocular infection still needs to be confirmed. An increasing number of studies indicate that innate immune responses arising from the epithelium and other innate immune cells, along with changes in matrix metalloproteinase activity, are important in the development of tissue damage and scarring. Current trachoma control measures, which are centred on repeated mass antibiotic treatment of populations, are logistically challenging and have the potential to drive antimicrobial resistance. A trachoma vaccine would offer significant advantages. However, limited understanding of the mechanisms of both protective immunity and immunopathology to Ct remain barriers to vaccine development. PMID- 23457654 TI - Nasal reconstruction. PMID- 23457655 TI - Rheumatoid arthritis. PMID- 23457656 TI - Head and neck reconstruction. PMID- 23457657 TI - Lower extremity reconstruction. PMID- 23457658 TI - Composite graft repair for distal fingertip amputation. PMID- 23457659 TI - Sternal wound reconstruction with omental flap for poststernotomy mediastinitis. PMID- 23457660 TI - Developing novel C-4 analogues of pyrrole-based antitubulin agents: weak but critical hydrogen bonding in the colchicine site. AB - The synthesis, biological evaluation and molecular modeling of a series of pyrrole compounds related to 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2 carboxylic acid that evaluates and optimizes C-4 substituents are reported. The key factor for microtubule depolymerization activity appears to be the presence of an appropriately positioned acceptor for Cys241beta in the otherwise hydrophobic subpocket A. PMID- 23457661 TI - Hybrid optical materials of plasmon-coupled CdSe/ZnS coreshells for photonic applications. AB - A hybrid optical nanostructure of plasmon-coupled SQDs was developed for photonic applications. The coupling distances between the mono-layers of Au nanoparticles with a surface concentration of ~9.18 * 10-4 nm-2 and CdSe/ZnS SQDs with that of ~3.7 * 10-3 nm-2 were controlled by PMMA plasma etching. Time-resolved spectroscopy of plasmon-coupled SQDs revealed a strong shortening of the longest lifetime and ~9-fold PL enhancement. Polarization-resolved PL spectroscopy displayed linear polarization and depolarization at near- and far-field plasmon coupling, respectively. The physical origin of PL enhancement could be attributable to both the large local field enhancement and the fast resonant energy transfer. PMID- 23457663 TI - Abstract Thinking in Space and Time: Using The Environment to Learn Words. AB - A substantial body of work has examined the gestures children and adults make when they talk and found them to be a revealing window on the processes of cognitive change. In her paper, Susan Wagner Cook (this volume) reviews this work along with her own recent work examining the gestures children and adults produce when they talk about math. She argues that the combined data point to a new view of our mathematical knowledge as embodied. Here I comment on Cook's arguments, highlighting how this view of math as embodied offers new insights for our understanding of classic developmental themes, in particular, the continuity versus discontinuity dichotomy. In addition, I present a brief summary of recent work on how children use their bodies in another realm typically thought of as abstract-understanding referential intent. I present an embodied account of how children disambiguate speaker intent in novel naming situations and argue that, as in the case of embodied math, an embodied view of cognition can help elucidate developmental mechanism. PMID- 23457662 TI - Integrated control of protein degradation in C. elegans muscle. AB - Protein degradation is a fundamental cellular process, the genomic control of which is incompletely understood. The advent of transgene-coded reporter proteins has enabled the development of C. elegans into a model for studying this problem. The regulation of muscle protein degradation is surprisingly complex, integrating multiple signals from hypodermis, intestine, neurons and muscle itself. Within the muscle, degradation is executed by separately regulated autophagy-lysosomal, ubiquitin-proteasome and calpain-mediated systems. The signal-transduction mechanisms, in some instances, involve modules previously identified for their roles in developmental processes, repurposed in terminally differentiated muscle to regulate the activities of pre-formed proteins. Here we review the genes, and mechanisms, which appear to coordinately control protein degradation within C. elegans muscle. We also consider these mechanisms in the context of development, physiology, pathophysiology and disease models. PMID- 23457664 TI - Extending MapMan Ontology to Tobacco for Visualization of Gene Expression. AB - Microarrays are a large-scale expression profiling method which has been used to study the transcriptome of plants under various environmental conditions. However, manual inspection of microarray data is difficult at the genome level because of the large number of genes (normally at least 30,000) and the many different processes that occur within any given plant. MapMan software, which was initially developed to visualize microarray data for Arabidopsis, has been adapted to other plant species by mapping other species onto MapMan ontology. This paper provides a detailed procedure and the relevant computing codes to generate a MapMan ontology mapping file for tobacco (Nicotiana tabacum L.) using potato and Arabidopsis as intermediates. The mapping file can be used directly with our custom made NimbleGen oligoarray, that contains gene sequences from both the tobacco gene space sequence and the tobacco gene index 4 (NTGI4) collection of ESTs. The generated data set will be informative for scientists working on tobacco as their model plant by providing a MapMan ontology mapping file to tobacco, homology between tobacco coding sequences and that of potato and Arabidopsis, as well as adapting our procedure and codes for other plant species where the complete genome is not yet available. PMID- 23457665 TI - The times they are a changin'. PMID- 23457667 TI - Ultrasound finding predictive of malignant pleural effusion. PMID- 23457668 TI - Solitary bone plasmacytoma. PMID- 23457669 TI - Spirometry in primary care. AB - Canadian Thoracic Society (CTS) clinical guidelines for asthma and chronic obstructive pulmonary disease (COPD) specify that spirometry should be used to diagnose these diseases. Given the burden of asthma and COPD, most people with these diseases will be diagnosed in the primary care setting. The present CTS position statement was developed to provide guidance on key factors affecting the quality of spirometry testing in the primary care setting. The present statement may also be used to inform and guide the accreditation process for spirometry in each province. Although many of the principles discussed are equally applicable to pulmonary function laboratories and interpretation of tests by respirologists, they are held to a higher standard and are outside the scope of the present statement. PMID- 23457670 TI - Role of monoclonal antibodies in the treatment of asthma. AB - BACKGROUND: Patients with severe refractory asthma represent a small subset of the asthmatic population (between 5% and 10% of all patients) but are the greatest burden to the health care system. New treatment approaches developed to manage some of the phenotypes of severe refractory asthma have included humanized monoclonal antibodies (hMabs). OBJECTIVE: To review the evidence and ascertain whether hMabs provide clinical benefit to patients with severe refractory asthma. METHODS: Studies that examined the efficacy of hMabs against immunoglobulin (Ig) E, tumour necrosis factor-alpha, interleukin (IL)-5, and IL-4/IL-13 in patients with severe refractory asthma were reviewed and summarized. RESULTS: Treatment with anti-IgE improved asthma control and reduced severe exacerbations in patients with severe asthma and elevated serum IgE levels. Treatments with hMabs that block tumour necrosis factor-alpha are unlikely to be useful in asthma treatment. In contrast, hMabs that block IL-5 have consistently shown benefit in reducing severe exacerbations in patients with severe refractory asthma with persistent eosinophilia. Finally, hMabs that block IL-13 may provide benefit in patients with elevated blood periostin levels. DISCUSSION: hMabs that block IgE are approved for the treatment of allergic asthma. It is likely that blocking IL 5 will also provide benefit in patients with severe asthma with persistent eosinophilia. These studies have emphasized the importance of careful phenotyping of patients with severe refractory asthma before embarking on treatment with hMabs. PMID- 23457671 TI - Oxidative stress in chronic obstructive pulmonary disease: a lung and systemic process. PMID- 23457672 TI - Sex as an independent prognostic factor in a population-based non-small cell lung cancer cohort. AB - BACKGROUND: Males with non-small cell lung cancer (NSCLC) tend to experience worse outcomes, as do those with nonadenocarcinoma histology; however, the independent effects of these factors remain unclear. OBJECTIVE: To evaluate the independent effect of sex and histology on mortality in a population of patients with NSCLC. METHODS: All patients with NSCLC in Manitoba from 1985 to 2004 were identified from the Manitoba Cancer Registry. Treatment data were extracted from the Manitoba Health administrative databases and linked to the registry. Cox regression analysis was used to determine the independent effect of sex on survival. RESULTS: A total of 10,908 patients (6665 male, 4243 female) with NSCLC were identified. Females had a median overall survival of 9.4 months versus 6.8 months for males (P<0.001). The adjusted HR for death for males compared with females was 1.13 (95% CI 1.04 to 1.23; P=0.004). Sex modified the effect of surgical treatment on survival (HR 1.26 [95% CI 1.13 to 1.40]; P<0.001). Adenocarcinoma histology modified the effect of sex on survival (HR 1.36 [95% CI 1.24 to 1.50]; P<0.001) when treatment was accounted for. CONCLUSION: Females experienced a significantly better survival rate than males independent of treatment, age, year of diagnosis and histology. This was greatest in surgically treated patients and in those with adenocarcinoma. PMID- 23457673 TI - Local and systemic oxidative stress status in chronic obstructive pulmonary disease patients. AB - BACKGROUND: Previous studies have indicated that oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). OBJECTIVES: To study local and systemic oxidative stress status in COPD patients, and to clarify the relationship between local and systemic oxidative stress. METHODS: Lipid peroxide malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and GSH peroxidase (GSH-PX) levels in induced sputum and plasma, as well as glucocorticoid receptor (GR) levels in peripheral blood leukocytes were examined in 43 acute exacerbation of COPD patients (group A), 35 patients with stable COPD (group B) and 28 healthy controls (14 smokers [group C]; 14 nonsmokers [group D]). RESULTS: MDA levels in induced sputum and plasma decreased progressively in groups A to D, with significant differences between any two groups (P<0.001). GSH, SOD and GSH-PX levels in both induced sputum and plasma increased progressively in groups A to D, with significant differences between any two groups (P<0.001). GR levels in peripheral blood leukocytes decreased progressively in groups D to A (all comparisons P<0.001). Pearson analysis revealed strong correlations between MDA, GSH, SOD and GSH-PX levels in plasma and induced sputum. The activity of SOD in plasma and sputum were both positively correlated with GR levels (partial correlation coefficients 0.522 and 0.574, respectively [P<0.001]). CONCLUSIONS: Oxidative stress levels were elevated in COPD patients. There was a correlation between local and systemic oxidative status in COPD, and between decreased SOD activity and decreased GR levels in COPD patients. PMID- 23457674 TI - Loud snoring is a risk factor for occupational injury in farmers. AB - BACKGROUND: Loud snoring is a common symptom in the general population. The evidence-based literature indicates that snoring may be associated with sleep fragmentation and sleep apnea, which may affect cognitive function and predispose to occupational injury. High rates of occupational injury occur on farms and may be related to personal and health factors. Thus, loud snoring may not be a trivial symptom and should be considered as important in medical assessments. METHODS: A prospective cohort study was conducted in Saskatchewan. Baseline questionnaires were completed for 5502 individuals by representatives from 2390 farms. Sleep patterns at baseline were categorized as the following: no reported sleep disorders; physician-diagnosed sleep apnea (treatment unknown); and loud snoring. Survival analyses were used to relate sleep patterns with subsequent injury. RESULTS: A total of 6.7% (369 of 5502) of participants reported a possible sleep disorder. Of these, 69.4% (256 of 369) reported loud snoring only. Loud snoring was only associated with a consistent increase in risk (eg, HR 1.45 [95 CI 1.07 to 1.99 for work-related injury]) for five farm injury outcomes. Relationships between physician-diagnosed sleep apnea and time to first injury were not significant, presumably because a diagnosis of sleep apnea implied treatment for sleep apnea. DISCUSSION: Sleep disorders are an important potential risk factor for occupational injury on farms. Substantial proportions of farm residents report loud snoring and this is related to subsequent injury. Some of these cases may represent sleep fragmentation or undiagnosed obstructive sleep apnea. Identification and clinical management of sleep disorders related to snoring should be part of health assessments conducted by physicians. PMID- 23457676 TI - Diffuse pulmonary lymphangiomatosis. AB - Diffuse pulmonary lymphangiomatosis (DPL) is a rare disease characterized by infiltration of the lung, pleura and mediastinum with thin-walled lymphangiomas. DPL can result in mass effect from infiltrative disease, restrictive and obstructive pulmonary physiology, chylous effusions and respiratory failure. The present article discusses clinical, radiographic and pathological features, and treatment options for DPL. PMID- 23457675 TI - Quantitative sputum cell counts to monitor bronchitis: a qualitative study of physician and patient perspectives. AB - Many common diseases affecting the airways are characterized by airway inflammation. The measurement of this inflammation has a significant role in the management of these diseases. Quantitative sputum cell counts provide a measurement of the type and severity of inflammation present. Sputum cell counts are used in routine clinical practice in some centres but their use is not widespread. The present study used a standardized questionnaire to determine both patients' and physicians' attitudes toward the use of sputum cell counts. The use of sputum cell counts was well accepted by patients and physicians. Ninety per cent of patients were satisfied with the test. Sixty per cent of family physicians were satisfied with the test and 80% were in favour of it being funded by the government. The authors recommend more widespread use of sputum cell counts to guide the management of airway diseases. PMID- 23457678 TI - The effect of inhaled menthol on upper airway resistance in humans: a randomized controlled crossover study. AB - BACKGROUND: Menthol (l-menthol) is a naturally-occurring cold receptor agonist commonly used to provide symptomatic relief for upper airway congestion. Menthol can also reduce the sensation of dyspnea. It is unclear whether the physiological action of menthol in dyspnea reduction is through its cold receptor agonist effect or whether associated mechanical changes occur in the upper airway. OBJECTIVE: To determine whether menthol inhalation alters upper airway resistance in humans. METHODS: A randomized, sham-controlled, single-blinded crossover study of inhaled menthol on upper airway resistance during semirecumbent quiet breathing in healthy subjects was conducted. Ten healthy participants (eight female) with a mean (+/- SD) age of 21+/-1.6 years completed the study. RESULTS: Nasal resistance before testing was similar on both occasions. No differences were found in respiratory frequency (mean +/- SEM) (menthol 17.0+/-1.1 cmH2O/L/s; sham 16.9+/-0.9 cmH2O/L/s), minute ventilation (menthol 7.7+/-0.5 cmH2O/L/s; sham 7.9+/-0.5 cmH2O/L/s) or total inspiratory time/total breath time (menthol 0.4+/ 0.1 cmH2O/L/s; sham 0.4+/-0.1 cmH2O/L/s). The upper airway resistance was similar during menthol (3.47+/-0.32 cmH2O/L/s) and sham (3.27+/-0.28 cmH2O/L/s) (P=0.33) inhalation. CONCLUSION: Inhalation of menthol does not alter upper airway resistance in awake human subjects. PMID- 23457679 TI - Twenty-four hour noninvasive ventilation in Duchenne muscular dystrophy: a safe alternative to tracheostomy. AB - BACKGROUND: Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative. METHODS: The authors' experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported. RESULTS: The mean (+/- SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8+/-3.5 years and 0.90+/-0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8+/-3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2 and, predominantly, by end-tidal CO2. While the results suggested improved CO2 levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years). CONCLUSIONS: Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone. PMID- 23457680 TI - Assessment of pain response in capsaicin-induced dynamic mechanical allodynia using a novel and fully automated brushing device. AB - BACKGROUND: Dynamic mechanical allodynia is traditionally induced by manual brushing of the skin. Brushing force and speed have been shown to influence the intensity of brush-evoked pain. There are still limited data available with respect to the optimal stroke number, length, force, angle and speed. Therefore, an automated brushing device (ABD) was developed, for which brushing angle and speed could be controlled to enable quantitative assessment of dynamic mechanical allodynia. OBJECTIVES: To compare the ABD with manual brushing using capsaicin induced allodynia, and to investigate the role of stroke angle and speed on pain intensity. METHODS: Experimental dynamic mechanical allodynia was induced by an intradermal injection of capsaicin (100 ug) into the volar forearm of 12 healthy, male volunteers. Dynamic mechanical allodynia was rated on a 10 cm visual analogue scale (VAS) after each set of strokes at angles of 30 degrees , 60 degrees and 90 degrees with speeds of 17 mm/s, 21 mm/s and 25 mm/s for each angle. A two-way ANOVA with repeated measures was performed to assess the influence of brushing parameters. To evaluate test-retest reliability, Bland Altman 95% limits of agreement, including a coefficient of repeatability and an intraclass correlation coefficient (ICC), were determined. RESULTS: The angle and speed exhibited a significant impact on pain intensity (P<0.001 and P<0.015, respectively). Post hoc analysis showed that the highest pain intensity was recorded with an angle of 30 degrees regardless of brushing speed. The ABD demonstrated superior test-retest reliability (coefficient of repeatability = 1.9 VAS; ICC=0.91) compared with manual brushing (coefficient of repeatability = 2.8 VAS; ICC=0.80; P<0.05). The most reliable combination of parameters (coefficient of repeatability = 1.3 VAS; ICC=0.97) was an angle of 60 degrees and a speed of 21 mm/s. CONCLUSIONS: A controlled, automatic brushing method can be used for quantitative investigations of allodynic reactions, and is more reliable for quantitative assessment of dynamic mechanical allodynia compared with traditional manual brushing. PMID- 23457681 TI - A controlled investigation of continuing pain education for long-term care staff. AB - BACKGROUND: The underassessment and undertreatment of pain in residents of long term care (LTC) facilities has been well documented. Gaps in staff knowledge and inaccurate beliefs have been identified as contributors. OBJECTIVES: To investigate the effectiveness of an expert-based continuing education program in pain assessment/management for LTC staff. METHODS: Participants included 131 LTC staff members who were randomly assigned to either an interactive pain education (PE) program, which addressed gaps in knowledge such as medication management, or an interactive control program consisting of general dementia education without a specific clinical focus. Participants attended three sessions, each lasting 3 h, and completed measures of pain-related knowledge and attitudes/beliefs before, immediately after and two weeks following the program. Focus groups were conducted with a subset of participants to gauge perception of the training program and barriers to implementing pain-related strategies. RESULTS: Analysis using ANOVA revealed that PE participants demonstrated larger gains compared with control participants with regard to pain knowledge and pain beliefs. Barriers to implementing pain-related strategies certainly exist. Nonetheless, qualitative analyses demonstrated that PE participants reported that they overcame many of these barriers and used pain management strategies four times more frequently than control participants. CONCLUSIONS: Contrary to previous research, the present study found that the interactive PE program was effective in changing pain beliefs and improving knowledge. Continuing PE in LTC has the potential to address knowledge gaps among front-line LTC providers. PMID- 23457682 TI - Patients' and professionals' views on managing fibromyalgia. AB - BACKGROUND: Managing fibromyalgia is a challenge for both health care systems and the professionals caring for these patients, due, in part, to the fact that the etiology of this disease is unknown, its symptoms are not specific and there is no standardized treatment. OBJECTIVE: The present study examines three aspects of fibromyalgia management, namely diagnostic approach, therapeutic management and the health professional-patient relationship, to explore specific areas of the health care process that professionals and patients may consider unsatisfactory. METHODS: A qualitative study involving semistructured interviews with 12 fibromyalgia patients and nine health professionals was performed. RESULTS: The most commonly recurring theme was the dissatisfaction of both patients and professionals with the management process as a whole. Both groups expressed dissatisfaction with the delay in reaching a diagnosis and obtaining effective treatment. Patients reported the need for greater moral support from professionals, whereas the latter often felt frustrated and of little help to patients. Patients and professionals agreed on one point: the uncertainty surrounding the management of fibromyalgia and, especially, its etiology. CONCLUSION: The present study contributes to a better understanding regarding why current management of fibromyalgia is neither effective nor satisfactory. It also provides insight into how health professionals can support fibromyalgia patients to achieve beneficial results. Health care services should offer greater support for these patients in the form of specific resources such as fibromyalgia clinics and health professionals with increased awareness of the disease. PMID- 23457683 TI - The ethics of Canadian entry-to-practice pain competencies: how are we doing? AB - BACKGROUND: Although unrelieved pain continues to represent a significant problem, prelicensure educational programs tend to include little content related to pain. Standards for professional competence strongly influence curricula and have the potential to ensure that health science students have the knowledge and skill to manage pain in a way that also allows them to meet professional ethical standards. OBJECTIVES: To perform a systematic, comprehensive examination to determine the entry-to-practice competencies related to pain required for Canadian health science and veterinary students, and to examine how the presence and absence of pain competencies relate to key competencies of an ethical nature. METHODS: Entry-to-practice competency requirements related to pain knowledge, skill and judgment were surveyed from national, provincial and territorial documents for dentistry, medicine, nursing, pharmacy, occupational therapy, physiotherapy, psychology and veterinary medicine. RESULTS: Dentistry included two and nursing included nine specific pain competencies. No references to competencies related to pain were found in the remaining health science documents. In contrast, the national competency requirements for veterinary medicine, surveyed as a comparison, included nine pain competencies. All documents included competencies pertaining to ethics. CONCLUSIONS: The lack of competencies related to pain has implications for advancing skillful and ethical practice. The lack of attention to pain competencies limits the capacity of health care professionals to alleviate suffering, foster autonomy and use resources justly. Influencing professional bodies to increase the number of required entry-to-practice pain competencies may ultimately have the greatest impact on education and practice. PMID- 23457684 TI - Daily changes in pain, mood and physical function in children hospitalized for sickle cell disease pain. AB - BACKGROUND: Youth with sickle cell disease (SCD) are commonly hospitalized for treatment of painful vaso-occlusive episodes (VOE). However, limited data are available concerning the course of hospitalization for these children and adolescents and, in particular, whether daily changes occur in pain, emotional status and physical function. OBJECTIVES: To characterize changes in daily pain intensity, physical function and mood over the course of hospitalization, and to determine whether specific clinical characteristics were associated with these changes. METHODS: Daily ratings of pain (0 to 10 numerical rating scale) and mood (Positive and Negative Affect Scale for Children) were completed by 25 youth (11 to 20 years of age) with SCD over a total of 152 days (mean [+/- SD] = 6.7+/-5.6 days) of hospitalization. Trained raters determined each youth's daily physical function. RESULTS: Linear mixed modelling was used to examine changes in pain, mood and physical function during hospital stay. The rate of change over the course of hospitalization was significant for reductions in pain intensity (P<0.001) and improvements in physical (motor) function (P=0.001). Positive affect over time was significantly associated with subjects' physical function scores (B 0.24 [95% CI 0.12 to 0.35]) but not with their pain scores. In contrast, negative affect was positively associated with pain and inversely associated with physical function scores (B 1.58 [95% CI 0.23 to 2.93]). CONCLUSIONS: The results of the present study demonstrated that children made daily improvements in physical function and pain over hospitalization for VOE. Mood was related to changes in pain and physical recovery. Assessment of physical function and mood during hospitalization may help guide strategies to better understand the pain experience in youth with SCD hospitalized with VOE. PMID- 23457685 TI - The effects of mindfulness-based attention on cold pressor pain in children. AB - BACKGROUND: Typical interventions for acute pain in children attempt to reduce pain by directing attention away from pain. Conversely, mindfulness involves devoting attention to one's experience in an accepting and nonjudgmental way. However, the effect that instructing children to mindfully devote attention to acute pain has on pain outcomes is unknown. OBJECTIVES: To examine whether mindful attention can help children attend to pain without increasing pain intensity or decreasing pain tolerance; to compare the effects of mindful attention with a well-established intervention designed to take attention away from pain (guided imagery); and to test whether baseline coping style or trait mindfulness alter the effects of these interventions. METHODS: A total of 82 children (10 to 14 years of age) completed measures of coping style and trait mindfulness. Participants then received either mindful attention or guided imagery instructions designed to direct attention toward or away from pain, respectively, before participating in a cold pressor task. RESULTS: The mindful attention group reported more awareness of the physical sensations of pain and thoughts about those sensations. Overall, there were no between-group differences in measures of pain intensity or pain tolerance during the cold pressor task, and no evidence of an interaction between baseline characteristics of the child and experimental condition. CONCLUSIONS: Mindful attention was successful in helping children focus attention on experimental pain without increasing pain intensity or decreasing tolerance compared with a well-established intervention for acute pain reduction. PMID- 23457687 TI - Patient and provider participation in health care provision. PMID- 23457686 TI - Drugs for chronic pain in children: a commentary on clinical practice and the absence of evidence. AB - Pediatric chronic pain is widespread, under-recognized and undertreated. Best management usually involves a multimodal approach coordinated by a multidisciplinary team. The present commentary specifically discusses common pharmacological approaches to chronic pain in children, identifies gaps in knowledge and suggests several research directions that would benefit future clinical care. PMID- 23457688 TI - Primary care intervention for primary insomnia. PMID- 23457689 TI - A double-blind randomised controlled study of a brief intervention of bedtime restriction for adult patients with primary insomnia. AB - INTRODUCTION: Bedtime restriction is effective for volunteer patients with primary insomnia. AIM: To determine the effectiveness of bedtime restriction in adult volunteers with primary insomnia. METHODS: Patients were recruited in response to articles in local newspapers. The study hypothesis was not given in the articles. Patients were assessed as to whether or not they had primary insomnia. They completed a two-week sleep diary after which they met the investigators and were randomised to either bedtime restriction and basic sleep hygiene or the control group with basic sleep hygiene only. A total of 224 potential participants applied to be in the study. Of the 52 who had primary insomnia, 45 were randomly allocated to either control or intervention group and only two did not complete the study. Randomisation was concealed and participants were blinded regarding the treatment. The primary outcome was also measured in a blinded fashion. RESULTS: The outcome evaluated was patient description of 'better' or 'much better' quality of sleep versus the 'same', 'worse' or 'much worse' quality of sleep at six weeks. Overall, 73% (16/22) of those in the intervention group were either having better or much better quality of sleep after treatment, while in the control group this was 35% (8/23). The number needed to treat was 3 [95% CI 2-11] for bedtime restriction and sleep hygiene versus sleep hygiene alone. DISCUSSION: This is the first study using bedtime restriction designed to be feasible in primary care by using a brief intervention and a patient-oriented outcome. PMID- 23457690 TI - Forgone health care among secondary school students in New Zealand. AB - INTRODUCTION: Perceived lack of confidential health care is an important barrier for young people accessing health care services in New Zealand (NZ). AIM: To determine the prevalence of forgone health care among a nationally representative sample of NZ secondary school students and to describe the health concerns and specific health issues for which young people had difficulty accessing health care. METHODS: Random sample of 9107 NZ secondary school students participated in a 2007 health survey using internet tablets. Questions about access to health care included whether there had been a time when they had not accessed health care when needed, reasons for difficulty in accessing health care, current health concerns and health risk behaviours. RESULTS: One in six students (17%) had not seen a doctor or nurse when needed in the last 12 months. Female Maori and Pacific students and those living in neighbourhoods with high levels of deprivation were more likely to report forgone health care. Students with chronic health problems, those engaging in health risk behaviours or experiencing symptoms of depression were more likely to report being unable to access health care when needed. Students reporting privacy concerns were more likely to report difficulty accessing health care for sensitive health issues, such as sexual health, emotional problems, pregnancy-related issues, stopping cigarette smoking, or alcohol or drug use. DISCUSSION: NZ secondary school students who forgo health care are at increased risk of physical and mental health problems and in need of accessible and confidential health services. PMID- 23457691 TI - Characteristics of nurses providing diabetes community and outpatient care in Auckland. AB - INTRODUCTION: There is a worldwide trend for diabetes care to be undertaken in primary care. Nurses are expected to take a leading role in diabetes management, but their roles in primary care are unclear in New Zealand, as are the systems of care they work in as well as their training. AIM: To describe and compare demographic details, education and diabetes experience, practice setting and facilities available for the three main groups of primary health care nurses working in the largest urban area in New Zealand. METHOD: Of the total number of practice nurses, district nurses and specialist nurses working in Auckland (n=1091), 31% were randomly selected to undertake a self-administered questionnaire and telephone interview in 2006-2008. RESULTS: Overall response was 86% (n=284 self-administered questionnaires, n=287 telephone interviews). Almost half (43%) of primary care nurses were aged over 50 years. A greater proportion of specialist nurses (89%) and practice nurses (84%) had post-registration diabetes education compared with district nurses (65%, p=0.005), from a range of educational settings including workshops, workplaces, conferences and tertiary institutions. More district nurses (35%) and practice nurses (32%) had worked in their current workplace for >10 years compared with specialist nurses (14%, p=0.004). Over 20% of practice nurses and district nurses lacked access to the internet, and the latter group had the least administrative facilities and felt least valued. DISCUSSION: These findings highlight an ageing primary health care nursing workforce, lack of a national primary health care post-registration qualification and a lack of internet access. PMID- 23457692 TI - Could the polypill improve adherence? The patient perspective. AB - INTRODUCTION: Multiple medications are recommended for the management of ischaemic heart disease. Unfortunately, increasing the number of medicines reduces adherence to medicines therapy. The concept of a polypill with a fixed dose combination of the common cardiovascular medicines (aspirin, statin, two blood pressure-lowering medicines) has been promoted. Patient perceptions about this concept have not been explored. METHODS: People taking at least three cardiovascular medicines were interviewed using a semi-structured interview about their views on a polypill that could reduce the number of tablets they would need to take. FINDINGS: The participants considered that the polypill would be very convenient, especially when travelling and would reduce the pill burden. If the polypill was subsidised by the government, they would have reduced dispensing fee costs. There were concerns around the inflexibility of dosing of individual components of the polypill, and some concerns about safety and efficacy. Medical practitioners were identified as having an important role in influencing participants about the acceptability of the polypill. CONCLUSION: Generally the concept of the polypill was acceptable to participants, primarily because of the convenience and reduced number of tablets required daily. There were concerns about whether the polypill would be as effective and safe as the individual medicines. PMID- 23457693 TI - Exploring the opinions and perspectives of general practitioners towards the use of social networking sites for concussion management. AB - INTRODUCTION: Social networking sites (SNSs) are increasingly being used for health-related purposes. Many patients now use sites such as Facebook to discuss symptoms, seek support, and search for advice on health conditions, including concussion. Innovative methods of delivering health information using these technologies are starting to emerge and it is important to seek the input of key stakeholder groups (including general practitioners) to establish their feasibility and to highlight areas of concern. AIM: This study aimed to seek the opinions of general practitioners towards the use of SNSs in concussion management. METHODS: Semi-structured interviews were captured with a digital voice recorder and analysed using interpretative description methodology. Participants were general practitioners whose caseload included persons with a concussion between the ages of 16 and 30 years, and who had treated a patient with a concussion in the past 12 months. FINDINGS: The clinical experience of the participants ranged from 3 to 35 years and 50% of the participants had a Facebook account themselves. While all participants were positive towards the use of SNSs for this purpose, concerns were raised regarding the issues of privacy and moderation. CONCLUSION: SNSs, particularly Facebook, have the potential (if correctly utilised) to be a viable adjunct to traditional concussion management programmes. In order for SNSs to be successfully used in this manner, the quality of information shared needs to be accurate and patients using them need to ensure that they get adequate cognitive rest. PMID- 23457694 TI - Management of skin infections in Pacific children prior to hospitalisation. AB - INTRODUCTION: Hospital admissions for childhood skin infections in New Zealand (NZ) are on the increase. Pacific children make up a high number of those who are admitted. This study describes the parents of Pacific children's understanding and management of skin sores in the home prior to the sores becoming infected and requiring hospital admission. METHODS: A descriptive qualitative approach combined with the Pacific research frameworks of Fa'afaletui and the Metaphor of Kakala were used to elicit parents' understanding and management of children's skin sores in the home. The semi-structured interviews were conducted in English or Samoan, and all transcribed into English. FINDINGS: Mothers of 11 Pacific children admitted with skin infections between 2006 and 2008 were interviewed. The children's infections started with insect bites in some cases. Parents actively sought treatment to ensure children's optimal health was maintained. Initial management included a 'watch and see' approach for some, until deterioration was noted. CONCLUSION: This is the first known study in New Zealand that has captured children's experiences when sustaining a skin infection/s and the activities that took place while seeking treatment in the community. Although most of the children received medical attention in primary health care (PHC), this did not prevent the need for hospital admission. The acuteness and seriousness of children's health on admission shows that preventive efforts need to increase and the early management of infections in PHC settings needs to be better understood. PMID- 23457696 TI - General practitioners can offer effective nutrition care to patients with lifestyle-related chronic disease. AB - INTRODUCTION: Nutrition is a key priority for the management of lifestyle-related chronic disease, and the demand on general practitioners (GPs) to provide nutrition care is increasing. AIM: The aim of this systematic review was to investigate the effectiveness of nutrition care provided by GPs in improving the nutrition-related behaviour and subsequent health outcomes of individuals with lifestyle-related chronic disease. METHODS: A systematic literature review was conducted using the Cochrane Library, MEDLINE and ISI Web of Knowledge databases. Randomised controlled trials that investigated a nutrition care intervention feasible within general practice consultations, and that utilised outcome measures relevant to nutritionrelated behaviour or indicators of health, were included in the review. RESULTS: Of the 131 articles screened for inclusion, nine studies, totalling 9564 participants, were included in the review. Five interventions observed improvements in the nutrition behaviour of participants, such as a reduction of energy consumption, reduction of meat consumption, increase in fruit and vegetable intake, increase in fish intake and increase in fibre intake. Seven interventions observed improvements in risk factors, including in weight, serum lipid levels and blood pressure. Some inconsistencies in findings were observed in the reviewed studies. DISCUSSION: This systematic review demonstrates that GPs have the potential to provide nutrition care that improves the nutrition behaviour and risk factors in individuals with lifestyle related chronic disease. However, the consistency and clinical significance of the intervention outcomes are unclear. Further investigation regarding the development of nutrition care protocols and the attributes of nutrition care that result in improved outcomes are required. PMID- 23457695 TI - Interprofessional education for physiotherapy, medical and dietetics students: a pilot programme. AB - INTRODUCTION: Interprofessional education (IPE) has been shown to enhance interprofessional practice among health professionals. Until recently there has been limited opportunity to undertake such initiatives within existing pre registration degree courses in New Zealand. AIM: This study aimed to test the feasibility of delivering an interprofessional component within existing health professional courses for medicine, physiotherapy and dietetics at the University of Otago, Wellington, New Zealand. METHODS: An interprofessional case-based course component (on chronic condition management) was developed by academic clinical teachers from schools of medicine, physiotherapy and dietetics at the same location. Evaluation was undertaken using a previously validated pre- and post-survey tool, to ascertain changes in attitude among students towards interprofessional practice, IPE and the effectiveness of health care teams. Focus groups were conducted with students and teachers. RESULTS: Survey results indicated pre-existing positive attitudes to interprofessional practice and education among students. There was a statistically significant increase in positive attitude towards such practice and education, and increased confidence in the effectiveness of heath care teams. Focus group findings were consistent with the survey results for students, and highlighted challenges experienced by the teachers. DISCUSSION: Students and teachers alike enjoyed the interprofessional interaction and benefited from a collaborative approach to chronic condition management. The timing and nature of learning activities and assessment methods created logistical challenges. Such course components have potential to improve collaborative practice and the quality and safety of health care among graduates. Interprofessional course components need to be equitable across disciplines and embedded in the unidisciplinary courses. PMID- 23457697 TI - Assessing readiness to work in primary health care: the content validity of a self-check tool for physiotherapists and other health professionals. AB - INTRODUCTION: The New Zealand Primary Health Care Strategy has emphasised the importance of well-coordinated service teams in managing complex chronic conditions. There is international evidence that physiotherapists can contribute effectively to the prevention and management of these conditions. However, there are few examples of physiotherapists in New Zealand (NZ) engaging in primary health care (PHC). It has been recognised that professional development is necessary to optimise physiotherapists' participation in PHC. AIM: The aim of this study was to both design a self-check tool that physiotherapists could use as an initial step in preparing to work in PHC and to assess the content validity of the tool. METHODS: A literature review informed the development of the self check tool. The tool was reviewed by members of the Physiotherapy New Zealand PHC working party to establish content validity. RESULTS: The tool was found to have excellent content validity with an overall score of 0.937, exceeding the acceptable index of 0.8. Item validity was excellent or acceptable for all except two items, which were subsequently modified in the final tool. DISCUSSION: This investigation provides initial support for the tool's potential use by physiotherapists as a means of determining their readiness to work in PHC. It could have application beyond individual professional development to the wider context of team and organisational development. Additionally, with minor modifications the tool could have broader application to other professional groups. PMID- 23457698 TI - Medical professionalism requires that the best interest of the patient must always come first: yes. PMID- 23457699 TI - Medical professionalism requires that the best interest of the patient must always come first: no. PMID- 23457700 TI - Probiotics. PMID- 23457701 TI - Reporting suicide: safety isn't everything. PMID- 23457702 TI - Highly sensitive label-free fluorescent detection of Hg2+ ions by DNA molecular machine-based Ag nanoclusters. AB - We present here a highly selective and sensitive label-free method to detect Hg(2+) ions in aqueous solution by using DNA molecular machine-based fluorescent Ag nanoclusters (AgNCs). This mechanism is based on the Hg(2+) ions triggering machine-like operations of DNA and the "product" of the machine being used to stabilize fluorescent AgNCs. In this method, a tailored DNA, containing a sequence for Hg(2+) ions recognition, a sequence-specific nicking site for Nb BbvC I and a sequence complementary to the DNA as a template for the synthesis of fluorescent AgNCs, was firstly designed. In the presence of Hg(2+) ions, the machine's function operations were triggered. A series of machine-like operations, including replication, scission, and displacement then occurred with the addition of polymerase/dNTPs/Nb BbvC I, which manufactured lots of "product" DNA. The "product" DNA could act as a template for the preparation of fluorescent AgNCs. Thus the fluorescence of the AgNCs could be used as a signal transduction of this DNA machine, which was related to the concentration of the Hg(2+) ions. The repeated synthesis of the "product" and its template effect for AgNCs synthesis led to signal amplification in the assay of Hg(2+) ions. A linear response to the concentration of Hg(2+) ions was observed in the range from 0.08 nM to 20 nM and a detection limit of 0.08 nM was obtained. By contrast, the operation of the machine could not be executed in an Hg(2+) ion-free system. Moreover, the detection was not only label-free but also specific for Hg(2+) ions without being affected by other metal ions. PMID- 23457703 TI - A highly efficient PET switch on-off-on fluorescence receptor based on calix[4]arene for the selective recognition of Cd2+ and Sr2+. AB - A novel PET (photoinduced electron transfer) based substituted calix[4]arene fluoroionophore has been synthesized and used for the selective recognition of Cd(2+) and Sr(2+) by emission spectra. The detection limit of the synthesized receptor was found to be 0.94 pM for Cd(2+) and 1.04 pM for Sr(2+). Moreover, this probe has been applied to the recognition of Cd(2+) and Sr(2+) in waste water. PMID- 23457704 TI - Bionic radical generation and antioxidant capacity sensing with photocatalytic graphene oxide-titanium dioxide composites under visible light. AB - OH radicals as reactive oxygen species in an organism were applied to assay antioxidant capacity since the obtained results present high biological relevance. As a proper photocatalyst, titanium dioxide was employed to generate OH radicals under ultraviolet light irradiation. However, ultraviolet light can damage molecular probe (DNA or protein) during the detection of antioxidant capacity, which interferes with the results. In this article, a novel composite graphene oxide-titanium dioxide (GO-TiO2) nanostructure was synthesized, which can generate numerous OH radicals just under visible light irradiation. In addition, a novel electrochemical antioxidant capacity sensor was designed with GO-TiO2 composites as source of OH radicals and DNA as a molecular probe. Antioxidants were measured by using the suppression of the decline of reduction current of methylene blue used as an intercalating agent for DNA after irradiation and OH-mediated DNA damage. Using gallic acid (GA) as a mode antioxidant species, the detection of GA at levels as low as 0.85 mg L(-1) was possible. The antioxidant capacity of other antioxidants was also assayed. Finally, the novel sensor was applied to the determination of antioxidant capacity in tea. PMID- 23457705 TI - Non-destructive enhancement of latent fingerprints on stainless steel surfaces by electrochemiluminescence. AB - Visualization and detection of latent fingerprints (LFPs) on metal surfaces are of highly practical importance, e.g., in identifying gun cartridges. We report herein the visualization of LFPs on stainless steel surfaces by electrochemiluminescence (ECL). Since organic residues, such as fatty acids, in the fingerprint deposit make the underlying surface electrochemically inert or less active, an ECL reaction occurs only on the metal portions untouched by the fingertip, hence generating a negative image of the fingerprint. The popular ECL reaction solution, consisting of ruthenium(ii) tris(2,2'-bipyridyl) and tri-n propylamine, was used for this imaging purpose. Factors, including the applied potential and the concentration of ECL luminophore, as well as the stability of ECL negative images, were investigated to achieve a satisfactory visualization enhancement. This imaging approach is simple, rapid, non-invasive, and no pre treatment either on the background or on the fingerprint itself is needed. It constitutes a powerful tool for visualizing LFPs on metal surfaces. This method was also demonstrated to be suitable for enhancing LFPs collected from various surfaces. PMID- 23457706 TI - Cell electrospinning: a novel tool for functionalising fibres, scaffolds and membranes with living cells and other advanced materials for regenerative biology and medicine. AB - Recent years have seen interest in approaches for directly generating fibers and scaffolds following a rising trend for their exploration in the health sciences. In this review the author wishes to briefly highlight the many approaches explored to date for generating such structures, while underlining their advantages and disadvantages, and their contribution in particular to the biomedical sciences. Such structures have been demonstrated as having implications in both the laboratory and the clinic, as they mimic the native extra cellular matrix. Interestingly the only materials investigated until very recently for generating fibrous architectures employed either natural or synthetic polymers with or without the addition of functional molecule(s). Arguably although such constructs have been demonstrated to have many applications, they lack the one unit most important for carrying out the ability to directly reconstruct a three-dimensional functional tissue, namely living cells. Therefore recent findings have demonstrated the ability to directly form cell-laden fibers and scaffolds in useful quantities from which functional three dimensional living tissues can be conceived. These recent developments have far reaching ramifications to many areas of research and development, a few of which range from tissue engineering and regenerative medicine, a novel approach to analyzing cell behavior and function in real time in three-dimensions, to the advanced controlled and targeted delivery of experimental and/or medical cells and/or genes for localized treatment. At present these developments have passed all in vitro and in vivo mouse model based challenge trials and are now spearheading their journey towards initiating human clinical trials. PMID- 23457707 TI - Simple and disposable potentiometric sensors based on graphene or multi-walled carbon nanotubes--carbon-plastic potentiometric sensors. AB - A simple procedure leading to disposable potentiometric sensors using as a supporting electrode - electrical lead and transducer - a layer of carbon nanostructured material, either graphene or multi-walled nanotubes, is proposed, and the effect of the material used on the properties of the sensor is discussed. The obtained layers were partially covered with a conventional poly(vinyl chloride) (PVC) based ion-selective membrane to result in simple, planar, and disposable potentiometric sensors. The analytical performance of the thus obtained electrodes was compared with that of classical macroscopic all-solid state ion-selective electrodes (e.g. employing poly(octylthiophene) as a solid contact and a similar ion-selective membrane). It was superior (taking into account detection limits or selectivity towards Na(+) ions) compared to that of other disposable sensors proposed recently. The observed excellent analytical performance was attributed to the applied method of preparation of carbon nanostructured materials, which does not require addition of a surfactant to obtain a stable suspension (ink) used to prepare the electrical lead and the transducer of the sensor. Although the proposed sensors are predominantly intended for disposable use, pronounced stability of potential readings was obtained in within-day experiments. Moreover, due to their high conductivity carbon-plastic electrodes can be also applied in polarized potentiometric measurements. PMID- 23457708 TI - Dianthracene-cyclen conjugate: the first equal-equivalent responding fluorescent chemosensor for Pb2+ in aqueous solution. AB - A dianthracene-cyclen conjugate was synthesized via 'click' chemistry, which could serve as an equal-equivalent responding chemosensor for Pb(2+) in aqueous solution. Moreover, it could be successfully applied in the detection of Pb(2+) in living cells and fetal calf serum. PMID- 23457709 TI - Chitosan-capped silver nanoparticles as a highly selective colorimetric probe for visual detection of aromatic ortho-trihydroxy phenols. AB - We reported a new application of silver nanoparticles (NPs) for the visual sensing of aromatic polyphenols, such as gallic acid, pyrogallol and tannic acid, which is based on the intensified plasmon absorbance signals and visual changes from yellow to orange due to hydrogen-bonding recognition and subsequent catalytic oxidation of the target phenols by chitosan-capped Ag NPs (Ch-Ag NPs). The Ch-Ag NPs are generated by the well-known reaction of AgNO3 with NaBH4 and stabilized with chitosan which is a polysaccharide biopolymer with excellent dispersive properties and stability in aqueous media. After optimizing some experimental conditions, a very simple and facile sensing system has been developed for the detection of gallic acid, pyrogallol and tannic acid in water samples. The proposed system promises high selectivity toward gallic acid, pyrogallol and tannic acid, and other phenolic compounds including p-aminobenzoic acid, pentachlorophenol, 2,4,6-trinitrophenol, 2,4-dinitrophenol, p-nitrophenol, 1-naphthol, beta-naphthol, p-aminophenol, catechol, hydroquinone, m dihydroxybenzene, phloroglucin and phenol could not induce a color change even at 0.1 mM. The outstanding selectivity property of the proposed method for gallic acid, pyrogallol and tannic acid resulted from the Ch-Ag NPs-mediated reduction of Ag(+) by the target phenols. Also, a wide linear response range was obtained for the three targets. The linear response ranges for gallic acid, pyrogallol, and tannic acid were from 1 * 10(-5) to 1 * 10(-3) M, 1 * 10(-5) to 1 * 10(-2) M and 1 * 10(-6) to 1 * 10(-4) M with a respective detection limit (DL) of 1 * 10( 5), 1 * 10(-5), and 1 * 10(-6) M. The proposed method was successfully applied to detect target phenols in environmental water samples. Furthermore, because the color change from yellow to orange is observable by the naked eye, it is easy to realize visual detection of the target phenols without any instrumentation or complicated design. The experimental results reported here open up an innovative application of the catalytic reactivity of Ag NPs. PMID- 23457710 TI - Energy based pharmacophore mapping of HDAC inhibitors against class I HDAC enzymes. AB - Histone deacetylases (HDACs) are important class of enzymes that deacetylate the epsilon-amino group of the lysine residues in the histone tails to form a closed chromatin configuration resulting in the regulation of gene expression. Inhibition of these HDACs enzymes have been identified as one of the promising approaches for cancer treatment. The type-specific inhibition of class I HDAC enzymes is known to elicit improved therapeutic effects and thus, the search for promising type-specific HDAC inhibitors compunds remains an ongoing research interest in cancer drug discovery. Several different strategies are eployed to identify the features that could identify the isoform specificity factors in these HDAC enzymes. This study combines the insilico docking and energy-optomized pharmacophore (e-pharmacophore) mapping of several known HDACi's to identify the structural variants that are significant for the interactions against each of the four class I HDAC enzymes. Our hybrid approach shows that all the inhibitors with at least one aromatic ring in their linker regions hold higher affinities against target enzymes, while those without any aromatic rings remain as poor binders. We hypothesize the e-pharmacophore models for the HDACi's against all the four Class I HDAC enzymes which are not reported elsewhere. The results from this work will be useful in the rational design and virtual screening of more isoform specific HDACi's against the class I HDAC family of proteins. PMID- 23457711 TI - Key aromatic residues at subsites +2 and +3 of glycoside hydrolase family 31 alpha-glucosidase contribute to recognition of long-chain substrates. AB - Glycoside hydrolase family 31 alpha-glucosidases (31AGs) show various specificities for maltooligosaccharides according to chain length. Aspergillus niger alpha-glucosidase (ANG) is specific for short-chain substrates with the highest k(cat)/K(m) for maltotriose, while sugar beet alpha-glucosidase (SBG) prefers long-chain substrates and soluble starch. Multiple sequence alignment of 31AGs indicated a high degree of diversity at the long loop (N-loop), which forms one wall of the active pocket. Mutations of Phe236 in the N-loop of SBG (F236A/S) decreased k(cat)/K(m) values for substrates longer than maltose. Providing a phenylalanine residue at a similar position in ANG (T228F) altered the k(cat)/K(m) values for maltooligosaccharides compared with wild-type ANG, i.e., the mutant enzyme showed the highest k(cat)/K(m) value of maltotetraose. Subsite affinity analysis indicated that modification of subsite affinities at +2 and +3 caused alterations of substrate specificity in the mutant enzymes. These results indicated that the aromatic residue in the N-loop contributes to determining the chain-length specificity of 31AGs. PMID- 23457712 TI - Future prospects for pharmacogenetics in the quest for personalized medicine. AB - Understanding pharmacogenetic differences in drug response and tolerability has been an important area of research in personalized medicine, but the clinical utility of pharmacogenetics testing has not been established. Identification of genetic polymorphisms due to single nucleotide polymorphisms is the most common approach, but this does not take into account the potential relevance of copy number variants, noncoding RNA gene regulation, gene-gene and gene-interactions, and epigenetic modifications, which increase the complexity of pharmacogenomics research. PMID- 23457713 TI - Gender differences in adolescent depression. AB - Depression in adolescents is more common in girls; this gender disparity becomes more apparent during the teen years when girls have close to twice the rate of depression compared with boys. Vulnerability-stress models help explain these differences, and a tendency toward rumination may play a role both in the development and continuation of depressive symptoms. Psychiatric nursing interventions must focus on reappraisal of relationships, challenging rumination, and promoting autonomy. PMID- 23457714 TI - Innovative teaching strategy for pharmacology in psychiatric-mental health nursing: moving from content to concepts. AB - Faculty teaching an undergraduate psychiatricmental health nursing course noted that the vast content related to psychotropic medication interventions needed to be conceptualized creatively to help students develop expertise. In this article, an innovative pedagogical approach is presented for teaching nursing students psychopharmacology by moving from content to concepts. PMID- 23457715 TI - Code-51: keeping suicidal veterans safe in the emergency department. AB - Safety of suicidal veterans is a national issue. Veterans have a higher rate of depressive disorder than the general population, which puts them at higher risk for suicide. The staff in the emergency department (ED) of one Department of Veterans Affairs hospital developed and implemented an innovative process that increases the safety of suicidal veterans in the hospital setting. This process is called Code-51 and is similar to a military unit watch. This is one of the first unit watches implemented throughout an entire Veteran Affairs hospital, not only in the ED. The Code-51 process is a model for other EDs in both public and private sectors to help keep suicidal patients safe. PMID- 23457716 TI - Prevention of metabolic syndrome from atypical antipsychotic medications: applying Rogers' diffusion of innovations model in clinical practice. AB - Patients who are taking atypical antipsychotic medications have a high incidence of metabolic complications, including increased weight, waist circumference, blood sugar, lipid levels, and blood pressure. In 2004, the American Diabetic Association and three other associations, including the American Psychiatric Association, developed guidelines to screen for metabolic syndrome, but in practice, adherence to the guidelines varies. This article describes a process to implement the guidelines in a suburban psychiatric day treatment hospital using Rogers' Diffusion of Innovations model. Measurement of waist circumference was identified as an opportunity to improve the current metabolic screening protocol. Post-intervention evaluation revealed increased adherence to the guidelines (0% pre versus 95% post). Adherence to the guidelines demonstrates the effect of the systematic application of Rogers' model on acceptance of practice change. Fully implementing the guidelines meets recommendations for the standard of practice and can improve the health and quality of life of patients prescribed atypical antipsychotic medications. PMID- 23457717 TI - Retraction notice to "Surgical treatment of an amniotic fluid embolism with cardiopulmonary collapse" [Ann Thorac Surg 90 (2010) 1694-1696]. PMID- 23457718 TI - Protein targeting to subcellular organelles via MRNA localization. AB - Cells have complex membranous organelles for the compartmentalization and the regulation of most intracellular processes. Organelle biogenesis and maintenance requires newly synthesized proteins, each of which needs to go from the ribosome translating its mRNA to the correct membrane for insertion or transclocation to an a organellar subcompartment. Decades of research have revealed how proteins are targeted to the correct organelle and translocated across one or more organelle membranes ro the compartment where they function. The paradigm examples involve interactions between a peptide sequence in the protein, localization factors, and various membrane embedded translocation machineries. Membrane translocation is either cotranslational or posttranslational depending on the protein and target organelle. Meanwhile research in embryos, neurons and yeast revealed an alternative targeting mechanism in which the mRNA is localized and only then translated to synthesize the protein in the correct location. In these cases, the targeting information is coded by the cis-acting sequences in the mRNA ("Zipcodes") that interact with localization factors and, in many cases, are transported by the molecular motors on the cytoskeletal filaments. Recently, evidence has been found for this "mRNA based" mechanism in organelle protein targeting to endoplasmic reticulum, mitochondria, and the photosynthetic membranes within chloroplasts. Here we review known and potential roles of mRNA localization in protein targeting to and within organelles. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 23457719 TI - Retraction note: Dispersal of the radionuclide caesium-137 (137Cs) from point sources in the Barents and Norwegian Seas and its potential contamination of the Arctic marine food chain: coupling numerical ocean models with geographical fish distribution data [Environ. Pollut. 164 (2012) 1-10]. PMID- 23457720 TI - Beyond prejudice: relational inequality, collective action, and social change revisited. AB - This response clarifies, qualifies, and develops our critique of the limits of intergroup liking as a means of challenging intergroup inequality. It does not dispute that dominant groups may espouse negative attitudes towards subordinate groups. Nor does it dispute that prejudice reduction can be an effective way of tackling resulting forms of intergroup hostility. What it does dispute is the assumption that getting dominant group members and subordinate group members to like each other more is the best way of improving intergroup relations that are characterized by relatively stable, institutionally embedded, relations of inequality. In other words, the main target of our critique is the model of change that underlies prejudice reduction interventions and the mainstream concept of "prejudice" on which they are based. PMID- 23457721 TI - Increased gene expression of Toll-like receptor 4 on peripheral blood mononuclear cells in patients with psoriasis. AB - BACKGROUND: A role for the innate immune system in driving the autoimmune T cell cascade in psoriasis has been proposed. Toll-like receptors-(TLR)-2 and -4 play a role in inflammation, atherosclerosis, and their specific role in psoriasis remains unclear. OBJECTIVE: To evaluate TLR2 and TLR4 gene expression levels in peripheral blood mononuclear cells from psoriatic patients. METHODS: Changes in TLR2 / 4 gene expressions were evaluated using quantitative real-time reverse transcription polymerase chain reaction in peripheral blood mononuclear cells, from twenty-one patients with severe psoriasis, and analysed whether there was any correlation with cytokine plasma levels (T-helper 0-, T-helper 1-, T-helper 2 or regulatory T cells-type), or Calprotectin and with S100A8 and S100A9 gene expression levels. Eleven non-psoriatic healthy controls were analysed. RESULTS: A clear increase in TLR4 gene expression was observed (3.84 +/- 0.93, n = 21) together with a moderate increase in TLR2 expression (1.522 +/- 0.31, n = 21). Both TLR4 and TLR2 gene expressions were significantly augmented in psoriatic patients compared with controls (all P < 0.001). Correlations between TLR2 and S100A9 gene expressions (r = 0.5145, P = 0.0170, n = 21); and between TLR2 expression and plasma interleukin-2 (r = 0.5667, P = 0.0074); interleukin-4 (r = 0.4766, P = 0.0289), interleukin-10 (r = 0.4355, P = 0.0484) and interleukin-13 (r = 0.4603, P = 0.0358), were found. When patients with atheroma plaque were considered (n = 7), both TLR4 (3.47 +/- 0.99, P = 0.0156) and TLR2 (1.63 +/- 0.31, P = 0.0156) expressions were significantly increased vs. controls and correlated with plasma TNF-a (r = 0.8929, P = 0.0123, in both cases). CONCLUSION: Differential TLR4 / 2 gene expressions on psoriatic peripheral blood mononuclear cells and correlations with regulatory and / or proinflammatory cytokines and / or damage-associated molecular pattern molecule S100A9 emphasize innate immune response role in psoriasis. PMID- 23457722 TI - Preoperative skin tumours thickness determination by high-frequency ultrasound on head and neck region. AB - BACKGROUND: High-frequency ultrasound is non-invasive imaging method for examination of skin tumours. OBJECTIVE: The aim of our study was to examine validity of 20-MHz ultrasound in preoperative determination of skin tumour thickness localized on head and neck region as a potentially useful tool for planning of the surgical intervention. METHODS: Seventy-three different skin tumours were preoperatively examined using Dermascan C (Cortex Technology, Denmark) 20-MHz ultrasound equipment. Maximal vertical thickness of tumours was preoperatively determined by ultrasound, and after surgical excision of tumours, on pathohistological preparations using Nippon-Kogaku ocular micrometre. All patohistological specimens were controlled for presence of tumour cells on specimens' margins. RESULTS: Obtained correlation was very high, r = 0.82, without significant statistical difference (P < 0.01) between dimensions determined by 20-MHz ultrasound and histometry. There were no pathohistological specimens with tumours cells found on margins. CONCLUSION: Examination of skin tumours by 20-MHz ultrasound gives reliable additional information about tumour dimensions, sometimes important for therapeutic strategy. PMID- 23457723 TI - Insulin-like growth factor-I gene polymorphism in acne vulgaris. AB - BACKGROUND: Acne vulgaris is a multifactorial disease of the skin. Several studies have shown that elevated levels of serum insulin-like growth factor-I (IGF-I) correlate with overproduction of sebum and acne. Recently functional relationship between IGF-I (CA) polymorphism and circulating IGF-I levels in adults has been reported. AIMS: The aim of our study was to investigate for the first time whether IGF-I (CA) polymorphism might be involved in the pathogenesis of acne or not. METHODS: We included 115 acne patients and 117 healthy subjects to the study. The clinical grade of acne was assessed based on the Global Acne Grading System. Participants were questioned about diabetes mellitus, PCOS and other systemic disease. We searched for the IGF-I (CA) 19 polymorphism in this study. The IGF-I (CA) 19 polymorphism was performed by polymerase chain reaction. RESULTS: We categorized the IGF-I (CA) 19 polymorphism area into three groups as lower than 192 bp, 192-194 bp and higher than 194 bp. We found that the frequency of genotype IGF-1 (CA) 19 gene was significantly different between control and acne patients (P = 0.0002). A significant association between IGF-I (CA) genotypes and severity of acne was found (P = 0.015). No significant difference was found between male and female patients (P > 0.05). CONCLUSIONS: Our results suggest that IGF-I (CA) 19 polymorphism may contribute to a predisposition to acne in Turkish patients. PMID- 23457725 TI - How relevant is cost-effectiveness anyway? PMID- 23457724 TI - Response to letters regarding article, "High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease". PMID- 23457726 TI - Cocoa and cardiology: the defence counsel is still working hard. PMID- 23457727 TI - The sky's the limit. PMID- 23457728 TI - [Learning to search on the Web of Science: a reply to the Aluja, Becona, Botella, Colom, Echeburua, Forns, Perez and Vila (2011) study]. PMID- 23457729 TI - [Survey: Canadians underestimate the risk of hypertension and overestimate their efforts for hypertension prevention]. PMID- 23457730 TI - EHRs turning out to be not as wonderful as expected. PMID- 23457731 TI - Are we on the way to a real 'learning health care system'? PMID- 23457732 TI - [Autopsy of a fetus with Apert syndrome and review of the literature]. PMID- 23457734 TI - New Directive comes into force in the EU. PMID- 23457733 TI - Response. PMID- 23457735 TI - Response. PMID- 23457737 TI - Starting over: Leaving the violence in Iraq for a Penn dental medicine education. PMID- 23457736 TI - Exploring new ways to champion diversity. PMID- 23457738 TI - Exploring the link between oral health and systemic health. PMID- 23457739 TI - MoMed: second to one. Blowing our own horn. PMID- 23457740 TI - Telomeres, cancer & aging: live long & prosper? AB - Like our clothes, our chromosomes fray at the edges with age. Some believe that if we could discover a molecular tailor to patch our age-abraded chromosome ends, we could become modern Methuselahs. Notably, cancer cells achieve immortality by protecting their chromosome ends. Drugs that selectively fray the ends of cancer cell chromosomes would be potent and general anti-cancer therapies. Here, I summarize data on the role of chromosome ends in cellular and organismal aging. PMID- 23457741 TI - The lady doth protest too much, methinks. PMID- 23457742 TI - Can hospital-owned medical practices survive in the long run? PMID- 23457743 TI - Pirate or partner--is hospital employment right for you? PMID- 23457744 TI - Guiding principles for physicians entering into employment and contractual arrangements. PMID- 23457745 TI - Drivers of health care costs. A physicians foundation white paper--first of a three-part series. PMID- 23457746 TI - Be careful what you wish for. PMID- 23457747 TI - Be alert and engaged in the legislative process. PMID- 23457748 TI - Say what? Integrating hearing into an ophthalmology practice. AB - More people experience hearing loss than any other undiagnosed medical problem. Vision and hearing are our two most important senses. Your patients must see and hear sufficiently to maximize their quality of life; it makes sense to treat them together. This hearing testing program is part of your ophthalmology practice; effectively administering the program and delivering the message is what works. The patients are already in your office, i.e., same age demographic as for hearing loss. They and their family wish their ophthalmologist had a program to address their hearing related needs. They trust their ophthalmic physician. They know that they receive quality care. PMID- 23457749 TI - Hearing tests in ophthalmology offices? I don't like the sound of that! PMID- 23457750 TI - The 'middle hear'. Physicians must always serve as their patients' fiduciary with honesty & good faith. PMID- 23457751 TI - The Eye Handbook: a mobile app in ophthalmic medicine. PMID- 23457752 TI - Improving compliance with eye drop medications. PMID- 23457753 TI - I'm sorry, but I must object. PMID- 23457754 TI - Assessment of dangerousness in clinical practice. AB - Physicians, especially psychiatrists, face the daunting task of assessing the risk of dangerousness in clinical settings. This article reviews the research on mental illness and violence and identifies the specific psychiatric symptoms that have been associated with an increased risk of violence. PMID- 23457756 TI - Utilization of phase II cardiac rehabilitation in Veterans Administration patients. AB - Cardiac rehabilitation (CR) is underutilized across the United States. Reported national average varies from 14-35% after acute myocardial infraction and 31% after coronary artery bypass grafting surgery. No study to date has examined the utilization of CR in eligible veteran population. In this retrospective study, computerized veteran medical records at a single Veterans Administration (VA) hospital were screened between January 1, 2006 and December 31, 2009. Patients who met the inclusion and exclusion criteria were surveyed telephonically and asked a series of questions relating to delivery and utilization of phase II CR. Data was collected using a pre-printed questionnaire and patient responses were number coded. Utilization rate of phase II CR in veterans was noted to be 21%. Common reasons reported for underutilization of CR included time and distance problems, orthopedic- and stroke-related muscle weakness and lack of motivation. Participation in Phase II CR led to better adherence to exercise long term. Also, 65-70% of the veterans expressed interest in a tailored home based CR program. CR is underutilized in eligible veterans. Compliance could possibly be improved if the veterans were offered a tailored CR program. PMID- 23457755 TI - Matters of the heart: cardiovascular disease in U.S. women. AB - Cardiovascular disease is the leading cause of death in United States women and accounts for approximately 500,000 deaths annually. Over half of cardiovascular disease-related deaths in women result from coronary artery disease including acute coronary syndromes. This paper reviews gender specific issues in women as they relate to current cardiovascular disease epidemiology, trends in cardiovascular disease epidemiology, coronary artery disease detection, risk factor modification, and prevention of cardiovascular disease-related events. PMID- 23457757 TI - Pain management mini-series. Part I. A review of management of acute pain. AB - Acute pain is a complex process involving activation of nociceptors, chemical mediators and inflammation. Medications can be used to target each of the key elements within the pain pathway and eliminate or reduce the sensation of pain. Pain management begins, when possible, prior to the tissue trauma and continues throughout the perioperative period. When acute pain is appropriately managed, patient's clinical outcomes and satisfaction are improved. PMID- 23457758 TI - Infectious spondylodiscitis: diagnosis and treatment. AB - Infectious spondylodiscitis presents a diagnostic conundrum, and establishing the diagnosis often requires expensive testing and workup. But because of the potentially irreversible neurologic consequences and the great expense and time required to adequately treat this rare infection, establishing a diagnosis is paramount. Below, we present a representative case from clinical practice and examine the prevalence of certain signs and symptoms and the utility of various diagnostic modalities health care providers can use to accurately diagnose afflicted patients and avoid disastrous complications. PMID- 23457759 TI - News at Biochemia Medica: research integrity corner, updated guidelines to authors, revised author statement form and adopted ICMJE Conflict-of-Interest Form. AB - From the issue 23(1) we have implemented several major changes in the editorial policies and procedures. We hope that those changes will raise awareness of our potential authors and reviewers for research and publication integrity issues as well as to improve the quality of our submissions and published articles. Among those changes is the launch of a special journal section called Research Integrity Corner. In this section we aim to publish educational articles dealing with different research and publication misconduct issues. Moreover, we have done a comprehensive revision of our Instructions to authors. Whereas our former Instructions to authors have mostly been concerned with recommendations for manuscript preparation and submission, the revised document additionally describes the editorial procedure for all submitted articles and provides exact journal policies towards research integrity, authorship, copyright and conflict of interest. By putting these Guidelines into action, we hope that our main ethical policies and requirements are now visible and available to all our potential authors. We have also revised the former Authorship and copyright form which is now called the Author statement form. This form now contains statements on the authorship, originality of work, research ethics, patient privacy and confidentiality, and copyright transfer. Finally, Journal has adopted the ICMJE Form for Disclosure of Potential Conflicts of Interest. From this issue, for each submitted article, authors are requested to fill out the "ICMJE Form for Disclosure of Potential Conflicts of Interest" as well as the Author statement form and upload those forms during the online manuscript submission process. We honestly believe that our authors and readers will appreciate such endeavors. In this Editorial article we briefly explain the background and the nature of those recent major editorial changes. PMID- 23457760 TI - Redefinition of gestational diabetes mellitus: implications for laboratory practice in Croatia. AB - An increasing prevalence of gestational diabetes has become a very challenging task in prenatal care worldwide. International Association of Diabetes and Pregnancy Study Groups (IADPSG) has recently issued recommendations on the diagnosis and classification of hyperglycaemia in pregnancy. These recommendations, the first to provide harmonised, evidence-based criteria for the diagnosis and classification of diabetes in pregnancy, are currently being discussed and accepted worldwide by the relevant authorities. As the acceptance of the proposed criteria has major implications for both clinical and laboratory settings, a concerted action towards necessary changes in practice has to be carefully planned and adjusted to national health-care specificities. IADPSG criteria have been strongly advocated by the Croatian Perinatology Society, resulting in a new strategy for the detection and diagnosis of hyperglycaemic disorders in pregnancy. To address the respective laboratory requirements, in April 2012, the Croatian Chamber of Medical Biochemists appointed a Working Group to provide a standardised procedure for the diagnosis of gestational diabetes, applicable to all laboratories involved in prenatal care, in both primary and specialised health-care facilities. In this paper we discuss key laboratory related issues regarding succesful implementation of the IADPSG criteria in Croatia. PMID- 23457761 TI - Bias in research. AB - By writing scientific articles we communicate science among colleagues and peers. By doing this, it is our responsibility to adhere to some basic principles like transparency and accuracy. Authors, journal editors and reviewers need to be concerned about the quality of the work submitted for publication and ensure that only studies which have been designed, conducted and reported in a transparent way, honestly and without any deviation from the truth get to be published. Any such trend or deviation from the truth in data collection, analysis, interpretation and publication is called bias. Bias in research can occur either intentionally or unintentionally. Bias causes false conclusions and is potentially misleading. Therefore, it is immoral and unethical to conduct biased research. Every scientist should thus be aware of all potential sources of bias and undertake all possible actions to reduce or minimize the deviation from the truth. This article describes some basic issues related to bias in research. PMID- 23457762 TI - Patchwork plagiarism--a jigsaw of stolen puzzle pieces. AB - Plagiarism remains at the top in terms of interest to the scientific community. In its many vicious forms, patchwork plagiarism is characterized by numerous unresolved issues and often passes "below the radar" of editors and reviewers. The problem of detecting the complexity of misconduct has been partially resolved by plagiarism detection software. However, interpretation of relevant reports is not always obvious or easy. This article deals with plagiarism in general and patchwork plagiarism in particular, as well as related problems that editors must deal with to maintain the integrity of scientific journals. PMID- 23457763 TI - Preanalytical considerations in blood gas analysis. AB - Blood gas testing is a commonly ordered test in hospital settings, where the results almost always have the potential to dictate an immediate or urgent response. The preanalytical steps in testing, from choosing the correct tests to ensuring the specimen is introduced into the instrument correctly, must be perfectly coordinated to ensure that the patient receives appropriate and timely therapy in response to the analytical results. While many of the preanalytical steps in blood gas testing are common to all laboratory tests, such as accurate specimen labeling, some are unique to this testing because of the physicochemical properties of the analytes being measured. The common sources of preanalytical variation in blood gas testing are reviewed here. PMID- 23457764 TI - Serological markers of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory disorders of the gastrointestinal tract with two main distinguishable entities, Crohn's disease (CD) and ulcerative colitis (UC). IBD-unclassified (IBD-U) is a diagnosis that covers the "grey" zone of diagnostic uncertainty between UC and CD. Current diagnosis of IBD relies on the clinical, endoscopic, radiological, histological and biochemical features, but this approach has shortcomings especially in cases of overlapping symptoms of CD and UC. The need for a diagnostic tool that would improve the conventional methods in IBD diagnosis directed the search towards potential immunological markers, since an aberrant immune response against microbial or endogenous antigens in a genetically susceptible host seems to be implicated in IBD pathogenesis. The spectrum of antibodies to different microbial antigens and autoantibodies associated with IBD is rapidly expanding. Most of these antibodies are associated with CD like anti glycan antibodies: anti-Saccharomices cerevisiae (ASCA) and the recently described anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti mannobioside (AMCA), anti-laminarin (anti-L) and anti-chitin (anti-C) antibodies; in addition to other antibodies that target microbial antigens: anti-outer membrane porin C (anti-OmpC), anti-Cbir1 flagellin and anti-12 antibody. Also, autoantibodies targeting the exocrine pancreas (PAB) were shown to be highly specific for CD. In contrast, UC has been associated with anti-neutrophil cytoplasmic autoantibodies (pANCA) and antibodies against goblet cells (GAB). Current evidence suggests that serologic panels of multiple antibodies are useful in differential diagnosis of CD versus UC and can be a valuable aid in stratifying patients according to disease phenotype and risk of complications. PMID- 23457766 TI - Evaluation of sample hemolysis in blood collected by S-Monovette using vacuum or aspiration mode. AB - BACKGROUND: In vitro hemolysis can be induced by several biological and technical sources, and may be worsened by forced aspiration of blood in vacuum tubes. This study was aimed to compare the probability of hemolysis by drawing blood with a commercial evacuated blood collection tube, and S-Monovette used either in the "vacuum" or "aspiration" mode. MATERIALS AND METHODS: The study population consisted in 20 healthy volunteers. A sample was drawn into 4.0 mL BD Vacutainer serum tube from a vein of one upper arm. Two other samples were drawn with a second venipuncture from a vein of the opposite arm, into 4.0 mL S-Monovette serum tubes, by both vacuum an aspiration modes. After separation, serum potassium, lactate dehydrogenase (LD) and hemolysis index (HI) were tested on Beckman Coulter DxC. RESULTS: In no case the HI exceed the limit of significant hemolysis. As compared with BD Vacutainer, no significant differences were observed for potassium and LD using S-Monovette with vacuum method. Significant increased values of both parameters were however found in serum collected into BD Vacutainer and S-Monovette by vacuum mode, compared to serum drawn by S-Monovette in aspiration mode. The mean potassium bias was 2.2% versus BD Vacutainer and 2.4% versus S-Monovette in vacuum mode, that of LD was 2.7% versus BD Vacutainer and 2.1% versus S-Monovette in vacuum mode. None of these variations exceeded the allowable total error. CONCLUSIONS: Although no significant macro-hemolysis was observed with any collection system, the less chance of producing micro-hemolysis by S-Monovette in aspiration mode suggest that this device may be used when a difficult venipuncture combined with the vacuum may increase the probability of spurious hemolysis. PMID- 23457767 TI - The effect of storage time and freeze-thaw cycles on the stability of serum samples. AB - INTRODUCTION: Optimal storage of serum specimens in central laboratories for a long period for multicenter reference interval studies, or epidemiologic studies remains to be determined. We aimed to examine the analytical stability of chemistry analytes following numerous freeze-thaw and long-term storage. MATERIALS AND METHODS: Serum samples were obtained from 15 patients. Following baseline measurement, sera of each subject were aliquoted and stored at -20 degrees C for two experiments. A group of sera were kept frozen for up to 1, 2 and 3 months and then analyzed for stability. The other experiment consisted of one to ten times of freeze and thaw cycles. Total of 17 chemistry analytes were assayed at each time point. The results were compared with those obtained from the initial analysis of fresh samples. Median or mean changes from baseline (T(0)) concentrations were evaluated both statistically and clinically according to the desirable bias. RESULTS: Of the analytes studied, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), gamma-glutamyl transferase (GGT), direct bilirubin, glucose, creatinine, cholesterol, triglycerides, high density lipoprotein (HDL) were stable in all conditions. Blood urea nitrogen (BUN), uric acid, total protein, albumin, total bilirubin, calcium, lactate dehydrogenase (LD) were changed significantly (P < 0.005). CONCLUSIONS: As a result, common clinical chemistry analytes, with considering the variability of unstable analytes, showed adequote stability after 3 months of storage in sera at -20 degrees C, or up to ten times of freeze-thaw cycle. All the same, such analysis can only be performed for exceptional cases, and this should be taken into account while planning studies. PMID- 23457765 TI - Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts. AB - Bone and immune system are functionally interconnected. Immune and bone cells derive from same progenitors in the bone marrow, they share a common microenvironment and are being influenced by similar mediators. The evidence on increased bone resorption associated with inappropriate activation of T cells such as during inflammation, is well established. However, the molecular mechanisms beyond this clinical observation have begun to be intensively studied with the advancement of osteoimmunology. Now days, we have firm evidence on the influence of numerous proinflammatory cytokines on bone cells, with the majority of data focused on osteoclasts, the bone resorbing cells. It has been shown that some proinflammatory cytokines could possess osteoclastogenic and/or anti osteoclastogenic properties and can target osteoclasts directly or via receptor activator of nuclear factor kappaB (RANK)/RANK ligand(RANKL)/osteoprotegerin (OPG) system. Several studies have reported opposing data regarding (anti)osteoclastogenic properties of these cytokines. Therefore, the first part of this review is summarizing current evidence on the influence of pro inflammatory cytokines on osteoclasts and thus on bone resorption. In the second part, the evidence on the role of pro-inflammatory cytokines in osteoporosis and osteoarthritis is reviewed to show that unravelling the mechanisms beyond such complex bone diseases, is almost impossible without considering skeletal and immune systems as an indivisible integrated system. PMID- 23457768 TI - Glycogen phosphorylase isoenzyme BB in the diagnosis of acute myocardial infarction: a meta-analysis. AB - BACKGROUND: Early diagnosis is crucial for management of patients with suspected acute myocardial infarction (AMI). Among innovative and promising biomarkers, the recent interest raised on glycogen phosphorylase isoenzyme BB (GPBB) has prompted us to perform a meta-analysis of published studies. MATERIALS AND METHODS: A systematic electronic search was carried out on PubMed, Web of Science and Google Scholar, with no date restriction, to retrieve all articles that have investigated the early diagnostic performance of GPBB in patients with suspected AMI, and directly reported or allowed calculation of sensitivity and specificity. A meta-analysis of the reported sensitivity and specificity of each study and pooled area under the curve (AUC) was then performed by random effect approach. Heterogeneity was assessed by I-square statistics. RESULTS: Eight studies were finally selected for analysis (941 subjects; 506 cases and 435 controls), with a high heterogeneity (I-squared, 86.3%). The resulting pooled estimates and 95% confidence interval were 0.854 (0.801-0.891) for sensitivity, 0.767 (0.713-0.815) for specificity, 0.826 (0.774-0.870) for negative predictive value, 0.802 (0.754 0.844) for positive predictive value, and 0.754 (9.602-0.907) for AUC. In those studies that have simultaneously assessed GPBB and a troponin immunoassay, the combination of these biomarkers did not significantly improve the performance of troponin alone. CONCLUSION: GPBB does not meet the current requirements for an efficient diagnosis of AMI when used as a stand-alone test, whereas its combination with troponin merits further investigation in larger trials. PMID- 23457769 TI - The importance of having a flexible scope ISO 15189 accreditation and quality specifications based on biological variation--the case of validation of the biochemistry analyzer Dimension Vista. AB - INTRODUCTION: Technological innovation requires the laboratories to ensure that modifications or incorporations of new techniques do not alter the quality of their results. In an ISO 15189 accredited laboratory, flexible scope accreditation facilitates the inclusion of these changes prior to accreditation body evaluation. A strategy to perform the validation of a biochemistry analyzer in an accredited laboratory having a flexible scope is shown. MATERIALS AND METHODS: A validation procedure including the evaluation of imprecision and bias of two Dimension Vista analysers 1500 was conducted. Comparability of patient results between one of them and the lately replaced Dimension RxL Max was evaluated. All studies followed the respective Clinical and Laboratory Standards Institute (CLSI) protocols. 30 chemistry assays were studied. Coefficients of variation, percent bias and total error were calculated for all tests and biological variation was considered as acceptance criteria. Quality control material and patient samples were used as test materials. Interchangeability of the results was established by processing forty patients' samples in both devices. RESULTS: 27 of the 30 studied parameters met allowable performance criteria. Sodium, chloride and magnesium did not fulfil acceptance criteria. Evidence of interchangeability of patient results was obtained for all parameters except magnesium, NT-proBNP, cTroponin I and C-reactive protein. CONCLUSIONS: A laboratory having a well structured and documented validation procedure can opt to get a flexible scope of accreditation. In addition, performing these activities prior to use on patient samples may evidence technical issues which must be corrected to minimize their impact on patient results. PMID- 23457770 TI - Economic evaluation of different screening alternatives for patients with clinically suspected acute deep vein thrombosis. AB - INTRODUCTION: We examined the cost-effectiveness of the three different D-dimer measurements in the screening of DVT in models with and without calculation of pre-test probability (PTP) score. Moreover, we calculated the minimal cost in DVT detection. MATERIAL AND METHODS: In the group of 192 patients with clinically suspected acute DVT, we examined the three different D-dimer measurements (Innovance D-dimer, Hemosil D-dimer HS and Vidas D-dimer Exclusion II) in combination with and without PTP assessment. RESULTS: The diagnostic alternative employing Vidas D-dimer Exclusion II assay without and with PTP calculation gave lower incremental cost-effectiveness ratio (ICER) than the alternative employing Hemosil D-dimer HS assay (0.187 Euros vs. 0.998 Euros per one additional DVT positive patient selected for CUS in model without PTP assessment and 0.450 vs. 0.753 Euros per one DVT positive patient selected for CUS in model with PTP assessment). According to sensitivity analysis, the Hemosil D-dimer HS assay was the most cost effective alternative when one patient was admitted to the vascular ambulance per day. Vidas D-dimer Exclusion II assay was the most cost effective alternative when more than one patient were admitted to the vascular ambulance per day. Cost minimisation analysis indicated that selection of patients according to PTP score followed by D-dimer analysis decreases the cost of DVT diagnosis. CONCLUSIONS: ICER analysis enables laboratories to choose optimal laboratory tests according to number of patients admitted to laboratory. Results support the feasibility of using PTP scoring and D-dimer measurement before CUS examination in DVT screening. PMID- 23457771 TI - Increased plasma zonulin in patients with sepsis. AB - INTRODUCTION: Zonulin is a eukaryotic protein structurally similar to Vibrio cholerae's zonula occludens toxin. It plays an important role in the opening of small intestine tight junctions. The loss of gut wall integrity during sepsis might be pivotal and has been described in various experimental as well as human studies. Increased levels of zonulin could be demonstrated in diseases associated with increased intestinal inflammation, such as celiac disease and type 1 diabetes. We therefore investigated the role of plasma levels of zonulin in patients with sepsis as a non-invasive marker of gut wall integrity. MATERIALS AND METHODS: Plasma level of zonulin was measured in 25 patients with sepsis, severe sepsis or septic shock according to ACCP/SCCM criteria at the first day of diagnosed sepsis. 18 non-septic post-surgical ICU-patients and 20 healthy volunteers served as control. Plasma levels were determined by using commercially available ELISA kit. Data are given as median and interquartile range (IQR). RESULTS: Significantly higher plasma concentration of zonulin were found in the sepsis group: 6.61 ng/mL (IQR 3.51-9.46), as compared to the to the post-surgical control group: 3.40 ng/mL (IQR 2.14-5.70) (P = 0.025), as well as to the healthy group: 3.55 ng/mL (IQR 3.14-4.14) (P = 0.008). CONCLUSION: We were able demonstrate elevated levels of plasma zonulin, a potential marker of intestinal permeability in septic patients. Increased zonulin may serve as an additional mechanism for the observed increased intestinal permeability during sepsis and SIRS. PMID- 23457772 TI - Hepatitis during respiratory syncytial virus infection--a case report. AB - INTRODUCTION: Respiratory syncytial virus (RSV) infection is the most common cause of hospitalization in infants and small children. The aim was to present a 13-months old boy diagnosed with acute airway infection, acute otitis media (AOM) and hepatitis during the RSV-infection. MATERIAL AND METHODS: Serum catalytic activities of alkaline phosphatase (ALP), aspartate aminotranspherase (AST), alanine aminotranspherase (ALT), gamma glutamyl transpherase (GGT), lactate dehydrogenase (LD), and concentrations of bilirubin were monitored during hospitalization and at control examination. RESULTS: The child had clinical signs and symptoms of respiratory failure, AOM, and laboratory findings of virus infection and liver disease. On admission, catalytic activities of enzymes were markedly increased, especially the activity of ALP (10333 U/L, i.e. 24-fold increase in comparison with the upper reference limit). The highest increased in AST (339 U/L, 4.5-fold), ALT (475 U/L, 10.3-fold) and LD (545 U/L, 1.5-fold) were registered on the 3rd day, and the highest increase in GGT (68 U/L, 3.1-fold) occurred on the 11th day. Seven weeks after discharge AST, ALT, GGT and LD decreased into reference range, and ALP remain mildly increased (478 U/L, 1.1 fold increase). RSV was confirmed in nasal lavage fluid. CONCLUSION: Laboratory results in patient with RSV infection needs to be interpreted in the light of both, respiratory and extrapulmonary manifestations of the infection, respectively. PMID- 23457774 TI - [Childhood brain tumors]. AB - Brain tumors are the second most common pediatric neoplastic disease after leukemias. As causes of mortality and morbidity they add up to the most significant group of tumors. Treatment is based on thorough surgical excision of the tumor. Additional treatment with cytotoxic agents and radiotherapy is applied to malignant tumors. Treatment results have improved so that approximately three children out of four will make complete recovery from brain tumor. Long-term problems are, however, common and often significantly weakening the quality of life. PMID- 23457773 TI - [Maternal diabetes and fetal hypoxia]. AB - Perinatal mortality has not decreased in type 1 diabetic pregnancies during the last 30 years. Fetal deaths are five times and neonatal deaths three times higher compared with the general population. Chronic intrauterine hypoxia caused by maternal diabetes is the most likely cause of stillbirths during the last weeks of pregnancy. Both fetal hyperglycemia and hyperinsulinemia can independently cause fetal chronic hypoxia by increasing fetal oxygen consumption. Fetal chronic hypoxia can be detected antenatally by measuring amniotic fluid erythropoietin concentration. Prepregnancy visits for advice and glycemic control should be increased among diabetic women. Furthermore, pregnancy surveillance should be enhanced and therapeutic strategies changed in order to improve perinatal outcome among diabetic pregnancies. PMID- 23457775 TI - [Posterior variant of Alzheimer's disease and other atypical symptom pictures]. AB - Neuropathologically confirmed Alzheimer's disease may begin with symptoms other than memory problems, for instance visual perceptual disorders, difficulties in linguistic functions and expression in spoken language or executive functioning, occasionally even with behavioral symptoms. Among the forms of Alzheimer's disease appearing with atypical symptoms, the best know is the so-called posterior variant. The diagnosis is based on neuropsychological examination and findings in imaging. Additional diagnostic help is provided by the determination of markers for Alzheimer's disease in cerebrospinal fluid, as changes in markers correspond to the findings in traditional Alzheimer's disease. PMID- 23457776 TI - [Update on current care guidelines: spinal cord injury]. AB - Traumatic spinal cord injury is most common among men between 16 and 30 years. Prevention should be targeted both on traffic safety and individual behaviour Key issues in patient care are safe transfer from the place of injury to a hospital, diagnostic imaging (primarily CT, MRI if needed) and assessment of neurological injury by AIS-questionnaire, early surgical decompression and stabilisation for most cases, and treatment and rehabilitation starting from the emergency room and extending to life-long care carried out by a multi-professional team. PMID- 23457777 TI - [Treatment of acute ST-elevation myocardial infarction]. AB - The best treatment for acute ST-elevation myocardial infarction is an immediately performed balloon angioplasty. If is performed early enough, it reduces patient morbidity and results in significantly decreased mortality. The technique and instruments of this procedure have improved during the last few years, and the results have continued to become better. Properly conducted preventive drug therapy for coronary artery disease is also a prerequisite for good long-term results. Seamless collaboration between different units and logistic aspects are essential for getting the patients into medical care early enough. PMID- 23457778 TI - [Can strokes be prevented by cardiac catheterization procedures?]. AB - Most strokes associated with atrial fibrillation are caused by thrombi generated at the left auricle of the heart. Anticoagulation effectively prevents strokes associated with atrial fibrillation, but may in some patients cause severe bleeding complications that lead to cessation of therapy. Catheter closure of the left auricle of the heart is an effective but technically demanding treatment alternative in cases where severe bleedings prevent anticoagulation therapy and the patient carries a high risk of developing stroke. Some strokes of unknown origin may also be caused by a patent foramen ovale. PMID- 23457779 TI - [Percutaneous treatment of pulmonary artery stenoses]. AB - Pulmonary artery stenoses are a common problem in pediatric cardiology. They may interfere with the growth and development of the lung and cause pressure overload on the right heart and by increasing pulmonary arterial valvular insufficiency, also volume overload on the right ventricle. This may predispose the patient to cardiac failure, limitation of exercise tolerance and arrhythmias. Percutaneous treatment of pulmonary artery stenoses has undergone significant development over the last 20 years. Above all, the development of high pressure balloon catheters and stents has made treatment results better. PMID- 23457780 TI - [Treatment of valvular heart diseases with catheterization techniques]. AB - While valve surgery is an established form of treatment in significant valvular heart diseases, open heart surgery is not possible for all patients, owing to the risks involved. The incidence of valvular heart diseases increases sharply with age, and it is common that operative risks are overestimated due to age and associated diseases. This review deals with two catheter therapies that are in clinical use for valvular heart diseases: insertion of aortic valve prosthesis through a catheter and treatment of mitral valve insufficiency by clip implantation via the transvenous access. PMID- 23457781 TI - [Microbial production of chondroitin sulfate: a review]. AB - Chondroitin sulfate (CS) is the typical sulfation glycosaminoglycan and widely applied in the industries of pharmaceutical, health products and cosmetic for its peculiar properties. CS is the main component of cartilage proteoglycans in animal and capsular polysaccharide in a few bacteria. CS can be extracted from animal sources and produced via microbial fermentation. In this article, development of chondroitin sulfate by fermentation, biosynthesis and regulating mechanisms of CS in bacteria are described. Furthermore, prospect and tendency of chondroitin sulfate from bacterial fermentation are addressed. PMID- 23457782 TI - [Cloning and antimicrobial activity of pigeon avian beta-defensin 5]. AB - The objective of the study was to clone avian beta-defensin (AvBD) 5 gene from pigeon bone marrow tissues and liver tissues, to express the recombinant AvBD5 protein in E. coli, and to determine its antimicrobial activity. The mRNA of duck AvBD5 was cloned from pigeon bone marrow tissues and liver tissues by RT-PCR. In addition, phylogenetic relationships between amino acid sequence of the pigeon AvBD5, AvBDs from other avian species, and some mammalian beta-defensin-5 were analyzed. The cDNA of pigeon AvBD5 was sub-cloned into pGEX-6p-1 vector to construct recombinant plasmid pGEX-pigeon AvBD5. The recombinant protein was expressed into E. coli and purified. Antimicrobial activity and physical-chemical stability of the recombinant fusion protein were measured in vitro. The complete nucleotide sequence of both cDNAs contained 201 bp nucleotides, encoding a polypeptide of 66 amino acids. Both beta-defensins have six conserved cysteines. Phylogenetic relationships were analyzed. Both pigeon AvBDs shared the highest amino acid homology (87.9% and 78.8%) with duck AvBD5. So it was named as pigeon AvBD5alpha (bone marrow) and AvBD5beta (liver). Both recombinant plasmids were transformed into E. coli BL21 and the bacteria were induced with Isopropyl beta-D 1-Thiogalactopyranoside (IPTG). After purification, antibacterial activity of the purified was investigated. In addition, effect of ionic strength on the antibacterial activity, and hemolytic recombinant protein activity of the purified recombinant protein were investigated. A 32 kDa protein was highly expressed. Both purified recombinant pigeon AvBD5alpha and AvBD5beta exhibited extensive antimicrobial activities against 12 bacteria, including Gram-positive and Gram-negative. In high salt ions concentrations, antibacterial activity of both recombinant proteins was decreased. In addition, the hemolysis activity of recombinant protein was extremely low. PMID- 23457783 TI - [Effects of SREBP-1 over-expression on fatty acid metabolism related genes expression in goats]. AB - The aim of the study was to construct a recombinant adenovirus overexpression vector for Sterol Regulatory Element Binding Protein-1 (SREBP-1) of Xinong Saanen dairy goat, and to detect its effect on genes related to fatty acid metabolism in goat mammary epithelial cells, to establish foundation for further study of its roles in metabolism of fatty acid synthesis and lactation. First, we designed primers based on the SREBP-1 gene sequence in GenBank for PCR amplification and inserted the sequence into shuttle vector pAdTrack-CMV. The recombinant plasmid pAdTrack-CMV-SREBP-1 linearized by Pme I was transformed into E. coli BJ5183 competence cell containing the backbone vector pAdEasy-1 to obtain recombinant vector pAd-SREBP-1 by homologous recombination. pAd-SREBP-1 was linearized by Pac I and transfected into HEK 293 cell. Then we infected goat mammary epithelial cells with recombinant adenovirus which was packaged in HEK 293 cell line. The results showed that the recombinant adenovirus vector containing SREBP-1 was successfully constructed, and the titer of virus was 10(9) U/mL. Compared with the control group, mRNA level of SREBP-1 increased by about 15 times after infected for 48 h and 30 times after infected for 72 h. Fatty acid synthase (FASN) and Acetyl-CoA carboxylase (ACC) was upregulated by almost 2 times. The expression level of Peroxisome proliferator activated receptorgamma (PPARgamma) increased by 1.5 times. Liver X receptoralpha (LXRalpha) and Adipose triglyceride lipase (ATGL) upregulated by 1.2 times compared with that of control. But Stearoyl-coenzyme A desaturase (SCD) had no obvious change. In conclusion, SREBP 1 can activate the expression of genes related to fatty acid synthesis in mammary epithelial cells of Xinong Saanen dairy goat, demonstrated a regulatory function on the fatty acid metabolism in goat mammary gland. PMID- 23457784 TI - Generation and epitope mapping of a monoclonal antibody against nucleoprotein of Ebola virus. AB - Ebola virus (EBOV) causes highly lethal hemorrhagic fever in humans and nonhuman primates and has a significant impact on public health. The nucleoprotein (NP) of EBOV (EBOV-NP) plays a central role in virus replication and has been used as a target molecule for disease diagnosis. In this study, we generated a monoclonal antibody (MAb) against EBOV-NP and mapped the epitope motif required for recognition by the MAb. The MAb generated via immunization of mice with prokaryotically expressed recombinant NP of the Zaire Ebola virus (ZEBOV-NP) was specific to ZEBOV-NP and able to recognize ZEBOV-NP expressed in prokaryotic and eukaryotic cells. The MAb cross-reacted with the NP of the Reston Ebola virus (REBOV), the Cote-d'Ivoire Ebola virus (CIEBOV) and the Bundibugyo Ebola virus (BEBOV) but not with the NP of the Sudan Ebola virus (SEBOV) or the Marburg virus (MARV). The minimal epitope sequence required for recognition by the MAb was the motif PPLESD, which is located between amino acid residues 583 and 588 at the C terminus of ZEBOV-NP and well conserved among all 16 strains of ZEBOV, CIEBOV and BEBOV deposited in GenBank. The epitope motif is conserved in four out of five strains of REBOV. PMID- 23457785 TI - [Butanol pathway construction and promoter optimization in Escherichia coli]. AB - Promoter optimization is a useful tool in synthetic biology. Fusing promoters of various strengths to genes is a good method to get the best gene overexpression level. Butanol can be used as an intermediate in chemical synthesis and as a solvent for a wide variety of chemical and textile industry applications. At present, multiple metabolic engineering strategies have been attempted for butanol production in non-native host Escherichia coli. But there were little work on promoter optimization. We fused thlA (thiolase) with strong promoter Alper PLTetO1 or weak promoter Alper BB, operon with strong promoter Braatsch 20 or weak promoter Braatsch 10 by fast assemble method DNA assembler in Escherichia coli. The experimental results showed thlA with strong promoter Alper PLTetO1, operon with weak promoter Braatsch 10 got best butanol concentration 28 mg/L, which increased at least 3-5 fold compared with other combination. PMID- 23457786 TI - [Isolation of high osmotic-tolerant mutants of Escherichia coli for succinic acid production by metabolic evolution]. AB - Succinic acid production was inhibited by high osmotic pressure caused by the accumulation of sodium ions in the process of two-stage fermentation by Escherichia coli using Na2CO3 as the pH regulator. To enhance the resistance of this strain to osmotic stress, the possibility to isolate high NaCl-tolerant mutant strain of Escherichia coli for succinic acid production by metabolic evolution was investigated. The metabolic evolution system was used as a mutant generating system, allowing the cells to be continuously cultured at the maximum specific growth rate. The mutant strain can grow at maximum rate in the condition of high osmotic by gradually improving the concentration of NaCl in a continuous culture. Then the high osmotic-tolerant mutant strain of E. coli XB4 was selected with NaCl as the osmo-regulator. When using Na2CO3 as the pH regulator, E. coli XB4 was used in a 7.0 L fermenter during two-stage fermentation. After 60 h anaerobic fermentation, the mutant strain XB4 produced 69.5 g/L succinic acid with a productivity of 1.18 g/(L x h), which were increased by 18.6% and 20% compared with that of the parent strain. PMID- 23457787 TI - [Asymmetric synthesis of aromatic L-amino acids catalyzed by transaminase]. AB - Aromatic L-Amino acids are important chiral building blocks for the synthesis of many drugs, pesticides, fine chemicals and food additives. Due to the high activity and steroselectivity, enzymatic synthesis of chiral building blocks has become the main research direction in asymmetric synthesis field. Guided by the phylogenetic analysis of transaminases from different sources, two representative aromatic transaminases TyrB and Aro8 in type I subfamily, from the prokaryote Escherichia coli and eukaryote Saccharomyces cerevisia, respectively, were applied for the comparative study of asymmetric transamination reaction process and catalytic efficiency of reversely converting keto acids to the corresponding aromatic L-amino acid. Both TyrB and Aro8 could efficiently synthesize the natural aromatic amino acids phenylalanine and tyrosine as well as non-natural amino acid phenylglycine. The chiral HPLC analysis showed the produced amino acids were L-configuration and the e.e value was 100%. L-alanine was the optimal amino donor, and the transaminase TyrB and Aro8 could not use D-amino acids as amino donor. The optimal molar ratio of amino donor (L-alanine) and amino acceptor (aromatic alpha-keto acids) was 4:1. Both of the substituted group on the aromatic ring and the length of fatty acid carbon chain part in the molecular structure of aromatic substrate alpha-keto acid have the significant impact on the enzyme-catalyzed transamination efficiency. In the experiments of preparative scale transamination synthesis of L-phenylglycine, L-phenylalanine and L tyrosine, the specific production rate catalyzed by TryB were 0.28 g/(g x h), 0.31 g/(g x h) and 0.60 g/(g x h) and the specific production rate catalyzed by Aro8 were 0.61 g/(g x h), 0.48 g/(g x h) and 0.59 g/(g x h). The results obtained here were useful for applying the transaminases to asymmetric synthesis of L amino acids by reversing the reaction balance in industry. PMID- 23457788 TI - [Effects of calcium on synthesis of rosmarinic acid and related enzymes in suspension cultures of Salvia miltiorrhiza]. AB - We studied the influence of the concentration of Ca2+ (0-50 mmol/L) in culture medium on the synthesis of rosmarinic acid (RA) and related enzymes in Salvia miltiorrhiza suspension cultures. Using verpamil (VP, a calcium channel antagonist) and ionophore A23187, we studied the mechanism of secondary metabolites of Salvia miltiorrhiza suspension cultures influenced by the concentration of Ca2+ in the culture medium. The synthesis of intracellular RA in 6-day incubation was significantly dependent on the medium Ca2+ concentration. At the optimal Ca2+ concentration of 10 mmol/L, a maximal RA content of 20.149 mg/g biomass dry weight was reached, which was about 37.3% and 20.4% higher than that at Ca2+ concentrations of 1 and 3 mmol/L, respectively. The variation of the activity of PAL and TAT, two key enzymes of the two branches of RA, could be affected by the concentration of Ca2+ in culture medium. The change of their activity occurred prior to the accumulation of RA, which suggested both of the key enzymes be involved in the synthesis of RA. Meanwhile, the enzymatic action of PAL was more distinct than TAT. The treatment of VP and A23187, respectively, indicated that the influence of RA affected by the concentration of Ca2+ in the culture medium was accomplished by the intracellular Ca2+, and the flow of Ca2+ from the extracellular to the intracellular environment could also participate in this process. PMID- 23457789 TI - [Two conformations of pHLA-A*2402: a supplement to Wolynes' theory]. AB - Wolynes argued that the track of a protein's folding was directed by the tendency of lowering its energy, and thus when a local minimum of its energy was reached, a relatively stable conformation was formed. However not all of the local minimums will lead the protein to a biologically useful conformation, for those otherwise are called energy traps. Wolynes energy landscape theory and natural selection have well explained the high efficiency of protein folding in vivo, instead of being stuck in energy traps. As to whether a protein can assume different conformations with the same bioactivity, there is no clear answer yet. In this paper, two conformational states of a pHLA-A*2402 are discovered after refolding, and by studying their interactions with TCR and CD8alphaalpha, two conformations of pHLA-A*2402 are confirmed of having escaped from natural selection. PMID- 23457790 TI - [Membrane protein characterization by photoactivatable localization microscopy]. AB - The on-site labeling and localization tracking of membrane proteins in pathogenic bacteria are tedious work. In order to develop a novel protein labeling technology at super resolution level (nanometer scale) using the photoactivatable localization microscopy (PALM), the chimeric protein of the outer membrane protein A (OmpA) of Mycobacterium tuberculosis and the photoactivatable mEos2m protein were expressed in the non-pathogenic Mycobacterium smegmatis. The recombinant bacteria were fixed on slide, activated by 405 nm laser and subject to PALM imaging to capture photons released by the fusion protein. Meanwhile, colony and cell morphology were visualized under regular fluorescent stereomicroscope and upright fluorescent microscope to characterize fluorescence conversion and protein localization. The fusion proteins formed a "belt"-like structure on cell membrane of M. smegmatis under PALM, providing direct evidence of on-site imaging of membrane proteins. Expression of fusion protein did not compromise the localization properties of OmpA. Thus, mEos2m could be used as a labeling probe to track localizations of non-oligomer oriented membrane proteins. This indicates non-pathogenic M. smegmatis could be served as a model strain to characterize the function and localization of the proteins derived from pathogenic M. tuberculosis. This is the first report using PALM to characterize localization of membrane proteins. PMID- 23457791 TI - [Prokaryotic expression, purification and enzymatic properties of nuclease P1]. AB - To establish a prokaryotic expression and purification protocol for nuclease P1 (NP1), we first obtained a synthetic NP1 by splicing 22 oligonucleotides with overlapping PCR. We constructed and transformed a secretory expression vector pMAL-p4X-NP1 into Escherichia coli host strains T7 Express and Origami B (DE3) separately. Then, the recombinant NP1 was purified by amylose affinity chromatography, and its activity, thermo-stability and metal-ion dependence were investigated systematically. The results indicated that the expressed fusion proteins MBP-NP1 (Maltose binding protein-NP1) existed mainly in soluble form both in host strains T7 Express and Origami B (DE3), but the specific activity of recombinant protein from Origami B(DE3) strain was higher than T7 Express strain (75.48 U/mg : 51.50 U/mg). When the MBP-tag was cleaved by protease Factor Xa, the specific activity both increased up to 258.1 U/mg and 139.2 U/mg. The thermal inactivation experiments demonstrated that the recombinant NP1 was quite stable, and it retained more than 90% of original activity after incubated for 30 min at 80 degrees C. Zn2+ (2.0 mmol/L) could increase enzyme activity (to 119.1%), on the contrary, the enzyme activity was reduced by 2.0 mmol/L Cu2+ (to 63.12%). This research realized the functional expression of NP1 in the prokaryotic system for the first time, and provided an alternative pathway for NP1 preparation. PMID- 23457792 TI - [Norovirus epidemic strain GII. 4 evolution--a review]. AB - Noroviruses are regarded as the leading cause of epidemic gastroenteritis all over the world, with a wealth of genetic diversity. And GII. 4 is regarded as the predominant strain, which has constantly infected humans attributed to a fast rate of evolution in the past two decades. With the discovery of virus binding receptor and understanding of immune specificity, the research of evolution mechanism of the virus has been continuously developed recently. It has been hypothesized that the receptor switching and antigenic drift maintains GII. 4 persistence in human populations. Also the RNA viruses, high mutation rate and the limited space of genomic variation have also affected the direction of norovirus evolution. PMID- 23457793 TI - [Biodiversity of Rhizobia associated with Acacia melanoxylon grown in South China]. AB - OBJECTIVE: This study aimed to investigate the genetic diversity of 174 isolates of symbiotic bacteria associated with Acacia melanoxylon obtained from 15 sampling sites in Guangdong, Fujian and Jiangxi provinces of China. METHODS: The 16S rDNA restriction fragment length polymorphism (RFLP) and phylogenetic analyses of the 16S rDNA and housekeeping genes (recA, glnII and atpD). RESULTS: In the 16S rDNA PCR-RFLP analysis, 9 rDNA types were identified among the 174 isolates; Phylogenetic analyses based on 16S rDNA and housekeeping gene sequences indicated that 34 representative isolates belonged to the genus Bradyrhizobium, Rhizobium, Mesorhizobium in Alpha-Proteobacteria, and the most closely related strains are Bradyrhizobium liaoningense, Bradyrhizobium betae, Bradyrhizobium cytisi, Rhizobium multihospitium and Mesorhizobium plurifarium. CONCLUSION: All of the isolates could be identified to general, and Bradyrhizobium, Rhizobium or Mesorhizobium could be the dominant microsymbiont. The microsymbionts associated with Acacia melanoxylon showed relative genetic diversity. PMID- 23457794 TI - Agrobacterium tumefaciens-mediated transformation as a tool for insertional mutagenesis in thermophilic fungus Thermomyces lanuginosus. AB - OBJECTIVE: To establish a stable transformation system of the thermophilic fungus Thermomyces lanuginosus for its insertional mutagenesis. METHODS: Agrobacterium tumefaciens-mediated transformation (ATMT) was applied to establish transformation system of T. lanuginosus. Southern blotting of hph gene and cloning of transforming DNA (T-DNA) flanking sequences were used to determine insert number and site of T-DNA in the fungal genome, respectively. RESULTS: A reliable transformation method is established for T. lanuginosus. Specifically, pre-germinating spores of T. lanuginosus used at co-cultivated period was a prerequisite. T. lanuginosus germinating spores co-cultivated with Agrobacterium tumefaciens at 28 degrees C for 48 h achieved the highest transformation efficiency. Addition of Acetosyringone (AS) during pre-culture of A. tumefaciens and co-cultivation of T. lanuginosus germinating spores with A. tumefaciens was essentially required, and the best results were obtained with AS at the concentration of 500 microM. Southern blotting analysis showed that majority of transformants (79.2%) contained a single insertion of T-DNA. Thermal asymmetric interlaced PCR (TAIL-PCR) analysis showed random insertion of T-DNA in the fungal genome. Using the transformation system, some stable phenotypic mutants of T. lanuginosus were obtained. CONCLUSION: We report, for the first time, a simple and efficient method for transforming T. lanuginosus by using ATMT. This approach provides a tool for insertional mutagenesis gene tagging in this thermophilic fungus. PMID- 23457795 TI - [Function of transporter genes fscTI and fscTII in the biosynthetic cluster of candicidin/FR-008]. AB - OBJECTIVE To investigate function of transporter genes fscTI and fscTII in the biosynthetic gene cluster of candicidin/FR-008. METHODS: We constructed a plasmid pJTU4137 for disruption of transporter genes fscTI and fscTII by conjugation and homologous recombinant. The transporter genes were also PCR amplified and cloned into the high-copy plasmid pJTU1278 for overexpression in strain ZYJ-6 derived from Streptomyces sp. FR-008. RESULTS: The disruption mutant LX10 was unable to produce candicidin and its analogues. Overexpression of FscTI and FscTII in ZYJ-6 caused a 1.5-fold increase in FR-008-III production compared with the control. CONCLUSION: We confirmed that fscTI and fscTII are function as ATP dependent ATP binding cassetle (ABC) transporters in the biosynthetic gene cluster of FR-008. Furthermore, a positive example was provided for improving antibiotic production in other polyene producing strains based on the results that overexpression of fscTI and fscTI increased candicidin production. PMID- 23457796 TI - [Asparaginase mediated acid adaptation of mycobacteria]. AB - OBJECTIVE: Mycobacterium tuberculosis can survive inside host cells for a long time. To elucidate the acid adaptation mechanism mediated by the asparagine (Asn) metabolic pathway, the activity of asparaginase (AnsA) and growth of mycobacteria were characterized. METHODS: The nonpathogenic M. bovis BCG was used as a model strain to characterize AnsA function. The recombinant AnsA was further expressed in E. coli, purified by Co2+ charged resin, and analyzed by enzymatic method. M. bovis BCG mutant (DansA) was constructed by homologous recombination. The growth and ammonia generation by M. bovis BCG wild type and mutant were evaluated in acidic medium. RESULTS: Ammonia was detected in the presence of AnsA and Asn. Deletion of ansA significantly delayed the growth of M. bovis BCG for 10 days in acidic medium. Asn was used by M. bovis BCG to produce ammonia, increasing pH. CONCLUSION: The acid adaptation of M. bovis BCG was mediated by ammonia, the metabolic product of asparagine. This provides new clue to uncover the survival mechanism of M. tuberculosis inside the acidic niche environment of host macrophage. PMID- 23457797 TI - [Influence of incubation time on metabolites in mycelia of Paecilomyces militaris]. AB - OBJECTIVE: To determine the secondary metabolites production in mycelia of Paecilomyces militaris. METHODS: Mycelia were cultured in plates with sabouraud dextrose agar yeast medium at 25 degrees C for 9 days. Sampling was done every day from the second to the ninth day. The secondary metabolites in the mycelia of Paecilomyces militaris were extracted with either methanol or ethyl acetate. The extracts were blended and analyzed by liquid chromatography-mass spectrometry (LC MS). LC-MS data were collected and analyzed by MetaboAnalyst software. RESULT: Principal component analysis indicates different secondary metabolites accumulation with incubation times. Hierarchical clustering analysis shows that the metabolic process of cationic compounds such as alkaloids, peptides and nucleosides can be divided into three stages, and that the metabolic process of anionic compounds such as organic acids and saccharides can be divided into two stages. Metabolites difference and heat map analysis show that: (1) The number of metabolites with significant increased contents was raised significantly in mycelia of Paecilomyces militaris on the second and third incubation days. The main species with increased contents were esters and their hydrolized products, destruxin B, variotin and some unidentified nitrogin contained compounds. (2) The number of metabolites with significant raised contents was decreased significantly on the fourth and fifth incubation days. The main species with increased contents were ophiocordin and destruxin A. (3) Apart from peptide antibiotics such as several beauverolides, the content increased metabolites included also several organic acids, amino acids, rhamnose, trehalose, cerebroside and riboflavine during the sixth to ninth incubation days. CONCLUSION: The secondary metabolites in mycelia of Paecilomyces militaris were related significantly to the incubation time. PMID- 23457798 TI - [Bacterial diversity of different successional stage forest soils in Dinghushan]. AB - OBJECTIVE: The aim of the present study was to investigate the soil bacterial diversity of pine forest (PF), pine-broadleaf mixed forest (MF) and monsoon evergreen broadleaf forest (MEBF), the typical forest types that represent early, middle and late successional stage forests in Dinghushan, respectively. The results obtained will also provide information for further examination of the relationship between the soil bacterial diversity and ecological function of the forests. METHOD: Three total DNA samples were extracted directly from soil samples collected from PF, MF and MEBF, and then the 16S rDNA sequences were PCR amplified and the libraries were constructed, respectively. For each of the three libraries constructed, 150 positive clones were picked randomly and the inserted 16S rDNA were sequenced. The soil bacterial diversity of the forests was analyzed by Mothur based on the sequences obtained. RESULT: A total of 122, 118 and 120 valid 16S rDNA sequences were obtained from PF, MF and MEBF, which represented 70, 64 and 72 operational taxonomic units (OTUs, definition at a level of 97% similarity), respectively. Bacteria belonging to 8 phyla were identified. Among them, Acidobacteria accounted for 53.3%, 67.8% and 60%, while Proteobacteria took up 29.5%, 20.3% and 32.5% in PF, MF and MEBF, respectively. The other bacterial phyla identified each accounted for less than 10%. The bacterial community structure differed significantly at species level among three soil samples (P < 0.05) with the percentages of the shared OTUs between any two soil samples lower than 25%. MEBF had the highest Chao index (414.2), Shannon index (3.90) and the lowest Simpson dominance index (0.0249). CONCLUSION: The soil bacterial community structure differed significantly at species level among PF, MF and MEBF in Dinghushan, while they have a similar structure at phyla or class levels with Acidobacteria predominated followed by Proteobacteria. PMID- 23457799 TI - [Arsenic metabolism in purple nonsulfur bacteria]. AB - OBJECTIVE: To elucidate the arsenic metabolic pathway of purple nonsulfur bacteria (PNSB). METHODS: We investigated the distribution within their genomes, organization, composition, arrangement, core genes and coding proteins of arsenic gene clusters found in complete genome from 17 strains of PNSB by comparing the genomes analysis, and studied the arsenic metabolism in 3 members of PNSB under anaerobic conditions by UV-Vis and HPLC-ICP-MS. RESULTS: Arsenate reduction and arsenite methylation pathways mediated by ars operon are the dominating arsenic metabolic processes. The arsenic gene clusters differ vastly in composition and arrangement. Some members of PNSB evolved two independently families of arsenate reduction genes (arsC). The cells of Rhodopseudomonas palustris CQV97, Rhodobacter azotoformans 134K20 and Rhodobacter capsulatus XJ-1 could reduce As (V) to As (III), whereas As (III) could not be transformed back to As (V). Higher concentration phosphate competitively inhibited arsenate toxicity to cells. CONCLUSION: Our investigations shed light on the evolution and functional implications in arsenic gene clusters of PNSB, and support the notion that arsenate reduction and arsenite methylation appears to be the dominant process in PNSB. PMID- 23457800 TI - [Protective immune responses induced by a recombinant Listeria monocytogenes delivering HPV16 E7]. AB - OBJECTIVE: To investigate specific immune responses elicited by a recombinant Listeria monocytogenes strain LM4 deltahly::E7 and assess protective effect in C57BL/6 mice. METHODS: C57BL/6 mice were intraperitoneally immunized with LM4 deltahly:: E7 at 1-week intervals. After the second immunization, cellular immunity elicited by this recombinant L. monocytogenes strain was analyzed via an ELISPOT assay, Cytotoxic T lymphocytes (CTL) measurement assay and analysis of effector T cells proportion in the splenocytes. Also, the serum antibodies against HPV16 E7 protein were determined in an ELISA assay. Finally, protective effect was assessed against the challenge with TC-1 tumor cells. RESULTS: The immune responses elicited by LM4 deltahly::E7 were biased towards Th1 type in the ELISPOT assay. Also, LM4 deltahly::E7 was able to induce E7-specific CTL activity, with average specific lysis of 72%, which was highly significant difference compared with the controls (P<0.01). Moreover, the proportion of effector T cells in the spleens were increased in mice immunized with recombinant L. monocytogenes strain (P<0.05). The titer of E7-specific antibodies in mice immunized with LM4 delta hly::E7 was 1:400 in the ELISA assay. Furthermore, immunization with LM deltahly::E7 protected all mice against the lethal tumor cell challenge. CONCLUSION: The data suggest that attenuated Listeria monocytogenes delivering HPV16 E7 antigen could induce both E7-specific cell mediated immunity and humoral immunity, and had a protective effect against challenge with TC-1 tumor cells. PMID- 23457801 TI - [Establishment and application of a Vero cell line stably expressing raccoon dog SLAM, the cellular receptor of canine distemper virus]. AB - OBJECTIVE: The signaling lymphocyte activation molecule (SLAM, also known as CD150), is used as a cellular receptor by canine distemper virus (CDV). Wild-type strains of CDVs can be isolated and propagated efficiently in non-lymphoid cells expressing this protein. Our aim is to establish a Vero cells expressing raccoon dog SLAM (rSLAM) to efficiently isolate CDV from pathological samples. METHODS: A eukaryotic expression plasmid, pIRES2-EGFP-rSLAMhis, containing rSLAM gene fused with six histidine-coding sequence, EGFP gene, and neomycin resistance gene was constructed. After transfection with the plasmid, a stable cell line, Vero-rSLAM, was screened from Vero cells with the identification of EGFP reporter and G418 resistance. Three CD positive specimens from infected foxes and raccoon dogs were inoculated to Vero-rSLAM cells for CDV isolation. Foxes and raccoon dogs were inoculated subcutaneously LN (10)fl strain with 4 x 10(2.39)TCID50 dose to evaluate pathogenicity of CDV isolations. RESULTS: The rSLAMh fused gene was shown to transcript and express stably in Vero-rSLAM cells by RT-PCR and Immunohistochemistry assay. Three CDV strains were isolated successfully in Vero rSLAM cells 36 -48 hours after inoculation with spleen or lung specimens from foxes and raccoon dogs with distemper. By contrast, no CDV was recovered from those CD positive specimens when Vero cells were used for virus isolation. Infected foxes and raccoon dogs with LN(10)f1 strain all showed typical CD symptoms and high mortality (2/3 for foxes and 3/3 for raccoon dogs) in 22 days post challenge. CONCLUSION: Our results indicate that Vero-rSLAM cells stably expressing raccoon dog SLAM are highly sensitive to CDV in clinical specimens and the CDV isolation can maintain high virulence to its host animals. PMID- 23457802 TI - [Cloning, expression and activity of K99 fimbrial operon gene from enterotoxigenic Escherichia coli]. AB - OBJECTIVE: To clone and express fan operon gene clusters of K99 fimbriae in enterotoxigenic Escherichia coli (ETEC) in vitro, and study the activity of the recombinant E. coli expressing K99 fimbriae. METHODS: K99 fimbriae gene clusters were amplified by long-PCR method, using the genomic DNA of K99-fimbriae E. coli C8307 as the DNA template. The 5.7Kb PCR products were inserted into expressing vector pBR322 with restriction endonuclease, then positive clones were screened. The positive recombinant plasmid was transformed into non-fimbriae E. coli SE5000 strains, and pBR322 plasmid was also transformed into SE5000 for negative control strain. RESULTS: The recombination E. coli expressing K99 fimbriae was tested with agglutination assay, using monoclonal antibody serum and brush border vesicles from the piglet small intestinal epithelia cells. The expressed fimbriae on the surface of the recombinant E. coli SE5000 were observed by transmissible electromicroscope. Heat extraction method was employed to isolate and purify K99 fimbriae, which was exerted SDS-PAGE, and 18.5 kDa protein band was detected. The mouse sera produced from recombinant fimbriae was used to test K99-fimbriae strains C83907, C83914, C83260 with positive agglutination results, while negative results were found with E. coli contain other kinds of fimbriae. The assays of SDS-PAGE, Western blot, agglutination assay were used to evaluate antigenicity and biologic activity between C83907 and recombinant strain. Adhesion test with HeLa cell line demonstrated the recombinant strain and wild type have the similar adherence ability, and this adhesion can be inhibited with mouse serum containing polyclonal antibody against recombinant K99 fimbriae. CONCLUSION: This study has laid a good foundation for further study on bioactivity of K99. PMID- 23457803 TI - [Nonribosomal peptides synthetases gene clusters and core domain in Pseudoalteromonas sp. NJ631]. AB - OBJECTIVE: We studied nonribosomal peptides synthetases (NRPSs) gene clusters and the core module of NRPSs in Pseudoalteromonas sp. NJ631 using genome mining approach. METHODS: The genome of Pseudoalteromonas sp. NJ631 was constructed by the next genome sequencing (NGS) technology. We adopted an online available software called NRPS-PKS knowledgebase to identify potential NRPSs gene clusters within genes involved in the biosynthesis of secondary metabolite of Pseudoalteromonas sp. NJ631. The genes encoding adenylation (A) domains, the core module of NRPSs, were collected and analyzed using genome mining method. RESULTS: We identified three typical NRPS gene clusters comprising three ORFs which encode six continuous modular NRPSs. The result of genome mining indicates that genome of Pseudoalteromonas sp. NJ631 contains 38 A domain genes which show 60% similarity below to their closest relatives. The substrate of these A domains was predicted to specifically bind 18 types of amino acids using the specificity conferring selection rule. CONCLUSION: This is the first reported on the systematic screening and analysis of NRPSs gene clusters and A domains in genus Pseudoalteromonas, suggesting that the genus Pseudoalteromonas possesses a vast array of secondary metabolite biosynthesis genes that were previously found mostly in actinomycetes and fungi. The information on secondary metabolite genes from Pseudoalteromonas sp. NJ631 will facilitate us to isolate novel nonribosomal peptides. PMID- 23457804 TI - Road traffic injuries: are we winning the war in Kenya? PMID- 23457805 TI - Effects of enforcement of the traffic act on injury severity among patients admitted at the Rift Valley Provincial General Hospital, Nakuru. AB - BACKGROUND: The Traffic Act was enforced in Kenya from 1st February 2004. Systematic evaluations of the effects of this enforcement on injury severity are unavailable. OBJECTIVE: To compare injury severity among victims of public service vehicle (PSV) crashes in the periods one year before and one year after the enforcement of the Traffic Act. DESIGN: A retrospective pre and post intervention survey. SETTING: Rift Valley Provincial General Hospital, Nakuru. RESULTS: There were no changes in injury severity levels among the sampled patients before and after the enforcement of the Traffic Act (Most Absolute difference = 0.087, Kolmogorov-Smimov Z = 0.722, p > 0.05). The patients stayed in hospital for a median of three days in both policy periods. The mean age of the patients was 31.49 years (SD = 14.58) while three quarters of the patients were males. The age and sex profiles of the admitted patients did not change with the enforcement of the Traffic Act. CONCLUSION: The enforcement of the Traffic Act did not have any effect on injury severity among admitted PSV crash victims. Measures to lessen the burden of road traffic injury deserve greater attention. PMID- 23457806 TI - Risk factors for death in HIV-infected adult African patients receiving anti retroviral therapy. AB - OBJECTIVE: To determine risk factors for death in HIV-infected African patients on anti-retroviral therapy (ART). DESIGN: Retrospective Case-control study. SETTING: The MOH-USAID-AMPATH Partnership ambulatory HIV-care clinics in western Kenya. RESULTS: Between November 2001 and December 2005 demographic, clinical and laboratory data from 527 deceased and 1054 living patients receiving ART were compared to determine independent risk factors for death. Median age at ART initiation was 38 versus 36 years for the deceased and living patients respectively (p<0.0148). Median time from enrollment at AMPATH to initiation of ART was two weeks for both groups while median time on ART was eight weeks for the deceased and fourty two weeks for the living (p<0.0001). Patients with CD4 cell counts <100/mm3 were more likely to die than those with counts >100/mm3 (HR=1.553. 95% CI (1.156, 2.087), p<0.003). Patients attending rural clinics had threefold higher risk of dying compared to patients attending clinic at a tertiary referral hospital (p<0.0001). Two years after initiating treatment fifty percent of non-adherent patients were alive compared to 75% of adherent patients. Male gender, WHO Stage and haemoglobin level <10 grams% were associated with time to death while age, marital status, educational level, employment status and weight were not. CONCLUSION: Profoundly immunosuppressed patients were more likely to die early in the course of treatment. Also, patients receiving care in rural clinics were at greater risk of dying than those receiving care in the tertiary referral hospital. PMID- 23457807 TI - Etiology and pathogenesis of anterior open bite: a review. AB - OBJECTIVE: To review the etiology and pathogenesis of anterior open bite malocclusion. DATA SOURCE: Review of literature was affected through Pubmed, Google scholar and Science direct. References identified from articles found from the primary search were also reviewed. STUDY SELECTION: Published data on etiology and pathogenesis of anterior open bite over the last five decades (1960 2009) were utilised. DATA EXTRACTION: Full articles, abstracts and relevant book chapters were read and analysed to determine the relevant material for this article. DATA ANALYSIS: All relevant articles were reviewed in full and necessary information eextracted as necessary. CONCLUSION: A clear understanding of the etiology and pathogenesis of anterior open bite is essential in the diagnosis, prevention and management of this malocclusion. PMID- 23457808 TI - Experience with Norplant at a Nigerian teaching hospital. AB - OBJECTIVES: To determine the acceptance of Norplant implants while it was in use and share our experience with other Norplant providers. DESIGN: Retrospective descriptive study. SETTING: The family planning clinic of the Jos University Teaching Hospital, Jos, Nigeria. RESULTS: During the 21-year period, January 1985 to December 2005, a total of eighteen thousand, two hundred and ninety one (18,291) new clients accepted various modern contraceptive methods in the family planning clinic of Jos University Teaching Hospital, Nigeria. Norplant was accepted by 1,333 clients (4.9%) as against the intrauterine devices (IUDs) 25.4%, and Oral Contraceptive Pills (OCP) 22.9%. Female sterilisation was a contraceptive method of choice in 21.2%, the injectables in 13.9%, and the male condom in 9.3%. Failure rate was 0.37% and continuity rate was high among users. The Norplant contraceptive implant was accepted by women of mean age of 29.6 years and women of all parity. The acceptance pattern demonstrated a multi-nodal pattern from the time of introduction in 1985 to December 2005 when supply came to an abrupt stop. The greatest barriers to Norplant use were non- availability and high cost of the commodity. CONCLUSION: Norplantimplants provided contraceptive protection with high reliability, safety, independence from user compliance, rapid return of pre-existing fertility after removal, good tolerability, and relatively simple and quick insertion and removal. The capsules will definitely be used as a reference for similar contraceptive products in the contraceptive market. PMID- 23457809 TI - Indications for removal of etonogestrel implant within two years of use in Jos, Nigeria. AB - BACKGROUND: Implanon is a new long-term and reversible sub-dermal contraceptive implant in Nigeria. It is a single rod containing 68mg of etonogestrel meant to offer contraception for three years and marketed by Organon. OBJECTIVE: To determine the indications for removal of Implanon rods from clients within a two year period. DESIGN: A retrospective review of 30 consecutive Implanon removals within the study period. SETTING: The fertility regulation unit of the department of obstetrics and gynaecology of the Jos University Teaching Hospital, North Central Nigeria. RESULTS: A total of 30 clients requested for and had their Implanon rods removed out of 669 insertions constituting 95.5% crude continuation rate in the second year. The clients were of mean age 31.4 +/- 6.2 years, mean parity 2.9 +/- 1.8 and mean number of living children 2.7 +/- 1.6. There was an average weight gain of 1.9 kg. The most common indication for removal was menstrual disruption (33.3%). Desire for another pregnancy closely followed (30.0%). Weight gain was another indication for discontinuation (13.3%). Two women were pregnant at insertion of the implant. There was one failure of the method with pregnancy as a result. Spousal disapproval was an indication for removal in two cases. CONCLUSION: Like all progestin-only contraceptive methods, menstrual disruption was the most common indication for removal of implants. Inadvertent insertion of implants with existing pregnancy is of concern and should be avoided as much as is possible. In doubtful cases at insertion, this insertion should be deferred or serum beta-HCG should be assessed to exclude chemical pregnancy. PMID- 23457810 TI - Emergency mental health and psychosocial support for survivors of post-election violence in Eldoret, Kenya. AB - OBJECTIVE: To describe the design and delivery of emergency mental health and psychosocial support services for the survivors of Post-Election Violence in Eldoret, Kenya. DESIGN: A longitudinal intervention. SETTING: The North Rift Valley region in Western Kenya. SUBJECTS: A total of 80,772 survivors received mental health and psychosocial support services. RESULTS: Counselling and Psychological First Aid services were successfully offered to most survivors in the North Rift Valley region. Common issues addressed included looking for lost relatives, sudden traumatic death of relatives, anger at their attackers, feelings of revenge, fear of seeing the corpse, loss of all property and source of livelihood and denial. CONCLUSION: It is possible and necessary to integrate a mental health and psychosocial support intervention into a disaster response even in limited resource settings. Further studies are recommended to evaluate the effectiveness of this approach. PMID- 23457811 TI - Poland syndrome with dextrocardia: case report. AB - Poland syndrome is a rare congenital condition presentingwith typical features including an absent costosternal head of pectoralis major andipsilateral brachysyndactyly. There are many clinical variations of the syndrome including rib defects, absence of shoulder girdle muscle and breast hypoplasia or agenesis. Dextrocardia is rarely associated with Poland Syndrome with only 22 cases being previously reported in the worldwide literature. Whereas 'classical' Poland syndrome is predominantly right sided, all cases associated with dextrocardia have been left sided. We report a further case of left sided Poland syndrome with dextrocardia which might have important implications for the understanding of the pathogenesis of this unusual condition. PMID- 23457812 TI - General medical conditions among patients with mental illness. PMID- 23457814 TI - Familiarity with modern health management trends by West African surgeons. AB - OBJECTIVES: To collate the self-reported assessment of familiarity with some aspects of managerial competencies on the part of some surgeons and their observations on the managerial environment of their health institutions and draw appropriate policy implications. DESIGN: Cross-sectional study using a structured questionnaire. SETTING: The study was conducted during the 50th Annual Scientific Conference of the West African College of Surgeons, which was held in Calabar, Nigeria, from 6th to It 12th February 2010. SUBJECTS: One hundred and ten out of 150 surgeons who were attending the conference returned their filled questionnaires. RESULTS: Their familiarity with business and financial concepts was lacking on crucial ones related to marketing strategies. Respondent largely found the listed objections to advertisement of medical services as very appropriate. They preferred largely to interact with themselves in professional associations rather than with others in cross-cultural groupings. Funding (66.4%) and political/ethnic influences (43.9%) were rated as impacting very negatively on their health institutions, while the deployment of information communication technology to institutional processes was adjudged to be unsatisfactory. CONCLUSIONS: Most of the indices of core competencies in modern health leadership and management appeared deficient among our study participants and their health institutions managerial environments were equally deficient. We recommend for a well-focussed short time duration health management course for all physicians particularly specialists. PMID- 23457813 TI - Superficial mycoses among psychiatric patients in Mathari Hospital, Nairobi, Kenya. AB - OBJECTIVE: To determine the prevalence of superficial mycoses among psychiatric patients. DESIGN: Randomised Prospective study SETTING: Mathari Mental Hospital, and Jomo Kenyatta University of Agriculture and Technology, Nairobi Kenya. RESULTS: A study was conducted on prevalence of superficial fungal infections among psychiatric patients in Mathari Hospital, Nairobi, Kenya during the period of July to November 2009. 152 patients were assessed and samples collected from 25 patients with clinically suggestive symptoms of dermatomycosis revealed a 12.5% prevalence of superficial mycosis. There was no significant difference between males and females with superficial mycosis (P>0.05). Twenty percent of the patients who were on topical application had no viable organisms. Microsporum was the predominant species isolated while the skin was the site most commonly affected (64 %). Epidermophyton was the least prevalent. Terbinafin was the most effective antifungal while ketoconazole was the least effective. CONCLUSION: All patients admitted at Mathari hospital should be screened for fungal infection and treated. Terbinafin can be used as first line treatment of dermatomycosis after screening all psychiatric patients in Mathari Mental Hospital. PMID- 23457815 TI - Two-year survival of glass ionomer sealants placed as part of proximal atraumatic restorative treatment restorations. AB - OBJECTIVE: To evaluate after two years, the survival rate of glass ionomer cement (GIC) sealants placed in primary molars of six to eight year-olds and as part of proximal atraumatic restorative treatment (ART) restoration. DESIGN: A longitudinal clinical study. SETTING: Matungulu/Kangundo rural divisions, Machakos district, Kenya. SUBJECT: A total of 804 six to eight year-olds from rural Kenya received a sealant as part of a proximal restoration placed in a primary molar using the atraumatic restorative treatment (ART) approach. RESULTS: The two-year cumulative survival of the sealants was 10.9%, and the survival of the sealants was not significantly affected by the GIC material brand and the tooth-isolation method used. However, slightly more sealants survived when Fuji IX and rubber dam tooth- isolation method were used. CONCLUSION: The two-year survival rate of the sealants was poor and was not significantly influenced by the GIC material or the tooth-isolation method used. PMID- 23457816 TI - Ergonomics in the computer workstation. AB - BACKGROUND: Awareness of effects of long term use of computer and application of ergonomics in the computer workstation is important for preventing musculoskeletal disorders, eyestrain and psychosocial effects. OBJECTIVES: To determine the awareness of physical and psychological effects of prolonged computer usage and application of ergonomicsin the workstation. DESIGN: One hundred and eighty one people were interviewed from tertiary educational institutions, telecommunications and media houses within Nairobi, Kenya. SUBJECTS: Descriptive cross sectional study. RESULTS: Majority (89.8%) of the respondents felt that prolonged computer use had an adverse effect on their health, with only 12.4% having received formal training on the same. Assessment of their workstations revealed the most applied ergonomic measure as feet placement on the floor: 100% (181) followed by correct monitor placement with 94.4% (171) fulfilling the requirements. The least applied ergonomic measures were non reflecting wall paint: 5% (9) and adjustable desk 9.9% (18). CONCLUSION: There is awareness among computer users on the effects of prolonged computer use but there is limited application of ergonomic measures. PMID- 23457817 TI - Hearing disorders in HIV positive adult patients not on anti-retroviral drugs at Kenyatta National Hospital. AB - OBJECTIVES: To determine the prevalence and type of hearing disorders in HIV positive patients not on anti - retroviral drugs (ARVs) and correlate this with the world health Organization (WHO) stage of HIV disease and CD4 positive cell counts. DESIGN: Case control study. SETTING: Comprehensive Care Clinic (CCC) and Voluntary Counseling and testing centre at Kenyatta National Hospital. SUBJECTS: One hundread and ninety four HIV positive patients attending CCC and 124 HIV negative subjects recruited from voluntary counseling and testing (VCT) centre. RESULTS: Hearing loss (HL) was present in 33.5% of HIV positive compared to 8.1% in negative subjects. No gender bias in HL Sensorineural hearing loss (SNHL) was the most common and the frequencies most 'affected were four-anti eight kHz CONCLUSION: Hearing loss is more prevalent in HIV positive individuals not on anti-retroviral drugs than negative normal subjects. Low CD4 cell count and advanced HIV diseases were associated with increased chance of having a hearing loss. Otological care should be part of the comprehensive care of HIV positive patients. PMID- 23457818 TI - Harlequin ichthyosis in an African child: case report. AB - Severe congenital skin abnormalities are a rare event. This case is unique in that it is a case of harlequin ichthyosis in sub-sahara Africa in a child of African origin and elaborates the challenges faced in its management. We present a neonate who was managed for this condition at Chogoria Mission Hospital. In presenting this case, we aim to sensitise healthcare providers to promptly recognise and manage this rare skin condition. PMID- 23457819 TI - [Mistrust]. PMID- 23457820 TI - [What is the remaining burden of rheumatic heart disease worldwide?]. PMID- 23457821 TI - [Hemolytic uremic syndrome caused by Shiga-toxin-producing Escherichia coli]. AB - Every year in France, approximately one hundred children, aged from 6 months to 3 years, develop hemolytic uremic syndrome (HUS) secondary to Shiga toxin-producing Escherichia coli (STEC) infection, mostly the O157:H7 serotype. Except during outbreaks, STEC-HUS is less frequent in adults. The main route of transmission is the consumption of undercooked ground beef or unpasteurized dairy products, or household contacts with STEC diarrhea. Mortality is 1 to 2%. Half of patients require dialysis at the acute phase, the majority will recover normal renal function but approximately 30% will suffer renal sequelae. The risk of sequelae is important if the duration of anuria has been more than 5 days. Treatment of STEC-HUS is mostly supportive. The efficacy of plasma exchanges is not demonstrated and that of eculizumab, a complement blocker, especially in case of central nervous system or cardiac involvement, uncertain. Prevention of STEC-HUS relies on simple methods, often unknown of parents of young children, with the French general population being scarcely informed. However, the surveillance of STEC-infections/HUS by the Institut de veille sanitaire and the Reference Center for E. coli infections allows the early detection of outbreaks and their source of contamination. This prevents the emergence of new cases by withdrawing the suspected food from the market and diffusing the information to the population (return of suspected food). PMID- 23457822 TI - [Acute mountain sickness and high altitude cerebral and pulmonary edema]. AB - Altitude hypoxia is responsible for acute mountain sickness. It can worsen and generate a high altitude cerebral edema, which can be fatal. After reminding the reader clinical and epidemiological facts, this review aims to present new insights of the physiopathological continuity between these two illnesses and the current preventive and treatment tools. Have new medications, as sumatriptans, kept their promises? Have recent studies provide evidence of empirical use of old drugs as aspirin or ibuprofen? What are acetazolamide and dexamethasone places? This wide range of medication doesn't replace non-pharmacological tools. PMID- 23457823 TI - [Heterotopic bone formation in a 38 years-old man after large burned injury]. PMID- 23457824 TI - [Medical and social management of homeless individuals. A one year prospective observational study in the south part of France, Pyrenees-Orientales]. AB - In 2007, a national survey estimated to up to 800,000 the number of homeless individuals in France. Ten percent of them live constantly in the street; often very dissocialized and in precarious conditions. Thereby it remains difficult for homeless to have access to a medical and social support. In order to identify the medical and social needs of this population, we performed a one year observational prospective study in two reception centres in Perpignan. 629 (99%) out of 635 answers were analysed. The most represented age group is 39-49 years (29,2%) with an over-representation of males (82,7%). The most frequent pathologies are psychological distress (43,9% of requests, including anxious problems 23%, and sleep disturbances 24,4%). Medical affections represented 15,7% of the cases (mainly nutritional deficiency), and skin diseases 15,%. Addictive behaviour was frequent including tobacco (84%), alcohol (17%), and drug addiction (9%). 21,7% of this population had a regular work, and 97,8% with fixed term contracts, but 45,1% did not have any health cover 17,6% of homeless did not obtain any answer to their medical request (lack of suitable medicine, or an impossibility to pull out further tests in order). To solve some aspects of that problem, family doctor can rely on a medical and social network (PASS, MAO, ANPAA). PMID- 23457825 TI - [Ophthalmology, between spectacular advances and gaps in managed care]. PMID- 23457826 TI - [Actuality in cataract treatment]. AB - Cataract surgery improves vision by restoring eye transparency and also by correcting previous refractive defects. Surgery has only to be done when the patient's quality of life is significantly impaired by vision troubles. Among patients with cognitive and behaviour troubles (i.e Alzheimer disease), surgery may improve cognitive scores, and autonomy. Multifocal intraocular lenses are sometimes indicated for correcting presbyopia. However, impairment of contrast sensitivity is constant, among adverse effects causing sometimes dissatisfaction. Therefore "monovision", with monofocal intraocular lenses may be proposed, in order to manage the loss of accommodation constant after cataract surgey. Patient's satisfaction level is high when the dominant eye is dedicated to far vision, and the other eye to near vision. Combining femtosecond laser technology and cataract surgery may in the future improve reproductibility and surgical outcomes, but is not currently responsible for obvious therapeutic benefits. PMID- 23457827 TI - [New retinal imaging techniques]. AB - Retinal imaging techniques progress rapidly. In many cases, the diagnosis of macular diseases can be done by the combination of fundus photography (color, monochromatic or autofluorescence images) and optical coherence tomography (OCT). Fluorescein or indocyanine green angiography remains useful when the other exams are not conclusive. Fundus angiography can be coupled with OCT. Other new investigation methods have appeared such as wide-field retinography on the one hand, or adaptive optics on the other hand which allows visualising photoreceptors in a very small field. Screening for diabetic retinopathy is based on color fundus photos. When the diagnostic of diabetic retinopathy is obvious, a more comprehensive fundus examination is warranted to decide on the treatment and follow-up. PMID- 23457828 TI - [Therapeutic innovations in diabetic retinopathy]. PMID- 23457829 TI - [Changes in AMD treatment]. AB - Treatment of wet AMD has dramatically changed since the last 5 years. It is now based on repeated intravitreal injections of anti-VEGF agents, and a monthly monitoring. This allows 60% of the patients to preserve their vision, and 30% of the patients to have a significant improvement. Prevention of AMD is based in selected patients on food complements with omega3 and carotenoids, while waiting for the results of the AREDS2 Study. There is no treatment for dry AMD with demonstrated benefit. PMID- 23457830 TI - [Ocular toxicity of drugs]. AB - Numerous systemic medications have a potential ocular toxicity leading to permanent visual loss. Physiopathologic mechanisms associated with these toxic effects are yet unclear and, besides discontinuation of the drug, when possible, there is no current validated treatment once visual loss is present. Prevention lies on an awareness of potential risks of both the patient and the practitioner, a constant evaluation of the risk/benefice ratio of any treatment and, for some drugs, regular visual evaluations according to now more standardized protocols. In that respect, a tight link between the ophthalmologist and the referring practitioner is critical. Among oculotoxic drugs, anti-malarial treatment represents the most commonly prescribed. A better recognition of clinical characteristics of ocular toxicity along with progress in functional and structural evaluation of the visual system has modified follow-up protocols to obtain the earliest detection but a better knowledge in toxic mechanisms is still necessary. PMID- 23457831 TI - [Therapeutic innovation in AMD and other retinal diseases]. AB - Age-related macular degeneration (AMD) is a leading cause of severe visual impairment in individuals over 50 years in developed countries. Latest advances in imaging techniques have led to improved and accurate diagnosis of AMD. We witness a major breakthrough in the treatment of the neovascular form of AMD with the antiangiogenic (anti-VEGF) drugs. However, no therapy is yet available for the atrophic dry form of AMD. Innovative strategies gene therapy, cell therapy, nanotechnology neuroprotection- and multidisciplinary approaches are emerging to prevent the decline in vision in aging populations and its health implications. PMID- 23457832 TI - [Twitter: chat or watch?]. PMID- 23457833 TI - [How to take care in prison]. PMID- 23457835 TI - [Infectious diseases in prison]. PMID- 23457834 TI - [Correctional health care]. AB - Court decisions taking away someone's freedom by requiring them to serve a jail sentence should not deny them access to the same health care available to free citizens in full compliance with patient confidentiality. Health institutions, responsible for administering somatic care, offer a comprehensive response to the medical needs of those under justice control, both in jails and conventional care units. For a physician, working in the correctional setting implies accepting its constraints, and violence, and protecting and enforcing fundamental rights, as well as rights to dignity, confidential care and freedom to accept or refuse a treatment. PMID- 23457836 TI - [Specific aspects and management of psychiatric conditions in correctional settings]. AB - Correctional psychiatry is a patient-centered medicine, similar to that practiced anywhere else, independent, governed by the same objectives (deliver the highest standard of care) and the same obligations (respect patients' dignity, their informed consent and the confidentiality they are entitled to). However, it has been a victim of its own success. As correctional psychiatry was expanding, so was the psychiatric morbidity among inmates. Consequently, the initial clinical hypothesis, which was based on the integrative function of correctional psychiatry, created in the early eighties, comes up against the segregating impact of an intramural specialty practice. PMID- 23457837 TI - [Care in prison for people with disabilities]. PMID- 23457838 TI - [Difficulties medical care of persons placed under hand of justice]. AB - The "controleur general des lieux de privation de liberte", french, national mechanism of prevention is an independant authorithy in charge of making sure since 2008 that rights of deprivation of freedom people--particularly access to health--are respected, in any place they are in captivity. The reports of the controllers present that the care of these persons is still a subject of concern as well for them--as the number of letters received by the Controleur general shows--as for professionals working in these places. The exercising of these health professionals in these institutions is a care mission to be done in a real partnership with the other actors. PMID- 23457839 TI - [In JAMA once a year]. PMID- 23457840 TI - [Multiple bone myeloma]. PMID- 23457841 TI - [Myasthenia]. PMID- 23457842 TI - [Chronic lymphoid leukaemia]. PMID- 23457843 TI - [Sanitary risks linked with water and food. Food poisoning]. PMID- 23457844 TI - [Acute respiratory distress in the adult. Foreign bodies of the upper respiratory tract]. PMID- 23457845 TI - [Ancient Egyptian roots in the Greek medicine]. PMID- 23457846 TI - Bilateral HIV related ocular surface squamous neoplasia: a paradigm shift. AB - Four patients with bilateral ocular surface squamous neoplasia attended to at Sekuru Kaguvi Hospital Eye Unit are being presented to alert practitioners that OSSN is potentially a bilateral disease and its prevalence is likely to increase as the life expectancy of HIV infected patients is being positively affected by antiretroviral therapy. Reports on ocular diseases should be clear on laterality to avoid confusion between number of patients affected and number of eyes involved since the two cannot be used interchangeably. PMID- 23457847 TI - Use of cotrimoxazole prophylaxis in HIV infected in patients at a referral hospital. AB - OBJECTIVE: To assess the extent of use of cotrimoxazole prophylaxis in the prevention of opportunistic infections in HIV infected patients. SETTING: Parirenyatwa Hospital, a major referral and teaching hospital. DESIGN: A retrospective study. SUBJECTS: 234 HIV infected patients admitted between January and June 2004, with a history of symptoms falling into the WHO stage 3 AIDS, were included. MAIN OUTCOME MEASURES: Cotrimoxazole prophylaxis, PCP prevalence, and mortality. RESULTS: 234 patients' records were reviewed and 19% of the patients had received cotrimoxazole prophylaxis. PCP prevalence was 36% which was diagnosed mainly by clinical examination and sometimes with the additional help of chest X-rays. Of those who were on prophylaxis, 75% were on primary prophylaxis and the rest on secondary prophylaxis. All patients on prophylaxis were using cotrimoxazole, with the 960 mg once daily dosing being the most common regimen (96%). Receiving prophylaxis was associated with being female (p = 0.0067), widowed (p = 0.012), and taking ARV therapy (p = 0.0026). Prophylaxis significantly reduced mortality (p = 0.0017). The development of PCP was associated with a history oftuberculosis relapse (p = 0.022). CONCLUSION: Cotrimoxazole prophylaxis is important in reducing hospital admissions due to opportunistic infections and increasing survival especially in areas with limited access to antiretroviral therapy. PMID- 23457848 TI - Annual distribution of births and deaths outcomes at Harare Maternity Hospital, Zimbabwe. AB - OBJECTIVES: To assess socio-demographic and reproductive/obstetric risk factors for stillbirth, preterm births and low birth weight (LBW). To explore the probability of death at birth by antenatal care attendance, and by delivery with a Caesarean section. DESIGN: Using information available in obstetric records, we conducted a retrospective analysis of data, covering a twelve month period. SETTING: Harare Maternity Hospital, Zimbabwe SUBJECTS: All deliveries (17,174 births) occurring from October 1997 to September 1998 MAIN OUTCOME MEASURES: Stillbirth, preterm births and LBW. RESULTS: The annual stillbirth rate was 57 per 1000, preterm birth 215 per 1000 and LBW was 243 per 1000 total births. Women delivering stillbirths, preterm births and LBW infants were less likely to attend antenatal care (adjusted relative risk [RR] = 2.56 95% confidence intervals [CI]: 2.18 to 3.00, RR= 3.02 95% CI: 2,77 to 3.29, and RR = 2.38; 95% CI: 1.58-3.60), or to be deliveredby Caesarean section (RR= 0.61; 95% CI: 0.49 to 0.76, RR = 0.68; 95% CI: 0.61 to 0.76 and RR = 0.82; 95% CI: 0.75 to 0.90), but more likely to deliver a breech (RR = 3.17; 95% CI: 2.62 to 3.85, RR = 4.16; 95% CI: 3.72 to 4.64 and RR = 5.34; 95% CI: 4.88 to 5.85), respectively. Stillbirths were more likely to be a preterm birth (RR = 6.53; 95% CI: 5.65 to 7.79) or a LBW infant (RR= 6.42; 95% CI: 5.49 to 7.52). CONCLUSION: The annual frequency of poor birth outcomes at Harare Maternity Hospital, which is a referral hospital, also catering for a proportion of patients coming from distant health centers and from rural areas, is high. This high prevalence of birth outcomes is associated with lack of prenatal care, and breech delivery. Infants born too early or small have an increased risk of mortality. Early prenatal care, improved obstetric care, accessibility to care, use of emergency care services, and early access to Caesarean section, could save life, and could assist in reducing the frequency of poor birth outcomes in this population. PMID- 23457849 TI - A potentially treatable cause of dementia. AB - Idiopathic hypoparathyroidism is an uncommon medical condition, which may present with dementia. This may be misdiagnosed as 'senile dementia' in elderly patients. We report such a case, made more remarkable by associated extensive cerebral calcification and we review the background literature. PMID- 23457850 TI - Postoperative fatal hypothermia in hydranencephaly with pre-operative hypothermia and a nerve palsy: a case report and review of the literature. AB - Hydranencephaly is a rare condition characterised by complete or near complete absence of the cerebral hemispheres within relatively normal sized meninges and skull, the resulting cavity being filled with cerebrospinal fluid. The following is a case report of a five month old hydranencephalic child with right upper motor facial nerve palsy who presented with signs of hydrocephalus who developed intractable hypothermia rapidly post ventriculo-peritoneal shunt insertion and demised. Her preoperative condition was associated with hypothermia. PMID- 23457851 TI - Haematological features in children less than 12 years on cotrimoxazole prophylaxis seen in opportunistic infection clinics at Harare and Parirenyatwa Teaching Hospitals. AB - OBJECTIVE: To determine the prevalence of peripheral haematological abnormalities in children receiving cotrimoxazole prophylaxis. DESIGN: An outpatient hospital based cross sectional study. SETTING: The study was conducted at two tertiary peadiatric HIV clinics that offer comprehensive care to children living with HIV. SUBJECTS: 202 HIV infected, antiretroviral therapy naive children aged between 3 months and 12 years who were receiving cotrimoxazole prophylaxis for at least 1 month with more than95% adherence to prophylaxis were included. MAIN OUTCOME MEASURES: Haematological abnormalities on full blood count and peripheral film. RESULTS: The prevalence of anaemia was 62% with normocytic normochromic anaemia being the most frequent type (45%). The commonest red blood cell abnormality was rouleaux formation on the peripheral film. Monocytosis occurred in 62%, leucopaenia in 39%, eosinophilia in 34%, neutropaenia in 18% and lymphopaenia in 10% of the children. CONCLUSION: This study showed a high prevalence ofhaematological abnormalities in HIV infected children on cotrimoxazole prophylaxis. It emphasizes the need for evaluation for anaemia and its management in children on cotrimoxazole prophylaxis. PMID- 23457852 TI - An audit of malaria mortality using the "malaria death investigation form" at United Bulawayo Hospitals, Zimbabwe: 1996-2000. AB - OBJECTIVE: To identify the main causes of confirmed malaria deaths and assess the validity and the relevance of use of the MDIF in determining areas for improvement of care. DESIGN: A cross sectional study. SETTING: United Bulawayo Hospitals, a tertiary hospital in Zimbabwe. SUBJECTS: Patients whose cause of death was malaria using MIDF. RESULTS: Of 470 confirmed cases admitted in UBH during the study period, 53 (11.2%) died and were included in the study. Most deaths occurred in the over 15 years age group (88.6%) with only 3 deaths each in the other groups. All patients were referred or admitted to UBH with complicated and severe malaria; 39(74 %) had more than one complication such as CM and acute renal failure (ARP). Most patients came from or had visited a rural area and did not implement basic prophylactic and therapeutic measures put in place by the NMCP such as early self-medication. Three pregnant women aborted. Guidelines regarding investigations and treatment were not strictly adhered to. Delay in seeking treatment and in referring was generally observed at all levels of the health system. Cases of malaria deaths were found in the city in people who had not travelled to rural area. The MDIF was used in one case only. CONCLUSION: Malaria mortality accounted for 11 % of confirmed cases. Main causes of death were CM and ARP Parameters contained in the MDIF were those utilised by most authors who have investigated malaria mortality in Africa and there was a similarity in the observations. In view of the information it could provide if properly used, the MDIF is a valid tool for collecting data that the NMCP needs in order to rationalise its strategies at UBH and in other health facilities. Its use should be generalised and compulsory. PMID- 23457853 TI - Low level technology tool (LLTT) in screening for blindness: test qualities in the outpatients department of a tertiary eye unit using the Snellen chart. AB - OBJECTIVE: To validate the use of finger counting (low level technology tool) in screening for blindness in the outpatients department of a tertiary eye unit with the view of employing the test for screening illiterate people in hard to reach parts of the country where the conventional visual acuity charts are not available. DESIGN: Aperformance evaluation of counting fingers (LLTT) in screening for blindness against the standard test (Snellen chart). SETTING: Sekuru Kaguvi Eye Unit, Parirenyatwa Hospital, Zimbabwe. SUBJECTS: Patients presenting to the Eye Outpatient Department at Sekuru Kaguvi Eye Unit with various eye problems. MAIN OUTCOME MEASURE: Sensitivity of low level technology tool (LLTT) in identifying blind people. RESULTS: Sensitivity and specificity of LLTT in detecting blindness in all age groups combined was 100% and 88.5% respectively. Although sensitivity was not affected by patient age, specificity decreased with increasing age. The overall positive predictive value for the test was 53.3% and the prevalence of blindness among outpatient attendees was 11.6%. CONCLUSION: Finger counting is an effective tool that can be employed in screening for blindness in communities which are hard to reach, have low literacy rate and when conventional methods of testing visual acuity are not available. PMID- 23457854 TI - Agnathia-synotia-microstomia (otocephaly): a case report in an African woman. AB - Pharyngeal arches appear in the 4th and 5th weeks of development of the human embryo. The 1st pharyngeal arch develops into the incus and malleus, premaxilla, maxilla, zygomatic bone; part of the temporal bone, the mandible and it contributes to the formation of bones of the middle ear. The musculature of the 1st pharyngeal arch includes muscles of mastication, anterior belly of the digastric mylohyoid, tensor tympani and tensor palatini. The second pharyngeal arch gives rise to the stapes, styloid process of the temporal bone, stylohyoid ligament, the lesser horn and upper part of the body of the hyoid bone. The stapedius muscle, stylohyoid, posterior belly of the digastric, auricular and muscles of facial expressional all derive from the 2nd pharyngeal arch. Otocephaly has been classified as a defect of blastogenesis, with structural defects primarily involving the first and second branchial arch derivatives. It may also result in dysmorphogenesis of other midline craniofacial field structures, such as the forebrain and axial body structures. PMID- 23457855 TI - Thyroid dysfunction in HIV/AIDS--cause or consequence? PMID- 23457856 TI - Thyroid function among HIV/AIDS patients on highly active anti-retroviral therapy. AB - OBJECTIVES: To assess the thyroid function among Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) patients on anti-retroviral drugs: stavudine, lamivudine and nevirapine and to establish the prevalence of non-thyroid illness. DESIGN: Laboratory based comparative cross-sectional study. SETTING: Comprehensive care clinics at KNH and Mbagathi District Hospital. SUBJECTS: Eighty four HIV-infected patients on treatment with ARVs (ARV +ve) and an ARV naive (ARV naive) group of 26 HIV-infected patients. RESULTS: Thyroid stimulating hormone levels were not altered following treatment whereas the levels of FT4 decreased. The frequency of those with low FT4 were increasing with continued ARV use. The prevalence of non-thyroidal illness state defined by TSH within reference ranges and low FT4 was comparable among the ARV +ve and ARV naive groups (44 and 46% respectively). CONCLUSION: Progressive use of HAART causes decline in FT4 hormone levels. It is debatable whether interventions for low FT4 is necessary in ARV treatment but a longitudinal study would explain the progressive trend of thyroid hormones and implications with HAART treatment. The prevalence of NTI is comparable to both HAART users and non-users. Low levels of thyroid hormone (FT 4) may be an adaptive response by thyroid gland to minimize calorie utilisation as in chronic diseases. PMID- 23457857 TI - The prevalence, clinical features, risk factors and outcome associated with cryptococcal meningitis in HIV positive patients in Kenya. AB - OBJECTIVES: To determine the prevalence, clinical features, risk factors and outcomes associated with cryptococcal meningitis (CM) in human immunodeficiency virus (HIV) positive patients at two referral hospitals in Nairobi, Kenya. DESIGN: Prospective, observational study. SETTING: Kenyatta National Hospital (KNH) and Mbagathi District Hospital (MDH), Nairobi, Kenya. SUBJECTS: Three hundred and forty HIV patients presenting with suspected CM. RESULTS: Of three hundred and forty suspected CM patients, 111 (33%) were diagnosed with CM by CrAg. Among CM patients, in-hospital mortality was 36% (38/106), median age was 35 years (range, 19-60 years) and median CD4 count was 41 cells/microL (n = 89, range 2-720 cells/microL). Common clinical manifestations among CM patients included headache 103 (93%), neck stiffness 76 (69%) and weight loss 53 (48%). Factors independently associated with CM were male sex, headache, blurred vision and previous antifungal drug use. Night sweats and current use of anti-retroviral therapy were associated with reduced risk for CM. CONCLUSIONS: There is a high prevalence of CM and CM-associated mortality in HIV patients at KNH and MDH despite treatment with antifungal and anti-retroviral drugs. This study demonstrates the need to address the existing inadequacies of CM patient outcomes in Kenya. PMID- 23457858 TI - Adherence to national guidelines in prevention of mother to child transmission of HIV. AB - BACKGROUND: Mother-to-child transmission (MTCT) of Human Immunodeficiency Virus (HIV) contributes to over 90% of the paediatric HIV infections. The national PMTCT guidelines make recommendations for specific interventions to reduce perinatal transmission. Data on adherence to the guidelines by caregivers and quality of PMTCT care is however limited. OBJECTIVE: To evaluate the extent to which PMTCT care offered to HIV positive women admitted for delivery at Kenyatta National Hospital (KNH) and Pumwani Maternity Hospital (PMH) adheres to National Guidelines in order to reduce vertical transmission of HIV during labour and delivery. DESIGN: A cross-sectional study. SETTING: Kenyatta National Hospital and Pumwani Maternity Hospital from January to April 2009. SUBJECTS: All consenting HIV positive women admitted to the labour wards at the two facilities and planned for delivery. RESULTS: A total of 370 women were enrolled, 266 at Pumwani Maternity Hospital and 104 at Kenyatta National Hospital. Among the enrolled women 357 (96.4%) had been counselled on vertical transmission and 205 (55.4%) had HIV disease staging by CD4 cell count. There were no significant differences between the two study sites in the proportion of women counselled on MTCT (p = 0.398) and receiving HIV disease staging by CD4 testing (p = 0.28). Three hundred and forty nine (94.3%) women were offered varied ARV regimens for PMTCT. 101(27.3%) received HAART, 94 (26.9%) were given single dose nevirapine and 130 (37%) received AZT+NVP combination prophylaxis. Twenty one women received no ARV prophylaxis. Overall, 268 women (72.5%) had spontaneous vertex delivery. An episiotomy rate of 7% was observed and no vacuum delivery was recorded. A Caesarean section rate of 27.5% was recorded with PMTCT as an indication in almost half of the cases. Women delivered at KNH were more likely to receive HAART (p < 0.001) and to be delivered by elective caesarean (p < 0.001). CONCLUSION: A great majority of HIV positive women admitted for delivery received counseling on vertical transmission and were offered ARVs for PMTCT. Many women did not get CD4 measurement and clinical staging as recommended in the National guidelines. PMID- 23457859 TI - Urine markers of kidney disorders and their risk associations in HIV-infected patients attending Nyanza Provincial General Hospital in Kisumu, Western Kenya. AB - OBJECTIVE: To identify abnormal levels of urine metabolites and cells that serve as markers of existing kidney disorders in ambulatory HIV-infected patients. DESIGN: A cross sectional study. SETTING: Nyanza Provincial General Hospital's patient support centre. SUBJECTS: A total of 593 HIV infected patients were studied. INTERVENTION: Dipstick urinalysis test was used to screen mid stream urine to detect constituents with altered levels. RESULTS: Out of the 593 participants, the urine of 214 (36.1%) had abnormally altered levels of urine constituents, with more females afflicted than males [41.5% vs. 27.8%; OR 1.84 (1.28-2.63), chi2 = 11.08, p = 0.0009]. Urobilinogen was the most common urine metabolite while ketones were least commonly present. More participants had altered levels of leucocytes than erythrocytes in urine. Patients with pyuria were three times more likely to have elevated erythrocytes in their urine as well (chi2 = 34.37, p < 0.0001). Similarly, the risk of having proteinuria was three times higher in patients with pyuria (p < 0.0003, Fisher's test). Patients with erythrocytes in urine also had a threefold likelihood of having proteinuria (P < 0.0003, Fisher's test). Fewer ARV users had abnormal urine markers [15.7% vs 24.3% OR 0.62 (0.41-0.94), chi2 = 5.2, p < 0.05]. CONCLUSION: Metabolites and cellular markers of kidney disorders were prevalent in the urine of HIV patients especially females and those with pronounced immune depletion (CD4 counts equal to or below 500). ARVs use was associated with reduced manifestation of these markers. PMID- 23457860 TI - Comparison of Doppler studies in obstetrics with foetal outcome. AB - OBJECTIVE: To compare umbilical and middle cerebral artery Doppler ultrasound values in high and low risk pregnancies withfoetal outcome. DESIGN: Descriptive prospective study. SETTING: Aga Khan University Hospital, Nairobi between the months of February and November 2007. SUBJECTS: One hundread and twenty one consecutive female subjects, between 24 and 443 years of age, at or over 28 weeks gestation, referred to the Radiology Department of Aga Khan University Hospital for obstetric Doppler ultrasonography. MAIN OUTCOME MEASURES: Foetal outcome was defined as poor by using either APCAR score (below eight out of ten at five minutes), weight, head circumference and length below tenth percentile for gestation at delivery or by mortality. RESULTS: Outcome was available for 100 of the 121 patients. Twenty six percent of pregnancies had poor outcome. Of these 73% (19) and 27% (7) were classified as high risk and low risk respectively. Accuracy for umbilical artery Doppler in predicting foetal outcome was 80.8 and 82.9% for high and low risk pregnancies respectively. Accuracy for middle cerebral artery Doppler was 71.2% and 97.6% for high and low risk pregnancies respectively. Overall, accuracy for umbilical artery and middle cerebral artery Doppler in predicting foetal outcome was 76 and 82% respectively. Umbilical artery alone or in combination with middle cerebral artery Doppler was shown to have 100% specificity for predicting foetal outcome. However, sensitivities and negative predictive values were poor, ranging from 8-21% and 17-35% respectively. Middle cerebral artery specificities were lower at 80 and 85% for high and low risk pregnancies respectively. CONCLUSION: Umbilical and middle cerebral artery Doppler values in pregnancy are fair predictors of foetal outcome. However, these Doppler indices are useful in pregnancy to exclude foetal compromise. PMID- 23457861 TI - Factors influencing utilisation of insecticide treated nets and prevalence of malaria among children under five years. AB - OBJECTIVE: To determine factors influencing the use of Insecticide Treated Nets (ITN) in the prevention of Malaria to children under five years. DESIGN: A descriptive cross-sectional study. SETTING: Kiambu District, Central Province of Kenya. RESULTS: One hundred and thirty nine (50.7%) attained primary education. Two hundred and seventy two (99.3%) were of Christian faith. One hundred and sixty four (59.8%) didn't have formal employment. Two hundred and fourty three (88.7%) were married. One hundred forty two (51.8%) were house wives. Two hundred and fourty seven (65.0%) used ITNs. Two hundred and fourty one (88.0%) had not received ITN from government. One hundred and eighty three (66.8%) had ITN in households. One hundred and twenty eight (46.7%) indicated price of ITN was affordable. Two hundred and fourty eight (90.5%) knew that Malaria is transmitted by Mosquito. One hundred and fourty five (52.9%) heard about ITN from Health Workers. Two hundred and fifty six (93.4%) liked using ITN. One hundred and ninten (43.4%) children suffered malaria in previous six month. One hundred and seventy four (63.5%) had their treatment booklet. One hundred and sixty seven (60.9%) had ITN in homestead. Two hundred and fourty one (88.0%) had health facility near homestead. Health facility recorded 1062 in--patient Malaria cases in 2006, 1343 in 2007 and 866 in 2008. Case fatality Rate in 2008 was 12.5%. Sixteen (5.8%) kept chemoprophylaxis drugs. Variables significant with ITN utilisation were; mother's chi2 (P = 0.007), income (P = 0.001), having heard of ITN (P = 0.001), free ITN (P = 0.001), ITN availability (P = 0.001), ITN affordability, Malaria prevention and liking to use ITN. Insignificant variable with utilisation include; Mother's education (P = 0.112), marital status (P = 0.303), religion (P = 0.616), malaria transmission (P = 0.385) and Malaria infection (P = 0.141). CONCLUSION: Mothers were young, married and educated. Almost all were Christians. They knew that Malaria was transmitted by Mosquito and utilisation was high. Government of Kenya did not provide ITN to many respondents. ITN was bought because the price was affordable. Majority had ITN in their households. Some children had suffered malaria. Majority indicated it was important for the child to sleep under ITN. PMID- 23457862 TI - Placenta accreta and the developing world--a review. AB - BACKGROUND: The rising Caesarean section rate in the developing world implies that the incidence of placenta accreta might be on the increase and this might worsen the maternal mortality burden. OBJECTIVE: To draw the attention of Obstetricians and other relevant professionals to this emerging but challenging trend. DATA SOURCES: Original research findings and reviews published in the English literature. Additional information was obtained from texts and electronic books such as CD ROMS. DATA EXTRACTION: Online searches of electronic database (Medline, Pubmed and Embase), requests for reprints from corresponding authors and institutional/private subscriptions. DATA SYNTHESIS: Information obtained was categorised accordingly. CONCLUSION: Optimal treatment of women with placenta accreta requires recognition of the clinical risk factors, accurate pre-operative diagnosis and meticulous planning to ensure safety at the time of delivery. In view of the rising incidence of this condition, and the absence of a highly reliable antenatal diagnostic method especially in developing countries, a high index of suspicion and advanced preparation is required to reduce its associated maternal morbidity and mortality. PMID- 23457863 TI - A successful treatment of a Kenyan case of unresponsive cutaneous leishmaniasis with a combination of pentostam and oral allopurinol: case report. AB - A nine year aged male presented with facial lesions and the problem of responding to conventional treatment of leishmaniasis. Multiple injections of antimony and several topical ointments had been administered in hospital but fresh lesions erupted with potential to disfigure. Smears examined from nodular lesions confirmed presence of Leishmania amastigotes and parenteral pentostam was commenced for over eight weeks. A partial clinical outcome was achieved judged by extent of re-epithelialisation. Combined therapy of pentostam and oral allopurinol at a dose of 7mg/kg/day was started and finalised at 120 days. All facial lesions receded and 100% re-epithelialisation of the lesions established. PMID- 23457864 TI - Challenges for undergraduate medical education in Africa. PMID- 23457865 TI - Knowledge, attitudes and practices among pregnant women on intermittent presumptive therapy in Guruve District, Zimbabwe. AB - OBJECTIVE: To determine knowledge, attitudes and practices on intermittent presumptive therapy among pregnant women. DESIGN: A descriptive survey design. SETTING: A rural district in Zimbabwe in a Malaria endemic area lying in the Zambezi valley. SUBJECTS: A convenience sample of forty pregnant women living in Guruve District and on the intermittent presumptive therapy (IPI) programme. There were no drop outs. MAIN OUTCOME MEASURES: Selected indicators of knowledge, attitudes and practices were analyzed using descriptive statistics. RESULTS: The principal results were that the majority of the respondents (67) had knowledge about the intermittent presumptive therapy (IPT) but (67%) lacked awareness of the benefits of the programme activities. Seventy respondents (43%) said that information about the programme was not readily available. Eleven (27.5%) believed that drugs used in IPI programme could cause fatal congenital abnormalities. All the respondents (100%) believed that malaria could be prevented. Twenty-nine (72.5%) took drugs for IPI accurately under supervision by the nurse and eleven (27.5%) took drugs incorrectly. CONCLUSION: Drug compliance improves if drugs are taken under direct supervision. The results revealed that the majority was knowledgeable of the existence of the IPT, but were not aware of the benefits. There was also a problem of information dissemination leading to ignorance, and myths and misconceptions. Therefore, health education and promotion has to be intensified to give accurate information and motivation. PMID- 23457866 TI - Directly observed treatment short course (DOTS) appears to have reduced the self care role of the-pulmonary tuberculosis patient: evidence from a correlational study between personal health beliefs (PHB) and self-care practices (SCP). AB - OBJECTIVE: To examine the relationship between personal health beliefs and self care practices among 69 PTB patients aged 25 to 65 years at a tuberculosis clinic in Zimbabwe, in order to determine the role patients can play in self-care. DESIGN: Analysis of collected demographic data, personal health beliefs (PH B) and self-care practices (SCP) of PTB patients. SETTINGS: Gwanda Provincial Hospital (GPH) Tuberculosis Clinic. PARTICIPANTS: PTB patients in the (GPH) register who were taking treatment. INTERVENTIONS: Key components of the study included administration of an interview schedule to 69 PTB patients on treatment, and the analysis and comparison of personal health beliefs and self-care practices. MAIN OUTCOME MEASURES: Scores of personal health beliefs, self-care practices, perceived self-efficacy, perceived threats, and cost-benefit analysis. RESULTS: Sixty- nine PTB patients with a median age of 38, screened during the month of March, 2009, showed a weak positive Pearson's correlational coefficient of (R2=0.177), indicating that personal health beliefs may have some influence on self-care practices. The regression analysis showed an association of 3.1%, thus health beliefs are responsible for self-care undertaken by 3.1 in a 100 PTB patients. CONCLUSIONS: Directly Observed Treatment Short Course (DOTS) seems to have reduced the self-care practice of PTS patients. It seems the PTB patient has a potential role to play in the management of his own treatment. PMID- 23457867 TI - A report on the Zimbabwe Antiretroviral Therapy (ART) programme progress towards achieving MGD6 target 6B: achievement and challenges. AB - Zimbabwe's target to achieve Universal Access to treatment for HIV and AIDS, was severely affected by a decade long economic recession that threatened to reverse all the country's social and economic indicators. Despite these challenges, by September 2010, 282,916 adults and children (47.7% of those in need of treatment) were on treatment at 509 sites countrywide since national scale up started. ART services are predominantly offered through the public sector, with the private sector being an untapped potential resource for ART services for the future. Challenges of skilled and adequately trained human resources have hindered progress towards service availability. Providing access to children in particular has been constrained by lack of clinical mentorship for health workers, weak systems for support supervision, and inadequate HIV diagnostic services especially for children under 18 months and challenges with follow up of the HIV exposed infants. Though the country has not met its target of Universal Access by 2010, significant progress has been made with over a 30-fold increase in service availability. PMID- 23457868 TI - Tubular ectasia of the rete testis associated with azoospermia: a case report. AB - Tubular ectasia of the rete testis (TERT) is a rare benign condition of the testis due to dilatation of the tubules of the rete testis. It must be differentiated from neoplastic disease of the testis clinically by patient's age, mode of presentation, tumour marker status and characteristic ultrasound and colour Doppler findings. Awareness and diagnosis of TERT should prevent unnecessary surgical intervention such as orchidectomy or biopsy. We report a case of severe bilateral tubular ectasia of the rete testis associated with azoospermia and review the relevant literature. This association has not been reported before in the literature to the best of our knowledge. PMID- 23457870 TI - Socio-demographic characteristics and challenges experienced by disabled patients living with HIV/AIDS in a tertiary hospital in Ibadan, Nigeria. AB - BACKGROUND: HIV/AIDS is highly prevalent in sub-Saharan Africa and few studies had looked at physically and mentally challenged people living with HIV/AIDS (PLHIV) in this environment. This study aimed to describe the socio-demographic characteristics and challenges faced by these patients attending University College Hospital, Ibadan. METHODS: A descriptive cross-sectional study design was done. A semi-structured interviewer administered questionnaire was administered to consecutive disabled PLHIV over a period of six months. Data obtained were analyzed using descriptive and inferential statistics. RESULTS: A total of ninety nine patients were seen during the study period. The mean age of these patients was 39.9 +/- 9.4 years (range 23-60 years). There were 30 (30.3%) males and 69 (69.7%) females. Twenty-four percent had no formal education while 12% had tertiary education. All respondents had suffered stigmatization/discrimination while most were poor. Eighty-seven percent had AIDS at presentation. Musculoskeletal impairments (46.5%), hearing loss (16.2%) and visual impairment (31.3%) were the commonest disability. Over twenty-three percent had prior history of road traffic accident as the cause of disability. CONCLUSION: Physically and mentally challenged people living with HIV/AIDS are poor and highly stigmatized. They require special assistance to cope and need economic empowerment to reduce their poverty level. PMID- 23457869 TI - Intra-abdominal gossypiboma: a report of two cases and a review of literature. AB - Post operative foreign body in the abdominal cavily, though rare continues to occur in surgical practice. Symptoms may start early with abdominal pain but usually have a varying course, ofter leading 10 the formation of gossypiboma. This is usually a great source of embarrassment to the surgeon and the centre, and of serious detrimental effect to the patient. A case report of a 27-year-old trader with intra-abdominal foreign body is presented to highlig at the similarity in presentation with abdominal lymphoma and the need to explore carefully masses in the abdominal cavity especially in patients who have had surgery in the past. A high index of suspicious is required on the part of the clinician in addition to appropriate radiological and sonologic assessment. Prompt diagnosis and treatment ameliorates the patients suffering and brings them back to life. PMID- 23457871 TI - Risk factors for rampant caries in children from southwestern Nigeria. AB - OBJECTIVE: The cross sectional study tried to identify some risk factors for rampant caries in a hospital based population of Nigerian children. METHOD: 205 consecutive eligible children seen in the paediatric units of two hospitals in Nigeria were recruited into the study. All enrolled children were healthy with no chronic medical condition. Consent for study participation was received from their accompanying parent. The accompanying parent of each child was questioned on the duration of breast and bottle feeding, and form of breast feeding and the frequency of daily intake of sugary diet. The associations between sex, age of the child, frequency of daily consumption of sugar, birth rank, duration of breast feeding, form of breast feeding and duration of bottle feeding and rampant caries were established. RESULTS: No association was found between the occurrence of rampant caries and sex, birth rank, duration of breast feeding, form of breast feeding and duration of bottle feeding. However, and association existed between the rampant caries, the age (p < 0.001) of the child and frequency of daily consumption of sugar (p = 0.026). The odds for rampant caries was 0.63 for every year decrease in age (95% CI 0.53 to 0.76) p < 0.001. Also, the odds for rampant caries was 1.46 for every increase in frequency of daily consumption of sugar (95% CI 1.10 to 1.95) p = 0.009. However, threshold for rampant caries was established at a frequency of daily consumption of sugar greater than three times a day. At this threshold, the risk for rampant caries increased by 0.26 when the frequency of daily consumption of sugar is greater than 3 times a day (95% CI 0.023 to 0.50) p = 0.032. CONCLUSION: Children who report consuming sugary diet more than three times a day should be managed as a high risk patient for rampant caries. PMID- 23457872 TI - Barriers to cataract surgery of persons screened at camps in Ibadan, Nigeria. AB - PURPOSE: To determine barriers to uptake of cataract surgery by outreach patients at the University College Hospital, Ibadan and to make appropriate recommendations for improved cataract surgery uptake METHODS: Consenting cataract blind/visually impaired (presenting vision < 6/18) outreach patients identified from the outreach patient register of the University College Hospital, (UCH) Ibadan during a five months period (January to May 2009) were followed up for a visit in late June and July 2009. A semi-structured questionnaire schedule was used for data collection. People who did not use the services were administered a barriers questionnaire-schedule while those who accepted the services were administered a questionnaire schedule to elicit motivating factors for acceptance of services. Subjects were also examined using standard ophthalmic equipment (pen torch, ETDRS vision charts and ophthalmoscope) and information obtained recorded in a data entry form. RESULTS: A total of 186 subjects comprising 115 who had undergone cataract surgery and 71 who were yet to access cataract surgery services were followed up and included in the study. Reason for accessing surgery included awareness of quality service 63 (57.0%), was referred 32(29.0%) and pressure from family or friends 13(12.0%). Barriers to access included, untreated medical problems 21 (29.0%), not able to afford total (direct and indirect) cost of treatment 15 (21.0%), cataract not mature 10 (14.0%), not able to afford cost of surgery 9 (13.0%) and Dr's appointment 8 (11.0%). CONCLUSION: barriers to surgery uptake by outreach camp patients include cost of services, underlying medical problems and preferred doctors' practice. Adoption and scaling up of health insurance to cover those most in need as well as a change in preferred practice amongst eye care practitioners are possible areas for intervention. PMID- 23457873 TI - Oro-facial squamous cell carcinoma--a twenty-year retrospective clinicopathological study. AB - BACKGROUND: Squamous cell carcinoma of the orofacial region is a potentially life threatening malignant epithelial neoplasm. There have been few studies on the relationship between clinical variables and histological grade among patients with oro-facial carcinoma. We sought to find correlation (if any) between clinical profile, anatomical location and histological grade of these tumours. METHODOLOGY: A retrospective study of all histologically diagnosed oro-facial squamous cell carcinoma cases seen at the University College Hospital, Ibadan between 1990 and 2009. RESULTS: Squamous cell carcinomas constituted 176 (38%) of all oro-facial malignancies. They comprised 91 males and 85 females with mean age of 57 (+/- 16.4) years. The maxillary region was most frequently affected (25%) while the lip was least involved (3.4%). Well-differentiated squamous cell carcinomas constituted 49%, moderately differentiated carcinoma accounted for 36.8% while poorly-differentiated squamous cell carcinomas constituted 14.2%. Well-differentiated and moderately differentiated tumours were relatively more common among subjects older than 50 years of age and poorly-differentiated tumours were more common before 50 years of age (p= 0.001). Degree of tumour differentiation was not correlated with gender (p = 0.88), and anatomical location (p = 0.17). CONCLUSION: Further clinical studies may be required to determine whether oro-facial carcinoma in patients less than 50 years of age has a more aggressive behaviour than in older patients. PMID- 23457874 TI - delGA (rs67491583) variant and colorectal cancer risk in an indigenous African population. AB - BACKGROUND: A recent study showed a higher frequency of GA deletion at rs67491583 in African American colorectal cancer (CRC) patients compared to controls, suggesting a likely contribution of this allele to racial disparity in CRC risk predisposition. We conducted a pilot study in an indigenous African population to evaluate this potential CRC risk variant. METHODS: We collected epidemiological data and biological specimen from consenting consecutive CRC cases and controls presenting at the Oncology Clinic of University College Hospital, Ibadan from 2001 to 2007. We examined germline DNA for delGA by PCR-amplification of two overlapping fragments using standard primers. The products were directly sequenced using Applied Biosystems BigDye v3.1 sequencing chemistry and AB 13730 automatic DNA sequencer. RESULTS: There were 45 cases and 45 controls of which genotyping was successful in 39 cases and 38 controls. There were 5 heterozygous and 2 homozygous GA deletions with frequency of 11.54% (9/78) among cases whereas there were 8 heterozygous and 1 homozygous GA deletions among controls with frequency of 13.15% (10/76). (p= 0.79, OR 0.88, 95% CI 0.34-2.28). CONCLUSION: This study suggests that there is no association between the delGA (rs67491583) variant and CRC risk in this indigenous African population. However our sample size was small and the participants were not ethnically homogenous. Further studies are required to evaluate this marker in African CRC. PMID- 23457875 TI - Dental health service utilisation by resident doctors/medical officers in the University College Hospital, Ibadan, Oyo State, Nigeria. AB - BACKGROUND: Dental disease is still a serious health problem universally possibly because dental health awareness and dental service utilization is still very low. The reported prevalence of dental diseases, especially periodontal disease, is higher among the black race while their rate of dental service utilization is lower in comparison to Caucasians. AIM: The aim of this study was to assess the rate of dental service utilization and identify the factors influencing such utilization by medical doctors and dentists in the University College Hospital, Ibadan. METHODOLOGY: Two hundred 26-item questionnaires were distributed among the resident doctors/medical officers in the University College Hospital, Ibadan, Oyo state. The questionnaire sought to know if there is any previous dental visits, the reason for such visits and any other follow-up visits afterward. One hundred and ninety of the doctors returned the filled questionnaires giving a response rate of 95%. Data analysis was done using Statistical Package for Social Sciences (SPSS) version 14.0. Level of statistical significance was set at p < 0.05. RESULTS: Majority of the respondents (65.3%) had a previous dental visit but only 25.3% was within the last one year of the study. Among those that had visited a dentist before, 59.7% did so for the symptomatic treatment of one ailment or the other and only 13.7% of them went back for the follow-up appointment after the resolution of their symptoms. There was a statistically significant difference between the rate of dental service utilization and the gender of the respondents (p < 0.001). There was no statistical significant relationship between the rate of dental service utilization and age of the respondents. CONCLUSION: The study showed that the rate of dental service utilization is low when compared with that of developed countries. Some factors identified as contributing to the lack of dental service utilization among the participants include prolonged and repeated dental appointments and the demand of their work. PMID- 23457876 TI - Phenotypic and genotypic expression of alpha thalassaemia in Ibadan, Nigeria. AB - BACKGROUND: Alpha thalassaemia is a common monogenic disorder found in most parts of the world but the severe form is restricted in its distribution while the mild deletional form of alpha- thalassaemia has a wider geographical distribution. METHODS: One hundred and fifty one Nigerians which included 29 patients with unexplained recurrent haemolytic anaemia had their a-thalassaemia status determined by gap PCR after being screened using red cell indices. RESULTS: Only the -alpha(3.7) deletion occurs among Nigerians with a gene frequency of 0.21. Forty-two per cent of the study population are heterozygotes, 9% are homozygotes while 49% are normal for this deletion. The mean haematocrit for the study population is 37.5%: homozygote, heterozygotes and normal subjects had a mean haematocrit of 37.3%, 37.5% and 37.7% respectively. The mean mean corpuscular haemoglobin (MCH) and haematocrit are significantly lower for patients than controls (24 +/- 2.9 pg vs. 26.6 +/- 2.5 pg (p = .000), 29% vs. 40% (p = .000) respectively). Forty three percent of both patients and controls had MCH of less than 27 pg but only 10% of patients had MCH that is greater than 27pg. Homozygote patients had a higher mean haematocrit than patients who are normal for the deletion (34.7% vs. 25.4%, p = 0.06) but homozygote patients had a lower mean haematocrit than homozygote controls (34.7% vs. 38.5%, p = 0.4). CONCLUSION: This would suggest that alpha-thalassaemia is not responsible for the recurrent haemolytic anaemia observed in these patients and that the high prevalence of microcytosis among the normal populace needs further exploration. PMID- 23457877 TI - Correlation of cag-A serological status with histological parameters of chronic gastritis among dyspeptic patients in south western Nigeria. AB - BACKGROUND: The aim of this study was to determine the sero-prevalence of Cag-A strains of Helicobacter pylori in both dyspeptic and non-dyspeptic individuals and also correlate the serological status of Gag-A strain of H. pylori with the various graded histological variables of chronic gastritis in the dyspeptic patients. METHODS: Using helicobacter p120 Cag-A enzyme linked immunosorbent assay, Cag-A serology test was carried out on 65 dyspeptic patients and 65 age and sex matched non-dyspeptic controls. The gastric biopsies of the patients were also histologically examined to ascertain the presence, nature and degree of the following histological variables of gastritis: colonisation by H. pylori; inflammation, intestinal metaplasia and mucosal atrophy. The CagA serological status was then correlated with the graded variables. RESULTS: A prevalence of 46.2% and 58.8% seropositivity for Cag-A strain of H. pylori was found among dyspeptic patients and control individuals respectively. Cag-A seropositive patients accounted for nine(81.8%) of the 11 cases with moderate to severe activity and 75% of both cases with mucosal atrophy and cases with intestinal metaplasia. CONCLUSION: Infection with Cag-A positive Helicobacter pylori was equally prevalent among both dyspeptic patients and control subjects studied. CagA seropositivity, however, appeared to be associated with higher inflammatory activity in the mucosa of patients with chronic gastritis and may be associated with intestinal metaplasia and mucosal atrophy in H. pylori-induced chronic gastritis. PMID- 23457878 TI - Accuracy of age estimation using Demirjian method among Nigerian children. AB - INTRODUCTION: Accurate age determination is important in paediatric dentistry, orthodontics, forensic identification of deceased persons, among other reasons. In developing countries where accurate birth records are lacking, scientific methods of accurately assessing patients' ages are relevant. Many methods for age determination using the dentition exist but the most widely used is that proposed by Demirjian in 1973. This study aimed to determine the accuracy of age determination using the Demirjian method among Nigerian children. METHODOLOGY: Orthopanthomograms of children seen at the orthodontic clinic of the University College Hospital, Ibadan were reviewed. Chronological age was calculated from date of birth recorded at registration to the nearest decimal. Dental age was calculated using the Demirjian criteria (1973). Boys and girls were analysed separately to allow for gender related variations in dental development. The paired t-test and correlation analysis were used to compare the chronological age and calculated dental age. RESULTS: Ninety-three children (41 boys and 52 girls) with ages ranging from 4.42 to 16.75 years (mean 10.69 years for boys and 10.50 years for girls) were assessed using the Demirjian method. There was a significant difference between the chronological and dental age among the boys (p = 0.009); the converse was the case among the girls (p = 0.051). The chronological and dental age of the children showed high correlation (p < 0.01). CONCLUSION: There are variations between chronological age and dental development among Nigerian children. Other methods of age determination should be explored for this population. PMID- 23457879 TI - Factors influencing the immediate postoperative outcome in operated head injured patients in Ibadan, Nigeria. AB - INTRODUCTION: The injured brain is subjected to anaesthetic agents and various intravenous fluids which may exacerbate haemodynamic instability, increase cerebral blood volume and intracranial pressure. OBJECTIVE: The study examined factors that influenced the immediate postoperative outcome in head injured patients who underwent general anaesthesia in a tertiary health care facility. METHODS: The demographic and outcome data of all head injured patients who had neurosurgical procedures under general anaesthesia in our centre between January and December 2010 were compiled prospectively. Outcome was measured using the Glasgow Coma Scale (GCS), good outcome was defined as an improvement in the GCS/recovery while poor outcome as worsening of GCS / mortality post operatively. The data were analyzed using SPSS 16.0 and p value was set at 0.05. RESULTS: Ninety nine patients were recruited. The patients' median age was 37.0 years and 81.8% were males. The most affected age group was 17-49 years. Indications for surgery were compound depressed skull fracture 28.3%, intracerebral haematoma 17.2%, subdural 35.4% and extradural haematoma 13.1% and impacted intracranial foreign body 6%. Eighty six percent of the patients had their head injury following road traffic accident. Fatality rate was 16.2%. Outcome was poor in patients with severe head injury (13%) compared with patients with mild (1.1%) and moderate head injury (2%) p = 0.001, and poor in American Society of Anaesthesiologist's (ASA) 3 (9%) and 4 (6%) classification compared to ASA 2 (1%) (p = 0.0069). Outcome was also poor in patients with intracerebral haematoma (9%) and acute subdural haematoma (2%) compared to that of depressed skull fracture (1%) (P=0.002) and in patients with intraoperative hypotension (13.1%) compared with those with normal blood pressure (1%) (p = 0.001). CONCLUSION: Road traffic accident is the leading cause of head injury, increasing ASA, decreasing GCS, type of cranial lesion and intraoperative hypotension are some of the factors affecting outcome in operated head injuries. Efforts should be made to reduce the incidence of intra operative hypotension to increase good outcome in operated head injured patients. PMID- 23457880 TI - Morphologic multiplicity of smooth muscle cell monolayers from extreme lung parenchyma of high-altitude-hypoxia sheep. AB - BACKGROUND: Chronic hypoxia causes lung pathology but little is known about how morphologic changes occur or about the progenitor cells of lung remodeling. Since the alveolar region is the first site of environmental challenge, smooth muscle cell (SMC) monolayers derived from close to the alveoli were studied for morphologic patterns. Thus we aimed to deduce any impact of environmental challenge on juxta-alveolar cells and identify phenotypical changes that are suspect precedence to lung pathologies such as cancer. METHODS.: Lung tissues from freshly sacrificed adult sheep that had been kept in high altitude hypoxia for approximately 4 months were used. The lung tissues were studied for macroscopic signs of pathology. Lung parenchymal explants from approximately 0.5 1.5 mm to the lung edge were cultured for isolation of upper generation SMCs which are closer to the air/blood interphase. The cells were characterized by fluorescence immunohistochemistry using a monoclonal antibody against alpha smooth muscle actin. The monolayer morphologies of the derived stable cell lines were compared. RESULTS: We observed that the distal lung parenchyma of the chronically hypoxic sheep yielded six distinct smooth muscle cell morphological varieties: apoptotic, sub-confluent, spindle-form, hill and valley, swirl, and rhomboid monolayers. The control sheep lungs yielded two varieties of smooth muscle cells: swirl and hill-and-valley monolayer formations at confluence. All the cell lines were jointly generated from the terminals of the vascular and bronchiolar trees. CONCLUSION: Chronic high altitude hypoxia appears to induce morphological variation in juxta-alveolar smooth muscle cells in the ovine lung. PMID- 23457881 TI - Office based muscle biopsy using Vacora vacuum assisted biopsy system. AB - INTRODUCTION: Muscle biopsy is a minor surgical procedure that has been conducted over several decades in clinical practice. Over the years, the technique to implement this procedure has been modified to make it easier to perform and more tolerable for the patient. This study aimed to assess the feasibility of muscle biopsy as an office based procedure, by using a vacuum Assisted Biopsy System. METHOD: The procedure was successfully carried out on 57 individuals with/without diabetes, currently involved in the African American Diabetes Mellitus Study. One specimen was collected percutaneously from the vastus lateralis, under local anesthesia. A 16-gauge needle was used. RESULTS: Muscle biopsies were successfully carried out on all study participants. The study participants reported no complications after the procedure. CONCLUSION: The findings from our study show that muscle biopsy can be feasibly implemented as an office based procedure, involving minimal muscle invasion, less trauma, hospital stay time, and expenses. PMID- 23457882 TI - Pseudoangiosarcomatous squamous cell carcinoma in an old surgical scar of an African woman. AB - BACKGROUND: Squamous cell carcinoma, a malignant proliferation of keratinocytes, can be found in many regions of the body covered by stratified squamous epithelium and in areas covered by other epithelia but which had undergone squamous metaplasia. Squamous cell carcinoma has many variants. METHODOLOGY: We, retrospectively, reviewed the case file and histological features of a 75 year old trader with a rare variant of squamous cell carcinoma arising from an old surgical scar. CASE REPORT: The 75-year-old African female trader presented to the hospital with three and a-half month history of a swelling in the anterior aspect of the left leg arising from an old surgical scar. Clinical examination showed an irregularly shaped ulcer measuring 14 x 16 cm with an everted edge and a hyperpigmented floor. Histologic sections of the specimen showed the infiltration of the papillary and reticular dermis of the skin by sheets of atypical spindle cells with areas of squamous differentiation. There was a contiguous area of capillary-like structures constituting about 30% of the sections examined. The neoplastic cells were positive for vimentin and cytokeratin but were negative for CD34. The diagnosis was pseudoangiosarcomatous squamous cell carcinoma. CONCLUSION: This tumour can be found in Africans and in an old surgical scar. It can coexist with other variants of squamous cell carcinoma. There may be need in the future to add a new mixed variant to the current classification scheme. PMID- 23457883 TI - Interim prosthetic rehabilitation of postmandibulectomy defect using a single piece acrylic denture: a case report. AB - INTRODUCTION: Prosthetic rehabilitation of mandibular discontinuity defects poses a great challenge to prosthodontists especially when surgical reconstruction is not carried out prior to rehabilitation. METHOD: A 25-year-old young man was referred to the prosthetic unit of the Dental Centre, University College Hospital Ibadan with an anterior discontinuity defect following resection of a mandibular tumour. After clinical and laboratory procedures, the prosthesis used to rehabilitate the patient is unique because it is simple, made of heat cure acrylic resin, affordable and aesthetically pleasing. It is essentially a single piece removable acrylic partial denture retained with wrought wire clasps. RESULT: Patient was satisfied with the prosthesis. DISCUSSION: Although a number of studies have reported procedures for prosthetic rehabilitation of mandibular discontinuity defects, there is a dearth of information on single piece acrylic prosthesis in the management of discontinuity defects. The effect of acrylic denture on residual soft tissue was weighed against the quality of life of patient if left untreated. CONCLUSION: It is recommended that the National Health Insurance Scheme includes simple interim prostheses as part of its package to improve the quality of life of the people. PMID- 23457884 TI - Transcatheter closure of patent ductus arteriosus: report of the first case in Nigeria. AB - BACKGROUND: Since the first report on device closure of patent ductus arteriosus (PDA) by Porstmann et al in 1967, the procedure has gained wide acceptance and has been used all over the world, including parts of Africa. The advantages when compared to surgical closure include shorter procedure time and hospital stay and no scar being left. This mode of treatment was not available in Nigeria prior to this with patients having to travel abroad to benefit. PATIENT AND METHOD: Cardiac catheterisation laboratory became available in Lagos, Nigeria in 2009 and in October 2010, the laboratory collaborated with Lagos State University College of Medicine (LASUCOM) and Lagos State University Teaching Hospital (LASUTH), to perform a device closure on a 3-year old girl with PDA who had presented to LASUTH with heart failure at the age of 6 months. To the best of our knowledge, this is the first time the procedure has been performed in Nigeria RESULTS: The patient made a successful recovery and is haemodynamically stable, on no medications. CONCLUSION: Device closure of PDA is now safe and available in Nigeria. PMID- 23457885 TI - Results of a pilot study to reduce methamphetamine use and sexual risk behaviors among methamphetamine-using men who have sex with men (MSM) not currently in treatment. AB - Methamphetamine use, which has been linked to unprotected anal intercourse and incident HIV infection, is an important contributor to HIV transmission among men who have sex with men (MSM). The purpose of this study was to develop and pilot test a single-session motivational interviewing (MI) intervention for reducing HIV risk among an out-of-treatment sample of MSM who use methamphetamine. MSM who use methamphetamine (n = 39) were recruited in 2008 and 2009 in North Carolina. They completed baseline data collection and a single-session MI intervention. Eighty percent completed a follow-up interview two months after enrollment. Men reported reductions in methamphetamine use during the previous 60 days from an average of 9.4 days at baseline to 3.3 days at follow-up (p < 0.05) and unprotected anal intercourse from an average of 4.8 sex partners during the previous 60 days at baseline to 2.9 at follow-up (p < 0.05). Self-reported unprotected anal intercourse at last sex with a nonprimary partner decreased significantly (from 81% at baseline to 25% at follow-up; p = 0.001). These results suggest that a single-session MI intervention may be useful for reducing methamphetamine use and sexual risk among MSM who use methamphetamine, especially in settings where multisession interventions are not feasible. PMID- 23457886 TI - Drugs and sexual behavior. AB - This study investigated the association between drugs and sexual behavior in a sample of polydrug substance abusers recruited from several Italian therapeutic communities; participants were 90 polydrug substance abusers (opiates, cocaine, amphetamine, inhalants, marijuana/sedatives or hallucinogens abusers) who were compared with 90 nonsubstance-abusing individuals. Sexual behavior was measured by the Italian version of the Sex and the Average Woman (or Man; SAWM), a questionnaire that assesses different kind of sexual attitudes. Results showed that drug-abusing individuals are particularly inclined to search for sexual intercourse and are open to different kinds of sexual experiences; however, they have difficulties in establishing committed and deep relationships with their partners, showing signs of inhibition, affective detachment or anger. Their sexual lives are also surrounded by negative emotions, disturbing thoughts and maladjusted behaviors. The importance of integrating sexual problems into therapeutic strategies is discussed. PMID- 23457887 TI - Helium inhalation in adolescents: characteristics of users and prevalence of use. AB - Although helium-related fatalities and concerns about potentially harmful effects of helium use have increased in recent years, virtually nothing is known about the epidemiology of helium inhalation in adolescents. This exploratory investigation examined the prevalence and correlates of helium inhalation in a large sample of at-risk youth. Study participants were 723 Missouri adolescents (M age = 15.5, SD = 1.2) in residential treatment for delinquent behavior. More than one-in-nine (N = 81, 11.5%) adolescents had inhaled helium with the intention of getting high, and one-third (N = 27, 34.2%) of helium users reported they actually did get high when they inhaled helium. Helium users were significantly more likely to be Caucasian, to live in rural/small town areas, and to have histories of mental illness, auditory hallucinations, and alcohol and marijuana use than nonusers. Helium users also reported significantly more current psychiatric distress, suicidality, traumatic life experiences, and antisocial attitudes, traits, and behaviors than nonusers. Helium inhalation was prevalent in this sample and many such users reported getting high while using helium. Helium users had psychosocial profiles similar to those of volatile solvent users, suggesting that they may be at substantial risk for a variety of adverse health outcomes. PMID- 23457888 TI - Developing the climate schools: ecstasy module--a universal Internet-based drug prevention program. AB - The Climate Schools: Ecstasy module is a universal harm-minimisation school-based prevention program for adolescents aged 14 to 16 years. The program was developed to address the need for Ecstasy prevention given the increasing use of Ecstasy use among young Australians. The core content of the program is delivered over the Internet using cartoon storylines to engage students, and the teacher-driven activities reinforce the core information. The three-lesson program is embedded within the school health curriculum and is easy to implement with minimal teacher training required. The program was developed in 2010 through extensive collaboration with students (n = 8), teachers (n = 10) and health professionals (n = 10) in Sydney, Australia. This article describes the formative research and process of planning that formed the development of the program and the evidence base underpinning the approach. PMID- 23457889 TI - Mental health symptoms and their relationship to cannabis use in adolescents attending residential treatment. AB - The present study examined mental health symptoms and their relationship to cannabis use and treatment outcomes in a sample of adolescents who received treatment for cannabis dependence through a residential substance use program. The sample included 132 adolescents who nominated cannabis as their primary drug of concern upon admission and who completed at least 30 days of treatment. This study found that mental health symptoms of young cannabis users reduced significantly from admission to three-month follow-up. Further, pretreatment symptoms of anxiety were associated with greater pretreatment cannabis use, while symptoms of phobic anxiety were associated with less pretreatment cannabis use. Pretreatment obsessive-compulsive and somatization symptoms were associated with greater follow-up cannabis use, whereas pretreatment paranoid ideation symptoms were associated with less follow-up cannabis use. Further, follow-up somatization, obsessive-compulsive symptoms, hostility, and phobic anxiety were associated with greater follow-up cannabis use while follow-up symptoms of interpersonal sensitivity were associated with less follow-up cannabis use. These findings highlight a variety of areas for further investigation in order to enhance current treatment for cannabis use. PMID- 23457890 TI - Adolescents' experiences of a strengths-based treatment program for substance abuse. AB - Substance abuse is a growing issue among adolescents. While not every adolescent who struggles with this issue seeks treatment, those who do frequently fail to complete treatment or tend to relapse following treatment. To improve adolescent treatments for substance abuse issues it is important to understand adolescent experiences while in treatment, along with the factors that contribute to positive treatment outcomes. Qualitative methods were used to examine 52 post treatment interviews conducted with adolescents following their completion of a five-week strengths-based residential program for substance use issues. The adolescent narratives were analyzed to answer three research questions: (1) what aspects of the treatment program were found to be most helpful by youth, (2) which specific strengths did youth identify to be the most helpful throughout the treatment process and in beginning to overcome their substance use issues, and (3) did youth begin to adopt strengths-based thinking strategies over the course of treatment? Results include descriptive answers to these questions based on common themes across participant responses. Implications for future research are discussed. PMID- 23457892 TI - Illicit use of LSD or psilocybin, but not MDMA or nonpsychedelic drugs, is associated with mystical experiences in a dose-dependent manner. AB - Psychedelic drugs have long been known to be capable of inducing mystical or transcendental experiences. However, given the common "recreational" nature of much present-day psychedelic use, with typical doses tending to be lower than those commonly taken in the 1960s, the extent to which illicit use of psychedelics today is associated with mystical experiences is not known. Furthermore the mild psychedelic MDMA ("Ecstasy") is more popular today than "full" psychedelics such as LSD or psilocybin, and the contribution of illicit MDMA use to mystical experiences is not known. The present study recruited 337 adults from the website and newsletter of the Multidisciplinary Association for Psychedelic Studies (MAPS), most of whom reported use of a variety of drugs both licit and illicit including psychedelics. Although only a quarter of the sample reported "spiritual" motives for using psychedelics, use of LSD and psilocybin was significantly positively related to scores on two well-known indices of mystical experiences in a dose-related manner, whereas use of MDMA, cannabis, cocaine, opiates and alcohol was not. Results suggest that even in today's context of "recreational" drug use, psychedelics such as LSD and psilocybin, when taken at higher doses, continue to induce mystical experiences in many users. PMID- 23457893 TI - Neuroenhancement among German university students: motives, expectations, and relationship with psychoactive lifestyle drugs. AB - Recent research has indicated that neuroenhancement (NE), the use of legal or illegal drugs by healthy individuals to improve their cognitive performance, is widely practiced among students in both the United States and Germany. The primary objective of this study was to identify the motives for and beliefs regarding the benefits and risks of practicing NE among a sample of German university students and graduates. The secondary objective was to determine the relationship between the use of neuroenhancers and the use of several common psychoactive lifestyle drugs. A web-based survey was used to interview students and postgraduates. Of the 1,324 participants, 93 reported having practiced NE for the primary motives of improving concentration (55%) and increasing vigilance (49%). Participants who reported having practiced NE were more likely to assess NE as more beneficial and less harmful compared to participants who reported not having practiced NE. The former also reported greater use of all lifestyle drugs except alcohol compared to the latter. The primary motives for practicing NE are associated with management of a high level of stress and a large academic workload. As such, decreasing the prevalence of NE among students requires implementation of strategies targeting stress reduction and workload management. PMID- 23457891 TI - Early intervention of intravenous KB220IV--neuroadaptagen amino-acid therapy (NAAT) improves behavioral outcomes in a residential addiction treatment program: a pilot study. AB - Substance use disorders (SUD) are inheritable and the culprit is hypodopaminergic function regulated by reward genes. We evaluated a natural dopaminergic agonist; KB220 intravenous (IV) and oral variants, to improve dopaminergic function in SUD. Our pilot experiment found a significant reduction of chronic symptoms, measured by the Chronic Abstinence Symptom Severity (CASS) Scale. The combined group (IV and oral) did significantly better than the oral-only group over the first week and 30-day follow-up period. Next, the combination was given to 129 subjects and three factors; Emotion, Somatic, and Impaired Cognition, with eigenvalues greater than one were extracted for baseline CASS-Revised (CASS-R) variables. Paired sample t-tests for pre and post-treatment scales showed significant declines (p = .00001) from pre- to post-treatment: t = 19.1 for Emotion, t = 16.1 for Somatic, and t = 14.9 for Impaired Cognition. In a two-year follow-up of 23 subjects who underwent KB220IV therapy (at least five IV treatments over seven days) plus orals for 30+ days: 21 (91%) were sober at six months, 19 (82%) having no relapse; 19 (82%) were sober at one year, 18 (78%) having no relapse; and 21 (91%) were sober two-years post-treatment, 16(70%) having no relapse. We await additional research and advise caution in interpreting these encouraging results. PMID- 23457894 TI - Racial and ethnic differences in reported criminal justice referral at treatment admission. AB - In the U.S. and elsewhere, the criminal justice system is a frequent referral source for substance abuse treatment admission. To expand and improve pathways to treatment, outreach efforts need additional information about different demographic groups. Locally, clinicians observed racial and ethnic differences between minority groups in self-identifying criminal justice as the referral sources for admission. To test this clinical observation, reported criminal justice referral was examined by race/ethnicity and gender in multiple years of both national and local treatment admissions. Confirming the clinical observations, racial/ethnic referral source by gender systematically differed across years nationally (p < .001) and in an examination of verbatim recorded presenting problems locally (p < .001). African Americans and Puerto Ricans were less likely to have criminal justice referral sources than the White reference group, whereas American Indians, Arab Americans, Asian Americans, and other Hispanic ethnicities were more likely to have criminal justice referral sources. Racial/ethnic groups systematically differed in reported criminal justice involvement, suggesting hypotheses potentially impacting clinical treatment and outreach. Published primary referral sources may underestimate criminal justice involvement in treatment admissions. PMID- 23457895 TI - A case of treating cathinone dependence and comorbid depression using bupropion. AB - Cathinone is a potent CNS stimulant found in khat leaves. Cathinone and synthetic cathinone-derivatives have become popular recreational drugs in recent years, commonly marketed as "legal highs." In addition to acute physical and psychiatric adverse effects, dependence on these substances is a concern. The following case reports describes a young man with cathinone dependence and depression that was treated using bupropion. Bupropion is a cathinone-derivative with a dual dopamine norepinephrine reuptake inhibiting mechanism, which is approved for the treatment of depression and smoking cessation. Clinical awareness to the addictive potential of cathinone and cathinone-derivatives is important. Research regarding the potential effectiveness of bupropion in these cases is needed. PMID- 23457897 TI - Training today. PMID- 23457898 TI - Indications for cone-beam computed tomography in the area of oral and maxillofacial surgery. AB - The aim of this study was to identify specific indications for dental cone-beam computed tomography (CBCT) in the field of oral and maxillofacial surgery. To this end, we compared the efficacy of CBCT to that of panoramic radiography, the standard imaging modality, for the evaluation of different surgical questions in the oral and maxillofacial region. Dentall CBCT proved to be particularly useful in cases where visualization of a second plane is necessary for implant planning or for pre-surgical evaluation of retained and displaced teeth posing a risk to adjacent structures. It is also indicated for precise localization of luxated teeth and dental implants dislocated into surrounding areas, localization of the mandibular canal to assess its anatomical relationship to overfilled root canal filling materials, assessment ofthe extent of osseous lesions, and evaluation of patients with suspected mandibular or condylar fractures. The main advantages of CBCT are reduction of the risks of surgery due to the free selection of imaging planes, maindibular canal marking, 1:1 magnification, and the ability to use DICOM data in other implant or surgical planning software. Adequate user experience is important for proper evaluation of dental CBCT scans, as is the diagnosis of incidental findings falling into areas not primarily related to dentistry and therefore requiring additional investigation. PMID- 23457896 TI - An examination of the Fagerstrom Test for Nicotine Dependence among concurrent tobacco and khat users. AB - The current study examined the psychometric properties of the Fagerstrom Test for Nicotine Dependence (FTND) among tobacco smokers who use khat (Catha edulis), a widely used substance in East Africa and Arabian Peninsula. We also explored gender differences in response to FTND items because little attention has been paid to women's smoking behavior in Middle Eastern societies. A total of 103 (38 women) concurrent users (mean age +/- SD: 24.4 +/- 5.2) were recruited from two universities in Yemen. An Arabic version of FTND was developed using back translation method. Chronbach's alpha was used to examine the reliability and principal component analysis was conducted to test the factor structure of the scale. The scale was found to have low internal consistency reliability (Chronbach's alpha = .58). Two factors were identified, accounting for 57% of the total variance. A series of chi-square analyses found that men indicated more symptoms associated with nicotine dependence than women (ps < .05). Although the poor reliability observed in the present sample argues for a cautious approach when assessing nicotine dependence among khat users, the findings on factor structure and gender differences may provide support for the validity of the scale. Taking into account sociocultural factors associated with patterns of smoking behavior among this population should improve the psychometric properties of FTND. PMID- 23457899 TI - Comparison of cone beam computed tomography scans with and without simulation of head motion. AB - PURPOSE: To test for differences in image quality between 3D volumetric datasets acquired by cone beam computed tomography (CBCT) with and without simulation of head motion by visual analysis of individual image sections and by comparison of scan-based distance and Hounsfield unit (HU) measurements. MATERIALS AND METHODS: A total of 200 volumetric datasets were acquired with and without remote controlled, simulated movement of a human cadaver head using the KaVo 3D eXam CBCT system. RESULTS: The "Landscape 8 x 8 cm Slide" mode provided a sufficient field of view at a low radiation dose. All datasets showed reproducible results. Our analysis showed that the level of image quality and image detail increased with increasing resolution. Linear distance measurements and HU measurements in the cone beam CT scans acquired without simulation of head motion were absolutely comparable to those obtained with head motion simulation. CONCLUSIONS: There is no practical difference in image quality between CBCT scans acquired with and without head motion if no long-term change in head position occurs during the acquisition process. Slight head movement has no clinically relevant effect on the geometric accuracy or visual image quality of cone beam CT scans. PMID- 23457900 TI - Clinical relevance of surface EMG of the masticatory muscles. (Part 1): Resting activity, maximal and submaximal voluntary contraction, symmetry of EMG activity. AB - Based on a comprehensive computerized literature search supplemented by a specific manual search of the literature, the present review article focuses on concrete aspects of the application of surface electromyography (EMG) for evaluation of the masticatory muscles in general and of the masseter and anterior temporal muscles in particular, and presents the current base of knowledge on the clinical relevance of surface EMG in dental applications. In the first stage of the review, publications from the year 2000 or later reporting the results of controlled clinical trials (randomized as far as available) of patients with craniomandibular or temporomandibular disorders (TMD) were analyzed. Data from the selected publications were systematically compiled and divided into subject areas as follows: Resting activity, maximal and sub-maximal voluntary contraction, symmetry of EMG activity, and fatigue effects; EMG activity during mastication, factors (including pain) that affect EMG activity, and the impact of adjusting static and dynamic occlusal relationships; Effects of occlusal splints and other occlusal treatments. Surface electromyography is in principle a suitable tool for neuromuscular function analysis in the field of dentistry. If used according to the specific recommendations and in conjunction with a thorough and conscientious clinical history and physical examination, surface EMG measurements can provide objective, documentable, valid, and reproducible data on the functional condition of the masticatory muscles of an individual patient. PMID- 23457901 TI - Accuracy of CAD/CAM crown fit with infrared and LED cameras. AB - PURPOSE: The intraoral recording of digital images is a critical component of fabricating accurate Cerec restorations. This study evaluated the marginal fit and internal adaptation of Cerec ceramic crowns fabricated using different cameras, alternative powdering materials, and multiple image capture sequences. MATERIALS AND METHODS: A master epoxy resin model was fabricated using a polyvinylsiloxane (PVS) impression of a typodont with an all-ceramic crown preparation on tooth 14. A titanium dioxide powder/mechanical sprayer and an aerosol contrast spray were used to create a uniformly reflective surface. An infrared laser Cerec 3/RedCam unit and LED Cerec AC/BlueCam unit were used to record images for crown fabrication. Three different image capture sequences were performed to record the data. Crowns were made for each test group using a Cerec AC unit with V3.80 software. The crowns were milled from blocks of IPS EmpressCAD. Marginal fit and internal adaptation of the crowns to the master model of the preparation was assessed with a measuring microscope at 20X. The data was analyzed using a two-way ANOVA. RESULTS: No significant differences were found in the marginal fit, axial wall adaptation, or occlusal wall adaptation between any of the test groups (p < 0.05). CONCLUSION: Within the confines of this in vitro study, there were no significant differences between the marginal fit and internal adaptation of Cerec CAD/CAM ceramic crowns fabricated with: 1) the infrared laser camera (RedCam) and the LED camera (BlueCam), 2) titanium dioxide powder or aerosol contrast spray, or 3) multiple imaging sequences for recording the preparation and adjacent teeth. PMID- 23457902 TI - Chairside dental imaging processing with DentalMagic. PMID- 23457903 TI - Long-term follow-up after percutaneous coronary intervention with polytetrafluoroethylene-covered Symbiot stents compared to bare metal stents, with and without FilterWire embolic protection, in diseased saphenous vein grafts. AB - OBJECTIVES: The long-term clinical outcome of covered stents in the percutaneous treatment of diseased saphenous vein graft (SVG) has been disappointing. The single self-expanding polytetrafluoroethylene (PTFE)-covered Symbiot stent with a unique profile may present advantages that translate into superior long-term clinical outcomes. This study evaluated the safety, effectiveness and clinical outcome of the Symbiot covered stent system (Boston Scientific, Natick, Mass.) and FilterWire EX (Boston Scientific, Natick, Mass.) versus bare metal stents (BMS) in SVG intervention. METHODS AND RESULTS: Between January 2003 and August 2005, 90 patients with degenerative SVG lesions were prospectively randomized at 6 study sites to Symbiot implantation (n = 30), BMS with FilterWire as embolic protection device (EPD, n = 30), or BMS without EPD (control group, n = 30). The primary end point was reduction in peri-procedural cardiac enzyme rise. The major secondary end points were in-hospital, 6-month and long-term target vessel failure rates, defined as the cumulative of death, myocardial infarction and clinically driven target lesion revascularization. There was no significant reduction in median [IQR] post-procedural troponin-I rise in the Symbiot group compared to the FilterWire or the control group (0.08 [0-1.40] microg/l; 0.06 [0 0.28] microg/l; and 0.04 [0-0.31] microg/l, P = 0.58). At 7.4 +/- 1.3 (mean +/- SD) years, there were numerically less deaths in the Symbiot group, although this did not reach statistical significance (P = 0.20). There was no significant difference in TVF-free survival between the treatment groups (P = 0.98). CONCLUSION: This study failed to show a procedural or long-term clinical advantage for the Symbiot PTFE-covered stent in the treatment of degenerated SVG. PMID- 23457904 TI - Risk stratification models in elderly patients: recalibrating or remodeling? AB - OBJECTIVE: Risk stratification models perform poorly regarding elderly patients. This study aims to evaluate the performance of the Italian Coronary Artery Bypass Graft Outcome Project (ItCABG) model and the logistic European System for Cardiac Operative Risk Evaluation (LogEuroSCORE) model by age group to build a model specifically for elderly patients. METHODS AND RESULTS: Data from the ItCABG and Mattone Outcome-BYPASS study (MO-BYPASS) have been used. ItCABG and LogEuroSCORE models were applied to the ItCABG population (n = 34,310) stratified by four age classes: < 60, 60-69, 70-79, > or = 80 years. Each model's ability to predict 30 day mortality was assessed for accuracy (Brier score and pseudo-R2), calibration (Hosmer-Lemeshow test, X(H-L)) and discrimination (area under the receiver operating characteristic curve, AUC) in age classes. To estimate the elderly risk function a logistic regression was performed on 2,255 octogenarian patients from ItCABG and MO-BYPASS. Elderly model's performance was tested. Model accuracy is fair in all age classes although the explained variance is poor. ItCABG and LogEuroSCORE models revealed good discrimination power in patients aged < (60, 60 69, and 70-79 years, but not in patients aged > or = 80 years (AUCs: 0.82, 0.77, 0.76, 0.64, and 0.78, 0.75, 0.74, 0.65, respectively). Calibration of both models is poor in patients 80 years (ItCABG: X(H-L) = 18.1, P = 0.05; LogEuroSCORE: X(H L) = 129.7, P < 0.001). When a new model specific to octogenarian patients was built, discrimination power remained poor (AUC = 0.66), although calibration power improved (X(H-L) = 3.93, P = 0.86). CONCLUSIONS: ItCABG and LogEuroSCORE models were poor predictors of mortality in octogenarian patients. Elderly specific risk factors must be assessed to improve risk stratification in patients aged 80 years and older. PMID- 23457905 TI - The relationship between coronary artery ectasia and eNOS intron 4a/b gene polymorphisms. AB - BACKGROUND: Little is known about the pathogenesis and genetics of coronary artery ectasia (CAE). We studied eNOS gene intron 4a/b polymorphism in this patient population. METHODS: The study group included 30 patients with non obstructive CAD besides CAE on coronary angiogram performed due to positive non invasive diagnostic test results. The control group included 20 patients with normal coronary arteries. Agarose gel electrophoresis was used to identify eNOS gene polymorphisms. RESULTS: Only one coronary vessel was involved in most of the study cohort and the left anterior descending artery (LAD) was the most frequently involved vessel. The frequencies of eNOS gene phenotypes in the CAE group were 3.3% for"aa", 53.3% for"ab" and they were higher than in the control group. However, statistical significance was not reached (chi2 = 5.10, P = 0.08). When compared with the control group the presence of "a" type allele of eNOS gene was significantly more frequent in the CAE group (chi2 = 4.88, P = 0.027). By univariate analysis, eNOS gene polymorphism was correlated with CAE but this significance was attenuated after additional adjustment for potential confounding. CONCLUSION: Patients who have the "a" type allele of the eNOS gene may have an increased risk for CAE. PMID- 23457907 TI - Off-label use of Amplatzer devices in congenital heart disorders during childhood. AB - BACKGROUND: Certain medical devices used to treat congenital cardiac lesions in the cardiac catheterization laboratory are used on an off-label and non-routine basis. This article discusses the non-routine use of Amplatzer medical devices. METHODS: In a retrospective study, from November 2006 to December 2011, Amplatzer devices used in our paediatric cardiology ward were reviewed. RESULTS: Children (n = 436) were catheterized to close their defects (438 defects) using Amplatzer devices. The mean age and body weight of the patients were 5.87 +/- 4.2 years and 20.8 +/- 13.6 kg. On-label devices were used for 421 patients (96.1%) and off label devices for 17 patients (3.9%). The off-label use indications and used devices were the Amplatzer septal occluder (aortopulmonary window closure), the muscular ventricular septal occluder (perimembranous ventricular septal defect occlusion, patent ductus arteriosus occlusion, and right pulmonary artery to left atrium fistulous connection closure), the vascular plug (coronary fistula occlusion, left ventricle pseudoaneurysm occlusion, atypical patent ductus arteriosus occlusion, and anomalous pulmonary venous drainage occlusion), and the ductal occluder (ventricular septal defect occlusion). These devices were successfully implanted in exclusively extraordinary, difficult, or extreme cases. CONCLUSIONS: The use of a medical device outside of its approved purpose is commonly referred to as "off-label use". This study showed that the issue of off label, non-routine use of devices exists in paediatric cardiology. Furthermore, the percutaneous closure of defects with non-routine Amplatzer devices is safe and effective, with a high success rate and a high follow-up term outcome. PMID- 23457906 TI - Neurobehavioural functioning in school-aged children with a corrected septal heart defect. AB - OBJECTIVE: This cross-sectional study assesses neurobehavioural consequences after surgical treatment for acyanotic congenital heart defect at the age of 5 to 12 years. METHODS AND RESULTS: Fifteen school-aged children who underwent surgical intervention for a septal heart defect were examined with the short form Wechsler Intelligence Scale for Children-third Edition, Dutch Version (WISC-III NL), and a neuropsychological assessment with the Nepsy. Performances were compared to a matched healthy control group. Parents completed the Child Behaviour Checklist and were interviewed to rate the child's cognitive and emotional functioning. Children older than eight years filled out a self perception questionnaire. Analyses revealed significant differences between the study groups on several cognitive and behavioural domains. Estimated intelligence scores were in the average range. Domains of attention and fine motor skills, and the subtest level of language abilities, elicited significant group differences, with less favourable outcomes for the patient group. Parents of patients reported more withdrawn behaviour, social difficulties, thought problems, attentional shortcomings and lower competence for activities. These parents also indicated poor problem solving skills in everyday activities. CONCLUSIONS: Surgical patients displayed subtle neuropsychological difficulties concerning language and fine motor skills. Behavioural difficulties were common. Future research should address risk factors for adverse neurobehavioural manifestations in this patient group. PMID- 23457908 TI - Cardiac resynchronization therapy with or without defibrillator: experience from a high-volume Belgian implantation centre. AB - OBJECTIVE: Cardiac resynchronization therapy (CRT) is an important treatment modality for heart failure with reduced ejection fraction and ventricular conduction delay. Considering limited health care budgets in an aging population, adding a defibrillator function to CRT remains a matter of debate. Our aim was to describe the experience of a high-volume Belgian implantation centre with CRT with/without defibrillator (CRT-D/P). METHODS AND RESULTS: Consecutive CRT patients (n = 221), implanted between October 2008 and April 2011 in Ziekenhuis Oost-Limburg (Genk), were reviewed. From 209 primo-implantations, 74 CRT-D and 98 CRT-P patients with complete follow-up inside the centre, were analysed. Despite differences in baseline characteristics, both groups demonstrated similar reverse left ventricular remodelling, improvement in New York Heart Association functional class and maximal aerobic capacity. During mean follow-up of 18 +/- 9 months, 21 patients died and 83 spent a total of 1200 days in hospital. Annual mortality was 8% and equal among the groups. The mode of death differed between CRT-D (predominantly pump failure) and CRT-P patients (pump failure, comorbidity and sudden death). The yearly population attributable risk of malignant ventricular arrhythmia was 8.16% in CRT-D and 1.38% in CRT-P patients. CONCLUSIONS: With current guidelines applied to the Belgian reimbursement criteria and at physicians'discretion, patient selection for CRT-D/ CRT-P was appropriate, with similar reverse remodelling, functional capacity improvement and good clinical outcome in both groups. High-risk patients for malignant ventricular arrhythmia were more likely to receive CRT-D, although the yearly attributable risk remained 1.38% in CRT-P patients. PMID- 23457909 TI - Effect of enhanced external counterpulsation depends on arterial compliance. AB - Enhanced external counterpulsation (EECP) is a non-invasive therapy offered to patients with refractory angina pectoris. Previous studies have demonstrated that its clinical effect depends on the diastolic/systolic augmentation ratio (D/S ratio). We hypothesized that the D/S ratio is associated with arterial stiffness measured as pulse wave velocity (PWV) and brachial pulse pressure (PP). Twenty patients with known refractory angina (17 men, 3 women; mean age 64 years) were included and underwent one hour of EECP treatment (Vasomedical Inc., Westbury, NY, USA). Three sets of cuffs were applied around the lower extremities. Gated by electrocardiography (ECG), air was inflated in diastole at a pressure of 260 mmHg and deflated at the start of systole. The D/S ratio was monitored with finger plethysmography. Carotid-femoral pulse wave velocity (PWV) was measured with mechanotransducers (Complior SP, Artech Medical, France). PWV and brachial BP were measured at baseline before EECP. The mean (SD) BP was 140 (23.5)/77 (9.9) mmHg, PP 62.8 (18.3) mmHg and PWV 10.8 (4.4) m/s. EECP treatment increased the D/S ratio during a one-hour session compared with baseline (1.30 (0.11) vs. 0.56 (0.04) P < 0.001), and the D/S ratio at 45 min. was significantly correlated with PWV (r = 0.49, P < 0.05) and PP (r = 0.58, P < 0.05). We demonstrated that the diastolic augmentation (D/S ratio) during EECP treatment depends on arterial stiffness. The results suggest that arterial compliance has a crucial influence on the effect of EECP and that large-artery stiffness may reduce the effect of EECP. PMID- 23457910 TI - Survival and heart failure therapy in chronic dialysis patients with heart failure and reduced left ventricular ejection fraction: an observational retrospective study. AB - AIMS: We retrospectively followed 250 patients who started dialysis between 2005 and 2009 to clarify the prevalence, the prognosis and the prescribed heart failure treatment of systolic heart failure patients on dialysis. METHODS AND RESULTS: This cohort was divided according to left ventricular ejection fraction (LVEF): group A with a reduced LVEF (< or = 45%, n = 45) versus group B with a preserved LVEF (> 45%, n = 205). Patients in group A had a significantly worse survival after 12 and 24 months (68.9% and 55.5% vs. 87.3% and 73.0%, respectively, P = 0.0001). Hazard ratio for all-cause mortality was 2.70 (C.I. 95% 1.6 - 4.56, P = 0.0002). In the subgroup of patients with a LVEF < 30% the hazard ratio increased to 3.45 (C.I. 95% 1.71 - 6.94, P = 0.0005). The cumulative incidence of cardiovascular death was significantly higher in group A (hazard ratio: 4.78 (C.I. 95% 1.99- 11.50, P = 0.0005), especially in the subgroup with a LVEF < 30%. In group A 71%, 31% and 9% of the patients received a beta blocker, an ACE inhibitor and an angiotensin-receptor blocker, respectively. Only 27% were treated with the combination of a beta blocker and a RAAS inhibitor, while 18% did not receive any heart failure therapy. Most patients only received a low dose of neurohormonal blockers (< or = 25% of the recommended daily dose). The use of these heart failure medications was not significantly different between group A and B. CONCLUSION: After initiation of dialysis, patients with heart failure and reduced LVEF have a bad prognosis. Only a minority of these patients receive adequate specific heart failure treatment. PMID- 23457911 TI - Practical recommendations on the use of echocardiography to assess pulmonary arterial hypertension--a Belgian expert consensus endorsed by the Working Group on Non-Invasive Cardiac Imaging. AB - Pulmonary hypertension (PH) is defined by a sustained increase in mean pulmonary arterial pressure > 25 mmHg. Due to its widespread availability, echocardiography (ECHO) is used as the first-line imaging modality to detect pulmonary PH and assess right ventricular (RV) function in daily routine. As such, ECHO is the key examination to detect the presence of PH, to provide valuable prognostic information and to give an orientation to therapeutic strategies. In addition to detection and screening, ECHO also provides clues for the differential diagnosis of PH. The present document, based on a consensus of experts, provides practical recommendations for the use of ECHO in the evaluation of PH and of its consequences on the right ventricle. PMID- 23457912 TI - Coronary spasm is not a benign entity. AB - We present a case of unrecognized recurrent severe coronary spasm treated by percutaneous coronary interventions leading to catastrophic complications ultimately requiring emergency coronary artery bypass grafting and later, following occlusion of the grafts, recanalization of a totally occluded left coronary artery. Throughout the case history the recognition and management of this challenging coronary phenomenon is discussed. PMID- 23457913 TI - [Putting ego aside is necessary to work together]. PMID- 23457914 TI - [Doping]. PMID- 23457915 TI - [Trends from the GD monitoring]. PMID- 23457916 TI - [Abortion in sheep and goats]. PMID- 23457917 TI - Drinking water for dairy cattle: always a benefit or a microbiological risk? AB - Drinking water can be considered an essential nutrient for dairy cattle. However, because it comes from different sources, its chemical and microbiological quality does not always reach accepted standards. Moreover, water quality is not routinely assessed on dairy farms. The microecology of drinking water sources and distribution systems is rather complex and still not fully understood. Water quality is adversely affected by the formation of biofilms in distribution systems, which form a persistent reservoir for potentially pathogenic bacteria. Saprophytic microorganisms associated with such biofilms interact with organic and inorganic matter in water, with pathogens, and even with each other. In addition, the presence of biofilms in water distribution systems makes cleaning and disinfection difficult and sometimes impossible. This article describes the complex dynamics of microorganisms in water distribution systems. Water quality is diminished primarily as a result of faecal contamination and rarely as a result of putrefaction in water distribution systems. The design of such systems (with/ without anti-backflow valves and pressure) and the materials used (polyethylene enhances biofilm; stainless steel does not) affect the quality of water they provide. The best option is an open, funnel-shaped galvanized drinking trough, possibly with a pressure system, air inlet, and anti-backflow valves. A poor microbiological quality of drinking water may adversely affect feed intake, and herd health and productivity. In turn, public health may be affected because cattle can become a reservoir of microorganisms hazardous to humans, such as some strains of E. coli, Yersinia enterocolitica, and Campylobacter jejuni. A better understanding of the biological processes in water sources and distribution systems and of the viability of microorganisms in these systems may contribute to better advice on herd health and productivity at a farm level. Certain on-farm risk factors for water quality have been identified. A practical approach will facilitate the control and management of these risks, and thereby improve herd health and productivity. PMID- 23457918 TI - [Tick borne diseases in horses in the Netherlands]. PMID- 23457919 TI - [An un-appetizing obsession]. PMID- 23457920 TI - [A clinical case: a cat with hemolytic E. coli]. PMID- 23457921 TI - [Society is changing... do the veterinarians also change?]. PMID- 23457922 TI - [Gene technology renews diagnosis of animal diseases]. PMID- 23457923 TI - [Nancy Rietbroek: 'Patient care is the main task of the university clinic of the horse']. PMID- 23457924 TI - [An animal is not a vacation souvenir]. PMID- 23457925 TI - [A mistake can happen..how you deal with it, is a conscious decision]. PMID- 23457926 TI - [Predicting postoperative recurrence of renal cell carcinoma using serum vascular endothelial growth factor]. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is known as one of the key molecules in molecular targeting therapy for patients with renal cell carcinoma (RCC). Several studies have shown that VEGF might be useful for predicting prognosis in RCC. We examined whether pretreatment serum VEGF can be used as a predictor of recurrence-free survival in non-metastatic RCC. MATERIALS AND METHODS: We studied 85 patients with non-metastatic clear cell RCC who underwent nephrectomy between 2001 and 2010. Serum samples were collected for VEGF before operation. We evaluated the recurrence-free survival by univariate and multivariate analysis. RESULTS: 9 patients (10.6%) showed recurrence. Serum level of VEGF in patients with recurrence showed significantly higher than those in patients without recurrence (p = 0.0310). A cutoff level of 416 pg/mL for the separation of low and high serum VEGF levels was established based on the receiver operating characteristic (ROC) curve. The recurrence-free survival rate was significantly lower in patients with a high serum VEGF level (p = 0.0039). Multivariate analysis showed that pretreatment serum VEGF value was a significant predictor of postoperative recurrence in non-metastatic clear cell RCC (p = 0.0062). CONCLUSIONS: Pretreatment level of serum VEGF might be useful for prediction of postoperative recurrence in non-metastatic clear cell RCC. PMID- 23457927 TI - [Clinical study of renal cell carcinoma in dialysis patients: a single center experience]. AB - PURPOSE: Because of a higher incidence in dialysis patients, regular screening for renal cell carcinoma (RCC) is considered beneficial in this population. RCC is associated with a high incidence of acquired cystic disease of the kidney (ACDK), and it has been suggested that these conditions are related. This study was designed to examine the efficacy of RCC screening for dialysis patients and the relationship between RCC and ACDK. PATIENTS AND METHODS: This study enrolled 624 dialysis patients treated between August 2005 and June 2011 at our hospital. Screening for RCC was performed by annual abdominal ultrasonography. Factors analyzed were as follows: RCC morbidity, incidence, diagnostic method, and survival rate; and the RCC and ACDK comorbidity rate. RESULT: RCC was diagnosed in 12 patients. RCC morbidity and incidence rates were 2.08% and 0.33%, respectively. Diagnosis of RCC was made by abdominal ultrasonography screening (N = 7, group A), abdominal ultrasonography or computed tomography for other disease (N = 2, group B) or detailed examination after appearance of symptoms (N = 3, group C). With the exception of one death from other disease, all group A and group B patients survived the follow-up period. In contrast, all group C patients died of RCC within 6 months of diagnosis; only one of these patients underwent RCC screening. The RCC/ACDK comorbidity rate was 91.7% (p = 0.0026). CONCLUSION: Results indicate that regular screening of dialysis patients for RCC is beneficial. RCC was associated with a high incidence of ACDK, indicating that there is a relationship between these two diseases. PMID- 23457928 TI - [Laparoscopic excision of infected urachal remnant: a case report]. AB - A 18-year-old man presented with fever and periumbilical nodule. Computed tomography (CT) showed complicated abscess of urachal remnant and laparoscopic surgery was performed transperitoneally via 3 ports. Laparoscopic excision of urachal remnant was first demonstrated in 1992 by Neufung et al, and in Japan first case was reported in 1998 by Ohmori et al. Some cases of laparoscopic surgery for urachal remnant were reported, but the surgical techniques, including port configuration, have not been standardized. In this case, we performed laparoscopic surgery with camera port in the umbilicus and two working ports in the bilateral positions. Our port configuration may be promising in ensuring good viewing during surgery and excising urachal remnant completely including umbilicus. PMID- 23457929 TI - [Bilateral adrenal hemorrhage due to adrenal metastasis of lung cancer]. AB - A 58-year-old man presented with nausea and left flank pain. The patient was referred to our hospital based on clear detection of anemia and computed tomography findings of bilateral adrenal tumors with hemorrhage and a mass in the apex of the left lung. Right adrenal artery embolization had no effect on enlargement of the right adrenal hematoma or advanced anemia. Right adrenalectomy was then performed in an attempt to control hemorrhaging and make a definitive diagnosis, and the patient's anemia improved following the operation. Histopathological diagnosis suggested adrenal metastasis of lung adenocarcinoma, which was subsequently diagnosed given similarities in transbronchial biopsy findings to those in the right adrenal gland. Adrenal hemorrhage due to metastasis of lung cancer is an extremely rare condition; indeed, to our knowledge, the present case is only the 26th reported worldwide. However, prognosis for this mortal condition may be improved should patients receive adrenalectomy followed by an appropriate treatment regimen. PMID- 23457931 TI - [Plasmacytoid variant of urothelial carcinoma of urinary bladder: a case report]. AB - We reported the experience with a case of plasmacytoid variant of urothelial carcinoma of urinary bladder. A 75-year-old woman complained of gross hematuria. She was hospitalized to be diagnosed as the bladder tumor on abdominal CT. TUR-BT was performed and pathological finding was invasive urothelial carcinoma. But she refused radical cystectomy. 2 months later, she was hospitalized again with worsening hematuria. Simple cystectomy was performed. Histological examination revealed a plasmacytoid appearance of the infiltrating tumor cells. Immunohistochemical stains for lymphoid markers were negative. Those findings lead to the diagnosis of plasmacytoid variant of urothelial carcinoma. She died due to local recurrence for 1.5 months after simple cystectomy. PMID- 23457930 TI - [A case of isolated polyarteritis nodosa appeared in bilateral epididymides with asynchronous onset]. AB - A 78-year-old man visited a hospital with a complaint of painful and swelling scrotums for 7 months. Although left epididymitis was suspected, antibiotic and non-steroidal anti-inflammatory drugs (NSAIDs) had no effects. After visit to our department, we performed left orchiectomy for the diagnosis and pain control. Pathological examinations showed necrotizing vasculitis in the epididymis, so he was diagnosed as polyarteritis nodosa (PN) in the left epididymis. He had no systemic symptoms, which made the diagnosis of isolated PN. One and a half years after operation, he felt the same pain in the right scrotum. We performed right orchiectomy. Pathological findings showed necrotizing vasculitis in the epididymis. Blood examinations revealed negative for myeloperoxidase anti neutrophil cytoplasmic antibody (ANCA) and proteinase 3-ANCA, and computed tomography revealed that other organs were not involved. One year later, he had no recurrence. PMID- 23457932 TI - [Uretero-fallopian fistula secondary to low anterior resection for rectal cancer]. AB - A 71-year-old woman presented with lower abdominal pain and urinary incontinence 18 days after low anterior resection for rectal cancer. Computed tomography and magnetic resonance urography revealed right hydronephrosis, cystic mass in the right pelvic cavity and hydrometra. Positron emission tomography showed dilated right upper urinary tract communicating with dilated right fallopian tube and uterine body, and the finding was quite characteristic. Laboratory studies revealed that the serum and the fluid from hydrometra levels of creatinine were 1.06 mg/dL and 6.15 mg/dL, respectively. We diagnosed this case as uretero fallopian fistula. Since the conservative management of uretero-fallopian fistula with ureteral stent was not accomplished, she underwent right ureteroureterostomy and adnexectomy. The intraoperative findings included dilated right ureter and fallopian tube adherent to the stenotic right ureteral segment ligated by suture during prior surgery. The histopathological findings showed endometriosis and inflammatory changes of uterine appendages. Follow-up at 3 months demonstrated resolution of the urinary incontinence and the ureteral obstruction and fistula. PMID- 23457933 TI - [Pathological complete response to gemcitabine and cisplatin chemotherapy for advanced upper tract urothelial carcinoma: a case report]. AB - A 61-year-old man was referred to our hospital with the chief complaint of right leg weakness. Abdominal magnetic resonance imaging (MRI) and computed tomography (CT) demonstrated a ureteral tumor and a neighboring massive retroperitoneal tumor in addition to retroperitoneal lymph node and right renal metastases. The tumor was diagnosed as upper tract urothelial carcinoma (cT4N1M1) by percutaneous tumor biopsy. As the patient achieved a partial response after three courses of combination chemotherapy with gemcitabine and cisplatin, he received total nephroureterectomy and lymph node dissection. The pathology showed no viable cancer cells, demonstrating a pathological complete response. He remains alive after 26 months with no evidence of disease. PMID- 23457934 TI - [Paradigm shift of therapeutic strategy for the patients with vascular disease]. PMID- 23457935 TI - [Purpose and role of ethics committee in Japanese Surgical Society]. PMID- 23457936 TI - [Clinical implication of lymph node micrometastasis in cancer]. PMID- 23457937 TI - [A novel diagnostic method for detection of lymph node metastases]. AB - In order to improve the sensitivity of diagnosis of regional lymph node metastases in cancer patients, the novel molecular method called the one-step nucleic acid amplification (OSNA) assay using cytokeratin 19 mRNA as a molecular marker was developed. In this method, the supernatant of a homogenized lymph node solution is directly analyzed without the mRNA purification process that is usually required in RT-PCR. Therefore the results are available within 30 min via a simple procedure, and the results correlate well with the number of cancer cells in the lymph node. We conducted multicenter clinical trials in Japan to evaluate the OSNA assay for the detection of lymph node metastases in breast cancer, colorectal cancer, gastric cancer, and lung cancer. The results showed that the OSNA assay provides a judgment performance equivalent to that of 2-mm interval histopathologic examinations of lymph nodes in each type of cancer. Furthermore, the OSNA assay is unlikely to yield false-positives for histopathologically negative lymph nodes. Following these results, the OSNA assay was approved as a diagnostic method for lymph node status in breast, colorectal, and gastric cancer patients by the Japanese Ministry of Health, Labor and Welfare. The OSNA assay is promising as a quick, simple, subjective, quantitative method for the detection of lymph node metastases in various cancers. PMID- 23457938 TI - [Clinical significance of micrometastases in patients with esophageal cancer]. AB - Hematoxylin and eosin (HE) and immunohistochemical (IHC) staining have been commonly used in combination with thin serial sectioning of frozen and paraffin embedded specimens for the detection of micrometastatic disease in the lymph nodes of patients with esophageal cancer. The application of IHC has markedly improved the sensitivity of micrometastatic disease detection in the lymph nodes beyond the capability of routine HE staining alone. Increasing the sensitivity of occult tumor cell detection in the lymph nodes using molecular-based analysis should enable a more accurate understanding of the clinical significance of various patterns of micrometastatic nodal disease. Further studies will explore the clinical significance of micrometastases or isolated tumor cells in the lymph nodes in patients with esophageal cancer. Individualized selective and modified lymphadenectomy targeting sentinel nodes for clinically NO early esophageal cancer may become feasible and clinically useful as a less invasive surgical procedure. PMID- 23457939 TI - [Lymph node micrometastases in gastric cancer]. AB - Lymph node micrometastases in gastric cancer are based on the definition in the 6th version of the TNM classification of malignant tumours edited by the International Union Against Cancer, which is also quoted in the 14th version of the Japanese Classification of Gastric Carcinoma. Histopathologic examination such as immunohistochemistry and molecular biological techniques including RT-PCR and one-step nucleic acid amplification are used for the detection of micrometastases. Because the time required for such detection is shortened to 30 to 40 min, intraoperative detection is feasible. Many papers have reported the correlation between micrometastases and prognosis in gastric cancer, although whether micrometastases are correlated with poor prognosis even when completely resected remains unknown. Intraoperative detection of micrometastases is important to decide the operative procedure in sentinel node navigation surgery. PMID- 23457940 TI - [Lymph node micrometastases in colorectal cancer]. AB - Lymph node (LN) micrometastases in colorectal cancer (CRC) has been discussed for a long time. Previous reports showed that micrometastases detected by immunohistochemistry (IHC) appeared to have no clinical impact, but that occult disease detected by molecular techniques such as RT-PCR might be associated with poor prognosis. At present, several factors are proposed as high risks for disease recurrence of stage II CRC, including T4 invasiveness, vascular invasion, poorly differentiated adenocarcinoma or mucinous carcinoma, tumor budding, wall perforation, and insufficient assessment of dissected LNs. However, it was reported that 75% of 24,847 stage II CRC patients retained specific risk factors, and the efficacy of chemotherapy in such patients has not been confirmed. A recent meta-analysis by Weitz et al. has concluded that occult disease was significantly associated with poor prognosis of node-negative CRC, irrespective of the detection method, i.e., IHC or RT-PCR. For efficient selection of high risk stage II CRC patients, a prospective, large-scale clinical trial is essential using a convenient, simple molecular modality such as the one-step nucleic acid amplification assay. PMID- 23457941 TI - [Clinical significance of sentinel lymph node micrometastases in invasive breast carcinoma]. AB - Axillary lymph node status is one of the most important prognostic factors in patients with invasive breast carcinoma. Sentinel lymph node biopsy leads to more accurate examination of the lymph nodes and has resulted in an increased detection rate of small cancer deposits. Patients with micrometastatic foci can have nonsentinel lymph node involvement, including macrometastatic foci. Sentinel lymph node micrometastases are associated with an adverse impact on disease recurrence or survival. Axillary clearance offers no advantage in reducing the incidence of disease recurrence and survival. However, the long-term outcomes can be improved with the use of adjuvant systemic therapy, and it would be reasonable to consider systemic treatment in these patients. PMID- 23457942 TI - [Clinical significance of micrometastases in the lymph nodes of patients with resectable lung cancer]. AB - Clinical evaluation of micrometastases in the lymph nodes of lung cancer patients is not currently recommended in guidelines because of several different results concerning their prevalence and prognostic implications. However, a recent large, prospective, multicenter clinical study has shown a significant prognostic impact of micrometasteses in the lymph nodes of patients with resectable lung cancer; therefore, the clinical significance of micrometastases as predictive markers of recurrence and prognosis has begun to be clarified. From the viewpoint of surgery for lung cancer, sentinel node navigation surgery, segmentectomy, and individualized therapies such as adjuvant chemotherapy are expected to be developed. In the near future, standardization and improvement of the efficiency of diagnostic procedures will be necessary in common clinical practice. Recently, minimal residual cancer cell research, such as circulating tumor cells in the peripheral blood and disseminated tumor cells in the bone marrow, has made good progress. As research in this field continues, it is expected that the mechanism of metastasis and novel therapeutic strategies targeting minimal residual cancer cells will become better understood. PMID- 23457943 TI - [Lymph node micrometastases of thyroid cancer]. AB - It is not uncommon for micrometastases to be detected in the regional lymph nodes in patients with thyroid cancer. It remains controversial whether lymph node dissection improves patient outcomes. According to the clinical guidelines edited by the Japan Association of Endocrine Surgeons and Japanese Society of Thyroid Surgeons, there is no evidence that prophylactic central compartment dissection improves the cause-specific survival of papillary carcinoma patients. However, it is recommended at initial surgery because reoperation for recurrence in this compartment may induce severe complications. On the other hand, prophylactic lateral node dissection can reduce the risk of recurrence to the nodes and improve disease-free survival rates, although evidence is lacking on whether it improves cause-specific survival. Surgeons should be aware that pathologically identified metastatic lymph nodes are less common than actual metastatic lesions and determine the disease entity of ectopic thyroid tissue in lymph nodes. Recently, useful new techniques such as thyroglobulin measurement of fine-needle aspiration specimens or sentinel lymph node biopsy have become established. PMID- 23457944 TI - [Strategy for unresectable multiple colorectal liver metastases]. PMID- 23457946 TI - [What we can learn from a case of medical malpractice--breach of duty for failing to provide full disclosure of risks and complications associated with anesthesia to a patient who developed lower extremity pain, numbness, and other symptoms after the anesthesia]. PMID- 23457945 TI - [Treatment strategy for multiple colorectal liver metastases: role for two-stage hepatectomy]. AB - Hepatic resection is recognized as a potentially curative treatment for colorectal liver metastases. Recent progress in chemotherapy and molecular target agents has made initially unresectable colorectal liver metastases converted to resectable and may prolong survival. The definition of unresectable colorectal liver metastases was because of the lack of the future remnant liver volume due to multiple bilobar metastases. The two-stage hepatectomy combined with portal vein embolization may contribute to treatment for such multiple bilobar metastases. We describe an advantage and adverse effect of two-stage hepatectomy on treatment for multiple bilobar colorectal liver metastases. PMID- 23457947 TI - [Tips and pitfalls of arch replacement]. PMID- 23457948 TI - [Survey of opinions of Japan Medical Association members in Fukuoka Prefecture supported by Ministry of Health, Labor and Welfare of Japan]. PMID- 23457949 TI - [Participation in the trial project of education and training for nurse practitioner of critical care domain. Report focused on clinical field of surgery]. PMID- 23457950 TI - [The role of perianesthesia nurse in Japan--education and clinical practice]. PMID- 23457951 TI - [Gentle medical treatment to the earth: the approach of the Jikei Daisan Hospital and view to eco-surgery]. PMID- 23457952 TI - [Initial experience of split liver transplantation in National Center for Child Health and Development, Japan]. AB - PURPOSE: We reviewed our initial experience of deceased split liver transplantation in National Center for Child Health and Development and report the results herein. SUBJECTS AND METHODS: We have listed 50 patients with end stage liver disease for deceased liver transplantation, and done 6 cases of split liver transplantation during October 2010 through October 2012. Variables including indication of liver transplantation outcome were reviewed. RESULTS: The indication for split liver transplantation was acute liver failure in 4, re transplantation in 1 and primary sclerosing cholangitis in 1. The age of recipient ranged 17 days-15 yeras and body weight ranged 2.4 kg-55 kg. The split grafts were hyper-reduced left lateral segment in 1, left lateral segment in 3, left lobe in 1 and right lobe in 1. Although case #2 received retransplantation with living donor, all the patients are currently doing well with acceptable liver function with minimum follow-up of 2 months. CONCLUSION: Satisfactory result can be achieved on initial experience of split liver transplantation in National Center for Child Health and Development. The follow-up period was too short to make definitive conclusion, however, split liver transplantation could be expand potential donor pool and may reduce the waiting list mortality without alterations of the results. PMID- 23457953 TI - [What is a surgical assistant like--one who has seen surgery best]. PMID- 23457954 TI - [A case report of a female surgeon who continues full-time working while raising a small child]. PMID- 23457955 TI - [Use of Gianturco-Wallace and tornado coils in perforators embolisation in chronic venous ulcers treatment]. AB - AIM OF THE STUDY: Embolisation is a endovascular technique of vessels closure using embolisation material, which is applied into vessels throw catheter. As an embolisation material coils Gianturco-Wallace i Tornado (Cook) were used. Length and size of coils was determined individually during precedure. MATERIALS AND METHODS: 38 patients of Vascular Surgery Department and Radiology Department of Medical University in Wroclaw were treated by endovascular embolisation of insufficient perforators. Procedures were made on 40 limbs with post-thrombotic complex and venous ulcers (6th degree of CEAP classification). 68 endovascular procedures were made, 143 metal coils were used. RESULTS: Using endovascular method 85% of ulcers were comletely cured. CONCLUSIONS: Endovascular embolisation is safe and effective method of veonous ulcers curing. Itmay be used at outpatients clinic. PMID- 23457956 TI - [Modern treatment of rupturted abdominal aortic aneurysms with the use of synthetic endovascular prostheses]. AB - AIM OF STUDY: We analyzed the case of two patients with ruptured aortic aneurysm treated with the usage of the endowascular method. MATERIALS AND METHODS: Treatment of ruptured abdominal aortic aneurysms is burdened with a high mortality rate during the perioperative period. The implantation of forked stent grafts and uni-grafts significantly reduced the mortality rate in this group of patients. Usage of this treatment requires the hybrid operating room. An essential element is to have the appropriate amount of equipment available to find a suitable intravascular prostheses. Uni-grafts are a good alternative for smaller divisions and for physicians with less experience in endovascular surgery. CONCLUSION: Endowascular procedures have a great chance to became a golden treatment standard. PMID- 23457957 TI - [The treatment of dissected thoraco-abdominal aorta aneurysm with the use hybrid procedure]. AB - AIM OF STUDY: We analyzed the case of a patient treated in Vascular Surgery Department with the use of the hybrid procedure with a good results. MATERIALS AND METHODS: Acute cases of dissected aortic aneurysm are commonly known as an immediate danger of human live and determinate a big challenge for physicians. The collaboration of classic and endovascular methods (hybrid procedures) gives much more chances to improve patient's survival and resumption to normal life activity. Endovascular procedures are limiting the operation shock, improving recovery time. That means rising the chances of survival so advanced surgical procedure. CONCLUSION: Hybrid procedures are a modern technic that gives good results. PMID- 23457958 TI - [The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release]. AB - AIM OF STUDY: Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. MATERIALS AND METHODS: Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. RESULTS: The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration-dissolving of a tablet, is conducive to the reduction of gastrointestinal side effects and better tolerance of the therapeutic product by a patient. The study on pharmaceutical availability indicated relevant kinetic differences between tested therapeutic products. They are particularly visible between standard formulations and the one with prolonged release (Glucophage XR500). Its release profile bears features of kinetics similar to zero-order reactions. CONCLUSIONS: Tested therapeutic products contain a large amount of the biologically active substance in relation to the content of excipients. A higher content of excipients in a single tablet mass distinguishes Siofor in comparison with Glucophage i Metformax. The excipients used in the formulations of tested preparations are comparable. A higher percentage of binding agents (HPMC, PVP) is observed, but there is a lack of typical disintegrants which results in a longer disintegration time up to 15 minutes. Siofor disintegrates at the same time as Formetic, but longer than Glucophage i Metformax. Considering the large content of the active substance and pharmacological properties of metformin hydrochloride, such a disintegration might have beneficial consequences, because the amount of the free active substance in the gastrointestinal tract will increase over the longer time period what will reduce the level of gastrointestinal side effects. The release profiles of metformin hydrochloride from tested therapeutic products are comparable. The Glucophage XR 500 formulation with the release kinetics of metformin hydrochloride similar to the zero-order kinetics is completely different from the others. The above is confirmed by the mathematical analysis of release profiles of metformin hydrochloride from tested preparations where equations of lines describing the release profile are characterized by similar values of correlation coefficients. PMID- 23457959 TI - Extraction and characterization of mango peel pectin as pharmaceutical excipient. AB - AIM OF STUDY: Present study includes extraction and characterization the mango peel derived pectin as a pharmaceutical excipients. MATERIAL AND METHODS: Pectin was obtained using acidified water based extraction in soxhlet apparatus. To characterize the extracted pectin phytochemical screening was done and micromeritic properties, flow behavior, surface tension, viscosity and swelling index were calculated. RESULTS: Using water based extraction method 25.26% yield of pectin was obtained. The result revealed the fact that extracted mango peel pectin exhibited good flow properties (angle of repose 28.01), 41.90 +/- 2.62 dynes/cm2 surface tension, 0.46% w/w total ash, 0.76% loss on drying and pH was found 4.15, showed that this can be used in dosage form, without any irritation. Extracted pectin was soluble in warm water while insoluble in organic solvents. CONCLUSIONS: Results of evaluated parameters showed that mango peel derived pectin can be used as pharmaceutical excipient to prepare solid oral dosage form. PMID- 23457960 TI - Natural polymers, gums and mucilages as excipients in drug delivery. AB - Use of natural polymers, gums and mucilages in drug delivery systems has been weighed down by the synthetic materials. Natural based excipients offered advantages such as non-toxicity, less cost and abundantly availablity. Aqueous solubility of natural excipients plays an important role in their selection for designing immediate, controlled or sustained release formulations. This review article provide an overview of natural gum, polymers and mucilages as excipients in dosage forms as well as novel drug delivery systems. PMID- 23457961 TI - [Intergeneration continuity and adherence to the traditions of fundamental physiological science--the basis for present and guarantee of future advancements in space physiology and medicine]. AB - Sprung from the national physiological science and aviation medicine, space physiology and medicine of today is an intensely evolving discipline cradled and fostered by the Russian scientists who made major contributions both to individual branches of physiology and general research methodology. Upholding the best traditions, space physiology and medicine specialists retain leadership in many areas and ensure intergeneration continuity in research work. Among these areas are investigations into the physiological mechanisms of water-electrolyte turnover in animals and humans in the course of space flight and ground-based model experiments. PMID- 23457962 TI - [Distance methods of cardiologic monitoring in diagnostics of high loading effects on organism of sportsman and cosmonaut]. AB - Increase of cardiovascular tension is a common thing for professional athletic training. Cardiovascular pathologies can be prevented by permanent physiological monitoring using, among others, the methods of cardiologic monitoring so far available in stationary diagnostic centers. On-line remote diagnostics during training is potent to enhance effectiveness and efficiency of sporting people's health management. In addition, RD will also enable extensive investigations of the bodily responses of individually determined training loads. The paper gives an overview of the current RM technologies. PMID- 23457964 TI - [Studies of red blood cells biochemistry and erythropoiesis intensity in humans during the 520-day isolation study]. AB - Erythrocyte metabolism and erythropoiesis intensity were investigated in the humans subjects (6 males, 25 to 37 yrs. of age) volunteered for experimental simulation of such factors in a mission to Mars as very long duration (520-d) of isolation and confinement, autonomy, delayed communication, emergencies, and limited consumable resources. Venous blood and extracted erythrocytes were analyzed in the baseline data collection period (2 wks. before the experiment), on days 60, 120, 170, 240, 300, 360, 417 and 510 of the experiment and on days 7 8 after its completion. Erythrocyte metabolic and plasmatic membrane parameters were measured. Blood serum was analyzed for iron turnover; erythropoiesis intensity was evaluated by the erythropoietin level. According to the results of the investigation, there were phase-type shifts in the parameters throughout the experiment that were particularly significant on days 60 and 120. Inhibition of energy-production and enhancement of reparative processes in the cell could be tokens of compensatory reactions aimed to control oxidation processes and to raise antioxidation efficiency of the cell. The phase-type changes in membrane lipids and phospholipids point to increased microviscosity of the plasmatic membrane at the beginning and then end of the experiment. Hemoglobin content in blood and erythrocytes showed a significant increase on day-510 of isolation and in the ensuing recovery period. Data about iron turnover and erythropoietin level evidence an adequate bone marrow response to the changed hemoglobin content in blood. PMID- 23457963 TI - [Topics of cosmonauts' work and rest management on board the International Space Station]. AB - Intensity of the rest and work cycle (WRC) of the ISS cosmonauts was examined in terms of overplanning, as well as frequency of sleep shifting and incidence of crew overstrain evidenced from the weekly reports of MCC-M medical operators. Level of WRC intensity in the recent ISS missions was compared with the WRC chronicles of early missions made by three crewmembers including one cosmonaut, and subsequent missions by six crewmembers including 2 or 3 cosmonauts. Though weak, a trend toward a WRC reduction in the period of 2010-2011 was achieved through a more realistic task planning for an average cosmonaut. PMID- 23457965 TI - [Effects of distorted geomagnetic field on the functioning of systems supporting rat's bone matrix adaptation and metabolism in open field]. AB - Physiological responses of rats to daily 30-minute exposure to distorted geomagnetic field (DGMF) over 3 and 7 days and their reaction to open field following the exposure were studied. Increases in blood 11-oxycorticosteroids (11 OCS) were observed equally after 3- and 7-day DGMF exposure, whereas adrenal 11 OCS was found increased only on DGMF day-3; neither adrenaline in the adrenals nor glycogen in the liver were affected. On DGMF day-7, activation of bone matrix demineralization manifested itself by increased phosphorus and decreased calcium in blood, and activation of acidic phosphatase in serum. Rats reacted to open field by increases in blood and hepatic 11-OCS, reduction in adrenaline in the adrenals and glycogen in the liver, increase in serum free oxyproline and acidic phosphatase activation, and inhibition of alkaline phosphatase. Seven-day DGMF heightened or aggravated the reaction to open field. PMID- 23457966 TI - [Dynamics of chromosomal aberrations in primates subject to continuous and fractionated gamma-irradiation by equally effective residual doses]. AB - The paper deals with a comparative study of two regimens of Macaca mulatta continuous 2-week gamma- and double fractionated acute irradiation by the total absorbed doses of 250 and 132 cGy, respectively; data about chromosomal aberration rates in peripheral lymphocytes were correlated. Based on calculations it was hypothesized that, regardless of regimen, by day-12 of irradiation the effective residual dose would be same, i.e. approximately 100 cGy. Analysis of instable aberration chromosomes showed similarity of the effect of gamma irradiation by 137Cs at earlier time points (on days 2-21). In primates with the gamma-irradiation profile close to chronic (Gamma 25) the total rate of chromosomal aberrations and rate of radiation markers remain high, whereas animals exposed to fractionated radiation (Gamma 66) displayed a statistically significant (p < 0.05) reduction in cytogenetic parameters on days 36, 50 and 85. Cytogenetic analysis of peripheral lymphocytes permits the conclusion that though markedly different in dose values and rates, both regimens produce an essentially equal early damaging effect. PMID- 23457967 TI - [Multi-month dynamics of the functional condition of organism of normal male northeners of Russia]. AB - In conjunction with the Mars-500 project, 17 male residents (25-46 y.o.) of the North of Russia (62 degrees 40'N) were examined monthly using hard- and software EKOSAN-2007. In the period of June, 2010 through to November, 2011 they visited a standard laboratory to go through comprehensive anthropophysiometric, psychophysiological and physiological investigations at rest and combined with exercise, standing and cold tests aimed at tracking the seasonal responses of the body functional parameters. The larger part of group-average psychomotor, breathing and circulation measurements as well as heart rate variability did not exhibit statistically significant differences between months or seasons. Reliable seasonal variations were documented in the life index, body and cutaneous temperature, myocardium index and regulatory systems activity. A correlation between environmental and some body functional parameters was established. In the course of the multi-month monitoring there were periods when essentially healthy people were diagnosed as prenosologic and even premorbid. Some findings in the functioning of male northerner's organism are clearly attributable to living in the high-altitude area. PMID- 23457968 TI - [Comparative studies of antihypoxic, neuroprotective and analgesic action of succinate-containing drugs]. AB - Experiments with mice showed that, unlike reamberin (100 mg/kg), mexidol (100 mg/kg) and cytoflavin (1 ml/kg) act as antihypoxants in pressure and hermetic chambers but not in case of acute hemic and histotoxic hypoxia. Amtisol succinate (100 mg/kg), a reference antihypoxant, excels the other tried succinate containing drugs in all models of acute hypoxia except the hermetic chamber. In addition, the neuroprotective action of mexidol (100 mg/kg/d) and cytoflavin (100 ml/kg/d) in rats with induced ischemic stroke which was stronger than that of reamberin and amtisol succinate (100 mg/kg/d). Besides, mexidol (100 mg/kg) but not cytoflavin (1 ml/kg), reamberin or amtisol succinate (100 mg/kg) had a distinct analgesic effect in rabbits. On the neuronal level, mexidol interacts with the GABAA- benzodiazepine-receptor complex in nearly 60% cells and inhibits ion currents through the NMDA-receptor ion channels in nearly 80% neurons. PMID- 23457969 TI - [Radiomodifying properties of deuterium-depleted water with poor content of heavier isotopes of oxygen]. AB - Experiments were performed with outbreed mice CD-I and hybrid mice (CBA' C57BI)F1. Seven to 21 days before irradiation, the mice had continuously consumed light-isotope water (35 ppm) produced by rectification w/o secondary treatment. Dose of single gamma-irradiation ranged from 4 to 8.5 Gy. The radiomodifying effects included statistically reliable reductions in survivability and life span, loss of body mass, and decreases in marrow myelokaryocytes and peripheral leukocytes. In 8-9 days after irradiation, spleen mass in the experimental mice was found enlarged as compared with the controls. PMID- 23457970 TI - [Some peculiar traits of cerebrovascular diseases of aviation personnel]. AB - Growing incidence of stroke and cerebrovascular diseases poses a threat to flight safety. The results of comprehensive medical examination of 43 aircrew members at the age of 55 and 58 years were analyzed to trace the progress of cerebral atherosclerosis by EEG readings, cognitive evoked potentials and psychological test data. The study is helpful in evaluation of the compensatory reserves of cerebral circulation, objective expert judgment, as well as in early diagnostics of conditions that may be a risk to flight safety. Knowledge of the cerebral circulation functional status enables optimization of the choice of prophylactic and therapeutic methods of prolonging the flight career. PMID- 23457971 TI - [A new approach to shielding function calculation: radiation dose estimation for a phantome inside space station compartment]. AB - The article presents a new procedure of calculating the shielding functions for irregular objects formed from a set of nonintersecting (adjacent) triangles covering completely the surface of each object. Calculated and experimentally derived distributions of space ionizing radiation doses in the spherical tissue equivalent phantom (experiment MATRYOSHKA-R) inside the International space station were in good agreement in the mass of phantom depths with allowance for measurement error (-10%). The procedure can be applied in modeling radiation loads on cosmonauts, calculating effectiveness of secondary protection in spacecraft, and design review of radiation protection for future space exploration missions. PMID- 23457972 TI - [Enhancement of electrocardiogram information capability by identification of the ECG spectrum phases]. AB - The authors discuss feasibility to extract additional information about electrical activity of the heart from the ECG magnitude and phase spectrum. Fifty digitized ECG fragments from the MIT-BIH Arrhythmia Database and PhysioBank ECG repository data were analyzed. It was shown that ECG phase harmonics contains valuable information about the ECG signal that can be used eventually for the development of advanced ECG analysis tools. PMID- 23457973 TI - [Asymmetry of oxygenation and deoxygenation of a thick blood layer]. AB - A cell for convoluted blood film was used to study the processes of oxygenation and deoxygenation in a 5-mm deep layer of whole blood contacting peripherally with a gas medium. It was shown that nitrogen replacement by oxygen or vice versa with steady 5% CO2 accelerates significantly blood oxygenation but not deoxygenation. On consideration of possible reasons a conclusion has been made in favor of geometric rather than physical-chemical factors. This phenomenon should be accounted for when encountering with stagnation state in organism, vascular occlusion and other circulation disorders. PMID- 23457974 TI - [The achievements and the way of innovative development of phthisiology]. PMID- 23457975 TI - [Chemotherapy of tuberculosis: problems and perspectives]. AB - Challenges of tuberculosis chemotherapy under conditions of high drug resistant (DR) tuberculosis burden are discussed. Ultimate results of treatment by standard regimens of 1658 patients with new tuberculosis cases and relapses were analyzed. Favorable ultimate results were observed among both patients with new tuberculosis cases and relapses having drugs sensitivity. Efficacy of tuberculosis treatment by standard regimens of chemotherapy is decreasing as a result of DR amplification. Risk factors of unfavorable ultimate result among pulmonary tuberculosis patients are primary resistance to isoniazid (OR = 2.1) and multiple drug resistance of M. tuberculosis (OR = 8.0). Earlier onset of treatment and correct individual therapy with second line drugs as a result of rapid methods of DR tuberculosis diagnostics are those approaches which provide the best therapeutic effect among multiple drug resistant tuberculosis patients both in culture conversion (97.7%) and cavity closure rate (82.7%). PMID- 23457976 TI - [Optimisation of diagnostics and differential diagnostics disseminated pulmonary tuberculosis]. AB - One of the reasons of dramatic situation with tuberculosis in Russia is untimely diagnostics of tuberculosis. The aim of the study was to identify the causes of diagnostic mistakes when we deal with disseminated pulmonary tuberculosis at current stage and to modernize the diagnostic process. The analysis of the diagnostic activity of the consultative diagnostic center of Central Tuberculosis Research Institute of Russian Academy Medical Sciences for 2011 was performed with special attention on the results of the survey of 505 patients with pulmonary dissemination. The frequency of discrepancies of disseminated pulmonary tuberculosis diagnostics was 96.1%. Based on the studies carried out the main causes diagnostic mistakes in patients with disseminated pulmonary tuberculosis were determined. New directions of improving of tuberculosis diagnostics were developed: overall high-technology examination of patient, adherence to the diagnostic procedure, developed by consultative diagnostic center of Central Tuberculosis Research Institute (CTRI), timely performing fiber-optic bronchoscopy with complex biopsy and diagnostic surgery procedures, further training of primary health care doctors. Implementation of proposed activities will significantly (by 3-5 times) reduce the time for diagnostics of respiratory system disease. PMID- 23457977 TI - [Selective effects of pulmonary surfactant on various subpopulations of alveolar macrophages in the model of experimental tuberculosis]. AB - Pulmonary surfactant is necessary component for maintenance of high level of phagocytic activity of alveolar macrophages. Tuberculosis inflammation reduces the production of surfactant by type II cells and phagocytic activity of alveolar macrophages. The effects of exogenous pulmonary surfactant on the ultrastructural changes of various subpopulations of alveolar macrophages were studied by TEM method. For investigations the bronchial alveolar lavage fluid from guinea pigs infected of M. tuberculosis and treated by isoniatid or isoniazid + exogenous pulmonary surfactant were used. It was shown that isoniazid + exogenous pulmonary surfactant normalizes the heterogeneous population of alveolar macrophages providing stimulating effects on their maturation and phagocytic activity more effectively than isoniazid therapy. PMID- 23457978 TI - [Features of metabolic activity of vascular endothelium in patients with pulmonary tuberculosis]. AB - 81 patients with active pulmonary tuberculosis were investigated. The morpho functional status of vascular endothelium was evaluated by plasma levels of stable metabolites of nitric oxide, endothelin-1 and von Willebrand factor antigen. Typical increase of endothelin-1 in positive correlation with systemic inflammatory response syndrome (SIRS) expression was established. Nitric oxide level decreased in patients with chronic and severe course of disease. Decrease of nitric oxide level was not associated with SIRS but was consequence of specific intoxication. von Willebrand factor antigen decreased in patients with recent and limited spread of tissue damage but increased progressively with intensity of SIRS. This complex of changes (contrast shifts of nitric oxide and endothelin-1 and von Willebrand factor antigen increase) manifested in endothelium metabolic dysfunction syndrome and developed pre-conditions for microcirculation disturbances. PMID- 23457979 TI - [Cytologic features of bronchoalveolar lavage in evaluation of course of exogenous allergic alveolitis]. AB - Application of complex of modern cytologic methods of research bronchoalveolar lavage allowed to allocate most characteristics of development of lymphocytic and macrophagic reaction of bronchial tree in different course of exogenous allergic alveolitis. The most indicative in assessment of origin of exogenous allergic alveolitis development is the characteristics of macrophagic population. In acute course of exogenous allergic alveolitis the considerable number of young activated and non-activated macrophages, increased number of mature phagocytes is observed. Even more significant increase of phagocytic macrophages is observed at dissemination which is primarily is connected with participation of these cells in lymphocytic apoptosis which takes place in high percentage of lymphocytes (up to 49%). Increased number of mature phagocytes is observed at chronic course of exogenous allergic alveolitis that is an important diagnostic pattern of this option of development of exogenous allergic alveolitis in association with the lowest T-helpers/T-supressors index. PMID- 23457980 TI - [New therapy schemes for acute, subacute and chronic variants of extrinsic allergic alveolitis]. AB - In order to improve treatment of patients with exogenous allergic alveolitis morphologically different variants of the disease, i.e. acute, subacute and chronic were identified and confirmed. For each variant of exogenous allergic alveolitis new therapy schemes were proposed. The study included 74 patients who were divided into 5 groups. In the first group with acute exogenous allergic alveolitis inhalation glycocorticosteroids in high doses in combination with plasmapheresis were prescribed, in the second group standard therapy with systemic glycocorticosteroids was prescribed. The third and the fourth group consisted of patients with subacute exogenous allergic alveolitis. The protracted ambroxol inhalation using nebulizers and the reduced dose of systemic glycocorticosteroids were used in the third group; and the standard dose of systemic glycocorticosteroids was used in the fourth. The fifth group consisted of patients with chronic exogenous allergic alveolitis, who received the standard dose of glycocorticosteroids and cytostatic drugs. After one month of therapy, it was ascertained that the use of high doses of inhalation glycocorticosteroids in combination with plasmapheresis in patients with acute exogenous allergic alveolitis led to significant improvements in clinical and CT presentation, physical activity tolerance, as well as the use of systemic glycocorticosteroids. The use of ambroxol inhalation in patients with subacute exogenous allergic alveolitis led to a significant improvement in clinical symptomatology, functional parameters and CT presentation, thus enabling to reduce the dose of glycocorticosteroids used and to avoid unwanted side effects. PMID- 23457981 TI - [Prevention of tuberculosis: current approaches to development of vaccines]. AB - This review is focused on recent advances in development of new vaccines for the prevention of tuberculosis. The main reasons for lack of BCG vaccine efficacy in different populations and geographic regions are presented. Design of new vaccines based on live modified strains of Mycobacterium bovis BCG, attenuated strains of Mycobacterium tuberculosis, recombinant proteins and viral vectors is considered in the specific examples. The usage of the heterologous "prime-boost" vaccination strategy against tuberculosis is discussed. PMID- 23457982 TI - [Impact of subclinical primary hyperparathyroidism on cardiovascular manifestations of essential arterial hypertension]. AB - At 95 patients with essential arterial hypertension features of structural and functional remodeling of left ventricular and humeral artery depending on a level parathyroid hormone in blood are studied. It is shown that while increasing of plasma parathyroid hormone level frequency and expressiveness of left ventricular and humeral artery remodeling increases whereas diastolic function and endothelium-dependent vasodilatation considerably decrease. Subclinical primary hyperparathyroidism in patients with essential arterial hypertension is detected in 22.1% of cases. PMID- 23457983 TI - [The role of interleukin-1 and associated cytokines in gastric carcinogenesis]. AB - This review presents detailed analysis of scientific data on influence of the associated with interleukin-1 cytokines on the development of malignant tumors of stomach with the definition of spectrum of diagnostic and therapeutic possibilities. Cytokines associated with interleukin-1 directly and indirectly involved into gastric carcinogenesis. Implementation of pro- and contreoncogenic effects depends on many factors. The serological and genetic criteria changes of interleukin-1 have high diagnostic value and prognostic significance opening new differential approaches to the treatment of precancer conditions and gastric cancer. PMID- 23457985 TI - [Features of the regulation of legal relations in the field of sanitary and epidemiological welfare in the Eurasian Economic Community member-states]. AB - The aim of this work was identification of both general trends and approaches, and the differences in the regulation of relations in the field of sanitary and epidemiological welfare of the population, determination of the necessary measures to harmonize legislation states in the countries - members of the Eurasian Economic Community (EurAsEC) in the noted sphere. As a result of the present research recommendations about unification and harmonization of legislations in member states of EurAsEC are developed for formation of uniform economic policy in noted sphere. PMID- 23457986 TI - [Some issues concerning epidemiological and sanitary studies]. AB - Epidemiological studies serve as a basis for evaluating the impact of risk factors on population health. The main goal of such research is to identify the relation between the morbidity rate and the environmental factors. The main task is to analyze and assess the patterns of disease emergence and spread in various social and age groups in the territories under study in different periods of time. The most labor-consuming stage of epidemiological researches is receiving basic data about a condition of environmental nd population health, especially in performing of longitudinal retrospective studies. PMID- 23457984 TI - [Hygienic substantiation of the permissible levels for tetracycline-group antibiotics in food]. AB - For the purpose of justification of the hygienic standard for tetracycline-group antibiotics in the food production established in the Russian Federation at more rigid level, than maximum and admissible levels (MAL) of the Codex Alimentarius Commission, the analysis of data of literature on negative nature of impact of low concentration of these antibiotics on an organism and the environmental conditions and risk for health has been performed. Inadequacy of the accepted admissible daily dose (ADD) accepted by The Joint FAO/WHO Expert Committee on Food Additives (JECFA) on action on selection of resistant E. coli in intestines, for the wide contingent of consumers in connection with ignoring of obvious factors of uncertainty (gastrointestinal dysbiosis, age and individual variations in the microbiota of people synergy with other antibiotics residues in food and indirect impact on an organism through microflora from the natural habitat (resistance genes, modified causative organisms with altered properties).. By the analysis of information received with the use of modern molecular and genetic methods, the role of Subinhibitory concentrations (sub-MICs) of tetracyclines as biologically active substances, signaling molecules which, without causing obvious negative consequences in a macroorganism, serve as a major factor of regulation of a transcription in microorganisms and activation of a horizontal gene transfer coding resistance, transferred on conjugative transposons of Tn916 Tn1545 family. Reasonable scientific data on a dominating contribution of minor levels of tetracyclines in globalization in the nature of the most adverse transmissive type of the antibiotic resistance interfaced to formation new bacterial pathotypes, as consequences of irrationally high scales of application in agriculture and strengthened impact on microbic ecosystems of live organisms and objects of habitat are presented. For minimization of this mediated risk for health the need of preservation of operating level of the tetracyclines residues (by < or = 0,01 mg/kg of a product), MAL which were unlike Codex MAL (< or = 0,1 1,2 mg/kg) in a zone of concentrations below 0,1 Misc not capable to initiation of the above described changes has been proved, till up to receipt of new scientific data on influence on macro - or microorganisms of the doses equal or below this value on macro - or microorganisms. PMID- 23457987 TI - [Optimization of the health level assessment of healthy individuals in the system of primary health care in the relation with social and hygienic monitoring of population health]. AB - It is proposed to extend the program of social and hygienic monitoring of public health by virtue of inclusion of risk factors for diseases according both to lifestyle and corresponding periodic health examination groups. Information can be obtained on the basis of materials of "Health centers". PMID- 23457988 TI - [Systematization and hygienic standardization of environmental factors on the basis of common graphic models]. AB - On the basis of graphic models of the human response to environmental factors, two main types of complex quantitative influence as well as interrelation between determined effects at the level of an individual, and stochastic effects on population were revealed. Two main kinds of factors have been suggested to be distinguished. They are essential factors and accidental factors. The essential factors are common for environment. The accidental factors are foreign for environment. The above two kinds are different in approaches of hygienic standardization Accidental factors need a dot-like approach, whereas a two-level range approach is suitable for the essential factors. PMID- 23457989 TI - [Characteristics of quantitative values of regional factors of exposure in the studied areas]. AB - In the paper the results of a comparative evaluation of the Russian and the standard, recommended by US EPA, factors of population exposure in seven areas of different federal districts of Russia are presented. Concerning the adult population differences reach 3.5 times, for children (1-6 years) - 4.2 times. An example of the effect of regional differences and standard factors on levels of exposure and risk is considered. Promising areas for further research on regional factors to improve the accuracy and reliability of the forecast assessments of the risks to public health have been identified. PMID- 23457991 TI - [Assessment of the influence of socio-economic factors on health and demographic indices]. AB - THE THEME: assessment of the influence of socio-economic factors on health and demographic indicators. OBJECTS: population of municipalities of the Voronezh region. THE NATURE AND AIM OF THE WORK: the justification of the system of measures aimed at stabilizing the medical-demographic situation at the regional level. METHODS: methods of Health Statistics; questionnaire. THE RESULTS OF THE WORK: the low socio-economic status of the population is set in the territories, depressed at the level of demographic development. The contribution of socio economic indicators in health and demographic situation has been determined Reliable cause-effect relationships between health and demographic indicators and the level of socio-economic development of the population have been identified. PMID- 23457990 TI - [Detection of potentially carcinogenic compounds persisting in atmospheric air and having high priority for hygienic regulation]. AB - The algorithm for the choice of potentially carcinogenic compounds (PCS) among emitted into air and results of the study, undertaken for realization of this algorithm are presented. The investigation was carried out in Magnitogorsk - Russian town of black metallurgy - in frames of the other study, aimed to evaluation of the influence of atmospheric pollution on children's health and genomic instability. The 11 PCS for further profound study of biological activity were selected out of more than 300 PCS, persisting in the air. The carcinogenic activity for 6 compounds out of these 11 ones was already have been found out before, that testifies correctness of the created approach and its adequacy for detection PCS in atmospheric air. PMID- 23457992 TI - [The urgency of the application of the medical sanitary passport in the system for chemical safety in the areas of location of high-risk chemical facilities in the Russian Federation]. AB - The main provisions concerning the need for a creation of medical and sanitary passport for territories in the protective measures zones (PMZ) of storage facilities and facilities for the destruction of chemical weapons (FDCW) are presented in the article. The assessment of results of certification of the territory of PMZ and FDCW in "Maradykovsky" in the Kirov region has been done. PMID- 23457994 TI - [The use of waste-derived adsorbents for improvement of the human environment]. AB - Nanostructured adsorbents based on plant waste have been derived. Optimal technological parameters of process have been established Practical application of adsorbents produced with the use of nanotechnologies gives an opportunity to improve the indices of the refining of sunflower oil and increase the extent of the purification of sewage from heavy metal ions. PMID- 23457993 TI - [Changes in the cytokine profile in residents with chronic obstructive lung disease exposed to urban air pollutants]. AB - The complex of urban air pollutants was established to affect the cytokine profile in Moscow residents with chronic obstructive pulmonary disease (COPD)), as it causes a significant reduction of L-6 and TNF-alpha in their blood samples. The identified changes indicate to inhibition of the functional activity of cells of the reticuloendothelial system, which can lead to the persistence of seasonal bacterial-viral infections and more rapid chronization of the basic disease. PMID- 23457995 TI - [Scientific and practical substantiation of the methodology for sanitary epidemiological auditing procedure for educational institutions]. AB - The implementation of sanitary and epidemiological auditing - a promising trend in the sanitary-epidemiological well-being of the population including children. Thus, it provides pupils' rights on the safety conditions of educational activities for their life and health without toughening of administrative influence. PMID- 23457996 TI - [State of common responsiveness of teenagers living in regions with different levels of ambient air pollution]. AB - The integral indices based on element ratio of hemogram as well as alpha-1 antitripsin, interleukins 2 and 10 contents in the adolescents living in industrial town with a high pollution level are represented in this paper. The increase in the processes of the nonspecific phagocytic protection and exertion of adaptive mechanisms has been revealed. PMID- 23457997 TI - [Prevalence of the chronic respiratory tract pathology in teenagers: role of some factors]. AB - Based on the medical examination data the prevalence of chronic diseases of respiratory tract in the teenagers in the industrial centers of East-Siberia has been studied. The prevalence in a group exposed to the high ambient air pollution was found to be 2.7 times higher than in the region with the moderate ambient air pollution level. The informativity of a factor of the environment, the lifestyle and the anamnesis may testify the high significance of the direct and the mediated inhalation chemical load informing the chronic pathology of a respiratory tract in the teenagers. PMID- 23457998 TI - [The impact of social and hygienic lifestyle factors on health status of students]. AB - The complex estimation of the impact of socio-hygienic lifestyle factors on the health of students has been performed. In the work the data of sociological analysis (questionnaire), the methods of multivariate statistics (correlation, regression analysis, method of correlation pleiades by P. V. Terentiev) were used. Among the analyzed components the average monthly income was found to make the greatest contribution of the health state and physical capacity of the studied contingent of students. The influence of this factor is most pronounced in a group of students with an average wealth. The quality of nutrition and the mode of life depend on the level of material well-being of students. Students with a deficiency or excess body weight are more susceptible to the effects of such lifestyle factors such as nutrition, physical activity, bad habits and prosperity. PMID- 23457999 TI - [Effect of multi-walled carbon nanotubes on the morphofunctional state of the small intestine cells of mice]. AB - The experiment was conducted in male mice SBAchS57Vl/6 and Balb/c, which consumed water, obtained from the use of carbon nanotubes. in a free drinking regimen for 2 weeks (mice SBAchS57Vl/6) and 2 months (mice Balb/c) Control group consisted of three groups of animals: intact and mice received fine coal in the same concentrations as under the impact of the nanotubes. Under exposure to the maximal of the studied concentration of carbon nanotubes a significant change in the fine structure of the villi of the small intestine was found in the form of increasing the number of unstructured villi and proliferation of epithelial cells, most pronounced in duration of exposure until 2 months. PMID- 23458000 TI - [Toxicological characteristic of indole as a basis for its hygienic regulation]. AB - The toxic properties of indole have been studied in terms of LD50 indole was established to refer to moderately hazardous substances: in case of indole introducing into the stomach in rats and mice, DL50 is 1200 mg/kg and 750 mg/kg respectively Indole has a weak ability to cumulation, and has a strong irritant effect to the eyes and a moderate one to the skin. Indole has indiscriminate irritating effect on the respiratory tract: Limir is at Limac (77,8 mg/m3). The occupational exposure of indole in the working area is 1 mg/m3. PMID- 23458001 TI - [The study of antimicrobial properties of silver nanoparticles in the form of a colloidal solution in the matrix of finely dispersed silica]. AB - In the experimental study obtained with chemical method colloid solution of nanoparticles (NPs) of silver (Ag) and a composite on his base in the matrix of finely dispersed silica with particle size of 8-12 nm and NPs concentration in basic solution of 0,0016% (0,016 mg/cm3) were established to exhibit high antimicrobial activity against the test organisms: E. coli, P. aeruginosa, S. Aureus and C. Albicans, which depended on a set of factors. Antibacterial properties of tissue impregnated with Ag-NPs were studied. As stabilizing substances a mixture of surface-active substance sodium dodecyl sulfate and polymer polyvinylpyrrolidone was used Before the beginning of the study effective neutralizer was tailored. Times of preservation of antimicrobial activity of test samples have been established, and also their stability throughout long term of supervision (24 months) has been shown. Effect of organic pollution on antimicrobal activity of the samples has been studied. Based on obtained results the algorithm of the study of antimicrobial properties of nanopreparations has been elaborated. PMID- 23458002 TI - [Cytogenetic monitoring for assessment of human environmental safety]. AB - Cytogenetic monitoring allows to identify groups and individuals with elevated levels of genomic instability, to determine the presence of genotoxic factors in the inspected area to justify the conduct of hygienic measures. An algorithm for cytogenetic monitoring with the usy of multi-organ karyological test, baseline of indices of cytogenetic effect, cell proliferation and apoptosis are presented, the index of accumulation of cytogenetic damage as a the basis for assessment of the three level of risk of cytogenetic abnormalities, is proposed. PMID- 23458003 TI - [Chromosomal aberrations and genetic polymorphism in genes of the xenobiotic detoxification and DNA repair enzymes in thermoelectric power plant employers]. AB - The results of the investigation of the interrelationship between frequency of chromosomal aberrations and detoxification enzymes (GSTM1, GSTT1) and DNA repair (hOGG1, XPD) genes in the employees of fuel energy complex in Kemerovo are presented In the group of the workers frequency of metaphases with aberrations (3,9 +/- 0,2%: n = 288) was shown to be significantly higher than in the comparison group (2,1 0, 2%: n = +/- 141). In the group of workers and control donors statistically significant differences were revealed in the frequency of distribution of the GSTT1 and hOGG1 genes. The level of chromosomal aberrations was established to be higher in patients with GSTM1 genotype "0/0" in the group of control donors. PMID- 23458005 TI - [Cypridopsis vidua as a test-model for the assessment of the toxicity of chemical substances, their mixtures and objects of the environment]. AB - The results of experimental studies on development a new test-model for the evaluation of toxicity, based on the application as a test-object aquatic crustaceans Cypridopsis vidua (Ostracoda), typical for ecosystems of Belarus and compares favorably with standardized test models (ease of maintenance in laboratory cultures, high reproducibility and sensitivity) are presented. The sensitivity of the test model to common environmental pollutants has been shown. The opportunity of using it to assess the acute toxicity of chemical substances and their mixtures, integral toxicity of water in Natural Bodies & Sewage. Systems, industrial waste, extracts of products has been proved. The recommendations for use in testing specific groups of substances have been proposed. PMID- 23458004 TI - [Interaction of genetic and radiation factors in the realization of effects of radiation in humans]. AB - The results of the study of the interaction of genetic and radiation factors in the effects of radiation in humans exposed to external and (or) internal radiation are presented. In most cases, with relatively less radiation exposure genotypic differences in the effects of exposure were established to be absent. At high intensities of radiation exposure, however, these differences as a rule have reliable character. Interaction of genetic and radiation factors manifested in a wide range: from the mutual stimulation of primarily inactive factors to the higher than multiplicative one. PMID- 23458006 TI - [Stereotypes of adaptive adjustment of the organism and their manifestations in the structure of morbidity in population and professional groups]. AB - The results of theoretical analysis and generalizations of long-term works of the author on the physiological-hygienic and clinical studies of the body in the adult population, exposed to influence of extremely pronounced environmental factors and conditions of employment are reported. The result of generalization - the theory of adaptive adjustment of the organism in extreme conditions - is presented as a system of postulates. The features of disease as a manifestations of the phenomenon of the side effects of adaptive adjustment of the organism are considered. PMID- 23458007 TI - [The possibility of using neural networks for the 3D visualization of hygienic studies of the health status on the example of the physical development of the child population]. AB - In the course of the research the possibility of using 3d visualization of the results of hygienic investigations using software package STATISTICA Neural Networks as exemplified by the physical development of children in the Kursk region has been demonstrated, assessment of the possibility of application the proposed method has been done. PMID- 23458008 TI - [To the problem of evaluation of public health: screening for gastroduodenal pathology on the example of atrophic gastritis in mass medical examination of the population]. AB - Assessment of health status of the population - the most important issue in preventive medicine. The objective of this work - to determine the possibility of nonendoscopic screening for gastroduodenal pathology, by the example of atrophic gastritis, in mass medical examinations of working residents in Moscow. Minimally invasive diagnostic test system GastroPanel ("Biohit", Finland) has been used. It allows with the ELISA method to determine both serum indicators of the function of the stomach -pepsinogen 1, gastrin 17 and the presence of H. pylori infection. 758 persons have been examined. The performed study confirms the possibility with the use of a set of mentioned indicators to identify individuals suspected for the presence of gastroduodenal disorders, especially atrophic gastritis, recognized as a precancerous condition. The use in preventive medicine complex diagnostic system, firstly, will make assessment of the health of the population more correct, increase the effectiveness of preventive measures and quality of life, and secondly, will contribute to the diagnosis of diseases of the stomach and duodenum in the early stages. PMID- 23458009 TI - [Substantiation of both safety indices for control over the use of chemicals for water disinfection and need to harmonize them with international requirements]. AB - The domestic and also foreign indices applied for control over the safety of chemical disinfecting of water are considered. The data confirming need of extension of the list of legislatively approved indices are provided of water, efficiency and safety indicators, harmful impurity, transformation products. On the basis of the performed analysis of literature data and own investigations the following indices for inclusion in the processed. Sanitary standards and rules on drinking water are suggested: the total content of THM, the total content of haloacetic acids, the total maintenance of up to AHC index (adsorbed halogen containing organic compounds) in water chlorination; chlorite- and chlorate ions in application of dioxide of chlorine; control over efficiency of water disinfection up to the steadiest microorganisms depending on an applied method. Introduction of settlement about necessity of control over the content of dangerous monomers and impurities in a commodity products in application of polymeric reagents and means of water disinfection is proved. PMID- 23458010 TI - [Improvement of effectivity of photo disinfection of water from bacterial contaminants in the presence of heterogeneous sensitizers based on phthalocyanines grafted to aminopropyl silicagel]. AB - The possibility of using 12 heterogeneous sensitizers (HS) based on phthalocyanines covalently grafted to aminopropyl silicagel for disinfection of water from bacteria has been studied. For reliable water quality control the technique of performing bacteriological analysis in the presence of HS beads in the sample has been elaborated. The conditions increasing the efficiency of photo disinfection in the presence of HS were studied. Algorithm for estimation of photo disinfectant effect of HS against bacteria was substantiated. Obtained data confirm the perspective of further studies on the substantiation of the possibility of the application of HS for water disinfection. PMID- 23458011 TI - [The value of glucose-positive coliform bacteria and potentially pathogenic bacteria as indicators of epidemiological safety of tap water]. AB - Due to intensive anthropogenic pollution of water environment generally accepted indicators of epidemic security of water bodies - common bacteria and thermotolerant coliform bacteria do not always permit to obtain an objective characterization of bacterial contamination of tap water. From the point of view of authors the integral index - glucose positive coliform bacteria most adequately reflect the sanitary-hygienic and epidemiological situation of water bodies. In monitoring for bacterial quality of tap water it is advisable to determine glucose positive coliform bacteria, that will provide the relevance of estimation of the epidemiological safety of water use. According to the method developed by the authors the calculation of the index of population risk of acute intestinal infections occurrence in dependence on the quality of tap water in Azov and Tsimlyansk towns. PMID- 23458012 TI - [Sense organs on palps and fore tarsi of gamasid mites (Parasitiformes, Rhinonyssidae), parasites of the nasal cavity of the great tit, the rock dove, and the Eurasian coot]. AB - The main sensory organs (the palpal organ and the tarsal sensory complex) were examined by scanning electron microscopy method in parasites of the nasal cavity of the great tit Parus major (Ptilonyssus sairae, Ptilonyssus pari), the rock dove Columba livia (Mesonyssus melloi), and the Eurasian coot Fulica atra (Rallinyssus caudistigmus). It was shown that differences in the topography of sensilla within the tarsal complex correspond to the taxonomic relations between species and genera, whereas differences in the structure of the palpal organ are not associated with the taxonomy and, probably, reflect ecological peculiarities of parasitism. PMID- 23458013 TI - [Identification of Ixodes persulcatus and Ixodes pavlovskyi occidentalis (Ixodidae) by the analysis of the gene fragment COXI (cytochrome oxidase subunit I)]. AB - Ticks of the genus Ixodes were collected in 2010 in the lowland part of Toguchinsk district of Novosibirsk Province (Russia) and in the forest-park area of Novosibirsk Scientific Centre and its outskirts (Sovetskiy district of Novosibirsk), and identified as Ixodes persulcatus (Schulze, 1930) (18 females and 13 males) and Ixodes pavlovskyi (13 females and 10 males). Ten specimens of each sex from each collecting site were examined. The following nine characters were used: the length and width of the scutum (conscutum) and of the gnathosoma in ventral view; the length of palpal segments II-III; the width of the hypostome; the length of idiosoma with scapula, of leg I, of the medial spur on fore coxa (Taiga..., 1985; Filippova, Musatov, 1996; Filippova, Panova, 1998). According to morphometric characters, specimens of Ixodes pavlovskyi collected in the forest-park area of the Novosibirsk Scientific Centre were identified as the subspecies I. p. occidentalis Filippova et Panova, 1998. Nucleotide sequences of the COI mitochondrial gene fragment were determined for 56 ticks. Phylogenetic analysis of the COI gene fragment in representatives of the persulcatus-ricinus species-group dwelling in Asia demonstrated high degree of conservatism. Molecular-genetic methods allow reliable identification of morphologically similar species I. pavlovskyi and I. persulcatus, pathogenic for humans. PMID- 23458014 TI - [The fauna of bloodsucking insects of the "gnus" complex (Diptera) in Leningrad Province and Saint-Petersburg]. AB - The history of the study of bloodsucking mosquitoes, sand flies, black flies, and horse flies in St. Petersburg and Leningrad Province is observed. At present, 38 mosquito species of 5 genera, 67 black fly species of 17 genera, 24 species of bloodsucking sand flies of the genus Culicoides, and 36 horse fly species of 6 genera were revealed in the territory of the region. The analysis of 267 collecting sites of 165 species of 30 genera of bloodsucking insects allowed revealing the most widespread species. The species composition of bloodsucking dipterans in the region is examined insufficiently. Till present, eastern and central (near the Ladoga Lake) parts of the region examined, and also the northern part of the Karelian Isthmus remain poorly studied. The last collections of bloodsucking insects of the "gnus" complex were performed more that 30 years ago. PMID- 23458015 TI - [Changes in the ranges of pasture ixodid ticks of the genus Ixodes Latr., 1795 (Parasitiformes, Ixodinae) in Western Siberia]. AB - The character of distribution of two species from the genus Ixodes, the Taiga tick Ixodes persulcatus and Ixodes pavlovskyi in the plain part of Western Siberia is analyzed. The northern border of the range of I. persulcatus in HMAO Ugra was clarified on the basis of long-term data on the population density of adult and immature ticks (1960-2011). The shift of the southern border of the species range in Western Siberia at the background of anthropogenic transformation (forest restoring activity, stopped sanitary forest cutting, road construction etc) is demonstrated; peculiarities of the distribution of the Taiga tick in some localities of the southwestern Siberia is analyzed. The modern state of the tick population in the joint dwelling zone of I. persulcatus and I. pavlovskyi is characterized. Possible reasons of changes in the structure of tick communities toward total prevalence of I. pavlovskyi in recreation zones of Novosibirsk and Tomsk are discussed. It is noted that the most significant changes in the character of distribution of these two tick species in Western Siberia had evidently occurred after 1990. Just in this period, local stable populations of the Taiga tick to the south of its main range in Western Siberia (within Omsk and Novosibirsk Provinces) were formed; the character of its distribution in the right bank of the Ob River (Novosibirsk Province) and in the valley of the Tom River (Tomsk Province) had changed; I. pavlovskyi became the dominating species. PMID- 23458016 TI - [Trematodes (Trematoda) of bats (Chiroptera) from the Middle Volga Region]. AB - The data on species diversity of trematodes from bats collected in the Middle Volga Region are summarized. According to original and literary data, 20 trematode species were recorded in bats of the region examined. Plagiorchis elegans, Lecithodendrium skrjabini, L. rysavyi, Prosthodendrium hurkovaae, and Pycnoporus megacotyle are specified for the bat fauna of Russia for the first time. For 11 species of parasites, new hosts are recorded. The analysis of bat helminthes demonstrated that the fauna of trematodes of the northern bat (12 species of trematodes), of the pond, and of the Brandt's bats is the most diverse, constituting more than 10 parasite species per bat species. The largest number of final hosts in the Middle Volga Region is characteristic of Plagiorchis koreanus and Prosthodendrium chilostomum; the latter species were revealed in 8 and 7 bat species, respectively. Trematodes of bats possess a high degree of host specificity. 17 species parasitize exclusively in bats out of 20 parasite species registered for the order Chiroptera. Only 3 species (Plagiorchis elegans, P. vespertilionis, and Prosthodendrium chilostomum) show wide degree of specificity, being found in other animals. Taxonomic position, the circle of hosts, collecting sites, and brief data in biology and geographical distribution for each helminth species are specified. Morphological descriptions and original figures for all the trematode species revealed in bats of the Middle Volga Region are given. PMID- 23458017 TI - [Molecular genetic analysis of trematodes of the genus Leucochloridium dwelling in the territory of Leningrad Province]. AB - The color of the broodsac sporocyst traditionally serves as the main taxonomic criterion for distinguishing of trematodes of the genus Leucochloridium. Broodsacs of L. paradoxum (Cams, 1835) are green, while broodsacs of L. perturbation (Pojmanska, 1969) are brown. We used molecular genetic analysis of sporocyst rDNA for verifying the accuracy of the mentioned morphological criteria. Trematode infected snails Succinea sp. were collected in Vyritsa and Lyuban (Leningrad Province, Russia). Nucleotide sequences of L. paradoxum (n = 18) and L. perturbatum (n = 10) rDNA including transcribed spacers (ITS1 and ITS2) and 5.8 S rRNA gene were received, rDNA fragments of Leucochloridium sp. sporocysts of the same color were identical. The difference in the ITS1 (2.6%) and ITS2 (6.7%) between sequences of L. paradoxum and L. perturbatum was revealed. Specific nucleotide sequences are deposited at the GeneBank. PMID- 23458018 TI - [Morphological variability and population structure of the cestode Proteocephalus longicollis (Zeder, 1800) in aquaculture]. AB - Morphological variability of the cestode Proteocephalus longicollis (Zeder, 1800) from Coregonus peled (Gmelin, 1789) was studied in natural host population from the Pelyadka River and in aquaculture from the Kuchak Lake. Variability of morphometric characters of the parasite is recorded. Sample from the Kuchak Lake differs from the sample collected in the Pelyadka River by a greater number of testes, larger size of worms, smaller size of cirrus bursa and smaller ratio of the cirrus bursa length and the width of proglottid. PMID- 23458019 TI - [Population biology of cestode genus Triaenophorus in natural and man-made water bodies]. AB - A comparative study of the frequencies of occurrence and distribution of the abundances of pike parasites, tapeworms of the genus Triaenophorus, was carried out in natural lakes and water bodies contaminated by the Kostomuksha mining and concentration mill (Northern Karelia). We demonstrate that the wide presence of T. crassus and T. nodulosus in natural northern lakes is due to the diversity of aquatic organisms and the structure of trophic relations. The abundance of both species is modeled by the negative binomial distribution. Relations in the host parasite system are stable. Estimates of the parameter k of the negative binomial distribution reflect the changes in the interactions in the host-parasite system. T. nodulosus has survived in the man-made water body storing the highly mineralized recirculated water from the mill. Disturbance-related distinctions were detected in the parameters of the T. nodulosus abundance distribution in the host population. In the Okunevoye Lake, where the water discharged from the tailings dump is more diluted, the infection rates in pike did not differ from those in undisturbed water bodies. PMID- 23458020 TI - [Trematode distribution in Littorina saxatilis populations can support the reproductive potential of the host: "toilers" and "idlers" among female periwinkles]. AB - Co-evolution between parasites and their hosts can involve adaptations on the individual and population levels likely to be especially prominent in the systems where parasites have a direct strong impact on the hosts fitness, as is the case with castrating trematodes and their gastropod hosts. We studied populations of the rough periwinkles Littorina saxatilis in the White Sea infested by castrating trematodes to determine whether spatial and temporal variations in the trematode prevalence affect the demographic structure of the host population. Sex, age, reproductive status and infestation of L. saxatilis from 19 populations with different trematode burdens (from < 1 % to 30-50%); in two of these 19 populations (RI and KLN) a long-term monitoring over the period of 15-20 years was also performed. These analyses showed that (1) the average age of gravid females did not correlate with the trematode prevalence of the population, (2) the ratio was skewed towards females, (3) the trematode prevalence in females tended to be higher than in males, (4) the proportion of the non-infested gravid females of the younger ages classes (2-4 years) did not correlate with trematode prevalence of the population. The proportion of young non-infested females that were not reproducing ("idlers") decreased significantly with increasing infestation prevalence when compared among different populations of L. saxatilis, but remained relatively stable within two heavily infested populations RI and KLN despite the year-to-year fluctuations of the infestation prevalence. Thus, a demographic mechanism to compensate for the parasite pressure in L. saxatilis populations may involve the maintenance of a relatively constant proportion of uninfected gravid female ("toilers") at the expense of uninfected, but not reproducing females of fertile age ("idlers"); the latter can be viewed a reproductive reserve of the population tapped into under the conditions of high infestation prevalence. This mechanism, in combination with the previously described elevated individual fecundity of females in heavily infested populations, may compensate for the parasite-induced decrease in the reproductive potential of the host population and ensure the stability of the host-parasite system. PMID- 23458021 TI - [Tapeworm Oochoristica tuberculata (Rudolphi, 1819)--parasite of the lizard Eremias argus Peters, 1869 in Zabaikalie]. AB - Morphological characteristics of the tapeworm Oochoristica tuberculata from the lizard Eremias argus is given from the northern border of the host areal. The complexes of most stable and most variable characters of this tapeworm are determined. The list of hosts is given for Oochoristica tuberculata. PMID- 23458022 TI - [Monitoring of the helminth of insectivorous mammals of meliorative canal banks in Belorussian Polesie]. AB - The helminth fauna of insectivorous mammals inhabiting meliorative canal banks has been examined in western part of Belorussian Polesie during 2005-2010. 33 species of helminthes were found in 4 species of small mammals, and total infection was 94.2%. The results of monitoring were compared with the observations carried out in the same territory in 1996-1999. Common shrew was found to be the dominant species among insectivorous mammals. The helminth complex in the insectivorous mammals inhabiting meliorativ canal banks is formed mainly from the helminths of this host species. PMID- 23458023 TI - [Using of antibodies against Microsporia Hsp70 family proteins for analysis of secretome of intracellular parasites]. AB - Microsporidia is a large group of fungi-related unicellular parasites with obligate intracellular lifestyle. Unlike other protozoan intracellular parasites (Kinetoplastida and Apicomplexa), most microsporidian species develop in direct contact with the host cell cytoplasm. This fact, acquisition of unique transporters to exploit host metabolic system (alongside the strong minimization of own machinery) and predicted repertoire of microsporidia secretome altogether suggest an active role of parasite proteins in the control of infected cell. Lack of information about secretome of microsporidia intracellular stages is largely due to the methodological difficulties of working with the obligate intracellular parasites. An important problem of such study is the contamination of preparations of host cell cytoplasm by inner (nonsecreted) parasite proteins. Even the homogenization of infected tissue in mild conditions and removal of parasite cells by low-speed centrifugation may result in their partial disruption. We expressed the fragments of three Hsp70 family chaperones from the microsporidium Paranosema (Antonospora) locustae in bacteria Escherichia coli. Immunoblotting with proteins of microsporidia intracellular stages and infected host tissue (locust fat bodies) demonstrated that antibodies against recombinant polypeptides may be used to monitor the integrity of parasite cells during homogenization of infected host tissue and subsequent removal of parasites by centrifugation. PMID- 23458024 TI - [On the methods of investigation of the actinosporean development phase of myxosporidians]. AB - The paper describes the techniques of the actinospores investigation under field and laboratory conditions. The methylene blue solution for staining of actinospore processes and estimating of daughter cells of sporoplasm is proposed. PMID- 23458025 TI - Prevalence of Escherichia coli O-types and Shiga toxin genes in fecal samples from feedlot cattle. AB - While efforts to control foodborne illness associated with the Shiga toxin producing Escherichia coli (E. coli) O157 through processes and procedures implemented at harvest facilities have been very successful, there is concern about the burden of illness associated with other Shiga toxin-producing E. coli. The U.S. Department of Agriculture Food Safety and Inspection Service announced plans to classify an additional six non-O157 Shiga toxin-producing E. coli as adulterants. Little is known about the prevalence and distribution of these E. coli in the animal production environment. An investigation of the prevalence of O157 and the six major non-O157 E. coli serogroups was conducted in 21 feedlots over the period July 2011 to October 2011. Individual fecal swabs were collected from cattle approximately 60 days after their arrival in the feedlot and were pooled for evaluation using a polymerase chain reaction assay to identify the presence of seven E. coli O-types (O157, O45, O103, O121, O145, O26, and O111) and four virulence genes (stx1, stx2, eaeA, and ehxA). Overall, 1145 fecal pools were evaluated, with 506 (44.2%) being positive for one or more of the E. coli O serogroups. The pool prevalences for E. coli O157, O45, O26, O103, O121, O145, and O111 were 19.7%, 13.8%, 9.9%, 9.3%, 5.5%, 1.1%, and 0.5%, respectively. Nearly all pools were positive for ehxA (99.7%) or stx2 (98.6%). The pool level prevalence for stx1 and eae was 65.5% and 69.3%, respectively. Pools that were positive for one or more of the other E. coli O-serogroups were 1.37 times more likely to be positive for E. coli O157. Conversely, pools that were positive for E. coli O157 were 1.43 times more likely to be positive for at least one of the other E. coli O-serogroups evaluated. These data will be useful to understand the expected prevalence of potential Shiga toxin-producing E. coli in cattle feedlots. PMID- 23458026 TI - Antimicrobial resistance trends among Salmonella isolates obtained from dairy cattle in the northeastern United States, 2004-2011. AB - Monitoring antimicrobial resistance trends among bacteria isolated from food animals and people is necessary to inform public policy regarding appropriate antimicrobial use. Our objectives were to describe the antimicrobial resistance status of Salmonella isolates from dairy cattle in the northeastern United States and to identify trends in resistance to various antimicrobial agents over time. Data were collected retrospectively for all bovine Salmonella isolates that were obtained from samples submitted to Cornell University's Animal Health Diagnostic Center between January 1, 2004 and December 31, 2011. Temporal trends in the prevalence of resistant Salmonella were investigated for each antimicrobial agent using the Cochran-Armitage trend test. Antimicrobial susceptibility testing was performed on 2745 bovine Salmonella isolates from clinical samples submitted during the study period. Overall resistance to each antimicrobial agent ranged from 0% (amikacin, ciprofloxacin, and nalidixic acid) to 72.0% (sulfadimethoxine). There was evidence of a significantly decreasing trend in prevalence of resistance to most agents: amoxicillin/clavulanic acid (AUG), ampicillin (AMP), cefoxitin (FOX), ceftiofur (TIO), ceftriaxone (AXO), chloramphenicol (CHL), chlortetracycline (CTET), florfenicol (FFN), kanamycin (KAN), neomycin (NEO), oxytetracycline (OXY), spectinomycin (SPE), streptomycin (STR), sulfadimethoxine (SDM), sulfisoxazole (FIS), and tetracycline (TET). Among the 265 isolates that were tested using the National Antimicrobial Resistance Monitoring System (NARMS) panel, the most common resistance patterns were pansusceptible (54.0%), AUG-AMP-FOX-TIO-AXO-CHL-KAN-STR-FIS-TET (18.1%), and AUG AMP-FOX-TIO-AXO-CHL-STR-FIS-TET (12.1%). Increasing prevalence of S. enterica serovar Cerro over the course of the study period presumably had an impact on the observed resistance trends. Nevertheless, these results do not support the notion that the current level of antimicrobial use in dairy cattle is driving an increase in the emergence and dissemination of drug-resistant Salmonella in the region served by the laboratory. PMID- 23458027 TI - Population structure of Staphylococcus aureus isolated from bulk tank goat's milk. AB - The presence of Staphylococcus aureus in raw milk can represent a potential threat to human health, due to the introduction of pathogenic strains into dairy food supply chain. The present study was performed to investigate the genetic variation among S. aureus strains isolated from bulk tank goat's milk. The virulence profiles were also assessed to link the isolates with the potential source of milk contamination. A population study was performed on 60 strains using distance-based methods such as pulsed-field gel electrophoresis (PFGE), and the output was analyzed using Structure statistical software (University of Chicago; http://pritch.bsd.uchicago.edu/structure.html ). This Bayesian clustering model tool allows one to assign individuals into a population with no predefined structure. In order to assess partition of genetic variability among isolates, groups obtained by Structure were also investigated using analysis of molecular variance. S. aureus was recovered in 60 out of 78 samples (76.9%) collected from 26 farms. According to PFGE analysis, the strains were divided into 25 different pulsotypes and grouped into two main clusters. Restriction profiles, analyzed by Structure, allowed us to identify two distinct S. aureus genetic groups. Within each group, the strains showed a high coefficient of membership. A great part of genetic variability was attributable to within-groups variation. On the basis of the virulence profile, 45% of the isolates were linked to "animal" biovar, while 6.7% could be assigned to "human" biovar. Out of 60 strains, 27 were characterized by in vitro production of either enterotoxins A (5.0%), C (38.3%), or D (1.7%). The present study showed a high prevalence of bulk tank goat's milk contamination with S. aureus of animal origin. The presence in goat's milk of S. aureus strains able to produce enterotoxins and their potential introduction into dairy chain may represent a serious threat to human health. PMID- 23458028 TI - Knowledge and awareness of children's food safety among school-based street food vendors in Dhaka, Bangladesh. AB - We carried out a cross-sectional study to determine the level of knowledge and awareness regarding children's food safety issues among the school-based street food vendors in Dhaka city. A total of 250 school-based street food vendors were interviewed employing a pre-tested structured questionnaire comprising foodborne illness and food hygiene-related questions. We used a scoring system based on the responses obtained from them, and categorized the overall level of knowledge and awareness into "adequate" and "inadequate." Multivariable logistic regression was used to explore the association between selected sociodemographic characteristics and the level of knowledge and awareness. The most common food item vended by school-based street food vendors was chotpoti/fuchka (37.2%). The median number of schoolchildren customers was 120 per vendor per day. All (100%) vendors were male with a mean age of 30.95+/-8.8 years, and their mean daily income was 131.16+/-62.54 Bangladeshi Taka (1.97+/-0.94 USD). Most (40.1%) of the respondents belonged to the age group 25-34 years, and the majority (43.6%) did not have any formal education. More than two-thirds (68%) vendors could not show adequate level of knowledge and awareness of children's food safety issues. The most common source of obtaining food safety information by vendors was electronic media (91.8%). Elderly (>=45 years) vendors were 17.73 times more likely to have adequate level of knowledge and awareness than the vendors belonging to age group 15-24 years (p<0.001; adjusted OR=17.73; 95% CI=4.38-71.73). Individuals who had an education of higher than primary level were 9.87 times more likely to possess adequate level of knowledge and awareness than those who did not have any formal education (p<0.01; adjusted OR=9.87; 95% CI=2.07-46.93). The majority of school based street food vendors showed an inadequate level of knowledge and awareness of children's food safety issues. PMID- 23458029 TI - Forensic identification of Indian snakeroot (Rauvolfia serpentina Benth. ex Kurz) using DNA barcoding. AB - Indian snakeroot (Rauvolfia serpentina) is a valuable forest product, root extracts of which are used as an antihypertensive drug. Increasing demand led to overharvesting in the wild. Control of international trade is hampered by the inability to identify root samples to the species level. We therefore evaluated the potential of molecular identification by searching for species-specific DNA polymorphisms. We found two species-specific indels in the rps16 intron region for R. serpentina. Our DNA barcoding method was tested for its specificity, reproducibility, sensitivity and stability. We included samples of various tissues and ages, which had been treated differently for preservation. DNA extractions were tested in a range of amplification settings and dilutions. Species-specific rps16 intron sequences were obtained from 79 herbarium accessions and one confiscated root, encompassing 39 different species. Our results demonstrate that molecular analysis provides new perspectives for forensic identification of Indian snakeroot. PMID- 23458031 TI - Coagulation disorders and aortic stenosis: a chicken and egg question? PMID- 23458030 TI - Perinatal bereavement: a principle-based concept analysis. AB - AIM: To report an analysis of the concept of perinatal bereavement. BACKGROUND: The concept of perinatal bereavement emerged in the scientific literature during the 1970s. Perinatal bereavement is a practice-based concept, although it is not well-defined in the scientific literature and is often intermingled with the concepts of mourning and grief. DESIGN: Concept Analysis. DATA SOURCES: Using the term 'perinatal bereavement' and limits of only English and human, Pub Med and CINAHL were searched to yield 278 available references dating from 1974-2011. Articles specific to the experience of perinatal bereavement were reviewed. The final data set was 143 articles. REVIEW METHODS: The methods of principle-based concept analysis were used. Results reveal conceptual components (antecedents, attributes and outcomes) which are delineated to create a theoretical definition of perinatal bereavement. RESULTS: The concept is epistemologically immature, with few explicit definitions to describe the phenomenon. Inconsistency in conceptual meaning threatens the construct validity of measurement tools for perinatal bereavement and contributes to incongruent theoretical definitions. This has implications for both nursing science (how the concept is studied and theoretically integrated) and clinical practice (timing and delivery of support interventions). CONCLUSIONS: Perinatal bereavement is a multifaceted global phenomenon that follows perinatal loss. Lack of conceptual clarity and lack of a clearly articulated conceptual definition impede the synthesis and translation of research findings into practice. A theoretical definition of perinatal bereavement is offered as a platform for researchers to advance the concept through research and theory development. PMID- 23458033 TI - Interface-confined oxide nanostructures for catalytic oxidation reactions. AB - Heterogeneous catalysts, often consisting of metal nanoparticles supported on high-surface-area oxide solids, are common in industrial chemical reactions. Researchers have increasingly recognized the importance of oxides in heterogeneous catalysts: that they are not just a support to help the dispersion of supported metal nanoparticles, but rather interact with supported metal nanoparticles and affect the catalysis. The critical role of oxides in catalytic reactions can become very prominent when oxides cover metal surfaces forming the inverse catalysts. The source of the catalytic activity in homogeneous catalysts and metalloenzymes is often coordinatively unsaturated (CUS) transition metal (TM) cations, which can undergo facile electron transfer and promote catalytic reactions. Organic ligands and proteins confine these CUS cations, making them highly active and stable. In heterogeneous catalysis, however, confining these highly active CUS centers on an inorganic solid so that they are robust enough to endure the reaction environment while staying flexible enough to perform their catalysis remains a challenge. In this Account, we describe a strategy to confine the active CUS centers on the solid surface at the interface between a TM oxide (TMO) and a noble metal (NM). Among metals, NMs have high electron negativity and low oxygen affinity. This means that TM cations of the oxide bind strongly to NM atoms at the interface, forming oxygen-terminated-bilayer TMO nanostructures. The resulting CUS sites at the edges of the TMO nanostructure are highly active for catalytic oxidation reactions. Meanwhile, the strong interactions between TMOs and NMs prevent further oxidation of the bilayer TMO phases, which would otherwise result in the saturation of oxygen coordination and the deactivation of the CUS cations. We report that we can also tune the oxide-metal interactions to modulate the bonding of reactants with CUS centers, optimizing their catalytic performance. We review our recent progress on oxide-on-metal inverse catalysts, mainly the TMO-on-Pt (TM = Fe, Co, and Ni) systems and discuss the interface confinement effect, an important factor in the behavior of these catalytic systems. We have studied both model catalyst systems and real supported nanocatalysts. Surface science studies and density functional theory calculations in model systems illustrate the importance of the oxide-metal interfaces in the creation and stabilization of surface active centers, and reveal the reaction mechanism at these active sites. In real catalysts, we describe facile preparation processes for fabricating the oxide-on-metal nanostructures. We have demonstrated excellent performance of the inverse catalysts in oxidation reactions such as CO oxidation. We believe that the interface confinement effect can be employed to design highly efficient novel catalysts and that the inverse oxide-on-metal catalysts may find wide applications in heterogeneous catalysis. PMID- 23458032 TI - Extended pathology reporting of resection specimens of colorectal liver metastases: the significance of a tumour pseudocapsule. AB - INTRODUCTION: The aim of this study was to analyse the influence of factors reported in the minimum histopathology dataset for colorectal liver metastases (CRLM) and other pre-operative factors compared with additional data relating to the presence of tumour pseudocapsules and necrosis on recurrence 1 year after a resection. METHODS: For a period of 14 months, extended histological reporting of CRLM specimens was performed, including the presence of pseudocapsules and necrosis in each tumour. The details of recurrence were obtained from surveillance imaging. RESULTS: In 66 patients there were 27 recurrences within 1 year. The rates were lower for patients with tumour pseudocapsules (8/27) than for patients without (19/36) (P = 0.030). Pseudocapsules were associated with a younger age (P = 0.005), nodal stage of the primary colorectal tumour (P = 0.025) and metachronous tumours (P = 0.004). In patients with synchronous disease and pseudocapsules, the recurrence rate was 2/12 compared with 13/23 patients without pseudocapsules (P = 0.026). DISCUSSION: These findings demonstrate that histological examination of resection specimens can provide significant additional prognostic information for patients after resection of CRLM, compared with clinical and radiological data. The present finding that the absence of a pseudocapsule in patients with synchronous CRLM is associated with a dramatically worse outcome may help direct patient-specific adjuvant treatment and care. PMID- 23458034 TI - Hydrogen-induced morphotropic phase transformation of single-crystalline vanadium dioxide nanobeams. AB - We report a morphotropic phase transformation in vanadium dioxide (VO2) nanobeams annealed in a high-pressure hydrogen gas, which leads to the stabilization of metallic phases. Structural analyses show that the annealed VO2 nanobeams are hexagonal-close-packed structures with roughened surfaces at room temperature, unlike as-grown VO2 nanobeams with the monoclinic structure and with clean surfaces. Quantitative chemical examination reveals that the hydrogen significantly reduces oxygen in the nanobeams with characteristic nonlinear reduction kinetics which depend on the annealing time. Surprisingly, the work function and the electrical resistance of the reduced nanobeams follow a similar trend to the compositional variation due mainly to the oxygen-deficiency-related defects formed at the roughened surfaces. The electronic transport characteristics indicate that the reduced nanobeams are metallic over a large range of temperatures (room temperature to 383 K). Our results demonstrate the interplay between oxygen deficiency and structural/electronic phase transitions, with implications for engineering electronic properties in vanadium oxide systems. PMID- 23458035 TI - Patterns of diversity and adaptation in Glomeromycota from three prairie grasslands. AB - Arbuscular mycorrhizal (AM) fungi are widespread root symbionts that often improve the fitness of their plant hosts. We tested whether local adaptation in mycorrhizal symbioses would shape the community structure of these root symbionts in a way that maximizes their symbiotic functioning. We grew a native prairie grass (Andropogon gerardii) with all possible combinations of soils and AM fungal inocula from three different prairies that varied in soil characteristics and disturbance history (two native prairie remnants and one recently restored). We identified the AM fungi colonizing A. gerardii roots using PCR amplification and cloning of the small subunit rRNA gene. We observed 13 operational taxonomic units (OTUs) belonging to six genera in three families. Taxonomic richness was higher in the restored than the native prairies with one member of the Gigaspora dominating the roots of plants grown with inocula from native prairies. Inoculum source and the soil environment influenced the composition of AM fungi that colonized plant roots. Correspondingly, host plants and AM fungi responded significantly to the soil-inoculum combinations such that home fungi often had the highest fitness and provided the greatest benefit to A. gerardii. Similar patterns were observed within the soil-inoculum combinations originating from two native prairies, where five sequence types of a single Gigaspora OTU were virtually the only root colonizers. Our results indicate that indigenous assemblages of AM fungi were adapted to the local soil environment and that this process occurred both at a community scale and at the scale of fungal sequence types within a dominant OTU. PMID- 23458036 TI - Development of cancer services: potential specific complexities in the perspective of health economic evaluation. PMID- 23458037 TI - Effect of addition of tramadol to one MAC sevoflurane on the haemodynamic response to laryngoscopy and tracheal intubation. AB - OBJECTIVE: To evaluate the effect of tramadol 2 mg/kg on haemodynamic response to tracheal intubation where the end tidal concentration of sevoflurane was kept constant at 1 MAC (2%). STUDY DESIGN: Double blind randomized controlled trial. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from January 2009 to April 2009. METHODOLOGY: Thirty-four patients scheduled for surgery under general anaesthesia were randomly allocated to two groups, sevoflurane alone (2%) or sevoflurane (2%) and tramadol (2 mg/kg) combination. Anaesthesia was induced with thiopentone and atracurium and with either tramadol or placebo according to group allocation. Sevoflurane was administrated along with N2O and oxygen through the face mask till end tidal minimum alveolar concentration (MAC) of one (2%) was achieved. Haemodynamic changes were noted at 1, 2 and 3 minutes post induction and every minute upto 7 minutes post-intubation and compared with baseline values. RESULTS: A significant difference in heart rate was seen at 2 and 3 minutes post-induction and 1, 2 and 3 minutes postintubation between two groups with values higher in sevoflurane alone group. No significant difference was seen in systolic, diastolic, and mean blood pressure compared to baseline between the two groups. CONCLUSION: HR and SBP values following laryngoscopy and tracheal intubation in both groups were less than 20% of baseline. Addition of tramadol 2 mg/kg to 1 MAC sevoflurane displayed further depression of chronotropic response to laryngoscopy and intubation as compared to sevoflurane alone following thiopentone and atracurium induction. PMID- 23458038 TI - Factors associated with breast arterial calcification on mammography. AB - OBJECTIVE: To determine the frequency of breast arterial calcifications (BAC) as seen on mammographic examination and to determine the association between BAC and hypertension, age, parity and weight of the person. STUDY DESIGN: Cross-sectional analytic study. PLACE AND DURATION OF STUDY: Department of Diagnostic Radiology, Military Hospital, Rawalpindi, from January 2006 to January 2007. METHODOLOGY: Two hundred patients undergoing mammography were studied to evaluate the association of BAC with raised blood pressure, age and parity. Previous history of lactation and the patients' weight were also recorded. Proportions of classes were compared using chi-square test. RESULTS: 13.5% of the subjects (n = 200) were positive for BAC on mammograms. Mean age of the BAC positive subjects was higher than their counterparts found negative for BAC. Women bearing 5 - 6 children showed the highest frequency of BAC. Seventy seven (10.38%) of the BAC positive cases had previous history of lactation, whereas 15.44% (n = 123) had not breast fed their children and showed BAC. No significant association of presence of BAC was noted with the weight of the subjects. CONCLUSION: The frequency of presence of BAC on mammography was associated with systemic hypertension and higher age. It also increased with the reproductive parameters of a woman. PMID- 23458039 TI - Cosmetic outcome of Y-V medial canthoplasty in blepharophimosis syndrome. AB - OBJECTIVE: To determine the cosmetic outcome of Y-V medial canthoplasty with medial canthal tendon shortening in Blepharophimosis syndrome. STUDY DESIGN: Quasi experimental study. PLACE AND DURATION OF STUDY: Department of Ophthalmology, Khyber Teaching Hospital, Peshawar, Pakistan, from June 2005 to April 2008. METHODOLOGY: Thirteen patients of Blepharophimosis syndrome aged 4 years and above were included in the study. Oculoplastic assessment including measurement of horizontal length of palpebral fissure, ptosis and intercanthal distance were done. All patients underwent Y-V medial canthoplasty with medial canthal tendon shortening by a single surgeon. Same measurements were repeated one week postoperatively and then 6 weeks after surgery and results compared with pre-operative findings. RESULTS: Twenty six eyes of 13 patients were included in the study. Ten (77%) patients were female and 3 (23%) were male. Mean age of all patients was 13.54 +/- 6.99 years with a range from 4 to 28 years. Mean horizontal length of palpebral fissure of all 26 eyes was 22.88 mm before surgery and increased to 26.77 mm after surgery. Vertical pre-operative and postoperative height of palpebral fissure was 5.69 mm and 5.34 mm respectively. Mean pre operative intercanthal distance of 37.46 mm was reduced to 32.08 mm postoperatively. Epicanthus inversus which was present in all (100%) eyes before surgery was successfully treated in 22 (84.6%) eyes after surgery. CONCLUSION: Y V medial canthoplasty with medial canthal shortening in Blepharophimosis syndrome has excellent cosmetic outcome. PMID- 23458040 TI - Should we routinely expose recurrent laryngeal nerve(s) during thyroid surgery? AB - OBJECTIVE: To compare the frequency of recurrent laryngeal nerve(s) (RLNs) palsy after various thyroid procedures with and without identification of recurrent laryngeal nerve during the operation. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Surgery, Military Hospital, Rawalpindi, from August 2008 to April 2010. METHODOLOGY: Patients undergoing indirect laryngoscopy with normal vocal cords and those with carcinoma and re-do surgery having normal vocal cord were included in the study. Patients with hoarseness of voice, abnormal vocal cord movements and with solitary nodule in the isthmus were excluded. These patients were randomly divided into 2 groups of 50 each using random number tables. RLN was identified by exposing the inferior thyroid artery and traced along its entire course in group-A. Whereas, in group B, nerves were not identified during the operations. Immediate postoperative direct laryngoscopy was performed by a surgeon with the help of an anaesthesiologist for the assessment of vocal cords. Patients with persistent hoarseness of voice were followed-up with indirect laryngoscopy at 3 and 6 months. RESULTS: Temporary unilateral recurrent laryngeal nerve palsies occurred in 2 (4%) patients in group-A where the voice and cord movements returned to normal in 6 months. In group-B, it occurred in 8 (16%) patients, 2 bilateral (4%) injuries requiring tracheostomy and 6 unilateral injuries (12%). Among the 2 bilateral recurrent laryngeal nerve injuries, the tracheostomy was removed in one case after 6 months with persistent hoarseness of voice but no respiratory difficulty during routine activities. Tracheostomy was permanent in the other case. Among the 6 cases of unilateral nerve injuries, the voice improved considerably in 4 cases within 6 months but in 2 cases hoarseness persisted even after 6 months. Frequency of recurrent laryngeal nerve palsies was significantly lower in group-A as compared to group-B (p = 0.046). CONCLUSION: For safe thyroid surgery, recurrent laryngeal nerve(s) should be routinely exposed in its entire course. PMID- 23458041 TI - Diagnostic laparoscopic findings in chronic pelvic pain. AB - OBJECTIVE: To assess the cause of pain on diagnostic laparoscopy in women with chronic pelvic pain and equivocal clinical and ultrasound examination. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Red Crescent General Hospital, Hyderabad, Sindh, from January 2007 to December 2009. METHODOLOGY: All the women presenting with chronic pelvic pain for more than 6 months duration, without any obvious pathological findings on clinical as well as on ultrasound examination were recruited. Women with chronic pelvic pain and having pelvic pathological lesions detected on clinical and/or ultrasound examination were excluded. Clinical, ultrasound, and laparoscopic data was collected and analyzed on SPSS version 14. The results were described as frequency, proportion, compared by chi-square test with significance at p < 0.05. RESULTS: Highest frequency of chronic pelvic pain was observed in women aged between 26 - 35 years (62.4%), 53 out of 85 women. Most of these women were married (90.6%) and nulliparous (47.1%). Pain was reported as dull and sharp by 35 women (41.2%), infertility (n = 46, 54.1%) and dyspareunia (n = 45, 52.9%) were the commonest co-existent complaints. On laparoscopic examination, pathological lesions were detected in 65, tuberculosis in 17 (20%) endometriosis in 11 women (12.9%), pelvic inflammatory diseases and pelvic adhesion in 8 (9.4%) women each and ovarian cyst in 6 women (7.1%). CONCLUSION: Positive laparoscopic yield was high in women with pelvic pain. Pelvic tuberculosis was the most common pathology detected followed by endometriosis, pelvic inflammatory disease and adhesions. PMID- 23458042 TI - Etiology, clinical spectrum and outcome of metabolic liver diseases in children. AB - OBJECTIVE: To determine the etiology, clinical spectrum and outcome of metabolic liver diseases (MLD) in children admitted in a tertiary care hospital of Eastern India. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Paediatric Liver Clinic and Paediatrics Inpatient Department of Nilratan Sircar Medical College and Hospital, Kolkata, Eastern India, from April 2009 to March 2011. METHODOLOGY: All children aged 0 - 12 years having characteristic clinical features along with diagnostic hallmark of any MLDs were included in this study and data were collected on a pre-designed proforma. After appropriate management and discharge, all patients were followed-up for next 6 months. RESULTS: Fifty one children with mean age 4.34 +/- 3.78 years (range 2 days - 12 years), male: female ratio 1.55:1, were studied. The etiologies were Wilson's disease (33.33%, n = 17); glycogen storage disorder (23.53%, n = 12); galactosemia (19.61%, n = 10); non-alcoholic fatty liver disease (11.76%, n = 6); Gaucher disease (5.88%, n = 3); mucopolysaccharidoses (3.92%, n = 2) and familial hyperlipoproteinemia type I (1.96%, n = 1). Jaundice (n = 24) and hepatomegaly (n = 47), was the commonest symptom and sign respectively. Of the 17 non-responders, most were Wilson's disease (n = 7) cases. There was statistical difference in outcome with respect to INR > 1.3 at diagnosis (p = 0.026). CONCLUSION: High index of suspicion, early detection and screening, simple dietary modification and cost effective drugs along with good compliance are sufficient to treat and even prevent evolution of most causes of the MLDs. PMID- 23458043 TI - Outcome of recurrent pterygium with intraoperative 0.02% mitomycin C and free flap limbal conjunctival autograft. AB - OBJECTIVE: To determine the re-recurrence and the postoperative complications in recurrent pterygium cases treated by intraoperative 0.02% Mitomycin C (MMC) and conjunctival autograft (CAG). STUDY DESIGN: Quasi-experimental. PLACE AND DURATION OF STUDY: Department of Ophthalmology, Liaquat University of Medical and Health Sciences, Jamshoro, Hyderabad and Chandka Medical College Hospital, Larkana, from January to December 2010. METHODOLOGY: Cases with recurrent pterygium were included in this study. Cases with history of first time pterygium and pterygium with conjunctival scarring, dry eye, glaucoma and vitreoretinal disease were excluded. After topical and subconjunctival anaesthesia, pterygium was excised in single piece. Intraoperative 0.02% MMC was applied on bare sclera for 2 minutes. CAG was excised from supero-temporal conjunctiva, and implanted on bare sclera. All cases were followed-up for 6 months. Re-recurrence was defined as postoperative fibrovascular re-growth of 1.0 mm or more crossing the corneo scleral limbus. Data was analysed as descriptive statistics. RESULTS: A total of 65 eyes of 65 cases were studied having mean age of 43.26 +/- 12.81 years. Among those, 41 (63.1%) were males and 48 (73.8%) belonged to rural area. The size of pterygium on cornea was 2-3 mm in 44 (67.7%) cases and 4-5 mm in 21 (32.3%) cases. Re-recurrence of pterygium was seen in 3 (4.6%) cases. Postoperative complications included conjunctival granuloma in 2 (3.1%) cases, graft necrosis in 2 (3.1%) cases, graft oedema in 3 (4.6%) cases and graft displacement in 3 (4.6%) cases. CONCLUSION: The intraoperative application of 0.02% MMC with CAG markedly reduces the risk of re-recurrence of pterygium and postoperative complications. PMID- 23458044 TI - Outcome of intramedullary interlocking SIGN nail in tibial diaphyseal fracture. AB - OBJECTIVE: To determine the outcome of intramedullary interlocking surgical implant generation network (SIGN) nail in diaphyseal tibial fractures in terms of union and failure of implant (breakage of nail or interlocking screws). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Orthopaedics and Spinal Surgery, Ghurki Trust Teaching Hospital, Lahore Medical and Dental College, Lahore, from September 2008 to August 2009. METHODOLOGY: Fifty patients aged 14 - 60 years, of either gender were included, who had closed and Gustilo type I and II open fractures reported in 2 weeks, whose closed reduction was not possible or was unsatisfactory and fracture was located 7 cm below knee joint to 7 cm above ankle joint. Fractures previously treated with external fixator, infected fractures and unfit patients were excluded. All fractures were fixed with intramedullary interlocking SIGN nail and were followed clinically and radiographically for union and for any implant failure. RESULTS: Forty one (88%) patients had united fracture within 6 months, 5 (10%) patients had delayed union while 4 (8%) patients had non-union. Mean duration for achieving union was 163 + 30.6 days. Interlocking screws were broken in 2 patients while no nail was broken in any patient. CONCLUSION: Intramedullary interlocking nailing is an effective measure in treating closed and grade I and II open tibial fractures. It provides a high rate of union less complications and early return to function. PMID- 23458045 TI - Comparison of the patients' satisfaction after inpatient and outpatient operations for haemorrhoidal disease. AB - OBJECTIVE: To compare the patients' satisfaction between outpatient and inpatient haemorrhoidectomy. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran, from January to July 2011. METHODOLOGY: A total of 208 patients were involved in this cross-sectional study. All patients were examined by their specialists and after definite diagnosis of haemorrhoid, they were randomly allocated to two groups: outpatient and inpatient. Data for this study was collected by a satisfaction questionnaire. RESULTS: There was no statistical significant difference between the two groups' satisfaction. Both groups were quite satisfied. Also, there was no statistical significance regarding the variable of time of visit. In addition, there was no association between the patients' satisfaction and with, occupation, and level of education. CONCLUSION: Based on the results of the study, minor operations such as haemorrhoidectomy are better to be done in clinics since they do not differ from the operating room regarding the patients' satisfaction. PMID- 23458046 TI - A diagnostic pitfall: pancreatic tuberculosis, not pancreatic cancer. AB - Abdominal tuberculosis (TB) is one of the most common forms of extra-pulmonary tuberculosis and is responsible for considerable morbidity and mortality globally. Tuberculosis can involve any part of the gastrointestinal tract from mouth to anus, the peritoneum, liver, spleen and the pancreatobiliary system. The occurrence of abdominal TB is independent of pulmonary disease in most patients, with a reported incidence of co-existing pulmonary disease varying from 6 to 38% worldwide. We report a case of pancreatic tuberculosis also involving the vertebrae, which was initially treated as a case of pancreatic cancer. PMID- 23458047 TI - Congenital hypothyroidism presenting with postpartum bradycardia. AB - Congenital hypothyroidism is a clinical condition characterized by lack of thyroid hormone because of thyroid gland developmental and thyroid hormone biosynthesis disorders. The most common cause of permanent hypothyroidism is congenital factors. Prompt diagnosis is critical. However, overt signs of hypothyroidism are rarely present at birth, and 95% of affected babies are asymptomatic. Hypoxemia, apnea, acidosis, increased intracranial pressure, vagal stimulus and central nerve system abnormalities represent the most common causes of bradycardia in the neonate. Bradycardia associated with congenital hypothyroidism is very rare. In this paper, a case of severe congenital hypothyroidism, induced by maternal blocker antibodies, who presented with bradycardia, is reported. PMID- 23458048 TI - Prenatal diagnosis and treatment perspective of fetal hypothyroidism with goiter. AB - We describe two cases of fetal goiter in women with no history of thyroid disease. Diagnosis of fetal goiter during antenatal care was made by ultrasound and MRI. Congenital hypothyroidism was confirmed by fetal blood sampling that was treated with weekly intra-amniotic injections of L-thyroxin. One fetus was initially treated with four weekly intra-amniotic injections of 200 MUgms of L thyroxin, later increased to 400 MUgms. The other fetus was treated with only three weekly intraamniotic injections of 400 MUgms of L-thyroxin. Therapeutic response was monitored by repeated ultrasound and MRI along with fetal blood sampling. At birth, none of the babies had goiter and were put on oral thyroxin. Post-natal studies were suggestive of congenital hypothyroidism due to dyshormogenesis. No abnormality was detected at follow-up. These cases highlight the role of intra-amniotic thyroxine in management of fetal hypothyroidism with goiter. PMID- 23458049 TI - Congenital terminal transverse deformity of upper limb: clinical and radiological findings in a sporadic care. AB - Congenital transverse limb anomalies are rare, which affect upper and/or lower limbs and may accompany several syndromic malformations. We present a sporadic male subject with congenital, unilateral transverse arrest of the left hand. The affected arm was observed to be short with reduced zeugopod and truncated palm. Fingers were represented by five bead-like nubbins. Roentgenographic examination revealed short radius and ulna with hypoplastic distal heads, absent carpals/metacarpals, and a hypoplastic bony island in each nubbin. Consanguinity was denied, and the subject had no symptoms in the orofacial, neurological and skeletal systems. Detailed clinical data with literature survey is presented. PMID- 23458050 TI - Severe hypo-osmotic hyponatraemia due to chylous leak following radical neck dissection. AB - Chylous leak is a documented complication of radical neck dissection with well recognised morbidities, including wound breakdown, hypovolaemia and hypoalbuminaemia. Other less well-documented electrolyte imbalances can also ensue. We aim to raise awareness about hypo-osmotic hyponatraemia as a potentially fatal, commonly overlooked complication of high-output chylous leaks. Following identification of his hyponatraemia, this patient underwent successful management in the intensive therapy unit, followed by surgical repair of his chylous leak. Hypo-osmotic hyponatraemia as a complication of chylous leak is not well documented, is likely to be overlooked when present, and is potentially life threatening. It should be sought after in any patient with a high-output chylous leak following neck dissection. PMID- 23458051 TI - Emphysema and bronchiectasis secondary to alpha-1 antitrypsin deficiency. AB - A 47-year-old Caucasian male presented to the chest clinic with a 4-week history of exertional dyspnea. A chest radiograph showed mild hyperinflation without any focal pathology and spirometry showed a mild obstructive defect. In view of symptoms being disproportionate to spirometric and radiologic abnormalities, a thoracic CT scan was obtained. It revealed that there was evidence of bronchiectasis and mild emphysema in basal distribution. Subsequently, he was confirmed to have severe alpha1-Antitrypsin deficiency. This case illustrates the importance of considering alpha1-Antitrypsin deficiency in patients with combination of emphysema and bronchiectasis in a basal distribution. Although basal emphysema is well-recognized pulmonary manifestation of alpha1-Antitrypsin deficiency, it is extremely unusual to have bronchiectasis with very mild degree of emphysema. PMID- 23458052 TI - Primary pancreatic tuberculosis: a rare and elusive diagnosis. AB - Primary pancreatic tuberculosis is an extremely rare entity, even in tuberculosis endemic areas. A 22-year-old male presented with features of obstructive jaundice. Ultrasonography and computed tomography scan showed mass in the pancreatic head for which he underwent a pancreatoduodenectomy. Histological examination of the specimen showed caseating granulomas. Antituberculous medicines were started and he remained well 18 months after surgery. Pancreatic tuberculosis is rare and is frequently confused with pancreatic cancer on clinical presentation as well as on imaging studies. A high index of suspicion is vital to avoid surgeries in this medically treatable, often misdiagnosed condition. PMID- 23458053 TI - Bronchial carcinoid presenting as multiple lung abscesses. AB - Bronchial carcinoid tumours is a rare group of pulmonary malignant neoplasm that is derived from neuroendocrine system. Bronchial carcinoid usually present with hilar masses, atelactasis, bronchiectasis, or post-obstructive pneumonia. This case describes a very unusual presentation of bronchial carcinoid tumour with multiple lung abscesses involving the whole lung. This report is of an adult lady who presented with multiple lung abscesses involving her whole of the right lung. She was found to have an endo-bronchial lesion in her right main bronchus which eventually turned out to be carcinoid tumour. She responded to resection and antibiotic therapy. PMID- 23458054 TI - Dengue fever outbreak in Lahore. AB - Dengue fever has now affected all the major cities of country. About 41,354 patients underwent antibody screening for dengue fever from Shaukat Khanum Memorial Cancer Hospital, Lahore, during the epidemic period (October 1st 2010 to December 20th 2010). Out of them, 1294 (3.1%) patients were positive for IgM antibodies, and 124 (0.3%) for IgG antibodies. A total of 722 (1.7%) patients were borderline positive for IgM antibodies and 108 (0.26%) were borderline positive for IgG antibodies. Dengue fever has emerged as a global problem over the last 5 years. It has also hit Lahore badly especially after the floods in 2010. High index of suspicion should be there in case of related symptoms. PMID- 23458055 TI - Thoracoscopic evacuation of retained post-traumatic hemothorax. AB - Post-traumatic retained hemothorax is a major risk factor for empyema thoracis leading to prolonged hospitalization, entrapped lung and a need for decortication. VATS (Video Assisted Thoracoscopy) for retained hemothorax shortens the duration of chest tube drainage and length of stay. From December 2004 to July 2009, 110 consecutive patients underwent VATS for retained or clotted hemothoraces at the Department of Thoracic Surgery, Jinnah Postgraduate Medical Centre, Karachi. Majority of the patients were males (n = 91; 82.7%). Sixty-five patients (59.1%) underwent VATS within 6 days and 45 patients (40.9%) between 7 - 14 days of injury. In 8 patients (7.3%) VATS was abandoned for thoracotomy. Post VATS full lung expansion was achieved in 87 patients (79.0) with complete evacuation of hemothorax. Chest tubes were removed within the first week in 100 patients (90.9%). In hemodynamically stable patients, VATS is a safe, reliable and effective technique for the evacuation of retained hemothorax. Early intervention within 6 days of injury avoids the need for a thoracotomy and is associated with a better short and long-term outcome. PMID- 23458056 TI - Nanomedicine: the other face of the mirror. PMID- 23458057 TI - A strategic behaviour guidance tool in paediatric dentistry: 'reframing'--an experience. PMID- 23458058 TI - Job demands and musculoskeletal symptoms among female geriatric nurses: the moderating role of psychosocial resources. AB - The present study examined whether job resources (job control, social support, and distributive justice) moderate the associations of high job demands induced by physical and mental workload with musculoskeletal symptoms among geriatric nurses. The data were drawn in Finland from 975 female nurses working in 152 geriatric units who responded to a survey questionnaire. Information on the objective workload in terms of resident characteristics and structural factors was also collected at the unit level. After adjusting for the objective workload, multilevel logistic regression analyses showed that self-reported physical workload was associated with higher risk of musculoskeletal symptoms (OR = 1.93, 95 % CI [1.38, 2.72]) among nurses with low social support. In addition, mental workload was associated with higher risk of musculoskeletal symptoms (OR = 1.72, 95% CI [1.12, 2.62]) for those with low distributive justice. The results suggest that social support and fair reward systems may help to buffer against the detrimental effects of heavy job demands on nurses' musculoskeletal symptoms. PMID- 23458059 TI - Self-determination, control, and reactions to changes in workload: a work simulation. AB - The objective of this experimental study is to capture the dynamic temporal processes that occur in changing work settings and to test how work control and individuals' motivational predispositions interact to predict reactions to these changes. To this aim, we examine the moderating effects of global self-determined and non-self-determined motivation, at different levels of work control, on participants' adaptation and stress reactivity to changes in workload during four trials of an inbox activity. Workload was increased or decreased at Trial 3, and adaptation to this change was examined via fluctuations in anxiety, coping, motivation, and performance. In support of the hypotheses, results revealed that, for non-self-determined individuals, low work control was stress-buffering and high work control was stress-exacerbating when predicting anxiety and intrinsic motivation. In contrast, for self-determined individuals, high work control facilitated the adaptive use of planning coping in response to a change in workload. Overall, this pattern of results demonstrates that, while high work control was anxiety-provoking and demotivating for non-self-determined individuals, self-determined individuals used high work control to implement an adaptive antecedent-focused emotion regulation strategy (i.e., planning coping) to meet situational demands. Other interactive effects of global motivation emerged on anxiety, active coping, and task performance. These results and their practical implications are discussed. PMID- 23458060 TI - Mental disorders and their association with perceived work stress: an investigation of the 2010 Canadian Community Health Survey. AB - The economic repercussions of mental disorders in the workplace are vast. Research has found that individuals in high-stress jobs tend to have higher prevalence of mental disorders. The current cross-sectional study examined the relationships between work-related stress and mental disorders in a recent representative population-based sample-the 2010 Canadian Community Health Survey by Statistics Canada (CCHS; 2010a; Retrieved from http://www23.statcan.gc.ca/imdb bmdi/instrument/3226_Q1_V7-eng.pdf). Respondents in the highest level of perceived work stress had higher odds of ever being treated for an emotional or mental-health problem and for being treated in the past 12 months. These high stress respondents also had higher odds of being diagnosed for mood and anxiety disorders than their nonstressed counterparts. These associations highlight the continued need to examine and promote mental health and well-being in the workplace. PMID- 23458061 TI - The moderating role of attention-deficit/hyperactivity disorder in the work engagement-performance process. AB - Attention-deficit/hyperactivity disorder (ADHD) is a cognitive disability that affects millions. Although individuals with ADHD are employed throughout many organizations and there is evidence that their performance is lower, scant research exists describing how ADHD impacts an individual's performance. In this article, we extend attentional control theory to examine how ADHD impacts both the effectiveness and efficiency of employee performance. Across 3 samples, 2 of general working adults (n = 257 and 170) and 1 of nurses (n = 243), we found that ADHD was associated with lower performance (rated via self-, coworker, and supervisor ratings) and that the relationship was strongest for in-role performance, suggesting that employees with ADHD may be diverting attention away from task-relevant behaviors. Furthermore, although work engagement was associated with higher performance, that relationship was diminished among those who experienced higher levels of ADHD, suggesting lower performance efficiency. We discuss the implications of these findings for research on attentional control and the management of those with ADHD at work. PMID- 23458062 TI - Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C. AB - AIM: Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-beta signaling. TGF-beta type I receptor and pro inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro carcinogenesis, particularly via phospho-Smad signaling. METHODS: We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non HCC group), and 12 patients who developed HCC despite SVR (HCC group). RESULTS: Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling. CONCLUSION: HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro carcinogenic process has already begun before HCV clearance. PMID- 23458063 TI - Once weekly fluconazole for antifungal prophylaxis post-liver transplantation. AB - BACKGROUND: Invasive fungal infections (IFI) remain a significant cause of morbidity and mortality in orthotopic liver transplantation (OLT) recipients. In this retrospective study, the outcomes of a protocol using once weekly fluconazole for 3 months after OLT in low- and high-risk patients were reviewed. METHODS: In total, 221 OLTs were evaluated in the 3-year period after institution of the new protocol to determine the incidence of IFI within 6 months post-OLT. RESULTS: In this cohort, 11 IFIs developed during the 6-month post-transplant period, with the majority being non-albicans Candida. High-risk patients had a greater rate of IFI (16.7% versus 3.4%, P = 0.038) and a significantly longer intensive unit care (ICU) and hospital lengths of stay compared with low-risk patients. Patient and graft survival were similar between the groups. Our patient population appeared to be at low risk for IFI, with 92% of the entire cohort considered low risk. DISCUSSION: Given the low incidence of IFI in the low-risk group and the possibility of such protocol selecting out for fluconazole resistant fungi, the use of weekly fluconazole for 3 months may not be justifiable in low-risk OLT recipients. Given the increased resource utilization observed with IFI, further examination of a more intensive prophylactic strategy in high-risk patients may be warranted. PMID- 23458064 TI - Catheter-associated bloodstream infections in pediatric hematology-oncology patients. AB - Catheter-associated bloodstream infections (CABSIs) are common complications encountered with cancer treatment. The aims of this study were to analyze the factors associated with recurrent infection and catheter removal in pediatric hematology-oncology patients. All cases of CABSIs in patients attending the Department of Pediatric Hematology-Oncology between January 2008 and December 2010 were reviewed. A total of 44 episodes of CABSIs, including multiple episodes involving the same catheter, were identified in 31 children with cancer. The overall CABSIs rate was 7.4 infections per 1000 central venous catheter (CVC) days. The most frequent organism isolated was coagulase-negative Staphylococcus (CONS). The CVC was removed in nine (20.4%) episodes. We found that hypotension, persistent bacteremia, Candida infection, exit-side infection, neutropenia, and prolonged duration of neutropenia were the factors for catheter removal. There were 23 (52.2%) episodes of recurrence or reinfection. Mortality rate was found to be 9.6% in children with CABSIs. In this study, we found that CABSIs rate was 7.4 infections per 1000 catheter-days. CABSIs rates in our hematology-oncology patients are comparable to prior reports. Because CONS is the most common isolated microorganism in CABSIs, vancomycin can be considered part of the initial empirical regimen. PMID- 23458066 TI - Diabetic population mortality and cardiovascular risk attributable to hypertension: a decade follow-up from the Tehran Lipid and Glucose Study. AB - To determine the extent to which burden of cardiovascular disease (CVD) outcomes among diabetic population is attributable to hypertension. Nine-year follow-up data were secured for 7068 participants aged >= 20 years old, free from CVD at baseline. Cox proportional hazards regression was implemented to estimate hazard ratios (HRs) of hypertension. Population-attributable hazard fraction (PAHF) was used to assess proportion of diabetic population hazard of CVD events and mortality attributable to hypertension. In the whole population, irrespective of diabetes or hypertension status, incidence rate (95% CI) of CVD, coronary heart disease (CHD), as well as CVD and all-cause mortality per 1000 person-year were 8.3 (7.6-9.0), 7.1 (6.5-7.8), 1.8 (1.5-2.1) and 3.9 (3.5-4.5), respectively. Among diabetes participants, hypertension was a risk factor for CHD (HR = 1.63, 95% CI 1.15-2.03), CVD (HR = 1.74, 95% CI 1.50-2.41), CVD mortality (HR = 1.65, 95% CI 0.87-3.12) and all-cause mortality (HR = 1.53, 95% CI 0.97-2.42). HRs, however, were not statistically significant for all-cause or CVD mortality. PAHFs (%) of hypertension was 27.5 (95% CI 8.3-42.6) for CHD, 29.6 (95% CI 10.6-44.4) for CVD, 27.9 (95% CI - 17.2 to 55.7) for CVD mortality and 22.6 (95% CI - 5.9 to 43.4) for all-cause mortality. Our study shows that there is an excess risk of CVD in hypertensive patients with diabetes related to inadequate control of blood pressure. PMID- 23458065 TI - Biosynthetic assembly of the Bacteroides fragilis capsular polysaccharide A precursor bactoprenyl diphosphate-linked acetamido-4-amino-6 deoxygalactopyranose. AB - The sugar capsule capsular polysaccharide A (CPSA), which coats the surface of the mammalian symbiont Bacteroides fragilis, is a key mediator of mammalian immune system development. In addition, this sugar polymer has shown therapeutic potential in animal models of multiple sclerosis and other autoimmune disorders. The structure of the CPSA polymer includes a rare stereoconfiguration sugar acetamido-4-amino-6-deoxygalactopyranose (AADGal) that we propose is the first sugar linked to a bactoprenyl diphosphate scaffold in the production of CPSA. In this report, we have utilized a heterologous system to reconstitute bactoprenyl diphosphate-linked AADGal production. Construction of this system included a previously reported Campylobacter jejuni dehydratase, PglF, coupled to a B. fragilis-encoded aminotransferase (WcfR) and initiating hexose-1-phosphate transferase (WcfS). The function of the aminotransferase was confirmed by capillary electrophoresis and a novel high-performance liquid chromatography (HPLC) method. Production of the rare uridine diphosphate (UDP)-AADGal was confirmed through a series of one- and two-dimensional nuclear magnetic resonance experiments and high-resolution mass spectrometry. A spectroscopically unique analogue of bactoprenyl phosphate was utilized to characterize the transfer reaction catalyzed by WcfS and allowed HPLC-based isolation of the isoprenoid linked sugar product. Importantly, the entire heterologous system was utilized in a single-pot reaction to biosynthesize the bactoprenyl-linked sugar. This work provides the first critical step in the in vitro reconstitution of CPSA biosynthesis. PMID- 23458067 TI - Insulin signaling: a potential signaling pathway for the stimulatory effect of kaempferitrin on glucose uptake in skeletal muscle. AB - The aim of the study was to investigate the in vitro effect and the mechanism of action of kaempferitrin on glucose uptake in an insulin target (soleus muscle). A stimulatory effect of kaempferitrin on glucose uptake was observed when rat soleus muscle was incubated with 10, 100 and 1000 etaM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), HNMPA(AM)3, an insulin receptor tyrosine kinase activity inhibitor, colchicine, a microtubule-depolymerizing agent, SB239063, an inhibitor of P38 MAPK and cycloheximide, an inhibitor of protein synthesis showed that kaempferitrin triggers different metabolic and nuclear pathways in skeletal muscle. Besides the influence on glycogen storage, the metabolic action involves the insulin receptor, PI3K, atypical PKC activity and the translocation of GLUT4. Additionally, the nuclear pathways (via MAPK and MEK) provide evidence of the stimulation of the expression of glucose transporters or other signaling proteins, reinforcing proposals that skeletal muscle represents a primary site at which kaempferitrin exerts its effect promoting glucose homeostasis. Also, these similarities with the signaling pathways of insulin constitute strong evidence for the insulin-mimetic role of kaempferitrin in glucose homeostasis. PMID- 23458068 TI - In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. AB - To investigate the enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. Six compounds, namely rhodamine B, sodium-fluorescein, fluorescein isothiocyanate (FITC) dextrans of 4, 10, 20 and 40 kDa were selected as model drugs. Permeation studies were performed using excised cornea of rabbits by a Franz-type diffusion apparatus. The safety of borneol was assessed on the basis of corneal hydration level and Draize eye test. The application of 0.2% borneol to the cornea increased the apparent permeability coefficient by 1.82-(P<0.05), 2.49-(P<0.05), 4.18-(P<0.05) and 1.11-fold (not significant) for rhodamine B, sodium fluorescein, FITC-dextrans of 4 and 10 kDa, respectively. No significant permeability enhancement of FITC dextrans of 10, 20 and 40 kDa with borneol was found compared to control. The permeability coefficient enhanced by 0.2% borneol was linear correlated to the molecular weight of model drugs (R(2)=0.9976). With the 0.05%, 0.1% and 0.2% borneol application, the corneal hydration values were <83% and Draize scores were <4. Borneol may improve the transcorneal penetration of both hydrophilic and lipophilic compounds without causing toxic reactions, especially hydrophilic ones. Furthermore, 0.2% borneol can enhance the permeation of hydrophilic compounds with molecular weight <=4 kDa. Hence, borneol can be considered as a safe and effective penetration enhancer for ocular drug administration. PMID- 23458070 TI - Bortezomib influences the expression of malignant plasma cells membrane antigens. AB - Multiple myeloma cells can be characterized immunophenotypically as the expression levels of several membrane antigens differ from those of normal plasma cells. These antigens are important for making a diagnostic of multiple myeloma; they have a significant role in survival and proliferation of multiple myeloma cells. Analyzing the effect of bortezomib on the expression of surface antigens CD138, CD56, CD27, CD28, CD45 and CD221 and xenograft models, we have found that bortezomib increases the level of CD45 and decreases all other antigens. Bortezomib induces the reduction of IGF-1R (CD221) and syndecan 1 (CD138). This effect was associated with the reduced activation of Ras/MAPK, mTOR/p70S6K and JAK/STAT pathways in response to IGF-1 and IL-6. These results suggest that bortezomib may influence the sensitivity of myeloma cells to soluble growth factors by down-regulation of membrane receptors. PMID- 23458071 TI - Day-case tonsillectomy for children in Glasgow: the impact of changing indications and deprivation. AB - OBJECTIVE: To determine the number of children undergoing tonsillectomy that could have this performed as a day surgery procedure. METHODS: This paper reports a prospective cohort study, which entailed a comparison of children's eligibility for day-case surgery between 2001 and 2011 and an assessment of the Scottish Index of Multiple Deprivation scores. RESULTS: In total, 148 children were enrolled. In 2011, 60 children (42 per cent) were eligible for surgery with same day discharge compared with 27 per cent in 2001. The percentage of children undergoing tonsillectomy for sleep-related breathing disorders or obstructive sleep apnoea hypopnoea syndrome increased from 26 per cent to 55 per cent. CONCLUSION: Eligibility for tonsillectomy with same day discharge has increased. This appears to be related to an increase in the number of children who are able to fulfil the social criteria for same day discharge. The results indicate an association between deprivation and tonsillectomy, particularly surgery carried out for the symptoms of sleep-related breathing disorders or obstructive sleep apnoea hypopnoea syndrome. There has been a significant increase in the percentage of children undergoing tonsillectomy for the indication of sleep related breathing disorders or obstructive sleep apnoea hypopnoea syndrome. PMID- 23458069 TI - Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats. AB - Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor gamma-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID- 23458072 TI - Expanded porous MOF-505 analogue exhibiting large hydrogen storage capacity and selective carbon dioxide adsorption. AB - An expanded 4,4-paddlewheel-connected porous MOF-505-type metal-organic framework (MOF), [Cu2(PDEB)(H2O)2].xS (NJU-Bai12; NJU-Bai represents the Nanjing University Bai group and S represents noncoordinated solvent molecules) has been designed from a nanosized rectangular diisophthalate linker containing alkyne groups 5,5' (1,4-phenylenedi-2,1-ethynediyl)bis(1,3-benzenecarboxylic acid). This MOF material possesses permanent microporosity with the highest Brunauer-Emmett Teller surface area of 3038 m(2).g(-1) and the largest unsaturated total hydrogen storage capacity of 62.7 mg.g(-1) at 77 K and 20 bar among reported MOF-505 analogues. Additionally, NJU-Bai12 also exhibits excellent carbon dioxide (CO2) uptake capacity (23.83 and 19.85 mmol.g(-1) at 20 bar for 273 and 298 K, respectively) and selective gas adsorption properties with CO2/CH4 selectivity of 5.0 and CO2/N2 selectivity of 24.6 at room temperature. PMID- 23458073 TI - In Silico identification of M. TB proteins with diagnostic potential. AB - TB, caused by Mycobacterium tuberculosis (MTB), is one of the major global infectious diseases. For the pandemic control, early diagnosis with sensitive and specific methods is fundamental. With the advent of bioinformatics' tools, the identification of several proteins involved in the pathogenesis of TB (TB) has been possible. In the present work, the MTB genome was explored to look for molecules with possible antigenic properties for their evaluation as part of new generation diagnostic kits based on the release of cytokines. Seven proteins from the MTB proteome and some of their combinations suited the computational test and the results suggested their potential use for the diagnosis of infection in the following population groups: Cuba, Mexico, Malaysia and sub-Saharan Africa. Our predictions were performed using public bioinformatics tools plus three computer programs, developed by our group, to facilitate information retrieval and processing. PMID- 23458074 TI - Recognition and treatment of obstructive sleep apnea. PMID- 23458076 TI - Assessment of the aggregation propensity of the beta -amyloid peptide during the synthesis and when free in solution. AB - This work developed an alternative approach targeting the evaluation of the aggregation propensity of the (1-42) beta-amyloid peptide (Alzheimer's disease) and some segments, either attached to a polymer during their synthesis or when free in solution. The solvation behavior of peptide-resins was gauged by measuring the swelling of beads in a microscope and the degree of chain motion through EPR spectra of previously labeled resins with an amino acid-type probe. In terms of comparative solvent dissociation power towards aggregated structures, the findings revealed greater values of peptide-resin swelling, peptide chain mobility and solubility when in strong electron donor dimethylsulfoxide than in strong electron acceptor trifluoroethanol. Otherwise, the weakest chain-chain disruption power was verified for acetonitrile, an internally neutral solvent in terms of Lewis acid/base properties. In complement, fluorescence and light scattering experiments depicted that the 15-35 region plays an essential role in the amyloid peptide fibril formation capacity. PMID- 23458075 TI - Mechanisms of splenic hypertrophy following hepatic resection. AB - BACKGROUND: Following hepatic resection, liver regeneration has been associated with concurrent splenic hypertrophy. The mechanisms of this phenomenon are unknown, may be multiple and include: splanchnic sequestration caused by a reduction in the hepatic mass; hepatic growth factors that may indirectly act on the spleen, and the redistribution of the total reticuloendothelial system. METHODS: Seventy-five patients (40 males; median age: 60 years) who underwent minor (16%) or major (84%) hepatectomy between September 2004 and October 2009 were included. Prospective measurements of liver and spleen volumes were obtained preoperatively and postoperatively 1 month after hepatectomy using computed tomography (CT). The future remnant liver volume (RLV) was calculated on preoperative CT and the extent of resection was expressed as the RLV divided by total liver volume (TLV). Liver and spleen hypertrophy were expressed according to the absolute gain or relative increase in the initial volumes (%).The presence of fibrosis >F1, associated extrahepatic resection (except minor resections), and previous hepatectomy (major or minor) within 3 months represented exclusion criteria. RESULTS: Mean +/- standard deviation (SD) liver volume at 1 month was higher than RLV (1187 +/- 286 cm(3) versus 764 +/- 421 cm(3) ; P < 0.001). Mean +/- SD splenic volume increased from 252 +/- 100 cm(3) preoperatively to 300 +/- 111 cm(3) at 1 month (P < 0.001). Liver and splenic hypertrophy were significant after major hepatectomies (+100% and +26%, respectively; P < 0.001), but not after minor hepatectomies. Liver hypertrophy was inversely correlated to RLV/TLV (r = -0.687, P < 0.001). Splenic hypertrophy was not correlated to RLV/TLV. Liver and splenic hypertrophy were linearly correlated (r = 0.495, P < 0.001). Neoadjuvant chemotherapy (n = 37), preoperative portal vein embolization (n = 10) and postoperative complications (overall: n = 25; major: n = 10; infectious: n = 6) had no impact on hepatic or splenic hypertrophy. CONCLUSIONS: Splenic hypertrophy occurred after major hepatectomy, but was not correlated to the extent of resection, by contrast with liver hypertrophy. Nevertheless, there was a linear correlation between splenic and liver hypertrophy. This correlation suggests the hypothesis of a splenic action of hepatic growth factors or a redistribution of the total reticuloendothelial system rather than an effect of reduction of the portal bed or hepatic outflow. PMID- 23458077 TI - Differential binding of L- vs. D-isomers of cationic antimicrobial peptides to the biofilm exopolysaccharide alginate. AB - Alginate is a biofilm exopolysaccharide secreted by the opportunistic pathogen Pseudomonas aeruginosa that acts to prevent the diffusion of antibiotics toward the bacterial cell membrane. Cationic antimicrobial peptides (CAPs) have been increasingly recognized as a viable alternative for prospective antimicrobial agents. The D-isomer chiral counterparts of active L-isomer CAPs tend to show slightly greater antimicrobial activities because bacteria lack proteases to hydrolyze the unnatural D-isomers. Using an enantiomeric pair of synthetic CAPs designed in our laboratory (L-4Leu in the sequence KKKKKKALFALWLAFLA-NH2 and its D-analog D-4Leu), we studied the binding and interactions of Lvs. D-isomers of CAPs with alginate using circular dichroism and Raman spectroscopic techniques. We found that the peptide D-4Leu underwent a more rapid structural transition over time from an initial alginate-induced alpha-helical conformation to a less soluble beta-sheet conformation than L-4Leu, indicating that the D-isomer of this peptide has a relatively greater affinity for alginate. Through Raman spectroscopy it was observed that Raman modes at 1297 cm-1 and 1453 cm-1 wavenumbers were found to differ between the spectra obtained from the insoluble complexes formed between L-4Leu vs. D-4Leu and alginate. These modes were tentatively assigned to CH, and CH3 deformation modes, respectively. Our findings reveal previously undetected subtleties in the binding of this diastereomeric pair of peptides in the microenvironment of a biofilm exopolysaccharide, and provide guidelines for future development of antimicrobial peptides. PMID- 23458078 TI - Developing online continuing education content for enhancing caring among Taiwan nurses. AB - BACKGROUND: To promote the quality of nursing care, a hospital in Taiwan committed to implementing its SHARE framework for clinical practice. This study was conducted to develop caring content for the SHARE framework in the form of online continuing education videos. METHODS: Five focus group interviews were conducted with 19 exemplary nurses. A constant comparative method was used to extract caring themes that were integrated into the five components of SHARE: S: Sense patient's needs; H: Help patient out; A: Acknowledge patient's feelings; R: Respect patient's dignity and privacy; E: Explain what is happening. RESULTS: Concrete caring behaviors consistent with SHARE were identified. Real-world scenarios were used to produce five videos demonstrating the components of SHARE for use in online caring education. CONCLUSION: This project offers a new strategy for strengthening caring behavior in nurse-patient interactions and may help to establish a model for caring in nursing continuing education in Taiwan. PMID- 23458079 TI - Transition to nursing practice of accelerated second-degree baccalaureate students using clinical coaches. AB - Among the challenges currently facing nursing is the need for new graduates who are competent to begin providing complex patient care. Innovations in nursing education must lead to outcomes that bridge the gap between nursing education and the beginning competencies that employers need in newly hired graduates. One method for preparing students for patient care is the clinical coach model. This model involves placing a student nurse with an experienced, baccalaureate prepared staff nurse for 12 months of clinical experience. The student works the same schedule as the coach rather than with a series of preceptors on different units. Coaches attend training conducted by school of nursing faculty, using high fidelity simulation with clinical scenarios. Coaches and students are supported through weekly visits by clinical faculty. This model of clinical education is one method that provides innovation for clinical nursing education and a foundation for further research. PMID- 23458080 TI - A survey of nurses' perceived competence and educational needs in performing resuscitation. AB - BACKGROUND: Effective training is needed for high-quality performance of staff nurses, who are often the first responders in initiating resuscitation. There is insufficient evidence to identify specific educational strategies that improve outcomes, including early recognition and rescue of the critical patient. This study was conducted to identify perceived competence and educational needs as well as to examine factors influencing perceived competence in resuscitation among staff nurses to build a resuscitation training curriculum. METHODS: A convenience sample of 502 staff nurses was recruited from 11 hospitals in a single city. Staff nurses were asked to complete a self-administered questionnaire. RESULTS: On a five-point scale, chest compression was the lowest rated technical skill (M = 3.33, SD = 0.80), whereas staying calm and focusing on required tasks was the lowest-rated non-technical skill (M = 3.30, SD = 0.80). Work duration, the usefulness of simulation, recent code experience, and recent simulation-based training were significant factors in perceived competence, F(4, 496) = 45.94, p < .001. Simulation-based resuscitation training was the most preferred training modality, and cardiac arrest was the most preferred training topic. CONCLUSION: Based on this needs assessment, a simulation-based resuscitation training curriculum with cardiac arrest scenarios is suggested to improve the resuscitation skills of staff nurses. PMID- 23458081 TI - Effect of hCG administration during corpus luteum establishment on subsequent corpus luteum development and circulating progesterone concentrations in beef heifers. AB - This study examined the effect of a single administration of human chorionic gonadotrophin (hCG) on Day 1 to 4 after oestrus on corpus luteum (CL) development and circulating progesterone (P4). Oestrus-synchronized heifers (n=43) were administered a single intramuscular injection of saline on Day 1 (control) or 3000IU hCG on Day 1, 2, 3 or 4 after oestrus. Administration of hCG on Day 1 had no effect on CL area, on Day 2 increased CL area from Day 6 to 12 (P<0.05), on Day 3 increased CL area from Day 9 to 11, while on Day 4 increased CL size on Days 9 and 10 (P<0.05). Administration of hCG on Day 4 induced the formation of an accessory CL in 89% of heifers, resulting in a significant increase in total luteal tissue area on the ovaries compared with all other groups. Consistent with the effects on the CL, hCG on Day 1 did not affect P4 concentrations, on Day 2 significantly increased P4 compared with the control from Day 6 to 11 (P<0.05), on Day 3 resulted in a non-significant increase in P4 while hCG on Day 4 increased P4 from Day 8 to 13 compared with the control (P<0.05). In conclusion, administration of hCG as early as Day 2 after oestrus results in increased P4 in circulation from Day 6, which should have beneficial downstream effects in terms of uterine receptivity and conceptus elongation. PMID- 23458082 TI - Development and preliminary validation of the Level of Care Index (LOCI) from the Personality Assessment Inventory (PAI) in a psychiatric sample. AB - Research over the last decade has been promising in terms of the incremental utility of psychometric tools in predicting important clinical outcomes, such as mental health service utilization and inpatient psychiatric hospitalization. The purpose of this study was to develop and validate a new Level of Care Index (LOCI) from the Personality Assessment Inventory (PAI). Logistic regression was initially used in a development sample (n = 253) of psychiatric patients to identify unique PAI indicators associated with inpatient (n = 75) as opposed to outpatient (n = 178) status. Five PAI variables were ultimately retained (Suicidal Ideation, Antisocial Personality-Stimulus Seeking, Paranoia Persecution, Negative Impression Management, and Depression-Affective) and were then aggregated into a single LOCI and independently evaluated in a second validation sample (n = 252). Results indicated the LOCI effectively differentiated inpatients from outpatients after controlling for demographic variables and was significantly associated with both internalizing and externalizing risk factors for psychiatric admission (range of ds = 0.46 for history of arrests to 0.88 for history of suicidal ideation). The LOCI was additionally found to be meaningfully associated with measures of normal personality, performance-based tests of psychological functioning, and measures of neurocognitive (executive) functioning. The clinical implications of these findings and potential utility of the LOCI are discussed. PMID- 23458083 TI - Quality of life assessment in patients treated for metastatic cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: Treatment for metastatic cutaneous head and neck squamous cell carcinoma is usually multimodal and associated with morbidity. This study aimed to evaluate the impact of treatment on patients' quality of life. METHOD: Cross sectional survey of 42 patients (35 men, 7 women) at least 6 months after metastatic cutaneous head and neck squamous cell carcinoma treatment, using two standardised quality of life questionnaires: the Functional Assessment of Cancer Therapy - Head and Neck questionnaire and the Facial Disability Index, with statistical analysis to identify potential predictors of outcome. RESULTS: Female gender correlated with significantly lower Facial Disability Index physical function scores (p = 0.017). Alcohol consumption correlated with significantly better scores for Functional Assessment social well-being (p = 0.016), general total score (p = 0.041) and overall total score (p = 0.033), and for Facial Disability Index physical function (p = 0.034). Marital status, education, employment, chemotherapy, time from last treatment, parotidectomy and facial nerve sacrifice did not affect quality of life. The commonest patient complaints were dry mouth (76 per cent), altered voice quality and strength (55 per cent), and physical appearance (45 per cent). CONCLUSION: Female gender predicts worse quality of life, while alcohol consumption (versus none) predicted for better quality of life. PMID- 23458084 TI - Reconciling intuitive physics and Newtonian mechanics for colliding objects. AB - People have strong intuitions about the influence objects exert upon one another when they collide. Because people's judgments appear to deviate from Newtonian mechanics, psychologists have suggested that people depend on a variety of task specific heuristics. This leaves open the question of how these heuristics could be chosen, and how to integrate them into a unified model that can explain human judgments across a wide range of physical reasoning tasks. We propose an alternative framework, in which people's judgments are based on optimal statistical inference over a Newtonian physical model that incorporates sensory noise and intrinsic uncertainty about the physical properties of the objects being viewed. This noisy Newton framework can be applied to a multitude of judgments, with people's answers determined by the uncertainty they have for physical variables and the constraints of Newtonian mechanics. We investigate a range of effects in mass judgments that have been taken as strong evidence for heuristic use and show that they are well explained by the interplay between Newtonian constraints and sensory uncertainty. We also consider an extended model that handles causality judgments, and obtain good quantitative agreement with human judgments across tasks that involve different judgment types with a single consistent set of parameters. PMID- 23458086 TI - The co-evolution of knowledge and event memory. AB - We present a theoretical framework and a simplified simulation model for the co evolution of knowledge and event memory, both termed SARKAE (Storing and Retrieving Knowledge and Events). Knowledge is formed through the accrual of individual events, a process that operates in tandem with the storage of individual event memories. In 2 studies, new knowledge about Chinese characters is trained over several weeks, different characters receiving differential training, followed by tests of episodic recognition memory, pseudo-lexical decision, and forced-choice perceptual identification. The large effects of training frequency in both studies demonstrated an important role of pure frequency in addition to differential context and differential similarity. The SARKAE theory provides a framework within which models for various tasks can be developed; we illustrate the way this could operate, and we make the verbal descriptions of the theory more precise with a simplified simulation model applied to the results. PMID- 23458085 TI - Rational temporal predictions can underlie apparent failures to delay gratification. AB - An important category of seemingly maladaptive decisions involves failure to postpone gratification. A person pursuing a desirable long-run outcome may abandon it in favor of a short-run alternative that has been available all along. Here we present a theoretical framework in which this seemingly irrational behavior emerges from stable preferences and veridical judgments. Our account recognizes that decision makers generally face uncertainty regarding the time at which future outcomes will materialize. When timing is uncertain, the value of persistence depends crucially on the nature of a decision maker's prior temporal beliefs. Certain forms of temporal beliefs imply that a delay's predicted remaining length increases as a function of time already waited. In this type of situation, the rational, utility-maximizing strategy is to persist for a limited amount of time and then give up. We show empirically that people's explicit predictions of remaining delay lengths indeed increase as a function of elapsed time in several relevant domains, implying that temporal judgments offer a rational basis for limiting persistence. We then develop our framework into a simple working model and show how it accounts for individual differences in a laboratory task (the well-known "marshmallow test"). We conclude that delay-of gratification failure, generally viewed as a manifestation of limited self control capacity, can instead arise as an adaptive response to the perceived statistics of one's environment. PMID- 23458087 TI - Assessment of salt intake: how accurate is it? AB - The aims of this review paper are to provide an overview of the association of sodium intake with cardiovascular health, to identify sodium in our global food supply and to describe problems associated with assessment of dietary sodium intake. Excess sodium intake may contribute to the development of hypertension in some individuals, consequently increasing CVD risk. The average intake of sodium in populations around the world far exceeds the actual body's needs. Processed and restaurant foods contribute the most dietary sodium for Americans and other populations worldwide. There is a worldwide focus on reducing sodium content of food products in an effort to reduce health related issues associated with excessive salt and sodium intake in individuals. In several countries, regulations have been introduced to lower the sodium content of foods. Manufacturers are complying with these regulations by formulating new products to meet these standards. However, the variability in food sodium content poses challenges to researchers to accurately assess dietary sodium intakes of individuals. There are differences in sodium content of foods in databases compared with nutritional information provided by manufacturers for the same food products. Variations also exist in restaurant foods, where values differ from those available on restaurant websites. Sodium may be either underestimated or overestimated; it is not always on target. Awareness of the variability among food products is crucial but capturing sodium content of every food in the market is not feasible. Whenever possible, updating databases is critical. In conclusion, it is not feasible to capture the sodium content of every food in the marketplace but being aware of these differences is essential to assessing actual sodium consumption. Since biological determinations are burdensome and impractical, it is imperative for researchers and other health professionals to participate in the development and implementation of tools to accurately assess sodium intake in individuals. PMID- 23458089 TI - Addressing the social determinants of health through health system strengthening and inter-sectoral convergence: the case of the Indian National Rural Health Mission. AB - BACKGROUND: At the turn of the 21st century, India was plagued by significant rural-urban, inter-state and inter-district inequities in health. For example, in 2004, the infant mortality rate (IMR) was 24 points higher in rural areas compared to urban areas. To address these inequities, to strengthen the rural health system (a major determinant of health in itself) and to facilitate action on other determinants of health, India launched the National Rural Health Mission (NRHM) in April 2005. METHODS: Under the NRHM, Rs. 666 billion (US$12.1 billion) was invested in rural areas from April 2005 to March 2012. There was also a substantially higher allocation for 18 high-focus states and 264 high-focus districts, identified on the basis of poor health and demographic indicators. Other determinants of health, especially nutrition and decentralized action, were addressed through mechanisms like State/District Health Missions, Village Health, Sanitation and Nutrition Committees, and Village Health and Nutrition Days. RESULTS: Consequently, in bigger high-focus states, rural IMR fell by 15.6 points between 2004 and 2011, as compared to 9 points in urban areas. Similarly, the maternal mortality rate in high-focus states declined by 17.9% between 2004-2006 and 2007-2009 compared to 14.6% in other states. CONCLUSION: The article, on the basis of the above approaches employed under NRHM, proposes the NRHM model to 'reduce health inequities and initiate action on SDH'. PMID- 23458088 TI - Supplementary immunization activities (SIAs) in South Africa: comprehensive economic evaluation of an integrated child health delivery platform. AB - BACKGROUND: Supplementary immunization activity (SIA) campaigns provide children with an additional dose of measles vaccine and deliver other interventions, including vitamin A supplements, deworming medications, and oral polio vaccines. OBJECTIVE: To assess the cost-effectiveness of the full SIA delivery platform in South Africa (SA). DESIGN: We used an epidemiologic cost model to estimate the cost-effectiveness of the 2010 SIA campaign. We used province-level campaign data sourced from the District Health Information System, SA, and from planning records of provincial coordinators of the Expanded Programme on Immunization. The data included the number of children immunized with measles and polio vaccines, the number of children given vitamin A supplements and Albendazole tablets, and costs. RESULTS: The campaign cost $37 million and averted a total of 1,150 deaths (95% uncertainty range: 990-1,360). This ranged from 380 deaths averted in KwaZulu-Natal to 20 deaths averted in the Northern Cape. Vitamin A supplementation alone averted 820 deaths (95% UR: 670-1,040); measles vaccination alone averted 330 deaths (95% UR: 280-370). Incremental cost-effectiveness was $27,100 (95% UR: $18,500-34,400) per death averted nationally, ranging from $11,300 per death averted in the Free State to $91,300 per death averted in the Eastern Cape. CONCLUSIONS: Cost-effectiveness of the SIA child health delivery platform varies substantially across SA provinces, and it is substantially more cost-effective when vitamin A supplementation is included in the interventions administered. Cost-effectiveness assessments should consider health system delivery platforms that integrate multiple interventions, and they should be conducted at the sub-national level. PMID- 23458090 TI - Revisiting Geschwind's hypothesis on brain lateralisation: a functional MRI study of digit ratio (2D:4D) and sex interaction effects on spatial working memory. AB - The Geschwind-Behan-Galaburda (GBG) hypothesis links cerebral lateralisation with prenatal testosterone exposure. Digit ratio measures in adults have been established as potential markers of foetal sex hormonal milieu. The aim of the study was to evaluate the sex-dependent interaction of digit ratio measures and cerebral lateralization as well as their neurohemodynamic correlates using functional MRI (fMRI). Digit ratio measures-ratio of index finger (2D) length to ring finger (4D) length (2D:4D) and difference between 2D:4D of two hands, i.e., right minus left (DR-L)-were calculated using high resolution digital images in 70 right-handed participants (42 men) based on reliable and valid method. fMRI was acquired during the performance of a spatial working memory task in a subset of 25 individuals (14 men), and analysed using Statistical Parametric Mapping 8 (SPM8) and the Laterality Index toolbox for SPM8. Men had significantly less bilateral 2D:4D than women. There was a significant negative correlation between right 2D:4D and 2-Back task accuracy (2BACC) in women. A significant sex-by-right 2D:4D interaction was observed in left parahippocampal gyrus activation. Additionally, sex-by-DR-L interaction was observed in left IPL activation. DR-L showed a significant positive correlation with the whole brain Laterality Index (LI), and LI, in turn, demonstrated a significant negative correlation with 2BACC. Our study observations suggest several novel sex-differential relationships between 2D:4D measures and fMRI activation during spatial working memory task performance. Given the pre-existing background data supporting digit ratio measures as putative indicator of prenatal sex hormonal milieu, our study findings add support to the Geschwind-Behan-Galaburda (GBG) hypothesis. PMID- 23458091 TI - Assessment of left ventricular dyssynchrony in dipper and non-dipper hypertension. AB - BACKGROUND: Ventricular dyssynchrony is an co-determinant of progression and exacerbation of heart failure (HF). The co-existence of ventricular dyssynchrony with hypertension (HT) and HF were shown, however there is no data regarding the effect of circadian rhythm of blood pressure (BP) on ventricular synchrony. Therefore, we aimed to study the left ventricular synchrony in dipper and non dipper normotensive and hypertensive participants. METHODS: Participants (n = 142) were categorized into four groups as "Normotensive-Dipper" (NT-D) (n = 40), "Normotensive-Non-dipper" (NT-ND) (n = 30), "Hypertensive-Dipper" (HT-D) (n = 38) and "Hypertensive-Non-dipper" (HT-ND) (n = 34). Left ventricular dyssynchrony was investigated by color-coded tissue Doppler imaging. RESULTS: Non-dippers had higher 24-h and night-time BP both in normotensives and hypertensives. The incidence of ventricular dyssynchrony (a Ts-SD-12 > 34.4 ms) was higher in the hypertensive group (47.2% vs 24.3%, p = 0.005). The frequency of ventricular dyssynchrony was higher in the HT-ND group than the HT-D group (58.8% vs 36.8%, p = 0.05); however, the frequency of ventricular dyssynchrony was similar among the normotensives (26.7% vs 22.5%, p = 0.45). Ts-SD-12 and Ts-12 were higher in NT-ND group than the NT-D group. CONCLUSIONS: Non-dipping BP pattern was associated with impaired left ventricular contraction synchrony in both normotensive and hypertensive participants, which may be related with short- and long-term effects of HT on myocardium. PMID- 23458092 TI - The COUP-TFII variant lacking a DNA-binding domain inhibits the activation of the Cyp7a1 promoter through physical interaction with COUP-TFII. AB - The COUP-TFII (chicken ovalbumin upstream promoter-transcription factor II) nuclear receptor, which is composed of a DNA-binding domain and a ligand-binding domain, exerts pleiotropic effects on development and cell differentiation by regulating the transcription of its target genes, including Cyp7a1 (cytochrome P450, family 7, subfamily a, polypeptide 1), which plays important roles in catabolism of cholesterol in the liver. Although multiple variants of COUP-TFII exist, their roles in the regulation of Cyp7a1 expression have not been elucidated. In the present study, we investigated the roles of COUP-TFII-V2 (variant 2), which lacks a DNA-binding domain, in the regulation of the transcriptional control of the Cyp7a1 gene by COUP-TFII in hepatocellular carcinoma cells. We found that COUP-TFII-V2 was significantly expressed in Huh7 cells, in which Cyp7a1 was not expressed. Furthermore, knockdown of COUP-TFII-V2 enhanced endogenous Cyp7a1 expression in Huh7 cells. Although COUP-TFII activates the Cyp7a1 promoter through direct binding to DNA, this activation was affected by COUP-TFII-V2, which physically interacted with COUP-TFII and inhibited its DNA binding ability. Chromatin immunoprecipitation assays showed that COUP-TFII-V2 inhibited the binding of endogenous COUP-TFII to the intact Cyp7a1 promoter. The results of the present study suggest that COUP-TFII-V2 negatively regulates the function of COUP-TFII by inhibiting its binding to DNA to decrease Cyp7a1 expression. PMID- 23458093 TI - Blastocyst rate of in vitro embryo production in sheep is affected by season. AB - It has been reported that the number and quality of in vitro produced embryos is season related. This study was conducted to assess the effect of season on cleavage, blastocyst and lambing rates of in vitro produced ovine embryos during 3 years of collection data. Ovaries of Sarda sheep were collected from a slaughterhouse. In total, 5035 oocytes were recovered and matured in TCM-199 with 4 mg/ml bovine serum albumin (BSA), 100 MUM cysteamine, 0.3 mM Na pyruvate, 0.1 UI/ml recombinant follicle-stimulating hormone (r-FSH), 0.1 UI/ml recombinant luteinising hormone (r-LH), and 1 MUg/ml estradiol-17beta. Matured oocytes were fertilized with fresh semen in synthetic oviductal fluid (SOF) with 20% heat inactivated estrous sheep serum. The presumptive zygotes were cultured for 6-7 days (blastocyst stage) in SOF medium supplemented with 1% Basel Medium Eagle (BME), 1% Minimum Essential Medium, 1 mM glutamine and 8 mg/ml fatty acid-free BSA. The embryos produced were vitrified and a total of 165 blastocysts (80 from the breeding season and 85 from the anoestrous season) were transferred in pairs into recipient ewes during the reproductive period. There were no significant differences in cleavage rates between seasons in any of the 3 years examined (84% versus 83%, 81% versus 80% and 80% versus 79%, respectively). The blastocyst rate varied significantly between seasons in 2005 and 2007 (P < 0.05), and in 2006 (P < 0.001). There were no differences in pregnancy and lambing rates between embryos during anoestrous versus during the breeding season. In conclusion, only the blastocyst rate appeared to have been affected by season, possibly due to variation in the number of developmentally competent oocytes. PMID- 23458094 TI - Congruency effects in interpersonal coordination. AB - Research on interpersonal coordination has demonstrated that incongruent tasks lead to unintended movements in the orthogonal plane. These effects have been interpreted using both an embodied simulation and coordination dynamics approach. To distinguish between these two perspectives, two experiments examined whether this congruency effect is best defined spatially or anatomically. In the first experiment, participants coordinated congruent and incongruent rhythmic arm movements with an actor. To dissociate spatial and anatomical congruency, the actor was rotated 90 degrees in the coronal plane for half of the trials. In the second experiment, participants coordinated movements of different limbs (leg and arm). Spatial and anatomical congruency was dissociated here by rotating the actor in the transverse plane. In both experiments, the unintended movements associated with the congruency effect emerged as a function of spatial congruency; there was no congruency effect associated with anatomical congruency. The data suggests that these unintended movements represent the recruitment of additional df necessary to stabilize an unstable form of coordination. PMID- 23458095 TI - Automatic feature-based grouping during multiple object tracking. AB - Contour interpolation automatically binds targets with distractors to impair multiple object tracking (Keane, Mettler, Tsoi, & Kellman, 2011). Is interpolation special in this regard or can other features produce the same effect? To address this question, we examined the influence of eight features on tracking: color, contrast polarity, orientation, size, shape, depth, interpolation, and a combination (shape, color, size). In each case, subjects tracked 4 of 8 objects that began as undifferentiated shapes, changed features as motion began (to enable grouping), and returned to their undifferentiated states before halting. We found that intertarget grouping improved performance for all feature types except orientation and interpolation (Experiment 1 and Experiment 2). Most importantly, target-distractor grouping impaired performance for color, size, shape, combination, and interpolation. The impairments were, at times, large (>15% decrement in accuracy) and occurred relative to a homogeneous condition in which all objects had the same features at each moment of a trial (Experiment 2), and relative to a "diversity" condition in which targets and distractors had different features at each moment (Experiment 3). We conclude that feature-based grouping occurs for a variety of features besides interpolation, even when irrelevant to task instructions and contrary to the task demands, suggesting that interpolation is not unique in promoting automatic grouping in tracking tasks. Our results also imply that various kinds of features are encoded automatically and in parallel during tracking. PMID- 23458096 TI - Analgesic medication errors in North Carolina nursing homes. AB - The objective of this study was to characterize analgesic medication errors and to evaluate their association with patient harm. The authors conducted a cross sectional analysis of individual medication error incidents reported by North Carolina nursing homes to the Medication Error Quality Initiative (MEQI) during fiscal years 2010-2011. Bivariate associations between analgesic medication errors with patient factors, error-related factors, and impact on patients were tested with chi-square tests. A multivariate logistic regression model explored the relationship between type of analgesic medication errors and patient harm, controlling for patient- and error-related factors. A total of 32,176 individual medication error incidents were reported over a 2-year period in North Carolina nursing homes, 12.3% (n = 3949) of which were analgesic medication errors. Of these analgesic medication errors, opioid and nonopioid analgesics were involved in 3105 and 844 errors, respectively. Opioid errors were more likely to be wrong drug errors, wrong dose errors, and administration errors compared with nonopioid errors (P < .0001 for all comparisons). In the multivariate model, opioid errors were found to have higher odds of patient harm compared with nonopioid errors (odds ratio [OR] = 3, 95% confodence interval [CI]: 1.1-7.8). The authors conclude that opioid analgesics represent the majority of analgesic error reports, and these error reports reflect an increased likelihood of patient harm compared with nonopioid analgesics. PMID- 23458097 TI - Specific and differential prediction of health anxiety by disgust sensitivity and propensity. AB - Current models of health anxiety suggest that fear resulting from false alarms to perceived threats to one's health results in the development of hypochondriasis and related disorders. Disgust has been proposed as an affective response that may function as an etiological and maintenance mechanism in health anxiety. Moreover, the way in which an individual perceives the disgust response (disgust sensitivity) may affect health anxiety, separately from their likelihood of experiencing disgust (disgust propensity). The present study utilized multiple hierarchical regression analysis to investigate the degree to which self-reported disgust sensitivity and disgust propensity differentially predict elevated health anxiety in a sample of 620 non-treatment-seeking undergraduates. Further, this effect is tested in comparison to that of anxiety sensitivity, a construct demonstrated to be strongly related to health anxiety. Analyses indicate that disgust sensitivity, rather than disgust propensity, is primarily responsible for this relation. An additional analysis tested the specificity of disgust sensitivity relative to anxiety sensitivity. Disgust sensitivity was no longer significant after including anxiety sensitivity in the model. Suggestions for further evaluation of this relation are provided. These results suggest that although disgust sensitivity may appear related to health anxiety, this relation may be confounded by anxiety sensitivity. PMID- 23458099 TI - An eye-tracking study of exploitations of spatial constraints in diagrammatic reasoning. AB - Semantic studies on diagrammatic notations (Barwise & Etchemendy, 1990; Shimojima, 1995; Stenning & Lemon, 2001) have revealed that the "non-deductive," "emergent," or "perceptual" effects of diagrams (Chandrasekaran, Kurup, Banerjee, Josephson, & Winkler, 2004; Kulpa, 2003; Larkin & Simon, 1987; Lindsay, 1988) are all rooted in the exploitation of spatial constraints on graphical structures. Thus, theoretically, this process is a key factor in inference with diagrams, explaining the frequently observed reduction of inferential load. The purpose of this study was to examine the empirical basis for this theoretical suggestion, focusing on the reality of the constraint-exploitation strategy in actual practices of diagrammatic reasoning. Eye movements were recorded while participants used simple position diagrams to solve three- or four-term transitive inference problems. Our experiments revealed that the participants could exploit spatial constraints on graphical structures even when (a) they were not in the position of actually manipulating diagrams, (b) the semantic rule for the provided diagrams did not match their preferences, and (c) the constraint exploitation strategy invited a partly adverse effect. These findings indicate that the hypothesized process is in fact robust, with the potential to broadly account for the inferential advantage of diagrams. PMID- 23458098 TI - Broadening access to medical care during a severe influenza pandemic: the CDC nurse triage line project. AB - The impact of a severe influenza pandemic could be overwhelming to hospital emergency departments, clinics, and medical offices if large numbers of ill people were to simultaneously seek care. While current planning guidance to reduce surge on hospitals and other medical facilities during a pandemic largely focuses on improving the "supply" of medical care services, attention on reducing "demand" for such services is needed by better matching patient needs with alternative types and sites of care. Based on lessons learned during the 2009 H1N1 pandemic, the Centers for Disease Control and Prevention and its partners are currently exploring the acceptability and feasibility of using a coordinated network of nurse triage telephone lines during a pandemic to assess the health status of callers, help callers determine the most appropriate site for care (eg, hospital ED, outpatient center, home), disseminate information, provide clinical advice, and provide access to antiviral medications for ill people, if appropriate. As part of this effort, the integration and coordination of poison control centers, existing nurse advice lines, 2-1-1 information lines, and other hotlines are being investigated. PMID- 23458100 TI - An unusual case of multiple-gunshot suicide of an alcohol-intoxicated cancer sufferer with prolonged physical activity. AB - Multishot firearm suicides are relatively rare and suggest the possibility of homicide. Physical activity following gunshots to the head, the neck, and the thorax does occur, and immediate incapacitation does not occur in every fatal gunshot wound that penetrates the head or perforates the heart. Cancer patients appear to be at increased suicide risk, but alcohol intoxication is less common in such cases. We present-to the best of our knowledge for the first time-a case of a 54-year old, male, liver cancer sufferer, who under the influence of alcohol, discharged his revolver three times, suffered, among other wounds, a heart-perforating wound, and died after c. 1.5 h, being able to talk until just before he died. Our case underlines the importance of keeping an open critical mind when dealing with multiple-gunshot fatalities, especially when posttraumatic physical activity might be crucial in differentiating homicide from suicide. PMID- 23458101 TI - ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins. AB - ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation. PMID- 23458102 TI - Effect of concurrent use of anti-retroviral therapy and levonorgestrel sub-dermal implant for contraception on CD4 counts: a prospective cohort study in Kenya. AB - INTRODUCTION: Simultaneous use of contraceptive hormones and anti-retroviral therapy (ART) may theoretically lessen the effectiveness of both. Women on ART need assurance that hormonal contraception is safe and effective. The sub-dermal implant is an ideal product to study: low and steady progestin release and no adherence uncertainties. We sought to determine if the medications' effectiveness is compromised. METHODS: We conducted a prospective cohort study among women on first line ART (stavudine or zidovudine and lamivudine+nevirapine). We recruited new implant users and matched them to women not using hormonal contraception, based on age and baseline CD4. Participants were followed prospectively for up to two years, recording serial CD4 measures and medical histories. We used generalized growth curve models and Wald chi-square tests to compare changes in CD4 counts across study groups. Prospective CD4 measures were censored (excluded) if any of the following events occurred: change in ART, implant removal or use of any hormonal contraception among controls. We examined incidence of opportunistic infection and pregnancy. RESULTS: We matched 48 implant users to 33 non-hormonal controls. Over time, CD4 counts for both groups rose slightly but did not deviate significantly from each other (p=0.44). Opportunistic infection rates did not differ between the groups. None of the implant users and one of the non-hormonal controls became pregnant during follow-up. CONCLUSIONS: This small study found concurrent use of contraceptive implants and ART to be safe and effective. Although other hormonal contraceptive products and ART regimens may interact in unknown ways, the results of this study are reassuring. PMID- 23458103 TI - Evolution of stickleback feeding behaviour: genetics of population divergence at different ontogenetic stages. AB - The evolutionary significance of individual consistency in a given behaviour - called animal personality - has been subject to a lot of recent research. However, the genetic underpinnings of population divergence in mean personality have rarely been studied, especially across different ontogenetic stages. Previous work has shown that marine vs. pond populations of nine-spined sticklebacks (Pungitius pungitius) have undergone adaptive divergence in a series of fitness-related traits, including behaviour. One particular behavioural trait important in this system is feeding activity: giant pond sticklebacks are more active feeders than their normal sized marine conspecifics. In a common garden experiment, we raised individuals from pure and hybrid F1 -generation crosses of a highly divergent marine - pond population pair to see if (i) feeding activity and/or its ontogenetic change was consistent between individuals, and if (ii) population divergence at different ontogenetic stages could be explained by additive genetic, nonadditive genetic or maternal effects. We found that feeding activity decreased with age, but that these changes were consistently different among both individuals and crosses. The among cross patterns were consistent with a nonadditive genetic scenario: in the early period pond sticklebacks expressed dominance for high feeding activity, while in the late period marine sticklebacks expressed dominance for low feeding activity. We conclude that nine-spined sticklebacks exhibit different feeding personalities, and that the population divergence in feeding personality is explainable by age-dependent expression of genetic dominance. PMID- 23458104 TI - Pegylated versus standard interferon plus ribavirin in chronic hepatitis C genotype 4: A systematic review and meta-analysis. AB - AIM: Treatment of hepatitis C genotype 4 (HCV-G4) with pegylated interferon (PEG IFN) has not been adequately studied and is considered to be challenging. The aim of this meta-analysis is to systematically review and evaluate the effectiveness of 48 weeks of combined PEG IFN plus ribavirin (RBV) compared to standard interferon (IFN) plus RBV. The outcome of interest is sustained virological response (SVR). METHODS: We searched for eligible randomized controlled trials (RCT) through May 2012. Random effects meta-analysis was used to pool the risk ratio (RR) of achieving SVR across trials. RESULTS: Five RCT enrolling 386 patients were included. The PEG IFN/RBV group had increased likelihood of achieving SVR (RR = 1.51, 95% confidence interval [CI] = 1.08-2.10). SVR was significantly higher in PEG IFN-alpha-2a compared to the -alpha-2b group (P = 0.02). There was no statistically significant effect of ribavirin dosage on SVR (P = 0.55). The quality of evidence was moderate overall and limited by heterogeneity. CONCLUSION: In treatment-naive patients with HCV-G4, treatment with PEG IFN plus RBV achieves higher SVR rate than treatment with IFN plus RBV. PMID- 23458105 TI - Combined use of intraoperative ultrasound and indocyanine green fluorescence imaging to detect liver metastases from colorectal cancer. AB - OBJECTIVES: Surgical excision is the standard strategy for managing liver metastases from colorectal carcinoma. The achievement of negative (R0) margins is a major determinant of disease-free survival in these patients. Current imaging techniques are of limited value in achieving this goal. A new approach to the intraoperative detection of colorectal liver metastatic tissue based on the emission of indocyanine green (ICG) fluorescence was evaluated. METHODS: A total of 25 consecutive patients with liver metastases from primary colorectal cancers who were eligible for liver resection received a bolus of ICG (0.5 mg/kg body weight) 24 h before surgery. During surgery, ICG fluorescence, which accumulates around lesions as a result of defective biliary clearance, was detected with a near-infrared camera system, the Photodynamic Eye (PDE). Numbers of lesions detected by, respectively, PDE + ICG, intraoperative ultrasound (IOUS) and preoperative computed tomography (CT) were recorded. RESULTS: The near-infrared camera plus ICG revealed a total of 77 metastatic liver nodules. Preoperative CT demonstrated 45 (58.4%) and IOUS showed 55 (71.4%). Preoperative CT and IOUS alone were inferior to the combined use of PDE + ICG and IOUS in the detection of lesions of <= 3 mm in size. CONCLUSIONS: This experience suggests that PDE + ICG, combined with IOUS, may represent a safe and effective tool for ensuring the complete surgical eradication of liver metastases from colorectal cancer. PMID- 23458106 TI - Sexual dysfunction and quality of life in patients on maintenance dialysis. PMID- 23458107 TI - Advanced rural skills training: are recently qualified GPs using their procedural skills? AB - INTRODUCTION: The number of GPs providing procedural services in rural areas is declining; however, few studies have investigated issues directly relevant to recently qualified doctors. Limited published data and anecdotal reports in Australia suggest that a large proportion of doctors leave rural procedural practice soon after training. This study aimed to: (1) describe where GPs practice in the 5 years after advanced rural skills training; (2) describe the proportion of doctors using their advanced skills; (3) measure doctors' ratings of the quality of support and how critical the year directly following training is in future career choices; and (4) measure the association between support and use of advanced skills. METHODS: A cross-sectional, postal survey was undertaken of doctors who had completed advanced rural skills training in Queensland between 1995 and June 2009. Data were collected on a three-page, structured questionnaire. General practice colleges, the three Queensland regional training providers and one national training provider were approached in order to identify and mail questionnaires to eligible doctors. Descriptive statistics were prepared for practice history information, and attitudinal ratings. A chi(2) test was used to analyse the association between support and use of skills. RESULTS: Sixty-one completed questionnaires were returned resulting in an unadjusted response rate of 51.7%. Respondents had completed a range of training posts: obstetrics and gynaecology (37.7%), anaesthetics (18%), anaesthetics and obstetrics and gynaecology (11.5%) and Aboriginal and Torres Strait Islander health (11.5%). Thirty-nine respondents (63.9%) were using skills related to their advanced training at the time of the study. In the first 5 years after training, the percentage of doctors using their advanced rural skills decreased from 75.4% to 61.1%. The year directly following advanced training was rated as 'critical' or 'very critical' in their future career choices by 68.9% of respondents. However, ratings of the quality of support received in that year were varied, with 21.4% reporting 'very poor' support. There was a statistically significant association between ratings of support in the year directly following training and the use of skills 3 years after training (chi(2) = 8.715, df = 2, p = 0.013). CONCLUSIONS: This study has shown that while the majority of doctors are using skills related to their advanced rural skills training, there is room for improvement through training and career planning support, extending formal support mechanisms into the first year after training, improving opportunities to use advanced skills and improving systems to re-engage doctors into procedural practice. PMID- 23458108 TI - The use of biological grafts for reconstruction of the inferior vena cava is a safe and valid alternative: results in 32 patients in a single institution. AB - BACKGROUND: Resection and reconstruction of the inferior vena cava (IVC) is occasionally required in the surgical treatment of intra-abdominal tumours. IVC reconstruction can be performed with biological or synthetic graft material, with most centres preferring synthetic grafts. In spite of the potential advantages of biological grafts in terms of handling characteristics, and safety, very limited data are available about their use in patients requiring an IVC resection. METHODS: Medical records of 32 patients who underwent an IVC resection and reconstruction from 1990 and 2011 with autogenous peritoneo-fascial (N = 22) and bovine pericardial (N = 10) grafts were reviewed. RESULTS: A tangential resection with patch repair was performed in 10 patients, whereas in the remaining 22 it was necessary to resect and replace a segment or all of the retrohepatic IVC. A concomitant liver resection was performed in 14 patients, nephrectomy in 10 and pancreaticoduodenectomy in 2 patients. There were no acute or late complications related to graft thrombosis or infection. Three patients died as a consequence of multi-organ failure. Overall survival at 1 and 5 years was 78% and 48%, respectively. CONCLUSIONS: The preferential use of synthetic grafts in IVC replacement is not evidence based. Selection of an appropriate prosthetic graft for IVC reconstruction should be based on the safety and its handling features. The use of biological grafts for IVC repair is a valid alternative to current synthetic materials and may in fact be superior in terms of biocompatability, ease of handling, reduced rate of infection and improved long-term patency without permanent anticoagulation. PMID- 23458110 TI - Column chromatography-free solution-phase synthesis of a natural piper-amide-like compound library. AB - We have achieved an efficient solution-phase parallel synthesis of a library of natural piper-amide-like compounds from the bifunctional beta-phosphono-N-hydroxy succinimidyl ester intermediate. The primary important feature in our study is the construction of natural-product-like molecules through the adaptation of sophisticated organic reactions that create water-soluble byproducts for a chromatography-free purification. This simple and efficient method rapidly provides a combinatorial library of high yield and purity. The library was evaluated against GPCR targets to demonstrate its potential use as a tool for drug discovery and in chemical biology. PMID- 23458109 TI - The effect of hepatic steatosis on survival following resection of colorectal liver metastases in patients without preoperative chemotherapy. AB - BACKGROUND: Hepatic steatosis, a common condition associated with insulin resistance and excess body weight, is reported to be associated with an increased risk for perioperative mortality in patients undergoing resection of colorectal liver metastases (CLM), but its impact upon longterm survival is less well documented. METHODS: The effects of background liver pathology, categorized as 'normal', 'with steatosis' and 'other', on perioperative mortality, overall survival (OS) and cancer-specific survival (CSS) were assessed in patients undergoing resection for CLM according to data maintained in the LiverMetSurvey database. As preoperative chemotherapy may confound the effects of steatosis, patients who had been given preoperative chemotherapy were excluded. Survival analyses included log-rank tests for comparisons, and multivariate Cox models, including well-established prognosticators. RESULTS: Of 5853 patients who underwent first-time liver resection without preoperative chemotherapy, 1793 (30.6%) had background steatosis. Rates of 90-day perioperative mortality in patients with normal, steatosis and other pathologies were 2.8%, 2.1% and 4.9%, respectively. Steatosis was associated with improved 5-year OS (47.4% versus 43.0%; log rank, P = 0.0017) and CSS (56.1% versus 50.3%; P = 0.002) compared with normal background liver. After adjustments, the survival advantage associated with steatosis remained (hazard ratio = 0.806, 95% confidence interval 0.717-0.905 for CSS). DISCUSSION: The paradoxical survival advantage observed in patients with steatosis undergoing liver resection for CLM generates a hypothesis that peri-diagnosis of excess body adiposity has a survival protective effect that warrants further research. PMID- 23458111 TI - Commentary specifically on the article by S. Harling et al. PMID- 23458112 TI - Schema change without schema therapy: the role of early maladaptive schemata for a successful treatment of major depression. AB - Early maladaptive schemata (EMS) have repeatedly been shown to be associated with several psychopathological conditions, including depression. Schema therapy proposes interventions that aim at altering EMS. In the present study, we examined the effect of an integrative psychodynamic inpatient therapy without explicit focus on EMS in a sample with major depression. Forty-seven (38 female, 9 male) patients filled out the Symptom Checklist (SCL-90-R) and the Young Schema Questionnaire (YSQ) at the beginning and end of the treatment. Results revealed that EMS were significantly reduced in three out of five schema domains. Strong endorsement of EMS at the beginning of treatment tended to predict symptom reduction. More importantly, the reduction of symptom distress during treatment was strongly associated with a reduction in EMS of the schema domain Impaired Autonomy/Performance. We discuss that changes in EMS are highly relevant for changes in symptom distress but that EMS can not only be changed by schema therapy but also by other approaches, like psychodynamic therapy. PMID- 23458113 TI - Iraq and Afghanistan veterans: national findings from VA residential treatment programs. AB - A quality improvement effort was undertaken in Department of Veterans Affairs' (VA) residential treatment programs for Posttraumatic Stress Disorder (PTSD) across the United States. Qualitative interviews were conducted with over 250 directors, providers, and staff during site visits of 38 programs. The aims of this report are to describe clinical issues and distinctive challenges in working with veterans from Iraq and Afghanistan and approaches to addressing their needs. Providers indicated that the most commonly reported problems were: acute PTSD symptomatology; other complex mental health symptom presentations; broad readjustment problems; and difficulty with time demands of and readiness for intensive treatment. Additional concerns included working with active duty personnel and mixing different eras in therapy. Programmatic solutions address structure (e.g., blended versus era-specific therapy), content (e.g., physical activity), and adaptations (e.g., inclusion of family; shortened length of stay). Clinical implications for VA managers and policy makers as well as non-VA health care systems and individual health care providers are noted. PMID- 23458114 TI - Defense mechanisms in schizotypal, borderline, antisocial, and narcissistic personality disorders. AB - Numerous authors have theorized that defense mechanisms play a role in personality disorders. We reviewed theoretical writings and empirical studies about defenses in schizotypal, borderline, antisocial, and narcissistic personality disorders, developing hypotheses about these differential relationships. We then examined these hypotheses using dynamic interview data rated for defenses in a study of participants (n = 107) diagnosed with these four personality disorder types. Overall, the prevalence of immature defenses was substantial, and all four disorders fit within the broad borderline personality organization construct. Defenses predicted the most variance in borderline and the least variance in schizotypal personality disorder, suggesting that dynamic factors played the largest role in borderline and the least in schizotypal personality. Central to borderline personality were strong associations with major image-distorting defenses, primarily splitting of self and other's images, and the hysterical level defenses, dissociation and repression. Narcissistic and antisocial personality disorders shared minor image-distorting defenses, such as omnipotence or devaluation, while narcissistic also used splitting of self-images and antisocial used disavowal defenses like denial. Overall, differential relationships between specific defenses and personality disorder types were largely consistent with the literature, and consistent with the importance that the treatment literature ascribes to working with defenses. PMID- 23458115 TI - Entrapment and defeat perceptions in depressive symptomatology: through an evolutionary approach. AB - The social rank and arrested defenses model for mood disorders bridges between animal and human models of psychopathology. There is increasing evidence that depression is associated with subordinated and loss of social rank, feeling inferior, shame, submissive behavior, and feeling defeated. These stressful states activate threat coping responses of fight and flight. If these are aroused but blocked, feelings of entrapment emerge with a negative impact on mood. The current study builds on previous studies and explores the association between depressive symptoms, social rank variables (of social comparison and submissive behavior), entrapment, and defeat in a sample of patients (n = 106) with major depression and in a sample of healthy controls (n = 116). Results showed that social rank variables, entrapment, and defeat were strongly associated with depressive symptoms in both samples. Entrapment and defeat showed significant association with other social rank variables. Logistic regression analysis revealed that defeat and internal entrapment were significant predictors of the belonging to the clinical or control groups. The present study extends previous research and supports the importance of defeat and external entrapment in clinical depression. PMID- 23458116 TI - An attachment model of depression: integrating findings from the mood disorder laboratory. AB - This paper is written from a psychodynamic clinician's perspective, juxtaposing a psychoanalytic-attachment model of depression with recent developments in neuroscience. Three main components of the attachment approach are described: the role of loss, of childhood trauma predisposing to depression in later life, and failure of co-regulation of role of primitive emotions, such as fear, despair, and helplessness. Blatt's distinction between anaclitic and introjective depression is delineated and related to hyper- and de-activation of the attachment dynamic. Recent advances in evolutionary, sociological, epigenetic, biochemical, and neuro-imaging studies of depression are reviewed. A dynamic model of depression is proposed, linking interpersonal and intra-psychic perspectives with neuro-anatomical models. The final section of the paper considers the specific role of psychodynamic approaches to the treatment of refractory depression. These include length of treatment, capacity to rework implicit memories, and focus on transference and counter-transference. PMID- 23458119 TI - Correction. PMID- 23458121 TI - Plasmonic smart dust for probing local chemical reactions. AB - Locally probing chemical reactions or catalytic processes on surfaces under realistic reaction conditions has remained one of the main challenges in materials science and heterogeneous catalysis. Where conventional surface interrogation techniques usually require high-vacuum conditions or ensemble average measurements, plasmonic nanoparticles excel in extreme light focusing and can produce highly confined electromagnetic fields in subwavelength volumes without the need for complex near-field microscopes. Here, we demonstrate an all optical probing technique based on plasmonic smart dust for monitoring local chemical reactions in real time. The silica shell-isolated gold nanoparticles that form the smart dust can work as strong light concentrators and optically report subtle environmental changes at their pinning sites on the probed surface during reaction processes. As a model system, we investigate the hydrogen dissociation and subsequent uptake trajectory in palladium with both "dust-on film" and "film-on-dust" platforms. Using time-resolved single particle measurements, we demonstrate that our technique can in situ encode chemical reaction information as optical signals for a variety of surface morphologies. The presented technique offers a unique scheme for real-time, label-free, and high-resolution probing of local reaction kinetics in a plethora of important chemical reactions on surfaces, paving the way toward the development of inexpensive and high-output reaction sensors for real-world applications. PMID- 23458120 TI - The hidden harm of home-based care: pulmonary tuberculosis symptoms among children providing home medical care to HIV/AIDS-affected adults in South Africa. AB - Millions of children in sub-Saharan Africa undertake personal and medical care for family members who are unwell with AIDS. To date, no research has investigated whether such care provision places children at heightened risk for pulmonary tuberculosis. This study aimed to address this gap by identifying risk factors for paediatric pulmonary tuberculosis symptomatology. In 2009-2011, 6002 children aged 10-17 years were surveyed using door-to-door household sampling of census enumeration areas. These were randomly sampled from six urban and rural sites with over 30% HIV prevalence, within South Africa's three highest tuberculosis-burden provinces. Validated scales and clinical tuberculosis symptom checklists were modelled in multivariate logistic regressions, controlling for socio-demographic co-factors. Findings showed that, among children, severe pulmonary tuberculosis symptomatology was predicted by primary caregiver HIV/AIDS illness [odds ratio (OR): 1.63, confidence interval (CI): 1.23-2.15, p<0.001], and AIDS-orphanhood (OR: 1.44, CI: 1.04-2.00, p<0.029). Three-fold increases in severe tuberculosis symptoms were predicted by the child's exposure to body fluids through providing personal or medical care to an ill adult (OR: 3.12, CI: 1.96-4.95, p<0.001). Symptoms were also predicted by socio-economic factors of food insecurity (OR: 1.52, CI: 1.15-2.02, p<0.003) and household overcrowding (OR: 1.35, CI: 1.06-1.72, p<0.017). Percentage probability of severe tuberculosis symptoms rose from 1.4% amongst least-exposed children, to 18.1% amongst those exposed to all above-stated risk factors, independent of biological relationship of primary caregiver-child and other socio-demographics. Amongst symptomatic children, 75% had never been tested for tuberculosis. These findings identify the risk of tuberculosis among children providing home medical care to their unwell caregivers, and suggest that there are gaps in the health system to screen and detect these cases of paediatric tuberculosis. There is a need for effective interventions to reduce childhood risk, as well as further support for community based contact-tracing, tuberculosis screening and anti-tuberculosis treatment for children caring for ill adults in contexts with a high burden of HIV and tuberculosis. PMID- 23458122 TI - Ultrasound-assisted synthesis of 2,4-thiazolidinedione and rhodanine derivatives catalyzed by task-specific ionic liquid: [TMG][Lac]. AB - BACKGROUND: Synthesized arylidene derivatives of rhodanine and 2,4 thiazolidiendione have potent pharmacological activities, and these are also key substrates for the preparation of clinically used antidiabetics. FINDINGS: Some 1,1,3,3-tetramethylguanidine-based task-specific ionic liquids (TSILs) 1a-1e were prepared and employed to the catalyzed solvent-free Knoevenagel condensation of 2,4-thiazolidinedione 3a and rhodanine 3b with a variety of aldehydes. CONCLUSIONS: Best results were obtained with 1,1,3,3-tetramethylguanidine lactate ([TMG][Lac]) 1c. The TSIL used can be easily recovered and recycled, yielding products 4-5 in excellent yields under ultrasonic environment without the formation of any side products or toxic waste. PMID- 23458123 TI - Seipin differentially regulates lipogenesis and adipogenesis through a conserved core sequence and an evolutionarily acquired C-terminus. AB - Homozygous mutations in BSCL2 (Berardinelli-Seip congenital lipodystrophy)/seipin cause CGL2 (congenital generalized lipodystrophy type 2). Recent data suggest that seipin regulates LD (lipid droplet) dynamics and adipocyte differentiation, but whether these roles are mechanistically linked remains unclear. To understand how seipin regulates these processes, we investigated the evolutionary changes of seipin orthologues, and studied individual domains in regulating lipid accumulation in non-adipocytes and adipocytes. Mammalian seipins comprise at least two distinct functional domains, a conserved core sequence and an evolutionarily acquired C-terminus. Despite its requirement for adipocyte formation, seipin overexpression inhibited oleate-induced LD formation and accumulation in nonadipocytes, which was mediated by the core sequence. In contrast, seipin overexpression did not inhibit LD accumulation during adipocyte differentiation or the adipogenic process in 3T3-L1 cells. However, adipogenesis and LD accumulation were impaired in 3T3-L1 cells expressing a seipin mutant lacking the C-terminus. Furthermore, expression of the same mutant without the C terminus failed to rescue the adipogenic defects in seipin-knockdown cells, demonstrating the importance of the C-terminus for seipin's function in adipocyte development. We propose that seipin is involved in lipid homoeostasis by restricting lipogenesis and LD accumulation in non-adipocytes, while promoting adipogenesis to accommodate excess energy storage. PMID- 23458125 TI - Two cases of hemihyperplasia-multiple lipomatosis syndrome and review of asymmetric hemihyperplasia syndromes. AB - Hemihyperplasia-multiple lipomatosis syndrome (HHML) is a condition characterized by asymmetric nonprogressive overgrowth, multiple lipomas, and superficial vascular malformations. We present two cases of HHML to enhance the diagnostic acumen of dermatologists and avoid potential misdiagnosis of this rare but probably underrecognized entity. We also provide a brief review of asymmetric overgrowth syndromes, which have overlapping yet distinct clinical manifestations. PMID- 23458124 TI - Nonconserved active site residues modulate CheY autophosphorylation kinetics and phosphodonor preference. AB - In two-component signal transduction, response regulator proteins contain the catalytic machinery for their own covalent phosphorylation and can catalyze phosphotransfer from a partner sensor kinase or autophosphorylate using various small molecule phosphodonors. Although response regulator autophosphorylation is physiologically relevant and a powerful experimental tool, the kinetic determinants of the autophosphorylation reaction and how those determinants might vary for different response regulators and phosphodonors are largely unknown. We characterized the autophosphorylation kinetics of 21 variants of the model response regulator Escherichia coli CheY that contained substitutions primarily at nonconserved active site positions D + 2 (CheY residue 59) and T + 2 (CheY residue 89), two residues C-terminal to conserved D57 and T87, respectively. Overall, the CheY variants exhibited a >10(5)-fold range of rate constants (kphos/KS) for reaction with phosphoramidate, acetyl phosphate, or monophosphoimidazole, with the great majority of rates enhanced versus that of wild-type CheY. Although phosphodonor preference varied substantially, nearly all the CheY variants reacted faster with phosphoramidate than acetyl phosphate. Correlation between the increased positive charge of the D + 2 and T + 2 side chains and faster rates indicated electrostatic interactions are a kinetic determinant. Moreover, sensitivities of rate constants to ionic strength indicated that both long-range and localized electrostatic interactions influence autophosphorylation kinetics. The increased nonpolar surface area of the D + 2 and T + 2 side chains also correlated with an enhanced autophosphorylation rate, especially for reaction with phosphoramidate and monophosphoimidazole. Computer docking suggested that highly accelerated monophosphoimidazole autophosphorylation rates for CheY variants with a tyrosine at position T + 2 likely reflect structural mimicry of phosphotransfer from the sensor kinase histidyl phosphate. PMID- 23458126 TI - pH-controlled coordination mode rearrangements of "clickable" Huisgen-based multidentate ligands with [M(I)(CO)3]+ (M = Re, (99m)Tc). AB - The viability of the Huisgen cycloaddition reaction for clickable radiopharmaceutical probes was explored with an alkyne-functionalized 2-[(pyridin 2-ylmethyl)amino]acetic acid (PMAA) ligand system, 3, and fac [M(I)(OH2)3(CO)3](+) (M = Re, (99m)Tc). Two synthetic strategies, (1) click, then chelate and (2) chelate, then click, were investigated to determine the impact of assembly order on the reactivity of the system. In the click, then chelate approach, fac-[M(I)(OH2)3(CO)3](+) was reacted with the PMAA ligand "clicked" to the benzyl azide, 5, to yield two unique coordination species, fac [M(I)(CO)3(O,N(amine),N(py)-5)], M = Re (8), (99m)Tc (8A), and fac [M(I)(CO)3(N(tri),N(amine),N(py)-5)], M = Re (9), (99m)Tc (9A), where coordination is through the triazole (N(tri)), central amine (N(amine)), pyridine (N(py)), or carboxylate (O). Depending on the reaction pH, different ratios of complexes 8(A) and 9(A) were observed, but single species were obtained of (O,N(amine),N(py)) coordination, 8(A), in basic pHs (>9) and (N(tri),N(amine),N(py)) coordination, 9(A), in slightly acidic pHs (<4). In the chelate, then click approach, the (O,N(amine),N(py)) coordination of [M(I)(CO)3](+) was preorganized in the alkyne-functionalized fac [M(I)(CO)3(O,N(amine),N(py)-3)], M = Re (6), (99m)Tc (6A), followed by standard Cu(I)-catalyzed Huisgen "click" conditions at pH ~ 7.4, where the (O,N(amine),N(py)) coordination mode remained unchanged upon formation of the triazole product in the clicked molecule. Despite the slow substitution kinetics of the low-spin d(6) metal, the coordination modes (O,N(amine),N(py)) and (N(tri),N(amine),N(py)) were found to reversibly intraconvert between 8(A) and 9(A) based upon changes in pH that mirrored the (O,N(amine),N(py)) coordination in basic pHs and (N(tri),N(amine),N(py)) coordination in acidic pHs. Comparison of the Re and (99m)Tc analogs also revealed faster intraconversion between the coordination modes for (99m)Tc. PMID- 23458128 TI - Isolation of monodisperse nanodisc-reconstituted membrane proteins using free flow electrophoresis. AB - Free flow electrophoresis is used for rapid and high-recovery isolation of homogeneous preparations of functionally active membrane proteins inserted into nanodiscs. The approach enables isolation of integral and membrane anchored proteins and is also applicable following introduction of, e.g., fluorescent tags. Preparative separation of membrane protein loaded nanodiscs from empty nanodiscs and protein aggregates results in monodisperse nanodisc preparations ideal for structural and functional characterization using biophysical methods. PMID- 23458127 TI - Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation? AB - BACKGROUND: In cirrhotic patients with hepatocellular carcinoma (HCC), poor differentiation in pre-liver transplantation (LT) biopsy of the largest tumour is used as a criterion for exclusion from LT in some centres. The potential role of pre-LT biopsy at one centre was explored. METHODS: A prospective database of patients undergoing orthotopic LT for radiologically diagnosed HCC at St James's University Hospital, Leeds during 2006-2011 was analysed. RESULTS: A total of 60 predominantly male (85.0%) patients with viral hepatitis were identified. There were discrepancies between radiological and histopathological findings with respect to the number of tumours identified (in 27 patients, 45.0%) and their size (in 63 tumours, 64.3%). In four (6.7%) patients, the largest lesion, which would theoretically have been targeted for biopsy, was not the largest in the explant. Nine (31.0%) patients with multifocal HCC had tumours of differing grades. In two (6.9%) patients, the largest tumour was well differentiated, but smaller tumours in the explant were poorly differentiated. In one patient, the largest lesion was benign and smaller invasive tumours were confirmed histologically. CONCLUSIONS: The need to optimize selection for LT in HCC remains. In the present series, the largest tumour was not always representative of overall tumour burden or biological aggression and its potential use to exclude patients from LT is questionable. PMID- 23458129 TI - Anti-biofouling 3D porous systems: the blend effect of oxazoline-based oligomers on chitosan scaffolds. AB - The production, characterization and anti-biofouling activity of 3D porous scaffolds combining different blends of chitosan and oxazoline-based antimicrobial oligomers is reported. The incorporation of ammonium quaternized oligo(2-oxazoline)s into the composition of the scaffold enhances the stability of the chitosan scaffold under physiological conditions as well as its ability to repel protein adsorption. The blended scaffolds showed mean pore sizes in the range of 18-32 MUm, a good pore interconnectivity and high porosity, as well as a large surface area, ultimate key features for anti-biofouling applications. Bovine serum albumin (BSA) adhesion profiles showed that the composition of the scaffolds plays a critical role in the chitosan-oligooxazoline system. Oligobisoxazoline-enriched scaffolds (20% w/w, CB8020) decreased protein adsorption (BSA) by up to 70%. Moreover, 1 mg of CB8020 was able to kill 99.9% of Escherichia coli cells upon contact, demonstrating its potential as promising material for production of tailored non-fouling 3D structures to be used in the construction of novel devices with applications in the biomedical field and water treatment processes. PMID- 23458130 TI - Normal and abnormal pulmonary arteriovenous shunting: occurrence and mechanisms. AB - Severe cyanosis due to pulmonary arteriovenous fistulas occurs often after a bidirectional superior cavopulmonary anastomosis (Glenn operation) and also in some congenital anomalies in which hepatic venous blood bypasses the lungs in the first passage. Relocation of hepatic flow into the lungs usually causes these fistulas to disappear. Similar pulmonary arteriovenous fistulas are observed in hereditary haemorrhagic telangiectasia, and in liver disease (hepatopulmonary syndrome). There is no convincing identification yet of a responsible hepatic factor that produces these lesions. Candidates for such a factor are reviewed, and the possibility of angiotensin or bradykinin contributing to the fistulas is discussed. PMID- 23458131 TI - Impact of preoperative therapy on patterns of recurrence in pancreatic cancer. AB - BACKGROUND: A theoretical advantage of preoperative therapy in pancreatic adenocarcinoma is that it facilitates the early treatment of micrometastases and reduces postoperative systemic recurrence. METHODS: Medical records of 309 consecutive patients undergoing resection of adenocarcinoma in the head of the pancreas were reviewed. Survival was calculated using the Kaplan-Meier method. Associations between preoperative therapy and patterns of recurrence were determined using chi-squared analysis. RESULTS: Preoperative therapy was administered to 108 patients and upfront surgery was performed in 201 patients. Preoperative therapy was associated with a significantly longer median disease free survival of 14 months compared with 12 months in patients submitted to upfront surgery (P = 0.035). The rate of local disease as a component of first site of recurrence was significantly lower with preoperative therapy (11.3%) than with upfront surgery (22.9%) (P = 0.016). Preoperative therapy was associated with a lower rate of hepatic metastasis (21.7%) than upfront surgery (34.3%) (P = 0.026). Preoperative therapy did not affect rates of peritoneal or pulmonary metastasis. CONCLUSIONS: Preoperative therapy for pancreatic cancer was associated with longer disease-free survival and lower rates of local and hepatic recurrences. These data support the use of preoperative therapy to reduce systemic and local failures after resection. PMID- 23458132 TI - Follow-up of the patients after stem cell transplantation for pediatric dilated cardiomyopathy. AB - Dilated cardiomyopathy is a serious problem in pediatric cardiology. Despite the relatively low incidence, the mortality is high. The conservative therapy does not improve the prognosis, and possibilities of heart transplantation are limited. There are multiple trials of use of stem cells for ischemic heart disease in the adult population. This allows us to believe that the method has perspectives in pediatric cardiology. We performed the cell therapy for seven patients, six of them had complete one yr follow-up after procedure. Five to 30 milliliters of bone marrow was aspirated from the iliac crest and 17 to 122 million BMCs were isolated. The average basal EF was 33.5%. We observed increasing of EF up to 54% (=9.54, p=0.00154) in a 6-month period and up to 54.5% (=10.82, p= 0.00315) after one yr. The changes of LVEDV also were observed. The LVEDV decreased in average per 13.05%. There were no observed side effects or heart rhythm disorders. Intramyocardial administration of bone marrow-derived progenitor cells proved to be a technically feasible and safe method. Up until now, the results obtained have been promising and we suppose that bone marrow derived progenitor cell intramyocardial transplantation can be used. PMID- 23458133 TI - The need for an interdisciplinary approach in forensic sciences: perspectives from a peculiar case of mummification. AB - The finding of a mummified body raises many problems, also because of the limits of the medico-legal investigations in case of mummification. Psychological autopsy and behavioral analysis have demonstrated a significant impact in case of equivocal death. The mummified corpse of a woman was found sealed in a wardrobe during the death investigation of a 36-year-old man, later discovered to be the woman's son. The woman's corpse was well preserved and no external injuries were found. Autopsy could not ascertain the cause of death. The state of the premises and the writings on the walls offered an opportunity to investigate the man's psychological profile and to better understand how the events might have taken place. The role of an accurate investigative analysis of the crime scene is a cornerstone of forensic pathology and the case presented underlies the importance of an interdisciplinary approach in forensic sciences. PMID- 23458135 TI - Emergency medicine and medical administration: exploring the crossroads. PMID- 23458137 TI - Your profession needs you (lessons in medical leadership). PMID- 23458138 TI - The Canadian National EMS Research Agenda: a mixed methods consensus study. AB - INTRODUCTION: Research is essential for the development of evidence-based emergency medical services (EMS) systems of care. When resources are scarce and gaps in evidence are large, a national agenda may inform the growth of EMS research in Canada. This mixed methods consensus study explores current barriers and existing strengths within Canadian EMS research, provides recommendations, and suggests EMS topics for future study. METHODS: Purposeful sampling was employed to invite EMS research stakeholders from various roles across the country. Study phases consisted of 1) baseline interviews of a subsample, 2) roundtable discussion, and 3) an online Delphi survey, in which participants scored each statement for importance. Consensus was defined a priori and met if 80% scored a statement as "important" or "very important." RESULTS: Fifty-three stakeholders participated, representing researchers (37.7%), EMS administrators (24.6%), clinicians/providers (20.7%), and educators (17.0%). Participation rates were as follows: interviews, 13 of 13 (100%); roundtable, 47 of 53 (89%); survey round 1, 50 of 53 (94%); survey round 2, 47 of 53 (89%); and survey round 3, 40 of 53 (75%). A total of 141 statements were identified as important: 20 barriers, 54 strengths/opportunities, 31 recommendations, and 36 suggested topics for future research. Like statements were synthesized, resulting in barriers (n = 10), strengths/opportunities (n = 24), and recommendations (n = 19), which were categorized as time, opportunities, and funding; education and mentorship; culture of research and collaboration; structure, process, and outcome of research; EMS and paramedic practice; and the future of the EMS Research Agenda. CONCLUSION: Consensus-based key messages from this agenda should be considered when designing, funding, and publishing EMS research and will advance EMS research locally, regionally, and nationally. PMID- 23458139 TI - Developing a Canadian emergency medical services research agenda: a baseline study of stakeholder opinions. AB - PURPOSE: This study forms the first phase in the development of the Canadian National EMS Research Agenda. The purpose was to understand the current state of emergency medical services (EMS) research through the barriers and opportunities perceived by key stakeholders in the Canadian system and to identify the recommendations this group had for moving forward. METHODS: This qualitative study was conducted in the spring of 2011 using one-on-one semistructured telephone interviews. Purposeful sampling was used to recruit a cross section of EMS research stakeholders, representing a breadth of geographic regions and roles. Data were collected until thematic saturation was reached. A constant comparative approach was used to develop a basic coding framework and identify emerging themes. RESULTS: Twenty stakeholders were invited to participate, and saturation was reached after 13 interviews. Thematic saturation was used to ensure that the findings were grounded in the data. Four major themes were identified: 1) the need for additional research education within EMS; 2) the importance of creating an infrastructure to support pan-Canadian research collaboration; 3) addressing the complexities of involving EMS providers in research; and 4) considerations for a national research agenda. CONCLUSION: This hypothesis-generating study reveals key areas regarding EMS research in Canada and through the guidance it provides is a first step in the development of a comprehensive national research agenda. Our intention is to collate the identified themes with the results of a larger roundtable discussion and Delphi survey and, in doing so, guide development of a Canadian national EMS research agenda. PMID- 23458140 TI - Do injection drug users have more adverse events during procedural sedation and analgesia for incision and drainage of cutaneous abscesses? AB - OBJECTIVE: Injection drug users (IDUs) often undergo procedural sedation and analgesia (PSA) in the emergency department (ED). We compared adverse events (AEs) for IDUs to those for non-IDUs receiving PSA for incision and drainage of cutaneous abscesses. METHODS: This was a retrospective analysis of a PSA safety audit. IDU status was prospectively documented among consecutive patients undergoing PSA at two urban EDs. Structured data describing comorbidities, vital signs, sedation regimens, and adverse events were collected. Primary outcome was the proportion of patients in each group experiencing an AE, whereas the secondary outcomes included recovery times. RESULTS: Of 525 consecutive patients receiving PSA for incision and drainage of an abscess, 244 were deemed IDUs and 281 non-IDUs. IDUs received higher doses of sedatives and analgesics, and 14 experienced AEs (5.7%), whereas 10 non-IDUs had AEs (3.6%), for a risk difference of 2.1% (95% CI -1.8, 6.5). Median recovery times were 18 minutes (interquartile range [IQR] 10-36) for IDUs and 12 minutes (IQR 7-19) for non-IDUs, for a difference of 6 minutes (95% CI 2-9 minutes). Median sedation times were also longer in IDUs, for a difference of 6 minutes (95% CI 5-10 minutes). Of 20 IDU patients and 1 non-IDU patient admitted to hospital, none had experienced an AE related to PSA. CONCLUSIONS: For ED patients requiring PSA for incision and drainage, IDUs had an AE rate similar to that of non-IDUs but longer sedation and recovery times. In experienced hands, PSA may be as safe in IDUs as in patients who do not use injection drugs. PMID- 23458141 TI - Evaluating a clinical practice intervention to promote delivery of salbutamol by metered-dose inhalers with holding chambers in a pediatric emergency department. AB - OBJECTIVE: The primary objective of this study was to quantify the impact of a clinical practice intervention to promote the delivery of salbutamol by metered dose inhaler (MDI) in a pediatric emergency department (PED). A secondary objective was to retrospectively document the components of the intervention. METHODS: PED inventory data for salbutamol inhalation solution (nebules), MDIs, and holding chambers were obtained from the pharmacy department. Patient data were obtained from the hospital's decision support unit. Interrupted time series analysis was used to evaluate trends in salbutamol inventory data, patient triage acuity, and hospital admissions from January 1, 2003, to May 31, 2010. Interviews and administrative documents were used to identify components of the intervention, which began in 2006. RESULTS: There was a 1,215% increase in the proportion of salbutamol delivered as MDIs compared to total inhaled salbutamol (MDI plus nebulization solution) following the intervention (95% CI 1,032% to 1,396%, p < 0.001). Increases in salbutamol MDI use were associated with the implementation of an institution-specific asthma care map. A relative decrease of 32% in the hospital admission rate (absolute -7.25%: 95% CI -8.31 to -6.19, p < 0.001) was associated with the change in salbutamol MDI use and the use of the asthma care map. CONCLUSIONS: A multifaceted intervention, designed and implemented by local PED clinical leaders, resulted in a pronounced change in salbutamol inhalation practice, with an associated decrease in admission rates. This intervention demonstrated many of the criteria for successful health system change. Findings from this research may be contextualized to inform change elsewhere. PMID- 23458142 TI - Does Powerpoint enhance learning? AB - The ubiquitous nature of PowerPoint begs the question, does PowerPoint enhance learning? This narrative explores the evidence for the effectiveness of PowerPoint and multimedia presentations in learning and information processing. Practical recommendations are provided for presentations. PMID- 23458143 TI - Can the combination of a negative computed tomography result and a negative lumbar puncture safely exclude the diagnosis of subarachnoid hemorrhage in patients with thunderclap headache? AB - CLINICAL QUESTION: How many patients who had a negative computed tomography and lumbar puncture result on initial evaluation were diagnosed with subarachnoid hemorrhage in the subsequent 6 months to 3 years? ARTICLE CHOSEN: Perry J, Spacek A, Forbes M, et al. Is the combination of negative computed tomography result and negative lumbar puncture result sufficient to rule out subarachnoid hemorrhage? Ann Emerg Med 2008;51:707-13. OBJECTIVE: To determine the sensitivity of both a negative computed tomography and a negative lumbar puncture in ruling out subarachnoid hemorrhage. PMID- 23458144 TI - Why is my arm swollen? PMID- 23458146 TI - Spontaneous rectus sheath hematoma diagnosed by point-of-care ultrasonography. AB - Spontaneous rectus sheath hematoma is an uncommon condition that can mimic other conditions associated with an acute abdomen. We report the case of a patient with a spontaneous rectus sheath hematoma due to a ruptured inferior epigastric artery pseudoaneurysm who presented with hypotension and severe abdominal pain and was diagnosed using emergency department point-of-care ultrasonography. Point-of-care ultrasonography has been increasingly used in the evaluation of emergency department patients with acute abdomen and hypotension to expedite the diagnosis and management of aortic aneurysm and intraperitoneal bleeding. Resuscitation and urgent surgical and interventional radiology consultations resulted in the successful embolization of a branch of the inferior epigastric artery and a good outcome. PMID- 23458147 TI - Avulsion fracture of the lesser trochanter: an unusual cause of hip pain in an adolescent. AB - Sports injuries involving the hip and groin are common. Special consideration must be given to musculoskeletal injuries in children and adolescents as their immature skeletons have growth plates that are relatively weaker than the tendons and ossified bone to which they connect. We present a case of an adolescent athlete with acute-onset groin pain who was found to have an avulsion fracture of the lesser trochanter. PMID- 23458148 TI - What nephrologists need to know about vascular access cannulation. AB - This article describes cannulation events, especially problems, common and rare, minor and major, to aid the nephrologist (and mid-level providers e.g. nurse practitioner and physician's assistant) in decision-making to prevent or treat cannulation-related adverse outcomes. The usual management, potential outcomes, nephrologist intervention, and prevention are discussed and include: assessment of arteriovenous (AV) access and readiness for cannulation; initial cannulation of both arteriovenous fistulas and grafts; needle size and adequacy; needle direction and potential for recirculation; limited cannulation sites/buttonhole; pain and fear of pain; prevention of bleeding; management of infiltrations/extravasations; prevention and management of "one-site-itis"; prevention and management of infection. It concludes with the importance of the medical director as the leader of the continuous quality improvement (CQI) team in preventing/reducing cannulation-related adverse events. PMID- 23458149 TI - Ultrasensitive optical shape characterization of gold nanoantennas using second harmonic generation. AB - Second harmonic generation from plasmonic nanoantennas is investigated numerically using a surface integral formulation for the calculation of both the fundamental and the second harmonic electric field. The comparison between a realistic and an idealized gold nanoantenna shows that second harmonic generation is extremely sensitive to asymmetry in the nanostructure shape even in cases where the linear response is barely modified. Interestingly, minute geometry asymmetry and surface roughness are clearly revealed by far-field analysis, demonstrating that second harmonic generation is a promising tool for the sensitive optical characterization of plasmonic nanostructures. Furthermore, defects located where the linear field is strong (e.g., in the antenna gap) do not necessarily have the strongest impact on the second harmonic signal. PMID- 23458150 TI - Gene responses in the central nervous system of zebrafish embryos exposed to the neurotoxicant methyl mercury. AB - Methyl mercury (MeHg) is a neurotoxicant with adverse effects on the development of the nervous system from fish to man. Despite a detailed understanding of the molecular mechanisms by which MeHg affects cellular homeostasis, it is still not clear how MeHg causes developmental neurotoxicity. We performed here a genome wide transcriptional analysis of MeHg-exposed zebrafish embryos and combined this with a whole-mount in situ expression analysis of 88 MeHg-affected genes. The majority of the analyzed genes showed tissue- and region-restricted responses in various organs and tissues. The genes were linked to gene ontology terms like oxidative stress, transport and cell protection. Areas even within the central nervous system (CNS) are affected differently resulting in distinct cellular stress responses. Our study revealed an unexpected heterogeneity in gene responses to MeHg exposure in different tissues and neuronal subregions, even though the known molecular action of MeHg would predict a similar burden of exposed cells. The overall structure of the developing brain of MeHg-exposed embryos appeared normal, suggesting that the mechanism leading to differentiation of the CNS is not overtly affected by exposure to MeHg. We propose that MeHg disturbs the function of the CNS by disturbing the cellular homeostasis. As these cellular stress responses comprise genes that are also involved in normal neuronal activity and learning, MeHg may affect the developing CNS in a subtle manner that manifests itself in behavioral deficits. PMID- 23458151 TI - Effects of ornamentation and phylogeny on the evolution of wing shape in stalk eyed flies (Diopsidae). AB - Exaggerated male ornaments are predicted to be costly to their bearers, but these negative effects may be offset by the correlated evolution of compensatory traits. However, when locomotor systems, such as wings in flying species, evolve to decrease such costs, it remains unclear whether functional changes across related species are achieved via the same morphological route or via alternate changes that have similar function. We conducted a comparative analysis of wing shape in relation to eye-stalk elongation across 24 species of stalk-eyed flies, using geometric morphometrics to determine how species with increased eye span, a sexually selected trait, have modified wing morphology as a compensatory mechanism. Using traditional and phylogenetically informed multivariate analyses of shape in combination with phenotypic trajectory analysis, we found a strong phylogenetic signal in wing shape. However, dimorphic species possessed shifted wing veins with the result of lengthening and narrowing wings compared to monomorphic species. Dimorphic species also had changes that seem unrelated to wing size, but instead may govern wing flexion. Nevertheless, the lack of a uniform, compensatory pattern suggests that stalk-eyed flies used alternative modifications in wing structure to increase wing area and aspect ratio, thus taking divergent morphological routes to compensate for exaggerated eye stalks. PMID- 23458152 TI - Simultaneous colorectal and hepatic procedures for colorectal cancer result in increased morbidity but equivalent mortality compared with colorectal or hepatic procedures alone: outcomes from the National Surgical Quality Improvement Program. AB - BACKGROUND: Simultaneous colorectal and hepatic surgery for colorectal cancer (CRC) is increasing as surgery becomes safer and less invasive. There is controversy regarding the morbidity associated with simultaneous, compared with separate or staged, resections. METHODS: Data for 2005-2008 from the National Surgical Quality Improvement Program (NSQIP) were used to compare morbidity after 19,925 colorectal procedures for CRC (CR group), 2295 hepatic resections for metastatic CRC (HEP group), and 314 simultaneous colorectal and hepatic resections (SIM group). RESULTS: An increasing number of simultaneous resections were performed per year. Fewer major colorectal and liver resections were performed in the SIM than in the CR and HEP groups. Patients in the SIM group had a longer operative time and postoperative length of stay compared with those in either the CR or HEP groups. Simultaneous procedures resulted in higher rates of postoperative morbidity and major morbidity than CR procedures, but not HEP procedures. This difference was driven by higher rates of wound and organ space infections, and a greater incidence of septic shock. Mortality rates did not differ among the groups. CONCLUSIONS: Hospitals in the NSQIP are performing more simultaneous colonic and hepatic resections for CRC. These procedures are associated with increases in operative time, length of stay and rate of perioperative complications. Simultaneous procedures do not, however, increase perioperative mortality. PMID- 23458153 TI - Oxidation of methionine 216 in sheep and elk prion protein is highly dependent upon the amino acid at position 218 but is not important for prion propagation. AB - We employed a sensitive mass spectrometry-based method to deconstruct, confirm, and quantitate the prions present in elk naturally infected with chronic wasting disease and sheep naturally infected with scrapie. We used this approach to study the oxidation of a methionine at position 216 (Met216), because this oxidation (MetSO216) has been implicated in prion formation. Three polymorphisms (Ile218, Val218, and Thr218) of sheep recombinant prion protein were prepared. Our analysis showed the novel result that the proportion of MetSO216 was highly dependent upon the amino acid residue at position 218 (I > V > T), indicating that Ile218 in sheep and elk prion protein (PrP) renders the Met216 intrinsically more susceptible to oxidation than the Val218 or Thr218 analogue. We were able to quantitate the prions in the attomole range. The presence of prions was verified by the detection of two confirmatory peptides: GENFTETDIK (sheep and elk) and ESQAYYQR (sheep) or ESEAYYQR (elk). This approach required much smaller amounts of tissue (600 MUg) than traditional methods of detection (enzyme-linked immunosorbent assay, Western blot, and immunohistochemical analysis) (60 mg). In sheep and elk, a normal cellular prion protein containing MetSO216 is not actively recruited and converted to prions, although we observed that this Met216 is intrinsically more susceptible to oxidation. PMID- 23458154 TI - Metabolic changes of human dental pulp after rapid palatal expansion. AB - OBJECTIVES: To investigate rapid palatal expansion (RPE)-induced metabolic changes in human dental pulp by measuring the expression and activity of aspartate aminotransferase (AST). METHODS: mRNA and protein levels of AST in human dental pulp were measured by quantitative real-time polymerase chain reaction and Western blot, respectively. Furthermore, the activity of AST was measured by a full automatic biochemical analyzer. RESULTS: AST mRNA and protein levels were found to be expressed in normal dental pulp. Moreover, the expression of AST was increased significantly after 14 days of RPE and then decreased at 1 month in retention. Three and 6 months after RPE, the AST expression level was gradually decreased to its baseline level. Similarly, AST activity was significantly elevated after 14 days of RPE, which was then down-regulated at 1 month in retention but was still kept at a higher level as compared with the control group. The enzymatic activity of AST was slowly decreased to its baseline level at 3 and 6 months in retention. CONCLUSIONS: These results showed that significant reversible metabolic changes occurred in dental pulp during RPE, which revealed the high capacity of the pulp tissue for adaptation to this orthopedic method. PMID- 23458155 TI - Epidemiological features of amyotrophic lateral sclerosis in a large clinic-based African American population. AB - Our objective was to identify the main clinical and epidemiological features of ALS in a large cohort of African American (AA) patients and compare them to Caucasian (CA) patients in a clinic-based population. We retrospectively identified 207 patients who were diagnosed with ALS based on the revised El Escorial criteria (60 AA and 147 CA subjects). Patients were seen in the Neuromuscular Division at the University Medical Center. We compared epidemiological and clinical features of these two groups, focusing on age of onset and diagnosis, clinical presentation and survival. Results showed that AA patients had a significantly younger age of disease onset (55 years vs. 61 years for CA, p = 0.011) and were diagnosed at an earlier age (56 years vs. 62 years, p = 0.012). In younger ALS patients (< 45 years of age), there was a significant difference in gender frequency, with females predominating in the AA population and males in the CA population (p = 0.025). In a multivariable Cox proportional hazard model, survival rates were not different between the groups. In both groups, survival significantly increased with younger age. In conclusion, AA patients presented at an earlier age, but there was no difference in survival compared to CA patients. A gender reversal occurred in younger ALS patients, with AA patients more likely to be female and CA patients more likely to be male. PMID- 23458156 TI - Co-operative function and mutual stabilization of the half ATP-binding cassette transporters HAF-4 and HAF-9 in Caenorhabditis elegans. AB - Caenorhabditis elegans HAF-4 and HAF-9 are half ABC (ATP-binding-cassette) transporters that are highly homologous to the human lysosomal peptide transporter TAPL [TAP (transporter associated with antigen processing)-like; ABCB9]. We reported previously that both HAF-4 and HAF-9 localize to the membrane of a subset of intestinal organelles, and are required for the formation of these organelles and other physiological aspects. In the present paper, we report the genetic and physical interactions between HAF-4 and HAF-9. Overexpression of HAF 4 and HAF-9 did not rescue the intestinal organelle defect of the haf-9 and haf-4 deletion mutants respectively, indicating that they cannot substitute for each other. Double haf-4 and haf-9 mutants do not exhibit more severe phenotypes than the single mutants, suggesting their co-operative function. Immunoprecipitation experiments demonstrated their physical interaction. The results of the present study suggest that HAF-4 and HAF-9 form a heterodimer. Furthermore, Western blot analysis of the deletion mutants and RNAi (RNA interference) knockdown experiments in GFP (green fluorescent protein)-tagged HAF-4 or HAF-9 transgenic worms suggest that HAF-4-HAF-9 heterodimer formation is required for their stabilization. The findings provide a clue as to how ABC transporters adopt a stable functional form. PMID- 23458157 TI - Congenital kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon successfully treated with low-dose radiation therapy. AB - Kaposiform hemangioendothelioma (KHE) associated with Kasabach-Merritt phenomenon is a life-threatening vasculopathy. The current mainstay treatment for KHEs is corticosteroids and chemotherapy, but these medications do not work for all patients and carry significant side effects. We report a neonate with a large congenital KHE who responded extremely well to low-dose radiation therapy. PMID- 23458158 TI - Peptide models of Cu(I) and Zn(II) metallochaperones: the effect of pH on coordination and mechanistic implications. AB - The first NMR structures of Cu(I) and Zn(II) peptide complexes as models of metallochaperones were derived with no predetermined binding mode. The cyclic peptide MDCSGCSRPG was reacted with Cu(I) and Zn(II) at low and moderate pH. This peptide features the conserved sequence of copper chaperones but with Asp at position 2 as appears in the zinc binding domain of ZntA. The structures were compared with those of the Cu(I) complexes of the wild-type sequence peptide MTCSGCSRPG. All analyses were conducted first with no metal-binding constraints to ensure accurate binding ligand assignment. Several structures included metal Met binding, raising a possible role of Met in the metal transport mechanism. Both Cu(I) and Zn(II) gave different complexes when reacted with the peptide of the native-like sequence under different pH conditions, raising the possibility of pH-dependent transport mechanisms. Cu(I) bound the MTCSGCSRPG peptide through one Cys and the Met under acidic conditions and differently under basic conditions; Zn(II) bound the MDCSGCSRPG peptide through two Cys and the Met residues under acidic conditions and through one Cys and the Met under basic conditions, while Cu(I) bound the non-native Asp mutant peptide through the Asp and one Cys under both conditions, suggesting that Asp may inhibit pH-dependent binding for Cu(I). NOESY and ESI-HRMS supported the presence of an aqua ligand for Zn(II), which likely deprotonated under basic conditions to give a hydroxo group. Coordination similarities were detected among the model system and native proteins, which overall suggest that coordination flexibility is required for the function of metallochaperones. PMID- 23458159 TI - Structure of inclusions of Huntington's disease brain revealed by synchrotron infrared microspectroscopy: polymorphism and relevance to cytotoxicity. AB - Huntington's disease is caused by a polyglutamine expansion in huntingtin. Affected brain regions contain characteristic aggregates of the misfolded expanded protein. Studies in cells and animals show that aggregates are polymorphic and that the secondary structure of the aggregates is likely to condition their cytotoxicity. Therefore knowing the structure of aggregates is important as neurotoxic secondary structures may be specifically targeted during the search for prophylactic or therapeutic drugs. The structure of aggregates in the brain of patients is still unknown. Using synchrotron based infrared microspectroscopy we demonstrate that the brains of patients with Huntington disease contain putative oligomers and various kinds of microscopic aggregates (inclusions) that can be distinguished by their differential absorbance at 1627 cm(-1) (amyloid beta sheets) and 1639 cm(-1) (beta sheets/unordered). We also describe the parallel/antiparallel organization of the beta strands. As the inclusions enriched in both beta sheets and beta sheets/unordered structures are characteristic of severely affected brain regions, we conclude that this kind of amyloid inclusions is likely to be particularly toxic to neurons. PMID- 23458161 TI - Application of metabolomics to understanding biofilms in water distribution systems: a pilot study. AB - Biofilms formed in pipes are known to contribute to waterborne diseases, accelerate corrosion and cause aesthetic taste and odour issues within the potable water supply network. This paper describes a pilot study, undertaken to assess the potential of using metabolomics to monitor bacterial activity in biofilms of an urban water network. Using samples from a water mains flushing programme, it was found that a profile of intracellular and extracellular metabolites associated with microbial activity could be obtained by analysing samples using gas chromatography mass spectrometry. Chemometric analysis of the chromatograms in conjunction with data from the mass spectrometer showed that it is possible to differentiate between biofilms from different pipe materials and planktonic bacteria. This research demonstrates that metabolomics has the potential for investigating biofilms and other microbial activity within water networks, and could provide a means for enhancing monitoring programmes, understanding the source of water quality complaints, and optimising water network management strategies. PMID- 23458160 TI - Pre-operative cardiopulmonary exercise testing predicts adverse post-operative events and non-progression to adjuvant therapy after major pancreatic surgery. AB - BACKGROUND: Surgery followed by chemotherapy is the primary modality of cure for patients with resectable pancreatic cancer but is associated with significant morbidity. The aim of the present study was to evaluate the role of cardiopulmonary exercise testing (CPET) in predicting post-operative adverse events and fitness for chemotherapy after major pancreatic surgery. METHODS: Patients who underwent a pancreaticoduodenectomy or total pancreatectomy for pancreatic head lesions and had undergone pre-operative CPET were included in this retrospective study. Data on patient demographics, comorbidity and results of pre-operative evaluation were collected. Post-operative adverse events, hospital stay and receipt of adjuvant therapy were outcome measures. RESULTS: One hundred patients were included. Patients with an anaerobic threshold less than 10 ml/kg/min had a significantly greater incidence of a post-operative pancreatic fistula [International Study Group for Pancreatic Surgery (ISGPS) Grades A-C, 35.4% versus 16%, P = 0.028] and major intra-abdominal abscesses [Clavien-Dindo (CD) Grades III-V, 22.4% versus 7.8%, P = 0.042] and were less likely to receive adjuvant therapy [hazard ratio (HR) 6.30, 95% confidence interval (CI) 1.25 31.75, P = 0.026]. A low anaerobic threshold was also associated with a prolonged hospital stay (median 20 versus 14 days, P = 0.005) but not with other adverse events. DISCUSSION: CPET predicts a post-operative pancreatic fistula, major intra-abdominal abscesses as well as length of hospital stay after major pancreatic surgery. Patients with a low anaerobic threshold are less likely to receive adjuvant therapy. PMID- 23458162 TI - A multicentre, randomized clinical trial comparing the VerisetTM haemostatic patch with fibrin sealant for the management of bleeding during hepatic surgery. AB - BACKGROUND: Bleeding during hepatic surgery is associated with prolonged hospitalization and increased morbidity and mortality. The VerisetTM haemostatic patch is a topical haemostat comprised of an absorbable backing made of oxidized cellulose and self-adhesive hydrogel components. It is designed to achieve haemostasis quickly and adhere to tissues without fixation. METHODS: A prospective, randomized, multicentre, single-blinded study (n = 50) was performed to compare the use of a VerisetTM haemostatic patch with a fibrin sealant patch (TachoSil((r)) ) (control) in the management of diffuse bleeding after hepatic surgery. Patients were randomized following the confirmation of diffuse bleeding requiring the use of a topical haemostat. Time to haemostasis was assessed at preset intervals until haemostasis was achieved. RESULTS: Both groups were similar in comorbidities and procedural techniques. The median time to haemostasis in the group using the VerisetTM haemostatic patch was 1.0 min compared with 3.0 min in the control group (P < 0.001; 3-min minimum application time for the control patch). This result was independent of bleeding severity and surface area. Both products had similar safety profiles and no statistical differences were observed in the occurrence of adverse or device-related events. CONCLUSIONS: Regardless of bleeding severity or surface area, the VerisetTM haemostatic patch achieved haemostasis in this setting significantly faster than the control device in patients undergoing hepatic resection. It was safe and easy to handle in open hepatic surgery. PMID- 23458163 TI - Advantages of early replacement therapy for mucopolysaccharidosis type VI: echocardiographic follow-up of siblings. AB - Mucopolysaccharidosis type VI (Marateaux-Lamy syndrome) is an autosomal recessive disorder caused by deficient activity of the enzyme N-acetylgalactosamine-4 sulphatase (arylsulphatase B). Cytoplasmic vacuoles full of dermatan sulphate are observed in endothelial cells, myocyte, and fibroblasts, compromising the function of cardiovascular structures and contributing significantly towards morbidity and mortality. The primary objective of this study was to assess the advantages of early replacement therapy with recombinant human arylsulphatase B through the echocardiographic follow-up of sisters who started treatment at quite different ages: one at 9 years and the other at 1 year and 7 months. The older sibling showed striking mitral and aortic valve compromise when she was only 2 years old and finally needed cardiac surgery at the age of 8, even before starting enzyme replacement. Differently, the younger one has developed only mild mitral and aortic lesions throughout the follow-up period of 3 years. The two siblings had left ventricle cardiomyopathy, but partial reverse remodelling was induced by enzyme replacement therapy in both cases. The younger sibling has never received any cardiovascular drugs, whereas the older one has been using beta-blockers and diuretics in addition to enzyme therapy to cope with heart failure. Comparing the outcomes of these two sisters with a very aggressive phenotype of mucopolysaccharidosis type VI, the conclusion was that early onset of therapy may slow down the disease progression and prevent severe cardiac lesions to be established. Moreover, patients' compliance is essential for the success of treatment, as sequential echocardiographic evaluation demonstrated worsening of some cardiac lesions whenever infusions were missed. PMID- 23458164 TI - Identifying candidate oocyte reprogramming factors using cross-species global transcriptional analysis. AB - There is mounting evidence to suggest that the epigenetic reprogramming capacity of the oocyte is superior to that of the current factor-based reprogramming approaches and that some factor-reprogrammed induced pluripotent stem cells (iPSCs) retain a degree of epigenetic memory that can influence differentiation capacity and may be linked to the observed expression of immunogenicity genes in iPSC derivatives. One hypothesis for this differential reprogramming capacity is the "chromatin loosening/enhanced reprogramming" concept, as previously described by John Gurdon and Ian Wilmut, as well as others, which postulates that the oocyte possesses factors that loosen the somatic cell chromatin structure, providing the epigenetic and transcriptional regulatory factors more ready access to repressed genes and thereby significantly increasing epigenetic reprogramming. However, to empirically test this hypothesis a list of candidate oocyte reprogramming factors (CORFs) must be ascertained that are significantly expressed in metaphase II oocytes. Previous studies have focused on intraspecies or cross-species transcriptional analysis of up to two different species of oocytes. In this study, we have identified eight CORFs (ARID2, ASF1A, ASF1B, DPPA3, ING3, MSL3, H1FOO, and KDM6B) based on unbiased global transcriptional analysis of oocytes from three different species (human, rhesus monkey, and mouse) that both demonstrate significant (p<0.05, FC>3) expression in oocytes of all three species and have well-established roles in loosening/opening up chromatin structure. We also identified an additional 15 CORFs that fit within our proposed "chromatin opening/fate transformative" (COFT) model. These CORFs may be able to augment Shinya Yamanaka's previously identified reprogramming factors (OCT4, SOX2, KLF4, and cMYC) and potentially facilitate the removal of epigenetic memory in iPSCs and/or reduce the expression of immunogenicity genes in iPSC derivatives, and may have applications in future personalized pluripotent stem cell based therapeutics. PMID- 23458166 TI - Age estimation from radiographic images of the knee. AB - This study examines the reliability of age estimation utilizing the Pyle and Hoerr atlas in relation to a modern Scottish population. The knee radiographs of 442 individuals (168 females, 274 males) were age assessed using the Pyle and Hoerr atlas. Analysis showed that there was a strong correlation between chronological age and estimated age (females R2=0.968, males R2=0.952). For females, the atlas method was most accurate between the ages of 9 and 15 years of age with an underage of 2.27 months and an overage of 2.38 months. For males, the atlas consistently overestimated age from the age of 9 years to the age of 16 years from between 0.14 and 8.81 months. The standard deviation for females was 9.86 months and for males was 10.75 months. This study showed that the Pyle and Hoerr atlas can be applied to a modern population with small modifications. PMID- 23458165 TI - Arterial compliance is increased in children with type 2 diabetes compared with normal weight peers but not obese peers. AB - BACKGROUND: We reported that obesity was associated with increased arterial compliance in children, possibly due to accelerated vascular maturation. Here, we explored the additional burden of type 2 diabetes (T2DM) on vascular function in children. METHODS: Fifty normal weight [body mass index (BMI) 25-75%], 58 obese (BMI >= 95%), and 34 children with T2DM diagnosed by American Diabetes Association (ADA) criteria ages 10-18 yr were studied. Large and small artery elasticity (LAEI and SAEI, respectively) were measured by diastolic pulse-wave contour analysis. RESULTS: SAEI was 27% higher in children with T2DM compared to normal weight children (p = 0.005). Mean LAEI for those with T2DM not different from either group. In the group with T2DM, both SAEI and LAEI increased with age up to 16 yr, but declined thereafter. The strongest multivariable model predicting SAEI in children with T2DM combined lean mass, systolic blood pressure (SBP), and glucose (r2 = 0.59); for predicting LAEI, the strongest model included height, SBP, and low-density lipid-cholesterol (r2 = 0.61). CONCLUSION: The lower arterial compliance in older adolescents with T2DM compared to that of their peers without diabetes may indicate a premature maturation of the vascular system; however, follow-up will clarify whether these vascular changes portend an early increase in diabetes-associated cardiovascular disease risk. PMID- 23458167 TI - Harnessing plasmon-induced ionic noise in metallic nanopores. AB - The ionic properties of a metal-coated silicon nanopore were examined in a nanofluidic system. We observed a strong increase of the ionic noise upon laser light illumination. The effect appeared to be strongly mediated by the resonant excitation of surface plasmons in the nanopore as was demonstrated by means of ionic mapping of the plasmonic electromagnetic field. Evidence from both simulations and experiments ruled out plasmonic heating as the main source of the noise, and point toward photoinduced electrochemical catalysis at the semiconductor-electrolyte interface. This ionic mapping technique described is opening up new opportunities on noninvasive applications ranging from biosensing to energy conversion. PMID- 23458168 TI - Incidental pT2-T3 gallbladder cancer after a cholecystectomy: outcome of staging at 3 months prior to a radical resection. AB - INTRODUCTION: Patients with incidental pT2-T3 gallbladder cancer (IGC) after a cholecystectomy may benefit from a radical re-resection although their optimal treatment strategy is not well defined. In this Unit, such patients undergo delayed staging at 3 months after a cholecystectomy to assess the evidence of a residual tumour, extra hepatic spread and the biological behaviour of the tumour. The aim of this study was to evaluate the outcome of patients who had delayed staging at 3 months after a cholecystectomy. METHODS: From July 2003 to July 2011, 56 patients with T2-T3 gallbladder cancer were referred to this Unit of which 49 were diagnosed incidentally on histology after a cholecystectomy. All 49 patients underwent delayed pre-operative staging using multi-detector computed tomography (MDCT) followed selectively by laparoscopy at 3 months after a cholecystectomy. Data were collected from a prospectively held database. The peri operative and long-term outcomes of patients were analysed. SPSS software was used for statistical analysis. RESULTS: There were 38 pT2 and 11 pT3 tumours. After delayed staging, 24/49 (49%) patients underwent a radical resection, 24/49 (49%) were found to be inoperable on pre-operative assessment and 1/49 (2%) patient underwent an exploratory laparotomy and were found to be unresectable. The overall median survival from referral was 20.7 months (54.8 months for the group who had a radical re-resection versus 9.7 months for the group who had unresectable disease, P < 0.001). These results compare favourably with the reported outcome of fast-track management for incidental pT2-T3 gallbladder cancer from other major series in the literature. CONCLUSION: Delayed staging in patients with incidental T2-T3 gallbladder cancer after a cholecystectomy is a useful strategy to select patients who will benefit from a resection and avoid unnecessary major surgery. PMID- 23458169 TI - Distinct transcriptional profiles of angioblasts derived from human embryonic stem cells. AB - Identification of differentially expressed genes in angioblasts derived from human embryonic stem cells (hESCs) is of great interest for elucidating the molecular mechanisms underlying human vasculogenesis. The aim of this study was to define hESC-derived angioblasts at the clonal level and to perform comparative transcriptional analysis to characterize their distinct gene expression profiles. In a clonal analysis performed in cell-specific differentiation media, hESC derived CD34(+)CD31(+) cells were identified as angioblasts in that they exhibited a significantly higher ability to form endothelial cell (EC) and smooth muscle cell (SMC) colonies than CD34(+)CD31(-) and CD34(-) cell populations did. Microarray analysis showed that many genes involved in vascular development and signaling transduction were overexpressed in hESC-derived CD34(+)CD31(+) cells, whereas those related to mitosis, the DNA damage response, and translation were substantially downregulated. In addition, comparative gene expression profiling of hESC-derived CD34(+)CD31(+) cells and human somatic primary vascular cells demonstrated that hESC-derived CD34(+)CD31(+) cells expressed key genes involved in the EC and SMC differentiation processes, which supports the result that hESC derived CD34(+)CD31(+) cells are bipotent angioblasts. Our results may provide insights into the identity and function of hESC-derived angioblasts and may also facilitate further investigation of the molecular mechanisms regulating human embryonic vasculogenesis. PMID- 23458170 TI - A survey of current procedural practices of Australian and New Zealand nephrologists. AB - The aim of this study was to describe the range and extent of current procedural practices of Nephrologists and trainees in Australia and New Zealand with a specific focus on renal biopsy. A web-based survey was constructed based on a 2009 pilot survey conducted by the authors. The survey was distributed by email. A total of 118 responses were received from 60 centers, including six pediatric centers; Nephrologists or trainees performed the following procedures: urine microscopy 36.4%; diagnostic ultrasound 10.2%; renal biopsy 93.2%; simple vascath insertion 64.4%; cuffed vascath insertion 22%; peritoneal catheter insertion 16.9%; fistula ultrasound 20.3%; and fistulography 5%. Trainees performed most renal biopsies (67.8% of respondents) and real-time ultrasound was the commonest technique (97%). The majority of respondents believe that renal biopsy is an essential skill for trainees (78.8%); 10-25 biopsies are required for trainee proficiency (59.3%); an online training module would assist in teaching renal biopsies (67.8%). Cuffed catheter insertion and fistulography were more often performed in nonmetropolitan than in metropolitan centers. Procedures are part of Australian and New Zealand Nephrology, including specialized procedures in a minority of centers. Vascular access procedures are more common in nonmetropolitan centers. Renal biopsy is an important skill, considered essential for trainees by most. PMID- 23458171 TI - Quantification of the uptake of silver nanoparticles and ions to HepG2 cells. AB - The toxic mechanism of silver nanoparticles (AgNPs) is still debating, partially because of the common co-occurrence and the lack of methods for separation of AgNPs and Ag(+) in biological matrices. For the first time, Triton-X 114-based cloud point extraction (CPE) was proposed to separate AgNPs and Ag(+) in the cell lysates of exposed HepG2 cells. Cell lysates were subjected to CPE after adding Na2S2O3, which facilitated the transfer of AgNPs into the nether Triton X-114 rich phase by salt effect and the preserve of Ag(+) in the upper aqueous phase through the formation of hydrophilic complex. Then the AgNP and Ag(+) contents in the exposed cells were determined by ICP-MS after microwave digestion of the two phases, respectively. Under the optimized conditions, over 67% of AgNPs in cell lysates were extracted into the Triton X-114-rich phase while 94% of Ag(+) remained in the aqueous phase, and the limits of detection for AgNPs and Ag(+) were 2.94 MUg/L and 2.40 MUg/L, respectively. This developed analytical method was applied to quantify the uptake of AgNPs to the HepG2 cells. After exposure to 10 mg/L AgNPs for 24 h, about 67.8 ng Ag were assimilated per 10(4) cells, in which about 10.3% silver existed as Ag(+). Compared to the pristine AgNPs (with 5.2% Ag(+)) for exposure, the higher ratio of Ag(+) to AgNPs in the exposed cells (10.3% Ag(+)) suggests the transformation of AgNPs into Ag(+) in the cells and/or the higher uptake rate of Ag(+) than that of AgNPs. Given that the toxicity of Ag(+) is much higher than that of AgNPs, the substantial content of Ag(+) in the exposed cells suggests that the contribution of Ag(+) should be taken into account in evaluating the toxicity of AgNPs to organisms, and previous results obtained by regarding the total Ag content in organisms as AgNPs should be reconsidered. PMID- 23458172 TI - Long-term outcome and prognostic factors of idiopathic membranous nephropathy in the Chinese population. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is a representative form of nephrotic syndrome in China. Although IMN is thought to run a more benign course in Asian patients than in the Caucasian population, there has been no persuasive study to determine the long-term prognosis and risk factors for IMN in the Chinese population. METHODS: A retrospective chart review. All patients admitted to Nanjing Institution of Nephrology from January 1985 to December 2007 with biopsy-proven IMN were enrolled. The primary outcome was the renal survival rate and risk factors at renal biopsy. RESULT: A total of 217 patients were included in the study, and the overall renal survival rates were 96.9%, 93.5%, and 86.6% at 5, 10, and 15 years after renal biopsy, respectively. When the clinical features at biopsy were evaluated, patients with hypertension (p = 0.023), decreased eGFR (p < 0.001), nephrotic-range proteinuria (p = 0.047), elevated urinary NAG (p = 0.045) and RBP (p = 0.007) had a worse prognosis. Cox multivariate analysis showed that decreased eGFR and chronic tubulointerstitial lesion were independent risk factors for ESRF (end-stage renal failure). CONCLUSION: IMN is a disease with a comparatively good prognosis in the Chinese population, with a renal survival rate of more than 90% at 10 years after renal biopsy. Decreased eGFR at biopsy and chronic tubulointerstitial lesion are independent risk factors of ESRF. Partial or complete remission of proteinuria improved the prognosis. PMID- 23458173 TI - Efficacy and safety of leflunomide in treatment of steroid-dependent and steroid resistant adult onset minimal change disease. AB - OBJECTIVE: To observe the efficacy and safety of leflunomide combined with prednisone therapy (LEF therapy) in the treatment of patients with adult onset steroid-dependent and steroid-resistant minimal change disease (MCD). METHODS: 16 MCD patients who had been treated with LEF therapy were retrospectively analyzed. 87.5% (14/16) of the patients were steroid-dependent and 12.5% (2/16) of the patients were steroid-resistant. The initial dose of LEF was 10 - 20 mg/day combined with prednisone 0.25 - 1.0 mg/kg/day, gradually tapering after 8 weeks. Clinical and laboratory data at baseline, 2nd, 4th, 8th, 12th, 24th, and 48th week were analyzed compared with initial course of prednisone monotherapy (PRED monotherapy) and cyclophosphamide combined with prednisone therapy (CTX therapy). RESULTS: All the 16 patients achieved different levels of remission in LEF therapy. 93.8% (15/16) of the patients, including the two steroid-resistant patients, achieved complete remission. During the treatment, 8 patients had adverse effects which could be well tolerated. Compared LEF therapy with PRED monotherapy (n = 16), the dose of prednisone to maintain remission was reduced (from median 22.5 mg/day to median 7.5 mg/day, p = 0.041); relapse rate during the follow-up decreased from 100% to 31.3% (p = 0.002); the median time before relapse increased from 20.3 weeks to 32.5 weeks. Compared LEF therapy with CTX therapy (n = 12), the dose of prednisone to maintain remission was reduced significantly (from median 22.5 mg/day to median 5.0 mg/day, p = 0.003); relapse rate during the follow-up decreased from 100% to 31.3% (p = 0.001); the median time before relapse increased from 11.7 weeks to 32.5 weeks. CONCLUSIONS: LEF therapy seems to be effective in steroid-resistant and steroiddependent MCD. This therapy may reduce the amount of prednisone to maintain remission and reduce the relapse rate compared with PRED monothrerapy and CTX therapy. LEF therapy was usually well tolerated. PMID- 23458174 TI - Assessment of genetic risk factors for thromboembolic complications in adults with idiopathic nephrotic syndrome. AB - AIMS: Nephrotic syndrome (NS) may occur with acquired hypercoagulability, however, the fact that it is accompanied by an underlying hereditary thrombophilia, especially combined hereditary thrombophilia would lead to thrombotic events. In this study, we aimed to evaluate the contribution of genetic thrombophilia to development of thrombotic events in adult patients with NS. MATERIAL AND METHODS: Factor V Leiden (FVL), prothrombin, and methylenetetrahydrofolate reductase (MTHFR) gene mutation were studied in 51 newly diagnosed idiopathic NS patients and age- and gender-matched 20 healthy control subjects included in the study. Renal vein Doppler ultrasound was conducted in order to investigate the prevalence of subclinical renal vein thrombosis. RESULTS: Of 51 patients, 6 (11.8%) were established to have thromboembolic (TE) complications at the time of diagnosis (4 symptomatic, 2 subclinical), and no recurring thrombotic episode was observed. Genetic mutation was established in all patients that were found to have TE complications. Acquired hypercoagulability factors were similar in patients without and with TE complication. CONCLUSIONS: The coexistence of inherited thrombophilia in NS may facilitate thromboembolic complications. If the cause of thrombosis cannot be explained by the usual factors attributed to the occurrence of thrombosis in NS, screening for the other factors, such as FVL, MTHFR, and prothrombin gene mutation, may be beneficial. PMID- 23458175 TI - Identification of perirenal or renal splenosis from undetermined masses: case report and review of the literature. AB - The incidental finding of tumor-llke perirenal or renal splenosis (PRS) creates a challenge to the renal physicians, because its benign nature has to be distinguished from a malignancy. This paper describes the case of a 40-year-old man referred from a local clinic for further evaluation of an incidental finding of left abdominal masses by ultrasonogram suspecting neoplasm, but was eventually confirmed as PRS by obtaining a history of splenectomy that pointed to splenosis and subsequently by a fusion image from single photon emission computed tomography using 99mTc-labelled heat-denatured erythrocytes and computed tomography (hybrid SPECT/CT). In addition, a review of 27 cases of PRS in a MEDLINE search including the present case revealed the following: all the masses were found incidentally and were associated with a history of previous splenectomy or splenic injury; the initial impressions were neoplastic tumor/PRS (n = 9), PRS (n = 10), and neoplastic tumor without consideration of splenosis (n = 8); surgical exploration was undertaken in all the 8 cases of suspected neoplastic tumor only, whereas non-invasive radiological or radionuclide imaging confirmed splenosis in the rest of the cases (n = 19). To avoid unnecessary tests and invasive surgery for undetermined perirenal or renal masses accompanying previous splenic injury, we stress the paramount importance of careful history taking, physical examination, and a high index of suspicion for splenosis. Also, fusion imaging of hybrid SPECT/CT was reconfirmed as a useful diagnostic technique for accurately detecting and localizing splenic tissues by PRS. PMID- 23458176 TI - Association between osteoprotegerin, fetuin-A, carotid intima media thickness, and urinary albumin excretion in Type 2 diabetes. AB - AIMS: Vascular calcification and atherosclerosis play a vital role in the development of cardiovascular morbidity and mortality in diabetic patients, especially when complications of diabetic nephropathy occur. Osteoprotegerin (OPG) and fetuin-A are two markers of vascular calcification. We evaluated the association between these vascular markers and urinary albumin excretion in diabetic patients. METHOD: Three groups were arranged containing 40 patients: normoalbuminuric (Group 1), microalbuminuric (Group 2), and macroalbuminuric (Group 3). In addition to the obtained data, levels of hs-CRP (high sensitivity CRP) and homocysteine were examined. RESULTS: OPG levels of patients in Group 2 were higher than in Group 1 (p = 0.058). OPG levels in Group 3 were lower than in Groups 1 or 2 (p = 0.014 and 0.000, respectively). Levels of fetuin-A in Group 2 were determined to be lower than in Groups 1 and 3 (p = 0.001 and 0.000, respectively). Carotid intima media thickness (CIMT) in Group 3 was higher than in Group 1 (p = 0.002). CIMT in Group 2 was also higher than in Group 1 (p = 0.039). A positive correlation between fetuin-A and OPG was found (p = 0.012, r = 0.393). Additionally, a positive correlation between hs-CRP and fetuin-A in Group 2 (p = 0.020, r = 0.367) and a negative correlation between hs-CRP and OPG in Group 3 (p = 0.036, r = -0.333) were observed. CONCLUSIONS: The differences found between albuminuria and OPG or fetuin-A may be due to the different doses and variety of medications the patients received, in addition to genetic and racial factors. So far, in our country, polymorphisms related to OPG and fetuin-A have not been defined. Further detailed studies about polymorphisms will have additional value. PMID- 23458177 TI - A case of sarcoidosis with severe acute renal failure requiring dialysis. AB - We report here a 79-year-old male having sarcoidosis without presentation of typical findings, such as respiratory symptoms, ocular signs, or skin lesions. Two weeks prior to admission to our hospital, he presented to a different hospital with acute renal failure, with blood urea nitrogen (BUN) and serum creatinine (Cr) levels of 67.9 mg/dl and 7.97 mg/dl, respectively, and was initiated on hemodialysis. The patient also exhibited fever, severe anorexia, and fatigue. We initially experienced difficulty in performing kidney biopsy due to a thrombocytopenia complication and severe general debility. Tuberculosis and other malignancies were not found. However, bone marrow biopsy revealed noncaseating granuloma with multinucleated giant cells, and the patient's serum angiotensin converting enzyme (ACE) level was slightly elevated at 24.3 U/l. We informed the patient and his family of the risk of a kidney biopsy and subsequently received informed consent for the procedure. The biopsy showed many epitheloid granulomas with multinucleated giant cells in the interstitium, from which we diagnosed sarcoidosis. The thrombocytopenia was subsequently found to be due to heparin induced thrombocytopenia (HIT). After administering 20 mg/day of oral prednisolone, the patient's general condition improved rapidly. Therefore, it is important to take sarcoidosis into account as a differential diagnosis of acute renal failure, and kidney biopsy offers useful information in these cases. PMID- 23458178 TI - Prevalence of metabolic syndrome and its risk factors in patients with continuous ambulatory peritoneal dialysis in South China. AB - BACKGROUND: Metabolic syndrome (MS) is prevalent and widely proved as a predictor of cardiovascular disease (CVD) and Type 2 diabetes mellitus (T2DM) in general population. However, there was no large sample study concerning MS in patients on continuous ambulatory peritoneal dialysis (CAPD). We aimed to study the prevalence, risk factors of MS, and the relationship between CVD and MS in CAPD patients in South China. METHODS: This singlecenter cross-sectional study was conducted in patients on CAPD. Demographic, clinical, and anthropometric data were collected and compared between the patients with and without MS. Logistic Regression analysis was used to identify the independent risk factors of MS. RESULTS: A total of 511 CAPD patients were enrolled. Compared to patients without MS, patients with MS tended to be diabetic, female, and older. Fasting waist circumference, waist-to-hip ratio, visceral fat area, as well as white blood cell, platelet, globulin, and high sensitivity C reactive protein in peripheral blood were significantly higher in MS than in non-MS group. But diastolic blood pressure was significantly lower in patients with MS than in patients without MS. Logistic regression showed old age (OR: 1.50, p < 0.001), higher level of WBC (OR: 1.41, p < 0.001), and glucose load of dialysate (GLD) (OR: 1.50, p = 0.002) were independent associated factors of MS and MS was an independent associated factor of CVD (OR: 2.37, p < 0.001). CONCLUSIONS: MS was prevalent in CAPD patients in our center and an independent associated factor of CVD. Old age, higher levels of WBC, and GLD were associated with MS independently. PMID- 23458181 TI - Stored blood transfusion induces transient pulmonary arterial hypertension without impairing coagulation in an ovine model of nontraumatic haemorrhage. AB - BACKGROUND AND OBJECTIVES: Transfusion of blood products in particular older products is associated with patient morbidity. Previously, we demonstrated a higher incidence of acute lung injury in lipopolysaccharide-treated sheep transfused with stored blood products. As transfusion following haemorrhage is more common, we aimed to determine whether a 'first hit' of isolated haemorrhage would precipitate similar detrimental effects following transfusion and also disrupt haemostasis. MATERIALS AND METHODS: Anaesthetized sheep had 33% of their total blood volume collected into Leukotrap bags (Pall Medical), which were processed into packed red blood cells and cross-matched for transfusion into other sheep. After 30 mins, the sheep were resuscitated with either: fresh (<5 days old) or stored (35-42 days old) ovine blood followed by 4% albumin to replacement volume, albumin alone or normal saline alone and monitored for 4 h. RESULTS: The first hit of haemorrhage precipitated substantial decreases in mean arterial pressure however haemostasis was preserved. Transfusion of stored ovine blood induced (1) transient pulmonary arterial hypertension but no oedema and (2) reduced fibrinogen levels more than fresh blood, but neither induced coagulopathy. Thus, transfusion of stored blood affected pulmonary function even in the absence of overt organ injury. CONCLUSION: The fact that stored blood transfusions: (1) did not induce acute lung injury in contrast to previous lipopolysaccharide-primed animal models identifies the 'first hit' as an important determinant of the severity of transfusion-mediated injury; (2) impaired pulmonary dynamics verifies the sensitivity and vulnerability of the pulmonary system to injury. PMID- 23458182 TI - Characteristics and neural-like differentiation of mesenchymal stem cells derived from foetal porcine bone marrow. AB - MSCs (mesenchymal stem cells) are a stem cell source that can be easily obtained from bone marrow. Despite the increasing importance of the pig as a large animal model, little is known about foetal pMSCs (porcine MSCs). In this study, we observed the gene expression of pluripotent markers in foetal pMSCs and the capacity of pMSCs to differentiate into adipocytes, osteocytes and neural-like cells using quantitative RT-PCR (reverse transcription-PCR), normal histological staining and immunohistochemistry. Foetal pMSCs have either a spindle or a flattened shape, and flow cytometry revealed the expression of the MSC-related proteins CD44 and CD105 (endoglin) but not CD34 and CD45. pMSCs express pluripotent markers such as Oct4 (octamer-binding transcription factor 4) and Nanog at the protein and mRNA levels. qRT-PCR (quantitative real-time PCR) analyses revealed that pMSCs expressed nestin [for NSCs (neural stem cells)]. Immunocytochemical and RT-PCR data showed that 29% and 23% of pMSCs expressed MAP2 (microtubule-associated protein 2) for neurons and beta-tubulin III (Tuj1) for immature neurons, respectively, after induction of neural differentiation. These findings demonstrate the plasticity of pMSCs and their potential for use in cellular replacement therapy for neural diseases. PMID- 23458184 TI - Nucleolar molecular signature of pluripotent stem cells. AB - Induced pluripotent stem cells (iPSC) are generated by reprogramming somatic cells to the pluripotent state. Identification and quantitative characterization of changes in the molecular organization of the cell during the process of cellular reprogramming is valuable for stem cell research and advancement of its therapeutic applications. Here we employ quantitative Raman microspectroscopy and biomolecular component analysis (BCA) for a comparative analysis of the molecular composition of nucleoli in skin fibroblasts and iPSC derived from them. We report that the cultured fibroblasts obtained from different human subjects, share comparable concentrations of proteins, RNA, DNA, and lipids in the molecular composition of nucleoli. The nucleolar molecular environment is drastically changed in the corresponding iPSC. We measured that the transition from skin fibroblasts to iPSC is accompanied by a statistically significant increase in protein concentrations ~1.3-fold, RNA concentrations ~1.3-fold, and DNA concentrations ~1.4-fold, while no statistically significant difference was found for the lipid concentrations. The analysis of molecular vibrations associated with diverse aminoacids and protein conformations indicates that nucleoli of skin fibroblasts contain similar subsets of proteins, with prevalence of tyrosine. In iPSC, we observed a higher signal from tryptophan with an increase in the random coil and alpha helix protein conformations, indicating changes in the subset of nucleolar proteins during cell reprogramming. At the same time, the concentrations of major types of macromolecules and protein conformations in the nucleoli of iPSC and human embryonic stem cells (hESC) were found to be similar. We discuss these results in the context of nucleolar function and conclude that the nucleolar molecular content is correlated with the cellular differentiation status. The approach described here shows the potential for spectroscopically monitoring changes in macromolecular organization of the cell at different stages of reprogramming. PMID- 23458186 TI - Bis(oxazolinyl)phenyl-ligated rare-earth-metal complexes: highly regioselective catalysts for cis-1,4-polymerization of isoprene. AB - NCN-pincer (S,S)-2,6-bis(4'-isopropyl-2'-oxazolinyl)phenyl-ligated rare-earth metal dichlorides [(S,S)-Phebox-(i)Pr]LnCl2(THF)2 (Ln = Sc (1); Y (2); Dy (3); Ho (4); Tm (5); Lu (6)) were synthesized via transmetalation between [(S,S)-Phebox (i)Pr]Li and LnCl3 in THF solvent. Interestingly, treatment of LaCl3 by the same method generated tris(ligand) lanthanum complex [(S,S)-Phebox-(i)Pr]3La (7). Molecular structures of complexes 1, 2, 3, and 7 were established by single crystal X-ray diffraction study. Pincer ligand (S,S)-Phebox-(i)Pr adopts a kappaC:kappaN:kappaN' tridentate coordination mode to the central metal ion. Upon activation with [PhNHMe2][B(C6F5)4] and Al(i)Bu3, complexes 2-5 exhibited highly catalytic activities and more than 98% cis-1,4-selectivity for isoprene polymerization while complexes 1 and 6 were inactive for this reaction. When use of the catalyst system consisted of complex 2, [PhNHMe2][B(C6F5)4], and Al(i)Bu3 for isoprene polymerization, the resultant polymer has a high cis-1,4-selectivity up to 99.5%. The reaction temperature had little effect on the regioselectivity, and high cis-1,4-selectivity almost remained even at 80 degrees C. PMID- 23458185 TI - An experimental study to identify the potential role of pharmacogenomics in determining the occurrence of oxaliplatin-induced liver injury. AB - BACKGROUND: Oxaliplatin-based chemotherapy has been linked to the development of sinusoidal obstruction syndrome (SOS), which is detrimental to outcome after liver resection for colorectal liver metastases (CLM). The aim of this study was to determine how the expression of genes involved in the transport and metabolism of FOLFOX chemotherapy impacts on tissue injury in a murine model of CLM. METHODS: Experimental CLM was established in C57/B16 mice and treated with FOLFOX chemotherapy. After 3 weeks, the animals were killed and RNA extracted from liver, spleen and tumour tissue. DNA damage was assessed by immunohistochemistry for gammaH2AX. Gene expression was determined by reverse transcriptase polymerase chain reaction. RESULTS: FOLFOX treatment was associated with an increase in the number of gammaH2AX-positive cells in both the spleen (P < 0.01) and tumour tissue (P < 0.01), but not the liver. Tissue resistance to injury following FOLFOX was associated with high expression of the copper transporter ATP7B. Differences in the expression of genes related to 5-fluorouracil metabolism or DNA repair did not correlate with the severity of tissue injury. CONCLUSIONS: High levels of expression of ATP7B are associated with resistance to tissue injury following FOLFOX chemotherapy. Polymorphisms in the ATP7B gene may explain varying susceptibility to SOS among patients following oxaliplatin-based chemotherapy. PMID- 23458187 TI - A comparison of common swabbing materials for the recovery of organic and inorganic explosive residues. AB - The efficiency of solvent based extraction methods used to remove explosive residues from four different swab types was investigated. Known amounts of organic and inorganic residues were spiked onto a swab surface with acetonitrile or ethanol:water combined with ultrasonication or physical manipulation used to extract the residues from each swab. The efficiency of each procedure was then calculated using liquid chromatography-ultraviolet detection for organic residues and ion chromatography for inorganic residues. Results indicated that acetonitrile combined with physical agitation proved to be the most efficient method; returning analyte recoveries c. 95% for both alcohol based swabs and cotton balls. Inorganic residues were efficiently extracted using ethanol:water, while the use of acetonitrile followed by water significantly reduced the recovery of inorganic residues. Swab storage conditions were then investigated with results indicating decreased storage temperatures are required to retain the more volatile explosives. PMID- 23458188 TI - Types of pediatric diabetes mellitus defined by anti-islet autoimmunity and random C-peptide at diagnosis. AB - OBJECTIVE: To test the hypothesis that anti-islet autoantibody expression and random serum C-peptide obtained at diagnosis define phenotypes of pediatric diabetes with distinct clinical features. SUBJECTS: We analyzed 607 children aged <19 yr consecutively diagnosed with diabetes after exclusion of 13% of cases with secondary diabetes (e.g., cystic fibrosis related, steroid induced) and 7.3% of cases lacking measurement of C-peptide and/or autoantibodies. METHODS: Autoantibody positivity (A+) was defined as >= 1 positive out of GAD65, insulin, and ICA512 antibodies. Preserved beta-cell function (beta+) was defined as random serum C-peptide at diagnosis >= 0.6 ng/mL. Body mass index (BMI) was measured at median 1.2 months after diagnosis. Characteristics at diagnosis and 2 yr (range 18-30 months) after diagnosis were compared among groups. RESULTS: Autoantibody expression and C-peptide at diagnosis defined the following groups: A+beta- (52.1% of the children), A+beta+ (32.8%), A-beta+ (12.5%), and A-beta- (2.6%). These four groups differed in gender, race/ethnicity, and clinical characteristics at diagnosis [i.e., age, pubertal development, obesity/overweight, diabetic ketoacidosis, glycemia, and hemoglobin A1c (HbA1c)] and at 2 yr (i.e., clinical diagnosis, treatment, and HbA1c) (all p < 0.0001). Among all beta+ children, C-peptide >2 ng/mL was associated with lower HbA1c at onset (p = 0.0001) and, in the A+beta+ subgroup, with higher frequency of achieving HbA1c < 7% at 2 yr (p = 0.03). All three patients (0.7% of total) with monogenic diabetes (maturity onset diabetes of the young, MODY) were A-beta+ with C-peptide between 0.6 and 2 ng/mL. CONCLUSIONS: Anti-islet autoantibodies status and serum random C-peptide at diagnosis define four distinct phenotypes of pediatric diabetes with prognostic value. PMID- 23458189 TI - Preliminary risk assessment of radon in groundwater: a case study from Eskisehir, Turkey. AB - The aim of this study was to determine the radon concentrations in the water supplies of a residential area of central west Anatolia, Turkey. This research provides a preliminary risk assessment for inhabitants in the study area which can be applied for other regions. In 14 out of the 19 water supplies analysed, radon concentrations exceeded the maximum contaminant level (11.1 Bq l(-1)). The total annual effective doses of 10 for the wet season and 14 for the dry season out of the 19 water supplies are greater than the values recommended by EPA [Cancer Risk Coefficients for Environmental Exposure to Radionuclides, Federal Guidance Report No. 13 (US Environmental Protection Agency, Washington, DC, 1999) < http://www.epa.gov/rpdweb00/docs/federal/402-r-99-001.pdf >] (0.1 mSv a(-1)). The elevated radon concentrations in water resources are most probably linked with geological origin which contains significant amounts of radioactive minerals. PMID- 23458190 TI - Double right coronary artery and its clinical implications. AB - Congenital anomalies of the coronary arteries are present in 0.2-1.4% of the general population. These anomalies represent one of the most confusing issues in the field of cardiology and challenges for interventional cardiologists and cardiac surgeons if the anomalies are unrecognised. Double right coronary artery is one of the rarest coronary arteries. Previously, the probability of developing atherosclerotic changes in patients with a double right coronary artery was considered to be equal to that in those without it. In reality, however, a high prevalence of atherosclerotic coronary artery disease was found in patients with a double right coronary artery originating from a single ostium after our comprehensive literature search through the PubMed database. Owing to the fact that double right coronary artery is both a congenital and potentially atherosclerotic coronary artery disease at diagnosis, coronary intervention or cardiac operation is more complicated than previously believed. Individuals with a double right coronary artery may be unaware of its presence until an accidental finding during coronary angiography or cardiac operation and are at risk for unsuspected complications of atherosclerotic coronary artery disease or during cardiac operation. Therefore, it is important to obtain information on the anatomic variants of this congenital coronary anomaly in patients who are undergoing either coronary intervention, aortic root operation or myocardial revascularisation. To our knowledge, this is the first comprehensive article to discuss the anomalies and their clinical implications. PMID- 23458192 TI - Lifestyle impact on meal-induced insulin sensitization in health and prediabetes: a focus on diet, antioxidants, and exercise interventions. AB - The augmented whole-body glucose uptake response to insulin during the postprandial state is described as meal-induced insulin sensitization (MIS). MIS occurs when the presence of food in the upper gastrointestinal tract activates 2 feeding signals (activation of hepatic parasympathetic nerves and elevation of hepatic glutathione level), and causes insulin to release hepatic insulin sensitizing substance (HISS), which stimulates glucose uptake in skeletal muscle, heart, and kidneys. HISS action results in nutrient storage, primarily as glycogen. Impairment of HISS release results in the absence of meal-induced insulin sensitization (AMIS), which causes postprandial hyperglycemia and hyperinsulinemia, and chronically leads to the progression to a cluster of metabolic, vascular, and cardiac dysfunctions, which we refer to as components of the AMIS syndrome. Manipulation of the MIS process in health and in disease, by pharmacological and nonpharmacological interventions, is outlined in this review. High fat or sugar supplemented diet reduces MIS; exercise elevates MIS; and antioxidants protect MIS against reductions associated with diet and age. PMID- 23458191 TI - Comparison of sensory neuron growth cone and filopodial responses to structurally diverse aggrecan variants, in vitro. AB - Following spinal cord injury, a regenerating neurite encounters a glial scar enriched in chondroitin sulfate proteoglycans (CSPGs), which presents a major barrier. There are two points at which a neurite makes contact with glial scar CSPGs: initially, filopodia surrounding the growth cone extend and make contact with CSPGs, then the peripheral domain of the entire growth cone makes CSPG contact. Aggrecan is a CSPG commonly used to model the effect CSPGs have on elongating or regenerating neurites. In this study, we investigated filopodia and growth cone responses to contact with structurally diverse aggrecan variants using the common stripe assay. Using time-lapse imaging with 15-s intervals, we measured growth cone area, growth cone width, growth cone length, filopodia number, total filopodia length, and the length of the longest filopodia following contact with aggrecan. Responses were measured after both filopodia and growth cone contact with five different preparations of aggrecan: two forms of aggrecan derived from bovine articular cartilage (purified and prepared using different techniques), recombinant aggrecan lacking chondroitin sulfate side chains (produced in CHO-745 cells) and two additional recombinant aggrecan preparations with varying lengths of chondroitin sulfate side chains (produced in CHO-K1 and COS-7 cells). Responses in filopodia and growth cone behavior differed between the structurally diverse aggrecan variants. Mutant CHO-745 aggrecan (lacking chondroitin sulfate chains) permitted extensive growth across the PG stripe. Filopodia contact with the CHO-745 aggrecan caused a significant increase in growth cone width and filopodia length (112.7% +/- 4.9 and 150.9% +/- 7.2 respectively, p<0.05), and subsequently upon growth cone contact, growth cone width remained elevated along with a reduction in filopodia number (121.9% +/- 4.2; 72.39% +/- 6.4, p<0.05). COS-7 derived aggrecan inhibited neurite outgrowth following growth cone contact. Filopodia contact produced an increase in growth cone area and width (126.5% +/- 8.1; 150.3% +/- 13.31, p<0.001), and while these parameters returned to baseline upon growth cone contact, a reduction in filopodia number and length was observed (73.94% +/- 5.8, 75.3% +/- 6.2, p<0.05). CHO-K1 derived aggrecan inhibited neurite outgrowth following filopodia contact, and caused an increase in growth cone area and length (157.6% +/- 6.2; 117.0% +/- 2.8, p<0.001). Interestingly, the two bovine articular cartilage aggrecan preparations differed in their effects on neurite outgrowth. The proprietary aggrecan (BA I, Sigma-Aldrich) inhibited neurites at the point of growth cone contact, while our chemically purified aggrecan (BA II) inhibited neurite outgrowth at the point of filopodia contact. BA I caused a reduction in growth cone width following filopodia contact (91.7% +/- 2.5, p<0.05). Upon growth cone contact, there was a further reduction in growth cone width and area (66.4% +/- 2.2; 75.6% +/- 2.9; p<0.05), as well as reductions in filopodia number, total length, and max length (75.9% +/- 5.7, p<0.05; 68.8% +/- 6.0; 69.6% +/- 3.5, p<0.001). Upon filopodia contact, BA II caused a significant increase in growth cone area, and reductions in filopodia number and total filopodia length (115.9% +/- 5.4, p<0.05; 72.5% +/- 2.7; 77.7% +/- 3.2, p<0.001). In addition, filopodia contact with BA I caused a significant reduction in growth cone velocity (38.6 nm/s +/- 1.3 before contact, 17.1 nm/s +/- 3.6 after contact). These data showed that neuron morphology and behavior are differentially dependent upon aggrecan structure. Furthermore, the behavioral changes associated with the approaching growth cone may be predictive of inhibition or growth. PMID- 23458193 TI - Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity. AB - This study investigated the effect of aldose reductase (AR) inhibitors on hypertension in diabetes. Diabetes was induced with streptozotocin, while AR inhibitors zopolrestat and ferulic acid were administered at 2 weeks after streptozotocin treatment and for 6 weeks afterwards. Then, blood pressure (BP) and serum level of glucose were determined. Concentration-response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) were obtained in isolated aorta. In addition, ACh-induced NO and reactive oxygen species (ROS) generation in aorta and histopathology were examined. Compared with the control animals, diabetes increased diastolic and systolic BP. AR inhibitors reduced diastolic BP elevation without affecting the developed hyperglycaemia. Diabetes increased the contractile response of aorta to KCl, and decreased the relaxation response to Ach, while administering AR inhibitors prevented an impaired response to ACh. Incubation of aorta isolated from diabetic animals with AR inhibitors did not affect the impaired relaxation response to ACh. In addition, AR inhibitors negated the impaired Ach-stimulated NO generation seen in aorta isolated from diabetic animals. Furthermore, diabetes was accompanied with marked infiltration of leukocytes in aortic adventitia, endothelial cell pyknosis, and increased ROS formation. AR inhibitors reduced leukocyte infiltration and inhibited endothelial pyknosis and ROS formation. In conclusion, AR inhibitors negate diabetes-evoked hypertension via ameliorating impaired endothelial relaxation and NO production. PMID- 23458194 TI - Magnesium orotate elicits acute cardioprotection at reperfusion in isolated and in vivo rat hearts. AB - Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia-reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and MgCl2 treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R. PMID- 23458195 TI - Kalpaamruthaa ameliorates myocardial and aortic damage in cardiovascular complications associated with type 2 diabetes mellitus. AB - Myocardial and aortic damage in cardiovascular complications (CVD) associated with type 2 diabetes mellitus and the protective efficacy of Kalpaamruthaa (KA) are evaluated in this study. CVD developed in 8 weeks after type 2 diabetes mellitus was induced by the administration of a high-fat diet for 2 weeks, and then with streptozotocin (2 * 35 mg.(kg body mass)(-1), by intraperitonal injection, at 24 h intervals) in male Sprague-Dawley rats. CVD-induced rats were treated with KA at 200 mg.(kg body mass)(-1).(day)(-1) orally for 28 days. Increased oxidative stress in CVD-induced rats lowers antioxidant defense in the aorta. Treatment with KA reduced oxidative stress by increasing antioxidant status with decreased lipid peroxides in CVD-induced rats. Histological examination of the myocardium and aorta provided support for the cytoprotective effect of KA in CVD. Ultrastructural changes in the myocardium of CVD-induced rats were improved by KA treatment. Aortic damage was observed through decreased endothelial nitric oxide synthase and increased NADPH oxidase mRNA expressions in CVD-induced rats. KA reduced the aortic damage by ameliorating these levels back to normal. KA treatment reduced the pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin 6 in CVD-induced rats. Immunohistochemical expressions of matrix metalloproteinase-2 and -9 were observed to be elevated in the myocardium of CVD-induced rats, but these were decreased by the administration of KA. This study demonstrates the cardiovascular protective effect of KA in type 2 diabetes. PMID- 23458196 TI - Abnormal amounts of intracellular calcium regulatory proteins in SHRSP.Z Lepr(fa)/IzmDmcr rats with metabolic syndrome and cardiac dysfunction. AB - Metabolic syndrome is known to increase the risk of abnormal cardiac structure and function, which are considered to contribute to increased incidence of cardiovascular disease and mortality. We previously demonstrated that ventricular hypertrophy and diastolic dysfunction occur in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP fatty) rats with metabolic syndrome. The aim of this study was to investigate the possible mechanisms underlying abnormal heart function in SHRSP fatty rats. The amount of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) 2a, phospholamban (PLB) protein, and Ser(16)-phosphorylated PLB was decreased in cardiomyocytes from SHRSP fatty rats compared with those from control Wistar-Kyoto rats at 18 weeks of age, and the PLB-to-SERCA2a ratio was increased. Left ventricular developed pressure was unchanged, and coronary flow rate and maximum rate of left ventricular pressure decline (-dP/dt) was decreased in SHRSP fatty rats. Treatment with telmisartan reversed the abnormalities of PLB amount, coronary flow rate, and -dP/dt in SHRSP fatty rats. These results indicate that abnormal amounts of intracellular Ca(2+) regulatory proteins in cardiomyocytes, leading to reduced intracellular Ca(2+) reuptake into the sarcoplasmic reticulum, may play a role in the diastolic dysfunction in SHRSP fatty rats and that these effects are partially related to decreased coronary circulation. Telmisartan may be beneficial in protecting against disturbances in cardiac function associated with metabolic syndrome. PMID- 23458197 TI - Oral treatment with gallic acid and quercetin alleviates lindane-induced cardiotoxicity in rats. AB - Lindane is a man-made organochlorine pesticide used for agricultural purposes. Since lindane-induced toxicity is mediated by free radical generation, this investigation was carried out to study the protective effects of gallic acid and quercetin against lindane-induced cardiotoxicity. Lindane (100 mg.(kg body mass)( 1)) was administered orally to rats for 30 days. Histological analysis revealed pathological changes in the heart of lindane-treated rats. Biochemical analysis of the lindane-treated animals showed elevated activity for serum marker enzymes, lipid peroxidation (LPO), and membrane-bound Ca(2+) ATPase, with a concomitant decrease in the level of non-enzymic antioxidant (GSH), enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase (GPx), and glutathione S-transferase (GST), and membrane-bound ATPases like Na(+)/K(+) ATPase and Mg(2+) ATPase in heart tissue. The results suggest that gallic acid and quercetin offer protection against lindane-induced myocardial damage, possibly through maintaining levels of endogenous antioxidant enzymes and membrane bound ATPase activity, as well as inhibiting lipid peroxidation. PMID- 23458198 TI - Suppression of LPS-induced inflammatory responses by inflexanin B in BV2 microglial cells. AB - Microglia are a type of resident macrophage that functions as an inflammation modulator in the central nervous system. Over-activation of microglia by a range of stimuli disrupts the physiological homeostasis of the brain, and induces inflammatory response and degenerative processes, such as those implicated in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, we investigated the possible anti-inflammatory mechanisms of inflexanin B in murine microglial BV2 cells. Lipopolysaccharide (LPS) activated BV2 cells and induced the production of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and cytokines (interleukins-1beta and -6, and tumour necrosis factor alpha). The LPS-induced production of pro-inflammatory mediators was associated with the enhancement of nuclear factor-kappaB (NF kappaB) nuclear translocation and the activation of mitogen-activated protein kinase (MAPK) including ERK1/2 and JNK. Conversely, pretreatment of cells with inflexanin B (10 and 20 MUg/mL) significantly reduced the production of pro inflammatory mediators. This was accompanied with the reduced nuclear translocation of NF-kappaB and reduced activation of MAPKs. These results suggest that inflexanin B attenuated the LPS-induced inflammatory process by inhibiting the activation of NF-kappaB and MAPKs. PMID- 23458199 TI - Beneficial influence of fungal metabolite nigerloxin on diabetes-induced oxidative stress in experimental rats. AB - Oxidative stress plays a key role in the progression of diabetes and its complications. In this study, the beneficial influence of the fungal metabolite nigerloxin, a new aldose reductase inhibitor and a free-radical scavenger, was investigated on oxidative stress in streptozotocin-induced diabetic rats. Groups of diabetic rats were orally administered nigerloxin for 30 days at a dose of 25 and 100 mg.(kg body mass)(-1).day(-1). Diabetic rats showed significantly increased lipid peroxide levels in blood and liver, which was accompanied by lowered concentrations of antioxidant molecules and activities of antioxidant enzymes in blood and liver. Administration of nigerloxin for 30 days at a daily dose of 100 mg?(kg body mass)(-1) to diabetic rats significantly decreased plasma and liver lipid peroxides, elevated the nonenzymatic antioxidants ascorbic acid, reduced glutathione, and total thiols, and elevated the activities of antioxidant enzymes in blood and liver. Nigerloxin showed a tendency to counter lipid abnormalities in diabetic animals, while fasting glucose and body mass were unaffected by nigerloxin treatment. Thus, this animal study has indicated the beneficial influence of nigerloxin on oxidative stress associated with diabetes that may have an implication in delaying or ameliorating the secondary complications. PMID- 23458200 TI - Connexins and steroidogenesis in mouse Leydig cells. AB - Connexin43 has been recognized as forming gap junctions in Leydig cells. However, previous work has shown that mouse Leydig cells lacking this connexin do not suffer any limitation of their ability to produce testosterone when stimulated with luteinizing hormone. The objective of this study was to identify additional connexins in mouse Leydig cells that could be required for steroidogenesis. A reverse transcription - polymerase chain reaction screen involving isolated adult Leydig cells identified connexin36 and connexin45 as expressed along with connexin43. Treatment of dissociated testes with carbenoxolone, a nonspecific blocker of gap junctional coupling, significantly reduced testosterone output as did treatment with quinine, which disrupts coupling provided by connexin36 and connexin45 gap junctions but not those composed of connexin43, indicating that either or both of connexins 36 and 45 could be involved in supporting Leydig cell steroidogenesis. Immunolabeling of adult mouse testis sections confirmed the localization of connexin36 along with connexin43 in Leydig cell gap junctions but not connexin45, which is distributed throughout the cells. It was concluded that connexin36, connexin43, and connexin45 are coexpressed in Leydig cells with connexins 36 and 43 contributing to gap junctions. The role of connexin45 remains to be elucidated. PMID- 23458201 TI - Coenzyme Q(10) and selenium in statin-associated myopathy treatment. AB - The objective of this study was to evaluate the possible benefits of coenzyme Q10 and selenium supplementation administered to patients with statin-associated myopathy (SAM). Sixty eligible patients entered the pilot study. Laboratory examination (CoQ10, selenium, creatin kinase) and intensity of SAM (visual scale) were performed at baseline, after 1 month, and at the end of study at month 3. Plasma levels of CoQ10 increased from 0.81 +/- 0.39 to 3.31 +/- 1.72 MUmol/L in the active group of patients treated by CoQ10, compared with the placebo (p = 0.001). Also, the symptoms of SAM significantly improved in the active group (p < 0.001): the intensity of muscle pain decreased from 6.7 +/- 1.72 to 3.2 +/- 2.1 (p < 0.01, -53.4 +/- 28.2%); muscle weakness decreased from 7.0 +/- 1.63 to 2.8 +/- 2.34 (p < 0.01, -60 +/- 24.0%); muscle cramps decreased from 5.33 +/- 2.06 to 1.86 +/- 2.42, p < 0.01, -65 +/- 28%); tiredness decreased from the initial 6.7 +/- 1.34 to 1.2 +/- 1.32 (p < 0.01, -82 +/- 22%). We did not observe any significant changes in the placebo group. In conclusion, supplementation of statin-treated patients with CoQ10 resulted in a decrease in the symptoms of SAM, both in absolute numbers and intensity. Additional selenium supplementation was not associated with any statistically significant decrease of SAM. However, it is not possible to draw any definite conclusions, even though this study was carried out in double-blind fashion, because it involved a small number of patients. PMID- 23458202 TI - Influence of treatment with quercetin on lipid parameters and oxidative stress of pregnant diabetic rats. AB - Among the numerous coadjuvant therapies that could influence the incidence and progression of diabetic complications, antioxidants and flavonoids are currently being tested in clinical trials. We investigated the effect of quercetin on biochemical parameters in streptozotocin-induced (60 mg/kg body mass, by intraperitoneal injection) diabetic rats. A total of 32 female Wistar rats were distributed among 4 groups as follows: control (G1); control treated with quercetin (G2); diabetic (G3); and diabetic treated with quercetin (G4). Quercetin administered to pregnant diabetic rats controlled dyslipidemia and improved lipid profiles in diabetes mellitus, regulated oxidative stress by reducing the generation of lipid hydroperoxides, and increased the activity of the antioxidant enzyme glutathione peroxidase. PMID- 23458203 TI - Prediction of hepatic plasma clearance in vivo from gel-entrapped rat and human hepatocytes. AB - This paper aimed to evaluate the applicability of gel-entrapped rat and human hepatocytes in the prediction of hepatic plasma clearance (CLh,plasma) in vivo. The in vitro intrinsic clearances (CLint,in vitro) for the selected compounds were determined from the substrate disappearance rate, and further used to predict CLh,plasma using 3 classical mathematical models (well-stirred, parallel tube, and dispersion) and disregarding drug binding. As a result, the predicted values from gel-entrapped rat hepatocytes were mostly within 2 SE of the literature data with a high correlation coefficient (R(2)) of 0.88-0.91. The predicted data with human hepatocytes also fitted well with the clinical data, indicating a high accuracy in prediction of in-vivo clearance. With respect to the mathematical model for predicting CLh,plasma, the parallel-tube and dispersion models produced a better prediction than the well-stirred model, and we suggest using the parallel-tube model because it is less complex mathematically. In conclusion, gel-entrapped hepatocytes predicted the drug clearance well and seemed to be a useful tool in the process of drug discovery. PMID- 23458204 TI - The effect of acetaminophen ingestion on cortico-spinal excitability. AB - Acetaminophen (ACT) facilitates the inhibition of voltage-gated calcium and sodium currents, which may effect cortico-spinal excitability. Twelve subjects ingested acetaminophen or a placebo and underwent transcranial magnetic stimulation to assess the motor evoked potential (MEP), and cortical silent period (CSP). ACT significantly increased MEP response (P > 0.05) but had no effect on CSP (P > 0.05). This indicates that ACT increases MEP and should be controlled for in studies where these measures are of interest. PMID- 23458206 TI - Response to patient-initiated plant extract treatment for atopic dermatitis. AB - Ethnomedical practices are increasing in all parts of the world, including many urban centers. We describe a unique case of a 7-year-old girl with atopic dermatitis who was responsive to parent-initiated treatment with the extract of a plant from the Chenopodium genus. A brief discussion raises awareness of such practices to the practicing dermatologist. PMID- 23458207 TI - The impact of transvenous cardiac devices on vascular access patency in hemodialysis patients. AB - Creating a vascular access in the presence of a cardiovascular implantable electronic device (CIED) in a patient with or approaching end-stage renal disease can be challenging. In this study, we aimed to evaluate the impact of a CIED on the outcomes of vascular access creation in hemodialysis patients and determine their effects on vascular access patency. This is a single-center retrospective review of hemodialysis patients who underwent vascular access creation after CIED placement. Outcomes of vascular access creation and need for endovascular interventions were compared between patients with vascular access created ipsilateral and contralateral to the site of CIED. Comparing patients with arteriovenous (AV) access created ipsilateral to CIED placement (n=19) versus the contralateral side (n=17), the primary failure rate was 78.9% versus 35.3% (p=0.02). For AV accesses that were matured, the median primary patency durations for AV accesses created ipsilateral to the CIED was 11.2 months compared to 7.8 months for AV accesses created contralateral to the CIED (p=1.00). AV accesses created ipsilateral to a CIED have a higher primary failure rate compared with the contralateral arm and should be avoided as much as possible. PMID- 23458208 TI - Does pre-operative chemoradiation for initially unresectable or borderline resectable pancreatic adenocarcinoma increase post-operative morbidity? A case matched analysis. AB - BACKGROUND: Neoadjuvant chemoradiation therapy for locally unresectable and borderline resectable pancreatic cancer may allow some patients to a undergo a resection, but whether or not this increases post-operative morbidity remains unclear. METHODS: The post-operative morbidity of 29 patients with initially locally unresectable/borderline pancreatic cancer who underwent a resection were compared with 29 patients with initially resectable tumours matched for age, gender, the presence of comorbidities (yes/no), American Society of Anesthesiology (ASA) score, tumour location (head/body-tail), procedure (pancreaticoduodenectomy/distal pancreatectomy) and vascular resection (yes /no). Wilcoxon's signed ranks test was used for continuous variables and McNemar's chi square test for categorical variables. RESULTS: Compared with patients with initially resectable tumours, patients who underwent a resection after pre operative chemoradiation therapy had similar rates of overall post-operative complications (55% versus 41%, P = 0.42), major complications (21% versus 21%, P = 1), pancreatic leaks and fistulae (7% versus 10%, P = 1) and mortality (0% versus 1.7%, P = 1). CONCLUSION: Although some previous studies have suggested differences in post-operative morbidity after chemoradiation, our case-matched analysis did not find statistical differences in surgical morbidity and mortality associated with pre-operative chemoradiation therapy. PMID- 23458209 TI - Relaparotomy for a pancreatic fistula after a pancreaticoduodenectomy: a comparison of different surgical strategies. AB - INTRODUCTION: A relaparotomy for a pancreatic fistula (PF) after a pancreaticoduodenectomy (PD) is a formidable operation, and the appropriate treatment of anastomotic leakage is under debate. The objective of this study was to compare the outcomes of different strategies in managing the pancreatic remnant during a relaparotomy for PF after a PD. METHODS: In this retrospective study on prospectively collected data, 669 PD were performed between 2004 and 2011. The study group comprised 31 patients requiring a relaparotomy, because of delayed haemorrhage (n = 19) or sepsis (n = 12). The pancreatic stump was treated either using pancreas-preserving techniques (simple drainage or duct occlusion) or completion of a pancreatectomy (CP). In 2008, autologous islet transplantation (AIT) was introduced for endocrine tissue rescue of CP. RESULTS: The mortality rate, blood loss and transfusion requirement were similar for all techniques. Patients undergoing a CP required a further relaparotomy less frequently than patients with pancreas preservation (7% versus 59%, P < 0.01), and the intensive care unit (ICU) stay was reduced after CP (P = 0.058). PF persisted at discharge in 66% of patients after pancreas-preserving techniques. AIT was associated with CP in 7 patients, of whom one died post-operatively. Long-term graft function was maintained in four out of six surviving patients, with one insulin-independent patient at 36 months after transplantation. CONCLUSIONS: When a PF requires a relaparotomy, CP has become our favoured technique. AIT can reduce the metabolic impact of the procedure. PMID- 23458211 TI - Linear and nonlinear optical characterization of aluminum nanoantennas. AB - We experimentally determine the order of multiphoton induced luminescence of aluminum nanoantennas fabricated on a nonconductive substrate using electron-beam lithography to be 2.11 (+/-0.10). Furthermore, we optically characterize these nanostructures via linear dark-field microscopy and nonlinear multiphoton laser excitation. We hereby observe different spectral response functions that can be seen as a splitting of peak positions when the antenna arm length is increased to Larm > 150 nm which has not yet been reported for aluminum nanostructures. PMID- 23458210 TI - Molecular epidemiology of HIV type 1 subtypes in Rwanda. AB - HIV-1 infection is characterized by genetic diversity, with multiple subtypes and recombinant variants circulating, particularly in sub-Saharan Africa. During the Rwandan genocide, many women experienced multiple rapes and some became HIV-1 infected. We studied plasma and peripheral blood mononuclear cells (PBMCs) from 30 infected women comprising two exposure groups: those with numerous contacts, raped multiple times, and women with one lifetime sexual partner and no history of rape. Population-based sequences from gag, pol, and env genes were analyzed to determine HIV-1 subtypes and intersubtype recombination. Individual plasma derived variants from 12 women were also analyzed. Subtype A was found in 24/30 (80%), intersubtype recombination (AC and AD) in 4/30 (13%), and subtypes C and D in 1/30 each. In two subjects, the pattern of HIV-1 recombination differed between plasma and PBMC-derived sequences. Intersubtype recombination was common, although there were no significant differences in subtype or recombination rates between exposure groups. PMID- 23458212 TI - Comparing embodied greenhouse gas emissions of modern computing and electronics products. AB - Information and communications technology (ICT) contributes substantially to global greenhouse gas (GHG) pollutant emissions, but it is time-consuming to estimate the environmental impacts caused by the production of ICT devices, and the literature lacks coverage for newer products. Using a process-sum life cycle assessment (LCA) approach, we estimate and compare the embodied GHG emissions of 11 ICT products, including large- and small-form-factor desktop and laptop personal computers, a thin client device, an LCD monitor, newer mobile devices (an Apple iPad, an iPod Touch, and an Amazon Kindle), a rack server, and a network switch. Full bills of materials are provided via hand disassembly and weighing and are mapped to processes in the ecoinvent v2.2 database to produce impact estimates. Results are analyzed to develop simplified impact estimation models using linear regressions based on product characteristics. A simple and robust linear relationship between mass and embodied emissions is identified; a more sophisticated linear model using display mass, battery mass, and circuit board mass as inputs is slightly more accurate. Embodied GHG emissions for newer products are 50-60% lower than corresponding older products with similar functionality, largely due to decreased material usage, especially reductions in integrated circuit content. PMID- 23458213 TI - Pregnancy and normal sexual function. Are they compatible? PMID- 23458215 TI - Gay saunas and the risks of HIV and syphilis transmissions in China--results of a meta-analysis. AB - INTRODUCTION: Previous studies suggest the risk of human immunodeficiency virus (HIV) transmission among men who have sex with men (MSM) is associated with characteristics of venues. However, very few studies have systematically compared HIV/sexually transmitted disease (STD) prevalence among MSM according to key venue type for sourcing sex partners. AIMS: The aim of this study was to investigate the associations between HIV/syphilis prevalence and the types of venues, namely saunas, parks, gay bars, and the Internet, which are mostly used for sourcing male sex partners by MSM in China. METHODS: Meta-analyses using fixed-effect and random-effect methods were conducted. Secondary data were obtained from 10 concurrent surveys conducted in 10 cities basing on a common protocol. Pairwise comparisons (e.g., "saunas" vs. "parks") were made. MAIN OUTCOMES MEASURES: Odds ratios (OR) for HIV/syphilis infection in relations to venue type for partner sourcing. RESULTS: The distribution of the most commonly used source to recruit male sex partner was 59.32% (Internet), 18.47% (gay bars), 14.18% (gay saunas), and 8.02% (parks). The median prevalence of HIV/syphilis was 10.49% and 19.38% (gay saunas), 2.12% and 16.25% (parks), 6.06% and 15.45% (Internet), and 4.41% and 11.90% (gay bars). We found significant between-group differences when comparing "sauna" against "Internet" (HIV: OR= 2.27, 95% confidence interval [CI] = 1.65-3.12; syphilis: OR = 1.61, 95% CI= 1.07-2.41), "sauna" against "bars" (HIV: OR= 1.65, 95% CI= 1.14-2.39; syphilis: OR= 1.35, 95% CI= 1.02-1.78), and "parks" against "Internet" (syphilis: OR= 1.55, 95% CI= 1.12 2.15) as the main source to recruit male sex partners. Other pairwise comparisons were not statistically significant. CONCLUSIONS: The results of this study suggest that those sourcing partners mainly from gay saunas have higher prevalence of HIV/syphilis when compared with those doing so via the Internet or gay bars. Venue based (sauna-based) interventions using socio-ecological approaches are greatly warranted in order to reduce HIV and syphilis prevalence among MSM in China. PMID- 23458217 TI - Focusing on breast cancer overdiagnosis and overtreatment: the promise of molecular medicine. PMID- 23458218 TI - Primary large-cell neuroendocrine tumor of the breast. PMID- 23458219 TI - Should we manage all cases of granulomatous mastitis conservatively? A 14 year experience. PMID- 23458220 TI - Clinical experience using accelerated partial breast irradiation for ductal carcinoma in situ. PMID- 23458221 TI - Breast imaging: understanding how accuracy is measured when lesion are the unit of analysis. PMID- 23458222 TI - Response to the "letter to the editor" by Dr. Thomas Filleron. PMID- 23458223 TI - Low-resolution structure of the soluble domain GPAA1 (yGPAA170-247) of the glycosylphosphatidylinositol transamidase subunit GPAA1 from Saccharomyces cerevisiae. AB - The GPI (glycosylphosphatidylinositol) transamidase complex catalyses the attachment of GPI anchors to eukaryotic proteins in the lumen of ER (endoplasmic reticulum). The Saccharomyces cerevisiae GPI transamidase complex consists of the subunits yPIG-K (Gpi8p), yPIG-S (Gpi17p), yPIG-T (Gpi16p), yPIG-U (CDC91/GAB1) and yGPAA1. We present the production of the two recombinant proteins yGPAA170 247 and yGPAA170-339 of the luminal domain of S. cerevisiae GPAA1, covering the amino acids 70-247 and 70-339 respectively. The secondary structural content of the stable and monodisperse yGPAA170-247 has been determined to be 28% alpha helix and 27% beta-sheet. SAXS (small-angle X-ray scattering) data showed that yGPAA170-247 has an R(g) (radius of gyration) of 2.72+/-0.025 nm and D(max) (maximum dimension) of 9.14 nm. These data enabled the determination of the two domain low-resolution solution structure of yGPAA170-247. The large elliptical shape of yGPAA170-247 is connected via a short stalk to the smaller hook-like domain of 0.8 nm in length and 3.5 nm in width. The topological arrangement of yGPAA170-247 will be discussed together with the recently determined low resolution structures of yPIG-K24-337 and yPIG-S38-467 from S. cerevisiae in the GPI transamidase complex. PMID- 23458224 TI - Effects of different substituents on the crystal structures and antimicrobial activities of six Ag(I) quinoline compounds. AB - The syntheses and single crystal X-ray structures of [Ag(5-nitroquinoline)2]NO3 (1), [Ag(8-nitroquinoline)2]NO3.H2O (2), [Ag(6-methoxy-8-nitroquinoline)(NO3)]n (3), [Ag(3-quinolinecarbonitrile)(NO3)]n (4), [Ag(3-quinolinecarbonitrile)2]NO3 (5), and [Ag(6-quinolinecarboxylic acid)2]NO3 (6) are described. As an alternative to solution chemistry, solid-state grinding could be used to prepare compounds 1 and 3, but the preparation of 4 and 5 in this way failed. The Ag(I) ions in the monomeric compounds 1, 2, 5, and 6 are coordinated to two ligands via the nitrogen atoms of the quinoline rings, thereby forming a distorted linear coordination geometry with Ag-N bond distances of 2.142(2)-2.336(2) A and N-Ag-N bond angles of 163.62(13) degrees -172.25(13) degrees . The 1D coordination polymers 3 and 4 contain Ag(I) centers coordinating one ligand and two bridging nitrate groups, thereby forming a distorted trigonal planar coordination geometry with Ag-N bond distances of 2.2700(14) and 2.224(5) A, Ag-O bond distances of 2.261(4)-2.536(5) A, and N-Ag-O bond angles of 115.23(5) degrees -155.56(5) degrees . Hirshfeld surface analyses of compounds 1-6 are presented as d(norm) and curvedness maps. The d(norm) maps show different interaction sites around the Ag(I) ions, i.e., Ag...Ag interactions and possible O-H...O, C-H...O, C-H...N, and C-H...C hydrogen bonds. Curvedness maps are a good way of visualizing pi-pi stacking interactions between molecules. The antimicrobial activities of compounds 1, 2, and 6 were screened against 15 different multidrug-resistant strains of bacteria isolated from diabetic foot ulcers and compared to the antimicrobial activities of the clinically used silver sulfadiazine (SS). Compound 2 showed activity similar to SS against this set of test organisms, being active against all strains and having slightly better average silver efficiency than SS (5 vs 6 MUg Ag/mL). Against the standard nonresistant bacterial strains of Staphylococcus aureus , Pseudomonas aeruginosa , Proteus mirabilis , and Streptococcus pyogenes , compound 1 performed better than silver nitrate, with an average MIC of 6 MUg Ag/mL versus 18 MUg Ag/mL for the reference AgNO3. Electrospray ionization mass spectrometry (ESI-MS) analyses of compounds 3 and 6 in DMSO/MeOH confirm the two-coordinated Ag(+) complexes in solution, and the results of the (1)H NMR titrations of DMSO solutions of 5-nitroquinoline and 8-nitroquinoline with AgNO3 in DMSO suggest that 5-nitroquinoline is more strongly coordinated to the silver ion. PMID- 23458225 TI - Time to onset of analgesia following local infiltration of liposome bupivacaine in healthy volunteers: a randomized, single-blind, sequential cohort, crossover study. AB - BACKGROUND/OBJECTIVE: Bupivacaine liposome injectable suspension is a novel, prolonged-release formulation of bupivacaine. The time to onset of analgesia following an injection of liposome bupivacaine compared with placebo (normal saline) was investigated using a novel incisional pain model. Bupivacaine HCl was used as a positive control, compared with placebo to verify the validity of the study. MATERIALS AND METHODS: In this Phase 1, single-blind, crossover study, healthy volunteers (n = 132) were randomized to four sequential cohorts to receive subcutaneous normal saline in one arm and either liposome bupivacaine 40 mg or bupivacaine HCl 7.5 mg in the other. At 30, 15, 5, and 2 minutes after study drug administration for Cohorts 1 - 4 respectively, an incision was made in each arm and 18% acetic acid solution was applied to elicit pain. The primary outcome measure was a subject's assessment of pain intensity on a 100 mm visual analog scale. RESULTS: Statistically significant differences in pain intensity scores between liposome bupivacaine and normal saline were observed at 30, 15, 5, and 2 minutes postdose; similar findings were reported for bupivacaine HCl vs. normal saline. Both liposome bupivacaine and bupivacaine HCl were well tolerated and achieved > 30% pain reduction, normalized to placebo, within 5 minutes. CONCLUSIONS: These results indicate that liposome bupivacaine offers time to onset characteristics similar to traditional bupivacaine HCl: clinically meaningful analgesia within 2 minutes after administration and substantial analgesia by 5 minutes. PMID- 23458226 TI - The effect of food on the absorption and pharmacokinetics of rivaroxaban. AB - OBJECTIVE: Doses of 10 mg, 15 mg, and 20 mg of rivaroxaban are approved for the treatment and prevention of thromboembolic disorders in adult patients. In six Phase I studies, the pharmacokinetics, safety, and tolerability of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg rivaroxaban were investigated in healthy male subjects, and the influence of food on these parameters was investigated for the 10 mg, 15 mg, and 20 mg tablet doses. In addition, an oral suspension containing 1 mg/ml rivaroxaban, which is under investigation for future use in the pediatric population, was investigated at doses of 10 mg and 20 mg. MATERIALS: Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany. METHODS: Six independent, single-dose, cross-over studies were performed in healthy male subjects (between 13 and 24 subjects were enrolled in each study) to determine the pharmacokinetics, safety, and tolerability of rivaroxaban under fasting and fed conditions. Study 1 was an absolute bioavailability study that compared 5 mg and 20 mg tablet doses with a 1 mg intravenous solution. Studies 2 and 3 were confirmatory food-effect studies that assessed 10 mg and 20 mg tablet doses, respectively, under fed and fasting conditions. Study 4 was a formulation study that evaluated oral suspensions of 10 mg (fasting) and 20 mg (fasting and fed) rivaroxaban vs. a 10 mg tablet (fasted). Study 5 was a dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg tablets under fasting conditions. Study 6 was a dose-proportionality study that assessed tablet doses of 10 mg, 15 mg, and 20 mg under fed conditions. Pharmacokinetic parameters, including the area under the plasma concentration-time curve after a single dose, the maximum drug concentration in plasma after a single dose, dose-adjusted values of area under the plasma concentration-time curve and maximum drug concentration in plasma after a single dose, half-life associated with the terminal slope, and time to maximum concentration in plasma after a single dose were evaluated. Adverse events were classified according to their degree of severity and were summarized using Medical Dictionary for Regulatory Activities preferred terms. RESULTS: At all doses, rivaroxaban showed an acceptable safety profile and was well tolerated in healthy individuals. Independent of food and formulation, pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability (>= 80%). Under fasting conditions, pharmacokinetic parameters of 15 mg and 20 mg rivaroxaban increased with dose but were less than dose proportional. However, when taken with food, high bioavailability (>= 80%) of these doses was achieved independent of formulation. CONCLUSION: Pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability independent of food or whether administered as tablet or solution. High bioavailability (>= 80%) of 15 mg and 20 mg rivaroxaban was achieved when taken with food; therefore, these doses need to be taken with food. PMID- 23458227 TI - Impact of allergic rhinitis and its treatment on the pharmacokinetics of nasally administered fentanyl. AB - OBJECTIVES: Fentanyl pectin nasal spray (FPNS, Lazanda(r) in the US and PecFent(r) in Europe and Australia) is a novel analgesic approved for the management of breakthrough pain in cancer patients. Given that the fentanyl is nasally administered, it is important to understand whether concomitant allergic rhinitis, or its treatment with a vasoconstrictor, would affect its absorption and, potentially, its efficacy or safety. METHODS AND SUBJECTS: Subjects with a history of allergic rhinitis were screened to identify subjects who developed at least moderate rhinitis symptoms on exposure to pollen allergen (either ragweed or tree) in an environmental exposure chamber (EEC). These were entered into a randomized, three-way crossover study in which each subject received 100 MUg of FPNS under three exposure conditions; Control (no rhinitis), Rhinitis (symptomatic without decongestant), Treated (symptomatic with concomitant oxymetazoline). Blood samples for fentanyl were collected over a 24-hour period. RESULTS: A total of 132 subjects was screened to identify 54 for inclusion in the study; 31 were evaluable for pharmacokinetics. Measures of fentanyl absorption (mean or median) were similar between Control and Rhinitis conditions: Cmax 453.0 vs. 467.8 pg/ml; AUCt 1,292.3 vs. 1,325.4 pg*h/ml, AUC0-infinity 1,430.6 vs. 1,387 pg*h/ml and tmax 20 vs. 17 minutes. When oxymetazoline was co-administered, overall fentanyl absorption was slightly reduced (AUC0-infinity 1,362.4 pg*h/ml); but, more clinically relevant were the delayed rate of absorption (tmax 53 minutes) and reduced Cmax (235.3 pg/ml). CONCLUSIONS: Patients treated with FPNS will be unaffected by the development of allergic rhinitis; but, if oxymetazoline is prescribed, the patient would benefit from added supervision when oxymetazoline is started and stopped. PMID- 23458228 TI - Population pharmacokinetic and pharmacodynamic analyses of teicoplanin in Japanese patients with systemic MRSA infection. AB - BACKGROUND: Teicoplanin is a glycopeptide antibiotic used for the treatment of MRSA infection. An initial loading dose of 400 mg every 12 hours for three doses is the standard dosing regimen. This study aimed to assess whether this regimen was appropriate based on the pharmacokinetic/pharmacodynamic (PK/PD) analyses in Japanese patients. METHODS: We conducted a population pharmacokinetic (PPK) analysis of teicoplanin by NONMEM using serum drug concentrations obtained from 116 patients with MRSA infection. PD of the drug was analyzed by a model assuming that the variability of therapeutic responses (assessed by body temperature, serum C-reactive protein concentrations, and white blood cell counts) on the 3rd, 7th or 14th day of treatment is associated with the logarithm of serum unbound drug concentration (Cmax,unbound) divided by the MIC against MRSA (log[Cmax,unbound/MIC]). RESULTS: The final PPK model showed that creatinine clearance and serum albumin concentration were significant (p < 0.01) covariates of systemic clearance and peripheral volume of distribution of teicoplanin, respectively. The PD analyses indicated that log[Cmax,unbound/MIC] of 0.30 on Day 3 of teicoplanin therapy was the threshold for achieving successful clinical responses. Integrating the PK and PD data, we consider that the standard loading dose regimen would attain the threshold serum level within the initial 3 days in only less than 50% of the patients. CONCLUSION: We propose that an extended loading regimen (400 mg every 12 hours for the first 5 doses) would be a treatment option to maximize the therapeutic effects of teicoplanin in patients with systemic MRSA infection. PMID- 23458229 TI - Pharmacokinetics and efficacy of ropivacaine in Chinese patients following intra articular administration. AB - OBJECTIVE: The purpose of the present study was to investigate the pharmacokinetics and efficacy of ropivacaine in Chinese patients by intra articular administration after arthroscopic knee surgery, in order to assess the safety and efficacy. PATIENTS AND METHODS: 21 ASA I-II patients received a single dose of ropivacaine 150 mg in a 20 ml intra-articular injection at the end of surgery. Plasma samples were collected prior to and after ropivacaine administration. Plasma concentrations of ropivacaine were measured by HPLC. Pharmacokinetic parameters were calculated using noncompartmental analysis. Population pharmacokinetic modeling was performed to yield estimates of clearance, volume of distribution, and absorption rate constant. An analysis of covariates on the pharmacokinetic parameters was also carried out. Pain assessments were made using a verbal rating scale at intervals of 2, 4, 8, 12, 24, 36, 48 and 72 hours after surgery. RESULTS: The results show that the peak plasma concentrations occurred at an average of 0.93 +/- 0.56 h (0.25 - 2 h), with a mean of 0.91 +/- 0.4 mg/l (range 0.35 - 1.54 mg/l). The peak plasma concentrations and the times to reach the peak plasma concentration exhibited a marked variability among the subjects. All concentrations were well below the estimated toxic threshold (2.2 mg/l). No patient experienced adverse events that may have been related to ropivacaine administration. The intra-articular use of ropivacaine provided excellent control of pain after knee arthroscopy. CONCLUSION: Ropivacaine 150 mg provided satisfactory postoperative pain relief and can be safely administered by intraarticular injection in Chinese patients after arthroscopic knee surgery and the pharmacokinetic profiles of ropivacaine exhibited marked variability among the subjects. The high variability of pharmacokinetic profiles in this study may be caused by gender and body weight. PMID- 23458230 TI - Initial dosage regimens of vancomycin for Chinese adult patients based on population pharmacokinetic analysis. AB - OBJECTIVE: To build a population pharmacokinetic model for Chinese adult patients and develop initial dosage regimens for patients with different degrees of renal function to achieve target steady-state trough concentrations in the range of 10 15 and 15 - 20 mg/l. METHOD: Data on serum vancomycin concentration was collected from a retrospective study including 72 Chinese adult patients. NONMEM was used to build the population pharmacokinetic model, and a one-compartment model was chosen to describe the vancomycin concentration-time profile. Internal evaluation by bootstrap and visual predictive check (VPC) was performed to evaluate the robustness and prediction of the final model. Monte Carlo simulations were conducted to develop initial dosage regimens to achieve target trough concentrations. RESULTS: A one-compartment model was built with creatinine clearance (CLcr) as the key covariate influencing drug clearance. The estimated drug clearance for patients with normal renal function (CLcr >= 80 ml/min) was 4.90 l/h, and 0.0654 * CLcr if CLcr was < 80 ml/min. The apparent volume of the central compartment was 47.76 l and no covariate was found to affect it. The results of bootstrap analysis were in agreement with the original parameters of the final model, and VPC of the final model demonstrated good predictability. Initial dosage regimens were developed based on the simulations of the population pharmacokinetic model. CONCLUSION: A one-compartment model fitted the retrospective data and CLcr had a significant effect on drug clearance. Initial dosage regimens for vancomycin were proposed to provide some help to individual therapy for Chinese adult patients with different renal functions. PMID- 23458231 TI - Dynamic full-field infrared imaging with multiple synchrotron beams. AB - Microspectroscopic imaging in the infrared (IR) spectral region allows for the examination of spatially resolved chemical composition on the microscale. More than a decade ago, it was demonstrated that diffraction-limited spatial resolution can be achieved when an apertured, single-pixel IR microscope is coupled to the high brightness of a synchrotron light source. Nowadays, many IR microscopes are equipped with multipixel Focal Plane Array (FPA) detectors, which dramatically improve data acquisition times for imaging large areas. Recently, progress been made toward efficiently coupling synchrotron IR beamlines to multipixel detectors, but they utilize expensive and highly customized optical schemes. Here we demonstrate the development and application of a simple optical configuration that can be implemented on most existing synchrotron IR beamlines to achieve full-field IR imaging with diffraction-limited spatial resolution. Specifically, the synchrotron radiation fan is extracted from the bending magnet and split into four beams that are combined on the sample, allowing it to fill a large section of the FPA. With this optical configuration, we are able to oversample an image by more than a factor of 2, even at the shortest wavelengths, making image restoration through deconvolution algorithms possible. High chemical sensitivity, rapid acquisition times, and superior signal-to-noise characteristics of the instrument are demonstrated. The unique characteristics of this setup enabled the real-time study of heterogeneous chemical dynamics with diffraction-limited spatial resolution for the first time. PMID- 23458232 TI - Effects of a short-term parental education program on childhood atopic dermatitis: a randomized controlled trial. AB - Parental education is important in managing childhood atopic dermatitis (AD). We evaluated the long-term effects of a 2-day parental education program (PEP) on childhood AD. In an investigator-blinded, randomized controlled trial, 59 children age 6 months to 6 years with moderate to severe AD and their mothers were recruited in Japan. Participants were given a booklet about AD and received conventional treatment alone or in combination with a 2-day PEP comprising three lectures, three practical sessions, and a group discussion. The primary outcome was evaluation of eczema severity using SCORing Atopic Dermatitis (SCORAD) at 6 months. Secondary outcomes included changes in symptom scores, amount of corticosteroid used, parental quality of life as determined according to the Dermatitis Family Impact questionnaire, and change in parental anxiety regarding the use of corticosteroids in their children. Participants in the PEP group had a significantly lower SCORAD score than those in the control group at 6 months (mean difference 10.0, 95% confidence interval [CI] = 2.3-17.7, p = 0.01) and objective SCORAD score (mean difference 7.1, 95% CI = 0.8-13.5, p = 0.03). The sleeplessness symptom score (mean difference 1.6, 95% CI = 0.0-3.1, p = 0.048) and corticosteroid anxiety score (p = 0.02) in the PEP group were significantly better than in the control group at 6 months. There was no significant difference between groups in the amount of corticosteroid used or quality of life. The PEP had positive long-term effects on eczema severity and parental anxiety about corticosteroid usage. PMID- 23458234 TI - Evaluation of efficacy of 18 strains of entomopathogenic nematodes (Rhabditida) against Planococcus citri (Risso, 1813) (Hemiptera: Pseudococcidae) under laboratory conditions. AB - Planococcus citri (Risso, 1813) (Hemiptera: Pseudococcidae) is an important plant virus vector in grapevine crops in Brazil and other countries. The mealybug grows in roots and leaves of the grapes. Entomopathogenic nematodes (EPNs) are efficient control agents against insects associated to the soil and could be applied with the same equipment used for chemical insecticides. The aim of this study was to select effective EPNs for controlling P. citri females in laboratory conditions (25+/-1 degrees C, UR 60+/-10%). We tested 17 native [Steinernema rarum (6 strains), Steinernema glaseri, Steinernema feltiae, Steinernema riobrave, Steinernema sp., Heterorhabditis bacteriophora (7 strains)] and only one exotic strain (Steinernema carpocapsae ALL). The bioassays were done on Petri dishes infested with females of P. citri, which were sprayed with EPNs juveniles. The strain with larger pathogenicity and virulence in laboratory was H. bacteriophora RS33 (from 69.0% to 92.2% of mortality), native of Rio Grande do Sul. PMID- 23458235 TI - A RAB family antigen of Angiostrongylus cantonensis induces a Th1-type immune response in vitro and in vivo. AB - A cDNA library was constructed from an Angiostrongylus cantonensis young adult and the encoded proteins were expressed in Escherichia coli. One reactive antigen, a RAB-2 protein, was selected using an immunoscreening technique. The expression of the Th1-type cytokine IFN-gamma was elicited in mouse splenic cells that were co-cultured with the recombinant RAB-2 protein and in the sera of mice that were immunised with this protein and adjuvant (50 MUg at 2-week intervals). In the A. cantonensis-infected groups, the mice were orally infected with 35 infective larvae, and a subset of the infected mice were immunised with the recombinant RAB-2 protein in adjuvant. Serum samples were collected every week for ELISA, and the pathological examinations were performed at 14 days post infection (dpi). An increase in IFN-gamma expression was noted in the blood, and the brain sections revealed moderate eosinophilic meningitis in the immunised mice. The RAB-2 antigen of A. cantonensis induced a Th1-type immune response both in vitro and in vivo. PMID- 23458233 TI - A comparison between patients with gastrointestinal stromal tumours diagnosed with isolated liver metastases and liver metastases plus sarcomatosis. AB - OBJECTIVES: This study was conducted to compare overall survival (OS) in patients presenting with isolated hepatic metastases with that of patients with synchronous metastatic disease to the liver and sarcomatosis on a background of gastrointestinal stromal tumours (GISTs). METHODS: Patients presenting with metastatic GISTs during 1999-2009 were identified. Survival outcomes were compared between groups. RESULTS: Of the 193 patients with GISTs, 43 patients presented with isolated hepatic metastases and 16 presented with synchronous metastases to the liver and sarcomatosis. Thirteen patients with metastases to the liver and sarcomatosis underwent surgery, and 34 patients with metastatic disease solely to the liver underwent hepatic resection. The proportion of patients treated with preoperative tyrosine kinase inhibitor (TKI) therapy was similar in both groups. Similar OS was observed in both groups (isolated liver metastases group: 40.5 months; liver metastases and sarcomatosis group: 28.7 months; P = 0.620). CONCLUSIONS: Overall survival in patients with GIST and metastatic disease to the liver and sarcomatosis is similar to that in patients with isolated metastatic liver disease. Although patients with a greater disease burden might be expected to show worse survival, these data do not reflect this assumption. PMID- 23458236 TI - Analysis of Fcgamma receptor IIa (cd32) gene polymorphism and anti-malarial IgG subclass antibodies to asexual blood-stage antigen of Plasmodium falciparum in an unstable malaria endemic area of Iran. AB - One of the main host genetic factors involved in inflammation, immune responses and pathogenesis of malaria is FcgammaRIIa (cd32) gene. A single point mutation at position 131 replace an arginine (R) with a histidine (H) that can affect the affinity of the receptor for human IgG subclasses. This investigation was designed to explore the polymorphisms at FcgammaRIIa gene in association with both anti-malarial total IgG antibody and IgG subclass profiles to C-terminal region of Plasmodium falciparum merozoite surface protein 1 (PfMSP-1(19)). In this study, 166 infected patients with P. falciparum who are living in a malaria endemic area of Iran were studied using PCR-RFLP and ELISA methods. The results showed that the frequency of FcgammaRIIa-R/R131, -R/H131 and -H/H131 genotypes was 9.6%, 42.8% and 47.6%, respectively. Level of total IgG to recombinant PfMSP 1(19) antigen showed that there was no difference among the FcgammaRIIa-R/R131, R/H131 and -H/H131 groups. With regards to the IgG subclasses, the anti-malarial IgG1 antibodies predominated. Also, there was a significant difference between the frequency of positive responders for anti-PfMSP-1(19) IgG and IgG1 antibodies in P. falciparum-infected individuals with FcgammaRIIa-R/R131, -R/H131 or -H/H131 genotypes (P<0.05, X(2) test). Regarding to IgG2-PfMSP-1(19) antibody, 27.27% (FcgammaRIIa-R/R131), 25.71% (FcgammaRIIa-R/H131) and 22.2% (FcgammaRIIa-H/H131) of IgG responders showed positive antibody response. Taken together, this study is the first report that exhibits the high frequency of both FcgammaRIIa-H131H genotypes and H131 allele in the Baluchi ethnic group, which was similar to the Fulani ethnic group. The present results provide additional data to understand the role of FcgammaRIIa-131 genotypes in the pathogenesis of malaria. PMID- 23458237 TI - General synthesis of sugar-derived azepane nitrones: precursors of azepane iminosugars. AB - A general and efficient method has been developed for the synthesis of sugar derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones, which are precursors of various azepane iminosugars. PMID- 23458238 TI - Characteristics of forensic imaging performance--an analysis of forensic imaging bottlenecks. AB - Disk imaging involves copying all of the data from a source disk drive to a target. Typically, the target for the copy is another disk drive. Forensic processes developed years ago do not appear to be adequate for current storage technology. For example, with disk drive capacities now exceeding 1 Terabyte, a typical disk imaging can take over 8 hours at typical rates. With disk drive capacities increasing, forensic copying is expected to take even longer. Along with increase in disk capacity, the industry has also seen an increase in data transfer rates. In many cases, forensic imaging is taking longer than necessary. To identify the bottlenecks, an examination of different methods used to transfer data from a source disk was performed. Factors considered were differing disk access technologies. One finding is that the USB disk access technology (version 2.0 and earlier) is a significant bottleneck for data transfer rates, especially when the USB device is a write-blocker. Other factors that contribute to the efficiency of a forensic copy are the file system used to write a forensic image and the data transfer size used when reading from a disk drive. Optimal parameters for performing a forensic acquisition from a disk drive are identified. PMID- 23458239 TI - Elevated troponin levels in previously healthy children: value of diagnostic modalities and the importance of a drug screen. AB - BACKGROUND: Myocardial injury in previously healthy children is rare, with a wide range of aetiologies. It is increasingly being identified on the basis of elevated troponin levels during routine evaluation of cardiorespiratory symptoms. Establishing the aetiology remains challenging because of the lack of an accepted work-up algorithm. Our objective was to delineate the contribution of diagnostic modalities and troponin patterns towards the final diagnosis. METHODS: A retrospective chart review of previously healthy patients admitted to the Pediatric Cardiology Service with myocardial injury was carried out. Data analysed included echocardiograms, electrocardiograms, cardiac catheterisations, magnetic resonance imaging, drug screen tests, troponin values, and final diagnosis. RESULTS: A total of 32 patients were identified. The diagnoses were: myocarditis in 16 patients, vasospasm due to drug use in seven, myopericarditis in six, anomalous coronary artery origins in two, and Prinzmetal's angina in one patient. The electrocardiograms were abnormal in 27 of the 32 patients (84%), echocardiograms in 18 of the 32 patients (56%), cardiac magnetic resonance imaging in two of the four patients (50%), urine drug screen in five of the 25 patients (20%), and cardiac catheterisations in two of the 15 patients (13%). CONCLUSIONS: Myocarditis is the most common aetiology of myocardial injury in children. Clinical history remains the basic screening tool; drug screens help identify coronary vasospasms secondary to drug use (22% of our cohort). Patients with anomalous coronaries had exertional symptoms. Initial troponin levels and progression were not diagnostic or prognostic. Catheterisation is of limited value and did not change management. Magnetic resonance imaging with gadolinium enhancement is probably the most useful test when initial evaluation is not diagnostic. PMID- 23458240 TI - Coronary-subclavian steal syndrome in a hemodialysis patient, a case report and review of literature. AB - Dialysis vascular access associated coronary-subclavian steal or hypoperfusion syndrome is an uncommon but potentially life threatening condition. Awareness of this syndrome is important in the management of vascular access in hemodialysis patients. We report a case of dialysis vascular access associated coronary subclavian steal syndrome and review the literature on its pathogenesis and therapeutic implications. PMID- 23458241 TI - Depression as a major impact on the quality of life of HIV-positive Brazilians. AB - Given that mental symptoms might interfere with the quality of life (QOL) of people living with HIV/AIDS (PLHAs), the goal of this paper was to examine the correlation between depression, anxiety, and QOL in a sample of HIV-positive Brazilians. A cross-sectional study was designed to analyze the correlations between the presence of mental symptoms and the QOL scores of PLHAs. Depression and anxiety symptoms were measured using the Beck Depression Inventory and the State-Trait Anxiety Inventory, respectively. The QOL was assessed using the World Health Organization Quality of Life instrument - HIV module. A convenience sample of 308 men and women living with HIV (131 asymptomatic, 91 symptomatic, and 86 with AIDS) in Porto Alegre/RS-Brazil was selected. The depression scores were higher in patients with AIDS compared with asymptomatic and symptomatic patients, yet there were no differences in the anxiety scores between the stages of infection. Better QOL scores were observed in the earlier stages of infection (asymptomatic and symptomatic groups). In the correlation between mental symptoms and QOL scores, the Pearson's coefficient values were of a moderate (r = .47) to a large (r = .65) magnitude for depressive symptoms, and the scores for the anxiety symptoms were small to moderate (r <= .35). After adjusting for the disease stage and clinical and sociodemographic variables in a multiple regression model (using QOL as the dependent variable), the depressive symptoms showed significantly higher beta-coefficient values compared with the remaining variables. The data obtained from this study indicate that the QOL of PLHAs is primarily affected by depression. Thus, it has been strongly recommended that treatment programs dedicated to PLHAs assess depressive symptoms, providing subsequent referrals and treatments. Treating depression might be effective for PLHAs and might potentially improve both the overall QOL and the health outcomes. PMID- 23458242 TI - Feasibility of the Glissonian approach during right hepatectomy. AB - OBJECTIVE: The Glissonian approach during hepatectomy is a selective vascular clamping procedure associated with low rates of technical failure and complications. The aim of the present study was to assess the feasibility of a right Glissonian approach in relation to portal vein anatomy. METHODS: This was a prospective study conducted over a 12-month period, which included 32 patients for whom preoperative three-dimensional reconstruction using contrast-enhanced computed tomography in the portal venous phase and portography for right portal vein embolization were available, and in whom a right Glissonian approach was applied during right hepatectomy. Preoperative imaging data were correlated with intraoperative Doppler ultrasound findings (considered as the reference dataset). Causes of failures and complications specifically related to the Glissonian approach were identified. RESULTS: Right hepatectomy was performed for colorectal liver metastases (n = 25), hepatocellular carcinoma on cirrhosis (n = 6) and intrahepatic cholangiocarcinoma (n = 1). The Glissonian approach was effective in 24 (75%) patients. In the remaining eight (25%) patients, failure was caused by incomplete clamping (n = 2) or clamping of the left portal pedicle (n = 6). The portal anatomy was aberrant in six patients with failure, showing portal trifurcation (n = 1), right portal trifurcation (n = 1) and a common trunk between the right anterior and left portal branch (n = 4). An angle of less than 50 degrees between the portal vein and left portal branch was reported in association with extended clamping to the left portal branch (selectivity = 72%, specificity = 71%). Intraoperative bleeding and biliary fistula occurred in two patients with non-normal portal anatomy. CONCLUSIONS: The right Glissonian approach was effective in 75% of patients. Failure of the procedure (including the extension of clamping to the left pedicle) mostly occurred in patients with portal vein variations, which can be accurately assessed using a combination of preoperative imaging and intraoperative Doppler ultrasound. PMID- 23458243 TI - Sequence variability in p6 gag protein and gag/pol coevolution in human immunodeficiency type 1 subtype F genomes. AB - Polymorphisms occurring at the p6gag protein of HIV-1 have been previously found to have an impact on viral fitness and antiretroviral (ARV) resistance, mainly on subtype B genomes. We compared p6gag variability in a large group of 165 subtype F gag-pol sequences, with 36 subtype B sequences from the same study source, and identified sites of gag-pol coevolution under ARV selection pressure. Subtype specific differences in the frequency of point mutations, insertions, and deletions previously associated with ARV resistance were found. Also, in our dataset of subtype F genomes a strong association between mutation P5L in the p1/p6 cleavage region of gag and the nelfinavir (NFV) resistance mutation N88D(PR) was found with no impact on the preference for any of the NFV resistance pathways. PMID- 23458244 TI - Sources and processes contributing to nitrogen deposition: an adjoint model analysis applied to biodiversity hotspots worldwide. AB - Anthropogenic enrichment of reactive nitrogen (Nr) deposition is an ecological concern. We use the adjoint of a global 3-D chemical transport model (GEOS-Chem) to identify the sources and processes that control Nr deposition to an ensemble of biodiversity hotspots worldwide and two U.S. national parks (Cuyahoga and Rocky Mountain). We find that anthropogenic sources dominate deposition at all continental sites and are mainly regional (less than 1000 km) in origin. In Hawaii, Nr supply is controlled by oceanic emissions of ammonia (50%) and anthropogenic sources (50%), with important contributions from Asia and North America. Nr deposition is also sensitive in complicated ways to emissions of SO2, which affect Nr gas-aerosol partitioning, and of volatile organic compounds (VOCs), which affect oxidant concentrations and produce organic nitrate reservoirs. For example, VOC emissions generally inhibit deposition of locally emitted NOx but significantly increase Nr deposition downwind. However, in polluted boreal regions, anthropogenic VOC emissions can promote Nr deposition in winter. Uncertainties in chemical rate constants for OH + NO2 and NO2 hydrolysis also complicate the determination of source-receptor relationships for polluted sites in winter. Application of our adjoint sensitivities to the representative concentration pathways (RCPs) scenarios for 2010-2050 indicates that future decreases in Nr deposition due to NOx emission controls will be offset by concurrent increases in ammonia emissions from agriculture. PMID- 23458245 TI - Outcome of video-assisted translumbar retroperitoneal necrosectomy and closed lavage for severe necrotizing pancreatitis. AB - INTRODUCTION AND OBJECTIVE: Surgery for necrotizing pancreatitis is associated with a high rate of morbidity and mortality. We present a series of 26 patients who underwent video-assisted translumbar retroperitoneal necrosectomy and analyse their outcomes. METHODS: Records of 26 patients who underwent video-assisted translumbar retroperitoneal necrosectomy and closed drainage for infected pancreatitic necrosis between January 2008 and March 2012 were reviewed, retrospectively. RESULTS: Twenty-three out of 26 patients were males, with a mean age of 38.6 (+/-9.9) years. Alcohol was the aetiology in 18 patients, gall stones in 7, and in 1 it was idiopathic. The mean duration of symptoms before patients were taken up for surgery was 47.2 (+/-34.8) days. The mean computed tomography severity index was 7.7 (+/-1.2). All patients had undergone video-assisted retroperitoneal necrosectomy through a limited left lumbar incision. Post operative lavage was given through drains placed in the retroperitoneum. Three patients required re-exploration. Eleven patients developed complications and there were two mortalities. The median intensive care unit (ICU) stay was 4 days (range 2-14 days). The mean post-operative hospital stay was 22.5 (+/-6.6) days. CONCLUSION: Video-assisted translumbar retroperitoneal necrosectomy followed by closed lavage of infected pancreatic necrosis in select cases of infected pancreatic necrosis was associated with a low rate of ICU stay, hospital stay and need for re-entry. PMID- 23458246 TI - Tricycloalternarene derivatives from endophytic fungus Alternaria tenuissima SY-P 07. AB - A new tricycloalternarene, TCA 11a (1), was isolated from the culture broth of an endophytic fungus, Alternaria tenuissima SY-P-07, along with four known structurally related compounds 2-5. The structure of compound 1 was elucidated by extensive spectroscopic methods, especially 2D NMR, and the absolute stereochemistry of 1 was suggested on the basis of the CD spectral analysis and NOESY data. PMID- 23458247 TI - Elizabeth Warrington Prize Lecture. Seeing why they cannot see: understanding the syndrome and causes of posterior cortical atrophy. AB - Posterior cortical atrophy (PCA) is a syndrome defined by focal neurodegeneration of the parietal, occipital, and occipito-temporal cortices and associated with progressive dysfunction of visual processing, praxis, numeracy and reading. The condition is most commonly caused by (and viewed as an atypical presentation of) Alzheimer's disease, although can also be caused by other degenerative diseases. The current paper examines the relationship of PCA to other degenerative syndromes, and considers what comparisons of these syndromes and disease phenotypes can tell us about underlying disease mechanisms. The focus then turns to neuropsychological investigations of the cognitive basis of symptoms which, although unusual in the broader context of a dementia clinic, are particularly characteristic of the PCA syndrome, before exploring implications for clinical management and patient and carer support. PMID- 23458249 TI - Decarbonylative halogenation by a vanadium complex. AB - Metal-catalyzed halogenation of the C-H bond and decarbonylation of aldehyde are conventionally done in nature. However, metal-mediated decarbonylative halogenation is unknown. We have developed the first metal-mediated decarbonylative halogenation reaction starting from the divanadium oxoperoxo complex K3V(5+)2(O2(2-))4(O(2-))2(MU-OH) (1). A concerted decarbonylative halogenation reaction was proposed based on experimental observations. PMID- 23458248 TI - Phosphoryl transfer by protein kinase A is captured in a crystal lattice. AB - The catalytic (C) subunit of cAMP-dependent protein kinase (PKA) is a serine/threonine kinase responsible for most of the effects of cAMP signaling, and PKA serves as a prototype for the entire kinase family. Despite multiple studies of PKA, the steps involved in phosphoryl transfer, the roles of the catalytically essential magnesium ions, and the processes that govern the rate limiting step of ADP release are unresolved. Here we identified conditions that yielded slow phosphoryl transfer of the gamma-phosphate from the generally nonhydrolyzable analog of ATP, adenosine-5'-(beta,gamma-imido)triphosphate (AMP PNP), onto a substrate peptide within protein crystals. By trapping both products in the crystal lattice, we now have a complete resolution profile of all the catalytic steps. One crystal structure refined to 1.55 A resolution shows two states of the protein with 55% displaying intact AMP-PNP and an unphosphorylated substrate and 45% displaying transfer of the gamma-phosphate of AMP-PNP onto the substrate peptide yielding AMP-PN and a phosphorylated substrate. Another structure refined to 2.15 A resolution displays complete phosphoryl transfer to the substrate. These structures, in addition to trapping both products in the crystal lattice, implicate one magnesium ion, previously termed Mg2, as the more stably bound ion. Following phosphoryl transfer, Mg2 recruits a water molecule to retain an octahedral coordination geometry suggesting the strong binding character of this magnesium ion, and Mg2 remains in the active site following complete phosphoryl transfer while Mg1 is expelled. Loss of Mg1 may thus be an important part of the rate-limiting step of ADP release. PMID- 23458250 TI - Commentary: complete melanoma microstaging. PMID- 23458251 TI - Commentary on repigmentation of poliosis after epithelial grafting for vitiligo. PMID- 23458252 TI - Adamantinoid basal cell carcinoma: a predictor of more aggressive clinical behavior. PMID- 23458253 TI - Judicious discontinuation of antithrombotic medications in skin surgery. PMID- 23458254 TI - Cell phone-assisted identification of surgery site. PMID- 23458255 TI - Burnout and career choice motivation in medical students. AB - BACKGROUND: Burnout is a stress-induced syndrome, which affects medical students. Some environmental and personal factors can favor burnout onset and its serious consequences as dropping out, sleep disorders, depression, and suicide. The motivation for choosing medicine is a personal aspect that can modulate the distress with academic demands. METHODS: We applied self-administered questionnaires in 277 medical students to investigate the predictive role of career choice motivations on burnout dimensions. Specifically, we studied the influence of the main reasons for choosing medicine on emotional exhaustion, cynicism, and academic efficacy. RESULTS: Intellectual curiosity, professional autonomy, altruism, and interest in human relationships were the most common reasons for choosing medicine. However, the medical students motivated by personal illness or family member's illness or death revealed a significant greater emotional exhaustion when compared with the students with other motivations. CONCLUSION: The students who apply for medical school motivated by illness/death experiences are at a great risk for burnout. We suggest that students who are at risk for emotional exhaustion can be identified at the admission of medical school. Primary prevention strategies for burnout should consider this risk group. PMID- 23458256 TI - Programmable nanoparticle ensembles via high-throughput directed self-assembly. AB - We present a simple and facile strategy for the directed self-assembly of nanoparticles into complex geometries using a minimal set of post guiding features patterned on a substrate. This understanding is based on extensive studies of nanoparticle self-assembly into linear, dense-packed, circular, and star-shaped ensembles when coated onto patterned substrates of predefined post arrays. We determined the conditions under which nanoparticles assemble and "connect" two adjacent post features, thereby forming the desired shapes. We demonstrate that with rational design of the post patterns to enforce the required pairwise interactions with posts, we can create arbitrary arrangements of nanoparticles-for example, to write "IBM" in a deterministic manner. This demonstration of programmable, high-throughput directed self-assembly of nanoparticles shows an alternative route to generate functional nanoparticle assemblies. PMID- 23458257 TI - Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease. AB - Autonomic dysfunction has been reported in patients with NAFLD (non-alcoholic fatty liver disease) and is associated with clinical presentations. To date, there are no therapies to improve autonomic regulation in people with NAFLD. The present study defines the impact of a short-term exercise programme on cardiac autonomic and haemodynamic regulation in patients with NAFLD. A total of 17 patients with clinically defined NAFLD [age, 55+/-12 years; BMI (body mass index), 33+/-5 kg/m2; liver fat, 17+/-9%] were randomized to 8 weeks of resistance exercise or a control group to continue standard care. Resting and submaximal exercise (50% of peak oxygen consumption) autonomic and cardiac haemodynamic measures were assessed before and after the intervention. Resistance exercise resulted in a 14% reduction in HR (heart rate) and 7% lower SBP (systolic blood pressure) during submaximal exercise (16 beats/min, P=0.03 and 16 mmHg, P=0.22). Sympathovagal balance, expressed as LF/HF (low-frequency/high frequency) ratio of the mean HR beat-to-beat (R-R) interval, was reduced by 37% (P=0.26). Similarly sympathovagal balance of DBP (diastolic blood pressure) and SBP variability decreased by 29% (P=0.33) and 19% (P=0.55), respectively in the exercise group only. BRS (baroreflex sensitivity) increased by 31% (P=0.08) following exercise. The mean R-R interval increased by 23% (159 ms, P=0.09). Parasympathetic regulation was decreased by 17% (P=0.05) and overall sympathovagal balance in BP regulation (LF/HF ratio) increased by 26% (P=0.02) following resistance exercise. Resting haemodynamic measures remained similar between groups. Resistance exercise therapy seems to improve autonomic and submaximal exercise haemodynamic regulation in NAFLD. Further studies are required to define its role in clinical management of the condition. PMID- 23458259 TI - Longitudinal measures of proteostasis in live neurons: features that determine fate in models of neurodegenerative disease. AB - Protein misfolding and proteostasis decline is a common feature of many neurodegenerative diseases. However, modeling the complexity of proteostasis and the global cellular consequences of its disruption is a challenge, particularly in live neurons. Although conventional approaches, based on population measures and single "snapshots", can identify cellular changes during neurodegeneration, they fail to determine if these cellular events drive cell death or act as adaptive responses. Alternatively, a "systems" cell biology approach known as longitudinal survival analysis enables single neurons to be followed over the course of neurodegeneration. By capturing the dynamics of misfolded proteins and the multiple cellular events that occur along the way, the relationship of these events to each other and their importance and role during cell death can be determined. Quantitative models of proteostasis dysfunction may yield unique insight and novel therapeutic strategies for neurodegenerative disease. PMID- 23458258 TI - A flash in the pan: dissecting dynamic amyloid intermediates using fluorescence. AB - Several widespread and severe degenerative diseases are characterized by the deposition of amyloid protein aggregates in affected tissues. While there is great interest in the complete description of the aggregation pathway of the proteins involved, a molecular level understanding is hindered by the complexity of the self-assembly process. In particular, the early stages of aggregation, where dynamic, heterogeneous and often toxic intermediates are populated, are resistant to high-resolution structural characterization. Fluorescence spectroscopy is a powerful and versatile tool for such analysis. In this review, we survey its application to provide residue-specific information about amyloid intermediate states for three selected proteins: IAPP, alpha-synuclein, and tau. PMID- 23458260 TI - Qualitative confirmation of 9 synthetic cannabinoids and 20 metabolites in human urine using LC-MS/MS and library search. AB - INTRODUCTION: Synthetic cannabinoids are an emerging illicit drug class. The variety of available substances is large and ever-changing, making it difficult for laboratories to remain current. We present a qualitative LC-MS/MS method identifying urinary metabolites of JWH-018, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, RCS-4, and AM2201 and the parent compounds JWH-018, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, RCS-4, AM2201, and MAM2201. METHODS: After enzymatic hydrolysis, urinary proteins were precipitated with acetonitrile. Chromatography utilized a 10 min gradient on a Kinetex XB-C18 column with 0.1% formic acid in water and acetonitrile. Scheduled multiple reaction monitoring "survey scans" were followed by information-dependent acquisition-enhanced product ion scan experiments on an ABSciex 5500 QTRAP mass spectrometer. Analytes were identified by software-assisted library searching against reference spectra. RESULTS: The method was fully validated, including proof of selectivity (no exogenous or endogenous interferences were observed), assessment of matrix effects (95-122%) and recovery (53-95%), determination of limits of detection (0.5-10 ng/mL), carry-over studies (thresholds between 100 and 1000 ng/mL), and determination of autosampler stability (samples were stable for at least 3 days). Hydrolysis efficiency was thoroughly investigated for a wide range of glucuronides and for the reference standard, JWH-018 5-hydroxypentyl glucuronide. PMID- 23458261 TI - Five days of postoperative antimicrobial therapy decreases infectious complications following pancreaticoduodenectomy in patients at risk for bile contamination. AB - OBJECTIVES: Pancreaticoduodenectomy (PD) is associated with high morbidity, in part as a result of infectious complications increased by preoperative bile contamination. The aim of the present study was to assess the effect on the incidence of infectious complications of short-term antimicrobial therapy (AMT) in high-risk patients. METHODS: Patients with a high risk for positive intraoperative bile culture (i.e. those with ampulloma or pancreatic adenocarcinoma with preoperative endoscopic procedures) (high-risk group, n = 99) were compared with low-risk patients (i.e. those with pancreatic adenocarcinoma without preoperative endoscopic procedures) (low-risk group, n = 76). The high risk group received a 5-day course of perioperative AMT secondarily adapted to the bile antibiogram. The low-risk group received only the usual antimicrobial prophylaxis. RESULTS: Positive bile cultures were significantly more frequent in high-risk patients (81% versus 12%; P < 0.001). The overall rate of infectious complications was lower in the high-risk group (29% versus 46%; P = 0.018). The statistically significant decrease in the rate of infectious complications reflected reduced rates of urinary tract infections, pulmonary infections and septicaemia. Rates of wound infection (3% versus 5%; P = 0.639) and intra abdominal abscess (7% versus 7%; P = 0.886) were similar in the high- and low risk groups, as was the need for curative AMT. CONCLUSIONS: This exploratory study suggests that a postoperative short course of AMT in patients at high risk for biliary contamination reduces the overall rate of infectious complications after PD. The adaptation of perioperative antimicrobial policy to the patient's risk for bile contamination seems promising and should be further evaluated. PMID- 23458262 TI - Concomitant dysregulation of microRNAs miR-151-3p and miR-126 correlates with improved survival in resected cholangiocarcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding genes which become dysregulated in cancer and may predict survival. The role of miRNAs in outcomes in cholangiocarcinoma (CC) has not been reported. METHODS: RNA was extracted from 32 resected CCs along with adjacent uninvolved bile duct epithelium. A total of 43 miRNAs were quantified using NanoStringTM. Clinicopathologic characteristics and outcomes were captured and compared. Overall survival curves were created using the Kaplan-Meier method; factors, including miRNA expression, were compared by log-rank, chi-squared or Cox regression analyses. RESULTS: Absolute expression of each miRNA was compared with overall survival after excluding perioperative deaths (n= 3). One upregulated (miR-151-3p; P= 0.003) and one downregulated (miR 126; P= 0.023) miRNA in resected CC relative to adjacent normal bile duct epithelium correlated with survival on univariate analysis. Clinical factors and these miRNAs were compared. Dysregulated miR-151-3p and miR-126, respectively, were the only factors that correlated with improved overall survival [41.5 months vs. 12.3 months (P= 0.002) and 21.9 months vs. 15.1 months (P= 0.02), respectively]. In eight patients, both miRNAs were dysregulated. In the remainder, only one or neither showed dysregulation. Concomitant dysregulation correlated with the best overall survival (58.7 months vs. 15.1 months; P < 0.000; n= 8); clinicopathologic factors in these groups were otherwise similar. CONCLUSIONS: In resected CC, the concomitant dysregulation of both miR-151-3p and miR-126 was the factor related to the greatest improvement in overall survival. Further analysis of the targets of these miRNAs may yield potential therapeutic targets or prognostic biomarkers. PMID- 23458263 TI - A highly specific gold nanoprobe for live-cell single-molecule imaging. AB - Single molecule tracking in live cells is the ultimate tool to study subcellular protein dynamics, but it is often limited by the probe size and photostability. Because of these issues, long-term tracking of proteins in confined and crowded environments, such as intracellular spaces, remains challenging. We have developed a novel optical probe consisting of 5 nm gold nanoparticles functionalized with a small fragment of camelid antibodies that recognize widely used green fluorescent proteins (GFPs) with a very high affinity, which we call GFP-nanobodies. These small gold nanoparticles can be detected and tracked using photothermal imaging for arbitrarily long periods of time. Surface and intracellular GFP-proteins were effectively labeled even in very crowded environments such as adhesion sites and cytoskeletal structures both in vitro and in live cell cultures. These nanobody-coated gold nanoparticles are probes with unparalleled capabilities; small size, perfect photostability, high specificity, and versatility afforded by combination with the vast existing library of GFP tagged proteins. PMID- 23458264 TI - The colon: an overlooked site for therapeutics in dialysis patients. AB - Morbidity and mortality related to chronic kidney disease remain unacceptably high, despite tremendous progress in its prevention and treatment. In an ongoing quest to improve outcome in chronic kidney disease patients, the colon might be an appealing, but largely underexplored, therapeutic target. A clear bi directional functional relationship exists between the colon and kidney, also referred as to the colo-renal axis. Uremia has an important impact on the colonic microbiome. The microbiome, in turn, is an important source of uremic toxins, with p-cresyl sulfate and indoxyl sulfate as important prototypes. These co metabolites accumulate in the face of a falling kidney function, and may accelerate the progression of renal and cardiovascular disease. Several therapeutic interventions, including prebiotics and adsorbants, specifically target these colon-derived uremic toxins originating from bacterial metabolism. As kidney function declines, the colon also gains importance in the homeostasis and disposal of potassium and oxalate. Their colonic secretion may be increased by drugs increasing the expression of cAMP and by probiotics (e.g., Oxalobacter formigenes). PMID- 23458265 TI - Newborn transepidermal water loss values: a reference dataset. AB - Transepidermal water loss (TEWL) is a simple noninvasive measurement of inside out skin barrier function. The goal of this research was to establish normal values for TEWL in early life using data gathered from the Cork BASELINE Birth Cohort Study. TEWL was recorded in a standardized fashion using a well-validated open-chamber system. A mean of three readings was recorded from 1,036 neonates (37-42 weeks gestational age) and 18 late preterm infants (34-37 weeks gestational age) within 96 hours of birth in an environmentally controlled room. Full-term neonatal TEWL measurements have a normal distribution (mean 7.06 +/- 3.41 g of water/m(2) per hour) and mean preterm neonatal TEWL measurements were 7.76 +/- 2.85 g of water/m(2) per hour. This is the largest evaluation to date of TEWL in a normal-term neonatal population. It therefore constitutes a reference dataset for this measurement using an open-chamber system. PMID- 23458266 TI - Scimitar syndrome and anomalous origin of the circumflex artery from the main pulmonary artery in infancy: a case report. AB - We present a neonate with an antenatal diagnosis of Scimitar syndrome and aortic arch hypoplasia. After delivery, computerised tomography scan additionally revealed an anomalous origin of the circumflex coronary artery from the main pulmonary artery. The management of this rare combination is discussed. PMID- 23458267 TI - Examination of rare missense variants in the CHRNA5-A3-B4 gene cluster to level of response to alcohol in the San Diego Sibling Pair study. AB - BACKGROUND: Common variants in the CHRNA5-A3-B4 gene cluster have been shown to be associated with nicotine dependence and alcohol use disorders (AUDs) and related traits, including the level of response (LR) to alcohol. Recently, rare variants (MAF < 0.05) in CHRNB4 have been reported to be associated with a decreased risk of developing nicotine dependence. However, the role of rare variants in the CHRNA5-A3-B4 gene cluster to the LR to alcohol has not yet been established. METHODS: To determine whether rare variants in the CHRNA5-A3-B4 gene cluster contribute to the LR to alcohol, the coding regions of these 3 genes were sequenced in 538 subjects from the San Diego Sibling Pair study. RESULTS: The analyses identified 16 rare missense variants, 9 of which were predicted to be damaging using in silico analysis tools. Carriers of these variants were compared to noncarriers using a family-based design for each gene and for the gene cluster as a whole. In these analyses, a CHRNA5 carrier status was significantly associated with the phenotype related to the feeling of intoxication experienced during the alcohol challenge (p = 0.039). CONCLUSIONS: These results indicate that rare genetic variation in the CHRNA5-A3-B4 gene cluster contributes modestly to the LR to alcohol in the San Diego Sibling Pair study and may protect against AUDs. However, replication studies are needed to confirm our findings. PMID- 23458268 TI - Psychological hardiness predicts neuroimmunological responses to stress. AB - Psychological hardiness characterizes people who remain healthy under psychosocial stress. The present exploratory study investigates possible links between hardiness and several immune and neuroendocrine markers: IL-6, IL-12, IL 4, IL-10, & neuropeptide-Y. A total of 21 Norwegian navy cadets were studied in the context of a highly stressful military field exercise. Blood samples were collected midway, and again late in the exercise when stress levels were highest. Psychological hardiness (including commitment, control, and challenge) was measured two days before the exercise. While all subjects scored high in hardiness, some were high only in commitment and control, but relatively low in challenge. These "unbalanced" hardiness subjects were also more stress reactive, showing suppressed proinflammatory cytokines (IL-12), increased anti-inflammatory cytokines (IL-4, IL-10), and lower neuropeptide-Y levels as compared to the hardiness-balanced group. This study thus shows that being high in hardiness with a balanced profile is linked to more moderate and healthy immune and neuroendocrine responses to stress. PMID- 23458269 TI - Contrast enhancement of bite mark images using the grayscale mixer in ACR in Photoshop(r). AB - Enhanced images may improve bite mark edge definition, assisting forensic analysis. Current contrast enhancement involves color extraction, viewing layered images by channel. A novel technique, producing a single enhanced image using the grayscale mix panel within Adobe Camera Raw(r), has been developed and assessed here, allowing adjustments of multiple color channels simultaneously. Stage 1 measured RGB values in 72 versions of a color chart image; eight sliders in Photoshop(r) were adjusted at 25% intervals, all corresponding colors affected. Stage 2 used a bite mark image, and found only red, orange, and yellow sliders had discernable effects. Stage 3 assessed modality preference between color, grayscale, and enhanced images; on average, the 22 survey participants chose the enhanced image as better defined for nine out of 10 bite marks. The study has shown potential benefits for this new technique. However, further research is needed before use in the analysis of bite marks. PMID- 23458270 TI - Cortical ependymoma with unusual histologic features. AB - Cortical ependymomas are rare gliomas with classic ependymal features but are unusual in primarily involving the cerebral cortex. Here, we present a 19-year old woman with new-onset seizures who was found to have a large, cortically based non-enhancing lesion with scalloping of the overlying calvarium. Abundant ependymal features were present including classic ependymal cytology, diffuse GFAP and dot-like EMA positivity, and well developed cilia, microvilli, and intercellular junctions on ultrastructural analysis. Additionally, the tumor showed areas of infiltrative growth similar to angiocentric glioma as well as striking mucin-filled microcystic spaces somewhat reminiscent of myxopapillary ependymoma. Thus far, the patient shows no evidence of recurrence following gross total resection. This case demonstrates detailed morphologic, immunohistochemical, and ultrastructural evidence supporting a relationship between cortical ependymoma and angiocentric glioma and suggesting that cortical ependymomas can have myxopapillary as well as classic features. PMID- 23458271 TI - Different profiles of onion bulb in CIDP and CMT1A in relation to extracellular matrix. AB - Hypertrophic neuropathy is usually intractable, and chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease Type 1A (CMT1A) are the representative disorders. The two disorders are sometimes confused both clinically and pathologically. The aim of this study was to clarify the differences in the pathology of large onion bulbs, focusing on the extracellular matrix (ECM) proteins. Nine patients with CIDP and 14 with CMT1A were included. The opened interspaces in OB were frequently shown in CMT1A patients. In CIDP, interspaces of OB packed with collagen fibers were prominent. The mean ratio of opened OB was significantly increased in CMT1A (37.9%) compared to CIDP patients (10.6%) (p = 0.003). Among the ECM examined, tenascin-C (TNC) showed a distinct difference in the pattern of immunoreactivity of OB. The mean ratio of OB showing TNC immunoreactivity was significantly larger in CIDP (29.7%, p = 0.005) than in CMT1A (5.0%). TNC immunoreactivity was confined to the area around myelin sheaths in CMT1A. The increased deposition of collagen fibers in CIDP suggests the activity of nerve regeneration. TNC expression in Schwann cell lamellae comprising OB may also suggest the activity of regeneration. Schwann cell phenotypes in CIDP may be different from CMT1A regarding the production of ECM proteins. PMID- 23458272 TI - Regioselective electrophilic access to naphtho[1,2-b:8,7-b']- and -[1,2-b:5,6 b']dithiophenes. AB - A two-step one purification access to dichloronaphtho[1,2-b:8,7-b'] and [1,2 b:5,6-b']dithiophenes using bis-alkylnaphthyl alkynes and phthalimidesulfenyl chloride as starting materials has been developed. The functionalization of the carbon-chlorine bonds allowed further modification of NDT core, broadening the potential of the methodology. PMID- 23458273 TI - Dysregulated fear predicts social wariness and social anxiety symptoms during kindergarten. AB - Fearful temperament is associated with risk for the development of social anxiety disorder in childhood; however, not all fearful children become anxious. Identifying maladaptive trajectories is thus important for clarifying which fearful children are at risk. In an unselected sample of 111 two-year-olds (55% male, 95% Caucasian), Buss ( 2011 ) identified a pattern of fearful behavior, dysregulated fear, characterized by high fear in low threat situations. This pattern of behavior predicted parent- and teacher-reported withdrawn/anxious behaviors in preschool and at kindergarten entry. The current study extended original findings and examined whether dysregulated fear predicted observed social wariness with adults and peers, and social anxiety symptoms at age 6. We also examined prosocial adjustment during kindergarten as a moderator of the link between dysregulated fear and social wariness. Consistent with predictions, children with greater dysregulated fear at age 2 were more socially wary of adults and unfamiliar peers in the laboratory, were reported as having more social anxiety symptoms, and were nearly 4 times more likely to manifest social anxiety symptoms than other children with elevated wariness in kindergarten. Results demonstrated stability in the dysregulated fear profile and increased risk for social anxiety symptom development. Dysregulated fear predicted more social wariness with unfamiliar peers only when children became less prosocial during kindergarten. Findings are discussed in relation to the utility of the dysregulated fear construct for specifying maladaptive trajectories of risk for anxiety disorder development. PMID- 23458274 TI - Preparation of telluro- and selenoalumoxanes under mild conditions. AB - Syntheses of the heavy chalcogen-containing alumoxanes [(Me)LAl(SeH)]2(MU-O) (4) and ((Me)LAl)2(MU-Te)(MU-O) (7) were accomplished by the reaction of ((Me)LAlH)2(MU-O) (2; (Me)L = HC[(CMe)N(2,4,6-Me3C6H2)]2(-)) with either red selenium or metallic tellurium. The aluminum hydrogenselenide [(Me)LAl(SeH)]2(MU Se) (3) was also prepared from the reaction of red selenium and (Me)LAlH2 (1). All compounds were characterized by spectroscopic methods and X-ray diffraction studies. Density functional theory calculations were performed on 4 and 7. PMID- 23458275 TI - Computed tomography attenuation and patient characteristics as predictors of complications after pancreaticoduodenectomy. AB - OBJECTIVES: Morbidity after pancreaticoduodenectomy (PD) remains high. Computed tomography (CT) of intra-abdominal tissue has not been thoroughly evaluated to establish associations with the occurrence of complications after PD. The current study sought to determine whether differences in non-enhanced visceral attenuation predicted complications after PD. METHODS: Outcomes in patients undergoing PD were analysed according to the Clavien system for classifying complications and the International Study Group on Pancreatic Fistula system for classifying postoperative pancreatic fistula (POPF). Preoperative non-enhanced CT scans were evaluated by a blinded investigator for attenuation of abdominal viscera and fat thickness. Data on pancreatic firmness and pancreatic duct size were collected. Univariate and multivariate analyses were performed. RESULTS: A total of 134 patients underwent PD for malignant and benign disease. Rates of morbidity, mortality and POPF at 90 days were 61%, 4% and 23%, respectively. Patients with a body mass index of > 25 kg/m(2) had higher rates of POPF (P = 0.05) and complications (P < 0.01). In multivariate analysis, patients were more likely to develop any complication as CT attenuation decreased for paraspinus muscle (P < 0.01), spleen (P < 0.03) and liver (P = 0.01) parenchyma. CONCLUSIONS: Postoperative complications after PD remain prevalent. Decreased CT attenuation of abdominal viscera is an independent predictor of morbidity after PD and suggests a high-risk patient physiology for pancreatic resection. PMID- 23458276 TI - Ex Situ CO2 capture by carbonation of steelmaking slag coupled with metalworking wastewater in a rotating packed bed. AB - Both basic oxygen furnace (BOF) slag and cold-rolling wastewater (CRW) exhibiting highly alkaline characteristics require stabilization and neutralization prior to utilization and/or final disposal. Using CO2 from flue gases as the stabilizing and neutralizing agents could also diminish CO2 emissions. In this investigation, ex situ hot stove gas containing 30 vol% CO2 in the steelmaking process was captured by accelerated carbonation of BOF slag coupled with CRW in a rotating packed bed (RPB). The developed RPB process exhibits superior results, with significant CO2 removal efficiency (eta) of 96-99% in flue gas achieved within a short reaction time of 1 min at 25 degrees C and 1 atm. Calcite (CaCO3) was identified as the main product according to XRD and SEM-XEDS observations. In addition, the elimination of lime and Ca(OH)2 in the BOF slag during carbonation is beneficial to its further use as construction material. Consequently, the developed RPB process could capture the CO2 from the flue gas, neutralize the CRW, and demonstrate the utilization potential for BOF slag. It was also concluded that carbonation of BOF slag coupled with CRW in an RPB is a viable method for CO2 capture due to its higher mass transfer rate and CO2 removal efficiency in a short reaction time. PMID- 23458277 TI - Phonon line emission revealed by self-assembly of colloidal nanoplatelets. AB - We show that colloidal nanoplatelets can self-assemble to form a 1D superlattice. When self-assembled, an additional emission line appears in the photoluminescence spectrum at low temperatures. This emission line is a collective effect, greatly enhanced when the NPLs are self-assembled. It is attributed to the longitudinal optical (LO) phonon replica of the band-edge exciton, and its presence in self assembled nanoplatelets is explained using a model based on an efficient photons reabsorption between neighboring nanoplatelets. The presence of phonon replica at low temperatures in ensemble measurements suggests the possibility to design a laser, based on self-assembled nanoplatelets. PMID- 23458278 TI - Winning matches in Grand Slam men's singles: an analysis of player performance related variables from 1991 to 2008. AB - This study examines factors that lead to winning matches in men's singles Grand Slam tennis, and proposes guidelines for coaches and professional tennis players both in training and preparation for Grand Slam competitions. Using longitudinal data between 1991 and 2008 retrieved from the official website of the Association of Tennis Professionals, we analysed player performance over 9,144 matches in men's singles Grand Slam tournaments. To predict match outcome, 16 variables were classified into one of three categories: player skills and performance, player characteristics and match characteristics. The three categories were entered sequentially into a logistic regression model to predict the dependent variable: the chance of winning a men's singles Grand Slam match. The final altered model explains 79.4% of the variance (Nagelkerke's pseudo R (2)) in match outcomes and correctly predicted 90.6% of cases. The importance of serving, receiving, and break points is further confirmed. The positive effect of stature diminishes when players are taller than 186 cm. We recommend more training in returning skills; to avoid overestimation of the positive impact of stature, left hand and professional experience; and that a male player begins his professional tennis career by participating in the US Open or Wimbledon. PMID- 23458279 TI - Comparison of arch width, alveolar width and buccolingual inclination of teeth between Class II division 1 malocclusion and Class I occlusion. AB - OBJECTIVE: To compare the arch width, alveolar width, and buccolingual inclination of maxillary and mandibular posterior teeth between Class II division 1 malocclusion and Class I occlusion. MATERIALS AND METHODS: Forty-five subjects with Class I occlusion and 45 subjects with Class II division 1 malocclusion were selected to measure the maxillary and mandibular arch width and alveolar width of premolars and first molars with digital caliper. Buccolingual inclination of maxillary and mandibular premolars and first molars were measured with a modified universal bevel protractor. RESULTS: All of the posterior teeth in both groups were lingually tilted. The maxillary premolars and first molars were significantly more lingually tilted (P < .05) in Class II division 1 malocclusion than in Class I occlusion. Mandibular first premolars were significantly less lingually tilted in Class II division 1 malocclusion than in Class I occlusion. No significant difference of buccolingual inclination was found in mandibular second premolars and first molars between the two groups. No significant difference in maxillary and mandibular arch width and alveolar width was found between the two groups. CONCLUSIONS: Buccolingual inclination rather than arch width and alveolar width plays an important role in transverse discrepancy of Class II division 1 malocclusion. PMID- 23458280 TI - It's a small world...after all. PMID- 23458281 TI - Re: The 100 top-cited articles in orthodontics from 1975 to 2011 by Jifang Hui, Zongkai Han, Guannan Geng, Weijun Yan and Ping Shao. The Angle Orthodontist; on line early: http://dx.doi.org/10.2319/040512-284.1. PMID- 23458282 TI - Re response to: the 100 top-cited articles in orthodontics from 1975 to 2011 by Jifang Hui, Zongkai Han, Guannan Geng, Weijun Yan and Ping Shao. The Angle Orthodontist; on line early: http://dx.doi.org/10.2319/040512-284.1. PMID- 23458284 TI - Caregiving in first-episode psychosis: social characteristics associated with perceived 'burden' and associations with compulsory treatment. AB - AIMS: High incidence of psychosis and compulsory treatment within black and minority ethnic (BME) groups in the UK remain a concern. Psychosis has an impact on families and family involvement is important in predicting compulsory treatment. We therefore aimed to report the levels and predictors of caregiver burden in first-episode psychosis, in white British, and BME groups of carers, and investigate their relevance to compulsory treatment. METHODS: A total of 124 caregivers were interviewed soon after the onset of psychosis using the General Health Questionnaire, GHQ-28, the Experience of Caregiving Inventory, the Personal and Psychiatric History Schedule, and the MRC Sociodemographic Schedule. RESULTS: The overall level of distress as measured by GHQ-28 was high (mean 50, SD 11.4). Feelings of carer burden were also high (mean total negative score 72.5, SD 34.8), increased in men, and with carer age. Neither ethnicity nor social class nor social support was associated with distress or burden. Compulsory treatment was predicted by carer burden (as indicated by carer reports of 'problems with services' (OR 1.08; 95% CI 1.01, 1.15; P = 0.023)); this was particularly evident in the black Caribbean group of carers (OR 1.28; 95% CI 1.04, 1.57; P = 0.02) CONCLUSION: Carers of adults with first-episode psychosis experience considerable psychological distress and feelings of burden. There was a specific association between carer burden, specifically in terms of experience of services, and compulsory admission of service users, particularly in the black Caribbean group. Better ways of liaising with carers and targeted efforts to reduce carer burden at illness onset are needed. PMID- 23458286 TI - Social support, physical functioning, and cognitive functioning among older African American adults. AB - Social support and functional ability are related to a number of outcomes in later life among African Americans, including cognitive performance. This study examined how providing and receiving social support was related to fluid and crystallized cognitive abilities among aging African American adults after accounting for functional limitations, age, education, sex, income, and self reported health. Data from 602 African American adults (M = 69.08, SD = 9.74; 25% male) were analyzed using latent variable modeling. Fluid ability was a second order factor indicated by measures that assessed verbal memory, working memory, perceptual speed, and inductive reasoning. Crystallized ability was a first-order factor indicated by three measures that assessed vocabulary (Shipley Verbal Meaning Test and parts A and B of the ETS Vocabulary Test). Results indicated that the receipt of social support was negatively related to both fluid and crystallized abilities, while the provision of support was positively related to fluid and crystallized ability. Follow-up tests found that the receipt of support was more strongly related to fluid ability than crystallized ability. There was no significant difference regarding the relationship of provision of support with fluid ability compared to crystallized ability. Results discuss the importance of considering the social context of older adults when examining cognitive ability. PMID- 23458285 TI - The osteochondral dilemma: review of current management and future trends. AB - The management of articular cartilage defects remains challenging and controversial. Hyaline cartilage has limited capacity for self-repair and post injury cartilage is predominantly replaced by fibrocartilage through healing from the subchondral bone. Fibrocartilage lacks the key properties that characterize hyaline cartilage such as capacity for compression, hydrodynamic permeability and smoothness of the articular surface. Many reports relate compromised function associated with repaired cartilage and loss of function of the articular surface. Novel methods have been proposed with the key aim to regenerate hyaline cartilage for repair of osteochondral defects. Over the past decade, with many exciting developments in tissue engineering and regenerative cell-based technologies, we are now able to consider new combinatorial approaches to overcome the problems associated with osteochondral injuries and damage. In this review, the currently accepted surgical approaches are reviewed and considered; debridement, marrow stimulation, whole tissue transplantation and cellular repair. More recent products, which employ tissue engineering approaches to enhance the traditional methods of repair, are discussed. Future trends must not only focus on recreating the composition of articular cartilage, but more importantly recapitulate the nano-structure of articular cartilage to improve the functional strength and integration of repair tissue. PMID- 23458287 TI - Effects of aging on hypothalamic-pituitary-adrenal (HPA) axis activity and reactivity in virgin male and female California mice (Peromyscus californicus). AB - Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (~18-20months) and young (~4months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity and reproductive outcomes in young and old breeding adults would be illuminating. PMID- 23458288 TI - Myostatin induces atrophy of trout myotubes through inhibiting the TORC1 signaling and promoting Ubiquitin-Proteasome and Autophagy-Lysosome degradative pathways. AB - Myostatin (MSTN) is well known as a potent inhibitor of muscle growth in mammals and has been shown to both inhibit the growth promoting TORC1 signaling pathway and promote Ubiquitin-Proteasomal and Autophagy-Lysosomal degradative routes. In contrast, in non-mammalian species, despite high structural conservation of MSTN sequence, functional conservation is only assumed. Here, we show that treatment of cultured trout myotubes with human recombinant MSTN (huMSTN) resulted in a significant decrease of their diameter by up to 20%, validating the use of heterologous huMSTN in our in vitro model to monitor the processes by which this growth factor promotes muscle wasting in fish. Accordingly, huMSTN stimulation prevented the full activation by IGF1 of the TORC1 signaling pathway, as revealed by the analysis of the phosphorylation status of 4E-BP1. Moreover, the levels of the proteasome-dependent protein Atrogin1 exhibited an increase in huMSTN treated cells. Likewise, we observed a stimulatory effect of huMSTN treatment on the levels of LC3-II, the more reliable marker of the Autophagy-Lysosomal degradative system. Overall, these results show for the first time in a piscine species the effect of MSTN on several atrophic and hypertrophic pathways and support a functional conservation of this growth factor between lower and higher vertebrates. PMID- 23458289 TI - Evidence of steroid hormone activity in the chorioallantoic membrane of a Turtle (Pseudemys nelsoni). AB - Endocrine properties of extraembryonic membranes have traditionally been viewed as a characteristic of placental amniotes. However, our laboratory recently demonstrated that this ability extends to the extraembryonic membranes of two oviparous amniotes (chicken and alligator) indicating that endocrine extraembryonic membranes are not an innovation of placental amniotes and suggesting that this could be a shared amniote characteristic. In this study, we test our hypothesis that the chorioallantoic membrane (CAM) obtained from non archosaurian obligate oviparous amniotes such as turtles, have the potential for steroid hormone activity. To investigate synthesis of a major placental hormone, we performed explant culture and found that the turtle CAM synthesizes progesterone in vitro in the presence of a steroid precursor. In addition, to examine whether the CAM has the ability to respond to steroid signaling, we quantified mRNA expression of the progesterone, androgen, and two estrogen receptors. Finally, to determine if steroid receptor mRNA is translated to protein, we performed immunolocalization of the progesterone receptor. Our data demonstrate that the turtle CAM exhibits steroid synthesis and has steroid hormone signaling capabilities. To that end, steroid hormone activity has now been demonstrated in the CAMs of three oviparous species that represent three independent lineages within oviparous Reptilia that have never exhibited viviparity; thus these data support our hypothesis that endocrine activity of extraembryonic membranes is a conserved trait of Amniota. PMID- 23458290 TI - Effects of intravenous administration of pentoxifylline in pancreatic ischaemia reperfusion injury. AB - BACKGROUND: Therapeutic strategies to reduce the occurrence of pancreatic ischaemia-reperfusion (I-R) injury might improve outcomes in human pancreas and kidney transplantation. In addition to its haemorrheologic effects, pentoxifylline has an anti-inflammatory effect by inhibiting NF-kappaB activation. This group has previously demonstrated that pentoxifylline induces an anti-inflammatory response in acute pancreatitis and liver I-R models. This led to the hypothesis that pentoxifylline might reduce pancreatic and renal lesions and the systemic inflammatory response in pancreatic I-R injury. The aim of this experimental study was to evaluate the effect of pentoxifylline administration in a rat model of pancreatic I-R injury. METHODS: Pancreatic I-R was performed in Wistar rats over 1 h by clamping the splenic vessels. The animals submitted to I R were divided into two groups: Group 1 (n = 20, control) rats received saline solution administered i.v. at 45 min after ischaemia, and Group 2 (n = 20) rats received pentoxifylline (25 mg/kg) administered i.v. at 45 min after ischaemia. Blood samples were collected to enable the determination of amylase, creatinine, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10. Pancreatic malondialdehyde (MDA) content, pancreas histology and pulmonary myeloperoxidase (MPO) were also assessed. RESULTS: Significant reductions in serum TNF-alpha, IL-6 and IL-10 were observed in Group 2 compared with Group 1 (P < 0.05). No differences in pancreatic MDA content or serum amylase levels were observed between the two groups. The histologic score was significantly lower in pentoxifylline-treated animals, denoting less severe pancreatic histologic damage. CONCLUSIONS: Pentoxifylline administration reduced the systemic inflammatory response, the pancreatic histological lesion and renal dysfunction in pancreatic I-R injury and may be a useful tool in pancreas and kidney transplantation. PMID- 23458291 TI - Surnames in Albania: a study of the population of Albania through isonymy. AB - In order to describe the isonymic structure of Albania, the distribution of 3,068,447 surnames was studied in the 12 prefectures and their administrative subdivisions: the 36 districts and 321 communes. The number of different surnames found was 37,184. Effective surname number for the entire country was 1327, the average for prefectures was 653.3 +/- 84.3, for districts 365.9 +/- 42.0 and for communes 122.6 +/- 8.7. These values display a variation of inbreeding between administrative levels in the Albanian population, which can be attributed to the previously published "Prefecture effect". Matrices of isonymic distances between units within administrative levels were tested for correlation with geographic distances. The correlations were highest for prefectures (r = 0.71 +/- 0.06 for Euclidean distance) and lowest for communes (r = 0.37 +/- 0.011 for Nei's distance). The multivariate analyses (Principal component analysis and Multidimensional Scaling) of prefectures identify three main clusters, one toward the North, the second in Central Albania, and the third in the South. This pattern is consistent with important subclusters from districts and communes, which point out that the country may have been colonised by diffusion of groups in the North-South direction, and from Macedonia in the East, over a pre-existing Illiryan population. PMID- 23458292 TI - Pre-operative identification of an anomalous left coronary artery from the pulmonary artery in association with tetralogy of Fallot and an aortopulmonary window. AB - A newborn baby girl was diagnosed with tetralogy of Fallot and an aortopulmonary window. At 3 weeks of age, the coexistent diagnosis of an anomalous left coronary artery from the pulmonary artery was made. Initial surgical intervention included a Takeuchi baffle of the left coronary artery, closure of the aortopulmonary window, and placement of a right Blalock-Taussig shunt. Complete repair was undertaken at 12 months of age. Close pre-operative assessment of the coronary arterial anomaly is crucial in patients with an aortopulmonary window and tetralogy of Fallot. PMID- 23458293 TI - A simple and universal gel permeation chromatography technique for precise molecular weight characterization of well-defined poly(ionic liquid)s. AB - Poly(ionic liquid)s (PILs) are an important class of technologically relevant materials. However, characterization of well-defined polyionic materials remains a challenge. Herein, we have developed a simple and versatile gel permeation chromatography (GPC) methodology for molecular weight (MW) characterization of PILs with a variety of anions. PILs with narrow MW distributions were synthesized via atom transfer radical polymerization, and the MWs obtained from GPC were further confirmed via nuclear magnetic resonance end group analysis. PMID- 23458294 TI - The convergence of medicine and neurotoxins: a focus on botulinum toxin type A and its application in aesthetic medicine--a global, evidence-based botulinum toxin consensus education initiative: part I: botulinum toxin in clinical and cosmetic practice. AB - BACKGROUND: The U.S. Food and Drug Administration has approved four distinct formulations of botulinum toxin (BoNT) serotypes A and B (BoNTA and BoNTB) for medical use. These four products are indicated for many medical applications, but the three BoNTA formulations are the most widely used worldwide and are the only products approved for aesthetic use. The latest approval of a BoNTA with no complexing proteins (incobotulinumtoxinA) necessitates a review and discussion of differences between available formulations and the effect that these differences may have on clinical practice. OBJECTIVES: To review the history, science, safety information, and current and emerging applications of BoNT in clinical and cosmetic practice and to compare commercially available BoNTA formulations. METHODS AND MATERIALS: Publications, clinical trials, and author experience were used as a basis for an up-to-date review of BoNT and its use in human medicine. The similarities and differences between formulations are presented, and diffusion, spread, equivalency ratios, stability, and storage are discussed. RESULTS: Each commercial formulation has unique characteristics that may influence its use in aesthetic medicine. Familiarity with the similarities and differences between products will aid physicians in making patient care decisions. CONCLUSION: New formulations, emerging uses, and continued research into the science and uses of BoNTA will lead to increasingly refined therapeutic approaches and applications. Continued education is important for physicians to optimize use of the agent according to the most current evidence and approaches. PMID- 23458295 TI - The convergence of medicine and neurotoxins: a focus on botulinum toxin type A and its application in aesthetic medicine--a global, evidence-based botulinum toxin consensus education initiative: part II: incorporating botulinum toxin into aesthetic clinical practice. AB - BACKGROUND: The new world of safe aesthetic injectables has become increasingly popular with patients. Not only is there less risk than with surgery, but there is also significantly less downtime to interfere with patients' normal work and social schedules. Botulinum toxin (BoNT) type A (BoNTA) is an indispensable tool used in aesthetic medicine, and its broad appeal has made it a hallmark of modern culture. The key to using BoNTA to its best effect is to understand patient specific factors that will determine the treatment plan and the physician's ability to personalize injection strategies. OBJECTIVES: To present international expert viewpoints and consensus on some of the contemporary best practices in aesthetic BoNTA, so that beginner and advanced injectors may find pearls that provide practical benefits. METHODS AND MATERIALS: Expert aesthetic physicians convened to discuss their approaches to treatment with BoNT. The discussions and consensus from this meeting were used to provide an up-to-date review of treatment strategies to improve patient results. Information is presented on patient management and assessment, documentation and consent, aesthetic scales, injection strategies, dilution, dosing, and adverse events. CONCLUSION: A range of product- and patient-specific factors influence the treatment plan. Truly optimized outcomes are possible only when the treating physician has the requisite knowledge, experience, and vision to use BoNTA as part of a unique solution for each patient's specific needs. PMID- 23458297 TI - Highly sensitive and selective nonenzymatic detection of glucose using three dimensional porous nickel nanostructures. AB - Highly sensitive and selective nonenzymatic detection of glucose has been achieved using a novel disposable electrochemical sensor based on three dimensional (3D) porous nickel nanostructures. The enzyme-free sensor was fabricated through in situ growing porous nickel networks on a homemade screen printed carbon electrode substrate via electrochemically reducing the Ni(2+) precursor, along with continuously liberating hydrogen bubbles. The resulting nickel-modified electrode was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectrometry (EDX), powder X-ray diffractometry (XRD), and electrochemical techniques. Cyclic voltammetric, alternating-current impedance, and amperometric methods were used to investigate the catalytic properties of the assembled sensor for glucose electro-oxidation in alkaline media. Under optimized conditions, the enzymeless sensor exhibited excellent performance for glucose analysis selectively, offering a much wider linear range (from 0.5 MUM to 4 mM), an extremely low detection limit (0.07 MUM, signal-to-noise ratio (S/N) of 3), and an ultrahigh sensitivity of 2.9 mA/(cm(2) mM). Importantly, favorable reproducibility and long-term performance stability were obtained thanks to the robust frameworks. Application of the proposed sensor in monitoring blood glucose was also demonstrated. PMID- 23458298 TI - Surgical management of cephalic arch occlusive lesions: are there predictors for outcomes? AB - Cephalic arch lesions are common cause for dysfunction of brachiocephalic arteriovenous fistulas. For lesions resistant or not amenable to endovascular interventions, we used a term "cephalic arch occlusive lesions" (CAO) that included cephalic arch total occlusion, frequently recurrent stenosis (requiring angioplasty in <3-month intervals), high-grade elastic stenosis (residual stenosis >50% after angioplasty), or other lesions not amenable to endovascular interventions. Herein, we report 40 patients who underwent surgical revisions for total occlusions (17/40), frequently recurrent stenosis (17/40), high-grade elastic stenosis (5/40), and zigzag stenosis (1/40). The revisions included cephalic transposition and venovenostomy (CTV = 37/40), basilic transposition and venovenostomy (1/40), stenotic segment resection (1/40), and cephalic-jugular vein bypass graft (1/40). At 12-month post-CTV, the primary patency of the transposed cephalic vein, the fistula assisted primary and secondary patency rates were 25%, 82% and 97%, respectively. Notably, pre-CTV angioplasty of the proximal cephalic vein was the only significant predictor for the low primary patency rate (hazard ratio 4.5, p = 0.002). Accordingly, the primary patency rates were 12% and 58% in patients with and without pre-CTV angioplasty, respectively. In summary, surgical interventions are effective in salvaging fistulas complicated with CAO. Importantly, pre-CTV angioplasty of the proximal cephalic vein might adversely affect the outcome of CTV. PMID- 23458299 TI - Topological variability of fingerprint ridge density in a sub-Saharan population sample for application in personal identification. AB - Variability in ridge density in a sub-Saharan population sample was studied by counting ridges in three fingerprint areas (two distal regions, radial and ulnar, and one proximal region) on the epidermal surface of the distal phalanx. Study material was obtained from the fingerprint impressions of 100 male sub-Saharan subjects aged between 18- and 48-years old. The results were compared with those obtained from a Spanish population sample. Sub-Saharan males presented lower ridge density than Spanish males in the distal regions (radial and ulnar) of all fingers, whereas differences in the proximal region were only observed on some fingers. Using the differences observed between these populations, the likelihood ratio for inferring membership of one of the populations from a fingerprint of unknown origin was calculated; therefore, a ridge density of 14 or less for both areas (ulnar and radial), support an origin sub-Saharan versus Spanish population. PMID- 23458300 TI - Predictors of initial and sustained remission from alcohol use disorders: findings from the 30-year follow-up of the San Diego Prospective Study. AB - BACKGROUND: Individuals who report problematic drinking early in life often recover from alcohol-related disorders, with or without formal treatment. While risk factors associated with developing alcohol use disorders (AUDs), such as a family history of alcoholism and the genetically influenced low level of response (LR) to alcohol, have been identified, less is known about characteristics that relate to remission from AUDs. METHODS: The male subjects (98% Caucasian) for this study were 129 probands from the San Diego Prospective Study who were first evaluated at age 20 as drinking but not alcohol-dependent young men, most of whom were college graduates by follow-up. The individuals evaluated here met criteria for an AUD at their first follow-up at ages 28 to 33 and were followed every 5 years for the next 2 decades. Discrete-time survival analysis was used to examine rates of initial and sustained AUD remission and to evaluate the relationships of premorbid characteristics and other risk factors to these outcomes. RESULTS: Sixty percent of the sample met criteria for an initial AUD remission of 5 or more years, including 45% with sustained remission (i.e., no subsequent AUD diagnosis). Higher education, lower drinking frequency, and having a diagnosis of alcohol abuse (rather than dependence) were associated with higher rates of initial AUD remission. A lower LR to alcohol at age 20, as well as lower drinking frequency, having received formal alcohol treatment, and older age at the first follow-up all predicted a greater likelihood of sustained AUD remission. CONCLUSIONS: This study identified key factors associated with initial and sustained AUD remission in subjects diagnosed with AUD in young adulthood. Characteristics associated with better outcomes early in the life span, such as lower drinking frequency and early treatment, appear to have a lasting impact on remission from AUD across adulthood. PMID- 23458301 TI - Using wavelet denoising and mathematical morphology in the segmentation technique applied to blood cells images. AB - Accurate image segmentation is used in medical diagnosis since this technique is a noninvasive pre-processing step for biomedical treatment. In this work we present an efficient segmentation method for medical image analysis. In particular, with this method blood cells can be segmented. For that, we combine the wavelet transform with morphological operations. Moreover, the wavelet thresholding technique is used to eliminate the noise and prepare the image for suitable segmentation. In wavelet denoising we determine the best wavelet that shows a segmentation with the largest area in the cell. We study different wavelet families and we conclude that the wavelet db1 is the best and it can serve for posterior works on blood pathologies. The proposed method generates goods results when it is applied on several images. Finally, the proposed algorithm made in MatLab environment is verified for a selected blood cells. PMID- 23458302 TI - Longitudinal displacement in viscoelastic arteries: a novel fluid-structure interaction computational model, and experimental validation. AB - Recent in vivo studies, utilizing ultrasound contour and speckle tracking methods, have identified significant longitudinal displacements of the intima media complex, and viscoelastic arterial wall properties over a cardiac cycle. Existing computational models that use thin structure approximations of arterial walls have so far been limited to models that capture only radial wall displacements. The purpose of this work is to present a simple fluid-struture interaction (FSI) model and a stable, partitioned numerical scheme, which capture both longitudinal and radial displacements, as well as viscoelastic arterial wall properties. To test the computational model, longitudinal displacement of the common carotid artery and of the stenosed coronary arteries were compared with experimental data found in literature, showing excellent agreement. We found that, unlike radial displacement, longitudinal displacement in stenotic lesions is highly dependent on the stenotic geometry. We also showed that longitudinal displacement in atherosclerotic arteries is smaller than in healthy arteries, which is in line with the recent in vivo measurements that associate plaque burden with reduced total longitudinal wall displacement. This work presents a first step in understanding the role of longitudinal displacement in physiology and pathophysiology of arterial wall mechanics using computer simulations. PMID- 23458303 TI - Modeling of the kinetics of vitamin D(3) in osteoblastic cells. AB - A one-dimensional model for the transport of vitamin D(3) in an osteoblast cell is proposed, from its entry through the membrane to its activation of RANKL synthesis in the nucleus. In the membrane and cytoplasm, the transport of D(3) and RANKL is described by a diffusion process, while their interaction in the nucleus is modeled by a reaction-diffusion process. For the latter, an integral equation involving the boundary conditions, as well as an asymptotic solution in the regime of small concentrations, are derived. Numerical simulations are also performed to investigate the kinetics of D(3) and RANKL through the entire cell. Comparison between the asymptotics and numerics in the nucleus shows an excellent agreement. To our knowledge, this is the first time, albeit using a simple model, a description of the complete passage of D(3) through the cell membrane, the cytoplasm, into the cell nucleus, and finally the production of RANKL with its passage to the exterior of the cell, has been modeled. PMID- 23458305 TI - Lyapunov functions and global stability for SIR and SEIR models with age dependent susceptibility. AB - We consider global asymptotic properties for the SIR and SEIR age structured models for infectious diseases where the susceptibility depends on the age. Using the direct Lyapunov method with Volterra type Lyapunov functions, we establish conditions for the global stability of a unique endemic steady state and the infection-free steady state. PMID- 23458304 TI - Uniqueness of limit cycles and multiple attractors in a Gause-type predator-prey model with nonmonotonic functional response and Allee effect on prey. AB - The main purpose of this work is to analyze a Gause type predator-prey model in which two ecological phenomena are considered: the Allee effect affecting the prey growth function and the formation of group defence by prey in order to avoid the predation. We prove the existence of a separatrix curves in the phase plane, determined by the stable manifold of the equilibrium point associated to the Allee effect, implying that the solutions are highly sensitive to the initial conditions. Trajectories starting at one side of this separatrix curve have the equilibrium point (0,0) as their omega-limit, while trajectories starting at the other side will approach to one of the following three attractors: a stable limit cycle, a stable coexistence point or the stable equilibrium point (K,0) in which the predators disappear and prey attains their carrying capacity. We obtain conditions on the parameter values for the existence of one or two positive hyperbolic equilibrium points and the existence of a limit cycle surrounding one of them. Both ecological processes under study, namely the nonmonotonic functional response and the Allee effect on prey, exert a strong influence on the system dynamics, resulting in multiple domains of attraction. Using Liapunov quantities we demonstrate the uniqueness of limit cycle, which constitutes one of the main differences with the model where the Allee effect is not considered. Computer simulations are also given in support of the conclusions. PMID- 23458306 TI - An extension of Gompertzian growth dynamics: Weibull and Frechet models. AB - In this work a new probabilistic and dynamical approach to an extension of the Gompertz law is proposed. A generalized family of probability density functions, designated by Beta * (p,q), which is proportional to the right hand side of the Tsoularis-Wallace model, is studied. In particular, for p=2, the investigation is extended to the extreme value models of Weibull and Frechet type. These models, described by differential equations, are proportional to the hyper-Gompertz growth model. It is proved that the Beta* (2,q) densities are a power of betas mixture, and that its dynamics are determined by a non-linear coupling of probabilities. The dynamical analysis is performed using techniques of symbolic dynamics and the system complexity is measured using topological entropy. Generally, the natural history of a malignant tumour is reflected through bifurcation diagrams, in which are identified regions of regression, stability, bifurcation, chaos and terminus. PMID- 23458307 TI - Mathematical modelling and control of echinococcus in Qinghai province, China. AB - In this paper, two mathematical models, the baseline model and the intervention model, are proposed to study the transmission dynamics of echinococcus. A global forward bifurcation completely characterizes the dynamical behavior of the baseline model. That is, when the basic reproductive number is less than one, the disease-free equilibrium is asymptotically globally stable; when the number is greater than one, the endemic equilibrium is asymptotically globally stable. For the intervention model, however, the basic reproduction number alone is not enough to describe the dynamics, particularly for the case where the basic reproductive number is less then one. The emergence of a backward bifurcation enriches the dynamical behavior of the model. Applying these mathematical models to Qinghai Province, China, we found that the infection of echinococcus is in an endemic state. Furthermore, the model appears to be supportive of human interventions in order to change the landscape of echinococcus infection in this region. PMID- 23458308 TI - Dynamics of an infectious diseases with media/psychology induced non-smooth incidence. AB - This paper proposes and analyzes a mathematical model on an infectious disease system with a piecewise smooth incidence rate concerning media/psychological effect. The proposed models extend the classic models with media coverage by including a piecewise smooth incidence rate to represent that the reduction factor because of media coverage depends on both the number of cases and the rate of changes in case number. On the basis of properties of Lambert W function the implicitly defined model has been converted into a piecewise smooth system with explicit definition, and the global dynamic behavior is theoretically examined. The disease-free is globally asymptotically stable when a certain threshold is less than unity, while the endemic equilibrium is globally asymptotically stable for otherwise. The media/psychological impact although does not affect the epidemic threshold, delays the epidemic peak and results in a lower size of outbreak (or equilibrium level of infected individuals). PMID- 23458309 TI - On latencies in malaria infections and their impact on the disease dynamics. AB - In this paper, we modify the classic Ross-Macdonald model for malaria disease dynamics by incorporating latencies both for human beings and female mosquitoes. One novelty of our model is that we introduce two general probability functions (P 1 (t) and P 2 (t)) to reflect the fact that the latencies differ from individuals to individuals. We justify the well-posedness of the new model, identify the basic reproduction number R0 for the model and analyze the dynamics of the model. We show that when R 0 <1, the disease free equilibrium E0 is globally asymptotically stable, meaning that the malaria disease will eventually die out; and if R 0 >1, E 0 becomes unstable. When R 0 >1, we consider two specific forms for P 1 (t) and P 2 (t): (i) P 1 (t) and P 2 (t) are both exponential functions; (ii) P 1 (t) and P 2 (t) are both step functions. For (i), the model reduces to an ODE system, and for (ii), the long term disease dynamics are governed by a DDE system. In both cases, we are able to show that when R 0 >1 then the disease will persist; moreover if there is no recovery (gamma1=0), then all admissible positive solutions will converge to the unique endemic equilibrium. A significant impact of the latencies is that they reduce the basic reproduction number, regardless of the forms of the distributions. PMID- 23458310 TI - Global threshold dynamics in an HIV virus model with nonlinear infection rate and distributed invasion and production delays. AB - We consider a mathematical model that describes the interactions of the HIV virus, CD4 cells and CTLs within host, which is a modification of some existing models by incorporating (i) two distributed kernels reflecting the variance of time for virus to invade into cells and the variance of time for invaded virions to reproduce within cells; (ii) a nonlinear incidence function f for virus infections, and (iii) a nonlinear removal rate function h for infected cells. By constructing Lyapunov functionals and subtle estimates of the derivatives of these Lyapunov functionals, we shown that the model has the threshold dynamics: if the basic reproduction number (BRN) is less than or equal to one, then the infection free equilibrium is globally asymptotically stable, meaning that HIV virus will be cleared; whereas if the BRN is larger than one, then there exist an infected equilibrium which is globally asymptotically stable, implying that the HIV-1 infection will persist in the host and the viral concentration will approach a positive constant level. This together with the dependence/independence of the BRN on f and h reveals the effect of the adoption of these nonlinear functions. PMID- 23458311 TI - Effects of childhood aggression on parenting during adolescence: the role of parental psychological need satisfaction. AB - The current study examined the explanatory role of satisfaction of parental psychological needs in effects of childhood aggression on various adolescent perceived parenting behaviors in middle adolescence. Research questions were examined in a large multi-informant, prospective community study of ethnic majority Belgian families (N = 609, 49.7% girls). Aggression was rated by parents when children were in middle childhood (M age = 7.5 years) using the Child Behavior Checklist. Parents reported on satisfaction of their needs for autonomy, competence, and relatedness when children were in preadolescence (M age = 10.5 years) and early adolescence (M age = 13.5 years) using the Parenting Stress Index. Parenting behaviors were rated by adolescents in early adolescence (M age = 13.5 years) and in middle adolescence (M age = 15.5 years), using the Parenting Scale (overreactive discipline), the Psychological Control Scale, Youth Self Report (psychological control), and the Parenting Practices Questionnaire (warmth). Mediation of associations from aggression to parenting by parents' psychological needs was examined using multiple mediation structural equation modeling analyses. Childhood aggression was related to decreased satisfaction of parents' needs for competence, relatedness, and autonomy in early adolescence. Satisfaction of parents' needs for relatedness and, to a lesser extent, competence affected later parenting, and satisfaction of all three needs affected changes in parenting. Relations were specific for the different parenting constructs but similar across parental gender. Targeting parents' psychological needs may aid effectiveness of interventions that are aimed at decreasing (psychologically, overreactive) controlling parenting and at increasing supportive parenting. PMID- 23458312 TI - Gold-catalyzed cycloisomerization of 1,7-enyne esters to structurally diverse cis 1,2,3,6-tetrahydropyridin-4-yl ketones. AB - A synthetic method that relies on gold(I)-catalyzed cycloisomerization of 1,7 enyne esters to prepare highly functionalized cis-1,2,3,6-tetrahydropyridin-4-yl ketone derivatives in good to excellent yields and as a single regio-, diastereo , and enantiomer is described. By taking advantage of the distinctive differences in the electronic and steric properties between an NHC (NHC = N-heterocyclic carbene) and phosphine ligand in the respective gold(I) complexes, a divergence in product selectivity was observed. In the presence of [PhCNAuIPr](+)SbF6(-) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) as the catalyst, tandem 1,3-acyloxy migration/6-exo-trig cyclization/1,5-acyl migration of the substrate was found to selectively occur to give the delta-diketone-substituted 1,2,3,6 tetrahydropyridine adduct. In contrast, reactions with the gold(I) phosphine complex [MeCNAu(JohnPhos)](+)SbF6(-) (JohnPhos = (1,1'-biphenyl-2-yl)-di-tert butylphosphine) as the catalyst was discovered to result in preferential 1,3 acyloxy migration/6-exo-trig cyclization/hydrolysis of the 1,7-enyne ester and formation of the cis-1,2,3,6-tetrahydropyridin-4-yl ketone derivative. The utility of this piperidine forming strategy as a synthetic tool that makes use of 1,7-enyne esters was exemplified by its application to the synthesis of an enantiopure analogue of the bioactive 2,3,4,4a,5,9b-hexahydroindeno[1,2 c]pyridine family of compounds. PMID- 23458313 TI - Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis. AB - OBJECTIVES: Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics. METHODS: Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of >=3. RESULTS: All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of <=14.35 cm/s together with a cross-section area of >=1.55 cm(2) was found to predict SI with sensitivity of 100% and specificity of 78%. CONCLUSIONS: Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively. PMID- 23458314 TI - Anti-inflammatory properties of yellow and orange pigments from Monascus purpureus NTU 568. AB - The Monascus species has been used in foods for thousands of years in China. In this study, 10 azaphilone pigments, including four yellow and six orange pigments, were isolated from the fermented rice and dioscorea of Monascus purpureus NTU 568. By employing lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells, we determined the inhibitory activities of these pigments on nitric oxide (NO) production. As a result, four orange pigments, monaphilols A-D, showed the highest activities (IC50 = 1.0-3.8 MUM), compared with the other two orange pigments, monascorubrin (IC50 > 40 MUM) and rubropunctatin (IC50 = 21.2 MUM), and the four yellow pigments ankaflavin (IC50 = 21.8 MUM), monascin (IC50 = 29.1 MUM), monaphilone A (IC50 = 19.3 MUM), and monaphilone B (IC50 = 22.6 MUM). Using Western blot and ELISA kits, we found that treatments with 30 MUM of the yellow pigments and 5 MUM of the orange pigments could down-regulate the protein expression of inducible nitric oxide synthase (iNOS) and suppress the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6). We also used two animal experiments to evaluate the anti-inflammatory effects of these pigments. In a 12 O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema model, eight of these pigments (0.5 mg/ear) could prevent ear edema against TPA administrations on the ears of BALB/c mice. In an LPS-injection mice model, several of these pigments (10 mg/kg) could inhibit the NO, TNF-alpha, IL-1beta, and IL-6 levels in the plasma of BALB/c mice. As concluded from the in vitro and in vivo studies, six azaphilonoid pigments, namely, ankaflavin, monaphilone A, and monaphilols A-D, showed high potential to be developed into chemopreventive foods or drugs against inflammation-associated diseases. PMID- 23458315 TI - Perspectives of a self-selected sample of former patients on the long-term health outcomes of interferon-based hepatitis C treatments: an exploratory study. AB - Research indicates that patients treated with interferon-based regimens can experience persistent neurotoxicity after treatment ceases and new symptoms attributable to the regimens can emerge post-treatment. To explore post-hepatitis C virus (HCV) treatment outcomes, in-depth interviews were conducted with a self selected sample of people from two Australian states who had completed an interferon-based regimen at least 24-weeks prior to being interviewed. Participants comprised almost equal numbers of men and women aged from 26 to 57 years, who were treated for HCV genotypes 1 through to 4, and included treatment responders, non-responders and those who had relapsed after treatment. Of 27 participants who volunteered to be part of this study, 25 reported persistent physical and psychological side-effects after treatment. Participants perceived a direct causal link between the treatment regimen and their ongoing symptoms. Reportedly, recovery from treatment was inhibited by an absence of a follow-up protocol that identified and addressed patients' post-treatment needs, including medical care for persistent side-effects, referral, and information and advice about lifestyle issues. Although the study's sample was not representative of all people treated for HCV, it is likely that persistent side-effects and their impact can affect other patients following completion of HCV treatments. Further prospective studies of HCV treatment outcomes are needed. In the meantime, the systematic implementation of a follow-up protocol in liver clinics might expedite recovery in patients who experience ongoing adverse health. PMID- 23458316 TI - Effect of nanoparticle stabilization and physicochemical properties on exposure outcome: acute toxicity of silver nanoparticle preparations in zebrafish (Danio rerio). AB - Nanotechnology has vast potential for expanded development and novel application in numerous sectors of society. With growing use and applications, substantial production volumes and associated environmental release can be anticipated. Exposure effect of nanoparticles (NP) on biological systems may be intrinsic to their physicochemical properties introducing unknown associated risk. Herein, we expand the knowledge of health and environmental impact of silver nanoparticles (AgNPs), testing the acute toxicity of 14 AgNP preparations on developing zebrafish embryos (Danio rerio). Toxicological end points, including mortality, hatching rate, and heart rate were recorded. Concentration, stabilization agent and physicochemical properties were monitored as contributing outcome factors. Our findings indicate wide ranging LC50 24 h postfertilization values (0.487 ppm (0.315, 0.744 95% CI) to 47.89 ppm (18.45, 203.49 95% CI)), and indicate surface charge and ionic dissolution as key contributory factors in AgNP exposure outcome. PMID- 23458318 TI - Excited-state dynamics in rigid media: evidence for long-range energy transfer. AB - In semirigid PEG-DMA550 films with the added anthracene derivatives PEG-An and Acr-An, energy transfer quenching of the metal-to-ligand charge transfer excited state Ru(bpy)3(2+)* to give -(3)An occurs by both rapid, static, and slow, diffusional quenching processes. The appearance of -(3)An was verified by transient absorption measurements. The kinetics of the two quenching processes have been analyzed by a Stern-Volmer kinetic analysis. The data for static quenching are consistent with energy transfer quenching with a distance dependence consistent with Dexter (exchange) energy transfer. On the basis of this analysis Bohr radii were found to be 26 and 11 A for PEG-An and Acr-An, respectively. Evidence for triplet-triplet annihilation between triplet anthracene excited states in the films was obtained from the concentration dependences of excited-state decay. These results provide evidence for long-range energy migration between derivatized anthracenes in rigid, cross-linked PEG DMA550 films. PMID- 23458317 TI - Review of the investigation and surgical management of resectable ampullary adenocarcinoma. AB - BACKGROUND: Ampullary adenocarcinoma is considered to have a better prognosis than either pancreatic or bile duct adenocarcinoma. Pancreaticoduodenectomy is associated with significant mortality and morbidity. Some recent publications have advocated the use of endoscopic papillectomy for the treatment of early ampullary adenocarcinoma. This article reviews investigations and surgical treatment options of ampullary tumours. METHODS: A systematic review of English language articles was carried out using an electronic search of the Ovid MEDLINE (from 1996 onwards), PubMed and Cochrane Database of Systematic Reviews databases to identify studies related to the investigation and management of ampullary tumours. RESULTS: Distinguishing between ampullary adenoma and adenocarcinoma is challenging given the inaccuracy of endoscopic biopsy, for which high false negative rates of 25-50% have been reported. Endoscopic ultrasound is the most accurate method for local staging of ampullary lesions, but distinguishing between T1 and T2 adenocarcinomas is difficult. Lymph node metastasis occurs early in the disease process; it is lowest for T1 tumours, but the risk is still high at 8-45%. Case reports of successful endoscopic resection and transduodenal ampullectomy of T1 adenocarcinomas have been published, but their duration of follow-up is limited. CONCLUSIONS: Optimal staging should be used to distinguish between ampullary adenoma and adenocarcinoma. Pancreaticoduodenectomy remains the treatment of choice for all ampullary adenocarcinomas. PMID- 23458319 TI - Comorbidity and internet-delivered transdiagnostic cognitive behavioural therapy for anxiety disorders. AB - Internet-delivered transdiagnostic anxiety interventions aim to reduce symptoms across several anxiety disorders using one treatment protocol. However, it is unclear whether comorbidity affects outcomes of such treatment. This study re examined data from a recent randomised controlled trial (N = 129) that evaluated the efficacy of an Internet-delivered transdiagnostic cognitive behavioural therapy (iCBT) intervention for participants with principal diagnoses of generalised anxiety disorder (GAD), social phobia (SP) panic disorder and agoraphobia (PDA), of whom 72% met criteria for a comorbid anxiety disorder or depression. Participants were divided into two groups based on whether or not they had a comorbid disorder before treatment. Participants with comorbid conditions reported higher symptom levels at pre-treatment, post-treatment, and follow-up across a range of measures. Both groups showed significant reductions in symptoms over treatment; however, participants with comorbid disorders showed greater reductions in measures of GAD, PDA, SP, depression, and neuroticism. In addition, treatment significantly reduced the number of comorbid diagnoses at follow-up. These results indicate transdiagnostic iCBT protocols have the potential to reduce comorbidity. PMID- 23458321 TI - Unexpectedly high yield carbon nanotube synthesis from low-activity carbon feedstocks at high concentrations. AB - We report a new direction for highly efficient carbon nanotube (CNT) synthesis where, in place of conventional highly reactive carbon feedstocks at low concentrations, highly stable carbon feedstocks at high concentrations were shown to produce superior yields. We found that a saturated hydrocarbon that is considered to possess a low reactivity, delivered at high concentrations, could achieve an extremely high growth yield (2.5 times that when using ethylene). This result stems from the unique behavior where the CNT yield linearly increased with carbon concentration, in contrast to more reactive carbon feedstocks, where the yield peaks. We propose that the mechanisms for the growth kinetics for high- and low-reactivity carbon feedstocks are fundamentally different, where the latter benefits from a longer catalyst lifetime because of a relatively low production rate of carbon impurities. PMID- 23458320 TI - Percutaneous radiofrequency ablation versus surgical radiofrequency ablation for malignant liver tumours: the long-term results. AB - BACKGROUND: Radiofrequency ablation (RFA) has been used to treat hepatocellular carcinoma (HCC) and liver metastases for more than 10 years with promising early outcomes. Preliminary results comparing percutaneous and surgical approaches have shown no difference in short-term outcomes. In this study, the longer-term outcomes were presented. METHODS: Patients with liver malignancies treated by RFA were prospectively studied from 2003 to 2011. Post-ablation assessment by computed tomography (CT) scan and serum biochemistry was performed at regular intervals. Recurrence rates and long-term survival were analysed. RESULTS: A total of 233 patients with liver malignancies (75.5% HCC and 24.5% liver metastases) were analysed. Three RFA approaches were used (percutaneous 58.4%, laparoscopic 9.4% and open 32.2%). The median follow-up time was 29 months. Complete ablation was achieved in 83.7%, with no difference between the two approaches. More wound and chest complications were observed in the surgical group. Intra-hepatic recurrences were observed in 69.5%; extra-hepatic recurrences were detected in 22.3%, with no difference between the two groups. There was no statistical difference between the two approaches in overall 1-, 3- and 5-year survival. CONCLUSION: An extended period of follow-up in patients with liver malignancies showed that RFA is an effective treatment. No difference was demonstrated between the percutaneous and surgical approach, in terms of recurrence and survival. PMID- 23458322 TI - Modelling dendritic ecological networks in space: an integrated network perspective. AB - Dendritic ecological networks (DENs) are a unique form of ecological networks that exhibit a dendritic network topology (e.g. stream and cave networks or plant architecture). DENs have a dual spatial representation; as points within the network and as points in geographical space. Consequently, some analytical methods used to quantify relationships in other types of ecological networks, or in 2-D space, may be inadequate for studying the influence of structure and connectivity on ecological processes within DENs. We propose a conceptual taxonomy of network analysis methods that account for DEN characteristics to varying degrees and provide a synthesis of the different approaches within the context of stream ecology. Within this context, we summarise the key innovations of a new family of spatial statistical models that describe spatial relationships in DENs. Finally, we discuss how different network analyses may be combined to address more complex and novel research questions. While our main focus is streams, the taxonomy of network analyses is also relevant anywhere spatial patterns in both network and 2-D space can be used to explore the influence of multi-scale processes on biota and their habitat (e.g. plant morphology and pest infestation, or preferential migration along stream or road corridors). PMID- 23458323 TI - Carbon atoms in ethanol do not contribute equally to formation of single-walled carbon nanotubes. AB - We propose a unique experimental technique in which isotopically labeled ethanol, e.g., 12CH3-13CH2-OH, is used to trace the carbon atoms during the formation of single-walled carbon nanotubes (SWNTs) by chemical vapor deposition (CVD). The proportion of 13C is determined from Raman spectra of the obtained SWNTs, yielding the respective contribution of ethanol's two different carbon atoms to SWNT formation. Surprisingly, the carbon away from the hydroxyl group is preferably incorporated into the SWNT structure, and this preference is significantly affected by growth temperature, presence of secondary catalyst metal species such as Mo, and even by the substrate material. These experiments provide solid evidence confirming that the active carbon source is not limited to products of gas-phase decomposition such as ethylene and acetylene, but ethanol itself is arriving at and reacting with the metal catalyst particles. Furthermore, even the substrate or other catalytically inactive species directly influences the formation of SWNTs, possibly by changing the local environment around the catalyst or even the reaction pathway of SWNT formation. These unexpected effects, which are inaccessible by conventional techniques, paint a clearer picture regarding the decomposition and bond breaking process of the ethanol precursor during the entire CVD process and how this might influence the quality of the obtained SWNTs. PMID- 23458324 TI - SEEKING and depression in stroke patients: an exploratory study. AB - The concept of SEEKING describes a predisposition to search enthusiastically for rewards in the environment. While SEEKING and its underlying functional anatomy have been extensively investigated in animals, such processes in humans, especially brain-damaged individuals, remain understudied. We therefore conducted an exploratory behavioral study in stroke patients to investigate the effects of brain lesions that anatomically could be interpreted to impact the SEEKING system and predicted relationships to depression. Patients with lesions in anterior, medial, and/or subcortical lesions showed significantly lower SEEKING scores and higher depression scores than nonlesioned subjects in the control group. Based on our data and related work on animals, we propose central involvement of the anterior subcortical-cortical midline system as core of the limbic system in SEEKING in humans. PMID- 23458325 TI - The disappearance of onchocerciasis from the Itwara focus, western Uganda after elimination of the vector Simulium neavei and 19 years of annual ivermectin treatments. AB - The Itwara onchocerciasis focus is located around the Itwara forest reserve in western Uganda. In 1991, annual treatments with ivermectin started in the focus. They were supplemented in 1995 by the control of the vector Simulium neavei, which was subsequently eliminated from the focus. The impact of the two interventions on the disease was assessed in 2010 by nodule palpations, examinations of skin snips by microscopy and PCR, and Ov16 recombinant ELISA. There was no evidence of any microfilaria in 688 skin snips and only 2 (0.06%) of 3316 children examined for IgG4 were slightly above the arbitrary cut off of 40. A follow up of the same children 21 months later in 2012 confirmed that both were negative for diagnostic antigen Ov-16, skin snip microscopy and PCR. Based on the World Health Organization (WHO) elimination criteria of 2001 and the Uganda onchocerciasis certification guidelines, it was concluded that the disease has disappeared from the Itwara focus after 19 years of ivermectin treatments and the elimination of the vector around 2001. Ivermectin treatments were recommended to be halted. PMID- 23458326 TI - Pancreaticoduodenectomy following chemoradiotherapy for locally advanced adenocarcinoma of the pancreatic head. AB - OBJECTIVES: The aim of this study was to assess oncological outcomes in patients treated with pancreaticoduodenectomy for advanced pancreatic head adenocarcinoma after preoperative chemoradiotherapy and to compare these with outcomes in patients treated with surgery alone. METHODS: From 2004 to 2009, patients treated with pancreaticoduodenectomy for pancreatic head adenocarcinoma were included in a retrospective comparative study. Patients with locally advanced adenocarcinoma were treated with preoperative chemoradiotherapy (CRT group) and were compared with those treated with surgery alone (SURG group). RESULTS: A total of 111 patients were included; these comprised 72 patients in the SURG group and 39 patients in the CRT group. The median follow-up was 21 months. Patients in the CRT group presented with a more advanced tumoral status. Microscopic resection rates were similar in both groups, but nodal status and vascular or lymphatic emboli were lower in the CRT group. At 3 years, the SURG and CRT groups exhibited similar overall (36% and 51%, respectively) and disease-free (35% and 37%, respectively) survival (P = 0.10). CONCLUSIONS: In patients with advanced pancreatic head adenocarcinoma, a good response after preoperative chemoradiotherapy results in a survival rate similar to that in patients treated with surgery alone in whom the initial prognosis is better. PMID- 23458327 TI - The spectrum of BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas. AB - We sought to identify the full range of founder mutations in BRCA1 and BRCA2 in the Bahamas and to estimate the proportion of all BRCA1 and BRCA2 mutations that are accounted for by founder mutations. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history. A founder mutation had previously been identified in 49 patients. We conducted full sequencing of the BRCA1 and BRCA2 genes and multiplex ligation-dependent probe amplification (MLPA) for 156 patients. A novel founder mutation in BRCA2 (exon 17 818delA) was seen in four different patients and five other unique mutations in BRCA1 and BRCA2, including a large deletion (exons 8-9) in BRCA1. In total, a mutation was seen in 58 of the 214 patients (27%); 92% of carriers carried one of the seven founder mutations. Approximately 27% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in BRCA1 or BRCA2, a prevalence which far exceeds that of any other country. The majority of women who carry a mutation in the Bahamas, carry one of the seven founder mutations, making it possible to offer genetic testing to all women at risk for breast cancer in the Bahamas. PMID- 23458329 TI - From Obamacare to markets in artificial organs. PMID- 23458330 TI - Czech marathon in the research of heart assist systems and total artificial heart. PMID- 23458331 TI - Artificial Organs 2012: a year in review. AB - In this editor's review, articles published in 2012 are organized by category and briefly summarized. We aim to provide a brief reflection of the currently available worldwide knowledge that is intended to advance and better human life while providing insight for continued application of technologies and methods of organ replacement, recovery, and regeneration. As the official journal of the International Federation for Artificial Organs, the International Faculty for Artificial Organs, and the International Society for Rotary Blood Pumps, Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ replacement, recovery, and regeneration from all over the world. We take this time also to express our gratitude to our authors for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide such meaningful suggestions to the author's work whether eventually accepted or rejected, and especially to those whose native tongue is not English. Without these excellent and dedicated reviewers, the quality expected from such a journal could not be possible. We also express our special thanks to our publisher, Wiley Periodicals, for their expert attention and support in the production and marketing of Artificial Organs. We look forward to recording further advances in the coming years. PMID- 23458333 TI - Synthetic control over photoinduced electron transfer in phosphorescence zinc sensors. AB - Despite the promising photofunctionalities, phosphorescent probes have been examined only to a limited extent, and the molecular features that provide convenient handles for controlling the phosphorescence response have yet to be identified. We synthesized a series of phosphorescence zinc sensors based on a cyclometalated heteroleptic Ir(III) complex. The sensor construct includes two anionic cyclometalating ligands and a neutral diimine ligand that tethers a di(2 picolyl)amine (DPA) zinc receptor. A series of cyclometalating ligands with a range of electron densities and band gap energies were used to create phosphorescence sensors. The sensor series was characterized by variable temperature steady-state and transient photoluminescence spectroscopy studies, electrochemical measurements, and quantum chemical calculations based on time dependent density functional theory. The studies demonstrated that the suppression of nonradiative photoinduced electron transfer (PeT) from DPA to the photoexcited Ir(IV) species provided the underlying mechanism that governed the phosphorescent response to zinc ions. Importantly, the Coulombic barrier, which was located on either the cyclometalating ligand or the diimine ligand, negligibly influenced the PeT process. Phosphorescence modulation by PeT strictly obeyed the Rehm-Weller principle, and the process occurred in the Marcus-normal region. These findings provide important guidelines for improving sensing performance; an efficient phosphorescence sensor should include a cyclometalating ligand with a wide band gap energy and a deep oxidation potential. Finally, the actions of the sensor were demonstrated by visualizing the intracellular zinc ion distribution in HeLa cells using a confocal laser scanning microscope and a photoluminescence lifetime imaging microscope. PMID- 23458334 TI - Voluntary survey completion among team members: implications of noncompliance and missing data for multilevel research. AB - We explored whether voluntary survey completion by team members (in aggregate) is predictable from team members' collective evaluations of team-emergent states. In doing so, we reanalyze less-than-complete survey data on 110 teams from a published field study, using so-called traditional and modern missing data techniques to probe the sensitivity of these team-level relationships to data missingness. The multivariate findings revealed that a greater within-team participation rate was indeed related to a higher team-level (mean) score on team mental efficacy (across all four missing-data techniques) and less dispersion among team member judgments about internal cohesion (when the 2 modern methods were used). In addition, results show that a commonly used approach of retaining only those teams with high participation rates produces inflated standardized effect size (i.e., R2) estimates and decreased statistical power. Suggestions include research design considerations and a comprehensive methodology to account for team member data missingness. PMID- 23458335 TI - Beyond step-down analysis: a new test for decomposing the importance of dependent variables in MANOVA. AB - Multivariate analysis of variance (MANOVA) is often categorized as a tool for experimental psychologists. However, it also continues to be a popular statistical procedure used by organizational scientists. Unfortunately, when the dependent variables (DV) are correlated with one another, interpreting the significant omnibus test in MANOVA becomes difficult. The present article proposes a novel way of interpreting a significant MANOVA that draws from work dedicated to understanding the relative importance of correlated predictors in multiple regression. Relative importance analyses are specifically designed to overcome the limitations caused by correlated variables and permit researchers to appropriately partition shared variance. We derive and extend relative weight analysis to MANOVA designs and demonstrate how these weights may be used to draw inferences concerning the relative contribution of each DV to the overall multivariate effect. Through our example, we illustrate how researchers must consider the correlations among the DVs when interpreting a significant multivariate effect, and our procedure provides an effective mechanism for doing just that. PMID- 23458336 TI - Justice at the millennium, a decade later: a meta-analytic test of social exchange and affect-based perspectives. AB - Although a flurry of meta-analyses summarized the justice literature at the turn of the millennium, interest in the topic has surged in the decade since. In particular, the past decade has witnessed the rise of social exchange theory as the dominant lens for examining reactions to justice, and the emergence of affect as a complementary lens for understanding such reactions. The purpose of this meta-analytic review was to test direct, mediating, and moderating hypotheses that were inspired by those 2 perspectives, to gauge their adequacy as theoretical guides for justice research. Drawing on a review of 493 independent samples, our findings revealed a number of insights that were not included in prior meta-analyses. With respect to social exchange theory, our results revealed that the significant relationships between justice and both task performance and citizenship behavior were mediated by indicators of social exchange quality (trust, organizational commitment, perceived organizational support, and leader member exchange), though such mediation was not apparent for counterproductive behavior. The strength of those relationships did not vary according to whether the focus of the justice matched the target of the performance behavior, contrary to popular assumptions in the literature, or according to whether justice was referenced to a specific event or a more general entity. With respect to affect, our results showed that justice-performance relationships were mediated by positive and negative affect, with the relevant affect dimension varying across justice and performance variables. Our discussion of these findings focuses on the merit in integrating the social exchange and affect lenses in future research. PMID- 23458337 TI - Missing link in the service profit chain: a meta-analytic review of the antecedents, consequences, and moderators of service climate. AB - Service climate captures employees' consensual perceptions of organizations' emphasis on service quality. Although many studies have examined the foundation issues and outcomes of service climate, there is a lack of a comprehensive model explicating the antecedents, outcomes, and moderators of service climate. The current study fills this void in the literature. By conducting a meta-analysis of 58 independent samples (N = 9,363), we found support for service climate as a critical linkage between internal and external service parameters. In addition, we found differential effects of service-oriented versus general human resource practices and leadership on service climate, as well as disparate impacts of service climate contingent on types of service, measures of service climate, and sources of rating. Research and practical implications are discussed. PMID- 23458328 TI - Nutritional countermeasures targeting reactive oxygen species in cancer: from mechanisms to biomarkers and clinical evidence. AB - Reactive oxygen species (ROS) exert various biological effects and contribute to signaling events during physiological and pathological processes. Enhanced levels of ROS are highly associated with different tumors, a Western lifestyle, and a nutritional regime. The supplementation of food with traditional antioxidants was shown to be protective against cancer in a number of studies both in vitro and in vivo. However, recent large-scale human trials in well-nourished populations did not confirm the beneficial role of antioxidants in cancer, whereas there is a well-established connection between longevity of several human populations and increased amount of antioxidants in their diets. Although our knowledge about ROS generators, ROS scavengers, and ROS signaling has improved, the knowledge about the direct link between nutrition, ROS levels, and cancer is limited. These limitations are partly due to lack of standardized reliable ROS measurement methods, easily usable biomarkers, knowledge of ROS action in cellular compartments, and individual genetic predispositions. The current review summarizes ROS formation due to nutrition with respect to macronutrients and antioxidant micronutrients in the context of cancer and discusses signaling mechanisms, used biomarkers, and its limitations along with large-scale human trials. PMID- 23458338 TI - Being bullied by same- versus other-sex peers: does it matter for adolescent victims? AB - The negative consequences of peer victimization on psychosocial adjustment are well documented. The consequences, however, may depend on who the bullies are. In this study, we examined the consequences of same- versus other-sex victimization. The sample consisted of 4,941 Finnish adolescents (ages 14-15; 47.7% boys). We used structural equation modeling to examine both concurrent and longitudinal associations of same- and other-sex victimization with depression, negative perception of peers, and social self-esteem. Both same- and other-sex victimization were related to psychosocial adjustment. Concurrently, the victimization experiences with same-sex peers in particular were associated with generalized cognitions about peers, whereas being bullied by other-sex peers was related to adolescents' social self-esteem more strongly than victimization by same-sex peers. The longitudinal associations, in turn, showed that only being bullied by boys had carry-over effects on girls' adjustment. Other-sex victimization can have serious consequences especially on girls' psychosocial adjustment. PMID- 23458339 TI - Hyposoter didymator uses a combination of passive and active strategies to escape from the Spodoptera frugiperda cellular immune response. AB - An endoparasitic life style is widespread among Hymenoptera, and various different strategies allowing parasitoids to escape from the host encapsulation response have been reported. Species carrying polydnaviruses (PDVs), such as the ichneumonid Hyposoter didymator, generally rely on the viral symbionts to evade host immune responses. In this work, we show that H. didymator eggs can evade encapsulation by the host in the absence of calyx fluid (containing the viral particles), whereas protection of the larvae requires the presence of calyx fluid. This evasion by the eggs depends on proteins associated with the exochorion. This type of local passive strategy has been described for a few species carrying PDVs. Immune evasion by braconid eggs appears to be related to PDVs or proteins synthesized in the oviducts being associated with the egg. We report that in H. didymator, by contrast, proteins already present in the ovarian follicles are responsible for the eggs avoiding encapsulation. Mass spectrometry analysis of the egg surface proteins revealed the presence of host immune-related proteins, including one with similarities with apolipophorin-III, and also the presence of three viral proteins encoded by IVSPERs (Ichnovirus Structural Protein Encoding Regions). PMID- 23458340 TI - Long-term effect of systemic RNA interference on circadian clock genes in hemimetabolous insects. AB - RNA interference (RNAi) strategy, which enables gene-specific knock-down of transcripts, has been spread across a wide area of insect studies for investigating gene function without regard to model and non-model insects. This technique is of particular benefit to promote molecular studies on non-model insects. However, the optimal conditions for RNAi are still not well understood because of its variable efficiency depending on the species, target genes, and experimental conditions. To apply RNAi technique to long-running experiments such as chronobiological studies, the effects of RNAi have to persist throughout the experiment. In this study, we attempted to determine the optimal concentration of double-stranded RNA (dsRNA) for systemic RNAi and its effective period in two different insect species, the cricket Gryllus bimaculatus and the firebrat Thermobia domestica. In both species, higher concentrations of dsRNA principally yielded a more efficient knock-down of mRNA levels of tested clock genes, although the effect depended on the gene and the species. Surprisingly, the effect of the RNAi reached its maximum effect 1-2 weeks and 1 month after the injection of dsRNA in the crickets and the firebrats, respectively, suggesting a slow but long-term effect of RNAi. Our study provides fundamental information for utilizing RNAi technique in any long-running experiment. PMID- 23458341 TI - Local Coulomb explosion of boron nitride nanotubes under electron beam irradiation. AB - In many previous reports, the engineering of nanostructures using electron beam irradiation (EBI) in a high vacuum has primarily been based on the knock-on atom displacement. Herein, we report a new phenomenon under EBI that can also be effectively used to engineer a nanostructure: local Coulomb explosion (LCE) of cantilevered multiwalled boron nitride nanotubes (BNNTs) resulted from their profound positive charging. The nanotubes are gradually shortened, while the tubular shells at free ends are torn into graphene-like pieces and then removed during LCE. The phenomenon is dependent not only on the characteristics of an incident electron beam, as in the case of a common knock-on process, but also on the cantilevered tube length. Only after the electron beam density and tube length exceed the threshold values can LCE take place, and the threshold value for one of the parameters decreases with increasing the value of the other one. A model based on the diffusion of electron-irradiation-induced holes along a BNNT is proposed to describe the positive charge accumulation and can well explain the observed LCE. LCE opens up an efficient and versatile way to engineer BNNTs and other dielectric nanostructures with a shorter time and a lower beam density than those required for the knock-on effect-based engineering. PMID- 23458342 TI - The combined effects of storage temperature and packaging on the sensory, chemical, and physical properties of a Cabernet Sauvignon wine. AB - A Californian Cabernet Sauvignon was stored for 6 months at three different constant temperatures to study the combined effects of storage temperature and packaging configuration. Glass bottles with natural cork, synthetic cork, and screw cap closure, as well as two Bag-in-Box treatments, were used in the experiment. A trained sensory panel was able to detect significant changes in aroma, flavor, taste, mouthfeel, and color attributes among the samples, differences that were found also with various chemical and physical measurements (volatile profile, polyphenol pattern, enological parameters, color space). Additionally, two commonly used polyphenol assays were compared to each other in terms of their ability to detect the changes in the polyphenol profile. Generally, sample changes were more pronounced due to the different storage temperatures, with 30 sensory attributes differing significantly among the three different storage temperatures, while only 17 sensory attributes showed a significant packaging effect. With increasing storage temperature the packaging effect became more pronounced, resulting in the largest changes in the Bag-in-Box samples stored at the highest temperature of 40 degrees C. At the highest storage temperature, all wines showed oxidized characters, independent of the wine packaging configurations, but to a varying degree. Generally, wines that received highest oxygen amounts and storage temperatures were much lighter, less red, and more brown-yellow at the end of the 6-month storage period, compared to their counterparts stored at 10 degrees C. These changes in color and polyphenols, respectively, were also detected with the two spectrophotometric assays. With increasing storage temperature both assays measured reduced concentrations in total phenols and total anthocyanins, while total tannins, degree of ionized anthocyanins, and color density increased. Various volatile compounds differed significantly among the samples, with largest relative concentration changes in acetates, organic acids, and alcohols, in good agreement with previous literature reports, with some being well correlated to specific sensory attributes too; for example, various acetates correlated to cherry and fruit aromas and flavors. The study shows that storage at elevated temperatures could be a valuable tool for wine packaging screening and testing new and improved wine packaging types under the worst conditions, which are unfortunately not unrealistic. PMID- 23458343 TI - Responding to the treatment challenge of patients with severe BPD: results of three pilot studies of inpatient schema therapy. AB - BACKGROUND: Schema Therapy (ST), a psychotherapy model integrating cognitive, experiential and behavioural interventions, was initially developed and evaluated as an outpatient treatment for patients with severe and chronic disorders, among them Borderline Personality Disorder (BPD). Two randomized controlled trials have demonstrated the effectiveness of ST for BPD, delivered in an individual or group format, in the outpatient setting. However, the most severely impaired BPD patients are referred to inpatient treatment due to suicidality and severe self harm. Specialized inpatient treatment programs are limited, with little evaluative research. AIMS: The pilot studies are designed to be first steps in naturalistic clinical settings to evaluate the effects of an intensive inpatient ST treatment program. METHOD: This report presents the results of three independent uncontrolled pilot studies with a total of 92 BPD patients. The programs combine individual and group modalities and are consistent theoretically with the ST model for BPD patients. RESULTS: RESULTS show that inpatient ST can significantly reduce symptoms of severe BPD and global severity of psychopathology with effect sizes ranging from Cohen's d = 2.84 to Cohen's d = .43. CONCLUSIONS: Differences in the effect sizes across the three pilot studies could be explained by length of treatment, number of group psychotherapists and their training. Although there are limitations to the presented pilot studies such as differences in the samples, treatment settings, variations in the treatment itself and the use of different measures, which may have influenced outcome, they are a starting point for describing and evaluating inpatient treatment for BPD in naturalistic settings. PMID- 23458344 TI - Effect of temperature on bone tissue: histological changes. AB - The analysis of burned human remains has been of great interest among forensic anthropologists largely due to the difficulty that their recovery, classification, reconstruction, and identification present. The main purpose of this analysis is to present histological methodology for the interpretation of bones altered by thermal processes. We include analyses of the microscopic changes among bones exposed to different temperatures, with the goal of establishing categories of histological morphology in relation to fire temperature. Samples of bone (ilium) were exposed systematically to controlled temperatures. Analysis of the resulting histological changes has allowed the formation of a clear four-stage classification of the alterations observed. This classification should prove useful in assessing bone changes in relation to temperature of exposure, particularly in cases where this temperature was previously not known. PMID- 23458345 TI - Novel and nontraditional use of stable isotope tracers to study metal bioavailability from natural particles. AB - We devised a novel tracing approach that involves enriching test organisms with a stable metal isotope of low natural abundance prior to characterizing metal bioavailability from natural inorganic particles. In addition to circumventing uncertainties associated with labeling natural particles and distinguishing background metals, the proposed "reverse labeling" technique overcomes many drawbacks inherent to using radioisotope tracers. Specifically, we chronically exposed freshwater snails ( Lymnaea stagnalis ) to synthetic water spiked with Cu that was 99.4% (65)Cu to increase the relative abundance of (65)Cu in the snail's tissues from ~32% to >80%. The isotopically enriched snails were then exposed to benthic algae mixed with Cu-bearing Fe-Al particles collected from the Animas River (Colorado), an acid mine drainage impacted river. We used (63)Cu to trace Cu uptake from the natural particles and inferred their bioavailability from calculation of Cu assimilation into tissues. Cu assimilation from these particles was 44%, indicating that 44% of the particulate Cu was absorbed by the invertebrate. This demonstrates that inorganic particulate Cu can be bioavailable. The reverse labeling approach shows great potential in various scientific areas such as environmental contamination and nutrition for addressing questions involving uptake of an element that naturally has multiple isotopes. PMID- 23458346 TI - Second international congress on immunopharmacology: delivery systems and current strategies for drug design. PMID- 23458347 TI - Expression of p53 protein after nonablative rejuvenation: the other side of the coin. AB - BACKGROUND: Disturbance of p53 expression may play an important role in the pathogenesis of ultraviolet (UV) light-induced skin cancer as well as photoaging. OBJECTIVES: To objectively evaluate the potential effect of nonablative facial rejuvenation on p53 expression. PARTICIPANTS AND METHODS: Thirty patients with Fitzpatrick skin type III to IV were divided into five groups. Each group underwent a different nonablative modality: radiofrequency (RF), intense pulsed light (IPL), electro-optical synergy (ELOS) (combined RF and IPL), 1,320-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and 2,940-nm erbium-doped (Er):YAG laser minipeel. Skin biopsies were obtained before treatment, by the end of treatment, and 3 months after treatment. Biopsies were also taken from 30 controls. Quantitative evaluation of p53 was performed using computer image analysis for immunostained tissues. RESULTS: P53 expression was statistically significantly greater at the end of IPL (p = .02) and ELOS (p = .02) treatments than before treatment but was statistically insignificantly lower (p > .05) 3 months after treatment than at the end of treatment. No significant differences (p > .05) were observed in p53 level after RF, 1,320-nm Nd:YAG, and 2,940-nm Er:YAG mini-peel treatments from baseline. CONCLUSIONS: The increase in epidermal p53 expression after IPL treatment could increase the risk of skin neoplasia by intense pulsed light-induced DNA damage which may lead to dysregulation of apoptosis and initiation of skin cancer. PMID- 23458348 TI - Huge mitral annular caseoma: complementary role of multimodality imaging. PMID- 23458349 TI - Modeling of dielectric properties of complex fluids with an equation of state. AB - The static permittivity is a key property for describing solutions containing polar and hydrogen bonding compounds. However, the precise relationship between the molecular and dielectric properties is not well-established. Here we show that the relative permittivity at zero frequency (static permittivity) can be modeled simultaneously with thermodynamic properties. The static permittivity is calculated from an extension of the framework developed by Onsager, Kirkwood, and Frohlich to associating mixtures. The thermodynamic properties are calculated from the cubic-plus-association (CPA) equation of state that includes the Wertheim association model as formulated in the statistical associating fluid theory (SAFT) to account for hydrogen bonding molecules. We show that, by using a simple description of the geometry of the association, we may calculate the Kirkwood g-factor as a function of the probability of hydrogen bond formation. The results show that it is possible to predict the static permittivity of complex mixtures over wide temperature and pressure ranges from simple extensions of well-established theories simultaneously with the calculation of thermodynamic properties. PMID- 23458350 TI - Mechanistic studies on the degradation and protein release characteristics of poly(lactic-co-glycolic-co-hydroxymethylglycolic acid) nanospheres. AB - The purpose of this study was to gain mechanistic insights into the effect of different formulation parameters on the degradation and release behavior of protein-loaded nanoparticulate carrier systems based on an aliphatic polyester with pendant hydroxyl groups, poly(lactic-co-glycolic-hydroxymethyl glycolic acid) (pLGHMGA). Bovine serum albumin (BSA) was used as a model protein. BSA loaded pLGHMGA nanospheres of 400-700 nm were prepared using a solvent evaporation method using pLGHMGA of different molecular weights and different compositions. Also, the concentration of pLGHMGA in the organic phase was varied. The nanospheres showed a continuous mass loss accompanied by continuous decrease in number average molecular weight, which indicates that the degradation of the nanospheres is by bulk degradation with a rapid release of water-soluble low molecular weight fragments. On the basis of NMR analysis, it is concluded that intramolecular transesterification precedes extensive hydrolysis of the polymer and degradation of the nanospheres. BSA-loaded freeze-dried nanospheres showed a significant burst release of 40-50% of the BSA loading. In contrast, nonfreeze dried samples showed a small burst of around 10-20%, indicating that freeze drying induced pore formation. Nonlyophilized nanospheres prepared from pLGHMGA with 64/18/18 lactic/glycolic/hydroxymethylglycolic acid (L/G/HMG) ratio showed a relatively fast release of BSA for the next 30 days. Nanospheres prepared from a more hydrophobic pLGHMGA (74/13/13, L/G/HMG) showed a two-phase release. Circular dichroism analysis showed that the secondary structure of the released protein was preserved. This study shows a correlation between release behavior and particle erosion rate, which can be modulated by the copolymer composition. PMID- 23458351 TI - Upper midline incision for liver resection. AB - OBJECTIVES: The optimal incision for liver resection in living donors or patients with small tumours should be revisited. This study introduces the upper midline incision (UMI) above the umbilicus for various liver resections using a conventional open-surgery technique. METHODS: A retrospective study based on a prospectively collected database of 308 liver resections performed by a single surgeon was conducted to evaluate the feasibility, safety and applicability of the UMI. RESULTS: From September 2006 to September 2010, this incision was used successfully in 308 consecutive liver resections in all patients with tumours measuring <= 5 cm and all living donors without any extension of the incision. The median length of the incision was 16.4 cm (range: 12-20 cm).The median operating time was 189 min (range: 54-305 min). The median postoperative hospital stay was 8 days (range: 6-17 days). One patient died in the postoperative period from heart failure. All other patients fully recovered and returned to their previous level of activity. Over a median follow-up of 31 months (range: 20-68 months), 25 complications (8.1%) developed. Seven wound infections (2.3%) occurred with no incisional hernia. CONCLUSIONS: The UMI can be used safely and effectively in conventional open surgery in various liver resections and should therefore be given priority as the first-line technique in living liver donors and patients with tumours measuring <= 5 cm. PMID- 23458352 TI - Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression. AB - BACKGROUND: Neo-adjuvant chemo-radiotherapy has been proposed to improve resectability of locally-advanced pancreatic cancer (LAPC). However, the ability of neo-adjuvant therapy to induce radiological tumour regression has not been reported. METHODS: Pre- and post-treatment computed tomography (CT) scans of patients undergoing neo-adjuvant chemo-radiotherapy for LAPC were reviewed. LAPC was sub-classified into borderline resectable disease [<= 180 degrees involvement of the superior mesenteric artery (SMA); short-segment encasement/abutment of the common hepatic artery; or tumour-associated deformity, abutment or short-segment occlusion of the superior mesenteric vein (SMV)/ portal vein (PV) that was amenable to vascular resection and reconstruction] and locally advanced un-resectable pancreatic cancer (vascular involvement more than that described for borderline resectable pancreatic cancer). The radiological response and surgical resection rates were assessed. RESULTS: Sixteen patients received neo-adjuvant therapy for LAPC during 2005-2008. Regression of major vascular involvement, i.e. un-encasement or regression of abutment of any involved vessels was not observed in any patient. Pre- and post-treatment tumour densities were not statistically different. Fifty per cent of patients with borderline resectable disease and none of the patients with locally advanced un-resectable pancreatic cancer eventually underwent surgical resection. CONCLUSION: Neo adjuvant treatment does not induce radiological tumour regression of LAPC with major vascular involvement. Patient selection for neo-adjuvant trial enrollment should remain focused on borderline disease which may have a potential for surgical resection. PMID- 23458353 TI - A multi-site study of functional outcomes following a themed approach to hand-arm bimanual intensive therapy for children with hemiplegia. AB - AIM: This study investigated the effects of a theme-based ('magic') variation of the hand-arm bimanual intensive therapy programme, in two different countries, in improving activity performance for children with hemiplegia, including those with severe movement restrictions. METHOD: Twenty-three children with spastic hemiplegia (13 males, 10 females; mean age 10y 7mo, range 7-15y; Manual Ability Classification System level I, two; level II, 13; level III, eight), participated in one of three, 2-week, summer camps. A within-participant experimental design was used with the Assisting Hand Assessment and Children's Hand Experience Questionnaire as primary outcome measures. Evaluations occurred immediately before the first day, on the last day, and 3 months after intervention. Two groups underwent additional assessments 2 weeks before the camp. RESULTS: Significant intervention effects were seen on the Assisting Hand Assessment (p=0.002) and on the Children's Hand Experience Questionnaire (p<0.001), the latter maintained at follow-up. The affected hand was reported to be used in 25% of bimanual activities before the camp, progressing to 93% after camp, and decreasing to 86% at follow-up. Severity of impairment did not influence progress. INTERPRETATION: This themed approach to intensive intervention showed positive results in bimanual use, with improvements in independence sustained at follow-up. Although children across camps and motor severity made progress, some questions remain about intensity and duration of intervention to optimize longer term outcomes. PMID- 23458354 TI - Estimation of joint incongruence in dysplastic canine elbows before and after dynamic proximal ulnar osteotomy. AB - OBJECTIVE: To characterize joint incongruence in dysplastic canine elbows before and after dynamic proximal ulnar osteotomy (DPUO). STUDY DESIGN: Clinical, prospective study. ANIMALS: Dogs (n = 10; 12 elbows) with >= 2 mm radioulnar incongruence (RUI), FCP, and/or OCD. METHODS: Computed tomography in a nonload bearing position was used to generate in silico 3D models of the elbow joint before DPUO, and this was repeated after DPUO union (median 3 months postoperatively). On these models, RUI, humeroradial and humeroulnar subchondral joint space width (SJSW) as well as alignment of the proximal ulnar segment were investigated. RESULTS: RUI at the medial coronoid process (MCP) decreased (P = .001), while it increased at the lateral coronoid process (P = .0005), and remained unchanged at the level of the trochlear ridge (P = .25). SJSW at the MCP increased (P = .001), changing from focal joint space collapse preoperatively to a more homogeneous pattern of moderate SJSW at follow-up. The proximal ulnar segment rotated in all 3 planes with caudal tipping at the level of the osteotomy and varus deformity, while no axial translation could be noted. CONCLUSIONS: DPUO results in reduction of RUI and amelioration of focal contact area at the MCP. This effect is the result of a complex three-dimensional rotation of the proximal ulnar segment, rather than axial shift. PMID- 23458355 TI - Evaluation of antioxidant activity and characterization of phenolic constituents of Phyllanthus amarus root. AB - The antioxidant property of the 70% aqueous ethanol extract of Phyllanthus amarus roots and its ether-soluble, ethyl acetate-soluble, and aqueous fractions were investigated by various in vitro assays. The root extracts showed higher DPPH, hydroxyl, superoxide, and nitric oxide radical scavenging and reducing power activity. Among all the samples, the ethyl acetate-soluble fraction demonstrated highest radical scavenging activity and total phenolics content. Twenty-eight different phenolic compounds were identified by LCMS/MS analysis of the ethyl acetate-soluble fraction. The majority of the compounds were found to exist as their glycosides, and many of these were gallic acid derivatives. Free epicatechin and gallic acid were also identified in the ethyl acetate-soluble fraction. The present investigation suggested that P. amarus root is a potent antioxidant and can be used for the prevention of diseases related to oxidative stress. PMID- 23458356 TI - Recorded scan times can limit the accuracy of sedimentation coefficients in analytical ultracentrifugation. AB - We report systematic and large inaccuracies in the recorded elapsed time in data files from the analytical ultracentrifuge, leading to overestimates of the sedimentation coefficients of up to 10%. This far exceeds previously considered factors contributing to the uncertainty in this parameter and has significant ramifications for derived parameters such as hydrodynamic shape and molar mass estimates. The source of this error is currently unknown, but we found it to be quantitatively consistent across different instruments, increasing with rotor speed. Furthermore, its occurrence appears to correlate with the use of the latest data acquisition software from the manufacturer, in use in some of our laboratories for nearly 2 years. Many of the recently published sedimentation coefficients may need to be reexamined. The problem can be easily recognized by comparing the file timestamps provided by the operating system with the elapsed scan times recorded within the data files. Therefore, we implemented a routine in SEDFIT that can automatically examine the data files, alert the user to significant discrepancies, and correct the scan times accordingly. This eliminates errors in the recorded scan times. PMID- 23458357 TI - Ecological validity of the Multiple Errands Test using predictive models of dysexecutive problems in everyday life. AB - The"dysexecutive syndrome" is composed of a range of cognitive, emotional, and behavioral deficits that are difficult to evaluate using traditional neuropsychological tests. The Multiple Errands Test (MET) was originally developed to systematize the assessment of the more elusive manifestations of the dysexecutive syndrome. The aims of this study were to examining the reliability of the MET and to investigate the predictive ability of its indices to explain a range of "dysexecutive"-related symptoms in everyday life. Thirty patients with acquired brain injury participated in this study. The MET showed an adequate inter-rater reliability and ecological validity. The main performance indices from the MET were able to significantly predict severity of everyday life executive problems, with different indices predicting particular manifestations of different components of executive functions. PMID- 23458358 TI - Direct evidence of stacking disorder in the mixed ionic-electronic conductor Sr4Fe6O12+delta. AB - Determining the structure-to-property relationship of materials becomes particularly challenging when the material under investigation is dominated by defects and structural disorder. Knowledge on the exact atomic arrangement at the defective structure is required to understand its influence on the functional properties. However, standard diffraction techniques deliver structural information that is averaged over many unit cells. In particular, information about defects and order-disorder phenomena is contained in the coherent diffuse scattering intensity which often is difficult to uniquely interpret. Thus, the examination of the local disorder in materials requires a direct method to study their structure on the atomic level with chemical sensitivity. Using aberration corrected scanning transmission electron microscopy in combination with atomic resolution electron energy-loss spectroscopy, we show that the controversial structural arrangement of the Fe2O2+delta layers in the mixed ionic-electronic conducting Sr4Fe6O12+delta perovskite can be unambiguously resolved. Our results provide direct experimental evidence for the presence of a nanomixture of "ordered" and "disordered" domains in an epitaxial Sr4Fe6O12+delta thin film. The most favorable arrangement is the disordered structure and is interpreted as a randomly occurring but well-defined local shift of the Fe-O chains in the Fe2O2+delta layers. By analyzing the electron energy-loss near-edge structure of the different building blocks in the Sr4Fe6O12+delta unit cell we find that the mobile holes in this mixed ionic-electronic conducting oxide are highly localized in the Fe2O2+delta layers, which are responsible for the oxide-ion conductivity. A possible link between disorder and oxygen-ion transport along the Fe2O2+delta layers is proposed by arguing that the disorder can effectively break the oxygen diffusion pathways. PMID- 23458361 TI - Left ventricular mechanical and energetic changes in long-term isoproterenol induced hypertrophied hearts of SERCA2a transgenic rats. AB - Overexpression of cardiac sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) has been suggested as a strategic intervention for cardiac failure. However, its benefit in wild-type (WT) rats with normal SERCA2a levels seems to be small. To investigate whether it would be beneficial in a cardiac failure model with down regulated SERCA2a levels, we made a cardiac hypertrophy model using isoproterenol infusion (1.2mgkg(-1)day(-1) for 1 or 4weeks; TG-ISO1w and TG-ISO4w, respectively) in SERCA2a transgenic (TG) rats and compared these rats with littermate WT rats that underwent the same treatments (WT-ISO1w and WT-ISO4w). We analyzed the left ventricular (LV) mechanoenergetics in the excised heart using our original cross-circulation system. The downward shift of curvilinear LV end systolic pressure-volume relations (ESPVRs) observed in WT-ISO4w rats was abolished in TG-ISO4w rats. The slope and VO2 intercept of the VO2 (myocardial oxygen consumption per beat)-PVA (systolic pressure-volume area: total mechanical energy per beat) linear relation did not differ in any of the groups. The most important finding was a significantly smaller O2 cost of LV contractility in the TG-ISO4w group, which means that less O2 is needed to exert the same LV contractility, compared with the other groups. The increased ratio of SERCA2a/phospholamban returned to the level of the WT-control group only in the TG-ISO4w group. Longer-term up-regulation of mitochondrial transcription factor A for genes of mitochondrial enzymes producing ATP was observed in TG rats. In conclusion, longer-term overexpression of SERCA2a will be beneficial in the present cardiac failure model with down-regulated SERCA2a levels. PMID- 23458360 TI - Limiting factors for liver regeneration after a major hepatic resection for colorectal cancer metastases. AB - BACKGROUND: Chemotherapy before resection of colorectal metastases in the liver is extensively used and has been shown to induce histopathological changes in the liver parenchyma, although little is known about the effect of chemotherapy on liver regeneration. The aim of this study was to determine if pre-operative chemotherapy influences the regenerated liver volume after a major liver resection. PATIENTS AND METHODS: This retrospective cohort study included 74 patients subjected to a major liver resection for colorectal metastases. Patients were divided into two groups depending on whether they had been treated with chemotherapy less than 3 months before surgery or not. Liver volumes were measured before and 1 year after resection. RESULTS: Pre-operative chemotherapy reduced volumetric liver regeneration (83 +/- 2% versus 91 +/- 2%; P = 0.007) as compared with patients without chemotherapy. There was a linear correlation between regenerated volume and time interval between the end of chemotherapy to resection (P = 0.031). CONCLUSIONS: Pre-operative chemotherapy in patients with colorectal liver metastases negatively affects volume regeneration after a partial hepatectomy. The time interval between chemotherapy and surgery determines the impact of these affects. PMID- 23458359 TI - Involvement of redox state in the aging of Drosophila melanogaster. AB - SIGNIFICANCE: The main objective of this review was to provide an exposition of investigations, conducted in Drosophila melanogaster, on the role of reactive oxygen species and redox state in the aging process. While early transgenic studies did not clearly support the validity of the oxidative stress hypothesis of aging, predicated on the accumulation of structural damage, they spawned a broader search for redox-related effects that might impact the aging process. RECENT ADVANCES: Initial evidence implicating the thiol redox state as a possible causative factor in aging has been obtained in Drosophila. Overexpression of genes, such as GCL, G6PD, Prx2, and Prx5, which are involved in the maintenance of thiol redox homeostasis, has strong positive effects on longevity. Further, the depletion of peroxiredoxin activity in the mitochondria through the double knockdown of Prx5 and Prx3 not only results in a redox crisis but also elicits a rapid aging phenotype. CRITICAL ISSUES: Herein, we summarize the present status of knowledge about the main components of the machinery controlling thiol redox homeostasis and describe how age-related redox fluctuations might impact aging more acutely through disruption of the redox-sensitive signaling mechanisms rather than via the simple accumulation of structural damage. FUTURE DIRECTIONS: Based on these initial insights into the plausible impact of redox fluctuations on redox signaling, future studies should focus on the pathways that have been explicitly implicated in aging, such as insulin signaling, TOR, and JNK/FOXO, with particular attention to elements that are redox sensitive. PMID- 23458362 TI - A novel role for receptor activator of nuclear factor (NF)-kappabeta ligand (RANKL) in atorvastatin-mediated mobilization of endothelial progenitor cells. PMID- 23458363 TI - The significance of adrenal hemorrhage: undiagnosed Waterhouse-Friderichsen syndrome, a case series. AB - A retrospective series of five cases of nontraumatic gross adrenal hemorrhage were identified in 800 consecutive forensic autopsies. All patients were males, of different ethnicities and with ages ranging from 2 to 48 years. All patients had a clinical history and autopsy findings suggestive of sepsis. Pre- or postmortem microbiological cultures were variably positive for Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, and methicillin resistant Staphylococcus aureus. The fifth case was positive for yeast and a coagulase negative staphylococcus; contamination of this culture medium cannot be excluded. No cases had a culture positive for Neisseria meningitidis. We find that the reviewed patients with grossly or microscopically identifiable adrenal hemorrhage were otherwise healthy individuals who died suddenly as a consequence of bacterial infection. In each case, signs and symptoms compatible with premortem adrenal insufficiency were reported; in no instance was the adrenal hemorrhage clinically identified. PMID- 23458366 TI - Healthcare reform in diabetes: more ranting about a broken system. PMID- 23458364 TI - Structures and comparative characterization of biosynthetic gene clusters for cyanosporasides, enediyne-derived natural products from marine actinomycetes. AB - Cyanosporasides are marine bacterial natural products containing a chlorinated cyclopenta[a]indene core of suspected enediyne polyketide biosynthetic origin. Herein, we report the isolation and characterization of novel cyanosporasides C-F (3-6) from the marine actinomycetes Salinispora pacifica CNS-143 and Streptomyces sp. CNT-179, highlighted by the unprecedented C-2' N-acetylcysteamine functionalized hexose group of 6. Cloning, sequencing, and mutagenesis of homologous ~50 kb cyanosporaside biosynthetic gene clusters from both bacteria afforded the first genetic evidence supporting cyanosporaside's enediyne, and thereby p-benzyne biradical, biosynthetic origin and revealed the molecular basis for nitrile and glycosyl functionalization. This study provides new opportunities for bioengineering of enediyne derivatives and expands the structural diversity afforded by enediyne gene clusters. PMID- 23458365 TI - Solvent effect on pathways and mechanisms for D-fructose conversion to 5 hydroxymethyl-2-furaldehyde: in situ 13C NMR study. AB - Noncatalytic reactions of D-fructose were kinetically investigated in dimethylsulfoxide (DMSO), water, and methanol as a function of time at temperatures of 30-150 degrees C by applying in situ (13)C NMR spectroscopy. The products were quantitatively analyzed with distinction of isomeric species by taking advantage of site-selective (13)C labeling technique. In DMSO, D-fructose was converted first into 3,4-dihydroxy-2-dihydroxymethyl-5 hydroxymethyltetrahydrofuran having no double bond in the ring, subsequently into 4-hydroxy-5-hydroxymethyl-4,5-dihydrofuran-2-carbaldehyde having one double bond through dehydration, and finally into 5-hydroxymethyl-2-furaldehyde (5-HMF) having two double bonds. No other reaction pathways were involved, as shown from the carbon mass balance. In water, 5-HMF, the final product in DMSO, was generated with the precursors undetected and furthermore transformed predominantly into formic and levulinic acids and slightly into 1,2,4 benzenetriol accompanied by polymerization. D-glucose was also produced through the reversible transformation of the reactant D-fructose. In methanol, some kinds of anhydro-D-fructoses were generated instead of 5-HMF. The reaction pathways can thus be controlled by taking advantage of the solvent effect. The D-fructose conversion reactions are of the first order with respect to the concentration of D-fructose and proceed on the order of minutes in DMSO but on the order of hours in water and methanol. The rate constant was three orders of magnitude larger in DMSO than in water or methanol. PMID- 23458367 TI - Development of a functional analytical nurse observation chart (FANOC). AB - BACKGROUND: There has been little evaluation or development of nurse observation charts on psychiatric in-patient units since they were first introduced. AIM: We aimed to develop a new nursing chart that adds a functional and contextual assessment of the observed behaviour. We describe its initial evaluation in an in patient setting. METHOD: A member of the staff coded a participant's behaviour as either an instance of an individual's daily life problem; or an improvement; or a non-clinically relevant behaviour. We evaluated the charts in 14 in-patients and compared the coding of the behaviour against that of one of the investigators. RESULTS: After brief training the inter-rater agreement resulted in Kappa = 0.496 with p < .001. Removal of a rating of neutral behaviours resulted in a higher Kappa = 0.546 with p < .001. CONCLUSIONS: The inter-rater reliability was only moderate for the Functional Analytical Nurse Observation Charts. Frequent training and support from management and therapy staff is required to maintain a psychologically informed environment and observation in an in-patient setting. An area for further research is to explore the impact that a FANOC has on staff satisfaction and an individual's experience of care, and whether it can assist in determining mediators of change before an improvement in symptoms. PMID- 23458368 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: the Danish experience. AB - AIM: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option with curative intent for selected patients with peritoneal carcinomatosis (PC). CRS and HIPEC have been implemented in Denmark at a single centre since 2006. Six years of data on these patients were analysed. METHOD: Patients with PC from colorectal or appendiceal cancer, pseudomyxoma peritonei or malignant peritoneal mesothelioma referred to the single national HIPEC centre were prospectively registered from June 2006 to July 2012. Morbidity, 30-day mortality and long-term survival of patients who underwent CRS and HIPEC were analysed. RESULTS: In total, 80 patients underwent CRS and HIPEC. PC originated from colorectal cancer in 34 patients, pseudomyxoma peritonei in 29, appendiceal cancer in 13 and malignant peritoneal mesothelioma in four patients. Thirty-two patients had one or more complications during the hospital stay. The 30-day mortality rate was 1.3%. The predicted 2-, 3- and 5 year survival was 60%, 47% and 38% in patients with PC from colorectal cancer, and 100%, 93% and 73% in pseudomyxoma peritonei patients. CONCLUSION: CRS and HIPEC is a safe procedure when centralized as in Denmark. Favourable long-term outcome was achieved in selected patients with PC from colorectal cancer and pseudomyxoma peritonei. Short-term and long-term outcomes were comparable to results from international centres. PMID- 23458369 TI - Behavioral mediators of the association between neighborhood environment and weight status in Nigerian adults. AB - PURPOSE: Neighborhood built environments are related to obesity and physical activity (PA), but inconsistently to sedentary behaviors. This study investigated the mediating effects of PA and sedentary time on the associations of neighborhood environmental factors and body mass index (BMI) among Nigerian adults. DESIGN: The study design was cross-sectional. SETTING: The study setting was metropolitan Maiduguri, Nigeria. SUBJECTS: Nigerian adults (n = 1411) were randomly selected from diverse neighborhoods and had complete data (43.1% women, 33.8% overweight or obese). MEASURES: PA, sedentary time, and 16 perceived neighborhood environmental factors were measured using Nigerian adaptations of validated international questionnaires. Outcomes were measured BMI and interviewer-led self-reports of moderate to vigorous PA, walking, total PA, and sitting time. ANALYSIS: The product-of-coefficient test using generalized linear models was used to assess the mediating effects of outcomes on the associations between environmental factors and BMI. RESULTS: Walking and total PA significantly mediated the association between BMI and perception of higher residential density (alphabeta = -.025 and -.037, respectively), absence of garbage (alphabeta = -.046 and -.076, respectively), and more safety from crime at night (alphabeta = -.044 and -.083, respectively). In addition, walking, moderate to vigorous PA, and total PA significantly mediated the association between BMI and perception of better aesthetics (alphabeta = -.035, -.022, and .071, respectively). Sedentary time was not a significant mediator of any associations between environmental factors and BMI. CONCLUSION: The association of several neighborhood environmental variables with BMI was partially mediated by PA in Nigerian adults. Including questions on specific types of sedentary behaviors in future prospective studies may improve understanding of the relative influence of sedentary behavior and physical activity on obesity control and prevention among sub-Saharan African adults. PMID- 23458371 TI - Social influences on smoking in American workers: the role of the presence of smokers in the workplace and in the home. AB - PURPOSE: To examine the relationship between the presence of smokers in the workplace and smokers in the home and current smoking status among employed men and women. DESIGN: Analysis of data from the second wave of the nationally representative Survey of Midlife Development in the United States (2004-2006). SUBJECTS: Sample of 627 currently employed men and women, aged 34 to 82 (M = 51), who had been regular cigarette smokers at some time. MEASURES: Survey items indexing presence of smokers in the respondents' immediate work area and home and their current smoking status. ANALYSIS: Multiple logistic regression analyses, controlling for age, gender, education, race, and job type. RESULTS: Examined together, smokers in the workplace (OR = 2.83) and smokers in the home (OR = 6.09) were uniquely associated with current smoking status. Moreover, smokers in the home reduced the association between smokers in the workplace and current smoking. The presence of smokers in the workplace was associated with a more than fourfold increase in current smoking among respondents with no smokers in the home, but was unrelated to current smoking among respondents with smokers in the home. CONCLUSIONS: Failure to consider the presence of smokers in the home significantly limits the potential impact of workplace smoking interventions. PMID- 23458370 TI - Physical activity and fruit and vegetable intake: correlations between and within adults in a longitudinal multiethnic cohort. AB - PURPOSE: To determine if changes in physical activity were associated with changes in fruit and vegetable intake. DESIGN: Prospective cohort. SETTING: Hawaii. SUBJECTS: Seven hundred adults (18+ years) sampled from the general population. MEASURES: Computer-assisted telephone interviews conducted at 0, 3, 6, 9, 12, 18, and 24 months; the International Physical Activity Questionnaire; the National Cancer Institute's Fruit and Vegetable Screener. ANALYSIS: Between individual correlations of each individual's mean physical activity and mean fruit and vegetable intake were estimated with Pearson correlations. Correlations of physical activity and fruit and vegetable intake within individuals over time were calculated from analysis of covariance models to factor out the variation between individuals. RESULTS: Individuals with a higher mean physical activity duration tended to eat more fruits and vegetables (r = .30, p < .0001). Within individuals, no average correlation between physical activity and intake of fruit and vegetables was observed over time (r = .03). The variation was great in that some individuals, these behaviors changed simultaneously, but in others, they did not. CONCLUSION: Although individuals who are more physically active tend to eat more fruits and vegetables (i.e., there is a weak correlation between individuals), on average, individuals do not simultaneously change these behaviors. Implications are that health behaviors may not covary, or that intervention is necessary to bring about covariation in health behaviors. The great variation from individual to individual in the extent to which these two behaviors covaried needs to be studied to determine if the individual tendency for behaviors to covary could be measured and used to individually tailor multiple behavior interventions. PMID- 23458372 TI - Associations between education and personal income with body mass index among Australian women residing in disadvantaged neighborhoods. AB - PURPOSE: The aims of the current study were to (1) determine the association between personal income and body mass index (BMI) and between individual education and BMI, and (2) examine the association between education and BMI across strata of personal income among women. DESIGN: The design of the study was a quantitative analysis of data from self-report questionnaires. SETTING: The study setting was socioeconomically disadvantaged neighborhoods in Victoria, Australia. SUBJECTS: The study included 4065 nonpregnant women (ages 18-45 years) living in socioeconomically disadvantaged areas. MEASURES: The study used a self report questionnaire measuring sociodemographic characteristics known to be associated with BMI. ANALYSIS: Multiple linear regressions with imputation were used to assess the association between education level, personal income, and BMI, while controlling for covariates. RESULTS: Mean (SD) observed BMI was 26.0 (6.1) kg/m2. Compared with women with low education, women with medium (b = -0.81; 95% confidence interval, -1.30 to -0.27; p = .004) and high (b = -1.71; 95% confidence interval, -2.34 to -1.09; p < .001) education had statistically significantly lower BMI values. No differences in BMI were observed between income categories. Stratified analyses suggested that the education-BMI association may be stronger in low-income than higher-income women. CONCLUSION: Our data show that among women living in socioeconomically disadvantaged areas, high education level rather than personal income may be protective against overweight/obesity. High personal income, however, may buffer the effects of low education on BMI. Obesity prevention efforts should target women with amplified disadvantage. PMID- 23458373 TI - Smoke-free workplace ballot campaigns: case studies from Missouri and lessons for policy and media advocacy. AB - PURPOSE: To assess the key components of smoke-free campaigns that may have influenced voting outcomes in three communities. DESIGN: Community case studies with content analysis of tobacco-related newspaper articles. SETTING: Three semiurban Missouri communities. SUBJECTS: One hundred eighty-one articles referencing tobacco published during the campaigns and five key informant interviews. MEASURES: Articles were coded for type, community referenced, tobacco control position, source of quotations, use of evidence, and frame. Semistructured interviews with key informants collected additional information. ANALYSIS: Descriptive statistics were utilized to examine media coverage in each community. Key themes and events for each campaign were identified from qualitative interviews. RESULTS: The only community that failed to pass its initiative had the highest proportion of letters to the editor (81.1%), anti tobacco control articles (34.2%), use of a rights frame (28.8%), no evidence used (36.9%), no neighboring communities with policies, strong Tea Party presence, and no support from the chamber of commerce. Across all communities, more articles incorporating health frames were pro-tobacco control (70.7%) and more articles with a rights frame were anti-tobacco control (62.0%), compared to other positions. CONCLUSION: Several factors can influence the policy process. Tobacco control policy advocates facing strong opposition should consider the many factors (demographics, proximity to other adopting localities, politics) driving the debate and use media as an avenue to influence the discussion, connect with the public and policymakers, and mobilize proponents. PMID- 23458374 TI - Pilot evaluation of a media literacy program for tobacco prevention targeting early adolescents shows mixed results. AB - PURPOSE: The purpose of this pilot study was to assess the impact of media literacy for tobacco prevention for youth delivered through a community site. DESIGN: A randomized pretest-posttest evaluation design with matched-contact treatment and control conditions. SETTING: The pilot study was delivered through the YMCA in a lower-income suburban and rural area of Southwest Virginia, a region long tied, both economically and culturally, to the tobacco industry. SUBJECTS: Children ages 8 to 14 (76% white, 58% female) participated in the study (n = 38). INTERVENTION: The intervention was an antismoking media literacy program (five 1-hour lessons) compared with a matched-contact creative writing control program. MEASURES: General media literacy, three domains of tobacco specific media literacy ("authors and audiences," "messages and meanings," and "representation and reality"), tobacco attitudes, and future expectations were assessed. ANALYSIS: Multiple regression modeling assessed the impact of the intervention, controlling for pretest measures, age, and sex. RESULTS: General media literacy and tobacco-specific "authors and audiences" media literacy improved significantly for treatment compared with control (p < .05); results for other tobacco-specific media literacy measures and for tobacco attitudes were not significant. Future expectations of smoking increased significantly for treatment participants ages 10 and younger (p < .05). CONCLUSION: Mixed results indicated that improvements in media literacy are accompanied by an increase in future expectations to smoke for younger children. PMID- 23458375 TI - Moderate to vigorous physical activity and weight outcomes: does every minute count? AB - PURPOSE: The purpose of this study was to test if moderate to vigorous physical activity (MVPA) in less than the recommended >=10-minute bouts related to weight outcomes. DESIGN: Secondary data analysis. SETTING: Random sample from the U.S. civilian noninstitutionalized population included in the National Health and Nutrition Examination Survey (NHANES). PARTICIPANTS: A total of 4511 adults aged 18 to 64 years from the 2003-2006 NHANES. METHOD: Clinically measured body mass index (BMI) and overweight/obese status were regressed on accelerometer measures of minutes per day in higher-intensity long bouts (>=10 minutes, >=2020 accelerometer counts per minute [cpm]), higher-intensity short bouts (<10 minutes, >=2020 cpm), lower-intensity long bouts (>=10 minutes, 760-2019 cpm), and lower-intensity short bouts (<10 minutes, 760-2019 cpm). Socioeconomic and demographic characteristics were controlled. RESULTS: Both higher-intensity short bouts and long bouts of PA related to lower BMI and risk of overweight/obesity. Neither lower-intensity short bouts nor long bouts related to BMI or risk of overweight/obesity. CONCLUSION: The current >=10-minute MVPA bouts guideline was based on health benefits other than weight outcomes. Our findings showed that for weight gain prevention, accumulated higher-intensity PA bouts of <10 minutes are highly beneficial, supporting the public health promotion message that "every minute counts." PMID- 23458376 TI - Neighborhood environment and urban schoolchildren's risk for being overweight. AB - PURPOSE: Child and adolescent obesity is increasingly prevalent and predisposes risk for poor physical and psychosocial health. Physical and social factors in the environment, such as neighborhood disorder, may be associated with childhood obesity. This study examines the association between living in a disordered neighborhood and being overweight among a sample of urban schoolchildren. DESIGN: Baseline interview data, including height, weight, and hip circumference, were obtained from 313 elementary school-aged participants in a community-based epidemiologic study. SETTING: The setting was Baltimore, Maryland, a large metropolitan city. SUBJECTS: Subjects were elementary school students ages 8 to 12 years. MEASURES: To assess neighborhood characteristics, independent evaluators conducted objective environmental assessments using the Neighborhood Inventory for Environmental Typology instrument on the block faces (defined as one side of a city block between two intersections) where the children resided. ANALYSIS: Logistic regression models with generalized estimating equations were used to examine the association between neighborhood disorder and children being overweight. RESULTS: Neighborhood disorder showed a trend toward a statistically significant association with being overweight during childhood (odds ratio [OR], 1.03; confidence interval [CI], .99-1.07; p = .07) in the unadjusted model. Gender was significantly associated with being overweight, with female gender increasing the odds of being overweight by 50% in the sample (OR, 1.50; CI, 1.18 1.92; p < .01). After controlling for race, age, and comparative time spent on a sport, multivariable analyses revealed that gender (adjusted odds ratio [AOR], 2.42; CI, 1.63-3.59; p < .01) and neighborhood disorder (AOR, 1.09; CI, 1.03 1.15; p < .01) were associated with being overweight. Further, an examination of interactions revealed girls (AOR, 2.40; CI, 1.65-3.49; p < .01) were more likely to be overweight compared with boys (AOR, 2.20; CI, 1.57-3.11; p < .01) living in neighborhoods with the same level of neighborhood disorder. CONCLUSION: Results suggest neighborhood hazards warrant additional consideration for their potential as obesogenic elements affecting gender-based disparities in weight among urban schoolchildren. Future studies in this area should include longitudinal examinations. PMID- 23458378 TI - Assessment of effluent contaminants from three facilities discharging Marcellus Shale wastewater to surface waters in Pennsylvania. AB - Unconventional natural gas development in Pennsylvania has created a new wastewater stream. In an effort to stop the discharge of Marcellus Shale unconventional natural gas development wastewaters into surface waters, on May 19, 2011 the Pennsylvania Department of Environmental Protection (PADEP) requested drilling companies stop disposing their wastewater through wastewater treatment plants (WWTPs). This research includes a chemical analysis of effluents discharged from three WWTPs before and after the aforementioned request. The WWTPs sampled included two municipal, publicly owned treatment works and a commercially operated industrial wastewater treatment plant. Analyte concentrations were quanitified and then compared to water quality criteria, including U.S. Environmental Protection Agency MCLs and "human health criteria." Certain analytes including barium, strontium, bromides, chlorides, total dissolved solids, and benzene were measured in the effluent at concentrations above criteria. Analyte concentrations measured in effluent samples before and after the PADEP's request were compared for each facility. Analyte concentrations in the effluents decreased in the majority of samples after the PADEP's request (p < .05). This research provides preliminary evidence that these and similar WWTPs may not be able to provide sufficient treatment for this wastewater stream, and more thorough monitoring is recommended. PMID- 23458379 TI - Immune adjuvant effect of V. cholerae O1 derived Proteoliposome coadministered by intranasal route with Vi polysaccharide from Salmonella Typhi. AB - The proteoliposome derived from Vibrio cholerae O1 (PLc) is a nanoscaled structure obtained by a detergent extraction process. Intranasal (i.n) administration of PLc was immunogenic at mucosal and systemic level vs. V. cholerae; however the adjuvant potential of this structure for non-cholera antigens has not been proven yet. The aim of this work was to evaluate the effect of coadministering PLc with the Vi polysaccharide antigen (Poli Vi) of S. Typhi by the i.n route. The results showed that Poli Vi coadministered with PLc (PLc+Poli Vi) induce a higher IgA response in saliva (p<0.01) and faeces (p<0.01) than Poli Vi administered alone. Likewise, the IgG response in sera was higher in animals immunised with PLc+Poli Vi (p<0.01). Furthermore, IgG induced in sera of mice immunised with PLc+Poli Vi was similar (p>0.05) to that induced in a group of mice immunised by the parenteral route with the Cuban anti-typhoid vaccine vax TyVi, although this vaccine did not induce a mucosal response. In conclusion, this work demonstrates that PLc can be used as a mucosal adjuvant to potentiate the immune response against a polysaccharide antigen like Poli Vi. PMID- 23458380 TI - Behaviours related to executive functions and learning skills at 11 years of age after extremely preterm birth: a Swedish national prospective follow-up study. AB - AIM: We investigated a national cohort of children born extremely immature (<26 weeks gestation, EI) regarding the nature, frequency and severity of the behavioural problems related to the executive functions (EF) and concerning learning skills, from the perspectives of parents and teachers. METHODS: At 11 years of age 86 of 89 survivors of this cohort were studied and compared with an equal number of controls. Behaviours related to EF, and learning skills were assessed by a validated instrument, namely the Five to Fifteen questionnaire sent by mail to parents and teachers. RESULTS: Compared with controls, parents of EI children reported significantly more problems in behaviours related to EF in all areas assessed (Attention, Hyperactivity/Impulsivity, Hypoactivity, Planning/Organizing, and Working Memory). Teachers' ratings showed a similar pattern. EI children also displayed deficient skills in the 4 standard measures of learning skills. Multivariate analysis revealed that prematurity, gender and behavioural composite score was associated with learning skills. Only a relatively small proportion of EI children (10-30%) exhibited clinically significant impairments. CONCLUSION: Despite a favourable outcome in many school age children born at the threshold of viability, these are at increased risk of developing behavioural problems related to EF. PMID- 23458381 TI - Retrospective study of the treatment of infantile hemangiomas using a combination of propranolol and pulsed dye laser. AB - BACKGROUND: Infantile hemangioma (IH) clearance may be slow or incomplete in response to pulsed dye laser (PDL) or propranolol alone. OBJECTIVES: To evaluate whether IH treated with PDL and propranolol displayed more rapid and complete clearance than IH treated with propranolol alone. MATERIALS AND METHODS: Retrospective review of facial-segmental IH treated with propranolol and PDL and controls treated with propranolol was conducted. Blinded physicians used patient photographs to select clearance level and the earliest date of near-complete clearance. Days of propranolol, PDL sessions, and propranolol dose, each until date of near-complete clearance; total days of propranolol; and total propranolol dose were recorded. RESULTS: Infantile hemangiomas treated concurrently with propranolol and PDL achieved complete clearance (6/12) more often than IH treated with propranolol followed by PDL (2/5) or IH treated with propranolol alone (1/8; difference in clearance scores p = .01) and achieved near-complete clearance after fewer days of propranolol (mean 92 days for concurrent propranolol and PDL vs 288 days for propranolol; p < .001). Cumulative propranolol dose until near complete clearance was lowest in the concurrent propranolol and PDL group (149.16 vs. 401.25 mg/kg for propranolol; p < .001). CONCLUSION: Facial-segmental IH treated with propranolol and PDL displayed morerapid and complete clearance and required a lower cumulative propranolol dose to achieve near-complete clearance. PMID- 23458382 TI - Estimating side-chain order in [U-2H;13CH3]-labeled high molecular weight proteins from analysis of HMQC/HSQC spectra. AB - A simple approach for quantification of methyl-containing side-chain mobility in high molecular weight methyl-protonated, uniformly deuterated proteins is described, based on the measurement of peak intensities in methyl (1)H-(13)C HMQC and HSQC correlation maps and relaxation rates of slowly decaying components of methyl (1)H-(13)C multiple-quantum coherences. A strength of the method is that [U-(2)H;(13)CH3]-labeled protein samples are required that are typically available at an early stage of any analysis. The utility of the methodology is demonstrated with applications to three protein systems ranging in molecular weight from 82 to 670 kDa. Although the approach is only semiquantitative, a high correlation between order parameters extracted via this scheme and other more established methods is nevertheless demonstrated. PMID- 23458383 TI - A 6-day clinical pathway after a pancreaticoduodenectomy is feasible, safe and efficient. AB - BACKGROUND: The utilization of post-operative clinical pathways leads to shorter hospital stays and decreased healthcare costs. This study evaluated patient outcomes after implementation of a 6-day discharge pathway after a pancreaticoduodenectomy. METHODS: A post-operative clinical pathway was developed and implemented for patients undergoing a pancreaticoduodenectomy at the present institution aimed at discharge by post-operative day six. Patient charts were retrospectively reviewed to determine the rates of adherence to the pathway at each step, readmission and post-operative complications. RESULTS: In total, 113 consecutive patients underwent a pancreaticoduodenectomy, receiving post operative care under the clinical pathway guidelines. The median length of stay was 7 days (mode 6 days); 41% of patients were discharged by post-operative day six, 62% by day seven and 79% by day eight. In univariate analysis, delayed gastric emptying was associated with a delayed discharge after post-operative day six (P = 0.002). There were no post-operative deaths and 16% of patients required readmission within 30 days of discharge. In univariate analysis, obesity was the only variable associated with an increased rate of readmission (P < 0.001). DISCUSSION: Clinical pathway utilization after a pancreaticoduodenectomy allows a high percentage of patients to be discharged within a week and is associated with a low rate of readmission. Clinical pathway implementation allows for safe and efficient patient care. PMID- 23458384 TI - Increasing survival of hepatocellular carcinoma patients in Scotland: a review of national cancer registry data. AB - OBJECTIVES: This study describes changes in the survival of patients with hepatocellular carcinoma (HCC) registered with the Scottish Cancer Registry between 1985 and 2008. METHODS: Data on patients diagnosed with HCC were extracted from the Scottish Cancer Registry, along with linked data on treatment and risk factors for liver disease. One-, 3- and 5-year relative survival rates were calculated for each time period and a Cox regression model was used to assess the impact of prior admissions on survival. RESULTS: The incidence of HCC increased between 1985 and 2008. The proportion of patients with prior alcohol related admissions rose over the time period studied from 16.0% to 27.1%. Five year relative survival increased in women between 1985-1989 and 2005-2007 from 0.5% [95% confidence interval (CI) 0.0-3.7] to 10.6% (95% CI 5.2-18.1). In men, 5 year relative survival increased from 0.4% (95% CI 0.2-2.2) to 4.4% (95% CI 1.5 9.9). Regression analysis showed that older age, history of alcohol-related admissions and deprivation were associated with lower survival, and hospitalization for viral hepatitis was associated with higher survival. CONCLUSIONS: Against the background of an increasing incidence of HCC in Scotland, survival times have increased substantially. PMID- 23458385 TI - Counterion condensation on heparin oligomers. AB - The electropherogram of native heparin shows a broad distribution of mobilities MU, which truncates abruptly at a notably high MU = 4.7 * 10(-4) cm(2) V(-1) s( 1). This highly skewed mobility distribution is also found for the 20-saccharide chain, which shows from mass spectrometry a more uniform (symmetrical) with respect to sulfation level. Since a partially degraded heparin exhibits oligomer peaks with MU> 5 * 10(-4) cm(2) V(-1) s(-1) (appearing to escape the limitation of the mobility value for native heparin), we examined the electrophoretic behavior of chain-length monodisperse heparin oligomers. Their mobilities varied inversely with the logarithm of the contour length, L, for L from 3 to 10 nm and reached an asymptotic limit for L > 20 nm. The generality of this effect was indicated by similar behavior for oligomers of poly(styrene sulfonate). A recent theory of polyelectrolyte end effects (Manning, G. S. Macromolecules2008, 41, 6217-6227), in which chain termini exhibit reduced counterion condensation was found to quantitatively account for these results. A qualitative explanation for the anomalously high value of MU of native heparin, 10-20% higher than those seen for synthetic polyelectrolytes of higher linear charge density, is suggested on the basis of similar junction effects (Manning, G. S. Macromolecules2008, 41, 6217-6227), which reduce counterion condensation at the interfaces of regions of high and low sulfation. We suggest that these effects should be considered in models for the biofunctionality of the regulated high and low sulfation (NS/NA) domains of heparan sulfate. PMID- 23458386 TI - Folate-appended beta-cyclodextrin as a promising tumor targeting carrier for antitumor drugs in vitro and in vivo. AB - A large number of antitumor drug delivery carriers based on passive targeting and/or active targeting have been developed. However, encapsulation of antitumor drugs into these drug carriers is often complicated, and antitumor activities of these targeting systems are not satisfactory. In the present study, we first prepared heptakis-6-folic acid (FA)-appended beta-cyclodextrin (beta-CyD) possessing two caproic acids between FA and a beta-CyD molecule as a spacer (Fol c(2)-beta-CyD) and evaluated the potential as a novel tumor targeting carrier for antitumor drugs through a complexation. Fol-c(2)-beta-CyD formed an inclusion complex with doxorubicin (DOX) at a 1:1 molar ratio with a markedly high stability constant (>10(6) M(-1)). Cellular uptake of DOX was increased by the addition of Fol-c(2)-beta-CyD in KB cells, a folate receptor-alpha (FR-alpha) positive cell line. Additionally, Fol-c(2)-beta-CyD increased in vitro antitumor activities of antitumor drugs such as DOX, vinblastine (VBL), and paclitaxel (PTX) in KB cells, but not in A549 cells, a FR-alpha-negative cell line. The complex of DOX with Fol-c(2)-beta-CyD markedly increased antitumor activity of DOX, not only after intratumoral administration but also after intravenous administration to mice subcutaneously inoculated Colon-26 cells, a FR-alpha positive cell line. These findings suggest that Fol-c(2)-beta-CyD could be useful as a promising antitumor drug carrier. PMID- 23458387 TI - Neonatal free testosterone and decreased head circumference in females: evidence of reduced inactivation of testosterone in the brain. PMID- 23458388 TI - Photoimmunosuppression: a brief overview. AB - Exposure to ultraviolet radiation can lead to suppression of many adaptive immune responses, both to antigens encountered within a short period of the irradiation (primary) and to antigens previously encountered (memory). The pathways involved are complex and not completely elucidated. This brief review summarizes the information available currently regarding the multiple steps involved, with the aim of providing a general overview of the main aspects of photoimmunosuppression and its clinical consequences. PMID- 23458389 TI - Current status of photoprotection by window glass, automobile glass, window films, and sunglasses. AB - Ultraviolet radiation (UVR) has known adverse effects on the skin and eyes. Practitioners are becoming more aware of the importance of outdoor photoprotection. However, little attention is directed to the exposure of the skin and eyes to UVR through the window glass or sunglasses. The amount of ultraviolet transmission through glass depends mainly on the type of the glass. All types of commercial and automobile glass block the majority of ultraviolet-B; however, the degree of ultraviolet-A transmission depends on the type of glass. Laminated glass offers better UVA protection than tempered glass; new safety regulations for automobiles may result in increased use of laminated glass for side windows. Window films can be applied to glass to increase UVR protection. Sunglasses need to be compliant with one of the national standards; a wraparound style or side shields offer the best protection. Increased understanding by practitioners on the transmission of UVR through glass, window films, and sunglasses would allow them to better educate the public and to better manage photosensitive patients. PMID- 23458390 TI - Risk of acute postoperative hypertension after topical photodynamic therapy for non-melanoma skin cancer. AB - BACKGROUND: Topical photodynamic therapy with methyl aminolevulinate (MAL-PDT) is a non-surgical treatment for actinic keratoses, Bowen's disease and basal cell carcinoma. MAL-PDT is particularly useful in elderly patients, who often present co-morbidities and/or in whom surgical excision could be contraindicated. MAL-PDT is generally well tolerated; the most frequent acute adverse events include pain and burning sensation localized to the treatment area. We describe our observation of the occurrence of acute postoperative hypertension (APH) and hypertensive crisis, after a MAL-PDT. METHODS: BP measurement was taken twice at 2-min intervals, both before and shortly after the MAL-PDT session. APH was defined as an increase in systolic BP by more than 20% or an increase in diastolic BP to above 110 mmHg. Hypertensive crisis was defined as a systolic BP >= 180 mmHg or a diastolic BP >= 110 mmHg, with or without acute target organ involvement. RESULTS: Prevalence of post-MAL-PDT APH was 22%; 11% of patients developed hypertensive crisis after MAL-PDT, requiring immediate treatment. CONCLUSION: We highlight the importance of blood pressure measurement both before and after MAL-PDT session to identify high-risk patients and to prevent potentially severe organ involvement subsequent to hypertensive crisis. PMID- 23458391 TI - Interoperability of 300 watt and 150 watt xenon arc solar simulators in sun protection factor and in UVA protection factor clinical testing. AB - BACKGROUND: The purpose of these clinical trials was to determine if 300 W and 150 W xenon arc solar simulators (SSs) deliver the same sun protection factor (SPF) and UVA protection factor (PFA). METHODS: First, the SPF of the P7 control standard and of the P2 control standard was determined, testing 20 subjects using the method described in the Food and Drug Administration (FDA) Final Monograph and using 150 W and 300 W SSs. In the second clinical trial, the PFA of the Japanese Cosmetic Industry Association (JCIA) control standard and of the P2 control standard was determined, testing 10 subjects using the method described in the JCIA Technical Bulletin and using 150 W and 300 W SSs. RESULTS: The SPF values for P7 control standard determined using the 150 W and 300 W SSs were 4.54 +/- 0.35 and 4.61 +/- 0.32, respectively. The SPF values for P2 control standard determined using the 150 W and 300 W SSs were 17.0 +/- 0.9 and 16.7 +/- 0.9, respectively. The resultant PFA values for JCIA control standard determined using the 150 W and 300 W SSs were 4.06 +/- 0.70 and 4.06 +/- 0.70, respectively. The resultant PFA values for P2 control standard determined using the 150 W and 300 W SSs were 3.28 +/- 0.25 and 3.44 +/- 0.39, respectively. CONCLUSION: As the values are essentially identical for SPF and for PFA, the 150 W and 300 W SSs can be used interchangeably for SPF and PFA determinations. PMID- 23458392 TI - Protective effect of mango (Mangifera indica L.) against UVB-induced skin aging in hairless mice. AB - BACKGROUND: Mangifera indica L. (Anacardiaceae) is a medicinal plant whose extracts have been described as an antioxidant with anti-inflammatory and immunomodulatory activities. PURPOSE: Skin aging is a consequence of chronic sun exposure to the sun and therefore ultraviolet (UV) radiation. Naturally occurring antioxidants are known to reduce skin aging. Therefore, the aim of the present study was to evaluate the protective role of mango extract against UVB-induced skin aging in hairless mice. METHODS: HR-1 hairless male mice (6 weeks old) were divided into three groups: control (n = 5), UVB-treated vehicle (n = 5), and UVB treated mango extract (n = 5) groups. UVB-irradiated mice from the mango extract group were orally administered 0.1 ml of water containing 100 mg of mango extract/kg body weight per day. The inhibitory activity of mango extract on wrinkle formation was determined by the analysis of the skin replica, epidermal thickness based on histological examination, and damage to collagen fiber. RESULTS: The mean length of wrinkles in UVB-treated vehicle group significantly improved after the oral administration of mango extract, which significantly inhibited the increase in epidermal thickness and epidermal hypertrophy (P < 0.05). Furthermore, a marked increase in collagen bundles was observed in the UVB treated group after the administration of mango extract by Masson's trichrome staining. CONCLUSION: These results indicate that mango extract showed anti photoaging activity in UVB-irradiated hairless mice. PMID- 23458393 TI - Effectiveness of photodynamic therapy with topical 5-aminolevulinic acid and intense pulsed light in Chinese acne vulgaris patients. AB - BACKGROUND: The success rates of conventional treatments to acne vulgaris are limited because of intolerance and resistance. Photodynamic therapy with topical 5-aminolevulinic acid (ALA) and red light has been introduced. However, the side effects especially pigmentation are common. OBJECTIVE: To study the efficacy and safety of ALA-photodynamic therapy (PDT) with 420-950 nm intense pulsed light (IPL) in Chinese patients with acne vulgaris. METHODS: Forty-one patients with moderate to severe facial acne were randomly assigned to ALA-IPL-PDT group and IPL group. Ten percent topical ALA was applied to patients in the ALA-IPL-PDT group, while placebos were applied to patients in the IPL group. After 1 h occlusion, all patients were illuminated with 420-950 nm IPL. The patients in both groups had four treatment sessions with 1-week intervals. One week after each treatment and 4, 8, and 12 weeks after four sessions, acne lesion counts and adverse events were observed. RESULTS: Twelve weeks after treatments, mean reductions of global lesion counts of ALA-IPL-PDT group and IPL group were 75.2% and 51.0%, respectively. Mean reductions of inflammatory and non-inflammatory lesion counts in ALA-IPL-PDT group were (83.6 +/- 4.1)% and (57.5 +/- 6.8)%, respectively. No severe adverse events were observed. CONCLUSION: ALA-IPL-PDT is an effective treatment for moderate to severe acne vulgaris, and side effects are mild and reversible. PMID- 23458394 TI - Two cases of eczematid-like purpura of Doucas and Kapetanakis responsive to narrow band ultraviolet B treatment. AB - Eczematid-like purpura of Doucas and Kapetanakis is a type of pigmented purpuric dermatoses (PPDs) with eczematous changes in the purpuric surface. A 10-year-old male and a 44-year-old male patients were admitted to our clinics for itching and flaking of the skin rashes. Based on the clinical and histopathological evaluations, the rashes were identified as eczematid-like PPDs of Doucas and Kapetanakis. Both patients were treated with narrow band ultraviolet B. The lesions were remarkably regressed following the treatment. These cases reported due its rarity and good response to narrow band ultraviolet B. PMID- 23458395 TI - Pentachrome vitiligo in a segmental pattern. AB - We describe a 22-year-old male with a pigmentary disorder that first appeared when he was 5 years of age. Examination revealed that these lesions were distributed in a segmental pattern on the left side of his trunk. Five shades of colors--white, tan, medium brown, dark brown, and black--were present. The patient told us there had been no preceding inflammation in the affected areas. A biopsy specimen from the inguinal region showed a complete absence of melanocytes, whereas most of the hyperpigmented areas were characterized by increased amounts of epidermal pigment and numbers of melanocytes. Based on the clinical appearance, pentachrome vitiligo in a segmental type was diagnosed. PMID- 23458396 TI - The effectiveness of early treatment in segmental vitiligo: retrospective study according to disease duration. AB - Segmental vitiligo (SV) is usually characterized by a unilateral-dermatomal distribution, earlier onset and rapid progression followed by stabilization. The response to phototherapy in patients with SV is limited. We evaluated the treatment response in 39 cases of SV according to disease duration. Ten cases (50.0%) of Group 1 (duration <= 5 months) and five cases (26.3%) of Group 2 (duration > 5 months) showed more than 50% repigmentation. Contrary to previous reports, patients in our study responded well to medical treatments like oral steroids, topical calcineurin inhibitors and phototherapy when treated early after onset. The results suggest that early treatment is important. PMID- 23458397 TI - Is non-alcoholic steatohepatitis a predisposing factor to porphyria cutanea tarda? AB - Porphyria cutanea tarda (PCT) is a disease caused by a deficiency of the fifth enzyme of the heme biosynthetic pathway in the liver that manifests in the skin as blistering and fragility of predominantly sun-exposed skin. It occurs in individuals with environmental and/or genetic risk factors such as estrogen use, hepatitis C infection and hemochromatosis gene mutations. This report highlights a case of PCT which manifested in an individual with non-alcoholic fatty liver disease (non-alcoholic steatohepatitis; NASH). We propose that NASH may have been a contributing factor for the development of PCT in our patient. PMID- 23458398 TI - Characteristics and enhanced antioxidant activity of egg white protein selenized by dry-heating in the presence of selenite. AB - This study reports a new method for the selenization of food proteins. Egg white protein (EWP) was selenized by dry-heating in the presence of selenite, and the physiochemical and functional properties of the selenized EWP were investigated. Selenization was accelerated with a decrease in pH from 7.0 to 3.0, an increase in heating time from 1 to 5 days, and an increase in incubation temperatures from 25 to 80 degrees C. The electrophoretic mobility of EWP increased with an increase in the level of selenization. Heat-induced polymerization of EWP was promoted by dry-heating in the presence of selenite. The selenite group was acid stable and base-labile, which suggests that it was bound to the hydroxyl group of an amino acid and formed an -O-SeHO2 linkage. (77)Se NMR spectral data also suggested that the selenite bond (-O-SeHO2) was bound to EWP. The digestibility of EWP was improved by selenization. The antioxidant activities of EWP, including ABTS(+) free radical scavenging capacity, hydroxyl radical scavenging capacity, reducing power, and the Fe(2+) chelating capacity, were remarkably enhanced by selenization. This finding is the first to describe that EWP can be selenized by dry-heating in the presence of selenite and that the antioxidant activities of EWP are markedly enhanced by selenization. This points to a potentially new method for generating antioxidant food protein and a new method for preparing organic Se. PMID- 23458399 TI - Inter- and intratester reliability of anthropometric assessment of limb circumference in labrador retrievers. AB - OBJECTIVE: To report a standardized method of, and determine inter- and intratester reliability for, anthropometric assessment of limb circumference in dogs. STUDY DESIGN: Prospective blinded study. ANIMALS: Labrador Retrievers (n = 20). METHOD: Unsedated dogs were manually restrained in lateral recumbency and triplicate measurements of limb circumference at the level of the proximal antebrachium, mid brachium, proximal crus, and mid-thigh were made using the Gulick II tape measure in the morning and afternoon of the same day. Observers were blinded to measurements made during each occasion and those made by co observers. Estimates of inter- and intratester reliability were made for first and mean measurements using intra-class correlation coefficients (ICC). RESULTS: Measurements of the proximal antebrachium were made with moderate to fair intratester reliability by all observers with ICC's ranging from 0.68-0.78 (1st measurement) and 0.67-0.78 (mean measurement), and moderate to fair intertester reliability with ICC's of 0.66-0.68 (1st measurement) and 0.70-0.72 (mean measurement). Measurements of the brachium, crus, and thigh typically had poor inter- and intratester reliability, ICC < 0.5. CONCLUSION: Using the described method of muscle measurement in Labrador Retrievers only measurement of the proximal antebrachium was reliable; a single (1st) measurement was as reliable as using the mean of triplicate measurements. PMID- 23458400 TI - Cognitive and behavioral aspects of executive functions in children born very preterm. AB - This study investigated whether children aged between 8 and 12 years born very preterm (VPT) and/or at very low birth weight (VLBW) performed lower than same aged term-born controls in cognitive and behavioral aspects of three executive functions: inhibition, working memory, and shifting. Special attention was given to sex differences. Fifty-two VPT/VLBW children (26 girls, 50%) born in the cohort of 1998-2003 and 36 same-aged term-born children (18 girls, 50%) were recruited. As cognitive measures, children completed tasks of inhibition (Color Word Interference Test, D-KEFS; Delis, Kaplan, & Kramer, 2001), working memory (digit span backwards, HAWIK-IV; Petermann & Petermann, 2008), and shifting (Trail Making Test, number-letter-switching, D-KEFS; Delis et al., 2001). As behavioral measures, mothers completed the Behavior Rating Inventory of Executive Function (BRIEF; Gioia, Isquith, Guy, & Kenworthy, 2000). Scales of interest were inhibit, working memory, and shift. Analyses of the cognitive aspects of executive functions revealed that VPT/VLBW children performed significantly lower than controls in the shifting task but not in the working memory and inhibition tasks. Analyses of behavioral aspects of executive functions revealed that VPT/VLBW children displayed more problems than the controls in working memory in everyday life but not in inhibition and shifting. No sex differences could be detected either in cognitive or behavioral aspects of executive functions. To conclude, cognitive and behavioral measures of executive functions were not congruent in VPT/VLBW children. In clinical practice, the combination of cognitive and behavioral instruments is required to disclose children's executive difficulties. PMID- 23458401 TI - Clinical statement on the requirements for surgeon certification for implantation of durable Ventricular Assist Devices (VADs). PMID- 23458402 TI - Certification for implantation of durable, implantable ventricular assist devices in the United States: the need for clarification of the process. PMID- 23458403 TI - Female ultrasonic vocalizations have no incentive value for male rats. AB - Ultrasonic vocalizations (USVs) are emitted in response to a sexual partner before, during, and after copulation. These vocalizations are the so-called 50 kHz USVs and can be subdivided into flat and frequency-modulated (FM) 50-kHz trill calls. In the present series of experiments, the potential unconditioned and conditioned incentive properties of female 50-kHz USVs for male rats were examined. USVs were recorded from sexually receptive females during the precopulatory phase. A complete 10-min song, or single flat or FM trill calls were selected as auditory stimuli for Experiments 1 and 2. As FM trill calls, a multistep call was used in Experiments 1 and 2a, and an upward ramp call was used in Experiment 2b. The auditory stimuli were played back with a loudspeaker to naive and sexually experienced male rats in a sexual incentive motivation test. The odor of a sexually receptive female rat was also used as an incentive stimulus for comparison. In a third experiment, a devocalized female, a sham female and a male rat were used as incentive stimuli. It was found that the auditory stimuli did not induce approach behavior in naive and sexually experienced male rats, but the olfactory stimulus did. In addition, the males spent equal amounts of time in the vicinity of devocalized and vocalizing females. These data show that 50-kHz USVs neither are unconditioned nor conditioned incentives for male rats. PMID- 23458404 TI - Updating of episodic memories depends on the strength of new learning after memory reactivation. AB - After reactivation, apparently stable memories may reenter an unstable state in which they are modifiable, requiring another phase of stabilization, called reconsolidation. Recent evidence shows that during reconsolidation, reactivated memories may be updated by the incorporation of new information. In the present study, we examined whether the updating of episodic memories depends on the strength of new encoding after reactivation. To this end, healthy participants learned negative and neutral pictures, reactivated them 1 week later, and learned new pictures either once or three times immediately after reactivation. A recognition test was performed another week later. Our results show that the impact of new learning after reactivation depended critically on the strength of new encoding: Whereas learning new pictures only once after reactivation had no effect on subsequent memory, learning new pictures three times after reactivation reduced subsequent memory accuracy, mainly due to intrusions from the newly learned pictures. Our findings indicate that the strength of new encoding after reactivation plays a critical role for the updating of episodic memories and may have important implications for therapeutic interventions that aim to alter unwanted memories after reactivation. PMID- 23458405 TI - Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia? AB - Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Its pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness. Both mitochondrial dysfunction and coenzyme Q10 (CoQ10) deficiency have been implicated in FM pathophysiology. We have investigated the effect of CoQ10 supplementation. We carried out a randomized, double-blind, placebo-controlled trial to evaluate clinical and gene expression effects of forty days of CoQ10 supplementation (300 mg/day) on 20 FM patients. This study was registered with controlled-trials.com (ISRCTN 21164124). An important clinical improvement was evident after CoQ10 versus placebo treatment showing a reduction of FIQ (p<0.001), and a most prominent reduction in pain (p<0.001), fatigue, and morning tiredness (p<0.01) subscales from FIQ. Furthermore, we observed an important reduction in the pain visual scale (p<0.01) and a reduction in tender points (p<0.01), including recovery of inflammation, antioxidant enzymes, mitochondrial biogenesis, and AMPK gene expression levels, associated with phosphorylation of the AMPK activity. These results lead to the hypothesis that CoQ10 have a potential therapeutic effect in FM, and indicate new potential molecular targets for the therapy of this disease. AMPK could be implicated in the pathophysiology of FM. PMID- 23458406 TI - Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies. AB - Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be a mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role of altered glycosylation in HCV resistance to broadly neutralizing antibodies is not fully understood. Here, we have generated potent HCV neutralizing antibodies hu5B3.v3 and MRCT10.v362 that, similar to the previously described AP33 and HCV1, bind to a highly conserved linear epitope on E2. We utilize a combination of in vitro resistance selections using the cell culture infectious HCV and structural analyses to identify mechanisms of HCV resistance to hu5B3.v3 and MRCT10.v362. Ultra deep sequencing from in vitro HCV resistance selection studies identified resistance mutations at asparagine N417 (N417S, N417T and N417G) as early as 5days post treatment. Comparison of the glycosylation status of soluble versions of the E2 glycoprotein containing the respective resistance mutations revealed a glycosylation shift from N417 to N415 in the N417S and N417T E2 proteins. The N417G E2 variant was glycosylated neither at residue 415 nor at residue 417 and remained sensitive to MRCT10.v362. Structural analyses of the E2 epitope bound to hu5B3.v3 Fab and MRCT10.v362 Fab using X-ray crystallography confirmed that residue N415 is buried within the antibody-peptide interface. Thus, in addition to previously described mutations at N415 that abrogate the beta-hairpin structure of this E2 linear epitope, we identify a second escape mechanism, termed glycan shifting, that decreases the efficacy of broadly neutralizing HCV antibodies. PMID- 23458408 TI - Combined micrococcal nuclease and exonuclease III digestion reveals precise positions of the nucleosome core/linker junctions: implications for high resolution nucleosome mapping. AB - Micrococcal nuclease (MNase) is extensively used in genome-wide mapping of nucleosomes but its preference for AT-rich DNA leads to errors in establishing precise positions of nucleosomes. Here, we show that the MNase digestion of nucleosomes assembled on a strong nucleosome positioning sequence, Widom's clone 601, releases nucleosome cores whose sizes are strongly affected by the linker DNA sequence. Our experiments produced nucleosomal DNA sizes varying between 147 and 155 bp, with positions of the MNase cuts reflecting positions of the A?T pairs rather than the nucleosome core/linker junctions determined by X-ray crystallography. Extent of chromatosomal DNA protection by linker histone H1 also depends on the linker DNA sequence. Remarkably, we found that a combined treatment with MNase and exonuclease III (exoIII) overcomes MNase sequence preference producing nucleosomal DNA trimmed symmetrically and precisely at the core/linker junctions regardless of the underlying DNA sequence. We propose that combined MNase/exoIII digestion can be applied to in situ chromatin for unbiased genome-wide mapping of nucleosome positions that is not influenced by DNA sequences at the core/linker junctions. The same approach can be also used for the precise mapping of the extent of linker DNA protection by H1 and other protein factors associated with nucleosome linkers. PMID- 23458407 TI - Distinct requirements within the Msh3 nucleotide binding pocket for mismatch and double-strand break repair. AB - In Saccharomyces cerevisiae, repair of insertion/deletion loops is carried out by Msh2-Msh3-mediated mismatch repair (MMR). Msh2-Msh3 is also required for 3' non homologous tail removal (3' NHTR) in double-strand break repair. In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions and initiates repair in an ATP-dependent manner. However, the kinetics of the two processes appear different; MMR is likely rapid in order to coordinate with the replication fork, whereas 3' NHTR has been shown to be a slower process. To understand the molecular requirements in both repair pathways, we performed an in vivo analysis of well-conserved residues in Msh3 that are hypothesized to be required for MMR and/or 3' NHTR. These residues are predicted to be involved in either communication between the DNA-binding and ATPase domains within the complex or nucleotide binding and/or exchange within Msh2-Msh3. We identified a set of aromatic residues within the FLY motif of the predicted Msh3 nucleotide binding pocket that are essential for Msh2-Msh3-mediated MMR but are largely dispensable for 3' NHTR. In contrast, mutations in other regions gave similar phenotypes in both assays. Based on these results, we suggest that the two pathways have distinct requirements with respect to the position of the bound ATP within Msh3. We propose that the differences are related, at least in part, to the kinetics of each pathway. Proper binding and positioning of ATP is required to induce rapid conformational changes at the replication fork, but is less important when more time is available for repair, as in 3' NHTR. PMID- 23458409 TI - Trastuzumab-conjugated vitamin E TPGS liposomes for sustained and targeted delivery of docetaxel. AB - OBJECTIVES: In this study, the authors developed D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) liposomes and further conjugated them to trastuzumab for controlled and targeted delivery of docetaxel (DTX) as a model hydrophobic drug. METHODS: DTX- or coumarin-6-loaded liposomes were prepared by solvent injection method and characterized for size and size distribution, surface charge, surface chemistry and drug encapsulation efficiency and drug release profile. SK-BR-3 cells were employed as an in vitro model for HER2-positive breast cancer and assessed for their cellular uptake and cytotoxicity of the two liposomal formulations. In vivo pharmacokinetics (PK) was investigated in Sprague-Dawley rats. RESULTS: The IC(50) value was found to be 20.23 +/- 1.95, 3.74 +/- 0.98, 0.08 +/- 0.4 MUg/ml for the marketed preparation of DTX, TPGS liposomes and trastuzumab-conjugated TPGS liposomes, respectively after 24 h incubation with SK-BR-3 cells. In vivo PK experiments showed that i.v. administration of trastuzumab-conjugated liposomes achieved 1.9 and 10 times longer half-life, respectively than PEG-coated liposomes and DTX. The area under the curve (AUC) was increased by 3.47- and 1.728-fold, respectively. CONCLUSION: The trastuzumab-conjugated vitamin E TPGS-coated liposomes showed greater potential for sustained and targeted chemotherapy in the treatment of HER2 overexpressing breast cancer. PMID- 23458410 TI - An evaluation of standardized software for processing GC/MS data from different vendors' instruments in a forensic laboratory. AB - Forensic science laboratories perform analyses on a variety of materials using gas chromatography/mass spectrometry (GC/MS). Instruments from different vendors may be used, requiring analysts to be proficient in the use of multiple proprietary software packages for collecting and processing data. There is no standardized GC/MS software available that can acquire data from different vendors' instruments. However, there are third-party processing software products that can import data files in different formats. The Centre of Forensic Sciences compared the data processing performance of one such product, ACD/MS Manager Suite, with three instrument vendors' software used for casework analysis. This product was tested for its compatibility with the existing software, its capability to load and present data, and to initiate searches of commercial libraries. The study shows that the MS Manager module provides a means for the forensic analyst to view, process, and report on data from different sources in one software package. PMID- 23458412 TI - Tailor-made highly luminescent and ambipolar transporting organic mixed stacked charge-transfer crystals: an isometric donor-acceptor approach. AB - We have rationally designed a densely packed 1:1 donor-acceptor (D-A) cocrystal system comprising two isometric distyrylbenzene- and dicyanodistyrylbenzene-based molecules, forming regular one-dimensional mixed stacks. The crystal exhibits strongly red-shifted, bright photoluminescence originating from an intermolecular charge-transfer state. The peculiar electronic situation gives rise to high and ambipolar p-/n-type field-effect mobility up to 6.7 * 10(-3) and 6.7 * 10(-2) cm(2) V(-1) s(-1), respectively, as observed in single-crystalline OFETs prepared via solvent vapor annealing process. The unique combination of favorable electric and optical properties arising from an appropriate design concept of isometric D A cocrystal has been demonstrated as a promising candidate for next generation (opto-)electronic materials. PMID- 23458411 TI - Biliary and vascular anomalies in living liver donors: the role and accuracy of pre-operative radiological mapping. AB - BACKGROUND: The aim of the present study was to determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) anatomic mapping in the detection of biliary and vascular anomalies prior to a living liver donor (LLD) operation. METHODS: A retrospective study of all LLD patient charts, operative and radiology reports from 1 January 2002 to 1 January 2012 was conducted. Primary post-operative outcomes assessed included mortality, re-operation, readmission and need for endoscopic or percutaneous intervention. Sensitivity and specificity of MR and CT pre-operative screening was calculated against the gold standard of intra-operative findings. RESULTS: A total of 34 donors had an average age of 38 years (range: 22-58) with a body mass index (BMI) of 25.6 kg/m(2) (range: 19.8-32.5) and a length of stay (LOS) of 10.1 days (range: 5-41). There were no donor mortalities. Sensitivity and specificity of CT was 70.0% and 91.3%, and of MRI screening 23.1% and 100.0%, respectively. Patients with inaccurate pre-operative CT or MRI did not have an increased risk of complications. CONCLUSIONS: Even although it was specific, pre-operative MR screening missed up to 77.0% of biliary anomalies. An impeccable surgical technique remains the key in preventing biliary complications of a living donor hepatectomy where pre-operative MRI screening is false. PMID- 23458413 TI - Hepatocyte growth factor gene-modified mesenchymal stem cells reduce radiation induced lung injury. AB - Abstract Effective therapeutic strategies for radiation-induced lung injury (RILI) are lacking. Mesenchymal stem cells (MSCs), as gene therapy delivery vehicles, possess the ability to repair injured lung. In this study, we conducted MSC-based hepatocyte growth factor (HGF) gene therapy for RILI. Mice received single-dose radiation with 20 Gy of gamma rays locally to the lung, and then were administered normal sodium, Ad-HGF-modified MSCs, or Ad-Null-modified MSCs. Ad HGF-modified MSCs (MSCs-HGF) improved histopathological and biochemical markers of lung injury. MSCs-HGF could reduce secretion and expression of proinflammatory cytokines, including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, and intercellular adhesion molecule-1, and increase the expression of antiinflammatory cytokine IL-10. It could also decrease expression levels of profibrosis factors transforming growth factor-beta, Col1a1 (collagen type 1, alpha1), and Col3a1, and inhibit fibrosis progress. MSCs-HGF could promote proliferation of lung epithelial cells and protect them from apoptosis, and improve the expression of endogenous HGF and its receptor c-Met significantly. We also found that sphingosine-1-phosphate receptor-1 expression was increased in injured lung. These results suggest MSC-based HGF gene therapy not only reduces inflammation but also inhibits lung fibrosis. PMID- 23458414 TI - Haemoplasmas: lessons learnt from cats. AB - The haemotropic mycoplasmas (haemoplasmas) are a group of bacteria that can induce anaemia in a wide variety of mammals, including domestic cats and wild felids. Different feline haemoplasma species of varying pathogenicity exist, with the more pathogenic Mycoplasma haemofelis (Mhf) capable of inducing severe haemolytic anaemia, whilst 'Candidatus Mycoplasma haemominutum' (CMhm) and 'Candidatus Mycoplasma turicensis' (CMt) are infrequently associated with clinical disease. Chronic haemoplasma infections are common and cats are frequently infected by two or more haemoplasmas, complicating the clinical picture. The natural route of transmission of haemoplasma infection between cats has not yet been determined; however, experimental transmission has been demonstrated via both oral and parenteral administration of infected blood. To date the haemoplasmas have been unable to be cultured in vitro, and accurate diagnosis is currently reliant on detection of bacterial DNA using PCR assays. Treatment of clinical haemoplasmosis is focussed on supportive care in combination with empirical treatment with antimicrobials (tetracyclines or fluoroquinolones). A significant number of asymptomatic cats are positive for haemoplasma infection. These cats may play a role in the maintenance of haemoplasma infection within a population, and need to be considered when choosing potential blood donors. Use of PCR assays has provided an accurate method of diagnosing haemoplasma infection and quantifying response to therapy, including in non-feline host animals, as presumed zoonotic haemoplasma infections are now being documented. Recent advances in genome sequencing techniques have allowed the whole genome sequences of the feline haemoplasmas Mhf and CMhm to be derived, as well as a number of non-feline haemoplasma species. These data have aided the identification of antigens for use in the development of serological tests, allowed the proteomic study of haemoplasmas and provided clues as to how the haemoplasmas can persist within the host. Future areas of study include investigation of their zoonotic potential, mechanisms of immune system evasion and transmission of these emerging pathogens. PMID- 23458415 TI - Theory of mind in patients with temporal lobe epilepsy. AB - Theory of mind (ToM) is a crucial aspect of social cognition and is mediated by a complex neural network. Studies on temporal lobe epilepsy (TLE) suggest that its neuropathological involvement includes several brain regions. Some regions seem to overlap the neural network responsible for ToM, and this overlap provides an opportunity to explore ToM in TLE patients. Another concern is psychosocial problems in TLE, and the study of ToM in TLE could serve as a basis for further understanding the nature of such psychosocial disturbances. Studies on whether TLE patients evidence ToM deficit, however, are scant and controversial. Consequently, we examine whether ToM deficit is evident in TLE. Thirty-one TLE patients and 24 matched controls were recruited and completed four tasks measuring different levels of ToM: false belief, faux pas recognition, processing of implied meanings, and cartoon ToM. The patients were impaired in both basic and advanced ToM. Right TLE had a more wide-ranging picture of deficit than left TLE. ToM appears to be vulnerable to TLE, especially on the right side. Since ToM might contribute to patients' psychosocial adjustment, we thus suggest that a ToM measure be included in regular neuropsychological assessments of such patients. PMID- 23458416 TI - Preparation of primary amine derivatives of the magic-size nanocluster (CdSe)13. AB - Four [(CdSe)13(RNH2)13] derivatives (R = n-propyl, n-pentyl, n-octyl, and oleyl) are prepared by reaction of Cd(OAc)2.2H2O and selenourea in the corresponding primary-amine solvent. Nanoclusters grow in spontaneously formed amine-bilayer templates and are characterized by elemental analysis, IR spectroscopy, UV-vis spectroscopy, TEM, and low-angle XRD. Derivative [(CdSe)13(n-propylamine)13] is isolated as a yellowish-white solid (MP 98 degrees C) on the gram scale. These compounds are the first derivatives of magic-size CdSe nanoclusters to be isolated in purity. PMID- 23458417 TI - Of mice and men... and models of metastatic colorectal carcinoma. PMID- 23458418 TI - Molecular epidemiology of methicillin-resistant Staphylococcus aureus in Switzerland: sampling only invasive isolates does not allow a representative description of the local diversity of clones. AB - We conducted a molecular study of MRSA isolated in Swiss hospitals, including the first five consecutive isolates recovered from blood cultures and the first ten isolates recovered from other sites in newly identified carriers. Among 73 MRSA isolates, 44 different double locus sequence typing (DLST) types and 32 spa types were observed. Most isolates belonged to the NewYork/Japan, the UK-EMRSA-15, the South German and the Berlin clones. In a country with a low to moderate MRSA incidence, inclusion of non-invasive isolates allowed a more accurate description of the diversity. PMID- 23458419 TI - Coordinated release of tissue factor and tissue factor pathway inhibitor in VLBW infants. AB - AIM: Tissue factor (TF), a mediator between coagulation and inflammation, is upregulated in alveolar compartment and circulation in very low birthweight (VLBW) infants. We investigated the contribution of TF to systemic regulation of coagulation in VLBW infants. METHODS: We measured TF, total and free tissue factor pathway inhibitor (TFPIt, TFPIf), prothrombin fragment (F1 + 2), and thrombin-antithrombin complexes (TAT) in plasma from 51 VLBW infants during their first week of life. RESULTS: F1 + 2 in cord plasma was high (1385 pmol/mL) and decreased postnatally to 17% (p = 0.002). TAT decreased from a high cord concentration to 3% postnatally (p < 0.001). Plasma TF increased and peaked on day 3, showing no correlation with F1 + 2 or TAT. TFPIt and TFPIf increased postnatally, correlating with TF (day 1 TFPIf: R = 0.595, p < 0.001, day 3 TFPIf: R = 0.582, p < 0.001). Based on the TF/TFPIf ratio, a relative excess of plasma TF over TFPIf probably prevailed on day 3. CONCLUSIONS: In VLBW infants plasma TF fails to associate with thrombin formation. This is partly explained by release of TFPI. Despite TFPI, the newborn VLBW infant is subjected to a substantial circulating pool of TF with potential proinflammatory effects. PMID- 23458420 TI - Thioflavin T and its photoirradiative derivatives: exploring their spectroscopic properties in the absence and presence of amyloid fibrils. AB - In this work, we found that, during storage or after UV irradiation, ThT is demethylated or oxidized, forming three derivatives. These three derivatives were purified by high performance liquid chromatography and characterized by mass and nuclear magnetic resonance spectroscopy and the spectroscopic properties of pure ThT and the derivatives carefully compared. Our results show that the emission peak at 450 nm results from oxidized ThT and not from the monomeric form of ThT, as previously proposed. The partial conversion of ThT into oxidized and demethylated derivatives has an effect on amyloid detection using ThT assay. Irradiated ThT has the same lag time as pure ThT in the amyloidogenesis of insulin, but the intensity of the emitted fluorescence is significantly decreased. PMID- 23458421 TI - Evaluation of specific humoral immune response and cross reactivity against Mycobacterium tuberculosis antigens induced in mice immunized with liposomes composed of total lipids extracted from Mycobacterium smegmatis. AB - The development of a new tuberculosis (TB) vaccine has become one of the main objectives of the scientific community. Protein antigens have been widely explored as subunit TB vaccines, however lipid antigens could be equally important to be used or included in such a vaccine. The aim of this study was to demonstrate the potential of a liposome formulation composed of an extract of lipids from Mycobacterium smegmatis (Ms) as a TB vaccine candidate. We evaluated the immunogenicity of this formulation as well as the cross reactive response against antigens from Mycobacterium tuberculosis (MTb) in BALB/c mice. We determined the anti-liposome IgG response in sera from TB patients and from healthy subjects who displayed a positive (PPD+) or negative (PPD-) tuberculin skin test. A significant increase in anti-liposome IgG (p<0.05) was detected in animals immunized with Bacille Calmette-Guerin (BCG) compared with all groups, and in the group immunized with liposomes from Ms (LMs) compared to animals immunized with either LMs adjuvanted with aluminium (LMs-A) or the negative control group (phosphate buffered saline, PBS) respectively. With respect to the cross reactive response against a cocktail of cell wall antigens (CWA) from MTb, significantly higher IgG levels were observed in animals immunized with BCG and LMs compared to negative controls and either, aluminium-adjuvanted liposomes (LMs A) or montanide (LMs-M) (p<0.05). Furthermore, the anti-liposome IgG response was significantly superior in sera from pulmonary TB patients compared to PPD+ and PPD- healthy subjects (p<0.001) suggesting the expression of these antigens in vivo during active MTb infection. The results obtained provide some evidence for the potential use of liposomes containing total lipid extracts of Ms as a TB vaccine candidate. PMID- 23458422 TI - Thermoresponsive bacterial cellulose whisker/poly(NIPAM-co-BMA) nanogel complexes: synthesis, characterization, and biological evaluation. AB - Dispersions of poly(N-isopropylacrylamide-co-butyl methacrylate) (PNB) nanogels are known to exhibit reversible thermosensitive sol-gel phase behavior and can consequently be used in a wide range of biomedical applications. However, some dissatisfactory mechanical properties of PNB nanogels can limit their applications. In this paper, bacterial cellulose (BC) whiskers were first prepared by sulfuric acid hydrolysis and then nanosized by high-pressure homogenization for subsequent use in the preparation of BC whisker/PNB nanogel complexes (designated as BC/PNB). The mechanical properties of PNB was successfully enhanced, resulting in good biosafety. The BC/PNB nanogel dispersions exhibited phase transitions from swollen gel to shrunken gel with increasing temperature. In addition, differential scanning calorimetry (DSC) data showed that the thermosensitivity of PNB nanogels was retained. Rheological tests also indicated that BC/PNB nanogel complexes had stronger gel strengths when compared with PNB nanogels. The concentrated dispersions showed shear thinning behavior and improved toughness, both of which can play a key role in the medical applications of nanogel complexes. Furthermore, the BC/PNB nanogel complexes were noncytotoxic according to cytotoxicity and hemolysis tests. Concentrated BC/PNB nanogel dispersion displayed gel a forming capacity in situ by catheter injection, which indicates potential for a wide range of medical applications. PMID- 23458423 TI - C-H stretch for probing kinetics of self-assembly into macromolecular chiral structures at interfaces by chiral sum frequency generation spectroscopy. AB - Self-assembly of molecules into chiral macromolecular and supramolecular structures at interfaces is important in various fields, such as biomedicine, polymer sciences, material sciences, and supramolecular chemistry. However, probing the kinetics at interfaces remains challenging because it requires a real time method that has selectivity to both interface and chirality. Here, we introduce an in situ approach of using the C-H stretch as a vibrational probe detected by chiral sum frequency generation spectroscopy (cSFG). We showed that the C-H stretch cSFG signals of an amphiphilic peptide (LK7beta) can reveal the kinetics of its self-assembly into chiral beta-sheet structures at the air-water interface. The cSFG experiments in conjunction with measurements of surface pressure allow us to propose a mechanism of the self-assembly process, which involves an immediate adsorption of disordered structures followed by a lag phase before the self-assembly into chiral antiparallel beta-sheet structures. Our method of using the C-H stretch signals implies a general application of cSFG to study the self-assembly of bioactive, simple organic, and polymeric molecules into chiral macromolecular and supramolecular structures at interfaces, which will be useful in tackling problems, such as protein aggregation, rational design of functional materials, and fabrication of molecular devices. PMID- 23458424 TI - A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways. AB - OBJECTIVES: Enhanced recovery after surgery (ERAS) or fast-track protocols have been implemented in different fields of surgery to attenuate the surgical stress response and accelerate recovery. The objective of this study was to systematically review the literature on outcomes of ERAS protocols applied in liver surgery. METHODS: The MEDLINE, EMBASE, PubMed and Cochrane Library databases were searched for randomized controlled trials (RCTs), case-control studies and case series published between January 1966 and October 2011 comparing adult patients undergoing elective liver surgery in an ERAS programme with those treated in a conventional manner. The primary outcome measure was hospital length of stay (LoS). Secondary outcome measures were time to functional recovery, and complication, readmission and mortality rates. RESULTS: A total of 307 articles were found, six of which were included in the review. These comprised two RCTs, three case-control studies and one retrospective case series. Median LoS ranged from 4 days in an ERAS group to 11 days in a control group. Morbidity, mortality and readmission rates did not differ significantly between the groups. Only two studies assessed time to functional recovery. Functional recovery in these studies was reached 2 days before discharge. CONCLUSIONS: This systematic review suggests that ERAS protocols can be successfully implemented in liver surgery. Length of stay is reduced without compromising morbidity, mortality or readmission rates. PMID- 23458425 TI - Design, synthesis, and functional activity of labeled CD1d glycolipid agonists. AB - Invariant natural killer T cells (iNKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, alpha-galactosyl ceramide (alpha-GalCer) 1, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to iNKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR-alpha GalCer-CD1d ternary complex identified the alpha-methylene unit in the fatty acid side chain, and more specifically the pro-S hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR-glycolipid-CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the pro-S, and not the pro-R, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (S)-10 displayed behavior comparable to that of ThrCer 5 itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely alpha-GalCer C20:2 4, was modified in a similar way, this time with a fluorescent label. The labeled alpha-GalCer C20:2 analogue (11) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the alpha-methylene unit in the fatty acid amide chain should be a suitable site for attaching a label to a range of CD1d agonists. The flexibility of the synthetic strategy, and late-stage incorporation of the label, opens up the possibility of using this labeling approach to study the in vivo behavior of a wide range of CD1d agonists. PMID- 23458427 TI - Tunneling under the digastricus muscle increases salivary duct exposure and completeness of excision in mandibular and sublingual sialoadenectomy in dogs. AB - OBJECTIVE: To document the extent of rostral salivary duct and glandular tissue excision achieved through a conventional lateral approach before and after tunneling under the digastricus muscle. STUDY DESIGN: Experimental cadaveric study. ANIMALS: Dog cadavers (n = 8). METHODS: Bilateral mandibular and sublingual sialoadenectomy was performed in 8 cadavers using a conventional lateral approach and the point of proposed salivary duct transection was marked with Evans blue dye. Remaining salivary duct was then tunneled under the digastricus muscle and dissection continued rostrally. The most rostral point of the gland/duct complex was marked before transection of the salivary duct. Once removed, the distance between the 2 marks was measured and recorded. Completeness of glandular tissue excision was confirmed by dissection and gross examination. RESULTS: The tunneling technique improved rostral exposure and increased the median (IQR) length of salivary duct excision by 1.8 (0.35) cm. Residual polystomatic sublingual salivary tissue remained in all cadavers after simulated resection without tunneling under the digastricus muscle. After tunneling, complete removal of rostral salivary tissue was achieved in 13 of 15 procedures. CONCLUSIONS: Tunneling under the digastricus muscle increases the length of rostral salivary duct and glandular tissue that can be removed through a conventional lateral approach. PMID- 23458426 TI - Detection of pancreatic cancer using serum protein profiling. AB - BACKGROUND: Currently, no suitable biomarkers for the early detection of pancreatic cancer (PC) are available. Proteins present in the serum could reflect a state of the disease. In this study, these profiles as a diagnostic marker for PC were evaluated. METHODS: Serum samples were obtained from PC patients (n = 50 calibration set, n = 39 validation set) and healthy volunteers (n = 110 and n = 75 respectively) according to a uniform standardized collection and processing protocol. For peptide and protein isolation, automated solid-phase extraction (SPE) with Weak Cation Exchange (WCX) magnetic beads (MB) was performed using a 96-channel liquid handling platform. Protein profiles were obtained by mass spectrometry (MS) and evaluated by linear discriminant analysis with double cross validation. RESULTS: A discriminating profile for PC has been identified, with a sensitivity of 78% and a specificity of 89% in the calibration set with an area under the curve (AUC) of 90%. These results were validated with a sensitivity of 74% and a specificity of 91% (AUC 90%). CONCLUSION: Serum profiles of healthy controls and PC can be discrimated between. Further research is warranted to evaluate specificity and whether this biosignature can be used for early detection in a high risk population. PMID- 23458428 TI - Michael Foundation Forum 2012, Berlin, Germany. PMID- 23458429 TI - Seizures and the neuro-cardio-endocrine axis. PMID- 23458430 TI - Cold-water immersion decreases cerebral oxygenation but improves recovery after intermittent-sprint exercise in the heat. AB - This study examined the effects of post-exercise cooling on recovery of neuromuscular, physiological, and cerebral hemodynamic responses after intermittent-sprint exercise in the heat. Nine participants underwent three post exercise recovery trials, including a control (CONT), mixed-method cooling (MIX), and cold-water immersion (10 degrees C; CWI). Voluntary force and activation were assessed simultaneously with cerebral oxygenation (near-infrared spectroscopy) pre- and post-exercise, post-intervention, and 1-h and 24-h post exercise. Measures of heart rate, core temperature, skin temperature, muscle damage, and inflammation were also collected. Both cooling interventions reduced heart rate, core, and skin temperature post-intervention (P < 0.05). CWI hastened the recovery of voluntary force by 12.7 +/- 11.7% (mean +/- SD) and 16.3 +/- 10.5% 1-h post-exercise compared to MIX and CONT, respectively (P < 0.01). Voluntary force remained elevated by 16.1 +/- 20.5% 24-h post-exercise after CWI compared to CONT (P < 0.05). Central activation was increased post-intervention and 1-h post-exercise with CWI compared to CONT (P < 0.05), without differences between conditions 24-h post-exercise (P > 0.05). CWI reduced cerebral oxygenation compared to MIX and CONT post-intervention (P < 0.01). Furthermore, cooling interventions reduced cortisol 1-h post-exercise (P < 0.01), although only CWI blunted creatine kinase 24-h post-exercise compared to CONT (P < 0.05). Accordingly, improvements in neuromuscular recovery after post-exercise cooling appear to be disassociated with cerebral oxygenation, rather reflecting reductions in thermoregulatory demands to sustain force production. PMID- 23458431 TI - On the analysis of non-photochemical chlorophyll fluorescence quenching curves: I. Theoretical considerations. AB - Non-photochemical quenching (NPQ) protects photosynthetic organisms against photodamage by high light. One of the key measuring parameters for characterizing NPQ is the high-light induced decrease in chlorophyll fluorescence. The originally measured data are maximal fluorescence (Fm') signals as a function of actinic illumination time (Fm'(t)). Usually these original data are converted into the so-called Stern-Volmer quenching function, NPQSV(t), which is then analyzed and interpreted in terms of various NPQ mechanisms and kinetics. However, the interpretation of this analysis essentially depends on the assumption that NPQ follows indeed a Stern-Volmer relationship. Here, we question this commonly assumed relationship, which surprisingly has never been proven. We demonstrate by simulation of quenching data that particularly the conversion of time-dependent quenching curves like Fm'(t) into NPQSV(t) is (mathematically) not "innocent" in terms of its effects. It distorts the kinetic quenching information contained in the originally measured function Fm'(t), leading to a severe (often sigmoidal) distortion of the time-dependence of quenching and has negative impact on the ability to uncover the underlying quenching mechanisms and their contribution to the quenching kinetics. We conclude that the commonly applied analysis of time-dependent NPQ in NPQSV(t) space should be reconsidered. First, there exists no sound theoretical basis for this common practice. Second, there occurs no loss of information whatsoever when analyzing and interpreting the originally measured Fm'(t) data directly. Consequently, the analysis of Fm'(t) data has a much higher potential to provide correct mechanistic answers when trying to correlate quenching data with other biochemical information related to quenching. PMID- 23458432 TI - The origins of altruism in offspring care. AB - The current review aims to unify existing views of altruism through an examination of the biological bases of a fundamental form of giving: altruistic responding. Altruistic responding is most salient during heroic acts of helping but is also observed any time one perceives another's distress or need, which in turn motivates one to help at a current cost to the self. Such aid is simple, observable across species, and rooted in the instincts and circuits that evolved to maximize inclusive fitness through the care of helpless offspring. By design, the system already biases aid to both kin and nonkin under conditions that are largely adaptive. These inherent benefits are also buttressed in primates and humans by known, later-arriving benefits to helping in group-living animals. Evidence for the proposed homology between altruistic responding and offspring retrieval is presented through 10 key shared factors. Conceptually, both require (a) participation by nonmothers, (b) motor competence and expertise, (c) an adaptive opponency between avoidance and approach, and a facilitating role of (d) neonatal vulnerability, (e) salient distress, and (f) rewarding close contact. Physiologically, they also share neurohormonal support from (g) oxytocin, (h) the domain-general mesolimbocortical system, (i) the cingulate cortex, and (j) the orbitofrontal cortex. The framework intermixes ultimate and proximate levels of analysis and unifies existing views by assuming that even complex human behaviors reflect ancient mammalian neural systems that evolved to solve key problems in adaptive ways, with far-reaching consequences for even our most venerated human traits. PMID- 23458433 TI - Disgust discussed: introduction to the special section. AB - The author introduces a special section of Psychological Bulletin devoted to the study of disgust. After discussing conflicts between its supposed role as a basic emotion and its more recently understood involvement in responding to moral transgressions, the author summarizes 3 articles contained in the special section. Widen and Russell (2013) present a developmental account of disgust highlighting the ages at which children experience, express, understand, verbalize, and recognize disgust. The article shows that disgust is present early but that recognition of disgust in others is considerably delayed. Chapman and Anderson (2013) review evidence pertaining to the question of whether genuine disgust is elicited by moral transgressions. Their review covers data from self report, brain imaging, facial behavior, and implicit measures gathered from both experimental and correlational studies. They conclude that moral transgressions elicit genuine disgust. Russell and Giner-Sorolla (2013) ask what types of moral transgressions are most likely to elicit pure disgust. They find that moral transgressions involving body violations are more likely than others to elicit such disgust. Moreover, they suggest that disgust elicited by body violations is likely to be more resistant to modification by context, situation, and efforts at rationalization. Taken together, the reviews support the view that rudiments of disgust to physical objects are present early in life but later become adapted to social influence and new moral purposes. Social implications are discussed. PMID- 23458434 TI - Children's recognition of disgust in others. AB - Disgust has been theorized to be a basic emotion with a facial signal that is easily, universally, automatically, and perhaps innately recognized by observers from an early age. This article questions one key part of that theory: the hypothesis that children recognize disgust from its purported facial signal. Over the first 5 years, children experience disgust, produce facial expressions of disgust, develop a concept of disgust, understand and produce the word disgust or a synonym, know about disgust's causes and consequences, and infer disgust in others from a situation or a behavior. Yet, only gradually do these children come to "recognize" disgust specifically from the "disgust face" found in standardized sets of the facial expressions of basic emotions. Improvement is gradual, with more than half of children matching the standard disgust face to disgust only at around 9 years of age and with subsequent improvement continuing gradually until the late teens or early adulthood. Up to age 8, a majority of children studied believe that the standard disgust face indicates anger. Rather than relying on an already known signal value, children may be actively learning to interpret the expression. PMID- 23458435 TI - Things rank and gross in nature: a review and synthesis of moral disgust. AB - Much like unpalatable foods, filthy restrooms, and bloody wounds, moral transgressions are often described as "disgusting." This linguistic similarity suggests that there is a link between moral disgust and more rudimentary forms of disgust associated with toxicity and disease. Critics have argued, however, that such references are purely metaphorical, or that moral disgust may be limited to transgressions that remind us of more basic disgust stimuli. Here we review the evidence that moral transgressions do genuinely evoke disgust, even when they do not reference physical disgust stimuli such as unusual sexual behaviors or the violation of purity norms. Moral transgressions presented verbally or visually and those presented as social transactions reliably elicit disgust, as assessed by implicit measures, explicit self-report, and facial behavior. Evoking physical disgust experimentally renders moral judgments more severe, and physical cleansing renders them more permissive or more stringent, depending on the object of the cleansing. Last, individual differences in the tendency to experience disgust toward physical stimuli are associated with variation in moral judgments and morally relevant sociopolitical attitudes. Taken together, these findings converge to support the conclusion that moral transgressions can in fact elicit disgust, suggesting that moral cognition may draw upon a primitive rejection response. We highlight a number of outstanding issues and conclude by describing 3 models of moral disgust, each of which aims to provide an account of the relationship between moral and physical disgust. PMID- 23458436 TI - Bodily moral disgust: what it is, how it is different from anger, and why it is an unreasoned emotion. AB - With the recent upswing in research interest on the moral implications of disgust, there has been uncertainty about what kind of situations elicit moral disgust and whether disgust is a rational or irrational player in moral decision making. We first outline the benefits of distinguishing between bodily violations (e.g., sexual taboos, such as pedophilia and incest) and nonbodily violations (e.g., deception or betrayal) when examining moral disgust. We review findings from our lab and others' showing that, although many existing studies do not control for anger when studying disgust, disgust at nonbodily violations is often associated with anger and hard to separate from it, while bodily violations more consistently predict disgust independently of anger. Building on this distinction, we present further empirical evidence that moral disgust, in the context of bodily violations, is a relatively primitively appraised moral emotion compared to others such as anger, and also that it is less flexible and less prone to external justifications. Our review and results underscore the need to distinguish between the different consequences of moral emotions. PMID- 23458438 TI - Functional language networks in sedentary and physically active older adults. AB - Functional magnetic resonance imaging (fMRI) studies have identified consistent age-related changes during various cognitive tasks, such that older individuals display more positive and less negative task-related activity than young adults. Recently, evidence shows that chronic physical exercise may alter aging-related changes in brain activity; however, the effect of exercise has not been studied for the neural substrates of language function. Additionally, the potential mechanisms by which aging alters neural recruitment remain understudied. To address these points, the present study enrolled elderly adults who were either sedentary or physically active to characterize the neural correlates of language function during semantic fluency between these groups in comparison to a young adult sample. Participants underwent fMRI during semantic fluency and transcranial magnetic stimulation to collect the ipsilateral silent period, a measure of interhemispheric inhibition. Results indicated that sedentary older adults displayed reductions in negative task-related activity compared to the active old group in areas of the attention network. Longer interhemispheric inhibition was associated with more negative task-related activity in the right and left posterior perisylvian cortex, suggesting that sedentary aging may result in losses in task facilitatory cortical inhibition. However, these losses may be mitigated by regular engagement in physical exercise. PMID- 23458437 TI - Signal transduction and molecular targets of selected flavonoids. AB - SIGNIFICANCE: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. RECENT ADVANCES: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. CRITICAL ISSUES: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. FUTURE DIRECTIONS: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. PMID- 23458440 TI - Modelling the activation of alkaline pH response transcription factor PacC in Aspergillus nidulans: involvement of a negative feedback loop. AB - Alkaline pH adaptation represents an important environmental stress response in Aspergillus nidulans. It is mediated by the pal signalling pathway and the PacC transcription factor. Although studied extensively experimentally, the activation mechanism of PacC has not been quantified, and it is not clear how this activation is regulated. Here, by constructing mathematical models, we first show that the pattern of PacC activation observed in previously published experiments cannot be explained based on existing knowledge about PacC activation. Extending the model with a negative feedback loop is necessary to produce simulation results that are consistent with the data, suggesting the existence of a negative feedback loop in the PacC activation process. This extended model is then validated against published measurements for cells with drug treatment and mutant cells. Furthermore, we investigate the role of an intermediate form of PacC in the PacC activation process, and propose experiments that can be used to test our predictions. Our work illustrates how mathematical models can be used to uncover regulatory mechanisms in the transcription regulation, and generate hypotheses that guide further laboratory investigations. PMID- 23458439 TI - Evaluation of stapler hepatectomy during a laparoscopic liver resection. AB - METHODS: An international database of 1499 laparoscopic liver resections was analysed using multivariate and Kaplan-Meier analysis. RESULTS: In total, 764 stapler hepatectomies (SH) were compared with 735 electrosurgical resections (ER). SH was employed in larger tumours (4.5 versus 3.8 cm; P < 0.003) with decreased operative times (2.6 versus 3.1 h; P < 0.001), blood loss (100 versus 200 cc; P < 0.001) and length of stay (3.0 versus 7.0 days; P < 0.001). SH incurred a trend towards higher complications (16% versus 13%; P = 0.057) including bile leaks (26/764, 3.4% versus 16/735, 2.2%: P = 0.091). To address group homogeneity, a subset analysis of lobar resections confirmed the benefits of SH. Kaplan-Meier analysis in non-cirrhotic and cirrhotic patients confirmed equivalent patient (P = 0.290 and 0.118) and disease-free survival (P = 0.120 and 0.268). Multivariate analysis confirmed the parenchymal transection technique did not increase the risk of cancer recurrence, whereas tumour size, the presence of cirrhosis and concomitant operations did. CONCLUSIONS: A SH provides several advantages including: diminished blood loss, transfusion requirements and shorter operative times. In spite of the smaller surgical margins in the SH group, equivalent recurrence and survival rates were observed when matched for parenchyma and extent of resection. PMID- 23458441 TI - Clinical and causality assessment in herbal hepatotoxicity. AB - INTRODUCTION: Herbal hepatotoxicity represents a poorly understood, neglected and multifaceted disease with numerous confounding variables and missing established causality in the majority of cases. This review discusses overt shortcomings in its clinical and causality assessment and suggests improvements. AREAS COVERED: A selective literature search of PubMed using the terms herbal hepatotoxicity, herb induced liver injury, drug hepatotoxicity and drug-induced liver injury was performed to identify published case reports, spontaneous case reports, case series and review articles regarding hepatotoxicity due to herbs, herbal drugs and herbal dietary supplements. Covered areas focused on confounding variables related to the documentation of the herbal product and the clinical course, hepatotoxicity and reexposure criteria, temporal association, comedication and alternative causes with special attention to preexisting diseases of the liver, bile ducts and the pancreas. Of particular interest were recent discussions of approaches designed and validated for hepatotoxicity causality, such as the scale of CIOMS (Council for International Organizations of Medical Sciences). EXPERT OPINION: The authors call for substantial improvements in data quality of herbal products and case characteristics and strongly recommend using the CIOMS scale to assess causality in suspected herbal hepatotoxicity. PMID- 23458442 TI - Influence of bacteriophage preparations on intracellular killing of bacteria by human phagocytes in vitro. AB - Bacteriophages are viruses that infect bacteria. It was shown that bacteriophage therapy is an effective method of combating bacterial infections, including infections caused by antibiotic-resistant bacterial strains. One of the main obstacles to widespread use of phage preparations is limited knowledge regarding the influence of bacteriophages on human organisms. In our study, we evaluated whether application of phage preparations impair bactericidal activities of human phagocytes (granulocytes and monocytes). In our study, we used preparations of phages T2 and T4 specific to Escherichia coli and A3 phage specific to Staphylococcus aureus. We found that bacteriophage preparations do not influence intracellular killing of bacteria by human phagocytes. The effect is irrespective of phage preparation type (lysate, purified phage preparation), phage titer of the preparation, and whether bacteria phagocytosed by phagocyte cells are sensitive or insensitive to phage (bacteriophages homologous and heterologous to bacteria). Although the results of our study are preliminary, they support previous data indicating safety of therapeutic application of phages. PMID- 23458443 TI - New proteoliposome vaccine formulation from N. meningitidis serogroup B, without aluminum hydroxide, retains its antimeningococcal protectogenic potential as well as Th-1 adjuvant capacity. AB - Proteoliposomes purified from the Outer Membrane of Neisseria meningitidis B, have been successfully used as core for adjuvants and vaccine formulations. We have tried to increase their structural definition and to conserve their efficacy and stability avoiding the addition of the aluminum hydroxide to the final formulation. Liposomal particle systems were prepared from components of defined molecular structure, such as a Neisseria meningitidis B protein complex, extracted and purified without forming vesicle structures. Liposomes were prepared from a mixture of dioleoyl phosphatidyl serine and cholesterol, using the classical dehydration-rehydration method. Transmission Electron Microscopy (TEM) was used to characterize the liposomes. BALB/c mice were used for animal testing procedures. Analysis of specific IgG response, serum bactericidal activity as well as DTH reaction was carried out. Isolation and purification of mRNA and real-time PCR, was performed to determine the dominating Th lymphokine pattern. The new antimeningococcal formulation without aluminum hydroxide prepared with components of defined molecular structure assembled itself into Neoproteoliposomes (NPL) ranging from 50 to 70 nm in diameter. The extraction and purification of selected membrane proteins to provide the antigen for this new formulation (PD-Tp), as well as the NPL-formulation favors a Th1 response pattern, suggested by the higher percentages of DTH, increased expression of proinflamatory lymphokine mRNAs when administered by intramuscular and intranasal routes. It stimulates a systemic bactericidal antibody response against Neisseria meningitidis B and immunologic memory similar to the Cuban VA-MENGOC-BC vaccine, even at lower dosages and is less reactogenic at the injection site in comparison with the formulation with aluminum hydroxide. This new adjuvant formulation could be applicable to the development of new and improved vaccines against meningococcal disease, and eventually as modulators of the immune response against other diseases. PMID- 23458444 TI - Retinal gene therapy coming of age. PMID- 23458445 TI - Cellulose-ethylenediaminetetraacetic acid conjugates protect mammalian cells from bacterial cells. AB - Cellulose-ethylenediaminetetraacetic acid (EDTA) conjugates were synthesized by the esterification of cellulose with ethylenediaminetetraacetic dianhydride (EDTAD). The new materials provided potent antimicrobial activities against Staphylococcus aureus (S. aureus, Gram-positive bacteria) and Pseudomonas aeruginosa (P. aeruginosa, Gram-negative bacteria), and inhibited the formation of bacterial biofilms. The biocompatibility of the new cellulose-EDTA conjugates was evaluated with mouse skin fibroblasts for up to 14 days. SEM observation and DNA content analysis suggested that the new materials sustained the viability of fibroblast cells. Moreover, in mouse skin fibroblast-bacteria co-culture systems, the new cellulose-EDTA conjugates prevented bacterial biofilm formation and protected the mammalian cells from the bacterial cells for at least one day. PMID- 23458446 TI - Herpesviruses in cerebrospinal fluid of children with meningitis in Luanda, Angola. PMID- 23458447 TI - Does fibrin glue sealant decrease the rate of anastomotic leak after a pancreaticoduodenectomy? Results of a prospective randomized trial. AB - BACKGROUND: The aim of this study was to evaluate the effect of topical fibrin glue applied externally to all anastomoses after a pancreaticoduodenectomy (PD) on drain lipase levels, anastomotic leaks, complication rates and length of hospital stay. METHODS: A standardized non-pylorus preserving PD was performed with or without fibrin glue applied to each anastomosis. RESULTS: Fifty-seven patients were randomized: 32 with and 25 without TISSEEL. There were no statistical differences in each group with respect to drain lipase levels (high 40% versus 43%, P = 0.794), complications including gastric or biliary leaks (24% versus 28%, P = 1.00), wound infection (16% versus 9%, P = 0.28) and a Clavien score of 3 or more (16% versus 25%, P = 0.757) or hospital stay (12 versus 17 days, P = 0.777). Most patients with elevated drain lipase levels had an unaltered clinical course not predictive of adverse outcomes. However, the operative finding of a soft pancreas (27 out of 57 patients) was associated with post-operative complications (P = 0.002). There were no peri-operative deaths. CONCLUSIONS: Fibrin glue application to all anastomoses does not alter drain lipase levels. Drain lipase levels are not a significant surrogate marker for clinically significant anastomotic leaks or complications. Fibrin glue application did not reduce the incidence of an anastomotic leak or complications. PMID- 23458448 TI - An antibiotic-resistant class 3 integron in an Enterobacter cloacae isolate from hospital effluent. AB - Hospital effluents are involved in dissemination of antibiotic-resistant integrons. We describe here a new class 3 integron, In3-5, detected in an Enterobacter cloacae isolate retrieved from a random French hospital effluent sample collected in 2009. In3-5 carries two gene cassettes: the new blaOXA -256 and an aac(6')-Ib variant, respectively conferring resistance to beta-lactams and aminoglycosides. In3-5 is located on an IncQ-like backbone plasmid. Class 3 integrons could thus be involved in the dissemination of antibiotic resistance in both clinical settings and the environment, and could participate in the exchange of antibiotic-resistance genes between these two ecosystems. PMID- 23458450 TI - Aniline-catalyzed reductive amination as a powerful method for the preparation of reducing end-"clickable" chitooligosaccharides. AB - Functionalized oligosaccharides are useful intermediates to prepare products for biological research or for the development of advanced functional materials. Here, we report the unprecedented use of aniline as an efficient organocatalyst reaction with "clickable" (azide or alkyne) amine for the transimination-mediated reductive amination of a chitooligosaccharide. Moreover, we demonstrate that alkyne-bearing aniline constitutes an excellent tool for the easy derivatization of chitosan oligosaccharides. Evidence for such improvement has been illustrated by the straightforward design of a FRET substrate to probe chitinase activity and of amphiphilic polycaprolactone-grafted-chitosan. This efficient methodology paves the way to the preparation of novel chitosan oligosaccharide-based advanced materials. PMID- 23458449 TI - A prospective, randomized trial of complete avoidance of steroids in liver transplantation with follow-up of over 7 years. AB - OBJECTIVES: Steroids are a mainstay of treatment in orthotopic liver transplantation (OLT) and are associated with significant morbidity. This trial was conducted to assess the efficacy of steroids avoidance. METHODS: Patients undergoing OLT between June 2002 and April 2005 were entered into a prospective, randomized trial of complete steroids avoidance and followed until November 2011. Recipients received either standard therapy (n = 50) or complete steroids avoidance (n = 50). Analyses were performed on an intention-to-treat basis. The mean follow-up of all recipients was 2095 +/- 117 days. Sixteen (32%) recipients randomized to the steroids avoidance group ultimately received steroids for clinical indications. RESULTS: Incidences of diabetes and hypertension prior to or after OLT were similar in both groups, as was the incidence of rejection. Patient and graft survival rates at 1, 3 and 5 years were lower in the steroids avoidance group than in the standard therapy group (patient survival: 1-year, 80% versus 86%; 3-year, 68% versus 76%; 5-year, 60% versus 72%; graft survival: 1 year, 76% versus 76%; 3-year, 64% versus 74%; 5-year, 56% versus 72%), but the differences were not statistically different. CONCLUSIONS: Complete steroids avoidance provides liver transplant recipients with minimal benefit and appears to result in a concerning trend towards decreased graft and recipient survival. The present data support the use of at least a short course of steroids after liver transplantation. PMID- 23458451 TI - Post-concussion symptom reporting after multiple mild traumatic brain injuries. AB - The relationship between previous mild traumatic brain injury/injuries (MTBI) and recovery from a subsequent MTBI may be complex. The present study investigated three factors hypothesized to influence this relation: (1) the number of prior MTBIs, (2) the interval between MTBIs, and (3) the certainty level of previous MTBIs. The study design was retrospective cross-sectional. Participants (N=105) were evaluated at a concussion clinic on average 1 month after sustaining an MTBI, defined by World Health Organization diagnostic criteria. Approximately half the sample had at least one previous MTBI. Subgroups with 0, 1, or 2+ previous MTBIs did not differ in levels of current post-concussion symptom reporting on the British Columbia Post-Concussion Symptom Inventory. Time since the most recent previous MTBI was significantly associated with current post concussion symptom reporting. This relation was best characterized as logarithmic; i.e., the impact of previous MTBI(s) lessens exponentially as time elapses to a subsequent MTBI. Defining previous MTBIs with a higher certainty level (i.e., probable versus possible) was not consistently associated with greater post-concussion symptom reporting. In conclusion, participants with multiple MTBIs did not report more post-concussion symptoms than those with no history of MTBI. Previous MTBI(s), however, were associated with increased symptom reporting from a subsequent MTBI to the extent they occurred closer in time. Having one or two previous remote MTBIs was not associated with worse outcome from subsequent MTBI in this sample. PMID- 23458452 TI - Where do golf driver swings go wrong? Factors influencing driver swing consistency. AB - One of the challenging skills in golfing is the driver swing. There have been a large number of studies characterizing golf swings, yielding insightful instructions on how to swing well. As a result, achieving a sub-18 handicap is no longer the top problem for golfers. Instead, players are now most troubled by a lack of consistency during swing execution. The goal of this study was to determine how to consistently execute good golf swings. Using 3D motion capture and full-body biomechanical modeling, 22 experienced golfers were analysed. For characterizing both successful and failed swings, 19 selected parameters (13 angles, 4 time parameters, and 2 distances) were used. The results showed that 14 parameters are highly sensitive and/or prone to motor control variations. These parameters sensitized five distinct areas of swing to variation: (a) ball positioning, (b) transverse club angle, (c) transition, (d) wrist control, and (e) posture migration between takeaway and impact. Suggestions were provided for how to address these five distinct problem areas. We hope our findings on how to achieve consistency in golf swings will benefit all levels of golf pedagogy and help maintain/develop interests to involve more golf/physical activity for a healthy lifestyle. PMID- 23458453 TI - [Co(bpy)3](3+/2+) and [Co(phen)3](3+/2+) electron mediators for overall water splitting under sunlight irradiation using Z-scheme photocatalyst system. AB - [Co(bpy)3](3+/2+) and [Co(phen)3](3+/2+) redox couples were revealed to play as electron mediators for Z-scheme photocatalyst systems composed of Ru/SrTiO3:Rh and BiVO4 powders for overall water splitting under visible light irradiation. These electron mediators were effective for only the combination of SrTiO3:Rh with BiVO4. They did not work when nondoped SrTiO3 and TiO2 of H2-evolving photocatalysts and WO3 of O2-evolving photocatalysts were employed. These results indicated that the affinity between photocatalysts and the Co-complex electron mediators was important. The photocatalytic activity depended on pH. Neutral pH conditions gave the highest activity for overall water splitting. Overall water splitting by the present system steadily proceeded for a long time. The Z-scheme photocatalyst system was also confirmed to split water under sunlight irradiation at the rates depending on weather. Moreover, overall water splitting by the Z scheme photocatalyst system with the Co-complex electron mediator using a reaction cell in which the Ru/SrTiO3:Rh suspension was divided from BiVO4 suspension by a membrane filter resulted in H2 evolution separated from that of O2. PMID- 23458454 TI - Quaternary arsenides AM(1.5)Tt(0.5)As2 (A = Na, K, Rb; M = Zn, Cd; Tt = Si, Ge, Sn): size effects in CaAl2Si2- and ThCr2Si2-type structures. AB - Ten quaternary arsenides AM(1.5)Tt(0.5)As2 (A = Na, K, Rb; M = Zn, Cd; Tt = Si, Ge, Sn) have been prepared by stoichiometric reactions of the elements at 600-650 degrees C. Seven of them (NaZn(1.5)Si(0.5)As2, NaZn(1.5)Ge(0.5)As2, NaZn(1.5)Sn(0.5)As2, NaCd(1.5)Sn(0.5)As2, KZn(1.5)Sn(0.5)As2, KCd(1.5)Sn(0.5)As2, RbCd(1.5)Sn(0.5)As2) adopt the trigonal CaAl2Si2-type structure (Pearson symbol hP5, space group P3m1, Z = 1, a = 4.0662(3)-4.4263(7) A, c = 7.4120(5)-8.4586(14) A), whereas the remaining three (KZn(1.5)Si(0.5)As2, KZn(1.5)Ge(0.5)As2, RbZn(1.5)Ge(0.5)As2) adopt the tetragonal ThCr2Si2-type structure (Pearson symbol tI10, space group I4/mmm, Z = 2, a = 4.0613(10)-4.1157(5) A, c = 14.258(3) 14.662(2) A). Both structure types contain anionic [M(1.5)Tt(0.5)As2] slabs that are built from edge-sharing tetrahedra and that stack alternately with nets of A cations. A structure map delineates the formation of these structure types for AM(1.5)Tt(0.5)As2 as a function of simple radius ratios. Although these arsenides have charge-balanced formulations, band structure calculations on NaZn(1.5)Tt(0.5)As2 (Tt = Si, Ge, Sn) indicate that semimetallic behavior is predicted as a result of overlap of the valence and conduction bands. PMID- 23458455 TI - High quality CdHgTe nanocrystals with strong near-infrared emission: relationship between composition and cytotoxic effects. AB - High quality CdHgTe quasi core/shell nanocrystals (NCs) were prepared via the one step method. The relationship between the composition, structure, and property was systematically investigated by the combination of X-ray photoelectron spectroscopy (XPS), inductively coupled plasma atomic emission (ICP), and the photoluminescence (PL) measurements. The quantum yield (QY) was ~50% when the feed ratio of Cd(2+) to Hg(2+) was equal to 1. The PL property was further polished, and the QY was improved to ~80% through the variance of the prepared conditions such as the ratio of ligand to metal ion and HTe(-) to metal ion, pH value, and temperature. In addition, the cytotoxic effects of CdHgTe NCs were systematically studied. The results showed that, for Cd0.21Hg0.79Te NCs, its quasi core/shell structure was very stable and little cadmium ions were released. As a result, such NCs showed little cytotoxicity and would find applications in tissue imaging or detection. PMID- 23458456 TI - Touch DNA collection versus firearm fingerprinting: comparing evidence production and identification outcomes. AB - A project by a metropolitan police agency in 2008-2009 had police use touch DNA kits to collect cell samples from seized firearms. To assess outcomes, results of touch DNA swabbing of firearms were compared to fingerprinting firearm evidence. The rationale was that fingerprinting, as the older technology, was the baseline against which to compare touch DNA. But little is known about ways to measure touch DNA productivity compared to fingerprinting. To examine differences between the two requires comparable measurements. Two measures were used: quantity of probative or investigative evidence produced and identification outcomes. When applied to firearms seized within an Indianapolis, IN police district, touch DNA produced a larger volume of evidence than fingerprinting, but identification outcomes for the two methods were equal. Because touch DNA was deployed by police patrol officers, there are implications for firearm forensics and the choice of forensic approaches used by police. PMID- 23458457 TI - Optogenetic manipulation of neural activity in C. elegans: from synapse to circuits and behaviour. AB - The emerging field of optogenetics allows for optical activation or inhibition of excitable cells. In 2005, optogenetic proteins were expressed in the nematode Caenorhabditis elegans for the first time. Since then, C. elegans has served as a powerful platform upon which to conduct optogenetic investigations of synaptic function, circuit dynamics and the neuronal basis of behaviour. The C. elegans nervous system, consisting of 302 neurons, whose connectivity and morphology has been mapped completely, drives a rich repertoire of behaviours that are quantifiable by video microscopy. This model organism's compact nervous system, quantifiable behaviour, genetic tractability and optical accessibility make it especially amenable to optogenetic interrogation. Channelrhodopsin-2 (ChR2), halorhodopsin (NpHR/Halo) and other common optogenetic proteins have all been expressed in C. elegans. Moreover, recent advances leveraging molecular genetics and patterned light illumination have now made it possible to target photoactivation and inhibition to single cells and to do so in worms as they behave freely. Here, we describe techniques and methods for optogenetic manipulation in C. elegans. We review recent work using optogenetics and C. elegans for neuroscience investigations at the level of synapses, circuits and behaviour. PMID- 23458458 TI - Enhancing the mechanical properties of engineered tissue through matrix remodeling via the signaling phospholipid lysophosphatidic acid. AB - Knee meniscus fibrocartilage is frequently injured, resulting in approximately 1 million procedures annually in the US and Europe. Its near-avascularity contributes heavily to its inability to heal, and places it as a prime candidate for replacement through regenerative medicine. Here, we describe a novel approach to increase extracellular matrix organization, rather than content, in order to augment the mechanical properties of engineered tissue. To synthesize fibrocartilage, we employ a self-assembling process, which is free of exogenous scaffolds and relies on cell-to-cell interactions to form all-biologic constructs. When treated with the signaling phospholipid lysophosphatidic acid (LPA), tissue constructs displayed increased tensile properties and collagen organization, while total collagen content remained unchanged. LPA-treated constructs exhibited greater DNA content, indicative that the molecule exerted a signaling effect. Furthermore, LPA-treated cells displayed significant cytoskeletal reorganization. We conclude that LPA induced cytoskeletal reorganization and cell-matrix traction, which resulted in matrix reorganization and increased tensile properties. This study emphasizes the potential of non traditional stimuli, such as signaling phospholipids, for use in tissue development studies. The extension of these results to other collagen-rich tissues represents a promising avenue for future exploration. PMID- 23458459 TI - Kruppel-like factor 12 negatively regulates human endometrial stromal cell decidualization. AB - Members of the KLFs family of transcription factors play roles in maternal endometrium development during embryo implantation. However, the specific role of KLF12 in endometrium development has not yet been described. In this study, we showed that KLF12 expression in human endometrial stromal cells (HESCs) was significantly decreased after decidualization stimulated by 8-Br-cAMP and medroxyprogesterone acetate (MPA). The adenovirus-mediated overexpression of KLF12 in HESCs significantly repressed the expression and secretion of decidualization biomarker genes and their products decidual prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP-1) induced by 8-Br-cAMP and MPA. Moreover, CHIP and luciferase reporter assays demonstrated that KLF12 bound to a CAGTGGG element within the decidual prolactin promoter and decreased decidual PRL promoter (dPRL/-2000Luc) activation in a sequence-specific manner. Taken together, these findings suggest KLF12 is a negative regulator of human endometrial stromal cell decidualization. PMID- 23458460 TI - Introduction--Treatment of psychiatric disorders in adults with epilepsy: what every epileptologist should know. PMID- 23458461 TI - The treatment of depressive disorders in epilepsy: what all neurologists should know. AB - One of every three patients with epilepsy (PWE) will experience a depressive disorder in the course of their life, often associated with anxiety symptoms or a full blown anxiety disorder. Clearly, the high prevalence of these psychiatric comorbidities calls for their early identification and management. This article provides practical strategies in the management of depressive episodes in PWE. Contrary to long-held beliefs, the use of antidepressant drugs are safe in PWE when used at therapeutic doses. Antidepressant drugs of the selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) families are the first line of therapy in depressive disorders, and failure to achieve complete symptom remission after a trial of an SSRI or SNRI at optimal doses should be followed by a second trial with a drug from the other antidepressant family. In developing countries, antidepressant drugs of these two antidepressant families are not always available, and tricyclic antidepressants (TCAs) are the drugs of choice. Although there are no differences in efficacy among the three families of antidepressants, TCAs have a lower tolerability and higher toxicity, with greater mortality risk associated with cardiotoxic effects in overdoses. Cognitive behavior therapy is another treatment modality that has been shown to be effective in the treatment of depressive disorders in patients with and without epilepsy. Its use should be considered together with pharmacotherapy or by itself. PMID- 23458462 TI - Treatment of anxiety disorders in epilepsy: an evidence-based approach. AB - During recent years growing attention has been paid to psychiatric comorbidities in epilepsy. However, anxiety disorders still remain underrecognized and undertreated. This is largely related to the lack of specific screening instruments and the frequent co-occurrence with mood disorders. Data on treatment are insufficient and clinical practice still relies heavily on individual experience. In this article we review evidence-based treatment strategies for primary major anxiety disorders and adapt them to the specific needs of patients with epilepsy. In panic disorder, a combined approach, namely serotonin-reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) is always indicated during the acute phase. Long-term maintenance treatment may include combined therapy or CBT alone depending on individual cases. For generalized anxiety disorders pregabalin has to be considered first choice for short-term and long term treatment. In social anxiety disorder and posttraumatic stress disorder SSRIs, in particular sertraline and paroxetine, can be safely used. Obsessive compulsive disorder represents a serious condition that needs to be approached in a psychiatric setting. CBT should be considered as the first choice in patients with epilepsy. If drug treatment is needed, epileptologists have to be aware that high-dose antidepressants are appropriate and that SSRIs, in particular sertraline, should be considered first choice. In these patients, careful clinical monitoring is indicated, in selected cases, for potential seizure precipitation and side effects due to pharmacodynamics interactions. PMID- 23458463 TI - Basic treatment principles for psychotic disorders in patients with epilepsy. AB - In patients with epilepsy, coexisting psychoses, either interictal (IIP) or postictal (PIP), are associated with serious disturbance in psychosocial function and well-being, and often require the care of a specialist. Unfortunately, evidence-based treatment systems for psychosis in patients with epilepsy have not yet been established. This article aims to propose concise and practical treatment procedures for IIP and PIP based on currently available data and international consensus statements, and primarily targeting nonpsychiatrist epileptologists who are often the first to be involved in the management of these complex patients. Accurate and early diagnosis of IIP and PIP and their staging in terms of acuity and severity form the essential first step in management. It is important to suspect the presence of psychosis whenever patients manifest unusual behavior. Knowledge of psychopathology and both individual and epilepsy related vulnerabilities relevant to IIP and PIP facilitate early diagnosis. Treatment for IIP involves (1) obtaining consent to psychiatric treatment from the patient, whenever possible, (2) optimization of antiepileptic drugs, and (3) initiation of antipsychotic pharmacotherapy in line with symptom severity and severity of behavioral and functional disturbance. Basic psychosocial interventions will help reinforce adherence to treatment and should be made available. Due consideration must be given to patients' ability to provide informed consent to treatment in the short term, with the issue being revisited regularly over time. Given the often prolonged and recurrent nature of IIP, treatment frequently needs to be long-term. Treatment of PIP consists of two aspects, that is, acute protective measures and preventive procedures in repetitive episodes. Protective measures prioritize the management of risk in the early stages, and may involve sedation with or without the use of antipsychotic drugs, and the judicious application of local mental health legislation if appropriate. As for preventative procedures, optimizing seizure control by adjusting antiepileptic drugs or by surgical treatment is necessary. PMID- 23458464 TI - Treatment of behavioral problems in intellectually disabled adult patients with epilepsy. AB - Behavioral disorders are common in people with epilepsy and intellectual disability. Although in some genetic disorders behavioral problems are part of the established phenotype, they may also be a manifestation of underlying physical or mental illness, or may be unrecognized seizure activity. In light of this, assessment of behavioral disorders should take into account person factors such as the physical health and mental state of the person and environmental factors such as the quality of their interactions with carers and their living conditions. Video-electroencephalography ( EEG) is recommended where possible. We review potential pharmacologic and behavioral management strategies for behavioral disorders in people with intellectual disability. PMID- 23458465 TI - Treatment issues for personality disorders in epilepsy. AB - This article supports a view that certain personality disturbances in epilepsy should be viewed as associated with the cerebral abnormalities that also lead to seizures. Herein I discuss two main variants: that related to temporal lobe epilepsy and that associated with juvenile myoclonic epilepsy. In view of its controversial nature, I also comment on the link between aggression and epilepsy. Recommendations for treatment include psychological and social therapies with further advice about the use of antiepileptic drugs (AEDs) and psychotropic medications in these conditions. PMID- 23458466 TI - Treatment of postsurgical psychiatric complications. AB - We describe the physical, psychological, and social complications and adaptation demands after epilepsy surgery and the risks of the development of psychiatric disorders when adequate stress processing fails. Practical strategies that can be followed in the prevention and treatment of postsurgical psychiatric complications are reviewed. The postoperative period is divided in three phases: (1) the early postoperative phase of stress processing until discharge from hospital; (2) the coping phase during the first months after discharge; and (3) the reorientation phase. The early postoperative course is often dominated by physical problems that hamper success in convalescence. They may initiate early psychiatric disturbances especially in patients with preoperative psychiatric comorbidity. The second phase after discharge from hospital is the typical time in which various psychiatric disorders may develop (either de novo or exacerbations of known disorders). At this time it is mandatory to keep in contact with patients, to start psychiatric treatments if necessary, and to assess for suicidal risk. The course of the third phase of reorientation depends on seizure outcome and on psychiatric state. Seizure-free persons without psychiatric comorbidities start to forget their epilepsy; those with less successful outcome conditions may need further support, especially for vocational integration. Epilepsy surgery brings about an overall strong improvement of psychiatric morbidity and quality of patients' life. Nevertheless, the first postoperative year is a fragile period that includes multiple physical, psychological, and social adaptation tasks. Patients with a history of psychiatric disorders are at a special risk of failing to cope with those health related demands, but also for nonpsychiatric patients the months after epilepsy surgery are often stressful and exhausting. Professional help must be available during the postoperative coping time. PMID- 23458467 TI - Management of psychogenic nonepileptic seizures. AB - The International League Against Epilepsy (ILAE) Neuropsychobiology Commission gave the charge to provide practical guidance for health professionals for the pharmacologic and nonpharmacologic treatment of patients with psychogenic nonepileptic seizures (PNES). Using a consensus review of the literature, an international group of clinician-researchers in epilepsy, neurology, neuropsychology, and neuropsychiatry evaluated key management approaches for PNES. These included the following: presentation of the diagnosis, early phase treatment, psychological and pharmacologic interventions, and maintenance management. The aim of this report is to provide greater clarity about the range and current evidence base for treatment for patients with PNES, with the intention of improving the care of patients with PNES and patients who develop PNES as a comorbidity of epilepsy. PMID- 23458469 TI - Facility implementation and comparative performance evaluation of probe-corrected TEM/STEM with Schottky and cold field emission illumination. AB - We report the installation and performance evaluation of a probe aberration corrected high-resolution JEOL JEM-ARM200F transmission electron microscope (TEM). We provide details on construction of the room that enables us to obtain scanning transmission electron microscope (STEM) data without any evident distortions/noise from the external environment. The microscope routinely delivers expected performance. We show that the highest STEM spatial resolution and energy resolution achieved with this microscope are 0.078 nm and 0.34 eV, respectively. We report a direct comparative evaluation of the performance of this microscope with a Schottky thermal field-emission gun versus a cold field emission gun. Cold field-emission illumination improves spatial resolution of the high current probe for analytical spectroscopy, the TEM information limit, and the electron energy resolution compared to the Schottky thermal field-emission source. PMID- 23458468 TI - Multicentre results of stereotactic body radiotherapy for secondary liver tumours. AB - BACKGROUND: Surgical resection is the standard treatment for liver metastases, although for the majority of patients this is not possible. Stereotactic body radiotherapy (SBRT) is an alternative local-regional therapy. The purpose of this study was to evaluate the results of SBRT for secondary liver tumours from a combined multicentre database. METHODS: Variables from patients treated with SBRT from four Academic Medical Centres were entered into a common database. Local tumour control and 1-year survival rates were calculated. RESULTS: In total, 153 patients (91 women) 59 +/- 8.4 years old with 363 metastatic liver lesions were treated with SBRT. The underlying primary tumour arose from gastrointestinal (GI), retroperitoneal and from extra-abdominal primaries in 56%, 8% and 36% of patients, respectively. Metastases, with a gross tumour volume (GTV) of 138.5 +/- 126.8 cm(3) , were treated with a total radiation dose of 37.5 +/- 8.2 Gy in 5 +/ 3 fractions. The 1-year overall survival was 51% with an overall local control rate of 62% at a mean follow-up of 25.2 +/- 5.9 months. A complete tumour response was observed in 32% of patients. Grade 3-5 adverse events were noted in 3% of patients. CONCLUSION: Secondary liver tumours treated with SBRT had a high rate of local control with a low incidence of adverse events. PMID- 23458470 TI - Phenolic acid intake, delivered via moderate champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation. AB - AIMS: While much data exist for the effects of flavonoid-rich foods on spatial memory in rodents, there are no such data for foods/beverages predominantly containing hydroxycinnamates and phenolic acids. To address this, we investigated the effects of moderate Champagne wine intake, which is rich in these components, on spatial memory and related mechanisms relative to the alcohol- and energy matched controls. RESULTS: In contrast to the isocaloric and alcohol-matched controls, supplementation with Champagne wine (1.78 ml/kg BW, alcohol 12.5% vol.) for 6 weeks led to an improvement in spatial working memory in aged rodents. Targeted protein arrays indicated that these behavioral effects were paralleled by the differential expression of a number of hippocampal and cortical proteins (relative to the isocaloric control group), including those involved in signal transduction, neuroplasticity, apoptosis, and cell cycle regulation. Western immunoblotting confirmed the differential modulation of brain-derived neurotrophic factor, cAMP response-element-binding protein (CREB), p38, dystrophin, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, mammalian target of rapamycin (mTOR), and Bcl-xL in response to Champagne supplementation compared to the control drink, and the modulation of mTOR, Bcl-xL, and CREB in response to alcohol supplementation. INNOVATION: Our data suggest that smaller phenolics such as gallic acid, protocatechuic acid, tyrosol, caftaric acid, and caffeic acid, in addition to flavonoids, are capable of exerting improvements in spatial memory via the modulation in hippocampal signaling and protein expression. CONCLUSION: Changes in spatial working memory induced by the Champagne supplementation are linked to the effects of absorbed phenolics on cytoskeletal proteins, neurotrophin expression, and the effects of alcohol on the regulation of apoptotic events in the hippocampus and cortex. PMID- 23458471 TI - Selective beta3-adrenoceptor agonists for the treatment of overactive bladder. AB - PURPOSE: The bladder effects of isoprenaline, and selective beta1 and beta2 adrenoceptor agonists reported in early studies suggest that bladder beta adrenoceptors are atypical. Since there is a lack of alternatives to antimuscarinics in the treatment of overactive bladder symptoms, there has been an intensive search for new drug targets. Discovery of the beta3-adrenoceptor with high expression in the bladder suggested that this receptor, which mediates detrusor relaxation, could be a target for overactive bladder symptoms. MATERIALS AND METHODS: An overview of the published literature on beta-adrenoceptor and the bladder was performed using MEDLINE. The United States Food and Drug Administration website, clinicaltrials.gov and controlled-trials.com online trial registries were searched for English language articles containing the terms beta3 adrenoceptors and beta3-adrenoceptor agonists. In addition, abstracts from recent international scientific meetings were searched for randomized, controlled trials of beta3-adrenoceptor agonists. RESULTS: Stimulation of beta3-adrenoceptors relaxes detrusor smooth muscle, decreases afferent signaling from the bladder, improves bladder compliance upon filling and increases bladder capacity. Randomized, controlled trials show that the selective beta3-adrenoceptor agonist mirabegron, for which most information is available and which is approved in Japan, the United States and Europe, decreases the number of micturitions and incontinence episodes in a 24-hour period compared with placebo. The most common adverse effects recorded are dry mouth (placebo level) and gastrointestinal disturbances, rated as mild to moderate. Small increases in mean heart rate (1 beat per minute) and blood pressure (1 mm Hg) were noted in patients with overactive bladder. CONCLUSIONS: Available information suggests that beta3 adrenoceptor agonists may be a promising alternative to antimuscarinics in the treatment of overactive bladder. However, further clinical experience outside clinical trials and information on long-term use in terms of efficacy, safety and tolerability are warranted to optimally characterize the position of beta3 adrenoceptor agonists in the treatment algorithm for overactive bladder. PMID- 23458473 TI - Isolation of thermally stable cellulose nanocrystals by phosphoric acid hydrolysis. AB - On account of their intriguing mechanical properties, low cost, and renewable nature, high-aspect-ratio cellulose nanocrystals (CNCs) are an attractive component for many nanomaterials. Due to hydrogen bonding between their surface hydroxyl groups, unmodified CNCs (H-CNCs) aggregate easily and are often difficult to disperse. It is shown here that on account of ionic repulsion between charged surface groups, slightly phosphorylated CNCs (P-CNCs, average dimensions 31 +/- 14 * 316 +/- 127 nm, surface charge density = 10.8 +/- 2.7 mmol/kg cellulose), prepared by controlled hydrolysis of cotton with phosphoric acid, are readily dispersible and form stable dispersions in polar solvents such as water, dimethyl sulfoxide, and dimethylformamide. Thermogravimetric analyses reveal that these P-CNCs exhibit a much higher thermal stability than partially sulfated CNCs (S-CNCs), which are frequently employed, but suffer from limited thermal stability. Nanocomposites of an ethylene oxide-epichlorohydrin copolymer and H-CNCs, S-CNCs, and P-CNCs were prepared, and their mechanical properties were studied by dynamic mechanical thermal analysis. The results show that P-CNCs offer a reinforcing capability that is comparable to that of H-CNCs or S-CNCs. PMID- 23458472 TI - Deviation of tracheal pressure from airway opening pressure during high-frequency oscillatory ventilation in a porcine lung model. AB - Oxygenation during high-frequency oscillatory ventilation is secured by a high level of mean airway pressure. Our objective was to identify a pressure difference between the airway opening of the respiratory circuit and the trachea during application of different oscillatory frequencies. Six female Pietrain pigs (57.1 +/- 3.6 kg) were first ventilated in a conventional mechanical ventilation mode. Subsequently, the animals were switched to high-frequency oscillatory ventilation by setting mean airway opening pressure 5 cmH(2)O above the one measured during controlled mechanical ventilation. Measurements at the airway opening and at tracheal levels were performed in healthy lungs and after induction of acute lung injury by surfactant depletion. During high-frequency oscillatory ventilation, the airway opening pressure was set at a constant level. The pressure amplitude was fixed at 90 cmH(2)O. Starting from an oscillatory frequency of 3 Hz, the frequency was increased in steps of 3 Hz to 15 Hz and then decreased accordingly. At each frequency, measurements were performed in the trachea through a side-lumen of the endotracheal tube and the airway opening pressure was recorded. The pressure difference was calculated. At every oscillatory frequency, a pressure loss towards the trachea could be shown. This pressure difference increased with higher oscillatory frequencies (3 Hz 2.2 +/- 2.1 cmH(2)O vs. 15 Hz 7.5 +/- 1.8 cmH(2)O). The results for healthy and injured lungs were similar. Tracheal pressures decreased with higher oscillatory frequencies. This may lead to pulmonary derecruitment. This has to be taken into consideration when increasing oscillatory frequencies and differentiated pressure settings are mandatory. PMID- 23458474 TI - Evaluation of the humoral immune response and cross reactivity against Mycobacterium tuberculosis of mice immunized with liposomes containing glycolipids of Mycobacterium smegmatis. AB - Mycobacterium smegmatis (Ms) is a nonpathogenic mycobacteria of rapid growth, which shares many characteristics with Mycobacterium tuberculosis (MTB), the major causative agent of tuberculosis. MTB has several cell wall glycolipids in common with Ms, which play an important role in the pathogenesis of tuberculosis and the induction of a protective immune response against MTB infection in some animal models. In this study, the humoral immune response and cross reactivity against MTB, of liposomes containing a mixture of cell wall glycolipids of Ms and commercial lipids was evaluated, in order to study its possible use as a component of a vaccine candidate against tuberculosis. Liposomes containing total lipids extracted from Ms, distearoyl phosphatidyl choline and cholesterol were prepared by the dehydration-rehydration technique. Balb/c mice were immunized with the liposomes obtained and the antibody response and cross reactivity against MTB were tested by ELISA. Total lipids extract from Ms showed the presence of several polar glycolipids in common with MTB, such as phosphatidylinositol mannosides. Liposomes that contained glycolipids of Ms were capable of inducing a specific IgG antibody response that allowed the recognition of surface antigens of MTB. The results of this study demonstrated the presence of immunogenic glycolipids in Ms, which could be included to enhance the protective effects of subunit vaccine formulations against tuberculosis. PMID- 23458475 TI - Real-ear output measures of ear level fluency devices. AB - OBJECTIVE: The purpose of this study was to measure real-ear aided and saturated responses of SpeechEasyTM devices and compare responses while devices delivered altered auditory feedback (AAF) and non-altered feedback (NAF). DESIGN: A repeated measures quasi-experimental design was employed. STUDY SAMPLE: Ten people fitted with completely-in-the-canal or open fit behind-the-ear devices participated. Probe microphone measures were obtained with speech, and 17 chirp stimuli presented at 75 dB and 85 dB SPL, respectively. Measurements were compared with devices delivering AAF (i.e. delayed and frequency shifted) versus NAF. RESULTS: Maximum outputs were approximately 100-105 dB SPL in the 2000-4000 Hz range. Statistically significant differences in device SPL output as a function of device setting (AAF vs. NAF) were found for seven chirp stimuli (p <.05) when levels were sampled at points that were not temporally aligned with the output chirps but not for speech stimulus (p = .17). Device output varied across individuals and with open fit devices dominated by ear canal resonance effects. CONCLUSIONS: Real-ear aided responses were equivalent with speech input when devices delivered AAF and NAF. Real-ear saturated responses were not, however, comparable between AAF and NAF settings and may be underestimated if AAF delay is not accounted for. PMID- 23458476 TI - Accuracy of short-term demographic data in projecting long-term fate of populations. AB - Short-term surveys are useful in conservation of species if they can be used to reliably predict the long-term fate of populations. However, statistical evaluations of reliability are rare. We studied how well short-term demographic data (1999-2002) of tartar catchfly (Silene tatarica), a perennial riparian plant, projected the fate and growth of 23 populations of this species up to the year 2010. Surveyed populations occurred along a river with natural flood dynamics and along a regulated river. Riparian plant populations are affected by flooding, which maintains unvegetated shores, while forest succession proceeds in areas with little flooding. Flooding is less severe along the regulated river, and vegetation overgrowth reduces abundance of tartar catchfly on unvegetated shores. We built matrix models to calculate population growth rates and estimated times to population extinction in natural and in regulated rivers, 13 and 10 populations, respectively. Models predicted population survival well (model predictions matched observed survival in 91% of populations) and accurately predicted abundance increases and decreases in 65% of populations. The observed and projected population growth rates differed significantly in all but 3 populations. In most cases, the model overestimated population growth. Model predictions did not improve when data from more years were used (1999-2006). In the regulated river, the poorest model predictions occurred in areas where cover of other plant species changed the fastest. Although vegetation cover increased in most populations, it decreased in 4 populations along the natural river. Our results highlight the need to combine disturbance and succession dynamics in demographic models and the importance of habitat management for species survival along regulated rivers. PMID- 23458478 TI - Is there health out there in the afrosphere? An analysis of health-related content posted by black bloggers. AB - We explored the extent to which Blacks use online blogs to communicate health information. We content analyzed blogs' main pages for: health-related text, badges, subject lists, and tag clouds. Half of the blogs possessed one of the aforementioned items referencing or depicting health. Violence/crime and health/healthcare were referenced most frequently. We also analyzed health related posts by coding for presumed posting purpose. We found that bloggers most often posted health content in order to share information; very few promoted healthier behavior. We assert that blogs have the potential to be an important health communication tool for reaching Black Americans. PMID- 23458477 TI - Redefining the R1 resection for pancreatic ductal adenocarcinoma: tumour lymph nodal burden and lymph node ratio are the only prognostic factors associated with survival. AB - INTRODUCTION: The presence of positive nodal disease (LND) and the number of lymph nodes involved (LNB) are known to be significant prognostic markers for resected adenocarcinoma of the pancreas. In addition, the ratio of the number of involved nodes to the number of nodes resected known as the lymph node ratio (LNR) is emerging as an important prognostic marker. The role of the resection margin (RM) as presently defined (R1 <= 1 mm) is unclear as results differ based on the dataset. The aim of this study was to assess the impact of nodal disease and a redefined RM on outcome. MATERIAL AND METHODS: Retrospective analysis of pancreatic head resections for adenocarcinomas from 2003-2009. The RM was re analysed based on tumour clearance and categorized into: histopathological evidence of a tumour; <= 0.5 mm, <= 1 mm, <= 1.5 mm, or <= 2.0 mm of the actual surgical resection margin. The impact of histopathological variables on cancer specific survival (CSS) and disease-free survival (DFS) was analysed. RESULTS: LND, LNB and LNR were independent prognostic markers for CSS (P = 0.048, 0.003, 0.016) but, did not influence DFS. A LNR < 0.143 was associated with a higher CSS [38.16 +/- 4.69 versus 20.59 +/- 2.20 months, P = 0.0042, hazard ratio (HR) 3.74 (95% confidence interval (CI) 1.52-9.23)]. An R1 RM was not associated with CSS or DFS on multivariate analysis, irrespective of the distance. LNB and LNR maintained independent significance irrespective of the size of the RM. CONCLUSION: LNB and LNR are the only prognostic factors for CSS in patients with pancreatic head adenocarcinoma, but do not predict recurrence. Microscopic RMs does not seem to influence the outcome even when redefined. Further prospective studies are indicated to substantiate these findings. PMID- 23458479 TI - Hospital publications: is this my link to a healthier life? AB - Hospitals use newsletters to reach their patient base. Within these newsletters, health narratives are communicated to inspire community members to choose that hospital for their health needs. Because health narratives inform our understanding of health care delivery, I employ Bakhtin's (1984) ideas on monologic and dialogic discourse to analyze newsletters published by a major hospital network. Results indicate a monologic rather than dialogic discourse, which excludes patient's unique experiences, advances normalization of medicine, and perpetuates hierarchical power dynamics. In summary, this study suggests practical implications for practitioners producing health knowledge for consumers of health information. PMID- 23458480 TI - Comparing effects of "my anti-drug" and "above the influence" on campaign evaluations and marijuana-related perceptions. AB - Two national campaigns--My Anti-Drug and Above the Influence--have been implemented to prevent youth substance use. Although Above the Influence was conceptualized as a major shift in messaging from My Anti-Drug, no studies have reported head-to-head tests of message effects on behavior-relevant outcomes. An experiment was conducted in which participants viewed ads from one of the campaigns and answered questions about ad appeal and emotional tone; campaign appeal; and marijuana-related beliefs. Compared to My Anti-Drug ads, Above the Influence ads were associated with more positive emotional tone and with lower perceptions of marijuana risk. Implications for message design and evaluation are discussed. PMID- 23458481 TI - Consumer acceptance of an SMS-assisted smoking cessation intervention: a multicountry study. AB - This study assesses smokers' perceptions, motivations, and intentions towards using an SMS-assisted smoking cessation intervention in Australia, France, and Mexico through an extended technology acceptance model with mediating variables. Data was collected through online surveys. Results show that perceived usefulness and vicarious innovativeness predict use intentions for all three countries. Perceived ease of use is significant only for Mexico. Subjective norms are significant only for Mexico and Australia. Perceived monetary value and perceived annoyance are significant mediating variables for all three countries, whereas perceived enjoyment is significant only for Mexico and Australia. These results contribute to theory and practice. PMID- 23458482 TI - But it's doctor recommended and I read the fine print: antecedents to drug companies' perceived credibility. AB - Using 2009 National Consumer Survey data from Experian Simmons, the authors found that dependence on doctor recommendations to assess the integrity of advertised drugs and the extent of reading small print in direct-to-consumer prescription drug advertising positively related to consumers' perceived credibility of health information from pharmaceutical companies, which in turn positively influenced willingness to ask their doctor for a specific medicine they saw or heard advertised. The potential effect of small print reading on willingness to request prescription was partially mediated by perceived credibility of information from drug companies. The findings are discussed in light of their practical implications. PMID- 23458483 TI - Who is likely to quit nursing jobs? A study in the Turkish Republic of Northern Cyprus. AB - The study reported in this article examines the nature of relationships between organizational and personal resources and nurses' turnover intentions. A sample of 124 nurses in the Turkish Republic of Northern Cyprus serves as the study setting. Results of the study reveal that a form of organizational support (empowerment) and two personal resources (customer orientation, job resourcefulness) are the best predictors of turnover intentions. Implications of these results are discussed and avenues for future research are offered. PMID- 23458484 TI - TGBp3 triggers the unfolded protein response and SKP1-dependent programmed cell death. AB - The Potato virus X (PVX) triple gene block protein 3 (TGBp3), an 8-kDa membrane binding protein, aids virus movement and induces the unfolded protein response (UPR) during PVX infection. TGBp3 was expressed from the Tobacco mosaic virus (TMV) genome (TMV-p3), and we noted the up-regulation of SKP1 and several endoplasmic reticulum (ER)-resident chaperones, including the ER luminal binding protein (BiP), protein disulphide isomerase (PDI), calreticulin (CRT) and calmodulin (CAM). Local lesions were seen on leaves inoculated with TMV-p3, but not TMV or PVX. Such lesions were the result of TGBp3-elicited programmed cell death (PCD), as shown by an increase in reactive oxygen species, DNA fragmentation and induction of SKP1 expression. UPR-related gene expression occurred within 8 h of TMV-p3 inoculation and declined before the onset of PCD. TGBp3-mediated cell death was suppressed in plants that overexpressed BiP, indicating that UPR induction by TGBp3 is a pro-survival mechanism. Anti apoptotic genes Bcl-xl, CED-9 and Op-IAP were expressed in transgenic plants and suppressed N gene-mediated resistance to TMV, but failed to alleviate TGBp3 induced PCD. However, TGBp3-mediated cell death was reduced in SKP1-silenced Nicotiana benthamiana plants. The combined data suggest that TGBp3 triggers the UPR and elicits PCD in plants. PMID- 23458485 TI - Identification of the amino acid residues and domains in the cysteine-rich protein of Chinese wheat mosaic virus that are important for RNA silencing suppression and subcellular localization. AB - Cysteine-rich proteins (CRPs) encoded by some plant viruses in diverse genera function as RNA silencing suppressors. Within the N-terminal portion of CRPs encoded by furoviruses, there are six conserved cysteine residues and a Cys-Gly-X X-His motif (Cys, cysteine; Gly, glycine; His, histidine; X, any amino acid residue) with unknown function. The central domains contain coiled-coil heptad amino acid repeats that usually mediate protein dimerization. Here, we present evidence that the conserved cysteine residues and Cys-Gly-X-X-His motif in the CRP of Chinese wheat mosaic virus (CWMV) are critical for protein stability and silencing suppression activity. Mutation of a leucine residue in the third coiled coil heptad impaired CWMV CRP activity for suppression of local silencing, but not for the promotion of cell-to-cell movement of Potato virus X (PVX). In planta and in vitro analysis of wild-type and mutant proteins indicated that the ability of the CRP to self-interact was correlated with its suppression activity. Deletion of up to 40 amino acids at the C-terminus did not abolish suppression activity, but disrupted the association of CRP with endoplasmic reticulum (ER), and reduced its activity in the enhancement of PVX symptom severity. Interestingly, a short region in the C-terminal domain, predicted to form an amphipathic alpha-helical structure, was responsible for the association of CWMV CRP with ER. Overall, our results demonstrate that the N-terminal and central regions are the functional domains for suppression activity, whereas the C terminal region primarily functions to target CWMV CRP to the ER. PMID- 23458486 TI - Impact of safe community program on motorcyclists' safety with focus on helmet usage in 14 cities of IR Iran. AB - The aim of this study was to evaluate the effectiveness of safe community interventions on motorcyclists' safety. Two cross sectional observations were conducted in 14 cities (five safe community practicing and nine safe community non-practicing cities) independently on 2005 and 2007. Ten percent of registered motorcycles were observed and interviewed (n=1114 in each observation). 87.9% used motorcycle for commercial purposes. All motorcyclists were male and mostly aged 18-29 years old. Death rate significantly rose from 122 to 254 per 100000 motorcyclists in Fars province since the first observation (p < 0.0001). Helmet usage rate was constant (13%). Recorded crashes increased from 16.4% to 23.1% in safe community setting (p < 0.0001). 11% carried more than one pillion. Heat disturbances, embarrassment, hearing blockage, and negligence were the most mentioned excuses for not using helmet. Law enforcement, public education, accessibility to helmets on discount rate, new legislation and, finally, access to new designed helmet were the most suggestions made by motorcyclists to promote helmet usage. No significant effect was noticed between two settings except in injury registration system in safe community. Community involvement in the safety programs could ensure sustainability of initiatives and continuity of interventions in safe communities. PMID- 23458487 TI - Endovascular treatment of acute ischaemic stroke after 6 h of symptom onset: safe but is it efficacious? PMID- 23458488 TI - Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection. AB - OBJECTIVES: Enhanced recovery after surgery (ERAS) protocols are coming to represent the standard of care in many surgical procedures, yet data on their use following hepatic surgery are scarce. The aim of this study was to review outcomes after the introduction of an ERAS programme for patients undergoing open hepatic resection. METHODS: A retrospective review of patients undergoing open hepatic resection from March 2005 to June 2011 was carried out. The primary outcome measure was total hospital length of stay (LoS) (including readmissions). Principles associated with enhanced recovery after surgery were documented and analysed as independent predictors of hospital LoS. RESULTS: A total of 120 patients underwent 128 consecutive hepatic resections, 84 (65.6%) of which were performed in patients with underlying colorectal metastases and 64 (50.0%) of which comprised major hepatic resections. The median hospital LoS was reduced from 6 days to 3 days from the first to the fourth quartiles of the study population (P = 0.021). The proportion of patients suffering complications (26.6%) remained constant across the series. Readmissions increased from the first quartile (none of 32 patients) to the fourth quartile (seven of 32 patients) (P = 0.044). Following multivariate analysis, only the development of a complication (P < 0.001), total postoperative i.v. fluid (P = 0.003) and formation of an anastomosis (P = 0.006) were independent predictors of hospital LoS. CONCLUSIONS: An ERAS programme can be successfully applied to patients undergoing open hepatic resection with a reduction in hospital LoS, but an increase in the rate of readmissions. PMID- 23458489 TI - Influence of conjugation chemistry and B epitope orientation on the immune response of branched peptide antigens. AB - Multimeric presentation, a well-proven way of enhancing peptide immunogenicity, has found substantial application in synthetic vaccine design. We have reported that a combination of four copies of a B-cell epitope with one of a T-cell epitope in a single branched construct results in a peptide vaccine conferring total protection against foot-and-mouth disease virus in swine, a natural host (Cubillos et al. (2008) J. Virol. 82, 7223-7230). More recently, a downsized version of this prototype with only two copies of the B epitope has proven as effective as the tetravalent one in mice. Here we evaluate three approaches to bivalent platforms of this latter type, involving different chemistries for the conjugation of two B epitope peptides to a branching T epitope. Comparison of classical thioether, "reverse" thioether (Monso et al. (2012) Org. Biomol. Chem. 10, 3116-3121) and thiol-ene conjugation chemistries in terms of synthetic efficiency clearly singles out the latter, maleimide-based strategy as most advantageous. We also examine how minor structural differences among the conjugates--including the N- or C-terminal attachment of the B epitope to the branching T epitope--bear on the immunogenicity of these vaccine candidates, with the maleimide-based conjugate again emerging as the most successful. PMID- 23458490 TI - A counting method for density packed cells based on sliding band filter image enhancement. AB - Cell loss and addition is an important biological event in pathology, and it usually provides central information to the changes of biological activity in the histological sections. To develop a reliable and accurate cell counting tools in tissue section, in this paper, we proposed a novel cell nuclei detecting method based on the sliding band filter which is a member of convergence index family. We evaluated the accuracy and performance of our method on density packed retinal outer nuclear layer cell confocal multivariate fluorescence microscopy image datasets. The results show our proposed method exhibited an excellent performance with its accuracy compared with human manual counting. It is worth noting that the proposed cell counting method can clearly benefit for retinal detachment and reattachment visual diagnostics close related to cell loss and addition. PMID- 23458491 TI - Localizing and extracting filament distributions from microscopy images. AB - Detailed quantitative measurements of biological filament networks represent a crucial step in understanding architecture and structure of cells and tissues, which in turn explain important biological events such as wound healing and cancer metastases. Confocal microscope images of biological specimens marked for different structural proteins constitute an important source for observing and measuring meaningful parameters of biological networks. Unfortunately, current efforts at quantitative estimation of architecture and orientation of biological filament networks from microscopy images are predominantly limited to visual estimation and indirect experimental inference. Here we describe a new method for localizing and extracting filament distributions from 2D confocal microscopy images. The method combines a filter-based detection of pixels likely to contain a filament with a constrained reverse diffusion-based approach for localizing the filaments centrelines. We show with qualitative and quantitative experiments, using both simulated and real data, that the new method can provide more accurate centreline estimates of filament in comparison to other approaches currently available. In addition, we show the algorithm is more robust with respect to variations in the initial filter-based filament detection step often used. We demonstrate the application of the method in extracting quantitative parameters from an experiment that seeks to quantify the effects of carbon nanotubes on actin cytoskeleton in live HeLa cells. We show that their presence can disrupt the overall actin cytoskeletal organization in such cells. PMID- 23458492 TI - Effects of the protein environment on the spectral properties of tryptophan radicals in Pseudomonas aeruginosa azurin. AB - Many biological electron-transfer reactions involve short-lived tryptophan radicals as key reactive intermediates. While these species are difficult to investigate, the recent photogeneration of a long-lived neutral tryptophan radical in two Pseudomonas aeruginosa azurin mutants (Az48W and ReAz108W) made it possible to characterize the electronic, vibrational, and magnetic properties of such species and their sensitivity to the molecular environment. Indeed, in Az48W the radical is embedded in the hydrophobic core while, in ReAz108W it is solvent exposed. Here we use density functional theory and multiconfigurational perturbation theory to construct quantum-mechanics/molecular-mechanics models of Az48W(*) and ReAz108W(*) capable of reproducing specific features of their observed UV-vis, resonance Raman, and electron paramagnetic resonance spectra. The results show that the models can correctly replicate the spectral changes imposed by the two contrasting hydrophobic and hydrophilic environments. Most importantly, the same models can be employed to disentangle the molecular-level interactions responsible for such changes. It is found that the control of the hydrogen bonding between the tryptophan radical and a single specific surface water molecule in ReAz108W(*) represents an effective means of spectral modulation. Similarly, a specific electrostatic interaction between the radical moiety and a Val residue is found to control the Az48W(*) excitation energy. These modulations appear to be mediated by the increase in nitrogen negative charge (and consequent increase in hydrogen bonding) of the spectroscopic D2 state with respect to the D0 state of the chromophore. Finally, the same protein models are used to predict the relaxed Az48W(*) and ReAz108W(*) D2 structures, showing that the effect of the environment on the corresponding fluorescence maxima must parallel that of D0 absorption spectra. PMID- 23458493 TI - Anal intraepithelial neoplasia in a sexually transmitted diseases outpatient clinic: correlation with cytological screening. AB - BACKGROUND: High-grade anal intraepithelial neoplasia (AIN) is currently considered a precursor of anal cancer. The population most susceptible to AIN is men who have sex with men (MSM), especially if they are infected by HIV. OBJECTIVES: We analysed the population diagnosed with AIN and evaluated anal cytology as a method of screening the at-risk population. METHODS: We undertook a retrospective review of patients diagnosed with AIN by means of a surgical biopsy between 2008 and 2010. We analysed the risk factors of the population affected and the degree of agreement with the cytology performed previously. RESULTS: During the study period 41 patients were diagnosed with AIN and seven with anal canal carcinoma in situ; 77% were men, most MSM. A history of receptive anal intercourse was found in 81% of the patients and in 71% there was an association with anogenital warts; 32 patients were HIV-positive, most of them men. Of the patients with anal dysplasia of any type in the cytology, 90% had some grade of AIN or carcinoma in situ in the later biopsy. The degree of agreement between the cytology and the biopsy was 94% in the high-grade dysplasias and 50% in the low grade dysplasias. CONCLUSIONS: Anal cytology in at-risk populations has a high degree of agreement with the biopsy when performed surgically, though less in low grade dysplasias, which must always be studied. More studies evaluating the degree of progression of AIN to anal cancer are necessary. PMID- 23458494 TI - Effect of the combinations between pea proteins and soluble fibres on cholesterolaemia and cholesterol metabolism in rats. AB - Many functional foods and dietary supplements have been reported to be beneficial for the management of dyslipidaemia, one of the major risk factors for CVD. Soluble fibres and legume proteins are known to be a safe and practical approach for cholesterol reduction. The present study aimed at investigating the hypocholesterolaemic effect of the combinations of these bioactive vegetable ingredients and their possible effects on the expression of genes regulating cholesterol homeostasis. A total of six groups of twelve rats each were fed, for 28 d, Nath's hypercholesterolaemic diets, differing in protein and fibre sources, being, respectively, casein and cellulose (control), pea proteins and cellulose (pea), casein and oat fibres (oat), casein and apple pectin (pectin), pea proteins and oat fibres (pea+oat) and pea proteins and apple pectin (pea+pectin). Administration of each vegetable-containing diet was associated with lower total cholesterol concentrations compared with the control. The combinations (pea+oat and pea+pectin) were more efficacious than fibres alone in modulating cholesterolaemia ( - 53 and - 54%, respectively, at 28 d; P< 0.005). In rats fed the diets containing oat fibres or apple pectin, alone or in combination with pea proteins, a lower hepatic cholesterol content (P< 0.005) and higher hepatic mRNA concentrations of CYP7A1 and NTCP were found when compared with the control rats (P< 0.05). In summary, the dietary combinations of pea proteins and oat fibres or apple pectin are extremely effective in lowering plasma cholesterol concentrations in rats and affect cellular cholesterol homeostasis by up regulating genes involved in hepatic cholesterol turnover. PMID- 23458495 TI - pH-Dependent aggregation and disaggregation of native beta-lactoglobulin in low salt. AB - The aggregation of beta-lactoglobulin (BLG) near its isoelectric point was studied as a function of ionic strength and pH. We compared the behavior of native BLG with those of its two isoforms, BLG-A and BLG-B, and with that of a protein with a very similar pI, bovine serum albumin (BSA). Rates of aggregation were obtained through a highly precise and convenient pH/turbidimetric titration that measures transmittance to +/-0.05 %T. A comparison of BLG and BSA suggests that the difference between pHmax (the pH of the maximum aggregation rate) and pI is systematically related to the nature of protein charge asymmetry, as further supported by the effect of localized charge density on the dramatically different aggregation rates of the two BLG isoforms. Kinetic measurements including very short time periods show well-differentiated first and second steps. BLG was analyzed by light scattering under conditions corresponding to maxima in the first and second steps. Dynamic light scattering (DLS) was used to monitor the kinetics, and static light scattering (SLS) was used to evaluate the aggregate structure fractal dimensions at different quench points. The rate of the first step is relatively symmetrical around pHmax and is attributed to the local charges within the negative domain of the free protein. In contrast, the remarkably linear pH dependence of the second step is related to the uniform reduction in global protein charge with increasing pH below pI, accompanied by an attractive force due to surface charge fluctuations. PMID- 23458496 TI - Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). AB - OBJECTIVE: Our objective was to characterize patterns of preventive medication use in persons with episodic migraine (EM) and chronic migraine (CM). BACKGROUND: Several classes of medications are used both on- and off-label for the prevention of migraine, including beta-blockers (eg, propranolol, timolol), tricyclic antidepressants (eg, amitriptyline), anti-epileptic drugs (eg, topiramate, valproic acid), and neurotoxins (eg, onabotulinumtoxinA). METHODS: Preventive medication use and reasons for discontinuation were collected in an international, Web-based, cross-sectional survey of adults with migraine during 2010. Descriptive analyses were conducted on demographics and headache-related disability as measured by the Migraine Disability Assessment Scale, stratified by use of preventive medication, and EM or CM. Univariate and multivariate logistic regression models were constructed to assess predictors of preventive medication use. RESULTS: One thousand one hundred and sixty-five respondents completed the survey. Only 28.3% of EM and 44.8% of CM respondents were currently using preventive medication; any use of prophylaxis (prior or current) was reported by 43.4% of those with EM and 65.9% with CM. The mean number of prophylactic medications ever used was 2.92 for EM and 3.94 for CM. Antidepressants were used most frequently (EM 60.9%; CM 54.7%), followed by beta-blockers (EM 35.4%; CM 36.8%) and anti-epileptics (EM 28.6%; CM 36.3%). Odds of preventive medication use were higher among CM than EM, adjusting for age, gender, race, years of daily headache, and country (odds ratio 2.72; 95% confidence interval 2.15 to 3.57). Greater headache-related disability and older age were also associated with greater odds of ever having used prophylaxis, regardless of headache frequency. CONCLUSIONS: Less than half the persons with EM and CM were currently using preventive medication for migraine, with treatment rates being higher for CM, as expected. Those with CM tried more medications than those with EM, possibly reflecting higher levels of treatment need. PMID- 23458497 TI - Reticulocytes: Plasmodium vivax target cells. AB - Reticulocytes represent the main invasion target for Plasmodium vivax, the second most prevalent parasite species around the world causing malaria in humans. In spite of these cells' importance in research into malaria, biological knowledge related to the nature of the host has been limited, given the technical difficulties present in working with them in the laboratory. Poor reticulocyte recovery from total blood, by different techniques, has hampered continuous in vitro P. vivax cultures being developed, thereby delaying basic investigation in this parasite species. Intense research during the last few years has led to advances being made in developing methodologies orientated towards obtaining enriched reticulocytes from differing sources, thereby providing invaluable information for developing new strategies aimed at preventing infection caused by malaria. This review describes the most recent studies related to obtaining reticulocytes and discusses approaches which could contribute towards knowledge regarding molecular interactions between target cell proteins and their main infective agent, P. vivax. PMID- 23458498 TI - Synthesis and preliminary evaluation in tumor bearing mice of new (18)F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography. AB - New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by Ki for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP 1/3/14. Two of these compounds were obtained in the (18)F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding Bmax/Kd = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of (18)F-labeled MMP inhibitors was about 30% that of [(18)F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin. PMID- 23458499 TI - Heteroleptic Cu(I) bis-diimine complexes of 6,6'-dimesityl-2,2'-bipyridine: a structural, theoretical and spectroscopic study. AB - A series of heteroleptic Cu(I) complexes containing 6,6'-dimesityl-2,2' bipyridine and phenanthroline-, bipyridine-, and biquinoline-based ligands is studied. The HETPHEN strategy is utilized to synthesize the heteroleptic complexes, which are stable in solution. The X-ray crystal structures of the complexes are presented; the solid-state four-coordinate Cu(I) geometries are quantified by using the tau4 parameter. A feature of the crystal structures is the intramolecular pi-stacking between the mesityl ring(s) and the diimine ligand; the phen-based complexes exhibit stacking between the phen ligand and one of the mesityl rings, creating a "Pac-Man" motif. On the other hand, the bpy based complexes show different types of packing interaction, with both mesityl rings "clamping down" on the bpy based ligand to give pi-stacking. Cyclic voltammetry is used to examine the redox chemistry of the complexes. The most positive potentials for the oxidation process are observed for the complexes with bulky substituents ortho to the coordination nitrogens atoms, i.e., 2,9-dimethyl 1,10-phenanthroline and 6,6'-dibromo-2,2'-bipyridine. The Cu(I) MLCT transitions of the complexes are investigated by resonance Raman spectroscopy in concert with TD-DFT calculations. The resonance Raman spectra of complexes containing substituted biquinolines are straightforward, in that vibrational bands of the biquinoline-based ligand are selectively enhanced over bpy(Mes)2 bands. This is consistent with the purple color of the complexes, due to the lower energy of the biquinoline-based LUMO compared to the bpy(Mes)2 LUMO. All the phen- and bpy based complexes show enhancement of bpy(Mes)2 bands. PMID- 23458501 TI - Reexamining the minimum viable population concept for long-lived species. AB - For decades conservation biologists have proposed general rules of thumb for minimum viable population size (MVP); typically, they range from hundreds to thousands of individuals. These rules have shifted conservation resources away from small and fragmented populations. We examined whether iteroparous, long lived species might constitute an exception to general MVP guidelines. On the basis of results from a 10-year capture-recapture study in eastern New York (U.S.A.), we developed a comprehensive demographic model for the globally threatened bog turtle (Glyptemys muhlenbergii), which is designated as endangered by the IUCN in 2011. We assessed population viability across a wide range of initial abundances and carrying capacities. Not accounting for inbreeding, our results suggest that bog turtle colonies with as few as 15 breeding females have >90% probability of persisting for >100 years, provided vital rates and environmental variance remain at currently estimated levels. On the basis of our results, we suggest that MVP thresholds may be 1-2 orders of magnitude too high for many long-lived organisms. Consequently, protection of small and fragmented populations may constitute a viable conservation option for such species, especially in a regional or metapopulation context. PMID- 23458500 TI - Ultrastructural imaging of endocytic sites in Saccharomyces cerevisiae by transmission electron microscopy and immunolabeling. AB - Defining the ultrastructure of endocytic sites and localization of endocytic proteins in Saccharomyces cerevisiae by immunoelectron microscopy is central in understanding the mechanisms of membrane deformation and scission during endocytosis. We show that an improved sample preparation protocol based on high pressure freezing, freeze substitution, and low-temperature embedding allows us to maintain the cellular fine structure and to immunolabel green fluorescent protein-tagged endocytic proteins or actin in the same sections. Using this technique we analyzed the stepwise deformation of endocytic membranes and immunolocalized the endocytic proteins Abp1p, Sla1p, Rvs167p, and actin, and were able to draw a clear ultrastructural distinction between endocytic sites and eisosomes by immunolocalizing Pil1p. In addition to defining the geometry and the fine structure of budding yeast endocytic sites, we observed associated actin filaments forming a cage-like meshwork around the endocytic membrane. PMID- 23458502 TI - Cyclooxygenase-2-related signaling in the hypothalamus plays differential roles in response to various acute stresses. AB - We previously suggested that cyclooxygenase (COX)-2 plays a role as a common mediator of stresses in the brain. In the present study, we evaluated the possible involvement of COX-2-related signaling in the activation of the hypothalamic-pituitary-adrenal (HPA) axis under three different stress conditions, namely infectious (lipopolysaccharide, LPS), hypoglycemic (2-deoxy-d glucose, 2DG) and restraint (1h) stresses in rats. Both an unselective COX inhibitor (indomethacin) and a selective COX-2 inhibitor (NS-398) significantly attenuated the increase of serum corticosterone levels after LPS and restraint stresses, but not after 2DG injection. COX-2 and microsomal prostaglandin E synthase (mPGES)-1 mRNA levels in the hypothalamus were significantly increased after LPS injection in intact rats. In adrenalectomized (ADX) rats, the expression of both genes was significantly increased after 2DG and restraint stresses, which was blocked by treatment with corticosterone. Interleukin-1beta (IL-1beta) mRNA levels in the hypothalamus in intact rats were increased only by LPS injection, though those in ADX rats were increased by all three stress stimuli. These results suggest that the relationship between COX-2-related signaling and activation of the HPA axis is stress-specific, and that COX-2 related signaling preferably mediates infectious and restraint stresses. Furthermore, the expression of COX-2 and mPGES-1 mRNA under the infectious stress condition was not negatively regulated by endogenous glucocorticoids, likely due to an increase in IL-1beta levels. PMID- 23458503 TI - A role for Sv2c in basal ganglia functions. AB - SV2C is an isoform of the synaptic vesicle 2 protein family that exhibits a particular pattern of brain expression with enriched expression in several basal ganglia nuclei. In the present study, we have investigated SV2C implication in both normal and pathological basal ganglia functioning with a peculiar attention to dopamine neuron containing regions. In SV2C-/- mice, the expression of tyrosine hydroxylase mRNA in midbrain dopaminergic neurons was largely and significantly increased and enkephalin mRNA expression was significantly decreased in the caudate-putamen and accumbens nucleus. The expression of SV2C was studied in two models of dopaminergic denervation (6-OHDA- and MPTP-induced lesions). In dopamine-depleted animals, SV2C mRNA expression was significant increased in the striatum. In order to further understand the role of SV2C, we performed behavioral experiments on SV2C-/- mice and on knock-down mice receiving an injection of adeno-associated virus expressing SV2C miRNA specifically in the ventral midbrain. These modifications of SV2C expression had little or no impact on behavior in open field and elevated plus maze. However, even if complete loss of SV2C had no impact on conditioned place preference induced by cocaine, the specific knock-down of SV2C expression in the dopaminergic neurons completely abolished the development of a CPP while the reaction to an acute drug injection remains similar in these mice compared to control mice. These results showed that SV2C, a poorly functionally characterized protein is strongly involved in normal operation of the basal ganglia network and could be also involved in system adaptation in basal ganglia pathological conditions. PMID- 23458504 TI - Altered auditory processing in a mouse model of fragile X syndrome. AB - This study provides the first description of auditory cortical processing in a mouse model of Fragile X Syndrome (FXS). FXS is a genetic cause of intellectual impairment and is an autism spectrum disorder. Human studies with auditory evoked potentials indicate that FXS is associated with abnormal auditory processing. The Fmr1 knock-out (KO) mouse is a useful model for studying FXS. The KO mice show acoustic hypersensitivity and propensity for audiogenic seizures, suggesting altered auditory responses. However, the nature of changes at the neuronal level is not known. Here we conducted in vivo single unit extracellular electrophysiology in the auditory cortex of urethane/xylazine-anesthetized Fmr1 KO mice in response to tones and frequency modulated (FM) sweeps. Using tones as stimuli, we report expanded frequency tuning, enhanced response magnitude, and more variable first spike latencies in Fmr1 KO mice compared to wild-type controls. FM sweep stimuli revealed altered sensitivity to the rate of frequency change indicating abnormal spectrotemporal processing. There was no difference in FM sweep direction selectivity. Consistent with studies of the somatosensory cortex, these data point to hyper-responsiveness of auditory neurons as a key processing abnormality in FXS. Auditory neural responses can serve as outcome measures in preclinical trials of therapeutics for FXS as well as serve as physiological probes to study their mechanisms of action. PMID- 23458505 TI - Functional down-regulation of axotomized rat facial motoneurons. AB - Functional alterations in injured motoneurons were quantitatively analyzed in axotomized rat facial nuclei. Choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAchT) and m2 muscarinic acetylcholine receptor (m2MAchR) were chosen as indicators of motoneuron function. Immunoblotting showed that the amounts of ChAT in the ipsilateral facial nucleus significantly decreased to below 20% from 3 to 14 days after transection. The decreased level of ChAT in injured motoneurons was ascertained by immunohistochemical study. However, at 4-5 weeks after transection the level of ChAT was restored to that of control side. The amounts of VAchT in the transected nucleus were observed to decrease to below 20% in the first 14 days after transection. The down-regulated levels of VAchT in injured motoneurons were confirmed by immunohistochemical results. The reduced VAchT levels returned to the control levels at 4-5 weeks following insult. The level of m2MAchR in the ipsilateral nucleus was recognized to decrease to below 10% starting on the 5th day after insult, and the low levels were sustained for 5 weeks. Nissl staining at 5 days and 12 days after insult revealed that facial motoneurons in the transected nucleus were almost all alive. Altogether, these results indicate that transected adult rat facial motoneurons are functionally depressed with down-regulated levels of ChAT, VAchT and m2MAchR during the first 14 days after insult, and during weeks 4-5 ChAT and VAchT levels are restored while the levels of m2MAchR remain low. PMID- 23458506 TI - Modern perspectives on factors predisposing to the development of gallbladder cancer. AB - BACKGROUND: Gallbladder cancer (GBC) is a rare malignancy, yet certain groups are at higher risk. Knowledge of predisposing factors may facilitate earlier diagnosis by enabling targeted investigations into otherwise non-specific presenting signs and symptoms. Detecting GBC in its initial stages offers patients their best chance of cure. METHODS: PubMed was searched for recent articles (2008-2012) on the topic of risk factors for GBC. Of 1490 initial entries, 32 manuscripts reporting on risk factors for GBC were included in this review. RESULTS: New molecular perspectives on cholesterol cycling, hormonal factors and bacterial infection provide fresh insights into the established risk factors of gallstones, female gender and geographic locality. The significance of polyps in predisposing to GBC is probably overstated given the known dysplasia carcinoma and adenoma-carcinoma sequences active in this disease. Bacteria such as Salmonella species may contribute to regional variations in disease prevalence and might represent powerful targets of therapy to reduce incidences in high-risk areas. Traditional risk factors such as porcelain gallbladder, Mirizzi's syndrome and bile reflux remain important as predisposing factors. CONCLUSIONS: Subcentimetre gallbladder polyps rarely become cancerous. Because gallbladder wall thickening is often the first sign of malignancy, all gallbladder imaging should be scrutinized carefully for this feature. PMID- 23458507 TI - Hypertension during vascular endothelial growth factor inhibition: focus on nitric oxide, endothelin-1, and oxidative stress. AB - SIGNIFICANCE: Angiogenesis inhibition with humanized antibodies targeting vascular endothelial growth factor (VEGF) or orally active small tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment modality for various forms of cancer. A common side effect of angiogenesis inhibition is the development of sometimes severe hypertension, which simultaneously appears to be predictive for a favorable antitumor response. RECENT ADVANCES: Since VEGF increases the expression and activity of endothelial nitric oxide synthase, it has been assumed that the mean blood pressure (MAP) rise during angiogenesis inhibition is caused by a decrease in nitric oxide bioavailability. Yet, the results from experimental and clinical studies exploring this possibility are conflicting. Recent studies provided evidence that the MAP rise during angiogenesis inhibition rather is mediated by activation of the endothelin-1 (ET 1) axis, which, among others, induces oxidative stress. Nevertheless, conclusive evidence for the involvement of reactive oxygen species in the MAP rise could not be obtained so far. CRITICAL ISSUES: The mechanism underlying activation of the ET-1 axis during angiogenesis inhibition is unclear, and this activation was not anticipated in view of studies showing that VEGF stimulates both the expression and production of ET-1 by endothelial cells. FUTURE DIRECTIONS: In fact, this activation of the ET-1 axis may support the use of ET receptor antagonists for the treatment of angiogenesis inhibition-induced hypertension, especially because ET receptor stimulation in vascular smooth muscle cells results in VEGF production and mitogenesis in a mitogen-activated protein kinase pathway dependent manner. PMID- 23458508 TI - Mediation, identification, and plausibility: an illustration using children's mental health services. AB - OBJECTIVE: Analyses of mediation are important for understanding the effects of mental health services and treatments. The most common approach is to add potential mediators as regressors and to estimate the direct and indirect effects of the treatment of interest. This practice makes the strong assumption that the mediator itself does not suffer from unobserved confounding--that it is as if randomly assigned. In many instances, this assumption seems rather implausible. The objective of this article is to describe the identification problem that represents the fundamental challenge of causal inference. It outlines how mediation complicates identification and considers several identification strategies. The goal of this article is not to propose a new method for handling mediation or to identify a best method for doing so. The latter, in fact, is impossible. The contribution of the article is to illustrate how one can think about possible approaches to mediation in the context of a specific empirical study. METHOD: Using data from a large evaluation of a demonstration project in children's mental health services (n = 763), the article illustrates identification strategies. That demonstration improved service delivery in several ways but primarily by offering services "intermediate" between inpatient and outpatient. These analyses focus on the impact of these intermediate services on 6-month improvement in a behavior checklist commonly used to measure psychopathology and competence among children and youths. RESULTS: The results highlight how different identification strategies produce different answers to key questions. These alternative findings have to be assessed in light of substantive knowledge of the program involved. CONCLUSIONS: The analyses generally support the notion that children and youths treated at the demonstration site who received intermediate services benefited from them. PMID- 23458509 TI - Relations between deterministic and stochastic thresholds for disease extinction in continuous- and discrete-time infectious disease models. AB - Thresholds for disease extinction provide essential information for control, eradication or management of diseases. Through relations between branching process theory and the corresponding deterministic model, it is shown that the deterministic and stochastic thresholds are in agreement for discrete-time and continuous-time infectious disease models with multiple infectious groups. Branching process theory can be applied in conjunction with the deterministic model to give additional information about disease extinction. These relations are illustrated, analytically and numerically, in two settings, a general stage structured model and a vector-host model applied to West Nile virus in mosquitoes and birds. PMID- 23458510 TI - Limiting characteristics for finite birth-death-catastrophe processes. AB - General nonstationary birth-death process with possible catastrophes on finite state space is studied. The approach for obtaining the bounds on the rates of convergence to the limiting characteristics is outlined. Method for construction of the limiting characteristics is proposed. We also show that, as a rule, the initial conditions quickly become irrelevant. An example of respective process is shown in details. PMID- 23458511 TI - Sunitinib malate for the treatment of pancreas malignancies--where does it fit? AB - INTRODUCTION: Sunitinib , a broad-spectrum multikinase inhibitor, was recently approved for use in progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs). Its mechanism of action affects various signaling cascades involving antiangiogenesis and tumor proliferation, including vascular endothelial growth factors and platelet-derived growth factors. AREAS COVERED: In this article, we review sunitinib's mechanism of action at a molecular level and review key preclinical and clinical studies for pNETs and more limited data regarding sunitinib's evaluation in pancreas adenocarcinoma. The data for sunitinib in pNETs are placed in the context of the changing landscape of therapeutic options for this cancer, and relevant ongoing clinical trials and future directions are highlighted. EXPERT OPINION: Sunitinib malate has become integrated into routine clinical management for pNETs; however, its role in pancreas adenocarcinoma is not established. PMID- 23458512 TI - Phage display of functional alphabeta single-chain T-cell receptor molecules specific for CD1b:Ac2SGL complexes from Mycobacterium tuberculosis-infected cells. AB - The development of molecules specific for M. tuberculosis-infected cells has important implications, as these tools may facilitate understanding of the mechanisms regulating host pathogen interactions in vivo. In addition, development of new tools capable to targeting M. tuberculosis-infected cells may have potential applications to diagnosis, treatment, and prevention of tuberculosis (TB). Due to the lack of CD1b polymorphism, M. tuberculosis lipid CD1b complexes could be considered as universal tuberculosis infection markers. The aim of the present study was to display on the PIII surface protein of m13 phage, a human alphabeta single-chain T-cell receptor molecule specific for CD1b:2-stearoyl-3-hydroxyphthioceranoyl-2'-sulfate-alpha-alpha'-D-trehalose (Ac2SGL) which is a complex presented by human cells infected with M. tuberculosis. The results showed the pIII fusion particle was successfully displayed on the phage surface. The study of the recognition of the recombinant phage in ELISA and immunohistochemistry showed the recognition of CD1b:Ac2SGL complexes and cells in human lung tissue from a tuberculosis patient respectively, suggesting the specific recognition of the lipid-CD1b complex. PMID- 23458513 TI - Postconcussive symptom complaints and potentially malleable positive predictors. AB - The purpose of this study was to examine the relationship between postconcussion symptom complaint (PCS) severity and positive coping factors (knowledge, self efficacy, and attributions) in a sample of individuals who have sustained a mild TBI, above and beyond the demographic and psychiatric predictors that have been most commonly examined. Ninety-one people with a history of reported mild TBI were surveyed. Hierarchical regression analyses revealed that demographic variables and psychiatric symptom severity predicted PCS severity. Consistent with our hypotheses, knowledge, self-efficacy, and attributions, when taken together, made an independent and significant contribution to prediction of PCS severity (21% of additional variance). The most potent factor was attribution, or the extent to which one attributes symptoms to mild TBI versus other causes. Those who attribute their symptoms to TBI are more likely to report greater symptom severity overall. Taken together, knowledge, self-efficacy, and attributions contribute independently to PCS severity. Additional research is needed to determine if these factors are amenable to intervention. PMID- 23458514 TI - Hanging manoeuver for a left hepatectomy using Glisson's approach with a focus on tape position in liver hilum. AB - BACKGROUND: Successful use of the hanging manoeuver during a hepatic resection requires the tape to be placed anatomically. The aim of this study is to describe the outcomes after variations in tape placement while using the hanging manoeuver during a left hepatectomy. METHODS: A whole cohort in whom the hanging manoeuver was attempted for a left hepatectomy from March 2003 to October 2011 was divided chronologically into three groups based on the tape position in the hilum along the ligamentum venosum (LV); conventionally between the right and left Glisson's pedicles (group 1), at the ventral side of the LV (group 2), and at the dorsal side of the LV (group 3). Patient characteristics, operative outcomes and complications defined using Clavien's classification were compared. RESULTS: A total of 151 patients were enrolled in one of three groups: group 1 (n = 54), group 2 (n = 35), and group 3 (n = 62). The hanging tape was successfully positioned in all patients as planned in the three groups. In group 2 and 3, the hanging manoeuver was continuously applied during a parenchymal transection. The Glisson's pedicle injury during hilar dissection was more common in group 2 (%, 51.4 versus 5.6 in group 1 and 3.2 in group 3; P = 0.001). Group 3 showed a shorter median operative time (min, 151 versus 210 in group 1 and 220 in group 2; P = 0.001), a shorter median hospital stay (days, 7 versus 10 in group 1 and 2; P = 0.012) and a lower complication rate (%, 1.6 versus 13.0 in group 1 and 37.1 in group 2; P = 0.001) without any operative mortality, major morbidity, blood transfusion or reoperation. CONCLUSIONS: The hanging manoeuver had 100% feasibility with good outcomes during a left hepatectomy. The tape should be positioned to surround the left Glisson's pedicle and LV together as this helps to protect the caudate lobe. PMID- 23458515 TI - A novel BMP2-coprecipitated, layer-by-layer assembled biomimetic calcium phosphate particle: a biodegradable and highly efficient osteoinducer. AB - PURPOSE: To repair large-size bone defects, most bone-defect-filling materials in clinic need to obtain osteoinductivity either by mixing them with particulate autologous bone or adsorbing bone morphogenetic protein 2 (BMP2). However, both approaches encounter various limitations. In this study, we hypothesized that our novel particles of biomimetic BMP2-coprecipitated calcium phosphate (BMP2 cop.BioCaP) could serve as an independent and biodegradable osteoinducer to induce bone formation efficiently for these bone-defect-filling materials, for example, deproteinized bovine bone (DBB). MATERIALS AND METHODS: We alternately layer-by-layer assembled amorphous and crystalline CaP triply to enable a "bamboo like" growth of the particles. We functionalized BioCaP by coprecipitating BMP2 into the most outer layer of BioCaP. We monitored the degradation, osteoinductivity, and foreign-body reaction of either BMP2-cop.BioCaP or its combination with DBB in an ectopic site in rats. RESULTS: After 5 weeks, the BMP2 cop.BioCaP significantly induced new bone formation not only alone but also when mixed with DBB. Its osteoinductive efficiency was 10-fold higher than the adsorbed BMP2. Furthermore, BMP2-cop.BioCaP also reduced significantly the host foreign-body reaction to DBB in comparison with the adsorbed BMP2. After a 5-week implantation, more than 90% of BMP2-cop.BioCaP degraded. CONCLUSIONS: These findings indicate a promising clinical potential for BMP2-cop.BioCaP in the repair of large-size bone defects. PMID- 23458516 TI - Peri-operative challenges and long-term outcomes in liver transplantation for polycystic liver disease. AB - BACKGROUND: The purpose of this study was to determine peri-operative mortality and long-term outcomes in patients undergoing liver transplantation in the US using the United Network for Organ Sharing (UNOS) database. METHODS: This study is a retrospective review of liver transplantations (LT) recorded in the UNOS database performed between 1988 and 2010. In total, 107 411 LT were performed in the US, 357 (0.3%) were for adult polycystic liver disease (PLD). A random group of 9416 adult patients transplanted for other diagnoses was created for comparison (10% of the adult non-PLD database). RESULTS: Two hundred and seventy one patients in the adult PLD group were females (75.9%), the mean age was 52.3 +/- 8.2 [standard deviation (SD)] years. The median length of transplantation hospital stay was 11 days (interquartile range 8-21). Patients from the PLD group versus the comparison group (9416 patients) consisted of more females, lower Model for End-Stage Liver Disease (MELD) scores (17 versus 21 points), more multi organ transplants (41% versus 4 %), chronic renal failure (creatinine 2.7 versus 1.5) and fewer patients with chronic hepatitis C (1.4% versus 32%). Peri operative mortality (<=30 days) was 9% in the PLD versus 6% in the comparison group; however, at 1 year PLD survival was similar (85% versus 85%) to other diagnoses and better at 3 (81% versus 77%) and 5 years (77% versus 71%, overall Log Rank P = 0.006). A similar PLD survival advantage was observed in isolated initial transplants (P = 0.019). CONCLUSION: In spite of early technical challenges and mortality, transplantation should be considered an option for selected patients with PLD as excellent long-term outcomes can be achieved. PMID- 23458517 TI - A different look at the management of chronic hepatitis B in a resource constrained country. PMID- 23458518 TI - Treatment of chronic Hepatitis B in resource-constrained countries: an economic solution is required. PMID- 23458519 TI - Telbivudine treatment in chronic hepatitis B: experience from China. AB - Telbivudine, one of the oral anti-hepatitis B virus (HBV) nucleoside analogues, has been used for more than 5 years to treat HBeAg-positive and -negative chronic hepatitis B (CHB) patients. This includes not only global Phase II and III trials, but also Chinese Phase III trials and several real-world clinical practice studies from China. The present review will first focus on 1-, 2- and 3 year data of telbivudine therapy on HBV DNA suppression, alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroconversion, viral resistance and safety in HBeAg-positive and -negative CHB patients. Second, telbivudine treatment predictors, including HBV DNA undetectability, ALT level and other immune-related markers at 12 and 24 weeks will be summarized to optimize therapy. Besides several retrospective studies, the Chinese EFFORT prospective study adapted from telbivudine virological response at 24 weeks has shown very promising results. Finally, the Chinese experience of using telbivudine in the second and third trimesters of pregnancy to prevent perinatal transmission of HBV infection will be touched on citing the latest studies. PMID- 23458520 TI - Telbivudine treatment is associated with high hepatitis B e antigen seroconversion and immune modulatory effects in chronic hepatitis B patients. AB - Chronic hepatitis B (CHB) is characterized by an impaired immune response to hepatitis B virus. Among the nucleos(t)ides used in CHB treatment, telbivudine is associated with the highest rates of hepatitis B e antigen (HBeAg) seroconversion rates, which are similar to those observed with pegylated interferon (PegIFN). Besides direct antiviral effect, modulation of the immune system may be an additional benefit for telbivudine-treated patients. Indeed, there is much clinical data indicating an IFN-like behaviour for telbivudine in contrast to other oral nucleos(t)ides, such as high HBeAg seroconversion, similar hepatitis B surface antigen (HBsAg) decline and biphasic viral kinetics. Clinical studies, animal models and in vitro studies suggest that both the innate and adaptive immune system responses contribute to high HBeAg seroconversion during telbivudine treatment through modulation of the function and/or expression of CD4+/CD8+ T cells, Th1/Th2, Treg, PD-1/PD-L1, Th17, IL-21 and TFH. The results described in this review suggest that the antiviral effect of telbivudine may be attributable not only to direct suppression of hepatitis B virus, but also to immunoregulatory effects. Hypothetically, telbivudine shares some common signal pathways with IFN. PMID- 23458521 TI - Rapid downregulation of programmed death-1 and interferon-gamma-inducible protein 10 expression is associated with favourable outcome during antiviral treatment of chronic hepatitis B. AB - The dynamics of programmed death-1 (PD-1) as well as cytokine/chemokine expression and its correlation with virological response in patients with chronic hepatitis B (CHB) is unclear. This study was conducted in 29 treatment-naive patients undergoing telbivudine treatment for 52 weeks. The results showed that PD-1 expression on both CD4+ and CD8+ T cells was positively correlated with hepatitis B virus (HBV) DNA levels (r = 0.621, P < 0.0001; r = 0.548, P = 0.002, respectively), and in virological responders, this decrease was directly correlated with a decrease in HBV DNA levels (r = 0.664, P = 0.002; r = 0.572, P = 0.01, respectively). Furthermore, at the end of 52 weeks, in virological responders, the decreased rate in the frequency of PD-1+ CD8+ T cells was significantly higher than in non-virological responders (58.3% vs 25.7%, P = 0.001), and at weeks 24 and 52, in virological responders, PD-1 expression on CD4+ and CD8+ T cells was lower than in non-virological responders (P = 0.01 and P = 0.035; P < 0.0001 and P < 0.0001, respectively). In 34 cytokines/chemokines detected in serum, IP-10 expression was positively correlated with viral load, level of ALT and PD-1 expression on CD8+ and CD4+ T cells at baseline (r = 0.36, P = 0.055, r = 0.635, P < 0.0001, r = 0.414, P = 0.026, and r = 0.402, P = 0.030, respectively). Moreover, the decrease in IP-10 in serum directly correlated with a decrease in ALT levels (r = 0.751, P < 0.0001). At weeks 24 and 25, IP-10 expression was significantly lower than baseline in virological responders (both P = 0.005); however, this was not observed in nonresponders. Based on the above findings, PD-1 and IP-10 may be used as predictors for virological response, and blockade of their pathway may improve the outcome of patients with CHB. PMID- 23458522 TI - PD-1/PDL1 and CD28/CD80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication. AB - alpha-Galactosylceramide (alpha-GalCer)-activated natural killer T (NKT) cells have antiviral properties against hepatitis B virus (HBV). However, alpha-GalCer activation of NKT cells can induce anergy. We hypothesized that this effect may be overcome by a treatment strategy that includes manipulation of CD28/CD80 costimulatory and PD-1/PDL1 coinhibitory signals of NKT cells, thereby enhancing the anti-HBV effect of alpha-GalCer. We established a transgenic mouse model of chronic HBV infection and investigated hepatic NKT cell frequencies, functions and expression of immunomodulatory factors. Our results showed that compared with uninfected control mice, hepatic NKT cells from HBV transgenic mice displayed lower frequencies (7.91% vs 16.74%, P < 0.05), impaired capabilities to produce interferon (IFN)-gamma (5.6% vs 1.4%, P < 0.05) and interleukin (IL)-4 (6.8% vs 0.3%, P < 0.05), higher expression of PD-1 (9.64% vs 6.36%, P < 0.05) and lower expression of CD28 (5.05% vs 28.88%, P < 0.05). However, when hepatic mononuclear cells (MNCs) were isolated from HBV transgenic mice, alpha-GalCer exposure in culture remarkably upregulated both PD-1(+) NKT cells (P < 0.05) and CD28(+) NKT cells (P < 0.05). Furthermore, when HBV transgenic mice were treated with combination therapies consisting of alpha-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-CD80/anti-CD28 mAbs, IFN-gamma(+) NKT cell frequency was selectively increased (P < 0.05) and HBV replication was suppressed; these effects were accompanied by varying degrees and types of liver damage. Surprisingly, activating CD28/CD80 signal in HBV transgenic mice was more effective but caused less liver injury than blocking PD-1/PDL1 signal in modulating alphaGalCer-activated NKT cell function to inhibit HBV infection. Our findings also show that combined therapy with blocking PD-1/PDL1 and activating CD28/CD80 signal in the presence of aGalCer cannot superimpose the effect of antivirus. alpha-GalCer combination therapy that modulates the CD28/CD80 pathways of NKT cells may represent a promising approach to inhibit HBV replication in chronically infected patients. PMID- 23458523 TI - Efficacy and safety of telbivudine plus adefovir dipivoxil combination therapy and entecavir monotherapy for HBeAg-positive chronic hepatitis B patients with resistance to adefovir dipivoxil. AB - The objective of this study was to compare the efficacy and safety of two rescue strategies for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with resistance to adefovir dipivoxil (ADV). This prospective study included 58 HBeAg-positive CHB patients with resistance to ADV; 30 patients underwent telbivudine (LdT) plus ADV combination therapy and 28 patients switched to entecavir (ETV) monotherapy. After 48 weeks of treatment, the rates of hepatitis B virus (HBV) DNA <3 log10 copies/mL in the LdT plus ADV group and the ETV group were not significantly different (73.3% vs 57.1%, P = 0.195). Six patients receiving LdT plus ADV had HBeAg seroconversion, while none of the patients receiving ETV alone had HBeAg seroconversion (20% vs 0%, P = 0.039). During the 48-week treatment period, two patients in the ETV monotherapy group had viral breakthrough and the strains were confirmed to be of a variant associated with ETV resistance (rtM204V+ rtL180M+ rtT184G), while one patient receiving LdT plus ADV had viral breakthrough and an LdT-associated resistance mutation (rtM204I) was detected. For the majority of the patients, both LdT plus ADV combination treatment or ETV monotherapy were generally well tolerated, and no serious side effects were observed. Both LdT plus ADV combination therapy and ETV monotherapy led to significant decreases in serum HBV DNA in HBeAg-positive CHB patients with resistance to ADV, and LdT plus ADV combination therapy exhibited a significantly higher rate of HBeAg seroconversion compared with ETV monotherapy. PMID- 23458524 TI - Efficacy of telbivudine treatment for hepatitis B e antigen-positive chronic hepatitis B patients with poor response to adefovir dipivoxil. AB - Telbivudine (LdT) has demonstrated potent antiviral activity in nucleos(t)ide analogue (NA)-naive chronic hepatitis B patients (CHB), but data on its efficacy in NA-experienced patients are limited. The aim of this study was to investigate the effect of LdT in hepatitis B e antigen-positive CHB patients with poor response to initial adefovir dipivoxil (ADV). Forty-two CHB patients with HBV DNA > 4 log10 copies/mL after 12 months of ADV monotherapy were enroled in the study and thereafter treated with LdT 600 mg daily for 18 months. Telbivudine led to a rapid decrease in viral load, and viral replication was persistently suppressed with a reduction of 2.26 log10 copies/mL 18 months after LdT treatment. The rates corresponding to virological and biochemical response at the end of observation were 97.6% (41/42) and 65.8% (25/38), respectively. HBeAg loss was found in 30.8% (12/39) of patients, while HBeAg/anti-HBe seroconversion was found in 17.9% (7/39). Only one patient was detected to have LdT-associated mutation, and no severe adverse events were reported. Optimization therapy with LdT monotherapy may be a good choice for CHB patients with poor response to ADV, and switching to LdT may be the most cost-effective rescue therapeutic strategy for patients with poor response to initial ADV monotherapy. PMID- 23458525 TI - Efficacy of sequential use of telbivudine in hepatitis B e antigen-positive chronic hepatitis B patients with partial responses to pegylated interferon: a pilot study. AB - The aim of this study was to investigate the efficacy of sequential use of telbivudine in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients with partial responses to pegylated interferon. Patients with partial responses to 48 weeks of pegylated interferon treatment were divided into two groups. In group A, patients stopped pegylated interferon directly without sequential treatment. In group B, patients received sequential treatment with telbivudine 600 mg/day. HBeAg, HBeAb, hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT) and creatine kinase levels were determined at baseline and at weeks 12, 24, 36 and 48. Responses and safety were assessed after 48 weeks of telbivudine treatment. Thirty-six patients were recruited. Eighteen of these patients stopped pegylated interferon without sequential treatment (group A). After 48 weeks of follow-up, five patients (28%) had undergone HBeAg seroconversion, nine patients (50%) had undetectable levels of HBV DNA, and 11 patients (61%) achieved normal alanine aminotransferase (ALT) levels. The other 18 patients received sequential telbivudine treatment (group B). After 48 weeks of treatment, 11 patients (61%) had undergone HBeAg seroconversion, and all patients had undetectable levels of HBV DNA and normal ALT levels. All patients tolerated sequential telbivudine treatment, and only slightly elevated creatine kinase levels were observed. Switching to telbivudine therapy was efficient and safe in HBeAg-positive chronic hepatitis B patients with partial responses to 48 weeks of pegylated interferon. Sequential treatment with telbivudine resulted in an HBeAg seroconversion rate of 61% and an HBV DNA loss rate of 100% after 48 weeks. This promising strategy warrants further investigation. PMID- 23458526 TI - Forty-eight-week retrospective study of telbivudine and lamivudine treatment in patients with hepatitis B-related cirrhosis. AB - The aim of this study was to evaluate the efficacy and safety of telbivudine 600 mg/day compared with lamivudine 100 mg/day for 48 weeks of treatment in patients with hepatitis B-related cirrhosis. Data were reviewed retrospectively from 165 hepatitis B-related cirrhotic patients (55 compensated patients and 110 decompensated) who received antiviral therapy with telbivudine or lamivudine. Serum alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA levels, hepatitis B e antigen (HBeAg) loss and seroconversion, histological improvement and various adverse events (AEs) were evaluated. Baseline characteristics were comparable. ALT levels declined but showed no significant difference in treatment with telbivudine or lamivudine (P > 0.05). Reduction in serum HBV DNA levels was evident by week 4 in compensated HBV-related cirrhosis patients (telbivudine, 2.34 log10 copies/mL; lamivudine, 2.07 log10 copies/mL; P = 0.02) and persisted by week 8. Patients administrated with telbivudine had slightly greater HBeAg loss and seroconversion than patients with lamivudine, but the difference was not statistically significant (P > 0.05). Accumulative HBeAg loss was seen at week 48 (25.0% vs 25.0% and 13.3% vs 10.0% for telbivudine vs lamivudine in compensated and decompensated cirrhotic groups, respectively), as well as HBeAg seroconversion (15.0% vs 8.3% and 8.9% vs 6.7%). Mean Knodell Histologic Activity Index scores decreased in both compensated and decompensated cirrhotic patients (3.92 vs 3.64, 3.85 vs 3.73, for telbivudine vs lamivudine). Telbivudine and lamivudine were both well tolerated with minor AEs. The results of this study support telbivudine as an effective therapy for patients with both compensated and decompensated HBV-related cirrhosis. PMID- 23458527 TI - Safety of telbivudine treatment for chronic hepatitis B for the entire pregnancy. AB - Orally administered nucleus(t)ide analogues (NA) have brought about a simple, safe and effective therapeutic approach for chronic hepatitis B (CHB). However, treatment duration is long and some female patients become pregnant during treatment. In recent years, there have been gradually increasing reports on the safety of telbivudine (LdT) treatment for chronic hepatitis B virus (HBV) infection in the third trimester of pregnancy to block mother-to-infant transmission (MTIT) of HBV; however, the safety of LdT treatment for chronic HBV infection for the entire pregnancy has not been reported. The aim of the present study was to evaluate the safety of LdT treatment for chronic HBV infection for the entire pregnancy and provide a reference for HBV-infected fertile women on how to block MTIT of HBV. Eighty-six pregnant women who received LdT treatment either before or in early pregnancy were enrolled in the study. Adverse events were prospectively observed for the entire pregnancy and perinatal period, and short-term and long-term follow-up of infants was conducted, monitoring the abnormalities of infants and blocking rate of MTIT with LdT treatment. Eighty-six pregnant women treated with LdT had a total of 89 pregnancies: 6 (6.7%) had early embryonic death or spontaneous abortion, 1 (1.1%) had ectopic pregnancy and three had a second pregnancy after initial abortion. Fifty-one mothers completed pregnancy: one had induction of labour at 24 weeks of pregnancy for cleft lip and palate of the foetus and 50 delivered 52 full-term live infants. One infant had right ear accessories, and the total occurrence of congenital abnormality was 3.8%. Thirty-nine infants were followed up for more than 6 months and completed all examinations for MTIT. None of the infants were HBsAg positive, resulting in a 100% success rate of blocking MTIT. All mothers maintained good liver function during the third trimester of pregnancy; 86% maintained complete virological response (HBV DNA <500 copies/mL) prior to delivery, and none developed progression of liver disease. Factors leading to increased adverse effects and drug resistance were not found. LdT treatment is safe and effective in chronic HBV-infected pregnant mothers for the entire pregnancy. PMID- 23458528 TI - Commentary: psychoeducation in the irritable bowel syndrome--talking the talk. PMID- 23458529 TI - Commentary: the chronic hepatitis C virus treatment satisfaction (HCVTSat) instrument. PMID- 23458531 TI - Letter: should immunosuppressive therapy be started with adalimumab in Crohn's disease? Authors' reply. PMID- 23458532 TI - Letter: should immunosuppressive therapy be started with adalimumab in Crohn's disease? PMID- 23458533 TI - Letter: retrospective reviews of liver-related case reports allegedly associated with Herbalife present insufficient and inaccurate data. PMID- 23458534 TI - Letter: retrospective reviews of liver-related case reports allegedly associated with Herbalife present insufficient and inaccurate data--authors' reply. PMID- 23458535 TI - Letter: an allergic phenotype in patients with eosinophilic oesophagitis and asthma. PMID- 23458536 TI - Letter: an allergic phenotype in patients with eosinophilic oesophagitis and asthma--authors' reply. PMID- 23458537 TI - Letter: curing Helicobacter pylori infection in a clinical setting. PMID- 23458538 TI - Letter: curing Helicobacter pylori infection in a clinical setting--authors' reply. PMID- 23458539 TI - Letter: complications of coeliac disease despite a gluten-free diet. PMID- 23458540 TI - Letter: mucosal healing and mortality in coeliac disease. PMID- 23458541 TI - Letter: Adnab-9 as a potential non-invasive biomarker for prediction of malignancy in coeliac disease. PMID- 23458542 TI - Letter: complications of coeliac disease despite a gluten-free diet--authors' reply. PMID- 23458543 TI - Letter: are infliximab and adalimumab similar for Crohn's disease in clinical practice? PMID- 23458544 TI - Letter: gastric cancer and pernicious anaemia--often Helicobacter pylori in disguise. PMID- 23458545 TI - Letter: gastric cancer and pernicious anaemia--often Helicobacter pylori in disguise--authors' reply. PMID- 23458547 TI - The costs and benefits of mind-wandering: a review. AB - Substantial evidence suggests that mind-wandering typically occurs at a significant cost to performance. Mind-wandering-related deficits in performance have been observed in many contexts, most notably reading, tests of sustained attention, and tests of aptitude. Mind-wandering has been shown to negatively impact reading comprehension and model building, impair the ability to withhold automatized responses, and disrupt performance on tests of working memory and intelligence. These empirically identified costs of mind-wandering have led to the suggestion that mind-wandering may represent a pure failure of cognitive control and thus pose little benefit. However, emerging evidence suggests that the role of mind-wandering is not entirely pernicious. Recent studies have shown that mind-wandering may play a crucial role in both autobiographical planning and creative problem solving, thus providing at least two possible adaptive functions of the phenomenon. This article reviews these observed costs and possible functions of mind-wandering and identifies important avenues of future inquiry. PMID- 23458546 TI - Bio-inspired liposomal thrombomodulin conjugate through bio-orthogonal chemistry. AB - We report the synthesis of bioinspired liposomal thrombomodulin (TM) conjugates by chemoselective and site-specific liposomal conjugation of recombinant TM at C terminus. TM is an endothelial cell membrane protein that acts as a major cofactor in the protein C anticoagulant pathway. To closely mimic membrane protein structural features of TM, we proposed membrane-mimetic re-expression of recombinant TM onto liposome. A recombinant TM containing the EGF-like 456 domains and an azidohomoalanine at C-terminus was expressed in E. coli. Conjugation of the recombinant TM onto liposome via Staudinger ligation and copper-free click chemistry were investigated as an optimal platform for exploring membrane protein TM's activity, respectively. The bioinspired liposomal TM conjugates were confirmed with Western blotting and protein C activation activity. The recombinant TM-liposome conjugates showed a 2-fold higher k(cat)/K(m) value for protein C activation than that of the recombinant TM alone, which indicated that the lipid membrane has a beneficiary effect on the recombinant TM's activity. The reported liposomal protein conjugate approach provides a rational design strategy for both studying membrane protein TM's functions and generating a membrane protein TM-based anticoagulant agent. PMID- 23458548 TI - Wandering in both mind and body: individual differences in mind wandering and inattention predict fidgeting. AB - Anecdotal reports suggest that during periods of inattention or mind wandering, people tend to experience increased fidgeting. In four studies, we examined whether individual differences in the tendency to be inattentive and to mind wander in everyday life are related to the tendency to make spontaneous and involuntary movements (i.e., to fidget). To do so, we developed self-report measures of spontaneous and deliberate mind wandering, as well as a self-report scale to index fidgeting. In addition, we used several existing self-report measures of inattentiveness, attentional control, and memory failures. Across our studies, a series of multiple regression analyses indicated that fidgeting was uniquely predicted by inattentiveness and spontaneous mind wandering but not by other related factors, including deliberate mind wandering, attentional control, and memory failures. As a result, we suggest that only spontaneously wandering thoughts are related to a wandering body. PMID- 23458549 TI - Penetrating the fog of the decoupled mind: the effects of visual salience in the sustained attention to response task. AB - An absence of coupling between cognition and perception can mean that the mind neglects the careful processing of information relevant to the task at hand and errors can ensue. Given that highly salient perceptual events can automatically capture attention, the current study explored whether the same neglect of task relevant information was possible for stimuli with high levels of perceptual saliency (e.g., identifiable by colour). In four experiments, participants performed a go/no-go task with a low frequency of no-go events. Across all experiments, response inhibition was more successful for coloured no-go targets than for stimuli that shared the same colour as the go targets. In addition, the response time (reaction time [RT]) for rare, coloured go targets was slower than when the same events were noncolored. Together, these results suggest that in relatively simple go/no-go tasks, highly salient perceptual events capture attention in an automatic fashion. Increased visual salience is argued to be beneficial when associated with no-go targets because it momentarily enforces coupling between attention and perception, disrupting ongoing behaviour at the precise moment when not responding is the correct action to take. These results suggest that although the mind may at times neglect events in the environment, salient perceptual events cannot be ignored in the same way. PMID- 23458550 TI - Working memory capacity does not always support future-oriented mind-wandering. AB - To evaluate the claim that mind-wandering demands executive resources, and more specifically that people with better executive control will have the resources to engage in more future-oriented thought than will those with poorer executive control, we reanalyzed thought-report data from 2 independently conducted studies (J. C. McVay & M. J. Kane, 2012, Why does working memory capacity predict variation in reading comprehension? On the influence of mind wandering and executive attention, Journal of Experimental Psychology: General, Vol. 141, pp. 302-320; N. Unsworth & B. D. McMillan, in press, Mind-wandering and reading comprehension: Examining the roles of working memory capacity, interest, motivation, and topic experience, Journal of Experimental Psychology: Learning, Memory, and Cognition) on working memory capacity (WMC), mind-wandering, and reading comprehension. Both of these individual-differences studies assessed large samples of university subjects' WMC abilities via multiple tasks and probed their immediate thought content while reading; in reporting any task-unrelated thoughts (TUTs), subjects indicated whether those thoughts were about the future or the past, if applicable. In contrast to previously published findings indicating that higher WMC subjects mind-wandered about the future more than did lower WMC subjects (B. Baird, J. Smallwood, & J. W. Schooler, 2011, Back to the future: Autobiographical planning and the functionality of mind-wandering, Consciousness and Cognition, Vol. 20, pp. 1604-1611), we found only weak to modest negative correlations between WMC and future-oriented TUTs. If anything, our findings suggest that higher WMC subjects' TUTs were somewhat less often future-oriented than were lower WMC subjects'. Either WMC is not truly associated with mind-wandering about the future, or we have identified some important boundary conditions around that association. PMID- 23458551 TI - Mind wandering in sentence reading: decoupling the link between mind and eye. AB - When people read, their thoughts sometimes drift away from the task at hand: They are "mind wandering." Recent research suggests that this change in task focus is reflected in eye movements and this was tested in an experiment using controlled stimuli. Participants were presented with a series of sentences containing high- and low-frequency words, which they read while being eye-tracked, and they were sometimes probed to indicate whether they were on task or mind wandering. The results showed multiple differences between reading prior to a mind-wandering response and reading when on task: Mind wandering led to slower reading times, longer average fixation duration, and an absence of the word frequency effect on gaze duration. Collectively, these findings confirm that task focus could be inferred from eye movements, and they indicate that the link between word identification and eye scanning is decoupled when the mind wanders. PMID- 23458553 TI - Native states of fast-folding proteins are kinetic traps. AB - It has been suggested that the native state of a protein acts as a kinetic hub that can facilitate transitions between nonnative states. Using recently developed tools to quantify mediation probabilities ("hub scores"), we quantify hub-like behavior in atomic resolution trajectories for the first time. We use a data set of trajectory ensembles for 12 fast-folding proteins previously published by D. E. Shaw Research (Lindorff-Larsen, K.; et al. How Fast-Folding Proteins Fold. Science2011, 334, 517) with an aggregate simulation time of over 8.2 ms. We visualize the free-energy landscape of each molecule using configuration space networks, and show that dynamic quantities can be qualitatively understood from visual inspection of the networks. Modularity optimization is used to provide a parameter-free means of tessellating the network into a group of communities. Using hub scores, we find that the percentage of trajectories that are mediated by the native state is 31% when averaged over all molecules, and reaches a maximum of 52% for the homeodomain and chignolin. Furthermore, for these mediated transitions, we use Markov models to determine whether the native state acts as a facilitator for the transition, or as a trap (i.e., an off-pathway detour). Although instances of facilitation are found in 4 of the 12 molecules, we conclude that the native state acts primarily as a trap, which is consistent with the idea of a funnel-like landscape. PMID- 23458554 TI - Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: factors predictive of severe SOS lesions and protective effect of bevacizumab. AB - OBJECTIVES: The most frequent presentation of chemotherapy-related toxicity in colorectal liver metastases (CRLM) is sinusoidal obstruction syndrome (SOS). The purpose of the present study was to identify preoperative factors predictive of SOS and to establish associations between type of chemotherapy and severity of SOS. METHODS: A retrospective study was carried out in a tertiary academic referral hospital. Patients suffering from CRLM who had undergone resection of at least one liver segment were included. Grading of SOS on the non-tumoral liver parenchyma was accomplished according to the Rubbia-Brandt criteria. A total of 151 patients were enrolled and divided into four groups according to the severity of SOS (grades 0-3). RESULTS: Multivariate analysis identified oxaliplatin and 5 fluorouracil as chemotherapeutic agents responsible for severe SOS lesions (P < 0.001 and P = 0.005, respectively). Bevacizumab was identified as having a protective effect against the occurrence of SOS lesions (P = 0.005). Univariate analysis identified the score on the aspartate aminotransferase : platelets ratio index (APRI) as the most significant biological factor predictive of severe SOS lesions. Splenomegaly is also significantly associated with the occurrence of severe SOS lesions. CONCLUSIONS: The APRI score and splenomegaly are effective as factors predictive of SOS. Bevacizumab has a protective effect against SOS. PMID- 23458555 TI - Screening of patients with tuberculosis for diabetes mellitus in India. AB - OBJECTIVE: To assess feasibility and results of screening patients with tuberculosis (TB) for diabetes mellitus (DM) within the routine healthcare setting across the country at: eight tertiary care hospitals and more than 60 peripheral health institutions in eight tuberculosis units. METHODS: Agreement on how to screen, monitor and record was reached in October 2011 at a stakeholders' meeting, and training was carried out for staff in the facilities in December 2011 and January 2012. Implementation started from January 2012, and we report on activities up to 30 September 2012. RESULTS: Of 8269 TB patients diagnosed and initiated on treatment in participating facilities, 8109 (98%) were assessed for DM and 1084 (13%) were found to have DM; of these, 682 (8%) had a previously known diagnosis of DM and 402 (5%) were newly diagnosed. There was a higher prevalence of DM in patients with TB diagnosed in tertiary care hospitals (16%) than in those diagnosed in tuberculosis units (9%) (P < 0.001) and amongst those from South India (20%) than from North India (10%) (P < 0.001). The screening and referral process worked well although significantly more patients with DM diagnosed in hospitals were referred to DM care (96%) than patients diagnosed in tuberculosis units (92%) (P < 0.05). CONCLUSION: This pilot project shows that it is important and feasible to screen patients with TB for DM in the routine setting, resulting in earlier identification of DM in some patients and opportunities for better management of comorbidity. A policy decision has since been made by the National TB Control Programme of India to implement this intervention countrywide. PMID- 23458556 TI - Factors affecting the 27K DNA methylation pattern in asthmatic and healthy children from locations with various environments. AB - Gene expression levels are significantly regulated by DNA methylation. Differences in gene expression profiles in the populations from various locations with different environmental conditions were repeatedly observed. In this study we compare the methylation profiles in 200 blood samples of children (aged 7-15 years) with and without bronchial asthma from two regions in the Czech Republic with different levels of air pollution (a highly polluted Ostrava region and a control Prachatice region). Samples were collected in March 2010 when the mean concentrations of benzo[a]pyrene (B[a]P) measured by stationary monitoring were 10.1+/-2.4ng/m(3) in Ostrava Bartovice (5.6 times higher than in the control region). Significantly higher concentrations of other pollutants (benzene, NO2, respirable air particles and metals) were also found in Ostrava. We applied the Infinium Methylation Assay, using the Human Methylation 27K BeadChip with 27,578 CpG loci for identification of the DNA methylation pattern in studied groups. Results demonstrate a significant impact of different environmental conditions on the DNA methylation patterns of children from the two regions. We found 9916 CpG sites with significantly different methylation (beta value) between children from Ostrava vs. Prachatice from which 58 CpG sites had differences >10%. The methylation of all these 58 CpG sites was lower in children from polluted Ostrava, which indicates a higher gene expression in comparison with the control Prachatice region. We did not find a difference in DNA methylation patterns between children with and without bronchial asthma in individual locations, but patterns in both asthmatics and healthy children differed between Ostrava and Prachatice. Further, we show differences in DNA methylation pattern depending on gender and urinary cotinine levels. Other factors including length of gestation, birth weight and length of full breastfeeding are suggested as possible factors that can impact the DNA methylation pattern in future life. PMID- 23458557 TI - Intraoperative use of diffusion tensor imaging-based tractography for resection of gliomas located near the pyramidal tract: comparison with subcortical stimulation mapping and contribution to surgical outcomes. AB - INTRODUCTION: For gliomas, the goal of surgery is maximal tumour removal with the preservation of neurological function. We evaluated the contribution of the combination of diffusion tensor imaging-based fibre tracking (DTI-FT) of the pyramidal tract (PT) integrated to the navigation and subcortical direct electrical stimulations (DESs) to surgical outcomes. METHOD: Ten patients underwent surgery for gliomas located in close relationship with the subcortical course of the PT. Preoperative DTI was performed with a three-Tesla magnetic resonance scanner applying an echo-planar sequence with 20 diffusion directions. DTI-FT data were systematically loaded into the navigation for intraoperative guidance. When the resection closely approached the PT as illustrated on navigation images, subcortical DESs were used to confirm the proximity of the PT by observing motor responses. The location of all subcortically stimulated points with positive motor response was correlated with the illustrated PT. Motor deficits were evaluated pre- and postoperatively, and compared with the extent of tumour removal. RESULTS: DTI-FT of the PT was successfully performed in all patients. A total of fifteen positive subcortical DESs were obtained in 8 of 10 patients; in these cases, the mean distance from the stimulated point to the PT was 6.2 +/- 3.6 mm. The mean tumoural volumetric resection was 90.8 +/- 10.4%, with a gross total resection in four patients. At one month after surgery, only one patient had a slight impairment of motor function (decreased fine motor hand skills). CONCLUSIONS: DTI-FT is an accurate technique to map the PT in the vicinity of brain tumours. By combining anatomical (DTI-FT) and functional (subcortical DES) studies for intraoperative localization of the PT, the authors achieved a good volumetric resection of tumours located in eloquent motor areas, with low morbidity. Careful use of this protocol requires the knowledge of some pitfalls, mainly the occurrence of brain shift during removal of large tumours. PMID- 23458558 TI - Opportunistic Fonsecaea pedrosoi brain abscess in a patient with non-cirrhotic portal fibrosis-induced hypersplenism--a novel association. AB - Non-cirrhotic portal fibrosis, a common cause of splenomegaly in tropical countries, can lead to hypersplenism and pancytopenia. Hypersplenism in this setting has not been associated with opportunistic infections. We describe a patient with hypersplenism secondary to non-cirrhotic portal fibrosis who developed a Fonsecaea pedrosoi brain abscess and succumbed to the illness despite aggressive management. PMID- 23458559 TI - The volumetric relationship of white matter lesion and contrast-enhanced lesion in delayed radiation brain injury: an MRI-based study. AB - PURPOSE: This study investigated the volumetric relationship of white matter lesion (WML) and contrast-enhanced lesion (CEL) in delayed radiation brain injury (RBI) during the course of evolution. MATERIALS AND METHODS: MRI results in 45 patients with RBI after receiving radiation for nasopharyngeal carcinoma were analyzed. In total there were 75 lobes with RBI and 114 MRI examinations in this study. WML and CEL lesion volumes were measured. The lesion volume change of less than 5% or 0.25 cm(3) was regarded as being static. RESULTS: The average WML volume was 16.33 cm(3) (ranging 0.11 cm(3) to 102.83 cm(3)), and the average CEL volume was 3.15 cm(3) (ranging 0.03 cm(3) to 27.85 cm(3)). WML was larger than CEL in 164 measurements, and CEL was larger than WML in 10 measurements. In 64.3% follow-ups WML and CEL evolved in the same pattern; and in most follow-ups (93.8%) WML and CEL did not evolve in the opposite directions. A larger WML volume tended to have a larger CEL volume though this relationship was not linear. CONCLUSION: Evolution of WML and CEL tended to follow the same pattern. WML tended to be larger than CEL, and larger WML tended to be associated with larger CEL. PMID- 23458560 TI - Diagnostic pitfalls associated with a large true posterior communicating artery aneurysm: a case report. AB - True posterior communicating artery (PCoA) aneurysm is an aneurysm that originates from the PCoA, and large or giant true PCoA aneurysms are rare. We report a case of a large true PCoA aneurysm successfully clipped after anterior clinoidectomy and discuss the diagnostic pitfalls associated with this rare clinical entity. PMID- 23458561 TI - The role of brain shift, patient age, and Parkinson's disease duration in the difference between anatomical and electrophysiological targets for subthalamic stimulation. AB - INTRODUCTION: Although microrecording is common in subthalamic stimulation, microelectrode monitoring prolongs surgical time and may increase the risk of haemorrhagic complications. The main reason for electrophysiological mapping is the discrepancy between the calculated anatomical and final electrophysiological targets. The aim of this paper is to describe the relationship between anatomical and electrophysiological targets defined as the best electrophysiological recordings from multiple parallel electrode tracts, explaining the target discrepancy with attention paid to the role of brain shift and patient- and disease-related factors. MATERIALS AND METHODS: Subthalamic electrodes were stereotactically implanted in 58 patients using microrecording by means of parallel electrodes at defined distances. The relationship between the final electrode placement to its anatomical trajectory and the relationship between the definitive electrodes implanted on the right and left sides were analysed, as was the influence of patient age, Parkinson's disease duration, and late motor complications duration. RESULTS: Final electrode placement matched the anatomical trajectory in 53.4% of patients on the right side and 43.1% of patients on the left side. Electrode positions were symmetrical in 38.3% of patients. The analysis of left and right electrode positions does not prove a statistically significant prevalence of lateral and posterior final electrode trajectories as could be expected from lateral and posterior movements of the brain caused by brain shift, although there was some tendency for a larger percentage of lateral electrodes on the left side. Age, Parkinson's disease duration, and L-DOPA effect duration were not confirmed as responsible factors. CONCLUSIONS: The difference between anatomical trajectory and final electrode placement supports the use of functional microelectrode monitoring in subthalamic deep brain stimulation. Brain shift is not the only causative factor of the difference. The possible roles of age, Parkinson's disease duration, and late motor complications duration were also not confirmed by study results. PMID- 23458562 TI - Kinetics of the gas phase reaction CH3 + HO2. AB - Reaction of methyl radicals with hydroperoxy radicals, CH3 + HO2 -> products (1) was studied using pulsed laser photolysis coupled to transient UV-vis absorption spectroscopy at 295 K and 1 bar (He). Photolysis of N2O/H2O2/CH4/H2O/He mixtures at 193.3 nm (ArF excimer laser) was used to simultaneously produce methyl radicals and hydroperoxy radicals in reactions of electronically excited oxygen atoms O((1)D) with CH4 and OH radicals with H2O2, respectively. Temporal profiles of CH3 and HO2 were recorded via absorption at 216.4 and 224 nm. The absolute intensity of the photolysis light inside the reactor was determined by an accurate in situ actinometry based on the ozone formation in the presence of molecular oxygen. The measured rate constant of reaction 1 is k1 = (3.7 +/- 1.8 * 10(-11) cm(3) molecule(-1) s(-1) (295 K, 1 bar, He). PMID- 23458563 TI - Sexual dysfunction and sex therapy: an historical perspective. AB - Summary Sexual dysfunction has been reported across cultures and across time. The Hindu literature and the Ayurvedic system offer insights into assessment and management of various kinds of sexual dysfunction. Behavioural regimes were fairly well known in the traditional Ayurvedic texts. Religious writings have often proved to be the richest source of information about sexual behaviour. The relationship between the nature of creation, the need for reproduction and the importance of sex in life has often been discussed in religions. Artificial sexual aids were well known in both ancient China and India. This paper attempts to draw an historical analysis of varieties of sexual dysfunction across various societies. It also comments on the historical development of sex therapy. PMID- 23458564 TI - Passive administration of purified secretory IgA from human colostrum induces protection against Mycobacterium tuberculosis in a murine model of progressive pulmonary infection. AB - BACKGROUND: Immunoglobulin A is the most abundant isotype in secretions from mucosal surfaces of the gastrointestinal, respiratory and genitourinary tracts and in external secretions such as colostrum, breast milk, tears and saliva. The high concentration of human secretory IgA (hsIgA) in human colostrum strongly suggests that it should play an important role in the passive immune protection against gastrointestinal and respiratory infections. MATERIALS AND METHODS: Human secretory IgA was purified from colostrum. The reactivity of hsIgA against mycobacterial antigens and its protective capacity against mycobacterial infection was evaluated. RESULTS: The passive administration of hsIgA reduces the pneumonic area before challenge with M. tuberculosis. The intratracheal administration of M. tuberculosis preincubated with hsIgA to mice greatly reduced the bacterial load in the lungs and diminished lung tissue injury. CONCLUSIONS: HsIgA purified from colostrum protects against M. tuberculosis infection in an experimental mouse model. PMID- 23458565 TI - Severe ulceronecrotic dermatitis associated with mite infestation in the critically endangered Amargosa vole (Microtus californicus scirpensis). AB - The entire range of the critically endangered Amargosa vole (Microtus californicus scirpensis) consists of less than 20 km(2) of riparian habitat in the Amargosa River drainage of the Mojave Desert in southern California. In September 2010, deformities on ears and chiggers on the ears and genitalia were detected, with some individuals so severely affected that they were missing ear pinnae altogether. Follow-up trapping was performed to document the presence of mites and mite-associated disease, and molecular characterization was performed on the mites. Of 151 Amargosa voles sampled from February to April of 2011, 60 (39.7%) voles had hard orange mites adhered to some part of their bodies, on ears of 46 (76.7%), on genitalia of 11 (18.3%), and near mammary tissue of 13 (21.7%) voles. Gross lesions were not detected on genitalia, but 47% of all individuals examined showed pinnal lesions and deformities, which included alopecia, swelling, marginal necrosis, and ulceration, as well as scarring, scabbing, and loss of pinna mass covering 25-100% of the pinnae. Biopsies revealed parakeratotic hyperkeratosis and acanthosis with diffuse neutrophilic exocytosis and dense necrotic granulocytes in the epidermis and superficial dermis associated with focal erosion and ulceration. In the underlying dermis, there were dense pleocellular inflammatory cell infiltrates composed primarily of necrotic granulocytes and multifocal hemorrhage. In some samples, mite mouthparts could be seen penetrating the superficial epidermis associated with focal necrosis, and mite fragments were found on the surface epidermis and within hair follicles. Microscopic examination of the mites documented that they were a larval trombiculid in the genus Neotrombicula with anatomical features that most closely resemble Neotrombicula microti, based on scutal shape, setation, and texture. PCR of 2 mite pools (each consisting of 3 mites from an individual animal) amplified 331 bp amplicons, which had 92-97% homology with the 18S rRNA gene of Leptotrombidium deliense, although coverage of Trombiculidae in GenBank is sparse. The severity and prevalence of lesions due to this chigger were atypical and distinct. Severe clinical trombiculiasis in this endangered species could negatively impact individual health and fitness. PMID- 23458566 TI - Nonremoval of immediate abutments in cases involving subcrestally placed postextractive tapered single implants: a randomized controlled clinical study. AB - PURPOSE: The aim of this trial was to assess if the nonremoval of abutments placed at the time of surgery would improve bone and gingival healing around single immediately restored implants placed in postextraction sockets. MATERIALS AND METHODS: All patients received a single square-threaded tapered implant placed in postextraction sockets and immediately restored. All the implants were placed 2.0 mm below the bone crest, avoiding any contact with the coronal portion of the buccal wall. Six months after surgery, 35 patients were treated following the control standard prosthetic protocol: the abutments were removed and impressions were made directly on the implant platform. Thirty-three patients underwent the "one abutment at one time" test protocol: impressions were made of the abutments using snap-on abutment copies. The dimensional changes of the soft and hard tissues were assessed using digital photography and cone beam computed tomography radiographs immediately after surgery and at 6-, 12-, and 24-month follow-up examinations. RESULTS: All implants were osseointegrated and clinically stable at the follow-up examinations. No statistically significant difference was evidenced between the two groups regarding the measurement of vertical bone healing. After the placement of the final restoration, a significant horizontal loss in the hard tissue portion over the implant platform was assessed (p = .03 mesial sites; p = .04 distal sites). An 87% increase of the mean recession of the buccal soft tissue was observed in the control group (+0.27 mm) in the same time frame. CONCLUSIONS: The nonremoval of abutments placed at the time of the surgery improves the stability of healed soft and hard tissues around the immediately restored, subcrestally placed tapered single maxillary implant. PMID- 23458567 TI - Liver resection for colorectal liver metastases with peri-operative chemotherapy: oncological results of R1 resections. AB - BACKGROUND: Retrospective analysis of outcomes of R0 (negative margin) versus R1 (positive margin) liver resections for colorectal metastases (CLM) in the context of peri-operative chemotherapy. METHODS: All CLM resections between 2000 and 2006 were reviewed. Exclusion criteria included: macroscopically incomplete (R2) resections, the use of local treatment modalities, the presence of extra-hepatic disease and no peri-operative chemotherapy. R0/R1 status was based on pathological examination. RESULTS: Of 86 eligible patients, 63 (73%) had R0 and 23 (27%) had R1 resections. The two groups were comparable for the number, size of metastases and type of hepatectomy. The R1 group had more bilobar CLM (52% versus 24%, P = 0.018). The median follow-up was 3.1 years. Five-year overall and disease-free survival were 54% and 21% for the R0 group and 49% and 22% for the R1 group (P = 0.55 and P = 0.39, respectively). An intra-hepatic recurrence was more frequent in the R1 group (52% versus 27%, P = 0.02) and occurred more frequently at the surgical margin (22% versus 3%, P = 0.01). DISCUSSION: R1 resections were associated with a higher risk of intra-hepatic and surgical margin recurrence but did not negatively impact survival suggesting that in the era of efficient chemotherapy, the risk of an R1 resection should not be considered as a contraindication to surgery. PMID- 23458568 TI - Primary versus delayed repair for bile duct injuries sustained during cholecystectomy: results of a survey of the Association Francaise de Chirurgie. AB - BACKGROUND: Bile duct injuries (BDIs) sustained during a cholecystectomy still remain a major surgical problem, and it is still not clear whether the injury should be repaired immediately or a delayed repair is preferred. METHODS: A retrospective national French survey was conducted to compare the results of immediate (at time of cholecystectomy), early (within 45 days after a cholecystectomy) and late (beyond 45 days after a cholecystectomy) surgical repair for BDI sustained during a cholecystectomy. RESULTS: Forty-seven surgical centres provided 640 cases of bile duct injury sustained during a cholecystectomy of which 543 were analysed for the purpose of the present study. The timing of repair was immediate in 194 cases (35.7%), early in 216 cases (39.8%) and late in 133 cases (24.5%). The type of repair was a suture repair in 157 cases (81%), and a bilio-digestive reconstruction in 37 cases (19%) for immediate repair; a suture repair in 119 cases (55.1%) and a bilio-digestive anastomosis in 96 cases (44.9%) for the early repair; and a bilio-digestive reconstruction in 129 cases (97%) and a suture repair in 4 cases (3%) for late repair. A second procedure was required in 110 cases (56.7%) for immediate repair, 80 cases (40.7%) for early repair (P < 0.05) and in 9 cases (6.8%) for late repair (P < 0.001). CONCLUSION: The timing of surgical repair for a bile duct injury sustained during a cholecystectomy influences significantly the rate of a second procedure and a late repair should be preferred option. PMID- 23458569 TI - Regioselective covalent immobilization of catalytically active glutathione S transferase on glass slides. AB - The high selectivity of protein farnesyltransferase was used to regioselectively append farnesyl analogues bearing bioorthogonal alkyne and azide functional groups to recombinant Schistosoma japonicum glutathione S-transferase (GSTase) and the active modified protein was covalently attached to glass surfaces. The cysteine residue in a C-terminal CVIA sequence appended to N-terminally His(6) tagged glutathione S-transferase (His(6)-GSTase-CVIA) was post-translationally modified by incubation of purified protein or cell-free homogenates from E. coli M15/pQE-His(6)-GSTase-CVIA with yeast protein farnesyltransferase (PFTase) and analogues of farnesyl diphosphate (FPP) containing omega-azide and alkyne moieties. The modified proteins were added to wells on silicone-matted glass slides whose surfaces were modified with PEG units containing complementary omega alkyne and azide moieties and covalently attached to the surface by a Cu(I) catalyzed Huisgen [3 + 2] cycloaddition. The wells were washed and assayed for GSTase activity by monitoring the increase in A(340) upon addition of 1-chloro 2,4-dinitrobenzene (CDNB) and reduced glutathione (GT). GSTase activity was substantially higher in the wells spotted with alkyne (His(6)-GSTase-CVIA-PE) or azide (His(6)-GSTase-CVIA-AZ) modified glutathione-S-transferase than in control wells spotted with farnesyl-modified enzyme (His(6)-GSTase-CVIA-F). PMID- 23458570 TI - Larval development and emergence sites of farm-associated Culicoides in the United Kingdom. AB - Culicoides biting midges (Diptera: Ceratopogonidae) are the biological vectors of internationally important arboviruses of livestock including bluetongue virus (BTV). Information on the habitats used by Culicoides for larval development is valuable for establishing targeted vector control strategies and for improving local scale models of vector abundance. This study combines emergence trap collections of adult Culicoides identified using molecular markers and physiochemical measurements of habitats to investigate larval development sites of Palaearctic Culicoides in South East England. The known range of larval habitats for several Culicoides species is extended and the potential BTV vector species C. obsoletus and C. scoticus are confirmed to co-occur in many larval habitats. The presence of emerging C. obsoletus was favoured by increasing substrate moisture level [odds ratio (OR) 6.94 (2.30; 20.90)] and substrate pH [OR 4.80 (1.66; 13.90)] [bias-corrected Dxy : 0.68; area under the curve (AUC): 0.86] rather than any particular larval habitat type, as expected for a species with relatively wide larval habitat preference. Of the newly emerged sub-genus Avaritia individuals collected, 23% were observed to have a degree of abdominal pigmentation commonly inferred to indicate parity. If consistent across species and locations, this observation represents a potential source of error for age structure analyses of Culicoides populations. PMID- 23458571 TI - Electrostatically driven second-sphere ligand switch between high and low reorganization energy forms of native cytochrome c. AB - We have employed a combination of protein film voltammetry, time-resolved vibrational spectroelectrochemistry and molecular dynamics simulations to evaluate the electron-transfer reorganization free energy (lambda) of cytochrome c (Cyt) in electrostatic complexes that mimic some basic features of protein protein and protein-lipid interactions. The results reveal the existence of two native-like conformations of Cyt that present significantly different lambda values. Conversion from the high to the low lambda forms is triggered by electrostatic interactions, and involves the rupture of a weak H-bond between first- (M80) and second-sphere (Y67) ligands of the heme iron, as a distinctive feature of the conformational switch. The two flexible Omega loops operate as transducers of the electrostatic signal. This fine-tuning effect is abolished in the Y67F Cyt mutant, which presents a lambda value similar to the WT protein in electrostatic complexes. We propose that interactions of Cyt with the natural redox partner proteins activate a similar mechanism to minimize the reorganization energy of interprotein electron transfer. PMID- 23458572 TI - Polyplex exposure inhibits cell cycle, increases inflammatory response, and can cause protein expression without cell division. AB - We sought to evaluate the relationship between cell division and protein expression when using commercial poly(ethylenimine) (PEI)-based polyplexes. The membrane dye PKH26 was used to assess cell division, and cyan fluorescent protein (CFP) was used to monitor protein expression. When analyzed at the whole population level, a greater number of cells divided than expressed protein, regardless of the level of protein expression observed, giving apparent consistency with the hypothesis that protein expression requires cells to pass through mitosis in order for the transgene to overcome the nuclear membrane. However, when the polyplex-exposed population was evaluated for the amount of division in the protein-expressing subpopulation, it was observed that substantial amounts of expression had occurred in the absence of division. Indeed, in HeLa S3 cells, this represented the majority of expressing cells. Of interest, the doubling time for both cell lines was slowed by ~2-fold upon exposure to polyplexes. This change was not altered by the origin of the plasmid DNA (pDNA) transgene promoter (cytomegalovirus (CMV) or elongation factor-1 alpha (EF1alpha)). Gene expression arrays in polyplex-exposed HeLa S3 cells showed upregulation of cell cycle arrest genes and downregulation of genes related to mitosis. Chemokine, interleukin, and toll-like receptor genes were also upregulated, suggesting activation of proinflammatory pathways. In summary, we find evidence that a cell division-independent expression pathway exists, and that polyplex exposure slows cell division and increases inflammatory response. PMID- 23458574 TI - Coagulopathy after a liver resection: is it over diagnosed and over treated? AB - BACKGROUND: Prothrombin time-international normalized ratio (PT-INR) is widely utilized to guide plasma therapy and initiation of thromboprophylaxis after a hepatectomy. Thrombelastography (TEG) monitors shear elasticity, which is sensitive to cellular and plasma components in blood, allowing for functional assessment of the life of the clot. The objective of this study was to prospectively compare PT-INR and TEG in liver resection patients. METHODS: Forty patients were enrolled before undergoing an elective hepatectomy. Patients underwent a liver resection utilizing a low central venous pressure (CVP) anaesthetic technique and intermittent Pringle manoeuver. PT-INR and TEG were drawn prior to incision, post-operatively, and post-operative days 1, 3 and 5. RESULTS: All post-operative PT-INR values increased significantly when compared with pre-operative PT-INR (P < 0.01). The time of onset to clot (R-value) decreased significantly at the post-operative time point (P = 0.04), consistent with a relative hypercoagulability. Subsequent R-values were not different compared with the pre-operative R-value. The strength of the clot (maximum amplitude, MA) was unchanged when comparing pre- and post-operative time points. DISCUSSION: In spite of an elevation in PT-INR, patients undergoing a liver resection demonstrated a brief hypercoagulable state, followed by normal coagulation function based on TEG. These data call into question the practice of utilizing PT-INR to guide plasma transfusion and timing of prophylactic anticoagulation after a liver resection. PMID- 23458575 TI - Targeting mitochondria for cardiac protection. AB - The critical role of mitochondria in cardiomyocyte survival and death has become an exciting field of research in cardiac biology. Indeed, it is accepted that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. Besides the obvious relevance of mitochondria in energy production, calcium homeostasis, and reactive oxygen species (ROS) production, new processes like mitochondrial fusion/fission, phosphorylation and nitrosylation modifications in mitochondrial proteins have been suggested to form part of a cast of key players in cardiac disease. This review describes currently studied drugs and compounds that target mitochondria in the scenario of cardiovascular diseases. PMID- 23458576 TI - Laboratory training in the retrosigmoid approach using cadaveric silicone injected cow brain. AB - BACKGROUND: A neurosurgical laboratory training model is designed for trainees in microneurosurgery to learn to handle surgical microscopes and microneurosurgical instruments. The silicone injection of a fresh cadaveric cow cranium is an alternative to using a cadaveric human brain for becoming familiar with the cerebellopontine angle (CPA) via the retrosigmoid approach. To report an improved method for training in the CPA via the retrosigmoid approach, using a fresh cadaveric cow cranium injected with silicone. METHODS: The material consists of a cadaveric cow brain injected with silicone. Preparation consists of irrigation of the major vessels followed by injection of silicone, coloured either red or blue. RESULTS: A three-step approach was designed to simulate microneurosurgical dissection along with the cerebellopontine angle and to dissect cranial nerves emerging from the brain stem. CONCLUSION: This laboratory training model is useful in allowing trainees to gain experience with the use of an operating microscope and familiarity with the CPA via the retrosigmoid approach. The aim of this study was to develop a novel model and to adapt it to create a life-like neurosurgical training system. PMID- 23458573 TI - PET studies in nonhuman primate models of cocaine abuse: translational research related to vulnerability and neuroadaptations. AB - The current review highlights the utility of positron emission tomography (PET) imaging to study the neurobiological substrates underlying vulnerability to cocaine addiction and subsequent adaptations following chronic cocaine self administration in nonhuman primate models of cocaine abuse. Environmental (e.g., social rank) and sex-specific influences on dopaminergic function and sensitivity to the reinforcing effects of cocaine are discussed. Cocaine-related cognitive deficits have been hypothesized to contribute to high rates of relapse and are described in nonhuman primate models. Lastly, the long-term consequences of cocaine on neurobiology are discussed. PET imaging and longitudinal, within subject behavioral studies in nonhuman primates have provided a strong framework for designing pharmacological and behavioral treatment strategies to aid drug dependent treatment seekers. Non-invasive PET imaging will allow for individualized treatment strategies. Recent advances in radiochemistry of novel PET ligands and other imaging modalities can further advance our understanding of stimulant use on the brain. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. PMID- 23458577 TI - The use of metered-dose inhalers in hospital environments. AB - BACKGROUND: Metered-dose inhalers (MDIs) have become a firsthand therapeutic strategy for the management of respiratory diseases, mainly for chronic obstructive pulmonary disease (COPD) and asthma. It has been determined, however, that patients do not always use these devices correctly. Our primary goal was to establish the level of technical knowledge of patients with COPD and/or asthma on the use of MDIs, as well as other associated factors related to the effective use of this delivery method. METHODOLOGY: This study was performed with 191 patients (49.2% male, 50.8% female) diagnosed with COPD and/or asthma at Hospital Universitario Mayor (Bogota, Colombia). The agreement between different observers on nine aspects of the use of the inhaler was assessed by testing the unweighted kappa correlation coefficient and its significance. The correlations between demographic variables, risk factors, and proper knowledge of the adequate use of inhalers were established by means of the Pearson chi-square test (also called Fisher exact test) (expected values less than 5). Statistical tests were evaluated at a significance level equivalent to 5% (p<0.05). RESULTS AND CONCLUSIONS: The study detected deficiencies in educational factors, specifically regarding the initial contact with the patient and regular follow-up by the team of health professionals. It also showed insufficient strategies for the training of patients in the use of the inhalers. There were no significant differences by gender (p>0.05) in the implementation of the various aspects of the proper use sequence for MDIs. However, there were significant differences related to education levels, socioeconomic status, age, and current occupation. A worse inhaler technique was associated with lower education level (0.034), higher age (p=0.003), and absence of job (p=0.005). Changes in the education of patients on the issue, together with the use of the spacer/valved holding chamber proved to be valid strategies that, with the support of the patients' health-care team, were able to improve the MDI technique of the studied group. PMID- 23458578 TI - Pilot scale production of the vaccine adjuvant Proteoliposome derived Cochleates (AFCo1) from Neisseria meningitidis serogroup B. AB - The use of new adjuvants in vaccine formulations is a subject of current research. Only few parenteral adjuvants have been licensed. We have developed a mucosal and parenteral adjuvant known as AFCo1 (Adjuvant Finlay Cochleate 1, derived from proteoliposomes of N. meningitidis B) using a dialysis procedure to produce them on lab scale. The immunogenicity of the AFCo1 produced by dialysis has been already evaluated, but it was necessary to demonstrate the feasibility of a larger-scale manufacturing process. Therefore, we used a crossflow diafiltration system (CFS) that allows easy scale up to obtain large batches in an aseptic environment. The aim of this work was to produce AFCo1 on pilot scale, while conserving the adjuvant properties. The proteoliposomes (raw material) were resuspended in a buffer containing sodium deoxycholate and were transformed into AFCo1 under the action of a calcium forming buffer. The detergent was removed from the protein solution by diafiltration to a constant volume. In this CFS, we used a hollow fiber cartridge from Amicon (polysulfona cartridge of 10 kDa porosity, 1mm channel diameter of fiber and 0.45 m2 area of filtration), allowing production of a batch of up to 20 L. AFCo1 were successfully produced by tangential filtration to pilot scale. The batch passed preliminary stability tests. Nasal immunization of BALB/c mice, induced specific saliva IgA and serum IgG. The induction of Th1 responses were demonstrated by the induction of IgG2a, IFNgamma and not IL-5. The adjuvant action over Neisseria (self) antigens and with co-administered (heterologous) antigens such as ovalbumin and a synthetic peptide from haemolytic Streptococcus B was also demonstrated. PMID- 23458580 TI - EMS spinal precautions and the use of the long backboard. AB - This is the official position of the National Association of EMS Physicians and the American College of Surgeons Committee on Trauma regarding emergency medical services spinal precautions and the use of the long backboard. PMID- 23458579 TI - Are two-stage hepatectomies associated with more complications than one-stage procedures? AB - BACKGROUND: Two-stage liver resections with portal vein occlusion have become standard in patients with low volume future liver remnants. Whether they are associated with more complications is unclear. The aim of this study was to compare complications of one- and two-stage resections in a retrospective study. METHODS: Patients with two-stage right liver resections with a previous portal vein occlusion were compared with patients with one-stage right liver resections between 2002 and 2010. Primary endpoints were the incidence of complications by severity. Secondary endpoints were mortality, post-operative liver- and kidney function tests, length of hospitalization and transfusion events. Logistic and linear regression analyses were performed to adjust for confounders. RESULTS: The groups were comparable except for right trisectionectomies, pre-operative chemotherapy and underlying liver disease. Overall complications occurred in 25 out of 35 patients with two-stage and 106 out of 163 in one-stage procedures. Severe complications were observed in 47 out of 163 patients versus 9 out of 35 patients, respectively. Two-stage procedures had no increased adjusted risk for complications [relative risk (RR) 0.9, P = 0.79]. Mortality (5.7% versus 3.7%) and post-operative liver failure rates (2.9% versus 3.1%) were low. Secondary endpoints showed no adjusted differences in risk. CONCLUSION: This study suggests that liver resections in two stages are not associated with more post-operative complications than one-stage resections. These results should support the adoption of two-stage liver resections in selected patients. PMID- 23458581 TI - Electronic transitions of protonated and deprotonated amino acids in aqueous solution in the region 145-300 nm studied by attenuated total reflection far ultraviolet spectroscopy. AB - The electronic transitions of 20 naturally occurring amino acids in aqueous solution were studied with attenuated total reflection far-ultraviolet (ATR-FUV) spectroscopy in the region from 145 to 300 nm. From the measured ATR spectra of sample solutions, the FUV absorption spectra attributed to the amino acids were separated from the intense solvent absorption by using a modified Kramers-Kronig transformation method. The FUV absorption spectra of the amino acids reflect the protonation states of the backbone and side-chain structures. The contributions of the side chains to the spectra were also examined from the difference spectra subtracting the corresponding Gly spectrum from each spectrum. The observed spectra were compared mostly with the electronic transition studies of the molecular fragments of the amino acids in gas phase. The FUV spectra of the amino acids exhibited the intra- and intermolecular electronic interactions of the solute-solute as well as the solute-solvent, and those are essential factors to elucidate UV photochemical processes of the amino acids in aqueous solution. PMID- 23458582 TI - High rates of uncontrolled blood pressure in the United States: does this represent a missed opportunity for healthcare providers? PMID- 23458583 TI - Lifestyle intervention and hypertension. PMID- 23458584 TI - Diastolic blood pressure and hypertension phenotypes: the US Food and Drug Administration has it right. PMID- 23458585 TI - ASH position paper: evaluation and treatment of orthostatic hypotension. AB - This paper provides recommendations on the treatment of orthostatic hypotension (OH) as reviewed by the American Society of Hypertension. It focuses on recent reports on the evaluation and management of OH and provides practical advice for clinicians on how to screen, diagnose, and treat patients using behavioral, nonpharmacologic, and pharmacologic strategies. The authors also provide a stepwise approach on how to apply new findings to successfully control OH and reduce the risk of syncope and falls in these patients. Treatment of OH is also discussed in special situations such as in hypertensive and hospitalized patients. It should be noted, however, that research in this area is mostly limited to studies in small numbers of patients. Unfortunately, the trials of the type needed to develop evidence-based guidelines are not available for this condition. PMID- 23458586 TI - Different definitions of prevalent hypertension impact: the clinical epidemiology of hypertension and attainment of Healthy People goals. AB - Prevalent hypertension in National Health and Nutrition Examination Surveys (NHANES) is traditionally defined as blood pressure (BP) >=140 mm Hg systolic and/or >=90 diastolic and/or currently taking antihypertensive medications. When estimating prevalent hypertension, American Heart Association (AHA) statistical updates include the traditional definition of hypertension (tHTN) and untreated individuals with nonhypertensive BP told twice that they were hypertensive (nontraditional [ntHTN]). The characteristics of ntHTN and their impact on the clinical epidemiology of hypertension and Healthy People prevention and control goals are undefined. NHANES 1999-2002, 2003-2006, and 2007-2010 were analyzed. The ntHTN group was younger and had less diabetes and lower BP than the tHTN group but higher BP than the normotensive group. When classifying ntHTN as hypertensive, prevalent hypertension increased approximately 3% and control 5% to 6% across NHANES periods. In 2007-2010, the Healthy People 2010 goal of controlling BP in 50% of all hypertensive patientss was attained when ntHTN was classified as hypertension (56.5% [95% confidence interval (CI), 54.2-58.7]) and nonhypertension (51.8% [95% CI, 49.6-53.9]). When including ntHTN in prevalent hypertension estimates, the Healthy People 2020 goal of controlling BP in 60% of hypertensive patients becomes more attainable, whereas reducing prevalent hypertension to 26.9% (31.8% [95% CI, 30.5-33.1]) vs 28.7% [95% CI, 27.5-30.0]) becomes more challenging. PMID- 23458587 TI - The interplay of exercise heart rate and blood pressure as a predictor of coronary artery disease and arterial hypertension. AB - Delayed blood pressure (BP) and heart rate (HR) decline at recovery post-exercise are independent predictors of incident coronary artery disease (CAD). Delayed BP recovery and exaggerated BP response to exercise are independent predictors of future arterial hypertension (AH). This study sought to examine whether the combination of two exercise parameters provides additional prognostic value than each variable alone. A total of 830 non-CAD patients (374 normotensive) were followed for new-onset CAD and/or AH for 5 years after diagnostic exercise testing (ET). At the end of follow-up, patients without overt CAD underwent a second ET. Stress imaging modalities and coronary angiography, where appropriate, ruled out CAD. New-onset CAD was detected in 110 participants (13.3%) whereas AH was detected in 41 former normotensives (11.0%). The adjusted (for confounders) relative risk (RR) of CAD in abnormal BP and HR recovery patients was 1.95 (95% confidence interval [CI], 1.28-2.98; P=.011) compared with delayed BP and normal HR recovery patients and 1.71 (95% CI, 1.08-2.75; P=.014) compared with normal BP and delayed HR recovery patients. The adjusted RR of AH in normotensives with abnormal BP recovery and response was 2.18 (95% CI, 1.03-4.72; P=.047) compared with delayed BP recovery and normal BP response patients and 2.48 (95% CI, 1.14 4.97; P=.038) compared with normal BP recovery and exaggerated BP response individuals. In conclusion, the combination of two independent exercise predictors is an even stronger CAD/AH predictor than its components. PMID- 23458588 TI - Estimated glomerular filtration rate reversal by blood pressure lowering in chronic kidney disease: Japan Multicenter Investigation for Cardiovascular DiseaseB CKD study. AB - Patients are diagnosed as having chronic kidney disease (CKD) if estimated glomerular filtration rate (eGFR) is <60 mL/min/1.73 m(2) . Low eGFR is likely to increase the incidence of cardiovascular events and lead to dialysis. Therefore, it is important to prevent eGFR from decreasing eGFR. However, it still remains unknown whether antihypertensive therapy can prevent low eGFR from becoming even lower and improve eGFR in hypertensive patients with CKD. The authors analyzed the results of the Japan Multicenter Investigation for Cardiovascular DiseaseB (JMIC-B) and investigated the effects of antihypertensive therapy on eGFR. In hypertensive patients with CKD (eGFR <60), eGFR was significantly increased from 51.87+/-6.21 (n=98) to 57.55+/-19.00 (P<.001) after 3 years of antihypertensive therapy. In patients without CKD (eGFR >=60), eGFR was significantly decreased from 91.84+/-23.27 (n=682) to 88.95+/-23.67 (P<.001). Regardless of the type of antihypertensive drugs used, eGFR was significantly increased in patients with CKD and was significantly decreased in patients without CKD. This paper shows that antihypertensive therapy can improve eGFR in hypertensive patients with CKD. J Clin Hypertens (Greenwich). 2012;00:00-00. (c)2012 Wiley Periodicals, Inc. PMID- 23458589 TI - Oscillometric carotid to femoral pulse wave velocity estimated with the Vicorder device. AB - Carotid to femoral pulse wave velocity (PWV) is associated with an increase in cardiovascular morbidity and all-cause mortality. Noninvasive approach has made this method applicable for the examination of larger populations. This study aimed to obtain reference values of PWV measured with the Vicorder device. PWV was obtained using the oscillometric Vicorder in 318 healthy, normotensive patients (165 women, 28.7+/-17.6 years, range 6-83 years). A plethysmographic sensor was placed over the right carotid region to pick up the carotid pulse wave and a blood pressure cuff was placed around the upper thigh to trace the femoral pulse wave. Path length was defined as the distance from the suprasternal notch to the top of the thigh cuff. Mean PWV was 6.1+/-1.4 m/s and significantly increased with age (r=.842; P<.0001). PWV was associated with mean arterial pressure (r=.546; P<.0001) and body mass index (r=.396; P<.0001). In a multiple linear regression model, age, mean arterial pressure, and body height emerged as independent markers for PWV. This study established reference values for carotid to femoral PWV derived by oscillometric measures that can now be used for risk stratification. PMID- 23458590 TI - Integrating self blood pressure monitoring into the routine management of uncontrolled hypertension: translating evidence to practice. AB - Improving hypertension control is a public health priority and could reduce health disparities. Self blood pressure monitoring (SBPM) is effective but not widely integrated into clinical care. A pragmatic study distributing blood pressure (BP) monitors was conducted to assess its effectiveness in the management of uncontrolled hypertension under conditions consistent with clinic resources. Patients, predominantly black and Hispanic adults from clinics in low income, medically underserved communities with uncontrolled BP were enrolled. Follow-up assessments were conducted 9 months after enrollment. Approximately half (53%) of the patients had controlled hypertension at follow-up. Systolic and diastolic BP decreased by 18.7 mm Hg and 8.5 mm Hg, respectively, at follow-up. Although attenuated, decreases persisted after adjustment for regression to the mean. Clinicians were supportive of the program, although collecting follow-up data from enrolled patients was a common challenge. The integration of SBPM into routine management of uncontrolled hypertension demonstrated substantial improvements in control. Systems to identify and track patients who are self monitoring may increase impact. PMID- 23458591 TI - Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. AB - Aldosterone inhibition with mineralcorticoid receptor antagonists (MRAs) is an effective treatment for resistant hypertension. Aldosterone synthase inhibitors (ASIs) are currently being investigated as a new therapeutic strategy to reduce aldosterone secretion from the adrenal gland. In this study, the efficacy and safety of the first-generation ASI LCI699 (0.25 mg twice daily, 1 mg 4 once daily, and 0.5 mg/1 mg twice daily) was compared with placebo and eplerenone (50 mg twice daily), in patients with resistant hypertension. Placebo-adjusted decreases in systolic blood pressure (BP) with LCI699 ranged from 2.6 mm Hg to 4.3 mm Hg at week 8; changes in diastolic BP ranged from +0.3 mm Hg to -1.2 mm Hg. However, reductions were smaller than observed with eplerenone 50 mg twice daily (9.9 mm Hg and 2.9 mm Hg for systolic and diastolic BP, respectively) and not statistically significant vs placebo. LCI699 suppressed plasma aldosterone levels in a dose-related manner with corresponding dose-dependent increases in plasma renin activity and plasma 11-deoxycorticosterone. LCI699 and eplerenone were well tolerated. These data demonstrate that aldosterone synthesis inhibition with LCI699 lowers BP modestly in patients with resistant hypertension. Aldosterone synthesis inhibition might offer an attractive adjunct to aldosterone receptor blockade, although the potential of a combination MRA/ASI has not yet been tested. PMID- 23458592 TI - The efficacy and safety of triple vs dual combination of angiotensin II receptor blocker and calcium channel blocker and diuretic: a systematic review and meta analysis. AB - Many hypertensive patients require >=2 drugs to achieve blood pressure targets. This study aims to review and analyze the clinical studies conducted with dual or triple combination of angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics. Medical literature between January 1990 and April 2012 was reviewed systematically and data from eligible studies were abstracted. Data were analyzed using random-effects models. Of the 224 studies screened, 7563 eligible patients from 11 studies were included. Triple combinations of ARBs (olmesartan or valsartan), CCBs (amlodipine), and diuretics (hydrochlorothiazide) at any dose provided more blood pressure reduction in office and 24-hour ambulatory measurements than any dual combination of these molecules (P<.0001 for both). Significantly more patients achieved blood pressure targets with triple combinations (odds ratio, 2.16; P<.0001). Triple combinations did not increase adverse event risk (odds ratio, 0.96; P=.426). Triple combinations at any dose seem to decrease blood pressure more effectively than dual combination of the same molecules without any remarkable risk elevation for adverse events. Further prospective studies evaluating the efficacy and safety of triple combinations, especially in the form of single pills, are required. PMID- 23458593 TI - Antihypertensive medication nonadherence in black men: direct and mediating effects of depressive symptoms, psychosocial stressors, and substance use. AB - Black men suffer disproportionately from hypertension. Antihypertensive medication nonadherence is a major contributor to poor blood pressure control, yet few studies consider how psychosocial functioning may impact black men's medication adherence. The authors examined the direct and mediating pathways between depressive symptoms, psychosocial stressors, and substance use on antihypertensive medication nonadherence in 196 black men enrolled in a clinical trial to improve hypertension care and control. The authors found that greater depressive symptoms were associated with more medication nonadherence (beta=0.05; standard error [SE], 0.01; P<.001). None of the psychosocial stressor variables were associated with antihypertensive medication nonadherence. Alcohol misuse was associated with increased medication nonadherence (beta=0.81; SE, 0.26; P<.01), but it did not mediate the association between depressive symptoms and medication nonadherence. Clinicians should consider screening for depressive symptoms and alcohol misuse if patients are found to be nonadherent and should treat or refer patients to appropriate resources to address those issues. PMID- 23458594 TI - Patients with hypertensive crises who are admitted to a coronary care unit: clinical characteristics and outcomes. AB - Patients with hypertensive crises, especially hypertensive emergencies, require immediate admittance to an intensive care unit for rapid blood pressure (BP) control. The authors analyzed the prevalence of hypertensive crisis, the clinical characteristics, and the evolution of patients with hypertensive emergencies and urgencies. Patients were divided into 3 groups according to their BP values: group I, predominant systolic hypertension (>=180/<=119 mm Hg); group II, severe systolic and diastolic hypertension (>=180/>=120 mm Hg); and group III, predominant diastolic hypertension (<=179/>=120 mm Hg). Of all of the patients admitted to a coronary care unit, 538 experienced a hypertensive crisis, which represented 5.08% of all admissions. Hypertensive emergency was predominant in 76.6% of the cases, which corresponded to acute coronary syndrome and acute decompensated heart failure in 59.5% and 25.2% of the cases, respectively. A pattern of predominant systolic hypertension (>=180/<=119 mm Hg) was most commonly observed in the hypertensive crisis group (71.4%) and the hypertensive emergency group (72.1%). The medications that were most commonly used at onset included intravenous vasodilators (nitroglycerin in 63.4% and sodium nitroprusside in 16.4% of the patients). The overall mortality rate was 3.7%. The mortality rate was 4.6% for hypertensive emergency cases and 0.8% for hypertensive urgencies cases. PMID- 23458595 TI - Malignant hypertension in patients treated with vascular endothelial growth factor inhibitors. PMID- 23458596 TI - Microvascular decompression surgery for refractory hypertension of neurogenic causes. PMID- 23458597 TI - Should physicians rely on pharmaceutical detailing for their education? PMID- 23458598 TI - Suppressing commercial speech is not in the best interests of physicians and patients. PMID- 23458600 TI - On the existence of designer magnetic superatoms. AB - The quantum states in small, compact metal clusters are bunched into electronic shells with electronic orbitals resembling those in atoms, enabling classification of stable clusters as superatoms. The filling of superatomic orbitals, however, does not generally follow Hund's rule, and it has been proposed that magnetic superatoms can be stabilized by doping simple metal clusters with magnetic atoms. Here, we present evidence of the existence of a magnetic superatom and the determination of its spin moment. Our approach combines first principles studies with negative ion photoelectron experiments and enables a unique identification of the ground state and spin multiplicity. The studies indicate VNa8 to be a magnetic superatom with a filled d-subshell and a magnetic moment of 5.0 MUB. Its low electron affinity is consistent with filled subshell and enhanced stability. The synthesis of this species opens the pathway to investigate the spin-dependent electronics of the new magnetic motifs. PMID- 23458599 TI - Recurrence after microwave ablation of liver malignancies: a single institution experience. AB - BACKGROUND: Microwave ablation (MWA) is increasingly used to achieve local control for liver tumours. This study sought to examine a monocentric experience with MWA, with a primary hypothesis that primary tumour histology was a significant predictor of early recurrence. METHODS: Retrospective single institution review identified consecutive patients with liver tumours treated by MWA. Cox proportional hazards models assessed significance of prognostic variables. RESULTS: Seventy-two patients (43 female, 60%) underwent 83 MWA procedures for 157 tumours. Tumour histologies included hepatocellular cancer (10 operations), colorectal metastases (39), metastatic carcinoid (20) and other (14). The median tumour size was 2.0 cm. A concomitant liver resection was performed in 50 cases (60%). Crude peri-operative morbidity and mortality rates were 16% and 1%, respectively. The median follow-up was 16 months. Ablations were complete for 149 out of 157 tumours (95%). The median overall and recurrence-free survivals were 36 and 18 months, respectively. There was no difference in time to recurrence between the primary tumour types. In multivariable models, recurrence free survival was independently associated with the use of neoadjuvant [hazard ratio (HR): 2.90, 95% confidence interval (CI): 1.09-7.76, P = 0.034] and adjuvant chemotherapy (HR: 0.36, 95% CI: 0.15-0.82, P = 0.016). CONCLUSIONS: MWA is a safe and feasible approach for local control of liver tumours. While chemotherapy administration was associated with time to recurrence after MWA, larger studies are needed to corroborate these findings. PMID- 23458601 TI - Is tumour size an underestimated feature in the current TNM system for malignancies of the pancreatic head? AB - BACKGROUND: As the long-term survival of pancreatic head malignancies remains dismal, efforts have been made for a better patient selection and a tailored treatment. Tumour size could also be used for patient stratification. METHODS: One hundred and fourteen patients underwent a pancreaticoduodenectomy for pancreatic adenocarcinoma, peri-ampullary and biliary cancer stratified according to: <=20 mm, 21-34 mm, 35-45 mm and >45 mm tumour size. RESULTS: Patients with tumour sizes of <=20 mm had a N1 rate of 41% and a R1/2 rate of 7%. The median survival was 3.4 years. N1 and R1/2 rates increased to 84% and 31% for tumour sizes of 21-34 mm (P = 0.0002 for N, P = 0.02 for R). The median survival decreased to 1.6 years (P = 0.0003). A further increase in tumour size of 35-45 mm revealed a further increase of N1 and R1/2 rates of 93% (P < 0.0001) and 33%, respectively. The median survival was 1.2 years (P = 0.004). Tumour sizes >45 mm were related to a further decreased median survival of 1.1 years (P = 0.2), whereas N1 and R1/2 rates were 87% and 20%, respectively. DISCUSSION: Tumour size is an important feature of pancreatic head malignancies. A tumour diameter of 20 mm seems to be the cut-off above which an increased rate of incomplete resections and metastatic lymph nodes must be encountered and the median survival is reduced. PMID- 23458602 TI - Survival analysis of high-intensity focused ultrasound ablation in patients with small hepatocellular carcinoma. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) ablation is a non-invasive treatment for hepatocellular carcinoma (HCC). At present, data on the treatment's long-term outcome are limited. This study analysed the survival outcome of HIFU ablation for HCCs smaller than 3 cm. PATIENTS AND METHODS: Forty-seven patients with HCCs smaller than 3 cm received HIFU treatment between October 2006 and September 2010. Fifty-nine patients who received percutaneous radiofrequency ablation (RFA) were selected for comparison. The two groups of patients were compared in terms of pre-operative variables and survival. RESULTS: More patients in the HIFU group patients had Child-Pugh B cirrhosis (34% versus 8.5%; P = 0.001). The 1- and 3-year overall survival rates of patients whose tumours were completely ablated in the HIFU group compared with the RFA group were 97.4% versus 94.6% and 81.2% versus 79.8%, respectively (P = 0.530). The corresponding 1- and 3-year disease-free survival rates were 63.6% versus 62.4% and 25.9% versus 34.1% (P = 0.683). CONCLUSIONS: HIFU ablation is a safe and effective method for small HCCs. It can achieve survival outcomes comparable to those of percutaneous RFA and thus serves as a good alternative ablation treatment for patients with cirrhosis. PMID- 23458603 TI - Protein kinase Cbeta is a modulator of the dopamine D2 autoreceptor-activated trafficking of the dopamine transporter. AB - The strength and duration of extracellular dopamine concentrations are regulated by the presynaptic dopamine transporter (DAT) and dopamine D2 autoreceptors (D2autoRs). There is a functional interaction between these two proteins. Activation of D2autoRs increases DAT trafficking to the surface whereas disruption of this interaction compromises activities of both proteins and alters dopaminergic transmission. Previously we reported that DAT expression and activity are subject to modulation by protein kinase Cbeta (PKCbeta). Here, we further demonstrate that PKCbeta is integral for the interaction between DAT and D2autoR. Inhibition or absence of PKCbeta abolished the communication between DAT and D2autoR. In mouse striatal synaptosomes and transfected N2A cells, the D2autoR-stimulated membrane insertion of DAT was abolished by PKCbeta inhibition. Moreover, D2autoR-stimulated DAT trafficking is mediated by a PKCbeta extracellular signal-regulated kinase signaling cascade where PKCbeta is upstream of extracellular signal-regulated kinase. The increased surface DAT expression upon D2autoR activation resulted from enhanced DAT recycling as opposed to reduced internalization. Further, PKCbeta promoted accelerated DAT recycling. Our study demonstrates that PKCbeta critically regulates D2autoR-activated DAT trafficking and dopaminergic signaling. PKCbeta is a potential drug target for correcting abnormal extracellular dopamine levels in diseases such as drug addiction and schizophrenia. PMID- 23458605 TI - Cross-cultural validity of the Self-Stigma of Seeking Help (SSOSH) scale: examination across six nations. AB - Researchers have found that the stigma associated with seeking therapy- particularly self-stigma--can inhibit the use of psychological services. Yet, most of the research on self-stigma has been conducted in the United States. This is a considerable limitation, as the role of self-stigma in the help-seeking process may vary across cultural groups. However, to examine cross-cultural variations, researchers must first develop culturally valid scales. Therefore, this study examined scale validity and reliability of the widely used Self-Stigma of Seeking Help scale (SSOSH; Vogel, Wade, & Haake, 2006) across samples from 6 different countries (England, Greece, Israel, Taiwan, Turkey, and the United States). Specifically, we used a confirmatory factor analysis framework to conduct measurement invariance analysis and latent mean comparisons of the SSOSH across the 6 sampled countries. Overall, the results suggested that the SSOSH has a similar univariate structure across countries and is sufficiently invariant across countries to be used to explore cultural differences in the way that self stigma relates to help-seeking behavior. PMID- 23458606 TI - Perfectionism moderates stereotype threat effects on STEM majors' academic performance. AB - Using a randomized, between-subjects experimental design, we tested hypotheses that self-critical perfectionism would moderate the effects of subtle stereotype threat (ST) for women and students in underrepresented racial/ethnic groups who are pursuing traditional degrees in science, technology, engineering, or math (STEM). A diverse sample of freshmen students (N = 294) was recruited from 2 major universities. Students were blocked by gender and race/ethnicity and randomly assigned to experience subtle ST or no ST. Participants in the subtle ST condition were primed to consider their gender, race, and ethnicity prior to completing measures of science self-efficacy. Those in the control condition completed the measures without such priming. Controlling for prior academic performance and university context, ST priming significantly interacted (a) with self-critical perfectionism to predict coping self-efficacy scores and (b) with race/ethnicity to predict end-of-semester STEM grades. A 3-way interaction of ST priming, sex, and self-critical perfectionism also predicted students' grades in courses wherein women and men were more proportionally represented. The Sex * Self-Critical Perfectionism interaction was not significant for those in the ST group but was for those in the control group. Men in the control group had higher grade-point averages (GPAs) at low levels of self-critical perfectionism than they had at higher levels of perfectionism. In contrast, women had lower GPAs when self-critical perfectionism was low, but their GPAs were higher when self critical perfectionism was high. The findings are discussed in terms of their implications for self-efficacy and performance in the pursuit of a STEM major. PMID- 23458604 TI - Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. AB - Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2), or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [(3)H]MPP(+) uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for [(3)H]spermidine increased more modestly above the background, up to 3-fold. This reflected up to 20-fold lower affinity for spermidine than for MPP(+); thus, K(0.5) for MPP(+) was ~50 MUM in OCT1, ~170 MUM in OCT2, and ~60 MUM in OCT3, whereas for spermidine, K(0.5) was ~1 mM in OCT1, OCT2, and OCT3. J(max) values for MPP(+) and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogues for effect on [(3)H]MPP(+) uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis and aid in the design of polyamine like OCT-targeted drugs. PMID- 23458607 TI - A psychometric examination of the Interpersonal Sexual Objectification Scale among college men. AB - Whereas sexual objectification has most commonly been studied among women, recent calls by counseling psychologists have urged for an extension of objectification research to more fully include men (e.g., Heimerdinger-Edwards, Vogel, & Hammer, 2011). The present study examined the factor structure of the Interpersonal Sexual Objectification Scale (ISOS; Kozee, Tylka, Augustus-Horvath, & Denchik, 2007) with men. Specifically, analyses included exploratory factor analysis (EFA) with a sample of 287 college men and confirmatory factor analysis (CFA) with an independent sample of 221 college men. A correlated 3-factor structure was suggested by multiple criteria in EFA and was further confirmed by CFA with a bifactor model illustrating the most item variance associated with a general interpersonal sexual objectification dimension for men. PMID- 23458609 TI - Polarity proteins as regulators of cell junction complexes: implications for breast cancer. AB - The epithelium of multicellular organisms possesses a well-defined architecture, referred to as polarity that coordinates the regulation of essential cell features. Polarity proteins are intimately linked to the protein complexes that make the tight, adherens and gap junctions; they contribute to the proper localization and assembly of these cell-cell junctions within cells and consequently to functional tissue organization. The establishment of cell-cell junctions and polarity are both implicated in the regulation of epithelial modifications in normal and cancer situations. Uncovering the mechanisms through which cell-cell junctions and epithelial polarization are established and how their interaction with the microenvironment directs cell and tissue organization has opened new venues for the development of cancer therapies. In this review, we focus on the breast epithelium to highlight how polarity and cell-cell junction proteins interact together in normal and cancerous contexts to regulate major cellular mechanisms such as migration. The impact of these proteins on epigenetic mechanisms responsible for resetting cells toward oncogenesis is discussed in light of increasing evidence that tissue polarity modulates chromatin function. Finally, we give an overview of recent breast cancer therapies that target proteins involved in cell-cell junctions. PMID- 23458608 TI - Notch inhibitors for cancer treatment. AB - Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs is still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient's treatment. PMID- 23458611 TI - Small interfering RNA-mediated knockdown of chicken interferon-gamma expression. AB - Interferon (IFN)-gamma is a cytokine with a variety of functions, including direct antiviral activities and the capacity to polarize T-cells. However, there is limited information available about the function of this cytokine in the avian immune system. To gain a better understanding of the biological relevance of IFN gamma in chicken immunity, gain-of-function (upregulation) and loss-of-function (downregulation) studies need to be conducted. RNA interference (RNAi), a technique employed for downregulating gene expression, is mediated by small interfering RNA (siRNA), which can trigger sequence-specific gene silencing. In this regard, sequence specificity and delivery of siRNA molecules remain critical issues, especially to cells of the immune system. Various direct and indirect approaches have been employed to deliver siRNA, including the use of viral vectors. The objectives of the present study were to determine whether RNAi could effectively downregulate expression of chicken IFN-gamma in vitro, and investigate the feasibility of recombinant adeno-associated virus to deliver siRNA in vitro as well. Three 27-mer Dicer substrate RNAs were selected based on the chicken IFN-gamma coding sequence and transfected into cells or delivered using a recombinant avian adeno-associated virus (rAAAV) into a chicken fibroblast cell line expressing chIFN-gamma. The expression of chIFN-gamma transcripts was significantly downregulated when a cocktail containing all three siRNAs was used. Expression of endogenous IFN-gamma was also significantly downregulated in primary cells after stimulation with a peptide. Further, significant suppression of IFN-gamma transcript was also observed in vitro in cells that were treated with rAAAV, expressing siRNA targeting IFN-gamma. Off target effects in the form of triggering IFN responses by RNAi, including expression of chicken 2',5'-oligoadenylate synthetase and IFN-alpha, were also examined. Our results suggest that siRNAs selected were effective at downregulating IFN-gamma in vitro both when delivered directly as well as when expressed by an rAAAV-based vector. PMID- 23458612 TI - Anterior segment changes following short-term reading and its correlation with corneal biomechanical characteristics. AB - PURPOSE: To investigate the changes in anterior segment following short-term reading and evaluate the correlation of such changes with corneal biomechanical characteristics (CBC). METHODS: Thirty-six right eyes of 36 healthy subjects were examined. Anterior segment parameters were measured using the Pentacam before and after 30 min of reading. Ocular Response Analyzer was used to record CBC after reading. The following were recorded: central corneal thickness (CCT), central corneal power (CCP), superior corneal power (SCP), inferior corneal power (ICP), anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA), corneal hysteresis (CH) and corneal resistance factor (CRF). Statistical analysis was performed with the paired student t-test and Pearson correlation test in SPSS 16. RESULTS: There were statistically significant decreases in CCP, SCP, ACD and ACV values following reading (p < 0.05). Our results showed a statistically significant negative correlation between CH and changes in ICP (r = 0.36, p = 0.02). Significant negative correlations were also found between CRF and changes in ICP (r = 0.41, p = 0.01) and SCP (r = 0.34, p = 0.04). On the other hand, statistical analysis indicated no correlation between CBC and other studied parameters (p > 0.05). CONCLUSION: This study demonstrated significant changes in some anterior segment parameters after reading. Being knowledgeable about these changes may have important implications in high accuracy examinations such as pre-operative assessment of corneal refractive surgery candidates. This could also help researchers have a better understanding of the factors that may influence near work related development of refractive errors. PMID- 23458613 TI - Complexity against complexity: multitarget drugs. PMID- 23458614 TI - Raman spectroscopy and imaging: promising optical diagnostic tools in pediatrics. AB - This review focuses on the use of Raman spectroscopy, an analytical technique based on the inelastic scattering of harmless laser light with biological tissues, as an innovative diagnostic tool in pediatrics. After a brief introduction to explain the fundamental concepts behind Raman spectroscopy and imaging, a short summary is given of the most important and common issues arising when handling spectral data with multivariate statistics. Then, the most relevant papers in which Raman spectroscopy or imaging has been applied with diagnostic purposes to pediatric patients are reviewed, and grouped according to the type of pathology: neoplastic, inflammatory, allergic, malformative as well as other kinds. Raman spectroscopy has been used both in vivo, mostly using optical fibers for tissue illumination, as well as on ex vivo tissue sections in a microscopic imaging approach defined as "spectral histopathology". According to the results reported so far, this technique showed a huge potential for mini- or non-invasive real-time, bedside and intra-operatory diagnosis, as well as for an ex vivo imaging tool in support to pathologists. Despite many studies are limited by the small sample size, this technique is extremely promising in terms of sensitivity and specificity. PMID- 23458615 TI - Perspectives offered by single-domain antibodies in clinical diagnostic of pediatric tumors. AB - The results accrued in the last few years have clearly showed that recombinant antibodies, and specifically single- domain antibodies, represent valid alternatives to conventional IgGs for in vivo imaging. It does not simply mean that antibody fragments can substitute full-length antibodies, but that they are substantially more suitable for some applications and can perform other functions for which no real alternative is available. Brain imaging with multi-functional probes is an evident example, but the promising results obtained with micro-PET and -SPECT in murine models could lead in short time to a revolutionary change in clinical diagnostics. Brilliant applications of single-domain antibody-dependent imaging have enabled us to understand how the tracer mass and avidity can be engineered to modulate pharmacokinetic features such as clearance, tumor penetration, and binding affinity with the aim of optimizing specific responses. The potential of these reagents and the increasing interest for them is evidenced by the exponential growth of publications and the multiplication of the proposed applications in which they are used. This review wishes to provide an update of this fast moving subject and to indicate what may be the next foreseeable technical progress. PMID- 23458610 TI - Neuroimmune communication in hypertension and obesity: a new therapeutic angle? AB - Hypertension is an epidemic health concern and a major risk factor for the development of cardiovascular disease. Although there are available treatment strategies for hypertension, numerous hypertensive patients do not have their clinical symptoms under control and it is imperative that new avenues to treat or prevent high blood pressure in these patients are developed. It is well established that increases in sympathetic nervous system (SNS) outflow and enhanced renin-angiotensin system (RAS) activity are common features of hypertension and various pathological conditions that predispose individuals to hypertension. More recently, hypertension has also become recognized as an immune condition and accumulating evidence suggests that interactions between the RAS, SNS and immune systems play a role in blood pressure regulation. This review summarizes what is known about the interconnections between the RAS, SNS and immune systems in the neural regulation of blood pressure. Based on the reviewed studies, a model for RAS/neuroimmune interactions during hypertension is proposed and the therapeutic potential of targeting RAS/neuroimmune interactions in hypertensive patients is discussed. Special emphasis is placed on the applicability of the proposed model to obesity-related hypertension. PMID- 23458616 TI - TRAIL-based therapeutic approaches for the treatment of pediatric malignancies. AB - Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a pro apoptotic ligand that has shown the exquisite ability to trigger extrinsic apoptosis in various types of cancer cells without significant toxicity toward normal cells, when compared to other pro-apoptotic ligands such as tumor necrosis factor (TNF) alpha or Fas ligand. Consequently, TRAIL-based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2. In this review, we start by highlighting the relevance of the tumor microenvironment in tumor development and elimination. We then address conventional and targeted therapeutic approaches for cancer treatment, highlighting the mechanisms involved or targeted. We describe the extrinsic and intrinsic pro-apoptotic pathways of TRAIL, together with the evidences for its pro-survival signaling, and with the relevance of these pathways in therapy. Possible mechanisms of resistance to TRAIL-induced apoptosis are highlighted (i.e. c-FLIP, Bcl-2, IAPs, p53, NF-kappa B) and the rationale for the combined administration of TRAIL with drugs targeting these mechanisms is provided. Preclinical data are reported and show encouraging evidences for TRAIL consideration in pediatric malignancies (i.e., leukemia, lymphomas, neuroblastoma, osteosarcoma, medulloblastoma). Clinical trials of TRAIL-based therapies on the overall population are in phase I or II, and we put particular focus on the pediatric population, on which only few trials have been conducted or are ongoing. Finally, we consider emerging cellular therapies based on TRAIL, such as TRAIL-engineered mesenchymal stem cells or 'inflammatory' dendritic cells. PMID- 23458617 TI - MDM2 non-genotoxic inhibitors as innovative therapeutic approaches for the treatment of pediatric malignancies. AB - Since the discovery of p53 as "guardian of the genome", a large number of efforts have been put in place in order to find molecular strategies aiming to restore p53 wild-type functions, particularly in the light of the fact that its pathway results ineffective in most tumors even though they have non-mutated p53. In this context, pediatric cancers, that are mostly p53 wild-type at the time of diagnosis, represent an ideal target for such therapeutic approach. Within the several mechanisms and proteins ruling p53 activity, the murine double minute 2 (MDM2) is its crucial negative regulator, frequently found overexpressed in p53 wild-type tumors. The development of new technologies such as nuclear magnetic resonance structure analyses, computational structure-based design studies, and library peptides screening have recently led to the discovery and characterization of a large number of compounds belonging to different chemical families that are able to target the interaction p53-MDM2, rescuing the p53 wild type pathway with an overall pro-apoptotic and anticancer activity. Within the preclinical assessment of these molecules, the cis-imidazoline analogue Nutlin-3 has definitely attracted great interest for its in vitro and in vivo antitumor activity in several pediatric cancer models, either as single agent on in combination with standard chemotherapy. In this light, the aim of this review is to summarize the main preclinical evidences of the potential of MDM2 inhibitors for the treatment of childhood cancers and the key suggestions coming from their assessment in the treatment of adult cancers as proof of concept for future pediatric clinical studies. PMID- 23458618 TI - Potential advantages of using synchrotron X-ray based techniques in pediatric research. AB - Synchrotron radiation (SR), which combines extremely high intensity, high collimation, tunability, and continuous energy spectrum, allows the development of advanced X-ray based techniques that are becoming a uniquely useful tool in life science research, along providing exciting opportunities in biomedical imaging and radiotherapy. This review summarize emerging techniques and their potential to greatly enhance the exploration of dynamical biological process occurring across various spatial and temporal regimes, from whole body physiology, down to the location of individual chemical species within single cells. In recent years pediatric research and clinic practice have started to profit from these new opportunities, particularly by extending the diagnostic and therapeutic capabilities of these X-ray based techniques. In diagnosis, technical advances in DEI and KES imaging modalities have been demonstrated as particularly valuable for children and women since SR allows dose minimization, with significant reductions compared to conventional approaches. However, the greatest expectations are in the field of SR based radiotherapy, increasingly studies are demonstrating SR radiotherapy provides improved chances of recovery; this is especially the case for pediatric patients. In addition, we report on the applicability of advanced X-ray microscopy techniques that offer exceptional spatial and quantitative resolution in elemental detection. These techniques, which are useful for in vitro studies, will be particularly advantageous where investigators seek deeper understanding of diseases where mismetabolism of metals, either physiological important (i.e. Cu, Zn) or outright toxic (i.e. Pb), underlies pathogenesis. PMID- 23458619 TI - Pharmacogenomic approaches for tailored anti-leukemic therapy in children. AB - Several lympholytic and cytotoxic agents are used in acute lymphoblastic leukemia (ALL) polychemotherapy. Genetic variants for cellular components involved in the pharmacokinetics and pharmacodynamics of these drugs can influence the pharmacological response, and molecular characterization of these genetic variants could be helpful for the comprehension of the mechanisms of resistance or increased sensitivity. The purpose of this review is to carry out an update of recent publications on genes that might influence ALL treatment in terms of outcome and/or toxicity and to underlie the role of genetic variants, particularly single nucleotide polymorphisms (SNP), in predicting clinical response, with particular reference to the current protocol for ALL therapy used in Italy, AIEOP-BFM ALL 2009. PMID- 23458620 TI - Potential use of polymeric nanoparticles for drug delivery across the blood-brain barrier. AB - Nanomedicine is certainly one of the scientific and technological challenges of the coming years. In particular, biodegradable nanoparticles formulated from poly (D,L-lactide-co-glycolide) (PLGA) have been extensively investigated for sustained and targeted delivery of different agents, including recombinant proteins, plasmid DNA, and low molecular weight compounds. PLGA NPs present some very attractive properties such as biodegradability and biocompatibility, protection of drug from degradation, possibility of sustained release, and the possibility to modify surface properties to target nanoparticles to specific organs or cells. Moreover, PLGA NPs have received the FDA and European Medicine Agency approval in drug delivery systems for parenteral administration, thus reducing the time for human clinical applications. This review in particular deals on surface modification of PLGA NPs and their possibility of clinical applications, including treatment for brain pathologies such as brain tumors and Lysosomal Storage Disorders with neurological involvement. Since a great number of pharmacologically active molecules are not able to cross the Blood-Brain Barrier (BBB) and reach the Central Nervous System (CNS), new brain targeted polymeric PLGA NPs modified with glycopeptides (g7- NPs) have been recently produced. In this review several in vivo biodistribution studies and pharmacological proof-of evidence of brain delivery of model drugs are reported, demonstrating the ability of g7-NPs to create BBB interaction and trigger an efficacious BBB crossing. Moreover, another relevant development of NPs surface engineering was achieved by conjugating to the surface of g7-NPs, some specific and selective antibodies to drive NPs directly to a specific cell type once inside the CNS parenchyma. PMID- 23458622 TI - Innovative approaches for the management of pediatric malignancies. PMID- 23458621 TI - Luminescent silica nanoparticles for cancer diagnosis. AB - Fluorescence imaging techniques are becoming essential for preclinical investigations, necessitating the development of suitable tools for in vivo measurements. Nanotechnology entered this field to help overcome many of the current technical limitations, and luminescent nanoparticles (NPs) are one of the most promising materials proposed for future diagnostic implementation. NPs also constitute a versatile platform that can allow facile multi-functionalization to perform multimodal imaging or theranostics (simultaneous diagnosis and therapy). In this contribution we have mainly focused on dye doped silica or silica-based NPs conjugated with targeting moieties to enable imaging of specific cancer cells. We also cite and briefly discuss a few non-targeted systems for completeness. We summarize common synthetic approaches to these materials, and then survey the most recent imaging applications of silica-based nanoparticles in cancer. The field of theranostics is particularly important and stimulating, so, even though it is not the central topic of this paper, we have included some significant examples. We conclude with a short section on NP-based systems already in clinical trials and examples of specific applications in childhood tumors. This review aims to describe and discuss, through focused examples, the great potential of these materials in the medical field, with the aim to encourage further research to implement applications, which today are still rare. PMID- 23458623 TI - The long-term effect of bile duct injuries on health-related quality of life: a meta-analysis. AB - BACKGROUND: The reported effects of biliary injury on health-related quality of life (HRQOL) have varied widely. Meta-analysis methodology was applied to examine the collective findings of the long-term effect of bile duct injury (BDI) on HRQOL. METHODS: A comprehensive literature search was conducted in March, 2012. Because the HRQOL surveys differed among reports, BDI and uncomplicated laparoscopic cholecystectomy (LC) groups' HRQOL scores were expressed as effect sizes (ES) in relation to a common, general population, standard. A negative ES indicated a reduced HRQOL, with a substantive reduction defined as an ES <= 0.50. Weighted logistic regression tested the effects of BDI (versus LC) and follow-up time on whether physical and mental HRQOL were substantively reduced. RESULTS: Data were abstracted from six publications, which encompass all reports of HRQOL after BDI in the current, peer-reviewed literature. The analytic database comprised 90 ES computations representing 831 patients and 11 unique study groups (six BDI and five LC). After controlling for follow-up time (P <= 0.001), BDI patients were more likely to have reduced long-term mental [odds ratio (OR) = 38.42, 95% confidence interval (CI) = 19.14-77.10; P < 0.001] but not physical (P = 0.993) HRQOL compared with LC patients. DISCUSSION: This meta analysis of findings from six peer-review reports indicates that, in comparison to LC, there is a long-term detrimental effect of BDI on mental HRQOL. PMID- 23458624 TI - Reduction in circulating pro-angiogenic and pro-inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega-3 fish oil. AB - BACKGROUND: Pancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well-established link between pro inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. METHODS: As part of a single arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega-3 rich lipid emulsion (n-3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression-free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. RESULTS: Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)-6 and -8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. DISCUSSION: Treatment with gemcitabine plus i.v. n-3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL-6 and -8 may be surrogate markers for outcome in patients with APC treated with this regimen. PMID- 23458625 TI - Proteogenomic analysis of human colon carcinoma cell lines LIM1215, LIM1899, and LIM2405. AB - As part of the genome-wide and chromosome-centric human proteomic project (C HPP), we have integrated shotgun proteomics approach and a genome-wide transcriptomic approach (RNA-Seq) of a set of human colon cancer cell lines (LIM1215, LIM1899 and LIM2405) that were selected to represent a wide range of pathological states of colorectal cancer. The combination of a standard proteomics approach (1D-gel electrophoresis coupled to LC/ion trap mass spectrometry) and RNA-Seq allowed us to exploit the greater depth of the transcriptomics measurement (~ 9800 transcripts per cell line) versus the protein observations (~ 1900 protein identifications per cell line). Conversely, the proteomics data were helpful in identifying both cancer associated proteins with differential expression patterns as well as protein networks and pathways which appear to be deregulated in these cell lines. Examples of potential markers include mortalin, nucleophosmin, ezrin, LASP1, alpha and beta forms of spectrin, exportin, the carcinoembryonic antigen family, EGFR and MET. Interaction analyses identified the large intermediate filament family, the protein folding network and adapter proteins in focal adhesion networks, which included the CDC42 and RHOA signaling pathways that may have potential for identifying phenotypic states representing poorly and moderately differentiated states of CRC, with or without metastases. PMID- 23458626 TI - Integration of sensory information via central thermoregulatory leptin targets. AB - The adipocyte derived hormone leptin acts in the brain to regulate body weight, food intake and energy expenditure. Even though it is well accepted that leptin regulates energy expenditure at least in part by modulating thermogenesis, the exact mechanisms are not clear. Particularly, it is unclear which central circuits regulate thermogenic leptin actions and if and how these may interact with feeding circuits. Within the last decade our understanding of central thermoregulatory circuits has increased substantially and allowed the identification of leptin target neurons (those expressing the long form leptin receptor - LepRb) that are involved in the sympathetic control of the heat generating brown adipose tissue (BAT). Indeed, LepRb neurons in the preoptic area and dorsomedial hypothalamus are part of the known thermoregulatory circuits controlling sympathetic premotor neurons that are located in the raphe pallidus. Thermoregulatory control and food intake are both regulated by leptin signaling pathways, even though distinct neuronal pathways have been described, respectively. Nevertheless, feeding status and control of body temperature and energy expenditure are tightly interconnected, but it is unknown how these aspects are connected within leptin signaling pathways to result in appropriate output signals (e.g. BAT thermogenesis). Indeed, cold-induced thermogenesis is potently blocked during fasting, which instead triggers an active decrease in energy expenditure and body temperature, a state known as torpor. In this article we will review recent data characterizing central thermoregulatory LepRb pathways and speculate on potential integration mechanisms that may relay anorexic and thermoregulatory leptin action to control energy homeostasis. PMID- 23458628 TI - Greater overall olfactory performance, explicit wanting for high fat foods and lipid intake during the mid-luteal phase of the menstrual cycle. AB - Increases in energy, lipid and carbohydrate intakes during the luteal phase have been previously observed. However, it is not known whether this is due to phase dependent variations in the reward value of certain foods. Moreover, increases in olfactory sensitivity have been proposed and may be involved in these changes in food reward. Therefore, we examined olfactory performance and the reward value of foods varying in fat content and taste. Seventeen women (Body mass index: 22.3+/ 1.6 kg/m(2); Body fat-DXA: 28.5+/-6.8%) were recruited to participate in 3 identical sessions, performed during distinct phases of the menstrual cycle - early follicular/menstruation, late follicular/ovulation and mid-luteal - verified by plasma sex-steroid hormones and oral temperature. Food preference, implicit wanting, and explicit wanting and liking for visual food cues, varying in fat content and taste, were measured with a validated experimental platform involving a forced choice computer task. Odour threshold, odour discrimination, odour identification and total odour scores were measured using odourized pens. Ad libitum energy and macronutrient intake was measured with a validated food menu. Results showed greater total odour scores (p<0.05), explicit wanting for high fat foods (p<0.05) and lipid intake (p<0.05) during the mid-luteal phase. Inter-correlations between these variables were non-significant. These findings support previous observations of increased lipid intake during the luteal phase and provide evidence for phase-dependent variation in overall olfactory performance and explicit wanting for high fat foods. PMID- 23458629 TI - Intrinsic and extrinsic influences on children's acceptance of new foods. AB - The foods that tend to be rejected by children include those which may have greatest importance for later health. This paper reviews some of the intrinsic and extrinsic influences on preschool children's eating behavior, with particular reference to their acceptance of new foods into their diet. Factors conceptualized as intrinsic to the child in this review include sensory processing, taste perception, neophobia, and temperament. The important extrinsic determinants of children's food acceptance which are reviewed include parental and peer modeling, the family food environment, infant feeding practices including breastfeeding and age at weaning, concurrent feeding practices including restriction, pressure to eat, prompting and reward, and the taste & energy content of foods. Children's willingness to accept new foods is influenced by a wide range of factors that likely have individual and also interactive effects on children's willingness to taste, and then continue to eat, new foods. The literature lacks longitudinal and experimental studies, which will be particularly important in determining interventions most likely to be effective in facilitating children's acceptance of healthy foods. PMID- 23458627 TI - Appetitive traits from infancy to adolescence: using behavioral and neural measures to investigate obesity risk. AB - We come into the world with enduring predispositions towards food, which interact with environmental factors to influence our eating behaviors and weight trajectories. But our fates are not sealed - by learning more about this process we can identify ways to intervene. To advance this goal this we need to be able to assess appetitive traits such as food cue responsiveness and satiety sensitivity at different developmental stages. Assessment methods might include behavioral measures (e.g. eating behavior tests, psychometric questionnaires), but also biomarkers such as brain responses to food cues measured using fMRI. Evidence from infants, children and adolescents suggests that these indices of appetite differ not only with body weight, but also with familial obesity risk as assessed by parent weight, which reflects both genetic and environmental influences, and may provide a useful predictor of obesity development. Behavioral and neural approaches have great potential to inform each other: examining eating behavior can help us identify meaningful appetitive endophenotypes whose neural bases can be probed, while increasing knowledge of the shared neurobiology underlying appetite, obesity, and related behaviors and disorders may ultimately lead to innovative generalized interventions. Another challenge will be to combine comprehensive behavioral and neural assessments of appetitive traits with measures of relevant genetic and environmental factors within long-term prospective studies. This approach may help to identify the biobehavioral precursors of obesity, and lay the foundations for targeted neurobehavioral interventions that can interrupt the pathway to excess weight. PMID- 23458630 TI - Circumventricular organs: targets for integration of circulating fluid and energy balance signals? AB - The subfornical organ (SFO), as one of the sensory circumventricular organs (CVOs), is among the only central nervous system structures which interfaces directly with circulating substances that do not cross the blood brain barrier. Here we describe a growing literature showing that circulating indicators of cardiovascular (angiotensin II, osmolarity, calcium, sodium) and metabolic (adiponectin, amylin, glucose, ghrelin, leptin) statuses influence the excitability of single SFO neurons. Single cell electrophysiological studies from our laboratory have demonstrated excitatory effects of angiotensin II on individual SFO neurons, and changes in angiotensin II receptor expression in this CVO in hypertensive states emphasize the dynamic contribution of SFO neurons to the regulation of fluid balance. Furthermore, we have shown both depolarizing and hyperpolarizing effects of the adipokines adiponectin and leptin in SFO cells, and highlight that conditions of fasting in the case of adiponectin, and obesity in the case of leptin, alter the sensitivity of SFO neurons to these circulating factors. The results examined in this review provide evidence for a role of the SFO as a mediator and integrative structure in the maintenance of cardiovascular and metabolic functions. PMID- 23458631 TI - Influence of estrous and circadian cycles on calcium intake of the rat. AB - The food, water and sodium intake of laboratory rats fluctuates over the circadian and estrous cycles. Blood calcium and calcium-regulating hormones also wax and wane in response to these cycles, raising the possibility that the same might be true of calcium intake. To investigate this, we monitored the fluid intakes of female Long-Evans rats given a choice between water and 10mM CaCl2 solution for two consecutive estrous cycles. We found that calcium solution intake changed over the circadian cycle in a similar manner to water intake; the preference scores for CaCl2 solution remained stable. We did not detect any changes in calcium solution intake or preference scores during the estrous cycle despite a decrease in fluid intake at estrus. Thus, fluctuations in intake of calcium solution during the circadian cycle appear to be nonspecific and probably the result of changes in fluid balance. Estrous changes either do not influence calcium intake or their effects are masked by other factors, resulting in stable levels of calcium intake. PMID- 23458632 TI - Mice from lines selectively bred for high voluntary wheel running exhibit lower blood pressure during withdrawal from wheel access. AB - Exercise is known to be rewarding and have positive effects on mental and physical health. Excessive exercise, however, can be the result of an underlying behavioral/physiological addiction. Both humans who exercise regularly and rodent models of exercise addiction sometimes display behavioral withdrawal symptoms, including depression and anxiety, when exercise is denied. However, few studies have examined the physiological state that occurs during this withdrawal period. Alterations in blood pressure (BP) are common physiological indicators of withdrawal in a variety of addictions. In this study, we examined exercise withdrawal in four replicate lines of mice selectively bred for high voluntary wheel running (HR lines). Mice from the HR lines run almost 3-fold greater distances on wheels than those from non-selected control lines, and have altered brain activity as well as increased behavioral despair when wheel access is removed. We tested the hypothesis that male HR mice have an altered cardiovascular response (heart rate, systolic, diastolic, and mean arterial pressure [MAP]) during exercise withdrawal. Measurements using an occlusion tail cuff system were taken during 8 days of baseline, 6 days of wheel access, and 2 days of withdrawal (wheel access blocked). During withdrawal, HR mice had significantly lower systolic BP, diastolic BP, and MAP than controls, potentially indicating a differential dependence on voluntary wheel running in HR mice. This is the first characterization of a cardiovascular withdrawal response in an animal model of high voluntary exercise. PMID- 23458633 TI - Why does water accelerate organic reactions under heterogeneous condition? AB - An exhaustive kinetic analysis has been carried out to offer the convincing evidence of the involvement of the oil-water interface in guiding "on water organic reaction" mechanism. We have tuned the interface to prove its indispensable efficacy to make on water reaction a unique type among water mediated organic reactions. Sensitive techniques have established the preferential solvation of polarizable ions at the water surface. The experimental methods have been developed to control the molecular structure of oil-water interface in situ. Temperature-dependent analyses have also been presented to understand the enthalpic and entropic modifications of the interfacial water molecules during a heterogeneous reaction. Both of our kinetic and thermodynamic outcomes have univocally established that the hydrogen-bonding ability of the surface water molecules plays a critical role in deciding the on water organic reaction mechanism. The results have important implications on understanding the role of small water molecules adjacent to the reactants during the reactions discussed in this investigation. PMID- 23458634 TI - Determining and surveying the role of carnitine and folic acid to decrease fatigue in beta-thalassemia minor subjects. AB - Beta-thalassemia minor (BTM) patients usually experience fatigue, bone pain complaint, and muscle weakness. Carnitine is an essential protein for transportation of long-chain fatty acids to the matrix for beta-oxidation. BTM patients have abnormally low plasma carnitine concentrations, which results in deficient ATP production. Carnitine and folic acid together may have a role in preventing bone pain complaint and fatigue in these patients. The aim of this study is to determine the effect of carnitine and folic acid supplementation in subjects with BTM. Seventy three BTM (mean age 11.06 +/- 5.46 years) and 23 healthy controls (mean age 8.48 +/- 3.78 years) were enrolled in the study. Fasting blood was drawn to determine baseline free and total carnitine levels, red blood cell folate concentration, and hemoglobin level. BTM were divided into three groups and received different types of supplementation for 3 months: Group 1, 50 mg/kg/day carnitine; Group 2, 50 mg/kg/day carnitine plus 1 mg/day folic acid; and Group 3, 1 mg/day folic acid. Controls did not receive supplementation. Laboratory parameters were again evaluated after 3 months' supplementation. A detailed quality of life questionnaire was designed to investigate muscle symptoms before and after supplementation. Free and total plasma carnitine concentration and hemoglobin levels in BTM subjects increased significantly after carnitine supplementation (P < .0001). Bone pain complaint and muscle weakness decreased with carnitine. Red blood cell folate level increased after folic acid supplementation. Carnitine and folic acid supplementation resulted in a decrease in bone pain complaint and muscle weakness in cases with beta-thalassemia minor. PMID- 23458636 TI - Synthesis and properties of two cationic narrow band gap conjugated polyelectrolytes. AB - We report the design, synthesis, and optical and electronic properties of two novel narrow band gap conjugated polyelectrolytes (NBGCPEs) based on a poly[2,6 (4,4-bis-alkyl-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-alt-4,7-(2,1,3 benzothiadiazole)] donor/acceptor backbone. Comparison with the properties of the neutral precursor material shows that the ionic component in these cationic NBGCPEs leads to a red-shift in the absorption spectra and to a modification of the polymer electronic energy levels. Both the HOMO and the LUMO are lowered in energy, with the net effect being dependent on the choice of counterion, i.e. bromide vs tetrakis(1-imidazolyl)borate. Moreover, we unexpectedly find n-type transport in thin-film transistors, as opposed to the widely studied p-type transport in neutral systems with isoelectronic backbones. From these observations we conclude that introduction of ionic functionalities adjacent to semiconducting polymers that exhibit charge-transfer excitations offers unique opportunities for materials design. PMID- 23458635 TI - Immunogenicity of recombinant Mycobacterium bovis bacille Calmette-Guerin clones expressing T and B cell epitopes of Mycobacterium tuberculosis antigens. AB - Recombinant Mycobacterium bovis bacille Calmette-Guerin (rBCG) expressing three T cell epitopes of Mycobacterium tuberculosis (MTB) Ag85B antigen (P1, P2, P3) fused to the Mtb8.4 protein (rBCG018) or a combination of these antigens fused to B cell epitopes from ESAT-6, CFP-10 and MTP40 proteins (rBCG032) were used to immunize Balb/c mice. Total IgG responses were determined against Mtb8.4 antigen and ESAT-6 and CFP-10 B cell epitopes after immunization with rBCG032. Mice immunized with rBCG032 showed a significant increase in IgG1 and IgG2a antibodies against ESAT-6 and MTP40 (P1) B cell epitopes and IgG3 against both P1 and P2 B cell epitopes of MPT40. Splenocytes from mice immunized with rBCG018 proliferated against Ag85B P2 and P3 T cell epitopes and Mtb8.4 protein whereas those from mice-immunized with rBCG032 responded against all Ag85B epitopes and the ESAT-6 B cell epitope. CD4+ and CD8+ lymphocytes from mice immunized with rBCG018 produced primarily Th1 type cytokines in response to the T cell epitopes. Similar pattern of recognition against the T cell epitopes were obtained with rBCG032 with the additional recognition of ESAT-6, CFP-10 and one of the MTP40 B cell epitopes with the same pattern of cytokines. This study demonstrates that rBCG constructs expressing either T or T and B cell epitopes of MTB induced appropriate immunogenicity against MTB. PMID- 23458637 TI - Low-income, pregnant, African American women's views on physical activity and diet. AB - INTRODUCTION: This research was conducted to gain insight into how low-income, pregnant, African American women viewed physical activity and approached nutrition during pregnancy. METHODS: Three focus groups with a total of 26 women were conducted utilizing open-ended questions related to physical activity and diet during pregnancy. Content analysis was used to analyze the verbatim transcripts. Groups were compared and contrasted at the within-group and between group levels to identify themes. RESULTS: Two themes that related to physical activity during pregnancy were identified: 1) fatigue and low energy dictate activity and 2) motivation to exercise is not there. Three themes were identified that related to diet: 1) despite best intentions, appetite, taste, and cravings drive eating behavior; 2) I'll decide for myself what to eat; and 3) eating out is a way of life. DISCUSSION: Women reported that being physically active and improving their diets was not easy. Women indicated that their levels of physical activity had decreased since becoming pregnant. Attempts at improving their diets were undermined by frequenting fast food restaurants and cravings for highly dense, palatable foods. Women ceded to the physical aspects of pregnancy, often choosing to ignore the advice of others. A combination of low levels of physical activity and calorie-dense diets increased the risk of excessive gestational weight gain in this sample of women, consequently increasing the risk for weight retention after pregnancy. Health care providers can promote healthy eating and physical activity by building on women's being "in tune with and listening to" their bodies. They can query women about their beliefs regarding physical activity and diet and offer information to ensure understanding of what contributes to healthy pregnancy outcomes. Intervention can focus on factors such as cravings and what tastes good, suggesting ways to manage pregnancy effects within a healthy diet. PMID- 23458639 TI - Veterinary clinical research - legal, ethical and welfare considerations. PMID- 23458638 TI - The management of hepatobiliary cystadenomas: lessons learned. AB - BACKGROUND: Mucinous cystic neoplasms of the liver (hepatobiliary cystadenomas) are rare neoplastic lesions. Such cysts are often incorrectly diagnosed and managed, and carry a risk of malignancy. The objective of this study was to review the surgical experience with these lesions over 15 years. METHODS: A retrospective chart review identified consecutive patients undergoing surgery for liver cystadenomas from 1997-2011. Clinical data were collected and summarized. RESULTS: Thirteen patients (mean age 51 years, 12/13 females) with cysts 4.6-18.1 cm were identified. Most cysts were located in the left lobe/centrally (11/12) and had septations (8/13). Mural nodularity was infrequent (3/13). Nine patients had liver resection/enucleation, whereas four had unroofing. Frozen section analysis had a high false-negative rate (4/6). All patients had cystadenomas, of which two had foci of invasive carcinoma (cystadenocarcinoma) within mural nodules. There was no 90-day mortality. All but one patient (myocardial infarction) were alive at a median follow-up of 23.1 months. No patient with unroofing has developed malignancy to date. CONCLUSIONS: Non-invasive hepatobiliary cystadenomas present as large central/left-sided cysts in young or middle-aged women. Associated malignancy was relatively uncommon and found within mural nodules. Intra-operative frozen section analysis was ineffective at ruling out cystadenomas. Complete excision is recommended, but close follow-up might be considered in patients with a prohibitive technical or medical risk, in the absence of nodularity on high-quality imaging. PMID- 23458640 TI - Ethical and evidential considerations on the use of novel therapies in veterinary practice. AB - Novel therapies may be necessary both in the interests of the individual animal and in the advancement of veterinary science. However, special consideration is necessary to safeguard the welfare of the animals, ensure fully informed consent from the owner, determine the procedure's value in other cases and appropriately disseminate results. This article reviews ethical and evidential considerations raised when novel therapies are undertaken in veterinary practice, based on a series of committee meetings and intervening discussions held between members of the British Small Animal Veterinary Association Scientific Committee and Officers (2010-2011). The aim of this article is to encourage the advancement of novel veterinary therapies while safeguarding the welfare of animals. PMID- 23458641 TI - Statistics: are we related? AB - This short addition to our series on clinical statistics concerns relationships, and answering questions such as "are blood pressure and weight related?" In a later article, we will answer the more interesting question about how they might be related. This article follows on logically from the previous one dealing with categorical data, the major difference being here that we will consider two continuous variables, which naturally leads to the use of a Pearson correlation or occasionally to a Spearman rank correlation coefficient. PMID- 23458642 TI - Characterisation of changes in the haemostasis system in dogs with thrombosis. AB - OBJECTIVE: To prospectively assess (2008 to 2009) all phases of coagulation including thromboelastography in dogs with thrombosis to determine if thrombosis is associated with hypercoagulable states. METHODS: Coagulation reaction in dogs with thrombosis (n = 7) diagnosed by diagnostic imaging or histopathology was compared with 56 control dogs. Dogs pretreated with antiplatelet and anticoagulation drugs were excluded. Thromboelastographic G-values >10 . 3 Kdyn/cm(2) were used to define a hypercoagulable state. RESULTS: Compared with the controls, there was a significantly higher mean platelet component indicating lower platelet activation status (17 . 99 +/-1 . 36 versus 20 . 48 +/-2 . 04 g/dL, P = 0 . 0004), increased thromboelastographic G-value (6 . 4 +/-1 . 6 versus 13 . 1 +/-6 . 2 Kdyn/cm(2) , P = 0 . 0029), activated partial thromboplastin time, fibrinogen, D-dimers (all: P < 0 . 0001) as well as decreased antithrombin (P = 0 . 0049), factor VIII (P < 0 . 0001), protein C (P < 0 . 0001), protein S (P = 0 . 0373) and activated protein C-ratio (P = 0 . 0013). On the basis of thromboelastographic G-value, three of six thromboelastographic tracings were classified as normocoagulable and three as hypercoagulable. CLINICAL RELEVANCE: In dogs with thrombosis, both normo- and hypercoagulable states are present and activated protein C resistance is common. PMID- 23458643 TI - STIR muscle hyperintensity in the cervical muscles associated with inflammatory spinal cord disease of unknown origin. AB - OBJECTIVES: To assess the relation of a distinctive pattern of short tau inversion recovery muscle hyperintensity with inflammatory cerebrospinal fluid result in dogs. METHODS: All dogs that had a short tau inversion recovery sequence performed in addition to other magnetic resonance sequences of the cervical spine and concurrent cerebrospinal fluid evaluation during the study period were included. All magnetic resonance studies were anonymised and reviewed by a board certified radiologist and board certified neurologist. A board certified pathologist examined the cerebrospinal fluid and the results were reviewed. RESULTS: Forty-nine cases fulfilled the inclusion criteria. Repeatable patterns of short tau inversion recovery hyperintensity were identified in 20 dogs. The clinical diagnosis in all these 20 cases was of meningoencephalomyelitis of unknown origin. This diagnosis was confirmed by inflammatory cerebrospinal fluid changes in 18 and suspected from clinical presentation and response to therapy in the remaining 2. CLINICAL SIGNIFICANCE: In this study, the short tau inversion recovery changes identified were restricted to cases with inflammatory spinal cord disease. The short tau inversion recovery change had a sensitivity of 78%, and a specificity of 92% in predicting inflammatory cerebrospinal fluid, suggesting that short tau inversion recovery sequences are a useful addition to the investigation of suspected inflammatory spinal cord disease. PMID- 23458644 TI - Canine breed predispositions for marked hypocobalaminaemia or decreased folate concentration assessed by a laboratory survey. AB - OBJECTIVE: The aim of this study was to determine canine breed predispositions for decreased serum folate or markedly decreased cobalamin concentrations. METHODS: Retrospective analysis of samples from dogs that had serum folate and cobalamin concentrations measured, from 1990 to 2002 at the Comparative Gastroenterology Laboratory of Liverpool, were enrolled. A total of 13,069 samples were analysed. Those with trypsin-like immunoreactivity < 5.0 lg/L were excluded, and only breeds with at least 30 individuals tested were further analyzed. Breed predisposition was determined by calculating odds ratios and 95% confidence intervals for hypocobalaminaemia or decreased folate concentration. Significance was tested with a two-sided Fisher's exact test, and the level of statistical significance was set at P<0.05. RESULTS: A total of 9960 dogs fulfilled the inclusion criteria. Forty breeds contained at least 30 individuals. Predispositions for hypocobalaminaemia were identified in shar peis, Staffordshire bull terriers, German shepherd dogs and mixed breeds. Predispositions for decreased folate concentration were found in golden retrievers and boxers. CLINICAL SIGNIFICANCE: Predisposition for marked hypocobalaminaemia and decreased folate concentration differed between breeds. The shar peis had a markedly increased odds ratio for hypocobalaminaemia, as previously reported in North America, but other at-risk breeds were also identified. PMID- 23458645 TI - Foetal echoencephalography and Doppler ultrasonography of the middle cerebral artery in canine foetuses. AB - OBJECTIVES: This study aimed to evaluate the characteristics of the brain and vascular indices of the middle cerebral artery of canine foetuses. METHODS: Twenty-five bitches were selected. Tissue development, echogenicity, echotexture and brain echobiometric data were studied, and the major structures were identified between the 5th and 8th gestational weeks. The area and volume of the brain mass (BMA and BMV), cranial area and volume (AC and VC), brain mass index (BMI) and brain volume index (BVI) were determined. A single ultrasound examination was performed during each studied week (6th, 7th and 8th). Doppler ultrasonography was performed to assess the maximum and minimum velocity, resistance and pulsatility index of middle cerebral artery of the foetuses. RESULTS: Echoencephalography was performed to evaluate the morphological characteristics of the central nervous system. Cerebral echobiometry indicated an increase in area and volume of the hemispheres and cranium (P<0.001) but no changes in BMI or BVI over the gestational period studied. Doppler ultrasonography identified increases in peak systolic velocity (P=0.0188) and end diastolic velocity (P=0.0274) and decreases in resistance index (P=0.0002) and pulsatility index (P<0.001). CLINICAL SIGNIFICANCE: Echoencephalography and spectral Doppler ultrasonography of the middle cerebral artery in canine foetuses might be a useful technique for prenatal care. PMID- 23458646 TI - Testicular torsion in a normally descended testicle in a cat. PMID- 23458648 TI - Journey from pediatric intensive care to palliative care. AB - BACKGROUND: Approximately two-thirds of patients who die in the pediatric intensive care unit (PICU) do so following withdrawal of intensive care treatment. Most often when intensive care treatment is withdrawn, the child remains in the PICU for end-of-life care. OBJECTIVES: This study aimed to examine the process of referral over a 6-year period of children from a PICU to children's hospices for end-of-life care. METHODS: This study carried out a retrospective review of all children referred from a large tertiary-level United Kingdom PICU to children's hospices over a 6-year period. Information was collected both from the PICU and from the hospices involved. RESULTS: A total of 12 children were transferred over the 6-year period. Discussions about limitation of treatment occurred after an average of 9 days of ventilation, with time from initial referral to transfer taking an additional 4 days such that the mean stay on the PICU prior to transfer was 13 days. Two-thirds of families had prior contact with the palliative care team involved. One-third of the patients were transported to the hospice while still dependent on mechanical invasive ventilatory support. All children were extubated by a PICU consultant within 90 minutes of arrival at the hospice. Overall, eight children died soon after transfer, with four children surviving beyond 2 weeks after transfer. CONCLUSION: This study suggests that there is a feasible alternative location for withdrawal of intensive care and/or compassionate extubation. The study found that one-third of children transferred to hospice for end-of-life care survived the initial withdrawal of intensive therapy; hence, parallel planning should be discussed prior to transfer to hospice. Information gained from this study has contributed toward the creation of a national care pathway to support extubation within a children's palliative care framework. PMID- 23458647 TI - Impact of total pancreatectomy: short- and long-term assessment. AB - BACKGROUND: The aim was to assess the outcome of a total pancreatectomy (TP). METHODS: From 1993 to 2010, 56 patients underwent an elective TP for intraductal papillary mucinous neoplasia (n = 42), endocrine tumours (n = 6), adenocarcinoma (n = 5), metastases (n = 2) and chronic pancreatitis (n = 1). Morbidity and survival were analysed. Long-term survivors were assessed prospectively using quality-of-life (QoL) questionnaires. RESULTS: Five patients developed gastric venous congestion intra-operatively. Post-operative morbidity and mortality rates were 45% and 3.6%, respectively. An anastomotic ulcer occurred in seven patients, but none after proton pump inhibitor therapy. There were five inappropriate TPs according to definitive pathological examination. Overall 3- and 5-year survival rates were 62% and 55% respectively; five deaths were related to TP (two postoperative deaths, one hypoglycaemia, one ketoacidosis and one anastomotic ulcer). Prospective evaluation of 25 patients found that 14 had been readmitted for diabetes and that all had hypoglycaemia within the past month. The glycated haemoglobin (HbA1c) was 7.8% (6.3-10.3). Fifteen patients experienced weight loss. The QLQ-C30 questionnaire showed a decrease in QoL predominantly because of fatigue and diarrhoea, and the QLQ-PAN26 showed an impact on bowel habit, flatulence and eating-related items. DISCUSSION: Morbidity and mortality rates of TP are acceptable, although diabetes- and TP-related mortality still occurs. Endocrine and exocrine insufficiency impacts on the long-term quality of life. PMID- 23458649 TI - Predictive factors of overall well-being using the EORTC QLQ-C15-PAL extracted from the EORTC QLQ-C30. AB - OBJECTIVE: The European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 15 Palliative (EORTC QLQ-C15-PAL) was developed to assess quality of life (QOL) for the palliative cancer population to decrease patient burden. The purpose of this study was to compare predictive factors for well-being in the QLQ-C15-PAL extracted from the EORTC Quality of Life Questionnaire - Core 30 (QLQ-C30) with the QLQ-C30 itself. METHODS AND MATERIALS: Patients with advanced cancer referred for treatment of bone metastases completed the QLQ-C30. Fifteen items from the QLQ-C15-PAL were extracted from the QLQ-C30. Univariate and multivariate analyses were used to determine predictive factors of the global QOL/health score in both tools. In the multivariate analyses, a p value of <0.003 indicated statistical significance. RESULTS: Overall, predictive factors were similar when analyzing data from both tools. Predictive factors for the QLQ-C30 were role functioning (p<0.0001), fatigue (p<0.0001), nausea/vomiting (p<0.0001), and financial problems (p<0.0001) and factors for the extracted QLQ-C15-PAL were physical functioning (p<0.0001) and fatigue (p<0.0001). CONCLUSIONS: Extraction of the QLQ-C15-PAL items from the QLQ-C30 resulted in similar predictive QOL domains for all patient subgroups analyzed individually. The QLQ-C15-PAL is reflective of the QLQ-C30 domains and is recommended for future studies involving patients in a palliative setting, as this shorter questionnaire reduces patient burden and may increase accrual and compliance, while maintaining a similar breadth of coverage and achieving the same predictive ability. PMID- 23458651 TI - Assessment of cancer pain management knowledge in southwest China: a survey of 259 physicians from small city and county hospitals. AB - BACKGROUND: Pain management is a critical issue in the care of cancer patients in China, especially in small city and county hospitals in southwest China. OBJECTIVE: The study intended to determine Chinese physicians' competence in cancer pain management and to assess their opinions on barriers to optimal pain management. DESIGN: A questionnaire on pain management was given to 259 fellows after their general orientation meeting at a tertiary teaching hospital. The questionnaire was adapted from an earlier study by the Eastern Cooperative Oncology Group (ECOG). RESULTS: The majority of the fellows believed that 70% of cancer patients suffer pain. Nearly 90% (224/259) indicated that their training in cancer pain management was poor. The fellows stated that concern about morphine addiction was the primary reason they hesitated to prescribe opioids, and they identified inadequate assessment of cancer pain as the most significant barrier to optimal management of cancer pain. CONCLUSION: The study reflects to some extent the state of pain management in hospitals in southwest China. Medical students and physicians in China need improved pain management education. PMID- 23458654 TI - Have you had your pet spayed or neutered? PMID- 23458655 TI - Hematologic and bone marrow changes in dogs experimentally infected with Rangelia vitalii. AB - BACKGROUND: Rangelia vitalii is a tick-transmitted piroplasm that causes both hemolytic and hemorrhagic disease in dogs in Brazil. OBJECTIVE: The aim of this study was to evaluate the response of the bone marrow in dogs experimentally infected with R vitalii during the acute stage of the disease. METHODS: For this study, 2 groups of a total of 12 young dogs were used. Group A was composed of healthy dogs (n = 5), and group B consisted of animals infected with R vitalii (n = 7). Blood samples were collected on days 0, 10, 20, and 30 post-inoculation and stored in EDTA tubes for a full hematology profile, including a reticulocyte count. On days 10 and 20, bone marrow samples were collected, stained, and examined. RESULTS: In infected dogs anemia was identified on days 10 and 20 post inoculation (P < .01), and on day 20 reticulocytosis was present. Infected dogs had leukopenia due to neutropenia and eosinopenia, along with lymphocytosis and monocytosis, when compared with control animals. In bone marrow, the myeloid:erythroid ratio was significantly decreased (P < .05) in infected dogs due to increased erythroid precursors. CONCLUSIONS: Dogs experimentally infected with R vitalii develop regenerative extravascular hemolytic anemia accompanied by erythroid hyperplasia in the bone marrow. During the acute phase of the disease, leukopenia due to neutropenia and eosinopenia suggests intense tissue recruitment of these cells in response to the endothelial damage caused by this parasite. PMID- 23458656 TI - Peripartal alterations of calcitonin gene-related peptide and minerals in dairy cows affected by milk fever. AB - BACKGROUND: Milk fever, a metabolic disease of dairy cattle, is associated with perturbations of calcium homeostasis, the pathogenesis of which is not yet completely understood. OBJECTIVE: The aim of this study was to investigate plasma concentrations of calcitonin gene-related peptide and selected minerals and metabolites in periparturient cows with and without milk fever. METHODS: Plasma concentrations of calcitonin gene-related peptide, as well as calcium, phosphate, magnesium, iron, glucose, lactate, and cortisol, were determined in multiple plasma samples from Jersey cows with and without spontaneous milk fever. RESULTS: Cows affected by milk fever (n = 5) had lower concentrations of calcitonin gene related peptide (P = .038) and inorganic phosphate (P < .001) in plasma than did the controls (n = 5). Also, these cows tended to have lower calcium concentrations (P = .071). Magnesium, iron, lactate, glucose, and cortisol concentrations were comparable between both groups of cows (P > .10). Around the day of calving, plasma concentrations of lactate, glucose, and cortisol increased and the concentration of iron decreased in all cows (P <= .01). CONCLUSIONS: Despite the limited number of cows evaluated, this report is the first to indicate lowered concentrations of calcitonin gene-related peptide as part of the metabolic changes during milk fever in cows. Further work with a larger cohort of animals is warranted to understand the precise role of calcitonin gene-related peptide and the potential associations with disturbances in plasma minerals typically observed during milk fever. PMID- 23458658 TI - Diagnosing synaesthesia with online colour pickers: maximising sensitivity and specificity. AB - The most commonly used method for formally assessing grapheme-colour synaesthesia (i.e., experiencing colours in response to letter and/or number stimuli) involves selecting colours from a large colour palette on several occasions and measuring consistency of the colours selected. However, the ability to diagnose synaesthesia using this method depends on several factors that have not been directly contrasted. These include the type of colour space used (e.g., RGB, HSV, CIELUV, CIELAB) and different measures of consistency (e.g., city block and Euclidean distance in colour space). This study aims to find the most reliable way of diagnosing grapheme-colour synaesthesia based on maximising sensitivity (i.e., ability of a test to identify true synaesthetes) and specificity (i.e., ability of a test to identify true non-synaesthetes). We show, applying ROC (receiver operating characteristics) to binary classification of a large sample of self-declared synaesthetes and non-synaesthetes, that the consistency criterion (i.e., cut-off value) for diagnosing synaesthesia is considerably higher than the current standard in the field. We also show that methods based on perceptual CIELUV and CIELAB colour models (rather than RGB and HSV colour representations) and Euclidean distances offer an even greater sensitivity and specificity than most currently used measures. Together, these findings offer improved heuristics for the behavioural assessment of grapheme-colour synaesthesia. PMID- 23458659 TI - Excimer laser deinsulation of Parylene-C on iridium for use in an activated iridium oxide film-coated Utah electrode array. AB - Implantable microelectrodes provide a measure to electrically stimulate neurons in the brain and spinal cord and record their electrophysiological activity. A material with a high charge capacity such as activated or sputter-deposited iridium oxide film (AIROF or SIROF) is used as an interface. The Utah electrode array (UEA) uses SIROF for its interface material with neural tissue and oxygen plasma etching (OPE) with an aluminium foil mask to expose the active area, where the interface between the electrode and neural tissue is formed. However, deinsulation of Parylene-C using OPE has limitations, including the lack of uniformity in the exposed area and reproducibility. While the deinsulation of Parylene-C using an excimer laser is proven to be an alternative for overcoming the limitations, the iridium oxide (IrOx) suffers from fracture when high laser fluence (>1000 mJ/cm2) is used. Iridium (Ir), which has a much higher fracture resistance than IrOx, can be deposited before excimer laser deinsulation and then the exposed Ir film area can be activated by electrochemical treatment to acquire the AIROF. Characterisation of the laser-ablated Ir film and AIROF by surface analysis (X-ray photoelectron spectroscopy, scanning electron microscope, and atomic force microscope) and electrochemical analysis (electrochemical impedance spectroscopy, and cyclic voltammetry) shows that the damage on the Ir film induced by laser irradiation is significantly less than that on SIROF, and the AIROF has a high charge storage capacity. The results show the potential of the laser deinsulation technique for use in high performance AIROF-coated UEA fabrication. PMID- 23458660 TI - The interplay of externalizing problems and physical and inductive discipline during childhood. AB - Children who are physically disciplined are at elevated risk for externalizing problems. Conversely, maternal reasoning and reminding of rules, or inductive discipline, is associated with fewer child externalizing problems. Few studies have simultaneously examined bidirectional associations between these forms of discipline and child adjustment using cross-informant, multimethod data. We hypothesized that less inductive and more physical discipline would predict more externalizing problems, children would have evocative effects on parenting, and high levels of either form of discipline would predict low levels of the other. In a study of 241 children-spanning ages 3, 5.5, and 10-structural equation modeling indicated that 3-year-olds with higher teacher ratings of externalizing problems received higher mother ratings of physical discipline at age 5.5. Mothers endorsing more inductive discipline at child age 3 reported less physical discipline and had children with fewer externalizing problems at age 5.5. Negative bidirectional associations emerged between physical and inductive discipline from ages 5.5 to 10. Findings suggested children's externalizing problems elicited physical discipline, and maternal inductive discipline might help prevent externalizing problems and physical discipline. PMID- 23458661 TI - Language matters: thirteen-month-olds understand that the language a speaker uses constrains conventionality. AB - Object labels are valuable communicative tools because their meanings are shared among the members of a particular linguistic community. The current research was conducted to investigate whether 13-month-old infants appreciate that object labels should not be generalized across individuals who have been shown to speak different languages. Using a visual habituation paradigm, Experiment 1 tested whether infants would generalize a new object label that was taught to them by a speaker of a foreign language to a speaker from the infant's own linguistic group. The results suggest that infants do not expect 2 individuals who have been shown to speak different languages to use the same label to refer to the same object. The results of Experiment 2 reveal that infants do not generalize a new object label that was taught to them by a speaker of their native language to an individual who had been shown to speak a foreign language. These findings offer the first evidence that by the end of the 1st year of life, infants are sensitive to the fact that the conventional nature of language is constrained by the language that a person has been shown to speak. PMID- 23458663 TI - How selective are 3-year-olds in imitating novel linguistic material? AB - In 3 studies we explored when 3-year-olds would imitate novel words in utterances produced by adult speakers. Child and experimenter took turns in requesting objects from a game master. The experimenter always went first and always preceded the object's familiar name with a novel adjective (e.g., "the dilsige duck"). In the first 2 experiments, we found that children were more likely to reproduce the adjective when there were 2 different instances of the same object present in the situation than when there was only 1 or when there were 2 objects of different types present. Thus, children seemed to be sensitive to the descriptive and contrastive function of the adjectives in determining which parts of the utterances to reproduce. Nonetheless, replication of even redundant material was over 50%, suggesting a strategy of somewhat blind copying. In the 3rd experiment, we found that children were less likely to reproduce a redundant adjective when the speaker indicated gesturally that he did not intend to produce it than when he clearly produced it intentionally. We distinguish insightful imitation (the copying of a speaker's goal and means when motivated by insight into why those particular means were chosen) and blind imitation (the copying of a speaker's goal and means with no awareness of why those specific means were chosen) from mimicry. We explore the roles that these modes of imitation might play in language development. PMID- 23458662 TI - The impact of the developmental timing of trauma exposure on PTSD symptoms and psychosocial functioning among older adults. AB - The present study examined the impact of the developmental timing of trauma exposure on posttraumatic stress disorder (PTSD) symptoms and psychosocial functioning in a large sample of community-dwelling older adults (N = 1,995). Specifically, we investigated whether the negative consequences of exposure to traumatic events were greater for traumas experienced during childhood, adolescence, young adulthood, midlife, or older adulthood. Each of these developmental periods is characterized by age-related changes in cognitive and social processes that may influence psychological adjustment following trauma exposure. Results revealed that older adults who experienced their currently most distressing traumatic event during childhood exhibited more severe symptoms of PTSD and lower subjective happiness compared with older adults who experienced their most distressing trauma after the transition to adulthood. Similar findings emerged for measures of social support and coping ability. The differential effects of childhood compared with later life traumas were not fully explained by differences in cumulative trauma exposure or by differences in the objective and subjective characteristics of the events. Our findings demonstrate the enduring nature of traumatic events encountered early in the life course and underscore the importance of examining the developmental context of trauma exposure in investigations of the long-term consequences of traumatic experiences. PMID- 23458664 TI - Metal stents: a bridge to surgery in hilar cholangiocarcinoma. AB - BACKGROUND: Obstructive jaundice in patients with hilar cholangiocarcinoma is a known risk factor for hepatic failure after liver resection. Plastic stents are most widely used for preoperative drainage. However, plastic stents are known to have limited patency time and therefore, in palliative settings, the self expanding metal stent (SEMS) is used. This type of stent has been shown to be superior because it allows for rapid biliary decompression and a reduced complication rate after insertion. This study explores the use of the SEMS for biliary decompression in patients with operable hilar cholangiocarcinoma. METHODS: A retrospective evaluation of a prospectively maintained database at a tertiary hepatobiliary referral centre was carried out. All patients with resectable cholangiocarcinoma were recorded. RESULTS: Of 260 patients referred to this unit with cholangiocarcinoma between January 2008 and April 2012, 50 patients presented with operable cholangiocarcinoma and 27 of these had obstructive jaundice requiring stenting. Ten patients were initially treated with SEMSs; no stent failure occurred in these patients. Seventeen patients initially received plastic stents, seven of which failed in the interval between stent placement and laparotomy. These stents were replaced by SEMSs in four patients and by plastic stents in three patients. Median time to laparotomy was 45 days and 68 days in patients with SEMSs and plastic stents, respectively. CONCLUSIONS: Self-expanding metal stents provide adequate and rapid biliary drainage in patients with obstruction caused by hilar cholangiocarcinoma. No re-interventions were required. This probably reflects the relatively short interval between stent placement and laparotomy. PMID- 23458665 TI - Hsp90 Inhibitor SNX-7081 dysregulates proteins involved with DNA repair and replication and the cell cycle in human chronic lymphocytic leukemia (CLL) cells. AB - The proteomic effects of the Hsp90 inhibitor, SNX-7081, have been determined on the p53-mutated B-cell chronic lymphocytic leukemia (CLL) cell line, MEC1. Following SNX-7081 treatment (500 nM, 24 h), 51 proteins changed abundance by more than 2-fold (p < 0.05); 7 proteins increased while 44 proteins decreased. Proteins identified as differentially abundant by LC-MS/MS were validated by Western blotting (DDB1, PCNA, MCM2, Hsp90, Hsp70, GRP78, PDIA6, HLA-DR). RT-PCR showed that SNX-7081 unexpectedly modulates a number of these proteins in MEC1 cells at the mRNA level (PCNA, MCM2, Nup155, Hsp70, GRP78, PDIA6, and HLA-DR). Pathway analysis determined that 3 of the differentially abundant proteins (cyclin D1, c-Myc and pRb) were functionally related. p53 levels did not change upon SNX-7081 treatment of p53 wild-type Raji cells or p53-mutated MEC1 and U266 cells, indicating that SNX-7081 has a p53-independent mechanism. The decreases in DDB1, MCM2, c-Myc, and PCNA and increases of pRb and cyclin D1 were confirmed in MEC1, U266, Raji, and p53 null HL60 cells by Western blotting. These data suggest that SNX-7081 arrests the cell cycle and inhibits DNA replication and r epair and provides evidence for the mechanism of the observed synergy between Hsp90 inhibitors and drugs that induce DNA strand breaks. PMID- 23458666 TI - Spleen-preserving distal pancreatectomy with and without splenic vessel ligation: a systematic review. AB - BACKGROUND: Splenic preservation during a distal pancreatectomy (SPDP) may be performed with splenic vessel ligation, known as Warshaw's Technique (WT) or splenic vessel preservation (SVP). The consensus on which approach is best is divided. A systematic review of evidence in the literature was undertaken with the aim of analysing the merits and disadvantages of both WT and SVP. METHODS: A systematic search of medical literature from 1985-2011 was undertaken to identify all comparative studies and case series on SPDP. Non-English papers, series with < 5 patients, technical reports and reviews were excluded. The remaining articles were reviewed considering the study design, surgical technique, outcomes and complications. RESULTS: In 23 relevant studies, 356 patients underwent WT and 572 underwent SVP. In WT patients, the mean operating time (160 versus 215 min, P < 0.001), mean estimated blood loss (301 versus 390 ml, P < 0.001) and length of stay (8 versus 11 days, P < 0.001) was significantly less than the SVP patients, respectively. Considering complications, splenic infarction and splenectomy occurred more frequently in WT patients (P < 0.05). DISCUSSION: WT is technically easier to perform than SVP but has a higher incidence of subsequent splenectomies. Surgeons should be able to perform both procedures and tailor the technique according to the patient. PMID- 23458667 TI - Effect of homocysteinylation on structure, chaperone activity and fibrillation propensity of lens alpha-crystallin. AB - Various chemical modifications can reduce chaperone activity of alpha-crystallin (alpha-Cry) and the loss of which has been implicated in the development of cataract diseases. The side chains of lysine residues are the target of both glycation and homocysteinylation, and lysine modification by the two reactions may similarly affect the structure and function of alpha- Cry. In this study, alpha-Cry was incubated with homocysteine thiolactone (HCTL), resulting in significant protein homocysteinylation, as determined with Ellman's assay. Homocysteinylation of alpha-Cry resulted in the reduction in surface hydrophobicity and alpha-helix to beta-sheet transition, as observed respectively with fluorescence and circular dichroism (CD) spectroscopy. The structural alteration of homocysteinylated alpha-Cry was accompanied by protein aggregation, including the formation of amyloid fibrils as detected by thioflavin T (ThT) fluorescence and Congo red (CR) absorption spectroscopy. The mobility shifts of homocysteinylated alpha-Cry on reducing and non-reducing SDS-PAGEs suggest that disulfide cross-linking in addition to lysine modification, also plays a role in aggregation of this protein. The chaperone activities of alpha-Cry, namely to prevent aggregation, to assist refolding and to restore activity of thermally stressed alpha-glucosidase (alpha-Gls) were reduced after homocysteinylation. Overall, this study suggests that similar to non-enzymatic glycation, homocysteinylation of alpha-Cry is a risk factor for the development of cataract disorders, for instance during hyperhomocysteinemia which is linked to the various ocular pathological disorders. PMID- 23458668 TI - In silico identification of common epitopes from pathogenic mycobacteria. AB - An in silico study was carried out to identify antigens for their possible collective use as vaccine candidates against diseases caused by different classes of pathogenic mycobacteria with significant clinical relevance. The genome sequences of the relevant causative agents were used in order to search for orthologous genes among them. Bioinformatics tools permitted us to identify several conserved sequences with 100% identity with no possibility of cross reactivity to the normal flora and human proteins. Nine different proteins were characterized using the strain H37Rv as reference and taking into account their functional category, their in vivo expression and subcellular location. T and B cell epitopes were identified in the selected sequences. Theoretical prediction of population coverage was calculated for individual epitopes as well as their combinations. Several identical sequences, belonging to six proteins containing T and B cell epitopes which are not present in selected microorganisms of the normal microbial flora or in human proteins were obtained. PMID- 23458669 TI - Spiropyran to merocyanine conversion: explicit versus implicit solvent modeling. AB - A polarizable continnum model study and explicit solvation in water investigated through GPU-accelerated ab initio molecular dynamics followed by quantum-chemical calculations have been applied to the process of spiropyran to merocyanine isomerization of two spiropyran derivatives. It has been found that interaction with only one or two water molecules is sufficient to stabilize the merocyanine with respect to the spiropyran form. It has been shown that the agreement between energies obtained in implicit and explicit solvent models depends on the structure of the system and possible specific interactions (hydrogen bonds). Both solvent models predict similar effects in absorption spectra. PMID- 23458670 TI - Association between the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene and sensitivity to analgesics and pain in patients undergoing painful cosmetic surgery. AB - To elucidate the mechanisms of individual differences in pain and analgesic sensitivity, we analyzed the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene. Alleles that were less than four repeats long and four or more repeats long were considered Short and Long, respectively. We found that the Short/Short genotype group was significantly more sensitive to pain and less sensitive to analgesics than the Short/Long+Long/Long genotype group. Our data suggest that this polymorphism may predict individual differences in pain and analgesic sensitivity and help achieve adequate pain control in the future. PMID- 23458671 TI - Intrafusal effects of botulinum toxin injections for spasticity: revisiting a previous paper. AB - Botulinum toxin, frequently used to manage focal limb spasticity, has been reported to affect both extrafusal and intrafusal fibers of the injected muscle. Since most studies have used spinal reflexes, it is difficult to isolate the intrafusal effects from extrafusal and central effects. In a paper by On et al. [7], both stretch and H-reflexes were used to examine the intrafusal effects of botulinum toxin injections. Revisiting the data from On et al. [7] presented a unique opportunity to describe a novel method of measuring the effect of botulinum toxin-A on muscle spindle activity in patients with spasticity. H reflex, maximum M-wave, and Achilles tendon reflex were serially assessed in ten patients with stroke pre-, 2, 4, and 12 weeks post-botulinum. In order to assess the intrafusal effects, we subtracted the %change in H-reflex amplitude from baseline (representing extrafusal and central effects) from the %change in Achilles tendon reflex amplitude from baseline (representing intrafusal, extrafusal and central effects). Using this formula, our results suggest that botulinum induces significant chemodenervation of the intrafusal muscle fibers (33% decreases). Intrafusal effects were greatest at 2 weeks, but tapered off by 12 weeks post-botulinum (p<0.017). We found a significant positive correlation between the intrafusal effects of botulinum toxin and changes in modified Ashworth scale. Our method of assessing the effects of botulinum toxin shows significant effect on intrafusal fibers, which correlates with clinical manifestation of spasticity. Future studies need to investigate ways to maximize intrafusal effects and minimize extrafusal effects of botulinum therapy. PMID- 23458672 TI - Memantine protects cholinergic and glutamatergic septal neurons from Abeta1-40 induced toxicity. AB - The medial septal region (medial septum and diagonal band of Broca, MS/DB) controls hippocampal excitability and synaptic plasticity. MS/DB cholinergic neurons degenerate early in Alzheimer's disease (AD). The presence of MS/DB glutamatergic neurons that project to the hippocampus and are vulnerable to Abeta suggests that excitotoxicity plays a role in AD septal degeneration and hippocampal dysfunction. To demonstrate the presence of excitotoxicity in Abeta induced septal damage, we compared rats injected with Abeta1-40 into the MS/DB with animals treated with memantine prior, during and after Abeta1-40 injections. Controls were injected with phosphate buffered saline (PBS). MS/DB cholinergic, glutamatergic and GABAergic neurons were immunochemically identified. The number of MS/DB neurons was estimated using stereology. Our results show that memantine blocks Abeta1-40-induced septal damage and suggest that excitotoxicity plays a role in basal forebrain neurodegeneration. PMID- 23458674 TI - Neuroprotective effects of uridine in a rat model of neonatal hypoxic-ischemic encephalopathy. AB - Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neurological disability requiring newer therapeutic strategies. Uridine is the principal circulating pyrimidine in humans and a substrate for nucleotides and membrane phospholipids. The objective of this study was to investigate the effects of uridine in a neonatal rat model of HIE. Rat pups subjected to hypoxic-ischemic insult on postnatal day 7 were injected intraperitoneally with either saline or uridine (100, 300 or 500mg/kg) for three consecutive days and brains were collected for evaluation of brain infarct volume and apoptosis. Compared with Control group, uridine at 300 and 500mg/kg doses significantly reduced percent infarct volume, TUNEL(+) cell ratio and active Caspase-3 immunoreactivity in the cortex, as well as in CA1 and CA3 regions of the hippocampus. Uridine (300 and 500mg/kg) also decreased active Caspase-3 expression in the ipsilateral hemisphere. These data indicate that uridine dose-dependently reduces brain injury in a rat model of neonatal HIE by decreasing apoptosis. PMID- 23458673 TI - DBH gene as predictor of response in a cocaine vaccine clinical trial. AB - We examined a pharmacogenetic association of the dopamine beta-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo controlled trial of 114 cocaine and opioid dependent subjects who received five vaccinations over the first 12 weeks was examined. We genotyped 71 subjects for the rs1611115 (-1021C>T) variant of the DBH gene and compared vaccine to placebo subjects on cocaine-free urines. Using repeated measures analysis of variance, corrected for population structure, vaccine pharmacotherapy reduced cocaine positive urines significantly based on DBH genotype. Patients with the low DbetaH level genotype dropped from 77% to 51% on vaccine (p=0.0001), while those with the normal DbetaH level genotype dropped from 83% to 72%. Placebo showed no effect on cocaine use overall or by genotype. This study indicates that a patient's DBH genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence. PMID- 23458675 TI - Event-related desynchronization (ERD) in the alpha band during a hand mental rotation task. AB - Recent studies have demonstrated that mentally rotating the hands involves participants engaging in motor imagery processing. However, far less is known about the possible neurophysiological basis of such processing. To contribute to a better understanding of hand mental rotation processing, event-related spectral perturbation (ERSP) methods were applied to electroencephalography (EEG) data collected from participants mentally rotating their hands. Time-frequency analyses revealed that alpha-band power suppression was larger over central parietal regions. This is in accordance with motor imagery findings suggesting that the motor regions may be involved in processing or detection of kinaesthetic information. Furthermore, the presence of a significant negative correlation between reaction times (RTs) and alpha-band power suppression over central regions is illustrated. These findings are consistent with the neural efficiency hypothesis, which proposes the non-use of many brain regions irrelevant for the task performance as well as the more focused use of specific task-related regions in individuals with better performance. These results indicate that ERSP provides some independent insights into the mental rotation process and further confirms that parietal and motor cortices are involved in mental rotation. PMID- 23458676 TI - Power spectra of the natural input to the visual system. AB - The efficient coding hypothesis posits that sensory systems are adapted to the regularities of their signal input so as to reduce redundancy in the resulting representations. It is therefore important to characterize the regularities of natural signals to gain insight into the processing of natural stimuli. While measurements of statistical regularity in vision have focused on photographic images of natural environments it has been much less investigated, how the specific imaging process embodied by the organism's eye induces statistical dependencies on the natural input to the visual system. This has allowed using the convenient assumption that natural image data are homogeneous across the visual field. Here we give up on this assumption and show how the imaging process in a human model eye influences the local statistics of the natural input to the visual system across the entire visual field. Artificial scenes with three dimensional edge elements were generated and the influence of the imaging projection onto the back of a spherical model eye were quantified. These distributions show a strong radial influence of the imaging process on the resulting edge statistics with increasing eccentricity from the model fovea. This influence is further quantified through computation of the second order intensity statistics as a function of eccentricity from the center of projection using samples from the dead leaves image model. Using data from a naturalistic virtual environment, which allows generation of correctly projected images onto the model eye across the entire field of view, we quantified the second order dependencies as function of the position in the visual field using a new generalized parameterization of the power spectra. Finally, we compared this analysis with a commonly used natural image database, the van Hateren database, and show good agreement within the small field of view available in these photographic images. We conclude by providing a detailed quantitative analysis of the second order statistical dependencies of the natural input to the visual system across the visual field and demonstrating the importance of considering the influence of the sensory system on the statistical regularities of the input to the visual system. PMID- 23458677 TI - Spatio-temporal topography of saccadic overestimation of time. AB - Rapid eye movements (saccades) induce visual misperceptions. A number of studies in recent years have investigated the spatio-temporal profiles of effects like saccadic suppression or perisaccadic mislocalization and revealed substantial functional similarities. Saccade induced chronostasis describes the subjective overestimation of stimulus duration when the stimulus onset falls within a saccade. In this study we aimed to functionally characterize saccade induced chronostasis in greater detail. Specifically we tested if chronostasis is influenced by or functionally related to saccadic suppression. In a first set of experiments, we measured the perceived duration of visual stimuli presented at different spatial positions as a function of presentation time relative to the saccade. We further compared perceived duration during saccades for isoluminant and luminant stimuli. Finally, we investigated whether or not saccade induced chronostasis is dependent on the execution of a saccade itself. We show that chronostasis occurs across the visual field with a clear spatio-temporal tuning. Furthermore, we report chronostasis during simulated saccades, indicating that spurious retinal motion induced by the saccade is a prime origin of the phenomenon. PMID- 23458678 TI - Body image and gestational weight gain: a prospective study. AB - INTRODUCTION: Approximately 50% of Australian adult women of childbearing age are overweight or obese, and, when pregnant, the majority gain excessive weight; this is also the case in the United States and other developed nations. High gestational weight gain (GWG) is the strongest predictor of maternal overweight/obesity postbirth and is also associated with an increased risk of childhood obesity. Understanding factors that contribute to excessive GWG is vital in combating obesity. The aim of the current study was to examine whether body image attitudes (eg, feeling fat, attractive, or strong and fit, and salience of weight and shape) predict GWG. METHODS: Pregnant women, recruited through advertisements on pregnancy online forums and parenting magazines, completed questionnaires assessing body image, demographic variables, and GWG. The Body Attitudes Questionnaire assessed body image in early-to-middle, middle, and late pregnancy (mean of 16.8, 24.7, and 33.0 weeks' gestation, respectively). Total GWG was calculated by subtracting self-reported pre pregnancy weight from self-reported weight at 36.8 weeks' gestation. RESULTS: A total of 150 pregnant women responded to the study's advertisements, and 72% (n = 108) took part. After controlling for pre pregnancy body mass index (BMI), lower attractiveness in early-to-middle pregnancy was associated with higher GWG. In late pregnancy, women who had the lowest feelings of fatness had greater GWG. Body image attitudes earlier in pregnancy did not predict whether GWG recommendations were exceeded. Women of higher BMI were more likely to gain excessive weight. DISCUSSION: The findings suggest that the type and timing of pregnancy, body attitudes, and the time of pregnancy when they are noted, predict GWG. However, more research in the area is needed, including assessment of the relationship between body image concerns, GWG, and other psychosocial factors. We recommend that midwives monitor body image concerns in pregnancy to help address factors affecting GWG in at-risk women. PMID- 23458679 TI - Triple approach strategy for patients with locally advanced pancreatic carcinoma. AB - BACKGROUND: Radiofrequency ablation (RFA) is a relatively new technique, applied to metastatic solid tumours which, in recent studies, has been shown to be feasible and safe on locally advanced pancreatic carcinoma (LAPC). RFA can be combined with radio-chemotherapy (RCT) and intra-arterial plus systemic chemotherapy (IASC). The aim of this study was to investigate the impact on the prognosis of a multimodal approach to LAPC and define the best timing of RFA. METHODS: This is a retrospective observational study of patients who have consecutively undergone RFA associated with multiple adjuvant approaches. RESULTS: Between February 2007 and December 2011, 168 consecutive patients were treated by RFA, of which 107 were eligible for at least 18 months of follow-up. Forty-seven patients (group 1) underwent RFA as an up-front treatment and 60 patients as second treatment (group 2) depending on clinician choice. The median overall survival (OS) of the whole series was 25.6 months: 14.7 months in the group 1 and 25.6 months in the group 2 (P = 0.004). Those patients who received the multimodal treatment (RFA, RCT and IASC-triple approach strategy) had an OS of 34.0 months. CONCLUSIONS: The multimodal approach seems to be feasible and associated with an improved longer survival rate. PMID- 23458680 TI - Tertiary and quaternary allostery in tetrameric hemoglobin from Scapharca inaequivalvis. AB - The clam Scapharca inaequivalvis possesses two cooperative oxygen binding hemoglobins in its red cells: a homodimeric HbI and a heterotetrameric A2B2 HbII. Each AB dimeric half of HbII is assembled in a manner very similar to that of the well-studied HbI. This study presents crystal structures of HbII along with oxygen binding data both in the crystalline state and in wet nanoporous silica gels. Despite very similar ligand-linked structural transitions observed in HbI and HbII crystals, HbII in the crystal or encapsulated in silica gels apparently exhibits minimal cooperativity in oxygen binding, in contrast with the full cooperativity exhibited by HbI crystals. However, oxygen binding curves in the crystal indicate the presence of a significant functional inequivalence of A and B chains. When this inequivalence is taken into account, both crystal and R state gel functional data are consistent with the conservation of a tertiary contribution to cooperative oxygen binding, quantitatively similar to that measured for HbI, and are in keeping with the structural information. Furthermore, our results indicate that to fully express cooperative ligand binding, HbII requires quaternary transitions hampered by crystal lattice and gel encapsulation, revealing greater complexity in cooperative function than the direct communication across a dimeric interface observed in HbI. PMID- 23458681 TI - Cost benefit analysis of mesh reinforcement of stapled left pancreatectomy. AB - OBJECTIVES: Pancreatic leak is a morbid complication following left pancreatectomy, which results in prolonged hospitalization, additional diagnostic testing and invasive procedures. The present authors have previously demonstrated that mesh reinforcement of stapled left pancreatectomy results in fewer pancreatic leaks. This study was conducted to investigate whether mesh reinforcement also results in cost benefits for the health care system. METHODS: A cost benefit model was developed to estimate net cost savings from the payer's perspective. The model is based on the results of a randomized, single-blinded trial of mesh versus no mesh reinforcement of the pancreatic remnant after left pancreatectomy. A two-way sensitivity analysis was conducted to determine the model's sensitivity to fluctuations in the cost of mesh and the effectiveness of the mesh in reducing clinically significant leaks. RESULTS: Average total costs for an episode of care were US$13 337 and US$15 505 for patients who did and did not receive mesh, respectively, which indicates savings of US$2168. Two-way sensitivity analysis showed that, given a probability of 1.9% for developing a clinically significant leak in patients in whom mesh reinforcement was used, the strategy would continue to save costs if mesh were priced at <=US$1804. CONCLUSIONS: Mesh reinforcement decreases clinically significant pancreatic leaks. Despite the additional cost of mesh reinforcement, the use of mesh reinforcement results in overall cost savings for the health care system because of the resultant decrease in the occurrence of clinically significant leaks. PMID- 23458682 TI - The allosteric modulation of thyroxine-binding globulin affinity is entropy driven. AB - BACKGROUND: Thyroxine-binding globulin (TBG) is a non-inhibitory member of the serpin family of proteins whose main structural element is the reactive center loop (RCL), that, upon cleavage by proteases, is inserted into the protein core adopting a beta-strand conformation (stressed to relaxed transition, S-to-R). After S-to-R transition thyroxine (T4) affinity decreases. However, crystallographic studies in the presence or absence of the hormone in different states are unable to show significant differences in the structure and interactions of the binding site. Experimental results also suggest the existence of several S states (differing in the number of inserted RCL residues), associated with a differential affinity. METHODS: To shed light into the molecular basis that regulates T4 affinity according to the degree of RCL insertion in TBG, we performed extended molecular dynamics simulations combined with several thermodynamic analysis of the T4 binding to TBG in three different S states, and in the R state. RESULTS: Our results show that, despite T4 binding in the protein by similar interactions in all states, a good correlation between the degree of RCL insertion and the binding affinity, driven by a change in TBG conformational entropy, was observed. CONCLUSION: TBG allosteric regulation is entropy driven. The presence of multiple S states may allow more efficient T4 release due to protease activity. GENERAL SIGNIFICANCE: The presented results are clear examples of how computer simulation methods can reveal the thermodynamic basis of allosteric effects, and provide a general framework for understanding serpin allosteric affinity regulation. PMID- 23458683 TI - Crystal structure of a Bombyx mori sigma-class glutathione transferase exhibiting prostaglandin E synthase activity. AB - BACKGROUND: Glutathione transferases (GSTs) are members of a major family of detoxification enzymes. Here, we report the crystal structure of a sigma-class GST of Bombyx mori, bmGSTS1, to gain insight into the mechanism catalysis. METHODS: The structure of bmGSTS1 and its complex with glutathione were determined at resolutions of 1.9A and 1.7A by synchrotron radiation and the molecular replacement method. RESULTS: The three-dimensional structure of bmGSTS1 shows that it exists as a dimer and is similar in structure to other GSTs with respect to its secondary and tertiary structures. Although striking similarities to the structure of prostaglandin D synthase were also detected, we were surprised to find that bmGSTS1 can convert prostaglandin H2 into its E2 form. Comparison of bmGSTS1 with its glutathione complex showed that bound glutathione was localized to the glutathione-binding site (G-site). Site-directed mutagenesis of bmGSTS1 mutants indicated that amino acid residues Tyr8, Leu14, Trp39, Lys43, Gln50, Met51, Gln63, and Ser64 in the G-site contribute to catalytic activity. CONCLUSION: We determined the tertiary structure of bmGSTS1 exhibiting prostaglandin E synthase activity. GENERAL SIGNIFICANCE: These results are, to our knowledge, the first report of a prostaglandin synthase activity in insects. PMID- 23458684 TI - Role of TRPM2 and TRPV1 cation channels in cellular responses to radiation induced DNA damage. AB - BACKGROUND: Radiation exposure causes DNA damage, and DNA repair systems are essential to rescue damaged cells. Although DNA damage or oxidative stress activates transient receptor potential melastatin 2 (TRPM2) and vanilloid 1 (TRPV1) cation channels, it has not been established whether these TRP channels are involved in cellular responses to radiation-induced DNA damage. Here, we investigated the contribution of TRPM2 and TRPV1 channels to gamma-irradiation- and UVB-induced DNA damage responses in human lung cancer A549 cells. METHODS: A549 cells were irradiated with gamma-rays (2.0Gy) or UVB (5-10mJ/cm(2)). gammaH2AX foci, ATM activation, 53BP1 accumulation and EGFR expression were evaluated by immunofluorescence staining. Extracellular ATP concentration was measured by luciferin-luciferase assay. Knockdown of TRPM2 and TRPV1 expression was done by siRNA transfection. RESULTS: gamma-Irradiation-induced gammaH2AX focus formation, ATM activation, 53BP1 accumulation and EGFR nuclear translocation, which are all associated with DNA repair, were suppressed by knockdown of TRPM2 and TRPV1 channels in A549 cells. Release of ATP, which mediates DNA damage response-associated activation of P2Y receptors, was suppressed by pre-treatment with catalase or knockdown of TRPM2 channel, but not TRPV1 channel. Similarly, UVB-induced gammaH2AX focus formation was suppressed in TRPM2- and TRPV1-knockdown cells, while UVB-induced ATP release was blocked in TRPM2- but not TRPV1-knockdown cells. CONCLUSION: Our results suggest that the activation of TRPM2 channel, which mediates ATP release, and TRPV1 channel plays significant roles in the cellular responses to DNA damage induced by gamma irradiation and UVB irradiation. GENERAL SIGNIFICANCE: Our results provide a new insight into the function of TRP channels from the viewpoint of radiation biology. PMID- 23458685 TI - MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein. AB - BACKGROUND: Bone is a common site of metastasis for lung cancer, and is associated with significant morbidity and a dismal prognosis. MicroRNAs (miRNAs) are increasingly implicated in regulating the progression of malignancies. METHODS: The efficacy of miR-33a or anti-miR-33a plasmid was assessed by Real time PCR. Luciferase assays were using One-Glo Luciferase Assay System. Measurement of secreted factors was determined by ELISA kit. RESULTS: We have found that miR-33a, which is downregulated in lung cancer cells, directly targets PTHrP (parathyroid hormone-related protein), a potent stimulator of osteoclastic bone resorption, leading to decreased osteolytic bone metastasis. We also found that miR-33a levels are inversely correlated with PTHrP expression between human normal bronchial cell line and lung cancer cell lines. The reintroduction of miR 33a reduces the stimulatory effect of A549 on the production of osteoclastogenesis activator RANKL (receptor activator of nuclear factor kappa-B ligand) and M-CSF (macrophage colony-stimulating factor) on osteoblasts, while the expression of PTHrP is decreased in A549 cells. miR-33a overexpression also reduces the inhibitory activity of A549 on the production of OPG (osteoprotegerin), an osteoclastogenesis inhibitor. In addition, miR-33a-mediated PTHrP downregulation results in decreased IL-8 secretion in A549, which contributes to decreased lung cancer-mediated osteoclast differentiation and bone resorption. CONCLUSIONS: These findings have led us to conclude that miR-33a may be a potent tumor suppressor, which inhibits direct and indirect osteoclastogenesis through repression of PTHrP. GENERAL SIGNIFICANCE: miR-33a may even predict a poor prognosis for lung cancer patients. PMID- 23458686 TI - Systematic reviews: an important anniversary, new reporting standards, and potential greater impact. PMID- 23458687 TI - Systems biology and birth defects prevention: blockade of the glucocorticoid receptor prevents arsenic-induced birth defects. AB - BACKGROUND: The biological mechanisms by which environmental metals are associated with birth defects are largely unknown. Systems biology-based approaches may help to identify key pathways that mediate metal-induced birth defects as well as potential targets for prevention. OBJECTIVES: First, we applied a novel computational approach to identify a prioritized biological pathway that associates metals with birth defects. Second, in a laboratory setting, we sought to determine whether inhibition of the identified pathway prevents developmental defects. METHODS: Seven environmental metals were selected for inclusion in the computational analysis: arsenic, cadmium, chromium, lead, mercury, nickel, and selenium. We used an in silico strategy to predict genes and pathways associated with both metal exposure and developmental defects. The most significant pathway was identified and tested using an in ovo whole chick embryo culture assay. We further evaluated the role of the pathway as a mediator of metal-induced toxicity using the in vitro midbrain micromass culture assay. RESULTS: The glucocorticoid receptor pathway was computationally predicted to be a key mediator of multiple metal-induced birth defects. In the chick embryo model, structural malformations induced by inorganic arsenic (iAs) were prevented when signaling of the glucocorticoid receptor pathway was inhibited. Further, glucocorticoid receptor inhibition demonstrated partial to complete protection from both iAs- and cadmium-induced neurodevelopmental toxicity in vitro. CONCLUSIONS: Our findings highlight a novel approach to computationally identify a targeted biological pathway for examining birth defects prevention. PMID- 23458688 TI - Using immunoproteomics to identify alpha-enolase as an autoantigen in liver fibrosis. AB - Liver fibrosis results from extracellular matrix accumulation during the wound healing process when the liver is insulted with chronic viral infection, inflammation, or alcoholic diseases. The current diagnosis of liver fibrosis is mainly dependent on biopsy, which is an invasive approach. Identification of serological biomarkers has been considered as the most promising way for early detection of the disease. Although several biomarkers in liver fibrosis have been identified, the problem is that these markers can be also detected in fibrogenesis that occurred in other organs. In this study, we have identified and characterized some cellular proteins that can be recognized by autoantibodies in the sera from patients with precirrhotic stage of liver fibrosis. Among 180 sera from patients with liver fibrosis, 14.4% (26/180) of sera contained autoantibody against a protein migrating around 47 kDa on SDS-PAGE gel. Indirect immunofluorescence assay using purified autoantibody against the 47-kDa protein showed that this protein mainly localized in the cytoplasm. Using immunoproteomic approach, the 47-kDa protein was identified as alpha-enolase. In further study, the frequency of antialpha-enolase antibody in sera from patients with precirrhotic stage of liver fibrosis (21.6%, 27/125) was significantly higher than that in sera from patients with cirrhosis (9.1%, 5/55) and liver cancer (14.3%, 12/84), as well as in sera from healthy individuals (4.1%, 3/74). Therefore, alpha-enolase is an autoantigen that elicits autoimmune response in liver fibrosis and can be a potential prognostic factor for liver fibrosis diagnosis. PMID- 23458689 TI - Crystal structure of the pilotin from the enterohemorrhagic Escherichia coli type II secretion system. AB - Bacteria contain several sophisticated macromolecular machineries responsible for translocating proteins across the cell envelope. One prominent example is the type II secretion system (T2SS), which contains a large outer membrane channel, called the secretin. These gated channels require specialized proteins, so-called pilotins, to reach and assemble in the outer membrane. Here we report the crystal structure of the pilotin GspS from the T2SS of enterohemorrhagic Escherichia coli (EHEC), an important pathogen that can cause severe disease in cases of food poisoning. In this four-helix protein, the straight helix alpha2, the curved helix alpha3 and the bent helix alpha4 surround the central N-terminal helix alpha1. The helices of GspS create a prominent groove, mainly formed by side chains of helices alpha1, alpha2 and alpha3. In the EHEC GspS structure this groove is occupied by extra electron density which is reminiscent of an alpha helix and corresponds well with a binding site observed in a homologous pilotin. The residues forming the groove are well conserved among homologs, pointing to a key role of this groove in this class of T2SS pilotins. At the same time, T2SS pilotins in different species can be entirely different in structure, and the pilotins for secretins in non-T2SS machineries have yet again unrelated folds, despite a common function. It is striking that a common complex function, such as targeting and assembling an outer membrane multimeric channel, can be performed by proteins with entirely different folds. PMID- 23458690 TI - The rhodopsin-transducin complex houses two distinct rhodopsin molecules. AB - Upon illumination the visual receptor rhodopsin (Rho) transitions to the activated form Rho(*), which binds the heterotrimeric G protein, transducin (Gt) causing GDP to GTP exchange and Gt dissociation. Using succinylated concanavalin A (sConA) as a probe, we visualized native Rho dimers solubilized in 1mM n dodecyl-beta-d-maltoside (DDM) and Rho monomers in 5mM DDM. By nucleotide depletion and affinity chromatography together with crosslinking and size exclusion chromatography, we trapped and purified nucleotide-free Rho(*).Gt and sConA-Rho(*).Gt complexes kept in solution by either DDM or lauryl-maltose neopentyl-glycol (LMNG). The 3 D envelope calculated from projections of negatively stained Rho(*).Gt-LMNG complexes accommodated two Rho molecules, one Gt heterotrimer and a detergent belt. Visualization of triple sConA-Rho(*).Gt complexes unequivocally demonstrated a pentameric assembly of the Rho(*).Gt complex in which the photoactivated Rho(*) dimer serves as a platform for binding the Gt heterotrimer. Importantly, individual monomers of the Rho(*) dimer in the heteropentameric complex exhibited different capabilities for regeneration with either 11-cis or 9-cis-retinal. PMID- 23458691 TI - Female fertility: a conceptual and dimensional analysis. AB - INTRODUCTION: Female fertility is commonly described as the biological nature of women, yet different meanings emerge when one takes a holistic approach to fertility while considering varying contexts and perspectives. An improved understanding of female fertility will enhance health care professionals' understanding of female fertility and improve communication with women and other health care professionals. This article presents a conceptual and dimensional analysis of female fertility. METHODS: A search of the literature included the databases CINAHL, PsycINFO, Philosopher's Index, and Web of Science. Concept and dimensional analyses were performed using the Rogers' methodology and the Caron and Bowers' framework to define female fertility and explore the concept. Articles were examined to identify definitions, dimensions, perspectives, antecedents, and consequences of female fertility. RESULTS: Biological self, psychosexual self, power, and paradox are the attributes of female fertility. The contexts of menarche, menstruation, menopause, infertility, fertility goals, society and culture, and health care were explored. Perspectives included those of women across many different fertility stages as well as perspectives of various clinicians. Necessary antecedents were sexual decision making and influences of culture and society. Consequences were realized fertility, stress, and an understanding of self. A definition of fertility was proposed: Female fertility is a paradoxical phenomenon of power between the biological and psychosexual self. DISCUSSION: Antecedents, attributes, and consequences derived from the fertility literature can be used by health care providers for patient education and therapeutic interventions. This concept analysis may assist in facilitation of a greater understanding of biological and psychosexual self, as they relate to fertility across the lifespan. PMID- 23458692 TI - Immunogenicity and cross-reactivity against Mycobacterium tuberculosis of proteoliposomes derived from Mycobacterium bovis BCG. AB - The only currently available vaccine against tuberculosis (TB) is Mycobacterium bovis Bacille Calmette-Guerin (BCG), which has inconsistent efficacy to protect against the disease in adults. M. tuberculosis (MTB) cell wall components have been implicated in the pathogenicity of TB and therefore have been a prime target for the identification and characterization of cell wall proteins with potential application in vaccine development. In this regard, proteoliposomes (PLs) derived from mycobacteria containing lipids and cell wall proteins could be potential vaccine candidates against TB. In the present study PLs derived from BCG were prepared. These homogeneous population of spherical microparticles was then immunized into Balb/c mice. Sera of immunized animals showed high IgG response and strong cross-reactivity against different MTB antigens.These results showed that BCG PLs could be potential vaccine candidates against TB. PMID- 23458694 TI - September through October 2010 multi-centre study in the Netherlands examining laboratory ability to detect enterovirus 68, an emerging respiratory pathogen. AB - During September and October 2010, the Dutch Public Health Institute detected an enterovirus (EV) 68 (EV68) epidemic in the Netherlands through general practitioner-based surveillance of acute respiratory infections. EV68 shares phenotypic and genotypic properties with human rhinovirus (HRV). Despite increased EV and HRV detections, Dutch clinical laboratories did not identify EV68. To assess the capability of Dutch clinical laboratories to detect EV68, ten laboratories with more than eight detected EV and HRV cases in September and October 2010 provided information about their detection algorithms and testing results for a 2010 Dutch EV68 strain. For EV detection mostly stool specimens (median 49%), respiratory specimens (median 27%) and cerebrospinal fluid (median 22%) were used. For HRV detection only respiratory specimens were used. Except for the Seeplex(r) RV15ACE EV-specific assay, all EV and 73% of HRV assays, including those of the Public Health Institute, were able to detect EV68. Two step EV RT-PCR protocols were the most sensitive. Thus, laboratories might have misidentified EV68 as HRV. In addition, EV68 cases might have also been missed because patients with respiratory diseases are usually not tested for EV infection. Therefore, clinical laboratories should include EV detection in the differential diagnosis of patients presenting with respiratory symptoms. PMID- 23458693 TI - Comparison of conventional lateral-flow assays and a new fluorescent immunoassay to detect influenza viruses. AB - Sofia, a novel, fluorescent lateral-flow immunoassay was compared with two conventional colorimetric assays, Quickvue Influenza A+B and Directigen FLU A+B, to identify influenza viral antigen from patient nasopharyngeal specimens. A total of 118 frozen original influenza-positive specimens and 57 prospective specimens were examined. Using rt-PCR as a referee assay, sensitivity values (%) for influenza A/B of 80.0/74.8, 73.3/59.3 and 73.3/40.7 were obtained using the Sofia, Quickvue and Directigen assays, respectively. All assays demonstrated reduced sensitivity for influenza B as compared with influenza A virus. With respect to the Sofia assay, the sensitivity of influenza B for the Directigen assay was significantly diminished. False positive results were not observed in the Sofia and Directigen assays. The Quickvue assay produced 3 false-positive results (2 influenza A and 1 influenza B) resulting in a specificity (%) of 96 and 98 for influenza A and B, respectively. Cross-reactivity to other respiratory viruses was not observed among immunoassays. A sensitivity rank (highest to low) of rt-PCR>culture>Sofia>Quickvue>Directigen was established using dilutions of influenza A and B. Sofia provides enhanced sensitivity and objective result interpretation over conventional colorimetric immunoassays. PMID- 23458696 TI - Fundamental frequency during couple conflict: an analysis of physiological, behavioral, and sex-linked information encoded in vocal expression. AB - The human voice is one of the sounds most frequently experienced by human beings. During couple conflict, higher fundamental frequency (f0), a physical property of human speech, has been linked to an increased risk of divorce, less beneficial response to couple therapy, and higher levels of dysfunctional communication behavior. F0 is generally considered to be a measure of emotional arousal, but it is not currently clear whether this interpretation is appropriate for understanding spouses' f0 during couple interaction. The goal of the current article is to clarify what forms of information are encoded in f0 during couple conflict by examining the relations between f0 range, physiological variables, and communication behavior during the conflict discussions of 67 German couples. In line with evolutionary models of speech production, associations emerged in the expected directions between f0 and: (a) physiological variables (e.g., heart rate, blood pressure, and cortisol); (b) self-reported communication behavior; and (c) observationally coded communication behavior. Additionally, simultaneous examination of physiological variables and observationally coded communication behaviors revealed that associations between both sets of variables and f0 range were largely independent of one another. Furthermore, women's range of f0 was significantly greater than men's range of f0. With regard to social signaling theories, f0 range can be understood as a nonverbal transmission of distress. Implications for future research on and use of f0 are discussed. PMID- 23458695 TI - Collateral benefits of the family check-up in early childhood: primary caregivers' social support and relationship satisfaction. AB - This research investigated potential collateral benefits of the Family Check-Up (FCU) intervention, namely, primary caregivers' perceived social support and couple relationship satisfaction. A subsample of 435 low-income families with a 2 year-old child was recruited to participate in a randomized controlled trial assessing preventative effects of the FCU. Longitudinal growth models were used to evaluate intention-to-treat effects of the FCU on increases in primary caregivers' ratings of social support satisfaction with perceived social support and significant-other relationships, and indirect effects on primary caregivers through improvements in children's behavior problems. Support was found for a model in which reductions in child problem behavior from ages 2 to 4 predicted positive change in caregiver-rated social support and relationship satisfaction over a 3-year period. This indirect effects model is discussed with respect to implications for early childhood prevention research focused on improving family functioning. PMID- 23458697 TI - Longitudinal relations between marital aggression and children's sleep: the role of emotional insecurity. AB - To gain a better understanding of relations between marital aggression and children's sleep problems, we examined children's emotional insecurity as a process variable and a moderator of effects using 3 waves of data spanning 5 years. Participants were 176 children at Time 1 (T1; M age = 8.68 years), 141 children at Time 2 (T2; M age = 10.70 years), and 113 children at Time 3 (T3; M age = 13.60 years) and their parents. Parents reported on marital aggression, children reported on their emotional insecurity about the parental marital relationship, and children's sleep was measured via self-reports and actigraphy. After controlling for autoregressive effects, marital aggression predicted increases in emotional insecurity 2 years later (T2), which in turn predicted an increase in sleep problems 3 years later (T3). Moderation analyses indicated that a higher level of emotional insecurity was a vulnerability factor for sleep problems in the context of greater marital aggression. Findings add to this emerging literature and illustrate the importance of considering sleep in the family context. PMID- 23458698 TI - Assessment of parental discipline in daily life. AB - The use of ecological momentary assessment (EMA) for studying parenting has been rare. We examined the psychometric properties and structural validity of an EMA Parenting Scale based on 32 mothers' reports of their parenting over a period of 10 consecutive days, and explored the acceptance of the scale and compliance with the procedure. The results suggested that the EMA Parenting Scale was well accepted for the assessment of daily parenting, and that it consistently captured the overreactive and lax dimensions of parenting across different episodes of child misbehavior. Moreover, multilevel analyses suggested that the scale was sensitive to change across different parenting episodes, and that it reliably assessed the dimensions at both the personal and situational levels. PMID- 23458699 TI - Stress in Latino families following an adolescent's childbearing: effects on family relationships and siblings. AB - This study examined how increased stress in Latino families following an adolescent's childbearing impacts family relationships and the adolescent's siblings. Participants were 243 Mexican American youth (mean age: 13.7 years; 62% girls), or 121 youth who had a pregnant adolescent sister and 122 youth who had an adolescent sister who had never been pregnant. Youth and their mothers were studied at 4 time points across 15 months: The families of pregnant adolescents were studied when the adolescent sister was in her third trimester of pregnancy, and at 2 months, 6 months, and 12 months postpartum; the families of never pregnant adolescents were studied at like intervals. Individual fixed-effects structural equation models were computed, which control for earlier measures of study constructs and thereby reduce omitted variable bias from preexisting family group differences. Results showed that an adolescent's childbearing was related to increases in family stress, which were related to increases in mothers' harsh parenting and mother-sibling conflict, which, in turn, were related to subsequent increases in siblings' problem behavior. Multiple group analyses revealed that the pathways through which a teenager's childbearing influences siblings operate similarly for girls and boys. Tests of an alternate ordering of model variables indicated a poor fit with the data. Findings provide evidence that the accumulation of stressful family changes following an adolescent's childbearing can negatively impact siblings. Findings also elucidate how family-level stress and disruption experienced across a family transition trickle down to affect family relationships and, in turn, child family members. PMID- 23458700 TI - The moderating role of child callous-unemotional traits in an Internet-based parent-management training program. AB - Although parent management training (PMT) is generally considered the treatment of choice for children with conduct problems, some specific adaptations might be essential for various subgroups of parents or children to benefit well from PMT. The aim of this study was to examine the influence of child callous-unemotional (CU) traits on the outcome of an Internet-based PMT program for parents of children with conduct problems (n = 57; mean age 6.65). Within a randomized controlled trial of PMT, children assigned to the intervention group were categorized and compared as either "high-CU" (n = 8) or "low-CU" (n = 49) based on a cut-off score on the CU subscale of the Antisocial Process Screening Device (APSD; Frick & Hare, 2001). CU traits in children were associated with more severe conduct problems at baseline, as well as more hyperactivity and peer related problems. Treatment outcome, in terms of conduct-problem reduction, was poor in the high-CU group compared with the low-CU group, despite the fact that parents in both groups improved equally in parenting skills. The same pattern of results emerged after controlling for initial difficulties of conduct problems and other pretreatment differences between the groups. Elevated levels of CU traits in children seem to contribute to an inferior treatment response in PMT. These findings call for more attention on empathy and emotional patterns in the assessment of children with conduct problems. PMID- 23458701 TI - Perceived economic strain exacerbates the effect of paternal depressed mood on hostility. AB - Depression in fathers has been associated with impaired parenting, which, in turn, may function as a central environmental mechanism underlying the adverse effects of paternal depression on children's development. Despite this, evidence suggests that many depressed fathers are able to maintain positive relationships with their children, and little is known about factors associated with better or worse parenting outcomes when fathers experience depression. Using two waves of prospective, longitudinal data from a community sample of fathers and their high school-aged adolescent offspring (N = 324), perceived economic strain was examined as a moderator of the effect of fathers' depressive symptoms on subsequent observer ratings of hostile parenting behaviors. Among fathers experiencing high levels of economic strain, depressive symptoms at offspring age 15 were a significant predictor of hostility toward their adolescent sons at age 18, controlling for family demographics and previous hostile parenting behaviors. Findings and directions for future research are discussed in relation to contemporary models of intergenerational psychopathology transmission. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23458702 TI - Potential of an age-stratified CA125 cut-off value to improve the prognostic classification of patients with endometrial cancer. AB - OBJECTIVE: It is not clear whether the prognostic value of pretreatment serum CA125 levels is independent or through association with other clinicopathological features in endometrial cancer. METHODS: All patients with endometrial cancer treated between 2000 and 2010 were retrospectively reviewed. The correlation of clinicopathological characteristics, CA125 and treatment outcomes was analyzed. Receiver operating characteristics (ROC) curves were used to determine the CA125 cut-off values. Cox proportional hazard regression was used for multivariate analysis. RESULTS: Of the 923 eligible patients, 757 had serum CA125 levels measured before treatment. We identified 264 (34.9%) patients with pretreatment serum CA125>35 U/mL. By multivariate analysis, advanced stage (P=0.001), serous or clear cell carcinoma (P=0.008), positive peritoneal cytology (P=0.042), and lymph node metastases (P=0.004) were significant risk factors for cancer-specific survival (CSS), while serum CA125>35 U/mL (P=0.067) was of borderline statistical significance. Using ROC curve stratified by age, we found that a serum CA125>35 U/mL was significant for CSS (HR=2.34, 95% CI=1.04-5.29) among patients >49 years old. After adjustment for confounding factors, serum CA125>105 U/mL was significant (HR=6.03, 95% CI=1.19-30.63) in patients <=49 years old. CONCLUSIONS: These results suggest that an age-stratified cut-off level for CA125 (35 U/mL in patients >49 years old and 105 U/mL in patients <=49 years old) can improve the prognostic stratification of patients with endometrial cancer. PMID- 23458704 TI - Wettability of graphene. AB - Graphene, an atomically thin two-dimensional material, has received significant attention due to its extraordinary electronic, optical, and mechanical properties. Studies focused on understanding the wettability of graphene for thermo-fluidic and surface-coating applications, however, have been sparse. Meanwhile, wettability results reported in literature via static contact angle measurement experiments have been contradictory and highlight the lack of clear understanding of the underlying physics that dictates wetting behavior. In this work, dynamic contact angle measurements and detailed graphene surface characterizations were performed to demonstrate that the defects present in CVD grown and transferred graphene coatings result in unusually high contact angle hysteresis (16-37 degrees ) on these otherwise smooth surfaces. Hence, understanding the effect of the underlying substrate based on static contact angle measurements as reported in literature is insufficient. The advancing contact angle measurements on mono-, bi-, and trilayer graphene sheets on copper, thermally grown silica (SiO2), and glass substrates were observed to be independent of the number of layers of graphene and in good agreement with corresponding molecular dynamics simulations and theoretical calculations. Irrespective of the number of graphene layers, the advancing contact angle values were also in good agreement with the advancing contact angle on highly ordered pyrolytic graphite (HOPG), reaffirming the negligible effect of the underlying substrate. These results suggest that the advancing contact angle is a true representation of a graphene-coated surface while the receding contact angle is significantly influenced by intrinsic defects introduced during the growth and transfer processes. These observations, where the underlying substrates do not affect the wettability of graphene coatings, is shown to be due to the large interlayer spacing resulting from the loose interlamellar coupling between the graphene sheet and the underlying substrate. The fundamental insights on graphene water interactions reported in this study is an important step towards developing graphene-assisted surface coatings for heat transfer and microfluidics devices. PMID- 23458703 TI - Focused open necrosectomy in necrotizing pancreatitis. AB - BACKGROUND: The control of sepsis is the primary goal of surgical intervention in patients with infected necrosis. Simple surgical approaches that are easy to reproduce may improve outcomes when specialists in endoscopy are not available. The aim of the present study was to describe the experience with a focused open necrosectomy (FON) in patients with infected necrosis. METHOD: A prospective pilot study conducted to compare a semi-open/closed drainage laparotomy and FON with the assistance of peri-operative ultrasound. The incidence of sepsis, dynamics of C-reactive protein (CRP), intensive care unit (ICU)/hospital stay, complication rate and mortality were compared and analysed. RESULTS: From a total of 58 patients, 36 patients underwent a conventional open necrosectomy and 22 patients underwent FON. The latter method resulted in a faster resolution of sepsis and a significant decrease in mean CRP on Day 3 after FON, P = 0.001. Post operative bleeding was in 1 versus 7 patients and the incidence of intestinal and pancreatic fistula was 2 versus 8 patients when comparing FON to the conventional approach. The median ICU stay was 11.6 versus 23 days and the hospital stay was significantly shorter, 57 versus 72 days, P = 0.024 when comparing FON versus the conventional group. One patient died in the FON group and seven patients died in the laparotomy group, P = 0.139. DISCUSSION: FON can be an alternative method to conventional open necrosectomy in patients with infected necrosis and unresolved sepsis. PMID- 23458705 TI - Kinetics of liver function tests after a hepatectomy for colorectal liver metastases predict post-operative liver failure as defined by the International Study Group for Liver Surgery. AB - BACKGROUND: Post-hepatectomy liver failure (PHLF) has been defined by the International Study Group for Liver Surgery (ISGLS). The purpose of the present study was to examine the kinetics of conventional liver function tests (LFT) after a major liver resection and is the first to examine their utility in predicting PHLF in groups defined by the ISGLS. METHODS: Consecutive patients undergoing a major liver resection for colorectal liver metastases were stratified into ISGLS groups and their LFT up to 1 year after surgery compared. Receiving-operating characteristic (ROC) analysis of LFT identified optimal thresholds in predicting category C liver failure. RESULTS: In total, 32, 22 and 19 patients belonged to ISGLS groups A, B and C, respectively. The median international normalized ratio (INR) and bilirubin values on post-operative days 1, 3, 5 and 7 were significantly different among the groups (all P-values <0.05). ROC analysis of day 1 INR (AUC 0.813) and day 5 bilirubin (AUC 0.798) revealed thresholds of 1.35 and 52 MUmol/l to have sensitivities of 85% and 81% and specificities of 63% and 73%, respectively, to predict group C liver failure. DISCUSSION: Post-operative LFT after a major liver resection differs significantly among the three ISGLS groups. Thresholds of bilirubin and INR can be used to identify patients who are at a maximum risk of complications. PMID- 23458706 TI - Further studies on the role of water in R67 dihydrofolate reductase. AB - Previous osmotic pressure studies of two nonhomologous dihydrofolate reductase (DHFR) enzymes found tighter binding of the nicotinamide adenine dinucleotide phosphate cofactor upon addition of neutral osmolytes. This result is consistent with water release accompanying binding. In contrast, osmotic stress studies found weaker binding of the dihydrofolate (DHF) substrate for both type I and type II DHFRs in the presence of osmolytes; this observation can be explained if dihydrofolate interacts with osmolytes and shifts the equilibrium from the enzyme bound state toward the unbound substrate. Nuclear magnetic resonance experiments support this hypothesis, finding that osmolytes interact with dihydrofolate. To consider binding without added osmolytes, a high-pressure approach was used. In this study, the type II enzyme, R67 DHFR, was subjected to high hydrostatic pressure (HHP). Both enzyme activity and fluorescence measurements find the protein tolerates pressures up to 200 MPa. Binding of the cofactor to R67 DHFR weakens with increasing pressure, and a positive association volume of 11.4 +/- 0.5 cm(3)/mol was measured. Additionally, an activation volume of 3.3 +/- 0.5 cm(3)/mol describing k(cat)/K(m(DHF)) was determined from progress curve analysis. Results from these HHP experiments suggest water release accompanies binding of both the cofactor and DHF to R67 DHFR. In an additional set of experiments, isothermal titration calorimetry studies in H2O and D2O find that water reorganization dominates the enthalpy associated with binding of DHF to R67 DHFR.NADP(+), while no obvious effects occur for cofactor binding. The combined results indicate that water plays an active role in ligand binding to R67 DHFR. PMID- 23458707 TI - Flow cytometry detection of infectious pancreatic necrosis virus (IPNV) within subpopulations of Atlantic salmon (Salmo salar L.) leucocytes after vaccination and during the time course of experimental infection. AB - In the present study, intracellular infectious pancreatic necrosis virus (IPNV) in salmon leucocytes was detected by flow cytometry after experimental cohabitant challenge. IPNV vaccinated, non-vaccinated and intraperitoneally (i.p.) infected salmon (virus shedders) were analysed at different times throughout the period when mortality occurred. Fish that had survived 61 days post challenge (carriers) were also analysed. In particular, we analysed the presence of IPNV in B-cells (C7G7+cells) and in neutrophils (E3D9+ cells) in head kidney leucocytes (HKL) and in peripheral blood leucocytes (PBL). IPNV was present in HKL and PBL from all challenged fish groups at all samplings, including carriers. IPNV was also found intracellular in other leucocytes than B-cells and neutrophils. During the time course of infection there were changes in proportion of B-cells and neutrophils and in proportions of IPNV+ cells. In vaccinated fish, a delay in the changes observed in the proportion of IPNV+ cells and in the proportions of the two subpopulations was identified. The vaccinated fish were protected against disease as no fish died compared to 30.8% of non-vaccinated cohabitant fish. All i.p. infected fish, except one, survived the challenge. This is consistent with previous studies and confirmed that the routes of infection can influence mortality. The analyses in this study could not identify any factors enlightening this absence of mortality in i.p. infected fish, but both flow cytometry and qRT PCR showed that i.p. infected fish were carriers of IPNV. The present study also found that IPNV was present in both B-cells and neutrophils as well as in other leucocytes in all carriers after cohabitant challenge. These fish had survived 9 weeks post challenge and 4 weeks after mortality has ceased. The fish harbouring virus within their leucocytes might become life long carriers and represent a risk for disease outbreaks, being virus shedders. Such fish are protected from later infections if the virus exposure has resulted in protective immunity. Flow cytometry was found to be very suitable for detection of intracellular virus after in vivo challenge and the sensitivity was demonstrated by the detection of virus in carriers. PMID- 23458708 TI - Lack of sigma-1 receptor exacerbates ALS progression in mice. AB - The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the CNS S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MNs). Mutations in S1R have been found in familial cases of amyotrophic lateral sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model. PMID- 23458709 TI - Focal cerebral ischemia induces the neurogenic potential of mouse Dach1 expressing cells in the dorsal part of the lateral ventricles. AB - The mouse Dach1 gene, involved in the development of the neocortex and the hippocampus, is expressed by neural stem cells (NSCs) during early neurogenesis, and its expression also continues in a subpopulation of cells in the dorsal part of the lateral ventricles (LV) of the adult mouse brain. In this study we aimed to elucidate the role of Dach1-expressing cells in adult neurogenesis/gliogenesis under physiological as well as post-ischemic conditions, employing transgenic mice in which the expression of green fluorescent protein (GFP) is controlled by the D6 promotor of the mouse Dach1 gene. A neurosphere-forming assay of GFP+ cells isolated from the dorsal part of the LV was carried out with subsequent differentiation in vitro. To elucidate the neurogenic/gliogenic potential of GFP+ cells in the dorsal part of the LV, in situ immunohistochemical/electrophysiological analyses of GFP+ cells in adult sham operated brains (controls) and those after middle cerebral artery occlusion (MCAo) were performed. The GFP+ cells isolated from the dorsal part of the LV of controls formed neurospheres and differentiated solely into a glial phenotype, while those isolated after MCAo also gave rise to cells with the properties of neuronal precursors. In situ analyses revealed that GFP+ cells express the phenotype of adult NSCs or neuroblasts in controls as well as following ischemia. Following MCAo we found a significantly increased number of GFP+ cells expressing doublecortin as well as a number of GFP+ cells migrating through the rostral migratory stream into the olfactory bulb, where they probably differentiated into calretinin+ interneurons. Collectively, our results suggest the involvement of the mouse Dach1 gene in adult neurogenesis; cells expressing this gene exhibit the properties of adult NSCs or neuroblasts and respond to MCAo by enhanced neurogenesis. PMID- 23458710 TI - PTEN inhibition prevents rat cortical neuron injury after hypoxia-ischemia. AB - Alterations in axon-dendrite polarity impair functional recovery in the developing CNS after hypoxia-ischemia (HI) injury. PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathway mediates the formation of neuronal polarity. However, its role in cerebral HI injury is not fully understood. In this study, we investigated the role of PTEN pathway in regulation of axon-dendrite polarity using an oxygen-glucose deprivation (OGD) model with rat cortical neurons. We found that the activity of PTEN and glycogen synthase kinase 3beta (GSK-3beta) was increased after OGD, along with the decrease of the activity in protein kinase B (Akt) and collapsin response mediator protein-2 (CRMP-2). Pretreatment with bpv, a potent inhibitor of PTEN, caused a decrease of the activity in PTEN and GSK-3beta, and a significant increase of the activity in Akt and CRMP-2. Simultaneously, the morphological polarity of neurons was maintained and neuronal apoptosis was reduced. Moreover, inhibition of PTEN rescued vesicle recycling in axons. These findings suggested that the PTEN/Akt/GSK-3beta/CRMP-2 pathway is involved in the regulation of axon-dendrite polarity, providing a novel route for protecting neurons following neonatal HI. PMID- 23458711 TI - Phencyclidine affects firing activity of ventral tegmental area neurons that are related to reward and social behaviors in rats. AB - Patients with schizophrenia exhibit deficits in motivation and affect, which suggests an impairment in the reward system. The psychotomimetic drug, phencyclidine (PCP), also induces schizophrenia-like negative symptoms, such as reduced motivation, blunted affect, and social withdrawal in both humans and animals. Previous studies have indicated that the dopaminergic neurons in the ventral tegmental area (VTA) play a pivotal role in the development of reward associated learning and motivation. However, how PCP affects the activity of VTA neurons during performance of a reward-related task and social interaction with others in unanesthetized animals remains unclear. Here, we recorded the unit activity of VTA neurons in freely moving rats before and after systemic administration of PCP in a classical conditioning paradigm, and during social interaction with an unfamiliar partner. In the classical conditioning task, two different tones were sequentially presented, one of which accompanied electrical stimulation of the medial forebrain bundle as an unconditioned stimulus. After identifying the response properties of recorded neurons in the classical conditioning task and social interaction, animals received an intraperitoneal injection of PCP. Our study demonstrated that most VTA neurons responsive to reward-associated stimuli were also activated during social interaction. Such activation of neurons was considerably suppressed by systemic administration of PCP, thus, PCP may affect the firing activity of VTA neurons that are involved in motivation, learning, and social interaction. Disruption of the response of VTA neurons to reward stimuli and socially interactive situations may be involved in PCP-induced impairments similar to the negative symptoms of schizophrenia. PMID- 23458712 TI - Patterning and regulatory associations of DNA methylation are mirrored by histone modifications in insects. AB - Epigenetic information is an important mediator of the relationship between genotype and phenotype in eukaryotic organisms. One of the most important and widely conserved forms of epigenetic information is the methylation of genes. However, the function of intragenic DNA methylation remains poorly understood. The goal of this study was to gain greater understanding of the nature of intragenic methylation by determining its role in the multilayered epigenetic landscape of insects. We first investigated the evolutionary lability of DNA methylation by examining whether methylation patterns were conserved in the fire ant and honey bee. We found that DNA methylation was targeted to largely overlapping sets of orthologs in both species. Next, we compared intragenic DNA methylation levels in the fire ant and honey bee to comprehensive epigenetic and gene-regulatory data from Drosophila melanogaster orthologs. We observed striking evidence of a conserved association between DNA methylation in fire ants and honey bees, and several active histone modifications, constitutive gene expression, and "broad" promoter architecture in D. melanogaster. Overall, our study illustrates that DNA methylation is a single component of a conserved, integrated, multilayered epigenetic and regulatory landscape in insect genomes. PMID- 23458713 TI - The impact of Crimean-Congo hemorrhagic fever virus on public health. AB - Climatic, environmental and economic changes, as well as the steadily increasing global trade and personal mobility provide ample opportunities for emerging pathogens with zoonotic potential to spread to previously unaffected countries. Crimean-Congo hemorrhagic fever virus (CCHFV) is considered to be one of the major emerging disease threats spreading to and within the European Union following an expanding distribution of its main vector, ticks of the genus Hyalomma. Every year more than 1000 human CCHF cases are reported from countries of southeastern Europe and Turkey. CCHFV can cause high case fatality rates and can be transmitted from human to human. There are no vaccine prophylaxis and therapeutic interventions available at present. Several EU-funded research projects focus currently on CCHFV which highlights the awareness for this problem at the European level. As public health deals with questions of prevention on a population level rather than healing and health on an individual level, the analysis of existing data plays a fundamental role to minimize its epidemic potential, by reducing infection risks, and to manage disease outbreaks. This review gives a summary of the current knowledge and data with focus at the interface between public health and CCHFV. Based on this knowledge, guidelines for the risk classification of a region and for outbreak prevention are given. This review will assist decision makers and public health authorities in understanding risk scenarios and in deciding on effective countermeasures, as well as human and veterinary scientists by highlighting existing gaps in knowledge. PMID- 23458714 TI - Antiviral resistance among highly pathogenic influenza A (H5N1) viruses isolated worldwide in 2002-2012 shows need for continued monitoring. AB - Highly pathogenic (HP) H5N1 influenza viruses are evolving pathogens with the potential to cause sustained human-to-human transmission and pandemic virus spread. Specific antiviral drugs can play an important role in the early stages of a pandemic, but the emergence of drug-resistant variants can limit control options. The available data on the susceptibility of HP H5N1 influenza viruses to neuraminidase (NA) inhibitors and adamantanes is scarce, and there is no extensive analysis. Here, we systematically examined the prevalence of NA inhibitor and adamantane resistance among HP H5N1 influenza viruses that circulated worldwide during 2002-2012. The phenotypic fluorescence-based assay showed that both human and avian HP H5N1 viruses are susceptible to NA inhibitors oseltamivir and zanamivir with little variability over time and ~5.5-fold less susceptibility to oseltamivir of viruses of hemagglutinin (HA) clade 2 than of clade 1. Analysis of available sequence data revealed a low incidence of NA inhibitor-resistant variants. The established markers of NA inhibitor resistance (E119A, H274Y, and N294S, N2 numbering) were found in 2.4% of human and 0.8% of avian isolates, and the markers of reduced susceptibility (I117V, K150N, I222V/T/K, and S246N) were found in 0.8% of human and 2.9% of avian isolates. The frequency of amantadine-resistant variants was higher among human (62.2%) than avian (31.6%) viruses with disproportionate distribution among different HA clades. As in human isolates, avian H5N1 viruses carry double L26I and S31N M2 mutations more often than a single S31N mutation. Overall, both human and avian HP H5N1 influenza viruses are susceptible to NA inhibitors; some proportion is still susceptible to amantadine in contrast to ~100% amantadine resistance among currently circulating seasonal human H1N1 and H3N2 viruses. Continued antiviral susceptibility monitoring of H5N1 viruses is needed to maintain therapeutic approaches for control of disease. PMID- 23458716 TI - MK-1 expression in gastric carcinoma with liver metastasis. AB - OBJECTIVE: The prognosis for gastric carcinoma patients with liver metastasis is very poor. This retrospective study investigated the prognostic significance of MK-1 expression in gastric carcinoma patients with liver metastasis. METHODS: Immunohistochemical staining using monoclonal antibody FU-MK-1 against MK-1 antigen was performed on paraffin-embedded tissues from 64 gastric carcinoma patients with liver metastasis. We attempted to determine the presence of any relationship between pathological prognostic factors and the expression of MK-1 in 64 gastric carcinoma patients with liver metastasis. RESULTS: MK-1 expression was found in 43 (67%) of 64 tumor samples. MK-1 expression was significantly higher in the intestinal type (73%) than in the diffuse type carcinoma (33%, P = 0.049). Multivariate analysis showed that MK-1 expression and lymph node metastasis were significant factors for overall survival. The difference between overall survival rates with positive or negative MK-1 expression was statistically significant as shown by Kaplan-Meier survival analysis (P < 0.0001; log-rank). In addition, the difference between cumulative disease-free survival rates with positive or negative MK-1 expression in gastric carcinoma patients with metachronous liver metastasis was statistically significant as well, as shown by Kaplan-Meier survival analysis (P = 0.0006; log-rank). CONCLUSIONS: The prognostic significance of MK-1 expression as a biological tumor marker was demonstrated in a series of gastric carcinoma patients with liver metastasis. MK 1 positivity may be a reliable marker for predicting and taking measures to control liver metastasis after curative gastrectomy for gastric carcinoma. PMID- 23458715 TI - Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line: effects on cell functions. AB - BACKGROUND: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERalpha, mERbeta, and GPER/GPR30), thereby initiating nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper. OBJECTIVE: To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)- and c-Jun-N-terminal kinase (JNK) specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release. METHODS: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay. RESULTS: BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10-15 to 10-7 M). When combined with 10-9 M E2, the physiologic estrogen's ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2. Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (<= 1 min) E2-induced PRL release. CONCLUSION: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release. PMID- 23458717 TI - Competitive displacement between two invasive whiteflies: insecticide application and host plant effects. AB - The cryptic species Middle East-Asia Minor 1 (MEAM1), formerly referred to as 'B biotype', of the whitefly Bemisia tabaci complex entered China in the mid 1990s, and the Mediterranean (MED) cryptic species, formerly referred to as 'Q biotype', of the same whitefly complex entered China around 2003. Field surveys in China after 2003 indicate that in many regions MED has been replacing the earlier invader MEAM1. The factors underlying this displacement are unclear. We conducted laboratory experiments and field sampling to examine the effects of insecticide application on the competitive interactions between MEAM1 and MED. In the laboratory, on cotton, a plant showing similar levels of suitability to both whitefly species, MEAM1 displaced MED in five generations when initial populations of the two species were equal and no insecticide was applied. In contrast, MED displaced MEAM1 in seven and two generations, respectively, when 12.5 and 50.0 mg l-1 imidacloprid was applied to the plants via soil drench. Field sampling indicated that in a single season MED displaced MEAM1 on crops heavily sprayed with neonicotinoid insecticides but the relative abundance of the two species changed little on crops without insecticide spray. We also examined the effects of host plants on the competitive interactions between the two species in the laboratory. When cohorts with equal abundance of MEAM1 and MED were set up on different host plants, MEAM1 displaced MED on cabbage and tomato in five and seven generations, respectively, but MED displaced MEAM1 on pepper in two generations. As field populations of MED have lower susceptibility than those of MEAM1 to nearly all commonly used insecticides including imidacloprid, insecticide application seems to have played a major role in shifting the species competitive interaction effects in favour of MED in the field across China. Host plants may also shape competition between the two species depending on the relative levels of plant suitability. PMID- 23458719 TI - Bayesian hypothesis testing for single-subject designs. AB - Researchers using single-subject designs are typically interested in score differences between intervention phases, such as differences in means or trends. If intervention effects are suspected in data, it is desirable to determine how much evidence the data show for an intervention effect. In Bayesian statistics, Bayes factors quantify the evidence in the data for competing hypotheses. We introduce new Bayes factor tests for single-subject data with 2 phases, taking serial dependency into account: a time-series extension of Rouder, Speckman, Sun, Morey, and Iverson's (2009) Jeffreys-Zellner-Siow Bayes factor for mean differences, and a time-series Bayes factor for testing differences in intercepts and slopes. The models we describe are closely related to interrupted time-series models (McDowall, McCleary, Meidinger, & Hay, 1980). PMID- 23458720 TI - Modeling actor and partner effects in dyadic data when outcomes are categorical. AB - When 2 people interact in a relationship, the outcome of each person can be affected by both his or her own inputs and his or her partner's inputs. For Gaussian dyadic outcomes, linear mixed models taking into account the correlation within dyads are frequently used to estimate actor's and partner's effects based on the actor-partner interdependence model. In this article, we explore the potential of generalized linear mixed models (GLMMs) for the analysis of non- Gaussian dyadic outcomes. Several approximation techniques that are available in standard software packages for these GLMMs are investigated. Despite the different modeling options related to these different techniques, none of these have an overall satisfactory performance in estimating actor and partner effects and the within-dyad correlation, especially when the latter is negative and/or the number of dyads is small. An approach based on generalized estimating equations for the analysis of non-Gaussian dyadic data turns out to be an interesting alternative. PMID- 23458718 TI - The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. AB - MuSK myasthenia gravis is a rare, severe autoimmune disease of the neuromuscular junction, only identified in 2001, with unclear pathogenic mechanisms. In this review we describe the clinical aspects that distinguish MuSK MG from AChR MG, review what is known about the role of MuSK in the development and function of the neuromuscular junction, and discuss the data that address how the antibodies to MuSK lead to neuromuscular transmission failure. PMID- 23458721 TI - Pragmatic trials of complex psychosocial interventions: methodological challenges. AB - Having first introduced the pragmatic health care trial, the discussion then focuses on a selected list of technical problems that are important for the design, analysis and inference from such trials. The first is lack of independence of participants' outcomes do to clustering either arising from a cluster randomized design or to the way treatment is delivered (therapist and group effects). The second and third concern the implications of non-adherence to treatment and subsequent loss to follow-up, particularly, when non-adherence is associated with missing outcome data. Finally, it is argued that pragmatism and a desire for a scientific explanation should not be regarded as mutually exclusive. PMID- 23458722 TI - The expression status of G protein-coupled receptor GPR30 is associated with the clinical characteristics of endometriosis. AB - INTRODUCTION: GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates endometrial cellular responses to estrogen. GPR30 is often highly expressed in cancer cells from aggressive tumors. The aim of this study was to evaluate the expression patterns of GPR30 in endometriosis during medical treatment. PATIENTS: A total of 38 females, 28 patients with endometriosis and 10 patients with leiomyoma who underwent laparoscopic surgery were included this study. INTERVENTION: Eutopic endometrial tissue sampling from women without endometriosis and ectopic endometrial tissue sampling from women with endometriosis. MAIN OUTCOME MEASURE: A quantitative real-time polymerase chain reaction analysis of the mRNA expression in eutopic and ectopic endometrial tissues with or without GnRH agonist treatment. The expression of GPR30 was confirmed by immunohistochemistry. RESULTS: There was an increased level of GPR30 mRNA in eutopic endometrium during the proliferative phase, whereas higher expression was observed in the ectopic endometrium during the secretory phase. Increased GPR30 mRNA was observed in ectopic endometrium in comparison to eutopic endometrium. GnRH agonist treatment before laparoscopic surgery decreased GPR30 mRNA in ectopic endometrium. The immunohistochemical analysis also revealed that GPR30 was strongly expressed in epithelial cells in ectopic endometrium, whereas GnRH agonist treatment decreased the GPR30 expression. CONCLUSION: High levels of GPR30 expression can play an important role in the progression of endometriosis. PMID- 23458723 TI - N-acetylcysteine administration does not improve patient outcome after liver resection. AB - BACKGROUND: Post-operative hepatic dysfunction is a major cause of concern when undertaking a liver resection. The generation of reactive oxygen species (ROS) as a result of hepatic ischaemia/reperfusion (I/R) injury can result in hepatocellular injury. Experimental evidence suggests that N-acetylcysteine may ameliorate ROS-mediated liver injury. METHODS: A cohort of 44 patients who had undergone a liver resection and receiving peri-operative N-acetylcysteine (NAC) were compared with a further cohort of 44 patients who did not. Liver function tests were compared on post-operative days 1, 3 and 5. Peri-operative outcome data were retrieved from a prospectively maintained database within our unit. RESULTS: Administration of NAC was associated with a prolonged prothrombin time on the third post-operative day (18.4 versus 16.4 s; P = 0.002). The incidence of grades B and C liver failure was lower in the NAC group although this difference did not reach statistical significance (6.9% versus 14%; P = 0.287). The overall complication rate was similar between groups (32% versus 25%; P = ns). There were two peri-operative deaths in the NAC group and one in the control group (P = NS). CONCLUSION: In spite of promising experimental evidence, this study was not able to demonstrate any advantage in the routine administration of peri-operative NAC in patients undergoing a liver resection. PMID- 23458724 TI - A proteoliposome formulation derived from Bordetella pertussis induces protection in two murine challenge models. AB - Whooping cough remains a health problem despite high vaccination coverage. It has been recommended that development of new strategies provide long-lasting immunity. The aim of this work was to evaluate the potential of proteoliposomes (PL) extracted from Bordetella pertussis as a vaccine candidate against whooping cough. The size of the B. pertussis PL was estimated to be 96.7 +/- 50.9 nm by Scanning Correlation Spectroscopy and the polydispersity index was 0.268. Western blots using monoclonal antibodies revealed the presence of pertussis toxin, pertactin, and fimbriae 3. The Limulus Amebocyte Lisate (LAL) assay showed endotoxin levels lower than those reported for whole cell pertussis licensed vaccines, while the Pyrogen Test indicated 75 ng/mL/Kg. The PL showed high protection capacity in mouse challenge models. There was 89.7% survival in the intracerebral challenge and total reduction of the number of CFU in the intranasal challenge. No significant differences (p > 0.05) were observed between mice immunized with B. pertussis PL and the Cuban DTwP vaccine, whichever challenge model used. These results encouraged us to continue the development of the B. pertussis PL as a component of a new combined vaccine formulated with tetanus and diphtheria toxoids or as a booster dose for adolescents and adults. PMID- 23458725 TI - In-vitro maintenance and functionality of primary renal tubules and their application in the study of relative renal toxicity of nephrotoxic drugs. AB - INTRODUCTION: The renal tubules play important roles in substance re-absorption from primary urine of the kidney, drug metabolism and gluconeogenesis in fasting and are vulnerable targets of nephrotoxic chemicals. Therefore, an appropriate functional model of renal tubules would enable the study of their functionality and chemical-induced toxicity. We have developed a method to maintain primary renal tubules and sustain their biochemical functionality in culture for an extended period of time. METHODS: Primary rat renal tubules were isolated from male rat kidneys by collagenase perfusion and the tubules maintained in culture as a suspension by a gyratory culture method. RESULTS: The tubule fragments gradually formed renal tubule aggregates within 6days and were maintained in culture for up to 12days without apparent morphological changes. Biochemical functions including glucose release, galactose uptake and pyruvate uptake were retained for the observed period of 12days after isolation. The aggregates showed significant cytochrome P450 1A1 activity recovery from day 6 after isolation and this was maintained thereafter during the 12-day period of in-vitro culture. A new toxicity test termed the cell spreading inhibition test (CSIT) of renal tubule aggregates was developed to study the effect of toxicants on cell spreading/growth and determine the minimum concentration of each toxicant that caused cell spreading inhibition (CSI-C). The CSI-Cs of selected nephrotoxic drugs were determined as chlorpromazine (60MUM), cisplatin (200MUM), diclofenac (800MUM), valproic acid (10mM), and gentamycin (30mM). DISCUSSION: The gyratory method of primary renal tubule aggregate culture can retain tubular cell functions such as glucose release, galactose uptake and allow cytochrome P450 1A1 activity to recover, which are essential for an in-vitro model. Therefore, renal tubule aggregates can be used as a model for studies of biochemical functions of renal tubules and relative renal toxicity of nephrotoxic agents. PMID- 23458726 TI - Preparation of archival formalin-fixed paraffin-embedded mouse liver samples for use with the Agilent gene expression microarray platform. AB - INTRODUCTION: Tissue samples are routinely formalin-fixed and paraffin-embedded (FFPE) for long term preservation. Gene expression analysis of archival FFPE tissues may advance knowledge of the molecular perturbations contributing to disease. However, formalin causes extensive degradation of RNA. METHODS: We compared RNA quality/yield from FFPE samples using six commercial FFPE RNA extraction kits. In addition we compared four DNA microarray protocols for the Agilent 8*60K platform using 16year old FFPE mouse liver samples treated with phenobarbital or vehicle. RESULTS: Despite low quality RNA, archival phenobarbital samples exhibited strong induction of the positive control genes Cyp2b9 and Cyp2b10 by quantitative real-time PCR (qPCR). We tested one- and two color microarray designs and evaluated the effects of increasing the amount of hybridized cDNA. Canonical gene responders to phenobarbital were measurably induced under each experimental condition. Increasing the amount of labeled cDNA did not improve the overall signal intensity. One-color experiments yielded larger fold changes than two-color and the number of differentially expressed genes varied between protocols. Gene expression changes were validated by qPCR and literature searches. Individual protocols exhibited high rates of false positives; however, pathway analysis revealed that nine of the top ten canonical pathways were consistent across experiments. Genes that were differentially expressed in more than one experiment were more likely to be validated. Thus, we recommend that experiments on FFPE samples be done in duplicate to reduce false positives. DISCUSSION: In this analysis of archival FFPE samples we were able to identify pathways that are consistent with phenobarbital's mechanism of action. Therefore, we conclude that FFPE samples can be used for meaningful microarray gene expression analyses. PMID- 23458727 TI - Design, synthesis, and biological evaluation of highly potent small molecule peptide conjugates as new HIV-1 fusion inhibitors. AB - The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5 dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole (A12) target a hydrophobic pocket of HIV-1 gp41 and have moderate anti-HIV-1 activity. In this paper, we report the design, synthesis, and structure-activity relationship of a group of hybrid molecules in which the pocket-binding domain segment of the C34 peptide was replaced with NB-2 and A12 derivatives. In addition, the synergistic effect between the small molecule and peptide moieties was analyzed, and lead compounds with a novel scaffold were discovered. We found that either the nonpeptide or peptide part alone showed weak activity against HIV 1-mediated cell-cell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc-betaAla-P26 and Noc-betaAla-P26 exhibited a low nanomolar IC50 in the cell-cell fusion assay and effectively inhibited T20-sensitive and -resistant HIV-1 strains. Furthermore, the new molecules exhibited better stability against proteinase K digestion than T20 and C34. PMID- 23458728 TI - Block copolymer micelles as nanoreactors for self-assembled morphologies of gold nanoparticles. AB - Self-assembled gold (Au) nanoparticles (NPs) were synthesized in micelle surface cavities of a L121 block polymer in the presence of zwitterionic (viz. DPS, TPS, and HPS) and sugar surfactants (OG and DDM) in aqueous phase at 70 degrees C by using the surface cavities of L121 as reducing sites for converting Au(III) into Au(0). All reactions were monitored simultaneously by UV-visible spectroscopy to determine the growth kinetics in gold nucleating centers on the basis of surface plasmon resonance that also helped in tracing the structure micelle transitions over a wide temperature range of 10-70 degrees C. The surfactant/L121 mole ratio was changed systematically from 0.5 to 2.5 by keeping L121 and HAuCl4 concentrations constant at 10 and 0.25 mM, respectively, to determine the shape and size of the micelles and their relation to the self-assembled behavior of Au NPs. TEM studies were used to have a direct insight into the morphology of micelle templates and their shape and size for self-assembled NPs. L121 along with DPS (C12 carbon chain) produced well-defined micelles loaded with tiny NPs of 3-6 nm in the L121-rich region of the mixture, while large flower-like compound micelles with a clear core-shell morphology were produced in the DPS rich region. TPS and HPS (C14 and C16 hydrocarbon chains, respectively) with stronger hydrophobicity than DPS also produced almost similar micelles loaded with tiny NPs in the L121-rich region, but they disappear in the surfactant-rich region. Replacement of zwitterionic with ionic surfactants did not yield micelle templates for self-assembled NPs. Results conclude that well-defined micelles of L121 are the fine templates for self-assembled NPs that can only be achieved in the presence of a neutral surfactant with low concentration and low hydrophobicity. PMID- 23458729 TI - Delayed closure of complex defects with serial tightening of loop sutures - clinical outcome in 64 consecutive patients. AB - BACKGROUND: Direct wound closure, flaps or grafts are considered to be gold standards for the reconstruction of defects. However, these techniques may not be applicable in all cases, especially for the challenging closure of large defects. OBJECTIVE: We developed a technique to close large defects, of varying size and shape, using serial tightening loop sutures. In 64 consecutive patients, loop sutures were applied to defects from 3 cm(2) up to 173 cm(2) for a maximum of 42 days with tightening every 2-7 days. RESULTS: The median size of the defects was 20 cm(2). In 58 patients (91%) the defects were closed by direct approximation of the wound edges within a median time of 11 days (range: 4-42 days). Two patients received a skin transplant after a significant reduction of the defect size and four remaining defects healed by secondary intention. The skin stretching of defects located on the trunk was faster compared with defects on the extremities. Defects located on the scalp were closed hair bearing with little scarring. Overall, aesthetic results were satisfying. CONCLUSION: The use of loop sutures allows the delayed closure of large defects avoiding the need for skin flaps or grafts in most cases. PMID- 23458730 TI - Concentration-dependent inhibitory effects of baicalin on the metabolism of dextromethorphan, a dual probe of CYP2D and CYP3A, in rats. AB - Baicalin has been shown to possess many pharmacological effects, including antiviral, antioxidant, anti-cancer and anti-inflammatory properties. In the current study, we reveal the inhibitory effects of baicalin on the metabolism of dextromethorphan (DXM), a dual probe substrate of CYP2D and CYP3A, in rats. Lineweaver-Burk plots demonstrated that baicalin inhibited the activities of CYP2D and CYP3A in a non-competitive manner in rat liver microsomes (RLMs). Concomitant administration of baicalin (0.90 g/kg, i.v.) and DXM (10 mg/kg, i.v.) increased the maximum drug concentration (C(max)) (37%) and the area under concentration-time curve (AUC) (42%) and decreased the clearance (CL) (27%) of DXM in a randomised, crossover study in rats (P < 0.01). The change in the AUC of DXM was significantly correlated with the C(max) and AUC of baicalin (P < 0.05). The inhibitory effects of multiple doses of baicalin (0.90 g/kg, i.v., 12 days) on the metabolism of DXM were similar to those observed following a single dose in rats. The activity of CYP3A in excised liver samples from rats following multiple baicalin treatment was significantly decreased compared to that of the control group (P < 0.05), whereas multiple doses of baicalin had no obvious effect on the activity of CYP2D. Taken together, these data demonstrate that baicalin inhibits the metabolism of DXM in a concentration-dependent manner in rats, possibly through inhibiting hepatic CYP2D and CYP3A activities. PMID- 23458731 TI - STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia. AB - We recently reported that chronic myeloid leukaemia (CML) patients harbour high levels of STAT5 when they progress to advanced phases of disease. Advanced disease is characterized by an increased incidence of BCR-ABL1 mutations. We now describe a highly significant correlation between STAT5 expression and the incidence of BCR-ABL1 mutations in primary CML. Forced expression of STAT5 in murine BCR-ABL1 transformed cells sufficed to enhance the production of reactive oxygen species (ROS) and to trigger DNA damage. STAT5-mediated ROS production is independent of JAK2 but requires concomitant BCR-ABL1 signalling as forced STAT5 expression in untransformed BCR-ABL1 negative cells has no impact on ROS levels. Only within the context of a BCR-ABL1 positive cell does STAT5 transcriptionally regulate a target gene or set of genes that causes the enhanced ROS production. Our study suggests the existence of a feed-forward loop accelerating disease progression, in which BCR-ABL1 enhances its own mutation rate in a STAT5-ROS dependent manner. This model explains the increased occurrence of inhibitor resistant BCR-ABL1 mutations in advanced disease stages driven and characterized by high STAT5 expression. PMID- 23458733 TI - Nanomechanical torsional resonators for frequency-shift infrared thermal sensing. AB - We investigate use of nanomechanical torsional resonators for frequency-shift based infrared (IR) thermal sensing. Nanoscale torsion rods, ~1 MUm long and 50 100 nm in diameter, provide both extraordinary thermal isolation and excellent angular displacement and torque sensitivities, of order ~10(-7) rad.Hz(-1/2) and ~10(-22) (N.m) Hz(-1/2), respectively. Furthermore, these nanorods act as linear torsional springs, yielding a maximum angular displacement of 3.6 degrees and a dynamic range of over 100 dB; this exceeds the performance of flexural modes by as much as 5 orders of magnitude. These attributes lead to superior noise performance for torsional-mode sensing. We demonstrate the operational principles of torsional-mode IR detection, attaining an uncooled noise equivalent temperature difference (NETD) of 390 mK. By modeling the fundamental noise processes, we project that further reduction of device size can significantly improve thermal responsivity; a room-temperature NETD below 10 mK appears feasible. PMID- 23458734 TI - Effect of N-acetylcysteine supplementation on intracellular glutathione, urine isoprostanes, clinical score, and survival in hospitalized ill dogs. AB - BACKGROUND: Antioxidant depletion and lipid peroxidation have been correlated with disease severity and associated with poor outcomes. HYPOTHESIS/OBJECTIVES: Supplementing dogs with N-acetylcysteine (NAC) during the first 48 hours of hospitalization will increase cysteine, normalize glutathione concentrations, and decrease the degree of lipid peroxidation associated with illness. ANIMALS: Sixty systemically ill hospitalized client-owned dogs and 14 healthy control dogs. METHODS: Randomized investigator-blinded, placebo-controlled prospective study. Dogs were randomized to treatment with NAC (n = 30) versus placebo (n = 30). Antioxidants, urine 8-isoprostane/creatinine (IP/Cr), and clinical score were determined before and after treatment with NAC. Glutathione, cysteine, and vitamin E concentrations were quantified using high-performance liquid chromatography. Atomic absorption spectroscopy and enzyme-linked immunosorbent assays were used to quantify selenium and isoprostane concentrations, respectively. RESULTS: Ill dogs had significantly lower vitamin E concentrations (27 versus 55 MUg/mL; P = .0005) as well as elevated IP/Cr ratios (872 versus 399 pg/mg; P = .0007) versus healthy dogs. NAC supplementation significantly increased plasma cysteine (8.67 versus 15.1 MUM; P < .0001) while maintaining glutathione concentrations. Dogs in the placebo group experienced a statistically significant decrease in glutathione concentrations (1.49 versus 1.44 mM; P = .0463). Illness severity and survival were unchanged after short duration NAC supplementation. CONCLUSIONS: Ill dogs experience systemic oxidative stress. Supplementation with NAC during the first 48 hours of hospitalization stabilized erythrocyte glutathione concentrations. The clinical impact of this supplementation and glutathione concentration stabilization was undetermined. PMID- 23458736 TI - Current world literature. PMID- 23458735 TI - Modular synthesis of alkyne-substituted ruthenium polypyridyl complexes suitable for "click" coupling. AB - A modular synthetic method has been developed for the preparation of Ru polypyridyl complexes bearing a terminal alkyne. This method proceeds through a readily accessible intermediate with a silyl-protected alkyne and allows access to a variety of five- and six-coordinate Ru complexes. These complexes can be easily attached to azide-functionalized electrode surfaces with only slight perturbation of the redox properties of the parent complex. PMID- 23458732 TI - Structural biology of the writers, readers, and erasers in mono- and poly(ADP ribose) mediated signaling. AB - ADP-ribosylation of proteins regulates protein activities in various processes including transcription control, chromatin organization, organelle assembly, protein degradation, and DNA repair. Modulating the proteins involved in the metabolism of ADP-ribosylation can have therapeutic benefits in various disease states. Protein crystal structures can help understand the biological functions, facilitate detailed analysis of single residues, as well as provide a basis for development of small molecule effectors. Here we review recent advances in our understanding of the structural biology of the writers, readers, and erasers of ADP-ribosylation. PMID- 23458738 TI - Age and meloxicam modify the response of the glutamate vesicular transporters (VGLUTs) after transient global cerebral ischemia in the rat brain. AB - AIMS: This study analyzes how age and inflammation modify the response of the vesicular glutamate transporters (VGLUTs), VGLUT1-3 to global brain ischemia/reperfusion (I/R) in brain areas with different I/R vulnerabilities. RESULTS: Global ischemia was induced in 3- and 18-month-old male Sprague-Dawley rats and CA1 and CA3 hippocampal areas, dentate gyrus and cerebral cortex of sham operated and I/R animals were removed 48 h after insult. Real-time PCR analysis revealed that I/R challenge resulted in a significant decrease of the VGLUT mRNA levels in young animals. Western blot assays showed a lessened age-dependent response to the ischemic damage in VGLUT1 and VGLUT3, while VGLUT2 presented an age and structure-dependent response to challenge. The use of the anti inflammatory agent meloxicam following challenge showed that COX2 inhibition promotes the expression of VGLUTs in both sham and injured animals, which results in a lessened response to I/R injury. CONCLUSIONS: VGLUT1 and VGLUT3 presented an age-dependent response to ischemic damage, while this VGLUT response was age both and structure-dependent. In addition, COX-2 inhibition resulted in an increase of VGLUT1 and VGLUT2 protein amounts both in sham and injured animals together with a lessening of the transporters' response to ischemia. PMID- 23458739 TI - Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory. AB - Theanine, gamma-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after birth on mild stress-induced attenuation of hippocamapal CA1 long-term potentiation (LTP), the present study evaluated the effect of theanine intake after weaning on stress-induced impairments of LTP and recognition memory. Young rats were fed water containing 0.3% theanine for 3 weeks after weaning and subjected to water immersion stress for 30min, which was more severe than tail suspension stress for 30s used previously. Serum corticosterone levels were lower in theanine administered rats than in the control rats even after exposure to stress. CA1 LTP induced by a 100-Hz tetanus for 1s was inhibited in the presence of 2-amino-5 phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, in hippocampal slices from the control rats and was attenuated by water immersion stress. In contrast, CA1 LTP was not significantly inhibited in the presence of APV in hippocampal slices from theanine-administered rats and was not attenuated by the stress. Furthermore, object recognition memory was impaired in the control rats, but not in theanine-administered rats. The present study indicates the preventive effect of theanine intake after weaning on stress-induced impairments of hippocampal LTP and recognition memory. It is likely that the modification of corticosterone secretion after theanine intake is involved in the preventive effect. PMID- 23458740 TI - Not all stress is equal: CREB is not necessary for restraint stress reinstatement of cocaine-conditioned reward. AB - Stress elicits relapse to cocaine seeking in humans and in animal models. Cyclic AMP response element binding protein (CREB) is required for swim stress-induced reinstatement of cocaine conditioned place preference. However, the role of CREB in other stress-induced reinstatement models has not been examined. To determine whether CREB is required across different stressors we examined the ability of restraint to elicit reinstatement of cocaine-conditioned place preference in wild type and CREBalphaDelta mutant mice. In contrast to previously published differences in swim stress-induced reinstatement, both wild-type and CREBalphaDelta mutant mice demonstrated restraint stress elicited reinstatement of cocaine-conditioned reward. While CREB is necessary for swim stress-elicited zif268 expression within the nucleus accubmens (NAc) shell and prelimbic cortex (PrL), restraint-stress-elicited comparable increases in zif268 expression within these regions in both wild-type and CREBalphaDelta mutant mice. Our findings suggest that not all stressors engage the same circuits or molecular mechanisms to elicit reinstatement behavior. PMID- 23458742 TI - Neuroanatomical correlates of olfactory loss in normal aged subjects. AB - In non-demented older persons, smell dysfunction, measured premortem, has been associated with postmortem brain degeneration similar to that of Alzheimer's disease. We hypothesized that distinct measures of gray and white matter integrity evaluated through magnetic resonance imaging (MRI) techniques could detect degenerative changes associated with age-related olfactory dysfunction. High-resolution T1-weighted images and diffusion-tensor images (DTI) of 30 clinically healthy subjects aged 51-77 were acquired with a 3-Tesla MRI scanner. Odor identification performance was assessed by means of the University of Pennsylvania Smell Identification Test (UPSIT). UPSIT scores correlated with right amygdalar volume and bilateral perirhinal and entorhinal cortices gray matter volume. Olfactory performance also correlated with postcentral gyrus cortical thickness and with fractional anisotropy and mean diffusivity levels in the splenium of the corpus callosum and the superior longitudinal fasciculi. Our results suggest that age-related olfactory loss is accompanied by diffuse degenerative changes that might correspond to the preclinical stages of neurodegenerative processes. PMID- 23458741 TI - Differential effects of serotonin-specific and excitotoxic lesions of OFC on conditioned reinforcer devaluation and extinction in rats. AB - The orbitofrontal cortex (OFC) is critical for behavioral adaptation in response to changes in reward value. Here we investigated, in rats, the role of OFC and, specifically, serotonergic neurotransmission within OFC in a reinforcer devaluation task (which measures behavioral flexibility). This task used two visual cues, each predicting one of two foods, with the spatial position (left right) of the cues above two levers pseudorandomized across trials. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received either excitotoxic OFC lesions made by NMDA (N-methyl-d aspartic acid), serotonin-specific OFC lesions made by 5,7-DHT (5,7 dihydroxytryptamine), or sham lesions. In sham-lesioned rats, devaluation of one food (by feeding to satiety) significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. Both types of OFC lesions disrupted the devaluation effect. In contrast, extinction learning was not affected by serotonin-specific lesions and was only mildly retarded in rats with excitotoxic lesions. Thus, serotonin within OFC is necessary for appropriately adjusting behavior toward cues that predict reward but not for reducing responses in the absence of reward. Our results are the first to demonstrate that serotonin in OFC is necessary for reinforcer devaluation, but not extinction. PMID- 23458743 TI - Expression of CRFR1 and Glu5R mRNA in different brain areas following repeated testing in mice that differ in habituation behaviour. AB - Our recent studies revealed a profound impairment to habituate in 129P3 mice compared to BALB/c mice after repeated exposure to an initially novel environment. This was accompanied by strain-specific c-Fos expression in the prelimbic cortex, a brain area related to emotional and cognitive processing. The metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP increased c-Fos expression in brain areas related to cognition while it decreased c-Fos expression in brain areas processing emotions in 129P3 animals. We hypothesised that the non-adaptive response of 129P3 mice to a novel environment may be the result of impaired neural processing between the prelimbic cortex and emotion processing brain areas, possibly regulated by glutamatergic neurotransmission. To explore this hypothesis, we compared c-Fos activity in between naive and repeatedly tested animals. Further, we investigated mRNA expression of CRFR1 and mGlu5R in the prelimbic cortex and amygdala, since these transmitter systems are not only involved in the regulation of anxiety, but are indicated to be co expressed in relevant brain areas. Behavioural results confirmed strain-specific habituation profiles and strain-specific c-Fos expression in brain areas regulating cognitive and emotional processes in BALB/c and 129P3 mice. We found that repeated testing resulted in contrasting behavioural responses in both strains, and this was accompanied by strain-specific effects on c-Fos and receptor-expression. From these results it may be concluded that habituation in BALB/c mice reflects a shift from a primary emotional response to a more cognitively controlled behaviour, and that this shift over time may be impaired in 129P3 animals. PMID- 23458744 TI - Rapid diagnosis of the economically important fruit fly, Bactrocera correcta (Diptera: Tephritidae) based on a species-specific barcoding cytochrome oxidase I marker. AB - The guava fruit fly, Bactrocera correcta (Bezzi) (Diptera: Tephritidae), is an invasive pest of fruit and vegetable crops that primarily inhabits Southeast Asia and which has the potential to become a major threat within both the Oriental and Australian oceanic regions as well as California and Florida. In light of the threat posed, it is important to develop a rapid, accurate and reliable method to identify B. correcta in quarantine work in order to provide an early warning to prevent its widespread invasion. In the present study, we describe a species specific polymerase chain reaction assay for the diagnosis of B. correcta using mitochondrial DNA cytochrome oxidase I (mtDNA COI) barcoding genes. A B. correcta specific primer pair was designed according to variations in the mtDNA COI barcode sequences among 14 fruit fly species. The specificity and sensitivity of the B. correcta-specific primer pair was tested based on the presence or absence of a band in the gel profile. A pair of species-specific B. correcta primers was successfully designed and named BCOR-F/BCOR-R. An ~280 bp fragment was amplified from specimens belonging to 17 geographical populations and four life stages of B. correcta, while no such diagnostic bands were present in any of the 14 other related fruit fly species examined. Sensitivity test results demonstrated that successful amplification can be obtained with as little as 1 ng MUl-1 of template DNA. The species-specific PCR analysis was able to successfully diagnose B. correcta, even in immature life stages, and from adult body parts. This method proved to be a robust single-step molecular technique for the diagnosis of B. correcta with respect to potential plant quarantine. PMID- 23458745 TI - A diffusion-compensated model for the analysis of DCE-MRI data: theory, simulations and experimental results. AB - Accurate quantification of pharmacokinetic parameters in dynamic contrast enhanced (DCE) MRI may be affected by the passive diffusion of contrast agent (CA) within the tissue. By introducing an additional term into the standard Tofts Kety (STK) model, we correct for the effects of CA diffusion. We first develop the theory describing a CA diffusion corrected STK model (DTK). The model is then tested in simulation with simple models of diffusion. The DTK model is also fit to 18 in vivo DCE-MRI acquisitions from murine models of cancer and results are compared to those from the STK model. The DTK model returned estimates with significantly lower error than the STK model (p ? 0.001). In poorly perfused (i.e., K(trans) <= 0.05 min(-1)) regions the STK model returned unphysical ve values, while the DTK model estimated ve with less than 7% error in noise-free simulations. Results in vivo data revealed similar trends. For voxels with low K(trans) values and late peak concentration times the STK model returned ve estimates >1.0 in 40% of the voxels as compared to only 16% for the DTK model. The DTK model presented here shows promise in estimating accurate kinetic parameters in the presence of passive contrast agent diffusion. PMID- 23458746 TI - Jujube honey from China: physicochemical characteristics and mineral contents. AB - We investigated and compared the physicochemical properties (moisture, color, ash, pH, electrical conductivity, free acidity, lactonic acidity, total acidity, fructose, glucose, sucrose, diastase activity, and HMF) and mineral contents (Al, Ca, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Ni, As, Cd, Pb, and Zn), as well as total proline and total protein contents of 23 jujube honey samples collected from different regions of China. The mineral content was determined by inductively coupled plasma-optical emission spectrometry (ICP-OES). The physicochemical values were in the range of approved limits (conforming to EU legislation) in all 23 samples. The physicochemical properties of jujube honey showed significant variations among samples. The mean pH value of the jujube honeys was 6.71. The most abundant minerals were potassium, calcium, sodium, and magnesium, ranging between 1081.4 and 2642.9, 97.1 and 194.2, 7.79 and 127.8, and 10.36 and 24.67 mg/kg, respectively, and potassium made up 71% of the total mineral content. This study demonstrated remarkable variation in physicochemical parameters and mineral contents of jujube honey, mainly depending on its geographic source. PMID- 23458747 TI - Compositional characteristics of materials recovered from headed gutted silver carp (Hypophthalmichthys molitrix) by isoelectric solubilization and precipitation using organic acids. AB - Protein was recovered from headed gutted silver carp by isoelectric solubilization at pH 2.5, 3.0, 11.5, or 12.0 and precipitation (ISP) at pH 5.5 using acetic (AA) or a 30% formic and lactic acid combination (F&L) and 10 N sodium hydroxide. Total protein and fat recovery yields, proximate composition and mineral analyses of fractions were determined. Protein and lipid recovery yields when solubilized under basic conditions were comparable to yields reported from other studies using hydrochloric acid; however, the recovered fractions were less pure. Processing at basic pH using AA was more effective than F&L at removing impurities (P < 0.05) from the recovered protein fraction and impurities were effectively removed from recovered lipids regardless of processing pH or acid type (P > 0.05). For the most part, sodium was greater (P < 0.05) and there was less calcium, phosphorus, magnesium, and iron (P < 0.05) in the recovered protein regardless of acid used when compared to the initial paste. This research shows that organic acids have the potential to recover protein and lipid by ISP processing. PRACTICAL APPLICATION: This research presents a reliable method for extracting nutritionally valuable fish protein and oils from otherwise hard to process fish and its byproducts. Replacing the traditionally used strong acids with organic acids might further accomplish bacterial load reduction while resulting in similar to or improved protein recovery yields. Therefore, this technology may increase the commercial viability of hard to process fish. PMID- 23458748 TI - Authentication of pure L-leucine products manufactured in China by discriminating between plant and animal sources using nitrogen stable isotope technique. AB - L-leucine products among other branched chain amino acid supplements are highly susceptible to economically motivated adulteration. Curbing this menace is critical and timely. Hence, the delta(15) N composition of the L-leucine derived from plants and animals sources was estimated. The trophic enrichment phenomenon of delta(15) N composition was utilized to elucidate the sources. We finally established the distinction between the respective sources. Samples of plant sources (maize and soybean) and that of animal sources (pig fur and duck feather) were analyzed for delta(15) N isotopic signatures. An elemental analyzer which was connected to an isotope ratio mass spectrometer operated in the continuous flow mode was utilized. The raw materials were obtained from China. Statistical analysis was performed using descriptive statistics and one-way analysis of variance. The results indicated lower delta(15) N values of range -0.73440/00 to 2.3840/00 and 1.0320/00 to 2.0640/00 for maize and soybean samples, respectively. Whereas, a range of 3.8600/00 to 6.0110/00 and 5.8750/00 to 6.0110/00 was, respectively, detected in pig fur and duck feather samples. The delta(15) N difference in plants and animals samples was significant (F = 165.0; P = 1.675 E 10 for maize and pig fur samples; F = 212.8; P = 0.0001284 for soybean and duck feather samples). It was observed that delta(15) N trophic enrichment is helpful in elucidating the respective sources. The authors can emphatically assert that the range of delta(15) N composition of L-leucine derived from plants sources within the study area is -1.0000/00 to 3.0000/00 whereas the range in animal sources is 4.0000/00 to 9.0000/00. Practical Application This study provides a reliable approach in verifying the authenticity of not only L-leucine products but also other branched chain amino acid supplements and thereby would help in fraud detection of any economically motivated adulteration and mislabeling of these products. When coupled with H and O stable isotope techniques, the region of-origin of the detected adulteration can also be traced successfully. It therefore serves as a guide to food regulatory bodies, food scientists, retailers of these products, consumers, and the general public at large. PMID- 23458750 TI - A simple and fast detection method for bovine milk residues in foods: a 2-site monoclonal antibody immunochromatography assay. AB - The ingredient declaration on food labels assumes paramount importance in the protection of food-allergic consumers. China has not implemented Food allergen labeling. A gold immunochromatography assay (GICA) was developed using 2 monoclonal antibodies (mAb) against the milk allergen beta-lactoglobulin in this study. The GICA was specific for pure milk samples with a sensitivity of 0.2 ng/mL. Milk protein traces extracted from 110 food products were detected by this method. The labels of 106 were confirmed by our GICA method: 57 food samples originally labeled as containing milk were positive for beta-lactoglobulin and 49 food samples labeled as not containing milk were negative for beta-lactoglobulin. However, 3 food samples falsely labeled as containing milk were found to contain no beta-lactoglobulin whereas 1 food sample labeled as not containing milk actually contained beta-lactoglobulin. First, these negatives could be because of the addition of a casein fraction. Second, some countries demand that food manufacturers label all ingredients derived from milk as "containing milk" even though the ingredients contain no detectable milk protein by any method. Our GICA method could thus provide a fast and simple method for semiquantitatation of beta lactoglobulin in foods. PRACTICAL APPLICATION: The present method provides a fast, simple, semiquantitative method for the determination of milk allergens in foods. PMID- 23458751 TI - Characterization of cucumber fermentation spoilage bacteria by enrichment culture and 16S rDNA cloning. AB - Commercial cucumber fermentations are typically carried out in 40000 L fermentation tanks. A secondary fermentation can occur after sugars are consumed that results in the formation of acetic, propionic, and butyric acids, concomitantly with the loss of lactic acid and an increase in pH. Spoilage fermentations can result in significant economic loss for industrial producers. The microbiota that result in spoilage remain incompletely defined. Previous studies have implicated yeasts, lactic acid bacteria, enterobacteriaceae, and Clostridia as having a role in spoilage fermentations. We report that Propionibacterium and Pectinatus isolates from cucumber fermentation spoilage converted lactic acid to propionic acid, increasing pH. The analysis of 16S rDNA cloning libraries confirmed and expanded the knowledge gained from previous studies using classical microbiological methods. Our data show that Gram-negative anaerobic bacteria supersede Gram-positive Fermincutes species after the pH rises from around 3.2 to pH 5, and propionic and butyric acids are produced. Characterization of the spoilage microbiota is an important first step in efforts to prevent cucumber fermentation spoilage. PRACTICAL APPLICATION: An understanding of the microorganisms that cause commercial cucumber fermentation spoilage may aid in developing methods to prevent the spoilage from occurring. PMID- 23458752 TI - Technological approaches to minimize industrial trans fatty acids in foods. AB - Trans fatty acids (TFAs) mainly arise from 2 major sources: natural ruminal hydrogenation and industrial partial catalytic hydrogenation. Increasing evidence suggests that most TFAs and their isomers cause harmful health effects (that is, increased risk of cardiovascular diseases). Nevertheless, in spite of the existence of an international policy consensus regarding the need for public health action, several countries (for example, France) do not adopt sufficient voluntary approaches (for example, governmental regulations and systematic consumer rejections) nor sufficient industrial strategies (for example, development of healthier manufacturing practices and innovative processes such as fat interesterifications) to eliminate deleterious TFAs from processed foods while ensuring the overall quality of the final product (for example, nutritional value and stability). In this manuscript, we first review the physical-chemical properties of TFAs, their occurrence in processed foods, their main effects on health, and the routine analytical methods to characterize TFAs, before emphasizing on the major industrial methods (that is, fat food reformulation, fat interesterification, genetically modified FAs composition) that can be used worldwide to reduce TFAs in foods. PMID- 23458753 TI - Degradation Index for quality evaluation of commercial dietary supplements of bilberry extract. AB - In recent years, many anthocyanin-containing dietary supplements of various dosages and formulations have been sold through advertising their large number of beneficial effects. On the other hand, there is an increased risk of distributing deteriorated supplements to consumers due to lax regulations, because in Japan these supplements are classified as food. Spectrophotometric methods are commonly used to control the quality of supplements. However, these methods have limitations with regard to assessing deterioration. In this study, we evaluated a new index for detection of deteriorated products. The stability of 3 formulations and the quality of 20 supplements were investigated by ultra-high performance liquid chromatography, which is superior to spectrophotometry for identifying and quantifying individual anthocyanins. The stability was not only affected by storage temperature but also by formulation. We defined "Degradation Index" (DI) as an indicator of the deterioration of supplements. Of 20 supplements investigated, the DI of 5 supplements was more than 3-fold the value of Bilberon 25, and the worst one was 12.7-fold. These results suggest that DI could be a useful quality control index for detecting deteriorated supplements. PMID- 23458754 TI - Development of Pistachio (Pistacia vera L.) spread. AB - Pistachio nut (Pistacia vera L.) is one of the most delicious and nutritious nuts in the world. Pistachio spreads were developed using pistachio paste as the main component, icing sugar, soy protein isolate (SPI), and red palm oil (RPO), at different ratios. The highest mean scores of all the sensory attributes were depicted by spreads that were made without addition of SPI. It was found that the work of shear was 0 to 11.0 kg s for an acceptable spread. Sensory spreadability, overall texture, spreadability, and overall acceptability were negatively correlated (R > 0.83) with the work of shear of spreads. The findings indicated that the presence of RPO had a direct effect on the viscoelastic behavior of the pistachio spreads. The a values, which are related to the green color of the pistachio product ranged from 1.7 to 3.9 for spread without addition of RPO, and 4.0 to 5.3 in the presence of RPO. PRACTICAL APPLICATION: The development of pistachio spread would potentially increase the food uses of pistachio and introduce consumers with a healthier snack food. PMID- 23458755 TI - Journal of Food Science. New author guidelines launched. PMID- 23458757 TI - The use of TrkA-PathHunter assay in high-throughput screening to identify compounds that affect nerve growth factor signaling. AB - The TrkA-PathHunter cell-based assay was used in high-throughput screening (HTS) to identify compounds that inhibit nerve growth factor (NGF)/TrkA signaling. The assay was conducted in a 384-well format, and typical Z' values during HTS ranged from 0.3 to 0.8. The reproducibility of IC50 values was good, and the use of cryopreserved cells was well tolerated, as judged by assay parameters such as Z' and S/B and by comparison of IC50 values obtained with cells in culture. During hit deconvolution, TrkA-kinase inhibitors were identified with ATP-competitive as well as non-ATP-competitive mechanisms of action. Furthermore, other mechanisms of action such as NGF and TrkA antagonists were also identified. Because of the different molecular mechanisms identified, it is possible that subsequent optimization work to increase affinity and selectivity might lead to compounds that could have a better chance to evoke clinical efficacy without the adverse effects observed for nonselective TrkA inhibitors. PMID- 23458758 TI - Unveiling chemical reactivity and structural transformation of two-dimensional layered nanocrystals. AB - Two-dimensional (2D) layered nanostructures are emerging fast due to their exceptional materials properties. While the importance of physical approaches (e.g., guest intercalation and exfoliation) of 2D layered nanomaterials has been recognized, an understanding of basic chemical reactions of these materials, especially in nanoscale regime, is obscure. Here, we show how chemical stimuli can influence the fate of reaction pathways of 2D layered nanocrystals. Depending on the chemical characteristics (Lewis acid ((1)O2) or base (H2O)) of external stimuli, TiS2 nanocrystal is respectively transformed to either a TiO2 nanodisc through a "compositional metathesis" or a TiO2 toroid through multistage "edge selective structural transformation" processes. These chemical reactions can serve as the new design concept for functional 2D layered nanostructures. For example, TiS2(disc)-TiO2(shell) nanocrystal constitutes a high performance type II heterojunction which not only a wide range solar energy coverage (~80%) with near-infrared absorption edge, but also possesses enhanced electron transfer property. PMID- 23458759 TI - Loss of 5-hydroxymethylcytosine and ten-eleven translocation 2 protein expression in malignant melanoma. AB - Several research groups have recently reported on markedly reduced levels of 5 hydroxymethylcytosine (5hmC) in human breast, liver, lung, pancreatic, colon, prostate, brain, and myeloid cancers. We studied benign compound nevi (BCN, n=17), dysplastic compound nevi (DCN, n=15), superficial spreading melanomas [SSM, stratified in <1 mm (n=19) and >4 mm (n=18) Breslow tumor thickness], and cutaneous metastatic disease (CMD, n=24). Immunohistochemistry included specific antibodies against 5hmC, 5-methylcytosine (5mC), and ten-eleven translocation 2 protein (TET2). Immunohistological scoring showed significantly (P<0.0001) higher median 5hmC levels in BCN and DCN than in thin SSM, thick SSM, and CMD. 5mC immunoreactivity did not differ significantly (P=0.15) between nevi and melanoma. The intensity of TET2 expression was predominantly weak but was found to be significantly (P<0.0001) more often in nevi than in thin SSM, thick SSM, and CMD. We have shown that 5hmC levels and TET2 expression are significantly reduced in advanced melanomas compared with nevi and thin melanomas. It is suggested that 5hmC and TET2 possibly play an important role in the epigenetic regulation of melanoma development and progression. PMID- 23458756 TI - The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. AB - BACKGROUND: Concerns for arsenic exposure are not limited to toxic waste sites and massive poisoning events. Chronic exposure continues to be a major public health problem worldwide, affecting hundreds of millions of persons. OBJECTIVES: We reviewed recent information on worldwide concerns for arsenic exposures and public health to heighten awareness of the current scope of arsenic exposure and health outcomes and the importance of reducing exposure, particularly during pregnancy and early life. METHODS: We synthesized the large body of current research pertaining to arsenic exposure and health outcomes with an emphasis on recent publications. DISCUSSION: Locations of high arsenic exposure via drinking water span from Bangladesh, Chile, and Taiwan to the United States. The U.S. Environmental Protection Agency maximum contaminant level (MCL) in drinking water is 10 ug/L; however, concentrations of > 3,000 ug/L have been found in wells in the United States. In addition, exposure through diet is of growing concern. Knowledge of the scope of arsenic-associated health effects has broadened; arsenic leaves essentially no bodily system untouched. Arsenic is a known carcinogen associated with skin, lung, bladder, kidney, and liver cancer. Dermatological, developmental, neurological, respiratory, cardiovascular, immunological, and endocrine effects are also evident. Most remarkably, early life exposure may be related to increased risks for several types of cancer and other diseases during adulthood. CONCLUSIONS: These data call for heightened awareness of arsenic-related pathologies in broader contexts than previously perceived. Testing foods and drinking water for arsenic, including individual private wells, should be a top priority to reduce exposure, particularly for pregnant women and children, given the potential for life-long effects of developmental exposure. PMID- 23458760 TI - Ipilimumab-induced acute severe colitis treated by infliximab. AB - Ipilimumab (anti-CTLA-4 antibody) is a new tool for the treatment of metastatic melanoma patients that has led to an improvement in survival rates worldwide. New types of toxicities have been described with ipilimumab called 'immune-related adverse events' or irAEs. Here, we report an acute and steroid resistant case of ipilimumab-induced colitis treated with infliximab in a melanoma stage IV AJCC patient. The patient presented with acute grade 3 diarrhea after the second perfusion of ipilimumab. After the administration of intravenous steroids, the patient continued to have grade 2 diarrhea with erythematous mucous with several ulceration sites on rectosigmoidoscopy. Infliximab perfusion (5 mg/kg) was performed and resulted in resolution of symptoms within 2 days with complete healing was observed by rectal sigmoidoscopy on day 7. After failure of two further lines of chemotherapy, the patient died 10 months after the diagnosis of stage IVM1C melanoma. Treatment algorithms exist for the management of these digestive adverse events; however, some points remain unclear. No predictive marker for the occurrence of this digestive toxicity has been validated to date. Modes of administration of steroids and dosage are not clearly defined, except in cases of acute abdomen; surgery is difficult to propose for patients with a poor prognosis. Infliximab is another option for the treatment of steroid-resistant ipilimumab-induced colitis but its use in metastatic melanoma raises questions of its possible impact on the evolution of cancer. We reviewed at least 19 cases published of infliximab administration for ipilimumab-mediated colitis. Unfortunately, tolerance and cancer evolution have scarcely been reported. Thus, because more patients are being treated with CTLA-4 blockade, management of ipilimumab-induced colitis requires further studies. PMID- 23458761 TI - Trends in the risks of melanoma as a second primary cancer among cancer patients in the Netherlands, 1989-2008. AB - The aim of this study is to assess time trends of the risk of melanoma as a second primary cancer (MSPC) among cancer patients in the Netherlands during 1989 2008. Data from the population-based Netherlands Cancer Registry (NCR) were used for an analysis of time trends in the risk of MSPC in a fixed inception cohorts design (1989-1990, 1996-1997, and 2003), with similar lengths of follow-up. Standardized incidence ratios and absolute excess risks (AERs) were calculated to estimate the relative risks and excess absolute risks of MSPC. Differential time trends of risk in MSPC were observed, that is, decreasing for standardized incidence ratios and increasing for AERs in both sexes, but not reaching significance. Over time, AER changed from 24 to 72 per 10 000 person years (P for trend=0.01) in male patients with a previous melanoma during 2-5 years of follow up, whereas among women with a first squamous cell carcinoma of skin, AER increased markedly (P for trend=0.3) over time during the first year of follow up, coinciding with a decrease during the 2-5 years of the follow-up period (P for trend=0.1). MSPCs diagnosed later during follow-up were thicker than those diagnosed earlier, this difference being only statistically significant among male patients with a previous melanoma. The observed favorable risk trend among female patients coincided with thicker MSPCs than male patients. Differential risk trends were observed for MSPC among cancer patients during the past two decades in the Netherlands that did not seem to be affected by greater awareness of the disease. As the stage distribution of MSPCs worsened during follow-up, efforts should be made towards an earlier diagnosis of MSPC. PMID- 23458762 TI - Therapeutic potential of the Streptococcus pneumoniae competence regulon. PMID- 23458763 TI - Treating multidrug-resistant Acinetobacter baumannii infection by blocking its virulence factors. PMID- 23458765 TI - Assessing adherence to antiretroviral therapy in randomized HIV clinical trials: a review of currently used methods. AB - Antiretroviral therapy for the treatment of HIV infection requires high levels of adherence to both maintain plasma HIV RNA at undetectable levels and prevent the emergence of drug resistance. As adherence to treatment is a major criterion for the evaluation of therapeutic outcomes, randomized clinical trials (RCTs) conducted among HIV-infected patients commonly include an assessment of adherence. However, there is still no gold-standard tool for assessing adherence behaviors in HIV RCTs. The methods currently used to collect and analyze adherence data are varied, which makes the comparison of results between studies difficult. The scope of this article is to review and discuss the range of adherence measures currently used in RCTs conducted among HIV-infected adults. PMID- 23458767 TI - Diagnostic and prognostic markers in sepsis. AB - Sepsis is a common and serious complication in intensive care unit patients. An important factor in optimizing survival rates in septic patients is the ability to start treatment early in the course of disease; there is, therefore, a need for accurate diagnostic tests. In recent years, there has been a move away from the rather vague and nonspecific signs that were previously used to diagnose sepsis towards the possible adjunctive role of biomarkers. Many biomarkers have been proposed and assessed clinically, but none alone is specific enough to definitively determine diagnosis. The future direction of research is most likely a greater focus on the use of panels or combinations of markers with clinical signs. Some biomarkers may also be useful for prognosis and guiding therapy. Here, the authors will review our changing approaches to sepsis diagnosis and discuss some of the markers that seem most relevant at the present time. PMID- 23458768 TI - Investigation of antibiotic resistance in the genomic era of multidrug-resistant Gram-negative bacilli, especially Enterobacteriaceae, Pseudomonas and Acinetobacter. AB - The increase and spread of multidrug-resistant (MDR) Gram-negative bacteria, including Enterobacteriaceae, Pseudomonas and Acinetobacter species, have become major concerns worldwide. Although the frequent misuse of antibiotic drugs has greatly contributed to worldwide antibiotic resistance by causing a large dispersal of resistance determinants, recent studies demonstrate that these resistance determinants could have emerged from ancient or environmental sources. Moreover, during the last 10 years, we have been witnessing the emergence and development of technologies for high-throughput sequencing, coinciding with an exponential increase in the number of bacterial genomes sequenced. These sequencing technologies allow a complete study of MDR bacterial genomes and are the best way to investigate the genetic determinants of antimicrobial resistance. Accordingly, studies using genome sequencing to decipher resistance determinants in Enterobacteriaceae, Pseudomonas and Acinetobacter species have demonstrated several advantages including, among others: an exhaustive identification of resistance determinants from any clinical, epidemiological or environmental MDR bacterium; identification of the acquisition mechanisms for resistance determinants exchanged between bacterial species through mobile genetic elements and elucidation and understanding, in record time (less than 1 week), of some critical or epidemic events caused by particular pathogenic bacteria. Therefore, it is clear today that the bacterial genome sequencing approach has revolutionized all fields of scientific research and represents a powerful tool to explore the world of microorganisms. PMID- 23458766 TI - HIV/HBV coinfection in children and antiviral therapy. AB - Small cohort studies from countries where both HIV and HBV are endemic demonstrate prevalence rates of chronic hepatitis B in HIV-infected children of between 1 and 49%. While data on coinfected children are limited, results from studies in adults with HIV/HBV coinfection raise the concern that coinfected children may be at a higher risk of liver disease, hepatic fibrosis and cirrhosis. With the scale-up of combination antiretroviral therapy worldwide, of which lamivudine is included in most first-line regimens, coinfected children treated with lamivudine risk development of HBV resistance mutations. This article summarizes the current literature relevant to HIV/HBV coinfection in children, the options for treatment and highlights priorities for future research. PMID- 23458769 TI - Clinical relevance of the ESKAPE pathogens. AB - In recent years, the Infectious Diseases Society of America has highlighted a faction of antibiotic-resistant bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) - acronymically dubbed 'the ESKAPE pathogens' - capable of 'escaping' the biocidal action of antibiotics and mutually representing new paradigms in pathogenesis, transmission and resistance. This review aims to consolidate clinically relevant background information on the ESKAPE pathogens and provide a contemporary summary of bacterial resistance, alongside pertinent microbiological considerations necessary to face the mounting threat of antimicrobial resistance. PMID- 23458770 TI - Current use of daptomycin in cardiac surgery and postoperative intensive care. AB - Infections due to multidrug-resistant pathogens have an increasing impact on patients undergoing cardiac surgery. Preoperative infections, such as endocarditis, and postoperative infections, including wound and device infection, influence patient outcomes. Special interest needs to be taken in patients admitted to cardiac surgical intensive care units, as these patients are at high risk for infections, particularly nosocomial pneumonia, catheter-related and wound infections. The increasing numbers of infections due to Gram-positive multidrug-resistant pathogens underline the necessity for newer antibiotics with bactericidal effects and a more favorable profile of side effects. Daptomycin, a lipopeptide antimicrobial agent with bactericide activity against Gram-positive organisms, has been successfully used in the treatment of complicated infections due to Gram-positive multidrug-resistant pathogens, especially regarding endocarditis, wound infections, device and catheter-related infections in intensive care units. In this review, the authors will summarize therapeutic potential of daptomycin in cardiac surgery and postoperative intensive care. PMID- 23458771 TI - Impact of antimicrobial multidrug resistance on inpatient care cost: an evaluation of the evidence. AB - This article evaluates the in-hospital costs attributable to antimicrobial multidrug resistance, defined as the difference in averaged costs of the patients infected with a multidrug-resistant (MDR) versus a non-MDR organism. PubMed and Scopus databases were searched to identify relevant studies. Twenty four studies were included: four on carbapenem-resistant or MDR Gram negative nonfermenters, eight on extended-spectrum b-lactamase-producing Enterobacteriaceae and 12 on methicillin-resistant Staphylococcus aureus. In two studies on carbapenem resistant nonfermenters, the attributable mean hospital charges were US$58,457 and 85,299, respectively. The attributable mean total costs were US$4484 in a study referring to MDR Acinetobacter baumannii, while that varied from US$1584 to 30,093 among studies on extended-spectrum b-lactamase-producing Enterobacteriaceae. With respect to methicillin-resistant S. aureus, the attributable mean total costs varied from US$1014 to 40,090. The in-hospital costs attributable to multidrug resistance are alarmingly high, justifying the application of strict infection control measures in medical institutions with increased rate of MDR infections. PMID- 23458773 TI - Beneficial effect of melatonin on blastocyst in vitro production from heat stressed bovine oocytes. AB - Melatonin may play an important role in protecting gametes and embryos from the potential harmful effects of oxidative stress. In this study, we first examined two different heat stress (HS) treatments for in vitro oocyte maturation (Experiment 1: 38.5 vs 41.0 degrees C, during the first 20 h; Experiment 2: 38.5 vs 41.5 degrees C, during the entire period) on bovine oocyte maturation and embryo development. Second, we tested different melatonin concentrations added to the maturation and culture medium (Experiment 3: 0, 10(-12) , 10(-9) , 10(-4) m; Experiment 4: 0, 10(-3) m), both with and without HS (38.5 or 41.5 degrees C, respectively). In Experiment 1, the HS treatment resulted in a lower maturation rate and number of cells/blastocyst (C/B) and a higher blastocyst rate than that in the control group. In Experiment 2, oocytes/embryos from heat-stressed oocytes (HSO) had a lower maturation, cleavage and blastocyst rates, as well as a lower C/B compared with the control. In Experiment 3, in HSO groups, 10(-4) m melatonin resulted in an increased blastocyst rate compared with 0 m melatonin, with a similar blastocyst rate to the non-HSO without melatonin. Melatonin did not have any effect in embryos from non-HSO groups compared with the control. In Experiment 4, 10(-3) m melatonin produced lower cleavage and blastocyst rates in HSO and lower blastocyst rate in non-HSO when compared to melatonin-untreated oocytes/embryos. In conclusion, 10(-4) m melatonin was found to alleviate bovine oocytes from the harmful effects of HS. PMID- 23458774 TI - Left atrium volume index is influenced by aortic stiffness and central pulse pressure in type 2 diabetes mellitus patients: a hemodynamic and echocardiographic study. AB - BACKGROUND: Left atrial volume index (LAVI) has recently emerged as a useful biomarker for risk stratification and risk monitoring in many clinical settings. Many hemodynamic factors such as preload and afterload have an effect on evaluating left atrium function. This study was performed to investigate the relationship between LAVI and aortic stiffness index (ASI) and selected markers characterizing hemodynamic state in patients with type 2 diabetes mellitus (DM2). MATERIAL AND METHODS: The study population consisted of 100 patients (56 men, 44 women), 67.2 (+/-10.9) years old DM2, scheduled for routine coronary angiography. Standard transthoracic echocardiography was used to measure parameters needed for calculation of LAVI and ASI. During invasive procedures, central pulse pressure (CPP) in the ascendens aorta and left ventricle end-diastolic pressure (LVEDP) were recorded. Selected laboratory parameters were obtained, including lipidogram, serum uric acid, hs-CRP, fibrinogen, cTnT, myoglobin, BNP, HbA1C, creatinine, and GFR. RESULTS: Both LAVI and ASI were greater and CPP and LVEDP were markedly elevated in DM2 patients compared to controls. The independent predictors of LAVI were ASI (beta=0.331; p=0.011), CPP (beta=0.312; p=0.020), LVEDP (beta=0.381; p=0.006), HbA1C (beta=0.379; p=0.008), and BNP (beta=0,423; p<0,001). CONCLUSIONS: The strong correlation between HbA1C and both LAVI and ASI is a sign of negative influence of poor glycemia control on the left ventricle diastolic function and compliance of the aorta. The independent correlation between LAVI and ASI, CPP, and LVEDP improved by association of LAVI and ASI with specific biochemical markers suggests an association between LAVI and elastic properties of the aorta, as well as CPP in DM2 patients. PMID- 23458775 TI - Guanidino anthrathiophenediones as G-quadruplex binders: uptake, intracellular localization, and anti-Harvey-Ras gene activity in bladder cancer cells. AB - We prepared a series of anthrathiophenediones (ATPDs) with guanidino-alkyl side chains of different length (compounds 1, 10-13). The aim was to investigate their interaction with DNA and RNA G-quadruplexes, their uptake in malignant and nonmalignant cells, and their capacity to modulate gene expression and inhibit cell growth. Flow cytometry showed that the ATPDs enter more efficiently in malignant T24 bladder cells than in nonmalignant embryonic kidney 293 or fibroblast NIH 3T3 cells. In T24 malignant cells, compound 1, with two ethyl side chains, is taken up by endocytosis, while 12 and 13, with respectively propyl and butyl side chains, are transported by passive diffusion. The designed ATPDs localize in the cytoplasm and nucleus and tightly bind to DNA and RNA G quadruplexes. They also decrease HRAS expression, increase the cell population in G0/G1, and strongly inhibit proliferation in malignant T24 bladder cells, but not in nonmalignant 293 or NIH 3T3 cells. PMID- 23458777 TI - Structural brain plasticity in adult learning and development. AB - Recent research using magnetic resonance imaging has documented changes in the adult human brain's grey matter structure induced by alterations in experiential demands. We review this research and relate it to models of brain plasticity from related strands of research, such as work on animal models. This allows us to generate recommendations and predictions for future research that may advance the understanding of the function, sequential progression, and microstructural nature of experience-dependent changes in regional brain volumes. Informed by recent evidence on adult age differences in structural brain plasticity, we show how understanding learning-related changes in human brain structure can expand our knowledge about adult development and aging. We hope that this review will promote research on the mechanisms regulating experience-dependent structural plasticity of the adult human brain. PMID- 23458778 TI - Cannabis, psychosis and the thalamus: a theoretical review. AB - The role of cannabis in the etiology of schizophrenia has been documented as possibly the strongest environmental risk factor. However, the pathomechanism whereby cannabis use increases this risk has not yet been identified. We argue that this pathomechanism may involve direct effects of exogenous cannabinoids on T-type calcium channels in the thalamus. These channels are crucial for amplification of corticothalamic inputs, as well as for the ability of the thalamus to generate neuronal burst firing. Cortically induced thalamic burst firing has been found to be important in trans-thalamic cortico-cortical interactions. Therefore, any potential interference with the burst firing mode in the thalamus could lead to an impairment in these interactions, which in turn causes a relative disconnection between cortical areas. This in turn could result in reduced ability to recognize re-afferent sensory inputs and psychosis. We also argue that the effects of Delta(9)THC are more detrimental compared with the effects of cannabidiol, as the former may increase the excitability of thalamic neurons by its direct effect on T-type calcium channels. PMID- 23458779 TI - Lymphopenia as risk factor for development of severe infections in patients with systemic lupus erythematosus: a case-control study. AB - OBJECTIVES: Hematological abnormalities, particularly lymphopenia, are common in patients with systemic lupus erythematosus (SLE), whether the disease is active or not. The aim of this study is to assess whether lymphopenia (blood counts <=1000 K/ul) is a risk factor for severe infections in patients with SLE. METHODS: A retrospective case-control study was performed. We reviewed the clinical records of 167 SLE patients throughout a 5-year period. SLE patients with severe infections were compared with those without infection and the presence of lymphopenia was obtained from the blood count previous to the infection date. Also, other clinical and laboratory features as well as immunosuppressive therapy and SLE disease activity index (SLEDAI) were recorded. RESULTS: Univariate analysis shows multiple risk factors for severe infections in SLE, such as lymphopenia, high SLEDAI index, prednisone (PDN) and mycophenolate mofetil treatment and low levels of C3 and C4. Moreover, hydroxychloroquine treatment conferred protection. However, after multivariate analysis, only lymphopenia [odds ratio (OR) 5.2, 95% confidence interval (CI) 2.39-11.3], PDN treatment (OR 4.8, 95% CI 2.1-11.9) and low levels of C3 (OR 2.97, 95% CI 1.1 7.9) remained as independent risk factors. CONCLUSIONS: Our data suggest that lymphopenia, PDN treatment and low levels of C3 are independent risk factors for the development of severe infections in SLE patients, including diverse microorganisms, not only opportunistic infections. PMID- 23458776 TI - Moment-to-moment brain signal variability: a next frontier in human brain mapping? AB - Neuroscientists have long observed that brain activity is naturally variable from moment-to-moment, but neuroimaging research has largely ignored the potential importance of this phenomenon. An emerging research focus on within-person brain signal variability is providing novel insights, and offering highly predictive, complementary, and even orthogonal views of brain function in relation to human lifespan development, cognitive performance, and various clinical conditions. As a result, brain signal variability is evolving as a bona fide signal of interest, and should no longer be dismissed as meaningless noise when mapping the human brain. PMID- 23458780 TI - Usefulness of electrocardiographic and radiographic changes in the diagnosis of acute pulmonary embolism. PMID- 23458781 TI - Selumetinib promotes radioiodine uptake in thyroid cancers. PMID- 23458782 TI - Somatic hotspot mutations in APA. PMID- 23458783 TI - Thyroid gland: Can a nomogram predict death in patients with thyroid cancer? PMID- 23458784 TI - Treating congenital hypothyroidism--which levothyroxine? PMID- 23458786 TI - Light extraction efficiency analysis of GaN-based light-emitting diodes with nanopatterned sapphire substrates. AB - In this paper, we propose a method to analyze the light extraction efficiency (LEE) enhancement of a nanopatterned sapphire substrates (NPSS) light-emitting diode (LED) by comparing wave optics software with ray optics software. Finite difference time-domain (FDTD) simulations represent the wave optics software and Light Tools (LTs) simulations represent the ray optics software. First, we find the trends of and an optimal solution for the LEE enhancement when the 2D-FDTD simulations are used to save on simulation time and computational memory. The rigorous coupled-wave analysis method is utilized to explain the trend we get from the 2D-FDTD algorithm. The optimal solution is then applied in 3D-FDTD and LTs simulations. The results are similar and the difference in LEE enhancement between the two simulations does not exceed 8.5% in the small LED chip area. More than 10(4) times computational memory is saved during the LTs simulation in comparison to the 3D-FDTD simulation. Moreover, LEE enhancement from the side of the LED can be obtained in the LTs simulation. An actual-size NPSS LED is simulated using the LTs. The results show a more than 307% improvement in the total LEE enhancement of the NPSS LED with the optimal solution compared to the conventional LED. PMID- 23458785 TI - A prospective randomized comparison of neoprene vs thermoplast hand-based thumb spica splinting for trapeziometacarpal arthrosis. AB - OBJECTIVE: In patients with trapeziometacarpal arthrosis, we tested the hypothesis that there is no difference in arm-specific disability 5-15 weeks after prescription of a pre-fabricated neoprene or a custom-made thermoplast hand based thumb spica splint with the metacarpophalangeal joint included and the first interphalangeal joint free. METHOD: One hundred nineteen patients with a diagnosis of trapeziometacarpal arthrosis were prospectively randomized to wear either a neoprene or a thermoplast hand-based thumb spica splint. At enrollment, patients completed a set of validated questionnaires. An average of 9 weeks later, patients returned for a second visit. Bivariable analyses assessed factors associated with disability, pain and satisfaction. Analysis was by intention-to treat. RESULTS: Sixty-two patients (32 with a neoprene and 30 with a thermoplast splint) completed the study, 51 patients (43%) did not return for the second visit, and six did not complete the protocol for other reasons. Non-completers were significantly younger than completers (P < 0.00044). On average completers rated the neoprene splint as more comfortable (P = 0.048), but there were no detectable differences in Disabilities of the Arm, Shoulder and Hand (DASH), change in DASH, pain, satisfaction, pinch or grip strength between the two splint types in our sample. CONCLUSION: When compared to custom-made thermoplast splints, pre-fabricated neoprene hand-based thumb spica splints are, on average, more comfortable, less expensive, and as effective in treating trapeziometacarpal arthrosis. This trial was registered at Clinicaltrials.gov (NCT00438763). PMID- 23458787 TI - Laser damage resistance of ion-beam sputtered Sc2O3/SiO2 mixture optical coatings. AB - We report on the correlation between the laser damage resistance, the optical and the physical properties of Sc(2)O(3)/SiO(2) mixture coatings. Several sets of samples with ten different mixture ratios have been prepared by ion-beam sputtering. The atomic compositions of the mixture thin films are quantified employing x-ray photoelectron spectroscopy depth profiles. Laser-induced damage thresholds are determined with single subpicosecond pulses (500 fs) at 1030 nm. Furthermore, Son1 multishot measurements are realized in the ultraviolet wavelength range (355 nm) at pulse durations of 5 ns. In addition, the influence of two different substrate polishing qualities on the radiation resistance of the composite thin films is discussed. PMID- 23458788 TI - Design and fabrication of an achromatic infrared wave plate with Sb-Ge-Sn-S system chalcogenide glass. AB - We designed and fabricated an achromatic infrared wave plate. To examine its phase retardation characteristics, the birefringence was calculated using the effective medium theory. A wave plate with a subwavelength grating was fabricated by direct imprint lithography on a low toxic chalcogenide glass (Sb-Ge-Sn-S system) based on calculated results. As a result of imprinting onto chalcogenide glass by a glassy carbon mold, a grating with 1.63 MUm depth, a fill factor of 0.7, and a 3 MUm period was obtained. The phase retardation of the elements reached around 30 degrees in the 8.5-10.5 MUm wavelength range. The fabrication of the infrared wave plate is less costly compared with conventional crystalline wave plates. PMID- 23458789 TI - Organic-based plasmonic emitters for sensing applications. AB - Plasmonic emissions generated by excitation of an organic layer on a metal grating structure are demonstrated. The emissions correspond to the resonant condition of surface plasmon (SP) modes on the Alq(3)/Au interface, and the grating structure is coupled to the Au/air interface to provide light emissions. Experimental variations in pitch to control plasmonic bandgap obtained highly directional plasmonic emissions with enhanced intensity. This method is readily applicable for detecting refractive index changes by using SP-coupled fluorophores to obtain emissions of varying wavelengths and viewing angles. The calculations showed that the wavelength of the plasmonic emitter changed from 480 to 680 nm at certain viewing angles, while the concentration of contacting glucose increased from 10% to 40%. Accordingly, a device with a pitch size of 500 nm had a sensitivity of Deltathetae/Deltan=37.76 degrees and Deltan/Delta=1.681*10(-4) RIU (refractive index unit). Therefore, the proposed approach has potential applications in low-cost, disposable, point-of-care biosensors. PMID- 23458790 TI - Theoretical and experimental determination of steering mechanism for Risley prism systems. AB - Two different analytical methods, the first-order paraxial approximation method and the nonparaxial ray tracing method, are applied to determine the steering mechanism of the Risley prism system, including the pointing prediction and the complete and exact inverse orientation solutions. The analytical results obtained with the two different methods are investigated in detail about the pointing prediction and the two groups of inverse orientation solutions, respectively. Risley prism equipment for wide angular range beam scanning is assembled and the experimental setup is built to test the steering mechanism of the Risley prism system. Experimental results validate the availability of the nonparaxial ray tracing method to discuss the beam steering mechanism for the Risley prism system. PMID- 23458791 TI - Highly Er(3+)-doped ZrF4-based fluoride glasses for 2.7 MUm laser materials. AB - A new type of fluoride glasses with high erbium-doping concentration (up to 6 mol. % Er(3+)) is investigated. The intensive 2.7 MUm fluorescence is demonstrated with minimized concentration quenching. The intensity parameters and radiative properties are determined from the absorption spectrum based on the Judd-Ofelt theory. The prepared Er(3+)-doped ZBYA glass possesses high predicted spontaneous-transition probability (28.92 s(-1)) and large calculated emission cross section (9.8*10(-21) cm(2)). All these results indicate that this Er(3+) doped ZrF(4)-based fluoride glass has potential applications in 2.7 MUm laser materials. PMID- 23458792 TI - Reducing the memory usage for effective computer-generated hologram calculation using compressed look-up table in full-color holographic display. AB - A fast algorithm with low memory usage is proposed to generate the hologram for full-color 3D display based on a compressed look-up table (C-LUT). The C-LUT is described and built to reduce the memory usage and speed up the calculation of the computer-generated hologram (CGH). Numerical simulations and optical experiments are performed to confirm this method, and several other algorithms are compared. The results show that the memory usage of the C-LUT is kept low when number of depth layers of the 3D object is increased, and the time for building the C-LUT is independent of the number of depth layers of the 3D object. The algorithm based on C-LUT is an efficient method for saving memory usage and calculation time, and it is expected that it could be used for realizing real time and full-color 3D holographic display in the future. PMID- 23458793 TI - Feasibility of nanofluid-based optical filters. AB - In this article we report recent modeling and design work indicating that mixtures of nanoparticles in liquids can be used as an alternative to conventional optical filters. The major motivation for creating liquid optical filters is that they can be pumped in and out of a system to meet transient needs in an application. To demonstrate the versatility of this new class of filters, we present the design of nanofluids for use as long-pass, short-pass, and bandpass optical filters using a simple Monte Carlo optimization procedure. With relatively simple mixtures, we achieve filters with <15% mean-squared deviation in transmittance from conventional filters. We also discuss the current commercial feasibility of nanofluid-based optical filters by including an estimation of today's off-the-shelf cost of the materials. While the limited availability of quality commercial nanoparticles makes it hard to compete with conventional filters, new synthesis methods and economies of scale could enable nanofluid-based optical filters in the near future. As such, this study lays the groundwork for creating a new class of selective optical filters for a wide range of applications, namely communications, electronics, optical sensors, lighting, photography, medicine, and many more. PMID- 23458794 TI - Industrial applications of photon density wave spectroscopy for in-line particle sizing [Invited]. AB - Optical spectroscopy in highly turbid liquid material is often restricted by simultaneous occurrence of absorption and scattering of light. Photon Density Wave (PDW) spectroscopy is one of the very few, yet widely unknown, technologies for the independent quantification of these two optical processes. Here, a concise overview about modern PDW spectroscopy is given, including all necessary equations concerning the optical description of the investigated material, dependent light scattering, particle sizing, and PDW spectroscopy itself. Additionally, it is shown how the ambiguity in particle sizing, arising from Mie theory, can be correctly solved. Due to its high temporal resolution, its applicability to highest particle concentrations, and its purely fiber-optical probe, PDW spectroscopy possesses all fundamental characteristics for optical in line process analysis. Several application examples from the chemical industry are presented. PMID- 23458795 TI - High-quality fiber fabrication in buffered hydrofluoric acid solution with ultrasonic agitation. AB - An etching method for preparing high-quality fiber-optic sensors using a buffered etchant with ultrasonic agitation is proposed. The effects of etching conditions on the etch rate and surface morphology of the etched fibers are investigated. The effect of surface roughness is discussed on the fibers' optical properties. Linear etching behavior and a smooth fiber surface can be repeatedly obtained by adjusting the ultrasonic power and etchant pH. The fibers' spectral quality is improved as the ratio of the pit depth to size decreases, and the fibers with smooth surfaces are more sensitive to a bacterial suspension than those with rough surfaces. PMID- 23458796 TI - In-fiber quasi-Michelson interferometer with a core-cladding-mode fiber end-face mirror. AB - An in-fiber quasi-Michelson interferometer working on reflection is proposed and experimentally demonstrated. The device consists of a short section of multimode fiber (MMF) followed by a single-mode fiber (SMF) whose end face is terminated by a thick silver film. The MMF excites cladding modes into downstream SMF via the mismatched-core splicing interface. The core-cladding modes are reflected back by the silver film and recoupled to the core of lead-in SMF through the MMF. A well defined interference pattern is obtained as the result of core-cladding mode interference. A configuration with a 40 mm pigtail SMF at a wavelength of 1528 nm exhibits a water level sensitivity of -49.8 pm/mm and a liquid refractive index sensitivity of -574.6 (pm/mm)/RIU (refractive index unit). In addition, the selected dip provides a considered temperature sensitivity of -61.26 pm/ degrees C and a high displacement sensitivity of -1018.6 pm/mm. PMID- 23458797 TI - Precise frequency measurements of iodine hyperfine transitions at 671 nm. AB - We report absolute frequency measurements on the a(1), a(10), and a(15) hyperfine components of the R(78) 4-6 line of (127)I(2). An external-cavity diode laser system at 671 nm is frequency-stabilized to the saturated absorption center obtained by modulation transfer spectroscopy in an iodine vapor cell. Its absolute frequency is measured by an optical frequency comb. The effect of pressure shift is investigated to obtain the absolute transition frequency at zero pressure. Our determination of the line centers reaches a precision of better than 40 kHz and will provide useful input for theoretical calculations. This frequency-stabilized laser can be used as a reference laser for the spectroscopy of lithium D lines. PMID- 23458798 TI - Quantitative phase maps denoising of long holographic sequences by using SPADEDH algorithm. AB - We propose a denoising method for digital holography mod 2pi wrapped phase map by using an adaptation of the SPArsity DEnoising of Digital Holograms (SPADEDH) algorithm. SPADEDH is a l(1) minimization algorithm able to suppress the noise components on digital holograms without any prior knowledge or estimation about the statistics of noise. We test our algorithm with either general numerical simulated wrapped phase, quantifying the performance with different efficiency parameters and comparing it with two popular denoising strategies, i.e., median and Gaussian filters, and specific experimental tests, by focusing our attention on long-sequence wrapped quantitative phase maps (QPMs) of in vitro cells, which aim to have uncorrupted QPMs. In addition, we prove that the proposed algorithm can be used as a helper for the typical local phase unwrapping algorithms. PMID- 23458799 TI - Temperature response of an all-solid photonic bandgap fiber for sensing applications. AB - The spectral shift due to temperature in the photonic bandgap (PBG) of an all solid PBG fiber is investigated, aiming at discrete and distributed temperature sensing. A temperature rise induces a red shift in the bandgap spectra, which can be easily and precisely monitored by measuring the fiber transmission near one of the band edges. Two different situations that are potentially compatible with distributed and quasi-distributed sensing were investigated: heating a 2 m section of a longer (~10 m) fiber, and heating the whole extension of a fiber that is tens of centimeters in length and was spliced to conventional fibers on both sides. The latter setup yielded bandgap spectral shifts up to ~35 pm/ degrees C. Aiming at discrete sensing, a short (~50 mm) fiber section was subjected to a tight bend so as to exhibit increased temperature sensitivity. Choosing the position of the bend allows for reconfiguration, on demand, of the sensor. A semi-analytical method to identify the spectral position of bandgaps was used to model the fiber transmission, as well as the bandgap shift with temperature, with consistent results. PMID- 23458800 TI - Fringe pattern demodulation using the one-dimensional continuous wavelet transform: field-programmable gate array implementation. AB - This paper presents a thorough discussion of the proposed field-programmable gate array (FPGA) implementation for fringe pattern demodulation using the one dimensional continuous wavelet transform (1D-CWT) algorithm. This algorithm is also known as wavelet transform profilometry. Initially, the 1D-CWT is programmed using the C programming language and compiled into VHDL using the ImpulseC tool. This VHDL code is implemented on the Altera Cyclone IV GX EP4CGX150DF31C7 FPGA. A fringe pattern image with a size of 512*512 pixels is presented to the FPGA, which processes the image using the 1D-CWT algorithm. The FPGA requires approximately 100 ms to process the image and produce a wrapped phase map. For performance comparison purposes, the 1D-CWT algorithm is programmed using the C language. The C code is then compiled using the Intel compiler version 13.0. The compiled code is run on a Dell Precision state-of-the-art workstation. The time required to process the fringe pattern image is approximately 1 s. In order to further reduce the execution time, the 1D-CWT is reprogramed using Intel Integrated Primitive Performance (IPP) Library Version 7.1. The execution time was reduced to approximately 650 ms. This confirms that at least sixfold speedup was gained using FPGA implementation over a state-of-the-art workstation that executes heavily optimized implementation of the 1D-CWT algorithm. PMID- 23458801 TI - Generating random rough edges, surfaces, and volumes. AB - Numerical methods of generating rough edges, surfaces, and volumes for subsequent simulations are commonly employed, but result in data with a variance that is downward biased from the desired value. Thus, it is highly desirable to quantify and to minimize this bias. Here, the degree of bias is determined through analytical derivations and numerical simulations as a function of the correlation length and the roughness exponent of several model power spectral density functions. The bias can be minimized by proper choice of grid size for a fixed number of data points, and this optimum grid size scales as the correlation length. The common approach of using a fixed grid size for such simulations leads to varying amounts of bias, which can easily be confounded with the physical effects being investigated. PMID- 23458802 TI - Alternative method for design and optimization of the ring resonator used in micro-optic gyro. AB - The ring resonator is one of the key elements in the micro-optic gyro system, but there is not a uniform method for designing the parameters of a ring resonator, especially for its size. In this paper, an alternative method is presented for designing the ring resonator used in micro-optic gyro. Maximization of the resonator output is proposed to be the principle in design and optimization for the first time to our knowledge. The scale factor accuracy and the full range of the gyro system are taken into account to obtain the optimum diameter of the ring. A theoretical optimal diameter of 0.25 m is achieved for SiO(2) waveguide resonator with a dynamic range of +/-500 degrees /s by analyzing the influence of resonator parameters on the output in detail, and the corresponding sensitivity of the gyro is less than 1.28 degrees /h, which can meet the demands of a tactical inertia system. PMID- 23458803 TI - In-band optical signal-to-noise ratio monitoring technique based on Brillouin fiber ring laser. AB - We propose an improved technique for in-band optical signal-to-noise ratio (OSNR) monitoring based on a Brillouin fiber ring laser seeded by the optical channel to be monitored. This technique shows a reduction of the required input power into the monitor along with a large and tunable dynamic OSNR monitoring range. It is demonstrated experimentally and numerically for various bit rates and modulation formats. PMID- 23458804 TI - Fully interferometric three-dimensional imaging spectrometry using hyperbolic type volume interferogram. AB - A signal-processing method is proposed in the fully interferometric three dimensional (3D) imaging spectrometry. This processing computes a 3D interferogram, in which recorded fringe patterns do not directly reflect wavefront forms propagated from a polychromatic light source under measurement. This paper presents a procedure for signal processing including a synthesis of the 3D interferogram and retrieval of a set of spectral components of 3D images. We demonstrate retrieving 3D images for spectral components of two planar light sources by means of the proposed method. The procedure to synthesize the 3D interferogram in this method suggests the possibility of direct measurement of the 3D interferogram. PMID- 23458805 TI - Modeling the mean Mueller matrix of randomly orientated nonspherical particles. AB - A fast graphics processing unit implementation of the finite-difference time domain model was used to determine the computational effort required to accurately characterize the mean scattering functions of randomly orientated aspherical particles. The influence of the number of randomized rotational positions on the accuracy of the mean scattering phase function curve was appraised. In general, multiplying the number of orientations by 100 gives increased accuracy of factor 10. Dependent on particle shape, certain regions of the phase function were insensitive to particle orientation. In addition, an error in a key previous publication on scattering by aspherical particles was identified. PMID- 23458806 TI - Broadband thin-film polarizers for high-power laser systems. AB - We propose to construct broadband thin-film polarizers (TFPs) by combining the polarizing regions of long-wave pass and short-wave pass stacks. The polarization bandwidth can be broader than traditional TFPs by roughly a factor of 2. We designed and fabricated two HfO(2)/SiO(2) Brewster's angle TFPs with a high contrast ratio in the spectral range of 1064+/-25 nm. The laser-induced damage was investigated and illustrates that the two designs possess quite different laser damage properties due to the different electric field distributions. Nevertheless, broadband TFPs with high laser-induced damage threshold can be achieved with proper coating design. PMID- 23458807 TI - Efficient amplification of a femtosecond Ti:sapphire laser with a ring regenerative amplifier. AB - A high-stability and high-efficiency ring Ti:sapphire regenerative amplifier is demonstrated based on a double-gating pulse picker at a repetition rate of 1 kHz. Pulse energy up to 5.7 mJ is obtained using a pump energy of 20.0 mJ at 527 nm, corresponding to a relatively high slope efficiency of 30.3%. After a grating compressor, the laser pulse is compressed to 37.2 fs with an energy of 4.1 mJ. The beam quality factors M(2) are 1.4 and 1.3 in tangential and sagittal directions, respectively. The measured root mean square energy stability is better than 0.31% over an 11 h period. PMID- 23458808 TI - Hybrid chaos-based communication system consisting of three chaotic semiconductor ring lasers. AB - We report on the realization of a hybrid chaos-based communication scheme using three chaotic semiconductor ring lasers (SRLs). In this scheme, two slave SRLs (S SRLs) are identically driven by a master SRL (M-SRL) subject to delayed optical feedback. Under proper conditions, the S-SRLs are completely synchronized with each other due to the symmetric operation, and they are also synchronized with the M-SRL through the injection-locking effect. The results also show that a message encrypted through chaos shift keying at the M-SRL end can be successfully decrypted by the two S-SRLs, while the two uncoupled S-SRLs allow for dual channel chaos communication when both counterpropagating modes of one S-SRL are encoded with a message. PMID- 23458809 TI - Resonance domain surface relief diffractive lens for the visible spectral region. AB - Early expectations for a role of diffractive lenses were dramatically lessened by their high order overlapping foci, low optical powers, and competing advances in refractive micro-optics. By bringing the Bragg properties of volume holograms to diffractive lenses we got rid of ghost diffractive orders and the critical trade off between diffraction efficiency, number of phase levels, and spatial feature size. Binary off-axis resonance domain diffractive lens with high numerical aperture of 0.16 was designed with analytical effective grating theory, fabricated by direct e-beam writing, etched in fused silica and experimentally investigated. More than 81% measured diffraction efficiency exceeds twice the limits of thin binary optics. PMID- 23458810 TI - Coherent diffractive imaging beyond the Fresnel approximation using a deterministic phase-retrieval method with an aperture-array filter. AB - Previously, we have proposed a lensless coherent imaging using a nonholographic and noniterative phase-retrieval method that allows the reconstruction of a complex-valued object from a single diffraction intensity measured with an aperture-array filter. The proof-of-concept experiment of this method has been demonstrated under the Fresnel diffraction approximation. In applications to microscopy, however, the measurement of the diffraction intensity with high numerical aperture beyond the Fresnel approximation is required to obtain the object information at high spatial resolution. Thus we have also presented an extension procedure to apply the method to the cases beyond the Fresnel approximation by means of computer simulations. Here the effectiveness of the procedure is demonstrated by the experiments, in which the reconstruction with about 10 times the resolution of our previous experiment has been achieved and the object information in depth direction has been retrieved. PMID- 23458811 TI - Passive time-multiplexing super-resolved technique for axially moving targets. AB - In this paper we present a super-resolving approach for detecting an axially moving target that is based upon a time-multiplexing concept and that overcomes the diffraction limit set by the optics of an imaging camera by a priori knowledge of the high-resolution background in front of which the target is moving. As the movement trajectory is axial, the approach can be applied to targets that are approaching or moving away from the camera. By recording a set of low-resolution images at different target axial positions, the super-resolving algorithm weights each image by demultiplexing them using the high-resolution background image and provides a super-resolved image of the target. Theoretical analyses as well as simulations and preliminary experimental validation are presented to validate the proposed approach. PMID- 23458812 TI - Smart CMOS image sensor for lightning detection and imaging. AB - We present a CMOS image sensor dedicated to lightning detection and imaging. The detector has been designed to evaluate the potentiality of an on-chip lightning detection solution based on a smart sensor. This evaluation is performed in the frame of the predevelopment phase of the lightning detector that will be implemented in the Meteosat Third Generation Imager satellite for the European Space Agency. The lightning detection process is performed by a smart detector combining an in-pixel frame-to-frame difference comparison with an adjustable threshold and on-chip digital processing allowing an efficient localization of a faint lightning pulse on the entire large format array at a frequency of 1 kHz. A CMOS prototype sensor with a 256*256 pixel array and a 60 MUm pixel pitch has been fabricated using a 0.35 MUm 2P 5M technology and tested to validate the selected detection approach. PMID- 23458813 TI - Open-access operating algorithms for commercial videokeratographer and improvement of corneal sampling. AB - We present an algorithm to process images of reflected Placido rings captured by a commercial videokeratoscope. Raw data are obtained with no Cartesian-to-polar coordinate conversion, thus avoiding interpolation and associated numerical artifacts. The method provides a characteristic equation for the device and is able to process around 6 times more corneal data than the commercial software. Our proposal allows complete control over the whole process from the capture of corneal images until the computation of curvature radii. PMID- 23458814 TI - Unitary discrete linear canonical transform: analysis and application. AB - The numerical approximation of the linear canonical transforms (LCTs) is important in modeling coherent wave field propagation through first-order optical systems and in many digital signal processing applications. The continuous LCTs are unitary, but discretization can destroy this property. We present a sufficient condition on the sampling rates chosen in the discretization to ensure unitarity. We discuss the various subsets of the unitary matrices examined in this paper that have been proposed elsewhere. We offer a proof of the existence of all of the unitary matrices we discuss. We examine the consequences of these results, particularly in relation to the use of discrete transforms in iterative phase retrieval applications. PMID- 23458815 TI - High precision two-step calibration method for the fish-eye camera. AB - Fish-eye cameras are widely used on many occasions due to their ultrawide field of view (about 180 degrees ). In this paper, we present a high-precision two-step calibration method to calibrate fish-eye cameras. The two steps are the global polynomial projection model fitting and local line-fitting calibration optimization. In the first step, we obtain the projection model of the fish-eye camera and apply a quartic polynomial to fit the projection model over the entire image. In the second step, the fish-eye image is partitioned into several sections and line fitting is adopted in each section in order to further reduce the residual error of the first calibration step. Experiments show that the new method is able to correct the distortion of the real scene image well. In addition, its average reprojection error is 0.15 pixel better than 0.40 pixel of the general projection model described. The reason that higher calibration precision is obtained is that this method not only considers the global projection model of the fish-eye camera but also considers the local characteristics, such as small tangential distortion and asymmetry. PMID- 23458816 TI - Performance quantification of a millimeter-wavelength imaging system based on inexpensive glow-discharge-detector focal-plane array. AB - Inexpensive millimeter-wavelength (MMW) optical digital imaging raises a challenge of evaluating the imaging performance and image quality because of the large electromagnetic wavelengths and pixel sensor sizes, which are 2 to 3 orders of magnitude larger than those of ordinary thermal or visual imaging systems, and also because of the noisiness of the inexpensive glow discharge detectors that compose the focal-plane array. This study quantifies the performances of this MMW imaging system. Its point-spread function and modulation transfer function were investigated. The experimental results and the analysis indicate that the image quality of this MMW imaging system is limited mostly by the noise, and the blur is dominated by the pixel sensor size. Therefore, the MMW image might be improved by oversampling, given that noise reduction is achieved. Demonstration of MMW image improvement through oversampling is presented. PMID- 23458817 TI - Extending the depth of focus in tomography systems for glass lattice three dimensional mapping. AB - This paper deals with the development of a computed optical tomography system designed and built to inspect glass lattices to locate various impurities inside the bulk. We focus on the investigation of the potential benefit in the usage of extended depth of focus optics for that application. The quality of 3D reconstruction for the application of glass lattice defect identification is tested numerically and experimentally against the corresponding result obtained with conventional optics. PMID- 23458818 TI - Information capacity as a figure of merit for spectral imagers: the trade-off between resolution and coregistration. AB - The performance of spectral imagers is customarily described by several characteristics including resolution, noise, and coregistration. These must be traded off against each other in a practical imager design. This paper proposes a way to use the information capacity, in an information-theoretic sense, as a figure of merit for spectral imagers. In particular, it is shown how a metric [Opt. Express 20, 918 (2012)] can be used to incorporate coregistration performance in a definition of total noise, which in turn can be used in the definition of information capacity. As an example, it is shown how the information capacity can be used to optimize the pixel size in a simple case that can be treated analytically. Generally, the information capacity is attractive as a fundamental, application-independent figure of merit for spectral imager optimization and benchmarking. PMID- 23458819 TI - Rapid multiexposure in vivo brain imaging system using vertical cavity surface emitting lasers as a light source. AB - We demonstrate an imaging technique implementing vertical cavity lasers with extremely low transient times for a greatly simplified realization of a multiexposure laser speckle contrast imaging system. Data from multiexposure laser speckle imaging was observed to more closely agree with absolute velocity measurements using time of flight technique, when compared to long-exposure laser speckle imaging. Furthermore, additional depth information of the vasculature morphology was inferred by accounting for the change in the static scattering from tissue above vessels with respect to the total scattering from blood flow and tissue. PMID- 23458820 TI - Pixel scaling in infrared focal plane arrays. AB - We discuss effects that arise in pixels of IR focal plane arrays (FPAs) when pixel size scales down to approach the wavelength of the incident radiation. To study these effects, we perform first-principles electromagnetic simulations of pixel structures based on a mercury-cadmium-telluride photoconductor for use in FPAs. Specifically, we calculate the pixel quantum efficiency and crosstalk as pixel size scales from 16 MUm, which is in the range of current detectors, down to 0.75 MUm, corresponding to subwavelength detectors. Our numerical results indicate the possibility of wavelength-size (~4 MUm) and even subwavelength-size (~1 MUm) pixels for IR FPAs. In addition, we explore opportunities that emerge for controlling light with subwavelength structures inside FPA pixels. As an illustration, we find that the low-pass filtering effect of a metal film aperture can exemplify the impact and the possible role that wavelength-scale optics plays in very small pixels. PMID- 23458821 TI - Calibration of a digital in-line holographic microscopy system: depth of focus and bioprocess analysis. AB - Digital in-line holographic microscopy (DIHM) allows access to both intensity and phase information with conventional microscopic lateral resolutions. Such imaging techniques can, however, be used to increase the depth of focus compared to conventional compound microscopes. We present a simple DIHM capable of imaging weakly scattering 10 MUm diameter microspheres as well as Hs578T cells over a depth of 1 mm; i.e., we demonstrate an increase by a factor of 100 over the depth of focus of a conventional microscope. PMID- 23458822 TI - Design, tolerance, and fabrication of an optical see-through head-mounted display with free-form surface elements. AB - Free-form surfaces (FFSs) provide more freedom to design an optical system with fewer elements and hence to reduce the size and weight of the overall system than rotationally symmetric optical surfaces. In this paper, an optical see-through (OST), head-mounted display (HMD) consisting of a free-form, wedge-shaped prism and a free-form lens is designed and fabricated through the injection molding method. The free-form prism for the projection system is designed with a field-of view (FOV) of 36 degrees ; the free-form lens is cemented to the prism for the see-through system to achieve a FOV of 50 degrees . The free-form prism and lens are expanded at the edge area during the design stage in order to reduce the effects of surface deformation in the working area in molding fabrication process and to improve ergonomic fit with the head of a user. The tolerance analyzes considering the mold design for the free-form optical systems are carried out using the Monte Carlo method. The FFS optical elements are successfully fabricated and the system performance is carefully examined. The results indicate that the performance of the OST-HMD is sufficient for both entertainment and scientific applications. PMID- 23458823 TI - Imaging systems and applications. AB - Imaging systems have numerous applications in industrial, military, consumer, and medical settings. Assembling a complete imaging system requires the integration of optics, sensing, image processing, and display rendering. This issue features original research ranging from fundamental theories to novel imaging modalities and provides a systems perspective to imaging. PMID- 23458824 TI - Serum adhesion molecules as predictors of bacteremia in adult severe sepsis patients at the emergency department. AB - BACKGROUND: Bacteremia is a severe bacterial infection with significant mortality. Clinical parameters that reliably predict it are less elucidated. We assessed the potential of serum adhesion molecules for predicting bacteremia and compare it with current available infection biomarkers to determine a more timely predictor of adult severe sepsis patients on admission to the emergency department (ED). METHODS: Sixty-seven consecutive non-traumatic, non-surgical adult patients with severe sepsis admitted to the ED were evaluated. Serum samples were collected and assessed while serum adhesion molecules were analyzed. RESULTS: Thirty-one (46.2%) study patients had bacteremia. There were significant differences in both sICAM-1 and sE-selectin on admission between bacteremic and non-bacteremic patients. By stepwise logistic regression model, only sE-selectin was independently associated with bacteremia and any 1 ng/ml increase in level increased bacteremia rate by 0.8%. The cut-off value of sE-selectin level for predicting bacteremia was 117 ng/ml (84% sensitivity and 69% specificity). CONCLUSION: Although serum cell adhesion markers are not specific for predicting bacteremia in septic patients, higher mean serum cell adhesion molecules levels on admission may imply both more severe infection and presence of bacteremia. Assay of serum adhesion molecules may be added as an infectious marker among the panel of bacteremic parameters in clinical practice, especially since early diagnosis and prompt antimicrobial therapy are essentially for survival. PMID- 23458825 TI - The challenges of evaluating scientists by H-index and citations in different biomedical research platforms. PMID- 23458827 TI - Plutonium transport in the environment. AB - The recent estimated global stockpile of separated plutonium (Pu) worldwide is about 500 t, with equal contributions from nuclear weapons and civilian nuclear energy. Independent of the United States' future nuclear energy policy, the current large and increasing stockpile of Pu needs to be safely isolated from the biosphere and stored for thousands of years. Recent laboratory and field studies have demonstrated the ability of colloids (1-1000 nm particles) to facilitate the migration of strongly sorbing contaminants such as Pu. In understanding the dominant processes that may facilitate the transport of Pu, the initial source chemistry and groundwater chemistry are important factors, as no one process can explain all the different field observations of Pu transport. Very little is known about the molecular-scale geochemical and biochemical mechanisms controlling Pu transport, leaving our conceptual model incomplete. Equally uncertain are the conditions that inhibit the cycling and mobility of Pu in the subsurface. Without a better mechanistic understanding for Pu at the molecular level, we cannot advance our ability to model its transport behavior and achieve confidence in predicting long-term transport. Without a conceptual model that can successfully predict long-term Pu behavior and ultimately isolation from the biosphere, the public will remain skeptical that nuclear energy is a viable and an attractive alternative to counter global warming effects of carbon-based energy alternatives. This review summarizes our current understanding of the relevant conditions and processes controlling the behavior of Pu in the environment, gaps in our scientific knowledge, and future research needs. PMID- 23458826 TI - Sonographic characteristics of carotid artery plaques: Implications for follow-up planning? AB - The aim of our study was to analyze the ultrasound characteristics of carotid plaques in an outpatient population and to determine their implications for planning the ultrasound follow-up. MATERIALS AND METHODS: We studied 747 consecutive outpatients (397 [53%] of whom were women) who underwent color Doppler sonography of the carotid arteries. Most of the patients presented multiple cardiovascular risk factors or were being followed-up for carotid artery stenosis. RESULTS: Stenosis ranging from 1% to 69% was observed at the level of the right internal carotid arteries (ICA) in 419 (56.1%) of the 747 patients and in the left ICA in 408 of 747 (54.5%). One hundred twenty-four (29.5%) of the 419 RICA plaques and 77 (18.8%) of the 408 LICA plaques were classified as type 1 or type 2 according to the modified Gray-Weale classification. CONCLUSIONS: Type 1 and type 2 plaques, which are referred to as "vulnerable plaques," were found in 160 (21.4%) of the 747 patients we examined. These patients should be subjected to closer ultrasound follow-up, even if they have only moderate carotid artery stenosis. PMID- 23458828 TI - Renal replacement therapy in healthy adult horses. AB - BACKGROUND: Renal replacement therapy (RRT) has been implemented extensively in people to facilitate recovery from acute renal failure (ARF). RRT has not been explored in horses, but might provide a further treatment option in horses with ARF. OBJECTIVE: To investigate efficacy and safety of RRT in horses. ANIMALS: Five healthy adult horses. METHODS: A prospective study was performed on horses restrained in stocks and intravenously connected to a commercial RRT machine to allow continuous venovenous hemodiafiltration to be performed for 6 hours. The RRT machine was set at the following flow rates: blood flow rate 250 mL/min; dialysate rate 3,000 mL/h; prefilter replacement pump 3,000 mL/h; and postfilter replacement pump rate 2,000 mL/h. Balanced electrolyte solution was used as dialysate and replacement fluid. Heart rate, respiratory rate, body temperature, direct arterial blood pressure, urine output, and various clinicopathologic parameters were measured over the study period. RESULTS: Renal replacement therapy was successfully performed in horses, resulting in a mean creatinine clearance of 0.127 mL/kg/min (68.9 mL/min) and urea reduction ratio of 24%. No adverse effects were detected although a significant decrease in rectal temperature was observed (P <= .007). A significant increase in serum phosphorus (P <= .001) and decrease in BUN (P < .001) were also noted. A significant prolongation of prothrombin (P < .01) and partial thromboplastin time (P < .0001) were observed along with a decrease in platelet count (P <= .04). CONCLUSIONS AND CLINICAL IMPORTANCE: Renal replacement therapy can safely and effectively be used in adult horses. PMID- 23458829 TI - An HPLC-ESI-MS method for analysis of loureirin A and B in dragon's blood and application in pharmacokinetics and tissue distribution in rats. AB - A sensitive HPLC-ESI-MS method for the simultaneous determination of loureirin A (LA) and loureirin B (LB) in rat plasma and tissues was developed, and the pharmacokinetic and tissue distribution characteristics of LA and LB were investigated after gavage administration. The samples were pretreated by protein precipitation with ethyl acetate and then separated on a Welch Ultimate XB-C18 column with water-acetonitrile (42:58, v/v) containing 0.1% glacial acetic acid as the mobile phase. The analytes were detected with no interference in multiple reaction monitoring (MRM) mode on an electrospray ionization ion trap mass spectrometer. The analytes showed good linearity over a wide concentration range and the lowest limit of quantification (LLOQ) was 5 ng/mL for LA and 2ng/mL for LB in matrices. The pharmacokinetic curves of both analytes were best fitted to one-compartment model. It suggested that the analytes absorbed and distributed very quickly in rats. Tissue distribution results showed that the analytes had a wide distribution in tissues and the highest levels for LA and LB were observed in liver followed by kidney, lung, spleen, heart and cerebrum. This work provided the pharmacokinetics and tissue distribution characteristics of LA and LB, which would be instructive for their clinical regiment design. PMID- 23458830 TI - Selective growth of dual-color-emitting heterogeneous microdumbbells composed of organic charge-transfer complexes. AB - We report a simple yet versatile solution route for constructing heterojunctions from luminescent organic charge-transfer (CT) complexes through a two-step seeded growth method. Using this method, we achieved anisotropic and selective growth of anthracene-1,2,4,5-tetracyanobenzene (TCNB) complexes onto the tips of naphthalene-TCNB microtubes, resulting in the formation of microdumbbells. Significantly, the two-component microdumbbells appear as dual-color-emitting heterojunctions arising from integration of two distinct color-emitting materials. We further elucidated the two-step seeded-growth mechanism of the dumbbell-like organic heterostructures on the basis of structural analysis of the two crystals and surface-interface energy balance. In principle, the present synthetic route may be used to fabricate a wide range of sophisticated dual- or multicolor-emitting organic heterostructures via judicious choice of the CT complexes. PMID- 23458831 TI - Resistance of alphaAI-1 transgenic chickpea (Cicer arietinum) and cowpea (Vigna unguiculata) dry grains to bruchid beetles (Coleoptera: Chrysomelidae). AB - Dry grain legume seeds possessing alphaAI-1, an alpha-amylase inhibitor from common bean (Phaseolus vulgaris), under the control of a cotyledon-specific promoter have been shown to be highly resistant to several important bruchid pest species. One transgenic chickpea and four cowpea lines expressing alphaAI-1, their respective controls, as well as nine conventional chickpea cultivars were assessed for their resistance to the bruchids Acanthoscelides obtectus (Say), Callosobruchus chinensis L. and Callosobruchus maculatus F. All transgenic lines were highly resistant to both Callosobruchus species. A. obtectus, known to be tolerant to alphaAI-1, was able to develop in all transgenic lines. While the cotyledons of all non-transgenic cultivars were highly susceptible to all bruchids, C. chinensis and C. maculatus larvae suffered from significantly increased mortality rates inside transgenic seeds. The main factor responsible for the partial resistance in the non-transgenic cultivars was deduced to reside in the seed coat. The alphaAI-1 present in seeds of transgenic chickpea and cowpea lines significantly increases their resistance to two important bruchid pest species (C. chinensis and C. maculatus) essentially to immunity. To control alphaAI-1 tolerant bruchid species such as A. obtectus and to avoid the development of resistance to alphaAI-1, varieties carrying this transgene should be protected with additional control measures. PMID- 23458833 TI - Transcriptional activation of Odf2/Cenexin by cell cycle arrest and the stress activated signaling pathway (JNK pathway). AB - The centrosome/basal body protein ODF2/Cenexin is necessary for the formation of the primary cilium. Primary cilia are essential organelles that sense and transduce environmental signals. Primary cilia are therefore critical for embryonic and postnatal development as well as for tissue homeostasis in adulthood. Impaired function of primary cilia causes severe human diseases. ODF2 deficiency prevents formation of the primary cilium and is embryonically lethal. To explore the regulation of primary cilia formation we analyzed the promoter region of Odf2 and its transcriptional activity. In cycling cells, Odf2 transcription is depressed but becomes up-regulated in quiescent cells. Low transcriptional activity is mediated by sequences located upstream from the basal promoter, and neither transcription factors with predicted binding sites in the Odf2 promoter nor Rfx3 or Foxj, which are known to control ciliary gene expression, could activate Odf2 transcription. However, co-expression of either C/EBPalpha, c-Jun or c-Jun and its regulator MEKK1 enhances Odf2 transcription in cycling cells. Our results provide the first analysis of transcriptional regulation of a ciliary gene. Furthermore, we suggest that transcription of even more ciliary genes is largely inhibited in cycling cells but could be activated by cell cycle arrest and by the stress signaling JNK pathway. PMID- 23458832 TI - Neutrophils exert a suppressive effect on Th1 responses to intracellular pathogen Brucella abortus. AB - Polymorphonuclear neutrophils (PMNs) are the first line of defense against microbial pathogens. In addition to their role in innate immunity, PMNs may also regulate events related to adaptive immunity. To investigate the influence of PMNs in the immune response during chronic bacterial infections, we explored the course of brucellosis in antibody PMN-depleted C57BL/6 mice and in neutropenic mutant Genista mouse model. We demonstrate that at later times of infection, Brucella abortus is killed more efficiently in the absence of PMNs than in their presence. The higher bacterial removal was concomitant to the: i) comparatively reduced spleen swelling; ii) augmented infiltration of epithelioid histiocytes corresponding to macrophages/dendritic cells (DCs); iii) higher recruitment of monocytes and monocyte/DCs phenotype; iv) significant activation of B and T lymphocytes, and v) increased levels of INF-gamma and negligible levels of IL4 indicating a balance of Th1 over Th2 response. These results reveal that PMNs have an unexpected influence in dampening the immune response against intracellular Brucella infection and strengthen the notion that PMNs actively participate in regulatory circuits shaping both innate and adaptive immunity. PMID- 23458834 TI - MgcRacGAP, a cytoskeleton regulator, inhibits HIF-1 transcriptional activity by blocking its dimerization. AB - Hypoxia inducible factor-1 (HIF-1), a dimeric transcription factor of the bHLH PAS family, is comprised of HIF-1alpha, which is inducible by hypoxia and ARNT or HIF-1beta, which is constitutively expressed. HIF-1 is involved in cellular homeostasis under hypoxia, in development and in several diseases affected by oxygen availability, particularly cancer. Since its expression is positively correlated with poor outcome prognosis for cancer patients, HIF-1 is a target for pharmaceutical therapy. We have previously shown that male germ cell Rac GTPase activating protein (MgcRacGAP), a regulator of Rho proteins which are principally involved in cytoskeletal organization, binds to HIF-1alpha and inhibits its transcriptional activity. In this work, we have explored the mechanism of the MgcRacGAP-mediated HIF-1 inactivation. We show that the Myo domain of MgcRacGAP, which is both necessary and sufficient for HIF-1 repression, binds to the PAS-B domain of HIF-1alpha. Furthermore MgcRacGAP competes with ARNT for binding to the HIF-1alpha PAS-B domain, as shown by in vitro binding pull down assays. In mammalian cells, ARNT overexpression can overcome the MgcRacGAP-mediated inhibition and MgcRacGAP binding to HIF-1alpha in vivo inhibits its dimerization with ARNT. We additionally present results indicating that MgcRacGAP binding to HIF-1alpha is specific, since it does not affect the transcriptional activity of HIF-2, a close evolutionary relative of HIF-1 also involved in hypoxia regulation and cancer. Our results reveal a new mechanism for HIF-1 transcriptional activity regulation, suggest a novel hypoxia-cytoskeleton link and provide new tools for selective HIF-1 inhibition. PMID- 23458835 TI - STIM1 participates in the contractile rhythmicity of HL-1 cells by moderating T type Ca(2+) channel activity. AB - STIM1 plays a crucial role in Ca(2+) homeostasis, particularly in replenishing the intracellular Ca(2+) store following its depletion. In cardiomyocytes, the Ca(2+) content of the sarcoplasmic reticulum must be tightly controlled to sustain contractile activity. The presence of STIM1 in cardiomyocytes suggests that it may play a role in regulating the contraction of cardiomyocytes. The aim of the present study was to determine how STIM1 participates in the regulation of cardiac contractility. Atomic force microscopy revealed that knocking down STIM1 disrupts the contractility of cardiomyocyte-derived HL-1 cells. Ca(2+) imaging also revealed that knocking down STIM1 causes irregular spontaneous Ca(2+) oscillations in HL-1 cells. Action potential recordings further showed that knocking down STIM1 induces early and delayed afterdepolarizations. Knocking down STIM1 increased the peak amplitude and current density of T-type voltage dependent Ca(2+) channels (T-VDCC) and shifted the activation curve toward more negative membrane potentials in HL-1 cells. Biotinylation assays revealed that knocking down STIM1 increased T-VDCC surface expression and co immunoprecipitation assays suggested that STIM1 directly regulates T-VDCC activity. Thus, STIM1 is a negative regulator of T-VDCC activity and maintains a constant cardiac rhythm by preventing a Ca(2+) overload that elicits arrhythmogenic events. PMID- 23458837 TI - Complete genome sequence of Marinomonas posidonica type strain (IVIA-Po-181(T)). AB - Marinomonas posidonica IVIA-Po-181(T) Lucas-Elio et al. 2011 belongs to the family Oceanospirillaceae within the phylum Proteobacteria. Different species of the genus Marinomonas can be readily isolated from the seagrass Posidonia oceanica. M. posidonica is among the most abundant species of the genus detected in the cultured microbiota of P. oceanica, suggesting a close relationship with this plant, which has a great ecological value in the Mediterranean Sea, covering an estimated surface of 38,000 Km(2). Here we describe the genomic features of M. posidonica. The 3,899,940 bp long genome harbors 3,544 protein-coding genes and 107 RNA genes and is a part of the GenomicEncyclopedia ofBacteriaandArchaea project. PMID- 23458836 TI - Vimentin phosphorylation and assembly are regulated by the small GTPase Rab7a. AB - Intermediate filaments are cytoskeletal elements important for cell architecture. Recently it has been discovered that intermediate filaments are highly dynamic and that they are fundamental for organelle positioning, transport and function thus being an important regulatory component of membrane traffic. We have identified, using the yeast two-hybrid system, vimentin, a class III intermediate filament protein, as a Rab7a interacting protein. Rab7a is a member of the Rab family of small GTPases and it controls vesicular membrane traffic to late endosomes and lysosomes. In addition, Rab7a is important for maturation of phagosomes and autophagic vacuoles. We confirmed the interaction in HeLa cells by co-immunoprecipitation and pull-down experiments, and established that the interaction is direct using bacterially expressed recombinant proteins. Immunofluorescence analysis on HeLa cells indicate that Rab7a-positive vesicles sometimes overlap with vimentin filaments. Overexpression of Rab7a causes an increase in vimentin phosphorylation at different sites and causes redistribution of vimentin in the soluble fraction. Consistently, Rab7a silencing causes an increase of vimentin present in the insoluble fraction (assembled). Also, expression of Charcot-Marie-Tooth 2B-causing Rab7a mutant proteins induces vimentin phosphorylation and increases the amount of vimentin in the soluble fraction. Thus, modulation of expression levels of Rab7a wt or expression of Rab7a mutant proteins changes the assembly of vimentin and its phosphorylation state indicating that Rab7a is important for the regulation of vimentin function. PMID- 23458838 TI - Potential external contamination with bisphenol A and other ubiquitous organic environmental chemicals during biomonitoring analysis: an elusive laboratory challenge. AB - BACKGROUND: Biomonitoring studies are conducted to assess internal dose (i.e., body burden) to environmental chemicals. However, because of the ubiquitous presence in the environment of some of these chemicals, such as bisphenol A (BPA), external contamination during handling and analysis of the biospecimens collected for biomonitoring evaluations could compromise the reported concentrations of such chemicals. OBJECTIVES: We examined the contamination with the target analytes during analysis of biological specimens in biomonitoring laboratories equipped with state-of-the-art analytical instrumentation. DISCUSSIONS: We present several case studies using the quantitative determination of BPA and other organic chemicals (i.e., benzophenone-3, triclosan, parabens) in human urine, milk, and serum to identify potential contamination sources when the biomarkers measured are ubiquitous environmental contaminants. CONCLUSIONS: Contamination with target analytes during biomonitoring analysis could result from solvents and reagents, the experimental apparatus used, the laboratory environment, and/or even the analyst. For biomonotoring data to be valid-even when obtained from high-quality analytical methods and good laboratory practices the following practices must be followed to identify and track unintended contamination with the target analytes during analysis of the biological specimens: strict quality control measures including use of laboratory blanks; replicate analyses; engineering controls (e.g., clean rooms, biosafety cabinets) as needed; and homogeneous matrix-based quality control materials within the expected concentration ranges of the study samples. PMID- 23458839 TI - 75 years of the Division of Analytical Chemistry of the American Chemical Society. AB - The Division of Analytical Chemistry is celebrating the 75th anniversary of its founding in 1938. We celebrate the continuing high importance of our discipline for all aspects of chemical science and for its applications in so many aspects of everyday life. We especially celebrate the accomplishments of our fellow analytical chemists through the years, and the impact we have had on the profession. This article is a short history of the Division within the context of the parallel development of our profession and our science. PMID- 23458840 TI - Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat. AB - Axonal injury is an important contributor to the behavioral deficits observed following traumatic brain injury (TBI). Additionally, loss of myelin and/or oligodendrocytes can negatively influence signal transduction and axon integrity. Apoptotic oligodendrocytes, changes in the oligodendrocyte progenitor cell (OPC) population and loss of myelin were evaluated at 2, 7 and 21 days following TBI. We used the central fluid percussion injury model (n = 18 and three controls) and the lateral fluid percussion injury model (n = 15 and three controls). The external capsule, fimbriae and corpus callosum were analysed. With Luxol Fast Blue and RIP staining, myelin loss was observed in both models, in all evaluated regions and at all post-injury time points, as compared with sham-injured controls (P <= 0.05). Accumulation of beta-amyloid precursor protein was observed in white matter tracts in both models in areas with preserved and reduced myelin staining. White matter microglial/macrophage activation, evaluated by isolectin B4 immunostaining, was marked at the early time points. In contrast, the glial scar, evaluated by glial fibrillary acidic protein staining, showed its highest intensity 21 days post-injury in both models. The number of apoptotic oligodendrocytes, detected by CC1/caspase-3 co-labeling, was increased in both models in all evaluated regions. Finally, the numbers of OPCs, evaluated with the markers Tcf4 and Olig2, were increased from day 2 (Olig2) or day 7 (Tcf4) post injury (P <= 0.05). Our results indicate that TBI induces oligodendrocyte apoptosis and widespread myelin loss, followed by a concomitant increase in the number of OPCs. Prevention of myelin loss and oligodendrocyte death may represent novel therapeutic targets for TBI. PMID- 23458841 TI - Metalloenzyme inhibitors for the treatment of Gram-negative bacterial infections: a patent review (2009-2012). AB - INTRODUCTION: Bacteria were divided into two main classes in consideration of their ability to retain Gram staining. Gram-positive bacteria are able to retain the blue/violet staining, whereas Gram-negative bacteria are not, as they possess a thinner peptidoglycan wall, which is surrounded by an additional outer lipopolysaccharide membrane. This constitutes a serious hurdle for antibiotics to pass through, thereby representing a mechanism of bacterial defence and drug resistance. Targeting bacterial metalloenzymes represents an attractive approach for the development of new anti-infective drugs. In particular, small molecules able to inhibit metalloenzymes are of interest for their use alone or in association with known antibiotics with the aim to reduce mutations and various drug resistance mechanisms. AREAS COVERED: The article deals with a selection of patents claiming the use of small molecules as inhibitors of gram-negative bacterial metalloenzymes and therefore useful for the treatment of infections caused or propagated by such pathogens. EXPERT OPINION: Inhibition of bacterial metalloenzymes from Gram-negative bacteria, such as histidinol dehydrogenase, UDP (3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase, peptide deformylase, bacterial extracellular metalloprotease, and carbonic anhydrases, was reported in the scientific and patent literature. Such metalloenzyme inhibitors, amenable to the development of conceptually novel antibiotics, represent a promising approach for the development of novel anti-infectives. PMID- 23458842 TI - Comment on 'Monte Carlo simulation on a gold nanoparticle irradiated by electron beams'. AB - A recent paper by Chow et al (Phys. Med. Biol 57 3323-31) quantifies the dose due to secondary electrons created by gold nanoparticles when irradiated by electron beams. That paper fails to compare this dose to the overall dose from the electron beam. EGSnrc calculations are performed to show that, even for the unrealistically favourable case presented by Chow et al of a very narrow electron beam directed only at the nanoparticle, the dose outside the nanoparticle due to the secondary electrons generated by the nanoparticle is negligible compared to the dose from the primaries. Thus, it is irrelevant whether the dose from secondary particles is enhanced by the nanoparticles or not and there appears to be no advantage to using gold nanoparticles in electron beams, unlike the case for photon beams. PMID- 23458843 TI - First evidence of the possible implication of the 11-deoxycorticosterone (DOC) in immune activity of Eurasian perch (Perca fluviatilis, L.): comparison with cortisol. AB - Cortisol, the main corticosteroid in fish, is frequently described as a modulator of fish immune system. Moreover, 11-deoxycorticosterone (DOC) was shown to bind and transcriptionally activate the mineralocorticoid receptor and may act as a mineralocorticoid in fish. Immune modulations induced by intraperitoneal injections of these two corticosteroids were assessed in Eurasian perch juveniles. Cortisol and DOC were injected at 0.8 mg kg(-1) and 0.08 mg kg(-1) body weight respectively. Cortisol increased plasma lysozyme activity 72 h post injection, C-type lysozyme expression in spleen from 1 to 72 h post-injection, and favoured blood neutrophils at the expense of a mixture of lymphocytes and thrombocytes. Moreover, 6 h after injection, cortisol reduced expression levels of the pro-inflammatory cytokine TNF-alpha in spleen. DOC had no effects on the immune variables measured in plasma, but increased expression levels of C-type lysozyme and apolipoprotein A1 mRNA in both gills and spleen. Meanwhile, DOC stimulated its putative signalling pathway by increasing expression of mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase-2 in spleen. These results confirmed the role of cortisol as an innate, short term immune stimulator. For the first time, DOC is described as a possible immune stimulator in fish. PMID- 23458844 TI - Cation sensing by a luminescent metal-organic framework with multiple Lewis basic sites. AB - A series of novel lanthanide metal-organic frameworks were synthesized using a ligand featuring three carboxylate groups stationed on a triazinyl central motif. The readily accessible multiple Lewis basic triazinyl N atoms allow for complexation of incoming metal ions. Such interactions have been established quantitatively. PMID- 23458845 TI - Study on clinical presentation of ear and nose foreign bodies. AB - Ear and nose foreign bodies are common problems affecting the children but adults are not an exception. A prospective study involving 87 patients is undertaken concentrating on presentation of patients with various types of ear or nasal foreign bodies. In the present study common presenting complaints and uncommon presentation scenarios encountered by us like a nasal foreign body with intra cranial complications, an impacted middle ear foreign body with mastoiditis is discussed. The present article emphasizes the need of considering presence of foreign bodies even in the absence of appropriate clinical signs and symptoms suggestive of a foreign body in ear or nose. PMID- 23458847 TI - Anaerobic and aerobic cleavage of the steroid core ring structure by Steroidobacter denitrificans. AB - The aerobic degradation of steroids by bacteria has been studied in some detail. In contrast, only little is known about the anaerobic steroid catabolism. Steroidobacter denitrificans can utilize testosterone under both oxic and anoxic conditions. By conducting metabolomic investigations, we demonstrated that S. denitrificans adopts the 9,10-seco-pathway to degrade testosterone under oxic conditions. This pathway depends on the use of oxygenases for oxygenolytic ring fission. Conversely, the detected degradation intermediates under anoxic conditions suggest a novel, oxygenase-independent testosterone catabolic pathway, the 2,3-seco-pathway, which differs significantly from the aerobic route. In this anaerobic pathway, testosterone is first transformed to 1-dehydrotestosterone, which is then reduced to produce 1-testosterone followed by water addition to the C-1/C-2 double bond of 1-testosterone. Subsequently, the C-1 hydroxyl group is oxidized to produce 17-hydroxy-androstan-1,3-dione. The A-ring of this compound is cleaved by hydrolysis as evidenced by H2(18)O-incorporation experiments. Regardless of the growth conditions, testosterone is initially transformed to 1 dehydrotestosterone. This intermediate is a divergence point at which the downstream degradation pathway is governed by oxygen availability. Our results shed light into the previously unknown cleavage of the sterane ring structure without oxygen. We show that, under anoxic conditions, the microbial cleavage of steroidal core ring system begins at the A-ring. PMID- 23458848 TI - Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. AB - OBJECTIVES: To investigate environmental, personal, and hereditary risk factors associated with the occurrence of intraductal papillary mucinous neoplasms of the pancreas (IPMNs). METHODS: Multicentre case-control study. Risk factors were identified from a questionnaire collecting data on family and medical history, and environmental factors. Cases were prevalent IPMNs seen at the participating units within an 18-month timeframe. Matched controls were enrolled alongside patients seen at outpatient clinics. RESULTS: Three-hundred and ninety patients with IPMN and 390 matched controls (166 males, mean age 65 in each group) were enrolled. Of the IPMNs, 310 had branch-duct involvement and 80 main-duct involvement. The only cancer with a 1st degree family history significantly higher in IPMN was pancreatic ductal adenocarcinoma (PDAC) (5.4% vs. 1.5%). Previous history of diabetes (13.6% vs. 7.5%), chronic pancreatitis (CP) (3.1% vs. 0.3%), peptic ulcer (7.2% vs. 4.3%), and insulin use (4.9% vs. 1.1%) were all more frequent with IPMNs. Logistic regression multivariate analysis revealed that history of diabetes (odds ratio (OR): 1.79, confidence interval (CI) 95%: 1.08 2.98), CP (OR: 10.10, CI 95%: 1.30-78.32), and family histories of PDAC (OR: 2.94, CI 95%: 1.17-7.39) were all independent risk factors. However, when analysis was restricted to diabetics who had taken insulin, risk of IPMN became stronger (OR: 6.03, CI 95%: 1.74-20.84). The association with all these risk factors seemed stronger for the subgroup with main duct involvement. CONCLUSIONS: A previous history of diabetes, especially with insulin use, CP, and family history of PDAC are all relevant risk factors for the development of IPMN. These results suggest an overlap between certain risk factors for PDAC and IPMN. PMID- 23458849 TI - A randomized controlled trial of an online intervention to improve gluten-free diet adherence in celiac disease. AB - OBJECTIVES: To test the effectiveness of an interactive online intervention to improve gluten free diet adherence in adults with celiac disease. METHODS: A Randomized controlled trial was conducted. A total of 189 adults with biopsy confirmed celiac disease were recruited and randomized to receive the intervention (n=101) or to a waitlist control condition (n=88). Post-intervention data was available for 70 intervention and 64 waitlist participants. Three month follow-up data was obtained for 46/50 completers from the intervention group. The primary outcome measure was gluten-free diet adherence. Secondary outcomes were gluten-free diet knowledge, quality of life and psychological symptoms. RESULTS: Results were based on intention-to-treat analyses. The intervention group evidenced significantly improved gluten-free diet adherence, and gluten-free diet knowledge following the treatment period relative to the waitlist control group. The change in knowledge did not contribute to the change in adherence. These improvements were maintained at 3-month' follow-up. CONCLUSIONS: The online program was effective in improving adherence and represents a promising resource for individuals with celiac disease who are struggling to achieve or maintain adequate gluten free diet adherence. PMID- 23458850 TI - Efficacy and safety of pneumatic dilatation for achalasia in the treatment of post-myotomy symptom relapse. AB - OBJECTIVES: There is no consensus on how best to treat symptom recurrence following previous therapy with Heller myotomy. Our aim was to determine the safety and the short and long-term efficacy of pneumatic dilatation to treat symptomatic recurrence in patients previously treated with Heller myotomy for idiopathic achalasia. METHODS: We identified 27 eligible patients treated with pneumatic dilatation, for symptom recurrence following Heller myotomy as their initial or secondary treatment, from a prospectively acquired database of 450 patients with a diagnosis of achalasia seen between 1995 and 2010. Our treatment protocol involved sequential, graded pneumatic dilatations (30-35-40 mm) over a 2 6 week period until an initial therapeutic response was achieved. The subsequent relapse rate, defined as the need for any subsequent therapy, was determined. Relapsers were offered further pneumatic dilatation "on demand". A cross sectional analysis was also performed using a validated achalasia severity questionnaire to determine the overall long-term remission rate. RESULTS: Of 27 eligible patients, 25 (93%) complied with the institutional dilatation protocol. The two drop-outs did so after the initial 30 mm dilatation and were deemed treatment failures. One additional patient did not respond despite protocol compliance. Therefore, 24 of 27 (89%) patients were responders on intention to treat analysis at 12 months, while the per protocol response rate was 24 of 25 (96%). Among the 24 responders 16, 25, and 42% relapsed at 2, 3 and 4 years, respectively. Overall long-term remission, with on demand dilatations as required, was 95% (median follow-up 30 months). There were no perforations in a total of 50 dilatations in 27 patients. CONCLUSIONS: In treating symptom recurrence, following prior Heller myotomy, pneumatic dilatation is safe and yields an excellent short-term response rate. Although the long-term relapse rate is substantial, subsequent on demand pneumatic dilatation in this population is highly effective with a long-term remission rate of 95%. These data also highlight the need to keep these patients under long-term review. PMID- 23458851 TI - Food and symptom generation in functional gastrointestinal disorders: physiological aspects. AB - The response of the gastrointestinal tract (GIT) to ingestion of food is a complex and closely controlled process, which allows optimization of propulsion, digestion, absorption of nutrients, and removal of indigestible remnants. This review summarizes current knowledge on the mechanisms that control the response of the GIT to food intake. During the cephalic phase, triggered by cortical food related influences, the GIT prepares for receiving nutrients. The gastric phase is dominated by the mechanical effect of the meal volume. Accumulation of food in the stomach activates tension-sensitive mechanoreceptors, which in turn stimulate gastric accommodation and gastric acid secretion through the intrinsic and vago vagal reflex pathways. After meal ingestion, the tightly controlled process of gastric emptying starts, with arrival of nutrients in the duodenum triggering negative feedback on emptying and stimulating secretion of digestive enzymes through the neural (mainly vago-vagal reflex, but also intrinsic) and endocrine (release of peptides from entero-endocrine cells) pathways. Several types of specialized receptors detect the presence of all main categories of nutrients. In addition, the gastrointestinal mucosa expresses receptors of the T1R and T2R families (taste receptors) and several members of the transient receptor potential channel family, all of which are putatively involved in the detection of specific tastants in the lumen. Activation of nutrient and taste sensors also activates the extrinsic and intrinsic neural, as well as entero-endocrine, pathways. During passage through the small bowel, nutrients are progressively extracted, and electrolyte-rich liquid intestinal content with non-digestible residue is delivered to the colon. The colon provides absorption of the water and electrolytes, storage of non-digestible remnants of food, aboral propulsion of contents, and finally evacuation through defecation. PMID- 23458852 TI - Disease remission in a horse with EHV-5-associated lymphoma. PMID- 23458846 TI - Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers. AB - The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases. PMID- 23458853 TI - Usefulness of examining hepatic functional volume using technetium-99m galactosyl serum albumin scintigraphy in hepatocellular carcinoma. AB - OBJECTIVES: The aim of the study was to clarify the clinical significance of single-photon emission computed tomography/computed tomography (SPECT/CT) imaging in terms of technetium-99m galactosyl human serum albumin (99mTc-GSA) scintigraphy. To this end, we examined the relationship using data from surgical records of 67 patients with hepatocellular carcinoma who underwent hepatectomy. MATERIALS AND METHODS: Liver functional parameters or functional volume was estimated by 99mTc-GSA scintigraphy and computed tomography volumetry was used to estimate morphological volume. RESULTS: Liver uptake ratio at 15 min (LHL15) was correlated with the indocyanine green retention rate at 15 min (ICGR15; R=-0.608, P<0.01); however, five patients (7.5%) had values outside this correlation. In these patients, LHL15 reflected clinical status and patient outcomes more. Although morphological and functional volumes were well correlated (P<0.01), functional volume was decreased in the diseased liver with portal vein tumor thrombus or portal vein embolization. By applying 99mTc-GSA volumetry, portal pressure and alkaline phosphatase level were correlated with decreased volume of the embolized liver, and platelet count and cholesterol level were correlated with increased volume of the nonembolized liver (P<0.05). By measuring functional volume, four patients who were functionally borderline on the basis of the ICGR15 test safely underwent scheduled major hepatectomy. CONCLUSION: Under the ICGR15 test as the standard for preoperative hepatic function, auxiliary application of LHL15 and functional volumetry provides useful information on hepatocellular carcinoma patients undergoing hepatectomy. PMID- 23458854 TI - The application of SPECT/CT for preoperative planning in patients with secondary hyperparathyroidism. AB - BACKGROUND AND PURPOSE: Secondary hyperparathyroidism (SHPT) is a frequent and challenging issue in patients undergoing dialysis for chronic kidney disease. Surgical intervention in the form of parathyroidectomy is generally considered only in cases of severe SHPT. However, identification of the exact location of the parathyroid glands (PTGs) before parathyroidectomy is a challenge. The aim of this study was to evaluate the role of 99mTc sestamibi single-photon emission computed tomography (SPECT)/computed tomography (CT) in the detection of parathyroids to guide operative therapy in patients with SHPT. PATIENTS AND METHODS: Ninety patients with SHPT who were on hemodialysis were evaluated preoperatively with double-phase 99mTc sestamibi static planar and SPECT/CT parathyroid scintigraphy to evaluate for parathyroids before parathyroidectomy. The sensitivity, specificity, and accuracy of 99mTc sestamibi static planar and SPECT/CT scintigraphy were determined. RESULTS: Compared with static planar scintigraphy, 99mTc sestamibi SPECT/CT was able to detect a larger number of PTGs per study, as well as PTGs of smaller diameter and PTGs of smaller size. The sensitivity, specificity, and accuracy of 99mTc sestamibi SPECT/CT in detecting PTGs were 78.9, 100, and 78.9%, respectively, compared with 55.6, 100, and 55.6% for static planar 99mTc sestamibi. CONCLUSION: Our study indicates that 99mTc sestamibi SPECT/CT has a higher sensitivity compared with static planar scintigraphy in the preoperative evaluation of hemodialysis patients with SHPT because of chronic kidney disease. SPECT/CT can not only detect a larger number of PTGs but can also depict the precise location of PTGs more accurately when compared with static planar scintigraphy. PMID- 23458855 TI - Utility of intrastriatal ratios of FDOPA to differentiate idiopathic Parkinson's disease from atypical parkinsonian disorders. AB - AIM: The striatal-to-occipital ratio (SOR) is commonly used as an analytical parameter in L-3,4-dihydroxy-6-18F-fluorophenylalanine (FDOPA) PET studies. It has been shown to be useful in differentiating idiopathic Parkinson's disease (IPD) patients from healthy individuals. We assessed the performance of SORs and subregional ratio of striatal-to-occipital ratios (RSORs) in the clinical assessment of nigrostriatal dopaminergic function for differentiating typical IPD from atypical parkinsonian disorders (APD). MATERIALS AND METHODS: A total of 117 patients referred from movement disorder clinics in speciality neurology centres underwent an FDOPA PET study and were kept under follow-up for at least 2 years. Sixty-five patients (43 IPD and 22 APD) completed the 2-year follow-up and were included in the final analysis. Their PET images were spatially normalized to occipital counts and analysed with three striatal subregional regions of interest (caudate, anterior putamen and posterior putamen) and two occipital regions of interest. The RSORs of the caudate and posterior putamen, the caudate and anterior putamen, the caudate and whole putamen and the anterior putamen and posterior putamen were also calculated and compared between the IPD and APD groups using the t-test. RESULTS: The P values for these SORs were found to be insignificant between IPD and APD patients (caudate: 0.1325; anterior putamem: 0.5469; and posterior putamen: 0.9835). However, the RSORs of the caudate and posterior putamen showed significant differences between these two populations of patients. CONCLUSION: The SOR method is already known to be a good diagnostic tool to differentiate between IPD patients and the normal population. SOR, however, fails to distinguish IPD from APD patients, and hence the RSOR of the caudate and posterior putamen can be utilized to differentiate between them. PMID- 23458857 TI - Genome organization: Supercoiled roles. PMID- 23458858 TI - Gene expression: Influences on noise. PMID- 23458856 TI - Emerging methods in protein co-evolution. AB - Co-evolution is a fundamental component of the theory of evolution and is essential for understanding the relationships between species in complex ecological networks. A wide range of co-evolution-inspired computational methods has been designed to predict molecular interactions, but it is only recently that important advances have been made. Breakthroughs in the handling of phylogenetic information and in disentangling indirect relationships have resulted in an improved capacity to predict interactions between proteins and contacts between different protein residues. Here, we review the main co-evolution-based computational approaches, their theoretical basis, potential applications and foreseeable developments. PMID- 23458859 TI - Quality in post-analytical phase: indirect reference intervals for erythrocyte parameters of neonates. AB - OBJECTIVES: This study aims to gain an estimation of the reference intervals for erythrocyte parameters of neonates in the venous blood, in their first day of life, aiming to achieve quality assurance in post-analytical phase according to the requirement of the ISO standard 15189:2007: Medical laboratories-particular requirements for quality and competence. DESIGN AND METHODS: The study was performed on a group of 845 subjects selected from the laboratory database. The blood test was performed with the Nihon Celltac F automatic hematology analyzer. In order to find the reference interval, the Hoffmann indirect method was used to process the study group. RESULTS: The results give the reference intervals for red blood cell (RBC=3.45-5.26*10(6)/MUL), hemoglobin (HGB=12.5-19.48g/dL), hematocrit (HCT=37.18-55.65%), mean cell volume (MCV=99.63-111.92fL), mean corpuscular hemoglobin (MCH=33.55-39.28pg) and mean corpuscular hemoglobin concentration (MCHC=32.33-36.23g/dL), along with the corresponding confidence intervals. CONCLUSIONS: Neonates are a special category of population to which the application of the direct method for determining the reference intervals is difficult and raises ethical issues. Thus, the indirect method is a reasonable alternative. The reported approach is easy to apply and accessible to any laboratory. PMID- 23458860 TI - Presentation of renal disease in children. AB - CME EDUCATIONAL OBJECTIVES: 1.Review the modes of presentation of renal disease in children.2.Understand the role of the pediatrician in the management of children with renal disease.3.Outline the reasons for patient referral to the pediatric nephrologist. PMID- 23458861 TI - Urinalysis interpretation for pediatricians. AB - CME EDUCATIONAL OBJECTIVES: 1.Cost-effectively evaluate microscopic hematuria and proteinuria.2.Recognize important conditions associated with isolated microscopic hematuria.3.Review important conditions associated with asymptomatic proteinuria. PMID- 23458862 TI - A review of guidelines for urinary tract infections in children younger than 2 years. AB - CME EDUCATIONAL OBJECTIVES: 1.Review recent guidelines for diagnosis and treatment of urinary tract infections in children younger than 2 years.2.Review recent recommendations for imaging children with urinary tract infection.3.Understand rationale for recent treatment recommendations and prophylaxis of children with urinary tract infection. PMID- 23458863 TI - A conversation with Mark H. Sawyer, MD. Interview by Stanford T Shulman. PMID- 23458864 TI - Pitting the Second Amendment against the First. PMID- 23458866 TI - Participation in organized sports and physical fitness. PMID- 23458867 TI - A 13-year-old boy with elevated BUN and creatinine. PMID- 23458868 TI - Getting an eyeful of preseptal cellulitis. PMID- 23458869 TI - A 10-year-old girl with nontraumatic loss of central incisors. PMID- 23458870 TI - Pediatric nephrology. PMID- 23458871 TI - A review of acute chest syndrome in pediatric sickle cell disease. PMID- 23458872 TI - Adolescent knee pain management. PMID- 23458873 TI - Nijmegen breakage syndrome: the clearance pathway for mutant nibrin protein is allele specific. AB - The autosomal recessive disorder Nijmegen breakage syndrome (NBS) is caused by mutations in the NBN gene which codes for the protein nibrin (NBS1; p95). In the majority of cases, a 5bp deletion, a founder mutation, leads to a hypomorphic 70kD protein, p70-nibrin, after alternative initiation of translation. Protein levels are of relevance for the clinical course of the disease, particularly with regard to malignancy. Here, mechanisms and efficiency of mutant protein clearance were examined in order to establish whether these have an impact on nibrin abundance. Cell lines from NBS patients and retroviral transductants were treated with proteasome and lysosome inhibitors and examined by semi-quantitative immunoblotting for p70-nibrin and p95-nibrin levels. The results show that p70 nibrin is degraded by the proteasome with varying efficiency in cell lines from different NBS patients leading to lower or higher steady state levels of this partially active protein fragment. In contrast, a previously described NBN missense mutation, which disturbs protein folding due to the substitution of a critical arginine by tryptophan, was found to be cleared by lysosomal microautophagy leading also to lower cellular levels. The data show that truncated nibrin and misfolded nibrin have different clearance pathways. PMID- 23458874 TI - Molecular cloning and characterization of an Hsp90/70 organizing protein gene from Frankliniella occidentalis (Insecta: Thysanoptera, Thripidae). AB - The heat shock 90/70 organizing protein (Hop), also known as Sti-1 (stress induced protein-1), is a co-chaperone that usually mediates the interaction of Hsp90 and Hsp70 and has been extensively characterized in mammals and plants. However, its role in insects remains unknown. In the present study, we isolated and characterized a Hop homologue gene from Frankliniella occidentalis (Fohop). The Fohop contains a 1659bp ORF encoding a protein of 552 amino acids with a caculated molecular mass of approximately 62.25kDa, which displays a reasonable degree of identity with the known Hops and shares several canonical motifs, including three tetratricopeptide repeated motif domains (TPR1, TPR2A and TPR2B) and two aspartic acid-proline (DP) repeat motifs (DP1 and DP2). As in other hops, Fohop contains introns, but the number and the position are quite variable. The mRNA expression patterns indicated that Fohop was constitutively expressed throughout the developmental stages, but was obviously upregulated by heat stress both in larvae and adults. Our studies imply that Hop, as in other Hsps, may play an important role in heat shock response of F. occidentalis. PMID- 23458875 TI - Waclaw Szybalski: Lwow, Gdansk, Madison -- life of scientist and philanthropist. PMID- 23458876 TI - ACE I/D and MTHFR C677T polymorphisms are significantly associated with type 2 diabetes in Arab ethnicity: a meta-analysis. AB - In this meta-analysis study, SNPs were investigated for their association with type 2 diabetes (T2D) in both Arab and Caucasian ethnicities. A total of 55 SNPs were analyzed, of which 11 fulfilled the selection criteria, and were used for analysis. It was found that TCF7L2 rs7903146 was significantly associated with a pooled OR of 1.155 (95%C.I.=1.059-1.259), p<0.0001 and I(2)=78.30% among the Arab population, whereas among Caucasians, the pooled OR was 1.45 (95%C.I.=1.386 1.516), p<0.0001 and I(2)=77.20%. KCNJ11 rs5219 was significantly associated in both the populations with a pooled OR of 1.176(1.092-1.268), p<0.0001 and I(2)=32.40% in Caucasians and a pooled OR of 1.28(1.111-1.475), p=0.001 among Arabs. The ACE I/D polymorphism was found to be significantly associated with a pooled OR of 1.992 (95%C.I.=1.774-2.236), p<0.0001 and I(2)=83.20% among the Arab population, whereas among Caucasians, the pooled OR was 1.078 (95%C.I.=0.993 1.17), p=0.073 and I(2)=0%. Similarly, MTHFR C677T polymorphism was also found to be significantly associated among Arabs with a pooled OR of 1.924 (95%C.I.=1.606 2.304), p<0.0001 and I(2)=27.20%, whereas among Caucasians, the pooled OR was 0.986 (95%C.I.=0.868-1.122), p=0.835 and I(2)=0%. Meanwhile PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, IGF2BP2 rs4402960, HHEX rs7923837, CDKAL1 rs7754840, EXT2 rs1113132 and SLC30A8 rs13266634 were found to have no significant association with T2D among Arabs. In conclusion, it seems from this study that both Arabs and Caucasians have different SNPs associated with T2D. Moreover, this study sheds light on the profound necessity for further investigations addressing the question of the genetic components of T2D in Arabs. PMID- 23458877 TI - WITHDRAWN: Single nucleotide polymorphisms, haplotype association and tumour expression of the vascular endothelial growth factor (VEGF) gene with lung carcinoma. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23458878 TI - NQO1 609C>T polymorphism interaction with tobacco smoking and alcohol drinking increases colorectal cancer risk in a Chinese population. AB - BACKGROUND: NAD (P)H:quinone oxidoreductase (NQO1) catalyzes the activation of some environmental procarcinogens present in tobacco smoke or the diet. We conducted a hospital-based case-control study to evaluate the potential association between NQO1 609C>T polymorphisms and colorectal cancer risk in a Chinese population. METHODS: The study population comprised 672 histologically confirmed colorectal cancer patients and 672 frequency-matched control subjects without cancer or systemic illness. We used PCR restriction fragment length polymorphism-based methods for genotyping analyses and unconditional logistic regression model for statistical evaluations. RESULTS: The risk of colorectal cancer increased with the level of smoking and decreased with the consumption of tea, fresh fruits, and vegetables. In addition, we found that the NQO1 609 CT and TT genotypes were associated with an increased risk of colorectal cancer (CT: adjusted OR=2.02, 95% CI=1.55-2.57; TT: adjusted OR=2.51, 95% CI=1.82-3.47), compared with the CC genotype. Moreover, NQO1 609C>T appeared to have a multiplicative joint effect with both tobacco smoking and alcoholic drinking (P for multiplicative interactions were 0.0001 and 0.013, respectively) on colorectal cancer risk. CONCLUSION: Our findings suggest that the NQO1 609C>T polymorphism plays an important role in the development of colorectal cancer in the Chinese population, which is strengthened by alcohol drinking or tobacco smoking. PMID- 23458879 TI - Cell cycle arrest in Batten disease lymphoblast cells. AB - Batten disease is an inherited neurodegenerative disorder caused by a CLN3 gene mutation. Batten disease is characterized by blindness, seizures, cognitive decline, and early death. Although apoptotic cell death is one of the pathological hallmarks of Batten disease, little is known about the regulatory mechanism of apoptosis in this disease. Since the CLN3 gene is suggested to be involved in the cell cycle in a yeast model, we investigated the cell cycle profile and its regulatory factors in lymphoblast cells from Batten disease patients. We found G1/G0 cell cycle arrest in Batten disease cells, with overexpression of p21, sphingosine, glucosylceramide, and sulfatide as possible cell cycle regulators. PMID- 23458881 TI - Identity of Schizaphis species (Hemiptera: Aphididae) in the United Kingdom: are they a threat to crops? AB - The greenbug, Schizaphis graminum (Rondani), is a major pest of cereals in some parts of the world and is of particular concern because it can be resistant to some insecticides and overcome the resistance of crops. In the UK, it has never been found on crops, but two rather little-known and closely-related species (Schizaphis holci and Schizaphis agrostis) are associated with the wild grasses, Holcus lanatus and Agrostis stolonifera. Since 1987, winged (alate) aphids morphologically resembling the greenbug have been found in increasing numbers in 12.2 m high suction-trap samples of the Rothamsted Insect Survey (RIS); hence, studies were undertaken to establish their identity. Clones (=asexual lineages) established from populations collected from H. lanatus in southern England showed strong preference for Holcus over Agrostis and Hordeum in laboratory tests and produced sexual morphs when transferred to short-day conditions, the males being apterous, as expected for S. holci. Multivariate morphometric comparisons of alatae caught in UK RIS suction traps in 2007 and 2011 with named specimens from museum collections, including S. graminum from many countries, indicated that the suction-trapped alatae were mostly S. agrostis and S. holci. Cytochrome c oxidase subunit I (COI) mtDNA obtained from 62 UK specimens from suction-traps had 95.4 100% sequence identity with US specimens of S. graminum. Two of the UK specimens had identical COI sequence to the US sorghum-adapted form of S. graminum, and these specimens also had 100% identity with a 640 bp fragment of nDNA CytC, indicating that this form of S. graminum may already be present in the UK. Present and future economic implications of these results are discussed. PMID- 23458880 TI - RNA sequencing and transcriptomal analysis of human monocyte to macrophage differentiation. AB - Monocytes can be differentiated into macrophages in vivo and these cells play an important role in innate and adaptive immune responses. To reveal the global gene transcription change that occurs during monocyte to macrophage differentiation, we performed genome-wide RNA sequencing and analyses in human primary monocytes and monocyte-derived macrophages. We show that 1208 genes (with >twofold differences) were differentially expressed in macrophages compared with monocytes, including 800 upregulated and 408 downregulated genes. Gene ontology, pathway, and protein-protein interaction analyses indicated that the upregulated genes were related to macrophage functions in phagocytosis, metabolic processes, and cell cycle. The majority of downregulated genes comprised genes involved in the inflammatory response and locomotion. Genes encoding transcription regulatory factors, such as FOXO1, RUNX3, NF-kappaB1, and C/EBP delta, were highly expressed in monocytes and appeared to function in significant transcriptional repression, resulting in slight metabolic activity. Our transcriptome comparison between human monocytes and monocyte-derived macrophages using RNA sequencing revealed novel molecules and pathways associated with the differentiation process. These molecules and pathways may represent candidate targets involved in the pathophysiology of these important immune cells. PMID- 23458882 TI - Hydrodynamic flow through loading and in vitro secondary caries development. AB - This in vitro study investigated the effect of hydrodynamic flow through mechanical loading on development of secondary caries lesions. Forty-eight bovine tooth specimens (enamel and dentin; sizes 3.2 x 3.2 x 2.0 mm) were restored with resin-composite on polystyrene bars; 18 samples were bonded, and 30 were not bonded. Specimens were suspended in a lactic acid solution (pH = 5; 14 days) in a modified brushing machine, and artificial caries lesions were formed. During caries development, specimens were mechanically loaded at the surface of the polystyrene bar, bent so that the tooth- composite interfaces were subjected to opening forces (16x/min). Loads applied were either none (Control Bonded, CB, n = 6; and Control Non-bonded, CNB, n = 6), 200 gr (NB200, n = 12), or 350 gr (NB350 and B350, both n = 12). Before and after caries development, specimens were imaged with transverse wavelength-independent microradiography (T-WIM), and lesion depth (LD) and mineral loss (ML) were calculated at 4 different locations. An independent t test was used to compare the LD and ML at the 4 different locations. A statistically significant effect of the level of loading (comparing groups NB200 and NB350) and of bonding (comparing groups NB350 and B350) could be observed, with a higher load and absence of bonding leading to more advanced lesions. PMID- 23458884 TI - Effects of goal- and task-oriented motivation in the guilty action test. AB - The present study examined the effectiveness of the Guilty Action Test in detecting critical information from goal-oriented and task-oriented informed innocent examinees. A mock crime procedure was employed and informed innocent participants were either motivated to prove innocence (goal-oriented motivation) or to prove innocence by being cooperative on the test (task-oriented motivation). Half of the participants in each motivation condition were promised course credit reward for successful completion of their mission to prove innocence or to be cooperative (high incentive level). The other half were promised no reward (low incentive level). A fifth group of uninformed innocent participants served for control purposes. Electrodemal, respiration, and cardiovascular measures were used to indicate the motivation effects. Results showed that the combination of goal-oriented instructions and an incentive for success contributed to enhanced responses to the crime-related information. The combination of task-oriented instructions and an incentive for success attenuated these responses. Skin conductance responses were most sensitive to these effects. Theoretical and practical aspects of the results were discussed. PMID- 23458883 TI - Adult human gingival epithelial cells as a source for whole-tooth bioengineering. AB - Teeth develop from interactions between embryonic oral epithelium and neural crest-derived mesenchyme. These cells can be separated into single-cell populations and recombined to form normal teeth, providing a basis for bioengineering new teeth if suitable, non-embryonic cell sources can be identified. We show here that cells can be isolated from adult human gingival tissue that can be expanded in vitro and, when combined with mouse embryonic tooth mesenchyme cells, form teeth. Teeth with developing roots can be produced from this cell combination following transplantation into renal capsules. These bioengineered teeth contain dentin and enamel with ameloblast-like cells and rests of Malassez of human origin. PMID- 23458887 TI - Effects of proton acceptors on formation of a non-heme iron(IV)-oxo complex via proton-coupled electron transfer. AB - Rates of formation of a non-heme iron(IV)-oxo complex, [Fe(IV)(O)(N4Py)](2+) (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), via electron transfer oxidation of [Fe(III)(OH)(N4Py)](2+) in acetonitrile (MeCN) containing H2O (0.56 M) were accelerated as much as 390-fold by addition of proton acceptors such as CF3COO(-), TsO(-) (p-MeC6H4SO3(-)), NsO(-) (o-NO2C6H4SO3(-)), DNsO(-) (2,4-(NO2)2C6H3SO3(-)), and TfO(-) (CF3SO3(-)). The acceleration effect of proton acceptors increases with increasing basicity of the proton acceptors. The one electron oxidation potential of [Fe(III)(OH)(N4Py)](2+) was shifted from 1.24 to 0.96 V vs SCE in the presence of TsO(-) (10 mM). The electron-transfer oxidation of Fe(III)-OH complex was coupled with the deprotonation process by proton acceptors in which deuterium kinetic isotope effects were observed when H2O was replaced by D2O. PMID- 23458885 TI - Should the STAIR criteria be modified for preconditioning studies? AB - Diverse preconditioning (PC) stimuli protect against a wide variety of neuronal insults in animal models, engendering enthusiasm that PC could be used to protect the brain clinically. Candidate clinical applications include cardiac and vascular surgery, after subarachnoid hemorrhage, and prior to conditions in which acute neuronal injury is anticipated. However, disappointments in clinical validation of multiple neuroprotectants suggest potential problems translating animal data into successful human therapies. Thus, despite strong promise of preclinical PC studies, caution should be maintained in translating these findings into clinical applications. The Stroke Therapy Academic Industry Roundtable (STAIR) working group and the National institute of Neurological Diseases and Stroke (NINDS) proposed working guidelines to improve the utility of preclinical studies that form the foundation of therapies for neurological disease. Here, we review the applicability of these consensus criteria to preconditioning studies and discuss additional considerations for PC studies. We propose that special attention should be paid to several areas, including 1) safety and dosage of PC treatments; 2) meticulously matching preclinical modeling to the human condition to be tested; and 3) timing of both the initiation and discontinuation of the PC stimulus relative to injury ictus. PMID- 23458888 TI - Peri-articular histiocytic sarcoma and previous joint disease in Bernese Mountain Dogs. AB - BACKGROUND: Peri-articular histiocytic sarcoma (PAHS) occurs in dogs, including Bernese Mountain Dogs (BMD). An etiologic relationship with previous joint disease has not been documented. HYPOTHESIS: Peri-articular histiocytic sarcoma in BMD will be more frequently encountered around previously diseased joints compared with normal joints. ANIMALS: 920 European BMD. METHODS: A retrospective study, in which data were obtained through an Internet questionnaire and from 2 veterinary pathology laboratories. Archived samples of hematoxylin-eosin (H&E) staining diagnosed PAHS and synovial cell sarcoma (SCS) were immunolabeled with CD18 and pancytokeratin. Descriptive, comparative, and actuarial statistics comprise the data analysis. RESULTS: All primary synovial tumors were identified as PAHS based on their morphology, positive CD18, and negative pancytokeratin labeling. Joint disease was diagnosed in 226 BMD, of which 15 developed PAHS in a previously diseased joint and 3 in a nondiseased joint. Of the remaining 694 BMD without joint disease, 9 developed PAHS. The odds ratio for a dog with previous joint disease developing PAHS is calculated as 5.4 (95% CI: 2.3-12.5; P < .0001) compared with no previous joint problem. A significant association between previous joint disease and PAHS in the same joint was demonstrated for the left elbow (P = .016), right elbow (P = .006), right shoulder (P = .047), left and right stifle (P < .001), and left carpal joint (P = .010). CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this study suggest a relation between previous joint disease and the development of PAHS in the same joint of European BMD. Owners of BMD should monitor dogs for peri-articular swellings, particularly around previously diseased joints. PMID- 23458889 TI - Characterization of printable cellular micro-fluidic channels for tissue engineering. AB - Tissue engineering has been a promising field of research, offering hope of bridging the gap between organ shortage and transplantation needs. However, building three-dimensional (3D) vascularized organs remains the main technological barrier to be overcome. One of the major challenges is the inclusion of a vascular network to support cell viability in terms of nutrients and oxygen perfusion. This paper introduces a new approach to the fabrication of vessel-like microfluidic channels that has the potential to be used in thick tissue or organ fabrication in the future. In this research, we investigate the manufacturability of printable micro-fluidic channels, where micro-fluidic channels support mechanical integrity as well as enable fluid transport in 3D. A pressure-assisted solid freeform fabrication platform is developed with a coaxial needle dispenser unit to print hollow hydrogel filaments. The dispensing rheology is studied, and effects of material properties on structural formation of hollow filaments are analyzed. Sample structures are printed through the developed computer-controlled system. In addition, cell viability and gene expression studies are presented in this paper. Cell viability shows that cartilage progenitor cells (CPCs) maintained their viability right after bioprinting and during prolonged in vitro culture. Real-time PCR analysis yielded a relatively higher expression of cartilage-specific genes in alginate hollow filament encapsulating CPCs, compared with monolayer cultured CPCs, which revealed that printable semi-permeable micro-fluidic channels provided an ideal environment for cell growth and function. PMID- 23458890 TI - First-line therapy in adult Crohn's disease: who should receive anti-TNF agents? AB - Therapy for Crohn's disease has long been based on a step-up approach, with monoclonal antibodies against TNF as a final option before surgery. Despite the introduction of these monoclonal antibodies, no major changes have occurred in the natural history of Crohn's disease, with half of all patients still requiring intestinal resection at 10 years. Labelling for anti-TNF agents does not take into account prognostic factors. In this Review, we propose that treatment of Crohn's disease be based on the following three disease stages: mild, moderate and severe. In patients with Crohn's disease who have complicated disease or bowel damage, and with poor prognostic factors and/or severe disease, anti-TNF treatment should be considered as first-line therapy. For patients living in areas of high risk of developing tuberculosis, as well as for patients with mild to-moderate Crohn's disease without poor prognostic factors and with uncomplicated disease, steroids and thiopurine should be the first-line therapy. By treating patients with Crohn's disease in accordance with these disease stages, we might be able to alter disease course and reduce overtreatment. Upcoming disease-modification trials are expected to provide information to guide decision-making, ultimately changing the course of disease and improving patient quality of life. PMID- 23458892 TI - GERD: Feeling the pull: a new device for sphincter augmentation. PMID- 23458893 TI - Colorectal cancer: CTC for diagnosing symptomatic colorectal cancer. PMID- 23458894 TI - Crotonaldehyde-exposed macrophages induce IL-8 release from airway epithelial cells through NF-kappaB and AP-1 pathways. AB - Crotonaldehyde, a highly toxic alpha, beta-unsaturated aldehyde, is a major component of cigarette smoke and a ubiquitous environmental pollutant. Crotonaldehyde exposure is known to have adverse effects on respiratory health, but the underlying mechanisms remain obscure. To examine the interaction between macrophages and airway epithelial cells after exposure to crotonaldehyde, BEAS-2B and A549 cells were treated with conditioned media from a human monocytic leukemia cell line (THP-1) cells stimulated with crotonaldehyde. We demonstrate that conditioned media from THP-1 cells stimulated with crotonaldehyde increased interleukin (IL)-8 production, enhanced nuclear factor (NF)-kappaB and AP-1 DNA binding activity in BEAS-2B and A549 cells. Analysis of these conditioned media revealed marked increases in tumor necrosis factor (TNF)-alpha, IL-1beta and IL-8 levels. Preincubation of conditioned media with either TNF-alpha- or IL-1beta neutralizing antibodies reduced IL-8 production. Furthermore, BEAS-2B and A549 cells directly treated with crotonaldehyde induced increase in IL-8 production. These data suggest that crotonaldehyde is capable of directly stimulating the production of IL-8 in both macrophages and airway epithelial cells. Crotonaldehyde-stimulated macrophages also amplify the inflammatory response by enhancing IL-8 release from airway epithelial cells mediated by NF-kappaB and AP 1 pathways through a mechanism involving TNF-alpha and IL-1beta. These findings indicate that crotonaldehyde can cause lung inflammatory response via multiple mechanisms, and may contribute to chronic airway inflammation in smokers. PMID- 23458891 TI - NAFLD in Asia--as common and important as in the West. AB - NAFLD--regarded as a consequence of the modern sedentary, food-abundant lifestyle prevalent in the West--was recorded in Japan nearly 50 years ago and its changing epidemiology during the past three decades is well-documented. NAFLD, and its pathologically more severe form NASH, occur in genetically susceptible people who are over-nourished. Asian people are particularly susceptible, partly owing to body composition differences in fat and muscle. Community prevalence ranges between 20% (China), 27% (Hong Kong), and 15-45% (South Asia, South-East Asia, Korea, Japan and Taiwan). This Review presents emerging data on genetic polymorphisms that predispose Asian people to NAFLD, NASH and cirrhosis, and discusses the clinical and pathological outcomes of these disorders. NAFLD is unlikely to be less severe in Asians than in other populations, but the associated obesity and diabetes pandemics have occurred more recently in Asia than in Europe and the USA, and occur with reduced degrees of adiposity. Cases of cryptogenic cirrhosis and hepatocellular carcinoma have also been attributed to NAFLD. Public health efforts to curb over-nutrition and insulin resistance are needed to prevent and/or reverse NAFLD, as well as its adverse health outcomes of type 2 diabetes, cardiovascular events, cirrhosis and liver cancer. PMID- 23458895 TI - Increased vulnerability to beta-cell destruction and diabetes in mice lacking NAD(P)H:quinone oxidoreductase 1. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) has been known to protect cells against stressors, including the diabetogenic reagent streptozotocin (STZ). The present study demonstrated that NQO1 deficiency resulted in increased pancreatic beta cell death induced by multiple low dose of STZ (MLDS) injections. NQO1 knockout (KO) mice showed hyperglycemia, body weight loss, impaired glucose clearance rate and a lower plasma insulin level after MLDS treatment. Moreover, beta-cell mass and pancreatic insulin content were significantly lower in KO mice than in wild type (WT) mice after MLDS treatment. Five days after the first STZ treatment, the islets of KO mice had substantially more TUNEL-positive beta-cells than those of WT mice, but there was no difference in the regeneration of beta-cells between KO mice and WT mice. At the same time, MLDS-treated KO mice showed significantly increased apoptotic markers in beta-cells, including cleaved caspase 3, Smac/DIABLO and AIF (apoptosis inducing factor) in the cytoplasm. These results suggest that mice deficient in NQO1 are vulnerable to MLDS-induced beta-cell destruction and diabetes, caused by increase of beta-cell apoptosis in pancreas. PMID- 23458896 TI - Mechanisms of chemokine responses by polycyclic aromatic hydrocarbons in bronchial epithelial cells: sensitization through toll-like receptor-3 priming. AB - We have previously observed that 1-nitropyrene (1-NP) and its amine metabolite 1 aminopyrene (1-AP) induce differential chemokine responses in human bronchial epithelial cells (BEAS-2B) characterized by maximum responses for CXCL8 (IL-8) and CCL5 (RANTES), respectively. In the present study, we further explored the effects of 1-NP and 1-AP on chemokine responses. The results suggest that the differential effect of 1-NP and 1-AP on CXCL8 and CCL5 in BEAS-2B cells was mainly related to effects at higher concentrations, which in the case of 1-NP seemed to be linked to ROS-formation and/or metabolic activation by CYP-enzymes. However, at a low concentration (1 MUM) where neither 1-NP, 1-AP nor unsubstituted pyrene had any effect on chemokine responses, we found that all three PAHs potentiated CXCL8 and CCL5 responses induced by the TLR3 ligand polyinosinic:polycytidylic acid (Poly I:C) in BEAS-2B cells. As neither benzo[a]pyrene nor beta-naphthoflavone induced a similar effect in Poly I:C primed cells, the response seemed independent of aryl hydrocarbon receptor mediated mechanisms. The results show that priming cells with an inflammogenic stimuli like Poly I:C sensitizes the cells toward additional pro-inflammatory effects of certain PAHs. The study underscores that testing on healthy cells or animals may not be sufficient to fully evaluate chemokine responses and the pro inflammatory potential of organic chemicals. PMID- 23458897 TI - Sub-acute, moderate-dose, but not short-term, low-dose dietary pre-exposure of mice to perfluorooctanoate aggravates concanavalin A-induced hepatitis. AB - Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w=3+/-0.7mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w=70+/-2MUg/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN gamma) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by sub-acute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation. PMID- 23458898 TI - The C. elegans CDK8 Mediator module regulates axon guidance decisions in the ventral nerve cord and during dorsal axon navigation. AB - Receptors expressed on the growth cone of outgrowing axons detect cues required for proper navigation. The pathway choices available to an axon are in part defined by the set of guidance receptors present on the growth cone. Regulated expression of receptors and genes controlling the localization and activity of receptors ensures that axons respond only to guidance cues relevant for reaching their targets. In genetic screens for axon guidance mutants, we isolated an allele of let-19/mdt-13, a component of the Mediator, a large ~30 subunit protein complex essential for gene transcription by RNA polymerase II. LET-19/MDT-13 is part of the CDK8 module of the Mediator. By testing other Mediator components, we found that all subunits of the CDK8 module as well as some other Mediator components are required for specific axon navigation decisions in a subset of neurons. Expression profiling demonstrated that let-19/mdt-13 regulates the expression of a large number of genes in interneurons. A mutation in the sax-3 gene, encoding a receptor for the repulsive guidance cue SLT-1, suppresses the commissure navigation defects found in cdk-8 mutants. This suggests that the CDK8 module specifically represses the SAX-3/ROBO pathway to ensure proper commissure navigation. PMID- 23458900 TI - Effects of dietary cholesterol on astaxanthin transport in plasma of Atlantic salmon (Salmo salar). AB - The effect of dietary cholesterol on astaxanthin (Ax) absorption and transport in the plasma of Atlantic salmon was investigated. Under controlled conditions, three experimental diets, non-pigmented diet (NPD), NPD with 40 mg Ax kg(-1), and NPD with 40 mg Ax kg(-1) and 2% cholesterol, were fed to juvenile salmon reared in sea water. After 12 weeks, blood was collected and plasma separated for analysis of plasma Ax and cholesterol content. In addition, plasma samples from each group of fish were fractionated into lipoproteins using a sucrose density gradient and ultracentrifugation. The apolipoprotein components of VLDL, LDL and HDL from each sample fraction were separated using SDS-PAGE. The addition of 2% cholesterol to the Ax-containing diet significantly increased the concentration of Ax and cholesterol in fish plasma. The protein-rich fraction was found to be the major carrier of Ax in salmon plasma. Cholesterol supplementation significantly increased Ax in plasma and VLDL as well as increasing plasma cholesterol. The VLDL fraction showed the most significant change in fish fed diet supplemented with cholesterol resulting in higher levels of Ax in this lipoprotein. The results clearly show that dietary cholesterol had a significant effect on the Ax transport process in the blood. PMID- 23458901 TI - Duplicated crabp1 and crabp2 genes in medaka (Oryzias latipes): gene structure, phylogenetic relationship and tissue-specific distribution of transcripts. AB - Here we report the genomic organization of duplicated cellular retinoic acid binding protein genes, crabp1 and crabp2, in medaka (Japanese ricefish; Oryzias latipes), the phylogenetic relationship of medaka Crabp1a, Crabp1b, Crabp2a and Crabp2b with other Crabp/CRABP sequences from teleosts/tetrapods, and the tissue specific distribution of crabp1a, crabp1b, crabp2a, and crabp2b transcripts in adult medaka. The duplicated medaka crabp1 and crabp2 genes contain four exons separated by three introns, which encode polypeptides of 137 and 142 amino acids, respectively. Sequence alignment revealed that medaka Crabp sequences share highest sequence identity and similarity with their orthologs from vertebrates. Phylogenetic analysis confirmed the orthology of the medaka Crabps as they form a distinct clade with their orthologous polypeptides from vertebrates. Conserved gene synteny was evident between the duplicated crabp1 and crabp2 genes from medaka, and CRABP1 and CRABP2 genes from human, which provides compelling evidence that the identified duplicated crabp1 and crabp2 genes from medaka most likely arose owing to teleost-specific whole-genome duplication. The tissue specific distribution of zebrafish (Danio rerio) and medaka crabp1a, crabp1b, crabp2a, and crabp2b gene transcripts suggests acquisition of new function by these genes in medaka, which may explain potential evolutionary processes that led to the retention of sister duplicates of crabp1 and crabp2 genes in the medaka genome. PMID- 23458899 TI - Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. AB - During limb skeletogenesis the cartilaginous long bone anlagen and their growth plates become delimited by perichondrium with which they interact functionally. Yet, little is known about how, despite being so intimately associated with cartilage, perichondrium acquires and maintains its distinct phenotype and exerts its border function. Because perichondrium becomes deranged and interrupted by cartilaginous outgrowths in Hereditary Multiple Exostoses (HME), a pediatric disorder caused by EXT mutations and consequent heparan sulfate (HS) deficiency, we asked whether EXT genes and HS normally have roles in establishing its phenotype and function. Indeed, conditional Ext1 ablation in perichondrium and lateral chondrocytes flanking the epiphyseal region of mouse embryo long bone anlagen - a region encompassing the groove of Ranvier - caused ectopic cartilage formation. A similar response was observed when HS function was disrupted in long bone anlagen explants by genetic, pharmacological or enzymatic means, a response preceded by ectopic BMP signaling within perichondrium. These treatments also triggered excess chondrogenesis and cartilage nodule formation and overexpression of chondrogenic and matrix genes in limb bud mesenchymal cells in micromass culture. Interestingly, the treatments disrupted the peripheral definition and border of the cartilage nodules in such a way that many nodules overgrew and fused with each other into large amorphous cartilaginous masses. Interference with HS function reduced the physical association and interactions of BMP2 with HS and increased the cell responsiveness to endogenous and exogenous BMP proteins. In sum, Ext genes and HS are needed to establish and maintain perichondrium's phenotype and border function, restrain pro-chondrogenic signaling proteins including BMPs, and restrict chondrogenesis. Alterations in these mechanisms may contribute to exostosis formation in HME, particularly at the expense of regions rich in progenitor cells including the groove of Ranvier. PMID- 23458902 TI - Gene expression and activity of digestive enzymes during the larval development of Asian seabass (Lates calcarifer). AB - Knowledge of digestive enzyme development during larval stages provides a better understanding of the digestive and nutritional physiology of fish larvae. This study characterized the ontogeny of key digestive enzymes in Asian seabass larvae from hatching to juvenile stage (30 days post hatch, dph) using molecular and biochemical approaches. Gene expression and activity of pepsinogen (pg), trypsinogen (try), chymotrypsinogen (ctr), bile salt-activated lipase (bal), alpha-amylase (amy), leucine aminopeptidase (lap) and alkaline phosphatase (alp) were determined. Gene expression and enzyme activity of all digestive enzymes were detectable from hatching. Pepsinogen mRNA levels were close to detection limit during 0-15 dph, but were highly expressed from 18 dph and onwards. This coincided with a marked increase in specific and individual pepsin activity, indicating complete development of digestive function. Expression levels of try, ctr, amy and bal were high between 3 and 15 dph and thereafter a decreasing trend was observed. Intestinal enzymes, lap and alp, showed highest expression levels during the yolk sac stage, and thereafter levels decreased. Activity of all digestive enzymes increased from around 18 dph and onwards. In conclusion, the development of main digestive enzymes in Asian seabass larvae shows a similar pattern to that of other marine fish species. PMID- 23458903 TI - Solid-state and solution-state coordination chemistry of lanthanide(III) complexes with (pyrazol-1-yl)acetic acid. AB - As a precursor of carboxyl-functionalized task-specific ionic liquids (TSILs) for f-element separations, (pyrazol-1-yl)acetic acid (L) can be deprotonated as a functionalized pyrazolate anion to coordinate with hard metal cations. However, the coordination chemistry of L with f-elements remains unexplored. We reacted L with lanthanides in aqueous solution at pH = 5 and synthesized four lanthanide complexes of general formula [Ln(L)3(H2O)2].nH2O (1, Ln = La, n = 2; 2, Ln = Ce, n = 2; 3, Ln = Pr, n = 2; 4, Ln = Nd, n = 1). All complexes were characterized by single crystal X-ray diffraction analysis revealing one-dimensional chain formations. Two distinct crystallographic structures are governed by the different coordination modes of carboxylate groups in L: terminal bidentate and bridging tridentate (1-3); terminal bidentate, bridging bidentate, and tridentate coordination in 4. Comparison of the solid state UV-vis-NIR diffuse reflectance spectra with solution state UV-vis-NIR spectra suggests a different species in solution and solid state. The different coordination in solid state and solution was verified by distinctive (13)C NMR signals of the carboxylate groups in the solid state NMR. PMID- 23458904 TI - A/J and C57BL/6J mice differ in chorda tympani responses to NaCl. AB - The molecular mechanisms of sodium taste transduction are not completely understood, especially those responsible for the portion of NaCl's taste in rodents that is not blocked by amiloride. As a prelude to conducting genetic analyses of peripheral NaCl taste responsiveness, we performed multiunit electrophysiological recordings from the chorda tympani (CT) nerve in C57BL/6J (B6) and A/J mice. Mice were anesthetized, the CT was accessed, and taste solutions were flowed over the tongue in order to measure the integrated whole nerve response. NaCl was delivered before and during application of 100MUM amiloride. Pre-amiloride responses were significantly larger in A/J than B6 mice for 1-8mM NaCl. Responses to NaCl were suppressed significantly by amiloride in both strains and to similar degrees. However, the size of the amiloride insensitive NaCl response component was significantly larger in A/J mice than in B6 mice for NaCl at 2-16mM. These data help to explain the prior observation that the strains differ in behavioral taste thresholds for NaCl. Specifically, the results suggest that perception of sodium-specific taste by mice depends on the ratio of amiloride-sensitive and -insensitive responses in the CT, rather than on the absolute level of the whole-nerve response to NaCl or on the size of the amiloride-sensitive component alone. Because the B6 and A/J mice differed in the size of their amiloride-insensitive components, they may prove useful in future genetic work designed to characterize the underlying transduction mechanisms. PMID- 23458905 TI - Advances in biology for nursing research. PMID- 23458906 TI - Parenting enhancement, interpersonal psychotherapy to reduce depression in low income mothers of infants and toddlers: a randomized trial. AB - BACKGROUND: Depressive symptoms and clinical depression are highly prevalent in low-income mothers and negatively affect their infants and toddlers. OBJECTIVES: The aim of this study was to test interpersonal psychotherapy combined with parenting enhancement on depressive symptoms and parenting behavior, compared with an equal attention-control condition. METHODS: Mothers (n = 226) of Early Head Start infants and toddlers from the southeastern and northeastern United States were randomized to the intervention delivered in-home by psychiatric mental health advanced practice nurses or an equal attention-control condition delivered by generalist nurses. Rigorous clinical depressive symptom and depression assessments and videotaped, coded mother-child interactions were used as baseline and 14-, 22-, and 26-week postintervention measures. RESULTS: Both the intervention and control groups had significantly reduced Hamilton Rating Scale for Depression scores at each subsequent time point compared with baseline (p < .0001). However, only mothers receiving the intervention showed a significant increase in positive involvement with their child, as measured by closeness, positive effect, affection, and warm touch at T4 (t = 2.22, df = 156, p < .03). DISCUSSION: Both intervention and control conditions resulted in symptom reduction, but only the intervention mothers showed significant interaction changes with their child, an essential step in reducing the negative child outcomes associated with maternal depressive symptoms. Results suggest that a combination of generalist and specialist nurses could be used to treat depressive symptoms in these mothers. Further study with longer postintervention observation is needed to see if, over time, the intervention led to longer lasting symptom reduction. PMID- 23458907 TI - Reduced sleep duration and daytime naps in pregnant women in Taiwan. AB - BACKGROUND: Napping is highly prevalent in pregnant women, but the relation between nighttime sleep and daytime naps in pregnant women is poorly understood. OBJECTIVES: The aim of this study was to examine the temporal association of nighttime sleep quality and quantity with subsequent daytime naps and the temporal association of daytime naps with sleep quality and quantity the following night in women during the third trimester of pregnancy in Taiwan. METHODS: Sleep was assessed in 80 Taiwanese nulliparous women aged 31.70 years (SD = 4.58 years) using actigraphy and diaries for 7 consecutive days. Subjective sleep quality was examined using the Pittsburgh Sleep Quality Index. Multiple linear regressions with generalized estimating equations were used to examine the temporal associations of nighttime sleep and daytime naps. RESULTS: All women napped sometime during the study week, and mean Pittsburgh Sleep Quality Index global score was 6.6, indicating poor sleep quality. Fewer weekly work hours and shorter sleep duration the preceding night were associated with longer nap duration the next day. More work hours, longer nap duration, and more intense fatigue were associated with shorter sleep duration the following night. DISCUSSION: Naps during pregnancy might indicate insufficient nighttime sleep, and longer daytime naps could compromise subsequent nighttime sleep. Further research is needed to determine if short sleep duration and longer daytime naps are associated with negative pregnancy outcomes. PMID- 23458908 TI - Influence of patient characteristics on assessment of diabetes self-management support. AB - BACKGROUND: Factors contributing to patient-reported experiences of diabetes self management support are not understood well, particularly over time. OBJECTIVES: The aim of the study was to identify the contribution of patient characteristics to patient-reported quality of SMS. METHODS: Using secondary data from a prospective clinical trial (n = 339) comparing three approaches of providing diabetes self-management support (Group Medical Visits, Automated Telephone Support, and Usual Care) in a diverse, underserved population, the influence of patient characteristics (e.g., age, gender, income, and health status) was examined on Patient Assessment of Chronic Illness Care ratings. RESULTS: At baseline, older age (p = .014), being female (p = .038), and having lower income (p = .001) were associated with lower ratings. Income and interactions involving income combined explained 12% of the variance in baseline ratings. Compared with White patients, African American and Asian patients tended to have higher baseline ratings (p = .076 and p = .045, respectively). Race or ethnicity influenced perceptions throughout the trial, explaining 5% of the variance at baseline and 2% of the variance in 1-year changes in Patient Assessment of Chronic Illness Care ratings. As expected, over 1 year, ratings increased more for patients in both intervention groups compared with the control group (p < .001). DISCUSSION: Ratings of healthcare quality are influenced by patient characteristics independent of the nature of the care provided. Understanding more precisely how these differences are associated with differences in clinical processes will be particularly important for efforts aiming to integrate patient reported measures into assessments of healthcare quality during routine clinical care and clinical trials. PMID- 23458909 TI - Using temporal mining to examine the development of lymphedema in breast cancer survivors. AB - BACKGROUND: Secondary lymphedema is a lifetime risk for breast cancer survivors and can severely affect quality of life. Early detection and treatment are crucial for successful lymphedema management. Limb volume measurements can be utilized not only to diagnose lymphedema but also to track progression of limb volume changes before lymphedema, which has the potential to provide insight into the development of this condition. OBJECTIVES: This study aims to identify commonly occurring patterns in limb volume changes in breast cancer survivors before the development of lymphedema and to determine if there were differences in these patterns between certain patient subgroups. Furthermore, pattern differences were studied between patients who developed lymphedema quickly and those whose onset was delayed. METHODS: A temporal data mining technique was used to identify and compare common patterns in limb volume measurements in patient subgroups of study participants (n = 232). Patterns were filtered initially by support and confidence values, and then t tests were used to determine statistical significance of the remaining patterns. RESULTS: Higher body mass index and the presence of postoperative swelling are supported as risk factors for lymphedema. In addition, a difference in trajectory to the lymphedema state was observed. DISCUSSION: The results have potential to guide clinical guidelines for assessment of latent and early-onset lymphedema. PMID- 23458910 TI - Dancing for balance: feasibility and efficacy in oldest-old adults with visual impairment. AB - BACKGROUND: Fall risk increases with age and visual impairment, yet the oldest old adults (>85 years) are rarely studied. Partnered dance improves mobility, balance, and quality of life in older individuals with movement impairment. OBJECTIVE: The aim of the study was to determine the feasibility and participant satisfaction of an adapted tango program amongst these oldest-old adults with visual impairment. Exploratory analyses were conducted to determine efficacy of the program in improving balance and gait. METHODS: In a repeated-measures, one group experimental design, 13 older adults (7 women; age: M = 86.9 years, SD = 5.9 years, range = 77-95 years) with visual impairment (best eye acuity: M = 0.63, SD = 0.6 logMAR) participated in an adapted tango program of twenty 1.5 hour lessons, within 11 weeks. Feasibility included evaluation of facility access, safety, volunteer assistant retention, and participant retention and satisfaction. Participants were evaluated for balance, lower body strength, and quality of life in two baseline observations, immediately after the program and 1 month later. RESULTS: Twelve participants completed the program. The facility was adequate, no injuries were sustained, and participants and volunteers were retained throughout. Participants reported enjoyment and improvements in physical well-being. Exploratory measures of dynamic postural control (p < .001), lower body strength (p = .056), and general vision-related quality of life (p = .032) scores showed improvements following training. DISCUSSION: These older individuals with visual impairment benefitted from 30 hours of tango instruction adapted for their capabilities. PMID- 23458914 TI - Mechanical properties' improvement of a tricalcium phosphate scaffold with poly-l lactic acid in selective laser sintering. AB - To improve the mechanical properties of a scaffold fabricated via selective laser sintering (SLS), a small amount (0.5-3 wt%) of poly-l-lactic acid (PLLA) is added to the beta-tricalcium phosphate (beta-TCP) powder. The fracture toughness of the scaffold prepared with the mixture powder containing 1 wt% PLLA increases by 18.18% and the compressive strength increases by 4.45% compared to the scaffold prepared from the beta-TCP powder. The strengthening and toughening is related to the enhancement of beta-TCP sintering characteristics via introducing a transient liquid phase in SLS. Moreover, the microcracks caused by the volume expansion due to the beta-alpha phase transformation of TCP are reduced because of the PLLA inhibition function on the phase transformation. However, PLLA additive above 1 wt% would lead to a PLLA residue which will decrease the mechanical properties. The experimental results show that PLLA is an effective sintering aid to improve the mechanical properties of a TCP scaffold. PMID- 23458913 TI - Factors associated with high-risk behaviour among migrants in the state of maharashtra, India. AB - Studies among migrants show that they are more susceptible to HIV infection than the general population and thereby spread the epidemic from high prevalence to low prevalence areas. It is therefore critical to enhance the body of knowledge on factors associated with condom use among migrants. This study, conducted in 2009 in the State of Maharashtra, covers 4595 single in-migrants aged 15-49 years and aims at understanding the factors associated with non-use of condoms consistently. Information was collected using a Structured Interview Schedule covering demographic, socioeconomic profile, sexual history, knowledge, behaviour and stigma and discrimination indicators. Logistic regression analysis was used to understand the association between unprotected sex and various socio demographic and environmental factors. The models were run using the Enter method. The goodness-of-fit of the model was assessed using Hosmer and Lemeshow chi-squared statistics. A significant association is observed between sex with sex workers and older migrants (>24 years), the literate, those who are mobile, unmarried, employed in the textile, quarry and construction industries, who often consume alcohol and who watch pornographic films. The factors associated with unprotected sex are age between 30 and 34 years and no literacy. Migrants who are mobile and consume alcohol show a significant association with unprotected sex. The findings suggest a need for a comprehensive HIV prevention programme including strategies to address the stressful work conditions. The prevention programmes should focus not only on skills for safer sex practices, but also on alcohol use reduction. PMID- 23458915 TI - Web-based kidney education: supporting patient self-management. AB - Connecting patients to appropriate information-and to each other for social support-can help them self-manage chronic kidney disease (CKD) more effectively. For CKD patients, the Internet offers a wealth of resources to meet many educational needs. Understanding the types of Internet sources CKD patients use today can help renal professionals point patients in the right direction. This article will briefly review the state of CKD patient education and social support in the United States, then outline types of Internet-based patient education, and review the value of each type for both education and social support. PMID- 23458916 TI - Usefulness of a Cook(r) airway exchange catheter in laryngeal mask airway-guided fiberoptic intubation in a neonate with Pierre Robin syndrome -A case report-. AB - The case of a 33-day-old boy with Pierre Robin syndrome using a Cook(r) airway exchange catheter in laryngeal mask airway-guided fiberoptic intubation is presented. After induction with sevoflurane, classical reusable laryngeal mask airway (LMA) #1 was inserted and ultrathin fiberoptic bronchoscope (FOB) was passed through. A Cook(r) airway exchange catheter (1.6 mm ID, 2.7 mm OD) was passed through the LMA under the guidance of the FOB but failed to enter the trachea despite many trials. Then, an endotracheal tube (3.0 mm ID) was mounted on the FOB and railroaded over the FOB. After successful intubation, the Cook(r) airway exchange catheter was placed in the midtrachea through the lumen of the endotracheal tube. Even though the tracheal tube was accidentally displaced out of the trachea during LMA removal, the endotracheal tube could be easily railroaded over the airway exchange catheter. PMID- 23458917 TI - Ethnopharmacological survey of medicinal plants used by traditional healers in Bangladesh for gastrointestinal disorders. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gastrointestinal diseases are common worldwide, including Bangladesh where majority of the rural people depend on water from unprotected sources. The people from Bangladesh use medicinal plants as their first line of health care to cure and prevent different types of gastrointestinal disorders. AIM OF THE STUDY: To compile plants used for the treatment of different gastrointestinal disorders in Bangladesh. MATERIALS AND METHODS: The field survey was carried out in a period of 18 months. Fieldwork was undertaken in total of eleven districts of Bangladesh. Open-ended and semi structured questionnaire were used to interview a total of 1280 people including traditional healers, Ayurvedic/Unani drug manufacturers and local people. RESULTS: A total of 250 plant species of 93 families were listed. Leaves were the most cited plant part used against gastrointestinal disorders. Most of the reported species were tree in nature and decoction is the mode of preparation of major portions of the plant species. Most of the plant species were very common and were cultivated or planted in homestead or roadsides. The doses of the plants for different treatments varied widely. CONCLUSION: In view of the fact that the plants were selected based on their medicinal usage for treating different kinds of gastrointestinal diseases including diarrhoea, the activities reported here need more works for validation and could be rationalised by the presence of active compounds found in those plants. The documentation represents the preliminary information in need of future phytochemical investigation and is important for the conservation of these plants. PMID- 23458918 TI - Fuyuan Decoction inhibits nitric oxide production via inactivation of nuclear factor-kappaB in SW1353 chondrosarcoma cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fuyuan Decoction (FYD) is an empirical formula of treating Bi Zheng in traditional Chinese medicine (TCM). Despite the fact that the efficiency of FYD on treating osteoarthritis has been verified in clinic, the underlying mechanisms are not totally understood. This study was to investigate the effects and mechanisms of FYD on nitric oxide (NO) production and nuclear factor (NF)-kappaB activation in interleukin (IL)-1beta-stimulated chondrocytes. MATERIALS AND METHODS: SW1353 human chondrosarcoma cells were pretreated with various concentrations of FYD-containing serum (FYD-CS), and then were stimulated by IL-1beta. Amounts of NO were determined by Griess reaction assay. Inducible NO synthase (iNOS) expression, inhibitor-kappaBalpha (IkappaBalpha) degradation and nuclear translocation of p65 protein were determined by Western blot assay. DNA binding activity of NF-kappaB was determined by ELISA assay using Trans AM(TM) kit for p65. RESULTS: 10% and 20% (v/v) FYD-CS significantly decreased NO production in a concentration-dependent manner (p<0.05 or p<0.01) as compared to control in IL-1beta-induced SW1353 cells. Besides, 10% and 20% FYD-CS also significantly reduced iNOS protein expression by about 60% and 70% (both p<0.01), respectively. Furthermore, 10% and 20% FYD-CS markedly decreased IkappaBalpha degradation by about 45% and 26% (p<0.01 or p<0.05), lessened P65 content in the nucleus by about 28% and 60% (both p<0.01), and repressed DNA binding activity of P65 by about 30% and 45% (both p<0.01) in IL-1beta-induced SW1353 cells. CONCLUSIONS: These findings suggested that FYD could inhibit NO production and iNOS expression in IL-1beta-induced chondrocytes through suppressing NF-kappaB activation. PMID- 23458919 TI - Identification of the major metabolites of hyperoside produced by the human intestinal bacteria using the ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM), used in clinical practice for thousands of years, has been taken as a new way to tackle chronic diseases. In Chinese medicine, many ingredients which are known to have biological effects just pass through the gut, they do not get into the bloodstream. Study on interactions of these active ingredients with the intestinal bacteria is very helpful to unravel how TCM works. AIM OF THE STUDY: Hyperoside is a major active constituent in many medicinal plants which are traditionally used in Chinese medicines for their neuroprotective, anti inflammatory and anti-oxidative effects. It would be metabolized by intestinal bacteria after oral administration which leads to the variation of ethnopharmacological profile of these traditional medicines. Thus, it is necessary to investigate the metabolic routes and metabolites of hyperoside produced by human intestinal bacteria. MATERIALS AND METHODS: Ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/QTOF-MS) technique combined with Metabolynx(TM) software was used for analysis of the metabolic profile of hyperoside by the isolated human intestinal bacteria from the human feces. RESULTS: Parent compound and 6 metabolites (M1-M7) were detected in the isolated bacterial samples compared with blank samples. Quercetin, 3, 4 dihydroxyphenylacetic acid and 3, 4-dihydroxyphenylbenzoic acid (M2-M4) were only found in the sample of Bacteroides sp. 45. Dehydroxylation of hyperoside and the conjugates: acetylation and hydroxylation of hyperoside (M5-M7) were identified in the majority of isolated intestinal bacterial samples. CONCLUSIONS: Only Bacteroides sp. 45 could metabolize hyperoside to form its aglycone quercetin, thereafter, quercetin was further metabolized to 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid. Furthermore, the majority of bacteria could metabolize hyperoside to dehydroxylation of hyperoside and the conjugates: hydroxylation and acetylation of hyperoside. In this study, the metabolic routes and metabolites of hyperoside produced by the different intestinal bacteria were investigated for the first time. Furthermore, the production of metabolites of hyperoside might influence the effects of traditional medicines. Thus, the study on the metabolism of hyperoside by human intestinal bacteria is of great importance to an understanding of the effects of traditional medicines. PMID- 23458920 TI - Preclinical toxicological evaluations of the sclerotium of Lignosus rhinocerus (Cooke), the Tiger Milk mushroom. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lignosus rhinocerus (Tiger Milk mushroom) is distributed in South China, Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea. In Malaysia, it is the most popular medicinal mushroom used by the indigenous communities to relieve fever, cough, asthma, cancer, food poisoning and as a general tonic. In China, this mushroom is an expensive traditional medicine used to treat liver cancer, chronic hepatitis and gastric ulcers. The sclerotium of the mushroom is the part with medicinal value. This rare mushroom has recently been successfully cultivated making it possible to be fully exploited for its medicinal and functional benefits. The present study was carried out to evaluate the chronic toxicity of the sclerotial powder of Lignosus rhinocerus cultivar (termed TM02), its anti-fertility and teratogenic effects as well as genotoxicity. MATERIALS AND METHODS: Sprague Dawley rats (10 rats/group/sex) were fed orally with 250, 500 and 1000 mg/kg of sclerotial powder of TM02. The sclerotial powder was orally administered once daily and consecutively for 180 days. At the completion of the oral feeding period, analysis of hematological and clinical biochemical parameters, urine profiles, organ weight as well as histopathological analysis were carried out. The effect of the sclerotial powder on fertility and its possible teratogenicity were examined by feeding rats orally with 100 mg/kg sclerotial powder consecutively for 7-8 weeks. Genotoxicity was evaluated by Ames test using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and Escherichia coli WP2 uvrA. RESULTS: The results showed that oral administration of the sclerotial powder of the Lignosus rhinocerus cultivar at daily dose of up to 1000 mg/kg for 180 days had no adverse effect on the general clinical observations, body weight, hematology, clinical biochemistry, urinalysis, absolute organ weight as well as relative organ weight, nor induced histological changes in the organs. Oral administration of 100 mg/kg sclerotial powder of the Lignosus rhinocerus for 7-8 weeks did not affect the fertility of the rats nor induce teratogenic effect on their offspring. Lignosus rhinocerus sclerotial powder up to 5000 MUg/plate in the presence and absence of metabolic activation did not cause gene mutations by base pair changes or frameshifts in the genome of the tester strains used. CONCLUSION: Our results showed that the no-observed-adverse-effect level (NOAEL) dose of the sclerotial powder of Lignosus rhinocerus in 180-day chronic toxicity study is more than 1000 mg/kg. Oral feeding of the sclerotial powder at 100mg/kg did not induce adverse effect on rats' fertility nor causing teratogenic effect on their offspring. In the reverse mutation Ames test, the sclerotial powder at all tested concentration did not show any genotoxicity. PMID- 23458921 TI - Clinical research on traditional drugs and food items--the potential of comparative effectiveness research for interdisciplinary research. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In the traditional context, herbs are often used as herbal whole system therapies, however, most clinical trials included highly selected patients and applied standardized treatment protocols with the aim to exclude as much bias as possible. These studies have contributed important information on the efficacy of herbal medicine extracts; however, their results are only marginally helpful to understand the value of herbal medicine and food items in a more traditional usual care context. METHODS: The new development of comparative effectiveness research (CER) will be introduced and synergies with ethnopharmacology will be outlined. RESULTS: CER provides great opportunities for guiding researchers and clinicians in improving management of disease. CER compares two or more health interventions in order to determine which of these options works best for which types of patients in settings that are similar to those in which the intervention will be used in practice. CER uses a broad spectrum of methodologies including randomized pragmatic trials that can also be applied to herbal whole system therapies. Ethnopharmacological research can provide highly relevant information for CER including data on characteristics of typical patients as well as traditional usage including methods of collection, extraction, and preparation. Recommendations for future research on traditional herbal medicine and food items are (1) a systematic cooperation between ethnopharmacology and clinical researchers and (2) a call for more CER on traditional herbal medicines and food items. CONCLUSION: Multiple stakeholders, including ethnopharmacologists, should cooperate to identify relevant study questions as well share their knowledge to determine the optimal placement of a clinical trial in the efficacy-effectiveness-continuum. PMID- 23458922 TI - Purified active lotus plumule (Nelumbo nucifera Gaertn) polysaccharides exert anti-inflammatory activity through decreasing toll-like receptor-2 and -4 expressions using mouse primary splenocytes. AB - ETHNOPHARMACOLOGICAL SIGNIFICANCE: Lotus plumule is widely used as traditional Chinese medicine. Among the active components in lotus plumule, polysaccharides exhibit promising potential for its potent anti-inflammatory effects. However, the anti-inflammatory mechanism of purified polysaccharides from lotus plumule remains unknown. To evaluate their anti-inflammatory potential and possible mechanisms of purified polysaccharides in lotus plumule, two active lotus plumule polysaccharides, fractions F1 and F2, were subjected to assay their anti inflammatory potential and possible mechanisms using murine primary splenocytes in the absence or presence of lipopolysaccharide (LPS). MATERIALS AND METHODS: Two purified active lotus plumule polysaccharides, F1 and F2, were cultured independently with murine primary splenocytes in the absence or presence of LPS under four different experiment models in vitro. Changes in pro-inflammatory IL 1beta, IL-6 and TNF-alpha, as well as anti-inflammatory IL-10 cytokines secreted by the treated splenocytes were determined using an enzyme-linked immunosorbent assay (ELISA). The amount of toll-like receptor (TLR)-2 and TLR-4 mRNA expression levels in the cells were quantitated using a two-step real-time polymerase chain reaction (PCR) assay. RESULTS: The results showed that F1 and F2 treatments alone, particularly F2, significantly (P<0.05) decreased pro-/anti-inflammatory (IL-1beta/IL-10 and TNF-alpha/IL-10) cytokine secretion ratios dose-dependently. F1 and F2 treatments in the presence of LPS significantly decreased TLR-2 and/or TLR-4 mRNA expression levels in the splenocytes under inflammatory and repair experiment models. CONCLUSIONS: The present study proved that F1 and F2 had strong anti-inflammatory effects through inhibiting TLR-2 and/or TLR-4 expressions in the splenocytes in normal, inflammatory and repair situations. Our results further suggest that F2, which is a glycoprotein with low molecular weight of 25.7 kDa, may serve as a promising lead for the development of selective TLR antagonistic agents for inflammatory diseases. PMID- 23458923 TI - PET-based geometrical calibration of a pinhole SPECT add-on for an animal PET scanner. AB - We developed SPECT imaging capability on an animal PET scanner to provide a cost effective option for animal SPECT imaging. The SPECT add-on sub-system was enabled by mechanically integrating a multiple-pinhole collimator in the PET detector ring. This study introduces a method to calibrate the geometrical parameters of the SPECT add-on using the PET imaging capability of the scanner. The proposed PET imaging-based calibration method consists of two steps: (1) paint the pinhole apertures of the collimator with a positron emitting radioactive solution; and (2) image the collimator inside the scanner in PET mode. The geometrical parameters of the multi-pinhole SPECT add-on can then be derived directly from a set of PET images by simple linear calculation and used in defining the SPECT system. The method was compared to our implementation of a SPECT calibration approach with model-based fitting of SPECT projection data. The procedure for carrying out the PET imaging-based calibration method is simpler and faster than that of our implementation of the SPECT model-based calibration method. Since it does not require model fitting, the uniqueness of the calibration result is warranted. Better quality SPECT images were reconstructed using the PET-derived calibration parameters rather than our implementation of the SPECT model-based calibration parameters. We conclude that the proposed PET imaging-based calibration method provides a highly effective means for enabling SPECT imaging on a PET scanner. PMID- 23458925 TI - Acute kidney injury: Creatinine and AKI--through a glass, darkly. PMID- 23458924 TI - Community-acquired acute kidney injury in tropical countries. AB - Community-acquired acute kidney injury (AKI) in developing tropical countries is markedly different from AKI in developed countries with a temperate climate, which exemplifies the influence that environment can have on the epidemiology of human diseases. The aetiology and presentation of AKI reflect the ethnicity, socioeconomic factors, climatic and ecological characteristics in tropical countries. Tropical zones are characterized by high year-round temperatures and the absence of frost, which supports the propagation of infections that can cause AKI, including malaria, leptospirosis, HIV and diarrhoeal diseases. Other major causes of AKI in tropical countries are envenomation; ingestion of toxic herbs or chemicals; poisoning; and obstetric complications. These factors are associated with low levels of income, poor access to treatment, and social or cultural practices (such as the use of traditional herbal medicines and treatments) that contribute to poor outcomes of patients with AKI. Most causes of AKI in developing tropical countries are preventable, but strategies to improve the outcomes and reduce the burden of tropical AKI require both improvements in basic public health, achieved through effective interventions, and increased access to effective medical care (especially for patients with established AKI). PMID- 23458927 TI - Transplantation: The promise of co-stimulatory blockade in transplantation. PMID- 23458928 TI - Gut microbiota: Gut microbes: a role in melamine-induced renal toxicity? PMID- 23458926 TI - Angiogenesis and hypoxia in the kidney. AB - Loss of glomerular function associated with the presence of tubulointerstitial lesions, which are characterized by peritubular capillary loss, is a common finding in progressive renal disorders. Dysregulated expression of angiogenic factors (such as vascular endothelial growth factor [VEGF] and angiopoietins) and endogenous angiogenic inhibitors (such as thrombospondin-1, angiostatin and endostatin) underlie these conditions and negatively influence the balance between capillary formation and regression, resulting in capillary rarefaction. Recent studies have provided unequivocal evidence for a pathogenic role of tubulointerstitial hypoxia and the involvement of hypoxia-inducible transcription factors in the advanced stages of chronic kidney disease. The mainstay of potential angiogenic therapies is the application of angiogenic factors with the primary aim of ameliorating reduced oxygenation in the ischaemic tubulointerstitium. However, this strategy is strongly associated with inflammation and changes in vascular permeability. For example, supraphysiological expression of VEGF results in glomerular expansion and proteinuria, whereas VEGF blockade using neutralizing antibodies can cause hypertension and thrombotic microangiopathy. These effects highlight the importance of tight regulation of angiogenic factors and inhibitors. Novel therapeutic approaches that target vascular maturation and normalization are now being developed to protect kidneys from capillary rarefaction and hypoxic injury. PMID- 23458929 TI - Polycystic kidney disease: Role of TRPV4 in renal cystogenesis. PMID- 23458930 TI - Critical care: Serious safety concerns regarding use of hydroxyethyl starch for acute fluid resuscitation. PMID- 23458931 TI - Prevailing genotypes of hepatitis C virus in Saudi Arabia: a systematic analysis of evidence. AB - BACKGROUND AND OBJECTIVES: Although hepatitis C virus (HCV) genotype 4 has been reported to be prevalent in some countries of the Middle East, the genotype distribution in some geographical areas is not conclusive. We aimed to perform a meta-analysis on available literature on this issue in an attempt to identify or confirm the prevailing HCV genotypes in Saudi Arabia. METHODS: We searched for reports describing genotypes in Saudi Arabia. A meta-analysis was performed on the samples in 18 studies, published between 1995 and 2011, in which HCV genotypes were identified. RESULTS: A total of 2277 specimens from 18 studies showed that 617, 82, 119 and 1198 subjects were HCV-positive for genotypes 1, 2, 3 and 4, respectively. The meta-analyses showed that there is a great deal of heterogeneity in estimated prevalence among the studies. The highest prevalence was found in genotype HCV-4, followed by HCV-1, HCV-3, and HCV-2. CONCLUSION: Our meta-analysei emphasizes that HCV genotype 4 is the most prevalent, followed by genotype 1. Further studies on genotype determination and subtype distribution are warranted. PMID- 23458932 TI - Central nervous system and spinal tuberculosis in children at a tertiary care center in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Tuberculosis (TB) remains a global health problem. There is limited data on pediatric central nervous system tuberculosis (CNSTB) in Saudi Arabia on diagnosis and therapy. DESIGN AND SETTING: Retrospective review of health record of pediatric patients < 14 years old who were diagnosed as having CNSTB or spinal TB and admitted to a tertiary care center. PATIENTS AND METHODS: Health records and microbiology data of pediatric patients diagnosed with CNSTB were over 20-year period were reviewed. Data on demographics, clinical presentation, surgical interventions, neuroimaging, mycobacterial cultures and susceptibility and treatment were collected. RESULTS: Thirteen children were diagnosed with CNSTB or spinal TB. Tuberculoma was the most frequent in 8 cases (62%), followed by TB of the spine in 4 cases (31%), and one case of meningitis. Six patients had a history of TB contact (46%) and 8 (62%) patients had a positive tuberculin skin test (TST). Seizure and weakness was the most frequent symptoms (38% each), while fever was less frequently encountered (23%). Tissue cultures (brain tissues/spinal tissues) showed a high yield (92%) of Mycobacterium tuberculosis with positive cultures for 11 surgical specimens out of 12 for whom cultures were done. There were no surgical complications from biopsies. All of MTB isolates were sensitive to first-line agents. CONCLUSIONS: Brain or spinal biopsy is safe and has a high culture yield for MTB so it is advisable to perform a biopsy for any child in whom CNSTB is suspected and when there is no other less risky involved site for biopsy. All MTB isolates in this series were sensitive to first-line anti-tubercular agents. PMID- 23458933 TI - HCV genotypes among 1013 Saudi nationals: a multicenter study. AB - BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) genotype (G) knowledge is essential for determining type, duration and rate of response to antiviral therapy, possible route of HCV transmission, and future vaccine development. Our aim was to study HCV genotypes and to provide precise data on genotype distribution in both genders and different age groups amongst Saudi patients. DESIGN AND SETTING: Genotype data from molecular laboratories at four different tertiary care hospitals in Riyadh from January 2006 until December 2010 were collected and analyzed. PATIENTS AND METHODS: Consecutive data on genotype, sex and age was collected from 1013 Saudi patients. Genotyping was done by selective hybridization of amplicons to HCV genotype-specific oligonucleotides. RESULTS: We found G1 in 262 patients (25.9%), G2 in 44 (4.4 %), G3 in 29 (2.9 %), G4 in 608 (60%), and 3 patients (0.3%) each of G5 and G6. In addition, 64 (6.3%) patients had mixed genotypes, mostly G4 and G1. On subtyping in 191 G1 patients, 67 (35.1%) were G1a, and 124 (64.9 %) G1b. Age distribution showed that 18 (1.7%) were 0-20 years, 173 (17.1 %) 21-40 years, 521 (51.4%) 41-60 years and 301(29.7%) > 60 years. There was no significant difference in frequency of G1, G3 and G4 among the two genders. CONCLUSION: G1 and G4 are the predominant genotypes in Saudi patients infected with HCV (85.9%), with a similar distribution among the two sexes and no significant changes in genotype distribution over the past decade. PMID- 23458934 TI - Prevalence of high-risk human papillomavirus infections in healthy Saudi women attending gynecologic clinics in the western region of Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Infection with human papillomavirus (HPV) is the major cause of cervical cancer. There is little published data on the prevalence of HPV infection among Saudi women. The aim of this study was to determine the prevalence of HPV in a group of women in the western region of Saudi Arabia. DESIGN AND SETTING: A prospective study of Saudi women seeking gynecologic care at King Abdulaziz University Hospital from March 2010 to January 2011. PATIENTS AND METHODS: Four hundred eighty-five Saudi women of different age groups attending gynecology clinic were tested for high-risk HPV DNA. HPV DNA was detected in cervical scrapes using Hybrid Capture 2 (HC2) high-risk HPV DNA test. The prevalence of HPV DNA positivity in different age groups was calculated. RESULTS: Out of the 485 specimens, 27 (5.6%) were positive for the high-risk HPV. The highest percentage was among women aged 60 years and older. Patients in the age group 40-49 years were more likely to accept HPV testing with a total of 188 patients. CONCLUSION: The prevalence of HPV in this group of Saudi women is similar to what was reported in some Arab countries and lower than that reported in developed countries. This information could be used to help in establishing a primary screening program using HPV DNA testing in Saudi Arabia. PMID- 23458935 TI - Prevalence of iron overload complications among patients with b-thalassemia major treated at Dubai Thalassemia Centre. AB - BACKGROUND AND OBJECTIVES: Authors and team members of the Dubai Thalassemia Centre obtained data on the prevalence of iron overload complications among patients with b-thalassemia major (b-TM) and compared it to international data to improve patient care and evaluate the effectiveness of earlier used treatment modalities. The information obtained is also expected to be useful in genetic counseling. DESIGN AND SETTING: Cross-sectional study of all living transfusion dependent b-TM patients registered at the Thalassemia Centre in Dubai, United Arab Emirates, until the end of 2007 (n=382). PATIENTS AND METHODS: Diagnosis of TM was based on clinical history and laboratory confirmation by hemoglobin electrophoresis and DNA testing. All were uniformly treated with desferrioxamine and monitored by serial serum ferritin. results: The mean (SD) age of patients was 15.4 (7.6) years, with 50.5% males. Mean (SD) serum ferritin was 2597.2 (1976.8) micro g/L. The frequency of iron overload complications were as follows: hypogonadism (n=99, 52.7%), hypoparathyroidism (n=40, 10.5%), diabetes mellitus (n=40, 10.5%), hypothyroidism (n=24, 6.5%) and cardiomyopathies (n=7, 1.8%). Hypogonadism was the most common endocrine abnormality in our study and other reported series. However, cardiomyopathies were less prevalent among our patients with higher rates of diabetes and hypoparathyroidism compared to rates reported internationally. Females had statistically significant lower serum ferritin (2530.8 (1931.2), P < .05) with a lower cardiomyopathies rate. CONCLUSION: Iron overload related complications among our patients with thalassemia major were different from those reported internationally. Studying the genetic status of patients from our area may uncover the underlying genetic modifiers of iron overload mediated organs injury. PMID- 23458936 TI - Distinct sonographic features of acute appendicitis in sickle cell disease. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to report sonographic findings of appendicitis in patients with positive screening tests for sickle cell compared to normal control patients. DESIGN AND SETTING: A retrospective study of the medical records of 396 patients who underwent appendectomy during a 3-year period from March 2005-2008. PATIENTS AND METHODS: The study included 216 males and 180 females, whose ages ranged from 7 to 55 years. Four patients (0.9%) had sickle cell disease (SCD), 101 had sickle cell trait (SCT) (25%) and 291 (74%) patients were without sickle cell anemia (control group). RESULTS: Positive sonographic findings of appendicitis were identified in 95 (90%) SCT patients and in 253 (87%) control patients. The mean maximal mural thickness was higher in sickle cell patients (4.5 [1.4] mm) in comparison with the control group (3.0 [2.2] mm) (P < .0001). Appendicolith was significantly detected in 53% of the control group and in 8.5% of the sickle cell group (P < .0001). Color Doppler showed hypervascularity in 72% of patients with appendicitis in the control group with a significant difference compared to only 12 cases (11%) of SC patients (P < .05). Ultrasonography findings suggesting perforation were found in 35 sickle cell patients and in 75% (3 of the 4 patients) with SCD. Findings suggesting perforation were found only in 49 patients (17%) of the control group. Perforated appendix was significantly higher in sickle cell patients in preoperative US and intraoperatively (P < .05) CONCLUSION: Positive sonographic findings of appendicitis in sickle cell patients are different from the general population. These findings include mural thickening with a low incidence of appendicolith and wall hypervascularity. Also sonographic features of perforation in sickle cell patients are more common suggesting a need for more urgent operative intervention. PMID- 23458937 TI - Saudi womens acceptance and attitudes towards companion support during labor: should we implement an antenatal awareness program? AB - BACKGROUND AND OBJECTIVES: Despite the known benefits of support during chilbirth, most hospitals in Saudi Arabia do not allow a companion during labor. This can be due to cultural beliefs among pregnant Saudi women. The aims of this study are to describe Saudi women's preferences towards supportive companions during labor and to explore their attitudes and knowledge about the importance of support during childbirth. DESIGN AND SETTING: Prospective cohort study conducted in three governmental tertiary hospitals within Riyadh. SUBJECTS AND METHODS: Women who consented were interviewed during their postpartum hospital stay using a validated standardized Arabic questionnaire. Participants were asked about their preferences and attitudes towards companions during childbirth, as well as about their knowledge on the importance of such support. RESULTS: Of 402 women who participated in the study, 182 women (45.3%) preferred the presence of a companion during childbirth and only 57 of all interviewed women (14.2%) had ever had a supportive companion during any of their previous childbirths. The mother (58%) or husband (51%) was the most preferred person as a childbirth companion. Age, level of educational, or antenatal, intrapartum or postpartum status had no impact on their decision. However, women who had some sort of antenatal educational classes and/or read educational material about childbirth were more likely to prefer support during labor. More than one-third of participants (35.9%) thought that having a companion as support during labor would not help, but the most common reason for not preferring to have a companion was their fear of being exposed most of the time to their companion (64.1%). CONCLUSIONS: A significant percentage of surveyed Saudi women preferred not to have a supportive companion during childbirth. The reason might be a lack of understanding of the positive role of a companion during childbirth or because of cultural beliefs. Education of women during their antenatal care about the importance and the implementation of such a practice are warranted. PMID- 23458938 TI - Fertility and pregnancy outcomes following resectoscopic septum division with and without intrauterine balloon stenting: a randomized pilot study. AB - BACKGROUND AND OBJECTIVES: Although uterine stenting is performed routinely following hysteroscopic metroplasty, we were unable to find any evidence documenting its value with regards to septum reformation and/or obstetrical performance. To evaluate the benefits of intrauterine Foley catheter/balloon splinting after resectoscopic septum division on septum reformation, fertility, and pregnancy outcomes. DESIGN AND SETTING: Prospective, randomized controlled pilot study (Canadian Task Force Classification I) conducted in university affiliated teaching hospital. PATIENTS AND METHODS: Twenty-eight women with infertility and/or adverse pregnancy outcomes diagnosed with intrauterine septum were randomized into having a No. 14 pediatric Foley catheter/balloon for 5 days (n=13) vs. no balloon (n=15) following resectoscopic septum division. None of the patients received preoperative endometrial thinning, antibiotic prophylaxis or adjuvant postoperative hormone therapy. All uterine septa were divided under general anaesthesia using a 26 F (9 mm) resectoscope with a monopolar electrical knife using glycine irrigant solution (1.5%) and 120 watts of power of low voltage (cut) waveform. RESULTS: The median age (range) was 29 years (23-38) and 32 years (22-40), respectively (P=.59). The groups were comparable by age, past obstetrical performance and comorbidities including endometriosis stage I-IV in 3 and 4 women, in the catheter/balloon and balloon group, respectively, and one in each group of polycystic ovarian syndrome and Crohn disease and one case of tubal obstruction in the balloon group. There were no intra- or postoperative complications. At 3 months, a hysterosalpingogram was done in 10 (77%) and 13 (87%) women, respectively, the results of which were normal. At 12-18 months, 1 woman in the balloon and 3 in the control group were not trying to conceive and 1 in each group had not conceived. Of the remaining women, 11 (92%) in each group had conceived and pregnancy outcomes included spontaneous abortion 3 (25%) and 4 (33.3%), ectopic pregnancy 0 and 1, second trimester loss 1 (8.3%) and 0 and term pregnancy 8 (66.6%) in both groups. Conception through assisted reproductive technology occurred in 2 and 1 woman, respectively. CONCLUSIONS: Following resectoscopic septum division with monopolar knife electrode, splinting the uterine cavity with Foley catheter provided no advantage in septum reformation, clinical pregnancy rate, and pregnancy outcomes. PMID- 23458939 TI - Gleason grading of prostate cancer in needle core biopsies: a comparison of general and urologic pathologists. AB - BACKGROUND AND OBJECTIVES: The Gleason grading of prostate carcinoma (PCa) in needle core biopsies is a major determinant used in management planning. The objective of this study was to evaluate the concordance between general pathologists Gleason grading and that of a urologic pathologist in our community. DESIGN AND SETTING: Retrospective review conducted at three tertiary care hospitals in Jeddah and Riyadh for all prostatic biopsies with carcinoma from January 2002 to January 2011. METHODS: Gleason scores assigned by the original pathologist were compared with that of the reviewing urologic pathologists. Biopsies were originally obtained and diagnosed at different referring hospitals and independent laboratories. The kappa test was used to evaluate agreement between the original and review scores. RESULTS: For 212 biopsies the exact concordance of the Gleason score assigned by the original pathologist and the reviewer was 38.7% (82/212). However, when grouped into the main four-score categories of 2-4, 5-6, 7, and 8 or greater, disagreement was noted in 88 (41.5%) biopsies; 87 were upgraded and 1 was downgraded on review. When grouped into two score categories of low grade (<=6) and high grade (>=7), disagreement was noted in 32 (15%) of the biopsies. CONCLUSION: Gleason grade score shows that there was only slight to fair agreement between outside and review scoring (kappa=0.43). When using only low versus high grade categorization, there was good agreement (kappa=0.69). Almost all of the cases with score disagreement were upgraded on review. PMID- 23458940 TI - Thyroglossal cysts in a pediatric population: apparent differences from adult thyroglossal cysts. AB - BACKGROUND AND OBJECTIVES: The clinical presentation of thyroglossal cyst and its variation from adult thyroglossal cyst has not been well studied. This study is to determine if the clinical presentation of thyroglossal duct cysts (TGDC) varies between children and adults and whether this affects the optimal management of individual cases. DESIGN AND SETTING: Retrospective study of all cases operated on for TGDC from February 2008 to November 2011 in a tertiary care teaching hospital. SUBJECTS AND METHODS: The gender, age, clinical presentation, radiologic imaging, surgical management, post operative complications, and recurrence rates between the children ( 18 years) were compared. RESULTS: Of the 46 patients, 30 were adults and 16 pediatric; 46.5% of the adults and 74% of the children were females (P=.11). The mean (SD) age in adults was 40.5 (16.0) years, while in children the mean (SD) age was 9.0 (1.4) years, suggesting a bimodal presentation. Hypothyroidism was present in 6.7% of the adults and 56.3% of pediatric cases (P=.0004). Twenty percent of the adults had either an infected TGDC or fistulae, but none of the children had either infection (P=.0001). In both adults and children the duration of disease was significantly shorter in females. In the pediatric group, males had a larger compared to females (P=.006). The most common location of TGDC was the infrahyoid region. The Sistrunk procedure resulted in cure with no recurrences and complications in all. CONCLUSION: TGDC is commoner in adults with no sex predilection. Children have a shorter duration of disease. Male children present with larger cysts. Hypothyroidism is more common in pediatric TGDC. Infected TGDC and fistulae are uncommon in children. The Sistrunk procedure is adequate for both groups. PMID- 23458941 TI - Celiac disease presenting as rickets in Saudi children. AB - BACKGROUND AND OBJECTIVES: Rickets is commonly seen as a sign of malabsorption like celiac disease if it is not treated appropriately with vitamin D and calcium supplements. The aim of this study was to examine the frequency of diagnosis of celiac disease among children with unexplained rickets in Saudi children at a tertiary hospital setting. DESIGN AND SETTING: Retrospective review of records of patients referred over 10 years to a pediatric gastroenterology and hepatology unit. PATIENTS AND METHODS: The study included all patients referred for evaluation of unexplained rickets and osteomalacia and screened for celiac disease. The diagnosis of rickets was made on the basis of history, physical examination, biochemical and radiological investigations. The diagnosis of celiac disease was made based on the ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) criteria. RESULTS: Twenty-six children with a mean (SD) age of 9.5 (4.6) years (5 males, range 1-15 years) were referred for evaluation of unexplained rickets and were screened for celiac disease. The diagnosis of celiac disease based on small bowel biopsy findings was confirmed in 10 (38.4%) patients with rickets. Serological markers for celiac disease including antiendomyseal antibodies and antitissue transglutaminase antibodies were positive in all ten children. CONCLUSION: Rickets is not an uncommon presentation of celiac disease in Saudi children and pediatricians should consider celiac disease as an underlying cause for rickets. PMID- 23458942 TI - Epidemiology of traumatic head injury in children and adolescents in a major trauma center in Saudi Arabia: implications for injury prevention. AB - BACKGROUND AND OBJECTIVES: Injury to the head is the most common affected body part in pediatric trauma and could be associated with deleterious consequences. It presents a challenge for developing countries since many injuries are preventable and there are few epidemiological data to support injury prevention programs. The current study aimed to determine demographic characteristics, etiology and outcome of head injury in the pediatric population and compare findings to international figures. DESIGN AND SETTINGS: Retrospective review of consecutive cases registered in major trauma center database, Riyadh, from 2001 to 2009. PATIENTS AND METHODS: The database registry was limited to hospitalized patients following injury. Any head injury in a patient <=18 years was included. RESULTS: Of 3796 patients identified, 1219 patients (32.1%) suffered head injury (mean age 8.6 years; males 78.4%). Children under 12 years comprised 66.3%. Motor vehicle crash (MVC) was the commonest cause (34.2%), followed by pedestrian injury (30.3%) and falls (28.4%). When stratified by age, falls (45.6%) were the most common etiology under 6 years while MVC was the leading cause in high school students (74.4%). The latter group had the lowest mean (SD) Glascow coma scale scores ( 8.58 [4.7]), highest mean injury severity scale scores (23.4 [21]), highest rate of craniotomy (7%) and highest mortality (20%). CONCLUSION: One third of pediatric trauma requiring hospital admission suffered head injury. Preschoolers and elementary school students were mostly affected. The striking incidence of pedestrian and fall injuries call for organized national prevention programs. Additionally, more attention should be directed to reduce MVC among high school students given their comparative high rate of severe injuries and deaths following trauma. PMID- 23458943 TI - Oxytocin ameliorates cisplatin-induced nephrotoxicity in Wistar rats. AB - BACKGROUND AND OBJECTIVES: The clinical use of cisplatin (CP) is highly limited because of its renal toxicity and the production of reactive oxygen species (ROS) that intensify the cytotoxic effects. Oxytocin (OT) was previously shown to have antioxidant activity. DESIGN AND SETTING: Experimental study on male Wistar albino rats performed in the Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia. METHODS: Forty-eight male Wistar albino rats were classified into four equal groups: a control group, OT only-treated group which received OT twice (500 micro g/kg intraperitoneally (ip) 30 minutes and just before saline administration), a CP-induced nephrotoxicity group that received a single dose of CP (7.5 mg/kg ip) and treated with saline, and CP+OT group treated with the same previous doses. Seventy-two hours after CP administration, the rats were sacrificed and blood was withdrawn for determination of urea, creatinine, albumin and lactate dehydrogenase (LDH). The kidneys were extracted for histopathological examination and determination of the tissue levels of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and nitric oxide end product nitrite (NO(2)). Glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed. RESULTS: CP-induced renal injury was evidenced histopathologically and manifested by a significant increase in serum LDH activity as well as urea and creatinine levels. Moreover, renal injury was associated with decreased renal tissue activities of CAT, SOD, GPx and GST as well as GSH level. On the other hand, renal tissue content of TBARS and NO(2) as well as the activity of MPO were increased. Alterations in these biochemical and histopathological indices due to CP were attenuated by OT. CONCLUSION: OT protected rats from CP-induced nephrotoxicity. Such protection is attributed, at least in part, to its antioxidant activity. PMID- 23458944 TI - Assessment of symptoms of menopause and their severity among Saudi women in Riyadh. AB - BACKGROUND AND OBJECTIVES: Research on menopause in Arab women is limited. The aim of our study was to assess the commonly experienced symptoms of menopause and their severity among Saudi women. DESIGN AND SETTING: A cross-sectional study conducted at King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia. PATIENTS AND METHODS: Four hundred and ninety healthy women aged 40-55 years and either attending KKUH themselves or accompanying their relatives in outpatient clinics participated in the study. The Menopause Rating Scale (MRS) was used to assess menopausal symptoms and severity. RESULTS: The mean (SD) age of the women in menopause was 47.9 (6.03) years. The most frequent symptoms were muscle and joint problems occurring in 411 women (83.9%), physical and mental exhaustion in 393 (80.2%), heart discomfort in 358 (73.1%), sleeping disorders in 349 (71.2%), hot flashes in 348 (71.0%), and irritability in 348 (71.0%); in addition, 179 (36.5%) of these women experienced severe psychological distress. Perimenopausal women had higher total and subscales scorings for somatic symptoms than did premenopausal and postmenopausal women (P=.008). CONCLUSION: The number of Saudi women reporting hot flashes and night sweats was comparable to the number of Western women. In addition, somatic symptoms were more prevalent among perimenopausal than among premenopausal women. PMID- 23458945 TI - RE: Prevalence of hepatitis C virus infection and human immunodeficiency virus in a cohort of Egyptian hemophiliac children. PMID- 23458946 TI - Reply: To PMID 22366833. PMID- 23458947 TI - Ophthalmic complications of dengue: pathogenesis and prevention. PMID- 23458948 TI - Reply: To PMID 22871625. PMID- 23458949 TI - Beading-expanded conus branch after overfilling with contrast medium. PMID- 23458950 TI - Antioxidant and anti-inflammatory meroterpenoids from the brown alga Cystoseira usneoides. AB - A chemical study of the alga Cystoseira usneoides has led to the isolation of six new meroterpenoids, cystodiones A-F (1-6), together with six known related compounds (7-12). The structures of the new metabolites have been established by spectroscopic techniques. In antioxidant assays all of the tested meroterpenes, and in particular cystodiones A (1) and B (2), 6-cis-amentadione-1'-methyl ether (7), and amentadione-1'-methyl ether (8), exhibited strong radical-scavenging activity. In anti-inflammatory assays, usneoidone Z (11) and its corresponding 6E isomer (12) showed significant activity as inhibitors of the production of the proinflammatory cytokine TNF-alpha in LPS-stimulated THP-1 human macrophages. PMID- 23458951 TI - Recapturing the art of therapeutic breast massage during breastfeeding. AB - Milk expression is a normal part of breastfeeding, but in developed countries in particular, the focus tends to center on mechanical expression. In Russia, there is a long tradition of hands-on techniques that continues in the present day and includes mothers turning to providers trained in hand expression and breast massage techniques to resolve breastfeeding complications including engorgement, plugged ducts, and mastitis. As observed over the course of several trips to Russia, Russian clinicians routinely combine hand expression with breast massage for the treatment of milk stasis, engorgement, and plugged ducts. A better understanding of these hands-on techniques to assist in resolution of complications may provide additional treatment options for the lactation community. PMID- 23458952 TI - Maternal vitamin D supplementation to meet the needs of the breastfed infant: a systematic review. AB - Maternal vitamin D insufficiency during lactation, related to lack of sun exposure and minimal intake of vitamin D from the diet, contributes to low breast milk vitamin D content and, therefore, infant vitamin D deficiency. The objective of this review was to examine the literature regarding evidence for achieving maternal vitamin D status that promotes sufficient vitamin D transfer from mother to infant exclusively from breast milk. PubMed and CINAHL databases were searched using the terms lactation or breastfeeding or milk, human and vitamin D. The resulting articles were further limited to those written in English, published within the last 10 years, and involving clinical or randomized controlled trials of humans. The search yielded 13 studies, 3 of which provide evidence for maternal intake of vitamin D and the correlation with exclusively breastfed infants' serum 25-hydroxyvitamin D level. A strong positive correlation exists between maternal vitamin D intake during exclusive breastfeeding and infant serum 25-hydroxyvitamin D levels. There is support to conclude that when maternal vitamin D intake is sufficient, vitamin D transfer via breast milk is adequate to meet infant needs. In the reviewed studies, doses up to 10 times the current recommended daily intake of vitamin D were needed to produce sufficient transfer from mother to breastfed infant. Further research is needed to refine the dose and gestational timing of maternal vitamin D supplementation. Due to the high rates of vitamin D deficiency during lactation and the correlations between vitamin D deficiency and multiple diseases, providers should consider monitoring lactating mothers' vitamin D status. PMID- 23458953 TI - Impact of influenza A(H1N1)pdm09 virus on circulation dynamics of seasonal influenza strains in Kenya. AB - We describe virus variations from patients with influenza-like illness before and after the appearance of influenza A(H1N1)pdm09 in Kenya during January 2008-July 2011. A total of 11,592 nasopharyngeal swabs were collected from consenting patients. Seasonal influenza B, A/H1N1, A/H3N2, A/H5N1, and influenza A(H1N1)pdm09 viruses were detected by real-time reverse transcription-polymerase chain reaction. Of patients enrolled, 2073 (17.9%) had influenza. A total of 1,524 (73.4%) of 2,073 samples were positive for influenza A virus and 549 (26.6%) were positive for influenza B virus. Influenza B virus predominated in 2008 and seasonal A(H1N1) virus predominated in the first half of 2009. Influenza A(H1N1)pdm09 virus predominated in the second half of 2009. Influenza A/H3N2 virus predominated in 2010, and co-circulation of influenza A(H1N1)pdm09 virus and influenza B virus predominated the first half of 2011. The reduction and displacement of seasonal A(H1N1) virus was the most obvious effect of the arrival of influenza A(H1N1)pdm09 virus. The decision of the World Health Organization to replace seasonal A(H1N1) virus with the pandemic virus strain for the southern hemisphere vaccine was appropriate for Kenya. PMID- 23458954 TI - Optimization and validation of a plaque reduction neutralization test for the detection of neutralizing antibodies to four serotypes of dengue virus used in support of dengue vaccine development. AB - A dengue plaque reduction neutralization test (PRNT) to measure dengue serotype specific neutralizing antibodies for all four virus serotypes was developed, optimized, and validated in accordance with guidelines for validation of bioanalytical test methods using human serum samples from dengue-infected persons and persons receiving a dengue vaccine candidate. Production and characterization of dengue challenge viruses used in the assay was standardized. Once virus stocks were characterized, the dengue PRNT(50) for each of the four serotypes was optimized according to a factorial design of experiments approach for critical test parameters, including days of cell seeding before testing, percentage of overlay carboxymethylcellulose medium, and days of incubation post-infection to generate a robust assay. The PRNT(50) was then validated and demonstrated to be suitable to detect and measure dengue serotype-specific neutralizing antibodies in human serum samples with acceptable intra-assay and inter-assay precision, accuracy/dilutability, specificity, and with a lower limit of quantitation of 10. PMID- 23458955 TI - Molecular epidemiology of Blastocystis in Lebanon and correlation between subtype 1 and gastrointestinal symptoms. AB - Blastocystis is the most common eukaryotic parasite in the intestinal tract of humans. Because of its potential impact in public health, we acquired the first data concerning the prevalence of this parasite and the frequency of the Blastocystis subtypes (STs) in the Lebanese population. In this study, fecal samples from 220 Lebanese symptomatic and asymptomatic patients were collected and a total of 42 patients (19%) were identified as positive for this parasite by direct-light microscopy of smears. Among these, 36 Blastocystis isolates were genotyped using partial small subunit ribosomal RNA gene sequencing. The ST distribution in the present Lebanese population was as follows: ST3 (33.3%), ST2 (33.3%), ST1 (30.6%), and ST4 (2.8%). These data were compared with those available in other Middle Eastern and neighboring countries. Finally, ST1 was significantly more prevalent among symptomatic patients of this Lebanese population. PMID- 23458956 TI - The effect of indoor residual spraying on malaria and anemia in a high transmission area of northern Uganda. AB - Indoor residual spraying (IRS) with insecticide is now recommended for malaria control in high-transmission settings. However, concerns about insecticide resistance have increased. We conducted a cross-sectional household survey in high-transmission northern Uganda in two districts previously sprayed with pyrethroids before documentation of pyrethroid resistance and at least one round of carbamates and in one contiguous district that was not sprayed. Parasitemia prevalence among children < 5 years of age was lower in the two IRS districts compared with the non-sprayed district: 37.0% and 16.7% versus 49.8%, P < 0.001. Anemia prevalence was also significantly lower in the two IRS districts: 38.8% and 36.8% versus 53.0%, P < 0.001. Multivariable Poisson regression models indicated that a child living in a sprayed district had a 46% and 32% lower risk of parasitemia and anemia, respectively, than a child in a non-sprayed district (P < 0.001). Carefully managed IRS can significantly reduce malaria burden in high-transmission settings. PMID- 23458957 TI - Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras. AB - Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras. PMID- 23458958 TI - Risk factors for the presence of Aedes aegypti and Aedes albopictus in domestic water-holding containers in areas impacted by the Nam Theun 2 hydroelectric project, Laos. AB - We assessed risk factors for vectors of dengue and chikungunya viruses near a new hydroelectric project, Nam Theun 2, in Laos. Immature stages of Aedes aegypti were found only in sites within 40 km of the urban provincial capital, but Aedes albopictus was found throughout. Aedes aegypti pupae were most common in water storage jars (odds ratio [OR] = 4.72) and tires (OR = 2.99), and Ae. albopictus pupae were associated with tires in 2009 (OR = 10.87) and drums, tires, and jars in 2010 (drums OR = 3.05; tires OR = 3.45, jars OR = 6.59). Compared with water storage vessels, containers used for hygiene, cooking, and drinking were 80% less likely to harbor Ae. albopictus pupae in 2010 (OR = 0.20), and discarded waste was associated with a 3.64 increased odds of infestation. Vector control efforts should focus on source reduction of water storage containers, particularly concrete jars and tires. PMID- 23458959 TI - Impact of indoor residual spraying of lambda-cyhalothrin on malaria prevalence and anemia in an epidemic-prone district of Muleba, north-western Tanzania. AB - The Government of Tanzania introduced indoor residual spraying (IRS) in Muleba district in north-western Tanzania after frequent malaria epidemics. Malaria parasitological baseline and two cross-sectional follow-up surveys were conducted in villages under the IRS program and those not under IRS to assess the impact of IRS intervention. After two rounds of IRS intervention there was a significant reduction of malaria parasitological indices in both two villages. In IRS villages overall, parasitemia prevalence was reduced by 67.2%, splenomegaly was reduced by 75.8%, whereas anemia was reduced by 50.5%. There was also a decline of malaria parasite density from 896.4 at baseline to 128.8 at second follow-up survey. Similarly, there was also a reduction of malaria parasitological indices in non-IRS villages; however, parasitological indices in IRS villages remained far below the levels in non-IRS villages. The reduction of malaria parasitological indices in non-IRS villages might have been contributed by interventions other than IRS. PMID- 23458960 TI - Molecular and biological diagnostic tests for monitoring benzimidazole resistance in human soil-transmitted helminths. AB - In endemic countries with soil-transmitted helminths mass drug administration with albendazole or mebendazole are being implemented as a control strategy. However, it is well known in veterinary helminths that the use of the same benzimidazole drugs can place selection on the beta-tubulin gene, leading to resistance. Given the concern that resistance could arise in human soil transmitted helminths, there is an urgent need to develop accurate diagnostic tools for monitoring resistance. In this study, we developed molecular assays to detect putative resistance genetic changes in Ascaris lumbricoides, Trichuris trichiura, and hookworms, and we optimized an egg hatch assay for the canine hookworm Ancylostoma caninum and applied it to Necator americanus. Both assays were tested on field samples. The molecular assays demonstrated their reproducibility and capacity to detect the presence of worms carrying putative resistance-associated genetic changes. However, further investigations are needed to validate our molecular and biological tests on additional field isolates. PMID- 23458962 TI - Adipose-derived stem cells: fatty potentials for therapy. AB - Adipose-derived stem cells (ASCs) are the mesenchymal stem cell (MSC) population found in the stromal-vascular fraction (SVF) of fat tissue. White adipose tissue (WAT), with well-established roles in lipid storage and adipokine secretion, is advantageous over bone marrow as the source of MSCs due to relative abundance and ease of isolation of the tissue. ASCs reside perivascularly within WAT and physiologically undergo adipogenesis to support WAT expansion in response to increased energy intake. Apart from adipogenesis, ASCs can be induced in vitro to differentiate into osteoblasts, chondroblasts, myocytes, neurons and other cell types. ASCs can also be reprogrammed to induced pluripotent stem (iPS) cells more efficiently than other cell types. ASCs are immunoprivileged cells and secrete immunomodulatory, angiogenic, anti-apoptotic and haematopoietic factors that facilitate tissue repair. The multi-lineage differentiation capacity, unique immunobiological properties and secretome of ASCs offer tremendous therapeutic potentials in regenerative medicine. PMID- 23458961 TI - Travel characteristics and yellow fever vaccine usage among US Global TravEpiNet travelers visiting countries with risk of yellow fever virus transmission, 2009 2011. AB - Yellow fever (YF) vaccine-associated serious adverse events and changing YF epidemiology have challenged healthcare providers to vaccinate only travelers whose risk of YF during travel is greater than their risk of adverse events. We describe the travel characteristics and YF vaccine use among US travelers visiting Global TravEpiNet clinics from January of 2009 to March of 2011. Of 16,660 travelers, 5,588 (34%) had itineraries to areas with risk of YF virus transmission. Of those travelers visiting one country with YF risk (N = 4,517), 71% were vaccinated at the visit, and 20% were presumed to be immune from prior vaccination. However, travelers visiting friends and relatives (odds ratio [OR] = 2.57, 95% confidence interval [95% CI] = 1.27-5.22) or going to Nigeria (OR = 3.01, 95% CI = 1.37-6.62) were significantly more likely to decline vaccination. To optimize YF vaccine use, clinicians should discuss an individual's risk benefit assessment of vaccination and close knowledge gaps regarding vaccine use among at-risk populations. PMID- 23458963 TI - Li-gazing at the crest: modulation of the neural crest by the ubiquitin pathway. AB - Neural crest cells are a transient population of stem cells that give rise to a diverse range of cell types during embryonic development. Through gain-of function and loss-of-function studies in several model organisms many key signalling pathways and cell-type specific transcription factors essential for neural crest cell development have been identified. However, the role of post translational regulation remains largely unexplored. Here we review this cell type with a foray into the known and potential roles of the ubiquitination pathway in key signalling events during neural crest cell development. PMID- 23458964 TI - Effect of zinc supplementation on acetone-butanol-ethanol fermentation by Clostridium acetobutylicum. AB - In this article, effect of zinc supplementation on acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum was studied. It was found that when 0.001 g/L ZnSO4.7H2O was supplemented into the medium, solventogenesis was initiated earlier, with 21.0 g/L ABE (12.6 g/L butanol, 6.7 g/L acetone and 1.7 g/L ethanol) produced with a fermentation time of 40 h, compared to 19.4 g/L ABE (11.7 g/L butanol, 6.4 g/L acetone and 1.3g/L ethanol) produced with a fermentation time of 64 h in the control without zinc supplementation, and correspondingly ABE and butanol productivities were increased to 0.53 and 0.32 g/L/h from 0.30 and 0.18 g/L/h, increases of 76.7% and 77.8%, respectively, but their yields were not compromised. The reason for this phenomenon was attributed to rapid acids re-assimilation for more efficient ABE production, which was in accordance with relatively high pH and ORP levels maintained during the fermentation process. The maximum cell density increased by 23.8%, indicating that zinc supplementation stimulated cell growth, and consequently facilitated glucose utilization. However, more zinc supplementation exhibited an inhibitory effect, indicating that zinc supplementation at very low levels such as 0.001 g/L ZnSO4.7H2O will be an economically competitive strategy for improving butanol production. PMID- 23458965 TI - Utility of temporally distinct baculovirus promoters for constitutive and baculovirus-inducible transgene expression in transformed insect cells. AB - Genetically transformed lepidopteran insect cell lines have biotechnological applications as constitutive recombinant protein production platforms and improved hosts for baculovirus-mediated recombinant protein production. Insect cell transformation is often accomplished with a DNA construct(s) encoding a foreign protein(s) under the transcriptional control of a baculovirus immediate early promoter, such as the ie1 promoter. However, the potential utility of increasingly stronger promoters from later baculovirus gene classes, such as delayed early (39K), late (p6.9), and very late (polh), has not been systematically assessed. Hence, we produced DNA constructs encoding secreted alkaline phosphatase (SEAP) under the transcriptional control of each of the four temporally distinct classes of baculovirus promoters, used them to transform insect cells, and compared the levels of SEAP RNA and protein production obtained before and after baculovirus infection. The ie1 construct was the only one that supported SEAP protein production by transformed insect cells prior to baculovirus infection, confirming that only immediate early promoters can be used to isolate transformed insect cells for constitutive recombinant protein production. However, baculovirus infection activated transgene expression by all four classes of baculovirus promoters. After infection, cells transformed with the very late (polh) and late (p6.9) promoter constructs produced the highest levels of SEAP RNA, but only low levels of SEAP protein. Conversely, cells transformed with the immediate early (ie1) and delayed early (39K) promoter constructs produced lower levels of RNA, but equal or higher levels of SEAP protein. Unexpectedly, the 39K promoter construct provided tightly regulated, baculovirus-inducible protein production at higher levels than the later promoter constructs. Thus, this study demonstrated the utility of the 39K promoter for insect cell engineering, particularly when one requires higher levels of effector protein production than obtained with ie1 and/or when constitutive transgene expression adversely impacts host cell fitness and/or genetic stability. PMID- 23458966 TI - Zinc oxide nanoparticle induced autophagic cell death and mitochondrial damage via reactive oxygen species generation. AB - Zinc oxide nanoparticles (ZnO-np) are used in an increasing number of industrial products such as paint, coating and cosmetics, and in other biological applications. There have been many suggestions of a ZnO-np toxicity paradigm but the underlying molecular mechanisms about the toxicity of ZnO-np remain unclear. This study was done to determine the potential toxicity of ZnO-np and to assess the toxicity mechanism in normal skin cells. Synthesized ZnO-np generated reactive oxygen species (ROS), as determined by electron spin resonance. After uptake into cells, ZnO-np induced ROS in a concentration- and time-dependent manner. To demonstrate ZnO-np toxicity mechanism related to ROS, we detected abnormal autophagic vacuoles accumulation and mitochondria dysfunction after ZnO np treatment. Furthermore mitochondria membrane potential and adenosine-5' triphosphate (ATP) production are decreased for culture with ZnO-np. We conclude that ZnO-np leads to cell death through autophagic vacuole accumulation and mitochondria damage in normal skin cells via ROS induction. Accordingly, ZnO-np may cause toxicity and the results highlight and need for careful regulation of ZnO-np production and use. PMID- 23458967 TI - Artificial neural network analysis of data from multiple in vitro assays for prediction of skin sensitization potency of chemicals. AB - In order to develop in vitro risk assessment systems for skin sensitization, it is important to predict a threshold from the murine local lymph node assay (LLNA). We first confirmed that the combination of the human Cell Line Activation Test (h-CLAT) and the SH test improved the accuracy and sensitivity of prediction of LLNA data compared with each individual test. Next, we assessed the mutual correlations among maximum amount of change of cell-surface thiols (MAC value) in the SH test, CV75 value (concentration giving 75% cell viability) in a cytotoxicity assay, EC150 and EC200 values (thresholds concentrations of CD86 and CD54 expression, respectively) in h-CLAT and published LLNA thresholds of 64 chemicals. Based on the results, we selected MAC value and the minimum of CV75, EC150 (CD86) and EC200 (CD54) as descriptors for the input layer of an artificial neural network (ANN) system. The ANN-predicted values were well correlated with reported LLNA thresholds. We also found a correlation between the SH test and the peptide-binding assay used to evaluate hapten-protein complex formation. Thus, this model, which we designate as the "iSENS ver. 1", may be useful for risk assessment of skin sensitization potential of chemicals from in vitro test data. PMID- 23458968 TI - Methylglyoxal induces DNA crosslinks in ECV304 cells via a reactive oxygen species-independent protein carbonylation pathway. AB - Methylglyoxal (MG) is a reactive dicarbonyl compound that is produced endogenously from glycolytic intermediates and via gluconeogenesis. Elevated MG levels in diabetes patients are believed to cause diabetic complications. MG induced crosslinking products from the covalent binding of DNA or protein alone or together could be relevant to carcinogenesis and multiple complications in diabetes. However, the mechanisms governing DNA crosslink formation by MG are unclear. We investigated whether MG could induce DNA crosslinks in human ECV304 cells and the possible mechanism of this action. The level of DNA crosslinks and reactive oxygen species production were assayed by a modified alkaline Comet assay and a 2',7' dichlorofluorescin diacetate (DCHF-DA) assay, respectively. MG caused a time- and dose-dependent increase in DNA crosslinks and a dose-dependent increase in protein carbonylation in ECV304 cells. Addition of 2mM MG resulted in a transient increase in protein carbonylation, and this increase peaked within 2h and then rapidly decreased. Most notably, MG did not cause significantly enhanced ROS generation in ECV304 cells. Co-treatment with carbonyl-scavenging drugs, such as aminoguanidine, N-acetyl-L-cysteine, and glutathione, significantly inhibited the formation of DNA crosslinks by MG, whereas co-treatment with the antioxidant ascorbic acid did not. In conclusion, our results imply that MG induces DNA crosslink formation in ECV304 cells via a reactive oxygen species-independent protein carbonylation pathway. Our findings also suggest that non-toxic aminothiol antioxidants with carbonyl scavenging capabilities are potential therapeutic agent for MG-related diseases, such as diabetes and neurodegeneration. Furthermore, our findings also imply that DNA nonbinding proteins, bovine serum albumin might be able to crosslink calf thymus DNA in the presence of MG. PMID- 23458969 TI - Macro Monte Carlo for dose calculation of proton beams. AB - Although the Monte Carlo (MC) method allows accurate dose calculation for proton radiotherapy, its usage is limited due to long computing time. In order to gain efficiency, a new macro MC (MMC) technique for proton dose calculations has been developed. The basic principle of the MMC transport is a local to global MC approach. The local simulations using GEANT4 consist of mono-energetic proton pencil beams impinging perpendicularly on slabs of different thicknesses and different materials (water, air, lung, adipose, muscle, spongiosa, cortical bone). During the local simulation multiple scattering, ionization as well as elastic and inelastic interactions have been taken into account and the physical characteristics such as lateral displacement, direction distributions and energy loss have been scored for primary and secondary particles. The scored data from appropriate slabs is then used for the stepwise transport of the protons in the MMC simulation while calculating the energy loss along the path between entrance and exit position. Additionally, based on local simulations the radiation transport of neutrons and the generated ions are included into the MMC simulations for the dose calculations. In order to validate the MMC transport, calculated dose distributions using the MMC transport and GEANT4 have been compared for different mono-energetic proton pencil beams impinging on different phantoms including homogeneous and inhomogeneous situations as well as on a patient CT scan. The agreement of calculated integral depth dose curves is better than 1% or 1 mm for all pencil beams and phantoms considered. For the dose profiles the agreement is within 1% or 1 mm in all phantoms for all energies and depths. The comparison of the dose distribution calculated using either GEANT4 or MMC in the patient also shows an agreement of within 1% or 1 mm. The efficiency of MMC is up to 200 times higher than for GEANT4. The very good level of agreement in the dose comparisons demonstrate that the newly developed MMC transport results in very accurate and efficient dose calculations for proton beams. PMID- 23458971 TI - Alzheimer disease: BIN1 variant increases risk of Alzheimer disease through tau. PMID- 23458970 TI - Communication between remote moieties in linear Ru-Ru-Ru trimetallic cyanide bridged complexes. AB - In this article, we report the structural, spectroscopic, and electrochemical properties of the cyanide-bridged complex salts trans-[(NC)Ru(II)(L)4(MU CN)Ru(II)(py)4Cl]PF6 and trans-[Ru(II)(L)4{(MU-CN)Ru(II)(py)4Cl}2](PF6)2 (L = pyridine or 4-methoxypyridine). The mixed-valence forms of these compounds show a variety of metal-to-metal charge-transfer bands, including one arising from charge transfer between the remote ruthenium units. The latter is more intense when L = 4-methoxypyridine and points to the role of the bridging ruthenium unit in promoting mixing between the dpi orbitals of the terminal fragments. PMID- 23458972 TI - Neuroimmunology: Treatment of anti-NMDA receptor encephalitis--time to be bold? PMID- 23458974 TI - Parkinson disease: Unravelling the genetic contributors and their functional roles in sporadic PD. PMID- 23458975 TI - Tissue-type plasminogen activator and plasminogen embedded in casein rule its degradation under physiological situations: manipulation with casein hydrolysate. AB - The aims of this study were to test the assumption that tissue-type plasminogen activator (t-PA) and plasminogen (PG) are closely associated with the casein micelle and form a functional complex that rules casein degradation. This assumption was essentially verified for bovine milk under conditions wherein the plasmin system was activated by treatment with casein hydrolysate. It was also shown that urokinase-type PA (u-PA), the second type of plasminogen activator present in milk, was not involved in casein degradation. In agreement with previous studies, we show that treatment with casein hydrolysate precipitously reduced mammary secretion, disrupted the tight junction integrity (increase in Na+ and decrease in K+ concentrations), induced hydrolysis of casein, and activated various elements of the innate and acquired immune system. In the present study, we have identified t-PA as the principal PA, which is responsible for the conversion of PG to plasmin. It was found that t-PA and plasminogen are present in freshly secreted milk (less than 10 min from its secretion), suggesting that they are secreted as a complex by the mammary gland epithelial cells. Further research is needed to provide the direct evidence to verify this concept. PMID- 23458973 TI - Chronic neuropathologies of single and repetitive TBI: substrates of dementia? AB - Traumatic brain injury (TBI) has long been recognized to be a risk factor for dementia. This association has, however, only recently gained widespread attention through the increased awareness of 'chronic traumatic encephalopathy' (CTE) in athletes exposed to repetitive head injury. Originally termed 'dementia pugilistica' and linked to a career in boxing, descriptions of the neuropathological features of CTE include brain atrophy, cavum septum pellucidum, and amyloid-beta, tau and TDP-43 pathologies, many of which might contribute to clinical syndromes of cognitive impairment. Similar chronic pathologies are also commonly found years after just a single moderate to severe TBI. However, little consensus currently exists on specific features of these post-TBI syndromes that might permit their confident clinical and/or pathological diagnosis. Moreover, the mechanisms contributing to neurodegeneration following TBI largely remain unknown. Here, we review the current literature and controversies in the study of chronic neuropathological changes after TBI. PMID- 23458976 TI - Comparison of ultra-widefield fluorescein angiography with the Heidelberg Spectralis((r)) noncontact ultra-widefield module versus the Optos((r)) Optomap((r)). AB - PURPOSE: To compare ultra-widefield fluorescein angiography imaging using the Optos((r)) Optomap((r)) and the Heidelberg Spectralis((r)) noncontact ultra widefield module. METHODS: Five patients (ten eyes) underwent ultra-widefield fluorescein angiography using the Optos((r)) panoramic P200Tx imaging system and the noncontact ultra-widefield module in the Heidelberg Spectralis((r)) HRA+OCT system. The images were obtained as a single, nonsteered shot centered on the macula. The area of imaged retina was outlined and quantified using Adobe((r)) Photoshop((r)) C5 software. The total area and area within each of four visualized quadrants was calculated and compared between the two imaging modalities. Three masked reviewers also evaluated each quadrant per eye (40 total quadrants) to determine which modality imaged the retinal vasculature most peripherally. RESULTS: Optos((r)) imaging captured a total retinal area averaging 151,362 pixels, ranging from 116,998 to 205,833 pixels, while the area captured using the Heidelberg Spectralis((r)) was 101,786 pixels, ranging from 73,424 to 116,319 (P = 0.0002). The average area per individual quadrant imaged by Optos((r)) versus the Heidelberg Spectralis((r)) superiorly was 32,373 vs 32,789 pixels, respectively (P = 0.91), inferiorly was 24,665 vs 26,117 pixels, respectively (P = 0.71), temporally was 47,948 vs 20,645 pixels, respectively (P = 0.0001), and nasally was 46,374 vs 22,234 pixels, respectively (P = 0.0001). The Heidelberg Spectralis((r)) was able to image the superior and inferior retinal vasculature to a more distal point than was the Optos((r)), in nine of ten eyes (18 of 20 quadrants). The Optos((r)) was able to image the nasal and temporal retinal vasculature to a more distal point than was the Heidelberg Spectralis((r)), in ten of ten eyes (20 of 20 quadrants). CONCLUSION: The ultra widefield fluorescein angiography obtained with the Optos((r)) and Heidelberg Spectralis((r)) ultra-widefield imaging systems are both excellent modalities that provide views of the peripheral retina. On a single nonsteered image, the Optos((r)) Optomap((r)) covered a significantly larger total retinal surface area, with greater image variability, than did the Heidelberg Spectralis((r)) ultra-widefield module. The Optos((r)) captured an appreciably wider view of the retina temporally and nasally, albeit with peripheral distortion, while the ultra widefield Heidelberg Spectralis((r)) module was able to image the superior and inferior retinal vasculature more peripherally. The clinical significance of these findings as well as the area imaged on steered montaged images remains to be determined. PMID- 23458977 TI - Refractive changes from hyperopic orthokeratology monovision in presbyopes. AB - PURPOSE: To investigate the time course of refractive and corneal topographic changes in overnight hyperopic orthokeratology (OK) for emmetropic presbyopes. METHODS: Sixteen adult emmetropic presbyopic subjects were fitted with rigid hyperopic OK lenses (BE Enterprises, Brisbane, Australia/Capricornia, Slacks Creek, Australia) targeted to correct +2.00 D, in one eye only. The fellow eye acted as a non-lens-wearing control. Thirteen subjects completed the study. Lenses were worn overnight for a 7-day period, and changes in subjective refraction and corneal topography were measured in the morning on lens removal (A.M.) and 8 hr after lens removal (P.M.). RESULTS: There were statistically significant changes from baseline in all variables at all visits in lens-wearing eyes. Hyperopic OK caused a -1.00 (0.33) D shift in best vision sphere refraction at Day1 A.M., and -1.11 (0.61) D, at Day7 A.M., with -0.91 D of best vision sphere change from baseline still apparent by Day7 P.M. (mean [SD]). This led to an improvement in monocular near visual acuity (VA) from Jaeger 10.8 (2.4) at baseline to Jaeger 4.6 (2.5) at Day1 A.M., Jaeger 3.2 (2.3) at Day7 A.M., and Jaeger 3.9 (3.0) at Day7 P.M. Binocular distance VA did not change from baseline. The central cornea steepened, and the mid-peripheral nasal cornea flattened at lens removal after one night of wear. There was no significant difference in central corneal steepening between A.M. visits, but there was longer retention of effect by Day7 P.M. Nasal paracentral corneal flattening also showed a greater effect and longer retention of effect by Day7. CONCLUSIONS: Hyperopic OK induced central corneal steepening and paracentral corneal flattening, which led to a monovision myopic shift in refraction that was sufficient to provide functional correction of near vision. Lack of change in binocular distance VA indicates that hyperopic OK offers a viable option for providing monovision correction in emmetropic presbyopia. PMID- 23458978 TI - Myopization factors affecting urban elementary school students in Taiwan. AB - PURPOSE: To investigate factors that may contribute to the myopization of urban elementary school students in Taiwan. METHODS: Grades 1 to 6 students of the same racial background (n = 1894; mean age, 6.3-11.3 years) in three schools, located in Tamsui, Taichung, and Tainan, were refracted to obtain the best corrected visual acuity. The refractive power needed for best corrected visual acuity was used for subsequent statistical analysis. On behalf of their children, parents also completed a questionnaire on six categories of potential myopization variables. Correlation between these variables and the increase or decrease in the refractive error was assessed. The predictive value of each variable was also calculated based on linear regression analysis. RESULTS: The overall mean refractive error in grades 1 to 6 was -0.37, -0.68, -1.33, -1.60, -1.90, and 2.51 D, respectively. The prevalence of myopia (-1.00 D or more minus) showed a significant difference between grades 2 and 3 and, again, between grades 5 and 6. In addition, 20 potential modulating factors were evaluated; 65.9% of the change in the refractive error could be explained by four: (1) lag in optimal correction, defined as a -1.00-D deficit between new refractive error and current optical correction; (2) outdoor spectacle wear; (3) spectacles for different working distances; and (4) hours spent on reading and writing on weekdays. In contrast, outdoor time and the intake frequency of 36 food items both held very low predictive values of 0.2% and 2.5%, respectively. CONCLUSIONS: Each variable associated with the refractive error has a different predictive value, either positive or negative. Ultimately, the interplay of these variables decides the outcome of the pattern and the degree of school myopia. PMID- 23458979 TI - Relation between uncorrected astigmatism and visual acuity in pseudophakia. AB - PURPOSE.: The end point of astigmatic correction after cataract surgery will depend on how uncorrected astigmatism impacts distance and near vision of pseudophakic eyes. This study determined the impact of induced astigmatism and pupil size on the distance and near acuity of otherwise emmetropic pseudophakic eyes implanted with monofocal intraocular lenses. METHODS.: Monocular high contrast distance (4 m) and near (40 cm) logMAR acuity was determined in 15 subjects (mean +/- 1 SD, 57.9 +/- 9.0 years) without astigmatism and with 2.5 diopters (D) myopic to 2.0 D hyperopic astigmatic lenses induced in 0.5-D steps at 0-, 45-, 90-, and 135-degree axes. This experiment was repeated for the same range of induced astigmatism with 1.5-, 3-, and 6-mm artificial pupil diameters placed before one eye of 10 subjects dilated with 10% phenylephrine HCl. RESULTS.: Distance acuity deteriorated with astigmatism for all axes tested (p < 0.01). Near acuity deteriorated with hyperopic astigmatism (p < 0.1), whereas it improved with up to 1 D of myopic astigmatism before saturating for all axes tested (p < 0.01). Distance and near acuity improved with a reduction in pupil diameter (p < 0.01). The change in distance and near acuity with induced astigmatism was smaller for 1.5-mm than for 3-mm and 6-mm pupil diameters (p < 0.01). CONCLUSIONS.: Partial restoration of near acuity with uncorrected myopic astigmatism comes with a proportional loss of distance acuity in pseudophakic eyes. Uncorrected myopic astigmatism more than 1 D results in a large loss of distance acuity at no additional benefit to near acuity. Both distance and near acuities with and without astigmatism are benefited with a reduction in pupil diameter. Uncorrected hyperopic astigmatism results in deterioration of both distance and near acuities of pseudophakic eyes. PMID- 23458980 TI - Compliance with lens replacement and the interval between eye examinations. AB - PURPOSE: Eye care practitioners (ECPs) acknowledge that their patients do not always follow recommendations for lens replacement, but many may not realize the possible implications for their offices. The study was conducted to investigate whether there is a relationship between contact lens compliance and the interval between full eye examinations (IEE). METHODS: The study was conducted in ECP offices in the United States. Eye care practitioners and patients independently completed linked questionnaires, evaluating their contact lens wear and care. Patients were required to be current wearers of daily disposable (DD) lenses or reusable silicone hydrogel lenses with a manufacturer-recommended replacement frequency (MRRF) of 2 weeks (2WR) or 1 month (1MR). RESULTS: A total of 2147 questionnaires from 141 offices were eligible. Fifty-four percent of patients were wearing 2WR, 37% 1MR, and 9% DD lenses. Wearers of 2WR lenses were significantly less compliant with replacement than wearers of both DD and 1MR lenses (34% vs. 74% and 67%, both p < 0.001); patients purchasing an annual supply were more compliant (55% vs. 45%, p < 0.001). The mean IEE was 16 months and was longer for wearers who were noncompliant with the MRRF (17.4 months vs. 14.5 months, p < 0.001). Other factors affecting IEE were household income (p = 0.030), insurance (p < 0.001), purchase source (p < 0.001), and sex (p = 0.007). CONCLUSIONS: Patients who were not compliant with the MRRF had longer IEEs and were less likely to purchase an annual supply of lenses. Patients who purchased lenses from their ECP, had a higher household income, had eye examination insurance, and were female had shorter IEEs. Patients failing to replace their lenses when scheduled were also found to be less compliant with lens care procedures. Eye care practitioners should reinforce the importance of all aspects of lens wear and care with their patients, with the overall aim of reducing possible complications and retaining successful contact lens wearers in their offices. PMID- 23458981 TI - Template-based correction of high-order aberration in keratoconus. AB - PURPOSE: The common change in corneal morphology that is seen in keratoconus (KC) suggests the presence of common high-order aberration (HOA) structures and the potential for HOA corrections that apply to more than one eye. The purpose of this investigation is to classify a sample of KC eyes into subgroups based on similar HOA characteristics and simulate optical performance of common HOA corrections on members of each subgroup. METHODS: High-order aberrations were recorded over a 5-mm pupil on 111 KC eyes. The eyes were divided into five subgroups based on observed commonality in HOA structure. From each subgroup, two eyes were removed for later evaluation of corrections. Principal components analysis was performed on the remaining eyes of each subgroup. The first principal component was scaled to form a set of corrections. Simulated optical correction of the test eyes was performed by identifying the magnitude of the inner-group correction providing the lowest level of residual higher order root mean square wavefront error (HORMS). Residual uncorrected HORMS was compared with levels found in uncorrected normal eyes and KC eyes wearing rigid gas-permeable corrections. RESULTS: Ninety (81%) of the 111 eyes were included in one of the five subgroups. All 10 test eyes experienced a reduction in HORMS with a template correction compared with their uncorrected levels. Median HORMS reduced from uncorrected levels of 2.14 to 0.97 MUm. On average, the 10 subjects experienced a 51% reduction in HORMS (minimum, 16%; maximum, 81%; p < 0.01). When scaled to a 4 mm pupil, five of the 10 eyes experienced residual uncorrected HORMS within limits associated with gas-permeable wear. CONCLUSIONS: Overlap exists across these templates because of the dominance of vertical coma in the HOA structure. All eyes evaluated received reduced HORMS with a template-based correction. PMID- 23458982 TI - [Site-specific colorectal cancer; how is it different?]. AB - One of the most critical characteristics of colorectal cancer (CRC) is the difference between proximal (right-sided colon cancer, RCC) and distal (left sided colon cancer, LCC) disease. The recent CRC studies showed the unique characteristics of RCC; RCCs were more prevalent in women than men and old patients, and the age difference between RCC and LCC was more apparent in women. Moreover, relatively poor protection against RCC by colonoscopy is a clearly hot issue for alarm. Thus, the left and right colon have been considered as dichotomous or even different organs in the view of molecular, histopathological, epidemiologic and clinical bases for over three decades. However, the evolutionary data suggesting linearity from the rectum to ascending colon beyond the simple right-left dichotomization in the views of cancer molecular features and site-specific clinicopathological differences, support the need for a paradigm shift to the colorectal continuum model rather than the traditional two colon concept. This new multi-segmental or colorectal continuum hypothesis would provide both the better understanding of the complex etiology of colorectal carcinogenesis and the tailored preventive and therapeutic strategies for CRC including individualized CRC screening programs. PMID- 23458983 TI - [Clinicopathologic feature of esophageal submucosal tumors treated by surgical approach]. AB - BACKGROUND/AIMS: Submucosal tumors of the esophagus are rare lesions among all esophageal neoplasms. The purpose of this study was to evaluate the clinicopathologic features of esophageal submucosal tumors treated by surgical approach. METHODS: We analyzed the clinicopathologic and endoscopic ultrasonographic features of 18 esophageal submucosal tumors which were treated by surgical approach at Boramae Medical Center and Seoul National University Bundang Hospital from January 2005 to June 2012. RESULTS: The mean age was 48.9 years old and male to female ratio was 2.6 : 1. Asymptomatic patients were most common (77.8%). In endoscopic ultrasonographic finding, the majority tumor arouse in the middle (55.6%) and lower (44.4%) esophagus, and appeared as hypoechoic lesion (72.2%) in the 4th layer (83.3%). The most common indication for surgical approach was unclear biological behavior of the tumor. Minimally-invasive technique using thoracoscopy was applied for the enucleation (83.3%). The mean diameter of the tumor was 5.4 cm, and the final diagnosis was leiomyoma (89.9%) and gastrointestinal stromal tumor (11.1%). CONCLUSIONS: Leiomyoma was the most common submucosal tumor in esophagus. However, endoscopic ultrasonography was not able to differentiate between leiomyoma and gastrointesinal stromal tumor. For more accurate diagnosis and treatment, minimally-invasive approaches may be suitable for the surgical enucleation of indicated esophageal submucosal tumor. PMID- 23458984 TI - [Clinical characteristics and treatment outcome of colonic diverticulitis in young patients]. AB - BACKGROUND/AIMS: The clinical course and the most appropriate management of colonic diverticulitis in young patients are currently unresolved. This retrospective study was designed to compare young patients (<=40 years) with older patients (>40 years) regarding clinical characteristics of acute colonic diverticulitis and to determine whether differences exist in treatment outcome. METHODS: Three-hundred sixty eight patients presenting with acute colonic diverticulitis from March 2001 through April 2011 at Ewha Womans University Mokdong Hospital were reviewed retrospectively. The differences in clinical characteristics, treatment modality and recurrence between each group were analyzed. RESULTS: Two-hundred and six patients were aged 40 years or younger and 162 patients were older than 40 years. The older group was diagnosed more frequently with severe diverticulitis. Surgical treatment was significantly more frequent in the older group than in the younger group (15.4% vs. 4.4%, p<0.001). No significant difference was found in preatment modality between the two groups in patients with recurrence. The difference in recurrence between groups was not statistically significant. In multivariate analysis, left colonic diverticulitis was significantly associated with severe diverticulitis (OR, 14.651; 95% CI, 4.829-44.457) and emergency surgery (OR, 13.745; 95% CI, 4.390-43.031). CONCLUSIONS: When patients with colonic diverticulitis are treated conservatively, young age is no longer an independent risk factor for subsequent poor outcome. Diverticulitis in young patients does not have a particularly aggressive or fulminant course. Therefore, we recommend that diverticulitis management should be based on the severity and location of the disease, and not on the age of the patient. PMID- 23458985 TI - Prognostic significance of Ki-67 expression in rectal carcinoid tumors. AB - BACKGROUND/AIMS: Rectal carcinoid tumors can be resected with endoscopy, and it is important to assess their prognostic factors. We evaluated the potential of Ki 67 expression as a prognostic factor in rectal carcinoid tumors. METHODS: We retrospectively reviewed the medical records of 37 patients with rectal carcinoid tumors who got endoscopic resection from January 2001 to January 2011 at Inje University Seoul Paik Hospital. We analyzed their endoscopic and histologic findings, Ki-67 expression, clinical outcome, and prognosis. RESULTS: The mean age (+/-SD) of the patients was 56.3+/-10.7 years, and the male : female ratio was 3.6 : 1. The mean tumor size was 0.5+/-0.4 cm, 33 patients showed grade 1 tumors (89.2%) and the average Ki-67 expression was 0.7+/-1.2%. Thirty five patients underwent endoscopic mucosal resection, and two required endoscopic submucosal dissection. Eight patients had positive margins after resection, but no cases of lymphovascular invasion were identified. The median follow-up duration was 21.4+/-25.4 months, and no recurrences were observed. CONCLUSIONS: In low grade rectal carcinoid tumors which are lack of central depression on colonoscopy, the expression of a molecular marker of malignant potential, Ki-67, was low. Therefore, endoscopic resection seemed to be a safe and effective treatment for these tumors. PMID- 23458986 TI - [The efficacy and tolerability of sugared polyethylene glycol for colonoscopy]. AB - BACKGROUND/AIMS: Although polyethylene glycol (PEG) solution is commonly used for colonoscopic bowel preparation because of its safety and effectiveness, its salty taste decreases patient's compliance. The aim of this study was to compare the sugared PEG solution with the standard PEG solution in regard to the quality of bowel preparation and patient's compliance. METHODS: From January through June in 2012, 100 patients who underwent colonoscopy in Gangneung Asan Hospital were prospectively enrolled. They were randomly assigned to receive either standard PEG solution or sugared PEG solution. The quality of bowel preparation was assessed by a doctor's questionnaire and the patient's compliance was assessed by a patient's questionnaire. RESULTS: There was no significant difference in the quality of bowel preparation (4.2+/-2.0 vs. 4.1+/-1.5, p=0.783), and endoscopist's satisfaction score (8.2+/-1.8 vs. 8.5+/-1.3, p=0.253) between two groups. However, The degree of disgust was lower in the sugared PEG group than the standard PEG group (6.4+/-2.3 vs. 3.9+/-2.9, p=0.000). The willingness to repeat same regimen was higher in the sugared PEG group than the standard PEG group (2.0+/-0.6 vs. 2.3+/-0.7, p=0.004). There was no difference in side effects between two groups. CONCLUSIONS: The sugared PEG solution as a bowel preparation method revealed a higher patient's compliance and was effective as the standard PEG solution. When the patient dislike the taste and saltness of the standard PEG solution, the sugared PEG solution will be good alternative method. PMID- 23458987 TI - [A case of esophageal actinomycosis in a patient with normal immunity]. AB - Actinomycosis is a chronic suppurative disease and caused by Actinomycosis species, principally Actinomyces israelii, which are part of the normal inhabitant on the mucous membrane of the oropharynx, gastrointestinal tract, and urogenital tract. It usually affects cervicofacial, thoracic and abdominal tissue. Cervicofacial type has the highest percentage of occurrence with 50%. Actinomycosis frequently occurs following dental extraction, jaw surgery, chronic infection or poor oral hygiene. It may also be considered as an opportunistic infection in immunocompromised patients such as malignancy, human immunodeficiency virus infection, diabetes mellitus, steroid usage or alcoholism. But, actinomycosis rarely occurs in adults with normal immunity and rare in the esophagus. We report an unusual case of esophageal actinomycosis which was developed in a patient with normal immunity and improved by therapy with intravenous penicillin G followed oral amoxicillin, and we also reviewed the associated literature. PMID- 23458988 TI - Crohn's duodeno-colonic fistula preoperatively closed using a detachable endoloop and hemoclips: a case report. AB - Duodeno-colonic fistula is an enterocolonic fistula that occurs as a complication of Crohn's disease. Symptoms of duodeno-colonic fistula are similar to those of Crohn's disease, such as weight loss and diarrhea. The treatment of choice is surgery, although medical treatment may also be considered. However, surgery is recommended when all available medical therapies have been ineffective. In this case, we report a secondary duodeno-colonic fistula due to Crohn's disease that was temporarily managed by an endoscopic procedure with a detached endoloop and hemoclips as a bridging therapy to final surgical repair. PMID- 23458989 TI - [A case of Clostridium liver abscess with sepsis]. AB - Clostridial septicemia usually occurrs in patients with immunocompromised diseases such as diabetes and malignancy. Clostridial liver abscess is very rare but highly fatal. We experienced a case of Clostridial septicemia due to liver abscess in a 73-year-old man. He was presented with fever and chills. On admission, abdominal CT scan showed about 35 mm sized hypoattenuated lesion with multiple central air-bubbles. After the diagnosis of liver abscess, the patient underwent prompt empirical antimicrobial therapy and percutaneous drainage. In spite of early therapy, the patient had gone into shock and death. PMID- 23458990 TI - Simultaneous occurrence of gallbladder cancer in a laundry couple: association between gallbladder cancer and benzene. AB - Gallbladder (GB) cancer occurs predominately as a biliary tract malignant tumor. It generally has a very poor prognosis, and early detection is often difficult. A variety of carcinogens have been implicated as an important cause for GB cancer. Benzene is a well-known carcinogen for hematologic malignancy, and its casual relationship with GB cancer has been suggested. We report a case of two patients who had operated a laundry cleaning facility together and later simultaneously got GB cancer after prolonged benzene exposure. PMID- 23458991 TI - Fetal alcohol spectrum disorder--poverty trap? PMID- 23458992 TI - Project MARS: Design of a Multi-Behavior Intervention Trial for Justice-Involved Youth. AB - BACKGROUND: Marijuana and alcohol use are associated with increased sexual risk behavior among justice-involved youth. A multi-behavior intervention may reduce all three risk behaviors. PURPOSE: To examine the relationships among multiple risk behaviors and the Theory of Planned Behavior (TPB) constructs guiding the development of the MARS (Motivating Adolescents to Reduce Sexual risk) intervention. We describe the MARS study design to inform the process through which a multi-behavior intervention trial can be implemented and evaluated. METHODS: Participants completed questionnaires prior to randomization to one of three interventions. RESULTS: Relationships were found between TPB constructs and risk behavior. A single latent variable was inadequate to capture all three risk behaviors. CONCLUSIONS: Interventions to reduce sexual risk behavior can include content related to the role of substance use in influencing sexual risk behavior with only minimal modifications to the curriculum, and preliminary data suggest a common theory can apply across risk behaviors. PMID- 23458993 TI - Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age. AB - Epilepsy is a common neurological disorder in the pediatric population, affecting up to one percent of children, and for which the mainstay of treatment is anticonvulsant medication. Despite the frequent use of anticonvulsant drugs, remarkably little is known about the safety and efficacy of most of these medications in the pediatric epilepsy population. Of 34 anticonvulsants currently approved for use by the US Food and Drug Administration (FDA), only 13 have been approved for use in children. Although infants and young children are disproportionately affected by epilepsy, there are currently only three anticonvulsant medications that have been specifically evaluated and approved for use in children younger than 2 years of age. In 2012, the FDA approved levetiracetam as an adjunctive treatment for partial onset seizures in infants and children from one month of age. Here we review the available data on levetiracetam in the pediatric epilepsy population. We first discuss the pharmacological profile of levetiracetam, including its mechanism of action, formulations and dosing, and pharmacokinetics in children. We then review the available efficacy, safety, and tolerability data in children from one month of age with partial onset seizures. We conclude that the current data leading to the approval of levetiracetam for use in infants and children with partial onset seizures is encouraging, although more work needs to be done before definitive conclusions can be drawn about the efficacy of levetiracetam across different pediatric age groups. PMID- 23458995 TI - Considering the impact drug-like properties have on the chance of success. AB - Many definitions of 'drug-like' compound properties have been published; based on the analysis of simple molecular properties of successful drugs. These are typically presented as rules that define acceptable boundaries for these properties. When a compound does not 'fit' within these boundaries then its properties differ from those of the majority of drugs, which could indicate a higher risk of poor pharmacokinetics or safety outcomes in vivo. Here, we review the strengths and weaknesses of these rules and note, in particular, that the overly rigid application of strict cut-off points can introduce artificial distinctions between similar compounds, running the risk of missing valuable opportunities. Alternatively, compounds can be ranked according to their similarity to marketed drugs using a continuous measure of drug-likeness. However, being similar to known drugs does not necessarily mean that a compound is more likely to become a drug and we demonstrate how a new approach, employing Bayesian methods, can be used to compare a set of successful drugs with a set of non-drug compounds to identify those properties that give the greatest distinction between the two sets, and hence the greatest increase in the likelihood of a compound becoming a successful drug. This analysis further illustrates that guidelines for drug-likeness might not be generally applicable across all compound and target classes or therapeutic indications. Therefore, it might be more appropriate to consider specific guidelines for drug-likeness that are project specific. PMID- 23458996 TI - Cellular localization of BARF1 oncoprotein and its cell stimulating activity in human epithelial cell. AB - BARF1 gene encoded by Epstein-Barr virus is capable of immortalizing the primary monkey epithelial cells and of inducing malignant transformation in human EBV negative B cell lines as well as rodent fibroblast. This oncoprotein is a secreted protein capable of acting as a powerful mitogen. We have studied the effect of BARF1 protein in transfected or BARF1 protein treated human HaCaT epithelial cells. In BARF1-transfected cells, cell growth was activated and its protein was found both in culture medium and cellular compartment (membrane, cytoplasm and nuclei). When purified BARF1 protein was exogenously added in the cell culture medium of HaCaT cells in absence of fetal calf serum led to its entrance into cells and its intracellular localization in cytoplasm, nuclear periphery and nuclei at 14h treatment, determined by confocal and immunoelectron microscopy. Cell fractionation confirmed its nuclear localization. Nuclear localization was observed in both systems. More interestingly, purified BARF1 protein p29 exogenously added in the cell culture medium activated cell passage of G1 to S phase. S phase activation by its autocrine activity and its tumorigenic activity would be associated with the development of EBV-associated carcinomas. PMID- 23458994 TI - The effectiveness of mobile-health technologies to improve health care service delivery processes: a systematic review and meta-analysis. AB - BACKGROUND: Mobile health interventions could have beneficial effects on health care delivery processes. We aimed to conduct a systematic review of controlled trials of mobile technology interventions to improve health care delivery processes. METHODS AND FINDINGS: We searched for all controlled trials of mobile technology based health interventions using MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science, Cochrane Library, UK NHS HTA (Jan 1990-Sept 2010). Two authors independently extracted data on allocation concealment, allocation sequence, blinding, completeness of follow-up, and measures of effect. We calculated effect estimates and we used random effects meta-analysis to give pooled estimates. We identified 42 trials. None of the trials had low risk of bias. Seven trials of health care provider support reported 25 outcomes regarding appropriate disease management, of which 11 showed statistically significant benefits. One trial reported a statistically significant improvement in nurse/surgeon communication using mobile phones. Two trials reported statistically significant reductions in correct diagnoses using mobile technology photos compared to gold standard. The pooled effect on appointment attendance using text message (short message service or SMS) reminders versus no reminder was increased, with a relative risk (RR) of 1.06 (95% CI 1.05-1.07, I(2) = 6%). The pooled effects on the number of cancelled appointments was not significantly increased RR 1.08 (95% CI 0.89-1.30). There was no difference in attendance using SMS reminders versus other reminders (RR 0.98, 95% CI 0.94-1.02, respectively). To address the limitation of the older search, we also reviewed more recent literature. CONCLUSIONS: The results for health care provider support interventions on diagnosis and management outcomes are generally consistent with modest benefits. Trials using mobile technology-based photos reported reductions in correct diagnoses when compared to the gold standard. SMS appointment reminders have modest benefits and may be appropriate for implementation. High quality trials measuring clinical outcomes are needed. Please see later in the article for the Editors' Summary. PMID- 23458997 TI - Expression of type I interferon-induced antiviral state and pro-apoptosis markers during experimental infection with low or high virulence bovine viral diarrhea virus in beef calves. AB - The objective of this study was to compare the mRNA expression of host genes involved in type-I interferon-induced antiviral state (IFN-alpha, IFN-beta, Mx-1, PKR, OAS-1 and ISG-15), and apoptosis (caspase-3, -8, and -9), after experimental infection of beef calves with low or high virulence noncytopathic (ncp) bovine viral diarrhea virus (BVDV) strains. Thirty BVDV-naive, clinically normal calves were randomly assigned to three groups. Calves were intranasally inoculated with low (LV; n=10, strain SD-1) or high (HV; n=10, strain 1373) virulence ncp BVDV or BVDV-free cell culture medium (Control, n=10). Quantitative RT-PCR was used to determine the target gene expression in tracheo-bronchial lymph nodes and spleen 5 days after infection. Interferon-alpha and -beta mRNA levels were up-regulated in tracheo-bronchial lymph nodes (P<0.05) in the HV group, but not in the LV group, compared with the control group. There was an up-regulation of type I interferon-induced genes in spleen and tracheo-bronchial lymph nodes of HV and LV groups, compared with the control group (P<0.01). mRNA levels of OAS-1 and ISG-15 were significantly higher in LV than HV calves (P<0.05). A significant up regulation of caspase-8 and -9 was observed in tracheo-bronchial lymph nodes in the LV group (P=0.01), but not in the HV group. In conclusion, experimental infection with either high or low virulence BVDV strains induced a significant expression of the type I interferon-induced genes in beef calves. There was a differential expression of some interferon-induced genes (OAS-1 and ISG-15) and pro-apoptosis markers based on BVDV virulence and genotype. PMID- 23459000 TI - The Utility of 3D Ultramicroscopy for Evaluating Cellular Therapies After Spinal Cord Injury. AB - Cell therapies have shown promise for repairing the injured spinal cord in experimental models and are now being evaluated in clinical trials for the treatment of human spinal cord injury (SCI). To date, experimental evaluation of implanted cell survival, migration, and integration within the injured central nervous system (CNS) of animals has been technically demanding, requiring tissue sectioning, staining, imaging, and manual reconstruction of 2-dimensional (2D) specimens in 3 dimensions (3D). Not only are these histological procedures laborious and fraught with processing artifacts during manual 3D reconstruction, but they are time-intensive. Herein we describe the utility of 3D ultramicroscopy for assessment of cell therapies after SCI, a new state-of-the-art imaging modality in which whole brain and spinal cord samples are optically sectioned to allow evaluation of intact, macroscopic specimens with microscopic resolution. PMID- 23458999 TI - Allogeneic partially HLA-matched dendritic cells pulsed with autologous tumor cell lysate as a vaccine in metastatic renal cell cancer: a clinical phase I/II study. AB - Multi-kinase inhibitors have been established for the treatment of advanced renal cell cancer, but long-term results are still disappointing and immunotherapeutic approaches remain an interesting experimental option particularly in patients with a low tumor burden. DC are crucial for antigen-specific MHC-restricted T cell immunity. Furthermore, allogeneic HLA-molecules pose a strong immunogenic signal and may help to induce tumor-specific T cell responses. In this phase I/II trial, 7 patients with histologically confirmed progressive metastatic RCC were immunized repetitively with 1 * 10 (7) allogeneic partially HLA-matched DC pulsed with autologous tumor lysate following a schedule of 8 vaccinations over 20 weeks. Patients also received 3 Mio IE IL-2 s.c. once daily starting in week 4. Primary endpoints of the study were feasibility and safety. Secondary endpoints were immunological and clinical responses. Vaccination was feasible and safe with no severe toxicity being observed. No objective response could be documented. However, while all patients had documented progress at study entry, 29% of the patients showed SD throughout the study with a mean TTP of 24.6 weeks (range 5 to 96 weeks). In 3/7 patients, TH1-polarized immune responses against RCC-associated antigens were observed. In one patient showing a minimal clinical response and a TTP of 96 weeks, clonally proliferated T cells against yet undefined antigens were induced by the vaccine. Vaccination with tumor antigen loaded DC remains an interesting experimental approach, but should rather be applied in the situation of minimal residual disease after systemic therapy. Additional depletion of regulatory cells might be a promising strategy. PMID- 23458998 TI - H5N1 pathogenesis studies in mammalian models. AB - H5N1 influenza viruses are capable of causing severe disease and death in humans, and represent a potential pandemic subtype should they acquire a transmissible phenotype. Due to the expanding host and geographic range of this virus subtype, there is an urgent need to better understand the contribution of both virus and host responses following H5N1 virus infection to prevent and control human disease. The use of mammalian models, notably the mouse and ferret, has enabled the detailed study of both complex virus-host interactions as well as the contribution of individual viral proteins and point mutations which influence virulence. In this review, we describe the behavior of H5N1 viruses which exhibit high and low virulence in numerous mammalian species, and highlight the contribution of inoculation route to virus pathogenicity. The involvement of host responses as studied in both inbred and outbred mammalian models is discussed. The roles of individual viral gene products and molecular determinants which modulate the severity of H5N1 disease in vivo are presented. This research contributes not only to our understanding of influenza virus pathogenesis, but also identifies novel preventative and therapeutic targets to mitigate the disease burden caused by avian influenza viruses. PMID- 23459003 TI - Operational quantities adieu Reply to 'Health risks associated with environmental radiation exposures' PMID- 23459002 TI - Theoretical Risk and Prevention Model for Secondary Health Conditions and Mortality After SCI: 15 Years of Research. AB - BACKGROUND: To successfully prevent secondary health conditions (SHCs) and promote longevity after spinal cord injury (SCI), we must first understand the risk factors precipitating their occurrence and develop strategies to address these risk factors. Conceptual models may aid in identifying the nature of SHCs and guide research, clinical practice, and the development of prevention strategies. OBJECTIVE: Our purpose is to review and refine an existing theoretical risk and prevention model (TRPM) as a means of classifying risk and protective factors for SHCs and mortality after SCI and for identifying points of intervention. METHODS: We describe conceptual work within the field of SCI research and SHCs, including a description of the TRPM, a review of research using the TRPM, and conceptual enhancements to the TRPM based on previous research. CONCLUSIONS: The enhanced TRPM directs research to the timing and chronicity of the SHCs and their relationship with overall health and physiologic decline. Future research should identify differences in the nature of SHCs, the extent to which they relate to risk and protective factors, and the degree to which they may be prevented with appropriate research-based strategies. PMID- 23459001 TI - Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells. AB - Hedgehog interacting protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis. PMID- 23459004 TI - Comparative evaluation of two dose optimization methods for image-guided, highly conformal, tandem and ovoids cervix brachytherapy planning. AB - Although the Manchester system is still extensively used to prescribe dose in brachytherapy (BT) for locally advanced cervix cancer, many radiation oncology centers are transitioning to 3D image-guided BT, owing to the excellent anatomy definition offered by modern imaging modalities. As automatic dose optimization is highly desirable for 3D image-based BT, this study comparatively evaluates the performance of two optimization methods used in BT treatment planning--Nelder Mead simplex (NMS) and simulated annealing (SA)--for a cervix BT computer simulation model incorporating a Manchester-style applicator. Eight model cases were constructed based on anatomical structure data (for high risk-clinical target volume (HR-CTV), bladder, rectum and sigmoid) obtained from measurements on fused MR-CT images for BT patients. D90 and V100 for HR-CTV, D2cc for organs at risk (OARs), dose to point A, conformation index and the sum of dwell times within the tandem and ovoids were calculated for optimized treatment plans designed to treat the HR-CTV in a highly conformal manner. Compared to the NMS algorithm, SA was found to be superior as it could perform optimization starting from a range of initial dwell times, while the performance of NMS was strongly dependent on their initial choice. SA-optimized plans also exhibited lower D2cc to OARs, especially the bladder and sigmoid, and reduced tandem dwell times. For cases with smaller HR-CTV having good separation from adjoining OARs, multiple SA optimized solutions were found which differed markedly from each other and were associated with different choices for initial dwell times. Finally and importantly, the SA method yielded plans with lower dwell time variability compared with the NMS method. PMID- 23459005 TI - Resolution of tracheostomy complications by decanulation and conversion to noninvasive management for a patient with high-level tetraplegia. AB - OBJECTIVES: To report conversion from tracheostomy (TIV) to noninvasive intermittent positive pressure ventilation (NIV) for a continuously ventilator dependent patient with high-level spinal cord injury (SCI) with no measurable vital capacity (VC = 0 mL) to resolve tracheostomy-associated complications. METHODS: A case report of a 38-year-old female in a chronic care facility in Japan with a 10-year history of ventilator-dependent tetraplegia (C1 ASIA-A) presented for increasing difficulty vocalizing. She had been using a fenestrated cuffed tracheostomy tube to produce speech with the cuff deflated. Speech was increasingly hypophonic, because of tracheostoma enlargement, tube migration, and tracheal granulation. RESULTS: The NIV was provided via nasal and oral interfaces, the ostomy was surgically closed, and vocalization resumed. Airway secretions were expulsed using manually assisted coughing. The patient returned to the community. CONCLUSION: Conversion to NIV should be considered for ventilator-dependent patients with SCI who have adequate bulbar-innervated muscle function to permit effective speech and assisted coughing. PMID- 23459006 TI - Non-contiguous finished genome sequence and description of Paenibacillus senegalensis sp. nov. AB - Paenibacillus senegalensis strain JC66(T), is the type strain of Paenibacillus senegalensis sp. nov., a new species within the genus Paenibacillus. This strain, whose genome is described here, was isolated from the fecal flora of a healthy patient. P. senegalensis strain JC66(T) is a facultative Gram-negative anaerobic rod-shaped bacterium. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 5,581,254 bp long genome (1 chromosome but no plasmid) exhibits a G+C content of 48.2% and contains 5,008 protein-coding and 51 RNA genes, including 9 rRNA genes. PMID- 23459008 TI - [1,2]- and [1,4]-Wittig Rearrangements of alpha-Alkoxysilanes: Effect of Substitutions at both the Migrating Benzylic Carbon and the Terminal sp2 Carbon of the Allyl Moiety. AB - Substituted alpha-alkoxysilanes can be deprotonated by alkyllithium bases and made to undergo Wittig rearrangements to afford the #x0005B;1,4]- and [1,2] rearranged products in varying ratios. Substitution at the benzylic migrating carbon and/or at the allylic carbon of the allyl moiety impacts the rearrangement reaction, influencing the reactivity as well as the [1,4]-/[1,2]-selectivity. Diastereomeric alpha-alkoxysilanes show different reactivities with the syn diastereomer being the more reactive isomer. PMID- 23459010 TI - Osteoarthritis: miR-125b--a new target in cartilage destruction? PMID- 23459007 TI - Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. AB - HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research. PMID- 23459016 TI - Evolution of a soldier caste specialized to lay unfertilized eggs in the ant genus Crematogaster (subgenus Orthocrema). AB - Among social Hymenoptera, only some ant genera have more than one morphological kind of non-reproductive adults. Individuals that are bigger than ordinary workers can function for defence and/or food storage. In Crematogaster (Orthocrema) smithi from Arizona, a third caste exists in addition to winged queens and workers; it is intermediate in size, weight and morphology, and individuals lay many unfertilized eggs that are mostly eaten by larvae (Heinze et al., 1995, 1999). We studied another three species belonging to the subgenus Orthocrema: Crematogaster pygmaea from Brazil, Crematogaster biroi and Crematogaster schimmeri from Taiwan. Using scanning electron microscopy and ovarian dissections, we show that 'intermediates' are a patchwork of queen-like and worker-like traits, just as in C. smithi; importantly the combinations differ across species. 'Intermediates' are numerically few in the colonies, and in C. pygmaea they are produced seasonally. Using histology we confirmed the lack of a spermatheca, thus they are not ergatoid queens. Based on the similarity of their mosaic phenotypes with those in other ant lineages, we suggest that Orthocrema 'intermediates' are a soldier caste with a specialized trophic function. This soldier caste has been reported in other Orthocrema species from Madagascar, Guinea and Costa Rica, suggesting that it is widespread in this subgenus. PMID- 23459015 TI - Long-term bladeless LASIK outcomes with the FS200 Femtosecond and EX500 Excimer Laser workstation: the Refractive Suite. AB - PURPOSE: The evaluation of the safety, efficacy, and long-term stability of LASIK procedures utilizing novel platform comprising a femtosecond and excimer laser and multiple networked diagnostics. SETTING: Private clinical ophthalmology practice. PATIENTS AND METHODS: In consecutive cases of myopic LASIK procedure with a novel refractive platform (FS200 Femtosecond and EX500 Excimer Laser), 190 eyes (from 109 different patients) were evaluated pre- and postoperatively for the following parameters: refractive error, best corrected distance visual acuity, uncorrected distance visual acuity, topography (Placido-disc based) and tomography (Scheimpflug-image based), wavefront analysis, pupillometry, and contrast sensitivity. Follow-up visits were conducted for at least 12 months. RESULTS: The change from pre- to postoperative mean refractive error was from 5.29 +/- 2.39 diopters (D) (range -8.0 to -0.50 D) to -0.27 +/- 0.09 D at the 3 month visit, -0.27 +/- 0.10 D at the 6-month visit, and -0.39 +/- 0.08 D at the 1 year visit. The change from pre- to postoperative refractive astigmatism was 1.07 +/- 0.91 D (range -4.25 to 0 D) to -0.14 +/- 0.04 D at 3 months, -0.15 +/- 0.04 at 6 months, and -0.16 +/- 0.04 at the 1-year visit. The proportion of the eyes with postoperative astigmatism within 0.5 D ranged between 95.6% and 99%. The proportion of eyes achieving uncorrected distance visual acuity of 1.0 (decimal) was 93.0%. CONCLUSION: The myopic LASIK clinical results with the FS200 Femtosecond Laser and EX500 Excimer Laser showed outstanding efficacy, great safety, and long-term stability. PMID- 23459017 TI - Unilateral attico antral ear disease with bilateral intracranial complications. AB - A 12 year old female patient, who had attico antral type of ear disease on right side, was brought to tertiary care centre for the management of fever, vomiting and headache. Patient had unilateral attico antral type of ear disease with bilateral intracranial complication. Along with the right attico antral type of ear disease and right lateral sinus thrombosis, patient had brain abscess in the left occipital lobe. Brain abscess was drained first and later mastoidectomy was done to eradicate the source of infection and to prevent further complications due to ear disease. Patient recovered well and patient was free from any problem during follow up period of 6 months. Bilateral intra cranial complications occurring simultaneously in a patient with a unilateral attico antral type of ear disease is not reported in the literature. PMID- 23459013 TI - To Wnt or not to Wnt: the bone and joint health dilemma. AB - The Wnt signalling cascades have essential roles in development, growth and homeostasis of joints and the skeleton. Progress in basic research, particularly relating to our understanding of intracellular signalling cascades and fine regulation of receptor activation in the extracellular space, has provided novel insights into the roles of Wnt signalling in chronic arthritis. Cartilage and bone homeostasis require finely tuned Wnt signalling; both activation and suppression of the Wnt-beta-catenin cascade can lead to osteoarthritis in rodent models. Genetic associations with the Wnt antagonist encoded by FRZB and the transcriptional regulator encoded by Dot1l with osteoarthritis further corroborate the essential part played by Wnts in the joint. In rheumatoid arthritis, inhibition of Wnt signalling has a role in the persistence of bone erosions, whereas Wnts have been associated with the ankylosing phenotype in spondyloarthritis. Together, these observations identify the Wnt pathway as an attractive target for therapeutic intervention; however, the complexity of the Wnt signalling cascades and the potential secondary effects of drug interventions targeting them highlight the need for further research and suggest that our understanding of this exciting pathway is still in its infancy. PMID- 23459018 TI - Tapia's syndrome following cervical laminoplasty -A case report-. AB - Tapia's syndrome is the palsy of the 10th and 12th cranial nerves, resulting in ipsilateral paralysis of the vocal cord and tongue. It is a rare complication which is related to the anesthetic airway management and positioning of the patient's head during the surgery. We describe a patient with a postoperative unilateral Tapia's syndrome, after general anesthesia, with uncomplicated endotracheal intubation. The patient's symptoms improved gradually for three months. PMID- 23459019 TI - Structure-based molecular simulations reveal the enhancement of biased Brownian motions in single-headed kinesin. AB - Kinesin is a family of molecular motors that move unidirectionally along microtubules (MT) using ATP hydrolysis free energy. In the family, the conventional two-headed kinesin was experimentally characterized to move unidirectionally through "walking" in a hand-over-hand fashion by coordinated motions of the two heads. Interestingly a single-headed kinesin, a truncated KIF1A, still can generate a biased Brownian movement along MT, as observed by in vitro single molecule experiments. Thus, KIF1A must use a different mechanism from the conventional kinesin to achieve the unidirectional motions. Based on the energy landscape view of proteins, for the first time, we conducted a set of molecular simulations of the truncated KIF1A movements over an ATP hydrolysis cycle and found a mechanism exhibiting and enhancing stochastic forward-biased movements in a similar way to those in experiments. First, simulating stand-alone KIF1A, we did not find any biased movements, while we found that KIF1A with a large friction cargo-analog attached to the C-terminus can generate clearly biased Brownian movements upon an ATP hydrolysis cycle. The linked cargo-analog enhanced the detachment of the KIF1A from MT. Once detached, diffusion of the KIF1A head was restricted around the large cargo which was located in front of the head at the time of detachment, thus generating a forward bias of the diffusion. The cargo plays the role of a diffusional anchor, or cane, in KIF1A "walking." PMID- 23459020 TI - Size- and pathotropism-driven targeting and washout-resistant effects of boronic acid-rich protein nanoparticles for liver cancer regression. AB - 40nm-sized boronic acid-rich protein nanoparticles composed of bovine serum albumin and poly(N-3-acrylamidophenylboronic acid) were prepared by polymerizing N-3-acrylamidophenylboronic acid in the presence of albumin. The content of boronic acid-containing poly(N-3-acrylamidophenylboronic acid) in the nanoparticles can be tuned from 80% to 32% at constant nanoparticle size. When used to deliver doxorubicin in vivo, such sized nanoparticles show dominantly liver-targeting, and significant washout-resistant ability compared to those boronic acid-absent nanoparticles due to the interaction between sialic acid residues in the liver and boronic acid groups in the nanoparticles. The sialic acid overexpression on hepatic H22 tumor cells is demonstrated to be much higher than that on hepatocytes, resulting in the preferential accumulation of boronic acid-rich nanoparticles in liver cancer cells. In vivo antitumor examination in orthotopic liver cancer model shows that these doxorubicin-loaded nanoparticles not only have significantly superior ability in impeding tumor growth, but also induce distinct tumor regression with no hepatic and cardiac toxicities. PMID- 23459021 TI - Aplysqualenols A and B: Squalene-Derived Polyethers with Antitumoral and Antiviral Activity from the Caribbean Sea Slug Aplysia dactylomela. AB - The novel bromotriterpene polyethers aplysqualenol A (1) and aplysqualenol B (2) have been isolated from the Caribbean sea slug Aplysia dactylomela collected in Puerto Rico, and their structures and relative configurational assignments established from spectroscopic data aided by quantum mechanical calculations of NMR chemical shifts. Although both these compounds may be conceived as polyoxycyclic derivatives of the C30 squalene skeleton, remarkably 1 and 2 possess an unprecedented C15 to C24 flexible chain of 14S* spatial disposition that contains a unique ether bridge between C16 and C19. Biological activity screening tests revealed that, although aplysqualenol A (1) does not have significant anti-infective properties, it possesses potent antitumoral and antiviral activities. PMID- 23459023 TI - Use of platelet rich plasma for the treatment of bicipital tendinopathy in spinal cord injury:: a pilot study. AB - The purpose of study is to explore the efficacy and safety of platelet rich plasma (PRP) in the nonoperative management of shoulder tendinopathy amongst individuals with spinal cord injury. This objective was met by completing a pilot study on the effectiveness and safety of a PRP injection into the biceps tendon demonstrating clinical and ultrasonagraphic pathology. Recent analysis of the preliminary pilot data has demonstrated remarkably convincing results demonstrating both the safety and efficacy of this novel intervention. PMID- 23459022 TI - Lipid management in 13,000 high risk cardiovascular patients treated under daily practice conditions: LIMA Registry. AB - AIMS: We aimed to document the drug management of patients at high cardiovascular risk in daily practice, with the special focus on lipid-lowering treatment. METHODS AND RESULTS: In this prospective noninterventional study in 2387 outpatient centers throughout Germany, a total of 13,942 high-risk patients (mean age 65.7 years, 61.6% males) were treated with simvastatin 40 mg/day at entry as monotherapy. All patients were followed up for 12 months in terms of drug utilization, laboratory values, target attainment, and clinical events (including death, hospitalization, vascular events, and dialysis). Patients had coronary heart disease in 35.0%, diabetes mellitus in 24.4%, and the combination of coronary heart disease plus diabetes mellitus in 25.7%. In 21% of patients, a cholesterol absorption inhibitor was added to statin therapy at the entry visit, and in 23%, this was added at the follow up visit 6 months later. The target values for low-density lipoprotein-cholesterol (<2.6 mmol/L) were reached by 31.8% of patients at entry and by 50.0% at the end of this registry after 12 months. Mean blood pressure decreased (from 135.9/80.5 mmHg at baseline) by 3.1/1.9 mmHg after 12 months. In patients with documented diabetes, the targeted glycated hemoglobin (HbA1c <6.5%) was reached by 33.5% at baseline and by 40.0% after 12 months. Clinical events occurred in 11.7% of patients between baseline and month 6, and in 12.0% between months 6 and 12. CONCLUSION: In patients at high risk for cardiovascular events, comprehensive management under daily practice conditions leads to improvement of lipid, glucose, and blood pressure parameters. There is a need to improve secondary prevention among high-risk patients. PMID- 23459024 TI - The influence of family ties on men's prostate cancer screening, biopsy, and treatment decisions. AB - Extensive research has focused on understanding family dynamics of men with prostate cancer. However, little qualitative work has examined the role of family ties on men's prostate cancer decisions across the spectrum of screening, diagnosis, and treatment. Using data from a larger study, we qualitatively explored the influence of family ties on men's prostate cancer decisions. Semistructured interviews were conducted with men ages >=50 (N = 64), and data were analyzed using a grounded theory approach and a series of immersion/crystallization cycles. Three major themes of spousal/family member influence were identified: (a) spousal/family member alliance marked by open communication and shared decision making, (b) men who actively opposed spouse/family member pressure and made final decisions themselves, and (c) men who yielded to spouse/family member pressure. Our findings provide insights into men's relational dynamics that are important to consider for the shared decision making process across the prostate cancer spectrum. PMID- 23459025 TI - Predictors of Self-Stigma in Schizophrenia: New Insights Using Mobile Technologies. AB - OBJECTIVE: Self-stigma has significant negative impact on the recovery of individuals with severe mental illness, but its varying course is not well understood. Individual levels of self-stigma may vary over time and fluctuate in response to both external/contextual (i.e., location, activity, social company) and internal (i.e., psychiatric symptoms, mood) factors. The aim of this study was to examine the relationship between self-stigmatizing beliefs and these factors, as they occur in the daily life of individuals with schizophrenia. METHODS: Mobile technologies were used to longitudinally track momentary levels of self-stigma, psychotic symptoms, negative affect, positive affect, activity, and immediate social and physical environment in twenty-four individuals with schizophrenia, multiple times daily, over a one-week period. RESULTS: Multilevel modeling showed that participants' current activity was associated with changes in self-stigma (chi2= 10.53, p <0.05), but immediate location and social company were not. Time-lagged analyses found that increases in negative affect (beta=0.11, p<0.01) and psychotic symptom severity (beta=0.16, p<0.01) predicted increases in the intensity of self-stigmatizing beliefs. Psychotic symptoms were found to be both an antecedent and a consequence (beta=0.08, p<0.01) of increased self-stigma. CONCLUSIONS: Our findings support a framework for understanding self stigma as an experience that changes based on alterations in internal states and external circumstances. Mobile technologies are an effective methodology to study self-stigma and have potential to be used to deliver clinical interventions. PMID- 23459027 TI - Pushrim kinetics during advanced wheelchair skills in manual wheelchair users with spinal cord injury. AB - OBJECTIVE: To assess the peak force during wheelchair propulsion of individuals with spinal cord injury propelling over obstacles from the Wheelchair Skills Test. PARTICIPANTS/METHODS: Twenty-three individuals with spinal cord injury (SCI) who are full-time manual wheelchair users were included in this prospective study. A SmartWheel (Three Rivers Holdings, LLC) was used to analyze each push while subjects negotiated standardized obstacles used in the Wheelchair Skills Test, including tile, carpet, soft surface, 5 degrees and 10 degrees ramps, 2 cm, 5 cm, and 15 cm curbs. RESULTS: When the peak forces of the advanced skills were compared to level 10 m tile/10 m carpet, there was a statistically significant increase in all peak forces (P value ranged from .0001 to .0268). DISCUSSION: It is well documented that a large number of individuals with SCI develop upper limb pain. One of the recommendations to preserve the upper limb is to minimize force during repetitive tasks. CONCLUSION: Advanced wheelchair skills require an increase in force to accomplish. The increase in forces ranged from 18% to 130% over that required for level 10 m tile/10 m carpet. PMID- 23459028 TI - Improved dead-time correction for PET scanners: application to small-animal PET. AB - Pile-up and dead-time are two main causes of nonlinearity in the response of a PET scanner as a function of activity in the field of view (FOV). For a given scanner and acquisition system, pile-up effects depend on the material and size of the object being imaged and on the distribution of activity inside and outside the FOV, because these factors change the singles-to-coincidences ratio (SCR). Thus, it is difficult to devise an accurate correction that would be valid for any acquisition. In this work, we demonstrate a linear relationship between SCR and effective dead-time, which measures the effects of both dead-time (losses) and pile-up (gains and losses). This relationship allows us to propose a simple method to accurately estimate dead-time and pile-up corrections using only two calibration acquisitions with, respectively, a high and low SCR. The method has been tested with simulations and experimental data for two different scanner geometries: a scanner with large area detectors and no pile-up rejection, and a scanner composed of two full rings of smaller detectors. Our results show that the SCR correction method is accurate within 7%, even for high activities in the FOV, and avoids the bias of the standard single-parameter method. PMID- 23459026 TI - Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger. AB - A considerable number of studies demonstrate that acute and chronic stressors prime CNS innate immune responses to subsequent pro-inflammatory challenges and that glucocorticoids mediate, in part, stress-induced sensitization of pro inflammatory immune responses. Here, we explore the notion that GCs produce a persisting sensitization of CNS innate immune effectors (e.g. microglia) so that they will generate a potentiated pro-inflammatory response after the GC rise has dissipated, thereby enhancing the sickness response to infection or injury and maximizing the animal's ability to neutralize danger. The stress-induced GC response is conceptualized here as an neuroendocrine warning signal or alarmin to the innate immune system, which prepares or sensitizes the innate immune response to potential danger. Thus, a new understanding of the stress response and its function (priming CNS innate immune responses to infection or injury during a fight/flight emergency) would be suggested. PMID- 23459029 TI - Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. AB - OBJECTIVE: Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. MATERIALS AND METHODS: Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). CONCLUSION: This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients. PMID- 23459030 TI - The effect of cryoprotection on the use of PLGA encapsulated iron oxide nanoparticles for magnetic cell labeling. AB - Magnetic PLGA nanoparticles are a significant advancement in the quest to translate MRI-based cell tracking to the clinic. The benefits of these types of particles are that they encapsulate large amounts of iron oxide nanocrystals within an FDA-approved polymer matrix, combining the best aspects of inert micron sized iron oxide particles, or MPIOs, and biodegradable small particles of iron oxide, or SPIOs. Practically, PLGA nanoparticle fabrication and storage requires some form of cryoprotectant to both protect the particle during freeze drying and to promote resuspension. While this is a commonly employed procedure in the fabrication of drug loaded PLGA nanoparticles, it has yet to be investigated for magnetic particles and what effect this might have on internalization of magnetic particles. As such, in this study, magnetic PLGA nanoparticles were fabricated with various concentrations of two common cryoprotectants, dextrose and sucrose, and analyzed for their ability to magnetically label cells. It was found that cryoprotection with either sugar significantly enhanced the ability to resuspend nanoparticles without aggregation. Magnetic cell labeling was impacted by sugar concentration, with higher sugar concentrations used during freeze drying more significantly reducing magnetic cell labeling than lower concentrations. These studies suggest that cryoprotection with 1% dextrose is an optimal compromise that preserves monodispersity following resuspension and high magnetic cell labeling. PMID- 23459032 TI - Hijacking the vasculature in ccRCC--co-option, remodelling and angiogenesis. AB - The most common type of malignancy in the adult kidney is clear cell renal cell carcinoma (ccRCC), for which antiangiogenic therapy with surgery is currently the standard treatment. Although overall survival of patients with metastatic ccRCC has been substantially extended by antiangiogenic therapy with agents such as sorafenib and sunitinib, patients almost certainly go on to develop resistance, or present at the time of treatment with primary resistance. This eventuality implies that our knowledge of the processes involved in tumour angiogenesis in ccRCC is superficial. Increasing evidence has shown that a solid tumour can, during invasion and expansion, 'hijack' pre-existing blood vessels and integrate them into the tumour vasculature. This approach to expanding the tumour vasculature is referred to as vessel co-option. In this Perspectives article, I argue that vessel co-option likely occurs in ccRCC, along with the complementary processes of vessel remodelling and extratumoural angiogenesis. Exploring the underlying molecular mechanisms of these complicated vasculature developments in ccRCC might provide new opportunities to enhance the efficacy of antiangiogenic therapy. PMID- 23459031 TI - In vivo functional properties of juxtaglomerular neurons in the mouse olfactory bulb. AB - Juxtaglomerular neurons represent one of the largest cellular populations in the mammalian olfactory bulb yet their role for signal processing remains unclear. We used two-photon imaging and electrophysiological recordings to clarify the in vivo properties of these cells and their functional organization in the juxtaglomerular space. Juxtaglomerular neurons coded for many perceptual characteristics of the olfactory stimulus such as (1) identity of the odorant, (2) odorant concentration, (3) odorant onset, and (4) offset. The odor-responsive neurons clustered within a narrow area surrounding the glomerulus with the same odorant specificity, with ~80% of responding cells located <=20 MUm from the glomerular border. This stereotypic spatial pattern of activated cells persisted at different odorant concentrations and was found for neurons both activated and inhibited by the odorant. Our data identify a principal glomerulus with a narrow shell of juxtaglomerular neurons as a basic odor coding unit in the glomerular layer and underline the important role of intraglomerular circuitry. PMID- 23459034 TI - Prostate cancer: targeting prostate tumour angiogenesis with cediranib. PMID- 23459035 TI - Bladder cancer: aurora kinase inhibitors light up the therapeutic horizon in bladder cancer. PMID- 23459033 TI - Oncological and renal medical importance of kidney-sparing surgery. AB - In the past decade, the medical and oncological rationale for kidney-sparing surgical approaches for small renal masses has been clarified. Although radical nephrectomy is still necessary for many patients diagnosed with large renal tumours, accumulating evidence indicates that partial nephrectomy provides equivalent oncological outcomes while also preserving renal function and preventing the adverse cardiovascular effects of chronic kidney disease. Furthermore, approximately 45% of resected small renal tumours are benign or indolent, with limited--if any--metastatic potential. Patients who develop kidney cancer often have medical comorbidities that can affect kidney function, such as diabetes and hypertension, and histological examination of the non-tumour-bearing elements of the kidney demonstrate significant pathological changes in the vast majority of patients. For elderly patients or patients with comorbidities, active surveillance provides an alternative kidney-sparing approach, and is associated with extremely low rates of clinical disease progression and metastases. Despite these important advances in understanding, which support the use of partial nephrectomy for the treatment of small renal masses, the technique remains underused. PMID- 23459036 TI - Urothelial carcinoma: vinflunine offers modest but important survival benefit. PMID- 23459041 TI - Patient knowledge about disease self-management in cirrhosis. AB - OBJECTIVES: We aimed to understand and improve patient knowledge about self management of cirrhosis. METHODS: We gave 150 outpatients with cirrhosis a survey to test disease self-management knowledge. We then gave them a concise educational booklet and, 3 months later, a follow-up survey. We analyzed demographic and clinical correlates of baseline knowledge, and compared knowledge scores before and after the intervention. RESULTS: Only 53% of the 15 questions were answered correctly in the baseline survey. The most commonly missed items related to diet, such as the sodium content of sea salt, as well as the safety of medications, such as acetaminophen and statins. After the intervention, 77% of patients returned the follow-up survey. This group's median knowledge score improved from 53% to 67%; improvement occurred across all domains tested. CONCLUSIONS: Cirrhosis patients lack the knowledge to effectively manage their disease. A simple educational intervention may improve patient knowledge. PMID- 23459037 TI - Massive mitochondrial gene transfer in a parasitic flowering plant clade. AB - Recent studies have suggested that plant genomes have undergone potentially rampant horizontal gene transfer (HGT), especially in the mitochondrial genome. Parasitic plants have provided the strongest evidence of HGT, which appears to be facilitated by the intimate physical association between the parasites and their hosts. A recent phylogenomic study demonstrated that in the holoparasite Rafflesia cantleyi (Rafflesiaceae), whose close relatives possess the world's largest flowers, about 2.1% of nuclear gene transcripts were likely acquired from its obligate host. Here, we used next-generation sequencing to obtain the 38 protein-coding and ribosomal RNA genes common to the mitochondrial genomes of angiosperms from R. cantleyi and five additional species, including two of its closest relatives and two host species. Strikingly, our phylogenetic analyses conservatively indicate that 24%-41% of these gene sequences show evidence of HGT in Rafflesiaceae, depending on the species. Most of these transgenic sequences possess intact reading frames and are actively transcribed, indicating that they are potentially functional. Additionally, some of these transgenes maintain synteny with their donor and recipient lineages, suggesting that native genes have likely been displaced via homologous recombination. Our study is the first to comprehensively assess the magnitude of HGT in plants involving a genome (i.e., mitochondria) and a species interaction (i.e., parasitism) where it has been hypothesized to be potentially rampant. Our results establish for the first time that, although the magnitude of HGT involving nuclear genes is appreciable in these parasitic plants, HGT involving mitochondrial genes is substantially higher. This may represent a more general pattern for other parasitic plant clades and perhaps more broadly for angiosperms. PMID- 23459042 TI - Images of the month: Arytenoid swelling causing dysphagia secondary to ingestion of a hot object. PMID- 23459045 TI - Editorial: Predicting the risk of Barrett's esophagus: does the BERET fit? AB - Symptoms of gastroesophageal reflux are the only commonly used criterion for endoscopic screening for esophageal adenocarcinoma (EAC). Recent research has elucidated multiple other risk factors for both EAC and Barrett's esophagus (BE). Utilization of these risk factors may allow for the selection of a screening population with a much higher pre-test probability of disease. A recently developed risk-prediction model for BE is a significant step in the right direction; however, further refinements in this model will likely be necessary to optimize utility. Our inability to prognosticate cancer risk in BE does temper enthusiasm for increasing the pool of patients under endoscopic surveillance for BE, and again highlights the need for better, cheaper, and more accurate means of stratifying cancer risk in BE. PMID- 23459046 TI - Editorial: Should patients with suspected eosinophilic esophagitis undergo a therapeutic trial of proton pump inhibition? AB - Interaction with gastroesophageal reflux disease (GERD) has been a fundamental consideration in eosinophilic esophagitis (EoE) since the initial reports of this emerging entity. While studies from the '80s identified the presence of esophageal eosinophilia as being a histologic marker for the diagnosis of GERD, studies in the '90s demonstrated that high levels of esophageal eosinophilia were characteristic for a novel immune/antigen-mediated esophageal disease, EoE, that was seemingly quite distinct from GERD. However, several recent studies have demonstrated the effectiveness of proton pump inhibition (PPI) in reducing symptoms and histopathology in a subset of patients with esophageal eosinophilia and suspected EoE, leading to the terminology "PPI responsive esophageal eosinophilia." It remains uncertain as to whether these patients have EoE, GERD, or a PPI responsive esophageal inflammatory condition that is distinct from either GERD or EoE. Emerging translational research has evidenced mechanisms by which PPI response in patients with esophageal eosinophilia may be a consequence of PPI effects on the immune pathogenesis of EoE. Therefore, a symptom and histologic response to PPI in patients with esophageal eosinophilia does not necessarily "rule in" GERD. Until further studies better define the pathogenesis of PPI responsive esophageal eosinophilia, a trial of PPI therapy remains an important prerequisite to the diagnosis EoE. Following this diagnostic approach allows for the clinical application of available evidence that is derived from research trials in EoE that exclude PPI responsive eosinophilia. PMID- 23459047 TI - Editorial: Better ammunition for use of weight loss in managing gastroesophageal reflux disease. AB - The report from the HUNT Study provides the most convincing evidence yet that weight loss has beneficial effects on occurrence and severity of heartburn and regurgitation and their response to acid suppressant therapy. These data should re-invigorate clinicians to encourage weight loss in their reflux disease patients. PMID- 23459048 TI - Editorial: Are thiopurines and anti-TNFalpha agents safe to use in pregnant patients with inflammatory bowel disease? AB - Inflammatory bowel disease affects women in their peak reproductive years. Increased disease activity during pregnancy has been associated with adverse outcomes. Thus, it is recommended that immunosuppressant medications be continued during pregnancy. However, data regarding the safety of these medications during pregnancy are sparse and often conflicting. The study by Casanova et al. (1) adds to the growing evidence that the use of thiopurines and anti-TNFalpha agents during pregnancy does not increase the risk of birth defects. Results from prospective studies with longer follow-up are needed to fully understand the impact of thiopurines and anti-TNFalpha agents on child development and maturation of the immune system. PMID- 23459049 TI - Early endoscopic retrograde cholangiopancreatography in acute biliary pancreatitis. PMID- 23459050 TI - Response to Tse and Yuan. PMID- 23459051 TI - Response to Molina-Infante et al. PMID- 23459052 TI - Lymphocytic enteropathy, HLA-DQ2/DQ8 genotype and wheat-dependent symptoms: non celiac wheat sensitivity or Marsh I celiac disease? PMID- 23459053 TI - Tissue biomarkers distinguishing EoE from GERD: concerns about the control group. PMID- 23459054 TI - Response to Molina-Infante and Katzka. PMID- 23459055 TI - A novel method for treating bilious vomiting following endoscopic ultrasound guided hepaticogastrostomy. PMID- 23459056 TI - Cytomegalovirus pneumonia: a possible cause of death in patients with Crohn's disease. PMID- 23459057 TI - Celiac disease in children with inflammatory bowel disease: a prospective cohort study. PMID- 23459058 TI - Factitious disorder as a cause of gastrointestinal bleeding: use of a gastroenterologist's "Secondary Survey". PMID- 23459063 TI - Use of previous maternal health services has a limited role in reattendance for skilled institutional delivery: cross-sectional survey in Northwest Ethiopia. AB - BACKGROUND: Maternal mortality rates are unacceptably high in Ethiopia. Institutional delivery with skilled care of the mother is one of the interventions proven to reduce the risk of complications that can cause maternal and neonatal mortality. Quality of service given during antenatal visits and childbirth are important measures. The purpose of this study was to investigate the use of skilled institutional delivery and its repeat use during a subsequent pregnancy and to identify any reasons why women avoid institutional delivery. METHODS: A community-based cross-sectional study was conducted from March to June 2012 in Chilga Woreda, Northwest Ethiopia. Data were collected from women who gave birth during the year preceding the survey. Information was entered and cleaned using the Statistical Package for Social Sciences. Multivariate and binary logistic regression was used to identify the relative effect of each explanatory variable on the outcome. RESULTS: A total of 402 (84.2%) women gave birth at home. Previous experience of skilled institutional delivery had a limited role in subsequent acceptance or use of institutional delivery. Most mothers who had previously had institutional delivery gave birth at home. Although 111 (40.8%) women visited the health facility during their pregnancy only because of illness, 184 (38.8%) did not know when to visit for antenatal care. In multivariate analysis, lower maternal education, being a rural resident, previous use of institutional delivery, remoteness of the health facility, and multiparity were factors significantly associated with less likelihood of institutional delivery. Number of months pregnant at the time of the first antenatal visit had no role in increasing the likelihood of institutional delivery. CONCLUSION: The quality of the obstetric services presently available for women living in Ethiopia needs review. PMID- 23459064 TI - Variational methods for time-dependent classical many-particle systems. AB - A variational method for the classical Liouville equation is introduced that facilitates the development of theories for non-equilibrium classical systems. The method is based on the introduction of a complex-valued auxiliary quantity Psi that is related to the classical position-momentum probability density rho via rho = Psi*Psi. A functional of Psi is developed whose extrema imply that rho satisfies the Liouville equation. Multiscale methods are used to develop trial functions to be optimized by the variational principle. The present variational principle with multiscale trial functions can capture both the microscopic and the coarse-grained descriptions, thereby yielding theories that account for the two way exchange of information across multiple scales in space and time. Equations of the Smoluchowski form for the coarse-grained state probability density are obtained. Constraints on the initial state of the N-particle probability density for which the aforementioned equation is closed and conserves probability are presented. The methodology has applicability to a wide range of systems including macromolecular assemblies, ionic liquids, and nanoparticles. PMID- 23459065 TI - QT interval instability: an added piece for an incomplete jigsaw puzzle. PMID- 23459066 TI - Controversy surrounding the best time for ICD implantation after myocardial infarction. PMID- 23459067 TI - Synthesis of a paraffin phase change material microencapsulated in a siloxane polymer. AB - The coemulsification method suitable for the formulation of microcapsules of n eicosane coated with a polysiloxane is developed. This method allows to synthesize core-shell microcapsules of paraffin which have the shape of spheres or distorted spheres and are designed for the use as phase change materials. The microcapsules are formed in aqueous phase by the precipitation of n-eicosane together with modified polyhydromethylsiloxane from a common solvent which is miscible with aqueous media. The polysiloxane is modified by the attachment of silylvinyl and alkoxy functions before coemulsification with the paraffin. It also contains the Pt(0) Karstedt catalyst. The microcapsules formed by coemulsification are stabilized by the in situ cross-linking of the polysiloxane shell. The shell is additionally modified by the in situ generation of silanol groups which provide colloidal stabilization of microspheres in aqueous phase. Microcapsules were studied by DSC, SEM, optical polarized microscope, and by thermooptical analysis (TOA). PMID- 23459068 TI - Hexavalent Chromium Reduction and Accumulation by Acinetobacter AB1 Isolated from Fez Tanneries in Morocco. AB - Hexavalent chromium reduction and accumulation by Acinetobacter AB1 isolated from Fez tanneries effluents were tested. The effects of some environmental factors such as pH, temperature, and exposure time on Cr(VI) reduction and resistance were investigated. We found that this strain was able to resist to concentrations as high as 400 mg/l of Cr(VI). Moreover, pH 10 and the temperature 30 degrees C constitute favourable conditions to the growth and reduction of Acinetobacter AB1. Complete reduction of Cr(VI) was observed at low initial Cr(VI) concentrations of 50 mg/l after 72 h of incubation. Furthermore, Transmission electron microscope (TEM) analysis showed morphological changes in AB1 strain due 48H exposure to 100 mg/l chromate concentration and revealed circular electron dense (dark black point) inclusion within the cell cytoplasm suggesting chromium deposition within the cells. PMID- 23459069 TI - Lumbosacral plexus injury following vaginal delivery with epidural analgesia -A case report-. AB - A 26 year old, healthy, 41 week primiparous woman received a patient-controlled epidural analgesia (PCEA) and experienced paraplegia 11 hours later after a vaginal delivery. This was thought to be the result of complications from PCEA but there was no specific abnormality on magnetic resonance imaging (MRI) of the lumbosacral spine. On an electromyography (EMG) study performed 15 days following delivery, signs of tibial neuropathy were present and peripheral nerve injury during vaginal delivery was suspected. Motor weakness and hypoesthesia of both lower extremities improved rapidly, but a decrease in the desire to urinate or defecate, followed by urinary incontinence and constipation persisted, We suspected the sacral plexus had been severely damaged during vaginal delivery. Seven months later, the patient's conditions improved but had not fully recovered. PMID- 23459070 TI - Astragaloside IV suppresses collagen production of activated hepatic stellate cells via oxidative stress-mediated p38 MAPK pathway. AB - Oxidative stress is involved in hepatic fibrogenesis. Activation of hepatic stellate cells (HSCs), the key effectors in hepatic fibrogenesis, is characterized by overproduction of extracellular matrix. Astragaloside IV, the active component of Radix Astragali, has antioxidant properties and antifibrotic potential in renal fibrosis. Little is known about the role of astragaloside IV in liver and its involvement in hepatic fibrosis. This study aims at evaluating the antifibrotic potential of astragaloside IV and characterizing involved signal transduction pathways in culture-activated HSCs. Our results show that astragaloside IV attenuates oxidative stress in culture-activated HSCs, as demonstrated by scavenging reactive oxygen species and reducing lipid peroxidation, and elevates the level of cellular glutathione by stimulating Nrf2gene expression. Depletion of cellular glutathione by buthionine sulfoximine or abrogation of p38 MAPK by SB-203580 evidently eliminates the inhibitory effects of astragaloside IV on genes relevant to HSC activation. These results demonstrate that astragaloside IV inhibits HSC activation by inhibiting generation of oxidative stress and associated p38 MAPK activation and provide novel insights into the mechanisms of astragaloside IV as an antifibrogenic candidate in the prevention and treatment of liver fibrosis. PMID- 23459071 TI - Mad1 mediates hypoxia-induced doxorubicin resistance in colon cancer cells by inhibiting mitochondrial function. AB - Cancer cells acquire resistance to chemotherapy under hypoxia, which is mainly driven by the transcription factor HIF (hypoxia-inducible factor). Yet, it is uncertain which molecules mediate such resistance. While profiling gene expression in colon cancer cells, we found that Mad1 (MAX dimerization protein 1) is substantially induced during hypoxia. The hypoxic induction of Mad1 was confirmed by RT-PCR and Western blotting. The Mad1 expression was attenuated by HIF-1alpha small interfering (si) RNAs, but less so by HIF-2alpha siRNAs. Moreover, luciferase reporter and chromatin immunoprecipitation analyses revealed that HIF-1 transactivates the MAD1 gene by directly targeting a putative hypoxia response element in the MAD1 promoter. We next investigated if Mad1 is responsible for the hypoxia-induced drug resistance. We treated colon cancer cells with doxorubicin and found that the cells under hypoxia survived more than those under normoxia. The doxorubicin resistance was not induced in Mad1-knocked down cells even under hypoxia. Mad1 knockdown reactivated the caspase-9/caspase 3/PARP apoptotic pathway under hypoxia. Moreover, doxorubicin-induced production of reactive oxygen species was significantly reduced under hypoxia, which was reversed by Mad1 knockdown. During hypoxia, mitochondria became bigger in size and less active in respiration, both of which were attenuated by Mad1 knockdown. These data indicate that hypoxia-induced Mad1 lowers doxorubicin-stimulated generation of reactive oxygen species through mitochondrial inhibition and subsequently contributes to tumor resistance to doxorubicin. Therefore, Mad1 could be a potential target for sensitizing cancer cells to redox-cycling drugs such as doxorubicin. PMID- 23459072 TI - Nitroxyl (HNO) suppresses vascular Nox2 oxidase activity. AB - Nox2 oxidase activity underlies the oxidative stress and vascular dysfunction associated with several vascular-related diseases. We have reported that nitric oxide (NO) decreases reactive oxygen species production by endothelial Nox2. This study tested the hypothesis that nitroxyl (HNO), the redox sibling of NO, also suppresses vascular Nox2 oxidase activity. Specifically, we examined the influence of two well-characterized HNO donors, Angeli's salt and isopropylamine NONOate (IPA/NO), on Nox2-dependent responses to angiotensin II (reactive oxygen species production and vasoconstriction) in mouse cerebral arteries. Angiotensin II (0.1MUmol/L)-stimulated superoxide (measured by lucigenin-enhanced chemiluminescence) and hydrogen peroxide (Amplex red fluorescence) levels in cerebral arteries (pooled basilar and middle cerebral (MCA)) from wild-type (WT) mice were ~60% lower (P<0.05) in the presence of either Angeli's salt (1MUmol/L) or IPA/NO (1MUmol/L). Similarly, phorbyl 12,13-dibutyrate (10MUmol/L; Nox2 activator)-stimulated hydrogen peroxide levels were ~40% lower in the presence of IPA/NO (1MUmol/L; P<0.05). The ability of IPA/NO to decrease superoxide levels was reversible and abolished by the HNO scavenger l-cysteine (3mmol/L; P<0.05), but was unaffected by hydroxocobalamin (100MUmol/L; NO scavenger), ODQ (10MUmol/L; soluble guanylyl cyclase (sGC) inhibitor), or Rp-8-pCPT-cGMPS (10MUmol/L; cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor). Angiotensin II-stimulated superoxide was substantially less in arteries from Nox2-deficient (Nox2(-/y)) versus WT mice (P<0.05). In contrast to WT, IPA/NO (1MUmol/L) had no effect on superoxide levels in arteries from Nox2( /y) mice. Finally, angiotensin II (1-1000MUmol/L)-induced constriction of WT MCA was virtually abolished by IPA/NO (1MUmol/L), whereas constrictor responses to either the thromboxane A2 mimetic U46619 (1-100 nmol/L) or high potassium (122.7mmol/L) were unaffected. In conclusion, HNO suppresses vascular Nox2 oxidase activity via a sGC-cGMP-independent pathway. Thus, HNO donors might be useful therapeutic agents to limit and/or prevent Nox2-dependent vascular dysfunction. PMID- 23459073 TI - Dietary restriction attenuates the accelerated aging phenotype of Sod1(-/-) mice. AB - Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the antiaging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1(-/-) mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1(-/-) mice 30%, returning it to that of wild-type, control mice fed ad libitum. Oxidative damage in Sod1(-/-) mice was markedly reduced by dietary restriction, as indicated by a reduction in liver and brain F2 isoprostanes, a marker of lipid peroxidation. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1(-/-) mice fed the dietary-restricted diet compared to Sod1(-/-) mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver-specific pathology, the burden and severity of both neoplastic and nonneoplastic lesions was also significantly reduced in the Sod1(-/-) mice fed the dietary-restricted diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1(-/-) mice that arises from increased oxidative stress/damage. PMID- 23459074 TI - Influence of a mutation in IFN-gamma receptor 2 (IFNGR2) in human cells on the generation of Th17 cells in memory T cells. AB - The T cell subsets involved in inflammatory reactions are mainly the IFN-gamma secreting Th1 cells and IL17-producing Th17 cells. Although Th17 cells are primed in the thymus, there is evidence that Th17 cells can be generated from effector memory CD4(+) T cells. Cytokines as IL-6, TGF-beta, IL-21 and IL-23 involved in development of Th17 cells are well described. Here we analyzed the impact of a mutation in the IFN-gamma receptor 2 (IFN-gammaR2) on the induction of Th17 cells. By isolation of T cells and monocytes of a patient with this mutation we could demonstrate an inhibitory role of IFN-gamma signaling as IFN-gammaR2 deficient monocytes induce a higher percentage of IL-17(+) cells from both healthy and IFN-gammaR2-deficient CD4(+) T cells. This data confirm the interference of these two T helper subsets and points to a balance of Th1 and Th17 cells obtained by their own cytokine production and their interplay with APCs. PMID- 23459075 TI - Association of TNF level with production of circulating cellular microparticles during clinical manifestation of human cerebral malaria. AB - Microparticles (MPs) resulting from vesiculation of different cell types in Plasmodium falciparum infection correlate with the level of proinflammatory cytokine TNF that may thereby determine the disease severity. Using TruCount tube based flow cytometric method for the exact quantification of MP and enzyme linked immunosorbent assay for the measurement of TNF, we conducted a hospital based case control study on P. falciparum malaria patients to scrutinize and infer the link between the two. In 52 cerebral malaria (CM), 21 multi-organ-dysfunction (MOD), 12 non cerebral severe malaria (NCSM) and 43 uncomplicated malaria patients, the MP level was found to be significantly elevated in febrile malaria patients compared to healthy controls and a striking decrease in MP level was observed with the clearance of the P. falciparum infection in the patients upon follow-up. The lowering of the parasite density with the level of plasma TNF and the positive correlation of the cytokine with the cell derived MPs and negative correlation with the respective cell count in human malaria patients suggests that TNF may be a key stimulant to the cells resulting in the release of MPs in malaria infection. PMID- 23459076 TI - Mycobacterium tuberculosis may escape helper T cell recognition by infecting human fibroblasts. AB - The host immune response can limit Mycobacterium tuberculosis (Mtb) spreading in primary tuberculosis (TB) without eradicating all bacilli, which can persist causing latent TB infection and are responsible for reactivation TB. Persistent Mtb is confined to granulomas within phagocytes, but it is also found in other non-immune cells. We focused on fibroblasts since these cells participate to the granuloma formation and were shown to be infected in latent TB infections. We show that in vitro both Mtb and Bacille Calmette-Guerin actively replicate in human fibroblasts. Mycobacterial infection of fibroblasts causes a significant inhibition of interferon (IFN)-gamma induced membrane expression of major histocompatibility complex class II molecules in these cells. The functional consequence of in vitro infection is a significant reduction of the fibroblast capacity to present peptides and soluble proteins to autologous specific CD4(+) T cell clones. Moreover, fibroblasts are capable of presenting antigen derived from the processing of heat-killed Mtb, but not from viable Mtb. Data indicate that IFN-gamma treated fibroblasts are capable of presenting antigens derived from the processing of whole bacteria in addition to the capacity to present peptides and isolated proteins. Interestingly, Mtb infected fibroblasts lose this capacity, suggesting that Mtb may evade T helper immune surveillance by infecting fibroblasts. PMID- 23459077 TI - Structure, expression pattern and biological activity of molecular complex TREM 2/DAP12. AB - DNAX-activating protein of 12kDa (DAP12) is a member of type I transmembrane adapter proteins containing immunoreceptor tyrosine-based activation motifs (ITAMs). In humans DAP12 gene is located on chromosome 19q13.1. DAP12 forms a molecular complex with triggering receptor expressed on myeloid cells two (TREM 2). TREM-2 ligation leads to the activation of Src family kinases, phosphorylation of tyrosine residues in the ITAM of DAP12, recruitment of the Syk and ZAP70 tyrosine kinases and initiation of an intracellular signaling cascade. Depending on the cell type, DAP12/TREM-2 activation plays an important role in activation and differentiation of osteoclasts, phagocytosis of bacteria, brain and bone homeostasis and inhibition of the toll-like receptor (TLR) signaling in macrophages and dendritic cells. A proper understanding of the function of this complex receptor has been restrained because of the elusive nature of TREM-2 ligands. Here we review the structure, biological functions and signaling pathways of DAP12 and its associated receptor TREM-2. PMID- 23459078 TI - Genetic study confirms association of HLA-DPA1(*)01:03 subtype with ankylosing spondylitis in HLA-B27-positive populations. AB - The association of human leukocyte antigen (HLA)-B27 with ankylosing spondylitis (AS) has been known for over 38 years. However, it is not the only gene associated with AS. The aim of this study was to confirm the association of HLA markers around HLA-DPA1/DPB1 region with AS in HLA-B27 positive populations. Five SNPs (rs422544, rs6914849, rs92777535, rs3128968 and rs2295119) from the HLA DPA1/DPB1 region were genotyped in 340 individuals HLA-B27-positive from Portugal (137 AS patients and 203 healthy controls). Characterizations of HLA-DPA1/DPB1 alleles were also performed. rs422544 revealed a significant association with AS (P<0.05) and sliding windows (SW) analysis showed association of some groups of adjacent SNPs within HLA-DPA1/DPB1 region with AS (P<0.05). We also found association of the HLA-DPA1(*)01:03 allele with AS (P<0.05). This is the first study that confirms the association of HLA markers and haplotypes around HLA-DPA1 and HLA-DPB1 with AS. PMID- 23459079 TI - Genetic variants of FOXP3 influence graft survival in kidney transplant patients. AB - FOXP3(+) regulatory T cells (Treg) play a role in controlling alloreactivity. It has been shown that short (GT)n dinucleotide repeats (<=(GT)15; S) in the promoter region of the FOXP3 gene enhance the promoter activity when compared to long (GT)n repeats (>=(GT)16; L). The present study retrospectively investigated the influence of this (GT)n FOXP3 gene polymorphism on renal allograft survival. A total of 599 consecutive first-time kidney transplant patients (median follow up time 7.7 years) were subdivided according to their FOXP3 genotype into the S genotype group (SG) and the L-genotype group (LG). The SG was superior to the LG in both general graft survival censored for death (logrank test, p=0.013) and graft survival following acute rejection (p=0.021). Multivariate analysis defined the (GT)n FOXP3 dinucleotide repeat polymorphism as an independent factor and confirmed an advantage for the SG in renal allograft survival (HR=0.67, 95% CI 0.48-0.94, p=0.02). This gene association study identified a beneficial effect of FOXP3 genetic variants on graft survival in kidney transplant patients. PMID- 23459080 TI - Human leukocyte antigen class I alleles and haplotypes associated with primary hepatocellular carcinoma in persistent HBV-infected patients. AB - Many studies have shown that Human leukocyte antigen (HLA) class I alleles are associated with the development of various cancers. However, its role in hepatocellular carcinoma (HCC) is still unknown. To investigate whether HLA class I allelic polymorphism is related to the development of hepatitis B virus(HBV) associated HCC, a total of 326 HBV-infected patients (138 individuals with HCC and 188 well-matched controls without HCC) were enrolled in this study. HLA-A, B, and -C were genotyped by polymerase chain reaction-sequencing based typing (PCR-SBT) method. We identified HLA-B(*)35:01:01G as a risk factor for HBV related HCC development independent of our previous findings in HLA region (OR, 12.04; p, 0.0028; pc, 0.04). HLA-A(*)11:01:01G, B(*)58:01:01G, C(*)03:02:01G and some of their extended haplotypes were found as potential susceptible factors for HCC development. HLA-B(*)46:01:01G and some of its extended haplotypes were found as potential protective factors for HCC development. Our results support that specific HLA class I alleles and haplotypes may affect the risk of HBV-related HCC development. The findings may help to determine better approaches for prevention and treatment of HCC in these patients. PMID- 23459083 TI - A SIMULTANEOUS CONFIDENCE BAND FOR SPARSE LONGITUDINAL REGRESSION. AB - Functional data analysis has received considerable recent attention and a number of successful applications have been reported. In this paper, asymptotically simultaneous confidence bands are obtained for the mean function of the functional regression model, using piecewise constant spline estimation. Simulation experiments corroborate the asymptotic theory. The confidence band procedure is illustrated by analyzing CD4 cell counts of HIV infected patients. PMID- 23459081 TI - Multi-population classical HLA type imputation. AB - Statistical imputation of classical HLA alleles in case-control studies has become established as a valuable tool for identifying and fine-mapping signals of disease association in the MHC. Imputation into diverse populations has, however, remained challenging, mainly because of the additional haplotypic heterogeneity introduced by combining reference panels of different sources. We present an HLA type imputation model, HLA*IMP:02, designed to operate on a multi-population reference panel. HLA*IMP:02 is based on a graphical representation of haplotype structure. We present a probabilistic algorithm to build such models for the HLA region, accommodating genotyping error, haplotypic heterogeneity and the need for maximum accuracy at the HLA loci, generalizing the work of Browning and Browning (2007) and Ron et al. (1998). HLA*IMP:02 achieves an average 4-digit imputation accuracy on diverse European panels of 97% (call rate 97%). On non-European samples, 2-digit performance is over 90% for most loci and ethnicities where data available. HLA*IMP:02 supports imputation of HLA-DPB1 and HLA-DRB3-5, is highly tolerant of missing data in the imputation panel and works on standard genotype data from popular genotyping chips. It is publicly available in source code and as a user-friendly web service framework. PMID- 23459085 TI - Echovirus 30 outbreak associated with a high meningitis attack rate in Thrace, Greece. AB - Between late May and July 2012, 105 children (62 boys) originating from 2 cities of Thrace were examined because of fever, headache and abdominal pain. Thirty three of them were hospitalized. They had normal hemograms, and mild to moderate cerebrospinal fluid pleocytosis. Echovirus 30 was isolated from fecal and cerebrospinal fluid samples. Among confirmed cases of echoviral illness, the meningitis attack rate was 51.9%. PMID- 23459084 TI - Central obesity in males affected by a dyslipidemia-associated genetic polymorphism on APOA1/C3/A4/A5 gene cluster. AB - BACKGROUND: Central obesity is a rising epidemic, and often occurs in parallel with dyslipidemia. Furthermore, enhancement of ectopic fat deposition has been observed in both human studies and animal models of altered lipidemic control. Though APOA1/C3/A4/A5 genetic polymorphisms are associated with dyslipidemia, their effect on central obesity is less known. METHOD: The anthropometric and metabolic parameters were taken from obese (body mass index (BMI) ?25 kg m(-2)) and non-obese healthy (BMI <25) Taiwanese patients at the initiation weight-loss intervention and 6 months later. The effects of APOA1/C3/A4/A5 genetic polymorphisms were analyzed cross-sectionally and longitudinally. Gender contributions were specifically examined. PATIENTS: Three hundred and ninety eight participants (obese n=262; non-obese healthy n=136) were recruited in total, and 130 obese patients underwent weight-loss treatments. RESULTS: APOA5 rs662799 minor allele carriage was associated with unfavorable metabolic profiles in obese but not non-obese individuals at baseline. Further analysis identified gender-genotype interactions in waist-hip ratio (WHR), and that one rs662799 minor allele increased 0.032 WHR unit in obese males as analyzed by linear regression adjusted for age, BMI and plasma triglyceride (TG) (95% confidence interval (CI)=0.014-0.050, P=0.001). The rs662799-associated WHR elevation resulted in increased frequency of central obesity (WHR ?1.0) in rs662799 carrying obese males as analyzed by binary logistic regression adjusted for age, BMI and plasma TG (odds ratio=6.52, 95% CI=1.87-22.73, P=0.003). In contrast, APOA5 rs662799 and central obesity were no longer correlated 6 months into weight loss treatments, owing to significant WHR reductions in male rs662799 minor allele carriers (P=0.001). Meanwhile, hypertriglyceridemia was more prevalent in both male and female obese rs662799 minor allele carriers at baseline (males, P=0.034, females, P=0.007). CONCLUSION: This study highlights the gender-specific and weight-sensitive effects of APOA5 rs662799 on central obesity in Taiwanese individuals, and that these effects are dyslipidemia-independent and weight-loss responsive. PMID- 23459086 TI - Transition to injecting 3,4-methylene-dioxy-pyrovalerone (MDPV) among needle exchange program participants in Hungary. AB - In 2011, anecdotal data indicated that 3,4-methylene-dioxy-pyrovalerone (MDPV) might become popular among needle exchange program (NEP) clients in Hungary as a possible substitute for formerly used substances such as amphetamines and heroin. The aim of the study reported here was to examine how the emergence of MDPV influenced the choice of the injecting substance among NEP clients. A total of 183 injecting drug users (IDUs) participating in the largest NEP in Budapest agreed to participate in the study and report on their drug use habits. During 2011, remarkable changes occurred in the structure of the primary injected substances. Amphetamine was cited as the primary injected substance by 45.9% of the respondents and MDPV by 48.1%. Close to half of the former amphetamine injectors had switched to MDPV (64 persons, 45.1%) as had 10 (41.7%) of the former heroin injectors and 11 (78.6%) of those using other substances (cocaine and mephedrone). The appearance of MDPV on the illegal drug market had a substantial effect on the drug use patterns of the IDU population. Further research should be conducted to explain the changes, that might include the purity, price and availability of amphetamine and heroin. PMID- 23459087 TI - Patients' perspectives on pain. AB - Nociceptive and neuropathic pain (NP) are common consequences following spinal cord injury (SCI), with large impact on sleep, mood, work, and quality of life. NP affects 40% to 50% of individuals with SCI and is sometimes considered the major problem following SCI. Current treatment recommendations for SCI-NP primarily focus on pharmacological strategies suggesting the use of anticonvulsant and antidepressant drugs, followed by tramadol and opioid medications. Unfortunately, these are only partly successful in relieving pain. Qualitative studies report that individuals with SCI-related long-lasting pain seek alternatives to medication due to the limited efficacy, unwanted side effects, and perceived risk of dependency. They spend time and money searching for additional treatments. Many have learned coping strategies on their own, including various forms of warmth, relaxation, massage, stretching, distraction, and physical activity. Studies indicate that many individuals with SCI are dissatisfied with their pain management and with the information given to them about their pain, and they want to know more about causes and strategies to manage pain. They express a desire to improve communication with their physicians and learn about reliable alternative sources for obtaining information about their pain and pain management. The discrepancy between treatment algorithms and patient expectations is significant. Clinicians will benefit from hearing the patient's voice. PMID- 23459089 TI - The Maternal Obesity Management (MOM) Trial Protocol: a lifestyle intervention during pregnancy to minimize downstream obesity. AB - BACKGROUND: Maternal obesity and/or high gestational weight gain (GWG) are associated with downstream child obesity. Pregnancy represents a critical period for prevention as women are highly motivated and more receptive to behavior change. OBJECTIVE: This pilot study was developed to test the feasibility of intervening with the mother, specifically keeping her GWG within the Institute of Medicine (IOM) limits, with the intended target of preventing obesity in her child downstream. We are testing the practicality of delivering a structured physical activity and nutrition intervention to pregnant women during gestation and then following mom and baby to 24 months of age. STUDY DESIGN: This study is a two-arm, parallel group, randomized controlled trial being conducted in Ottawa. Pregnant women, with pregravid BMI >18.5, between 12 and 20 weeks gestation are randomized to one of two groups: intervention (n=30) who receive the MOM trial Handbook (guide to healthy gestation) plus a structured physical activity and nutrition program, or a standard clinical care control group (n=30). The intervention lasts 25-28 weeks (6 months) depending on anticipated delivery date, with follow-up assessment on mother and child at 3, 6, 12 and 24 months post delivery. SIGNIFICANCE: Pregnancy, a critical time of growth, development and physiological change, provides an opportunity for early lifestyle intervention. The goal of identifying an effective lifestyle program for the gestational period that leads to healthy fetal development and subsequently normal weight offspring, less likely to develop obesity and its co-morbidities, is unique and could possibly attenuate the inter-generational cycle of obesity. PMID- 23459090 TI - Is a controlled randomised trial the non-plus-ultra design? A contribution to discussion on comparative, controlled, non-randomised trials. AB - BACKGROUND: Clinical studies provide formalised experience for evidence-based medicine (EBM). Many people consider a controlled randomised trial (CRT, identical to a randomised controlled trial RCT) to be the non-plus-ultra design. However, CRTs also have limitations. The problem is not randomisation itself but informed consent for randomisation and masking of therapies according to today's legal and ethical standards. We do not want to de-rate CRTs, but we would like to contribute to the discussion on clinical research methodology. SITUATION: Informed consent to a CRT and masking of therapies plainly select patients. The excellent internal validity of CRTs can be counterbalanced by poor external validity, because internal and external validity act as antagonists. In a CRT, patients may feel like guinea pigs, this can decrease compliance, cause protocol violations, reduce self-healing properties, suppress unspecific therapeutic effects and possibly even modify specific efficacy. DISCUSSION: A control group (comparative study) is most important for the degree of evidence achieved by a trial. Study control by detailed protocol and good clinical practice (controlled study) is second in importance and randomisation and masking is third (thus the sequence CRT instead of RCT). Controlled non-randomised trials are just as ambitious and detailed as CRTs. RECOMMENDATION: We recommend clinicians and biometricians to take high quality controlled non-randomised trials into consideration more often. They combine good internal and external validity, better suit daily medical practice, show better patient compliance and fewer protocol violations, deliver estimators unbiased by alienated patients, and perhaps provide a clearer explanation of the achieved success. PMID- 23459088 TI - Concepts and practices used to develop functional PLGA-based nanoparticulate systems. AB - The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shell-type lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner. PMID- 23459091 TI - hERG channel function: beyond long QT. AB - To date, research on the human ether-a-go-go related gene (hERG) has focused on this potassium channel's role in cardiac repolarization and Long QT Syndrome (LQTS). However, growing evidence implicates hERG in a diversity of physiologic and pathological processes. Here we discuss these other functions of hERG, particularly their impact on diseases beyond cardiac arrhythmia. PMID- 23459092 TI - Long-term effects of alendronate on fracture healing and bone remodeling of femoral shaft in ovariectomized rats. AB - AIM: To investigate the long-term effects of alendronate (Aln), a widely used oral bisphosphonate, on fracture healing and bone remodeling in ovariectomized rats. METHODS: Adult female SD rats underwent ovariectomy, and then bilateral femoral osteotomy at 12 weeks post-ovariectomy. From d 2 post-ovariectomy, the animals were divided into 3 groups, and treated with Aln (3 mg.kg(-1).d(-1), po) for 28 weeks (Aln/Aln), Aln for 12 weeks and saline for 16 weeks (Aln/Saline) or saline for 28 weeks (Saline/Saline). At 6 and 16 weeks post-fracture, the fracture calluses were examined with X-ray radiography, and biomechanical testing and histological analysis were performed. The calluses were labeled with tetracycline and calcein to evaluate the mineral apposition rate (MAR). RESULTS: The fracture line was less distinct in the 2 Aln-treated groups at 6 weeks post fracture, and disappeared in all the 3 groups at 16 weeks post-fracture. The size of the callus and radiographic density of the femora in the Aln/Aln group were the highest among the 3 groups at 6 and 16 weeks post-fracture. Similar results were observed in the ultimate load at failure and energy absorption. However, the treatment with Aln delayed endochondral ossification of the callus, and significantly increased the total sagittal-sectional area, percentage callus area and callus thickness, and decreased the MAR at 6 and 16 weeks post-fracture. CONCLUSION: In the ovariectomized rat model, Aln is beneficial for the mechanical properties of the callus, but delays callus remodeling by suppressing the remodeling of woven bone into lamellar bone. PMID- 23459094 TI - Diagnostic and Statistical Manual of Mental Disorders-5: implications for older adults and their families. AB - The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is targeted for publication in May 2013. Older adults and their families should be aware of the potential impact that changes in this important document may have on diagnosis and treatment of mental health concerns. Two specific changes related to a new category of Neurocognitive Disorders and a new interpretation of criteria for depression after bereavement are discussed in this article. Nurses can help older adults and their families understand the new DSM-5 terminology and encourage them to discuss risks, benefits, and likely outcomes of diagnoses, procedures, and treatments that may seem unfamiliar. PMID- 23459093 TI - The Efficacy of Cognitive Behavioral Therapy: A Review of Meta-analyses. AB - Cognitive behavioral therapy (CBT) refers to a popular therapeutic approach that has been applied to a variety of problems. The goal of this review was to provide a comprehensive survey of meta-analyses examining the efficacy of CBT. We identified 269 meta-analytic studies and reviewed of those a representative sample of 106 meta-analyses examining CBT for the following problems: substance use disorder, schizophrenia and other psychotic disorders, depression and dysthymia, bipolar disorder, anxiety disorders, somatoform disorders, eating disorders, insomnia, personality disorders, anger and aggression, criminal behaviors, general stress, distress due to general medical conditions, chronic pain and fatigue, distress related to pregnancy complications and female hormonal conditions. Additional meta-analytic reviews examined the efficacy of CBT for various problems in children and elderly adults. The strongest support exists for CBT of anxiety disorders, somatoform disorders, bulimia, anger control problems, and general stress. Eleven studies compared response rates between CBT and other treatments or control conditions. CBT showed higher response rates than the comparison conditions in 7 of these reviews and only one review reported that CBT had lower response rates than comparison treatments. In general, the evidence base of CBT is very strong. However, additional research is needed to examine the efficacy of CBT for randomized-controlled studies. Moreover, except for children and elderly populations, no meta-analytic studies of CBT have been reported on specific subgroups, such as ethnic minorities and low income samples. PMID- 23459095 TI - A high-density tissue microarray from patients with clinically localized prostate cancer reveals ERG and TATI exclusivity in tumor cells. AB - BACKGROUND: Prostate cancer (PCa) is characterized by high tumor heterogeneity. In 2005, the fusion between the androgen-regulated gene TMPRSS2 and members of the ETS family was discovered in prostate cancer. In particular, fusion of TMPRSS2 with ERG was found in approximately 50% of prostate cancers and considered as an early event in the onset of the disease. The prognostic value of this fusion is still contradictory. Bioinformatics showed that overexpression of SPINK1 gene in a subset of fusion-gene-negative prostate cancers was associated with a poor prognosis. In theory, overexpression of the tumor-associated trypsin inhibitor (TATI) protein encoded by SPINK1 in fusion-gene-negative tumor cells opens the way to selected treatments for genotypically different cases. However, their expression has never been assessed at the cellular level in the same tissue samples. METHODS: As ERG expression has been shown to be a surrogate of fusion gene occurrence in prostate cancer, we have used double immunohistochemical staining to assess expression of ERG and TATI on a large tissue microarray comprising 4177 cases of localized prostate cancer. RESULTS: We did not detect any co-expression of ERG and TATI in the same cancer cells, which confirms previous suggestions from in silico studies. ERG was associated with Gleason score (GS), surgical margins and pathological stage, but had no prognostic value in this cohort. TATI was weakly associated with pathological stage but had no significant association with outcome. CONCLUSIONS: We here provide a morphological basis for ERG and TATI exclusivity in prostate cancer cells. Future therapies should be based on a combination of different targets in order to eradicate tumor cells with gene fusions and cells expressing other tumor associated antigens. Further studies are needed to understand why ERG and TATI are not co-expressed in the same prostatic tumor cells. PMID- 23459096 TI - Hyperglycemia and prostate cancer recurrence in men treated for localized prostate cancer. AB - BACKGROUND: Obesity is consistently linked with prostate cancer (PCa) recurrence and mortality, though the mechanism is unknown. Impaired glucose regulation, which is common among obese individuals, has been hypothesized as a potential mechanism for PCa tumor growth. In this study, we explore the relationship between serum glucose at time of treatment and risk of PCa recurrence following initial therapy. METHODS: The study group comprised 1734 men treated with radical prostatectomy (RP) or radiation therapy (RT) for localized PCa between 2001-2010. Serum glucose levels closest to date of diagnosis were determined. PCa recurrence was determined based on PSA progression (nadir PSA+2 for RT; PSA>=0.2 for RP) or secondary therapy. Multivariate Cox regression was performed to determine whether glucose level was associated with biochemical recurrence after adjusting for age, race, body mass index, comorbidity, diagnosis of diabetes, Gleason Sum, PSA, treatment and treatment year. RESULTS: Recurrence was identified in 16% of men over a mean follow-up period of 41 months (range 1-121 months). Those with elevated glucose (>=100 mg/dl) had a 50% increased risk of recurrence (HR 1.5, 95% CI: 1.1-2.0) compared with those with a normal glucose level (<100 mg/dl). This effect was seen in both those undergoing RP (HR 1.9, 95% CI: 1.0-3.6) and those treated with RT (HR 1.4, 95% CI: 1.0-2.0). CONCLUSIONS: Glucose levels at the time of PCa diagnosis are an independent predictor of PCa recurrence for men undergoing treatment for localized disease. PMID- 23459097 TI - Association between lncrna PCGEM1 polymorphisms and prostate cancer risk. AB - BACKGROUND: Prostate cancer (PCa) gene expression marker 1 (PCGEM1), a long noncoding RNA, has drawn increasing attention for its important role in PCa. However, the association between genetic variations in the PCGEM1 gene and risk of PCa has not been investigated yet. METHODS: We investigated the effect of two tagging single-nucleotide polymorphism (tSNPs; rs6434568 and rs16834898) in PCGEM1 gene on PCa risk in the Chinese men. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. RESULTS: We found a significantly decreased risk of PCa for rs6434568 AC and AC/AA genotype (adjusted OR=0.76, 95% CI=0.60-0.97 for AC; adjusted OR=0.76, 95% CI=0.61-0.96 for AC/AA), as well as rs16834898 AC and AC/CC genotype (adjusted OR=0.76, 95% CI=0.59-0.97 for AC; adjusted OR=0.79, 95% CI=0.62-0.99 for AC/CC), compared with the CC and AA genotypes, respectively. When we evaluated these two tSNPs together based on the risk alleles (that is, rs6434568 C and rs16834898 A), we found that the combined genotypes with four risk alleles were associated with an increased risk of PCa compared with those carrying 0-3 risk alleles (1.53, 1.19-1.97), and this increased risk was more pronounced among subjects of<=70 years (1.80, 1.24-2.62), Gleason score>=7 (1.68, 1.28-2.22) and PSA level>=20 (1.64, 1.24-2.18). CONCLUSIONS: Our results indicated that PCGEM1 polymorphisms may contribute to PCa risk in Chinese men. Additional functional analyses are required to detect the detailed mechanism underlying the observed association. PMID- 23459098 TI - Development and evaluation of a pharmacogenomics educational program for pharmacists. AB - Objectives. To evaluate hospital and outpatient pharmacists' pharmacogenomics knowledge before and 2 months after participating in a targeted, case-based pharmacogenomics continuing education program.Design. As part of a continuing education program accredited by the Accreditation Council for Pharmacy Education (ACPE), pharmacists were provided with a fundamental pharmacogenomics education program.Evaluation. An 11-question, multiple-choice, electronic survey instrument was distributed to 272 eligible pharmacists at a single campus of a large, academic healthcare system. Pharmacists improved their pharmacogenomics test scores by 0.7 questions (pretest average 46%; posttest average 53%, p=0.0003).Conclusions. Although pharmacists demonstrated improvement, overall retention of educational goals and objectives was marginal. These results suggest that the complex topic of pharmacogenomics requires a large educational effort in order to increase pharmacists' knowledge and comfort level with this emerging therapeutic opportunity. PMID- 23459100 TI - Optical properties of GaN-based nanowires containing a single Al(0.14)Ga(0.86)N/GaN quantum disc. AB - The optical properties of wurtzite GaN nanowires containing single Al0.14Ga0.86N/GaN quantum discs of different thickness have been investigated. The dependence of the photoluminescence (PL) transition energy on the quantum disc thickness and the thickness of a lateral AlGaN shell has been simulated in the framework of a three-dimensional effective mass model, accounting for the presence of a lateral AlGaN shell, strain state and the piezoelectric and spontaneous polarization. The predicted transition energies are in good agreement with the statistics realized on more than 40 single nanowire emission spectra and PL spectra of ensembles of nanowires. The emission spectra of the single quantum discs exhibit a Lorentzian shape with a homogeneous line width as low as 3 meV. Finally, we discuss the dependence of the interband transition energy on diameter. PMID- 23459099 TI - Targeted and random mutagenesis of Ehrlichia chaffeensis for the identification of genes required for in vivo infection. AB - Ehrlichia chaffeensis is a tick transmitted pathogen responsible for the disease human monocytic ehrlichiosis. Research to elucidate gene function in rickettsial pathogens is limited by the lack of genetic manipulation methods. Mutational analysis was performed, targeting to specific and random insertion sites within the bacterium's genome. Targeted mutagenesis at six genomic locations by homologous recombination and mobile group II intron-based methods led to the consistent identification of mutants in two genes and in one intergenic site; the mutants persisted in culture for 8 days. Three independent experiments using Himar1 transposon mutagenesis of E. chaffeensis resulted in the identification of multiple mutants; these mutants grew continuously in macrophage and tick cell lines. Nine mutations were confirmed by sequence analysis. Six insertions were located within non-coding regions and three were present in the coding regions of three transcriptionally active genes. The intragenic mutations prevented transcription of all three genes. Transposon mutants containing a pool of five different insertions were assessed for their ability to infect deer and subsequent acquisition by Amblyomma americanum ticks, the natural reservoir and vector, respectively. Three of the five mutants with insertions into non-coding regions grew well in deer. Transposition into a differentially expressed hypothetical gene, Ech_0379, and at 18 nucleotides downstream to Ech_0230 gene coding sequence resulted in the inhibition of growth in deer, which is further evidenced by their failed acquisition by ticks. Similarly, a mutation into the coding region of ECH_0660 gene inhibited the in vivo growth in deer. This is the first study evaluating targeted and random mutagenesis in E. chaffeensis, and the first to report the generation of stable mutants in this obligate intracellular bacterium. We further demonstrate that in vitro mutagenesis coupled with in vivo infection assessment is a successful strategy in identifying genomic regions required for the pathogen's in vivo growth. PMID- 23459101 TI - Evaluation of the performance of the reduced local lymph node assay for skin sensitization testing. AB - The local lymph node assay (LLNA) is the preferred method for classification of sensitizers within REACH. To reduce the number of mice for the identification of sensitizers the reduced LLNA was proposed, which uses only the high dose group of the LLNA. To evaluate the performance of this method for classification, LLNA data from REACH registrations were used and classification based on all dose groups was compared to classification based on the high dose group. We confirmed previous examinations of the reduced LLNA showing that this method is less sensitive compared to the LLNA. The reduced LLNA misclassified 3.3% of the sensitizers identified in the LLNA and misclassification occurred in all potency classes and that there was no clear association with irritant properties. It is therefore not possible to predict beforehand which substances might be misclassified. Another limitation of the reduced LLNA is that skin sensitizing potency cannot be assessed. For these reasons, it is not recommended to use the reduced LLNA as a stand-alone assay for skin sensitization testing within REACH. In the future, the reduced LLNA might be of added value in a weight of evidence approach to confirm negative results obtained with non-animal approaches. PMID- 23459102 TI - Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? A systematic review. AB - Low and oscillatory wall shear stress is widely assumed to play a key role in the initiation and development of atherosclerosis. Indeed, some studies have relied on the low shear theory when developing diagnostic and treatment strategies for cardiovascular disease. We wished to ascertain if this consensus is justified by published data. We performed a systematic review of papers that compare the localization of atherosclerotic lesions with the distribution of haemodynamic indicators calculated using computational fluid dynamics. The review showed that although many articles claim their results conform to the theory, it has been interpreted in different ways: a range of metrics has been used to characterize the distribution of disease, and they have been compared with a range of haemodynamic factors. Several studies, including all of those making systematic point-by-point comparisons of shear and disease, failed to find the expected relation. The various pre- and post-processing techniques used by different groups have reduced the range of shears over which correlations were sought, and in some cases are mutually incompatible. Finally, only a subset of the known patterns of disease has been investigated. The evidence for the low/oscillatory shear theory is less robust than commonly assumed. Longitudinal studies starting from the healthy state, or the collection of average flow metrics derived from large numbers of healthy vessels, both in conjunction with point-by-point comparisons using appropriate statistical techniques, will be necessary to improve our understanding of the relation between blood flow and atherogenesis. PMID- 23459104 TI - Determinants of symptoms in gastroesophageal reflux disease: nonerosive reflux disease, symptomatic, and silent erosive reflux disease. AB - BACKGROUND: Nonerosive reflux disease (NERD) is detected frequently. Furthermore, as general checkups including endoscopy have become popular, silent erosive esophagitis (EE), which is defined as EE without the typical symptoms of gastroesophageal reflux disease (GERD), is also frequently encountered. We investigated the determinants of symptom presentation in symptomatic EE, NERD, and silent EE, which are representative GERD groups. MATERIALS AND METHODS: Participants in a prospective health-screening cohort underwent upper endoscopy from June 2009 to September 2010. GERD was defined as heartburn and/or acid regurgitation at least weekly or EE by endoscopy. All participants were asked to complete a validated questionnaire, which included questions about gastrointestinal symptoms and the somatization symptom checklist (SSC). RESULTS: Among 4565 participants (men, 51.9%; mean age, 46.0+/-10.2 years), GERD was found in 678 participants (14.9%) and EE in 335 participants (7.3%). Each group of participants was classified into the following three categories: (i) symptomatic EE (n=38, 5.6%); (ii) NERD (n=343, 50.6%); and (iii) silent EE (n=297, 43.8%). Male sex and obesity were common predictors in both the symptomatic and the silent EE groups compared with the control group. Higher scores on the SSC [odds ratio (OR), 3.7; 95% confidence interval (CI), 1.8-7.8] and overlap of functional dyspepsia (OR, 35.4; 95% CI, 14.9-84.3) were predictors of symptomatic EE compared with asymptomatic EE. Symptomatic EE was more strongly associated with male sex (OR, 7.8; 95% CI, 2.9-20.9) than was NERD. CONCLUSION: Somatization was the most important determinant of GERD symptoms. Silent EE was prevalent among participants with GERD, even though its natural history and clinical significance are unknown. PMID- 23459103 TI - Biomechanical factors in the biology of aortic wall and aortic valve diseases. AB - The biomechanical factors that result from the haemodynamic load on the cardiovascular system are a common denominator of several vascular pathologies. Thickening and calcification of the aortic valve will lead to reduced opening and the development of left ventricular outflow obstruction, referred to as aortic valve stenosis. The most common pathology of the aorta is the formation of an aneurysm, morphologically defined as a progressive dilatation of a vessel segment by more than 50% of its normal diameter. The aortic valve is exposed to both haemodynamic forces and structural leaflet deformation as it opens and closes with each heartbeat to assure unidirectional flow from the left ventricle to the aorta. The arterial pressure is translated into tension-dominated mechanical wall stress in the aorta. In addition, stress and strain are related through the aortic stiffness. Furthermore, blood flow over the valvular and vascular endothelial layer induces wall shear stress. Several pathophysiological processes of aortic valve stenosis and aortic aneurysms, such as macromolecule transport, gene expression alterations, cell death pathways, calcification, inflammation, and neoangiogenesis directly depend on biomechanical factors. PMID- 23459105 TI - Interobserver concordance in controlled attenuation parameter measurement, a novel tool for the assessment of hepatic steatosis on the basis of transient elastography. AB - BACKGROUND: The combination of transient elastometry with a controlled attenuation parameter (CAP) is available to evaluate hepatic steatosis (HS) along with liver stiffness. AIMS: To assess the concordance of CAP measurements between two independent observers in patients infected by HIV and/or hepatitis virus, as well as to determine the concordance of classification of the grade of HS using two cut-off values. MATERIALS AND METHODS: In a cross-sectional prospective study, CAP-enabled transient elastometry acquisitions were performed by two independent observers in patients with HIV or hepatitis virus infection. The interobserver concordance between the CAP examinations was assessed using the intraclass correlation coefficient and the concordance in the classification of patients in the grades of HS was characterized using the kappa index. RESULTS: A total of 118 patients were included. Twenty (17%) patients were HIV monoinfected, 44 (37.3%) were hepatitis C virus monoinfected, and 52 (44%) had HIV/hepatitis C virus coinfection. The median (Q1-Q3) of the absolute difference of CAP values between the two observers was 20 (10-41) dB/m. The overall intraclass correlation coefficient was 0.84 (95% confidence interval: 0.77-0.88). The corresponding figures for liver stiffness measurements were 0.9 (0.4-2.6) kPa and 0.96 (95% confidence interval: 0.94-0.97). The kappa indexes for the concordance of classification for the presence of HS, cut-off of 215 dB/m, and significant HS, cut-off of 252 dB/m, were 0.53 and 0.62, respectively. CONCLUSION: The determination of HS by means of CAP in HIV and/or hepatitis virus infection represents an observer-independent and easily performable method. However, the use of cut-off values for the classification of patients is suboptimal. PMID- 23459106 TI - Coping and participation in youth with spinal cord injury. AB - BACKGROUND: Coping and participation are important adjustment outcomes of youth with spinal cord injury (SCI). Research addressing how these outcomes are related is limited. OBJECTIVE: This cross-sectional study examined relationships between coping and participation in youth with SCI. METHOD: Youth ages 7 to 18 years were recruited from 3 hospitals specializing in rehabilitation of youth with SCI. The Kidcope assessed coping strategies, and the Children's Assessment of Participation and Enjoyment (CAPE) examined participation patterns. Point biserial and Pearson correlations assessed relationships among variables, and hierarchical multiple regression analyses examined whether coping significantly contributed to participation above and beyond significant demographic and injury related factors. RESULTS: The sample included 294 participants: 45% female, 65% Caucasian, 67% with paraplegia. Mean age was 13.71 years (SD = 3.46), and mean duration of injury was 5.39 years (SD = 4.49). Results indicated that higher levels of social support and lower levels of self-criticism predicted higher participation in informal activities, lower levels of social withdrawal predicted participation in informal activities with a greater diversity of individuals, lower levels of blaming others predicted higher enjoyment of informal activities, and higher levels of cognitive restructuring predicted participation in formal activities with a greater diversity of individuals and in settings further from home. CONCLUSION: Results suggest higher levels of social support and cognitive restructuring and lower levels of self-criticism, social withdrawal, and blaming others predicted favorable participation outcomes. Interventions for youth with SCI that encourage higher levels of positive coping strategies and lower levels of negative and avoidant strategies may promote positive participation outcomes. PMID- 23459107 TI - In vitro and in vivo evaluation of superparamagnetic iron oxide nanoparticles coated by bisphosphonates: the effects of electrical charge and molecule length. AB - Physicochemical coating properties are often considered to be determining factors for in vivo characteristics of superparamagnetic iron oxide nanoparticles, used as contrast agent in Magnetic Resonance Imaging (MRI). To investigate the electrical charge (modified by zero, one or two ammonium groups) and the molecule length (3, 5 or 7 methylene chains) effects of bisphosphonate-type coatings, we assessed the complement activation, in vivo plasma and tissue relaxation time alterations of intravenously injected small iron oxide nanoparticles (<25 nm) on male healthy Wistar rats. The presence of ammonium groups induces a weak activation of the complement whatever the size and the concentration of particles, whereas hydroxyethylenebisphosphonate (HEBP)-coated particles are poor complement activators only at the lowest concentration. In vivo, HEBP-coated nanoparticles have the greatest prolonged relaxation time effects, despite their higher negative electrical charge, contrary to two ammonium bearing coatings. No significant differences were observed between mono-ammonium molecular coatings. PMID- 23459108 TI - A way to follow the viability of encapsulated Bifidobacterium bifidum subjected to a freeze-drying process in order to target the colon: interest of flow cytometry. AB - The aim of this work was to apply flow cytometry in order to assess and compare the viability of freeze-dried entrapped bacteria with an usual technique by quantification by plate count techniques. It also aimed at studying the effect of various cryoprotectants on the viability of an entrapped Bifidobacterium bifidum subjected to freeze-drying to check their ability to be delivered all along the gastro-intestinal tract. The alginate-pectinate beads were chosen as the encapsulation matrix added with different protectants. The beads were characterized by scanning electron microscopy and the viability was checked by both methods. The best combination to improve viability of entrapped bacteria subjected to freeze-drying is made of glycerol 20% (one cryoprotectant) and sodium ascorbate 10% (one anti-oxidative compound). This study also demonstrates that flow cytometry allows assessment of entrapped bacteria viability. Indeed we showed that viability evaluated by plate method is correlated to that obtained by flow cytometry. So, flow cytometry is a rapid method to determine cell viability after encapsulation and freeze-drying. Finally, these beads seem to be a promising probiotic delivery system to target the colon. PMID- 23459109 TI - Differential surface properties of commercial crystalline telmisartan samples. AB - The aim of the present study was to investigate differences in surface chemistry of commercially available telmisartan (TMS) samples in Indian market and to correlate them to the surface molecular environment. Comprehensive characterization of material properties of four TMS samples from different sources showed that all samples exhibited same polymorphic form, but different particle shape, particle size distribution, surface energetics and surface chemistry. Wettability and surface free energy were determined using sessile drop contact angle technique. TMS samples exhibited significant variations in their wetting behavior. The role of crystal shape, particle size distribution, surface energetics and surface chemistry in controlling TMS powder wettability was collectively explored by contact angle experiments. Evaluation of work of adhesion (Wa), immersion (Wi) and spreading (Ws) indicated that samples had differential wetting behavior. The surface chemistry was elucidated by X-ray photoelectron spectroscopy (XPS). The surface polarity index was determined by XPS and expressed as (oxygen+nitrogen)-to-(carbon) atomic concentration ratio. It was found to be different for all four TMS samples. Crystal morphology of TMS polymorph A was predicted using Bravais-Friedel Donnay-Harker (BFDH) method. Molecular lipophilic surface potential (MLSP) data for TMS showed the varied surface lipophilic environment throughout the molecule. Hence it can be concluded that the differential abundance of surface elements play an important role in controlling the biopharmaceutical performance of TMS powder samples. PMID- 23459110 TI - Sample size requirements to detect an intervention by time interaction in longitudinal cluster randomized clinical trials with random slopes. AB - In longitudinal cluster randomized clinical trials (cluster-RCT), subjects are nested within a higher level unit such as clinics and are evaluated for outcome repeatedly over the study period. This study design results in a three level hierarchical data structure. When the primary goal is to test the hypothesis that an intervention has an effect on the rate of change in the outcome over time and the between-subject variation in slopes is substantial, the subject-specific slopes are often modeled as random coefficients in a mixed-effects linear model. In this paper, we propose approaches for determining the samples size for each level of a 3-level hierarchical trial design based on ordinary least squares (OLS) estimates for detecting a difference in mean slopes between two intervention groups when the slopes are modeled as random. Notably, the sample size is not a function of the variances of either the second or the third level random intercepts and depends on the number of second and third level data units only through their product. Simulation results indicate that the OLS-based power and sample sizes are virtually identical to the empirical maximum likelihood based estimates even with varying cluster sizes. Sample sizes for random versus fixed slope models are also compared. The effects of the variance of the random slope on the sample size determinations are shown to be enormous. Therefore, when between-subject variations in outcome trends are anticipated to be significant, sample size determinations based on a fixed slope model can result in a seriously underpowered study. PMID- 23459111 TI - Complement c5a generation by staphylococcal biofilms. AB - Biofilms production is a central feature of nosocomial infection of catheters and other medical devices used in resuscitation and critical care. However, the very effective biofilm forming pathogen Staphylococcus epidermidis often produces a modest host inflammatory response and few of the signs and symptoms associated with more virulent pathogens. To examine the impact of bacterial biofilm formation on provocation of an innate immune response, we studied the elaboration of the major complement anaphylatoxin C5a by human serum upon contact with S. epidermidis biofilms. Wild-type S. epidermidis and mutants of sarA (a regulatory protein that promotes synthesis of the biofilm-forming polysaccharide intercellular adhesin [PIA]) and icaB (responsible for postexport processing of PIA) were studied. C5a release, as a function of exposed biofilm surface area, was on the order of 1 fmol . cm . s and was dependent on the presence of PIA. Experimental results were used to inform a physiologically based pharmacokinetic model of C5a release by an infected central venous catheter, one of S. epidermidis' primary means of causing human disease. These simulations revealed that the magnitude of C5a release on a superior vena cava catheter completely covered with S. epidermidis would be lower than necessary to alert circulating leukocytes. Combined, the experimental and computational results are highly consistent with clinical observations in which the clinical signs of central line associated bloodstream infection are often muted in association with this important pathogen. PMID- 23459112 TI - Trauma-induced secondary cardiac injury is associated with hyperacute elevations in inflammatory cytokines. AB - INTRODUCTION: Clinical evidence supports the existence of a trauma-induced secondary cardiac injury. Experimental research suggests inflammation as a possible mechanism. The study aimed to determine if there was an early association between inflammation and secondary cardiac injury in trauma patients. METHODS: A cohort study of critically injured patients between January 2008 and January 2010 was undertaken. Levels of the cardiac biomarkers troponin I and heart-specific fatty acid-binding protein and the cytokines tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-1beta, and IL-8 were measured on admission to hospital, and again at 24 and 72 h. Participants were reviewed for adverse cardiac events (ACEs) and in-hospital mortality. RESULTS: Of 135 patients recruited, 18 (13%) had an ACE. Patients with ACEs had higher admission plasma levels of TNF-alpha (5.4 vs. 3.8 pg/mL; P = 0.03), IL-6 (140 vs. 58.9 pg/mL, P = 0.009), and IL-8 (19.3 vs. 9.1 pg/mL, P = 0.03) compared with those without events. Hour 24 cytokines were not associated with events, but IL-8 (14.5 vs. 5.8 pg/mL; P = 0.01) and IL-1beta (0.55 vs. 0.19 pg/mL; P = 0.04) were higher in patients with ACEs at 72 hours. Admission IL-6 was independently associated with heart-specific fatty acid-binding protein increase (P < 0.05). Patients who presented with an elevated troponin I combined with either an elevated TNF-alpha (relative risk [RR], 11.0; 95% confidence interval [CI], 1.8-66.9; P = 0.015), elevated IL-6 (RR, 17.3; 95% CI, 2.9-101.4; P = 0.001), or elevated IL-8 (RR, 15.0; 95% CI, 3.1-72.9; P = 0.008) were at the highest risk of in-hospital death when compared with individuals with normal biomarker and cytokine values. CONCLUSIONS: There is an association between hyperacute elevations in inflammatory cytokines with cardiac injury and ACEs in critically injured patients. Biomarker evidence of cardiac injury and inflammation on admission is associated with a higher risk of in-hospital death. PMID- 23459115 TI - DG-RAR for the treatment of symptomatic grade III and grade IV haemorrhoids: a 12 month multi-centre, prospective observational study. AB - BACKGROUND: Ultrasound-guided techniques represent a new treatment option in the treatment of haemorrhoids. Doppler-guided haemorrhoidal artery ligation (DG-HAL) proved efficacious in early haemorrhoidal disease, but lacks efficacy for stages III/IV. For these patients, haemorrhoidal artery ligation (HAL) has been combined with a running suture to reduce prolapsing haemorrhoidal tissue (recto-anal repair (RAR)). METHODS: A prospective observational study was conducted in 184 patients with grade III (58 %) or grade IV (42 %) haemorrhoids in seven coloproctological centres. Primary endpoints were the recurrence of symptoms and need of further treatment (medical or surgical). RESULTS: Post-operative complications were seen in 8 % of patients. After a follow-up of 3 months, 91 % of patients were free of symptoms and 91 % of patients were satisfied with the result. After a follow-up of 12 months, 89 % of patients were free of symptoms and 88 % were satisfied with the result. Nineteen per cent of patients received further medical or surgical treatment. CONCLUSIONS: Doppler-guided recto-anal repair (DG-RAR) proves to be an effective treatment option for the treatment of advanced haemorrhoidal disease that shows equal results to other established treatment options. PMID- 23459114 TI - Transformation of context-dependent sensory dynamics into motor behavior. AB - The intrinsic dynamics of sensory networks play an important role in the sensory motor transformation. In this paper we use conductance based models and electrophysiological recordings to address the study of the dual role of a sensory network to organize two behavioral context-dependent motor programs in the mollusk Clione limacina. We show that: (i) a winner take-all dynamics in the gravimetric sensory network model drives the typical repetitive rhythm in the wing central pattern generator (CPG) during routine swimming; (ii) the winnerless competition dynamics of the same sensory network organizes the irregular pattern observed in the wing CPG during hunting behavior. Our model also shows that although the timing of the activity is irregular, the sequence of the switching among the sensory cells is preserved whenever the same set of neurons are activated in a given time window. These activation phase locks in the sensory signals are transformed into specific events in the motor activity. The activation phase locks can play an important role in motor coordination driven by the intrinsic dynamics of a multifunctional sensory organ. PMID- 23459117 TI - Evaluation of facial asymmetry using digital photographs with computer aided analysis. AB - Facial asymmetries exist in all individuals. Due to these facial asymmetries that exist, a standardized approach in locating the occlusal plane that is parallel to the ala-tragus and interpupillary lines, may result in less than ideal esthetics in the final restoration. The challenge for the prosthodontist is to determine an acceptable occlusal plane with an individualized approach that can be used as a guide for alignment of the maxillary anterior teeth in cases that require their replacement or extensive restoration. The present study uses an inexpensive and standardized digital photographic technique along with computer assisted analysis to measure the asymmetries of the human face. Statistical Analysis used-Karl pearson's correlation coeffient was used. The correlation coefficient was then subjected to 't' test and 'p' value was used to find out the level of statistical significance. Left side of the face was found to be at a higher level than the right side. PMID- 23459116 TI - Should Posterior Vitrectomy be Made a Priority in Ophthalmic Facilities of Sub Sahara Africa? AB - BACKGROUND: Posterior vitrectomy facilities are lacking in Sub Sahara Africa due to paucity of trained personnel in vitreo retinal subspecialty. More cases are seen needing vitrectomy, especially cases with vitreous opacities and complications of cataract surgery as more residents are being trained. The review will aim to determine whether vitrectomy facility should be a priority as part of ophthalmic facility in the region. METHOD: A 3 year review was carried out. All cases of posterior vitrectomy performed at the retinal unit of the University College Hospital, Ibadan, Africa between 2008 and 20011 were retrieved. Indications, and visual outcome were documented. Proportions and percentages were used to analyse the data. RESULTS: Sixty six posterior vitrectomies were performed during the period. The most common indication for vitrectomy was vitreous hemorrhage n=30 [45.5%].Complication of cataract surgery such as dropped intraocular lens 7 [10.7%], sclera fixated intra ocular lens 6 [9.2%], and dropped nucleus 5 [7.5%] were emerging indications. Other indications noted include complicated retinal detachments 4 (6.1%), membranectomy for posterior capsule opacity from pediatric cataract surgery 3 (4.5%) and congenital lens subluxation 2 (3.0%). Improved visual outcome was noted after surgery. Forty nine [75%] eyes were blind [visual acuity of < 3/60] before vitrectomy. This proportion dropped to 24 [37%] after vitrectomy with an additional 24% regaining navigational vision [visual acuity of 3/60 to Counting fingers at 1meter] . CONCLUSION: Vitrectomy should be an integral part of eye care and its availability should be made a priority in ophthalmic facilities of Sub Sahara Africa, especially those involved in ophthalmology training. PMID- 23459118 TI - New considerations in the design of clinical trials for the treatment of acute leukemia. AB - There is great need for improved therapy for patients with acute leukemia. The current systems of clinical drug development and delivery of leukemia care are imperfectly adapted to the optimal identification and testing of future regimens. Novel clinical trial design with increased enrolment and appropriate end point selection would facilitate more efficient validation of candidate therapies. Clinical outcomes registries and biological sample storage would allow patient and leukemic factor substratification for the development of the next generation of targeted personalized therapy. We believe that the standard of care for patients in the USA diagnosed with acute leukemia, if treated with curative intent, is referral to a specialized center where an appropriate clinical trial can be offered. PMID- 23459119 TI - The Drosophila flavopilosa species group (Diptera, Drosophilidae): an array of exciting questions. AB - The D. flavopilosa group encompasses an ecologically restricted set of species strictly adapted to hosting flowers of Cestrum (Solanaceae). This group presents potential to be used as a model to the study of different questions regarding ecologically restricted species macro and microevolutionary responses, geographical vs. ecological speciation and intra and interspecific competition. This review aims to revisit and reanalyze the patterns and processes that are subjacent to the interesting ecological and evolutionary properties of these species. Biotic and abiotic niche properties of some species were reanalyzed in face of ecological niche modeling approaches in order to get some insights into their ecological evolution. A test of the potential of DNA-Barcoding provided evidences that this technology may be a way of overcoming difficulties related to cryptic species differentiation. The new focus replenishes the scenario with new questions, presenting a case where neither geographical nor ecological speciation may be as yet suggested. PMID- 23459120 TI - Psychosocial outcomes among youth with spinal cord injury and their primary caregivers. AB - BACKGROUND: Past research has found youth with disabilities to experience poor psychosocial outcomes, but little is known about factors related to psychosocial health among youth with spinal cord injury (SCI). OBJECTIVE: To describe psychosocial health among youth with SCI, examine relationships between psychosocial outcomes and demographic and injury-related factors, and examine relationships between aspects of psychosocial health. Youth activity, participation, quality of life (QOL), coping, anxiety and depression, and caregiver mental health were included. METHODS: Data were collected as part of a prospective study of 420 youth with SCI ages 1-18 and their primary caregivers. Activity data were also presented from a study developing a computerized adaptive testing (CAT) platform with 226 youth with SCI ages 8-21. RESULTS: Although relationships varied by factor, youth outcomes were related to youth age, sex, age at injury/injury duration, and level/extent of injury. Caregiver mental health related to child age and age at injury. Further, relationships were uncovered between aspects of psychosocial health: aspects of youth mental health were related to youth participation and QOL, youth coping was related to youth mental health, participation, and QOL, and caregiver mental health was related to child mental health and QOL. CONCLUSION: Psychosocial outcomes relate to each other and vary by child and injury-related factors and should be understood in a comprehensive, developmental context. Identifying best measures of activity and psychosocial functioning among youth with SCI and understanding factors related to their psychosocial health is critical to improving outcomes for the pediatric onset SCI population. PMID- 23459121 TI - Elbow problems in paraplegic spinal cord injured patients: frequency and related risk factors--a preliminary controlled study. AB - STUDY DESIGN: Cross-sectional controlled study. OBJECTIVES: To evaluate the elbow joint with ultrasound in paraplegic patients, determine the related factors and compare it with healthy controls. SETTING: A training and research rehabilitation hospital in Istanbul. METHODS: A total of 30 paraplegic patients and 20 healthy controls were included in the study. Patients demographic data, pain in the elbow joint, level and duration of injury, ambulation status, type of wheelchair used, daily duration of wheelchair and other ambulation equipment usage, transfers being dependent or independent, daily number of push-ups were recorded. Elbow joints were evaluated with ultrasound for presence of fluid and thickness of the triceps tendon. RESULTS: Mean triceps tendon thickness values of the right side were larger in spinal cord injury (SCI) patients when compared with those of healthy controls'. Joint effusion on the right elbow joint was also found to be more common in SCI patients than in normal subjects. Triceps tendon thickness measurements were not found to be correlated with demographic and clinical factors. Seven paraplegic patients (23%) reported that they have pain in the elbow. CONCLUSION: In this preliminary study, our results showed that right elbow effusion was more frequent and right triceps tendon was thicker in SCI patients when compared with healthy subjects. PMID- 23459122 TI - The Walking Index for Spinal Cord Injury (WISCI/WISCI II): nature, metric properties, use and misuse. AB - STUDY DESIGN: Literature review. OBJECTIVE: To critically review all publications/internet sites that have described/used the Walking Index for Spinal Cord Injury (WISCI II), as a measure of impairment of walking function after spinal cord injury (SCI), in order to identify its psychometric properties, clarify its nature, specify misuse and incorporate the findings in an updated guide. METHOD: A systematic literature search was done of Ovid MEDLINE, CINAHL, PsychINFO, Cochrane Central Register of Controlled Trials, Scopus and electronic sites using key words: WISCI or WISCI II, SCI, paraplegia/ tetraplegia/ quadriplegia and ambulation/gait/walking. Among 1235 citations retrieved, 154 relevant articles/sites were identified, classified and examined by the authors; recommendations were made based on findings. RESULTS AND DISCUSSION: The validity (face/concurrent/content/construct/convergent/criterion) and reliability of the WISCI II has been documented in clinical trials and clinical series, and considered adequate by systematic reviewers. In chronic SCI subjects, reliable determination of the maximum (as opposed to self-selected) WISCI II level requires more time and experience by the assessor. The correct use of WISCI II is clarified for testing acute/chronic phases of recovery after SCI, age of subjects, devices and settings. The WISCI II and walking speed measures may be performed simultaneously. CONCLUSION: The increased use of the WISCI II is attributed to its unique characteristics as a capacity measure of walking function and its strong metric properties. Appropriate use of the WISCI II was clarified and incorporated into a new guide for its use. Combining it with a walking speed measure needs further study. PMID- 23459123 TI - Cervical spine injuries and collar complications in severely injured paediatric trauma patients. AB - STUDY DESIGN: A retrospective registry review. OBJECTIVES: To determine the incidence of cervical spine (CS) injuries and collar complications in severely injured paediatric trauma patients. SETTING: Regional Trauma Centre, Children's Hospital. METHODS: A retrospective review of 365 paediatric severe trauma patients (0-17 years), defined as an Injury Severity Score (ISS)>=12, admitted to the paediatric intensive care unit (PICU). RESULTS: Clinically significant CS injuries occurred in 5% (n=18/365) of trauma patients, in 9% (n=13/149) of traumatic brain injury (TBI) patients and in 11% (n=6/56) of in-hospital trauma deaths. CS injuries were suspected before imaging in 33% (n=6/18) of patients based on either motor/sensory impairment or shock. CS injuries were deemed unstable in 61% (n=11/18) of patients. Patients with CS injuries had higher ISS, and longer PICU and hospital stays (P<0.05). CS collar complications occurred in 10% of patients, mainly identified by day 6 and consisting of either erythema or ulcers. Patients with CS collar complications were older and more likely to have TBI, lower Glasgow Coma Scale (GCS) scores, longer PICU and hospital stays, and increased days to CS clearance (P<0.05). Three CS X-rays, together with flexion/extension views, were used most frequently for CS clearance. CONCLUSION: CS injuries were prevalent in severely injured paediatric trauma patients, particularly in those with TBI and in nonsurvivors. CS collar complications were associated with a lower GCS and longer CS clearance times. Attention to CS collar management protocols and earlier CS clearance with computed tomography/magnetic resonance imaging in obtunded patients might reduce CS collar complications. PMID- 23459125 TI - Gender Differences in the Relationship Between Physical Activity and Smoking Among Psychiatrically Hospitalized Adolescents. AB - Physical activity has been identified as a protective factor with regard to tobacco use, such that physically active adolescents are less likely to initiate smoking, and smokers are less physically active than non-smokers. These findings, along with the well-documented benefits of exercise on mood and well-being in adults, have stimulated interest in exercise-based smoking cessation interventions. However, little research has explored the relationship between physical activity and smoking characteristics within adolescent smokers. Also, gender differences in adolescents' motives for smoking and exercise may have implications for intervention development, especially in clinical populations. The current study explored the relationship between physical activity and smoking in a sample of adolescent smokers (N = 191) and non-smokers (N = 48) receiving inpatient psychiatric treatment (61% female, mean age 15.3 years). Results indicated that smokers were less likely to be physically active than non-smokers. Additionally, there was a consistent pattern of gender differences in the relationship between smoking and physical activity within smokers. Specifically, physically active male smokers were less nicotine dependent and less prone to withdrawal, and had a trend toward greater motivation to quit, than their non active counterparts. In contrast, physically active female smokers did not differ in dependence or withdrawal and were less motivated to quit than non-active female smokers. Taken together, these results suggest that within clinical populations of adolescent females, smoking and exercise may be used jointly as weight control strategies. Exercise-based interventions for smoking cessation for adolescent females, especially clinical populations, should address weight and body image concerns. PMID- 23459124 TI - Early diagnosis of autism and impact on prognosis: a narrative review. AB - Autism spectrum disorders involve a set of clinical phenotypes that mirror an early onset of neurodevelopmental deviations, with core symptoms that can probably be related to a deficiency in the social instinct. Underlying the cognitive impairments there are physiological brain problems, caused by a large number of medical factors. This narrative review of systematic reviews and meta analyses from the last 5 years (2008-2012) presents aspects from many areas in autism spectrum disorder research, with a particular focus on early intervention and the subsequent impact on prognosis. Other major areas discussed are epidemiology, early symptoms and screening, early diagnosis, neuropsychology, medical factors, and the existence of comorbidities. There is limited evidence that any of the broadband "early intervention" programs are effective in changing the natural long-term outcome for many individuals with an early diagnosis of autism. However, there is some evidence that Early Intensive Behavioral Intervention (EIBI) is an effective treatment for some children with ASD. Nevertheless, there is emerging consensus that early diagnosis and information are needed in order that an autism-friendly environment be "created" around affected individuals. PMID- 23459126 TI - Graphene oxide supported Au-Ag alloy nanoparticles with different shapes and their high catalytic activities. AB - A simple method was developed to fabricate Au-Ag nanoparticle/graphene oxide nanocomposites (Au-Ag/GO) by using simultaneous redox reactions between AgNO3, HAuCl4 and GO. The Au-Ag/GO was characterized by x-ray photoelectron spectroscopy, transmission electron microscopy and energy dispersive x-ray spectroscopy. The GO nanosheets acted as the reducing agent and the support for the Au-Ag alloy nanoparticles. In addition, Au-Ag alloy nanoparticles with different shapes including core-shell-like, dendrimer-like and flower-like were obtained by simply modifying the concentration of the reactants and the reaction temperature. With no reducing or stabilizing agents added, the Au-Ag/GO nanocomposites show superior catalytic performance for the reduction of 4 nitrophenol and for the aerobic homocoupling of phenylboronic acid. PMID- 23459128 TI - Structural overview of toxin-antitoxin systems in infectious bacteria: a target for developing antimicrobial agents. AB - The bacterial toxin-antitoxin (TA) system is a module that may play a role in cell survival under stress conditions. Generally, toxin molecules act as negative regulators in cell survival and antitoxin molecules as positive regulators. Thus, the expression levels and interactions between toxins and antitoxins should be systematically harmonized so that bacteria can escape such harmful conditions. Since TA systems are able to control the fate of bacteria, they are considered potent targets for the development of new antimicrobial agents. TA systems are widely prevalent with a variety of systems existing in bacteria: there are three types of bacterial TA systems depending on the property of the antitoxin which binds either the protein toxin or mRNA coding the toxin protein. Moreover, the multiplicity of TA genes has been observed even in species of bacteria. Therefore, knowledge on TA systems such as the individual characteristics of TA systems, integrative working mechanisms of various TA systems in bacteria, interactions between toxin molecules and cellular targets, and so on is currently limited due to their complexity. In this regard, it would be helpful to know the structural characteristics of TA modules for understanding TA systems in bacteria. Until now, 85 out of the total structures deposited in PDB have been bacterial TA system proteins including TA complexes or isolated toxins/antitoxins. Here, we summarized the structural information of TA systems and analyzed the structural characteristics of known TA modules from several bacteria, especially focusing on the TA modules of several infectious bacteria. PMID- 23459127 TI - An engineered heme-copper center in myoglobin: CO migration and binding. AB - We have investigated CO migration and binding in CuBMb, a copper-binding myoglobin double mutant (L29H-F43H), by using Fourier transform infrared spectroscopy and flash photolysis over a wide temperature range. This mutant was originally engineered with the aim to mimic the catalytic site of heme-copper oxidases. Comparison of the wild-type protein Mb and CuBMb shows that the copper ion in the distal pocket gives rise to significant effects on ligand binding to the heme iron. In Mb and copper-free CuBMb, primary and secondary ligand docking sites are accessible upon photodissociation. In copper-bound CuBMb, ligands do not migrate to secondary docking sites but rather coordinate to the copper ion. Ligands entering the heme pocket from the outside normally would not be captured efficiently by the tight distal pocket housing the two additional large imidazole rings. Binding at the Cu ion, however, ensures efficient trapping in CuBMb. The Cu ion also restricts the motions of the His64 side chain, which is the entry/exit door for ligand movement into the active site, and this restriction results in enhanced geminate and slow bimolecular CO rebinding. These results support current mechanistic views of ligand binding in hemoglobins and the role of the CuB in the active of heme-copper oxidases. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23459129 TI - Assembling a xylanase-lichenase chimera through all-atom molecular dynamics simulations. AB - Multifunctional enzyme engineering can improve enzyme cocktails for emerging biofuel technology. Molecular dynamics through structure-based models (SB) is an effective tool for assessing the tridimensional arrangement of chimeric enzymes as well as for inferring the functional practicability before experimental validation. This study describes the computational design of a bifunctional xylanase-lichenase chimera (XylLich) using the xynA and bglS genes from Bacillus subtilis. In silico analysis of the average solvent accessible surface area (SAS) and the root mean square fluctuation (RMSF) predicted a fully functional chimera, with minor fluctuations and variations along the polypeptide chains. Afterwards, the chimeric enzyme was built by fusing the xynA and bglS genes. XylLich was evaluated through small-angle X-ray scattering (SAXS) experiments, resulting in scattering curves with a very accurate fit to the theoretical protein model. The chimera preserved the biochemical characteristics of the parental enzymes, with the exception of a slight variation in the temperature of operation and the catalytic efficiency (kcat/Km). The absence of substantial shifts in the catalytic mode of operation was also verified. Furthermore, the production of chimeric enzymes could be more profitable than producing a single enzyme separately, based on comparing the recombinant protein production yield and the hydrolytic activity achieved for XylLich with that of the parental enzymes. PMID- 23459130 TI - Addressing Perinatal Disparities in Urban Setting: Using Community Based Participatory Research. AB - Striking racial disparities in infant mortality exist in the United States, with rates of infant death among African Americans (AA) nearly twice the national average. Community-based participatory research (CBPR) approaches have been successful in fostering collaborative relationships between communities and researchers focused on developing effective and sustainable interventions and programs targeting needs of the community. The current paper details use of the Perinatal Period of Risk (PPOR) model as a method to engage communities by identifying factors influencing racial disparities in infant mortality and examining changes in those factors over a ten year period. PMID- 23459131 TI - Use of a three-dimensional virtual environment to teach drug-receptor interactions. AB - Objective. To determine whether using 3-dimensional (3D) technology to teach pharmacy students about the molecular basis of the interactions between drugs and their targets is more effective than traditional lecture using 2-dimensional (2D) graphics.Design. Second-year students enrolled in a 4-year masters of pharmacy program in the United Kingdom were randomly assigned to attend either a 3D or 2D presentation on 3 drug targets, the beta-adrenoceptor, the Na(+)-K(+) ATPase, and the nicotinic acetylcholine receptor.Assessment. A test was administered to assess the ability of both groups of students to solve problems that required analysis of molecular interactions in 3D space. The group that participated in the 3D teaching presentation performed significantly better on the test than the group who attended the traditional lecture with 2D graphics. A questionnaire was also administered to solicit students' perceptions about the 3D experience. The majority of students enjoyed the 3D session and agreed that the experience increased their enthusiasm for the course.Conclusions. Viewing a 3D presentation of drug-receptor interactions improved student learning compared to learning from a traditional lecture and 2D graphics. PMID- 23459132 TI - Preoperative delay of more than 1 hour increases the risk of surgical site infection. AB - STUDY DESIGN: Retrospective institutional database review. OBJECTIVE: To determine whether preoperative in-room time is a risk factor for surgical site infection (SSI). SUMMARY OF BACKGROUND DATA: Prior to spine surgery, while the patient is in the operating room, several procedures may be performed that may delay surgery. During this time, the sterile field may be exposed and may become contaminated. The hypothesis of this study was that the length of time in the operative room prior to surgical incision (anesthesia ready time [ART]) was related to the risk of SSI. METHODS: From 2005 to 2009, we identified 276 patients who developed SSI out of 7991 cases that underwent spine surgery from 2005 to 2009. Patient demographic factors, American Society of Anesthesiologists score, wound classification, number of levels, anatomic region, type of surgical approach, and length of surgery were extrapolated. ART was calculated as the time after the patient was brought into the operating room prior to surgical incision. Multivariate analysis was performed to identify risk factors for SSI. RESULTS: Mean ART was significantly (P = 0.001) higher in patients with infection (68 min) compared with those without infection (60 min). The infection rate was higher in cases with ART more than 1 hour compared with those with less than 1 hour (4.9% vs. 2.3%, P = 0.001). In multivariate analysis, ART more than 1 hour was an independent risk factor for SSI, along with number of levels, American Society of Anesthesiologists score and posterior approach. The highest percentage of cases with ART more than 1 hour occurred in August and September. CONCLUSION: Preoperative in-room time prior to the start of surgical incision is an independent risk factor for SSI. All possible steps should be taken prior to entry into the operating theater to reduce in-room time and opening of surgical sterile instrumentation be delayed until the surgery is ready to proceed. PMID- 23459133 TI - Clavicle chest cage angle difference (CCAD): a novel predictor of postoperative shoulder imbalance in patients with adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective case series of surgically treated patients with adolescent scoliosis. OBJECTIVE: To establish a new radiographical measurement method to determine the best preoperative predictor of postoperative shoulder balance. SUMMARY OF BACKGROUND DATA: Shoulder balance is an important aspect of the overall cosmetic balance in patients with adolescent idiopathic scoliosis. Despite recent reports, it is still difficult to estimate the postoperative shoulder balance accurately. METHODS: A retrospective review of 89 consecutive patients who had thoracic fusion with a minimum 2-year follow-up (mean, 3.1 yr) was conducted to investigate the radiographical measurements and patient demographics. The shoulder height difference (SHD) was measured as the graded height difference of the soft tissue shadows. SHD more than 2 cm indicated an unbalanced shoulder. The clavicle chest cage angle difference (CCAD) was established and evaluated. The CCAD was graded as grade A: no imbalance (<0 degrees ), grade B: mild imbalance (0 degrees -10 degrees ), and grade C: significant imbalance (>10 degrees ). RESULTS: Of the 89 patients, 22 patients had a moderate or significant SHD at 2 years postoperatively and were categorized as the unbalanced shoulder group (unbalanced SD). A significant difference was observed in preoperative CCAD between the balanced and unbalanced SD groups (P = 0.01). The intraclass correlation coefficient for CCAD was 0.94 among the observers. CCAD was consistent from the preoperative to the final postoperative follow-ups in both groups. The classification of the CCAD preoperatively indicated that 12 of 22 (54.4%) patients who were classified into the postoperative unbalanced SD group showed grade 3 CCAD preoperatively, whereas only 9 of 67 (13.4%) patients who were classified in the postoperative balanced SD group had grade 3 CCAD preoperatively. CONCLUSION: The developed method to predict postoperative shoulder balance was demonstrated to be easy to perform, reliable, and practical. Additionally, we classified the estimation of postoperative shoulder imbalance by preoperation CCAD. The results of this comprehensive review will guide spinal surgeons in their preoperative planning and in the surgical management of adolescent idiopathic scoliosis to reduce postoperative shoulder imbalance. LEVEL OF EVIDENCE: 4. PMID- 23459134 TI - Prescription opioids for back pain and use of medications for erectile dysfunction. AB - STUDY DESIGN: Cross-sectional analysis of electronic medical and pharmacy records. OBJECTIVE: To examine associations between use of medication for erectile dysfunction or testosterone replacement and use of opioid therapy, patient age, depression, and smoking status. SUMMARY OF BACKGROUND DATA: Males with chronic pain may experience erectile dysfunction related to depression, smoking, age, or opioid-related hypogonadism. The prevalence of this problem in back pain populations and the relative importance of several risk factors are unknown. METHODS: We examined electronic pharmacy and medical records for males with back pain in a large group model health maintenance organization during 2004. Relevant prescriptions were considered for 6 months before and after the index visit. RESULTS: There were 11,327 males with a diagnosis of back pain. Males who received medications for erectile dysfunction or testosterone replacement (n = 909) were significantly older than those who did not and had greater comorbidity, depression, smoking, and use of sedative-hypnotics. In logistic regressions, the long-term use of opioids was associated with greater use of medications for erectile dysfunction or testosterone replacement compared with no opioid use (odds ratio, 1.45; 95% confidence interval, 1.12-1.87, P < 0.01). Age, comorbidity, depression, and use of sedative-hypnotics were also independently associated with the use of medications for erectile dysfunction or testosterone replacement. Patients prescribed daily opioid doses of 120 mg of morphine-equivalents or more had greater use of medication for erectile dysfunction or testosterone replacement than patients without opioid use (odds ratio, 1.58; 95% confidence interval, 1.03-2.43), even with adjustment for the duration of opioid therapy. CONCLUSION: Dose and duration of opioid use, as well as age, comorbidity, depression, and use of sedative-hypnotics, were associated with evidence of erectile dysfunction. These findings may be important in the process of decision making for the long-term use of opioids. LEVEL OF EVIDENCE: 4. PMID- 23459135 TI - Predictors of treatment outcomes in geriatric patients with odontoid fractures: AOSpine North America multi-centre prospective GOF study. AB - STUDY DESIGN: Multicenter prospective cohort study. OBJECTIVE: To identify patient and treatment characteristics associated with treatment success or failure in the management of odontoid fractures. SUMMARY OF BACKGROUND DATA: Odontoid fractures are the most common cervical spine fractures in the elderly and represent a significant management challenge with widely divergent views regarding operative versus nonoperative management. METHODS: A total of 159 patients 65 years and older with radiographically confirmed type II odontoid fractures were enrolled at 10 sites in the United States and 1 site in Canada between January 2006 and May 2009. Subjects were followed at 6 and 12 months post initial treatment with Neck Disability Index and SF-36v2 scores. Final treatment outcome was classified as failure or success. Treatment failure was defined as death by any cause, decline in Neck Disability Index by more than 9.5 absolute points, or occurrence of a major treatment-related complication. Baseline characteristics between the groups were compared using t test for the continuous variables and chi2 test for the categorical variables. Baseline characteristics associated with treatment outcomes were identified by multiple logistic stepwise regression analysis. RESULTS: A total of 101 (63.5%) patients were treated surgically and 58 (36.5%) conservatively. Forty-four (27.7%) patients had a successful outcome and 86 (54.1%) had a treatment failure; for 29 patients (18.2%), treatment status could not be determined (3 withdrew; 26 were lost to follow-up). Twenty-nine (18.2%) patients expired before the 12-month follow-up. Follow-up information was available for 103 of 127 surviving (81.1%) patients. Twelve-month SF-36v2 scores were worse in the failure group. The characteristics associated with treatment failure were older age (odds ratio [OR] = 1.08 for each year of age); initial nonsurgical treatment (OR = 3.09); male sex (OR = 4.33), and baseline neurological system comorbidity (OR = 4.13). CONCLUSION: Older age, initial nonsurgical treatment, and male sex are associated with failure of treatment in patients with geriatric odontoid fractures. PMID- 23459136 TI - Early predictors of functional disability after spine trauma: a level 1 trauma center study. AB - STUDY DESIGN: Retrospective review on prospective cohort and explicit chart review. OBJECTIVE: To identify early spine trauma predictors of functional disability and to assess management compliance to established spine trauma treatment algorithms. SUMMARY OF BACKGROUND DATA: Identification of early (within 48 hours) spine trauma predictors of functional disability is novel and may assist in the management of patients with trauma. Also, with significant global variation, spine trauma treatment algorithms are essential. METHODS: Analysis was performed on patients with spine trauma from May 1, 2009, to January 1, 2011. Functional outcomes were determined using the Glasgow Outcome Scale (GOS) at 1 year. Univariate and multivariate regressions were applied to investigate the effects of the injury severity score, age, blood sugar level, vital signs, traumatic brain injury, comorbidities, coagulation profile, neurology, and spine injury characteristics. A compliance study was performed using the SLIC and TLICS spine trauma algorithms. RESULTS: The completion rate for the GOS was 58.8%. The completed GOS cohort was 4.2 years younger in terms of mean age, had more number of patients with severe polytrauma, but less number of patients with severe spinal cord injuries (ASIA [American Spinal Injury Association] A, B, and C) in comparison with the uncompleted GOS cohort. Multivariate logistic regression revealed 3 independent early spine trauma predictors of functional disability with statistical significance (P < 0.05). They were (1) hypotension (OR [odds ratio] = 1.98; CI [confidence interval] = 1.13-3.49), (2) hyperglycemia (OR = 1.67; CI = 1.09-2.56), and (3) moderate/severe traumatic brain injury (OR = 5.88; CI = 1.71-20.16). There were 305 patients with subaxial cervical spine injuries and 653 patients with thoracolumbar spine injuries. The subaxial cervical spine injury classification and thoracolumbar injury classification and severity score compliance studies returned agreements of 96.1% and 98.9%, respectively. CONCLUSION: Early independent spine trauma predictors of functional disability identified in a level 1 trauma center with high compliance to the subaxial cervical spine injury classification and thoracolumbar injury classification and severity score algorithms were hypotension, hyperglycemia, and moderate or severe traumatic brain injury. Spine trauma injury variables alone were shown not to be predictive of functional disability. LEVEL OF EVIDENCE: 3. PMID- 23459137 TI - Association between overweight and low back pain: a population-based prospective cohort study of adolescents. AB - STUDY DESIGN: A prospective cohort study in adolescents aged 7 to 19 years. OBJECTIVE: To evaluate whether persistent overweight increases the risk of low back pain (LBP) among adolescents. SUMMARY OF BACKGROUND DATA: Overweight and LBP are common health problems in adolescents. Their relationship is still controversial among adolescents, as well as among adults. METHODS: The study population, the Oulu Back Study, was drawn from the Northern Finland Birth Cohort 1986. The final study sample included 1660 adolescents (56% females). The subcohort of 786 subjects (57% females) was used in the analysis of waist circumference. The association between the area under the curve of body mass index from 7 to 16 years, and from 16 to 18 years, and area under the curve of waist circumference from 16 to 19 years, and LBP during the past 6 months was evaluated separately for incident (reporting LBP at 18 or 19 yr but not at 16 yr) and persistent LBP (reporting LBP at 16 and 18 yr or 19 yr). Relative risks (RR) and their 95% confidence intervals (95% CI) were adjusted for smoking, leisure time physical activity, and family socioeconomic status at 16 years and stratified by sex. RESULTS: Body mass index from 16 to 18 years among girls and body mass index from 7 to 16 years among boys predicted incident LBP at 18 years (girls: RR, 1.09; 95% CI, 1.01-1.18; boys: RR, 1.15; 95% CI, 1.00-1.32). Among boys, waist circumference from 16 to 19 years was also associated with incident LBP (RR, 1.16; 95% CI, 1.02-1.32). Overweight was not associated with persistent LBP. CONCLUSION: In this population-based cohort study, persistent overweight slightly increased the risk of incident LBP, but the time period during which overweight was related to incident LBP differed between sexes. LEVEL OF EVIDENCE: 2. PMID- 23459138 TI - Association between beliefs and care-seeking behavior for low back pain. AB - STUDY DESIGN: Cross sectional population-based survey. OBJECTIVE: To investigate the relationship between low back pain (LBP) beliefs and care seeking in LBP. SUMMARY OF BACKGROUND DATA: Not all people experiencing LBP seek care for their problem. Consistent predictors of care-seeking behavior seem to be female sex and high perceived disability; the role of beliefs about LBP has not been investigated sufficiently. METHODS: A questionnaire booklet was mailed to a random sample of 2860 individuals otherwise participating in an epidemiological study of musculoskeletal health. It contained the Back Beliefs Questionnaire (BBQ), the Fear-Avoidance Beliefs Questionnaire (FABQ; physical activity and work scales), and questions about sociodemographics, LBP characteristics, and LBP related care seeking in the last month ("yes" = visit to specialist, general practitioner, physiotherapist, or other health care practitioner; "no" = none of these). Logistic regression was used to identify whether beliefs made a significant contribution to care-seeking behavior, beyond known predictors conceptualized in the behavioral model of health services use. RESULTS: A total of 2507 of 2860 (88%) individuals completed the questionnaire; 1071 (43%) reported current LBP, 301 (28%) of which had sought care. In univariate analyses the following were all significantly related to care seeking (all P < 0.01): female sex; increasing age; not working full time; lower income; greater LBP frequency, LBP intensity, and limitations in activities of daily living; worse general health; higher FABQ-Physical Activity, FABQ-Work, and Back Beliefs Questionnaire scores. In multiple regression, female sex (odds ratio [OR], 1.731; 95% confidence interval [CI], 1.174-2.551; P = 0.006), LBP frequency (OR, 1.492; 95% CI, 1.249-1.783; P < 0.0001), limitations in activities of daily living (OR, 1.010; 95% CI, 1.001-1.020; P = 0.037), and high FABQ-Work Scores (OR, 1.025; 95% CI, 1.005-1.044, P = 0.012) contributed significantly to the final model. CONCLUSION: That the odds of seeking care are higher in fear-avoidant individuals, even when controlling for other established predictors, emphasizes the importance of addressing such beliefs during the consultation; public health education programs may serve to underpin the delivery of positive messages, ultimately reducing health care demands. PMID- 23459140 TI - Use of online machine translation for nursing literature: a questionnaire-based survey. AB - BACKGROUND: The language barrier is a significant obstacle for nurses who are not native English speakers to obtain information from international journals. Freely accessible online machine translation (MT) offers a possible solution to this problem. AIM: To explore how Japanese nursing professionals use online MT and perceive its usability in reading English articles and to discuss what should be considered for better utilisation of online MT lessening the language barrier. METHOD: In total, 250 randomly selected assistants and research associates at nursing colleges across Japan answered a questionnaire examining the current use of online MT and perceived usability among Japanese nurses, along with the number of articles read in English and the perceived language barrier. The items were rated on Likert scales, and t-test, ANOVA, chi-square test, and Spearman's correlation were used for analyses. RESULTS: Of the participants, 73.8% had used online MT. More than half of them felt it was usable. The language barrier was strongly felt, and academic degrees and English proficiency level were associated factors. The perceived language barrier was related to the frequency of online MT use. No associated factor was found for the perceived usability of online MT. CONCLUSION: Language proficiency is an important factor for optimum utilisation of MT. A need for education in the English language, reading scientific papers, and online MT training was indicated. Cooperation with developers and providers of MT for the improvement of their systems is required. PMID- 23459139 TI - Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility. AB - Peroxisomes are subcellular organelles involved in lipid metabolic processes, including those of very-long-chain fatty acids and branched-chain fatty acids, among others. Peroxisome matrix proteins are synthesized in the cytoplasm. Targeting signals (PTS or peroxisomal targeting signal) at the C-terminus (PTS1) or N-terminus (PTS2) of peroxisomal matrix proteins mediate their import into the organelle. In the case of PTS2-containing proteins, the PTS2 signal is cleaved from the protein when transported into peroxisomes. The functional mechanism of PTS2 processing, however, is poorly understood. Previously we identified Tysnd1 (Trypsin domain containing 1) and biochemically characterized it as a peroxisomal cysteine endopeptidase that directly processes PTS2-containing prethiolase Acaa1 and PTS1-containing Acox1, Hsd17b4, and ScpX. The latter three enzymes are crucial components of the very-long-chain fatty acids beta-oxidation pathway. To clarify the in vivo functions and physiological role of Tysnd1, we analyzed the phenotype of Tysnd1(-/-) mice. Male Tysnd1(-/-) mice are infertile, and the epididymal sperms lack the acrosomal cap. These phenotypic features are most likely the result of changes in the molecular species composition of choline and ethanolamine plasmalogens. Tysnd1(-/-) mice also developed liver dysfunctions when the phytanic acid precursor phytol was orally administered. Phyh and Agps are known PTS2-containing proteins, but were identified as novel Tysnd1 substrates. Loss of Tysnd1 interferes with the peroxisomal localization of Acaa1, Phyh, and Agps, which might cause the mild Zellweger syndrome spectrum-resembling phenotypes. Our data established that peroxisomal processing protease Tysnd1 is necessary to mediate the physiological functions of PTS2-containing substrates. PMID- 23459141 TI - Spatial and temporal MRI profile of ischemic tissue after the acute stages of a permanent mouse model of stroke. AB - OBJECT: To characterize the progression of injured tissue resulting from a permanent focal cerebral ischemia after the acute phase, Magnetic Resonance Imaging (MRI) monitoring was performed on adult male C57BL/6J mice in the subacute stages, and correlated to histological analyses. MATERIAL AND METHODS: Lesions were induced by electrocoagulation of the middle cerebral artery. Serial MRI measurements and weighted-images (T2, T1, T2* and Diffusion Tensor Imaging) were performed on a 9.4T scanner. Histological data (Cresyl-Violet staining and laminin-, Iba1- and GFAP-immunostainings) were obtained 1 and 2 weeks after the stroke. RESULTS: Two days after stroke, tissues assumed to correspond to the infarct core, were detected as a hyperintensity signal area in T2-weighted images. One week later, low-intensity signal areas appeared. Longitudinal MRI study showed that these areas remained present over the following week, and was mainly linked to a drop of the T2 relaxation time value in the corresponding tissues. Correlation with histological data and immuno-histochemistry showed that these areas corresponded to microglial cells. CONCLUSION: The present data provide, for the first time detailed MRI parameters of microglial cells dynamics, allowing its non-invasive monitoring during the chronic stages of a stroke. This could be particularly interesting in regards to emerging anti-inflammatory stroke therapies. PMID- 23459142 TI - The non-estrogenic alternative for the treatment of climacteric complaints: Black cohosh (Cimicifuga or Actaea racemosa). AB - In postmenopausal women estrogens in combination with progestins have beneficial effects on climacteric complaints and on osteoporosis but this hormone replacement therapy (HRT) bears the risk of increased mammary carcinomas and cardiovascular diseases. Phytoestrogens at low doses have little or no effects on climacteric complaints, at high doses they mimic the effects of estrogens. Therefore other plant derived substances are currently intensively investigated. Extracts of the rhizome of black cohosh (Cimicifuga racemosa=CR) did not bind to estrogen receptors and were shown to be devoid of estrogenic effects on mammary cancer cells in vitro and on mammary gland and uterine histology in ovariectomized rats. In addition in this rat model the special extract CR BNO 1055 inhibited the occurrence of hot flushes and development of osteoporosis. In postmenopausal women CR BNO 1055 reduced major climacteric complaints as effectively as conjugated estrogens and significantly more than placebo. Similar data were published for other European CR preparations whereas 2 US American preparations were ineffective. This was most likely due to the too high doses or due to the adulteration with Asian Cimicifuga preparations. In all European studies neither effects in the uterus nor in mammary glands were observed. The effective compounds in CR are most likely neurotransmitter-mimetic in nature: dopaminergic, noradrenergic, serotoninergic and GABAergic effects were demonstrated and some have been structurally identified. We conclude that CR extracts at low doses are effective to ameliorate climacteric complaints but are devoid of adverse estrogenic effects. These finding strengthens the role of CR extracts as substitutes for HRT. This article is part of a special issue entitled: Special Issue on Phytoestrogens. PMID- 23459143 TI - Synthesis of combretastatin A4 analogues on steroidal framework and their anti breast cancer activity. AB - Combretastatin A4 analogues were synthesized on steroidal framework from gallic acid with a possibility of anti-breast cancer agents. Twenty two analogues were synthesized and evaluated for cytotoxicity against human breast cancer cell lines (MCF-7 & MDA-MB 231). The best analogue 22 showed potent antitubulin effect. Docking experiments also supported strong binding affinity of 22 to microtubule polymerase. In cell cycle analysis, 22 induced apoptosis in MCF-7 cells significantly. It was found to be non-toxic up to 300 mg/kg dose in Swiss albino mice in acute oral toxicity. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID- 23459144 TI - Effects of concurrent respiratory resistance training on health-related quality of life in wheelchair rugby athletes: a pilot study. AB - PURPOSE: To compare the effects of 9 weeks of training with a concurrent flow resistance (CFR) device versus a concurrent pressure threshold resistance (CPTR) device on health-related quality of life (HRQoL) in wheelchair rugby (WR) athletes. METHOD: Twenty-four male WR athletes (22 with tetraplegia, 1 with a spastic cerebral palsy, and 1 with congenital upper and lower limb deformities) were matched by lesion level, completeness of injury, and rugby classification prior to being randomly assigned to 1 of 3 groups: (1) CPTR (n=8), (2) CFR (n=8), or (3) controls (CON, n=8). Pre/post testing included assessment of HRQoL as measured by the Short-Form Health Survey Version 2.0 (SF-36v2). Manufacturer protocol guidelines for the CFR and CPTR groups were followed for breathing exercises. RESULTS: Sixteen participants completed the study (CPTR=4, CFR=5, CON=7). The Mann-Whitney U rank order revealed significantly greater reductions in bodily pain (P = .038) and improvements in vitality (P = .028) for CFR versus CON. CONCLUSION: Results from this study suggest that training with a CFR device improves some aspects of HRQoL (eg, vitality and bodily pain) in WR athletes. Further research with a larger sample size is needed to examine the impact of these devices on improving HRQoL for wheelchair athletes. PMID- 23459145 TI - Abnormal spontaneous muscle activity in plegic limb appears to initiate distal to the upper motor neuron: a case report in a stroke patient. AB - OBJECTIVE: To study the effect of the cutaneous silent period (CSP) on spontaneous muscle activity occurring after an upper motor injury from stroke, with a goal of developing an insight into the origin of the pathological activity. METHODS: A patient with an acute right centrum semiovale ischemic stroke had left hemiparesis. Fibrillation potentials and positive sharp waves were recorded in several left arm muscles. CSP silent period studies were performed in both arms. RESULTS: The CSP inhibited the volitional activity in the unaffected right arm. In the plegic left arm, fibrillation potentials and positive sharp waves persisted during the time period during which the CSP would have been expected, based upon the right-sided studies. CONCLUSIONS: Spontaneous activity after a cerebrovascular accident was resistant to inhibition from CSP. These findings suggest that the localization of the origin of the spontaneous activity is distal to the upper motor neuron. A confirmatory study with more patients and in a variety of stroke subtypes would strengthen this conclusion. PMID- 23459146 TI - Effects of sodium fluoride on reproductive function in female rats. AB - The aim of this study was to investigate the effects of sodium fluoride (NaF) on female reproductive function and examine the morphology of the ovaries and uteri of rats exposed to NaF. Eighty female Sprague-Dawley (SD) rats were divided randomly into four groups of 20: one control group and three NaF treated groups. The three NaF treated groups received 100, 150, and 200 ppm, respectively, of NaF for 6 months via their drinking water, while the control group (GC) received distilled water. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), progesterone (P) and estradiol (E2) were measured using an enzyme-linked immunosorbent assay. Pathomorphological evaluation of the uteri and ovaries was conducted after staining with hematoxylin-eosin and immunohistochemistry. The rate of successful pregnancy in the NaF-treated groups declined in a dose-dependent manner. The concentration of reproductive hormones was significantly lower in the three NaF-treated groups, and the endometrium was damaged. The maturation of follicles was inhibited. In addition, the total number of follicles of all types was significantly lower in the NaF-treated groups. These results suggest that female reproductive function is inhibited by NaF and that exposure to NaF causes ovarian and uterine structural damage. NaF may thus significantly reduce the fertility of female rats. PMID- 23459147 TI - Ninety-day dietary toxicity study of apple polyphenol extracts in Crl: CD (SD) rats. AB - To examine the safety of Dietary Applephenon(r) (AP) in feed, Crl: CD (SD) rats of each sex were divided into four groups and given diets containing AP at 0%, 1.25%, 2.5%, or 5.0% for 90 days. All rats survived and toxic changes were not observed throughout the study. Body weight and food efficiency in the 5.0% AP group of both sexes were significantly decreased compared with that in controls. These changes were considered to be caused by the physiological effects of AP (including the inhibitory effects on pancreatic lipase activity). Slight hypertrophy in acinar cells in the parotid and submandibular glands appeared in the 2.5% and 5.0% groups. These were suggested not to be toxicological but physiologic adaptive responses to oral stimuli by the lower pH of AP-containing diets. In conclusion, dietary AP in feed, up to a maximum level of 5.0% for 90 days, given to rats did not induce toxicological effects. PMID- 23459148 TI - Chemical composition and anticancer, antiinflammatory, antioxidant and antimalarial activities of leaves essential oil of Cedrelopsis grevei. AB - The essential oil from Cedrelopsis grevei leaves, an aromatic and medicinal plant from Madagascar, is widely used in folk medicine. Essential oil was characterized by GC-MS and quantified by GC-FID. Sixty-four components were identified. The major constituents were: (E)-beta-farnesene (27.61%), delta-cadinene (14.48%), alpha-copaene (7.65%) and beta-elemene (6.96%). The essential oil contained a complex mixture consisting mainly sesquiterpene hydrocarbons (83.42%) and generally sesquiterpenes (98.91%). The essential oil was tested cytotoxic (on human breast cancer cells MCF-7), antimalarial (Plasmodium falciparum), antiinflammatory and antioxidant (ABTS and DPPH assays) activities. C. grevei essential oil was active against MCF-7 cell lines (IC50=21.5 mg/L), against P. falciparum, (IC50=17.5mg/L) and antiinflammatory (IC50=21.33 mg/L). The essential oil exhibited poor antioxidant activity against DPPH (IC50>1000 mg/L) and ABTS (IC50=110 mg/L) assays. A bibliographical review was carried out of all essential oils identified and tested with respect to antiplasmodial, anticancer and antiinflammatory activities. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial, anticancer and antiinflammatory). According to the obtained correlations, 1,4-cadinadiene (R(2)=0.61) presented a higher relationship with antimalarial activity. However, only (Z)-beta-farnesene (R(2)=0.73) showed a significant correlation for anticancer activity. PMID- 23459149 TI - Analytical chemistry, toxicology, epidemiology and health impact assessment of melamine in infant formula: recent progress and developments. AB - This review summarizes the most recent scientific literature and regulations regarding analytical chemistry, toxicology, epidemiology, exposure, and risk assessment of melamine in infant formula. For analyses, enzyme-linked immunosorbent assay, high-performance liquid chromatography, capillary electrophoresis, gas chromatography coupled with mass spectrometry and liquid chromatography coupled with tandem mass spectrometry have commonly been used. Organization of proficiency test programs provided good evidence to facilitate granting laboratories accreditation and to ascertain the measurement reliability of melamine methods. Metabolic studies demonstrated that melamine is predominantly restricted to blood or extracellular fluid and is not extensively distributed to organs and tissues. Studies of human renal histopathology and clinical diagnoses indicated that melamine-related obstructive nephropathy derives from melamine precipitation in the lower urinary tract, with stones that are thought to be melamine-uric acid complexes. Epidemiologic studies showed that the occurrence of melamine-related urolithiasis is related to both the concentration of melamine in ingested milk products and the duration of ingestion. Long-term follow-up cohort studies should be continued to further investigate the epidemic and chronic hazard of melamine-induced nephrotoxicity. The World Health Organization set a tolerable daily intake of 0.2 mg/kg bw/day to be applied to "the whole population including infants". Other authorities and research institutes have set/proposed lower values. PMID- 23459150 TI - Functional electrical stimulation in spinal cord injury:: from theory to practice. AB - This article outlines steps to practical application of functional electrical stimulation (FES) within activity-based restorative therapy (ABRT). Drawing from current evidence, specific applications of FES intended to help restore function lost to spinal cord injury and associated neurologic disease are discussed. The medical and therapeutic indications, precautions, and contraindications are reviewed to help participants with appropriate patient selection, treatment planning, and assessment. Also included are the physiological implications of FES and alterable parameters, including dosing and timing, for a desired response. Finally, approaches to improve cortical representation and motor learning and to transition emerging movement into functional tasks are reviewed. PMID- 23459151 TI - Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres. AB - Human single-strand (ss) DNA binding proteins 1 and 2 (hSSB1 and 2) are components of the hSSB1/2-INTS3-C9orf80 heterotrimeric protein complex shown to participate in DNA damage response and maintenance of genome stability. However, their roles at telomeres remain unknown. Here, we generated murine SSB1 conditional knockout mice and cells and found that mSSB1 plays a critical role in telomere end protection. Both mSSB1 and mSSB2 localize to a subset of telomeres and are required to repair TRF2-deficient telomeres. Deletion of mSSB1 resulted in increased chromatid-type fusions involving both leading- and lagging-strand telomeric DNA, suggesting that it is required for the protection of G-overhangs. mSSB1's interaction with INTS3 is required for its localization to damaged DNA. mSSB1 interacts with Pot1a, but not Pot1b, and its association with telomeric ssDNA requires Pot1a. mSSB1(Delta/Delta) mice die at birth with developmental abnormalities, while mice with the hypomorphic mSSB1(F/F) allele are born alive and display increased sensitivity to ionizing radiation (IR). Our results suggest that mSSB1 is required to maintain genome stability, and document a previously unrecognized role for mSSB1/2 in the protection of newly replicated leading- and lagging-strand telomeres. PMID- 23459152 TI - Transcranial electrical stimulation accelerates human sleep homeostasis. AB - The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO) in the human electro-encephalogram (EEG). A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling during stimulation, which is compensated by a reduced drive after stimulation. We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep. PMID- 23459154 TI - Witnessing Phenotypic and Molecular Evolution in the Fruit Fly. AB - This multi-day exercise is designed for a college Genetics and Evolution laboratory to demonstrate concepts of inheritance and phenotypic and molecular evolution using a live model organism, Drosophila simulans. Students set up an experimental fruit fly population consisting of ten white eyed flies and one red eyed fly. Having red eyes is advantageous compared to having white eyes, allowing students to track the spread of this advantageous trait over several generations. Ultimately, the students perform PCR and gel electrophoresis at two neutral markers, one located in close proximity to the eye-color locus, and one located at the other end of the chromosome. Students observe that most flies have red eyes, and these red-eyed flies have lost variation at the near marker, but maintained variation at the far marker, hence observing a "selective sweep" and the "hitchhiking" of a nearby neutral variant. Students literally observe phenotypic and molecular evolution in their classroom! PMID- 23459153 TI - Interleukins 1beta and 10 expressions in the periimplant crevicular fluid from patients with untreated periimplant disease. AB - PURPOSE: To analyze the interleukin (IL)-1beta and IL-10 expressions in periimplant crevicular fluid (PICF) in healthy and diseased regions to elucidate the inflammatory process around implants and its influence on clinical diagnosis. MATERIALS AND METHODS: PICF samples from 30 patients were analyzed for IL-1beta and IL-10 concentrations by enzyme-linked immunosorbent assay. Patients were divided in Groups A (health), B (mucositis), and C (periimplantitis). Plaque accumulation, periodontal phenotype (PP), depth on probing, and history of periodontitis (HP) were evaluated. RESULTS: IL-1beta levels were lower in healthy group compared with Groups B (P < 0.0005) and C (P < 0.001). IL-10 levels were higher in Groups A compared with B (P = 0.033) and C (P = 0.0001). Patients with HP and thin PP had 9 and 4.5 times more chance of presenting disease, respectively. CONCLUSIONS: Lower IL-1beta and higher IL-10 levels characterized healthy periimplant conditions, which demonstrate the anti-inflammatory predominance in sites without disease signs. IL-10 levels decrease significantly according to increase of disease status. Therefore, its levels can differentiate healthy, mucositis, and periimplantitis. Thin PP and HP are associated with periimplant disease. These findings suggest the use of ILs as a biochemical marker for early diagnosis of periimplant disease. PMID- 23459155 TI - Age related metabolic syndrome among hemodialysis patients in gorgan, iran. AB - People with metabolic syndrome are at high risk for developing cardiovascular disease. The present study aimed to determine the age related metabolic syndrome of hemodialysis patients. The biochemical parameters and demographic information were registered. The prevalence of metabolic syndrome was significantly high in ages 50-59 and 60-69 years in hemodialysis patients when compared with other age groups (P< 0.05). There was elevated frequency of metabolic syndrome from age 50 59 and 40-49 years in male and female hemodialysis patients, respectively. The frequency of metabolic syndrome in female subjects (65.27%) was higher than male (47.14%, P<0.05). The prevalence of metabolic syndrome was high in ages 50-59 years in males and females. There was a significant difference in hemodialysis patients with metabolic syndrome in ages 50-59 years in males and from ages 40 49, 50-59 and 60-69 years in females (P< 0.05). Our results show that 25.71%, 18.57% and 2.86% males and 36.11%, 20.83% and 8.33% females had three, four and five criteria for metabolic syndrome, respectively. The results of this study showed that females patients were more affected than males. This may depended on the specific lifestyle alterations among females and males patients in this area. PMID- 23459156 TI - Mycobacterium avium-intracellulare otomastoiditis in a young AIDS patient: case report and review of the literature. AB - Mycobacterium avium-intracellulare (MAI) complex is a common opportunistic infection that generally occurs in patients with a CD4 cell count less than 75. Current recommendations for prophylaxis include using a macrolide once a week, while treatment usually requires a multidrug regimen. Disseminated MAI infections often occur in patients who are not compliant with prophylaxis or their highly active antiretroviral therapy (HAART). Many manifestations of MAI infection are well documented in human immunodeficiency virus (HIV) patients, including pulmonary and cutaneous manifestations, but other unusual manifestations such as pericarditis, pleurisy, peritonitis, brain abscess, otitis media, and mastoiditis are sporadically reported in the infectious diseases literature. This case report is of a 22-year-old female who contracted HIV at a young age and who was subsequently noncompliant with HAART, MAI prophylaxis, and prior treatment for disseminated MAI infection. Unsurprisingly, the patient developed recurrent disseminated MAI infection. The patient's presentation was atypical, as she developed severe otomastoiditis and posterior reversible encephalopathy syndrome. The posterior reversible encephalopathy syndrome was thought to be due to the disseminated MAI infection or to immune reconstitution inflammatory syndrome. The infection was confirmed to be secondary to MAI by culture of the mastoid bone. Microbiological analysis of the MAI strain cultured showed resistance to several first-line antibiotics used for prophylaxis against and treatment of MAI. This was likely due to the patient's chronic noncompliance. Otomastoiditis secondary to MAI is predominantly a pediatric disease and a rare entity in general. It has been reported in three case reports and one case series in pediatric patients, and now in this case report of an adult patient with HIV [corrected]. Improved clinician education in the diagnosis, treatment, and, most important, prevention of MAI and other opportunistic infections is needed. Greater HIV screening, appropriate HAART medication administration, and availability of infectious disease specialists is needed in at-risk populations to help prevent such serious infections. Patient education and greater access to care should serve to prevent medication nonadherence and to enhance affordability of HAART and prophylactic antibiotics. PMID- 23459157 TI - Analysis of age-dependence of the anterior and posterior cornea with scheimpflug imaging. AB - PURPOSE: To assess keratometric and higher-order aberrations of the anterior and posterior cornea and their age-related changes. METHODS: This study investigated one healthy eye of 227 patients (mean age: 55.15 +/- 21.2 years; range: 16 to 90 years; 135 right eyes, 92 left eyes). Images were captured from each eye with Pentacam HR (Oculus Optikgerate GmbH, Wetzlar, Germany) using automatic mode. Keratometric, astigmatism data, and corneal higher-order aberrations were analyzed. RESULTS: With respect to laterality, no deviance was found in any of the parameters (P > .05). Mean refractive error was 0.52 +/- 0.23 diopters. The level of astigmatism decreased significantly with advancing age for both the anterior and posterior corneal surfaces (P < .05). The overall root mean square of the higher-order aberration increased continuously with age (r = 0.517; P < .01), which can be explained by the combined effect of the increased in both the anterior and posterior corneal root mean square higher-order aberrations. Of the higher-order aberrations, the constant increase of the primary and secondary spherical aberration with aging (P < .01) is caused by the spherical aberration growth of the anterior surface. Apart from these, only the vertical coma aberration of the posterior surface and the vertical trefoil aberrations of both the anterior and posterior surfaces showed a significantly positive correlation with aging (P < .05). CONCLUSIONS: Corneal astigmatism showed a significant decrease with aging. Of the higher-order aberrations, primary and secondary spherical aberrations, vertical coma, and vertical trefoil significantly increase with age, whereas other higher-order aberrations show no correlation with aging. PMID- 23459158 TI - Human cooperation by lethal group competition. AB - Why humans are prone to cooperate puzzles biologists, psychologists and economists alike. Between-group conflict has been hypothesized to drive within group cooperation. However, such conflicts did not have lasting effects in laboratory experiments, because they were about luxury goods, not needed for survival ("looting"). Here, we find within-group cooperation to last when between group conflict is implemented as "all-out war" (eliminating the weakest groups). Human subjects invested in helping group members to avoid having the lowest collective pay-off, whereas they failed to cooperate in control treatments with random group elimination or with no subdivision in groups. When the game was repeated, experience was found to promote helping. Thus, not within-group interactions alone, not random group elimination, but pay-off-dependent group elimination was found to drive within-group cooperation in our experiment. We suggest that some forms of human cooperation are maintained by multi-level selection: reciprocity within groups and lethal competition among groups acting together. PMID- 23459159 TI - Structure-based comparative analysis and prediction of N-linked glycosylation sites in evolutionarily distant eukaryotes. AB - The asparagine-X-serine/threonine (NXS/T) motif, where X is any amino acid except proline, is the consensus motif for N-linked glycosylation. Significant numbers of high-resolution crystal structures of glycosylated proteins allow us to carry out structural analysis of the N-linked glycosylation sites (NGS). Our analysis shows that there is enough structural information from diverse glycoproteins to allow the development of rules which can be used to predict NGS. A Python-based tool was developed to investigate asparagines implicated in N-glycosylation in five species: Homo sapiens, Mus musculus, Drosophila melanogaster, Arabidopsis thaliana and Saccharomyces cerevisiae. Our analysis shows that 78% of all asparagines of NXS/T motif involved in N-glycosylation are localized in the loop/turn conformation in the human proteome. Similar distribution was revealed for all the other species examined. Comparative analysis of the occurrence of NXS/T motifs not known to be glycosylated and their reverse sequence (S/TXN) shows a similar distribution across the secondary structural elements, indicating that the NXS/T motif in itself is not biologically relevant. Based on our analysis, we have defined rules to determine NGS. Using machine learning methods based on these rules we can predict with 93% accuracy if a particular site will be glycosylated. If structural information is not available the tool uses structural prediction results resulting in 74% accuracy. The tool was used to identify glycosylation sites in 108 human proteins with structures and 2247 proteins without structures that have acquired NXS/T site/s due to non-synonymous variation. The tool, Structure Feature Analysis Tool (SFAT), is freely available to the public at http://hive.biochemistry.gwu.edu/tools/sfat. PMID- 23459160 TI - Onyx embolization of anterior condylar confluence dural arteriovenous fistula. AB - The anterior condylar confluence (ACC) is a small complex venous structure located medial to the jugular vein and adjacent to the hypoglossal canal. To our knowledge, this is the first report of transvenous Onyx embolization for ACC dural arteriovenous fistula (DAVF). Three patients with ACC DAVF were treated using the Onyx liquid embolic agent with or without detachable coils. Complete angiographic obliteration of the fistulas was achieved in all cases without permanent lower cranial neuropathy. This report suggests that the controlled penetration of Onyx is advantageous in order to obliterate ACC DAVFs with a small amount of embolic material. PMID- 23459161 TI - Simultaneous Bayesian inference for skew-normal semiparametric nonlinear mixed effects models with covariate measurement errors. AB - Longitudinal data arise frequently in medical studies and it is a common practice to analyze such complex data with nonlinear mixed-effects (NLME) models which enable us to account for between-subject and within-subject variations. To partially explain the variations, covariates are usually introduced to these models. Some covariates, however, may be often measured with substantial errors. It is often the case that model random error is assumed to be distributed normally, but the normality assumption may not always give robust and reliable results, particularly if the data exhibit skewness. Although there has been considerable interest in accommodating either skewness or covariate measurement error in the literature, there is relatively little work that considers both features simultaneously. In this article, our objectives are to address simultaneous impact of skewness and covariate measurement error by jointly modeling the response and covariate processes under a general framework of Bayesian semiparametric nonlinear mixed-effects models. The method is illustrated in an AIDS data example to compare potential models which have different distributional specifications. The findings from this study suggest that the models with a skew-normal distribution may provide more reasonable results if the data exhibit skewness and/or have measurement errors in covariates. PMID- 23459162 TI - New 'chimie douce' approach to the synthesis of hybrid nanosheets of MoS2 on CNT and their anti-friction and anti-wear properties. AB - Hybrid organic-inorganic oleylamine@MoS2-CNT nanocomposites with different compositions were obtained by thermal decomposition of tetrathiomolybdate in the presence of oleylamine and high quality multiwalled carbon nanotubes (CNTs) previously prepared by the CCVD technique. The nanocomposite samples were characterized by the TEM, SEM TG-MS, Raman and XRD techniques and successfully tested as anti-friction and anti-wear additives for grease lubricants. PMID- 23459164 TI - Helicobacter pylori seropositivity in patients with hyperemesis gravidarum. AB - BACKGROUND: Nausea and vomiting during pregnancy are the most common conditions affecting pregnancy, occurring in about 80% of all pregnancies and always disappearing on the 16th to 18th weeks of gestation. This may be mild and it does not affect the general condition of the patient (the condition is called emesis gravidarum), or it may be severe enough to affect the patient physically and psychologically, causing intractable vomiting, electrolyte imbalance, weight loss >5%, impairment of liver and kidney functions and dehydration. Helicobacter pylori is one of the most common bacterium affecting humans. It is a gram negative helix-shaped microaerophilic bacterium transmitted by the oro-oral or feco-oral route. It is more prevalent in developing countries and affects young children. Acute infection manifests as acute gastritis and stomach pain, whereas chronic infection causes chronic gastritis and peptic ulcer, 2% of which may develop into stomach cancer. The authors tried to investigate the association between H pylori infection and hyperemesis gravidarum. METHODS: Fifty patients with hyperemesis gravidarum and 50 patients with normal pregnancy were included in the study. H pylori infection was determined using a 1-step H pylori test device (serum/plasma), which is a qualitative membrane-based immunoassay. RESULTS: Regarding maternal age, gestational age and socioeconomic status, there is no statistical difference between both groups. There is a marked statistical difference between both groups in terms of Helicobacter pylori seropositivity and frequency of vomiting. CONCLUSIONS: There is a powerful correlation between H pylori and hyperemesis gravidarum. PMID- 23459163 TI - Depression in Homebound Older Adults: Recent Advances in Screening and Psychosocial Interventions. AB - Homebound older adults are more likely than their ambulatory peers to suffer from depression. Unfortunately, the effectiveness of antidepressant medications alone in such cases is limited. Greater benefits might be realized if patients received both pharmacotherapy and psychotherapy to enhance their skills to cope with their multiple chronic medical conditions, isolation, and mobility impairment; however, referrals to specialty mental health services seldom succeed due to inaccessibility, shortage of geriatric mental health providers, and cost. Since a large proportion of homebound older adults receive case management and other services from aging services network agencies, the integration of mental health services into these agencies is likely to be cost-efficient and effective. This review summarizes recent advances in home-based assessment and psychosocial treatment of depression in homebound recipients of aging services. PMID- 23459165 TI - Genetic polymorphisms in MTHFR (C677T, A1298C), MTR (A2756G) and MTRR (A66G) genes associated with pathological characteristics of prostate cancer in the Ecuadorian population. AB - INTRODUCTION: The methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and MTR reductase (MTRR) enzymes act in the folate metabolism, which is essential in methylation and synthesis of nucleic acids. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G and MTRR A66G, cause alteration in the homocysteine levels and reduced enzymatic activity that generates deficiency in the assimilation of folates associated with DNA damage; that is, why it is important to know if the single nucleotide polymorphisms are associated with the pathological characteristics and development of prostate cancer, through a case-control retrospective study. METHODS: DNA was extracted from 110 healthy and 104 affected men. The genotypes were determined by means of the polymerase chain reaction-restriction fragment length polymorphism and confirmed with genomic sequencing. RESULTS: We found significant association between the genotypes of the MTHFR C677T polymorphism: C/T (odds ratio [OR] = 2.2; 95% confidence interval [CI] = 1.3-3.9; P = 0.008) and C/T + T/T (OR = 2.2; 95% CI = 1.3-3.9; P = 0.009) with the risk of prostate cancer development, and a slight association with MTRR A66G. Regarding pathological characteristics, we found significant risk between the C/T + T/T genotypes and the Gleason score (7 10) of poorly differentiated carcinoma (OR = 5.2; 95% CI = 1.7-16.2; P = 0.007). On the other hand, a significant association between A1298C, A66G, and A2756G with the pathological characteristics was not found (P > 0.05). CONCLUSIONS: The MTHFR C677T polymorphism has significant effects on susceptibility to prostate cancer in Ecuadorian population, especially with the Gleason grade. PMID- 23459166 TI - A Training Strategy for Learning Pattern Recognition Control for Myoelectric Prostheses. AB - Pattern recognition-based control of myoelectric prostheses offers amputees a natural, intuitive way of controlling the increasing functionality of modern myoelectric prostheses. While this approach to prosthesis control is certainly attractive, it is a significant departure from existing control methods. The transition from the more traditional methods of direct or proportional control to pattern recognition-based control presents a training challenge that will be unique to each amputee. In this paper we describe specific ways that a transradial amputee, prosthetist, and occupational therapist team can overcome these challenges by developing consistent and distinguishable muscle patterns. A central part of this process is the employment of a computer-based pattern recognition training system with which an amputee can learn and improve pattern recognition skills throughout the process of prosthesis fitting and testing. We describe in detail the manner in which four transradial amputees trained to improve their pattern recognition-based control of a virtual prosthesis by focusing on building consistent, distinguishable muscle patterns. We also describe a three-phase framework for instruction and training: 1) initial demonstration and conceptual instruction, 2) in-clinic testing and initial training, and 3) at-home training. PMID- 23459167 TI - Differential phosphoproteome of the striatum from pleiotrophin knockout and midkine knockout mice treated with amphetamine: correlations with amphetamine induced neurotoxicity. AB - The neurotrophic factors pleiotrophin (PTN) and midkine (MK) have been shown to modulate amphetamine-induced neurotoxicity. Accordingly, PTN-/- and MK-/- mice show an increased vulnerability to amphetamine-induced neurotoxic effects. In an effort to uncover new pharmacological targets to prevent amphetamine neurotoxic effects, we have now used a proteomic approach to study protein phosphorylation, in which we combined phosphoprotein enrichment, by immobilized metal affinity chromatography (IMAC), with two-dimensional gel electrophoresis and mass spectrometry, in order to identify the phosphoproteins regulated in the striatum of PTN-/-, MK-/- and wild type (WT) mice treated with amphetamine. We identified 13 differentially expressed phosphoproteins that are judged to be relevant in the neuroprotective roles of PTN and MK against amphetamine-induced neurotoxicity. It is very interesting to note that 4 of these phosphoproteins, annexin A7 (ANXA7), COP9 signalosome subunit 5 (COPS5), aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and creatine kinase U-type (CKMT1), are known to be involved in Parkinson's disease, a result of significant importance since PTN and MK have been also demonstrated to limit Parkinson's disease (PD) progress and have been suggested to be among the important genetic factors possibly preventing the development of PD in methamphetamine abusers. The data identify phosphoproteins differentially regulated by amphetamine treatment and/or the presence of endogenous PTN/MK which may be relevant mediators of PTN/MK neuroprotective effects against amphetamine-induced neurotoxicity. The data support further studies to validate the phosphoproteins here identified as possible new pharmacological targets to prevent amphetamine neurotoxic effects. PMID- 23459168 TI - An oncology pharmacy practice elective course for third-year pharmacy students. AB - Objective. To develop and implement a 1-credit-hour oncology pharmacy practice elective course for third-year pharmacy students and assess its impact on examination scores in a required pharmacotherapeutics course.Design. Major topics were identified to focus on therapeutic management and supportive care of the oncology patient. Psychosocial topics were incorporated to help pharmacy students better relate to oncology patients.Assessment. Learning was assessed by means of 2 computer-based examinations, weekly reflection posts, and a completed oncology service-learning project and reflection paper. Students enrolled in the course achieved higher pharmacotherapeutics oncology section examination scores than students who had not taken the course. Also, this course increased students' interest in oncology pharmacy.Conclusion. The oncology pharmacy elective course has received overwhelmingly positive feedback from students and student enrollment continues to grow. We will continue to offer this course to future practitioners. PMID- 23459169 TI - Ionotropic receptors (IRs): chemosensory ionotropic glutamate receptors in Drosophila and beyond. AB - Ionotropic Receptors (IRs) are a recently characterized family of olfactory receptors in the fruit fly, Drosophila melanogaster. IRs are not related to insect Odorant Receptors (ORs), but rather have evolved from ionotropic glutamate receptors (iGluRs), a conserved family of synaptic ligand-gated ion channels. Here, we review the expression and function of IRs in Drosophila, highlighting similarities and differences with iGluRs. We also briefly describe the organization of the neuronal circuits in which IRs function, comparing and contrasting them with the sensory pathways expressing ORs. Finally, we summarize the bioinformatic identification and initial characterization of IRs in other species, which imply an evolutionarily conserved role for these receptors in chemosensation in insects and other protostomes. PMID- 23459170 TI - Molecular characterization of the flightin gene in the wing-dimorphic planthopper, Nilaparvata lugens, and its evolution in Pancrustacea. AB - Flightin was initially identified in Drosophila melanogaster. Previous work has shown that Drosophila flightin plays a key role in indirect flight muscle (IFM) function and has limited expression in the IFM. In this study, we demonstrated that flightin is conserved across the Pancrustacea species, including winged insects, non-winged insects, non-insect hexapods and several crustaceans. The brown planthopper (BPH), Nilaparvata lugens (Stal) (Hemiptera: Delphacidae), a long-distance migration insect with wing dimorphism, is the most destructive rice pest in Asia. We showed that flightin was one of the most differentially expressed genes in macropterous and brachypterous BPH adults. In female BPHs, flightin was expressed in the IFM of macropterous adults, no expression was detected in brachypterous ones; while in male BPHs, flightin was not only expressed in the IFM of macropterous adults, but also in the dorsal longitudinal muscle (DLM) in the basal two abdominal segments of both macropterous and brachypterous ones. RNAi and transmission electron microscopy results showed that flightin played key roles in maintaining IFM and male DLM structure, which drive wing movements in macropterous adults and the vibration of the male-specific tymbal, respectively. Using Daphnia magna as an example of a crustacean species, we observed that flightin was expressed in juvenile instars and adults, and was localized in the antenna muscles. These results illustrate the functional variations of flightin in insects and other arthropod species and provide clues as to how insects with flight apparatuses evolved from ancient pancrustaceans. PMID- 23459171 TI - Distributed storage healthcare - the basis of a planet-wide public health care network. AB - BACKGROUND: As health providers move towards higher levels of information technology (IT) integration, they become increasingly dependent on the availability of the electronic health record (EHR). Current solutions of individually managed storage by each healthcare provider focus on efforts to ensure data security, availability and redundancy. Such models, however, scale poorly to a future of a planet-wide public health-care network (PWPHN). Our aim was to review the research literature on distributed storage systems and propose methods that may aid the implementation of a PWPHN. METHODS: A systematic review was carried out of the research dealing with distributed storage systems and EHR. A literature search was conducted on five electronic databases: Pubmed/Medline, Cinalh, EMBASE, Web of Science (ISI) and Google Scholar and then expanded to include non-authoritative sources. RESULTS: The English National Health Service Spine represents the most established country-wide PHN but is limited in deployment and remains underused. Other, literature identified and established distributed EHR attempts are more limited in scope. We discuss the currently available distributed file storage solutions and propose a schema of how one of these technologies can be used to deploy a distributed storage of EHR with benefits in terms of enhanced fault tolerance and global availability within the PWPHN. We conclude that a PWPHN distributed health care record storage system is technically feasible over current Internet infrastructure. Nonetheless, the socioeconomic viability of PWPHN implementations remains to be determined. PMID- 23459173 TI - The prognostic impact of the stroke unit care versus conventional care in treatment of patients with transient ischemic attack: a prospective population based German study. AB - BACKGROUND AND PURPOSE: The risk of a stroke after a transient ischemic attack (TIA) is high in the short time following a TIA. The German Stroke Society recommends an early hospitalization of patients with TIA preferably in a stroke unit (SU). This study aims to compare the impact of SU care with conventional care (CC) in patients with TIA. METHODS: In a prospective study, during a 36 month phase (starting November 2007), patients with TIA who were admitted to the hospital within 48 h of symptom onset were enrolled. Stroke rate during hospitalization and the 90-day rates of stroke and mortality were studied. Logistic regression analyses were used to estimate the odds ratio (OR). RESULTS: Of 2,200 patients (mean age, 17.6 +/- 12 years, 49% female), 1,347 (61%) treated in a SU and 853 (39%) received CC at general departments. Patients treated in SU were significantly younger than those received a CC (69.9 vs. 71.7 years; P = 0.001). TIA patients treated on SU received more ultrasound investigations of the neck arteries (98 vs. 96%; P = 0.003) and of the brain arteries (97 vs. 82%; P < 0.001) than those of CC. The primary outcomes (stroke during hospitalization, stroke after 90 days, and mortality after 90 days) did not show a difference between the SU and CC groups. In patients of male sex, the 90-day stroke rate was significantly lower in the SU group than the CC group (1.8 vs. 4.5%; P = 0.033). Using the adjusted logistic regression analysis, treatment in a SU revealed a reduction of 90-day stroke rate in patients of male sex (OR 0.38; 95% CI 0.15 0.95; P = 0.04). CONCLUSION: The impact of evaluation and treatment of patients with TIA in SU and CC appears to differ only among patients of male sex. Further randomized trials are necessary. PMID- 23459172 TI - Compatibility in the Ustilago maydis-maize interaction requires inhibition of host cysteine proteases by the fungal effector Pit2. AB - The basidiomycete Ustilago maydis causes smut disease in maize, with large plant tumors being formed as the most prominent disease symptoms. During all steps of infection, U. maydis depends on a biotrophic interaction, which requires an efficient suppression of plant immunity. In a previous study, we identified the secreted effector protein Pit2, which is essential for maintenance of biotrophy and induction of tumors. Deletion mutants for pit2 successfully penetrate host cells but elicit various defense responses, which stops further fungal proliferation. We now show that Pit2 functions as an inhibitor of a set of apoplastic maize cysteine proteases, whose activity is directly linked with salicylic-acid-associated plant defenses. Consequently, protease inhibition by Pit2 is required for U. maydis virulence. Sequence comparisons with Pit2 orthologs from related smut fungi identified a conserved sequence motif. Mutation of this sequence caused loss of Pit2 function. Consequently, expression of the mutated protein in U. maydis could not restore virulence of the pit2 deletion mutant, indicating that the protease inhibition by Pit2 is essential for fungal virulence. Moreover, synthetic peptides of the conserved sequence motif showed full activity as protease inhibitor, which identifies this domain as a new, minimal protease inhibitor domain in plant-pathogenic fungi. PMID- 23459174 TI - Risk factors for posttraumatic stress disorder in persons with spinal cord injury. AB - PURPOSE: Many of the events that cause spinal cord injury (SCI) are traumatic events that can result in posttraumatic stress disorder (PTSD). It therefore appears that most persons with SCI are at risk for developing PTSD. This study retrospectively examined risk factors for PTSD symptoms in a sample of 71 persons with SCI. METHOD: The Structured Clinical Interview for DSM-IV was used to assess full and partial PTSD diagnoses. Self-administered questionnaires were used to measure potential risk factors. RESULTS: Results indicated that 11% of the participants met the criteria for full PTSD, and an additional 20% met the criteria for partial PTSD at some point after their SCI. Hierarchical linear regression analyses revealed that trauma history, peritraumatic reactions, and intolerance of uncertainty predicted the number of PTSD symptoms. CONCLUSION: This study highlights the importance of trauma history, peritraumatic reactions, and intolerance of uncertainty in the development of PTSD symptoms. Patients at risk for PTSD should be identified early in the rehabilitation process and could benefit from psychological interventions with the aim of preventing PTSD development. PMID- 23459175 TI - Secondary Complications in SCI Across the Continuum: Using Operations Research to Predict the Impact and Optimize Management Strategies. AB - Secondary complications following traumatic spinal cord injury (tSCI) have a tremendous impact on quality of life and health care costs. Although some complications result from the injury itself, many originate from the care provided; complications arising early in the tSCI journey can predispose an individual to recurrence later. To measure the total impact of secondary complications on patient outcomes and health care costs, all the stages of care, from first response to life in the community, must be spanned. Interventions to ameliorate secondary complications need to consider the effects on the whole system and not just individual phases of care; however, such an approach is not common in the literature. To measure the impact of complications as well as the effect of proposed interventions, a partnership between clinical researchers and operations research professionals was formed to develop a discrete-event simulation model of the entire continuum of tSCI care. In this article, we focus on the part of the model concerning common secondary complications (eg, pressure ulcers, pneumonia). We first describe early results from the model, discuss how the effects from the complications impact care throughout the tSCI continuum, and review assumptions of the model. The article concludes with a discussion as to the possible uses of the model, their strengths/limitations, and future directions. PMID- 23459176 TI - Trajectories of health care service utilization and differences in patient characteristics among adults with specific chronic pain: analysis of health plan member claims. AB - INTRODUCTION: The lack of consistency surrounding the diagnosis of chronic non cancer pain, treatment approaches, and patient management suggests the need for further research to better characterize the chronic non-cancer pain population. OBJECTIVE: The purpose of this study was to identify distinct trajectories of health care service utilization of chronic non-cancer pain patients and describe the characteristic differences between trajectory groups. PATIENTS AND METHODS: This study utilized the MarketScan claims databases. A total of 71,392 patients diagnosed with either low back pain or osteoarthritis between 2006 and 2009 served as the study sample. Each subject's claims data were divided into three time periods around an initial diagnosis date: pre-period, post-Year 1, and post Year 2. Subjects were categorized as either high (H) or low (L) cost at each post period, resulting in the creation of four trajectory groups based on the post Year 1 and 2 cost pattern: H-H, H-L, L-H, and L-L. Multivariate statistical tests were used to predict and discriminate between trajectory group memberships. RESULTS: The H-H, L-H, and H-L groups each utilized significantly greater pre period high-cost venue services, post-Year 1 outpatient services, and post-Year 1 opioids compared to the L-L group (P < 0.001). Additionally, the H-H and L-H groups displayed elevated Charlson comorbidity index scores compared with the L-L group (P < 0.001), with each showing increased odds of having both opioid dependence and cardiovascular disease diagnoses (P < 0.01). CONCLUSION: This study identified patient characteristics among chronic pain patients that discriminated between different levels of post-index high-cost venue service utilization and trajectories of change in the same. With implications for managed care program implementation and resource management, this study highlights results from a developed algorithm that employed a variety of accessible data elements to effectively discriminate between patients based on their pattern of high-cost venue service utilization over time. PMID- 23459177 TI - Psychiatric judgments across cultural contexts: relativist, clinical ethnographic, and universalist-scientific perspectives. AB - Psychiatrists encounter persons from diverse cultures who profess experiences (e.g., communicating with spirits) that evoke intuitions of abnormality. This view might not be shared with the person or her/his cultural peers, raising questions concerning the justification of such intuitions. This article explores three positions relevant to the process of justification. The relativist position transfers powers of judgment to the subject's peers yet neglects individual values and operates with a discredited holistic view of culture. The clinical ethnographic position remedies this by suspending judgment subject to understanding the individual in a sociocultural context yet finds objections with the universalist-scientific position: objective standards exist and could justify intuitions of abnormality cross-culturally. This article argues that the claim to objectivity is value-laden, reflecting instead a brand of normality and relationship to reality further upheld through epistemological utility and valued technological progress. In conclusion, it is suggested that the clinical ethnographic position takes personal values and context seriously, both of which are crucial for responsible clinical practice. PMID- 23459178 TI - Why we essentialize mental disorders. AB - Essentialism is one of the most pervasive problems in mental health research. Many psychiatrists still hold the view that their nosologies will enable them, sooner or later, to carve nature at its joints and to identify and chart the essence of mental disorders. Moreover, according to recent research in social psychology, some laypeople tend to think along similar essentialist lines. The main aim of this article is to highlight a number of processes that possibly explain the persistent presence and popularity of essentialist conceptions of mental disorders. One such process is the general tendency of laypeople to essentialize conceptual structures, including biological, social, and psychiatric categories. Another process involves the allure of biological psychiatry. Advocating a categorical and biological approach, this strand of psychiatry probably reinforced the already existing lay essentialism about mental disorders. As such, the question regarding why we essentialize mental disorders is a salient example of how cultural trends zero in on natural tendencies, and vice versa, and how both can boost each other. PMID- 23459179 TI - D. Alan Shewmon and the PCBE's White Paper on Brain Death: are brain-dead patients dead? AB - The December 2008 White Paper (WP) on "Brain Death" published by the President's Council on Bioethics (PCBE) reaffirmed its support for the traditional neurological criteria for human death. It spends considerable time explaining and critiquing what it takes to be the most challenging recent argument opposing the neurological criteria formulated by D. Alan Shewmon, a leading critic of the "whole brain death" standard. The purpose of this essay is to evaluate and critique the PCBE's argument. The essay begins with a brief background on the history of the neurological criteria in the United States and on the preparation of the 2008 WP. After introducing the WP's contents, the essay sets forth Shewmon's challenge to the traditional neurological criteria and the PCBE's reply to Shewmon. The essay concludes by critiquing the WP's novel justification for reaffirming the traditional conclusion, a justification the essay finds wanting. PMID- 23459180 TI - The role of moral imagination in patients' decision-making. AB - This article reviews recent developments within a number of academic disciplines pointing toward an increasing importance of imagination for understanding morality and cognition. Using elements from hermeneutics and metaphor theory, it works toward a framework for a more context-sensitive understanding of human agency, especially focusing on moral deliberation and change. The analytic framework is used to analyze the story of a patient making tough decisions in the context of prenatal diagnosis. We show how a relatively stable outlook on the world, here called the "baseline of choice," is challenged by unexpected events and how imaginative processes enter into the active creation of a new moral order. The ensuing interpretation is then placed within a broader philosophical landscape. John Dewey's notion of "dramatic rehearsal" is put forward as one particularly promising way of understanding moral imagination, deliberation, and decision-making. PMID- 23459181 TI - Droplet-fused microreactors for room temperature synthesis of nanoscale needle like hydroxyapatite. AB - A microfluidic device using droplet-fused microreactors is introduced for room temperature synthesis of nanoscale needle-shaped hydroxyapatite (HAp, Ca10(PO4)6(OH)2). The device is integrated with multifunctional units, e.g., T junctions for droplet generation and fusion, winding channels for rapid mixing, and a delay line for simple visualization of the HAp formation process. The necessary conditions such as surfactant and fluid flow rate for an aqueous stream to merge with water-in-oil droplets are investigated. The nanoscale morphologies of the HAp produced by this method are also compared with HAp prepared by conventional bulk mixing. This paper shows that further reaction could be initiated by flowing additional reagent streams directly into the droplets of the initial reaction mixture, which is a novel approach for synthesizing a needle like morphology of the HAp with a high aspect ratio under room temperature. PMID- 23459182 TI - Reestablishment of Notopygos megalops McIntosh, description of N. caribea sp. n. from the Greater Caribbean and barcoding of "amphiamerican" Notopygos species (Annelida, Amphinomidae). AB - The species of the genus Notopygos Grube, 1855 are characterized by an ovate body, a prominent caruncle with three lobes, dendritic branchiae, and double dorsal cirri. Twenty-two species belonging to Notopygos have been described, mostly from the Indo-Pacific region. In America, few species are frequently recorded: Notopygos crinita Grube, 1855 from St. Helena Island (Atlantic) and Notopygos ornata Grube and Orsted in Grube 1857 from Costa Rica (Pacific). Notopygos crinita is a widely distributed species in the Western Atlantic with additional reports in the Mediterranean Sea (as a questionable alien species) and in the Pacific Ocean. However, only the genus features have been considered, consequently some records could be misidentifications. During a revision of materials from collections and the barcode project, 'Mexican Barcode of Life, MEXBOL', we found specimens of Notopygos megalops and an undescribed species from reef zones in the Caribbean; the former had been considered a junior synonym of Notopygos crinita. Herein, Notopygos megalops is reestablished and Notopygos caribeasp. n. is described. A morphological and DNA barcode approach was used to explain the records of Notopygos ornata in the Atlantic and to show the differences with the new species, since both species share features such as complex pigmentation patterns, and circular projections in the median lobe of the caruncle. PMID- 23459184 TI - Effect of green tea (Camellia sinensis) extract on healing process of surgical wounds in rat. AB - Green tea (Camellia sinensis) has anti-oxidant and anti-inflammatory properties and may enhance wound healing process. The present study, therefore, was aimed to examine the effect of green tea ethanolic extract on wound healing process. For this experimental study, 36 healthy male Wistar rats were randomly designated to three groups of A, B, and C which, respectively treated with, Vaseline + 0.6% green tea extract, Vaseline and normal saline for 21 days. Wounds' length and area were measured by caliper every other day and specimens were taken at 3rd, 12th, and 21st day for microscopical examinations. Data were analyzed by SPSS 16 using survival analysis (Breslow test), repeated measured ANOVA, one-way ANOVA and Mann-Whitney. P < 0.05 was considered as statistically significant. The mean healing duration of surgical wounds in groups A and B was 14.66 and 20.66 (P = 0.018), respectively. Decrease in healing duration in the group A was significantly higher within the first two weeks compared with control groups (P = 0.05). Microscopic examinations also indicated a significant difference in wound healing process between groups A and C throughout the whole study duration as well as groups A and B during the 3rd week of the study (P < 0.05). Green tea extract could help wound healing process, probably effective on surgical wounds healing. PMID- 23459185 TI - Abdominal cocoon: a case series. AB - We describe a series of 18 cases of abdominal cocoon in patients presenting with features of small intestinal obstruction or perforative peritonitis, nine of whom had tubercular aetiology while the rest were idiopathic. Manifestations of abdominal tuberculosis such as mesenteric abscesses, enlarged and caseating mesenteric lymph nodes, and tubercles over the bowel serosa were found in only 55% patients who were ultimately diagnosed to have Tubercular aetiology. We conclude that a high index of suspicion for this rare cause of a common surgical emergency is desirable. PMID- 23459183 TI - Hirsutella sinensis mycelium suppresses interleukin-1beta and interleukin-18 secretion by inhibiting both canonical and non-canonical inflammasomes. AB - Cordyceps sinensis is a medicinal mushroom used for centuries in Asian countries as a health supplement and tonic. Hirsutella sinensis-the anamorphic, mycelial form of C. sinensis-possesses similar properties, and is increasingly used as a health supplement. Recently, C. sinensis extracts were shown to inhibit the production of the pro-inflammatory cytokine IL-1beta in lipopolysaccharide treated macrophages. However, the molecular mechanism underlying this process has remained unclear. In addition, whether H. sinensis mycelium (HSM) extracts also inhibit the production of IL-1beta has not been investigated. In the present study, the HSM extract suppresses IL-1beta and IL-18 secretion, and ATP-induced activation of caspase-1. Notably, we observed that HSM not only reduced expression of the inflammasome component NLRP1 and the P2X7R but also reduced the activation of caspase-4, and ATP-induced ROS production. These findings reveal that the HSM extract has anti-inflammatory properties attributed to its ability to inhibit both canonical and non-canonical inflammasomes. PMID- 23459186 TI - Financial impact of surgical training on hospital economics: an income analysis of 1184 out-patient clinic consultations. AB - INTRODUCTION: In many countries healthcare commissioning bodies (state or insurance-based) reimburse hospitals for their activity. The costs associated with post-graduate clinical training as part of this are poorly understood. This study quantified the financial revenue generated by surgical trainees in the out patient clinic setting. METHODS: A retrospective analysis of surgical out-patient ambulatory care appointments under 6 full-time equivalent Consultants (Attendings) in one hospital over 2 months. Clinic attendance lists were generated from the Patient Access System. Appointments were categorised as: 'new', 'review' or 'procedure' as per the Department of Health Payment by Results (PbR) Outpatient Tariff (Outpatient Treatment Function Code 104; Outpatient Procedure Code OPRSI1). RESULTS: During the study period 78 clinics offered 1184 appointments; 133 of these were not attended (11.2%). Of those attended 1029 had sufficient detail for analysis (98%). 261 (25.4%) patients were seen by a trainee. Applying PbR reimbursement criteria to these gave a projected annual income of LGBP 218,712 (?EU 266,527; $USD 353,657) generated by 6 surgical trainees (Residents). This is equivalent to approximately LGBP 36,452 (?EU 44,415; $USD 58,943) per trainee annually compared to LGBP 48,732 (?EU 59,378; $USD 78,800) per Consultant. This projected yearly income off-set 95% of the trainee's basic salary. CONCLUSION: Surgical trainees generated a quarter of the out-patient clinic activity related income in this study, with each trainee producing three-quarters of that generated by a Consultant. This offers considerable commercial value to hospitals. Although this must offset productivity differences and overall running costs, training bodies should ensure hospitals offer an appropriate return. In a competitive market hospitals could be invited to compete for trainees, with preference given to those providing excellence in training. PMID- 23459187 TI - Immunological faecal occult blood testing: a discriminatory test to identify colorectal cancer in symptomatic patients. AB - INTRODUCTION: Current investigation for patients with colorectal symptoms without overt rectal bleeding is undertaken by colonoscopy or by flexible sigmoidoscopy and barium enema. A large majority of patients do not have colorectal cancer. There exists no instant, objective measure to discriminate patients who are likely to have colorectal cancer and therefore require expedient investigation. AIM: To evaluate the sensitivity and specificity of immunological faecal occult blood testing (FOBT) in patients with colorectal symptoms without overt rectal bleeding. METHODS: Consecutive patients referred for urgent colonic investigation, were prospectively studied. A faecal sample was obtained from each one and subjected to immunological FOB which tested either negative or positive. All patients then underwent complete colonic imaging. The correlation between FOBT status and results from colonic imaging was studied. RESULTS: Of 126 tested, thirty patients (26.8%) were FOBT positive. One hundred and twelve patients underwent complete colonic imaging. In the FOBT positive group colonic imaging identified 17 cases of histologically proven adenocarcinoma, 1 recurrent squamous cell carcinoma of anus, 1 adenomatous polyp, 6 cases of diverticulosis, and no pathology in 5 cases. In the 82 FOBT negative patients, no cancers were found. Overall the Immunological Faecal Occult Blood Test was found to have 100% sensitivity and 86.3% specificity. CONCLUSION: Immunological faecal occult blood testing is a sensitive and specific test in identifying colorectal cancer and may be useful in identifying those patients who warrant urgent investigation. Routine clinical application may be useful in the allocation of resources. PMID- 23459188 TI - Staple line reinforcement during laparoscopic sleeve gastrectomy: does it affect clinical outcomes? AB - Although laparoscopic sleeve gastrectomy (LSG) is safe and efficacious treatment for morbid obesity, this procedure is associated with major staple line complications including leakage and bleeding. Staple-line reinforcement (SLR) either through suturing or buttressing with biological or synthetic material has been suggested as a method to prevent these complications. A Best Evidence Topic was constructed to address the question of whether SLR reduced these and other complications. MEDLINE, EMBASE and CINAHL searches up to October 2012 returned 97 unique results, of which nine (one meta-analysis, two randomised controlled trials (RCTs), six prospective cohort studies) provided the best evidence to answer this clinical question. We conclude that current evidence suggests that staple-line reinforcement reduces the incidence of leakage and postoperative complications than non-reinforcement but does not significantly reduce bleeding complications. However, we cannot as yet recommend staple-line reinforcement as the strength of the presented evidence is limited by the variable quality of the published studies. The full-length publication of several abstracts of randomised, controlled trials presented at various recent conferences is awaited. This may provide more data on the effect of staple-line reinforcement on other outcomes largely neglected by currently available studies. PMID- 23459189 TI - Braile vena cava filter and greenfield filter in terms of centralization. AB - The aim of this study was to evaluate complications experienced during implantation of the Braile Vena Cava filter (VCF) and the efficacy of the centralization mechanism of the filter. This retrospective cohort study evaluated all Braile Biomedica VCFs implanted from 2004 to 2009 in Hospital de Base Medicine School in Sao Jose do Rio Preto, Brazil. Of particular concern was the filter's symmetry during implantation and complications experienced during the procedure. All the angiographic examinations performed during the implantation of the filters were analyzed in respect to the following parameters: migration of the filter, non-opening or difficulties in the implantation and centralization of the filter. A total of 112 Braile CVFs were implanted and there were no reports of filter opening difficulties or in respect to migration. Asymmetry was observed in 1/112 (0.9%) cases. A statistically significant difference was seen on comparing historical data on decentralization of the Greenfield filter with the data of this study. The Braile Biomedico filter is an evolution of the Greenfield filter providing improved embolus capture and better implantation symmetry. PMID- 23459190 TI - The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? AB - Neutrophils in the tumor host may promote tumor progression by enhancing angiogenesis, invasion and metastasis. Granulocytic myeloid-derived suppressor cells (MDSC) share many features with neutrophils. Classically, MDSC are viewed as and defined as immunosuppressive cells. In this article we summarize and critically review evidence for a role of MDSC in promoting angiogenesis, invasion and metastasis of solid tumors. We also attempt to provide a critical evaluation of the relationship between neutrophils and G-MDSC in the tumor host with a particular focus on human cancer. PMID- 23459191 TI - Statistical methodology in oral and dental research: pitfalls and recommendations. AB - OBJECTIVES: This study describes the pitfalls for commonly used statistical techniques in dental research and gives some recommendations for avoiding them. It also explores the potential of some of the newer statistical techniques for dental research. METHODS: Each of the commonly used techniques e.g. descriptive statistics, correlation and regression, hypothesis tests (parametric and non parametric) and survival analysis are explored with examples and recommendations for their use are provided. Common sources of error including those of study design, insufficient information, ignoring the impact of clustering and underuse of confidence intervals are outlined. The potential of statistical techniques such as multivariate survival models, generalized estimating equations and multilevel models are also explored. CONCLUSIONS: Reviews of published dental research repeatedly identify statistical errors in the design, analysis and conclusions of the study. Educating researchers on common pitfalls and giving recommendations for avoiding them may help researchers to eliminate statistical errors. Developments in statistical methodology should be routinely monitored to ensure the most appropriate statistical methods are used in dental research. PMID- 23459193 TI - Incretin-based therapy for type 2 diabetes mellitus: pancreatic and extrapancreatic effects. AB - The prevalence of type 2 diabetes mellitus has increased at an alarming rate in recent years. Recent estimations project that 366 million people could have diabetes by 2030. The incretin system emerges as a new target for type 2 diabetes therapy, and new molecules are being approved for its use in humans since the year 2005. These agents could be divided into 2 main groups, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors. Endogenous GLP-1 is an incretin hormone composed by a 30-amino acid peptide and is secreted from L-cells in distal small intestine in response to calorie intake, causing a glucose-dependent beta-cell response resulting in a restoration of the first-phase insulin response. Additionally, GLP-1 regulates glucagon production, which leads to inhibition of glucogenolysis and gluconeogenesis in the liver. Synthetic molecules such as exenatide and liraglutide have been developed to bind GLP-1 receptor and mimic GLP-1 effects in pancreatic cells and other target organs. PMID- 23459194 TI - Effect of Anticoagulants on Amyloid beta-Protein Precursor and Amyloid Beta Levels in Plasma. AB - Altered levels of amyloid beta-protein precursor (AbetaPP) and/or amyloid beta (Abeta) are characteristic of several neurological disorders including Alzheimer's disease (AD), Down syndrome (DS), Fragile X syndrome (FXS), Parkinson's disease (PD), autism and epilepsy. Thus, these proteins could serve as valuable blood-based biomarkers for assessing disease severity and pharmacological efficacy. We have observed significant differences in Abeta1-42 levels in human plasma dependent on the anticoagulant utilized during blood collection. Our data suggests that anticoagulants alter AbetaPP processing and that care needs to be used in comparing published studies that have not utilized the same blood collection methodology. PMID- 23459192 TI - Development and validation of a novel diagnostic test for human brucellosis using a glyco-engineered antigen coupled to magnetic beads. AB - Brucellosis is a highly contagious zoonosis and still a major human health problem in endemic areas of the world. Although several diagnostic tools are available, most of them are difficult to implement especially in developing countries where complex health facilities are limited. Taking advantage of the identical structure and composition of the Brucella spp. and Yersinia enterocolitica O:9 O-polysaccharide, we explored the application of a recombinant Y. enterocolitica O:9-polysaccharide-protein conjugate (OAg-AcrA) as a novel antigen for diagnosis of human brucellosis. We have developed and validated an indirect immunoassay using OAg-AcrA coupled to magnetic beads. OAg-AcrA was produced and purified with high yields in Y. enterocolitica O:9 cells co expressing the oligosaccharyltransferase PglB and the protein acceptor AcrA of Campylobacter jejuni without the need for culturing Brucella. Expression of PglB and AcrA in Y. enterocolitica resulted in the transfer of the host O polysaccharide from its lipid carrier to AcrA. To validate the assay and determine the cutoff values, a receiver-operating characteristic analysis was performed using a panel of characterized serum samples obtained from healthy individuals and patients of different clinical groups. Our results indicate that, using this assay, it is possible to detect infection caused by the three main human brucellosis agents (B. abortus, B. melitensis and B. suis) and select different cutoff points to adjust sensitivity and specificity levels as needed. A cutoff value of 13.20% gave a sensitivity of 100% and a specificity of 98.57%, and a cutoff value of 16.15% resulted in a test sensitivity and specificity of 93.48% and 100%, respectively. The high diagnostic accuracy, low cost, reduced assay time and simplicity of this new glycoconjugate-magnetic beads assay makes it an attractive diagnostic tool for using not only in clinics and brucellosis reference laboratories but also in locations with limited laboratory infrastructure and/or minimally trained community health workers. PMID- 23459195 TI - Globular adiponectin enhances muscle insulin action via microvascular recruitment and increased insulin delivery. AB - RATIONALE: Adiponectin enhances insulin action and induces nitric oxide-dependent vasodilatation. Insulin delivery to muscle microcirculation and transendothelial transport are 2 discrete steps that limit insulin's action. We have shown that expansion of muscle microvascular surface area increases muscle insulin delivery and action. OBJECTIVE: To examine whether adiponectin modulates muscle microvascular recruitment thus insulin delivery and action in vivo. METHODS AND RESULTS: Overnight fasted adult male rats were studied. We determined the effects of adiponectin on muscle microvascular recruitment, using contrast-enhanced ultrasound, on insulin-mediated microvascular recruitment and whole-body glucose disposal, using contrast-enhanced ultrasound and insulin clamp, and on muscle insulin clearance and uptake with (125)I-insulin. Globular adiponectin potently increased muscle microvascular blood volume without altering microvascular blood flow velocity, leading to a significantly increased microvascular blood flow. This was paralleled by a ~30% to 40% increase in muscle insulin uptake and clearance, and ~30% increase in insulin-stimulated whole-body glucose disposal. Inhibition of endothelial nitric oxide synthase abolished globular adiponectin mediated muscle microvascular recruitment and insulin uptake. In cultured endothelial cells, globular adiponectin dose-dependently increased endothelial nitric oxide synthase phosphorylation but had no effect on endothelial cell internalization of insulin. CONCLUSIONS: Globular adiponectin increases muscle insulin uptake by recruiting muscle microvasculature, which contributes to its insulin-sensitizing action. PMID- 23459197 TI - FITNESS BENEFITS OF COALITIONARY AGGRESSION IN MALE CHIMPANZEES. AB - Coalitionary aggression occurs when at least two individuals jointly direct aggression at one or more conspecific targets. Scientists have long argued that this common form of cooperation has positive fitness consequences. Nevertheless, despite evidence that social bond strength (which is thought to promote coalition formation) is correlated with fitness in primates, cetaceans, and ungulates, few studies have directly examined whether coalitionary aggression improves reproductive success. We tested the hypothesis that among free-ranging chimpanzees (Pan troglodytes schweinfurthii), participation in coalitionary aggression increases reproductive output. Using 14 years of genetic and behavioral data from Gombe National Park, Tanzania, we found that coalitionary aggression increased a male's chances of A) siring offspring, compared to other males of similar dominance rank, and B) ascending in rank, a correlate of future reproductive output. Because male chimpanzees form coalitions with many others within a complex network, we used social network analysis to identify the types of connections correlated with these fitness benefits. The beneficiaries of coalitionary aggression were males with the highest 'betweenness' - that is, those who tended to have coalition partners who themselves did not form coalitions with each other. This suggests that beyond simply recognizing third party relationships, chimpanzees may use this knowledge to choose coalition partners. If so, this is a significant step forward in our knowledge of the adaptive value of social intelligence. Regardless of mechanism, however, this is the first evidence of genetic benefits of coalitionary aggression in this species, and therefore has important implications for understanding the evolution of cooperation. PMID- 23459196 TI - HIV prevention in care and treatment settings: baseline risk behaviors among HIV patients in Kenya, Namibia, and Tanzania. AB - HIV care and treatment settings provide an opportunity to reach people living with HIV/AIDS (PLHIV) with prevention messages and services. Population-based surveys in sub-Saharan Africa have identified HIV risk behaviors among PLHIV, yet data are limited regarding HIV risk behaviors of PLHIV in clinical care. This paper describes the baseline sociodemographic, HIV transmission risk behaviors, and clinical data of a study evaluating an HIV prevention intervention package for HIV care and treatment clinics in Africa. The study was a longitudinal group randomized trial in 9 intervention clinics and 9 comparison clinics in Kenya, Namibia, and Tanzania (N = 3538). Baseline participants were mostly female, married, had less than a primary education, and were relatively recently diagnosed with HIV. Fifty-two percent of participants had a partner of negative or unknown status, 24% were not using condoms consistently, and 11% reported STI symptoms in the last 6 months. There were differences in demographic and HIV transmission risk variables by country, indicating the need to consider local context in designing studies and using caution when generalizing findings across African countries. Baseline data from this study indicate that participants were often engaging in HIV transmission risk behaviors, which supports the need for prevention with PLHIV (PwP). TRIAL REGISTRATION: ClinicalTrials.gov NCT01256463. PMID- 23459198 TI - High School Economic Composition and College Persistence. AB - Using a longitudinal sample of Texas high school seniors of 2002 who enrolled in college within the calendar year of high school graduation, we examine variation in college persistence according to the economic composition of their high schools, which serves as a proxy for unmeasured high school attributes that are conductive to postsecondary success. Students who graduated from affluent high schools have the highest persistence rates and those who attended poor high schools have the lowest rates. Multivariate analyses indicate that the advantages in persistence and on-time graduation from four-year colleges enjoyed by graduates of affluent high schools cannot be fully explained by high school college orientation and academic rigor, family background, pre-college academic preparedness or the institutional characteristics. High school college orientation, family background and pre-college academic preparation largely explain why graduates from affluent high schools who first enroll in two-year colleges have higher transfer rates to four-year institutions; however these factors and college characteristics do not explain the lower transfer rates for students from poor high schools. The conclusion discusses the implications of the empirical findings in light of several recent studies that call attention to the policy importance of high schools as a lever to improve persistence and completion rates via better institutional matches. PMID- 23459199 TI - Redesign of a large lecture course into a small-group learning course. AB - Objective. To describe the redesign of a large self-care course previously delivered in a traditional lecture format to a small-group case-based course.Design. Prereadings and study guides were used to facilitate students' independent learning prior to class. Large lecture classes were replaced with smaller group-based learning classes. This change in delivery format allowed students to spend the majority of class time conducting small-group learning activities, such as case studies to promote communication, problem solving, and interpersonal skills.Assessment. Changes in course delivery were assessed over a 2-year period by comparing students' grades and satisfaction ratings on course evaluations. A comparison of course evaluations between the class formats revealed that students were provided more opportunities to develop verbal communication skills and tackle and resolve unfamiliar problems in the revised course. The activities resulted in better overall course grades.Conclusions. Redesigning to a small-group discussion format for a self-care course can be accomplished by increasing student accountability for acquiring factual content outside the classroom. Compared with student experiences in the previous large lecture-based class, students in the smaller-class format reported a preference for working in teams and achieved significantly better academic grades with the new course format. PMID- 23459200 TI - Using the early postoperative intraocular pressure to predict pressure control after a trabeculectomy. AB - PURPOSE: The goal of this study was to identify the early postoperative intraocular pressure (IOP) that predicts low pressure control after a trabeculectomy with mitomycin C. MATERIALS AND METHODS: This study retrospectively analyzed the medical records of the initial trabeculectomy with mitomycin C in patients with primary open-angle glaucoma. We established 2 target postoperative IOPs, <=11 and <=15 mm Hg. The preoperative and early postoperative factors contributing to the success and failure of postoperative IOP control were studied by multiple regression analyses. These factors included the sex and age of patients, record of cataract surgery, number of preoperative medications, preoperative IOP, IOP recorded 2 weeks after surgery, laser suture lysis after surgery, and the presence of a shallow anterior chamber and choroidal detachment during the first month after surgery. The optimal IOP levels 2 weeks after surgery for long-term IOP control were examined using the Kaplan-Meier survival analyses. RESULTS: Sixty-six patients (66 eyes) with open-angle glaucoma participated in the study. The age and IOP 2 weeks after surgery were selected as the confounding factors affecting the probability of successfully satisfying both target IOPs;<=11 and<=15 mmHg postoperatively. An IOP under 8 mm Hg at 2 weeks after surgery was found to be associated with maintaining the postoperative IOP at either <=11 and <=15 mm Hg for an extended period. CONCLUSIONS: An IOP of 8 mm Hg was associated with successful outcomes in patients undergoing trabeculectomy. Also, younger age was found to be a risk factor for surgical failure. PMID- 23459201 TI - Symmetry of retinal parameters measured by spectral-domain OCT in normal young adults. AB - PURPOSE: To determine interocular differences in retinal parameters in a population of young adults using spectral-domain optical coherence tomography. METHODS: In the Sydney Adolescent Vascular Eye Study, young adults aged 16 to 19 years received a standardized eye examination encompassing retinal photography, spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) and best-corrected visual acuity. Interocular differences in retinal nerve fiber layer (RNFL) and macular parameters together with sex and ethnic variations for these differences were determined. RESULTS: In the 1500 subjects tested, right eyes had thicker average RNFL than left eyes (0.3 MUm, P=0.0074). There were no significant interocular differences in central macular or macular cube average thickness. After adjusting for interocular difference in axial length, right eyes had slightly smaller total macular volume than left eyes ( 0.0082 mm, P=0.008). The 2.5% to 97.5% limits of asymmetry were 9.3 MUm for average RNFL, 8 MUm for average macular thickness, and 0.20 mm for total macular volume. In the outer inferior quadrant, there was a greater macular thickness asymmetry in females than males (-0.7 MUm, P=0.037). In the inferior RNFL quadrant (-2.6 MUm, P=0.0013) and in the outer inferior macular quadrant (1.6 MUm, P=0.0018), white individuals had greater symmetry than East Asians. CONCLUSIONS: In this study, we report the degree of interocular symmetry of RNFL and macular parameters measured by Cirrus HD-OCT in healthy young adults. PMID- 23459202 TI - Biopedagogy. PMID- 23459203 TI - Spinning plates and juggling balls. Project managing your PhD. PMID- 23459204 TI - ORE1 balances leaf senescence against maintenance by antagonizing G2-like mediated transcription. AB - Leaf senescence is a key physiological process in all plants. Its onset is tightly controlled by transcription factors, of which NAC factor ORE1 (ANAC092) is crucial in Arabidopsis thaliana. Enhanced expression of ORE1 triggers early senescence by controlling a downstream gene network that includes various senescence-associated genes. Here, we report that unexpectedly ORE1 interacts with the G2-like transcription factors GLK1 and GLK2, which are important for chloroplast development and maintenance, and thereby for leaf maintenance. ORE1 antagonizes GLK transcriptional activity, shifting the balance from chloroplast maintenance towards deterioration. Our finding identifies a new mechanism important for the control of senescence by ORE1. PMID- 23459205 TI - Ubiquilin4 is an adaptor protein that recruits Ubiquilin1 to the autophagy machinery. AB - Ubiquilins (Ubqlns)-a family of ubiquitin-binding proteins-are involved in several protein degradation pathways and have been implicated in various neurodegenerative diseases. Ubqln1 regulates autophagosome maturation during autophagy-mediated degradation. We now show that Ubqln4 mediates the interaction between Ubqln1 and the autophagy machinery by recruiting Ubqln1 to LC3. This targeting of Ubqln1 to autophagosomes requires the Ubqln4 UBL domain and the Ubqln1 UBA domain. This study identifies a new role for Ubqln4, expanding the role for Ubqlns in protein degradation. PMID- 23459207 TI - Thyroid hormones as predictors of short- and long-term mortality in very old hospitalized patients. AB - BACKGROUND: Although extensively investigated, the prognostic role of thyroid hormone abnormalities in older participants remains uncertain. We investigated the relationship between thyroid hormones and mortality during hospitalization and in a prolonged follow-up in frail older patients. METHODS: A nonconcurrent cohort study was conducted by enrolling 450 participants hospitalized for an acute disease, who were classified into four groups (euthyroidism, hypothyroidism, hyperthyroidism, and low triiodothyronine [T3] syndrome), according to clinical and laboratory data. Multidimensional geriatric assessment variables were considered in order to identify short- and long-term predictors of death. RESULTS: Participants were very old (mean age: 84 years) and frail, as indicated by severely impaired functional status, extensive comorbidity, high prevalence of dementia, and hospital mortality (8%). Prevalence of any thyroid dysfunction was 40.7%; 32% of participants had low T3 syndrome, which was associated with an excess hospital mortality risk (odds ratio: 2.7, 95% confidence interval [CI]: 1.1-6.5; p = .025), adjusted for demographic, clinical, functional, and laboratory data. Conversely, long-term mortality was unrelated to low T3 syndrome. In euthyroid participants, increasing levels of free thyroxine (FT4) were associated with a slightly greater mortality (hazard ratio, CI: 2.12, 0.99-4.54; p = .053) in adjusted Cox regression models. CONCLUSIONS: This observational study on a cohort of very old, frail hospitalized patients gives support to the independent prognostic short-term, but not long-term, role of low T3 syndrome. Moreover, in older euthyroid participants, increasing levels of FT4 are a weak marker of poorer long-term survival. Thyroid hormones may help monitor changes in general health status and predict short- and long-term clinical outcomes in very old, frail patients. PMID- 23459206 TI - Long-term supplementation with a cystine-based antioxidant delays loss of muscle mass in aging. AB - Oxidative stress increases with age and is postulated to be a major causal factor for sarcopenia in aging. Here, we examined whether the administration of a cystine-based antioxidant (F1) can alleviate/delay age-specific changes in skeletal muscles. C57BL6 male mice aged 17 months (middle aged) were fed with normal diet with or without supplementation of F1 (3 mg/kg food) for 6 months. Compared with young (5 months old) mice old mice exhibited increased markers of oxidative stress, inflammation, and muscle cell apoptosis and decreased muscle weight. These age-related changes were further associated with inactivation of adenosine-5'-monophosphate-activated protein kinase (AMPK), increased lipogenesis, activation of c-Jun NH2-terminal kinase, and decreased expression of Delta 1, phospho-Akt, and proliferating cell nuclear antigen in aged skeletal muscle. Such alterations were significantly prevented by F1. These results demonstrate the beneficial effects of F1 to attenuate loss of muscle mass associated with aging. PMID- 23459208 TI - Association between serum 25-hydroxyvitamin d levels, bone geometry, and bone mineral density in healthy older adults. AB - PURPOSE: The association between serum 25-hydroxyvitamin D values and cortical/trabecular bone parameters in older adults has been incompletely explored. This study was designed to investigate the relationship between serum 25-hydroxyvitamin D levels and bone parameters for the tibia and radius using peripheral quantitative computed tomography in free-living healthy older adults. METHODS: The study involved 134 older adults attending a twice-weekly low intensity fitness program. In addition to clinical history and serum parameters, we assessed fat-free mass using dual-energy X-ray absorptiometry, total bone and cortical bone cross-sectional areas, and trabecular and cortical bone mineral density for the tibia and radius by peripheral quantitative computed tomography. RESULTS: After applying multivariate linear regression models, adjusting for sex, age, body mass index, fat mass and fat-free mass, and creatinine, the association between 25-hydroxyvitamin D and bone parameters was significant for total bone and cortical bone cross-sectional areas in the radius (partial R (2) = 0.05 and 0.09, respectively) and for trabecular bone mineral density and cortical bone cross-sectional area in the tibia (partial R (2) = 0.11 and 0.02, respectively). CONCLUSION: These findings support the idea that serum 25-hydroxyvitamin D levels and bone parameters are linked in older adults. Longitudinal studies are needed to establish whether vitamin D levels over time are associated with changes in these parameters. PMID- 23459210 TI - Usefulness of non-enzymatic post-translational modification derived products (PTMDPs) as biomarkers of chronic diseases. AB - Molecular aging of proteins results from the complex association of different reactions that lead to the progressive alteration of their structural and functional properties. These reactions, which include oxidation, glycoxidation, carbonylation and carbamylation, occur during aging and are amplified in various chronic diseases such as diabetes or chronic renal failure. Specific compounds generated throughout this process called post-translational modification derived products (PTMDPs) have been suggested to be promising biomarkers for the management of chronic diseases. During the last decades, the emergence of mass spectrometry and proteomics has largely contributed to the development of sensitive and specific analytical methods devoted to PTMDP quantification in biological fluids. This review aimed at providing evidences for the clinical relevance of PTMDPs as biomarkers in chronic diseases, and at emphasizing on the contribution of mass spectrometric and proteomic methods in this field. Different issues that should be addressed in order to ensure the implementation of these biomarkers in clinical practice have been highlighted. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23459211 TI - Efficient proteolysis strategies based on microchip bioreactors. AB - In proteome research, proteolysis is an important procedure prior to the mass spectrometric identification of proteins. The typical time of conventional in solution proteolysis is as long as several hours to half a day. To enhance proteolysis efficiency, a variety of microchip bioreactors have been developed for the rapid digestion and identification of proteins in the past decade. This review mainly focuses on the recent advances and the key strategies of microchip bioreactors in protein digestion. The subjects covered include microchip proteolysis systems, the immobilization of proteases in microchannels, the applications of microchip bioreactors in highly efficient proteolysis, and future prospects. It is expected that microchip bioreactors will become powerful tools in protein analysis and will find a wide range of applications in high-throughput protein identification. PMID- 23459209 TI - ImmunoChip study implicates antigen presentation to T cells in narcolepsy. AB - Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease. PMID- 23459212 TI - Bovine milk proteome: quantitative changes in normal milk exosomes, milk fat globule membranes and whey proteomes resulting from Staphylococcus aureus mastitis. AB - Milk protein expression in healthy cows and cows with mastitis will provide information important for the dairy food industry and immune function in the mammary gland. To facilitate protein discovery, milk was fractioned into whey, milk fat globule membranes (MFGM) and exosomes from healthy and Staphylococcus aureus infected cows. Amine-reactive isobaric tags (iTRAQ) were used to quantify protein changes between milk fractions isolated from healthy and S. aureus infected cows. 2971 milk proteins were identified with a false discovery rate of 0.1%. Greater than 300 milk proteins associated with host defense were identified and 94 were significantly differentially regulated in S. aureus infected milk compared to their uninfected controls. These differentially regulated host defense proteins were selectively segregated in the 3 milk compartments examined. An example of this segregation of host defense proteins was the partitioning and high concentration of proteins indicative of neutrophil extracellular traps (NETs) formation in the MFGM preparations from S. aureus infected milk as compared to exosomes or whey. Protein composition changes found in milk exosomes, MFGM and whey during an infection provides new and comprehensive information on milk protein composition in general as well as changes occurring during an infection. BIOLOGICAL SIGNIFICANCE: The significance of this study is the identification and quantification of the individual components of the neutrophil extracellular traps (NET) functional proteome in an apparent stable complex with MFGM and/or milk fat globules during an intra-mammary infection. NETs could be functionally relevant in intra-mammary infection, as it is known that during an infection neutrophils ingest large amounts of milk fat that down regulates many of their traditional immune functions. Thus the presence of NETs in milk fat provides new insights to mammary immune function and suggests a role for NETs in clinical mastitis. These in vivo NETs can now be tested to determine if they retain functional antimicrobial activity when primarily associated with milk fat. Then we can estimate their real world functional relevance during an intra mammary infection, which is one key to understanding clinical mastitis in dairy cows. PMID- 23459213 TI - Cross-contamination: Comparison of Nasal and Chronic Leg Ulcer Staphylococcus aureus Strains Isolated from the Same Patient. AB - The aim of this study was to investigate the occurrence of bacterial cross contamination between the nasal cavity and leg ulcers. Sixteen patients were included in the study. Staphylococcus aureus was isolated from the leg ulcer of 13 patients and 6 of these patients also harboured S. aureus in the nasal cavity. Klebsiella oxytoca was found in the ulcer and the nasal cavity of one patient. PFGE analysis revealed that patients harbouring S. aureus both in the nasal cavity and the leg ulcer had the same bacterial type at both sites. None of the S. aureus isolates were methicillin resistant. PMID- 23459214 TI - Value of Other Endovascular Techniques Among Patients with MERCI Device Failure during the Treatment of Acute Ischemic Stroke: What to do when MERCI fails? AB - BACKGROUND: The MERCI Retrieval system (Concentric Medical, Mountain View, CA) was the first FDA -approved device for mechanical thrombectomy in patients with acute ischemic stroke. It remains one of the most commonly used devices today despite its failure to restore blood flow in approximately 50% of the occlusions after technically successful deployment and retrieval. It remains unclear whether additional endovascular techniques or continued use of MERCI device can achieve recanalization post- MERCI failure. OBJECTIVE: To analyze the outcome of continued MERCI retriever use compared with other endovascular techniques after initial failure. METHODS: Failure of MERCI retriever was defined by successful deployment and retrieval of MERCI across target occlusion without recanalization in a single pass.. Pre- and post- treatment cerebral angiogram was classified using the Qureshi Grading Scale (QGS). Recanalization was defined by a reduction in >= 1 QGS grade between pre- and post- treatment cerebral angiogram in the Qureshi Grading Scale (QGS).We ascertained and compared the angiographic and clinical results with continued use of MERCI retriever or other endovascular techniques in patients following MERCI failure. RESULTS: A total of 40 patients (53% men) had MERCI retrieval in this cohort with a mean age (+/-standard deviation) of 66.8 years +/- 16 years and a mean admission National Institutes of Health Stroke Scale (NIHSS) score of 16.8 +/- 6.7. Of the 40 patients treated with MERCI retrieval, there were 26 patients with MERCI failure. In group 1, there were 11 patients who underwent continued MERCI use and group 2 consisted of 15 patients who underwent an alternate endovascular technique. There was no significant difference in age, risk factors, or outcomes between the groups. The rate of recanalization (82% versus 80%, p=1.0), asymptomatic intra cerebral hemorrhage (18% versus 13%, p =0.77) and favorable outcome at discharge (27% versus 20%, p =0.66) were similar amongst the two groups. CONCLUSIONS: Continued attempts using the MERCI device did not result in higher recanalization rates when compared to alternate endovascular treatment modalities following initial MERCI failure. Both techniques produced comparable rates of recanalization and favorable outcome. PMID- 23459215 TI - Correlates of unsupervised bathing of infants: a cross-sectional study. AB - Drowning represents the third leading cause of fatal unintentional injury in infants (0-1 years). The aim of this study is to investigate correlates of unsupervised bathing. This cross-sectional study included 1,410 parents with an infant. Parents completed a questionnaire regarding supervision during bathing, socio-demographic factors, and Protection Motivation Theory-constructs. To determine correlates of parents who leave their infant unsupervised, logistic regression analyses were performed. Of the parents, 6.2% left their child unsupervised in the bathtub. Parents with older children (OR 1.24; 95%CI 1.00 1.54) were more likely to leave their child unsupervised in the bathtub. First time parents (OR 0.59; 95%CI 0.36-0.97) and non-Western migrant fathers (OR 0.18; 95%CI 0.05-0.63) were less likely to leave their child unsupervised in the bathtub. Furthermore, parents who perceived higher self-efficacy (OR 0.57; 95%CI 0.47-0.69), higher response efficacy (OR 0.34; 95%CI 0.24-0.48), and higher severity (OR 0.74; 95%CI 0.58-0.93) were less likely to leave their child unsupervised. Since young children are at great risk of drowning if supervision is absent, effective strategies for drowning prevention should be developed and evaluated. In the meantime, health care professionals should inform parents with regard to the importance of supervision during bathing. PMID- 23459216 TI - Assessment of the talk test and rating of perceived exertion for exercise intensity prescription in persons with paraplegia. AB - BACKGROUND: Physical activity recommendations require accurate estimations of exercise intensity. Rating of Perceived Exertion (RPE) and talk test (TT) are 2 commonly recommended techniques to gauge intensity. It is not known whether these are valid to select an exercise intensity that would elicit a training effect for persons with spinal cord injury (SCI). OBJECTIVE: To define the exercise intensity of each TT stage and RPE exercise intensity category and assess whether persons with paraplegia are able to use the TT to select a "comfortable" exercise workload they could maintain for 15 minutes. METHODS: Twelve participants with paraplegia completed 2 arm crank exercise tests on nonconsecutive days within 14 days. Test 1 was an incremental peak effort assessment. Test 2 was a 15-minute simulated exercise session at a participant-selected fixed workload. During each test, participants reported their RPE and performed a TT at 2-minute intervals. RESULTS: The intensity of the first negative TT stage was vigorous (75 +/- 15 %VO2R); at low and moderate intensities, perceived effort was greater than measured intensity; at vigorous and maximal intensities, perceived effort matched measured intensity. Individuals successfully used the TT to select an exercise workload they could maintain for 15 minutes. RPE, but not exercise intensity, increased during the 15-minute session. CONCLUSIONS: During arm crank exercise when speaking is not comfortable (ie, first negative TT), persons with paraplegia are exercising at vigorous intensity, which is sufficient to elicit training effects. During incremental peak exercise testing, RPE does not appear to accurately index low-moderate exercise intensities. During the simulated exercise session, RPE appeared to index peripheral fatigue. PMID- 23459217 TI - Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: a physiologically based pharmacokinetic model study. AB - BACKGROUND: In vitro observations support the lipid sink theory of therapeutic action by confirming the capacity of lipid emulsions to successfully uptake bupivacaine from aqueous media. However, competing hypotheses and some in/ex vivo small animal studies suggest that a metabolic or positive inotropic effect underlies the dramatic effects of lipid therapy. Controlled clinical tests to establish causality and mechanism of action are an impossibility. In an effort to quantitatively probe the merits of a "sink" mechanism, a physiologically based pharmacokinetic model has been developed that considers the binding action of plasma lipid. METHODS: The model includes no fitting parameters and accounts for concentration dependence of plasma protein and lipid:anesthetic binding as well as the metabolism of the lipid scavenger. Predicted pharmacokinetics were validated by comparison with data from healthy volunteers administered a nontoxic dose of bupivacaine. The model was augmented to simulate lipid therapy and extended to the case of accidental IV infusion of bupivacaine at levels known to cause systemic toxicity. RESULTS: The model yielded quantitative agreement with available pharmacokinetic data. Simulated lipid infusion following an IV overdose was predicted to yield (1) an increase in total plasma concentration, (2) a decrease in unbound concentration, and (3) a decrease in tissue content of bupivacaine. CONCLUSIONS: Results suggest that the timescale on which tissue content is reduced varies from organ to organ, with the concentration in the heart falling by 11% within 3 min. This initial study suggests that, in isolation, the lipid sink is insufficient to guarantee a reversal of systemic toxicity. PMID- 23459218 TI - Sevoflurane preconditioning attenuates the fall in adenosine triphosphate levels, but does not alter the changes in sodium and potassium levels during hypoxia in rat hippocampal slices. AB - BACKGROUND: Sevoflurane preconditioning improves recovery after hypoxia. Sevoflurane administered before and during hypoxia improved recovery and attenuated the changes in intracellular sodium, potassium, and adenosine triphosphate (ATP) levels during hypoxia. In this study, the authors examine the effects of sevoflurane applied only before hypoxia on sodium, potassium, and ATP. METHODS: Hippocampal slices from adult male Sprague-Dawley rats were pretreated with 4% sevoflurane, washed, and then subjected to hypoxia (n>=8 animals/group). The cornus ammonis 1 regions of the hippocampal slices were micro-dissected and sodium, potassium, and ATP concentrations measured. RESULTS: Pretreatment with sevoflurane for 15 or 60 min did not attenuate the increase in intracellular sodium or the decrease in intracellular potassium during hypoxia. After 60 min of preconditioning and 5 min of hypoxia, sodium increased 57% (vs. nonpreconditioned hypoxia 54% increase) and potassium decreased 31% (vs. 26%). These changes were not statistically significant versus untreated hypoxia. The 60-min sevoflurane preconditioning group had statistically significant higher ATP levels at 5 min of hypoxia (3.8 nmol/mg dry wt.) when compared to untreated hypoxic tissue (2.1 nmol/mg). There was no significant difference in ATP levels between the sevoflurane preconditioned and the untreated tissue before hypoxia (8.9 vs. 8.5 nmoles/mg, respectively). CONCLUSION: Preconditioning with sevoflurane for 60 min before hypoxia does not alter changes in intracellular sodium and potassium during hypoxia but does attenuate the fall in intracellular ATP levels during hypoxia. Thus, there are differences between anesthetic preconditioning and when anesthetics are present before and during hypoxia. PMID- 23459219 TI - Skeletal muscle ryanodine receptor mutations associated with malignant hyperthermia showed enhanced intensity and sensitivity to triggering drugs when expressed in human embryonic kidney cells. AB - BACKGROUND: Mutations within the gene encoding the skeletal muscle calcium channel ryanodine receptor can result in malignant hyperthermia. Although it is important to characterize the functional effects of candidate mutations to establish a genetic test for diagnosis, ex vivo methods are limited because of the low incidence of the disorder and sample unavailability. More than 250 candidate mutations have been identified, but only a few mutations have been functionally characterized. METHODS: The human skeletal muscle ryanodine receptor complementary DNA was cloned with or without a disease-related variant. Wild-type and mutant calcium channel proteins were transiently expressed in human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40, and functional analysis was carried out using calcium imaging with fura-2 AM. Six human malignant hyperthermia-related mutants such as R44C, R163C, R401C, R533C, R533H, and H4833Y were analyzed. Cells were stimulated with a specific ryanodine receptor agonist 4-chloro-m-cresol, and intracellular calcium mobility was analyzed to determine the functional aspects of mutant channels. RESULTS: Mutant proteins that contained a variant linked to malignant hyperthermia showed higher sensitivity to the agonist. Compared with the wild type (EC50=453.2 uM, n=18), all six mutants showed a lower EC50 (21.2-170.4 uM, n=12-23), indicating susceptibility against triggering agents. CONCLUSIONS: These six mutations cause functional abnormality of the calcium channel, leading to higher sensitivity to a specific agonist, and therefore could be considered potentially causative of malignant hyperthermia reactions. PMID- 23459220 TI - When do negative and positive emotions modulate working memory performance? AB - The present study investigated when emotion modulates working memory from the perspective of neural activation. Using fMRI, we measured brain activity during the encoding and retrieval phases of a reading span test (RST) that used emotional contexts. The emotional RST required participants to read sentences that elicited negative, neural or positive emotional states while they were memorizing target words from the sentences. Compared with the neutral RST, the negative RST activated the right amygdala during the reading phase. Significant activation was also found in the parahippocampal gyrus, albeit only after activation of the amygdala became comparable to that in the neutral RST. In contrast, the positive RST activated the substantia nigra during the reading phase relative to the neutral RST. These findings suggest that negative and positive emotions modulate working memory through distinctive neural circuits. We also discuss possible relationships between emotional modulation and working memory capacity. PMID- 23459221 TI - Role of ultrasound and color Doppler imaging in the detection of carotid paragangliomas. AB - INTRODUCTION: Carotid body paragangliomas (PGLs) are highly vascularized lesions that arise from the paraganglia located at the carotid bifurcation. PURPOSE: To evaluate the usefulness of gray-scale ultrasound (US) and color Doppler ultrasound (CDUS) in the detection and follow-up of carotid PGLs of the neck. MATERIALS AND METHODS: The authors retrospectively reviewed US and CDUS examinations of the neck performed in 40 patients with PGL syndrome type 1 and single or bilateral neck PGLs confirmed by CT or MRI; the patients had a total of 60 PGLs of the neck. US and CDUS outcome was compared to the outcome of second line imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT). The following findings were considered: presence/absence of focal lesions at US imaging and difference in maximum diameter of the lesion measured at US and MRI/CT. Results were compared using the Student's t-test. RESULTS: Of the 60 PGLs of the neck only 5 (8.3%) were not visualized at US or CDUS examination. The difference in maximum diameter of these lesions measured at CT/MRI and US/CDUS ranged between -5 mm and +16 mm (mean difference 2.2 +/- 6.0). This difference was statistically significant (p = 0.008). CONCLUSIONS: US and CDUS are useful methods for identifying carotid PGLs also measuring less than 10 mm in diameter. However, diagnostic accuracy of US and CDUS is reduced in the measurement of the exact dimensions of the lesions. PMID- 23459222 TI - Enhancement of the second-harmonic generation in a quantum dot-metallic nanoparticle hybrid system. AB - We have investigated the second-harmonic generation (SHG) and dipole-dipole interaction in a quantum dot and metallic nanoparticle hybrid system. A strong probe field is applied to create two-photon absorption in the quantum dot and metallic nanoparticle. SHG photons and SHG surface plasmon polaritons are emitted by the quantum dot and metallic nanoparticle, respectively. Induced dipoles are created in the quantum dot and the metallic nanoparticle due to two-photon absorption and hence both systems interact with each other via the dipole-dipole interaction. It is found that SHG signals produced by the quantum dot and nanoparticle are enhanced by the dipole-dipole interaction and also that the SHG signal can be switched on and off by applying a control field. The theoretical findings of this paper are supported by recent experimental studies. The present hybrid system can be used to fabricate nano-sensors and all-optical nano switching devices. PMID- 23459223 TI - Acromioclavicular joint arthritis in persons with spinal cord injury compared to able-bodied persons. PMID- 23459224 TI - Optimizing safety of COPD treatments: role of the nurse practitioner. AB - As the prevalence of chronic obstructive pulmonary disease (COPD) continues to grow, management of the disease still faces considerable challenges. Despite the existence of effective pharmacological treatments, patient adherence is often poor. Side effects of medications and patients' concerns about potential side effects may contribute to poor adherence. Situated as they are at the frontline of patient care in the clinic, nurse practitioners play an important role in the management of COPD. This review discusses the current literature on medications available for management of COPD, focusing primarily on their safety and tolerability. This information can be particularly important for nurse practitioners, who can be invaluable in identifying side effects, and providing education to patients with COPD on the available treatments and the associated side effects. By helping patients to understand the balance of benefits and risks of treatment, nurse practitioners may be able to help improve adherence and thereby improve patient outcomes. PMID- 23459225 TI - Increasing physical activity of high intensity to reduce the prevalence of chronic diseases and improve public health. AB - High incidence and prevalence of chronic diseases, increasing obesity and inactivity as well as rising health expenditure represent a set of developments that cannot be considered sustainable, and will have dire long-term consequences given the increasing proportion of elderly people in our society. Based on a review of the experiences from previous large scale population-based prevention programs and the documented effects of increased physical activity and cardiorespiratory fitness on chronic diseases and its risk factors, we argue that increased physical activity, especially vigorous physical activity, is a major way to reduce the prevalence of chronic diseases and improve public health. We conclude that a coordinated population-based intervention program for improved health through increased physical activity in the entire population, with a special focus on high intensity exercise, urgently needs to be implemented nationally and internationally. PMID- 23459226 TI - Resting parietal EEG asymmetry and cardiac vagal tone predict attentional control. AB - The present study explores both resting cortical EEG asymmetry and vagally mediated heart rate variability (HRV), as an index for vagal tone, as physiological correlates of self-reported attentional control in a sample of 53 healthy young adults. Regression analyses indicate that higher vagally-mediated HRV and lower right-sided parietal activity in the beta2 frequency range (20 30Hz) are significant predictors of larger attentional control. Results are in line with some of the basic features of the neurovisceral integration model and stress the role of parietal areas in attentional control capabilities, thus aiming to consider attentional control as a trait-like disposition. PMID- 23459228 TI - Interaction between sphingomyelin and oxysterols contributes to atherosclerosis and sudden death. AB - Despite major public health efforts, coronary heart disease continues to be the leading cause of death in the United States. Oxidized lipids contribute to heart disease both by increasing deposition of calcium on the arterial wall, a major hallmark of atherosclerosis, and by interrupting blood flow, a major contributor to heart attack and sudden death. Oxidized cholesterol (oxysterols) enhances the production of sphingomyelin, a phospholipid found in the cellular membranes of the coronary artery. This increases the sphingomyelin content in the cell membrane, which in turn enhances the interaction between the membrane and ionic calcium (Ca(2+)), thereby increasing the risk of arterial calcification. Patients undergoing bypass surgery had greater concentrations of oxysterols in their plasma than cardiac catheterized controls with no stenosis, and had five times more sphingomyelin in their arteries than in the artery of the placenta of a newborn. The oxysterols found in the plasma of these patients were also found in the plasma of rabbits that had been fed oxidized cholesterol and in frying fats and powdered egg yolk intended for human consumption. Together these findings suggest that oxysterols found in the diet are absorbed and contribute to arterial calcification. Oxidized low-density lipoprotein (OxLDL) further contributes to heart disease by increasing the synthesis of thromboxane in platelets, which increases blood clotting. Cigarette smoke and trans fatty acids, found in partially hydrogenated soybean oil, both inhibit the synthesis of prostacyclin, which inhibits blood clotting. By increasing the ratio of thromboxane to prostacyclin, these factors interact to interrupt blood flow, thereby contributing to heart attack and sudden death. Levels of oxysterols and OxLDL increase primarily as a result of three diet or lifestyle factors: the consumption of oxysterols from commercially fried foods such as fried chicken, fish, and french fries; oxidation of cholesterol in vivo driven by consumption of excess polyunsaturated fatty acids from vegetable oils; and cigarette smoking. Along with the consumption of trans fatty acids from partially hydrogenated vegetable oil, these diet and lifestyle factors likely underlie the persistent national burden of heart disease. PMID- 23459229 TI - African American Women's Reports of Racism during Hurricane Katrina: Variation by Interviewer Race. AB - This study investigated the effects of interviewer race on low-income African American female hurricane survivors' reports of racism during Hurricane Katrina and its aftermath (N = 41). Respondents were asked directly about the role of racism during the storm and evacuation by one of three interviewers (two White females and one African American female). Contrary to expectations, respondents were not significantly more likely to agree that racism played a role during the hurricane and its aftermath when with an African American interviewer compared to a White interviewer. However, when speaking to the White interviewers versus the African American interviewer, respondents were significantly more likely to use qualifying and contradictory statements and to make references to other races also being victims of the hurricane. PMID- 23459230 TI - An integrated linkage, chromosome, and genome map for the yellow fever mosquito Aedes aegypti. AB - BACKGROUND: Aedes aegypti, the yellow fever mosquito, is an efficient vector of arboviruses and a convenient model system for laboratory research. Extensive linkage mapping of morphological and molecular markers localized a number of quantitative trait loci (QTLs) related to the mosquito's ability to transmit various pathogens. However, linking the QTLs to Ae. aegypti chromosomes and genomic sequences has been challenging because of the poor quality of polytene chromosomes and the highly fragmented genome assembly for this species. METHODOLOGY/PRINCIPAL FINDINGS: Based on the approach developed in our previous study, we constructed idiograms for mitotic chromosomes of Ae. aegypti based on their banding patterns at early metaphase. These idiograms represent the first cytogenetic map developed for mitotic chromosomes of Ae. aegypti. One hundred bacterial artificial chromosome clones carrying major genetic markers were hybridized to the chromosomes using fluorescent in situ hybridization. As a result, QTLs related to the transmission of the filarioid nematode Brugia malayi, the avian malaria parasite Plasmodium gallinaceum, and the dengue virus, as well as sex determination locus and 183 Mbp of genomic sequences were anchored to the exact positions on Ae. aegypti chromosomes. A linear regression analysis demonstrated a good correlation between positions of the markers on the physical and linkage maps. As a result of the recombination rate variation along the chromosomes, 12 QTLs on the linkage map were combined into five major clusters of QTLs on the chromosome map. CONCLUSION: This study developed an integrated linkage, chromosome, and genome map-iMap-for the yellow fever mosquito. Our discovery of the localization of multiple QTLs in a few major chromosome clusters suggests a possibility that the transmission of various pathogens is controlled by the same genomic loci. Thus, the iMap will facilitate the identification of genomic determinants of traits responsible for susceptibility or refractoriness of the mosquito to diverse pathogens. PMID- 23459227 TI - Modeling Huntington's disease with induced pluripotent stem cells. AB - Huntington's disease (HD) causes severe motor dysfunction, behavioral abnormalities, cognitive impairment and death. Investigations into its molecular pathology have primarily relied on murine tissues; however, the recent discovery of induced pluripotent stem cells (iPSCs) has opened new possibilities to model neurodegenerative disease using cells derived directly from patients, and therefore may provide a human-cell-based platform for unique insights into the pathogenesis of HD. Here, we will examine the practical implementation of iPSCs to study HD, such as approaches to differentiate embryonic stem cells (ESCs) or iPSCs into medium spiny neurons, the cell type most susceptible in HD. We will explore the HD-related phenotypes identified in iPSCs and ESCs and review how brain development and neurogenesis may actually be altered early, before the onset of HD symptoms, which could inform the search for drugs that delay disease onset. Finally, we will speculate on the exciting possibility that ESCs or iPSCs might be used as therapeutics to restore or replace dying neurons in HD brains. PMID- 23459231 TI - EGFR Expression and KRAS and BRAF Mutational Status in Intestinal-Type Sinonasal Adenocarcinoma. AB - Accumulation of molecular alterations, including EGFR overexpression and mutations in KRAS and BRAF, contribute to colorectal carcinogenesis. Since intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinus has morphologic and phenotypic features that are usually indistinguishable from colorectal cancer (CRC), it is likely that both tumor types share equivalent genetic alterations. Data from a series of 43 patients treated surgically for ITAC in Montpellier, France between November 1998 and December 2012 were collected. Tumors were characterized for mutations in KRAS and BRAF as well as EGFR overexpression. Kaplan-Meier survival curves were constructed using overall survival as the primary end points. Patient survival was analyzed using the hazards ratio. Twenty seven tumors (63%) showed EGFR positivity and 30% exhibited a high expression level (+2/+3). KRAS mutations were detected in 43% of cases. BRAF mutations were identified in 3.6% of specimens. Patients with age superior to 60 years, metastatic status, and KRAS mutations had significant overall survival values (p = 0.026, p = 0.001 and p = 0.03, respectively). Our results indicate that KRAS mutations and EGFR expression are frequent in ITAC and that KRAS mutations predict good patient prognosis in ITAC. Finally, EGFR directed molecular treatments could be investigated in a subset of patients affected by ITAC. PMID- 23459232 TI - Blood translation elongation factor-1delta is a novel marker for cadmium exposure. AB - Translation elongation factor-1d (TEF-1delta) has been identified as a novel cadmium-responsive proto-oncogene. However, it is still unclear whether TEF 1delta could be a potential biomarker of cadmium exposure. Rats were treated with CdCl2 at different concentrations (high dose 1.225, mid-dose 0.612 and low dose 0.306 mg/kg body weight, respectively) for 14 weeks, and the cadmium levels, weight coefficients, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (SCR), 24-h urine protein (24hPro), urinary creatinine (Cr) and pathological features were determined. The TEF-1delta expression in white blood cells and multiple organs were examined by reverse transcription polymerase chain reaction (PCR) and were also confirmed with fluorescence quantitative PCR. A cadmium dose-dependent increase (p < 0.05) of cadmium levels in blood, urine, liver, kidney, heart and lung, and the weight coefficients was observed. The liver and renal function indictors including AST, ALT, SCR, BUN and 24hPro, were elevated in a cadmium dose-dependent manner (p < 0.05). Significant pathological changes in liver, kidney, heart and lung were indicated. The TEF-1delta expression was up-regulated in both blood and organs (p < 0.05). Moreover, the expression level of blood TEF 1delta was positively correlated to TEF-1delta expression level, cadmium level and toxicity in the organs (p < 0.01). This study indicates that blood TEF-1delta is a novel valuable biomarker for cadmium exposure and its organ toxicity. PMID- 23459233 TI - Comparative Analysis of the Symbiotic Efficiency of Medicago truncatula and Medicago sativa under Phosphorus Deficiency. AB - Phosphorus (P)-deficiency is a major abiotic stress that limits legume growth in many types of soils. The relationship between Medicago and Sinorhizobium, is known to be affected by different environmental conditions. Recent reports have shown that, in combination with S. meliloti 2011, Medicago truncatula had a lower symbiotic efficiency than Medicago sativa. However, little is known about how Medicago-Sinorhizobium is affected by P-deficiency at the whole-plant level. The objective of the present study was to compare and characterize the symbiotic efficiency of N2 fixation of M. truncatula and M. sativa grown in sand under P limitation. Under this condition, M. truncatula exhibited a significantly higher rate of N2 fixation. The specific activity of the nodules was much higher in M. truncatula in comparison to M. sativa, partially as a result of an increase in electron allocation to N2 versus H+. Although the main organic acid, succinate, exhibited a strong tendency to decrease under P-deficiency, the more efficient symbiotic ability observed in M. truncatula coincided with an apparent increase in the content of malate in its nodules. Our results indicate that the higher efficiency of the M. truncatula symbiotic system is related to the ability to increase malate content under limited P-conditions. PMID- 23459234 TI - Insight into differential responses of upland and paddy rice to drought stress by comparative expression profiling analysis. AB - In this study, the drought responses of two genotypes, IRAT109 and Zhenshan 97 (ZS97), representing upland and paddy rice, respectively, were systematically compared at the morphological, physiological and transcriptional levels. IRAT109 has better performance in traits related to drought avoidance, such as leaf rolling, root volumes, the ratio of leaf water loss and relative conductivity. At the transcriptional level, more genes were induced by drought in IRAT109 at the early drought stage, but more genes had dynamic expression patterns in ZS97 at different drought degrees. Under drought conditions, more genes related to reproductive development and establishment of localization were repressed in IRAT109, but more genes involved in degradation of cellular components were induced in ZS97. By checking the expression patterns of 36 drought-responsive genes (located in 14 quantitative trail loci [QTL] intervals) in ZS97, IRAT109 and near isogenic lines (NILs) of the QTL intervals, we found that more than half of these genes had their expression patterns or expression levels changed in the NILs when compared to that in ZS97 or IRAT109. Our results may provide valuable information for dissecting the genetic bases of traits related to drought resistance, as well as for narrowing the candidate genes for the traits. PMID- 23459235 TI - A Cancer-Indicative microRNA Pattern in Normal Prostate Tissue. AB - We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ. PMID- 23459236 TI - Feasibility study of walking for exercise in individuals living in assisted living settings. AB - BACKGROUND AND PURPOSE: Decreased physical activity levels are an increasing concern, specifically for the aging population. Older adults (>65 years) are able to achieve health benefits from participating in a regular exercise program based on studies done in younger community-dwelling older adults. There is less research investigating the efficacy of exercise for improving physical function among the older adult population in assisted living settings. This study investigated using a treadmill with a harness system, to engage older adults in aerobic exercise. The primary objective of the study was to assess the feasibility of a large trial by evaluating the recruitment and short-term retention rate of older adults with limited mobility. Secondary objectives were to determine whether older adults could achieve the frequency, intensity, and duration of aerobic exercise recommended by the American College of Sports Medicine. METHODS: A feasibility study of residents of an assisted living facility who had care needs ranging from retirement home to palliative care. The feasibility of recruitment and retention was determined by recording the number of older adults who consented to participate in treadmill walking for 3 weeks, declined treadmill participation including reasons why, and completed the 6 treadmill sessions. All participating residents completed a baseline assessment, including a medical chart review, and had the choice to walk on the treadmill or not. To determine whether participants could achieve what is recommended in physical activity guidelines, exercise, frequency, intensity, and duration achieved after the final treadmill sessions were reported. RESULTS: Among eligible residents, 30% consented to participate in the study. There were no significant differences between treadmill participants and those who chose not to walk on the treadmill. The average compliance to treadmill sessions was 94.4% +/- 10.8%. Treadmill participants achieved an average intensity of 50.3% heart rate reserve (SD = 30.2%) and an average frequency of 3 sessions in 1 week. Average duration of the final session was 14 minutes 53 seconds +/- 6 minutes 43 seconds. CONCLUSION: This study provides preliminary evidence that it is feasible to recruit and retain older adults in assisted living facilities to participate in a short-term treadmill walking study; however, it may be difficult to recruit a large number of individuals. Treadmill participants were able to achieve the American College of Sports Medicine's recommended intensity and frequency for aerobic exercise. For older adults in assisted living settings to achieve 20 minutes a day, they may need more than 3 weeks of progression or multiple sessions per day. PMID- 23459237 TI - True or apparent leg length discrepancy: which is a better predictor of short term functional outcomes after total hip arthroplasty? AB - BACKGROUND AND PURPOSE: The associations between leg length discrepancy (LLD) and patient-perceived inequality and functional outcomes after total hip arthroplasty (THA) are unclear in the literature. The aim of this study was to determine the types of LLD after THA and to identify the best predictor of patient-perceived LLD and functional outcome in the short term after THA. METHODS: We subdivided LLD into true and apparent types and prospectively studied 53 consecutive patients undergoing unilateral primary THA to determine whether there is an association between the type of LLD and functional outcome 2 months after the operation. Apparent LLD was measured by the block test and true LLD was measured by hip radiography. We classified the patients into 4 groups: true, apparent, mixed, and no-LLD groups. The questionnaire included a visual analog scale of pain, the Western Ontario and McMaster Universities Osteoarthritis Index, and patient-perceived inequality. Physical performance was measured using walking speed and the Timed Up and Go test. RESULTS: The apparent and mixed LLD groups had a higher prevalence of patient-perceived inequality than the true and no-LLD groups. The results of physical performance showed that the walking speed of the mixed LLD group and the results of the Timed Up and Go Test of the apparent LLD group were significantly slower than those of the true LLD group. DISCUSSION: We suggested that the true LLD group may have a weak relationship with functional outcome after THA while the apparent LLD resulting from pelvic obliquity due to hip contracture or scoliosis is correlated with the short-term functional outcome after THA. CONCLUSION: Apparent LLD can be a better predictor of patient perceived inequality and physical performance than true LLD. PMID- 23459238 TI - Facilitating the use of implicit memory and learning in the physical therapy management of individuals with Alzheimer disease: a case series. AB - BACKGROUND AND PURPOSE: Physical rehabilitation of individuals with Alzheimer disease (AD) is often complicated by impairments in explicit memory and learning. Rehabilitation strategies that facilitate the use of the preserved implicit memory system may be effective in treating patients with AD. The purpose of this case series is to describe the application of these strategies, including high repetition practice, errorless learning (EL), and spaced retrieval, to the physical therapy management of individuals with moderate AD. CASE DESCRIPTION: Three women aged 89 to 95 years with moderate AD who resided in an assisted living facility participated in physical therapy to address their mobility limitations. INTERVENTION: Twelve physical therapy sessions were scheduled over a period of 4 weeks. Interventions were individually designed to address the mobility needs of each patient, and rehabilitation strategies based on implicit learning principles were integrated into the interventions. OUTCOMES: All patients participated in at least 10 of the 12 physical therapy sessions. Improvements in performance of objective measures of balance were observed in all patients, although only 1 patient's balance score exceeded the minimal detectable change. No significant clinical change was observed in any patients on the Timed Up and Go Test or self-selected gait speed. DISCUSSION: Principles of implicit learning were integrated into the interventions for these patients with moderate AD. However, the feasibility of applying the EL paradigm was limited. Further research on the effectiveness of EL, spaced retrieval, and other rehabilitation strategies that facilitate implicit learning of mobility skills in patients with AD is needed to promote optimal physical therapy outcomes in this patient population. PMID- 23459239 TI - Switching of ferroelectric liquid crystal doped with cetyltrimethylammonium bromide-assisted CdS nanostructures. AB - Large scale high yield cadmium sulfide (CdS) nanowires with uniform diameter were synthesized using a rapid and simple solvo-chemical and hydrothermal route assisted by the surfactant cetyltrimethylammonium bromide (CTAB). Unique CdS nanowires of different morphologies could be selectively produced by only varying the concentration of CTAB in the reaction system with cadmium acetate, sulfur powder and ethylenediamine. We obtained CdS nanowires with diameters of 64-65 nm and lengths of up to several micrometers. A comparative study of the optical properties of ferroelectric liquid crystal (FLC) Felix-017/100 doped with 1% of CdS nanowires was performed. Response times of the order of from 160 to 180 MUs, rotational viscosities of the order of from 5000 to 3000 mN s m(-2) and polarizations of the order of from 10 to 70 nC cm(-2) were measured. We also observed an anti-ferroelectric to ferroelectric transition for CdS doped FLC instead of the ferroelectric to paraelectric transition for pure FLC. PMID- 23459240 TI - Teaching ultrasound in tropical countries. AB - INTRODUCTION: This paper reports my experience as a teacher of clinical ultrasound (US) in an African hospital. While US in tropical countries has received some attention and a few papers - though possibly fewer than deserved by this issue-are available in the medical literature on this subject, very little has been done in terms of assessment of teaching. MATERIALS AND METHODS: Given the increasing number of groups, NGOs and volunteers that go to Africa and other resource limited settings to do this, I thought that sharing my experience with those who have walked or are thinking of walking the same path could be mutually beneficial. RESULTS: The first section of the article presents the situation where I've been working in the past 13 years, the second section details our teaching programme. DISCUSSION: This report describes the rationale for the implementation of ultrasound training programmes in rural areas of Africa and lessons learnt with 13 years experience from the UK with recommendations for the way forward. PMID- 23459241 TI - Diabetic retinopathy and VEGF. AB - Diabetic retinopathy remains the leading vascular-associated cause of blindness throughout the world. Its treatment requires a multidisciplinary interventional approach at both systemic and local levels. Current management includes laser photocoagulation, intravitreal steroids, and anti-vascular endothelial growth factor (VEGF) treatment along with systemic blood sugar control. Anti-VEGF therapies, which are less destructive and safer than laser treatments, are being explored as primary therapy for the management of vision-threatening complications of diabetic retinopathy such as diabetic macular edema (DME). This review provides comprehensive information related to VEGF and describes its role in the pathogenesis of diabetic retinopathy, and in addition, examines the mechanisms of action for different antiangiogenic agents in relation to the management of this disease. Medline (Pubmed) searches were carried out with keywords "VEGF", "diabetic retinopathy", and "diabetes" without any year limitation to review relevant manuscripts used for this article. PMID- 23459242 TI - Novel Therapeutics: NSAIDs, Derivatives, and Phosphodiesterases. AB - The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for colorectal cancer has been well documented. However, long-term use of NSAIDs is precluded owing to potentially fatal toxicities associated with their mechanism of action involving cyclooxygenase (COX) inhibition. But studies have shown that their anticancer activity may be due, in part, to an off-target effect. Cyclic guanosine monophosphate (cGMP) phosphodiesterases (PDEs), which are responsible for negative regulation of cGMP signaling, are an attractive COX-independent target. cGMP signaling is aberrantly suppressed in cancer cells and its activation appears to be sufficient to inhibit tumor cell growth. Chemically modifying sulindac has produced a series of new derivatives that lack COX inhibitory activity but have improved cGMP PDE inhibitory activity. This approach is proving to be a promising strategy for the discovery of improved agents for the prevention and/or treatment of colorectal cancer. PMID- 23459243 TI - Subjective measures of exercise intensity to gauge substrate partitioning in persons with paraplegia. AB - BACKGROUND: The Borg Rating of Perceived Exertion (RPE) Scale and talk test (TT) are commonly recommended for persons to gauge exercise intensity. It is not known whether they are suitable to estimate substrate partitioning between carbohydrate and fat in persons with SCI. OBJECTIVE: Investigate substrate partitioning/utilization patterns associated with RPE and TT. METHODS: Twelve participants with chronic paraplegia underwent 2 arm crank exercise tests on nonconsecutive days within 2 weeks. Test 1 was a graded exercise test (GXT) to volitional exhaustion. Test 2 was a 15-minute self-selected steady state (SS) voluntary arm exercise bout simulating a brief, yet typical exercise session. RESULTS: For the GXT, very light intensity exercise (RPE < 9) and TT stage before last positive were associated with highest contribution of fat oxidation (~35% 50%) to total energy expenditure (TEE). Fat oxidation was low at all stages, with the highest rate (0.13 +/- 0.07 g/min) occurring at stage 1 (10 W). Corresponding average RPE was 7 +/- 2 and the TT was positive for all participants at this stage. For the SS, fuel partitioning throughout exercise was dominated by carbohydrate oxidation (1.47 +/- 0.08 g/min), accounting for almost all (~94%) of TEE with only a minute contribution from fat oxidation (0.02 +/- 0.004 g/min). A positive TT was associated with an average contribution of fat oxidation of ~10%. CONCLUSIONS: RPE but not the TT appears suitable to predict exercise intensities associated with the highest levels of fat oxidation. However, such intensities are below authoritative intensity thresholds for cardiorespiratory fitness promotion, and therefore the applicability of such a prediction for exercise prescriptions is likely limited to individuals with low exercise tolerance. PMID- 23459244 TI - MUSIC APPRECIATION AND TRAINING FOR COCHLEAR IMPLANT RECIPIENTS: A REVIEW. AB - In recent years, there has been increasing interest in music perception of cochlear implant (CI) recipients, and a growing body of research conducted in this area. The majority of these studies have examined perceptual accuracy for pitch, rhythm, and timbre. Another important, but less commonly studied aspect of music listening is appreciation, or appraisal. Despite the ongoing research into potential technological improvements that may improve music perception for recipients, both perceptual accuracy and appreciation generally remain poor for most recipients. Whilst perceptual accuracy for music is important, appreciation and enjoyment also warrants research as it also contributes to clinical outcomes and perceived benefits. Music training is being shown to offer excellent potential for improving music perception and appreciation for recipients.Therefore, the primary topics of this review are music appreciation and training. However, a brief overview of the psychoacoustic, technical, and physiological factors associated with a recipient's perception of music is provided, as these are important factors in understanding the listening experience for CI recipients. The purpose of this review is to summarize key papers that have investigated these issues, in order to demonstrate that i) music enjoyment and appraisal is an important and valid consideration in evaluating music outcomes for recipients, and ii) that music training can improve music listening for many recipients, and is something that can be offered to persons using current technology. PMID- 23459245 TI - Prostate-specific antigen testing in men aged 40-64 years: impact of publication of clinical trials. AB - We assessed the impact of the publication of trials and changes in recommendations on the rates of prostate-specific antigen (PSA) screening in men aged 40 to 64 years by analyzing monthly medical claims for PSA testing in a commercial insurance database from 2001 to 2011, covering more than 1.5 million men in each year. The testing rates for men aged 40 to 49 years, 50 to 59 years, and 60 to 64 years were 12.1%, 32.7%, and 42.7%, respectively, in 2001 vs 15.7%, 34.2%, and 42.0%, respectively, in 2011. Men aged 40 to 49 years experienced a gradual increase in testing rate from 2001 through 2008 (annual change in PSA testing per 10,000 men [AC] = 4.37; P < .001), which became flat from mid-2009 through 2011(AC = -0.06; P =.98). The slope of PSA testing rates did not change in men aged 50 to 59 years or 60 to 64 years with the publication of the results of the large trials in 2009 or with the subsequent changes in recommendations on PSA testing. PMID- 23459246 TI - Motor and gait improvement in patients with incomplete spinal cord injury induced by high-frequency repetitive transcranial magnetic stimulation. AB - OBJECTIVE: To assess the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) on lower extremities motor score (LEMS) and gait in patients with motor incomplete spinal cord injury (SCI). METHOD: The prospective longitudinal randomized, double-blind study assessed 17 SCI patients ASIA D. We assessed LEMS, modified Ashworth Scale (MAS), 10-m walking test (10MWT), Walking Index for SCI (WISCI II) scale, step length, cadence, and Timed Up and Go (TUG) test at baseline, after the last of 15 daily sessions of rTMS and 2 weeks later. Patients were randomized to active rTMS or sham stimulation. Three patients from the initial group of 10 randomized to sham stimulation entered the active rTMS group after a 3-week washout period. Therefore a total of 10 patients completed each study condition. Both groups were homogeneous for age, gender, time since injury, etiology, and ASIA scale. Active rTMS consisted of 15 days of daily sessions of 20 trains of 40 pulses at 20 Hz and an intensity of 90% of resting motor threshold. rTMS was applied with a double cone coil to the leg motor area. RESULTS: There was a significant improvement in LEMS in the active group (28.4 at baseline and 33.2 after stimulation; P = .004) but not in the sham group (29.6 at baseline, and 30.9 after stimulation; P = .6). The active group also showed significant improvements in the MAS, 10MWT, cadence, step length, and TUG, and these improvements were maintained 2 weeks later. Following sham stimulation, significant improvement was found only for step length and TUG. No significant changes were observed in the WISCI II scale in either group. CONCLUSION: High frequency rTMS over the leg motor area can improve LEMS, spasticity, and gait in patients with motor incomplete SCI. PMID- 23459249 TI - An assessment program using standardized clients to determine student readiness for clinical practice. AB - Objective. To develop, implement, and review a competence-assessment program to identify students at risk of underperforming at advanced pharmacy practice experience (APPE) sites and to facilitate remediation before they assume responsibility for patient care.Design. As part of the standardized client program, pharmacy students were examined in realistic live client-encounter simulations. Authentic scenarios were developed, and actors were recruited and trained to portray clients so students could be examined solving multiple pharmacy problems. Evaluations of students were conducted in the broad areas of knowledge and live performance.Assessment. Measurements included student experience survey instruments used to evaluate case realism and challenge; videos used to determine the fidelity of standardized clients, and clerkship performance predictions used to identify students who required individual attention and improvement prior to clerkship courses.Conclusions. The assessment program showed promise as a means of discriminating between students who are prepared for APPEs and those at risk for underperforming. PMID- 23459250 TI - Feasibility and outcomes of endovascular embolization of cerebral arteriovenous malformations at a low-volume centre. AB - BACKGROUND AND PURPOSE: Herein, we report our initial experience with the endovascular management of cerebral arteriovenous malformations (AVMs) using the liquid embolic agent Onyx and n-butyl cyanoacrylate for AVM embolization. METHODS: We reviewed data from 15 patients with brain AVMs, who were observed at our endovascular facility from January 2008 to July 2011. All cases were embolized with Onyx and/or n-butyl cyanoacrylate. There were 8 women and 7 men with a mean age of 27.2 years (range 17-43 years). The clinical presentations included intracerebral haemorrhage (n = 7), seizures (n = 4), headache (n = 2), and focal neurological deficits (n = 2); according to the Spetzler-Martin classification (Spetzler R and Martin N (1986) J NeurosurgV65 446-83), 8 AVMs were grades I-II, 5 were grade III, and 2 were grades IV-V. RESULTS: A total of 31 embolization procedures were performed in 15 patients, and 44 feeding pedicles were embolized, ranging from 1 to 5 per patient, with an average size reduction of 70% (median 75%, range 40-100%). Total obliteration was achieved for 3 AVMs (20%) (2 patients had single feeders and 1 patient had double feeders), and a partial embolization was achieved in 12 patients (80%). The procedure was related to a permanent disabling morbidity in one patient (6.6%), and no mortalities occurred. CONCLUSIONS: The outcome of (AVM) embolization in our centre is comparable to the reported outcome in other larger-volume centres. The feasibility and safety of AVM embolization in our low-volume centre are similar to the outcomes reported at high-volume centre. PMID- 23459248 TI - The social fabric of the RNA degradosome. AB - Bacterial transcripts each have a characteristic half-life, suggesting that the processes of RNA degradation work in an active and selective manner. Moreover, the processes are well controlled, thereby ensuring that degradation is orderly and coordinated. Throughout much of the bacterial kingdom, RNA degradation processes originate through the actions of assemblies of key RNA enzymes, known as RNA degradosomes. Neither conserved in composition, nor unified by common evolutionary ancestry, RNA degradosomes nonetheless can be found in divergent bacterial lineages, implicating a common requirement for the co-localisation of RNA metabolic activities. We describe how the cooperation of components in the representative degradosome of Escherichia coli may enable controlled access to transcripts, so that they have defined and programmable lifetimes. We also discuss how this cooperation contributes to precursor processing and to the riboregulation of intricate post-transcriptional networks in the control of gene expression. The E. coli degradosome interacts with the cytoplasmic membrane, and we discuss how this interaction may spatially organise the assembly and contribute to subunit cooperation and substrate capture. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23459247 TI - Regulation of molecular chaperones through post-translational modifications: decrypting the chaperone code. AB - Molecular chaperones and their associated cofactors form a group of highly specialized proteins that orchestrate the folding and unfolding of other proteins and the assembly and disassembly of protein complexes. Chaperones are found in all cell types and organisms, and their activity must be tightly regulated to maintain normal cell function. Indeed, deregulation of protein folding and protein complex assembly is the cause of various human diseases. Here, we present the results of an extensive review of the literature revealing that the post translational modification (PTM) of chaperones has been selected during evolution as an efficient mean to regulate the activity and specificity of these key proteins. Because the addition and reciprocal removal of chemical groups can be triggered very rapidly, this mechanism provides an efficient switch to precisely regulate the activity of chaperones on specific substrates. The large number of PTMs detected in chaperones suggests that a combinatory code is at play to regulate function, activity, localization, and substrate specificity for this group of biologically important proteins. This review surveys the core information currently available as a starting point toward the more ambitious endeavor of deciphering the "chaperone code". PMID- 23459252 TI - Diffuse Disconnectivity in tBi: a resting state fMri anD Dti stuDy. AB - Diffuse axonal injury is a common pathological consequence of Traumatic Brain Injury (TBI). Diffusion Tensor Imaging is an ideal technique to study white matter integrity using the Fractional Anisotropy (FA) index which is a measure of axonal integrity and coherence. There have been several reports showing reduced FA in individuals with TBI, which suggest demyelination or reduced fiber density in white matter tracts secondary to injury. Individuals with TBI are usually diagnosed with cognitive deficits such as reduced attention span, memory and executive function. In this study we sought to investigate correlations between brain functional networks, white matter integrity, and TBI severity in individuals with TBI ranging from mild to severe. A resting state functional magnetic resonance imaging protocol was used to study the default mode network in subjects at rest. FA values were decreased throughout all white matter tracts in the mild to severe TBI subjects. FA values were also negatively correlated with TBI injury severity ratings. The default mode network showed several brain regions in which connectivity measures were higher among individuals with TBI relative to control subjects. These findings suggest that, subsequent to TBI, the brain may undergo adaptation responses at the cellular level to compensate for functional impairment due to axonal injury. PMID- 23459251 TI - High adenylyl cyclase activity and in vivo cAMP fluctuations in corals suggest central physiological role. AB - Corals are an ecologically and evolutionarily significant group, providing the framework for coral reef biodiversity while representing one of the most basal of metazoan phyla. However, little is known about fundamental signaling pathways in corals. Here we investigate the dynamics of cAMP, a conserved signaling molecule that can regulate virtually every physiological process. Bioinformatics revealed corals have both transmembrane and soluble adenylyl cyclases (AC). Endogenous cAMP levels in live corals followed a potential diel cycle, as they were higher during the day compared to the middle of the night. Coral homogenates exhibited some of the highest cAMP production rates ever to be recorded in any organism; this activity was inhibited by calcium ions and stimulated by bicarbonate. In contrast, zooxanthellae or mucus had >1000-fold lower AC activity. These results suggest that cAMP is an important regulator of coral physiology, especially in response to light, acid/base disturbances and inorganic carbon levels. PMID- 23459253 TI - Improved soil carbonate determination by FT-IR and X-ray analysis. AB - In forest soils on calcareous parent material, carbonate is a key component that influences both chemical and physical soil properties and thus fertility and productivity. At low organic carbon contents, it is difficult to distinguish between organic and inorganic carbon, e.g. carbonates, in soils. The common gas volumetric method to determine carbonate has a number of disadvantages. We hypothesize that a combination of two spectroscopic methods, which account for different forms of carbonate, can be used to model soil carbonate in our region. Fourier transform mid-infrared spectroscopy was combined with X-ray diffraction to develop a model based on partial least squares regression. Results of the gas volumetric Scheibler method were corrected for the calcite/dolomite ratio. The best model performance was achieved when we combined the two analytical methods using four principal components. The root mean squared error of prediction decreased from 13.07 to 11.57, while full cross-validation explained 94.5 % of the variance of the carbonate content. This is the first time that a combination of the proposed methods has been used to predict carbonate in forest soils, offering a simple method to precisely estimate soil carbonate contents while increasing accuracy in comparison with spectroscopic approaches proposed earlier. This approach has the potential to complement or substitute gas-volumetric methods, specifically in study areas with low soil heterogeneity and similar parent material or in long-term monitoring by consecutive sampling. PMID- 23459254 TI - Placental histopathological changes associated with Plasmodium vivax infection during pregnancy. AB - Histological evidence of Plasmodium in the placenta is indicative of placental malaria, a condition associated with severe outcomes for mother and child. Histological lesions found in placentas from Plasmodium-exposed women include syncytial knotting, syncytial rupture, thickening of the placental barrier, necrosis of villous tissue and intervillositis. These histological changes have been associated with P. falciparum infections, but little is known about the contribution of P. vivax to such changes. We conducted a cross-sectional study with pregnant women at delivery and assigned them to three groups according to their Plasmodium exposure during pregnancy: no Plasmodium exposure (n = 41), P. vivax exposure (n = 59) or P. falciparum exposure (n = 19). We evaluated their placentas for signs of Plasmodium and placental lesions using ten histological parameters: syncytial knotting, syncytial rupture, placental barrier thickness, villi necrosis, intervillous space area, intervillous leucocytes, intervillous mononucleates, intervillous polymorphonucleates, parasitized erythrocytes and hemozoin. Placentas from P. vivax-exposed women showed little evidence of Plasmodium or hemozoin but still exhibited more lesions than placentas from women not exposed to Plasmodium, especially when infections occurred twice or more during pregnancy. In the Brazilian state of Acre, where diagnosis and primary treatment are readily available and placental lesions occur in the absence of detected placental parasites, relying on the presence of Plasmodium in the placenta to evaluate Plasmodium-induced placental pathology is not feasible. Multivariate logistic analysis revealed that syncytial knotting (odds ratio [OR], 4.21, P = 0.045), placental barrier thickness (OR, 25.59, P = 0.021) and mononuclear cells (OR, 4.02, P = 0.046) were increased in placentas from P. vivax exposed women when compared to women not exposed to Plasmodium during pregnancy. A vivax-score was developed using these three parameters (and not evidence of Plasmodium) that differentiates between placentas from P. vivax-exposed and unexposed women. This score illustrates the importance of adequate management of P. vivax malaria during pregnancy. PMID- 23459255 TI - A regulatory pathway, ecdysone-transcription factor relish-cathepsin L, is involved in insect fat body dissociation. AB - Insect fat body is the organ for intermediary metabolism, comparable to vertebrate liver and adipose tissue. Larval fat body is disintegrated to individual fat body cells and then adult fat body is remodeled at the pupal stage. However, little is known about the dissociation mechanism. We find that the moth Helicoverpa armigera cathepsin L (Har-CL) is expressed heavily in the fat body and is released from fat body cells into the extracellular matrix. The inhibitor and RNAi experiments demonstrate that Har-CL functions in the fat body dissociation in H. armigera. Further, a nuclear protein is identified to be transcription factor Har-Relish, which was found in insect immune response and specifically binds to the promoter of Har-CL gene to regulate its activity. Har Relish also responds to the steroid hormone ecdysone. Thus, the dissociation of the larval fat body is involved in the hormone (ecdysone)-transcription factor (Relish)-target gene (cathepsin L) regulatory pathway. PMID- 23459256 TI - Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity and sinoatrial nodal pacemaker cell energetics. AB - : Ca(2+)-activated basal adenylate cyclase (AC) in rabbit sinoatrial node cells (SANC) guarantees, via basal cAMP/PKA-calmodulin/CaMKII-dependent protein phosphorylation, the occurrence of rhythmic, sarcoplasmic-reticulum generated, sub-membrane Ca(2+) releases that prompt rhythmic, spontaneous action potentials (APs). This high-throughput signaling consumes ATP. AIMS: We have previously demonstrated that basal AC-cAMP/PKA signaling directly, and Ca(2+) indirectly, regulate mitochondrial ATP production. While, clearly, Ca(2+)-calmodulin-CaMKII activity regulates ATP consumption, whether it has a role in the control of ATP production is unknown. METHODS AND RESULTS: We superfused single, isolated rabbit SANC at 37 degrees C with physiological saline containing CaMKII inhibitors, (KN 93 or autocamtide-2 Related Inhibitory Peptide (AIP)), or a calmodulin inhibitor (W-7) and measured cytosolic Ca(2+), flavoprotein fluorescence and spontaneous AP firing rate. We measured cAMP, ATP and O2 consumption in cell suspensions. Graded reductions in basal CaMKII activity by KN-93 (0.5-3 umol/L) or AIP (2-10 umol/L) markedly slow the kinetics of intracellular Ca(2+) cycling, decrease the spontaneous AP firing rate, decrease cAMP, and reduce O2 consumption and flavoprotein fluorescence. In this context of graded reductions in ATP demand, however, ATP also becomes depleted, indicating reduced ATP production. CONCLUSIONS: CaMKII signaling, a crucial element of normal automaticity in rabbit SANC, is also involved in SANC bioenergetics. PMID- 23459257 TI - The signalling imprints of nanoparticle uptake by bone marrow derived dendritic cells. AB - Nanoparticles (NP) possess remarkable adjuvant and carrier capacity, therefore are used in the development of various vaccine formulations. Our previous studies demonstrated that inert non-toxic 40-50 nm polystyrene NP (PS-NP) can promote strong CD8 T cell and antibody responses to the antigen, in the absence of observable inflammatory responses. Furthermore, instillation of PS-NP inhibited the development of allergic airway inflammation by induction of an immunological imprint via modulation of dendritic cell (DC) function without inducing oxidative stress in the lungs in mice. This is in contrast to many studies which show that a variety of ambient and man-made NP promote lung immunopathology, raising concerns generally about the safe use of NPs in biomedicine. Most NPs are capable of inducing inflammatory pathways in DC largely mediated by signalling via the extracellular signal-regulated kinase 1/2 (ERK). Herein, we investigate whether PS-NPs also activate ERK in DC in vitro. Our data show that PS-NP do not induce ERK activation in two different types of bone marrow derived (BM) DC cultures (expanded with GM-CSF or with GM-CSF together with IL-4). The absence of such signalling was not due to lack of PS-NP uptake by BM-DC as confirmed by confocal microscopy and flow cytometry. The process of NP uptake by DC usually initiates ERK signalling, suggesting an unusual uptake pathway may be engaged by PS-NPs. Indeed, data herein showns that uptake of PS-NP by BM-DC was substantially inhibited by phorbol myristate acetate (PMA) but not cytochalasin D (CCD), suggesting an uptake pathway utilising caveole for PS-NP. Together these data show that BM-DC take up PS-NP via a caveole-dependent pathway which does not trigger ERK signalling which may explain their efficient uptake by DC, without the concomitant activation of conventional inflammatory pathways. PMID- 23459258 TI - Firing statistics of inhibitory neuron with delayed feedback. II: Non-Markovian behavior. AB - The instantaneous state of a neural network consists of both the degree of excitation of each neuron the network is composed of and positions of impulses in communication lines between the neurons. In neurophysiological experiments, the neuronal firing moments are registered, but not the state of communication lines. But future spiking moments depend essentially on the past positions of impulses in the lines. This suggests, that the sequence of intervals between firing moments (inter-spike intervals, ISIs) in the network could be non-Markovian. In this paper, we address this question for a simplest possible neural "net", namely, a single inhibitory neuron with delayed feedback. The neuron receives excitatory input from the driving Poisson stream and inhibitory impulses from its own output through the feedback line. We obtain analytic expressions for conditional probability density P(tn+1|tn, ..., t1, t0), which gives the probability to get an output ISI of duration tn+1 provided the previous (n+1) output ISIs had durations tn, ..., t1, t0. It is proven exactly, that P(tn+1|tn, ..., t1, t0) does not reduce to P(tn+1|tn, ..., t1) for any n>=0. This means that the output ISIs stream cannot be represented as a Markov chain of any finite order. PMID- 23459259 TI - Effect of operating microscope light on brain temperature during craniotomy. AB - BACKGROUND: Operating microscopes used during neurosurgery are fitted with xenon light. Burn injuries have been reported because of xenon microscope lighting as the intensity of xenon light is 300 W. We designed this study to find out if the light of operating microscope causes an increase in temperature of the brain tissue, which is exposed underneath. METHODS: Twenty-one adult patients scheduled for elective craniotomies were enrolled. Distal esophageal temperature (T Eso), brain temperature under the microscope light (T Brain), and brain temperature under dura mater (T Dura) were measured continuously at 15-minute intervals during microscope use. The irrigation fluid temperature, room temperature, intensity of the microscope light, and the distance of the microscope from the brain surface were kept constant. RESULTS: The average age of the patients was 44+/-15 years (18 males and 3 females). The mean duration of microscope use was 140+/-39 minutes. There were no significant changes in T Brain and T Dura and T Eso over time. T Dura was significantly lower than T Brain both at time 0 and 60 minutes but not at 90 minutes. T Brain was significantly lower than T Eso both at time 0 and 60 minutes but not at 90 minutes. The T Dura remained significantly lower than T Eso at 0, 60, and 90 minutes. CONCLUSION: Our study shows that there is no significant rise in brain temperature under xenon microscope light up to 120 minutes duration, at intensity of 60% to 70%, from a distance of 20 to 25 cm from the brain surface. PMID- 23459260 TI - Treatment of varus deformities of the lower limbs in patients with achondroplasia and hypochondroplasia. AB - Angular deformities of the lower limbs are a common clinical problem encountered in pediatric orthopaedic practices particularly in patients with osteochondrodysplasias. The varus deformity is more common than the valgus deformity in achondroplasia and hypochondroplasia patients because of the unusual growth of the fibulae than that of the tibiae. We retrospectively reviewed six patients (four patients with achondroplasia and two patients with hypochondroplsia) with relevant limb deformities due to the above-mentioned entities. All patients manifested significant varus deformity of the lower limbs. Detailed phenotypic characterization, radiologic and genetic testing was carried out as baseline diagnostic tool. We described the re-alignment procedures, which have been applied accordingly. Therefore, bilateral multi-level procedures, multi apical planning and limb lengthening have been successfully applied. While recognition of the underlying syndromic association in patients who are manifesting angular deformities is the baseline for proper orthopaedic management, this paper demonstrates how to evaluate and treat these complex patients. PMID- 23459261 TI - A new method for ultrasonographic measurement of kidney size in healthy dogs. AB - INTRODUCTION: The authors propose a simple method for assessment of canine kidney size derived from the radiological technique described by Finco et al in 1971. MATERIALS AND METHODS: In 26 healthy dogs ultrasonography was used to measure the length, height, and thickness of each kidney. These measurements were correlated with the lengths of the fifth and sixth lumbar vertebrae (L5 and L6), also measured by ultrasound. The resulting values were compared with the linear correlation method and the ratios defined using descriptive statistics. RESULTS: No significant differences were observed between the dimensions of the right and left kidneys. The length of both kidneys displayed significant correlation with both the length of L5 and that of L6. In both cases, the renal:vertebral length ratios ranged from 1.3 to 2.7. DISCUSSION: The ratio of kidney length to the length of L5 or L6 can be considered a useful parameter for assessing the size of the kidneys in healthy dogs. The normal range we identified in this study (from 1.3 to 2.7) is sufficiently narrow to allow sonographic detection of even limited changes in renal length. PMID- 23459262 TI - Takotsubo cardiomyopathy: reversible stress-induced cardiac insult - a stress protective mechanism. AB - Takotsubo cardiomyopathy (TCM) is characterized by a typical pattern of wall motion abnormalities (basal hyperkinesis with mid-ventricular and apical hypokinesis) in the absence of obstructive coronary artery disease. The clinical presentation often mimics acute coronary syndrome with anginal and anginal equivalent symptoms, dynamic ECG changes, and elevated cardiac biomarkers. Patients are predominantly postmenopausal women. In the vast majority of cases an extremely stressful inciting event can be identified. The catecholamine surge occurring in response to stress has been implicated as the trigger for this peculiar myocardial response. It appears the specific type of beta-adrenergic receptor activation, relative epinephrine to norepinephrine activity, and a genetic predisposition all play a role. This apparently paradoxical response to stress may, in fact, be an important evolutionary safety net preventing catecholamine induced myocardial collapse. PMID- 23459263 TI - Ultra-sensitive analysis of a cantilevered single-walled carbon nanocone-based mass detector. AB - The ultra-sensitivity of mass detectors using individual cantilevered single walled carbon nanocone (SWCNC) resonators is first investigated. A higher-order gradient theory, derived at the atomic level, is applied for modeling SWCNC resonators. Numerical simulations using a mesh-free computational framework based on moving Kriging interpolation are conducted to investigate the mass sensitivity of cantilevered SWCNC resonators with extra mass loading as well as with equivalent single-walled carbon nanotube (SWCNT) resonators. Comparison of the magnitude of resonant frequency shifts, the key criterion for mass sensitivity, of these two kinds of resonators demonstrates a far higher mass sensitivity for SWCNC resonators than for SWCNT resonators, thus suggesting a new method for ultra-sensitive mass detection via SWCNC resonators. The dependence of the mass sensitivity of SWCNC resonators on height and top radii has been examined. A reduction in the height of SWCNC resonators gives rise to a considerable increase in mass sensitivity. The mass sensitivity of a 6 nm high SWCNC resonator can even reach a level of 10(-22) g. It is noteworthy that the top radii of SWCNC resonators have a slight effect on frequency shifts. Another interesting observed phenomenon is that a deviation in the height of 19.2 degrees SWCNC resonators leads to little loss in precision of mass detection when the attached mass is smaller than 10(-20) g. This superior characteristic indicates that SWCNC-based mass detectors have great potential in practical applications. PMID- 23459264 TI - The moderating effects of skin color and ethnic identity affirmation on suicide risk among low-SES African American women. AB - This study examined the influence of concurrent racism and sexism experiences (i.e. gendered racism) on African American women's suicidal ideation and behavior in the context of disadvantaged socioeconomic status. Drawing on a stress process framework, the moderating effects of ethnic identity and skin color were explored using multiple regression analyses. Data were from 204 low-income African American women in the B-WISE (Black Women in a Study of Epidemics) project. Findings suggested that experiencing gendered racism significantly increased these women's risk for suicidal ideation or behavior, though only among women with medium or dark skin color. Also, having strong ethnic identity buffered the harmful effects of gendered racism. The moderating properties of skin color and ethnic identity affirmation likely operate through psychosocial pathways, blocking internalization of negative stereotypes and reducing the level of distress experienced in response to gendered racism. PMID- 23459265 TI - Continuing with life as normal:: positive psychological outcomes following spinal cord injury. AB - BACKGROUND: Research into the psychological sequelae of spinal cord injury (SCI) has focused on reports of psychological distress, despite the low prevalence rates of mental health difficulties. Positive psychological frameworks have begun to explore how some individuals do not report psychological distress, while appraisals have been posited as possible mediators of psychological outcome. Research into positive psychological outcomes in people with SCI is still in its infancy. OBJECTIVE: To provide a description of the positive psychological outcomes experienced by people reporting low levels of psychological distress, to generate an understanding of how these individuals explain their positive outcomes, and to consider the implications for research, theory, and practice. METHOD: Six participants (2 female, 4 male) reporting low levels of psychological distress were interviewed using a semi-structured interview schedule exploring their experiences. Interpretative phenomenological analysis was used to analyze data. RESULTS: THREE SUPERORDINATE THEMES WERE IDENTIFIED: "living a normal life, just doing things differently," "overcoming challenges: determination to succeed," and "using the resources available to me." The description and explanation of a positive psychological outcome was complex. For participants, positive psychological outcomes did not exclude experiencing psychological difficulty; moreover, they described an ability to overcome difficulty. Challenge focused appraisals, social support, and meaningful activity were identified by participants as being important to psychological outcome. CONCLUSIONS: Positive psychological outcomes following SCI are complex, and research and theory need to better understand the experience of individuals following SCI in order to inform clinical practice. PMID- 23459266 TI - A facile route to synthesize nanogels doped with silver nanoparticles. AB - In this work, we describe a simple method to prepare hybrid nanogels consisting of a biocompatible core-shell polymer host containing silver nanoparticles. First, the nanogels (NG, ~160 nm) containing a lysozyme rich core and a dextran rich shell, are prepared via Maillard and heat-gelation reactions. Second, silver nanoparticles (Ag NPs, ~5nm) are synthesized in situ in the NG solution without requiring additional reducing agents. This approach leads to stable Ag NPs located in the NG. Furthermore, we demonstrate that the amount of Ag NPs in the NG can be tuned by varying silver precursor concentration. Hybrid nanogels with silver nanoparticles have potential in antimicrobial, optical and therapeutic applications. PMID- 23459269 TI - An introprofessional geriatric medication activity within a senior mentor program. AB - Objective. To determine whether a required interprofessional geriatric medication activity within a senior mentor program changed pharmacy and medical students' attitudes regarding interprofessional collaboration.Design. Interprofessional teams, consisting of 1 third-year pharmacy student and 2 second-year medical students, conducted an in-home interview and medication history with a senior mentor (geriatric patient). The team members then collaboratively analyzed and discussed the patient's medication use and wrote an essay in which they identified the patient's medication problems and reflected on the interprofessional experience.Assessment. Students completed a validated survey instrument to measure pharmacist-physician attitudes about interprofessional collaboration before and after the experience. Pharmacy and medical students' already generally positive attitudes regarding interprofessional relationships were maintained and, in some instances, significantly improved. Students found the activity enhanced their geriatric training and increased their understanding of an interprofessional team.Conclusion. Incorporation of a geriatric medication activity within a senior mentor program maintained or improved pharmacy and medical students' positive attitudes about interprofessional collaboration and enhanced geriatric training within the curriculum. PMID- 23459270 TI - Toronto rehabilitation institute-hand function test: assessment of gross motor function in individuals with spinal cord injury. AB - PURPOSE: The objective of this study was to evaluate the interrater reliability, construct validity, and sensitivity of Toronto Rehabilitation Institute-Hand Function Test (TRI-HFT), within an interventional randomized control trial. METHOD: Twenty-one participants with subacute C4 to C7 spinal cord injury (SCI) were recruited. Based on randomization, participants were allocated to either the functional electrical stimulation therapy group or the conventional occupational therapy group. Baseline and follow-up assessments of participants were videotaped. For testing interrater reliability, videotaped images were transferred to DVDs that were later observed by 2 observers. Construct validity was determined by comparing total scores on TRI-HFT to self-care subscore components of the Spinal Cord Independence Measure (SCIM) and FIM. To establish sensitivity of TRI-HFT, we compared pre- and posttreatment scores on all 3 measures (ie, TRI-HFT, FIM, and SCIM). RESULTS: TRI-HFT was found to have high interrater reliability with an intercorrelation coefficient (ICC) of 0.98. Moderate to strong correlations were found between TRI-HFT total scores and self care components of FIM and SCIM for both hands individually post therapy. Due to a floor effect of the FIM and SCIM, there was weak correlation between pretherapy scores of the said measures and TRI-HFT. TRI-HFT was found to be highly sensitive in determining difference in function pre and post therapy. CONCLUSIONS: This study demonstrated that the TRI-HFT is a reliable and sensitive measure to assess unilateral hand gross motor function in persons with tetraplegia, with moderate to strong construct validity. PMID- 23459271 TI - C1-C2 fusion: promoting stability, reducing morbidity. PMID- 23459272 TI - The high road or the low road. PMID- 23459273 TI - Unexpected neurological deterioration after spinal surgery. PMID- 23459274 TI - Orbital lymphangiomas. PMID- 23459275 TI - Far medial versus far lateral approach: the need of a chamaleontic perspective to unlock a skull base region. PMID- 23459276 TI - Stereotactic radiosurgery for functioning pituitary adenomas--a higher dose is better but only up to a point. PMID- 23459277 TI - Should we adopt micro-interintimal dissection: a novel and worthwhile advance in carotid surgery technique, but does it prevent restenosis and early neurological deficits? PMID- 23459278 TI - Radiosurgical dose selection for secreting pituitary adenomas. PMID- 23459279 TI - Computed tomography angiography and the incidence of unruptured aneurysms. PMID- 23459281 TI - Pre-post pilot study of noise levels at a university hospital center pharmacy department. AB - CONTEXT: Noise interferes with attention, speech understanding, detection of other auditory stimuli, and leads to interruptions. OBJECTIVES: This is a pre post cross-sectional observational study aimed at measuring noise levels in a 500 bed mother-child university hospital center pharmacy department after the implementation of corrective measures, such as work zone reorganization, digitization of the prescription process, and education about the impact of some work habits. RESULTS: A total of 24 measurement points (70 noise level measurements) were taken in 2007 (pre) compared to 30 measurement points (59 noise level measurements) in 2012 (post). There was a statistically significant difference in the average values of the day and night noise measurements (day 59.4 +/- 5.3 dB(A) vs night 52.3 +/- 8.0 dB(A); P < .001). There were no statistically significant differences in the average values of the noise measurements taken during daytime between the prestudy and poststudy phases (pre 59.4 +/- 5.3 vs post 58.07 +/- 6.01 dB(A); P = .22). CONCLUSION: Few data exist on the noise levels in hospital pharmacy departments. In spite of the corrective measures implemented, reducing noise levels in pharmacy departments was difficult to achieve. Average values of approximately 60 dB(A) seem to be unacceptable for work that requires a high level of attention. PMID- 23459280 TI - The pterional and suprabrow approaches for aneurysm surgery: a systematic review of intraoperative rupture rates in 9488 aneurysms. AB - OBJECTIVE: To assess the safety of the suprabrow approach (SBCA) for aneurysm surgery by comparing intraoperative rupture rates with those for the standard pterional approach. METHODS: A systematic review of all literature published in or after 1997 was performed using specified search words. All articles described aneurysm surgery by one of two approaches--pterional or suprabrow--and mentioned the rate of intraoperative rupture. A total of 41 articles were found fit for inclusion for the final analysis. Articles that focused on giant, bilateral, posterior fossa, or previously coiled aneurysms were not included. The chi(2) test was used to compare the two cohorts and various subgroup analyses were carried out. A P value of <0.05 was considered significant. RESULTS: The search of literature yielded 9488 aneurysm reports (41 articles), 7535 operated by the pterional approach and 1953 aneurysms by the SBCA. The overall intraoperative rupture (IOR) rate for the entire group was 9.20%. In the pterional craniotomy approach (PtCA) group, the rate of IOR was 10.09% and in the SBCA group, IOR occurred in 5.78%. The IOR rate in the PtCA group was almost double that in the SBCA group and the odds ratio (OR) for this difference was 1.8 (95% confidence interval [CI] 1.49-2.26; P< 0.001). A total of 3039 ruptured aneurysms were analyzed--2848 aneurysms in the PtCA group and 191 in the SBCA group. The rate of IOR was 14.15% for the overall group, 13.8% in the PtCA group, and 19.37% in the SBCA group. The difference in IOR between the PtCA group and the SBCA group for ruptured aneurysms was found to be significant (OR 1.5, 95% CI 1.003-2.119; P< 0.05). The number of unruptured aneurysms in the PtCA group was 862 (39.4%) and in the SBCA group, it was 232 (49.1%). The difference in the number of unruptured aneurysms between the groups was significant (P< 0.001). The rate of IOR was significantly less with the SBCA than with the pterional approach. CONCLUSIONS: The rate of intraoperative rupture is significantly higher when ruptured aneurysms are operated with the SBCA (in comparison to the pterional approach). However, the SBCA may be safer for unruptured and middle cerebral artery aneurysms with a lower rate of IOR. PMID- 23459282 TI - Guidance for the discontinuation or switching of antidepressant therapies in adults. AB - Antidepressants (ADs) are commonly used for the treatment of various psychological and other medical disorders. Patient response and regimen duration with individual agents varies, necessitating discontinuation (DC) and/or switching between ADs. However, withdrawal symptoms may occur upon DC of the AD, and clinical symptom control may be compromised if the change to a new AD agent is not initiated appropriately. The purpose of this evaluation was to review the available literature and resources to compile documented methods for discontinuing or changing AD regimens in the clinical setting into a single guidance document. The results of this evaluation have yielded both detailed and general recommendations for practitioners to use and consider in discontinuing an AD and making changes between AD agents. The information provided herein is intended to provide useful guidance for clinicians and other health care professionals in their management of patients discontinuing or switching between selected AD agents. PMID- 23459283 TI - Primer on clinical practice guidelines. AB - Clinical practice guidelines (CPGs) are valuable tools for health care providers and support evidence-based medicine (EBM). Many organizations, including medical associations and government-affiliated agencies, develop and publish guidelines using varying methods. Unfortunately, many guidelines are not appropriately developed and certain recommendations are not based on the best available evidence. Recent efforts by EBM advocates are contributing to the improved quality of CPGs and more tools are becoming available to promote high-quality guideline development and use. This article describes the guideline development process and associated concerns and the advances in the field of CPGs. Tools to access and evaluate guidelines are also provided. Health care professionals equipped with an understanding of the process of guideline creation and tools for evaluation can appropriately utilize guidelines to improve patient care. PMID- 23459284 TI - Health and medication information resources on the World Wide Web. AB - Health care practitioners have increasingly used the Internet to obtain health and medication information. The vast number of Internet Web sites providing such information and concerns with their reliability makes it essential for users to carefully select and evaluate Web sites prior to use. To this end, this article reviews the general principles to consider in this process. Moreover, as cost may limit access to subscription-based health and medication information resources with established reputability, freely accessible online resources that may serve as an invaluable addition to one's reference collection are highlighted. These include government- and organization-sponsored resources (eg, US Food and Drug Administration Web site and the American Society of Health-System Pharmacists' Drug Shortage Resource Center Web site, respectively) as well as commercial Web sites (eg, Medscape, Google Scholar). Familiarity with such online resources can assist health care professionals in their ability to efficiently navigate the Web and may potentially expedite the information gathering and decision-making process, thereby improving patient care. PMID- 23459285 TI - Unapproved drugs--the drug information pharmacists' perspective. AB - Pharmacists in all areas of practice frequently dispense or recommend drugs without realizing that some commonly used medications have never received Food and Drug Administration (FDA) approval. Most of these medications have been available for many years and are usually misconceived as generic drugs, when in fact they never went through the required quality, safety, and efficacy testing required by FDA. As a result, unapproved drugs can pose serious safety risks to patients and create uncertainty in the market. FDA established the "Unapproved Drugs Initiative" to protect public health by decreasing the number of available unapproved drugs with minimal disruptions to the market. Unapproved drugs remain in the market for various historical reasons. It is important for health care providers, particularly pharmacists, to be knowledgeable about unapproved products and consider switching patients to FDA-approved alternatives if possible when selecting drug therapy. Several resources are available on the FDA Website to determine approval status. Although FDA is working to remove unapproved drugs from the market, there will be circumstances when the use of unapproved drugs is medically necessary and appropriate. In these cases, pharmacists can monitor for and report adverse events and stay informed regarding any changes in approval status. PMID- 23459286 TI - Contemporary approaches for evidence-based pharmacotherapy. AB - Evidence-based medicine (EBM) is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. This article provides simple ways to practice everyday EBM by (1) asking patient-specific clinical questions, (2) finding the most relevant, best evidence, (3) critically appraising evidence to ensure validity, (4) applying evidence to practice, and (5) using available tools to stay abreast of relevant and valid evidence as it becomes available. PMID- 23459291 TI - Secretory expression and efficient purification of recombinant anthrax toxin lethal factor with full biological activity in E. coli. AB - Lethal factor (LF), a virulence factor of Bacillus anthracis, plays key roles in anthrax pathogenesis and host-pathogen interactions. The detailed mechanisms by which LF contributes to infection are still under investigation. While these studies require pure, homogeneous and reliable LF preparations, most methods reported for production of recombinant LF (rLF) in B. anthracis or Escherichia coli either are complicated or add extra residues to the protein. In this work, we modified our previous method by codon optimization and chromatograph workflow refinement and developed an improved strategy for efficient production of rLF from the periplasm of E. coli. We were able to obtain fully functional rLF with a purity above 95% and with a considerable yield of 5 mg/L. The preparation was characterized by SDS-PAGE, Western blot, and N-terminal sequencing, and the activity was validated by intoxication of macrophages and Fischer 344 rats. Our final product is suitable for most research involving drug development and mechanism analysis of anthrax pathogenesis. PMID- 23459290 TI - Bacterial expression and antibiotic activities of recombinant variants of human beta-defensins on pathogenic bacteria and M. tuberculosis. AB - Five variants of human beta-defensins (HBDs) were expressed in Escherichia coli using two vector systems (pET28a(+) and pQE30) with inducible expression by IPTG. The last vector has not been previously reported as an expression system for HBDs. The recombinant peptides were different in their lengths and overall charge. The HBDs were expressed as soluble or insoluble proteins depending on the expression system used, and the final protein yields ranged from 0.5 to 1.6 mg of peptide/g of wet weight cells, with purities higher than 90%. The recombinant HBDs demonstrated a direct correlation between antimicrobial activity and the number of basic charged residues; that is, their antimicrobial activity was as follows: HBD3-M-HBD2 > HBD3 = HBD3-M = HB2-KLK > HBD2 when assayed against E. coli, Staphylococcus aureus and Pseudomonas aeruginosa. Interestingly, HBD2 had the best antimicrobial activity against the Mycobacterium tuberculosis strain H37Rv (1.5 MUM) and the heterologous tandem peptide, HBD3-M-HBD2, had the best minimal inhibitory concentration (MIC) value (2.7 MUM) against a multidrug resistance strain (MDR) of M. tuberculosis, demonstrating the feasibility of the use of HBDs against pathogenic M. tuberculosis reported to be resistant to commercial antibiotics. PMID- 23459292 TI - Co-expression of human cytochrome b5 increases expression of cytochrome P450 3A4 in Escherichia coli by stabilizing mRNA. AB - CYP3A4 is the most abundant cytochrome P450 in the human liver. The expression level of CYP3A4 when coexpressed with cytochrome b(5) (cyt b(5)) in Escherichia coli was 20-60% higher than that when it was expressed alone over an extended period (48-72 h). This time-dependent elevation in coexpression with cyt b(5) was a result of an increase in CYP3A4 mRNA half-life; no significant change in CYP3A4 degradation was seen in the bacterial protease fraction. These results suggest that the higher CYP3A4 levels observed upon coexpression with cyt b(5) primarily resulted from CYP3A4 mRNA stabilization by cyt b(5). PMID- 23459293 TI - Value of Other Endovascular Techniques Among Patients with MERCI Device Failure during the Treatment of Acute Ischemic Stroke: What to do when MERCI fails? AB - BACKGROUND: The MERCI Retrieval system (Concentric Medical, Mountain View, CA) was the first FDA -approved device for mechanical thrombectomy in patients with acute ischemic stroke. It remains one of the most commonly used devices today despite its failure to restore blood flow in approximately 50% of the occlusions after technically successful deployment and retrieval. It remains unclear whether additional endovascular techniques or continued use of MERCI device can achieve recanalization post- MERCI failure. OBJECTIVE: To analyze the outcome of continued MERCI retriever use compared to other endovascular techniques after initial failure. METHODS: Failure of MERCI retriever was defined by successful deployment and retrieval of MERCI across target occlusion without recanalization in a single pass.. Pre- and post- treatment cerebral angiogram was classified using the Qureshi Grading Scale (QGS). Recanalization was defined by a reduction in >= 1 grade between pre- and post- treatment cerebral angiogram in the Qureshi Grading Scale (QGS). We ascertained and compared the angiographic and clinical results with continued use of MERCI retriever and other endovascular techniques in patients with MERCI failure. RESULTS: A total of 40 patients (53% men) had MERCI retrieval in this cohort with a mean age (+/-standard deviation) of 66.8 years +/- 16 years and a mean admission NIHSS score of 16.8 +/- 6.7. Of the 40 patients treated with MERCI retrieval, there were 26 patients with MERCI failure. In group 1, there were 11 patients who underwent continued MERCI use and group 2 consisted of 15 patients who had an alternate endovascular technique. There was no significant difference in age, risk factors, or outcomes between the groups. The rate of recanalization (82% versus 80%, p=1.0), asymptomatic intra cerebral hemorrhage (18% versus 13%, p =0.77) and favorable outcome at discharge (27% versus 20%, p =0.66) were similar amongst the two groups. CONCLUSIONS: Continued attempts using the MERCI device did not result in higher recanalization rates when compared to alternate endovascular treatment modalities following initial MERCI failure. Both techniques produced comparable rates of recanalization and favorable outcome. PMID- 23459294 TI - Polyglycerol-Dendronized Perylenediimides as Stable, Water-Soluble Fluorophores. AB - The synthesis and photophysical properties of water-soluble, fluorescent polyglycerol-dendronized perylenediimides 1-4 are reported. The polyglycerol dendrons, which are known to be highly biocompatible, are found to confer high water-solubility on the perylenediimide in aqueous media while retaining its excellent fluorescent properties. Furthermore, intramolecular cross-linking of the polyglycerol dendrons using the ring-closing metathesis reaction not only enhances the photostability but also reduces the size of perylenediimide-cored dendrimers. The permeability of the various dendritic shells is probed using heavy metal ion quenchers and compared to non-dendritic but water-soluble perylenediimide 5. PMID- 23459295 TI - Shedding light on cutaneous innate immune responses: the intravital microscopy approach. AB - The skin is under constant assault by environmental factors and microbes. Innate immune cells in epidermis and dermis regulate immune responses against pathogens while maintaining tolerance against commensal bacteria and autoantigens. The introduction of intravital imaging approaches, in particular multiphoton microscopy, has enabled studying the cellular and molecular regulation of cutaneous immunity in real time within intact skin. Here, we discuss recent advances in our understanding of innate immune cell behaviour in the skin, as unravelled by intravital microscopy, with emphasis on the function of myeloid cells, including dendritic cells, neutrophils and monocytes. PMID- 23459297 TI - Insights on the formulation of herbal beverages with medicinal claims according with their antioxidant properties. AB - Several herbal beverages claim medicinal benefits due to their antioxidant properties. However, operational factors such as the extracted herbal component, preparation method or concentration levels, might influence their biological activity. To assess this effect, the antioxidant activity of beverages prepared with Camellia sinensis, Aspalathus linearis or Cochlospermum angolensis, used solely or mixed with different fruit, plant or algae extracts, was studied using different formulations (bags, leaves, roots, granulates, powders, liquids) and different preparation methods (infusion, solubilisation or promptly used). The DF50 (dilution factor responsible for 50% of antioxidant activity) values were calculated to compare their antioxidant activity. A linear discriminant analysis was used to categorize the assayed samples according to their antioxidant activity and bioactive molecules profiles. The results indicated that antioxidant activity and antioxidant compounds are significantly affected by formulation and preparation method, but overall the labelled antioxidant benefits were validated. Green tea showed the highest activity, but with different behaviour within each used formulation. The high DF50 values calculated for some products might be used to adjust the dietary dose or formulation, preventing also putative pro-oxidant effects. Hence, the obtained results might be useful to define the formulation of these highly consumed herbal beverages, enhancing their health effects. PMID- 23459298 TI - Synthesis and cytotoxicity of novel 10-substituted dihydroartemisinin derivatives containing N-arylphenyl-ethenesulfonamide groups. AB - The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC50 values in the single-digit MUM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI 38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N phenyl ring were found to be most active compounds against the six tested cancer cell lines. PMID- 23459296 TI - Combination of bendamustine and entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apoptosis and DNA damage response. AB - Bendamustine, a hybrid molecule of purine analog and alkylator, induces cell death by activation of apoptosis, DNA damage response, and mitotic catastrophe. Entinostat, a selective class I inhibitor of histone deacetylase (HDAC), exerts anti-tumor activity in various cancer types, including multiple myeloma (MM). We sought to determine the combinatorial effects of bendamustine and entinostat on MM cells. Cell growth assays showed that bendamustine or entinostat inhibited proliferation in a dose-dependent manner, and their combinations synergistically induced growth inhibition in all MM cells tested. An apoptotic-ELISA and western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that bendamustine in combination with entinostat exhibited a much more potent activity than either agent alone to promote the MM cells undergoing apoptosis in a dose dependent manner. Flow cytometric analysis found that entinostat exhibited distinct effects on cell cycle progression in different lines and bendamustine mainly arrested the cells at S phase, whereas their combinations dramatically blocked the S cells entering G2/M phase. Furthermore, studies on DNA damage response indicated that phospho-histone H2A.X (P-H2A.X), a hall marker of DNA double strand break, along with phosphorylated CHK2 (P-CHK2) was significantly enhanced by the combinations of bendamustine and entinostat as compared to either agent alone. These molecular changes were correlated with the increases in mitotic catastrophe. Collectively, our data demonstrate that bendamustine in combination with entinostat exhibit potent anti-proliferative/anti-survival activity in MM cells via induction of apoptosis and DNA damage response. Regimens consisting of bendamustine and/or entinostat may represent novel therapeutic strategies against MM. PMID- 23459299 TI - New tacrine analogs as acetylcholinesterase inhibitors - theoretical study with chemometric analysis. AB - Computer simulations constitute the basis of the design and discovery of new drugs. This approach is not only significant with regards to finding new structures, but also for selecting the molecules with the highest probability of being useful in the diagnostic process and treatment of numerous diseases. In our work, we used computational software to analyze 32 new acetylcholinesterase (AChE) inhibitors and formulate ADMET predictions. To understand the influence of the structure of our derivatives on binding mode, we docked all structures to the active site of AChE and assigned some pharmacophoric features. Finally, we undertook a chemometric analysis of all the compounds on the basis of FT-IR, which gave us the possibility of performing a fast categorization of the analyzed compounds and design compounds with similar structures. PMID- 23459300 TI - A new 5alpha,8alpha-Epidioxysterol from the soft coral Sinularia gaweli. AB - A new sterol, (22R,23R,24R)-5alpha,8alpha-epidioxy-22,23-methylene-24-methyl cholest-6,9(11)-dien-3beta-ol (1), and two known sterols, (22R,23R,24R) 5alpha,8alpha-epidioxy-22,23-methylene-24-methylcholest-6-en-3beta-ol (2) and 24 methylenecholestane-1alpha,3beta,5alpha, 6beta,11alpha-pentol (3), were isolated from the soft coral Sinularia gaweli. The structure of sterol 1 was established by spectroscopic methods and by comparison of the spectral data with those of known analogues. The cytotoxicity of sterols 1-3 towards various tumor cells is reported. PMID- 23459301 TI - Discovery of hybrid dual N-acylhydrazone and diaryl urea derivatives as potent antitumor agents: design, synthesis and cytotoxicity evaluation. AB - Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB 231 cell lines, with IC50 values of 0.22, 0.34 and 0.41 MUM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC 1. The promising compound 2g thus emerges as a lead for further structural modifications. PMID- 23459302 TI - 5-Episinuleptolide acetate, a norcembranoidal diterpene from the formosan soft coral Sinularia sp., induces leukemia cell apoptosis through Hsp90 inhibition. AB - 5-Episinuleptolide acetate (5EPA), a cytotoxic norcembranoidal diterpene recently identified from the Formosan soft coral Sinularia sp., exhibited potent activity against the K562, Molt 4 and HL 60 cancer cell lines. The antiproliferative assay, as well as the annexin V-FITC/propidium iodide (PI) apoptotic assay, indicated that the HL 60 cell line is the most sensitive one towards 5EPA. This diterpenoid led to caspases -3, -8, and -9 activation as well as PARP cleavage. It also induced ROS generation, calcium accumulation and disruption of mitochondrial membrane potential. Additionally, the expression levels of Hsp90 protein and several client proteins were downregulated in response to 5EPA treatment. These results suggest that 5EPA's cytotoxic effect on HL 60 cells may be attributed to the inhibition of Hsp90 as well as the induction of mitochondrial stress which finally results in apoptotic cell death. PMID- 23459304 TI - Photo-induced cycloaddition reactions of alpha-diketones and transformations of the photocycloadducts. AB - Photocycloaddition, along with subsequent transformation of the photocycloadducts, provides expeditious ways to construct various structures. The photo-induced reactions of alpha-diketones have been reported to proceed via different reaction pathways with the involvement of one or two of the carbonyl groups. Photoinduced reactions of cyclic alpha-diketones including N acetylisatin, phenanthrenequinone and isoquinolinetrione with different C=C containing compounds could take place via [2 + 2], [4 + 2] or [4 + 4] photocycloaddition pathways. We have investigated the photoreactions of these cyclic alpha-diketones with different types of alkenes and alkynes, with a focus on the unusual cascade reactions initiated by the photocycloaddition reactions of these cyclic alpha-diketones and the applications of these photocycloaddition reactions along with the transformation of the photocycloadducts. In this paper, we discuss the diverse photo-cycloaddition pathways found in the photocycloaddition of o-diones leading to various photocycloadducts and the potential applications of these reactions via further transformation reactions of the adducts. PMID- 23459303 TI - Simultaneous determination of flavonoids, isochlorogenic acids and triterpenoids in Ilex hainanensis Using high performance liquid chromatography coupled with diode array and evaporative light scattering detection. AB - A high performance liquid chromatography coupled with diode array and evaporative light scattering detection (HPLC-DAD-ELSD) method for simultaneous determination of eight major bioactive compounds including two flavonoids (rutin and eriodictyol-7-O-beta-D-glucopyranoside), two isochlorogenic acids (isochlorogenic acid A and isochlorogenic acid C) and four triterpenoids (ilexhainanoside D, ilexsaponin A1, ilexgenin A and ursolic acid) in Ilex hainanensis has been developed for the first time. The 283 nm wavelength was chosen for determination of two flavonoids and two isochlorogenic acids. ELSD was applied to determine four triterpenoids. The analysis was performed on an Agilent Zorbax SB-C18 column (250 * 4.6 mm i.d., 5 um) with gradient elution of 0.2% formic acid in water and acetonitrile. The method was validated for linearity, limit of detection, limit of quantification, precision, repeatability and accuracy. The proposed method has been successfully applied for simultaneous quantification of the analytes in four samples of Ilex hainanensis, which is helpful for quality control of this plant. PMID- 23459305 TI - Rare syringyl acylated flavonol glycosides from the aerial parts of Leonurus japonicus Houtt. AB - Five new syringyl acylated flavonol glycosides, named leonurusoides A (1), B (2), C (3), D (4), and E (5), together with one known one 6 were obtained from the aerial parts of Leonurus japonicus. Their structures were elucidated by chemical and spectroscopic methods (UV, IR, HRESI-TOF-MS, 1D and 2D NMR). Compounds 1-6 showed triglyceride (TG) accumulation inhibitory effects in free fatty acid induced HepG2 cells. PMID- 23459306 TI - The identification and characterization of chitotriosidase activity in pancreatin from porcine pancreas. AB - The versatile oligosaccharide biopolymers, chitin and chitosan, are typically produced using enzymatic processes. However, these processes are usually costly because chitinases and chitosanases are available in limited quantities. Fortunately, a number of commercial enzymes can hydrolyze chitin and chitosan to produce long chain chitin or chitosan oligosaccharides. Here, a platform to screen for enzymes with chitinase and chitosanase activities using a single gel with glycol chitin or glycol chitosan as a substrate was applied. SDS-resistant chitinase and chitosanase activities were observed for pancreatin. Its chitotriosidase had an optimal hydrolysis pH of 4 in the substrate specificity assay. This activity was thermally unstable, but independent of 2 mercaptoethanol. This is the first time a chitotriosidase has been identified in the hog. This finding suggests that oligochitosaccharides can be mass-produced inexpensively using pancreatin. PMID- 23459307 TI - Spin seebeck effect and thermal colossal magnetoresistance in graphene nanoribbon heterojunction. AB - Spin caloritronics devices are very important for future development of low-power consumption technology. We propose a new spin caloritronics device based on zigzag graphene nanoribbon (ZGNR), which is a heterojunction consisting of single hydrogen-terminated ZGNR (ZGNR-H) and double-hydrogen-terminated ZGNR (ZGNR-H2). We predict that spin-up and spin-down currents flowing in opposite directions can be induced by temperature difference instead of external electrical bias. The thermal spin-up current is considerably large and greatly improved compared with previous work in graphene. Moreover, the thermal colossal magnetoresistance is obtained in our research, which could be used to fabricate highly-efficient spin caloritronics MR devices. PMID- 23459309 TI - Perceptions of emotion expression and sibling-parent emotion communication in Latino and non-Latino white siblings of children with intellectual disabilities. AB - OBJECTIVE: Examine general emotion expression and sibling-parent emotion communication among Latino and non-Latino white (NLW) siblings of children with intellectual disabilities (ID) and matched comparisons. METHODS: 200 siblings (ages 8-15 years) completed the newly developed Sibling-Parent Emotion Communication Scale and existing measures of general emotion expression and psychosocial functioning. Preliminary analyses evaluated scale psychometrics across ethnicity. RESULTS: Structure and internal consistency of the emotion expression and communication measures differed by respondent ethnicity. Latino siblings endorsed more general emotion expression problems and marginally lower sibling-parent emotion communication than NLW siblings. Siblings of children with ID reported marginally more general emotion expression problems than comparisons. Emotion expression problems and lower sibling-parent emotion communication predicted more internalizing and somatic symptoms and poorer personal adjustment, regardless of ID status. Siblings of children with ID endorsed poorer personal adjustment. CONCLUSION: Cultural differences in emotion expression and communication may increase Latino siblings' risk for emotional adjustment difficulties. PMID- 23459310 TI - Construct validity of selected measures of physical activity beliefs and motives in fifth and sixth grade boys and girls. AB - OBJECTIVE: Scales used to measure selected social-cognitive beliefs and motives for physical activity were tested among boys and girls. METHODS: Covariance modeling was applied to responses obtained from large multi-ethnic samples of students in the fifth and sixth grades. RESULTS: Theoretically and statistically sound models were developed, supporting the factorial validity of the scales in all groups. Multi-group longitudinal invariance was confirmed between boys and girls, overweight and normal weight students, and non-Hispanic black and white children. The construct validity of the scales was supported by hypothesized convergent and discriminant relationships within a measurement model that included correlations with physical activity (MET * min/day) measured by an accelerometer. CONCLUSIONS: Scores from the scales provide valid assessments of selected beliefs and motives that are putative mediators of change in physical activity among boys and girls, as they begin the understudied transition from the fifth grade into middle school, when physical activity naturally declines. PMID- 23459311 TI - Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. AB - The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF), a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF-mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace. PMID- 23459312 TI - Effects of ulinastatin on coagulation in high-risk patients undergoing off-pump coronary artery bypass graft surgery. AB - BACKGROUND: Both systemic inflammatory reaction and regional myocardial ischemia/reperfusion injury may elicit hypercoagulability after off-pump coronary artery bypass grafting (OPCAB). We investigated the influence of ulinastatin, which suppresses the activity of polymorphonuclear leukocyte elastase and production of pro-inflammatory cytokines, on coagulation in patients with elevated high-sensitivity C-reactive protein (hsCRP) undergoing OPCAB. METHODS: Fifty patients whose preoperative hsCRP > 3.0 mg/L were randomly allocated into the ulinastatin (600,000 U) or control group. Serum concentrations of thrombin antithrombin complex (TAT) and prothrombin fragment 1+2 (F1+2) were measured preoperatively, immediately after surgery, and at 24 h after surgery, respectively. Secondary endpoints included platelet factor (PF)-4, amount of blood loss, and transfusion requirement. RESULTS: All baseline values of TAT, F1+2, and PF-4 were higher than the normal range in both groups. F1+2 was elevated in both groups at immediate, and at 24 h after surgery as compared to baseline value, without any significant intergroup differences. Remaining coagulation parameters, transfusion requirement and blood loss during operation and postoperative 24 h were not different between the two groups. CONCLUSIONS: Intraoperative administration of ulinastatin did not convey beneficial influence in terms of coagulation and blood loss in high-risk patients with elevated hsCRP undergoing multivessel OPCAB, who already exhibited hypercoagulability before surgery. PMID- 23459313 TI - Polymorphisms in migraine-associated gene, atp1a2, and ischemic stroke risk in a biracial population: the genetics of early onset stroke study. AB - In a recent meta-analysis migraine was associated with a two-fold increase in stroke risk. While the mechanism driving this association is unknown, one intriguing hypothesis is that migraineurs are genetically predisposed to developing ischemic stroke. Mutations in the ATP1A2 gene are implicated in familial hemiplegic migraine type II and increase the severity of ischemic brain injury in animal models. To further explore these observations, we assessed the association between ATP1A2 polymorphisms, migraine, and the risk of ischemic stroke in participants of the Genetics of Early-Onset Stroke Study, a population based case-control study of ischemic stroke among men and women aged 15-49. Using responses to a headache symptoms questionnaire, subjects were classified as having no migraine, or migraine with or without visual aura. Evaluating a total of 134 ATP1A2 polymorphisms genotyped using a combination of Illumina platforms (Cardiovascular Gene-centric 50 K SNP Array and HumanOmni1-Quad_v1-0_B Bead Chip), only one polymorphism (rs2070704) demonstrated a nominally significant association with stroke in an age-, gender-, ethnicity-adjusted model (OR = 0.83, 95% CI = 0.71-0.98, p = 0.025) and in a vascular risk factor model adjusting for age, gender, ethnicity, hypertension, diabetes, smoking, and myocardial infarction (OR = 0.74, 95% CI = 0.63-0.89, p = 0.001). Ethnicity-stratified analyses demonstrated a significant association for rs2070704 among African Americans (OR = 0.68, 95% CI = 0.53-0.90, p = 0.005) but not Caucasians (OR = 0.82, 95% CI = 0.64-1.04, p = 0.107). These associations were unchanged when migraine subtypes were included as co-variates. We did not observe an association between ATP1A2 polymorphisms and migraine. While our results do not demonstrate a strong relationship between ATP1A2 polymorphisms and migraine associated stroke risk, the results are hypothesis generating and indicate that an association between ATP1A2 polymorphisms and stroke risk may exist. Additional studies are required. PMID- 23459314 TI - In vivo microdamage is an indicator of susceptibility to initiation and propagation of microdamage in human femoral trabecular bone. AB - Microdamage has been cited as an important element of trabecular bone quality and fracture risk, as materials with flaws have lower modulus and strength than equivalent undamaged materials. However, the magnitude of the effect of damage on failure properties depends on its tendency to propagate. Human femoral trabecular bone from the neck and greater trochanter was subjected to one of compressive, torsional, or combined compression and torsion. The in vivo, new, and propagating damage were then quantified in thick sections under epifluorescent microscopy. Multiaxial loading, which was intended to represent an off-axis load such as a fall or accident, caused much more damage than either simple compression or shear, and similarly caused the greatest stiffness loss. In all cases, initiation of new damage far exceeded the propagation of existing damage. This may reflect stress redistribution away from damaged trabeculae, resulting in new damage sites. However, the accumulation of new damage was positively correlated with quantity of pre-existing damage in all loading modes, indicating that damaged bone is inherently more prone to further damage formation. Moreover, about 50% of in vivo microcracks propagated under each type of loading. Finally, damage formation was positively correlated to decreased compressive stiffness following both axial and shear loading. Taken together, these results demonstrate that damage in trabecular bone adversely affects its mechanical properties, and is indicative of bone that is more susceptible to further damage. PMID- 23459317 TI - Variation in infliximab administration practices in the treatment of pediatric inflammatory bowel disease. AB - OBJECTIVES: Infliximab is used increasingly to treat inflammatory bowel disease (IBD). Infliximab is supplied in 100-mg vials. Doses that are typically calculated as 5 mg . kg-1 . dose-1 are commonly rounded up or down to the nearest 100 mg. Variation in dosing practices is unknown. Underdosing based on weight may increase the risk for disease exacerbation, whereas overimmune suppression could increase the risk of infection. Children may be at greater risk from dosage rounding. We aimed to characterize infliximab dosing practices, the use of corticosteroid premedication, and duration of infusions among pediatric practitioners participating in the ImproveCareNow Network, a national collaboration to improve IBD care and outcomes. METHODS: A national survey of infliximab dosing practices was sent to 279 pediatric IBD practitioners from March to December 2011. Double data reconciliation, t test, and chi2 analyses were performed. RESULTS: The response rate was 74% (N = 207). Thirty-eight percent (78/207) indicated that their practice has no uniform approach to the rounding of doses. Of 114 respondents indicating a uniform approach to rounding doses, 43% always round up to the nearest 100 mg, 33% always round up or down to the nearest 100 mg, and 14% never round doses. In addition, 28% of respondents always premedicate with corticosteroids and 12% never premedicate. Of respondents indicating "it depends," 95% premedicate if there has been a previous infusion reaction, 46% if there has been a prolonged lapse between treatment doses, 40% if antibodies to infliximab are present, and 11% if giving infliximab monotherapy. The duration of infusions is most often 2 hours, but varies between 1 and 4 hours. CONCLUSIONS: Wide variation exists in the practice of infliximab administration in pediatric IBD. The effect of these variations on outcomes is unknown. PMID- 23459318 TI - Authors' response. PMID- 23459315 TI - Therapeutic efficacy of antibodies lacking Fcgamma receptor binding against lethal dengue virus infection is due to neutralizing potency and blocking of enhancing antibodies [corrected]. AB - Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease. PMID- 23459319 TI - Unique method to manage ingested magnets. PMID- 23459320 TI - Increasing incidence of paediatric inflammatory bowel disease in northern Stockholm County, 2002-2007. AB - OBJECTIVES: A sharp increase in paediatric (younger than 16 years) inflammatory bowel disease (IBD) incidence was observed in northern Stockholm County, Sweden, in 1990-2001. The increasing incidence was primarily explained by a rising incidence of Crohn disease (CD). Here, we present an update on the trends in incidence of paediatric IBD, 2002-2007. METHOD: Medical records of all children diagnosed as having suspected IBD in northern Stockholm County, 2002-2007, were scrutinised using defined diagnostic criteria. Disease extension, localisation, and behaviour at diagnosis were classified within the framework of the Paris classification. RESULT: A total of 133 children were diagnosed as having IBD 2002 2007 corresponding to a sex- and age-standardised incidence (per 10 person-years) for paediatric IBD of 12.8 (95% CI 10.8-15.2). The standardised incidence was 9.2 (95% CI 7.5-11.2) for CD and 2.8 (95% CI 1.9-4.0) for ulcerative colitis (UC). A significant increasing incidence of UC (P < 0.05) was observed during the study period. No temporal trend was observed for the incidence of CD. CONCLUSIONS: The incidence rate of paediatric IBD in northern Stockholm was significantly higher in 2002-2007 than that observed in our earlier study covering 1990-2001. The former sharp increase in incidence of paediatric CD seems, however, to have levelled out, although at a higher rate than reported from most other regions in the world. Although CD was still predominant, the observed increase in incidence of UC during the study period is notable. PMID- 23459321 TI - Body fat reference percentiles on healthy affluent Indian children and adolescents to screen for adiposity. AB - BACKGROUND: Indian children and adolescents have higher body fat percentage at a given body mass index than their Western counterparts. OBJECTIVE: To create gender-specific percentile curves for total body fat percentage (TBFP), total body fat mass (TBFM), fat mass index (FMI) and android:gynoid (A:G) ratio for screening adiposity in healthy Indian children. METHODS: Data on body composition by dual-energy X-ray absorptiometry were obtained from a cross-sectional study conducted from May 2006-July 2010 on 888 (462 boys) apparently healthy children from affluent area schools and colleges in Pune city, India. Reference percentile curves were derived for boys and girls for TBFP, TBFM, FMI and A:G ratio. These percentile curves were validated using data on metabolic syndrome risk components in separate sample of 332 (148 boys) children. RESULTS: The median TBFP increased little (4%) from 5 to 18 years of age in boys compared with that in girls (19%). TBFP percentiles showed plateau after 13 years of age in boys, whereas a steady increase was seen till 18 years in girls. The median TBFM increased less (7 kg) from 5 to 18 years in boys compared with that in girls (13.4 kg). The curve for median FMI in boys was relatively flat with FMI remaining near 3 kg m(-2) after 13 years of age, whereas in girls median FMI increased with age till about 15 years of age. A:G ratio curves increased with age in both boys and girls up to 18 years of age. In a separate sample of 332 children, according to percentiles developed in the current study, children with TBFP/TBFM/FMI percentiles between 85th and 95th or >95th percentile had significantly higher metabolic risk parameters as compared with those with <85th percentile (P<0.05). CONCLUSIONS: Percentile curves developed in the current study would be useful in assessment of adiposity and thus cardiometabolic risk in Indian children. PMID- 23459322 TI - Cortico-limbic responsiveness to high-calorie food images predicts weight status among women. AB - OBJECTIVES: Excessive weight gain and obesity are currently among the world's major threats to health. Women show significantly higher rates of obesity and eating disorders relative to men, but the factors contributing to these gender differences remain uncertain. We examined the correlations between regional brain responses to images of high-calorie versus low-calorie foods and self-reported motivational status, including ratings of general appetite, overeating propensity, state hunger and desire for specific foods. SUBJECTS: Thirty-eight healthy right-handed adults (22 male; 16 female) ages 18-45 participated. There were no differences between males and females with regard to age or body mass index (BMI). RESULTS: Overall, motivational status correlated significantly with activation within the amygdala, insula and orbitofrontal cortex. Regional activation was then used to predict BMI, an indicator of long-term food consumption and energy expenditure. The combined model was significant, accounting for 76% of the variance in BMI for women, whereas the same regions were not predictive of weight status among men. CONCLUSIONS: Findings suggest that long-term weight status is related to visual responsiveness to calorie-dense food imagery among women. PMID- 23459323 TI - Randomized controlled trial of behavioral treatment for comorbid obesity and depression in women: the Be Active Trial. AB - OBJECTIVE: Depression is associated with increased risk for obesity and worse weight loss treatment outcomes. The purpose of the present study was to test the hypothesis that delivering evidence-based behavior therapy for depression before a lifestyle weight loss intervention improves both weight loss and depression. DESIGN: In a randomized controlled trial, obese women with major depressive disorder (N=161, mean age=45.9 (s.d.: 10.8) years) were randomized to brief behavior therapy for depression treatment followed by a lifestyle intervention (BA) or a lifestyle intervention only (LI). Follow-up occurred at 6 and 12 months. Main outcome measures included weight loss and depression symptoms. RESULTS: Intention-to-treat analyses revealed both conditions lost significant weight, but no differences between conditions in weight change at 6 months (BA= 3.0%, s.e.=-0.65%; LI=-3.7%, s.e.=0.63%; P=0.48) or 12 months (BA=-2.6%, s.e.=0.77%; LI=-3.1%, s.e.=0.74%; P=0.72). However, the BA condition evidenced significantly greater improvement in Beck Depression Inventory-II scores relative to the LI condition at both 6 months (BA mean change=-12.5, s.d.=0.85; LI mean change=-9.2, s.d.=0.80, P=0.005) and 12 months (BA mean change=-12.6, s.d.=0.97; LI mean change=-9.9, s.d.=0.93; P=0.045). Participants who experienced depression remission by 6 months (61.2%) lost greater weight (mean=-4.31%; s.e.=0.052) than those who did not (39.7%; mean=-2.47%, s.e.=0.53; P=.001). CONCLUSION: Adding behavior therapy to a lifestyle intervention results in greater depression remission but does not improve weight loss within 1 year. Improvement in depression is associated with greater weight loss. PMID- 23459324 TI - Correlation between body mass index and gut concentrations of Lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. AB - BACKGROUND: Genus and species level analysis is the best way to characterize alterations in the human gut microbiota that are associated with obesity, because the clustering of obese and lean microbiotas increases with the taxonomic depth of the analysis. Bifidobacterium genus members have been associated with a lean status, whereas different Lactobacillus species are associated both with a lean and an obese status. OBJECTIVES AND METHODS: We analyzed the fecal concentrations of Bacteroidetes, Firmicutes, Methanobrevibacter smithii, the genus Lactobacillus, five other Lactobacillus species previously linked with lean or obese populations, Escherichia coli and Bifidobacterium animalis in 263 individuals, including 134 obese, 38 overweight, 76 lean and 15 anorexic subjects to test for the correlation between bacterial concentration and body mass index (BMI). Of these subjects, 137 were used in our previous study. FINDINGS: Firmicutes were found in >98.5%, Bacteroidetes in 67%, M. smithii in 64%, E. coli in 51%, Lactobacillus species between 17 and 25% and B. animalis in 11% of individuals. The fecal concentration of Lactobacillus reuteri was positively correlated with BMI (coefficient=0.85; 95% confidence interval (CI) 0.12-0.58; P=0.02) in agreement with what was reported for Lactobacillus sakei. As reported, B. animalis (coefficient=-0.84; 95% CI -1.61 to -0.07; P=0.03) and M. smithii (coefficient=-0.43, 95% CI -0.90 to 0.05; P=0.08) were negatively associated with the BMI. Unexpectedly, E. coli was found here for the first time to negatively correlate with the BMI (coefficient=-1.05; 95% CI -1.60 to -0.50; P<0.001). CONCLUSION: Our findings confirm the specificity of the obese microbiota and emphasize the correlation between the concentration of certain Lactobacillus species and obesity. PMID- 23459326 TI - Rupture Following Biceps-to-Triceps Tendon Transfer in Adolescents and Young Adults With Spinal Cord Injury:: An Analysis of Potential Causes. AB - BACKGROUND: Tendon transfer surgery can restore elbow extension in approximately 70% of persons with tetraplegia and often results in antigravity elbow extension strength. However, we have noted an almost 15% rupture/attenuation rate. OBJECTIVE: This investigation was conducted to analyze potential causes in adolescents/young adults with spinal cord injury (SCI) who experienced tendon rupture or attenuation after biceps-to-triceps transfer. METHODS: Medical charts of young adults with SCI who underwent biceps-to-triceps transfer and experienced tendon rupture or attenuation were reviewed. Data collected by retrospective chart review included general demographics, surgical procedure(s), use and duration of antibiotic treatment, time from tendon transfer surgery to rupture/attenuation, and method of diagnosis. RESULTS: Twelve subjects with tetraplegia (mean age, 19 years) who underwent biceps-to-triceps reconstruction with subsequent tendon rupture or attenuation were evaluated. Mean age at time of tendon transfer was 18 years (range, 14-21 years). A fluoroquinolone was prescribed for 42% (n=5) of subjects. Tendon rupture was noted in 67% (n=8), and attenuation was noted in 33% (n=4). Average length of time from surgery to tendon rupture/attenuation was 5.7 months (range, 3-10 months). CONCLUSION: Potential contributing causes of tendon rupture/attenuation after transfer include surgical technique, rehabilitation, co-contraction of the transfer, poor patient compliance, and medications. In this cohort, 5 subjects were prescribed fluoroquinolones that have a US Food and Drug Administration black box concerning tendon ruptures. Currently, all candidates for upper extremity tendon transfer reconstruction are counseled on the effects of fluoroquinolones and the potential risk for tendon rupture. PMID- 23459325 TI - Pharmaceutical utilisation and costs before and after bariatric surgery. AB - OBJECTIVE: To determine whether pharmaceutical utilisation and costs change after bariatric surgery. SUBJECTS: Total population of Australians receiving Medicare subsidised laparoscopic adjustable gastric banding (LAGB) in 2007 (n=9542). DESIGN: Computerised data linkage with Medicare, Australia's universal tax-funded health insurance scheme. Pharmaceuticals relating to obesity-related disease and postsurgical management were assigned to therapeutic categories and analysed. The mean annual numbers of pharmaceutical prescriptions for each category were compared over the 4-year period from the year before LAGB (2006) to 2 years after LAGB (2009) using utilisation incidence rate ratios (IRRs). RESULTS: The population was mainly female (77.7%) and age was normally distributed with the majority (60.7%) of subjects aged between 35-54 years. Utilisation rates decreased significantly after LAGB in the following therapeutic categories: diabetes (IRR 0.51, IRR 95% CI 0.50-0.53, mean annual cost differences per person $30), cardiovascular (0.81, 0.80-0.82, $29), psychiatric (0.95, 0.93-0.97, $13), rheumatic and inflammatory disorders (0.51, 0.49-0.53, $10) and asthma (0.78, 0.75-0.81, $9). In contrast, significantly greater utilisation was observed in the pain (1.28, 1.23-1.32, $12), gastrointestinal tract disorder (1.04, 1.02 1.07, $5) and anaemia/vitamins (2.34, 2.01-2.73, $4) therapeutic categories. When the defined categories were combined, a net reduction in pharmaceutical utilisation was observed, from 10.5 to 9.6 pharmaceuticals prescribed per person/year, and costs decreased from $AUD517 to $AUD435 per year in 2009 prices. CONCLUSION: Relative to the year before LAGB, overall pharmaceutical utilisation was reduced in the 2 years after the year of LAGB surgery, demonstrating that bariatric surgery can lead to reductions in pharmaceutical utilisation in the 'real world' setting. The greatest absolute cost reductions were observed in the therapies to treat diabetes and cardiovascular disease. PMID- 23459327 TI - One-year follow-up of femtosecond laser-assisted penetrating keratoplasty. AB - BACKGROUND: The purpose of this report is to describe the initial outcomes of femtosecond laser-assisted penetrating keratoplasty. METHODS: This retrospective surgical case series consisted of 10 eyes from 10 patients undergoing penetrating keratoplasty at a tertiary center. Femtosecond laser was used to perform a zig square incision on the donor cornea with matched dimensions on the recipient cornea. Outcomes measured included: unaided visual acuity and best spectacle corrected visual acuity preoperatively and at one, 3, 6, and 12 months postoperatively; manifest refractive and topographic astigmatism at 3, 6, and 12 months postoperatively; and endothelial cell density loss, calculated at the end of the one-year follow-up period. RESULTS: At one-year follow-up, there was an improvement in unaided visual acuity from a mean preoperative logMAR of 1.67 to 0.44, and best spectacle-corrected visual acuity from a mean preoperative logMAR of 1.33 to 0.13. By postoperative month 3, mean manifest refractive and topographic astigmatism was 2.31 +/- 1.41 D and 2.59 +/- 1.57 D, respectively. The mean reduction in endothelial cell density was 20.7% after one year of follow up. CONCLUSION: Femtosecond laser-assisted penetrating keratoplasty provided a good visual outcome and early visual rehabilitation due to precise graft-host alignment and reduced astigmatism in the early postoperative months. PMID- 23459328 TI - Extracts, anthocyanins and procyanidins from Aronia melanocarpa as radical scavengers and enzyme inhibitors. AB - Extracts, subfractions, isolated anthocyanins and isolated procyanidins B2, B5 and C1 from the berries and bark of Aronia melanocarpa were investigated for their antioxidant and enzyme inhibitory activities. Four different bioassays were used, namely scavenging of the diphenylpicrylhydrazyl (DPPH) radical, inhibition of 15-lipoxygenase (15-LO), inhibition of xanthine oxidase (XO) and inhibition of alpha-glucosidase. Among the anthocyanins, cyanidin 3-arabinoside possessed the strongest and cyanidin 3-xyloside the weakest radical scavenging and enzyme inhibitory activity. These effects seem to be influenced by the sugar units linked to the anthocyanidin. Subfractions enriched in procyanidins were found to be potent alpha-glucosidase inhibitors; they possessed high radical scavenging properties, strong inhibitory activity towards 15-LO and moderate inhibitory activity towards XO. Trimeric procyanidin C1 showed higher activity in the biological assays compared to the dimeric procyanidins B2 and B5. This study suggests that different polyphenolic compounds of A. melanocarpa can have beneficial effects in reducing blood glucose levels due to inhibition of alpha glucosidase and may have a potential to alleviate oxidative stress. PMID- 23459329 TI - Developing a heme iron database for meats according to meat type, cooking method and doneness level. AB - BACKGROUND: Animal studies have demonstrated that iron may be related to carcinogenesis, and human studies found that heme iron can increase the formation of N-nitroso compounds, which are known carcinogens. OBJECTIVES: One of the postulated mechanisms linking red meat intake to cancer risk involves iron. Epidemiologic studies attempt to investigate the association between heme iron intake and cancer by applying a standard factor to total iron from meat. However, laboratory studies suggest that heme iron levels in meat vary according to cooking method and doneness level. We measured heme iron in meats cooked by different cooking methods to a range of doneness levels to use in conjunction with a food frequency questionnaire to estimate heme iron intake. METHODS: Composite meat samples were made to represent each meat type, cooking method and doneness level. Heme iron was measured using atomic absorption spectrometry and inductively coupled plasma-atomic emission spectrometry. RESULTS: Steak and hamburgers contained the highest levels of heme iron, pork and chicken thigh meat had slightly lower levels, and chicken breast meat had the lowest. CONCLUSIONS: Although heme iron levels varied, there was no clear effect of cooking method or doneness level. We outline the methods used to create a heme iron database to be used in conjunction with food frequency questionnaires to estimate heme iron intake in relation to disease outcome. PMID- 23459330 TI - Effects of hypothyroidism on expression of CRMP2B and ARPC5 during development of the rat frontal cortex. AB - Congenital hypothyroidism (CH) can lead to irreversible central nervous system (CNS) damage. However, the pathogenesis of the developmental brain disorders caused by CH has not been completely elucidated. ARPC5 and CRMP2 are closely associated with neurite outgrowth in brain development. Thus, the aim of the present study was to determine whether CRMP2B and ARPC5 expression is altered in the developing cerebral cortex of rats with CH. Control rats and rats with hypothyroidism were sacrificed at birth and at 15 days postpartum. We performed qRT-PCR to detect differences in the crmp2B and arpc5 mRNA expression in the right half of the frontal cortex of these rats. Western blotting was then used to detect differences in CRMP2B and ARPC5 protein expression. Furthermore, immunohistochemical analysis was performed on the left half of the frontal cortex to detect abnormal localization of CRMP2B and ARPC5. Results showed increased expression of the nuclear short isoform of CRMP2B and decreased expression of full-length CRMP2B and ARPC5 in cortical neurons of rats with hypothyroidism. These findings demonstrate that reduced levels of thyroid hormones can inhibit the expression of full-length CRMP2B and ARPC5 and promote nuclear transformation of the short isoform of CRMP2B. CRMP2B and ARPC5 may participate in CNS injury mediated by hypothyroidism by inducing neurite outgrowth inhibition and cytoskeletal protein disorganization. PMID- 23459331 TI - The "seagull cry" in a patient with a cerebral arteriovenous malformation. AB - INTRODUCTION: The "seagull cry" is an acoustic phenomenon heard during duplex ultrasound. It is caused by harmonic covibrations of a vessel wall in the presence of high-velocity blood flow. It has been reported in a few cases of cerebrovascular disease, such as severe intracranial stenosis, vasospasm or carotid-cavernous fistula. MATERIAL AND METHODS: A 35-year-old man underwent transcranial color-coded sonography (TCCS) for work-up of a severe new-onset headache. RESULTS: Doppler spectral analysis of the right intracranial carotid bifurcation revealed multiple pairs of mirror-image parallel strings, and a high frequency seagull cry was heard. Computed tomography-angiography and magnetic resonance imaging of the brain showed an arteriovenous malformation in the right temporal lobe. DISCUSSION: The seagull cry is a "musical murmur" with single or multiple frequency that sounds like a musical tone. This is the first report of this phenomenon in a cerebral arteriovenous malformation. PMID- 23459332 TI - Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28. AB - In embryonic stem cells, removal of oxidatively damaged proteins is triggered upon the first signs of cell fate specification but the underlying mechanism is not known. Here, we report that this phase of differentiation encompasses an unexpected induction of genes encoding the proteasome activator PA28alphabeta (11S), subunits of the immunoproteasome (20Si), and the 20Si regulator TNFalpha. This induction is accompanied by assembly of mature PA28-20S(i) proteasomes and elevated proteasome activity. Inhibiting accumulation of PA28alpha using miRNA counteracted the removal of damaged proteins demonstrating that PA28alphabeta has a hitherto unidentified role required for resetting the levels of protein damage at the transition from self-renewal to cell differentiation. PMID- 23459333 TI - Order-disorder transition in the molecular orientation during initial growth of organic thin film. AB - We report on the identification of molecular orientation and its order-disorder transition during the initial growth of 1,3-bis(N-carbazolyl)benzene (mCP) thin films on a highly ordered pyrolytic graphite (HOPG) surface by using photoelectron spectroscopy (PES). Theoretical PES amplitudes using a quantum mechanical calculation that adapts independent atomic center approximation (IAC) were calculated to compare with experimental observations. At low coverage, an equilibrium orientation of isolated adsorbate was estimated. As the coverage increases, the interaction between adsorbates becomes dominant and raises the disorder, which results in changes in the PES shapes as well as the line broadening of each peak. PMID- 23459335 TI - Striking multiple synergies created by combining reduced graphene oxides and carbon nanotubes for polymer nanocomposites. AB - The extraordinary properties of carbon nanotubes (CNTs) and graphene stimulate the development of advanced composites. Recently, several studies have reported significant synergies in the mechanical, electrical and thermal conductivity properties of polymer nanocomposites by incorporating their nanohybrids. In this work, we created polypropylene nanocomposites with homogeneous dispersion of CNTs and reduced graphene oxides via a facile polymer-latex-coating plus melt-mixing strategy, and investigated their synergistic effects in their viscoelastic, gas barrier, and flammability properties. Interestingly, the results show remarkable synergies, enhancing their melt modulus and viscosity, O2 barrier, and flame retardancy properties and respectively exhibiting a synergy percentage of 15.9%, 45.3%, and 20.3%. As previously reported, we also observed remarkable synergistic effects in their tensile strength (14.3%) and Young's modulus (27.1%), electrical conductivity (32.3%) and thermal conductivity (34.6%). These impressive results clearly point towards a new strategy to create advanced materials by adding binary combinations of different types of nanofillers. PMID- 23459334 TI - A direct comparison of efficacy between desloratadine and rupatadine in seasonal allergic rhinoconjunctivitis: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: H1-antihistamines are recommended as the first-line symptomatic treatment of allergic rhinitis. The objective of this study was to evaluate the effects of rupatadine (RUP) versus desloratadine (DES) in subjects with seasonal allergic rhinitis (SAR). METHOD: To assess the efficacy and safety of RUP in SAR in comparison with placebo (PL) and DES. A randomized, double-blind, multicenter, international, and PL-controlled study was carried out. The main selection criteria included SAR patients over 12 years old with a positive prick test to a relevant seasonal allergen for the geographic area. Symptomatic patients at screening with a nasal symptom sum score of >=6 points (nasal discharge, nasal obstruction, sneezing, and nasal pruritus), a non-nasal score of >=3 points (ocular pruritus, ocular redness, and tearing eyes), and a rhinorrhea score of >=2 points with laboratory test results and electrocardiography within acceptable limits were included in the study. Change from baseline in the total symptom score (T7SS) over the 4-week treatment period (reflective evaluation) was considered the primary efficacy variable. Secondary efficacy measures included total nasal symptom score (T4NSS) and conjunctival symptom score (T3NNSS), both of which are reflective and instantaneous evaluations. Furthermore questions related to quality of life (eg, sleep disturbances or impairment of daily activities) have also been evaluated. Safety was assessed according to adverse events reported, as well as laboratory and electrocardiography controls. RESULTS: A total of 379 patients were randomized, of which 356 were included and allocated to PL (n = 122), RUP (n = 117), or DES (n = 117). Mean change of T7SS over the 4 week treatment period was significantly reduced in the RUP (-46.1%, P = 0.03) and DES (-48.9%, P = 0.01) groups, compared with PL. Similarly, RUP and DES were comparable and significantly superior to PL for all secondary endpoints, including nasal and conjunctival symptoms and patients' and investigator's overall clinical opinions. Symptom score evaluation (both reflective and instantaneous evaluations) throughout the treatment period showed a progressive and maintained significant improvement with both treatments at day 7 (P = 0.01), day 14 (P = 0.007), and day 21 (P = 0.01) in comparison with PL. Adverse events were scarce and were similar in both treatment groups. Electrocardiography (QTc) and lab test results did not show any relevant findings. CONCLUSION: RUP is a very good choice for SAR due to its contribution to the improvement of nasal (including obstruction) and non-nasal symptoms to a similar degree as DES. PMID- 23459336 TI - Proposed International Spinal Cord Injury Pain (ISCIP) Classification:: Preliminary Validation Data. PMID- 23459337 TI - The potential influence of masculine identity on health-improving behavior in midlife and older African American men. AB - OBJECTIVE: To gain a greater understanding of masculinity and its potential influence on health-improving behavior in midlife and older African American (AA) men. METHODS: Forty-nine AA men aged 45-88 years completed in-depth interviews to ascertain their perspectives on masculinity, how masculine identity in this population might be influenced by age and physical activity level, or how it might impact health. Taped interviews were transcribed and organized for analysis with common themes identified by multiple researchers. RESULTS: Most often cited attributes of someone considered "manly" included a leader of a family/household, provider, strong work ethic, and masculine physique. Terms such as responsible, principled, and man of character also described the typical man. Potential negative and positive influences of manhood on health included avoiding health care appointments and being a good example to children/others, respectively. Themes associated with age-related changes in manhood were acceptance and being more health conscious. Elements associated with how manhood was influenced by AA race included stress and perseverance. CONCLUSIONS: Midlife and older AA men in this study primarily expressed views of masculinity that fit the traditional perception of manhood. However, the attributes revealed, such as family provider, responsibility, self-reliance, and perseverance, were viewed as having potential for both negative and positive impacts on health and health-improving behaviors. It will be essential to integrate these prevalent attributes of masculine identity into health promotion interventions such that they facilitate positive behavior change while not competing with gender role norms among this vulnerable group of men. PMID- 23459338 TI - Dichlorido{N-[2-(diphenylphosphanyl)benzylidene]-2-methylaniline}palladium(II) acetonitrile monosolvate. AB - The title imino-phosphine compound, [PdCl2(C26H22NP)].CH3CN, was prepared by reaction of N-[2-(diphenylphosphanyl)benzylidene]-2-methylaniline with dichlorido(cycloocta-1,5-diene)palladium(II) in dry CH2Cl2. The Pd(II) cation is coordinated by the P and N atoms of the bidentate chelating ligand and by two chloride anions, generating a distorted square-planar coordination geometry. There is a detectable trans influence for the chloride ligands. The methyl group present in this structure has an influence on the crystal packing. PMID- 23459339 TI - A polymeric cobalt(II) complex derived from citric acid (H4cit) and 2,6 diaminopurine (dap): {[Co4(cit)2(dap)4(H2O)4].6.35H2O}n. AB - Poly[[tetraaquadi-MU4-citrato-tetrakis(2,6-diaminopurine)tetracobalt(II)] 6.35 hydrate], {[Co4(C6H4O7)2(C5H6N6)4(H2O)4].6.35H2O}n, presents three different types of Co(II) cations in the asymmetric unit, two of them lying on symmetry elements (one on an inversion centre and the other on a twofold axis). The main fragment is further composed of one fully deprotonated citrate (cit) tetraanion, two 2,6-diaminopurine (dap) molecules and two aqua ligands. The structure is completed by a mixture of fully occupied and disordered solvent water molecules. The two independent dap ligands are neutral and the cit tetraanion provides for charge balance, compensating the 4+ cationic charge. There are two well defined coordination geometries in the structure. The simplest is mononuclear, with the Co(II) cation arranged in a regular centrosymmetric octahedral array, coordinated by two aqua ligands, two dap ligands and two O atoms from the beta-carboxylate groups of the bridging cit tetraanions. The second, more complex, group is trinuclear, bisected by a twofold axis, with the metal centres coordinated by two cit tetraanions through their alpha- and beta-carboxylate and alpha-hydroxy groups, and by two dap ligands bridging through one of their pyridine and one of their imidazole N atoms. The resulting coordination geometry around each metal centre is distorted octahedral. Both groups are linked alternately to each other, defining parallel chains along [201], laterally interleaved and well connected via hydrogen bonding to form a strongly coupled three-dimensional network. The compound presents a novel MU4-kappa(5)O:O,O':O',O'',O''':O'''' mode of coordination of the cit tetraanion. PMID- 23459340 TI - A two-dimensional silver-iodide organic network constructed from a unique [Ag6I6] hexagonal prism-based one-dimensional column motif. AB - A novel two-dimensional coordination polymer, poly[[MU2-1,3-bis(2-methyl-1H imidazol-1-yl)propane]di-MU4-iodido-di-MU3-iodido-silver(I)], [Ag4I4(C11H16N4)]n, (I), has been synthesized by solvothermal reaction of AgNO3, KI and 1,3-bis(2 methyl-1H-imidazol-1-yl)propane (bmimp). In (I), the two unique Ag(I) cations have AgNI3 and AgI4 four-coordinated tetrahedral geometries. The bmimp ligand has imposed twofold symmetry. The Ag(I) cations and iodide anions form a unique one dimensional polymeric column motif incorporating [Ag6I6] hexagonal prisms, which are then connected by bmimp ligands to form two-dimensional organic-inorganic layers. The layers are arranged in parallel in an ABAB fashion and are packed into the resultant three-dimensional supramolecular framework by van der Waals interactions. PMID- 23459341 TI - Cadmium(II) iodide and thiocyanate complexes adopted by polycyclic 1,4 bis(pyridazin-4-yl)benzene: interplay of coordination and pi-pi stacking interactions. AB - New complexes containing the 1,4-bis(pyridazin-4-yl)benzene ligand, namely diaquatetrakis[1,4-bis(pyridazin-4-yl)benzene-kappaN(2)]cadmium(II) hexaiodidodicadmate(II), [Cd(C14H10N4)4(H2O)2][Cd2I6], (I), and poly[[MU-1,4 bis(pyridazin-4-yl)benzene-kappa(2)N(2):N(2')]bis(MU-thiocyanato kappa(2)N:S)cadmium(II)], [Cd(NCS)2(C14H10N4)]n, (II), demonstrate the adaptability of the coordination geometries towards the demands of slipped pi-pi stacking interactions between the extended organic ligands. In (I), the discrete cationic [Cd-N = 2.408 (3) and 2.413 (3) A] and anionic [Cd-I = 2.709 (2)-3.1201 (14) A] entities are situated across centres of inversion. The cations associate via complementary O-H...N(2') hydrogen bonding [O...N = 2.748 (4) and 2.765 (4) A] and extensive triple pi-pi stacking interactions between pairs of pyridazine and phenylene rings [centroid-centroid distances (CCD) = 3.782 (4)-4.286 (3) A] to yield two-dimensional square nets. The [Cd2I6](2-) anions reside in channels generated by packing of successive nets. In (II), the Cd(II) cation lies on a centre of inversion and the ligand is situated across a centre of inversion. A two-dimensional coordination array is formed by crosslinking of linear [Cd(MU NCS)2]n chains [Cd-N = 2.3004 (14) A and Cd-S = 2.7804 (5) A] with N(2):N(2') bidentate organic bridges [Cd-N = 2.3893 (12) A], which generate pi-pi stacks by double-slipped interactions between phenylene and pyridazine rings [CCD = 3.721 (2) A]. PMID- 23459342 TI - A novel amido-pyrophosphate Mn(II) chelate complex with the synthetic ligand O{P(O)[NHC(CH3)3]2}2 (L): [Mn(L)2{OC(H)N(CH3)2}2]Cl2.2H2O. AB - The title complex, trans-bis(dimethylformamide-kappaO)bis{N,N'-N'',N'''-tetra tert-butyl[oxybis(phosphonic diamide-kappaO)]}manganese(II) dichloride dihydrate, [Mn(C16H40N4O3P2)2(C3H7NO)2]Cl2.2H2O, is the first example of a bis-chelate amido pyrophosphate (pyrophosphoramide) complex containing an O[P(O)(NH)2]2 fragment. Its asymmetric unit contains half of the complex dication, one chloride anion and one water molecule. The Mn(II) atom, located on an inversion centre, is octahedrally coordinated, with a slight elongation towards the monodentate dimethylformamide ligand. Structural features of the title complex, such as the P=O bond lengths and the planarity of the chelate ring, are compared with those of previously reported complexes with six-membered chelates involving the fragments C(O)NHP(O), (X)NP(O) [X = C(O), C(S), S(O)2 and P(O)] and O[P(O)(N)2]2. This analysis shows that the six-membered chelate rings are less puckered in pyrophosphoramide complexes containing a P(O)OP(O) skeleton, such as the title compound. The extended structure of the title complex involves a linear aggregate mediated by N-H...O and N-H...Cl hydrogen bonds, in which the chloride anion is an acceptor in two additional O-H...Cl hydrogen bonds. PMID- 23459343 TI - A helical coordination polymer of zinc(II), 4-hydroxybenzohydrazide and sulfate ions. AB - In the structure of the novel zinc complex catena-poly[[diaqua(4 hydroxybenzohydrazide)zinc(II)]-MU-sulfato], [Zn(SO4)(C7H8N2O2)(H2O)2]n, the complex cations are linked by sulfate counter-ions into helical polymeric chains extending along the b axis. Each helix is stabilized by six intrachain hydrogen bonds involving stronger O-H...O (1.83-2.06 A) and weaker N-H...O (2.20-2.49 A) interactions. The Zn(II) atom displays a distorted octahedral geometry formed by the 4-hydroxybenzohydrazide ligand, two water molecules and two SO4(2-) ions, which is very similar to the metal-atom environment in a previously reported Co(II) complex [Zaslona, Drozdzewski & Kubiak (2010). J. Mol. Struct. 982, 1-8], especially the Zn-O and Zn-N bond lengths of 2.0453 (12)-2.1602 (9) and 2.1118 (12) A, respectively. PMID- 23459344 TI - Cobalt(II) and cadmium(II) square grids supported with 4,4'-bipyrazole and accommodating 3-carboxyadamantane-1-carboxylate. AB - In poly[[bis(MU-4,4'-bi-1H-pyrazole-kappa(2)N(2):N(2'))bis(3-carboxyadamantane-1 carboxylato-kappaO(1))cobalt(II)] dihydrate], {[Co(C12H15O4)2(C6H6N4)2].2H2O}n, (I), the Co(2+) cation lies on an inversion centre and the 4,4'-bipyrazole (4,4' bpz) ligands are also situated across centres of inversion. In its non isomorphous cadmium analogue, {[Cd(C12H15O4)2(C6H6N4)2].2H2O}n, (II), the Cd(2+) cation lies on a twofold axis. In both compounds, the metal cations adopt an octahedral coordination, with four pyrazole N atoms in the equatorial plane [Co-N = 2.156 (2) and 2.162 (2) A; Cd-N = 2.298 (2) and 2.321 (2) A] and two axial carboxylate O atoms [Co-O = 2.1547 (18) A and Cd-O = 2.347 (2) A]. In both structures, interligand hydrogen bonding [N...O = 2.682 (3)-2.819 (3) A] is essential for stabilization of the MN4O2 environment with its unusually high (for bulky adamantanecarboxylates) number of coordinated N-donor co-ligands. The compounds adopt two-dimensional coordination connectivities and exist as square grid [M(4,4'-bpz)2]n networks accommodating monodentate carboxylate ligands. The interlayer linkage is provided by hydrogen bonds from the carboxylic acid groups via the solvent water molecules [O...O = 2.565 (3) and 2.616 (3) A] to the carboxylate groups in the next layer [O...O = 2.717 (3)-2.841 (3) A], thereby extending the structures in the third dimension. PMID- 23459345 TI - A potential molecular ferroelectric material: poly[[bis(1-aza-4 azoniabicyclo[2.2.2]octane)di-MU3-chlorido-tetra-MU2-chlorido dichloridotricadmium(II)] dihydrate]. AB - The title compound, {[Cd3(C6H13N2)2Cl8].2H2O}n, consists of pendant protonated cationic diamine ligands bonded to an anionic one-dimensional coordination polymer chloridocadmate scaffold. Each coordination chain features two kinds of Cd(II) centre, each with distorted octahedral coordination geometry. One Cd(II) cation lies on a centre of inversion and is coordinated by six bridging chloride ligands, while the other is coordinated by four bridging chloride ligands, one terminal chloride ligand and a 1-aza-4-azoniabicyclo[2.2.2]octane aza N atom. This gives a reversible corner-sharing half-cubic linear polymer that lies along the crystallographic a direction. The chains interact through hydrogen bonding with solvent water, with each water molecule accepting one N-H...O interaction from a cation and donating to two O-H...Cl interactions with anionic chains, thus linking three separate chains and completing the packing structure. PMID- 23459346 TI - A one-dimensional coordination polymer with a three-dimensional supramolecular framework: catena-poly[[[(3,4,7,8-tetramethyl-1,10-phenanthroline)cadmium(II)] MU3-4,4'-sulfonyldibenzoato] trihydrate]. AB - In the title mixed-ligand metal-organic polymeric compound, {[Cd(C14H8O6S)(C16H16N2)].3H2O}n, the asymmetric unit contains a crystallographically unique Cd(II) atom, one doubly deprotonated 4,4' sulfonyldibenzoic acid (H2SDBA) ligand, one 3,4,7,8-tetramethyl-1,10 phenanthroline (TMPHEN) molecule and three solvent water molecules. Each Cd(II) centre is six-coordinated by two O atoms from a chelating carboxylate group of a SDBA(2-) ligand, two O atoms from monodentate carboxylate groups of two different SDBA(2-) ligands and two N atoms from a chelating TMPHEN ligand. There are two coordination patterns for the carboxylate groups of the SDBA(2-) ligand, with one in a MU1-eta(1):eta(1) chelating mode and the other in a MU2-eta(1):eta(1) bis monodentate mode. Single-crystal X-ray diffraction analysis revealed that the title compound is a one-dimensional double-chain polymer containing 28-membered rings based on the [Cd2(CO2)2] rhomboid subunit. More interestingly, a chair shaped water hexamer cluster is observed in the compound. PMID- 23459347 TI - A one-dimensional coordination polymer based on Cd2O2 clusters: poly[aqua(MU3 4,4'-sulfonyldibenzoato)(3,4,7,8-tetramethyl-1,10-phenanthroline kappa(2)N,N')cadmium(II)]. AB - In the title mixed-ligand metal-organic polymeric complex [Cd(C14H8O6S)(C16H16N2)(H2O)]n, the asymmetric unit contains a crystallographically unique Cd(II) atom, one doubly deprotonated 4,4' sulfonyldibenzoic acid ligand (H2SDBA), one 3,4,7,8-tetramethyl-1,10 phenanthroline (TMPHEN) molecule and one water molecule. Each Cd(II) centre is coordinated by two N atoms from the chelating TMPHEN ligand, three O atoms from monodentate carboxylate groups of three different SDBA(2-) ligands and one O atom from a coordinated water molecule, giving a distorted CdN2O4 octahedral geometry. Single-crystal X-ray diffraction analysis reveals that the compound is a one dimensional double-chain polymer containing 28-membered rings based on Cd2O2 clusters, with a Cd...Cd separation of 3.6889 (4) A. These chains are linked by O H...O and C-H...O hydrogen bonds to form a three-dimensional supramolecular framework. The framework is reinforced by pi-pi and C-O...pi interactions. PMID- 23459348 TI - A tetrabromo-1,4-ethanonaphthalene and related dibromo-1,4-ethenonaphthalene. AB - (1RS,3RS,4RS,10SR)-2,2,3,10-Tetrabromo-1,2,3,4-tetrahydro-1,4-ethanonaphthalene, C12H10Br4, (I), is the first structure to be reported with four Br atoms bound to a 1,4-ethanonaphthalene framework and also the first which possesses three Br atoms in exo positions. Interactions between the Br atoms [three short intramolecular Br...Br distances of 3.1094 (4), 3.2669 (4) and 3.4415 (5) A] have little effect on the C-C bond lengths but lead to significant twisting of the cage structure compared with the parent hydrocarbon, which is expected to be fully eclipsed at the two saturated C2H4 bridge positions. Chemically related (1SR,4RS)-2,3-dibromo-1,4-ethenonaphthalene, C12H8Br2, (II), obtained by double dehydrobromination of (I), represents the first structure of any halogen substituted benzobarrelene. This cis-dibromide shows little evidence of steric congestion at the double bond [Br...Br = 3.5276 (8) A] as a consequence of the large C-C-Br angles [average C=C-Br angle = 126.15 (10) degrees ]. PMID- 23459349 TI - A new methanol solvate and Hirshfeld analysis of pi-stacking in 2,3,6,7,10,11 hexahydroxytriphenylene solvates. AB - The structure of 2,3,6,7,10,11-hexahydroxytriphenylene (hhtp) methanol monosolvate, C18H12O6.CH3OH, has triclinic symmetry (space group P-1). The compound has a three-dimensional layered network structure formed by intermolecular hydrogen bonding. Structure analysis with Hirshfeld surfaces is shown to be a sensitive method for comparing pi-stacking effects in the five known solvates of hhtp. The title structure shows slightly weaker pi-stacking than the dihydrate, but stronger pi-stacking than the other three solvates. PMID- 23459350 TI - The perchlorotriphenylmethyl (PTM) radical. AB - In spite of the considerable understanding and development of perchlorotriphenylmethyl (PTM) radical derivatives, the preparation of crystals of the pure unsubstituted PTM radical, C19Cl15, suitable for single-crystal X-ray diffraction has remained a challenge since its discovery, and only two studies dealing with the crystal structure of the unsubstituted PTM radical have been published. In one study, the radical forms clathrates with aromatic solvents [Veciana, Carilla, Miravitlles & Molins (1987). J. Chem. Soc. Chem. Commun. pp. 812-814], and in the other the structure was determined ab initio from powder X ray diffraction data [Rius, Miravitlles, Molins, Crespo & Veciana (1990). Mol. Cryst. Liq. Cryst. 187, 155-163]. We report here the preparation of PTM crystals for single-crystal X-ray diffraction and their resolution. The structure, which shows monoclinic symmetry (C2/c), revealed a nonsymmetric molecular propeller conformation (D3 symmetry) caused by the steric strain between the ortho-Cl atoms, which protect the central C atom (sp(2)-hybridization and major spin density) and give high chemical and thermal persistence to the PTM. The supramolecular structure of PTM shows short Cl...Cl intermolecular interactions and can be described in terms of layers formed by rows of molecules positioned in a head-to-tail manner along the c axis. PMID- 23459351 TI - An X-ray crystallographic and density functional theory study of (3Z)-4-(5 ethylsulfonyl-2-hydroxyanilino)pent-3-en-2-one and (3Z)-4-(5-tert-butyl-2 hydroxyanilino)pent-3-en-2-one. AB - The Schiff base enaminones (3Z)-4-(5-ethylsulfonyl-2-hydroxyanilino)pent-3-en-2 one, C13H17NO4S, (I), and (3Z)-4-(5-tert-butyl-2-hydroxyanilino)pent-3-en-2-one, C15H21NO2, (II), were studied by X-ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C C=C-N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino-phenol group canted relative to the rest of the molecule; the twist about the N(enamine) C(aryl) bond leads to dihedral angles of 40.5 (2) and -116.7 (1) degrees for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N-H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one-dimensional hydrogen-bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H-O hydrogen bond, and consequently also forms a one dimensional hydrogen-bonded chain. The DFT-calculated structures [in vacuo, B3LYP/6-311G(d,p) level] for the keto tautomers compare favourably with the X-ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol(-1) lower in energy than the enol tautomers for (I) and (II), respectively. PMID- 23459352 TI - Zoledronic acid: monoclinic and triclinic polymorphs from powder diffraction data. AB - The crystal structures of the monoclinic and triclinic polymorphs of zoledronic acid, C5H10N2O7P2, have been established from laboratory powder X-ray diffraction data. The molecules in both polymorphs are described as zwitterions, namely 1-(2 hydroxy-2-phosphonato-2-phosphonoethyl)-1H-imidazol-3-ium. Strong intermolecular hydrogen bonds (with donor-acceptor distances of 2.60 A or less) link the molecules into layers, parallel to the (100) plane in the monoclinic polymorph and to the (1-10) plane in the triclinic polymorph. The phosphonic acid groups form the inner side of each layer, while the imidazolium groups lie to the outside of the layer, protruding in opposite directions. In both polymorphs, layers related by translation along [100] interact through weak hydrogen bonds (with donor-acceptor distances greater than 2.70 A), forming three-dimensional layered structures. In the monoclinic polymorph, there are hydrogen-bonded centrosymmetric dimers linked by four strong O-H...O hydrogen bonds, which are not present in the triclinic polymorph. PMID- 23459353 TI - An additional methylene group driving the conformation and assembly of two arylsulfonamide para-alkoxychalcone hybrids. AB - The structures of two arylsulfonamide para-alkoxychalcones, namely, N-{4-[(E)-3 (4-methoxyphenyl)prop-2-enoyl]phenyl}benzenesulfonamide, C22H19NO4S, (I), and N {4-[(E)-3-(4-ethoxyphenyl)prop-2-enoyl]phenyl}benzenesulfonamide, C23H21NO4S, (II), reveal the effect of the inclusion of one -CH2- group between the CH3 branch and the alkoxy O atom on the conformation and crystal structure. Although the molecular conformations and one-dimensional chain motifs are the same in both structures, their crystallographic symmetry, number of independent molecules and crystal packing are different. The crystal packing of (I) is stabilized by weak C H...pi and pi-pi interactions, while only C-H...pi contacts occur in the structure of (II). The role of the additional methylene group in the crystal packing can also be seen in the fact that the alkoxy O atom is an acceptor in nonclassical hydrogen bonds only in the para-ethoxy analogue, (II). The remarkable similarity between the crystal packing features of (I) and (II) lies in the formation of N-H...O hydrogen-bonded ribbons, a synthon commonly found in related compounds. PMID- 23459354 TI - The low-melting compounds 1,4-diethyl-, 1,2-diethyl- and ethylbenzene. AB - Crystals of 1,4-diethyl- and 1,2-diethylbenzene, both C10H14, and ethylbenzene, C8H9, have been grown in situ. The molecules of 1,4-diethyl- and 1,2 diethylbenzene are located about a centre of inversion and across a twofold axis, respectively. In both molecules, the terminal methyl groups are located on opposite sides of the plane of the aromatic ring. In the crystal structures of all three compounds, molecules are linked together by (Ar)C-H...pi and CH2...pi contacts. The methyl H atoms do not form close contacts with any of the aromatic pi systems. PMID- 23459355 TI - Two phosphonodehydrotripeptides: Boc0-Gly1-Delta(Z)Phe2-alpha-Abu3PO3Me2 and Boc0 Gly1-Delta(Z)Phe2-alpha-Nva3PO3Et2. AB - The present paper reports the crystal structures of two short phosphonotripeptides (one in two crystal forms) containing one DeltaPhe (dehydrophenylalanine) residue, namely dimethyl (3-{[tert-butoxycarbonylglycyl alpha,beta-(Z)-dehydrophenylalanyl]amino}propyl)phosphonate, Boc(0)-Gly(1) Delta(Z)Phe(2)-alpha-Abu(3)PO3Me2, C21H32N3O7P, (I), and diethyl (4-{[tert butoxycarbonylglycyl-alpha,beta-(Z)-dehydrophenylalanyl]amino}butyl)phosphonate, Boc(0)-Gly(1)-Delta(Z)Phe(2)-alpha-Nva(3)PO3Et2, as the propan-2-ol monosolvate 0.122-hydrate, C24H38N3O7P.C3H8O.0.122H2O, (II), and the ethanol monosolvate 0.076-hydrate, C24H38N3O7P.C2H6O.0.076H2O, (III). The crystals of (II) and (III) are isomorphous but differ in the type of solvent. The phosphono group is linked directly to the last Calpha atom in the main chain for all three peptides. All the amino acids are trans linked in the main chains. The crystal structures exhibit no intramolecular hydrogen bonds and are stabilized by intermolecular hydrogen bonds only. PMID- 23459356 TI - 2,2'-Anhydro-1-(3',5'-di-O-acetyl-beta-D-arabinofuranosyl)uracil, a cyclouridine nucleoside with a C4'-endo furanosyl conformation. AB - 2,2'-Anhydro-1-(3',5'-di-O-acetyl-beta-D-arabinofuranosyl)uracil, C13H14N2O7, was obtained by refluxing 2',3'-O-(methoxymethylene)uridine in acetic anhydride. The structure exhibits a nearly perfect C4'-endo ((4)E) conformation. The best four atom plane of the five-membered furanose ring is O-C-C-C, involving the C atoms of the fused five-membered oxazolidine ring, and the torsion angle is only -0.4 (2) degrees . The oxazolidine ring is essentially coplanar with the six-membered uracil ring [r.m.s. deviation = 0.012 (5) A and dihedral angle = -3.2 (3) degrees ]. The conformation at the exocyclic C-C bond is gauche-trans which is stabilized by various C-H...pi and C-O...pi interactions. PMID- 23459357 TI - Solid-state tautomeric structure and invariom refinement of a novel and potent HIV integrase inhibitor. AB - The conformation and tautomeric structure of (Z)-4-[5-(2,6-difluorobenzyl)-1-(2 fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1 yl)but-3-enamide, C27H22F3N3O5, in the solid state has been resolved by single crystal X-ray crystallography. The electron distribution in the molecule was evaluated by refinements with invarioms, aspherical scattering factors by the method of Dittrich et al. [Acta Cryst. (2005), A61, 314-320] that are based on the Hansen-Coppens multipole model [Hansen & Coppens (1978). Acta Cryst. A34, 909 921]. The beta-diketo portion of the molecule exists in the enol form. The enol OH hydrogen forms a strong asymmetric hydrogen bond with the carbonyl O atom on the beta-C atom of the chain. Weak intramolecular hydrogen bonds exist between the weakly acidic alpha-CH hydrogen of the keto-enol group and the pyridinone carbonyl O atom, and also between the hydrazine N-H group and the carbonyl group in the beta-position from the hydrazine N-H group. The electrostatic properties of the molecule were derived from the molecular charge density. The molecule is in a lengthened conformation and the rings of the two benzyl groups are nearly orthogonal. Results from a high-field (1)H and (13)C NMR correlation spectroscopy study confirm that the same tautomer exists in solution as in the solid state. PMID- 23459358 TI - Supramolecular networks of 10-(2-hydroxyethyl)acridin-9(10H)-one and 10-(2 chloroethyl)acridin-9(10H)-one. AB - Both 10-(2-hydroxyethyl)acridin-9(10H)-one, C15H13NO2, and 10-(2 chloroethyl)acridin-9(10H)-one, C15H12ClNO, have monoclinic (P21/c) symmetry and supramolecular three-dimensional networks. But the differences in the intermolecular interactions displayed by the hydroxy group and the chlorine substituent lead to stronger intermolecular pi-stacking interactions and hydrogen bonding, and hence a significantly higher melting point for the former. PMID- 23459359 TI - Three 2-(methysulfanyl)nicotinamides. AB - The molecular conformations of three N-alkyl-2-(methylsulfanyl)nicotinamide derivatives, namely N-cyclohexyl-2-(methylsulfanyl)nicotinamide, C13H18N2OS, (I), N-isopropyl-2-(methylsulfanyl)nicotinamide, C10H14N2OS, (II), in which there are two molecules in the asymmetric unit which were chosen to form a hydrogen-bonded pair, and N-(2-hydroxyethyl)-2-(methylsulfanyl)nicotinamide dihydrate, C9H12N2O2S.2H2O, (III), are compared with those of four unsubstituted N alkylnicotinamide compounds. The substituted compounds show a higher degree of torsion of the pyridine ring with respect to the amide group than do the unsubstituted compounds, with dihedral angles in the range 40-60 degrees for the former and 20-35 degrees for the latter. In (I) and (II), the supramolecular structure is defined by amide-N to carbonyl-O chains. In (III), the nicotinamide molecules are linked by hydrogen bonds to two water molecules resulting in two linked chains of rings which form the three-dimensional network. PMID- 23459360 TI - Two polymorphs of afobazole from powder diffraction data. AB - Afobazole {systematic name: 2-[2-(morpholin-4-yl)ethylsulfanyl]-1H-benzimidazole} is a new anxiolytic drug and Actins, Auzins & Petkune [(2012). Eur. Patent EP10163962] described four polymorphic modifications. In the present study, the crystal structures of two monoclinic polymorphs, 5-ethoxy-2-[2-(morpholin-4-ium-4 yl)ethylsulfanyl]-1H-benzimidazol-3-ium dichloride, C15H23N3O2S(2+).2Cl(-), (II) and (IV), have been established from laboratory powder diffraction data. The crystal packing and conformation of the dications in (II) and (IV) are different. In (II), there are channels in the [001] direction, which offer atmospheric water molecules an easy way of penetrating into the crystal structure, thus explaining the higher hygroscopicity of (II) compared with (IV). PMID- 23459361 TI - Relative configuration, absolute configuration and absolute structure of three isomeric 8-benzyl-2-[(4-bromophenyl)(hydroxy)methyl]-8-azabicyclo[3.2.1]octan-3 ones. AB - The title compounds, C21H22BrNO2, are isomeric 8-benzyl-2-[(4 bromophenyl)(hydroxy)methyl]-8-azabicyclo[3.2.1]octan-3-ones. Compound (I), the (+/-)-exo,syn-(1RS,2SR,5SR,9SR) isomer, crystallizes in the hexagonal space group R-3, while compounds (II) [the (+)-exo,anti-(1R,2S,5S,9R) isomer] and (III) [the (+/-)-exo,anti-(1RS,2SR,5SR,9RS) isomer] crystallize in the orthorhombic space groups P212121 and Pna21, respectively. The absolute configuration was determined for enantiomerically pure (II). For the noncentrosymmetric crystal of (III), its absolute structure was established. In the crystal structures of (I) and (II), an intramolecular hydrogen bond is formed between the hydroxy group and the heterocyclic N atom. In the crystal structure of racemic (III), hydrogen-bonded chains of molecules are formed via intermolecular O-H...O interactions. Additionally, face-to-edge pi-pi interactions are present in the crystal structures of (I) and (II). In all three structures, the piperidinone rings adopt chair conformations and the N-benzyl substituents occupy the equatorial positions. PMID- 23459362 TI - Three closely related thienyl-substituted 1,4-epoxynaphtho[1,2-b]azepines: hydrogen-bonded assembly in one, two and three dimensions. AB - (2R,4S)-2-(3-Methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2 b]azepine, C19H17NOS, (I), crystallizes with a single enantiomer in each crystal, whereas its geometrical isomer (2RS,4SR)-2-(5-methylthiophen-2-yl)-2,3,4,5 tetrahydro-1,4-epoxy-naphtho[1,2-b]azepine, (II), and (2RS,4SR)-2-(5 bromothiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, C18H14BrNOS, (III), both crystallize as racemic mixtures. A combination of one C H...O hydrogen bond and two C-H...pi(arene) hydrogen bonds links the molecules of (I) into a three-dimensional framework; the molecules of (II) are linked into a C(4)C(4)[R2(2)(7)] chain of rings by a combination of C-H...N and C-H...O hydrogen bonds; and in (III), where Z' = 2, a combination of four C-H...pi(arene) hydrogen bonds and two C-H...pi(thienyl) hydrogen bonds links the molecules into complex sheets. Comparisons are made with the assembly patterns in some aryl substituted 1,4-epoxynaphtho[1,2-b]azepines. PMID- 23459363 TI - Fetal growth and prenatal exposure to bisphenol A: the generation R study. AB - BACKGROUND: Prenatal exposure to bisphenol A (BPA) has been associated with adverse birth outcomes, but findings of previous studies have been inconsistent. OBJECTIVE: We investigated the relation of prenatal BPA exposure with intrauterine growth and evaluated the effect of the number of measurements per subject on observed associations. METHODS: This study was embedded in a Dutch population-based prospective cohort study, with urine samples collected during early, mid-, and late pregnancy. The study comprised 219 women, of whom 99 had one measurement, 40 had two measurements, and 80 had three measurements of urinary BPA. Fetal growth characteristics were repeatedly measured by ultrasound during pregnancy and combined with measurements at birth. Linear regression models for repeated measurements of both BPA and fetal growth were used to estimate associations between urinary concentrations of creatinine-based BPA (BPACB) and intrauterine growth. RESULTS: The relationship between BPACB and fetal growth was sensitive to the number of BPA measurements per woman. Among 80 women with three BPA measurements, women with BPACB > 4.22 MUg/g crea (creatinine) had lower growth rates for fetal weight and head circumference than did women with BPACB < 1.54 MUg/g crea, with estimated differences in mean values at birth of -683 g (20.3% of mean) and -3.9 cm (11.5% of mean), respectively. When fewer measurements were available per woman, the exposure-response relationship became progressively attenuated and statistically nonsignificant. CONCLUSION: Our findings suggest that maternal urinary BPA may impair fetal growth. Because previous studies have shown contradictory findings, further evidence is needed to corroborate these findings in the general population. PMID- 23459364 TI - Female mice lacking cholecystokinin 1 receptors have compromised neurogenesis, and fewer dopaminergic cells in the olfactory bulb. AB - Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle and subgranular zone (SGZ) of the dentate gyrus (DG). We examined whether cholecystokinin (CCK) through actions mediated by CCK1 receptors (CCK1R) is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 h prior to death or by immunoreactivity against Ki67, were reduced by 37 and 42%, respectively, in female (but not male) mice lacking CCK1Rs (CCK1R(-/-)) compared to wild-type (WT). Generation of neuroblasts in the SVZ and rostral migratory stream (RMS) was also affected, since the number of doublecortin (DCX) immunoreactive (ir) neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R(-/-) mice, BrdU-positive (+), and Ki67-ir cells were reduced by 38 and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R(-/-) mice was examined. In the OB granule cell layer (GCL), the number of neuronal nuclei (NeuN)-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI) was similar. Compared to WT, the granule cell layer of the DG in female CCK1R(-/-) mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL) of CCK1R(-/ ) female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is altered. PMID- 23459365 TI - Integrating medical humanities into a pharmaceutical care seminar on dementia. AB - Objective. To design, integrate, and assess the effectiveness of a medical humanities teaching module that focuses on pharmaceutical care for dementia patients.Design. Visual and textual dementia narratives were presented using a combination of teacher and learner-centered approaches with the aim being to highlight patients' and caregivers' needs for empathy and counselling.Assessment. As gauged from pre- and post-experience questionnaires, students highly rated this approach to teaching medical humanities. In-class presentations demonstrated students' increased sensitivity to patient and caregiver needs, while objective learning outcomes demonstrated students' increased knowledge and awareness.Conclusions. Pharmacy students were open to and successfully learned from reading and discussing patient and caregiver narratives, which furthers the discussion on the value of integrating the medical humanities into the curricula of pharmacy and other health sciences. PMID- 23459367 TI - Sequencing Disadvantage: Barriers to Employment Facing Young Black and White Men with Criminal Records. AB - In this article, the authors report the results of a large-scale field experiment conducted in New York City investigating the effects of race and a prison record on employment. Teams of black and white men were matched and sent to apply for low-wage jobs throughout the city, presenting equivalent resumes and differing only in their race and criminal background. The authors find a significant negative effect of a criminal record on employment outcomes that appears substantially larger for African Americans. The sequence of interactions preceding hiring decisions suggests that black applicants are less often invited to interview, thereby providing fewer opportunities to establish rapport with the employer. Furthermore, employers' general reluctance to discuss the criminal record of an applicant appears especially harmful for black ex-offenders. Overall, these results point to the importance of rapport-building for finding work, something that the stigmatizing characteristics of minority and criminal status make more difficult to achieve. PMID- 23459366 TI - Identification of the SlmA active site responsible for blocking bacterial cytokinetic ring assembly over the chromosome. AB - Bacterial cells use chromosome-associated division inhibitors to help coordinate the processes of DNA replication and segregation with cytokinesis. SlmA from Escherichia coli, a member of the tetracycline repressor (TetR)-like protein family, is one example of this class of regulator. It blocks the assembly of the bacterial cytokinetic ring by interfering with the polymerization of the tubulin like FtsZ protein in a manner that is dramatically stimulated upon specific DNA binding. Here we used a combination of molecular genetics and biochemistry to identify the active site of SlmA responsible for disrupting FtsZ polymerization. Interestingly, this site maps to a region of SlmA that in the published DNA-free structure is partially occluded by the DNA-binding domains. In this conformation, the SlmA structure resembles the drug/inducer-bound conformers of other TetR-like proteins, which in the absence of inducer require an inward rotation of their DNA binding domains to bind successive major grooves on operator DNA. Our results are therefore consistent with a model in which DNA-binding activates SlmA by promoting a rotational movement of the DNA-binding domains that fully exposes the FtsZ-binding sites. SlmA may thus represent a special subclass of TetR-like proteins that have adapted conformational changes normally associated with inducer sensing in order to modulate an interaction with a partner protein. In this case, the adaptation ensures that SlmA only blocks cytokinesis in regions of the cell occupied by the origin-proximal portion of the chromosome where SlmA binding sites are enriched. PMID- 23459368 TI - Comparison of hepatic and renal function between inhalation anesthesia with sevoflurane and remifentanil and total intravenous anesthesia with propofol and remifentanil for thyroidectomy. AB - BACKGROUND: Inhalation anesthetics are an important factor for postoperative hepatic and renal dysfunction. In this regard, TIVA can reduce the risk of hepatic and renal dysfunction inherited to inhalation anesthetics. The present study was conducted to determine whether hepatic and renal functions differ after anesthesia with sevoflurane and propofol. METHODS: Two hundred patients, ASA physical status class I, II, scheduled for an elective thyroidectomy were randomly divided into two groups. Anesthesia was maintained with sevoflurane 1-2% and remifentanil in the sevoflurane group (Group S) and propofol 2-5 ug/ml and remifentanil 2-5 ng/ml at the effect site, using a target controlled infusion (TCI) pump in the TIVA group (Group T) to maintain BIS of 40-60. To evaluate the hepatic and renal function, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine were tested at preoperation (baseline), postoperative 1 day and 3 days. RESULTS: AST was increased at postoperative 1 day and 3 days, compared with that of the preoperation in Group S, and postoperative 1 day in Group T, but the values were within its normal limit. ALT was not changed after anesthesia in both groups. BUN was increased at postoperative 1 day, compared with that of the preoperation in Group S, but the value was within its normal limit. Creatinine was not changed after anesthesia in both groups. CONCLUSIONS: The changes of hepatic and renal function after inhalation anesthesia with sevoflurane and TIVA with propofol and remifentanil for thyroidectomy were clinically insignificant, and there was no difference between the two methods. PMID- 23459369 TI - Adolescent-onset alcohol abuse exacerbates the influence of childhood conduct disorder on late adolescent and early adult antisocial behaviour. AB - This study tested the hypothesis that adolescent-onset alcohol abuse (AOAA) would both mediate and moderate the effect of childhood conduct disorder on antisocial behaviour in late adolescence and early adulthood. A sample comprising 504 young men and women strategically recruited from the community were grouped using the criteria of the Diagnostic and Statistical Manual (DSM-IV, American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: APA), as follows: neither childhood conduct disorder (CCD) nor alcohol abuse/dependence; CCD but no alcohol abuse or dependence; alcohol abuse/dependence but no CCD; both CCD and alcohol abuse/dependence. The outcome measure was the sum of positive responses to 55 interview items capturing a variety of antisocial behaviours engaged in since age 15. Severity of lifetime alcohol-related and CCD problems served as predictor variables in regression analysis. Antisocial behaviour problems were greatest in individuals with a history of co-occurring conduct disorder (CD) and alcohol abuse/dependence. While CCD was strongly predictive of adult antisocial behaviour, this effect was both mediated and moderated (exacerbated) by AOAA. PMID- 23459370 TI - Time series analysis of onchocerciasis data from Mexico: a trend towards elimination. AB - BACKGROUND: In Latin America, there are 13 geographically isolated endemic foci distributed among Mexico, Guatemala, Colombia, Venezuela, Brazil and Ecuador. The communities of the three endemic foci found within Mexico have been receiving ivermectin treatment since 1989. In this study, we predicted the trend of occurrence of cases in Mexico by applying time series analysis to monthly onchocerciasis data reported by the Mexican Secretariat of Health between 1988 and 2011 using the software R. RESULTS: A total of 15,584 cases were reported in Mexico from 1988 to 2011. The data of onchocerciasis cases are mainly from the main endemic foci of Chiapas and Oaxaca. The last case in Oaxaca was reported in 1998, but new cases were reported in the Chiapas foci up to 2011. Time series analysis performed for the foci in Mexico showed a decreasing trend of the disease over time. The best-fitted models with the smallest Akaike Information Criterion (AIC) were Auto-Regressive Integrated Moving Average (ARIMA) models, which were used to predict the tendency of onchocerciasis cases for two years ahead. According to the ARIMA models predictions, the cases in very low number (below 1) are expected for the disease between 2012 and 2013 in Chiapas, the last endemic region in Mexico. CONCLUSION: The endemic regions of Mexico evolved from high onchocerciasis-endemic states to the interruption of transmission due to the strategies followed by the MSH, based on treatment with ivermectin. The extremely low level of expected cases as predicted by ARIMA models for the next two years suggest that the onchocerciasis is being eliminated in Mexico. To our knowledge, it is the first study utilizing time series for predicting case dynamics of onchocerciasis, which could be used as a benchmark during monitoring and post treatment surveillance. PMID- 23459371 TI - A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro. AB - For many cancers, there is a real need for more effective therapies. Although many drugs show promising results in vitro, most fail to translate into an in vivo model system, and only ~5% show anti-tumor activity in clinical trials. It remains a significant challenge to accurately replicate in vitro the complex in vivo microenvironment in which cancers thrive, but this will be key to increasing the success of translating novel therapies into clinical practice. Three dimensional (3D) cell culture models may better mimic primary tumors in vivo than traditional two-dimensional (2D) cultures. Therefore, we established and characterized 3D in vitro models of 31 epithelial ovarian cancer (EOC) cell lines, compared their biological and molecular features with 2D cultures and primary tumors, and tested their efficacy as models for evaluating chemoresponse. When cultured in 3D using polyhydroxoethylamethacrylate-coated plastics, EOC lines formed multicellular aggregates that could be classified as 'large dense', 'large loose', and 'small', based on size, light permeability, and proportion of cells incorporated into the complex structures. Features of histological differentiation characteristic of primary tumors that were not present in 2D cultures were restored in 3D. For many cell lines, the transition from a 2D to 3D microenvironment induced changes in the expression of several biomarkers relevant to disease. Generally, EOC cell lines proliferated more slowly and were more chemoresistant in 3D compared with 2D culture. In summary, 3D models of EOCs better reflect the histological, biological, and molecular features of primary tumors than the same cells cultured using traditional 2D techniques; 3D in vitro models also exhibit different sensitivities to chemotherapeutic agents compared with 2D models, which may have a significant impact on the success of drug testing pipelines for EOC. These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types. PMID- 23459372 TI - Optimization of tumor xenograft dissociation for the profiling of cell surface markers and nutrient transporters. AB - Metabolic adaptations and changes in the expression of nutrient transporters are known to accompany tumorigenic processes. Nevertheless, in the context of solid tumors, studies of metabolism are hindered by a paucity of tools allowing the identification of cell surface transporters on individual cells. Here, we developed a method for the dissociation of human breast cancer tumor xenografts combined with quantification of cell surface markers, including metabolite transporters. The expression profiles of four relevant nutrient transporters for cancer cells' metabolism, Glut1, ASCT2, PiT1 and PiT2 (participating to glucose, glutamine and inorganic phosphate, respectively), as detected by new retroviral envelope glycoprotein-derived ligands, were distinctive of each tumor, unveiling underlying differences in metabolic pathways. Our tumor dissociation procedure and nutrient transporter profiling technology provides opportunities for future basic research, clinical diagnosis, prognosis and evaluation of therapeutic responses, as well as for drug discovery and development. PMID- 23459373 TI - Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503. AB - The great majority of gastrointestinal stromal tumors (GISTs) have gain-of function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup Ser501Ala502 at a concentration of 0.1 MUM, whereas it inhibited that of KIT-Dup Ala502Tyr503 at a concentration of 10 MUM. Constitutive activation of KIT-Dup Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 MUM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 MUM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed long-term stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-Dup-Ser501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib- and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup Ala502Tyr503. PMID- 23459374 TI - Successful treatment of preadolescents with small cell carcinoma of the ovary hypercalcemic type. AB - BACKGROUND: Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare tumor with a peak incidence in young adulthood that historically has carried a poor prognosis. OBSERVATIONS: We present 2 advanced stage cases of SCCOHT in preadolescents successfully treated with a combination of cisplatin-based chemotherapy and surgical resection. The more recent patient also underwent consolidative high-dose chemotherapy with stem cell rescue and external beam radiotherapy. Her therapy was concluded with a maintenance course of bevacizumab. The patients are now disease-free 7 years and 30 months, respectively, after diagnosis. CONCLUSIONS: With aggressive multimodal therapy SCCOHT is curable in children. PMID- 23459375 TI - Successful treatment of refractory immune thrombocytopenia with rituximab in a 10 week-old infant. AB - Immune thrombocytopenic purpura (ITP) that is unresponsive to conventional treatment is uncommon. In this situation, additional therapeutic options are limited and management is challenging. We describe the case of a 10-week-old infant that developed life-threatening ITP that was unresponsive to immunoglobulin and corticosteroids that was successfully managed with the monoclonal antibody rituximab. The literature on the use of rituximab in nonresponsive ITP is reviewed. PMID- 23459376 TI - Small cell carcinoma of the ovary of the hypercalcemic type presenting in a 5 year-old girl. AB - Small cell carcinoma of the ovary, hypercalcemic type is a very rare, highly aggressive tumor associated with a poor prognosis. Diagnosis is typically challenging secondary to undifferentiated cells and the rarity of the tumor. We report our experience with a 5-year-old girl who presented with stage IV disease. PMID- 23459378 TI - Ramsay Hunt syndrome in a girl with acute lymphoblastic leukemia during maintenance therapy. AB - A 5-year-old girl with precursor B-cell acute lymphoblastic leukemia developed peripheral-type right facial palsy and very faint erythema on her right pinna during maintenance therapy. Acyclovir was started for possible zoster infection. The following day, vesicles appeared and a diagnosis of Ramsay Hunt syndrome was made. Prednisolone was started on day 5 after onset. Her facial palsy recovered within 6 months. Ramsay Hunt syndrome is a rare cause of facial palsy in patients with acute lymphoblastic leukemia, and this is the first case report. Preemptive therapy with acyclovir before the development of vesicles should help the patient recover from facial palsy. PMID- 23459377 TI - Severe thrombocytopenia in a child secondary to passive platelet antibody transfer from a plasma transfusion. AB - Although rare, passive transfer of platelet antibodies through blood products can result in thrombocytopenia, acute transfusion reactions, and death. We report a case of severe alloimmune thrombocytopenia from a plasma transfusion. A postliver transplant patient with a normal platelet count received fresh frozen plasma before liver biopsy. Postbiopsy, she developed cardiorespiratory distress, petechiae, and severe thrombocytopenia (platelet count 2000/MUL). Her platelet count recovered to normal after 1 week. This diagnosis should be considered whenever an unexpected drop in the platelet count occurs after a plasma-rich transfusion. Conservative transfusion practices and more targeted donor screening may prevent similar events. PMID- 23459379 TI - Focal cranial hyperostosis from meningioma: a complication from previous radiation treatment for childhood T-cell acute lymphoblastic leukemia. AB - Nearly 75% of childhood cancer survivors will experience an adverse late effect from previous therapy. In patients previously treated with cranial irradiation, the late effect can manifest as secondary central nervous system tumors. Presented is a case of a 20 year man with a history of T-cell lymphoblastic leukemia diagnosed at age 22 months, treated with chemotherapy and cranial irradiation. He had developed increasing prominence of the top of his head over several months. Plain radiograph showed frontal calvarium thickening with focal "hair-on-end" periosteal reaction. Magnetic resonance imaging revealed an enhancing dural-based mass with transcalvarial extension, confirmed after resection to be meningioma (World Health Organization Grade I). This case illustrates an atypical presentation of a late effect of childhood cancer treatment and highlights the need to be informed about prior treatments received and potential attendant complications. PMID- 23459380 TI - Successful treatment of metastatic relapse of medulloblastoma in childhood with single session stereotactic radiosurgery: a report of 3 cases. AB - Stereotactic radiosurgery (SRS) is an increasingly used treatment modality in adults, but its use and effectiveness in pediatric brain tumors is still uncertain. We describe 3 patients with metastatic relapse of medulloblastoma, who were treated with SRS, and achieved prolonged, progression-free survival. Tolerability of the treatment was excellent with no adverse effects reported. This work adds to the growing evidence that SRS may have an important role to play in the treatment of pediatric brain tumors. PMID- 23459381 TI - Physical performance of nontransplanted childhood ALL survivors is comparable to healthy controls. AB - Physical fitness is an essential feature of overall health. Our objective was to compare the physical performance between nontransplanted acute lymphoblastic leukemia (ALL) patients (study patients), healthy controls, and ALL patients after stem cell transplantation (SCT). Forty-five ALL patients (median age, 13.3 y) treated without cranial irradiation were compared with 34 ALL patients (12.0 y) treated with SCT and total body irradiation and 522 age-matched and sex matched controls. Their physical performance was assessed by 6 muscle tests measuring speed and dynamic endurance, flexibility, acceleration, maximal speed, and speed differentiation. The patients were tested at a minimum of 3 years after treatment. The muscle test results of the study patients did not differ from that of the healthy controls. The study patients had normal body mass indexes (BMI). Only 42% of them exercised at least once a week. Those who exercised >3 times a week and those with a BMI below median had better results. SCT patients had inferior results in 4 out of 6 tests. The physical performance of nontransplanted ALL patients did not differ from that of healthy controls. A higher physical exercise activity and a BMI below median positively correlated with better muscle performance, supporting the importance of encouraging ALL survivors to exercise and avoid obesity. PMID- 23459382 TI - MicroRNA functionalized microporous titanium oxide surface by lyophilization with enhanced osteogenic activity. AB - Developing biomedical titanium (Ti) implants with high osteogenic ability and consequent rigid osseointegration is a constant requirement from the clinic. In this study, we fabricate novel miRNA functionalized microporous Ti implants by lyophilizing miRNA lipoplexes onto a microporous titanium oxide surface formed by microarc oxidation (MAO). The microporous titanium oxide surface provides a larger surface area for miRNA loading and enables spatial retention of the miRNAs within the pores until cellular delivery. The loading of lipoplexes into the micropores on the MAO Ti surface is facilitated by the superhydrophilicity and Ti OH groups gathering of the MAO surface after UV irradiation followed by lyophilization. A high miRNA transfection efficiency was observed in mesenchymal stem cells (MSCs) seeded onto the miRNA functionalized surface with no apparent cytotoxicity. When functionalizing the Ti surface with miR-29b that enhances osteogenic activity and antimiR-138 that inhibits miR-138 inhibition of endogenous osteogenesis, clear stimulation of MSC osteogenic differentiation was observed, in terms of up-regulating osteogenic expression and enhancing alkaline phosphatase production, collagen secretion and ECM mineralization. The novel miRNA functionalized Ti implants with enhanced osteogenic activity promisingly lead to more rapid and robust osseointegration of a clinical bone implant interface. Our study implies that lyophilization may constitute a versatile method for miRNA loading to other biomaterials with the aim of controlling cellular function. PMID- 23459383 TI - Oral available agents in the treatment of relapsing remitting multiple sclerosis: an overview of merits and culprits. AB - Multiple sclerosis (MS) is a chronic immunological disease of the central nervous system characterized by early inflammatory demyelination and subsequent neurodegeneration. Major therapeutic progress has occurred during the past decade, in particular since the introduction of immunomodulatory agents, however, MS is still an incurable disease. In addition, parenteral application of the currently licensed drugs is associated with injection-related adverse events (AEs) and low patient compliance. Thus, there remains an unmet need for the development of more effective and well tolerated oral therapies for the treatment of MS. A number of new orally administered agents including fingolimod, laquinimod, teriflunomide, cladribine, and BG-12 have been licensed recently or are currently under investigation in relapsing remitting MS patients. In multi center, randomized, placebo-controlled phase III clinical studies, all of these agents have already shown their efficacy on both clinical disease parameters and magnetic resonance imaging-based measures of disease activity in patients with relapsing remitting MS. However, there are essential differences concerning their clinical efficacy and side-effect profiles. Additionally, the mechanisms by which these substances exert clinical efficacy have not been fully elucidated. In this article, we review the pharmaceutical properties of fingolimod, laquinimod, teriflunomide, cladribine, and BG-12; and their suggested mechanisms of action, clinical efficacy, and side-effect profiles. PMID- 23459384 TI - Bridging nanocontacts to macroscale gecko adhesion by sliding soft lamellar skin supported setal array. AB - The study of the mechanism of the controlled adhesion of geckos, which is important for the design and fabrication of bio-inspired dry and reversible adhesive surfaces, is widely discussed below the setal level. In this work, the role of the soft lamellar skin in gecko toe adhesion was experimentally revealed. The lamellar skin acting as a soft spring sustains most of the normal deformation during preloading and maintains a wide range of adhesive state rather than a repulsive state. The sequential engagement and peeling off of setal array are responsible for the reliable gecko adhesion and friction control. This soft spring supported pillar structure should be adopted in future bio-inspired adhesives design. A hybrid three-legged spring/setae clamp was developed to transfer a horizontally placed silicon wafer. It indicates the importance of integration and optimization of nanoscale structures as well as the incorporation of their unique, size-dependent properties into functional macroscale devices. PMID- 23459385 TI - SAD-based stereo vision machine on a System-on-Programmable-Chip (SoPC). AB - This paper, proposes a novel solution for a stereo vision machine based on the System-on-Programmable-Chip (SoPC) architecture. The SOPC technology provides great convenience for accessing many hardware devices such as DDRII, SSRAM, Flash, etc., by IP reuse. The system hardware is implemented in a single FPGA chip involving a 32-bit Nios II microprocessor, which is a configurable soft IP core in charge of managing the image buffer and users' configuration data. The Sum of Absolute Differences (SAD) algorithm is used for dense disparity map computation. The circuits of the algorithmic module are modeled by the Matlab based DSP Builder. With a set of configuration interfaces, the machine can process many different sizes of stereo pair images. The maximum image size is up to 512 K pixels. This machine is designed to focus on real time stereo vision applications. The stereo vision machine offers good performance and high efficiency in real time. Considering a hardware FPGA clock of 90 MHz, 23 frames of 640 * 480 disparity maps can be obtained in one second with 5 * 5 matching window and maximum 64 disparity pixels. PMID- 23459386 TI - High temperature optical fiber sensor based on compact fattened long-period fiber gratings. AB - A compact high temperature fiber sensor where the sensor head consists of a short fattened long period fiber grating (F-LPFG) of at least 2 mm in length and background loss of -5 dBm is reported. On purpose two different F-LPFGs were used to measure temperature variations, taking advantage of their broad spectrum and the slope characteristics of the erbium light source. This approach affected the spectrum gain as the linear band shifting took place. The measured sensitivity of the long period fiber gratings were about 72 pm/ degrees C in a range from 25 to 500 degrees C. Here, the temperature rate of the experiment was 0.17 degrees C/s and the temperature response time was within 3 s. Moreover, temperature changes were detected with an InGaAs photodetector, where a sensitivity of 0.05 mV/ degrees C was achieved. PMID- 23459388 TI - A rank-ordered marginal filter for deinterlacing. AB - This paper proposes a new interpolation filter for deinterlacing, which is achievedby enhancing the edge preserving ability of the conventional edge-based line average methods. This filter consists of three steps: pre-processing step, fuzzy metric-based weight assignation step, and rank-ordered marginal filter step. The proposed method is able to interpolate the missing lines without introducing annoying articles. Simulation results show that the images filtered with the proposed algorithm restrain less annoying pixels than the ones acquired by other methods. PMID- 23459387 TI - A novel cell-based hybrid acoustic wave biosensor with impedimetric sensing capabilities. AB - A novel multiparametric biosensor system based on living cells will be presented. The biosensor system includes two biosensing techniques on a single device: resonant frequency measurements and electric cell-substrate impedance sensing (ECIS). The multiparametric sensor system is based on the innovative use of the upper electrode of a quartz crystal microbalance (QCM) resonator as working electrode for the ECIS technique. The QCM acoustic wave sensor consists of a thin AT-cut quartz substrate with two gold electrodes on opposite sides. For integration of the QCM with the ECIS technique a semicircular counter electrode was fabricated near the upper electrode on the same side of the quartz crystal. Bovine aortic endothelial live cells (BAECs) were successfully cultured on this hybrid biosensor. Finite element modeling of the bulk acoustic wave resonator using COMSOL simulations was performed. Simultaneous gravimetric and impedimetric measurements performed over a period of time on the same cell culture were conducted to validate the device's sensitivity. The time necessary for the BAEC cells to attach and form a compact monolayer on the biosensor was 35~45 minutes for 1.5 * 10(4) cells/cm2 BAECs; 60 minutes for 2.0 * 10(4) cells/cm2 BAECs; 70 minutes for 3.0 * 10(4) cells/cm2 BAECs; and 100 minutes for 5.0 * 104 cells/cm2 BAECs. It was demonstrated that this time is the same for both gravimetric and impedimetric measurements. This hybrid biosensor will be employed in the future for water toxicity detection. PMID- 23459389 TI - Link-quality measurement and reporting in wireless sensor networks. AB - Wireless Sensor networks (WSNs) are created by small hardware devices that possess the necessary functionalities to measure and exchange a variety of environmental data in their deployment setting. In this paper, we discuss the experiments in deploying a testbed as a first step towards creating a fully functional heterogeneous wireless network-based underground monitoring system. The system is mainly composed of mobile and static ZigBee nodes, which are deployed on the underground mine galleries for measuring ambient temperature. In addition, we describe the measured results of link characteristics such as received signal strength, latency and throughput for different scenarios. PMID- 23459390 TI - A low-power bio-potential acquisition system with flexible PDMS dry electrodes for portable ubiquitous healthcare applications. AB - This work describes a bio-potential acquisition system for portable ubiquitous healthcare applications using flexible polydimethylsiloxane dry electrodes (FPDEs) and a low-power recording circuit. This novel FPDE used Au as the skin contact layer, which was made using a CO2 laser and replica method technology. The FPDE was revised from a commercial bio-potential electrode with a conductive snap using dry electrodes rather than wet electrodes that proposed reliable and robust attachment for the purpose of measurement, and attaching velcro made it wearable on the forearm for bio-potential applications. Furthermore, this study proposes a recording device to store bio-potential signal data and provides portability and low-power consumption for the proposed acquisition system. To acquire differential bio-potentials, such as electrocardiogram (ECG) signals, the proposed recording device includes a low-power front-end acquisition chip fabricated using a complementary metal-oxide-semiconductor (CMOS) process, a commercial microcontroller (MSP430F149), and a secure digital (SD) card for portable healthcare applications. The proposed system can obtain ECG signals efficiently and are comfortable to the skin. The power consumption of the system is about 85 mW for continuous working over a 3 day period with two AA batteries. It can also be used as a compact Holter ECG system. PMID- 23459391 TI - A strip-type microthrottle pump: modeling, design and fabrication. AB - A novel design for a strip-type microthrottle pump with a rectangular actuator geometry is proposed, with more efficient chip surface consumption compared to existing micropumps with circular actuators. Due to the complex structure and operation of the proposed device, determination of detailed structural parameters is essential. Therefore, we developed an advanced, fully coupled 3D electro-fluid solid mechanics simulation model in COMSOL that includes fluid inertial effects and a hyperelastic model for PDMS and no-slip boundary condition in fluid-wall interface. Numerical simulation resulted in accurate virtual prototyping of the proposed device only after inclusion of all mentioned effects. Here, we provide analysis of device operation at various frequencies which describes the basic pumping effects, role of excitation amplitude and backpressure and provides optimization of critical design parameters such as optimal position and height of the microthrottles. Micropump prototypes were then fabricated and characterized. Measured characteristics proved expected micropump operation, achieving maximal flow-rate 0.43 mL.min(-1) and maximal backpressure 12.4 kPa at 300 V excitation. Good agreement between simulation and measurements on fabricated devices confirmed the correctness of the developed simulation model. PMID- 23459392 TI - Analysis of core region from egg white lysozyme forming amyloid fibrils. AB - Some of the lysozyme mutants in humans cause systemic amyloidosis. Hen egg white lysozyme (HEWL) has been well studied as a model protein of amyloid fibrils formation. We previously identified an amyloid core region consisting of nine amino acids (designated as the K peptide), which is present at 54-62 in HEWL. The K peptide, with tryptophan at its C- terminus, has the ability of self aggregation. In the present work we focused on its structural properties in relation to the formation of fibrils. The K peptide alone formed definite fibrils having beta-sheet structures by incubation of 7 days under acidic conditions at 37 degrees C. A substantial number of fibrils were generated under this pH condition and incubation period. Deletion and substitution of tryptophan in the K peptide resulted in no formation of fibrils. Tryptophan 62 in lysozyme was suggested to be especially crucial to forming amyloid fibrils. We also show that amyloid fibrils formation of the K peptide requires not only tryptophan 62 but also a certain length containing hydrophobic amino acids. A core region is involved in the significant formation of amyloid fibrils of lysozyme. PMID- 23459393 TI - Method for individualized evaluation of antiemetic effect induced by 5-HT3 receptor antagonist. AB - 5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5 hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 +/- 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective. PMID- 23459394 TI - Minimal detectable change for spatial and temporal measurements of gait after incomplete spinal cord injury. AB - BACKGROUND AND PURPOSE: Gait deviations in individuals after incomplete spinal cord injury (ISCI) that are quantified using spatiotemporal (ST) parameters are often targeted during therapeutic interventions. The purpose of our study was to establish reliability and responsiveness of ST parameters of gait after ISCI using an instrumented walkway (GaitMat II). METHODS: Sixteen individuals with ISCI participated in the study. Each subject completed at least 2 walking trials at self-selected (SS) walking speed. Intraclass correlation coefficients model 2, 1 (ICC2,1) with 95% confidence intervals (CIs), standard error of measurement (SEM), SEM percent change (SEM%), the minimal detectable change (MDC), and the MDC percent change (MDC%) were determined for 8 ST parameters including step length, single limb support, and double limb support time for the more and less impaired limb, cadence, and speed. RESULTS: Excellent test-retest agreement (0.84 0.99) was observed in all ST parameters. SEM% ranged from 8% to 29%, while MDC% ranged from 21% (cadence) to 80% (double limb support time). MDC% values were relatively higher (5-12 MDC%) for the more versus less impaired limb. DISCUSSION: SEM% results indicate that small to moderate changes were needed to indicate a real change in walking performance. Differences in MDC% values between limbs indicated that variability in parameters might be sensitive to level of motor impairment. CONCLUSION: In individuals with ISCI, different gait, balance, or strength training programs can be compared and contrasted based on a quantifiable and meaningful change in the ST parameter of interest. PMID- 23459396 TI - Radiofrequency ablation of metastatic lesions from breast cancer. AB - INTRODUCTION: Breast cancer (BC) is the most common malignancy in women. Various studies [5,6] have shown that surgical resection of single liver or lung metastases in patients with metastases from BC increases survival. Radiofrequency ablation (RFA) can be an alternative to resection in some patients when resection is not feasible. MATERIALS AND METHODS: From January 2002 to December 2008, 491 patients with liver metastases underwent US-guided percutaneous RFA. Of these patients 5 (5/491; 1%) had BC. In the same period, 32 patients with pulmonary metastases underwent CT-guided RFA. Of these patients 3 (3/32; 9%) had BC. Mean age was 61.3 years. All patients were postmenopausal and receiving polychemotherapy according to international guidelines. Inclusion criteria for RFA treatment of metastases from BC applied are identical or in some cases more restrictive than those reported in the literature. RESULTS: There were no deaths or severe complications and no treatment failures. Disease free and overall median survival were respectively 7.65 and 25.7 months after US-guided RFA and 13.4 and 34.8 months after CT-guided RFA. During follow-up (mean follow-up 26 months, range 4-63 months) 5/8 (62.5%) patients exhibited recurrence: 3/5 (60%) had local recurrence and 2/5 (40%) had non-local recurrence; 4/5 patients with recurrence were re-treated. DISCUSSION: The authors' experience confirms that RFA is an effective, safe and repeatable technique in the treatment of metastases from BC. Metastatic recurrence rate confirms that metastatic BC is a disease which requires a multidisciplinary approach and that the role of chemotherapy is indisputable. Effects on survival are promising but further confirmation is needed through prospective randomized studies. PMID- 23459395 TI - The Ups and Downs of Insulin Resistance and Type 2 Diabetes: Lessons from Genomic Analyses in Humans. AB - We are in the midst of a worldwide epidemic of type 2 diabetes (T2D) and obesity. Understanding the mechanisms underlying these diseases is critical if we are to halt their progression and ultimately prevent their development. The advent and widespread implementation of microarray technology has allowed analysis of small samples of human skeletal muscle, adipose, liver, pancreas and blood. While patterns differ in each tissue, several dominant themes have emerged from these studies, including altered expression of genes indicating increased inflammation and altered lipid and mitochondrial oxidative metabolism and insulin signaling in patients with T2D, and in some cases, in those at risk for disease. Unraveling which changes in gene expression are primary, and which are secondary to an insulin resistant or diabetes metabolic milieu remains a scientific challenge but we are one step closer. PMID- 23459397 TI - Emotional prosody modulates attention in schizophrenia patients with hallucinations. AB - Recent findings have demonstrated that emotional prosody (EP) attracts attention involuntarily (Grandjean et al., 2008). The automat shift of attention toward emotionally salient stimuli can be overcome by attentional control (Hahn et al., 2010). Attentional control is impaired in schizophrenia, especially in schizophrenic patients with hallucinations because the "voices" capture attention increasing the processing load and competing for top-down resources. The present study investigates how involuntary attention is driven by implicit EP in schizophrenia with auditory verbal hallucinations (AVH) and without (NAVH). Fifteen AVH patients, 12 NAVH patients and 16 healthy controls (HC) completed a dual-task dichotic listening paradigm, in which an emotional vocal outburst was paired with a neutral vocalization spoken in male and female voices. Participants were asked to report the speaker's gender while attending to either the left or right ear. NAVH patients and HC revealed shorter response times for stimuli presented to the attended left ear than the attended right ear. This laterality effect was not present in AVH patients. In addition, NAVH patients and HC showed faster responses when the EP stimulus was presented to the unattended ear, probably because of less interference between the attention-controlled gender voice identification task and involuntary EP processing. AVH patients did not benefit from presenting emotional stimuli to the unattended ear. The findings suggest that similar to HC, NAVH patients show a right hemispheric bias for EP processing. AVH patients seem to be less lateralized for EP and therefore might be more susceptible to interfering involuntary EP processing; regardless which ear/hemisphere receives the bottom up input. PMID- 23459398 TI - The primary practice physician program for chronic pain ((c) 4PCP): outcomes of a primary physician-pain specialist collaboration for community-based training and support. AB - OBJECTIVES: One in 3 patients sees a primary care physician (PCP) for chronic pain yet most PCPs receive no training in this field. We evaluated the impact of 4PCP ((c) Primary Practice Physician Program for Chronic Pain) comprising of a specialist-PCP training collaboration integrated with clinical support. METHODS: This prospective, controlled pilot study randomly assigned 31 physicians to receive a training program either immediately or after a 1-year control period. 4PCP includes: (1) an active learning arm, providing patient-focused, practice based learning collaboration emphasizing the biopsychosocial pain model; (2) a PCP-led clinical support arm facilitating rehabilitative matrix style care by teams of pain-informed health providers. Main outcome measures included a 19-item chronic pain physician perspectives questionnaire, physician engagement through continuing medical education hours earned, and an array of established measures of patient pain and function. RESULTS: PCPs receiving the intervention reported improvements in diagnosing and managing chronic pain (P=0.023), especially its functional consequences (P=0.008), in treatment satisfaction, and in involving other disciplines. Mean visit time dropped from 20 to 11 minutes (P<0.03) with improved patient outcomes, which correlated with 4PCP physician engagement. Significant benefit began at 10 continuing medical education hours and proved durable 1 year after trial. DISCUSSION: This pilot study demonstrates successful interdisciplinary chronic pain management by PCPs with durability of training effect, improved patient outcomes, visit efficiency, and job satisfaction. 4PCP provides a promising framework to propel the national concept of PCP-specialist collaboration for chronic pain management. PMID- 23459399 TI - Coronary artery disease: to cath or not to cath? When and how best to cath: those are the remaining questions. AB - Coronary artery disease is the leading cause of death worldwide and it often clinically manifests as stable angina. The optimal diagnostic and therapeutic strategy of patients with stable angina may be controversial. Coronary revascularization with percutaneous coronary intervention (PCI) is associated with a reduction in cardiovascular events in patients with acute coronary syndrome, whereas recent trials have failed to demonstrate the superiority of myocardial revascularization over optimal medical therapy in stable angina. The treatment of a patient with stable angina is still challenging, as the definition of "stable" and "unstable" is not so clear. Moreover, the benefit of PCI in terms of quality of life is evident, and independent from its neutral effect on survival. To date, the best timing of coronary angiography and the role of further investigations on myocardial ischemia still need to be defined. On the other hand, in spite of the clear benefit on clinical outcome of an early invasive treatment of patients with acute coronary syndrome, elderly are often undertreated, whereas the overtreatment with PCI of stable patients undergoing non cardiac surgery might even increase ischemic events due to the premature discontinuation of the antiplatelet therapy, without reducing the perioperative risk. PMID- 23459400 TI - A General, Enantioselective Synthesis of 1-Azabicyclo[m.n.0]alkane Ring Systems. AB - In this Letter, we describe a novel approach for the general and enantioselective synthesis of a diverse array of small to large 1-azabicyclo[m.n.0]alkyl ring systems with an embedded olefin handle for further functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated allylation of an Ellman sulfinimine in greater than 9:1 dr., which is readily separable by column chromatography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabicyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent overall yields and, for many systems, the only enantioselective preparation reported to date. PMID- 23459402 TI - Influence of postoperative infectious complications on long-term survival of lung cancer patients: a population-based cohort study. AB - INTRODUCTION: Surgery is essential to any curative plan for lung cancer, but is associated with a high complication rate. We sought to determine the impact of complications on long-term survival after a curative surgery for lung cancer, independent of the effect on early postoperative mortality. METHODS: We studied a population-based cohort of patients with lung cancer who underwent curative intent surgery in the province of Quebec, Canada, from 2000 to 2005. Kaplan-Meier survival analysis was used to compare unadjusted overall survival (OS) beyond postoperative day 90 for patients with and without complications. Cox regression was used to determine the prognostic impact of 30-day postoperative complications on the OS after adjusting for several confounders. RESULTS: The overall 30-day postoperative complication rate was 58.2% among 4033 eligible patients. A major infectious complication (pneumonia, empyema, or mediastinitis) occurred in 378 patients. The 5-year OS was lower for those with any postoperative complication (62.8%) than those without (73.8%; p < 0.001). Those with major infectious complications had the lowest OS (56.3%; p < 0.001). Postoperative complication was an independent prognostic factor after adjusting for several patient and treatment factors (hazard ratio = 1.37; 95% confidence interval, 1.21-1.54). Adjusted hazard ratio for major infectious complications was 1.67 (95% confidence interval, 1.39-2.01). CONCLUSIONS: Postoperative complications, particularly of a major infectious type, are strong negative predictors of long-term survival in lung cancer patients. The strong association between major infectious complications and survival may also open the door to investigational therapies targeting bacterial antigens in the perioperative period in patients who undergo lung cancer surgery. PMID- 23459401 TI - Advances with RNA interference in Alzheimer's disease research. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized clinically by memory and cognitive dysfunction. Unfortunately, there is no effective therapeutic method for AD treatment or ways to halt disease progression. Many mechanisms are involved in the disease, including genes mutation and protein dysfunction. RNA interference (RNAi) technology may potentially be able to control AD. It can inhibit the protein expression of specific genes by activating a sequence-specific RNA degradation process. This is a powerful tool with which to study gene function, investigate the mechanism of the disease, and validate drug targets. In this review, we highlight the advances in RNAi technology in the investigation and treatment of AD. PMID- 23459403 TI - Long-term outcome of proton therapy and carbon-ion therapy for large (T2a T2bN0M0) non-small-cell lung cancer. AB - INTRODUCTION: : Although many reports have shown the safety and efficacy of stereotactic body radiotherapy (SBRT) for T1N0M0 non-small-cell lung cancer (NSCLC), it is rather difficult to treat T2N0M0 NSCLC, especially T2b (>5 cm) tumor, with SBRT. Our hypothesis was that particle therapy might be superior to SBRT in T2 patients. We evaluated the clinical outcome of particle therapy for T2a/bN0M0 NSCLC staged according to the 7th edition of the International Union Against Cancer (UICC) tumor, node, metastasis classification. METHODS: : From April 2003 to December 2009, 70 histologically confirmed patients were treated with proton (n = 43) or carbon-ion (n = 27) therapy according to institutional protocols. Forty-seven patients had a T2a tumor and 23 had a T2b tumor. The total dose and fraction (fr) number were 60 (Gray equivalent) GyE/10 fr in 20 patients, 52.8 GyE/4 fr in 16, 66 GyE/10 fr in 16, 80 GyE/20 fr in 14, and other in four patients, respectively. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, Version 4.0. RESULTS: : The median follow-up period for living patients was 51 months (range, 24-103). For all 70 patients, the 4-year overall survival, local control, and progression-free survival rates were 58% (T2a, 53%; T2b, 67%), 75% (T2a, 70%; T2b, 84%), and 46% (T2a, 43%; T2b, 52%), respectively, with no significant differences between the two groups. The 4-year regional recurrence rate was 17%. Grade 3 pulmonary toxicity was observed in only two patients. CONCLUSION: : Particle therapy is well tolerated and effective for T2a/bN0M0 NSCLC. To further improve treatment outcome, adjuvant chemotherapy seems a reasonable option, whenever possible. PMID- 23459404 TI - Pharmacy school survey standards revisited. AB - In a series of 3 papers on survey practices published from 2008 to 2009, the editors of the American Journal of Pharmaceutical Education presented guidelines for reporting survey research, and these criteria are reflected in the Author Instructions provided on the Journal's Web site. This paper discusses the relevance of these criteria for publication of survey research regarding pharmacy colleges and schools. In addition, observations are offered about surveying of small "universes" like that comprised of US colleges and schools of pharmacy. The reason for revisiting this issue is the authors' concern that, despite the best of intentions, overly constraining publication standards might discourage research on US colleges and schools of pharmacy at a time when the interest in the growth of colleges and schools, curricular content, clinical education, competence at graduation, and other areas is historically high. In the best traditions of academia, the authors share these observations with the community of pharmacy educators in the hope that the publication standards for survey research about US pharmacy schools will encourage investigators to collect and disseminate valuable information. PMID- 23459405 TI - Thin single-wall BN-nanotubes formed inside carbon nanotubes. AB - We report a high yield synthesis of single-wall boron nitride nanotubes (SWBNNTs) inside single-wall carbon nanotubes (SWCNTs), a nano-templated reaction, using ammonia borane complexes (ABC) as a precursor. Transmission electron microscope (TEM), high angle annular dark field (HAADF)-scanning TEM (STEM), electron energy loss spectra (EELS) and high resolution EELS mapping using aberration-corrected TEM system clearly show the formation of thin SWBNNTs inside SWCNTs. We have found that the yield of the SWBNNT formation is high and that the most of ABC molecules decompose and fuse to form the thin BNNTs at a temperature of 1,673 K having a narrow diameter distribution of 0.7 +/- 0.1 nm. Optical absorption measurements suggest that the band gap of the thin SWBNNTs is about 6.0 eV, which provide the ideal insulator nanotubes with very small diameters. PMID- 23459406 TI - Novel molecular imaging of atherosclerosis with gallium-68-labeled apolipoprotein A-I mimetic peptide and positron emission tomography. AB - BACKGROUND: High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport. Many researchers have been working to enhance the biochemical function of HDL for use in therapy. Although HDL therapy using injections of apolipoprotein (apo)-A-I mimetics, apo A-I Milano or full-length apo A-I is dramatically effective, it is still unclear whether apo A-I or apo A-I mimetics actually enter atherosclerotic plaque and remove cholesterol from the lipid burden. We synthesized a novel 24-amino acid apo A-I mimetic peptide (known as FAMP) that potently removes cholesterol via specific ATP-binding cassette transporter A1. We then investigated the potential of FAMP to image developing plaque lesions in vivo. METHODS AND RESULTS: FAMP was modified with 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with gallium-68 ((68)Ga) for noninvasive positron emission tomography (PET) in an animal model (familial hypercholesterolemic myocardial infarction-prone rabbits: WHHL-MI) with atherosclerotic lesions. The (68)Ga-DOTA-FAMP was dramatically taken up by atherosclerotic tissues in the blood vessels and aorta of WHHL-MI rabbits, but not the control rabbits. CONCLUSIONS: An apo A-I mimetic peptide with (68)Ga-DOTA is a promising candidate diagnostic tracer for PET imaging of the atherosclerotic lipid burden and may contribute to the development of a tool for the diagnosis of plaque with PET. PMID- 23459407 TI - Reduction in morning blood pressure is a key factor for ameliorating urinary albumin excretion in patients with morning hypertension irrespective of treatment regimen. AB - BACKGROUND: The Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study has shown that losartan/hydrochlorothiazide (HCTZ) combination is superior to high-dose losartan in not only reducing morning systolic blood pressure (SBP) but also ameliorating urinary albumin excretion (UAE) after 3-month treatment. The purpose of the present study was to investigate factors associated with UAE reduction in on treatment patients with morning hypertension. METHODS AND RESULTS: A total of 95 patients registered in the MAPPY study were analyzed. Patients were treated with either a losartan/HCTZ combination regimen (n=47) or a high-dose losartan regimen (n=48). Three-month treatment significantly reduced morning SBP, evening SBP, and clinic SBP (P<0.001, P<0.05, and P<0.01, respectively). UAE and serum uric acid were significantly decreased (P<0.01 for both) without the change in estimated glomerular filtration rate. Multiple linear regression analysis indicated that %morning SBP reduction and baseline UAE were independent determinants of the UAE reduction (P=0.001 for both). After adjustments for the reduction in morning evening SBP difference, baseline UAE, and %uric acid reduction, estimated %UAE reduction level was positively correlated with the tertiles of the increasing %morning SBP reduction level (P=0.031 for trend). Moreover, subgroup analysis showed that morning SBP reduction was an independent determinant of UAE reduction in both treatment regimens. CONCLUSIONS: Reduction in morning SBP was a key factor in UAE reduction in patients with morning hypertension, irrespective of treatment regimen. PMID- 23459408 TI - Overlapping phenotypes in OFD type II and OFD type VI: report of two cases. AB - Mohr syndrome [orofaciodigital (OFD) syndrome type II] is an autosomal recessive condition that presents with short stature, broad or a bifid nasal tip, orofacial clefts, hypertrophied oral frenulae, tongue nodules or lobulated tongue, and digital anomalies. The features of OFD type II overlap with those of OFD type VI, Joubert syndrome, and short rib polydactyly (Majewski syndrome). Patients with OFD seen in our genetics in the last 4 years were reviewed. Of the five patients with OFD seen, two had Y-shaped metacarpals and other abnormalities consistent with the phenotypic spectrum of Mohr syndrome. They also had the additional radiological features of hypoplastic middle phalanges of index fingers and a hypertrophied or enlarged metatarsal with multiple phalanges arising from it. We hypothesize that type II and type VI OFD syndromes represent a continuum of the same phenotypic spectrum with severe central nervous system abnormalities at the more severe end of the spectrum. PMID- 23459410 TI - Stretching skin: The physiological limit and beyond. AB - The goal of this manuscript is to establish a novel computational model for skin to characterize its constitutive behavior when stretched within and beyond its physiological limits. Within the physiological regime, skin displays a reversible, highly nonlinear, stretch locking, and anisotropic behavior. We model these characteristics using a transversely isotropic chain network model composed of eight wormlike chains. Beyond the physiological limit, skin undergoes an irreversible area growth triggered through mechanical stretch. We model skin growth as a transversely isotropic process characterized through a single internal variable, the scalar-valued growth multiplier. To discretize the evolution of growth in time, we apply an unconditionally stable, implicit Euler backward scheme. To discretize it in space, we utilize the finite element method. For maximum algorithmic efficiency and optimal convergence, we suggest an inner Newton iteration to locally update the growth multiplier at each integration point. This iteration is embedded within an outer Newton iteration to globally update the deformation at each finite element node. To illustrate the characteristic features of skin growth, we first compare the two simple model problems of displacement- and force-driven growth. Then, we model the process of stretch-induced skin growth during tissue expansion. In particular, we compare the spatio-temporal evolution of stress, strain, and area gain for four commonly available tissue expander geometries. We believe that the proposed model has the potential to open new avenues in reconstructive surgery and rationalize critical process parameters in tissue expansion, such as expander geometry, expander size, expander placement, and inflation timing. PMID- 23459411 TI - A surrogate-based metaheuristic global search method for beam angle selection in radiation treatment planning. AB - An important element of radiation treatment planning for cancer therapy is the selection of beam angles (out of all possible coplanar and non-coplanar angles in relation to the patient) in order to maximize the delivery of radiation to the tumor site and minimize radiation damage to nearby organs-at-risk. This category of combinatorial optimization problem is particularly difficult because direct evaluation of the quality of treatment corresponding to any proposed selection of beams requires the solution of a large-scale dose optimization problem involving many thousands of variables that represent doses delivered to volume elements (voxels) in the patient. However, if the quality of angle sets can be accurately estimated without expensive computation, a large number of angle sets can be considered, increasing the likelihood of identifying a very high quality set. Using a computationally efficient surrogate beam set evaluation procedure based on single-beam data extracted from plans employing equallyspaced beams (eplans), we have developed a global search metaheuristic process based on the nested partitions framework for this combinatorial optimization problem. The surrogate scoring mechanism allows us to assess thousands of beam set samples within a clinically acceptable time frame. Tests on difficult clinical cases demonstrate that the beam sets obtained via our method are of superior quality. PMID- 23459409 TI - Evidence-based Guidelines for Precision Risk Stratification-Based Screening (PRSBS) for Colorectal Cancer: Lessons learned from the US Armed Forces: Consensus and Future Directions. AB - Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States (U.S.), with estimates of 143,460 new cases and 51,690 deaths for the year 2012. Numerous organizations have published guidelines for CRC screening; however, these numerical estimates of incidence and disease-specific mortality have remained stable from years prior. Technological, genetic profiling, molecular and surgical advances in our modern era should allow us to improve risk stratification of patients with CRC and identify those who may benefit from preventive measures, early aggressive treatment, alternative treatment strategies, and/or frequent surveillance for the early detection of disease recurrence. To better negotiate future economic constraints and enhance patient outcomes, ultimately, we propose to apply the principals of personalized and precise cancer care to risk-stratify patients for CRC screening (Precision Risk Stratification-Based Screening, PRSBS). We believe that genetic, molecular, ethnic and socioeconomic disparities impact oncological outcomes in general, those related to CRC, in particular. This document highlights evidence-based screening recommendations and risk stratification methods in response to our CRC working group private-public consensus meeting held in March 2012. Our aim was to address how we could improve CRC risk stratification-based screening, and to provide a vision for the future to achieving superior survival rates for patients diagnosed with CRC. PMID- 23459412 TI - Supercapacitor studies on NiO nanoflakes synthesized through a microwave route. AB - NiO nanomaterial was synthesized at different calcination temperatures using cetyltrimethyl ammonium bromide (CTAB) as surfactant via microwave method. Thermogravimetric studies revealed the decomposition details of Ni(OH)2 precursor. The structure and morphology of the NiO was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). NiO calcined at 300 degrees C shows a nanoflake-like structure. A possible formation mechanism has been discussed with time evolution study. Electrochemical studies indicate that the sample calcined at 300 degrees C exhibits better charge storage. The NiO nanoflakes exhibit maximum specific capacitance of 401 F g(-1) at a current density of 0.5 mA cm(-2). The energy generated and hence the charges collected from wind and solar panels are slow but in many applications the power delivery has to be at a faster rate. Considering this aspect, slow-charge and fast-discharge tests have been performed and reported. The NiO nanoflakes appear to be a promising electrode material for supercapacitor application. PMID- 23459414 TI - Antiviral drugs. PMID- 23459415 TI - Planning and structuring spinal cord injury rehabilitation: the needs assessment checklist. AB - The study aimed to evaluate the Needs Assessment Checklist (NAC) as a clinically appropriate assessment tool for use during spinal cord injury (SCI) rehabilitation. Data were obtained during routine clinical assessments from 193 patients admitted to the National Spinal Injuries Centre, UK, from September 2007 to November 2009. Reliability analyses yielded high internal consistency coefficients (mean alpha = .889, SD .051), and the mean item internal validity correlation was .534 (SD .136). All subscales of the NAC were found to be highly significant to change between administrations (mean P <.001). Several differences were found on the NAC subscales with respect to gender, age, and mobility. Pain and psychological issues were associated with poorer rehabilitation outcomes. The NAC is demonstrated to be a clinically reliable assessment tool that can be used to structure rehabilitation progress by the generation of person-centered goals. The results highlight the importance of assessing psychological issues and pain during SCI rehabilitation. PMID- 23459413 TI - Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics. AB - Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Here we describe red, single-wavelength GECIs, "RCaMPs," engineered from circular permutation of the thermostable red fluorescent protein mRuby. High resolution crystal structures of mRuby, the red sensor RCaMP, and the recently published red GECI R-GECO1 give insight into the chromophore environments of the Ca(2+)-bound state of the sensors and the engineered protein domain interfaces of the different indicators. We characterized the biophysical properties and performance of RCaMP sensors in vitro and in vivo in Caenorhabditis elegans, Drosophila larvae, and larval zebrafish. Further, we demonstrate 2-color calcium imaging both within the same cell (registering mitochondrial and somatic [Ca(2+)]) and between two populations of cells: neurons and astrocytes. Finally, we perform integrated optogenetics experiments, wherein neural activation via channelrhodopsin-2 (ChR2) or a red-shifted variant, and activity imaging via RCaMP or GCaMP, are conducted simultaneously, with the ChR2/RCaMP pair providing independently addressable spectral channels. Using this paradigm, we measure calcium responses of naturalistic and ChR2-evoked muscle contractions in vivo in crawling C. elegans. We systematically compare the RCaMP sensors to R-GECO1, in terms of action potential-evoked fluorescence increases in neurons, photobleaching, and photoswitching. R-GECO1 displays higher Ca(2+) affinity and larger dynamic range than RCaMP, but exhibits significant photoactivation with blue and green light, suggesting that integrated channelrhodopsin-based optogenetics using R-GECO1 may be subject to artifact. Finally, we create and test blue, cyan, and yellow variants engineered from GCaMP by rational design. This engineered set of chromatic variants facilitates new experiments in functional imaging and optogenetics. PMID- 23459416 TI - The archipelago ubiquitin ligase subunit acts in target tissue to restrict tracheal terminal cell branching and hypoxic-induced gene expression. AB - The Drosophila melanogaster gene archipelago (ago) encodes the F-box/WD-repeat protein substrate specificity factor for an SCF (Skp/Cullin/F-box)-type polyubiquitin ligase that inhibits tumor-like growth by targeting proteins for degradation by the proteasome. The Ago protein is expressed widely in the fly embryo and larva and promotes degradation of pro-proliferative proteins in mitotically active cells. However the requirement for Ago in post-mitotic developmental processes remains largely unexplored. Here we show that Ago is an antagonist of the physiologic response to low oxygen (hypoxia). Reducing Ago activity in larval muscle cells elicits enhanced branching of nearby tracheal terminal cells in normoxia. This tracheogenic phenotype shows a genetic dependence on sima, which encodes the HIF-1alpha subunit of the hypoxia-inducible transcription factor dHIF and its target the FGF ligand branchless (bnl), and is enhanced by depletion of the Drosophila Von Hippel Lindau (dVHL) factor, which is a subunit of an oxygen-dependent ubiquitin ligase that degrades Sima/HIF-1alpha protein in metazoan cells. Genetic reduction of ago results in constitutive expression of some hypoxia-inducible genes in normoxia, increases the sensitivity of others to mild hypoxic stimulus, and enhances the ability of adult flies to recover from hypoxic stupor. As a molecular correlate to these genetic data, we find that Ago physically associates with Sima and restricts Sima levels in vivo. Collectively, these findings identify Ago as a required element of a circuit that suppresses the tracheogenic activity of larval muscle cells by antagonizing the Sima-mediated transcriptional response to hypoxia. PMID- 23459418 TI - Efficient Synthesis of ESI-09, A Novel Non-cyclic Nucleotide EPAC Antagonist. AB - A concise and efficient synthetic approach to producing a novel non-cyclic nucleotide EPAC antagonist ESI-09 and its new analogs is reported. Key features of the synthesis include a mild and reliable one-pot procedure for an isoxazole synthon, as well as a modified one-pot protocol for the cyanomethyl ketone key intermediate. The synthesis requires inexpensive starting materials and only three linear steps for the completion in a total yield of 53%. PMID- 23459417 TI - Bifurcation theory and cardiac arrhythmias. AB - In this paper we review two types of dynamic behaviors defined by the bifurcation theory that are found to be particularly useful in describing two forms of cardiac electrical instabilities that are of considerable importance in cardiac arrhythmogenesis. The first is action potential duration (APD) alternans with an underlying dynamics consistent with the period doubling bifurcation theory. This form of electrical instability could lead to spatially discordant APD alternans leading to wavebreak and reentrant form of tachyarrhythmias. Factors that modulate the APD alternans are discussed. The second form of bifurcation of importance to cardiac arrhythmogenesis is the Hopf-homoclinic bifurcation that adequately describes the dynamics of the onset of early afterdepolarization (EAD) mediated triggered activity (Hopf) that may cause ventricular tachycardia and ventricular fibrillation (VT/VF respectively). The self-termination of the triggered activity is compatible with the homoclinic bifurcation. Ionic and intracellular calcium dynamics underlying these dynamics are discussed using available experimental and simulation data. The dynamic analysis provides novel insights into the mechanisms of VT/VF, a major cause of sudden cardiac death in the US. PMID- 23459419 TI - A comparison of participation and performance in age-group finishers competing in and qualifying for Ironman Hawaii. AB - BACKGROUND: Athletes intending to compete in Ironman Hawaii need to qualify in an age-group based qualification system. We compared participation and top ten performances of athletes in various age groups between Ironman Hawaii and its qualifier races. METHODS: Finishes in Ironman Hawaii and in its qualifier races in 2010 were analyzed in terms of performance, age, and sex. Athletes were categorized into age groups from 18-24 to 75-79 years and split and race times were determined for the top ten athletes in each age group. RESULTS: A higher proportion of athletes aged 25-49 years finished in the qualifier races than in Ironman Hawaii. In athletes aged 18-24 and 50-79 years, the percentage of finishes was higher in Ironman Hawaii than in the qualifier races. For women, the fastest race times were slower in Ironman Hawaii than in the qualifier races for those aged 18-24 (P<0.001), 25-29 (P<0.05), and 60-64 (P<0.05) years. Swim split times were slower in Ironman Hawaii than in the qualifier races for all age groups (P<0.05). Cycling times were slower in Ironman Hawaii for 18-24, 25-29, 40 44, 50-54, and 60-64 years (P<0.05) in age groups. For men, finishers aged 18-24 (P<0.001), 40-44 (P<0.001), 50-54 (P<0.01), 55-59 (P<0.001), 60-64 (P<0.01), and 65-69 (P<0.001) years were slower in Ironman Hawaii than in the qualifier races. Swim split times were slower in Ironman Hawaii than in the qualifier races for all age groups (P<0.05). Cycling times were slower in Ironman Hawaii for those aged 18-24 and those aged 40 years and older (P<0.05). CONCLUSION: There are differences in terms of participation and performance for athletes in different age groups between Ironman Hawaii and its qualifier races. Triathletes aged 25-49 years and men generally were underrepresented in Ironman Hawaii compared with in its Ironman qualifier races. These athletes may have had less chance to qualify for Ironman Hawaii than female athletes or younger (<25 years) and older (>50 years) athletes. PMID- 23459420 TI - Latent-class methods to evaluate diagnostics tests for Echinococcus infections in dogs. AB - BACKGROUND: The diagnosis of canine echinococcosis can be a challenge in surveillance studies because there is no perfect gold standard that can be used routinely. However, unknown test specificities and sensitivities can be overcome using latent-class analysis with appropriate data. METHODOLOGY: We utilised a set of faecal and purge samples used previously to explore the epidemiology of canine echinococcosis on the Tibetan plateau. Previously only the purge results were reported and analysed in a largely deterministic way. In the present study, additional diagnostic tests of copro-PCR and copro-antigen ELISA were undertaken on the faecal samples. This enabled a Bayesian analysis in a latent-class model to examine the diagnostic performance of a genus specific copro-antigen ELISA, species-specific copro-PCR and arecoline purgation. Potential covariates including co-infection with Taenia, age and sex of the dog were also explored. The dependence structure of these diagnostic tests could also be analysed. PRINCIPLE FINDINGS: The most parsimonious result, indicated by deviance information criteria, suggested that co-infection with Taenia spp. was a significant covariate with the Echinococcus infection. The copro-PCRs had estimated sensitivities of 89% and 84% respectively for the diagnoses of Echinococcus multilocularis and E. granulosus. The specificities for the copro PCR were estimated at 93 and 83% respectively. Copro-antigen ELISA had sensitivities of 55 and 57% for the diagnosis of E. multilocularis and E. granulosus and specificities of 71 and 69% respectively. Arecoline purgation with an assumed specificity of 100% had estimated sensitivities of 76% and 85% respectively. SIGNIFICANCE: This study also shows that incorporating diagnostic uncertainty, in other words assuming no perfect gold standard, and including potential covariates like sex or Taenia co-infection into the epidemiological analysis may give different results than if the diagnosis of infection status is assumed to be deterministic and this approach should therefore be used whenever possible. PMID- 23459422 TI - Photo- and electroluminescent properties europium complexes using bistriazole ligands. AB - Luminescent properties of two heteroleptic dibenzoylmethanate europium(III) complexes with 1,3-bis(5-pyridin-2-yl-1,2,4-triazol-3-yl)propane (H2L1) and 1,4 bis(5-pyridin-2-yl-1,2,4-triazol-3-yl)butane (H2L2) as ancillary ligands are described. The two double-layer-type electroluminescent cells with the structures: (1) ITO/NPB(40 nm)/Eu(DBM)2HL1 (40 nm)/LiF (1 nm)/Al (100 nm) and (2) ITO/NPB(40 nm)/Eu(DBM)2HL2 (40 nm)/LiF (1 nm)/Al (100 nm) emit red light originating from the europium complexes. The device 2 gives the maximum brightness of 455 cd/m2 at 19.2 V. PMID- 23459423 TI - Caring for your village. PMID- 23459424 TI - High stakes challenges in trauma care: The 15th Annual Society of Trauma Nurses' Conference, Las Vegas, Nevada; April 3-5, 2013. PMID- 23459421 TI - Something old and something new about molecular diagnostics in gliomas. AB - Progress in our understanding of the molecular biology of neoplasms has been driven by remarkable improvements in molecular biology techniques. This has created a rapidly moving field in which even subspecialists struggle to keep abreast of the current literature. Nowhere is this more clearly demonstrated than in neuro-oncology, wherein molecular diagnostics can now wring more clinically useful information out of very small biopsies than ever before. Herein the biologic and practical aspects of four key molecular biomarkers in gliomas are discussed, including two that have been known for some time (1p/19q codeletion and EGFR amplification) as well as two whose relevance was discovered via advanced whole-genome assays (IDH1/2 mutations and BRAF alterations). PMID- 23459425 TI - Perceptions of injury and prevention practices among pregnant and parenting teenagers. AB - Injury is a leading cause of death for young children, and the children of teenaged parents may be at increased risk. This qualitative study explored pregnant and parenting teenagers' child safety beliefs and practices related to 4 topics: preventing accidental suffocation via safe sleeping practices, motor vehicle collision safety, prevention of inflicted head trauma, and drowning prevention. Twenty-four focus groups were held with 93 pregnant and/or parenting teenagers. Participants reported variation in their sleeping arrangements, transportation methods, caregivers, and childcare settings. Confusion over safety information was common. Child safety practices were influenced by boyfriends/husbands, parents, grandparents, and teachers. PMID- 23459426 TI - Morphine versus fentanyl for pain due to traumatic injury in the emergency department. AB - The analgesic response and safety of intravenous morphine versus fentanyl for adult trauma patients who presented to the emergency department (ED) were evaluated. Median pain reduction on the numeric rating scale (0-10; 0 = no pain and 10 = worst possible pain) after opioid administration was similar between the groups (2 vs 2; P = .67). The lowest postdose pain score was recorded sooner in the fentanyl group than in the morphine group (22 vs 47 minutes, respectively; P < .001). There were no significant differences in drug-induced adverse effects between groups. Fentanyl produced a similar but more rapid analgesic response compared with morphine in trauma patients. PMID- 23459427 TI - Implementation of a screening, brief intervention, and referral to treatment program using the electronic medical record in a pediatric trauma center. AB - The purpose of this project was to develop and implement a consistent process for (1) screening adolescents by history for alcohol and substance abuse and (2) providing a motivational interview for change and appropriate referrals as needed. In the 18 months since we implemented the program, 534 patients were eligible for screening. Of these, 442 actually underwent screening and of these, 32 screened positive, thus receiving a brief intervention by social work and referral for further treatment. Use of the electronic medical record was key to the implementation and sustainability of this project. PMID- 23459428 TI - Meeting the needs of a community: teaching evidence-based youth violence prevention initiatives to members of strategic communities. AB - Youth violence is among the most serious health threats in the nation today. Violence disproportionately affects young people and people of color. Although the national rates of violent injury and homicide have shown a decline in most regions of the United States over the past 15 years, the rates of violence and related injuries among youth remain unacceptably high. The prevention of youth violence has been a priority of health departments nationwide, including the Cook County Department of Public Health. The goal of this project was to provide key community leaders, social service workers, and nurses within suburban Cook County with educational sessions on Blueprints for Violence Prevention, an initiative to promote evidence-based youth violence prevention programs. PMID- 23459429 TI - Distracted driving and implications for injury prevention in adults. AB - Distracted driving, a significant public safety issue, is typically categorized as cell phone use and texting. The increase of distracted driving behavior (DDB) has resulted in an increase in injury and death. The purpose of this study was to identify the frequency and perception of DDB in adults. A 7-question SurveyMonkey questionnaire was distributed to a convenience sample of adults. Standard demographics included age, gender, and highest levels of education. Primary outcome questions were related to frequency of DDB, and overall perceptions specific to distracted driving. Results were compared on the basis of demographics. Chi-square testing and the Kruskal-Wallis analysis of variance were applied, with statistical significance defined as P <= .05. There were 1857 respondents to the survey: 1721 were aged 23-64 years (93%); 1511 were women (81%); 1461 had high school education or greater (79%). A total of 168 respondents (9%) reported being involved in a car accident while distracted. The highest reported frequency of DDB included cell phone use (69%), eating/drinking (67%), and reaching for an object in the care (49%). Younger age (18-34 years) and higher level of education (bachelor's degree or greater) were statistically associated with these DDB; gender demonstrated no statistical significance. Text messaging was reported by 538 respondents (29%), with a statistically significant association with age (18-34 years), higher education (bachelor's degree or greater), and gender (males). A total of 1143 respondents (63%) believed that they could drive safely while distracted. This study demonstrates that DDB in adults is not restricted to reading and sending text messages. Moreover, these results indicated that people fail to perceive the dangers inherent in distracted driving. Prevention and outreach education should not be limited to texting and cell phone use but should target all forms of DDB. The age group 18-34 years should be the primary target in the adult population. PMID- 23459431 TI - Traumatic shock: the fifth shock. AB - Although, historically, shock associated with traumatic injury has been evaluated through knowledge of the 4 recognized shock patterns--cardiogenic, obstructive, distributive, and hypovolemic--many trauma practitioners view traumatic shock as a unique fifth shock pattern. Although secondary to a systemic inflammatory response syndrome triggered by endogenous danger signals, traumatic shock represents a unique pathological condition that begins with multiple, usually blunt, trauma and may conclude with multiple organ dysfunction syndrome and death. While varying mechanisms of injury may lead to different presentations of shock and cardiovascular decompensation, a unifying theme of traumatic shock is an overwhelming inflammatory response driven by proinflammatory cytokines, and the downstream results of this cytokine storm including, but not limited to, acute respiratory distress syndrome, coagulopathy, sepsis, and multiple organ dysfunction syndrome. Treatment is primarily supportive; however, research into novel therapeutics for traumatic shock is ongoing and promises some direction for future care. PMID- 23459432 TI - Using proactive coping to manage the stress of trauma patient care. AB - Some emergency nurses are resilient following trauma patient care, while others report severe traumatic stress. The purpose of this study was to determine proactive coping behaviors used by emergency nurses to prevent traumatic stress. A cross-sectional research design was used with a national sample of emergency nurses. Participants completed a 5-component Web-based survey. Data analyses included 1-tailed partial correlations. The correlation of proactive coping score to traumatic stress was significant. Proactive coping strategies that focus on the planning and preparation to provide care for traumatically injured patients may be effective at preventing traumatic stress. PMID- 23459433 TI - Assessing the academic and professional needs of trauma nurse practitioners and physician assistants. AB - Because of multiple changes in the health care environment, the use of services of physician assistants (PAs) and nurse practitioners (NPs) in trauma and critical care has expanded. Appropriate training and ongoing professional development for these providers are essential to optimize clinical outcomes. This study offers a baseline assessment of the academic and professional needs of the contemporary trauma PAs/NPs in the United States. A 14-question electronic survey, using SurveyMonkey, was distributed to PAs/NPs at trauma centers identified through the American College of Surgeons Web site and other online resources. Demographic questions included trauma center level, provider type, level of education, and professional affiliations. Likert scale questions were incorporated to assess level of mentorship, comfort level with training, and individual perceived needs for academic and professional development. There were 120 survey respondents: 60 NPs and 60 PAs. Sixty-two respondents (52%) worked at level I trauma centers and 95 (79%) were hospital-employed. Nearly half (49%) reported working in trauma centers for 3 years or less. One hundred nineteen respondents (99%) acknowledged the importance of trauma-specific education; 98 (82%) were required by their institution to obtain such training. Thirty-five respondents (32%) reported receiving $1000 per year or less as a continuing medical education benefit. Insufficient mentorship, professional development, and academic development were identified by 22 (18%), 16 (13%), and 30 (25%) respondents, respectively. Opportunities to network with trauma PAs/NPs outside their home institution were identified as insufficient by 79 (66%). While PAs/NPs in trauma centers recognize the importance of continued contemporary trauma care and evidence-based practices, attending trauma-related education is not universally required by their employers. Financial restrictions may pose an additional impediment to academic development. Therefore, resource-efficient opportunities should be a prime consideration for advanced practitioners education, especially since half of the reported workforce has 3 years or less experience. The Eastern Association of Trauma and other organizations can provide an ideal venue for mentorship, academic development, and networking that is vital to PA/NP professional development and, ultimately, quality patient care. PMID- 23459434 TI - Long-term outcomes after blunt injury to the boney thorax: an integrative literature review. AB - Management of blunt injury to the boney thorax centers on the hospital; yet, these injuries continue to impact patients long after hospitalization. The purpose of this literature review was to identify long-term outcomes associated with this injury. A literature search found 616 studies and, after screening, yielded 6 articles for review. Patient and injury characteristics and postinjury assessment findings were explored. The impact of this injury can be prolonged and life altering, prompting the need for further investigation. A greater understanding of injury-specific posthospitalization outcomes could elucidate the impact of these injuries on patients, families, and society. PMID- 23459436 TI - Community gun safety in Central Pennsylvania. AB - Firearm-related injuries are a public health issue in the United States. In rural Pennsylvania, it is a familiar way of life to have a gun or guns in the home. Safety behaviors along with gun storage in the home, specifically where there are young children (aged 6 years and younger), are a concern for this level I regional resource center in rural Pennsylvania. Head Start families were surveyed regarding gun safety habits before and after safety educational activities. A noteworthy number of families reported changing behaviors regarding better safety habits for storing and use of firearms in the home postsurvey. PMID- 23459437 TI - Factors Associated With H1N1 Influenza Vaccine Receipt in a High-Risk Population During the 2009-2010 H1N1 Influenza Pandemic. AB - BACKGROUND: Persons with spinal cord injuries and disorders (SCI/D) are at high risk for respiratory complications from influenza. During pandemic situations, where resources may be scarce, uncertainties may arise in veterans with SCI/D. OBJECTIVE: To describe concerns, knowledge, and perceptions of information received during the 2009-2010 H1N1 influenza pandemic and to examine variables associated with H1N1 vaccine receipt. METHODS: In August 2010, a cross-sectional survey was mailed to a national sample of veterans with traumatic and nontraumatic SCI/D. RESULTS: During the pandemic, 58% of veterans with SCI/D received the H1N1 vaccine. Less than two-thirds of non-H1N1 vaccine recipients indicated intentions to get the next season's influenza vaccine. Being >=50 years of age and depressed were significantly associated with higher odds of H1N1 vaccination. Being worried about vaccine side effects was associated with lower odds of H1N1 receipt. Compared to individuals who reported receiving an adequate amount of information about the pandemic, those who received too little information had significantly lower odds of receiving the H1N1 vaccine. Those who received accurate/clear information (vs confusing/conflicting) had 2 times greater odds of H1N1 vaccine receipt. CONCLUSIONS: H1N1 influenza vaccination was low in veterans with SCI/D. Of H1N1 vaccine nonrecipients, only 63% intend to get a seasonal vaccine next season. Providing an adequate amount of accurate and clear information is vital during uncertain times, as was demonstrated by the positive associations with H1N1 vaccination. Information-sharing efforts are needed, so that carry-over effects from the pandemic do not avert future healthy infection prevention behaviors. PMID- 23459438 TI - The effects of desflurane and sevoflurane on the intraocular pressure associated with endotracheal intubation in pediatric ophthalmic surgery. AB - BACKGROUND: For ophthalmic surgery anesthesia, it is vital that intraocular pressure (IOP) is controlled. Most anesthetic drugs affect IOP dose-dependently, and inhalational anesthetics dose-dependently decrease IOP. In this study, we compared the effects of desflurane and sevoflurane on IOP and hemodynamics in pediatric ophthalmic surgery. METHODS: Thirty eight pediatric patients from the age of 6 to 15 years, who were scheduled for strabismus surgery and entropion surgery, were randomized to be administered desflurane (group D, n = 19) or sevoflurane (group S, n = 19). IOPs and hemodynamic parameters were measured before induction of anesthesia (B), after induction but immediately before intubation (AI), 1 min after intubation (T1), 3 min after intubation (T3), and 5 min after intubation (T5). RESULTS: The mean arterial pressure (MAP) at T1 and heart rates (HRs) at T1 and T3 were significantly higher in group D than those in group S. There was no significant difference between the groups in IOP, cardiac index (CI) and stroke index (SI). There was a significant difference within the group in IOP, SI, MAP and HR. There was no significant difference within the group in CI. CONCLUSIONS: There was no significant difference between the groups in IOP and hemodynamic parameters. The two anesthetic agents maintained IOP and hemodynamic parameters in the normal range during anesthetic induction. PMID- 23459439 TI - Safe medication use based on knowledge of information about contraindications concerning cross allergy and comprehensive clinical intervention. AB - BACKGROUND: An investigation of safety issues regarding information on contraindications related to cross allergy was conducted to promote clinical awareness and prevent medical errors in a 2200-bed tertiary care teaching hospital. METHODS: Prescribing information on contraindications concerning cross allergy was collected from an information system and package inserts. Data mining and descriptive analysis were performed. A risk register was used for project management and risk assessment. A Plan, Do, Check, Act cycle was used as part of continuous quality improvement. Records of drug counseling and medical errors were collected from an online reporting system. A pharmacist-led multidisciplinary team initiated an intervention program on cross allergy in August 2008. RESULTS: Four years of risk management at our hospital achieved successful outcomes, ie, the number of medical errors related to cross allergies decreased by 97% (10 cases monthly before August 2008 versus three cases yearly in 2012) and risk rating decreased significantly [initial risk rating: 25(high risk) before August 2008 versus final risk rating:6 (medium-risk) in December 2012]. CONCLUSION: We conclude that comprehensive clinical interventions are very effective through team cooperation. Medication use has potential for safety risks if sufficient attention is not paid to contraindications concerning cross allergy. The potential for cross allergy involving drugs which belong to completely different pharmacological classes is easily overlooked and can be dangerous. Pharmacists can play an important role in reducing the risk of cross allergy as well as recommending therapeutic alternatives. PMID- 23459440 TI - Quantifying the Association between Personality Similarity and Marital Adjustment Using Profile Correlations: A Cautionary Tale. AB - Profile correlations are sometimes used to quantify personality trait similarity between relationship partners. These coefficients are then used to test whether similar couples are happier couples. The current paper describes several different methods of calculating profile correlations and outlines procedures for testing whether these coefficients are related to marital adjustment in a sample of 1,643 couples. There was little evidence that profile correlations were related to marital adjustment after accounting for normativeness (i.e., the degree to which individual's matched the typical personality profile) and when accounting for each individual's personality attributes. Results suggest that researchers using profile correlations should be cautious given that the interpretation and psychological meaning of results often depend on how the coefficients are calculated. PMID- 23459441 TI - Pharmacists' expectations for entry-level practitioner competency. AB - Objective. To determine if defined subgroups of pharmacists' have variability in their expectations for competency of entry-level practitioners.Methods. Rating scale data collected from the 2009 National Pharmacy Practice Survey were analyzed to determine to what extent pharmacists' degree, practice setting, and experience as a preceptor were associated with the ratings they assigned to 43 competency statements for entry-level practitioners. The competency statements determine the content on the North American Pharmacist Licensure Examination (NAPLEX).Results. Pharmacists with a doctor of pharmacy (PharmD) degree rated the co mpetency statements higher in terms of criticality to entry-level practice than did those with a bachelor of science (BS) degree (p< 0.05). Pharmacists working in inpatient settings gave slightly higher ratings to the competency statements than did pharmacists working in outpatient settings, pharmacists without direct patient care responsibilities, and those in academia. However, there were no significant differences among practitioner subgroups' criticality ratings with regard to practice setting. Preceptor pharmacists' criticality ratings of the competency statements were not significantly different from those of non-preceptor practitioners. Conclusion. Pharmacists exhibited a fair amount of agreement in their expectations for the competence of entry-level practitioners independent of their practice sites and professional roles. As the pharmacy profession embraces patient-centered clinical practice, evaluating practicing pharmacists' expectations for entry-level practitioners will provide useful information to the practitioners and academicians involved in training future pharmacists. Stakeholders in pharmacy education and regulation have vested interests in the alignment of the education of future practitioners with the needs of the profession. PMID- 23459442 TI - COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. AB - The catechol-O-methyltransferase (COMT) Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological and cognitive effects of intravenous (IV) nicotine use in African Americans (AAs; n=56) and European Americans (EAs; n=68) smokers. Overnight abstinent smokers received saline followed by 0.5 and 1.0 mg per 70 kg doses of nicotine, administered 30 min apart. Smokers with valine (Val)/Val genotype, compared with methionine (Met) carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers. PMID- 23459445 TI - Eleven new species of theridiosomatid spiders from southern China (Araneae, Theridiosomatidae). AB - Two new genera of the spider family Theridiosomatidae, Alariagen.n. with the type species Alaria chengguanensissp. n., Mengluniagen.n. with the type species Menglunia inaffectasp. n., are described from Guizhou and Yunnan, China. Nine more new species from Guangxi, Guizhou, Hainan and Yunnan Provinces of southern China are described: Baalzebub rastrariussp. n.,Baalzebub youyiensissp. n., Karstia nitidasp. n., Karstia prolatasp. n.,Ogulnius hapalussp. n., Theridiosoma plumariasp. n., Theridiosoma triumphalissp. n., Theridiosoma vimineumsp. n., Zoma fasciasp. n. The type specimens are deposited in the Institute of Zoology, Chinese Academy of Sciences in Beijing. PMID- 23459444 TI - Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen. AB - Compelling evidence points to a key role for insulin-like growth factor 1 (IGF1) signaling in breast cancer development and progression. In addition, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling. Recent translational studies support a cross talk between IGF1R and ERalpha at different levels and data suggest enhanced IGF1R signaling as a causative mechanism of tamoxifen (TAM) resistance. We tested whether functional germline variations in the IGF pathway are associated with clinical outcome in ER-positive primary invasive breast cancer patients, who were treated with surgery and adjuvant TAM. Tissue samples of 222 patients with ER+ primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue samples and six functional IGF1 pathway polymorphisms were analyzed using direct DNA sequencing and PCR-restriction fragment length polymorphism. In multivariable analysis, patients with primary invasive breast cancer carrying IGF1R_rs2016347 G allele had a significantly increased risk of early tumor progression (hazard ratio (HR) 2.01; adjusted P=0.004) and death (HR 1.84; adjusted P=0.023) compared with patients carrying G/T or T/T, independent of established clinicopathological determinants. This association remained significant after adjusting for multiple testing. In addition, we were able to demonstrate that IRS1_rs1801123 and IGFBP3_rs2854744 were significantly associated with lymph node involvement and tumor size, respectively. We provide the first evidence for IGF1R_rs2016347 as an independent prognostic marker for ER+ breast cancer patients treated with TAM and support a rational for combined treatment strategies. PMID- 23459446 TI - Gender difference in coronary sinus anatomy and left ventricular lead pacing parameters in patients with cardiac resynchronization therapy. AB - BACKGROUND: Recent studies have suggested better outcomes from cardiac resynchronization therapy (CRT) in women. Gender differences in coronary sinus (CS) anatomy and left ventricular (LV) lead parameters in patients undergoing CRT, however, have not been well studied. METHODS AND RESULTS: Two hundred and twenty-three consecutive patients, undergoing CRT at the University of California in San Diego Medical Center from 2003 to 2011 were included in this study. The location of the LV lead was assessed on coronary venography and chest X-ray recorded at the time of device implantation. Optimal LV lead position was defined as either mid-lateral or posterolateral LV wall. The relationship between LV lead position (optimal or non-optimal position) and LV lead parameters at completion of implant were compared between genders. No statistically significant gender differences were noted in baseline characteristics. LV lead implantation was successful in 217 patients (97.3%). Lateral or posterolateral CS branches were unavailable in more women than men (26.3% vs. 10.8%, P=0.011). Women had a higher LV lead pacing threshold than men (P=0.003) and gender was an independent risk factor of high LV lead pacing threshold (P=0.008). CONCLUSIONS: Women had an anatomical disadvantage for LV lead placement and had higher LV lead pacing threshold compared to men. Implanting physicians should be aware of gender differences during LV lead placement in order to maximize CRT benefits. PMID- 23459448 TI - High-resolution simulations of the thermophysiological effects of human exposure to 100 MHz RF energy. AB - Human exposure to radio frequency (RF) electromagnetic energy is known to result in tissue heating and can raise temperatures substantially in some situations. Standards for safe exposure to RF do not reflect bio-heat transfer considerations however. Thermoregulatory function (vasodilation, sweating) may mitigate RF heating effects in some environments and exposure scenarios. Conversely, a combination of an extreme environment (high temperature, high humidity), high activity levels and thermally insulating garments may exacerbate RF exposure and pose a risk of unsafe temperature elevation, even for power densities which might be acceptable in a normothermic environment. A high-resolution thermophysiological model, incorporating a heterogeneous tissue model of a seated adult has been developed and used to replicate a series of whole-body exposures at a frequency (100 MHz) which approximates that of human whole-body resonance. Exposures were simulated at three power densities (4, 6 and 8 mW cm(-2)) plus a sham exposure and at three different ambient temperatures (24, 28 and 31 degrees C). The maximum hypothalamic temperature increase over the course of a 45 min exposure was 0.28 degrees C and occurred in the most extreme conditions (T(AMB) = 31 degrees C, PD = 8 mW cm(-2)). Skin temperature increases attributable to RF exposure were modest, with the exception of a 'hot spot' in the vicinity of the ankle where skin temperatures exceeded 39 degrees C. Temperature increases in internal organs and tissues were small, except for connective tissue and bone in the lower leg and foot. Temperature elevation also was noted in the spinal cord, consistent with a hot spot previously identified in the literature. PMID- 23459447 TI - Sex-based differences in clinical practice and outcomes for Japanese patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Limited data are available for sex-based differences in Japanese patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: The study patients comprised 1,197 women and 3,182 men who underwent primary PCI for AMI in 2005-2007. Compared with the men, the women were significantly older, and had significantly longer onset-to-balloon time and lower rate of follow-up coronary angiography. In hospital mortality was higher among women than men (8.7% vs. 4.9%, P<0.001). Although the cumulative incidence of all-cause death at 3 years was also higher for women (17.7% vs. 10.7%, P<0.001), the adjusted risk for all-cause death was comparable [hazard ratio (HR, women vs. men)=0.94, 95% confidence interval (CI): 0.71-1.24, P=0.66]. The incidence (12.1% vs. 12.4%, P=0.77) and the adjusted risk (HR=0.99, 95% CI 0.78-1.24, P=0.92) for any clinically-driven coronary revascularization were both comparable. However, regarding any non-clinically driven coronary revascularization, the incidence (19.6% vs. 27.8%, P<0.001) and the adjusted risk (HR=0.79, 95% CI 0.65-0.95, P=0.012) were both lower in women relative to men. CONCLUSIONS: In current Japanese clinical practice for AMI, onset-to-balloon time was significantly longer in women than in men. Female sex was associated with lower follow-up coronary angiography rate and lower incidence of any non-clinically-driven coronary revascularization, whereas the incidence of any clinically-driven coronary revascularization was comparable between the sexes. PMID- 23459449 TI - Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. AB - Several retrospective studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. We thus prospectively screened for PAOD in patients with chronic phase chronic myeloid leukemia (CP CML) being treated with tyrosine kinase inhibitors (TKI), including imatinib and nilotinib. One hundred and fifty-nine consecutive patients were evaluated for clinical and biochemical risk factors for cardiovascular disease. Non-invasive assessment for PAOD included determination of the ankle brachial index (ABI) and duplex ultrasonography. A second cohort consisted of patients with clinically manifest PAOD recruited from additional collaborating centers. Pathological ABI were significantly more frequent in patients on first line nilotinib (7 of 27; 26%) and in patients on second-line nilotinib (10 of 28; 35.7%) as compared with patients on first-line imatinib (3 of 48; 6.3%). Clinically manifest PAOD was identified in five patients, all with current or previous nilotinib exposure only. Relative risk for PAOD determined by a pathological ABI in first-line nilotinib-treated patients as compared with first line imatinib-treated patients was 10.3. PAOD is more frequently observed in patients receiving nilotinib as compared with imatinib. Owing to the severe nature of clinically manifest PAOD, longitudinal non-invasive monitoring and careful assessment of risk factors is warranted. PMID- 23459443 TI - Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. AB - Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross sectional meta-analyses were null (Pinteraction>5.0 * 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects. PMID- 23459450 TI - Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. AB - Peripheral arterial occlusive disease (PAOD) occurs in patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs). The risk of developing PAOD on TKI therapy is unknown and causality has not been established. Patients with CML-CP from three randomized phase III studies (IRIS, TOPS and ENESTnd) were divided into three cohorts: no TKI (cohort 1; n=533), nilotinib (cohort 2; n=556) and imatinib (cohort 3; n=1301). Patients with atherosclerotic risk factors were not excluded. Data were queried for terms indicative of PAOD. Overall, 3, 7 and 2 patients in cohorts 1, 2 and 3, respectively, had PAOD; 11/12 patients had baseline PAOD risk factors. Compared with that of cohort 1, exposure-adjusted risks of PAOD for cohorts 2 and 3 were 0.9 (95% CI, 0.2-3.3) and 0.1 (95% CI, 0.0-0.5), respectively. Multivariate logistic regression revealed that nilotinib had no impact on PAOD rates compared with no TKI, whereas imatinib had decreased rates of PAOD compared with no TKI. Nilotinib was associated with higher rates of PAOD versus imatinib. Baseline assessments, preferably within clinical studies, of PAOD and associated risk factors should occur when initiating TKI therapy in CML; patients should receive monitoring and treatment according to the standard of care for these comorbidities. PMID- 23459451 TI - Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. AB - JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect. PMID- 23459452 TI - Copolythiophene-derived colorimetric and fluorometric sensor for lysophosphatidic acid based on multipoint interactions. AB - 3-Phenylthiophene-based water-soluble copolythiophenes (CPT9) were designed for colorimetric and fluorometric detection of lysophosphatidic acid (LPA) based on electrostatic interaction, hydrophobic interaction, and hydrogen bonding. Other negatively charged species gave nearly no interference, and the detection limit reached to 0.6 MUM, which is below the requisite detection limits for LPA in human plasma samples. The appealing performance of CPT9 was demonstrated to originate from the multipoint interaction-induced conformational change of conjugated backbone and weakened electron transfer effect. To our best knowledge, this is the first polythiophene based optical sensor which displays emission peak red-shift followed with fluorescence enhancement. PMID- 23459453 TI - Molecular staging of node negative patients with colorectal cancer. AB - Metastatic disease is the principle cause of death from colorectal cancer. In that context, the most significant indicator of overall survival and therapeutic response to adjuvant chemotherapy is the presence of metastatic tumor cells in regional lymph nodes. Although histopathologic analysis of lymph nodes is central to all colorectal cancer staging paradigms, its prognostic and predictive value is limited. Indeed, about 30% of patients with histopathology-negative lymph nodes (pN0) die from metastatic disease, reflected by microscopic lymph node metastases that are overlooked by standard techniques. These unrecognized tumor cells are especially important when considering racial disparities in outcomes in colorectal cancer patients, where blacks with lymph node-negative disease have the largest discrepancies in outcomes, with more than 40% excess mortality compared to Caucasian patients. However, the significance of tumor cells in regional lymph nodes remains uncertain, and approximately 50% of colorectal cancer patients with nodal metastases detected by histopathology remain free of recurrent disease. Accurate identification of occult metastases in regional lymph nodes, and defining their value as prognostic markers of recurrence risk and predictive markers of response to adjuvant chemotherapy remains one challenge in the management of colorectal cancer patients. Guanylyl cyclase C (GUCY2C), a receptor which is expressed primarily in intestinal cells normally, but is universally over-expressed by colorectal cancer cells, has been validated to detect prognostically significant occult metastases using quantitative RT-PCR (RT qPCR). Biomarker validation was achieved through a prospective, multicenter, blinded clinical trial. In that trial, occult tumor burden estimated across all regional lymph nodes by GUCY2C RT-qPCR predicted clinical outcomes, identifying node-negative patients with a low (near zero) risk, and those with >80% risk, of developing disease recurrence. Moreover, there was disproportionately higher occult tumor burden in black, compared to white, patients which contributes to racial disparities in outcomes in colorectal cancer. The diagnostic paradigm quantifying occult tumor burden using GUCY2C qRT-PCR is positioned to reduce racial disparities in colorectal cancer mortality. PMID- 23459455 TI - Feasibility of a braided composite for orthopedic bone cast. AB - A tubular braided composite bone cast for improving the efficiency and quality of bone fracture treatment is investigated. Finite element analysis was used to evaluate stress concentrations in fracture sites supported with plate and tubular casts. The stress in a plated bone is 768 % of that in a whole bone at the same location, while it is only 47 % in a bone with a tubular cast. Three unbroken synthetic humeri were mechanically tested using an in-vitro long bone testing procedure developed in-house to find their stiffness at 20 degrees and 60 degrees abduction; these were found to be 116.8 +/- 1.5 N/mm and 20.63 +/- 0.02 N/mm, respectively. A 2 cm gap osteotomy was cut through the diaphysis in each bone. The bones were casted with a Kevlar/Cold cure composite, with calculated braid angles and thicknesses that Closely matched bone propoerties. The stiffness tests were repeated, and the results were within 10 % of the unbroken bone. This novel method of bone casting is promising if other clinical challenges can be minimized. PMID- 23459454 TI - Failure to filter: anxious individuals show inefficient gating of threat from working memory. AB - Dispositional anxiety is a well-established risk factor for the development of psychiatric disorders along the internalizing spectrum, including anxiety and depression. Importantly, many of the maladaptive behaviors characteristic of anxiety, such as anticipatory apprehension, occur when threat is absent. This raises the possibility that anxious individuals are less efficient at gating threat's access to working memory, a limited capacity workspace where information is actively retained, manipulated, and used to flexibly guide goal-directed behavior when it is no longer present in the external environment. Using a well validated neurophysiological index of working memory storage, we demonstrate that threat-related distracters were difficult to filter on average and that this difficulty was exaggerated among anxious individuals. These results indicate that dispositionally anxious individuals allocate excessive working memory storage to threat, even when it is irrelevant to the task at hand. More broadly, these results provide a novel framework for understanding the maladaptive thoughts and actions characteristic of internalizing disorders. PMID- 23459456 TI - In brief: Auvi-Q--a new epinephrine auto-injector. PMID- 23459457 TI - Mirabegron (Myrbetriq) for overactive bladder. PMID- 23459458 TI - PPIs and fracture risk. PMID- 23459459 TI - Effects of nicotine on spinal cord injury pain: a randomized, double-blind, placebo controlled crossover trial. AB - BACKGROUND: One factor affecting spinal cord injury (SCI)-related pain may be nicotine. Case reports have described a worsening of neuropathic pain from smoking and relief from abstinence. Neurobiological correlates also implicate the potential effect of nicotine on SCI-related pain. METHOD: The current study employed a randomized, placebo-controlled crossover design to examine the effect of nicotine exposure on subtypes of SCI-related pain among smokers and nonsmokers. RESULTS: Whereas nonsmokers with SCI showed a reduction in mixed forms of pain following nicotine exposure, smokers with SCI showed a converse increase in pain with regard to both mixed and neuropathic forms of pain. The exacerbation of pain in chronic nicotine or tobacco users may not only elucidate possible pain mechanisms but may also be of use in smoking cessation counseling among those with SCI. PMID- 23459461 TI - Efficacy and safety of stepwise introduction of insulin lispro mix 50 in Japanese patients with type 2 diabetes inadequately controlled by oral therapy. AB - The objective of this study was to evaluate the efficacy and safety of stepwise introduction of insulin lispro mix 50 (LM50) from once to 3 times daily in Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy. This was a multicenter, open-label, non-randomized trial consisting of three 16-week periods (48 weeks total); all patients were given once-daily injections of LM50 in Period 1. The regimen was intensified to twice daily in Period 2, and 3 times daily in Period 3 if HbA1c was >= 6.9% before the start of the period. A total of 135 patients were enrolled, and 116 patients completed the study. Main baseline characteristics of enrolled patients were a mean age of 60.3 years, mean diabetes duration of 11.4 years, mean BMI of 25.2 kg/m(2), and mean HbA1c of 8.71%. The percentages of patients who achieved HbA1c levels <6.9% and <7.4% at endpoint were 18.5% (25/135 patients) and 52.6% (71/135 patients), respectively. Mean HbA1c decreased significantly from 8.70% to 7.44% (p<0.001). The incidence of hypoglycemic episodes over the treatment periods was 65.9% (89/135 patients); severe hypoglycemia occurred in 2.2% (3/135 patients). There were no other clinically significant safety issues related to the study drug. Stepwise introduction of LM50 from once to 3 times daily can be a safe, effective, and simple therapy for Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy. PMID- 23459460 TI - miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1. AB - As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR 199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFbeta exposure, and ectopic expression of miR-199a 5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFbeta signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. PMID- 23459462 TI - Papillary thyroid carcinoma in one of identical twin patients with Pendred syndrome. AB - Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter. Several cases of Pendred syndrome with follicular thyroid carcinomas were reported previously. Here we report identical twin patients with Pendred syndrome, who had thyroid tumors with distinct histopathological findings. 34-year-old identical twins with congenital deafness and goiter were referred to our hospital with complaint of neck discomfort. The genetic testing showed that these twin patients were compound heterozygotes carrying the same two mutations in the Pendred's syndrome (PDS / SLC26A4) gene (c2168A > G and ins2110GCTGG), which confirmed the diagnoses of Pendred syndrome. They underwent thyroidectomy. Histological examination of the thyroid tumors resected from these twin patients revealed follicular variant of papillary thyroid carcinoma, and diffuse and nodular goiter without any evidence of malignancy, respectively. To our knowledge, the former is the first case of follicular variant of papillary thyroid carcinoma in Pendred Syndrome. PMID- 23459463 TI - Early postprandial glucagon surge affects postprandial glucose levels in obese and non-obese patients with type 2 diabetes. AB - Postprandial glucagon secretion was shown to be dysregulated in patients with type 2 diabetes. However, the differences in secretory patterns between obese and non-obese patients and their physiological effects on plasma glucose levels are not fully understood. This study population consisted of 21 (10 obese and 11 non obese) consecutive patients with type 2 diabetes admitted for glycemic control. A 3-hour mixed-meal tolerance test was performed after glycemic control improved. Six non-diabetic subjects were also enrolled in the test. Postprandial glucagon levels increased after 30 min in diabetic patients but not in non-diabetic subjects. The glucagon levels in obese diabetic patients were significantly higher than those in non-obese diabetic patients, while the percent values of postprandial glucagon levels were not different between these groups. In diabetic patients, there were significant positive correlations between the percent value at 30 min and the early postprandial glucose levels at 0, 15 and 30 min and the areas under the curve (AUC0-30 and AUC30-90). Interestingly, the ratio of this percent glucagon value to the C-peptide level at 30 min was significantly associated with the late half of the postprandial glucose levels at 90, 120, 150 and 180 min and the AUC90-180. This is the first report that demonstrates the glucagon secretory patterns and the close correlations in detailed time course between the early postprandial glucagon response and the early and the late half of the postprandial glucose levels in obese and non-obese patients with type 2 diabetes. PMID- 23459464 TI - Tuning the magneto-optical response of iron oxide nanocrystals in Au- and Ag based plasmonic media. AB - We investigated the magneto-optical response of chemically synthesized iron oxide magnetic nanocrystals, optically coupled with ordered planar arrays of plasmonic nanoparticles. We compare the signals from two classes of systems, featuring either Au or Ag as the plasmonic counterpart. The localized surface plasmon resonance of the Ag and Au nanoparticles arrays were superimposed or detuned, respectively, with respect to the dominant magneto-optical transitions of the magnetic material. Under resonance, a significant enhancement of the magneto optical signal was observed. In both cases, we could separate the purely plasmonic and the magnetic contributions in the magneto-optical spectrum of the optically coupled composite based on their different magnetic-field dependence. PMID- 23459465 TI - Investigation of the motion of a viscous fluid in the vitreous cavity induced by eye rotations and implications for drug delivery. AB - Intravitreal drug delivery is a commonly used treatment for several retinal diseases. The objective of this research is to characterize and quantify the role of the vitreous humor motion, induced by saccadic movements, on drug transport processes in the vitreous chamber. A Perspex model of the human vitreous chamber was created, and filled with a purely viscous fluid, representing eyes with a liquefied vitreous humor or those containing viscous tamponade fluids. Periodic movements were applied to the model and the resulting three-dimensional (3D) flow fields were measured. Drug delivery within the vitreous chamber was investigated by calculating particle trajectories using integration over time of the experimental velocity fields. The motion of the vitreous humor generated by saccadic eye movements is intrinsically 3D. Advective mass transport largely overcomes molecular diffusive transport and is significantly anisotropic, leading to a much faster drug dispersion than in the case of stationary vitreous humor. Disregarding the effects of vitreous humor motion due to eye movements when predicting the efficiency of drug delivery treatments leads to significant underestimation of the drug transport coefficients, and this, in turn, will lead to significantly erroneous predictions of the concentration levels on the retina. PMID- 23459466 TI - The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia. AB - We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 (MIR137) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia (n=510; F1,506=17.7, P=3.1 * 10(-5)). In an imaging genetics subsample that included additional matched controls (n=213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity (F3,209=13.6, P=3.88 * 10(-8)) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls. PMID- 23459470 TI - Monte Carlo estimation of total variation distance of Markov chains on large spaces, with application to phylogenetics. AB - Markov chains are widely used for modeling in many areas of molecular biology and genetics. As the complexity of such models advances, it becomes increasingly important to assess the rate at which a Markov chain converges to its stationary distribution in order to carry out accurate inference. A common measure of convergence to the stationary distribution is the total variation distance, but this measure can be difficult to compute when the state space of the chain is large. We propose a Monte Carlo method to estimate the total variation distance that can be applied in this situation, and we demonstrate how the method can be efficiently implemented by taking advantage of GPU computing techniques. We apply the method to two Markov chains on the space of phylogenetic trees, and discuss the implications of our findings for the development of algorithms for phylogenetic inference. PMID- 23459468 TI - The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. AB - The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P<=0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes. PMID- 23459472 TI - Convenient Synthesis of Multivalent Zinc(II)-Dipicolylamine Complexes for Molecular Recognition. AB - A pair of novel dipicolylamine ligands bearing isothiocyanate groups were used as conjugation reagents to prepare multivalent molecules with anionic recognition capability. The isothiocyanates were reacted with two classes of dendritic scaffolds bearing primary amines, squaraine rotaxanes and PAMAM dendrimers, and the products were converted into water soluble zinc(II) coordination complexes. The multivalent squaraine rotaxanes exhibit high fluorescence quantum yields in water and are very well suited for biological imaging applications. PMID- 23459471 TI - Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents. AB - Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date. PMID- 23459473 TI - Electrospinning covalently cross-linking biocompatible hydrogelators. AB - Many hydrogel materials of interest are homogeneous on the micrometer scale. Electrospinning, the formation of sub-micrometer to micrometer diameter fibers by a jet of fluid formed under an electric field, is one process being explored to create rich microstructures. However, electrospinning a hydrogel system as it reacts requires an understanding of the gelation kinetics and corresponding rheology near the liquid-solid transition. In this study, we correlate the structure of electrospun fibers of a covalently cross-linked hydrogelator with the corresponding gelation transition and kinetics. Polyethylene oxide (PEO) is used as a carrier polymer in a chemically cross-linking poly(ethylene glycol) high molecular weight heparin (PEG-HMWH) hydrogel. Using measurements of gelation kinetics from multiple particle tracking microrheology (MPT), we correlate the material rheology with the the formation of stable fibers. An equilibrated, cross linked hydrogel is then spun and the PEO is dissolved. In both cases, microstructural features of the electrospun fibers are retained, confirming the covalent nature of the network. The ability to spin fibers of a cross-linking hydrogel system ultimately enables the engineering of materials and microstructural length scales suitable for biological applications. PMID- 23459474 TI - Cytosporone B, an inhibitor of the type III secretion system of Salmonella enterica serovar Typhimurium. AB - Bacterial virulence factors have been increasingly regarded as attractive targets for development of novel antibacterial agents. Virulence inhibitors are less likely to generate bacterial resistance, which makes them superior to traditional antibiotics that target bacterial viability. Salmonella enterica serovar Typhimurium, an important food-borne human pathogen, has type III secretion system (T3SS) as its major virulence factor. T3SS secretes effector proteins to facilitate invasion into host cells. In this study, we identified several analogs of cytosporone B (Csn-B) that strongly block the secretion of Salmonella pathogenicity island 1 (SPI-1)-associated effector proteins, without affecting the secretion of flagellar protein FliC in vitro. Csn-B and two other derivatives exhibited a strong inhibitory effect on SPI-1-mediated invasion to HeLa cells, while no significant toxicity to bacteria was observed. Nucleoid proteins Hha and H-NS bind to the promoters of SPI-1 regulator genes hilD, hilC, and rtsA to repress their expression and consequently regulate the expression of SPI-1 apparatus and effector genes. We found that Csn-B upregulated the transcription of hha and hns, implying that Csn-B probably affected the secretion of effectors through the Hha-H-NS regulatory pathway. In summary, this study presented an effective SPI-1 inhibitor, Csn-B, which may have potential in drug development against antibiotic-resistant Salmonella. PMID- 23459475 TI - Effect of oseltamivir carboxylate consumption on emergence of drug-resistant H5N2 avian influenza virus in Mallard ducks. AB - Oseltamivir carboxylate (OC) has been detected in environmental waters at various levels during recent influenza seasons in humans, reflecting levels of usage and stability of this drug. In consideration of the role of waterfowl as hosts for influenza viruses that may contribute to human infections, we evaluated the effect of consumption of low doses of OC on development of oseltamivir-resistant influenza virus mutants in mallard ducks (Anas platyrhynchos) infected with two different low-pathogenic (LP) H5N2 avian influenza viruses (AIV). We detected development of virus variants carrying a known molecular marker of oseltamivir resistance (neuraminidase E119V) in 4 out of 6 mallards infected with A/Mallard/Minnesota/182742/1998 (H5N2) and exposed to 1,000 ng/liter OC. The mutation first appeared as a minor population on days 5 to 6 and was the dominant genotype on days 6 to 8. Oseltamivir-resistant mutations were not detected in virus from ducks not exposed to the drug or in ducks infected with a second strain of virus and similarly exposed to OC. Virus isolates carrying the E119V mutation displayed in vitro replication kinetics similar to those of the wild type virus, but in vivo, the E119V virus rapidly reverted back to wild type in the absence of OC, and only the wild-type parental strain was transmitted to contact ducks. These results indicate that consumption by wild waterfowl of OC in drinking water may promote selection of the E119V resistance mutation in some strains of H5N2 AIV that could contribute to viruses infecting human populations. PMID- 23459476 TI - Characterization of porin expression in Klebsiella pneumoniae Carbapenemase (KPC) producing K. pneumoniae identifies isolates most susceptible to the combination of colistin and carbapenems. AB - We characterized carbapenem resistance mechanisms among 12 Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (referred to here as KPC K. pneumoniae) clinical isolates and evaluated their effects on the activity of 2- and 3-drug combinations of colistin, doripenem, and ertapenem. All isolates were resistant to ertapenem and doripenem; 75% (9/12) were resistant to colistin. Isolates belonged to the ST258 clonal group and harbored blaKPC-2, blaSHV-12, and blaTEM-1. As determined by time-kill assays, doripenem (8 MUg/ml) and ertapenem (2 MUg/ml) were inactive against 92% (11/12) and 100% (12/12) of isolates, respectively. Colistin (2.5 MUg/ml) exerted some activity (range, 0.39 to 2.5 log10) against 78% (7/9) of colistin-resistant isolates. Colistin-ertapenem, colistin-doripenem, and colistin-doripenem-ertapenem exhibited synergy against 42% (5/12), 50% (6/12), and 67% (8/12) of isolates, respectively. Expression of ompK35 and ompK36 porins correlated with each other (R(2) = 0.80). Levels of porin expression did not correlate with colistin-doripenem or colistin-ertapenem synergy. However, synergy with colistin-doripenem-ertapenem was more likely against isolates with high porin expression than those with low expression (100% [8/8] versus 0% [0/4]; P = 0.002). Moreover, bactericidal activity (area under the bacterial killing curve) against isolates with high porin expression was greater for colistin-doripenem-ertapenem than colistin-doripenem or colistin ertapenem (P <= 0.049). In conclusion, colistin-carbapenem combinations may provide optimal activity against KPC K. pneumoniae, including colistin-resistant isolates. Screening for porin expression may identify isolates that are most likely to respond to a triple combination of colistin-doripenem-ertapenem. In the future, molecular characterization of KPC K. pneumoniae isolates may be a practical tool for identifying effective combination regimens. PMID- 23459477 TI - Pharmacokinetics of phase I nevirapine metabolites following a single dose and at steady state. AB - Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200-mg oral dose of nevirapine in 10 HIV-negative African Americans and a steady-state 200-mg twice-daily dose in 10 HIV-infected Cambodians. Nevirapine was assayed by high-performance liquid chromatography (HPLC). The 2-, 3-, 8- and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Pharmacokinetic parameters were calculated by noncompartmental analysis. The metabolic index for each metabolite was defined as the ratio of the metabolite area under the concentration-time curve (AUC) to the nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12 hydroxynevirapine. From single dose to steady state, the metabolic index increased for 3-hydroxynevirapine (P < 0.01) but decreased for 2 hydroxynevirapine (P < 0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (P < 0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (2-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4 carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways and implications for drug efficacy and toxicity. PMID- 23459478 TI - Epidemiology of antituberculosis drug resistance in Saudi Arabia: findings of the first national survey. AB - The real magnitude of antituberculosis (anti-TB) drug resistance in Saudi Arabia is still unknown because the available data are based on retrospective laboratory studies that were limited to hospitals or cities. A representative national survey was therefore conducted to investigate the levels and patterns of anti-TB drug resistance and explore risk factors. Between August 2009 and July 2010, all culture-positive TB patients diagnosed in any of the tuberculosis reference laboratories of the country were enrolled. Isolates obtained from each patient were tested for susceptibility to first-line anti-TB drugs by the automated Bactec MGIT 960 method. Of the 2,235 patients enrolled, 75 cases (3.4%) were lost due to culture contamination and 256 (11.5%) yielded nontuberculous mycobacteria (NTM). Finally, 1,904 patients (85.2% of those enrolled) had available drug susceptibility testing results. Monoresistance to streptomycin (8.1%; 95% confidence interval [CI], 7.2 to 9.1), isoniazid (5.4%; 95% CI, 4.7 to 6.2), rifampin (1%; 95% CI, 0.7 to 1.3) and ethambutol (0.8%; 95% CI, 0.5 to 1.2) were observed. Multidrug-resistant TB (MDR-TB) was found in 1.8% (95% CI, 1.4 to 2.4) and 15.9% (95% CI, 15.4 to 16.5) of new and previously treated TB cases, respectively. A treatment history of active TB, being foreign-born, having pulmonary TB, and living in the Western part of the country were the strongest independent predictors of MDR-TB. Results from the first representative national anti-TB drug resistance survey in Saudi Arabia suggest that the proportion of MDR TB is relatively low, though there is a higher primary drug resistance. A strengthened continuous surveillance system to monitor trends over time and second-line anti-TB drug resistance as well as implementation of innovative control measures, particularly among immigrants, is warranted. PMID- 23459479 TI - Polymyxin resistance of Pseudomonas aeruginosa phoQ mutants is dependent on additional two-component regulatory systems. AB - Pseudomonas aeruginosa can develop resistance to polymyxin as a consequence of mutations in the PhoPQ regulatory system, mediated by covalent lipid A modification. Transposon mutagenesis of a polymyxin-resistant phoQ mutant defined 41 novel loci required for resistance, including two regulatory systems, ColRS and CprRS. Deletion of the colRS genes, individually or in tandem, abrogated the polymyxin resistance of a DeltaphoQ mutant, as did individual or tandem deletion of cprRS. Individual deletion of colR or colS in a DeltaphoQ mutant also suppressed 4-amino-L-arabinose addition to lipid A, consistent with the known role of this modification in polymyxin resistance. Surprisingly, tandem deletion of colRS or cprRS in the DeltaphoQ mutant or individual deletion of cprR or cprS failed to suppress 4-amino-L-arabinose addition to lipid A, indicating that this modification alone is not sufficient for PhoPQ-mediated polymyxin resistance in P. aeruginosa. Episomal expression of colRS or cprRS in tandem or of cprR individually complemented the Pm resistance phenotype in the DeltaphoQ mutant, while episomal expression of colR, colS, or cprS individually did not. Highly polymyxin-resistant phoQ mutants of P. aeruginosa isolated from polymyxin-treated cystic fibrosis patients harbored mutant alleles of colRS and cprS; when expressed in a DeltaphoQ background, these mutant alleles enhanced polymyxin resistance. These results define ColRS and CprRS as two-component systems regulating polymyxin resistance in P. aeruginosa, indicate that addition of 4 amino-L-arabinose to lipid A is not the only PhoPQ-regulated biochemical mechanism required for resistance, and demonstrate that colRS and cprS mutations can contribute to high-level clinical resistance. PMID- 23459480 TI - Comparative antimicrobial activities of aerosolized sodium hypochlorite, chlorine dioxide, and electrochemically activated solutions evaluated using a novel standardized assay. AB - The main aim of this study was to develop a standardized experimental assay to enable differential antimicrobial comparisons of test biocidal aerosols. This study represents the first chlorine-matched comparative assessment of the antimicrobial activities of aerosolized sodium hypochlorite, chlorine dioxide, and electrochemically activated solution (ECAS) to determine their relative abilities to decontaminate various surface-associated health care-relevant microbial challenges. Standard microbiological challenges were developed by surface-associating typed Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis spores, or a clinical methicillin-resistant S. aureus (MRSA) strain on stainless steel, polypropylene, or fabric. All test coupons were subjected to 20 min biocidal aerosols of chlorine-matched (100 ppm) sodium hypochlorite, chlorine dioxide, or ECAS within a standard aerosolization chamber using a commercial humidifier under defined conditions. Biocidal treatment type and material surface had a significant effect on the number of microorganisms recovered from various material surfaces following treatment exposure. Under the conditions of the assay, the order of antimicrobial efficacy of biocidal aerosol treatment was as follows: ECAS > chlorine dioxide > sodium hypochlorite. For all biocides, greater antimicrobial reductions were seen when treating stainless steel and fabric than when treating plastic-associated microorganisms. The experimental fogging system and assay protocol designed within this study were shown capable of differentiating the comparative efficacies of multiple chlorine-matched biocidal aerosols against a spectrum of target organisms on a range of test surface materials and would be appropriate for testing other biocidal aerosol treatments or material surfaces. PMID- 23459482 TI - Comparative in vitro activities of GSK2251052, a novel boron-containing leucyl tRNA synthetase inhibitor, against 916 anaerobic organisms. AB - We studied the comparative in vitro activity of GSK2251052, a novel boron leucyl tRNA synthetase inhibitor, against 916 clinical anaerobic isolates using CLSI methods. The GSK MIC50/MIC90 for all isolates tested were 2 and 4 MUg/ml, and the MIC90s against 302 Bacteroides fragilis and Bacteroides thetaiotaomicron strains were 4 and 8 MUg/ml, respectively. All Clostridium perfringens strains had GSK2251052 MICs of >32 MUg/ml. There was no relationship between increased MICs for any other antibiotics and that of GSK2251052. PMID- 23459481 TI - Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252. AB - This study examines the alteration in Staphylococcus aureus gene expression following treatment with the type 2 fatty acid synthesis inhibitor AFN-1252. An Affymetrix array study showed that AFN-1252 rapidly increased the expression of fatty acid synthetic genes and repressed the expression of virulence genes controlled by the SaeRS 2-component regulator in exponentially growing cells. AFN 1252 did not alter virulence mRNA levels in a saeR deletion strain or in strain Newman expressing a constitutively active SaeS kinase. AFN-1252 caused a more pronounced increase in fabH mRNA levels in cells entering stationary phase, whereas the depression of virulence factor transcription was attenuated. The effect of AFN-1252 on gene expression in vivo was determined using a mouse subcutaneous granuloma infection model. AFN-1252 was therapeutically effective, and the exposure (area under the concentration-time curve from 0 to 48 h [AUC(0 48)]) of AFN-1252 in the pouch fluid was comparable to the plasma levels in orally dosed animals. The inhibition of fatty acid biosynthesis by AFN-1252 in the infected pouches was signified by the substantial and sustained increase in fabH mRNA levels in pouch-associated bacteria, whereas depression of virulence factor mRNA levels in the AFN-1252-treated pouch bacteria was not as evident as it was in exponentially growing cells in vitro. The trends in fabH and virulence factor gene expression in the animal were similar to those in slower-growing bacteria in vitro. These data indicate that the effects of AFN-1252 on virulence factor gene expression depend on the physiological state of the bacteria. PMID- 23459483 TI - Coproduction of 16S rRNA methyltransferase RmtD or RmtG with KPC-2 and CTX-M group extended-spectrum beta-lactamases in Klebsiella pneumoniae. AB - Eight Klebsiella pneumoniae clinical strains with high-level aminoglycoside resistance were collected from eight hospitals in Sao Paulo State, Brazil, in 2010 and 2011. Three of them produced an RmtD group 16S rRNA methyltransferase, RmtD1 or RmtD2. Five strains were found to produce a novel 16S rRNA methyltransferase, designated RmtG, which shared 57 to 58% amino acid identity with RmtD1 and RmtD2. Seven strains coproduced KPC-2 with or without various CTX M group extended-spectrum beta-lactamases, while the remaining strain coproduced CTX-M-2. PMID- 23459484 TI - Real-time microscopic observation of Candida biofilm development and effects due to micafungin and fluconazole. AB - To understand the process of Candida biofilm development and the effects of antifungal agents on biofilms, we analyzed real-time data comprising time-lapse images taken at times separated by brief intervals. The growth rate was calculated by measuring the change of biofilm thickness every hour. For the antifungal study, 5-h-old biofilms of Candida albicans were treated with either micafungin (MCFG) or fluconazole (FLCZ). MCFG began to suppress biofilm growth a few minutes after the initiation of the treatment, and this effect was maintained over the course of the observation period. In contrast, the suppressive effects of FLCZ on biofilm growth took longer to manifest: biofilms grew in the first 5 h after treatment, and then their growth was suppressed over the next 10 h, finally producing results similar to those observed with MCFG. MCFG was also involved in the disruption of cells in the biofilms, releasing string-like structures (undefined extracellular component) from the burst hyphae. Thus, MCFG inhibited the detachment of yeast cell clusters from the tips of hyphae. In contrast, FLCZ did not disrupt biofilm cells. MCFG also showed fast antifungal activity against Candida parapsilosis biofilms. In conclusion, our results show that inhibition of glucan synthesis due to MCFG contributed not only to fungicidal activity but also to the immediate suppression of biofilm growth, while FLCZ suppressed growth by inhibiting ergosterol synthesis. Therefore, those characteristic differences should be considered when treating clinical biofilm infections. PMID- 23459485 TI - NDM-8 metallo-beta-lactamase in a multidrug-resistant Escherichia coli strain isolated in Nepal. AB - A novel metallo-beta-lactamase, NDM-8, was identified in a multidrug-resistant Escherichia coli isolate, IOMTU11 (NCGM37), obtained from the respiratory tract of a patient in Nepal. The amino acid sequence of NDM-8 has substitutions at positions 130 (Asp to Gly) and 154 (Met to Leu) compared with NDM-1. NDM-8 showed enzymatic activities against beta-lactams similar to those of NDM-1. PMID- 23459486 TI - Mechanism of action of efinaconazole, a novel triazole antifungal agent. AB - The mechanism of action of efinaconazole, a new triazole antifungal, was investigated with Trichophyton mentagrophytes and Candida albicans. Efinaconazole dose-dependently decreased ergosterol production and accumulated 4,4 dimethylsterols and 4alpha-methylsterols at concentrations below its MICs. Efinaconazole induced morphological and ultrastructural changes in T. mentagrophytes hyphae that became more prominent with increasing drug concentrations. In conclusion, the primary mechanism of action of efinaconazole is blockage of ergosterol biosynthesis, presumably through sterol 14alpha demethylase inhibition, leading to secondary degenerative changes. PMID- 23459487 TI - Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. AB - Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14 day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies. PMID- 23459489 TI - Detection of linezolid-resistant Staphylococcus aureus with 23S rRNA and novel L4 riboprotein mutations in a cystic fibrosis patient in Spain. PMID- 23459488 TI - Mutational activation of the AmgRS two-component system in aminoglycoside resistant Pseudomonas aeruginosa. AB - The amgRS operon encodes a presumed membrane stress-responsive two-component system linked to intrinsic aminoglycoside resistance in Pseudomonas aeruginosa. Genome sequencing of a lab isolate showing modest pan-aminoglycoside resistance, strain K2979, revealed a number of mutations, including a substitution in amgS that produced an R182C change in the AmgS sensor kinase product of this gene. Introduction of this mutation into an otherwise wild-type strain recapitulated the resistance phenotype, while correcting the mutation in the resistant mutant abrogated the resistant phenotype, confirming that the amgS mutation is responsible for the aminoglycoside resistance of strain K2979. The amgSR182 mutation promoted an AmgR-dependent, 2- to 3-fold increase in expression of the AmgRS target genes htpX and PA5528, mirroring the impact of aminoglycoside exposure of wild-type cells on htpX and PA5528 expression. This suggests that amgSR182 is a gain-of-function mutation that activates AmgS and the AmgRS two component system in promoting modest resistance to aminoglycosides. Screening of several pan-aminoglycoside-resistant clinical isolates of P. aeruginosa revealed three that showed elevated htpX and PA5528 expression and harbored single amino acid-altering mutations in amgS (V121G or D106N) and no mutations in amgR. Introduction of the amgSV121G mutation into wild-type P. aeruginosa generated a resistance phenotype reminiscent of the amgSR182 mutant and produced a 2- to 3 fold increase in htpX and PA5528 expression, confirming that it, too, is a gain of-function aminoglycoside resistance-promoting mutation. These results highlight the contribution of amgS mutations and activation of the AmgRS two-component system to acquired aminoglycoside resistance in lab and clinical isolates of P. aeruginosa. PMID- 23459490 TI - Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. AB - The nucleoprotein (NP) binds the viral RNA genome and associates with the polymerase in a ribonucleoprotein complex (RNP) required for transcription and replication of influenza A virus. NP has no cellular counterpart, and the NP sequence is highly conserved, which led to considering NP a hot target in the search for antivirals. We report here that monomeric nucleoprotein can be inhibited by a small molecule binding in its RNA binding groove, resulting in a novel antiviral against influenza A virus. We identified naproxen, an anti inflammatory drug that targeted the nucleoprotein to inhibit NP-RNA association required for NP function, by virtual screening. Further docking and molecular dynamics (MD) simulations identified in the RNA groove two NP-naproxen complexes of similar levels of interaction energy. The predicted naproxen binding sites were tested using the Y148A, R152A, R355A, and R361A proteins carrying single point mutations. Surface plasmon resonance, fluorescence, and other in vitro experiments supported the notion that naproxen binds at a site identified by MD simulations and showed that naproxen competed with RNA binding to wild-type (WT) NP and protected active monomers of the nucleoprotein against proteolytic cleavage. Naproxen protected Madin-Darby canine kidney (MDCK) cells against viral challenges with the H1N1 and H3N2 viral strains and was much more effective than other cyclooxygenase inhibitors in decreasing viral titers of MDCK cells. In a mouse model of intranasal infection, naproxen treatment decreased the viral titers in mice lungs. In conclusion, naproxen is a promising lead compound for novel antivirals against influenza A virus that targets the nucleoprotein in its RNA binding groove. PMID- 23459491 TI - Effect of farnesol on growth, ergosterol biosynthesis, and cell permeability in Coccidioides posadasii. AB - Coccidioidomycosis is a systemic mycosis caused by the dimorphic fungi Coccidioides spp. The treatment for chronic and/or disseminated coccidioidomycosis can be prolonged and complicated. Therefore, the search for new drugs is necessary. Farnesol is a precursor in the sterol biosynthesis pathway that has been shown to present antifungal activity. Thus, the objective of this study was to evaluate the in vitro antifungal activity of farnesol alone and in combination with antifungal agents against clinical and environmental strains of Coccidioides posadasii as well as to determine their effect on the synthesis of ergosterol and on cell permeability. This study employed the broth macrodilution method to determine the MIC of farnesol against 18 strains of C. posadasii. Quantification of ergosterol was performed with 10 strains of C. posadasii after exposure to subinhibitory concentrations of farnesol. Finally, the activity of farnesol was evaluated in the presence of osmotic stress, induced by the addition of NaCl to the culture medium, during the susceptibility tests. The results showed that farnesol exhibited low MICs (ranging from 0.00171 to 0.01369 mg/liter) against all tested strains. The combination of farnesol with the antifungals showed synergistic effects (fractional inhibitory concentration index [FICI] <= 0.5). As for the ergosterol quantification, it was observed that exposure to subinhibitory concentrations of farnesol decreased the amount of ergosterol extracted from the fungal cells. Furthermore, farnesol also showed lower MIC values when the strains were subjected to osmotic stress, indicating the action of this compound on the fungal membrane. Thus, due to the high in vitro antifungal activity, this work brings perspectives for the performance of in vivo studies to further elucidate the effects of farnesol on the host cells. PMID- 23459492 TI - Is fecal carriage of extended-spectrum-beta-lactamase-producing Escherichia coli in urban rats a risk for public health? PMID- 23459493 TI - Dissemination of a class I integron carrying VIM-2 carbapenemase in Pseudomonas aeruginosa clinical isolates from a hospital intensive care unit in Annaba, Algeria. PMID- 23459494 TI - Weight drives caspofungin pharmacokinetic variability in overweight and obese people: fractal power signatures beyond two-thirds or three-fourths. AB - Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergillosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)(3/4). The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)(3/2), an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.). PMID- 23459495 TI - Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection. AB - An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 MUg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT(MIC)) of 24.5% +/- 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% +/- 9.5% was associated with a -1-log-unit drop, and one of 32.1% +/- 8.1% was associated with a -2-log-unit drop. The MSSA and MRSA strains had similar fT(MIC) values. fT(MIC) values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT(MIC). fT(MIC)s of <50% were associated with growth on 4* MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of <= 2 MUg/ml. An fT(MIC) of 25 to 30% would make a suitable pharmacodynamic index target, but fTMIC values of >= 50% are needed to suppress the emergence of resistance and require clinical evaluation. PMID- 23459496 TI - Adherence profiles and therapeutic responses of treatment-naive HIV-infected patients starting boosted atazanavir-based therapy in the ANRS 134-COPHAR 3 trial. AB - The adherence profile of HIV-infected patients predicts the therapeutic outcome, in particular during the early phase of antiretroviral therapy (ART). We conducted a prospective observational multicenter trial monitoring adherence and virological and immunological parameters over the initial 6 months of treatment. Thirty-five subjects were starting a treatment regimen including atazanavir, ritonavir, and emtricitabine-tenofovir. Adherence was assessed using self completed questionnaires, announced pill counts, and the medication event monitoring system (MEMS) for each drug. Three MEMS measures were defined: the percentages of doses taken, days with the correct dosing, and doses taken on time (+/- 3 h). Dynamic virological suppression (DVS) was defined as a reduction in the plasma HIV-RNA level of >1 log10 per month or <40 copies/ml. The cumulative treatment time was 5,526 days. A high level of adherence was observed. The MEMS defined adherence for correct dosing (-0.68% per 4-week period, P < 0.03) and timing compliance (-1.60% per 4-week period, P < 0.003) decreased significantly over time. The MEMS-defined adherence data were concordant with the pill counts during the trial but not with the data from the questionnaires. The median [range] percentages of doses taken (100% [50 to 102]), days with the correct dosing (95% [41 to 100]), and doses taken on time (86% [32 to 100]) were significantly associated with DVS in separate models. Among these three measures, the percentage of doses taken on time had the greatest ability to predict DVS. Timing compliance should be supported to optimize DVS during the early phase of treatment by once-daily boosted protease inhibitor-based ART. (This study has been registered at ClinicalTrials.gov under registration no. NCT00528060.). PMID- 23459497 TI - Therapeutic efficacy of macrolides, minocycline, and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae pneumonia in pediatric patients. AB - The importance of macrolide-resistant (MR) Mycoplasma pneumoniae has become much more apparent in the past decade. We investigated differences in the therapeutic efficacies of macrolides, minocycline, and tosufloxacin against MR M. pneumoniae. A total of 188 children with M. pneumoniae pneumonia confirmed by culture and PCR were analyzed. Of these, 150 patients had a strain with an MR gene and 134 had one with an A-to-G mutation at position 2063 of M. pneumoniae 23S rRNA domain V. Azithromycin (n = 27), clarithromycin (n = 23), tosufloxacin (n = 62), or minocycline (n = 38) was used for definitive treatment of patients with MR M. pneumoniae. Defervescence within 48 h after the initiation of antibiotic therapy was observed in 41% of the patients in the azithromycin group, 48% of those in the clarithromycin group, 69% of those in the tosufloxacin group, and 87% of those in the minocycline group. The average number of days of fever after the administration of antibiotic treatment was lower in the minocycline and tosufloxacin groups than in the macrolide groups. The decrease in the M. pneumoniae burden, as estimated by the number of DNA copies, after 48 to 96 h of treatment was more rapid in patients receiving minocycline (P = 0.016) than in those receiving tosufloxacin (P = 0.049), azithromycin (P = 0.273), or clarithromycin (P = 0.107). We found that the clinical and bacteriological efficacies of macrolides against MR M. pneumoniae pneumonia was low. Our results indicated that minocycline rather than tosufloxacin can be considered the first choice drug for the treatment of M. pneumoniae pneumonia in children aged >= 8 years. PMID- 23459499 TI - Comparison of palonosetron with ondansetron in prevention of postoperative nausea and vomiting in patients receiving intravenous patient-controlled analgesia after gynecological laparoscopic surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are common complications after anesthesia and surgery. This study was designed to compare the effects of palonosetron and ondansetron in preventing PONV in high-risk patients receiving intravenous opioid-based patient-controlled analgesia (IV-PCA) after gynecological laparoscopic surgery. METHODS: One hundred non-smoking female patients scheduled for gynecological laparoscopic surgery were randomly assigned into the palonosetron group (n = 50) or the ondansetron group (n = 50). Palonosetron 0.075 mg was injected as a bolus in the palonosetron group. Ondansetron 8 mg was injected as a bolus and 16 mg was added to the IV-PCA in the ondansetron group. The incidences of nausea, vomiting and side effects was recorded at 2 h, 24 h, 48 h and 72 h, postoperatively. RESULTS: There were no significant differences between the groups in the incidence of PONV during 72 h after operation. However, the incidence of vomiting was lower in the palonosetron group than in the ondansetron group (18% vs. 4%, P = 0.025). No differences were observed in use of antiemetics and the side effects between the groups. CONCLUSIONS: The effects of palonosetron and ondansetron in preventing PONV were similar in high-risk patients undergoing gynecological laparoscopic surgery and receiving opioid-based IV-PCA. PMID- 23459500 TI - A boron dipyrromethene-phthalocyanine pentad as an artificial photosynthetic model. AB - A silicon(IV) phthalocyanine with two axial p-phenylene-linked boron dipyrromethene and monostyryl boron dipyrromethene moieties has been prepared. The resulting pentad absorbs strongly in most of the UV-visible region and serves as an artificial photosynthetic antenna-reaction centre model. PMID- 23459498 TI - 31st g. Heiner sell lectureship: secondary medical consequences of spinal cord injury. AB - Persons with spinal cord injury (SCI) have secondary medical consequences of paralysis and/or the consequences of extreme inactivity. The metabolic changes that result from reduced activity include insulin resistance with carbohydrate disorders and dyslipidemia. A higher prevalence of coronary artery calcification was found in persons with SCI than that in matched able-bodied controls. A depression in anabolic hormones, circulating testosterone and growth hormone, has been described. Adverse soft tissue body composition changes of increased adiposity and reduced skeletal muscle are appreciated. Immobilization is the cause for sublesional disuse osteoporosis with an associated increased risk of fragility fracture. Bowel dysmotility affects all segments of the gastrointestinal tract, with an interest in better defining and addressing gastroesophageal reflux disease and difficulty with evacuation. Developing and testing more effective approaches to cleanse the bowel for elective colonoscopy are being evaluated. The extent of respiratory dysfunction depends on the level and completeness of SCI. Individuals with higher spinal lesions have both restrictive and obstructive airway disease. Pharmacological approaches and expiratory muscle training are being studied as interventions to improve pulmonary function and cough strength with the objective of reducing pulmonary complications. Persons with spinal lesions above the 6th thoracic level lack both cardiac and peripheral vascular mechanisms to maintain blood pressure, and they are frequently hypotensive, with even worse hypotension with upright posture. Persistent and/or orthostatic hypotension may predispose those with SCI to cognitive impairments. The safety and efficacy of anti-hypotensive agents to normalize blood pressure in persons with higher level cord lesions is being investigated. PMID- 23459501 TI - Latent infection with Leishmania donovani in highly endemic villages in Bihar, India. AB - INTRODUCTION: Asymptomatic persons infected with the parasites causing visceral leishmaniasis (VL) usually outnumber clinically apparent cases by a ratio of 4-10 to 1. We describe patterns of markers of Leishmania donovani infection and clinical VL in relation to age in Bihar, India. METHODS: We selected eleven villages highly endemic for Leishmania donovani. During a 1-year interval we conducted two house to house surveys during which we collected blood samples on filter paper from all consenting individuals aged 2 years and above. Samples were tested for anti-leishmania serology by Direct Agglutination Test (DAT) and rK39 ELISA. Data collected during the surveys included information on episodes of clinical VL among study participants. RESULTS: We enrolled 13,163 persons; 6.2% were reactive to DAT and 5.9% to rK39. Agreement between the tests was weak (kappa = 0.30). Among those who were negative on both tests at baseline, 3.6% had converted to sero-positive on either of the two tests one year later. Proportions of sero-positives and sero-converters increased steadily with age. Clinical VL occurred mainly among children and young adults (median age 19 years). DISCUSSION: Although infection with L. donovani is assumed to be permanent, serological markers revert to negative. Most VL cases occur at younger ages, yet we observed a steady increase with age in the frequency of sero-positivity and sero-conversion. Our findings can be explained by a boosting effect upon repeated exposure to the parasite or by intermittent release of parasites in infected subjects from safe target cells. A certain proportion of sero-negative subjects could have been infected but below the threshold of antibody abundance for our serologic testing. PMID- 23459502 TI - Predictors of Academic Achievement for School Age Children with Sickle Cell Disease. AB - BACKGROUND: Children with sickle cell disease (SCD) are at risk for neurocognitive impairment and poor academic achievement, although there is limited research on factors predicting academic achievement in this population. This study explores the relative contribution to academic achievement of a comprehensive set of factors, such as environmental (socioeconomic status), disease-related (stroke, transfusion therapy, adherence), and psychosocial variables (child behavior, child quality of life (QoL)), controlling for intellectual functioning (IQ). METHODS: Eighty-two children with SCD completed measures assessing IQ and academic achievement, while parents completed questionnaires assessing adherence, child behavior, and child quality of life. Medical chart reviews were conducted to determine disease-related factors. RESULTS: Hierarchical regression analyses indicated that 55% of the variance in academic skills was accounted for by IQ, parent education, chronic transfusion status, and QoL [R2 = .55, F(5, 77) = 18.34, p < .01]. Follow-up analyses for broad reading [R2 = .52, F(5, 77) = 16.37, p < .01], and math calculation [R2 = .44, F(5, 77) = 12.14, p < .01] were also significant. CONCLUSION: The findings suggest a significant contribution of factors beyond IQ to academic achievement. Findings allow for identification of children with SCD at risk for academic difficulties for whom psychoeducational interventions may enhance academic achievement. PMID- 23459503 TI - Pharmacy student performance on constructed-response versus selected-response calculations questions. AB - Objective. To introduce PharmD students to changes in calculations question types (constructed-response versus selected-response questions); measure and compare student performance on constructed-response and selected-response questions in a pharmaceutics course; and collect student feedback on the use of differing question types.Methods A pharmaceutics/pharmaceutical calculations examination was administered that included 15 pairs of questions; each pair consisted of a constructed-response question and a similar selected-response question. An online questionnaire was conducted to collect student feedback.Results. Of the 15 topics, the class scored higher on the constructed-response question for 4 topics and higher on the selected-response question for 10 topics. Eighty percent of the class preferred selected-response questions, although 47.8% felt constructed response questions better prepared them for a career in healthcare.Conclusions. Students correctly answered more selected-response questions than constructed response questions and felt more confident in doing so. Additional constructed response teaching and testing methods should be incorporated into pharmacy education. PMID- 23459504 TI - Referent tracking for treatment optimisation in schizophrenic patients: A case study in applying philosophical ontology to diagnostic algorithms. AB - The IPAP Schizophrenia Algorithm was originally designed in the form of a flow chart to help physicians optimise the treatment of schizophrenic patients in the spirit of guideline-based medicine. We take this algorithm as our starting point in investigating how artifacts of this sort can benefit from the facilities of high-quality ontologies. The IPAP algorithm exists thus far only in a form suitable for use by human beings. We draw on the resources of Basic Formal Ontology (BFO) in order to show how such an algorithm can be enhanced in such a way that it can be used in Semantic Web and related applications. We found that BFO provides a framework that is able to capture in a rigorous way all the types of entities represented in the IPAP Schizophrenia Algorithm in way which yields a computational tool that can be used by software agents to perform monitoring and control of schizophrenic patients. We discuss the issues involved in building an application ontology for this purpose, issues which are important for any Semantic Web application in the life science and healthcare domains. PMID- 23459505 TI - Cardio-ankle vascular index in subjects with dyslipidaemia and other cardiovascular risk factors. AB - AIM: The cardio-ankle vascular index (CAVI) is a novel non-invasive marker of arterial stiffness and atherosclerosis. The aim of this work was to examine whether the CAVI value in patients with dyslipidaemia (DLP) is increased by the presence of other cardiovascular risk factors: hypertension, diabetes mellitus, and smoking. METHODS: A total of 392 subjects with DLP (166 male, 226 female), with a median age of 58.5 and 5-95 percentile range 32.2-73.9 years were examined. CAVI was measured using the VaSera 1500 system. RESULTS: CAVI correlated significantly with age (p<0.001) and both systolic (p<0.001) and diastolic (p=0.002) blood pressure; higher values were found in men (p=0.034) than in women in the 56-65 age group. There was no significant difference in CAVI between smokers and non-smokers (p= 0.217) and between subjects with and without diabetes mellitus (p= 0.424). CAVI was significantly higher in subjects with hypertension than in the normotensive group (p<0.001) and in statin-treated subjects than in those without statins (p<0.001); however, CAVI values adjusted for age and sex did not differ significantly between these groups. Adjusted CAVI values were higher only in smokers than in non-smokers (former smokers) (p<0.001). CONCLUSION: The study proves conclusively that the CAVI value in DLP patients is not significantly affected by hypertension and diabetes mellitus, but it is increased by smoking. PMID- 23459506 TI - Palliative systemic therapy for women with recurrent epithelial ovarian cancer: current options. AB - OBJECTIVES: To review the available systemic treatments for women with recurrent ovarian cancer. METHODS: A literature review was conducted for recurrent ovarian cancer articles in English, including randomized trials, Phase II trials, or reviews. RESULTS: We discuss the efficacy and toxicity outcomes associated with systemic therapy for platinum-sensitive and platinum-resistant ovarian cancer. Clearly, platinum-based combination systemic therapy shows a prolonged progression-free interval compared with single-agent chemotherapy with a low toxicity profile. No clear superior management strategy exists for platinum resistant/refractory disease. Novel targeted antiangiogenic agents (eg, bevacizumab), angiopoeitin inhibitors (eg, AMG 386), and poly ADP ribose polymerase inhibitors (eg, olaparib) are reviewed. CONCLUSION: Although combination platinum-based chemotherapy has shown benefits for women with platinum-sensitive recurrent ovarian cancer, the optimal treatment strategy for those with platinum-resistant or platinum-refractory disease is not clear. Molecular and genetic targeted therapies may provide opportunities for those women with tumor profiles that show sensitivity for specific agents. PMID- 23459507 TI - Comparison of Analysis Tools for miRNA High Throughput Sequencing Using Nerve Crush as a Model. AB - Recent advances in sample preparation and analysis for next generation sequencing have made it possible to profile and discover new miRNAs in a high throughput manner. In the case of neurological disease and injury, these types of experiments have been more limited. Possibly because tissues such as the brain and spinal cord are inaccessible for direct sampling in living patients, and indirect sampling of blood and cerebrospinal fluid are affected by low amounts of RNA. We used a mouse model to examine changes in miRNA expression in response to acute nerve crush. We assayed miRNA from both muscle tissue and blood plasma. We examined how the depth of coverage (the number of mapped reads) changed the number of detectable miRNAs in each sample type. We also found that samples with very low starting amounts of RNA (mouse plasma) made high depth of mature miRNA coverage more difficult to obtain. Each tissue must be assessed independently for the depth of coverage required to adequately power detection of differential expression, weighed against the cost of sequencing that sample to the adequate depth. We explored the changes in total mapped reads and differential expression results generated by three different software packages: miRDeep2, miRNAKey, and miRExpress and two different analysis packages, DESeq and EdgeR. We also examine the accuracy of using miRDeep2 to predict novel miRNAs and subsequently detect them in the samples using qRT-PCR. PMID- 23459508 TI - A new species of Centris ( Centris) (Fabricius) from northeastern Brazil, with taxonomic notes on C. ( C.) pulchra Moure, Oliveira & Viana (Hymenoptera, Apidae). AB - We describe a new species of the bee genus Centris, Centris (Centris) byrsonimae Mahlmann & Oliveira sp. n., whose name has appeared as a nomen nudum in the literature since 1985. Further, a new species group of Centris s.str. is proposed, the pulchra group, based on morphological characters, which comprises the species Centris pulchra Moure, Oliveira & Viana, 2003 and Centris byrsonimaesp. n..Based on information from specimen labels studied and data from the literature, a list of plant species visited by the pulchra group is presented. The male genitalia and hidden metasomal sterna 7 and 8 of Centris pulchra are described for the first time. Typographic errors pertaining to the paratype labels reported in the original description of Centris pulchra are corrected. One female paratype of Centris pulchra is designated herein as a paratype of Centris byrsonimaesp. n. An updated list of species of Centris s.str. from northeastern Brazil is provided including references about geographic distributions as well as an identification key to the pulchra species group. PMID- 23459510 TI - Community needs of people living with spinal cord injury and their family. PMID- 23459509 TI - A phyletically rare gene promotes the niche-specific fitness of an E. coli pathogen during bacteremia. AB - In bacteria, laterally acquired genes are often concentrated within chromosomal regions known as genomic islands. Using a recently developed zebrafish infection model, we set out to identify unique factors encoded within genomic islands that contribute to the fitness and virulence of a reference urosepsis isolate extraintestinal pathogenic Escherichia coli strain CFT073. By screening a series of deletion mutants, we discovered a previously uncharacterized gene, neaT, that is conditionally required by the pathogen during systemic infections. In vitro assays indicate that neaT can limit bacterial interactions with host phagocytes and alter the aggregative properties of CFT073. The neaT gene is localized within an integrated P2-like bacteriophage in CFT073, but was rarely found within other proteobacterial genomes. Sequence-based analyses revealed that neaT homologues are present, but discordantly conserved, within a phyletically diverse set of bacterial species. In CFT073, neaT appears to be unameliorated, having an exceptionally A+T-rich composition along with a notably altered codon bias. These data suggest that neaT was recently brought into the proteobacterial pan-genome from an extra-phyletic source. Interestingly, even in G+C-poor genomes, as found within the Firmicutes lineage, neaT-like genes are often unameliorated. Sequence level features of neaT homologues challenge the common supposition that the A+T rich nature of many recently acquired genes reflects the nucleotide composition of their genomes of origin. In total, these findings highlight the complexity of the evolutionary forces that can affect the acquisition, utilization, and assimilation of rare genes that promote the niche-dependent fitness and virulence of a bacterial pathogen. PMID- 23459511 TI - Advances in CT Colonography for Colorectal Cancer Screening and Diagnosis. AB - CT colonography (CTC) is a validated colorectal cancer test that provides an additional minimally-invasive screening option which is likely to be preferred by some patients. Important examination prerequisites include adequate colonic cleansing and distention. Tagging of residual material aids in the differentiation of true polyps from stool. Low radiation dose technique should be employed routinely for screening studies. Readers must be skilled in the use of both 2D and 3D interpretation methods. PMID- 23459513 TI - Desmoplastic fibroma: a case report with three years of clinical and radiographic observation and review of the literature. AB - BACKGROUND: Desmoplastic fibroma (DF) is an extremely rare locally aggressive bone tumor with an incidence of 0.11% of all primary bone tumors. The typical clinical presentation is pain and swelling above the affected area. The most common sites of involvement are the mandible and the metaphysis of long bones. Histologically and biologically, desmoplastic fibroma mimics extra-abdominal desmoid tumor of soft tissue. CASE PRESENTATION AND LITERATURE REVIEW: A case of a 27-year old man with DF in the ilium, including the clinical, radiological and histological findings over a 4-year period is presented here. CT scans performed in 3-year intervals prior to surgical intervention were compared with respect to tumor extension and cortical breakthrough. The patient was treated with curettage and grafting based on anatomical considerations. Follow-up CT scans over 18 months are also documented here. Additionally, a review and analysis of 271 cases including the presented case with particular emphasis on imaging patterns in MRI and CT as well as treatment modalities and outcomes are presented. CONCLUSION: In patients with desmoplastic fibroma, CT is the preferred imaging technique for both the diagnosis of intraosseus tumor extension and assessment of cortical involvement, whereas MRI is favored for the assessment of extraosseus tumor growth and preoperative planning. While tumor resection remains the preferred treatment for DF, curettage and grafting prove to be an acceptable alternative treatment modality with close follow-up when resection is not possible. Curettage and grafting have been shown to provide good clinical results and are associated with long recurrence free intervals. PMID- 23459512 TI - The mixed instrumental controller: using value of information to combine habitual choice and mental simulation. AB - Instrumental behavior depends on both goal-directed and habitual mechanisms of choice. Normative views cast these mechanisms in terms of model-free and model based methods of reinforcement learning, respectively. An influential proposal hypothesizes that model-free and model-based mechanisms coexist and compete in the brain according to their relative uncertainty. In this paper we propose a novel view in which a single Mixed Instrumental Controller produces both goal directed and habitual behavior by flexibly balancing and combining model-based and model-free computations. The Mixed Instrumental Controller performs a cost benefits analysis to decide whether to chose an action immediately based on the available "cached" value of actions (linked to model-free mechanisms) or to improve value estimation by mentally simulating the expected outcome values (linked to model-based mechanisms). Since mental simulation entails cognitive effort and increases the reward delay, it is activated only when the associated "Value of Information" exceeds its costs. The model proposes a method to compute the Value of Information, based on the uncertainty of action values and on the distance of alternative cached action values. Overall, the model by default chooses on the basis of lighter model-free estimates, and integrates them with costly model-based predictions only when useful. Mental simulation uses a sampling method to produce reward expectancies, which are used to update the cached value of one or more actions; in turn, this updated value is used for the choice. The key predictions of the model are tested in different settings of a double T-maze scenario. Results are discussed in relation with neurobiological evidence on the hippocampus - ventral striatum circuit in rodents, which has been linked to goal-directed spatial navigation. PMID- 23459514 TI - A mini-intronic plasmid (MIP): a novel robust transgene expression vector in vivo and in vitro. AB - The bacterial backbone (BB) sequences contained within a canonical plasmid DNA dampen exogenous transgene expression by tenfold to 1,000-fold over a period of a few weeks following transfection into quiescent tissues such as the liver. Minicircle DNA vectors devoid of bacterial plasmid backbone sequences overcome transgene silencing providing persistent transgene expression. Because, we recently established that the length rather than sequence of the DNA flanking the transgene expression cassette is the major parameter affecting transgene silencing, we developed an alternative plasmid propagation process in which the essential bacterial elements for plasmid replication and selection are placed within an engineered intron contained within the eukaryotic expression cassette. As with the minicircle vector, the mini-intronic plasmid (MIP) vector system overcomes transgene silencing observed with plasmids but in addition provides between 2 and often 10 times or higher levels of transgene expression compared with minicircle vectors containing the same expression cassette in vivo and in vitro. These improved plasmids will benefit all studies involving gene transfer/therapy approaches. PMID- 23459516 TI - Ethical Dimensions and Filial Caregiving. AB - The elderly are growing rapidly today as life expectancy increases. As this longevity has increased, so has the need for filial caregivers. While much has been written about caregiving stress, little has been written regarding the ethical dimensions of filial responsibility and daughter and son caregivers' perceptions of responsibility and moral demands. This paper will address the concept of family caregiving and contextual family characteristics. Family characteristics will expand awareness of the interrelationship value between the nature of the prior filial relationship, image of caregiving, and ethical views that underscore acceptance of the filial obligation. An explanation of both the interview process and selected measurements that speak to ethical perspective, sense of caregiving image, and expectations of filial caregiving will also be addressed. Therefore, the purpose of this paper is to elucidate how adult children may be helped in an anticipatory and proactive manner as more and more adult children take on parent care for longer durations of time. PMID- 23459517 TI - [Diagnosis and treatment of symptomatic radiation necrosis in the brain]. PMID- 23459515 TI - Rescue of impaired NK cell activity in hodgkin lymphoma with bispecific antibodies in vitro and in patients. AB - Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically. PMID- 23459518 TI - [Mood States in outpatients with lesional epilepsy at the neurosurgical clinic and improvement in mood States after lamotrigine addiction]. AB - People with epilepsy have a high incidence of mood disorders that may affect their quality of life. Lamotrigine(LTG)is one of the antiepileptic drugs that are commercially available in Japan these days and its mood-stabilizing qualities were well known. First, 66 outpatients with epilepsy were evaluated for changes in mood states by the Profile of Mood States(POMS)and the Japanese-edition Beck Depression Inventory-Second Edition(BDI-II)on self report. The POMS questionnaire includes 30 items that address six components of mood. At baseline, one third of the outpatients with epilepsy had mood problems compared by POMS health reference. The mean BDI-II baseline score was 14.9+/-10.1, and one third of these epilepsy patients exhibited moderate or severe depression. Second, in the twelve patients with epilepsy, LTG was added to other antiepileptic drugs, and the POMS and BDI-II were administered at baseline and after addiction to LTG. 4 out of 8(50%)patients with simple partial seizure and 5 out of 8(62.5%)patients after the adjunctive therapy experienced at least a 50% reduction in the number of seizures compared with the self-reported baseline before the adjunctive therapy. The component scores of Depression-Dejection, Anger-Hostility and Confusion Bewilderment in POMS were statistically improved in these patients completing adjunctive LTG(pared t-test, p<0.05). In these patients, the mean BDI-II baseline score was 25.8+/-13.1. Following administration of LTG, there was a significant decrease in the mean BDI-II scores(15.0+/-6.6)between baseline and the end of adjunctive LTG. This study suggests that, in addition to seizure control, LTG may have a mood-stabilizing effect and improve the quality of life in patients with epilepsy. PMID- 23459519 TI - [Intraoperative monitoring of motor evoked potentials during glioma removal]. AB - OBJECTIVE: To determine whether motor evoked potentials(MEPs)provide reliable monitoring of the motor system during resection of gliomas in or adjacent to the motor cortex or pyramidal tract. MATERIALS AND METHODS: MEP recording was performed during 64 operations in 55 patients harboring gliomas. Intraoperative MEP findings were classified into 3 groups:Group A was defined as having no significant MEP changes, Group B as having reversible MEP changes(?50% amplitude decrease or loss), and Group C as having irreversible changes. Postoperative motor function was evaluated according to the presence/absence of deterioration immediately after surgery and 1 month later, as compared to preoperative motor status RESULTS: Immediately after surgery, 13 of 39(33%)patients in Group A, 6 of 17(35%)in Group B, and 7 of 8(88%)in Group C experienced deterioration of motor function. One month after surgery, 4 of 39(10%)patients in Group A, 3 of 17(18%)in Group B, and 4 of 8(50%)showed deterioration of motor function. Both immediately(chi2=8.3, p<0.05)and 1 month(chi2=6.9, p<0.05)after surgery, MEP alterations correlated significantly with postoperative deterioration of motor function. Despite MEPs being stable throughout surgery(Group A), there were some patients with deterioration of motor function initially appearing to represent false negative monitoring. However, these deteriorations were confirmed to have been caused by secondary hemorrhage, venous return dysfunction, postoperative convulsion, or resection of the supplementary motor area. CONCLUSIONS: MEP monitoring provides reliable information on the motor system during glioma surgery. Although false negative MEP results may exist in some patients, most data were not influenced by intraoperative manipulation but rather were attributable to secondary postoperative events. PMID- 23459520 TI - [Blood blister-like aneurysm on the posterior wall of the internal carotid artery causing subarachnoid hemorrhage: a case report]. AB - We report a case of blood blister-like aneurysm(BBA)on the posterior wall of the internal carotid artery(ICA)causing subarachnoid hemorrhage(SAH). A 45-year-old man suffering from SAH(WFNS grade 5)was referred to our hospital. 3D-CT angiography showed a BBA on the posterior wall of the ICA. The aneurysm had been enlarged for a few days. Therefore we performed coil embolization. Four weeks after the operation, the aneurysm was found to have regrown. In the second operation the aneurysm was successfully treated by the ICA proximal occlusion with extracranial-intracranial bypass. Postoperative follow-up cerebral angiography detected no aneurysm. To our knowledge, BBA on the posterior wall of the ICA is rare. Radical surgery with bypass should be performed as soon as possible when the BBA is found to regrow. We discuss the clinical characteristics with a review of the literature. PMID- 23459521 TI - [An operated case of a meningioma causing acute subdural hematoma]. AB - We report a rare case of a meningioma causing acute hematoma. A 67-year-old woman presented with sudden headache. No evidence of trauma was seen. CT demonstrated a subdural hematoma in the convexity of the fronto-temporal lobe. Magnetic resonance imaging showed marked signal heterogeneity in the convexity of the frontal lobe. One week later, the patient underwent hematoma evacuation and tumor resection including the attached dura mater. The histological diagnosis was meningothelial meningioma. The clot was connected directly to the tumor and the origin of the subdural hematoma was identified as the meningioma. Postoperative course was uneventful, and the headache improved. Meningiomas have a relatively benign course but rarely present with hemorrhage. Surgical exploration is the effective and recommended treatment. PMID- 23459522 TI - [Hemifacial spasm caused by a dissecting aneurysm of the vertebral artery, and resulting in acute exacerbation]. AB - The authors report a rare case of a symptomatic hemifacial spasm caused by a dissecting vertebral artery aneurysm and by an anterior inferior cerebellar artery(AICA). A 54-year-old man presented with left hemifacial spasm persisting for 5 years, and the spasm had undergone acute aggravation. Brain magnetic resonance imaging and digital subtraction angiography showed a vertebral artery dissecting aneurysm and an AICA compressing the root exit zone of the left facial nerve. Microvascular decompression of the facial nerve with proximal clipping of the vertebral artery dissecting aneurysm was successfully performed. The hemifacial spasm disappeared immediately after the surgery. PMID- 23459523 TI - [Thoracocervical giant perimedullary arteriovenous fistula treated with transarterial embolization: a case report]. AB - A 43-year-old woman with progressive gait disturbance and dysesthesia of the limbs and trunk visited our hospital. Upon examination, a thoracocervical giant perimedullary arteriovenous fistula(GPMAVF)was detected. The GPMAVF was fed by both of the highest intercostal arteries and the thyrocervical trunk. The dilated drainage vein widely compressed the spinal cord from the upper thoracic to the cervical regions. Transarterial embolization with n-butyl 2-cyanoacrylate was performed, and the fistula was completely obliterated. The dilated drainage vein was thrombosed, and it decreased in size after treatment. The patient's symptoms and magnetic resonance imaging results significantly improved. We suggest that endovascular treatment is effective for GPMAVFs, given sufficient analysis of the anatomical architecture. PMID- 23459524 TI - [A case of synovial sarcoma with brain metastasis treated with surgical resection and stereotactic radiosurgery]. AB - Synovial sarcomas compromise between 5 to 10% of all soft tissue sarcomas in adults. Synovial sarcoma commonly occurs in the vicinity of the large joints and cranial metastasis is rare. Here, we describe a case with intracranial metastases of a synovial sarcoma. A 41-year-old woman was admitted to our department with sensory aphasia. She had a history of a left inguinal synovial sarcoma and underwent surgery and chemotherapy for primary and metastatic lesions. Head MRI revealed three gadolinium-enhancing lesions in the left frontal, parietal and parietotemporal lobe. Gross total resection was achieved in the left parietotemporal lesion and pathological diagnosis was synovial sarcoma. Two weeks after surgery, she received cyber-knife radiosurgery and her neurological deficit was almost completely resolved. Intracranial metastatic synovial sarcoma is rare. Surgical resection and stereotaxic radiosurgery was very effective in the present case. PMID- 23459525 TI - [Cranioplasty following decompressive craniectomy in children: clinical pitfalls]. PMID- 23459526 TI - [(7)Basics of carotid artery stenting]. PMID- 23459527 TI - Coordinating Mental Health Care Across Primary Care and Schools: ADHD as a Case Example. AB - Although primary care practices and schools are major venues for the delivery of mental health services to children, these systems are disconnected, contributing to fragmentation in service delivery. This paper describes barriers to collaboration across the primary care and school systems, including administrative and fiscal pressures, conceptual and linguistic differences between healthcare and educational professionals, role restrictions among professionals, and privacy laws. Strategies for overcoming these barriers that can be applied in both primary care and school settings are described. The paper has a primary focus on children with ADHD, but the principles and strategies described are applicable to children with a range of mental health and health conditions. PMID- 23459528 TI - [Gastroenterology in the era of trans-science]. PMID- 23459529 TI - [Mechanisms for carcinogenesis in inflammatory bowel diseases]. PMID- 23459530 TI - [Histopathologic characteristics and biopsy diagnosis of colorectal carcinoma in ulcerative colitis]. PMID- 23459531 TI - [Endoscopic surveillance for ulcerative colitis-associated colorectal neoplasia]. PMID- 23459532 TI - [Surgical treatment of colorectal cancer associated with ulcerative colitis]. PMID- 23459533 TI - [Management of rectal cancer including cancer in the anal fistula with Crohn's disease]. PMID- 23459534 TI - [Radiofrequency ablation for hepatocellular carcinoma in elderly patients]. AB - The efficacy and safety of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) were compared between elderly (age>=75 years, n=82) and non elderly groups (age<75 years, n=158). No significant differences were observed in complications between the two groups. Elderly patients had a lower survival rate compared to the non-elderly patients. Multivariate analysis showed that age was not a significant factor for survival on tumor recurrence. Matching by propensity score revealed no significant differences were observed in survival on tumor recurrence rate. The prognosis of elderly patients undergoing RFA might be considered poorer than that of non-elderly patients. However, when considering the clinical background, RFA might be safe and effective in elderly patients, as well as non-elderly patients. PMID- 23459535 TI - [A case of extrahepatic bile duct metastasis from gastric cancer]. AB - A 56-year-old man was admitted with obstructive jaundice. Abdominal computed tomography and endoscopic retrograde cholangiopancreatography showed circumferential stenosis with irregular wall in lower bile duct, but the cytology of biliary brushing was no malignancy. The patient was given a diagnosis of gastric carcinoma with bone and skin metastasis. He died 2 months after the first hospital admission and autopsy was performed. The histological findings of gastric and bile duct tumor revealed signet ring cell carcinoma. The immunohistological findings of both tumors were identical. We definitively diagnosed this case as metastasis of gastric carcinoma to the bile duct. PMID- 23459536 TI - [A case of basaloid cell carcinoma of the anal canal in which complete response was obtained by chemoradiation therapy]. AB - The patient was a 69-year-old woman with a chief complaint of melena, who had a palpable firm mass and tenderness on digital rectal examination. Colonoscopy (CS) showed a depressed hemorrhagic lesion 2cm in diameter on the left anterior wall of the anal canal near the dentate line. Biopsy examination yielded a diagnosis of basaloid cell carcinoma. On the basis of a diagnosis of clinical stage I (T1N0M0) anal canal cancer, chemoradiotherapy was performed. After treatment, no tumor cells were detected on biopsy. Basaloid cell carcinoma, accounting for about 1.6% of anal canal cancers, is rare. Only 4 among 62 reported cases (including our patient) received chemoradiation therapy. PMID- 23459537 TI - [Spontaneous splenic vein rupture complicating liver cirrhosis: an autopsy case report]. AB - A 70-year-old woman, who had hepatitis-C related liver cirrhosis died suddenly. Autopsy showed a massive retroperitoneal hematoma and ruptured splenic vein, as well as densely bloody ascites. This suggested that chronic and unnoticed retroperitoneal leak from the ruptured vein preceded the acute and fatal outcome of the intra-abdominal bleeding. Spontaneous rupture of the splenic vein is rarely reported in liver cirrhosis despite the presence of portal hypertension. This rare association is discussed with a literature review. PMID- 23459538 TI - [A case of adult-onset type II citrullinemia in an elderly patient]. AB - A 72-year-old man presented with consciousness disturbance. The results of brain magnetic resonance imaging and cerebrospinal fluid examination were normal, but triphasic waves were noted on electroencephalography. His plasma ammonia level was elevated due to which encephalopathy secondary to hyperammonemia was suspected. However, his liver function was normal, and no evidence of cirrhosis or portal-systemic shunt was noted. The patient's medical history revealed that he had a tendency to excessively consume pulse products since childhood, and an amino acid analysis showed elevation of citrulline and arginine levels. Thus, we diagnosed the patient with an extremely rare case of adult-onset type II citrullinemia, which was triggered by cessation of the intake of pulse foods (soybeans and peanuts) due to dental problems. PMID- 23459539 TI - [Tumor lysis syndrome after transarterial embolization for hepatocellular carcinoma]. AB - A man in his 70's was admitted to our hospital for treatment of a huge hepatocellular carcinoma (HCC) by transcatheter hepatic arterial embolization (TAE). After treatment, anuria occurred, and laboratory examinations revealed a diagnosis of tumor lysis syndrome (TLS). He underwent conservative therapy including hemodialysis, resulting in complete remission of TLS. On the other hand, poor hepatic functional reserve was seen temporarily. After conservative therapy, biochemical markers returned dramatically. TLS is a group of metabolic complications in cancer therapy. It may occur in highly sensitive tumors, resulting from a rapid release of cytoplasmic degradation products of malignant cells. Generally it is rare in the treatment of solid tumors. In the case of TAE for huge HCC, we should keep the possibility of TLS in mind. PMID- 23459540 TI - [A case of serous cystadenoma of the pancreas communicating with the main pancreatic duct synchronously diagnosed with pancreatic ductal carcinoma]. AB - A 65-year-old woman who had been followed up for a cystic lesion of the tail of the pancreas was found to have cancer of the body of the pancreas. ERP showed stenosis of the main pancreatic duct (MPD) with dilatation of the distal side of the duct, and communication between the cystic lesion and MPD. She underwent distal pancreatectomy under a diagnosis of intraductal papillary-mucinous neoplasm associated with cancer of the body of the pancreas. Clinicopathologic investigation revealed that the diagnosis of the cystic lesion was serous cystadenoma having the communication with MPD. It was also indicated by the histopathologic findings that inflammatory changes of MPD caused by stenosis might contribute to the development of serous cystadenoma. PMID- 23459541 TI - [A case of clonorchiasis complicated with the expansion of liver cyst]. AB - A 61-year-old man was admitted to our hospital for examination of the cause of rapid growth of a liver cyst. We found a slight dilatation of bile duct in the vicinity of the liver cyst. Then, we underwent ERCP and found a communication between the bile duct and liver cyst. Bile cytodiagnosis revealed a large quantity of clonorchis eggs. The patient like to do eat raw freshwater fish and we suspected that the acute expansion of the cyst was due to clonorchiasis. Following administration of 40mg/kg praziquantel, the blood clonorchis antibody disappeared and the liver cyst also disappeared after 6 months. We encountered a case of clonorchiasis complicated with growth of a liver cyst. Medical interviews should be conducted carefully along with meticulous examinations. PMID- 23459542 TI - Facile conversion of chromane-6-triflate to chromane-6-alanines under Palladium conditions. AB - Conversion of chromane-6-triflate 5 to chromane-6-dehydroalanine 9 or 10 via its Bpin-derivative 6 followed by Suzuki coupling with protected dehydroalanine bromides 7 or 8 were reported (86%). Alternatively, a palladium-catalyzed stannation of 5 with Bu6Sn2 afforded the tributyltin derivative 11, and iodination (12) followed by coupling with 13 gave chromane-6-alanine 15 (75%). Either approach constitutes a conversion from chromane-6-triflate to the corresponding protected chromane-6-alanine or its dehydro analog. PMID- 23459543 TI - Exciton multiplication from first principles. AB - Third-generation photovolatics require demanding cost and power conversion efficiency standards, which may be achieved through efficient exciton multiplication. Therefore, generating more than one electron-hole pair from the absorption of a single photon has vast ramifications on solar power conversion technology. Unlike their bulk counterparts, irradiated semiconductor quantum dots exhibit efficient exciton multiplication, due to confinement-enhanced Coulomb interactions and slower nonradiative losses. The exact characterization of the complicated photoexcited processes within quantum-dot photovoltaics is a work in progress. In this Account, we focus on the photophysics of nanocrystals and investigate three constituent processes of exciton multiplication, including photoexcitation, phonon-induced dephasing, and impact ionization. We quantify the role of each process in exciton multiplication through ab initio computation and analysis of many-electron wave functions. The probability of observing a multiple exciton in a photoexcited state is proportional to the magnitude of electron correlation, where correlated electrons can be simultaneously promoted across the band gap. Energies of multiple excitons are determined directly from the excited state wave functions, defining the threshold for multiple exciton generation. This threshold is strongly perturbed in the presence of surface defects, dopants, and ionization. Within a few femtoseconds following photoexcitation, the quantum state loses coherence through interactions with the vibrating atomic lattice. The phase relationship between single excitons and multiple excitons dissipates first, followed by multiple exciton fission. Single excitons are coupled to multiple excitons through Coulomb and electron-phonon interactions, and as a consequence, single excitons convert to multiple excitons and vice versa. Here, exciton multiplication depends on the initial energy and coupling magnitude and competes with electron-phonon energy relaxation. Multiple excitons are generated through impact ionization within picoseconds. The basis of exciton multiplication in quantum dots is the collective result of photoexcitation, dephasing, and nonadiabatic evolution. Each process is characterized by a distinct time-scale, and the overall multiple exciton generation dynamics is complete by about 10 ps. Without relying on semiempirical parameters, we computed quantum mechanical probabilities of multiple excitons for small model systems. Because exciton correlations and coherences are microscopic, quantum properties, results for small model systems can be extrapolated to larger, realistic quantum dots. PMID- 23459544 TI - From particles to nanowires. PMID- 23459545 TI - Measurement of mobility in dual-gated MoS2 transistors. PMID- 23459546 TI - Reply to 'Measurement of mobility in dual-gated MoS2 transistors'. PMID- 23459547 TI - Majorana's wires. PMID- 23459548 TI - Skyrmions on the track. PMID- 23459550 TI - Electronic devices: Nanotube arrays made to order. PMID- 23459551 TI - Molecular spintronics: Stretch for a moment. PMID- 23459552 TI - Microtubule assembly: Switched on with magnets. PMID- 23459553 TI - Foresight Technical Conference 2013: Illuminating Feynman's vision. PMID- 23459555 TI - Specialized respiratory management for acute cervical spinal cord injury:: a retrospective analysis. AB - BACKGROUND: In individuals with cervical spinal cord injury (SCI), respiratory complications arise within hours to days of injury. Paralysis of the respiratory muscles predisposes the patient toward respiratory failure. Respiratory complications after cervical SCI include hypoventilation, hypercapnea, reduction in surfactant production, mucus plugging, atelectasis, and pneumonia. Ultimately, the patient must use increased work to breathe, which results in respiratory fatigue and may eventually require intubation for mechanical ventilation. Without specialized respiratory management for individuals with tetraplegia, recurrent pneumonias, bronchoscopies, and difficulty in maintaining a stable respiratory status will persist. OBJECTIVE: This retrospective analysis examined the effectiveness of specialized respiratory management utilized in a regional SCI center. METHODS: Individuals with C1-C4 SCI (N = 24) were the focus of this study as these neurological levels present with the most complicated respiratory status. RESULTS: All of the study patients' respiratory status improved with the specialized respiratory management administered in the SCI specialty unit. For a majority of these patients, respiratory improvements were noted within 1 week of admission to our SCI unit. CONCLUSION: Utilization of high tidal volume ventilation, high frequency percussive ventilation, and mechanical insufflation- exsufflation have demonstrated efficacy in stabilizing the respiratory status of these individuals. Optimizing respiratory status enables the patients to participate in rehabilitation therapies, allows for the opportunity to vocalize, and results in fewer days on mechanical ventilation for patients who are weanable. PMID- 23459557 TI - The structure of prion: is it enough for interpreting the diverse phenotypes of prion diseases? AB - Prion diseases, or transmissible spongiform encephalopathies, are neurodegenerative diseases, which affect human and many species of animals with 100% fatality rate. The most accepted etiology for prion disease is 'prion', which arises from the conversion from cellular PrP(C) to the pathological PrP(Sc). This review discussed the characteristic structure of PrP, including PRNP gene, PrP(C), PrP(Sc), PrP amyloid, and prion strains. PMID- 23459556 TI - Iron overload favors the elimination of Leishmania infantum from mouse tissues through interaction with reactive oxygen and nitrogen species. AB - Iron plays a central role in host-parasite interactions, since both intervenients need iron for survival and growth, but are sensitive to iron-mediated toxicity. The host's iron overload is often associated with susceptibility to infection. However, it has been previously reported that iron overload prevented the growth of Leishmania major, an agent of cutaneous leishmaniasis, in BALB/c mice. In order to further clarify the impact of iron modulation on the growth of Leishmania in vivo, we studied the effects of iron supplementation or deprivation on the growth of L. infantum, the causative agent of Mediterranean visceral leishmaniasis, in the mouse model. We found that dietary iron deficiency did not affect the protozoan growth, whereas iron overload decreased its replication in the liver and spleen of a susceptible mouse strain. The fact that the iron induced inhibitory effect could not be seen in mice deficient in NADPH dependent oxidase or nitric oxide synthase 2 suggests that iron eliminates L. infantum in vivo through the interaction with reactive oxygen and nitrogen species. Iron overload did not significantly alter the mouse adaptive immune response against L. infantum. Furthermore, the inhibitory action of iron towards L. infantum was also observed, in a dose dependent manner, in axenic cultures of promastigotes and amastigotes. Importantly, high iron concentrations were needed to achieve such effects. In conclusion, externally added iron synergizes with the host's oxidative mechanisms of defense in eliminating L. infantum from mouse tissues. Additionally, the direct toxicity of iron against Leishmania suggests a potential use of this metal as a therapeutic tool or the further exploration of iron anti parasitic mechanisms for the design of new drugs. PMID- 23459558 TI - Role of autophagy in prion protein-induced neurodegenerative diseases. AB - Prion diseases, characterized by spongiform degeneration and the accumulation of misfolded and aggregated PrP(Sc) in the central nervous system, are one of fatal neurodegenerative and infectious disorders of humans and animals. In earlier studies, autophagy vacuoles in neurons were frequently observed in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases as well as prion diseases. Autophagy is a highly conserved homeostatic process by which several cytoplasmic components (proteins or organelles) are sequestered in a double-membrane-bound vesicle termed 'autophagosome' and degraded upon their fusion with lysosome. The pathway of intercellular self digestion at basal physiological levels is indispensable for maintaining the healthy status of tissues and organs. In case of prion infection, increasing evidence indicates that autophagy has a crucial ability of eliminating pathological PrP(Sc) accumulated within neurons. In contrast, autophagy dysfunction in affected neurons may contribute to the formation of spongiform changes. In this review, we summarized recent findings about the effect of mammalian autophagy in neurodegenerative disorders, particularly in prion diseases. We also summarized the therapeutic potential of some small molecules (such as lithium, rapamycin, Sirtuin 1 and resveratrol) targets to mitigate such diseases on brain function. Furthermore, we discussed the controversial role of autophagy, whether it mediates neuronal toxicity or serves a protective function in neurodegenerative disorders. PMID- 23459559 TI - Academic help-seeking behavior among student pharmacists. AB - Objectives. To identify factors associated with academic help-seeking behavior among student pharmacists at a public university.Methods. Semi-structured focus group interviews were conducted to explore in depth perceptions of facilitators of and barriers to the help-seeking behavior and academic achievement of student pharmacists who had received a D or F grade in any year. A 4-part survey instrument was developed and administered to all student pharmacists and included sections for (1) attitudes and academic help-seeking behavior, (2) health status, (3) demographics, and (4) open comments. A structural equation modeling approach was used to assess relationships among domains of interest.Results. Three student focus groups noted that helpfulness of faculty members and school administrators were 2 prominent facilitators of help-seeking behavior and academic achievement. Diminished quality of life caused by stress and depression was the primary barrier to help-seeking and achievement. Three hundred four (68.6%) student pharmacists completed the survey instrument. Academic help-seeking behavior was influenced mostly by perceived academic competence and perceived faculty helpfulness. In contrast, ambivalence and perception of help-seeking as threatening were 2 factors that were negatively associated with academic help seeking behavior.Conclusions. Academic help-seeking behavior was positively related to greater perceived academic competence and positive relationships among student pharmacists and faculty members. PMID- 23459560 TI - Age differences in attention lapses mask age differences in memory failures: a methodological note on suppression. AB - Although objective measures of memory performance typically indicate memory declines with age, self-reported memory failures often show no relation to age. In contrast, self-reported attention failures are reliably negatively correlated with age. This contrast suggests the possibility that age-related awareness and reporting of memory failures might be masked by a concurrent decrease in attention failures, which would reduce encoding failures with age and hence reduce perceived memory failures. Self-reported problems of attention and memory were evaluated in two samples with the ages spanning eight decades. Initial analysis indicated that attention failures significantly decreased with age, whereas memory problems did not to differ across age. The association of self reported memory failures became significantly positive, however, when residualized on attention lapses. In contrast, the correlation between attention lapses and age was modestly affected when memory failures were controlled. These results highlight the close relation of attention lapses and memory problems and, beyond the implications of individual differences in attention for memory research, suggest the advisability of assessing attention failures for a full evaluation of memory problems. PMID- 23459561 TI - Serum-based DNA methylation biomarkers in colorectal cancer: potential for screening and early detection. AB - Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States. Early identification and treatment of pre-cancerous colorectal lesions, or node-negative CRC are highly effective interventions that substantially reduce disease-specific mortality. Colonoscopy remains a highly effective primary screening tool based on its excellent diagnostic accuracy, and its ability to remove pre-cancerous lesions. However, the nature of the procedure limits compliance with colonoscopy intended for population-based CRC screening. A significant advance in the screening and care of these patients could be realized by blood-based biomarkers, which could accurately identify patients at-risk for CRC development whom might benefit from early and/or more frequent surveillance for disease. We reviewed and herein discuss the potential for serum based DNA methylation biomarkers for screening and early detection of CRC. PMID- 23459562 TI - Small dose of propofol combined with dexamethasone for postoperative vomiting in pediatric Moyamoya disease patients: a prospective, observer-blinded, randomized controlled study. AB - BACKGROUND: For effective postoperative antiemetic management in pediatric moyamoya disease patients receiving fentanyl based postoperative analgesia, a multimodal approach has been recommended. The uncertain efficacy of ondansetron for pediatric neurosurgical patients or the possible antiemetic effect of small dose of propofol motivated us to evaluate the preventive effect of a subhypnotic dose of propofol combined with dexamethasone on postoperative vomiting (POV), especially during immediate postoperative periods. METHODS: In a prospective observer-blind randomized controlled study, we compared dexamethasone 0.15 mg/kg alone (Group D) with dexamethasone combined with propofol of 0.5 mg/kg (Group DP) in 60 pediatric patients, aged 4-17 years, who underwent indirect bypass surgery and received fentanyl-based postoperative analgesia. Occurrence of vomiting and pain score (Wong-Baker facial score) and requirement of rescue analgesic and antiemetic were continually measured (0-2, 2-6, 6-12 and 12-24 postoperative hours). For statistical analysis, in addition to the Fisher's exact test, a generalized linear mixed model (GLMM) and the linear mixed model (LMM) for repeated measures were used for vomiting and pain scores, respectively. RESULTS: There was no statistical significance of POV incidence, requirement of rescue analgesic and pain score between the two groups at any measured intervals. The incidence of POV was 53.3% during 24 hours in both groups, and was especially 6.7% and 13.3% (P = 0.671) during 0-2 hr and 16.7% and 23.3% (P = 0.748) during 2 6 hr in group D and group DP, respectively. CONCLUSIONS: A small dose of propofol combined with dexamethasone appears ineffective to preventing POV in pediatric moyamoya patients receiving continuous fentanyl infusion. PMID- 23459563 TI - Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms. AB - In recent papers, there has been a lively exchange concerning theories for enzyme catalysis, especially the role of protein dynamics/pre-chemistry conformational changes in the catalytic cycle of enzymes. Of particular interest is the notion that substrate-induced conformational changes that assemble the polymerase active site prior to chemistry are required for DNA synthesis and impact fidelity (i.e., substrate specificity). High-resolution crystal structures of DNA polymerase beta representing intermediates of substrate complexes prior to the chemical step are available. These structures indicate that conformational adjustments in both the protein and substrates must occur to achieve the requisite geometry of the reactive participants for catalysis. We discuss computational and kinetic methods to examine possible conformational change pathways that lead from the observed crystal structure intermediates to the final structures poised for chemistry. The results, as well as kinetic data from site-directed mutagenesis studies, are consistent with models requiring pre-chemistry conformational adjustments in order to achieve high fidelity DNA synthesis. Thus, substrate-induced conformational changes that assemble the polymerase active site prior to chemistry contribute to DNA synthesis even when they do not represent actual rate determining steps for chemistry. PMID- 23459564 TI - Genetic polymorphisms may influence the development and healing of sitting acquired pressure ulcers following spinal cord injury. PMID- 23459565 TI - How Crawling and Manual Object Exploration are Related to the Mental Rotation Abilities of 9-Month-Old Infants. AB - The present experiment examined whether the mental rotation ability of 9-month old infants was related to their abilities to crawl and manually explore objects. Forty-eight 9-month-old infants were tested; half of them had been crawling for an average of 9.3 weeks. The infants were habituated to a video of a simplified Shepard-Metzler object rotating back and forth through a 240 degrees angle around the longitudinal axis of the object. They were tested with videos of the same object rotating through a previously unseen 120 degrees angle and with a mirror image of the display. All of the infants also participated in a manual object exploration task, in which they freely explored five toy blocks. The results showed that the crawlers looked significantly longer at the novel (mirror) object than at the familiar object, independent of their manual exploration scores. The non-crawlers looking times, in contrast, were influenced by the manual exploration scores. The infants who did not spontaneously explore the toy blocks tended to show a familiarity preference, whereas those who explored the toy blocks preferred to look at the novel object. Thus, all of the infants were able to master the mental rotation task but it seemed to be the most complex process for infants who had no crawling experience and who did not spontaneously explore objects. PMID- 23459566 TI - Description of Trichodryas slipinskii sp. n. from China (Coleoptera, Dermestidae, Trinodinae). AB - Trichodryas slipinskiisp. n. from Yunnan Province of China is described and illustrated. A key to the known species of this genus is provided. PMID- 23459567 TI - Alemtuzumab improves contrast sensitivity in patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND: Alemtuzumab is a monoclonal antibody directed against CD52 that depletes T and B lymphocytes. OBJECTIVE: To evaluate the treatment effect of alemtuzumab on low-contrast vision in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: This was a pre-defined exploratory analysis within a randomized, rater-blinded trial (CAMMS223) that was run at 49 academic medical centers in the US and in Europe. Patients with untreated, early, RRMS (McDonald, n = 334) were randomized 1:1:1 to subcutaneous interferon beta-1a (IFNB-1a), or alemtuzumab 12 mg or 24 mg. Visual contrast sensitivity was measured for each eye at baseline and quarterly, with Pelli-Robson charts. RESULTS: The eyes of patients in the pooled alemtuzumab group (versus IFNB-1a) had a greater than 2 fold higher rate of both 3-month and 6-month sustained visual improvement, of at least 0.3 log units (2 triplets, 6 letters) (At 3 months the hazard ratio (HR) = 2.26; CI = 1.19 to 4.31; P = 0.013; and at 6 months the HR = 2.44; CI =1.16 to 5.15; P = 0.019), and they had a lower risk of 3- and 6-month sustained worsening of at least 0.15 log units (1 triplet, 3 letters) (At 3 months the HR = 0.58; CI = 0.38 to 0.89; P = 0.012; and at 6 months HR = 0.55; CI=0.35 to 0.87; P = 0.010). Over the 36-month study period, the eyes of patients in the pooled alemtuzumab group improved in mean contrast sensitivity to a greater extent than those in the IFNB-1a group (0.080 log units versus 0.038 log units; P = 0.0102). CONCLUSIONS: Alemtuzumab was associated with a greater chance of improved contrast sensitivity in patients with RRMS and may delay the worsening of visual function. Contrast sensitivity testing was sensitive to treatment effects, even within an active comparator study design. These results support the validity of low-contrast vision testing as a clinical outcome in MS trials. PMID- 23459568 TI - Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis. AB - BACKGROUND: Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression. METHODS: Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D. RESULTS: CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = -0.275, p = 0.009) and SDMT (r = -0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance. CONCLUSIONS: These findings suggest a role of WM lesions in the development of cognitive deficits, especially information-processing speed, which may be higher than previously assumed. ABBREVIATIONS CES-D: Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing-remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter. PMID- 23459569 TI - A new computerised cognitive test for the detection of information processing speed impairment in multiple sclerosis. AB - BACKGROUND: Cognitive impairment in multiple sclerosis (MS) primarily applies to information processing speed (IPS). OBJECTIVE: To evaluate psychometric properties of a new digit/symbol substitution test in healthy subjects and patients with MS, and assess its ability to detect IPS impairment in patients with MS. METHODS: A sample of MS patients, 60 relapsing-remitting (RRMS) and 41 primary progressive MS (PPMS), and 415 healthy controls (HCs) underwent an IPS battery, including assessment of reaction times of subtests of the Test of Attentional Performance battery and a newly developed in-house digit/symbol substitution task, the Computerised Speed Cognitive Test (CSCT). The CSCT was additionally evaluated in a second cohort of 31 RRMS and 12 progressive MS patients, for comparison with the Symbol Digit Modalities Test (SDMT). RESULTS: The CSCT had good reliability in both HCs and patients with MS. It showed a weak practice effect at the 6-month time point. This test had good ecological validity in MS patients. There was a strong correlation between the CSCT with the SDMT and with other IPS tests in patients with MS. The CSCT had the best sensitivity for predicting IPS impairment and was one of the most accurate tests among the IPS battery. CONCLUSION: The CSCT appeared as a good candidate for detecting IPS impairment in MS patients. PMID- 23459570 TI - Clinical significance of atrophy and white matter mean diffusivity within the thalamus of multiple sclerosis patients. AB - BACKGROUND: Gray-matter (GM) atrophy is strongly predictive of cognitive impairment in multiple sclerosis (MS) patients. The thalamus is the region where the atrophy/cognition correlation is most robust. However, few studies have assessed diffusion tensor imaging (DTI) metrics within the thalamus. OBJECTIVE: This study was designed to determine if thalamus white matter DTI predicts cognitive impairment after accounting for the effects of volume loss. METHODS: We enrolled 75 MS patients and 18 healthy controls undergoing 3T brain magnetic resonance imaging (MRI). Thalamus volumes were calculated on 3D T1 images. Voxelwise analyses of DTI metrics were performed within the thalamic white matter tracts. Neuropsychological (NP) testing, acquired using consensus standard methods, contributed measures of memory, cognitive processing speed and executive function. RESULTS: All cognitive tests were significantly predicted (R (2) =0.31, p<0.001) by thalamus volume after accounting for influence of demographics. Mean diffusivity was retained in regression models predicting all cognitive tests, adding from 7-13% of additional explained variance (p<0.02) after accounting for thalamus volume. CONCLUSIONS: We confirm the significant role of thalamus atrophy in MS-associated cognitive disorder, and further report that subtle thalamus pathology as detected by DTI adds incremental explained variance in predicting cognitive impairment. PMID- 23459571 TI - Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. AB - JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients >= 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use. PMID- 23459572 TI - Potential uses of G-quadruplex-forming aptamers. AB - Guanine quadruplex (G-quadruplex) structures are one of a number of structures which are capable of adopting aptamers. G-rich DNA or RNA has an increased propensity to form quadruplex structures which have unusual biophysical and biological properties. G-rich aptamers which form G-quadruplexes have several advantages over unstructured sequences: G-quadruplexes are non-immunogenic, thermodynamically and chemically stable and they have both higher resistance to various serum nucleases and an enhanced cellular uptake. These advantages have led to a number of synthetic oligonucleotides being studied for their potential use as therapeutic agents for cancer therapy and in the treatment of various other diseases. In addition to their suitability in the fields of medicine and biotechnology, these, highly specified, aptameric G-quadruplexes also have great potential in the further development of nano-devices; e.g. basic components in microarrays, microfluidics, sandwich assays and electrochemical biosensors. This review summarizes the biophysical properties of G-quadruplexes and highlights the importance of the stability and recognition properties of aptamers. Examples of the application of aptamers in medical therapy and in biosensors are also discussed. PMID- 23459573 TI - Exploring the contribution of estrogen to amyloid-Beta regulation: a novel multifactorial computational modeling approach. AB - According to the amyloid hypothesis, Alzheimer Disease results from the accumulation beyond normative levels of the peptide amyloid-beta (Abeta). Perhaps because of its pathological potential, Abeta and the enzymes that produce it are heavily regulated by the molecular interactions occurring within cells, including neurons. This regulation involves a highly complex system of intertwined normative and pathological processes, and the sex hormone estrogen contributes to it by influencing the Abeta-regulation system at many different points. Owing to its high complexity, Abeta regulation and the contribution of estrogen are very difficult to reason about. This report describes a computational model of the contribution of estrogen to Abeta regulation that provides new insights and generates experimentally testable and therapeutically relevant predictions. The computational model is written in the declarative programming language known as Maude, which allows not only simulation but also analysis of the system using temporal-logic. The model illustrates how the various effects of estrogen could work together to reduce Abeta levels, or prevent them from rising, in the presence of pathological triggers. The model predicts that estrogen itself should be more effective in reducing Abeta than agonists of estrogen receptor alpha (ERalpha), and that agonists of ERbeta should be ineffective. The model shows how estrogen itself could dramatically reduce Abeta, and predicts that non-steroidal anti-inflammatory drugs should provide a small additional benefit. It also predicts that certain compounds, but not others, could augment the reduction in Abeta due to estrogen. The model is intended as a starting point for a computational/experimental interaction in which model predictions are tested experimentally, the results are used to confirm, correct, and expand the model, new predictions are generated, and the process continues, producing a model of ever increasing explanatory power and predictive value. PMID- 23459575 TI - Prevalence, incidence, and implications of silent myocardial infarctions in patients with diabetes mellitus. PMID- 23459574 TI - Behavioral Approach System (BAS)-Relevant Cognitive Styles in Individuals with High vs. Moderate BAS Sensitivity: A Behavioral High-Risk Design. AB - This study used a behavioral high-risk design to evaluate cognitive styles relevant to the Behavioral Approach System (BAS) among individuals at high (n = 171) versus low (n = 119) risk of first onset of bipolar disorder based on BAS sensitivity, a known risk factor for bipolar disorder. Cognitive styles in high BAS participants paralleled those implicated in bipolar disorder. Linear regressions indicated that individuals with high BAS sensitivity exhibited greater levels of goal striving, positive overgeneralization, rumination on positive affect, depressive brooding, perfectionism, and hypomanic personality. Furthermore, of the cognitive styles, emotion-focused rumination on positive affect mediated the association between BAS sensitivity and current levels of hypomanic symptoms. These results provide evidence that individuals at risk for the development of bipolar disorder have higher levels of BAS-relevant cognitive styles and hypomanic personality than do individuals with lower risk, indicating that these styles are not simply markers of prior (hypo)manic episodes. PMID- 23459576 TI - Glucose-insulin-potassium revived: current status in acute coronary syndromes and the energy-depleted heart. PMID- 23459577 TI - Extremely rare case of vascular dysphagia in an elderly man. PMID- 23459578 TI - Two's company: double-chambered right ventricle[corrected]. PMID- 23459580 TI - Letter by Andreassi regarding article, "systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies". PMID- 23459581 TI - Letter by Phillips and O'Leary regarding article, "systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies". PMID- 23459582 TI - Letter by Irion regarding article, "systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies". PMID- 23459583 TI - An introduction of CO2 conversion by dry reforming with methane and new route of low-temperature methanol synthesis. AB - Carbon dioxide is one of the highest contributors to the greenhouse effect, as well as a cheap and nontoxic building block for single carbon source chemistry. As such, CO2 conversion is one of most important research areas in energy and environment sciences, as well as in catalysis technology. For chemical conversion of CO2, natural gas (mainly CH4) is a promising counterpart molecule to the CO2 related reaction, due to its high availability and low price. More importantly, being able to convert CH4 to useful fuels and molecules is advantageous, because it is also a kind of "greenhouse effect" gas, and can be an energy alternative to petroleum oil. In this Account, we discuss our development of efficient catalysts with precisely designed nanostructure for CO2 reforming of CH4 to produce syngas (mixture of CO and H2), which can then be converted to many chemicals and energy products. This new production flow can establish a GTL (gas-to-liquid) industry, being currently pushed by the shale gas revolution. From the viewpoint of GTL industry, developing a catalyst for CO2 reforming of CH4 is a challenge, because they need a very high production rate to make the huge GTL methane reformer as small as possible. In addition, since both CO2 and CH4 give off carbon deposits that deactivate non-precious metallic catalysts very quickly, the total design of catalyst support and supported metallic nanoparticles is necessary. We present a simple but useful method to prepare bimodal catalyst support, where small pores are formed inside large ones during the self-organization of nanoparticles from solution. Large pores enhance the mass transfer rate, while small pores provide large surface areas to disperse active metallic nanoparticles. More importantly, building materials for small pores can also be used as promoters or cocatalysts to further enhance the total activity and stability. Produced syngas from methane reforming is generally catalytically converted in situ via one of two main routes. The first is to use Fischer-Tropsch synthesis (FTS), a process that catalytically converts syngas to hydrocarbons of varying molecular weights. The second is methanol synthesis. The latter has better atomic economy, since the oxygen atom in CO is included in the product and CO2 can be blended into syngas as a reactant. However, production of methanol is very inefficient in this reaction: only 10-15% one-pass conversion typically at 5.0-10.0 MPa and 523-573 K, due to the severe thermodynamic limitations of this exothermal reaction (CO + 2H2 = CH3OH). In this Account, we propose and develop a new route of low temperature methanol synthesis from CO2-containing syngas only by adding alcohols, including methanol itself. These alcohols act as homogeneous cocatalysts and the solvent, realizing 70-100% one-pass conversion at only 5.0 MPa and 443 K. The key step is the reaction of the adsorbed formate species with alcohols to yield ester species at low temperatures, followed by the hydrogenation of ester by hydrogen atoms on metallic Cu. This changes the normal reaction path of conventional, high-temperature methanol synthesis from formate via methoxy to methanol. PMID- 23459585 TI - Qualitative detection and quantitative determination of single-walled carbon nanotubes in mixtures of carbon nanotubes with a portable Raman spectrometer. AB - The main aim of this work is to develop a one-step method for the characterization of mixtures of single- and multi-walled carbon nanotubes using a simple and inexpensive tool, a portable Raman spectrometer. In order to overcome the problem of heat dissipation in solid samples, the suitability of three surfactants-SDS, Triton X-100 and CTAB-to disperse nanotubes has been evaluated. A systematic study of the wavelength and relative intensity of the D and G bands has been carried out with six samples of multiwalled carbon nanotubes (MWNTs) and one of single-walled carbon nanotubes (SWNTs) dispersed in these surfactants, and this has been compared with solid samples. Finally, the possibility has been demonstrated to identify and (semi)quantify the presence of SWNTs in a mixture containing MWNTs. PMID- 23459584 TI - Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases. AB - As one of the largest protein families, protein kinases (PKs) regulate nearly all processes within the cell and are considered important drug targets. Much research has been conducted on inhibitors for PKs, leading to a wealth of compounds that target PKs that have potential to be lead anthelmintic drugs. Identifying compounds that have already been developed to treat neglected tropical diseases is an attractive way to obtain lead compounds inexpensively that can be developed into much needed drugs, especially for use in developing countries. In this study, PKs from nematodes, hosts, and DrugBank were identified and classified into kinase families and subfamilies. Nematode proteins were placed into orthologous groups that span the phylum Nematoda. A minimal kinome for the phylum Nematoda was identified, and properties of the minimal kinome were explored. Orthologous groups from the minimal kinome were prioritized for experimental testing based on RNAi phenotype of the Caenorhabditis elegans ortholog, transcript expression over the life-cycle and anatomic expression patterns. Compounds linked to targets in DrugBank belonging to the same kinase families and subfamilies in the minimal nematode kinome were extracted. Thirty five compounds were tested in the non-parasitic C. elegans and active compounds progressed to testing against nematode species with different modes of parasitism, the blood-feeding Haemonchus contortus and the filarial Brugia malayi. Eighteen compounds showed efficacy in C. elegans, and six compounds also showed efficacy in at least one of the parasitic species. Hypotheses regarding the pathway the compounds may target and their molecular mechanism for activity are discussed. PMID- 23459586 TI - Current progress in tonoplast proteomics reveals insights into the function of the large central vacuole. AB - Vacuoles of plants fulfill various biologically important functions, like turgor generation and maintenance, detoxification, solute sequestration, or protein storage. Different types of plant vacuoles (lytic versus protein storage) are characterized by different functional properties apparently caused by a different composition/abundance and regulation of transport proteins in the surrounding membrane, the tonoplast. Proteome analyses allow the identification of vacuolar proteins and provide an informative basis for assigning observed transport processes to specific carriers or channels. This review summarizes techniques required for vacuolar proteome analyses, like e.g., isolation of the large central vacuole or tonoplast membrane purification. Moreover, an overview about diverse published vacuolar proteome studies is provided. It becomes evident that qualitative proteomes from different plant species represent just the tip of the iceberg. During the past few years, mass spectrometry achieved immense improvement concerning its accuracy, sensitivity, and application. As a consequence, modern tonoplast proteome approaches are suited for detecting alterations in membrane protein abundance in response to changing environmental/physiological conditions and help to clarify the regulation of tonoplast transport processes. PMID- 23459587 TI - Response of Rhesus Macaques (Macaca mulatta) to the Body of a Group Member That Died from a Fatal Attack. AB - Among animals that form social bonds, the death of a conspecific may be a significant social event, representing the loss of an ally and resulting in disruptions to the dominance hierarchy. Despite this potential biological importance, we have only limited knowledge of animals' reactions to the death of a group member. This is particularly true of responses to dead adults, as most reports describe the responses of mothers to dead infants. Here, we describe in detail and provide video evidence of the behavioral responses of a group of free ranging rhesus macaques (Macaca mulatta) immediately after the death of a mid ranking adult male as a result of a fatal attack. High-ranking male members of the group, suspected to have carried out the attack, dragged and bit the dead body, exhibiting a rate of aggression 20 times greater than baseline levels. Lower-ranking individuals approached and inspected the body by looking closely, smelling, and grooming the fur. There was inconclusive evidence that these rhesus macaques found the death of a conspecific stressful: Levels of grooming between group members after the fatal attack were significantly higher than baseline levels, and higher than levels of grooming after nonfatal attacks. However, when grooming levels were adjusted based on the assumption that individuals positioned close to the body, i.e., those visible to researchers, were more likely to be engaged in grooming than those positioned farther away, this difference from baseline was no longer significant. The rate of self-directed behaviors after the fatal attack was also not different from baseline. Many of the behaviors we observed directed toward the body (aggression, inspection) have been previously reported in chimpanzees and geladas, and are similar to reactions sometimes displayed by humans. As such, this report represents a potentially valuable contribution the nascent field of nonhuman primate thanatology. PMID- 23459589 TI - Low temperature chemically synthesized rutile TiO2 photoanodes with high electron lifetime for organic dye-sensitized solar cells. AB - Electron lifetime in mesoporous nanostructured rutile TiO2 photoanodes, synthesized via a simple, cost-effective, low temperature (50-55 degrees C) wet chemical process, annealed at 350 degrees C for 1 h and not employing any sprayed TiO2 compact layer, was successfully tailored with 0.2 mM TiCl4 surface treatment that resulted in light to electric power conversion efficiency up to 4.4%. PMID- 23459590 TI - Guideline-recommended management of community-acquired pneumonia in veterans with spinal cord injury. AB - BACKGROUND: Pneumonia is a leading cause of death in persons with spinal cord injuries and disorders (SCI/D), but little is known about guideline-based management for this disease in persons with SCI/D. OBJECTIVES: The goal of this study was to describe guideline-based medical care for community-acquired pneumonia (CAP) in veterans with SCI/D. METHODS: A retrospective medical record review was conducted at 7 Department of Veterans Affairs (VA) medical centers where veterans with SCI/D and CAP between 2005 and 2008 were included. Outcomes assessed were receipt of blood or sputum culture, antibiotic timeliness, appropriateness of empiric antibiotic treatment, and vaccination. RESULTS: In 70 patients, 77 CAP episodes occurred and 83.1% were treated in the inpatient setting. The average age was 70.0 years and 64.9% had tetraplegia. Sputum culture was completed in 24.7% and blood culture in 59.7% of cases. Of inpatients, 79.7% had antibiotic treatment within 8 hours and 45.1% received guideline-recommended empirical antibiotics. More than 90% of inpatients received antibiotic treatment within 3 days of presentation and 78.1% received recommended treatment. The rates of pneumococcal pneumonia (89.9%) and influenza (79.7%) vaccinations were high in CAP cases. CONCLUSIONS: Diagnostic testing and early guideline-recommended treatment is variable in veterans with SCI/D and CAP. However vaccination against influenza and pneumococcal pneumonia is high. Specific guidelines for management of CAP in SCI/D patients may be needed, which reflect the unique risk factors and needs of this population. These data can be used as a benchmark for improvements in care processes for treating and managing CAP in persons with SCI/D. PMID- 23459588 TI - alphaCaMKII autophosphorylation controls the establishment of alcohol drinking behavior. AB - The alpha-Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of alphaCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of alphaCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction related behavior in mice. We found that alcohol drinking was initially diminished in alphaCaMKII autophosphorylation-deficient alphaCaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in alphaCaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that alphaCaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in alphaCaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation related area of the gene. Together, our data suggest alphaCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism. PMID- 23459591 TI - Nonstandard Maternal Work Schedules: Implications for African American Children's Early Language Outcomes. AB - In this study, observed maternal positive engagement and perception of work family spillover were examined as mediators of the association between maternal nonstandard work schedules and children's expressive language outcomes in 231 African American families living in rural households. Mothers reported their work schedules when their child was 24 months of age and children's expressive language development was assessed during a picture book task at 24 months and with a standardized assessment at 36 months. After controlling for family demographics, child, and maternal characteristics, maternal employment in nonstandard schedules at the 24 month timepoint was associated with lower expressive language ability among African American children concurrently and at 36 months of age. Importantly, the negative association between nonstandard schedules and children's expressive language ability at 24 months of age was mediated by maternal positive engagement and negative work-family spillover, while at 36 months of age, the association was mediated only by negative work family spillover. These findings suggest complex links between mothers' work environments and African American children's developmental outcomes. PMID- 23459593 TI - Admission variables predictive of academic struggle in a PharmD program. AB - Objective. To characterize and describe admission variables predictive of poor grade attainment by students in 2 pathways to a doctor of pharmacy (PharmD) program.Methods. A retrospective analysis of course grades of PharmD students admitted from 2000 to 2009 (N= 1,019) in the traditional degree pathway ("1 plus 5" degree program) and the provisional pathway (admitted directly from high school) was performed.Results. Four hundred three grades of D or less were earned by 183 (18%) students. There were more grades of D or less in the first pharmacy year. Receipt of an unsatisfactory grade was associated with all Pharmacy College Admission Test (PCAT) subcategory scores, PCAT composite score, cumulative prepharmacy coursework hours, prepharmacy grade point average (GPA), prepharmacy science and math GPA, and interview score for accepted students in the traditional pathway. For students in the provisional pathway, PCAT-quantitative analysis, PCAT composite score, prepharmacy cumulative GPA, prepharmacy science and math GPA, English American College Testing (ACT) score, and composite ACT score predicted poor grades. Conclusion. Admissions committees should heed PCAT scores and GPAs, regardless of program pathway, while progression committees should focus on early program coursework when designing strategies to optimize retention. PMID- 23459592 TI - A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma. AB - Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi 3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers. PMID- 23459594 TI - Colonoscopy for colorectal cancer screening. AB - Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Many, if not most, cases arise from premalignant lesions (adenomas) which may be identified and removed prior to becoming frankly malignant. For over a decade, colonoscopy has been the preferred modality for both CRC screening and prevention in the US. Early reports suggested that colonoscopic screening imparted a 90% risk reduction for colorectal cancer. Subsequent studies showed that estimate to be overly optimistic. While still an outstanding CRC screening and detection tool, colonoscopy has several important limitations. Some of these limitations relate to the mechanics of the procedure such as the risk of colonic perforation, bleeding, adverse consequences of sedation, and the inability to detect all colonic polyps. Other limitations reflect issues with patient perception regarding colonoscopy which, at least in part, drive patient non adherence to recommended testing. This review examines the literature to address several important issues. First, we analyze the effect of colonoscopy on CRC incidence and mortality. Second, we consider the patient-based, periprocedural, and intraprocedural factors which may limit colonoscopy as a screening modality. Third, we explore new techniques and technologies which may enhance the efficacy of colonoscopy for adenoma detection. Finally, we discuss the short and long-term future of colonoscopy for CRC screening and the factors which may affect this future. PMID- 23459596 TI - A randomized, double-blind study to evaluate the efficacy of ramosetron and palonosetron for prevention of postoperative nausea and vomiting after gynecological laparoscopic surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after anesthesia and surgery; 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have been considered as a first-line therapy. Ramosetron and palonosetron are more recently developed drugs and have greater receptor affinity and a longer elimination half-life compared with older 5-HT3 receptor antagonists. The purpose of this study was to determine which drug is more effective for preventing PONV between ramosetron and palonosetron. METHODS: We enrolled 100 patients undergoing gynecological laparoscopic surgery into this study. The subjects were divided into ramosetron group and palonosetron group. The medications were provided immediately before the induction of anesthesia. The occurrence of nausea and vomiting, severity of nausea according to a visual analogue scale, and rescue anti-emetic drug use were monitored immediately after the end of surgery and at 0-6 h, 6-24 h, and 24-48 h post-surgery. RESULTS: The incidence of vomiting was significantly lower in the palonosetron group than in the ramosetron group during 0-6 h (6% vs 26%, P = 0.012) and 0-48 h (14% vs 34%, P = 0.034). The incidence of nausea and overall PONV, and the use of rescue antiemetic were not significantly different during all time intervals. The severity of nausea was not different between the two groups. CONCLUSIONS: In conclusion, the incidence of PONV between the ramosetron and the palonosetron group have not shown the difference during 0-48 h, although palonosetron results in a lower incidence of vomiting during 0-6 h post-surgery. PMID- 23459597 TI - Beronaphaenops paphlagonicus, a new anophthalmous genus and species of Trechini (Coleoptera, Carabidae) from Turkey. AB - Beronaphaenopsgen. n.paphlagonicussp. n., a new remarkable, eyeless species of Trechini is described from Asian Turkey (type locality: cave Esek Cukuru Magarasi 2, Milli Park Kure Daglari, Pinarbasi District, Kastamonu Province). This specialized, troglobite species is characterized by a very peculiar combination of features, including several autapotypic features: mentum tooth large, long and porrect, at distal position reaching or slightly exceeding the level of epilobes, rather slanting ventrally, deeply bifid at the tip; short and fragile paraglossae, hardly surpassing the anterior margin of ligula; absence of posterolateral setae of the pronotum; absence of posterior discal pore in elytral stria 3; apical stylomere shortened, with basal part unusually broadened. The systematic position of the genus amongst the trechine beetles from the peri Pontic area is discussed. A key to the Anatolian genera of the tribe is prepared. PMID- 23459595 TI - The Arabidopsis Cytosolic Ribosomal Proteome: From form to Function. AB - The cytosolic ribosomal proteome of Arabidopsis thaliana has been studied intensively by a range of proteomics approaches and is now one of the most well characterized eukaryotic ribosomal proteomes. Plant cytosolic ribosomes are distinguished from other eukaryotic ribosomes by unique proteins, unique post translational modifications and an abundance of ribosomal proteins for which multiple divergent paralogs are expressed and incorporated. Study of the A. thaliana ribosome has now progressed well beyond a simple cataloging of protein parts and is focused strongly on elucidating the functions of specific ribosomal proteins, their paralogous isoforms and covalent modifications. This review summarises current knowledge concerning the Arabidopsis cytosolic ribosomal proteome and highlights potentially fruitful areas of future research in this fast moving and important area. PMID- 23459598 TI - Neuroscientific model of motivational process. AB - Considering the neuroscientific findings on reward, learning, value, decision making, and cognitive control, motivation can be parsed into three sub processes, a process of generating motivation, a process of maintaining motivation, and a process of regulating motivation. I propose a tentative neuroscientific model of motivational processes which consists of three distinct but continuous sub processes, namely reward-driven approach, value-based decision-making, and goal directed control. Reward-driven approach is the process in which motivation is generated by reward anticipation and selective approach behaviors toward reward. This process recruits the ventral striatum (reward area) in which basic stimulus action association is formed, and is classified as an automatic motivation to which relatively less attention is assigned. By contrast, value-based decision making is the process of evaluating various outcomes of actions, learning through positive prediction error, and calculating the value continuously. The striatum and the orbitofrontal cortex (valuation area) play crucial roles in sustaining motivation. Lastly, the goal-directed control is the process of regulating motivation through cognitive control to achieve goals. This consciously controlled motivation is associated with higher-level cognitive functions such as planning, retaining the goal, monitoring the performance, and regulating action. The anterior cingulate cortex (attention area) and the dorsolateral prefrontal cortex (cognitive control area) are the main neural circuits related to regulation of motivation. These three sub processes interact with each other by sending reward prediction error signals through dopaminergic pathway from the striatum and to the prefrontal cortex. The neuroscientific model of motivational process suggests several educational implications with regard to the generation, maintenance, and regulation of motivation to learn in the learning environment. PMID- 23459599 TI - Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats. AB - BACKGROUND: We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT(1)-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1-7) in the absence of significant changes in plasma Ang II. METHODS: mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5 mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin angiotensin system (RAS) were measured at the completion of the experiments. RESULTS: Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1-7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1-7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1-7) receptor antagonist except for a mild further increase in plasma renin concentration. CONCLUSIONS: Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT(1)-R blockade. Ang (1-7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT(1)-R blockade. PMID- 23459600 TI - Sequence Analysis of Native Oligosaccharides Using Negative ESI Tandem MS. AB - Carbohydrates exhibit many physiologically and pharmacologically important activities, yet their complicated structure and sequence pose major analytical challenges. Although their structural complexity makes analysis of carbohydrate difficult, mass spectrometry (MS) with high sensitivity, resolution and accuracy has become a vital tool in many applications related to analysis of carbohydrates or oligosaccharides. This application is essentially based on soft ionization technique which facilitates the ionization and vaporization of large, polar and thermally labile biomolecules. Electrospray-ionization (ESI), one of the soft ionization technique, tandem MS has been used in the sequencing of peptides, proteins, lipids, nucleic acids and more recently carbohydrates. The development of the ESI and tandem MS has begun to make carbohydrate analysis more routine. This review will focus on the application of the ESI tandem MS for the sequence analysis of native oligosaccharides, including neutral saccharides with multiple linkages, and the uronic acid polymers, alginate and glycosaminoglycans structures containing epimers. PMID- 23459602 TI - Comparison of respiratory muscle training methods in individuals with motor complete tetraplegia. AB - OBJECTIVE: To compare the effects of inspiratory resistance training (IRT) and isocapnic hyperpnea (IH) versus incentive spirometry (placebo) on respiratory function, voice, and quality of life in individuals with motor complete tetraplegia. METHODS: In this randomized controlled trial, 24 individuals with traumatic, motor complete (AIS A) tetraplegia (C5-C8), 6 to 8 months post injury, were randomly assigned to 1 of 3 groups. They completed either 90 repetitions of IRT, 10 minutes of IH, or 16 repetitions of placebo training in 32 supervised training sessions over 8 weeks. Before and after the training period, the following tests were performed: bodyplethysmography, inspiratory and expiratory muscle strength, subjective breathing parameters using the visual analogue scale (VAS), voice measurements, and an adapted SF-12 quality of life questionnaire. A Friedman test and Cohen's effect sizes for IRT and IH versus placebo were calculated for differences between pre- and posttraining values. RESULTS: Compared to placebo training, IRT showed high effect sizes for inspiratory muscle strength (d = 1.19), VAS values of "cleaning the nose" (d = 0.99), and the physical component of subjective quality of life (d = 0.84). IH compared to placebo training showed only medium and low effect sizes. The Friedman analysis showed a significant effect for IRT versus placebo on inspiratory muscle strength (P = .030). Neither all other parameters of respiratory function nor voice measurements, subjective breathing parameters, or quality of life were significantly improved by one of the tested training methods. CONCLUSION: In individuals with motor complete tetraplegia, inspiratory muscle strength can be improved by IRT. Therefore, IRT is advantageous compared to IH for this group of patients and during the first year post injury. PMID- 23459603 TI - pi-Complexes from acyl cyanides and lithium dimethylcuprate(I). AB - Rapid injection of pyruvonitrile or benzoyl cyanide into solutions of Me2CuLi in THF-d8 at -100 degrees C gave complexes that were stable at this temperature. 1D NMR with multiply labelled substrates ((13)C/(15)N) and 2D NMR ((1)H/(13)C) identified them as the first cuprate-carbonyl pi-complexes. PMID- 23459604 TI - BOX SPLINE BASED 3D TOMOGRAPHIC RECONSTRUCTION OF DIFFUSION PROPAGATORS FROM MRI DATA. AB - This paper introduces a tomographic approach for reconstruction of diffusion propagators, P( r ), in a box spline framework. Box splines are chosen as basis functions for high-order approximation of P( r ) from the diffusion signal. Box splines are a generalization of B-splines to multivariate setting that are particularly useful in the context of tomographic reconstruction. The X-Ray or Radon transform of a (tensor-product B-spline or a non-separable) box spline is a box spline - the space of box splines is closed under the Radon transform.We present synthetic and real multi-shell diffusion-weighted MR data experiments that demonstrate the increased accuracy of P( r ) reconstruction as the order of basis functions is increased. PMID- 23459601 TI - Decreased right temporal activation and increased interhemispheric connectivity in response to speech in preterm infants at term-equivalent age. AB - Preterm infants are at increased risk of language-related problems later in life; however, few studies have examined the effects of preterm birth on cerebral responses to speech at very early developmental stages. This study examined cerebral activation and functional connectivity in response to infant-directed speech (IDS) and adult-directed speech (ADS) in full-term neonates and preterm infants at term-equivalent age using 94-channel near-infrared spectroscopy. The results showed that compared with ADS, IDS increased activity in larger brain areas such as the bilateral frontotemporal, temporal, and temporoparietal regions, both in full-term and preterm infants. Preterm infants exhibited decreased activity in response to speech stimuli in the right temporal region compared with full-term infants, although the significance was low. Moreover, preterm infants exhibited increased interhemispheric connectivity compared with full-term controls, especially in the temporal and temporoparietal regions. These differences suggest that preterm infants may follow different developmental trajectories from those born at term owing to differences in intrauterine and extrauterine development. PMID- 23459605 TI - Cardiac resuscitation: Is an advanced airway harmful during out-of-hospital CPR? AB - In a new, observational study, survival and neurological outcome at 1 month after out-of-hospital cardiac arrest were worse in patients treated with an advanced airway than in those treated with bag-mask ventilation. These results contradict the common assumption that advanced airway management is associated with improved outcome. PMID- 23459606 TI - How can resistant hypertension be identified and prevented? AB - Resistant hypertension is highly prevalent, and is the form of arterial hypertension that is most difficult to treat. Many patients diagnosed with this disease do not have resistant hypertension, but rather have mismanaged primary hypertension. In many cases blood pressure can be controlled by directly addressing underlying causes such as primary aldosteronism, obstructive sleep apnoea, or excessive neurogenic stimulation. Clinicians should ensure that appropriate blood-pressure measurements are used to diagnose resistant hypertension, explore a variety of drug combinations, and battle clinical inertia. Patients should comply with medication schedules and dietary modifications. Correction of these factors will greatly diminish the prevalence of 'resistant' hypertension and avoid the consequences of a persistently elevated blood pressure in these patients. PMID- 23459607 TI - Interventional cardiology: Antithrombotic therapy for PCI--getting the balance right. PMID- 23459608 TI - Refeeding hypophosphatemia in adolescents with anorexia nervosa: a systematic review. AB - The rate of adolescents presenting with anorexia nervosa (AN) is increasing. Medically unstable adolescents are admitted to the hospital for nutrition restoration. A lack of global consensus on appropriate refeeding practices of malnourished patients has resulted in inconsistent refeeding practices. Refeeding hypophosphatemia (RH) is the most common complication associated with refeeding the malnourished patient. This review sought to identify the range of refeeding rates adopted globally and the implication that total energy intake and malnutrition may have on RH while refeeding adolescents with anorexia nervosa. Studies were identified by a systematic electronic search of medical databases from 1980 to September 2012. Seventeen publications were identified, including 6 chart reviews, 1 observational study, and 10 case reports, with a total of 1039 subjects. The average refeeding energy intake was 1186 kcal/d, ranging from 125 1900 kcal/d, with a mean percentage median body mass index (% mBMI) of 78%. The average incidence rate of RH was 14%. A significant correlation between malnutrition (% mBMI) and post-refeeding phosphate was identified (R (2) = 0.6, P = .01). This review highlights the disparity in refeeding rates adopted internationally in treating malnourished adolescents with anorexia nervosa. Based on this review, the severity of malnutrition seems to be a marker for the development of RH more so than total energy intake. PMID- 23459609 TI - Just say no to intensive care unit starvation: a nutrition education program for surgery residents. AB - BACKGROUND: In 2009, the Society of Critical Care Medicine (SCCM)/American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) published "Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient." To improve our surgery residents' understanding of intensive care unit (ICU) nutrition, we developed a nutrition education program based on these guidelines. The purpose of this pilot study was to assess its effectiveness. We hypothesized that our nutrition education program would improve our residents' knowledge of ICU nutrition. MATERIALS AND METHODS: This was a prospective observational pilot study performed in the surgical ICU of an academic medical center. Based on the SCCM/A.S.P.E.N. nutrition guidelines, we developed a nutrition education program (lectures covering selected guidelines and interactive case studies). Pre- and posttesting were performed to assess short-term comprehension. Long-term retention was assessed 3 months after the initial education program. The primary outcome measure was the change in ICU nutrition knowledge. Significance was set at P < .05. RESULTS: Over 12 months, 8 surgery residents completed the nutrition education program. Their mean age was 27.8 +/- 1.2 years, and 50% were male. The mean test scores were as follows: pretest, 45% +/- 9%; posttest, 81% +/- 5%; and 3-month test, 65% +/- 8%. The differences between the pretest and both posttest scores were significant (P < .01). CONCLUSION: Residents have little understanding of ICU nutrition. This is confirmed by the pretest results of the current study. Our nutrition education program improved both short-term and long-term ICU nutrition knowledge of our surgery residents. Future studies should evaluate the effect such education has on the clinical outcomes of ICU patients. PMID- 23459610 TI - Programmed protection of foreign DNA from restriction allows pathogenicity island exchange during pneumococcal transformation. AB - In bacteria, transformation and restriction-modification (R-M) systems play potentially antagonistic roles. While the former, proposed as a form of sexuality, relies on internalized foreign DNA to create genetic diversity, the latter degrade foreign DNA to protect from bacteriophage attack. The human pathogen Streptococcus pneumoniae is transformable and possesses either of two R M systems, DpnI and DpnII, which respectively restrict methylated or unmethylated double-stranded (ds) DNA. S. pneumoniae DpnII strains possess DpnM, which methylates dsDNA to protect it from DpnII restriction, and a second methylase, DpnA, which is induced during competence for genetic transformation and is unusual in that it methylates single-stranded (ss) DNA. DpnA was tentatively ascribed the role of protecting internalized plasmids from DpnII restriction, but this seems unlikely in light of recent results establishing that pneumococcal transformation was not evolved to favor plasmid exchange. Here we validate an alternative hypothesis, showing that DpnA plays a crucial role in the protection of internalized foreign DNA, enabling exchange of pathogenicity islands and more generally of variable regions between pneumococcal isolates. We show that transformation of a 21.7 kb heterologous region is reduced by more than 4 logs in dpnA mutant cells and provide evidence that the specific induction of dpnA during competence is critical for full protection. We suggest that the integration of a restrictase/ssDNA-methylase couplet into the competence regulon maintains protection from bacteriophage attack whilst simultaneously enabling exchange of pathogenicicy islands. This protective role of DpnA is likely to be of particular importance for pneumococcal virulence by allowing free variation of capsule serotype in DpnII strains via integration of DpnI capsule loci, contributing to the documented escape of pneumococci from capsule-based vaccines. Generally, this finding is the first evidence for a mechanism that actively promotes genetic diversity of S. pneumoniae through programmed protection and incorporation of foreign DNA. PMID- 23459612 TI - Platelet transfusion improves liver function in patients with chronic liver disease and cirrhosis. AB - Chronic liver disease (CLD), such as hepatitis C, is a progressive disease consisting of the destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. Platelets contain various growth factors and may play important roles in liver regeneration. Thus, to investigate whether platelet transfusion improves liver function in patients with CLD and cirrhosis, we conducted an exploratory clinical trial. The study included 10 patients with CLD and cirrhosis (Child-Pugh class A or B), who all presented thrombocytopenia (platelet counts between 50,000 and 100,000 /ul). The subjects received 10 units of platelet concentrate once a week for 12 weeks. They were followed up for 9 months after the last transfusion. One patient discontinued platelet transfusion because of pruritus, and 2 patients discontinued because of platelet transfusion refractoriness. One patient was excluded from the analysis for receiving a procedural treatment after 12 platelet transfusions. Thus, the remaining 6 patients were analyzed. The platelet count did not increase significantly after the last transfusion. Significant improvement of serum albumin was observed at 1 month and 3 months after the last transfusion. Serum cholinesterase improved significantly at 1 week, 3 months, and 9 months after the last transfusion. Serum hyaluronic acid showed a tendency toward improvement after the last transfusion. In conclusion, platelet transfusion improved some of the indicators of liver function in patients with CLD and cirrhosis, though adverse events related to platelet transfusion were observed in some patients. Platelet increment therapy could be a new strategy for treating CLD and cirrhosis. PMID- 23459611 TI - Reciprocal connectivity between mitral cells and external plexiform layer interneurons in the mouse olfactory bulb. AB - Proper brain function relies on exquisite balance between excitation and inhibition, where inhibitory circuits play fundamental roles toward sculpting principle neuron output and information processing. In prominent models of olfactory bulb circuitry, inhibition of mitral cells by local interneurons sharpens odor tuning and provides contrast enhancement. Mitral cell inhibition occurs at both mitral cell apical dendrites and deep-layer dendrodendritic synapses between granule cells, the most abundant population of inhibitory interneurons in the olfactory bulb. However, it remains unclear whether other local interneurons make inhibitory connections onto mitral cells. Here, we report a novel circuitry with strong and reciprocal connectivity between a subpopulation of previously uncharacterized Corticotropin-Releasing Hormone (CRH)-expressing interneurons located in the external plexiform layer (EPL), and mitral cells. Using cell type-specific genetic manipulations, imaging, optogenetic stimulation, and electrophysiological recordings, we reveal that CRH-expressing EPL interneurons strongly inhibit mitral cell firing, and that they are reciprocally excited by fast glutamatergic mitral cell input. These findings functionally identify a novel subpopulation of olfactory bulb interneurons that show reciprocal connectivity with mitral cells, uncovering a previously unknown, and potentially critical player in olfactory bulb circuitry that may influence lateral interactions and/or facilitate odor processing. PMID- 23459613 TI - Discovery of O-Alkylamino Tethered Niclosamide Derivatives as Potent and Orally Bioavailable Anticancer Agents. AB - Niclosamide has been identified to potently inhibit the activation, nuclear translocation, and transactivation of STAT3. Nevertheless, the poor aqueous solubility and bioavailability of niclosamide has hindered its further clinical development for cancer therapy. To discover new molecules with enhanced drug-like properties, a series of novel O-alkylamino tethered derivatives of niclosamide have been designed, synthesized, and biologically evaluated. Among them, compound 11 (HJC0152) has been demonstrated to significantly suppress MDA-MB-231 xenograft tumor growth in vivo (i.p. & p.o.), indicating its great potential as efficacious and orally bioavailable therapeutics for human cancer. PMID- 23459614 TI - Late outcomes of mitral valve repair for mitral regurgitation due to degenerative disease. AB - BACKGROUND: The pathological spectrum of degenerative diseases of the mitral valve (MV) that causes mitral regurgitation (MR) is broad, and there is limited information on late outcomes of MV repair in various subgroups of patients and pathologies. This study examines this issue. METHODS AND RESULTS: All 840 patients who had MV repair for MR due to degenerative diseases from 1985 to 2004 were prospectively followed with clinical and echocardiographic evaluations at biennial intervals up to 26 years, median of 10.4 years. Clinical, hemodynamic, and pathological variables were evaluated for their association with outcomes. Age, left ventricular ejection fraction, and functional class were predictors of late cardiac- and valve-related deaths by multivariable analysis. MV repair failed to restore life span to normal in patients with functional class IV. Thirty-eight patients had repeat MV surgery, and the probability of reoperation at 20 years was 5.9%. During the follow-up, recurrent severe MR developed in 37 patients, and moderate MR developed in 61. Age, isolated prolapse of the anterior leaflet, the degree of myxomatous changes in the MV, lack of mitral annuloplasty, and duration of cardiopulmonary bypass were associated with increased risk of recurrent MR. At 20 years, the freedom from recurrent severe MR was 90.7%, and the freedom from moderate or severe MR was 69.2%. CONCLUSIONS: MV repair for degenerative MR restored life span to normal except in patients with symptoms at rest and impaired left ventricular function. Advanced age and complex mitral valve pathologies increased the risk of late recurrent MR. PMID- 23459615 TI - MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. AB - BACKGROUND: Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production. METHODS AND RESULTS: Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week, or 2 weeks to induce CHF. Atrial miR29b expression decreased within 24 hours in both whole atrial tissue and atrial fibroblasts (-87% and -92% versus control, respectively; p<0.001 for both) and remained decreased throughout the time course. Expression of miR29b extracellular matrix target genes collagen-1A1 (COL1A1), collagen-3A1 (COL3A1), and fibrillin increased significantly in CHF fibroblasts. Lentivirus-mediated miR29b knockdown in canine atrial fibroblasts (-68%; p<0.01) enhanced COL1A1, COL3A1, and fibrillin mRNA expression by 28% (p<0.01), 19% (p<0.05), and 20% (p<0.05), respectively, versus empty virus-infected fibroblasts and increased COL1A1 protein expression by 90% (p<0.05). In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1, and fibrillin mRNA by 65%, 62%, and 61% (all p<0.001), respectively, versus scrambled control and decreased COL1A1 protein by 60% (p<0.05). MiR29b plasma levels were decreased in patients with CHF or AF (by 53% and 54%, respectively; both p<0.001) and were further decreased in patients with both AF and CHF (by 84%; p<0.001). MiR29b expression was also reduced in the atria of chronic AF patients (by 54% versus sinus rhythm; p<0.05). Adenoassociated viral-mediated knockdown of miR29b in mice significantly increased atrial COL1A1 mRNA expression and cardiac tissue collagen content. CONCLUSIONS: MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target. PMID- 23459616 TI - Hypersomnia in children affected by migraine without aura: a questionnaire-based case-control study. AB - BACKGROUND: The relationship between sleep and headache is meaningful and complex. Children affected by migraines tend to show many sleep disorders, such as insufficient sleep duration and excessive daytime somnolence. Therefore, the aim of this study is to assess the rate of reported sleep habits and self reported sleepiness in a large pediatric sample of individuals affected by migraine without aura (MoA). METHODS: The study population consisted of 271 children aged between 6 and 13 years affected by MoA. The control group was composed of 305 typically developing children. To assess the sleep habits of all individuals (MoA and control), parents filled out the Sleep Disturbance Scale for Children, and to check the degree of subjective perceived daytime sleepiness, all subjects were administered the Pediatric Daytime Sleepiness Scale. RESULTS: The two study groups were matched for age (P = 0.124), sex distribution (P = 0.775), and body mass index z-score (P = 0.107). Parents of children affected by MoA reported a higher total score of sleep disorder symptoms (P <0.001), disorders of initiating and maintaining (P < 0.001), and disorders of arousal (P < 0.001) than did parents of controls. No significant differences were found in disorders of excessive somnolence. Conversely, in the Pediatric Daytime Sleepiness Scale, migraine children had higher scores (24.67 +/- 3.19 vs 11.94 +/- 4.81; P < 0.001) and a reduction in referred total sleep time mean duration (469.83 +/- 98.112 vs 527.94 +/- 83.02; P < 0.001) than typically developing children. CONCLUSION: Our study identified differences in sleep habits and found a high prevalence of daytime somnolence in children affected by MoA, suggesting the need for routine sleep screening in the pediatric management of children with migraines. PMID- 23459617 TI - Automated Delineation of Lung Tumors from CT Images Using a Single Click Ensemble Segmentation Approach. AB - A single click ensemble segmentation (SCES) approach based on an existing "Click&Grow" algorithm is presented. The SCES approach requires only one operator selected seed point as compared with multiple operator inputs, which are typically needed. This facilitates processing large numbers of cases. Evaluation on a set of 129 CT lung tumor images using a similarity index (SI) was done. The average SI is above 93% using 20 different start seeds, showing stability. The average SI for 2 different readers was 79.53%. We then compared the SCES algorithm with the two readers, the level set algorithm and the skeleton graph cut algorithm obtaining an average SI of 78.29%, 77.72%, 63.77% and 63.76% respectively. We can conclude that the newly developed automatic lung lesion segmentation algorithm is stable, accurate and automated. PMID- 23459619 TI - Physiological responses to exergaming after spinal cord injury. AB - PURPOSE: To investigate whether exergaming satisfies guideline-based intensity standards for exercise conditioning (40%/50% oxygen uptake reserve [VO2R] or heart rate reserve (HRR), or 64%/70% of peak heart rate [HRpeak]) in persons with paraplegia. METHODS: Nine men and women (18-65 years old) with chronic paraplegia (T1-L1, AIS A-C) underwent intensity-graded arm cycle exercise (AE) to evaluate VO2peak and HRpeak. On 2 randomized nonconsecutive days, participants underwent graded exercise using a custom arm cycle ergometer that controls the video display of a Nintendo Gamecube (GameCycle; Three Rivers Holdings LLC, Mesa, AZ) or 15 minutes of incrementally wrist-weighted tennis gameplay against a televised opponent (XaviX Tennis System; SSD Co Ltd, Kusatsu, Japan). RESULTS: GameCycle exergaming (GCE) resistance settings >=0.88 Nm evoked on average >=50% VO2R. During XaviX Tennis System exergaming (XTSE) with wrist weights >=2 lbs, average VO2 reached a plateau of ~40% VO2R. Measurements of HR were highly variable and reached average values >=50% HRR during GCE at resistance settings >=0.88 Nm. During XTSE, average HR did not reach threshold levels based on HRR for any wrist weight (20%-35% HRR). CONCLUSIONS: On average, intensity responses to GCE at resistance setting >=0.88 Nm were sufficient to elicit exercise intensities needed to promote cardiorespiratory fitness in individuals with SCI. The ability of XTSE to elicit cardiorespiratory fitness benefits is most likely limited to individuals with very low fitness levels and may become subminimal with time if used as a conditioning stimulus. PMID- 23459620 TI - 2,3-Dicyclohexylsuccinimide as a directing/protecting group for the regioselective glycosylation or alkylation of purines. AB - Here we describe the synthesis and application of a novel 2,3 dicyclohexylsuccinimide (Cy2SI) protecting group towards regioselective purine glycosylation and alkylation reactions. This bulky protecting group promotes high regioselectivity during the glycosylation (as well as diastereoselectivity) or alkylation of purines using Hoffer's chlorosugar or tert-butyl bromoacetate, respectively. Cy2SI offers the additional synthetic advantage that other base labile protecting groups, such as toluoyl esters, can be selectively removed in its presence without affecting the imide. PMID- 23459618 TI - The function of metabotropic glutamate receptors in thalamus and cortex. AB - Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S] alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies. PMID- 23459621 TI - Use and views on social networking sites of pharmacy students in the United kingdom. AB - Objective. To investigate students' use and views on social networking sites and assess differences in attitudes between genders and years in the program.Methods. All pharmacy undergraduate students were invited via e-mail to complete an electronic questionnaire consisting of 21 questions relating to social networking.Results. Most (91.8%) of the 377 respondents reported using social networking Web sites, with 98.6% using Facebook and 33.7% using Twitter. Female students were more likely than male students to agree that they had been made sufficiently aware of the professional behavior expected of them when using social networking sites (76.6% vs 58.1% p=0.002) and to agree that students should have the same professional standards whether on placement or using social networking sites (76.3% vs 61.6%; p<0.001).Conclusions. A high level of social networking use and potentially inappropriate attitudes towards professionalism were found among pharmacy students. Further training may be useful to ensure pharmacy students are aware of how to apply codes of conduct when using social networking sites. PMID- 23459622 TI - Significance of infectious agents in colorectal cancer development. AB - Colorectal cancer (CRC) is a major burden to healthcare systems worldwide accounting for approximately one million of new cancer cases worldwide. Even though, CRC mortality has decreased over the last 20 years, it remains the third most common cause of cancer-related mortality, accounting for approximately 600,000 deaths in 2008 worldwide. A multitude of risk factors have been linked to CRC, including hereditary factors, environmental factors and inflammatory syndromes affecting the gastrointestinal tract. Recently, various pathogens were added to the growing list of risk factors for a number of common epithelial cancers, but despite the multitude of correlative studies, only suggestions remain about the possible relationship between selected viruses and bacteria of interest and the CRC risk. United States military service members are exposed to various risk factors impacting the incidence of cancer development. These exposures are often different from that of many sectors of the civilian population. Thereby, cancer risk identification, screening and early detection are imperative for both the military health care beneficiaries and the population as a whole. In this review, we will focus on several pathogens and their potential roles in development of CRC, highlighting the clinical trials evaluating this correlation and provide our personal opinion about the importance of risk reduction, health promotion and disease prevention for military health care beneficiaries. PMID- 23459624 TI - Validation and clinical utility of prostate cancer biomarkers. AB - To improve future drug development and patient management for patients with castration-resistant prostate cancer (CRPC), surrogate biomarkers that are linked to relevant outcomes are urgently needed. A biomarker must be measurable, reproducible, linked to relevant clinical outcomes, and demonstrate clinical utility. This area is rapidly evolving, with recent trials in patients with CRPC incorporating the detection of circulating tumour cells (CTCs), imaging, and patient-reported outcome biomarkers. We discuss the framework for the development of biomarkers for CRPC, including different categories and contexts of use. We also highlight the requirements of analytical validation, the sequence of trials needed for clinical validation and regulatory approval, and the future outlook for imaging and CTC biomarkers. PMID- 23459628 TI - Effects of dipyridamole coadministration on the pharmacokinetics of ribavirin in healthy volunteers. AB - Ribavirin (RBV), a guanosine analog for treatment of hepatitis C, is a substrate of a nucleoside transporter, solute carrier family 29 member 1 (SLC29A1). To clarify the impact of SLC29A1 on the pharmacokinetics of RBV, an open-label, crossover study of single-dose RBV (200 mg, p.o.) with and without coadministration of dipyridamole (DP), an inhibitor of SLC29A1, was performed. Plasma and erythrocyte concentrations of RBV in the control phase and DP phase (25 mg, 3 times daily for 4 days) were compared in 10 healthy volunteers. SLC29A1 mRNA expression in peripheral blood mononuclear cells was also determined. In the DP phase, area under the concentration-time curves (AUC) of RBV in plasma and erythrocytes showed reductions of 23% and 17%, respectively (p < 0.05), with increases in apparent oral clearance of 18% and 25%, respectively (p < 0.05). The reduction rate of the AUC of erythrocyte RBV in the DP phase was associated with SLC29A1 mRNA expression: higher mRNA expression showed greater AUC reduction. The elimination half-life of both plasma and erythrocyte RBV did not differ between the 2 phases. These results suggest that RBV/DP coadministration reduces the concentration of RBV in blood by inhibiting an important role of SLC29A1 in gastrointestinal absorption of RBV. PMID- 23459629 TI - Folding single-stranded DNA to form the smallest 3D DNA triangular prism. AB - The smallest DNA 3D object, a triangular prism with only one turn on each edge, was constructed from a single-stranded DNA. We confirmed its structure using scanning tunneling microscopy. This work proves that single-stranded DNA can escape from kinetic traps to form stable topology. PMID- 23459630 TI - Santocellus (Neuroptera, Chrysopidae, Leucochrysini): taxonomic changes, new description, and a key to the species. AB - Santocellus is a small Neotropical genus of leucochrysine lacewings that only recently was separated from Leucochrysa. Here, the features of the Leucochrysa risi Esben-Petersen holotype (a female) are described and shown to support the species' transfer to Santocellus and the continued retention of the genus Santocellus as separate from Leucochrysa. The valid name for the species becomes Santocellus risi (Esben-Petersen, 1933), comb. n., and Santocellus bullata (Tauber, 2007) is recognized as a syn. n. of Santocellus risi. Currently, this species is reported only from Peru. An illustrated key is provided for distinguishing the known species in the genus Santocellus. PMID- 23459631 TI - The prophylactic effects of gabapentin on postoperative sore throat after thyroid surgery. AB - BACKGROUND: Postoperative sore throat (POST) is considered a usual complication after tracheal intubation, especially, thyroid surgery. Gabapentin is a widely studied multimodal perioperative drug, which can be used to treat acute postoperative pain. The primary endpoints of this study was a reduction of the incidence of POST at rest and during the swallowing movements after thyroid surgery. And the second endpoints was a reduction of the intensity of the POST after thyroid surgery. METHODS: Seventy-one patients that underwent elective thyroid surgery received either gabapentin (NeurontinTM 600 mg) or placebo, orally, one hour before anesthesia. The VAS scores and incidences of POST and adverse effects were determined at 1 hr, 6 hr, 12 hr, and 24 hr after surgery at rest and during swallowing movement. RESULTS: The gabapentin group (N = 36) showed a lower incidence of POST than the placebo group (N = 35) (47% vs. 78%, P = 0.038), and had significant lower VAS score at 6 and 24 hours after surgery in the resting state. However, during the movement, no intergroup differences were found in terms of the incidence of POST (83% vs. 91%, P = 0.305) or VAS score. Furthermore, no significant difference was observed between the two groups, in adverse effects. CONCLUSIONS: Gabapentin (NeurontinTM 600 mg) administered 1 hr before anesthesia reduced the intensity and incidence of POST during the resting state without a significant adverse event, during the 24 hr after thyroid surgery. However, gabapentin did not reduce the intensity and incidence of POST during the swallowing movement. PMID- 23459632 TI - Mesenchymal stem cells are mobilized from the bone marrow during inflammation. AB - Mesenchymal stem cells (MSCs) show great therapeutic potential for the treatment of various immune mediated diseases, including Multiple Sclerosis (MS). Systemic administration of MSCs during experimental allergic encephalomyelitis (EAE), an animal model for MS, was shown to reduce the infiltration of T cells, B cells, and macrophages into the CNS. Whether endogenous MSCs are mobilized and potentially modulate the severity of disease is not known. Here we show that during the acute phase of EAE, MSCs numbers in the bone marrow were severely reduced, which restored to control levels during the progressive phase of the disease. The number of bone marrow MSCs inversely correlated with the number of both CD4 and CD8 T cells present in the bone marrow indicating a link between activated T cells and MSC mobilization. Analysis of CD70-transgenic mice, which have a constitutively activated immune system and elevated number of activated T cells in the bone marrow, showed severely reduced number of bone marrow MSCs. Transfer of T cells that were activated through their CD27 receptor reduced the number of bone marrow MSCs dependent on IFN-y. These data provide a mechanism by which MSCs can be mobilized from the bone marrow in order to contribute to tissue repair at a distant location. PMID- 23459626 TI - Emerging targeted agents in metastatic breast cancer. AB - Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents. PMID- 23459633 TI - Cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children: implications for vaccine development. AB - BACKGROUND: Recently, enterovirus 71 (EV71) has caused life-threatening outbreaks involving neurological and cardiopulmonary complications in Asian children with unknown mechanism. EV71 has one single serotype but can be phylogenetically classified into 3 main genogroups (A, B and C) and 11 genotypes (A, B1~B5 and C1~C5). In Taiwan, nationwide EV71 epidemics with different predominant genotypes occurred in 1998 (C2), 2000-2001 (B4), 2004-2005 (C4), and 2008 (B5). In this study, sera were collected to measure cross-reactive neutralizing antibody titers against different genotypes. METHODS: We collected historical sera from children who developed an EV71 infection in 1998, 2000, 2005, 2008, or 2010 and measured cross-reactive neutralizing antibody titers against all 11 EV71 genotypes. In addition, we aligned and compared the amino acid sequences of P1 proteins of the tested viruses. RESULTS: Serology data showed that children infected with genogroups B and C consistently have lower neutralizing antibody titers against genogroup A (>4-fold difference). The sequence comparisons revealed that five amino acid signatures (N143D in VP2; K18R, H116Y, D167E, and S275A in VP1) are specific for genogroup A and may be related to the observed antigenic variations. CONCLUSIONS: This study documented antigenic variations among different EV71 genogroups and identified potential immunodominant amino acid positions. Enterovirus surveillance and vaccine development should monitor these positions. PMID- 23459635 TI - Intermittent catheterization and recurrent urinary tract infection in spinal cord injury. AB - PURPOSE: To study the association of recurrent symptomatic urinary tract infections (UTIs) with the long-term use of clean intermittent catheterization (CIC) for the management of neurogenic bladder in patients with spinal cord injury (SCI). METHODS: Retrospective study of 61 SCI patients with neurogenic bladder managed by CIC. Subjects were selected from 210 SCI patients seen at the Yale Urology Medical Group between 2000 and 2010. Medical UTI prophylaxis (PRx) with oral antimicrobials or methenamine/ascorbic acid was used to identify patients with recurrent UTI. The number of positive cultures (>=10(3) cfu/mL) within a year prior to starting PRx was used to confirm the recurrence of UTI. RESULTS: Fifty-one male and 10 female subjects were managed with CIC. Forty-one (67%) subjects were placed on medical PRx for symptomatic recurrent UTI. Seventeen (28%) subjects had at least 3 positive cultures within the year prior to starting PRx. Fifteen of 20 (75%) subjects not on PRx had no complaints of UTI symptoms in the final year of follow-up. CONCLUSION: Recurrent symptomatic UTIs remain a major complication of long-term CIC in SCI patients. Although CIC is believed to have the fewest number of complications, many SCI patients managed with long-term CIC are started on medical PRx early in the course of management. Future studies are needed to determine the efficacy of routine UTI PRx in these patients as well as determine what factors influence why many patients on CIC experience frequent infections and others do not. PMID- 23459634 TI - NETosis and NADPH oxidase: at the intersection of host defense, inflammation, and injury. AB - Neutrophils are armed with both oxidant-dependent and -independent pathways for killing pathogens. Activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase constitutes an emergency response to infectious threat and results in the generation of antimicrobial reactive oxidants. In addition, NADPH oxidase activation in neutrophils is linked to activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the release of nuclear and granular components that can target extracellular pathogens. NETosis is activated during microbial threat and in certain conditions mimicking sepsis, and can result in both augmented host defense and inflammatory injury. In contrast, apoptosis, the physiological form of neutrophil death, not only leads to non-inflammatory cell death but also contributes to alleviate inflammation. Although there are significant gaps in knowledge regarding the specific contribution of NETs to host defense, we speculate that the coordinated activation of NADPH oxidase and NETosis maximizes microbial killing. Work in engineered mice and limited patient experience point to varying susceptibility of bacterial and fungal pathogens to NADPH oxidase versus NET constituents. Since reactive oxidants and NET constituents can injure host tissue, it is important that these pathways be tightly regulated. Recent work supports a role for NETosis in both acute lung injury and in autoimmunity. Knowledge gained about mechanisms that modulate NETosis may lead to novel therapeutic approaches to limit inflammation-associated injury. PMID- 23459636 TI - Rosuvastatin was Effective in Acute Heart Failure and Slow Coronary Flow: A Hypothesis-generating Case Report. AB - Slow coronary flow phenomenon (SCFP) is characterized by angiographically normal coronary arteries with delayed run-off of contrast medium across the vasculature. Its etiology and clinical significance are still not completely known; however, acute congestive heart failure (CHF) is rare in this context. A 71 year-old woman with SCFP presented with acute CHF complicated by ventricular tachycardia. Treated with rosuvastatin (20 mg/day for 6 days) and inotropic drug infusion she had a complete recovery of left ventricular function and normalization of serum levels of the high-sensitivity C-reactive protein (hs-CRP), which were increased (3.6 mg/L) during the acute phase. This case illustrates that the anti inflammatory properties of rosuvastatin may deserve specific clinical tests not only during the chronic phase but also in the acute phase of CHF patients. PMID- 23459638 TI - Direct synthesis of novel homogeneous nanocomposites of Li2MnSiO4 and carbon as a potential Li-ion battery cathode material. AB - Homogeneous nanocomposites of nanocrystalline Li2MnSiO4 and carbon as well as a carbon nanotubes-embedded nanocomposite are synthesized directly by a novel method using organic-inorganic hybrid polymers which consist of covalently bonded phenolic oligomer and siloxane parts. The nanocomposites show superior charge discharge performance at room temperature in spite of low carbon contents. PMID- 23459639 TI - A Probabilistic Graphical Model for Ab Initio Folding. AB - Despite significant progress in recent years, ab initio folding is still one of the most challenging problems in structural biology. This paper presents a probabilistic graphical model for ab initio folding, which employs Conditional Random Fields (CRFs) and directional statistics to model the relationship between the primary sequence of a protein and its three-dimensional structure. Different from the widely-used fragment assembly method and the lattice model for protein folding, our graphical model can explore protein conformations in a continuous space according to their probability. The probability of a protein conformation reflects its stability and is estimated from PSI-BLAST sequence profile and predicted secondary structure. Experimental results indicate that this new method compares favorably with the fragment assembly method and the lattice model. PMID- 23459637 TI - Trait anxiety modulates fronto-limbic processing of emotional interference in borderline personality disorder. AB - Previous studies of cognitive alterations in borderline personality disorder (BPD) have yielded conflicting results. Given that a core feature of BPD is affective instability, which is characterized by emotional hyperreactivity and deficits in emotion regulation, it seems conceivable that short-lasting emotional distress might exert temporary detrimental effects on cognitive performance. Here we used functional magnetic resonance imaging (fMRI) to investigate how task irrelevant emotional stimuli (fearful faces) affect performance and fronto-limbic neural activity patterns during attention-demanding cognitive processing in 16 female, unmedicated BPD patients relative to 24 age-matched healthy controls. In a modified flanker task, emotionally negative, socially salient pictures (fearful vs. neutral faces) were presented as distracters in the background. Patients, but not controls, showed an atypical response pattern of the right amygdala with increased activation during emotional interference in the (difficult) incongruent flanker condition, but emotion-related amygdala deactivation in the congruent condition. A direct comparison of the emotional conditions between the two groups revealed that the strongest diagnosis-related differences could be observed in the dorsal and, to a lesser extent, also in the rostral anterior cingulate cortex (dACC, rACC) where patients exhibited an increased neural response to emotional relative to neutral distracters. Moreover, in the incongruent condition, both the dACC and rACC fMRI responses during emotional interference were negatively correlated with trait anxiety in the patients, but not in the healthy controls. As higher trait anxiety was also associated with longer reaction times (RTs) in the BPD patients, we suggest that in BPD patients the ACC might mediate compensatory cognitive processes during emotional interference and that such neurocognitive compensation that can be adversely affected by high levels of anxiety. PMID- 23459640 TI - Influence of electrolytes on contact angles of droplets under electric field. AB - The change of contact angle is one of the major subjects in the studies of electrowetting on dielectrics. A larger change in contact angle with a less applied electric potential has been pursued by the researchers on digital microfluidics. From previous research it is concluded that the effect of free charges in electrolytes on contact angles can almost be neglected. In this article, obvious influences of free charges on contact angles are presented and discussed. To verify the influence of free charges, both weak electrolyte (boric acid) and strong electrolyte (sodium chloride) are used as sources of free charges in our experiment. It was found that the increase of ion concentration enhances the contact angle variation due to the attraction between the bound surface charges in the dielectric layer and the free counter-ions in the solution. The saturated contact angle occurs with a lower electric potential compared with de-ionized water due to the shielding of the electric field by the free counter-ions. When a strong electrolyte is used, the contact angle varies at a much higher rate than with de-ionized water, and the huge amount of accumulated free ions shields the driving field, causing the contact angle to saturate at a much lower electric potential. The saturated contact angle in strong electrolyte solution is markedly larger than those in weak electrolyte solutions and de ionized water. PMID- 23459641 TI - Activity-based Therapies in Spinal Cord Injury:: Clinical Focus and Empirical Evidence in Three Independent Programs. AB - This article summarizes presentations of a symposium examining the potential impact of activity-based therapies (ABT) in promoting neurological and functional recovery after spinal cord injury (SCI). The symposium addressed 3 key questions concerning activity-based therapy in SCI: (1) What clinical approaches are used? (2) Is there empirical evidence supporting efficacy of ABT in promoting neurological recovery and improving overall function, health, and quality of life? (3) What are the issues related to long-term viability of ABT? PMID- 23459642 TI - [Management of the older person with diabetes mellitus]. PMID- 23459643 TI - [Comprehensive geriatric assessment and multi-disciplilary care approach]. PMID- 23459644 TI - [Management of elderly patients with atrial fibrillation]. PMID- 23459646 TI - [Oral and swallowing dysfunctions]. PMID- 23459645 TI - [Management of chronic obstructive pulmonary disease in the elderly]. PMID- 23459647 TI - [Disorder of urination and defecation in elderly]. PMID- 23459648 TI - [Long-term care prevention]. PMID- 23459649 TI - [Can a newly-established test for assessing standing and balance function be an alternative to the timed up-and-go test?--functional assessment of gait and balance in elderly patients for a comprehensive geriatric assessment initiative named 'Dr. SUPERMAN']. AB - AIM: To identify elderly patients who are at high risk for falls, we used the timed up-and-go test (TUG) as an assessment tool for gait and balance function in a comprehensive geriatric assessment (CGA) initiative named 'Dr. SUPERMAN'. However, this test is difficult to perform in a small area because it requires at least 3 meters of movement space. Therefore, we investigated whether another, newly-developed test, based on the Berg balance test, could be an alternative to the TUG test. METHODS: We enrolled a total of 99 eligible subjects out of 105 elderly patients with disorders such as Alzheimer disease, Parkinson disease, cerebral infarction, osteoporosis and vascular risk factors, and administered the TUG test and the newly-developed standing and balance test (SBT). Of these 99, 6 patients could not stand independently. While the time to accomplish TUG was determined, any unsteadiness during TUG was also recorded. The SBT consists of 3 components: standing up independently, standing on a narrow base for 15 seconds without any swaying of the trunk, and a timed one-leg standing test (TOLS) for 15 seconds on both sides. Taking more than 14 seconds to accomplish the TUG or abnormal unsteadiness during the test was defined as positive, and each cut-off point was measured on the TOLS, with or without swaying of the trunk. RESULTS: The time to accomplish TUG significantly increased with age, and positive TUG findings were observed in 43 subjects. The mean TOLS time significantly and suddenly worsened at over 75 years of age, including among those subjects who showed swaying of the trunk and who could only perform the TOLS for less than 1 second. The receiver operating curve indicated that a TOLS cut-off point of less than 3 seconds, together with standing with help or swaying of the trunk during the SBT, most efficiently determined a positive TUG score, with high sensitivity (86%), high specificity (87.5%), and a high positive predictive value (84.1%). CONCLUSION: In a narrow space, the SBT can adequately determine gait and balance abnormalities among elderly patients, indicating it to be an alternative to the TUG test. Subjects who could stand dependently, who showed swaying of the trunk in SBT, or who had a TOLS cut-off point of less than 3 seconds, were at high risk for falls. Further assessment of similar patients is necessary. PMID- 23459650 TI - [The risk of diabetic complications in older elderly diabetic patients]. AB - AIM: We examined the risk of the diabetic complications among older elderly diabetic patients. METHODS: We compared the HbA1c levels of 117 type 2 diabetic patients >= 75 years old over a 5-year period, before patients received a diagnosis of diabetic complications, with those of diabetic patients without diabetic complications. RESULTS: The HbA1c levels of diabetic retinopathy patients were significantly higher than those of patients without diabetic retinopathy (7.9% vs. 6.8%, p<0.01). Similarly, the HbA1c levels of patients with diabetic nephropathy were significantly higher than those of patients without diabetic nephropathy (7.3% vs. 6.7%, p<0.01). The HbA1c levels of diabetic patients with cerebral infarction or ischemic heart disease were also higher than those in diabetic patients without these vascular complications (7.7% vs. 7.0%, p<0.05). CONCLUSION: The current findings emphasize the importance of careful glycemic control for the prevention of diabetic complications in older elderly patients. PMID- 23459651 TI - [A retrospective study of outcome of percutaneous endoscopic gastrostomy in older adults with advanced cognitive impairment and severely reduced activities of daily living]. AB - AIM: To investigate the outcome of percutaneous endoscopic gastrostomy (PEG) in elderly patients with swallowing difficulties who required high-level nursing care. METHODS: We extracted the data of 57 patients (24 men and 33 women) who were admitted to our hospital with a diagnosis of pneumonia over a 5-year study period between January 2006 and December 2010. Evaluation included activities of daily living (ADL), nursing care level (NCL) based on assessment of care requirement, pre-existing disease, blood test data, swallowing function before PEG, and outcome. RESULTS: The mean age of the patients was 84.7+/-8.3 years old. The mean total functional independence measure (FIM) score was 29.7+/-16.2 and the median NCL value was 4. The most frequently observed pre-existing diseases were degenerative central nervous system disorders including Alzheimer's disease and cerebrovascular disease, which occurred in approximately 80% of participants. A low serum albumin value and high c-reactive protein (CRP) level were also often observed, suggesting chronic inflammatory conditions. For swallowing function, the median value according to the Fujishima swallowing grading system was 5, and aspiration and pharyngeal residues were observed on videofluoroscopic examination of swallowing (VF) (82.5% and 100% of all cases, respectively). The median survival time after PEG was 451.0+/-79.7 days, with a one-year survival rate of approximately 56%. A total of 51 patients (89.5%) died after PEG and the mean duration from the PEG to death was 518.5+/-471.7 days. Of these 51, 45 (88.2%) died of pneumonia. CONCLUSIONS: In patients with advanced cognitive impairment and severely reduced ADL, there appears to be little benefit on ADL and the prevention of pneumonia by PEG, and most outcomes following PEG were not favorable in the current results. PMID- 23459652 TI - [Observation over three seasons of respiratory syncytial virus infection in a geriatric health service facility]. AB - AIM: To characterize the impact of respiratory syncytial virus (RSV) infection on respiratory illness in a geriatric health service facility. METHOD: All facility residents were observed for respiratory symptoms from January 2010 to March 2012. The presence of an RSV antigen was examined in selected patients using rapid antigen test. RESULTS: I observed one outbreak of RSV and four outbreaks of respiratory infection without RSV. I also observed two cases of sporadic RSV infection, one of which had pneumonia. An RSV outbreak in the facility was observed only when RSV cases from pediatricians were four times more frequently reported than the usual seasonal average. More patients with severe respiratory illness were observed during an RSV outbreak than during other outbreaks. CONCLUSION: RSV can cause severe respiratory illness in elderly patients. Repeated invasion from surrounding infectious environments may be essential for an RSV outbreak to occur. Moreover, although the sensitivity of rapid RSV antigen tests may have influenced the results of the current study, such sensitivity in elderly patients is reportedly diverse in the literature, and the reasons for such variation have not yet been elucidated. We postulate that a reason for such variation is a viral co-infection, in particular of the bocavirus, which has a reported high incidence of co-infection and which affects viral shedding. Furthermore, human metapneumovirus has been reported to influence the severity of RSV infection. Most of these knowledges concerning the influence of co-infection were obtained from pediatric studies, therefore we need further investigations targetting elderly patients. PMID- 23459653 TI - [A case of alveolar hemorrhage 35 years after propylthiouracil treatment]. AB - A 69-year-old woman had received oral treatment of propylthiouracil (PTU) under a diagnosis of hyperthyroidism for 35 years. In the first 10 days of January 2009, she noticed the development of a cough. In February of the same year, she consulted a clinic with bloody sputum. Chest X-ray films revealed diffuse infiltration in both lungs, and she came to our hospital for further examination. An alveolar hemorrhage was identified by bronchial alveolar lavage testing. Because the cough was relieved by stopping PTU administration and there has been no relapse during 2-year follow-up, this case was diagnosed as PTU-induced diffuse alveolar hemorrhage. Her myeloperoxidase (MPO) -anti-neutrophil cytoplasmic antibody (ANCA) level was 55 EU, suggesting ANCA-associated angitis. However, as a drug lymphocyte stimulation test to PTU was also positive and her MPO-ANCA level was not elevated, the onset mechanism of this case was unclear. PMID- 23459654 TI - [Pseudoaldosteronism in an elderly man believed to be caused by the health food Shin-Gojoshin]. AB - CASE: We report a 67-year-old man in whom pseudoaldosteronism developed following consumption of the health food Shin-Gojoshin. The patient began consuming Shin Gojoshin in February 2007. His serum potassium level, which was within the normal range until he began consumption, gradually decreased to 3.0 mEq/L. The administration of potassium supplements and spironolactone was initiated. However, his hypokalemia persisted, and in December 2009, he was referred to our hospital for further examination. Laboratory data revealed hypokalemia, metabolic alkalosis, urinary potassium wasting, low plasma renin activity, and a low plasma aldosterone concentration. Pseudoaldosteronism was suspected and he was admitted. Although he reported no history of consumption of other traditional herbal medicines at the initial medical outpatient examination, he reported the consumption of Shin-Gojoshin in a medical interview taken on admission. Discontinuation of Shin-Gojoshin and potassium supplementation on admission successfully normalized his electrolyte imbalance. CONCLUSION: The present case describes the occurrence of pseudoaldosteronism induced by consumption of Shin Gojoshin. A history of consumption of traditional herbal medicines and other health foods should be obtained, particularly in elderly individuals presenting with symptoms of pseudoaldosteronism. PMID- 23459655 TI - [Treatment of visual hallucinations with ramelteon in two patients with dementia Lewy bodies]. AB - Herein, I report the improvement of visual hallucinations (VHs) in 2 patients with a clinical diagnosis of probable dementia with Lewy bodies (DLB) through the use of ramelteon, a selective MT1/MT2 melatonin receptor agonist. When first seen with complaints of VHs and insomnia in our memory clinic, their scores on the Mini-Mental State Examination were 25 and 20. One patient developed VHs at the age of 72 and could describe them in detail (e.g., a large crowd attending a midnight party). The other patient had dreamed of his deceased wife since the age of 78. He developed VHs at the age of 81 and could describe them in detail: his deceased wife was present and he tried to talk to her, but she did not respond. Both patients lived alone and telephoned their family with complaints of VHs in the middle of night, resulting in an increase in the burdens of care. Because cholinesterase inhibitors had been prescribed for both patients, further pharmacotherapeutic interventions targeted their insomnia rather than their VHs to avoid neuroleptic drug sensitivity, a recommendation of the DLB guidelines. Furthermore, ramelteon has few adverse effects. RESULTS: Within 8 weeks of initiating ramelteon, the VHs had disappeared and the insomnia had improved in both patients. Melatonin is recommended for the treatment of REM sleep behavior disorder (RBD), which is a frequent feature of DLB. The efficacy of ramelteon for VHs suggests a possible association of RBD with psychiatric symptoms in patients with DLB. PMID- 23459656 TI - [A case of collagenous colitis with watery diarrhea due to lansoprazole use in an elderly woman]. AB - We report a case of a 75-year-old woman with urgent watery diarrhea, occurring 5 to 8 times per day, which began after starting lansoprazole (30 mg/day) for erosive gastritis. Her chronic watery diarrhea persisted for over 2 years with mild weight loss. Colonoscopy was performed and biopsies showed collagenous colitis in her transverse colon. We therefore replaced lansoprazole with famotidine (20 mg/day). Within 3 days after the discontinuation of lansoprazole, her watery diarrhea resolved and she recovered, and reported normal feces. Increasing age and female gender are major risk factors for collagenous colitis. The differential diagnosis of collagenous colitis should include: 1) an appropriate clinical history, excluding other etiologies, 2) normal or near normal endoscopic and/or radiographic findings, and 3) colonoscopic biopsy histopathologic findings consistent with collagenous colitis. The histopathologic findings of colonoscopic biopsy are important for diagnosis. However, because of the colonoscopic burden in elderly patients, we first recommend the discontinuation of medications suspected to cause collagenous colitis. PMID- 23459657 TI - [JGS guidelines for decision-making process in elderly care focusing on indications of artificial hydration and nutrition]. PMID- 23459658 TI - [Does going to hospital or clinic have a negative effect on subjective view of health in middle-aged and elderly population in rural area?]. PMID- 23459659 TI - Human cancerous and healthy cell cytotoxicity studies of a chiral MU-dicarbene digold(I) metallamacrocycle. AB - A novel eighteen membered chiral macrocyclic dicarbene-digold complex [(MU diNHC)Au(I)]2[OTF]2 (8-(+/-)) was synthesized and characterized. Starting with enantiopure diNHC imidazolium salt ligand precursors enables access to the enantiopure versions of the digold(I) metallamacrocycles, 8-(+) and 8-(-). In vitro cytotoxicity studies indicate 8-(+/-) is moderately cytotoxic to both healthy and cancerous cell-lines, with no specificity. Confocal microscopy indicates the digold metallamacrocycle penetrates the cell membrane and causes cell death via apoptosis, as evidenced by DNA electrophoresis. The complex 8-(+/ ) is characterized by a combination of NMR techniques (gDQCOSY, gHSQC, gHMBC and ROESY), single crystal X-ray diffraction, and combustion analysis. PMID- 23459661 TI - Functional electrical stimulation in spinal cord injury respiratory care. AB - The management of chronic respiratory insufficiency and/or long-term inability to breathe independently has traditionally been via positive-pressure ventilation through a mechanical ventilator. Although life-sustaining, it is associated with limitations of function, lack of independence, decreased quality of life, sleep disturbance, and increased risk for infections. In addition, its mechanical and electronic complexity requires full understanding of the possible malfunctions by patients and caregivers. Ventilator-associated pneumonia, tracheal injury, and equipment malfunction account for common complications of prolonged ventilation, and respiratory infections are the most common cause of death in spinal cord injured patients. The development of functional electric stimulation (FES) as an alternative to mechanical ventilation has been motivated by a goal to improve the quality of life of affected individuals. In this article, we will review the physiology, types, characteristics, risks and benefits, surgical techniques, and complications of the 2 commercially available FES strategies - phrenic nerve pacing (PNP) and diaphragm motor point pacing (DMPP). PMID- 23459660 TI - Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: implications for host range and adaptation. AB - The influenza A virus (IAV) HA protein must be activated by host cells proteases in order to prime the molecule for fusion. Consequently, the availability of activating proteases and the susceptibility of HA to protease activity represents key factors in facilitating virus infection. As such, understanding the intricacies of HA cleavage by various proteases is necessary to derive insights into the emergence of pandemic viruses. To examine these properties, we generated a panel of HAs that are representative of the 16 HA subtypes that circulate in aquatic birds, as well as HAs representative of the subtypes that have infected the human population over the last century. We examined the susceptibility of the panel of HA proteins to trypsin, as well as human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2). Additionally, we examined the pH at which these HAs mediated membrane fusion, as this property is related to the stability of the HA molecule and influences the capacity of influenza viruses to remain infectious in natural environments. Our results show that cleavage efficiency can vary significantly for individual HAs, depending on the protease, and that some HA subtypes display stringent selectivity for specific proteases as activators of fusion function. Additionally, we found that the pH of fusion varies by 0.7 pH units among the subtypes, and notably, we observed that the pH of fusion for most HAs from human isolates was lower than that observed from avian isolates of the same subtype. Overall, these data provide the first broad-spectrum analysis of cleavage-activation and membrane fusion characteristics for all of the IAV HA subtypes, and also show that there are substantial differences between the subtypes that may influence transmission among hosts and establishment in new species. PMID- 23459662 TI - Triterpenoids and flavonoids from Cecropia schreberiana Miq. (Urticaceae). AB - Phytochemical investigation of the leaves of Cecropia schreberiana Miq. (Urticaceae) led to the isolation of four triterpenoids (1-4), three flavone C glycosides (5-7), two flavan-3-ols (8, 9), two flavanolignans (10, 11), and two proanthocyanidins (12, 13). All compounds were isolated from C. schreberiana for the first time. This is the first report demonstrating the presence of arjunolic acid (4), cinchonain Ia (10), and cinchonain Ib (11) in the Urticaceae family. The occurrence of flavanolignans within the family Urticaceae supports the likelihood that such compounds are more common within the class Magnoliopsida than previously thought. PMID- 23459663 TI - Acoustically controlled enhancement of molecular sensing to assess oxidative stress in cells. AB - We demonstrate a microfluidic platform for the controlled aggregation of colloidal silver nanoparticles using surface acoustic waves (SAWs), enabling surface enhanced Raman scattering (SERS) analysis of oxidative damage in cells. We show that by varying the frequency and the power of the acoustic energy, it is possible to modulate the aggregation of the colloid within the sample and hence to optimise the SERS analysis. PMID- 23459665 TI - Resolving DNA at efficiencies of more than a million plates per meter using bare narrow open capillaries without sieving matrices. AB - We report a novel approach for effectively separating DNA molecules in free solution. The method uses a bare narrow open capillary without any sieving matrices to resolve a wide size-range of DNA fragments at efficiencies of more than a million plates per meter routinely. PMID- 23459664 TI - Postpartum depression: psychoneuroimmunological underpinnings and treatment. AB - Postpartum depression (PPD) is common, occurring in 10%-15% of women. Due to concerns about teratogenicity of medications in the suckling infant, the treatment of PPD has often been restricted to psychotherapy. We review here the biological underpinnings to PPD, suggesting a powerful role for the tryptophan catabolites, indoleamine 2,3-dixoygenase, serotonin, and autoimmunity in mediating the consequences of immuno-inflammation and oxidative and nitrosative stress. It is suggested that the increased inflammatory potential, the decreases in endogenous anti-inflammatory compounds together with decreased omega-3 poly unsaturated fatty acids, in the postnatal period cause an inflammatory environment. The latter may result in the utilization of peripheral inflammatory products, especially kynurenine, in driving the central processes producing postnatal depression. The pharmacological treatment of PPD is placed in this context, and recommendations for more refined and safer treatments are made, including the better utilization of the antidepressant, and the anti-inflammatory and antioxidant effects of melatonin. PMID- 23459666 TI - Colorectal cancer biomarkers and the potential role of cancer stem cells. AB - Over 50% of patients with colorectal cancer (CRC) will progress and/or develop metastases. Biomarkers capable of predicting progression, risk stratification and therapeutic benefit are needed. Cancer stem cells are thought to be responsible for tumor initiation, dissemination and treatment failure. Therefore, we hypothesized that CRC stem cell markers (CRCSC) can identify a group of patients whom are at increased risk for recurrence or progression of disease. If proven correct, these CRCSC biomarkers may herald a paradigm shift in the treatment of this deadly disease. This manuscript reviews current CRC evidence based screening modalities, patient stratification, and summarizes the current state of biomarkers and discusses the novel concept of putative CRCSC's as prognostic biomarkers. PMID- 23459667 TI - Do undergraduate student research participants read psychological research consent forms? Examining memory effects, condition effects, and individual differences. AB - While research has examined factors influencing understanding of informed consent in biomedical and forensic research, less is known about participants' attention to details in consent documents in psychological survey research. The present study used a randomized experimental design and found the majority of participants were unable to recall information from the consent form in both in person and online formats. Participants were also relatively poor at recognizing important aspects of the consent form including risks to participants and confidentiality procedures. Memory effects and individual difference characteristics also appeared to influence recall and recognition of consent form information. PMID- 23459668 TI - Twentieth century occurrence of the Long-Beaked Echidna Zaglossus bruijnii in the Kimberley region of Australia. AB - The monotreme genus Zaglossus, the largest egg-laying mammal, comprises several endangered taxa today known only from New Guinea. Zaglossus is considered to be extinct in Australia, where its apparent occurrence (in addition to the large echidna genus Megalibgwilia) is recorded by Pleistocene fossil remains, as well as from convincing representations in Aboriginal rock art from Arnhem Land (Northern Territory). Here we report on the existence and history of a well documented but previously overlooked museum specimen (skin and skull) of the Western Long-Beaked Echidna (Zaglossus bruijnii) collected by John T. Tunney at Mount Anderson in the West Kimberley region of northern Western Australia in 1901, now deposited in the Natural History Museum, London. Possible accounts from living memory of Zaglossus are provided by Aboriginal inhabitants from Kununurra in the East Kimberley. We conclude that, like Tachyglossus, Zaglossus is part of the modern fauna of the Kimberley region of Western Australia, where it apparently survived as a rare element into the twentieth century, and may still survive. PMID- 23459669 TI - Occurrence of Agriotes wireworms in Austrian agricultural land. AB - Agriotes wireworms (Coleoptera: Elateridae) are abundant soil-dwelling herbivores which can inflict considerable damage to field crops. In Europe up to 40 species occur, differing in their ecology and pest status. Their distribution in the larval stage, however, has rarely been assessed because of the considerable effort in collecting wireworms and the difficulties in identifying them to species-level. Here, we examined the occurrence of Agriotes wireworms in Austrian agricultural land with regard to their association with climatic and soil parameters. Using a molecular identification system, 1348 field-collected larvae from 85 sites were identified to species-level. Three species, Agriotes obscurus, Agriotes brevis, Agriotes ustulatus, and two that could not be discerned molecularly (Agriotes lineatus and Agriotes proximus), were assigned to two ecological groups: (i) A.brevis/A. ustulatus, found in areas with a warmer, drier climate and alkaline soils, and (ii) A. obscurus/A. lineatus/proximus which occur mainly at higher altitude characterised by lower temperatures, higher precipitation and acidic, humus-rich soils. Agriotes sputator was abundant throughout Austria, confirming its euryoecious nature. Only one larva of Agriotes litigiosus was found, prohibiting further analysis. These data contribute to a characterisation of species-specific traits in Agriotes larvae in agricultural land, an important prerequisite to develop efficient control strategies for these wireworms. PMID- 23459671 TI - Predicting noninvasive mechanical ventilation outcome: early may be too early! PMID- 23459670 TI - Molecular Neurobiology of Depression: PET Findings on the Elusive Correlation with Symptom Severity. AB - Molecular mechanisms in the brain are assumed to cause the symptoms and severity of neuropsychiatric disorders. This review concerns the elusive nature of relationships between the severity of depressive disorders and neuromolecular processes studied by positron emission tomography (PET). Recent PET studies of human depression have focused on serotonergic, dopaminergic, muscarinic, nicotinic, and GABAergic receptors, as well as central processes dependent on monoamine oxidase, phosphodiesterase type 4, amyloid plaques, neurofibrillar tangles, and P-glycoprotein. We find that reliable causal links between neuromolecular mechanisms and relief from depressive disorders have yet to be convincingly demonstrated. This situation may contribute to the currently limited use of PET for exploring the neuropathways that are currently viewed as being responsible for beneficial effects of antidepressant treatment regimes. PMID- 23459672 TI - Perceived Exercise Barriers and Odds of Exercise Participation Among Persons With SCI Living in High-Income Households. AB - OBJECTIVE: To define the prevalence of and the degree to which exercise barriers decrease odds of exercise participation among persons with SCI reporting annual household income greater than $50,000. METHOD: In this cross-sectional study, 180 individuals completed a Web survey of personal characteristics and exercise barriers. Over half (n=89) reported annual household incomes greater than $50,000. Chi-square and Mann-Whitney U identified personal characteristic differences between exercisers and nonexercisers. Odds ratios (OR) determined barriers that decreased odds of exercise participation. Significance was set at alpha < 0.05. RESULTS: Eighty-seven percent of respondents were currently exercising (n=61). No differences discriminated exercisers and nonexercisers by gender, age, race, age at injury, injury level or completeness, education level, and total comorbidities or medications. A higher percentage of exercisers were full-time employed or married. Nonexercisers reported more barriers (4.9 +/- 2.4 vs 2.21 +/- 1.8). Only one barrier was highly prevalent and impactful (lack of motivation). The most impactful barrier, "too lazy to exercise," was the 9th most prevalent barrier (14%). Persons reporting this as a barrier were 19 times less likely to be exercising. CONCLUSION: Among high-income households, highly prevalent barriers may not decrease odds of exercise participation. Knowledge and psychological barriers had the greatest impact on odds of exercise participation. PMID- 23459673 TI - Cholera outbreaks in Nigeria are associated with multidrug resistant atypical El Tor and non-O1/non-O139 Vibrio cholerae. AB - BACKGROUND: The current millennium has seen a steep rise in the number, size and case-fatalities of cholera outbreaks in many African countries. Over 40,000 cases of cholera were reported from Nigeria in 2010. Variants of Vibrio cholerae O1 El Tor biotype have emerged but very little is known about strains causing cholera outbreaks in West Africa, which is crucial for the implementation of interventions to control epidemic cholera. METHODOLOGY/PRINCIPAL FINDINGS: V. cholerae isolates from outbreaks of acute watery diarrhea in Nigeria from December, 2009 to October, 2010 were identified by standard culture methods. Fifteen O1 and five non-O1/non-O139 strains were analyzed; PCR and sequencing targeted regions associated with virulence, resistance and biotype were performed. We also studied genetic interrelatedness among the strains by multilocus sequence analysis and pulsed-field gel electrophoresis. The antibiotic susceptibility was tested by the disk diffusion method and E-test. We found that multidrug resistant atypical El Tor strains, with reduced susceptibility to ciprofloxacin and chloramphenicol, characterized by the presence of the SXT element, and gyrA(Ser83Ile)/parC(Ser85Leu) alleles as well CTX phage and TCP cluster characterized by rstR(ElTor), ctxB-7 and tcpA(CIRS) alleles, respectively, were largely responsible for cholera outbreaks in 2009 and 2010. We also identified and characterized a V. cholerae non-O1/non-O139 lineage from cholera-like diarrhea cases in Nigeria. CONCLUSIONS/SIGNIFICANCE: The recent Nigeria outbreaks have been determined by multidrug resistant atypical El Tor and non-O1/non-O139 V. cholerae strains, and it seems that the typical El Tor, from the beginning of seventh cholera pandemic, is no longer epidemic/endemic in this country. This scenario is similar to the East Africa, Asia and Caribbean countries. The detection of a highly virulent, antimicrobial resistant lineage in Nigeria is worrisome and points to a need for vaccine-based control of the disease. This study has also revealed the putative importance of non-O1/non-O139 V. cholerae in diarrheal disease in Nigeria. PMID- 23459675 TI - The synergistic effect of gentamicin and clindamycin on rocuronium-induced neuromuscular blockade. AB - BACKGROUND: Gentamicin reduces acetylcholine release and clindamycin causes end plate ion channel blockade. Because of these reasons, two drugs show muscular relaxant effect and potentiate the action of nondepolarizing neuromuscular agents. This study was intended to evaluate the effect of gentamicin and clindamycin on rocuronium-induced neuromuscular blockade and the interaction between these drugs. METHODS: Male Sprague-Dawley rats' phrenic nerves and diaphragms were installed in a bath containing Krebs solution. They were divided into three study groups. The first group was pre-treated with 0.1 (n = 3), 0.2 (n = 4) or 0.5 (n = 3) mM gentamicin and the tension was measured as the concentration of rocuronium was increased. The second group was experimented by increasing gentamicin on 0.25 (n = 5), 0.5 (n = 6) or 1.0 (n = 6) mM clindamycin. The final group was pre-treated with various combinations of gentamicin and clindamycin. The drug concentration was gradually increased until single twitch tension decreased by around 80%. Effective concentration was calculated using a probit model and interaction indices derived the Loewe additivity. RESULTS: The administration of gentamicin and the combination of gentamicin and clindamycin enhanced rocuronium-induced neuromuscular blockade. At 0.2 and 0.5 mM gentamicin, synergistic interactions with rocuronium were observed. Likewise, at 0.5 and 1.0 mM clindamycin, synergistic interactions with gentamicin appeared. When all three drugs were combined, in the tetanic fade, all the groups except for those administered with 0.01 mM gentamicin and 0.25 mM clindamycin showed synergistic interactions. CONCLUSIONS: This study demonstrate that gentamicin and clindamycin potentiated rocuronium induced neuromuscular blockade. Moreover, it was found that these drugs interacted synergistically. PMID- 23459676 TI - Traversing the translational trail for trials. AB - The principles of spinal cord injury clinical trial programs are briefly reviewed as one example of the challenge faced by most human studies of neurologically directed therapeutic interventions, including rehabilitation strategies. Different trial protocols are reviewed, as are inclusion/exclusion criteria for study subjects, the choice of clinical endpoints, and the statistical approaches that might be used in a trial program. Potential factors that might confound the accurate interpretation of trial data are also identified. Regardless of the specific therapeutic target or the rehabilitation strategy to be evaluated, there are many unresolved issues that will have to be answered before specific and effective prescriptions can be delivered. PMID- 23459677 TI - Congregating to create for social change: Urban youth media production and sense of community. AB - This case study explored how adolescents were empowered through after school media production activities and, in the process, re-imagined themselves as active and engaged citizens within their community. Through analyzing interviews, participant observations, and media artifacts of 14 participants (aged 15-19) over a period of 18 months, three main themes emerged from the triangulation of data: (1) sociocultural capital through group ownership; (2) safe space for creative expression; and (3) developing a sense of community with diverse voices. These young people exercised their collective voice toward pro-social actions by writing and producing their stories and showcasing their works at community screenings. They hoped that their videos would promote individual and community transformations. Building on youth development, community psychology, and media literacy frameworks, this article discusses educational implications like advocating for the power of youth media production to bridge participants' personal and private artistry to public and political statements. PMID- 23459674 TI - Biophysical insights into how surfaces, including lipid membranes, modulate protein aggregation related to neurodegeneration. AB - There are a vast number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), associated with the rearrangement of specific proteins to non-native conformations that promotes aggregation and deposition within tissues and/or cellular compartments. These diseases are commonly classified as protein-misfolding or amyloid diseases. The interaction of these proteins with liquid/surface interfaces is a fundamental phenomenon with potential implications for protein-misfolding diseases. Kinetic and thermodynamic studies indicate that significant conformational changes can be induced in proteins encountering surfaces, which can play a critical role in nucleating aggregate formation or stabilizing specific aggregation states. Surfaces of particular interest in neurodegenerative diseases are cellular and subcellular membranes that are predominately comprised of lipid components. The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions. Importantly for misfolding diseases, these bilayer properties can not only modulate protein conformation, but also exert influence on aggregation state. A detailed understanding of the influence of (sub)cellular surfaces in driving protein aggregation and/or stabilizing specific aggregate forms could provide new insights into toxic mechanisms associated with these diseases. Here, we review the influence of surfaces in driving and stabilizing protein aggregation with a specific emphasis on lipid membranes. PMID- 23459678 TI - Dysphagia and associated respiratory considerations in cervical spinal cord injury. AB - BACKGROUND: Dysphagia is a relatively common secondary complication that occurs after acute cervical spinal cord injury (SCI). The detrimental consequences of dysphagia in SCI include transient hypoxemia, chemical pneumonitis, atelectasis, bronchospasm, and pneumonia. The expedient diagnosis of dysphagia is imperative to reduce the risk of the development of life-threatening complications. OBJECTIVE: The objective of this study was to identify risk factors for dysphagia after SCI and associated respiratory considerations in acute cervical SCI. METHODS: Bedside swallow evaluation (BSE) was conducted in 68 individuals with acute cervical SCI who were admitted to an SCI specialty unit. Videofluroscopy swallow study was conducted within 72 hours of BSE when possible. RESULTS: This prospective study found dysphagia in 30.9% (21 out of 68) of individuals with acute cervical SCI. Tracheostomy (P = .028), ventilator use (P = .012), and nasogastric tube (P = .049) were found to be significant associated factors for dysphagia. Furthermore, individuals with dysphagia had statistically higher occurrences of pneumonia when compared with persons without dysphagia (P < .001). There was also a trend for individuals with dysphagia to have longer length of stay (P = .087). CONCLUSION: The role of respiratory care practitioners in the care of individuals with SCI who have dysphagia needs to be recognized. Aggressive respiratory care enables individuals with potential dysphagia to be evaluated by a speech pathologist in a timely manner. Early evaluation and intervention for dysphagia could decrease morbidity and improve overall clinical outcomes. PMID- 23459679 TI - Who Do You Think Is in Control in Addiction? A Pilot Study on Drug-related Locus of Control Beliefs. AB - OBJECTIVES: The drug-related locus of control scale (DR-LOC) is a new instrument for assessing a person's belief of "being in control" in situations involving drug abuse. It consists of 16-item pairs presented in a forced-choice format, based on the conceptual model outlined by Rotter. The model characterizes the extent to which a person believes that the outcome of an event is under their personal control (internal locus of control) or the influence of external circumstances (external locus of control). METHODS: A total of 592 volunteers completed the DR-LOC and the Rotter's I-E scale. Approximately half of the respondents were enrolled in a drug treatment program for opiates, stimulants and/or alcohol dependence (n = 282), and the remainder (n = 310) had no history of drug dependence. RESULTS: Factor analysis of DR-LOC items revealed 2 factors reflecting control beliefs regarding (i) the successful recovery from addiction, and (ii) decisions to use drugs. The extent to which a person attributes control in drug-related situations is significantly influenced by their personal or professional experiences with drug addiction. Drug-dependent individuals have a greater internal sense of control with regard to addiction recovery or drug taking behaviors than health professionals and/or non-dependent control volunteers. CONCLUSIONS: The DR-LOC has shown to effectively translate generalized expectancies of control into a measure of control expectancies for drug-related situations, making it more sensitive for drug-dependent individuals than Rotter's I-E scale. Further research is needed to demonstrate its performance at discriminating between heterogeneous clinical groups such as between treatment-seeking versus non-treatment-seeking drug users. PMID- 23459680 TI - European rodent on the edge: status and distribution of the Vojvodina blind mole rat. AB - Recent research of blind mole rats of the species complex Nannospalax (superspecies leucodon) identified a small and fragmented population of these rodents on both sides of the Hungarian-Serbian border. Cytogenetic investigations proved that this population karyologically identical with the Vojvodina blind mole rat described earlier as Nannospalax (leucodon) montanosyrmiensis. Based on cytochrome b gene sequences obtained from three specimens originating from separate locations, these blind mole rats form a discrete phylogenetic clade which, with a difference of about 10%, is well separated from other blind mole rat taxa inhabiting the Carpathian Basin. The taxon has only two extant populations that are 150 km apart from each other. The combined occupied area is estimated to be less than 10 km(2), and the total estimated number of individuals is less than 300. These two remaining populations are heavily fragmented and under imminent threat by the establishment of tree plantations, small-scale and agro-industrial farms and land development. The situation is further aggravated by the fact that 80% of the individuals inhabit unprotected areas. A study of the landscape history of the wider area surrounding one of the populations - based on military maps spanning over the last 200 years - has shown a drastic decrease in the extent and quality of potential habitats. Based on our present knowledge, the Vojvodina blind mole rat is one of the most seriously threatened, rarest mammal in Europe, the remaining population of which can be wiped out within years unless immediate conservation action is taken. PMID- 23459681 TI - Gene expression profiles in primary duodenal chick cells following transfection with avian influenza virus H5 DNA plasmid encapsulated in silver nanoparticles. AB - In order to develop a systemically administered safe and effective nonviral gene delivery system against avian influenza virus (AIV) that induced cytokine expression, the hemagglutinin (H5) gene of AIV, A/Ck/Malaysia/5858/04 (H5N1) and green fluorescent protein were cloned into a coexpression vector pIRES (pIREGFP H5) and formulated using green synthesis of silver nanoparticles (AgNPs) with poly(ethylene glycol) and transfected into primary duodenal cells taken from 18 day-old specific-pathogen-free chick embryos. The AgNPs were prepared using moderated temperature and characterized for particle size, surface charge, ultraviolet-visible spectra, DNA loading, and stability. AgNPs and AgNP-pIREGFP H5 were prepared in the size range of 13.9 nm and 25 nm with a positive charge of +78 +/- 0.6 mV and +40 +/- 6.2 mV, respectively. AgNPs with a positive surface charge could encapsulate pIREGFP-H5 efficiently. The ultraviolet-visible spectra for AgNP-pIREGFP-H5 treated with DNase I showed that the AgNPs were able to encapsulate pIREGFP-H5 efficiently. Polymerase chain reaction showed that AgNP pIREGFP-H5 entered into primary duodenal cells rapidly, as early as one hour after transfection. Green fluorescent protein expression was observed after 36 hours, peaked at 48 hours, and remained stable for up to 60 hours. In addition, green fluorescent protein expression generally increased with increasing DNA concentration and time. Cells were transfected using Lipocurax in vitro transfection reagent as a positive control. A multiplex quantitative mRNA gene expression assay in the transfected primary duodenal cells via the transfection reagent and AgNPs with pIREGFP-H5 revealed expression of interleukin (IL)-18, IL 15, and IL-12beta. PMID- 23459682 TI - Magnetic resonance imaging of pressure sores in spinal cord injured patients: accuracy in predicting osteomyelitis. AB - OBJECTIVE: Identify key magnetic resonance imaging (MRI) features that have a significant correlation with osteomyelitis of pressure ulcers in spinal injury patients. DESIGN: Retrospective review study. PARTICIPANTS: Adult patients admitted to the National Spinal Injuries Centre with spinal cord injury (SCI) and signs of pressure ulceration investigated with MRI. METHODS: Analysis of MRI examinations and clinical records collected over a 4-year period. Images were independently assessed by 2 experienced radiologists for osteomyelitis based on assigned predictive indicators including cortical bone erosion, soft tissue edema, deep collections, heterotopic new bone, hip effusion, and abnormal signal change of the marrow. RESULTS: Thirty-seven patients underwent 41 MRI scans. The prevalence of osteomyelitis was highly correlated with cortical bone erosion (r = 0.84) and abnormal bone marrow changes on T1-weighted images (r = 0.82). PMID- 23459683 TI - Additive interaction of intrathecal ginsenosides and neostigmine in the rat formalin test. AB - BACKGROUND: The authors evaluated the effect of intrathecal mixture of ginsenosides with neostigmine on formalin-induced nociception and made further clear the role of the spinal muscarinic (M) receptors on the activity of ginsenosides. METHODS: A catheter was located in the intrathecal space of male Sprague-Dawley rats. Pain was evoked by injection of formalin solution (5%, 50 ul) to the hindpaw. Isobolographic analysis was done to characterize drug interaction between ginsenosides and neostigmine. The antagonism of ginsenosides mediated antinociception was determined with M1 receptor antagonist (pirenzepine), M2 receptor antagonist (methoctramine), M3 receptor antagonist (4 DAMP), M4 receptor antagonist (tropicamide). The expression of muscarinic receptor subtypes was examined with RT-PCR. RESULTS: Intrathecal ginsenosides and neostigmine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed an additive interaction between ginsenosides and neostigmine in both phases. Intrathecal pirenzepine, methoctramine, 4-DAMP, and tropicamide reversed the antinociception of ginsenosides in both phases. M1-M4 receptors mRNA detected in spinal cord of naive rats and the injection of formalin decreased the expression of M1 receptor mRNA, but it had no effect on the expression of other three muscarinic receptors mRNA. Intrathecal ginsenosides little affected the expression of all of muscarinic receptors mRNA in formalin-injected rats. CONCLUSIONS: Intrathecal ginsenosides additively interacted with neostigmine in the formalin test. Furthermore, M1-M4 receptors exist in the spinal cord, all of which contribute to the antinocieption of intrathecal ginsenosides. PMID- 23459684 TI - Sterically bulky caging for light-inducible protein activation. AB - A method for caging a target protein with steric regulator molecules was developed to enable simple, strict, light-induced control of protein activity. PMID- 23459686 TI - Strongly separated pairs of core electrons in computed ground states of small molecules. AB - We have performed full configuration interaction computations of the ground states of the molecules Be, BeH2, Li, LiH, B, and BH and verified that the core electrons constitute "separated electron pairs." These separated pairs of core electrons have nontrivial structure; the core pair does not simply occupy a single spatial orbital. Our method of establishing the presence of separated electron pairs is direct and conclusive. We do not fit a separated pair model; we work with the wavefunctions of interest directly. To establish that a given group of spin-orbitals contains a quasi-separated pair, we verify by direct computation that the quantum state of the electrons that occupy those spin-orbitals is nearly a pure 2-electron state. PMID- 23459685 TI - Ancient DNA reveals prehistoric gene-flow from siberia in the complex human population history of North East Europe. AB - North East Europe harbors a high diversity of cultures and languages, suggesting a complex genetic history. Archaeological, anthropological, and genetic research has revealed a series of influences from Western and Eastern Eurasia in the past. While genetic data from modern-day populations is commonly used to make inferences about their origins and past migrations, ancient DNA provides a powerful test of such hypotheses by giving a snapshot of the past genetic diversity. In order to better understand the dynamics that have shaped the gene pool of North East Europeans, we generated and analyzed 34 mitochondrial genotypes from the skeletal remains of three archaeological sites in northwest Russia. These sites were dated to the Mesolithic and the Early Metal Age (7,500 and 3,500 uncalibrated years Before Present). We applied a suite of population genetic analyses (principal component analysis, genetic distance mapping, haplotype sharing analyses) and compared past demographic models through coalescent simulations using Bayesian Serial SimCoal and Approximate Bayesian Computation. Comparisons of genetic data from ancient and modern-day populations revealed significant changes in the mitochondrial makeup of North East Europeans through time. Mesolithic foragers showed high frequencies and diversity of haplogroups U (U2e, U4, U5a), a pattern observed previously in European hunter gatherers from Iberia to Scandinavia. In contrast, the presence of mitochondrial DNA haplogroups C, D, and Z in Early Metal Age individuals suggested discontinuity with Mesolithic hunter-gatherers and genetic influx from central/eastern Siberia. We identified remarkable genetic dissimilarities between prehistoric and modern-day North East Europeans/Saami, which suggests an important role of post-Mesolithic migrations from Western Europe and subsequent population replacement/extinctions. This work demonstrates how ancient DNA can improve our understanding of human population movements across Eurasia. It contributes to the description of the spatio-temporal distribution of mitochondrial diversity and will be of significance for future reconstructions of the history of Europeans. PMID- 23459688 TI - Cardiometabolic risk profiles in pre- versus postmenopausal women with spinal cord injury:: preliminary findings. AB - OBJECTIVE: To compare the cardiometabolic risk (CMR) profile of premenopausal and postmenopausal women with spinal cord injury (SCI). METHOD: Post hoc analysis of a multicenter cross-sectional study assessing CMR. Seventeen women with ASIA Impairment Scale (AIS) A or B SCI between C5 and T12 were stratified into 2 groups according to menopausal status (11 premenopausal vs 6 postmenopausal women). Data collected included demographic, social, medical, menopausal, hormone use, and menstrual histories. Assessments included physical, anthropometric, and blood pressure measures; fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and hemoglobin A1C (Hb1Ac); calculated low-density lipoprotein (LDL-C); and an oral glucose tolerance test. RESULTS: The premenopausal group had a mean age of 32.4 years compared with 56.0 years in the postmenopausal group. Similar group findings included body mass index (BMI) (22.4 vs 22.2), HDL-C (52.5 vs 53 mg/dL), HbA1c (4.9 vs 5.1%), fasting blood glucose (FBG) (79.3 vs 84.8 mg/dL), and systolic blood pressure (SBP) (104.6 vs 111.8 mm Hg). TG, TC and LDL-C were significantly higher in postmenopausal group (55.7 vs 101.8 mg/dL, P = .01; 158.3 vs 191.6 mg/dL, P = .04; 94.7 vs 118.2 mg/dL, P = .04). CONCLUSIONS: The findings from this study suggest that postmenopausal women with SCI have CMR trends similar to those observed in nondisabled women, characterized by increases in TG, TC, and LDL-C despite favorable BMIs and glycemic indices. Even though the present study includes significant limitations, future evidence may also suggest that heightened surveillance and guideline-driven interventions are indicated for perimenopausal and postmenopausal women with SCI. PMID- 23459687 TI - Stress, the HPA axis, and nonhuman primate well-being: A review. AB - Numerous stressors are routinely encountered by wild-living primates (e.g., food scarcity, predation, aggressive interactions, and parasitism). Although many of these stressors are eliminated in laboratory environments, other stressors may be present in that access to space and social partners is often restricted. Stress affects many physiological systems including the hypothalamic-pituitary adrenocortical (HPA) axis, which is the focus of this review. The glucocorticoid, cortisol, is the ultimate output of this system in nonhuman primates, and levels of this hormone are used as an index of stress. Researchers can measure cortisol from several sampling matrices that include blood, saliva, urine, faeces, and hair. A comparison of the advantages and disadvantages of each sampling matrix is provided to aid researchers in selecting an optimal strategy for their research. Stress and its relationship to welfare have been examined in nonhuman primates using two complimentary approaches: comparing baseline cortisol levels under different conditions, or determining the reactivity of the system through exposure to a stressor. Much of this work is focused on colony management practices and developmental models of abnormal behaviour. Certain colony practices are known to increase stress at least temporarily. Both blood sampling and relocation are examples of this effect, and efforts have been made to reduce some of the more stressful aspects of these procedures. In contrast, other colony management practices such as social housing and environmental enrichment are hypothesized to reduce stress. Testing this hypothesis by comparing baseline cortisol levels has not proved useful, probably due to "floor" effects; however, social buffering studies have shown the powerful role of social housing in mitigating reactions of nonhuman primates to stressful events. Models of abnormal behaviour come from two sources: experimentally induced alterations in early experience (e.g., nursery rearing), and the spontaneous development of behavioural pathology (e.g., self-injurious behaviour). Investigators have often assumed that abnormal behaviour is a marker for stress and thus such monkeys are predicted to have higher cortisol levels than controls. However, an emerging finding is that monkeys with abnormal behaviour are more likely to show a pattern of lowered cortisol concentrations which may reflect either an altered set point or a blunting of the stress response system. These findings parallel human clinical studies demonstrating that neuropsychiatric disorders may be associated with either increased or decreased activity of the HPA system, depending on the aetiology and manifestation of the disorder and their potential influence in provoking allostatic shifts in system functioning. PMID- 23459689 TI - Born to Lead? A Twin Design and Genetic Association Study of Leadership Role Occupancy. AB - We address leadership emergence and the possibility that there is a partially innate predisposition to occupy a leadership role. Employing twin design methods on data from the National Longitudinal Study of Adolescent Health, we estimate the heritability of leadership role occupancy at 24%. Twin studies do not point to specific genes or neurological processes that might be involved. We therefore also conduct association analysis on the available genetic markers. The results show that leadership role occupancy is associated with rs4950, a single nucleotide polymorphism (SNP) residing on a neuronal acetylcholine receptor gene (CHRNB3). We replicate this family-based genetic association result on an independent sample in the Framingham Heart Study. This is the first study to identify a specific genotype associated with the tendency to occupy a leadership position. The results suggest that what determines whether an individual occupies a leadership position is the complex product of genetic and environmental influences; with a particular role for rs4950. PMID- 23459690 TI - Advances in biophotonics detection of field carcinogenesis for colon cancer risk stratification. AB - The process of neoplastic transformation of the colon involves a progression through hyperproliferative epithelium through the aberrant crypt foci->small adenoma->large adenoma->invasive cancer->metastatic disease. These are orchestrated by sequential genetic and epigenetic events which provide the underpinnings of cellular alterations such as early induction in proliferation/suppression of apoptosis, along with the late stage increase in invasiveness. Colorectal cancer (CRC) averages 49-111 mutations per tumor encompassing 10-15 critical signaling pathways[1]. Accumulating such a high number of mutations requires a fertile mutational field, which is the hallmark of colon carcinogenesis.While genetic susceptibility to colorectal cancer is well known, at least half of the risk is believed to be due to exogeneous factors (e.g., obesity, diet, exercise). Understanding these risk factors represents a promising mode of tailoring screening modality and intensity. However, previous attempts using these factors (i.e., NCI risk calculator) have only been modestly successful with an area under receiver operating characteristics (ROC) curve (AUC) of just 0.61. One of the most important concepts is that risk is the interaction between these genetic and environmental components and is driven by the variety of polymorphisms. Thus, predicting risk is difficult given the complexity. On the other hand, the colonic mucosa represents the end product of the complex interplay between these multiple factors. The power of field carcinogenesis is that it reflects this interplay between genetics and environment. PMID- 23459691 TI - PML Surfs into HIPPO Tumor Suppressor Pathway. AB - Growth arrest, inhibition of cell proliferation, apoptosis, senescence, and differentiation are the most characterized effects of a given tumor suppressor response. It is becoming increasingly clear that tumor suppression results from the integrated and synergistic activities of different pathways. This implies that tumor suppression includes linear, as well as lateral, crosstalk signaling. The latter may happen through the concomitant involvement of common nodal proteins. Here, we discuss the role of Promyelocytic leukemia protein (PML) in functional cross-talks with the HIPPO and the p53 family tumor suppressor pathways. PML, in addition to its own anti-tumor activity, contributes to the assembly of an integrated and superior network that may be necessary for the maximization of the tumor suppressor response to diverse oncogenic insults. PMID- 23459692 TI - Preparation and Characterization of Molecularly Imprinted Polymeric Nanoparticles for Atrial Natriuretic Peptide (ANP). AB - Natriuretic peptide receptor A (NPRA), the receptor for the cardiac hormone atrial natriuretic peptide (ANP), is expressed abundantly on cancer cells and disruption of ANP-NPRA signaling inhibits tumor burden and metastasis. Since antagonists of NPRA signaling have not provided reproducible results, we reasoned that a synthetic neutralizing antibody to ANP, which has high selectivity and affinity for ANP, could be used to regulate ANP levels and attenuate NPRA signaling. In this study, we prepared molecularly imprinted polymer nanoparticles (MIPNPs) for ANP using a short peptide of ANP as the template and determined their binding affinity and selectivity. The MIPNPs were prepared by precipitation polymerization using NH2-SLRRSS-CONH2, which is a short peptide from ANP as template, methacrylic acid (MAA) and N-isopropylacrylamide (NIPAm) as functional monomers, bis-acrylamide (BIS) as crosslinker. The average diameter of MIPNPs and non-imprinted nanoparticles (NIPNPs) in water is 215.8 +/-4.6 nm and 197.7+/-3.1 nm respectively. The binding isotherm analysis showed that MIPNPs have a much higher binding affinity for template peptide and ANP than NIPNPs. Scatchard analysis gave an equilibrium dissociation constant, Kd of 7.3 MUM with a binding capacity 106.7 MUmol/g for template peptide and Kd of 7.9 MUM with a binding capacity of 36.0 MUmol/g for ANP. Measurements of binding kinetics revealed that MIPNPs reach protein adsorption equilibrium in 30 min. MIPNPs found to have high specificity for ANP with little affinity for BSA or scrambled ANP peptide. MIPNPs also recognized and adsorbed ANP in cell culture media spiked with ANP and human plasma. Taken together, these results indicate that MIPNPs have high affinity and selectivity for ANP and can be used as a synthetic antibody for modulating ANP NPRA signaling in cancers. PMID- 23459694 TI - Microelectrode arrays in combination with in vitro models of spinal cord injury as tools to investigate pathological changes in network activity: facts and promises. AB - Microelectrode arrays (MEAs) represent an important tool to study the basic characteristics of spinal networks that control locomotion in physiological conditions. Fundamental properties of this neuronal rhythmicity like burst origin, propagation, coordination, and resilience can, thus, be investigated at multiple sites within a certain spinal topography and neighboring circuits. A novel challenge will be to apply this technology to unveil the mechanisms underlying pathological processes evoked by spinal cord injury (SCI). To achieve this goal, it is necessary to fully identify spinal networks that make up the locomotor central pattern generator (CPG) and to understand their operational rules. In this review, the use of isolated spinal cord preparations from rodents, or organotypic spinal slice cultures is discussed to study rhythmic activity. In particular, this review surveys our recently developed in vitro models of SCI by evoking excitotoxic (or even hypoxic/dysmetabolic) damage to spinal networks and assessing the impact on rhythmic activity and cell survival. These pathological processes which evolve via different cell death mechanisms are discussed as a paradigm to apply MEA recording for detailed mapping of the functional damage and its time-dependent evolution. PMID- 23459693 TI - Nox2 modification of LDL is essential for optimal apolipoprotein B-mediated control of agr type III Staphylococcus aureus quorum-sensing. AB - Staphylococcus aureus contains an autoinducing quorum-sensing system encoded within the agr operon that coordinates expression of virulence genes required for invasive infection. Allelic variation within agr has generated four agr specific groups, agr I-IV, each of which secretes a distinct autoinducing peptide pheromone (AIP1-4) that drives agr signaling. Because agr signaling mediates a phenotypic change in this pathogen from an adherent colonizing phenotype to one associated with considerable tissue injury and invasiveness, we postulated that a significant contribution to host defense against tissue damaging and invasive infections could be provided by innate immune mechanisms that antagonize agr signaling. We determined whether two host defense factors that inhibit AIP1 induced agrI signaling, Nox2 and apolipoprotein B (apoB), also contribute to innate control of AIP3-induced agrIII signaling. We hypothesized that apoB and Nox2 would function differently against AIP3, which differs from AIP1 in amino acid sequence and length. Here we show that unlike AIP1, AIP3 is resistant to direct oxidant inactivation by Nox2 characteristic ROS. Rather, the contribution of Nox2 to defense against agrIII signaling is through oxidation of LDL. ApoB in the context of oxLDL, and not LDL, provides optimal host defense against S. aureus agrIII infection by binding the secreted signaling peptide, AIP3, and preventing expression of the agr-driven virulence factors which mediate invasive infection. ApoB within the context of oxLDL also binds AIP 1-4 and oxLDL antagonizes agr signaling by all four agr alleles. Our results suggest that Nox2 mediated oxidation of LDL facilitates a conformational change in apoB to one sufficient for binding and sequestration of all four AIPs, demonstrating the interdependence of apoB and Nox2 in host defense against agr signaling. These data reveal a novel role for oxLDL in host defense against S. aureus quorum sensing signaling. PMID- 23459695 TI - Evaluating the Mobility of Arsenic in Synthetic Iron-containing Solids Using a Modified Sequential Extraction Method. AB - Many water treatment technologies for arsenic removal that are used today produce arsenic-bearing residuals which are disposed in non-hazardous landfills. Previous works have established that many of these residuals will release arsenic to a much greater extent than predicted by standard regulatory leaching tests (e.g. the toxicity characteristic leaching procedure, TCLP) and, consequently, require stabilization to ensure benign behavior after disposal. In this work, a four-step sequential extraction method was developed in an effort to determine the proportion of arsenic in various phases in untreated as well as stabilized iron based solid matrices. The solids synthesized using various potential stabilization techniques included: amorphous arsenic-iron sludge (ASL), reduced ASL via reaction with zero valent iron (RASL), amorphous ferrous arsenate (PFA), a mixture of PFA and SL (M1), crystalline ferrous arsenate (HPFA), and a mixture of HPFA and SL (M2). The overall arsenic mobility of the tested samples increased in the following order: ASL > RASL > PFA > M1 > HPFA > M2. PMID- 23459696 TI - Selective and adaptable access to N,N'-asymmetrically substituted imidazol-2 ylidene bis-NHC ligands: Pd(II) complexes featuring wide variation in N-alkyl and aryl steric bulk. AB - N,N'-Asymmetrically substituted, methylene-linked bis(imidazol-2-ylidene) complexes have been prepared subsequent to a selective synthesis of the bis(imidazolium) salt precursors involving the quarternisation of N-alkyl and aryl imidazoles with N-halomethyl imidazolium salts. The adaptability of the ligand precursor synthesis is illustrated through access to the N-Me/N'-Mes and N Mes/N'-2,6-(i-Pr)2Ph systems, leading to the Pd(II) complexes [{(MeIm)(MesIm)CH2}Pd(L)2](n+), L = Cl/I (n = 0) and NCMe (n = 2), and [{(MesIm)[2,6-(i-Pr)2PhIm]CH2}Pd(L)2], L = Cl/I. The dicationic hybrid N,N' alkyl/aryl complex was inactive in the copolymerisation of ethylene/carbon monoxide, displaying reactivity akin to N,N'-dialkyl analogues. PMID- 23459697 TI - Doxorubicin Cardiotoxicity and Cardiac Function Improvement After Stem Cell Therapy Diagnosed by Strain Echocardiography. AB - Doxorubicin (Dox) is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiotoxicity. Evaluation of left ventricular function relies on measurements based on M-mode echocardiography. A new technique based on quantification of myocardial motion and deformation, strain echocardiography, has been showed promising profile for early detection of cardiac dysfunction. Different therapy strategies, such as flavonoid plant extracts and stem cells, have been investigated to improve heart function in toxic cardiomyopathy. This work aimed to assess early cardiac function improvement after treatments with either flavonoid extract from Camellia sinensis or mesenchymal stem cells in Dox cardiotoxicity using strain echocardiography. Twenty Wistar rats were randomly assigned to four groups. They received water (control, Dox, Dox + stem cells) or 100 mg/kg C. sinensis extract (Dox + C. sinensis) via gavage, daily, for four weeks. Animals also received saline (control) or 5 mg/kg doxorubicin (Dox, Dox + C. sinensis, Dox + stem cells) via intraperitoneal injection, weekly, for four weeks. Stem cells were injected (3 * 106 cells) through tail vein prior the beginning of the experiment (Dox + stem cells). Animals were evaluated by hematological, electrocardiography, echocardiography, and histopathological examinations. Dox cardiotoxicity was only diagnosed with strain echocardiography, detecting a decrease in ventricular function. C. sinensis extract did not prevent ventricular dysfunction induced by Dox. However, strain echocardiography examination revealed that Dox cardiotoxicity was significantly suppressed in rats treated with stem cells. In conclusion, strain echocardiography was able to detect precocity signs of heart failure and stem cell therapy showed cardioprotection effect against Dox cardiotoxicity. PMID- 23459698 TI - Surgical restoration of arm and hand function in people with tetraplegia. AB - Improved hand and arm function is the most sought after function for people living with a cervical spinal cord injury (SCI). Surgical techniques have been established to increase upper extremity function for tetraplegics, focusing on restoring elbow extension, wrist movement, and hand opening and closing. Additionally, more innovative treatments that have been developed (implanted neuroprostheses and nerve transfers) provide more options for improving function and quality of life. One of the most important steps in the process of restoring upper extremity function in people with tetraplegia is identifying appropriate candidates - typically those with American Spinal Injury Association (ASIA) motor level C5 or greater. Secondary complications of SCI can pose barriers to restoring function, particularly upper extremity spasticity. A novel approach to managing spasticity through high-frequency alternating currents designed to block unwanted spasticity is being researched at the Cleveland FES Center and may improve the impact of reconstructive surgery for these individuals. The impact of these surgeries is best measured within the framework of the World Health Organization's International Classification of Function, Disability and Health. Outcome measures should be chosen to reflect changes within the domains of body functions and structures, activity, and participation. There is a need to strengthen the evidence in the area of reconstructive procedures for people with tetraplegia. Research continues to advance, providing more options for improved function in this population than ever before. The contribution of well-designed outcome studies to this evidence base will ultimately help to address the complications surrounding access to the procedures. PMID- 23459699 TI - The frequency of anti-infliximab antibodies in patients with rheumatoid arthritis treated in routine care and the associations with adverse drug reactions and treatment failure. AB - OBJECTIVES: To investigate the frequency of anti-infliximab antibodies in patients with RA and the associations with adverse drug reactions and treatment failure. METHODS: Based on the DANBIO registry, patients with RA who initiated treatment with infliximab at Hvidovre Hospital between 2000 and 2008 and had available serum samples were identified. The patients were followed for 52 weeks. Anti-infliximab antibodies were determined prior to infusion at baseline and during follow-up (weeks 2, 6, 14 and 52 or at withdrawal) using the IMPACT indirect assay (Roche Diagnostics) and merged with clinical data prospectively registered in the DANBIO registry. RESULTS: A total of 218 patients with RA were included (80% females, median age 56 years, disease duration 10 years, 65% RF positive, median DAS28 = 5.0). During the 52-week follow-up, 28 patients (13%) withdrew due to adverse events and 50 (23%) due to treatment failure. Antibodies were detected in 118 patients (54%) during follow-up. Patients with detectable anti-infliximab antibodies after 6 weeks had an increased risk of adverse drug reactions [hazard ratio (HR) = 5.06, 95% CI 2.36, 10.84; P < 0.0001] compared with patients without anti-infliximab antibodies. Similar results were observed in patients with anti-infliximab antibodies after 14 weeks (HR = 3.30, 95% CI 1.56, 6.99; P = 0.0009). Patients with detectable anti-infliximab antibodies during the 52-week follow-up were less likely to achieve sustained minimal disease activity and remission. CONCLUSION: Early anti-infliximab antibody formation increased the risk of adverse drug reactions, including infusion reactions. Anti-infliximab antibody formation during the 52-week follow-up decreased the likelihood of minimal disease activity and remission in patients with RA treated in routine care. PMID- 23459700 TI - The production of ginsenosides in hairy root cultures of American Ginseng, Panax quinquefolium L. and their antimicrobial activity. AB - Panax quinquefolium, American ginseng, is valued for its triterpene saponins, known as ginsenosides. These constituents possess a number of pharmacological properties and hairy root cultures can synthesize similar saponins to those of field-cultivated roots. The antibacterial activity of extracts from three hairy root clones of P. quinquefolium L. was tested against a range of standard bacterial and yeast strains. The agar diffusion method was used to evaluate inhibition of microbial growth at various extract concentrations. Commercial antibiotics were used as positive reference standards to determine the sensitivity of the strains. Susceptibility testing to antibiotics was also tested using the disk diffusion method. The minimal inhibitory concentration values of the extracts, obtained by agar diffusion, ranged from 0.8 to 1.4 mg/ml. The results showed that extracts from hairy root cultures inhibited the growth of bacteria and yeast strains and suggest that they may be useful in the treatment of infections caused by pathogenic microorganisms. PMID- 23459701 TI - Z-palatoplasty and tongue radiofrequency for patients with small tonsils. AB - OBJECTIVE: To explore the feasibility and efficacy of Z-palatoplasty for the management of severe obstructive sleep apnea-hypopnea syndrome in patients with tonsils. STUDY DESIGN: Case series and chart review. SETTING: University hospital. METHODS: Z-palatoplasty and coblation channeling of the tongue were performed in 36 patients with body mass index <40 kg/m(2) and size 1 or 2 tonsils. All patients' tonsils were preserved. Follow-up continued for at least 1 year. Success was defined as a postoperative apnea-hypopnea index <15 events per hour and at least 50% less than the preoperative value. RESULTS: The surgical success rate was 58.3% (21/36 patients). Furthermore, 66.7% (24/36 patients) had a >= 50% reduction in the apnea-hypopnea index to less than 20 episodes per hour. There were statistically significant differences in preoperative nadir oxygen saturation, percentage of time with oxygen saturation less than 90%, microarousal index, and Friedman tongue position between those who responded to surgery and those who did not. Six patients had temporary velopharyngeal insufficiency. After 3 months, all the patients had normal deglutition. No major perioperative complications occurred. CONCLUSION: Our findings suggest that Z-palatoplasty can improve disease-specific quality of life and sleep apnea symptoms in patients with obstructive sleep apnea-hypopnea syndrome and size 1 or 2 tonsils. PMID- 23459702 TI - Castleman disease in the pediatric neck: a literature review. AB - OBJECTIVE: To investigate the common features of cervical pediatric Castleman disease. DATA SOURCES: Literature review of pediatric patients with cervical Castleman disease. REVIEW METHODS: Online medical journal databases were searched for patients aged 18 years or younger. Eighteen published studies were found, comprising 29 patients. CONCLUSIONS: An asymptomatic or slowly enlarging neck mass was the most common presentation. No sex differences were noted. Magnetic resonance imaging demonstrates a homogeneous, isointense to slightly hyperintense T1-weighted signal and high signal intensity on T2-weighted imaging. Lymphoma was the most common differential diagnosis. All patients were treated with complete surgical excision and diagnosed as hyaline-vascular type on histology, except for 1 patient for whom histologic type was not reported. No reports of multicentric disease, plasma cell, or mixed histology were found. No recurrences were reported. IMPLICATIONS FOR PRACTICE: In this article, we provide the largest known literature review of pediatric patients with cervical Castleman disease. Although Castleman disease is rare, it should be considered on the differential for a pediatric neck mass, particularly when presenting with an asymptomatic posterior neck mass and equivocal workup. Fortunately, our study suggests that if diagnosed as Castleman disease, the most likely diagnosis is hyaline-vascular type, for which the long-term prognosis is good. Surgical excision is both diagnostic and therapeutic. PMID- 23459704 TI - In situ synthesis of silver nanoparticle decorated vertical nanowalls in a microfluidic device for ultrasensitive in-channel SERS sensing. AB - A microfluidic device with integrated novel silver nanoparticle (Ag NPs) decorated nanowall structures was fabricated via in situ electrodeposition of Cu core/C-sheath nanowalls, followed by a facile in-channel silver galvanic replacement reaction method at room temperature. The integrated microfluidic devices with Ag NPs decorated nanowalls, serving as a highly active Raman substrate, were then applied for in-channel surface-enhanced Raman scattering (SERS) sensing using crystal violet as the model compound. The results show that the presence of a PDMS microfluidic channel does not significantly affect the Raman signal and crystal violet as low as 50 pM is prominently detected. The calculated apparent enhancement factor is 1.1 * 10(9), which allows for the ultra sensitive detection of analytes in microfluidic devices. The superior enhancement of the in-channel Raman signal and excellent analyte sensitivity can be attributed to the synergistic effect of several distinct traits of the Ag NPs decorated nanowalls - a large available surface for analyte adsorption, a large number of nanocavities surrounded by nanowalls laterally confining the surface plasmons, and numerous "hot spots" resulting from close-contacted Ag NPs and/or the proximate edges of Ag decorated nanowalls. Because preparation of the active SERS substrate and subsequent finger-print SERS detection is completed within a microfluidic device, the developed method opens a new venue to integrate active SERS substrate within microfluidic channels and provides an excellent microfluidic SERS sensor platform for ultrasensitive and selective chemical and biological sensing. PMID- 23459703 TI - Vertical dome division: a quality-of-life outcome study. AB - OBJECTIVE: To assess quality-of-life outcomes in patients undergoing nasal tip surgery with the vertical dome division technique using validated instruments (Rhinoplasty Outcome Evaluation [ROE] and Nasal Obstruction Symptom Evaluation [NOSE]). STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary university center. SUBJECT AND METHODS: Patients undergoing primary cosmetic and functional rhinoseptoplasty using vertical dome division were consecutively evaluated. The ROE, NOSE, and 100-mm visual analog scale (VAS) were administered pre- and postoperatively. RESULTS: Forty-four patients were included and completed pre- and postoperative questionnaires. Their median age was 28 years, 27 (61%) were female, and the median duration of follow-up was 5 months (range, 3-9 months). Median postoperative ROE, NOSE, and VAS scores (79 [66; 87], 20 [15; 23], and 88 [61; 97], respectively) showed significant improvement compared with preoperative scores (29 [16; 41], 75 [60; 95], and 65 [46; 82], respectively; P < .001). The change in median ROE score was significantly greater in normal- and thin-skinned patients than in thick-skinned patients (54 vs 33; P = .033). Median changes in NOSE-p (-48.5 vs -68.0; P = .10) and VAS (69.0 vs 48.0; P =.083) scores did not differ between normal-/thin- and thick-skinned patients. CONCLUSION: Vertical dome division is a versatile technique for nasal tip refinement that resulted in significant improvement in quality-of-life outcomes related to rhinoplasty and nasal obstruction, as well as satisfaction with nasal appearance in a short-term follow-up period. The vertical dome division technique does not seem to be indicated only in patients with thick skin. PMID- 23459705 TI - Simultaneously high gravimetric and volumetric methane uptake characteristics of the metal-organic framework NU-111. AB - We show that the MOF NU-111 exhibits equally high volumetric and gravimetric methane uptake values, both within ~75% of the DOE targets at 300 K. Upon reducing the temperature to 270 K, the uptake increases to 0.5 g g(-1) and 284 cc(STP) per cc at 65 bar. Adsorption of CO2 and H2 is also reported. Simulated isotherms are in excellent agreement with those obtained from experiments. PMID- 23459706 TI - Wheelchair skill performance of manual wheelchair users with spinal cord injury. PMID- 23459707 TI - Nanosized sustained-release pyridostigmine bromide microcapsules: process optimization and evaluation of characteristics. AB - BACKGROUND: Pyridostigmine bromide (3-[[(dimethylamino)-carbonyl]oxy]-1 methylpyridinium bromide), a reversible inhibitor of cholinesterase, is given orally in tablet form, and a treatment schedule of multiple daily doses is recommended for adult patients. Nanotechnology was used in this study to develop an alternative sustained-release delivery system for pyridostigmine, a synthetic drug with high solubility and poor oral bioavailability, hence a Class III drug according to the Biopharmaceutics Classification System. Novel nanosized pyridostigmine-poly(lactic acid) microcapsules (PPNMCs) were expected to have a longer duration of action than free pyridostigmine and previously reported sustained-release formulations of pyridostigmine. METHODS: The PPNMCs were prepared using a double emulsion-solvent evaporation method to achieve sustained release characteristics for pyridostigmine. The preparation process for the PPNMCs was optimized by single-factor experiments. The size distribution, zeta potential, and sustained-release behavior were evaluated in different types of release medium. RESULTS: The optimal volume ratio of inner phase to external phase, poly(lactic acid) concentration, polyvinyl alcohol concentration, and amount of pyridostigmine were 1:10, 6%, 3% and 40 mg, respectively. The negatively charged PPNMCs had an average particle size of 937.9 nm. Compared with free pyridostigmine, PPNMCs showed an initial burst release and a subsequent very slow release in vitro. The release profiles for the PPNMCs in four different types of dissolution medium were fitted to the Ritger-Peppas and Weibull models. The similarity between pairs of dissolution profiles for the PPNMCs in different types of medium was statistically significant, and the difference between the release curves for PPNMCs and free pyridostigmine was also statistically significant. CONCLUSION: PPNMCs prepared by the optimized protocol described here were in the nanometer range and had good uniformity, with significantly slower pyridostigmine release than from free pyridostigmine. This novel sustained release delivery nanosystem for pyridostigmine might alleviate the need to identify new acetylcholinesterase inhibitors. PMID- 23459709 TI - Interruption of bispectral index monitoring by nerve integrity monitoring during tympanoplasty -A case report-. AB - We report that intraoperative NIM-2 monitoring devices can interfere with bispectral index monitoring. A 45-year-old male with chronic otits media underwent tympanolasty under general anesthesia with NIM-2 monitoring and bispectral index monitoring at our institution. And then, bispectral index monitoring was severely interrupted by facial nerve monitoring. PMID- 23459708 TI - The prefoldin bud27 mediates the assembly of the eukaryotic RNA polymerases in an rpb5-dependent manner. AB - The unconventional prefoldin URI/RMP, in humans, and its orthologue in yeast, Bud27, have been proposed to participate in the biogenesis of the RNA polymerases. However, this role of Bud27 has not been confirmed and is poorly elucidated. Our data help clarify the mechanisms governing biogenesis of the three eukaryotic RNA pols. We show evidence that Bud27 is the first example of a protein that participates in the biogenesis of the three eukaryotic RNA polymerases and the first example of a protein modulating their assembly instead of their nuclear transport. In addition we demonstrate that the role of Bud27 in RNA pols biogenesis depends on Rpb5. In fact, lack of BUD27 affects growth and leads to a substantial accumulation of the three RNA polymerases in the cytoplasm, defects offset by the overexpression of RPB5. Supporting this, our data demonstrate that the lack of Bud27 affects the correct assembly of Rpb5 and Rpb6 to the three RNA polymerases, suggesting that this process occurs in the cytoplasm and is a required step prior to nuclear import. Also, our data support the view that Rpb5 and Rpb6 assemble somewhat later than the rest of the complexes. Furthermore, Bud27 Rpb5-binding but not PFD-binding domain is necessary for RNA polymerases biogenesis. In agreement, we also demonstrate genetic interactions between BUD27, RPB5, and RPB6. Bud27 shuttles between the nucleus and the cytoplasm in an Xpo1-independent manner, and also independently of microtubule polarization and possibly independently of its association with the RNA pols. Our data also suggest that the role of Bud27 in RNA pols biogenesis is independent of the chaperone prefoldin (PFD) complex and of Iwr1. Finally, the role of URI seems to be conserved in humans, suggesting conserved mechanisms in RNA pols biogenesis. PMID- 23459711 TI - Postnatal cardiomyocyte growth and mitochondrial reorganization cause multiple changes in the proteome of human cardiomyocytes. AB - Fetal (fCM) and adult cardiomyocytes (aCM) significantly differ from each other both by structure and biochemical properties. aCM own a higher mitochondrial mass compared to fCM due to increased energy demand and show a greater density and higher degree of structural organization of myofibrils. The energy metabolism in aCM relies virtually completely on beta-oxidation of fatty acids while fCM use carbohydrates. Rewinding of the aCM phenotype (de-differentiation) arises frequently in diseased hearts spurring questions about its functional relevance and the extent of de-differentiation. Yet, surprisingly little is known about the changes in the human proteome occurring during maturation of fCM to aCM. Here, we examined differences between human fetal and adult hearts resulting in the quantification of 3500 proteins. Moreover, we analyzed mitochondrial proteomes from both stages to obtain more detailed insight into underlying biochemical differences. We found that the majority of changes between fCM and aCM were attributed to growth and maturation of cardiomyocytes. As expected, adult hearts showed higher mitochondrial mass and expressed increased levels of proteins involved in energy metabolism but relatively lower copy numbers of mitochondrial DNA (mtDNA) per total cell volume. We uncovered that the TFAM/mtDNA ratio was kept constant during postnatal development despite a significant increase of mitochondrial protein per mtDNA in adult mitochondria, which revises previous concepts. PMID- 23459712 TI - Prediction of Cytochrome P450 Profiles of Environmental Chemicals with QSAR Models Built from Drug-like Molecules. AB - The human cytochrome P450 (CYP) enzyme family is involved in the biotransformation of many xenobiotics. As part of the U.S. Tox21 Phase I effort, we profiled the CYP activity of approximately three thousand compounds, primarily those of environmental concern, against human CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 isoforms in a quantitative high throughput screening (qHTS) format. In order to evaluate the extent to which computational models built from a drug-like library screened in these five CYP assays under the same conditions can accurately predict the outcome of an environmental compound library, five support vector machines (SVM) models built from over 17,000 drug-like compounds were challenged to predict the CYP activities of the Tox21 compound collection. Although a large fraction of the test compounds fall outside of the applicability domain (AD) of the models, as measured by k-nearest neighbor (k-NN) similarities, the predictions were largely accurate for CYP1A2, CYP2C9, and CYP3A4 ioszymes with area under the receiver operator characteristic curves (AUC-ROC) ranging between 0.82 and 0.84. The lower predictive power of the CYP2C19 model (AUC-ROC = 0.76) is caused by experimental errors and that of the CYP2D6 model (AUC-ROC = 0.76) can be rescued by rebalancing the training data. Our results demonstrate that decomposing molecules into atom types enhanced the coverage of the AD and that computational models built from drug-like molecules can be used to predict the ability of non-drug like compounds to interact with these CYPs. PMID- 23459713 TI - ADA Compliance and Accessibility of Fitness Facilities in Western Wisconsin. AB - PURPOSE: The study expands the research on fitness facility accessibility by determining how compliant fitness facilities in rural western Wisconsin were with Title III of the Americans with Disabilities Act (ADA). Comparisons were made with 4 other studies that were conducted in different geographical regions. The study also examined fitness professionals' disability knowledge and awareness. METHOD: An ADA fitness facility compliance instrument and a fitness professional disability awareness survey were used. Direct observation and physical measurements were taken during on-site visits to 16 of 36 eligible fitness facilities in rural western Wisconsin. Ten fitness professionals from participating facilities completed an online survey. Frequencies were used to analyze the results. RESULTS: None of the participating facilities were in 100% compliance with ADA. Customer service desk (84%) and path of travel throughout the facility (72%) were the highest compliance areas. Telephone (6%) and locker rooms (32%) were the lowest compliance areas. No fitness professional was trained in wheelchair transfers and very few had received training in providing services to individuals with disabilities. CONCLUSION: Fitness facility accessibility remains a concern nationally. Continued efforts need to be made to raise the awareness of ADA compliance among fitness professionals across the United States, especially in rural areas where fitness facility availability is limited. PMID- 23459714 TI - Effect of Bra Use during Radiotherapy for Large-Breasted Women: Acute Toxicity and Treated Heart and Lung Volumes. AB - PURPOSE: Large breast size presents special problems during radiation simulation, planning and patient treatment, including increased skin toxicity, in women undergoing breast-conserving surgery and radiotherapy (BCT). We report our experience using a bra during radiation in large-breasted women and its effect on acute toxicity and heart and lung dosimetry. MATERIALS AND METHODS: From 2001 to 2006, 246 consecutive large-breasted women (bra size >= 38 and/or >= D cup) were treated with BCT using either 3D conformal (3D-CRT) or Intensity Modulated Radiation (IMRT). In 58 cases, at the physicians' discretion, a custom-fit bra was used during simulation and treatment. Endpoints were acute radiation dermatitis, and dosimetric comparison of heart and lung volumes in a subgroup of 12 left-sided breast cancer patients planned with and without a bra. RESULTS: The majority of acute skin toxicities were grade 2 and were experienced by 90% of patients in a bra compared to 70% of patients not in a bra (p=0.003). On multivariate analysis significant predictors of grade 2/3 skin toxicity included 3D-CRT instead of IMRT (OR=3.9, 95% CI:1.8-8.5) and the use of a bra (OR=5.5, 95% CI:1.6-18.8). For left-sided patients, use of a bra was associated with a volume of heart in the treatment fields decreased by 63.4% (p=0.002), a volume of left lung decreased by 18.5% (p=0.25), and chest wall separation decreased by a mean of 1 cm (p=0.03). CONCLUSIONS: The use of a bra to augment breast shape and position in large-breasted women is an alternative to prone positioning and associated with reduced chest wall separation and reduced heart volume within the treatment field. PMID- 23459715 TI - N-heterocyclic carbene-initiated hydrosilylation of styryl alcohols with dihydrosilanes: a mechanistic investigation. AB - Investigation of the mechanism of the NHC-initiated hydrosilylation of styryl alcohols in the presence of a dihydrosilane suggests a general base catalysis mechanism and not the activation of the dihydrosilane by the NHC. PMID- 23459716 TI - Patients at risk for peritoneal surface malignancy of colorectal cancer origin: the role of second look laparotomy. AB - Peritoneal surface malignancy (PSM) is a frequent occurrence in the natural history of colorectal cancer (CRC). Although significant advances have been made in screening of CRC, similar progress has yet to be made in the early detection of PSM of colorectal cancer origin. The fact that advanced CRC can be confined to the peritoneal surface without distant dissemination forms the basis for aggressive multi-modality therapy consisting of cytoreductive surgery (CRS) plus hyperthermic intra-peritoneal chemotherapy (HIPEC), and neoadjuvant and/or adjuvant systemic therapy. Reported overall survival with complete CRS+HIPEC exceeds that of systemic therapy alone for the treatment of PSM from CRC, underscoring the advantage of this multi-modality therapeutic approach. Patients with limited peritoneal disease from CRC can undergo complete cytoreduction, which is associated with the best reported outcomes. As early or limited peritoneal carcinomatosis is undetectable by conventional imaging modalities, second look laparotomy is an important means to identify disease in high-risk patients at a stage most amenable to complete cytoreduction. This review focuses on the identification of patients at risk for PSM from CRC and discusses the role of second look laparotomy. PMID- 23459717 TI - Synthesis of highly substituted oxetanes via [2+2] cycloaddition reactions of allenoates catalyzed by a guanidine Lewis base. AB - The first synthesis of highly substituted 3-alkyl-oxetan-2-ylidenes from allenoates was developed by using the bicyclic guanidine 1,5,7 triazabicyclo[4.4.0]dec-5-ene (TBD) as an exceptionally active nitrogen Lewis base catalyst. PMID- 23459718 TI - Potentially prognostic miRNAs in HPV-associated oropharyngeal carcinoma. AB - PURPOSE: Deregulation of miRNAs is associated with almost all human malignancies. Human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) has a significantly more favorable outcome compared with HPV-negative OPCs; however, the underlying mechanisms are not well understood. Hence, the objectives of this study were to determine whether miRNA expression differed as a function of HPV status and to assess whether such miRNAs provide prognostic value beyond HPV status. METHODS: Global miRNA profilings were conducted on 88 formalin-fixed and paraffin-embedded (FFPE) OPC biopsies (p16-positive: 56; p16-negative: 32), wherein the expression levels of 365 miRNAs plus 3 endogenous controls were simultaneously measured using quantitative real-time (qRT)-PCR. Seven FFPE specimens of histologically normal tonsils were used as controls. RESULTS: Overall, 224 miRNAs were expressed in more than 80% of the investigated samples, with 128 (57%) being significantly differentially expressed between tumor versus normal tissues (P < 0.05). Upregulated miR-20b, miR-9, and miR-9* were significantly associated with HPV/p16-status. Three miRNA sets were significantly associated with overall survival (miR-107, miR-151, miR-492; P = 0.0002), disease free survival (miR-20b, miR-107, miR-151, miR-182, miR-361; P = 0.0001), and distant metastasis (miR-151, miR-152, miR-324-5p, miR-361, miR492; P = 0.0087), which retained significance even after adjusting for p16 status. The associated biologic functions of these miRNAs include immune surveillance, treatment resistance, invasion, and metastasis. CONCLUSION: We have identified several miRNAs, which associate with HPV status in OPC; furthermore, three candidate prognostic sets of miRNAs seem to correlate with clinical outcome, independent of p16 status. Furthermore, evaluations will offer biologic insights into the mechanisms underlying the differences between HPV-positive versus HPV-negative OPC. PMID- 23459719 TI - Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. AB - The treatment landscape and biologic understanding of neuroendocrine tumors (NET) has shifted dramatically in recent years. Recent studies have shown that somatostatin analogues have the potential not only to control symptoms of hormone hypersecretion but also have the ability to slow tumor growth in patients with advanced carcinoid. The results of clinical trials have further shown that the VEGF pathway inhibitor sunitinib and the mTOR inhibitor everolimus have efficacy in patients with advanced pancreatic NETs. The efficacy of these targeted therapies in NET suggests that the molecular characterization of NETs may provide an avenue to predict both which patients may benefit most from the treatment and to overcome potential drug resistance. Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. These observations offer the potential for new therapeutic and diagnostic advances for patients with NET. PMID- 23459721 TI - America's health deficit: dying from policy neglect. PMID- 23459720 TI - An international collaboration to harmonize the quantitative plasma Epstein-Barr virus DNA assay for future biomarker-guided trials in nasopharyngeal carcinoma. AB - PURPOSE: Persistently elevated posttreatment plasma EBV DNA is a robust predictor of relapse in nasopharyngeal carcinoma (NPC). However, assay standardization is necessary for use in biomarker-driven trials. We conducted a study to harmonize the method between four centers with expertise in EBV DNA quantitation. EXPERIMENTAL DESIGN: Plasma samples of 40 patients with NPC were distributed to four centers. DNA was extracted and EBV DNA copy number was determined by real time quantitative PCR (BamHI-W primer/probe). Centers used the same protocol but generated their own calibrators. A harmonization study was then conducted using the same calibrators and PCR master mix and validated with ten pooled samples. RESULTS: The initial intraclass correlations (ICC) for the first 40 samples between each center and the index center were 0.62 [95% confidence interval (CI): 0.39-0.78], 0.70 (0.50-0.83), and 0.59 (0.35-0.76). The largest variability was the use of different PCR master mixes and calibrators. Standardization improved ICC to 0.83 (0.5-0.95), 0.95 (0.83-0.99) and 0.96 (0.86-0.99), respectively, for ten archival frozen samples. For fresh plasma with spiked-in EBV DNA, correlations were more than 0.99 between the centers. At 5 EBV DNA copies per reaction or above, the coefficient of variance (CV) was less than 10% for the cycle threshold (Ct) among all centers, suggesting this concentration can be reliably used as a cutoff for defining the presence of detectable EBV DNA. CONCLUSIONS: Quantitative PCR assays, even when conducted in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers without harmonization. The use of common calibrators and PCR master mix can help to reduce variability. PMID- 23459722 TI - After Newtown: mental illness and violence. AB - In the wake of the latest mass shooting, there are calls to marshal the evidence and take steps to identify and treat mental illness early in life. PMID- 23459723 TI - Even as mortality fell in most US counties, female mortality nonetheless rose in 42.8 percent of counties from 1992 to 2006. AB - Researchers increasingly track variations in health outcomes across counties in the United States, but current ranking methods do not reflect changes in health outcomes over time. We examined trends in male and female mortality rates from 1992-96 to 2002-06 in 3,140 US counties. We found that female mortality rates increased in 42.8 percent of counties, while male mortality rates increased in only 3.4 percent. Several factors, including higher education levels, not being in the South or West, and low smoking rates, were associated with lower mortality rates. Medical care variables, such as proportions of primary care providers, were not associated with lower rates. These findings suggest that improving health outcomes across the United States will require increased public and private investment in the social and environmental determinants of health-beyond an exclusive focus on access to care or individual health behavior. PMID- 23459724 TI - Mortality under age 50 accounts for much of the fact that US life expectancy lags that of other high-income countries. AB - Life expectancy at birth in the United States is among the lowest of all high income countries. Most recent studies have concentrated on older ages, finding that Americans have a lower life expectancy at age fifty and experience higher levels of disease and disability than do their counterparts in other industrialized nations. Using cross-national mortality data to identify the key age groups and causes of death responsible for these shortfalls, I found that mortality differences below age fifty account for two-thirds of the gap in life expectancy at birth between American males and their counterparts in sixteen comparison countries. Among females, the figure is two-fifths. The major causes of death responsible for the below-fifty trends are unintentional injuries, including drug overdose--a fact that constitutes the most striking finding from this study; noncommunicable diseases; perinatal conditions, such as pregnancy complications and birth trauma; and homicide. In all, this study highlights the importance of focusing on younger ages and on policies both to prevent the major causes of death below age fifty and to reduce social inequalities. PMID- 23459725 TI - Wellness incentives in the workplace: cost savings through cost shifting to unhealthy workers. AB - The Affordable Care Act encourages workplace wellness programs, chiefly by promoting programs that reward employees for changing health-related behavior or improving measurable health outcomes. Recognizing the risk that unhealthy employees might be punished rather than helped by such programs, the act also forbids health-based discrimination. We reviewed results of randomized controlled trials and identified challenges for workplace wellness programs to function as the act intends. For example, research results raise doubts that employees with health risk factors, such as obesity and tobacco use, spend more on medical care than others. Such groups may not be especially promising targets for financial incentives meant to save costs through health improvement. Although there may be other valid reasons, beyond lowering costs, to institute workplace wellness programs, we found little evidence that such programs can easily save costs through health improvement without being discriminatory. Our evidence suggests that savings to employers may come from cost shifting, with the most vulnerable employees--those from lower socioeconomic strata with the most health risks- probably bearing greater costs that in effect subsidize their healthier colleagues. PMID- 23459726 TI - A hospital system's wellness program linked to health plan enrollment cut hospitalizations but not overall costs. AB - Many policy makers believe that health status would be improved and health care spending reduced if people managed their health better. This study examined the effectiveness of a program put in place by BJC HealthCare, a hospital system based in St. Louis, Missouri, that tied employees' eligibility to participate in the system's most generous health plan with participation in a wellness program. The intervention, which began in 2005, was associated with a 41 percent decrease, relative to a comparison group, in hospitalizations for conditions targeted by the wellness program but with no significant decrease in other hospitalizations. We found reductions in inpatient costs but similar increases in non-inpatient costs. Therefore, we conclude that although the program did cut some hospitalizations, it did not save money for the employer in the short term. This finding underscores that wellness program incentives under the Affordable Care Act are unlikely to greatly reduce health care spending over the short run. PMID- 23459727 TI - Survey finds public support for legal interventions directed at health behavior to fight noncommunicable disease. AB - The high prevalence of chronic diseases in the United States with lifestyle related risk factors, such as obesity and tobacco use, has sparked interest in legal strategies to influence health behavior. However, little is known about the public's willingness to accept these policies as legitimate, which in turn may affect compliance. We present results from a national survey of 1,817 US adults concerning the acceptability of different public health legal interventions that address noncommunicable, or chronic, diseases. We found that support for these new interventions is high overall; substantially greater among African Americans and Hispanics than among whites; and tied to perceptions of democratic representation in policy making. There was much support for strategies that enable people to exercise healthful choices--for example, menu labeling and improving access to nicotine patches--but considerably less for more coercive measures, such as insurance premium surcharges. These findings suggest that the least coercive path will be the smoothest and that support for interventions may be widespread among different social groups. In addition, the findings underscore the need for policy makers to involve the public in decision making, understand the public's values, and communicate how policy decisions reflect this understanding. PMID- 23459728 TI - Medicaid incentive programs to encourage healthy behavior show mixed results to date and should be studied and improved. AB - In September 2011 the Centers for Medicare and Medicaid Services awarded $85 million in grants to ten states to test financial incentive programs to encourage healthy behavior among Medicaid enrollees with chronic diseases. There is little published evidence about the effectiveness of such incentives within the Medicaid program. We evaluated the available research from three earlier Medicaid incentive programs and found mixed results. On the one hand, in Florida only about half of the $41.3 million in available credits was "claimed" by enrollees between 2006 and 2011. On the other, Idaho's incentive program was credited with improving the proportion of children who were up-to-date on well-child visits. Our findings suggest that Medicaid incentive programs should be designed so that enrollees can understand them and so that the incentives are attractive enough to motivate participation. Medicaid incentive programs also should be subject to rigorous evaluation to more clearly establish their effectiveness. PMID- 23459729 TI - Adherence with recommended well-child visits has grown, but large gaps persist among various socioeconomic groups. AB - A goal of federal policy is to improve preventive health care for children. However, little is known about how adherence to recommendations by the American Academy of Pediatrics for well-child visits has changed over time. Using the 1996 2008 Medical Expenditure Panel Surveys, we examined trends in adherence and whether differences across population subgroups narrowed or widened over time. We found that the ratio of actual to recommended well-child visits rose from 46.3 percent during the 1996-98 time period to 58.9 percent during the 2007-08 time period. Although this increase in adherence is important, improvement occurred unevenly. We observed large differences in adherence at the start of the study period across income, race or ethnicity, parent education, region, insurance coverage, and having a usual source of care. None of these differences had narrowed significantly by the end of the study period. Indeed, differences widened across parent education, between those with and without insurance coverage, by usual source of care, and between the Northeast and the Midwest and West regions. Our results highlight the importance of provisions in the Affordable Care Act to expand coverage, strengthen incentives for preventive services, and improve the measurement of preventive services. PMID- 23459730 TI - Redesigning primary care: a strategic vision to improve value by organizing around patients' needs. AB - Primary care in the United States currently struggles to attract new physicians and to garner investments in infrastructure required to meet patients' needs. We believe that the absence of a robust overall strategy for the entire spectrum of primary care is a fundamental cause of these struggles. To address the absence of an overall strategy and vision for primary care, we offer a framework based on value for patients to sustain and improve primary care practice. First, primary care should be organized around subgroups of patients with similar needs. Second, team-based services should be provided to each patient subgroup over its full care cycle. Third, each patient's outcomes and true costs should be measured by subgroup as a routine part of care. Fourth, payment should be modified to bundle reimbursement for each subgroup and reward value improvement. Finally, primary care patient subgroup teams should be integrated with relevant specialty providers. We believe that redesigning primary care using this framework can improve the ability of primary care to play its essential role in the health care system. PMID- 23459731 TI - Solving the value equation in health care. AB - In seeking to foster greater value in health care, Michael Porter and colleagues have advanced ideas for a very different delivery and payment system. PMID- 23459732 TI - Cesarean delivery rates vary tenfold among US hospitals; reducing variation may address quality and cost issues. AB - Cesarean delivery is the most commonly performed surgical procedure in the United States, and cesarean rates are increasing. Working with 2009 data from 593 US hospitals nationwide, we found that cesarean rates varied tenfold across hospitals, from 7.1 percent to 69.9 percent. Even for women with lower-risk pregnancies, in which more limited variation might be expected, cesarean rates varied fifteenfold, from 2.4 percent to 36.5 percent. Thus, vast differences in practice patterns are likely to be driving the costly overuse of cesarean delivery in many US hospitals. Because Medicaid pays for nearly half of US births, government efforts to decrease variation are warranted. We focus on four promising directions for reducing these variations, including better coordinating maternity care, collecting and measuring more data, tying Medicaid payment to quality improvement, and enhancing patient-centered decision making through public reporting. PMID- 23459733 TI - Publicly reported quality-of-care measures influenced Wisconsin physician groups to improve performance. AB - Public reporting of how physicians and hospitals perform on certain quality of care measures is increasingly common, but little is known about whether such disclosures have an impact on the quality of care delivered to patients. We analyzed fourteen publicly reported quality of ambulatory care measures from 2004 to 2009 for the Wisconsin Collaborative for Healthcare Quality, a voluntary consortium of physician groups. We also fielded a survey of the collaborative's members and analyzed Medicare billing data to independently compare members' performance to that of providers in the rest of Wisconsin, neighboring states, and the rest of the United States. We found that physician groups in the collaborative improved their performance during the study period on many measures, such as cholesterol control and breast cancer screening. Physician groups reported on the survey that publicly reported performance data motivated them to act on some, but not all, of the quality measures. Our study suggests that large group practices will engage in quality improvement efforts in response to public reporting, especially when comparative performance is displayed, as it was in this case on the collaborative's website. PMID- 23459734 TI - Strong social support services, such as transportation and help for caregivers, can lead to lower health care use and costs. AB - A growing evidence base suggests services that address social factors with an impact on health, such as transportation and caregiver support, must be integrated into new models of care if the Institute for Healthcare Improvement's Triple Aim is to be realized. We examined early evidence from seven innovative care models currently in use, each with strong social support services components. The evidence suggests that coordinated efforts to identify and meet the social needs of patients can lead to lower health care use and costs, and better outcomes for patients. For example, Senior Care Options--a Massachusetts program that coordinates the direct delivery of social support services for patients with chronic conditions and adults with disabilities--reported that hospital days per 1,000 members were just 55 percent of those generated by comparable patients not receiving the program's extended services. More research is required to determine which social service components yield desired outcomes for specific patient populations. Gaining these deeper insights and disseminating them widely offer the promise of considerable benefit for patients and the health care system as a whole. PMID- 23459736 TI - A survey analysis suggests that electronic health records will yield revenue gains for some practices and losses for many. AB - Health care providers remain uncertain about how they will fare financially if they adopt electronic health record (EHR) systems. We used survey data from forty nine community practices in a large EHR pilot, the Massachusetts eHealth Collaborative, to project five-year returns on investment. We found that the average physician would lose $43,743 over five years; just 27 percent of practices would have achieved a positive return on investment; and only an additional 14 percent of practices would have come out ahead had they received the $44,000 federal meaningful-use incentive. The largest difference between practices with a positive return on investment and those with a negative return was the extent to which they used their EHRs to increase revenue, primarily by seeing more patients per day or by improved billing that resulted in fewer rejected claims and more accurate coding. Almost half of the practices did not realize savings in paper medical records because they continued to keep records on paper. We conclude that current meaningful use incentives alone may not ensure that most practices, particularly smaller ones, achieve a positive return on investment from EHR adoption. Policies that provide additional support, such as expanding the regional extension center program, could help ensure that practices make the changes required to realize a positive return on investment from EHRs. PMID- 23459735 TI - Hospice enrollment saves money for Medicare and improves care quality across a number of different lengths-of-stay. AB - Despite its demonstrated potential to both improve quality of care and lower costs, the Medicare hospice benefit has been seen as producing savings only for patients enrolled 53-105 days before death. Using data from the Health and Retirement Study, 2002-08, and individual Medicare claims, and overcoming limitations of previous work, we found $2,561 in savings to Medicare for each patient enrolled in hospice 53-105 days before death, compared to a matched, nonhospice control. Even higher savings were seen, however, with more common, shorter enrollment periods: $2,650, $5,040, and $6,430 per patient enrolled 1-7, 8-14, and 15-30 days prior to death, respectively. Within all periods examined, hospice patients also had significantly lower rates of hospital service use and in-hospital death than matched controls. Instead of attempting to limit Medicare hospice participation, the Centers for Medicare and Medicaid Services should focus on ensuring the timely enrollment of qualified patients who desire the benefit. PMID- 23459737 TI - Insurance expansion in Massachusetts did not reduce access among previously insured Medicare patients. AB - Critics of Massachusetts's health reform, a model for the Affordable Care Act, have argued that insurance expansion probably had a negative spillover effect leading to worse outcomes among already insured patients, such as vulnerable Medicare patients. Using Medicare data from 2004 to 2009, we examined trends in preventable hospitalizations for conditions such as uncontrolled hypertension and diabetes--markers of access to effective primary care--in Massachusetts compared to control states. We found that after Massachusetts's health reform, preventable hospitalization rates for Medicare patients actually decreased more in Massachusetts than in control states (a reduction of 101 admissions per 100,000 patients per quarter compared to a reduction of 83 admissions). Therefore, we found no evidence that Massachusetts's insurance expansion had a deleterious spillover effect on preventable hospitalizations among the previously insured. Our findings should offer some reassurance that it is possible to expand access to uninsured Americans without negatively affecting important clinical outcomes for those who are already insured. PMID- 23459738 TI - An increase in the number of nurses with baccalaureate degrees is linked to lower rates of postsurgery mortality. AB - An Institute of Medicine report has called for registered nurses to achieve higher levels of education, but health care policy makers and others have limited evidence to support a substantial increase in the number of nurses with baccalaureate degrees. Using Pennsylvania nurse survey and patient discharge data from 1999 and 2006, we found that a ten-point increase in the percentage of nurses holding a baccalaureate degree in nursing within a hospital was associated with an average reduction of 2.12 deaths for every 1,000 patients--and for a subset of patients with complications, an average reduction of 7.47 deaths per 1,000 patients. We estimate that if all 134 hospitals in our study had increased the percentage of their nurses with baccalaureates by ten points during our study's time period, some 500 deaths among general, orthopedic, and vascular surgery patients might have been prevented. The findings provide support for efforts to increase the production and employment of baccalaureate nurses. PMID- 23459739 TI - Attributing patients to accountable care organizations: performance year approach aligns stakeholders' interests. AB - The accountable care organization (ACO) model of health care delivery is rapidly being implemented under government and private-sector initiatives. The model requires that each ACO have a defined patient population for which the ACO will be held accountable for both total cost of care and quality performance. However, there is no empirical evidence about the best way to define how patients are assigned to these groups of doctors, hospitals, and other health care providers. We examined the two major methods of defining, or attributing, patient populations to ACOs: the prospective method and the performance year method. The prospective method uses data from one year to assign patients to an ACO for the following performance year. The performance year method assigns patients to an ACO at the end of the performance year based on the population served during the performance year. We used Medicare fee-for-service claims data from 2008 and 2009 to simulate a set of ACOs to compare the two methods. Although both methods have benefits and drawbacks, we found that attributing patients using the performance year method yielded greater overlap of attributed patients and patients treated during the performance year and resulted in a higher proportion of care concentrated within an accountable care organization. Together, these results suggest that performance year attribution may more fully and accurately reflect an ACO's patient population and may better position an ACO to achieve shared savings. PMID- 23459740 TI - Prostate cancer screening in men ages 75 and older fell by 8 percentage points after Task Force recommendation. AB - In 2008 the US Preventive Services Task Force recommended against screening men ages 75 and older for prostate cancer. Using Medicare Current Beneficiary Survey Access to Care files and linked claims, we compared trends in prostate-specific antigen (PSA) testing rates between men ages 75 and older and men ages 65-74. We estimate that the revised recommendation led to a 7.9-percentage-point decline in annual PSA testing rates over two years among men ages 75 and older. Although 42 percent of men in this age group continue to receive PSA tests, our results highlight the potential of guidelines with negative recommendations to reduce the use of low-value medical care. PMID- 23459741 TI - How 'person-centered' care helped guide me toward recovery from mental illness. AB - A community psychiatry researcher reflects on the treatment she received in her youth for post-traumatic stress disorder and depression--and calls for more recovery-oriented care to be available nationwide. PMID- 23459742 TI - Making health information technology usable. PMID- 23459743 TI - Health information technology's problems. PMID- 23459744 TI - Health information technology: authors' reply. PMID- 23459745 TI - Treating alcohol and drug use disorders. PMID- 23459746 TI - Alcohol and drug use: the authors reply. PMID- 23459747 TI - The need to reduce unnecessary use. PMID- 23459748 TI - Infidelity, jealousy, and wife abuse among Tsimane forager-farmers: Testing evolutionary hypotheses of marital conflict. PMID- 23459749 TI - Electroconvulsive therapy response in major depressive disorder: a pilot functional network connectivity resting state FMRI investigation. AB - Major depressive disorder (MDD) is associated with increased functional connectivity in specific neural networks. Electroconvulsive therapy (ECT), the gold-standard treatment for acute, treatment-resistant MDD, but temporal dependencies between networks associated with ECT response have yet to be investigated. In the present longitudinal, case-control investigation, we used independent component analysis to identify distinct networks of brain regions with temporally coherent hemodynamic signal change and functional network connectivity (FNC) to assess component time course correlations across these networks. MDD subjects completed imaging and clinical assessments immediately prior to the ECT series and a minimum of 5 days after the last ECT treatment. We focused our analysis on four networks affected in MDD: the subcallosal cingulate gyrus, default mode, dorsal lateral prefrontal cortex, and dorsal medial prefrontal cortex (DMPFC). In an older sample of ECT subjects (n = 12) with MDD, remission associated with the ECT series reverses the relationship from negative to positive between the posterior default mode (p_DM) and two other networks: the DMPFC and left dorsal lateral prefrontal cortex (l_DLPFC). Relative to demographically healthy subjects (n = 12), the FNC between the p_DM areas and the DMPFC normalizes with ECT response. The FNC changes following treatment did not correlate with symptom improvement; however, a direct comparison between ECT remitters and non-remitters showed the pattern of increased FNC between the p_DM and l_DLPFC following ECT to be specific to those who responded to the treatment. The differences between ECT remitters and non-remitters suggest that this increased FNC between p_DM areas and the left dorsolateral prefrontal cortex is a neural correlate and potential biomarker of recovery from a depressed episode. PMID- 23459750 TI - Why critically ill patients are protein deprived. AB - Critical illness dramatically increases muscle proteolysis and more than doubles the dietary protein requirement. Yet surprisingly, most critically ill patients receive less than half the recommended amount of protein during their stay in a modern intensive care unit. What could explain the wide gap between the recommendations in clinical care guidelines and actual clinical practice? We suggest that an important aspect of the problem is the failure of guidelines to explain the pathophysiology of protein-energy malnutrition and the ways critical illness modifies protein metabolism. The difficulty created by the lack of a framework for reasoning about appropriate protein provision in critical illness is compounded by the many ambiguous and often contradictory ways the word malnutrition is used in the critical care literature. Failing to elucidate these matters, the recommendations for protein provision in the guidelines are incoherent, unconvincing, and easy to ignore. PMID- 23459751 TI - Direct in vivo imaging of essential bioinorganics in Caenorhabditis elegans. AB - Metals are essential in biochemistry, with highly regulated localisation and concentration. To continue elucidating the impact of inorganic physiology on cellular process in health and disease requires development of suitable eukaryotic models and experimental approaches. The multicellular organism Caenorhabditis elegans has been widely adopted as a model system and proved to be highly valuable in biomedical research, and here we record the distribution of physiologically important 4th row elements throughout anesthetised, hydrated adult C. elegans without the need for chemical fixation or mechanical sectioning. Probing the partitioning of elements between intact anatomical structures at subcellular length scales allowed the impact of preparation techniques commonly in use for analytical microanalysis to be assessed. In addition, taking advantage of C. elegans as a research tool, these studies were carried out across a cohort of genetically homogenous individuals with specific expression of green fluorescent protein within intestinal cells. These studies allowed direct visualisation of elemental co-localisation with anatomical structures and facilitated analysis of inter-animal variability in biometal abundance and localisation. These data reflect stochastic metabolic activity and confirm C. elegans as a sensitive system in which to explore the effects of altered metal homeostasis. PMID- 23459752 TI - Roux-en-Y gastric bypass reverses the effects of diet-induced obesity to inhibit the responsiveness of central vagal motoneurones. AB - Diet-induced obesity (DIO) has been shown to alter the biophysical properties and pharmacological responsiveness of vagal afferent neurones and fibres, although the effects of DIO on central vagal neurones or vagal efferent functions have never been investigated. The aims of this study were to investigate whether high fat diet-induced DIO also affects the properties of vagal efferent motoneurones, and to investigate whether these effects were reversed following weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Whole-cell patch-clamp recordings were made from rat dorsal motor nucleus of the vagus (DMV) neurones in thin brainstem slices. The DMV neurones from rats exposed to high-fat diet for 12 14 weeks were less excitable, with a decreased membrane input resistance and decreased ability to fire action potentials in response to direct current pulse injection. The DMV neurones were also less responsive to superfusion with the satiety neuropeptides cholecystokinin and glucagon-like peptide 1. Roux-en-Y gastric bypass reversed all of these DIO-induced effects. Diet-induced obesity also affected the morphological properties of DMV neurones, increasing their size and dendritic arborization; RYGB did not reverse these morphological alterations. Remarkably, independent of diet, RYGB also reversed age-related changes of membrane properties and occurrence of charybdotoxin-sensitive (BK) calcium dependent potassium current. These results demonstrate that DIO also affects the properties of central autonomic neurones by decreasing the membrane excitability and pharmacological responsiveness of central vagal motoneurones and that these changes were reversed following RYGB. In contrast, DIO-induced changes in morphological properties of DMV neurones were not reversed following gastric bypass surgery, suggesting that they may be due to diet, rather than obesity. These findings represent the first direct evidence for the plausible effect of RYGB to improve vagal neuronal health in the brain by reversing some effects of chronic high-fat diet as well as ageing. Vagovagal neurocircuits appear to remain open to modulation and adaptation throughout life, and understanding of these mechanisms may help in development of novel interventions to alleviate environmental (e.g. dietary) ailments and also alter neuronal ageing. PMID- 23459753 TI - Timing and distribution of protein ingestion during prolonged recovery from resistance exercise alters myofibrillar protein synthesis. AB - Quantity and timing of protein ingestion are major factors regulating myofibrillar protein synthesis (MPS). However, the effect of specific ingestion patterns on MPS throughout a 12 h period is unknown. We determined how different distributions of protein feeding during 12 h recovery after resistance exercise affects anabolic responses in skeletal muscle. Twenty-four healthy trained males were assigned to three groups (n = 8/group) and undertook a bout of resistance exercise followed by ingestion of 80 g of whey protein throughout 12 h recovery in one of the following protocols: 8 * 10 g every 1.5 h (PULSE); 4 * 20 g every 3 h (intermediate: INT); or 2 * 40 g every 6 h (BOLUS). Muscle biopsies were obtained at rest and after 1, 4, 6, 7 and 12 h post exercise. Resting and post exercise MPS (l-[ring-(13)C6] phenylalanine), and muscle mRNA abundance and cell signalling were assessed. All ingestion protocols increased MPS above rest throughout 1-12 h recovery (88-148%, P < 0.02), but INT elicited greater MPS than PULSE and BOLUS (31-48%, P < 0.02). In general signalling showed a BOLUS>INT>PULSE hierarchy in magnitude of phosphorylation. MuRF-1 and SLC38A2 mRNA were differentially expressed with BOLUS. In conclusion, 20 g of whey protein consumed every 3 h was superior to either PULSE or BOLUS feeding patterns for stimulating MPS throughout the day. This study provides novel information on the effect of modulating the distribution of protein intake on anabolic responses in skeletal muscle and has the potential to maximize outcomes of resistance training for attaining peak muscle mass. PMID- 23459754 TI - The evaporative requirement for heat balance determines whole-body sweat rate during exercise under conditions permitting full evaporation. AB - Although the requirements for heat dissipation during exercise are determined by the necessity for heat balance, few studies have considered them when examining sweat production and its potential modulators. Rather, the majority of studies have used an experimental protocol based on a fixed percentage of maximum oxygen uptake (% ). Using multiple regression analysis, we examined the independent contribution of the evaporative requirement for heat balance (Ereq) and % to whole-body sweat rate (WBSR) during exercise. We hypothesised that WBSR would be determined by Ereq and not by % . A total of 23 males performed two separate experiments during which they exercised for 90 min at different rates of metabolic heat production (200, 350, 500 W) at a fixed air temperature (30 degrees C, n = 8), or at a fixed rate of metabolic heat production (290 W) at different air temperatures (30, 35, 40 degrees C, n = 15 and 45 degrees C, n = 7). Whole-body evaporative heat loss was measured by direct calorimetry and used to calculate absolute WBSR in grams per minute. The conditions employed resulted in a wide range of Ereq (131-487 W) and % (15-55%). The individual variation in non-steady-state (0-30 min) and steady-state (30-90 min) WBSR correlated significantly with Ereq (P < 0.001). In contrast, % correlated negatively with the residual variation in WBSR not explained by Ereq, and marginally increased (~2%) the amount of total variability in WBSR described by Ereq alone (non-steady state: R(2) = 0.885; steady state: R(2) = 0.930). These data provide clear evidence that absolute WBSR during exercise is determined by Ereq, not by % . Future studies should therefore use an experimental protocol which ensures a fixed Ereq when examining absolute WBSR between individuals, irrespective of potential differences in relative exercise intensity. PMID- 23459755 TI - Physiological and morphological properties of Dbx1-derived respiratory neurons in the pre-Botzinger complex of neonatal mice. AB - Breathing in mammals depends on an inspiratory-related rhythm that is generated by glutamatergic neurons in the pre-Botzinger complex (preBotC) of the lower brainstem. A substantial subset of putative rhythm-generating preBotC neurons derive from a single genetic line that expresses the transcription factor Dbx1, but the cellular mechanisms of rhythmogenesis remain incompletely understood. To elucidate these mechanisms, we carried out a comparative analysis of Dbx1 expressing neurons (Dbx1(+)) and non-Dbx1-derived (Dbx1(-)) neurons in the preBotC. Whole-cell recordings in rhythmically active newborn mouse slice preparations showed that Dbx1(+) neurons activate earlier in the respiratory cycle and discharge greater magnitude inspiratory bursts compared with Dbx1(-) neurons. Furthermore, Dbx1(+) neurons required less input current to discharge spikes (rheobase) in the context of network activity. The expression of intrinsic membrane properties indicative of A-current (IA) and hyperpolarization-activated current (Ih) tended to be mutually exclusive in Dbx1(+) neurons. In contrast, there was no such relationship in the expression of currents IA and Ih in Dbx1(-) neurons. Confocal imaging and digital morphological reconstruction of recorded neurons revealed dendritic spines on Dbx1(-) neurons, but Dbx1(+) neurons were spineless. The morphology of Dbx1(+) neurons was largely confined to the transverse plane, whereas Dbx1(-) neurons projected dendrites to a greater extent in the parasagittal plane. The putative rhythmogenic nature of Dbx1(+) neurons may be attributable, in part, to a higher level of intrinsic excitability in the context of network synaptic activity. Furthermore, Dbx1(+) neuronal morphology may facilitate temporal summation and integration of local synaptic inputs from other Dbx1(+) neurons, taking place largely in the dendrites, which could be important for initiating and maintaining bursts and synchronizing activity during the inspiratory phase. PMID- 23459756 TI - Complete blockade of the vasorelaxant effects of angiotensin-(1-7) and bradykinin in murine microvessels by antagonists of the receptor Mas. AB - The heptapeptide angiotensin-(1-7) is a biologically active metabolite of angiotensin II, the predominant peptide of the renin-angiotensin system. Recently, we have shown that the receptor Mas is associated with angiotensin-(1 7)-induced signalling and mediates, at least in part, the vasodilatory properties of angiotensin-(1-7). However, it remained controversial whether an additional receptor could account for angiotensin-(1-7)-induced vasorelaxation. Here, we used two different angiotensin-(1-7) antagonists, A779 and d-Pro-angiotensin-(1 7), to address this question and also to study their influence on the vasodilatation induced by bradykinin. Isolated mesenteric microvessels from both wild-type and Mas-deficient C57Bl/6 mice were precontracted with noradrenaline, and vascular reactivity to angiotensin-(1-7) and bradykinin was subsequently studied using a small-vessel myograph. Furthermore, mechanisms for Mas effects were investigated in primary human umbilical vein endothelial cells. Both angiotensin-(1-7) and bradykinin triggered a concentration-dependent vasodilatation in wild-type microvessels, which was absent in the presence of a nitric oxide synthase inhibitor. In these vessels, the pre-incubation with the Mas antagonists A779 or d-Pro-angiotensin-(1-7) totally abolished the vasodilatory capacity of both angiotensin-(1-7) and bradykinin, which was nitric oxide mediated. Accordingly, Mas-deficient microvessels lacked the capacity to relax in response to either angiotensin-(1-7) or bradykinin. Pre-incubation of human umbilical vein endothelial cells with A779 prevented bradykinin-mediated NO generation and NO synthase phosphorylation at serine 1177. The angiotensin-(1-7) antagonists A779 and d-Pro-angiotensin-(1-7) equally block Mas, which completely controls the angiotensin-(1-7)-induced vasodilatation in mesenteric microvessels. Importantly, Mas also appears to be a critical player in NO-mediated vasodilatation induced by renin-angiotensin system-independent agonists by altering phosphorylation of NO synthase. PMID- 23459757 TI - Single Ca2+ channels and exocytosis at sensory synapses. AB - Hair cell synapses in the ear and photoreceptor synapses in the eye are the first synapses in the auditory and visual system. These specialized synapses transmit a large amount of sensory information in a fast and efficient manner. Moreover, both small and large signals with widely variable kinetics must be quickly encoded and reliably transmitted to allow an animal to rapidly monitor and react to its environment. Here we briefly review some aspects of these primary synapses, which are characterized by a synaptic ribbon in their active zones of transmitter release. We propose that these synapses are themselves highly specialized for the task at hand. Photoreceptor and bipolar cell ribbon synapses in the retina appear to have versatile properties that permit both tonic and phasic transmitter release. This allows them to transmit changes of both luminance and contrast within a visual field at different ambient light levels. By contrast, hair cell ribbon synapses are specialized for a highly synchronous form of multivesicular release that may be critical for phase locking to low frequency sound-evoked signals at both low and high sound intensities. The microarchitecture of a hair cell synapse may be such that the opening of a single Ca(2+) channel evokes the simultaneous exocytosis of multiple synaptic vesicles. Thus, the differing demands of sensory encoding in the eye and ear generate diverse designs and capabilities for their ribbon synapses. PMID- 23459758 TI - Sensing hypoxia: physiology, genetics and epigenetics. AB - The carotid body is a sensory organ for detecting arterial blood O2 levels and reflexly mediates systemic cardiac, vascular and respiratory responses to hypoxia. This article presents a brief review of the roles of gaseous messengers in the sensory transduction at the carotid body, genetic and epigenetic influences on hypoxic sensing and the role of the carotid body chemoreflex in cardiorespiratory diseases. Type I (also called glomus) cells, the site of O2 sensing in the carotid body, express haem oxygenase-2 and cystathionine-gamma lyase, the enzymes which catalyse the generation of CO and H2S, respectively. Physiological studies have shown that CO is an inhibitory gas messenger, which contributes to the low sensory activity during normoxia, whereas H2S is excitatory and mediates sensory stimulation by hypoxia. Hypoxia-evoked H2S generation in the carotid body requires the interaction of cystathionine-gamma lyase with haem oxygenase-2, which generates CO. Hypoxia-inducible factors 1 and 2 constitute important components of the genetic make-up in the carotid body, which influence hypoxic sensing by regulating the intracellular redox state via transcriptional regulation of pro- and antioxidant enzymes. Recent studies suggest that developmental programming of the carotid body response to hypoxia involves epigenetic changes, e.g. DNA methylation of genes encoding redox regulating enzymes. Emerging evidence implicates heightened carotid body chemoreflex in the progression of autonomic morbidities associated with cardiorespiratory diseases, such as sleep-disordered breathing with apnoea, congestive heart failure and essential hypertension. PMID- 23459759 TI - Hormone replacement therapy improves contractile function and myonuclear organization of single muscle fibres from postmenopausal monozygotic female twin pairs. AB - Ageing is associated with a decline in muscle mass and strength leading to increased physical dependency in old age. Postmenopausal women experience a greater decline than men of similar age in parallel with the decrease in female sex steroid hormone production. We recruited six monozygous female twin pairs (55 59 years old) where only one twin pair was on hormone replacement therapy (HRT use = 7.8 +/- 4.3 years) to investigate the association of HRT with the cytoplasmic volume supported by individual myonuclei (myonuclear domain (MND) size,) together with specific force at the single fibre level. HRT use was associated with a significantly smaller (~27%; P < 0.05) mean MND size in muscle fibres expressing the type I but not the IIa myosin heavy chain (MyHC) isoform. In comparison to non-users, higher specific force was recorded in HRT users both in muscle fibres expressing type I (~27%; P < 0.05) and type IIa (~23%; P < 0.05) MyHC isoforms. These differences were fibre-type dependent, i.e. the higher specific force in fast-twitch muscle fibres was primarily caused by higher force per cross-bridge while slow-twitch fibres relied on both a higher number and force per cross-bridge. HRT use had no effect on fibre cross-sectional area (CSA), velocity of unloaded shortening (V0) and relative proportion of MyHC isoforms. In conclusion, HRT appears to have significant positive effects on both regulation of muscle contraction and myonuclei organization in postmenopausal women. PMID- 23459760 TI - Only one isoform of Drosophila melanogaster CTP synthase forms the cytoophidium. AB - CTP synthase is an essential enzyme that plays a key role in energy metabolism. Several independent studies have demonstrated that CTP synthase can form an evolutionarily conserved subcellular structure termed cytoophidium. In budding yeast, there are two isoforms of CTP synthase and both isoforms localize in cytoophidium. However, little is known about the distribution of CTP synthase isoforms in Drosophila melanogaster. Here, we report that three transcripts generated at the CTP synthase gene locus exhibit different expression profiles, and three isoforms encoded by this gene locus show a distinct subcellular distribution. While isoform A localizes in the nucleus, isoform B distributes diffusely in the cytoplasm, and only isoform C forms the cytoophidium. In the two isoform C-specific mutants, cytoophidia disappear in the germline cells. Although isoform A does not localize to the cytoophidium, a mutation disrupting mostly isoform A expression results in the disassembly of cytoophidia. Overexpression of isoform C can induce the growth of the cytoophidium in a cell-autonomous manner. Ectopic expression of the cytoophidium-forming isoform does not cause any defect in the embryos. In addition, we identify that a small segment at the amino terminus of isoform C is necessary but not sufficient for cytoophidium formation. Finally, we demonstrate that an excess of the synthetase domain of CTP synthase disrupts cytoophidium formation. Thus, the study of multiple isoforms of CTP synthase in Drosophila provides a good opportunity to dissect the biogenesis and function of the cytoophidum in a genetically tractable organism. PMID- 23459761 TI - Thymic function recovery after unrelated donor cord blood or T-cell depleted HLA haploidentical stem cell transplantation correlates with leukemia relapse. AB - Use of alternative donors/sources of hematopoietic stem cells (HSC), such as cord blood (CB) or HLA-haploidentical (Haplo)-related donors, is associated with a significant delay in immune reconstitution after transplantation. Long-term T cell immune reconstitution largely relies on the generation of new T cells in the recipient thymus, which can be evaluated through signal joint (sj) and beta T cell-Receptor Excision Circles (TREC) quantification. We studied two groups of 33 and 24 children receiving, respectively, HSC Transplantation (HSCT) from an HLA haploidentical family donor or an unrelated CB donor, for both malignant (46) and non-malignant disorders (11). Relative and absolute sj and beta-TREC values indicated comparable thymic function reconstitution at 3 and 6 months after the allograft in both groups. Compared to children with non-malignant disorders, those with hematological malignancies had significantly lower pre-transplantation TREC counts. Patients who relapsed after HSCT had a significantly less efficient thymic function both before and 6 months after HSCT with especially low beta-TREC values, this finding suggesting an impact of early intra-thymic T-cell differentiation on the occurrence of leukemia relapse. PMID- 23459763 TI - Assemblies of Functional Peptides and Their Applications in Building Blocks for Biosensors. AB - We highlight our recent applications of functional peptide nanotubes, self assembled from short peptides with recognition elements, as building blocks to develop sensors. Peptide nanotubes with high aspect ratios are excellent building blocks for directed assembly into device configurations, and their combining structures with the nanometric diameters and the micrometric lengths enables to bridge the nano-world and the micro-world. PMID- 23459764 TI - Multilayer lectin-glyconanoparticles architectures for QCM enhanced detection of sugar-protein interaction. AB - Multivalent biorecognition of lectin layers by glyconanoparticle sugar-clusters has been used to generate multilayer nanoplatform architectures in a QCM sensing setup. PMID- 23459766 TI - What's to blame for falls and fractures? Poor sleep or the sleeping medication?: Comment on "Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents". PMID- 23459765 TI - Effects of PPP1R1B (DARPP-32) Polymorphism on Feedback-Related Brain Potentials Across the Life Span. AB - Maximizing gains during probabilistic reinforcement learning requires the updating of choice - outcome expectations at the time when the feedback about a specific choice or action is given. Extant theories and evidence suggest that dopaminergic modulation plays a crucial role in reinforcement learning and the updating of choice - outcome expectations. Furthermore, recently a positive component of the event-related potential about 200 ms (P2) after feedback has been suggested to reflect such updating. The efficacy of dopaminergic modulation changes across the life span. However, to date investigations of age-related differences in feedback-related P2 during reinforcement learning are still scarce. The present study thus aims to investigate whether individual differences in the feedback-related P2 would be associated with polymorphic variations in a dopamine relevant gene PPP1R1B (also known as DARPP-32) and whether the genetic effect may differ between age groups. We observed larger P2 amplitudes in individuals carrying the genotype associated with higher dopamine receptor efficacy, i.e., a allele homozygotes of a single nucleotide polymorphism (rs907094) of the PPP1R1B gene. Moreover, this effect was more pronounced in children and older adults in comparison to adolescents and younger adults. Together, our findings indicate that polymorphic variations in a dopamine relevant gene are associated with individual differences in brain-evoked potentials of outcome updating and hint at the possibility that genotype effects on neurocognitive phenotypes may vary as a function of brain maturation and aging. PMID- 23459767 TI - [Competence in biocentric ethics.] AB - ResumenEste articulo explora el origen y la conceptualizacion de la bioetica en tanto etica biocentrica, definida por el pionero Fritz Jahr como un imperativo hipotetico que llama a respetar la vida en todas sus formas. Tras describirla como proceso social, procedimiento tecnico y producto academico, se enumeran y comentan algunas competencias que debieran presidir el empleo del discurso bioetico en cualquier punto del complejo social "investigacion medica": miembros de comites de etica de investigacion, investigadores, empresarios, administradores. Cada uno de estos grupos, en su "cultura epistemica" propia, define y explicita los principios basicos en tanto expresion de valores y leyes generales. PMID- 23459769 TI - Evaluation of mechanical properties of five cements for orthodontic band cementation. AB - The aim of this in vitro study was to compare the flexural, compressive and diametral tensile strengths of five cements used in orthodontics for band cementation. Twelve specimens of each cement were tested: 1 - GC Fuji Ortho Band (FJ), GC America Inc.; 2 - Meron (MR), Voco; 3 - Multi-Cure Glass Ionomer Band Cement (MC), 3M Unitek; 4 - Band-Lok (BL), Reliance Orthodontic Products; and 5 - Ketac Cem (KC), 3M ESPE. The results (mean) for diametral tensile strength were: 10.51 MPa (FJ), 9.60 MPa (MR), 20.04 MPa (MC), 42.80 MPa (BL), and 4.08 MPa (KC). The results for compressive strength were (in the same order): 64.50 MPa, 77.71 MPa, 94.21 MPa, 193.88 MPa, and 81.93 MPa. The results for flexural strength were (in the same order): 20.72 MPa, 25.84 MPa, 53.41 MPa, 137.41 MPa, and 20.50 MPa. The statistical analysis was performed by two-way ANOVA and Tukey tests with p value L 0.05. In terms of diametral tensile strength, BL showed the highest strength statistically, and MC, the second highest. In terms of compressive tensile strength, BL showed the highest strength statistically, and FJ did not attain the minimum recommended strength. In terms of flexural tensile strength, BL cement was superior to MC, and MR, FJ and KC were equivalent and inferior to BL and MC. PMID- 23459768 TI - Colorectal cancer screening in an equal access healthcare system. AB - INTRODUCTION: The military health system (MHS) a unique setting to analyze implementation programs as well as outcomes for colorectal cancer (CRC). Here we look at the efficacy of different CRC screening methods, attributes and results within the MHS, and current barriers to increase compliance. MATERIALS AND METHODS: A literature search was conducted utilizing PubMed and the Cochrane library. Key-word combinations included colorectal cancer screening, racial disparity, risk factors, colorectal cancer, screening modalities, and randomized control trials. Directed searches were also performed of embedded references. RESULTS: Despite screening guidelines from several national organizations, extensive barriers to widespread screening remain, especially for minority populations. These barriers are diverse, ranging from education and access problems to personal beliefs. Screening rates in MHS have been reported to be generally higher at 71% compared to national averages of 50-65%. CONCLUSION: CRC screening can be highly effective at improving detection of both pre-malignant and early cancers. Improved patient education and directed efforts are needed to improve CRC screening both nationally and within the MHS. PMID- 23459770 TI - Influence of photo-activation source on enamel demineralization around restorative materials. AB - This study evaluated the effects of the photoactivation source and restorative material on the development of caries-like lesions on human enamel after an in vitro pH challenge. Enamel cavities were prepared in 36 blocks, which were assigned to two groups according to the restorative material: resin-modified glass ionomer (RMGI) and composite resin (CR). Samples were exposed to quartz tungsten-halogen lamp, argon-ion laser, or light-emitting diode (n = 6). The Knoop microhardness (KHN) values of the top surface of all materials were evaluated. Restored enamel blocks were thermocycled and subjected to 10 demineralization-remineralization cycles at 37 degrees C. KHN analysis of the superficial enamel was performed by four indentations located 100 MUm from the restoration margin. The material KHN was not affected by the photoactivation source. No significant difference in KHN was noted between CR and RMGI. The enamel surface around RMGI exhibited a higher KHN (272.8 KHN) than the enamel around CR (93.3 KHN), regardless of the photoactivation source. Enamel demineralization around the dental restoration was not influenced by the photoactivation source. Less enamel demineralization was observed around the RMGI than around the CR restoration. PMID- 23459771 TI - Quality of life and general health in patients with temporomandibular disorders. AB - The aim of this study was to associate minor psychiatric disorders (general health) and quality of life with temporomandibular disorders (TMD) in patients diagnosed with different TMD classifications and subclassifications with varying levels of severity. Among 150 patients reporting TMD symptoms, 43 were included in the present study. Fonseca's anamnestic index was used for initial screening while axis I of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC-TMD) was used for TMD diagnosis (muscle-related, joint-related or muscle and joint-related). Minor psychiatric disorders were evaluated through the General Health Questionnaire (GHQ) and quality of life was assessed using the World Health Organization Quality Of Life-Brief Version (WHOQOL-BREF). An association was found between minor psychiatric disorders and TMD severity, except for stress. A stronger association was found with mild TMD. Considering TMD classifications and severity together, only the item "death wish" from the GHQ was related to severe muscle-related TMD (p = 0.049). For quality of life, an association was found between disc displacement with reduction and social domain (p = 0.01). Physical domains were associated with TMD classifications and severity and the association was stronger for muscle and joint-related TMD (p = 0.37) and mild TMD (p = 0.042). It was concluded that patients with TMD require multiple focuses of attention since psychological indicators of general health and quality of life are likely associated with dysfunction. PMID- 23459772 TI - Agreement between parents and adolescents on dental fluorosis: a population-based study. AB - This study evaluated the prevalence and severity of dental fluorosis and compared the reports from adolescents aged 12 to 18 years with those of their parents regarding the perceptions and concerns arising from this disease. The study was conducted in the cities of Vicosa and Sobral and the District of Rafael Arruda (Sobral), Ceara. A cross-sectional study was conducted from October 2010 to March 2011, with 891 students examined and 780 parents or guardians interviewed. Dental fluorosis was measured using the Dean's Index, and the Child's and Parent's Questionnaire about Teeth Appearance was used to assess the reports from parents and adolescents. A chi-squared test for trends was used to compare the opinions of parents and adolescents about fluorosis, and the agreement was measured using the weighted kappa. For the dichotomous variables, we used the unweighted kappa coefficient. The prevalence of fluorosis was 29.7%, but in the District of Rafael Arruda, evidence of very mild and mild fluorosis was found in 32.5% of the subjects, and moderate and severe fluorosis was found in 28.7%. There was poor agreement between the data reported by the adolescents and their parents or guardians regarding areas of concern and their perceived satisfaction with the appearance and color of their teeth. The prevalence of dental fluorosis was high in one of the communities studied, but the clinical diagnosis of this condition should not necessarily equate with concern and dissatisfaction with aesthetic appearances among teenagers and their parents. PMID- 23459773 TI - Effects of cement-curing mode and light-curing unit on the bond durability of ceramic cemented to dentin. AB - The aim of this study was to evaluate the effects of different light-curing units and resin cement curing types on the bond durability of a feldspathic ceramic bonded to dentin. The crowns of 40 human molars were sectioned, exposing the dentin. Forty ceramic blocks of VITA VM7 were produced according to the manufacturer's recommendations. The ceramic surface was etched with 10% hydrofluoric acid / 60s and silanized. The dentin was treated with 37% phosphoric acid / 15s, and the adhesive was applied. The ceramic blocks were divided and cemented to dentin according to resin cement / RC curing type (dual- and photo cured), light-curing unit (halogen light / QTH and LED), and storage conditions (dry and storage / 150 days + 12,000 cycles / thermocycling). All blocks were stored in distilled water (37 degrees C / 24h) and sectioned (n = 10): G1 - QTH + RC Photo, G2 - QTH + RC Dual, G3 - LED + RC Photo, G4 - LED + RC Dual. Groups G5, G6, G7, and G8 were obtained exactly as G1 through G4, respectively, and then stored and thermocycled. Microtensile bond strength tests were performed (EMIC), and data were statistically analyzed by ANOVA and Tukey's test (5%). The bond strength values (MPa) were: G1 - 12.95 (6.40)ab; G2 - 12.02 (4.59)ab; G3 - 13.09 (5.62)ab; G4 - 15.96 (6.32)a; G5 - 6.22 (5.90)c; G6 - 9.48 (5.99)bc; G7 - 12.78 (11.30)ab; and G8 - 8.34 (5.98)bc. The same superscript letters indicate no significant differences. Different light-curing units affected the bond strength between ceramic cemented to dentin when the photo-cured cement was used, and only after aging (LED > QTH). There was no difference between the effects of dual- and photo-cured resin-luting agents on the microtensile bond strength of the cement used in this study. PMID- 23459774 TI - Silorane- and high filled-based "low-shrinkage" resin composites: shrinkage, flexural strength and modulus. AB - This study compared the volumetric shrinkage (VS), flexural strength (FS) and flexural modulus (FM) properties of the low-shrinkage resin composite Aelite LS (Bisco) to those of Filtek LS (3M ESPE) and two regular dimethacrylate-based resin composites, the microfilled Heliomolar (Ivoclar Vivadent) and the microhybrid Aelite Universal (Bisco). The composites (n = 5) were placed on the Teflon pedestal of a video-imaging device, and VS was recorded every minute for 5 min after 40 s of light exposure. For the FS and FM tests, resin discs (0.6 mm in thickness and 6.0 mm in diameter) were obtained (n = 12) and submitted to a piston-ring biaxial test in a universal testing machine. VS, FS, and FM data were submitted to two-way repeated measures and one-way ANOVA, respectively, followed by Tukey's post-hoc test (a = 5%). Filtek LS showed lower VS than did Aelite LS, which in turn showed lower shrinkage than did the other composites. Aelite Universal and Filtek LS exhibited higher FS than did Heliomolar and Aelite LS, both of which exhibited the highest FM. No significant difference in FM was noted between Filtek LS and Aelite Universal, while Heliomolar exhibited the lowest values. Aelite LS was not as effective as Filtek LS regarding shrinkage, although both low-shrinkage composites showed lower VS than did the other composites. Only Filtek LS exhibited FS and FM comparable to those of the regular microhybrid dimethacrylate-based resin composite. PMID- 23459775 TI - Assessment of open source software for CBCT in detecting additional mental foramina. AB - The purpose of this study was to evaluate which post-processing imaging protocol would be better to analyze the additional mental foramen (AMF) in preoperative planning with cone-beam computed tomography (CBCT) exams, and to test reproducibility of measurements, using open source software (OsiriX). The software was used to detect the cases of AMF from among 58 exams for dental implant planning in edentulous mandible areas-three cases were found. The case images were submitted to qualitative analysis using 2D orthogonal MPR, 3D-MPR and 3D volume rendering protocols by two oral and maxillofacial radiologists. Quantitative analysis used the 3D-MPR protocol; the closed polygon tool measured the mental foramen (MF) and the AMF areas; the length tool measured the distance between foramina. The measurements were performed independently by the examiners, at two different times. Intra- and interexaminer agreement was assessed using the intraclass correlation coefficient. The panoramic view did not show the MF and the AMF clearly. The AMF could be detected in the parasagittal view. 2D Orthogonal MPR was effective to observe the AMF in some cases. The 3D-MPR and 3D view protocols were the most effective to locate and analyze the AMF. In conclusion, a 3D view improves visualization when anatomical points are not clearly visible. 3D-MPR was considered a more effective post-processing imaging protocol to observe foramina relationships. The high reproducibility of measurements for anatomical MF variations was established using specific tools featured in open source software for CBCT. OsiriX is realistic and recommended for preoperative planning. PMID- 23459777 TI - Effects of preemptive analgesia with celecoxib or acetaminophen on postoperative pain relief following lower extremity orthopedic surgery. AB - BACKGROUND: Efficacy of preemptive analgesia with nonsteroidal antiinflammatory drugs (NSAIDs) in comparison with acetaminophen is controversial. The present study evaluates the preemptive analgesia efficacy of celecoxib and acetaminophen in comparison with placebo for postoperative pain relief in patients who underwent orthopedic surgery under general anesthesia. MATERIALS AND METHODS: NINETYPATIENTS ELIGIBLE FOR ELECTIVE DISTAL EXTREMITY SURGERY WERE CATEGORIZED IN THREE GROUPS: group C includedpatients who received oral celecoxib 200 mg 2 h before surgery; group A included those who received oral acetaminophen 320 mg 2 h before surgery; and group P included those who received oral placebo 2 h before surgery. Pain scores were recorded at 4, 12, and 24 h after operation. RESULTS: The pain scores 4 h after operation was significantly less in group C than in groups A and P (4.7+/-1.7 vs. 5+/-1.5 vs. 6.8+/-1.7, respectively, P = 0.015). No significant difference was noted in pain scores at 12 h (4.6+/-2, 4.9+/-1.9, 4.3+/-1.4 in group A, group C, group P, respectively P > 0.05) and 24 h (3.1+/ 1.7, 3.0+/-1.4, 3.3+/-1.7 in group A, group C, group P, respectively, P > 0.05) after operation among the three groups. CONCLUSION: Using oral celecoxib 200 mg 2 h before operation is better thanusing oral acetaminophen 320 mg 2 h before the beginning of surgery for control of postoperative pain in patients who underwent lower extremity orthopedic surgery under general anesthesia. PMID- 23459779 TI - [Extensive pneumatization of the posterior skull]. AB - Hyperpneumatization of the craniocervical bones is a very rare disorder and there are only assumptions as to the cause of this potentially dangerous condition. This article reports the case of a 44-year-old patient with severe pneumatization who became symptomatic after a minor skiing accident without any direct trauma. PMID- 23459778 TI - Caffeine-Induced Global Reductions in Resting-State BOLD Connectivity Reflect Widespread Decreases in MEG Connectivity. AB - In resting-state functional magnetic resonance imaging (fMRI), the temporal correlation between spontaneous fluctuations of the blood oxygenation level dependent (BOLD) signal from different brain regions is used to assess functional connectivity. However, because the BOLD signal is an indirect measure of neuronal activity, its complex hemodynamic nature can complicate the interpretation of differences in connectivity that are observed across conditions or subjects. For example, prior studies have shown that caffeine leads to widespread reductions in BOLD connectivity but were not able to determine if neural or vascular factors were primarily responsible for the observed decrease. In this study, we used source-localized magnetoencephalography (MEG) in conjunction with fMRI to further examine the origins of the caffeine-induced changes in BOLD connectivity. We observed widespread and significant (p < 0.01) reductions in both MEG and fMRI connectivity measures, suggesting that decreases in the connectivity of resting state neuro-electric power fluctuations were primarily responsible for the observed BOLD connectivity changes. The MEG connectivity decreases were most pronounced in the beta band. By demonstrating the similarity in MEG and fMRI based connectivity changes, these results provide evidence for the neural basis of resting-state fMRI networks and further support the potential of MEG as a tool to characterize resting-state connectivity. PMID- 23459780 TI - Anesthetic experience using total intravenous anesthesia in a patient with Isaacs' syndrome -A case report-. AB - We report on an anesthetic experience with a 74-year-old female with Isaacs' syndrome, who underwent elective surgery for open rotator cuff repair. Isaacs' syndrome is a rare peripheral motor neuron disorder with clinical manifestations such as involuntary muscle twitching, cramps, mild weakness and increased sweating. To avoid prolonged neuromuscular blockade, the patient was observed with neuromuscular monitoring during total intravenous anesthesia with propofol, remifentanil, and atracurium. No adverse events were observed during the anesthetic management, and the patient recovered smoothly from the neuromuscular blockade. We describe the clinical characteristics of Isaacs' syndrome and its specific considerations in anesthesia. PMID- 23459781 TI - The FoodCast research image database (FRIDa). AB - In recent years we have witnessed an increasing interest in food processing and eating behaviors. This is probably due to several reasons. The biological relevance of food choices, the complexity of the food-rich environment in which we presently live (making food-intake regulation difficult), and the increasing health care cost due to illness associated with food (food hazards, food contamination, and aberrant food-intake). Despite the importance of the issues and the relevance of this research, comprehensive and validated databases of stimuli are rather limited, outdated, or not available for non-commercial purposes to independent researchers who aim at developing their own research program. The FoodCast Research Image Database (FRIDa) we present here includes 877 images belonging to eight different categories: natural-food (e.g., strawberry), transformed-food (e.g., french fries), rotten-food (e.g., moldy banana), natural-non-food items (e.g., pinecone), artificial food-related objects (e.g., teacup), artificial objects (e.g., guitar), animals (e.g., camel), and scenes (e.g., airport). FRIDa has been validated on a sample of healthy participants (N = 73) on standard variables (e.g., valence, familiarity, etc.) as well as on other variables specifically related to food items (e.g., perceived calorie content); it also includes data on the visual features of the stimuli (e.g., brightness, high frequency power, etc.). FRIDa is a well-controlled, flexible, validated, and freely available (http://foodcast.sissa.it/neuroscience/) tool for researchers in a wide range of academic fields and industry. PMID- 23459782 TI - Visualizing nanoparticle mobility in liquid at atomic resolution. AB - Gold nanorods are widely known for their photothermal properties to treat solid tumors. Our work demonstrates the unrealized capacity to image these reagents in liquid at high resolution using Transmission Electron Microscopy (TEM). Here we perform the first atomic measurements of functionalized nanorods in solution while visualizing their dynamic behaviour with TEM. PMID- 23459783 TI - Dysphagia and respiratory care in individuals with tetraplegia: incidence, associated factors, and preventable complications. AB - Dysphagia occurs in a significant number of individuals with spinal cord injury (SCI) presenting to acute care and inpatient rehabilitation. This prospective study has found dysphagia in nearly 40% of individuals with tetraplegia. Tracheostomy, mechanical ventilation, nasogastric tube, and age are significant risk factors. The detrimental complications of dysphagia in SCI can cause significant morbidity and delays in rehabilitation. Thus, early and accurate diagnosis of dysphagia is imperative to reduce the risk of developing life threatening complications. Incidence and risk factors of dysphagia and the use of the bedside swallow evaluation (BSE) and videofluoroscopy swallow study (VFSS) to diagnose dysphagia are presented. The often underappreciated role of respiratory therapists, including assist cough, high tidal volume ventilation, and the use of Passy-Muir valve, in the care of individuals with SCI who have dysphagia is discussed. Improved secretion management and respiratory stabilization enable the individuals with dysphagia to be evaluated sooner and safely by a speech pathologist. Early evaluation and intervention could improve upon morbidity and delayed rehabilitation, thus improving overall clinical outcomes. PMID- 23459784 TI - Concepts and technologies for tracking bioactive compounds in natural product extracts: generation of libraries, and hyphenation of analytical processes with bioassays. AB - Since the advent of high-throughput screening (HTS) in the early 1990s, a wealth of innovative technologies have been proposed and implemented for the effective localization and characterization of bioactive constituents in complex matrices. The latest developments in this field are reviewed under the perspective of their applicability to natural product-based drug discovery. The approaches discussed here include TLC-based bioautography, HPLC-based assays with on-line, at-line and off-line detection, as well as affinity-based methods, such as frontal affinity chromatography, pulsed ultrafiltration mass spectrometry, imprinted polymers, and affinity capillary electrophoresis. Selected practical examples are given to illustrate the strengths and limitations of these approaches in contemporary natural product lead discovery. In addition, compatibility issues of natural product extracts and HTS are addressed, and selected protocols for the generation of high quality libraries are presented. PMID- 23459785 TI - [In situ lymphoma and other early stage malignant non-Hodgkin lymphomas]. AB - The increasing use of immunohistochemical and molecular investigations of lymphatic tissues results in more frequent detection of early lymphoid proliferations. These show some but not all features of malignant lymphomas without fulfilling the diagnostic criteria for the diagnosis of lymphoid malignancy. In addition to well-known premalignant B-cell proliferations, such as monoclonal gammopathy of unknown significance (MGUS) and monoclonal B-cell lymphocytosis (MBL), so-called in situ lymphomas have recently been described with minimal infiltrates of clonal B-cells in morphologically reactive lymphoid tissues which show the phenotypic and genetic features of specific B-cell lymphoma subtypes and often show a characteristic topographical distribution. This article addresses a group of clonal lymphoproliferations with usually localized disease and excellent clinical prognosis, such as pediatric follicular lymphoma and nodal marginal zone lymphoma. Another group of early lesions not addressed in this review are virally induced lymphoproliferations which represent a grey zone between purely reactive lesions and malignant lymphomas and may pose significant diagnostic as well as clinical problems. In this review diagnostic criteria for early or in situ lesions and their distinction from partial infiltration by malignant lymphoma are described. PMID- 23459786 TI - AngII-induced glomerular mesangial cell proliferation inhibited by losartan via changes in intracellular calcium ion concentration. AB - This study investigated the changes in intracellular [Ca(2+)](i) (intracellular calcium ion concentration) and TRPC6 (transient receptor potential channel 6) expression during angiotensin II (AngII)-induced glomerular mesangial cell (GMC) proliferation, as well as the inhibitory effect of losartan. GMC cultures were split into four groups treated for 24 h: Group N (blank control group), Group A (10(-7 )mol/L AngII), Group LT (10(-7 )mol/L AngII and 10(-5 )mol/L losartan), and Group Pred (10(-7 )mol/L AngII and 10(-5 )mol/L prednisone). GMCs proliferation was measured by the MTT and trypan blue assays. The distribution of TRPC6 was monitored by immunofluorescence, the expression of TRPC6 was detected by RT-PCR and Western blotting, and [Ca(2+)](i) was measured by laser scanning confocal microscopy. The results showed that the maximal proliferation of GMCs was induced by treatment with 10(-7 )mol/L AngII for 24 h. In Group A, the distribution of TRPC6 was not uniform in the cell membrane, there was increased accumulation of this protein within the cytoplasm, and the increased expression of TRPC6 and [Ca(2+)](i) was consistent with the proliferation of cells. In Group LT, losartan inhibited the proliferation of GMCs significantly, the levels of TRPC6 and [Ca(2+)](i) were diminished, and the distribution of TRPC6 was improved. Prednisone also significantly inhibited the proliferation of GMCs and had no effects on the expression of TRPC6 and [Ca(2+)](i) in Group Pred. These findings suggested that AngII could enhance the expression of TRPC6, increase [Ca(2+)](i,) and demonstrate a time-dose-response relationship with the proliferation of GMCs, while losartan reversed the effect of AngII on GMC proliferation. PMID- 23459787 TI - Aorto-hepatic bypass in liver transplantation in the MELD-era: outcomes after supraceliac and infrarenal bypasses. AB - PURPOSE: Poor arterial inflow during orthotopic liver transplantation (OLT) may necessitate arterial revascularisation using aorto-hepatic bypasses with supraceliac (SC) or infrarenal (IR) allografts. This study compared both techniques focusing on the patients' preoperative conditions, postoperative graft/organ function, complications and survival. METHODS: Fifteen out of 114 OLT patients underwent revascularisation (7 IR/8 SC) between 2005 and 2008 and were included in the study. The patients' records were reviewed retrospectively. RESULTS: IR patients presented with a higher BMI, received more male donor organs and their reperfusion sequence was predominately portal venous (SC: primary arterial). SC patients presented a significantly worse preoperative creatinine clearance and a trend towards a higher MELD score. The postoperative graft/organ function, morbidity and mortality did not differ between the groups despite a trend towards a worse survival in the SC group. A deteriorated preoperative creatinine clearance and higher MELD score negatively impacted the survival. Postoperative bleeding episodes and major re-interventions also affected the outcome. CONCLUSIONS: We found no evidence for superiority of either bypass technique in our OLT patients. The trend toward a worse survival in SC patients was most likely caused by the worse preoperative conditions of these patients and highlights the importance of the impact of the MELD score on the outcome after OLT. PMID- 23459788 TI - Liver injury following blunt abdominal trauma: a new mechanism-driven classification. AB - PURPOSES: The current classifications for blunt liver trauma focus only on the extent of liver injury. However, these scores are independent from the localization of liver injury and mechanism of trauma. METHODS: The type of liver injury after blunt abdominal trauma was newly classified as type A when it was along the falciform ligament with involvement of segments IVa/b, III, or II, and type B when there was involvement of segments V-VIII. With the use of a prospectively established database, the clinical, perioperative, and outcome data were analyzed regarding the trauma mechanism, as well as the radiological and intraoperative findings. RESULTS: In 64 patients, the type of liver injury following blunt abdominal trauma was clearly linked with the mechanism of trauma: type A injuries (n = 28) were associated with a frontal trauma, whereas type B injuries (n = 36) were found after complex trauma mechanisms. The demographic data, mortality, ICU stay, and hospital stay showed no significant differences between the two groups. Interestingly, all patients with type A ruptures required immediate surgical intervention, whereas six patients (16.7 %) with type B ruptures could be managed conservatively. CONCLUSIONS: This new classification for blunt traumatic hepatic injury is based on the localization of parenchymal disruption and correlates with the mechanism of trauma. The type of liver injury correlated with the necessity for surgical therapy. PMID- 23459790 TI - "Emotion": The History of a Keyword in Crisis. AB - The word "emotion" has named a psychological category and a subject for systematic enquiry only since the 19th century. Before then, relevant mental states were categorised variously as "appetites," "passions," "affections," or "sentiments." The word "emotion" has existed in English since the 17th century, originating as a translation of the French emotion, meaning a physical disturbance. It came into much wider use in 18th-century English, often to refer to mental experiences, becoming a fully fledged theoretical term in the following century, especially through the influence of two Scottish philosopher-physicians, Thomas Brown and Charles Bell. This article relates this intellectual and semantic history to contemporary debates about the usefulness and meaning of "emotion" as a scientific term. PMID- 23459789 TI - Impact of cardiac stem cell sheet transplantation on myocardial infarction. AB - PURPOSE: Myocardial infarction (MI) remains a major cause of mortality because of the limited regenerative capacity of the myocardium. Transplantation of somatic tissue-derived cells into the heart has been shown to enhance the endogenous healing process, but the magnitude of its therapeutic effects is dependent upon the cell-source or cell-delivery method. We investigated the therapeutic effects of C-Kit positive cardiac cell (CSC) cell-sheet transplantation therapy in a rat model of MI. METHODS AND RESULTS: CSCs of human origin were sorted and cultured to generate scaffold-free CSC cell-sheets. One-layered or 3-layered cell-sheets were transplanted into nude rats 1 h after left coronary artery ligation. We observed a significant increase in the left ventricular ejection fraction and a significant decrease in left ventricular systolic dimension at 2 and 4 weeks in the 3-layer group, but not in the 1-layer or sham groups. Consistently, there was less accumulation of interstitial fibrosis in the 3-layer group than in the 1 layer or sham groups. Moreover, capillary density was significantly greater in the 3-layer group than in the 1-layer or sham groups. CONCLUSIONS: The 3-layered cell-sheet improved cardiac function associated with angiogenic and anti-fibrotic effects. Thus, CSC is a promising cell-source to use with the cell-sheet method for the treatment of cardiac failure, as long as a sufficient number of cells are delivered. PMID- 23459791 TI - A novel hexanuclear silver(I) cluster containing a regular Ag6 ring with short Ag Ag distances and an argentophilic interaction. AB - The hexanuclear complex [HQ][Ag(p-mpspa)] (H2-p-mpspa = 3-(4-methoxyphenyl)-2 sulfanylpropenoic acid) was prepared by reacting the precursor [Ag(H-p-mpspa)] with diisopropylamine (Q). The complex was characterized by spectroscopic techniques and the structure was solved by a single crystal X-ray diffraction study. The crystal contains hydrogen-bonded diisopropylammonium cations and [Ag6(p-mpspa)6](6-) anions that are based on a regular Ag6 ring with each S-donor atom of the sulfanylcarboxylate ligand bridging two Ag atoms. The Ag-Ag bond distances, 2.8036(6) A, are very short and suggest a closed shell d(10)...d(10) argentophilic interaction. To analyze the relative role of this interaction and that of the S-bridging atom the anionic [Ag6(p-mpspa)6](6-) moiety has been studied theoretically at the Hartree-Fock (HF) and 2(nd) order Moller-Plesset perturbation theory (MP2) levels on a very simple [Ag6(SH)6] A model system. A large model system [Ag6(p-mpspa)6](6-)B has also been studied by applying the ONIOM (QM/MM) approach using HF/UFF and MP2/UFF combinations as levels of theory. The six experimentally observed Ag(I)...Ag(I) supported interactions are reproduced when dispersion-type interactions are considered in the theory levels MP2 and ONIOM MP2/UFF for models A and B, respectively. The use of HF and ONIOM HF/UFF levels led to a similar hexanuclear structure but displayed a large hexagonal disposition without argentophilic contacts for both models A and B. The steric hindrance exerted by the ligands did not preclude the formation of argentophilic interactions, as observed experimentally. PMID- 23459792 TI - Statins Protect the Blood Brain Barrier Acutely after Experimental Intracerebral Hemorrhage. AB - OBJECTIVES: The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). METHODS: Primary ICH was induced in 27 male Wistar rats by stereotactic injection of 100 uL of autologous blood into the striatum. Rats were divided into three groups (n= 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phosphate buffered saline daily starting 24-hours post-ICH and continuing daily for the next 3 days. On the fourth day, the animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blotting was performed. RESULTS: MRI data for animals receiving simvastatin treatment showed significantly reduced BBB dysfunction and improved CBF in the ICH rim compared to controls (P<0.05) 4 days after ICH. Simvastatin also significantly reduced edema (T2) in the rim at 4 days after ICH (P<0.05). Both statin-treated groups demonstrated increased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB function (P<0.05) and increased number of blood vessels (P<0.05). CONCLUSIONS: Simvastatin treatment administered acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by MRI measurement. PMID- 23459793 TI - Re: Lindstrom et al. veno-right ventricular cannulation reduces recirculation in extracorporeal membrane oxygenation. PMID- 23459794 TI - Bayesian Spatial Quantile Regression. AB - Tropospheric ozone is one of the six criteria pollutants regulated by the United States Environmental Protection Agency under the Clean Air Act and has been linked with several adverse health effects, including mortality. Due to the strong dependence on weather conditions, ozone may be sensitive to climate change and there is great interest in studying the potential effect of climate change on ozone, and how this change may affect public health. In this paper we develop a Bayesian spatial model to predict ozone under different meteorological conditions, and use this model to study spatial and temporal trends and to forecast ozone concentrations under different climate scenarios. We develop a spatial quantile regression model that does not assume normality and allows the covariates to affect the entire conditional distribution, rather than just the mean. The conditional distribution is allowed to vary from site-to-site and is smoothed with a spatial prior. For extremely large datasets our model is computationally infeasible, and we develop an approximate method. We apply the approximate version of our model to summer ozone from 1997-2005 in the Eastern U.S., and use deterministic climate models to project ozone under future climate conditions. Our analysis suggests that holding all other factors fixed, an increase in daily average temperature will lead to the largest increase in ozone in the Industrial Midwest and Northeast. PMID- 23459795 TI - Reversing gears: discontinuing medication therapy to prevent adverse events. PMID- 23459800 TI - Open access. PMID- 23459797 TI - Long-Term Non-Progression and Broad HIV-1-Specific Proliferative T-Cell Responses. AB - Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1(+) patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1(+) patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates. PMID- 23459801 TI - Against the tide: current perspectives in Brazilian drug policy. PMID- 23459799 TI - The Diagnostic and Prognostic Role of microRNA in Colorectal Cancer - a Comprehensive review. AB - The discovery of microRNA, a group of regulatory short RNA fragments, has added a new dimension to the diagnosis and management of neoplastic diseases. Differential expression of microRNA in a unique pattern in a wide range of tumor types enables researches to develop a microRNA-based assay for source identification of metastatic disease of unknown origin. This is just one example of many microRNA-based cancer diagnostic and prognostic assays in various phases of clinical research.Since colorectal cancer (CRC) is a phenotypic expression of multiple molecular pathways including chromosomal instability (CIN), micro satellite instability (MIS) and CpG islands promoter hypermethylation (CIMP), there is no one-unique pattern of microRNA expression expected in this disease and indeed, there are multiple reports published, describing different patterns of microRNA expression in CRC.The scope of this manuscript is to provide a comprehensive review of the scientific literature describing the dysregulation of and the potential role for microRNA in the management of CRC. A Pubmed search was conducted using the following MeSH terms, "microRNA" and "colorectal cancer". Of the 493 publications screened, there were 57 papers describing dysregulation of microRNA in CRC. PMID- 23459802 TI - Household food insecurity and excess weight/obesity among Brazilian women and children: a life-course approach. AB - Household food insecurity (HFI) may increase obesity risk, but results are not consistent across the life course or between developed/underdeveloped settings. The objective of this paper is to review findings from previous analyses in Brazil among adult women, female adolescents, and children up to five. Data were derived from the 2006 Brazilian Demographic and Health Survey. Associations between HFI (measured with the Brazilian Food Insecurity Scale) and excess weight/obesity were investigated through Poisson regression models. While severe HFI was associated with obesity risk among adult women (PR: 1.49; 95%CI: 1.17 1.90), moderate HFI was associated with excess weight among female adolescents (PR: 1.96; 95%CI: 1.18-3.27). There was no association between HFI and obesity among children (either boys or girls). The nutrition transition in Brazil may be shaping the differential deleterious effect of HFI on body fat accumulation across the life course; the association is already evident among female adolescents and adult women but still not among children. PMID- 23459803 TI - A life course approach yields breakthroughs in understanding food insecurity and obesity among Brazilian females. PMID- 23459804 TI - Confronting myths about household food insecurity and excess weight. PMID- 23459805 TI - Using a life course approach and a bio-cultural perspective to understand the food insecurity and obesity paradox. PMID- 23459806 TI - Conceptual and methodological reflections on the article by Schlussel et al. PMID- 23459807 TI - Food insecurity in countries with low development: new trends. PMID- 23459808 TI - Methodological reflections on food insecurity, nutritional status, and poverty. PMID- 23459809 TI - Obesity, poverty, and food insecurity in Brazilian males and females. PMID- 23459810 TI - The authors reply. PMID- 23459811 TI - Breastfeeding up to two years of age or beyond and its influence on child growth and development: a systematic review. AB - A systematic review was undertaken to identify studies describing the global prevalence of breastfeeding up to two years of age or beyond and its effects on child growth and development. The MEDLINE and LILACS databases were searched without any language or date restrictions, retrieving 3,561 titles. All retrieved titles, 453 abstracts and 49 full-text articles were read. Articles with maximum breastfeeding duration of over two years were included. An analysis was carried out of 19 articles that met the inclusion criteria resulting in a combined prevalence of breastfeeding at two years of age of 33 % (95%CI: 0.23; 0.42). Increasing trends towards breastfeeding up to two years of age or beyond were observed in the past decades in South Asia. The six studies analyzing the effects of breastfeeding up to two years of age or beyond on child growth showed contradictory results. No association was found with child development. It is concluded that evidence on the medium-term effects of breastfeeding up to two years of age or beyond is scarce and contradictory. Hence, further research is needed regarding this practice. PMID- 23459812 TI - Impact of vaccination on the incidence of measles in Mozambique in the period 2000 to 2011. AB - The aim of this study was to contribute to the better planning of measles elimination actions in Mozambique, by considering the impact of vaccination actions over the period 2000 to 2011. Descriptive and ecological studies and case records made available by the Ministry of Health were used to analyze measles vaccination coverage. Statistical analysis was performed using time series and spatial analysis. Vaccine coverage rates ranged from 82% to 99%. Coverage rates in Maputo city were under 70% and in Niassa province they were over 100%. Coverage showed a clustered pattern in the districts. The measles incidence rate was 1.58 per 100,000 inhabitants (0.00-40.08 per 100,000 inhabitants); districts bordering neighboring countries presented high incidence rates. Although measles morbidity and mortality has decreased in Mozambique, vaccine coverage has been insufficient to interrupt measles transmission. Enhanced surveillance, including investigation of cases and outbreaks, and improvements in measles vaccination are recommended in order to achieve a homogenous coverage rate of >= 95% for both routine and mass vaccination campaigns. PMID- 23459813 TI - [Prevalence of leisure-time physical activity and associated factors: a population-based study in Sao Paulo, Brazil, 2008-2009]. AB - The purpose of this study was to ascertain the prevalence of self-reported leisure-time physical activity and related factors in the city of Sao Paulo, Brazil, 2008-2009. A population- based cross-sectional study interviewed 2,691 individuals of both sexes, 12 years or older. A two-stage cluster (census tract, household) random sample provided data using home interviews in 2008 and 2009. Leisure-time physical activity was measured with IPAQ, long version. Complex sample-adjusted descriptive statistics provided prevalence estimates, chi-square tests screened associations, and prevalence ratios (PR) expressed effects. Multiple Poisson regression was used to ascertain adjusted effects, and design effects were calculated. Of the interviewees, 16.4% (95%CI: 14.3-18.7) reported leisure-time physical activity. The findings indicate the importance of encouraging leisure-time physical activity, which was associated with male sex, higher income, younger age (12 to 29 years), not smoking, and not reporting frequent fatigue. PMID- 23459814 TI - [Patient safety culture and related factors in a network of Spanish public hospitals]. AB - The objectives were to describe Patient Safety Culture (PSC) in a regional network of public hospitals, according to the perceptions of health professionals, and analyze the influence of socio-professional factors. A survey was conducted with 1,113 professionals from eight Spanish hospitals, using a questionnaire that explores 12 dimensions of PSC. Perceptions were described through the Percentage of Positive (PPR) and Negative Responses (PNR) by dimension, and the association of factors was analyzed using multivariate linear regression. The dimension "Teamwork within the same Unit" had the highest PPR (73.5), and "Staffing" the highest PNR (61). The variables "Service" (Pharmacy, Surgical Center) and "Profession" (Nurses) were significantly associated to positive assessments. Thus, strategies to improve PSC should prioritize rational distribution of human resources, and take advantage of the positive perceived relationship within Units. Moreover, pharmaceutical and surgical services, as well as nurses should probably be benchmarked by other services and professionals. PMID- 23459815 TI - [Coverage of the basic immunization schedule in the first year of life in State capitals in Northeast Brazil]. AB - Vaccination coverage in the so-called "developing countries" is still lower than expected. Such coverage is an important indicator of population health and the quality of care provided by the health care system. The current study describes the results of a household survey to estimate coverage of the basic immunization schedule in the first year of life in State capitals in Northeast Brazil, for the 2005 birth cohort. The methodology used was that recommended by the Pan American Health Organization for surveys on vaccination coverage. According to the data, vaccination coverage fell short of the goals set by the National Immunization Program for this age group, at high risk of acquiring vaccine-preventable diseases. The lowest coverage rates were found at the two extremes of socioeconomic strata. Assessment of vaccination coverage indicates whether the infant population is immunized and helps identify weak points in vaccination activities. PMID- 23459816 TI - "Stuck in the muck": an eco-idiom of distress from childhood respiratory diseases in an urban mangrove in Northeast Brazil. AB - Situated in neo-democratic globalizing Northeast Brazil, this anthropological study probes the role of ecological context in framing, experiencing, and expressing human distress. Ethnographic interviews, narratives, and "contextualized semantic analysis" reveal the lived experience of childhood respiratory diseases among 22 urban mangrove dwellers. Informants speak an "eco idiom of respiratory distress" based on a popular "eco-logic", reflecting the harsh reality of "living in dampness". "Higher-up" residents legitimize their feelings of superiority by stigmatizing "lowlanders" as taboo, diseased (with porcine cysticercosis, swine flu) "filthy pigs, stuck in the muck" (atolados na lama). Animalizing inhabitants' identities demotes them to nonpersons. Besides infections, children suffer social stigma, ostracism, and barriers for accessing care. Promoting a "favorable environment" requires reducing ecological risk, challenging class-based prejudice, and restoring human dignity. PMID- 23459817 TI - [Prevalence of abdominal obesity and associated factors among individuals 25 to 59 years of age in Pernambuco State, Brazil]. AB - In order to estimate the prevalence of abdominal obesity and associated factors in Pernambuco State, Brazil, a cross-sectional population-based study was conducted in 2006, including 1,580 adults 25 to 59 years of age. Abdominal obesity was defined as waist circumference (WC) >= 80 cm in women and >= 94 cm in men. The conceptual model included demographic, socioeconomic, reproductive, and behavioral variables. Prevalence of abdominal obesity was 27.1% (95%CI: 23.8 30.7) in males and 69.9% (95%CI: 66.8-72.8) in females (p < 0.001). Multivariate analysis showed higher prevalence in men 50 years or older in the metropolitan area and those with higher income, former smokers, and drinkers. Among women, obesity was more prevalent above 30 years of age, in former smokers, and in women with first pregnancy before age 18. Central adiposity is clearly a multifactor condition in the State of Pernambuco, and the determinants of obesity differ between the sexes. PMID- 23459818 TI - [Chronic pain among elderly residents in Sao Paulo, Brazil: prevalence, characteristics, and association with functional capacity and mobility (SABE Study)]. AB - The objective was to identify the prevalence and characteristics of chronic pain and the association with functional capacity. This was a cross-sectional study with a population sample of community-dwelling elderly residents in the city of Sao Paulo, Brazil, using home interviews. Statistical analysis used the RaoScott test of association with p < 0.05. Prevalence of chronic pain was 29.7% (95%CI: 25.4-33.9), most frequent in the lower back (25.4%) and lower limbs (21.9%), and moderate in 45.8% and intense in 46% of the sample. Chronic pain was associated with increased dependence and decreased mobility (p < 0.001). PMID- 23459819 TI - [Food insecurity in households with adolescents in the Brazilian Amazon: prevalence and associated factors]. AB - This cross-sectional population-based study in 2007 focused on prevalence of food insecurity and associated factors in households with adolescents in four towns in the Legal Amazonia located along highway BR-163, from Cuiaba, Mato Grosso State, to Santarem, Para State, Brazil. The study applied the Brazilian Food Insecurity Scale to a sample of 363 households. Anthropometric assessment was performed on 534 adolescents from 10 to 19 years of age. A Poisson model was used in the multiple regression analysis. The results showed 23.1% prevalence of moderate to severe food insecurity, suggesting association with the following: low income, poor sanitation, head of household born in Mato Grosso State, and the adolescent's race (black). The results emphasize the need for improved access to basic sanitation, training of human resources to generate employment/income, and educational activities to improve understanding of food insecurity and its determinants. PMID- 23459820 TI - [Birth weight in Brazilian children under two years of age]. AB - Low birth weight is associated with increased risk of dying in the first year of life. This study was motivated by recent changes in the determination of birth weight patterns with the advent of the perinatal epidemiological transition. We analyzed data from the Brazilian National Survey of Demographic and Health of Children and Women including only children < 24 months. Prevalence of low birth weight in Brazil was 6.1%. Risk factors included female gender, residence in the South and Southeast geographic regions, low maternal education, and maternal smoking. The low birth weight profile changed, with higher prevalence in more economically developed regions, reflecting the neonatal epidemiological transition determined by changes in patterns of childbirth care and incorporation of perinatal life support technologies, in addition to the previously known biological risks associated with poverty and misinformation. PMID- 23459821 TI - Biological and environmental factors associated with risk of schistosomiasis mansoni transmission in Porto de Galinhas, Pernambuco State, Brazil. AB - Schistosomiasis has expanded to the coast of Pernambuco State, Brazil, where there are frequent reports of Biomphalaria glabrata snails and human cases of the disease. This study analyzes factors related to schistosomiasis transmission risk in Porto de Galinhas. A one-year malacological survey was conducted to identify biological, abiotic, and environmental factors related to the host snail breeding sites. Data analysis used Excel 2010, GTM Pro, and ArcGis 10. A total of 11,012 B. glabrata snails were captured in 36 breeding sites, and 11 schistosomiasis transmission foci were identified. A negative correlation was found between breeding site temperature and snail density and infection rate, and a positive correlation with pH and salinity. The rainy season showed a positive correlation with snail density and infection rate. The study emphasizes the factors involved in the maintenance of schistosomiasis breeding sites, in light of persistence of this disease in Porto de Galinhas for more than 10 years. PMID- 23459822 TI - [Identification and spatial distribution of key premises for Aedes aegypti in the Porto Dantas neighborhood, Aracaju, Sergipe State, Brazil, 2007-2008]. AB - Currently the best way to avoid new dengue epidemics is to control the mosquito vector Aedes aegypti. This study thus aimed to identify and analyze the spatial distribution of "key premises" for Ae. aegypti in Aracaju, Sergipe State, Brazil. Three entomological surveys were performed prior to, during, and after the dengue epidemic and in different conditions of precipitation: the end of the rainy season, beginning of the rainy season, and the dry season. Key premises were identified by positivity in more than one survey and presence of pupae. Spatial distribution and dispersal of mosquitoes used analysis of point patterns, with the kernel and buffer density estimator. Key premises were responsible for maintaining infestation of the area, independently of environmental conditions and the period in the epidemic, serving as foci generating mosquitoes that can spread to areas adjacent to the neighborhood. Thus, in order to be more effective, vector control measures should target these properties. PMID- 23459823 TI - [Reproducibility and relative validity of the Food Frequency Questionnaire used in the ELSA-Brasil]. AB - This study evaluated the reproducibility and relative validity of the Food Frequency Questionnaire (FFQ) used in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Participants (n = 281) completed the FFQ and three food records on two occasions during a 12-month period. Energy and nutrient values from food records were disattenuated and log-transformed. Reproducibility and validity were assessed by the intra-class correlation coefficient (ICC). Agreement between the two methods was evaluated by classification in tertiles. In the evaluation of reproducibility, ICC estimated ranged from 0.55 to 0.83 for protein and vitamin E, respectively. On relative validity, ICC ranged from 0.20 to 0.72 for selenium and calcium, respectively. Exact and adjacent agreement between methods varied from 82.9% for vitamin E to 89% for lipids and calcium (mean 86%). Average disagreement was 13.6%. In conclusion, this FFQ showed satisfactory reliability for all nutrients and reasonable validity, especially for energy, macronutrients, calcium, potassium, and vitamins E and C. PMID- 23459824 TI - [Female homicide victims in Recife, Pernambuco State, Brazil, 2009-2010: a descriptive study]. AB - This study investigated the epidemiological profile of female homicide victims in Recife, Pernambuco State, Northeast Brazil. An observational descriptive and prospective study included all homicides from March 2009 to February 2010 with female victims from Recife, 10 to 49 years of age. A questionnaire was used to record socioeconomic, demographic, and biological risk factors. Relatives of the victims were interviewed, and data were collected from death certificates. We identified 60 homicides during the study period. Most victims were adult women with brown skin color and low schooling and low income. Other characteristics included smoking in 39.7%, alcohol and illicit drugs in 48.3% and 24.1%, respectively, and physical and/or sexual violence in the 12 months prior to the murder in 29.3%. Firearms were used in 69% of these homicides. PMID- 23459825 TI - [Infant breastfeeding prevalence in the city of Sao Paulo, Brazil, 2008]. AB - This cross-sectional epidemiological study based on AMAMUNIC aimed to evaluate infant breastfeeding (BF) prevalence and duration in Sao Paulo, Brazil. Sample size was based on a cluster calculation, selecting 35 primary care units and 35 infants (< 1 year of age) per unit. A total of 1,424 interviews with mothers were performed (56 items on feeding in the previous 24 hours) in August 2008, subsequently analyzed according to residential areas: Central West, East, North, Southeast, and South. Prevalence of exclusive breastfeeding (EBF) was 52% up to three months and 39% up to six months, as follows: 44% (Central West), 57% (East), 62% (North), 43% (Southeast), and 48% (South) up to three months and 36% (Central West), 46% (East), 39% (North), 36% (Southeast), and 33% (South) up to six months. Prevalence of EBF according to infant age was 58% in the first month, 50% in the second and third, and 13% in the sixth. In conclusion, EBF prevalence up to six months is still heterogeneous in the city, suggesting the need for programs to encourage BF that are differentiated according to region. PMID- 23459826 TI - [Conceptual, semantic, and instrumental equivalences: preliminary analysis of the Brazilian Portuguese version of the Male Body Dissatisfaction Scale (MBDS)]. AB - This study aimed to describe the translation into Brazilian Portuguese and the analysis of conceptual, semantic, and instrumental equivalences and assessment of internal consistency of the Male Body Dissatisfaction Scale (MBDS). The study included the steps of (1) translation; (2) synthesis of translation; (3) back translation; (4) review by experts - judges - analysis of the semantic and instrumental equivalences; (5) pre-test - assessment of verbal understanding of the instrument by specialists and male students; (6) analysis of the internal consistency by Cronbach's alpha coefficient. The MBDS was translated and adapted into Brazilian Portuguese maintaining its original 25 items, showed good verbal comprehension, and had an internal consistency coefficient of 0.92. The scale was translated and adapted with satisfactory results, thus confirming its initial psychometric qualities. The instrument requires further analysis of internal and external validity, and reproducibility. PMID- 23459827 TI - [Patterns of physical activity during a typical adult day in Niteroi, Rio de Janeiro, Brazil: a non-representative population sample]. PMID- 23459828 TI - [The authors reply]. PMID- 23459829 TI - Do HIV-specific CTL continue to have an antiviral function during antiretroviral therapy? If not, why not, and what can be done about it? AB - Pharmacological reactivation of human immunodeficiency virus (HIV) expression from latent proviruses coupled with fully suppressive antiretroviral therapy (ART) has been suggested as a strategy to eradicate HIV infection. In order for this strategy to be effective, latently infected cells must be killed either by the cytopathic effect of reactivated HIV gene expression, or by HIV-specific cytotoxic T lymphocyte (CTL). However, a review of current data reveals little evidence that CTL retain an antiviral effector capacity in patients on fully suppressive ART, implying that the HIV-specific CTL present in these patients will not be able to eliminate HIV-infected CD4(+) T cells effectively. If this is due to functional impairment or a quantitative deficit of HIV-specific CTL during ART, then therapeutic vaccination may improve the prospects for eradicating latent reservoirs. However, data from the macaque simian immunodeficiency virus (SIV) model indicate that in vivo, SIV-specific CTL are only effective during the early stages of the viral replication cycle, and this constitutes an alternative explanation why HIV-specific CTL do not appear to have an impact on HIV reservoirs during ART. In that case, immunotoxins that target HIV-expressing cells may be a more promising approach for HIV eradication. PMID- 23459830 TI - Inhibitor of growth 1 (ING1) acts at early steps of multiple DNA repair pathways. AB - ING proteins are tumor suppressors involved in the regulation of gene transcription, cell cycle arrest, apoptosis, and senescence. Here, we show that ING1b expression is upregulated by several DNA-damaging agents, in a p53 independent manner. ING1b stimulates DNA repair of a variety of DNA lesions requiring activation of multiple DNA repair pathways. Moreover, Ing1(-/-) cells showed impaired genomic DNA repair after H2O2 and neocarzinostatin treatment and this defect was reverted by overexpression of ING1b. Two tumor-derived ING1 mutants failed to promote DNA repair highlighting the physiological importance of the integrity of the PHD domain for ING1b DNA repair activity and suggesting a role in the prevention of tumor progression. Ing(-/-) cells showed higher basal levels of gamma-H2AX and, upon DNA damage, gamma-H2AX increase was greater and with faster kinetics compared to wild-type cells. Chromatin relaxation by Trichostatin A led to an exacerbated damage signal in both types of cells, but this effect was dependent on Ing1 status, and more pronounced in wild-type cells. Our results suggest that ING1 acts at early stages of the DNA damage response activating a variety of repair mechanisms and that this function of ING1 is targeted in tumors. PMID- 23459831 TI - Lateralized difference in tympanic membrane temperature: emotion and hemispheric activity. AB - We review literature examining relationships between tympanic membrane temperature (TMT), affective/motivational orientation, and hemispheric activity. Lateralized differences in TMT might enable real-time monitoring of hemispheric activity in real-world conditions, and could serve as a corroborating marker of mental illnesses associated with specific affective dysregulation. We support the proposal that TMT holds potential for broadly indexing lateralized brain physiology during tasks demanding the processing and representation of emotional and/or motivational states, and for predicting trait-related affective/motivational orientations. The precise nature of the relationship between TMT and brain physiology, however, remains elusive. Indeed the limited extant research has sampled different participant populations and employed largely different procedures and measures, making for seemingly discrepant findings and implications. We propose, however, that many of these discrepancies can be resolved by considering how emotional states map onto motivational systems, and further examining how validated methods for inducing lateralized brain activity might affect TMT. PMID- 23459834 TI - Photoemission electron microscopy study of sub-200 nm self-assembled La0.7SrLa0.3MnO3 epitaxial islands. AB - The chemical composition and the magnetic structure of individual La0.7Sr0.3MnO3 (LSMO) ferromagnetic manganite epitaxial nanostructures less than 200 nm in width are explored using Photoemission Electron Microscopy (PEEM). X-ray absorption spectra (XAS) provide separate information on the surface and the bulk composition of the nanoislands and give evidence of Mn(2+) present on the surface of otherwise stoichiometric nanostructures. Ferromagnetic domains less than 70 nm are resolved using X-ray magnetic circular dichroism (XMCD), which allows for the detection of magnetic vortex states in both (001)LSMO square and (111)LSMO triangular manganite nanoislands. The evolution of single nanostructures under an in-plane magnetic field is seen to depend on the specific nanoisland size and geometry. In particular, PEEM XMCD imaging allows detecting opposite chiralities as well as a variety of magnetization behaviors for different nanoislands. PMID- 23459832 TI - Facilitating comparative effectiveness research in cancer genomics: evaluating stakeholder perceptions of the engagement process. AB - AIMS: The Center for Comparative Effectiveness Research in Cancer Genomics completed a 2-year stakeholder-guided process for the prioritization of genomic tests for comparative effectiveness research studies. We sought to evaluate the effectiveness of engagement procedures in achieving project goals and to identify opportunities for future improvements. MATERIALS & METHODS: The evaluation included an online questionnaire, one-on-one telephone interviews and facilitated discussion. Responses to the online questionnaire were tabulated for descriptive purposes, while transcripts from key informant interviews were analyzed using a directed content analysis approach. RESULTS: A total of 11 out of 13 stakeholders completed both the online questionnaire and interview process, while nine participated in the facilitated discussion. Eighty-nine percent of questionnaire items received overall ratings of agree or strongly agree; 11% of responses were rated as neutral with the exception of a single rating of disagreement with an item regarding the clarity of how stakeholder input was incorporated into project decisions. Recommendations for future improvement included developing standard recruitment practices, role descriptions and processes for improved communication with clinical and comparative effectiveness research investigators. CONCLUSIONS: Evaluation of the stakeholder engagement process provided constructive feedback for future improvements and should be routinely conducted to ensure maximal effectiveness of stakeholder involvement. PMID- 23459835 TI - On-surface polymerization of 1,4-diethynylbenzene on Cu(111). AB - The polymerization of 1,4-diethynylbenzene was studied on a Cu(111) surface using scanning tunneling microscopy (STM) under ultra-high vacuum conditions. Thermal activation yielded disordered covalent networks, where distinct basic structural motifs indicate different coupling reactions. PMID- 23459836 TI - [What medical students want - evaluation of medical recruitment ads by future physicians]. AB - OBJECTIVE: Three-quarters of all hospitals in Germany are now struggling to fill open positions for doctors. The medical job ad is a vital tool for human resources marketing and an important image factor. The present study examines the importance of information and offers in medical recruitment ads on application decisions by medical students. METHOD: A total of 184 future physicians from clinical semesters participated voluntarily in an anonymous cross-sectional survey. Using a standardised questionnaire, the importance of 49 -individual items extracted from medical recruitment ads were rated with the help of a 4 point Likert Scale. Finally, the study participants prioritised their reasons for an application as a physician. RESULTS: Primary influence on the application decision on medical recruitment ads by medical students had offers/information in relation to education and training aspects and work-life balance. Payment rates for physicians and work load played an important role for the application motivation. Additional earnings for, e. g., emergency calls, providing of medical expertise and assistance with housing, relocation and reimbursement of interview expenses were less crucial. In prioritising key reasons for selecting a prospective employer "regular working hours," an "individual training concept" and an "attractive work-life balance" scored the highest priority. The "opportunity for scientific work" was assigned only a small significance. CONCLUSION: High importance for the application decision by future physicians on medical recruitment ads is placed on jobs with an opportunity for personal development and aspects that contribute to work-life balance. PMID- 23459837 TI - Dr. Andrew Huvos (1934-2006) retrospective: a tribute to the pathologist and the man. AB - Andrew G. Huvos was born in communist Budapest, Hungary, in March of 1934. At twenty-four he immigrated to New York City, working as a cytotechnologist at Delafield Hospital. Dr. Huvos attended the University of Gottingen Medical School in Germany, where he was awarded his MD degree. He completed a 1-year internship at New York Hospital, going on to Residency at Delafield Hospital and Fellowship at Presbyterian Hospital. Dr. Huvos ascended through the ranks to Attending Pathologist and Member at Memorial Hospital for Cancer and Allied diseases, at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. Concurrently, he was appointed to Weill Medical College of Cornell University, where he was Professor of Pathology for over two decades. Dr. Huvos was an editorial referee for over half a dozen highly esteemed publications, including the New England Journal of Medicine and Cancer. He trained over a thousand oncological surgical pathology fellows, head and neck fellows, and surgeons. Dr. Huvos spent nearly 40 years at MSKCC and his career was accompanied by his authorship of 388 peer reviewed publications and eighteen book chapters. His legacy leaves behind a generation of pathologists who have greatly benefited from his tutelage. PMID- 23459838 TI - What the EWSR1-ATF1 fusion has taught us about hyalinizing clear cell carcinoma. AB - Hyalinizing clear cell carcinoma (HCCC) is a unique low-grade tumor composed of cords and nests of clear cells in a hyalinized stroma that was first reported by Milchgrub et al. It was recognized as a separate entity from clear cell variants of epithelial-myoepithelial carcinoma, myoepithelial carcinoma and mucoepidermoid carcinoma. HCCC is included in a long list of clear cell-containing tumors of salivary gland, as well as odontogenic tumors and metastases (renal cell carcinoma). Up until now, it has been considered a diagnosis of exclusion, despite its very distinctive appearance, and labeled as "not otherwise specified" by the World Health Organization. The emergence of molecular data in salivary gland tumors, including HCCC now allow for a more rigorous appraisal of its spectrum. The EWSR1-ATF1 fusion has proven the concept of a "mucinous HCCC" and removes mucin as an exclusion criterion for this tumor. It has also proven a genetic link between clear cell odontogenic carcinoma and HCCC. Molecularly proven cases have also highlighted variant morphologies and shown that cases with overt squamous differentiation are true HCCC. This gives further weight to the classification of this tumor as squamous or adenosquamous in differentiation and as a specific entity rather than an "NOS" tumor. PMID- 23459839 TI - Unmasking MASC: bringing to light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands. AB - Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is characterized by its striking morphologic and molecular similarities to secretory carcinoma of the breast. This review highlights the characteristic clinical, histologic, immunophenotypic, and molecular features of MASC, and draws attention to the differential diagnosis of this increasingly recognized tumor. PMID- 23459840 TI - Fibro-osseous lesions of the maxillofacial bones. AB - Fibro-osseous lesions of the maxillofacial bones should be classified based on their radiographic growth pattern. This method can simplify this category of lesions, which have considerable overlapping histologic features. These neoplasms can be grouped into three categories: (a) fibrous dysplasia; (b) ossifying fibroma; (c) and osseous dysplasia. Important lesions in the differential diagnosis are osteoblastoma and giant cell reparative granuloma. PMID- 23459841 TI - Molecular heterogeneity in mucoepidermoid carcinoma: conceptual and practical implications. AB - Mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy of the upper aerodigestive tract and tracheobronchial tree, is also known for its considerable cellular heterogeneity including epidermoid, intermediate and mucin producing cells. Despite this structural and cellular heterogeneity, MEC is uniquely characterized by a specific translocation t(11; 19) (q12; p13), resulting in a fusion between the MECT1 and the MAML2 genes. Although the incidence of this fusion in MEC varies, it is generally accepted that more than 50 % of this entity manifest the MECT1-MAML2. Fusion-positive cases showed significantly better survival than fusion-negative cases, suggesting that MECT1 MAML2 represents a specific prognostic molecular marker in MEC. We contend that fusion in MEC represents a distinct mechanism in the development of this entity. In that context, fusion positive MEC, regardless of grade, manifest a more stable genome and better clinical behaviour, while fusion negative MEC represent a distinctly different pathway characterized by marked genomic instability and relatively aggressive tumors. PMID- 23459843 TI - Which patients are most likely to benefit from total joint arthroplasty? AB - OBJECTIVE: To evaluate patient predictors of good outcome following total joint arthroplasty (TJA). METHODS: A population cohort with hip/knee arthritis (osteoarthritis [OA] or inflammatory arthritis) ages >=55 years was recruited between 1996 and 1998 (baseline) and assessed annually for demographics, troublesome joints, health status, and overall hip/knee arthritis severity using the Western Ontario and McMaster Universities OA Index (WOMAC). Survey data were linked with administrative databases to identify primary TJAs. Good outcome was defined as an improvement in WOMAC summary score greater than or equal to the minimal important difference (MID; 0.5 SD of the mean change). Logistic regression and Akaike's information criterion were used to determine the optimal number of predictors and the best model of that size. Log Poisson regression was used to determine the relative risk (RR) for a good outcome. RESULTS: Primary TJA was performed in 202 patients (mean age 71.0 years; 79.7% female; 82.7% with >1 troublesome hip/knee; 65.8% knee replacements). Mean improvement in WOMAC summary score was 10.2 points (SD 18.05; MID 9 points). Of these patients, 53.5% experienced a good outcome. Four predictors were optimal. The best 4-variable model included pre-TJA WOMAC, comorbidity, number of troublesome hips/knees, and arthritis type (C statistic 0.80). The probability of a good outcome was greater with worse (higher) pre-TJA WOMAC summary scores (adjusted RR 1.32 per 10-point increase; P < 0.0001), fewer troublesome hips/knees (adjusted RR 0.82 per joint; P = 0.002), OA (adjusted RR for rheumatoid arthritis versus OA 0.33; P = 0.009), and fewer comorbidities (adjusted RR per condition 0.88; P = 0.01). CONCLUSION: In an OA cohort with a high prevalence of multiple troublesome joints and comorbidity, only half achieved a good TJA outcome, defined as improved pain and disability. A more comprehensive assessment of the benefits and risks of TJA is warranted. PMID- 23459845 TI - Cobalt(II), copper(II), zinc(II) and cadmium(II) complexes based on dibenzimidazolyl bidentate ligands with alkanyl linkers: crystal structure, weak interactions and conformations. AB - Eight metal complexes, {[Co(bibim-4)2(H2O)2](NO3)2}n (1), {[Cu(bibim 4)2(NO3)](NO3)}n (2), [Co(bibim-3)(TP)]n (3), [Zn2(bibim-3)]2(OAc)4] (4), [Co(bibim-2)(NO3)2]n (5), [Zn(bibim-4)(NO3)2]n (6), [Zn(bibim-4)(OAc)2]n (7) and [Cd(bibim-4)(NO3)2(DMF)]n (8) (bibim-2 = 1,2-bis(benzimidazol-l-yl)ethane, bibim 3 = 1,3-bis(benzimidazol-l-yl)propane, bibim-4 = 1,4-bis(benzimidazol-l-yl)butane and TP = terephthalate) have been prepared by means of the self-assembly of Co(II), Cu(II), Zn(II) or Cd(II) salts, dibenzimidazolyl bidentate ligands bearing alkanyl linkers and terephthalic acid. These complexes are structurally characterized by X-ray diffraction analyses. In complexes 1 and 2, 2D network layers with macrometallocycles are formed via metal centers and the ligand bibim 4. A 2D network layer with macrometallocycles in 3 is formed via Co(II) centers, the ligand bibim-3 and terephthalate molecules. In complex 4, a 20-membered macrometallocycle is formed by two bibim-3 ligands and two Zn(II) atoms. In complexes 5-8, 1D polymeric chains are formed via metal centers and the bibim-2 or bibim-4 ligands. In the crystal packings of complexes 1-8, 2D supramolecular layers and 3D supramolecular frameworks are formed via intermolecular weak interactions, including pi-pi interactions and hydrogen bonds. The different types of pi-pi interactions from the benzimidazole ring as well as the conformations of the ligands and metal complexes are described. Additionally, the fluorescence emission spectra of the ligands and metal complexes are reported. PMID- 23459847 TI - Getting to the heart of HIV and myocardial infarction. PMID- 23459848 TI - First report of Trypanosoma cruzi infection in naturally infected dogs from southern Bahia, Brazil. AB - In order to verify the Trypanosoma cruzi infection in domestic domiciled dogs in a rural endemic area from the south region of the State of Bahia, Polymerase Chain Reaction (PCR) were performed using S35 and S36 primers in 272 dogs living in the district of Vila Operaria, in the municipality of Buerarema. All animals were clinically evaluated; 2.5 mL of blood were collected through venipuncture for the performance of molecular tests. None of these animals showed clinical signs of the illness and only two were identified with the DNA parasite. This result is the first report of natural infection by T. cruzi in domestic dogs in southern Bahia. PMID- 23459849 TI - Detection of anti-Toxoplasma gondii antibodies in carthorses in the metropolitan region of Curitiba, Parana, Brazil. AB - Toxoplasma gondii, the agent for toxoplasmosis, has worldwide distribution. Horses normally play a secondary role in its life cycle, but movement around urban areas, feeding on grass and the increasing use of carthorses for gathering recyclable material in some urban areas of Brazil may increase their exposure to T. gondii infection. The aim of the present study was to investigate the frequency of anti-T. gondii antibodies in carthorses in the metropolitan region of Curitiba, PR. IgG antibodies against T. gondii were detected using the indirect fluorescence antibody test (IFAT) (titers >= 64). Seventeen (17.0%) of the 100 horses sampled were seropositive. There were no statistical differences in relation to sex (p = 0.28) or age (p = 0.15). Our findings suggest that carthorses are exposed to T. gondii infections and that no associations with age or sex exist. PMID- 23459844 TI - p110delta PI3 kinase pathway: emerging roles in cancer. AB - Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p110alpha, p110beta, and p110delta which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110alpha isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110beta or p110delta have been reported. Unlike p110alpha and p110beta which are ubiquitously expressed, p110delta is highly enriched in leukocytes and thus the p110delta PI3K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110delta PI3K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110delta PI3K in B cell functions and B-cell malignancies. Further data have documented that wild type p110delta becomes oncogenic when overexpressed in cell culture models and that p110delta is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110delta in mice models and highly-selective inhibitors of p110delta have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110delta signaling. In this review, we summarize our understanding of the p110delta PI3K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110delta in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110delta PI3K in cancer. PMID- 23459850 TI - Occurrence of Braga cigarra (Cymothoidae) parasitizing Galeocharax knerii (Characidae) from affluents of Jurumirim reservoir, Brazil. AB - The occurrence of the cymothoidae Braga cigarra is reported parasitizing the oral cavity of freshwater fish Galeocharax knerii from Veados, Paranapanema and Taquari Rivers, affluent of the Jurumirim Reservoir, State of Sao Paulo, Brazil is reported. The isopod species were identified based on the multilaminar pleopods, narrow pleon and short pleotelson in females. The overall prevalences of isopods were 31.7%, 7.7% and 5.7%, respectively, in the Paranapanema, Veados and Taquari Rivers. This note contributes to the knowledge of the geographical distribution and fauna of parasite crustaceans known to date in these important ecosystems. PMID- 23459851 TI - Cardiac resident nestin(+) cells participate in reparative vascularisation. AB - The rodent heart contains a population of nestin((+)) cells derived from the embryonic neural crest and migrate to the scar after myocardial infarction (MI). The present study tested the hypothesis that intron 2 of the nestin gene drives expression and a subpopulation of nestin((+)) cells participate in reparative vascularisation. The directed expression of the green fluorescent protein (GFP) by the second intron of the nestin gene identified GFP/nestin((+)) cells intercalated among ventricular myocytes in the heart of normal transgenic mice. Ischemic injury led to the migration of GFP((+)) cells to the scar and a subpopulation was detected in CD31/nestin((+)) endothelial cells of newly formed blood vessels. The direct contribution to reparative vascularisation provided the impetus to test the hypothesis that increasing the population of nestin((+)) cells in the infarcted heart will improve scar healing. Skin-derived cells isolated from E18 Sprague-Dawley rats grew as spheres, expressed nestin, sox2, neural crest-related transcriptional genes and a panel of peptide growth factors. Skin-derived cells transplanted in the non-infarcted left ventricle of 3-day post MI rats migrated to the peri-infarct/infarct region and remained engrafted for 21 days. A significantly smaller infarct, increased number of small calibre blood vessels and improved ventricular function were observed in engrafted infarcted rat hearts. Thus, the second intron of the nestin gene drives expression in the mouse heart and a subpopulation of GFP/nestin((+)) cells directly participate in reparative vascularisation. Increasing the population of nestin((+)) cells via the transplantation of skin-derived cells represents a potential approach to limit ischemic damage to the heart. PMID- 23459852 TI - Creating accountable care for carotid angioplasty and stenting: A multidisciplinary carotid revascularization board. AB - BACKGROUND: We tested the feasibility of a mandated multidisciplinary carotid revascularization board (MDCB) to review, approve and monitor all carotid artery and stenting (CAS) procedures and outcomes at our institution. METHODS: The board was composed of vascular surgeons, cardiologists, interventional neuroradiologists, neurosurgeons, and neurologists, who met weekly to facilitate an evidence-based, consensus recommendation to ensure appropriate CAS referral. RESULTS: The board successfully reviewed and continues to review and approve all CAS procedures at our center. Of the 69 patients considered high risk for standard surgical treatment, 42 patients were symptomatic and 27 patients were asymptomatic. Their mean age was 70.5-year-old and the median degree of stenosis was 79%. In the 74 procedures, periprocedural complications occurred at the following rates: 2.7% death, 2.7% major stroke, 2.7% minor stroke, and 2.7% myocardial infarction (MI) within 30 days of the procedure. At 1 year the primary endpoints of ipsilateral stroke and neurovascular-related death were observed in 8.1% and 2.7% of the patients, respectively. At mean follow-up of 21 months, 18.8% of the patients (13/69) had died (including all causes), and 14.5% (10/69) experienced stroke (including nontarget strokes). Target vessel revascularization was needed in 2.9% patients. CONCLUSIONS: A mandated multidisciplinary carotid revascularization board MDCB is feasible and potentially advantageous in real clinical practice. It establishes a model for accountable care by providing a mechanism for institutional oversight, credentialing operators, quality review, standardizing care, cost containment and eliminating the "subspecialty silo mentality." PMID- 23459854 TI - Cardiovascular adaptations to resistance training in elderly postmenopausal women. AB - The purpose of this study was to investigate the effect of resistance training on resting blood pressure and heart rate variability in elderly postmenopausal women. 29 untrained, non-hypertensive elderly women were randomly assigned to 2 groups: an intervention group (n=15, 65.5+/-5.0 years, 57.3+/-6.5 kg, 156.7+/-5.1 cm) that underwent a supervised resistance training program (8 exercises, 2 sets, 10-15 repetitions, 3 times/week) or a control group (n=14, 66.2+/-4.1 years, 61.1+/-11.7 kg, 157.5+/-7.1 cm) that participated in a supervised stretching program (25-30 min/session, 2 times/week). Resting auscultatory blood pressure, heart rate variability, evaluated from short recordings in a seated position, and maximal dynamic strength (1-RM test) were measured at baseline and after 12 weeks. A group x time ANOVA revealed that muscular strength increased significantly in the resistance training group (+ 10.2% for bench press and +12.7% for leg extension, P<0.05). Systolic blood pressure was reduced significantly in the resistance training group from pre- to post-intervention period (- 5 mmHg; P<0.05), while no significant effect was noted for diastolic blood pressure and heart rate variability indexes (P>0.05). None of these variables changed in the control group throughout the study. In conclusion, a supervised resistance training program improved muscular strength and reduced systolic blood pressure without affecting diastolic blood pressure and heart rate variability in elderly postmenopausal women. PMID- 23459853 TI - Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas. AB - Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death. PMID- 23459855 TI - Soccer skill development in talented players. AB - The aim of the study was to gain insight into the development of soccer-specific skills and whether differences between talented players exist on the Loughborough Soccer Passing Test (LSPT). Two scores were derived from the LSPT: 1) execution time: time to complete 16 passes (speed) and 2) skill performance time: execution time including bonus and penalty time for accuracy. The study consisted of 2 parts, the first of which incorporated a quasi-longitudinal design with 270 talented players aged 10-18 years performing the LSPT (661 measurement occasions); multilevel modelling was applied. Secondly, differences between those players allowed to continue in the development program (selected, n=269) and players who were forced to leave (de-selected, n=50) were investigated using independent sample t-tests. The longitudinal data showed that the predicted execution time (i. e., speed) improved approximately 18% from age 10-18 years (P<0.05), skill performance time (i. e., combination of speed and accuracy) was predicted to improve approximately 32% (P<0.05). The second part showed that selected players outscored de-selected players only on skill performance time (P<0.05), not on execution time (P>0.05). In conclusion, in high-level youth soccer, the combination of speed and accuracy in soccer skills might be more important than speed alone. PMID- 23459856 TI - Calculation of force and power during bench throws using a Smith machine: the importance of considering the effect of counterweights. AB - For achieving accurate and safe measurements of the force and power exerted on a load during resistance exercise, the Smith machine has been used instead of free weights. However, because some Smith machines possess counterweights, the equation for the calculation of force and power in this system should be different from the one used for free weights. The purpose of this investigation was to calculate force and power using an equation derived from a dynamic equation for a Smith machine with counterweights and to determine the differences in force and power calculated using 2 different equations. One equation was established ignoring the effect of the counterweights (Method 1). The other equation was derived from a dynamic equation for a barbell and counterweight system (Method 2). 9 female collegiate judo athletes performed bench throws using a Smith machine with a counterweight at 6 different loading conditions. Barbell displacement was recorded using a linear position transducer. The force and power were subsequently calculated by Methods 1 and 2. The results showed that the mean and peak power and force in Method 1 were significantly lower relative to those of Method 2 under all loading conditions. These results indicate that the mean and peak power and force during bench throwing using a Smith machine with counterweights would be underestimated when the calculations used to determine these parameters do not account for the effect of counterweights. PMID- 23459857 TI - Mesoporous silicate MCM-41 as a particulate carrier for octyl methoxycinnamate: Sunscreen release and photostability. AB - Octyl methoxycinnamate (OMC) is a widely used UV filter characterized by good absorbing properties; however, it shows light susceptibility (photoinstability) and potential skin permeation. This paper describes the application of a new particulate carrier to improve OMC safety and photostability. The UV filter was included into the pores of the mesoporous silicate MCM-41 and then entrapped there by plugging the pore openings. The last step was performed treating the MCM 41 inclusion product with a lipid cosmetic ingredient by the hot-melt method. The loaded samples were characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, and N2 adsorption isotherms. Photochemical studies demonstrated that the coated samples allow a broader photoprotection range and remarkable improvement of sunscreen photostability. Finally, they were properly formulated in an emulgel, and the sunscreen release was studied in vitro by Franz diffusion cell and compared with those obtained from the same formulation containing the free filter. Sunscreen release from the studied formulations resulted negligible, meaning that the proposed approach represents a valuable strategy for UV filters stabilization toward light and safety improvement. PMID- 23459860 TI - Highly atom-economic synthesis of graphene/Mn3O4 hybrid composites for electrochemical supercapacitors. AB - A highly atom-economic procedure for the preparation of reduced graphene oxide/Mn3O4 (rGO/Mn3O4) composites is reported. Pristine graphene oxide/manganese sulfate (GO/MnSO4) suspension produced by modified Hummers method is utilized with high efficiency, which has been in situ converted into GO/Mn3O4 hybrid composite by air oxidation, then into rGO/Mn3O4 composite by means of dielectric barrier discharge (DBD) plasma-assisted deoxygenation. The Mn3O4 content of the rGO/Mn3O4 composites can be readily tailored. It is observed that Mn3O4 nanoparticles of 15-24 nm are well-dispersed on graphene sheets with Mn3O4 loading as high as 90%. The specific capacitance of the as-prepared rGO/Mn3O4 hybrids with 90% Mn3O4 reaches 193 F g(-1) when employed as the electrode material in neutral Na2SO4 electrolyte solutions (76 F g(-1) for pristine graphene and 95 F g(-1) for pure Mn3O4), which indicates the positive synergetic effects from both graphene and attached Mn3O4. The method developed in this study should offer a new technique for the large scale and highly atom-economic production of graphene/MnOx composites for many applications. PMID- 23459858 TI - Temporal profile of astrocytes and changes of oligodendrocyte-based myelin following middle cerebral artery occlusion in diabetic and non-diabetic rats. AB - The long-term impacts of cerebral ischemia and diabetic ischemia on astrocytes and oligodendrocytes have not been defined. The objective of this study is to define profile of astrocyte and changes of myelin in diabetic and non-diabetic rats subjected to focal ischemia.Focal cerebral ischemia of 30-min duration was induced in streptozotocin-induced diabetic and vehicle-injected normoglycemic rats. The brains were harvested for immunohistochemistry of glial fibrillary acidic protein (GFAP) and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) at various reperfusion endpoints ranging from 30 min up to 28 days. The results showed that activate astrocytes were observed after 30 min and peaked at 3 h to 1 day after reperfusion in ischemic penumbra, and peaked at 7 days of reperfusion in ischemic core. Diabetes inhibited the activation of astrocytes in ischemic hemisphere. Demyelination occurred after 30 min of reperfusion in ischemic core and peaked at 1 day. Diabetes caused more severe demyelination compared with non diabetic rats. Remyelination started at 7 days and completed at 14 and 28 days in ischemic region. Diabetes inhibited the remyelination processes. It is concluded that ischemia activates astrocytes and induces demyelination. Diabetes inhibits the activation of astrocytes, exacerbates the demyelination and delays the remyelination processes. These may contribute to the detrimental effects of hyperglycemia on ischemic brain damage. PMID- 23459859 TI - NK cells: a double-edged sword in chronic hepatitis B virus infection. AB - There is natural enrichment of NK cells in the human liver and this intrahepatic predominance underscores their potential importance in the control of infections with hepatotropic viruses such as hepatitis B virus (HBV). The contribution of innate components during chronic HBV infection has been a relatively under investigated area. However, recent data have highlighted that NK cells are capable of exerting antiviral and immunoregulatory functions whilst also contributing to the pathogenesis of liver injury via death receptor pathways. We will present an overview of current knowledge regarding the complex biology of NK cells in the context of their antiviral versus pathogenic role in chronic hepatitis B as a clinically relevant avenue for further investigation. PMID- 23459864 TI - Bridged bis(amidinate) lanthanide aryloxides: syntheses, structures, and catalytic activity for addition of amines to carbodiimides. AB - Various lanthanide aryloxide complexes supported by bridged bis(amidinate) ligand L, LLnOAr(DME) (L = Me3SiNC(Ph)N(CH2)3NC(Ph)NSiMe3, DME = dimethoxyethane, Ln = Y, Ar = 2,6-(Me)2C6H3 (1), 2,6-((i)Pr)2C6H3 (2), 2,6-((t)Bu)2-4-(Me)C6H2 (3); Ar = 2,6-((t)Bu)2-4-(Me)C6H2, Ln = Nd (4), Sm (5), Yb (6)) were synthesized, and complexes 1, 2 and 4-6 were characterized by single crystal X-ray diffraction. All the complexes are efficient precatalysts for catalytic addition of amines to carbodiimides. The catalytic activity is influenced by lanthanide metals and the aryloxide groups (Nd (4) Sm (5) < Y (3) Yb (6) and -2,6-(Me)2C6H3 < -2,6 ((i)Pr)2C6H3 < -2,6-((t)Bu)2-4-(Me)C6H2). The catalytic addition reaction with 3 showed a good scope of substrates. The mechanism investigation revealed the real active intermediate being the monoguanidinate complexes supported by an aryloxide and an amidine-functionalized amidinate group, L'Ln[O2,6-((t)Bu)2-4 (Me)C6H2][RNCNHRN(Ar')] (L' = Me3SiNHC(Ph)N(CH2)3NC(Ph)NSiMe3, R = (i)Pr, Ar' = phenyl, Ln = Yb (8), Y (11); R = Cy, Ar' = phenyl, Ln = Yb (10), Y (12); R = (i)Pr, Ar' = 4-ClC6H4, Ln = Yb (9)), which were isolated from the reactions of 6 (or 3) with amine and carbodiimide in a molar ratio of 1:1:1 and structurally characterized. The Ln-active group in the present precatalyst is a Ln-amidinate species, not the Ln-OAr group. PMID- 23459863 TI - HIV infection and the risk of acute myocardial infarction. AB - IMPORTANCE: Whether people infected with human immunodeficiency virus (HIV) are at an increased risk of acute myocardial infarction (AMI) compared with uninfected people is not clear. Without demographically and behaviorally similar uninfected comparators and without uniformly measured clinical data on risk factors and fatal and nonfatal AMI events, any potential association between HIV status and AMI may be confounded. OBJECTIVE: To investigate whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care. DESIGN AND SETTING: Participants in the Veterans Aging Cohort Study Virtual Cohort from April 1, 2003, through December 31, 2009. PARTICIPANTS: After eliminating those with baseline cardiovascular disease, we analyzed data on HIV status, age, sex, race/ethnicity, hypertension, diabetes mellitus, dyslipidemia, smoking, hepatitis C infection, body mass index, renal disease, anemia, substance use, CD4 cell count, HIV-1 RNA, antiretroviral therapy, and incidence of AMI. MAIN OUTCOME MEASURE: Acute myocardial infarction. RESULTS: We analyzed data on 82 459 participants. During a median follow-up of 5.9 years, there were 871 AMI events. Across 3 decades of age, the mean (95% CI) AMI events per 1000 person-years was consistently and significantly higher for HIV-positive compared with uninfected veterans: for those aged 40 to 49 years, 2.0 (1.6-2.4) vs 1.5 (1.3-1.7); for those aged 50 to 59 years, 3.9 (3.3-4.5) vs 2.2 (1.9-2.5); and for those aged 60 to 69 years, 5.0 (3.8-6.7) vs 3.3 (2.6-4.2) (P < .05 for all). After adjusting for Framingham risk factors, comorbidities, and substance use, HIV-positive veterans had an increased risk of incident AMI compared with uninfected veterans (hazard ratio, 1.48; 95% CI, 1.27-1.72). An excess risk remained among those achieving an HIV-1 RNA level less than 500 copies/mL compared with uninfected veterans in time-updated analyses (hazard ratio, 1.39; 95% CI, 1.17-1.66). CONCLUSIONS AND RELEVANCE: Infection with HIV is associated with a 50% increased risk of AMI beyond that explained by recognized risk factors. PMID- 23459862 TI - Expression patterns of an isoflavone reductase-like gene and its possible roles in secondary metabolism in Ginkgo biloba. AB - KEY MESSAGE: Our results showed that GbIRL1 belongs to the PCBER protein family. Besides, IRL1 gene was a novel gene regulating lignin change and also effecting the accumulation of flavonoids in Ginkgo. A cDNA encoding the IFR-like protein was isolated from the leaves of Ginkgo biloba L., designated as GbIRL1 (Accession no. KC244282). The cDNA of GbIRL1 was 1,203 bp containing a 921 bp open reading frame encoding a polypeptide of 306 amino acids. Comparative and bioinformatic analyses revealed that GbIRL1 showed extensive homology with IFLs from other gymnosperm species. Phylogenetic tree analysis revealed that GbIRL1 shared the same ancestor in evolution with other PCBERs protein and had a further relationship with other gymnosperm species. The recombinant protein was successfully expressed in E. coli strain with pET-28a vector. The vitro enzyme activity assay by HPLC indicated that recombinant GbIRL1 protein could catalyze the formation the TDDC, IDDDC from DDDC, DDC. Tissue expression pattern analysis showed that GbIRL1 was constitutively expressed in stem and roots, especially in the parts of the pest and fungal infection, with the lower expression being found in 1- or 2-year old stem. The increased expression of GbIRL1 was detected when the seedlings were treated with Ultraviole-B, ALA, wounding and ethephon, abscisic acid, salicylic acid. Correlation analysis between GbIRL1 activity and flavonoid accumulation during Ginkgo leaf growth indicated that GbIRL1 might be the rate-limiting enzyme in the biosynthesis pathway of flavonoids in Ginkgo leaves. Results of RT-PCR analysis showed that the transcription level of change in GbIRL1 power correlated with flavonoid contents, suggesting IRL1 gene as a novel gene regulating lignin change and also effecting the accumulation of flavonoids in Ginkgo. PMID- 23459866 TI - Pt-Ni nanodendrites with high hydrogenation activity. AB - Bimetallic highly branched Pt-Ni nanocrystals were obtained by a one-pot strategy. The dendritic alloyed structure of the as-prepared nanoparticles was fully characterized and their formation mechanism was investigated. Nitrobenzene hydrogenation reactions indicated that these obtained Pt-Ni nanodendrites exhibited enhanced catalytic activities compared with Pt-Ni nanoparticles. PMID- 23459865 TI - Metaphorical motion in mathematical reasoning: further evidence for pre-motor implementation of structure mapping in abstract domains. AB - The theory of computation and category theory both employ arrow-based notations that suggest that the basic metaphor "state changes are like motions" plays a fundamental role in all mathematical reasoning involving formal manipulations. If this is correct, structure-mapping inferences implemented by the pre-motor action planning system can be expected to be involved in solving any mathematics problems not solvable by table lookups and number line manipulations alone. Available functional imaging studies of multi-digit arithmetic, algebra, geometry and calculus problem solving are consistent with this expectation. PMID- 23459867 TI - Ultrasound imaging in neurosurgery: approaches to minimize surgically induced image artefacts for improved resection control. AB - BACKGROUND: Intraoperative ultrasound imaging is used in brain tumor surgery to identify tumor remnants. The ultrasound images may in some cases be more difficult to interpret in the later stages of the operation than in the beginning of the operation. The aim of this paper is to explain the causes of surgically induced ultrasound artefacts and how they can be recognized and reduced. METHODS: The theoretical reasons for artefacts are addressed and the impact of surgery is discussed. Different setups for ultrasound acquisition and different acoustic coupling fluids to fill up the resection cavity are evaluated with respect to improved image quality. RESULTS: The enhancement artefact caused by differences in attenuation of the resection cavity fluid and the surrounding brain is the most dominating surgically induced ultrasound artefact. The influence of the artefact may be reduced by inserting ultrasound probes with small footprint into the resection cavity for a close-up view of the areas with suspected tumor remnants. A novel acoustic coupling fluid developed for use during ultrasound imaging in brain tumor surgery has the potential to reduce surgically induced ultrasound artefacts to a minimum. CONCLUSIONS: Surgeons should be aware of artefacts in ultrasound images that may occur during brain tumor surgery. Techniques to identify and reduce image artefacts are useful and should be known to users of ultrasound in brain tumor surgery. PMID- 23459868 TI - Diagnostic value of 99mTc-MDP SPECT/spiral CT in assessing indeterminate spinal solitary lesion of patients without malignant history. AB - OBJECTIVE: Metastases and benign conditions of spine are common, however, the diagnoses of imaging modalities in the nature of spinal lesions are difficult, especially for the solitary lesions in spine. This study aims to retrospectively evaluate the diagnostic value of single photon emission computed tomography (SPECT)/spiral computed tomography (CT) in assessing indeterminate spinal solitary lesion of patients without certain medical history of malignancies. METHODS: A total of 48 patients (28 male, 20 female, average 54.9 +/- 14.8 years) without malignant history but with a solitary lesion of spine on the Tc-99m methylene diphosphonate planar scintigraphy, were enrolled in this study. SPECT/spiral CT was simultaneously performed on the abnormal lesions of the spine. SPECT alone and SPECT/spiral CT images were independently analyzed and interpreted by two experienced nuclear medicine physicians. Finally, the indeterminate spinal single lesion was confirmed with pathological results. The agreements of the SPECT and SPECT/spiral CT diagnoses with the pathology were evaluated using a weighted kappa score, respectively. RESULTS: Among 48 patients, the pathological results revealed 37.5 % (18/48) benign and 62.5 % (30/48) malignant lesions. For SPECT alone, 6 of 18 benign cases and 28 of 30 malignant conditions were correctly diagnosed. For SPECT/spiral CT, 9 of 18 benign and 29 of 31 malignant lesions were exactly judged. For these patients without malignant history, the diagnostic accuracy, specificity, positive predictive value, and negative predictive value of SPECT and SPECT/spiral CT in assessing abnormal spinal solitary lesion were 70.8 % (34/48) vs 79.2 % (38/48), 33.3 % (6/18) vs 50.0 % (9/18), 70.0 % (28/40) vs 76.3 % (29/38), 75.0 % (6/8) vs 90.0 % (9/10), respectively. Moreover, the kappa scores for the agreement of SPECT alone and SPECT/spiral CT with the pathological confirmation were 0.300 and 0.512, respectively (both P < 0.005). CONCLUSIONS: Compared with SPECT imaging, hybrid SPECT/spiral CT imaging improves the diagnostic accuracy and specificity in evaluating indeterminate spinal solitary lesion of patients without certain malignant history. Moreover, based on whole-body bone scan with high sensitivity, cheap price, widespread and time-saving use, SPECT/spiral CT is a good imaging modality for the diagnosis and evaluation of the nature of solitary lesion in spine. PMID- 23459869 TI - Not like me = bad: infants prefer those who harm dissimilar others. AB - Adults tend to like individuals who are similar to themselves, and a growing body of recent research suggests that even infants and young children prefer individuals who share their attributes or personal tastes over those who do not. In this study, we examined the nature and development of attitudes toward similar and dissimilar others in human infancy. Across two experiments with combined samples of more than 200 infant participants, we found that 9- and 14-month-old infants prefer individuals who treat similar others well and treat dissimilar others poorly. A developmental trend was observed, such that 14-month-olds' responses were more robust than were 9-month-olds'. These findings suggest that the identification of common and contrasting personal attributes influences social attitudes and judgments in powerful ways, even very early in life. PMID- 23459870 TI - Out of mind, out of sight: perceptual consequences of memory suppression. AB - In the present study, the effect of memory suppression on subsequent perceptual processing of visual objects was examined within a modified think/no-think paradigm. Suppressing memories of visual objects significantly impaired subsequent perceptual identification of those objects when they were briefly encountered (Experiment 1) and when they were presented in noise (Experiment 2), relative to performance on baseline items for which participants did not undergo suppression training. However, in Experiment 3, when perceptual identification was performed on mirror-reversed images of to-be-suppressed objects, no impairment was observed. These findings, analogous to those showing forgetting of suppressed words in long-term memory, suggest that suppressing memories of visual objects might be mediated by direct inhibition of perceptual representations, which, in turn, impairs later perception of them. This study provides strong support for the role of inhibitory mechanisms in memory control and suggests a tight link between higher-order cognitive operations and perceptual processing. PMID- 23459871 TI - Feeling worse to feel better: pain-offset relief simultaneously stimulates positive affect and reduces negative affect. AB - Although pain itself induces negative affect, the removal (or offset) of pain induces a powerful state of relief. Despite being implicated in a wide range of psychological and behavioral phenomena, relief remains a poorly understood emotion. In particular, some theorists associate relief with increased positive affect, whereas others associate relief with diminished negative affect. In the present study, we examined the affective nature of relief in a pain-offset paradigm with psychophysiological measures that were specific to negative valence (startle eyeblink reactivity) and positive valence (startle postauricular reactivity). Results revealed that pain offset simultaneously stimulates positive affect and diminishes negative affect for at least several seconds. Results also indicated that pain intensity differentially affects the positive and negative valence aspects of relief. These findings clarify the affective nature of relief and provide insight into why people engage in both normal and abnormal behaviors associated with relief. PMID- 23459872 TI - Effects of autocrine vascular endothelial growth factor (VEGF) in non-small cell lung cancer cell line A549. AB - It is reported that the autocrine loop of the vascular endothelial growth factor (VEGF) is crucial for the survival and proliferation of non-small cell lung cancer (NSCLC) tumors. In this study we aimed to systematically investigate the role of autocrine vascular VEGF in NSCLC cell line A549 through inhibition of endogenous VEGF. A549 cells were transfected with florescence-labeled VEGF oligodeoxynucleotide with lipofectamine. For the experimental group, cells were transfected with VEGF anti-sense oligodeoxynucleotide (ASODN), sense oligodeoxynucleotide (SODN) and mutant oligodeoxynuleotide (MODN) respectively. For the control group cells were mock transfected with lipofectamine or culture medium. At indicated time point after transfection, the expression levels of VEGF mRNA and protein in A549 cells were analyzed by RT-PCR and ELISA respectively. Cell viability was measured by the MTT assay. Cell cycle distribution was detected by flow cytometry. As revealed by RT-PCR assay, the mRNA level of VEGF in cells transfected with ASDON was significantly lower than the other four groups (P < 0.05) at 24 and 48 h after transfection. ELISA assay yielded similar result with significantly decreased level of VEGF protein expression (P < 0.05). The survival fraction of A549 cells transfected with ASDON was significantly lower than the other four groups (P < 0.05) at 24 h after transfection. Also the percentage of G2 phase cells of ASODN group was significantly lower than other four groups. Our data indicate that VEGF expression is efficiently inhibited in A549 cells by ASODN transfection and this inhibition leads to inhibited cell growth and impaired cell cycle distribution. PMID- 23459874 TI - [Psychiatry - finally de-stigmatized?]. PMID- 23459875 TI - [Generation y: problematic consequences for psychiatry and psychotherapy - pro & contra]. PMID- 23459876 TI - [Generation y: problematic consequences for psychiatry and psychotherapy - pro & contra]. PMID- 23459873 TI - N400 ERPs for actions: building meaning in context. AB - Converging neuroscientific evidence suggests the existence of close links between language and sensorimotor cognition. Accordingly, during the comprehension of meaningful actions, our brain would recruit semantic-related operations similar to those associated with the processing of language information. Consistent with this view, electrophysiological findings show that the N400 component, traditionally linked to the semantic processing of linguistic material, can also be elicited by action-related material. This review outlines recent data from N400 studies that examine the understanding of action events. We focus on three specific domains, including everyday action comprehension, co-speech gesture integration, and the semantics involved in motor planning and execution. Based on the reviewed findings, we suggest that both negativities (the N400 and the action N400) reflect a common neurocognitive mechanism involved in the construction of meaning through the expectancies created by previous experiences and current contextual information. To shed light on how this process is instantiated in the brain, a testable contextual fronto-temporo-parietal model is proposed. PMID- 23459877 TI - [A myth of Jekyll and Hyde?]. AB - AIM: People widely believe that schizophrenia goes along with a split personality. Little is known, however, about the consequences of this belief. In this study, we tested whether the split-personality-belief is associated with stigmatization of schizophrenia. METHODS: A sample of 416 persons was recruited from the general population. In an online-survey, the split-personality-belief, the stereotypes dangerousness and unpredictability/incompetence and individual discrimination (i. e. desired social distance) of persons diagnosed with schizophrenia were assessed by self-report. RESULTS: The split-personality-belief was associated with increased perceived dangerousness, unpredictability/incompetence and desired social distance. Both stereotypes mediated the relationship of split-personality-belief and desired social distance. CONCLUSION: The split-personality-belief is associated with and may even contribute to stigmatiziation of persons with schizophrenia. Efforts to reduce stigmatization are likely to benefit from battling this misconception. PMID- 23459878 TI - [Calling it "Burnout" Instead of "Depression" - A Strategy to Avoid Stigma?]. AB - OBJECTIVE: To find out to what extent the German public uses the term "burnout" to label a depressive episode, and to examine how this label relates to stigmatizing attitudes and treatment recommendations. METHODS: Representative population surveys in Germany 2001 (n = 5025) and 2011 (n = 3642), using unlabeled case vignettes of mental disorders. RESULTS: Labeling a depressive episode "burnout" increased from 0.3 % in 2001 to 10.2 % in 2011. Schizophrenia and alcohol dependence were labeled "burnout" far less frequently. Compared to the label "depression", "burnout" was associated with less desire for social distance, but also with less recommendation of psychotherapy, medication, and seeing a psychiatrist. CONCLUSION: While provoking less desire for social distance than "depression", using the label "burnout" carries the risk of increasing the proportion of untreated depressive episodes. PMID- 23459879 TI - [Traumatic experiences: a blind spot in stigma research?]. PMID- 23459882 TI - Meniscus confined fabrication of multidimensional conducting polymer nanostructures with scanning electrochemical cell microscopy (SECCM). AB - Scanning electrochemical cell microscopy (SECCM) is demonstrated as a new approach for the construction of extended multi-dimensional conducting polymer (polyaniline) nanostructures, making use of a mobile dual-channel theta pipette cell to control and monitor the location, rate and extent of electropolymerisation. PMID- 23459884 TI - Challenges for nursing human resources. PMID- 23459883 TI - Interferon induced IFIT family genes in host antiviral defense. AB - Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IFN-stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5; however, bird, marsupial, frog and fish have only IFIT5. Regardless of species, IFIT5 is always adjacent to SLC16A12. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. However, some viruses can escape the antiviral functions of the IFIT family by suppressing IFIT family genes expression or methylation of 5' cap of viral molecules. In addition, the variants of IFIT family genes could significantly influence the outcome of hepatitis C virus (HCV) therapy. We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals. PMID- 23459885 TI - Quality of life of seniors living in the community and in long term care facilities: a comparative study. AB - OBJECTIVES: to compare the perceptions of quality of life (QOL) and to identify factors associated with QOL among seniors living in the community in Porto Alegre, RS and institutionalized seniors from the countryside of Minas Gerais, Brazil. METHOD: this study used secondary data from two cross-sectional epidemiological studies. The sample consisted of 288 seniors living in the community and 76 institutionalized seniors. An instrument addressing socio demographic data and the WHOQOL-BREF were administered. RESULTS: bivariate analysis showed that age, gender, schooling, self-reported health, and leisure presented statistically significant differences between institutionalized and non institutionalized seniors. The Psychological and Social Relationships domains also presented statistically significant differences. The variables that presented significant correlation in multivariate analysis in relation to the Psychological domain were education, assessments of health, leisure and in relation to the Social domain, education and age. CONCLUSION: being institutionalized did not influence the older adults' perceptions of QOL, but the socio-demographic characteristics and self-assessments of health did. PMID- 23459886 TI - Prevalence of fatigue and associated factors in chronic low back pain patients. AB - OBJECTIVES: to determine the prevalence and key factors associated with fatigue in chronic low back pain patients. METHODS: cross-sectional study of 215 chronic low back pain patients from three health care centers and two industrial corporations. The crude prevalence of fatigue and its 95% confidence interval (CI) were calculated. Associations between fatigue and the independent variables were measured. RESULTS: the prevalence of fatigue among the participants was 26.0% [95% CI: 20.3-32.5]. Fatigue was independently associated with depression and self-efficacy. An increase of one unit in the score of depression increased the risk of fatigue by 9%; an increase of one unit in the score of self-efficacy reduced the risk of fatigue by 2%. CONCLUSIONS: fatigue was prevalent in chronic low back pain patients and associated with depression and self-efficacy. Knowing these factors can direct strategies for prevention and control of fatigue in chronic low back pain patients. PMID- 23459887 TI - Home visit improves knowledge, self-care and adhesion in heart failure: Randomized Clinical Trial HELEN-I. AB - OBJECTIVE: To verify the effect of an educative nursing intervention composed of home visits and phone calls on patients' knowledge about the disease, self-care and adhesion to the treatment. METHODS: Randomized clinical trial with patients with recent hospitalization caused by decompensated heart failure. There were two groups: the intervention group, which has received four home visits and four phone calls to reinforce the guidelines during six months of follow up; and the control group, which has received conventional follow up with no visits or phone calls. RESULTS: Two hundred patients were randomized (101 in the intervention group and 99 in the control group). After six months, a significant improvement was observed in self-care and knowledge about the disease in the intervention group (P=0.001 and P<0.001), respectively; the adhesion to the treatment, measured and compared between the groups, was significantly higher in the intervention group (P=0.001). CONCLUSION: the strategy of home visits to patients who were recently hospitalized with decompensated heart failure was effective in improving the outcomes assessed and its implementation deserves to be considered in Brazil aiming at avoiding unplanned hospitalizations. NCT-01213862. PMID- 23459888 TI - The representations of human vulnerability held by health workers--development and validation of a scale. AB - OBJECTIVES: This study's objective consisted of the construction and validation of a scale to identify the representation of human vulnerability in the health field. METHOD: its development was divided into three steps: a bibliographic review and exploratory interviews were conducted to establish the items and their subsequent aggregation into dimensions; evaluation by an expert committee; and pre-test. The scale's psychometric properties were evaluated based on its application to a sample of individuals (nurses, physicians, and senior nursing and medical undergraduate students). Validity, reliability, and internal consistency tests were performed. RESULTS: the scale obtained consists of four dimensions (knowledge of intrinsic vulnerability, knowledge of extrinsic vulnerability, experience of vulnerability, and perception of vulnerability in patients). The scale presents good internal consistency with high Cronbach's alpha coefficient values. CONCLUSION: The Representation of Human Vulnerability in Health Workers Scale is easy to apply and presents reliable psychometric properties. It is an innovative tool that can be used in the development of studies addressing human vulnerability. PMID- 23459889 TI - Nurses in advanced roles: a review of acceptability in Portugal. AB - OBJECTIVE: This paper focuses on the policy context for the deployment of nurses in advanced roles, with particular reference to Portugal. The health sector in Portugal, as in all countries, is labour intensive, and the scope to utilise nurses in more advanced roles is currently being debated. METHODS: Mixed methods were used: an analysis of international data on the nursing workforce; an analysis of documents and media articles; interviews with key-informants; an online survey of managers, and a technical workshop with key-informants. CONCLUSIONS: The limited evidence base on nurses in advanced roles in Portugal is a constraint on progress, but it is not an excuse for inaction. Further research in Portugal on health professionals in innovative roles would assist in informing policy direction. There is the need to move forward with a fully informed policy dialogue, taking account of the current political, economic and health service realities of Portugal. PMID- 23459890 TI - Effectiveness of 10% povidone-iodine drying time before peripheral intravascular catheter insertion: preliminary results from an explorative quasi-experimental study. AB - AIM: to investigate the effectiveness of 10% povidone-iodine after a 30-second or 2-minute drying time on microbial count reduction at the point of a Peripheral Intravascular Catheter (PIC) insertion. A quasi-experimental design was adopted. In total, 53 patients were enrolled, 25 were exposed to a 2-m drying time and 28 to a 30-s drying time. From the preliminary results of this study, no differences in the occurrence of contamination have emerged between patients receiving 30-s and 2-m drying time for 10% povidone-iodine solutions. PMID- 23459891 TI - Evaluation of elderly persons' functionality and care needs. AB - OBJECTIVE: To evaluate the elderly persons' functionality, based on the International Classification of Functionality. METHODS: a cross-sectional, descriptive study; a stratified random sample of 903 elderly persons; a confidence level of 95%; and a margin of error of 2.5%. Questionnaire based on the International Classification of Functionality; data was collected based on structured interviews undertaken by health professionals in the health centers in the Alentejo region of Portugal. RESULTS: 30.7% of the elderly persons stated that they were illiterate, and 22.9% lived alone. Feeding/dietary (18.7%), housing (19.2%) and health needs (26.0%) were not met. Orientation functions were maintained in 83.4%; 58% of the elderly persons referred to pain so intense that it required care; 73.3% of the elderly persons did not have functional dentition. Levels of performance were superior to 80% in the participation activities: washing oneself (82.6%), toileting (92.2%), dressing, eating, and drinking (89%). CONCLUSION: although a progressive decline in functionality is observed as age advances, the majority of dimensions are preserved until around 75 years of age. PMID- 23459892 TI - Psychosocial study about the consequences of work in hospital nurses as human resource management. AB - OBJECTIVES: To analyze the relation between psychosocial and sociodemographic variables in nursing professionals. To discover the levels of job satisfaction, psychosomatic symptoms and psychological well-being in nurses. METHOD: The research was conducted in a sample of 476 nurses / as from nine hospitals in the region of Murcia (Spain). An occupational health protocol was distributed among the sample participants for completion, which contained tools for measuring and describing psychosocial and sociodemographic variables. RESULTS: Although there is no high risk for psychological problems among the sample participants, psychosomatic symptoms, job dissatisfaction, and low psychological wellbeing are present. CONCLUSIONS: The results contribute to research on the subject by identifying the presence of psychosocial disorders in nursing professionals, associated with job conditions and certain psychosocial and sociodemographic variables. PMID- 23459893 TI - Evaluation of self-esteem in nursing teachers at public and private universities. AB - The aim of this study was to evaluate the self-esteem of Nursing faculty in public and private universities and compare the measures presented by two groups of teachers. This descriptive, correlational, cross-sectional quantitative study was conducted with 71 teachers from two universities (public and private) from a municipality in the south of the State of Minas Gerais. After pilot testing and validation, A questionnaire and the Rosenberg Self-Esteem Scale were used. It was found that most teachers had high self-esteem, with no significant difference between the two groups. When the continuous scores on this scale were analyzed, there was a significant difference between universities, showing that the private university teachers had lower self-esteem scores. The Rosenberg Self-Esteem Scale showed high value for coefficient alpha. It was concluded that self-esteem was high predominantly in the studied teachers, but those from the private university had lower scores. These data may help institutions to reflect on the issue and invest in building healthy environments, with the worker/teacher of Nursing as the protagonist, which represents advancement in the knowledge of the subject in the field of Nursing. PMID- 23459894 TI - Moral distress in nursing personnel. AB - OBJECTIVE: to analyze the frequency and intensity of moral distress experienced by nursing personnel in southern Brazil, covering elements of their professional practice. METHOD: a survey was undertaken in two hospitals in Rio Grande do Sul, Brazil, with 247 nurses. Data was collected by means of the adapted Moral Distress Scale. RESULTS: the perception of situations that lead to moral distress is enhanced in nurses and in nursing staff working in institutions with greater openness to dialogue, which hold team meetings, with fewer working hours and a greater ratio of professionals to patients. CONCLUSION: understanding moral distress allows us to go beyond solving the problems of the workers themselves, enabling the development of an ethics of active individuals and wide opportunities, defined mainly by the relationship with oneself. PMID- 23459895 TI - Clinical validation of the nursing diagnosis labor pain. AB - OBJECTIVE: The study intends to identify the presence of clinical indicators of pain during labor and to correlate the verbal reference of pain intensity with uterine contractions as a proposal to validate the clinical nursing diagnosis Labor Pain. METHOD: Observational study of the 22 clinical indicators that represented the defining characteristics for the diagnosis. RESULTS: There were 55 participants in labor (18 in the initial active stage, 6 in the final active stage and 31 in both stages), over 18 years old, in their first pregnancy, with effective contractions and cervical dilation of 4 cm or more. Among the 22 defining characteristics tested, 6 were present in most participants during the two stages: verbal or codified report, noted evidence of uterine contraction, altered muscle tension, noted evidence of pain, expressive behavior and facial expression of pain. There were differences between the stages in relation to perspiration, facial expression of pain, protective gestures, anodyne position, distractive behavior, self-focus and perineum pressure feeling. CONCLUSIONS: A positive linear correlation was noted between pain intensity scores and the extent of intra-uterine pressure in the initial stage. Labor pain was proven to be compatible with a nursing diagnosis. PMID- 23459896 TI - Validation of the concept risk for decreased cardiac output. AB - OBJECTIVES: to validate the concept "risk for decreased cardiac output". METHOD: Six of the eight steps suggested in the technique developed by Walker & Avant were adopted to analyze the concept of the phenomenon under study and the proposal made by Hoskins was used for content validation, taking into account agreement achieved among five experts. RESULTS: the concept "decreased cardiac output" was found in the nursing and medical fields and refers to the heart's pumping capacity while the concept "risk" is found in a large number of disciplines. In regard to the defining attributes, "impaired pumping capacity" was the main attribute of decreased cardiac output and "probability" was the main attribute of risk. The uses and defining attributes of the concepts "decreased cardiac output" and "risk" were analyzed as well as their antecedent and consequent events in order to establish the definition of "risk for decreased cardiac output", which was validated by 100% of the experts. CONCLUSION: The obtained data indicate that the risk for decreased cardiac output phenomenon can be a nursing diagnosis and refining it can contribute to the advancement of nursing classifications in this context. PMID- 23459897 TI - Oral Anticoagulation: the impact of the therapy in health-related quality of life at six-month follow-up. AB - OBJECTIVE: to study the changes in health-related quality of life from beginning of anticoagulation therapy to six-month follow-up, and to study associations of sociodemographic and clinical characteristics with measures of quality of life and general health status at six-month follow-up, in individuals using oral anticoagulation due to various medical indications for the therapy. METHOD: prospective study performed at a city in the state of Parana, Brazil, composed of 78 patients. Measures included the Duke Anticoagulation Satisfaction Scale and the Medical Outcomes Survey Short Form SF-36. RESULTS: mean age was 57 years (S.D.= 16) and 54% were women. Compared to the beginning of therapy, there was a statistically significant improvement in health-related quality of life at six month follow-up. Linear regression analyses explained 32% and 30%, respectively, of the variance of the Duke Anticoagulation Satisfaction Scale and of the general health status. There was improvement in all components of the SF-36, except Mental Health. CONCLUSION: The use of oral anticoagulation therapy was associated with improvement in health-related quality of life in the first six months of therapy. This study is longitudinal and therefore, has fewer limitations than cross-sectional studies published to date in the Nursing literature in Brazil. PMID- 23459898 TI - Ethics constructed through the process of nurse training: conceptions, spaces and strategies. AB - OBJECTIVE: to discuss the professors' conceptions about the ethical dimension of nurse training based on the relationships which this establishes with the competencies with the professional profile; and to identify the spaces and strategies for the teaching of ethics in this process. METHOD: A qualitative study delineated as a case study. The data was collected based on focus groups with professors from six undergraduate nursing courses in the state of Santa Catarina, Brazil, totaling 50 subjects. Based on the professors' discourse, the conceptions and mutual relations between professional competencies, the formative process and ethics were analyzed. RESULTS: The results were organized and the discussion explored through the thematic categories: The ethics constructed in the process of training nurses - the professors' conceptions, and spaces and strategies for the teaching of ethics in nurse training. CONCLUSIONS: The issue of ethics was shown to be transversal in the formative process. The study evidenced the challenge of creating spaces and strategies for teaching and fosters discussion about the new demands for changes placed upon the nursing schools, about the suitability of the care setting, and about the exercising of critical and problem-based education. PMID- 23459899 TI - Individualized teaching programming for a virtual learning environment: development of content concerning nursing records. AB - OBJECTIVE: Describe the planning of contents on nursing records for use in a virtual learning environment, based on Individualized Teaching Programming, a didactic resource that uses basic principles of behavioral analysis. METHOD: Final objectives were specified, after defining the intermediary components to achieve each final objective, as well as the preliminary requirements for each intermediary component. At the end of this process, teaching activities were planned and organized in steps the students need to develop. RESULTS: By breaking up the contents into behaviors, seven action categories emerged: impartiality, organization, honesty, objectiveness, coherence, readability and discernment. CONCLUSION: the use of Individualized Teaching Programming as a didactic resource to plan contents on nursing records is feasible to identify the units and modules for the development of a course in a virtual learning environment for nursing professionals. PMID- 23459900 TI - Secondary health care: best practices in the health services network. AB - OBJECTIVE: to understand the organization of health practices, based on the interactions at the secondary care level, and to analyze how the actions and services at this level of care contribute to the development of best practice in health. METHOD: a qualitative approach, based in Grounded Theory. Data was obtained from individual interviews, with managers, health care professionals and health service users making up the sample group representing the secondary level of healthcare. The theoretical model was formulated based on four categories, analyzed based in the elements of the network modeling of health care theoretical framework. RESULTS: The organization of health practices at a secondary level is in the process of consolidation and is contributing to the development of best practices in the locale studied. CONCLUSION: The broadening of access to consultations and specialized procedures, and the articulation of the network's points, are aspects of this level of care which are considered essential for care which is effective and integral. This study contributes to the analysis of health practices from the perspective of network modeling, based on the interactions between secondary care and the health system's other health facilities, which are shown as going through a process of consolidation in the locale studied. PMID- 23459901 TI - Clinical validation of the Preterm Oral Feeding Readiness Assessment Scale. AB - INTRODUCTION: Health professionals have great difficulties to establish the adequate and safe time to start breast feeding in preterm infants. There is a need to develop a standardized tool to help health professionals to comprehensively evaluate preterm infant readiness to transition preterm infants' feeding from gastric to oral, and encourage breast feeding practice in neonatal units. AIMS: To clinical validate the accuracy of a Preterm Oral Feeding Readiness Assessment Scale with 60 clinically stable preterm infants. METHODS: Global accuracy, sensitivity and specificity of Preterm Oral Feeding Readiness Assessment Scale cut-offs, compared to milk intake through translactation, were estimated through ROC curves (Receiver Operating Characteristic Curves). RESULTS: The global accuracy of Preterm Oral Feeding Readiness Assessment Scale was 74.38%. The highest sensitivity and specificity were obtained for three cut-offs: 28, 29 and 30. Since higher specificity (75.68%) for the Preterm Oral Feeding Readiness Assessment Scale was found at a score cut-off=of 30 showed higher specificity (75.68%), it should be used as a cut-off score to select initiate breastfeeding the preterm newborns' oral feeding readiness. CONCLUSION: The Preterm Oral Feeding Readiness Assessment Scale is considered valid to assist health professionals to initiate preterm feeding in view of promoting safe and objective breastfeeding. PMID- 23459902 TI - Nursing workload and patient safety--a mixed method study with an ecological restorative approach. AB - OBJECTIVE: The aim of this study was to analyze the potential association between nursing workload and patient safety in the medical and surgical inpatient units of a teaching hospital. METHOD: a mixed method strategy (sequential explanatory design). RESULTS: the initial quantitative stage of the study suggest that increases in the number of patients assigned to each nursing team lead to increased rates of bed-related falls, central line-associated bloodstream infections, nursing staff turnover, and absenteeism. During the subsequent qualitative stage of the research, the nursing team stressed medication administration, bed baths, and patient transport as the aspects of care that have the greatest impact on workload and pose the greatest hazards to patient, provider, and environment safety. CONCLUSIONS: The findings demonstrated significant associations between nursing workload and patient safety. We observed that nursing staff with fewer patients presented best results of care-related and management-related patient safety indicators. In addition, the tenets of ecological and restorative thinking contributed to the understanding of some of the aspects in this intricate relationship from the standpoint of nursing providers. They also promoted a participatory approach in this study. PMID- 23459903 TI - Stress and depression among students of the last semester in two nursing courses. AB - OBJECTIVE: to identify the presence of stress and depression among final year students of two nursing courses, and the association between these variables. METHOD: an exploratory-descriptive study, undertaken with final-year students from the Bachelor's degree and Licenciate's degree courses at the Ribeirao Preto College of Nursing, of the University of Sao Paulo. The Perceived Stress Scale (PSS) and Beck Depression Inventory (BDI) were applied. RESULTS: of the total of 88 participants in the study, 69.8% have no depression, 18.2% presented dysphoria, 6.8% moderate depression, and 5.7% severe depression, which is a low rate compared to the general population. Medium stress levels were the most frequent (76.9%). There was no significant statistical difference in the stress score between the two groups of students (Student's t-test: p=0.295>0.05). The data showed a relation between the stress and the presence of indicative signs of depression, especially severe depression (Pearson: r-0.755 and p<0.01). DISCUSSION: The majority did not show signs of depression. The depressive states found among the students on the two courses accompanied proportionately those who obtained high stress scores, as recorded by other studies on this issue. CONCLUSION: Students with higher levels of stress are more prone to present depression, deserving educators' attention. PMID- 23459904 TI - Rasch Analysis of the Power as Knowing Participation in Change Tool--the Brazilian version. AB - OBJECTIVES: the objective of this study was to evaluate the items contained in the Brazilian version of the Power as Knowing Participation in Change Tool (PKPCT). METHOD: investigation of the psychometric properties of the mentioned questionnaire through Rasch analysis. RESULTS: the data from 952 nursing assistants and 627 baccalaureate nurses were analyzed (average age 44.1 (SD=9.5); 13.0% men). The subscales Choices, Awareness, Freedom and Involvement were tested separately and presented unidimensionality; the categories of the responses given to the items were compiled from 7 to 3 levels and the items fit the model well, except for the following/leading item, in which the infit and outfit values were above 1.4; this item has also presented Differential Item Functioning (DIF) according to the participant's role. The reliability of the items was of 0.99 and the reliability of the participants ranged from 0.80 to 0.84 in the subscales. Items with extremely high levels of difficulty were not identified. CONCLUSIONS: the PKPCT should not be viewed as unidimensional, items with extremely high levels of difficulty in the scale need to be created and the differential functioning of some items has to be further investigated. PMID- 23459905 TI - Primary care nurses' approach to cases of violence against children. AB - In Primary Care, the field of nursing comes face-to-face with the complexity of violence, leading these professionals to constantly re-evaluate their habitus. OBJECTIVE: to analyze how cases of violence against children and adolescents are approached by primary care nurses, identifying limits and possibilities for dealing with these cases. METHOD: a qualitative study, undertaken in 2011, through semi-structured interviews with 8 out of 48 nurses in the Family Health teams in the city of Uberaba in the state of Minas Gerais, the analysis of which followed the interpretation of meanings, based in dialectical hermeneutics. RESULTS: the following stand out: non-identification of violence as a problem for the nurses; denunciations and notifications as a role of the nurses; and the limits found in the face of violence. CONCLUSION: it is determined that the habitus of nursing directed at health promotion and prevention of violence must be restructured, overcoming the biomedical paradigm and involving intersectorial and multidisciplinary actions. PMID- 23459906 TI - The "Moving Heart Program": an intervention to improve physical activity among patients with coronary heart disease. AB - AIM: this paper reports the results of a nursing-administered theory-based intervention, the "Moving Heart Program", based on the implementation intention theory and pointed at improving physical activity adherence among coronary heart disease outpatients in Brazil. METHODS: this experimental study applied assessments at baseline, 1 and 2 months after baseline. The Consolidated Standards of Reporting Trials statement was followed. Participants were randomly assigned to intervention, comprising action and coping plans on how to deal with anticipated barriers (n=69), or a standard-care control group (n=67). RESULTS: participants submitted to the intervention showed significant higher levels of physical activity 2 months after baseline and were significantly more active than the control group. CONCLUSIONS: the results indicate that the intervention is feasible for patients with coronary heart disease and can be a useful tool to facilitate intended lifestyle changes. This study brings relevant contributions to the Nursing field and other health-related areas, once the intervention presents low cost to health services and can be applied in cardiac rehabilitation programs, showing significant benefits to participants. PMID- 23459907 TI - Early diagnosis of tuberculosis in the health services in different regions of Brazil. AB - OBJECTIVE: To analyze the infected person's first contact with the health services, for the early diagnosis of tuberculosis (TB) in different regions of Brazil. METHOD: a cross-sectional study undertaken in 6 municipalities in the South-east, South and North-east regions of Brazil. Data collection involved secondary sources and interviews with the patients. The data was analyzed using descriptive techniques and multiple correspondence factor analysis. RESULTS: Primary Health Care (PHC) presented the longest time to diagnosis and the lowest proportion of diagnoses. The services associated with diagnosis in the first consultation were the specialized services and the Tuberculosis Control Programs, which offer consultations and tests on-site. CONCLUSION: For the control of TB, it is necessary to organize the work in an integrated way between the different services' teams. In Primary Health Care, it is also necessary to observe the extent of incorporation and sustainability in the implementation of these actions into the health services' daily practice. PMID- 23459908 TI - Organizational influence on the occurrence of work accidents involving exposure to biological material. AB - OBJECTIVES: to analyze work accidents involving exposure to biological materials which took place among personnel working in nursing and to evaluate the influence of the organizational culture on the occurrence of these accidents. METHOD: a retrospective, analytical study, carried out in two stages in a hospital that was part of the Network for the Prevention of Work Accidents. The first stage involved the analysis of the characteristics of the work accidents involving exposure to biological materials as recorded over a seven-year period by the nursing staff in the hospital studied, and registered in the Network databank. The second stage involved the analysis of 122 nursing staff members' perception of the institutional culture, who were allocated to the control group (workers who had not had an accident) and the case group (workers who had had an accident). RESULTS: 386 accidents had been recorded: percutaneous lesions occurred in 79% of the cases, needles were the materials involved in 69.7% of the accidents, and in 81.9% of the accident there was contact with blood. Regarding the influence of the organizational culture on the occurrence of accidents, the results obtained through the analysis of the two groups did not demonstrate significant differences between the average scores attributed by the workers in each organizational value or practice category. It is concluded that accidents involving exposure to biological material need to be avoided, however, it was not possible to confirm the influence of organizational values or practices on workers' behavior concerning the occurrence of these accidents. PMID- 23459909 TI - Conceptual framework for research and clinical practice concerning cardiovascular health-related behaviors. AB - OBJECTIVE: To present a conceptual framework based on the PRECEDE model conceived to guide research and the clinical practice of nurses in the clinical follow-up of patients with cardiovascular diseases. METHOD: The conceptual bases as well as the study designs used in the framework are discussed. The contextualization of the proposed structure is presented in the clinical follow-up of hypertensive patients. Examples of the intervention planning steps according to the intervention mapping protocol are provided. RESULTS: This conceptual framework coherently and rationally guided the diagnostic steps related to excessive salt intake among hypertensive individuals, as well as the development and assessment of specific interventions designed to change this eating behavior. CONCLUSION: The use of this conceptual framework enables a greater understanding of health related behaviors implied in the development and progression of cardiovascular risk factors and is useful in proposing nursing interventions with a greater chance of success. This model is a feasible strategy to improve the cardiovascular health of patients cared for by the Brazilian Unified Health System. PMID- 23459911 TI - Nursing workload in the emergency department: a methodological proposal. AB - OBJECTIVE: This study aimed to propose a methodology for identifying the nursing workload in the Emergency Department (ED). METHODS: this is methodological research, undertaken in a public general hospital in the municipality of Sao Paulo, Brazil, in the areas: triage, shock room, emergency room, suturing room, and medication/procedures for adult and pediatric patients rooms, using different strategies and instruments. Due to the characteristics of the data collection, distinct samples were obtained in each of the areas. RESULTS: The average daily workload, in hours, corresponded to: triage 48; shock room 30.9; emergency 170.6; observation of adult patients 293.6; observation of pediatric patients 108.7; medication/procedures in adult patients 175.5; medication/procedures in pediatric patients 60.4; and suturing 7.9. CONCLUSION: The instruments used for data collection were shown to be appropriate and made it possible to construct a methodological proposal for identification of workload of nursing professionals in E.D. in a general public hospital. PMID- 23459910 TI - Transition of care for the elderly after cerebrovascular accidents--from hospital to the home. AB - OBJECTIVE: to examine the transition of care in families caring for elderly persons who suffered the first episode of a cerebrovascular accident. METHODOLOGY: an instrumental ethnographic case study was used. The sample comprised 20 subjects: 10 caregivers and 10 elderly persons aged 65 or over, of both sexes, with diagnoses of first episode of cerebrovascular accident, capable of communicating, and requiring care from a main carer in their family. The data was collected through interviews, observation, existing documentation and field notes. Qualitative analysis techniques were used to codify and classify the data and to formulate significant categories, which generated typologies of care. RESULTS AND DISCUSSION: The central idea was the Transition of Care and showed the context in three typologies: The care process for the dependent elderly person, Strategies for the care process and Impact and acceptance of the limitations. CONCLUSION: The data indicates that caring for an elderly person after a cerebrovascular accident is a challenge for the family. The data permitted it possible to elaborate a proposal for a model for the organization of the work, with a view to holistic care delivery in the health services, forming a care network, which constitutes an advance for the area of nursing. PMID- 23459912 TI - Prospective risk analysis of the anti-infective medication administration process. AB - OBJECTIVE: The objective of this study was to analyze the potential risks involved in the administration process of intravenous anti-infective medication at a medical clinic, using the Failure Mode and Effect Analysis. METHOD: This exploratory study was conducted at the medical clinic of a hospital in the State of Goias. For data collection we convened a team comprised of six professionals involved in medication treatment: a doctor, nurse, nursing technician, pharmacist, a nursing and a risk manager. A total of 24 meetings were held, for a total of 56 hours. The data were transcribed into an electronic database within Microsoft Excel(r), and the Xfmea4 software was used. RESULT: The results indicated 52 failure modes, 79 effects of failure, and 285 causes of failure. The causes were related to: the management of organizational processes, human resources, physical and material structure. A total of 298 actions for improvement were recommended for 215 causes of high and average priority, 81.9% of which were short-term priorities. The simulation of the impact of the proposed interventions revealed a 79.7% reduction of the high-priority failure modes. CONCLUSION: It was concluded that the study identified potential risks to patients and recommended proactive actions, of rapid application and low cost, evaluated positively in the reduction of risk of occurrence of avoidable incidents, increasing reliability and safety of the medication administration process. Studies like this demonstrate that, with the application of a method of risk analysis, nurses can effectively assist in preventing medication incidents. PMID- 23459913 TI - Nursing teamwork and time to respond to call lights: an exploratory study. AB - AIM: The aim of this exploratory study was to determine whether the level of nursing teamwork is correlated to call light answering time in acute care hospital patient care units. BACKGROUND: Teamwork has been shown to improve productivity. In this study, we examine the relationship between unit call light response time as a measure of productivity and the level of teamwork on the unit. METHOD: The Nursing Teamwork Survey was administered to nursing staff on 18 inpatient units in 3 hospitals. In addition to the overall teamwork score, the NTS has 5 subscales. Call light response times were collected from electronic systems which measures the time it takes for nursing staff on a given unit to respond to patient call lights. RESULTS: There was no significant relationship between call light response time and teamwork overall or on the five subscales. Shared mental models, which comprise the conceptual understanding of the roles and responsibilities of each team member, however was moderately correlated with call-light answering times. CONCLUSIONS: It is logical that shared mental models would be associated with call light response time since a common problem in patient units is the "it's not my job syndrome" where nursing staff do not answer call lights for patients assigned to someone else. More research with a larger number of patient units is needed to validate these findings. PMID- 23459914 TI - Clinical validation of the nursing diagnosis Risk for Aspiration among patients who experienced a cerebrovascular accident. AB - OBJECTIVE: the study's objective was the clinical validation of the nursing diagnosis Risk for Aspiration among patients who experienced cerebrovascular accidents (CVA). METHOD: a prospective cohort study was conducted with 24 patients hospitalized due to a CVA. The instrument used to collect the data addressed the risk factors for respiratory aspiration, validated by concept analysis and by experts. RESULTS: the most frequent risk factors for respiratory aspiration were: dysphagia (54.2%) and impaired physical mobility (41.7%). The prevalence of the nursing diagnosis Risk for Aspiration was 58.3% and the prevalence of respiratory aspiration over the span of 48 hours (monitoring period) was 37.5%. Risk factors for dysphagia and impaired physical mobility were significantly associated with respiratory aspiration. CONCLUSION: the risk factors dysphagia and impaired physical mobility are good predictors of the nursing diagnosis Risk for Aspiration. This study contributed to improving the NANDA-I Taxonomy and the systematization of the nursing process. PMID- 23459915 TI - Waste management in non-hospital emergency units. AB - OBJECTIVE: to analyze waste management in urgency and emergency non-hospital health care service units. METHOD: Epidemiological cross-sectional study undertaken at three Non-Hospital Emergency Units. The data were collected using systematic observation, registered daily in a spreadsheet and checklist, and analyzed through descriptive statistics. RESULTS: the generation of waste varied from 0.087 to 0.138 kg per patient per day. Waste management showed inadequacies in all stages, especially in the separation stage. Infectious waste was found together with common waste, preventing recycling, and piercing and cutting objects were mixed with waste from different groups, increasing the risk of occupational accidents. CONCLUSION: the study reveals the lack of an institutional waste management policy, as demonstrated by the failure of operational stages, involving problems related to management, physical structure, material and human resources at the units. This is relevant for health care units, considering the quality of patient care and its interface with sustainability. PMID- 23459916 TI - Effectiveness of educational programs on reducing the burden of caregivers of elderly individuals with dementia: a systematic review. AB - OBJECTIVE: This study's objective was to analyze the effectiveness of educational and support programs for caregivers on reducing their burden. METHOD: The method used was a systematic review. The following were searched; MEDLINE, LILACS, Embase, Cochrane, Web of Science, SciELO and CINAHL. RESULTS: Seven randomized clinical studies were included. These studies compared an educational program with standard care delivery, assessing the burden of caregivers through the Zarit Burden Interview. After the analysis of sensitivity, four studies were grouped in the meta-analysis showing a statistically significant reduction in caregiver burden among the participants of educational and support programs. CONCLUSION: The evidence obtained in this study suggests that educational and support programs have a positive impact on the reduction of caregiver burden when compared to standard care. Therefore, the inclusion of these programs in institutions providing care to the elderly is effective and should be encouraged. These programs should also share non-pharmacological management strategies for the behavioral and psychological symptoms of dementia. PMID- 23459917 TI - Construction and transformation of social representations of AIDS and implications for health care. AB - OBJECTIVES: to analyze the process of the constitution and evolution of social representations and practices referent to aids, based on studies carried out in the last eleven years among health professionals. METHOD: a comparison of representational structures of aids in different decades was undertaken, accompanied by a study of the silent zone, involving health professionals. Data collection and analysis included techniques of free association, structural analysis, and study of the silent zone. RESULTS: the existence of a process of change was observed in the social representations of aids, with the introduction of the possibility of co-existence with the disease and the reduction of the importance of death. CONCLUSIONS: this process is presented as the result of a complex movement of symbolic constructions arising from human interactions, contributing to knowledge of ways of thinking associated with the syndrome and to professional practices in healthcare. PMID- 23459918 TI - A ruthenium(II) arene complex showing emission enhancement and photocleavage activity towards DNA from singlet and triplet excited states respectively. AB - The emission enhancement behavior and photocleavage activity of a ruthenium(II) arene complex, [(eta(6)-p-cymene)Ru(dppn)(py)](2+) (1) (dppn = 4,5,9,16-tetraaza dibenzo[a,c]naphthacene, py = pyridine), towards DNA were compared with [(eta(6) p-cymene)Ru(bpy)(py)](2+) (2), [Ru(bpy)2(dppz)](2+) (3) and [Ru(bpy)2(dppn)](2+) (4) (bpy = 2,2'-bipyridine, dppz = dipyrido-[3,2-a:2',3'-c]phenazine). It was found that 1 emits fluorescence from the dppn-based ligand-centered (LC) singlet excited state and generates singlet oxygen ((1)O2) from the dppn-based LC triplet excited state. As a result, 1 displays emission enhancement behavior and photocleavage activity towards DNA simultaneously. In contrast, 3 is the most classical DNA light switch but shows poor DNA photocleavage activity, while 4 is an efficient DNA photocleaver but cannot report DNA binding by luminescence enhancement. An increased cytotoxicity against human lung carcinoma cells A549 by about 10-fold was also observed for 1 upon visible light activation. These intriguing properties result from the unique combination of the Ru(II) arene and dppn subunits. PMID- 23459919 TI - Cortical output to fast and slow muscles of the ankle in the rhesus macaque. AB - The cortical control of fast and slow muscles of the ankle has been the subject of numerous reports yielding conflicting results. Although it is generally agreed that cortical stimulation yields short latency facilitation of fast muscles, the effects on the slow muscle, soleus, remain controversial. Some studies have shown predominant facilitation of soleus from the cortex while others have provided evidence of differential control in which soleus is predominantly inhibited from the cortex. The objective of this study was to investigate the cortical control of fast and slow muscles of the ankle using stimulus triggered averaging (StTA) of EMG activity, which is a sensitive method of detecting output effects on muscle activity. This method also has relatively high spatial resolution and can be applied in awake, behaving subjects. Two rhesus macaques were trained to perform a hindlimb push-pull task. Stimulus triggered averages (StTAs) of EMG activity (15, 30, and 60 MUA at 15 Hz) were computed for four muscles of the ankle [tibialis anterior (TA), medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus] as the monkeys performed the task. Poststimulus facilitation (PStF) was observed in both the fast muscles (TA, MG, and LG) as well as the slow muscle (soleus) and was as common and as strong in soleus as in the fast muscles. However, while poststimulus suppression (PStS) was observed in all muscles, it was more common in the slow muscle compared to the fast muscles and was as common as facilitation at low stimulus intensities. Overall, our results demonstrate that cortical facilitation of soleus has an organization that is very similar to that of the fast ankle muscles. However, cortical inhibition is organized differently allowing for more prominent suppression of soleus motoneurons. PMID- 23459920 TI - Spontaneously amplified homochiral organic-inorganic nano-helix complexes via self-proliferation. AB - Most spiral coiled biomaterials in nature, such as gastropod shells, are homochiral, and the favoured chiral feature can be precisely inherited. This inspired us that selected material structures, including chirality, could be specifically replicated into the self-similar populations; however, a physicochemical understanding of the material-based heritage is unknown. We study the homochirality by using calcium phosphate mineralization in the presence of racemic amphiphilic molecules and biological protein. The organic-inorganic hybrid materials with spiral coiling characteristics are produced at the nanoscale. The resulted helixes are chiral with the left- and right-handed characteristics, which are agglomerated hierarchically to from clusters and networks. It is interesting that each cluster or network is homochiral so that the enantiomorphs can be separated readily. Actually, each homochiral architecture is evolved from an original chiral helix, demonstrating the heritage of the matrix chirality during the material proliferation under a racemic condition. By using the Ginzburg-Landaue expression we find that the chiral recognition in the organic-inorganic hybrid formation may be determined by a spontaneous chiral separation and immobilization of asymmetric amphiphilic molecules on the mineral surface, which transferred the structural information from the mother matrix to the descendants by an energetic control. This study shows how biomolecules guide the selective amplification of chiral materials via spontaneous self-replication. Such a strategy can be applied generally in the design and production of artificial materials with self-similar structure characteristics. PMID- 23459921 TI - [Transurethral resection of the prostate and current modifications (bipolar, electrovaporization)]. AB - Transurethral resection of the prostate (TURP) is the surgical standard which is truly minimally invasive by using a natural orifice and is also of durable efficacy. The use of TURP removes tissue from benign prostatic hyperplasia (BPH) and leads to clinically relevant improvement in symptoms and quality of life as well as in micturition parameters and obstruction. Tissue is removed by high frequency (HF) current with synchronous hemostasis. Many modifications of TURP, such as the use of video, have become generally accepted and improved the standard. Other modifications were developed because the balance between cutting and hemostasis needed improvement in favor of hemostasis. Several modifications of TURP, such as modulation of HF pulses, band loops and bipolar resection and new procedures, such as vaporization and enucleation showed improved hemostasis. These modifications and procedures, however, have not yet replaced standard TURP but have become established as additional options. PMID- 23459922 TI - [Management of ureteral stones]. AB - Ureteral stones are normally clinically symptomatic as colic or flank pain. The investigation of acute flank pain by diagnostic imaging targets on the confirmation of the suspected ureteral stone and the exclusion of other diseases. Furthermore, imaging using unenhanced computed tomography (NCCT) or excretory urography (IVU) serves as a basis for treatment planning. Depending on the size and location of ureteral stones a spontaneous stone passage, medical expulsive therapy (MET), extracorporeal shock wave lithotripsy (SWL), ureterorenoscopy (URS) or initially just simple stenting can be considered. The aim of this review is to provide the reader with the necessary decision criteria for optimal care of patients in the daily routine. PMID- 23459923 TI - [The care situation of patients with interstitial cystitis in Germany: results of a survey of 270 patients]. AB - BACKGROUND: Using a comprehensive questionnaire the care situation of 270 patients with interstitial cystitis (IC) and bladder pain syndrome in Germany was recorded. Despite comprehensive literature on IC (62,000 citations in PubMed) almost nothing is known of the everyday care and quality of patient care in Germany. RESULTS: In total 94% of the patients were women and 6% men, the average age of women was 53.5 years and that of men 67 years and 47.77% of the patients felt that they were well or very well informed about the disease whereby the internet was the source of information in many cases. The exchange of information among patients will increase further through social networks. The diagnosis of IC was made most frequently (62.22%) by biopsy and histological examination followed by urodynamics, potassium test, hydrodistension and cystoscopy. The average duration of the diagnosis was 9 years, 46.67% of the patients consulted a doctor more than 20 times before the diagnosis was made and 51.84% had to pass water more than 14 times per day. Frequency, nocturia and pain were the leading symptoms and 25% of the patients complained of urge incontinence. Among oral medications, analgesics were taken most frequently (61.7%) followed by pentosan polysulphate, antidepressants, antiepileptic drugs, antispasmodics and remedies for urinary urgency. In the self-assessment of the success of treatment with oral medications (helped very well and well), pentosan polysulphate, analgesics, antidepressants and antiepileptic drugs were considered to be the best. Medications that restore the glucosamine lining of the bladder were used predominantly for instillation into the bladder included hyaluronic acid, chondroitin sulphate and a combination of both and pentosan polysulphate. In the self-assessment of the success of treatment with instillation therapy (helped very well or well) the order was: chondroitin sulphate (62.69%), hyaluronic acid (55.77%), a combination of both (53.66%) and pentosan polysulphate (46.30%). The electromotive drug administration (EMDA) procedure with the use of direct current to introduce medications into the bladder wall was mentioned surprisingly often, namely, in 119 patients. In the self-assessment success (helped very well or well) was considered the best for intravesical procedures with 61.34%. CONCLUSIONS: Compared with all drug procedures instillation of medications into the bladder was mentioned 368 times and was assessed by the patients as having helped very well and noticeably by 53.53%, followed by special invasive procedures at 50.56%/271 mentions, alternative therapies at 41.11%/287 mentions and oral medication at 39.75%/1,024 mentions. Hyaluronic acid and chondroitin sulphate products, the combination of both and pentosan polysulphate (oral and intravesical) are not reimbursed by the statutory health insurance. Over 40% of patients treated with these therefore discontinued the treatment for reasons of cost. PMID- 23459925 TI - Lessons for Parkinson disease from the parkin genotype. PMID- 23459924 TI - Rabies virus and canine distemper virus in wild and domestic carnivores in Northern Kenya: are domestic dogs the reservoir? AB - Rabies virus (RV) and canine distemper virus (CDV) can cause significant mortality in wild carnivore populations, and RV threatens human lives. We investigated serological patterns of exposure to CDV and RV in domestic dogs (Canis familiaris), African wild dogs (Lycaon pictus), black-backed jackals (Canis mesomelas), spotted hyenas (Crocuta crocuta), striped hyenas (Hyaena hyaena) and African lions (Panthera leo), over a 10-year period, in a Kenyan rangeland to assess the role domestic dogs may play in the transmission dynamics of these two important canid pathogens. Observed patterns of RV exposure suggested that repeated introduction, rather than maintenance, occurred in the wild carnivore species studied. However, RV appeared to have been maintained in domestic dogs: exposure was more likely in domestic dogs than in the wild carnivores; was detected consistently over time without variation among years; and was detected in juveniles (<=1-year-old) as well as adults (>1-year-old). We conclude that this domestic dog population could be a RV reservoir. By contrast, the absence of evidence of CDV exposure for each carnivore species examined in the study area, for specific years, suggested repeated introduction, rather than maintenance, and that CDV may require a larger reservoir population than RV. This reservoir could be a larger domestic dog population; another wildlife species; or a "metareservoir" consisting of multiple interconnected carnivore populations. Our findings suggest that RV risks to people and wild carnivores might be controlled by domestic dog vaccination, but that CDV control, if required, would need to target the species of concern. PMID- 23459926 TI - Protective effects of resveratrol on glutamate-induced damages in murine brain cultures. AB - Resveratrol interacts with the complex III of the respiratory chain, is a radical scavenger and also suppressor of radical formation in the mitochondria. It reduces the intracellular calcium levels in pre- and postsynaptic neurons and also may inhibit the pro-apoptotic factors in glutamate overflow that occurs, e.g. in excitotoxicity. In cell cultures, glutamate overflow leads to formation of free radicals and results in apoptosis. This increase of radical concentration is enhanced by influx of cations like iron or copper ions into the cell. In present study, the beneficial action of resveratrol was investigated in glutamate affected dissociated cultures of mice mesencephalic primary cultures. On the 10th day in vitro, 5 mM of glutamate was administered for 15 min and the cultures were further maintained in medium containing 0, 0.01, 0.1 or 1 MUM of resveratrol. Resveratrol reduced glutamate-induced damages. The number of dopaminergic neurons was increased and their morphology ameliorated when resveratrol followed glutamate treatment. A significant reduction of glutamate-induced radical formation in cultures treated with resveratrol corresponded with a considerable high antioxidative potential of this stilbene determined using the DPPH assay. In addition, ICP-OES was set up to measure the tissues' copper and iron contents in organotypic cortical cultures of glutamate treated (0 or 30 MUM) slices and those in which resveratrol (0, 0.01, 0.1 or 1 MUM) was co-administered. Levels of copper were dose-dependently increased, and also the concentration of iron was higher in resveratrol-treated organotypic cultures. The hypothesis that resveratrol has beneficial actions against glutamate damages was verified. PMID- 23459927 TI - "You just have to live with it": coping with sickle cell disease in Jamaica. AB - Research has shown that living with sickle cell disease (SCD) can be a considerable challenge. Unfortunately, although it is Jamaica's most common genetic disorder, to date, no qualitative research has been conducted on Jamaicans' experiences of SCD. We conducted thematic analysis on transcripts of in-depth semistructured interviews with 30 patients and found two interlinked themes bound up in life with SCD: loss and control. Faced with important losses, respondents used cognitive and behavioral coping strategies to reestablish control over their response to SCD, others' responses to SCD, and SCD's physical manifestations. Although the adaptive nature of some of these strategies is debatable, many facilitate management of the illness. Health care practitioners should encourage positive coping strategies and have nonjudgmental discussions with patients about (potentially) negative ones. They should also share information with nonspecialist doctors and nurses to reduce stigmatization around the illness. More exploration of this underresearched topic is needed. PMID- 23459930 TI - Molecular characterization and genetic structure of Quercus acutissima germplasm in China using microsatellites. AB - Quercus acutissima is native to eastern Asia. It has a wide distribution in China and China is an important component in understanding the ecology and genetic structure of this species. Q. acutissima attained high economic value for hardwood product and can be managed as an energy tree species. To investigate the genetic variation of Q. acutissima provenances, 12 microsatellite primer pairs were used to analyze 672 trees sampled from 28 provenances of Q. acutissima in China. All of the tested microsatellite loci proved to be effective for the studied Q. acutissima provenances. The results revealed that allele numbers varied from 5 to 13 per locus, with an average of 8 alleles per locus. The mean observed heterozygosity and expected heterozygosity were 0.4927 and 0.7023, respectively. The relatedness of the provenances was studied using the arithmetic mean algorithm based on Nei's genetic distance and principal coordinates analysis. Interestingly, both approaches revealed two main groups: one consisted of the eastern Chinese provenances, and the other comprised of the western Chinese provenances. An analysis of molecular variance indicated that most genetic variation was contained within populations (84 %). The two microsatellite markers developed in this study may be employed for genetic characterization of other oak species. Considering the management or breeding programs of Q. acutissima provenances in China, we should treat each main group as a single gene resource. PMID- 23459931 TI - PINK1 rendered temperature sensitive by disease-associated and engineered mutations. AB - Mutations in Parkin or PINK1 are the most common cause of recessively inherited parkinsonism. Parkin and PINK1 function in a conserved mitochondrial quality control pathway, in which PINK1, a putative mitochondrial kinase, directs Parkin, a cytosolic E3 ubiquitin ligase, selectively to dysfunctional mitochondria to promote their isolation, immobilization and degradation by macroautophagy (hereafter, mitophagy). As Parkin recruitment to mitochondria is robustly induced by PINK1 expression on the outer mitochondrial membrane, Parkin recruitment to mitochondria was used as an assay for PINK1 function. Unexpectedly, mutation of serine residues within the activation segment of PINK1 uncovered a temperature sensitive variant of PINK1 (tsPINK1). tsPINK1 allowed for the first time the disassociation of PINK1 activity from its expression and localization. Additionally, extensive mutagenesis identified three disease-associated variants in the activation segment and one in an alpha-helix N-terminal to kinase domain (Q126P) that are similarly thermally labile, suggesting that their activity could be restored post-translationally (e.g. by reducing the temperature or by a chemical or pharmacologic chaperone). Together, these findings suggest that tsPINK1 may represent a valuable tool for the analysis of the PINK1/Parkin pathway in human cells; additionally, as the serine residue promoting thermal lability is conserved among Mus musculus, Danio rerio, Drosophila melanogaster and Caenorhabditis elegans, it may serve as the basis for developing other temperature-sensitive models for the study of recessive parkinsonism and mitophagy. Finally, these results suggest that PINK1 kinase function could be restored for a subset of patients with PINK1 mutations, and perhaps alter the course of their disease. PMID- 23459929 TI - The role of markers of inflammation in traumatic brain injury. AB - Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase following Traumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI. PMID- 23459932 TI - Otitis media in the Tgif knockout mouse implicates TGFbeta signalling in chronic middle ear inflammatory disease. AB - Otitis media with effusion (OME) is the most common cause of hearing loss in children and tympanostomy to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of OM are known to have a very significant genetic component, however, until recently little was known of the underlying genes involved. The identification of mouse models of chronic OM has indicated a role of transforming growth factor beta (TGFbeta) signalling and its impact on responses to hypoxia in the inflamed middle ear. We have, therefore, investigated the role of TGFbeta signalling and identified and characterized a new model of chronic OM carrying a mutation in the gene for transforming growth interacting factor 1 (Tgif1). Tgif1 homozygous mutant mice have significantly raised auditory thresholds due to a conductive deafness arising from a chronic effusion starting at around 3 weeks of age. The OM is accompanied by a significant thickening of the middle ear mucosa lining, expansion of mucin-secreting goblet cell populations and raised levels of vascular endothelial growth factor, TNF-alpha and IL-1beta in ear fluids. We also identified downstream effects on TGFbeta signalling in middle ear epithelia at the time of development of chronic OM. Both phosphorylated SMAD2 and p21 levels were lowered in the homozygous mutant, demonstrating a suppression of the TGFbeta pathway. The identification and characterization of the Tgif mutant supports the role of TGFbeta signalling in the development of chronic OM and provides an important candidate gene for genetic studies in the human population. PMID- 23459933 TI - Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis splicing. AB - Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing. PMID- 23459934 TI - Temporal requirement for SMN in motoneuron development. AB - Proper function of the motor unit is dependent upon the correct development of dendrites and axons. The infant/childhood onset motoneuron disease spinal muscular atrophy (SMA), caused by low levels of the survival motor neuron (SMN) protein, is characterized by muscle denervation and paralysis. Although different SMA models have shown neuromuscular junction defects and/or motor axon defects, a comprehensive analysis of motoneuron development in vivo under conditions of low SMN will give insight into why the motor unit becomes dysfunctional. We have generated genetic mutants in zebrafish expressing low levels of SMN from the earliest stages of development. Analysis of motoneurons in these mutants revealed motor axons were often shorter and had fewer branches. We also found that motoneurons had significantly fewer dendritic branches and those present were shorter. Analysis of motor axon filopodial dynamics in live embryos revealed that mutants had fewer filopodia and their average half-life was shorter. To determine when SMN was needed to rescue motoneuron development, SMN was conditionally induced in smn mutants during embryonic stages. Only when SMN was added back soon after motoneurons were born, could later motor axon development be rescued. Importantly, analysis of motor behavior revealed that animals with motor axon defects had significant deficits in motor output. We also show that SMN is required earlier for motoneuron development than for survival. These data support that SMN is needed early in development of motoneuron dendrites and axons to develop normally and that this is essential for proper connectivity and movement. PMID- 23459935 TI - Exclusive skeletal muscle correction does not modulate dystrophic heart disease in the aged mdx model of Duchenne cardiomyopathy. AB - Duchenne muscular dystrophy (DMD) is characterized by severe degeneration and necrosis of both skeletal and cardiac muscle. While many experimental therapies have shown great promise in treating skeletal muscle disease, an effective therapy for Duchenne cardiomyopathy remains a challenge in large animal models and human patients. The current views on cardiac consequences of skeletal muscle centered therapy are controversial. Studies performed in young adult mdx mice (a mild DMD mouse model) have yielded opposing results. Since mdx mice do not develop dystrophic cardiomyopathy until >=21 months of age, we reasoned that old mdx mice may represent a better model to assess the impact of skeletal muscle rescue on dystrophic heart disease. Here, we aged skeletal muscle-specific micro dystrophin transgenic mdx mice to 23 months and examined the cardiac phenotype. As expected, transgenic mdx mice had minimal skeletal muscle disease and they also outperformed original mdx mice on treadmill running. On cardiac examination, the dystrophin-null heart of transgenic mdx mice displayed severe cardiomyopathy matching that of non-transgenic mdx mice. Specifically, both the strains showed similar heart fibrosis and cardiac function deterioration in systole and diastole. Cardiac output and ejection fraction were also equally compromised. Our results suggest that skeletal muscle rescue neither aggravates nor alleviates cardiomyopathy in aged mdx mice. These findings underscore the importance of treating both skeletal and cardiac muscles in DMD therapy. PMID- 23459936 TI - Exploring the genetic basis of chronic periodontitis: a genome-wide association study. AB - Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age-62 years, moderate CP 43% and severe CP-17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 * 10( 6)) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)-NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28-1.73, P = 3.5 * 10(-7)))]; moderate CP (n = 2293) NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24-1.59, P = 7.5 * 10(-8)), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52-2.65, P = 8.2 * 10(-7)). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 * 10(-9)) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP. PMID- 23459937 TI - The differential effects of wild-type and mutated K-Ras on MST2 signaling are determined by K-Ras activation kinetics. AB - K-Ras is frequently mutated in human cancers. Mutant (mt) K-Ras can stimulate both oncogenic transformation and apoptosis through activation of extracellular signal-regulated kinase (ERK) and AKT pathways and the MST2 pathway, respectively. The biological outcome is determined by the balance and cross talk between these pathways. In colorectal cancer (CRC), a K-Ras mutation is negatively correlated with MST2 expression, as mt K-Ras can induce apoptosis by activating the MST2 pathway. However, wild-type (wt) K-Ras can prevent the activation of the MST2 pathway upon growth factor stimulation and enable transformation by mt K-Ras in CRC cells that express MST2. Here we have investigated the mechanism by which wt and mt K-Ras differentially regulate the MST2 pathway and MST2-dependent apoptosis. The ability of K-Ras to activate MST2 and MST2-dependent apoptosis is determined by the differential activation kinetics of mt K-Ras and wt K-Ras. Chronic activation of K-Ras by mutation or overexpression of Ras exchange factors results in the activation of MST2 and LATS1, increased MST2-LATS1 complex formation, and apoptosis. In contrast, transient K-Ras activation upon epidermal growth factor (EGF) stimulation prevents the formation of the MST2-LATS1 complex in an AKT-dependent manner. Our data suggest that the close relationship between Ras prosurvival and proapoptotic signaling is coordinated via the differential regulation of the MST2-LATS1 interaction by transient and chronic stimuli. PMID- 23459938 TI - Acyl coenzyme A thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity. AB - Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7(N-/-), revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7(N-/-) mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7(N-/-) mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity. PMID- 23459940 TI - Drosophila SETs its sights on cancer: Trr/MLL3/4 COMPASS-like complexes in development and disease. PMID- 23459939 TI - Developmentally programmed 3' CpG island methylation confers tissue- and cell type-specific transcriptional activation. AB - During development, a small but significant number of CpG islands (CGIs) become methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here, we used genome-wide DNA methylation microarrays to identify epigenetic changes during human embryonic stem cell (hESC) differentiation. We discovered a group of CGIs associated with developmental genes that gain methylation after hESCs differentiate. Conversely, erasure of methylation was observed at the identified CGIs during subsequent reprogramming to induced pluripotent stem cells (iPSCs), further supporting a functional role for the CGI methylation. Both global gene expression profiling and quantitative reverse transcription-PCR (RT-PCR) validation indicated opposing effects of CGI methylation in transcriptional regulation during differentiation, with promoter CGI methylation repressing and 3' CGI methylation activating transcription. By studying diverse human tissues and mouse models, we further confirmed that developmentally programmed 3' CGI methylation confers tissue- and cell-type-specific gene activation in vivo. Importantly, luciferase reporter assays provided evidence that 3' CGI methylation regulates transcriptional activation via a CTCF-dependent enhancer-blocking mechanism. These findings expand the classic view of mammalian CGI methylation as a mechanism for transcriptional silencing and indicate a functional role for 3' CGI methylation in developmental gene regulation. PMID- 23459941 TI - The Drosophila ortholog of MLL3 and MLL4, trithorax related, functions as a negative regulator of tissue growth. AB - The human MLL genes (MLL1 to MLL4) and their Drosophila orthologs, trithorax (trx) and trithorax related (trr), encode proteins capable of methylating histone H3 on lysine 4. MLL1 and MLL2 are most similar to trx, while MLL3 and MLL4 are more closely related to trr. Several MLL genes are mutated in human cancers, but how these proteins regulate cell proliferation is not known. Here we show that trr mutant cells have a growth advantage over their wild-type neighbors and display changes in the levels of multiple proteins that regulate growth and cell division, including Notch, Capicua, and cyclin B. trr mutant clones display markedly reduced levels of H3K4 monomethylation without obvious changes in the levels of H3K4 di- and trimethylation. The trr mutant phenotype resembles that of Utx, which encodes a H3K27 demethylase, consistent with the observation that Trr and Utx are found in the same protein complex. In contrast to the overgrowth displayed by trr mutant tissue, trx clones are underrepresented, express low levels of the antiapoptotic protein Diap1, and exhibit only modest changes in global levels of H3K4 methylation. Thus, in Drosophila eye imaginal discs, Trr, likely functioning together with Utx, restricts tissue growth. In contrast, Trx appears to promote cell survival. PMID- 23459942 TI - Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed IkappaB kinase activation. AB - Tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation has been believed to depend on TRAF2- and cIAP1-mediated RIP1 ubiquitination. However, recent findings have challenged the notion that these proteins play essential roles in NF-kappaB activation. Here, by assessing the kinetics and amplitude of IkappaB kinase (IKK) activation, we report that TNF-alpha-induced immediate and robust activation of IKK requires K63-linked and linearly linked ubiquitination of RIP1 and that in the absence of RIP1 expression, TRAF2 and cIAP1 cooperatively induce delayed IKK activation by recruiting LUBAC to TNFR1. Knockdown of HOIP (a component of LUBAC) in RIP1-deficient cells completely impairs the recruitment and activation of IKK but does not affect K63-linked ubiquitination of TRAF2 and recruitment of TAK1 to TNFR1, suggesting that the K63-linked ubiquitin chain is not capable of recruiting IKK in vivo. We also demonstrate that TRAF2 and cIAP1 together, but not either one alone, directly catalyze linearly linked ubiquitination of RIP1. Importantly, in embryonic hepatocytes, TNF-alpha activates NF-kappaB through a RIP1-independent pathway. Thus, our findings clarify molecular details of this important signaling mechanism by providing evidence for the existence of two phases of IKK activation: the immediate phase, induced by TRAF2/cIAP1-mediated ubiquitination of RIP1, and the delayed phase, activated by TRAF2/cIAP1-dependent recruitment of LUBAC. PMID- 23459943 TI - Common partner Smad-independent canonical bone morphogenetic protein signaling in the specification process of the anterior rhombic lip during cerebellum development. AB - Bone morphogenetic protein (BMP) signaling is critical for cerebellum development. However, the details of receptor regulated-Smad (R-Smad) and common partner Smad (Co-Smad, or Smad4) involvement are unclear. Here, we report that cerebellum-specific double conditional inactivation of Smad1 and Smad5 (Smad1/5) results in cerebellar hypoplasia, reduced granule cell numbers, and disorganized Purkinje neuron migration during embryonic development. However, single conditional inactivation of either Smad1 or Smad5 did not result in cerebellar abnormalities. Surprisingly, conditional inactivation of Smad4, which is considered to be the central mediator of canonical BMP-Smad signaling, resulted only in very mild cerebellar defects. Conditional inactivation of Smad1/5 led to developmental defects in the anterior rhombic lip (ARL), as shown by reduced cell proliferation and loss of Pax6 and Atoh1 expression. These defects subsequently caused the loss of the nuclear transitory zone and a region of the deep cerebellar nuclei. The normal maturation of the remaining granule cell precursors in the external granular layer (EGL) suggests Smad1/5 signaling is required for the specification process in ARL but not for the subsequent EGL development. Our results demonstrate functional redundancy for Smad1 and Smad5 but functional discrepancy between Smad1/5 and Smad4 during cerebellum development. PMID- 23459944 TI - MicroRNAs 185, 96, and 223 repress selective high-density lipoprotein cholesterol uptake through posttranscriptional inhibition. AB - Hepatic scavenger receptor class B type I (SR-BI) plays an important role in selective high-density lipoprotein cholesterol (HDL-C) uptake, which is a pivotal step of reverse cholesterol transport. In this study, the potential involvement of microRNAs (miRNAs) in posttranscriptional regulation of hepatic SR-BI and selective HDL-C uptake was investigated. The level of SR-BI expression was repressed by miRNA 185 (miR-185), miR-96, and miR-223, while the uptake of 1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-HDL was decreased by 31.9% (P < 0.001), 23.9% (P < 0.05), and 15.4% (P < 0.05), respectively, in HepG2 cells. The inhibition of these miRNAs by their anti-miRNAs had opposite effects in these hepatic cells. The critical effect of miR-185 was further validated by the loss of regulation in constructs with mutated miR-185 target sites. In addition, these miRNAs directly targeted the 3' untranslated region (UTR) of SR-BI with a coordinated effect. Interestingly, the decrease of miR-96 and miR-185 coincided with the increase of SR-BI in the livers of ApoE KO mice on a high-fat diet. These data suggest that miR-185, miR-96, and miR-223 may repress selective HDL-C uptake through the inhibition of SR-BI in human hepatic cells, implying a novel mode of regulation of hepatic SR-BI and an important role of miRNAs in modulating cholesterol metabolism. PMID- 23459945 TI - Establishment of a cell-type-specific genetic network by the mediator complex component Med1. AB - The intense physiologic demand to generate vast numbers of red blood cells requires the establishment of a complex genetic network by the master regulatory transcription factor GATA-1 and its coregulators. This network dictates the genesis of enucleated erythrocytes by orchestrating the survival, proliferation, and differentiation of progenitor cells. In addition to the crucial GATA-1 coregulator Friend of GATA-1 (FOG-1), a component of the Mediator complex, Med1, facilitates GATA-1-dependent transcription at select target genes and controls erythropoiesis. It is not known to what extent Med1 contributes to GATA-1 function or whether Med1 controls a large or restricted cohort of genes that are not regulated by GATA-1. Using a genetic complementation assay in GATA-1-null erythroid cells, we demonstrate that Med1 and another Mediator component, Med25, regulate a restricted cohort of genes that are predominantly not controlled by GATA-1. Most of these genes were not regulated by Med1 in fibroblasts. Loss-of function analyses with GATA-1-independent Med1 target genes indicate that Rrad, which encodes a small GTPase induced during human erythropoiesis, conferred erythroid cell survival. Thus, while Med1 is a context-dependent GATA-1 coregulator, it also exerts specialized functions in erythroid cells to control GATA-1-independent, cell-type-specific genes, which include candidate regulators of erythroid cell development and function. PMID- 23459946 TI - Nucleophosmin, a critical Bax cofactor in ischemia-induced cell death. AB - We hypothesized that nucleophosmin (NPM), a nucleolar phosphoprotein, is critical for Bax-mediated cell death. To test this hypothesis, Bax activation was induced by metabolic stress. During stress, nucleolar NPM translocated into the cytosol, NPM-Bax complexes formed, and both NPM and Bax accumulated in mitochondria. Expression of a cytosol-restricted NPM mutant (NPM-DeltaNLS), but not a nucleus restricted NPM mutant, increased NPM-Bax complex formation, mitochondrial NPM and Bax accumulation, mitochondrial membrane injury, caspase 3 activation, and ischemia-induced cell death. Coexpression of NPM-DeltaNLS with constitutively active Bax mutants caused nearly universal cell death in the absence of metabolic stress, whereas expression of active Bax or NPM-DeltaNLS alone did not. A Bax peptide that disrupts NPM-Bax interaction significantly reduced cell death caused by exposure to metabolic inhibitors in vitro and preserved kidney function after ischemia in vivo. Thus, NPM-Bax interaction enhances mitochondrial Bax accumulation, organelle injury, and cell death. NPM-Bax complex formation is a novel target for preventing ischemic tissue injury. PMID- 23459947 TI - Differentiation in the protein synthesis-dependency of persistent synaptic plasticity in mossy fiber and associational/commissural CA3 synapses in vivo. AB - Long-term potentiation (LTP) and long-term depression (LTD) are two mechanisms involved in the long-term storage of information in hippocampal synapses. In the hippocampal CA1 region, the late phases of LTP and LTD are protein-synthesis dependent. In the dentate gyrus, late-LTP but not LTD requires protein synthesis. The protein synthesis-dependency of persistent plasticity at CA3 synapses has not yet been characterized. Here, the roles of protein transcription and translation at mossy fiber (mf) and associational/commissural (AC)- synapses were studied in freely behaving rats. In control animals, low-frequency stimulation (LFS) evoked robust LTD (>24 h), whereas high-frequency stimulation (HFS) elicited robust LTP (>24 h) at both mf-CA3 and AC-CA3 synapses. Translation inhibitors prevented early and late phases of LTP and LTD at mf-CA3 synapses. In contrast, at AC-CA3 synapses, translation inhibitors prevented intermediate/late-LTP and late-LTD only. Transcription effects were also synapse-specific: whereas transcription inhibitors inhibited late-LTP and late-LTD (>3 h) at mf-CA3 synapses, at AC-CA3 synapses, protein transcription affected early-LTP and late-LTD. These results show that the AC-CA3 and mf-CA3 synapses display different properties in terms of their protein synthesis dependency, suggesting different roles in the processing of short- and long term synaptic plasticity. PMID- 23459948 TI - Differences in epidemiologic risk factors for colorectal adenomas and serrated polyps by lesion severity and anatomical site. AB - Using a case-control design, we evaluated differences in risk factors for colorectal polyps according to histological type, anatomical site, and severity. Participants were enrollees in the Group Health Cooperative aged 20-79 years who underwent colonoscopy in Seattle, Washington, between 1998 and 2007 and comprised 628 adenoma cases, 594 serrated polyp cases, 247 cases with both types of polyps, and 1,037 polyp-free controls. Participants completed a structured interview, and polyps were evaluated via standardized pathology review. We used multivariable polytomous logistic regression to compare case groups with controls and with the other case groups. Factors for which the strength of the association varied significantly between adenomas and serrated polyps were sex (P < 0.001), use of estrogen-only postmenopausal hormone therapy (P = 0.01), and smoking status (P < 0.001). For lesion severity, prior endoscopy (P < 0.001) and age (P = 0.05) had significantly stronger associations with advanced adenomas than with nonadvanced adenomas; and higher education was positively correlated with sessile serrated polyps but not with other serrated polyps (P = 0.02). Statistically significant, site-specific associations were observed for current cigarette smoking (P = 0.05 among adenomas and P < 0.001 among serrated polyps), postmenopausal estrogen-only therapy (P = 0.01 among adenomas), and obesity (P = 0.01 among serrated polyps). These findings further illustrate the epidemiologic heterogeneity of colorectal neoplasia and may help elucidate carcinogenic mechanisms for distinct pathways. PMID- 23459950 TI - Infection fatality risk of the pandemic A(H1N1)2009 virus in Hong Kong. AB - One measure of the severity of a pandemic influenza outbreak at the individual level is the risk of death among people infected by the new virus. However, there are complications in estimating both the numerator and denominator. Regarding the numerator, statistical estimates of the excess deaths associated with influenza virus infections tend to exceed the number of deaths associated with laboratory confirmed infection. Regarding the denominator, few infections are laboratory confirmed, while differences in case definitions and approaches to case ascertainment can lead to wide variation in case fatality risk estimates. Serological surveillance can be used to estimate the cumulative incidence of infection as a denominator that is more comparable across studies. We estimated that the first wave of the influenza A(H1N1)pdm09 virus in 2009 was associated with approximately 232 (95% confidence interval: 136, 328) excess deaths of all ages in Hong Kong, mainly among the elderly. The point estimates of the risk of death on a per-infection basis increased substantially with age, from below 1 per 100,000 infections in children to 1,099 per 100,000 infections in those 60-69 years of age. Substantial variation in the age-specific infection fatality risk complicates comparison of the severity of different influenza strains. PMID- 23459951 TI - [Electroconvulsive therapy as a "last resort" in the treatment of depression?]. AB - OBJECTIVE: The use of electroconvulsive therapy (ECT) in treatment-resistant depressed patients is supported by numerous international guidelines. This study aims to describe what type of patients are actually referred to treatment with ECT. METHODS: We included all patients referred to two main ECT-treatment centers in Switzerland during the period of August 2008 to February 2011. We collected data on the diagnosis, severity of illness, and the history of treatment. RESULTS: Most of the patients (n = 104) were referred after an average of 124 weeks of an index episode of unipolar depression. The patients were severely and chronically ill and had been treated on average for more than a decade. Eighty three percent of the patients were referred for ECT treatment for the first time. CONCLUSIONS: The surveyed practice of referral does not concur with evidence based guidelines for the use of ECT in the treatment of depression. PMID- 23459952 TI - [Diphenhydramine addiction and detoxification. A systematic review and case report]. AB - OBJECTIVE: In many countries diphenhydramine (DPH) is commonly available over the counter, frequently used, and generally regarded as a harmless drug. It is used as a sedative, antiallergic or antiemetic substance. METHODS: We present a systematic review of literature search in Pubmed from 1972 to 2012 describing DPH addiction. The literature search in reveals that the addictive potential of DPH can be regarded as proved, based on cases series, eight case reports, a pharmacological overview, one uncontrolled, and one randomized, placebo controlled study. In addition we report a case of an abstinent alcoholic patient treated in our department for DPH-dependency. CONCLUSION: Especially when treating patients with a history of addiction, physicians should consider and check the possibility of a DPH dependency. PMID- 23459954 TI - Modification of Sn/S cages with bis-functionalized ferrocenyl units. AB - Bis-functionalized ferrocenyl units have been attached to organo-functionalized [(R(F)Sn)4S6] double-decker clusters as criss-cross-type intramolecular straps. Two different ways of linking result in different crystal structures and different electrochemical stabilities of the resulting compounds. PMID- 23459953 TI - [Hospitalization and dementia: what was new in 2012?: literature review]. AB - The present work provides a review of literature published in 2012 that were found in a PubMed search with the terms "hospitalization and dementia. Further information was obtained from personal contacts. The rate of publications was ten times higher in 2012 as in previous years. Frequency of dementia, hospital admission, acute coronary syndrome, femoral neck fracture, stroke, complications during hospital stay, outcomes after hospitalization, prediction, rehabilitation, and training are the common topics. PMID- 23459956 TI - Magnetic field control of the ordering of two-component suspension of hard rods. AB - The Onsager theory of hard rod dispersion in a neutral solvent is extended to a case of two-component dispersion consisting of both non-magnetic and magnetic rods. It was found that the alignment of magneto-sensitive dispersion component by a magnetic field leads to the alignment of non-magnetic component in the dispersion and to an elimination of the isotropic phase. This effect is significant even at low relative concentrations of magnetic rods and leads to a magnetically induced anisotropy in a non-magnetic dispersion of rods mixed with the magnetic ones. PMID- 23459955 TI - Supermodels: sorghum and maize provide mutual insight into the genetics of flowering time. AB - Nested association mapping (NAM) offers power to dissect complex, quantitative traits. This study made use of a recently developed sorghum backcross (BC)-NAM population to dissect the genetic architecture of flowering time in sorghum; to compare the QTL identified with other genomic regions identified in previous sorghum and maize flowering time studies and to highlight the implications of our findings for plant breeding. A subset of the sorghum BC-NAM population consisting of over 1,300 individuals from 24 families was evaluated for flowering time across multiple environments. Two QTL analysis methodologies were used to identify 40 QTLs with predominately small, additive effects on flowering time; 24 of these co-located with previously identified QTL for flowering time in sorghum and 16 were novel in sorghum. Significant synteny was also detected with the QTL for flowering time detected in a comparable NAM resource recently developed for maize (Zea mays) by Buckler et al. (Science 325:714-718, 2009). The use of the sorghum BC-NAM population allowed us to catalogue allelic variants at a maximal number of QTL and understand their contribution to the flowering time phenotype and distribution across diverse germplasm. The successful demonstration of the power of the sorghum BC-NAM population is exemplified not only by correspondence of QTL previously identified in sorghum, but also by correspondence of QTL in different taxa, specifically maize in this case. The unification across taxa of the candidate genes influencing complex traits, such as flowering time can further facilitate the detailed dissection of the genetic control and causal genes. PMID- 23459957 TI - The influence of suspended nanoparticles on the Frederiks threshold of the nematic host. AB - In recent years, several papers reported an enhanced dielectric anisotropy when ferroelectric particles were suspended in a liquid crystal. These results seem to be sensitive to the liquid crystal used and the preparation method of the ferroelectric particles. In this paper, we compare different preparation methods of suspended barium titanate in two different liquid crystal hosts. As a control experiment, we followed similar preparation steps with non-ferroelectric silica particles. In all cases, we found a broadening of the optical Frederiks transition but no change in the dielectric anisotropy. Raman spectroscopy has been used to investigate the loss of tetragonal structure in the barium titanate as a function of milling time and particle size. As reported in the earlier literature, barium titanate does not exhibit a well-defined tetragonal crystal structure below a certain particle size and loses its ferroelectric features. This provides a simple rationalization for the absence of any dielectric enhancement. PMID- 23459958 TI - Liquid-crystal-enabled electrophoresis of spheres in a nematic medium with negative dielectric anisotropy. AB - We describe electrophoresis of spherical dielectric particles in a uniformly aligned nematic medium with a negative dielectric anisotropy. A spherical particle that orients the liquid crystal (LC) perpendicularly to its surface moves under the application of a uniform direct current or alternating current electric field. The electric field causes no distortions of the LC director far away from the sphere. Electrophoresis in the nematic LC shows two types of nonlinearity in the velocity versus field dependence. The velocity component parallel to the applied electric field grows linearly with the field, but when the field is high enough, it also shows a cubic dependence. The most interesting is the second type of nonlinear electrophoresis that causes the sphere to move perpendicularly to the applied field. This perpendicular component of velocity is proportional to the square of the field. The effect exists only in an LC and disappears when the material is melted into an isotropic fluid. The quadratic effect is caused by the dipolar symmetry of director distortions around the sphere and is classified as an LC-enabled electrophoresis (LCEEP). The nonlinear electrophoretic mobility of particles in LCEEP offers a rich variety of control parameters to design three-dimensional trajectories of particles for microfluidic and optofluidic applications. PMID- 23459959 TI - Hydrophobic gold nanoparticles via silane conjugation: chemically and thermally robust nanoparticles as dopants for nematic liquid crystals. AB - We examine for the first time how chemically and thermally stable gold nanoparticles (NPs), prepared by a silane conjugation approach, affect both the thermal and the electro-optical properties of a nematic liquid crystal (LC), when doped at concentrations ranging from 0.25 to 7.5 wt%. We find that the octadecylsilane-conjugated gold NPs stabilize both the enantiotropic nematic and the monotropic smectic-A phases of the LC host with a maximum stabilization of 2( degrees )C for the nematic and 3.5( degrees )C for the smectic-A phases for the mixture containing 1 wt% of the silanized particles. The same mixture shows the lowest values for the Freedericksz transition threshold voltage and the highest value for the dielectric anisotropy. Generally, all NP-containing mixtures, except mixtures with NP concentrations exceeding 5 wt%, reduce the threshold voltage, increase the dielectric anisotropy and reduce both rise and decay time; the latter particularly at temperatures at least 10( degrees )C below the isotropic-nematic phase transition on cooling. PMID- 23459960 TI - Electro-induced orientational ordering of anisotropic pigment nanoparticles. AB - The response of anisotropic pigment particle suspensions to externally applied electric fields has been explored for possible application in reflective display technologies. Three different types of pigment particle were suspended in dodecane, using a polymeric stabilizer, and showed Schlieren textures between crossed polarizers at high concentrations (greater than 25-30 wt%), indicating the formation of colloidal nematic phases. Orientational order parameters were determined by X-ray scattering, and the influence of polydispersity on the values is discussed. X-ray scattering measurements also demonstrated a change in the structure factor consistent with the onset of a colloidal nematic phase. In addition, the pigment particles were dispersed into various liquid crystal hosts at low concentrations (less than 5 wt%) with and without the presence of mesogenic mimic stabilizers. However, the influence of these stabilizers on orientational ordering could not be confirmed. The electro-induced ordering determined via scattering was related to the electro-optical response of each suspension using a simple model. The particles in nematic hosts not only showed a high degree of orientational ordering at lower electric field strengths, but also showed a reduction in stability. Although these systems have shown strong orientational ordering, the optical response has been limited by the intrinsic shape of the pigment particles and the distribution of the transition dipoles moments within them. Nevertheless, the feasibility of developing materials for display applications has been demonstrated. PMID- 23459961 TI - Tuning the defect configurations in nematic and smectic liquid crystalline shells. AB - Thin liquid crystalline shells surrounding and surrounded by aqueous phases can be conveniently produced using a nested capillary microfluidic system, as was first demonstrated by Fernandez-Nieves et al. in 2007. By choosing particular combinations of stabilizers in the internal and external phases, different types of alignment, uniform or hybrid, can be ensured within the shell. Here, we investigate shells in the nematic and smectic phases under varying boundary conditions, focusing in particular on textural transformations during phase transitions, on the interaction between topological defects in the director field and inclusions in the liquid crystal (LC), and on the possibility to relocate defects within the shell by rotating the shell in the gravitational field. We demonstrate that inclusions in a shell can seed defects that cannot form in a pristine shell, adding a further means of tuning the defect configuration, and that shells in which the internal aqueous phase is not density matched with the LC will gently rearrange the internal structure upon a rotation that changes the influence of gravity. Because the defects can act as anchor points for added linker molecules, allowing self-assembly of adjacent shells, the various arrangements of defects developing in these shells and the possibility of tuning the result by modifying boundary conditions, LC phase, thickness and diameter of the shell or applying external forces make this new LC configuration very attractive. PMID- 23459963 TI - On the effect of carbon nanotubes on properties of liquid crystals. AB - Liquid crystals (LCs), with their fluidity and self-organization, are attractive hosts for the dispersion and manipulation of macro- and nanoparticles, allowing the realization of their ordered assemblies. In addition, new functional materials can be created owing to the particle properties. Among the nanoparticles, carbon nanotubes (CNTs) stand out for their exceptional electrical, thermal and mechanical properties. While LCs can be used for manipulating CNTs, the nanotube properties are attractive also for influencing and tuning LC properties. In this paper, we discuss different aspects of the CNT LC combination, briefly introducing their dispersion and interaction and then, more extensively, evaluating the CNT effect on selected properties of LCs relevant to display-related applications. We show that some previously reported improvements cannot be considered an intrinsic feature of CNT-doped LCs. In addition, we are also able to follow locally the Frederiks transition of CNT doped LCs by Raman spectroscopy, revealing the direct effect of bundles of CNTs on LC reorientation. PMID- 23459962 TI - Bulk fluid phase behaviour of colloidal platelet-sphere and platelet-polymer mixtures. AB - Using a geometry-based fundamental measure density functional theory, we calculate bulk fluid phase diagrams of colloidal mixtures of vanishingly thin hard circular platelets and hard spheres. We find isotropic-nematic phase separation, with strong broadening of the biphasic region, upon increasing the pressure. In mixtures with large size ratio of platelet and sphere diameters, there is also demixing between two nematic phases with differing platelet concentrations. We formulate a fundamental measure density functional for mixtures of colloidal platelets and freely overlapping spheres, which represent ideal polymers, and use it to obtain phase diagrams. We find that, for low platelet-polymer size ratio, in addition to isotropic-nematic and nematic-nematic phase coexistence, platelet-polymer mixtures also display isotropic-isotropic demixing. By contrast, we do not find isotropic-isotropic demixing in hard-core platelet-sphere mixtures for the size ratios considered. PMID- 23459964 TI - Modifying the structure and flow behaviour of aqueous montmorillonite suspensions with surfactant. AB - Colloidal suspensions of plate-like particles undergo a variety of phase transitions. The predicted isotropic/nematic transition is often pre-empted by a sol/gel transition, especially in suspensions of the most commonly used natural swelling clay montmorillonite (MMT). A number of factors, including charge interactions, flexibility and salt concentration, may contribute to this competition. In this study, the effect of surfactant adsorption on suspensions of MMT was studied using rheology, small-angle X-ray scattering, static light scattering and optical microscopy. The addition of a polyetheramine surfactant reduced the moduli of the system and shifted the sol/gel transition to a much higher clay concentration, compared with suspensions of bare clay particles. Yet, scattering data revealed no change in suspension structure on length scales up to around a micrometre. Primary aggregates remain at this length scale and no nematic phase is formed. There is, however, a change in structure at large length scales (of order 20 MUm) where light scattering indicates the presence of string like aggregates that disappear on addition of surfactant. Microscope images of dried suspensions also revealed a string-like structure. The dried strings show strong birefringence and may consist of concentric cylinders, self-assembled from clay sheets. PMID- 23459965 TI - Liquid crystal phase transitions in suspensions of mineral colloids: new life from old roots. AB - A review is given of the field of mineral colloidal liquid crystals: liquid crystal phases formed by individual mineral particles within colloidal suspensions. Starting from their discovery in the 1920s, we discuss developments on the levels of both fundamentals and applications. We conclude by highlighting some promising results from recent years, which may point the way towards future developments. PMID- 23459966 TI - Pushing, pulling and twisting liquid crystal systems: exploring new directions with laser manipulation. AB - Optical tweezers are exciting tools with which to explore liquid crystal (LC) systems; the motion of particles held in laser traps through LCs is perhaps the only approach that allows a low Ericksen number regime to be accessed. This offers a new method of studying the microrheology associated with micrometre sized particles suspended in LC media--and such hybrid systems are of increasing importance as novel soft-matter systems. This paper describes the microrheology experiments that are possible in nematic materials and discusses the sometimes unexpected results that ensue. It also presents observations made in the inverse system; micrometre-sized droplets of LC suspended in an isotropic medium. PMID- 23459967 TI - Nematic colloids, topology and photonics. AB - We review and discuss recent progress in the field of nematic colloids, with an emphasis on possible future applications in photonics. The role of the topology is described, based on experimental manipulations of the topological defects in nematic colloids. The topology of the ordering field in nematics provides the forces between colloidal particles that are unique to these materials. We also discuss recent progress in the new field of active microphotonic devices based on liquid crystals (LCs), where chiral nematic microlasers and tuneable nematic microresonators are just two of the recently discovered examples. We conclude that the combination of topology and microphotonic devices based on LCs provides an interesting platform for future progress in the field of LCs. PMID- 23459968 TI - Liquid crystals of carbon nanotubes and graphene. AB - Liquid crystal ordering is an opportunity to develop novel materials and applications with spontaneously aligned nanotubes or graphene particles. Nevertheless, achieving high orientational order parameter and large monodomains remains a challenge. In addition, our restricted knowledge of the structure of the currently available materials is a limitation for fundamental studies and future applications. This paper presents recent methodologies that have been developed to achieve large monodomains of nematic liquid crystals. These allow quantification and increase of their order parameters. Nematic ordering provides an efficient way to prepare conductive films that exhibit anisotropic properties. In particular, it is shown how the electrical conductivity anisotropy increases with the order parameter of the nematic liquid crystal. The order parameter can be tuned by controlling the length and entanglement of the nanotubes. In the second part of the paper, recent results on graphene liquid crystals are reported. The possibility to obtain water-based liquid crystals stabilized by surfactant molecules is demonstrated. Structural and thermodynamic characterizations provide indirect but statistical information on the dimensions of the graphene flakes. From a general point of view, this work presents experimental approaches to optimize the use of nanocarbons as liquid crystals and provides new methodologies for the still challenging characterization of such materials. PMID- 23459969 TI - New frontiers in anisotropic fluid-particle composites. PMID- 23459970 TI - Postprandial interleukin-6 response in elderly with abdominal obesity and metabolic syndrome. AB - OBJECTIVE: The aim of this study is to evaluate the contribution of central obesity to inflammatory responses in the postprandial state in elderly patients with and without metabolic syndrome (MetS). MATERIAL/METHODS: We evaluated 80 elderly individuals who were distributed into three groups: MetS, abdominal obesity (AbObes) and Control, according to ATPIII criteria. Interleukin-6 (IL-6) serum concentration was measured at 0, 2, 4 and 6 hours after the ingestion of a physiological meal without an overload of fat. RESULTS: Serum IL-6 increased 6 hours after the meal in all of the groups (P<0.001). Comparing the groups, there was no difference in the area under the curve (AUC) of IL-6 in the postprandial state. There was a correlation between the 6-hour changes in the concentrations of IL-6 and the homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.25, P<0.05). CONCLUSION: In this study, differences in abdominal circumference (AC) have not determined a different behavior of IL-6 in the postprandial state, despite the correlation between AC and IL-6. However, we found that, in the elderly, there is a rise in serum IL-6 at 6 hours. PMID- 23459971 TI - Predictive equations overestimate the resting metabolic rate in postmenopausal women. AB - The resting energetic dispenses on postmenopausal stage should be well known in order to elaborate obesity prevention programs. OBJECTIVE: The aim of this study was to compare the resting metabolic rate (RMR) measured by indirect calorimetry (RMRmeasured) with predictive equations (RMRestimated) and verify which preexisting equation is more indicated for this population, in inactive, postmenopausal women. DESIGN: 43 postmenopausal women volunteered for the present study. MEASUREMENTS: RMRestimated value was achieved by indirect calorimetry. The predictive equations used were: Harris-Benedict equation (HB), Henry e Ree (HR), Mifflin-St Jeor equation (MSJ), World Health Organization equation (WHO) and Female Brazilian Population (FBP). Body composition was obtained through skinfolds method. RESULTS: All equations showed significant difference values for kcal/day (p<0.00001) (HB 1313.07+/-73.46; HR 1310.95+/-81.41; MSJ 1207.93+/ 93.17; WHO 1375.73+/-61.01 and FBP 1250.05+/-73.54 kcal/day) in relation to RMRestimated (1063.79+/-157.82). The WHO equation was the one which most overestimated the RMR values with a difference of more than 300 kcal/day. CONCLUSION: None of the equations to approach, in this study showed precision in the estimative of RMR, all prediction equations overestimated RMR values in Brazilians' postmenopausal women, although the MSJ predictive equation showed the greater approximation of RMRmeasured for this population. PMID- 23459972 TI - Intramuscular adipose tissue attenuates gains in muscle quality in older adults at high risk for falling. A brief report. AB - OBJECTIVES: To examine the influence of intramuscular adipose tissue (IMAT) on muscle quality (MQ) changes in older adults after 12 weeks of exercise training. DESIGN: Prospective cohort design. SETTING: Academic health science center clinical exercise facility. PARTICIPANTS: 70 older (mean age 73.4 +/- 6.3 years) adults with a history of falls. INTERVENTION: Resistance, endurance and balance exercise three times weekly for 12 weeks. MEASUREMENTS: Quadriceps strength was determined by maximum voluntary isometric contraction. An MRI of the thigh was used to determine cross-sectional area of lean tissue and IMAT. MQ was calculated as the force per unit area of lean tissue. Individuals were stratified into tertiles (Low IMAT, Middle IMAT, High IMAT) based on pre-IMAT levels. Changes in MQ, lean and IMAT were compared across groups. RESULTS: No significant changes in lean or IMAT occurred in any group with training. MQ increased only in the Low IMAT group. The Middle and High IMAT groups did not demonstrate a significant change in MQ following 12 weeks of training. Low IMAT, pre = 2.7 [0.6] post= 3.0 [0.6]; Middle IMAT, pre =2.54 [0.8] post =2.75 [0.7]; High IMAT, pre =2.6 [0.6] to post =2.5 [0.6]. CONCLUSION: High levels of thigh IMAT appear to blunt the adaptive MQ response to training. High levels of thigh IMAT may be a potential reason why some older adults do not change their MQ following training. Future research should confirm these results and determine why IMAT impairs MQ and the adaptive response to training in older adults. PMID- 23459973 TI - Biomarkers of oxidative stress in patients with wet age related macular degeneration. AB - OBJECTIVE: The aim of this study was to analyze biomarkers of oxidative stress in patients with wet age related macular degeneration (AMD). PARTICIPANTS AND MEASUREMENTS: Case-control study that includes 163 patients with wet AMD (age group of 55-82 years with the mean age of 71 years and 170 age-matched healthy controls in the age group of 55-78 years with the mean age of 71 years. The following parameters were determined: reduced and oxidized Glutathione (GSH/GSSH), protein carbonyl groups, total antioxidant activity in plasma and the activity of endogenous antioxidant enzymes, such as, gluthatione peroxidase, gluthatione reductase and superoxide dismutase. RESULTS: We observed total antioxidant activity higher in control group (CG) compared with patients with wet AMD (7.1 +/- 1.2 MUM Trolox vs 5.8 +/- 1.1 MUM Trolox). Values of superoxide dismutase activity (SOD), gluthatione reductase (GR) and gluthatione peroxidase (GPx) are higher in control group than in patients with wet AMD. According to the GSH/GSSH results, average values were higher in the CG than in patients with wet AMD and data were not significantly different.. Values of protein carbonyl groups were higher in patients with wet AMD than in CG and significant differences were found. CONCLUSIONS: The finding of the present study suggests that the patients with wet AMD are an altered metabolic state of oxidation-reduction and that it is convenient to give therapeutic interventions with antioxidants. We have demonstrated that systematic oxidative stress, measured by different biomarkers is closely associated with the wet AMD. PMID- 23459974 TI - Dietary nucleotides extend the life span in Sprague-Dawley rats. AB - OBJECTIVE: To observe the effect of prolonged feeding of dietary nucleotides (NTs), and to clarify the effect of NTs on life extension of Sprague-Dawley rats. METHODS: There were 50 Sprague-Dawley rats in each group (male:female ratio=1:1), which were fed diets supplemented with NTs at concentrations of 0%, 0.01%, 0.04%, 0.16% and 0.64% (wt/wt) from the age of 4 weeks until natural death. We investigated the moribundity and mortality, survival time, spontaneous tumor incidence, and serum oxidative status. RESULTS: NTs have significantly influence body weight of first 3 month old and food consumption of male rats throughout the life span; it did dose-dependently inhibit the age-related decrease in the activities of antioxidant enzymes and the age-related increase in the levels of lipid peroxidation product in both sexes. NTs notably increased the mean life span, and the maximal life span. Compared to the control group, the incidence of death from tumors was decreased in NTs groups of both sexes. CONCLUSIONS: Long term feeding of NTs could dose-dependently increase life span in Sprague-Dawley rats, especially, the tumor-bearing ones. Moreover, the antioxidative property of NTs may be responsible for the increased life span. PMID- 23459975 TI - Hypovitaminosis D in psychogeriatric inpatients. AB - OBJECTIVES: This study investigated the rate of hypovitaminosis D in psychogeriatric inpatients and explored whether any associations exist between vitamin D levels, cognitive function, and psychiatric diagnoses. DESIGN: Retrospective medical record review from November 2000 through November 2010. SETTING: Geriatric psychiatric ward of an academic tertiary care hospital. PARTICIPANTS: Psychiatric inpatients aged 65 years or older. MEASUREMENTS AND ANALYSIS METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels were measured at admission. Associations between 25(OH)D levels, Mini-Mental State Examination (MMSE) scores were analyzed using Spearman correlations, and psychiatric diagnoses were analyzed using logistic regression models and Fisher's exact tests. RESULTS: In 141 subjects (mean age, 77.8 years; 86 [61%] female; 135 [96%] white), the most frequent diagnoses were major depressive disorder in 81 patients (57%), dementia in 38 (27%), delirium in 13 (9%), anxiety in 12 (8.5%), and bipolar disorder in 11 (8%). Mean MMSE score was 24+/-6.4 (range, 3-30). Forty three subjects (30.4%) had mild to moderate vitamin D deficiency [25(OH)D, 10-24 ng/mL], and 6 (4.2%) had severe deficiency [25(OH)D <10 ng/mL]. CONCLUSIONS: Hypovitaminosis D was common in elderly psychiatric inpatients. No associations were found between vitamin D levels and global cognitive function or psychiatric diagnoses. PMID- 23459976 TI - Gait variability at fast-pace walking speed: a biomarker of mild cognitive impairment? AB - BACKGROUND: The interpretation of the increase in stride-to-stride variability of stride time (STV) regarding the evolution of cognitive deficits across the dementia spectrum is matter of debate. OBJECTIVE: The aim of this study was to compare STV at usual and fast-pace walking speeds of MCI patients with that of cognitively healthy individuals (CHI) and Alzheimer's disease (AD) patients with mild dementia, while considering the effects of potential confounders. METHODS: STV while walking at usual and fast-pace walking speeds was recorded with the GAITRite(r) system from 116 older adults (mean age 75.6+/-6.5 years; 55.2% female) divided into 3 groups according to their cognitive status (44 CHI, 39 MCI patients and 33 AD patients with mild dementia). RESULTS: The full adjusted multiple linear regression models showed that high STV was associated with slow gait speed at usual-pace walking speed (P=0.002) and with the MCI status at fast pace walking speed (P=0.015). CONCLUSIONS: High STV at fast-pace walking speed was a specific gait disturbance of MCI patients in the sample of studied participants, and thus could be used in the future as a specific biomarker of MCI patients. PMID- 23459977 TI - Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease. AB - An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer's disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer's disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE epsilon4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs. PMID- 23459978 TI - A review of multidomain interventions to support healthy cognitive ageing. AB - OBJECTIVE: The risk for cognitive decline and for developing Alzheimer's disease increases with age. The aetiology is assumed to be of multi-factorial origin, and treatment opportunities are lacking. Despite the multi-factorial origin, many intervention studies focused on single factors to influence cognitive health with inconsistent findings. In this view, more and more intervention studies aim to intervene on multiple factors simultaneously to affect or slow down cognitive decline. The purpose of this paper is to give an overview of these multidomain intervention trials. METHODS: We conducted a non-systematic literature search in Medline, Scopus, Cochrane Library, and clinical trials databases up to October 2011 to review multidomain interventions that investigated effects of combined lifestyle-related factors on cognitive decline and the progression of dementia. RESULTS: Interest in multidomain interventions increased over the past years. We identified six completed and published trials and eight ongoing or not yet published studies that investigated effects on cognitive outcomes. First completed trials yielded promising results for the combination of exercise and mental training and diet and behavioural weight management. Results of ongoing multidomain trials are awaited. CONCLUSIONS: Some evidence suggests that strategies which target multiple factors simultaneously may prove more effective than those focusing on a single mechanism or domain. Larger high-quality randomized controlled trials are required to systematically investigate the cognitive effect of programs comprising physical and mental activity as well as nutritional aspects. PMID- 23459979 TI - Mortality as an adverse outcome of sarcopenia. AB - Sarcopenia has an important impact in elderly. Recently the European Working Group on Sarcopenia in Older People (EWGSOP) defined sarcopenia as the loss of muscle mass plus low muscle strength or low physical performance. Lack of clinical sounding outcomes (ie external validity), is one of the flaws of this algorithm. The aim of our study was to determine the association of sarcopenia and mortality in a group of Mexican elderly. A total of 345 elderly were recruited in Mexico City, and followed up for three years. The EWGSOP algorithm was integrated by: gait speed, grip strength and calf circumference. Other covariates were assessed in order to test the independent association of sarcopenia with mortality. Of the 345 subjects, 53.3% were women; with a mean age of 78.5 (SD 7) years. During the three year follow-up a total of 43 (12.4%) subjects died. Age, cognition, ADL, IADL, health self-perception, ischemic heart disease and sarcopenia were associated in the bivariate analysis with survival. Negative predictive value for sarcopenia regarding mortality was of 90%. Kaplan Meier curves along with their respective log-rank test were significant for sarcopenia. The components of the final Cox-regression multivariate model were age, ischemic heart disease, ADL and sarcopenia. Adjusted HR for age was 3.24 (CI 95% 1.55-6.78 p 0.002), IHD 5.07 (CI 95% 1.89-13.59 p 0.001), health self perception 5.07 (CI 95% 1.9-13.6 p 0.001), ADL 0.75 (CI 95% 0.56-0.99 p 0.048) and sarcopenia 2.39 (CI 95% 1.05-5.43 p 0.037). PMID- 23459980 TI - In-hospital fall-risk screening in 4,735 geriatric patients from the LUCAS project. AB - OBJECTIVES: In-hospital falls in older patients are frequent, but the identification of patients at risk of falling is challenging. Aim of this study was to improve the identification of high-risk patients. Therefore, a simplified screening-tool was developed, validated, and compared to the STRATIFY predictive accuracy. DESIGN: Retrospective analysis of 4,735 patients; evaluation of predictive accuracy of STRATIFY and its single risk factors, as well as age, gender and psychotropic medication; splitting the dataset into a learning and a validation sample for modelling fall-risk screening and independent, temporal validation. SETTING: Geriatric clinic at an academic teaching hospital in Hamburg, Germany. PARTICIPANTS: 4,735 hospitalised patients >=65 years. MEASUREMENTS: Sensitivity, specificity, positive and negative predictive value, Odds Ratios, Youden-Index and the rates of falls and fallers were calculated. RESULTS: There were 10.7% fallers, and the fall rate was 7.9/1,000 hospital days. In the learning sample, mental alteration (OR 2.9), fall history (OR 2.1), and insecure mobility (Barthel-Index items 'transfer' + 'walking' score = 5, 10 or 15) (OR 2.3) had the most strongest association to falls. The LUCAS Fall-Risk Screening uses these risk factors, and patients with >=2 risk factors contributed to the high-risk group (30.9%). In the validation sample, STRATIFY SENS was 56.8, SPEC 59.6, PPV 13.5 and NPV 92.6 vs. LUCAS Fall-Risk Screening was SENS 46.0, SPEC 71.1, PPV 14.9 and NPV 92.3. CONCLUSIONS: Both the STRATIFY and the LUCAS Fall-Risk Screening showed comparable results in defining a high-risk group. Impaired mobility and cognitive status were closely associated to falls. The results do underscore the importance of functional status as essential fall-risk factor in older hospitalised patients. PMID- 23459981 TI - Institutional factors associated with the nutritional status of residents from 10 German nursing homes (ErnSTES study). AB - OBJECTIVES: In nursing homes malnutrition among residents is widespread. Because residents place part of their personal freedom of choice into institutional hands, institution-specific factors may influence nutritional status of residents. DESIGN: Multi-centre cross-sectional study. SETTING: 10 nation-wide German nursing homes. PARTICIPANTS: 714 exclusively orally fed residents (aged 65 years and older, not in final weeks of life). MEASUREMENTS: Participants' characteristics (e. g. gender, age, level of care, dementia diagnosis), body mass index (BMI), mini nutritional assessment (MNA), energy intake (3-day dietary record, BLS II.3), and selected institution-specific factors (size of institution, daily rate for food supply, number of residents per care staff member). Metric data are given as median (P25, P75). RESULTS: 11 % of residents (81 % female, 85 (81, 91) years) had a BMI <20 kg/m2 (n=658). According to MNA, 10 % of the residents were malnourished (n=650). Capacity of institutions was 116 (56, 139) beds, care staff ratio was 4.1 (3.5, 4.2) residents per care person (mean over all care levels), and daily food budget was 4.45 (4.10, 4.71) Euro/d. Low daily food budget was associated with a higher risk for a BMI <20 kg/m2 (OR 3.30 [95 %CI 1.70-6.42]). Higher food budget also decreased malnutrition risk (OR 0.66 [0.46-0.95]) according to MNA. Residents' mean energy intake was 6.1 (5.2, 7.1; n=565) MJ/day in women and 7.1 (6.2, 8.2; n=132) MJ/day in men. Intake was higher with small facility size, higher food budget, and lower care staff ratio (P <0.05). CONCLUSION: The institutional environment affects the nutritional status of nursing home residents as an independent risk factor. The results suggest promotion of small facilities and the provision of more care staff and more financial resources for food in the structural design of residential homes. PMID- 23459982 TI - Malnutrition and falls risk in community-dwelling older adults. AB - BACKGROUND AND AIMS: Falls and fall-related injuries result in reduced functioning, loss of independence, premature nursing home admissions and mortality. Malnutrition is associated with falls in the acute setting, but little is known about malnutrition and falls risk in the community. The aim of this study was to assess the association between malnutrition risk, falls risk and falls over a one-year period in community-dwelling older adults. METHODS: Two hundred and fifty four subjects >65 years of age were recruited to participate in a study in order to identify risk factors for falls. Malnutrition risk was determined using the Mini Nutritional Assessment-Short Form. RESULTS: 28.6% had experienced a fall and according to the Mini Nutritional Assessment-Short Form 3.9% (n=10) of subjects were at risk of malnutrition. There were no associations between malnutrition risk, the risk of falls, nor actual falls in healthy older adults in the community setting. CONCLUSIONS: There was a low prevalence of malnutrition risk in this sample of community-dwelling older adults and no association between nutritional risk and falls. Screening as part of a falls prevention program should focus on the risk of developing malnutrition as this is associated with falls. PMID- 23459983 TI - Selenium is inversely associated with interleukin-6 in the elderly. AB - BACKGROUND: Selenium is an essential trace element with antioxidant property. Decreased serum selenium concentration with aging had been found in previous report. In this study, we aim to investigate the association between serum selenium and the inflammatory cytokine interleukin-6 in the elderly living in long-term care facilities in Taiwan. MATERIALS AND METHODS: A total of 336 subjects aged 65 years and older (range of age: 65 - 101 years) were recruited from eight long-term care facilities in 2002-2003. Baseline characteristics, anthropometric indices, and biochemical data were obtained. Selenium deficiency was defined as serum selenium concentration < 80 MUg/L. Multiple logistic and linear regression analyses were used to examine the relationships between selenium deficiency and interleukin-6 (divided into quartiles). RESULTS: The prevalence of selenium deficiency was 35.6% in men and 43.2% in women, respectively. After adjusting for potential confounders using multiple logistic regression analysis, interleukin-6 quartiles were significantly associated with selenium deficiency. Compared to the interleukin-6 quartile I, the adjusted odds ratios of having selenium deficiency for interleukin-6 quartile II, III, IV were 1.00(0.50~2.01), 1.24 (0.62~2.50), and 2.35(1.15~4.83), respectively. The increasing odds ratios for selenium deficiency in higher interleukin-6 quartiles revealed dose-response effects (p < 0.05). Moreover, multiple linear regression analysis showed that serum selenium was significantly inversely associated with interleukin-6 after adjusting for potential confounders. CONCLUSIONS: Serum selenium was inversely associated with inflammatory cytokine interleukin-6 among elderly living in long-term care facilities in Taiwan. Monitoring serum selenium should be considered in these institutionalized elderly. PMID- 23459985 TI - Analysis of sensitivity enhancement by dynamic nuclear polarization in solid state NMR: a case study of functionalized mesoporous materials. AB - We systematically studied the enhancement factor (per scan) and the sensitivity enhancement (per unit time) in (13)C and (29)Si cross-polarization magic angle spinning (CP-MAS) NMR boosted by dynamic nuclear polarization (DNP) of functionalized mesoporous silica nanoparticles (MSNs). Specifically, we separated contributions due to: (i) microwave irradiation, (ii) quenching by paramagnetic effects, (iii) the presence of frozen solvent, (iv) the temperature, as well as changes in (v) relaxation and (vi) cross-polarization behaviour. No line broadening effects were observed for MSNs when lowering the temperature from 300 to 100 K. Notwithstanding a significant signal reduction due to quenching by TOTAPOL radicals, DNP-CP-MAS at 100 K provided global sensitivity enhancements of 23 and 45 for (13)C and (29)Si, respectively, relative to standard CP-MAS measurements at room temperature. The effects of DNP were also ascertained by comparing with state-of-the-art two-dimensional heteronuclear (1)H{(13)C} and (29)Si{(1)H} correlation spectra, using, respectively, indirect detection or Carr Purcell-Meiboom-Gill (CPMG) refocusing to boost signal acquisition. This study highlights opportunities for further improvements through the development of high field DNP, better polarizing agents, and improved capabilities for low temperature MAS. PMID- 23459987 TI - Activation of Transient Receptor Potential Vanilloid 4 Increases NMDA-Activated Current in Hippocampal Pyramidal Neurons. AB - The glutamate excitotoxicity, mediated through N-methyl-d-aspartate receptors (NMDARs), plays an important role in cerebral ischemia injury. Transient receptor potential vanilloid 4 (TRPV4) can be activated by multiple stimuli that may happen during stroke. The present study evaluated the effect of TRPV4 activation on NMDA-activated current (INMDA) and that of blocking TRPV4 on brain injury after focal cerebral ischemia in mice. We herein report that activation of TRPV4 by 4alpha-PDD and hypotonic stimulation increased INMDA in hippocampal CA1 pyramidal neurons, which was sensitive to TRPV4 antagonist 10 MU M/2 MU 1/mouse [DOSAGE ERROR CORRECTED] and NMDAR antagonist AP-5, indicating that TRPV4 activation potentiates NMDAR response. In addition, the increase in INMDA by hypotonicity was sensitive to the antagonist of NMDAR NR2B subunit, but not of NR2A subunit. Furthermore, antagonists of calcium/calmodulin-dependent protein kinase II (CaMKII) significantly attenuated hypotonicity-induced increase in INMDA, while antagonists of protein kinase C or casein kinase II had no such effect, indicating that phosphorylation of NR2B subunit by CaMKII is responsible for TRPV4-potentiated NMDAR response. Finally, we found that intracerebroventricular injection of 10 MU m/2 MU 1/mouse [DOSAGE ERROR CORRECTED] after 60 min middle cerebral artery occlusion reduced the cerebral infarction with at least a 12 h efficacious time-window. These findings indicate that activation of TRPV4 increases NMDAR function, which may facilitate glutamate excitotoxicity. Closing TRPV4 may exert potent neuroprotection against cerebral ischemia injury through many mechanisms at least including the prevention of NMDAR-mediated glutamate excitotoxicity. PMID- 23459986 TI - Parkin disease: a clinicopathologic entity? AB - IMPORTANCE: Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE: To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS: We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS: Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE: These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies. PMID- 23459988 TI - Construction of flame retardant nanocoating on ramie fabric via layer-by-layer assembly of carbon nanotube and ammonium polyphosphate. AB - A new flame retardant nanocoating has been constructed by the alternate adsorption of polyelectrolyte amino-functionalized multiwall carbon nanotube (MWNT-NH2) and ammonium polyphosphate (APP) onto flexible and porous ramie fabric. Scanning electron microscopy indicates that the adsorbed carbon nanotube coating is a randomly oriented and overlapped network structure, which is a promising candidate for flame retardancy applications. Attenuated total reflection Fourier transform infrared spectroscopy and energy-dispersive X-ray analysis confirm that the APP is successfully incorporated into the multilayers sequentially. Assessment of the thermal and flammability properties for the pristine and nanocoated ramie fabrics shows that the thermal stability, flame retardancy and residual char are enhanced as the concentration of MWNT-NH2 suspension and number of deposition cycles increases. The enhancements are mostly attributed to the barrier effect of intumescent network structure, which is composed of MWNT-NH2 and the absorbed APP. PMID- 23459989 TI - Side reactions in the SPPS of Cys-containing peptides. AB - Alkylation of sensitive amino acids during synthesis of biologically important peptides is a common and well-documented problem in Fmoc-based strategy. Herein, we probed for the first time an unexpected S-alkylation of Cys-containing peptides that occur during the final TFA cleavage of peptides from the Wang solid support. Through a battery of approaches (NMR, UV and LC-MS) the formed by product was assigned as the alkylation of the cysteine sulfydryl group by the p hydroxyl benzyl group derived from the acidic Wang linker decomposition. Factors affecting this side reaction were monitored and a protocol that minimizes the presence of the by-product is reported. PMID- 23459990 TI - An exploration into diffusion tensor imaging in the bovine ocular lens. AB - We describe our development of the diffusion tensor imaging modality for the bovine ocular lens. Diffusion gradients were added to a spin-echo pulse sequence and the relevant parameters of the sequence were refined to achieve good diffusion weighting in the lens tissue, which demonstrated heterogeneous regions of diffusive signal attenuation. Decay curves for b-value (loosely summarizes the strength of diffusion weighting) and TE (determines the amount of magnetic resonance imaging-obtained signal) were used to estimate apparent diffusion coefficients (ADC) and T2 in different lens regions. The ADCs varied by over an order of magnitude and revealed diffusive anisotropy in the lens. Up to 30 diffusion gradient directions, and 8 signal acquisition averages, were applied to lenses in culture in order to improve maps of diffusion tensor eigenvalues, equivalent to ADC, across the lens. From these maps, fractional anisotropy maps were calculated and compared to known spatial distributions of anisotropic molecular fluxes in the lens. This comparison suggested new hypotheses and experiments to quantitatively assess models of circulation in the avascular lens. PMID- 23459991 TI - Global impact of Salmonella pathogenicity island 2-secreted effectors on the host phosphoproteome. AB - During the late stages of infection, Salmonella secretes numerous effectors through a type III secretion system that is encoded within Salmonella pathogenicity island 2 (SPI2). Despite the importance of SPI2 as a major virulence factor leading to the systemic spread of the bacteria and diseases, a global view of its effects on host responses is still lacking. Here, we measured global impacts of SPI2 effectors on the host phosphorylation and protein expression levels in RAW264.7 and in HeLa cells, as macrophage and nonphagocytic models of infection. We observe that SPI2 effectors differentially modulate the host phosphoproteome and cellular processes (e.g. protein trafficking, cytoskeletal regulation, and immune signaling) in a host cell-dependent manner. Our unbiased approach reveals the involvement of many previously unrecognized proteins, including E3 ligases (HERC4, RanBP2, and RAD18), kinases (CDK, SIK3, and WNK1), and histones (H2B1F, H4, and H15), in late stages of Salmonella infection. Furthermore, from this phosphoproteome analysis and other quantitative screens, we identified HSP27 as a direct in vitro and in vivo molecular target of the only type III secreted kinase, SteC. Using biochemical and cell biological assays, we demonstrate that SteC phosphorylates multiple sites in HSP27 and induces actin rearrangement through this protein. Together, these results provide a broader landscape of host players contributing to specific processes/pathways mediated by SPI2 effectors than was previously appreciated. PMID- 23459992 TI - Failures (with some successes) of assisted reproduction and gamete donation programs. AB - BACKGROUND: Although the possibilities for the treatment of infertility have been improved tremendously, not every couple will be treated successfully. METHODS: Crude overall pregnancy rates of 50-65% per patient can be achieved nowadays, irrespective of the type of profertility treatment applied first. RESULTS: IVF only accounts for about 20% of the pregnancies achieved. Dropout is an important reason for not reaching the estimated pregnancy rate. Even after failed IVF, spontaneous pregnancies do occur. Sperm and oocyte donation (OD) offer additional chances to subfertile couples. Severity of the male factor (in sperm donation) and young donor age (in OD) are important determinants of success. CONCLUSIONS: Analysis of assisted reproduction technology outcomes would benefit from more universally accepted definitions and deserves better statistical analysis. Long term cumulative live birth rates of 80% may be expected if dropout can be limited. Milder stimulation, a patient-friendlier approach and better counseling may help to keep more patients in the program. PMID- 23459993 TI - A cyclic peptide-based redox-active model of rubredoxin. AB - A model of rubredoxin based on a cyclic peptide with a linear tail is presented. This model reproduces almost perfectly the fold, the spectroscopic characterizations and the redox activity of rubredoxins. PMID- 23459994 TI - Seizures during the management of high-grade gliomas: clinical relevance to disease progression. AB - This study was performed to evaluate the incidence of seizures with its implications on disease progression and the diagnostic value of post-ictal magnetic resonance images (MRI) during the management of high-grade gliomas (HGGs). A total of 406 consecutive patients with newly diagnosed HGGs were retrospectively reviewed. The incidence of seizures during the management was investigated. In patients who experienced a seizure, the causality between seizures and disease progression was assessed by pre-ictal, post-ictal (<1 month), and follow-up (<3 months) MRI. After a median follow-up of 17.4 months (range 0.1-88.3), seizures developed in 127 patients (31 %). Of the 127 patients, radiological progression at the post-ictal MRI was found in 83 patients (65 %) and the follow-up MRI confirmed progression in 79 patients (62 %). Four other patients (3 %) were shown to be progression-free. Among those without radiological progression at the post-ictal MRI, the follow-up MRI confirmed progression-free in 31 patients (24 %); however, 13 patients (10 %) revealed eventual progression. In the patients with a seizure, absence of preoperative seizures (p = 0.003), <95 % tumor resection (p = 0.001), and pre-ictal Karnofsky Performance Scale score <= 70 (p = 0.025) were significantly associated with disease progression. During the management of HGG, 31 % of patients experienced seizures; of these patients, 72 % harbored progressive disease. The post-ictal MRI is useful for detecting disease progression; however, there are pitfalls. Clinical settings should be considered together for diagnosing disease progression in patients with seizures. PMID- 23459996 TI - Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels. AB - The efficacy of targeting pH disruption to induce cell death in the acidic and hypoxic tumor microenvironment continues to be assessed. Here we analyzed the impact of varying levels of hypoxia in acidic conditions on fibroblast and tumor cell survival. Across all cell lines tested, hypoxia (1% O(2)) provided protection against acidosis induced cell death compared to normoxia. Meanwhile severe hypoxia (0.1% O(2)) removed this protection and in some cases exacerbated acidosis-induced cell death. Differential survival between cell types during external acidosis correlated with their respective intracellular pH regulating capabilities. Cellular ATP measurements were conducted to determine their contribution to cell survival under these combined stresses. In general, hypoxia (1% O(2)) maintained elevated ATP levels in acidic conditions while severe hypoxia did not. To further explore this interaction we combined acidosis with ATP depletion using 2-deoxyglucose and observed an enhanced rate of cell mortality. Striking results were also observed with hypoxia providing protection against cell death in spite of a severe metabolic stress induced by a combination of acidosis and oligomycin. Finally, we demonstrated that both HIF1alpha and HIF2alpha expression were drastically reduced in hypoxic and acidic conditions indicating a sensitivity of this protein to cellular pH conditions. This knockdown of HIF expression by acidosis has implications for the development of therapies targeting the disruption of cellular pH regulation. Our results reinforce the proof of concept that acidosis and metabolic disruption affecting ATP levels could be exploited as a tumor cell killing strategy. PMID- 23459995 TI - A phase II single-arm study of irinotecan in combination with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC and SIOPE-brain tumour study. AB - A multicenter, two stage phase II study, investigated irinotecan plus temozolomide in children with newly diagnosed high grade glioma. The primary endpoint was tumor response during a two-cycle treatment window, confirmed by external review committee. Patients received oral temozolomide 100 mg/(m(2) day) (days 1-5) and intravenous irinotecan 10 mg/(m(2) day) (days 1-5 and 8-12) for two 21-day cycles (three cycles for patients exhibiting objective tumor response). Standard treatment was then administered according to local investigator choice. In total 17 patients were enrolled and treated by local investigators. However, central pathology review found three patients did not have a diagnosis of high grade glioma and another four patients did not have evaluable disease according to independent central radiological review. The primary endpoint was based on the first ten evaluable patients as determined by the external review committee. Recruitment was stopped for futility after there were no complete or partial responses during the two-cycle treatment window in the first ten evaluable patients. Five patients had stable disease, and five progressed. Data for secondary endpoints including; time to tumor progression, time to treatment failure, and overall survival is reported. The safety profile of the treatment showed the combination was tolerable with two patients (11.8 %) having grade three nausea, and one (5.9 %) experiencing a grade four neutropenia, leading to permanent discontinuation from adjuvant treatment. Irinotecan plus temozolomide, although well tolerated did not improve outcome over historical controls in this setting. PMID- 23459997 TI - [High-resolution peripheral quantitative CT (HR-pQCT). New insights into arthritis]. AB - The detection of periarticular bone lesions is of crucial importance in the diagnosis and treatment monitoring of chronic inflammatory diseases such as, but not limited to, rheumatoid arthritis (RA). High-resolution peripheral quantitative computed tomography (HR-pQCT) was initially developed for the meticulous assessment of bone microstructure with a focus on bone density parameters. With an isotropic voxel size of 82 um HR-pQCT is, however, also well suited for quantitative evaluation of periarticular bone lesions, such as erosion, osteophytes as well as bone surface changes in arthritis. The present article gives an overview of the manifold possibilities of application of this novel imaging modality and addresses potential benefits of this technique for rheumatology in the future. PMID- 23459999 TI - Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug-bile interaction. AB - The aim of this study was to find out polymeric compounds that can inhibit the interaction between YM466, a novel anticoagulant, and bile to improve its oral bioavailability. In vitro ultrafiltration method using extract gall powder was useful to detect the formation of insoluble complex of YM466 with bile and also used to select a polymer that can inhibit the interaction between YM466 and bile. The in vitro studies revealed that aminoalkylmethacrylate (AAM) copolymer E, a polymethacrylate, dose-dependently inhibited the interaction between YM466 and bile and that this polymer could interact with bile salt, but not with YM466, possibly by electrostatic and/or hydrophobic interactions. The coadministration of AAM copolymer E with YM466 to rats dose-dependently increased the plasma concentration of YM466 and it was found that the oral dose of the polymer three times of YM466 (polymer to drug ratio in weight, P-D ratio, 3) significantly increased AUC0-1 h of YM466 to 2.6-fold of that of YM466 alone. Considering the condition of therapeutic use of YM466 and the maximum tolerated dose of the polymer, the formulation of P-D ratio 3 would be clinically practical and promising from the viewpoint of safety. PMID- 23459998 TI - [IgG4-related disease]. AB - IgG4-related disease is a systemic fibroinflammatory syndrome of unknown etiology characterized by local inflammatory swelling and tumefactive lesions in one or several organs. It unifies several diseases previously thought to be unrelated. Recently, diagnostic criteria for the disease have been formulated and were complemented by an international consensus on histopathological assessment. In general, the disease activity can be rapidly controlled by high doses of prednisolone (0.6 mg/kg body weight); however, relapses, either local or in other regions, are frequent during tapering of the steroid dose. Commonly used steroid sparing agents are only partially effective. Persistent local inflammatory activity may result in permanent organ damage. In refractory cases rituximab treatment has been used with good success. In the long-term care of affected patients a probable increased risk of malignancies (e.g. solid tumors and lymphoma) requires attention. PMID- 23460001 TI - Mycobacterial infections. PMID- 23460000 TI - Total joint replacement outcomes in patients with concomitant comorbidities: a glass half empty or half full? PMID- 23460002 TI - Global epidemiology of tuberculosis. AB - With 1.4 million deaths in 2011 and 8.7 million new cases, tuberculosis (TB) disease remains a global scourge. Global targets for reductions in the epidemiological burden of TB have been set for 2015 and 2050 within the context of the Millennium Development Goals (MDGs) and by the Stop TB Partnership. Achieving these targets is the focus of national and international efforts in TB control, and demonstrating whether or not they are achieved is of major importance to guide future and sustainable investments.This paper discusses the methods used to estimate the global burden of TB; estimates of incidence, prevalence, and mortality for 2011, combined with assessment of progress toward the 2015 targets for reductions in these indicators based on trends since 1990 and projections up to 2015; trends in TB notifications and in the implementation of the Stop TB Strategy; and prospects for elimination of TB by 2050. PMID- 23460003 TI - The changing landscape of diagnostic services for tuberculosis. AB - During the last decade there has been a dramatic change in the laboratory approach to tuberculosis (TB) diagnosis in the developing world. This change began with the realization that acid-fast bacillus smear microscopy alone was totally inadequate to deal with the dual problems of human immunodeficiency virus (HIV)-associated TB and drug-resistant TB that threaten to undermine global progress in TB control. Subsequently, increased financial resources for TB laboratory services and the establishment of a systematic process for endorsement of new TB diagnostic tools and approaches by the World Health Organization (WHO) have led to rapid expansion of TB laboratory services and the availability of several new diagnostic tests that have been introduced. These include both commercial automated and noncommercial systems for phenotypic mycobacterial liquid culture and drug susceptibility testing, a simple and inexpensive test for mycobacterial species identification in culture isolates, light-emitting diode fluorescence microscopy, and rapid molecular methods for TB case detection and the diagnosis of drug-resistant TB. The latter methodologies that include line probe assays and an automated cartridge-based real-time polymerase chain reaction (PCR)-based test are being scaled up at an unprecedented pace and are truly revolutionizing the diagnosis of drug-resistant TB. On the other hand, little progress has been made in the quest for a true point-of-care test for TB. Fortunately, this is being addressed in several discovery initiatives that hopefully will provide impetus for the development of rapid, accurate TB diagnostics for the lowest level of the health system. PMID- 23460004 TI - Tuberculosis and HIV coinfection. AB - The human immunodeficiency virus (HIV) pandemic has amplified the global burden of tuberculosis (TB), particularly in sub-Saharan Africa, where 82% of the world's TB/HIV coinfection exists. HIV infection significantly increases the risk of developing and dying from TB and was associated with 350,000 TB deaths in 2010. The diagnosis of HIV-associated TB is often challenging due to atypical clinical and radiographic manifestations, more frequent extrapulmonary disease, and higher rates of smear-negative pulmonary TB. Nucleic acid amplification tests, including the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA), improve our ability to rapidly diagnose both smear-negative and extrapulmonary TB. The standard 6-month anti-TB regimen is usually adequate for HIV coinfected persons, but intermittent dosing in the intensive phase should be avoided because of an increased risk of relapse with acquired rifamycin resistance. The comanagement of HIV and TB is challenging due to drug-drug interactions, overlapping drug toxicities, concerns about adherence, and the immune reconstitution inflammatory syndrome. However, the initiation of antiretroviral therapy (ART) during the course of TB treatment is necessary to improve survival, and the appropriate timing of ART is dependent on the level of immune suppression. Therefore, the management of TB must be well coordinated with HIV resources, prepared to rapidly diagnose HIV, assess immune status, and correctly treat both infections. PMID- 23460005 TI - Management of multidrug resistant tuberculosis. AB - Drug-resistant strains of Mycobacterium tuberculosis have emerged as a major threat to global tuberculosis control. Despite the availability of curative antituberculosis therapy for nearly half a century, inappropriate and inadequate treatment has allowed M. tuberculosis to acquire resistance to our most important antituberculosis drugs. The epidemic of drug-resistant tuberculosis has spread quickly in some areas due to the convergence of resistant strains of M. tuberculosis in high-risk patients (e.g., those with human immunodeficiency virus/acquired immunodeficiency syndrome) and high-risk environments (e.g., hospitals and prisons). The World Health Organization (WHO) estimates that there were 650,000 cases of multidrug resistant tuberculosis (MDR-TB) in 2010, defined as strains that are resistant to at least isoniazid (INH) and rifampicin (RIF). Globally, WHO estimates that 3.7% of new tuberculosis cases and 20% of re treatment cases have MDR-TB. By the end of 2012, 84 countries had reported at least one case of extensively drug resistant strains (XDR-TB), which are MDR-TB strains that have acquired additional resistance to fluoroquinolones and at least one second-line injectable. Recently, cases of "totally drug resistant" tuberculosis have been reported. It is estimated that only 10% of all MDR-TB cases are currently receiving therapy and only 2% are receiving quality-assured drugs. This article reviews the management of MDR and XDR-TB and highlights the updated 2011 WHO guidelines on the programmatic management of drug-resistant tuberculosis. PMID- 23460006 TI - Advances in the diagnosis of latent tuberculosis infection. AB - Accurate diagnosis of tuberculosis (TB) infection is an important component of tuberculosis control programs in many countries. Identification of persons with asymptomatic, or latent, tuberculosis infection allows for treatment of individuals at high risk for progressing to active disease so that the overall burden of tuberculosis disease is diminished. In the United States, targeted testing and treatment of latent tuberculosis infection (LTI) are major components of the Centers for Disease Control and Prevention's efforts at TB elimination. This review focuses on the comparative utility of tuberculin skin testing and interferon-gamma release assays (IGRAs) to diagnose LTI. Commercially available IGRAs have superior sensitivity and specificity compared with conventional tuberculin skin testingin some settings (particularly bacille-Calmette Guerin vaccinated individuals). Also discussed are the performance characteristics of these tests in specific populations, including foreign-born persons from high prevalence countries, close contacts of actively infected patients, immunocompromised populations, and health care workers. PMID- 23460007 TI - Treatment of latent tuberculosis infection. AB - Latent tuberculosis infection (LTBI) refers to a circumstance in which viable Mycobacterium tuberculosis (MTB) bacilli are present in an individual but symptoms and signs of active disease are lacking, and the bacilli are relatively inactive metabolically. In favorable circumstances, some of these inactive bacilli resume greater metabolic activity and replication, leading to the development of active tuberculosis disease. Treatment of this condition (TLTBI) is designed to prevent (soon, or in the distant future) this progression from asymptomatic infection to symptomatic, potentially lethal, active disease. This narrative review draws upon recent reviews of LTBI and seeks particularly to include recently published or presented data that are not included in those prior reviews. Adverse effects of treatment are considered, as are the special circumstances of human immunodeficiency virus-related LTBI, drug resistance, and use of TLTBI in the context of tumor necrosis factor alpha (TNF-alpha) inhibition. The review describes the main studies underpinning Centers for Disease Control and Prevention recommendations on use of the new 3-month isoniazid-rifapentine regimen and points to evolving data that may support future modification of those recommendations. PMID- 23460008 TI - Update on the epidemiology of pulmonary nontuberculous mycobacterial infections. AB - For decades, the incidence of pulmonary nontuberculous mycobacteria (NTM) has been reported to be increasing, yet formal epidemiological evaluation of this notion has been lacking until recently. Defining the epidemiology of NTM has been more challenging than with Mycobacterium tuberculosis (MTB). Unlike MTB, NTM are soil and water organisms, and infection is thought to be acquired from the environment rather than transmitted from person-to-person, with very rare exceptions. Due to their nearly ubiquitous presence in municipal water supplies, exposure to NTM is common. Further, NTM can colonize the respiratory tract without causing disease. NTM disease is not reportable to public health authorities; therefore, epidemiological and surveillance data are not readily available. Nonetheless, the prevalence of pulmonary NTM disease has increased dramatically in the United States and globally over the past 3 decades. Mycobacterium avium complex (MAC) accounts for the majority of NTM infections worldwide, but there is significant regional variability of various species. Additionally, novel species have been implicated in several countries in NTM pulmonary disease. PMID- 23460009 TI - Ecology of nontuberculous mycobacteria--where do human infections come from? AB - Nontuberculous mycobacteria (NTM) are environmental, opportunistic human pathogens whose reservoirs include peat-rich potting soil and drinking water in buildings and households. In fact, humans are likely surrounded by NTM. NTM are ideally adapted for residence in drinking water distribution systems and household and building plumbing as they are disinfectant-resistant, surface adherent, and able to grow on low concentrations of organic matter. For individuals at risk for NTM infection, measures can be taken to reduce NTM exposure. These include avoiding inhalation of dusts from peat-rich potting soil and aerosols from showers, hot tubs, and humidifiers. A riskanalysis of the presence of NTM in drinking water has not been initiated because the virulence of independent isolates of even single NTM species (e.g., Mycobacterium avium) is quite broad, and virulence determinants have not been identified. PMID- 23460010 TI - Diagnosis of nontuberculous mycobacterial infections. AB - The nontuberculous mycobacteria (NTM) are typically environmental organisms residing in soil and water. Although generally of low pathogenicity to humans, NTM can cause a wide array of clinical diseases; pulmonary disease is most frequent, followed by lymphadenitis in children, skin disease by M. marinum (particularly in fish tank fanciers), and other extrapulmonary or disseminated infections in severely immunocompromised patients. Of the >140 NTM species reported in the literature, 25 species have been strongly associated with NTM diseases; the remainder are environmental organisms rarely encountered in clinical samples. Correct species identification is very important because NTM species differ in their clinical relevance. Further, NTM differ strongly in their growth rate, temperature tolerance, and drug susceptibility. The diagnosis of NTM disease is complex and requires good communication between clinicians, radiologists, and microbiologists. Isolation of M. kansasii and (in northwestern Europe) M. malmoense from pulmonary specimens usually indicates disease, whereas Mycobacterium gordonae and, to a lesser extent, M. simiae or M. chelonae are typically contaminants rather than causative agents of true disease. Mycobacterium avium complex (MAC), M. xenopi, and M. abscessus form an intermediate category between these two extremes. This review covers the clinical and laboratory diagnosis of NTM diseases and particularities for the different disease types and patient populations. Because of limited sensitivity and specificity of symptoms, radiology, and direct microscopy of clinical samples, culture remains the gold standard. Yet culture is time consuming and demands the use of multiple media types and incubation temperatures to optimize the yield. Outside of reference centers, such elaborate culture algorithms are scarce. PMID- 23460011 TI - Underlying host risk factors for nontuberculous mycobacterial lung disease. AB - Nontuberculous mycobacteria (NTM) are environmental microbes that cause a variety of human diseases, particularly chronic lung infections. Despite the fact that NTM are widespread in the environment, relatively few people develop NTM lung disease, suggesting intrinsic vulnerability in some individuals. This paper reviews the evidence that underlying disorders predispose to NTM lung disease, in particular primary conditions that result in bronchiectasis, chronic obstructive pulmonary disease, alpha-1-antitrypsin anomalies, pneumoconiosis, pulmonary alveolar proteinosis, and frank immunosuppressive states such as that associated with the use of anti-tumor necrosis factor-alpha biologics, posttransplantation immunosuppression, and HIV infection. Over the past several decades, NTM lung disease has been increasingly identified in postmenopausal women with slender body habitus. Thus we will also review the clinical and experimental evidence which supports the observation that such individuals are predisposed to NTM lung disease. PMID- 23460012 TI - Nontuberculous mycobacteria in patients with cystic fibrosis. AB - As a result of their underlying lung disease, patients with cystic fibrosis (CF) have a higher risk of developing nontuberculous mycobacteria (NTM) infections compared with the general population. Although NTM may be present intermittently in low amounts in the airways of CF patients without an apparent clinical effect, progressive respiratory decline due to NTM disease may also occur. Identifying this latter group of patients can be challenging for clinicians because the usual symptoms exhibited by infected individuals without CF may be difficult to distinguish from the baseline respiratory dysfunction of a patient with CF. The distinction, however, is of utmost importance because those patients with clinical worsening may benefit considerably from antimycobacterial treatment. For CF patients under evaluation for lung transplantation, NTM can play a critical role in determining overall outcomes, and treatment in the pre- and post transplant period may be vital to success. A general approach to NTM in CF thus involves surveillance to detect NTM, careful monitoring for associated clinical decline, and consideration of treatment given for those with an otherwise unexplained deterioration. In this review, the epidemiology and clinical course of NTM in CF is described with an algorithm for management proposed. PMID- 23460013 TI - Management of nontuberculous mycobacterial (NTM) lung disease. AB - Nontuberculous mycobacterial (NTM) lung diseases present formidable obstacles to successful management, especially when compared with tuberculosis, beginning with diagnosis and extending through treatment. Factors peculiar to NTM disease such as extensive microbial resistance mechanisms and difficult to interpret, even misleading, in vitro drug susceptibility patterns are just two of the multiple and frustrating clinical management challenges. More conventional problems such as drug-drug interactions, medication side-effects, and nonadherence with therapy add further impediments to successful outcomes. In spite of these difficulties, the majority of NTM lung disease patients are still treated successfully. Because the prevalence of NTM is rising, it is increasingly necessary for clinicians to understand those unique aspects of NTM lung disease diagnosis and treatment that differ from tuberculosis and that contribute to limited treatment options. PMID- 23460014 TI - Management of extrapulmonary nontuberculous mycobacterial infections. AB - Nontuberculous mycobacteria represent a vast group of environmental organisms that have the potential to cause disease in humans. Unlike tuberculosis, these organisms are not known to be transmitted from human to human. The most common clinical presentation is pulmonary disease. Approximately 10% of infections manifest as extrapulmonary disease. The portals of entry are the respiratory tract, gastrointestinal tract, or direct inoculation via trauma or an invasive procedure. Like tuberculosis, the nontuberculous mycobacteria have the potential to infect any organ system given the opportunity in an immunocompromised host. The spectrum of disease is extensive ranging from self-limited furunculosis to life-threatening disseminated infection. Common extrapulmonary manifestations include lymphadenitis, disseminated disease, skin, soft tissue, and bone infection. Less common manifestations include keratitis, catheter-related bloodstream infections, septic arthritis, central nervous system infection, and peritonitis. The incidence of extrapulmonary infections is unknown. Outbreaks have been reported due to inadequate disinfection of surgical equipment or contamination of injected solutions or medications. A high index of suspicion is required when patients present with subacute or chronic complaints of extrapulmonary infection. This review addresses the management of the common extrapulmonary nontuberculous infections. PMID- 23460015 TI - Three-dimensional photolithographic micropatterning: a novel tool to probe the complexities of cell migration. AB - In order to independently study the numerous variables that influence cell movement, it will be necessary to employ novel tools and materials that allow for exquisite control of the cellular microenvironment. In this work, we have applied advanced 3D micropatterning technology, known as two-photon laser scanning lithography (TP-LSL), to poly(ethylene glycol) (PEG) hydrogels modified with bioactive peptides in order to fabricate precisely designed microenvironments to guide and quantitatively investigate cell migration. Specifically, TP-LSL was used to fabricate cell adhesive PEG-RGDS micropatterns on the surface of non degradable PEG-based hydrogels (2D) and in the interior of proteolytically degradable PEG-based hydrogels (3D). HT1080 cell migration was guided down these adhesive micropatterns in both 2D and 3D, as observed via time-lapse microscopy. Differences in cell speed, cell persistence, and cell shape were observed based on variation of adhesive ligand, hydrogel composition, and patterned area for both 2D and 3D migration. Results indicated that HT1080s migrate faster and with lower persistence on 2D surfaces, while HT1080s migrating in 3D were smaller and more elongated. Further, cell migration was shown to have a biphasic dependence on PEG-RGDS concentration and cells moving within PEG-RGDS micropatterns were seen to move faster and with more persistence over time. Importantly, the work presented here begins to elucidate the multiple complex factors involved in cell migration, with typical confounding factors being independently controlled. The development of this unique platform will allow researchers to probe how cells behave within increasingly complex 3D microenvironments that begin to mimic specifically chosen aspects of the in vivo landscape. PMID- 23460016 TI - Outcomes of partial mastectomy in male breast cancer patients: analysis of SEER, 1983-2009. AB - BACKGROUND: Although mastectomy is considered the gold standard for male breast cancer (MBC), the utilization of lumpectomy and its impact on outcomes in MBC patients has not been previously studied. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to identify all MBC patients who underwent either mastectomy or less than mastectomy (i.e., lumpectomy) between 1983 and 2009. RESULTS: A total of 4707 (86.8 %) men underwent mastectomy and 718 (13.2 %) underwent lumpectomy. A greater proportion of patients underwent lumpectomy later in the study period (1983 to 1986, 10.6 %, vs. 2007 to 2009, 15.1 %). A greater percentage of lumpectomy patients were 80 years or older (21.3 % vs. 16.3 %), had stage IV disease (7.3 % vs. 3.1 %), and received no lymph node sampling (34.3 % vs. 6.9 %). Only 35.4 % of patients underwent adjuvant radiotherapy after lumpectomy. Ten-year breast cancer-specific survival and overall survival were 82.8 % and 46.9 %, respectively, in lumpectomy patients vs. 77.3 % and 46.4 %, respectively, in mastectomy patients. On Cox proportional hazards regression, lumpectomy was not independently associated with worse breast cancer-specific survival (odds ratio 1.09, 95 % confidence interval 0.87-1.37) or overall survival (odds ratio 1.12, 95 % confidence interval 0.98-1.27) after controlling for age, race, stage, and grade, as well as whether radiotherapy was received. CONCLUSIONS: Lumpectomy is performed in a small but growing proportion of MBC patients. These patients are not only older and more likely to have advanced disease at the time of diagnosis, but they also are less likely to receive standard of care therapy, such as lymph node sampling and adjuvant radiotherapy. Despite these observations, breast cancer-specific survival is unaffected by the type of surgery. PMID- 23460017 TI - Volatile organic compounds and risk of asthma and allergy: a systematic review and meta-analysis of observational and interventional studies. PMID- 23460018 TI - Incidence of sinusoidal obstruction syndrome following Mylotarg (gemtuzumab ozogamicin): a prospective observational study of 482 patients in routine clinical practice. AB - The purpose of this prospective observational study was to determine the incidence of hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab ozogamicin (GO) therapy in routine clinical practice. Patients receiving GO for acute myeloid leukemia (AML) were eligible. Assessments were requested to be performed weekly for 6 weeks after the start of GO therapy or 4 weeks after the last dose (whichever was later), and after 6 months. The primary outcome variable was the incidence of SOS as judged by a panel of independent experts. A total of 512 patients were enrolled at 54 US centers and 482 were evaluable. The incidence of SOS in this study population was 9.1 % (44/482; 95 % confidence interval 6.9 12.0 %). Of the 44 patients classified as having SOS, 8 were mild, 17 moderate, and 19 severe; 33 died within 6 months (20 of disease progression and 13 of SOS and multiorgan failure). Most (68 %) patients in the study died within 6 months; most of these deaths (73 %) were due to progression of AML. Serious adverse events occurred in 85 % of patients, most (81 %) due to AML, febrile neutropenia, pyrexia, and sepsis. GO administered in routine clinical practice carries an overall 9.1 % risk of SOS and a 2.7 % risk of death from SOS and multiorgan failure. No risk factors were identified for the development of SOS. PMID- 23460019 TI - Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells. AB - AIMS/HYPOTHESIS: The proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex 1 (mTORC1) and among the most prominent Akt substrates in skeletal muscle. Yet the cellular functions of PRAS40 are incompletely defined. This study assessed the function of PRAS40 in insulin action in primary human skeletal muscle cells (hSkMC). METHODS: Insulin action was examined in hSkMC following small interfering RNA-mediated silencing of PRAS40 (also known as AKT1S1) under normal conditions and following chemokine induced insulin resistance. RESULTS: PRAS40 knockdown (PRAS40-KD) in hSkMC decreased insulin-mediated phosphorylation of Akt by 50% (p < 0.05) as well as of the Akt substrates glycogen synthase kinase 3 (40%) and tuberous sclerosis complex 2 (32%) (both p < 0.05). Furthermore, insulin-stimulated glucose uptake was reduced by 20% in PRAS40-KD myotubes (p < 0.05). Exposing PRAS40-KD myotubes to chemokines caused no additional deterioration of insulin action. PRAS40-KD further reduced insulin-mediated phosphorylation of the mTORC1-regulated proteins p70S6 kinase (p70S6K) (47%), S6 (43%), and eukaryotic elongation 4E-binding protein 1 (100%), as well as protein levels of growth factor receptor bound protein 10 (35%) (all p < 0.05). The inhibition of insulin action in PRAS40-KD myotubes was associated with a reduction in IRS1 protein levels (60%) (p < 0.05), and was reversed by pharmacological proteasome inhibition. Accordingly, expression of the genes encoding E3-ligases F-box protein 32 (also known as atrogin-1) and muscle RING-finger protein-1 and activity of the proteasome was elevated in PRAS40-KD myotubes. CONCLUSIONS/INTERPRETATION: Inhibition of insulin action in PRAS40-KD myotubes was found to associate with IRS1 degradation promoted by increased proteasome activity rather than hyperactivation of the p70S6K-negative-feedback loop. These findings identify PRAS40 as a modulator of insulin action. PMID- 23460020 TI - Fasting proinsulin levels are significantly associated with 20 year cancer mortality rates. The Hoorn Study. AB - AIMS/HYPOTHESIS: Proinsulin is possibly associated with cancer through activation of insulin receptor isoform A. We sought to investigate the associations between proinsulin and 20 year cancer mortality rates. METHODS: The study was performed within the Hoorn Study, a population-based study of glucose metabolism in individuals aged 50-75 years in the Dutch population. Fasting proinsulin levels were measured twice by a double-antibody radioimmunoassay. Participants were continuously followed to register mortality; causes of death were derived from medical records. Cox survival analyses were performed to assess the 20 year risk of death from cancer in relation to proinsulin. All analyses were adjusted for age and sex, with additional adjustments for traditional risk factors. The effect modification of glucose metabolism and sex was tested. RESULTS: Proinsulin levels were measured in 438 individuals (41% normal glucose tolerance, 35.7% impaired glucose metabolism, 23.3% type 2 diabetes). Of these participants, 53 died from cancer. After adjustment for age and sex, proinsulin >16.5 pmol/l (the upper tertile) was significantly associated with a twofold risk of cancer mortality (HR 2.01, 95% CI 1.16, 3.46) compared with individuals with lower proinsulin levels. Additional adjustment for glucose metabolism, BMI and smoking did not substantially change the results (HR 1.91, 95% CI 1.04, 3.52). No interaction with glucose metabolism or sex was observed. CONCLUSIONS/INTERPRETATION: Individuals with fasting proinsulin levels >16.5 pmol/l have a twofold risk of cancer mortality over a 20 year time span. These findings provide population based evidence for the independent association between high proinsulin levels and cancer mortality rates. PMID- 23460022 TI - Comparative study of image quality and radiation dose of cone beam and low-dose multislice computed tomography--an in-vitro investigation. AB - OBJECTIVES: The aim of this study was to evaluate the image quality and dose exposition of different cone-beam computed tomography (CBCT) and low-dose multislice spiral CT (MSCT) scanners. MATERIALS AND METHODS: A human cadaver head was examined with three MSCT and five CBCT scanners. The radiation dose was measured using an Alderson RANDO phantom. Standard protocols were used to obtain the CBCT data. For the MSCT devices, the tube voltage and tube current were modified to obtain acceptable image quality while keeping the radiation dose as low as possible. The image quality of MSCT and CBCT devices was determined by examining the enamel-dentin and dentin-pulp interface and the periodontal ligament space of 22 teeth. RESULTS: Inter- and intra-observer agreement was found for the different groups of raters. CBCT systems were rated superior to MSCT devices in terms of image quality for all dental structures. The differences in image quality among the studied CBCT and MSCT scanner groups did not turn out to be significant but were significant between CBCT and MSCT devices. The organ dose varied considerably between the different CBCT and MSCT devices. The differences concerning the organ dose were notably pronounced in the area of the eye lens. CONCLUSIONS: The tested devices exhibited significant differences with respect to the organ dose. The variance was particularly pronounced in the CBCT devices. With a dose exposition equal or lower than the CBCT, the image quality in the MSCT devices was judged to be significantly worse. PMID- 23460023 TI - Imaging cortical damage and dysfunction in multiple sclerosis. AB - In line with pathological investigations, in vivo magnetic resonance imaging has consistently shown both focal and diffuse damage in the cerebral cortex of patients with multiple sclerosis. Cortical injury tends to progress over time and is only partially related to white matter abnormalities. This review summarizes the main findings from studies using both conventional and modern quantitative magnetic resonance-based techniques for the assessment of cortical damage and dysfunction in patients with multiple sclerosis. PMID- 23460021 TI - Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. AB - AIMS/HYPOTHESIS: Although the substitution of saturated fatty acids with oleate has been recommended in the management of type 2 diabetes mellitus, the mechanisms by which oleate improves insulin resistance in skeletal muscle cells are not completely known. Here, we examined whether oleate, through activation of AMP-activated protein kinase (AMPK), prevented palmitate-induced endoplasmic reticulum (ER) stress, which is involved in the link between lipid-induced inflammation and insulin resistance. METHODS: Studies were conducted in mouse C2C12 myotubes and in the human myogenic cell line LHCN-M2. To analyse the involvement of AMPK, activators and inhibitors of this kinase and overexpression of a dominant negative AMPK construct (K45R) were used. RESULTS: Palmitate increased the levels of ER stress markers, whereas oleate did not. In palmitate exposed cells incubated with a lower concentration of oleate, the effects of palmitate were prevented. The induction of ER stress markers by palmitate was prevented by the presence of the AMPK activators AICAR and A-769662. Moreover, the ability of oleate to prevent palmitate-induced ER stress and inflammation (nuclear factor-kappa B [NF-kappaB] DNA-binding activity and expression and secretion of IL6) as well as insulin-stimulated Akt phosphorylation and 2 deoxyglucose uptake was reversed in the presence of the AMPK inhibitor compound C or by overexpression of a dominant negative AMPK construct. Finally, palmitate reduced phospho-AMPK levels, whereas this was not observed in oleate-exposed cells or in palmitate-exposed cells supplemented with oleate. CONCLUSIONS/INTERPRETATION: Overall, these findings indicate that oleate prevents ER stress, inflammation and insulin resistance in palmitate-exposed skeletal muscle cells by activating AMPK. PMID- 23460024 TI - Reactivity of metal oxide clusters with hydrogen peroxide and water--a DFT study evaluating the performance of different exchange-correlation functionals. AB - We have performed a density functional theory (DFT) investigation of the interactions of H2O2, H2O and HO radicals with clusters of ZrO2, TiO2 and Y2O3. Different modes of H2O adsorption onto the clusters were studied. In almost all the cases the dissociative adsorption is more exothermic than molecular adsorption. At the surfaces where H2O has undergone dissociative adsorption, the adsorption of H2O2 and the transition state for its decomposition are mediated by hydrogen bonding with the surface HO groups. Using the functionals B3LYP, B3LYP-D and M06 with clusters of 26 and 8 units of ZrO2, the M06 functional performed better than B3LYP in describing the reaction of decomposition of H2O2 and the adsorption of H2O. Additionally, we investigated clusters of the type (ZrO2)2, (TiO2)2 and (Y2O3) and the performance of the functionals B3LYP, B3LYP-D, B3LYP*, M06, M06-L, PBE0, PBE and PWPW91 in describing H2O2, H2O and HO adsorption and the energy barrier for decomposition of H2O2. The trends obtained for HO adsorption onto the clusters are discussed in terms of the ionization energy of the metal cation present in the oxide. In order to correctly account for the existence of an energy barrier for the decomposition of H2O2, the functional used must include Hartree-Fock exchange. Using minimal cluster models, the best performance in describing the energy barrier for H2O2 decomposition was obtained with the M06 and PBE0 functionals - the average absolute deviations from experiments are 6 kJ mol(-1) and 5 kJ mol(-1) respectively. With the M06 functional and a larger monoclinic (ZrO2)8 cluster model, the performance is in excellent agreement with experimental data. For the different oxides, PBE0 was found to be the most effective functional in terms of performance and computational time cost. PMID- 23460025 TI - The Staudinger reaction with 2-imino-1,3-thiaselenanes toward the synthesis of C4 spiro-beta-lactams. AB - The Staudinger ketene-imine [2 + 2] cycloaddition reaction for conversion of alpha-heteroatom-substituted exocyclic imines to C4 heterocyclic spiro-beta lactams has rarely been investigated due to their instability. Herein, we describe the Staudinger reaction between ketenes and alpha-selenium-substituted exocyclic imines to synthesize C4 spiro-beta-lactams. PMID- 23460026 TI - Exploring the overestimation of conjunctive probabilities. AB - People often overestimate probabilities of conjunctive events. The authors explored whether the accuracy of conjunctive probability estimates can be improved by increased experience with relevant constituent events and by using memory aids. The first experiment showed that increased experience with constituent events increased the correlation between the estimated and the objective conjunctive probabilities, but that it did not reduce overestimation of conjunctive probabilities. The second experiment showed that reducing cognitive load with memory aids for the constituent probabilities led to improved estimates of the conjunctive probabilities and to decreased overestimation of conjunctive probabilities. To explain the cognitive process underlying people's probability estimates, the configural weighted average model was tested against the normative multiplicative model. The configural weighted average model generates conjunctive probabilities that systematically overestimate objective probabilities although the generated probabilities still correlate strongly with the objective probabilities. For the majority of participants this model was better than the multiplicative model in predicting the probability estimates. However, when memory aids were provided, the predictive accuracy of the multiplicative model increased. In sum, memory tools can improve people's conjunctive probability estimates. PMID- 23460028 TI - Prognostic significance of low-grade intraventricular hemorrhage in the current era of neonatology. PMID- 23460027 TI - Cysteine protease enhances plant-mediated bollworm RNA interference. AB - Oral ingestion of plant-expressed double stranded RNA (dsRNA) triggers target gene suppression in insect. An important step of this process is the transmission of dsRNA from plant to midgut cells. Insect peritrophic matrix (PM) presents a barrier that prevents large molecules from entering midgut cells. Here, we show that uptake of plant cysteine proteases, such as GhCP1 from cotton (Gossypium hirsutum) and AtCP2 from Arabidopsis, by cotton bollworm (Helicoverpa armigera) larvae resulted in attenuating the PM. When GhCP1 or AtCP2 pre-fed larvae were transferred to gossypol-containing diet, the bollworm accumulated higher content of gossypol in midgut. Larvae previously ingested GhCP1 or AtCP2 were more susceptible to infection by Dendrolimus punctatus cytoplasmic polyhedrosis virus (DpCPV), a dsRNA virus. Furthermore, the pre-fed larvae exhibited enhanced RNAi effects after ingestion of the dsRNA-expressing plant. The bollworm P450 gene CYP6AE14 is involved in the larval tolerance to gossypol; cotton plants producing dsRNA of CYP6AE14 (dsCYP6AE14) were more resistant to bollworm feeding (Mao et al. in Transgenic Res 20:665-673, 2011). We found that cotton plants harboring both 35S:dsCYP6AE14 and 35S:GhCP1 were better protected from bollworm than either of the single-transgene lines. Our results demonstrate that plant cysteine proteases, which have the activity of increasing PM permeability, can be used to improve the plant-mediated RNAi against herbivorous insects. PMID- 23460030 TI - Biological dosimetry assessments of a serious radiation accident in Bulgaria in 2011. AB - In 2011, a serious radiation accident occurred in Stamboliyski, Bulgaria, in an industrial sterilisation facility using very-high-activity (60)Co sources. For the five persons accidentally exposed, biological dosimetry based on dicentric analysis was performed in Sofia and in Paris, where the patients were transferred for treatment. Before completing the chromosomal dose assessment, and for the most exposed person, a preliminary cytogenetic evaluation based on electronically transmitted metaphase images was made. The averaged acute whole-body dose estimates for the five patients ranged from 5.2 to 1.2 Gy, and good agreement was obtained between the two laboratories. The patients were also assessed by their prodromal responses and depressed blood cell counts over the first week. The cytogenetic dose estimates were in good accord with those derived from the blood counts, and both techniques indicated that, for the two most seriously exposed persons both techniques indicated that the initial prodromal reactions had suggested somewhat less severe exposure. PMID- 23460029 TI - The promoter activities of sucrose phosphate synthase genes in rice, OsSPS1 and OsSPS11, are controlled by light and circadian clock, but not by sucrose. AB - Although sucrose plays a role in sugar sensing and its signaling pathway, little is known about the regulatory mechanisms of the expressions of plant sucrose related genes. Our previous study on the expression of the sucrose phosphate synthase gene family in rice (OsSPSs) suggested the involvement of sucrose sensing and/or circadian rhythm in the transcriptional regulation of OsSPS. To examine whether the promoters of OsSPSs can be controlled by sugars and circadian clock, we produced transgenic rice plants harboring a promoter-luciferase construct for OsSPS1 or OsSPS11 and analyzed the changes in the promoter activities by monitoring bioluminescence from intact transgenic plants in real time. Transgenic plants fed sucrose, glucose, or mannitol under continuous light conditions showed no changes in bioluminescence intensity; meanwhile, the addition of sucrose increased the concentration of sucrose in the plants, and the mRNA levels of OsSPS remained constant. These results suggest that these OsSPS promoters may not be regulated by sucrose levels in the tissues. Next, we investigated the changes in the promoter activities under 12-h light/12-h dark cycles and continuous light conditions. Under the light-dark cycle, both OsSPS1 and OsSPS11 promoter activities were low in the dark and increased rapidly after the beginning of the light period. When the transgenic rice plants were moved to the continuous light condition, both P OsSPS1 ::LUC and P OsSPS11 ::LUC reporter plants exhibited circadian bioluminescence rhythms; bioluminescence peaked during the subjective day with a 27-h period: in the early morning as for OsSPS1 promoter and midday for OsSPS11 promoter. These results indicate that these OsSPS promoters are controlled by both light illumination and circadian clock and that the regulatory mechanism of promoter activity differs between the two OsSPS genes. PMID- 23460031 TI - An evaluation of in-plane shields during thoracic CT. AB - The object of this study was to compare organ dose and image quality effects of using bismuth and barium vinyl in-plane shields with standard and low tube current thoracic CT protocols. A RANDO phantom was scanned using a 64-slice CT scanner and three different thoracic protocols. Thermoluminescent dosemeters were positioned in six locations to record surface and absorbed breast and lung doses. Image quality was assessed quantitatively using region of interest measurements. Scanning was repeated using bismuth and barium vinyl in-plane shields to cover the breasts and the results were compared with standard and reduced dose protocols. Dose reductions were most evident in the breast, skin and anterior lung when shielding was used, with mean reductions of 34, 33 and 10 % for bismuth and 23, 18 and 11 % for barium, respectively. Bismuth was associated with significant increases in both noise and CT attenuation values for all the three protocols, especially anteriorly and centrally. Barium shielding had a reduced impact on image quality. Reducing the overall tube current reduced doses in all the locations by 20-27 % with similar increases in noise as shielding, without impacting on attenuation values. Reducing the overall tube current best optimises dose with minimal image quality impact. In-plane shields increase noise and attenuation values, while reducing anterior organ doses primarily. Shielding remains a useful optimisation tool in CT and barium is an effective alternative to bismuth especially when image quality is of concern. PMID- 23460032 TI - Characterization of hybrid materials by means of inverse gas chromatography and chemometrics. AB - The surface properties of hybrid materials (potential carriers for sustained release of active agents) have been examined by inverse gas chromatography. A nonsteroidal anti-inflammatory agent, ibuprofen, was used as a model for active compound. The following parameters have been used to characterize the interactions between the constituents of the hybrid material and the active agent: dispersive component of the surface free energy gamma(D) S ; KA and KD parameters describing the acidity and basicity, respectively; and Flory-Huggins parameter chi'23 (the magnitude of interactions). Principal component analysis (PCA) and the procedure based on the sum of ranking differences (SRD) were applied for the selection of hybrid materials and parameters for characterization of these materials. One loose cluster found by PCA grouping of hybrid materials is refined by SRD analysis: SRD grouping indicates three groups having somewhat dissimilar properties. PMID- 23460034 TI - Simultaneous determination of nalbuphine and its prodrug sebacoly dinalbuphine ester in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in humans. AB - A rapid, simple, sensitive and selective ultraperformance liquid chromatography tandem spectrometry (UPLC-MS/MS) method for the determination of nalbuphine and its prodrug sebacoly dinalbuphine ester (SDE) was developed and validated in human plasma. The sample pretreatment involves basification and iterative liquid liquid extraction with ethyl-ether-dichloromethane (7:3, v/v) solution, followed by LC separation and positive electrospray ionization (ESI) API-3000 mass spectrometry detection. The chromatography was on a Waters Acquity UPLC BEH HILIC column (2.1 * 100 mm, 1.7 um). The mobile phase was composed of acetonitrile and water (83:17, v/v) that contained 0.2% formic acid and 4 mm ammonium formate at a flow rate of 0.25 mL/min. Ethylmorphine and naloxine were selected as the SDE and nalbuphine internal standard (IS), respectively. The calibration curve for both was linear over the range from 0.05 to 20 ng/mL, with correlation coefficients >=0.995. The lower limit of quantification was set at 0.05 ng/mL. The intra- and inter-day precision values for nalbuphine and SDE were acceptable as per FDA guidelines. The method was applied successfully to determine nalbuphine concentration in human plasma samples obtained from four Taiwanese volunteers receiving intramuscularly administration of sebacoyl dinalbuphine ester. The method is sensitive, selective and directly applicable to human pharmacokinetic studies involving nalbuphine. PMID- 23460035 TI - Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study. AB - BACKGROUND: Patient preference is an important factor when choosing an inhaler device for asthma or chronic obstructive pulmonary disease (COPD). AIMS: To identify characteristics of patients with asthma or COPD who prefer a once-daily controller medication regimen. METHODS: This retrospective observational study used electronic patient records and linked outcomes from patient-completed questionnaires in a primary care database. We compared the characteristics of patients indicating a preference for once-daily therapy with those who were unsure or indicating no preference. RESULTS: Of 3,731 patients with asthma, 2,174 (58%) were women; the mean age was 46 years (range 2-94). Of 2,138 patients with COPD, 980 (46%) were women; the mean age was 70 years (range 35-98). Approximately half of the patients in each cohort indicated once-daily preference, one-quarter were unsure, and one-quarter did not prefer once-daily therapy. In patients with asthma or COPD, the preference for once-daily controller medication was significantly associated with poor adherence and higher concerns about medication. In asthma, good control and low self-perceived controller medication need were associated with once-daily preference. By contrast, in COPD, a high self-perceived need for controller medication was associated with once-daily preference. There was no significant relationship between once-daily preference and age, sex, disease severity, or exacerbation history. CONCLUSIONS: Understanding patient preferences may help prescribers to individualise therapy better for asthma and COPD. PMID- 23460036 TI - Sensitisation patterns and association with age, gender, and clinical symptoms in children with allergic rhinitis in primary care: a cross-sectional study. AB - BACKGROUND: Polysensitisation is a frequent phenomenon in patients with allergic rhinitis. However, few studies have investigated the characteristics of polysensitised children, especially in primary care. OBJECTIVES: This analysis describes the patterns of sensitisation to common allergens and the association with age, gender, and clinical symptoms in children in primary care diagnosed with allergic rhinitis. METHODS: Cross-sectional data from two randomised double blind placebo-controlled studies were used to select children aged 6-18 years (n=784) with a doctor's diagnosis of allergic rhinitis or use of relevant medication for allergic rhinitis in primary care. They were assessed for age, gender, specific IgE (type and number of sensitisations), nasal and eye symptom scores. RESULTS: In 699 of the 784 children (89%) with a doctor's diagnosis or relevant medication use, a positive IgE test for one or more allergens was found. Polysensitisation (>2 sensitisations) was found in 69% of all children. Sensitisation was more common in children aged 9-13 than in younger children aged 5-8 years (p=0.03). Monosensitisation and polysensitisation were not significantly different in girls and boys. The severity of clinical symptoms did not differ between polysensitised and monosensitised children, but symptoms were significantly lower in non-sensitised children. CONCLUSIONS: Polysensitisation to multiple allergens occurs frequently in children with allergic rhinitis in general practice. Overall, clinical symptoms are equally severe in polysensitised and monosensitised children. Treatment decisions for allergic rhinitis should be made on the basis of a clinical history and allergy testing. PMID- 23460037 TI - Diagnostic testing for mild hemophilia a in patients with discrepant one-stage, two-stage, and chromogenic factor VIII:C assays. AB - In recent years, there has been greater awareness among hemostasis scientists and clinicians that factor VIII coagulant activity (FVIII:C) measured in certain patients with mild hemophilia A can show different results depending on the assay system. A subgroup of mild hemophilia families have a method-related discrepancy in FVIII:C results, whereby the one-stage clotting assay (FVIII:C-1) is significantly higher than the two-stage clotting assay (FVIII:C-2) or the chromogenic assay (FVIII:C-chr). To identify such patients, the routine laboratory can use automated procedures for the FVIII:C-chr to replace the complex, manual FVIII:C-2 method. Laboratories must employ appropriate quality management to ensure accurate and precise results, especially in the abnormal range. This discrepant phenotype of hemophilia A is seen in up to 40% of mild hemophilia A cases and represents a clinically significant bleeding disorder. A small proportion of these cases have FVIII:C-1 within the normal range and risk a missed diagnosis if the FVIII:C-chr is unavailable. Other patients may be mismanaged if FVIII:C-1 gives an overestimate of FVIII:C and their bleeding risk is consequently underestimated. Affected family members in the discrepant group of patients have a limited range of FVIII (F8) gene missense mutations, causing alterations of the structure of the A1, A2, or A3 domains of FVIII. Therefore, both FVIII:C-chr and F8 gene mutation analysis are recommended to confirm the diagnosis of mild hemophilia A and assist with decisions about the patient's phenotype. PMID- 23460033 TI - Consumption of human milk glycoconjugates by infant-associated bifidobacteria: mechanisms and implications. AB - Human milk is a rich source of nutrients and energy, shaped by mammalian evolution to provide all the nutritive requirements of the newborn. In addition, several molecules in breast milk act as bioactive agents, playing an important role in infant protection and guiding a proper development. While major breast milk nutrients such as lactose, lipids and proteins are readily digested and consumed by the infant, other molecules, such as human milk oligosaccharides and glycosylated proteins and lipids, can escape intestinal digestion and transit through the gastrointestinal tract. In this environment, these molecules guide the composition of the developing infant intestinal microbiota by preventing the colonization of enteric pathogens and providing carbon and nitrogen sources for other colonic commensals. Only a few bacteria, in particular Bifidobacterium species, can gain access to the energetic content of milk as it is displayed in the colon, probably contributing to their predominance in the intestinal microbiota in the first year of life. Bifidobacteria deploy exquisite molecular mechanisms to utilize human milk oligosaccharides, and recent evidence indicates that their activities also target other human milk glycoconjugates. Here, we review advances in our understanding of how these microbes have been shaped by breast milk components and the strategies associated with their consumption of milk glycoconjugates. PMID- 23460038 TI - Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. AB - Cancerous stroma coevolves alongside tumour progression, thereby promoting the malignant conversion of epithelial carcinoma cells. To date, an abundance of data have supported crucial roles of the tumour microenvironment (TME) in providing cancer cells with proliferative, migratory, survival and invasive propensities favouring the processes of tumourigenesis. The cancerous reactive stroma is frequently populated by a large number of myofibroblasts (MFs), which are activated, non-transformed fibroblasts expressing alpha-smooth muscle actin (alpha-SMA). MFs together with non-MF cells present in the tumour-associated stroma are collectively referred to as carcinoma-associated fibroblasts (CAFs), one of the major stromal cell types recognised in various human carcinomas. Recruitment of fibroblasts and/or their progenitors to a tumour mass and their subsequent transdifferentiation into MFs, as well as ongoing maintenance of their activated state, are believed to be essential processes facilitating tumour progression. However, the complex networks of signalling pathways mediating the phenotypic conversion into CAFs, as well as those underlying their tumour promoting interactions with other tumour-constituting cells, have yet to be fully explored. Histopathological confirmation of the presence of large numbers of CAF MFs within TME and their altered gene expression profiles are known to be associated with disease progression and to serve as independent negative prognostic factors for a wide range of tumour types. In this review, we examine the current evidence shedding light on the emerging roles of tumour-promoting CAFs, cells that are pivotal for epithelial cancer development and progression, and discuss the therapeutic potential of targeting these cells. PMID- 23460039 TI - Clinical images: osteoblastoma of the ilium mimicking sacroiliitis. PMID- 23460040 TI - Two innovative pharmaceutical forms of leuprorelin: results from 818 patients with advanced prostate cancer. AB - OBJECTIVES: This study set out to examine the efficacy and tolerability of two innovative implant forms of leuprorelin acetate in men with advanced hormone dependent prostate cancer in everyday clinical practice. METHODS: Data were collected from 818 patients (from 273 centers across Germany) who were pretreated with slow-release luteinizing hormone-releasing hormone (LHRH) agonist formulations and who were about to be switched to the leuprorelin implants. Patients received three injections of 1- or 3-month leuprorelin implant and physicians were asked to complete a case report form specific to each of the three clinic visits. Documented parameters included laboratory measurements, such as testosterone and prostate-specific antigen (PSA) levels, adverse events, and patient- and physician-rated assessments of the therapy. RESULTS: Compared with baseline, a significant decrease in both testosterone and PSA levels were measured after the first and second injections of leuprorelin implant. These results were confirmed for both the 1-month and 3-month implants in separate analyses. Switching, without treatment interruption, from Trenantone(r) (Takeda Pharma GmBH, Aachen, Germany) to the leuprorelin implant resulted in a significant decrease in the mean serum testosterone concentrations (P < 0.05) and a nonsignificant increase in the proportion of patients reaching castrate testosterone levels, while the number of patients with PSA values <= 4 ng/mL significantly increased (P = 0.045). Similar results were obtained for patients previously treated with goserelin who switched to leuprorelin implant. For 94% of patients, treating physicians rated the efficacy of leuprorelin implant as "very good" or "good." Treatment with leuprorelin implant was well tolerated, with only 61 adverse events reported in 42 (5.1%) patients. Patients and physicians rated the tolerability of leuprorelin implant as "very good" or "good" in 95% and 91% of cases, respectively. CONCLUSIONS: These results confirm the efficacy, tolerability, and ease of use of the leuprorelin implants among a large population of men with advanced, hormone-dependent prostate cancer treated in a clinical practice setting. PMID- 23460041 TI - Relationship between anxiety, anxiety sensitivity and conduct disorder symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). AB - Attention-deficit hyperactivity disorder (ADHD) is often comorbid with anxiety disorders and previous studies observed that anxiety could have an impact on the clinical course of ADHD and comorbid disruptive behavioral disorders (conduct disorders and oppositional-defiant disorders). Anxiety sensitivity (AS) is a different concept from anxiety per se and it is believed to represent the constitutionally based sensitivity of individuals to anxiety and anxiety symptoms. We aimed to assess the associations between anxiety, AS and symptoms of disruptive behavioral disorders (DBD) in a clinical sample of children and adolescents with ADHD. The sample consisted of 274 treatment naive children with ADHD aged 8-17 years. The severity of ADHD symptoms and comorbid DBD were assessed via parent rated Turgay DSM-IV-Based Child and Adolescent Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S), Conners' Parent Rating Scale (CPRS), and Conners' Teacher Rating Scale (CTRS). AS and severity of anxiety symptoms of children were evaluated by self-report inventories. The association between anxiety, AS, and DBD was evaluated using structural equation modeling. Analyses revealed that AS social subscale scores negatively predicted symptoms of conduct disorder (CD) reported in T-DSM-IV-S. On the other hand, CD symptoms positively predicted severity of anxiety. No direct relationships were detected between anxiety, AS and oppositional-defiant behavior scores in any scales. These results may suggest a protective effect of AS social area on the development of conduct disorder in the presence of a diagnosis of ADHD, while the presence of symptoms of CD may be a vulnerability factor for the development of anxiety symptoms in children and adolescents with ADHD. PMID- 23460042 TI - Accuracy of a mitral valve segmentation method using J-splines for real-time 3D echocardiography data. AB - Patient-specific models of the heart's mitral valve (MV) exhibit potential for surgical planning. While advances in 3D echocardiography (3DE) have provided adequate resolution to extract MV leaflet geometry, no study has quantitatively assessed the accuracy of their modeled leaflets vs. a ground-truth standard for temporal frames beyond systolic closure or for differing valvular dysfunctions. The accuracy of a 3DE-based segmentation methodology based on J-splines was assessed for porcine MVs with known 4D leaflet coordinates within a pulsatile simulator during closure, peak closure, and opening for a control, prolapsed, and billowing MV model. For all time points, the mean distance error between the segmented models and ground-truth data were 0.40 +/- 0.32 mm, 0.52 +/- 0.51 mm, and 0.74 +/- 0.69 mm for the control, flail, and billowing models. For all models and temporal frames, 95% of the distance errors were below 1.64 mm. When applied to a patient data set, segmentation was able to confirm a regurgitant orifice and post-operative improvements in coaptation. This study provides an experimental platform for assessing the accuracy of an MV segmentation methodology at phases beyond systolic closure and for differing MV dysfunctions. Results demonstrate the accuracy of a MV segmentation methodology for the development of future surgical planning tools. PMID- 23460044 TI - The gender gap in multiple sclerosis: intersection of science and society. PMID- 23460045 TI - Associations between community characteristics and psychiatric admissions in an urban area. AB - PURPOSE: Neighbourhood characteristics are known to be associated with higher rates of hospital admission for psychiatric disorders. METHODS: An ecological study with aggregated data was carried out. All cases for schizophrenia and depression in the 42 city districts of Augsburg were identified over a 4-year period (2006-2009) and neighbourhood variables were obtained. Negative binomial regression adjusted the effects for year of admission and accommodation in inpatient centres. RESULTS: There was significant association of high unemployment rate, low proportion of working population and high population density with higher rates of admission for schizophrenia. An increase of 1 % in unemployment rate [incidence rate ration (IRR) 1.0451, 95 % CI 1.0175-1.0734] was associated with 5 % raise of admission rates for schizophrenia and an increase of 1 % in working population (IRR 0.9793, 95 % CI 0.9605-0.9985) with a decrease of admission rates by 2 %. High proportion of single households and high percentage of persons eligible for social security increased admission rate for depression. Thus 1 % increase in the proportion of single households (IRR 1.0095, 95 % CI 1.0030-1.0162) and of the proportion of persons eligible for social security (IRR 1.0148, 95 % CI 1.0002-1.0297) both independently were associated with an increased rate of admission for depression of 1 %. CONCLUSION: Our analysis demonstrated that measures of social isolation in neighbourhoods and social contacts at work influenced admission for schizophrenia and depression: in neighbourhoods with less social contacts and with a higher proportion of persons not working the admission rates increased. The problem of confounding in ecological studies need to be considered. PMID- 23460047 TI - Physical activity and health-related quality of life among adult women in Cali, Colombia: a cross-sectional study. AB - OBJECTIVES: To examine the associations of leisure-time physical activity (LTPA) and walking for transportation (WT) with the physical and mental dimensions of health-related quality of life (HR-QOL) among women. METHODS: A cross-sectional study was carried out in 2009 among 1,263 women ages 18-59 years living in neighborhoods with low and middle-low socioeconomic status in the urban area of Cali. HR-QOL was assessed using the Short Form 8 (SF-8). LTPA and WT were measured using the long version of the International Physical Activity Questionnaire (IPAQ). Associations were assessed using linear regression models adjusting for potential confounders. RESULTS: Low (10-149 min) and medium-high (at least 150 min) levels of WT were negatively associated with the mental and physical dimensions of HR-QOL. Low (10-149 min of moderate intensity PA, or 10-74 min of vigorous intensity PA) and medium-high (at least 150 or 75 min of moderate or vigorous intensity PA, respectively) levels of LTPA were positively associated with both dimensions. Significant interactions were observed between education level and perceived safety from traffic. CONCLUSIONS: This study found that WT and LTPA were associated with HR-QOL both in the physical and mental dimensions; however, the direction and magnitude of the association varied by domain. These results highlight the need to better understand the links between PA and HR-QOL in urban contexts from Latin America. PMID- 23460046 TI - Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC 1alpha signaling contributing to increased vulnerability in diabetic heart. AB - Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1alpha acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1alpha acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1alpha signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1alpha blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1alpha signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury. PMID- 23460043 TI - Cardiovascular diseases in older patients with osteoporotic hip fracture: prevalence, disturbances in mineral and bone metabolism, and bidirectional links. AB - BACKGROUND: Considerable controversy exists regarding the contribution of mineral/bone metabolism abnormalities to the association between cardiovascular diseases (CVDs) and osteoporotic fractures. AIMS AND METHODS: To determine the relationships between mineral/bone metabolism biomarkers and CVD in 746 older patients with hip fracture, clinical data were recorded and serum concentrations of parathyroid hormone (PTH), 25-hydroxyvitamin D, calcium, phosphate, magnesium, troponin I, parameters of bone turnover, and renal, liver, and thyroid functions were measured. RESULTS: CVDs were diagnosed in 472 (63.3%) patients. Vitamin D deficiency was similarly prevalent in patients with (78.0%) and without (82.1%) CVD. The CVD group had significantly higher mean PTH concentrations (7.6 vs 6.0 pmol/L, P < 0.001), a higher prevalence of secondary hyperparathyroidism (SPTH) (PTH > 6.8 pmol/L, 43.0% vs 23.3%, P < 0.001), and excess bone resorption (urinary deoxypyridinoline corrected by creatinine [DPD/Cr] > 7.5 nmol/MUmol, 87.9% vs 74.8%, P < 0.001). In multivariate regression analysis, SHPT (odds ratio [OR] 2.6, P = 0.007) and high DPD/Cr (OR 2.8, P = 0.016) were independent indictors of CVD. Compared to those with both PTH and DPD/Cr in the normal range, multivariate-adjusted ORs for the presence of CVD were 17.3 (P = 0.004) in subjects with SHPT and 9.7 (P < 0.001) in patients with high DPD/Cr. CVD was an independent predicator of SHPT (OR 2.8, P = 0.007) and excess DPD/Cr (OR 2.5, P = 0.031). CVD was predictive of postoperative myocardial injury, while SHPT was also an independent predictor of prolonged hospital stay and in-hospital death. CONCLUSION: SHPT and excess bone resorption are independent pathophysiological mediators underlying the bidirectional associations between CVD and hip fracture, and therefore are important diagnostic and therapeutic targets. PMID- 23460049 TI - LC-MS/MS determination and pharmacokinetic study of lacidipine in human plasma. AB - A robust, specific and fully validated LC-MS/MS method as per general practices of industry has been developed for estimation of lacidipine (LAC) with 100 MUL of human plasma using lacidipine-(13) C8 as an internal standard (IS). The API-4000 LC-MS/MS was operated under the multiple reaction-monitoring mode. A simple liquid-liquid extraction process was used to extract LAC and IS from human plasma. The total run time was 3.0 min and the elution of LAC and IS occurred at 1.96 and 1.97 min; this was achieved with a mobile phase consisting of 5 mm ammonium acetate buffer-acetontrile (15:85 v/v) at a flow rate of 0.60 mL/min on a Zorbax SB C18 (50 * 4.6 mm, 5 um) column. A linear response function was established for the range of concentrations 50-15,000 pg/mL (r > 0.998) for LAC. The current developed method has negligible matrix effect and is free from unwanted adducts and clusters which are formed owing to system such as solvent or mobile phase. The developed assay method was applied to an oral pharmacokinetic study in humans and successfully characterized the pharmacokinetic data up to 72 h. PMID- 23460050 TI - A naked-eye chemosensor for fluoride ions: a selective easy-to-prepare test paper. AB - A new naked-eye chromogenic chemosensor based on 2-thiohydantoin shows high selectivity for fluoride ions and is used to develop a test paper for detection of fluoride ions in the solid state. PMID- 23460051 TI - Fast and Famous: Looking for the Fastest Speed at Which a Face Can be Recognized. AB - Face recognition is supposed to be fast. However, the actual speed at which faces can be recognized remains unknown. To address this issue, we report two experiments run with speed constraints. In both experiments, famous faces had to be recognized among unknown ones using a large set of stimuli to prevent pre activation of features which would speed up recognition. In the first experiment (31 participants), recognition of famous faces was investigated using a rapid go/no-go task. In the second experiment, 101 participants performed a highly time constrained recognition task using the Speed and Accuracy Boosting procedure. Results indicate that the fastest speed at which a face can be recognized is around 360-390 ms. Such latencies are about 100 ms longer than the latencies recorded in similar tasks in which subjects have to detect faces among other stimuli. We discuss which model of activation of the visual ventral stream could account for such latencies. These latencies are not consistent with a purely feed forward pass of activity throughout the visual ventral stream. An alternative is that face recognition relies on the core network underlying face processing identified in fMRI studies (OFA, FFA, and pSTS) and reentrant loops to refine face representation. However, the model of activation favored is that of an activation of the whole visual ventral stream up to anterior areas, such as the perirhinal cortex, combined with parallel and feed-back processes. Further studies are needed to assess which of these three models of activation can best account for face recognition. PMID- 23460052 TI - Mesoporosity--a new dimension for zeolites. AB - Frameworks of precisely defined pores with diameters matching the size of small molecules endow crystalline zeolites with valuable size- and shape-selectivity. Being important selective adsorbers and separators, zeolites are also indispensable as solid acids in size-selective catalysis. However, despite being extremely beneficial, micropores impose restrictions on the mass transport of reactants, especially when bulky molecules are involved. The prospect to boost the catalytic power of zeolites and to extend their applications into new areas has prompted numerous efforts to synthesize mesoporous zeolitic materials that combine diffusional pathways on two different size scales. Our tutorial review will introduce the reader to this exciting recent development in zeolite science. We will give a general overview of the diverse strategies on how to implement a secondary pore system in zeolites. We will distinguish top-down from bottom-up and template-assisted from 'template-free' procedures. Advantages and limitations of the different methods will also be addressed. PMID- 23460053 TI - An automated intervention with stepped increases in support to increase uptake of colorectal cancer screening: a randomized trial. AB - BACKGROUND: Screening decreases colorectal cancer (CRC) incidence and mortality, yet almost half of age-eligible patients are not screened at recommended intervals. OBJECTIVE: To determine whether interventions using electronic health records (EHRs), automated mailings, and stepped increases in support improve CRC screening adherence over 2 years. DESIGN: 4-group, parallel-design, randomized, controlled comparative effectiveness trial with concealed allocation and blinded outcome assessments. (ClinicalTrials.gov: NCT00697047) SETTING: 21 primary care medical centers. PATIENTS: 4675 adults aged 50 to 73 years not current for CRC screening. INTERVENTION: Usual care, EHR-linked mailings ("automated"), automated plus telephone assistance ("assisted"), or automated and assisted plus nurse navigation to testing completion or refusal ("navigated"). Interventions were repeated in year 2. MEASUREMENTS: The proportion of participants current for screening in both years, defined as colonoscopy or sigmoidoscopy (year 1) or fecal occult blood testing (FOBT) in year 1 and FOBT, colonoscopy, or sigmoidoscopy (year 2). RESULTS: Compared with those in the usual care group, participants in the intervention groups were more likely to be current for CRC screening for both years with significant increases by intensity (usual care, 26.3% [95% CI, 23.4% to 29.2%]; automated, 50.8% [CI, 47.3% to 54.4%]; assisted, 57.5% [CI, 54.5% to 60.6%]; and navigated, 64.7% [CI, 62.5% to 67.0%]; P < 0.001 for all pair-wise comparisons). Increases in screening were primarily due to increased uptake of FOBT being completed in both years (usual care, 3.9% [CI, 2.8% to 5.1%]; automated, 27.5% [CI, 24.9% to 30.0%]; assisted, 30.5% [CI, 27.9% to 33.2%]; and navigated, 35.8% [CI, 33.1% to 38.6%]). LIMITATION: Participants were required to provide verbal consent and were more likely to be white and to participate in other types of cancer screening, limiting generalizability. CONCLUSION: Compared with usual care, a centralized, EHR-linked, mailed CRC screening program led to twice as many persons being current for screening over 2 years. Assisted and navigated interventions led to smaller but significant stepped increases compared with the automated intervention only. The rapid growth of EHRs provides opportunities for spreading this model broadly. PMID- 23460054 TI - Screening colonoscopy and risk for incident late-stage colorectal cancer diagnosis in average-risk adults: a nested case-control study. AB - BACKGROUND: The effectiveness of screening colonoscopy in average-risk adults is uncertain, particularly for right colon cancer. OBJECTIVE: To examine the association between screening colonoscopy and risk for incident late-stage colorectal cancer (CRC). DESIGN: Nested case-control study. SETTING: Four U.S. health plans. PATIENTS: 1039 average-risk adults enrolled for at least 5 years in one of the health plans. Case patients were aged 55 to 85 years on their diagnosis date (reference date) of stage IIB or higher (late-stage) CRC during 2006 to 2008. One or 2 control patients were selected for each case patient, matched on birth year, sex, health plan, and prior enrollment duration. MEASUREMENTS: Receipt of CRC screening 3 months to 10 years before the reference date, ascertained through medical record audits. Case patients and control patients were compared on receipt of screening colonoscopy or sigmoidoscopy by using conditional logistic regression that accounted for health history, socioeconomic status, and other screening exposures. RESULTS: In analyses restricted to 471 eligible case patients and their 509 matched control patients, 13 case patients (2.8%) and 46 control patients (9.0%) had undergone screening colonoscopy, which corresponded to an adjusted odds ratio (AOR) of 0.29 (95% CI, 0.15 to 0.58) for any late-stage CRC, 0.36 (CI, 0.16 to 0.80) for right colon cancer, and 0.26 (CI, 0.06 to 1.11; P = 0.069) for left colon/rectum cancer. Ninety-two case patients (19.5%) and 173 control patients (34.0%) had screening sigmoidoscopy, corresponding to an AOR of 0.50 (CI, 0.36 to 0.70) overall, 0.79 (CI, 0.51 to 1.23) for right colon late-stage cancer, and 0.26 (CI, 0.14 to 0.48) for left colon cancer. LIMITATION: The small number of screening colonoscopies affected the precision of the estimates. CONCLUSION: Screening with colonoscopy in average-risk persons was associated with reduced risk for diagnosis of incident late-stage CRC, including right-sided colon cancer. For sigmoidoscopy, this association was seen for left CRC, but the association for right colon late stage cancer was not statistically significant. PMID- 23460055 TI - Neisseria gonorrhoeae antimicrobial resistance among men who have sex with men and men who have sex exclusively with women: the Gonococcal Isolate Surveillance Project, 2005-2010. AB - BACKGROUND: Gonorrhea treatment has been complicated by antimicrobial resistance in Neisseria gonorrhoeae. Gonococcal fluoroquinolone resistance emerged more rapidly among men who have sex with men (MSM) than men who have sex exclusively with women (MSW). OBJECTIVE: To determine whether N. gonorrhoeae urethral isolates from MSM were more likely than isolates from MSW to exhibit resistance to or elevated minimum inhibitory concentrations (MICs) of antimicrobials used to treat gonorrhea. DESIGN: 6 years of surveillance data from the Gonococcal Isolate Surveillance Project. SETTING: Publicly funded sexually transmitted disease clinics in 30 U.S. cities. PATIENTS: Men with a total of 34 600 episodes of symptomatic urethral gonorrhea. MEASUREMENTS: Percentage of isolates exhibiting resistance or elevated MICs and adjusted odds ratios for resistance or elevated MICs among isolates from MSM compared with isolates from MSW. RESULTS: In all U.S. regions except the West, isolates from MSM were significantly more likely to exhibit elevated MICs of ceftriaxone and azithromycin than isolates from MSW (P < 0.050). Isolates from MSM had a high prevalence of resistance to ciprofloxacin, penicillin, and tetracycline and were significantly more likely to exhibit antimicrobial resistance than isolates from MSW (P < 0.001). LIMITATIONS: Sentinel surveillance may not be representative of all patients with gonorrhea. HIV status, travel history, and antimicrobial use data were missing for some patients. CONCLUSION: Men who have sex with men are vulnerable to the emerging threat of antimicrobial-resistant N. gonorrhoeae. Because antimicrobial susceptibility testing is not routinely done in clinical practice, clinicians should monitor for treatment failures among MSM diagnosed with gonorrhea. Strengthened prevention strategies for MSM and new antimicrobial treatment options are needed. PMID- 23460056 TI - Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. AB - BACKGROUND: Hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC). In the United States, this form of cancer occurs in approximately 15 000 persons annually. A systematic review of the evidence is needed to assess the benefits of treatment of HCV-infected persons on development of HCC. PURPOSE: To systematically review observational studies to determine the association between response to HCV therapy and development of HCC among persons at any stage of fibrosis and those with advanced liver disease. DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science, and the Database of Abstracts of Reviews and Effectiveness from inception through February 2012. STUDY SELECTION: English-language observational studies that compared therapy derived sustained virologic response (SVR) with no response to therapy among HCV infected persons, targeted an adult population, and had an average follow-up of at least 2 years. DATA EXTRACTION: Two investigators independently extracted data into uniform relative risk measures. The Grading of Recommendations Assessment, Development and Evaluation framework was used to determine the quality of the evidence. DATA SYNTHESIS: Thirty studies fulfilled the inclusion criteria, and 18 provided adjusted effect estimates that were used to calculate pooled relative risks. Among HCV-infected persons, SVR was associated with reduced risk for HCC (relative risk for all persons, 0.24 [95% CI, 0.18 to 0.31], moderate-quality evidence; advanced liver disease hazard ratio, 0.23 [CI, 0.16 to 0.35], moderate quality evidence). LIMITATION: In the meta-analyses, some variables could not be controlled for because of the observational design of the included studies. CONCLUSION: Sustained virologic response after treatment among HCV-infected persons at any stage of fibrosis is associated with reduced HCC. The evidence was determined to be of moderate quality. PMID- 23460058 TI - Coverage for undocumented migrants becomes more urgent. PMID- 23460057 TI - Cognitive impairment associated with atrial fibrillation: a meta-analysis. AB - BACKGROUND: Atrial fibrillation (AF) has been linked with an increased risk for cognitive impairment and dementia. PURPOSE: To complete a meta-analysis of studies examining the association between AF and cognitive impairment. DATA SOURCES: Search of MEDLINE, PsycINFO, Cochrane Library, CINAHL, and EMBASE databases and hand search of article references. STUDY SELECTION: Prospective and nonprospective studies reporting adjusted risk estimates for the association between AF and cognitive impairment. DATA EXTRACTION: Two abstracters independently extracted data on study characteristics, risk estimates, methods of AF and outcome ascertainment, and methodological quality. DATA SYNTHESIS: Twenty one studies were included in the meta-analysis. Atrial fibrillation was significantly associated with a higher risk for cognitive impairment in patients with first-ever or recurrent stroke (relative risk [RR], 2.70 [95% CI, 1.82 to 4.00]) and in a broader population including patients with or without a history of stroke (RR, 1.40 [CI, 1.19 to 1.64]). The association in the latter group remained significant independent proof of clinical stroke history (RR, 1.34 [CI, 1.13 to 1.58]). However, there was significant heterogeneity among studies of the broader population (I2 = 69.4%). Limiting the analysis to prospective studies yielded similar results (RR, 1.36 [CI, 1.12 to 1.65]). Restricting the analysis to studies of dementia eliminated the significant heterogeneity (P = 0.137) but did not alter the pooled estimate substantially (RR, 1.38 [CI, 1.22 to 1.56]). LIMITATIONS: There is an inherent bias because of confounding variables in observational studies. There was significant heterogeneity among included studies. CONCLUSION: Evidence suggests that AF is associated with a higher risk for cognitive impairment and dementia, with or without a history of clinical stroke. Further studies are required to elucidate the association between AF and subtypes of dementia as well as the cause of cognitive impairment. PMID- 23460061 TI - Patient safety strategies: a call for physician leadership. PMID- 23460060 TI - Strategies to improve patient safety: the evidence base matures. PMID- 23460063 TI - Missed it. PMID- 23460064 TI - Antipsychotics in adults with schizophrenia: does sponsorship of research articles affect the findings? PMID- 23460065 TI - Screening for chronic kidney disease. PMID- 23460066 TI - Antipsychotics in adults with schizophrenia: does sponsorship of research articles affect the findings? In response. PMID- 23460067 TI - The supreme court and the affordable care act. PMID- 23460068 TI - The supreme court and the affordable care act. In response. PMID- 23460069 TI - Iatrogenic fungal meningitis. PMID- 23460070 TI - Summaries for patients. Screening colonoscopy and colorectal cancer risk. PMID- 23460071 TI - In the Clinic. Transitions of care. PMID- 23460072 TI - Pigeons' choices with token stimuli in concurrent variable-interval schedules. AB - Twelve pigeons responded on concurrent variable-interval schedules that delivered token stimuli (stimulus lights for some pigeons, and white circles on the response keys for others). During exchange periods, each token could be exchanged for food on a fixed-ratio 1 schedule. Across conditions, the exchange requirements (number of tokens that had to be earned before they could be exchanged for food) varied between one and four for the two response keys. The main findings were that the pigeons' response percentages varied as a function of the number of tokens earned at any given moment, and they were determined by both the delays to food and by the number of food deliveries in the exchange periods. In some conditions, tokens had to be earned but were not visible during the variable-interval schedules for one or both keys. When one key had visible tokens and the other did not, the pigeons showed a preference for the key without visible tokens. A model based on the matching law and a hyperbolic delay discounting equation could account for the main patterns of choice responding, and for how response percentages changed as successive tokens were earned. The results are consistent with the view that the token stimuli served as discriminative stimuli that signaled the current delays to food. PMID- 23460073 TI - Responses of medial and ventrolateral prefrontal cortex to interpersonal conflict for resources. AB - Little is known about brain mechanisms recruited during the monitoring and appraisal of social conflicts--for instance, when individuals compete with each other for the same resources. We designed a novel experimental task inducing resource conflicts between two individuals. In an event-related functional magnetic resonance imaging (fMRI) design, participants played with another human participant or against a computer, who across trials chose either different (no conflict) or the same tokens (conflict trials) in order to obtain monetary gains. In conflict trials, the participants could decide whether they would share the token, and the resulting gain, with the other person or instead keep all points for themselves. Behaviorally, participants shared much more often when playing with a human partner than with a computer. fMRI results demonstrated that the dorsal mediofrontal cortex was selectively activated during human conflicts. This region might play a key role in detecting situations in which self- and social interest are incompatible and require behavioral adjustment. In addition, we found a conflict-related response in the right ventrolateral prefrontal cortex that correlated with measures of social relationship and individual sharing behavior. Taken together, these findings reveal a key role of these prefrontal areas for the appraisal and resolution of interpersonal resource conflicts. PMID- 23460075 TI - Mortality among workers at Oak Ridge National Laboratory. AB - BACKGROUND: Workers employed at the Oak Ridge National Laboratory (ORNL) were potentially exposed to a range of chemical and physical hazards, many of which are poorly characterized. We compared the observed deaths among workers to expectations based upon US mortality rates. METHODS: The cohort included 22,831 workers hired between January 1, 1943 and December 31, 1984. Vital status and cause of death information were ascertained through December 31, 2008. Standardized mortality ratios (SMRs) were computed separately for males and females using US and Tennessee mortality rates; SMRs for men were tabulated separately for monthly-, weekly-, and hourly-paid workers. RESULTS: Hourly-paid males had more deaths due to cancer of the pleura (SMR = 12.09, 95% CI: 4.44, 26.32), cancer of the bladder (SMR = 1.89, 95% CI: 1.26, 2.71), and leukemia (SMR = 1.33, 95% CI: 0.87, 1.93) than expected based on US mortality rates. Female workers also had more deaths than expected from cancer of the bladder (SMR = 2.20, 95% CI: 1.20, 3.69) and leukemia (SMR = 1.64, 95% CI: 1.09, 2.36). The pleural cancer excess has only appeared since the 1980s, approximately 40 years after the start of operations. The bladder cancer excess was larger among workers who also had worked at other Oak Ridge nuclear weapons facilities, while the leukemia excess was among people who had not worked at other DOE facilities. CONCLUSIONS: Occupational hazards including asbestos and ionizing radiation may contribute to these excesses. PMID- 23460074 TI - Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. AB - OBJECTIVE: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS: This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS: At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION: Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined. PMID- 23460076 TI - Regadenoson induced acute ST-segment elevation myocardial infarction and multivessel coronary thrombosis. PMID- 23460077 TI - Simultaneous dual-isotope imaging based on an artificial neural network for evaluating myocardial perfusion and fatty acid metabolism. AB - BACKGROUND: We contrived a scatter correction method based on an artificial neural network (ANN) and applied it to the simultaneous evaluation of myocardial perfusion and fatty acid metabolism in single-photon emission computed tomography (SPECT). METHODS: The count data of three energy windows were used as inputs of the ANN. The count ratios of the estimated primary-to-total photons for (99m)Tc and (123)I, which were used to reconstruct (99m)Tc and (123)I images, were calculated using the ANN. In a phantom study, single- and dual-isotope imaging with (99m)Tc/(123)I and (201)Tl/(123)I was performed by means of a cardiac phantom simulating patients with and without obesity. In a human study, five normal volunteers and ten patients with myocardial infarction underwent myocardial perfusion and fatty acid metabolism imaging with single and dual SPECT with combinations of (99m)Tc-methoxyisobutylisonitrile/(123)I-beta-methyl(p iodophenyl)pentadecanoic acid (BMIPP) and (201)Tl/(123)I-BMIPP as tracers. RESULTS: Technetium-99m yielded more homogeneous images than (201)Tl because of the lower degree of photon attenuation, especially in the condition of obese patients, resulting in clearer visualization of the perfusion-metabolism mismatch. Dual (99m)Tc/(123)I SPECT offered comparable images with single SPECT in assessing myocardial damage. CONCLUSIONS: The method effectively separated (99m)Tc and (123)I primary photons and proved applicable to (99m)Tc/(123)I dual isotope myocardial SPECT. PMID- 23460078 TI - Immunohistochemical analysis of O(6)-methylguanine-DNA methyltransferase in human melanoma in comparison with skin squamous cell carcinoma. AB - Alkylating agents, often used for chemotherapy in patients with melanoma, can produce O(6)-alkylguanine (O(6)AG) which is related to tumor cell killing after treatment with alkylating agents. O(6)AG is effectively eliminated by O(6) methylguanine-DNA methyltransferase (O(6)MGMT) and its level is correlative to the resistance to alkylating agents. However, little is known about the relationship of O(6)MGMT to the characteristics of melanoma. This study investigated the expression of O(6)MGMT in 12 melanomas and compared it with that in 11 skin squamous cell cancers (SCCs) immunohistochemically to evaluate the O(6)MGMT activity in melanoma and its clinical significance. All of the SCC samples had high O(6)MGMT expression, while the expression of O(6)MGMT in melanoma was diverse and 4 out of 12 samples had no or extremely low O(6)MGMT activity. Out of 6 lesions obtained from metastasis, 4 had a high O(6)MGMT activity. Two out of 3 cases with a low O(6)MGMT activity in each primary lesion did not show any evidence of metastasis or local recurrence. The evaluation of O(6)MGMT activity in melanoma may, therefore, be useful to determine the characteristics of tumor in each melanoma case. In addition, the present study implies the possibility of selective cancer chemotherapy for melanoma in the near future. PMID- 23460079 TI - A rare malignant tumor of scalp in a 3-month-old Taiwanese infancy: case report of primitive myxoid mesenchymal tumor of infancy with molecular study. AB - Primitive myxoid mesenchymal tumor of infancy is an extremely rare and recently recognized soft tissue tumor entity with a tendency for multiple recurrences. Only ten cases have been described in the literature and most cases are reported in Western countries. This tumor ranges in size from 2 to 15 cm and is characterized microscopically by a diffuse growth of primitive cells in a myxoid background with focal fascicles or a herringbone pattern. In this study, we describe a primitive myxoid mesenchymal tumor of infancy on the scalp of a 3 month-old Taiwanese boy. The histology showed typical morphology and the tumor cells showed vimentin and CD99 immunoreactivities. The translocation t(12,15)(p13;q25) was not found by fluorescence in situ hybridization. After complete surgical excision, no recurrence was noted during an 18-month follow-up. PMID- 23460080 TI - Oxygen-induced transcriptional dynamics in human osteoblasts are most prominent at the onset of mineralization. AB - Oxygen tension plays an important role in the regulation of cellular processes. During hematopoietic stem cell (HSC) differentiation, HSCs migrate from one stem cell niche to the next, each with a different oxygen tension that determines which signaling pathways are on and off, determining the differentiation stage of the cell. Oxygen tension influences osteoblast differentiation and mineralization. Low oxygen levels inhibit matrix formation and mineralization. We were interested in the regulatory mechanisms that underlie this inhibition and wondered whether a switch in oxygen tension could have varying effects depending on the differentiation phase of the osteoblasts. We performed an oxygen tension switch phase study in which we switched osteoblasts from high to low oxygen tension during their 3 week differentiation and mineralization process. We performed microarray expression profiling on samples collected during this 3 week period and analyzed biochemical and histo-chemical endpoint parameters to determine the effect of a switch in oxygen levels on mineralization. We found that low oxygen tension has the most profound impact on mineralization when administered during the period of matrix maturation. Additionally, a large set of genes was regulated by oxygen, independent of the differentiation phase. These genes were involved in cell metabolisms and matrix formation. Our study demonstrates that variation in oxygen tension strongly affects gene expression in differentiating osteoblasts. The magnitude of this change for either expression levels or the number of regulated probes, depends on the osteoblast differentiation stage, with the phase prior to the onset of mineralization being most sensitive. PMID- 23460081 TI - Zinc-rich inhibitor of apoptosis proteins (IAPs) as regulatory factors in the epithelium of normal and inflamed airways. AB - Integrity of the airway epithelium (AE) is important in the context of inhaled allergens and noxious substances, particularly during asthma-related airway inflammation where there is increased vulnerability of the AE to cell death. Apoptosis involves a number of signaling pathways which activate procaspases leading to cleavage of critical substrates. Understanding the factors which regulate AE caspases is important for development of strategies to minimize AE damage and airway inflammation, and therefore to better control asthma. One such factor is the essential dietary metal zinc. Zinc deficiency results in enhanced AE apoptosis, and worsened airway inflammation. This has implications for asthma, where abnormalities in zinc homeostasis have been observed. Zinc is thought to suppress the steps involved in caspase-3 activation. One target of zinc is the family of inhibitor of apoptosis proteins (IAPs) which are endogenous regulators of caspases. More studies are needed to identify the roles of IAPs in regulating apoptosis in normal and inflamed airways and to study their interaction with labile zinc ions. This new information will provide a framework for future clinical studies aimed at monitoring and management of airway zinc levels as well as minimising airway damage and inflammation in asthma. PMID- 23460083 TI - Transition-metal-catalyzed Suzuki-Miyaura cross-coupling reactions: a remarkable advance from palladium to nickel catalysts. AB - In the transition-metal-catalyzed cross-coupling reactions, the use of the first row transition metals as catalysts is much more appealing than the precious metals owing to the apparent advantages such as cheapness and earth abundance. Within the last two decades, particularly the last five years, explosive interests have been focused on the nickel-catalyzed Suzuki-Miyaura reactions. This has greatly advanced the chemistry of transition-metal-catalyzed cross coupling reactions. Most notably, a broad range of aryl electrophiles such as phenols, aryl ethers, esters, carbonates, carbamates, sulfamates, phosphates, phosphoramides, phosphonium salts, and fluorides, as well as various alkyl electrophiles, which are conventionally challenging, by applying palladium catalysts can now be coupled efficiently with boron reagents in the presence of nickel catalysts. In this review, we would like to summarize the progress in this reaction. PMID- 23460084 TI - Effects of Saccharomyces cerevisiae and monensin on digestion, ruminal parameters, and balance of nitrogenous compounds of beef cattle fed diets with different starch concentrations. AB - This study was carried out aiming to evaluate the effects of yeast or monensin supplementation on dry matter intake, nutrients digestibility, ruminal volatile fatty acids profile, ruminal pH and ammonia concentration, microbial protein synthesis, and the balance of nitrogen compounds of cattle fed high concentrate diet (80 % dry matter (DM) basis) with two different levels of starch. Eight crossbred beef steers fitted with rumen cannula were assigned to two simultaneous 4 * 4 Latin squares arranged in a 4 * 2 factorial design. Two different starch levels (23 and 38 % of DM) were assigned to each Latin square, independently. Within each Latin square, four treatments were randomly assigned to the experimental animals (control; monensin; 1-g yeast [1 g/100 kg body weight (BW)/day] treatment; and 2.5-g yeast [2.5 g/100 kg BW/day] treatment). Feed additives did not influence ruminal pH (P > 0.05). Total ruminal volatile fatty acids (VFA) concentration was greater (P<0.05) in the diet with the lowest starch level. Similarly, monensin and 1-g yeast treatments resulted in greater (P<0.05) VFA concentration in the rumen. Monensin inclusion in the diet with the highest starch level led to a decrease (P<0.05) in lactate concentration in the rumen. However, acetate levels were increased (P<0.05) by the inclusion of 1 g of yeast in the diet with lowest starch level. Ruminal concentrations of propionate and butyrate, and ammonia-N were not influenced (P>0.05) by none of the additives evaluated. However, propionate concentration was greater (P<0.05) in the low starch diets. Low-starch diets resulted in lower ruminal ammonia-N concentration and greater neutral detergent fiber digestibility (P<0.05). The excretion of urinary nitrogenous compounds, purine derivatives, synthesis of microbial protein, microbial efficiency, and balance of nitrogenous compounds were not affected by treatments evaluated (P>0.05). Monensin or yeast inclusion in high concentrate beef cattle diets in tropical regions as in Brazil is not justified by do not alter nutrient digestibility, nitrogen balance, and main ruminal parameters. PMID- 23460085 TI - Milk production performance of Friesian-Holstein cows fed diets containing Medicago sativa, Centrosema pubescens, or groundnut haulms (Arachis hypogaea). AB - To investigate the effect of feeding dairy cows diets containing lucerne hay, centrosema hay, and groundnut haulms (crop residue) on dry matter intake (DMI), milk yield, and milk composition, nine multiparous Friesian-Holstein cows in their mid-lactation stage were used in a 3 * 3 crossover design replicated three times. Dairy cows fed lucerne hay had significantly (p < 0.001) higher DMI than dairy cows fed centrosema hay. DMI for cows fed groundnut haulms and lucerne hay was not significantly different. Daily milk yield for dairy cows fed diet containing lucerne hay was significantly (p < 0.01) higher than that for dairy cows fed diets containing groundnut haulms or centrosema hay. Milk composition and body condition scores of the cows were not significantly affected by either lucerne hay, groundnut haulms, or centrosema hay. Overall, the results in this study indicated that feeding dairy cows diets containing lucerne hay increased milk yield. PMID- 23460086 TI - The role of apoptosis in preterm premature rupture of the human fetal membranes. AB - PURPOSE: The present study was designed to examine apoptotic cell death via the caspase-dependent pathway in human fetal membranes. METHODS: Amniotic membrane samples were collected from three groups of women: group 1, women with preterm premature rupture of fetal membranes (PPROM) after cesarean delivery (n = 10), group 2, women with preterm labor (PTL) with intact membranes after cesarean delivery (n = 9) and group 3, women with term labor and vaginal delivery after an uncomplicated pregnancy (controls) (n = 11). RESULTS: Active caspase-3 immunopositivity (ACPI) of the PPROM group was significantly higher than that of the control group (p < 0.05). ACPI was higher in the PTL with intact membranes group as compared to the control group; however, it did not reach statistical significance (p > 0.05). CONCLUSION: Active caspase-3 positivity is increased in the fetal membranes of those women with PPROM. PMID- 23460082 TI - Functional MRI in the investigation of blast-related traumatic brain injury. AB - This review focuses on the application of functional magnetic resonance imaging (fMRI) to the investigation of blast-related traumatic brain injury (bTBI). Relatively little is known about the exact mechanisms of neurophysiological injury and pathological and functional sequelae of bTBI. Furthermore, in mild bTBI, standard anatomical imaging techniques (MRI and computed tomography) generally fail to show focal lesions and most of the symptoms present as subjective clinical functional deficits. Therefore, an objective test of brain functionality has great potential to aid in patient diagnosis and provide a sensitive measurement to monitor disease progression and treatment. The goal of this review is to highlight the relevant body of blast-related TBI literature and present suggestions and considerations in the development of fMRI studies for the investigation of bTBI. The review begins with a summary of recent bTBI publications followed by discussions of various elements of blast-related injury. Brief reviews of some fMRI techniques that focus on mental processes commonly disrupted by bTBI, including working memory, selective attention, and emotional processing, are presented in addition to a short review of resting state fMRI. Potential strengths and weaknesses of these approaches as regards bTBI are discussed. Finally, this review presents considerations that must be made when designing fMRI studies for bTBI populations, given the heterogeneous nature of bTBI and its high rate of comorbidity with other physical and psychological injuries. PMID- 23460087 TI - Neuropathic pain in ankylosing spondylitis: a psychophysics and brain imaging study. AB - OBJECTIVE: To determine whether there is a neuropathic component in ankylosing spondylitis (AS) back pain and to delineate gray matter brain abnormalities associated with AS. METHODS: Seventeen patients with back pain secondary to AS who were not receiving biologic agents and 17 age- and sex-matched healthy controls consented to participate in the study and were assessed using the painDETECT instrument (scores of <=12 indicating low probability of neuropathic pain) and the McGill Pain Questionnaire. Mechanical and thermal thresholds were determined in all subjects, and brain gray matter was assessed by 3T magnetic resonance imaging. RESULTS: Eleven of the 17 AS patients had painDETECT scores of >12. The patients had decreased mechanical and cold sensitivity on the dorsum of their feet but did not have altered pain thresholds. Compared to controls, the AS patients exhibited cortical thinning in the primary somatosensory, insular, anterior cingulate, and anterior mid-cingulate cortices and the supplemental motor area, and increased gray matter volume in the thalamus and putamen. Scores on the painDETECT in AS patients were correlated with decreased gray matter in the primary somatosensory cortex and with increased gray matter in the motor cortex, anterior cingulate cortex, prefrontal cortex, thalamus, and striatum. CONCLUSION: The present findings indicate that neuropathic pain occurs in AS. Furthermore, abnormal brain gray matter and neural correlates of neuropathic pain are concordant with the clinical picture of AS, which includes sensorimotor and mood deficits as well as neuropathic pain symptoms. These results suggest that back pain in AS is a mixed pain condition that includes a neuropathic pain component. PMID- 23460088 TI - Suctioning and length of stay in infants hospitalized with bronchiolitis. AB - IMPORTANCE: Hospitalizations of infants for bronchiolitis are common and costly. Despite the high incidence and resource burden of bronchiolitis, the mainstay of treatment remains supportive care, which frequently includes nasal suctioning. OBJECTIVE: To examine the association between suctioning device type and suctioning lapses greater than 4 hours within the first 24 hours after hospital admission on length of stay (LOS) in infants with bronchiolitis. DESIGN: Retrospective cohort study. Data were extracted from the electronic health record. SETTING: Main hospital and satellite facility of a large quaternary care children's hospital from January 10, 2010, through April 30, 2011. PARTICIPANTS: A total of 740 infants aged 2 to 12 months and hospitalized with bronchiolitis. MAIN OUTCOME MEASURE: Hospital LOS. RESULTS: In the multivariable model adjusted for inverse weighting for propensity to receive deep suctioning, increased deep suction as a percentage of suction events was associated with increased LOS with a geometric mean of 1.75 days (95% CI, 1.56-1.95 days) in patients with no deep suction and 2.35 days (2.10-2.62 days) in patients with more than 60% deep suction. An increased number of suctioning lapses was also associated with increased LOS in a dose-dependent manner with a geometric mean of 1.62 days (95% CI, 1.43-1.83 days) in patients with no lapses and 2.64 days (2.30-3.04 days) in patients with 3 or 4 lapses. CONCLUSIONS AND RELEVANCE: For patients admitted with bronchiolitis, the use of deep suctioning in the first 24 hours after admission and lapses greater than 4 hours between suctioning events were associated with longer LOS. PMID- 23460089 TI - General phenolic characterisation, individual anthocyanin and antioxidant capacity of matured red wines from two Portuguese Appellations of Origins. AB - BACKGROUND: The main aim of this work was to evaluate the general phenolic composition, individual anthocyanin content and total antioxidant capacity from 20 commercial matured red wine samples (vintage from 2005 to 2008) produced in two Appellations of Origin from the north of Portugal: Douro and Dao. RESULTS: The results showed that the levels of general phenolic compounds, individual anthocyanins and antioxidant capacity in the 20 matured red wine samples analysed differed significantly. In addition, matured red wine samples aged in oak wood had a lower total individual anthocyanin content (from 13.85 to 56.79 mg L(-1), averaging 46.13 mg L(-1)) than wines aged in bottle (from 25.93 to 252.82 mg L( 1), averaging 94.17 mg L(-1)). The total antioxidant capacity values of the analysed wines showed quantitative differences among the values obtained from each antioxidant method applied as well as differences in the range of variation, especially for the values obtained by the DPPH method. CONCLUSION: The wines used in this study constitute quite a heterogeneous group, made from different Portuguese red grape varieties, with diverse ages and two ageing processes (bottle and oak wood barrels); and accordingly, they showed important differences, especially in their phenolic composition. Finally, the oak wood ageing process before bottling had a negative effect in individual anthocyanins content in contrast to matured red wines submitted only to a bottle ageing process. PMID- 23460090 TI - Tissue plasminogen activator and calcific emboli. PMID- 23460091 TI - The top patient safety strategies that can be encouraged for adoption now. PMID- 23460092 TI - Promoting a culture of safety as a patient safety strategy: a systematic review. AB - Developing a culture of safety is a core element of many efforts to improve patient safety and care quality. This systematic review identifies and assesses interventions used to promote safety culture or climate in acute care settings. The authors searched MEDLINE, CINAHL, PsycINFO, Cochrane, and EMBASE to identify relevant English-language studies published from January 2000 to October 2012. They selected studies that targeted health care workers practicing in inpatient settings and included data about change in patient safety culture or climate after a targeted intervention. Two raters independently screened 3679 abstracts (which yielded 33 eligible studies in 35 articles), extracted study data, and rated study quality and strength of evidence. Eight studies included executive walk rounds or interdisciplinary rounds; 8 evaluated multicomponent, unit-based interventions; and 20 included team training or communication initiatives. Twenty nine studies reported some improvement in safety culture or patient outcomes, but measured outcomes were highly heterogeneous. Strength of evidence was low, and most studies were pre-post evaluations of low to moderate quality. Within these limits, evidence suggests that interventions can improve perceptions of safety culture and potentially reduce patient harm. PMID- 23460093 TI - In-facility delirium prevention programs as a patient safety strategy: a systematic review. AB - Delirium, an acute decline in attention and cognition, occurs among hospitalized patients at rates estimated to range from 14% to 56% and increases the risk for morbidity and mortality. The purpose of this systematic review was to evaluate the effectiveness and safety of in-facility multicomponent delirium prevention programs. A search of 6 databases (including MEDLINE, EMBASE, and CINAHL) was conducted through September 2012. Randomized, controlled trials; controlled clinical trials; interrupted time series; and controlled before-after studies with a prospective postintervention portion were eligible for inclusion. The evidence from 19 studies that met the inclusion criteria suggests that most multicomponent interventions are effective in preventing onset of delirium in at risk patients in a hospital setting. Evidence was insufficient to determine the benefit of such programs in other care settings. Future comparative effectiveness studies with standardized protocols are needed to identify which components in multicomponent interventions are most effective for delirium prevention. PMID- 23460094 TI - Patient safety strategies targeted at diagnostic errors: a systematic review. AB - Missed, delayed, or incorrect diagnosis can lead to inappropriate patient care, poor patient outcomes, and increased cost. This systematic review analyzed evaluations of interventions to prevent diagnostic errors. Searches used MEDLINE (1966 to October 2012), the Agency for Healthcare Research and Quality's Patient Safety Network, bibliographies, and prior systematic reviews. Studies that evaluated any intervention to decrease diagnostic errors in any clinical setting and with any study design were eligible, provided that they addressed a patient related outcome. Two independent reviewers extracted study data and rated study quality. There were 109 studies that addressed 1 or more intervention categories: personnel changes (n = 6), educational interventions (n = 11), technique (n = 23), structured process changes (n = 27), technology-based systems interventions (n = 32), and review methods (n = 38). Of 14 randomized trials, which were rated as having mostly low to moderate risk of bias, 11 reported interventions that reduced diagnostic errors. Evidence seemed strongest for technology-based systems (for example, text message alerting) and specific techniques (for example, testing equipment adaptations). Studies provided no information on harms, cost, or contextual application of interventions. Overall, the review showed a growing field of diagnostic error research and categorized and identified promising interventions that warrant evaluation in large studies across diverse settings. PMID- 23460095 TI - Inpatient fall prevention programs as a patient safety strategy: a systematic review. AB - Falls are common among inpatients. Several reviews, including 4 meta-analyses involving 19 studies, show that multicomponent programs to prevent falls among inpatients reduce relative risk for falls by as much as 30%. The purpose of this updated review is to reassess the benefits and harms of fall prevention programs in acute care settings and to identify factors associated with successful implementation of these programs. We searched for new evidence using PubMed from 2005 to September 2012. Two new, large, randomized, controlled trials supported the conclusions of the existing meta-analyses. An optimal bundle of components was not identified. Harms were not systematically examined, but potential harms included increased use of restraints and sedating drugs and decreased efforts to mobilize patients. Eleven studies showed that the following themes were associated with successful implementation: leadership support, engagement of front-line staff in program design, guidance of the prevention program by a multidisciplinary committee, pilot-testing interventions, use of information technology systems to provide data about falls, staff education and training, and changes in nihilistic attitudes about fall prevention. Future research would advance knowledge by identifying optimal bundles of component interventions for particular patients and by determining whether effectiveness relies more on the mix of the components or use of certain implementation strategies. PMID- 23460096 TI - Medication reconciliation during transitions of care as a patient safety strategy: a systematic review. AB - Medication reconciliation identifies and resolves unintentional discrepancies between patients' medication lists across transitions in care. The purpose of this review is to summarize evidence about the effectiveness of hospital-based medication reconciliation interventions. Searches encompassed MEDLINE through November 2012 and EMBASE and the Cochrane Central Register of Controlled Trials through July 2012. Eligible studies evaluated the effects of hospital-based medication reconciliation on unintentional discrepancies with nontrivial risks for harm to patients or 30-day postdischarge emergency department visits and readmission. Two reviewers evaluated study eligibility, abstracted data, and assessed study quality. Eighteen studies evaluating 20 interventions met the selection criteria. Pharmacists performed medication reconciliation in 17 of the 20 interventions. Most unintentional discrepancies identified had no clinical significance. Medication reconciliation alone probably does not reduce postdischarge hospital utilization but may do so when bundled with interventions aimed at improving care transitions. PMID- 23460097 TI - Nurse-patient ratios as a patient safety strategy: a systematic review. AB - A small percentage of patients die during hospitalization or shortly thereafter, and it is widely believed that more or better nursing care could prevent some of these deaths. The author systematically reviewed the evidence about nurse staffing ratios and in-hospital death through September 2012. From 550 titles, 87 articles were reviewed and 15 new studies that augmented the 2 existing reviews were selected. The strongest evidence supporting a causal relationship between higher nurse staffing levels and decreased inpatient mortality comes from a longitudinal study in a single hospital that carefully accounted for nurse staffing and patient comorbid conditions and a meta-analysis that found a "dose response relationship" in observational studies of nurse staffing and death. No studies reported any serious harms associated with an increase in nurse staffing. Limiting any stronger conclusions is the lack of an evaluation of an intervention to increase nurse staffing ratios. The formal costs of increasing the nurse patient ratio cannot be calculated because there has been no evaluation of an intentional change in nurse staffing to improve patient outcomes. PMID- 23460098 TI - Preventing in-facility pressure ulcers as a patient safety strategy: a systematic review. AB - Complications from hospital-acquired pressure ulcers cause 60,000 deaths and significant morbidity annually in the United States. The objective of this systematic review is to review evidence regarding multicomponent strategies for preventing pressure ulcers and to examine the importance of contextual aspects of programs that aim to reduce facility-acquired pressure ulcers. CINAHL, the Cochrane Library, EMBASE, MEDLINE, and PreMEDLINE were searched for articles published from 2000 to 2012. Studies (any design) that implemented multicomponent initiatives to prevent pressure ulcers in adults in U.S. acute and long-term care settings and that reported pressure ulcer rates at least 6 months after implementation were selected. Two reviewers extracted study data and rated quality of evidence. Findings from 26 implementation studies (moderate strength of evidence) suggested that the integration of several core components improved processes of care and reduced pressure ulcer rates. Key components included the simplification and standardization of pressure ulcer-specific interventions and documentation, involvement of multidisciplinary teams and leadership, use of designated skin champions, ongoing staff education, and sustained audit and feedback. PMID- 23460100 TI - Simulation exercises as a patient safety strategy: a systematic review. AB - Simulation is a versatile technique used in a variety of health care settings for a variety of purposes, but the extent to which simulation may improve patient safety remains unknown. This systematic review examined evidence on the effects of simulation techniques on patient safety outcomes. PubMed and the Cochrane Library were searched from their beginning to 31 October 2012 to identify relevant studies. A single reviewer screened 913 abstracts and selected and abstracted data from 38 studies that reported outcomes during care of real patients after patient-, team-, or system-level simulation interventions. Studies varied widely in the quality of methodological design and description of simulation activities, but in general, simulation interventions improved the technical performance of individual clinicians and teams during critical events and complex procedures. Limited evidence suggested improvements in patient outcomes attributable to simulation exercises at the health system level. Future studies would benefit from standardized reporting of simulation components and identification of robust patient safety targets. PMID- 23460099 TI - Rapid-response systems as a patient safety strategy: a systematic review. AB - Rapid-response systems (RRSs) are a popular intervention in U.S. hospitals and are supported by accreditors and quality improvement organizations. The purpose of this review is to evaluate the effectiveness and implementation of these systems in acute care settings. A literature search was performed between 1 January 2000 through 30 October 2012 using PubMed, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials. Studies published in any language evaluating outcome changes that occurred after implementing an RRS and differences between groups using and not using an RRS (effectiveness) or describing methods used by RRSs (implementation) were reviewed. A single reviewer (checked by a second reviewer) abstracted data and rated study quality and strength of evidence. Moderate-strength evidence from a high-quality meta analysis of 18 studies and 26 lower-quality before-and-after studies published after that meta-analysis showed that RRSs are associated with reduced rates of cardiorespiratory arrest outside of the intensive care unit and reduced mortality. Eighteen studies examining facilitators of and barriers to implementation suggested that the rate of use of RRSs could be improved. PMID- 23460101 TI - Hospital-initiated transitional care interventions as a patient safety strategy: a systematic review. AB - Hospitals now have the responsibility to implement strategies to prevent adverse outcomes after discharge. This systematic review addressed the effectiveness of hospital-initiated care transition strategies aimed at preventing clinical adverse events (AEs), emergency department (ED) visits, and readmissions after discharge in general medical patients. MEDLINE, CINAHL, EMBASE, and Cochrane Database of Clinical Trials (January 1990 to September 2012) were searched, and 47 controlled studies of fair methodological quality were identified. Forty-six studies reported readmission rates, 26 reported ED visit rates, and 9 reported AE rates. A "bridging" strategy (incorporating both predischarge and postdischarge interventions) with a dedicated transition provider reduced readmission or ED visit rates in 10 studies, but the overall strength of evidence for this strategy was low. Because of scant evidence, no conclusions could be reached on methods to prevent postdischarge AEs. Most studies did not report intervention context, implementation, or cost. The strategies hospitals should implement to improve patient safety at hospital discharge remain unclear. PMID- 23460102 TI - [Gastrointestinal bleeding in the elderly]. AB - Peptic ulcer disease is a common cause of gastrointestinal bleeding, independent of the patient's age. With advancing age, an increase of lower gastrointestinal bleeding (diverticula, angiodysplasia) has been observed. The administration of non-steroidal anti-inflammatory drugs and aspirin is an important risk factor for upper and lower gastrointestinal bleeding, thus in patients aged 65 years and more a concomitant therapy with proton pump inhibitors is recommended in order to prevent ulcer bleeding. Even in very old individuals endoscopy should be used for the diagnosis of gastrointestinal bleeding, providing the opportunity for definite endoscopic bleeding therapy. In elderly patients with comorbidities and recurrent bleeding after endoscopic therapy or continuous blood loss, surgery or transarterial embolisation should be considered in good time. PMID- 23460103 TI - [Gender-specific influences on the results of vascular surgery]. AB - BACKGROUND: This overview comments on gender-specific differences in prevalence, treatment and outcome in patients with peripheral arterial disease (PAD), carotid stenosis, and abdominal aortic aneurysm (AAA). METHOD: For the literature review, the Medline database (PubMed) was searched under the key words "peripheral arterial disease AND gender", "carotid stenosis AND gender" and "abdominal aortic aneurysm AND gender". RESULTS: 1.) Women (preferably black women) with PAD experience rather than men bypass failure or amputation. Nevertheless, gender should not constitute a selection criterion for revascularisation therapy. Despite an older age and more advanced stages of disease in women, infrainguinal arterial reconstructions could achieve, in published series, patency and limb salvage rates which did not differ from those of men. 2.) The benefit of carotid endarterectomy (CEA) for asymptomatic carotid artery stenosis is less for women compared with men. However, registries exhibited at best for symptomatic women an increased perioperative risk of CEA compared with men, with CEA especially in women better than carotid artery stenting. The treatment of AAA shows significant gender differences. The risk of rupture for small aneurysms is significantly greater in women compared with men, and they have higher in-hospital mortality rates for both open and endovascular repair of ruptured and intact AAA. Yet women also benefit from endovascular repair of AAA compared to open repair, although their eligibility for endovascular repair is less than that of men due to anatomic conditions. CONCLUSION: As a rule, for the mentioned diseases less favourable results were reported in women. This may reflect biological disparities, or the differences are based on the fact that women develop arteriosclerotic changes later in life, requiring treatment in older age, with more advanced disease, and with higher comorbidity than men. In addition gender related differences in the use of secondary medical prevention of PAD have been described. Future studies on the potential impact of gender on the results of vascular surgery are needed. PMID- 23460104 TI - [From heparin to apixaban: anticoagulants cut both ways?]. AB - BACKGROUND: Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra(r)) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa(r)), rivaroxaban (Xarelto(r)) and apixaban (Eliquis(r)), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients. DISCUSSION AND CONCLUSION: Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs. PMID- 23460105 TI - [The staged approach--an overview on a strategy to reduce spinal cord injury in thoracoabdominal aortic aneurysm repair]. AB - The spinal cord is particularly susceptible to ischaemic injury following repair of extensive descending thoracic and thoracoabdominal aortic aneurysms (TAAA). For the past decade, the Mount Sinai group in New York has intensively studied the anatomy of the extensive vascular network surrounding the spinal cord, as well as its dynamic morphology in response to decreased blood pressure and flow. Along with clinical data, experimental findings gave rise to the Collateral Network Concept, by which spinal cord injury in open TAAA repair can be significantly reduced. With the more recent widespread use of endovascular repair, strategies to prevent ischaemic spinal cord damage after extensive segmental artery sacrifice/occlusion are still evolving. The hypothesis that dividing extensive aneurysm repair into two steps may mitigate the impact of diminished blood flow to the collateral network has led to a recently conducted series of staged repair experiments. By exploiting the resources of the collateral network, spinal cord injury could be minimised in staged open, as well as in staged hybrid repair and seems equally adoptable for endovascular procedures. The contribution presented herein provides an overview of clinical and experimental studies on the staged approach. Furthermore, it briefly assesses the anatomic rationale for the collateral network concept. PMID- 23460106 TI - [Extended skin and soft tissue defects after vascular wounds: plastic surgical concepts]. AB - INTRODUCTION: Skin and soft-tissue defects at the ischaemic lower extremity represent a challenging condition. Major amputations can be prevented by optimised surgical therapy. The aim of any intervention is the revascularisation and defect reconstruction of the extremity. METHODS: This article aims to provide a structured overview on up-to-date therapeutic strategies and differentiated indications for certain surgical flaps in combination with bypass surgery for the treatment of chronic "vascular" wounds. RESULTS: Optimised conservative wound therapy, skin grafts, pedicled or microsurgical free flaps in combination with vascular bypasses can be applied to salvage ischaemic extremities. These operations require an interdisciplinary cooperation between vascular surgeons and plastic surgeons. DISCUSSION: These procedures should accordingly only be performed in specialised high-volume centres with significant vascular surgical and microsurgical expertise. PMID- 23460107 TI - [Hemiarthroplasty for femoral neck fracture in the elderly--an operation suitable for teaching?]. AB - BACKGROUND: Hemiarthroplasty is a common procedure for treating femoral neck fractures in orthogeriatrics. For training purposes the operation may also be performed by supervised residents. Our study aims at evaluating the rates of early surgical complications after hemiarthroplasty in different age groups, comparing operations performed by consultants and residents. METHODS: All patients treated with hemiarthroplasty between December 2006 and July 2011 at our municipal, maximum-care-providing hospital were included in a retrospective cohort. The Excia(r) stem with a self-centering bipolar head (Aesculap, Tuttlingen) was used in all patients. Educational level of the operator (consultant vs. resident) and operation time were noted as well as early complications including luxation, infection, haematoma, seroma, and early periprosthetic fractures (e.g., intraoperative lesions of the greater trochanter). The complication rates were evaluated and compared by the chi-square test. RESULTS: 241 of 729 hemiarthroplasties were performed by supervised residents. Neither the overall complication rate nor the rates of specific complications differed significantly between the patients operated by consultants and those operated by residents. The result was still true if comparing the different age groups. On average operation time was 8 minutes longer in teaching operations. CONCLUSIONS: Focusing on early surgical complications, the teaching of hemiarthroplasty does not seem to increase the risk to patients of any age. We conclude that the hemiarthroplasty procedure is suitable for teaching younger colleagues in orthogeriatrics. As age is just one of several potential risk factors, additional studies on this topic should be undertaken. PMID- 23460108 TI - [Safety of resection of symptomatic and asymptomatic Meckel's diverticulum and literature review]. AB - BACKGROUND: Meckel's diverticulum (MD) is the most common diverticulum of the small bowel and an important finding in surgical practice. The aim of this study was to assess the safety of the resection of symptomatic and asymptomatic MD concerning postoperative complications. As MD are relatively rare, an overview of the literature is given. PATIENTS AND METHODS: All patients with MD at the department at general surgery of the Charite - Campus Benjamin Franklin between 1996 and 2010 were assessed. An analysis for symptomatic and incidental MD was performed for incidence, indication, intraoperative findings, histology and postoperative outcome. RESULTS: An MD was intraoperatively found in 71 of 29 682 patients (0.2 %). Of these, a symptomatic MD occurred in 26 patients (37 %). A symptomatic MD was causal in 6 of 7 patients with gastrointestinal bleeding (GIB, p = 0.005). All symptomatic MD and 30 (67 %) asymptomatic MD were resected. Ectopic gastric mucosa was found significantly more frequently in patients with symptomatic MD (p = 0.001). Patients with asymptomatic MD and resection had less complications as a trend (p = 0.057). CONCLUSION: Ectopic mucosa is more frequent in symptomatic MD, especially in bleeding MD. MD should always be considered in GIB of unknown origin. Resection of incidental MD can be recommended in patients without contraindications such as peritonitis, cancer, ascites or immunosuppression. PMID- 23460109 TI - [Primary interdisciplinary reconstruction of perineal defects to reduce wound complications after abdominoperineal resection]. AB - BACKGROUND: Multimodal treatment options for ultra-low neoplasms of the rectum or anal cancer include chemotherapy, radical abdominoperineal resection and/or radiation. Primary wound closure increases the risk of perineal wound complications that require secondary revision. Perineal wound complications may trigger delay of adjacent tumor therapy and thus have an impact on rate of local recurrence and long-term survival for rectal cancer. Simultaneous primary reconstruction of the perineal defect has been shown to reduce the incidence of perineal wound complications as well as hospital stay which enables timely adjacent therapy and may improve prognosis. PATIENTS AND METHODS: This study was designed to retrospectively evaluate wound complications after abdominoperineal resection by comparing a group with and one without primary perineal reconstruction. Between 2005 and 2011, patients were analysed and divided into cohorts 1 and 2. Cohort 1 included n = 33 patients without primary perineal reconstruction. Cohort 2 included n = 4 patients with primary perineal reconstruction. Risk factors were identified for increased wound complications and delay of adjacent therapy. RESULTS: Subgroup analysis revealed that 18 out of 33 patients of cohort 1 had wound complications. In five cases, prolonged wound healing resulted in a delay of adjacent therapies. Four patients suffered from progression of tumour, 2 out of these 4 patients had a history of delayed adjacent therapy. The main risk factor for prolonged wound healing due to postoperative complications was a history of neoadjuvant treatment resulting in a rate of 64.7 %. Cohort 2 undergoing primary reconstruction presented without wound complications or delay in adjuvant therapy. DISCUSSION: A primary perineal reconstruction after APRE can reduce the rate of perineal wound complications. Furthermore, neoadjuvant treatment was shown to carry a major risk for wound complications. Patients after radio-/chemotherapy should undergo a primary reconstruction to prevent procedure-related perioperative morbidity. Subsequently, delays in adjuvant therapy, and prolonged hospital stay can be inhibited. Moreover, quality of life can be increased. The interdisciplinary approach aims at identifying high-risk patients for perineal wound complications who may benefit from primary reconstruction in order to reduce rate of wound complications with potential impact on rate of local recurrence. All these measures contribute to an optimized surgical standard. PMID- 23460110 TI - Intestinal anti-inflammatory activity of luteolin: role of the aglycone in NF kappaB inactivation in macrophages co-cultured with intestinal epithelial cells. AB - The flavonoid luteolin is reported to exert anti-inflammatory properties. In this study, we investigated whether luteolin inhibits gut inflammation, using in vivo and in vitro inflammation models. In a dextran sulfate sodium (DSS)-induced colitis mouse model, luteolin (20 and 50 mg/kg) significantly ameliorated shortening of colon length and histological score. Immunohistochemical analysis showed that luteolin also significantly inhibited infiltration of macrophages and interferon (IFN)-gamma-producing CD4+ T cells into the colonic mucosa. Treatment with luteolin also improved IFN-gamma mRNA expression in the colon. At the cellular level, a co-culture consisting of intestinal epithelial Caco-2 and macrophage RAW264.7 cells, stimulated with lipopolysaccharide, the addition of luteolin (100 MUM) suppressed interleukin (IL)-8 mRNA expression in Caco-2 cells without epithelial monolayer disruption. Expression of tumor necrosis factor (TNF)-alpha protein and proinflammatory cytokines mRNA (TNF-alpha, IL-6, and IL 1beta) in RAW264.7 cells were also suppressed. HPLC analysis and subsequent cellular assay revealed that aglycone of luteolin was present in the basolateral supernatant of this system at a sufficient concentration to suppress TNF-alpha production and nuclear factor (NF)-kappaB activation of RAW264.7 cells. These results suggest that the luteolin aglycones released from the Caco-2 epithelium inhibits NF-kappaB nuclear translocation in RAW264.7 cells, followed by reduction of TNF-alpha mRNA expression, which results in downregulation of IL-8 mRNA expression in Caco-2 cells. The mechanism by which aglycone inhibits inflammation is important for understanding the roles of luteolin in diet. PMID- 23460111 TI - Remarkable effect of CF3CH2OH for the halogen induced oxidative rearrangement reaction of aminals leading to 3,4-dihydroquinazolines. AB - CF3CH2OH was found to be a useful solvent for the oxidative rearrangement reactions of aminals promoted by N-chlorosuccinimide, which proceed via the intermediacy of in situ formed chloro-aminals and that produce 3,4 dihydroquinazolines. PMID- 23460112 TI - Effect of atorvastatin on hematologic parameters in patients with hypercholesterolemia. AB - Hematologic parameters such as mean platelet volume (MPV), red cell distribution width (RDW), and neutrophil to lymphocyte (N/L) ratio are associated with increased cardiovascular risk. We investigated the effect of atorvastatin on hematologic parameters in patients with hypercholesterolemia. A total of 79 patients with hypercholesterolemia and 47 normocholesterolemic healthy participants were included. Patients with hypercholesterolemia received 10 to 80 mg/d atorvastatin during a 24-week period. Hematologic parameters were measured at baseline and after 6 months. Atorvastatin treatment produced a significant decrease in MPV levels (9.3 +/- 1.3 vs 9.1 +/- 1.2 fL, P = .008) and platelet count (259 +/- 61 vs 248 +/- 51 10(9)/L, P = .005). The N/L ratio decreased significantly after atorvastatin treatment from 2.9 +/- 1.2 to 2.6 +/- 1.1, (P = .014). The RDW and platelet distribution width levels were not different among the study groups, before and after treatment. Atorvastatin may beneficially reduce MPV levels and N/L ratio. This antiplatelet and anti-inflammatory effect of atorvastatin treatment could play a role in reducing cardiovascular risk. PMID- 23460113 TI - Impact of transradial coronary procedures on radial artery function. AB - We evaluated the impact of transradial coronary procedures on the vasodilatory function of the radial artery. A total of 65 patients who underwent transradial coronary procedures were enrolled. All patients were examined with B-mode high resolution ultrasound. Radial artery baseline diameter and response to flow mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) were measured in the right radial artery. The FMD of the right radial artery was 11.5%, 4.1%, and 0.7%, respectively, before the procedures, 1 day, and 3 months after the procedures (P < .05 at 1 day, P < .01 at 3 months). The NMD of the right radial artery was 17.6%, 5.4%, and 6.3%, respectively, before the procedures, 1 day, and 3 months after the procedures (P < .05 at 1 day, P < .05 at 3 months). Transradial coronary procedures decrease radial artery FMD and NMD resulting in immediate and persistent blunting of vasodilatory function. PMID- 23460115 TI - Operationalizing One Health: Stone Mountain and beyond. AB - Although the interconnection of humans, animals, and ecosystems has been recognized historically, increasing specialization of professionals in the twentieth century led to decreased communication and collaboration among sectors. In early 2000, a One Health vision of global interconnectedness began gaining in popularity and a series of meetings were held extolling the One Health vision. However, by 2009, detractors were claiming that the One Health approach was indeed all vision and no action. In response to this, international organizations sponsored a carefully planned and structured meeting to construct a way forward that would lead to tangible outcomes. The Stone Mountain meeting, Operationalizing "One Health": A Policy Perspective-Taking Stock and Shaping an Implementation Roadmap led to the formation of seven multi-national work groups with defined timelines and outputs. The process has garnered increasing participation and support, and the work groups are on track to demonstrate the value added of a One Health approach. PMID- 23460116 TI - Who pays for work-related traumatic injuries? Payer distribution in washington state by ethnicity, injury severity, and year (1998-2008). AB - BACKGROUND: Acute work-related trauma is a leading cause of death and disability for U.S. workers but it is difficult to obtain information about injured workers not covered by workers' compensation (WC). This study aimed to: (1) describe trends in expected payer and linkage to WC claims, (2) compare characteristics of injured workers who did and did not have a linked WC claim, and (3) describe variation in expected payer and linkage to WC claims by ethnicity and injury severity. METHODS: Data for injuries occurring from 1998 through 2008 were obtained from the Washington State Trauma Registry and linked to WC claims. RESULTS: We found that 27% of work-related traumatic injuries did not have WC listed as a payer, while 37% did not link to a WC claim. Among those with WC listed as a payer, the odds of having a linked WC claim were 57% lower for workers with other non-WC insurance compared with the otherwise uninsured. Latinos were more likely to have a linked WC claim compared with non-Latinos, but there was no significant difference after partially controlling for WC-covered employment and other insurance. CONCLUSIONS: This study demonstrated the importance of considering differential access to other insurance coverage and adaptation by health care settings to financial pressures when assessing trends in occupational injury incidence and reporting, especially when using WC as a proxy for work-relatedness. The addition of occupation, industry, and work status to trauma registries and hospital discharge databases would improve surveillance, research, policy and prevention efforts. PMID- 23460117 TI - CCL20 induces migration and proliferation on breast epithelial cells. AB - The communication between the tumor cells and the surrounding cells helps drive the process of tumor progression. Since the microenvironment of breast cancer includes CCL20 chemokine, the purpose of this study was to determine whether CCL20 modulates the physiology of healthy breast epithelial cells in areas adjacent to the tumor. Therefore, primary cultures of mammary cells taken from normal peritumoral areas were used. We assessed that breast cells expressed CCR6 CCL20 receptor. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated by CCR6 and involved in CCL20-induced breast cell proliferation and migration. The binding of 10 ng/ml CCL20 to CCR6 induced cell migration whilst higher concentrations (from 15 to 25 ng/ml) led to cell proliferation. CCL20 controlled cell migration and MMP-9 expression by PKC-alpha that activated Src, which caused the activation of downstream Akt, JNK, and NF-kB pathways. Furthermore, higher CCL20 concentrations increased cycE and decreased p27Kip expression ending in enhanced cell proliferation. Cell proliferation occurred through PKC-epsilon activation that transactivated EGFR and ERK1/2/MAPK pathway. Although activated by different CCL20 concentrations, these pathways function in parallel and crosstalk to some extent, inasmuch as Akt activation was responsible for ERK1/2 nuclear translocation and enhanced the transcription of of c-fos and c-myc, involved in cell proliferation. In summary, tumor cells exchange signals with the surrounding healthy cells modifying the extracellular matrix through enzyme secretion; thus, CCL20 might be a factor involved in the ontogeny of breast carcinoma. PMID- 23460118 TI - Mossbauer spectroscopy of the iron cores in human liver ferritin, ferritin in normal human spleen and ferritin in spleen from patient with primary myelofibrosis: preliminary results of comparative analysis. AB - Comparative study of human liver ferritin and spleen tissues from healthy human and patient with primary myelofibrosis was carried out using Mossbauer spectroscopy with a high velocity resolution at 295 and 90 K and with a low velocity resolution at 20 K. The results obtained demonstrated that the iron content in patient's spleen in the form of iron storage proteins was about ten times larger than that in normal tissue. However, in the case of patient with primary myelofibrosis the magnetic anisotropy energy barrier differed from that in normal case and, probably, the iron core size was supposed to be slightly larger than that in both normal spleen tissue and normal human liver ferritin in contrast to well-known data for iron overload in patients with thalassemia accompanied by the iron-core size increase. Therefore, the iron overload in the case of patient with primary myelofibrosis may be related to increase in the ferritin content mainly. It was also found that Mossbauer hyperfine parameters for normal and patient's spleen and normal human liver ferritin demonstrated some small differences related, probably, to some small structural variations in the ferritin iron cores of patient's spleen. PMID- 23460119 TI - High-quality boron nitride nanoribbons: unzipping during nanotube synthesis. PMID- 23460120 TI - Noradrenaline induces binding of Clathrin light chain A to alpha1-adrenoceptors in the human prostate. AB - BACKGROUND: Binding of clathrins or caveolin to G protein-coupled receptors may induce post-translational modifications of receptor function. Receptor regulation by clathrin requires cofactors ADP-ribosylation factor 6 (ARF6) and adaptin, while dynamin is required for clathrin- and caveolin-dependent mechanisms. OBJECTIVE: To investigate the expression and alpha1-adrenoceptor binding of clathrins, caveolin, and their cofactors in the human prostate. METHODS: Prostate tissue was obtained from radical prostatectomy. Expression of clathrin heavy chain (HC), clathrin light chain A and B (LCA, LCB), caveolin-1, ARF6, beta adaptin, and dynamin-2 was studied by RT-PCR, Western blot, immunohistochemistry, and fluorescence staining. Interaction of alpha1A-adrenoceptors with clathrins and caveolin-1 was studied by coimmunoprecipitation. RESULTS: mRNA and protein expression of clathrin HC, LCA, LCB, caveolin-1, dynamin-2, and beta-adaptin was detected in prostate tissues of each patient. Immunohistochemistry demonstrated the expression of clathrin HC, LCA, LCB, caveolin, dynamin, and beta-adaptin in stromal cells. Immunoreactivity for these proteins colocalized with alpha-smooth muscle actin and alpha1A-adrenoceptors in double fluorescence staining. Coimmunoprecipitation demonstrated that alpha1A-adrenoceptors in prostate tissue interact with clathrin HC and LCB under resting conditions, but not with caveolin 1. Stimulation of prostate tissues with noradrenaline (30 uM) in vitro induced binding of clathrin LCA to alpha1A-adrenoceptors. CONCLUSIONS: The prostatic alpha1-adrenoceptor population is at least partially bound to clathrin HC and LCB. Upon receptor activation, prostate alpha1A-adrenoceptors bind clathrin LCA. This points to a new concept of post-translational alpha1-adrenoceptor regulation in the prostate, which includes receptor interaction with accessory binding partners. PMID- 23460121 TI - [Bone marrow edema syndrome (BMES)]. AB - Bone marrow edema (BME) syndrome represents a pathologic accumulation of interstitial fluid in bone - with a traumatic BME being differentiated from a non traumatic, often ischemic, and a reactive as well as a mechanical BME. Atraumatic/ischemic BME is inconsistently described as a separate entity or as a reversible preliminary stage of osteonecrosis (ON). However, there is always the risk of transformation of BME into ON and subsequent joint destruction. The most common sites of BME are the hip, knee, and ankle. Magnetic resonance imaging is the diagnostic gold standard. Differential diagnoses of the transient BME as osteonecrosis, osteochondrosis dissecans, and a reflex dystrophy should be considered. Conservative or surgical treatment is considered, depending on the etiology of BME. BME syndrome is generally treated conservatively. Infusion of prostacycline or bisphosphonates is a promising option. Ischemic BME and early stages of ON can be successfully treated by core decompression. A combination of both treatment options may also offer advantages. PMID- 23460123 TI - Clostridium difficile Infection in children. AB - Clostridium difficile is the most common cause of health care-associated diarrhea among adults in the United States and is associated with significant morbidity and mortality. During the past decade, the epidemiology of C difficile infection (CDI) has changed, including a rise in the rate and severity of infection related to the emergence of a hypervirulent strain as well as an increase in disease among outpatients in community settings. Although less is known about CDI among pediatric patients, C difficile is increasingly recognized as an important pathogen among children. In this review, we discuss recent updates in the incidence and epidemiology of CDI among children, including risk factors for infection, and highlight the importance of CDI in special populations of children, particularly those with inflammatory bowel disease or cancer. In addition, we review current knowledge in the areas of diagnosis and management of CDI among children and highlight future areas for research. PMID- 23460125 TI - Large area periodic, systematically changing, multishape nanostructures by laser interference lithography and cell response to these topographies. AB - The fabrication details to form large area systematically changing multishape nanoscale structures on a chip by laser interference lithography (LIL) are described. The feasibility of fabricating different geometries including dots, ellipses, holes, and elliptical holes in both x- and y- directions on a single substrate is shown by implementing a Lloyd's interferometer. The fabricated structures at different substrate positions with respect to exposure time, exposure angle and associated light intensity profile are analyzed. Experimental details related to the fabrication of symmetric and biaxial periodic nanostructures on photoresist, silicon surfaces, and ion milled glass substrates are presented. Primary rat calvarial osteoblasts were grown on ion-milled glass substrates with nanotopography with a periodicity of 1200 nm. Fluorescent microscopy revealed that cells formed adhesions sites coincident with the nanotopography after 24 h of growth on the substrates. The results suggest that laser LIL is an easy and inexpensive method to fabricate systematically changing nanostructures for cell adhesion studies. The effect of the different periodicities and transition structures can be studied on a single substrate to reduce the number of samples significantly. PMID- 23460124 TI - Metabolic profiling predicts response to anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis. AB - OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) therapies are highly effective in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but a significant number of patients exhibit only a partial or no therapeutic response. Inflammation alters local and systemic metabolism, and TNF plays a role in this. We undertook this study to determine if the patient's metabolic fingerprint prior to therapy could predict responses to anti-TNF agents. METHODS: Urine was collected from 16 RA patients and 20 PsA patients before and during therapy with infliximab or etanercept. Urine metabolic profiles were assessed using nuclear magnetic resonance spectroscopy. Discriminating metabolites were identified, and the relationship between metabolic profiles and clinical outcomes was assessed. RESULTS: Baseline urine metabolic profiles discriminated between RA patients who did or did not have a good response to anti-TNF therapy according to European League Against Rheumatism criteria, with a sensitivity of 88.9% and a specificity of 85.7%, with several metabolites contributing (in particular histamine, glutamine, xanthurenic acid, and ethanolamine). There was a correlation between baseline metabolic profiles and the magnitude of change in the Disease Activity Score in 28 joints from baseline to 12 months in RA patients (P = 0.04). In both RA and PsA, urinary metabolic profiles changed between baseline and 12 weeks of anti-TNF therapy. Within the responders, urinary metabolite changes distinguished between etanercept and infliximab treatment. CONCLUSION: The clear relationship between urine metabolic profiles of RA patients at baseline and their response to anti-TNF therapy may allow development of novel approaches to the optimization of therapy. Differences in metabolic profiles during treatment with infliximab and etanercept in RA and PsA may reflect distinct mechanisms of action. PMID- 23460126 TI - Antioxidant activity and HPLC analysis of polyphenol-enriched extracts from industrial apple pomace. AB - BACKGROUND: Phenolic compounds are the predominant ingredients in apple pomace. However, polyphenols from industrial apple pomace, which usually consists of several cultivars, have not been studied in detail. The present work focused on the antioxidant assay and HPLC analysis of polyphenol-enriched extracts from industrial apple pomace. RESULTS: Six fractions of apple polyphenols, API to APVI, were acquired through extraction and purification using absorbent macroporous resin. Fraction APIII, eluted by 40% aqueous ethanol, had the highest content of total phenolics (1.48 +/- 0.03 g gallic acid equivalents g(-1) dry apple pomace), which consisted of chlorogenic acid, caffeic acid, syrigin, procyanidin B2, (-)-epicatechin, cinnamic acid, coumaric acid and quercetin. Antioxidant assays showed that APIII had the strongest antioxidant activity of DPPH radical scavenging rate (90.96% +/- 10.23%), ABTS radical inhibition rate (89.78% +/- 6.54%) and the strongest reducing power (8.30 +/- 0.71 umol Trolox equivalents kg(-1) dry apple pomace). It also indicated that procyanidin B2, chlorogenic acid, (-)-epicatechin and quercetin had stronger antioxidant capacity than other phenols. CONCLUSION: Our data suggested that extracts from industrial apple pomace were rich in phenols and exhibited potent antioxidant activity. Extraction of polyphenols from industrial apple pomace would bring a great benefit and improve development of apple juice and cider industries. PMID- 23460127 TI - Exploiting furan's versatile reactivity in reversible and irreversible orthogonal peptide labeling. AB - A general method for the facile and versatile decoration of peptides is proposed exploiting furan based cycloaddition and electrophilic aromatic substitution reactions. Given the commercial availability of furylalanine derivatives for peptide synthesis, the current work significantly enlarges the toolbox of available methodologies for site specific labeling and conjugation of peptide probes. PMID- 23460129 TI - Postmenopausal sex hormones: comparing apples and pears. PMID- 23460128 TI - Cardiopulmonary interactions during mechanical ventilation in critically ill patients. AB - Cardiopulmonary interactions induced by mechanical ventilation are complex and only partly understood. Applied tidal volumes and/or airway pressures largely mediate changes in right ventricular preload and afterload. Effects on left ventricular function are mostly secondary to changes in right ventricular loading conditions. It is imperative to dissect the several causes of haemodynamic compromise during mechanical ventilation as undiagnosed ventricular dysfunction may contribute to morbidity and mortality. PMID- 23460130 TI - Revolutionizing child welfare with outcomes management. AB - Outcomes management technology holds great promise for improving the quality of services provided to youth in the child welfare system. Advantages include better detection of behavioral health and trauma-related issues, early indicators of case progress or risk of failure, and program- and system-level learning. Yet organizational barriers to implementation persist. Attention is spent in this paper on addressing these barriers so the use of outcomes management technology becomes a common practice. A model for predicting resiliency is presented, along with case examples demonstrating its potential use for treatment planning and monitoring progress. PMID- 23460131 TI - Methylene-bridged bimetallic alpha-diimino nickel(II) complexes: synthesis and high efficiency in ethylene polymerization. AB - A series of 1,2-bis(arylimino)acenaphthylidenes (L1-L5) and their corresponding 4,4'-methylenebis(1-(2,6-diisopropylphenylimino)-2-(arylimino)acenaphthylene) derivatives (L6-L10) were synthesized and used to form mono-nuclear nickel bromides LnNiBr2 (n = 1-5, Ni1-Ni5) and bi-nuclear nickel halides LnNi2X4 (n = 6 10: X = Br, Ni2-1-Ni2-5; n = 4, X = Cl, Ni2-6). All the organic compounds were fully characterized by FT-IR spectra, NMR measurements and elemental analysis. The nickel complexes were characterized by FT-IR spectra and elemental analysis and the molecular structures of the representative complexes Ni1, Ni2-1 and Ni2-3 were confirmed by single-crystal X-ray diffraction. Upon activation with either Et2AlCl or MAO, all the nickel complex pre-catalysts exhibited high activity toward ethylene polymerization over the temperature range from ambient to 50 degrees C. In general, the bi-nuclear complexes showed a positive synergetic effect with higher activity than their mono nuclear analogs. The resultant polyethylene possessed higher molecular weight and a high degree of branching. PMID- 23460132 TI - Mitochondrial dysfunction in psychiatric and neurological diseases: cause(s), consequence(s), and implications of antioxidant therapy. AB - Mitochondrial dysfunction is at the base of development and progression of several psychiatric and neurologic diseases with different etiologies. MtDNA/nDNA mutational damage, failure of endogenous antioxidant defenses, hormonal malfunction, altered membrane permeability, metabolic dysregulation, disruption of calcium buffering capacity and ageing have been found to be the root causes of mitochondrial dysfunction in psychatric and neurodegenerative diseases. However, the overall consequences of mitochondrial dysfunction are only limited to increase in oxidative/nitrosative stress and cellular energy crises. Thus far, extensive efforts have been made to improve mitochondrial function through specific cause-dependent antioxidant therapy. However, owing to complex genetic and interlinked causes of mitochondrial dysfunction, it has not been possible to achieve any common, unique supportive antioxidant therapeutic strategy for the treatment of psychiatric and neurologic diseases. Hence, we propose an antioxidant therapeutic strategy for management of consequences of mitochondrial dysfunction in psychiatric and neurologic diseases. It is expected that this will not only reduces oxidative stress, but also promote anaerobic energy production. PMID- 23460133 TI - miR-152 controls migration and invasive potential by targeting TGFalpha in prostate cancer cell lines. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of short non-coding RNAs that function in diverse biological processes. Aberrant miR-152 expression has been frequently reported in various malignant tumors. However, the mechanism of miR-152 in prostate cancer (PCa) remains unclear. This study aims to determine the function of miR-152 in PCa cells and identify the novel molecular targets regulated by miR 152. METHODS: The expression levels of transforming growth factor-alpha (TGFalpha) were determined in three samples of PCa and adjacent non-tumorous tissues by Western blot analysis. miR-152 levels in 48 primary PCa and 15 non malignant tissue samples were measured by qRT-PCR. The effects of forced miR-152 expression or TGFalpha knockdown on PCa cells were evaluated by cell migration and invasion assays, as well as Western blot analysis. Dual-luciferase reporter assay was used to identify binding sites between miR-152 and TGFalpha 3'-UTR. RESULTS: TGFalpha was upregulated in PCa tissue samples compared with that in adjacent normal ones. miR-152 expression was significantly decreased in primary PCa samples compared with that in non-malignant samples. Patients with Gleason scores >7 exhibited lower miR-152 levels than those with lower scores. Moreover, low miR-152 expression is correlated with advanced pathological T-stages. Forced miR-152 expression or TGFalpha knockdown significantly reduced the migratory and invasive capabilities of PCa cells in vitro. TGFalpha is a direct target gene of miR-152. CONCLUSIONS: Our findings suggest that miR-152 can act as a tumor suppressor that targets TGFalpha. miR-152 is a promising molecular target that inhibits PCa cell migration and invasion. PMID- 23460136 TI - In vivo and in situ evaluation of a wireless magnetoelastic sensor array for plastic biliary stent monitoring. AB - This paper presents the in vivo and in situ evaluation of a system that wirelessly monitors the accumulation of biliary sludge in a plastic biliary stent. The sensing element, located within the stent, is a passive array of magnetoelastic resonators that is queried by a wireless electromagnetic signal. The in vivo and in situ testing uses commercially-available plastic biliary stents, each enhanced with an array of ribbon sensors (formed from MetglasTM 2826 MB). The sensor array is approximately 70 mm long and contains individual resonators that are 1 mm in width and have lengths of 10 mm, 14 mm, and 20 mm. The array is anchored into the 2.8 mm inner-diameter stent using a thermal staking technique. For the in situ testing, an instrumented stent is placed in various locations within the abdominal cavity of a female domestic swine carcass to evaluate the wireless range of the system; these results show that a wireless signal can be obtained from a range of at least 7.5 cm from a sensor array covered in bile. The in vivo testing includes the endoscopic implantation of an instrumented stent into the bile duct of a swine. After implantation, the swine was housed for a period of 4 weeks, during which the animal showed no ill effects and followed the expected growth curve from 29 kg to 42 kg. At the conclusion of the in vivo test, the animal was euthanized, and the instrumented stent explanted and examined. The results presented in this paper indicate that the monitoring system does not adversely affect the health of the animal and can feasibly provide sufficient wireless range after implantation. PMID- 23460137 TI - Synthesis of stable peptide nucleic acid-modified gold nanoparticles and their assembly onto gold surfaces. PMID- 23460134 TI - Lactoferricin mediates anti-inflammatory and anti-catabolic effects via inhibition of IL-1 and LPS activity in the intervertebral disc. AB - The catabolic cytokine interleukin-1 (IL-1) and endotoxin lipopolysaccharide (LPS) are well-known inflammatory mediators involved in degenerative disc disease, and inhibitors of IL-1 and LPS may potentially be used to slow or prevent disc degeneration in vivo. Here, we elucidate the striking anti-catabolic and anti-inflammatory effects of bovine lactoferricin (LfcinB) in the intervertebral disc (IVD) via antagonism of both IL-1 and LPS-mediated catabolic activity using in vitro and ex vivo analyses. Specifically, we demonstrate the biological counteraction of LfcinB against IL-1 and LPS-mediated proteoglycan (PG) depletion, matrix-degrading enzyme production, and enzyme activity in long term (alginate beads) and short-term (monolayer) culture models using bovine and human nucleus pulposus (NP) cells. LfcinB significantly attenuates the IL-1 and LPS-mediated suppression of PG production and synthesis, and thus restores PG accumulation and pericellular matrix formation. Simultaneously, LfcinB antagonizes catabolic factor mediated induction of multiple cartilage-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, in bovine NP cells at both mRNA and protein levels. LfcinB also suppresses the catabolic factor-induced stimulation of oxidative and inflammatory factors such as iNOS, IL 6, and toll-like receptor-2 (TLR-2) and TLR-4. Finally, the ability of LfcinB to antagonize IL-1 and LPS-mediated suppression of PG is upheld in an en bloc intradiscal microinjection model followed by ex vivo organ culture using both mouse and rabbit IVD tissue, suggesting a potential therapeutic benefit of LfcinB on degenerative disc disease in the future. PMID- 23460138 TI - Non-monogamous copulations and potential within-group mating competition in white faced saki monkeys (Pithecia pithecia). AB - Many primates display within-species variation in social organization and mating system. Individuals of these species may be confronted with both the challenges of between-group competition to exclude same-sex competitors as well as within group competition for mating opportunities. Free-ranging white-faced saki monkeys (Pithecia pithecia) live in both male-female pairs and small multi-male, multi female groups. Despite commonly held views that this species is monogamous, there are currently no published accounts of mating patterns in the genus Pithecia. I recorded copulations and sexual behavior from three free-ranging groups of white faced sakis at Brownsberg Naturepark, Suriname over a period of 17 months. Groups displayed both monogamous and polygynandrous mating. Individuals in polygynandrous groups were not observed to mate more frequently with certain partners. Copulation harassment occurred in 8.6% of copulations (total N = 81) and was performed by both sexes. This harassment successfully prevented ejaculation in six out of seven instances and harassment by males resulted in male-male aggression on four occasions. Two cases of female-directed sexual aggression by males were also observed, which may indicate that males use sexual coercion to influence female mating behavior. Although based on a small number of groups, these data show that white-faced sakis display variability in mating system and that this variability is not directly dictated by social organization. Furthermore, groups with promiscuous copulations exhibit behaviors indicative of within-group mating competition. PMID- 23460140 TI - What's new in glucose control in the ICU? PMID- 23460141 TI - Automation in haemostasis. AB - Automatia, an ancient Greece goddess of luck who makes things happen by themselves and on her own will without human engagement, is present in our daily life in the medical laboratory. Automation has been introduced and perfected by clinical chemistry and since then expanded into other fields such as haematology, immunology, molecular biology and also coagulation testing. The initial small and relatively simple standalone instruments have been replaced by more complex systems that allow for multitasking. Integration of automated coagulation testing into total laboratory automation has become possible in the most recent years. Automation has many strengths and opportunities if weaknesses and threats are respected. On the positive side, standardization, reduction of errors, reduction of cost and increase of throughput are clearly beneficial. Dependence on manufacturers, high initiation cost and somewhat expensive maintenance are less favourable factors. The modern lab and especially the todays lab technicians and academic personnel in the laboratory do not add value for the doctor and his patients by spending lots of time behind the machines. In the future the lab needs to contribute at the bedside suggesting laboratory testing and providing support and interpretation of the obtained results. The human factor will continue to play an important role in testing in haemostasis yet under different circumstances. PMID- 23460142 TI - Vacuolar-type proton pump ATPases: acidification and pathological relationships. AB - Vacuolar H(+)(-)translocating ATPase (V-ATPase) is a universal proton pump, and its activity is required for a variety of cell biological processes, such as membrane trafficking, receptor-mediated endocytosis, lysosomal degradation of macromolecules, osteoclastic bone resorption, and the maintenance of acid-base homeostasis by renal intercalated cells. V-ATPase is targeted to various membranes and has different compositions depending on its cellular location. Here, we focus on recent knowledge concerning the targeting mechanism of V ATPase, a process associated with a wide spectrum of diseases. We also discuss the functions of this enzyme in macrophages and cancer cells-2 characteristic cell types with clinical importance. PMID- 23460143 TI - Chronic cough and gastroesophageal reflux disease: how do we establish a causal link? PMID- 23460144 TI - Preventing DVT in peripherally inserted central catheters. PMID- 23460145 TI - Probiotics for ventilator-associated pneumonia: the need for a large, multicenter, randomized controlled trial. PMID- 23460139 TI - Neurodevelopmental outcomes of extremely low-gestational-age neonates with low grade periventricular-intraventricular hemorrhage. AB - IMPORTANCE: Low-grade periventricular-intraventricular hemorrhage is a common neurologic morbidity among extremely low-gestational-age neonates, yet the outcomes associated with this morbidity are not fully understood. In a contemporary multicenter cohort, we evaluated the impact of such hemorrhages on early (18-22 month) neurodevelopmental outcomes of extremely premature infants. OBJECTIVE: To compare neurodevelopmental outcomes at 18 to 22 months' corrected age for extremely low-gestational-age infants with low-grade (grade 1 or 2) periventricular-intraventricular hemorrhage with those of infants with either no hemorrhage or severe (grade 3 or 4) hemorrhage demonstrated on cranial ultrasonography. DESIGN: Longitudinal observational study. SETTING: Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. PARTICIPANTS: A total of 1472 infants born at less than 27 weeks' gestational age between January 1, 2006, and December 31, 2008, with ultrasonography results within the first 28 days of life and surviving to 18 to 22 months with complete follow-up assessments were eligible. MAIN EXPOSURE: Low-grade periventricular-intraventricular hemorrhage. MAIN OUTCOME MEASURES: Outcomes included cerebral palsy; gross motor functional limitation; cognitive and language scores according to the Bayley Scales of Infant Development, 3rd Edition; and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences. RESULTS: Low-grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared with infants without hemorrhage. Compared with low-grade hemorrhage, severe hemorrhage was associated with decreased adjusted continuous cognitive (beta, -3.91 [95% CI, -6.41 to -1.42]) and language (beta, -3.19 [-6.19 to -0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (odds ratio [OR], 1.46 [0.74 to 2.88]) and mild language impairment (OR, 1.35 [0.88 to 2.06]). CONCLUSIONS AND RELEVANCE: At 18 to 22 months, the neurodevelopmental outcomes of extremely low-gestational-age infants with low-grade periventricular intraventricular hemorrhage are not significantly different from those without hemorrhage. Additional study at school age and beyond would be informative. PMID- 23460146 TI - Lumps, bumps, spots, and shadows: the scary world of the solitary pulmonary nodule. PMID- 23460147 TI - Who will care for our critically ill? PMID- 23460149 TI - Point: should epidermal growth factor receptor mutations be routinely tested for in patients with lung cancer? Yes. PMID- 23460150 TI - Counterpoint: should epidermal growth factor receptor mutations be routinely tested for in patients with lung cancer? No. PMID- 23460151 TI - Rebuttal from Dr Sterman. PMID- 23460152 TI - Rebuttal from Dr Lam. PMID- 23460153 TI - Impact of the administration of probiotics on mortality in critically ill adult patients: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The objective of this study was to systematically review and quantitatively synthesize all randomized controlled trials (RCTs) that have compared important outcomes in critically ill patients who received an administration of probiotics. METHODS: A systematic literature search of PubMed, Scopus, and the Cochrane Central Register of Controlled Trials was conducted using specific search terms. Eligible studies were RCTs that compared the effect of prebiotics, probiotics, or synbiotics administration with control on ICU and hospital mortality rates in critically ill adult patients. Weighted mean differences (WMDs), pooled ORs, and 95% CIs were calculated using the Mantel Haenszel fixed- and random-effects models. RESULTS: Thirteen trials with 1,439 patients were analyzed. Probiotics did not significantly reduce ICU (OR, 0.85; 95% CI, 0.63-1.15) or hospital (OR, 0.90; 95% CI, 0.65-1.23) mortality. By contrast, probiotics administration reduced the incidence of ICU-acquired pneumonia (OR, 0.58; 95% CI, 0.42-0.79) and was associated with a shorter stay in the ICU (WMD, -1.49 days; 95% CI, -2.12 to -0.87 days). Finally, probiotics use was not associated with a shorter duration of mechanical ventilation (WMD, -0.18 days; 95% CI, -1.72-1.36 days) or a shorter hospital length of stay (WMD, -0.45 days; 95% CI, -1.41-0.52 days). CONCLUSIONS: The present meta-analysis suggests that the administration of probiotics did not significantly reduce ICU or hospital mortality rates but did reduce the incidence of ICU-acquired pneumonia and ICU length of stay. PMID- 23460154 TI - A novel extracorporeal CO(2) removal system: results of a pilot study of hypercapnic respiratory failure in patients with COPD. AB - BACKGROUND: Hypercapnic respiratory failure in patients with COPD frequently requires mechanical ventilatory support. Extracorporeal CO2 removal (ECCO2R) techniques have not been systematically evaluated in these patients. METHODS: This is a pilot study of a novel ECCO2R device that utilizes a single venous catheter with high CO2 removal rates at low blood flows. Twenty hypercapnic patients with COPD received ECCO2R. Group 1 (n = 7) consisted of patients receiving noninvasive ventilation with a high likelihood of requiring invasive ventilation, group 2 (n = 2) consisted of patients who could not be weaned from noninvasive ventilation, and group 3 (n = 11) consisted of patients on invasive ventilation who had failed attempts to wean. RESULTS: The device was well tolerated, with complications and rates similar to those seen with central venous catheterization. Blood flow through the system was 430.5 +/- 73.7 mL/min, and ECCO2R was 82.5 +/- 15.6 mL/min and did not change significantly with time. Invasive ventilation was avoided in all patients in group 1 and both patients in group 2 were weaned; PaCO2 decreased significantly (P < .003) with application of the device from 78.9 +/- 16.8 mm Hg to 65.9 +/- 11.5 mm Hg. In group 3, three patients were weaned, while the level of invasive ventilatory support was reduced in three patients. One patient in group 3 died due to a retroperitoneal bleed following catheterization. CONCLUSIONS: This single-catheter, low-flow ECCO2R system provided clinically useful levels of CO2 removal in these patients with COPD. The system appears to be a potentially valuable additional modality for the treatment of hypercapnic respiratory failure. PMID- 23460156 TI - Validity of the COPD assessment test translated into local languages for Asian patients. AB - OBJECTIVE: Our objective was to evaluate the validity of the COPD Assessment Test (CAT), translated locally, for measuring the health status of patients in Asian countries. METHODS: A pooled analysis of cross-sectional studies from Indonesia, Korea, Vietnam, and Hong Kong was performed. Smokers or ex-smokers, aged >= 40 years, with a smoking history of >= 10 pack-years and a COPD diagnosis in the past 6 months or more were recruited. Demographic, smoking, and COPD history and spirometry data were collected from patients who completed the CAT or St. George's Respiratory Questionnaire (SGRQ) and had their dyspnea assessed. RESULTS: The study included 333 patients with mean age of 69 +/- 9 years and smoking history of 38 +/- 25 pack-years; 82% had ceased smoking. One-third suffered from cardiovascular comorbidities, 72% reported at least one exacerbation in the past year, and 82% recorded at least moderate health impairment (CAT scores >= 10 units). The CAT score was positively correlated with the SGRQ score (r = 0.72, P < .001) and Medical Research Council (MRC) dyspnea score (r = 0.50, P < .001) and poorly correlated with the FEV1 (r = -0.23, P < .001) and number of exacerbations in the past year (r = 0.11, P = .04). The relationships between the CAT score and SGRQ score, MRC dyspnea score, or FEV1 did not differ between countries (P value for interaction term = 0.76, 0.75, and 0.06, respectively). CONCLUSIONS: The CAT correlated well with the SGRQ and MRC dyspnea score in all countries, and the relationship did not differ between countries despite varying patient characteristics. This suggests that a CAT score in one of these countries has the same clinical significance as the same score in another. PMID- 23460155 TI - Effect of emphysema on CT scan measures of airway dimensions in smokers. AB - BACKGROUND: In CT scans of smokers with COPD, the subsegmental airway wall area percent (WA%) is greater and more strongly correlated with FEV1 % predicted than WA% obtained in the segmental airways. Because emphysema is linked to loss of airway tethering and may limit airway expansion, increases in WA% may be related to emphysema and not solely to remodeling. We aimed to first determine whether the stronger association of subsegmental vs segmental WA% with FEV1 % predicted is mitigated by emphysema and, second, to assess the relationships among emphysema, WA%, and total bronchial area (TBA). METHODS: We analyzed CT scan segmental and subsegmental WA% (WA% = 100 * wall area/TBA) of six bronchial paths and corresponding lobar emphysema, lung function, and clinical data in 983 smokers with COPD. RESULTS: Compared with segmental WA%, the subsegmental WA% had a greater effect on FEV1% predicted (-0.8% to -1.7% vs -1.9% to -2.6% per 1-unit increase in WA%, respectively; P < .05 for most bronchial paths). After adjusting for emphysema, the association between subsegmental WA% and FEV1 % predicted was weakened in two bronchial paths. Increases in WA% between bronchial segments correlated directly with emphysema in all bronchial paths (P < .05). In multivariate regression models, emphysema was directly related to subsegmental WA% in most bronchial paths and inversely related to subsegmental TBA in all bronchial paths. CONCLUSION: The greater effect of subsegmental WA% on airflow obstruction is mitigated by emphysema. Part of the emphysema effect might be due to loss of airway tethering, leading to a reduction in TBA and an increase in WA%. PMID- 23460157 TI - Cardiovascular disease in COPD: mechanisms. AB - It is now well established that cardiovascular disease contributes significantly to both morbidity and mortality in COPD. Shared risk factors for cardiovascular disease and COPD, such as smoking, low socioeconomic class, and a sedentary lifestyle contribute to the natural history of each of these conditions. However, it is now apparent that alternative, novel mechanisms are involved in the pathogenesis of cardiovascular disease, and these may play an important role in driving the increased cardiovascular risk associated with COPD. In this article, we discuss the potential mechanisms that link COPD to an increased risk of cardiovascular disease. PMID- 23460158 TI - United States Critical Illness and Injury Trials Group. AB - The United States Critical Illness and Injury Trials (USCIIT) Group is an inclusive, grassroots "network of networks" with the dual missions of fostering investigator-initiated hypothesis testing and developing recommendations for strategic plans at a national level. The USCIIT Group's transformational approach enlists multidisciplinary investigative teams across institutions, critical illness and injury professional organizations, federal agencies that fund clinical and translational research, and industry partners. The USCIIT Group is endorsed by all major critical illness and injury professional organizations spanning the specialties of anesthesiology, emergency medicine, internal medicine, neurology, nursing, pediatrics, pharmacy and nutrition, surgery and trauma, and respiratory and physical therapy. Recent successes provide the opportunity to significantly increase the dialogue necessary to advance clinical and translational research on behalf of our community. More than 200 investigators are now involved across > 30 academic and community hospitals. Collectively, USCIIT Group investigators have enrolled > 10,000 patients from academic and community hospitals in studies during the last 3 years. To keep our readership "ahead of the curve," this article provides a vision for critical illness and injury research based on (1) programmatic organization of large scale, multicentered collaborative studies and (2) annual strategic planning at a national scale across disciplines and stakeholders. PMID- 23460160 TI - A practical algorithmic approach to the diagnosis and management of solitary pulmonary nodules: part 1: radiologic characteristics and imaging modalities. AB - The solitary pulmonary nodule (SPN) is frequently encountered on chest imaging and poses an important diagnostic challenge to clinicians. The differential diagnosis is broad, ranging from benign granulomata and infectious processes to malignancy. Important concepts in the evaluation of SPNs include the definition, morphologic characteristics via appropriate imaging modalities, and the calculation of pretest probability of malignancy. Morphologic differentiation of SPN into solid or subsolid types is important in the choice of follow-up and further management. In this first part of a two-part series, we describe the morphologic characteristics and various imaging modalities available to further characterize SPN. In Part 2, we will describe the determination of pretest probability of malignancy and an algorithmic approach to the diagnosis of SPN. PMID- 23460159 TI - Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. AB - Interstitial lung disease (ILD) is one of the most serious pulmonary complications associated with connective tissue diseases (CTDs), resulting in significant morbidity and mortality. Although the various CTDs associated with ILD often are considered together because of their shared autoimmune nature, there are substantial differences in the clinical presentations and management of ILD in each specific CTD. This heterogeneity and the cross-disciplinary nature of care have complicated the conduct of prospective multicenter treatment trials and hindered our understanding of the development of ILD in patients with CTD. In this update, we present new information regarding the diagnosis and treatment of patients with ILD secondary to systemic sclerosis, rheumatoid arthritis, dermatomyositis and polymyositis, and Sjogren syndrome. We review information on risk factors for the development of ILD in the setting of CTD. Diagnostic criteria for CTD are presented as well as elements of the clinical evaluation that increase suspicion for CTD-ILD. We review the use of medications in the treatment of CTD-ILD. Although a large, randomized study has examined the impact of immunosuppressive therapy for ILD secondary to systemic sclerosis, additional studies are needed to determine optimal treatment strategies for each distinct form of CTD-ILD. Finally, we review new information regarding the subgroup of patients with ILD who meet some, but not all, diagnostic criteria for a CTD. A careful and systematic approach to diagnosis in patients with ILD may reveal an unrecognized CTD or evidence of autoimmunity in those previously believed to have idiopathic ILD. PMID- 23460161 TI - A practical algorithmic approach to the diagnosis and management of solitary pulmonary nodules: part 2: pretest probability and algorithm. AB - In this second part of a two-part series, we describe an algorithmic approach to the diagnosis of the solitary pulmonary nodule (SPN). An essential aspect of the evaluation of SPN is determining the pretest probability of malignancy, taking into account the significant medical history and social habits of the individual patient, as well as morphologic characteristics of the nodule. Because pretest probability plays an important role in determining the next step in the evaluation, we describe various methods the physician may use to make this determination. Subsequently, we outline a simple yet comprehensive algorithm for diagnosing a SPN, with distinct pathways for the solid and subsolid SPN. PMID- 23460162 TI - Integrating advanced practice providers into medical critical care teams. AB - Because there is increasing demand for critical care providers in the United States, many medical ICUs for adults have begun to integrate nurse practitioners and physician assistants into their medical teams. Studies suggest that such advanced practice providers (APPs), when appropriately trained in acute care, can be highly effective in helping to deliver high-quality medical critical care and can be important elements of teams with multiple providers, including those with medical house staff. One aspect of building an integrated team is a practice model that features appropriate coding and billing of services by all providers. Therefore, it is important to understand an APP's scope of practice, when they are qualified for reimbursement, and how they may appropriately coordinate coding and billing with other team providers. In particular, understanding when and how to appropriately code for critical care services (Current Procedural Terminology [CPT] code 99291, critical care, evaluation and management of the critically ill or critically injured patient, first 30-74 min; CPT code 99292, critical care, each additional 30 min) and procedures is vital for creating a sustainable program. Because APPs will likely play a growing role in medical critical care units in the future, more studies are needed to compare different practice models and to determine the best way to deploy this talent in specific ICU settings. PMID- 23460163 TI - Critical care in the surgical global period. AB - This article explores the rules and regulations from Current Procedural Terminology (CPT) code set and US Medicare and Medicaid Services (Medicare) regarding multiple physicians reporting critical care services during the global period. The article takes into account the critical care definitions, regulations, documentation requirements, and services each provider can report to Medicare. A clinical scenario based on literature supporting the types of complications and care that might typically be included in the post-operative period for a patient who is surgically treated for a type A aortic dissection was analyzed. It was determined that multiple physicians may provide critical care services to a single patient during the global period. The physician who performed the primary procedure cannot report critical care separately unless documentation supporting use of modifier 25 (significant, separately identifiable services) or 24 (unrelated services) supports that critical care is unrelated to the global period. Other physicians may report critical care services separately if specific criteria are met. To report critical care services to Medicare, the patient's condition must meet the Medicare definition of critical care and the physicians should generally represent different specialties providing different aspects of care to the critically ill or injured patient as defined by Medicare. There should be no overlap in time of services provided by each physician. Each physician's documentation should clearly support medical necessity with the diagnosis demonstrating the critical nature of the patients' illness, the total time spent providing critical care, the critical care service provided, and other contributing factors. PMID- 23460164 TI - Asthma associated with incontinentia pigmenti and Fanconi anemia: variable airflow limitation without cellular bronchitis. AB - Airway inflammation is considered a central component of asthma and, therefore, international guidelines recommend antiinflammatory medications. We describe the clinical history of a 34-year-old woman with airway hyperresponsiveness and asthma who had a reduced ability to mount an inflammatory response due to two unrelated and rare genetic conditions: Fanconi anemia and incontinentia pigmenti. Absence of eosinophils in blood and sputum led to a successful reduction in the dose of corticosteroids without loss of asthma control demonstrating the clinical utility of monitoring treatment using biomarkers and the importance of recognizing the components of airway diseases that contribute to symptoms. PMID- 23460165 TI - Organizing pneumonia as a side effect of ipilimumab treatment of melanoma. AB - Ipilimumab is one of the newly developed human monoclonal antibodies used in the treatment of metastatic melanoma. Its primary mechanism of action is a specific blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a T-cell receptor responsible for inhibition of lymphocyte activation. By blocking CTLA-4, ipilimumab enhances immune responses against tumor cells, but also exposes normal tissues to an increased risk of autoimmune phenomena as a potential side effect. In this report, we describe the case of a 58-year-old woman with metastatic melanoma who was treated with ipilimumab in the weeks prior to the onset of severe nonresolving dyspnea and cough. Extensive workup revealed organizing pneumonia as the cause of her hypoxemic respiratory failure and treatment with steroids led to a resolution of her pulmonary disease. To our knowledge, this is the first report of pulmonary toxicity caused by ipilimumab, which manifested on pathology as organizing pneumonia. PMID- 23460166 TI - A 67-year-old woman with asthma, word finding difficulty, and an abnormal chest radiograph. PMID- 23460167 TI - A 70-year-old woman with acute chest pain and a paracardiac mass. PMID- 23460170 TI - Prognostic scores in pulmonary embolism. PMID- 23460171 TI - Response. PMID- 23460172 TI - Probiotics in critically ill patients: more data are needed. PMID- 23460173 TI - Are asymptomatic DVTs relevant?: one measure for all. PMID- 23460174 TI - Response. PMID- 23460175 TI - Resuscitation status may predict mortality in patients admitted to the ICU. PMID- 23460176 TI - Response. PMID- 23460177 TI - How much hypoxia is significant in pulmonary hypertension during air travel? PMID- 23460178 TI - Response. PMID- 23460179 TI - Chest ultrasonography as a replacement for chest radiography for community acquired pneumonia. PMID- 23460180 TI - Response. PMID- 23460183 TI - Beyond belief. PMID- 23460184 TI - Workplace bullying and sleep difficulties: a 2-year follow-up study. AB - PURPOSE: The aims of the present study were to investigate whether being subjected to bullying and witnessing bullying at the workplace was associated with concurrent sleep difficulties, whether frequently bullied/witnesses have more sleep difficulties than occasionally bullied/witnesses, and whether there were associations between being subjected to bullying or witnessing bullying at the workplace and subsequent sleep difficulties. METHODS: A total of 3,382 respondents (67 % women and 33 % men) completed a baseline questionnaire about their psychosocial work environment and health. The overall response rate was 46 %. At follow-up 2 years later, 1671 of those responded to a second questionnaire (49 % of the 3,382 respondents at baseline). Sleep difficulties were measured in terms of disturbed sleep, awakening problems, and poor quality of sleep. RESULTS: Bullied persons and witnesses reported more sleep difficulties than those who were neither bullied nor witnesses to bullying at baseline. Frequently bullied/witnesses reported more sleep difficulties than respondents who were occasionally bullied or witnessing bullying at baseline. Further, odds ratios for subsequent sleep difficulties were increased among the occasionally bullied, but not among witnesses. However, the associations weakened when adjusting for sleep difficulties at baseline. CONCLUSION: Being subjected to occasional bullying at baseline was predictive of subsequent sleep difficulties. Witnessing bullying at baseline did not predict sleep difficulties at follow-up. PMID- 23460186 TI - Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments. AB - OBJECTIVE: Matrix fragments, including fibronectin (FN) fragments, accumulate during the development of osteoarthritis (OA), stimulating the production of chondrocyte matrix metalloproteinase (MMP). The objective of this study was to determine the role of the small GTPase Rac1 in chondrocyte signaling stimulated by FN fragments, which results in MMP-13 production. METHODS: Normal human cartilage was obtained from tissue donors and OA cartilage from knee arthroplasty specimens. Rac1 activity was modulated with a chemical inhibitor, by knockdown with small interfering RNA (siRNA), or with constitutively active Rac or dominant negative Rac adenovirus. Cells were treated with FN fragments, with or without epidermal growth factor (EGF) or transforming growth factor alpha (TGFalpha), which are known activators of Rac. Rac1 activity was measured with a colorimetric activity enzyme-linked immunosorbent assay, a pulldown assay, and immunostaining with a monoclonal antibody against active Rac. RESULTS: Chemical inhibition of Rac1, as well as knockdown by siRNA and expression of dominant-negative Rac, blocked FN fragment-stimulated MMP-13 production, while expression of constitutively active Rac increased MMP-13 production. Inhibition of Rho associated kinase had no effect. EGF and TGFalpha, but not FN fragments, increased Rac1 activity and promoted the increase in MMP-13 above that achieved by stimulation with FN fragments alone. Active Rac was detected in OA cartilage by immunostaining. CONCLUSION: Rac1 is required for FN fragment-induced signaling that results in increased MMP-13 production. EGF receptor ligands, which activate Rac, can promote this effect. The presence of active Rac in OA cartilage and the ability of Rac to stimulate MMP-13 production suggest that it could play a role in the cartilage matrix destruction seen in OA. PMID- 23460187 TI - Recurarization after sugammadex following a prolonged rocuronium infusion for induced hypothermia. PMID- 23460188 TI - Lower interscalene approach for elbow surgery. PMID- 23460185 TI - mTOR signaling for biological control and cancer. AB - Mammalian target of rapamycin (mTOR) is a major intersection that connects signals from the extracellular milieu to corresponding changes in intracellular processes. When abnormally regulated, the mTOR signaling pathway is implicated in a wide spectrum of cancers, neurological diseases, and proliferative disorders. Therefore, pharmacological agents that restore the regulatory balance of the mTOR pathway could be beneficial for a great number of diseases. This review summarizes current understanding of mTOR signaling and some unanswered questions in the field. We describe the composition of the mTOR complexes, upstream signals that activate mTOR, and physiological processes that mTOR regulates. We also discuss the role of mTOR and its downstream effectors in cancer, obesity and diabetes, and autism. PMID- 23460190 TI - Pharmacological potentials of Syzygium cumini: a review. AB - In the last few years there has been an exponential growth in the field of herbal medicine, and these drugs are gaining popularity in both developing and developed countries because of their natural origin and lesser side effects. Syzygium cumini (syn. Eugenia jambolana, Syzygium jambolana, Eugenia cumini, Syzygium jambos), commonly known as jamun in India, is an evergreen tree distributed throughout the Indian subcontinent, Southeast Asia and East Africa. It is mainly utilised as a fruit producer and for its timber. Medicinally, the fruit is reported to have antidiabetic, antihyperlipidaemic, antioxidant, antiulcer, hepatoprotective, antiallergic, antiarthritic, antimicrobial, anti-inflammatory, antifertility, antipyretic, antiplaque, radioprotective, neuropsychopharmacological, nephroprotective and antidiarrhoeal activities. Among these beneficial physiological effects, the antidiabetic property of S. cumini has the most promising nutraceutical value. The health-beneficial effects of S. cumini are mainly attributed to various phytoconstituents such as tannins, alkaloids, steroids, flavonoids, terpenoids, fatty acids, phenols, minerals, carbohydrates and vitamins present in the fruit. This review paper presents an overview of experimental evidence for the pharmacological potential of S. cumini. PMID- 23460191 TI - Role of second-trimester ultrasound in screening for Down syndrome. PMID- 23460192 TI - Re: Intra- and interobserver agreement when describing adnexal masses using the International Ovarian Tumor Analysis terms and definitions: a study on three dimensional ultrasound volumes. P. Sladkevicius and L. Valentin. Ultrasound Obstet Gynecol 2013; 41: 318-327. PMID- 23460193 TI - Re: Does antenatal ultrasound labeling predict birth order in twin pregnancies? F. D'Antonio, T. Dias and B. Thilaganathan on behalf of the Southwest Thames Obstetric Research Collaborative (STORK). Ultrasound Obstet Gynecol 2013; 41: 274 277. PMID- 23460194 TI - Absent cavum with intact septum pellucidum and corpus callosum may indicate midline brain abnormalities. PMID- 23460195 TI - Reply: To PMID 23460194. PMID- 23460196 TI - ISUOG Practice Guidelines (updated): sonographic screening examination of the fetal heart. PMID- 23460197 TI - Corrective distal radius osteotomy: including bilateral differences in 3-D planning. AB - After a fracture of the distal radius, the bone segments may heal in a suboptimal position. This condition may lead to a reduced hand function, pain and finally osteoarthritis, sometimes requiring corrective surgery. Recent studies report computer-assisted 3-D planning techniques in which the mirrored contralateral unaffected radius serves as reference for planning the position of the distal radius before corrective osteotomy surgery. Bilateral asymmetry, however, may introduce length errors into this type of preoperative planning that can be compensated for by taking into account the concomitant ulnae asymmetry. This article investigates a method for planning a correction osteotomy of the distal radius, while compensating for bilateral length differences using a linear regression model that describes the relationship between radii and ulnae asymmetry. The method is evaluated quantitatively using CT scans of 20 healthy individuals, and qualitatively using CT scans of patients suffering from a malunion of the distal radius. The improved planning method reduces absolute length deviations by a factor of two and markedly reduces positioning variation, from 2.9 +/- 2.1 to 1.5 +/- 0.6 mm. We expect the method to be of great value for future 3-D planning of a corrective distal radius osteotomy. PMID- 23460198 TI - Pathological speech signal analysis and classification using empirical mode decomposition. AB - Automated classification of normal and pathological speech signals can provide an objective and accurate mechanism for pathological speech diagnosis, and is an active area of research. A large part of this research is based on analysis of acoustic measures extracted from sustained vowels. However, sustained vowels do not reflect real-world attributes of voice as effectively as continuous speech, which can take into account important attributes of speech such as rapid voice onset and termination, changes in voice frequency and amplitude, and sudden discontinuities in speech. This paper presents a methodology based on empirical mode decomposition (EMD) for classification of continuous normal and pathological speech signals obtained from a well-known database. EMD is used to decompose randomly chosen portions of speech signals into intrinsic mode functions, which are then analyzed to extract meaningful temporal and spectral features, including true instantaneous features which can capture discriminative information in signals hidden at local time-scales. A total of six features are extracted, and a linear classifier is used with the feature vector to classify continuous speech portions obtained from a database consisting of 51 normal and 161 pathological speakers. A classification accuracy of 95.7 % is obtained, thus demonstrating the effectiveness of the methodology. PMID- 23460199 TI - Biomolecules at interfaces: chiral, naturally. AB - Interfaces are a most important environment in natural and synthetic chemistries for a wide variety of processes, such as catalysis, recognition, separation, and so on. Naturally occurring systems have evolved to one handedness and the study of interfaces where biomolecules are located is a potentially revealing pursuit with regard to understanding the reasons and importance of stereochemistry in these environments. Equally, the spontaneous resolution of achiral and chiral compounds at interfaces could lead to explanations regarding the emergence of single handedness in proteins and sugars. Also, the attachment of biomolecules to surfaces leads to systems capable of stereoselective processes which may be useful for the applications mentioned above. The review covers systems ranging from small biomolecules studied under ultrapure conditions in vacuum to protein adsorption to surfaces in solution, and the techniques that can be used to study them. PMID- 23460201 TI - Oxidation of copper nanoparticles in water: mechanistic insights revealed by oxygen uptake and spectroscopic methods. AB - Oxidation of aqueous ~8 nm unprotected copper nanoparticles takes place under air in approximately 2 hours at 30 degrees C to give Cu(2+) as a final product through an intermediate Cu(+) species. At 5 degrees C the process is about 5 times slower; similarly, vitamin C, which plays a sacrificial role, also slows down the oxidation, while CuNP catalyses the oxidation. In this work, we present a detailed analysis of the oxidation mechanism of colloidal CuNP inferred through spectroscopic methods (UV-visible and EPR) combined with oxygen uptake measurements, with emphasis on factors affecting the oxidative process. PMID- 23460200 TI - Controlling helix formation in the gamma-peptide superfamily: heterogeneous foldamers with urea/amide and urea/carbamate backbones. PMID- 23460202 TI - Understanding the role of the Q338H MUTYH variant in oxidative damage repair. AB - The MUTYH DNA-glycosylase is indirectly engaged in the repair of the miscoding 7,8-dihydro-8-oxo-2'-deoxyguanine (8-oxodG) lesion by removing adenine erroneously incorporated opposite the oxidized purine. Inherited biallelic mutations in the MUTYH gene are responsible for a recessive syndrome, the MUTYH associated polyposis (MAP), which confers an increased risk of colorectal cancer. In this study, we functionally characterized the Q338H variant using recombinant proteins, as well as cell-based assays. This is a common variant among human colorectal cancer genes, which is generally considered, unrelated to the MAP phenotype but recently indicated as a low-penetrance allele. We demonstrate that the Q338H variant retains a wild-type DNA-glycosylase activity in vitro, but it shows a reduced ability to interact with the replication sensor RAD9:RAD1:HUS1 (9 1-1) complex. In comparison with Mutyh(-)(/)(-) mouse embryo fibroblasts expressing a wild-type MUTYH cDNA, the expression of Q338H variant was associated with increased levels of DNA 8-oxodG, hypersensitivity to oxidant and accumulation of the population in the S phase of the cell cycle. Thus, an inefficient interaction of MUTYH with the 9-1-1 complex leads to a repair defective phenotype, indicating that a proper communication between MUTYH enzymatic function and the S phase checkpoint is needed for effective repair of oxidative damage. PMID- 23460204 TI - Exon-phase symmetry and intrinsic structural disorder promote modular evolution in the human genome. AB - A key signature of module exchange in the genome is phase symmetry of exons, suggestive of exon shuffling events that occurred without disrupting translation reading frame. At the protein level, intrinsic structural disorder may be another key element because disordered regions often serve as functional elements that can be effectively integrated into a protein structure. Therefore, we asked whether exon-phase symmetry in the human genome and structural disorder in the human proteome are connected, signalling such evolutionary mechanisms in the assembly of multi-exon genes. We found an elevated level of structural disorder of regions encoded by symmetric exons and a preferred symmetry of exons encoding for mostly disordered regions (>70% predicted disorder). Alternatively spliced symmetric exons tend to correspond to the most disordered regions. The genes of mostly disordered proteins (>70% predicted disorder) tend to be assembled from symmetric exons, which often arise by internal tandem duplications. Preponderance of certain types of short motifs (e.g. SH3-binding motif) and domains (e.g. high mobility group domains) suggests that certain disordered modules have been particularly effective in exon-shuffling events. Our observations suggest that structural disorder has facilitated modular assembly of complex genes in evolution of the human genome. PMID- 23460203 TI - Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance. AB - Although quinolones are the most commonly prescribed antibacterials, their use is threatened by an increasing prevalence of resistance. The most common causes of quinolone resistance are mutations of a specific serine or acidic residue in the A subunit of gyrase or topoisomerase IV. These amino acids are proposed to serve as a critical enzyme-quinolone interaction site by anchoring a water-metal ion bridge that coordinates drug binding. To probe the role of the proposed water metal ion bridge, we characterized wild-type, GrlA(E85K), GrlA(S81F/E85K), GrlA(E85A), GrlA(S81F/E85A) and GrlA(S81F) Bacillus anthracis topoisomerase IV, their sensitivity to quinolones and related drugs and their use of metal ions. Mutations increased the Mg(2+) concentration required to produce maximal quinolone-induced DNA cleavage and restricted the divalent metal ions that could support quinolone activity. Individual mutation of Ser81 or Glu85 partially disrupted bridge function, whereas simultaneous mutation of both residues abrogated protein-quinolone interactions. Results provide functional evidence for the existence of the water-metal ion bridge, confirm that the serine and glutamic acid residues anchor the bridge, demonstrate that the bridge is the primary conduit for interactions between clinically relevant quinolones and topoisomerase IV and provide a likely mechanism for the most common causes of quinolone resistance. PMID- 23460205 TI - Comparison of DNA decatenation by Escherichia coli topoisomerase IV and topoisomerase III: implications for non-equilibrium topology simplification. AB - Type II topoisomerases are essential enzymes that regulate DNA topology through a strand-passage mechanism. Some type II topoisomerases relax supercoils, unknot and decatenate DNA to below thermodynamic equilibrium. Several models of this non equilibrium topology simplification phenomenon have been proposed. The kinetic proofreading (KPR) model postulates that strand passage requires a DNA-bound topoisomerase to collide twice in rapid succession with a second DNA segment, implying a quadratic relationship between DNA collision frequency and relaxation rate. To test this model, we used a single-molecule assay to measure the unlinking rate as a function of DNA collision frequency for Escherichia coli topoisomerase IV (topo IV) that displays efficient non-equilibrium topology simplification activity, and for E. coli topoisomerase III (topo III), a type IA topoisomerase that unlinks and unknots DNA to equilibrium levels. Contrary to the predictions of the KPR model, topo IV and topo III unlinking rates were linearly related to the DNA collision frequency. Furthermore, topo III exhibited decatenation activity comparable with that of topo IV, supporting proposed roles for topo III in DNA segregation. This study enables us to rule out the KPR model for non-equilibrium topology simplification. More generally, we establish an experimental approach to systematically control DNA collision frequency. PMID- 23460206 TI - Canonical correlation analysis for RNA-seq co-expression networks. AB - Digital transcriptome analysis by next-generation sequencing discovers substantial mRNA variants. Variation in gene expression underlies many biological processes and holds a key to unravelling mechanism of common diseases. However, the current methods for construction of co-expression networks using overall gene expression are originally designed for microarray expression data, and they overlook a large number of variations in gene expressions. To use information on exon, genomic positional level and allele-specific expressions, we develop novel component-based methods, single and bivariate canonical correlation analysis, for construction of co-expression networks with RNA-seq data. To evaluate the performance of our methods for co-expression network inference with RNA-seq data, they are applied to lung squamous cell cancer expression data from TCGA database and our bipolar disorder and schizophrenia RNA-seq study. The preliminary results demonstrate that the co-expression networks constructed by canonical correlation analysis and RNA-seq data provide rich genetic and molecular information to gain insight into biological processes and disease mechanism. Our new methods substantially outperform the current statistical methods for co-expression network construction with microarray expression data or RNA-seq data based on overall gene expression levels. PMID- 23460209 TI - Establishing federal laws. PMID- 23460208 TI - Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. AB - Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) systems in bacteria and archaea use RNA-guided nuclease activity to provide adaptive immunity against invading foreign nucleic acids. Here, we report the use of type II bacterial CRISPR-Cas system in Saccharomyces cerevisiae for genome engineering. The CRISPR-Cas components, Cas9 gene and a designer genome targeting CRISPR guide RNA (gRNA), show robust and specific RNA-guided endonuclease activity at targeted endogenous genomic loci in yeast. Using constitutive Cas9 expression and a transient gRNA cassette, we show that targeted double-strand breaks can increase homologous recombination rates of single- and double-stranded oligonucleotide donors by 5-fold and 130-fold, respectively. In addition, co-transformation of a gRNA plasmid and a donor DNA in cells constitutively expressing Cas9 resulted in near 100% donor DNA recombination frequency. Our approach provides foundations for a simple and powerful genome engineering tool for site-specific mutagenesis and allelic replacement in yeast. PMID- 23460207 TI - The Shu complex interacts with Rad51 through the Rad51 paralogues Rad55-Rad57 to mediate error-free recombination. AB - The Saccharomyces cerevisiae Shu complex, consisting of Shu1, Shu2, Csm2 and Psy3, promotes error-free homologous recombination (HR) by an unknown mechanism. Recent structural analysis of two Shu proteins, Csm2 and Psy3, has revealed that these proteins are Rad51 paralogues and mediate DNA binding of this complex. We show in vitro that the Csm2-Psy3 heterodimer preferentially binds synthetic forked DNA or 3'-DNA overhang substrates resembling structures used during HR in vivo. We find that Csm2 interacts with Rad51 and the Rad51 paralogues, the Rad55 Rad57 heterodimer and that the Shu complex functions in the same epistasis group as Rad55-Rad57. Importantly, Csm2's interaction with Rad51 is dependent on Rad55, whereas Csm2's interaction with Rad55 occurs independently of Rad51. Consistent with the Shu complex containing Rad51 paralogues, the methyl methanesulphonate sensitivity of Csm2 is exacerbated at colder temperatures. Furthermore, Csm2 and Psy3 are needed for efficient recruitment of Rad55 to DNA repair foci after DNA damage. Finally, we observe that the Shu complex preferentially promotes Rad51 dependent homologous recombination over Rad51-independent repair. Our data suggest a model in which Csm2-Psy3 recruit the Shu complex to HR substrates, where it interacts with Rad51 through Rad55-Rad57 to stimulate Rad51 filament assembly and stability, promoting error-free repair. PMID- 23460210 TI - Endoscopic view of an "empty nose". PMID- 23460211 TI - Acute laryngitis superimposed on chronic laryngitis. PMID- 23460212 TI - Secondary lymphoma of the parotid gland: clinical experience. PMID- 23460213 TI - Esophageal graft-versus-host disease. PMID- 23460214 TI - Recurrent post-tympanostomy tube otorrhea secondary to aerobic endospore-forming bacilli: a case report and brief literature review. AB - We report a unique case in which a 57-year-old man with an 8-year history of late recurrent post-tympanostomy tube otorrhea (PTTO) was found to harbor Bacillus subtilis, an aerobic endospore-forming bacillus that is typically resistant to chemical and physical agents because of its unique life cycle. Removal of the patient's tympanostomy tube resulted in complete resolution of his long-standing otorrhea. We also review the etiologies of and treatment strategies for early, late, chronic, and recurrent PTTO. We conclude that regardless of the etiology, a patient with persistent or recurrent PTTO should consider undergoing removal of the ventilation tube. PMID- 23460215 TI - A case of calcific retropharyngeal tendinitis: the significance of an early diagnosis. AB - The clinical presentation of calcific retropharyngeal tendinitis, a rare entity, can mimic more serious disorders. We describe the case of a 35-year-old man who was referred to us for evaluation of a suspected retropharyngeal abscess. At presentation, the patient reported severe cervical pain and stiffness. He exhibited mild fever, torticollis, and a moderately elevated white blood count; no swelling of the retropharyngeal wall was observed. Based on the results of plain radiography and computed tomography (CT), we diagnosed the patient with calcific retropharyngeal tendinitis. He was treated with a 7-day course of a nonsteroidal anti-inflammatory drug and a 3-day course of a steroid, and he recovered well. We suggest that the true incidence of calcific retropharyngeal tendinitis is actually higher than what is generally believed because this diagnosis is frequently missed. Contrast-enhanced CT can aid in diagnosing calcific retropharyngeal tendinitis. CT should be performed in patients who present with nonspecific symptoms such as severe neck pain, sore throat, odynophagia, and mild fever. PMID- 23460216 TI - Transoral surgery alone for human-papillomavirus-associated oropharyngeal squamous cell carcinoma. AB - The aim of this retrospective study was to describe the oncologic and functional results of treating oropharyngeal squamous cell carcinoma with transoral robotic surgery and neck dissection as monotherapy. A review was performed, including all patients who underwent transoral robotic surgery and neck dissection as the only means of therapy for oropharyngeal carcinoma from March 2007 to July 2009 at a single tertiary care academic medical center. We reviewed all cases with >=24 month follow-up. Functional outcomes included tracheostomy dependence and oral feeding ability. Oncologic outcomes were stratified by human papillomavirus (HPV) status and tobacco use and included local, regional, and distant disease control, as well as disease-specific and recurrence-free survival. Eighteen patients met study criteria. Ten patients (55.6%) were able to eat orally in the immediate postoperative period, and 8 (44.4%) required a temporary nasogastric tube for a mean duration of 13.6 days (range 3 to 24 days) before returning to an oral diet. No patient required placement of a gastrostomy tube, and all patients are tracheostomy-tube-free. Among the HPV-positive nonsmokers (12/18, 66.7%), Kaplan Meier estimated 3-year local, regional, and distant control rates were 90.9%, 100%, and 100%, respectively. Kaplan-Meier estimated disease-specific survival and recurrence-free survival were 100% and 90.9%, respectively. No complications occurred.This study suggests that carefully selected patients with HPV-positive oropharyngeal carcinoma can be effectively treated with surgery alone with excellent functional and oncologic outcomes. PMID- 23460217 TI - Recurrent Pindborg tumor of the maxilla: a case report and review of the literature. AB - We report a case of recurrent Pindborg tumor (calcifying epithelial odontogenic tumor) of the maxilla. The patient was a 34-year-old woman who had been previously diagnosed with Pindborg tumor and treated with curettage. She was subsequently referred to us for evaluation of nasal obstruction. Examination revealed the presence of a mass lesion in the right nasal cavity and right maxilla, which was identified as a recurrence of her earlier Pindborg tumor. The patient was treated with maxillectomy with orbital preservation. Pindborg tumor is a rare odontogenic tumor; when it does occur, it is more often seen in the mandible than in the maxilla. While this tumor is often treated with curettage alone, the aggressive nature of the recurrence in our patient necessitated radical surgery. We report this case to highlight the need to be suitably aggressive in treating these types of tumors in order to avoid recurrence. PMID- 23460218 TI - Absent stapedial reflex: otosclerosis or middle ear tumor? AB - We present an unusual case in which a patient diagnosed as having otosclerosis on the basis of clinical and audiologic findings actually had a middle ear facial nerve schwannoma. To the best of our knowledge, this is the first reported case in English literature in which a facial nerve schwannoma presented with conductive deafness of gradual onset and absent stapedial reflex with a normally functioning facial nerve. We also include a review of the literature. PMID- 23460219 TI - Idiopathic incus necrosis: Analysis of 4 cases. AB - We evaluated ossicular chain reconstruction in patients with idiopathic incus necrosis who have conductive hearing loss and an intact ear drum. The study included four patients (3 women and 1 man; the ages of the patients were 22, 31, 35, and 56 years, respectively) with unilateral conductive hearing loss, no history of chronic serous otitis media, an intact ear drum, normal middle ear mucosa, and necrosis of the long processes of the incus. On preoperative pure tone audiometry, air-bone gaps were 24, 25, 38, and 33 dB. Bilateral tympanometry and temporal bone computed tomography results were normal. All 4 patients underwent an exploratory tympanotomy. During the operation, the mucosa of the middle ear was normal, with a mobile stapes foot plate and malleus. No evidence of any granulation tissue was found; however, necrosis of the incus long processes was seen. For ossicular reconstruction, we used tragal cartilage between the incus and the stapes in 1 patient; in the other 3 patients, glass ionomer bone cement was used (an interposition cartilage graft also was used in the patients who received the glass ionomer bone cement). In all patients, air bone gaps under 20 dB were established in the first year after surgery. In the ossicular disorders within the middle ear, the incus is the most commonly affected ossicle. While, the most common cause of these disorders is chronic otitis media, it may be idiopathic rarely. Several ossicular reconstruction techniques have been used to repair incudostapedial discontinuity. PMID- 23460220 TI - The missing tracheoesophageal puncture prosthesis: evaluation and management. AB - Placement of a tracheoesophageal puncture prosthesis in the post-laryngectomy patient has significantly improved voice rehabilitation in this population. Rarely, the prosthesis may become dislodged, necessitating medical evaluation. We present the case of a 61-year-old man who presented to our Emergency Department with a missing prosthesis. We describe the evaluation and management of this patient and review the relevant literature. We conclude with the following algorithm: When a patient presents with a missing prosthesis, evaluation of the tracheobronchial tree must be performed. Once the pulmonary system is cleared, the prosthesis can be presumed in the gastrointestinal tract and allowed to pass. A new prosthesis or catheter should be placed in the tract to prevent aspiration. PMID- 23460221 TI - Hepatocellular carcinoma metastatic to the mandible. AB - We describe the case of a 55-year-old man with known multifocal hepatocellular carcinoma (HCC) who presented with a painful mandibular mass. Fine-needle aspiration cytology of the mass revealed the presence of bile canaliculi and bile formation, an extremely rare finding. Findings on immunoperoxidase staining of the aspirate were consistent with an HCC. Since the patient was known to have multiorgan metastatic disease, he was administered palliative radiation therapy to the mandibular metastasis for pain control, which was achieved. One year after presentation, the patient died as a result of disease progression. HCC rarely metastasizes to the mandible, as only about 70 such cases have been reported in the literature. We discuss the histopathologic appearance of HCC metastatic to the mandible, the radiologic findings, and the established treatment modalities. PMID- 23460222 TI - Malignant paraganglioma of the thyroid gland with synchronous bilateral carotid body tumors. AB - We describe a case of primary malignant paraganglioma of the thyroid gland that was found in a 55-year-old woman who had undergone surgery for bilateral carotid body tumors. The paraganglioma was treated with a total thyroidectomy followed by radiation therapy, and the patient was disease-free after more than 2 years of follow-up. Malignant paragangliomas of the thyroid gland are extremely rare. The diagnosis of malignancy is based on histopathologic findings, tumor behavior, and metastasis. These tumors can be misdiagnosed as other types of thyroid malignancies, thus resulting in less than optimal treatment. A genetic etiology was suspected in our patient. PMID- 23460223 TI - Pott puffy tumor in a 5-year-old girl with frontal sinusitis. AB - We describe the case of a 5-year-old girl with a Pott puffy tumor on her forehead. Computed tomography confirmed frontal sinusitis and an epidural abscess. This case is unusual in that the patient's age at presentation was younger than the age when the frontal sinuses are believed to develop. PMID- 23460224 TI - An extruded ossicular prosthesis. PMID- 23460225 TI - Primary papillary carcinoma of the thyroid arising in a branchial cyst: case report and review of the literature. AB - We report a case of papillary carcinoma of the thyroid that arose in a branchial cyst. The patient, a 45-year-old woman, presented with a left lateral neck mass of 3 months' duration. The cyst was removed intact. Because we could not rule out the possibility that a small primary malignancy was present within the gland, we performed a total thyroidectomy; however, no occult primary tumor of the thyroid was found. The patient was placed on thyroid hormone replacement therapy, and she was well at 2 years of follow-up. We briefly review the literature regarding the possible embryologic origin of such a phenomenon and the role of fine-needle aspiration cytology in differentiating a branchial cyst from a metastatic lymph node. To the best of our knowledge, this is only the 11th reported case of a thyroid papillary carcinoma arising in ectopic thyroid tissue within a branchial cyst, and the second such report from India. PMID- 23460226 TI - Central giant cell reparative granuloma of the ethmoids with bilateral proptosis and intracranial extension. AB - Central giant cell reparative granuloma is an infrequent, benign, proliferating lesion affecting the maxilla, mandible and, rarely, cranial bones. A 16-year-old girl presented with a 6-month history of recurrent nasal bleeding, a mass in the nose, difficulty in nasal breathing, a change in voice, and bilateral proptosis. Radiologically, an extensive ethmoidal mass was seen. Histologic examination revealed a central giant cell reparative granuloma. After endoscopic removal, the patient was symptom-free at the 12-month follow-up. The clinical picture of central giant cell reparative granuloma of the ethmoids is discussed, along with the differential diagnosis, histologic evaluation, appearance on computed tomography, and endoscopic management of this lesion. PMID- 23460230 TI - Picture of the month.. Carpal-tarsal osteolysis. PMID- 23460232 TI - Advice for patients. Treating headaches in children and adolescents. PMID- 23460233 TI - Deferiprone (GPO-L-ONE((r)) ) monotherapy reduces iron overload in transfusion dependent thalassemias: 1-year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study (GPO-L-ONE; A001) from Thailand. AB - Accessibility to iron chelators including deferoxamine and deferasirox remains obscured in many developing countries. To provide an alternative, the government pharmaceutical organization of Thailand (GPO) manufactured deferiprone which has similar bioequivalent to the standard product. Seventy-three pediatric patients with severe beta thalassemias, age range 3.2-19 years, were recruited to a 1-year multicenter prospective, single arm, open label, dose escalating Phase III study of deferiprone to determine its clinical efficacy and safety. Sixty-four patients (87.6%) completed the study with good compliance (>94%). Average deferiprone dose was 79.1+/-4.3 mg/kg/day. Overall, mean serum ferritin (SF) levels at 1 year were not significantly changed from baseline. However, 45% of patients (response group) had SF reduced >15% from baseline at 1 year with a median reduction of 1,065 ng ml(-1) . Baseline SF was the major factor that predicts clinical efficacy; patients with baseline SF>3,500 ng ml(-1) had the most significant fall of SF at 1 year. A subgroup analysis by MRI-T2* confirmed that the response group had higher baseline liver iron and deferiprone could significantly reduce liver iron overload and normalize levels of ALT at 1 year. Although, gastrointestinal irritation (20.5%) was the most common drug-related adverse events (AEs) followed by transaminitis (16.4%) and neutropenia (6.8%), all patients were well tolerated. There was no mortality and agranulocytosis found in this trial. Monotherapy of deferiprone with appropriate dose adjustment and monitoring for adverse events appeared to be an effective chelation therapy in some patients with good compliance and acceptable safety profiles. PMID- 23460235 TI - Information overload and missed test results in electronic health record-based settings. PMID- 23460234 TI - Impact of vitamin D fortified milk supplementation on vitamin D status of healthy school children aged 10-14 years. AB - Vitamin D deficiency is a major public health problem, needing immediate attention. We studied the effect of vitamin D fortification of milk in school children. Our results show that fortification of milk is safe and effective strategy to deal with widespread vitamin D deficiency. INTRODUCTION: Vitamin D deficiency among school children and adolescents is a well-documented major public health problem, needing immediate attention. To assess the effect of vitamin D fortified milk on serum 25 hydroxy vitamin D [S.25(OH)D] levels, we carried out a prospective double-blind randomized control trial in apparently healthy school children, aged 10-14 years. METHODS: Of 776 subjects recruited out of 796 who consented, 713 (boys-300; girls-413) completed the study. Subjects were randomized into three groups. Group A (n = 237) received 200 ml of unfortified milk per day while group B (n = 243) and group C (n = 233) received 200 ml of milk fortified with 600 IU (15 MUg) and 1,000 IU (25 MUg) of vitamin D per day for 12 weeks. Serum calcium, phosphate, alkaline phosphatase, S.25(OH)D, and urinary calcium/creatinine ratio were estimated at baseline and after supplementation. RESULTS: Hypovitaminosis D [25(OH)D < 20 ng/ml] was observed in 92.3 % subjects with mean S.25(OH)D level of 11.69 +/- 5.36 ng/ml. There was no significant difference in S.25(OH)D levels among the three groups at baseline. The mean percentage change in S.25(OH)D level in groups B (137.97 %) and C (177.29 %.) were significantly greater than group A (-5.25 %). The percentage of subjects having S.25(OH)D levels >20 ng/ml following supplementation were 5.9 % in group A, 69.95 % in group B, and 81.11 % in group C in comparison to 6.32 %, 4.9 % and 12 %, respectively, at baseline. CONCLUSION: Fortification of milk with vitamin D is an effective and safe strategy in improving S.25(OH)D levels in children aged 10-14 years. PMID- 23460237 TI - Questions on randomised trials by Dionigi and coworkers. PMID- 23460236 TI - Biomechanical comparison of a novel castless arthrodesis plate with T-plate and cross pin techniques for canine partial carpal arthrodesis. AB - OBJECTIVES: To describe a novel canine castless partial carpal arthrodesis plate (par-CA) and its ex vivo biomechanical comparison with T-plate and cross pinning techniques for canine partial carpal arthrodesis. METHODS: The three implant systems were applied to three cohorts of six forelimbs from Greyhounds euthanatized for reasons unrelated to the study. Intercarpal and carpometacarpal palmar fibrocartilage and ligaments were sectioned. Potentiometers were applied between the radial carpal and third metacarpal bones to measure micromotion, and limbs were loaded at 30% of bodyweight at 1 Hertz for 10,000 cycles on a servo hydraulic universal testing machine. Following assessment of micromotion, limbs were loaded to failure at 20 mm/s and ultimate strength, ultimate displacement, and stiffness were measured. RESULTS: The T-plate (p <0.01) and par-CA (p <0.01) had reduced micromotion relative to the cross pin constructs but there was no significant difference between the control, T-plate and par-CA constructs. There was no significant difference in ultimate strength between constructs. Ultimate displacement was reduced in the plated constructs. Stiffness did not differ between constructs. CLINICAL SIGNIFICANCE: The novel par-CA construct was biomechanically similar to the T-plate and both were superior to cross pins in resisting micromotion. There was no difference in load at failure between constructs. The par-CA plate permits radial and ulnar carpal bone compression, a more distal location of the plate to limit impingement, and placement of screws in two metacarpal bones; features which may offer clinical benefits over T-plate fixation. PMID- 23460238 TI - Initial experience with S-shaped electrode for continuous vagal nerve stimulation in thyroid surgery. AB - BACKGROUND: In thyroid surgery, intra-operative neuromonitoring of the recurrent laryngeal nerve (RLN) and vagal nerve (VN) are performed as an adjunct to the gold standard of optical visualisation of the RLN, to avoid injury of the RLN, and subsequently paralysis of the vocal cords. Intermittent RLN neuromonitoring diminished the temporary RLN palsy rate, but continuous neuromonitoring could have to potential of avoiding any damage. Since no study evaluated continuous vagal stimulation before, the objective of this study was to evaluate continuous neuromonitoring in a clinical setting, to assess its' value in predicting vocal cord injury. METHODS: A single centre prospective study was performed from September 2010 till February 2012, including 100 consecutive thyroidectomies with continuous VN stimulation using an S-shaped electrode. RESULTS: In this study, 100 thyroidectomies (80 total thyroidectomies and 20 hemi-thyroidectomies) were analysed. On 180 nerves at risk (NAR), there were four RLN palsies (2.2 %), of which only one definitive. In the cases with temporary palsies, an intra operative diminution of the amplitude occurred, recovering partially with release of traction. Loss of signal was seen in all four cases, with an abrupt loss of signal in the definitive one. The RLN function remained intact in the other 176 NAR. CONCLUSION: Continuous neuromonitoring of the VN is accurate and precise in predicting vocal cord palsy. It is of tremendous importance that the vagal electrode is a-traumatic and gives a stable signal. The exact parameters regarding "warning signs" have yet to be determined, but amplitude changes seem to play a major role. PMID- 23460239 TI - Adenosine, adenosine receptors and their role in glucose homeostasis and lipid metabolism. AB - Adenosine is an endogenous metabolite that is released from all tissues and cells including liver, pancreas, muscle and fat, particularly under stress, intense exercise, or during cell damage. The role of adenosine in glucose homeostasis has been attributed to its ability to regulate, through its membrane receptors, processes such as insulin secretion, glucose release and clearance, glycogenolysis, and glycogenesis. Additionally, adenosine and its multiple receptors have been connected to lipid metabolism by augmenting insulin-mediated inhibition of lipolysis, and the subsequent increase in free fatty acids and glycerol levels. Furthermore, adenosine was reported to control liver cholesterol synthesis, consequently affecting plasma levels of cholesterol and triglycerides, and the amount of fat tissue. Alterations in the balance of glucose and lipid homeostasis have implications in both cardiovascular disease and diabetes. The ability of different adenosine receptors to activate and inhibit the same signaling cascades has made it challenging to study the influence of adenosine, adenosine analogs and their receptors in health and disease. This review focuses on the role and significance of different adenosine receptors in mediating the effect of adenosine on glucose and lipid homeostasis. J. Cell. Physiol. (c) 2013 Wiley Periodicals, Inc. PMID- 23460240 TI - Rheumatoid arthritis in Latin Americans enriched for Amerindian ancestry is associated with loci in chromosomes 1, 12, and 13, and the HLA class II region. AB - OBJECTIVE: To identify susceptibility loci for rheumatoid arthritis (RA) in Latin American individuals with admixed European and Amerindian genetic ancestry. METHODS: Genotyping was performed in 1,475 patients with RA and 1,213 control subjects, using a customized BeadArray containing 196,524 markers covering loci previously associated with various autoimmune diseases. Principal components analysis (EigenSoft package) and Structure software were used to identify outliers and define the population substructure. REAP software was used to define cryptic relatedness and duplicates, and genetic association analyses were conducted using Plink statistical software. RESULTS: A strong genetic association between RA and the major histocompatibility complex region was observed, localized within BTNL2/DRA-DQB1- DQA2 (P = 7.6 * 10(-10) ), with 3 independent effects. We identified an association in the PLCH2-HES5-TNFRSF14-MMEL1 region of chromosome 1 (P = 9.77 * 10(-6) ), which was previously reported in Europeans, Asians, and Native Canadians. We identified one novel putative association in ENOX1 on chromosome 13 (P = 3.24 * 10(-7) ). Previously reported associations were observed in the current study, including PTPN22, SPRED2, STAT4, IRF5, CCL21, and IL2RA, although the significance was relatively moderate. Adjustment for Amerindian ancestry improved the association of a novel locus in chromosome 12 at C12orf30 (NAA25) (P = 3.9 * 10(-6) ). Associations with the HLA region, SPRED2, and PTPN22 improved in individuals positive for anti-cyclic citrullinated peptide antibodies. CONCLUSION: Our data define, for the first time, the contribution of Amerindian ancestry to the genetic architecture of RA in an admixed Latin American population by confirming the role of the HLA region and supporting the association with a locus in chromosome 1. In addition, we provide data for novel putative loci in chromosomes 12 and 13. PMID- 23460241 TI - Carney's triad. PMID- 23460242 TI - Nutrient composition, antioxidant properties, and anti-proliferative activity of Lignosus rhinocerus Cooke sclerotium. AB - BACKGROUND: Lignosus rhinocerus (tiger milk mushroom) is an important medicinal mushroom used in Southeast Asia and China, and its sclerotium can be developed into functional food/nutraceuticals. The nutrient composition, antioxidant properties, and anti-proliferative activity of wild type and a cultivated strain of L. rhinocerus sclerotia were investigated. RESULTS: The sclerotial powder has high carbohydrate but low fat content. Interestingly, the cultivated strain contains higher amounts of protein and water-soluble substances than the wild type. Phenolic content of hot-water, cold-water, and methanol extracts of the sclerotial powders ranged from 19.32 to 29.42 mg gallic acid equivalents g-1 extract, while the ferric reducing antioxidant power values ranged from 0.006 to 0.016 mmol min-1 g-1 extract. The DPPH* , ABTS*+ , and superoxide anion radical scavenging activities of the extracts ranged from 0.52 to 1.12, 0.05 to 0.20, and -0.98 to 11.23 mmol Trolox equivalents g-1 extract, respectively. Both strains exhibited strong superoxide anion radical scavenging activity comparable to rutin. The cold-water extracts exhibited anti-proliferative activity against human breast carcinoma (MCF-7) cells, with IC50 values of 206 ug mL-1 and 90 ug mL-1 for the wild type and cultivated strains, respectively. CONCLUSION: The cultivated L. rhinocerus sclerotium has the potential to be developed into functional food/nutraceuticals. PMID- 23460243 TI - Intraoperative high-dose-rate radiotherapy in the management of locoregionally recurrent head and neck cancer. AB - BACKGROUND: The purpose of this article was to present the Beth Israel Medical Center experience using high-dose-rate intraoperative radiotherapy (HDR-IORT) in the management of recurrent head and neck cancer. METHODS: We conducted a retrospective review of all patients with locally or regionally recurrent head and neck cancer who underwent HDR-IORT at our institution between 2001 and 2010. RESULTS: Seventy-six patients were identified who underwent treatment to a total of 87 sites after gross-total resection. The 2-year estimate of in-field tumor control was found to be 62%. Median overall survival was 19 months with 42% of the patients surviving at least 2 years. Significantly longer survival was found for patients achieving in-field control versus infield progression (33 months vs 17 months, respectively; p = .01). CONCLUSION: HDR-IORT is well tolerated and associated with encouraging in-field disease control. In-field control is associated with improved survival. Further study is warranted to more fully investigate HDR-IORT in the salvage setting. PMID- 23460245 TI - Multiple parallel 2D NMR acquisitions in a single scan. PMID- 23460246 TI - The prognostic impact of age in patients with triple-negative breast cancer. AB - The purpose of this study was to assess the prognostic impact of age in patients with triple-negative breast cancer (TNBC). 1,732 patients with primary TNBC were analyzed. Five age cohorts (<=30, 31-40, 41-50, 51-60, and >60 years) at diagnosis were correlated with clinical/pathological parameters. Univariate and multivariate analyses were used to examine the effect of age on disease-free (DFS), distant disease-free (DDFS), and overall survival (OS). In patients with TNBC, increasing age at diagnosis was inversely correlated with tumor grade (P < 0.0001); likelihood of being non-Caucasian (P = 0.0001); likelihood of getting chemotherapy (P < 0.0001); and positively correlated with DFS (P = 0.0003); DDFS (P < 0.0001); and OS (P < 0.0001). The median DFS for patients 31-40 and older than 60 years was 4 years [95 % confidence interval (95 % CI) 2-5] and 8 years (95 % CI 5-14, respectively, P = 0.0003). The DDFS and OS were also statistically significantly shorter for younger patients. In multivariate analysis, tumor size, nodal stage, tumor grade, and age remained significant independent prognostic variables. Clinical characteristics of TNBC differ by age group, patients <=40 years have poorer survival despite more aggressive systemic therapy. PMID- 23460247 TI - Body size throughout the life course and mammographic density in Mexican women. AB - Mammographic density (MD) is a strong risk factor for breast cancer, but the biological mechanism underlying this association is not clear. Current adult body mass index (BMI) is inversely associated with percent MD; however, few studies have included Hispanic women or evaluated associations with measures of body fatness earlier in life. ESMaestras was established in 2006, when 28,345 women ages >=35 responded to a detailed questionnaire that assessed possible disease risk factors, including body fatness in childhood, adolescence, and young adulthood. In 2007, 2084 ESMaestras participants underwent a clinical examination, which included measurements of weight, height, and sitting height and a mammogram. We measured percent MD using a computer-assisted method. The current analysis includes 972 premenopausal and 559 postmenopausal women. We used multivariable linear regression to evaluate associations between measures of body size and MD, independent of current BMI. Among pre- and postmenopausal women, we observed no significant associations between body fatness during childhood, adolescence, or young adulthood and percent MD. Among postmenopausal women, we observed a modest positive association between body fatness immediately before first pregnancy and between ages 25 and 35 after adjustment for current BMI, with differences of 4.9 and 3.6 % points, respectively, in percent MD between the heaviest and leanest women (p-trend = 0.02). There were no significant associations between height, sitting height, and percent MD among pre- or postmenopausal women in multivariable models adjusting for BMI. In general, we found no clear associations between measures of body size in early life, current sitting height, or current height, and percent MD, after adjusting for current BMI, in this population of Mexican women. Our observation of a positive association between early adult body fatness (i.e., before first pregnancy and ages 25-35) and percent MD among postmenopausal women is inconsistent with prior research and requires confirmation in other studies. PMID- 23460248 TI - Preservation versus non-preservation of the duodenal passage following total gastrectomy: a systematic review. AB - BACKGROUND: Various reconstruction procedures have been proposed for restoring the alimentary tract continuity after total gastrectomy. However, so far there is no consensus on the ideal post-gastrectomy reconstruction procedure. The necessity of preserving the duodenal passage is one of the major focuses of the debate concerning gastrointestinal reconstruction and is the objective of this study. METHODS: A systematic literature search of PubMed, EMBASE, the Cochrane Library, SCI, and Chinese Biomedical Literature Database (CBM) was carried out before March 2012 to obtain studies of randomized controlled trials (RCT). Analysis was performed using RevMan 5.0 software. RESULTS: Nine RCTs involving 642 participants met the selection criteria. The results of the meta-analyses showed that operative mortality and morbidity were not significantly different between the two procedures (preservation vs. non-preservation of duodenum). However, operative time was considerably prolonged by preserving the duodenal passage. Patients in the preservation group had an improved nutritional parameters (body weight, levels of serum iron and hemoglobin) in the short term (<6 months) after surgery. Beneficial effect on preventing postgastrectomy symptom (heartburn, dumping syndrome) was not found by maintaining the duodenal passage throughout a 2-year follow-up. Moreover, a qualitative measurement showed that no significant quality of life improvement for patients with a preserved duodenal passage. CONCLUSION: This systematic review failed to demonstrate obvious advantage in preserving duodenal passage after total gastrectomy. PMID- 23460249 TI - Actigraphic evaluation for patients with attention deficit/hyperactivity disorder. PMID- 23460250 TI - Defect nonunion of a metatarsal bone fracture in a cow: successful management with bone plating and autogenous cancellous bone graft. AB - A two-and-half-year-old cow was presented with a defect nonunion of the right metatarsal III/IV bone following a severely comminuted open fracture two months previously. The animal underwent open fixation using a 4.5 mm, broad, 10-hole, dynamic compression plate and autogenous cancellous bone graft collected from the contralateral iliac shaft. The animal started partial weight bearing after the third postoperative day and resumed complete weight bearing after the 10th day. Fracture healing was complete and the implants were removed after the 120th postoperative day. Stable fixation by means of a bone plate in conjunction with a cancellous bone graft facilitated complete healing and restoration of the bone column of the defect and the metatarsal fracture. The animal made a complete recovery. PMID- 23460251 TI - The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole. AB - The objective of this study is to characterize the outcomes of primary antifungal prophylaxis with voriconazole in patients receiving intensive chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). We conducted a single center, retrospective, cohort study of consecutive adult patients with AML or MDS at Mayo Clinic between January 1, 2006 and July 1, 2010. The study included patients undergoing induction or first relapse combination chemotherapy who received voriconazole 200 mg orally twice daily as prophylaxis during the neutropenic phase. Patient records were evaluated until 30 days after neutrophil recovery for development of invasive fungal infection (IFI) as defined per EORTC/MSG 2008 criteria with computed tomography scans independently reviewed by a radiologist. Therapeutic drug monitoring and reasons for voriconazole discontinuation were documented. Twenty four episodes of IFI were detected among 165 consecutive patients for an overall incidence of 145 per 1000 patients. The incidence of IFI was 24, 42, and 78 per 1000 patients for proven, probable, and possible infection, respectively. Four patients developed proven IFI (n = 2 Aspergillus spp., n = 2 Rhizopus spp.). Serum voriconazole trough concentrations were available in 39 patients, and no statistically significant difference in voriconazole trough level was observed between those with versus without an IFI. Voriconazole prophylaxis was discontinued in 81 patients due to suspected IFI (n = 24), fever of unknown origin (n = 19), adverse events (n = 23), and other causes (n = 17). Voriconazole as primary IFI prophylaxis is safe and may be beneficial in AML/MDS patients receiving intensive chemotherapy. PMID- 23460252 TI - Time to publication among completed clinical trials. PMID- 23460253 TI - Randomized clinical trial of donor-site wound dressings after split-skin grafting. AB - BACKGROUND: The aim was to study which dressing material was best for healing donor-site wounds (DSWs) after split-skin grafting as there is wide variation in existing methods, ranging from classical gauze dressings to modern silicone dressings. METHODS: This 14-centre, six-armed randomized clinical trial (stratified by centre) compared six wound dressing materials in adult patients with DSWs larger than 10 cm(2) . Primary outcomes were time to complete re epithelialization and pain scores measured on a visual analogue scale (VAS) over 4 weeks. Secondary outcomes included itching (VAS, over 4 weeks), adverse events and scarring after 12 weeks rated using the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: Between October 2009 and December 2011, 289 patients were randomized (of whom 288 were analysed) to either alginate (45), film (49), gauze (50), hydrocolloid (49), hydrofibre (47) or silicone (48) dressings. Time to complete re-epithelialization using hydrocolloid dressings was 7 days shorter than when any other dressing was used (median 16 versus 23 days; P < 0.001). Overall pain scores were low, and slightly lower with use of film dressings (P = 0.038). The infection rate among patients treated with gauze was twice as high as in those who had other dressings (18 versus 7.6 per cent; relative risk 2.38, 95 per cent confidence interval 1.14 to 4.99). Patients who had a film dressing were least satisfied with overall scar quality. CONCLUSION: This trial showed that use of hydrocolloid dressings led to the speediest healing of DSWs. Gauze dressing should be discontinued as they caused more infections. REGISTRATION NUMBER: NTR1849 (http://www.trialregister.nl). PMID- 23460254 TI - The potential of DBP gels containing intervertebral disc cells for annulus fibrosus supplementation: in vivo. AB - Demineralized bone particle (DBP), which is widely used as a biomaterial in the field of tissue engineering, contains various bioactive molecules, such as cytokines. For this reason, in this study we investigated the effects of injectable DBP gels on cell proliferation, inflammation and maintenance of the shape of DBP gels as a scaffold able to substitute for intervertebral discs (IVDs) in vivo. DBP gels were fabricated with different percentages (5% and 10%) of DBP powder and 3% acetic acid, including 0.02% pepsin. DBP gels with 1 * 10(6) annulus fibrosus (AF) cells were implanted into the dorsal subcutaneous region of BALB/C-nu mice for 1, 2 and 3 weeks. Cell proliferation was measured by MTT assay. The effect of DBP gels on the inflammatory response was analysed by measuring the amount of tumour necrosis factor-alpha (TNFalpha) released. Also, histological methods were carried out to analyse the response of DBP gels in vivo. This study demonstrated that injectable DBP gels are able to provide physical scaffolds for growing IVD cells in vivo. PMID- 23460255 TI - The contribution of overweight, obesity, and lack of physical activity to exit from paid employment: a meta-analysis. AB - OBJECTIVES: The objective of this review was to analyze systematically the association between overweight, obesity, and lack of physical activity (PA) and exit from paid employment through disability pension, unemployment, and early retirement. We also aimed to identify the influence of study population and study design on the magnitude of this association. METHODS: We searched PubMed and Embase for English language, longitudinal, quantitative studies that described the relationship between overweight, obesity, or lack of PA and exit from work. A short checklist was used to assess the internal and external validity of the studies. We first estimated the pooled effects using a random effects model and then analyzed the influence of study and population characteristics on associations by stratified meta-analyses. RESULTS: In total, 28 out of 1097 publications met the inclusion criteria. Obese [relative risk (RR)=1.53) and, to a lesser extent, overweight (RR=1.16) individuals had an increased likelihood of exit from paid employment through disability pension, but were not at statistically significant increased risk for unemployment or early retirement. Of 17 associations between a lack of PA and disability pension, 8 were statistically significant; this was also the case for 2 of 3 for unemployment. No associations were statistically significant for early retirement. CONCLUSIONS: Obesity is a risk factor for exit from paid employment through disability pension. There are also indications that a lack of PA is related to an increased risk of disability pension and unemployment. To protect workers against premature exit from paid employment, long-term interventions to prevent overweight and obesity and promote PA in the working population should be considered for implementation. PMID- 23460256 TI - Cutting edge of an aggressive surgical approach for perihilar cholangiocarcinoma. PMID- 23460257 TI - Repairing cartilage defects with bone marrow mesenchymal stem cells induced by CDMP and TGF-beta1. AB - The aim of this study was to explore the ability for chondrogenic differentiation of bone marrow mesenchymal stems cells (BMSCs) induced by either cartilage derived morphogenetic protein 1 (CDMP-1) alone or in the presence of transforming growth factor-beta1 (TGF-beta1) in vivo and in vitro. BMSCs and poly-lactic acid/glycolic acid copolymer (PLGA) scaffold were analyzed for chondrogenic capacity induced by CDMP-1 and TGF-beta1 in vivo and in vitro. Chondrogenic differentiation of BMSCs into chondrocytes using a high density pellet culture system was tested, whether they could be maintained in 3-D PLGA scaffold instead of pellet culture remains to be explored. Under the culture of high-density cell suspension and PLGA frame, BMSCs were observed the ability to repair cartilage defects by either CDMP-1 alone or in the presence of TGF-beta1 in vitro. Then the cell-scaffold complex was implanted into animals for 4 and 8 weeks for in vivo test. The content of collagen type II and proteoglycan appeared to increase over time in the constructs of the induced groups (CDMP in the presence of TGF-beta1), CDMP group and TGF group. However, the construct of the control group did not express them during the whole culture time. At 4 and 8 weeks, the collagen type II expression of the induced group was higher than the sum of TGF group and CDMP group by SSPS17.0 analysis. BMSCs and PLGA complex induced by CDMP-1 and TGF- beta1 can repair cartilage defects more effectively than that induced by CDMP-1 or TGF-beta1 only. PMID- 23460258 TI - Noninvasive diagnosis of liver fibrosis and cirrhosis in chronic hepatitis C patients. AB - BACKGROUND: We aimed to derive a simple noninvasive test for liver-fibrosis staging and then estimate its performance against four simple noninvasive tests in chronic hepatitis C (CHC) patients. METHODS: CHC patients were divided into two cohorts: an estimation set (n = 324) and a validation set (n = 524). Liver fibrosis was staged according to the METAVIR scoring system. Statistical analysis was done using stepwise linear discriminant analysis and area under receiver operating characteristic curves (AUCs). RESULTS: Biotechnology Research Center (BRC) score was constructed combining several blood markers that proved useful to stage liver fibrosis. Aspartate aminotransferase /alanine aminotransferase ratio (AAR), aspartate to platelet ratio index (APRI), Fibro-alpha, King, and BRC scores correlated with the histological fibrosis stages with correlation coefficient 0.26, 0.36, 0.58, 0.45, and 0.73, respectively. BRC score produced AUCs 0.87, 0.83, and 0.89 for significant (F2-F4), advanced fibrosis (F3-F4), and cirrhosis (F4), respectively. These results were reproduced in the validation study with no significant difference yielding AUCs 0.85 for F2-F4, 0.82 for F3 F4, and 0.88 for F4. CONCLUSION: BRC score, a novel noninvasive test, is a useful and easy tool to evaluate liver fibrosis in CHC patients and seems more efficient than AAR, APRI, Fibro-alpha score, and King's score in this group of Egyptian patients. PMID- 23460259 TI - GRK2 negatively regulates IGF-1R signaling pathway and cyclins' expression in HepG2 cells. AB - G protein coupled receptor kinase 2 (GRK2) plays a central role in the regulation of a variety of important signaling pathways. Alternation of GRK2 protein level and activity casts profound effects on cell physiological functions and causes diseases such as heart failure, rheumatoid arthritis, and obesity. We have previously reported that overexpression of GRK2 has an inhibitory role in cancer cell growth. To further examine the role of GRK2 in cancer, in this study, we investigated the effects of reduced protein level of GRK2 on insulin-like growth factor 1 receptor (IGF-1R) signaling pathway in human hepatocellular carcinoma (HCC) HepG2 cells. We created a GRK2 knockdown cell line using a lentiviral vector mediated expression of GRK2 specific short hairpin RNA (shRNA). Under IGF 1 stimulation, HepG2 cells with reduced level of GRK2 showed elevated total IGF 1R protein expression as well as tyrosine phosphorylation of receptor. In addition, HepG2 cells with reduced level of GRK2 also demonstrated increased tyrosine phosphorylation of IRS1 at the residue 612 and increased phosphorylation of Akt, indicating a stronger activation of IGF-1R signaling pathway. However, HepG2 cells with reduced level of GRK2 did not display any growth advantage in culture as compared with the scramble control cells. We further detected that reduced level of GRK2 induced a small cell cycle arrest at G2/M phase by enhancing the expression of cyclin A, B1, and E. Our results indicate that GRK2 has contrasting roles on HepG2 cell growth by negatively regulating the IGF-1R signaling pathway and cyclins' expression. PMID- 23460260 TI - Transcanal approach for implantation of a cochlear nerve electrode array. AB - OBJECTIVES/HYPOTHESIS: To evaluate a transcanal approach for placement of a stimulating electrode array in the cochlear nerve. STUDY DESIGN: Prospective cadaveric temporal bone study. METHODS: Ten human cadaveric temporal bones were dissected. Both a facial recess approach with mastoidectomy and a transcanal approach using the novel technique were performed in each bone. A middle fossa dissection of the internal auditory canal was performed to confirm the position of the electrode in the cochlear nerve. RESULTS: The transcanal approach offered a direct approach to the cochlear nerve in all 10 bones. The procedure was quicker than the facial recess approach and did not endanger the facial or chorda tympani nerves. Inspection of the medial end of the internal auditory canal confirmed correct placement of the electrode in the cochlear nerve. In contrast, anatomical constraints, specifically the position of the facial nerve, blocked access to the cochlear nerve by the facial recess approach in three of the specimens to achieve the exposure to place the electrode at a perpendicular angle to the cochlear nerve. Sacrifice of the chorda tympani was necessary in five of the seven bones in which the cochlear nerve could be accessed. CONCLUSIONS: The transcanal approach offers a simpler, safer approach for cochlear nerve implantation compared to the facial recess approach. This approach can be accomplished in less time and avoids the hazards of dissection around the facial nerve. Use of the proposed approach will facilitate development of intraneural stimulation for an improved auditory prosthesis. PMID- 23460261 TI - Hydrogen-bond-directed enantioselective decarboxylative Mannich reaction of beta ketoacids with ketimines: application to the synthesis of anti-HIV drug DPC 083. PMID- 23460262 TI - The intra-gastric balloon for pre-operative weight loss in bariatric surgery: is it worthwhile? AB - BACKGROUND: Super-obese patients in NHS Lothian during 2009-2010 were offered the intragastric balloon to assist with weight loss prior to definitive bariatric surgery along with participation in a structured weight management programme. Those who declined balloon placement continued to receive weight management alone (WM). The aim of this study was to compare the effectiveness of the structured weight management programme with and without the addition of the intragastric balloon. METHODS: Patients referred to the NHS Lothian Bariatric Service in 2009 with BMI > 55 kg/m(2) or weight > 200 kg and assessed as otherwise eligible for bariatric surgery were offered structured weight management with or without placement of an intragastric balloon with the aim of achieving a target of 10 % excess weight loss (EWL) over 6 months. RESULTS: Twenty-eight patients were recruited. Fifteen opted for balloon placement and 13 declined. Three patients in the balloon group required early balloon removal due to intolerance and three dropped out of the WM group through non-attendance. Of those remaining, two in the balloon group and three in the WM group failed to achieve the 10 % EWL target. Overall, median %EWL was 17.1 % for the balloon group and 16.1 % for the WM group (p = 0.295, Mann-Witney U-test). CONCLUSIONS: The additional use of intragastric balloon conferred no benefit over structured weight management alone in achieving pre-operative weight loss in a super-obese patient population. In the context of limited resources within NHS Lothian, the continued use of intragastric balloon in this way cannot be justified. PMID- 23460263 TI - Sleeve gastrectomy and gastro-oesophageal reflux disease: a complex relationship. AB - Sleeve gastrectomy is rapidly becoming popular as a standalone bariatric operation. At the same time, there are valid concerns regarding its long-term durability and postoperative gastro-oesophageal reflux disease. Though gastric bypass remains the gold standard bariatric operation, it is not suitable for all patients. Sleeve gastrectomy is sometimes the only viable option. Patients with inflammatory bowel disease, liver cirrhosis, significant intra-abdominal adhesions involving small bowel and those reluctant to undergo gastric bypass could fall in this category. It is widely recognised that some patients report worsening of their gastro-oesophageal reflux disease after sleeve gastrectomy. Still, others develop de novo reflux. This review examines if it is possible to identify these patients prior to surgery and thus prevent postoperative gastro oesophageal reflux disease after sleeve gastrectomy. PMID- 23460264 TI - Single-stage operative management of laparoscopic sleeve gastrectomy leaks without endoscopic stent placement. AB - BACKGROUND: Leaks occur in 1.4-20 % (Bohdjalian et al., Obes. Surg. 20:535-540, 2010; Nocca et al., Obes Surg. 18:560-565, 2008; Stroh et al., 19:632-640, 2009; Aurora et al., Surg. Endosc. 26:1509-1515, 2012) of patients following laparoscopic sleeve gastrectomy (LSG). Leaks may lead to major morbidity and prolonged hospitalization. Endoscopic stent placement is a potential management strategy that needs expertise and also has recognized complications (stent migration, significant dysphagia, and failure) (Rosenthal et al., Surg. Obes Relat. Dis. 8:8-19, 2012). A standard method of managing leaks following LSG has not been established. This study aims to evaluate the outcomes of consecutive patients with leaks following LSG managed at BMI Abu Dhabi Tertiary Multidisciplinary Bariatric Surgery, Abu Dhabi, UAE. METHODS: We examined all patients presenting to BMI Abu Dhabi between February 2010 and May 2012 with leaks following LSG. Data were obtained from the hospital medical record, and IRB approval was obtained. All patients were managed by utilizing a standardized operative management strategy without the use of endoscopic stenting. RESULTS: A total of five patients were referred to us for higher level of care; during the same time period, we performed 71 LSGs without a leak. Patients were optimized and resuscitated adequately before surgery. Intraoperatively, all patients had endoscopy, and a T tube was placed inside the leak if clearly identifiable. Otherwise, the leak site was drained adequately without attempting to place sutures, and a jejunostomy tube was inserted. All leaks healed following an initial period of hospital stay, followed by an outpatient period on jejunostomy tube feeding and nil per os. CONCLUSION: Single-stage operative management of leaks after LSG utilizing a standardized operative strategy without the use of endoscopic stenting is both safe and effective. PMID- 23460265 TI - In vivo binding of the dopamine-1 receptor PET tracers [11C]NNC112 and [11C]SCH23390: a comparison study in individuals with schizophrenia. AB - RATIONALE: A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction observed in patients with schizophrenia. However, the results from positron emission tomography imaging studies of D1 receptor levels in individuals with schizophrenia are mixed. OBJECTIVES: The aim of this investigation was to determine whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [(11)C]SCH23390 and [(11)C]NNC112, may have contributed to these discrepancies reported in the literature. METHODS: Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [(11)C]SCH23390 and [(11)C]NNC112. RESULTS: [(11)C]SCH23390 and [(11)C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were observed. CONCLUSIONS: The results of this study suggest that differences in the binding of [(11)C]SCH23390 and [(11)C]NNC112 observed in previous studies are not due to differences in the in vivo behavior of these tracers. PMID- 23460268 TI - Differential nuclear organization of translocation-prone genes in nonmalignant B cells from patients with t(14;16) as compared with t(4;14) or t(11;14) myeloma. AB - Gene organization in nonmalignant B cells from t(4;14) and t(11;14) multiple myeloma (MM) patients differs from that of healthy donors. Among recurrent IGH translocations in MM, the frequency of t(4;14) (IGH and FGFR3) or t(11;14) (IGH and CCND1) is greater than the frequency of t(14;16) (IGH and MAF). Gene organization in t(14;16) patients may influence translocation potential of MAF with IGH. In patients, three-dimensional FISH revealed the positions of IGH, CCND1, FGFR3, and MAF in nonmalignant B cells that are likely similar to those when MM first arose, compared with B cells from healthy donors. Overall, IGH occupies a more central nuclear position while MAF is more peripherally located. However, for B cells from t(4;14) and t(11;14) patients, IGH and FGFR3, or IGH and CCND1 are found in spatial proximity: IGH and MAF are not. This differs in B cells from t(14;16) patients and healthy donors where IGH is approximately equidistant to FGFR3, CCND1, and MAF, suggesting that gene organization in t(14;16) patients is different from that in t(4;14) or t(11;14) patients. Translocations between IGH and MAF may arise only in the absence of close proximity to the more frequent partners, as appears to be the case for individuals who develop t(14;16) MM. PMID- 23460266 TI - A double blind, placebo-controlled study of the effects of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity in cocaine dependent humans. AB - RATIONALE/OBJECTIVES: This study examined the effects of propranolol vs. placebo, administered immediately after a "retrieval" session of cocaine cue exposure (CCE), on craving and physiological responses occurring 24 h later during a subsequent "test" session of CCE. It was hypothesized that compared to placebo treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up. METHODS: CD participants received either 40 mg propranolol or placebo immediately following a "retrieval" CCE session. The next day, participants received a "test" session of CCE that was identical to the "retrieval" session except no medication was administered. Participants underwent a "follow-up" CCE session 1 week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions. RESULTS: Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use. CONCLUSIONS: This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered, and implications of the results for treatment were noted. PMID- 23460269 TI - Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice. AB - Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, Toll-like receptor (TLR)4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and nonimmune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically, parenchymal hepatocytes (HCs), myeloid cells, including Kupffer cells, and dendritic cells (DCs) subsequent to hepatic I/R. When HC-specific (Alb-TLR4(-/-) ) and myeloid-cell-specific (Lyz-TLR4(-/-) ) TLR4 knockout (KO) mice were subjected to warm hepatic ischemia, there was significant protection in these mice, compared to wild type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 KO (TLR4(-/-) ) mice. DC-specific TLR4(-/-) (CD11c-TLR4(-/-) ) mice had significantly increased hepatocellular damage, compared to WT mice. Circulating levels of high-mobility group box 1 (HMGB1) were significantly reduced in Alb TLR4(-/-) mice, compared to WT, Lyz-TLR4(-/-) , CD11c-TLR4(-/-) mice and equivalent to global TLR4(-/-) mice, suggesting that TLR4-mediated HMGB1 release from HCs may be a source of HMGB1 after I/R. HCs exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases, c-Jun-N-terminal kinase (JNK) and p38, in a TLR4-dependent manner; inhibition of JNK decreased release of HMGB1 after both hypoxia in vitro and I/R in vivo. CONCLUSION: These results provide insight into the individual cellular response of TLR4. The parenchymal HC is an active participant in sterile inflammatory response after I/R through TLR4-mediated activation of proinflammatory signaling and release of danger signals, such as HMGB1. PMID- 23460270 TI - Multiple recurrent extra-medullary relapses of high-grade diffuse large B-cell lymphoma presenting in acute leukemic phase. PMID- 23460271 TI - Charles Bonnet syndrome in cranio-maxillofacial surgery: case report. AB - BACKGROUND: Complex visual hallucinations in the presence of a clear mental state and in the absence of underlying neurological disorders have received increased recognition since Charles Bonnet reported visual hallucinations secondary to mature cataracts in 1760. The prevalence of Charles Bonnet syndrome (CBS) varies widely in the literature and might be underestimated in most settings. The current paper presents a case of acute-onset CBS due to a unilateral Frost suture after revision of an orbit floor fracture. CASE REPORT: A 68-year-old male patient underwent an operation to repair a unilateral orbital floor fracture and subsequent eye patching by a Frost suture. The patient complained of complex, colored visual hallucinations ~3 h after waking from general anesthesia. The visual hallucinations stopped during sleep and reappeared in the morning. The symptoms disappeared completely ~2 h after removal of the Frost suture. DISCUSSION: Frost sutures are commonly used in oculoplastic surgery and may result in acute onset of visual hallucinations. CBS is often neglected, and clinicians must be aware of the association between acute visual deprivation and CBS. PMID- 23460272 TI - Multiple and differentiated contributions to the male gene pool of pastoral and farmer populations of the African Sahel. AB - The African Sahel is conducive to studies of divergence/admixture genetic events as a result of its population history being so closely related with past climatic changes. Today, it is a place of the co-existence of two differing food-producing subsistence systems, i.e., that of sedentary farmers and nomadic pastoralists, whose populations have likely been formed from several dispersed indigenous hunter-gatherer groups. Using new methodology, we show here that the male gene pool of the extant populations of the African Sahel harbors signatures of multiple and differentiated contributions from different genetic sources. We also show that even if the Fulani pastoralists and their neighboring farmers share high frequencies of four Y chromosome subhaplogroups of E, they have drawn on molecularly differentiated subgroups at different times. These findings, based on combinations of SNP and STR polymorphisms, add to our previous knowledge and highlight the role of differences in the demographic history and displacements of the Sahelian populations as a major factor in the segregation of the Y chromosome lineages in Africa. Interestingly, within the Fulani pastoralist population as a whole, a differentiation of the groups from Niger is characterized by their high presence of R1b-M343 and E1b1b1-M35. Moreover, the R1b-M343 is represented in our dataset exclusively in the Fulani group and our analyses infer a north-to-south African migration route during a recent past. PMID- 23460273 TI - Abstracts of the 18th Congress of the Spanish Society for Surgical Investigations. Leon, Spain. October 2012. PMID- 23460274 TI - Bilateral calcaneal epiphysiolysis in a dog. AB - A case of bilateral calcaneal epiphysiolysis in a six-month-old female Dobermann Pinscher is described in this report. The absence of a traumatic event and the clinical, radiographic and histopathological abnormalities led us to the diagnosis of simultaneous bilateral epiphysiolysis of the calcaneus. A tension band and a type II transarticular external fixator were placed. The clinical signs were resolved only temporarily because of the gravity of the bone changes. PMID- 23460275 TI - The use of human amniotic fluid mesenchymal stem cells as the feeder layer to establish human embryonic stem cell lines. AB - Human embryonic stem cells (hESCs) are pluripotent cells that have the potential to differentiate into the three germ layers and possibly all tissues of the human body. To fulfil the clinical potentials for cell-based therapy, banks of hESC lines that express different combinations of the major histocompatibility genes should be established, preferably without exposing such cells to animal cells and proteins. In this study, we tested human amniotic fluid mesenchymal stem cells (AFMSCs) as feeder cells to support the growth of hESCs. Our results indicated that mitomycin-treated AFMSCs were able to support the newly established hESC lines CGLK-1 and CGLK-2. The hESC colonies cultured on AFMSCs expressed alkaline phosphatase (ALK-P), SSEA-4, TRA-1-60, TRA-1-81, Oct-4, Nanog and Sox-2, which are markers for undifferentiated hESCs. Chromosomal analyses of both hESC lines, CGLK-1 and CGLK-2, which were cultured on AFMSC feeders for 22 and 14 passages, respectively, were confirmed to be normal karyotypes (46, XX). The ability of AFMSCs as feeder cells to maintain the undifferentiated growth and pluripotency of hESCs was confirmed by in vivo formation of teratomas derived on AFMSC hESCs in severe combined immune-compromised mice. The use of AFMSCs for feeder cells to culture hESCs has several advantages, in that AFMSCs are not tumourigenic and can be expanded extensively with a short doubling time. PMID- 23460276 TI - Vascular endothelial growth factor-A and aldosterone: relevance to normal pregnancy and preeclampsia. AB - Aldosterone levels are markedly elevated during normal pregnancy but fall even though volume contracts when preeclampsia occurs. The level of aldosterone in either condition cannot be explained solely by the activity of the renin angiotensin II system. In normal gestation, vascular endothelial growth factor (VEGF) is thought to maintain vascular health, but its role in adrenal hormone production is unknown. We hypothesized that the role of VEGF in the adrenal gland is to maintain vascular health and regulate aldosterone production. Here, we demonstrate that supernatant of endothelial cells grown in the presence of VEGF enhanced aldosterone synthase activity in human adrenocortical cells. VEGF either alone or combined with angiotensin II increased aldosterone production in adrenal cells. These data suggest that endothelial cell-dependent and independent activation of aldosterone is regulated by VEGF. In contrast to angiotensin II, VEGF did not upregulate the steroidogenic acute regulatory protein. Consistent with this observation, angiotensin II stimulated both aldosterone and cortisol synthesis from progesterone, whereas VEGF stimulated selectively aldosterone production. In rats, overexpression of soluble fms-like tyrosine kinase-1, an endogenous VEGF inhibitor, led to adrenocortical capillary rarefaction and fall in aldosterone concentrations that correlated inversely with soluble fms-like tyrosine kinase-1 levels. These findings may explain why aldosterone increases so markedly during normal gestation and why preeclampsia, a condition characterized by high soluble fms-like tyrosine kinase-1, is associated with inappropriately low aldosterone levels in spite of relatively lower plasma volumes. PMID- 23460277 TI - What are the key arguments against uric acid as a true risk factor for hypertension? PMID- 23460278 TI - Redefining preeclampsia using placenta-derived biomarkers. PMID- 23460279 TI - Aldosterone, vascular endothelial growth factor, and preeclampsia: a mystery solved? PMID- 23460280 TI - Endothelial lipase modulates pressure overload-induced heart failure through alternative pathway for fatty acid uptake. AB - Lipoprotein lipase has been considered as the only enzyme capable of generating lipid-derived fatty acids for cardiac energy. Endothelial lipase is another member of the triglyceride lipase family and hydrolyzes high-density lipoproteins. Although endothelial lipase is expressed in the heart, its function remains unclear. We assessed the role of endothelial lipase in the genesis of heart failure. Pressure overload-induced cardiac hypertrophy was generated in endothelial lipase(-/-) and wild-type mice by ascending aortic banding. Endothelial lipase expression in cardiac tissues was markedly elevated in the early phase of cardiac hypertrophy in wild-type mice, whereas lipoprotein lipase expression was significantly reduced. Endothelial lipase(-/-) mice showed more severe systolic dysfunction with left-ventricular dilatation compared with wild type mice in response to pressure overload. The expression of mitochondrial fatty acid oxidation-related genes, such as carnitine palmitoyltransferase-1 and medium chain acyl coenzyme A dehydrogenase, was significantly lower in the heart of endothelial lipase(-/-) mice than in wild-type mice. Also, endothelial lipase(-/ ) mice had lower myocardial adenosine triphosphate levels than wild-type mice after aortic banding. In cultured cardiomyocytes, endothelial lipase was upregulated by inflammatory stimuli, whereas lipoprotein lipase was downregulated. Endothelial lipase-overexpression in cardiomyocytes resulted in an upregulation of fatty acid oxidation-related enzymes and intracellular adenosine triphosphate accumulation in the presence of high-density lipoprotein. Endothelial lipase may act as an alternative candidate to provide fatty acids to the heart and regulate cardiac function. This effect seemed relevant particularly in the diseased heart, where lipoprotein lipase action is downregulated. PMID- 23460281 TI - Roles of sex steroid hormones and nitric oxide in the regulation of sympathetic nerve activity in women. PMID- 23460282 TI - HYVET ambulatory blood pressure substudy. PMID- 23460283 TI - Nebivolol induces distinct changes in profibrosis microRNA expression compared with atenolol, in salt-sensitive hypertensive rats. AB - Nebivolol is a selective beta1-blocker with nitric oxide-enhancing effects. MicroRNAs are small noncoding RNA molecules that downregulate gene expression. We compared the effects of nebivolol and atenolol, a first generation beta1 selective blocker, on left ventricular hypertrophy, fibrosis, and function and microRNA expression in a rodent model of hypertension. Dahl salt-sensitive rats received either low-salt chow (control) or AIN-76A high-salt (8% NaCl) diet and randomized to vehicle (high-salt), nebivolol (20 mg/kg per day), or atenolol (50 mg/kg per day) for 8 weeks. High-salt induced left ventricular hypertrophy and fibrosis and decreased the expression of miR-27a, -29a, and -133a. Nebovolol attenuated deterioration of left ventricular systolic function, remodeling, and fibrosis more than atenolol, despite similar effects on heart rate and blood pressure. Nebivolol, but not atenolol, prevented the decrease in miR-27a and -29a induced by high-salt. Nebivolol and atenolol equally attenuated the decrease in miR-133a. In vitro overexpression of miR-27a,-29a, and -133a inhibited cardiomyocyte hypertrophy and reduced collagen expression. Both miR-27a and -29a target Sp1, and miR-133a targets Cdc42. Pharmacological inhibition of Sp1 and Cdc42 decreased myocardial fibrosis and hypertrophy. Our data support a differential microRNAs expression profile in salt-induced hypertension. Nebivolol substantially attenuated cardiac remodeling, hypertrophy, and fibrosis more than atenolol. These effects are related to attenuation of the hypertension-induced decrease in miR-27a and -29a (with a subsequent decrease in Sp1 expression) and miR-133a (with a subsequent decrease in Cdc42). PMID- 23460284 TI - High intake of dietary long-chain omega-3 fatty acids is associated with lower blood pressure in children born with low birth weight: NHANES 2003-2008. AB - Reduced fetal growth is associated with increased systolic blood pressure. Recently, we found an inverse association between serum omega-3 fatty acids and systolic blood pressure in young adults born with impaired fetal growth. We investigated the associations of dietary intake in childhood of the long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid with blood pressure parameters in children born with reduced birth weight. We analyzed data from 3457 children aged 8 to 15 years participating in the continuous National Health and Nutrition Examination Survey 2003-2004, 2005-2006, and 2007-2008. Dietary intake was assessed by two 24-hour dietary recalls, birth weight by questionnaire, and blood pressure was measured. Systolic blood pressure was 1.1 mm Hg higher in those with reduced (<10th centile) compared with normal birth weight (>= 10th centile), consistent with previous findings, although not statistically significant (P=0.40); however, pulse pressure was significantly higher in these children (3.4 mm Hg). In the 354 participants with reduced birth weight, when compared with children with the lowest tertile of intake, those who had the highest tertile of dietary eicosapentaenoic acid and docosahexaenoic acid intake had significantly lower systolic blood pressure (-4.9 mm Hg [95% confidence interval, -9.7 to -0.1]) and pulse pressure (-7.7 mm Hg [95% confidence interval, -15.0 to -0.4]). High-dietary intakes of eicosapentaenoic acid and docosahexaenoic acid are associated with lower systolic blood pressure and pulse pressure in children born with reduced birth weight. These data are consistent with the hypothesis that long-chain omega-3 fatty acids reduce blood pressure in those with impaired fetal growth. PMID- 23460285 TI - Epithelial sodium channel stiffens the vascular endothelium in vitro and in Liddle mice. AB - Liddle syndrome, an inherited form of hypertension, is caused by gain-of-function mutations in the epithelial Na(+) channel (ENaC), the principal mediator of Na(+) reabsorption in the kidney. Accordingly, the disease pathology was ascribed to a primary renal mechanism. Whether this is the sole responsible mechanism, however, remains uncertain as dysregulation of ENaC in other tissues may also be involved. Previous work indicates that ENaC in the vascular endothelium is crucial for the regulation of cellular mechanics and thus vascular function. The hormone aldosterone has been shown to concomitantly increase ENaC surface expression and stiffness of the cell cortex in vascular endothelial cells. The latter entails a reduced release of the vasodilator nitric oxide, which eventually leads to an increase in vascular tone and blood pressure. Using atomic force microscopy, we have found a direct correlation between ENaC surface expression and the formation of cortical stiffness in endothelial cells. Stable knockdown of alphaENaC in endothelial cells evoked a reduced channel surface density and a lower cortical stiffness compared with the mock control. In turn, an increased alphaENaC expression induced an elevated cortical stiffness. More importantly, using ex vivo preparations from a mouse model for Liddle syndrome, we show that this disorder evokes enhanced ENaC expression and increased cortical stiffness in vascular endothelial cells in situ. We conclude that ENaC in the vascular endothelium determines cellular mechanics and hence might participate in the control of vascular function. PMID- 23460286 TI - How high-density lipoprotein fuels the failing heart. PMID- 23460287 TI - Circulating angiogenic factors and urinary prolactin as predictors of adverse outcomes in women with preeclampsia. AB - Preeclampsia is characterized by an imbalance in angiogenic factors. Urinary prolactin (PRL) levels and its antiangiogenic PRL fragments have been associated with disease severity. In this study, we assessed whether these biomarkers are associated with an increased risk of adverse maternal and perinatal outcomes in preeclamptic women. We studied 501 women with preeclampsia attended at a tertiary care hospital. Serum concentrations of soluble fms-like tyrosine kinase-1 (sFlt 1), placental growth factor (PlGF), and soluble endoglin (sEng), as well as urinary PRL levels, were measured by enzymed-linked immunosorbent assay. Antiangiogenic PRL fragments were determined by immunoblotting. The risk for any adverse maternal outcome and for having a small-for-gestational-age infant was higher among women with sFlt-1/PlGF ratios, sEng, and urinary PRL level values in the highest quartile (odds ratios >= 2.7), compared with the lowest quartile. Both urinary PRL levels and the presence of antiangiogenic PRL fragments were more closely associated with the risk of specific adverse maternal outcomes (placental abruption, hepatic hematoma or rupture, acute renal failure, pulmonary edema, maternal death, and need for endotracheal intubation, positive inotropic drug support, and hemodialysis; odds ratios >= 5.7 and >= 4.7, respectively) than either sFlt-1/PlGF ratio or sEng alone. We concluded that in preeclamptic women at the time of initial evaluation, sFlt-1/PlGF ratio and sEng are associated with increased risk of combined adverse maternal outcomes. However, urinary PRL concentrations and its antiangiogenic fragments appear to be better predictors of an adverse maternal outcome and may be useful for risk stratification in preeclampsia. PMID- 23460288 TI - New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin. AB - Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren like IC50 and t1/2, and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher renin immunoreactivity levels, confirming the presence of prorenin. Unexpectedly, this approach did not work in VTP-27999-treated subjects, although an assay detecting the prosegment revealed that their blood still contained prorenin. Subsequent in vitro analysis showed that VTP-27999 increased renin immunoreactivity for a given amount of renin by >= 30% but did not unfold prorenin. Yet, it did bind to acid activated, intact prorenin and then again increased immunoreactivity in a renin assay. However, no such increase in immunoreactivity was seen when measuring acid activated prorenin bound to VTP-27999 with a prosegment-directed assay. The VTP 27999-induced rises in renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP 27999 increases renin immunoreactivity in renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on prorenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established. PMID- 23460289 TI - Quality of life after renal denervation. PMID- 23460291 TI - The amiloride-sensitive endothelial sodium channel and vascular tone. PMID- 23460290 TI - Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension. AB - Preeclampsia is a pregnancy-specific condition characterized by an imbalance of circulating angiogenic factors and new-onset hypertension. Although current treatment options are limited, recent studies suggest that pravastatin may improve angiogenic profile and reduce blood pressure in preeclampsia. We hypothesized pravastatin would restore angiogenic balance and reduce mean arterial pressure (MAP) in rats with reduced utero-placental perfusion pressure (RUPP)-induced hypertension. Pravastatin was administered intraperitoneally (1 mg/kg per day) in RUPP (RUPP+P) and normal pregnant rats (NP+P) from day 14 to 19 of pregnancy. On day 19, MAP was measured via catheter, conceptus data were recorded, and tissues collected. MAP was increased (P<0.05) in RUPP compared with NP dams, and pravastatin ameliorated this difference. Pravastatin attenuated decreased fetal weight and plasma vascular endothelial growth factor and the RUPP induced increased soluble fms-like tyrosine kinase-1 when compared with NP dams. Pravastatin treatment did not improve angiogenic potential in RUPP serum and decreased (P<0.05) endothelial tube formation in NP rats. RUPP rats presented with indices of oxidative stress, such as increased placental catalase activity and plasma thiobarbituric acid reactive substances along with decreased plasma total antioxidant capacity compared with NP controls, and pravastatin attenuated these effects. MAP, fetal weight, plasma vascular endothelial growth factor, and plasma soluble fms-like tyrosine kinase-1 were unchanged in NP+P compared with NP controls. The present data indicate that treatment with pravastatin attenuates oxidative stress and lowers MAP in placental ischemia-induced hypertension, but may have negative effects on circulating angiogenic potential during pregnancy. Further studies are needed to determine whether there are long-term deleterious effects on maternal or fetal health after pravastatin treatment during pregnancy induced hypertension or preeclampsia. PMID- 23460293 TI - Alcohol and alkalosis enhance excystation of Opisthorchis viverrini metacercariae. AB - The northeastern region of Thailand has long been known as an endemic area of the human liver fluke infection which is caused by Opisthorchis viverrini. Humans are infected by ingestion of uncooked cyprinoid fish in traditional dishes such as "koi-pla," "pla-som," "pla-jom," and "pla-ra." To date, the prevalence of this parasite infection remains high because of cultural behavior and local beliefs. The popular misunderstanding among people in this area is that alcohol, lemon juice, and fish sauce can kill the parasites. Thus, they believe that they can eat raw fish without the risk of infection. This study attempts to clarify the effects of ethyl alcohol and acidosis-alkalosis on O. viverrini metacercariae excystation. Metacercariae of O. viverrini were obtained from infected cyprinoid fish in a natural reservoir. Most metacercariae were obtained from small cyprinoid fish. Metacercariae were divided into three experimental groups and were treated with solutions containing four different concentrations of ethyl alcohol, four different concentrations of salt, and a range of acidic/basic pH. Metacercariae excystation was observed at the assigned times, and the data were then analyzed. Salt had no effect on excystation. Interestingly, the optimal conditions for O. viverrini excystation were pH 9 and 25 % ethyl alcohol. The present study suggests that raw fish should not be eaten while drinking alcohol or when consuming other ingredients with pH 9, because both alcohol and pH 9 could induce O. viverrini metacercariae excystation, leading to the early development of parasites in the hepatobiliary system. PMID- 23460294 TI - Guideline-adherent care vs quality care in cancer patients: twins or distant cousins? PMID- 23460292 TI - Congenic mapping and sequence analysis of the Renin locus. AB - Renin was the first blood pressure (BP) quantitative trait locus mapped by linkage analysis in the rat. Subsequent BP linkage and congenic studies capturing different portions of the renin region have returned conflicting results, suggesting that multiple interdependent BP loci may be residing in the chromosome 13 BP quantitative trait locus that includes Renin. We used SS-13(BN) congenic strains to map 2 BP loci in the Renin region (chr13: 45.2-49.0 Mb). We identified a 1.1-Mb protective Brown Norway region around Renin (chr13: 46.1-47.2 Mb) that significantly decreased BP by 32 mm Hg. The Renin protective BP locus was offset by an adjacent hypertensive locus (chr13: 47.2-49.0 Mb) that significantly increased BP by 29 mm Hg. Sequence analysis of the protective and hypertensive BP loci revealed 1433 and 2063 variants between Dahl salt-sensitive/Mcwi and Brown Norway rats, respectively. To further reduce the list of candidate variants, we regenotyped an overlapping SS-13(SR) congenic strain (S/renrr) with a previously reported BP phenotype. Sequence comparison among Dahl salt-sensitive, Dahl R, and Brown Norway reduced the number of candidate variants in the 2 BP loci by 42% for further study. Combined with previous studies, these data suggest that at least 4 BP loci reside within the 30-cM chromosome 13 BP quantitative trait locus that includes Renin. PMID- 23460295 TI - Playing shooter and driving videogames improves top-down guidance in visual search. AB - Playing action videogames is known to improve visual spatial attention and related skills. Here, we showed that playing action videogames also improves classic visual search, as well as the ability to locate targets in a dual search that mimics certain aspects of an action videogame. In Experiment 1A, first person shooter (FPS) videogame players were faster than nonplayers in both feature search and conjunction search, and in Experiment 1B, they were faster and more accurate in a peripheral search and identification task while simultaneously performing a central search. In Experiment 2, we showed that 10 h of play could improve the performance of nonplayers on each of these tasks. Three different genres of videogames were used for training: two action games and a 3-D puzzle game. Participants who played an action game (either an FPS or a driving game) achieved greater gains on all search tasks than did those who trained using the puzzle game. Feature searches were faster after playing an action videogame, suggesting that players developed a better target template to guide search in a top-down manner. The results of the dual search suggest that, in addition to enhancing the ability to divide attention, playing an action game improves the top-down guidance of attention to possible target locations. The results have practical implications for the development of training tools to improve perceptual and cognitive skills. PMID- 23460296 TI - Attentional spreading in object-based attention: the roles of target-object integration and target presentation time. AB - What is the best account to explain the object-based attentional benefit-that is, the spread of attention within an attended object or prioritization of search across possible target locations within an attended object? Using a task in which the location of the target was known with certainty, in the present study we systematically manipulated the type (letters or bites) and the presentation time (long or short) of the target and flankers in order to test the effects of target object integration and target presentation time on object-based attention. The results showed that an object-based effect could appear when the target was a bite, no matter whether the target presentation time was long or short; but when the target was a letter, an object-based effect was only observed when the target presentation time was short enough. These findings provide additional evidence supporting the argument of attentional spreading in object-based attention. However, this spreading is moderated jointly by target-object integration and the target presentation time. PMID- 23460297 TI - Chiroptical properties of bilirubin-serum albumin binding sites. AB - Although the interactions between bilirubin and serum albumin are among the most studied serum albumin-ligand interactions, the binding-site location and the participation of bilirubin-serum albumin complexes in pathological and physiological processes are under debate. In this article, we have benefited from the chiral structure of bilirubin and used CD spectroscopy to characterize the structure of bilirubin bound to human and bovine serum albumins. We determined that in a phosphate buffer at pH 7.8 there are three binding sites in both human and bovine serum albumins. While the primary binding sites in human and bovine serum albumins bind bilirubin with P- and M-helical conformations, respectively, the secondary binding sites in both albumins bind bilirubin in the P-helical conformation. We have shown that the bonding of bilirubin to the serum albumin matrix is a more favorable process than the self-association of bilirubin under the studied conditions, with a maximum of three bound bilirubins per serum albumin molecule. Although bilirubin bound to the primary binding site has attracted the most attention, the presented results have documented the impact of the secondary binding sites which are relevant in the displacement reactions between BR and drugs and in the phenomena where bilirubin plays antioxidant, antimutagenic, and anti-inflammatory roles. PMID- 23460298 TI - Sexual experience restores age-related decline in adult neurogenesis and hippocampal function. AB - Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age-related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle-aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle aged rats. Following continuous long-term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown. PMID- 23460300 TI - ToF-SIMS measurements with topographic information in combined images. AB - In 2D and 3D time-of-flight secondary ion mass spectrometric (ToF-SIMS) analysis, accentuated structures on the sample surface induce distorted element distributions in the measurement. The origin of this effect is the 45 degrees incidence angle of the analysis beam, recording planar images with distortion of the sample surface. For the generation of correct element distributions, these artifacts associated with the sample surface need to be eliminated by measuring the sample surface topography and applying suitable algorithms. For this purpose, the next generation of ToF-SIMS instruments will feature a scanning probe microscope directly implemented in the sample chamber which allows the performance of topography measurements in situ. This work presents the combination of 2D and 3D ToF-SIMS analysis with topographic measurements by ex situ techniques such as atomic force microscopy (AFM), confocal microscopy (CM), and digital holographic microscopy (DHM). The concept of the combination of topographic and ToF-SIMS measurements in a single representation was applied to organic and inorganic samples featuring surface structures in the nanometer and micrometer ranges. The correct representation of planar and distorted ToF-SIMS images was achieved by the combination of topographic data with images of 2D as well as 3D ToF-SIMS measurements, using either AFM, CM, or DHM for the recording of topographic data. PMID- 23460299 TI - Clinical correlates of Charcot-Marie-Tooth disease in patients with pes cavus deformities. AB - INTRODUCTION: Given its association with Charcot-Marie-Tooth disease (CMT), pes cavus is a common reason for referral to a neurologist. We investigated clinical features that may predict CMT in children with pes cavus. METHODS: In this study we retrospectively reviewed pes cavus patients referred to Boston Children's Hospital in the past 20 years. Patients were categorized as idiopathic or CMT, based on EMG/genetic testing, and their clinical features were compared. RESULTS: Of the 70 patients studied, 33 had idiopathic pes cavus, and 37 had genetically confirmed CMT. Symptoms of weakness, unsteady gait, family history of pes cavus and CMT, and signs of sensory deficits, distal atrophy and weakness, absent ankle jerks, and gait abnormalities were associated with CMT. CONCLUSIONS: In children with pes cavus, certain clinical features can predict CMT and assist in selection of patients for further, potentially uncomfortable (EMG) and expensive (genetic) confirmatory investigations. PMID- 23460301 TI - Plasticity of mouse brain docosahexaenoic acid: modulation by diet and age. AB - Decreases in brain docosahexaenoic acid (DHA) have been associated with losses in brain function leading to an interest in the conditions which lead to such brain decreases, and such variables as age. Also of relevance would be the rate of repletion of DHA when the n-3 dietary deficiency is reversed. This experiment describes dietary deficiency in n-3 fatty acids induced in weanling (3 week) and young adult (7 week) mice. There was an immediate and continuous loss of brain DHA with similar rates in the two age groups. Serum DHA declined more rapidly in younger animals with respect to similarly treated adults. Brain and serum docosapentaenoic acid (DPAn-6) increased more rapidly and to higher levels in the younger animals. A second experiment determined the rates of normalization of brain fatty acid profiles when alpha-linolenic acid was added to the diets of n-3 deficient mice. Brain DHA recovery occurred at a faster rate (half-time, T 1/2 = 1.4 weeks) when begun at weaning relative to young adult mice (T 1/2 = 3.5 weeks). Correspondingly, brain DPAn-6 recovered faster in the younger animals; the adult group had a half-time of more than twice that of the 3-week old group. This study therefore demonstrates that the young adult mouse brain DHA is somewhat plastic and can be partially depleted via a low n-3 fatty acid diet and subsequently restored when dietary n-3 fatty acids are repleted. Relevance of these findings for human nutrition is discussed. PMID- 23460302 TI - Combined activity of post-exercise concentrations of NA and eHsp72 on human neutrophil function: role of cAMP. AB - Extracellular heat shock proteins of 72 kDa (eHsp72) and noradrenaline (NA) can act as "danger signals" during exercise-induced stress by activating neutrophil function (chemotaxis, phagocytosis, and fungicidal capacity). In addition, post exercise concentrations of NA increase the expression and release of Hsp72 by human neutrophils, and adrenoreceptors and cAMP are involved in the stimulation of neutrophils by eHsp72. This suggests an interaction between the two molecules in the modulation of neutrophils during exercise-induced stress. Given this context, the aim of the present investigation was to study the combined activity of post-exercise circulating concentrations of NA and eHsp72 on the neutrophil phagocytic process, and to evaluate the role of cAMP as intracellular signal in these effects. Results showed an accumulative stimulation of chemotaxis induced by NA and eHsp72. However, while NA and eHsp72, separately, stimulate the phagocytosis and fungicidal activity of neutrophils, when they act together they do not modify these capacities of neutrophils. Similarly, post-exercise concentrations of NA and eHsp72 separately increased the intracellular level of cAMP, but NA and eHsp72 acting together did not modify the intracellular concentration of cAMP. These results confirm that cAMP can be involved in the autocrine/paracrine physiological regulation of phagocytosis and fungicidal capacity of human neutrophils mediated by NA and eHsp72 in the context of exercise-induced stress. PMID- 23460303 TI - Case of pleomorphic xanthoastrocytoma with anaplastic features in the pineal gland. AB - BACKGROUND AND IMPORTANCE: Different types of tumor have been reported in the pineal gland, but pleomorphic xanthoastrocytoma (PXA) in this region is extremely rare. CLINICAL PRESENTATIONS: A 61-year-old man had gait disturbance and dementia for 1 month. Radiological examination revealed a 22 * 26 * 22-mm-diameter mass in the pineal gland and remarkable hydrocephalus. Biopsy of the tumor was performed and histological examination confirmed diagnosis of PXA with anaplastic features. Radiation therapy with concomitant temozolomide was performed, and tumor reduction was achieved. CONCLUSION: We report the first case of PXA with anaplastic features in the pineal gland. This case indicates that temozolomide and radiation therapy are effective for treating PXA with anaplastic features. PMID- 23460304 TI - Highly enantioselective [3+2] annulation of cyclic enol silyl ethers with donor acceptor cyclopropanes: accessing 3a-hydroxy [n.3.0]carbobicycles. PMID- 23460305 TI - Premolar root morphology and metric variation in Pan troglodytes verus. AB - Premolar root form remains an important taxonomic character in hominin alpha taxonomy. Variation in detailed aspects of root structure remains poorly characterized in extant apes. This limited comparative context hinders evaluations of the significance of root form variation in hominin systematics. Using micro-computed tomography we examine morphological variation in premolars in 51 (n = 128 premolars) West African chimpanzees (Pan troglodytes verus). We categorize premolar root/canal form and number, based on the external root surface and pulp canal morphology, and test for a relationship between canal configuration and sex, jaw size, tooth/root size and cervix shape. Jaw size and root size/shape were quantified using standard metrics, and geometric morphometrics was used to examine root form and cervix shape. Our results confirm previous findings in external root form, but reveal previously undocumented variation in mandibular premolar canal number/form in this subspecies. The LP3 and UP4 exhibit variation in canal number/form, while the UP3 is restricted to external root configurations. The LP4 expresses only a single root/canal form. Generally, in LP3 and UP4 there is no correlation between canal form/number and sex, root size, and jaw size; UP4 canal variation covaried with cervix shape and size. Cervix size is significantly greater in three canal UP4s than two canal UP4s. Our results highlight canal form/number as an important aspect when characterizing root form. The implications of our results for the taxonomic utility of root form within the hominoid and hominin clades are discussed. PMID- 23460306 TI - Connectivity-based risk score for hepatocellular carcinoma prognosis. PMID- 23460307 TI - Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. AB - IMPORTANCE: The use of proton pump inhibitors (PPIs) has rapidly increased during the past several years. However, concern remains about risks associated with their long-term use in older populations. OBJECTIVE: To investigate the relationship between the use of PPIs and the risk of death or the combined end point of death or rehospitalization in older patients discharged from acute care hospitals. DESIGN: We investigated the relationship between PPI use and study outcomes using time-dependent Cox proportional hazards regression in patients 65 years or older discharged from acute care medical wards from April 1 to June 30, 2007. SETTING: Eleven acute care medical wards. PARTICIPANTS: Four hundred ninety one patients (mean [SD] age, 80.0 [5.9] years). MAIN OUTCOME MEASURES: Mortality and the combined end point of death or rehospitalization. RESULTS The use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03 2.77]) but not with the combined end point (1.49 [0.98-2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22-7.16]). CONCLUSIONS AND RELEVANCE: In older patients discharged from acute care hospitals, the use of high-dose PPIs is associated with increased 1-year mortality. Randomized controlled studies including older frail patients are needed. In the meantime, physicians need to use caution and balance benefits and harms in long-term prescription of high-dose PPIs. PMID- 23460308 TI - Prospective biomarkers of stem cells of human endometrium and fallopian tube compared with bone marrow. AB - The applicability of stem cells from the human endometrium and fallopian tube for regeneration is a fascinating area of research because of the role of these cells in dynamic tissue remodelling and their cyclical regenerative property during the menstrual cycle and pregnancy. Nevertheless, studies on the identity of biomarkers of these stem cells are limited and need to be extended. The present study has aimed at exploring the tissue-specific biomarkers of stem cells derived from the human endometrium and fallopian tube compared with those from bone marrow. Cells were isolated from human endometrium and fallopian tubes and characterized for biomarkers, including CD34, CD133, CD117, CD90, CD105, CD73, nestin, CD29, CD44, CD31, CD54, CD166, CD106, CD49d, CD45, ABCG2, SSEA4, OCT4, SOX2, CD140b and CD146, by flowcytometry. Both endometrium and fallopian tube sources exhibited positivity over a wide range of markers, as did bone marrow. In particular, they exhibited pluripotency, perivascular and mesenchymal stem cell markers and cell adhesion molecules, thereby suggesting their relevance in tissue repair and regeneration. Overall, the results of this study provide evidence for the presence of stem cells in the human endometrium and fallopian tube, which could thus represent additional stem cell sources for regenerative medicine. PMID- 23460310 TI - Transfection of mammalian cells using block copolypeptide vesicles. AB - An arginine-leucine block copolypeptide (R60 L20 ) is synthesized, which is capable of forming vesicles with controllable sizes, able to transport hydrophilic cargo across the cell membrane, and exhibit relatively low cytotoxicity. The R60 L20 vesicles also possess the ability to deliver DNA into mammalian cells for transfection. Although the transfection efficiency is lower than that of the commercially available transfection agent Lipofectamine 2000, the R60 L20 vesicles are able to achieve transfection with significantly lower cytotoxicity and immunogenicity. This behavior is potentially due to its stronger interaction with DNA which subsequently provides better protection against anionic heparin. PMID- 23460311 TI - Subclassification of lymphoproliferative disorders in serous effusions: a 10-year experience. AB - BACKGROUND: Rare studies have reported the application of multiple ancillary tests to the diagnosis of lymphoproliferative disorder in serous effusions. In the current study, the authors evaluated the effectiveness of using an algorithm for the triage of serous effusions and the contribution of ancillary studies to achieve a specific subtype of lymphoproliferative disorder. METHODS: Serous effusion samples that had a final diagnosis of lymphoproliferative disorder or suspicious for lymphoma were selected from cases that were diagnosed between 2001 and 2010. Data were collected on patient and sample characteristics as well as results from immunophenotype and molecular studies. RESULTS: In total, 168 serous effusions were identified from 110 patients. The most common site of involvement was the pleural cavity (n = 133) followed by the peritoneal cavity (n = 30) and pericardial cavity (n = 5). The volume of serous effusions ranged from 2 mL to 1000 mL (mean, 238 mL). In 42 patients (38.2%), serous effusions were the primary source of diagnosis. In 129 patients who had a diagnosis of LPD, either generic (n = 82) or specific (n = 47) ancillary tests were performed as a single test in 58 samples (67.4%) or as a combination of multiple studies in 19 samples (23.2%). Immunophenotyping was successful in almost all samples that had a specific subtype with 16 B-cell and 4 T-cell lymphomas being diagnosed. More samples with a specific subtype of lymphoma underwent molecular tests compared with those who had a generic diagnosis (19.1% vs 13.4%). CONCLUSIONS: Successful, specific subtyping of lymphoproliferative disorders was achieved in approximately 33% of cases that were tested for ancillary studies following an approach for the triage and aliquoting of serous effusion samples. PMID- 23460312 TI - Differential role of the dorsal hippocampus, ventro-intermediate hippocampus, and medial prefrontal cortex in updating the value of a spatial goal. AB - Encoding of a goal with a specific value while performing a place navigation task involves the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC), and depends on the coordination between mPFC and the ventro-intermediate hippocampus (vHPC).The present work investigates the contribution of mPFC, dHPC, and vHPC when the rat has to update the value of a goal. Rats were trained to navigate to an uncued goal in order to release a food pellet in a continuous place navigation task. When they had reached criterion performance level in the task, they were subjected to a single "flash session" in which they were exposed to an aversive strobe light during goal visits instead of receiving a food reward. Just before the flash session, the GABA(A) agonist muscimol was injected to temporarily inactivate mPFC, dHPC, or vHPC. The ability to recall the changed value of the goal was tested on the next day. We first demonstrate the aversive effect of the strobe light by showing that rats learn to avoid the goal much more rapidly in the flash session than during a simple extinction session in which goal visits are not rewarded. Furthermore, while dHPC inactivation had no effect on learning and recalling the new goal value, vHPC muscimol injections considerably delayed goal value updating during the flash session, which resulted in a slight deficit during recall. In contrast, mPFC muscimol injections induced faster goal value updating but the rats were markedly impaired on recalling the new goal value on the next day. These results suggest that, contrary to mPFC and dHPC, vHPC is required for updating the value of a goal. In contrast, mPFC is necessary for long-term retention of this updating. PMID- 23460313 TI - Twisted morphologies and novel chiral macroporous films from the self-assembly of optically active helical polyphosphazene block copolymers. AB - A series of optically active helical polyphosphazene block copolymers of general formula R-[N=P(O2C20H12)]n-b-[N=PMePh]m (R-7 a-c) was synthesized and characterized. The polymers were prepared by sequential living cationic polycondensation of N-silylphosphoranimines using the mono-end-capped initiator [Ph3 P=N=PCl3][PCl6] (5) and exhibit a low polydispersity index (ca. 1.3). The temperature dependence of the specific optical activity ([alpha]D) of R-7 a,b relative to that for the homopolymers R-[N=P(O2C20H12)]n (R-8 a) and the R/S analogues (R/S-7 a,b), revealed that the binaphthoxy-phosphazene segments induce a preferential helical conformation in the [N=PMePh] blocks through a "sergeant and-soldiers" mechanism, an effect that is unprecedented in polyphosphazenes. The self-assembly of drop-cast thin films of the chiral block copolymer R-7 b (bearing a long chiral and rigid R-[N=P(O2C20H12)] segment) evidenced a transfer of helicity mechanism, leading to the formation of twisted morphologies (twisted "pearl necklace"), not observed in the nonchiral R/S-7 b. The chiral R-7 a and the nonchiral R/S-7 a, self-assemble by a nondirected morphology reconstruction process into regular-shaped macroporous films with chiral-rich areas close to edge of the pore. This is the first nontemplate self-assembly route to chiral macroporous polymeric films with pore size larger than 50 nm. The solvent annealing (THF) of these films leads to the formation of regular spherical nanostructures (ca. 50 nm), a rare example of nanospheres exclusively formed by synthetic helical polymers. PMID- 23460314 TI - Left hepatic trisectionectomy for advanced perihilar cholangiocarcinoma. AB - BACKGROUND: Data on outcomes of left hepatic trisectionectomy (LT) for perihilar cholangiocarcinoma are limited. The aim of this study was to clarify short- and long-term outcomes of LT for perihilar cholangiocarcinoma. METHODS: Patients with perihilar cholangiocarcinoma who underwent LT between January 2000 and October 2011 were analysed. Surgical variables, mortality, morbidity (Clavien grade I-V), recurrence sites and survival were compared between subjects who underwent LT, right hemihepatectomy or left hemihepatectomy. RESULTS: A total 214 patients underwent resection for perihilar cholangiocarcinoma, 25 (11.7 per cent) of whom underwent LT, 88 (41.1 per cent) right hemihepatectomy and 94 (43.9 per cent) left hepatectomy. There were no deaths among those who had LT, but 20 patients developed complications. The incidence of grade IIIa complications was significantly higher among patients who underwent LT than in patients who had right or left hemihepatectomy (P = 0.001 and P < 0.001 respectively). Only one patient developed a grade IIIb or IV complication (liver failure) after LT. The overall 5-year survival rate after LT was 39 per cent and median survival was 45 months. There were no significant differences in survival between patients who underwent LT and those who had a right or left hemihepatectomy. CONCLUSION: LT may provide a good outcome for advanced perihilar cholangiocarcinoma. PMID- 23460315 TI - Clinical implications for diffusion-weighted MRI brain lesions associated with transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is increasingly used to treat patients with aortic stenosis deemed high or extreme surgical risk candidates. Despite improved survival and quality of life following the procedure, TAVR is not without its complications. Stroke is a major source of morbidity and mortality in patients undergoing the procedure, with rates similar to and often higher than those associated with surgery. Most studies show a consistent link between TAVR and embolic lesions visualized on diffusion-weighted magnetic resonance imaging. The question of whether these lesions lead to long-term cognitive consequences remains open, but given the large literature on silent strokes and cognition, this association is probable. Initial studies implementing cerebral embolic protection devices in TAVR have yielded promising results with decreased neurological complications and appearance of new lesions on imaging. In this article, we will review the evidence linking silent stroke with cognitive decline, and potential therapeutic options to prevent stroke related to TAVR, including cerebral protection devices currently under investigation. PMID- 23460316 TI - Dysplasia of all granulocyte lineages in myelodysplastic evolution of essential thrombocythemia. PMID- 23460317 TI - Easily perceived, easily remembered? Perceptual interference produces a double dissociation between metamemory and memory performance. AB - A recent candidate for explaining metamemory judgments is the perceptual fluency hypothesis, which proposes that easily perceived items are predicted to be remembered better, regardless of actual memory performance (Rhodes & Castel Journal of Experimental Psychology: General 137:615-625, 2008). In two experiments, we used the perceptual interference manipulation to test this hypothesis. In Experiment 1, participants were presented with intact and backward masked words during encoding, followed by a metamemory prediction (a list-wide judgment of learning, JOL) and then a free recall test. Participants predicted that intact words would be better recalled, despite better actual memory for words in the perceptual interference condition, yielding a crossed double dissociation between predicted and actual memory performance. In Experiment 2, JOLs were made after each study word. Item-by-item JOLs were likewise higher for intact than for backward-masked words, despite similar actual memory performance for both types of words. The results are consistent with the perceptual fluency hypothesis of metamemory and are discussed in terms of experience-based and theory-based metamemory judgments. PMID- 23460318 TI - A phase I trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood. AB - BACKGROUND: Arsenic trioxide (ATO) has demonstrated preclinical evidence of activity in the treatment of infiltrating astrocytomas. METHODS: We conducted a phase I trial of ATO given concomitantly with radiation therapy in children with newly diagnosed anaplastic astrocytoma, glioblastoma, or diffuse intrinsic pontine glioma. Eligible patients received a fixed daily dose of 0.15 mg/kg of ATO once a week, with each subsequent cohort of patients receiving an additional dose per week up to a planned frequency of ATO administration 5 days per week as tolerated. Twenty-four children were enrolled and 21 children were evaluable. RESULTS: ATO was well tolerated throughout the entire dose escalation, resulting in confirmation of safety when administered 5 days per week during irradiation. CONCLUSIONS: The recommended dose of ATO during conventional irradiation is 0.15 mg/kg given on a daily basis with each fraction of radiation therapy administered. PMID- 23460319 TI - Patterns of care and outcome for patients with glioblastoma diagnosed during 2008 2010 in Spain. AB - BACKGROUND: To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008-2010 in Spain. METHODS: Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals. RESULTS: We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01 1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT <=42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64-0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62-1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8-14.9 months), compared with 17.0 months (95% CI, 15.5-18.4 months; P = .034) among younger patients with GBM treated with the same regimen. CONCLUSIONS: In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT <=42 days was associated with better progression-free survival. PMID- 23460320 TI - Adoptive transfer of genetically modified Wilms' tumor 1-specific T cells in a novel malignant skull base meningioma model. AB - BACKGROUND: Meningiomas are the most commonly diagnosed primary intracranial neoplasms. Despite significant advances in modern therapies, the management of malignant meningioma and skull base meningioma remains a challenge. Thus, the development of new treatment modalities is urgently needed for these difficult-to treat meningiomas. The goal of this study was to investigate the potential of build-in short interfering RNA-based Wilms' tumor protein (WT1)-targeted adoptive immunotherapy in a reproducible mouse model of malignant skull base meningioma that we recently established. METHODS: We compared WT1 mRNA expression in human meningioma tissues and gliomas by quantitative real-time reverse-transcription polymerase chain reaction. Human malignant meningioma cells (IOMM-Lee cells) were labeled with green fluorescent protein (GFP) and implanted at the skull base of immunodeficient mice by using the postglenoid foramen injection (PGFi) technique. The animals were sacrificed at specific time points for analysis of tumor formation. Two groups of animals received adoptive immunotherapy with control peripheral blood mononuclear cells (PBMCs) or WT1-targeted PBMCs. RESULTS: High levels of WT1 mRNA expression were observed in many meningioma tissues and all meningioma cell lines. IOMM-Lee-GFP cells were successfully implanted using the PGFi technique, and malignant skull base meningiomas were induced in all mice. The systemically delivered WT1-targeted PBMCs infiltrated skull base meningiomas and significantly delayed tumor growth and increased survival time. CONCLUSIONS: We have established a reproducible mouse model of malignant skull base meningioma. WT1-targeted adoptive immunotherapy appears to be a promising approach for the treatment of difficult-to-treat meningiomas. PMID- 23460321 TI - SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. AB - BACKGROUND: We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). METHODS: Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. RESULTS: Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 +/- 0.02 vs 0.88 +/- 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 +/- 0.023 event-free and overall survival. CONCLUSIONS: Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease. PMID- 23460322 TI - Biopsy validation of 18F-DOPA PET and biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a prospective pilot study. AB - BACKGROUND: Delineation of glioma extent for surgical or radiotherapy planning is routinely based on MRI. There is increasing awareness that contrast enhancement on T1-weighted images (T1-CE) may not reflect the entire extent of disease. The amino acid tracer (18)F-DOPA (3,4-dihydroxy-6-[18F] fluoro-l-phenylalanine) has a high tumor-to-background signal and high sensitivity for glioma imaging. This study compares (18)F-DOPA PET against conventional MRI for neurosurgical biopsy targeting, resection planning, and radiotherapy target volume delineation. METHODS: Conventional MR and (18)F-DOPA PET/CT images were acquired in 10 patients with suspected malignant brain tumors. One to 3 biopsy locations per patient were chosen in regions of concordant and discordant (18)F-DOPA uptake and MR contrast enhancement. Histopathology was reviewed on 23 biopsies. (18)F-DOPA PET was quantified using standardized uptake values (SUV) and tumor-to-normal hemispheric tissue (T/N) ratios. RESULTS: Pathologic review confirmed glioma in 22 of 23 biopsy specimens. Thirteen of 16 high-grade biopsy specimens were obtained from regions of elevated (18)F-DOPA uptake, while T1-CE was present in only 6 of those 16 samples. Optimal (18)F-DOPA PET thresholds corresponding to high-grade disease based on histopathology were calculated as T/N > 2.0. In every patient, (18)F-DOPA uptake regions with T/N > 2.0 extended beyond T1-CE up to a maximum of 3.5 cm. SUV was found to correlate with grade and cellularity. CONCLUSIONS: (18)F-DOPA PET SUV(max) may more accurately identify regions of higher-grade/higher-density disease in patients with astrocytomas and will have utility in guiding stereotactic biopsy selection. Using SUV-based thresholds to define high-grade portions of disease may be valuable in delineating radiotherapy boost volumes. PMID- 23460323 TI - Involved field radiation therapy after surgical resection of solitary brain metastases--mature results. AB - BACKGROUND: Whole brain radiation therapy (WBRT) reduces local recurrence in patients after surgical resection of brain metastases without improving overall survival. Involved field radiation therapy (IFRT) has been used at our center to avoid delayed neurotoxicity associated with WBRT in well-selected patients with surgically resected single brain metastases. The purpose of this study was to evaluate the long-term outcomes of these patients. METHODS: Thirty-three consecutive patients with single brain metastases from a known primary tumor were treated with gross total resection followed by IFRT between 2006 and 2011. The postoperative surgical bed was treated to 40.05 Gy in 15 fractions of 2.67 Gy with conformal radiation therapy. Patients received serial MRIs and neurological exams in follow-up. Surgery, WBRT, or stereotactic radiosurgery was performed as salvage treatment when necessary. RESULTS: The median follow-up was 16 months (range: 2-65 months). Local control, distant brain recurrence-free survival, and overall survival at 12 and 24 months were 90.3% and 85.8%, 60.7% and 51.4%, and 65.6% and 61.5%, respectively. Overall, 5 (15%) patients developed recurrence at the resection cavity, and 13 (39%) patients experienced recurrence at a new intracranial site. Two patients received WBRT, 8 stereotactic radiosurgery, 2 surgery, and 2 both chemotherapy and IFRT as salvage. Four patients died from CNS disease progression. CONCLUSION: For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and is an excellent alternative to WBRT. PMID- 23460324 TI - Bevacizumab treatment of symptomatic pseudoprogression after boron neutron capture therapy for recurrent malignant gliomas. Report of 2 cases. AB - BACKGROUND: Bevacizumab, an anti-vascular endothelial growth factor antibody, has been used for the treatment of radiation necrosis. Thus far, however, there has been no definitive report on its use for the treatment of symptomatic pseudoprogression. Here we report 2 cases of successful treatment with bevacizumab for symptomatic pseudoprogression after boron neutron capture therapy (BNCT) was applied for recurrent malignant gliomas. METHODS: Two recurrent malignant gliomas received BNCT. Both cases were treated with intravenous administration of bevacizumab at the deterioration that seemed to be symptomatic pseudoprogression. RESULTS: The first case was recurrent glioblastoma multiforme and the second was recurrent anaplastic oligoastrocytoma. Both cases recurred after standard chemoradiotherapy and were referred to our institute for BNCT, which is tumor-selective particle radiation. Just prior to neutron irradiation, PET with an amino acid tracer was applied in each case to confirm tumor recurrence. Both cases showed deterioration in symptoms, as well as on MRI, at intervals of 4 months and 2 months, respectively, after BNCT. For the first case, a second PET was applied in order to confirm no increase in tracer uptake. We diagnosed both cases as symptomatic pseudoprogression and started the intravenous administration of 5 mg/kg bevacizumab biweekly with 6 cycles. Both cases responded well to this, showing rapid and dramatic improvement in neuroimaging and clinical symptoms. No tumor progression was observed 8 months after BNCT. CONCLUSIONS: Bevacizumab showed marked effects on symptomatic pseudoprogression after BNCT. BNCT combined with bevacizumab may prolong the survival of patients with recurrent malignant gliomas. PMID- 23460325 TI - Correlation of knee strength to functional outcomes in Becker muscular dystrophy. AB - INTRODUCTION: The correlation of strength with performance on functional outcomes has not been evaluated in Becker muscular dystrophy (BMD), yet the determination of proper outcome measures is critical to the success of upcoming trials designed to improve strength. METHODS: Lower extremity strength and performance on functional outcome measures were tested in 25 ambulatory subjects with BMD. RESULTS: All subjects demonstrated marked knee extensor and flexor muscle weakness. Knee extensor strength was correlated with performance on the Berg Balance Scale and stair climbing. Knee flexor strength was highly correlated with performance on all functional outcomes, including timed walking distances. CONCLUSIONS: This profile differs from that previously reported in other neuromuscular diseases and demonstrates the importance of designing outcome measures for clinical trials in muscle disorders with considerations for the disease process, the mode, and the target of intervention. The findings emphasize that 1 set of outcomes is not appropriate for all neuromuscular diseases. PMID- 23460326 TI - A prospective analysis of 179 type 2 superior labrum anterior and posterior repairs: outcomes and factors associated with success and failure. AB - BACKGROUND: There is a paucity of type 2 superior labrum anterior and posterior (SLAP) surgical outcomes with prospective data. PURPOSE: To prospectively analyze the clinical outcomes of the arthroscopic treatment of type 2 SLAP tears in a young, active patient population, and to determine factors associated with treatment success and failure. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Over a 4-year period, 225 patients with a type 2 SLAP tear were prospectively enrolled. Two sports/shoulder-fellowship-trained orthopaedic surgeons performed repairs with suture anchors and a vertical suture construct. Patients were excluded if they underwent any additional repairs, including rotator cuff repair, labrum repair outside of the SLAP region, biceps tenodesis or tenotomy, or distal clavicle excision. Dependent variables were preoperative and postoperative assessments with the American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE), and Western Ontario Shoulder Instability (WOSI) scores and independent physical examinations. A failure analysis was conducted to determine factors associated with failure: age, mechanism of injury, preoperative outcome scores, and smoking. Failure was defined as revision surgery, mean ASES score below 70, or an inability to return to sports and work duties, which was assessed statistically with the Student t test and stepwise logarithmic regression. RESULTS: There were 179 of 225 patients who completed the follow-up for the study (80%) at a mean of 40.4 months (range, 26-62 months). The mean preoperative scores (WOSI, 54%; SANE, 50%; ASES, 65) improved postoperatively (WOSI, 82%; SANE, 85%; ASES, 88) (P < .01). The mean postoperative range of motion was 159 degrees of flexion, 151 degrees of abduction, and 51 degrees of external rotation at the side, which was less than the mean preoperative range of motion (164 degrees of flexion, 166 degrees of abduction, and 56 degrees of external rotation at the side). Of the 179 patients, 66 patients (36.8%) met failure criteria. Fifty patients elected revision surgery. Advanced age within the cohort (>36 years) was the only factor associated with a statistically significant increase in the incidence of failure. Those who were deemed failed had a mean age of 39.2 years (range, 29-45 years) versus those who were deemed healed with a mean age of 29.7 years (range, 18-36 years) (P < .001). The relative risk for failure for patients older than 36 years was 3.45 (95% CI, 2.0-4.9). CONCLUSION: Arthroscopic SLAP repair provides a clinical and statistically significant improvement in shoulder outcomes. However, a reliable return to the previous activity level is limited; 37% of patients had failure, with a 28% revision rate. Age greater than 36 years was associated with a higher chance of failure. Additional work is necessary to determine the optimal diagnosis, indications, and surgical management for those with SLAP injuries. PMID- 23460327 TI - Medial patellofemoral ligament reconstruction: the superficial quad technique. AB - BACKGROUND: Medial patellofemoral ligament (MPFL) reconstruction is a routine procedure for patellar instability. The majority of the techniques require hardware fixation or a bony procedure at the patella. However, most of the complications described in the literature can be attributed to patellar fixation. The "superficial quad technique" uses the superficial slip of the quadriceps tendon as the graft material, which provides a better anatomic match to the native MPFL. HYPOTHESIS: The superficial quad technique provides anatomic patellar fixation without a bony procedure and without patellar complications. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The study included 32 patients (10 male, 22 female; mean age, 25 years) who underwent MPFL reconstruction using the superficial quad technique and who were followed for a mean duration of 38 months. Objective assessment was performed and Kujala scores were obtained preoperatively and at the time of final follow-up. RESULTS: There were no patellar complications, including redislocation, in the present study. The mean Kujala score improved to 91.25 (range, 73-100) from a preoperative score of 49.31 (range, 23-62). CONCLUSION: The results were comparable with those of other studies in the literature that used hamstring grafts, but without associated patellar complications. The superficial quad technique uses graft material that is a better anatomic match to the native MPFL. It provides anatomic patellar fixation without a bony procedure. PMID- 23460328 TI - The effect of early whole-body vibration therapy on neuromuscular control after anterior cruciate ligament reconstruction: a randomized controlled trial. AB - BACKGROUND: Despite rehabilitation training, deficiency in knee joint position sense, muscular performance, postural control, and functional ability is common after anterior cruciate ligament reconstruction (ACLR). Whole-body vibration therapy (WBVT), which is initiated from 3 months postoperatively, has proven benefits. However, the effect of earlier WBVT is unknown. PURPOSE: To investigate the effect of early WBVT on neuromuscular control after ACLR. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 48 patients with unilateral complete isolated ACL tears were recruited. Single bundle hamstring ACLR was performed in all patients. After surgery, they were randomly assigned to either the reference or treatment group. Reference group patients received conventional ACL rehabilitation, while treatment group patients received 8 weeks of WBVT in addition to conventional rehabilitation, starting from 1 month postoperatively. Joint position sense, postural control, and knee isokinetic performance were assessed before surgery and at 1, 3, and 6 months postoperatively using the Biodex dynamometer, Biodex Stability System, and Cybex NORM, respectively. Knee range of motion (ROM), stability (manual testing and KT 1000 arthrometer), and functional ability (single-legged hop test, triple hop test, shuttle run test, and carioca test) were also examined. Two-way repeated measures analysis of variance and the Mann-Whitney U test were used for statistical analysis. RESULTS: There was no complication throughout the rehabilitation. All patients achieved full knee ROM and stable knee joints at 6 months after surgery. The WBVT group demonstrated significantly better postural control, muscle performance, single-legged hop, and shuttle run (P < .05) than the reference group, but there was no significant difference in knee joint position sense, triple hop, carioca, ROM, and stability (P > .05). CONCLUSION: Early WBVT started from 1 month postoperatively was an effective training method without compromising knee ROM and stability. It improved postural control, isokinetic performance, single-legged hop, and shuttle run but not knee joint position sense, triple hop, and carioca. PMID- 23460329 TI - Results of 2 decades of injury surveillance and public release of data in the Australian Football League. AB - BACKGROUND: Injuries are common in all professional football codes (including soccer, rugby league and union, American football, Gaelic football, and Australian football). PURPOSE: To report the epidemiology of injuries in the Australian Football League (AFL) from 1992-2012 and to identify changes in injury patterns during that period. STUDY DESIGN: Descriptive epidemiology study. METHODS: The AFL commenced surveying injuries in 1992, with all teams and players included since 1996. An injury was defined as "any physical or medical condition that causes a player to miss a match in the regular season or finals (playoffs)." Administrative records of injury payments (which are compulsory as part of salary cap compliance) to players who do not play matches determined the occurrence of an injury. The seasonal incidence was measured in units of new injuries per club (of 40 players) per season (of 22 matches). RESULTS: There were 4492 players listed over the 21-year period who suffered 13,606 new injuries/illnesses and 1965 recurrent injuries/illnesses, which caused 51,919 matches to be missed. The lowest seasonal incidence was 30.3 new injuries per club per season recorded in 1993, and the highest was 40.3 recorded in 1998. The injury prevalence (missed matches through injury per club per season) varied from a low of 116.3 in 1994 to a high of 157.1 in 2011. The recurrence rate of injuries was highest at 25% in 1992 and lowest at 9% in 2012 and has steadily fallen across the 21 years (P < .01). The most frequent and prevalent injury was hamstring strain (average of 6 injuries per club per season, resulting in 20 missed matches per club per season; recurrence rate, 26%), although the rate of hamstring injuries has fallen in the past 2 seasons after a change to the structure of the interchange bench (P < .05). The rate of knee posterior cruciate ligament injuries fell in the years after a rule change to prevent knee-to-knee collisions in ruckmen (P < .01). CONCLUSION: Annual public reporting (by way of media release and reports available freely online) of injury rates, using units easily understood by laypeople, has been well received. It has also paved the way for rule changes with the primary goal of improving player safety. PMID- 23460330 TI - Effect of evidence and changes in reimbursement on the rate of arthroscopy for osteoarthritis. AB - BACKGROUND: The efficacy of arthroscopic debridement or lavage for knee osteoarthritis (OA) was cast into doubt after publication of several randomized controlled trials beginning in 2002. PURPOSE: The authors set out to determine whether evidence of ineffectiveness, along with subsequent changes in reimbursement, were followed by changes in utilization rates of arthroscopy for patients with OA. STUDY DESIGN: Cohort study (prevalence); Level of evidence, 2. METHODS: The Florida State Ambulatory Surgery Database was used to examine population-based rates of knee arthroscopy from 2000 to 2008 for patients with and without the diagnosis of OA; data were stratified between public and private payers. These trends were compared with patients who underwent arthroscopy for other diagnoses and were also compared with patients whose arthritis was not the primary indication for surgery. RESULTS: A 39% decrease in the adjusted population-based rate of knee arthroscopy for OA was observed, from 12.2 per 100,000 adults in 2000 (95% CI, 9.9-14.4) to 7.7 per 100,000 adults in 2008 (95% CI, 6.7-8.6). The overall rate among individuals with a primary diagnosis of OA significantly decreased for both public (P < .001) and private insurance (P = .001) and the rate of this decrease was similar between the two insurance types (P = .610). Although the unadjusted rates for all knee arthroscopy increased over the study period, the rate of increase was slowed in the years following the publication of several randomized controlled trials and subsequent changes in reimbursement. The average effect on arthroscopy rates attributed to these events was a reduction in 12 per 100,000 private arthroscopies (95% CI, -16.3 to 40.6; P = .404) and 35.7 per 100,000 publicly insured arthroscopies (95% CI, 15.0-56.4; P = .001). CONCLUSION: Evidence of the lack of efficacy of arthroscopy for knee OA, along with changes in reimbursement, preceded a significant decline in the population-based rates of this procedure in both publicly and privately insured patients in Florida. PMID- 23460331 TI - Anterior cruciate ligament fatigue failures in knees subjected to repeated simulated pivot landings. AB - BACKGROUND: It is not known whether the human anterior cruciate ligament (ACL) is susceptible to fatigue failure as a result of repetitive loading or whether certain knee morphologic characteristics increase that risk. HYPOTHESES: The number of knee loading cycles required to fail an ACL by fatigue failure is unaffected by the magnitude of the external load delivered to the knee joint. Furthermore, sex, ACL cross-sectional area, and lateral tibial slope will not affect the number of loading cycles to ACL failure. STUDY DESIGN: Controlled laboratory study. METHODS: Knee pairs from 10 cadaveric donors (5 female) of similar age, height, and weight were imaged with 3-T magnetic resonance imaging to measure lateral tibial slope and ACL cross-sectional area. One knee from each pair was then subjected to repeated application of a load of 3 times body weight (3*BW), while the other knee was subjected to a 4*BW load, both involving impulsive compression force, knee flexion moment, and internal tibial torque combined with realistic trans-knee muscle forces. The resulting 3-dimensional tibiofemoral kinematics and kinetics were recorded, along with ACL relative strain and quadriceps, hamstring, and gastrocnemius muscle forces. The loading cycle was repeated until the ACL ruptured, a 3-mm increase in cumulative anterior tibial translation occurred, or a minimum of 50 trials was reached. RESULTS: Eight of 10 knees failed under the 4*BW load (mean +/- SD cycles to failure, 21 +/- 18), while 5 of 10 knees failed under the 3*BW load (mean +/- SD cycles to failure, 52 +/- 10). Four knees exhibited a 3-mm increase in anterior tibial translation, 7 knees developed partial or complete visible ACL tears, and 2 knees developed complete ACL tibial avulsions. A Cox regression showed that the number of cycles to ACL failure was influenced by the simulated landing force (P = .012) and ACL cross-sectional area (P = .022). Donor sex and lateral tibial slope did not influence the number of cycles to ACL failure. CONCLUSION: The human ACL is susceptible to fatigue failure when pivot landings of 3*BW or more load the knee repeatedly within a short time span. An ACL with a smaller cross-sectional area is at greater risk for this type of failure. CLINICAL RELEVANCE: The results show that the human knee can only withstand a certain number of 3*BW or greater jump loading cycles within a short time period before the ACL will fail. Therefore, limiting the increase in the number and severity of pivot landing maneuvers performed over a week of training would make sense from an injury prevention viewpoint. PMID- 23460332 TI - Reconstruction of a bony bankart lesion: best fit based on radius of curvature. AB - BACKGROUND: The inferior coracoid process has traditionally been considered to be the gold standard for glenoid augmentation after anteroinferior bone loss. Other autograft sites, and more recently, osteochondral allograft sites, have been described as potential donor sources. PURPOSE: Potential autograft and osteochondral allograft sites were compared to identify the graft source that would provide the best fit for glenoid augmentation. STUDY DESIGN: Controlled laboratory study. METHODS: Mose circles, a geometric tool found on a standard goniometer, were used to make radius of curvature measurements of 10 anatomic locations in 17 cadaveric specimens. The bony surface of the glenoid, measured from superior to inferior (G-SI) and from anterior to posterior (G-AP), was used as the standard for comparison. Autograft sites were the inferior coracoid, lateral coracoid, and inner table of the iliac crest. Potential osteochondral allograft sites were the radial head, scaphoid fossa of the distal radius (S-DR), lunate fossa of the distal radius (L-DR), medial tibial plateau, and lateral distal tibia. An acceptable match for autograft sites was based on a paired analysis and defined as a radius of curvature within 5 mm of the G-SI or the G-AP of the same cadaveric specimen. Allograft sites were evaluated using an unpaired analysis in which an ideal fit was defined as a radius of curvature of 25 to 30 mm, based on the interquartile range of the G-SI and G-AP. RESULTS: The median (interquartile range) radii of curvature for the G-SI and G-AP were 30 mm (range, 25-30 mm) and 25 mm (range, 25-25 mm), respectively. The inferior coracoid was within 5 mm of the G-SI 59% of the time and the G-AP 94% of the time; no measurements from the lateral coracoid or iliac crest were within the range of the glenoid radius of curvature. Analysis of the allograft sites demonstrated an acceptable fit for 94% of the distal tibia, 68% of the medial tibial plateau, 12% of the S-DR, and 0% of the L-DR and the radial head specimens. CONCLUSION: An autograft of the inferior coracoid or an osteochondral allograft of the lateral distal tibia provided the best match to re-establish the native radius of curvature of the glenoid. CLINICAL RELEVANCE: To best re-create the native glenohumeral anatomy, surgeons should consider the use of an autograft of the inferior coracoid or an osteochondral allograft of the lateral distal tibia for the reconstruction of osseous glenoid defects. PMID- 23460333 TI - Assessment of early tibiofemoral joint space width changes after anterior cruciate ligament injury and reconstruction: a matched case-control study. AB - BACKGROUND: Progression of primary knee osteoarthritis (OA) is often quantified by measuring structural alterations of the joint such as those in tibiofemoral joint space width (JSW) over time. Limited information is available regarding changes that occur during the onset and progression of posttraumatic OA (PTOA) that are often associated with anterior cruciate ligament (ACL) injury. Furthermore, there is a paucity of information regarding JSW changes in healthy patients, making JSW interpretation challenging during early PTOA progression. PURPOSE: To evaluate tibiofemoral JSW after ACL injury, ACL reconstruction, and rehabilitation compared with healthy, matched controls. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 39 ACL-injured patients and 32 matched controls were evaluated. Injured patients were assessed at presurgical baseline and after ACL reconstruction (mean follow-up, 46 months), as were controls. Bilateral, standing, fluoroscopy-assisted, and posterior-anterior metatarsal-phalangeal view knee radiographs were obtained at each visit and JSW was measured. RESULTS: The JSW differences between knees in control patients were not significantly different and did not change over time. Baseline JSW differences in the ACL group were significantly different than in controls. Three patients (7.9% of total) had an increased JSW difference, and 1 patient (2.6%) had a decreased medial JSW difference. In the lateral compartment, 6 patients (15.8%) had a decreased JSW difference. At follow-up, 2 patients in the ACL group (5%) had a decreased medial JSW difference, and 3 (7.9%) had a significantly increased difference in relation to controls. Lateral compartment analyses revealed 7 (18.4%) patients with a significantly decreased JSW difference and no patients with an increased difference compared with controls. CONCLUSION: One third of ACL-injured knees underwent significant JSW change soon after injury; consequently, evaluation of within-knee JSW changes over time in ACL-injured patients may not be appropriate with a study based on case-control analysis. The JSWs in the healthy knee of ACL-injured patients do not change over time, allowing this knee to be used as a control for the injured knee. This is important when evaluating the earliest stages of PTOA after ACL injury, when patients are asymptomatic and intervention may be most beneficial. PMID- 23460334 TI - How to improve the prediction of quadrupled semitendinosus and gracilis autograft sizes with magnetic resonance imaging and ultrasonography. AB - BACKGROUND: Hamstring tendon grafts may have an unacceptable size for use in anterior cruciate ligament (ACL) reconstruction. Magnetic resonance imaging (MRI) has been proposed to predict the diameters of hamstring tendon grafts. HYPOTHESIS: Preoperative ultrasonography (US) might reliably anticipate intraoperative 4-strand semitendinosus and gracilis tendon (4ST-GT) graft sizes similarly to MRI. An MRI evaluation of the hamstring tendons with a higher magnification may improve the accuracy of the method. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A total of 33 patients undergoing ACL reconstruction with a 4ST-GT graft and MRI performed at our institution were included. The cross-sectional area (CSA) of each semitendinosus tendon (ST) and gracilis tendon (GT) was calculated preoperatively with US and with MRI under 2* and 4* magnification. Intraoperative measurement of the final diameter of the 4ST GT using a closed-hole sizing block with 0.5-mm increments was made. Pearson correlation coefficients were calculated to determine the relationship between the final intraoperative graft diameter of the 4ST-GT and the CSA of the ST and GT measured with US and MRI with 2* and 4* magnification. Simple linear regression was also calculated to attempt to predict the graft diameter based on given measurements. RESULTS: There were statistically significant correlations between the measured CSA with US and both MRI magnifications with the 4ST-GT diameter. However, MRI under 4* magnification showed a much higer correlation (0.86) than MRI under 2* magnification (0.54) or US (0.51). Final graft diameters >=8 mm were observed in 80.8% of patients with a CSA >14 mm(2), in 76.9% of patients with a CSA >25 mm2, and in 96.2% of patients with a CSA >17 mm2 measured with US, 2* magnification of MRI, and 4* magnification of MRI, respectively. CONCLUSION: Preoperative calculation of the CSA of the hamstring tendons with MRI and US can help to reliably estimate 4ST-GT grafts. In terms of correlation of the CSA with graft diameter, US was comparable to 2* MRI, but 4* MRI showed a much greater accuracy. Threshold values of the CSA of the ST and GT of 25 mm2, 17 mm2, and 14 mm2 with the 2* MRI, 4* MRI, and US methods, respectively, are needed to reliably predict a 4ST-GT graft with a minimum diameter of 8 mm. PMID- 23460335 TI - Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. AB - BACKGROUND: The ideal treatment for osteochondral lesions of the talus (OLTs) is still controversial, especially in older patients. Recently, mesenchymal stem cells (MSCs) have been suggested for use in the cell-based treatment of cartilage lesions. PURPOSE: To compare the clinical outcomes of MSC injection and arthroscopic marrow stimulation treatment with those of arthroscopic marrow stimulation treatment alone for the treatment of OLTs in older patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Among 107 patients with OLTs treated arthroscopically, only the patients older than 50 years (65 patients) were included in this study. Patients were divided into 2 groups: 35 patients (37 ankles) treated with arthroscopic marrow stimulation treatment alone (group A) and 30 patients (31 ankles) who underwent MSC injection along with arthroscopic marrow stimulation treatment (group B). Clinical outcomes were evaluated according to the visual analog scale (VAS) for pain, the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale, and the Roles and Maudsley score. The Tegner activity scale was used to determine outcomes in activity levels. RESULTS: The mean VAS score in each group was significantly improved (P < .05) from 7.2 +/- 1.1 to 4.0 +/- 0.7 in group A and from 7.1 +/- 1.0 to 3.2 +/- 0.9 in group B. The mean AOFAS score in each group was also significantly improved (P < .05) from 68.0 +/- 5.5 to 77.2 +/- 4.8 in group A and from 68.1 +/- 5.6 to 82.6 +/- 6.4 in group B. There were significant differences in mean VAS and AOFAS scores between the groups at final follow-up (mean, 21.8 months; range, 12-44 months) (P < .001). The Roles and Maudsley score showed significantly greater improvement in group B than in group A after surgery (P = .040). The Tegner activity scale score was significantly improved in group B (from 3.5 +/- 0.7 to 3.8 +/- 0.7; P = .041) but not in group A (from 3.5 +/- 0.8 to 3.6 +/- 0.6; P = .645). Large lesion size (>=109 mm(2)) and the existence of subchondral cysts were significant predictors of unsatisfactory clinical outcomes in group A (P = .04 and .03, respectively). These correlations were not observed in group B. CONCLUSION: Injection of MSCs with marrow stimulation treatment was encouraging in patients older than 50 years compared with patients treated with marrow stimulation treatment alone, especially when the lesion size was larger than 109 mm(2) or a subchondral cyst existed. Although still in the early stages of application, MSCs may have great potential in the treatment of OLTs in patients older than 50 years, and more evaluations of its effect should be performed. PMID- 23460336 TI - Clinical and microscopic signs of cervicitis and urethritis: correlation with Chlamydia trachomatis infection in female STI patients. AB - Chlamydia trachomatis is among the most prevalent genital infections and is an important cause of tubal factor infertility. The majority of infected females are asymptomatic. Evidence on the reliability of signs of inflammation used to predict chlamydia in female patients is inconsistent. This study examined associations between criteria routinely used in many Scandinavian sexually transmitted infection (STI) clinics and a positive chlamydia test in a high prevalence population. Clinical and microscopic signs of cervicitis and urethritis were recorded in 99 women attending due to chlamydia infection in a sexual partner. Mucopurulent cervical discharge, easily induced bleeding from the cervix, and more polymorpho-nuclear cells than epithelial cells in vaginal wet smear all correlated significantly with a positive Chlamydia trachomatis test (odds ratios: 3.4, 4.0 and 4.8, respectively). Increased numbers of polymorphonuclear leucocytes (>30 and >= 5 respectively) in stained cervical and urethral smears were not significantly correlated with chlamydia infection. Hence, routine collection of cervical and urethral smears in female STI patients is questionable. PMID- 23460337 TI - Effect of tibial insertion site for lateral suture stabilization on the kinematics of the cranial cruciate ligament deficient-stifle during early, middle and late stance: an in vitro study. AB - OBJECTIVE: To evaluate the effect of two tibial attachment sites for lateral suture stabilization (LSS) on the three-dimensional femorotibial translational and rotational movements of the cranial cruciate ligament- deficient canine stifle during the early, middle and late stance phases. STUDY DESIGN: In vitro biomechanical study: 32 hindlimbs from 16 canine cadavers. METHODS: Limbs were mounted in a testing jig and an electromagnetic tracking system was used to determine the three-dimensional femorotibial translational and rotational movements under 33% of body weight load during early, middle and late stance in the following sequence: cranial cruciate ligament-intact, cranial cruciate ligament-deficient and LSS with the distal anchor through the tibial tuberosity (LSSTT) or through the cranial eminence of the extensor groove (LSSEG). The proximal anchor point was the lateral femorofabellar ligament. RESULTS: Post-LSS stifle three-dimensional femorotibial translational and rotational movements were more comparable to normal than post-transection movements for both techniques. Both LSS techniques restored femorotibial movements in cranial cruciate ligament deficient stifles to varying amounts but neither technique successfully restored normal three-dimensional femorotibial movements. The LSSEG improved femorotibial movements of the cranial cruciate ligament-deficient stifle in the medial-lateral direction and axial rotation but performed poorly in restoring femorotibial movements in the cranial-caudal direction as compared to the LSSTT. CLINICAL SIGNIFICANCE: Both the LSSTT and LSSEG techniques failed to completely restore normal three-dimensional femorotibial translational and rotational movements in cranial cruciate ligament-deficient stifles in vitro. PMID- 23460338 TI - C6orf89 encodes three distinct HDAC enhancers that function in the nucleolus, the golgi and the midbody. AB - We report here that C6orf89, which encodes a protein that interacts with bombesin receptor subtype-3 and accelerates cell cycle progression and wound repair in human bronchial epithelial cells (Liu et al., 2011, PLoS ONE 6: e23072), encodes one soluble and two type II membrane proteins that function as histone deacetylases (HDAC) enhancers. Soluble 34/64sp is selectively targeted to the nucleolus and is retained in nucleolar organiser regions (NORs) in mitotic cells. Nucleolar 34/64sp is integrated into the ribosomal gene transcription machinery, colocalises and coimmunoprecipitates with the Pol I transcription factor UBF, and undergoes a dramatic relocalisation to the nucleolus upon the arrest of rDNA transcription, protein synthesis and PI3K/mTORC2 signalling. Membrane 42/116mp localises to the Golgi and the midbody, and its controlled ectopic expression provokes the disruption of the Golgi cisternae and hinders the separation of daughter cells and the completion of mitosis. The latter effect is also produced by the microinjection of an affinity-purified amfion antibody. The identification of C60rf89 as a gene that encodes three distinct proteins with the capacity to enhance the activity of histone deacetylases (HDACs) in the nucleolus, the Golgi and the midbody provides new information regarding the components of the acetylome and their capacity to interact with different functional groups in the cell. PMID- 23460339 TI - The dynamics and energetics of matrix assembly and mineralization. AB - Formation of biominerals commonly occurs within the context of an organic matrix composed of proteins, polysaccharides, and other macromolecules. Much has been learned about the structure of matrices and the spatial and molecular relationships between matrix and mineral. Only recently has quantitative study of matrix organization and subsequent mineralization been pursued. Here, we review findings from physical studies of matrix assembly in the system of microbial S layer proteins and of calcium carbonate nucleation on organic templates composed of organothiol self-assembled monolayers on noble metals. Studies on S-layers reveal the importance of multistage assembly pathways and kinetic traps associated with the conformational transformations required to build the basic oligomeric building blocks of the matrix. Experimental investigations of calcium carbonate nucleation on carboxyl-terminated self-assembled monolayers combined with theoretical analyses demonstrate the applicability of classical concepts of nucleation, even when cluster-aggregation pathways are considered, and reveal the underlying energetic and structural source of matrix control over the process. Taken together, these studies highlight the ways in which matrix assembly and mineralization deviate from our classical concepts of crystallization but clearly demonstrate that the concepts of physical chemistry that date back to the days of Gibbs and Ostwald still serve us well in understanding the nucleation and growth of organic matrices and mineral phases. PMID- 23460341 TI - MCP-1 expression is specifically regulated during activation of skeletal repair and remodeling. AB - Monocyte chemotactic protein-1 (MCP-1) belongs to the CC chemokine superfamily and plays a critical role in the recruitment and activation of leukocytes during acute inflammation. We hypothesize that MCP-1 is also an important chemokine that regulates the recruitment and activation of bone cells required for skeletal repair and remodeling. We used the ulnar stress fracture (SFx) model, which allows investigation of focal remodeling with a known time course and precise anatomical location. SFx were created in the right ulna of female Wistar rats using cyclic end loading. Unloaded animals were used as a control. Rats were killed 4 h and 1, 4, 7, and 14 days after loading (n = 10/group); RNA was extracted and converted to cDNA for quantitative PCR analysis using TaqMan gene expression assays. Four hours after loading, MCP-1 gene expression was increased ~30-fold (P < 0.001), remained elevated at 24 h (~12-fold, P < 0.001), then declined by day 14. Relative to the contralateral limb, expression of the receptors CCR1 and CCR2 increased over the 14 days, being significant by 4 days for CCR1 and 14 days for CCR2 (P < 0.05). Other inflammation-related chemokines (RANTES, MIP1a) were not increased at these early time points. Using in situ hybridization and immunohistochemistry in separate animal groups (n = 5/group, control, days 1, 4, 7), MCP-1 mRNA and protein were localized in periosteal osteoblasts associated with woven bone formation at the fracture exit point but not in osteocytes adjacent to the SFx. These data support an important role for MCP-1 in the early phase of SFx repair and activated remodeling. PMID- 23460340 TI - Trabecular and cortical microarchitecture in postmenopausal HIV-infected women. AB - Our objective was to assess the effects of HIV infection and antiretroviral therapy on trabecular and cortical microarchitecture in postmenopausal minority women. A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia. HIV infected women were slightly younger (58 +/- 1 vs. 61 +/- 1 years, p = 0.08), and had lower body mass index (BMI; 28 +/- 1 vs. 32 +/- 1 kg/m(2), p < 0.01). BMI adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip, and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5 +/- 2.4 vs. 120.6 +/- 2.0 mm(2), p < 0.01) and thickness (956 +/- 33 vs. 1,075 +/- 28 MUm, p < 0.01) at the tibia were approximately 11-12 % lower in HIV-infected women. Differences remained significant after adjusting for age, BMI, and race/ethnicity. In contrast, cortical porosity was similar in the two groups. Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip, and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia. PMID- 23460342 TI - Construction of eight-membered carbocycles through gold catalysis with acetylene tethered silyl enol ethers. PMID- 23460343 TI - Oral motor movements and swallowing in patients with myotonic dystrophy type 1. AB - Oropharyngeal dysphagia and esophageal motility disorders were found to be the most important causes of aspiration pneumonia in patients with myotonic dystrophy. The purpose of this report was to evaluate clinical characteristics of the oral motor movements and swallowing of individuals with myotonic dystrophy type 1 (DM1) using a standardized clinical protocol and surface electromyography (sEMG). Participants were 40 individuals divided in two groups: G1 composed of 20 adults with DM1 and G2 composed of 20 healthy volunteers paired by age and gender to the individuals in G1. Statistical analysis included one-way ANOVA with two factors for within- and between-group comparisons and Bonferroni correction for multiple comparisons. Patients with DM1 presented deficits in posture, position, and mobility of the oral motor structures, as well as compromised mastication and deglutition. The sEMG data indicated that these patients had longer muscle activations during swallowing events. The longer duration of sEMG in the group of patients with DM1 is possibly related to myotonia and/or incoordination of the muscles involved in the swallowing process or could reflect a physiological adaptation for safe swallowing. PMID- 23460344 TI - The relationship between residue and aspiration on the subsequent swallow: an application of the normalized residue ratio scale. AB - Postswallow residue is widely considered to be a sign of swallowing impairment and is assumed to pose risk for aspiration on subsequent swallows. We undertook a preliminary retrospective study to investigate the link between postswallow residue and penetration-aspiration on the immediately occurring subsequent clearing swallow (i.e., without introduction of a new bolus). Videofluoroscopy clips for 156 thin-liquid single bolus swallows by patients with neurogenic dysphagia were selected for study because they displayed multiple swallows per bolus. Residue for each subswallow (n = 407) was analyzed using the Normalized Residue Ratio Scale for the valleculae (NRRSv) and piriform sinuses. The association between residue presence at the end of a swallow and penetration aspiration on the next swallow was examined. Postswallow residue in one or both pharyngeal spaces was significantly associated with impaired swallowing safety on the subsequent clearing swallow for the same bolus. However, when analyzed separately by residue location, only vallecular residue was significantly associated with impaired swallowing safety on the next clearing swallow. The distribution of NRRSv scores by swallowing safety demonstrated an NRRSv cut-point of 0.09, above which there was a 2.07 times greater relative risk of penetration aspiration. Postswallow vallecular residue, measured using the NRRS, is significantly associated with penetration-aspiration on subsequent clearing swallows. A clinically meaningful cut-point of 0.09 on the NRRSv scale demarcates this risk. Further research with different bolus consistencies is needed. PMID- 23460345 TI - Potential consequences of healthcare recommendations: a focus on the U.S. Preventive Services Task Force. AB - Healthcare guidelines and recommendations have broad-reaching impact. They serve as the evidence to enforce medical testing by establishing a bar for standard of care through their intrinsic credibility but also by affecting reimbursement. In this article, we discuss the various organizations in the United States that develop healthcare policy and guidelines. We focus on the recent recommendations for hepatitis C virus (HCV) screening put forward by these agencies and the potential effect of these documents. Additional discussion is provided on the recent draft HCV screening recommendations provided by the United States Preventive Services Task Force (USPSTF), comparison of these to the Centers for Disease Control and Prevention (CDC) guidelines, and professional societies' response to these. CONCLUSION: As written, the USPSTF recommendations may reduce physician adoption of HCV screening in the 1945-1965 birth cohort as advocated by the CDC. Conflicting guidelines may further confuse providers and the public. This will ultimately hinder recognition of chronic HCV in an otherwise easily identifiable, high prevalence group, allowing progression of disease at a time when therapeutic advances make cure a realistic opportunity for many. PMID- 23460346 TI - Short-term environmental enrichment, in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner. AB - Environmental manipulations can enhance neuroplasticity in the brain, with enrichment-induced cognitive improvements being linked to increased expression of growth factors, such as neurotrophins, and enhanced hippocampal neurogenesis. There is, however, a great deal of variation in environmental enrichment protocols used in the literature, making it difficult to assess the role of particular aspects of enrichment upon memory and the underlying associated mechanisms. This study sought to evaluate the efficacy of environmental enrichment, in the absence of exercise, as a cognitive enhancer and assess the role of Nerve Growth Factor (NGF), neurogenesis and synaptogenesis in this process. We report that rats housed in an enriched environment for 3 and 6 weeks (wk) displayed improved recognition memory, while rats enriched for 6 wk also displayed improved spatial and working memory. Neurochemical analyses revealed significant increases in NGF concentration and subgranular progenitor cell survival (as measured by BrdU+ nuclei) in the dentate gyrus of rats enriched for 6 wk, suggesting that these cellular changes may mediate the enrichment-induced memory improvements. Further analysis revealed a significant positive correlation between recognition task performance and BrdU+ nuclei. In addition, rats enriched for 6 wk showed a significant increase in expression of synaptophysin and synapsin I in the dentate gyrus, indicating that environmental enrichment can increase synaptogenesis. These data indicate a time-dependent cognitive-enhancing effect of environmental enrichment that is independent of physical activity. These data also support a role for increased concentration of NGF in dentate gyrus, synaptogenesis, and neurogenesis in mediating this effect. PMID- 23460347 TI - Arraying cell cultures using PEG-DMA micromolding in standard culture dishes. AB - A robust and effortless procedure is presented, which allows for the microstructuring of standard cell culture dishes. Cell adhesion and proliferation are controlled by three-dimensional poly(ethylene glycol)-dimethacrylate (PEG DMA) microstructures. The spacing between microwells can be extended to millimeter size in order to enable the combination with robotic workstations. Cell arrays of microcolonies can be studied under boundary-free growth conditions by lift-off of the PEG-DMA layer in which the growth rate is accessible via the evolution of patch areas. Alternatively, PEG-DMA stencils can be used as templates for plasma-induced patterning. PMID- 23460348 TI - Effects of a human compact anti-ErbB2 antibody on gastric cancer. AB - BACKGROUND: Gastric cancer represents one of the most common causes of cancer deaths worldwide. Overexpression of ErbB2, a tyrosine kinase receptor involved in the pathogenesis of several human cancer types, has been reported also in gastric cancer. Thus, the inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable strategy for the therapy of this type of cancer. METHODS: We tested for the first time the antitumor effects on gastric cancer cells of Erb-hcAb, a novel fully human compact antibody, prepared in our laboratory, which targets a different epitope of ErbB2 with respect to trastuzumab, the only anti-ErbB2 antibody currently in clinical use for both breast and gastric cancer therapy. RESULTS: Herein we demonstrate that the in vitro and in vivo growth of gastric cancer cells is efficiently inhibited by Erb hcAb, which shows antitumor effects on the NCI-N87 cell line more potent than those observed for trastuzumab. CONCLUSIONS: Erb-hcAb could be a promising candidate in the immunotherapy of gastric cancer as it combines the antiproliferative effect associated with the inhibition of ErbB2 signaling on tumor target cells with the ability to induce antibody-dependent cellular cytotoxicity. PMID- 23460349 TI - Closure of patent ductus arteriosus in children, small infants, and premature babies with Amplatzer duct occluder II additional sizes: multicenter study. AB - OBJECTIVES: To evaluate safety and efficacy of closure of patent ductus arteriosus (PDA) with Amplatzer duct occluder II Additional Sizes (ADO II AS) and to report early and midterm results of the device in children and very young symptomatic infants. METHODS: Retrospective analysis of angiographic data of 60 children from four pediatric cardiology centers. RESULTS: The median patient age and weight were 6.5 (0.5-168) months and 6.8 (1.19-57) kg, respectively. In the study, 26 children had a body weight of <= 6 kg. Of these 26 children, 9 had a body weight of <= 3 kg. The median narrowest diameter of PDA was 2 (1.2-4) mm. Ductal anatomy was Type A in 29, Type B in 2, Type C in 11, Type D in 1, and Type E in 16 patients, and a residual PDA after surgery in 1 patient. Closure with ADO II AS was achieved in 58 (96.6%) of 60 attempted cases. In two infants, the device was not released because of significant residual shunt. ADO II was used in one, and the other was sent to surgery. Complete closure was observed in all ADO II AS deployed children by the next day on echocardiography. Median follow-up was 12 (1-18) months. Neither death nor any major complications occurred. CONCLUSIONS: Our study shows that closure of medium and small sized PDA by using ADO II AS device is effective and safe in children. The use of the device will expand the field of application of PDA closure in small infants. PMID- 23460350 TI - Independence of data points in the measurement of hand preferences in primates: statistical problem or urban myth? AB - Lack of independence of data points or the pooling fallacy has been suggested as a potential problem in the study of handedness in nonhuman primates, particularly as it relates to whether hand use responses should be recorded as individual events or bouts of activity. Here, I argue that there is no evidence that the concept of statistical independence of data points or the pooling fallacy is a problem in the evaluation of population-level handedness in previous studies in nonhuman primates. I further argue these statistical concepts have been misapplied to the characterization of individual hand preferences. Finally, I argue that recording hand use responses as bouts rather than events has no significant effect on reports of hand use in nonhuman primates and, in fact, may unintentionally bias hand use toward the null hypothesis. Several suggestions for improvement in the measurement and statistical determination of individual handedness are offered in the article. PMID- 23460351 TI - CD4(+) tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. AB - Despite the Revised International Prognostic Index's (R-IPI) undoubted utility in diffuse large B-cell lymphoma (DLBCL), significant clinical heterogeneity within R-IPI categories persists. Emerging evidence indicates that circulating host immunity is a robust and R-IPI independent prognosticator, most likely reflecting the immune status of the intratumoral microenvironment. We hypothesized that direct quantification of immunity within lymphomatous tissue would better permit stratification within R-IPI categories. We analyzed 122 newly diagnosed consecutive DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemo-immunotherapy. Median follow-up was 4 years. As expected, the R-IPI was a significant predictor of outcome with 5-year overall survival (OS) 87% for very good, 87% for good, and 51% for poor-risk R IPI scores (P < 0.001). Consistent with previous reports, systemic immunity also predicted outcome (86% OS for high lymphocyte to monocyte ratio [LMR], versus 63% with low LMR, P = 0.01). Multivariate analysis confirmed LMR as independently prognostic. Flow cytometry on fresh diagnostic lymphoma tissue, identified CD4(+) T-cell infiltration as the most significant predictor of outcome with >=23% infiltration dividing the cohort into high and low risk groups with regard to event-free survival (EFS, P = 0.007) and OS (P = 0.003). EFS and OS were independent of the R-IPI and LMR. Importantly, within very good/good R-IPI patients, CD4(+) T-cells still distinguished patients with different 5 year OS (high 96% versus low 63%, P = 0.02). These results illustrate the importance of circulating and local intratumoral immunity in DLBCL treated with R-CHOP. PMID- 23460352 TI - A "field in motion": researchers explore connections between physical activity and cancer. PMID- 23460353 TI - New research on melanoma risk in red-haired people. PMID- 23460354 TI - Ultrasound better than mammography for women younger than 40 years with symptoms of breast cancer. PMID- 23460355 TI - Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes. AB - Several genetically defined hereditary colorectal cancer (CRC) syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, Chi square, Fisher's exact and Wilcoxon rank-sum tests were used for statistical analysis methods. A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the PURIFICAR were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9-71 years); 67.7 % cases had more than 100 polyps and 41.9 % had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2 % of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2 %) prophylactic surgeries and 6 (19.4 %) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34-76 years). Genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8 %, compound heterozygous mutations (G382/Y165C) in 23 %, and non-G382/Y165C monoallelic mutations in 23 %. Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families affected with familial cancer syndromes promoting education, testing and surveillance of at-risk family members, and focusing on cancer prevention efforts. The fact that only 40 % of FAP patients had access to genetic testing stresses the need to promote the establishment of policies supporting genetic testing coverage by medical insurance companies in order to provide patients with the highest standard of care to prevent cancer. Furthermore, our results suggest that Hispanics may have uncommon mutations in adenomatous polyposis related genes, which emphasize the need for full gene sequencing to establish genetic diagnosis. PMID- 23460356 TI - Comparison of primary and delayed wound closure of dog-bite wounds. AB - BACKGROUND: Primary bite wound suturing in the emergency department remains controversial in some cases. OBJECTIVE: We conducted a study to investigate the infection rate and cosmetic appearance between primary wound closure and delayed wound closure in dog bite wounds in humans. METHODS: All patients with bite wounds were treated with oral antibiotic medications. We adopted a randomized cohort study, dividing the patients who needed wound closure into two groups: 60 patients for primary closure, and 60 patients for delayed closure, and compared the infection rate and wound cosmetic appearance scores. RESULTS: In the primary closure group, four people (6.7%) developed a wound infection without systemic infection. In the delayed closure group, three people (5%) developed a wound infection (p = 0.093), but there were not any patients that developed a systemic infection. Thirty-three patients (55%) in the primary closure group had optimal cosmetic scores, whereas 20 patients (33.3%) in the delayed closure group had optimal cosmetic scores (p = 0.012). CONCLUSION: Although primary wound closure for dog bites may be associated with a higher infection rate, the cosmetic appearance after primary closure was still acceptable. PMID- 23460357 TI - Weighing the potential harms of computed tomography: patient survey. PMID- 23460359 TI - [Not Available]. PMID- 23460358 TI - Quantifying the similarity of monotonic trajectories in rough and smooth fitness landscapes. AB - When selection is strong and mutations are rare, evolution can be thought of as an uphill trajectory in a rugged fitness landscape. In this context the fitness landscape is a directed acyclic graph in which nodes are genotypes and edges lead from lower to higher fitness genotypes that differ by a single mutation. Because the space of genotypes is vastly multi-dimensional, classification of fitness landscapes is challenging. Many proposed summary characteristics of fitness landscapes attempt to quantify biologically relevant and intuitive notions such as roughness or peak accessibility in alternative ways. Here we explore, in different types of landscapes, the behavior of the recently introduced mean path divergence which quantifies the degree of similarity among evolutionary trajectories with the same endpoints. We find that monotonic trajectories in empirical and model fitness landscapes are significantly more constrained, with low median path divergence, than those in purely additive landscapes. By contrast, transcription factor sequence specificity (aptamer binding affinity) landscapes are markedly smoother and allow substantial variability in monotonic paths that can be greater than that in fully additive landscapes. We propose that the smoothness of the specificity landscapes is a consequence of the simple dependence of the transcription factor binding affinity on the aptamer sequence in contrast to the complex sequence-fitness mapping in folding landscapes. PMID- 23460360 TI - Hydroxyapatite hierarchically nanostructured porous hollow microspheres: rapid, sustainable microwave-hydrothermal synthesis by using creatine phosphate as an organic phosphorus source and application in drug delivery and protein adsorption. AB - Hierarchically nanostructured porous hollow microspheres of hydroxyapatite (HAP) are a promising biomaterial, owing to their excellent biocompatibility and porous hollow structure. Traditionally, synthetic hydroxyapatite is prepared by using an inorganic phosphorus source. Herein, we report a new strategy for the rapid, sustainable synthesis of HAP hierarchically nanostructured porous hollow microspheres by using creatine phosphate disodium salt as an organic phosphorus source in aqueous solution through a microwave-assisted hydrothermal method. The as-obtained products are characterized by powder X-ray diffraction (XRD), Fourier transform IR (FTIR) spectroscopy, SEM, TEM, Brunauer-Emmett-Teller (BET) nitrogen sorptometry, dynamic light scattering (DLS), and thermogravimetric analysis (TGA). SEM and TEM micrographs show that HAP hierarchically nanostructured porous hollow microspheres consist of HAP nanosheets or nanorods as the building blocks and DLS measurements show that the diameters of HAP hollow microspheres are within the range 0.8-1.5 MUm. The specific surface area and average pore size of the HAP porous hollow microspheres are 87.3 m(2) g(-1) and 20.6 nm, respectively. The important role of creatine phosphate disodium salt and the influence of the experimental conditions on the products were systematically investigated. This method is facile, rapid, surfactant-free and environmentally friendly. The as prepared HAP porous hollow microspheres show a relatively high drug-loading capacity and protein-adsorption ability, as well as sustained drug and protein release, by using ibuprofen as a model drug and hemoglobin (Hb) as a model protein, respectively. These experiments indicate that the as-prepared HAP porous hollow microspheres are promising for applications in biomedical fields, such as drug delivery and protein adsorption. PMID- 23460361 TI - Fibroblast cytoskeletal remodeling induced by tissue stretch involves ATP signaling. AB - Fibroblasts in whole areolar connective tissue respond to static stretching of the tissue by expanding and remodeling their cytoskeleton within minutes both ex vivo and in vivo. This study tested the hypothesis that the mechanism of fibroblast expansion in response to tissue stretch involves extracellular ATP signaling. In response to tissue stretch ex vivo, ATP levels in the bath solution increased significantly, and this increase was sustained for 20 min, returning to baseline at 60 min. No increase in ATP was observed in tissue incubated without stretch or tissue stretched in the presence of the Rho kinase inhibitor Y27632. The increase in fibroblast cross sectional area in response to tissue stretch was blocked by both suramin (a purinergic receptor blocker) and apyrase (an enzyme that selectively degrades extracellular ATP). Furthermore, connexin channel blockers (octanol and carbenoxolone), but not VRAC (fluoxetine) or pannexin (probenecid) channel blockers, inhibited fibroblast expansion. Together, these results support a mechanism in which extracellular ATP signaling via connexin hemichannels mediate the active change in fibroblast shape that occurs in response to a static increase in tissue length. PMID- 23460362 TI - Young colorectal carcinoma patients do not have a poorer prognosis: a comparative review of 2,426 cases. AB - BACKGROUND: Colorectal cancer (CRC) in "young" patients under 50 years of age is uncommon. There have been conflicting reports regarding both the clinicopathological features of CRC in young patients and prognosis. The aim of this study was to review and compare the clinical characteristics, prognostic factors, and overall survival of patients in three different age groups (40 years and under, 41-50 years, over 50 years of age) and the prognosis of these patients. METHODS: A total of 2,426 consecutive patients who had undergone surgical resection for sporadic colorectal cancer at Singapore General Hospital in the period from 2000 to 2005 were retrieved from a prospectively collected computer database. There were 73 patients (3.0 %) in Group 1 (40 years old or less), 257 (10.6 %) in Group 2 (41-50 years old), and 2,096 (86.4 %) in Group 3 (>50 years old). Clinicopathological features were assessed using univariate analysis to evaluate significant differences, survival curves were constructed using the Kaplan-Meier method, and multivariate analysis was performed to evaluate the independent prognostic factors. RESULTS: Young CRC patients tend to present with a higher incidence of mucinous and signet ring cell tumors (Group 1 20.5 %, Group 2-8.2 %, Group 3-6.2 %, p < 0.001) and have more poorly differentiated tumors (Group 1-20.0 %, Group 2-9.7 %, Group 3-7.4 %, p = 0.014). Furthermore, young CRC patients tend to present with regional lymph node metastases (Group 1-65.7 %, Group 2-60.8 %, Group 3-51.0 %, p = 0.001) and distant metastases (Group 1-31.5 %, Group 2-24.1 %, Group 3-19.4 %, p = 0.006). Multivariate analysis reveals, however, that young age is not an independent prognostic factor for cancer-specific survival (CSS) (p = 0.392). Five-year CSS for Group 1 was 56.6 % (95 % confidence interval (CI) 44.8-68.4 %), Group 2 53.8 % (95 % CI 47.3-60.3 %), and Group 3 61.1 % (95 % CI 58.9-63.3 %). CONCLUSIONS: Although presenting with advanced tumors and with poorer prognostic factors such as presence of mucin and poor histological differentiation, young CRC patients do not have a worse prognosis. PMID- 23460363 TI - Buffer-stable chitosan-polyglutamic acid hybrid nanoparticles for biomedical applications. AB - In spite of their attractive features, widespread biomedical applications of CS nanoparticles are yet to be realized due to their poor stability in physiological conditions, such as in buffer system at pH 7.4. Buffer-stable chitosan-based hybrid NPs (HNPs) are reported and characterized. Buffer stability is achieved by introducing polyglutamic acid to chitosan. The effect of PGA to CS molar ratio and crosslinking on HNP integrity, buffer stability, and biodegradability are studied. Preliminary in vitro studies are carried out to evaluate targeted uptake efficiency of folate conjugated HNPs. Successful demonstration of buffer stability and cancer cell targeting by HNPs achieves important milestones for chitosan-based nanoparticle technology. PMID- 23460364 TI - C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. AB - Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9(+) macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-alpha)-producing CCR9(+) macrophages accumulated during the initiation of carbon tetrachloride (CCl4 )-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9(+) macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9(-/ ) mice compared with wild-type (WT) mice, assessed by alpha-smooth muscle actin (alpha-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of alpha-SMA, collagen 1alpha1, transforming growth factor (TGF)-beta1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b(+) macrophages in CCl4 -treated WT mice showed marked increases in TNF, NO synthase 2, and TGF-beta1 mRNA expression compared with CCR9(-/-) mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b(+) macrophages from CCl4 -treated WT mice (i.e., CCR9(+) macrophages), but not CD8(+) T lymphocytes or non-CD11b(+) cells, significantly activated HSCs in vitro compared with those from CCR9(-/-) mice. TNF-alpha or TGF-beta1 antagonism attenuated CCR9(+) macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. CONCLUSION: Accumulated CD11b(+) macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis. PMID- 23460365 TI - Massive aortic regurgitation following paravalvular balloon valvuloplasty of an Edwards SAPIEN valve treated by emergent CoreValve implantation: never cross a transcatheter aortic valve without a pigtail. AB - A 72-year-old patient, with a history of coronary artery bypass and aorto bifemoral graft, was diagnosed with a symptomatic severe aortic valve stenosis in the presence of moderately decreased left ventricular function. The Heart team decision was to implant an Edwards SAPIEN XT 26 mm valve by transapical approach, therefore avoiding access through the aorto-bifemoral graft. At the end of the procedure, grades 2-3 aortic regurgitation was observed. Since each run of rapid pacing ended in ventricular fibrillation, it was decided to treat the aortic regurgitation conservatively with the option of post-dilation in a second procedure if hemodynamic deterioration was observed. Six days later balloon valvuloplasty was performed because of heart failure requiring endotracheal intubation. Despite transesophageal echocardiography guidance the balloon was inadvertently advanced through the paravalvular space. As a consequence, balloon valvuloplasty was complicated by massive aortic regurgitation and severe hemodynamic instability which was resolved after emergency transfemoral implantation of a CoreValve. Without any further complications, the patient was discharged eight days later. PMID- 23460366 TI - Gene-environment interaction between DRD4 7-repeat VNTR and early child-care experiences predicts self-regulation abilities in prekindergarten. AB - Intervention studies indicate that children's early child-care experiences can be leveraged to foster their development of effective self-regulation skills. It is less clear whether typical child-care experiences play a similar role. In addition, evidence suggests that children with a common variant of the DRD4 gene (48-bp VNTR, 7-repeat) may be more sensitive to their experiences than those without this variant. Using data from the NICHD Study of Early Child Care and Youth Development, we considered the degree to which children's early child-care experiences-quantity, quality, and type-were associated with their attention and self-regulation abilities in prekindergarten, and, in particular, whether these relations were conditional on DRD4 genotype. G * E interactions were evident across multiple neuropsychological and observational measures of children's attention and self-regulation abilities. Across most outcome measures, DRD4 7+ children spending fewer hours in child care showed more effective attention/self regulation abilities. For those without a copy of the DRD4 7-repeat allele, such associations were typically null. The results for child-care quality and type indicated no interactions with genotype; the main-effect associations were somewhat inconsistent. PMID- 23460367 TI - Inactivation of p27kip1 promotes chemical hepatocarcinogenesis through enhancing inflammatory cytokine secretion and STAT3 signaling activation. AB - Although the expression of p27 has been regarded as a prognostic parameter in human liver cancer since the implication of decreased p27 expression levels in the genesis and progression of hepatocellular carcinoma (HCC), the molecular mechanism linking p27 deficiency and HCC development is still unclear. Here, we report an increase in tumorigenesis and progression as well as an enhanced inflammatory response in p27 deficient mice (p27(-/-)) and hypothesize the possible mechanism. We show that p27(-/-) mice display increased proliferation and decreased apoptosis of tumor cells, accompanied by an increase in the serum inflammatory cytokines IL-6 and TNF-alpha. Furthermore, our data indicated that the increased number and signal transducers and activator of transcription 3 (STAT3) phosphorylation status of infiltrated inflammatory cells was accompanied by increased IL-6 and TNF-alpha mRNA levels in tumor and normal liver tissue in the p27(-/-) mice. Moreover, using tumor cell and splenocytes co-culture and tumor homologous transplantation, we validated our hypothesis in vitro and in vivo. Collectively, these data demonstrate that the loss of p27 promotes carcinogens-induced HCC genesis and progression via the elevation of inflammatory cytokines and the augmented activation of STAT3 signaling in tumor cells and infiltrated inflammatory cells. Altogether, the loss of the cyclin kinase inhibitor p27, traditionally regarded as a consequence of DNA damage, can in turn promote HCC progression through enhancing the inflammatory response, potentially representing a promising therapeutic target in the prevention of HCC genesis and progression. PMID- 23460369 TI - New information on the modifications of the Neandertal suprainiac fossa during growth and development and on its etiology. AB - The question of whether suprainiac depressions observed on Neandertals and in other human samples are homologous is widely discussed. Recently (Balzeau and Rougier, 2010), we ascertained the autapomorphic status of the Neandertal suprainiac fossa as a depression showing specific external bone features together with a thinning of the diploic layer with no substantial remodeling nor variation in the external table thickness. A suprainiac fossa with these characteristics is systematically present on Neandertals from the earliest developmental stages on, and since the beginning of the differentiation of the Neandertal lineage. Here, we present a detailed analysis of the micro-CT dataset (resolution of 50 MUm) of the occipital bone of the La Ferrassie 8 Neandertal child, whose proposed age-at death is around 2 years, and we compare it to the adult condition as represented by La Chapelle-aux-Saints 1 (resolution of 122 MUm). We describe and quantify the boundaries between the different structural layers of the occipital bone, namely the external and internal tables and the diploic layer. We also describe very fine details of the diploic layer structure that had never before been observed on fossil hominins. This study illustrates for the first time that the internal particularities that make the suprainiac fossa a Neandertal autapomorphy are evident early during growth and development. Moreover, we demonstrate that the developmental pattern and causes of expression for the features observed in modern humans and Neandertals are certainly different, indicating that these features are not homologous traits from evolutionary and functional perspectives. Consequently, we confirm the autapomorphic status of the Neandertal suprainiac fossa. PMID- 23460368 TI - Effects of the GABA-uptake blocker NNC-711 on spontaneous sharp wave-ripple complexes in mouse hippocampal slices. AB - The precise temporal and spatial activity patterns of neurons in cortical networks are organized by different state-dependent types of network oscillations. GABAergic inhibition plays a key role in the underlying mechanisms of such oscillations and it has been suggested that the duration of widely distributed phasic inhibitory postsynaptic potentials (IPSPs) determines the frequency of the resulting network oscillation. Here, we test this hypothesis in an in vitro model of sharp wave-ripple (SPW-R) complexes, a particularly fast pattern of network oscillations at ~200 Hz which is involved in memory consolidation. We recorded SPW-R in mouse hippocampal slices in the absence and presence of NCC-711, an inhibitor of GABA uptake. The resulting prolongation of IPSP resulted in reduced occurrence of SPW-R, whereas the superimposed fast oscillations as well as the precision of rhythmic cell synchronization remained stable. Application of Diazepam which is a positive modulator of the GABAA receptor led to consistent results. We conclude that phasic inhibition is a major regulator of network excitability in CA3 (where SPW-Rs are generated), but does not set the frequency of hippocampal ripples. PMID- 23460370 TI - Dodecaploid H1 embryonic stem cells abolished pluripotency in L15F10 medium both with and without leukemia inhibitory factor. AB - Two lines of dodecaploid H1 embryonic stem cells, 12H1 and 12H1(-) cells (mouse originated cells), were established through polyploidization of two hexaploid H1 cells, 6H1 and 6H1(-) cells, which were cultured in L15F10 (7:3) medium with and without leukemia inhibitory factor (LIF), respectively. The G1, S, and G2/M phase fractions of 12H1 and 12H1(-) cells were almost the same as those of 6H1 and 6H1( ) cells, respectively, but the doubling time of cell proliferation was prolonged, suggesting that cell death occurred in 12H1 and 12H1(-)cells. The cell volumes of 12H1 and 12H1(-) cells were about double those of 6H1 and 6H1(-) cells, respectively. 12H1 and 12H1(-) cells showed near-negative activity of alkaline phosphatase and no ability to form teratocarcinomas in mouse abdomen, suggesting that 12H1 and 12H1(-) cells lost pluripotency. The DNA contents of 12H1 and 12H1( ) cells decayed in long-term culturing, suggesting that 12H1 and 12H1(-) cells were DNA-unstable. Possible explanations for the lost pluripotency and for the DNA decay in 12H1 and 12H1(-) cells are presented. PMID- 23460371 TI - Decreased EGR3 expression is related to poor prognosis in patients with gastric cancer. AB - The early growth response (EGR) family has a highly conserved DNA-binding domain and encodes zinc finger proteins, which show suppressive effects on tumour growth. However, the expression and significance of EGR3 in gastric cancer are still unknown. In this study, real-time PCR, immunohistochemistry and western blot assays were performed to detect the expression of EGR3 in gastric cancer tissues and matched non-tumour tissues and to further analyse the EGR3 expression associated with clinical pathological factors, including prognosis. Our results showed that EGR3 expression was significantly lower in gastric cancer tissues compared with matched non-tumour tissues and that patients with lower EGR3 expression had a poorer prognosis compared with patients with higher EGR3 expression. Our results suggest that decreased EGR3 expression might play a critical role in the differentiation, proliferation, metastasis and progression of gastric cancer cells and may also be a potential diagnostic marker for gastric cancer. PMID- 23460372 TI - Peptide fragment coupling using a continuous-flow photochemical rearrangement of nitrones. PMID- 23460373 TI - Ex vivo evaluation of the biomechanical effect of varying monocortical screw numbers on a plate-rod canine femoral gap model. AB - OBJECTIVE: To compare the biomechanical behaviour of plate-rod constructs with varying numbers of monocortical screws applied to an ex vivo canine femoral-gap ostectomy model. SAMPLE POPULATION: Twenty Greyhound dog cadaveric femurs. METHODS: Bone mineral density (BMD) was assessed with dual x-ray absorptiometry. Bones were assigned to four groups. Bones had a 12-hole 3.5 mm locking compression plate with one bicortical non-locking cortical screw in the most proximal and distal plate holes and an intramedullary Steinmann pin applied across a 20 mm mid-diaphyseal ostectomy. Additionally, one to four monocortical non-locking cortical screws were then placed (Groups 1-4 respectively) in the proximal and distal fragments. Stiffness and axial collapse were determined before and after cyclic axial loading (6000 cycles at 20%, 40%, and 60% of mean bodyweight [total: 18000 cycles]). Constructs subsequently underwent an additional 45000 cycles at 60% of bodyweight (total: 63000 cycles). Loading to failure was then performed and ultimate load and mode of failure recorded. RESULTS: The BMD did not differ significantly between groups. Construct stiffness for group 1 was significantly less than group 4 (p = 0.008). Stiffness showed a linear increase with an increasing number of monocortical screws (p = 0.001). All constructs survived fatigue loading. Load-to-failure was not significantly different between groups. Mean load- to-failure of all groups was >1350N. CLINICAL RELEVANCE: Ex vivo canine large-breed femurs showed adequate stability biomechanically and gradually increasing stiffness with increasing monocortical screw numbers. PMID- 23460374 TI - Comparison of MR and fluoroscopic mucous fistulography in the pre-operative evaluation of infants with anorectal malformation: a pilot study. AB - BACKGROUND: Anorectal malformations are often associated with rectal pouch fistulas. Surgical correction requires accurate evaluation of the presence and position of such fistulas. Fluoroscopy is currently the chosen modality for the detection of fistulas. The role of MRI is unexplored. OBJECTIVE: To compare the diagnostic accuracy of MR versus fluoroscopic fistulography in the pre-operative evaluation of infants with anorectal malformation. MATERIALS AND METHODS: We conducted a pilot study of infants requiring defunctioning colostomy for initial management of anorectal malformation. Dynamic sagittal steady-state free precession MRI of the pelvis was acquired during introduction of saline into the mucous fistulas. Findings were compared among MR fistulography, fluoroscopic fistulography and intraoperative inspection. RESULTS: Eight children were included. Median age at fistulography was 15 weeks, inter-quartile range 13-20 weeks; all were boys. There was full agreement among MR fistulography, fluoroscopic fistulography and surgical findings. CONCLUSION: The pilot data suggest that MR fistulography is promising in the pre-operative evaluation of children with anorectal malformation. PMID- 23460375 TI - Genetically proven cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a 3-year-old. AB - Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has always been considered to be a middle-age-onset disease. Diagnosis is confirmed by genetic testing and the finding of the Notch3 mutation or by skin biopsy. Imaging plays a pivotal and crucial role in confirming this diagnosis by identifying white matter changes early in the disease. This can be useful in screening symptomatic patients with a family history of the disease. CADASIL cases have been reported recently in children. We report our experience with CADASIL in a 3-year-old boy. PMID- 23460376 TI - [A rare cause of a chronic bleeding in the upper gastrointestinal tract]. PMID- 23460377 TI - Analysis of new classes of recreational drugs in sewage: synthetic cannabinoids and amphetamine-like substances. AB - The analysis of sewage for the residues of commonly used illicit drugs has successfully been applied as a suitable approach for estimating community illicit drug use. The drug market is increasingly dynamic with new substances continually being marketed for recreational purposes. In this study, ultra-high pressure liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was used to simultaneously and quantitatively detect the exogenous biomarkers of new classes of recreational drugs in sewage collected from three different Norwegian cities (Oslo, Bergen, Hamar). The samples were screened for the presence of khat (d-norpseudoephedrine and cathinone), mephedrone, pseudoephedrine, 7 aminoflunitrazepam, para-methoxyamphetamine (PMA), para-methoxy-N methylamphetamine (PMMA) and a selection of urinary metabolites of synthetic cannabinoids collectively termed 'Spice' (5-3-1-naphthoyl-1H-indol-1-yl-pentanoic acid (JWH 018 N-pentanoic acid), 1-5-hydroxypentyl-1H-indol-3-ylnaphthalen-1-yl methanone (JWH 018 N-5-hydroxypentyl), 4-3-1-naphthoyl-1H-indol-1-yl-butanoic acid (JWH 073 N-butanoic acid), 1-4-hydroxybutyl-1H-indol-3-ylnaphthalen-1-yl methanone (JWH 073 N-4-hydroxybutyl), 1-5-hydroxypentyl-1H-indol-3-yl4 methylnaphthalen-1-yl-methanone (JWH 122 N-5-hydroxypentyl), 1-5-fluoro-4 hydroxypentyl-1H-indol-3-ylnaphthalen-1-ylmethanone (AM2201 N-4-hydroxypentyl), and 1-5-hydroxypentyl-1H-indol-3-yl4-methoxyphenyl-methanone (RCS-4 N-5 hydroxypentyl)). Limits of detection were 1 ng/L for amphetamine like compounds and 5 ng/L for the metabolites of synthetic cannabinoids while the limits of quantification were 3 and 15 ng/L, respectively. Three of the fourteen selected biomarkers (cathine, pseudoephedrine and the synthetic cannabinoid metabolite JWH 018 N-5-hydroxypentyl) were detected in sewage, alongside the illicit drugs (and/or metabolites) typically found in sewage (cocaine, benzoylecognine, methamphetamine, MDMA, and THC-COOH). The khat biomarker d-norpseudoephedrine was detected in Oslo sewage at a mean concentration of 93 ng/L that represents a daily load of 54 mg/day/1000 inhabitants. Pseudoephedrine was present at mean concentrations of between 27 and 67 ng/L representing normalized daily loads of between 10 (Hamar) and 24 mg/day/1000 inhabitants (Bergen). The daily normalized loads of JWH-018 N-5-hydroxypentyl were between 49 (Oslo) and 62 mg/day/1000 inhabitants (Hamar). This study demonstrates for the first time that sewage biomarker analysis can be applied to evaluate not only the use the traditional illicit drugs (cocaine, cannabis and amphetamines), but also the use of certain new synthetic drugs. PMID- 23460378 TI - Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation. AB - Tacrolimus-associated posterior reversible encephalopathy syndrome (PRES) is a potential complication of allogeneic stem cell transplant (SCT). Due to the paucity of information on the management of PRES in SCT patients receiving tacrolimus, more information is needed on trends associated with the incidence of PRES and to characterize its management. A retrospective review was conducted of patients receiving tacrolimus for prevention of graft versus host disease (GVHD) after allogeneic SCT who developed PRES from September 2008 to July 2011. Nineteen patients were identified. Altered mental status, seizures, and visual abnormalities were experienced by 78.9%, 52.6%, and 31.5% of the patients, respectively, at time of PRES onset. Compared with baseline, patients with PRES were likely to have an increase in mean arterial pressure (P < 0.0001) and serum creatinine. Elevated tacrolimus levels and hypomagnesemia were not observed with PRES onset. Tacrolimus was managed in three general strategy groups: not held, held then continued, and switched to another agent. Survival was defined as survival to discharge from PRES hospitalization. When tacrolimus was not held, held then continued, or switched to another agent, 40% (2 of 5), 40% (4/10), and 50% (2/4) survived to discharge, respectively. PRES was associated with high blood pressure and adequate blood pressure control should be part of its management. No management strategy pertaining to tacrolimus usage appeared more beneficial over another. PMID- 23460380 TI - Controlled synthesis of thorium and uranium oxide nanocrystals. AB - Very little is known about the size and shape effects on the properties of actinide compounds. As a consequence, the controlled synthesis of well-defined actinide-based nanocrystals constitutes a fundamental step before studying their corresponding properties. In this paper, we report on the non-aqueous surfactant assisted synthesis of thorium and uranium oxide nanocrystals. The final characteristics of thorium and uranium oxide nanocrystals can be easily tuned by controlling a few experimental parameters such as the nature of the actinide precursor and the composition of the organic system (e.g., the chemical nature of the surfactants and their relative concentrations). Additionally, the influence of these parameters on the outcome of the synthesis is highly dependent on the nature of the actinide element (thorium versus uranium). By using optimised experimental conditions, monodisperse isotropic uranium oxide nanocrystals with different sizes (4.5 and 10.7 nm) as well as branched nanocrystals (overall size ca. 5 nm), nanodots (ca. 4 nm) and nanorods (with ultra-small diameters of 1 nm) of thorium oxide were synthesised. PMID- 23460379 TI - Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. AB - IMPORTANCE: Although febrile neutropenia (FN) is a major source of morbidity and mortality for patients with solid tumors, little is known about the use of guideline-based care. OBJECTIVES: To examine compliance with guideline-based recommendations for FN treatment, explore the factors that influence adherence to consensus guidelines, and analyze how the use of guideline-based care affects the outcomes. DESIGN: The Perspective database was used to examine the treatment of cancer patients with FN from January 1, 2000, through March 31, 2010. To capture initial decision making, we examined treatment within 48 hours of hospital admission. We determined use of guideline-based antibiotics and nonguideline based treatments, vancomycin, and granulocyte colony-stimulating factors (GCSF). Hierarchical models were developed to examine the factors associated with treatment. Patients were stratified into low- and high-risk groups, and the effect of the initial treatment on outcome (nonroutine hospital discharge and death) was examined. SETTING AND PARTICIPANTS: Twenty-five thousand two hundred thirty-one patients with solid tumors hospitalized for neutropenia. MAIN OUTCOME MEASURE: Use of guideline-based antibiotics, vancomycin, and GCSF and their affect on outcome. RESULTS: Among 25 231 patients admitted with FN, guideline based antibiotics were administered to 79%, vancomycin to 37%, and GCSF to 63%. Patients treated at high FN-volume hospitals (odds ratio [OR], 1.56; 95% CI, 1.34 1.81) by high FN-volume physicians (OR, 1.19; 95% CI, 1.03-1.38) and patients managed by hospitalists (OR, 1.49; 95% CI, 1.18-1.88) were more likely to receive guideline-based antibiotics (P < .05). Vancomycin use increased from 17% in 2000 to 55% in 2010, while GCSF use only decreased from 73% to 55%. Among low-risk patients with FN, prompt initiation of guideline-based antibiotics decreased discharge to a nursing facility (OR, 0.77; 95% CI, 0.65-0.92) and death (OR, 0.63; 95% CI, 0.42-0.95). CONCLUSIONS AND RELEVANCE: While use of guideline-based antibiotics is high, use of the nonguideline-based treatments, vancomycin, and GCSF is also high. Physician and hospital factors are the strongest predictors of both guideline- and nonguideline-based treatment. PMID- 23460381 TI - Interleukin-8 induces an elevation in the endotoxin activity assay (EAA) level: does the EAA truly measure the endotoxin level? AB - The endotoxin activity assay (EAA) is a FDA-approved blood endotoxin assay that is reported as a useful tool for the diagnosis of gram-negative bacterial infection. However, discrepancies between the results of the EAA and those of the limulus amebocyte lysate (LAL) assay have been reported. Thus, we verified these methods. Blood was incubated with anti-endotoxin antibody, the resultant polymorphonuclear activation to produce oxidants was measured and the EAA level calculated. As a reference endotoxin assay, we used an endotoxin-specific LAL assay. Significant increases in plasma LAL assay levels were observed only in patients with sepsis caused by gram-negative bacterial infections, whereas higher EAA levels were observed in almost all the sepsis cases and the SIRS cases, especially those with acute pancreatitis. Graded amounts of LPS (1-10,000 pg/ml) were spiked into normal blood to obtain dose-response curves: a good dose response curve, from 1 to 1,000 pg/ml, was obtained for the LAL assay. A good dose-response curve was barely obtained for the EAA; the lowest detection limit seemed to be 1,000 pg/ml. Addition of methylprednisolone decreased the EAA levels. Interleukin-8 (IL-8) induced elevation in EAA levels when IL-8 was added to volunteers' blood samples. Overall, the EAA kit could not measure clinically relevant doses of endotoxin. Because IL-8 induced an increase in EAA level, it is suggested that the EAA level reflects the primed state of polymorphonuclear leukocytes. PMID- 23460382 TI - Overexpressed-eIF3I interacted and activated oncogenic Akt1 is a theranostic target in human hepatocellular carcinoma. AB - Eukaryotic translation initiation factor 3 subunit I (eIF3I) with transforming capability is often overexpressed in human hepatocellular carcinoma (HCC) but its oncogenic mechanisms remain unknown. We demonstrate that eIF3I is overexpressed in various cancers along with activated Akt1 phosphorylation and kinase activity in an eIF3I dose-dependent manner. A novel eIF3I and Akt1 protein interaction was identified in HCC cell lines and tissues and was required for eIF3I-mediated activation of Akt1 signaling. Expression of either antisense eIF3I or dominant negative Akt1 mutant suppressed eIF3I-mediated Akt1 oncogenic signaling and various other tumorigenic effects. Oncogenic domain mapping of the eIF3I and Akt1 interaction suggested that the C-terminal eIF3I interacted with the Akt1 kinase domain and conferred the majority of oncogenic functions. In addition, eIF3I interaction with Akt1 prevented PP2A dephosphorylation of Akt1 and resulted in constitutively active Akt1 oncogenic signaling. Importantly, concordant expression of endogenous eIF3I and phospho-Akt1 was detected in HCC cell lines and tissues. Treatment of eIF3I overexpressing HCC cells with the Akt1 specific inhibitor API-2 suppressed eIF3I-mediated tumorigenesis in vitro and in vivo. CONCLUSION: We describe a constitutive Akt1 oncogenic mechanism resulting from interaction of overexpressed eIF3I with Akt1 that prevents PP2A-mediated dephosphorylation. Overexpression of eIF3I in HCC is oncogenic and is a surrogate marker and therapeutic target for treatment with Akt1 inhibitors. PMID- 23460383 TI - Thermoplastic polyurethanes from undecylenic acid-based soft segments: structural features and release properties. AB - A set of thermoplastic polyurethanes is synthesized, combining undecylenic acid derived telechelic diols as soft segments and 1,4-butanediol/4,4' methylenebis(phenylisocyanate) as a hard segment (HS). These polymers are fully chemically and physically characterized by means of NMR and Fourier transform IR (FTIR) spectroscopy, size-exclusion chromatography (SEC), DSC, thermogravimetric analysis (TGA), tensile testing, and contact angle measurements. The obtained results reveal that both the molecular weight of the diol and the HS content greatly influence the physical and mechanical properties of these polymers. In addition, given the potential use of these materials for biomedical applications, hydrolytic degradation, their biocompatibility using a human fibroblast cell line, and performance as drug delivery carriers are evaluated. PMID- 23460384 TI - Sex and litter effects on anxiety and DNA methylation levels of stress and neurotrophin genes in adolescent rats. AB - Maternal care variations associate with DNA methylation of the glucocorticoid receptor gene, Nr3c1, in hippocampus at a nerve-growth factor-inducible protein 1 binding site. Epigenetic regulation of brain-derived neurotrophin factor is affected by early stress. These systems contribute to anxiety and fear. Early stress has sex-dependent effects perhaps reflecting sex differences in maternal care. Altering litter gender composition affects maternal behavior and DNA methylation levels of another gene in hippocampus and nucleus accumbens (NAc). We now test if DNA methylation levels of Nr3c1, Egr1, and Bdnf differ by litter composition or sex. Rats from mixed- or single-sex litters were tested for anxiety and fear on postnatal day 35. Brain tissues were collected and analyzed using direct sequencing methods. Females showed hypermethylation of Nr3c1 of hippocampal DNA and litter composition modified sex effects on methylation of Egr1 in NAc. Few differences were seen for Bdnf. LGC modified some sex differences in behavior. PMID- 23460385 TI - Neointimal tissue component assessed by tissue characterization with 40 MHz intravascular ultrasound imaging: comparison of drug-eluting stents and bare metal stents. AB - OBJECTIVES: The present study used iMap IVUS system to compare neointimal tissue components between DES and bare-metal stents (BMSs). BACKGROUND: Drug-eluting stents (DESs) can cause impaired arterial healing, which constitutes the most important pathological substrate underlying late DES thrombosis. Intravascular ultrasound (IVUS)-based tissue characterization allows for the in vivo identification of neointimal tissue components. METHODS AND RESULTS: Follow-up IVUS data after coronary stenting (9.8 +/- 9.4 months from index procedures) was obtained from consecutive 61 lesions (34 in DES, 27 in BMS). The iMap tissue components (fibrotic, lipidic, necrotic, and calcified) were measured in every recorded frame and expressed as percentages of mean neointimal cross-sectional area for the stented segment. Patients' characteristics were comparable between DES and BMS. When compared with BMSs, smaller (2.9 +/- 0.4 mm vs. 3.2 +/- 0.4 mm, P = 0.004) and longer (34 +/- 18 mm vs. 26 +/- 14 mm, P = 0.03) DESs were implanted. When compared with BMS group, minimum lumen area at follow-up was significantly greater in DES group (3.9 +/- 1.8 mm(2) vs. 3.1 +/- 1.5 mm(2) , P < 0.04), mainly attributable to suppression of neointimal hyperplasia (1.7 +/- 0.8 mm(2) vs. 3.1 +/- 1.5 mm(2) , P < 0.0001). The iMap analyses showed that neointima after DES placement was composed of smaller fibrotic component (67 +/- 8% vs. 78 +/- 7%, P < 0.0001), larger necrotic (14 +/- 4% vs. 9 +/- 3%, P < 0.0001) and calcified (15 +/- 6% vs. 7 +/- 4%, P < 0.0001) components compared with BMS. Logistic regression analysis showed that only intra-DES neointima was a significant predictor of necrotic neointima at follow-up. CONCLUSIONS: DES implantation would be associated with iMap-derived necrotic and less-fibrotic neointimal formation. In vivo iMap evaluation of neointimal tissue may provide useful information in detecting impaired healing after stenting. PMID- 23460386 TI - Adherence to the preventive strategies for nonsteroidal anti-inflammatory drug- or low-dose aspirin-induced gastrointestinal injuries. AB - As the aging of the population advances, the use of nonsteroidal anti inflammatory drugs (NSAIDs) and/or low-dose aspirin (LDA) is increasing. Their use is accompanied by a risk of serious complications, such as hemorrhage or perforation of the gastrointestinal tract. Therefore, gastroprotective strategies upon the prescription of NSAIDs/LDA are outlined in several guidelines or recommendations. Because all NSAIDs including cyclooxygenase (COX)-2 inhibitors have cardiovascular (CV) toxicity, recent guidelines are based on not only GI risks but also CV risks of NSAID users. Assessment of the adherence to evidence based guidelines or recommendations for the safe prescription of NSAIDs/LDA in clinical practice is an important issue. Here, we summarize randomized controlled trials (RCTs) on the preventive effects of antisecretory drugs for NSAID- or LDA induced peptic ulcers. Then, we describe preventive strategies upon the prescription of NSAIDs/LDA outlined in several guidelines or recommendations, and describe studies on adherence and outcomes of adherence to these preventive strategies. Finally, we discuss strategies to increase the adherence rate, and changing pattern of GI events associated with NSAIDs/LDA. In Japan, the preventive strategies upon the prescription of NSAIDs/LDA are expected to spread rapidly because the use of proton pump inhibitors for the prevention of recurrence of NSAID- or LDA-induced peptic ulcers and the use of COX-2 for the palliation of acute pain were recently approved under the national health insurance system. Further studies on adherence to the preventive strategies and the outcomes of adherence, which include both GI events and CV events, in the Japanese population are required. PMID- 23460388 TI - Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning. AB - The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning. PMID- 23460387 TI - Predictors of delayed-type hypersensitivity to Candida albicans and anti-Epstein Barr virus antibody among children in Kilimanjaro, Tanzania. AB - We evaluated sex, age, nutritional status, and infectious disease (ID) as predictors of two biomarkers of cell-mediated immunity (CMI), delayed-type hypersensitivity to Candida albicans (DTH-Candida), and anti-Epstein-Barr virus antibody (EBV Ab), among 200 children in Kilimanjaro, Tanzania. DTH-Candida, which decreases with compromised CMI, was positively associated with age (OR: 1.27; 95% CI: 1.02, 1.57) and triceps skinfold (TSF; OR: 1.16; 95% CI: 1.02, 1.26), and inversely associated with height-for-age Z score (HAZ; OR: 0.86; 95% CI: 0.68, 1.08) and diagnosed ID (OR: 0.48; 95% CI: 0.22, 1.08). There was significant interaction between TSF and ID: DTH-Candida exhibited a strong inverse association with ID among children with low TSF (OR: 0.16; 95% CI: 0.05, 0.50) and a strong positive association with TSF among children with ID (OR: 2.64; 95% CI: 1.29, 5.42). EBV Ab, which increases with compromised CMI, was inversely associated with male sex (beta: -0.47; 95% CI: -0.70, -0.24) and TSF (beta: -0.04; 95% CI: -0.08, 0.00), and positively associated with HAZ (beta: 0.06; 95% CI: -0.03, 0.15). Among males, EBV Ab was positively associated with anemia. Among normal HAZ children, EBV Ab was inversely associated with TSF. There was no association between DTH-Candida and EBV Ab. While DTH-Candida provides a direct measure of CMI, our results suggest that interpretation of EBV Ab among Kilimanjaro children was complicated by its indirect relationship with CMI. Among our sample, CMI increased with age and adequate nutrition and was compromised during acute ID. The suggestive CMI-compromising effect of increasing height-for-age may bear further exploration. PMID- 23460390 TI - [Interleukin-1-mediated diseases]. AB - Interleukin-1 (IL-1)-mediated diseases are caused by an inappropriately high production and release of IL-1 beta which results in a multitude of symptoms, e.g. arthritis, exanthema, conjunctivitis, serositis, fever and loss of hearing. If IL-1-mediated diseases remain unrecognized or are recognized and treated too late, long-term complications, such as amyloidosis may occur. In recent years the diagnostic and therapeutic options with respect to IL-1-mediated diseases have drastically improved. These diseases often manifesting in childhood can now be treated with monoclonal antibodies against IL-1 or with IL-1 receptor antagonists. Increased IL-1 secretion does not only play a role in relatively rare hereditary diseases, such as cryopyrin-associated periodic fever syndromes or familial Mediterranean fever but also in widespread diseases, such as gout or type 2 diabetes. This article will focus on pathogenic, diagnostic and therapeutic aspects of IL-1-mediated inflammatory diseases. PMID- 23460391 TI - [Drug-induced malignant arrhythmias. IT prevents lethal drug mixtures]. AB - We report a case of nearly fatal ventricular tachyarrhythmia type Torsade de pointes caused by medication-induced prolongation of QTc duration (methadone, ondansetron, escitalopram). The etiology, pathophysiology, and trigger mechanisms of such malignant arrhythmias are discussed. In order to prevent similar iatrogenic complications in the future, we networked the qtdrug database with our medication interaction control program and installed an automatic electronic warning system for the physicians in charge in case of a digitally recorded prolonged QTc duration. PMID- 23460392 TI - Treatment of immigrants and residents suffering from neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome. AB - This study aimed at determining the clinical features and predictors for the outcome of patients with Neuro-Aids treated on a neurological intensive care unit (NICU) using retrospective analysis of all patients treated for Neuro-Aids in a tertiary Department of Neurology between 1996 and 2011. Chart review of the patients including the characteristics of intensive care was performed. As negative outcome, "death on the NICU or within 2 months following completion of NICU treatment" was defined. In total, 462 patients were identified of whom 87 were immigrants. 67 of all patients required NICU treatment (mean age 40.2 +/- 0.8 years; 64% male). The median of the duration between diagnosis of HIV infection and the onset of treatment on NICU was 8 days for immigrants and 10 years for residents (p < 0.001). 34 of the patients on the NICU died due to severe neuromanifestations. Negative predictors for death were: (1) artificial ventilation; (2) antiretroviral-naive immigrant; (3) primary cerebral lymphoma; (4) missing antiretroviral therapy upon admission to the NICU. Gender, age, ethnicity, CD4+ cell count, and viral load were no predictors of a negative outcome. The results indicated that the rate of death during treatment on a NICU is much higher as compared with treatment on an internal medicine ICU. A lot of research and effort will be necessary to improve this outcome especially for immigrants with Neuro-Aids. PMID- 23460393 TI - "L'union fait la force". PMID- 23460394 TI - Predictive value of health-related quality of life in progression of disability and depression in persons with multiple sclerosis: a 3-year study. AB - In our study, we examined whether health-related quality of life (HRQoL) could predict changes in disability, depression, and fatigue in patients with multiple sclerosis (MS) over a 3-year follow-up period. A group of 109 consecutive MS patients (McDonald's criteria) referring to the Institute of Neurology, Belgrade were enrolled in the study. At two time points during the study (baseline, and after a 3-year period) an HRQoL (measured by MSQoL-54), EDSS, Hamilton Rating Scale for Depression (HDRS) and Fatigue Severity Scale (FSS) were assessed. At the end of a 3-year follow-up, 12 out of 109 patients (11%) had dropped out. Multiple linear regression analysis showed that Physical Health scale of MSQoL-54 is significant independent predictor of change in EDSS after 3 years (p = 0.035). Mental health composite score of MSQoL-54 was predictor of change in HDRS score (p = 0.049). In separate regression analysis, only social function was independent predictor of the development of depression (p = 0.041). None of the HRQoL domains had predictive effect on the change of FSS. Our study suggests that baseline HRQoL scores, measured by MSQoL-54, could be applied as a prognostic marker for progression of both, disability, and severity of depressive symptoms in MS. PMID- 23460395 TI - Comparison of abdominal MRI with diffusion-weighted imaging to 68Ga-DOTATATE PET/CT in detection of neuroendocrine tumors of the pancreas. AB - PURPOSE: The aim of the study was to evaluate contrast-enhanced MRI, diffusion weighted MRI (DW MRI), and (68)Ga-DOTATATE positron emission tomography (PET)/CT in the detection of intermediate to well-differentiated neuroendocrine tumors (NET) of the pancreas. METHODS: Eighteen patients with pathologically proven pancreatic NET who underwent MRI including DW MRI and PET/CT within 6 weeks of each other were included in this retrospective study. Two radiologists evaluated T2-weighted (T2w), T2w + DW MRI, T2w + contrast-enhanced T1-weighted (CE T1w) MR images, and PET/CT for NET detection. The sensitivity and level of diagnostic confidence were compared among modalities using McNemar's test and a Wilcoxon signed rank test. Apparent diffusion coefficients (ADC) of pancreatic NETs and normal pancreatic tissue were compared with Student's t test. RESULTS: Of the NETs, 8/23 (34.8 %) and 9/23 (39.1 %) were detected on T2w images by observers 1 and 2, respectively. Detection rates improved significantly by combining T2w images with DW MRI (observer 1: 14/23 = 61 %; observer 2: 15/23 = 65.2 %; p < 0.05) or CE T1w images (observer 1: 14/23 = 61 %; observer 2: 15/23 = 65.2 %; p < 0.05). Detection rates of pancreatic NET with PET/CT (both observers: 23/23 = 100 %) were statistically significantly higher than with MRI (p < 0.05). The mean ADC value of NET (1.02 +/- 0.26 * 10(-3) mm(2)/s) was statistically significantly lower than that of normal pancreatic tissue (1.48 +/- 0.39 * 10(-3) mm(2)/s). CONCLUSION: DW MRI is a valuable adjunct to T2w imaging and comparable to CE T1w imaging in pancreatic NET detection, quantitatively differentiating between NET and normal pancreatic tissue with ADC measurements. (68)Ga-DOTATATE PET/CT is more sensitive than MRI in the detection of pancreatic NET. PMID- 23460396 TI - Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. AB - IMPORTANCE: Restless legs syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and a distressing, irresistible urge to move them. We conducted a systematic review to evaluate efficacy, safety, and comparative effectiveness of pharmacologic treatments for primary RLS. EVIDENCE ACQUISITION: We included randomized controlled trials (RCTs), published in English, reporting efficacy outcomes and harms of pharmacologic treatments for primary RLS of at least 4 weeks' duration. MEDLINE and other databases were searched through June 2012. Reviewers extracted outcomes and adverse events and rated the strength of evidence. RESULTS: We identified 29 eligible RCTs. We found high-strength evidence that the proportion of patients who had a clinically important response (International Restless Legs Syndrome [IRLS] responders), defined as a 50% or greater reduction from baseline in mean IRLS symptom scale scores, was greater with dopamine agonist therapy compared with placebo (61% vs 41%) (risk ratio, 1.60 [95% CI, 1.38-1.86]; 7 trials). Dopamine agonists also improved patient-reported sleep scale scores and quality-of-life measures. High strength evidence demonstrated that calcium channel alpha-2-delta ligands increased the proportion of IRLS responders compared with placebo (61% vs 37%) (risk ratio, 1.66 [95% CI, 1.33-2.09]; 3 trials). Adverse events associated with dopamine agonists included nausea, vomiting, and somnolence. Alpha-2-delta ligands adverse events included somnolence and unsteadiness or dizziness. CONCLUSIONS AND RELEVANCE: On the basis of short-term RCTs that enrolled highly selected populations with long-term high-moderate to very severe symptoms, dopamine agonists and calcium channel alpha-2-delta ligands reduced RLS symptoms and improved sleep outcomes and disease-specific quality of life. Adverse effects and treatment withdrawals due to adverse effects were common. PMID- 23460397 TI - Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. AB - Endometriosis is a common benign pathology, characterised by the presence of endometrial tissue outside the endometrial cavity with a prevalence of 10-15% in reproductive-aged women. The pathogenesis is not completely understood, and several theories have been proposed to explain the aetiology. Our group has recently described the presence of ectopic endometrium in a consistent number of human female foetuses analysed by autopsy, reinforcing the hypothesis that endometriosis may be generated by defects during the organogenesis of the female reproductive trait. Herein, in order to identify, at molecular level, changes involved in the disease, we compared the transcriptional profiling of ectopic endometrium with the corresponding eutopic one. Statistical analyses lead us to identify some genes specifically deregulated in the ectopic endometrium, that are involved in gonad developmental process or in wound healing process. Among them, we identified BMP4 and GREM1. BMP4 was never associated before to endometriosis and is involved in the mesoderm-Mullerian duct differentiation. GREM1 is needed for the initial step of the ureter growth and perhaps could possibly be involved in Muller ducts differentiation. These molecules might be related to the endometriosis aetiology since we showed that their expression is not related to the menstrual cycle phase both at RNA and at protein levels. These data support the theory that embryological defects could be responsible of the endometriosis generation. PMID- 23460398 TI - Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia. AB - Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis 1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small ~0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression. PMID- 23460399 TI - Solvent-induced crystalline-state emission and multichromism of a bent pi-surface system composed of dibenzocyclooctatetraene units. AB - All bent out of shape: The solvent of crystallization effectively enhances the emission of flexible, bent, pi-conjugated molecules in the crystalline state owing to control of the packing of the molecules in the structure. Multichromism such as thermochromism and vapochromism also arises from the solvent-controlled packing. This crystalline-state emission is attributable to the flexibility of cyclooctatetraene units of the bent pi-conjugated molecules in the solid state (see figure). PMID- 23460400 TI - Angiolymphoid hyperplasia with eosinophilia of the eyelid and orbit: the Western cousin of Kimura's disease? AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon disease most frequently occurring in the head and neck region. It occurs in all races. In spite of a clear distinction between ALHE and Kimura's disease on histological grounds for almost 20 years now, confusion and misdiagnosis still exist to date. Three Spanish patients presented to our institution over a 6 year period with mass lesions in the superior orbit, medial orbito-nasal wall and eyelid, respectively. All patients were of Caucasian extraction and were diagnosed with epithelioid haemangioma on histological tissue analysis. We report on the history and management of these patients which resulted in good functional and cosmetic outcome with no subsequent evidence of disease recurrence. PMID- 23460401 TI - Reply to Risk factors associated with hepatocellular carcinoma in primary biliary cirrhosis. PMID- 23460402 TI - Direct synthesis of fluorinated heteroarylether bioisosteres. PMID- 23460403 TI - Upper airway inflammation exacerbates bronchial hyperreactivity in mouse models of rhinosinusitis and allergic asthma. AB - BACKGROUND: Recent studies have suggested that upper airway inflammation has a strong impact on lower airway diseases. The purpose of this study was to assess whether nasal inflammation could exacerbate allergic asthma in a mouse model. METHODS: Mice were assigned to 4 groups: control (Cont), either rhinosinusitis (R) or allergic asthma (A) alone, and both rhinosinusitis and allergic asthma (R&A). Mice underwent induction of nasal inflammation (R and R&A) or sham surgery (Cont and A) on day 1. Mice in the A and R&A groups were sensitized to ovalbumin on days 1, 7, and 14, followed by aerosol challenge on days 18 to 20, whereas in the Cont and R groups only saline was administered. All mice were assessed for airway hyperresponsiveness (AHR) and were euthanized on day 21. The sera, bronchoalveolar lavage fluids (BALFs), and nasal and lung tissues were collected for further analyses. RESULTS: Histology findings confirmed upper and lower airway inflammation in experimental mice. Significantly increased AHR and total serum immunoglobulin E (IgE) were observed in the R&A group when compared with those of the Cont, R, and A groups. Responses to IgG2a induction were also found in sera and BALFs from mice with rhinosinusitis (R and R&A). Higher levels of interleukin 4 (IL-4) and IL-13, and increased eosinophilic inflammation were detected in BALFs and lung tissues from the experimental groups when compared with those from the Cont group. CONCLUSION: Our results confirm that upper airway inflammation could exacerbate allergic asthma, and provide support to the concept of "one airway, one disease. PMID- 23460404 TI - Ni(II)-NTA modified poly(ethylene imine) glycopolymers: physicochemical properties and first in vitro study of polyplexes formed with HIV-derived peptides. AB - Alternative delivery entities are desirable in immunotherapies in which polyplexes are widely formed by electrostatic interactions to induce cellular uptake processes for bioactive molecules. In our study, biocompatible Ni(II) nitrilo(triacetic acid)-modified poly(ethylene imine)-maltose (Ni-NTA-DG) is realized and evaluated as complexation agent against His-tagged peptides using fluorescence polarization and dynamic light scattering. The polyplexes are stable until a pH of 6.5-6.0, and also up to 50 mM of imidazole. A first uptake approach shows that polyplexes lead to an increase in peptide uptake in monocyte-derived immature dendritic cells. In summary, Ni-NTA-DG represents a promising (delivery) platform for forthcoming in vitro applications. PMID- 23460405 TI - A novel device for antegrade percutaneous balloon aortic valvuloplasty: feasibility of the looped Inoue balloon technique in swine model. AB - OBJECTIVES: The study aimed to assess the feasibility of a novel device and technique for antegrade percutaneous balloon aortic valvuloplasty (BAV) in a swine model. BACKGROUND: BAV is currently being applied more frequently compared to the past with the advent of transcatheter aortic valve replacement. Although the antegrade BAV approach offers several advantages over the retrograde approach, the antegrade approach is technically more complicated and demanding. METHODS: We developed a novel balloon catheter and a technique to simplify the antegrade BAV. The balloon catheter was designed to make a loop in left atrium by inserting two different sized stylets. The balloon catheter was easily dropped into the left ventricle via the mitral valve while maintaining the loop. The balloon catheter was advanced to the ascending aorta by holding the two stylets. Then, the balloon was inflated. We named the technique as the looped Inoue balloon technique. The feasibility of the looped Inoue balloon technique was assessed in a healthy swine with a body weight of 40 kg by four independent operators. Every operator conducted the procedure twice. RESULTS: The procedural success rate was 100% in all operators. The average procedure time was 170 +/- 35 sec. No procedure related complications were noted. CONCLUSIONS: The study results indicate that the antegrade BAV using the looped Inoue balloon technique is feasible and may simplify the antegrade approach. PMID- 23460406 TI - Intestinal colonisation and blood stream infections due to vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) in patients with haematological and oncological malignancies. PMID- 23460407 TI - Methicillin-resistant Staphylococcus aureus foot infection after fish pedicure. AB - Fish pedicure has become a popular cosmetic procedure involving immersion of the feet in a tank with freshwater fish (Garra rufa) that nibble off dead skin. There are concerns about the potential transmission of pathogens, but no cases of infections after this procedure have been published so far. We present a patient who developed foot infection with methicillin-resistant Staphylococcus aureus (MRSA) after fish pedicure. PMID- 23460408 TI - Activation of ATP-sensitive potassium channels by nicorandil is preserved in aged vascular smooth muscle cells in rats. AB - Nicorandil, an ATP-sensitive potassium (KATP) channel opener having the properties of a nitrate, causes vasodilation, particularly of coronary arteries, and has been reported to reduce the frequency of perioperative cardiac events. We previously demonstrated that isoflurane could activate vascular KATP channels through an intracellular signaling pathway, but that this isoflurane-induced channel opening is suppressed by aging. Here, we investigated whether advanced age modifies nicorandil-induced activation of vascular KATP channels. We used a cell-attached patch-clamp configuration to test the effects of nicorandil on KATP channel activity in vascular smooth muscle cells (VSMCs) obtained from 12- to 15 week-old (adult) and 24- to 25-month-old (aged) male Wistar rats. Bath application of nicorandil (0.1-100 MUM) activated KATP channels to a level similar to that observed in VSMCs from the arteries of both adult and aged rats. Furthermore, concomitant bath application of nicorandil in the aged group dose dependently ameliorated the age-related reduction in isoflurane-induced vascular KATP channel activation. Our findings indicate that nicorandil could be used effectively in elderly patients to directly activate vascular KATP channels during the perioperative period. PMID- 23460409 TI - Randomized evaluation of the size 2 laryngeal tube and classical laryngeal mask airway in different head and neck positions in children under positive pressure ventilation. AB - PURPOSE: The aim of this study was to evaluate the applicability of the laryngeal tube (LT) size 2 and the classical laryngeal mask airway (LMA) size 2 in different head-neck positions under positive pressure ventilation in children by measuring leak pressures, peak pressures and the achievable tidal volumes under positive pressure ventilation. METHODS: Forty children were randomized to receive airway management by either the LT or LMA as the primary device. Leak pressures, peak pressures and tidal volumes under positive pressure ventilation were measured in the neutral, anteflection, retroversion, left-rotation and right rotation head-neck positions. RESULTS: In all head-neck positions, the leak pressures were significantly higher for the LT than for the LMA (neutral 25.9 +/- 7.0 vs. 19.1 +/- 5.7 cmH2O; anteflection 29.7 +/- 7.1 vs. 24.2 +/- 8.9 cmH2O; retroversion 24.1 +/- 7.6 vs. 17.2 +/- 6.9 cmH2O). In both devices, the peak ventilation pressures were higher in the anteflection position (LT 27.1 +/- 6.3 cmH2O; LMA 17.8 +/- 6.7 cmH2O) than in the retroversion position (LT 13.7 +/- 3.9 cmH2O; LMA 12.7 +/- 3.6 cmH2O). Compared to the respirator settings, lower tidal volumes were achieved in the anteflection position (LT 65 +/- 48 vs. 129 +/- 38 ml, LMA 100 +/- 21 vs. 125 +/- 29 ml) as compared to the other positions. CONCLUSION: Based on our results, we suggest that in anaesthetized children, the size 2 LT, compared to the size 2 LMA, may be more suitable for positive pressure ventilation due to favorable leak and peak pressures. Both devices can be safely used in head-neck positions other than neutral. Most disadvantageous with regards to the measured parameters was the anteflection position, especially for the LT. PMID- 23460410 TI - Kinematic factors affecting postoperative knee flexion after cruciate-retaining total knee arthroplasty. AB - PURPOSE: The purpose of this study was to investigate kinematic factors affecting postoperative knee flexion after cruciate-retaining (CR) total knee arthroplasty (TKA) by analysing pre- and postoperative knee kinematics. METHODS: We retrospectively analysed 58 patients with osteoarthritis who received the same implant series. Pre- and postoperative kinematics were measured intraoperatively using a navigation system. As a clinical outcome, we measured the knee flexion angle before and one year after surgery. Correlations among pre- and postoperative kinematics and postoperative flexion were analysed using simple linear regression analyses. RESULTS: Preoperative knee kinematics, including tibial internal rotation and anterior translation (R = 0.87, P < 0.001; R = 0.53, P < 0.001, respectively), were significantly correlated with postoperative kinematics. Preoperative varus-valgus movements improved significantly postoperatively; however, tibial internal rotation remained unchanged. Furthermore, postoperative knee flexion angle was significantly correlated with postoperative tibial internal rotation (R = 0.45, P < 0.001). CONCLUSIONS: Preoperative knee kinematics were unchanged even after CR-TKA. Postoperative tibial internal rotation is one of the most important factors affecting postoperative knee flexion. PMID- 23460411 TI - Representational demands modulate involvement of perirhinal cortex in face processing. AB - The classic view holds that the medial temporal lobes (MTL) are dedicated to declarative memory functioning. Recent evidence, however, suggests that perirhinal cortex (PrC), a structure within the anterior MTL, may also play a role in perceptual discriminations when representations of complex conjunctions of features, or of gestalt-characteristics of objects must be generated. Interestingly, neuroimaging and electrophysiological recordings in nonhuman primates have also revealed a face patch in the anterior collateral sulcus with preferential responses to face stimuli in various task contexts. In the present fMRI study, we investigated the representational demands that influence PrC involvement in different types of judgments on human faces. Holding stimulus complexity constant, we independently manipulated the nature of the task and the orientation of the stimuli presented (through face inversion). Aspects of right PrC showed increased responses in a forced-choice recognition-memory and a perceptual-oddity task, as compared to a feature-search task that was included to probe visual detection of an isolated face feature. Effects of stimulus orientation in right PrC were observed when the recognition-memory condition for upright faces was compared with all other experimental conditions, including recognition-memory for inverted faces-a result that can be related to past work on the role of PrC in object unitization. Notably, both effects in right PrC paralleled activity patterns in broader networks of regions that also included the right fusiform gyrus and the amygdala, regions frequently implicated in face processing in prior research. As such, the current findings do not support the view that reference to a prior study episode clearly distinguishes the role of PrC from that of more posterior ventral visual pathway regions. They add to a growing body of evidence suggesting that the functional role of specific MTL structures may be best understood in terms of the representations that are required by the task and the stimuli at hand. PMID- 23460412 TI - Borderline personality features and harmful dysregulated behavior: the mediational effect of mindfulness. AB - OBJECTIVES: The current preliminary study investigated whether deficits in mindfulness (awareness, attentiveness, and acceptance of the present experience) may underlie the relationship of borderline personality disorder (BPD) features to self-injury and overall acts of harmful dysregulated behavior. METHOD: Nonparametric bootstrapping procedures were used to examine theoretical relationships among variables in a psychiatric sample of adults (N = 70). Participants were asked to imagine themselves in distress-inducing situations and then write what they would actually do to decrease distress in such situations. RESULTS: As hypothesized, mindfulness statistically mediated the relationship of BPD features to reported acts of (a) self-injury and (b) overall harmful dysregulated behaviors. CONCLUSIONS: Difficulties in the ability to be aware, attentive, and accepting of ongoing experience may play a role in the relationship of BPD features to harmful dysregulated behaviors. Future research should clarify potential reciprocal effects between BPD features and mindfulness with prospective, multioccasion designs. PMID- 23460413 TI - Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents. AB - IMPORTANCE: It is important to understand the relationship between sleep medication use and injurious falls in nursing home residents. OBJECTIVE: To conduct a case-crossover study to estimate the association between nonbenzodiazepine hypnotic drug use (zolpidem tartrate, eszopiclone, or zaleplon) and the risk for hip fracture among a nationwide sample of long-stay nursing home residents, overall and stratified by individual and facility-level characteristics. DESIGN AND SETTING: Case-crossover study performed in an academic research setting. PARTICIPANTS: The study participants included 15,528 long-stay US nursing home residents 50 years or older with a hip fracture documented in Medicare Part A and Part D fee-for-service claims between July 1, 2007, and December 31, 2008. MAIN OUTCOME MEASURES: Odds ratios (ORs) of hip fracture were estimated using conditional logistic regression models by comparing the exposure to nonbenzodiazepine hypnotic drugs during the 0 to 29 days before the hip fracture (hazard period) with the exposure during the 60 to 89 and 120 to 149 days before the hip fracture (control periods). Analyses were stratified by individual and facility-level characteristics. RESULTS: Among the study participants, 1715 (11.0%) were dispensed a nonbenzodiazepine hypnotic drug before the hip fracture, with 927 exposure-discordant pairs included in the analyses. The mean (SD) age of participants was 81.0 (9.7) years, and 77.6% were female. The risk for hip fracture was elevated among users of a nonbenzodiazepine hypnotic drug (OR, 1.66; 95% CI, 1.45-1.90). The association between nonbenzodiazepine hypnotic drug use and hip fracture was somes greater in new users (OR, 2.20; 95% CI, 1.76-2.74) and in residents with mild vs moderate to severe impairment in cognition (OR, 1.86 vs 1.43; P = .06), with moderate vs total or severe functional impairment (OR, 1.71 vs 1.16; P = .11), with limited vs full assistance required with transfers (OR, 2.02 vs 1.43; P = .02), or in a facility with fewer Medicaid beds (OR, 1.90 vs 1.46; P = .05). CONCLUSIONS AND RELEVANCE: The risk for hip fracture is elevated among nursing home residents using a nonbenzodiazepine hypnotic drug. New users and residents having mild to moderate cognitive impairment or requiring limited assistance with transfers may be most vulnerable to the use of these drugs. Caution should be exercised when prescribing sleep medications to nursing home residents. PMID- 23460414 TI - Long-term outcome after allogeneic stem-cell transplantation with reduced intensity conditioning in patients with multiple myeloma. AB - This study examines the long-term outcomes of a cohort of patients with myeloma who were treated with reduced-intensity conditioning (RIC) regimens after a minimum follow-up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem-cell transplantation (Allo-SCT) between January 2000 and January 2007 were identified. The median follow-up of living patients was 84 months (51-141). The median age of the MM patients was 50 (28-70) years. Fifty-one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo-SCT was 34 months (6-161), and the median time between auto-SCT and Allo-SCT was 10 months (1-89). Fifty-one patients (96%) received at least one auto-SCT; 24 patients (45%) received a tandem auto-Allo-SCT. At last follow-up, 21 patients (40%) are alive > 5 years post RIC Allo-SCT. At last follow-up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re-induction with one of the new anti-myeloma drugs (bortezomib or lenalidomide) after Allo-SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo-SCT. Disease status and occurrence of cGvHD were significantly associated with progression-free survival (PFS); hazard ratio (HR) = 0.62 (0.30 1.29, P = 0.20). Acute GvHD was correlated with higher transplant-related mortality; HR = 4.19 (1.05-16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long-term disease control can be expected in a subset of MM patients undergoing RIC Allo-SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo SCT stabilizes in time with a plateau after 6 years post Allo-SCT. PMID- 23460415 TI - Clinical, angiographic, and intravascular ultrasound results of the VestSaync II trial. AB - AIM: We sought to assess the long term efficacy of the novel VESTAsyncTM Eluting Stent (VES) combining a Cro-Co platform with a nanothin-microporous hydroxyapatite surface coating impregnated with a polymer-free low-dose of Sirolimus (55 MUg). METHODS: The Vestasync II trial was a randomized (2:1), double-blinded, multicenter comparison of the VES to its platform, the Gen X stent, with microporous hydroxyapatite surface coating without sirolimus. Patients were eligible if they presented de novo lesions in native coronary arteries with 3.0-3.5 mm diameter and <= 14 mm in length. Primary endpoint was 8 month in-stent late loss and % of stent obstruction. Lifelong aspirin and 6-month clopidogrel were prescribed to all patients. RESULTS: Seventy-five patients were enrolled (VES = 50 pts). Baseline characteristics included mean age of 58 years and 29% of diabetics. Reference vessel diameter and lesion length were 2.8 +/- 0.4 mm and 13.0 +/- 2.0 mm, respectively. In-stent late loss (0.39 +/- 0.20 vs. 0.74 +/- 0.52, P = 0.03) and % of neointima hyperplasia (9.3 +/- 6.6% vs. 17.6 +/ 9.4%, P = 0.0016) were significantly reduced in the VES cohort. Up to 1 year, there was a single case of myocardial infarction and one target lesion revascularization (TLR) (2%) in the VES group while in the control cohort there were one TLR (4%) and one cardiac death (4%). CONCLUSION: The VestSync II trial is a proof-of-concept study and demonstrates the sustained efficacy of this novel polymer-free sirolimus drug-eluting stents. A larger trial, with more complex lesions, clinical endpoints and longer FU period is warranted. (c) 2013 Wiley Periodicals, Inc. PMID- 23460416 TI - Tuning the photoisomerization of a N^C-chelate organoboron compound with a metal acetylide unit. AB - To examine the impact of metal moieties that have different triplet energies on the photoisomerization of B(ppy)Mes2 compounds (ppy = 2-phenyl pyridine, Mes = mesityl), three metal-functionalized B(ppy)Mes2 compounds, Re-B, Au-B, and Pt-B, have been synthesized and fully characterized. The metal moieties in these three compounds are Re(CO)3(tert-Bu2 bpy)(C=C), Au(PPh3)(C=C), and trans Pt(PPh3)2(C=C)2, respectively, which are connected to the ppy chelate through the alkyne linker. Our investigation has established that the Re(I) unit completely quenches the photoisomerization of the boron unit because of a low-lying intraligand charge transfer/MLCT triplet state. The Au(I) unit, albeit with a triplet energy that is much higher than that of B(ppy)Mes2 , upon conjugation with the ppy chelate unit, substantially increases the contribution of the pi >pi* transition, localized on the conjugated chelate backbone in the lowest triplet state, thereby leading to a decrease in the photoisomerization quantum efficiency (QE) of the boron chromophore when excited at 365 nm. At higher excitation energies, the photoisomerization QE of Au-B is comparable to that of the silyl-alkyne-functionalized B(ppy)Mes2 (TIPS-B), which was attributable to a triplet-state-sensitization effect by the Au(I) unit. The Pt(II) unit links two B(ppy)Mes2 together in Pt-B, thereby extending the pi-conjugation through both chelate backbones and leading to a very low QE of the photoisomerization. In addition, only one boron unit in Pt-B undergoes photoisomerization. The isomerization of the second boron unit is quenched by an intramolecular energy transfer of the excitation energy to the low-energy absorption band of the isomerized boron unit. TD-DFT computations and spectroscopic studies of the three metal-containing boron compounds confirm that the photoisomerization of the B(ppy)Mes2 chromophore proceeds through a triplet photoactive state and that metal units with suitable triplet energies can be used to tune this system. PMID- 23460417 TI - Southern pine beetle, Dendroctonus frontalis, antennal and behavioral responses to nonhost leaf and bark volatiles. AB - A growing body of evidence suggests that bark beetles detect and avoid release points of volatile compounds associated with nonhost species, and thus such nonhost volatiles may have potential utility in the management of bark beetles. We used a coupled gas chromatograph-electroantennographic detector (GC-EAD) to assay the olfactory sensitivity of the southern pine beetle, Dendroctonus frontalis Zimmermann, to volatiles from leaves and bark of eight species of nonhost angiosperm trees that are common in the range of D. frontalis. Tree species sampled were red maple (Acer rubrum L.), mockernut hickory [Carya alba (L.) Nutt. ex Ell.], sweetgum (Liquidambar styraciflua L.), black tupelo (Nyssa sylvatica Marsh.), black cherry (Prunus serotina Ehrh.), southern red oak (Quercus falcata Michx.), blackjack oak [Quercus marilandica (L.) Muenchh.], and water oak (Quercus nigra L.). Beetle antennae responded to a total of 28 identifiable compounds in these samples. The relative olfactory responsiveness to 14 of these, as well as to nonanoic acid and four additional volatiles reported to be associated with nonhost angiosperms, was assessed in GC-EAD analyses of synthetic dilutions spanning six orders of magnitude. The largest response voltage amplitudes were obtained with trans-conophthorin, nonanoic acid, terpinen 4-ol, phenylethyl alcohol, and eucalyptol, whereas the lowest response thresholds were to nonanoic acid, nonanal, linalool, (E)-2-hexen-1-ol, and phenylethyl alcohol. Funnel traps baited with various combinations of eleven antennally active angiosperm volatiles along with a standard attractant captured significantly fewer male and female D. frontalis than traps baited with the standard attractant alone. Our data suggest that a diversity of semiochemicals may be involved in host species discrimination by D. frontalis, and several may have utility in their management. PMID- 23460418 TI - Choice of loco-regional anesthetic technique affects operating room efficiency for carpal tunnel release. AB - Intravenous regional anesthesia (Bier block) is indicated for minor procedures such as carpal tunnel release but must be performed in the operating room. We hypothesize that preoperative peripheral nerve blocks decrease anesthesia controlled time compared to Bier block for carpal tunnel release. With IRB approval, we reviewed surgical case data from a tertiary care university hospital outpatient surgery center for 1 year. Unilateral carpal tunnel release cases were grouped by anesthetic technique: (1) preoperative nerve blocks, or (2) Bier block. The primary outcome was anesthesia-controlled time (minutes). Secondary outcomes included surgical time and time for nerve block performance in minutes, when applicable. Eighty-nine cases met criteria for analysis (40 nerve block and 49 Bier block). Anesthesia-controlled time [median (10th-90th percentiles)] was shorter for the nerve block group compared to Bier block [11 (6-18) vs. 13 (9-20) min, respectively; p = 0.02). Surgical time was also shorter for the nerve block group vs. the Bier block group [13 (8-21) and 17 (10-29) min, respectively; p < 0.01), but nerve blocks took 10 (5-28) min to perform. Ultrasound-guided nerve blocks performed preoperatively reduce anesthesia-controlled time compared to Bier block and may be a useful anesthetic modality in some practice environments. PMID- 23460419 TI - Heterozygous 24-polyalanine repeats in the PHOX2B gene with different manifestations across three generations. AB - Congenital central hypoventilation syndrome (CCHS) is an uncommon genetic disorder that is characterized by alveolar hypoventilation and autonomic dysregulation. More than 90% of the patients are heterozygous for polyalanine repeat expansion mutations in the paired-like homeobox 2b (PHOX2B) gene. The normal genotype has a 20-polyalanine sequence whereas expanded alleles are usually 25-33. Heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene has rarely been reported. We report three consecutive generations harboring heterozygous 24-polyalanine repeats in the PHOX2B gene with manifestations ranging from apparently asymptomatic to alveolar hypoventilation and apnea requiring mechanical ventilation. The 3-year-old proband developed cor pulmonale and central hypoventilation following an upper respiratory tract infection. Our findings add to the accumulating evidence that the 24-polyalanine repeat in the PHOX2B is a disease-causing mutation. In addition, a high index of suspicion and careful monitoring after anesthesia, sedation, or respiratory illnesses should be exercised when evaluating asymptomatic family members with this genotype. PMID- 23460420 TI - Granularity analysis for mathematical proofs. AB - Mathematical proofs generally allow for various levels of detail and conciseness, such that they can be adapted for a particular audience or purpose. Using automated reasoning approaches for teaching proof construction in mathematics presupposes that the step size of proofs in such a system is appropriate within the teaching context. This work proposes a framework that supports the granularity analysis of mathematical proofs, to be used in the automated assessment of students' proof attempts and for the presentation of hints and solutions at a suitable pace. Models for granularity are represented by classifiers, which can be generated by hand or inferred from a corpus of sample judgments via machine-learning techniques. This latter procedure is studied by modeling granularity judgments from four experts. The results provide support for the granularity of assertion-level proofs but also illustrate a degree of subjectivity in assessing step size. PMID- 23460421 TI - Risk factors associated with hepatocellular carcinoma in primary biliary cirrhosis. PMID- 23460424 TI - Nanoparticle-based therapy for respiratory diseases. AB - Nanotechnology is an emerging science with the potential to create new materials and strategies involving manipulation of matter at the nanometer scale (<100 nm). With size-dependent properties, nanoparticles have introduced a new paradigm in pharmacotherapy - the possibility of cell-targeted drug delivery with minimal systemic side effects and toxicity. The present review provides a summary of published findings, especially regarding to nanoparticle formulations for lung diseases. The available data have shown some benefits with nanoparticle-based therapy in the development of the disease and lung remodeling in respiratory diseases. However, there is a wide gap between the concepts of nanomedicine and the published experimental data and clinical reality. In addition, studies are still required to determine the potential of nanotherapy and the systemic toxicity of nanomaterials for future human use. PMID- 23460422 TI - Localization and divergent profiles of estrogen receptors and aromatase in the vocal and auditory networks of a fish with alternative mating tactics. AB - Estrogens play a salient role in the development and maintenance of both male and female nervous systems and behaviors. The plainfin midshipman (Porichthys notatus), a teleost fish, has two male reproductive morphs that follow alternative mating tactics and diverge in multiple somatic, hormonal, and neural traits, including the central control of morph-specific vocal behaviors. After we identified duplicate estrogen receptors (ERbeta1 and ERbeta2) in midshipman, we developed antibodies to localize protein expression in the central vocal-acoustic networks and saccule, the auditory division of the inner ear. As in other teleost species, ERbeta1 and ERbeta2 were robustly expressed in the telencephalon and hypothalamus in vocal-acoustic and other brain regions shown previously to exhibit strong expression of ERalpha and aromatase (estrogen synthetase, CYP19) in midshipman. Like aromatase, ERbeta1 label colocalized with glial fibrillary acidic protein (GFAP) in telencephalic radial glial cells. Quantitative polymerase chain reaction revealed similar patterns of transcript abundance across reproductive morphs for ERbeta1, ERbeta2, ERalpha, and aromatase in the forebrain and saccule. In contrast, transcript abundance for ERs and aromatase varied significantly between morphs in and around the sexually polymorphic vocal motor nucleus (VMN). Together, the results suggest that VMN is the major estrogen target within the estrogen-sensitive hindbrain vocal network that directly determines the duration, frequency, and amplitude of morph-specific vocalizations. Comparable regional differences in steroid receptor abundances likely regulate morph-specific behaviors in males and females of other species exhibiting alternative reproductive tactics. PMID- 23460423 TI - Brief report: incidence of selected opportunistic infections among children with juvenile idiopathic arthritis. AB - OBJECTIVE: To compare incidence rates of selected opportunistic infections among children with and children without juvenile idiopathic arthritis (JIA). METHODS: Using U.S. national Medicaid administrative claims data from 2000 through 2005, we identified a cohort of children with JIA based on physician diagnosis codes and dispensed medications. We also identified a non-JIA comparator cohort of children diagnosed as having attention deficit hyperactivity disorder (ADHD). We defined 15 types of opportunistic infection using physician diagnosis or hospital discharge codes; criteria for 7 of these types also included evidence of treatment with specific antimicrobial agents. We calculated infection incidence rates. The rates in the ADHD comparator cohort were standardized to the age, sex, and race distribution of the JIA cohort. We calculated incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) to compare infection rates. RESULTS: The JIA cohort included 8,503 children with 13,990 person-years of followup. The ADHD comparator cohort included 360,362 children with 477,050 person-years of followup. When all opportunistic infections were considered together as a single outcome, there were 42 infections in the JIA cohort (incidence rate 300 per 100,000 person-years; IRR 2.4 [95% CI 1.7-3.3] versus ADHD). The most common opportunistic infections among children with JIA were 3 cases of Coccidioides (incidence rate 21 per 100,000 person-years; IRR 101 [95% CI 8.1-5,319] versus ADHD), 5 cases of Salmonella (incidence rate 35 per 100,000 person-years; IRR 3.8 [95% CI 1.2-9.5]), and 32 cases of herpes zoster (incidence rate 225 per 100,000 person-years; IRR 2.1 [95% CI 1.4-3.0]). CONCLUSION: Opportunistic infections are rare among children with JIA. Nevertheless, children with JIA had a higher rate of opportunistic infections, including an increased rate of Coccidioides, Salmonella, and herpes zoster compared to children with ADHD. PMID- 23460425 TI - Morphological deformities in the osseous structure in spotted sorubim Pseudoplatystoma coruscans (Agassiz & Spix, 1829) with vitamin C deficiency. AB - Vitamin C is essential for fish diets because many species cannot syntethize it. This vitamin is needed for bone and cartilage formation. Moreover, it acts as antioxidant and improve the immunological system. The present work investigated the effects of vitamin C diet supplementation to spotted sorubim (Pseudoplatystoma coruscans) fingerlings by frequency of bone and cartilage deformation. Ascorbyl poliphosphate (AP) was used as source of vitamin C in the diets for spotted sorubim fingerlings during three months. Six diets were formulated: one diet control (0 mg/kg of vitamin C) and 500, 1,000, 1,500, 2,000 and 2,500 mg AP/kg diets. Fishes fed without vitamin C supplementation presented bone deformation in head and jaws, and fin fragilities. Thus, 500 mg AP/kg diet was enough to prevent deformation and the lack of vitamin C supplementation worsening the development of fingerlings. PMID- 23460426 TI - The relationship between sandy beach nematodes and environmental characteristics in two Brazilian sandy beaches (Guanabara Bay, Rio de Janeiro). AB - We investigated if the differences in density and nematode communities of intertidal sediments from two Brazilian sheltered sandy beaches were related to environmental characteristics. The upper tide level (UTL) and the low tide level (LTL) of both beaches were surveyed in January (austral summer) and June 2001 (austral winter) during low-spring tides, by collecting samples of nematodes and sediments. Differences in density between beaches, tidal level and seasons, and nematode community structure were investigated. Sediments from both beaches were composed of medium to very coarse sand. The highest nematode densities were found at the UTL, and significant differences between beaches, tidal levels and months were found. A total of 54 genera were found and the genera composition on both sheltered beaches was similar to other exposed worldwide sandy beaches. The density and structure of the nematode community at both beaches clearly varied along the spatial and temporal scales. Gravel percentage was the most important variable explaining the spatial distribution of the nematodes, determining the four sub-communities; this suggests that the sediment characteristics influence the nematode community, rather than physical hydrodynamic forces. Temperature and salinity were suggested to be important variables affecting the temporal variation. PMID- 23460427 TI - Soil microbial response to glucose and phosphorus addition under agricultural systems in the Brazilian Cerrado. AB - Conventional tillage (CT) and no-tillage (NT) management systems alter soil nutrient availability and consequently modify soil microbial response to nutrient additions such as carbon (C) and phosphorus (P). The objective of this study is to evaluate microbial response to the addition of C (glucose) and P (Na2HPO4.7H2O) under CT and NT in the brazilian Cerrado. In response to glucose addition, the NT system yielded higher microbial respiration rates and glucose consumption than the CT system. The best microbial response to C addition was after 0 - 12 h incubation in NT and 0 - 24 h in CT. The addition of P produced higher demand under CT than NT. After incubation, biochemical indicators such as microbial respiration, glucose consumption, dehydrogenase activity and metabolic yield confirmed the higher glucose demands under NT and higher phosphorus demands under CT. These results demonstrate that C and P addition alter significantly the microbial response, suggesting that soil microorganisms present nutrient differential demands between CT and NT management systems. PMID- 23460428 TI - Morphology of sympathetic chain in Saguinus niger. AB - Saguinus niger popularly known as Sauim, is a Brazilian North primate. Sympathetic chain investigation would support traumatic and/or cancer diagnosis which are little described in wild animals. The aim of this study was to describe the morphology and distribution of sympathetic chain in order to supply knowledge for neurocomparative research. Three female young animals that came death by natural causes were investigated. Animals were fixed in formaldehyde 10% and dissected along the sympathetic chain in neck, thorax and abdomen. Cranial cervical ganglion was located at the level of carotid bifurcation, related to carotid internal artery. In neck basis the vagosympathetic trunk divides into the sympathetic trunk and the parasympathetic vagal nerve. Sympathetic trunk ran in dorsal position and originated the stellate ganglia, formed by the fusion of caudal cervical and first thoracic ganglia. Vagal trunk laid ventrally to heart and formed the cardiac plexus. In abdomen, on the right side, were found the celiac ganglion and cranial mesenteric ganglion; in the left side these ganglia were fusioned into the celiac-mesenteric ganglion displaced closely to the celiac artery. In both sides, the caudal mesenteric ganglion was located near to the caudal mesenteric artery. PMID- 23460429 TI - Germination of Styrax camporum Pohl. seeds in response to substrate types, moisture contents and the seed morphology. AB - This study evaluated the contributions of Styrax camporum seed morphology (size of seeds, presence or absence of endocarp attached to the seed), different substrates (filter paper, vermiculite, sand and the soils of cerrado s. str., cerradao and a riparian forest), different water potentials (0, -0.1, -0.2, -0.3, -0.4 and -0.5 MPa), light and temperature to seed germination. Seed size did not affect the germination percentage when seeds were sown on vermiculite. Seeds were affected by small variations in the moisture content of the tested substrates, showing a significant decrease in germination under water potentials lower than 0.1 MPa, close to the field capacity of cerrado s. str. soils. At the temperatures of 15 and 20 degrees C, a significant decrease in germination was observed. Thus, the availability of water in cerrado soils associated to temperature modulate the distribution of germination in this species. Seed morphology contributes to the maintenance of seeds in the soil, and the lack of synchrony in seed germination spreads the distribution of germination in time. These peculiarities allow the emergency of seedlings at different time periods and establishment conditions, an adaptative response of S. camporum to the cerrado environment. PMID- 23460431 TI - Melliferous flora and pollen characterization of honey samples of Apis mellifera L., 1758 in apiaries in the counties of Ubirata and Nova Aurora, PR. AB - The aim of this study was to carry out a survey of the flora with potential for beekeeping in the counties of Ubirata and Nova Aurora-PR through the collection of plants and pollen analyses in honey samples collected monthly. 208 species of plants were recorded, distributed in 66 families. The families that showed the major richness of pollen types were: Asteraceae, Myrtaceae and Solanaceae. Approximately 80 pollen types were found in honey samples, most of them were characterized as heterofloral. Cultivated plants, such as Glycine max (soybean) and Eucalyptus spp., were representative in some months of the year. Exotic species, such as Ricinus communis and Melia azedarach, were also frequent. However, over than 50% of the pollen types belong to native species of the region, such as Schinus terebinthifolius, Baccharis spp. Alchornea triplinervia, Parapiptadenia rigida, Hexaclamys edulis, Zanthoxylum sp. and Serjania spp., indicating the importance of the native vegetation for the survival of the colonies. PMID- 23460432 TI - Feeding ecology of the Neotropical otter Lontra longicaudis in the Lower Arroio Grande River, southern Brazil. AB - The present study was based on the analysis of spraints (n = 294) collected between December 2005 and November 2007. The importance of each type of prey was determined by absolute and relative frequency. Niche breadth was also estimated. The results were reported as mean (+/- SD) of relative frequencies. Fish were the main prey found in spraints (57.8 +/- 7.0%). Fish from Callichthyidae family were the main prey, followed by Cichlidae, the species Hoplias malabaricus and the family Characidae. The frequencies of other fish and taxa were lower than 13.9% (absolute frequency) and 5.6% (relative frequency). Despite significant seasonal variations, (P = 0.001), niche breadth values were low in all seasons (0.39 +/- 0.11). Therefore, Lontra longicaudis presented a narrow niche breadth as a result of consistent fish predation. Based on these data, fish with rapid movement presenting territorial behavior and benthic fish with slow movements are the most consumed. Seasonal fluctuations are caused by the increase of secondary prey in the diet during some seasons. PMID- 23460433 TI - Morphogenetic characteristics of three Brachiaria brizantha cultivars submitted to nitrogen fertilization. AB - This study aims to evaluate the morphogenetic characteristics of three cultivars of Brachiaria brizantha subjected to nitrogen fertilization. The design was a randomized block in factorial arrangement 4x3; three cultivars of B. brizantha - Marandu, Piata, Xaraes and four nitrogen levels - 0, 80, 160 and 240 kg/ha, with three replications. The experimental units consisted of plastic pots filled with 5 dm3 of soil. Thereupon the establishment fertilization, varieties were sowed directly in the pots, leaving, after thinning, five plants per pot. Forty-five days after planting, it was done a standardization cut at 10 cm tall. Nitrogen levels were distributed according to the treatments, divided in three applications. The morphogenetic characteristics were evaluated in three tillers per sampling unit and data were submitted to analysis of variance and regression. For all evaluated characteristics there was no interaction between factors cultivar and nitrogen levels, verifying only the effects of nitrogen on the variables leaf appearance rate and phyllochron. The dose 240 kg/ha of N corresponds to the greater leaf appearance rate. Cultivar Marandu shows the higher leaf blade: pseudostem and ratio of leaf elongation rate and elongation pseudostem, which favors higher forage quality. PMID- 23460434 TI - Tmesiphantes hypogeus sp. nov. (Araneae, Theraphosidae), the first troglobitic tarantula from Brazil. AB - A new species of Tmesiphantes Simon, 1892, is described from sandstone/quartizitic caves of Chapada Diamantina, Bahia State, Brazil. This is the fifth species of the genus and the first record of a troglobitic mygalomorph in Brazil. A key is presented for all Tmesiphantes species. PMID- 23460435 TI - Effects of diet supplementation with Camu-camu (Myrciaria dubia HBK McVaugh) fruit in a rat model of diet-induced obesity. AB - Amazonian Camu-camu fruit (Myrciaria dubia HBK Mc Vaugh) has attracted interest from food and cosmetics industries because of its rich content of vitamin C, flavonoids and anthocyanins. The goal of this study was investigates the antiobesity action of the ingestion of the Camu-camu pulp in a rat model of diet induced obesity. Wistar rats with obesity induced by subcutaneous injection of monosodium glutamate receiving diet ad libitum. The rats were divided in two groups: an experimental group that ingested 25 mL/day of Camu-camu pulp (CCG) and a non treated group (CG). After 12 weeks, the animals were sacrificed. Blood, liver, heart, white adipose tissues were collected and weighted, biochemical and inflammatory profiles were determinate as well. Animals that received the pulp of Camu-camu reduced their weights of the fat in white adipose tissues, glucose, total cholesterol, triglycerides, LDL-c and insulin blood levels. There was an increase in HDL-c levels. No change was observed in inflammatory markers and liver enzymes. Camu-camu pulp was able to improve the biochemical profile of obesity in rats suggesting that this Amazonian fruit can be further used such a functional food ingredient in control of chronic diseases linked to obesity. PMID- 23460436 TI - Histological evaluation of the periodontal ligament from aged Wistar rats supplemented with ascorbic acid. AB - Ascorbic acid (AA) is able to neutralize reactive oxygen species and is essential for collagen synthesis. In aging process oxidative stress is elevated. This study aims to investigate the effects of AA supplementation on the periodontal ligament (PL) of rats during aging. Twenty five rats were used and divided into groups: J90 (90-day-old control), E345 (345-day-old control), E428 (428-day-old control), EA345 (345-day-old supplemented with AA from 90-day-old on) and EA428 (428-day old supplemented with AA from 90-day-old on). We analyzed the thickness, density of fibroblasts and blood vessels and collagen fibers types in the PL. In group J90 there was predominantly type III collagen fibers (87.64%). In animals supplemented with AA, the area filled by type I fibers (group EA345: 65.67%, group EA428: 52.23%) was higher than type III fibers. PL in group EA428 was thicker than the one observed in group E428 (P < 0.05). During natural aging process, AA promoted the maturation of collagen fibers and enhanced angiogenesis in periodontal ligament. One can conclude that the supplementation with AA represented a beneficial factor for the development of PL in aged rats. PMID- 23460437 TI - Fishing strategies among prehistoric populations at Saquarema Lagoonal Complex, Rio de Janeiro, Brazil. AB - Two distinct fishing technologies were identified among the shellmound builders of the Saquarema Lagoonal Complex, in the Brazilian state of Rio de Janeiro: bone point technology and worked fish spines. These technologies were related to the acquisition of specific fish resources; Worked fish spines were used in the capture of Micropogonias furnieri (Desmarest), and bone points used for fishing specimens of the Ariidae family. Worked spines technology was predominant between 6,726 cal. years BP and 3,699 cal. years BP, while the bone point technology was dominant after 3,699 cal. years BP. It is believed these different strategies for obtaining fishing resources before 3,699 years cal. BP was related to environmental. Notably the gradual regression of relative sea level occurred during the mid- and late Holocene. PMID- 23460438 TI - Maturation of Eugenia pyriformis seeds under different hydric and thermal conditions. AB - This study aims to analyze the maturation and dispersal of Eugenia pyriformis Cambess. seeds produced in different years, and the influence of variation in thermal and hydric environment on seed physical and physiological characteristics at dispersal. Fruits at different developmental stages were harvested in the city of Sao Paulo between 2003 and 2010, as well as in the cities of Campinas and Lavras, in 2009 and 2010 and analyzed for size and color. The seeds were extracted from the fruits and their dry mass, water content, germination and vigor were assessed. Results showed that seed maturation is unsynchronized to the maturation of the fruit, taking 45 days on average (430 growing degree-days), longer in rainy times or lower temperatures. Seeds with higher physiological quality were produced in rainy years and when the temperature range was larger. We concluded therefore that hydric and thermal environmental variations during development influence the maturation of Eugenia pyriformis seeds and are able to determine the formation cycle and the final seed quality. PMID- 23460439 TI - Construction of yellow fever virus subgenomic replicons by yeast-based homologous recombination cloning technique. AB - RNA replicon derived from Flavivirus genome is a valuable tool for studying viral replication independent of virion assembly and maturation, besides being a great potential for heterologous gene expression. In this study we described the construction of subgenomic replicons of yellow fever virus by yeast-based homologous recombination technique. The plasmid containing the yellow fever 17D strain replicon (pBSC-repYFV-17D), previously characterized, was handled to heterologous expression of the green fluorescent protein (repYFV-17D-GFP) and firefly luciferase (repYFV-17D-Luc) reporter genes. Both replicons were constructed by homologous recombination between the linearized vector pBSC-repYFV 17D and the PCR product containing homologous 25 nucleotides ends incorporated into PCR primers. The genomic organization of these constructs is similar to repYFV-17D, but with insertion of the reporter gene between the remaining 63 N terminal nucleotides of the capsid protein and 72 C-terminal nucleotides of the E protein. The replicons repYFV-17D-GFP and repYFV-17D-Luc showed efficient replication and expression of the reporter genes. The yeast-based homologous recombination technique used in this study proved to be applicable for manipulation of the yellow fever virus genome in order to construct subgenomic replicons. PMID- 23460440 TI - Administering ascorbic acid to rats undergoing ageing processes: effects on myosin-V immunoreactive myenteric neurons. AB - During the ageing process the enteric nervous system undergoes morphofunctional changes, such as enteric neurodegeneration. Neuronal death can be attributed to increase radicals free, and ascorbic acid (AA), known antioxidant, could minimize damage cause by oxidative stress. The objective of this study is to analyse the behaviour of morphoquantative myenteric neurons in the duodenum of adult Wistar rats with aged 90 (C90), 345 (E345) and 428 (E428) days, as well as animals of the same age who received ascorbic acid supplementation for 120 days (EA345 and EA428). Whole-mount preparations of muscle layer from the duodenum of the animals were immunostained by the method myosin V. 80 microscopic fields were quantified (14.8 mm2/animal) and measured 100 neuronal cell bodies per animal. During the aging process, there was a reduction in neuronal density in all animals groups, indicating that the effects of age were not attenuated with AA supplementation. The increase in the neuronal area of the cell bodies in 428-day-old animals proved the influence of age on this parameter. There was no observed a neuroprotective effect of AA (1 mL/g body weight) on the neuronal population myenteric myosin V immunoreactive. PMID- 23460442 TI - Conservation priorities of useful plants from different techniques of collection and analysis of ethnobotanical data. AB - This study analyzes three methods of data analysis to verify which one would be more appropriate to get information aiming the conservation, selecting the use value (VU) inventory in situ and conservation property index (IPC). It was developed in in Northeast Brazil, via interviewed householders (46 informants). The VU was calculated considering only the effective use of plants; the inventory in situ was made through the frequency of species occurrence in homes; and the IPC combining ethnobotanical and phytossociological data. It was observed a similar cast of the indicated species by VU and inventory in situ, being different from the IPC cast. As this study sought to analyze the best technique for species identification which were needing conservationist actions, and obtained different results among the chosen methods. It has been suggested the use of methods that unite in their analysis both ethnobotanical and ecological aspects, like in the plants list from the priority index of conservation, which demonstrated to be more efficient to identify rare species in the local vegetation. The VU and the inventory in situ are more efficient to identify the most known and used species in the communities, however without analyzing these plants in the local vegetation. PMID- 23460443 TI - Relationship between pollen morphology and chromosome numbers in Brazilian species of Lippia L. (Verbenaceae). AB - The pollen morphology and exine structure of 17 species of Lippia L. were investigated in this work using light and scanning electron microscopy. Among the species studied, 14 showed tricolporate pollen grains, two had tri- and tetracolporate pollen grains and a single species exhibited, only tetracolporate pollen. The amb ranged from triangular to square, and the shape varied from oblate-spheroidal to prolate-spheroidal. Three different types of exine ornamentation were observed: psilate, scabrate and perforate. In addition to morphological data, we found positive association between the chromosome numbers and size of pollen grains, and also between the length and width of the colpi. The results indicate that the characteristics of pollen grains in Lippia may be used as an additional taxonomic character of the genus. PMID- 23460444 TI - Amylin induces hypoglycemia in mice. AB - Amylin is a 37-aminoacid pancreatic protein that exerts control over several metabolic events such as glycemia and lacticemia. Amylin has long been shown to induce increases in arterial plasma glucose. We decided to investigate whether amylin plays additional roles in the glucose metabolism. We evaluated glucose homeostasis using whole blood from the tail tip of fasting, conscious, unrestrained normal and streptozotocyn-induced diabetic mice following subcutaneous administration of mouse amylin. Subcutaneous injection of 1 MUg mouse amylin caused a transient decrease in whole blood glucose in both normal and diabetic mice in the absence of insulin. The blood glucose levels were lowest approximately 2 hours after amylin administration, after that they gradually recovered to the levels of the control group. The hypoglycemic effect followed a dose-dependent response ranging from 0.1 to 50 ug / mouse. These results reveal the ability for amylin in the direct control of glycemia at low doses in the absence of insulin. PMID- 23460445 TI - Caspase-3 activation and increased procollagen type I in irradiated hearts. AB - The caspase-3-cleaved presence was evaluated in this study in the heart of irradiated rats, during the decline of ventricular function. Female Wistar rats were irradiated with a single dose of radiation (15 Gy) delivered directly to the heart and the molecular, histological and physiological evaluations were performed at thirteen months post-irradiation. The expressions of procollagen type I, TGF-beta1 and caspase-3-cleaved were analyzed using Western blotting. Cardiac structural and functional alterations were investigated by echocardiography and electron microscopy. In the irradiated group, the levels of procollagen type I, TGF-beta1 and caspase-3-cleaved are increased. Significant histological changes (degeneration of heart tissue and collagen deposition) and functional (reduced ejection fraction) were observed. Data suggest that the cardiac function decline after exposure to ionizing radiation is related, in part, to increased collagen and increased caspase-3-cleaved. PMID- 23460446 TI - Linking membrane dynamics and trafficking to autophagy and the unfolded protein response. AB - Cellular stressors typically induce two protective counter-responses-autophagy and the unfolded protein response (UPR). It is conceivable that these two endoplasmic reticulum (ER) membrane-based processes would intersect/interact somehow with the constitutive housekeeping process of exocytic membrane traffic from the ER. How exactly might this occur? Recent evidence indicates that a conserved Rab protein, Rab1/Ypt1p, has functional roles in UPR and autophagy. This molecular switch and its associated effectors may therefore serve to link up a network of cellular responses to stress through changes in membrane dynamics and protein turnover. The notion provides further explanations as to why elevation of Rab1/Ypt1p levels could counter the cytotoxicity of alpha-synuclein, and a similar mode of protection may well be at work against other stresses. PMID- 23460447 TI - Clinical classification of cardiovascular tumors and tumor-like lesions, and its incidences. AB - Tumors of the heart and the great vessels are very rare disease, and there are many disorders such as tumors originated from the heart and great vessels, metastatic tumors, and tumor-like lesions which do not fit into the usual concept of tumor or neoplasm; thus, it is very difficult to classify these tumors. We proposed a new classification of cardiovascular tumors for clinical use based on the accumulated biological analyses and clinical data of the reported literatures and our own study as benign tumors, malignant tumors, ectopic hyperplasia/ectopic tumors/others, and tumors of great vessels, with reference to the series of Atlas of tumor pathology of the Armed Forces Institute of Pathology and the recent World Health Organization classification of cardiac tumors issued in 2004. More than 50 disorders have been reported as tumors originated from the cardiovascular system, and various metastatic tumors from nearby organs, distant lesions, and intravascular extension tumors to the heart were reported. Based on the new classification, we reviewed epidemiology and incidence of cardiovascular tumors. Metastatic tumors are more frequent than tumors originated from the heart and great vessels, and cardiac myxoma is the most frequent tumors in all cardiac tumors. PMID- 23460448 TI - Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. AB - OBJECTIVE: Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy characterized by both degenerative and autoimmune features. In contrast to other inflammatory myopathies, myositis-specific autoantibodies had not been found in sIBM patients until recently. We used human skeletal muscle extracts as a source of antigens to detect autoantibodies in sIBM and to characterize the corresponding antigen. METHODS: Autoantibodies to skeletal muscle antigens were detected by immunoblotting. The target antigen was immunoaffinity-purified from skeletal muscle extracts and characterized by mass spectrometry. A cDNA encoding this protein was cloned and expressed in vitro, and its recognition by patient sera was analyzed in an immunoprecipitation assay. Epitopes were mapped using microarrays of overlapping peptides. RESULTS: An Mr 44,000 polypeptide (Mup44) was frequently targeted by sIBM autoantibodies. The target protein was purified, and subsequent mass spectrometry analysis revealed that Mup44 is the cytosolic 5' nucleotidase 1A (cN1A). By immunoprecipitation of recombinant cN1A, high concentrations of anti-Mup44 autoantibodies were detected in 33% of sIBM patient sera, whereas their prevalence in dermatomyositis, polymyositis, and other neuromuscular disorders appeared to be rare (4.2%, 4.5%, and 3.2%, respectively). Low concentrations of anti-Mup44 antibodies were found in myositis as well as other neuromuscular disorders, but not in healthy controls. Three major autoepitope regions of cN1A were mapped by using microarrays containing a set of overlapping peptides covering the complete cN1A amino acid sequence. INTERPRETATION: Anti-Mup44 autoantibodies, which are targeted to cN1A, represent the first serological biomarker for sIBM and may facilitate the diagnosis of this type of myositis. PMID- 23460449 TI - Coronary collateral circulation: its relevance. AB - The interest in coronary collateral circulation (CCC) as "natural bypasses" is growing, especially in patients in whom the extent of coronary atherosclerosis is too severe to allow for conventional revascularization. The anatomic foundation of CCC has been recognized for long time. Recently, reliable methods have become available for the assessment of the adequacy of collateral flow. However, the debate regarding the importance of CCC in the different clinical settings continues. In this article, we present the recent progress in the understanding of anatomy and physiology of the CCC and focus on the studies addressing their functional significance in acute, subacute, and chronic coronary artery disease. In addition, we provide a focused update on the essential role of collateral circulation in the management of coronary chronic total occlusions. PMID- 23460450 TI - Hippocampal NMDA receptor blockade impairs CREB phosphorylation in amygdala after contextual fear conditioning. AB - In contextual fear conditioning (CFC), hippocampus is thought to process environmental stimuli into a configural representation of the context and send it to amygdala nuclei, which current evidences point to be the site of CS-US association and fear memory storage. If it is true, hippocampus should influence learning-induced plasticity in the amygdala nuclei after CFC acquisition. To test this, we infused wistar rats with saline or AP5, a NMDA receptor antagonist, in the dorsal hippocampus just before a CFC session, in which they were conditioned to a single shock, exposed to the context with no shocks or received an immediate shock. The rats were perfused, their brains harvested and immunohistochemically stained for cAMP element binding protein (CREB) phosphorylation ratio (pCREB/CREB) in lateral (LA), basal (B) and central (CeA) amygdala nuclei. CFC showed a learning-specific increase in pCREB ratio in B and CeA, in conditioned saline rats compared to context and immediate shocked ones. Further, conditioned rats that received AP5 showed a decrease in pCREB ratio in LA, B and CeA. Our results support the current ideas that the role of hippocampus in contextual fear conditioning occurs by sending contextual information to amygdala to serve as conditioned stimulus. PMID- 23460451 TI - Effect of hydrogen on O2 adsorption and dissociation on a TiO2 anatase (001) surface. AB - The effect of hydrogen on the adsorption and dissociation of the oxygen molecule on a TiO2 anatase (001) surface is studied by first-principles calculations coupled with the nudged elastic band (NEB) method. Hydrogen adatoms on the surface can increase the absolute value of the adsorption energy of the oxygen molecule. A single H adatom on an anatase (001) surface can lower dramatically the dissociation barrier of the oxygen molecule. The adsorption energy of an O2 molecule is high enough to break the O=O bond. The system energy is lowered after dissociation. If two H adatoms are together on the surface, an oxygen molecule can be also strongly adsorbed, and the adsorption energy is high enough to break the O=O bond. However, the system energy increases after dissociation. Because dissociation of the oxygen molecule on a hydrogenated anatase (001) surface is more efficient, and the oxygen adatoms on the anatase surface can be used to oxidize other adsorbed toxic small gas molecules, hydrogenated anatase is a promising catalyst candidate. PMID- 23460452 TI - Complementary use of resection and radiofrequency ablation for the treatment of colorectal liver metastases: an analysis of 395 patients. AB - BACKGROUND: Liver resection and radiofrequency ablation (RFA) are two surgical options in the treatment of patients with colorectal liver metastases (CLM). The aim of this study was to analyze patient characteristics and outcomes after resection and RFA for CLM from a single center. METHODS: Between 2000 and 2010, 395 patients with CLM undergoing RFA (n = 295), liver resection (n = 94) or both (n = 6) were identified from a prospective IRB-approved database. Demographic, clinical and survival data were analyzed using univariate and multivariate analyses. RESULTS: RFA patients had more comorbidities, number of liver tumors and a higher incidence of extrahepatic disease compared to the Resection patients. The 5-year overall actual survival was 17 % in the RFA, 58 % in the Resection group (p = 0.001). On multivariate analysis, multiple liver tumors, dominant lesion >3 cm, and CEA >10 ng/ml were independent predictors of overall survival. Patients were followed for a median of 20 +/- 1 months. Liver and extrahepatic recurrences were seen in 69 %, and 29 % of the patients in the RFA, and 40 %, and 19 % of the patients in the Resection group, respectively. CONCLUSIONS: In this large surgical series, we described the characteristics and oncologic outcomes of patients undergoing resection or RFA for CLM. By having both options available, we were able to surgically treat a large number of patients presenting with different degrees of liver tumor burden and co morbidities, and also manage liver recurrences in follow-up. PMID- 23460453 TI - Skeletal muscle-derived cell cultures as potent models in regenerative medicine research. AB - Cell cultures have been used extensively by many scientists in recent decades to study various cell and tissue mechanisms. The use of cell cultures has many advantages over use of in vivo experimental models, but there are also limitations. As skeletal muscle-derived cell cultures become more commonly utilized in studies of muscle regeneration processes the question of their relevance in experimentation is highlighted with regard to in vivo experimental models. This article reviews studies that have been performed simultaneously in in vivo and in vitro experiments on skeletal muscle and assesses the correlation of results. Although they seem to correlate, no such studies on humans have been performed so far. PMID- 23460454 TI - The relationship between ankle-brachial index and estimated glomerular filtration rate in type 2 diabetes. PMID- 23460455 TI - The role of hyperthyroidism in patients with myocardial infarction with normal coronary arteries. PMID- 23460456 TI - Development of a Chinese childbearing attitude questionnaire for infertile women receiving in vitro fertilization treatment. AB - The purpose of this study was to report the second phase of instrument development, a culturally sensitive questionnaire of childbearing attitudes to assess the psychosocial responses of infertile women. Using a nonexperimental quantitative design, we investigated 238 women who are undergoing in vitro fertilization treatment. Data collection and relevant planning occurred in two phases: in-depth interviews of women to generate items for the questionnaire and establishing the questionnaire's content and construct validity. Through factor analysis, five factors were extracted from the "attitude toward childbearing questionnaire": gender identification with self and society, insurance of marriage and inheritance, happy family life, spiritual investment, and continuing the family line and procreation. The total variance of these five factors was 64.31%. Cronbach's alpha and test-retest reliability were between .72 and .87 and between .60 and .76, respectively, demonstrating acceptable internal consistency and stability. The information obtained through the questionnaire could be used to provide infertile women with personal counseling and appropriate psychological support during and after assisted reproductive technology. PMID- 23460457 TI - Culture and postpartum mood problems: similarities and differences in the experiences of first- and second-generation Canadian women. AB - PURPOSE: Few studies have examined the role of culture in a woman's experience of postpartum mood problems (PPMP). This study explored differences and similarities in experiences of PPMP between first- and second-generation Canadian women. DESIGN: In this exploratory qualitative study, we interviewed nine first generation and eight second-generation women who were clients of the Women's Health Centre at St. Joseph's Health Centre in Toronto, Canada. Using semistructured interviews, we explored how women perceived and experienced PPMP. FINDINGS: Four themes reflected cultural issues: PPMP stigma, relationship with parents/in-laws, internalization of society's expectations of motherhood, and identity issues/relationship with self. DISCUSSION: The results of this study contribute to a limited literature on possible contributing factors to PPMP and can inform development of resources for delivering culturally appropriate mental health care for women dealing with PPMP. PMID- 23460459 TI - UV-light-induced hydrogen transfer in guanosine-guanosine aggregates. AB - Aggregates of a lipophilic guanine (G) derivative have been studied in n-hexane by femtosecond-to-microsecond UV-visible broadband transient absorption, stationary infrared and UV-visible spectroscopy and by quantum chemical calculations. We report the first time-resolved spectroscopic detection of hydrogen transfer in GG aggregates, which leads to (G-H)(.) radicals by means of G(+)G(-) charge transfer followed by proton transfer. These radicals show a characteristic electronic spectrum in the range 300-550 nm. The calculated superimposed spectrum of the species that result from NH???N proton transfer agrees best with the experimental spectrum. PMID- 23460460 TI - Personal spiritual values and quality of life: evidence from Chinese college students. AB - Values are guiding principles in our life. While some studies found spiritual values to be "healthier," Sagiv and Schwartz (Eur J Soc Psychol 30:177-198, 2000) showed that people holding non-spiritual values were higher on affective well being. We examined the predictive power of these two types of values with a longitudinal data set collected from Chinese students mainly in Hong Kong. Structural equation modeling revealed that spiritual values (as well as family income) positively predicted quality of life a year later. Non-spiritual, self enhancement values, did not show any association. Results suggest that developing spiritual values may promote well-being through enabling individuals to find meaning and purpose in life. PMID- 23460461 TI - Effects of puberty on cystic fibrosis related pulmonary exacerbations in women versus men. AB - BACKGROUND: Epidemiologic data from studies of airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis indicate a gender disparity where women have worse outcomes. The explanation for this is largely unknown. We hypothesize that female sex hormones play a role in this gender disparity, predisposing women to more exacerbations and decreased lung function post-puberty. OBJECTIVE: In Cystic Fibrosis, to determine if puberty marks a point of increasing exacerbations and decreasing lung function in women relative to men. METHODS: Using the United States Cystic Fibrosis Foundation Patient Registry, we used linear regression to compare lung function and rate of pulmonary exacerbations in men versus women before and after puberty. RESULTS: Of 5,137 subjects who met inclusion criteria, 2,689 were male and 2,448 were female. Average age of puberty was found to be 13.2 +/- 2.2 years in men and 11.2 +/- 2.0 years of age in women. Percent predicted FEV1 pre- and post-puberty were no different between males versus females (P = 0.44 pre-puberty and P = 0.16 post puberty). In contrast, women had a significantly higher rate of pulmonary exacerbations post-puberty than men (1.17 +/- 1.35 exacerbations per year in women versus 0.95 +/- 1.27 in men; P < 0.001) despite controlling for morphometrics, co-morbidities, and microbiologic variables. CONCLUSION: After puberty, the rate of pulmonary exacerbations increased in adolescent women relative to men with cystic fibrosis, supporting a role for sex hormones in the disease process. Further understanding of the mechanisms that modulate sex hormone receptors in airway disease may serve as future targets for therapy. PMID- 23460463 TI - Mothers' awareness of anorectal malformations: a pointer to delayed diagnosis in a developing country. AB - INTRODUCTION: Delay in the presentation of babies with anorectal malformations (ARMs) to the pediatric surgeon accounts for a major cause of morbidity and mortality in developing countries. In countries lacking proper guidelines for screening and newborn physical examination, a lot of responsibility is placed on parents and caregivers; with mothers often being the first to note abnormalities in their babies. The aim of the study was to assess the awareness of mothers about ARM and their knowledge about normal or abnormal appearance of the anus. MATERIALS AND METHODS: A descriptive cross-sectional study involving mothers attending immunization clinics at two hospitals in a developing country was conducted using a structured interviewer administered questionnaire. Data were obtained on sociodemographic characteristics, awareness of ARM, and knowledge of appearance of the anus by requesting mothers to identify if three pictures of the perineum were normal or abnormal. RESULTS: A total of 365 mothers participated in the study with age ranging from 17 to 42 years. Only 71 (19.5%) mothers had ever heard about ARM. A picture of a girl with ARM and rectoperineal fistula was correctly identified by 66 (18.1%) and that of a boy with ARM and rectoperineal fistula by 71 (19.5%) mothers. A higher proportion (25.0%) of the mothers who were older than 30 years were aware of ARM than those younger than 30 years (16.0%), (p = 0.035). Participants with tertiary education were more likely to be aware of ARM than those with 12th grade or less education (31.1 vs. 6.9%, p < 0.001). Skilled workers were also more likely to be aware of ARM than unskilled workers and artisans (41.1 vs. 8.1%, p < 0.001). The predominant technique of "checking" the anus by the mothers was "inspection of their baby's perineum." CONCLUSION: Level of awareness of ARMs was low among women interviewed. Educational intervention targeting young mothers from low socioeconomic class is suggested. PMID- 23460462 TI - Torsion biomechanics of the spine following lumbar laminectomy: a human cadaver study. AB - PURPOSE: Lumbar laminectomy affects spinal stability in shear loading. However, the effects of laminectomy on torsion biomechanics are unknown. The purpose of this study was to investigate the effect of laminectomy on torsion stiffness and torsion strength of lumbar spinal segments following laminectomy and whether these biomechanical parameters are affected by disc degeneration and bone mineral density (BMD). METHODS: Ten human cadaveric lumbar spines were obtained (age 75.5, range 59-88). Disc degeneration (MRI) and BMD (DXA) were assessed. Disc degeneration was classified according to Pfirrmann and dichotomized in mild or severe. BMD was defined as high BMD (>=median BMD) or low BMD ( 48 hours hospital stay) in 18% (8/44); transient Horner syndrome in 18% (8/44-right 5, left 3); and recurrence of PH in 11% (5/44) of cases. In the recurrence group, 7% (3/44) were unilateral (right 2, left 1) and 5% (2/44) were bilateral. Redo operations were performed in 11% (5/44) of cases. Median time to redo was 2.6 years (range 8 months to 4.2 years). All three unilateral recurrent patients underwent respective sided redo. In the bilateral recurrence group (2/44), one patient had bilateral redo (remained dry), whereas the other patient underwent only right-sided operation (remained dry), as that sided operation was difficult and so the other side was not tried. FINAL OUTCOMES: The final outcomes were recurrence 3.5% (3/85-right 2, left 1) and technically failed operation 3.5% (3/85-both sides 1, one side 1). Success rate for thoracoscopic sympathetectomy was 93% (79/85) overall. CONCLUSION: TS for PH is a safe and feasible operation in children. It is successful in the majority; however, the procedure is not trouble free. PMID- 23460465 TI - The effect of whole gut irrigation on contractile responses of guinea pig gallbladder, ileum, and tissue cholecystokinin levels. AB - AIM: An experimental study was performed to evaluate the effect of whole gut irrigation (WGI) solutions on contractile responses of the gallbladder and ileum and also on tissue cholecystokinin (CCK) levels. MATERIALS AND METHODS: Thirty guinea pigs were enrolled into five groups including control group (CG) and WGI group (saline physiologic [SP], Ringer lactated [RL], polyethylene glycol [PEG], and dibasic sodium phosphate [DNP]). After median laparotomy, the distal esophagus was ligated and SP, PEG, RL, and DNP infusions (2 mL/kg/min) were performed via gastric catheter until rectal discharge became clear in WGI groups. Ileum and gallbladder samples were obtained for in vitro and biochemical studies without irrigation in CG and after irrigation with different WGI solutions. Isolated ileum and gallbladder preparations were suspended in organ baths for contractile responses of carbachol and CCK. Also, biochemical analysis of tissue CCK levels was performed in ileum and gallbladder samples. RESULTS: In PEG group, gallbladder and ileum CCK levels were significantly higher than CG (p < 0.05). Also, DNP irrigation caused increased CCK levels in gallbladder samples (p < 0.05). In lower carbachol concentrations, PEG group showed increased contraction responses in gallbladder samples when compared with controls (p < 0.05). However, ileal responses to carbachol did not show any significant difference between groups, contraction responses to CCK was decreased in PEG group when compared with CG (p < 0.05). CONCLUSION: Among WGI solutions, PEG caused the highest CCK levels in gallbladder and ileum samples. Different WGI solutions affected the contractile responses of gallbladder and ileum smooth muscles divergently. Increased levels of CCK in PEG group support the decreased contractile responses in ileum. Therefore, our results confirm that the effect of WGI on gallbladder and ileum contractility may be CCK related. PMID- 23460466 TI - The motion behind the symbols: a vital role for dynamism in the conceptualization of limits and continuity in expert mathematics. AB - The canonical history of mathematics suggests that the late 19th-century "arithmetization" of calculus marked a shift away from spatial-dynamic intuitions, grounding concepts in static, rigorous definitions. Instead, we argue that mathematicians, both historically and currently, rely on dynamic conceptualizations of mathematical concepts like continuity, limits, and functions. In this article, we present two studies of the role of dynamic conceptual systems in expert proof. The first is an analysis of co-speech gesture produced by mathematics graduate students while proving a theorem, which reveals a reliance on dynamic conceptual resources. The second is a cognitive-historical case study of an incident in 19th-century mathematics that suggests a functional role for such dynamism in the reasoning of the renowned mathematician Augustin Cauchy. Taken together, these two studies indicate that essential concepts in calculus that have been defined entirely in abstract, static terms are nevertheless conceptualized dynamically, in both contemporary and historical practice. PMID- 23460468 TI - In the eye of the B-holder: natural history of chronic hepatitis B. PMID- 23460467 TI - Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor alpha inhibitor therapy: results from the Danish Nationwide DANBIO Registry. AB - OBJECTIVE: To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor alpha inhibitor (TNFi) agents in routine care. METHODS: We conducted an observational cohort study based on the Danish nationwide DANBIO registry. Treatment outcomes were evaluated using the American College of Rheumatology criteria for 20% improvement (ACR20)/ACR50/ACR70, European League Against Rheumatism (EULAR) response criteria for good response, and the 28-joint count Disease Activity Score (DAS28) (remission). Kaplan-Meier and regression analyses were used for drug survival analyses and to identify predictors of outcome after treatment switching. RESULTS: Of 1,422 patients starting TNFi agents, 548 patients (39%) switched to a second biologic drug during up to 10 years of followup. Median followup was 2.3 years (interquartile range [IQR] 1.0-4.3 years). Switchers were more frequently women (56% versus 45%), had a shorter disease duration (3 versus 4 years), a higher median Health Assessment Questionnaire (HAQ) score (1.1 [IQR 0.6-1.6] versus 0.9 [IQR 0.5-1.4]), DAS28 (4.8 [4.0-5.7] versus 4.4 [3.6-5.2]), pain score on a visual analog scale (VAS) (65 mm [46-77] versus 62 mm [40-75]), and fatigue score on a VAS (69 mm [50-83] versus 64 mm [42-80] mm) (all P < 0.05 at start of first TNFi). During the first and second treatment, HAQ, DAS28, and VAS scores and C-reactive protein levels had decreased after 6 months (all P < 0.05), and median drug survival was 2.2 versus 1.3 years (P < 0.001). Lower fatigue score increased survival of the second TNFi. After switching, the proportions of patients achieving a sustained ACR20, ACR50, ACR70, EULAR good response, and DAS28 remission after 3-6 months were 22% (number needed to treat [NNT] 4.5), 13% (NNT 7.9), 5% (NNT 20), 19% (NNT 5.3), and 34% (NNT 2.9), respectively. Response rates were lower during the second treatment (all P < 0.01 versus first TNFi). At the 2-year visit, 47% of switchers had achieved an ACR20 response. No differences between drug-drug combinations were found. CONCLUSION: Thirty-nine percent of the patients with PsA switched TNFi agents. Response rates and drug survival were lower after switching; however, half of the switchers had an ACR20 response 2 years after starting the first TNFi. PMID- 23460469 TI - Tumour necrosis factor in infectious disease. AB - TNF signals through two distinct receptors, designated TNFR1 and TNFR2, which initiate diverse cellular effects that include cell survival, activation, differentiation, and proliferation and cell death. These cellular responses can promote immunological and inflammatory responses that eradicate infectious agents, but can also lead to local tissue injury at sites of infection and harmful systemic effects. Defining the molecular mechanisms involved in TNF responses, the effects of natural and experimental genetic diversity in TNF signalling and the effects of therapeutic blockade of TNF has increased our understanding of the key role that TNF plays in infectious disease. PMID- 23460470 TI - Connecting the dots from fatty acids to nonalcoholic steatohepatitis: epigenetics in the spotlight. PMID- 23460471 TI - Snail mediates PDGF-BB-induced invasion of rat bone marrow mesenchymal stem cells in 3D collagen and chick chorioallantoic membrane. AB - We previously reported that membrane type-1 matrix metalloproteinase (MT1-MMP) enables mesenchymal stem cells (MSCs) to move through both three-dimensional (3D) type I collagen and basement membrane barriers; however, its upstream regulating factors were unidentified. Here, we report that PDGF-BB upregulates both mRNA and protein expression of snail in rat bone marrow MSCs (rBMMSCs). PDGF-BB enhances rBMMSC invasion in 3D collagen, which is blocked by snail specific siRNA transfection. Snail overexpression induced by plasmid transfection results in increased rBMMSC invasion in 3D collagen. Snail expression induced by PDGF-BB in MSCs is inhibited by LY294002 and PD98059, which are inhibitors of the PI3K/AKT and MAPK1/2/ERK1/2 signaling pathways, respectively. MT1-MMP expression in rBMMSCs, both as mRNA and protein, is decreased by snail siRNA transfection, but increased by snail overexpression, indicating that they are controlled by snail. Finally, snail controls MSC transmigration through chorioallantoic membrane of 11 day-old chick embryos. Taken together, these in vitro and in vivo data identify snail as a critical mediator for rBMMSC invasion induced by PDGF-BB. PMID- 23460472 TI - First experience with a new balloon-expandable and re-collapsible vascular sheath in transfemoral percutaneous aortic valve replacement. AB - OBJECTIVE: To describe a novel method of transfemoral access via a first generation balloon-expandable and re-collapsible access system. METHODS: In a patient at very high risk for surgical aortic valve replacement and with a relative contraindication for transapical transcatheter aortic valve implantation (TAVI) (left ventricular ejection fraction = 12%), transfemoral TAVI was performed. Due to compromising peripheral vascular anatomy/disease, a novel balloon-expandable and re-collapsible sheath system (Onset Medical, a subdivision of Terumo Medical Corporation, Irvine, CA) was used to achieve transfemoral access for the implantation of a 31-mm Medtronic CoreValve(r) prosthesis. RESULT: The sheath with an initial outer diameter of ~13 French was introduced via the right common femoral artery and advanced into the descending aorta without difficulties and expanded with a pressure of 20 atm for 60 sec. After successful transfemoral TAVI, the sheath was deflated to a size of ~13 French and removed from the vessel. A ProStar(r) closure device was successfully used to achieve hemostasis. Routine access-site angiography revealed no signs of dissection, stenosis, or extravasation. During the further clinical stay, no further major vascular complication or need for transfusion occurred. The patient was discharged on day 7 after the procedure. CONCLUSION: The use of a balloon expandable re-collapsible transfemoral sheath appears to be a promising approach with the potential of less vascular trauma. Further studies will need to evaluate the potential benefit of this novel device in patients with peripheral artery disease and if vascular injury and subsequent access site complications can hereby further be reduced. PMID- 23460473 TI - Supramolecular Cl???H and O???H interactions in self-assembled 1,5 dichloroanthraquinone layers on Au(111). AB - The role of halogen bonds in self-assembled networks for systems with Br and I ligands has recently been studied with scanning tunneling microscopy (STM), which provides physical insight at the atomic scale. Here, we study the supramolecular interactions of 1,5-dichloroanthraquinone molecules on Au(111), including Cl ligands, by using STM. Two different molecular structures of chevron and square networks are observed, and their molecular models are proposed. Both molecular structures are stabilized by intermolecular Cl???H and O???H hydrogen bonds with marginal contributions from Cl-related halogen bonds, as revealed by density functional theory calculations. Our study shows that, in contrast to Br- and I related halogen bonds, Cl-related halogen bonds weakly contribute to the molecular structure due to a modest positive potential (sigma hole) of the Cl ligands. PMID- 23460474 TI - The Biginelli reaction with an imidazolium-tagged recyclable iron catalyst: kinetics, mechanism, and antitumoral activity. AB - The present work describes the synthesis, characterization, and application of a new ion-tagged iron catalyst. The catalyst was employed in the Biginelli reaction with impressive performance. High yields have been achieved when the reaction was carried out in imidazolium-based ionic liquids (BMI?PF6, BMI?NTf2, and BMI?BF4), thus showing that the ionic-liquid effects play a role in the reaction. Moreover, the ion-tagged catalyst could be recovered and reused up to eight times without any noticeable loss in activity. Mechanistic studies performed by using high resolution electrospray-ionization quadrupole-time-of-flight mass (HR-EI-QTOF) spectrometry and kinetic experiments indicate only one reaction pathway and rule out the other two possibilities under the development conditions. The theoretical calculations are in accordance with the proposed mechanism of action of the iron catalyst. Finally, the 37 dihydropyrimidinone derivatives, products of the Biginelli reaction, had their cytotoxicity evaluated in assays against MCF-7 cancer cell linages with encouraging results of some derivatives, which were virtually non-toxic against healthy cell linages (fibroblasts). PMID- 23460475 TI - Beneficial effect of crotamine in the treatment of myasthenic rats. AB - INTRODUCTION: Crotamine is a basic, low-molecular-weight peptide that, at low concentrations, improves neurotransmission in isolated neuromuscular preparations by modulating sodium channels. In this study, we compared the effects of crotamine and neostigmine on neuromuscular transmission in myasthenic rats. METHODS: We used a conventional electromyographic technique in in-situ neuromuscular preparations and a 4-week treadmill program. RESULTS: During the in situ electromyographic recording, neostigmine (17 MUg/kg) caused short-term facilitation, whereas crotamine induced progressive and sustained twitch-tension enhancement during 140 min of recording (50 +/- 5%, P < 0.05). On the treadmill evaluation, rats showed significant improvement in exercise tolerance, characterized by a decrease in the number of fatigue episodes after 2 weeks of a single-dose treatment with crotamine. CONCLUSIONS: These results indicate that crotamine is more efficient than neostigmine for enhancing muscular performance in myasthenic rats, possibly by improving the safety factor of neuromuscular transmission. PMID- 23460476 TI - Obliterative lower airway lesions in childhood: bronchoscopic diagnosis and clinical spectrum. AB - Previous reports have described structural airway abnormalities in children with non-cystic fibrosis chronic supportive lung disease as well as obliterative membranes in the major bronchi of cystic fibrosis patients. The putative paradigm proposed in the evolution of these membranes invokes intense inflammation resulting in granulation tissue and neovascularization with the formation of pyogenic granuloma and eventually fibrosis. Our series of four cases widens the spectrum of conditions that may be conducive to large airway obliteration to include non-suppurative chronic infections and possibly immunosuppression. Obliteration of lumina in proximal and distal airways was visualized on bronchoscopy, the latter by the use of the ultrathin bronchoscopes. An attempt at invasive intervention by transbronchial breaching of the obstruction was unsuccessful in three cases, and in one case, the obliterative process resolved spontaneously and without any radiologic trace, presumably by resorption or rupture or through development of collateral ventilation. This series highlights the use of bronchoscopy for diagnosis and occasionally for therapeutic intervention in hitherto little recognized obliterative airway lesions. These acquired obliterative lesions should be considered in the evaluation of patients with isolated non-resolving pulmonary infiltrates or other conditions in which bronchial and bronchiolar patency may be impaired. PMID- 23460477 TI - Numerical architecture. AB - The idea that there is a "Number Sense" (Dehaene, 1997) or "Core Knowledge" of number ensconced in a modular processing system (Carey, 2009) has gained popularity as the study of numerical cognition has matured. However, these claims are generally made with little, if any, detailed examination of which modular properties are instantiated in numerical processing. In this article, I aim to rectify this situation by detailing the modular properties on display in numerical cognitive processing. In the process, I review literature from across the cognitive sciences and describe how the evidence reported in these works supports the hypothesis that numerical cognitive processing is modular. I outline the properties that would suffice for deeming a certain processing system a modular processing system. Subsequently, I use behavioral, neuropsychological, philosophical, and anthropological evidence to show that the number module is domain specific, informationally encapsulated, neurally localizable, subject to specific pathological breakdowns, mandatory, fast, and inaccessible at the person level; in other words, I use the evidence to demonstrate that some of our numerical capacity is housed in modular casing. PMID- 23460478 TI - Adiabatic reduction of a model of stochastic gene expression with jump Markov process. AB - This paper considers adiabatic reduction in a model of stochastic gene expression with bursting transcription considered as a jump Markov process. In this model, the process of gene expression with auto-regulation is described by fast/slow dynamics. The production of mRNA is assumed to follow a compound Poisson process occurring at a rate depending on protein levels (the phenomena called bursting in molecular biology) and the production of protein is a linear function of mRNA numbers. When the dynamics of mRNA is assumed to be a fast process (due to faster mRNA degradation than that of protein) we prove that, with appropriate scalings in the burst rate, jump size or translational rate, the bursting phenomena can be transmitted to the slow variable. We show that, depending on the scaling, the reduced equation is either a stochastic differential equation with a jump Poisson process or a deterministic ordinary differential equation. These results are significant because adiabatic reduction techniques seem to have not been rigorously justified for a stochastic differential system containing a jump Markov process. We expect that the results can be generalized to adiabatic methods in more general stochastic hybrid systems. PMID- 23460479 TI - The impact of health worker migration on development dynamics: evidence of wealth effects from Africa. AB - This article examines three relevant hypotheses on the effect of health worker migration on human development and economic prosperity (at the macro- and micro levels) in Africa. Owing to the lack of relevant data on health human resource (HHR) migration for the continent, the subject matter has remained empirically void over the last decades despite the acute concern about health professional emigration. Using quantile regression, the following findings have been established. (1) The effect of HHR emigration is positive (negative) at low (high) levels of economic growth. (2) HHR emigration improves (mitigates) human development (GDP per capita growth) in low (high) quantiles of the distribution. (3) Specific differences in effects are found in top quantiles of human development and low quantiles of GDP per capita growth where the physician (nurse) emigration elasticities of development are positive (negative) and negative (positive), respectively. As a policy implication, blanket health-worker emigration control policies are unlikely to succeed across countries with different levels of human development and economic prosperity. Hence, the policies should be contingent on the prevailing levels of development and tailored differently across the most and least developed African countries. PMID- 23460480 TI - Rhodium(III)-catalyzed amidation of aryl ketone O-methyl oximes with isocyanates by C-H activation: convergent synthesis of 3-methyleneisoindolin-1-ones. PMID- 23460481 TI - Tumour necrosis factor and cancer. AB - Tumour necrosis factor (TNF) was originally described as a circulating factor that can induce haemorrhagic necrosis of tumours. It is now clear that TNF has many different functions in cancer biology. In addition to causing the death of cancer cells, TNF can activate cancer cell survival and proliferation pathways, trigger inflammatory cell infiltration of tumours and promote angiogenesis and tumour cell migration and invasion. These effects can be explained by the diverse cellular responses TNF can initiate through distinct signal transduction pathways, opening the way for more selective targeting of TNF signalling in cancer therapy. PMID- 23460483 TI - Staphylococcus aureus colonization among arthroplasty patients previously treated by a decolonization protocol: a pilot study. AB - BACKGROUND: Although testing and treatment for Staphylococcus aureus colonization before total joint arthroplasty (TJA) are well described and understood, the durability of decolonization has not been studied extensively. QUESTIONS/PURPOSES: The purpose of this pilot study is to determine the percentage of arthroplasty patients with S. aureus colonization despite previous decolonization at the time of TJA. METHODS: Over a 2-year period, all patients having TJA by one surgeon were screened and treated for nasal S. aureus. Of 634 patients, 139 had methicillin-sensitive S. aureus (15%) or methicillin-resistant S. aureus (6.6%) colonization before TJA. Fifty-eight of these 139 patients (42%) were retested at 3 to 30 months for persistent colonization by nasal culture. Data collection included age at time of TJA, type of TJA, and time from TJA to repeat testing. We performed no clonal analysis for strains. RESULTS: Thirty-nine of the 58 patients (67%) decolonized before surgery were negative on retesting and 19 (33%) were again positive for S. aureus colonization. Of the 19 patients who retested positive for colonization, 17 (89%) were colonized by bacteria with unchanged antibiotic sensitivity. CONCLUSIONS: We demonstrate that 33% (19 of 58) of postoperative arthroplasty patients test positive for S. aureus colonization at 3 to 30 months after surgery despite preoperative decolonization. Arthroplasty surgeons must be aware that a decolonization treatment does not guarantee that a patient will remain decolonized in the future. Although unchanged antibiotic sensitivity in 89% of these patients suggests a substantial role for persistence as opposed to eradication and repeat colonization, we were unable to retrospectively perform clonal analysis to confirm this conclusion. This group of patients demonstrating continued colonization with S. aureus after arthroplasty deserves further study, because it remains unclear whether there is a higher risk of late infection in this population. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 23460484 TI - Can fluoroscopy-based computer navigation improve entry point selection for intramedullary nailing of femur fractures? AB - BACKGROUND: The entry point is crucial to an accurate reduction in femoral nailing. Fluoroscopy-based navigation was developed to aid in reducing femur fractures and selecting entry points. QUESTIONS/PURPOSES: We asked: (1) Can the piriformis fossa (PF) and tip of the greater trochanter (TT) be identified with high reproducibility? (2) What is the range of nonneutral images clinically acceptable for entry point selection? (3) Does navigation improve accuracy and precision of landmarking the TT and PF? And (4) does off-angle fluoroscopy within the acceptable range affect landmark accuracy? METHODS: Three orthopaedic surgeons digitized the PF and TT under direct visualization on 10 cadaveric femurs, quantifying the reproducibility of the targeted PF and TT landmarks. Arcs of acceptable AP and lateral images of each femur were acquired in increments of 5 degrees with a C-arm. An experienced orthopaedic surgeon rejected or accepted images for entry point selection by qualitatively assessing the relative positions and sizes of the greater trochanter, lesser trochanter, and femoral neck. Entry points were identified on each image using fluoroscopy and navigation. Hierarchical linear modeling was used to compare accuracy and precision between navigation and fluoroscopy and the effects of image angle. RESULTS: A 29 degrees average arc of acceptable images was found. Reproducibility of the target landmarks for the PF and TT under direct visualization was excellent. Navigation had similar accuracy to fluoroscopy for PF localization but less for TT. Navigation increased precision compared to fluoroscopy for both PF and TT. Image angle affected accuracy of the PF and TT under fluoroscopy and navigation. CONCLUSIONS: Nonorthogonal images reduce accuracy of PF and TT identification with both navigation and fluoroscopy. Navigation increased precision but decreased accuracy and cannot overcome inaccuracies induced by nonorthogonal images. PMID- 23460482 TI - Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs. AB - We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon. PMID- 23460485 TI - Is there a difference in timing and cause of death after fractures in the elderly? AB - BACKGROUND: Patients who sustain osteoporotic fractures have excessive mortality compared to age-matched controls, which is most pronounced within the first 6 months postfracture. However, the timing and cause of death in the first 3 months after sustaining a fracture are unclear. QUESTIONS/PURPOSES: We therefore evaluated and compared the timing and cause of death in patients who sustained a pelvic, proximal femoral, spinal, or proximal humeral fracture 30 and 90 days after fracture. METHODS: From medical records, we recorded age at time of fracture, sex, fracture site, comorbidities, date of death, and cause of death of 1630 patients with 1630 fractures admitted to our department between 2001 and 2007. The median age at the time of fracture was 83 years and 89% of the patients were women. RESULTS: Fifty-eight patients died within 30 days after fracture (3.6%), and 122 patients (7.5%) died within 90 days after fracture. Cardiovascular causes of death were most frequent in all fracture groups. Patients who suffered from spinal fractures died earlier within 30 days after fracture than patients who suffered from other types of fractures. CONCLUSIONS: This shows the severity and impact of a spinal injury compared to other typical fragility fractures. PMID- 23460486 TI - Editor's spotlight/take 5: Comparative responsiveness and minimal clinically important differences for idiopathic ulnar impaction syndrome (DOI 10.1007/s11999 013-2843-8). PMID- 23460487 TI - Surgical technique: Results of stabilization of sternoclavicular joint luxations using a polydioxanone envelope plasty. AB - BACKGROUND: Surgical treatment options for sternoclavicular joint luxations described in the literature are numerous, although all have limitations. Therefore, there is no favorable surgical treatment for sternoclavicular luxations when nonoperative treatment has failed. DESCRIPTION OF TECHNIQUE: We developed the polydioxanone (PDS) envelope plasty, a modification of the figure of-eight technique, using a PDS ligament. METHODS: We retrospectively reviewed 39 patients (40 joints), treated with a PDS envelope plasty for invalidating sternoclavicular luxations. The minimum followup was 10 months (average, 52 months; range, 10-171 months). The Simple Shoulder Test (SST), Constant-Murley shoulder score, and subjective categorical results were recorded preoperatively and postoperatively. RESULTS: In most patients, postoperative functional shoulder scores were excellent (mean Constant-Murley score, 90, range, 52-100; mean SST, 10; range, 2-12). Ninety percent of patients had an improvement of shoulder function at followup. Only minor complications occurred. Thirteen percent of patients had spontaneous postoperative subluxations. However, the postoperative shoulder function improved in all these patients. CONCLUSIONS: The PDS envelope plasty is a simple procedure, a modification of the best-reported technique. We have promising results with high shoulder scores. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23460488 TI - Reply to letter to the editor: Intramedullary nails result in more reoperations than sliding hip screws in two-part intertrochanteric fractures. PMID- 23460489 TI - Factors implicated in pathogenesis of urinary tract infections in neurogenic bladders: some revered, few forgotten, others ignored. AB - AIMS: To comprehensively review factors implicated in the pathogenesis of urinary tract infection in patients with neurogenic bladders, and to stimulate research, especially in the somewhat ignored and forgotten areas of this important clinical subject. METHODS: In addition to reviewing relevant articles on pubmed, some important articles from previous times which were not available online were also procured and reviewed. RESULTS: Intrinsic defence mechanisms including protective flora, anti-adherence mechanisms, urothelial, and immunological responses to bacterial binding and the blood supply to the urinary bladder may be impaired in patients with neurogenic bladders. Further, bacterial washout mechanisms may be compromised as a result of inefficient voiding, reflux, and altered hydrokinetics. Finally, catheterization itself contributes to urinary tract infection in patients with neurogenic bladders. CONCLUSIONS: In order to address the issue of urinary tract infection in patients with neurogenic bladders, multiple factors need to be looked into and corrected. Further research is required, especially in the area of compromised host defence mechanisms. An individualized approach, which attempts to optimize each factor is recommended. PMID- 23460490 TI - Biofuel cells for biomedical applications: colonizing the animal kingdom. AB - Interdisciplinary research has combined the efforts of many scientists and engineers to gain an understanding of biotic and abiotic electrochemical processes, materials properties, biomedical, and engineering approaches for the development of alternative power-generating and/or energy-harvesting devices, aiming to solve health-related issues and to improve the quality of human life. This review intends to recapitulate the principles of biofuel cell development and the progress over the years, thanks to the contribution of cross-disciplinary researchers that have combined knowledge and innovative ideas to the field. The emergence of biofuel cells, as a response to the demand of electrical power devices that can operate under physiological conditions, are reviewed. Implantable biofuel cells operating inside living organisms have been envisioned for over fifty years, but few reports of implanted devices have existed up until very recently. The very first report of an implanted biofuel cell (implanted in a grape) was published only in 2003 by Adam Heller and his coworkers. This work was a result of earlier scientific efforts of this group to "wire" enzymes to the electrode surface. The last couple of years have, however, seen a multitude of biofuel cells being implanted and operating in different living organisms, including mammals. Herein, the evolution of the biofuel concept, the understanding and employment of catalyst and biocatalyst processes to mimic biological processes, are explored. These potentially green technology biodevices are designed to be applied for biomedical applications to power nano- and microelectronic devices, drug delivery systems, biosensors, and many more. PMID- 23460491 TI - Generalized random sign and alert delay models for imperfect maintenance. AB - This paper considers the modelling of the process of Corrective and condition based Preventive Maintenance, for complex repairable systems. In order to take into account the dependency between both types of maintenance and the possibility of imperfect maintenance, Generalized Competing Risks models have been introduced in "Doyen and Gaudoin (J Appl Probab 43:825-839, 2006)". In this paper, we study two classes of these models, the Generalized Random Sign and Generalized Alert Delay models. A Generalized Competing Risks model can be built as a generalization of a particular Usual Competing Risks model, either by using a virtual age framework or not. The models properties are studied and their parameterizations are discussed. Finally, simulation results and an application to real data are presented. PMID- 23460492 TI - Influences of cognitive control on numerical cognition--adaptation by binding for implicit learning. AB - Recently, an associative learning account of cognitive control has been suggested (Verguts & Notebaert, 2009). In this so-called adaptation by binding theory, Hebbian learning of stimulus-stimulus and stimulus-response associations is assumed to drive the adaptation of human behavior. In this study, we evaluated the validity of the adaptation-by-binding account for the case of implicit learning of regularities within a stimulus set (i.e., the frequency of specific unit digit combinations in a two-digit number magnitude comparison task) and their association with a particular response. Our data indicated that participants indeed learned these regularities and adapted their behavior accordingly. In particular, influences of cognitive control were even able to override the numerical distance effect--one of the most robust effects in numerical cognition research. Thus, the general cognitive processes involved in two-digit number magnitude comparison seem much more complex than previously assumed. Multi-digit number magnitude comparison may not be automatic and inflexible but influenced by processes of cognitive control being highly adaptive to stimulus set properties and task demands on multiple levels. PMID- 23460493 TI - Roughness parameter selection for novel manufacturing processes. AB - This work proposes a method of roughness parameter (RP) selection for novel manufacturing processes or processes where little knowledge exists about which RPs are important. The method selects a single parameter to represent a group of highly correlated parameters. Single point incremental forming (SPIF) is used as the case study for the manufacturing process. This methodology was successful in reducing the number of RPs investigated from 18 to 8 in the case study. PMID- 23460494 TI - Multicenter nit-occlud(r) PDA-R patent. Ductus arteriosus occlusion device trial: initial and six-month results. AB - BACKGROUND: Transcatheter closure of a moderate to large patent ductus arteriosus (PDA) using conventional techniques is challenging. The Nit-Occlud(r) PDA-R trial can close a PDA up to 8 mm in diameter. We sought to report procedural and six month efficacy and safety results of the multicenter Nit-Occlud(r) PDA-R trial. METHODS: From June 2010 to February 2011, 43 patients were enrolled in three centers from Argentina. Median age was 4.5 (range 1.4-18.4 years) years old at catheterization, 70% were females and weight was 17.7 (range 10-67 kg). RESULTS: PDAs mean diameter was 2.98 +/- 1.03 and ranged from 2 to 6.19 mm. About 11.6% were large (>=4 mm), whereas 32.6% were <2.5 mm. Median pulmonary artery mean pressure was 17 mm Hg (range 9-26 mm Hg). The device was implanted successfully in all patients. By echocardiography, trivial residual shunt was observed in 42% at the end of the procedure, in 28% at 24 hr, in 12.1% at one week, and none at three-months. There was one case of embolization (due to undersizing), that was treated successfully with a larger study device. There were no major short- or long-term complications. CONCLUSIONS: PDAs ranging from 2 to 6 mm can be effectively and safely closed using the Nit-Occlud(r) PDA-R device, with good procedural and six-month results. The Nit-Occlud(r) PDA-R emerges as an optimal alternative for closure of small to moderate PDAs. PMID- 23460495 TI - The management of a case of childhood empyema. PMID- 23460496 TI - Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure. AB - The aim of this study was to evaluate the long-term effects of pediatric intestinal failure (IF) on liver histology. Altogether, 38 IF patients (median age: 7.2 years; range, 0.2-27) underwent liver biopsy, gastroscopy, abdominal ultrasound, and laboratory tests. Sixteen patients were on parenteral nutrition (PN) after 74 PN months (range, 2.5-204). Twenty-two had weaned off PN 8.8 years (range, 0.3-27) earlier, after 35 PN months (range, 0.7-250). Fifteen transplant donor livers served as controls. Abnormal liver histology was found in 94% of patients on PN and 77% of patients weaned off PN (P = 0.370). During PN, liver histology weighted with cholestasis (38% of patients on PN versus 0% of patients weaned off PN; P = 0.003) and portal inflammation (38% versus 9%; P = 0.050) were found. Fibrosis (88% versus 64%; P = 0.143; Metavir stage: 1.6 [range, 0-4] versus 1.1 [range, 0-2]; P = 0.089) and steatosis (50% versus 45%; P = 1.000) were equally common during and after weaning off PN. Plasma alanine aminotransferase (78 U/L [range, 19-204] versus 34 [range, 9-129]; P = 0.009) and conjugated bilirubin (43 MUmol/L [range, 1-215] versus 4 [range, 1-23]; P = 0.037) were significantly higher during than after weaning off PN. Esophageal varices were encountered in 1 patient after weaning off PN. Metavir stage was associated with small bowel length (r = -0.486; P = 0.002) and number of septic episodes (r = 0.480; P = 0.002). In a multivariate analysis, age-adjusted small bowel length (beta = -0.533; P = 0.001), portal inflammation (beta = 0.291; P = 0.030), and absence of an ileocecal valve (beta = 0.267; P = 0.048) were predictive for fibrosis stage. CONCLUSION: Despite resolution of cholestasis and portal inflammation, significant liver fibrosis and steatosis persist after weaning off PN. Extensive small intestinal resection was the major predictor for liver fibrosis stage. PMID- 23460497 TI - MicroRNA transport: a new way in cell communication. AB - MicroRNAs (miRNAs) can efficiently regulate gene expression by targeting mRNA to cause mRNA cleavage or translational repression. Growing evidence indicates that miRNAs exist not only in cells but also in a variety of body fluids, which stimulates substantial interest in the transport mechanism and regulating process of extracellular miRNAs. This article reviews the basic biogenesis of miRNAs in detail to explore the origin of extracellular miRNAs. Different miRNA transporters have been summarized (e.g., exosomes, microvesicles, apoptosis bodies, and RNA-binding proteins). In addition, we discuss the regulators affecting miRNA transport (e.g., ATP and ceramide) and the selection mechanism for different miRNA transporters. Studies about miRNA transporters and the transport mechanism are new and developing. With the progress of the research, new functions of extracellular miRNAs may be uncovered in the future. PMID- 23460498 TI - Development of metal/organo catalytic systems for direct vinylogous Michael reactions to build chiral gamma,gamma-disubstituted butenolides. PMID- 23460499 TI - The stretching elasticity of biomembranes determines their line tension and bending rigidity. AB - In this work, some implications of a recent model for the mechanical behavior of biological membranes (Deseri et al. in Continuum Mech Thermodyn 20(5):255-273, 2008) are exploited by means of a prototypical one-dimensional problem. We show that the knowledge of the membrane stretching elasticity permits to establish a precise connection among surface tension, bending rigidities and line tension during phase transition phenomena. For a specific choice of the stretching energy density, we evaluate these quantities in a membrane with coexistent fluid phases, showing a satisfactory comparison with the available experimental measurements. Finally, we determine the thickness profile inside the boundary layer where the order-disorder transition is observed. PMID- 23460500 TI - Apoptosis induced by aqueous extracts of crocodile bile in human heptacarcinoma SMMC-7721. AB - In the present study, effects of aqueous extracts from Crocodylus siamensis bile (AE-CB) on SMMC-7721 cell growth, cell cycle, and apoptosis were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, inverted microscopy, fluorescence microscopy, propidium iodide (PI) single- and fluorescein isothiocyanate (FITC)/PI double-staining flow cytometry, and western blotting. Our data have revealed that AE-CB significantly inhibited the growth of SMMC-7721 cell and arrested cell cycle at G0/G1 phase. SMMC-7721 cells showed typical apoptotic morphological changes after treated with AE-CB for 48 h. Cell death assay indicated that SMMC-7721 cells underwent apoptosis in a dose dependent manner induced by AE-CB. In addition, AE-CB treatment could downregulate the protein level of Bcl-2 and upregulate the Bax, leading to the increase in the ratio of Bax to Bcl-2 in SMMC-7721 cells. Meanwhile, it was observed that the expression of Survivin and c-Myc decreased, but the expression of P53 increased. All these events were associated with increase of reactive oxygen species. The data indicated that mitochondrial pathway might play an important role in bile extract-induced apoptosis in SMMC-7721 cells. These results provide significant insight into the anticarcinogenic action of bile extract on SMMC-7721 cells. PMID- 23460501 TI - Transistor functions based on electrochemical rectification. PMID- 23460502 TI - Cucurbituril hosts in real-life action. AB - Stick it to them! Underwater adhesion becomes possible by taking advantage of highly stable host-guest complexes formed between cucurbit[7]uril hosts and ferrocenyl residues. The formation of multiple noncovalent complexes between the two complementary surfaces gives rise to strong adhesive forces resulting in a "supramolecular velcro" system that operates efficiently in the presence of water. PMID- 23460503 TI - Long-term safety, tolerability and efficacy of flexible-dose fesoterodine in elderly patients with overactive bladder: open-label extension of the SOFIA trial. AB - AIMS: To assess the long-term safety, tolerability, and efficacy of flexible-dose fesoterodine in elderly patients with OAB. METHODS: Patients aged >=65 years who completed a 12-week, randomized, double-blind, placebo-controlled trial were eligible for the 12-week, open-label (OL) extension phase. Patients who received double-blind placebo started on fesoterodine 4 mg and could increase to 8 mg after 4 or 8 weeks of OL treatment, while fesoterodine-treated patients continued on their double-blind dose; only one dose escalation or de-escalation was permitted. Discontinuations and adverse events (AEs) were monitored, and patients completed 3-day bladder diaries and patient-reported outcomes at the beginning and end of the 12-week OL phase. RESULTS: Six hundred fifty-four patients entered the 12-week OL extension (mean age 72 years; 52% women). AEs were reported by 30.7% and 48.1% of patients who had received double-blind fesoterodine and placebo, respectively; 1.9% and 9.4%, discontinued due to AEs, respectively. Patients who received double-blind fesoterodine maintained their efficacy response. After 12 weeks of OL treatment, efficacy outcomes in patients who received double-blind placebo were similar to those who had received double-blind fesoterodine. On average, the efficacy response was maintained for the duration of the study. CONCLUSIONS: Fesoterodine was well tolerated and improvements in OAB symptoms and quality of life measures were not diminished with longer-term treatment of patients aged >=65 years. PMID- 23460504 TI - Highly luminescent hybrid SiO2-coated CdTe quantum dots: synthesis and properties. AB - Novel hybrid SiO2-coated CdTe quantum dots (QDs) were created using CdTe QDs coated with a hybrid SiO2 shell containing Cd(2+) ions and a sulfur source via a sol-gel process in aqueous solution. Aqueous CdTe QDs with tunable emitting color created through a reaction between cadmium chloride and sodium hydrogen telluride was used as cores for the preparation of hybrid SiO2-coated CdTe QDs. In our experiments we found that the surface state of the cores and preparation conditions that affect the formation of the hybrid SiO2 shell also greatly affect photoluminescence of the hybrid SiO2-coated CdTe QDs. The generation of CdS-like clusters in the vicinity of the CdTe QDs, caused the quantum size effect of the QDs to be greatly reduced, which changes photoluminescence properties of the hybrid QDs fundamentally. Namely, the novel hybrid SiO2 shell played an important role in generating a series of specific optical properties. In addition, the novel hybrid SiO2 shell can be created if no CdTe QD is added. In order to gain an insight into the inter structure of the hybrid shell, we characterized the hybrid SiO2-coated CdTe QDs using X-ray diffraction analysis and discuss the formation mechanism of such a hybrid structure. This work is significant because the novel hybrid SiO2-coated CdTe QDs with its excellent properties can be used in many applications, such as biolabeling and optoelectronic devices. PMID- 23460505 TI - A computational modeling approach on three-digit number processing. AB - Recent findings indicate that the constituting digits of multi-digit numbers are processed, decomposed into units, tens, and so on, rather than integrated into one entity. This is suggested by interfering effects of unit digit processing on two-digit number comparison. In the present study, we extended the computational model for two-digit number magnitude comparison of Moeller, Huber, Nuerk, and Willmes (2011a) to the case of three-digit number comparison (e.g., 371_826). In a second step, we evaluated how hundred-decade and hundred-unit compatibility effects were moderated by varying the percentage of within-hundred (e.g., 539_582) and within-hundred-and-decade filler items (e.g., 483_489). From the results we predict that numerical distance as well as compatibility effects should indeed be modulated by the relevance of tens and units in three-digit number magnitude comparison: While in particular the hundred distance effect should decrease, we predict hundred-decade and hundred-unit compatibility effects to increase with the relevance of tens and units. PMID- 23460506 TI - Mycobacterium abscessus complex lung infection in a toddler with a tracheostomy. AB - Mycobacterium abscessus complex and other non-tuberculous mycobacteria are infrequently encountered respiratory pathogens in patients with tracheostomies. We report a 4-year-old girl with a tracheostomy, placed during infancy for management of severe bronchopulmonary dysplasia and laryngeal stenosis, who developed a M. abscessus complex lung infection. There was clear evidence of parenchymal involvement and true infection beyond colonization. She demonstrated dramatic clinical, laboratory, and radiographic improvement after prolonged anti mycobacterial therapy. PMID- 23460507 TI - Gold-catalyzed reactions of enynals/enynones with norbornenes: generation and trapping of cyclic o-quinodimethanes (o-QDMs). PMID- 23460508 TI - Association of polymorphisms in the leptin and leptin receptor genes with inflammatory mediators in patients with osteoporosis. AB - Bone mass and inflammation are implicated in the pathogenesis of osteoporosis. We hypothesized that leptin and leptin receptor gene might be associated with osteoporosis by activating the inflammatory pathway. Therefore, we analyzed polymorphisms of the leptin (gene symbol, LEP) and leptin receptor (gene symbol, LEPR) genes and determined their associations with proinflammatory cytokine levels in patients with osteoporosis. We assessed polymorphisms in LEP (-2548G > A) and LEPR (Lys109Arg, Gln223Arg, and Lys656Asn) and calculated odds ratios for the genotype and allele distributions between patients and controls. Serum leptin, soluble leptin receptor, interleukin (IL)-1, IL-6, IL-7, and tumor necrosis factor (TNF) levels were measured by enzyme-linked immunosorbent assays (ELISA) and were verified by in vitro lymphocyte proliferation assays and ELISAs. We found a higher frequency of the A allele for LEP at -2548 in patients with osteoporosis compared with the control group. The A allele was associated with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type G allele (p < 0.05). The G allele in Lys109Arg and Gln223Arg was associated with increased risk of osteoporosis and with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type A allele (p < 0.05). The Lys656Asn genotype was not associated with the risk of osteoporosis. In vitro lymphocyte proliferation assays and ELISAs confirmed these results. Polymorphisms in LEP and LEPR are associated with increased risk of osteoporosis, possibly by increasing the expression of proinflammatory cytokines. PMID- 23460509 TI - Replication of genetic effects of MC4R polymorphisms on body mass index in a Korean population. AB - Obesity is associated with a variety of adverse health risks. Several genome-wide association studies of obesity have identified candidate genes, including the fat mass and obesity-associated gene (FTO) and the melanocortin-4 receptor (MC4R) gene. We carried out a replication study of MC4R and FTO variants in a Korean cohort. A total of 2,281 subjects in the Bundang-gu region were analyzed using selected markers. Another 8,826 subjects in the Ansung/Ansan city were used for a meta-analysis. Two single nucleotide polymorphisms (SNPs) in FTO and one SNP in the MC4R gene were genotyped. Multivariate linear regression models were employed to test for genotypic effects on obesity traits while adjusting for age and sex using an additive model. The SNP rs17782313 near the MC4R gene was associated with mean body mass index in the Bundang-gu cohort (effect per allele 0.288 kg/m(2), p = 0.0023). The p value for meta-analysis of rs17782313 in all 11,107 individuals in the Bundang-gu and Ansung/Ansan cohorts was 2.82 * 10(-6) (effect per allele 0.22 kg/m(2)). Two SNPs in FTO were significantly associated with weight (effect per allele 0.969 kg, p = 0.011 for rs9939609; 0.943, p = 0.014 for rs8050136) but not with body mass index. This study demonstrates that genetic variants in MC4R influence obesity traits in Korean adults. PMID- 23460510 TI - Respiration based steering for high intensity focused ultrasound liver ablation. AB - PURPOSE: Respiratory motion makes hepatic ablation using high intensity focused ultrasound (HIFO) challenging. Previous HIFU liver treatment had required apnea induced during general anesthesia. We describe and test a system that allows treatment of the liver in the presence of breathing motion. METHODS: Mapping a signal from an external respiratory bellow to treatment locations within the liver allows the ultrasound transducer to be steered in real time to the target location. Using a moving phantom, three metrics were used to compare static, steered, and unsteered sonications: the area of sonications once a temperature rise of 15 degrees C was achieved, the energy deposition required to reach that temperature, and the average rate of temperature rise during the first 10 s of sonication. Steered HIFU in vivo ablations of the porcine liver were also performed and compared to breath-hold ablations. RESULTS: For the last phantom metric, all groups were found to be statistically significantly different (P <= 0.003). However, in the other two metrics, the static and unsteered sonications were not statistically different (P > 0.9999). Steered in vivo HIFU ablations were not statistically significantly different from ablations during breath holding. CONCLUSIONS: A system for performing HIFU steering during ablation of the liver with breathing motion is presented and shown to achieve results equivalent to ablation performed with breath-holding. PMID- 23460511 TI - The Plasmodium vivax merozoite surface protein 1 paralog is a novel erythrocyte binding ligand of P. vivax. AB - Merozoite surface protein 1 of Plasmodium vivax (PvMSP1), a glycosylphosphatidylinositol-anchored protein (GPI-AP), is a malaria vaccine candidate for P. vivax. The paralog of PvMSP1, named P. vivax merozoite surface protein 1 paralog (PvMSP1P; PlasmoDB PVX_099975), was recently identified and predicted as a GPI-AP. The similarities in genetic structural characteristics between PvMSP1 and PvMSP1P (e.g., size of open reading frames, two epidermal growth factor-like domains, and GPI anchor motif in the C terminus) led us to study this protein. In the present study, different regions of the PvMSP1P protein, demarcated based on the processed forms of PvMSP1, were expressed successfully as recombinant proteins [i.e., 83 (A, B, and C), 30, 38, 42, 33, and 19 fragments]. We studied the naturally acquired immune response against each fragment of recombinant PvMSP1P and the potential ability of each fragment to bind erythrocytes. The N-terminal fragment (83A) and two C-terminal fragments (33 and 19) reacted strongly with sera from P. vivax-infected patients, with 50 to 68% sensitivity and 95 to 96% specificity, respectively. Due to colocalization of PvMSP1P with PvMSP1, we supposed that PvMSP1P plays a similar role as PvMSP1 during erythrocyte invasion. An in vitro cytoadherence assay showed that PvMSP1P, especially the 19-kDa C-terminal region, could bind to erythrocytes. We also found that human sera from populations naturally exposed to vivax malaria and antisera obtained by immunization using the recombinant molecule PvMSP1P-19 inhibited in vitro binding of human erythrocytes to PvMSP1P-19. These results provide further evidence that the PvMSP1P might be an essential parasite adhesion molecule in the P. vivax merozoite and is a potential vaccine candidate against P. vivax. PMID- 23460512 TI - The formins FMNL1 and mDia1 regulate coiling phagocytosis of Borrelia burgdorferi by primary human macrophages. AB - Spirochetes of the Borrelia burgdorferi sensu lato complex are the causative agent of Lyme borreliosis, a tick-borne infectious disease primarily affecting the skin, nervous system, and joints. During infection, macrophages and dendritic cells are the first immune cells to encounter invading borreliae. Phagocytosis and intracellular processing of Borrelia by these cells is thus decisive for the eventual outcome of infection. Phagocytic uptake of Borrelia by macrophages proceeds preferentially through coiling phagocytosis, which is characterized by actin-rich unilateral pseudopods that capture and enwrap spirochetes. Actin dependent growth of these pseudopods necessitates de novo nucleation of actin filaments, which is regulated by actin-nucleating factors such as Arp2/3 complex. Here, we demonstrate that, in addition, also actin-regulatory proteins of the formin family are important for uptake of borreliae by primary human macrophages. Using immunofluorescence, live-cell imaging, and ratiometric analysis, we find specific enrichment of the formins FMNL1 and mDia1 at macrophage pseudopods that are in contact with borreliae. Consistently, small interfering RNA (siRNA) mediated knockdown of FMNL1 or mDia1 leads to decreased formation of Borrelia induced pseudopods and to decreased internalization of borreliae by macrophages. Our results suggest that macrophage coiling phagocytosis is a complex process involving several actin nucleation/regulatory factors. They also point specifically to the formins mDia1 and FMNL1 as novel regulators of spirochete uptake by human immune cells. PMID- 23460513 TI - Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by Streptococcus pneumoniae. AB - To establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection. PMID- 23460514 TI - Role of the GapA and CrmA cytadhesins of Mycoplasma gallisepticum in promoting virulence and host colonization. AB - Mycoplasma gallisepticum is an important avian pathogen that commonly induces chronic respiratory disease in chicken. To better understand the mycoplasma factors involved in host colonization, chickens were infected via aerosol with two hemadsorption-negative (HA(-)) mutants, mHAD3 and RCL2, that were derived from a low passage of the pathogenic strain R (Rlow) and are both deficient in the two major cytadhesins GapA and CrmA. After 9 days of infection, chickens were monitored for air sac lesions and for the presence of mycoplasmas in various organs. The data showed that mHAD3, in which the crmA gene has been disrupted, did not promote efficient colonization or significant air sac lesions. In contrast, the spontaneous HA(-) RCL2 mutant, which contains a point mutation in the gapA structural gene, successfully colonized the respiratory tract and displayed an attenuated virulence compared to that of Rlow. It has previously been shown in vitro that the point mutation of RCL2 spontaneously reverts with a high frequency, resulting in on-and-off switching of the HA phenotype. Detailed analyses further revealed that such an event is not responsible for the observed in vivo outcome, since 98.4% of the mycoplasma populations recovered from RCL2 infected chickens still display the mutation and the associated phenotype. Unlike Rlow, however, RCL2 was unable to colonize inner organs. These findings demonstrate the major role played by the GapA and CrmA proteins in M. gallisepticum host colonization and virulence. PMID- 23460515 TI - Murine vaginal colonization model for investigating asymptomatic mucosal carriage of Streptococcus pyogenes. AB - While many virulence factors promoting Streptococcus pyogenes invasive disease have been described, specific streptococcal factors and host properties influencing asymptomatic mucosal carriage remain uncertain. To address the need for a refined model of prolonged S. pyogenes asymptomatic mucosal colonization, we have adapted a preestrogenized murine vaginal colonization model for S. pyogenes. In this model, derivatives of strains HSC5, SF370, JRS4, NZ131, and MEW123 established a reproducible, asymptomatic colonization of the vaginal mucosa over a period of typically 3 to 4 weeks' duration at a relatively high colonization efficiency. Prior treatment with estradiol prolonged streptococcal colonization and was associated with reduced inflammation in the colonized vaginal epithelium as well as a decreased leukocyte presence in vaginal fluid compared to the levels of inflammation and leukocyte presence in non-estradiol treated control mice. The utility of our model for investigating S. pyogenes factors contributing to mucosal carriage was verified, as a mutant with a mutation in the transcriptional regulator catabolite control protein A (CcpA) demonstrated significant impairment in vaginal colonization. An assessment of in vivo transcriptional activity in the CcpA(-) strain for several known CcpA regulated genes identified significantly elevated transcription of lactate oxidase (lctO) correlating with excessive generation of hydrogen peroxide to self lethal levels. Deletion of lctO did not impair colonization, but deletion of lctO in a CcpA(-) strain prolonged carriage, exceeding even that of the wild-type strain. Thus, while LctO is not essential for vaginal colonization, its dysregulation is deleterious, highlighting the critical role of CcpA in promoting mucosal colonization. The vaginal colonization model should prove effective for future analyses of S. pyogenes mucosal colonization. PMID- 23460516 TI - Replication and distribution of Toxoplasma gondii in the small intestine after oral infection with tissue cysts. AB - Natural infection by Toxoplasma gondii occurs via oral ingestion of tissue cysts that rupture in the small intestine, releasing zoites that infect locally before disseminating throughout the host. The studies presented here used fluorescent parasites combined with flow cytometry and multiphoton microscopy techniques to understand the events associated with parasite replication in the mucosa. At 3 days postinfection with tissue cysts, parasites were localized in small foci and flow cytometry revealed parasites present in macrophages, neutrophils, and monocytes in the lamina propria. By day 6 postinfection, there were large foci of replicating parasites; however, foci unexpectedly varied in the number of villi involved and were associated with the presence of viable tachyzoites within the intestinal lumen. Consistent with the flow cytometry data, neutrophils and monocytes in the lamina propria were preferentially associated with parasite plaques. In contrast, dendritic cells comprised a small fraction of the infected immune cell population and were localized at the periphery of parasite plaques. Together, these findings reveal the formation of localized sites of parasite replication and inflammation early during infection and suggest that sustained replication of T. gondii in the gut may be a function of pathogen luminal spread. PMID- 23460517 TI - Roles of STAT3 in protein secretion pathways during the acute-phase response. AB - The acute-phase response is characteristic of perhaps all infections, including bacterial pneumonia. In conjunction with the acute-phase response, additional biological pathways are induced in the liver and are dependent on the transcription factors STAT3 and NF-kappaB, but these responses are poorly understood. Here, we demonstrate that pneumococcal pneumonia and other severe infections increase expression of multiple components of the cellular secretory machinery in the mouse liver, including the endoplasmic reticulum (ER) translocon complex, which mediates protein translation into the ER, and the coat protein complexes (COPI and COPII), which mediate vesicular transport of proteins to and from the ER. Hepatocyte-specific mutation of STAT3 prevented the induction of these secretory pathways during pneumonia, with similar results observed following pharmacological activation of ER stress by using tunicamycin. These findings implicate STAT3 in the unfolded protein response and suggest that STAT3 dependent optimization of secretion may apply broadly. Pneumonia also stimulated the binding of phosphorylated STAT3 to promoter regions of secretion-related genes in the liver, supporting a direct role for STAT3 in their transcription. Altogether, these results identify a novel function of STAT3 during the acute phase response, namely, the induction of secretory machinery in hepatocytes. This may facilitate the processing and delivery of newly synthesized loads of acute phase proteins, enhancing innate immunity and preventing liver injury during infection. PMID- 23460518 TI - The early dissemination defect attributed to disruption of decorin-binding proteins is abolished in chronic murine Lyme borreliosis. AB - The laboratory mouse model of Lyme disease has revealed that Borrelia burgdorferi differentially expresses numerous outer surface proteins that influence different stages of infection (tick-borne transmission, tissue colonization, dissemination, persistence, and tick acquisition). Deletion of two such outer surface proteins, decorin-binding proteins A and B (DbpA/B), has been documented to decrease infectivity, impede early dissemination, and, possibly, prevent persistence. In this study, DbpA/B-deficient spirochetes were confirmed to exhibit an early dissemination defect in immunocompetent, but not immunodeficient, mice, and the defect was found to resolve with chronicity. Development of disease (arthritis and carditis) was attenuated only in the early stage of infection with DbpA/B deficient spirochetes in both types of mice. Persistence of the DbpA/B-deficient spirochetes occurred in both immunocompetent and immunodeficient mice in a manner indistinguishable from that of wild-type spirochetes. Dissemination through the lymphatic system was evaluated as an underlying mechanism for the early dissemination defect. At 12 h, 3 days, 7 days, and 14 days postinoculation, DbpA/B-deficient spirochetes were significantly less prevalent and in lower numbers in lymph nodes than wild-type spirochetes. However, in immunodeficient mice, deficiency of DbpA/B did not significantly decrease the prevalence or spirochete numbers in lymph nodes. Complementation of DbpA/B restored a wild-type phenotype. Thus, the results indicated that deficiency of DbpA/B allows the acquired immune response to restrict early dissemination of spirochetes, which appears to be at least partially mediated through the lymphatic system. PMID- 23460519 TI - AhrC and Eep are biofilm infection-associated virulence factors in Enterococcus faecalis. AB - Enterococcus faecalis is part of the human intestinal microbiome and is a prominent cause of health care-associated infections. The pathogenesis of many E. faecalis infections, including endocarditis and catheter-associated urinary tract infection (CAUTI), is related to the ability of clinical isolates to form biofilms. To identify chromosomal genetic determinants responsible for E. faecalis biofilm-mediated infection, we used a rabbit model of endocarditis to test strains with transposon insertions or in-frame deletions in biofilm associated loci: ahrC, argR, atlA, opuBC, pyrC, recN, and sepF. Only the ahrC mutant was significantly attenuated in endocarditis. We demonstrate that the transcriptional regulator AhrC and the protease Eep, which we showed previously to be an endocarditis virulence factor, are also required for full virulence in murine CAUTI. Therefore, AhrC and Eep can be classified as enterococcal biofilm associated virulence factors. Loss of ahrC caused defects in early attachment and accumulation of biofilm biomass. Characterization of ahrC transcription revealed that the temporal expression of this locus observed in wild-type cells promotes initiation of early biofilm formation and the establishment of endocarditis. This is the first report of AhrC serving as a virulence factor in any bacterial species. PMID- 23460520 TI - Toll-like receptor 6 plays an important role in host innate resistance to Brucella abortus infection in mice. AB - Brucella abortus is recognized by several Toll-like receptor (TLR)-associated pathways triggering proinflammatory responses that affect both the nature and intensity of the immune response. Previously, we demonstrated that B. abortus mediated dendritic cell (DC) maturation and control of infection are dependent on the adaptor molecule MyD88. However, the involvement of all TLRs in response to B. abortus infection is not completely understood. Therefore, we decided to evaluate the requirement for TLR6 in host resistance to B. abortus. Here, we demonstrated that TLR6 is an important component for triggering an innate immune response against B. abortus. An in vitro luciferase assay indicated that TLR6 cooperates with TLR2 to sense Brucella and further activates NF-kappaB signaling. However, in vivo analysis showed that TLR6, not TLR2, is required for the efficient control of B. abortus infection. Additionally, B. abortus-infected dendritic cells require TLR6 to induce tumor necrosis factor alpha (TNF-alpha) and interleukin-12 (IL-12). Furthermore, our findings demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathway is impaired in TLR2, TLR6, and TLR2/6 knockout (KO) DCs when infected with B. abortus, which may account for the lower proinflammatory cytokine production observed in TLR6 KO mouse dendritic cells. In summary, the results presented here indicate that TLR6 is required to trigger innate immune responses against B. abortus in vivo and is required for the full activation of DCs to induce robust proinflammatory cytokine production. PMID- 23460521 TI - A lactotransferrin single nucleotide polymorphism demonstrates biological activity that can reduce susceptibility to caries. AB - Streptococcus mutans is prominently linked to dental caries. Saliva's influence on caries is incompletely understood. Our goal was to identify a salivary protein with anti-S. mutans activity, characterize its genotype, and determine genotypic variants associated with S. mutans activity and reduced caries. An S. mutans affinity column was used to isolate active moieties from saliva obtained from a subject with minimal caries. The bound and eluted protein was identified as lactotransferrin (LTF) by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis and confirmed by Western blotting with LTF antibody. A single nucleotide polymorphism (SNP) that produced a shift from arginine (R) to lysine (K) at amino acid position 47 in the LTF antimicrobial region (rs: 1126478) killed S. mutans in vitro. Saliva from a subject with moderate caries and with the LTF "wild-type" R form at position 47 had no such activity. A pilot genetic study (n = 30) showed that KK subjects were more likely to have anti-S. mutans activity than RR subjects (P = 0.001; relative risk = 3.6; 95% confidence interval [95% CI] = 1.5 to 11.13). Pretreatment of KK saliva with antibody to LTF reduced S. mutans killing in a dose-dependent manner (P = 0.02). KK subjects were less likely to have caries (P = 0.02). A synthetic 11-mer LTF/K peptide killed S. mutans and other caries-related bacteria, while the LTF/R peptide had no effect (P = 0.01). Our results provide functional evidence that the LTF/K variant results in both anti-S. mutans activity and reduced decay. We suggest that the LTF/K variant can influence oral microbial ecology in general and caries provoking microbes specifically. PMID- 23460522 TI - N-glycosylation of Campylobacter jejuni surface proteins promotes bacterial fitness. AB - Campylobacter jejuni is the etiologic agent of human bacterial gastroenteritis worldwide. In contrast, despite heavy colonization, C. jejuni maintains a commensal mode of existence in chickens. The consumption of contaminated chicken products is thought to be the principal mode of C. jejuni transmission to the human population. C. jejuni harbors a system for N-linked protein glycosylation that has been well characterized and modifies more than 60 periplasmic and membrane-bound proteins. However, the precise role of this modification in the biology of C. jejuni remains unexplored. We hypothesized that the N-glycans protect C. jejuni surface proteins from the action of gut proteases. The C. jejuni pglB mutant, deficient in the expression of the oligosaccharyltransferase, exhibited reduced growth in medium supplemented with chicken cecal contents (CCC) compared with that of wild-type (WT) cells. Inactivation of the cecal proteases by heat treatment or with protease inhibitors completely restored bacterial viability and partially rescued bacterial growth. Physiological concentrations of trypsin, but not chymotrypsin, also reduced C. jejuni pglB mutant CFU. Live or dead staining indicated that CCC preferentially influenced C. jejuni growth as opposed to bacterial viability. We identified multiple chicken cecal proteases by mass fingerprinting. The use of protease inhibitors that target specific classes indicated that both metalloproteases and serine proteases were involved in the attenuated growth of the oligosaccharyltransferase mutant. In conclusion, protein N-linked glycosylation of surface proteins may enhance C. jejuni fitness by protecting bacterial proteins from cleavage due to gut proteases. PMID- 23460523 TI - Gain-of-function mutations in PDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells. AB - Candida glabrata is an emerging opportunistic pathogen that is known to develop resistance to azole drugs due to increased drug efflux. The mechanism consists of CgPDR1-mediated upregulation of ATP-binding cassette transporters. A range of gain-of-function (GOF) mutations in CgPDR1 have been found to lead not only to azole resistance but also to enhanced virulence. This implicates CgPDR1 in the regulation of the interaction of C. glabrata with the host. To identify specific CgPDR1-regulated steps of the host-pathogen interaction, we investigated in this work the interaction of selected CgPDR1 GOF mutants with murine bone marrow derived macrophages and human acute monocytic leukemia cell line (THP-1)-derived macrophages, as well as different epithelial cell lines. GOF mutations in CgPDR1 did not influence survival and replication within macrophages following phagocytosis but led to decreased adherence to and uptake by macrophages. This may allow evasion from the host's innate cellular immune response. The interaction with epithelial cells revealed an opposite trend, suggesting that GOF mutations in CgPDR1 may favor epithelial colonization of the host by C. glabrata through increased adherence to epithelial cell layers. These data reveal that GOF mutations in CgPDR1 modulate the interaction with host cells in ways that may contribute to increased virulence. PMID- 23460524 TI - Preparation of the elusive [(por)Fe(NO)(O-ligand)] complex by diffusion of nitric oxide into a crystal of the precursor. PMID- 23460525 TI - Three colorimetric and off-on fluorescent chemosensors for Fe3+ in aqueous media. AB - Three Rhodamine B derivatives were synthesized and characterized by ESI-MS, NMR, HR-MS and IR. The probes exhibit high selectivity and sensitivity towards Fe(3+) over other metal ions in CH3CN-water. Upon the addition of Fe(3+), the spirocyclic ring of the probe was opened and a significant enhancement of visible color and fluorescence within the range of 540-700 nm was observed. The colorimetric and fluorescent response to Fe(3+) can be conveniently detected even by the naked eye, which provides a facile method for the visual detection of Fe(3+). Job's plot, fluorescence titration and MS indicated the formation of 1:2 complexes between the probes and Fe(3+). The reversibility of the reaction establishes the potential of these probes as chemosensors for Fe(3+) detection. PMID- 23460526 TI - Validation of the femoral component placement during hip resurfacing: a comparison between the conventional jig, patient-specific template, and CT-based navigation. AB - BACKGROUND: Appropriate insertion of a femoral guidewire is essential for hip resurfacing. A simulation study was planned using synthetic femoral bone models and the accuracy and precision of femoral guidewire alignment and insertion point were compared between conventional jigs, patient-specific templates, and computed tomography (CT) based navigation techniques. METHODS: Anteversion, stem-shaft angle, and the three-dimensional insertion point were measured postoperative with CT. Errors between planned and postoperative measurement and precision were evaluated. RESULTS: There were no statistically significant differences in error for anteversion or insertion point, although the mechanical jig showed greater error in the stem-shaft angle than the others. Patient-specific template and CT based navigation showed good precision with high intraclass correlation (ICC) (template, 0.908 to 1.000; navigation, 0.929 to 0.995) and small root mean square error (RMSE) (0.954 to 2.969; 1.468 to 3.213). The mechanical jig group performance was inferior to the others. CONCLUSIONS: Patient-specific templates and CT-based navigation had good accuracy and precision. The mechanical jig technique was inferior to the others. PMID- 23460528 TI - On-the-fly reconstruction of free-energy profiles using logarithmic mean-force dynamics. AB - Mean-force dynamics (MFD), which is a fictitious dynamics for a set of collective variables on a potential of mean-force, is a powerful algorithm to efficiently explore free-energy landscapes. Recently, we have introduced logarithmic MFD (LogMFD) (Morishita et al., Phys. Rev. E 2012, 85, 066702) which overcomes difficulties encounterd in free-energy calculations using standard approaches such as thermodynamic integration. Here, we present a guide to implementing LogMFD calculations paying attention to the practical issues in choosing the parameters in LogMFD. A primary focus is given to the effect of the parameters on the accuracy of the reconstructed free-energy profiles. A recipe for reducing the errors due to energy dissipation is presented. We also demonstrate that multidimensional free-energy landscapes can be reconstructed on-the-fly using LogMFD, which cannot be accomplished using any other free-energy calculation techniques. PMID- 23460527 TI - STAT3 activity is necessary and sufficient for the development of immune-mediated myocarditis in mice and promotes progression to dilated cardiomyopathy. AB - Myocarditis, often triggered by viral infection, may lead to heart auto-immunity and dilated cardiomyopathy. What determines the switch between disease resolution and progression is however incompletely understood. We show that pharmacological inhibition of STAT3, the main mediator of IL-6 signalling and of Th17-cell differentiation, protects mice from the development of Experimental Auto-immune Myocarditis reducing liver production of the complement component C3, and can act therapeutically when administered at disease peak. Further, we demonstrate that STAT3 is sufficient when constitutively active for triggering the onset of immune mediated myocarditis, involving enhanced complement C3 production and IL-6 signalling amplification in the liver. Disease development can be prevented by C3 depletion and IL-6 receptor neutralization. This appears to be relevant to disease pathogenesis in humans, since acute myocarditis patients display significantly elevated circulating IL-6 and C3 levels and activated heart STAT3. Thus, aberrant IL-6/STAT3-mediated induction of liver acute phase response genes including C3, which occurs as a consequence of pre-existing inflammatory conditions, might represent an important factor determining the degree of myocarditis and its clinical outcome. PMID- 23460530 TI - Waking the immune system at last. PMID- 23460531 TI - Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. AB - Immune system responses are under the control of extracellular biomolecules, which express functions in receptors present on the surface of cells of the immune system, and thus are amenable to be functionally modulated by monoclonal antibodies. Some of these mechanisms are activating and dictate whether the response ensues, while others play the role of powerful repressors. Antagonist antibodies acting on such repressors result in enhanced immune responses, a goal that is also achieved with agonist antibodies acting on the activating receptors. With these simple logics, a series of therapeutic agents are under clinical development and one of them directed at the CTL-associated antigen 4 (CTLA-4) inhibitory receptor (ipilimumab) has been approved for the treatment of metastatic melanoma. The list of antagonist agents acting on repressors under development includes anti-CTLA-4, anti-PD-1, anti-PD-L1 (B7-H1), anti-KIR, and anti-TGF-beta. Agonist antibodies currently being investigated in clinical trials target CD40, CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNF receptor (GITR). A blossoming preclinical pipeline suggests that other active targets will also be tested in patients in the near future. All of these antibodies are being developed as conventional monoclonal immunoglobulins, but other engineered antibody formats or RNA aptamers are under preclinical scrutiny. The "dark side" of these immune interventions is that they elicit autoimmune/inflammatory reactions that can be severe in some patients. A critical and, largely, pending subject is to identify reliable predictive biomarkers both for efficacy and immune toxicity. Preclinical and early clinical studies indicate a tremendous potential to further improve efficacy, using combinations from among these new agents that frequently act in a synergistic fashion. Combinations with other more conventional means of treatment such as radiotherapy, chemotherapy, or cancer vaccines also hold much promise. PMID- 23460532 TI - Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumor types. AB - Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising new approach of immunotherapy for cancer. The recent approval of the CTLA-4-blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IV melanoma. However, measuring response rates using standard Response Evaluation Criteria in Solid Tumors (RECIST) or modified World Health Organization criteria or progression-free survival does not accurately capture the potential for clinical benefit for ipilimumab-treated patients. As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti CD137 (urelumab), anti-OX40, anti-GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important. Identifying reliable biomarkers is a necessary step in personalizing the treatment of each patient's cancer through a baseline assessment of tumor gene expression and/or immune profile to optimize therapy for the best chance of therapeutic success. PMID- 23460533 TI - Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. AB - The immune suppressive molecule programmed death-1 (PD-1) is upregulated in activated T lymphocytes and inhibits T-cell function upon binding to its ligands B7-H1 (PD-L1, CD274) and B7-DC (PD-L2, CD273). Substantial experimental data from in vitro cell culture systems and animal models, and more recently from clinical trials, indicate that PD-1/PD-1-ligand interactions are a major mechanism of immune suppression within the tumor microenvironment. Initial clinical studies of antibodies directed against PD-1 and B7-H1 showed both an encouraging safety profile and remarkable antitumor activity in subsets of patients with metastatic disease, including malignancies--such as lung cancer--which were previously thought to be unresponsive to immunotherapy. Preliminary data have suggested a correlation between tumor membrane B7-H1 expression and clinical response to anti PD-1 antibodies. Several key challenges remain to optimize development of PD-1/B7 H1 pathway blockade, including defining the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment, developing more accurate predictive biomarkers of response, determining the breadth of activity in human malignancies, and developing rational combinations of therapy that address key mechanisms involved in positive and negative regulation of antitumor immune responses. PMID- 23460534 TI - Agonistic CD40 antibodies and cancer therapy. AB - Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small-molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anticancer immunity by various mechanisms. CD40 is a TNF receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many nonimmune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote antitumor T-cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain about dose, schedule, route of administration, and formulation. Recent findings about the role played by the IgG isotype and the Fc gamma receptor (FcgammaR) in mAb cross-linking, together with insights into mechanisms of action, particularly with regard to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field. PMID- 23460536 TI - Use of oligonucleotide aptamer ligands to modulate the function of immune receptors. AB - The paucity of costimulation at the tumor site compromises the ability of tumor specific T cells to eliminate the tumor. The recent U.S. Food and Drug Administration approval of ipilumimab, an antibody that blocks the inhibitory action of CTLA-4, and clinical trials targeting 4-1BB and PD-1 or PD-L1, have underscored the therapeutic potential of using immunomodulatory antibodies to stimulate protective immunity in human patients. Nonetheless, systemic administration of immunomodulatory antibodies has been associated with dose limiting autoimmune pathologies, conceivably reflecting also the activation of resident autoreactive T cells. Arguably, targeting immunomodulatory ligands to the disseminated tumor lesions of the patient would reduce such drug-associated toxicities. We have recently developed a new class of inhibitory (CTLA-4) and agonistic (4-1BB and OX-40) ligands composed of short oligonucleotide (ODN) aptamers that exhibited bioactivities comparable or superior to that of antibodies. To reduce toxicity, the immunomodulatory aptamers were targeted to the tumor by conjugation to a second aptamer that bound to a product expressed on the surface of the tumor cell, the targeting aptamer, generating a bispecific aptamer conjugate analogous to bispecific antibodies. In a proof-of-concept study in mice, we have shown that an agonistic 4-1BB-binding aptamer conjugated to a prostate-specific membrane antigen (PSMA)-binding aptamer led to the inhibition of PSMA-expressing tumors, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared with nontargeted costimulation with 4-1BB antibodies or 4-1BB aptamers. The cell-free chemically synthesized ODN aptamers offer significant advantages over antibodies in terms of synthesis, cost, as well as conjugation chemistry needed to generate bispecific ligand fusions. PMID- 23460535 TI - Agonist antibodies to TNFR molecules that costimulate T and NK cells. AB - Therapy for cancer can be achieved by artificially stimulating antitumor T and natural killer (NK) lymphocytes with agonist monoclonal antibodies (mAb). T and NK cells express several members of the TNF receptor (TNFR) family specialized in delivering a costimulatory signal on their surface. Engagement of these receptors is typically associated with proliferation, elevated effector functions, resistance to apoptosis, and differentiation into memory cells. These receptors lack any intrinsic enzymatic activity and their signal transduction relies on associations with TNFR-associated factor (TRAF) adaptor proteins. Stimulation of CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNFR (GITR; CD357) promotes impressive tumor-rejecting immunity in a variety of murine tumor models. The mechanisms of action depend on a complex interplay of CTL, T-helper cells, regulatory T cells, dendritic cells, and vascular endothelium in tumors. Agonist mAbs specific for CD137 have shown signs of objective clinical activity in patients with metastatic melanoma, whereas anti-OX40 and anti-GITR mAbs have entered clinical trials. Preclinical evidence suggests that engaging TNFR members would be particularly active with conventional cancer therapies and additional immunotherapeutic approaches. Indeed, T-cell responses elicited to tumor antigens by means of immunogenic tumor cell death are amplified by these immunostimulatory agonist mAbs. Furthermore, anti-CD137 mAbs have been shown to enhance NK-mediated cytotoxicity elicited by rituximab and trastuzumab. Combinations with other immunomodulatory mAb that block T-cell checkpoint blockade receptors such as CTLA 4 and PD-1 are also promising. PMID- 23460537 TI - Five-year results of a prospective case series of accelerated hypofractionated whole breast radiation with concomitant boost to the surgical bed after conserving surgery for early breast cancer. AB - Accelerated hypofractionation (HF) using larger dose per fraction, delivered in fewer fractions over a shorter overall treatment time, is presently a consistent possibility for adjuvant whole breast radiation (WBRT) after breast-conserving surgery for early breast cancer (EBC). Between 2005 and 2008, we submitted 375 consecutive patients to accelerated hypofractionated WBRT after breast-conserving surgery for EBC. The basic course of radiation consisted of 45 Gy in 20 fractions over 4 weeks to the whole breast (2.25 Gy daily) with an additional daily concomitant boost of 0.25 Gy up to 50 Gy to the surgical bed. Overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS) and local control (LC) were assessed. Late toxicity was scored according to the CTCAE v3.0; acute toxicity using the RTOG/EORTC toxicity scale. Cosmesis was assessed comparing treated and untreated breast. Quality of life (QoL) was determined using EORTC QLQ-C30/QLQ-BR23 questionnaires. With a median follow-up of 60 months (range 42-88), 5 years OS, CSS, DFS and LC were 97.6, 99.4, 96.6 and 100 %, respectively. Late skin and subcutaneous toxicity was generally mild, with few events > grade 2 observed. Cosmetic results were excellent in 75.7 % of patients, good in 20 % and fair in 4.3 %. QoL, assessed both through QLQ-C30/QLQ-BR23, was generally favorable, within the functioning and symptoms domains. Our study is another proof of principle that HF WBRT with a concurrent boost dose to the surgical cavity represents a safe and effective postoperative treatment modality with excellent local control and survival, consistent cosmetic results and mild toxicity. PMID- 23460538 TI - A ratiometric fluorescent probe for biological signaling molecule H2S: fast response and high selectivity. PMID- 23460539 TI - Resource recovery of scrap silicon solar battery cell. AB - In order to minimize pollution problems and to conserve limited natural resources, a hydrometallurgical procedure was developed in this study to recover the valuable resources of silicon (Si), silver (Ag) and aluminum (Al) from scrap silicon solar battery cells. In this study, several methods of leaching, crystallization, precipitation, electrolysis and replacement were employed to investigate the recovery efficiency of Ag and Al from defective monocrystalline silicon solar battery cells. The defective solar battery cells were ground into powder followed by composition analysis with inductively coupled plasma-atomic emission spectrometry. The target metals Ag and Al weight percentage were found to be 1.67 and 7.68 respectively. A leaching process was adopted with nitric acid (HNO3), hydrochloric acid, sulfuric acid (H2SO4) and sodium hydroxide as leaching reagent to recover Ag and Al from a ground solar battery cell. Aluminum was leached 100% with 18N H2SO4 at 70 degrees C and Ag was leached 100% with 6N HNO3. Pure Si of 100% was achieved from the leaching solution after the recovery of Ag and Al, and was analyzed by scanning electron microscope-energy dispersive spectroscopy. Aluminum was recovered by crystallization process and silver was recovered by precipitation, electrolysis and replacement processes. These processes were applied successfully in the recovery of valuable metal Ag of 98 100%. PMID- 23460540 TI - Energy efficiency monitoring--which sensors are really needed? AB - Plant balancing of waste-to-energy plants is a key issue in determining plant performance and operating efficiency. Traditionally, plant efficiency is determined only during the acceptance test by the means of an ex-post energy balance. For continuous operation, energy efficiency is estimated on a monthly or yearly basis using the waste throughput and average lower heating value. At Afval Energie Bedrijf in Amsterdam efficiency has to be reported on a monthly basis. Measured data from 83 positions is required to obtain the efficiency of the Hoog Rendement Central block with an ex-post energy balance on a continuous basis. This study investigated the importance of the different sensors. Efficiency calculations were performed after discarding the less important measuring positions. The measured data was replaced by the design value in the calculation. The total average margin of error per year for the efficiency value was found to be only 0.1% when the 23 most significant (instead of 83) measuring points were used, whereas individual values may differ by less than 0.5%. Operators of plants with fewer sensors can monitor their efficiency continuously if they know the most important positions. PMID- 23460541 TI - Hydraulic conductivity of compacted zeolites. AB - Hydraulic conductivities of compacted zeolites were investigated as a function of compaction water content and zeolite particle size. Initially, the compaction characteristics of zeolites were determined. The compaction test results showed that maximum dry unit weight (gamma(dmax)) of fine zeolite was greater than that of granular zeolites. The gamma(dmax) of compacted zeolites was between 1.01 and 1.17 Mg m(-3) and optimum water content (w(opt)) was between 38% and 53%. Regardless of zeolite particle size, compacted zeolites had low gamma(dmax) and high w(opt) when compared with compacted natural soils. Then, hydraulic conductivity tests were run on compacted zeolites. The hydraulic conductivity values were within the range of 2.0 * 10(-3) cm s(-1) to 1.1 * 10(-7) cm s(-1). Hydraulic conductivity of all compacted zeolites decreased almost 50 times as the water content increased. It is noteworthy that hydraulic conductivity of compacted zeolite was strongly dependent on the zeolite particle size. The hydraulic conductivity decreased almost three orders of magnitude up to 39% fine content; then, it remained almost unchanged beyond 39%. Only one report was found in the literature on the hydraulic conductivity of compacted zeolite, which is in agreement with the findings of this study. PMID- 23460542 TI - Pilot-based assessment of the economics of recycling construction demolition waste. AB - The significant amount of waste generated from construction demolition has become a chronic problem in many developing countries. Using data obtained from demolition contractors and various other sources, this paper proposes a framework for proper handling of construction demolition waste (CDW) to serve as a decision support tool in countries suffering from the lack of national CDW management guidelines. The framework is then demonstrated through a case study in the city of Beirut, Lebanon, and a sensitivity analysis is carried out to examine the economic feasibility of developing a recycling facility. The analysis showed that in order for a facility to be feasible, a gate fee should be charged in the presence of a market for recycled aggregates. The results confirm the significance of instigating and implementing legislation to control illegal dumping, constructing, and managing engineered landfills, and establishing markets for recycled CDW. PMID- 23460543 TI - Analysis of solid waste from ships and modeling of its generation on the river Danube in Serbia. AB - This study focuses on the issues related to the waste management in river ports in general and, particularly, in ports on the river Danube's flow through Serbia. The ports of Apatin, Bezdan, Backa Palanka, Novi Sad, Belgrade, Smederevo, Veliko Gradiste, Prahovo and Kladovo were analyzed. The input data (number of watercrafts, passengers and crew members) were obtained from harbor authorities for the period 2005-2009. The quantities of solid waste generated on both cruise and cargo ships are considered in this article. As there is no strategy for waste treatment in the ports in Serbia, these data are extremely valuable for further design of equipment for waste treatment and collection. Trends in data were analyzed and regression models were used to predict the waste quantities in each port in next 3 years. The obtained trends could be utilized as the basis for the calculation of the equipment capacities for waste selection, collection, storage and treatment. The results presented in this study establish the need for an organized management system for this type of waste, as well as suggest where the terminals for collection, storage and treatment of solid waste from ships should be located. PMID- 23460544 TI - Profile of medical waste management in two healthcare facilities in Lagos, Nigeria: a case study. AB - Proper management and safe disposal of medical waste (MW) is vital in the reduction of infection or illness through contact with discarded material and in the prevention of environmental contamination in hospital facilities. The management practices for MW in selected healthcare facilities in Lagos, Nigeria were assessed. The cross-sectional study involved the use of questionnaires, in depth interviews, focused group discussions and participant observation strategies. It also involved the collection, segregation, identification and weighing of waste types from wards and units in the representative facilities in Lagos, Nigeria, for qualitative and quantitative analysis of the MW streams. The findings indicated that the selected Nigerian healthcare facilities were lacking in the adoption of sound MW management (MWM) practices. The average MW ranged from 0.01 kg/bed/day to 3.98 kg/bed/day. Moreover, about 30% of the domestic waste from the healthcare facilities consisted of MW due to inappropriate co disposal practices. Multiple linear regression was applied to predict the volume of waste generated giving a correlation coefficient (R(2)) value of 0.99 confirming a good fit of the data. This study revealed that the current MWM practices and strategies in Lagos are weak, and suggests an urgent need for review to achieve vital reversals in the current trends. PMID- 23460545 TI - Recurrence of CCHS associated PHOX2B poly-alanine expansion mutation due to maternal mosaicism. AB - Heterozygous in frame trinucleotide duplications within the PHOX2B gene, leading to poly-alanine expansions, cause Congenital Central Hypoventilation Syndrome. Here we report about a CCHS patient, carrying a +13Ala PHOX2B expansion, whose asymptomatic mother resulted with a low level of mosaicism for the same mutation in peripheral blood cells. Her second pregnancy ended with the spontaneous miscarriage of a fetus who had inherited the PHOX2B mutation, thus confirming germline mosaicism in the mother and the need of proper genetic counseling to CCHS families. PMID- 23460546 TI - Toward functional molecular devices based on graphene-molecule junctions. PMID- 23460547 TI - Improving hybrid seed production in corn with glyphosate-mediated male sterility. AB - BACKGROUND: Hybrid corn varieties exhibit benefits associated with heterosis and account for most of the corn acreage in the USA. Hybrid seed corn is produced by crossing a female parent which is male-sterile and therefore incapable of self pollination with a male parent as the pollen donor. The majority of hybrid seed corn is produced by mechanical detasseling which involves physically removing the tassel, a process that is laborious and costly. RESULTS: Glyphosate-resistant corn was developed via expression of a glyphosate insensitive 5-enolpyruvyl shikimate 3-phosphate synthase enzyme (CP4-EPSPS). Experimentation with molecular expression elements resulted in selective reduction of CP4-EPSPS expression in male reproductive tissues. The resulting plant demonstrated sterile tassel following glyphosate application with little to no injury to the rest of the plant. Using (14)C-glyphosate as a marker, we also examined the translocation of glyphosate to the tassel via spray application in a track sprayer to simulate field application. The results allowed optimization of spray parameters such as dose, spray timing and target to maximize tassel delivery of glyphosate for efficient sterilization. CONCLUSION: The Roundup hybridization system (RHS) is a novel process for hybrid seed production based on glyphosate-mediated male sterility. RHS replaces mechanical detasseling with glyphosate spray and greatly simplifies the process of hybrid seed corn production. PMID- 23460549 TI - Strategies in tissue engineering and regenerative medicine. AB - "Strategies in Tissue Engineering": this special issue is edited by Prof. Katja Schenke-Layland and Prof. Heike Walles and covers many salient aspects of tissue engineering and regenerative medicine. The issue includes articles on Raman spectroscopy and its application in tissue engineering; bioreactor design and surface functionalization for tissue culture applications; improved method for RNA isolation from tissue samples and much more. PMID- 23460554 TI - A tissue-engineered human dermal construct utilizing fibroblasts and transforming growth factor beta1 to promote elastogenesis. AB - Numerous studies have shown that extracellular matrix (ECM)-based scaffolds are suitable for dermal constructs for the differentiation of various cell types in vitro and for constructive tissue remodeling after implantation in vivo. However, a shortcoming of these ECM materials is its limited elastogenesis. Elastic fibers constitute an essential component of mammalian connective tissue and the presence of elastic fibers is crucial for the proper function of the cardiovascular, pulmonary, and intestinal systems. Since it is still largely unknown how cells coordinate the molecular events of elastic-fiber assembly, understanding the ability to regenerate elastic fibers in tissues remains a significant challenge. For this reason, human neonatal dermal fibroblasts (HDFneo) were analyzed for their potential to serve as a cell culture model for elastic fiber assembly. Using optical technologies such as multiphoton laser-scanning microscopy (MPSLM) we demonstrate that HDFneo stimulated with transforming growth factor beta1 (TGF beta1) are able to produce a distinct and complex elastic fiber system in vitro. As shown by the desmosine and isodesmosine content, crosslinked elastic fibers were formed within the 3D ECM-based scaffold. This tissue-engineered dermal construct may prove to be an effective template for the development of medicinal approaches in regenerative soft skin tissue reconstruction through TGF-beta1 induction. PMID- 23460557 TI - Treatment of hypertrophic scars using laser and laser assisted corticosteroid delivery. AB - BACKGROUND AND OBJECTIVES: Hypertrophic scars and contractures are common following various types of trauma and procedures despite skilled surgical and wound care. Following ample time for healing and scar maturation, many millions of patients are burdened with persistent symptoms and functional impairments. Cutaneous scars can be complex and thus the approach to therapy is often multimodal. Intralesional corticosteroids have long been a staple in the treatment of hypertrophic and restrictive scars. Recent advances in laser technology and applications now provide additional options for improvements in function, symptoms, and cosmesis. Fractional ablative lasers create zones of ablation at variable depths of the skin with the subsequent induction of a wound healing and collagen remodeling response. Recent reports suggest these ablative zones may also be used in the immediate post-operative period to enhance delivery of drugs and other substances. We present a case series evaluating the efficacy of a novel combination therapy that incorporates the use of an ablative fractional laser with topically applied triamcinolone acetonide suspension in the immediate post-operative period. METHODS: This is a prospective case series including 15 consecutive subjects with hypertrophic scars resulting from burns, surgery or traumatic injuries. Subjects were treated according to typical institutional protocol with three to five treatment sessions at 2- to 3-month intervals consisting of fractional ablative laser treatment and immediate post operative topical application of triamcinolone acetonide suspension at a concentration of 10 or 20 mg/ml. Three blinded observers evaluated photographs taken at baseline and six months after the final treatment session. Scores were assigned using a modified Manchester quartile score to evaluate enhancements in dyschromia, hypertrophy, texture, and overall improvement. LIMITATIONS: Small sample size and lack of a control arm. RESULTS: Combination same session laser therapy and immediate post-operative corticosteroid delivery resulted in average overall improvement of 2.73/3.0. Dyschromia showed the least amount of improvement while texture showed the most improvement. CONCLUSION: Combination same-session therapy with ablative fractional laser-assisted delivery of triamcinolone acetonide potentially offers an efficient, safe and effective combination therapy for challenging hypertrophic and restrictive cutaneous scars. PMID- 23460558 TI - Neurotoxic effects of lambda-cyhalothrin modulated by piperonyl butoxide in the brain of Oreochromis niloticus. AB - The objective of this research was to investigate the neurotoxic effects of pyrethroid pesticide lambda-cyhalothrin by the modulation of cytochrome P450 with piperonyl butoxide in the brain of juvenile Oreochromis niloticus. The fish were exposed to 0.48 MUg L(-1) (1/6 of the 96-h LC50 ) lambda-cyhalothrin and 10 MUg L(-1) piperonyl butoxide for 96 h and 15 days. tGSH, GSSG, TBARS contents, GPx, GR, GST, and AChE enzymes activities were determined by spectrophotometrical methods and Hsp70 content was analyzed by ELISA technique. Lambda-cyhalothrin had no significant effect on the components of GSH redox system, lipid peroxidation and Hsp70 levels but inhibited AChE activity. In the presence of piperonyl butoxide, lambda-cyhalothrin caused increases in tGSH, GSSG, TBARS and Hsp70 contents, GST activity, and decrease in AChE activity. Present results showed that in the presence of piperonyl butoxide, lambda-cyhalothrin caused neurotoxic effects by increasing oxidative stress. Adaptation to its oxidative stress effects may be supplied by GSH-related antioxidant system. Piperonyl butoxide revealed neurotoxic effect of lambda-cyhalothrin. PMID- 23460559 TI - Management of malignant insulinoma. AB - AIM: Malignant insulinoma is an infrequent functional endocrine tumor of the pancreas. Adequate therapy is a demanding challenge for oncologists and endocrinologists. OBJECTIVE: To evaluate the results of multidisciplinary management of malignant insulinoma. MATERIALS AND METHODS: Retrospective review of patients with malignant insulinoma treated from 1995 to 2011. RESULTS: Seven patients with malignant insulinoma were included: four males and three females; median age was 61.8 years (range 37-78). Six tumors were sporadic and one was diagnosed in a patient with a type 1 multiple endocrine neoplasia (MEN-1). Surgery was performed in six cases and one patient was considered unresectable. Hypoglycemias persisted in all cases and somatostatin analogs, glucocorticoids and diazoxide were used. Two patients received everolimus. Other techniques were chemoembolization and internal radiation therapy with yttrium-90. Successful liver transplant was done in the patient with MEN-1. CONCLUSION: Hypoglycemia management is complex and requires multiple therapies. Further evaluations will be necessary to determine the best treatment. PMID- 23460560 TI - Estimate of the accelerated proliferation by protein tyrosine phosphatase (PTEN) over expression in postoperative radiotherapy of head and neck squamous cell carcinoma. AB - PURPOSE: To estimate the impact of PTEN expression in terms of effective doubling time (T(d)) and dose per fraction which compensates the accelerated proliferation during the radiotherapy (D(prolif)) when the overall treatment time (OTT) is reduced in accelerated radiotherapy of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Data were carried out from a recent paper comparing the local control rate (LCR) for patients with HNSCC that underwent a conventional (p-CF) or accelerated radiotherapy (p-CAIR) and a pretreatment assessment of PTEN expression. The impact of PTEN over expression was assessed using the Clinical Efficacy Factor (C) and assuming a plausible range of intrinsic radiosensitivity (alpha). Statistical analysis was made by evaluating the LCR from Kaplan-Meier curves and log-rank test with significance of 0.05. RESULTS: C indexes were 1.46 and 0.23 for the high- versus low-PTEN group, corresponding to a considerable reduction of doubling time of more than six times (6.6 versus 42.2 days). The median estimate of D(prolif) was 0.51 versus 0.08 Gy/day if referred to a median value in the adopted range of alpha. CONCLUSIONS: The PTEN expression has a significant implication on the clinical management of these patient groups. Our data support the hypothesis that the high-PTEN group would benefit from a hypo-fractionation with a reduction of the OTT to compensate for the increase in the proliferation rate, while the low-PTEN group could benefits from a hyper-fractionation which would result in a reduced toxicity for all the organs at risk. PMID- 23460561 TI - The anesthetic effects on vasopressor modulation of cerebral blood flow in an immature swine model. AB - BACKGROUND: The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit. METHODS: Fifteen 4-week old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 MUg/kg/h, n = 8) or ISO (isoflurane 1.5%-2% and fentanyl 100 MUg/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE). RESULTS: Baseline CBF was similar in the 2 groups (ISO 38 +/- 10 vs TIVA 35 +/- 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 +/- 11 vs 71 +/- 11 mm Hg; P < 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 +/- 4 vs 16 +/- 4 mm Hg and 11 +/- 8 vs 18 +/- 5 mm Hg; P < 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 +/- 4 vs 15 +/- 5 mm Hg; P < 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P < 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA. CONCLUSION: The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside. PMID- 23460562 TI - The interventricular septum: measurement and motion. PMID- 23460563 TI - Ketamine enhances human neural stem cell proliferation and induces neuronal apoptosis via reactive oxygen species-mediated mitochondrial pathway. AB - BACKGROUND: Growing evidence indicates that ketamine causes neurotoxicity in a variety of developing animal models, leading to a serious concern regarding the safety of pediatric anesthesia. However, if and how ketamine induces human neural cell toxicity is unknown. Recapitulation of neurogenesis from human embryonic stem cells (hESCs) in vitro allows investigation of the toxic effects of ketamine on neural stem cells (NSCs) and developing neurons, which is impossible to perform in humans. In the present study, we assessed the influence of ketamine on the hESC-derived NSCs and neurons. METHODS: hESCs were directly differentiated into neurons via NSCs. NSCs and 2-week-old neurons were treated with varying doses of ketamine for different durations. NSC proliferation capacity was analyzed by Ki67 immunofluorescence staining and bromodeoxyuridine assay. Neuroapoptosis was analyzed by TUNEL staining and caspase 3 activity measurement. The mitochondria-related neuronal apoptosis pathway including mitochondrial membrane potential, cytochrome c distribution within cells, mitochondrial fission, and reactive oxygen species (ROS) production were also investigated. RESULTS: Ketamine (100 uM) increased NSC proliferation after 6-hour exposure. However, significant neuronal apoptosis was only observed after 24 hours of ketamine treatment. In addition, ketamine decreased mitochondrial membrane potential and increased cytochrome c release from mitochondria into cytosol. Ketamine also enhanced mitochondrial fission as well as ROS production compared with no-treatment control. Importantly, Trolox, a ROS scavenger, significantly attenuated the increase of ketamine-induced ROS production and neuronal apoptosis. CONCLUSIONS: These data for the first time demonstrate that (1) ketamine increases NSC proliferation and causes neuronal apoptosis; (2) mitochondria are involved in ketamine-induced neuronal toxicity, which can be prevented by Trolox; and (3) the stem cell-associated neurogenesis system may provide a simple and promising in vitro model for rapidly screening anesthetic neurotoxicity and studying the underlying mechanisms as well as prevention strategies to avoid this toxic effect. PMID- 23460564 TI - Local toxicity from local anesthetic polymeric microparticles. AB - BACKGROUND: Local tissue injury from sustained-release formulations for local anesthetics can be severe. There is considerable variability in reporting of that injury. We investigated the influence of the intrinsic myotoxicity of the encapsulated local anesthetic (lidocaine, low; bupivacaine, high) on tissue reaction in rats. METHODS: Cytotoxicity from a range of lidocaine and bupivacaine concentrations was measured in C2C12 myotubes over 6 days. Rats were given sciatic nerve blocks with 4 microparticulate formulations of lidocaine and bupivacaine: 10% (w/w) lidocaine poly(lactic-co-glycolic) acid (PLGA), 10% (w/w) bupivacaine PLGA, 50% (w/w) lidocaine PLGA, and 50% (w/w) bupivacaine PLGA. Effectiveness of nerve blockade was assessed by a modified hotplate test and weightbearing measurements. Myotoxicity was scored in histologic sections of injection sites. Bupivacaine and lidocaine release kinetics from the particles were measured. RESULTS: Median sensory blockade duration for 50% (w/w) lidocaine was 255 (90-540) minutes versus 840 (277-1215) minutes for 50% (w/w) bupivacaine (P = 0.056). All microparticulate formulations resulted in myotoxicity. The choice of local anesthetic did not influence the severity of myotoxicity. Median myotoxicity scores for 50% (w/w) lidocaine compared with 50% (w/w) bupivacaine at 4 days were 3.4 (2.1-4.2) vs 3.3 (2.9-3.5) (P = 0.44) and at 14 days 1.9 (1.8 2.4) vs 1.7 (1.3-1.9) (P = 0.23), respectively. CONCLUSIONS: Lidocaine and bupivacaine PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. Intrinsic myotoxicity did not predict tissue injury from sustained release of these anesthetics. Caution is warranted in the use of such devices near muscle and nerve. PMID- 23460566 TI - The effect of lipid emulsion on pharmacokinetics and tissue distribution of bupivacaine in rats. AB - BACKGROUND: While lipid emulsion may reverse the systemic toxicity of bupivacaine, the pharmacokinetics and tissue distribution of bupivacaine after lipid emulsion infusion are not clear. In this study, we assessed the influence of lipid emulsion administration on the pharmacokinetics and tissue distribution of bupivacaine. METHODS: Rats in the lipid group were administered IV bupivacaine at the rate of 2 mg.kg(-1).min(-1) for 4 minutes, and then were treated with an infusion of 30% lipid emulsion at the rate of 3 mL.kg(-1).min(-1) for 5 minutes; saline was substituted in the control group (n = 6 for pharmacokinetics). We then randomly assigned 100 rats into the lipid group and control group (n = 50 for distribution). The toxicity model and treatment were the same as the pharmacokinetic portion. Plasma and tissues including brain, heart, liver, spleen, lung, kidney, omentum, and muscle were collected. The plasma concentration and tissue content of bupivacaine were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the pharmacokinetics of bupivacaine. RESULTS: All data are shown as mean +/- SD. After treatment with the lipid emulsion, t1/2beta of bupivacaine in the lipid group was significantly shorter (110 +/- 25 minutes vs 199 +/- 38 minutes, P = 0.001), the clearance was higher (14 +/- 4 mL.mg(-1).kg( 1) vs 9 +/- 4 mL.mg(-1).kg(-1), P = 0.038), and the t1/2alpha was longer than that of the control group (4 +/- 1 minutes vs 2 +/- 1 minutes, P = 0.014); the K12 in the lipid group was less than that of the control group (0.13 +/- 0.04 vs 0.32 +/- 0.13, P = 0.011). In the lipid group, the bupivacaine content in heart, brain, lung, kidney, and spleen was lower than that in the control group, but higher in the liver at 20, 30, and 45 minutes. CONCLUSION: The lipid sink phenomenon was observed in this study. The use of a lipid emulsion accelerated the elimination of bupivacaine. PMID- 23460565 TI - TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore potassium channel antagonists stimulate breathing in isoflurane-anesthetized rats. AB - BACKGROUND: TASK-1 and TASK-3 tandem pore potassium channel subunits provide a constitutive acidic pH- and hypoxia-inhibited potassium conductance. TASK channels are expressed in a number of tissues involved in regulation of breathing, and the TASK-1/TASK-3 heterodimer provides the predominant hypoxia sensitive potassium conductance in carotid body type 1 glomus chemosensing cells. The carotid bodies have an important role in regulation of breathing. Doxapram is a potent TASK-1 and TASK-3 potassium channel antagonist and a carotid body and breathing stimulant. PK-THPP and A1899 are potent and selective TASK-1 and TASK-3 antagonists. I hypothesized PK-THPP and A1899 are, like doxapram, breathing stimulants. METHODS: I studied rat TASK-3 potassium channel function by Ussing chamber using Fischer rat thyroid monolayers. To quantify breathing effects, I studied male Sprague-Dawley rats spontaneously breathing 1.5% isoflurane in room air by noninvasive plethysmography and by arterial blood gas analysis. RESULTS: PK-THPP, A1899, and doxapram inhibit rat TASK-3 potassium channel function with IC50s of 42 nM (33-52), 1.6 MUM (0.8-3.3), and 22 MUM (18-28) (n = 4-6; 95% confidence limits). IV PK-THPP, A1899, and doxapram stimulated breathing by plethysmography with a peak change in minute ventilation relative to baseline of 84% +/- 19% and 226% +/- 56% (for PK-THPP at 0.5 and 5 mg/kg; mean +/- SEM; n = 3 4; P < 0.05 and P < 0.001, respectively, relative to vehicle); 46% +/- 2% and 236% +/- 48% (for A1899 at 5 and 25 mg/kg; n = 3-4; P > 0.05 and P < 0.001, respectively); 103% +/- 20% (for doxapram at 25 mg/kg; n = 4), and 33% +/- 9% (for dimethylsulfoxide vehicle at 1 mL/kg; n = 4). PK-THPP and A1899, unlike doxapram, induced a profound and lasting respiratory alkalosis by arterial blood gas analysis. Thirty minutes after IV drug administration, I observed an arterial pH and carbon dioxide partial pressure of 7.62 +/- 0.02 and 23 +/- 0.8 mm Hg (for PK-THPP after 5 mg/kg; n = 4; P < 0.001 for both relative to vehicle), 7.49 +/- 0.02 and 31 +/- 2 mm Hg (for A1899 at 25 mg/kg; n = 6; P < 0.05 and 0.001, respectively), 7.43 +/- 0.03 and 39 +/- 4 mm Hg (for doxapram after 25 mg/kg; n = 4; P > 0.05 for both), and 7.38 +/- 0.03 and 48 +/- 4 mm Hg (for dimethylsulfoxide vehicle after 1 mL/kg; n = 3). CONCLUSIONS: PK-THPP and A1899 are potent rat TASK-3 antagonists and effective breathing stimulants. PK-THPP and A1899 effects on breathing were of greater magnitude and/or duration relative to that of doxapram. PK-THPP and A1899 or related compounds may have therapeutic potential for treating breathing disorders. PMID- 23460567 TI - Assessment of intraoperative awareness with explicit recall: a comparison of 2 methods. AB - BACKGROUND: Superiority of the modified Brice interview over quality assurance techniques in detecting intraoperative awareness with explicit recall has not been demonstrated definitively. METHODS: We studied a single patient cohort to compare the detection of definite awareness using a single modified Brice interview (postoperative day 28-30) versus quality assurance data (postoperative day 1). RESULTS: The incidence of awareness based on the modified Brice interview was 19 per 18,847 or 0.1%. Fewer awareness cases (incidence 0.02%) were detected by the quality assurance approach (P < 0.0001). CONCLUSION: The modified Brice interview is the preferred modality for assessing intraoperative awareness with explicit recall. PMID- 23460568 TI - An overview of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for the anesthesiologist. AB - Anesthesiologists face several perioperative challenges when patients need cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. To adequately care for these patients, anesthesiologists must understand the goals and objectives of the operation in addition to having a basic knowledge of the chemotherapeutic drugs that are frequently used. Optimal anesthetic management of patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion requires control of a complex interplay of physiologic mechanisms, including hyperthermia, abdominal hypertension, electrolyte abnormalities, coagulopathies, increased cardiac index, oxygen consumption, and decreased systemic vascular resistance. As this surgery continues to gain popularity among oncologic surgeons, further studies that clearly define the chemistry, pharmacokinetics, pharmacodynamics, and end points of efficacy need to be performed to elucidate optimal perioperative management. PMID- 23460569 TI - Society of cardiovascular anesthesiologists: the effect of blood pressure regulation during aortic coarctation repair on brain, kidney, and muscle oxygen saturation measured by near-infrared spectroscopy: a randomized, clinical trial. AB - BACKGROUND: In this study, we compared the effects of 3 frequently used arterial blood pressure-regulating agents on brain (rScO2), renal (SrO2), and muscle (SmO2) oxygen saturation, during aortic coarctation repair in children. Based on the reported adverse effect of sodium nitroprusside (SNP) on left-sided rScO2 during aortic coarctation repair, we tested the hypothesis that the alterations in left rScO2 occurring with SNP would not be present with sevoflurane and nitroglycerin (NTG). Additionally, we explored the effects of blood pressure regulation with SNP, NTG, or sevoflurane on right-sided rScO2, SrO2, and SmO2. METHODS: Children with isolated aortic coarctation undergoing surgical repair through a left thoracotomy without the use of cardiopulmonary bypass were considered eligible for the study. During aortic cross-clamping, control of mean arterial blood pressure (MAP) was conducted according to randomization by the use of SNP, NTG, or sevoflurane to obtain a mean target right brachial blood pressure of 120% to 150% of the MAP value before cross-clamping. Bilateral rScO2, SrO2, and SmO2 were recorded continuously with near-infrared spectroscopy. As a primary end point, the maximal relative change in left-sided rScO2 in response to aortic cross-clamping was compared among treatment groups. RESULTS: Ten patients per group were included. No significant difference among treatment groups was observed in maximal relative change in left-sided rScO2 (SNP versus sevoflurane: mean difference -0.7%, 99% confidence interval [CI] -31% to 29%, P = 1.0; SNP versus NTG: mean difference -1.8%, 99% CI -32% to 28%, P = 1.0; sevoflurane versus NTG: mean difference -1.1%, 99% CI -31% to 29%, P = 1.0). Additional analyses also detected no difference between groups in right rScO2 (P = 0.4). Compared with NTG, treatment with SNP resulted in a significantly larger (-64% +/ 17% vs -34% +/- 25%, P = 0.01) and faster (-9 +/- 4 %.min(-1) vs -4 +/- 3 %.min( 1), P = 0.004) decrease in SmO2. Right-sided rScO2 and MAP showed a poor correlation for NTG (r = -0.2, P = 0.93), whereas borderline for sevoflurane (r = 0.44, P = 0.09) and SNP (r = 0.56, P = 0.04). CONCLUSIONS: The mean differences in left-sided rScO2 among the patients treated with SNP, NTG, or sevoflurane for proximal hypertension during aortic cross-clamping were no more than 32%. Additional analysis demonstrated a low MAP-rScO2 dependence with the use of NTG. Because NTG also resulted in a smaller and slower decrease of oxygen saturation in peripheral tissues, our data suggest that its use might be preferable for proximal blood pressure control during surgical procedures involving aortic cross clamping. PMID- 23460570 TI - The influence of prone positioning on the accuracy of calibrated and uncalibrated pulse contour-derived cardiac index measurements. AB - BACKGROUND: Patients with lung failure who undergo prone positioning often receive extended hemodynamic monitoring. We investigated the influence of modified prone positioning (135 degrees ) on the accuracy of pulse contour derived calibrated cardiac index (CIPC) and uncalibrated cardiac index (CIVIG) in this patient population with transpulmonary thermodilution (TPTD) as reference technique. METHODS: We studied 16 critically ill and mechanically ventilated patients (11 men, 5 women, aged 20-71 years) with acute lung injury or acute respiratory distress syndrome. Patients were monitored by TPTD with an integrated calibrated pulse contour technique (PiCCO(r)) and by uncalibrated pulse contour analysis (FloTrac/VigileoTM). Before prone positioning, cardiac index (given in L.min(-1).m(-2)) was measured by TPTD (CITPTD) and CIPC was calibrated. After positioning, CIPC and CIVIG were read from the monitor and CITPTD was measured. After 8 to 10 hours, prone positioning was completed and measurements were performed analogously. Bland-Altman analysis based on a random-effects model was used to calculate limits of agreement (LOA) and percentage errors. Polar plots were used for trend analysis. RESULTS: Supine CITPTD was 3.3 +/- 0.9 (mean +/- SD) and CIVIG was 3.1 +/- 0.8. After proning, CIPC was 3.5 +/- 0.8, CIVIG 3.3 +/- 0.8, and CITPTD 3.6 +/- 0.8. Before repositioning, CITPTD was 3.5 +/- 0.7 and CIVIG 3.3 +/- 1.0. After repositioning, CITPTD was 3.1 +/- 0.7, CIPC 3.3 +/- 0.7, and CIVIG 2.9 +/- 0.6. Mean bias pooled for proning and repositioning was -0.1 (LOA -0.7 to 0.6) for CIPC (percentage error 19%) and 0.3 (LOA -1.3 to 1.9) for CIVIG (percentage error 48%). Changes in CI were too small for trending analysis. CONCLUSION: Although calibrated CI measurements are only marginally influenced by prone positioning, according to the criteria of Critchley and Critchley, uncalibrated CI values show a degree of error, too high to be considered clinically acceptable. PMID- 23460571 TI - Ephedrine shows synergistic motor blockade when combined with bupivacaine or lidocaine for spinal anesthesia in a rat model. AB - BACKGROUND: Ephedrine is a direct/indirect vasoactive drug. In addition, it also possesses intrinsic local anesthetic properties, mainly due to its sodium-channel blockage. We investigated whether ephedrine demonstrates a synergistic effect with bupivacaine and lidocaine when injected via a spinal catheter into the spinal space of rats. METHODS: Spinal catheters were surgically placed in 47 rats (n = 8 per group; 7 rats were excluded.) Bupivacaine, lidocaine, and ephedrine in various concentrations and constant volumes (60 MUL) were injected into the spinal catheters to determine the equipotency of each drug. Ephedrine in combination with either bupivacaine or lidocaine was then injected into the spinal catheters. RESULTS: Ephedrine demonstrated statistically significant synergistic effects with bupivacaine as well as with lidocaine in fixed combinations. The combination index reflecting a synergistic effect was 0.792 (95% confidence interval: 0.665-0.919) for ephedrine + bupivacaine and 0.663 (95% confidence interval: 0.532-0.794) for ephedrine + lidocaine. CONCLUSION: Ephedrine combined with either bupivacaine or lidocaine acted synergistically to block motor function and has the potential to reduce the amount of local anesthetic needed for spinal block. The synergistic effect of ephedrine in combination with local anesthetics is an interesting pharmacological phenomenon that warrants further clinical evaluation. PMID- 23460572 TI - Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex. AB - BACKGROUND: Accumulating evidence indicates that isoflurane and other, similarly acting anesthetics exert neurotoxic effects in neonatal animals. However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized. We conducted the present study to immunohistochemically identify the dying cells and to quantify the fraction of cells undergoing apoptotic death in neonatal mouse cortex, a substantially affected brain region. METHODS: Seven-day-old littermates (n = 36) were randomly assigned to a 6-hour exposure to either 1.5% isoflurane or fasting in room air. Animals were euthanized immediately after exposure and brain sections were double stained for activated caspase 3 and one of the following cellular markers: Neuronal Nuclei (NeuN) for neurons, glutamic acid decarboxylase (GAD)65 and GAD67 for GABAergic cells, as well as GFAP (glial fibrillary acidic protein) and S100beta for astrocytes. RESULTS: In 7-day-old mice, isoflurane exposure led to widespread increases in apoptotic cell death relative to controls, as measured by activated caspase 3 immunolabeling. Confocal analyses of caspase 3-labeled cells in cortical layers II and III revealed that the overwhelming majority of cells were postmitotic neurons, but some were astrocytes. We then quantified isoflurane induced neuronal apoptosis in visual cortex, an area of substantial injury. In unanesthetized control animals, 0.08% +/- 0.001% of NeuN-positive layer II/III cortical neurons were immunoreactive for caspase 3. By contrast, the rate of apoptotic NeuN-positive neurons increased at least 11-fold (lower end of the 95% confidence interval [CI]) to 2.0% +/- 0.004% of neurons immediately after isoflurane exposure (P = 0.0017 isoflurane versus control). In isoflurane-treated animals, 2.9% +/- 0.02% of all caspase 3-positive neurons in superficial cortex also coexpressed GAD67, indicating that inhibitory neurons may also be affected. Analysis of GABAergic neurons, however, proved unexpectedly complex. In addition to inducing apoptosis among some GAD67-immunoreactive neurons, anesthesia also coincided with a dramatic decrease in both GAD67 (0.98 vs 1.84 ng/mg protein, P < 0.00001, anesthesia versus control) and GAD65 (2.25 +/- 0.74 vs 23.03 +/- 8.47 ng/mg protein, P = 0.0008, anesthesia versus control) protein levels. CONCLUSIONS: Prolonged exposure to isoflurane increased neuronal apoptotic cell death in 7-day-old mice, eliminating approximately 2% of cortical neurons, of which some were identified as GABAergic interneurons. Moreover, isoflurane exposure interfered with the inhibitory nervous system by downregulating the central enzymes GAD65 and GAD67. Conversely, at this age, only a minority of degenerating cells were identified as astrocytes. The clinical relevance of these findings in animals remains to be determined. PMID- 23460573 TI - Two- and three-dimensional transesophageal echocardiography for aortic valve aneurysms on the right coronary cusp. PMID- 23460574 TI - Occurrence of rapid eye movement sleep deprivation after surgery under regional anesthesia. AB - BACKGROUND: Sleep disturbances after general surgery have been described. In this study, we assessed rapid eye movement (REM) sleep in patients undergoing knee replacement surgery using a regional anesthetic technique. METHODS: Ambulatory polysomnography (PSG) was performed on 3 nights: the night before surgery (PSG1), the first night after surgery (PSG2), and the fifth postoperative night (PSG3). Postoperative analgesia was maintained with peripheral nerve catheters for the first 3 days and with oral opioids thereafter. In addition, nonsteroidal antiinflammatory drugs were administered. Postoperative pain was monitored using a visual analog scale. RESULTS: PSG was performed in 12 patients, 6 men and 6 women, with a mean age of 61 (+/-12) years. REM sleep was reduced from PSG1 (median 16.4%) to PSG2 (median 6.3%; P = 0.02). The Hodges-Lehmann estimate for the median reduction is -7.8% (95% confidence interval -14.8% to -0.7%). During PSG3, significantly more REM sleep was detected (median 15.4%) compared with PSG2 (P = 0.01). The Hodges-Lehmann estimate for this median increase is 10.0% (95% confidence interval 1.7%-25.3%). CONCLUSION: Postoperative reduction of REM sleep also occurs after surgery and regional anesthesia. PMID- 23460575 TI - Chunggan extract (CGX), a traditional Korean herbal medicine, exerts hepatoprotective effects in a rat model of chronic alcohol consumption. AB - Chunggan extract, CGX, is a modification of a traditional herbal medicine that has been used for patients suffering from various liver disorders since 2001. Here, we investigated the hepatoprotective effects of CGX and its underlying mechanisms in a rat model of chronic alcohol consumption. Rats were orally administered 30% ethanol solution for 4 weeks with or without CGX (50, 100, 200 mg/kg). The histopathology, biochemistry, oxidative stress/antioxidant biomarkers, hepatofibrogenic cytokines, and serum endotoxin level were analyzed. Alcohol treatment markedly elevated the serum levels of aspartate transaminase, alkaline phosphatase, and total reactive oxygen species, and tissue levels of hydroxyproline and malondialdehyde (MDA), while reducing the total glutathione (GSH) contents and the activities of superoxide dismutase and catalase. These alterations were significantly attenuated by CGX treatment (mainly 100 and 200 mg/kg). CGX treatment normalized the elevation of fibrogenic cytokines, including transforming growth factor-beta, platelet derived growth factor-beta, and connective tissue growth factor in hepatic tissues and ameliorated the increase in serum endotoxin concentration. These results suggest that CGX protects liver tissue from alcohol injury through antioxidant actions and prevention of endotoxin reflux. . PMID- 23460576 TI - Surprises from the chromosome front: lessons from Arabidopsis on telomeres and telomerase. AB - Telomeres serve two vital functions: They act as a buffer against the end replication problem, and they prevent chromosome ends from being recognized as double-strand DNA (dsDNA) breaks. These functions are orchestrated by the telomerase reverse transcriptase and a variety of telomere protein complexes. Here, we discuss our recent studies with Arabidopsis thaliana that uncovered a new and highly conserved telomere complex called CST (Cdc13/CTC1, STN1, TEN1). Formerly believed to be yeast specific, CST has now been identified as a key component of both plant and vertebrate telomeres, which is essential for genome integrity and stem cell viability. We also describe the unexpected discovery of alternative telomerase ribonucleoprotein complexes in Arabidopsis. Fueled by duplication and diversification of the telomerase RNA subunit and telomerase accessory proteins, these telomerase complexes act in concert to maintain genome stability. In addition to the canonical telomerase enzyme, one of two alternative telomerase ribonucleoprotein (RNP) complexes functions as a novel negative regulator of enzyme activity in response to genotoxic stress. These contributions highlight the immense potential of Arabidopsis in probing the depths of the chromosome end. PMID- 23460578 TI - Is TOR1A a risk factor in adult-onset primary torsion dystonia? AB - BACKGROUND: Studies of genetic association between TOR1A and adult-onset primary torsion dystonia have contradictory results. METHODS: The authors genotyped TOR1A single nucleotide polymorphisms rs1801968, rs2296793, rs1182 and rs3842225 in a cohort of clinically well characterized cervical dystonia patients (n=367) and constructed haplotypes. The authors systematically reviewed the published case control TOR1A association studies in adult-onset primary torsion dystonia. RESULTS: In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance. However, in a selection of familial cases the functional variant p.Asp216His (rs1801968) was associated with increased dystonia risk (odds ratio 1.43; 95%CI 1.01-2.02). CONCLUSIONS: Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases. PMID- 23460577 TI - Use of single-site-functionalized PEG dendrons to prepare gene vectors that penetrate human mucus barriers. PMID- 23460579 TI - Effect of PPARbeta/delta agonist on the placentation and embryo-fetal development in rats. AB - BACKGROUND: The present study was conducted to evaluate the developmental toxicity in the endometrium and placenta due to GW501516 administration by gavage to pregnant rats. METHODS: GW501516 was orally administered repeatedly to pregnant rats from gestation day (GD) 6 to 17 at a dose of 0, 30, and 100 mg/kg/day. In next study, GW501516 was also orally administered to pregnant rats on GD 7, 8, 9, 10, or 11 at a single dose of 275 or 350 mg/kg. In these studies, caesarean section was performed to examine the pregnancy outcome on GD21. Additionally, GW501516 was orally administered to pregnant rats on GD 10 at a single dose of 275 mg/kg. Placentae were subjected for temporal histological examinations on GD 11, 13, 15, or 17. RESULTS: Placental malformation was induced by repeated administration of GW501516 at a dose of 100 mg/kg/day. Single oral administration of GW501516 at a dose of 275 and/or 350 mg/kg on GD 8, 9, 10, or 11 induced placental malformation, whereas GW501516 administered on GD 10 was the most effective for increasing placental malformation. Histopathologically, single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells started from GD 15 in the basal zone. CONCLUSIONS: High frequency of placental malformation was observed by the administration of GW501516. From GD 8 to 11, especially GD 10, is more sensitive period to induce the placental malformation. PMID- 23460580 TI - Phototoxic effect of photodynamic therapy on lung cancer cells grown as a monolayer and three dimensional multicellular spheroids. AB - BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a minimally invasive therapeutic modality for the treatment of neoplastic and non-neoplastic diseases. The photochemical interaction of light, photosensitizer (PS) and molecular oxygen produces singlet oxygen which induces cell death. The effectiveness of zinc sulfophthalocyanine (ZnPcSmix ) has been shown on A549 monolayers and not on MCTS. The objective of this study was to investigate whether the same pattern of cell death would be induced in lung cancer cells (A549) grown as monolayer cells compared to three dimensional multicellular tumor spheroids (MCTS) using the same laser parameters. MATERIALS AND METHODS: Commercially purchased A549 cells used in this study were cultured as monolayers and as MCTS. ZnPcSmix at different concentrations [0, 5, 10, 20, and 40 uM] was used and activated at a wavelength of 680 nm with 5 J/cm2. Lysosomal and mitochondrial damage after PDT and reactive oxygen species (ROS) production were determined by fluorescent microscopy. Changes in cellular responses were evaluated using cell morphology, viability, proliferation, cytotoxicity, and cell death analysis. RESULTS: Cells exposed to neither laser light nor PS, showed no changes in cell morphology, proliferation, cytotoxicity, and ROS production. However, cells treated with light activated ZnPcSmix resulted in a significant production of ROS and a dose dependant decrease in viability and proliferation as well as an increase in cell membrane damage in both monolayer and MCTSs. CONCLUSION: ZnPcSmix PS used in this study induced damage to vital organelles and was effective in inducing apoptosis in lung cancer cells grown as a monolayer and MTCS through ROS production. PMID- 23460581 TI - Transforming growth factor type beta 1 increases the expression of angiotensin II receptor type 2 by a SMAD- and p38 MAPK-dependent mechanism in skeletal muscle. AB - Excessive deposition of extracellular matrix (ECM) proteins, a condition known as fibrosis, is a hallmark of Duchenne muscular dystrophy. Among the factors that trigger muscle fibrosis are transforming growth factor beta (TGF-beta) and angiotensin II (Ang-II). Ang-II belongs to the renin-angiotensin system, and its biological effects are exerted by Ang-II receptors type 1 and type 2 (AT-1 and AT 2, respectively). This study aims to determine the effect of TGF-beta1 on the expression of AT-1 and AT-2 receptor in skeletal muscle. C2 C12 myoblasts exposed to TGF-beta1 showed a dose-dependent increase in AT-2 expression but with no effect on AT-1 levels. Injection of TGF-beta1 in the skeletal muscle of mice increased the levels of AT-2 and ECM protein but unchanged AT-1 levels. We also detected higher expression levels of AT-2 receptor in dystrophic skeletal muscle of mdx mice than in normal mice. The induction of AT-2 was mediated by the canonical TGF-beta pathway because under the inhibitory conditions of the kinase activity of TGFbeta receptor I or the knockdown of Smad2/3 levels, TGF-beta induced AT-2 receptor increase was strongly inhibited. Furthermore, we demonstrated that p38MAPK activity in response to TGF-beta is also required for AT-2 increase as evaluated by a p38MAPK inhibitor. Our results show that the levels of AT-2 but not AT-1 receptor are modulated by the pro-fibrotic factor TGF beta1 in myoblasts and mouse skeletal muscle. This finding suggests that AT-2 might be involved in the physiopathology of fibrosis in dystrophic skeletal muscle. PMID- 23460582 TI - Markers of oxidative stress in hepatopancreas of crayfish (Orconectes limosus, raf) experimentally exposed to nanosilver. AB - Silver nanoparticles, chemically neutral particles in the size range of 1-100 nm, express strong antimicrobial activity and therefore have a broad range of applications. The increased use of consumer products with nanosilver (nanoAg) may result in its release into the environment, and may particularly affect aquatic systems. The mechanisms of the harmful effects of nanoAg against aquatic organisms are unclear. Therefore, in the present study we investigate the pro oxidative potential of these nanoparticles in experimentally exposed crayfish Orconectes limosus. Markers of oxidative stress and parameters of the antioxidant cell defense system such as total glutathione, glutathione reductase and the level of sulfhydryl groups were examined in the hepatopancreas of both sexes of O. limosus collected seasonally from Biale Lake (Poland) and subsequently exposed to nanoAg particles for 2 weeks. Exposure to nanoAg led to a high concentration dependent increase in the rate of lipid peroxidation and a decrease of protein bound SH groups which indicates protein oxidation. These markers of oxidative stress were accompanied by decreased levels of thiols and reduced activity of glutathione reductase. These results indicate a deficiency of reduced glutathione and suggest that the exposed organisms have less efficient antioxidative mechanisms available to counter ROS-mediated cellular stress. Furthermore, we find that confocal microscopy is of limited utility in monitoring the presence of silver nanoparticles in tissues of exposed crayfish. PMID- 23460583 TI - A protein-interaction array inside a living cell. PMID- 23460584 TI - Obesity: upsetting the public health balance. PMID- 23460585 TI - Burden of injury from explosive remnants of conflict in Lao PDR and Cambodia. AB - In postconflict settings, a substantial number of injuries and related disabilities are caused by land mines and explosive remnants of war. This article reviews the literature on the prevalence of these injuries and subsequent disabilities in Cambodia and Lao PDR. Three major electronic databases were systematically for publications on the prevalence of these injuries. Six studies met the inclusion criteria. Five of these were in Cambodia and 1 in Lao PDR. None of these studies could estimate national prevalence rates of these injuries; only 2 considered the broader impact of related disabilities. The different methodological approaches and limitations of the studies prevented statistical synthesis. The studies reviewed suggested accurate estimates of the prevalence of war injuries and consequent disabilities are missing. There is a need for a comprehensive epidemiological research to quantify the burden that results from such injuries. PMID- 23460586 TI - Pesticide exposure and endocrine dysfunction in the cotton crop agricultural workers of southern Punjab, Pakistan. AB - This study evaluated pesticide effects on reproductive and thyroid hormones of cotton farmers of southern Punjab, Pakistan. A total of 88 cotton farmers (42 spray applicators and 46 cotton pickers) were randomly included with an equal number of age- and sex-matched controls. Sampling was done in high spraying and peak picking seasons. Serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, prolactin, thyroid-stimulating hormone (TSH), total triiodothyroxine (TT3), and free thyroxine (fT4) were carried out by enzymatic immunoassay. Plasma cholinesterase (PChE) levels were measured by Ellman's method. Serum FSH, LH, and testosterone levels were significantly high in spray applicators (P < .01).Serum FSH and testosterone levels were significantly raised in cotton pickers (P < .01). Serum prolactin was decreased significantly in both groups (P < .01).Serum fT4 was significantly reduced in cotton pickers (P < .01). Pesticide exposure is associated with thyroid and reproductive hormone levels disturbance. PMID- 23460587 TI - The organ transplantation act and recent trends in Korea. AB - The Organ Transplantation Act, including transplantation of organs from brain dead donors, entered into force in Korea on February 9, 2000. This article introduces the Organ Transplantation Act, focusing on scope of the Act, determination of brain death, removal of organs from brain-dead or deceased donors, removal from living donors, organ allocation, and prohibition of trade in human organs. Especially, some primary ethical dilemmas surrounding organ allocation arise from the shortage of available organs. The primary ethical problems surrounding organ allocation are as follows. A key purpose of the organ donation incentive system is to increase the number of organ transplants from brain-dead donors. In particular, the priority for kidney patient was allowed in consideration of doctor's strong desire to increase the brain-dead donors. Also, the organ allocation criteria based on the organ donation incentive system appear unfair, especially for the kidney patient, because the criteria do not fit the principles of distributive justice. In the future, the organ donation incentive system itself may need to be reexamined. PMID- 23460588 TI - Hemoglobin Shady Grove: a novel fetal methemoglobin variant. AB - Recommendations by the US Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children aim to increase congenital heart disease screening by pulse oximetry in the nursery. Here, we describe a novel fetal methemoglobin variant discovered in a newborn found to have oxygen saturations significantly below normal upon pulse oximetry screening for congenital heart disease. As universal newborn screening with pulse oximetry is implemented, hereditary variant hemoglobins should be considered in the diagnostic work-up in otherwise well newborns with low SpO2 . PMID- 23460589 TI - Assessment of the utility of the 2-u thulium laser in surgical removal of intracranial meningiomas. AB - BACKGROUND AND OBJECTIVE: Since the 1960s, lasers have been used in neurosurgery for surgical removal of intracranial tumors. Because of its limited penetration (2 mm) through tissues and its wavelength, which is useful in water medium, the 2 u thulium laser has been applied primarily in urology. Its features are attractive for application under microscope magnification during neurosurgical procedures. The aim of this study was to evaluate the usefulness of the 2-u thulium laser during microsurgical removal of intracranial meningiomas. MATERIALS AND METHODS: Twenty patients with a diagnosis of intracranial meningiomas were treated with surgical intervention using a 2-u thulium laser together with bipolar forceps, cavitron ultrasonic surgical aspirator (CUSA) and traditional microdissection instruments. Surgical removal was divided in four phases: (1) dissection from the external structures; (2) coagulation and debulking; (3) dissection from the deep structures; and (4) coagulation and removal of the basal implant. During all these steps, we evaluated the percentage of usage of the 2-u thulium laser comparing them with bipolar forceps and ultrasonic aspirator and blunt dissection. RESULTS: Thulium laser was used mainly during phases 2 and 4 for 43% and 48.7% of the total removal, respectively. Although also useful during phases 1 and 3, it was only used for 2.2% and 31.3%, respectively: traditional dissection with scissors and forceps was preferred. CONCLUSIONS: Thulium laser seems to be a useful aid in the surgery of intracranial meningiomas, especially to debulk, shrink, and coagulate the mass and the basal implant. PMID- 23460590 TI - Efficacy and toxicity of plerixafor for peripheral blood stem cell mobilization in children with high-risk neuroblastoma. AB - Six patients with high-risk neuroblastoma underwent the second stem cell collection round with G-CSF (5 MUg/kg/day) + plerixafor (0.24 mg/kg/day) because the amount of CD34(+) cells collected during the first collection round with G CSF alone was insufficient. The number of CD34(+) cells collected in the second collection round was higher in four patients and lower in two patients than in the first collection round. Four of the six patients experienced nightmares, nyctophobia, and visual hallucinations with G-CSF + plerixafor, which were not observed with G-CSF alone. Our findings suggest that plerixafor needs to be used with caution in children. PMID- 23460591 TI - Deriving metabolic engineering strategies from genome-scale modeling with flux ratio constraints. AB - Optimized production of bio-based fuels and chemicals from microbial cell factories is a central goal of systems metabolic engineering. To achieve this goal, a new computational method of using flux balance analysis with flux ratios (FBrAtio) was further developed in this research and applied to five case studies to evaluate and design metabolic engineering strategies. The approach was implemented using publicly available genome-scale metabolic flux models. Synthetic pathways were added to these models along with flux ratio constraints by FBrAtio to achieve increased (i) cellulose production from Arabidopsis thaliana; (ii) isobutanol production from Saccharomyces cerevisiae; (iii) acetone production from Synechocystis sp. PCC6803; (iv) H2 production from Escherichia coli MG1655; and (v) isopropanol, butanol, and ethanol (IBE) production from engineered Clostridium acetobutylicum. The FBrAtio approach was applied to each case to simulate a metabolic engineering strategy already implemented experimentally, and flux ratios were continually adjusted to find (i) the end limit of increased production using the existing strategy, (ii) new potential strategies to increase production, and (iii) the impact of these metabolic engineering strategies on product yield and culture growth. The FBrAtio approach has the potential to design "fine-tuned" metabolic engineering strategies in silico that can be implemented directly with available genomic tools. PMID- 23460592 TI - On the evolving nature of exposure therapy. AB - Four articles examining methodological applications of exposure therapy and its limited dissemination were briefly reviewed. Methodological articles included those by Abramowitz et al., Gryczkowski et al., and Weiner and McKay, which addressed couple treatment of obsessive-compulsive disorder (OCD), modification of evidence-based anxiety treatments for children, and novel exposure methods for depersonalization and derealization, respectively. The creative aspects of these innovations are highlighted as well as historical parallels in the empirical literature for both anxiety and other clinical phenomena. Underutilization and limited dissemination concerns are discussed in the context of the fourth article by Hipol and Deacon and as related to the field as a whole. A unique concept, exposaphobia, is hypothesized to explain the lack of clinicians' utilization of this technique, due to their own anxiety-driven inhibitions in using it. Suggestions for the future of exposure research and dissemination are made. PMID- 23460593 TI - Shape mapping: genetic mapping meets geometric morphometrics. AB - Knowledge about biological shape has important implications in biology and biomedicine, but the underlying genetic mechanisms for shape variation have not been well studied. Statistical models play a pivotal role in mapping specific quantitative trait loci (QTLs) that contribute to biological shape and its developmental trajectories. We describe and assess a statistical framework for shape gene identification that incorporates shape and image analysis into a mixture-model framework for QTL mapping. Statistical parameters that define genotype-specific differences in biological shape are estimated by implementing statistical and computational algorithms. A state-of-the-art procedure is described to examine the control patterns of specific QTLs on the origin, properties and functions of biological shape. The statistical framework described will help to address many integrative biological and genetic questions and challenges in shape variation faced by the life sciences community. PMID- 23460596 TI - Safety and feasibility of orbital atherectomy for the treatment of calcified coronary lesions: the ORBIT I trial. AB - OBJECTIVE: The ORBIT I trial evaluated the safety and performance of an orbital atherectomy system (OAS) for the treatment of de novo calcified coronary lesions. BACKGROUND: Severely calcified coronary arteries pose an ongoing treatment challenge. Stent placement in calcified lesions can result in stent under expansion, malapposition, and procedural complications. OAS treatment may change calcified lesion compliance to reduce procedural complications and facilitate stent placement. METHODS: The ORBIT I trial, a prospective, nonrandomized study, was conducted in two centers in India. Fifty patients with de novo calcified coronary lesions were enrolled. Patients were treated with the OAS followed by stent placement. RESULTS: The average age of the patients was 57.4 years and 90% were male. Mean lesion length was 13.4 mm. The average number of OAS devices used per patient was 1.3. Device success was 98%, and procedural success was 94%. The cumulative major adverse cardiac event rate was 4% in-hospital (two non-Q-wave myocardial infarctions), 6% at 30 days (one additional non-Q-wave myocardial infarction leading to target lesion revascularization), and 8% at 6 months (one additional event of cardiac death). Angiographic complications were observed in seven patients (six dissections and one perforation). CONCLUSION: The ORBIT I trial suggests that the OAS may offer an effective method to change compliance of calcified coronary lesions to facilitate optimal stent placement in these difficult to treat patients. A larger trial is required to establish safety and overall effectiveness of the OAS in treating calcified coronary lesions. PMID- 23460597 TI - Transapical transcatheter aortic valve implantation in a heart transplant recipient with severely depressed left ventricular function. AB - Transcatheter aortic valve implantation (TAVI) is becoming a valuable alternative to surgical aortic valve replacement in non-operable and high-risk surgical patients. As the population of heart donors and recipients ages, the prevalence of degenerative valvular disease after transplantation will increase. The optimal treatment strategy of valvulopathies in these patients with extensive comorbidity is still unknown because of insufficient published experience. We present a heart transplant recipient with renal failure, systolic heart failure and severe aortic stenosis who was successfully treated with transapical TAVI. PMID- 23460598 TI - Type A aortic dissection complicated with fistulization into the right atrium and right-to-left shunt. AB - Fistulization between the aorta and the right atrium is a rare complication of ascending aortic dissection. Because of the typical haemodynamic unstability, the diagnosis is often made by bedside or intraoperative transoesophageal echocardiography. The treatment is surgical, but with very high mortality. We describe a case of type A aortic dissection complicated with shock and fistulization into the right atrium with the right-to-left shunt through a patent foramen ovale. Surgical repair was successful. PMID- 23460599 TI - Inspiratory and expiratory computed tomographic volumetry for lung volume reduction surgery. AB - Three-dimensional (3D) computed tomographic (CT) volumetry has been introduced into the field of thoracic surgery, and a combination of inspiratory and expiratory 3D-CT volumetry provides useful data on regional pulmonary function as well as the volume of individual lung lobes. We report herein a case of a 62-year old man with severe emphysema who had undergone lung volume reduction surgery (LVRS) to assess this technique as a tool for the evaluation of regional lung function and volume before and after LVRS. His postoperative pulmonary function was maintained in good condition despite a gradual slight decrease 2 years after LVRS. This trend was also confirmed by a combination of inspiratory and expiratory 3D-CT volumetry. We confirm that a combination of inspiratory and expiratory 3D-CT volumetry might be effective for the preoperative assessment of LVRS in order to determine the amount of lung tissue to be resected as well as for postoperative evaluation. This novel technique could, therefore, be used more widely to assess local lung function. PMID- 23460600 TI - Brachial artery aneurysm accompanying a homozygous methylenetetrahydrofolate reductase mutation. AB - Elevated plasma homocysteine (Hcy) is one of the suggested risk factors for endothelial dysfunction. There is evidence of association between raised plasma Hcy and an increased risk of developing peripheral arterial disease. A causal relationship, however, has not been established. In this report, a 37-year old male patient with the complaints of intermittent hand pain is presented. Brachial artery aneurysm accompanying a homozygous methylenetetrahydrofolate reductase mutation was detected. PMID- 23460601 TI - Strategic and operational aspects of a transfusion-free neonatal arterial switch operation. AB - Blood transfusion-free complex congenital cardiac surgery in a neonate remains a challenge for multidisciplinary cardiac teams. At our institution, a 3.5 kg neonate, born to a family of Jehovah's Witnesses and postnatally diagnosed with dextro-transposition of the great arteries (d-TGA) and a small muscular ventricular septal defect, underwent a successful arterial switch operation without blood or platelet transfusion. Key points that contributed to success were optimal preoperative haematopoetic conditioning using erythropoietin and iron, a miniaturized cardiopulmonary bypass circuit including a low prime volume oxygenator and crystalloid cardioplegia, and a well-coordinated multidisciplinary team. We report an overview of the literature regarding blood transfusion-free complex congenital cardiac surgery. PMID- 23460602 TI - Catalytic conversion of cellulose to ethylene glycol over a low-cost binary catalyst of Raney Ni and tungstic acid. AB - Following our previous report on the selective transformation of cellulose to ethylene glycol (EG) over a binary catalyst composed of tungstic acid and Ru/C, we herein report a new low-cost but more effective binary catalyst by using Raney nickel in place of Ru/C (Raney Ni+H(2 WO(4) ). In addition to tungstic acid, other W compounds were also investigated in combination with Raney Ni. The results showed that the EG yield depended on the W compound: H(4)SiW(12)O(40) =256 mg/L. The MICs of cefoxitin, teicoplanin, vancomycin, gentamicin, enrofloxacin and d cycloserine were unaltered in the uppP mutant relative to the wild-type, as were susceptibilities to other stress agents (glycine, lysozyme, NaCl, SDS, low and high pH, oxidative stress and ethanol). CONCLUSIONS: The results demonstrate that low-level bacitracin resistance in E. faecalis is mediated by a BacA-type UppP. PMID- 23460608 TI - Effects of anatomy and diet on gastrointestinal pH in rodents. AB - The pH of the gastrointestinal tract can have profound influences on digestive processes. Rodents exhibit wide variation in both stomach morphology and dietary strategies, both of which may influence gut pH. Various rodent species have evolved bilocular (or semi-segmented) stomachs that may allow for more microbial growth compared to unilocular (single-chambered) stomachs. Additionally, herbivory has evolved multiple times in rodents. The high dietary fiber typical of an herbivorous diet is known to induce secretion of bicarbonate in the gut. We predicted that stomach segmentation might facilitate the separation of contents in the proximal chamber from that of the gastric stomach, facilitating a chemical environment suitable to microbial growth. To investigate the effect of stomach anatomy and diet on gut pH, several species of rodent with varying stomach morphology were fed either a high or low-fiber diet for 7 days, and pH of the proximal stomach, gastric stomach, small intestine, and cecum were measured. We discovered that rodents with bilocular stomach anatomy maintained a larger pH gradient between the proximal and gastric stomach compartments, and were able to achieve a lower absolute gastric pH compared to those with unilocular stomachs. Dietary fiber increased the pH of the small intestine, but not in any other gut regions. The stomach pH data supports the century old hypothesis that bilocular stomach anatomy creates an environment in the proximal stomach that is suitable for microbial growth. Additionally, the alkaline small intestinal pH on a high fiber diet may enhance digestion. PMID- 23460610 TI - Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1-mediated neutrophil recruitment during the acute inflammatory response. AB - Recruitment of polymorphonuclear neutrophils (PMNs) to sites of acute inflammation critically depends on beta2 integrins (CD11/CD18). Recently, the mammalian actin-binding protein 1 (mAbp1) was identified as an important adaptor protein regulating PMN trafficking downstream of beta2 integrins. Here, we show that mAbp1 constitutively co-immunoprecipitated with hematopoietic progenitor kinase 1 (HPK1) in neutrophil-like differentiated HL-60 (dHL-60) cells. HPK1 was enriched at the lamellipodium of polarized dHL-60 cells, where it colocalized with mAbp1 and actin. Functional analysis of PMNs from HPK1-deficient mice showed that HPK1 was critical for CXCL1-induced lymphocyte function-associated antigen 1 (LFA-1)-mediated PMN adhesion to ICAM-1 under flow conditions. Accordingly, CXCL1 mediated induction of high-affinity LFA-1 required HPK1, but macrophage antigen 1 (Mac-1) affinity regulation was independent of HPK1. Intravital microscopy of the mouse cremaster muscle confirmed the defect of CXCL1-induced leukocyte adhesion in HPK1-deficient mice. Furthermore, beta2 integrin-mediated post-adhesion processes-adhesion strengthening, spreading, and directed mechanotactic crawling of PMNs under flow conditions-involved HPK1 in vitro and in vivo. Upon intrascrotal administration of tumor necrosis factor alpha (TNF-alpha), PMN adhesion and extravasation were severely compromised in HPK1-deficient mice. In summary, our results indicate that HPK1 is critically involved in LFA-1-mediated PMN trafficking during acute inflammation. PMID- 23460609 TI - Critical role for mouse marginal zone B cells in PF4/heparin antibody production. AB - Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of platelet factor 4 (PF4), heparin, and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. However, the B-cell origin of HIT antibody production is not known. Here, we show that anti-PF4/heparin antibodies are readily generated in wild-type mice on challenge with PF4/heparin complexes, and that antibody production is severely impaired in B-cell-specific Notch2-deficient mice that lack marginal zone (MZ) B cells. As expected, Notch2 deficient mice responded normally to challenge with T-cell-dependent antigen nitrophenyl-chicken gamma globulin but not to the T-cell-independent antigen trinitrophenyl-Ficoll. In addition, wild-type, but not Notch2-deficient, B cells plus B-cell-depleted wild-type splenocytes adoptively transferred into B-cell deficient MUMT mice responded to PF4/heparin complex challenge. PF4/heparin specific antibodies produced by wild-type mice were IgG2b and IgG3 isotypes. An in vitro class-switching assay showed that MZ B cells were capable of producing antibodies of IgG2b and IgG3 isotypes. Lastly, MZ, but not follicular, B cells adoptively transferred into B-cell-deficient MUMT mice responded to PF4/heparin complex challenge by producing PF4/heparin-specific antibodies of IgG2b and IgG3 isotypes. Taken together, these data demonstrate that MZ B cells are critical for PF4/heparin-specific antibody production. PMID- 23460611 TI - Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of newly diagnosed lymphomas and has an overall cure rate of approximately 60%. Previously, we observed FOXO1 mutations in non-Hodgkin lymphoma patient samples. To explore the effects of FOXO1 mutations, we assessed FOXO1 status in 279 DLBCL patient samples and 22 DLBCL-derived cell lines. FOXO1 mutations were found in 8.6% (24/279) of DLBCL cases: 92.3% (24/26) of mutations were in the first exon, 46.2% (12/26) were recurrent mutations affecting the N-terminal region, and another 38.5% (10/26) affected the Forkhead DNA binding domain. Recurrent mutations in the N terminal region resulted in diminished T24 phosphorylation, loss of interaction with 14-3-3, and nuclear retention. FOXO1 mutation was associated with decreased overall survival in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (P = .037), independent of cell of origin (COO) and the revised International Prognostic Index (R-IPI). This association was particularly evident (P = .003) in patients in the low-risk R-IPI categories. The independent relationship of mutations in FOXO1 to survival, transcending the prognostic influence of the R-IPI and COO, indicates that FOXO1 mutation is a novel prognostic factor that plays an important role in DLBCL pathogenesis. PMID- 23460612 TI - FcgammaRIII (CD16) equips immature 6-sulfo LacNAc-expressing dendritic cells (slanDCs) with a unique capacity to handle IgG-complexed antigens. AB - Binding and uptake of immune complexes (ICs) via low-affinity Fcgamma receptors (FcgammaRs) on dendritic cells (DCs) is well known as a booster of immune responses. It can be helpful when stimulating immunity against pathogenic microbes but may be harmful when antibodies form complexes with autologous antigens. To date, no human DC subtype specialized in handling ICs has been identified. By incubating human blood mononuclear cells with ICs and studying their cellular binding, we identified 6-sulfo LacNAc-expressing DCs (slanDCs) as having an outstanding capacity to bind ICs compared with other myeloid DCs, plasmacytoid DCs, or monocytes. Using selective blocking of different (FcgammaRs), we identified CD16 (FcgammaRIII) as the major IC-binding structure on slanDCs. In addition, CD16 proved critical for phagocytosis of IgG-coated erythrocytes, and CD16-targeted antigen led to a more efficient proliferation of CD4(+) T cells than CD32 (FcgammaRII)-targeted antigen. Interestingly, these CD16 mediated functions are short-lived and restricted to the immature stage of slanDCs in blood. We show that CD16 is rapidly shed from the surface of maturing slanDCs, resulting from the combined action of the metalloproteinases ADAM10 and ADAM17. In conclusion, these data provide strong evidence that slanDCs play an important role in IC-driven immune responses. PMID- 23460613 TI - Extracellular protein disulfide isomerase regulates ligand-binding activity of alphaMbeta2 integrin and neutrophil recruitment during vascular inflammation. AB - beta2 integrins play a crucial role during neutrophil recruitment into the site of vascular inflammation. However, it remains unknown how ligand-binding activity of the integrin is regulated. Using fluorescence intravital microscopy in mice generated by crossing protein disulfide isomerase (PDI) floxed mice with lysozyme Cre transgenic mice, we demonstrate that neutrophil PDI is required for neutrophil adhesion and crawling during tumor necrosis factor-alpha-induced vascular inflammation in vivo. Rescue experiments show that the isomerase activity of extracellular PDI is critical for its regulatory effect on neutrophil recruitment. Studies with blocking anti-PDI antibodies and alphaLbeta2 or alphaMbeta2 null mice suggest that extracellular PDI regulates alphaMbeta2 integrin-mediated adhesive function of neutrophils during vascular inflammation. Consistently, we show that neutrophil surface PDI is important for alphaMbeta2 integrin-mediated adhesion of human neutrophils under shear and static conditions and for binding of soluble fibrinogen to activated alphaMbeta2 integrin. Confocal microscopy and biochemical studies reveal that neutrophil surface PDI interacts with alphaMbeta2 integrin in lipid rafts of stimulated neutrophils and regulates alphaMbeta2 integrin clustering, presumably by changing the redox state of the integrin. Thus, our results provide the first evidence that extracellular PDI could be a novel therapeutic target for preventing and treating inappropriate neutrophil sequestration. PMID- 23460614 TI - Targeting B-cell anergy in chronic lymphocytic leukemia. AB - B-cell receptor (BCR) triggering and responsiveness have a crucial role in the survival and expansion of chronic lymphocytic leukemia (CLL) clones. Analysis of in vitro response of CLL cells to BCR triggering allowed the definition of 2 main subsets of patients and lack of signaling capacity was associated with constitutive activation of extracellular-regulated kinases 1/2 (ERK1/2) and nuclear factor of activated T cells c1 (NF-ATc1), consistent with the idea that at least one group of CLL patients derives from the abnormal expansion of anergic B cells. In the present work, we further investigated the anergic subset of CLL (defined as the one with constitutive ERK1/2 phosphorylation) and found that it is characterized by low levels of surface immunoglobulin M and impairment of calcium mobilization after BCR engagement in vitro. Chronic BCR triggering promoted CLL cell survival selectively in phosphorylated ERK1/2 samples and the use of mitogen-activated protein kinase and NF-AT signaling inhibitors specifically induced apoptosis in this group of patients. Apoptosis induction was preceded by an initial phase of anergy reversal consisting in the loss of ERK phosphorylation and NF-AT nuclear translocation and by the restoration of BCR responsiveness, reinforcing the idea that the anergic program favors the survival of leukemic lymphocytes. PMID- 23460616 TI - What is the NIH toolbox, and what will it mean to neurology? PMID- 23460617 TI - Cassava food toxins, konzo disease, and neurodegeneration in sub-Sahara Africans. PMID- 23460618 TI - The history of cerebral PET scanning: from physiology to cutting-edge technology. AB - OBJECTIVE: To review the discoveries underpinning the introduction of cerebral PET scanning and highlight its modern applications. BACKGROUND: Important discoveries in neurophysiology, brain metabolism, and radiotracer development in the post-World War II period provided the necessary infrastructure for the first cerebral PET scan. METHODS: A complete review of the literature was undertaken to search for primary and secondary sources on the history of PET imaging. Searches were performed in PubMed, Google Scholar, and select individual journal Web sites. Written autobiographies were obtained through the Society for Neuroscience Web site at www.sfn.org. A reference book on the history of radiology, Naked to the Bone, was reviewed to corroborate facts and to locate references. The references listed in all the articles and books obtained were reviewed. RESULTS: The neurophysiologic sciences required to build cerebral PET imaging date back to 1878. The last 60 years have produced an evolution of technological advancements in brain metabolism and radiotracer development. These advancements facilitated the development of modern cerebral PET imaging. Several key scientists were involved in critical discoveries and among them were Angelo Mosso, Charles Roy, Charles Sherrington, John Fulton, Seymour Kety, Louis Sokoloff, David E. Kuhl, Gordon L. Brownell, Michael Ter-Pogossian, Michael Phelps, and Edward Hoffman. CONCLUSIONS: Neurophysiology, metabolism, and radiotracer development in the postwar era synergized the development of the technology necessary for cerebral PET scanning. Continued use of PET in clinical trials and current developments in PET-CT/MRI hybrids has led to advancement in diagnosis, management, and treatment of neurologic disorders. PMID- 23460620 TI - MR spectroscopy in pediatric Wernicke encephalopathy. PMID- 23460621 TI - Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the Guideline Development Subcommittee of the American Academy of Neurology. PMID- 23460622 TI - Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis. PMID- 23460623 TI - Clinical Reasoning: a 57-year-old man with jaw spasms. PMID- 23460624 TI - Teaching Video NeuroImages: sodium channel myotonia can present with stridor. PMID- 23460625 TI - Teaching NeuroImages: PET-CT hypermetabolism paralleling muscle hyperactivity in stiff-person syndrome. PMID- 23460626 TI - Education Research: can my electronic health record teach me something?: A multi institutional pilot study. PMID- 23460627 TI - Looking to Australia for help on health care. PMID- 23460628 TI - Physicians should be cautious when prescribing diclofenac. PMID- 23460629 TI - Distribution plan for kidney donations stirs ethical debate in United States. PMID- 23460630 TI - Association between use of contraband tobacco and smoking cessation outcomes: a population-based cohort study. AB - BACKGROUND: High tobacco prices, typically achieved through taxation, are an evidence-based strategy to reduce tobacco use. However, the presence of inexpensive contraband tobacco could undermine this effective intervention by providing an accessible alternative to quitting. We assessed whether the use of contraband tobacco negatively affects smoking cessation outcomes. METHODS: We evaluated data from 2786 people who smoked, aged 18 years or older, who participated in the population-based longitudinal Ontario Tobacco Survey. We analyzed associations between use of contraband tobacco and smoking cessation outcomes (attempting to quit, 30-d cessation and long-term cessation at 1 yr follow-up). RESULTS: Compared with people who smoked premium or discount cigarettes, people who reported usually smoking contraband cigarettes at baseline were heavier smokers, perceived greater addiction, identified more barriers to quitting and were more likely to have used pharmacotherapy for smoking cessation. People who smoked contraband cigarettes were less likely to report a period of 30 day cessation during the subsequent 6 months (adjusted relative risk [RR] 0.23, 95% confidence interval [CI] 0.09-0.61) and 1 year (adjusted RR 0.30, 95% CI 0.14 0.61), but they did not differ significantly from other people who smoked regarding attempts to quit (at 6 mo, adjusted RR 0.74, 95% CI 0.43-1.20) or long term cessation (adjusted RR 0.24, 95% CI 0.04-1.34). INTERPRETATION: Smoking contraband cigarettes was negatively associated with short-term smoking cessation. Access to contraband tobacco may therefore undermine public health efforts to reduce the use of tobacco at the population level. PMID- 23460631 TI - How can Canadian guideline recommendations be tested? PMID- 23460632 TI - Prison health care inequality. PMID- 23460633 TI - Hospitalizations from car collisions twice as likely during evening. PMID- 23460635 TI - Contraception in women over 40 years of age. PMID- 23460636 TI - Use of biologics in a patient with rheumatoid arthritis refractory to methotrexate. PMID- 23460637 TI - Enophthalmos as a sign of metastatic breast carcinoma. PMID- 23460638 TI - Advances in the treatment of late stage melanoma. PMID- 23460639 TI - Impaired intestinal calcium absorption in protein 4.1R-deficient mice due to altered expression of plasma membrane calcium ATPase 1b (PMCA1b). AB - Protein 4.1R was first identified in the erythrocyte membrane skeleton. It is now known that the protein is expressed in a variety of epithelial cell lines and in the epithelia of many tissues, including the small intestine. However, the physiological function of 4.1R in the epithelial cells of the small intestine has not so far been explored. Here, we show that 4.1R knock-out mice exhibited a significantly impaired small intestinal calcium absorption that resulted in secondary hyperparathyroidism as evidenced by increased serum 1,25-(OH)2-vitamin D3 and parathyroid hormone levels, decreased serum calcium levels, hyperplasia of the parathyroid, and demineralization of the bones. 4.1R is located on the basolateral membrane of enterocytes, where it co-localizes with PMCA1b (plasma membrane calcium ATPase 1b). Expression of PMCA1b in enterocytes was decreased in 4.1(-/-) mice. 4.1R directly associated with PMCA1b, and the association involved the membrane-binding domain of 4.1R and the second intracellular loop and C terminus of PMCA1b. Our findings have enabled us to define a functional role for 4.1R in small intestinal calcium absorption through regulation of membrane expression of PMCA1b. PMID- 23460640 TI - Oligomeric structure and functional characterization of Caenorhabditis elegans Innexin-6 gap junction protein. AB - Innexin is the molecular component of invertebrate gap junctions. Here we successfully expressed and purified Caenorhabditis elegans innexin-6 (INX-6) gap junction channels and characterized the molecular dimensions and channel permeability using electron microscopy (EM) and microinjection of fluorescent dye tracers, respectively. Negative staining and thin-section EM of isolated INX-6 gap junction membranes revealed a loosely packed hexagonal lattice and a greater cross-sectional width than that of connexin26 and connexin43 (Cx43)-GFP. In gel filtration analysis, the elution profile of purified INX-6 channels in dodecyl maltoside solution exhibited a peak at ~400 kDa that was shifted to ~800 kDa in octyl glucose neopentyl glycol. We also obtained the class averages of purified INX-6 channels from these peak fractions by single particle analysis. The class average from the ~800-kDa fraction showed features of the junction form with a longitudinal height of 220 A, a channel diameter of 110 A in the absence of detergent micelles, and an extracellular gap space of 60 A, whereas the class averages from the ~400-kDa fraction showed diameters of up to 140 A in the presence of detergent micelles. These findings indicate that the purified INX-6 channels are predominantly hemichannels in dodecyl maltoside and docked junction channels in octyl glucose neopentyl glycol. Dye transfer experiments revealed that the INX-6-GFP-His channels are permeable to 3- and 10-kDa tracers, whereas no significant amounts of these tracers passed through the Cx43-GFP channels. Based on these findings, INX-6 channels have a larger overall structure and greater permeability than connexin channels. PMID- 23460641 TI - Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development. AB - Cleft palate represents one of the most common congenital birth defects in humans. TGFbeta signaling, which is mediated by Smad-dependent and Smad independent pathways, plays a crucial role in regulating craniofacial development and patterning, particularly in palate development. However, it remains largely unknown whether the Smad-independent pathway contributes to TGFbeta signaling function during palatogenesis. In this study, we investigated the function of TGFbeta activated kinase 1 (Tak1), a key regulator of Smad-independent TGFbeta signaling in palate development. We show that Tak1 protein is expressed in both the epithelium and mesenchyme of the developing palatal shelves. Whereas deletion of Tak1 in the palatal epithelium or mesenchyme did not give rise to a cleft palate defect, inactivation of Tak1 in the neural crest lineage using the Wnt1 Cre transgenic allele resulted in failed palate elevation and subsequently the cleft palate formation. The failure in palate elevation in Wnt1-Cre;Tak1(F/F) mice results from a malformed tongue and micrognathia, resembling human Pierre Robin sequence cleft of the secondary palate. We found that the abnormal tongue development is associated with Fgf10 overexpression in the neural crest-derived tongue tissue. The failed palate elevation and cleft palate were recapitulated in an Fgf10-overexpressing mouse model. The repressive effect of the Tak1-mediated noncanonical TGFbeta signaling on Fgf10 expression was further confirmed by inhibition of p38, a downstream kinase of Tak1, in the primary cell culture of developing tongue. Tak1 thus functions to regulate tongue development by controlling Fgf10 expression and could represent a candidate gene for mutation in human PRS clefting. PMID- 23460642 TI - In vitro activity of Neisseria meningitidis PglL O-oligosaccharyltransferase with diverse synthetic lipid donors and a UDP-activated sugar. AB - Oligosaccharyltransferases (OTases) are enzymes that catalyze the transfer of an oligosaccharide from a lipid carrier to an acceptor molecule, commonly a protein. OTases are classified as N-OTases and O-OTases, depending on the nature of the glycosylation reaction. The N-OTases catalyze the glycan transfer to amide groups in asparagines in a reaction named N-linked glycosylation. The O-OTases are responsible for protein O-linked glycosylation, which involves the attachment of glycans to hydroxyl groups of serine or threonine residues. These enzymes exhibit a relaxed specificity and are able to transfer a variety of glycan structures to different protein acceptors. This property confers OTases with great biotechnological potential as these enzymes can produce glycoconjugates relevant to the pharmaceutical industry. Furthermore, OTases are thought to be involved in pathogenesis mechanisms. Several aspects of the functionality of OTases are not fully understood. In this work, we developed a novel approach to perform kinetic studies on PglL, the O-OTase from Neisseria meningitidis. We investigated the importance of the acyl moiety of the lipid glycan donor substrate on the functionality of PglL by testing the efficiency of glycosylation reactions using synthetic substrates carrying the same glycan structure but different acyl moieties. We found that PglL can function with many lipids as glycan donors, although the length and the conformation of the lipid moiety significantly influenced the catalytic efficiency. Interestingly, PglL was also able to transfer a monosaccharide employing its nucleotide-activated form, acting as a Leloir glycosyltransferase. These results provide new insights on the function and the evolution of oligosaccharyltransferases. PMID- 23460643 TI - Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) affects a large proportion of the American population. The spectrum of disease ranges from bland steatosis without inflammation to nonalcoholic steatohepatitis and cirrhosis. Bile acids are critical regulators of hepatic lipid and glucose metabolism and signal through two major receptor pathways: farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, and TGR5, a G protein-coupled bile acid receptor (GPBAR1). Both FXR and TGR5 demonstrate pleiotropic functions, including immune modulation. To evaluate the effects of these pathways in NAFLD, we treated obese db/db mice with a dual FXR/TGR5 agonist (INT-767) for 6 weeks. Treatment with the agonist significantly improved the histological features of nonalcoholic steatohepatitis. Furthermore, treatment increased the proportion of intrahepatic monocytes with the anti-inflammatory Ly6C(low) phenotype and increased intrahepatic expression of genes expressed by alternatively activated macrophages, including CD206, Retnla, and Clec7a. In vitro treatment of monocytes with INT-767 led to decreased Ly6C expression and increased IL-10 production through a cAMP-dependent pathway. Our data indicate that FXR/TGR5 activation coordinates the immune phenotype of monocytes and macrophages, both in vitro and in vivo, identifying potential targeting strategies for treatment of NAFLD. PMID- 23460644 TI - Decorin potentiates interferon-gamma activity in a model of allergic inflammation. AB - The proteoglycan decorin modulates leukocyte recruitment during delayed-type hypersensitivity responses. Decorin-deficient (Dcn(-/-)) mice show reduced edema formation during the first 24 h with a concurrent attenuated recruitment of CD8(+) leukocytes in the inflamed Dcn(-/-) ears. The aim of this study was to elucidate the molecular pathways affected by the loss of decorin. In vivo, reduced numbers of CD8(+) cells in Dcn(-/-) ears correlated with a reduced interferon-gamma (Ifn-gamma) and CXCL-10 expression. In vitro, Dcn(-/-) lymphocytes displayed an increased adhesion to brain microvascular (bEnd.3) endothelial cells. Decorin treatment of bEnd.3 increased Icam1 and down-regulated Vcam1 expression after TNF-alpha stimulation. However, Dcn(-/-) and wild-type lymphocytes produced IFN-gamma after activation with CD3epsilon. Upon incubation with decorin, endothelial cells and fibroblasts responded differently to IFN gamma and TNF-alpha; CCL2 in bEnd.3 cells was more prominently up-regulated by TNF-alpha compared with IFN-gamma. Notably, both factors were more potent in the presence of decorin. Compared with TNF-alpha, IFN-gamma treatment induced significantly more CXCL-10, and both factors increased synthesis of CXCL-10 in the presence of decorin. The response to IFN-gamma was similar in Dcn(-/-) and wild-type fibroblasts, an additional source of CXCL-10. However, addition of decorin yielded significantly more CXCL-10. Notably, decorin increased the stability of IFN-gamma in vitro and potentiated IFN-gamma-induced activation of STAT-1. Furthermore, only dermatan sulfate influenced IFN-gamma signaling by significantly increasing CXCL-10 expression in contrast to decorin protein core alone. Our data demonstrate that decorin modulates delayed-type hypersensitivity responses by augmenting the induction of downstream effector cytokines of IFN gamma and TNF-alpha, thereby influencing the recruitment of CD8(+) lymphocytes into the inflamed tissue. PMID- 23460645 TI - Identification of binding sites for myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 in MyD88 adapter-like (Mal). AB - Upon activation, Toll-like receptor 4 (TLR4) binds adapter proteins, including MyD88 (myeloid differentiation primary response gene 88) and Mal (MyD88 adapter like) for its signal transduction. TLR4 and the adapter proteins each contain a Toll/Il-1 receptor domain (TIR domain). In this study we used random mutagenesis and the mammalian two-hybrid method MAPPIT (mammalian protein-protein interaction trap) to identify mutations in Mal that disrupt its interaction with TLR4 and/or MyD88. Our study shows that four potential binding sites and the AB-loop in the Mal TIR domain all contribute to formation of the TLR4-Mal-MyD88 complex. Mutations in the symmetrical back-to-back Mal homodimer interface affect Mal homodimerization and interaction with MyD88 and TLR4. Our data suggest that Mal dimerization may lead to formation of potential binding platforms on the top and the side of the Mal dimer that bind MyD88 or TLR4. Mutations that affect the interaction of Mal with MyD88 also affect NF-kappaB activation induced by Mal overexpression. In MAPPIT, co-expression of the MyD88 TIR domain enhances Mal dimerization and Mal binding to TLR4. Similarly, co-expression of Mal and the MyD88 TIR domain strongly promotes dimerization of the TLR4 intracellular domain in MAPPIT. The different types of TIR-TIR interactions in the TLR4-Mal-MyD88 complex thus show cooperative binding in MAPPIT. We present plausible models for the TIR-TIR interactions in the TLR4-Mal-MyD88 complex. PMID- 23460646 TI - Recurrent pneumococcal meningitis in a child with congenital common cavity malformation of the inner ear. PMID- 23460647 TI - Eating disorder training and attitudes among primary care residents. AB - BACKGROUND: The ability to diagnose eating disorders (ED) is important and difficult for primary care physicians (PCPs). Previous reports suggest that PCPs feel their training is inadequate. OBJECTIVE: To explore residents' interest and comfort diagnosing and treating ED. METHODS: An internet survey was sent to primary care residencies. Logistic regression models were fitted to identify factors correlated with residents' interest and comfort in diagnosing and treating ED. RESULTS: Family Medicine and Internal Medicine residents had higher interest in ED than Pediatric residents, as did female residents and residents exposed to teenagers with unexplained weight loss. Residents in programs with an ED program and faculty interested in ED were more comfortable diagnosing ED. CONCLUSIONS: Interest in, and comfort diagnosing and treating ED are associated with specialty type, presence of an ED program, presence of faculty interested in ED, and resident exposure to ED outpatients and teenagers with unexplained weight loss. PMID- 23460648 TI - Infant with obstructive sleep apnea successfully treated with continuous positive airway pressure. PMID- 23460649 TI - Office-related antibiotic prescribing for Medicaid-enrolled children. AB - BACKGROUND: Prudent antibiotic prescribing practices are essential to limiting antibiotic resistance. OBJECTIVE: To assess the trend in percentage of office visits for acute respiratory infections (ARIs) linked with an antibiotic prescription. METHODS: Retrospective analysis of Montana Medicaid billing claims data for each year, 1999 to 2010, was done. Participants included continuously enrolled children aged <=14 years. Primary outcomes were ARI-related office visits and filled antibiotic prescriptions within 10 days of the office visit. RESULTS: Of the 873 244 office visits identified, 116 962 (13%) had an ARI as the primary diagnosis. Among ARI-related office visits, 64 250 (55%) were linked with an antibiotic prescription. From 1999 to 2010, the odds of ARI-related visits being linked with an antibiotic prescription did not change (odds ratio = 1.00; 95% confidence interval = 0.995-1.002). CONCLUSIONS: The percentage of ARI related visits linked with an antibiotic prescription did not decrease from 1999 to 2010. Further efforts are needed to reduce antibiotic treatment for ARIs. PMID- 23460650 TI - Complications in the subacute phase of invasive Streptococcus pyogenes infections in pediatrics: two case reports and review of the literature. PMID- 23460651 TI - Are components of the medical home differentially associated with child health care utilization, health, and health promoting behavior outcomes? AB - OBJECTIVE: To determine if specific components of the medical home are differentially associated with beneficial child outcomes. METHODS: Logistic regression was used to model each component (family-centeredness, comprehensive care, and care coordination) with health care utilization, child health, and health promoting behaviors in 81 232 subjects from the 2003 National Survey of Children's Health. RESULTS: Family-centeredness was associated with increased odds of children being read to (adjusted odds ratio [aOR] = 2.16). Comprehensive care was associated with decreased outpatient (aOR = 0.70) and emergency department (aOR = 0.79) sick visits and with increased child health per parental assessment (aOR = 1.50). Care coordination was associated with increased preventive care visits (aOR = 1.41) and increased outpatient (aOR = 1.21) and emergency department (aOR = 1.24) sick visits. Stratification by special health care needs demonstrated similar findings. CONCLUSIONS: Comprehensive care was associated with improved child health and health care utilization. Prospective studies are needed to further investigate the differential impact of components of the medical home on child health. PMID- 23460652 TI - Size matters: the importance of residency program size to pass rates on the american board of pediatrics certifying examination. PMID- 23460653 TI - Primary care practitioners' detection of youth violence involvement. AB - BACKGROUND: Youth violence is a widespread public health problem. Despite recommendations to address youth violence by the American Academy of Pediatrics, it is unclear how often primary care practitioners (PCPs) do so. PURPOSE: To determine PCPs' documentation of violence involvement. METHODS: Children 11 to 17 years old were enrolled while attending a clinic. They completed questionnaires assessing violence involvement confidentially without the knowledge of the PCP. The primary outcome, documented reference to violence involvement, was determined by chart review. RESULTS: A total of 165 youth participated: mean age = 14.5 years (standard deviation = 1.7), 43% male, 46% white. In all, 14.5% of charts documented any violence involvement. Of the 20% of youth who reported serious violence involvement, PCPs documented violence issues 19.4% of the time. Factors associated with documentation included nonwhite race (P < .05), having public (or no) insurance (P < .001), visit type (routine checkup (P < .05), and clinic site (P < .001). CONCLUSION: PCPs infrequently document discussion of violence-related issues, specifically in youth who are demonstrating risk. PMID- 23460654 TI - Evaluation of oral medication delivery devices provided by community pharmacies. AB - Oral liquids remain common medication dosage forms used for patients who have difficulty swallowing. However, liquids require a delivery device and thus have been linked to medication administration errors. This study identified medication delivery devices available at pharmacies. Delivery devices were obtained from area pharmacies and analyzed for units of measurement, abbreviations, and largest/smallest measurable volume. A total of 58 devices were collected from 22 pharmacies. All devices were marked with mL, and 79% were additionally marked in teaspoons. The 5-mL syringe was the only device dispensed at 14% of locations. Other devices included the dosing spoon, dropper, and cup. The largest measurable volume was 30 mL, whereas the smallest was 0.01 mL, with significant variability among devices. A more consistent approach in prescribing units of measurement is needed. Prescribing in milliliters is an optimal choice because of the accessibility of measuring devices containing this measurement. PMID- 23460655 TI - Periumbilical erythema in a neonate. PMID- 23460656 TI - A randomized clinical trial of the efficacy of extended smoking cessation treatment for adolescent smokers. AB - INTRODUCTION: Relatively few well-designed smoking cessation studies have been conducted with teen smokers. This study examined the efficacy of extended cognitive-behavioral treatment in promoting longer term smoking cessation among adolescents. METHODS: Open-label smoking cessation treatment consisted of 10 weeks of school-based, cognitive-behavioral group counseling along with 9 weeks of nicotine replacement (nicotine patch). A total of 141 adolescent smokers in continuation high schools in the San Francisco Bay Area were randomized to either 9 additional group sessions over a 14-week period (extended group) or 4 monthly smoking status calls (nonextended group). Intention-to-treat logistic regression analysis was used to assess the primary outcome of biologically confirmed (carbon monoxide < 9 ppm) point prevalence abstinence at Week 26 (6-month follow-up from baseline). RESULTS: At Week 26 follow-up, the extended treatment group had a significantly higher abstinence rate (21%) than the nonextended treatment (7%; OR = 4.24, 95% CI: 1.20-15.02). Females also were more likely to be abstinent at the follow-up than males (OR = 4.15, 95% CI: 1.17-14.71). CONCLUSIONS: The significantly higher abstinence rate at follow-up for the extended treatment group provides strong support for continued development of longer term interventions for adolescent smoking cessation. PMID- 23460657 TI - Wipe sampling for nicotine as a marker of thirdhand tobacco smoke contamination on surfaces in homes, cars, and hotels. AB - INTRODUCTION: Secondhand smoke contains a mixture of pollutants that can persist in air, dust, and on surfaces for months or longer. This persistent residue is known as thirdhand smoke (THS). Here, we detail a simple method of wipe sampling for nicotine as a marker of accumulated THS on surfaces. METHODS: We analyzed findings from 5 real-world studies to investigate the performance of wipe sampling for nicotine on surfaces in homes, cars, and hotels in relation to smoking behavior and smoking restrictions. RESULTS: The intraclass correlation coefficient for side-by-side samples was 0.91 (95% CI: 0.87-0.94). Wipe sampling for nicotine reliably distinguished between private homes, private cars, rental cars, and hotels with and without smoking bans and was significantly positively correlated with other measures of tobacco smoke contamination such as air and dust nicotine. The sensitivity and specificity of possible threshold values (0.1, 1, and 10 MUg/m(2)) were evaluated for distinguishing between nonsmoking and smoking environments. Sensitivity was highest at a threshold of 0.1 MUg/m(2), with 74%-100% of smoker environments showing nicotine levels above threshold. Specificity was highest at a threshold of 10 MUg/m(2), with 81%-100% of nonsmoker environments showing nicotine levels below threshold. The optimal threshold will depend on the desired balance of sensitivity and specificity and on the types of smoking and nonsmoking environments. CONCLUSIONS: Surface wipe sampling for nicotine is a reliable, valid, and relatively simple collection method to quantify THS contamination on surfaces across a wide range of field settings and to distinguish between nonsmoking and smoking environments. PMID- 23460658 TI - Sense of coherence, rather than exercise capacity, is the stronger predictor to obtain health-related quality of life in adults with congenital heart disease. AB - OBJECTIVE: Irrespective of their cardiovascular findings, quality of life in patients with congenital heart disease (CHD) is good or even superior to that in healthy controls. The sense of coherence (SOC), a psychological resource that focuses on factors that support human health and well-being, was suggested to act as a potential pathway for maintaining and improving quality of life independently from the disease status. PATIENTS AND METHODS: From April 2010 to May 2011, we consecutively included 546 young adults (236 female, median age 26.9 years, aged from 16 to 71 years) with various CHD into the study. Patients completed the SOC-13 questionnaire and the health-related quality of life questionnaire SF-36. Afterwards they performed a cardiopulmonary exercise test. RESULTS: In adults with CHD, SOC was slightly enhanced compared with reference values (CHD: median 74.0 [IQR: 63.8;81.0] vs. reference value: 69.7 [68.5;69.7]; p < 0.001) corresponding to 106.1% [91.8;116.7%] of predicted reference value. SOC was not associated with the underlying heart defect (Kruskal-Wallis test, p = 0.565) or heart defect severity (Spearman r = 0.044; p = 0.301). It was moderately related to all dimensions of quality of life (r = 0.260 to r = 0.686; p < 0.001) except to health transition. It was only poorly associated with exercise capacity (r = 0.098; p = 0.023) and age (r = -0.097; p = 0.023). CONCLUSIONS: Adults with CHD have an enhanced SOC. SOC is moderately correlated with quality of life, and seems to be a stronger predictor of health-related life quality than exercise capacity. SOC might explain the rather good quality of life in patients with CHD despite their reduction in exercise capacity. PMID- 23460659 TI - Association of a reduction in low-density lipoprotein cholesterol with incident cardiovascular and cerebrovascular events among people with type 2 diabetes mellitus. AB - BACKGROUND: Although there is overwhelming evidence that reducing low-density lipoprotein cholesterol (LDL-C) with statins leads to reductions in cardiovascular disease, less is known about the effects in persons with type 2 diabetes mellitus (T2DM) without pre-existing vascular events. METHODS AND RESULTS: Using the UK-based General Practice Research Database we conducted a retrospective cohort study of 21,998 T2DM patients aged 35-69 with >=2 prescriptions for lipid-modifying therapy (2000-2009). We categorized LDL-C change (mmol/l) between last available and baseline lipid values as reduction (>=3.0, 2.0-2.9, 1.0-1.9, 0.3-0.9), no-change (+/-0.2 of baseline), or increase (>0.2). Outcomes were incident composite cardiovascular (n = 621) and cerebrovascular events (n = 274). We estimated hazard ratios (HRs) of study outcomes and 95% confidence intervals (CIs) for LDL-C change compared with the no change group. Compared to no changes, adjusted HRs of cardiovascular events for a reduction >=3.0 and a reduction between 2.0-2.9 were 0.41 (95% CI: 0.23-0.71) and 0.51 (95% CI: 0.34-0.76) (p for linear trend <0.001). LDL-C reduction yielded a decreased cerebrovascular event risk compared to no change, even with the smallest reduction (adjusted HR = 0.59, 95% CI: 0.36-0.98). CONCLUSIONS: Decreasing LDL-C is associated with a reduced risk of cardiovascular and cerebrovascular events among T2DM patients without such pre-existing events. The magnitude of the protective effect on cerebrovascular events is less certain, and further studies are warranted. PMID- 23460660 TI - US hospitals are reducing early elective deliveries. PMID- 23460661 TI - Northern Ireland minister promises guidance on abortion. PMID- 23460662 TI - New Zealand moves towards plain packaging of cigarettes. PMID- 23460663 TI - Increase to India's health budget is not enough, say doctors. PMID- 23460664 TI - Trust took 10 years to deal with consultant whose competence was in question, report says. PMID- 23460665 TI - Judge was wrong to insist doctors should give "burdensome" treatment to minimally conscious patient, court rules. PMID- 23460666 TI - Doctor who treated torture victims in Iraq is suspended for 12 months. PMID- 23460667 TI - Side population in human glioblastoma is non-tumorigenic and characterizes brain endothelial cells. AB - The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the 'side population' phenotype based on efflux properties of ATP binding cassette transporters in freshly isolated human glioblastoma samples and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of endothelial cells are likely to compromise drug availability, transiently targeting ATP-binding cassette transporters may be a valuable therapeutic strategy to improve treatment effects in brain tumours. PMID- 23460668 TI - Relationship between lower extremity alignment and hallux valgus in women. AB - BACKGROUND: Most previous studies on hallux valgus focused on the possible relationship between this deformity and muscles and/or ligaments in the foot and lower leg. Very little is known about the relationship between hallux valgus and alignment of the proximal joints. The aims of the present study were to determine the extent to which lower extremity alignment characteristics of the hip, knee, ankle, and foot were related to the manifestation of hallux valgus and to identify variables predicting its development in women. METHODS: A group of 25 women with hallux valgus and 24 control women, age 51 to 80 years, were interviewed and screened for the current study. Measurements recorded were hallux valgus angle; intermetatarsal angle; a set of body physique measures (eg, height); range of motion at the hip, knee, ankle, and foot joints; general hypermobility; lower extremity alignment (eg, tibiofemoral angle); and 9 anatomical anomalies (eg, knee valgus/varum). RESULTS: Women with hallux valgus manifested notably higher range of motion at their joints, different lower extremity alignment, higher prevalence of general joint hypermobility, and higher prevalence of anatomical anomalies compared with controls. Estimated marginal means for most joint range of motion and lower extremity alignment measurements were notably higher for the hallux valgus group. CONCLUSION: Lower extremity alignment and joint range of motion were correlated with hallux valgus. Future studies could possibly identify anatomic risk factors for the development of hallux valgus, nonsurgical methods of prevention and adjunctive surgical methods of treatment. LEVEL OF EVIDENCE: Level III, comparative case series. PMID- 23460669 TI - Minimally invasive technique versus an extensile lateral approach for intra articular calcaneal fractures. AB - BACKGROUND: The optimal method for treating intra-articular fractures of the calcaneus remains controversial. Extensile approaches allow excellent fracture exposure, but high rates of wound complications are seen. Newer minimally invasive techniques for calcaneus fracture fixation offer a potentially lower wound complication rate, but long-term clinical results are not available. The aim of this study was to compare the outcomes of intra-articular calcaneus fractures treated with open reduction and internal fixation via an extensile approach versus those with a minimally invasive sinus tarsi approach. METHODS: We performed a retrospective review of all intra-articular calcaneal fractures treated operatively between October 2005 and December 2008. A total of 112 fractures were found that met our inclusion criteria; 79 were treated with an extensile lateral approach and 33 via a minimally invasive approach based on surgeon preference. Chart and radiographic results were thoroughly reviewed on all 112 fractures, specifically for wound healing complications and the need for further surgeries within the study period. Additionally, all patients were contacted and asked to return for a research visit that included radiography, clinical examination, and quality of life questionnaires (Short Form 36 [SF-36], foot function index [FFI], visual analog scale [VAS] pain). A total of 47 of 112 (42%) patients returned for a research visit (31 extensile, 16 minimally invasive). RESULTS: The 2 groups were comparable with regard to demographics (age, follow-up, male to female ratio, tobacco use, diabetes, workers' compensation status). In the extensile group, 53% of fractures were Sanders II and 47% were Sanders III, whereas in the minimally invasive group 61% were Sanders II and 39% were Sanders III. The overall wound complication rate was 29% in the extensile group (9% required operative intervention) versus 6% in the minimally invasive group (P = .005) (none required operative intervention). Overall, 20% of the extensile group required a secondary surgery within the study period versus 2% in the minimally invasive group (P = .007). In the group of patients who returned for research visits, the average FFI total score was 31 in the extensile group versus 22 in the minimally invasive group (P = .21). The average VAS pain score with activity was 36 in the extensile group versus 31 in the minimally invasive group (P = .48). Overall, 84% of patients in the extensile group were satisfied with their result versus 94% in the minimally invasive group (P = .32). Both groups had 100% union rates, and no differences were noted in the final postoperative Bohler's angle and angle of Gissane. CONCLUSION: Clinical results were similar between calcaneal fractures treated with an extensile approach and those treated with a minimally invasive approach. However, the minimally invasive approach had a significantly lower incidence of wound complications and secondary surgeries. The minimally invasive approach was a valuable method for the treatment of intra-articular calcaneal fractures, with low complication rates and results comparable to those treated with an extensile approach. LEVEL OF EVIDENCE: Level III, retrospective comparative case series. PMID- 23460670 TI - Reconstruction of calcaneal fracture malunion with osteotomy and subtalar joint salvage: technique and outcomes. AB - BACKGROUND: The goal of this study was to discuss the outcomes of treating calcaneal fracture malunion by restoring the subtalar joint with a reconstructive osteotomy. METHODS: From May 2005 to November 2008, 24 patients (26 feet) with calcaneal malunions after a displaced intra-articular calcaneal fracture were treated by osteotomy and autogenous bone graft. The subtalar joint was preserved. The mean time from initial injury to reconstructive operation was 5.7 months (95% confidence interval, 4.5-8.8 months). The displaced posterior facet was restored through a reconstructive osteotomy, whereas the bone defect in the calcaneus after reduction was filled with the exostosis that had been removed; iliac bone graft was used if necessary. All patients were evaluated clinically and radiographically at a minimum of 24 months. Twenty patients (21 feet) were followed for a mean of 34.2 months (29.0-39.4 months). RESULTS: According to American Orthopaedic Foot & Ankle Society (AOFAS) ankle and hindfoot score, the average score was 85.9 points (95% confidence interval, 81.5-90.4 points), which was significantly higher than the preoperative assessment. Radiographs showed that Bohler's angle, Gissane's angle, talus declination angle, and width and height of calcaneus were improved to a great extent. Six patients had wound edge necrosis, and 2 had superficial infection. One patient required a subtalar fusion for subtalar arthritis at 2 years after surgery. CONCLUSIONS: Restoring the subtalar joint with a reconstructive osteotomy and autogenous bone graft was an effective treatment method for selected calcaneal fracture malunions. It reconstructed calcaneal morphology and preserved the subtalar joint. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23460671 TI - Attitudes toward HPV vaccination among rural American Indian women and urban White women in the northern plains. AB - BACKGROUND: American Indian women in the Northern Plains have a high incidence of cervical cancer. We assessed attitudes on vaccination against human papillomavirus (HPV) in this population. METHOD: In partnership with two tribal communities, from 2007 to 2009, we surveyed women 18 to 65 years old attending two reservation clinics (n = 118 and n = 76) and an urban clinic in the same region serving primarily White women (n = 158) on HPV knowledge, vaccine familiarity, and willingness to vaccinate children against HPV. We used chi square tests and binary logistic regression to compare groups and identify correlates of willingness to vaccinate. RESULTS: American Indian women were less knowledgeable about HPV than White women (p < .001), especially its role in cervical cancer. Willingness to vaccinate children was differentially distributed across the three clinic samples (p < .001), but this association did not persist after adjusting for demographics and HPV knowledge. Among all samples, more correct answers to HPV knowledge questions was the only factor positively correlated with willingness to vaccinate (odds ratios = 1.2-1.5; p < .00-.05). CONCLUSIONS: These findings underscore the importance of locally relevant educational interventions to increase HPV vaccination rates among American Indian women. PMID- 23460672 TI - An organizational capacity-building program to enhance adolescent sexual and reproductive health. AB - OBJECTIVES: To present a new practice for promoting sexual health among youth, and a pilot evaluation. The Afterschool Health and Sexuality Education Project is a capacity-building program that provides staff training, technical assistance, resource materials, and policy recommendations to create organizational change that facilitates staff members' abilities to promote sexual and reproductive health for adolescents. METHOD: The evaluation included assessment of (a) sexual health educational materials, resources, and referral lists; (b) organizational policies that guide provision of sexual information and referrals; and (c) communication about sexual health. Data were collected prior to intervention, 7 months later, and 1 year later using anonymous surveys of staff and adolescents, and researcher observations. RESULTS: Results indicate that organizational support for addressing youth sexual health increased as did communication between staff and youth, with decreased barriers. Most, but not all, improvements were maintained at the 1-year follow-up. Organizational policies that support youth sexual health and the availability of educational materials, resources such as condoms, and referral lists also increased and were maintained at follow-up. CONCLUSIONS: Organizational systems change may create a broader, more sustainable environment for increasing communication between youth and adults and increasing resources to promote sexual health. PMID- 23460673 TI - The use of international service learning initiatives for global health education: case studies from Rwanda and Mexico. AB - Global health education and health promotion have the potential to engage students, scholars, and practitioners in ways that go beyond the classroom teaching routine. This engagement in global communities, can range from reflection on continuing deep-seated questions about human rights and civic responsibility to the use of health education and promotion-related theoretical, intellectual, and practical skills. In the arena of global health education and promotion, these skills also range from leadership and advocacy to decision making, critical and creative thinking, teamwork, and problem solving. In recent times, there has been a growing interest in cross-cultural collaborations and educational initiatives to improve stakeholder's understanding of global health principles and practices, to enrich the experiences of health professionals, and to improve the lives of those who are disenfranchised and live across borders. In this article of Health Promotion Practice, we highlight two unique cases of cross national collaborations and provide a glimpse of the various shapes and forms taken by cross-cultural educational initiatives for global health education and promotion. We summarize the history, philosophy, and current working practices relevant to these collaborations, keeping in view the global health domains, competencies, and activities. In addition, we also compare the key components and activities of these two case studies from Rwanda and Mexico, wherein communities in these two countries collaborated with academic institutions and health professionals in the United States. PMID- 23460674 TI - Martin Humphries: Attached to adhesion. Interview by Caitlin Sedwick. PMID- 23460675 TI - Review series: The functions and consequences of force at kinetochores. AB - Chromosome segregation requires the generation of force at the kinetochore-the multiprotein structure that facilitates attachment of chromosomes to spindle microtubules. This force is required both to move chromosomes and to signal the formation of proper bioriented attachments. To understand the role of force in these processes, it is critical to define how force is generated at kinetochores, the contributions of this force to chromosome movement, and how the kinetochore is structured and organized to withstand and respond to force. Classical studies and recent work provide a framework to dissect the mechanisms, functions, and consequences of force at kinetochores. PMID- 23460676 TI - Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans. AB - Some inducible yeast genes relocate to nuclear pores upon activation, but the general relevance of this phenomenon has remained largely unexplored. Here we show that the bidirectional hsp-16.2/41 promoter interacts with the nuclear pore complex upon activation by heat shock in the nematode Caenorhabditis elegans. Direct pore association was confirmed by both super-resolution microscopy and chromatin immunoprecipitation. The hsp-16.2 promoter was sufficient to mediate perinuclear positioning under basal level conditions of expression, both in integrated transgenes carrying from 1 to 74 copies of the promoter and in a single-copy genomic insertion. Perinuclear localization of the uninduced gene depended on promoter elements essential for induction and required the heat-shock transcription factor HSF-1, RNA polymerase II, and ENY-2, a factor that binds both SAGA and the THO/TREX mRNA export complex. After induction, colocalization with nuclear pores increased significantly at the promoter and along the coding sequence, dependent on the same promoter-associated factors, including active RNA polymerase II, and correlated with nascent transcripts. PMID- 23460677 TI - Tail-anchored PEX26 targets peroxisomes via a PEX19-dependent and TRC40 independent class I pathway. AB - Tail-anchored (TA) proteins are anchored into cellular membranes by a single transmembrane domain (TMD) close to the C terminus. Although the targeting of TA proteins to peroxisomes is dependent on PEX19, the mechanistic details of PEX19 dependent targeting and the signal that directs TA proteins to peroxisomes have remained elusive, particularly in mammals. The present study shows that PEX19 formed a complex with the peroxisomal TA protein PEX26 in the cytosol and translocated it directly to peroxisomes by interacting with the peroxisomal membrane protein PEX3. Unlike in yeast, the adenosine triphosphatase TRC40, which delivers TA proteins to the endoplasmic reticulum, was dispensable for the peroxisomal targeting of PEX26. Moreover, the basic amino acids within the luminal domain of PEX26 were essential for binding to PEX19 and thereby for peroxisomal targeting. Finally, our results suggest that a TMD that escapes capture by TRC40 and is followed by a highly basic luminal domain directs TA proteins to peroxisomes via the PEX19-dependent route. PMID- 23460679 TI - Residential segregation and obesity among a national sample of Hispanic adults. AB - We explored the role of residential segregation in obesity among a national sample of Hispanics for the first time. Data on the 8785 Hispanic adults in the 2000 Behavioral Risk Factor Surveillance System were linked to 2000 census data on the segregation of 290 metropolitan statistical areas. Multilevel modeling revealed that after controlling for individual-level variables, the odds of being obese for Hispanics residing in high-segregated metropolitan statistical areas were 26.4 percent higher than for those residing in low-segregated metropolitan statistical areas. This segregation effect might be mediated by the obesogenic features (e.g. paucity of recreational facilities and abundance of fast-food outlets) of segregated Hispanic neighborhoods. PMID- 23460678 TI - Notochord vacuoles are lysosome-related organelles that function in axis and spine morphogenesis. AB - The notochord plays critical structural and signaling roles during vertebrate development. At the center of the vertebrate notochord is a large fluid-filled organelle, the notochord vacuole. Although these highly conserved intracellular structures have been described for decades, little is known about the molecular mechanisms involved in their biogenesis and maintenance. Here we show that zebrafish notochord vacuoles are specialized lysosome-related organelles whose formation and maintenance requires late endosomal trafficking regulated by the vacuole-specific Rab32a and H(+)-ATPase-dependent acidification. We establish that notochord vacuoles are required for body axis elongation during embryonic development and identify a novel role in spine morphogenesis. Thus, the vertebrate notochord plays important structural roles beyond early development. PMID- 23460680 TI - Thrombotic storm in a teenager with previously undiagnosed ulcerative colitis. AB - Venous thrombosis can complicate inflammatory bowel diseases, both in adult and pediatric patients, and a few adult cases of thrombotic storm, ie, thrombosis at multiple sites occurring over a period of a few days to a few weeks, have been described. However, venous thrombosis as the first manifestation of an inflammatory bowel disease is extremely rare. We report the case of a 14-year-old girl presenting with ascites and marked hypertransaminasemia resulting from hepatic vein occlusion (Budd-Chiari syndrome). Despite anticoagulant therapy, in the following days she developed criteria suggestive of thrombotic storm to include cerebral vein, right atrial thrombosis, and bilateral pulmonary embolism. Thrombolytic treatment with recombinant-tissue plasminogen activator was started, with resolution of all venous thromboses and without bleeding complications. Additional examinations revealed a severely active ulcerative pancolitis, which did not respond to medical treatment and required surgery. No thrombophilia abnormality nor other risk factors for thrombosis were detected. We conclude that an underlying inflammatory state, such as ulcerative colitis, should be suspected in pediatric patients with venous thrombosis storm. PMID- 23460681 TI - Weight status of children with sickle cell disease. AB - OBJECTIVE: Historically, many children and adolescents with sickle cell disease (SCD) were underweight. Treatment advances like hydroxyurea have been associated with improved growth. We hypothesized that increased hemoglobin (Hb) levels would be associated with increased weight status of children with SCD. METHODS: Investigators at 6 institutions conducted a retrospective chart review of all patients aged 2 to 19 years of age for the calendar years 2007-2009. Height, weight, baseline Hb levels, demographic information, and select comorbidities were recorded from the most recent clinic visit. Overweight and obesity were defined as >=85th and >=95th BMI percentiles for age and gender, respectively, and underweight was defined as <5th BMI percentile. RESULTS: Data were collected on 675 children and adolescents in 3 New England states. In this sample, 22.4% were overweight or obese, whereas only 6.7% were underweight. Overweight or obese status was associated with sickle genotypes other than Hb SS or Hb Sbeta(0) disease, and were associated with higher baseline Hb levels. Underweight individuals were more likely to be male, older, and have had at least 1 SCD related complication. After adjusting for demographic factors, any SCD-related complication, SCD-directed treatments, and obesity-related conditions, there was a 36% increased odds of overweight/obesity for each 1 g/dL increase in baseline Hb levels. CONCLUSIONS: Nearly one-quarter of children and adolescents with SCD in New England are overweight or obese. Longitudinal studies are needed to determine the impact of elevated BMI on the morbidity and mortality of both children and adults with SCD. PMID- 23460683 TI - Surgical thrombectomy of two left ventricular thrombi in a child with acute myocarditis. AB - Myocarditis is a potentially life-threatening disease. Although ventricular thrombus formation in myocarditis is rare, it carries the risk of serious complications. We report on a 10-year-old previously healthy girl presenting with 2 large left ventricular thrombi in acute lymphocytic acute myocarditis. No coagulation disorder was found. Her clinical course and mobile thrombi characteristics prompted us to carry out an urgent surgical thrombectomy rather than primary anticoagulation therapy. The patient has recovered well without clinical signs of thromboembolism. PMID- 23460682 TI - Postpartum anxiety and maternal-infant health outcomes. AB - OBJECTIVE: Postpartum anxiety screening does not typically occur, despite changes in life roles and responsibility after childbirth. We sought to determine the prevalence of postpartum anxiety during the maternity hospitalization and its associations with maternal and child outcomes. We further aimed to compare correlates of anxiety with correlates of depression. METHODS: For a randomized controlled trial of mothers with "well" newborns >=34 weeks' gestation comparing 2 post-hospital discharge care models, mothers completed baseline in-person interviews during the postpartum stay and telephone surveys at 2 weeks, 2 months, and 6 months to assess health care use, breastfeeding duration, anxiety, and depression. All participants intended to breastfeed. State anxiety scores >=40 on the State Trait Anxiety Inventory (STAI) and depression scores >=12 on the Edinburgh Postnatal Depression Survey (EPDS) were considered positive. RESULTS: A total of 192 (17%) of 1123 participating mothers had a positive baseline STAI; 62 (6%) had a positive EPDS. Primiparity was associated with a positive STAI (20% vs 15%, P = .02), but not a positive EPDS (4% vs 7%, P = .05). Positive STAI scores were associated with cesarean delivery (22% vs 15%, P = .001), reduced duration of breastfeeding (P = .003), and increased maternal, but not infant total unplanned health care utilization within 2 weeks of delivery (P = .001). Positive STAI scores occurred more frequently than positive EPDS scores at each assessment through 6 months postpartum. CONCLUSIONS: Postpartum state anxiety is a common, acute phenomenon during the maternity hospitalization that is associated with increased maternal health care utilization after discharge and reduced breastfeeding duration. State anxiety screening during the postpartum stay could improve these outcomes. PMID- 23460685 TI - Integrating "Back to Sleep" recommendations into neonatal ICU practice. AB - BACKGROUND AND OBJECTIVES: The American Academy of Pediatrics stresses that NICUs should endorse and model the sudden infant deaths syndrome risk-reduction recommendations significantly before anticipated discharge of the infant. Medical personnel are critical role models for parents, and the way they position infants in the hospital strongly influences parental practices at home. The aims of this project were to increase the percentage of infants following safe sleep practices in the NICU before discharge and to determine if improving compliance with these practices would influence parent behavior at home. METHODS: An algorithm detailing when to start safe sleep practices, a "Back to Sleep" crib card, educational programs for nurses and parents, a crib audit tool, and postdischarge telephone reminders were developed as quality improvement intervention strategies. RESULTS: NICU compliance with supine positioning increased from 39% to 83% (P < .001), provision of a firm sleeping surface increased from 5% to 96% (P < .001), and the removal of soft objects from the bed improved from 45% to 75% (P = .001). Through the use of a postdischarge telephone survey, parental compliance with safe sleep practices was noted to improve from 23% to 82% (P < .001). CONCLUSIONS: Multifactorial interventions improved compliance with safe sleep practices in the NICU and at home. PMID- 23460684 TI - Triglyceride to HDL-C ratio and increased arterial stiffness in children, adolescents, and young adults. AB - BACKGROUND AND OBJECTIVE: Lipid levels are linked to early atherosclerosis. Risk stratification may be improved by using triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), which relates to arterial stiffness in adults. We tested whether TG/HDL-C was an independent predictor of arterial stiffness in youth. METHODS: Subjects 10 to 26 years old (mean 18.9 years, 39% male, 56% non Caucasian, n = 893) had laboratory, anthropometric, blood pressure, and arterial stiffness data collected (brachial distensibility, augmentation index, carotid femoral pulse-wave velocity). Subjects were stratified into tertiles of TG/HDL-C (low, n = 227; mid, n = 288; high, n = 379). RESULTS: There was a progressive rise in cardiovascular (CV) risk factors and arterial stiffness across TG/HDL-C ratio. The high TG/HDL-C ratio group had the stiffest vessels (all P < .03 by analysis of variance). TG/HDL-C as a continuous variable was an independent determinant of brachial distensibility in CV risk factor adjusted model and for carotid-femoral pulse-wave velocity in obese subjects, with trend for higher augmentation index. CONCLUSIONS: TG/HDL-C, an estimate of small, dense low density lipoprotein cholesterol, is an independent determinant of arterial stiffness in adolescents and young adults, especially in obese youth. These data suggest that use of TG/HDL-C may be helpful in identifying young adults requiring aggressive intervention to prevent atherosclerotic CV diseases. PMID- 23460686 TI - Challenges of newborn severe combined immunodeficiency screening among premature infants. AB - Newborn screening for severe combined immunodeficiency (SCID) is currently being performed in many states. It is important to address diagnostic challenges while outcomes are emerging from the first several years of screening. We present the case of a premature infant whose initial newborn screen was strongly positive for SCID. Subsequent lymphocyte subset analysis by flow cytometry was difficult to interpret due to the lack of age-matched reference values, a history of prenatal corticosteroid administration, and the possibility of maternal or posttransfusion engraftment. A repeat newborn screen for SCID ultimately revealed a normal result, confirming the initial newborn screen as a false positive. This case report reveals several of the diagnostic challenges unique to newborn SCID screening in premature infants and highlights the potential for states to address the feasibility of a standard protocol in this population. PMID- 23460687 TI - Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. AB - OBJECTIVE: We examined long-term outcomes of attention-deficit/hyperactivity disorder (ADHD) in a population-based sample of childhood ADHD cases and controls, prospectively assessed as adults. METHODS: Adults with childhood ADHD and non-ADHD controls from the same birth cohort (N = 5718) were invited to participate in a prospective outcome study. Vital status was determined for birth cohort members. Standardized mortality ratios (SMRs) were constructed to compare overall and cause-specific mortality between childhood ADHD cases and controls. Incarceration status was determined for childhood ADHD cases. A standardized neuropsychiatric interview was administered. RESULTS: Vital status for 367 childhood ADHD cases was determined: 7 (1.9%) were deceased, and 10 (2.7%) were currently incarcerated. The SMR for overall survival of childhood ADHD cases versus controls was 1.88 (95% confidence interval [CI], 0.83-4.26; P = .13) and for accidents only was 1.70 (95% CI, 0.49-5.97; P = .41). However, the cause specific mortality for suicide only was significantly higher among ADHD cases (SMR, 4.83; 95% CI, 1.14-20.46; P = .032). Among the childhood ADHD cases participating in the prospective assessment (N = 232; mean age, 27.0 years), ADHD persisted into adulthood for 29.3% (95% CI, 23.5-35.2). Participating childhood ADHD cases were more likely than controls (N = 335; mean age, 28.6 years) to have >=1 other psychiatric disorder (56.9% vs 34.9%; odds ratio, 2.6; 95% CI, 1.8-3.8; P < .01). CONCLUSIONS: Childhood ADHD is a chronic health problem, with significant risk for mortality, persistence of ADHD, and long-term morbidity in adulthood. PMID- 23460688 TI - A parent-focused intervention to reduce infant obesity risk behaviors: a randomized trial. AB - OBJECTIVE: To assess the effectiveness of a parent-focused intervention on infants' obesity-risk behaviors and BMI. METHODS: This cluster randomized controlled trial recruited 542 parents and their infants (mean age 3.8 months at baseline) from 62 first-time parent groups. Parents were offered six 2-hour dietitian-delivered sessions over 15 months focusing on parental knowledge, skills, and social support around infant feeding, diet, physical activity, and television viewing. Control group parents received 6 newsletters on nonobesity focused themes; all parents received usual care from child health nurses. The primary outcomes of interest were child diet (3 * 24-hour diet recalls), child physical activity (accelerometry), and child TV viewing (parent report). Secondary outcomes included BMI z-scores (measured). Data were collected when children were 4, 9, and 20 months of age. RESULTS: Unadjusted analyses showed that, compared with controls, intervention group children consumed fewer grams of noncore drinks (mean difference = -4.45; 95% confidence interval [CI]: -7.92 to 0.99; P = .01) and were less likely to consume any noncore drinks (odds ratio = 0.48; 95% CI: 0.24 to 0.95; P = .034) midintervention (mean age 9 months). At intervention conclusion (mean age 19.8 months), intervention group children consumed fewer grams of sweet snacks (mean difference = -3.69; 95% CI: -6.41 to 0.96; P = .008) and viewed fewer daily minutes of television (mean difference = 15.97: 95% CI: -25.97 to -5.96; P = .002). There was little statistical evidence of differences in fruit, vegetable, savory snack, or water consumption or in BMI z-scores or physical activity. CONCLUSIONS: This intervention resulted in reductions in sweet snack consumption and television viewing in 20-month-old children. PMID- 23460689 TI - Effect of rotavirus vaccine on diarrhea mortality in different socioeconomic regions of Mexico. AB - OBJECTIVE: In Mexico, declines in childhood diarrhea deaths have been documented during 2008-2010 after rotavirus vaccine introduction in 2007. Because of concerns about variation in rotavirus vaccine efficacy by socioeconomic status, we compared reductions in diarrhea mortality in the lesser developed southern region versus the more developed northern and central regions of Mexico. METHODS: We obtained data from national vital statistics on diarrhea deaths among children aged <5 years from 2002 through 2011. We compared region-specific diarrhea mortality before (2003-2006) and after (2009-2011) vaccine introduction. Regional vaccine coverage was estimated from administrative data, and socioeconomic status was assessed by using the Human Development Index. RESULTS: In northern, central, and southern Mexico, the 2007 Human Development Index was 0.84, 0.82, and 0.77, respectively, and by 2010 an estimated 99%, 84%, and 89% of children aged <12 months had completed rotavirus vaccination. Diarrhea mortality among children <5 years old declined from 8.3, 17.9, and 28.5 deaths per 100,000 children during 2003-2006 to 4.5, 8.1, and 16.2 in 2009-2011 in northern, central, and southern Mexico, respectively, corresponding to rate reductions of 45%, 55%, and 43%. No significant differences were observed in rate reductions between regions (P > .8). CONCLUSIONS: After introduction of rotavirus vaccination, marked and sustained declines in diarrhea deaths were seen among children in all regions of Mexico, including in the least developed southern region with the highest baseline diarrhea mortality. This finding indicates equitable vaccine delivery to children with varying risk of mortality and reaffirms the beneficial effects of rotavirus vaccination against fatal diarrheal disease. PMID- 23460690 TI - Predictors of phrase and fluent speech in children with autism and severe language delay. AB - OBJECTIVE: To examine the prevalence and predictors of language attainment in children with autism spectrum disorder (ASD) and severe language delay. We hypothesized greater autism symptomatology and lower intelligence among children who do not attain phrase/fluent speech, with nonverbal intelligence and social engagement emerging as the strongest predictors of outcome. METHODS: Data used for the current study were from 535 children with ASD who were at least 8 years of age (mean = 11.6 years, SD = 2.73 years) and who did not acquire phrase speech before age 4. Logistic and Cox proportionate hazards regression analyses examined predictors of phrase and fluent speech attainment and age at acquisition, respectively. RESULTS: A total of 372 children (70%) attained phrase speech and 253 children (47%) attained fluent speech at or after age 4. No demographic or child psychiatric characteristics were associated with phrase speech attainment after age 4, whereas slightly older age and increased internalizing symptoms were associated with fluent speech. In the multivariate analyses, higher nonverbal IQ and less social impairment were both independently associated with the acquisition of phrase and fluent speech, as well as earlier age at acquisition. Stereotyped behavior/repetitive interests and sensory interests were not associated with delayed speech acquisition. CONCLUSIONS: This study highlights that many severely language-delayed children in the present sample attained phrase or fluent speech at or after age 4 years. These data also implicate the importance of evaluating and considering nonverbal skills, both cognitive and social, when developing interventions and setting goals for language development. PMID- 23460691 TI - Editor's choice: Evaluating the potential for adverse interactions within genetically engineered breeding stacks. PMID- 23460692 TI - Let us get prison health care out of jail. PMID- 23460693 TI - Low-back pain. PMID- 23460694 TI - Low-back pain. PMID- 23460695 TI - Data to support PSA screening for younger men lacking. PMID- 23460696 TI - Structure and accessibility of HA trimers on intact 2009 H1N1 pandemic influenza virus to stem region-specific neutralizing antibodies. AB - Rapid antigenic variation of HA, the major virion surface protein of influenza A virus, remains the principal challenge to the development of broader and more effective vaccines. Some regions of HA, such as the stem region proximal to the viral membrane, are nevertheless highly conserved across strains and among most subtypes. A fundamental question in vaccine design is the extent to which HA stem regions on the surface of the virus are accessible to broadly neutralizing antibodies. Here we report 3D structures derived from cryoelectron tomography of HA on intact 2009 H1N1 pandemic virions in the presence and absence of the antibody C179, which neutralizes viruses expressing a broad range of HA subtypes, including H1, H2, H5, H6, and H9. By fitting previously derived crystallographic structures of trimeric HA into the density maps, we deduced the locations of the molecular surfaces of HA involved in interaction with C179. Using computational methods to distinguish individual unliganded HA trimers from those that have bound C179 antibody, we demonstrate that ~75% of HA trimers on the surface of the virus have C179 bound to the stem domain. Thus, despite their close packing on the viral membrane, the majority of HA trimers on intact virions are available to bind anti-stem antibodies that target conserved HA epitopes, establishing the feasibility of universal influenza vaccines that elicit such antibodies. PMID- 23460697 TI - Actin depolymerization under force is governed by lysine 113:glutamic acid 195 mediated catch-slip bonds. AB - As a key element in the cytoskeleton, actin filaments are highly dynamic structures that constantly sustain forces. However, the fundamental question of how force regulates actin dynamics is unclear. Using atomic force microscopy force-clamp experiments, we show that tensile force regulates G-actin/G-actin and G-actin/F-actin dissociation kinetics by prolonging bond lifetimes (catch bonds) at a low force range and by shortening bond lifetimes (slip bonds) beyond a threshold. Steered molecular dynamics simulations reveal force-induced formation of new interactions that include a lysine 113(K113):glutamic acid 195 (E195) salt bridge between actin subunits, thus suggesting a molecular basis for actin catch slip bonds. This structural mechanism is supported by the suppression of the catch bonds by the single-residue replacements K113 to serine (K113S) and E195 to serine (E195S) on yeast actin. These results demonstrate and provide a structural explanation for actin catch-slip bonds, which may provide a mechanoregulatory mechanism to control cell functions by regulating the depolymerization kinetics of force-bearing actin filaments throughout the cytoskeleton. PMID- 23460698 TI - Pubertally born neurons and glia are functionally integrated into limbic and hypothalamic circuits of the male Syrian hamster. AB - During puberty, the brain goes through extensive remodeling, involving the addition of new neurons and glia to brain regions beyond the canonical neurogenic regions (i.e., dentate gyrus and olfactory bulb), including limbic and hypothalamic cell groups associated with sex-typical behavior. Whether these pubertally born cells become functionally integrated into neural circuits remains unknown. To address this question, we gave male Syrian hamsters daily injections of the cell birthdate marker bromodeoxyuridine throughout puberty (postnatal day 28-49). Half of the animals were housed in enriched environments with access to a running wheel to determine whether enrichment increased the survival of pubertally born cells compared with the control environment. At 4 wk after the last BrdU injection, animals were allowed to interact with a receptive female and were then killed 1 h later. Triple-label immunofluorescence for BrdU, the mature neuron marker neuronal nuclear antigen, and the astrocytic marker glial fibrillary acidic protein revealed that a proportion of pubertally born cells in the medial preoptic area, arcuate nucleus, and medial amygdala differentiate into either mature neurons or astrocytes. Double-label immunofluorescence for BrdU and the protein Fos revealed that a subset of pubertally born cells in these regions is activated during sociosexual behavior, indicative of their functional incorporation into neural circuits. Enrichment affected the survival and activation of pubertally born cells in a brain region-specific manner. These results demonstrate that pubertally born cells located outside of the traditional neurogenic regions differentiate into neurons and glia and become functionally incorporated into neural circuits that subserve sex-typical behaviors. PMID- 23460699 TI - Viscoelastic properties of the nematode Caenorhabditis elegans, a self-similar, shear-thinning worm. AB - Undulatory motion is common to many creatures across many scales, from sperm to snakes. These organisms must push off against their external environment, such as a viscous medium, grains of sand, or a high-friction surface; additionally they must work to bend their own body. A full understanding of undulatory motion, and locomotion in general, requires the characterization of the material properties of the animal itself. The material properties of the model organism Caenorhabditis elegans were studied with a micromechanical experiment used to carry out a three-point bending measurement of the worm. Worms at various developmental stages (including dauer) were measured and different positions along the worm were probed. From these experiments we calculated the viscoelastic properties of the worm, including the effective spring constant and damping coefficient of bending. C. elegans moves by propagating sinusoidal waves along its body. Whereas previous viscoelastic approaches to describe the undulatory motion have used a Kelvin-Voigt model, where the elastic and viscous components are connected in parallel, our measurements show that the Maxwell model, where the elastic and viscous components are in series, is more appropriate. The viscous component of the worm was shown to be consistent with a non-Newtonian, shear-thinning fluid. We find that as the worm matures it is well described as a self-similar elastic object with a shear-thinning damping term and a stiffness that becomes smaller as one approaches the tail. PMID- 23460700 TI - Celebrating the 150th anniversary of the National Academy of Sciences. PMID- 23460701 TI - Personality may explain the association between cannabis use and neuropsychological impairment. PMID- 23460702 TI - Concatenation versus coalescence versus "concatalescence". PMID- 23460704 TI - The Effectiveness of Short- and Long-Acting Stimulant Medications for Adolescents With ADHD in a Naturalistic Secondary School Setting. AB - OBJECTIVE: Stimulant medication is an efficacious and first-line approach to treating ADHD in adolescence. However, less is known about the effectiveness of this approach as a treatment in real-world settings. The complicated nature of the secondary school environment and documented adolescent nonadherence with stimulant medication may undermine the exportability of this approach. METHOD: This study investigates stimulant medication effectiveness and adherence in a sample of adolescents with ADHD who were observed in their natural secondary school environment. RESULTS: Results indicated that the effect of stimulant medication on adolescent functioning is smaller in naturalistic settings than in previous analogue studies. Long-acting pemoline produced greater adherence than the short-acting methylphenidate (MPH), but parents and adolescents preferred the short-acting MPH. CONCLUSIONS: Overall, adolescents reported very low satisfaction with stimulant medication. Findings are discussed. PMID- 23460705 TI - Central venous catheter care for the patient with cancer: American Society of Clinical Oncology clinical practice guideline. AB - PURPOSE: To develop an evidence-based guideline on central venous catheter (CVC) care for patients with cancer that addresses catheter type, insertion site, and placement as well as prophylaxis and management of both catheter-related infection and thrombosis. METHODS: A systematic search of MEDLINE and the Cochrane Library (1980 to July 2012) identified relevant articles published in English. RESULTS: The overall quality of the randomized controlled trial evidence was rated as good. There is consistency among meta-analyses and guidelines compiled by other groups as well. RECOMMENDATIONS: There is insufficient evidence to recommend one CVC type or insertion site; femoral catheterization should be avoided. CVC should be placed by well-trained providers, and the use of a CVC clinical care bundle is recommended. The use of antimicrobial/antiseptic impregnated and/or heparin-impregnated CVCs is recommended to decrease the risk of catheter-related infections for short-term CVCs, particularly in high-risk groups; more research is needed. The prophylactic use of systemic antibiotics is not recommended before insertion. Data are not sufficient to recommend for or against routine use of antibiotic flush/lock therapy; more research is needed. Before starting antibiotic therapy, cultures should be obtained. Some life threatening infections require immediate catheter removal, but most can be treated with antimicrobial therapy while the CVC remains in place. Routine flushing with saline is recommended. Prophylactic use of warfarin or low molecular weight heparin is not recommended, although a tissue plasminogen activator (t-PA) is recommended to restore patency to occluded catheters. CVC removal is recommended when the catheter is no longer needed or if there is a radiologically confirmed thrombosis that worsens despite anticoagulation therapy. PMID- 23460706 TI - Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. AB - PURPOSE: The objective of this prospective study was to assess overall survival and event-free survival in patients with intraocular unilateral retinoblastoma (Reese-Ellsworth group V) treated by primary enucleation with or without adjuvant therapy depending on histopathologic risk factors. PATIENTS AND METHODS: Patients (n = 123) were divided into three groups on the basis of risk factors for extraocular relapse and metastasis assessed on centralized histologic examination of enucleated eyes. Group 1 (n = 70) had minimal or no choroidal involvement and/or prelaminar or no optic nerve involvement and received no adjuvant therapy. Group 2 (n = 52) had massive choroidal involvement and/or intra- or retrolaminar optic nerve involvement and/or anterior segment involvement and received four courses of adjuvant chemotherapy. Group 3 (n = 1) had invasion of the surgical margin of the optic nerve and/or microscopic extrascleral involvement and received six courses of adjuvant chemotherapy with intrathecal thiotepa, consolidation chemotherapy, and autologous stem-cell rescue. Genetic testing was also performed. RESULTS: Median follow-up for the 123 patients was 71 months. No disease progression, relapse, or distant metastasis occurred during follow-up. No second malignancies occurred. This requires confirmation with longer follow-up. Secondary bilateralization occurred in two patients with identified RB1 germline mutation. Adjuvant chemotherapy was well tolerated, with limited toxicity. Molecular testing found constitutional RB1 gene mutations in only nine of 100 evaluated patients. CONCLUSION: The survival rate of 100% was excellent, including 57% of patients who received no adjuvant therapy, suggesting that chemotherapy could be de-escalated in some patients, especially those with massive choroidal involvement. PMID- 23460708 TI - Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? PMID- 23460707 TI - Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. AB - PURPOSE: We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS: From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. RESULTS: Seventy two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. CONCLUSION: In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations. PMID- 23460709 TI - Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. AB - PURPOSE: The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS: Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization. RESULTS: Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION: Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS. PMID- 23460710 TI - Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. AB - PURPOSE: We aimed to validate a previously described genetic risk score, denoted the cell-cycle progression (CCP) score, in predicting contemporary radical prostatectomy (RP) outcomes. METHODS: RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. Recurrence was defined as two prostate specific antigen levels >= 0.2 ng/mL or any salvage treatment. Associations between CCP score and recurrence were examined, with adjustment for clinical and pathologic variables using Cox proportional hazards regression and partial likelihood ratio tests. The CCP score was assessed for independent prognostic utility beyond a standard postoperative risk assessment (Cancer of the Prostate Risk Assessment post-Surgical [CAPRA-S] score), and a score combining CAPRA-S and CCP was validated. RESULTS: Eighty-two (19.9%) of 413 men experienced recurrence. The hazard ratio (HR) for each unit increase in CCP score (range, -1.62 to 2.16) was 2.1 (95% CI, 1.6 to 2.9); with adjustment for CAPRA-S, the HR was 1.7 (95% CI, 1.3 to 2.4). The score was able to substratify patients with low clinical risk as defined by CAPRA-S <= 2 (HR, 2.3; 95% CI, 1.4 to 3.7). Combining the CCP and CAPRA-S improved the concordance index for both the overall cohort and low risk subset; the combined CAPRA-S + CCP score consistently predicted outcomes across the range of clinical risk. This combined score outperformed both individual scores on decision curve analysis. CONCLUSION: The CCP score was validated to have significant prognostic accuracy after controlling for all available clinical and pathologic data. The score may improve accuracy of risk stratification for men with clinically localized prostate cancer, including those with low-risk disease. PMID- 23460711 TI - Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. AB - PURPOSE: Elderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient's health status to better adapt treatment. PATIENTS AND METHODS: Elderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Federation Francophone de Cancerologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation. RESULTS: The geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was <= 1 in 75%, Mini-Mental State Examination (MMSE) score was <= 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE <= 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 * upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE <= 27/30 (OR, 4.56) and Geriatric Depression Scale <= 2 (OR, 5.52). CONCLUSION: Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy. PMID- 23460712 TI - Mullerian carcinosarcoma arising from intestinal endometriosis. PMID- 23460713 TI - Epidermal growth factor receptor targeting in head and neck cancer: have we been just skimming the surface? PMID- 23460715 TI - Extracranial oligometastases: a subset of metastases curable with stereotactic radiotherapy. PMID- 23460714 TI - Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. AB - PURPOSE: We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing. RESULTS: Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response. CONCLUSION: The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN. PMID- 23460716 TI - Vemurafenib for leptomeningeal melanomatosis. PMID- 23460717 TI - Technetium-bevacizumab in a patient with bone and lung metastatic colon adenocarcinoma. PMID- 23460720 TI - Thresholds and perception of cold pain, heat pain, and the thermal grill illusion in patients with major depressive disorder. AB - OBJECTIVE: The thermal grill illusion (TGI) in which interlacing cold and warm bars create the illusion of a painful sensation has been suggested as an experimental model for central pain states and pain processing. The aim of this study was to use this technique to gain further insights into the altered pain perception in major depressive disorder (MDD). METHODS: In 18 unmedicated patients with MDD, cold and heat pain thresholds (CPT/HPT) as well as the perception of the TGI were examined and compared with 18 matched controls. RESULTS: CPT and HPT were significantly increased in patients (7.9 degrees C and 47.5 degrees C) compared with controls (15.9 degrees C and 45.2 degrees C, respectively; p < .05). In the range of TGI stimuli that were perceived painful by controls, the patients did not indicate painful sensations, thereby indicating a shift of the stimulus-response curve of TGI pain perception toward higher stimulus intensities, that is, greater temperature differentials between cold and warm bars (11.5 degrees C for controls, 16.7 degrees C for patients). The patients rated the pain intensity perceived at the respective pain thresholds (CPT and HPT) in tendency higher than did the controls, whereas they perceived the TGI less painful despite increased stimulus intensities. Unpleasantness ratings were similar between groups. CONCLUSIONS: CPT, HPT and temperature differentials for the perception of the TGI, were increased in patients with MDD as compared with controls. Pain intensity, however, was rated differently for CPT and HPT, where patients indicated higher ratings in tendency, and for the TGI stimulation, where pain was perceived less intense. PMID- 23460721 TI - Job strain-associated inflammatory burden and long-term risk of coronary events: findings from the MONICA/KORA Augsburg case-cohort study. AB - BACKGROUND: We examined the association between job strain and coronary heart disease (CHD) and investigated the role of markers of inflammation and endothelial dysfunction as possible mediators of job strain-associated CHD risk. METHODS: The sample (n = 1027) included employed participants (35-64 years old, 68% male) from the population-based MONICA/KORA (Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg) studies. At baseline Karasek's Job Strain Index was assessed during standardized personal interviews, and nine biological markers were measured (1984-1995). Participants were followed (average, 12 years) to assess incident events (sudden cardiac death or fatal and nonfatal myocardial infarction). In this case-cohort design, the final sample contained 114 cases and 913 noncases. RESULTS: Baseline distributions of cardiometabolic risk factors were significantly different between cases and noncases, with no detectable job strain-specific differences. However, cases with high job strain had higher monocyte chemoattractant protein-1, interleukin (IL)-8, and IL-18 compared with noncases with high job strain. High-sensitivity C-reactive protein, IL-6, and soluble intercellular adhesion molecule-1 were increased in cases versus noncases, regardless of work stress. Job strain was associated with incident coronary events in Cox proportional hazards models adjusted for age, sex, and survey (hazard ratio = 2.57, 95% confidence interval = 1.09-6.07) and after adjustment for CHD risk factors (2.35, 1.003-5.49). Adjustment for monocyte chemoattractant protein-1 or IL-8 increased this risk estimate by 14.5% or 9.4%, respectively, whereas adjustment for C-reactive protein and soluble intercellular adhesion molecule-1 led to decreased hazard ratios (-9.9% and -5.5%, respectively). CONCLUSIONS: Job strain increased CHD risk in healthy workers; the associated inflammatory burden may contribute to stress-related coronary pathogenesis. PMID- 23460722 TI - Emotions and neural processing of respiratory sensations investigated with respiratory-related evoked potentials. AB - OBJECTIVE: Patients with respiratory diseases such as asthma and chronic obstructive pulmonary disease frequently experience respiratory sensations, which are often perceived as unpleasant or threatening. However, the accurate perception of respiratory sensations is important for the management and treatment of these diseases. Emotions can substantially influence the perception of respiratory sensations and might affect the course of respiratory diseases, but the underlying neural mechanisms are poorly understood. The respiratory related evoked potential (RREP) recorded from the electroencephalogram is a noninvasive technique that allowed first studies to examine the impact of emotions on the neural processing of respiratory sensations. METHODS: In this review, we will briefly introduce the importance of the perception of respiratory sensations and the influence of emotions on respiratory perception. We then provide an overview on the technique of RREP and present a systematic review on recent findings using this technique in the context of emotions. RESULTS AND CONCLUSIONS: The evidence currently available from studies in healthy individuals suggests that short-lasting emotional states and anxiety affect the later RREP components (N1, P2, P3) related to higher-order neural processing of respiratory sensations, but not the earlier RREP components (Nf, P1) related to first-order sensory processing. We conclude with a discussion of the implications of this work for future research that needs to focus on respiratory patient groups and the associated clinical outcomes. PMID- 23460723 TI - Giant neuroendocrine tumour localized to the thoracoabdomen. PMID- 23460724 TI - Outcome of full-thickness chest wall resection for isolated breast cancer recurrence. AB - OBJECTIVES: Local breast cancer recurrence is often viewed as an early sign of rapidly progressive metastatic disease for which chest wall resection (CWR) can provide no benefits. We retrospectively reviewed our experience with full thickness CWR to determine whether long-term outcomes warranted this aggressive procedure. METHODS: Between 2001 and 2012, 33 women (mean age, 50.7 years; range, 33-72 years) underwent en-bloc CWR with curative intent. Mean disease-free interval from initial tumour resection was 90.5 months (range, 2-252 months). Resection included skin, muscle and an average of 2.7 ribs (range, 1-8 ribs) and was extended to the sternum (n = 21), subclavian vessels (n = 9), lung (n = 8), pericardium (n = 8), phrenic nerve (n = 2) or T1 nerve root (n = 1). Complete R0 resection was achieved in 31 (94%) patients. Chest wall reconstruction was performed in 28 patients, with polytetrafluoroethylene mesh (n = 17) or titanium ribs (n = 11). A musculocutaneous flap was used in 17 (52%) patients. RESULTS: Postoperative morbidity was 36%, with no deaths. Median follow-up was 33 months (range, 3-96 months). Median survival was 69 months and 1-, 3- and 5-year survival rates were 100, 81 and 63%, respectively. Recurrence developed in 13 patients, including 12 with distant metastases. Disease-free survival rates were 77, 57 and 50% after 1, 3 and 5 years, respectively. By univariate analysis, only resection extended to intrathoracic structures was associated with better survival (P = 0.033). CONCLUSIONS: En-bloc full-thickness CWR eventually extended to adjacent structures provides acceptable morbidity and excellent long-term survival and should be considered the treatment of choice in locally recurrent breast cancer. PMID- 23460725 TI - Meta-analysis of coronary CT angiography in the emergency department. PMID- 23460719 TI - The role of estrogens in control of energy balance and glucose homeostasis. AB - Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet beta-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders. PMID- 23460726 TI - IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. AB - Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1(-/-) OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen specific cells that are granzyme B(+), have cytotoxic activity, and/ or produce interferon gamma (IFN-gamma). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-gamma when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory. PMID- 23460727 TI - IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis. AB - Infections of the central nervous system (CNS) with cytopathic viruses require efficient T cell responses to promote viral clearance, limit immunopathology, and enhance survival. We found that IL-1R1 is critical for effector T cell reactivation and limits inflammation within the CNS during murine West Nile virus (WNV) encephalitis. WNV-infected IL-1R1(-/-) mice display intact adaptive immunity in the periphery but succumb to WNV infection caused by loss of virologic control in the CNS with depressed local Th1 cytokine responses, despite parenchymal entry of virus-specific CD8(+) T cells. Ex vivo analysis of CD4(+) T cells from WNV-infected CNS of IL-1R1(-/-) mice revealed impaired effector responses, whereas CD8(+) T cells revealed no cell intrinsic defects in response to WNV antigen. WNV-infected, IL-1R1(-/-) mice also exhibited decreased activation of CNS CD11c(+)CD11b(-)CD103(+) and CD11c(+)CD11b(-)CD8alpha(+)Dec 205(+) cells with reduced up-regulation of the co-stimulatory molecules CD80, CD86, and CD68. Adoptive transfer of wild-type CD11c-EYFP(+) cells from WNV infected CNS into WNV-infected IL-1R1(-/-) mice trafficked into the CNS restored T cell functions and improved survival from otherwise lethal infection. These data indicate that IL-1R1 signaling promotes virologic control during WNV infection specifically within the CNS via modulation of CD11c(+) cell-mediated T cell reactivation at this site. PMID- 23460728 TI - IL-27 inhibits HIV-1 infection in human macrophages by down-regulating host factor SPTBN1 during monocyte to macrophage differentiation. AB - The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down regulating spectrin beta nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27-treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir. PMID- 23460729 TI - BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid. AB - CCR9 and alpha4beta7 are the major trafficking receptors for lymphocyte migration to the gut, and their expression is induced during lymphocyte activation under the influence of retinoic acid (RA). We report here that BATF (basic leucine zipper transcription factor, ATF-like), an AP-1 protein family factor, is required for optimal expression of CCR9 and alpha4beta7 by T helper cells. BATF deficient (knockout [KO]) mice had reduced numbers of effector T and regulatory T cells in the intestine. The intestinal T cells in BATF KO mice expressed CCR9 and alpha4beta7 at abnormally low levels compared with their wild-type (WT) counterparts, and BATF KO CD4(+) T cells failed to up-regulate the expression of CCR9 and alpha4beta7 to WT levels in response to RA. Defective binding of RARalpha and histone acetylation at the regulatory regions of the CCR9 and Itg alpha4 genes were observed in BATF KO T cells. As a result, BATF KO effector and FoxP3(+) T cells failed to populate the intestine, and neither population functioned normally in the induction and regulation of colitis. Our results establish BATF as a cellular factor required for normal expression of CCR9 and alpha4beta7 and for the homeostasis and effector functions of T cell populations in the intestine. PMID- 23460730 TI - Effects of maxillary protraction for early correction of class III malocclusion. AB - This prospective study investigated the skeletal, dental, and soft-tissue effects of a mini maxillary protractor appliance in class III subjects with maxillary retrusion and mandibular protrusion and compared these changes with those of untreated, well matched control sample with normal occlusions. Twenty patients with class III malocclusion (mean age 11.1 +/- 0.8 years) and 20 subjects with normal occlusion (mean age 10.9 +/- 0.4 years) were included to this study. The class III subjects were treated with the mini maxillary protractor appliance, and the others were used as control subjects. Paired t-test and Student's t-test were used to determine the within- and between-group differences, respectively. In the study group, the maxilla moved forward (SNA, 2.0 degrees and A-Y, 2.4mm) (P < 0.001) with a slight rotation of palatal and occlusal planes (SN-PP, -0.8 degree and SN-OP, -0.7 degree) (P > 0.05). The mandible displaced backwards and downwards (SNB, -1.1 degrees; SND, -0.9 degree; B-Y, -0.9 mm and Pog-Y, -0.3mm; P < 0.001). These movements in the maxilla and mandible caused a significant improvement in intermaxillary sagittal relationship (ANB, 3.0 degrees; Convexity, 6.3 degrees; Wits, 4.6mm; P < 0.001). The maxillary incisors moved forward (2.2 degrees) while the mandibular ones backward (-1.9 degrees). The improvement in overjet was 5.0mm, and 66.1 per cent of this change (3.3mm) was skeletal (A-Y; 2.4mm and B-Y; -0.9 mm), and the remaining (1.7 mm) dentoalveolar (U1-NA; 0.9 mm and L1-NB; -0.8mm). The change in Ls-E measurement was more in the study group (2.1mm), and the difference between the groups was statistically significant (P < 0.001). PMID- 23460731 TI - Sample size in orthodontic randomized controlled trials: are numbers justified? AB - Sample size calculations are advocated by the Consolidated Standards of Reporting Trials (CONSORT) group to justify sample sizes in randomized controlled trials (RCTs). This study aimed to analyse the reporting of sample size calculations in trials published as RCTs in orthodontic speciality journals. The performance of sample size calculations was assessed and calculations verified where possible. Related aspects, including number of authors; parallel, split-mouth, or other design; single- or multi-centre study; region of publication; type of data analysis (intention-to-treat or per-protocol basis); and number of participants recruited and lost to follow-up, were considered. Of 139 RCTs identified, complete sample size calculations were reported in 41 studies (29.5 per cent). Parallel designs were typically adopted (n = 113; 81 per cent), with 80 per cent (n = 111) involving two arms and 16 per cent having three arms. Data analysis was conducted on an intention-to-treat (ITT) basis in a small minority of studies (n = 18; 13 per cent). According to the calculations presented, overall, a median of 46 participants were required to demonstrate sufficient power to highlight meaningful differences (typically at a power of 80 per cent). The median number of participants recruited was 60, with a median of 4 participants being lost to follow-up. Our finding indicates good agreement between projected numbers required and those verified (median discrepancy: 5.3 per cent), although only a minority of trials (29.5 per cent) could be examined. Although sample size calculations are often reported in trials published as RCTs in orthodontic speciality journals, presentation is suboptimal and in need of significant improvement. PMID- 23460732 TI - Risk following hospitalization in stable chronic systolic heart failure. AB - AIMS: We explored the impact of being hospitalized due to worsening heart failure (WHF) or a myocardial infarction (MI) on subsequent mortality in a large contemporary data set of patients with stable chronic systolic heart failure (HF). METHODS AND RESULTS: A total of 6558 patients with stable systolic HF, 6505 with analysable data, with an EF of <=35%, who were included in the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), were followed for a median of 22.9 months with respect to hospitalizations and vital status. Among the 1288 patients who had at least one hospitalization due to WHF or MI, 455 (35.3%) died during follow-up compared with 600 (11.5%) among patients not hospitalized for these reasons. The risk for death was highest in the early phase after hospitalization. The risk declined rapidly during the first month but remained 3.5-fold (95% confidence interval 2.3-5.1) increased at 18 months after a first WHF hospitalization and 8.8-fold (95% confidence interval 3.6-21.6) increased at 18 months after a first MI hospitalization. CONCLUSION: The present study confirms previous findings that in patients with stable chronic systolic HF, a hospitalization for WHF or MI is associated with substantially increased risk for subsequent death even with contemporary extensive background pharmacological therapy. The risk is most pronounced in the early phase of hospitalization but remains elevated even after 18 months. Preventing HF hospitalization appears as an important therapeutic objective in such patients, and a hospitalization for WHF or MI should lead to a careful therapeutic reassessment. PMID- 23460733 TI - Alcohol-attributable mortality in France. AB - BACKGROUND: Alcohol consumption is high in France. AIM: Estimation of alcohol attributable mortality in France by sex, age and dose, for year 2009. METHOD: We combined survey and sales data to estimate the prevalence of alcohol consumption by age, sex and dose category. For each cause of death, the relative risk of death as a function of dose was obtained from a meta-analysis and combined with prevalence data to obtain the attributable fraction; this fraction multiplied by the number of deaths gave the alcohol-attributable mortality. RESULTS: A total of 36,500 deaths in men are attributable to alcohol in France in 2009 (13% of total mortality) versus 12,500 in women (5% of total mortality). Overall, this includes 15,000 deaths from cancer, 12,000 from circulatory disease, 8000 from digestive system disease, 8000 from external causes and 3000 from mental and behavioural disorder. The alcohol-attributable fractions are 22% and 18% in the population aged 15 to 34 and 35 to 64, respectively, versus 7% among individuals aged 65 or more. Alcohol is detrimental even at a low dose of 13 g per day, causing 1100 deaths. CONCLUSION: With 49 000 deaths in France for the year 2009, the alcohol toll is high, and the effect of alcohol is detrimental even at low dose. Alcohol consumption is responsible for a large proportion of premature deaths. These results stress the importance of public health policies aimed at reducing alcohol consumption in France. PMID- 23460734 TI - Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double-knockout mice. AB - Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by the lack of functional dystrophin. There is no cure, but several clinical trials aimed to restore the synthesis of functional dystrophin are underway. The dystrophin levels needed for improvement of muscle pathology, function, and overall vitality are not known. Here, we describe the mdx/utrn(-/-)/Xist(Deltahs) mouse model, which expresses a range of low dystrophin levels, depending on the degree of skewing of X inactivation in a utrophin-negative background. Mdx/utrn( /-) mice develop severe muscle weakness, kyphosis, respiratory and heart failure, and premature death closely resembling DMD pathology. We show that at dystrophin levels < 4%, survival and motor function in these animals are greatly improved. In mice expressing >4% dystrophin, histopathology is ameliorated, as well. These findings suggest that the dystrophin levels needed to benefit vitality and functioning of patients with DMD might be lower than those needed for full protection against muscle damage. PMID- 23460735 TI - Staphylococcus aureus phenol-soluble modulin peptides modulate dendritic cell functions and increase in vitro priming of regulatory T cells. AB - The major human pathogen Staphylococcus aureus has very efficient strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant S. aureus depends on phenol-soluble modulin (PSM) peptide toxins, which are known to attract and lyse neutrophils. However, their influences on other immune cells remain elusive. In this study, we analyzed the impact of PSMs on dendritic cells (DCs) playing an essential role in linking innate and adaptive immunity. In human neutrophils, PSMs exert their function by binding to the formyl peptide receptor (FPR) 2. We show that mouse DCs express the FPR2 homolog mFPR2 as well as its paralog mFPR1 and that PSMs are chemoattractants for DCs at noncytotoxic concentrations. PSMs reduced clathrin mediated endocytosis and inhibited TLR2 ligand-induced secretion of the proinflammatory cytokines TNF, IL-12, and IL-6, while inducing IL-10 secretion by DCs. As a consequence, treatment with PSMs impaired the capacity of DCs to induce activation and proliferation of CD4(+) T cells, characterized by reduced Th1 but increased frequency of FOXP3(+) regulatory T cells. These regulatory T cells secreted high amounts of IL-10, and their suppression capacity was dependent on IL-10 and TGF-beta. Interestingly, the induction of tolerogenic DCs by PSMs appeared to be independent of mFPRs, as shown by experiments with mice lacking mFPR2 (mFPR2(-/-)) and the cognate G protein (p110gamma(-/-)). Thus, PSMs from highly virulent pathogens affect DC functions, thereby modulating the adaptive immune response and probably increasing the tolerance toward the pathogen. PMID- 23460736 TI - The ataxia telangiectasia mutated kinase pathway regulates IL-23 expression by human dendritic cells. AB - Little is known of the regulation of IL-23 secretion in dendritic cells (DC) despite its importance for human Th17 responses. In this study, we show for first time, to our knowledge, that the ataxia telangiectasia mutated (ATM) pathway, involved in DNA damage sensing, acts as an IL-23 repressor. Inhibition of ATM with the highly selective antagonist KU55933 markedly increased IL-23 secretion in human monocyte-derived DC and freshly isolated myeloid DC. In contrast, inhibiting the closely related mammalian target of rapamycin had no effect on IL 23. Priming naive CD4(+) T cells with ATM-inhibited DC increased Th17 responses over and above those obtained with mature DC. Although ATM blockade increased the abundance of p19, p35, and p40 mRNA, IL-12p70 secretion was unaffected. To further examine a role for ATM in IL-23 regulation, we exposed DC to low doses of ionizing radiation. Exposure of DC to x-rays resulted in ATM phosphorylation and a corresponding depression of IL-23. Importantly, ATM inhibition with KU55933 prevented radiation-induced ATM phosphorylation and abrogated the capacity of x rays to suppress IL-23. To explore how ATM repressed IL-23, we examined a role for endoplasmic reticulum stress responses by measuring generation of the spliced form of X-box protein-1, a key endoplasmic reticulum stress transcription factor. Inhibition of ATM increased the abundance of X-box protein-1 mRNA, and this was followed 3 h later by increased peak p19 transcription and IL-23 release. In summary, ATM activation or inhibition, respectively, inhibited or augmented IL-23 release. This novel role of the ATM pathway represents a new therapeutic target in autoimmunity and vaccine development. PMID- 23460738 TI - The context of gene expression defines the immunodominance hierarchy of cytomegalovirus antigens. AB - Natural immunity to CMV dominates the CD4 and CD8 memory compartments of the CMV seropositive host. This property has been recently exploited for experimental CMV based vaccine vector strategies, and it has shown promise in animal models of AIDS and Ebola disease. Although it is generally agreed that CMV-based vaccine vectors may induce highly protective and persistent memory T cells, the influence of the gene expression context on Ag-specific T cell memory responses and immune protection induced by CMV vectors is not known. Using murine CMV (MCMV) recombinants expressing a single CD8 T cell epitope from HSV-1 fused to different MCMV genes, we show that magnitude and kinetics of T cell responses induced by CMV are dependent on the gene expression of CMV Ags. Interestingly, the kinetics of the immune response to the HSV-1 epitope was paralleled by a reciprocal depression of immune responses to endogenous MCMV Ags. Infection with a recombinant MCMV inducing a vigorous initial immune response to the recombinant peptide resulted in a depressed early response to endogenous MCMV Ag. Another recombinant virus, which induced a slowly developing "inflationary" T cell response to the HSV-1 peptide, induced weaker long-term responses to endogenous CMV Ags. Importantly, both mutants were able to protect mice from a challenge with HSV-1, mediating strong sterilizing immunity. Our data suggest that the context of gene expression markedly influences the T cell immunodominance hierarchy of CMV Ags, but the immune protection against HSV-1 does not require inflationary CD8 responses against the recombinant CMV-expressed epitope. PMID- 23460737 TI - GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development. AB - Thymocyte-expressed molecule involved in selection (THEMIS) is a recently identified regulator of thymocyte positive selection. THEMIS's mechanism of action is unknown, and whether it has a role in TCR-proximal signaling is controversial. In this article, we show that THEMIS and the adapter molecule growth factor receptor-bound protein 2 (GRB2) associate constitutively through binding of a conserved PxRPxK motif within the proline-rich region 1 of THEMIS to the C-terminal SH3-domain of GRB2. This association is indispensable for THEMIS recruitment to the immunological synapse via the transmembrane adapter linker for activation of T cells (LAT) and for THEMIS phosphorylation by Lck and ZAP-70. Two major sites of tyrosine phosphorylation were mapped to a YY-motif close to proline-rich region 1. The YY-motif was crucial for GRB2 binding, suggesting that this region of THEMIS might control local phosphorylation-dependent conformational changes important for THEMIS function. Finally, THEMIS binding to GRB2 was required for thymocyte development. Our data firmly assign THEMIS to the TCR-proximal signaling cascade as a participant in the LAT signalosome and suggest that the THEMIS-GRB2 complex might be involved in shaping the nature of Ras signaling, thereby governing thymic selection. PMID- 23460739 TI - Deciphering complement receptor type 1 interactions with recognition proteins of the lectin complement pathway. AB - Complement receptor type 1 (CR1) is a membrane receptor expressed on a wide range of cells. It is involved in immune complex clearance, phagocytosis, and complement regulation. Its ectodomain is composed of 30 complement control protein (CCP) modules, organized into four long homologous repeats (A-D). In addition to its main ligands C3b and C4b, CR1 was reported to interact with C1q and mannan-binding lectin (MBL) likely through its C-terminal region (CCP22-30). To decipher the interaction of human CR1 with the recognition proteins of the lectin complement pathway, a recombinant fragment encompassing CCP22-30 was expressed in eukaryotic cells, and its interaction with human MBL and ficolins was investigated using surface plasmon resonance spectroscopy. MBL and L-ficolin were shown to interact with immobilized soluble CR1 and CR1 CCP22-30 with apparent dissociation constants in the nanomolar range, indicative of high affinity. The binding site for CR1 was located at or near the MBL-associated serine protease (MASP) binding site in the collagen stalks of MBL and L-ficolin, as shown by competition experiments with MASP-3. Accordingly, the mutation of an MBL conserved lysine residue essential for MASP binding (K55) abolished binding to soluble CR1 and CCP22-30. The CR1 binding site for MBL/ficolins was mapped to CCP24-25 of long homologous repeat D using deletion mutants. In conclusion, we show that ficolins are new CR1 ligands and propose that MBL/L-ficolin binding involves major ionic interactions between conserved lysine residues of their collagen stalks and surface exposed acidic residues located in CR1 CCP24 and/or CCP25. PMID- 23460740 TI - Novel function of Trim44 promotes an antiviral response by stabilizing VISA. AB - Virus-induced signaling adaptor (VISA) functions as a critical adaptor in the regulation of both the production of type I IFNs and the subsequent control of the innate antiviral response. In this study, we demonstrate that tripartite motif (Trim)44 interacts with VISA and promotes VISA-mediated antiviral responses. The overexpression of Trim44 enhances the cellular response to viral infection, whereas Trim44 knockdown yields the opposite effect. Trim44 stabilizes VISA by preventing VISA ubiquitination and degradation. These findings suggest that Trim44 functions as a positive regulator of the virus-triggered immune response by enhancing the stability of VISA. PMID- 23460741 TI - Peyer's patch inducer cells play a leading role in the formation of B and T cell zone architecture. AB - Peripheral lymphoid tissues, such as lymph nodes and Peyer's patches (PPs), are organs required for mounting highly efficient immune responses to small quantities of Ag. The compartmentalization of the cellular components involved in the immune response into distinct zones supports the function of these tissues; however, little is known about how this compartmentalization is achieved. In this study, we analyzed neonatal PP development and present evidence that the CD3(-)IL 7Ralpha(+) PP inducer cells that initially play a pivotal role in the formation of the PP anlagen are involved in the formation of B and T cell zones in neonatal mice. PP inducer cells migrate between these zones by undergoing chemokine receptor switching. PMID- 23460742 TI - Identification of Der p 23, a peritrophin-like protein, as a new major Dermatophagoides pteronyssinus allergen associated with the peritrophic matrix of mite fecal pellets. AB - The house dust mite (HDM) Dermatophagoides pteronyssinus is one of most important allergen sources and a major elicitor of allergic asthma. We screened a D. pteronyssinus expression cDNA library with IgE Abs from HDM allergic patients. A cDNA coding for a new major allergen was isolated, which showed sequence homology to peritrophins, which contain chitin-binding domains and are part of the peritrophic matrix lining the gut of arthropods. The mature Der p 23 allergen was expressed in Escherichia coli as an 8-kDa protein without its hydrophobic leader sequence and purified to homogeneity. It reacted with IgE Abs from 74% of D. pteronyssinus allergic patients (n = 347) at levels comparable to the two major HDM allergens, Der p 1 and Der p 2. Thus, Der p 23 represents a new major D. pteronyssinus allergen. Furthermore, rDer p 23 exhibited high allergenic activity as demonstrated by upregulation of CD203c expression on basophils from D. pteronyssinus allergic patients. Immunogold electron microscopy localized the allergen in the peritrophic matrix lining the midgut of D. pteronyssinus as well as on the surface of the fecal pellets. Thus, we identified a new major D. pteronyssinus allergen as peritrophin-like protein. The high allergenic activity of Der p 23 and its frequent recognition as respiratory allergen may be explained by the fact that it becomes airborne and respirable through its association with mite feces. Der p 23 may be an essential component for diagnosis and specific immunotherapy of HDM allergy. PMID- 23460743 TI - Nucleotide oligomerization domain 1 enhances IFN-gamma signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. AB - Virulent Helicobacter pylori strains that specifically activate signaling in epithelial cells via the innate immune molecule, nucleotide oligomerization domain 1 (NOD1), are more frequently associated with IFN-gamma-dependent inflammation and with severe clinical outcomes (i.e., gastric cancer and peptic ulceration). In cell culture models, we showed that H. pylori activation of the NOD1 pathway caused enhanced proinflammatory signaling in epithelial cells in response to IFN-gamma stimulation through the direct effects of H. pylori on two components of the IFN-gamma signaling pathway, STAT1 and IFN regulatory factor 1 (IRF1). Specifically, H. pylori activation of the NOD1 pathway was shown to increase the levels of STAT1-Tyr(701)/Ser(727) phosphorylation and IRF1 expression/synthesis in cells, resulting in enhanced production of the NOD1- and IFN-gamma-regulated chemokines, IL-8- and IFN-gamma-induced protein 10, respectively. Consistent with the notion that heightened proinflammatory signaling in epithelial cells may have an impact on disease severity, we observed significantly increased expression levels of NOD1, CXCL8, IRF1, and CXCL10 in human gastric biopsies displaying severe gastritis, when compared with those without gastritis (p < 0.05, p < 0.001, p < 0.01, and p < 0.05, respectively). Interestingly, NOD1, CXCL8, and IRF1 expression levels were also significantly upregulated in gastric tumor tissues, when compared with paired nontumor samples (p < 0.0001, p < 0.05, and p < 0.05, respectively). Thus, we propose that cross talk between NOD1 and IFN-gamma signaling pathways contribute to H. pylori induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease. PMID- 23460744 TI - Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. AB - Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the immune response in cancer. However, their role in bone marrow (BM), the site of primary localization of multiple myeloma (MM), is poorly understood. In this study, we found a significant accumulation of CD11b(+)CD14(-)CD33(+) immunosuppressive MDSC in BM of patients with newly diagnosed MM. To assess the possible role of MDSC in MM, we used immunocompetent mouse models. Immunosuppressive MDSC accumulated in BM of mice as early as 1 wk after tumor inoculation. S100A9 knockout (KO) mice, which are deficient in their ability to accumulate MDSC in tumor-bearing hosts, demonstrated reduced MDSC accumulation in BM after injection of MM cells compared with wild-type mice. Growth of the immunogenic MM cells was significantly reduced in S100A9KO mice. This effect was associated with the accumulation of Ag-specific CD8(+) T cells in BM and spleens of S100A9KO mice, but not wild-type mice, and was abrogated by the administration of anti-CD8 Ab or adoptive transfer of MDSC. Thus, the accumulation of MDSC at early stages of MM plays a critical role in MM progression and suggests that MDSC can be considered a possible therapeutic target in this disease. PMID- 23460745 TI - Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating programmed cell death-1-mediated CD4+ T cell exhaustion. AB - The breakdown of L-arginine to ornithine and urea by host arginase supports Leishmania proliferation in macrophages. Studies using arginase-null mutants show that Leishmania-derived arginase plays an important role in disease pathogenesis. We investigated the role of parasite-derived arginase in secondary (memory) anti Leishmania immunity in the resistant C57BL/6 mice. We found that C57BL/6 mice infected with arginase-deficient (arg(-)) L. major failed to completely resolve their lesion and maintained chronic pathology after 16 wk, a time when the lesion induced by wild-type L. major is completely resolved. This chronic disease was associated with impaired Ag-specific proliferation and IFN-gamma production, a concomitant increase in programmed cell death-1 (PD-1) expression on CD4(+) T cells, and failure to induce protection against secondary L. major challenge. Treatment with anti-PD-1 mAb restored T cell proliferation and IFN-gamma production in vitro and led to complete resolution of chronic lesion in arg(-) L. major-infected mice. These results show that infection with arg(-) L. major results in chronic disease due in part to PD-1-mediated clonal exhaustion of T cells, suggesting that parasite-derived arginase contributes to the overall quality of the host immune response and subsequent disease outcome in L. major infected mice. They also indicate that persistent parasites alone do not regulate the quality of secondary anti-Leishmania immunity in mice and that the quality of the primary immune response may be playing a hitherto unrecognized dominant role in this process. PMID- 23460746 TI - Critical role of ASC inflammasomes and bacterial type IV secretion system in caspase-1 activation and host innate resistance to Brucella abortus infection. AB - Pathogens are detected by innate immune receptors that, upon activation, orchestrate an appropriate immune response. Recent studies revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella abortus infection. However, no report has elucidated the role of inflammasome receptors in Brucella recognition. Therefore, we decided to investigate the function of NLRC4, NLRP3, and AIM2 in sensing Brucella. In this study, we showed that NLRC4 is not required to induce caspase-1 activation and further secretion of IL-1beta by B. abortus in macrophages. In contrast, we determined that AIM2, which senses Brucella DNA, and NLRP3 are partially required for caspase-1 activation and IL-1beta secretion. Additionally, mitochondrial reactive oxygen species induced by Brucella were implicated in IL-1beta production. Furthermore, AIM2, NLRP3, ASC, and caspase-1 knockout mice were more susceptible to B. abortus infection than were wild-type animals, suggesting that multiple ASC-dependent inflammasomes contribute to host protection against infection. This protective effect is due to the inflammatory response caused by IL-1beta and IL-18 rather than pyroptosis, because we observed augmented bacterial burden in IL-1R and IL-18 knockout mice. Finally, we determined that bacterial type IV secretion system VirB and live, but not heat-killed, Brucella are required for full inflammasome activation in macrophages during infection. Taken together, our results indicate that Brucella is sensed by ASC inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response. PMID- 23460747 TI - An extraribosomal function of ribosomal protein L13a in macrophages resolves inflammation. AB - Inflammation is an obligatory attempt of the immune system to protect the host from infections. However, unregulated synthesis of proinflammatory products can have detrimental effects. Although mechanisms that lead to inflammation are well appreciated, those that restrain it are not adequately understood. Creating macrophage-specific L13a-knockout mice, we report that depletion of ribosomal protein L13a abrogates the endogenous translation control of several chemokines in macrophages. Upon LPS-induced endotoxemia, these animals displayed symptoms of severe inflammation caused by widespread infiltration of macrophages in major organs causing tissue injury and reduced survival rates. Macrophages from these knockout animals show unregulated expression of several chemokines (e.g., CXCL13, CCL22, CCL8, and CCR3). These macrophages failed to show L13a-dependent RNA binding complex formation on target mRNAs. In addition, increased polyribosomal abundance of these mRNAs shows a defect in translation control in the macrophages. Thus, to our knowledge, our studies provide the first evidence of an essential extraribosomal function of ribosomal protein L13a in resolving physiological inflammation in a mammalian host. PMID- 23460749 TI - Monocyte and myeloid dendritic cell activation occurs throughout HIV type 2 infection, an attenuated form of HIV disease. AB - Monocytes and myeloid dendritic cells (mDCs) are important orchestrators of innate and human immunodeficiency virus (HIV)-specific immune responses and of the generalized inflammation that characterizes AIDS progression. To our knowledge, we are the first to investigate monocyte and mDC imbalances in HIV type 2 (HIV-2)-positive patients, who typically feature reduced viremia and slow disease progression despite the recognized ability of HIV-2 to establish viral reservoirs and overcome host restriction factors in myeloid cells. We found a heightened state of monocyte and mDC activation throughout HIV-2 infection (characterized by CD14(bright)CD16(+) expansion, as well as increased levels of soluble CD14, HLA-DR, and CD86), together with progressive mDC depletion. Importantly, HIV-2-positive patients also featured overexpression of the inhibitory molecule PD-L1 on monocytes and mDCs, which may act by limiting the production of proinflammatory molecules. These data, from patients with a naturally occurring form of attenuated HIV disease, challenge current paradigms regarding the role of monocytes in HIV/AIDS and open new perspectives regarding potential strategies to modulate inflammatory states. PMID- 23460748 TI - Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. AB - BACKGROUND: Cerebrospinal fluid (CSF) and neuroimaging abnormalities demonstrate neuronal injury during chronic AIDS, but data on these biomarkers during primary human immunodeficiency virus (HIV) infection is limited. METHODS: We compared CSF concentrations of neurofilament light chain, t-tau, p-tau, amyloid precursor proteins, and amyloid-beta 42 in 92 subjects with primary HIV infection and 25 controls. We examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS)-based metabolites. RESULTS: Neurofilament light chain was elevated in primary HIV infection compared with controls (P = .0004) and correlated with CSF neopterin (r = 0.38; P = .0005), interferon gamma-induced protein 10 (r = 0.39; P = .002), white blood cells (r = 0.32; P = .004), protein (r = 0.59; P < .0001), and CSF/plasma albumin ratio (r = 0.60; P < .0001). Neurofilament light chain correlated with decreased N-acteylaspartate/creatine and glutamate/creatine in the anterior cingulate (r = -0.35, P = .02; r = -0.40, P = .009, respectively), frontal white matter (r = -0.43, P = .003; r = -0.30, P = .048, respectively), and parietal gray matter (r = -0.43, P = .003; r = -0.47, P = .001, respectively). Beta-amyloid was elevated in the primary infection group (P = .0005) and correlated with time infected (r = 0.34; P = .003). Neither marker correlated with neuropsychological abnormalities. T-tau and soluble amyloid precursor proteins did not differ between groups. CONCLUSIONS: Elevated neurofilament light chain and its correlation with MRS-based metabolites suggest early neuronal injury in a subset of participants with primary HIV infection through mechanisms involving central nervous system inflammation. PMID- 23460750 TI - Modeling dendritic cell vaccination for influenza prophylaxis: potential applications for niche populations. AB - BACKGROUND: Cancer patients can exhibit negligible responses to prophylactic vaccinations, including influenza vaccination. To help address this issue, we developed in vitro and in vivo models of dendritic cell (DC) immunotherapy for the prevention of influenza virus infection. METHODS: Human cord blood (CB) derived or mouse splenocyte-derived DCs were loaded with purified recombinant hemagglutinin (rHA). T-cell responses to HA-loaded CB-derived DCs were determined by ELISpot. Protective efficacy was determined by vaccination of BALB/c mice with a single injection of 10(6) autologous DCs. DC migration to peripheral lymphoid organs was verified by carboxyfluorescein succinimidyl ester staining, and HA specific antibody titers were determined by enzyme-linked immunosorbent assay. Mice were then challenged intranasally with BALB/c-adapted A/New Caledonia influenza virus derived from four consecutive lung pool passages. Antigen presenting cell (APC) dysfunction was modeled using the MAFIA transgenic system, in which the Csf1r promoter conditionally drives AP20178-inducible Fas. RESULTS: CB-derived human DCs were able to generate de novo T-cell responses against rHA, as determined by a system of rigorous controls. Mice vaccinated intraperitoneally developed HA titers detectable at serum dilutions of >1:1000. HA seroconverters survived virus challenge, whereas unvaccinated controls and vaccinated nonseroconverters lost weight and died. Furthermore, use of a model of APC specific immunosuppression revealed that DC vaccination could generate HA specific antibody titers under conditions in which protein vaccination could not. CONCLUSIONS: The model demonstrates that DC immunotherapy for the prevention of influenza is feasible, and studies are underway to determine whether populations of immunosuppressed individuals might ultimately benefit from the procedure. PMID- 23460752 TI - Arginine transport is impaired in C57Bl/6 mouse macrophages as a result of a deletion in the promoter of Slc7a2 (CAT2), and susceptibility to Leishmania infection is reduced. AB - Host genetic factors play a crucial role in immune response. To determine whether the differences between C57Bl/6 and BALB-C mice are due only to the production of cytokines by T-helper 1 cells or T-helper 2 cells, we obtained bone marrow derived macrophages from both strains and incubated them with these cytokines. Although the induction of Nos2 and Arg1 was similar in the 2 strains, infectivity to Leishmania major differed, as did macrophage uptake of arginine, which was higher in BALB-C macrophages. The levels of interferon gamma- and interleukin 4 dependent induction of the cationic amino acid transporter SLC7A2 (also known as "cationic amino acid transporter 2," or "CAT2") were decreased in macrophages from C57Bl/6 mice. This reduction was a result of a deletion in the promoter of one of the 4 AGGG repeats. These results demonstrate that the availability of arginine controls critical aspects of macrophage activation and reveal a factor for susceptibility to Leishmania infection. PMID- 23460751 TI - Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced intensity conditioning allogeneic stem cell transplantation. AB - BACKGROUND: The long-term impact of allogeneic hematopoietic stem cell transplantation (HSCT) on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is largely unknown. METHODS: We studied the effects of a reduced-intensity conditioning allogeneic HSCT from donors with wild-type-CCR5(+) cells on HIV-1 peripheral blood reservoirs in 2 patients heterozygous for the ccr5Delta32 mutation. In depth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses were performed on samples obtained before and up to 3.5 years after HSCT receipt. RESULTS: Although HIV-1 DNA was readily detected in peripheral blood mononuclear cells (PBMCs) before and 2-3 months after HSCT receipt, HIV-1 DNA and RNA were undetectable in PBMCs, CD4(+) T cells, or plasma up to 21 and 42 months after HSCT. The loss of detectable HIV-1 correlated temporally with full donor chimerism, development of graft-versus-host disease, and decreases in HIV-specific antibody levels. CONCLUSIONS: The ability of donor cells to engraft without evidence of ongoing HIV-1 infection suggests that HIV-1 replication may be fully suppressed during cART and does not contribute to maintenance of viral reservoirs in peripheral blood in our patients. HSCTs with wild-type-CCR5(+) donor cells can lead to a sustained reduction in the size of the peripheral reservoir of HIV-1. PMID- 23460753 TI - The convergence of new technology with the delivery of health care services. PMID- 23460754 TI - Personal and professional growth through an international sabbatical experience. PMID- 23460755 TI - The importance of survey research standards. AB - Every discipline within fields of research has instituted guidelines and templates for research endeavors and subsequent publications of findings, with the ultimate result being an increase in quality and acceptance by researchers within and across disciplines. These significant efforts are by nature ongoing, as well they should. These enhancements and guideline developments have been instituted in basic science disciplines, clinical pharmacy, and pharmacy administration relevant and related to subsequent scholarly publication of research findings. Specific research endeavors have included bench research, clinical trials and randomized clinical trials, meta analyses, outcomes research, and large scale database analyses. A similar need for quality and standardization also exists for survey research and scholarship. The purpose of this paper is to clarify why this is important and crucial for the Journal and our academy. PMID- 23460756 TI - The fungal meningitis tragedy: implications for pharmacy education and the profession. PMID- 23460757 TI - Challenges facing advanced pharmacy practice experience in Saudi Arabia. PMID- 23460758 TI - Slow light enhanced sensitivity of resonance modes in photonic crystal biosensors. AB - We demonstrate experimentally that in photonic crystal sensors with a side coupled cavity-waveguide configuration, group velocity of the propagating mode in the coupled waveguide at the frequency of the resonant mode plays an important role in enhancing the sensitivity. In linear L13 photonic crystal microcavities, with nearly same resonance mode quality factors ~7000 in silicon-on-insulator devices, sensitivity increased from 57 nm/RIU to 66 nm/RIU as group index in the coupled waveguide increased from 10.2 to 13.2. Engineering for highest sensitivity in such planar integrated sensors, thus, requires careful slow light design for optimized sensor sensitivity. PMID- 23460759 TI - Micromachined piezoelectric microphones with in-plane directivity. AB - Micromachined piezoelectric microphones with in-plane directivity are introduced. A beam rotates about center torsional pivots and is attached to piezoelectrically active end-springs. Rotation of the beam in response to sound pressure gradients produces spring deflections, which, in turn, produce an open-circuit voltage at the piezoelectric films. Prototypes are presented that contain a 20-MUm-thick silicon beam and end-springs with 900-nm-thick chemical solution deposited lead zirconate titanate atop the surface of the end-springs. Acoustic directivity measurements are presented that confirm device functionality. PMID- 23460760 TI - Full-field transmission x-ray imaging with confocal polycapillary x-ray optics. AB - A transmission x-ray imaging setup based on a confocal combination of a polycapillary focusing x-ray optic followed by a polycapillary collimating x-ray optic was designed and demonstrated to have good resolution, better than the unmagnified pixel size and unlimited by the x-ray tube spot size. This imaging setup has potential application in x-ray imaging for small samples, for example, for histology specimens. PMID- 23460761 TI - International standards for neurological classification of spinal cord injury, revised 2011. PMID- 23460762 TI - Competent care for persons with spinal cord injury and dysfunction in acute inpatient rehabilitation. PMID- 23460763 TI - International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI), First Edition 2012. PMID- 23460764 TI - Chronic obstructive pulmonary disease as a cardiovascular risk factor: results of a case-control study (CONSISTE study). PMID- 23460767 TI - Exploiting temporal continuity of views to learn visual object invariance. PMID- 23460768 TI - About the nature of contextual impairments revealed by FN400 abnormalities in schizophrenia. PMID- 23460769 TI - Bootstrapping the early lexicon: how do children use old knowledge to create new meanings? PMID- 23460770 TI - On opposing effects of emotion on contextual or relational memory. PMID- 23460771 TI - Editorial: Moving on in biomicrofluidics. PMID- 23460773 TI - Preface to special topic: microfluidics in cancer research. PMID- 23460772 TI - Chip in a lab: Microfluidics for next generation life science research. AB - Microfluidic circuits are characterized by fluidic channels and chambers with a linear dimension on the order of tens to hundreds of micrometers. Components of this size enable lab-on-a-chip technology that has much promise, for example, in the development of point-of-care diagnostics. Micro-scale fluidic circuits also yield practical, physical, and technological advantages for studying biological systems, enhancing the ability of researchers to make more precise quantitative measurements. Microfluidic technology has thus become a powerful tool in the life science research laboratory over the past decade. Here we focus on chip-in-a-lab applications of microfluidics and survey some examples of how small fluidic components have provided researchers with new tools for life science research. PMID- 23460779 TI - A comparison of inbreeding depression in tropical and widespread Drosophila species. AB - The evolutionary history of widespread and specialized species is likely to cause a different genetic architecture of key ecological traits in the two species groups. This may affect how these two groups respond to inbreeding. Here we investigate inbreeding effects in traits related to performance in 5 widespread and 5 tropical restricted species of Drosophila with the aim of testing whether the two species groups suffered differently from inbreeding depression. The traits investigated were egg-to-adult viability, developmental time and resistance to heat, cold and desiccation. Our results showed that levels of inbreeding depression were species and trait specific and did not differ between the species groups for stress resistance traits. However, for the life history traits developmental time and egg-to adult viability, more inbreeding depression was observed in the tropical species. The results reported suggest that for life history traits tropical species of Drosophila will suffer more from inbreeding depression than widespread species in case of increases in the rate of inbreeding e.g. due to declines in population sizes. PMID- 23460780 TI - 'What do I know? Should I participate?' Considerations on participation in HIV related research among HIV infected adults in Bangalore, South India. AB - BACKGROUND: India has the highest number of HIV infected persons in the world after South Africa. Much HIV related behavioral, clinical and laboratory based research is ongoing in India. Yet little is known on Indian HIV patients' knowledge of research, their processes of decision making and motives for participation. We aimed to explore these areas among HIV infected individuals to understand their reasons for participating in research. METHODOLOGY/PRINCIPAL FINDINGS: This is a cross sectional survey among 173 HIV infected adults at a tertiary level hospital in Bangalore, India, done between October 2010 and January 2011. A pre-tested questionnaire was administered to the participants by trained research assistants to assess their knowledge regarding research, willingness to participate, decision making and determinants of participation. Participants were presented with five hypothetical HIV research studies. Each study had a different level of intervention and time commitment. Of respondents, 103(60%), said that research meant 'to discover something new' and 138(80%) were willing to participate in research. A third of the respondents were unaware of their right to refuse participation. Willingness to participate in research varied with level of intervention. It was the lowest for the hypothetical study involving sensitive questions followed by the hypothetical drug trial; and was the highest for the hypothetical cross sectional questionnaire based study (p<0.0015). Individual health benefits and altruism were the primary motives for participation in research and indicate the presence of therapeutic misconception. Women were less likely to make autonomous decisions for participation in interventional studies. CONCLUSIONS/SIGNIFICANCE: Despite a majority willing to participate, over a third of respondents did not have any knowledge of research or the voluntary nature of participation. This has ethical implications. Researchers need to focus on enabling potential research participants understand the concepts of research, promote autonomous decisions, especially by women and restrict therapeutic misconception. PMID- 23460781 TI - CLMP is essential for intestinal development, but does not play a key role in cellular processes involved in intestinal epithelial development. AB - Loss-of-function mutations in CLMP have been found in patients with Congenital Short Bowel Syndrome (CSBS), suggesting that its encoded protein plays a major role in intestinal development. CLMP is a membrane protein that co-localizes with tight junction proteins, but its function is largely unknown. We expressed wild type (WT)-CLMP and a mutant-CLMP (associated with CSBS) in human intestinal epithelial T84 cells that, as we show here, do not produce endogenous CLMP. We investigated the effects of WT-CLMP and mutant-CLMP proteins on key cellular processes that are important for intestinal epithelial development, including migration, proliferation, viability and transepithelial resistance. Our data showed that expression of WT-CLMP or mutant-CLMP does not affect any of these processes. Moreover, our aggregation assays in CHO cells show that CLMP does not act as a strong adhesion molecule. Thus, our data suggest that, in the in vitro model systems we used, the key processes involved in intestinal epithelial development appear to be unaffected by WT-CLMP or mutant-CLMP. Further research is needed to determine the role of CLMP in the development of the intestine. PMID- 23460782 TI - Acute central neuropeptide Y administration increases food intake but does not affect hepatic very low-density lipoprotein (VLDL) production in mice. AB - OBJECTIVE: Central neuropeptide Y (NPY) administration stimulates food intake in rodents. In addition, acute modulation of central NPY signaling increases hepatic production of very low-density lipoprotein (VLDL)-triglyceride (TG) in rats. As hypertriglyceridemia is an important risk factor for atherosclerosis, for which well-established mouse models are available, we set out to validate the effect of NPY on hepatic VLDL-TG production in mice, to ultimately investigate whether NPY, by increasing VLDL production, contributes to the development of atherosclerosis. RESEARCH DESIGN AND METHODS: Male C57Bl/6J mice received an intracerebroventricular (i.c.v.) cannula into the lateral (LV) or third (3V) ventricle of the brain. One week later, after a 4 h fast, the animals received an intravenous (i.v.) injection of Tran(35)S (100 uCi) followed by tyloxapol (500 mg/kg body weight; BW), enabling the study of hepatic VLDL-apoB and VLDL-TG production, respectively. Immediately after the i.v. injection of tyloxapol, the animals received either an i.c.v. injection of NPY (0.2 mg/kg BW in artificial cerebrospinal fluid; aCSF), synthetic Y1 receptor antagonist GR231118 (0.5 mg/kg BW in aCSF) or vehicle (aCSF), or an i.v. injection of PYY3-36 (0.5 mg/kg BW in PBS) or vehicle (PBS). RESULTS: Administration of NPY into both the LV and 3V increased food intake within one hour after injection (+164%, p<0.001 and +367%, p<0.001, respectively). NPY administration neither in the LV nor in the 3V affected hepatic VLDL-TG or VLDL-apoB production. Likewise, antagonizing central NPY signaling by either PYY3-36 or GR231118 administration did not affect hepatic VLDL production. CONCLUSION: In mice, as opposed to rats, acute central administration of NPY increases food intake without affecting hepatic VLDL production. These results are of great significance when extrapolating findings on the central regulation of hepatic VLDL production between species. PMID- 23460783 TI - Action initiation in the human dorsal anterior cingulate cortex. AB - The dorsal anterior cingulate cortex (dACC) has previously been implicated in processes that influence action initiation. In humans however, there has been little direct evidence connecting dACC to the temporal onset of actions. We studied reactive behavior in patients undergoing therapeutic bilateral cingulotomy to determine the immediate effects of dACC ablation on action initiation. In a simple reaction task, three patients were instructed to respond to a specific visual cue with the movement of a joystick. Within minutes of dACC ablation, the frequency of false starts increased, where movements occurred prior to presentation of the visual cue. In a decision making task with three separate patients, the ablation effect on action initiation persisted even when action selection was intact. These findings suggest that human dACC influences action initiation, apart from its role in action selection. PMID- 23460784 TI - Symptoms and clinical course of EHEC O104 infection in hospitalized patients: a prospective single center study. AB - OBJECTIVES: Shiga-toxin producing O157:H7 Entero Haemorrhagic E. coli (STEC/EHEC) is one of the most common causes of Haemolytic Uraemic Syndrome (HUS) related to infectious haemorrhagic colitis. Nearly all recommendations on clinical management of EHEC infections refer to this strain. The 2011 outbreak in Northern Europe was the first to be caused by the serotype O104:H4. This EHEC strain was found to carry genetic features of Entero Aggregative E. coli (EAEC) and extended spectrum beta lactamase (ESBL). We report symptoms and complications in patients at one of the most affected centres of the 2011 EHEC O104 outbreak in Northern Germany. METHODS: The courses of patients admitted to our hospital due to bloody diarrhoea with suspected EHEC O104 infection were recorded prospectively. These data include the patients' histories, clinical findings, and complications. RESULTS: EHEC O104 infection was confirmed in 61 patients (female = 37; mean age: 44+/-2 years). The frequency of HUS was 59% (36/61) in our cohort. An enteric colonisation with co-pathogens was found in 57%. Thirty-one (51%) patients were treated with plasma-separation/plasmapheresis, 16 (26%) with haemodialysis, and 7 (11%) with Eculizumab. Patients receiving antibiotic treatment (n = 37; 61%) experienced no apparent change in their clinical course. Twenty-six (43%) patients suffered from neurological symptoms. One 83-year-old patient died due to comorbidities after HUS was successfully treated. CONCLUSIONS: EHEC O104:H4 infections differ markedly from earlier reports on O157:H7 induced enterocolitis in regard to epidemiology, symptomatology, and frequency of complications. We recommend a standard of practice for clinical monitoring and support the renaming of EHEC O104:H4 syndrome as "EAHEC disease". PMID- 23460785 TI - Remote monitoring of inhaled bronchodilator use and weekly feedback about asthma management: an open-group, short-term pilot study of the impact on asthma control. AB - OBJECTIVE: Adequate symptom control is a problem for many people with asthma. We asked whether weekly email reports on monitored use of inhaled, short-acting bronchodilators might improve scores on composite asthma-control measures. METHODS: Through an investigational electronic medication sensor attached to each participant's inhaler, we monitored 4 months' use of inhaled, short-acting bronchodilators. Participants completed surveys, including the Asthma Control Test(TM) (ACT), to assess asthma control at entry and monthly thereafter. After the first month, participants received weekly email reports for 3 months. The reports summarized inhaled bronchodilator use during the preceding week and provided suggestions derived from National Asthma Education and Prevention Program (NAEPP) guidelines. Paired t-tests and random-effects mixed models were implemented to assess changes in primary asthma endpoints. RESULTS: Thirty individuals participated in the 4-month study; 29 provided complete asthma control information. Mean age was 36.8 years (range: 19-74 years); 52% of respondents were female. Mean ACT scores were 17.6 (Standard Deviation [SD] = 3.35) at entry and 18.4 (SD = 3.60) at completion of the first month. No significant difference appeared between ACT values at entry and completion of the first month (p = 0.66); however, after participants began receiving email reports and online information about their inhaler use, mean ACT scores increased 1.40 points (95% CI: 0.61, 2.18) for each subsequent study month. Significant decreases occurred in 2-week histories of daytime symptoms (beta = -1.35, 95% CI: -2.65, -0.04) and nighttime symptoms (beta = -0.84, 95% CI: -1.25, -0.44); no significant change in activity limitation (beta = -0.21, 95% CI: -0.69, 0.26) was observed. Participants reported increased awareness and understanding of asthma patterns, level of control, bronchodilator use (timing, location) and triggers, and improved preventive practices. CONCLUSIONS: Weekly email reports and access to online charts summarizing remote monitoring of inhaled bronchodilator frequency and location were associated with improved asthma control and a decline in day-to-day asthma symptoms. PMID- 23460786 TI - "How much will I get charged for this?" Patient charges for top ten diagnoses in the emergency department. AB - OBJECTIVES: We examined the charges, their variability, and respective payer group for diagnosis and treatment of the ten most common outpatient conditions presenting to the Emergency department (ED). METHODS: We conducted a cross sectional study of the 2006-2008 Medical Expenditure Panel Survey. Analysis was limited to outpatient visits with non-elderly, adult (years 18-64) patients with a single discharge diagnosis. RESULTS: We studied 8,303 ED encounters, representing 76.6 million visits. Median charges ranged from $740 (95% CI $651 $817) for an upper respiratory infection to $3437 (95% CI $2917-$3877) for a kidney stone. The median charge for all ten outpatient conditions in the ED was $1233 (95% CI $1199- $1268), with a high degree of charge variability. All diagnoses had an interquartile range (IQR) greater than $800 with 60% of IQRs greater than $1550. CONCLUSION: Emergency department charges for common conditions are expensive with high charge variability. Greater acute care charge transparency will at least allow patients and providers to be aware of the emergency department charges patients may face in the current health care system. PMID- 23460787 TI - Possible causes of a harbour porpoise mass stranding in Danish waters in 2005. AB - An unprecedented 85 harbour porpoises stranded freshly dead along approximately 100 km of Danish coastline from 7-15 April, 2005. This total is considerably above the mean weekly stranding rate for the whole of Denmark, both for any time of year, 1.23 animals/week (ranging from 0 to 20 during 2003-2008, excluding April 2005), and specifically in April, 0.65 animals/week (0 to 4, same period). Bycatch was established as the cause of death for most of the individuals through typical indications of fisheries interactions, including net markings in the skin and around the flippers, and loss of tail flukes. Local fishermen confirmed unusually large porpoise bycatch in nets set for lumpfish (Cyclopterus lumpus) and the strandings were attributed to an early lumpfish season. However, lumpfish catches for 2005 were not unusual in terms of season onset, peak or total catch, when compared to 2003-2008. Consequently, human activity was combined with environmental factors and the variation in Danish fisheries landings (determined through a principal component analysis) in a two-part statistical model to assess the correlation of these factors with both the presence of fresh strandings and the numbers of strandings on the Danish west coast. The final statistical model (which was forward selected using Akaike information criterion; AIC) indicated that naval presence is correlated with higher rates of porpoise strandings, particularly in combination with certain fisheries, although it is not correlated with the actual presence of strandings. Military vessels from various countries were confirmed in the area from the 7th April, en route to the largest naval exercise in Danish waters to date (Loyal Mariner 2005, 11-28 April). Although sonar usage cannot be confirmed, it is likely that ships were testing various equipment prior to the main exercise. Thus naval activity cannot be ruled out as a possible contributing factor. PMID- 23460788 TI - A high throughput genotyping approach reveals distinctive autosomal genetic signatures for European and Near Eastern wild boar. AB - The lack of a Near Eastern genetic signature in modern European porcine breeds indicates that, although domestic pigs from the Fertile Crescent entered Europe during the Neolithic, they were completely replaced by their European counterparts in a short window of time. Whilst the absence of such genetic signature has been convincingly demonstrated at the mitochondrial level, variation at the autosomal genomes of European and Near Eastern Sus scrofa has not been compared yet. Herewith, we have explored the genetic relationships among 43 wild boar from Europe (N = 21), Near East (N = 19) and Korea (N = 3), and 40 Iberian (N = 16), Canarian (N = 4) and Mangalitza (N = 20) pigs by using a high throughput SNP genotyping platform. After data filtering, 37,167 autosomal SNPs were used to perform population genetics analyses. A multidimensional scaling plot based on genome-wide identity-by-state pairwise distances inferred with PLINK showed that Near Eastern and European wild boar populations are genetically differentiated. Maximum likelihood trees built with TreeMix supported this conclusion i.e. an early population split between Near Eastern and European Sus scrofa was observed. Moreover, analysis of the data with Structure evidenced that the sampled Iberian, Canarian and Mangalitza pigs did not carry any autosomal signature compatible with a Near Eastern ancestry, a finding that agrees well with previous mitochondrial studies. PMID- 23460789 TI - Study on the factors associated with postpartum visits in rural China. AB - BACKGROUND: Postpartum visits (PPVs) have been advocated as a way to improve health outcomes for mothers and their infants, but the rate of PPVs is still low in rural China. This study aims to investigate the utilization of PPVs and to explore the factors associated with PPVs in rural China. Parity is the most concerned factor in this study. METHODS: A cross-sectional household survey was performed in two counties of Zhejiang province. Questions include socio-economic, health services and women's delivery data. Chi-square tests and multivariate logistic regression analyses were performed to identify factors associated with PPVs. RESULTS: 223 women who had a delivery history in the recent five years were enrolled in analyses. 173 (78%) of them were primiparous. Among the primiparous women, 43 (25%) had not received any PPVs. The majority, 27 (55%) of the 49 multiparous women, had not received any PPVs. Multiparous women were less likely to receive PPVs than primiparous women. Among 223 puerperal women, 47 (21%) had been compensated for delivery fee expenses. Women who received compensation were found to be more likely to receive standard (at least 3) PPVs. CONCLUSIONS: It was found that women with "second babies" were less likely to use PPVs. This could be an unintended consequence of the "one-child policy", due to fear that contact with public health facilities could result in sanctions. This phenomenon should be taken seriously by government in order to improve the health of babies and their mothers. Financial compensation for delivery fee charges can improve the use of PPVs, thus free-of-charge delivery should be promoted. PMID- 23460790 TI - Stroma cell-derived factor-1alpha signaling enhances calcium transients and beating frequency in rat neonatal cardiomyocytes. AB - Stroma cell-derived factor-1alpha (SDF-1alpha) is a cardioprotective chemokine, acting through its G-protein coupled receptor CXCR4. In experimental acute myocardial infarction, administration of SDF-1alpha induces an early improvement of systolic function which is difficult to explain solely by an anti-apoptotic and angiogenic effect. We wondered whether SDF-1alpha signaling might have direct effects on calcium transients and beating frequency.Primary rat neonatal cardiomyocytes were culture-expanded and characterized by immunofluorescence staining. Calcium sparks were studied by fluorescence microscopy after calcium loading with the Fluo-4 acetoxymethyl ester sensor. The cardiomyocyte enriched cellular suspension expressed troponin I and CXCR4 but was vimentin negative. Addition of SDF-1alpha in the medium increased cytoplasmic calcium release. The calcium response was completely abolished by using a neutralizing anti-CXCR4 antibody and partially suppressed and delayed by preincubation with an inositol triphosphate receptor (IP3R) blocker, but not with a ryanodine receptor (RyR) antagonist. Calcium fluxes induced by caffeine, a RyR agonist, were decreased by an IP3R blocker. Treatment with forskolin or SDF-1alpha increased cardiomyocyte beating frequency and their effects were additive. In vivo, treatment with SDF 1alpha increased left ventricular dP/dtmax.These results suggest that in rat neonatal cardiomyocytes, the SDF-1alpha/CXCR4 signaling increases calcium transients in an IP3-gated fashion leading to a positive chronotropic and inotropic effect. PMID- 23460791 TI - Musical expertise and the ability to imagine loudness. AB - Most perceived parameters of sound (e.g. pitch, duration, timbre) can also be imagined in the absence of sound. These parameters are imagined more veridically by expert musicians than non-experts. Evidence for whether loudness is imagined, however, is conflicting. In music, the question of whether loudness is imagined is particularly relevant due to its role as a principal parameter of performance expression. This study addressed the hypothesis that the veridicality of imagined loudness improves with increasing musical expertise. Experts, novices and non musicians imagined short passages of well-known classical music under two counterbalanced conditions: 1) while adjusting a slider to indicate imagined loudness of the music and 2) while tapping out the rhythm to indicate imagined timing. Subtests assessed music listening abilities and working memory span to determine whether these factors, also hypothesised to improve with increasing musical expertise, could account for imagery task performance. Similarity between each participant's imagined and listening loudness profiles and reference recording intensity profiles was assessed using time series analysis and dynamic time warping. The results suggest a widespread ability to imagine the loudness of familiar music. The veridicality of imagined loudness tended to be greatest for the expert musicians, supporting the predicted relationship between musical expertise and musical imagery ability. PMID- 23460792 TI - Molecular basis of differential sensitivity of myeloma cells to clinically relevant bolus treatment with bortezomib. AB - The proteasome inhibitor bortezomib (Velcade) is prescribed for the treatment of multiple myeloma. Clinically achievable concentrations of bortezomib cause less than 85% inhibition of the chymotrypsin-like activity of the proteasome, but little attention has been paid as to whether in vitro studies are representative of this level of inhibition. Patients receive bortezomib as an intravenous or subcutaneous bolus injection, resulting in maximum proteasome inhibition within one hour followed by a gradual recovery of activity. In contrast, most in vitro studies use continuous treatment so that activity never recovers. Replacing continuous treatment with 1 h-pulse treatment increases differences in sensitivity in a panel of 7 multiple myeloma cell lines from 5.3-fold to 18-fold, and reveals that the more sensitive cell lines undergo apoptosis at faster rates. Clinically achievable inhibition of active sites was sufficient to induce cytotoxicity only in one cell line. At concentrations of bortezomib that produced similar inhibition of peptidase activities a different extent of inhibition of protein degradation was observed, providing an explanation for the differential sensitivity. The amount of protein degraded per number of active proteasomes correlated with sensitivity to bortezomib. Thus, (i) in vitro studies of proteasome inhibitors should be conducted at pharmacologically achievable concentrations and duration of treatment; (ii) a similar level of inhibition of active sites results in a different extent of inhibition of protein breakdown in different cell lines, and hence a difference in sensitivity. PMID- 23460793 TI - Wild bearded capuchin monkeys (Sapajus libidinosus) strategically place nuts in a stable position during nut-cracking. AB - Humans can use hand tools smoothly and effectively in varying circumstances; in other words, skillfully. A few other species of primates crack encased foods using hammer tools and anvils. Are they skilled? Positioning the food on the anvil so that it does not fall off when struck is a component of skilled cracking. We discovered that bearded capuchin monkeys deliberately place palm nuts in a relatively stable position on the anvil before striking them. In the first experiment, we marked the meridians of palm nuts where they stopped when rolled on a flat surface ("Stop meridian"). We videotaped monkeys as they cracked these nuts on an anvil. In playback we coded the position of the Stop meridian prior to each strike. Monkeys typically knocked the nuts on the anvil a few times before releasing them in a pit. They positioned the nuts so that the Stop meridian was within 30 degrees of vertical with respect to gravity more often than expected, and the nuts rarely moved after the monkeys released them. In the second experiment, 14 blindfolded people (7 men) asked to position marked nuts on an anvil as if to crack them reliably placed them with the Stop meridian in the same position as the monkeys did. In the third experiment, two people judged that palm nuts are most bilaterally symmetric along a meridian on, or close to, the Stop meridian. Thus the monkeys reliably placed the more symmetrical side of the nuts against the side of the pit, and the nuts reliably remained stationary when released. Monkeys apparently used information gained from knocking the nut to achieve this position. Thus, monkeys place the nuts skillfully, strategically managing the fit between the variable nuts and pits in the anvil, and skilled placement depends upon information generated by manual action. PMID- 23460794 TI - An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects. AB - Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI>=30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI>=30 kg/m(2) (n = 1575; p additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN. PMID- 23460795 TI - Long-lasting effect of perinatal exposure to L-tryptophan on circadian clock of primary cell lines established from male offspring born from mothers fed on dietary protein restriction. AB - BACKGROUND AIMS: Maternal undernutrition programs metabolic adaptations which are ultimately detrimental to adult. L-tryptophan supplementation was given to manipulate the long-term sequelae of early-life programming by undernutrition and explore whether cultured cells retain circadian clock dysregulation. METHODS: Male rat pups from mothers fed on low protein (8%, LP) or control (18%, CP) diet were given, one hour before light off, an oral bolus of L-tryptophan (125 mg/kg) between Day-12 and Day-21 of age. Body weight, food intake, blood glucose along with the capacity of colonization of primary cells from biopsies were measured during the young (45-55 days) and adult (110-130 days) phases. Circadian clock oscillations were re-induced by a serum shock over 30 hours on near-confluent cell monolayers to follow PERIOD1 and CLOCK proteins by Fluorescent Linked ImmunoSorbent Assay (FLISA) and period1 and bmal1 mRNA by RT-PCR. Cell survival in amino acid-free conditions were used to measure circadian expression of MAP LC3B, MAP-LC3B-FP and Survivin. RESULTS: Tryptophan supplementation did not alter body weight gain nor feeding pattern. By three-way ANOVA of blood glucose, sampling time was found significant during all phases. A significant interaction between daily bolus (Tryptophan, saline) and diets (LP, CP) were found during young (p = 0.0291) and adult (p = 0.0285) phases. In adult phase, the capacity of colonization at seeding of primary cells was twice lower for LP rats. By three way ANOVA of PERIOD1 perinuclear/nuclear immunoreactivity during young phase, we found a significant effect of diets (p = 0.049), daily bolus (p<0.0001) and synchronizer hours (p = 0.0002). All factors were significantly interacting (p = 0.0148). MAP-LC3B, MAP-LC3B-FP and Survivin were altered according to diets in young phase. CONCLUSIONS: Sequelae of early-life undernutrition and the effects of L-tryptophan supplementation can be monitored non-invasively by circadian sampling of blood D-glucose and on the expression of PERIOD1 protein in established primary cell lines. PMID- 23460796 TI - Long term remission of anorexia nervosa: factors involved in the outcome of female patients. AB - BACKGROUND: Anorexia nervosa (AN) is usually marked by difficult recovery. OBJECTIVE: To elicit, describe and characterize factors involved in successful AN remission for at least five years and post-recovery life. METHODS: A qualitative study design using semi-structured interviews according to grounded theory methodology was used. An intentional sample of 15 information rich AN patients was selected using two sampling procedures: the criterion and "snowball" techniques. Qualitative interviews were audiotaped, transcribed, and entered into a content analysis. Researchers coded transcripts and developed themes. RESULTS: Four core parameters were found to be associated with remission: (i) 'motivation to change/stimuli'; (ii) 'empowerment/autonomy'; (iii) 'media related factors'; (iv) 'treatment factors'. Clinical remission can be associated with residual symptoms. CONCLUSIONS: The recovery model involves not only one, but rather a set of inter-active variables, each one can partially explain remission. Media factors can take a new role on recovery. Remission, however, can be followed by remnants of the disease and functional limitations. PMID- 23460797 TI - Modeling the building blocks of biodiversity. AB - BACKGROUND: Networks of single interaction types, such as plant-pollinator mutualisms, are biodiversity's "building blocks". Yet, the structure of mutualistic and antagonistic networks differs, leaving no unified modeling framework across biodiversity's component pieces. METHODS/PRINCIPAL FINDINGS: We use a one-dimensional "niche model" to predict antagonistic and mutualistic species interactions, finding that accuracy decreases with the size of the network. We show that properties of the modeled network structure closely approximate empirical properties even where individual interactions are poorly predicted. Further, some aspects of the structure of the niche space were consistently different between network classes. CONCLUSIONS/SIGNIFICANCE: These novel results reveal fundamental differences between the ability to predict ecologically important features of the overall structure of a network and the ability to predict pair-wise species interactions. PMID- 23460798 TI - Partial MHC/neuroantigen peptide constructs: a potential neuroimmune-based treatment for methamphetamine addiction. AB - Relapse rates following current methamphetamine abuse treatments are very high (~40-60%), and the neuropsychiatric impairments (e.g., cognitive deficits, mood disorders) that arise and persist during remission from methamphetamine addiction likely contribute to these high relapse rates. Pharmacotherapeutic development of medications to treat addiction has focused on neurotransmitter systems with only limited success, and there are no Food and Drug Administration approved pharmacotherapies for methamphetamine addiction. A growing literature shows that methamphetamine alters peripheral and central immune functions and that immune factors such as cytokines, chemokines, and adhesion molecules play a role in the development and persistence of methamphetamine induced neuronal injury and neuropsychiatric impairments. The objective of this study was to evaluate the efficacy of a new immunotherapy, partial MHC/neuroantigen peptide construct (RTL551; pI-A(b)/mMOG-35-55), in treating learning and memory impairments induced by repeated methamphetamine exposure. C57BL/6J mice were exposed to two different methamphetamine treatment regimens (using repeated doses of 4 mg/kg or 10 mg/kg, s.c.). Cognitive performance was assessed using the Morris water maze and CNS cytokine levels were measured by multiplex assay. Immunotherapy with RTL551 improved the memory impairments induced by repeated methamphetamine exposure in both mouse models of chronic methamphetamine addiction. Treatment with RTL551 also attenuated the methamphetamine induced increases in hypothalamic interleukin 2 (IL-2) levels. Collectively, these initial results indicate that neuroimmune targeted therapies, and specifically RTL551, may have potential as treatments for methamphetamine-induced neuropsychiatric impairments. PMID- 23460799 TI - The interaction of the chemotherapeutic drug chlorambucil with human glutathione transferase A1-1: kinetic and structural analysis. AB - Glutathione transferases (GSTs) are enzymes that contribute to cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs. In the present work we investigated the interaction of the chemotherapeutic drug chlorambucil (CBL) with human GSTA1-1 (hGSTA1-1) using kinetic analysis, protein crystallography and molecular dynamics. In the presence of GSH, CBL behaves as an efficient substrate for hGSTA1-1. The rate-limiting step of the catalytic reaction between CBL and GSH is viscosity-dependent and kinetic data suggest that product release is rate-limiting. The crystal structure of the hGSTA1-1/CBL-GSH complex was solved at 2.1 A resolution by molecular replacement. CBL is bound at the H-site attached to the thiol group of GSH, is partially ordered and exposed to the solvent, making specific interactions with the enzyme. Molecular dynamics simulations based on the crystal structure indicated high mobility of the CBL moiety and stabilization of the C-terminal helix due to the presence of the adduct. In the absence of GSH, CBL is shown to be an alkylating irreversible inhibitor for hGSTA1-1. Inactivation of the enzyme by CBL followed a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of CBL per mol of dimeric enzyme being incorporated. Structural analysis suggested that the modifying residue is Cys112 which is located at the entrance of the H-site. The results are indicative of a structural communication between the subunits on the basis of mutually exclusive modification of Cys112, indicating that the two enzyme active sites are presumably coordinated. PMID- 23460800 TI - Genome-wide copy number variation analysis in extended families and unrelated individuals characterized for musical aptitude and creativity in music. AB - Music perception and practice represent complex cognitive functions of the human brain. Recently, evidence for the molecular genetic background of music related phenotypes has been obtained. In order to further elucidate the molecular background of musical phenotypes we analyzed genome wide copy number variations (CNVs) in five extended pedigrees and in 172 unrelated subjects characterized for musical aptitude and creative functions in music. Musical aptitude was defined by combination of the scores of three music tests (COMB scores): auditory structuring ability, Seashores test for pitch and for time. Data on creativity in music (herein composing, improvising and/or arranging music) was surveyed using a web-based questionnaire.Several CNVRs containing genes that affect neurodevelopment, learning and memory were detected. A deletion at 5q31.1 covering the protocadherin-alpha gene cluster (Pcdha 1-9) was found co segregating with low music test scores (COMB) in both sample sets. Pcdha is involved in neural migration, differentiation and synaptogenesis. Creativity in music was found to co-segregate with a duplication covering glucose mutarotase gene (GALM) at 2p22. GALM has influence on serotonin release and membrane trafficking of the human serotonin transporter. Interestingly, genes related to serotonergic systems have been shown to associate not only with psychiatric disorders but also with creativity and music perception. Both, Pcdha and GALM, are related to the serotonergic systems influencing cognitive and motor functions, important for music perception and practice. Finally, a 1.3 Mb duplication was identified in a subject with low COMB scores in the region previously linked with absolute pitch (AP) at 8q24. No differences in the CNV burden was detected among the high/low music test scores or creative/non-creative groups. In summary, CNVs and genes found in this study are related to cognitive functions. Our result suggests new candidate genes for music perception related traits and supports the previous results from AP study. PMID- 23460801 TI - Conformational and thermal stability improvements for the large-scale production of yeast-derived rabbit hemorrhagic disease virus-like particles as multipurpose vaccine. AB - Recombinant virus-like particles (VLP) antigenically similar to rabbit hemorrhagic disease virus (RHDV) were recently expressed at high levels inside Pichia pastoris cells. Based on the potential of RHDV VLP as platform for diverse vaccination purposes we undertook the design, development and scale-up of a production process. Conformational and stability issues were addressed to improve process control and optimization. Analyses on the structure, morphology and antigenicity of these multimers were carried out at different pH values during cell disruption and purification by size-exclusion chromatography. Process steps and environmental stresses in which aggregation or conformational instability can be detected were included. These analyses revealed higher stability and recoveries of properly assembled high-purity capsids at acidic and neutral pH in phosphate buffer. The use of stabilizers during long-term storage in solution showed that sucrose, sorbitol, trehalose and glycerol acted as useful aggregation reducing agents. The VLP emulsified in an oil-based adjuvant were subjected to accelerated thermal stress treatments. None to slight variations were detected in the stability of formulations and in the structure of recovered capsids. A comprehensive analysis on scale-up strategies was accomplished and a nine steps large-scale production process was established. VLP produced after chromatographic separation protected rabbits against a lethal challenge. The minimum protective dose was identified. Stabilized particles were ultimately assayed as carriers of a foreign viral epitope from another pathogen affecting a larger animal species. For that purpose, a linear protective B-cell epitope from Classical Swine Fever Virus (CSFV) E2 envelope protein was chemically coupled to RHDV VLP. Conjugates were able to present the E2 peptide fragment for immune recognition and significantly enhanced the peptide-specific antibody response in vaccinated pigs. Overall these results allowed establishing improved conditions regarding conformational stability and recovery of these multimers for their production at large-scale and potential use on different animal species or humans. PMID- 23460803 TI - Tremulatory and abdomen vibration signals enable communication through air in the stink bug Euschistus heros. AB - Communication by substrate-borne mechanical signals is widespread among animals but remains one of their least understood communication channels. Past studies of vibrational communication in insects have been oriented predominantly to communication during mating, showing that species- and sex-specific vibrational signals enable recognition and localization of potential mates on continuous solid substrates. No special attention has been paid to vibrational signals with less obvious specificity as well as to the possibility of vibrational communication across substrates that are not in physical contact. We aimed to reinvestigate emission of the aforementioned vibrational signals transmitted through a plant in the stink bug Euschistus heros (Pentatomidae: Pentatominae) and to check whether individuals are able to communicate across adjecent, physically separated substrates. We used laser vibrometry for registration of substrate-borne vibrational signals on a bean plant. Using two bean plants separated for 3 to 7 cm between two most adjacent leaves, we investigated the possibility of transmission of these signals through air. Our study showed that males and females of E. heros communicate using tremulatory, percussion and buzzing signals in addition to the previously described signals produced by vibrations of the abdomen. Contrary to the latter, the first three signal types did not differ between sexes or between pentatomid species. Experiments with two physically separated plants showed significant searching behaviour and localization of vibrational signals of an E. heros male or a female, in response to abdominal vibration produced signals of a pair duetting on the neighbouring plant, in comparison to control where no animals were on the neighbouring plant. We also confirmed that transmission through air causes amplitude and frequency decay of vibrational signals, which suggests high-amplitude, low-frequency tremulatory signals of these stink bugs their most plausible way of communication across discontinuous substrates. PMID- 23460802 TI - A patient-centered methodology that improves the accuracy of prognostic predictions in cancer. AB - Individualized approaches to prognosis are crucial to effective management of cancer patients. We developed a methodology to assign individualized 5-year disease-specific death probabilities to 1,222 patients with melanoma and to 1,225 patients with breast cancer. For each cancer, three risk subgroups were identified by stratifying patients according to initial stage, and prediction probabilities were generated based on the factors most closely related to 5-year disease-specific death. Separate subgroup probabilities were merged to form a single composite index, and its predictive efficacy was assessed by several measures, including the area (AUC) under its receiver operating characteristic (ROC) curve. The patient-centered methodology achieved an AUC of 0.867 in the prediction of 5-year disease-specific death, compared with 0.787 using the AJCC staging classification alone. When applied to breast cancer patients, it achieved an AUC of 0.907, compared with 0.802 using the AJCC staging classification alone. A prognostic algorithm produced from a randomly selected training subsample of 800 melanoma patients preserved 92.5% of its prognostic efficacy (as measured by AUC) when the same algorithm was applied to a validation subsample containing the remaining patients. Finally, the tailored prognostic approach enhanced the identification of high-risk candidates for adjuvant therapy in melanoma. These results describe a novel patient-centered prognostic methodology with improved predictive efficacy when compared with AJCC stage alone in two distinct malignancies drawn from two separate populations. PMID- 23460804 TI - A new insect-specific flavivirus from northern Australia suppresses replication of West Nile virus and Murray Valley encephalitis virus in co-infected mosquito cells. AB - Recent reports of a novel group of flaviviruses that replicate only in mosquitoes and appear to spread through insect populations via vertical transmission have emerged from around the globe. To date, there is no information on the presence or prevalence of these insect-specific flaviviruses (ISFs) in Australian mosquito species. To assess whether such viruses occur locally, we used reverse transcription-polymerase chain reaction (RT-PCR) and flavivirus universal primers that are specific to the NS5 gene to detect these viruses in mosquito pools collected from the Northern Territory. Of 94 pools of mosquitoes, 13 were RT-PCR positive, and of these, 6 flavivirus isolates were obtained by inoculation of mosquito cell culture. Sequence analysis of the NS5 gene revealed that these isolates are genetically and phylogenetically similar to ISFs reported from other parts of the world. The entire coding region of one isolate (designated 56) was sequenced and shown to have approximately 63.7% nucleotide identity and 66.6% amino acid identity with its closest known relative (Nakiwogo virus) indicating that the prototype Australian ISF represents a new species. All isolates were obtained from Coquillettidia xanthogaster mosquitoes. The new virus is tentatively named Palm Creek virus (PCV) after its place of isolation. We also demonstrated that prior infection of cultured mosquito cells with PCV suppressed subsequent replication of the medically significant West Nile and Murray Valley encephalitis viruses by 10-43 fold (1 to 1.63 log) at 48 hr post-infection, suggesting that superinfection exclusion can occur between ISFs and vertebrate infecting flaviviruses despite their high level of genetic diversity. We also generated several monoclonal antibodies (mAbs) that are specific to the NS1 protein of PCV, and these represent the first ISF-specific mAbs reported to date. PMID- 23460805 TI - Dose-response association of uncontrolled blood pressure and cardiovascular disease risk factors with hyperuricemia and gout. AB - BACKGROUND: First-line therapy of hypertension includes diuretics, known to exert a multiplicative increase on the risk of gout. Detailed insight into the underlying prevalence of hyperuricemia and gout in persons with uncontrolled blood pressure (BP) and common comorbidities is informative to practitioners initiating antihypertensive agents. We quantify the prevalence of hyperuricemia and gout in persons with uncontrolled BP and additional cardiovascular disease (CVD) risk factors. METHODS AND FINDINGS: We performed a cross-sectional study of non-institutionalized US adults, 18 years and older, using the National Health and Nutrition Examination Surveys in 1988-1994 and 1999-2010. Hyperuricemia was defined as serum uric acid >6.0 mg/dL in women; >7.0 mg/dL in men. Gout was ascertained by self-report of physician-diagnosed gout. Uncontrolled BP was based on measured systolic BP>=140 mmHg and diastolic BP>=90 mmHg. Additional CVD risk factors included obesity, reduced glomerular filtration rate, and dyslipidemia. The prevalence of hyperuricemia was 6-8% among healthy US adults, 10-15% among adults with uncontrolled BP, 22-25% with uncontrolled BP and one additional CVD risk factor, and 34-37% with uncontrolled BP and two additional CVD risk factors. Similarly, the prevalence of gout was successively greater, at 1-2%, 4-5%, 6-8%, and 8-12%, respectively, across these same health status categories. In 2007 2010, those with uncontrolled BP and 2 additional CVD risk factors compared to those without CVD risk factors had prevalence ratios of 4.5 (95% CI 3.5-5.6) and 4.5 (95% CI: 3.1-6.3) for hyperuricemia and gout respectively (P<0.01). CONCLUSIONS: Health care providers should be cognizant of the incrementally higher prevalence of hyperuricemia and gout among patients with uncontrolled BP and additional CVD risk factors. With one in three people affected by hyperuricemia among those with several CVD risk factors, physicians should consider their anti-hypertensive regimens carefully and potentially screen for hyperuricemia or gout. PMID- 23460807 TI - An improved population migration algorithm introducing the local search mechanism of the leap-frog algorithm and crossover operator. AB - The population migration algorithm (PMA) is a simulation of a population of the intelligent algorithm. Given the prematurity and low precision of PMA, this paper introduces a local search mechanism of the leap-frog algorithm and crossover operator to improve the PMA search speed and global convergence properties. The typical test function verifies the improved algorithm through its performance. Compared with the improved population migration and other intelligential algorithms, the result shows that the convergence rate of the improved PMA is very high and its convergence is proved. PMID- 23460806 TI - Micro-MRI study of cerebral aging: ex vivo detection of hippocampal subfield reorganization, microhemorrhages and amyloid plaques in mouse lemur primates. AB - Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 um in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages. PMID- 23460808 TI - Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor beta activation. AB - Renal cell carcinoma (RCC) originates in the lining of the proximal convoluted tubule and accounts for approximately 3% of adult malignancies. The RCC incidence rate increases annually and is twofold higher in males than in females. Female hormones such as estrogen may play important roles during RCC carcinogenesis and result in significantly different incidence rates between males and females. In this study, we found that estrogen receptor beta (ERbeta) was more highly expressed in RCC cell lines (A498, RCC-1, 786-O, ACHN, and Caki-1) than in breast cancer cell lines (MCF-7 and HBL-100); however, no androgen receptor (AR) or estrogen receptor alpha (ERalpha) could be detected by western blot. In addition, proliferation of RCC cell lines was significantly decreased after estrogen (17 beta-estradiol, E2) treatment. Since ERbeta had been documented to be a potential tumor suppressor gene, we hypothesized that estrogen activates ERbeta tumor suppressive function, which leads to different RCC incidence rates between males and females. We found that estrogen treatment inhibited cell proliferation, migration, invasion, and increased apoptosis of 786-O (high endogenous ERbeta), and ERbeta siRNA-induced silencing attenuated the estrogen-induced effects. Otherwise, ectopic ERbeta expression in A498 (low endogenous ERbeta) increased estrogen sensitivity and thus inhibited cell proliferation, migration, invasion, and increased apoptosis. Analysis of the molecular mechanisms revealed that estrogen-activated ERbeta not only remarkably reduced growth hormone downstream signaling activation of the AKT, ERK, and JAK signaling pathways but also increased apoptotic cascade activation. In conclusion, this study found that estrogen-activated ERbeta acts as a tumor suppressor. It may explain the different RCC incidence rates between males and females. Furthermore, it implies that ERbeta may be a useful prognostic marker for RCC progression and a novel developmental direction for RCC treatment improvement. PMID- 23460809 TI - Effects of management tactics on meeting conservation objectives for Western North American groundfish fisheries. AB - There is considerable variability in the status of fish populations around the world and a poor understanding of how specific management characteristics affect populations. Overfishing is a major problem in many fisheries, but in some regions the recent tendency has been to exploit stocks at levels below their maximum sustainable yield. In Western North American groundfish fisheries, the status of individual stocks and management systems among regions are highly variable. In this paper, we show the current status of groundfish stocks from Alaska, British Columbia, and the U.S. West Coast, and quantify the influence on stock status of six management tactics often hypothesized to affect groundfish. These tactics are: the use of harvest control rules with estimated biological reference points; seasonal closures; marine reserves; bycatch constraints; individual quotas (i.e., 'catch shares'); and gear type. Despite the high commercial value of many groundfish and consequent incentives for maintaining stocks at their most productive levels, most stocks were managed extremely conservatively, with current exploitation rates at only 40% of management targets and biomass 33% above target biomass on average. Catches rarely exceeded TACs but on occasion were far below TACs (mean catch:TAC ratio of 57%); approximately $150 million of potential landed value was foregone annually by underutilizing TACs. The use of individual quotas, marine reserves, and harvest control rules with estimated limit reference points had little overall effect on stock status. More valuable fisheries were maintained closer to management targets and were less variable over time than stocks with lower catches or ex-vessel prices. Together these results suggest there is no single effective management measure for meeting conservation objectives; if scientifically established quotas are set and enforced, a variety of means can be used to ensure that exploitation rates and biomass levels are near to or more conservative than management targets. PMID- 23460810 TI - Efficacy and safety of traditional chinese medicine for diabetes: a double-blind, randomised, controlled trial. AB - BACKGROUND: Treatment of diabetes mellitus with Traditional Chinese Medicine has a long history. The aim of this study is to establish the safety and efficacy of traditional Chinese medicine combined with glibenclamide to treat type 2 diabetes mellitus. METHODS: In a controlled, double blind, multicentre non-inferiority trial, 800 patients with unsatisfactory glycemic control (fasting glucose 7-13 mmol/L and HbA1c 7-11%) were randomly assigned to receive Xiaoke Pill, a compound of Chinese herbs combined with glibenclamide, or Glibenclamide in two study groups - drug naive group, and patients previously treated with metformin monotherapy (metformin group). Outcome measures at 48 weeks were the incidence and rate of hypoglycemia, mean difference in HbA1c, and proportion of patients with HbA1c<6.5%. FINDINGS: In drug naive group, the total hypoglycemia rate and the mild hypoglycemic episode in the Xiaoke Pill arm were 38% (p = 0.024) and 41% (p = 0.002) less compared to Glibenclamide arm; in Metformin group, the average annual rate of hypoglycemia was 62% lower in Xiaoke Pill arm (p = 0.003). Respective mean changes in HbA1c from baseline were -0.70% and -0.66% for Xiaoke Pill and Glibenclamide, with a between-group difference (95% CI) of -0.04% ( 0.20, 0.12) in the drug naive group, and those in metformin group were -0.45% and -0.59%, 0.14% (-0.12, 0.39) respectively. The respective proportions of patients with a HbA1c level <6.5% were 26.6% and 23.4% in the drug naive group and 20.1% and 18.9% in the metformin group. INTERPRETATION: In patients with type 2 diabetes and inadequate glycaemic control, treatment with Xiaoke Pill led to significant reduction in risk of hypoglycemia and similar improvements in glycemic control after 48 weeks compared to Glibenclamide. TRIAL REGISTRATION: Chinese Clinical Trial Register number, ChiCTR-TRC-08000074. PMID- 23460812 TI - Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery. AB - INTRODUCTION: Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. AIMS AND METHODS: Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. RESULTS: The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. CONCLUSION: This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials. PMID- 23460811 TI - Mice deficient in the respiratory chain gene Cox6a2 are protected against high fat diet-induced obesity and insulin resistance. AB - Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance. PMID- 23460814 TI - The role of recurrence plots in characterizing the output-unemployment relationship: an analysis. AB - We analyse the output-unemployment relationship using an approach based on cross recurrence plots and quantitative recurrence analysis. We use post-war period quarterly U.S. data. The results obtained show the emergence of a complex and interesting relationship. PMID- 23460813 TI - Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) is a major cause of respiratory illness in young children, leading to significant morbidity and mortality worldwide. Despite its medical importance, no vaccine or effective therapeutic interventions are currently available. Therefore, there is a pressing need to identify novel antiviral drugs to combat RSV infections. Hsp90, a cellular protein-folding factor, has been shown to play an important role in the replication of numerous viruses. We here demonstrate that RSV requires Hsp90 for replication. Mechanistic studies reveal that inhibition of Hsp90 during RSV infection leads to the degradation of a viral protein similar in size to the RSV L protein, the viral RNA-dependent RNA polymerase, implicating it as an Hsp90 client protein. Accordingly, Hsp90 inhibitors exhibit antiviral activity against laboratory and clinical isolates of RSV in both immortalized as well as primary differentiated airway epithelial cells. Interestingly, we find a high barrier to the emergence of drug resistance to Hsp90 inhibitors, as extensive growth of RSV under conditions of Hsp90 inhibition did not yield mutants with reduced sensitivity to these drugs. Our results suggest that Hsp90 inhibitors may present attractive antiviral therapeutics for treatment of RSV infections and highlight the potential of chaperone inhibitors as antivirals exhibiting high barriers to development of drug resistance. PMID- 23460815 TI - Levels of cholesterol in small LDL particles predict atherosclerosis progression and incident CHD in the HDL-Atherosclerosis Treatment Study (HATS). AB - OBJECTIVE: Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses. METHODS: Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments. RESULTS: The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2-24.6 nm) and LDL-IVa (23.3-24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values. CONCLUSIONS: Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000553. PMID- 23460816 TI - Reading "sun" and looking up: the influence of language on saccadic eye movements in the vertical dimension. AB - Traditionally, language processing has been attributed to a separate system in the brain, which supposedly works in an abstract propositional manner. However, there is increasing evidence suggesting that language processing is strongly interrelated with sensorimotor processing. Evidence for such an interrelation is typically drawn from interactions between language and perception or action. In the current study, the effect of words that refer to entities in the world with a typical location (e.g., sun, worm) on the planning of saccadic eye movements was investigated. Participants had to perform a lexical decision task on visually presented words and non-words. They responded by moving their eyes to a target in an upper (lower) screen position for a word (non-word) or vice versa. Eye movements were faster to locations compatible with the word's referent in the real world. These results provide evidence for the importance of linguistic stimuli in directing eye movements, even if the words do not directly transfer directional information. PMID- 23460817 TI - Warburg and Crabtree effects in premalignant Barrett's esophagus cell lines with active mitochondria. AB - BACKGROUND: Increased glycolysis is a hallmark of cancer metabolism, yet relatively little is known about this phenotype at premalignant stages of progression. Periodic ischemia occurs in the premalignant condition Barrett's esophagus (BE) due to tissue damage from chronic acid-bile reflux and may select for early adaptations to hypoxia, including upregulation of glycolysis. METHODOLOGY/PRINCIPAL FINDINGS: We compared rates of glycolysis and oxidative phosphorylation in four cell lines derived from patients with BE (CP-A, CP-B, CP C and CP-D) in response to metabolic inhibitors and changes in glucose concentration. We report that cell lines derived from patients with more advanced genetically unstable BE have up to two-fold higher glycolysis compared to a cell line derived from a patient with early genetically stable BE; however, all cell lines preserve active mitochondria. In response to the glycolytic inhibitor 2 deoxyglucose, the most glycolytic cell lines (CP-C and CP-D) had the greatest suppression of extra-cellular acidification, but were able to compensate with upregulation of oxidative phosphorylation. In addition, these cell lines showed the lowest compensatory increases in glycolysis in response to mitochondrial uncoupling by 2,4-dinitrophenol. Finally, these cell lines also upregulated their oxidative phosphorylation in response to glucose via the Crabtree effect, and demonstrate a greater range of modulation of oxygen consumption. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that cells from premalignant Barrett's esophagus tissue may adapt to an ever-changing selective microenvironment through changes in energy metabolic pathways typically associated with cancer cells. PMID- 23460818 TI - Enhancing bioaerosol sampling by Andersen impactors using mineral-oil-spread agar plate. AB - As a bioaerosol sampling standard, Andersen type impactor is widely used since its invention in 1950s, including the investigation of the anthrax attacks in the United States in 2001. However, its related problems such as impaction and desiccation stress as well as particle bounce have not been solved. Here, we improved its biological collection efficiencies by plating a mineral oil layer (100 uL) onto the agar plate. An Andersen six-stage sampler and a BioStage impactor were tested with mineral-oil-spread agar plates in collecting indoor and outdoor bacterial and fungal aerosols. The effects of sampling times (5, 10 and 20 min) were also studied using the BioStage impactor when sampling environmental bioaerosols as well as aerosolized Bacillus subtilis (G+) and Escherichia coli (G ). In addition, particle bounce reduction by mineral-oil-plate was also investigated using an optical particle counter (OPC). Experimental results revealed that use of mineral-oil-spread agar plate can substantially enhance culturable bioaerosol recoveries by Andersen type impactors (p-values<0.05). The recovery enhancement was shown to depend on bioaerosol size, type, sampling time and environment. In general, more enhancements (extra 20%) were observed for last stage of the Andersen six-stage samplers compared to the BioStage impactor for 10 min sampling. When sampling aerosolized B. subtilis, E. coli and environmental aerosols, the enhancement was shown to increase with increasing sampling time, ranging from 50% increase at 5 min to ~100% at 20 min. OPC results indicated that use of mineral oil can effectively reduce the particle bounce with an average of 66% for 10 min sampling. Our work suggests that enhancements for fungal aerosols were primarily attributed to the reduced impaction stress, while for bacterial aerosols reduced impaction, desiccation and particle bounce played major roles. The developed technology can readily enhance the agar-based techniques including those high volume portable samplers for bioaerosol monitoring. PMID- 23460819 TI - Biochemical and functional studies on the Burkholderia cepacia complex bceN gene, encoding a GDP-D-mannose 4,6-dehydratase. AB - This work reports the biochemical and functional analysis of the Burkholderia cenocepacia J2315 bceN gene, encoding a protein with GDP-D-mannose 4,6 dehydratase enzyme activity (E.C.4.2.1.47). Data presented indicate that the protein is active when in the tetrameric form, catalyzing the conversion of GDP-D mannose into GDP-4-keto-6-deoxy-D-mannose. This sugar nucleotide is the intermediary necessary for the biosynthesis of GDP-D-rhamnose, one of the sugar residues of cepacian, the major exopolysaccharide produced by environmental and human, animal and plant pathogenic isolates of the Burkholderia cepacia complex species. Vmax and Km values of 1.5+/-0.2 umol.min(-1).mg(-1) and 1024+/-123 uM, respectively, were obtained from the kinetic characterization of the B. cenocepacia J2315 BceN protein by NMR spectroscopy, at 25 degrees C and in the presence of 1 mol MgCl2 per mol of protein. The enzyme activity was strongly inhibited by the substrate, with an estimated Ki of 2913+/-350 uM. The lack of a functional bceN gene in a mutant derived from B. cepacia IST408 slightly reduced cepacian production. However, in the B. multivorans ATCC17616 with bceN as the single gene in its genome with predicted GMD activity, a bceN mutant did not produce cepacian, indicating that this gene product is required for cepacian biosynthesis. PMID- 23460820 TI - The timing of drug funding announcements relative to elections: a case study involving dementia medications. AB - BACKGROUND: Following initial regulatory approval of prescription drugs, many factors may influence insurers and health systems when they decide whether to add these drugs to their formularies. The role of political pressures on drug funding announcements has received relatively little attention, and elections represent an especially powerful form of political pressure. We examined the temporal relationship between decisions to add one class of drugs to publicly funded formularies in Canada's ten provinces and elections in these jurisdictions. METHODS: Dates of provincial formulary listings for cholinesterase inhibitors, which are drugs used to treat Alzheimer's disease and related dementias, were compared to the dates of provincial elections. Medical journal articles, media reports, and proceedings from provincial legislatures were reviewed to assemble information on the chronology of events. We tested whether there was a statistically significant increase in the probability of drug funding announcements within the 60-day intervals preceding provincial elections. RESULTS: Decisions to fund the cholinesterase inhibitors were made over a nine year span from 1999 to 2007 in the ten provinces. In four of ten provinces, the drugs were added to formularies in a time period closely preceding a provincial election (P = 0.032); funding announcements in these provinces were made between 2 and 47 days prior to elections. Statements made in provincial legislatures highlight the key role of political pressures in these funding announcements. CONCLUSIONS: Impending elections appeared to affect the timing of drug funding announcements in this case study. Despite an established structure for evidence based decision-making, drug funding remains a complex process open to influence from many sources. Awareness of such influences is critical to maintain effective drug policy and public health decision-making. PMID- 23460821 TI - Oxytocin increases the influence of public service advertisements. AB - This paper presents a neurophysiologic model of effective public service advertisements (PSAs) and reports two experiments that test the model. In Experiment 1, we show that after watching 16 PSAs participants who received oxytocin, compared to those given a placebo, donated to 57% more causes, donated 56% more money, and reported 17% greater concern for those in the ads. In Experiment 2, we measured adrenocorticotropin hormone (ACTH) and oxytocin levels in blood before and after participants watched a PSA. As predicted by the model, donations occurred when participants had increases in both ACTH and oxytocin. Our results indicate that PSAs with social content that cause OT release will be more effective than those that do not. Our results also explain why some individuals do not respond to PSAs. PMID- 23460822 TI - Recruitment, growth and mortality of an Antarctic hexactinellid sponge, Anoxycalyx joubini. AB - Polar ecosystems are sensitive to climate forcing, and we often lack baselines to evaluate changes. Here we report a nearly 50-year study in which a sudden shift in the population dynamics of an ecologically important, structure-forming hexactinellid sponge, Anoxycalyx joubini was observed. This is the largest Antarctic sponge, with individuals growing over two meters tall. In order to investigate life history characteristics of Antarctic marine invertebrates, artificial substrata were deployed at a number of sites in the southern portion of the Ross Sea between 1967 and 1975. Over a 22-year period, no growth or settlement was recorded for A. joubini on these substrata; however, in 2004 and 2010, A. joubini was observed to have settled and grown to large sizes on some but not all artificial substrata. This single settlement and growth event correlates with a region-wide shift in phytoplankton productivity driven by the calving of a massive iceberg. We also report almost complete mortality of large sponges followed over 40 years. Given our warming global climate, similar system wide changes are expected in the future. PMID- 23460823 TI - Analysis of proteome profile in germinating soybean seed, and its comparison with rice showing the styles of reserves mobilization in different crops. AB - BACKGROUND: Seed germination is a complex physiological process during which mobilization of nutrient reserves happens. In different crops, this event might be mediated by different regulatory and metabolic pathways. Proteome profiling has been proved to be an efficient way that can help us to construct these pathways. However, no such studies have been performed in soybean germinating seeds up to date. RESULTS: Proteome profiling was conducted through one dimensional gel electrophoresis followed by liquid chromatography and tandem mass spectrometry strategy in the germinating seeds of soybean (glycine max). Comprehensive comparisons were also carried out between rice and soybean germinating seeds. 764 proteins belonging to 14 functional groups were identified and metabolism related proteins were the largest group. Deep analyses of the proteins and pathways showed that lipids were degraded through lipoxygenase dependent pathway and proteins were degraded through both protease and 26S proteosome system, and the lipoxygenase could also help to remove the reactive oxygen species during the rapid mobilization of reserves of soybean germinating seeds. The differences between rice and soybean germinating seeds proteome profiles indicate that each crop species has distinct mechanism for reserves mobilization during germination. Different reserves could be converted into starches before they are totally utilized during the germination in different crops seeds. CONCLUSIONS: This study is the first comprehensive analysis of proteome profile in germinating soybean seeds to date. The data presented in this paper will improve our understanding of the physiological and biochemical status in the imbibed soybean seeds just prior to germination. Comparison of the protein profile with that of germinating rice seeds gives us new insights on mobilization of nutrient reserves during the germination of crops seeds. PMID- 23460824 TI - Protective effect of borage seed oil and gamma linolenic acid on DNA: in vivo and in vitro studies. AB - Borage (Borago officinalis L.) seed oil has been used as a treatment for various degenerative diseases. Many useful properties of this oil are attributed to its high gamma linolenic acid content (GLA, 18:3 omega-6). The purpose of this study was to demonstrate the safety and suitability of the use of borage seed oil, along with one of its active components, GLA, with respect to DNA integrity, and to establish possible in vivo toxic and in vitro cytotoxic effects. In order to measure these properties, five types of assays were carried out: toxicity, genotoxicity, antigenotoxicity, cytotoxicity (using the promyelocytic leukaemia HL60 cell line), and life span (in vivo analysis using the Drosophila model). Results showed that i) Borage seed oil is not toxic to D. melanogaster at physiological concentrations below 125 ul/ml and the studies on GLA indicated non toxicity at the lowest concentration analyzed ii) Borage seed oil and GLA are DNA safe (non-genotoxic) and antimutagenic compared to hydrogen peroxide, thereby confirming its antioxidant capacity; iii) Borage seed oil and GLA exhibited cytotoxic activity in low doses (IC50 of 1 ul/ml and 0.087 mM, respectively) iv) Low doses of borage seed oil (0.19%) increased the health span of D. melanogaster; and v) GLA significantly decreased the life span of D. melanogaster.Based on the antimutagenic and cytotoxic effects along with the ability to increase the health span, we propose supplementation with borage seed oil rather than GLA, because it protects DNA by modulating oxidative genetic damage in D. melanogaster, increases the health span and exerts cytotoxic activity towards promyelocytic HL60 cells. PMID- 23460825 TI - Functional rescue of a kidney anion exchanger 1 trafficking mutant in renal epithelial cells. AB - Mutations in the SLC4A1 gene encoding the anion exchanger 1 (AE1) can cause distal renal tubular acidosis (dRTA), a disease often due to mis-trafficking of the mutant protein. In this study, we investigated whether trafficking of a Golgi retained dRTA mutant, G701D kAE1, or two dRTA mutants retained in the endoplasmic reticulum, C479W and R589H kAE1, could be functionally rescued to the plasma membrane of Madin-Darby Canine Kidney (MDCK) cells. Treatments with DMSO, glycerol, the corrector VX-809, or low temperature incubations restored the basolateral trafficking of G701D kAE1 mutant. These treatments had no significant rescuing effect on trafficking of the mis-folded C479W or R589H kAE1 mutants. DMSO was the only treatment that partially restored G701D kAE1 function in the plasma membrane of MDCK cells. Our experiments show that trafficking of intracellularly retained dRTA kAE1 mutants can be partially restored, and that one chemical treatment rescued both trafficking and function of a dRTA mutant. These studies provide an opportunity to develop alternative therapeutic solutions for dRTA patients. PMID- 23460826 TI - Vegetative versus minimally conscious states: a study using TMS-EEG, sensory and event-related potentials. AB - Differential diagnoses between vegetative and minimally conscious states (VS and MCS, respectively) are frequently incorrect. Hence, further research is necessary to improve the diagnostic accuracy at the bedside. The main neuropathological feature of VS is the diffuse damage of cortical and subcortical connections. Starting with this premise, we used electroencephalography (EEG) recordings to evaluate the cortical reactivity and effective connectivity during transcranial magnetic stimulation (TMS) in chronic VS or MCS patients. Moreover, the TMS-EEG data were compared with the results from standard somatosensory-evoked potentials (SEPs) and event-related potentials (ERPs). Thirteen patients with chronic consciousness disorders were examined at their bedsides. A group of healthy volunteers served as the control group. The amplitudes (reactivity) and scalp distributions (connectivity) of the cortical potentials evoked by TMS (TEPs) of the primary motor cortex were measured. Short-latency median nerve SEPs and auditory ERPs were also recorded. Reproducible TEPs were present in all control subjects in both the ipsilateral and the contralateral hemispheres relative to the site of the TMS. The amplitudes of the ipsilateral and contralateral TEPs were reduced in four of the five MCS patients, and the TEPs were bilaterally absent in one MCS patient. Among the VS patients, five did not manifest ipsilateral or contralateral TEPs, and three of the patients exhibited only ipsilateral TEPs with reduced amplitudes. The SEPs were altered in five VS and two MCS patients but did not correlate with the clinical diagnosis. The ERPs were impaired in all patients and did not correlate with the clinical diagnosis. These TEP results suggest that cortical reactivity and connectivity are severely impaired in all VS patients, whereas in most MCS patients, the TEPs are preserved but with abnormal features. Therefore, TEPs may add valuable information to the current clinical and neurophysiological assessment of chronic consciousness disorders. PMID- 23460827 TI - Listeria monocytogenes alters mast cell phenotype, mediator and osteopontin secretion in a listeriolysin-dependent manner. AB - Whilst mast cells participate in the immune defence against the intracellular bacterium Listeria monocytogenes, there is conflicting evidence regarding the ability of L. monocytogenes to infect mast cells. It is known that the pore forming toxin listeriolysin (LLO) is important for mast cell activation, degranulation and the release of pro-inflammatory cytokines. Mast cells, however, are a potential source of a wide range of cytokines, chemokines and other mediators including osteopontin, which contributes to the clearing of L. monocytogenes infections in vivo, although its source is unknown. We therefore aimed to resolve the controversy of mast cell infection by L. monocytogenes and investigated the extent of mediator release in response to the bacterium. In this paper we show that the infection of bone marrow-derived mast cells by L. monocytogenes is inefficient and LLO-independent. LLO, however, is required for calcium-independent mast cell degranulation as well as for the transient and selective downregulation of cell surface CD117 (c-kit) on mast cells. We demonstrate that in addition to the key pro-inflammatory cytokines TNF-alpha and IL-6, mast cells release a wide range of other mediators in response to L. monocytogenes. Osteopontin, IL-2, IL-4, IL-13 and granulocyte macrophage colony stimulating factor (GM-CSF), and chemokines including CCL2, CCL3, CCL4 and CCL5 are released in a MyD88-dependent manner. The wide range of mediators released by mast cells in response to L. monocytogenes may play an important role in the recruitment and activation of a variety of immune cells in vivo. The cocktail of mediators, however, is unlikely to skew the immune response to a particular effector response. We propose that mast cells provide a hitherto unreported source of osteopontin, and may provide an important role in co-ordinating the immune response during Listeria infection. PMID- 23460829 TI - Reproduction of mucohaemorrhagic diarrhea and colitis indistinguishable from swine dysentery following experimental inoculation with "Brachyspira hampsonii" strain 30446. AB - BACKGROUND: Mucohaemorrhagic diarrhea caused by Brachyspira hyodysenteriae, swine dysentery, is a severe production limiting disease of swine. Recently, pigs in western Canada with clinical signs indistinguishable from swine dysentery were observed. Despite the presence of spirochetes on fecal smears, recognized Brachyspira spp. including B. hyodysenteriae could not be identified. A phylogenetically distinct Brachyspira, called "B. hampsonii" strain 30446, however was isolated. The purpose of this study was to experimentally reproduce mucohaemorrhagic colitis and characterize strain 30446 shedding following inoculation. METHODS AND FINDINGS: Eighteen 13-week-old pigs were randomly assigned to inoculation (n = 12) or control (n = 6) groups in each of two trials. In trial 1, pigs were inoculated with a tissue homogenate collected from clinically affected field cases. In trial 2, pigs were inoculated with a pure broth culture of strain 30446. In both trials, mucohaemorrhagic diarrhea was significantly more common in inoculated pigs than controls, all of which remained healthy. In animals with mucohaemorrhagic diarrhea, significantly more spirochetes were observed on Gram stained fecal smears, and higher numbers of strain 30446 genome equivalents were detected by quantitative PCR (qPCR). Strain 30446 was cultured from colon and/or feces of all affected but no control animals at necropsy. CONCLUSIONS: "Brachyspira hampsonii" strain 30446 causes mucohaemorrhagic diarrhea in pigs following a 4-9 day incubation period. Fecal shedding was detectable by day 4 post inoculation, and rarely preceded the onset of mucoid or haemorrhagic diarrhea by more than 2 days. Culture and 30446 specific qPCR are reliable methods of detection of this organism in feces and tissues of diarrheic pigs. The emergence of a novel Brachyspira spp., such as "B. hampsonii", creates diagnostic challenges including higher risk of false negative diagnostic tests. We therefore recommend diagnostic laboratories routinely use Brachyspira culture, nox-based and species-specific PCR, and DNA sequencing to diagnose Brachyspira-associated colitis in pigs. PMID- 23460828 TI - Acute BDNF treatment upregulates GluR1-SAP97 and GluR2-GRIP1 interactions: implications for sustained AMPA receptor expression. AB - Brain-derived neurotrophic factor (BDNF) plays several prominent roles in synaptic plasticity and in learning and memory formation. Reduced BDNF levels and altered BDNF signaling have been reported in several brain diseases and behavioral disorders, which also exhibit reduced levels of AMPAr subunits. BDNF treatment acutely regulates AMPA receptor expression and function, including synaptic AMPAr subunit trafficking, and implicates several well defined signaling molecules that are required to elicit long term potentiation and depression (LTP and LTD, respectively). Long term encoding of synaptic events, as in long term memory formation, requires AMPAr stabilization and maintenance. However, factors regulating AMPAr stabilization in neuronal cell membranes and synaptic sites are not well characterized. In this study, we examine the effects of acute BDNF treatment on levels of AMPAr-associated scaffolding proteins and on AMPAr subunit scaffolding protein interactions. We also examine the effects of BDNF-dependent enhanced interactions between AMPAr subunits with their specific scaffolding proteins on the accumulation of both types of proteins. Our results show that acute BDNF treatment upregulates the interactions between AMPAr subunits (GluR1 and GluR2) with their scaffold proteins SAP97 and GRIP1, respectively, leading to prolonged increased accumulation of both categories of proteins, albeit with distinct mechanisms for GluR1 and GluR2. Our findings reveal a new role for BDNF in the long term maintenance of AMPA receptor subunits and associated scaffolding proteins at synapses and further support the role of BDNF as a key regulator of synaptic consolidation. These results have potential implications for recent findings implicating BDNF and AMPAr subunits in various brain diseases and behavioral disorders. PMID- 23460830 TI - Host and phenology shifts in the evolution of the social moth genus Thaumetopoea. AB - The genus Thaumetopoea contains the processionary moths, a group of lepidopteran associated with forest trees, well known for the social behaviour of the larvae and for carrying urticating setae. The taxonomy of the genus is partly unresolved and a phylogenetic approach is lacking. The goal of this work is to produce a phylogeny for Thaumetopoea and to identify the main traits driving the evolution of this group. Eighteen mitochondrial and three nuclear genes were fully/partly sequenced. Markers were aligned and analysed singularly or in various combinations. Phylogenetic analyses were performed according to maximum likelihood and Bayesian inference methods. Trees obtained from largest data sets provided identical topologies that received strong statistical support. Three main clades were identified within Thaumetopoea and were further supported by several signatures located in the mitochondrial tRNAs and intergenic spacers. The reference topology was used to investigate the evolution of life history traits related to biogeography, host plant, ecology, and morphology. A multigenic approach allowed to produce a robust phylogenetic analysis of the genus Thaumetopoea, with the identification of three major clades linked to different ecological and life history traits. The first clade is associated with Angiosperm host plants and has a fast spring development of larvae on young foliage. The other clades have originated by one event of host plant shift to Gymnosperm Pinaceae, which implied a longer larval developmental time due to the lower nutritional quality of leaves. These clades showed different adaptations to such a constraint, the first with a switch of larval feeding to cold season (winter pine processionary moths), and the second with a retraction to high altitude and latitude and a development cycle extended over two years (summer pine processionary moths). Recent global warming is affecting all species and seems able to further shape the evolution of the group. PMID- 23460832 TI - Marine ecosystem response to the Atlantic Multidecadal Oscillation. AB - Against the backdrop of warming of the Northern Hemisphere it has recently been acknowledged that North Atlantic temperature changes undergo considerable variability over multidecadal periods. The leading component of natural low frequency temperature variability has been termed the Atlantic Multidecadal Oscillation (AMO). Presently, correlative studies on the biological impact of the AMO on marine ecosystems over the duration of a whole AMO cycle (~60 years) is largely unknown due to the rarity of continuously sustained biological observations at the same time period. To test whether there is multidecadal cyclic behaviour in biological time-series in the North Atlantic we used one of the world's longest continuously sustained marine biological time-series in oceanic waters, long-term fisheries data and historical records over the last century and beyond. Our findings suggest that the AMO is far from a trivial presence against the backdrop of continued temperature warming in the North Atlantic and accounts for the second most important macro-trend in North Atlantic plankton records; responsible for habitat switching (abrupt ecosystem/regime shifts) over multidecadal scales and influences the fortunes of various fisheries over many centuries. PMID- 23460831 TI - A diagnostic model incorporating P50 sensory gating and neuropsychological tests for schizophrenia. AB - OBJECTIVES: Endophenotypes in schizophrenia research is a contemporary approach to studying this heterogeneous mental illness, and several candidate neurophysiological markers (e.g. P50 sensory gating) and neuropsychological tests (e.g. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST)) have been proposed. However, the clinical utility of a single marker appears to be limited. In the present study, we aimed to construct a diagnostic model incorporating P50 sensory gating with other neuropsychological tests in order to improve the clinical utility. METHODS: We recruited clinically stable outpatients meeting DSM-IV criteria of schizophrenia and age- and gender-matched healthy controls. Participants underwent P50 sensory gating experimental sessions and batteries of neuropsychological tests, including CPT, WCST and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). RESULTS: A total of 106 schizophrenia patients and 74 healthy controls were enrolled. Compared with healthy controls, the patient group had significantly a larger S2 amplitude, and thus poorer P50 gating ratio (gating ratio = S2/S1). In addition, schizophrenia patients had a poorer performance on neuropsychological tests. We then developed a diagnostic model by using multivariable logistic regression analysis to differentiate patients from healthy controls. The final model included the following covariates: abnormal P50 gating (defined as P50 gating ratio >0.4), three subscales derived from the WAIS-III (Arithmetic, Block Design, and Performance IQ), sensitivity index from CPT and smoking status. This model had an adequate accuracy (concordant percentage = 90.4%; c-statistic = 0.904; Hosmer Lemeshow Goodness-of-Fit Test, p = 0.64>0.05). CONCLUSION: To the best of our knowledge, this is the largest study to date using P50 sensory gating in subjects of Chinese ethnicity and the first to use P50 sensory gating along with other neuropsychological tests to develop a diagnostic model for schizophrenia. Further research to validate the predictive accuracy of this model by applying it on other samples is warranted. PMID- 23460833 TI - An ensemble method for predicting subnuclear localizations from primary protein structures. AB - BACKGROUND: Predicting protein subnuclear localization is a challenging problem. Some previous works based on non-sequence information including Gene Ontology annotations and kernel fusion have respective limitations. The aim of this work is twofold: one is to propose a novel individual feature extraction method; another is to develop an ensemble method to improve prediction performance using comprehensive information represented in the form of high dimensional feature vector obtained by 11 feature extraction methods. METHODOLOGY/PRINCIPAL FINDINGS: A novel two-stage multiclass support vector machine is proposed to predict protein subnuclear localizations. It only considers those feature extraction methods based on amino acid classifications and physicochemical properties. In order to speed up our system, an automatic search method for the kernel parameter is used. The prediction performance of our method is evaluated on four datasets: Lei dataset, multi-localization dataset, SNL9 dataset and a new independent dataset. The overall accuracy of prediction for 6 localizations on Lei dataset is 75.2% and that for 9 localizations on SNL9 dataset is 72.1% in the leave-one-out cross validation, 71.7% for the multi-localization dataset and 69.8% for the new independent dataset, respectively. Comparisons with those existing methods show that our method performs better for both single-localization and multi localization proteins and achieves more balanced sensitivities and specificities on large-size and small-size subcellular localizations. The overall accuracy improvements are 4.0% and 4.7% for single-localization proteins and 6.5% for multi-localization proteins. The reliability and stability of our classification model are further confirmed by permutation analysis. CONCLUSIONS: It can be concluded that our method is effective and valuable for predicting protein subnuclear localizations. A web server has been designed to implement the proposed method. It is freely available at http://bioinformatics.awowshop.com/snlpred_page.php. PMID- 23460834 TI - The interleukin-10 promoter polymorphism rs1800872 (-592C>A), contributes to cancer susceptibility: meta-analysis of 16,785 cases and 19,713 controls. AB - Interleukin-10 (IL-10) is a multifunctional cytokine which participates in the development and progression of various malignant tumors. To date, a number of case-control studies were conducted to detect the association between IL-10 592C>A polymorphism and cancer risk in humans. However, the results of these studies on the association remain conflicting. In an effort to solve this controversy, we performed a meta-analysis based on 70 case-control studies from 65 articles, including 16 785 cancer cases and 19 713 controls. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall results suggested that the variant homozygote genotype AA of the IL-10-592C>A polymorphism was associated with a moderately decreased risk of all cancer types (OR = 0.90, 95% CI = 0.83-0.98 for homozygote comparison, OR = 0.92, 95% CI = 0.86-0.98 for recessive model). In the stratified analyses, the risk remained for studies of smoking-related cancer, Asian populations and hospital-based studies. These results suggested that the IL-10 592C>A polymorphism might contribute to the cancer susceptibility, especially in smoking-related cancer, Asians and hospital-based studies. Further studies are needed to confirm the relationship. PMID- 23460835 TI - Consumption of artificially-sweetened soft drinks in pregnancy and risk of child asthma and allergic rhinitis. AB - BACKGROUND: Past evidence has suggested a role of artificial sweeteners in allergic disease; yet, the evidence has been inconsistent and unclear. OBJECTIVE: To examine relation of intake of artificially-sweetened beverages during pregnancy with child asthma and allergic rhinitis at 18 months and 7 years. METHODS: We analyzed data from 60,466 women enrolled during pregnancy in the prospective longitudinal Danish National Birth Cohort between 1996 and 2003. At the 25th week of gestation we administered a validated Food Frequency Questionnaire which asked in detail about intake of artificially-sweetened soft drinks. At 18 months, we evaluated child asthma using interview data. We also assessed asthma and allergic rhinitis through a questionnaire at age 7 and by using national registries. Current asthma was defined as self-reported asthma diagnosis and wheeze in the past 12 months. We examined the relation between intake of artificially-sweetened soft drinks and child allergic disease outcomes and present here odds ratios with 95% CI comparing daily vs. no intake. RESULTS: At 18 months, we found that mothers who consumed more artificially-sweetened non carbonated soft drinks were 1.23 (95% CI: 1.13, 1.33) times more likely to report a child asthma diagnosis compared to non-consumers. Similar results were found for child wheeze. Consumers of artificially-sweetened carbonated drinks were more likely to have a child asthma diagnosis in the patient (1.30, 95% CI: 1.01, 1.66) and medication (1.13, 95% CI: 0.98, 1.29) registry, as well as self-reported allergic rhinitis (1.31, 95% CI: 0.98, 1.74) during the first 7 years of follow up. We found no associations for sugar-sweetened soft drinks. CONCLUSION: Carbonated artificially-sweetened soft drinks were associated with registry-based asthma and self-reported allergic rhinitis, while early childhood outcomes were related to non-carbonated soft drinks. These results suggest that consumption of artificially-sweetened soft drinks during pregnancy may play a role in offspring allergic disease development. PMID- 23460836 TI - A new atlas localization approach for subthalamic nucleus utilizing Chinese visible human head datasets. AB - OBJECTIVE: To study the possibility of Chinese visible human (CVH) head datasets as brain atlas for locating the subthalamic nucleus (STN) before deep brain stimulation (DBS) surgery. METHODS: Optimal head axial and coronal 3.0T, T2 weighted magnetic resonance images (MRI) of 30 patients were obtained. Cross sectional head images of four CVH head datasets were chosen to establish an average CVH model. All MRI sequences were registered to the CVH model via fiducials in X-, Y-, and Z-direction, respectively, within the same stereotactic space. The correlations between red nucleus (RN) and fiducials, the accuracy of MRI-to-CVH registration, and the coordinate value differences of RN gravity center between MRI and CVH were tested. RESULTS: The mean gravity center coordinate values and ranges of STN in CVH were measured; The X coordinate value of RN positively correlates with the most anterior point of putamen(PU-A), the lateral edges of putamens (PU-L), and width of the third ventricle, negatively correlated with the patients' age; The minimal mean errors were when no fiducials were used when locating RN between the MRI and the CVH average model; There were no significant differences of RN in X- and Y-direction between MRI sequences and CVH. CONCLUSION: CVH head datasets can be used as brain atlas for Chinese STN localization. Moreover, average coordinate values of the gravity center and the ranges of STN in CVH can be considered as references for locating STN. PMID- 23460837 TI - New insights on cytological and metabolic features of Ostreopsis cf. ovata Fukuyo (Dinophyceae): a multidisciplinary approach. AB - The harmful dinoflagellate Ostreopsis cf. ovata has been causing toxic events along the Mediterranean coasts and other temperate and tropical areas, with increasing frequency during the last decade. Despite many studies, important biological features of this species are still poorly known. An integrated study, using different microscopy and molecular techniques, Raman microspectroscopy and high resolution liquid chromatography-mass spectrometry (HR LC-MS), was undertaken to elucidate cytological aspects, and identify main metabolites including toxins. The species was genetically identified as O. cf. ovata, Atlantic-Mediterranean clade. The ultrastructural results show unique features of the mucilage network abundantly produced by this species to colonize benthic substrates, with a new role of trichocysts, never described before. The amorphous polysaccharidic component of mucilage appears to derive from pusule fibrous material and mucocysts. In all stages of growth, the cells show an abundant production of lipids. Different developmental stages of chloroplasts are found in the peripheral cytoplasm and in the centre of cell. In vivo Raman microspectroscopy confirms the presence of the carotenoid peridinin in O. cf. ovata, and detects in several specimen the abundant presence of unsaturated lipids structurally related to docosahexaenoic acid. The HR LC-MS analysis reveals that ovatoxin-a is the predominant toxin, together with decreasing amounts of ovatoxin-b, -d/e, -c and putative palytoxin. Toxins concentration on a per cell basis increases from exponential to senescent phase. The results suggest that benthic blooms of this species are probably related to features such as the ability to create a unique mucilaginous sheath covering the sea bottom, associated with the production of potent toxins as palytoxin-like compounds. In this way, O. cf. ovata may be able to rapidly colonize benthic substrates outcompeting other species. PMID- 23460838 TI - Bidirectional promoters as important drivers for the emergence of species specific transcripts. AB - The diversification of gene functions has been largely attributed to the process of gene duplication. Novel examples of genes originating from previously untranscribed regions have been recently described without regard to a unifying functional mechanism for their emergence. Here we propose a model mechanism that could generate a large number of lineage-specific novel transcripts in vertebrates through the activation of bidirectional transcription from unidirectional promoters. We examined this model in silico using human transcriptomic and genomic data and identified evidence consistent with the emergence of more than 1,000 primate-specific transcripts. These are transcripts with low coding potential and virtually no functional annotation. They initiate at less than 1 kb upstream of an oppositely transcribed conserved protein coding gene, in agreement with the generally accepted definition of bidirectional promoters. We found that the genomic regions upstream of ancestral promoters, where the novel transcripts in our dataset reside, are characterized by preferential accumulation of transposable elements. This enhances the sequence diversity of regions located upstream of ancestral promoters, further highlighting their evolutionary importance for the emergence of transcriptional novelties. By applying a newly developed test for positive selection to transposable element-derived fragments in our set of novel transcripts, we found evidence of adaptive evolution in the human lineage in nearly 3% of the novel transcripts in our dataset. These findings indicate that at least some novel transcripts could become functionally relevant, and thus highlight the evolutionary importance of promoters, through their capacity for bidirectional transcription, for the emergence of novel genes. PMID- 23460839 TI - Elevated transcription of the gene QSOX1 encoding quiescin Q6 sulfhydryl oxidase 1 in breast cancer. AB - The q arm of chromosome 1 is frequently amplified at the gene level in breast cancer. Since the significance of this is unclear we investigated whether 1q genes are overexpressed in this disease. The cDNA levels of 1q-located genes were analysed in a search for overexpressed genes. 26 genes mapping to the 1q arm show highly significant (P<=0.01) overexpression of transcripts in breast cancer compared to normal breast tissue. Amongst those showing the highest levels of overexpression in both expressed sequence tag (EST) and serial analysis of gene expression (SAGE) databases was enzyme quiescin Q6 sulfhydryl oxidase 1 (QSOX1). We investigated QSOX1 cDNA derived from T47D breast carcinoma cells by RT-PCR and 3'-RACE PCR and identified a novel extended form of QSOX1 transcript, containing a long 3'UTR, nearly double the size of the previously reported QSOX1 cDNA, and confirmed its 3' end nucleotide sequence using RACE-PCR. We also used quantitative real-time PCR to analyse a panel of cDNAs derived from 50 clinically graded normal and malignant breast tissue samples for the expression of QSOX1 mRNAs. QSOX1 transcription was elevated in an increasing proportion in the grade 2 and grade 3 tumours (graded according to the Nottingham prognostic index), with 10 of the 15 grade 3 tumours (67%) examined exceeding the normal range. There was a significant correlation between relative transcript level and clinical grade (P<=0.01) for all qPCR primer sets tested. QSOX1 mRNA levels, based on SAGE expression data, did not correlate with either Estrogen Receptor (ER) or Epidermal Growth Factor Receptor 2 (ErbB-2 or HER2/neu) expression. Our data indicate that QSOX1 is a potential new prognostic marker which may prove of use in the staging of breast tumours and the stratification of breast cancer patients. PMID- 23460840 TI - Induction of SerpinB2 and Th1/Th2 modulation by SerpinB2 during lentiviral infections in vivo. AB - SerpinB2, also known as plasminogen activator inhibitor type 2, is a major product of activated monocytes/macrophages and is often strongly induced during infection and inflammation; however, its physiological function remains somewhat elusive. Herein we show that SerpinB2 is induced in peripheral blood mononuclear cells following infection of pigtail macaques with CCR5-utilizing (macrophage tropic) SIVmac239, but not the rapidly pathogenic CXCR4-utilizing (T cell-tropic) SHIVmn229. To investigate the role of SerpinB2 in lentiviral infections, SerpinB2(-/-) mice were infected with EcoHIV, a chimeric HIV in which HIV gp120 has been replaced with gp80 from ecotropic murine leukemia virus. EcoHIV infected SerpinB2(-/-) mice produced significantly lower anti-gag IgG1 antibody titres than infected SerpinB2(+/+) mice, and showed slightly delayed clearance of EcoHIV. Analyses of published microarray studies showed significantly higher levels of SerpinB2 mRNA in monocytes from HIV-1 infected patients when compared with uninfected controls, as well as a significant negative correlation between SerpinB2 and T-bet mRNA levels in peripheral blood mononuclear cells. These data illustrate that SerpinB2 can be induced by lentiviral infection in vivo and support the emerging notion that a physiological role of SerpinB2 is modulation of Th1/Th2 responses. PMID- 23460841 TI - Collagen osteoid-like model allows kinetic gene expression studies of non collagenous proteins in relation with mineral development to understand bone biomineralization. AB - Among persisting questions on bone calcification, a major one is the link between protein expression and mineral deposition. A cell culture system is here proposed opening new integrative studies on biomineralization, improving our knowledge on the role played by non-collagenous proteins in bone. This experimental in vitro model consisted in human primary osteoblasts cultured for 60 days at the surface of a 3D collagen scaffold mimicking an osteoid matrix. Various techniques were used to analyze the results at the cellular and molecular level (adhesion and viability tests, histology and electron microscopy, RT- and qPCR) and to characterize the mineral phase (histological staining, EDX, ATG, SAED and RMN). On long term cultures human bone cells seeded on the osteoid-like matrix displayed a clear osteoblast phenotype as revealed by the osteoblast-like morphology, expression of specific protein such as alkaline phosphatase and expression of eight genes classically considered as osteoblast markers, including BGLAP, COL1A1, and BMP2. Von Kossa and alizarine red allowed us to identify divalent calcium ions at the surface of the matrix, EDX revealed the correct Ca/P ratio, and SAED showed the apatite crystal diffraction pattern. In addition RMN led to the conclusion that contaminant phases were absent and that the hydration state of the mineral was similar to fresh bone. A temporal correlation was established between quantified gene expression of DMP1 and IBSP, and the presence of hydroxyapatite, confirming the contribution of these proteins to the mineralization process. In parallel a difference was observed in the expression pattern of SPP1 and BGLAP, which questioned their attributed role in the literature. The present model opens new experimental possibilities to study spatio-temporal relations between bone cells, dense collagen scaffolds, NCPs and hydroxyapatite mineral deposition. It also emphasizes the importance of high collagen density environment in bone cell physiology. PMID- 23460843 TI - Evidence of cognitive dysfunction after soccer playing with ball heading using a novel tablet-based approach. AB - Does frequent head-to-ball contact cause cognitive dysfunctions and brain injury to soccer players? An iPad-based experiment was designed to examine the impact of ball-heading among high school female soccer players. We examined both direct, stimulus-driven, or reflexive point responses (Pro-Point) as well as indirect, goal-driven, or voluntary point responses (Anti-Point), thought to require cognitive functions in the frontal lobe. The results show that soccer players were significantly slower than controls in the Anti-Point task but displayed no difference in Pro-Point latencies, indicating a disruption specific to voluntary responses. These findings suggest that even subconcussive blows in soccer can result in cognitive function changes that are consistent with mild traumatic brain injury of the frontal lobes. There is great clinical and practical potential of a tablet-based application for quick detection and monitoring of cognitive dysfunction. PMID- 23460842 TI - Antibody maturation and viral diversification in HIV-infected women. AB - INTRODUCTION: The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women. METHODS: Samples collected at enrollment (N = 2,561) and 12-24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67). RESULTS: In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection. CONCLUSIONS: Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection. PMID- 23460844 TI - Cross-sectional assessment of nut consumption and obesity, metabolic syndrome and other cardiometabolic risk factors: the PREDIMED study. AB - INTRODUCTION: Prospective studies have consistently suggested that nut consumption is inversely related to fatal and non-fatal coronary heart disease. Limited data are available on the epidemiological associations between nut intake and cardiometabolic risk factors. OBJECTIVE: To evaluate associations between frequency of nut consumption and prevalence of cardiometabolic risk factors [obesity, metabolic syndrome (MetS), type-2 diabetes, hypertension, and dyslipidemia] in a Mediterranean population at high cardiovascular risk. MATERIALS AND METHODS: Cross-sectional study of 7,210 men and women (mean age, 67 y) recruited into the PREDIMED study. MetS was defined by the harmonized ATPIII and IDF criteria. Diabetes and hypertension were assessed by clinical diagnosis and dyslipidemia (high triglycerides, low HDL-cholesterol, and hypercholesterolemia) by lipid analyses. Nut consumption was assessed using a validated food frequency questionnaire and categorized as <1, 1-3, and >3 servings/wk. Control of confounding was done with multivariate logistic regression. RESULTS: Compared to participants consuming <1 serving/wk of nuts, those consuming >3 servings/wk had lower adjusted odds ratios (OR) for obesity (0.61, 95% confidence interval 0.54 to 0.68; P-trend <0.001), MetS (0.74, 0.65 to 0.85; P-trend<0.001), and diabetes (0.87, 0.78 to 0.99; P-trend = 0.043). Higher nut consumption was also associated with lower risk of the abdominal obesity MetS criterion (OR 0.68, 0.60 to 0.79; P-trend<0.001). No significant associations were observed for the MetS components high blood pressure, dyslipidemia, or elevated fasting glucose. CONCLUSIONS: Nut consumption was inversely associated with the prevalence of general obesity, central obesity, MetS, and diabetes in subjects at high cardiovascular risk. PMID- 23460845 TI - Play to become a surgeon: impact of Nintendo Wii training on laparoscopic skills. AB - BACKGROUND: Video-games have become an integral part of the new multimedia culture. Several studies assessed video-gaming enhancement of spatial attention and eye-hand coordination. Considering the technical difficulty of laparoscopic procedures, legal issues and time limitations, the validation of appropriate training even outside of the operating rooms is ongoing. We investigated the influence of a four-week structured Nintendo(r) WiiTM training on laparoscopic skills by analyzing performance metrics with a validated simulator (Lap MentorTM, SimbionixTM). METHODOLOGY/PRINCIPAL FINDINGS: We performed a prospective randomized study on 42 post-graduate I-II year residents in General, Vascular and Endoscopic Surgery. All participants were tested on a validated laparoscopic simulator and then randomized to group 1 (Controls, no training with the Nintendo(r) WiiTM), and group 2 (training with the Nintendo(r) WiiTM) with 21 subjects in each group, according to a computer-generated list. After four weeks, all residents underwent a testing session on the laparoscopic simulator of the same tasks as in the first session. All 42 subjects in both groups improved significantly from session 1 to session 2. Compared to controls, the Wii group showed a significant improvement in performance (p<0.05) for 13 of the 16 considered performance metrics. CONCLUSIONS/SIGNIFICANCE: The Nintendo(r) WiiTM might be helpful, inexpensive and entertaining part of the training of young laparoscopists, in addition to a standard surgical education based on simulators and the operating room. PMID- 23460846 TI - IL-22 is mainly produced by IFNgamma-secreting cells but is dispensable for host protection against Mycobacterium tuberculosis infection. AB - Anti-inflammatory treatment of autoimmune diseases is associated with an increased risk of reactivation tuberculosis (TB). Besides interleukin (IL-17)A, IL-22 represents a classical T helper (TH)17 cytokine and shares similar pathological effects in inflammatory diseases such as psoriasis or arthritis. Whereas IL-17A supports protective immune responses during mycobacterial infections, the role of IL-22 after infection with Mycobacterium tuberculosis (Mtb) is yet poorly characterized. Therefore, we here characterize the cell types producing IL-22 and the protective function of this cytokine during experimental TB in mice. Like IL-17A, IL-22 is expressed early after infection with Mtb in an IL-23-dependent manner. Surprisingly, the majority of IL-22-producing cells are not positive for IL-17A but have rather functional characteristics of interferon gamma-producing TH1 cells. Although we found minor differences in the number of naive and central memory T cells as well as in the frequency of TH1 and polyfunctional T cells in mice deficient for IL-22, the absence of IL-22 does not affect the outcome of Mtb infection. Our study revealed that although produced by TH1 cells, IL-22 is dispensable for protective immune responses during TB. Therefore, targeting of IL-22 in inflammatory disease may represent a therapeutic approach that does not incur the danger of reactivation TB. PMID- 23460847 TI - Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFalpha. AB - Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (Trsp(tG37) ) and/or a cancer driver TGFalpha transgene. The use of Trsp(tG37) altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. Trsp(tG37) transgenic and TGFalpha/Trsp(tG37) bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGFalpha transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGFalpha transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGFalpha-induced liver tumors. PMID- 23460848 TI - The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey. AB - The peroxisome is a key organelle of low abundance that fulfils various functions essential for human cell metabolism. Severe genetic diseases in humans are caused by defects in peroxisome biogenesis or deficiencies in the function of single peroxisomal proteins. To improve our knowledge of this important cellular structure, we studied for the first time human liver peroxisomes by quantitative proteomics. Peroxisomes were isolated by differential and Nycodenz density gradient centrifugation. A label-free quantitative study of 314 proteins across the density gradient was accomplished using high resolution mass spectrometry. By pairing statistical data evaluation, cDNA cloning and in vivo colocalization studies, we report the association of five new proteins with human liver peroxisomes. Among these, isochorismatase domain containing 1 protein points to the existence of a new metabolic pathway and hydroxysteroid dehydrogenase like 2 protein is likely involved in the transport or beta-oxidation of fatty acids in human peroxisomes. The detection of alcohol dehydrogenase 1A suggests the presence of an alternative alcohol-oxidizing system in hepatic peroxisomes. In addition, lactate dehydrogenase A and malate dehydrogenase 1 partially associate with human liver peroxisomes and enzyme activity profiles support the idea that NAD(+) becomes regenerated during fatty acid beta-oxidation by alternative shuttling processes in human peroxisomes involving lactate dehydrogenase and/or malate dehydrogenase. Taken together, our data represent a valuable resource for future studies of peroxisome biochemistry that will advance research of human peroxisomes in health and disease. PMID- 23460849 TI - Maternal touch moderates sex differences in juvenile social play behavior. AB - Additional somatosensory contact of preterm human infants improves a variety of developmental assessment scores, but less is known about its lasting consequences. In rodents, maternal contact may influence the programming of juvenile social play behavior. Therefore, we used a paradigm where we can control the levels of somatosensory contact associated with maternal care. We find that additional somatosensory contact of offspring can have lasting consequences on juvenile social play behavior in a sex-dependent manner. Specifically, additional somatosensory stimuli reduced male social play behavior, but did not change female play behavior. We then examined if this additional infant contact altered some neurobiological substrates associated with play within the juvenile amygdala. Control males had lower levels of 5HT2a receptor mRNA levels contrasted to females; however, similar to its sex-dependent effect on juvenile social play, males that received additional somatosensory contact had higher serotonin 5HT2a receptor mRNA levels than control males. No difference was found in females. As serotonin signaling typically opposes juvenile play behavior, these data suggest that maternal touch can program lasting differences in juvenile social play and 5HT2a receptors mRNA levels within the juvenile amygdala. PMID- 23460850 TI - Adventitial vasa vasorum arteriosclerosis in abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is a common disease among elderly individuals. However, the precise pathophysiology of AAA remains unknown. In AAA, an intraluminal thrombus prevents luminal perfusion of oxygen, allowing only the adventitial vaso vasorum (VV) to deliver oxygen and nutrients to the aortic wall. In this study, we examined changes in the adventitial VV wall in AAA to clarify the histopathological mechanisms underlying AAA. We found marked intimal hyperplasia of the adventitial VV in the AAA sac; further, immunohistological studies revealed proliferation of smooth muscle cells, which caused luminal stenosis of the VV. We also found decreased HemeB signals in the aortic wall of the sac as compared with those in the aortic wall of the neck region in AAA. The stenosis of adventitial VV in the AAA sac and the malperfusion of the aortic wall observed in the present study are new aspects of AAA pathology that are expected to enhance our understanding of this disease. PMID- 23460851 TI - The risk of cancer in patients with generalized anxiety disorder: a nationwide population-based study. AB - OBJECTIVE: To evaluate the risk of cancer among patients with generalized anxiety disorder (GAD) in a nationwide population-based dataset. METHODS: We recruited newly-diagnosed GAD patients aged 20 years or older without antecedent cancer from the Taiwan National Health Insurance Research database between 2000-2010. Standardized incidence ratios (SIRs) of cancers were calculated in GAD patients, and the subgroup of GAD patients diagnosed by psychiatric specialists. RESULTS: A total of 559 cancers developed among 19,793 GAD patients with a follow-up of 89,485 person-years (median follow-up of 4.34 years), leading to a significantly increased SIR of 1.14 [95% confidence interval (CI) 1.05-1.24]. Male GAD patients had a significantly increased SIR overall (1.30, 95% CI 1.15-1.46) and for lung and prostate cancer (1.77, 95% CI 1.33-2.30 and 2.17, 95% CI 1.56-2.93, respectively). Patients over 80 years of age also had a significantly increased SIR (1.56, 95% CI 1.25-1.92), especially in males. However, psychiatrist diagnosed GAD patients did not show increased cancer risk relative to the general population, perhaps due to having fewer physical comorbidities than non psychiatrist-diagnosed GAD patients. CONCLUSION: This study found that overall cancer risk is elevated among patients with GAD. The risk of lung and prostate cancer also increased in male patients with GAD. This increased cancer risk may be due to physical comorbidities and surveillance bias. Further prospective study is necessary to confirm these findings. PMID- 23460852 TI - Proteomic profiling of cereal aphid saliva reveals both ubiquitous and adaptive secreted proteins. AB - The secreted salivary proteins from two cereal aphid species, Sitobion avenae and Metopolophium dirhodum, were collected from artificial diets and analysed by tandem mass spectrometry. Protein identification was performed by searching MS data against the official protein set from the current pea aphid (Acyrthosiphon pisum) genome assembly and revealed 12 and 7 proteins in the saliva of S. avenae and M. dirhodum, respectively. When combined with a comparable dataset from A. pisum, only three individual proteins were common to all the aphid species; two paralogues of the GMC oxidoreductase family (glucose dehydrogenase; GLD) and ACYPI009881, an aphid specific protein previously identified as a putative component of the salivary sheath. Antibodies were designed from translated protein sequences obtained from partial cDNA sequences for ACYPI009881 and both saliva associated GLDs. The antibodies detected all parent proteins in secreted saliva from the three aphid species, but could only detect ACYPI009881, and not saliva associated GLDs, in protein extractions from the salivary glands. This result was confirmed by immunohistochemistry using whole and sectioned salivary glands, and in addition, localised ACYPI009881 to specific cell types within the principal salivary gland. The implications of these findings for the origin of salivary components and the putative role of the proteins identified are discussed in the context of our limited understanding of the functional relationship between aphid saliva and the plants they feed on. The mass spectrometry data have been deposited to the ProteomeXchange and can be accessed under the identifier PXD000113. PMID- 23460853 TI - Serial non-invasive assessment of antibody induced nephritis in mice using positron emission tomography. AB - Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an analytical tool for studying spontaneous lupus nephritis. The potential of Positron Emission Tomography (PET) was evaluated using 2-deoxy-2 [(18)F]fluoro-d-glucose (FDG) as a probe to monitor the progression of anti-GBM induced nephritis in a mouse model. The imaging results were compared to conventional measures of renal function and pathological changes. Serum and urinary vascular cell adhesion molecule-1 (VCAM-1) levels were used as measures of endothelial cell activation and inflammation. Following a challenge with anti glomerular antibodies, mice exhibited peak changes in serum creatinine, proteinuria, and glomerulonephritis score at 14 days post-challenge (p.c.). In contrast, VCAM levels peaked at day 7 p.c. On dynamic PET images (0-60 min) of day 7, kidneys of the anti-GBM nephritis mice demonstrated a unique pattern of FDG uptake. Compared to the time activity curve (TAC) prior to challenge, a rightward shift was observed after the challenge. By day 10 p.c., kidney FDG uptake was lower than baseline and remained so until the study ended at 21 days p.c. During this time frame measures of renal dysfunction remained high but VCAM 1 levels declined. These changes were accompanied by an increase in kidney volume as measured by Computed Tomography (CT) and intra-abdominal fluid collection. Our results suggest that FDG-PET-CT can be used as a non-invasive imaging tool to longitudinally monitor the progression of renal disease activity in antibody mediated nephritis and the magnitude of renal FDG retention correlates better with early markers of renal inflammation than renal dysfunction. PMID- 23460854 TI - Corneal endothelial cells provide evidence of accelerated cellular senescence associated with HIV infection: a case-control study. AB - BACKGROUND: Cellular senescence may be a key factor in HIV-related premature biological aging. We assessed features of the corneal endothelium that are known to be associated with biological aging, and cellular senescence markers in HIV infected adults. METHODS: Case-control study of 242 HIV-infected adults and 249 matched controls. Using specular microscopy, the corneal endothelium was assessed for features of aging (low endothelial cell density [ECD], high variation in cell size, and low hexagonality index). Data were analysed by multivariable regression. CDKN2A expression (a cell senescence mediator) was measured in peripheral blood leukocytes and 8-hydroxy-2'-deoxyguanosine (8-OHDG; an oxidative DNA damage marker) levels were measured in plasma. RESULTS: The median age of both groups was 40 years. Among HIV-infected adults, 88% were receiving antiretroviral therapy (ART); their median CD4 count was 468 cells/uL. HIV infection was associated with increased odds of variation in cell size (OR = 1.67; 95% CI: 1.00-2.78, p = 0.04). Among HIV-infected participants, low ECD was independently associated with current CD4 count <200 cells/uL (OR = 2.77; 95%CI: 1.12-6.81, p = 0.03). In participants on ART with undetectable viral load, CDKN2A expression and 8-OHDG levels were higher in those with accelerated aging, as reflected by lower ECD. CONCLUSIONS: The corneal endothelium shows features consistent with HIV-related accelerated senescence, especially among those with poor immune recovery. PMID- 23460855 TI - Preferential invasion by Plasmodium merozoites and the self-regulation of parasite burden. AB - The preferential invasion of particular red blood cell (RBC) age classes may offer a mechanism by which certain species of Plasmodia regulate their population growth. Asexual reproduction of the parasite within RBCs exponentially increases the number of circulating parasites; limiting this explosion in parasite density may be key to providing sufficient time for the parasite to reproduce, and for the host to develop a specific immune response. It is critical that the role of preferential invasion in infection is properly understood to model the within host dynamics of different Plasmodia species. We develop a simulation model to show that limiting the range of RBC age classes available for invasion is a credible mechanism for restricting parasite density, one which is equally as important as the maximum parasite replication rate and the duration of the erythrocytic cycle. Different species of Plasmodia that regularly infect humans exhibit different preferences for RBC invasion, with all species except P. falciparum appearing to exhibit a combination of characteristics which are able to self-regulate parasite density. PMID- 23460856 TI - Wave-processing of long-scale information by neuronal chains. AB - Investigation of mechanisms of information handling in neural assemblies involved in computational and cognitive tasks is a challenging problem. Synergetic cooperation of neurons in time domain, through synchronization of firing of multiple spatially distant neurons, has been widely spread as the main paradigm. Complementary, the brain may also employ information coding and processing in spatial dimension. Then, the result of computation depends also on the spatial distribution of long-scale information. The latter bi-dimensional alternative is notably less explored in the literature. Here, we propose and theoretically illustrate a concept of spatiotemporal representation and processing of long scale information in laminar neural structures. We argue that relevant information may be hidden in self-sustained traveling waves of neuronal activity and then their nonlinear interaction yields efficient wave-processing of spatiotemporal information. Using as a testbed a chain of FitzHugh-Nagumo neurons, we show that the wave-processing can be achieved by incorporating into the single-neuron dynamics an additional voltage-gated membrane current. This local mechanism provides a chain of such neurons with new emergent network properties. In particular, nonlinear waves as a carrier of long-scale information exhibit a variety of functionally different regimes of interaction: from complete or asymmetric annihilation to transparent crossing. Thus neuronal chains can work as computational units performing different operations over spatiotemporal information. Exploiting complexity resonance these composite units can discard stimuli of too high or too low frequencies, while selectively compress those in the natural frequency range. We also show how neuronal chains can contextually interpret raw wave information. The same stimulus can be processed differently or identically according to the context set by a periodic wave train injected at the opposite end of the chain. PMID- 23460858 TI - Energy in-equivalence in Australian marsupials: evidence for disruption of the continent's mammal assemblage, or are rules meant to be broken? AB - The energy equivalence rule (EER) is a macroecological hypothesis that posits that total population energy use (PEU) should be independent of species body mass, because population densities and energy metabolisms scale with body mass in a directly inverse manner. However, evidence supporting the EER is equivocal, and the use of basal metabolic rate (BMR) in such studies has been questioned; ecologically-relevant indices like field metabolic rate (FMR) are probably more appropriate. In this regard, Australian marsupials present a novel test for the EER because, unlike eutherians, marsupial BMRs and FMRs scale differently with body mass. Based on either FMR or BMR, Australian marsupial PEU did not obey an EER, and scaled positively with body mass based on ordinary least squares (OLS) regressions. Importantly, the scaling of marsupial population density with body mass had a slope of -0.37, significantly shallower than the expected slope of 0.75, and not directly inverse of body-mass scaling exponents for BMR (0.72) or FMR (0.62). The findings suggest that the EER may not be a causal, universal rule, or that for reasons not yet clear, it is not operating for Australia's unique native fauna. PMID- 23460857 TI - Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3beta pathway in mice. AB - BACKGROUND: Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR), an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA) induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs) and mouse lung fibroblasts (mLFs). METHODS: Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR) in response to increasing doses of methacholine were assessed. The TGFbeta1-induced epithelial-mesenchymal transition (EMT) in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s) of airway remodeling. RESULTS: In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFbeta1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFbeta1- induced activation of PI3K/AKT/GSK3beta pathway but not the phosphorylation of Smad2/3. CONCLUSION: Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFbeta1-induced Smad-independent and PI3K/AKT/GSK3beta-dependent pathway. PMID- 23460859 TI - Research on a community-based platform for promoting health and physical fitness in the elderly community. AB - This study aims to assess the acceptability of a fitness testing platform (iFit) for installation in an assisted living community with the aim of promoting fitness and slowing the onset of frailty. The iFit platform develops a means of testing Bureau of Health Promotion mandated health assessment items for the elderly (including flexibility tests, grip strength tests, balance tests, and reaction time tests) and integrates wireless remote sensors in a game-like environment to capture and store subject response data, thus providing individuals in elderly care contexts with a greater awareness of their own physical condition. In this study, we specifically evaluated the users' intention of using the iFit using a technology acceptance model (TAM). A total of 101 elderly subjects (27 males and 74 females) were recruited. A survey was conducted to measure technology acceptance, to verify that the platform could be used as intended to promote fitness among the elderly. Results indicate that perceived usefulness, perceived ease of use and usage attitude positively impact behavioral intention to use the platform. The iFit platform can offer user-friendly solutions for a community-based fitness care and monitoring of elderly subjects. In summary, iFit was determined by three key drivers and discussed as follows: risk factors among the frail elderly, mechanism for slowing the advance frailty, and technology acceptance and support for promoting physical fitness. PMID- 23460860 TI - Metagenomic detection of viral pathogens in Spanish honeybees: co-infection by Aphid Lethal Paralysis, Israel Acute Paralysis and Lake Sinai Viruses. AB - The situation in Europe concerning honeybees has in recent years become increasingly aggravated with steady decline in populations and/or catastrophic winter losses. This has largely been attributed to the occurrence of a variety of known and "unknown", emerging novel diseases. Previous studies have demonstrated that colonies often can harbour more than one pathogen, making identification of etiological agents with classical methods difficult. By employing an unbiased metagenomic approach, which allows the detection of both unexpected and previously unknown infectious agents, the detection of three viruses, Aphid Lethal Paralysis Virus (ALPV), Israel Acute Paralysis Virus (IAPV), and Lake Sinai Virus (LSV), in honeybees from Spain is reported in this article. The existence of a subgroup of ALPV with the ability to infect bees was only recently reported and this is the first identification of such a strain in Europe. Similarly, LSV appear to be a still unclassified group of viruses with unclear impact on colony health and these viruses have not previously been identified outside of the United States. Furthermore, our study also reveals that these bees carried a plant virus, Turnip Ringspot Virus (TuRSV), potentially serving as important vector organisms. Taken together, these results demonstrate the new possibilities opened up by high-throughput sequencing and metagenomic analysis to study emerging new diseases in domestic and wild animal populations, including honeybees. PMID- 23460861 TI - Delta-6 Desaturase substrate competition: dietary linoleic acid (18:2n-6) has only trivial effects on alpha-linolenic acid (18:3n-3) bioconversion in the teleost rainbow trout. AB - It is generally accepted that, in vertebrates, omega-3 (n-3) and omega-6 (n-6) poly-unsaturated fatty acids (PUFA) compete for Delta-6 desaturase enzyme in order to be bioconverted into long-chain PUFA (LC-PUFA). However, recent studies into teleost fatty acid metabolism suggest that these metabolic processes may not conform entirely to what has been previously observed in mammals and other animal models. Recent work on rainbow trout has led us to question specifically if linoleic acid (LA, 18?2n-6) and alpha-linolenic acid (ALA, 18?3n-3) (Delta-6 desaturase substrates) are in direct competition for access to Delta-6 desaturase. Two experimental diets were formulated with fixed levels of ALA, while LA levels were varied (high and low) to examine if increased availability of LA would result in decreased bioconversion of ALA to its LC-PUFA products through substrate competition. No significant difference in ALA metabolism towards n-3 LC-PUFA was exhibited between diets while significant differences were observed in LA metabolism towards n-6 LC-PUFA. These results are evidence for minor if any competition between substrates for Delta-6 desaturase, suggesting that, paradoxically, the activity of Delta-6 desaturase on n-3 and n-6 substrates is independent. These results call for a paradigm shift in the way we approach teleost fatty acid metabolism. The findings are also important with regard to diet formulation in the aquaculture industry as they indicate that there should be no concern for possible substrate competition between 18?3n-3 and 18?2n-6, when aiming at increased n-3 LC-PUFA bioconversion in vivo. PMID- 23460862 TI - Caveolin-1 regulates endothelial adhesion of lung cancer cells via reactive oxygen species-dependent mechanism. AB - The knowledge regarding the role of caveolin-1 (Cav-1) protein on endothelium adhesion of cancer cells is unclear. The present study revealed that Cav-1 plays a negative regulatory role on cancer-endothelium interaction. Endogenous Cav-1 was shown to down-regulate during cell detachment and the level of such a protein was conversely associated with tumor-endothelial adhesion. Furthermore, the ectopic overexpression of Cav-1 attenuated the ability of the cancer cells to adhere to endothelium while shRNA-mediated Cav-1 knock-down exhibited the opposite effect. We found that cell detachment increased cellular hydrogen peroxide and hydroxyl radical generation and such reactive oxygen species (ROS) were responsible for the increasing interaction between cancer cells and endothelial cells through vascular endothelial cell adhesion molecule-1 (VCAM-1). Importantly, Cav-1 was shown to suppress hydrogen peroxide and hydroxyl radical formation by sustaining the level of activated Akt which was critical for the role of Cav-1 in attenuating the cell adhesion. Together, the present study revealed the novel role of Cav-1 and underlying mechanism on tumor adhesion which explain and highlight an important role of Cav-1 on lung cancer cell metastasis. PMID- 23460863 TI - Newborn body fat: associations with maternal metabolic state and placental size. AB - BACKGROUND: Neonatal body composition has implications for the health of the newborn both in short and long term perspective. The objective of the current study was first to explore the association between maternal BMI and metabolic parameters associated with BMI and neonatal percentage body fat and to determine to which extent any associations were modified if adjusting for placental weight. Secondly, we examined the relations between maternal metabolic parameters associated with BMI and placental weight. METHODS: The present work was performed in a subcohort (n = 207) of the STORK study, an observational, prospective study on the determinants of fetal growth and birthweight in healthy pregnancies at Oslo University Hospital, Norway. Fasting glucose, insulin, triglycerides, free fatty acids, HDL- and total cholesterol were measured at week 30-32. Newborn body composition was determined by Dual-Energy X-Ray Absorptiometry (DXA). Placenta was weighed at birth. Linear regression models were used with newborn fat percentage and placental weight as main outcomes. RESULTS: Maternal BMI, fasting glucose and gestational age were independently associated with neonatal fat percentage. However, if placental weight was introduced as a covariate, only placental weight and gestational age remained significant. In the univariate model, the determinants of placenta weight included BMI, insulin, triglycerides, total- and HDL-cholesterol (negatively), gestational weight gain and parity. In the multivariable model, BMI, total cholesterol HDL-cholesterol, gestational weight gain and parity remained independent covariates. CONCLUSION: Maternal BMI and fasting glucose were independently associated with newborn percentage fat. This effect disappeared by introducing placental weight as a covariate. Several metabolic factors associated with maternal BMI were associated with placental weight, but not with neonatal body fat. Our findings are consistent with a concept that the effects of maternal BMI and a number of BMI-related metabolic factors on fetal fat accretion to a significant extent act by modifying placental weight. PMID- 23460864 TI - Repeat prostate biopsy strategies after initial negative biopsy: meta-regression comparing cancer detection of transperineal, transrectal saturation and MRI guided biopsy. AB - INTRODUCTION: There is no consensus on how to investigate men with negative transrectal ultrasound guided prostate biopsy (TRUS-B) but ongoing suspicion of cancer. Three strategies used are transperineal (TP-B), transrectal saturation (TS-B) and MRI-guided biopsy (MRI-B). We compared cancer yields of these strategies. METHODS: Papers were identified by search of Pubmed, Embase and Ovid Medline. Included studies investigated biopsy diagnostic yield in men with at least one negative TRUS-B and ongoing suspicion of prostate cancer. Data including age, PSA, number of previous biopsy episodes, number of cores at re biopsy, cancer yield, and Gleason score of detected cancers were extracted. Meta regression analyses were used to analyse the data. RESULTS: Forty-six studies were included; 12 of TS-B, 14 of TP-B, and 20 of MRI-B, representing 4,657 patients. Mean patient age, PSA and number of previous biopsy episodes were similar between the strategies. The mean number of biopsy cores obtained by TP-B and TS-B were greater than MRI-B. Cancer detection rates were 30.0%, 36.8%, and 37.6% for TS-B, TP-B, and MRI-B respectively. Meta-regression analysis showed that MRI-B had significantly higher cancer detection than TS-B. There were no significant differences however between MRI-B and TP-B, or TP-B and TS-B. In a sensitivity analysis incorporating number of previous biopsy episodes (36 studies) the difference between MRI-B and TP-B was not maintained resulting in no significant difference in cancer detection between the groups. There were no significant differences in median Gleason scores detected comparing the three strategies. CONCLUSIONS: In the re-biopsy setting, it is unclear which strategy offers the highest cancer detection rate. MRI-B may potentially detect more prostate cancers than other modalities and can achieve this with fewer biopsy cores. However, well-designed prospective studies with standardised outcome measures are needed to accurately compare modalities and define an optimum re biopsy approach. PMID- 23460865 TI - High humidity leads to loss of infectious influenza virus from simulated coughs. AB - BACKGROUND: The role of relative humidity in the aerosol transmission of influenza was examined in a simulated examination room containing coughing and breathing manikins. METHODS: Nebulized influenza was coughed into the examination room and Bioaerosol samplers collected size-fractionated aerosols (<1 uM, 1-4 uM, and >4 uM aerodynamic diameters) adjacent to the breathing manikin's mouth and also at other locations within the room. At constant temperature, the RH was varied from 7-73% and infectivity was assessed by the viral plaque assay. RESULTS: Total virus collected for 60 minutes retained 70.6-77.3% infectivity at relative humidity <=23% but only 14.6-22.2% at relative humidity >=43%. Analysis of the individual aerosol fractions showed a similar loss in infectivity among the fractions. Time interval analysis showed that most of the loss in infectivity within each aerosol fraction occurred 0-15 minutes after coughing. Thereafter, losses in infectivity continued up to 5 hours after coughing, however, the rate of decline at 45% relative humidity was not statistically different than that at 20% regardless of the aerosol fraction analyzed. CONCLUSION: At low relative humidity, influenza retains maximal infectivity and inactivation of the virus at higher relative humidity occurs rapidly after coughing. Although virus carried on aerosol particles <4 uM have the potential for remaining suspended in air currents longer and traveling further distances than those on larger particles, their rapid inactivation at high humidity tempers this concern. Maintaining indoor relative humidity >40% will significantly reduce the infectivity of aerosolized virus. PMID- 23460866 TI - Relationship of C5L2 receptor to skeletal muscle substrate utilization. AB - OBJECTIVE: To investigate the role of Acylation Stimulating Protein (ASP) receptor C5L2 in skeletal muscle fatty acid accumulation and metabolism as well as insulin sensitivity in both mice and human models of diet-induced insulin resistance. DESIGN AND METHODS: Male wildtype (WT) and C5L2 knockout (KO) mice were fed a low (LFD) or a high (HFD) fat diet for 10 weeks. Intramyocellular lipid (IMCL) accumulation (by oil red O staining) and beta-oxidation HADH enzyme activity were determined in skeletal muscle. Mitochondria were isolated from hindleg muscles for high-resolution respirometry. Muscle C5L2 protein content was also determined in obese type 2 diabetics and age- and BMI matched men. RESULTS: IMCL levels were increased by six-fold in C5L2KO-HFD compared to WT-HFD mice (p<0.05) and plasma insulin levels were markedly increased in C5L2KO-HFD mice (twofold, p<0.05). Muscle HADH activity was elevated in C5L2KO-LFD mice (+75%, p<0.001 vs. WT-LFD) and C5L2KO-HFD displayed increased mitochondrial fatty acid oxidative capacity compared to WT-HFD mice (+23%, p<0.05). In human subjects, C5L2 protein content was reduced (-48%, p<0.01) in type 2 diabetic patients when compared to obese controls. Further, exercise training increased C5L2 (+45%, p = 0.0019) and ASP (+80%, p<0.001) in obese insulin-resistant men. CONCLUSION: The results suggest that insulin sensitivity may be permissive for coupling of C5L2 levels to lipid storage and utilization. PMID- 23460867 TI - Natural experience modulates the processing of older adult faces in young adults and 3-year-old children. AB - Just like other face dimensions, age influences the way faces are processed by adults as well as by children. However, it remains unclear under what conditions exactly such influence occurs at both ages, in that there is some mixed evidence concerning the presence of a systematic processing advantage for peer faces (own age bias) across the lifespan. Inconsistency in the results may stem from the fact that the individual's face representation adapts to represent the most predominant age traits of the faces present in the environment, which is reflective of the individual's specific living conditions and social experience. In the current study we investigated the processing of younger and older adult faces in two groups of adults (Experiment 1) and two groups of 3-year-old children (Experiment 2) who accumulated different amounts of experience with elderly people. Contact with elderly adults influenced the extent to which both adult and child participants showed greater discrimination abilities and stronger sensitivity to configural/featural cues in younger versus older adult faces, as measured by the size of the inversion effect. In children, the size of the inversion effect for older adult faces was also significantly correlated with the amount of contact with elderly people. These results show that, in both adults and children, visual experience with older adult faces can tune perceptual processing strategies to the point of abolishing the discrimination disadvantage that participants typically manifest for those faces in comparison to younger adult faces. PMID- 23460868 TI - beta-catenin is essential for efficient in vitro premyogenic mesoderm formation but can be partially compensated by retinoic acid signalling. AB - Previous studies have shown that P19 cells expressing a dominant negative beta catenin mutant (beta-cat/EnR) cannot undergo myogenic differentiation in the presence or absence of muscle-inducing levels of retinoic acid (RA). While RA could upregulate premyogenic mesoderm expression, including Pax3/7 and Meox1, only Pax3/7 and Gli2 could be upregulated by RA in the presence of beta-cat/EnR. However, the use of a dominant negative construct that cannot be compensated by other factors is limiting due to the possibility of negative chromatin remodelling overriding compensatory mechanisms. In this study, we set out to determine if beta-catenin function is essential for myogenesis with and without RA, by creating P19 cells with reduced beta-catenin transcriptional activity using an shRNA approach, termed P19[shbeta-cat] cells. The loss of beta-catenin resulted in a reduction of skeletal myogenesis in the absence of RA as early as premyogenic mesoderm, with the loss of Pax3/7, Eya2, Six1, Meox1, Gli2, Foxc1/2, and Sox7 transcript levels. Chromatin immunoprecipitation identified an association of beta-catenin with the promoter region of the Sox7 gene. Differentiation of P19[shbeta-cat] cells in the presence of RA resulted in the upregulation or lack of repression of all of the precursor genes, on day 5 and/or 9, with the exception of Foxc2. However, expression of Sox7, Gli2, the myogenic regulatory factors and terminal differentiation markers remained inhibited on day 9 and overall skeletal myogenesis was reduced. Thus, beta-catenin is essential for in vitro formation of premyogenic mesoderm, leading to skeletal myogenesis. RA can at least partially compensate for the loss of beta-catenin in the expression of many myogenic precursor genes, but not for myoblast gene expression or overall myogenesis. PMID- 23460869 TI - Iron status and systemic inflammation, but not gut inflammation, strongly predict gender-specific concentrations of serum hepcidin in infants in rural Kenya. AB - Hepcidin regulation by competing stimuli such as infection and iron deficiency has not been studied in infants and it's yet unknown whether hepcidin regulatory pathways are fully functional in infants. In this cross-sectional study including 339 Kenyan infants aged 6.0+/-1.1 months (mean+/-SD), we assessed serum hepcidin 25, biomarkers of iron status and inflammation, and fecal calprotectin. Prevalence of inflammation, anemia, and iron deficiency was 31%, 71%, 26%, respectively. Geometric mean (+/-SD) serum hepcidin was 6.0 (+/-3.4) ng/mL, and was significantly lower in males than females. Inflammation (C-reactive protein and interleukin-6) and iron status (serum ferritin, zinc protoporphyrin and soluble transferrin receptor) were significant predictors of serum hepcidin, explaining nearly 60% of its variance. There were small, but significant differences in serum hepcidin comparing iron deficient anemic (IDA) infants without inflammation to iron-deficient anemic infants with inflammation (1.2 (+/ 4.9) vs. 3.4 (+/-4.9) ng/mL; P<0.001). Fecal calprotectin correlated with blood/mucus in the stool but not with hepcidin. Similarly, the gut-linked cytokines IL-12 and IL-17 did not correlate with hepcidin. We conclude that hepcidin regulatory pathways are already functional in infancy, but serum hepcidin alone may not clearly discriminate between iron-deficient anemic infants with and without infection. We propose gender-specific reference values for serum hepcidin in iron-replete infants without inflammation. PMID- 23460870 TI - Cytochrome P450 2E1 gene polymorphisms/haplotypes and anti-tuberculosis drug induced hepatitis in a Chinese cohort. AB - OBJECTIVE: The pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort. METHODS AND DESIGN: A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology. RESULTS: Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis. CONCLUSION: Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population. PMID- 23460871 TI - Complete chloroplast genome sequences of Mongolia medicine Artemisia frigida and phylogenetic relationships with other plants. AB - BACKGROUND: Artemisia frigida Willd. is an important Mongolian traditional medicinal plant with pharmacological functions of stanch and detumescence. However, there is little sequence and genomic information available for Artemisia frigida, which makes phylogenetic identification, evolutionary studies, and genetic improvement of its value very difficult. We report the complete chloroplast genome sequence of Artemisia frigida based on 454 pyrosequencing. METHODOLOGY/PRINCIPAL FINDINGS: The complete chloroplast genome of Artemisia frigida is 151,076 bp including a large single copy (LSC) region of 82,740 bp, a small single copy (SSC) region of 18,394 bp and a pair of inverted repeats (IRs) of 24,971 bp. The genome contains 114 unique genes and 18 duplicated genes. The chloroplast genome of Artemisia frigida contains a small 3.4 kb inversion within a large 23 kb inversion in the LSC region, a unique feature in Asteraceae. The gene order in the SSC region of Artemisia frigida is inverted compared with the other 6 Asteraceae species with the chloroplast genomes sequenced. This inversion is likely caused by an intramolecular recombination event only occurred in Artemisia frigida. The existence of rich SSR loci in the Artemisia frigida chloroplast genome provides a rare opportunity to study population genetics of this Mongolian medicinal plant. Phylogenetic analysis demonstrates a sister relationship between Artemisia frigida and four other species in Asteraceae, including Ageratina adenophora, Helianthus annuus, Guizotia abyssinica and Lactuca sativa, based on 61 protein-coding sequences. Furthermore, Artemisia frigida was placed in the tribe Anthemideae in the subfamily Asteroideae (Asteraceae) based on ndhF and trnL-F sequence comparisons. CONCLUSION: The chloroplast genome sequence of Artemisia frigida was assembled and analyzed in this study, representing the first plastid genome sequenced in the Anthemideae tribe. This complete chloroplast genome sequence will be useful for molecular ecology and molecular phylogeny studies within Artemisia species and also within the Asteraceae family. PMID- 23460872 TI - Transplantation of oligodendrocyte precursor cells improves locomotion deficits in rats with spinal cord irradiation injury. AB - Demyelination contributes to the functional impairment of irradiation injured spinal cord. One potential therapeutic strategy involves replacing the myelin forming cells. Here, we asked whether transplantation of Olig2(+)-GFP(+) oligodendrocyte precursor cells (OPCs), which are derived from Olig2-GFP-mouse embryonic stem cells (mESCs), could enhance remyelination and functional recovery after spinal cord irradiation injury. We differentiated Olig2-GFP-mESCs into purified Olig2(+)-GFP(+)-OPCs and transplanted them into the rats' cervical 4-5 dorsal spinal cord level at 4 months after irradiation injury. Eight weeks after transplantation, the Olig2(+)-GFP(+)-OPCs survived and integrated into the injured spinal cord. Immunofluorescence analysis showed that the grafted Olig2(+) GFP(+)-OPCs primarily differentiated into adenomatous polyposis coli (APC(+)) oligodendrocytes (54.6+/-10.5%). The staining with luxol fast blue, hematoxylin & eosin (LFB/H&E) and electron microscopy demonstrated that the engrafted Olig2(+) GFP(+)-OPCs attenuated the demyelination resulted from the irradiation. More importantly, the recovery of forelimb locomotor function was enhanced in animals receiving grafts of Olig2(+)-GFP(+)-OPCs. We concluded that OPC transplantation is a feasible therapy to repair the irradiated lesions in the central nervous system (CNS). PMID- 23460873 TI - Risk of cerebral palsy and childhood epilepsy related to infections before or during pregnancy. AB - BACKGROUND AND AIM: Maternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes. METHODS/PRINCIPAL FINDINGS: The study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34-1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13-1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21-1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03-1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96-1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06-1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy. CONCLUSIONS: These findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring. PMID- 23460875 TI - Migratory New World blackbirds (icterids) are more neophobic than closely related resident icterids. AB - Environments undergo short-term and long-term changes due to natural or human induced events. Animals differ in their ability to cope with such changes which can be related to their ecology. Changes in the environment often elicit avoidance reactions (neophobia) which protect animals from dangerous situations but can also inhibit exploration and familiarization with novel situations and thus, learning about new resources. Studies investigating the relationship between a species' ecology and its neophobia have so far been restricted to comparing only a few species and mainly in captivity. The current study investigated neophobia reactions to experimentally-induced changes in the natural environment of six closely-related blackbird species (Icteridae), including two species represented by two distinct populations. For analyses, neophobic reactions (difference in number of birds feeding and time spent feeding with and without novel objects) were related to several measures of ecological plasticity and the migratory strategy (resident or migratory) of the population. Phylogenetic relationships were incorporated into the analysis. The degree of neophobia was related to migratory strategy with migrants expressing much higher neophobia (fewer birds feeding and for a shorter time with objects present) than residents. Furthermore, neophobia showed a relationship to diet breadth with fewer individuals of diet generalists than specialists returning when objects were present supporting the dangerous niche hypothesis. Residents may have evolved lower neophobia as costs of missing out on opportunities may be higher for residents than migrants as the former are restricted to a smaller area. Lower neophobia allows them approaching changes in the environment (e.g. novel objects) quickly, thereby securing access to resources. Additionally, residents have a greater familiarity with similar situations in the area than migrants and the latter may, therefore, initially stay behind resident species. PMID- 23460874 TI - Molecular interactions of prodiginines with the BH3 domain of anti-apoptotic Bcl 2 family members. AB - Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti apoptotic BCL-2 proteins. PMID- 23460876 TI - Autoantibodies against muscarinic receptors in breast cancer: their role in tumor angiogenesis. AB - The presence of autoantibodies in cancer has become relevant in recent years. We demonstrated that autoantibodies purified from the sera of breast cancer patients activate muscarinic acetylcholine receptors in tumor cells. Immunoglobulin G (IgG) from breast cancer patients in T1N0Mx stage (tumor size<=2 cm, without lymph node metastasis) mimics the action of the muscarinic agonist carbachol stimulating MCF-7 cell proliferation, migration and invasion. Angiogenesis is a central step in tumor progression because it promotes tumor invasion and metastatic spread. Vascular endothelial growth factor-A (VEGF-A) is the main angiogenic mediator, and its levels have been correlated with poor prognosis in cancer. The aim of the present work was to investigate the effect of T1N0Mx-IgG on the expression of VEGF-A, and the in vivo neovascular response triggered by MCF-7 cells, via muscarinic receptor activation. We demonstrated that T1N0Mx-IgG (10(-8) M) and carbachol (10(-9) M) increased the constitutive expression of VEGF A in tumor cells, effect that was reverted by the muscarinic antagonist atropine. We also observed that T1N0Mx-IgG and carbachol enhanced the neovascular response produced by MCF-7 cells in the skin of NUDE mice. The action of IgG or carbachol was reduced in the presence of atropine. In conclusion, T1N0Mx-IgG and carbachol may promote VEGF-A production and neovascularization induced by breast tumor cells via muscarinic receptors activation. These effects may be accelerating breast tumor progression. PMID- 23460877 TI - Prelimbic and infralimbic neurons signal distinct aspects of appetitive instrumental behavior. AB - It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different aspects of appetitive behavior, however, physiological support for this hypothesis has been lacking. In the present study, we used multichannel single-unit recording to compare the response of neurons in the prelimbic (PL) and infralimbic (IL) subregions of the mPFC, in rats pressing a lever to obtain sucrose pellets on a variable interval schedule of reinforcement (VI-60). Approximately 25% of neurons in both structures exhibited prominent excitatory responses during rewarded, but not unrewarded, lever presses. The time courses of reward responses in PL and IL, however, were markedly different. Most PL neurons exhibited fast and transient responses at the delivery of sucrose pellets, whereas most IL neurons exhibited delayed and prolonged responses associated with the collection of earned sucrose pellets. We further examined the functional significance of reward responses in IL and PL with local pharmacological inactivation. IL inactivation significantly delayed the collection of earned sucrose pellets, whereas PL inactivation produced no discernible effects. These findings support the hypothesis that PL and IL signal distinct aspects of appetitive behavior, and suggest that IL signaling facilitates reward collection. PMID- 23460878 TI - Characterization of ascites-derived ovarian tumor cells from spontaneously occurring ovarian tumors of the chicken: evidence for E-cadherin upregulation. AB - Ovarian cancer, a highly metastatic disease, is the fifth leading cause of cancer related deaths in women. Chickens are widely used as a model for human ovarian cancer as they spontaneously develop epithelial ovarian tumors similar to humans. The cellular and molecular biology of chicken ovarian cancer (COVCAR) cells, however, have not been studied. Our objectives were to culture COVCAR cells and to characterize their invasiveness and expression of genes and proteins associated with ovarian cancer. COVCAR cell lines (n = 13) were successfully maintained in culture for up to19 passages, cryopreserved and found to be viable upon thawing and replating. E-cadherin, cytokeratin and alpha-smooth muscle actin were localized in COVCAR cells by immunostaining. COVCAR cells were found to be invasive in extracellular matrix and exhibited anchorage-independent growth forming colonies, acini and tube-like structures in soft agar. Using RT-PCR, COVCAR cells were found to express E-cadherin, N-cadherin, cytokeratin, vimentin, mesothelin, EpCAM, steroidogenic enzymes/proteins, inhibin subunits-alpha, betaA, betaB, anti-mullerian hormone, estrogen receptor [ER]-alpha, ER-beta, progesterone receptor, androgen receptor, and activin receptors. Quantitative PCR analysis revealed greater N-cadherin, vimentin, and VEGF mRNA levels and lesser cytokeratin mRNA levels in COVCAR cells as compared with normal ovarian surface epithelial (NOSE) cells, which was suggestive of epithelial-mesenchymal transformation. Western blotting analyses revealed significantly greater E cadherin levels in COVCAR cell lines compared with NOSE cells. Furthermore, cancerous ovaries and COVCAR cell lines expressed higher levels of an E-cadherin cleavage product when compared to normal ovaries and NOSE cells, respectively. Cancerous ovaries were found to express significantly higher ovalbumin levels whereas COVCAR cell lines did not express ovalbumin thus suggesting that the latter did not originate from oviduct. Taken together, COVCAR cell lines are likely to improve our understanding of the cellular and molecular biology of ovarian tumors and its metastasis. PMID- 23460879 TI - Behavior matters--cognitive predictors of survival in amyotrophic lateral sclerosis. AB - BACKGROUND: It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren't comparable with assessments in other dementias. METHODS: The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients. RESULTS: The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival. CONCLUSION: ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival. PMID- 23460880 TI - Prognostic value of HPV E6/E7 mRNA assay in women with negative colposcopy or CIN1 histology result: a follow-up study. AB - Pap test, and especially HPV DNA test, identify a large group of women who do not have any clinically relevant lesions, i.e., CIN2+ (Cervical Intraepithelial Neoplasia grade 2 or worse), but who are at greater risk of getting lesions in the future. The follow up of these women needs new biomarkers with prognostic value. The objective of this study is to evaluate the prognostic value of E6/E7 mRNA over-expression assay (PreTect HPV-Proofer, Norchip) for 5 HR-HPV types (16, 18, 31, 33, and 45) for progression to CIN2+ after a negative colposcopy. This prospective study, conducted at four Italian centres, enrolled 673 women with either a negative colposcopy or a negative or CIN1 histology. The clinical end point was histological confirmation of CIN2+. Women were classified at baseline according to mRNA results and managed according to local colposcopy protocols. At least one conclusive follow-up test was obtained for 347 women (25 months average lapse since recruitment, range 5-74). Only seven CIN2+ were detected during follow up, three among the 82 women positive for mRNA at baseline, two among the 250 negative (Fisher exact test, p = 0.02), and two among the 12 with an invalid test. Absolute CIN2+ risk was 6.7/1,000 person/years in the whole cohort. The absolute CIN2+ risk was 18.4/1,000 person/years and 3.6/1,000 person/years in mRNA-positive and mRNA-negative women, respectively. In conclusion, E6/E7 mRNA over-expression appears to be a good candidate as a prognostic biomarker to manage HR-HPV DNA-positive women with negative colposcopy or histology, particularly in order to decrease follow-up intensity in those who are negative. PMID- 23460881 TI - Running pace decrease during a marathon is positively related to blood markers of muscle damage. AB - BACKGROUND: Completing a marathon is one of the most challenging sports activities, yet the source of running fatigue during this event is not completely understood. The aim of this investigation was to determine the cause(s) of running fatigue during a marathon in warm weather. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 40 amateur runners (34 men and 6 women) for the study. Before the race, body core temperature, body mass, leg muscle power output during a countermovement jump, and blood samples were obtained. During the marathon (27 degrees C; 27% relative humidity) running fatigue was measured as the pace reduction from the first 5-km to the end of the race. Within 3 min after the marathon, the same pre-exercise variables were obtained. RESULTS: Marathoners reduced their running pace from 3.5 +/- 0.4 m/s after 5-km to 2.9 +/- 0.6 m/s at the end of the race (P<0.05), although the running fatigue experienced by the marathoners was uneven. Marathoners with greater running fatigue (> 15% pace reduction) had elevated post-race myoglobin (1318 +/- 1411 v 623 +/- 391 ug L( 1); P<0.05), lactate dehydrogenase (687 +/- 151 v 583 +/- 117 U L(-1); P<0.05), and creatine kinase (564 +/- 469 v 363 +/- 158 U L(-1); P = 0.07) in comparison with marathoners that preserved their running pace reasonably well throughout the race. However, they did not differ in their body mass change (-3.1 +/- 1.0 v -3.0 +/- 1.0%; P = 0.60) or post-race body temperature (38.7 +/- 0.7 v 38.9 +/- 0.9 degrees C; P = 0.35). CONCLUSIONS/SIGNIFICANCE: Running pace decline during a marathon was positively related with muscle breakdown blood markers. To elucidate if muscle damage during a marathon is related to mechanistic or metabolic factors requires further investigation. PMID- 23460882 TI - Crocodyliform feeding traces on juvenile ornithischian dinosaurs from the Upper Cretaceous (Campanian) Kaiparowits Formation, Utah. AB - Crocodyliforms serve as important taphonomic agents, accumulating and modifying vertebrate remains. Previous discussions of Mesozoic crocodyliform feeding in terrestrial and riverine ecosystems have often focused on larger taxa and their interactions with equally large dinosaurian prey. However, recent evidence suggests that the impact of smaller crocodyliforms on their environments should not be discounted. Here we present direct evidence of feeding by a small crocodyliform on juvenile specimens of a 'hypsilophodontid' dinosaur from the Upper Cretaceous (Campanian) Kaiparowits Formation of southern Utah. Diagnostic crocodyliform bite marks present on a left scapula and a right femur, as well as a partial probable crocodyliform tooth crown (ovoid in cross-section) preserved within a puncture on the right femur, comprise the bulk of the feeding evidence. Computed tomography scans of the femoral puncture reveal impact damage to the surrounding bone and that the distal tip of the embedded tooth was missing prior to the biting event. This is only the second reported incidence of a fossil crocodyliform tooth being found embedded directly into prey bone. These bite marks provide insight into the trophic interactions of the ecosystem preserved in the Kaiparowits Formation. The high diversity of crocodyliforms within this formation may have led to accentuated niche partitioning, which seems to have included juvenile dinosaurian prey. PMID- 23460883 TI - The complete chloroplast genome sequence of the medicinal plant Salvia miltiorrhiza. AB - Salvia miltiorrhiza is an important medicinal plant with great economic and medicinal value. The complete chloroplast (cp) genome sequence of Salvia miltiorrhiza, the first sequenced member of the Lamiaceae family, is reported here. The genome is 151,328 bp in length and exhibits a typical quadripartite structure of the large (LSC, 82,695 bp) and small (SSC, 17,555 bp) single-copy regions, separated by a pair of inverted repeats (IRs, 25,539 bp). It contains 114 unique genes, including 80 protein-coding genes, 30 tRNAs and four rRNAs. The genome structure, gene order, GC content and codon usage are similar to the typical angiosperm cp genomes. Four forward, three inverted and seven tandem repeats were detected in the Salvia miltiorrhiza cp genome. Simple sequence repeat (SSR) analysis among the 30 asterid cp genomes revealed that most SSRs are AT-rich, which contribute to the overall AT richness of these cp genomes. Additionally, fewer SSRs are distributed in the protein-coding sequences compared to the non-coding regions, indicating an uneven distribution of SSRs within the cp genomes. Entire cp genome comparison of Salvia miltiorrhiza and three other Lamiales cp genomes showed a high degree of sequence similarity and a relatively high divergence of intergenic spacers. Sequence divergence analysis discovered the ten most divergent and ten most conserved genes as well as their length variation, which will be helpful for phylogenetic studies in asterids. Our analysis also supports that both regional and functional constraints affect gene sequence evolution. Further, phylogenetic analysis demonstrated a sister relationship between Salvia miltiorrhiza and Sesamum indicum. The complete cp genome sequence of Salvia miltiorrhiza reported in this paper will facilitate population, phylogenetic and cp genetic engineering studies of this medicinal plant. PMID- 23460884 TI - Plant interactions alter the predictions of metabolic scaling theory. AB - Metabolic scaling theory (MST) is an attempt to link physiological processes of individual organisms with macroecology. It predicts a power law relationship with an exponent of -4/3 between mean individual biomass and density during density dependent mortality (self-thinning). Empirical tests have produced variable results, and the validity of MST is intensely debated. MST focuses on organisms' internal physiological mechanisms but we hypothesize that ecological interactions can be more important in determining plant mass-density relationships induced by density. We employ an individual-based model of plant stand development that includes three elements: a model of individual plant growth based on MST, different modes of local competition (size-symmetric vs. -asymmetric), and different resource levels. Our model is consistent with the observed variation in the slopes of self-thinning trajectories. Slopes were significantly shallower than -4/3 if competition was size-symmetric. We conclude that when the size of survivors is influenced by strong ecological interactions, these can override predictions of MST, whereas when surviving plants are less affected by interactions, individual-level metabolic processes can scale up to the population level. MST, like thermodynamics or biomechanics, sets limits within which organisms can live and function, but there may be stronger limits determined by ecological interactions. In such cases MST will not be predictive. PMID- 23460885 TI - The use of sensitive chemical antibodies for diagnosis: detection of low levels of EpCAM in breast cancer. AB - EpCAM is expressed at low levels in a variety of normal human epithelial tissues, but is overexpressed in 70-90% of carcinomas. From a clinico-pathological point of view, this has both prognostic and therapeutic significance. EpCAM was first suggested as a therapeutic target for the treatment of epithelial cancers in the 1990s. However, following several immunotherapy trials, the results have been mixed. It has been suggested that this is due, at least in part, to an unknown level of EpCAM expression in the tumors being targeted. Thus, selection of patients who would benefit from EpCAM immunotherapy by determining EpCAM status in the tumor biopsies is currently undergoing vigorous evaluation. However, current EpCAM antibodies are not robust enough to be able to detect EpCAM expression in all pathological tissues. Here we report a newly developed EpCAM RNA aptamer, also known as a chemical antibody, which is not only specific but also more sensitive than current antibodies for the detection of EpCAM in formalin-fixed paraffin-embedded primary breast cancers. This new aptamer, together with our previously described aptamer, showed no non-specific staining or cross-reactivity with tissues that do not express EpCAM. They were able to reliably detect target proteins in breast cancer xenograft where an anti-EpCAM antibody (323/A3) showed limited or no reactivity. Our results demonstrated a more robust detection of EpCAM using RNA aptamers over antibodies in clinical samples with chromogenic staining. This shows the potential of aptamers in the future of histopathological diagnosis and as a tool to guide targeted immunotherapy. PMID- 23460886 TI - Nuclear genetic diversity in human lice (Pediculus humanus) reveals continental differences and high inbreeding among worldwide populations. AB - Understanding the evolution of parasites is important to both basic and applied evolutionary biology. Knowledge of the genetic structure of parasite populations is critical for our ability to predict how an infection can spread through a host population and for the design of effective control methods. However, very little is known about the genetic structure of most human parasites, including the human louse (Pediculus humanus). This species is composed of two ecotypes: the head louse (Pediculus humanus capitis De Geer), and the clothing (body) louse (Pediculus humanus humanus Linnaeus). Hundreds of millions of head louse infestations affect children every year, and this number is on the rise, in part because of increased resistance to insecticides. Clothing lice affect mostly homeless and refugee-camp populations and although they are less prevalent than head lice, the medical consequences are more severe because they vector deadly bacterial pathogens. In this study we present the first assessment of the genetic structure of human louse populations by analyzing the nuclear genetic variation at 15 newly developed microsatellite loci in 93 human lice from 11 sites in four world regions. Both ecotypes showed heterozygote deficits relative to Hardy Weinberg equilibrium and high inbreeding values, an expected pattern given their parasitic life history. Bayesian clustering analyses assigned lice to four distinct genetic clusters that were geographically structured. The low levels of gene flow among louse populations suggested that the evolution of insecticide resistance in lice would most likely be affected by local selection pressures, underscoring the importance of tailoring control strategies to population specific genetic makeup and evolutionary history. Our panel of microsatellite markers provides powerful data to investigate not only ecological and evolutionary processes in lice, but also those in their human hosts because of the long-term coevolutionary association between lice and humans. PMID- 23460887 TI - In silico estimation of translation efficiency in human cell lines: potential evidence for widespread translational control. AB - Recently large scale transcriptome and proteome datasets for human cells have become available. A striking finding from these studies is that the level of an mRNA typically predicts no more than 40% of the abundance of protein. This correlation represents the overall figure for all genes. We present here a bioinformatic analysis of translation efficiency - the rate at which mRNA is translated into protein. We have analysed those human datasets that include genome wide mRNA and protein levels determined in the same study. The analysis comprises five distinct human cell lines that together provide comparable data for 8,170 genes. For each gene we have used levels of mRNA and protein combined with protein stability data from the HeLa cell line to estimate translation efficiency. This was possible for 3,990 genes in one or more cell lines and 1,807 genes in all five cell lines. Interestingly, our analysis and modelling shows that for many genes this estimated translation efficiency has considerable consistency between cell lines. Some deviations from this consistency likely result from the regulation of protein degradation. Others are likely due to known translational control mechanisms. These findings suggest it will be possible to build improved models for the interpretation of mRNA expression data. The results we present here provide a view of translation efficiency for many genes. We provide an online resource allowing the exploration of translation efficiency in genes of interest within different cell lines (http://bioanalysis.otago.ac.nz/TranslationEfficiency). PMID- 23460888 TI - Inhibition of the NAD-dependent protein deacetylase SIRT2 induces granulocytic differentiation in human leukemia cells. AB - Sirtuins, NAD-dependent protein deacetylases, play important roles in cellular functions such as metabolism and differentiation. Whether sirtuins function in tumorigenesis is still controversial, but sirtuins are aberrantly expressed in tumors, which may keep cancerous cells undifferentiated. Therefore, we investigated whether the inhibition of sirtuin family proteins induces cellular differentiation in leukemic cells. The sirtuin inhibitors tenovin-6 and BML-266 induce granulocytic differentiation in the acute promyelocytic leukemia (APL) cell line NB4. This differentiation is likely caused by an inhibition of SIRT2 deacetylase activity, judging from the accumulation of acetylated alpha-tubulin, a major SIRT2 substrate. Unlike the clinically used differentiation inducer all trans retinoic acid, tenovin-6 shows limited effects on promyelocytic leukemia retinoic acid receptor alpha (PML-RAR-alpha) stability and promyelocytic leukemia nuclear body formation in NB4 cells, suggesting that tenovin-6 does not directly target PML-RAR-alpha activity. In agreement with this, tenovin-6 induces cellular differentiation in the non-APL cell line HL-60, where PML-RAR-alpha does not exist. Knocking down SIRT2 by shRNA induces granulocytic differentiation in NB4 cells, which demonstrates that the inhibition of SIRT2 activity is sufficient to induce cell differentiation in NB4 cells. The overexpression of SIRT2 in NB4 cells decreases the level of granulocytic differentiation induced by tenovin-6, which indicates that tenovin-6 induces granulocytic differentiation by inhibiting SIRT2 activity. Taken together, our data suggest that targeting SIRT2 is a viable strategy to induce leukemic cell differentiation. PMID- 23460889 TI - Vitamin D status, filaggrin genotype, and cardiovascular risk factors: a Mendelian randomization approach. AB - BACKGROUND: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. METHODS: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. RESULTS: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. CONCLUSION: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results. PMID- 23460890 TI - A natural-like synthetic small molecule impairs bcr-abl signaling cascades and induces megakaryocyte differentiation in erythroleukemia cells. AB - Over the past years, we synthesized a series of new molecules that are hybrids of spirocyclic ketones as complexity-bearing cores with bi- and ter-phenyls as privileged fragments. Some of these newly-shaped small molecules showed antiproliferative, pro-apoptotic and differentiating activity in leukemia cell lines. In the present study, to investigate more in depth the mechanisms of action of these molecules, the protein expression profiles of K562 cells treated with or without the compounds IND_S1, MEL_T1, IND_S7 and MEL_S3 were analyzed using two-dimensional gel electrophoresis coupled with mass spectrometry. Proteome comparisons revealed several differentially expressed proteins, mainly related to cellular metabolism, chaperone activity, cytoskeletal organization and RNA biogenesis. The major results were validated by Western blot and qPCR. To attempt integrating findings into a cellular signaling context, proteomic data were explored using MetaCore. Network analysis highlighted relevant relationships between the identified proteins and additional potential effectors. Notably, qPCR validation of central hubs showed that the compound MEL_S3 induced high mRNA levels of the transcriptional factors EGR1 and HNF4-alpha; the latter to our knowledge is reported here for the first time to be present in K562 cells. Consistently with the known EGR1 involvement in the regulation of differentiation along megakaryocyte lineage, MEL_S3-treated leukemia cells showed a marked expression of glycoprotein IIb/IIIa (CD41) and glycoprotein Ib (CD42), two important cell markers in megakaryocytic differentiation, together with morphological aspects of megakaryoblasts and megakaryocytes. PMID- 23460891 TI - Cyanobactericidal effect of Streptomyces sp. HJC-D1 on Microcystis auruginosa. AB - An isolated strain Streptomyces sp. HJC-D1 was applied to inhibit the growth of cyanobacterium Microcystis aeruginosa FACHB-905. The effect of Streptomyces sp. HJC-D1 culture broth on the cell integrity and physiological characteristics of M. aeruginosa FACHB-905 was investigated using the flow cytometry (FCM), enzyme activity and transmission electron microscopy (TEM) methods. Results showed that the growth of M. aeruginosa FACHB-905 was significantly inhibited, and the percentage of live cells depended on the culture broth concentration and exposure time. The activities of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) increased with exposure concentration and exposure time, and the significant increase of reactive oxygen species (ROS) led to the disruption of the subcellular structure of M. aeruginosa FACHB-905, and caused the increase of malondialdehyde (MDA). Furthermore, TEM observation suggested the presence of three stages (cell breakage, organelle release and cell death) for the cyanobactericidal process of Streptomyces sp. HJC-D1. Therefore, Streptomyces sp. HJC-D1 not only affected antioxidant enzyme activities and ROS level, but also destroyed the subcellular structure of M. aeruginosa FACHB-905, demonstrating excellent cyanobactericidal properties. PMID- 23460892 TI - Variability in the correlation between Asian dust storms and chlorophyll a concentration from the North to Equatorial Pacific. AB - A long-term record of Asian dust storms showed seven high-occurrence-frequency centers in China. The intrusion of Asian dust into the downwind seas, including the China seas, the Sea of Japan, the subarctic North Pacific, the North Pacific subtropical gyre, and the western and eastern Equatorial Pacific, has been shown to add nutrients to ocean ecosystems and enhance their biological activities. To explore the relationship between the transported dust from various sources to the six seas and oceanic biological activities with different nutrient conditions, the correlation between monthly chlorophyll a concentration in each sea and monthly dust storm occurrence frequencies reaching the sea during 1997-2007 was examined in this study. No correlations were observed between dust and chlorophyll a concentration in the <50 m China seas because atmospheric deposition is commonly believed to exert less impact on coastal seas. Significant correlations existed between dust sources and many sea areas, suggesting a link between dust and chlorophyll a concentration in those seas. However, the correlation coefficients were highly variable. In general, the correlation coefficients (0.54-0.63) for the Sea of Japan were highest, except for that between the subarctic Pacific and the Taklimakan Desert, where it was as high as 0.7. For the >50 m China seas and the North Pacific subtropical gyre, the correlation coefficients were in the range 0.32-0.57. The correlation coefficients for the western and eastern Equatorial Pacific were relatively low (<0.36). These correlation coefficients were further interpreted in terms of the geographical distributions of dust sources, the transport pathways, the dust deposition, the nutrient conditions of oceans, and the probability of dust storms reaching the seas. PMID- 23460893 TI - Noninvasive and targeted gene delivery into the brain using microbubble facilitated focused ultrasound. AB - Recombinant adeno-associated viral (rAAV) vectors are potentially powerful tools for gene therapy of CNS diseases, but their penetration into brain parenchyma is severely limited by the blood-brain barrier (BBB) and current delivery relies on invasive stereotactic injection. Here we evaluate the local, targeted delivery of rAAV vectors into the brains of mice by noninvasive, reversible, microbubble facilitated focused ultrasound (FUS), resulting in BBB opening that can be monitored and controlled by magnetic resonance imaging (MRI). Using this method, we found that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (1*10(9) vg/g) can successfully penetrate the BBB-opened brain regions to express GFP. We show that MRI monitoring of BBB-opening could serve as an indicator of the scale and distribution of AAV transduction. Transduction peaked at 3 weeks and neurons and astrocytes were affected. This novel, noninvasive delivery approach could significantly broaden the application of AAV viral-vector-based genes for treatment of CNS diseases. PMID- 23460894 TI - Resampling nucleotide sequences with closest-neighbor trimming and its comparison to other methods. AB - A large number of nucleotide sequences of various pathogens are available in public databases. The growth of the datasets has resulted in an enormous increase in computational costs. Moreover, due to differences in surveillance activities, the number of sequences found in databases varies from one country to another and from year to year. Therefore, it is important to study resampling methods to reduce the sampling bias. A novel algorithm-called the closest-neighbor trimming method-that resamples a given number of sequences from a large nucleotide sequence dataset was proposed. The performance of the proposed algorithm was compared with other algorithms by using the nucleotide sequences of human H3N2 influenza viruses. We compared the closest-neighbor trimming method with the naive hierarchical clustering algorithm and [Formula: see text]-medoids clustering algorithm. Genetic information accumulated in public databases contains sampling bias. The closest-neighbor trimming method can thin out densely sampled sequences from a given dataset. Since nucleotide sequences are among the most widely used materials for life sciences, we anticipate that our algorithm to various datasets will result in reducing sampling bias. PMID- 23460895 TI - Minor groove binder distamycin remodels chromatin but inhibits transcription. AB - The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as "chromatin remodeling". In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance. PMID- 23460896 TI - Sex and caste-specific variation in compound eye morphology of five honeybee species. AB - Ranging from dwarfs to giants, the species of honeybees show remarkable differences in body size that have placed evolutionary constrains on the size of sensory organs and the brain. Colonies comprise three adult phenotypes, drones and two female castes, the reproductive queen and sterile workers. The phenotypes differ with respect to tasks and thus selection pressures which additionally constrain the shape of sensory systems. In a first step to explore the variability and interaction between species size-limitations and sex and caste specific selection pressures in sensory and neural structures in honeybees, we compared eye size, ommatidia number and distribution of facet lens diameters in drones, queens and workers of five species (Apis andreniformis, A. florea, A. dorsata, A. mellifera, A. cerana). In these species, male and female eyes show a consistent sex-specific organization with respect to eye size and regional specialization of facet diameters. Drones possess distinctly enlarged eyes with large dorsal facets. Aside from these general patterns, we found signs of unique adaptations in eyes of A. florea and A. dorsata drones. In both species, drone eyes are disproportionately enlarged. In A. dorsata the increased eye size results from enlarged facets, a likely adaptation to crepuscular mating flights. In contrast, the relative enlargement of A. florea drone eyes results from an increase in ommatidia number, suggesting strong selection for high spatial resolution. Comparison of eye morphology and published mating flight times indicates a correlation between overall light sensitivity and species-specific mating flight times. The correlation suggests an important role of ambient light intensities in the regulation of species-specific mating flight times and the evolution of the visual system. Our study further deepens insights into visual adaptations within the genus Apis and opens up future perspectives for research to better understand the timing mechanisms and sensory physiology of mating related signals. PMID- 23460897 TI - Curcumin modulates DNA methylation in colorectal cancer cells. AB - AIM: Recent evidence suggests that several dietary polyphenols may exert their chemopreventive effect through epigenetic modifications. Curcumin is one of the most widely studied dietary chemopreventive agents for colon cancer prevention, however, its effects on epigenetic alterations, particularly DNA methylation, remain unclear. Using systematic genome-wide approaches, we aimed to elucidate the effect of curcumin on DNA methylation alterations in colorectal cancer cells. MATERIALS AND METHODS: To evaluate the effect of curcumin on DNA methylation, three CRC cell lines, HCT116, HT29 and RKO, were treated with curcumin. 5-aza-2' deoxycytidine (5-aza-CdR) and trichostatin A treated cells were used as positive and negative controls for DNA methylation changes, respectively. Methylation status of LINE-1 repeat elements, DNA promoter methylation microarrays and gene expression arrays were used to assess global methylation and gene expression changes. Validation was performed using independent microarrays, quantitative bisulfite pyrosequencing, and qPCR. RESULTS: As expected, genome-wide methylation microarrays revealed significant DNA hypomethylation in 5-aza-CdR-treated cells (mean beta-values of 0.12), however, non-significant changes in mean beta-values were observed in curcumin-treated cells. In comparison to mock-treated cells, curcumin-induced DNA methylation alterations occurred in a time-dependent manner. In contrast to the generalized, non-specific global hypomethylation observed with 5-aza-CdR, curcumin treatment resulted in methylation changes at selected, partially-methylated loci, instead of fully-methylated CpG sites. DNA methylation alterations were supported by corresponding changes in gene expression at both up and down-regulated genes in various CRC cell lines. CONCLUSIONS: Our data provide previously unrecognized evidence for curcumin-mediated DNA methylation alterations as a potential mechanism of colon cancer chemoprevention. In contrast to non-specific global hypomethylation induced by 5-aza-CdR, curcumin-induced methylation changes occurred only in a subset of partially-methylated genes, which provides additional mechanistic insights into the potent chemopreventive effect of this dietary nutraceutical. PMID- 23460898 TI - Genome-wide identification and analysis of expression profiles of maize mitogen activated protein kinase kinase kinase. AB - Mitogen-activated protein kinase (MAPK) cascades are highly conserved signal transduction model in animals, yeast and plants. Plant MAPK cascades have been implicated in development and stress responses. Although MAPKKKs have been investigated in several plant species including Arabidopsis and rice, no systematic analysis has been conducted in maize. In this study, we performed a bioinformatics analysis of the entire maize genome and identified 74 MAPKKK genes. Phylogenetic analyses of MAPKKKs from maize, rice and Arabidopsis have classified them into three subgroups, which included Raf, ZIK and MEKK. Evolutionary relationships within subfamilies were also supported by exon-intron organizations and the conserved protein motifs. Further expression analysis of the MAPKKKs in microarray databases revealed that MAPKKKs were involved in important signaling pathways in maize different organs and developmental stages. Our genomics analysis of maize MAPKKK genes provides important information for evolutionary and functional characterization of this family in maize. PMID- 23460899 TI - Arbuscular-mycorrhizal networks inhibit Eucalyptus tetrodonta seedlings in rain forest soil microcosms. AB - Eucalyptus tetrodonta, a co-dominant tree species of tropical, northern Australian savannas, does not invade adjacent monsoon rain forest unless the forest is burnt intensely. Such facilitation by fire of seedling establishment is known as the "ashbed effect." Because the ashbed effect might involve disruption of common mycorrhizal networks, we hypothesized that in the absence of fire, intact rain forest arbuscular mycorrhizal (AM) networks inhibit E. tetrodonta seedlings. Although arbuscular mycorrhizas predominate in the rain forest, common tree species of the northern Australian savannas (including adult E. tetrodonta) host ectomycorrhizas. To test our hypothesis, we grew E. tetrodonta and Ceiba pentandra (an AM-responsive species used to confirm treatments) separately in microcosms of ambient or methyl-bromide fumigated rain forest soil with or without severing potential mycorrhizal fungus connections to an AM nurse plant, Litsea glutinosa. As expected, C. pentandra formed mycorrhizas in all treatments but had the most root colonization and grew fastest in ambient soil. E. tetrodonta seedlings also formed AM in all treatments, but severing hyphae in fumigated soil produced the least colonization and the best growth. Three of ten E. tetrodonta seedlings in ambient soil with intact network hyphae died. Because foliar chlorosis was symptomatic of iron deficiency, after 130 days we began to fertilize half the E. tetrodonta seedlings in ambient soil with an iron solution. Iron fertilization completely remedied chlorosis and stimulated leaf growth. Our microcosm results suggest that in intact rain forest, common AM networks mediate belowground competition and AM fungi may exacerbate iron deficiency, thereby enhancing resistance to E. tetrodonta invasion. Common AM networks-previously unrecognized as contributors to the ashbed effect-probably help to maintain the rain forest-savanna boundary. PMID- 23460901 TI - A global and spatially explicit assessment of climate change impacts on crop production and consumptive water use. AB - Food security and water scarcity have become two major concerns for future human's sustainable development, particularly in the context of climate change. Here we present a comprehensive assessment of climate change impacts on the production and water use of major cereal crops on a global scale with a spatial resolution of 30 arc-minutes for the 2030s (short term) and the 2090s (long term), respectively. Our findings show that impact uncertainties are higher on larger spatial scales (e.g., global and continental) but lower on smaller spatial scales (e.g., national and grid cell). Such patterns allow decision makers and investors to take adaptive measures without being puzzled by a highly uncertain future at the global level. Short-term gains in crop production from climate change are projected for many regions, particularly in African countries, but the gains will mostly vanish and turn to losses in the long run. Irrigation dependence in crop production is projected to increase in general. However, several water poor regions will rely less heavily on irrigation, conducive to alleviating regional water scarcity. The heterogeneity of spatial patterns and the non-linearity of temporal changes of the impacts call for site-specific adaptive measures with perspectives of reducing short- and long-term risks of future food and water security. PMID- 23460900 TI - TV time but not computer time is associated with cardiometabolic risk in Dutch young adults. AB - BACKGROUND: TV time and total sedentary time have been positively related to biomarkers of cardiometabolic risk in adults. We aim to examine the association of TV time and computer time separately with cardiometabolic biomarkers in young adults. Additionally, the mediating role of waist circumference (WC) is studied. METHODS AND FINDINGS: Data of 634 Dutch young adults (18-28 years; 39% male) were used. Cardiometabolic biomarkers included indicators of overweight, blood pressure, blood levels of fasting plasma insulin, cholesterol, glucose, triglycerides and a clustered cardiometabolic risk score. Linear regression analyses were used to assess the cross-sectional association of self-reported TV and computer time with cardiometabolic biomarkers, adjusting for demographic and lifestyle factors. Mediation by WC was checked using the product-of-coefficient method. TV time was significantly associated with triglycerides (B = 0.004; CI = [0.001;0.05]) and insulin (B = 0.10; CI = [0.01;0.20]). Computer time was not significantly associated with any of the cardiometabolic biomarkers. We found no evidence for WC to mediate the association of TV time or computer time with cardiometabolic biomarkers. CONCLUSIONS: We found a significantly positive association of TV time with cardiometabolic biomarkers. In addition, we found no evidence for WC as a mediator of this association. Our findings suggest a need to distinguish between TV time and computer time within future guidelines for screen time. PMID- 23460902 TI - Born at the wrong time: selection bias in the NHL draft. AB - Relative age effects (RAEs) occur when those who are relatively older for their age group are more likely to succeed. RAEs occur reliably in some educational and athletic contexts, yet the causal mechanisms remain unclear. Here we provide the first direct test of one mechanism, selection bias, which can be defined as evaluators granting fewer opportunities to relatively younger individuals than is warranted by their latent ability. Because RAEs are well-established in hockey, we analyzed National Hockey League (NHL) drafts from 1980 to 2006. Compared to those born in the first quarter (i.e., January-March), those born in the third and fourth quarters were drafted more than 40 slots later than their productivity warranted, and they were roughly twice as likely to reach career benchmarks, such as 400 games played or 200 points scored. This selection bias in drafting did not decrease over time, apparently continues to occur, and reduces the playing opportunities of relatively younger players. This bias is remarkable because it is exhibited by professional decision makers evaluating adults in a context where RAEs have been widely publicized. Thus, selection bias based on relative age may be pervasive. PMID- 23460903 TI - K+ efflux and retention in response to NaCl stress do not predict salt tolerance in contrasting genotypes of rice (Oryza sativa L.). AB - Sudden elevations in external sodium chloride (NaCl) accelerate potassium (K(+)) efflux across the plasma membrane of plant root cells. It has been proposed that the extent of this acceleration can predict salt tolerance among contrasting cultivars. However, this proposal has not been considered in the context of plant nutritional history, nor has it been explored in rice (Oryza sativa L.), which stands among the world's most important and salt-sensitive crop species. Using efflux analysis with (42)K, coupled with growth and tissue K(+) analyses, we examined the short- and long-term effects of NaCl exposure to plant performance within a nutritional matrix that significantly altered tissue-K(+) set points in three rice cultivars that differ in salt tolerance: IR29 (sensitive), IR72 (moderate), and Pokkali (tolerant). We show that total short-term K(+) release from roots in response to NaCl stress is small (no more than 26% over 45 min) in rice. Despite strong varietal differences, the extent of efflux is shown to be a poor predictor of plant performance on long-term NaCl stress. In fact, no measure of K(+) status was found to correlate with plant performance among cultivars either in the presence or absence of NaCl stress. By contrast, shoot Na(+) accumulation showed the strongest correlation (a negative one) with biomass, under long-term salinity. Pharmacological evidence suggests that NaCl-induced K(+) efflux is a result of membrane disintegrity, possibly as result of osmotic shock, and not due to ion-channel mediation. Taken together, we conclude that, in rice, K(+) status (including efflux) is a poor predictor of salt tolerance and overall plant performance and, instead, shoot Na(+) accumulation is the key factor in performance decline on NaCl stress. PMID- 23460904 TI - Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium. AB - The retinal pigment epithelium (RPE) is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM) is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1). REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox), Tyr-Cre+). Transmission electron microscopy (TEM) was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5 6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox), Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD) suggest that membrane traffic defects may contribute to the pathogenesis of AMD. PMID- 23460905 TI - Cost-utility analysis of lopinavir/ritonavir versus atazanavir + ritonavir administered as first-line therapy for the treatment of HIV infection in Italy: from randomised trial to real world. AB - OBJECTIVE: To estimate the lifetime cost utility of two antiretroviral regimens (once-daily atazanavir plus ritonavir [ATV+r] versus twice-daily lopinavir/ritonavir [LPV/r]) in Italian human immunodeficiency virus (HIV) infected patients naive to treatment. DESIGN: With this observational retrospective study we collected the clinical data of a cohort of HIV-infected patients receiving first-line treatment with LPV/r or ATV+r. METHODOLOGY: A Markov microsimulation model including direct costs and health outcomes of first- and second-line highly active retroviral therapy was developed from a third-party (Italian National Healthcare Service) payer's perspective. Health and monetary outcomes associated with the long-term use of ATV+r and LPV/r regimens were evaluated on the basis of eight health states, incidence of diarrhoea and hyperbilirubinemia, AIDS events, opportunistic infections, coronary heart disease events and, for the first time in an economic evaluation, chronic kidney disease (CKD) events. In order to account for possible deviations between real-life data and randomised controlled trial results, a second control arm (ATV+r 2) was created with differential transition probabilities taken from the literature. RESULTS: The average survival was 24.061 years for patients receiving LPV/r, 24.081 and 24.084 for those receiving ATV+r 1 and 2 respectively. The mean quality-adjusted life-years (QALYs) were higher for the patients receiving LPV/r than those receiving ATV+r (13.322 vs. 13.060 and 13.261 for ATV+r 1 and 2). The cost-utility values were 15,310.56 for LPV/r, 15,902.99 and 15,524.85 for ATV+r 1 and 2. CONCLUSIONS: Using real-life data, the model produced significantly different results compared with other studies. With the innovative addition of an evaluation of CKD events, the model showed a cost-utility value advantage for twice-daily LPV/r over once-daily ATV+r, thus providing evidence for its continued use in the treatment of HIV. PMID- 23460906 TI - Dung beetle community and functions along a habitat-disturbance gradient in the Amazon: a rapid assessment of ecological functions associated to biodiversity. AB - Although there is increasing interest in the effects of habitat disturbance on community attributes and the potential consequences for ecosystem functioning, objective approaches linking biodiversity loss to functional loss are uncommon. The objectives of this study were to implement simultaneous assessment of community attributes (richness, abundance and biomass, each calculated for total beetle assemblages as well as small- and large-beetle assemblages) and three ecological functions of dung beetles (dung removal, soil perturbation and secondary seed dispersal), to compare the effects of habitat disturbance on both sets of response variables, and their relations. We studied dung beetle community attributes and functions in five land-use systems representing a disturbance gradient in the Brazilian Amazon: primary forest, secondary forest, agroforestry, agriculture and pasture. All response variables were affected negatively by the intensification of habitat disturbance regimes, but community attributes and ecological functions did not follow the same pattern of decline. A hierarchical partitioning analysis showed that, although all community attributes had a significant effect on the three ecological functions (except the abundance of small beetles on all three ecological functions and the biomass of small beetles on secondary dispersal of large seed mimics), species richness and abundance of large beetles were the community attributes with the highest explanatory value. Our results show the importance of measuring ecological function empirically instead of deducing it from community metrics. PMID- 23460907 TI - Aerobactin synthesis genes iucA and iucC contribute to the pathogenicity of avian pathogenic Escherichia coli O2 strain E058. AB - Aerobactin genes are known to be present in virulent strains and absent from avirulent strains, but contributions of iucC and iucA, which are involved in aerobactin synthesis, to the pathogenicity of avian pathogenic Escherichia coli (APEC) have not been clarified. In this study, effects of double mutants (iucA/iutA or iucC/iutA) compared to those of single mutants (iucA, iucC or iutA) of aerobactin genes on the virulence of APEC strain E058 were examined both in vitro (aerobactin production, ingestion into HD-11 cells, survival in chicken serum) and in vivo (competitive growth against parental strain, colonization and persistence). In competitive co-infection assays, compared to the E058 parental strain, the E058DeltaiucA mutant was significantly reduced in the liver, kidney, spleen (all P<0.01), heart and lung (both P<0.001). The E058DeltaiutA mutant also was significantly reduced in the liver, lung, kidney (all P<0.01), heart and spleen (both P<0.001). The E058DeltaiucC mutant was significantly attenuated in the heart and kidney (both P<0.05) and showed a remarkable reduction in the liver, spleen and lung (P<0.01); meanwhile, both E058DeltaiucADeltaiutA and E058DeltaiucCDeltaiutA double mutants were sharply reduced as well (P<0.001). In colonization and persistence assays, compared with E058, recovered colonies of E058DeltaiucA were significantly reduced from the lung, liver, spleen and kidney (P<0.01) and significantly reduced in the heart (P<0.001). E058DeltaiutA was significantly reduced from the heart, lung, liver, spleen and kidney (P<0.01). E058DeltaiucC, E058DeltaiucADeltaiutA and E058DeltaiucCDeltaiutA were significantly decreased in all organs tested (P<0.001). These results suggest that iutA, iucA and iucC play important roles in the pathogenicity of APEC E058. PMID- 23460908 TI - Interleukin-1beta downregulates RBP4 secretion in human adipocytes. AB - AIMS/HYPOTHESIS: The excessive accumulation of adipose tissue in the obese state is linked to an altered secretion profile of adipocytes, chronic low-grade inflammation and metabolic complications. RBP4 has been implicated in these alterations, especially insulin resistance. The aim of the present study was to determine if a local inflammatory micro-environment in adipose tissue regulates RBP4 expression and secretion. METHODS: Human SGBS and primary adipocytes cultured with conditioned media from human THP-1 macrophages were used as an in vitro model for adipose inflammation. Adipocytes were exposed to recombinant TNF alpha, IL-1beta, IL-6 or IL-8. In addition, coexpression of IL-1beta and RBP4 was measured in adipose tissue samples from 18 healthy females. RBP4 expression was studied by quantitative PCR and ELISA. RESULTS: RBP4 mRNA expression and secretion was significantly reduced upon incubation with macrophage-conditioned media in SGBS adipocytes and human primary adipocytes. Out of several factors studied we identified IL-1beta as a new factor regulating RBP4. IL-1beta significantly downregulated RBP4 mRNA and secretion in a time- and dose-dependent manner. IL-1beta mediated its inhibitory effects on RBP4 expression via IL-1 receptor and NF-kappaB, as incubation with the IL-1 receptor blocking antibody and the NF-kappaB inhibitors CAPE and SC-514 reversed its effect. Most interestingly, RBP4 mRNA was negatively correlated with IL-1beta mRNA in subcutaneous adipose tissue. CONCLUSIONS: Adipose tissue inflammation as found in the obese state might lead to a downregulation in local RBP4 levels. IL-1beta was identified as a major factor contributing to the decrease in RBP4. The increase in circulating RBP4 that often precedes the development of systemic insulin resistance is most likely unrelated to inflammatory processes in adipose tissue. PMID- 23460909 TI - A deep sequencing approach to uncover the miRNOME in the human heart. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs of ~22 nucleotides in length, and constitute a novel class of gene regulators by imperfect base-pairing to the 3'UTR of protein encoding messenger RNAs. Growing evidence indicates that miRNAs are implicated in several pathological processes in myocardial disease. The past years, we have witnessed several profiling attempts using high-density oligonucleotide array-based approaches to identify the complete miRNA content (miRNOME) in the healthy and diseased mammalian heart. These efforts have demonstrated that the failing heart displays differential expression of several dozens of miRNAs. While the total number of experimentally validated human miRNAs is roughly two thousand, the number of expressed miRNAs in the human myocardium remains elusive. Our objective was to perform an unbiased assay to identify the miRNOME of the human heart, both under physiological and pathophysiological conditions. We used deep sequencing and bioinformatics to annotate and quantify microRNA expression in healthy and diseased human heart (heart failure secondary to hypertrophic or dilated cardiomyopathy). Our results indicate that the human heart expresses >800 miRNAs, the majority of which not being annotated nor described so far and some of which being unique to primate species. Furthermore, >250 miRNAs show differential and etiology-dependent expression in human dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). The human cardiac miRNOME still possesses a large number of miRNAs that remain virtually unexplored. The current study provides a starting point for a more comprehensive understanding of the role of miRNAs in regulating human heart disease. PMID- 23460910 TI - Anti-TNF therapy reduces serum levels of chemerin in rheumatoid arthritis: a new mechanism by which anti-TNF might reduce inflammation. AB - BACKGROUND: Chemerin is a specific chemoattractant for macrophages and dendritic cells (DC). In addition, it can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules and is able to activate fibroblast-like synoviocytes (FLS), suggesting a role in the pathogenesis of rheumatoid arthritis (RA). Chemerin is also an adipocytokine that has been related to the inflammatory state of endothelial cells and as such could be involved in the changes in endothelial cells in RA and perhaps increased cardiovascular morbidity. We investigated whether anti-Tumor Necrosis Factor (TNF) treatment affects chemerin levels. MATERIALS AND METHODS: 49 patients with active RA (disease activity score evaluated in 28 joints (DAS28) >=3.2) were started on adalimumab therapy. Blood was drawn from patients while fasting at baseline and 16 weeks after initiation of treatment. Chemerin serum levels were measured by ELISA and related to disease activity, mediators of inflammation and known risk factors for cardiovascular disease. RESULTS: Adalimumab therapy reduced chemerin serum levels, which was correlated with the reduction in DAS28 (r = 0.37, p = 0.009). In addition, the decrease in chemerin serum levels after anti-TNF treatment was associated with the decrease in serum levels of IL-6 (r = 0.39, p = 0.033) and macrophage migration inhibitory factor (MIF) (r = 0.31, p = 0.049). Baseline chemerin serum levels were not related to traditional risk factors for atherosclerosis, except perhaps for smoking (p = 0.07). CONCLUSIONS: This exploratory study shows that adalimumab therapy lowers chemerin levels, which is associated with the reduction in disease activity parameters, and inflammatory mediators IL-6 and MIF. This suggests a possible involvement of chemerin in the migration/retention of macrophages in the synovium. TRIAL REGISTRATION NEDERLANDS TRIAL REGISTER: NTR 857. PMID- 23460911 TI - The tandem PH domain-containing protein 2 (TAPP2) regulates chemokine-induced cytoskeletal reorganization and malignant B cell migration. AB - The intracellular signaling processes controlling malignant B cell migration and tissue localization remain largely undefined. Tandem PH domain-containing proteins TAPP1 and TAPP2 are adaptor proteins that specifically bind to phosphatidylinositol-3,4-bisphosphate, or PI(3,4)P2, a product of phosphoinositide 3-kinases (PI3K). While PI3K enzymes have a number of functions in cell biology, including cell migration, the functions of PI(3,4)P2 and its binding proteins are not well understood. Previously we found that TAPP2 is highly expressed in primary leukemic B cells that have strong migratory capacity. Here we find that SDF-1-dependent migration of human malignant B cells requires both PI3K signaling and TAPP2. Migration in a transwell assay is significantly impaired by pan-PI3K and isoform-selective PI3K inhibitors, or by TAPP2 shRNA knockdown (KD). Strikingly, TAPP2 KD in combination with PI3K inhibitor treatment nearly abolished the migration response, suggesting that TAPP2 may contribute some functions independent of the PI3K pathway. In microfluidic chamber cell tracking assays, TAPP2 KD cells show reduction in percentage of migrating cells, migration velocity and directionality. TAPP2 KD led to alterations in chemokine induced rearrangement of the actin cytoskeleton and failure to form polarized morphology. TAPP2 co-localized with the stable F-actin-binding protein utrophin, with both molecules reciprocally localizing against F-actin accumulated at the leading edge upon SDF-1 stimulation. In TAPP2 KD cells, Rac was over-activated and localized to multiple membrane protrusions, suggesting that TAPP2 may act in concert with utrophin and stable F-actin to spatially restrict Rac activation and reduce formation of multiple membrane protrusions. TAPP2 function in cell migration is also apparent in the more complex context of B cell migration into stromal cell layers - a process that is only partially dependent on PI3K and SDF 1. In summary, this study identified TAPP2 as a novel regulator of malignant B cell migration and a potential therapeutic intervention target. PMID- 23460912 TI - The relationship of sugar to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data. AB - While experimental and observational studies suggest that sugar intake is associated with the development of type 2 diabetes, independent of its role in obesity, it is unclear whether alterations in sugar intake can account for differences in diabetes prevalence among overall populations. Using econometric models of repeated cross-sectional data on diabetes and nutritional components of food from 175 countries, we found that every 150 kcal/person/day increase in sugar availability (about one can of soda/day) was associated with increased diabetes prevalence by 1.1% (p <0.001) after testing for potential selection biases and controlling for other food types (including fibers, meats, fruits, oils, cereals), total calories, overweight and obesity, period-effects, and several socioeconomic variables such as aging, urbanization and income. No other food types yielded significant individual associations with diabetes prevalence after controlling for obesity and other confounders. The impact of sugar on diabetes was independent of sedentary behavior and alcohol use, and the effect was modified but not confounded by obesity or overweight. Duration and degree of sugar exposure correlated significantly with diabetes prevalence in a dose dependent manner, while declines in sugar exposure correlated with significant subsequent declines in diabetes rates independently of other socioeconomic, dietary and obesity prevalence changes. Differences in sugar availability statistically explain variations in diabetes prevalence rates at a population level that are not explained by physical activity, overweight or obesity. PMID- 23460913 TI - Abnormal brain functional connectivity of the hypothalamus in cluster headaches. AB - The aim of this study was to detect the abnormality of the brain functional connectivity of the hypothalamus during acute spontaneous cluster headache (CH) attacks ('in attack') and headache-free intervals ('out of attack') using resting state functional magnetic resonance imaging (RS-fMRI) technique. The RS-fMRI data from twelve male CH patients during 'in attack' and 'out of attack' periods and twelve age- and sex-matched normal controls were analyzed by the region-of interest -based functional connectivity method using SPM5 software. Abnormal brain functional connectivity of the hypothalamus is present in CH, which is located mainly in the pain system during the spontaneous CH attacks. It extends beyond the pain system during CH attack intervals. PMID- 23460914 TI - The variability of the 16S rRNA gene in bacterial genomes and its consequences for bacterial community analyses. AB - 16S ribosomal RNA currently represents the most important target of study in bacterial ecology. Its use for the description of bacterial diversity is, however, limited by the presence of variable copy numbers in bacterial genomes and sequence variation within closely related taxa or within a genome. Here we use the information from sequenced bacterial genomes to explore the variability of 16S rRNA sequences and copy numbers at various taxonomic levels and apply it to estimate bacterial genome and DNA abundances. In total, 7,081 16S rRNA sequences were in silico extracted from 1,690 available bacterial genomes (1-15 per genome). While there are several phyla containing low 16S rRNA copy numbers, in certain taxa, e.g., the Firmicutes and Gammaproteobacteria, the variation is large. Genome sizes are more conserved at all tested taxonomic levels than 16S rRNA copy numbers. Only a minority of bacterial genomes harbors identical 16S rRNA gene copies, and sequence diversity increases with increasing copy numbers. While certain taxa harbor dissimilar 16S rRNA genes, others contain sequences common to multiple species. Sequence identity clusters (often termed operational taxonomic units) thus provide an imperfect representation of bacterial taxa of a certain phylogenetic rank. We have demonstrated that the information on 16S rRNA copy numbers and genome sizes of genome-sequenced bacteria may be used as an estimate for the closest related taxon in an environmental dataset to calculate alternative estimates of the relative abundance of individual bacterial taxa in environmental samples. Using an example from forest soil, this procedure would increase the abundance estimates of Acidobacteria and decrease these of Firmicutes. Using the currently available information, alternative estimates of bacterial community composition may be obtained in this way if the variation of 16S rRNA copy numbers among bacteria is considered. PMID- 23460916 TI - Identification of an internal RNA element essential for replication and translational enhancement of tobacco necrosis virus A(C). AB - Different regulatory elements function are involved in plant virus gene expression and replication by long-distance RNA-RNA interactions. A cap independent functional element of the Barley yellow dwarf virus (BYDV) - like translational enhancer (BTE) is present in Tobacco necrosis virus A (TNV-A), a Necrovirus member in the Tombusviridae family. In this paper, an RNA stretch flanking the 5' proximal end of the TNV-A(C) coat protein (CP) gene was shown to be essential for viral replication in Chenopodium amaranticolor plants and tobacco cells. This internal sequence functioned in transient expression of beta glucuronidase (GUS) when present at either the 5' or 3' sides of the GUS open reading frame. Serial deletion analyses revealed that nine nucleotides from nt 2609 to 2617 (-3 to +6 of the CP initiation site) within TNV-A(C) RNA are indispensable for viral replication in whole plants and tobacco cells. Fusion of this RNA element in mRNAs translated in tobacco cells resulted in a remarkable enhancement of luciferase expression from in vitro synthesised chimaeric RNAs or DNA expression vectors. Interestingly, the element also exhibited increased translational activity when fused downstream of the reporter genes, although the efficiency was lower than with upstream fusions. These results provide evidence that an internal RNA element in the genomic (g) RNA of TNV-A(C), ranging approximately from nt 2543 to 2617, plays a bifunctional role in viral replication and translation enhancement during infection, and that this element may use novel strategies differing from those previously reported for other viruses. PMID- 23460917 TI - The Thoc1 encoded ribonucleoprotein is a substrate for the NEDD4-1 E3 ubiquitin protein ligase. AB - Ribonucleoprotein (RNP) complexes form around nascent RNA during transcription to facilitate proper transcriptional elongation, RNA processing, and nuclear export. RNPs are highly heterogeneous, and different types of RNPs tend to package functionally related transcripts. These observations have inspired the hypothesis that RNP mediated mechanisms help specify coordinated gene expression. This hypothesis is supported by the observation that mutations in RNP components can cause defects in specific developmental pathways. How RNP biogenesis itself is regulated, however, is not well understood. The evolutionarily conserved THO RNP complex functions early during transcription to package nascent transcripts and facilitate subsequent RNP biogenesis. THO deficiency compromises transcriptional elongation as well as RNP mediated events like 3' end formation and nuclear export for some transcripts. Using molecularly manipulated cells and in vitro reconstituted biochemical reactions, we demonstrate that the essential THO protein component encoded by the Thoc1 gene is poly-ubiquitinated by the NEDD4-1 E3 ubiquitin ligase. Poly-ubiquitinated pThoc1 is degraded by the proteasome. These results indicate THO activity is regulated by the ubiquitin-proteasome pathway, and that this regulation is evolutionarily conserved between yeast and mammals. Manipulation of NEDD4-1 levels has modest effects on Thoc1 protein levels under steady state conditions, but destabilization of Thoc1 protein upon treatment with a transcriptional elongation inhibitor is dependent on NEDD4-1. This suggests NEDD4-1 functions in conjunction with other post-translational mechanisms to regulate Thoc1 protein and THO activity. PMID- 23460918 TI - Detection of arboviruses and other micro-organisms in experimentally infected mosquitoes using massively parallel sequencing. AB - Human disease incidence attributed to arbovirus infection is increasing throughout the world, with effective control interventions limited by issues of sustainability, insecticide resistance and the lack of effective vaccines. Several promising control strategies are currently under development, such as the release of mosquitoes trans-infected with virus-blocking Wolbachia bacteria. Implementation of any control program is dependent on effective virus surveillance and a thorough understanding of virus-vector interactions. Massively parallel sequencing has enormous potential for providing comprehensive genomic information that can be used to assess many aspects of arbovirus ecology, as well as to evaluate novel control strategies. To demonstrate proof-of-principle, we analyzed Aedes aegypti or Aedes albopictus experimentally infected with dengue, yellow fever or chikungunya viruses. Random amplification was used to prepare sufficient template for sequencing on the Personal Genome Machine. Viral sequences were present in all infected mosquitoes. In addition, in most cases, we were also able to identify the mosquito species and mosquito micro-organisms, including the bacterial endosymbiont Wolbachia. Importantly, naturally occurring Wolbachia strains could be differentiated from strains that had been trans infected into the mosquito. The method allowed us to assemble near full-length viral genomes and detect other micro-organisms without prior sequence knowledge, in a single reaction. This is a step toward the application of massively parallel sequencing as an arbovirus surveillance tool. It has the potential to provide insight into virus transmission dynamics, and has applicability to the post release monitoring of Wolbachia in mosquito populations. PMID- 23460915 TI - The internal transcribed spacer (ITS) region and trnH-psbA [corrected] are suitable candidate loci for DNA barcoding of tropical tree species of India. AB - BACKGROUND: DNA barcoding as a tool for species identification has been successful in animals and other organisms, including certain groups of plants. The exploration of this new tool for species identification, particularly in tree species, is very scanty from biodiversity-rich countries like India. rbcL and matK are standard barcode loci while ITS, and trnH-psbA are considered as supplementary loci for plants. METHODOLOGY AND PRINCIPAL FINDINGS: Plant barcode loci, namely, rbcL, matK, ITS, trnH-psbA, and the recently proposed ITS2, were tested for their efficacy as barcode loci using 300 accessions of tropical tree species. We tested these loci for PCR, sequencing success, and species discrimination ability using three methods. rbcL was the best locus as far as PCR and sequencing success rate were concerned, but not for the species discrimination ability of tropical tree species. ITS and trnH-psbA were the second best loci in PCR and sequencing success, respectively. The species discrimination ability of ITS ranged from 24.4 percent to 74.3 percent and that of trnH-psbA was 25.6 percent to 67.7 percent, depending upon the data set and the method used. matK provided the least PCR success, followed by ITS2 (59. 0%). Species resolution by ITS2 and rbcL ranged from 9.0 percent to 48.7 percent and 13.2 percent to 43.6 percent, respectively. Further, we observed that the NCBI nucleotide database is poorly represented by the sequences of barcode loci studied here for tree species. CONCLUSION: Although a conservative approach of a success rate of 60-70 percent by both ITS and trnH-psbA may not be considered as highly successful but would certainly help in large-scale biodiversity inventorization, particularly for tropical tree species, considering the standard success rate of plant DNA barcode program reported so far. The recommended matK and rbcL primers combination may not work in tropical tree species as barcode markers. PMID- 23460919 TI - An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia. AB - PURPOSE: To identify a novel pathogenic gene mutation present in a Chinese family with hereditary hemorrhagic telangiectasia (HHT) and to determine if an intron mutation may influence the transcriptional activity of the ACVRL1 gene. METHODS: HHT family members were ascertained following the presentation of proband and involved subjects. All family members (n = 5) and 113 healthy individuals were genotyped for the variant in intron 6 c.772+27G>C of ACVRL1 gene. The genomic structure of ACVRL1 in affected HHT patients and healthy individuals was determined by long range PCR and sequencing. The expression of ACVRL1 mRNA and protein in patients with HHT was evaluated using real-time polymerase chain reaction and immunoblot analysis. Luciferase activity assay and electrophoretic mobility shift assay (EMSA) were performed to uncover the mechanism of intron related transcriptional regulation. RESULTS: Only one novel mutation in intron 6 (c.772+27G>C) of ACVRL1 gene, no other mutation, abnormal splice, gross genomic deletion or rearrangement was found in this HHT2 family. Compared with healthy individuals, ACVRL1 mRNA and protein were significantly decreased in affected HHT2 individuals. Luciferase activity assay demonstrated that the transcriptional activity of the mutated ACVRL1 was significantly lower than that of the wild-type of intron 6; EMSA results showed that intron 6 c.772+27G>C mutation was able to inhibit the binding of transcriptional factor Sp1. CONCLUSIONS: A novel intron mutation in ACVRL1 gene is associated with familial HHT2. The mechanisms may be involved in the down-regulation of ACVRL1 gene transcription. PMID- 23460920 TI - Comparison of DNA extraction kits for detection of Burkholderia pseudomallei in spiked human whole blood using real-time PCR. AB - Burkholderia pseudomallei, the etiologic agent of melioidosis, is endemic in northern Australia and Southeast Asia and can cause severe septicemia that may lead to death in 20% to 50% of cases. Rapid detection of B. pseudomallei infection is crucial for timely treatment of septic patients. This study evaluated seven commercially available DNA extraction kits to determine the relative recovery of B. pseudomallei DNA from spiked EDTA-containing human whole blood. The evaluation included three manual kits: the QIAamp DNA Mini kit, the QIAamp DNA Blood Mini kit, and the High Pure PCR Template Preparation kit; and four automated systems: the MagNAPure LC using the DNA Isolation Kit I, the MagNAPure Compact using the Nucleic Acid Isolation Kit I, and the QIAcube using the QIAamp DNA Mini kit and the QIAamp DNA Blood Mini kit. Detection of B. pseudomallei DNA extracted by each kit was performed using the B. pseudomallei specific type III secretion real-time PCR (TTS1) assay. Crossing threshold (C T ) values were used to compare the limit of detection and reproducibility of each kit. This study also compared the DNA concentrations and DNA purity yielded for each kit. The following kits consistently yielded DNA that produced a detectable signal from blood spiked with 5.5*10(4) colony forming units per mL: the High Pure PCR Template Preparation, QIAamp DNA Mini, MagNA Pure Compact, and the QIAcube running the QIAamp DNA Mini and QIAamp DNA Blood Mini kits. The High Pure PCR Template Preparation kit yielded the lowest limit of detection with spiked blood, but when this kit was used with blood from patients with confirmed cases of melioidosis, the bacteria was not reliably detected indicating blood may not be an optimal specimen. PMID- 23460921 TI - Superior antitumor activity of nanoparticle albumin-bound paclitaxel in experimental gastric cancer. AB - Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 MUM to 1.51 MUM) and epirubicin (0.12 MUM to 0.25 MUM). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p = 0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p = 0.0007), oxaliplatin (40 days, p = 0.0007) or to docetaxel therapy (81 days, p = 0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker. PMID- 23460922 TI - Immune responses of a native and an invasive bird to Buggy Creek Virus (Togaviridae: Alphavirus) and its arthropod vector, the swallow bug (Oeciacus vicarius). AB - Invasive species often display different patterns of parasite burden and virulence compared to their native counterparts. These differences may be the result of variability in host-parasite co-evolutionary relationships, the occurrence of novel host-parasite encounters, or possibly innate differences in physiological responses to infection between invasive and native hosts. Here we examine the adaptive, humoral immune responses of a resistant, native bird and a susceptible, invasive bird to an arbovirus (Buggy Creek virus; Togaviridae: Alphavirus) and its ectoparasitic arthropod vector (the swallow bug; Oeciacus vicarius). Swallow bugs parasitize the native, colonially nesting cliff swallow (Petrochelidon pyrrhonota) and the introduced house sparrow (Passer domesticus) that occupies nests in cliff swallow colonies. We measured levels of BCRV specific and swallow bug-specific IgY levels before nesting (prior to swallow bug exposure) and after nesting (after swallow bug exposure) in house sparrows and cliff swallows in western Nebraska. Levels of BCRV-specific IgY increased significantly following nesting in the house sparrow but not in the cliff swallow. Additionally, house sparrows displayed consistently higher levels of swallow bug-specific antibodies both before and after nesting compared to cliff swallows. The higher levels of BCRV and swallow bug specific antibodies detected in house sparrows may be reflective of significant differences in both antiviral and anti-ectoparasite immune responses that exist between these two avian species. To our knowledge, this is the first study to compare the macro- and microparasite-specific immune responses of an invasive and a native avian host exposed to the same parasites. PMID- 23460923 TI - PRAME is a golgi-targeted protein that associates with the Elongin BC complex and is upregulated by interferon-gamma and bacterial PAMPs. AB - Preferentially expressed antigen in melanoma (PRAME) has been described as a cancer-testis antigen and is associated with leukaemias and solid tumours. Here we show that PRAME gene transcription in leukaemic cell lines is rapidly induced by exposure of cells to bacterial PAMPs (pathogen associated molecular patterns) in combination with type 2 interferon (IFNgamma). Treatment of HL60 cells with lipopolysaccharide or peptidoglycan in combination with IFNgamma resulted in a rapid and transient induction of PRAME transcription, and increased association of PRAME transcripts with polysomes. Moreover, treatment with PAMPs/IFNgamma also modulated the subcellular localisation of PRAME proteins in HL60 and U937 cells, resulting in targeting of cytoplasmic PRAME to the Golgi. Affinity purification studies revealed that PRAME associates with Elongin B and Elongin C, components of Cullin E3 ubiquitin ligase complexes. This occurs via direct interaction of PRAME with Elongin C, and PRAME colocalises with Elongins in the Golgi after PAMP/IFNgamma treatment. PRAME was also found to co-immunoprecipitate core histones, consistent with its partial localisation to the nucleus, and was found to bind directly to histone H3 in vitro. Thus, PRAME is upregulated by signalling pathways that are activated in response to infection/inflammation, and its product may have dual functions as a histone-binding protein, and in directing ubiquitylation of target proteins for processing in the Golgi. PMID- 23460924 TI - The effects of computed tomography with iterative reconstruction on solid pulmonary nodule volume quantification. AB - BACKGROUND: The objectives of this study were to evaluate the influence of iterative reconstruction (IR) on pulmonary nodule volumetry with chest computed tomography (CT). METHODS: Twenty patients (12 women and 8 men, mean age 61.9, range 32-87) underwent evaluation of pulmonary nodules with a 64-slice CT scanner. Data were reconstructed using filtered back projection (FBP) and IR (Philips Healthcare, iDose(4)-levels 2, 4 and 6) at similar radiation dose. Volumetric nodule measurements were performed with semi-automatic software on thin slice reconstructions. Only solid pulmonary nodules were measured, no additional selection criteria were used for the nature of nodules. For intra observer and inter-observer variability, measurements were performed once by one observer and twice by another observer. Algorithms were compared using the concordance correlation-coefficient (pc) and Friedman-test, and post-hoc analysis with the Wilcoxon-signed ranks-test with Bonferroni-correction (significance level p<0.017). RESULTS: Seventy-eight nodules were present including 56 small nodules (volume<200 mm(3), diameter<8 mm) and 22 large nodules (volume>=200 mm(3), diameter>=8 mm). No significant differences in measured pulmonary nodule volumes between FBP, iDose(4)-levels 2, 4 and 6 were found in both small nodules and large nodules. FBP and iDose(4)-levels 2, 4 and 6 were correlated with pc values of 0.98 or higher for both small and large nodules. Pc-values of intra observer and inter-observer variability were 0.98 or higher. CONCLUSIONS: Measurements of solid pulmonary nodule volume measured with standard-FBP were comparable with IR, regardless of the IR-level and no significant differences between measured volumes of both small and large solid nodules were found. PMID- 23460925 TI - Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC SIGN and DC-SIGNR. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins. PMID- 23460927 TI - Distributional learning of appearance. AB - Opportunities for associationist learning of word meaning, where a word is heard or read contemperaneously with information being available on its meaning, are considered too infrequent to account for the rate of language acquisition in children. It has been suggested that additional learning could occur in a distributional mode, where information is gleaned from the distributional statistics (word co-occurrence etc.) of natural language. Such statistics are relevant to meaning because of the Distributional Principle that 'words of similar meaning tend to occur in similar contexts'. Computational systems, such as Latent Semantic Analysis, have substantiated the viability of distributional learning of word meaning, by showing that semantic similarities between words can be accurately estimated from analysis of the distributional statistics of a natural language corpus. We consider whether appearance similarities can also be learnt in a distributional mode. As grounds for such a mode we advance the Appearance Hypothesis that 'words with referents of similar appearance tend to occur in similar contexts'. We assess the viability of such learning by looking at the performance of a computer system that interpolates, on the basis of distributional and appearance similarity, from words that it has been explicitly taught the appearance of, in order to identify and name objects that it has not been taught about. Our experiment tests with a set of 660 simple concrete noun words. Appearance information on words is modelled using sets of images of examples of the word. Distributional similarity is computed from a standard natural language corpus. Our computation results support the viability of distributional learning of appearance. PMID- 23460926 TI - Connexin43 hemichannel-mediated regulation of connexin43. AB - BACKGROUND: Many signaling molecules and pathways that regulate gap junctions (GJs) protein expression and function are, in fact, also controlled by GJs. We, therefore, speculated an existence of the GJ channel-mediated self-regulation of GJs. Using a cell culture model in which nonjunctional connexin43 (Cx43) hemichannels were activated by cadmium (Cd(2+)), we tested this hypothesis. PRINCIPAL FINDINGS: Incubation of Cx43-transfected LLC-PK1 cells with Cd(2+) led to an increased expression of Cx43. This effect of Cd(2+) was tightly associated with JNK activation. Inhibition of JNK abolished the elevation of Cx43. Further analysis revealed that the changes of JNK and Cx43 were controlled by GSH. Supplement of a membrane-permeable GSH analogue GSH ethyl ester or GSH precursor N-acetyl-cystein abrogated the effects of Cd(2+) on JNK activation and Cx43 expression. Indeed, Cd(2+) induced extracellular release of GSH. Blockade of Cx43 hemichannels with heptanol or Cx43 mimetic peptide Gap26 to prevent the efflux of GSH significantly attenuated the Cx43-elevating effects of Cd(2+). CONCLUSIONS: Collectively, our results thus indicate that Cd(2+)-induced upregulation of Cx43 is through activation of nonjunctional Cx43 hemichannels. Our findings thus support the existence of a hemichannel-mediated self-regulation of Cx43 and provide novel insights into the molecular mechanisms of Cx43 expression and function. PMID- 23460928 TI - A review of 105 subscapular-based flaps harvested using a new dorsal decubitus position: how far can we go? AB - OBJECTIVE: Interest in flaps based on the subscapular vascular system has decreased because of the need for intraoperative patient repositioning and the inability to employ a simultaneous 2-team approach. The aims of this study are to review our experience using dorsal decubitus patient positioning for subscapular based flap harvest and to demonstrate the effectiveness and safety of this approach. METHODS: A retrospective review of all subscapular-based flap cases performed by the senior author at 2 hospital centers from 1995 to 2010 was conducted. Variables studied included indications for reconstruction, flap characteristics, and postoperative complications. A longitudinal roll placed between the scapulae as well as an optional perpendicularly placed shoulder roll are used to achieve dorsal decubitus patient positioning. RESULTS: One hundred five flaps were performed during the study period, and dorsal decubitus positioning was used in all cases. Eighty-four flaps were free and 21 were pedicled. Indications for reconstruction included cancer resection (n = 58), trauma (n = 32), infection (n = 9), and others (n = 6). A simultaneous 2-team approach was carried out in 70 cases. Major complications included 9 cases of arterial or venous thrombosis/insufficiency, 2 of which resulted in total flap failure. Intraoperative conversion to lateral decubitus positioning was never required. CONCLUSIONS: Dorsal decubitus harvesting for subscapular-based flaps is a practical and effective technique that enables a simultaneous 2-team approach in complex reconstructive cases. Previous limitations of these highly versatile flaps, such as the need for intraoperative patient repositioning, can thus be avoided. This approach is employed for all subscapular-based flap reconstructions performed by the senior author. PMID- 23460929 TI - Spontaneous atraumatic extensor pollicis longus rupture in the nonrheumatoid population. AB - INTRODUCTION: Extensor pollicis longus (EPL) tendon rupture is a well-described phenomenon in patients with rheumatoid arthritis. Mechanisms of EPL tendon rupture in the nonrheumatoid population have also been described and include traumatic rupture, repetitive motion strain, and steroid injection into the tendon. METHODS: The operative records for patients undergoing extensor pollicis longus reconstruction by the senior author were reviewed. Patients with a history of trauma to the wrist or inflammatory arthropathy were excluded. RESULTS: We identified 3 patients who presented with spontaneous EPL tendon rupture. These patients reported no risk factors (as listed earlier) or inciting event. All 3 patients had some exposure to local steroids but this exposure was not at the site of subsequent tendon rupture. All patients were operatively repaired and went on to full recovery of EPL function. DISCUSSION: In patients with sudden loss of extension of the thumb interphalangeal joint, a thorough history of steroid exposure including local steroid exposure remote to the affected EPL tendon may be relevant. PMID- 23460930 TI - Surgical amputation of the digit: an investigation into the technical variations among hand surgeons. AB - OBJECTIVE: Digital injuries are common and frequently complicate occupational hazards and trauma. The management of these injuries often necessitates digital amputation, and a variety of different amputation techniques are advocated and employed by hand surgeons. In this survey study, we investigate the variation in technical detail among a group of hand surgeons when performing digital amputations, specifically the preferred management of the residual articular cartilage, transected nerves, and phalangeal contouring. METHODS: We reviewed the literature on techniques in digital amputation and created a 7-question survey that targeted controversial issues within this specific topic. We then sent this survey electronically to the members of the American Society for Surgery of the Hand and reviewed the responses of the respondents (n = 592, 20%). RESULTS: There was a mixed response regarding whether or not to remove the articular cartilage when disarticulating, nearly a 50% split between the respondents. Most would perform a "pull and resect" technique for transected nerves. Phalangeal contouring was generally agreed upon, though the technique in doing so varied from performing condylectomies, to bony contouring only, to some combination of both. CONCLUSIONS: We detected a substantial variation in technique among our group of hand surgeons regarding the treatment of articular cartilage and the method of phalangeal contouring. There was more consensus regarding the treatment of transected nerve. It is interesting that to date, the aforementioned issues in digital amputation have not been critically evaluated by definitive and well controlled studies. PMID- 23460931 TI - Knee wounds: a novel approach to reconstruction. PMID- 23460932 TI - The natural history of "contrast stasis" within aneurysm after embolization. AB - OBJECTIVE: Contrast stasis within residual aneurysm sac is sometimes seen after embolization of intracranial aneurysms and is thought to represent sluggish flow prone to thrombosis. We report the short- and intermediate-term angiographic outcomes of intra-aneurysmal contrast stasis following predominantly bioactive coil embolization procedures. DESIGN/METHODS: Contrast stasis was identified by retrospective review of 153 consecutive patients treated at two centers with endovascular embolizations for intracranial aneurysms. Contrast stasis was defined by persistent opacification despite clearance of contrast from parent artery assessed during angiography at 3-5 frames/second. The contrast stasis were classified based on relative area and location visualized on dynamic angiographic images as small (5-15% of the total aneurysm), large (> 15%), or occurring only in the aneurysm neck by an independent reviewer. RESULTS: There were 44 patients (23 women: mean age 54.3+/-12.5 years) who had contrast stasis; 36 patients had small and 8 had contrast stasis in the neck of the aneurysm. There were no patients with large contrast stasis. Of these 44 patients, 33 patients had a mean follow up angiogram in 269.5 days; 10 patients had no follow up. In 21 patients, (18 were small and 3 were in the neck) the area of contrast stasis had spontaneously thrombosed while in 7 patients there was no change in the contrast stasis. The remaining 5 patients had increase in area of contrast stasis and required re-embolization. Size of the contrast stasis (p= 0.02) was the only statistically significant factor although there was a trend dome to neck ratio > 2 (p= 0.16) and washout on the initial angiogram (p= 0.16) affecting the thrombosis of contrast stasis. CONCLUSIONS: Most small contrast stasis following coil embolization procedures spontaneously thrombose and do not require further treatment. A small proportion of patients had increase in the area of intra aneurysmal contrast stasis and required further treatment. ABBREVIATIONS: MRAmagnetic resonance angiographyDSAdigital subtraction angiography. PMID- 23460933 TI - Antibiotics and muscle relaxation. PMID- 23460934 TI - Anesthetic management of an adolescent with Dandy-Walker syndrome. PMID- 23460935 TI - Assessment of hemostatic function in pregnant women undergoing surgery using a Platelet Function Analyzer-100. PMID- 23460936 TI - Assessment of the right internal jugular vein cross-sectional area with different levels of positive end-expiratory pressure in patients with controlled ventilation during anesthesia. PMID- 23460937 TI - Temporary solution for one lung ventilation with isolated bronchial blocker of Univent(r) tube. PMID- 23460938 TI - A suspected case of air embolism in endonasal surgery using CO2 laser. PMID- 23460939 TI - Anesthetic complications due to extremely low ankle blood pressure caused by peripheral arterial disease. PMID- 23460940 TI - The Language of Love?-Verbal versus Implied Consent at First Heterosexual Intercourse: Implications for Contraceptive Use. AB - BACKGROUND: Little is known about how young people communicate about initiating intercourse. PURPOSE: This study was designed to gauge the prevalence of implied versus verbal consent at first intercourse in a U.S. college population, assess effects of consent type on contraceptive use, and explore the influences of gender, race and other factors. METHODS: We conducted and analyzed a cross sectional survey of non-Hispanic white and black students from four universities, exploring associations between verbal and nonverbal consent, contraceptive use and covariates. RESULTS: Among those with consensual first intercourse experiences (N=1883), half (49%) provided nonverbal consent. Black men were the most likely to provide nonverbal consent (61%), followed by white men (55%), black women (51%), and white women (43%). Respondents who used condoms at first intercourse were more likely to provide verbal consent, suggesting that condoms may prompt sexual discussions (or vice versa). In contrast, even when controlling for covariates, those who provided nonverbal consent were less likely to have used contraception (significantly so for women). DISCUSSION: These findings confirm the hypothesis that young people who do not discuss whether to engage in vaginal intercourse for the first time are less likely to use contraception. These results add an important layer to our current conceptual model of sexual development, in particular, how young people adopt, or fail to adopt, behaviors that will keep them healthy once they decide to become sexually active. TRANSLATION TO HEALTH EDUCATION PRACTICE: Enhanced sexual communication skills are greatly needed. Public health practitioners should investigate type of consent in future research and programming, with sensitivity to gender and racial influences. PMID- 23460941 TI - Changes in kinesin expression in the CNS of mice with dynein heavy chain 1 mutation. AB - Dysfunction of fast axonal transport, vital for motor neurons, may lead to neurodegeneration. Anterograde transport is mediated by N-kinesins (KIFs), while retrograde transport by dynein 1 and, to a minor extent, by C-kinesins. In our earlier studies we observed changes in expression of N- and C-kinesins (KIF5A, 5C, C2) in G93ASOD1-linked mouse model of motor neuron degeneration. In the present work we analyze the profile of expression of the same kinesins in mice with a dynein 1 heavy chain mutation (Dync1h1, called Cra1), presenting similar clinical symptoms, and in Cra1/SOD1 mice with milder disease progression than SOD1 transgenics. We found significantly higher levels of mRNA for KIF5A and KIF5C but not the KIFC2 in the frontal cortex of symptomatic Cra1/+ mice (aged 365 days) compared to the wild-type controls. No changes in kinesin expression were found in the spinal cord of any age group and only mild changes in the hippocampus. The expression of kinesins in the cerebellum of the presymptomatic and symptomatic mice (aged 140 and 365 days, respectively) was much lower than in age-matched controls. In Cra1/SOD1 mice the changes in KIFs expression were similar or more severe than in the Cra1/+ groups, and they also appeared in the spinal cord. Thus, in mice with the Dync1h1 mutation, which impairs dynein 1 dependent retrograde transport, expression of kinesin mRNA is affected in various structures of the CNS and the changes are similar or milder than in mice with double Dync1h1/hSOD1G93A mutations. PMID- 23460942 TI - ARMS-PCR for detection of BRAF V600E hotspot mutation in comparison with Real Time PCR-based techniques. AB - BRAF mutation testing is one of the best examples how modern genetic testing may help to effectively use targeted therapies in cancer patients. Since many different genetic techniques are employed to assess BRAF mutation status with no available comparison of their sensitivity and usefulness for different types of samples, we decided to evaluate our own PCR-based assay employing the amplification refractory mutation system (ARMS-PCR) to detect the most common hotspot mutation c. T1799A (p. V600E) by comparing it with two qPCR based assays: a commercially available test with hybridizing probes (TIB MOLBIOL) and high resolution melting (HRM). Positive results were verified with Sanger sequencing. DNA from two cancer cell lines with known mutation status and from tissue samples from melanoma and gastric cancer was used. ARMS-PCR was the most sensitive method with the level of detection of the mutant allele at 2%. Similar sensitivity was observed for the qPCR-based commercial test employing hybridizing probes; however, this test cannot exclude negative results from poor or low quality samples. Another qPCR-based method, HRM, had lower sensitivity with the detection level of approximately 20%. An additional drawback of HRM methodology was the inability to distinguish between wild type and mutant homozygotes in a straightforward assay, probably due to the character of this particular mutation (T?>A). Sanger sequencing had the sensitivity of the detection of mutant allele similar to HRM, approx. 20%. In conclusion, simple ARMS-PCR may be considered the method of choice for rapid, cost-effective screening for BRAF p. V600E mutation. PMID- 23460943 TI - [Metabolic syndrome in Sri Lanka]. PMID- 23460945 TI - Single-molecule approach to find out toxic oligomeric alpha-synuclein species formation. PMID- 23460944 TI - CASQ1 gene is an unlikely candidate for malignant hyperthermia susceptibility in the North American population. AB - BACKGROUND: Malignant hyperthermia (MH, MIM# 145600) is a complex pharmacogenetic disorder that is manifested in predisposed individuals as a potentially lethal reaction to volatile anesthetics and depolarizing muscle relaxants. Studies of CASQ1-null mice have shown that CASQ1, encoding calsequestrin 1, the major Ca2+ binding protein in the lumen of the sarcoplasmic reticulum, is a candidate gene for MH in mice. The aim of this study was to establish whether the CASQ1 gene is associated with MH in the North American population. METHODS: The entire coding region of CASQ1 in 75 unrelated patients diagnosed by caffeine-halothane contracture test as MH susceptible (MHS) was analyzed by DNA sequencing. Subsequently, three groups of unrelated individuals (130 MHS, 100 MH negative, and 192 normal controls) were genotyped for a variant that was identified by sequencing. Levels of CASQ1 expression in the muscle from unrelated MHS and MH negative individuals were estimated by Western blotting. RESULTS: Screening of the entire coding sequence of the CASQ1 gene in 75 MHS patients revealed a single variant c.260T > C (p.Met87Thr) in exon 1. This variant is unlikely to be pathogenic, because its allele frequency in the MHS group was not significantly different from that of controls. There was also no difference in calsequestrin 1 protein levels between muscle samples from MHS and controls, including those carrying the p.Met87Thr variant. CONCLUSIONS: This study revealed a low level of protein coding sequence variability within the human CASQ1 gene, indicating that CASQ1 is not a major MHS locus in the North American population. PMID- 23460946 TI - About predictors of acute kidney injury after lung resection. Reply. PMID- 23460947 TI - Pregabalin effective for the prevention of chronic postsurgical pain: really? Reply. PMID- 23460948 TI - Alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism are allelic disorders due to ATP1A3 gene mutations. PMID- 23460949 TI - The authors' response. PMID- 23460951 TI - Higher doses of pain medication linked to psychiatric problems. PMID- 23460950 TI - Raf kinase inhibitor protein expression combined with peritoneal involvement and lymphovascular invasion predicts prognosis in Dukes' B colorectal cancer patients. AB - AIMS: There is controversy regarding the use of adjuvant therapy in patients with Dukes' B colorectal cancer (CRC). New markers, identifying high-risk Dukes' B patients, are needed. Here, we examine the utility of Raf kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation. METHODS AND RESULTS: We used a tissue microarray of 220 patients with Dukes' B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status.RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator, along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing. CONCLUSIONS: Raf kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes' B CRC patients.This demonstrates the potential utility of RKIP in identifying 'high-risk' Dukes' B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy. PMID- 23460953 TI - Sitting-rising test predictive of all-cause mortality. PMID- 23460952 TI - Modular structure of HEL protein from Arabidopsis reveals new potential functions for PR-4 proteins. AB - Plants possess an innate immune system enabling them to defend themselves against pathogen attack.The accumulation of newly synthesized pathogenesis related proteins (PRs) is one of the most studied inducible plant defence response. In this paper, we report on the characterization of a class I PR4 vacuolar protein from Arabidopsis, named At HEL. The protein has a modular structure consisting of an N-terminal hevein-like domain(CB-HEL) and a C-terminal domain (CD-HEL) that are posttranslationally processed. Both domains show a strong antifungal activity, but they do not have chitinolitic properties.CD-HEL was found to be endowed with RNase, but not DNase activity. Molecular modeling carried out on both domains revealed that CB-HEL possesses a chitin binding site strictly conserved between hevein-type peptides and that the cavity involved in substrate interaction of CD-HEL do not show any residue substitution with respect to the orthologous wheatwin1 from wheat. Using a fishing for partners approach, CB-HEL was found to interact with a fungal fruiting body lectin. According to literature, we can hypothesize that CB-HEL could cross the pathogen hyphal membrane and that its interaction with a fungal lectin could knock out one of the weapons that the fungus uses. PMID- 23460954 TI - Deep brain stimulation being tested in AD patients. PMID- 23460955 TI - Study pinpoints ages adults are more receptive to health messages. PMID- 23460956 TI - Nursing staff detail communication challenges. PMID- 23460957 TI - Response. PMID- 23460958 TI - [Novel inhibitors against the bacterial signal peptidase I]. AB - New antibiotics with novel modes of action and structures are urgently needed to combat the emergence of multidrug-resistant bacteria. Bacterial signal peptidase I (SPase I) is an indispensable enzyme responsible for cleaving the signal peptide of preprotein to release the matured proteins. Increasing evidence suggests that SPase I plays a crucial role in bacterial pathogenesis by regulating the excretion of a variety of virulent factors, maturation of quorum sensing factor and the intrinsic resistance against beta-lactams. Recently, breakthrough has been achieved in the understanding of three-dimensional structure of SPase I as well as the mechanism of enzyme-inhibitors interaction. Three families of inhibitors are identified, i.e. signal peptide derivatives, beta-lactams and arylomycins. In this article, we summarize the recent advance in the study of structure, activity and structure-activity relationship of SPase I inhibitors. PMID- 23460959 TI - [Progress of anti-tumor study based on BRAF]. AB - BRAF is one of the most important pro-oncogenes, which is mutated in approximately 8% of human tumors. The most common BRAF mutation is a valine-to glutamate transition (V600E) that is expressed primarily in melanoma, colorectal cancer and thyroid carcinoma. MEK/ERK is constitutively activated in the cells expressing BRAFV600E, leading to tumor development, invasion, and metastasis. Therefore, BRAFV600E is a therapeutic target for melanoma and some other BRAFV600E tumors. Vemurafenib, a BRAFV600E inhibitor, which was approved by FDA for the treatment of late-stage melanoma in 2011, produces improved rates of overall and progression-free survival in patients with the BRAFV600E mutation, making a dramatic breakthrough in melanoma treatment. Vemurafenib is also an individual target drug based on genetic diagnosis. However, its therapeutic success is limited by the emergence of drug resistance. Therefore, it is important to explore the mechanisms underlying the resistance for developing new inhibitor drugs and for preventing or delaying the resistance evolution to BRAF inhibitor drugs. In this review, we described the role of BRAFV600E as an anti tumor drug target and the development of BRAF inhibitors. We also discussed the mechanisms leading to resistance of BRAFV600E inhibitors. Furthermore, therapeutic strategies that might be employed to overcome acquired resistance were proposed. PMID- 23460960 TI - [Modulation of nuclear receptors on drug-metabolizing enzymes and transporters]. AB - PXR, CAR and PPAR, widely distributed in the body, are important members of the nuclear receptors (NRs) family. The activities and gene expressions of drug metabolizing enzymes (DMEs) and transporters can be regulated by the activation of NRs, which effect the drug disposition. Multidrug resistance (MDR) is the leading cause of failure in cancer therapy. NRs, including PXR, CAR and PPAR, were shown to regulate the expressions of DMEs and transporters involved in the drug metabolism and clearance, suggesting that the modulation of NRs can be considered as a new target to overcome MDR. This review described the research progress of NR family members PXR, CAR, PPAR and their transcriptional activation mechanism, the regulation of DMEs and transporters by NRs, which may provide a valuable reference for clinical medication and overcome of MDR. PMID- 23460961 TI - [Research progress of self-assembled beads drug delivery system prepared from cyclodextrins and oils]. AB - Recently, increasing attention has been paid to beads, an innovative self assembled drug delivery system prepared from cyclodextrins and oils. Beads are new core-shell minispheres containing poorly water-soluble drugs or lipophilic drugs dissolved in the lipid core without the use of organic solvents and surfactants. Therefore, beads with high drug loading and improved oral bioavailability have great potential for oral delivery of poorly water-soluble drugs and lipophilic drugs. The preparation mechanisms, formulations and methods, the in vitro and in vivo properties of beads were reviewed in order to provide the theoretical basis for further application of beads. PMID- 23460962 TI - [Antibacterial activity and mechanism of baicalein]. AB - Baicalein (BAI) is an effective bactericide. The antibacterial activity and mechanism experiments were carried out by determining conductivity and content of macromolecules of membrane penetrability, the oxidative respiratory metabolism and protein synthesis changes and the inhibition of DNA topoisomerase activities. Electrical conductivity and the number of large molecules of BAI increased 2.48% and 1.8%, respectively, than that of the control. However, the membrane integrity did not destroyed by BAI directly. With BAI treatment, inhibition rates of activities for SDH and MDH were 56.2% and 57.4%, respectively, demonstrating that BAI could inhibit cell respiratory. After treated with BAI for 20 h, the total soluble content of proteins decreased by 42.83%. Moreover, the activities of DNA topoisomerase I and II were inhibited completely by 0.2 mmol x L(-1) BAI. These results indicated that BAI had obvious antibacterial activity on Staphylococcus aureus. The mechanism is that it could affect bacterial membrane penetrability, inhibit protein synthesis and influence SDH, MDH and DNA topoisomerase I and II activities to exert its antibacterial functions. PMID- 23460963 TI - [Inhibition of tumor cell invasion and induction of apoptosis by ubenimex]. AB - This study is to investigate the effects of ubenimex on tumor cell invasion and apoptosis, dose relationship and mechanism. Immunofluorescence staining was performed to detect the expression of CD13 in HT-1080 cells. MTT assay was used to analyze the effect of ubenimex on cell proliferation. Annexin V-EGFP/PI was used to detect apoptotic cells by flow cytometry. Cell cycle was analyzed using flow cytometry. Ala-pNA was used as substrate to evaluate the effect of ubenimex on the aminopeptidase activity. Transwell assay was used to analyze the effect of ubenimex on cell invasion and migration ability. Western blotting was used to detect the expression level of CD13. MMP activity was analyzed using gelatin zymography. The results showed that ubenimex at high concentration inhibited the proliferation of HT-1080 cells (IC50: 3.8 mg x mL(-1)), and induced cell apoptosis. Cell cycle was blocked at G1 phase. Ubenimex at low concentration inhibited the aminopeptidase activity of HT-1080 cells (IC50: 8.3 microg x mL( 1)) and inhibited cell invasion, but it had no effects on the cell migration and proliferation. Ubenimex had no effects on CD13 expression and MMP activity. In conclusion, ubenimex at low concentration can inhibit the invasion ability of tumor cells by directly inhibiting the aminopeptidase activity; ubenimex at high concentration can inhibit the proliferation of tumor cells and induce cell apoptosis by a CD13-independent pathway. PMID- 23460964 TI - [Establishment of BCRP expressed pig kidney cell line LLC-PK1/BCRP and its biological profile]. AB - To establish a pig kidney cell line LLC-PK1/BCRP in which human breast cancer resistance protein was highly expressed, the expression vector pcDNA3.1(+)-BCRP which contained BCRP gene was constructed and transfected into LLC-PKI cells via liposomes. After selecting with G418, population doubling time, flow cytometry and Western blotting analysis were used to evaluate the cell line. MTT assays were employed to determine the drug resistance index of mitoxantrone and doxorubicin. Invert fluorescent microscope was used to observe the efflux of fluorescence dye Hoechst 33342 by BCRP, furthermore, the BCRP's inhibitor GF120918 was applied to reverse the efflux of Hoechst 33342. The experiment results showed that the expression of BCRP protein increased in LLC-PK1/BCRP cell. The population doubling time of LLC-PK1/BCRP cell was a little longer than that of the parental cell LLC-PK1. The resistance indexes to mitoxantrone and doxorubicin were 51.95 and 6.09 times, respectively, higher than LLC-PK1 cell. The efflux of Hoechst 33342 was significantly enhanced and could be reversed by GF120918. So a LLC-PK1/BCRP cell line was established, which highly expressed BCRP protein successfully. This cell line could be a valuable model to further investigate the biological profile of BCRP and select the substrate and inhibitor of BCRP. PMID- 23460965 TI - [Screening and characterization of aptamers of Cepsilon3-Cepsilon4 protein]. AB - In order to obtain nucleotides aptamers bind to IgE, 80 bp nucleotides single stranded DNA library containing 40 random nucleotides was designed and synthesized. Oligonucleotides that bind to human Cepsilon3-Cepsilon4 protein were isolated from ssDNA pools by the systematic evolution of ligands by exponential enrichment (SELEX) method using nitrocellulose filters as screening medium. Through the optimization of critical PCR and asymmetric PCR parameters including annealing temperature, cycles, and molar ratios of target protein and ssDNA etc, a suitable screening system was established. The aptamers of Cepsilon3-Cepsilon4 protein with high affinity and high specificity were identified by ELISA with biotin-streptavidin-horseradish peroxidase system, and its primary sequence and second structure were analyzed by DNAMAN package and DNA folding sever after being cloned and sequenced. Moreover, target protein was bound to one aptamer and another aptamer modified with biotion together forming a sandwich-like complex, which was captured in microwell to detect IgE concentration using the optimal combination in the sandwich method named enzyme-linked aptamers sorption assay (ELASA). The method could be used for the quantitative detection of human IgE, and whose sensitivity reached to 120 ng x mL(-1). PMID- 23460966 TI - [Antidepressant activities of flavonoids from Glycyrrhiza uralensis and its neurogenesis protective effect in rats]. AB - Adult rats chronic unpredictable stress model of depression (CUS) was adopted to elucidate the antidepressant pharmacological activity and related neurogenesis protective effect of the total flavonoids extract (licorice flavonoids, LF) from the Glycyrrhiza uralensis Fisch. cultivated locally in Ningxia. The rats were exposed to 9 kinds of unpredictable sequence of stressors and were given flavonoids (300 mg x kg(-1), 100 mg x kg(-1) and 30 mg x kg(-1)) for 28 days. The antidepressant effect was elucidated by open field test, forced swimming test and tail suspension test. The level of serum corticosterone was detected by radioimmunoassay. 5'-Bromo-2'-deoxyuridine (BrdU) labeling experiments was employed to study the neurogenesis protective activities. The flavonoids can increase the sum of line crosses and number of rears, and decrease the number of fecal boli produced in the open field test of the CUS rats. Also the flavonoids can decrease the immobility time in forced swim test as well as in the tail suspension test. In addition, the flavonoids (300 mg x kg(-1)) can decrease the serum corticosterone level of the CUS rats, and increase the number of the new born BrdU positive progenitor cells at the subgranular zone (SGZ) of dentate gyrus (DG) region in hippocampus. The results demonstrated that the total flavonoids extract from the cultivated Glycyrrhiza uralensis Fisch. could produce the anti-depressive effect on chronic unpredictable stress of depression model rats and its mechanism may be associated with its neurogenesis protective effect. PMID- 23460967 TI - [Active ingredients in rhubarb with anti-proliferative effects on scar fibroblasts]. AB - This study is to explore the active ingredients of traditional Chinese medicine rhubarb with antiproliferative activity on hypertrophic scar fibroblasts (HSF). Rhubarb was extracted with Soxhlet extraction method by different polar solvents. MTS method was used to screen rhubarb solvent extracts (25 microg x mL(-1)) with anti-proliferative activity on HSF, and flow cytometry was used to detect their influences on cell cycle. Then, the active ingredients were analyzed by HPLC. The components with high activity were identified by UPLC-Q/TOF and verified by HE staining. The results showed that the ethyl acetate extract of rhubarb had higher anti-proliferative activity (P < 0.01), increased significantly the proportion of cells in G0/G1 phase (P < 0.01), and reduced the proliferation index (PI) (P < 0.01). The main active ingredients were anthraquinones. The results of confirming experiment showed that emodin, rhein and gallic acid could inhibit cell proliferation in a dose-dependent manner. In conclusion, the ethyl acetate extract of rhubarb showed anti-proliferative activity on HSF, and the anti proliferative ingredients might be anthraquinones. PMID- 23460968 TI - [Design, synthesis and antitumor activity of sorafenib analogues containing 2 picolinylhydrazide moiety]. AB - A novel series of sorafenib analogs containing 2-picolinyl hydrazide moiety were designed and synthesized. In vitro, most of synthesized compounds have antiproliferation activity on MDA-MB-231, ACHN, HepG2, Mia-PaCa-2 and SW1990 cell lines tested by MTT assay. It is worth noting that the antitumor activities of compounds 2c, 2d and 2f are more potent than that of sorafenib on pancreatic cancer cells Mia-PaCa-2 and SW1990, and the activities of compounds 3f and 3g are 2-3 times than that of sorafenib on human hepatocellular carcinoma HepG2 cell line. PMID- 23460969 TI - [Synthesis and PPAR activities of novel phenylacetic acid derivatives containing sulfonamide moiety]. AB - The discovery of high performance leading antidiabetic compounds containing sulfonamide and 4-aminophenylacetic acid moieties is reported. This was achieved by the synthesis of 6 intermediates and subsequently 20 target molecules using 4 aminophenylacetic acid as the starting materials, and through a few synthetic routes aided by multi-step reactions including sulfonylation of amino group, deacylation of amides and esterification of carboxyl group, as well as acylation of amino group. The chemical structures of the twenty-four new compounds were determined using 1H NMR, 13C NMR and HR-MS techniques. Screening in vitro of their peroxisome proliferator-activated receptor (PPAR) activation activities showed weak relative PPAR activation activities to most of the target molecules. However, 4 target molecules exhibit PPAR over 58%, and as high as 81.79% for TM2 i, presenting itself as potent leading compound for antidiabetic drugs. This research also confirms that it is probable to achieve esterification of carboxyl group and deacylation of fatty acid N-phenyl amides concurrently in SOCl2/alcohol solvent system. This provides new synthetic method for the selective reaction within molecules containing both carboxyl and N-aryl amido groups of fatty acids. PMID- 23460970 TI - [Synthesis and biological evaluation of tetrahydrocoptisine quaternary ammonium compounds]. AB - The goal of treatment of metabolic syndrome is the prevention of diabetes and cardiovascular events. A series of novel tetrahydrocoptisine quaternary ammonium compounds were prepared to evaluate their action of hypoglycemia and hypolipidemia for finding the therapeutic agents of metabolic syndrome. Starting from the coptisine hydrochloride (2), fifteen target compounds were synthesized by reduction and substitution of the 7-N position. All of the target compounds were characterized by 1H NMR and HR-MS. Their hypoglycemic activities were evaluated in HepG2 cell and hypolipidemic activities of compounds with better hypoglycemic activity were tested further in vivo. Results indicated that compounds 5, 7, 8 and 9 exhibited better hypoglycemic activities in vitro and compounds 5 and 8 exhibited good hypolipidemic activities in high-fat-diet (HFD) induced hyperlipidemia mice and (or) hamsters. However, the activity is not as good as simvastatin. PMID- 23460971 TI - Photo-activated DNA binding and antimicrobial activities of alkaloids from Glycosmis pentaphylla. AB - In our screening for photosensitizers from natural resources, four alkaloids were isolated from Glycosmis pentaphylla by various chromatography techniques. Their structures were identified as glycoborinine (1), glybomine B (2), carbalexin A (3) and N-p-coumaroyltyramine (4) by spectral analysis. Their photoactivated antimicrobial activities were evaluated by thin-layer chromatography (TLC) agar overlay assay against Staphylococcus aureus and Bacillus subtilis. It was found that compounds 1 and 4 showed photo-activated antimicrobial activities. Meantime, photo-activated DNA binding activities of these compounds were also assessed by using a specially prepared 1.8 kb DNA fragment and restriction enzymes. Under UVA irradiation, compound 1 showed moderate inhibition on Nde I, Xba I, Nco I and Bcl I which have either 5'-TpA or 5'-ApT and trace or no inhibition on other restriction enzymes. It showed a similar inhibition pattern with the reference 8 methoxypsoralen. However, compounds 2-4 showed no inhibition against any of the restriction enzymes. PMID- 23460972 TI - [A new method of calibration and positioning in quantitative analysis of multicomponents by single marker]. AB - This paper aims to establish a new method of calibration and positioning in quantitative analysis of multicomponents by single marker (QAMS), using Shuanghuanglian oral liquid as the research object. Establishing relative correction factors with reference chlorogenic acid to other 11 active components (neochlorogenic acid, cryptochlorogenic acid, cafferic acid, forsythoside A, scutellarin, isochlorogenic acid B, isochlorogenic acid A, isochlorogenic acid C, baicalin and phillyrin wogonoside) in Shuanghuanglian oral liquid by 3 correction methods (multipoint correction, slope correction and quantitative factor correction). At the same time chromatographic peak was positioned by linear regression method. Only one standard uas used to determine the content of 12 components in Shuanghuanglian oral liquid, in stead of needing too many reference substance in quality control. The results showed that within the linear ranges, no significant differences were found in the quantitative results of 12 active constituents in 3 batches of Shuanghuanglian oral liquid determined by 3 correction methods and external standard method (ESM) or standard curve method (SCM). And this method is simpler and quicker than literature methods. The results were accurate and reliable, and had good reproducibility. While the positioning chromatographic peaks by linear regression method was more accurate than relative retention time in literature. The slope and the quantitative factor correction controlling the quality of Chinese traditional medicine is feasible and accurate. PMID- 23460973 TI - Simultaneous determination of purity and potency of the components of gentamycin using high-performance liquid chromatography. AB - The quality of some earlier developed antibiotics is usually ensured by the combination of HPLC purity and microbiological potency measurement in the pharmacopoeias of various countries because the relationship between their purity and potency is not clearly quantified. Due to potency is assessed using certain units of measurement, it can not be directly traced to the international system of units (SI unit). This has become a hotspot in the study of the quantitative relationship between purity and potency of antibiotics. It would be quite an achievement to simultaneously determine both purity and potency using HPLC methods during quality control. This study evaluated a multicomponent antibiotic product, gentamycin, as a test sample. First, pure samples of the C components of gentamycin: C1a, C2, C2a and C1 were prepared, separately. Second, quantitative relationship (theoretical potency) between the purity and potency of each C component of gentamycin were determined using 1H NMR, HPLC-ELSD and microbiological assay method. One milligram of gentamycin C1a, C2, C2a and C1 was equal to 1 286.98, 1 095.74, 1 079.52 and 739.61 gentamycin units, respectively. Finally, a method for the determination of gentamycin potency was established based on the proportion and content of C components of gentamycin. The unification of purity and potency for gentamycin was achieved using only HPLC ELSD. It is also demonstrated that C components of gentamycin and micronomicin produce the same responses under ELSD, which means that it is not necessary to prepare separate reference standards for each C component of gentamycin and that quantitative testing can be performed accurately using only one micronomicin reference standard. This study simplified the previous method for the determination of the content of C components of gentamycin using HPLC-ELSD. The developed method is suitable for regular use as a part of quality control and can simplify the rigmarole quality control procedures provided in current pharmacopeias. PMID- 23460974 TI - [Determination of doping in human urine by gas chromatography-high resolution mass spectrometry]. AB - A method was evaluated for determination of twenty-one doping (including nandrolone, boldenone and methandienone) in human urine by gas chromatography high resolution mass spectrometry. Samples were prepared by liquid-liquid extraction, concentrated, TMS derivatization and limit of detection at ng x mL( 1) by MID/GC/HRMS. According to the code of the World Anti-Doping Agency (WADA), precision and recoveries of the procedure were evaluated by replicate analysis (n = 6), the recoveries in the range of 66%-103%, with the RSD below 10.0%. The precision within the day of the method with three different concentrations was also determined RSD were less than 9.5%, 10.0% and 9.7%. PMID- 23460975 TI - [Metabolite profiling of two anti-HIV lead compounds in rat liver microsomes]. AB - The metabolite profiling of DAPA-7012 and DAAN-4442, the lead compounds from two new kinds of non-nucleoside reverse transcriptase inhibitors (NNRTIs), was performed using an ultra-high performance liquid chromatography-quadrupole time of-flight mass spectrometry (UPLC-QTOF-MS/MS), with the assistance of a metabolite data processing software. By utilizing the mass defect filter (MDF) technique, the data acquired from the 0 h-incubation and the 2 h-incubation were compared and analyzed with the MetaboLynx software. After incubation, 14 metabolites of DAPA-7012 and 14 metabolites of DAAN-4442 were found in rat liver microsome. The MS2 spectra for some metabolites were obtained using the MS(E) technique to get fragment ions for structural elucidation. The results indicated that both compounds could undergo extensive metabolism in rat liver microsomes. The major phase I reaction was oxidation/hydroxylation. The major phase II reaction was S-glutathione conjugation. The metabolic pathways were similar between the two lead compounds, though they have different backbone structures. Besides, the 4-NO2 of ring B in DAAN-4442 was susceptible to reduction, the benzyl of ring C in DAPA-7012 was tend to be oxidized. The common metabolic soft spots were primary amine of ring B and two methyl groups of ring C. Early SAR results showed that the primary amine and methyl were necessary substituent groups. The stability of these active groups needs to be improved and optimized. The approach of combining metabolites information and structure-activity analysis can provide a reference for further structural optimization. PMID- 23460976 TI - Enhanced bioavailability of total paeony glycoside by self-microemulsifying drug delivery system. AB - Total paeony glycoside (TPG) is extracted and purified from a traditional Chinese herbal medicine. It has many biological and pharmacological activities. However, there are few dosage forms of TPG in the market because of its low bioavailability. Self-microemulsifying drug delivery system (SMEDDS) is a vital tool in solving low bioavailability of poor absorption drugs. So the objective of this study is to develop a new TPG-SMEDDS for the oral delivery of poorly soluble TPG. Through the construction of pseudo-ternary phase diagrams, the optimum prescription was obtained, which consisted of 18.70% TPG, 16.27% ethyl oleate as oil, 43.34% Cremophor RH40 as surfactant and 21.73% Transcutol P as cosurfactant. The characterizations of TPG-SMEDDS including morphological characterization, droplet size, zeta-potential, emulsification time, and dissolution study of TPG SMEDDS were evaluated. The results showed that TPG-SMEDDS is stable and its release rate is high in four different media (0.1 mol x L(-1) HCl, pH 6.8 PBS, pH 7.4 PBS, and water). The relative bioavailability of SMEDDS was dramatically enhanced in an average of 1.52-fold that of TPG-suspension. It is concluded that the bioavailability of TPG is enhanced greatly by SMEDDS. PMID- 23460977 TI - [Development of glipizide push-pull osmotic pump controlled release tablets by using expert system and artificial neural network]. AB - The purpose of this study is to develop glipizide push-pull osmotic pump (PPOP) tablets by using a formulation design expert system and an artificial neural network (ANN). Firstly, the expert system for the formulation design of osmotic pump of poor water-soluble drug was employed to design the formulation of glipizide PPOP, taking the dissolution test results of Glucotrol XL as the goal. Then glipizide PPOP was prepared according to the designed formulations and the in vitro dissolution was carried out. And in vivo evaluation was carried out between the samples which were similar to Glucotrol XL and the Glucotrol XL in Beagle dogs. The range of the factors of formulation and procedure, which could influence the drug release, was optimized using artificial neural network. Finally, the design space was found. It was found that the target formulation which was similar to Glucotrol XL in dissolution test could be obtained in a short period by using the expert system. The samples which were similar to Glucotrol XL were bio-equivalent to the Glucotrol XL in Beagle dogs. The design space of the key parameter coating weight gain was 9.5%-12.0%. It could be concluded that a well controlled product of glipizide PPOP was developed since the dissolution test standard of our product was more strict than that of Glucotrol XL. PMID- 23460978 TI - [Intestinal absorption of different combinations of active compounds from Gegenqinlian decoction by rat single pass intestinal perfusion in situ]. AB - The aim is to study the intestinal absorption of different combinations of active compounds out of Gegenqinlian decoction. Rat single pass intestinal perfusion model with jugular vein cannulated was used. Samples were obtained continuously from the outlet perfusate and the mesenteric vein. The levels of puerarin, daidzin, liquilitin, baicalin, wogonoside, jatrorrhizine, berberine and palmatine were determined by LC-MS/MS and their permeability coefficients were calculated. The results showed that Glycyrrhiza could promote the absorption of the active ingredients in Pueraria which is the monarch herb; meanwhile, Pueraria also played a role in promoting the absorption of liquilitin. Based on the Gegenqinlian decoction and the different combinations experiments, the results concerning the absorption of baicalin and wogonoside were as follows. For baicalin, Pueraria and Glycyrrhiza could promote its absorption and the effect of Pueraria was more obvious. For wogonoside, Pueraria could also promote its absorption, while Glycyrrhiza played a opposite role. Pueraria and Glycyrrhiza both played a part in promoting the absorption of jateorhizine, berberine and palmatine, the effective compounds in Coptis. PMID- 23460979 TI - [Molecular characterization of a mitogen-activated protein kinase gene DoMPK1 in Dendrobium officinale]. AB - The mitogen-activated protein kinase (MAPK) cascade, composed of MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK, is abundantly conserved in all eukaryotes. MAPK along with MAPK cascade plays a vital regulatory role in the plant-arbuscular mycorrhiza/rhizobium nodule symbioses. However, the biological function of MAPK in orchid mycorrhiza (OM) symbiosis remains elusive. In the present study, a MAPK gene, designated as DoMPK1 (GenBank accession No. JX297594), was identified from D. officinale roots infected by an OM fungus Mycena sp. using the reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) methods. The full length cDNA of DoMPK1 was 1 263 bp and encoded a 372 aa protein with a molecular weight of 42.61 kD and an isoelectric point (pI) of 6.07. The deduced DoMPK1 protein contained the conserved serine/threonine-protein kinase catalytic domain (39-325) and MAP kinase signature (77-177). Multiple sequence alignment and phylogenetic analysis demonstrated that DoMPK1 was highly homologous (71%-85%) to MAPK genes from various plant species and was closely related to those from monocots. Real time quantitative PCR (qPCR) analysis revealed that DoMPK1 was constitutively expressed in leaves, stems, roots and seeds, and the transcript abundance was not significantly different in the four included tissues. Furthermore, DoMPK1 transcript was markedly induced in roots at 30 d after fungal infection, with 7.91 fold compared to that of the mock inoculated roots, suggesting implication of DoMPK1 in the early D. officinale and Mycena sp. interaction and an essential role in the symbiosis. Our study characterized a MAPK gene associated with OM symbiosis for the first time, and will be helpful for further functional elucidation of DoMPK1 involving in D. officinale and Mycena sp. symbiotic interaction. PMID- 23460980 TI - [Identification of gentianae macrophyllae radix using the ITS2 barcodes]. AB - DNA barcoding is a rapidly developing frontier technology in the world and will be useful in promoting the quality control and standardization of traditional Chinese medicine. Until now, many studies concerning DNA barcoding have focused on leaf samples but rarely on Chinese herbal medicine. There are three issues involved in DNA barcoding for traditional Chinese medicinal materials: (1) the extraction methods for total DNA of the rhizomes of the medicinal materials; (2) intra-specific variation among samples from different places of origin; (3) accuracy and stability of this method. In this study, Gentianae Macrophyllae Radix was used to verify the stability and accuracy of DNA barcoding technology. Five regions (ITS2, psbA-trnH, matK, rbcL, and ITS) were tested for their ability to identify 86 samples of Gentianae Macrophyllae Radix and their adulterants. After improving the DNA extraction method, genomic DNA from all samples was successfully obtained. To evaluate each barcode's utility for species authentication, PCR amplification efficiency, genetic divergence, and species authentication were assessed. Among all tested regions only ITS2 locus showed 100% of PCR amplification and identification efficiencies. Based on the established method, we successfully identified two samples of Gentianae Macrophyllae Radix bought in pharmacy to the original species. PMID- 23460981 TI - [Effects on the pharmacokinetics of furosemide after acute exposure to high altitude at 4010 meters in rats]. AB - The paper is to report the pharmacokinetics of furosemide in rats living at plain area and high altitude. After intragastric administration of furosemide (2.87 mg x kg(-1)), serial blood samples (0.5 mL) were collected by retro-orbital puncture at 0, 20 min, 40 min, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h, samples were determined by LC-MS/MS, and plasma concentration-time data were analyzed by DAS 2.0 software to get the related pharmacokinetic parameters. The main pharmacokinetic parameters: area under curve (AUC), mean residence time (MRT), the biological half-life (t1/2) and the peak concentration (C(max)) of furosemide, were significantly increased at high altitude, the time to reach peak concentration (t(max)) and clearance (CL) was significantly decreased. This study found significant changes on the pharmacokinetics of furosemide under the special environment of high altitude. This finding may provide some references for clinical rational application of furosemide at high altitude. PMID- 23460982 TI - [25th Pecenka epidemiological days]. PMID- 23460984 TI - Reply: To PMID 22623561. PMID- 23460985 TI - Reply: To PMID 22623538. PMID- 23460986 TI - Reply: To PMID 22733900. PMID- 23460987 TI - Universal perceptron and DNA-like learning algorithm for binary neural networks: LSBF and PBF implementations. AB - Universal perceptron (UP), a generalization of Rosenblatt's perceptron, is considered in this paper, which is capable of implementing all Boolean functions (BFs). In the classification of BFs, there are: 1) linearly separable Boolean function (LSBF) class, 2) parity Boolean function (PBF) class, and 3) non-LSBF and non-PBF class. To implement these functions, UP takes different kinds of simple topological structures in which each contains at most one hidden layer along with the smallest possible number of hidden neurons. Inspired by the concept of DNA sequences in biological systems, a novel learning algorithm named DNA-like learning is developed, which is able to quickly train a network with any prescribed BF. The focus is on performing LSBF and PBF by a single-layer perceptron (SLP) with the new algorithm. Two criteria for LSBF and PBF are proposed, respectively, and a new measure for a BF, named nonlinearly separable degree (NLSD), is introduced. In the sense of this measure, the PBF is the most complex one. The new algorithm has many advantages including, in particular, fast running speed, good robustness, and no need of considering the convergence property. For example, the number of iterations and computations in implementing the basic 2-bit logic operations such as AND, OR, and XOR by using the new algorithm is far smaller than the ones needed by using other existing algorithms such as error-correction (EC) and backpropagation (BP) algorithms. Moreover, the synaptic weights and threshold values derived from UP can be directly used in designing of the template of cellular neural networks (CNNs), which has been considered as a new spatial-temporal sensory computing paradigm. PMID- 23460988 TI - Human granulocytic Anaplasmosis, Japan. AB - We retrospectively confirmed 2 cases of human Anaplasma phagocytophilum infection. Patient blood samples contained unique p44/msp2 for the pathogen, and antibodies bound to A. phagocytophilum antigens propagated in THP-1 rather than HL60 cells. Unless both cell lines are used for serodiagnosis of rickettsiosis like infections, cases of human granulocytic anaplasmosis could go undetected. PMID- 23460989 TI - Acute Schmallenberg virus infections, France, 2012. PMID- 23460990 TI - Toscana virus isolated from sandflies, Tunisia. PMID- 23460991 TI - Delayed diagnosis of Dirofilariasis and complex ocular surgery, Russia. PMID- 23460992 TI - Lymphocytic choriomeningitis virus infections among American Indians. PMID- 23460993 TI - Streptococcus suis meningitis in swine worker, Minnesota, USA. PMID- 23460994 TI - Hepatitis E virus seroprevalence among men who have sex with men, United Kingdom. PMID- 23460995 TI - Clustered cases of Rickettsia sibirica mongolitimonae infection, France. PMID- 23460996 TI - Rickettsiae in ticks, Japan, 2007-2011. PMID- 23460997 TI - Healthy housing. PMID- 23460998 TI - Newborn health screenings. PMID- 23460999 TI - Program features and targeting are the keys to successful Medicare care coordination interventions. PMID- 23461000 TI - Commercial speech in crisis: Crisis Pregnancy Center regulations and definitions of commercial speech. AB - Recent attempts to regulate Crisis Pregnancy Centers, pseudoclinics that surreptitiously aim to dissuade pregnant women from choosing abortion, have confronted the thorny problem of how to define commercial speech. The Supreme Court has offered three potential answers to this definitional quandary. This Note uses the Crisis Pregnancy Center cases to demonstrate that courts should use one of these solutions, the factor-based approach of Bolger v. Youngs Drugs Products Corp., to define commercial speech in the Crisis Pregnancy Center cases and elsewhere. In principle and in application, the Bolger factor-based approach succeeds in structuring commercial speech analysis at the margins of the doctrine. PMID- 23461001 TI - DNA profiles, computer searches, and the Fourth Amendment. AB - Pursuant to federal statutes and to laws in all fifty states, the United States government has assembled a database containing the DNA profiles of over eleven million citizens. Without judicial authorization, the government searches each of these profiles one-hundred thousand times every day, seeking to link database subjects to crimes they are not suspected of committing. Yet, courts and scholars that have addressed DNA databasing have focused their attention almost exclusively on the constitutionality of the government's seizure of the biological samples from which the profiles are generated. This Note fills a gap in the scholarship by examining the Fourth Amendment problems that arise when the government searches its vast DNA database. This Note argues that each attempt to match two DNA profiles constitutes a Fourth Amendment search because each attempted match infringes upon database subjects' expectations of privacy in their biological relationships and physical movements. The Note further argues that database searches are unreasonable as they are currently conducted, and it suggests an adaptation of computer-search procedures to remedy the constitutional deficiency. PMID- 23461003 TI - Impact of genetic targets on cancer therapy. Forward. PMID- 23461002 TI - Custom, contract, and kidney exchange. AB - In this Essay, we examine a case in which the organizational and logistical demands of a novel form of organ exchange (the nonsimultaneous, extended, altruistic donor (NEAD) chain) do not map cleanly onto standard cultural schemas for either market or gift exchange, resulting in sociological ambiguity and legal uncertainty. In some ways, a NEAD chain resembles a form of generalized exchange, an ancient and widespread instance of the norm of reciprocity that can be thought of simply as the obligation to "pay it forward" rather than the obligation to reciprocate directly with the original giver. At the same time, a NEAD chain resembles a string of promises and commitments to deliver something in exchange for some valuable consideration--that is, a series of contracts. Neither of these salient "social imaginaries" of exchange--gift giving or formal contract- perfectly meets the practical demands of the NEAD system. As a result, neither contract nor generalized exchange drives the practice of NEAD chains. Rather, the majority of actual exchanges still resemble a simpler form of exchange: direct, simultaneous exchange between parties with no time delay or opportunity to back out. If NEAD chains are to reach their full promise for large-scale, nonsimultaneous organ transfer, legal uncertainties and sociological ambiguities must be finessed, both in the practices of the coordinating agencies and in the minds of NEAD-chain participants. This might happen either through the further elaboration of gift-like language and practices, or through a creative use of the cultural form and motivational vocabulary, but not necessarily the legal and institutional machinery, of contract. PMID- 23461004 TI - [The burden on relatives in families of patients with schizophrenia ("family burden")]. PMID- 23461005 TI - [Mexidol: the spectrum of pharmacological effects]. PMID- 23461006 TI - Work limitations and their relationship to morbidity burden among academic health center employees with diabetes. Reply. PMID- 23461007 TI - [Pharmacological activity of n-(1-phenethyl-4-piperidyl) propionanilide modified by encapsulation in PLGA nanoparticles]. AB - Technological parameters for the effective encapsulation of n-(1-phenethyl-4 piperidyl)propionanilide in poly(lactid-co-glycolide) (PLG) nanoparticles have been determined. Depending on the ratio of drug fractions adsorbed on the particle surface and associated with the polymer matrix, n-(1-phenethyl-4 piperidyl)propionanilide (200 microg/kg, i/m) loaded PLG nanospheres accelerated time onset and increased duration of sleep in rats: by a factor of 1.6 - 2.0 for polymer associated drug fraction within 40 - 60% and by a factor of 2.2 - 2.6 for polymer associated drug fraction within 60 - 80%. A similar increase of sleep duration was observed when free n-(1-phenethyl-4-piperidyl)-propionanilide was administered at doses within 400 - 500 microg/kg. PMID- 23461008 TI - [Effect of mexidol (2-ethyl-6-methyl-3-oxypyridine succinate) on the quality of life and depressive symptoms in women with rheumatoid arthritis]. AB - A prospective, randomized controlled study of the effects of 2-ethyl-6-methyl-3 oxypyridine succinate (mexidol) on the dynamics of articular syndrome, quality of life, and clinical manifestations of depression has been performed in a group of 62 women with rheumatoid arthritis diagnosis during therapy for two weeks. The use of mexidol in the complex treatment contributed to a decrease of the intensity of rheumatoid inflammation, reduction in the severity of depressive symptoms, and improvement of the functional status and quality of life. PMID- 23461009 TI - [Efficacy of pathogenetic therapy in patients with acute gastrointestinal infections using succinic acid derivatives (reamberin)]. AB - Comparative study of efficacy of the official therapy of acute gastro-intestinal infections (65 patients) and a complex therapy using a succinic acid derivative reamberin (71 patients) has been carried out. It is established that the introduction of reamberin into infusion therapy in patients with acute gastro intestinal infections leads to a faster reduction of basic symptoms of intoxication and gastroenteritis, normalization of leukocyte intoxication index, and correction of basic indices of thrombocytes aggregation. These results allow reamberin 1.5% infusion to be recommended for the treatment of patients with acute gastro-intestinal infections. PMID- 23461010 TI - [Antidepressant pharmacokinetics during pregnancy]. AB - The influence of pregnancy state on the cytochrome P-450 dependent bioconversion and pharmacokinetics of antidepressants has been studied. Specific features of the bioconversion of some antidepressants are determined. Results of pharmacokinetic investigations based on the dynamics of antidepressant concentration in the blood plasma of pregnant women are considered. The necessity of changing the daily dose of antidepressants during pregnancy is discussed. Data on the ratio of the plasma concentration of antidepressants in a newborn to that in the mother and on the role of transporter proteins in the transplacentar transfer of antidepressant drugs are presented. PMID- 23461011 TI - [Studying kinetics of oxime-induced reactivation of malathion-inhibited cholinesterase]. AB - The kinetics of oxime-induced reactivation of malathion-inhibited cholinesterase has been experimentally studied in vitro. It is shown that oximes do not restore the activity of inhibited butyrylcholinesterase. Acetylcholinesterase reactivation peak (5-mins long) was found to take place upon introduction of dipyroxime (32.5%), pralidoxime (18%), carboxyme (16%) at a concentration of 2.5 x 10(-4) mol/l or toxogonine (26%) at a concentration of 5 x 10(-4) mol/l. Toxogonine demonstrated the maximum affinity to phosphorylated enzyme, while dipyroxime is characterized by a high reactivity with respect to oxime. Significant reactivating ability of these preparations (kR -2300 mol(-1) min(-1) makes them promising solution for the treatment of malathion intoxication. PMID- 23461012 TI - [Preventive administration of new UDCA derivatives in experimental alcoholic steatohepatitis]. AB - We have studied the prophylactic effect of new derivatives of ursodeoxycholic acid (UDCA), including UDCA-N-acetylcysteine, UDCA-L-acetylcysteine, and nor-UDCA (in doses equivalent to 40 mg/kg of UDCA) on the development of experimental alcoholic steatohepatitis induced by the Lieber-DeCarli liquid ethanol-containing diet. Results demonstrated that most of the investigated compounds produced a hepatoprotective effect, improving biochemical tests and liver morphology, as manifested by decreasing steatosis intensity, activity of alkaline phosphatase and gamma-glutamyltranspeptidase, triglyceride level in blood serum and liver, and TNF alpha content. However, nor-UDCA was most effective as compared to UDCA in preventing the accumulation of triglycerides in the liver. PMID- 23461013 TI - [Effect of opioid receptor blockade on antibody response and proliferative response under stress conditions]. AB - It is established that rotation and immobilization stress produces bidirectional effect on AFC number in spleen and on proliferative response of splenocytes. The rotation stress results in augmentation of AFC formation and promotion of spontaneous proliferative activity of splenocytes. The micro-opioid receptor blockade with naloxone, but not delta-receptor blockade with naltrindole, abolished the effects of rotation. In contrast, the immobilization stress caused the suppression of the parameters of humoral immune response and lowered spontaneous and induced proliferative activity of splenocytes. The opioid receptor blockade with naloxone was found to level the suppressive effects of immobilization, while naltrindole exhibited a less pronounced effect. Both variants of stress demonstrated the involvement of opioid system in regulation of AFC number during induction of the immune response. PMID- 23461014 TI - [Effects of strontium ranelate on mononuclear leukocyte culture]. AB - Strontium ranelate (SR) effect on the functional parameters of human blood mononuclear leukocytes culture has been investigated. SR in concentrations of 2.9, 29, and 290 mg/ml produces a dose-dependent decrease in the activity of alkaline phosphatase and the content of calcium and potassium ions in supernatants. In concentrations of 2.9 and 29 mg/ml, SR decreases, while in a concentration of 290 mg/ml it increases the intercellular phosphate ion content. Fibroblast- and osteoblast-like cells, which are capable of regulating mineral compound of intercellular liquid, are SR cellular targets in human blood mononuclear leukocytes culture. PMID- 23461015 TI - [State of thiol exchange in patients with psoriasis and its possible correction]. AB - Experiments on erythrocytes of patients were used to study the influence of remaxol and ademetionin on the exchange of thiols. The values of thioldisulfide exchange indicators were determined in the beginning of the period of observation and at the end of every week within one month. Patients who received hepato protectors in combination with higher-level thiols showed positive dynamics in disease treatment as compared to patients receiving standard therapy. The concentration of restored glutathione and proteins of hydrosulfide groups and the activity of glutathione peroxidase are informative criteria for estimating the course of disease current and the efficiency of therapy of widespread forms of psoriasis. PMID- 23461017 TI - [A hundred years of medical research in Israel]. PMID- 23461016 TI - [Structure and physiological role of NHE1 and pharmacological regulation of its activity]. AB - This article summarizes results of preclinical and clinical trials concerning the effects of NHE1 inhibitors and prospects for their clinical application. NHE1 has been identified as the most abundant isoform of Na+/H+ exchanger in the heart of mammals. NHE1 regulates pH homeostasis, cell proliferation, migration, adhesion, and apoptosis. Ischemic activation of the NHE1 in myocardium results in intracellular calcium overload, which aggravates ischemic/reperfusion injury. In accordance with results of preclinical experimental studies, selective inhibition of the sarcolemmal NHE1 can delay progression of injury during ischemia, thereby reducing myocardial necrosis and improving recovery of ventricular function upon reperfusion. Inhibitors of NHE1, which can provide beneficial effect in the clinical treatment of these conditions, are currently under preclinical and clinical tests. At present, there are 481 NHE inhibitors known according to the Thomson Reuters Integrity database. PMID- 23461018 TI - [Work ability index questionnaire--first utilization of the Hebrew translation in Israel]. AB - The work ability questionnaire is widely used in many countries and for different groups of workers. We present the first use of the Hebrew translation of the questionnaire in a target group of community nurses. The calculated mean values of the index, using a standardized questionnaire, were compared with independent questions regarding various characteristics of work conditions and occupational stress. High correlations were found between mean work ability index (WAI) values and the independent questions attesting to the validity and usefulness of this simple tool for ascertaining the work ability of individual workers or as a research tool. PMID- 23461019 TI - [In-vitro fertilization cycles and outcomes in Maccabi Healthcare Services in Israel 2007-2010]. AB - INTRODUCTION: While Israel is by far number one in the world of in-vitro fertilization (IVF) treatments per capita, detailed information about the outcome of these treatments is not available. OBJECTIVES: To describe IVF activity during the years 2007-2010 in Maccabi Healthcare Services, an independent health provider that reimburses IVF treatments. METHODS: Data on IVF cycles and live births were collected from the Maccabi Healthcare Services infertility registry and analyzed by year and age at cycle start. RESULTS: During the four years surveyed, the average patients' age rose from 35.12 to 36.19 years. The number of IVF treatments increased by 50%, while the "live birth" rate fell from 18.8% in 2007, to 14.8% in 2010. A drop in success rate was noted in patients >35 years of age, and more so in patients >40 years of age. Beyond 43 years of age, the success rate was in the low one digit range. The estimated cost of a single live birth in this age group is NIS 399,000. SUMMARY: The clinical results are not encouraging relative to IVF outcomes in Europe and the U.S.A. SurprisingLy, and contrary to worldwide trends, the success rate in Israel decreased during the surveyed years. We speculate that the main reason is that many IVF treatments are conducted in patients that a priori have a very low chance of success. A nationwide prospective IVF registry should be implemented. PMID- 23461020 TI - [The effect of an intervention on rates of central vascular catheter-related bloodstream infection in intensive care units at the Hadassah Medical Center]. AB - INTRODUCTION: Catheter-related bloodstream infection (CR-BSI) is a significant source for morbidity and mortality in addition to increased hospital costs. Patients in intensive care units (ICUs) have a greater risk for CR-BSI. Continuous monitoring and control of intravascular central catheters insertion (CCI) by using checklists have a key role in reducing the rate of infections and improving patient health care quality and safety. OBJECTIVES: To determine the rate of CR-BSI, and to evaluate the adherence of ICU teams to infection control guidelines during CCI prior to and following an intervention program in ICU patients. METHODS: The present study was conducted in six ICUs at the Hadassah Medical Center, during a period of 15 months. The rate of CR-BSI was determined in 320 patients with central catheters during the first period of the study. Assessment of adherence to infection control guidelines during CCI was carried out by observations. Educational intervention consisted of the introduction of physician guidelines for CCI, implementing a checklist to ensure adherence to the guidelines and lectures for the teams, beginning in the second period of the study. During the third period of the study, the rate of CR-BSI was determined in 336 patients with central catheters in the same ICUs, by the same research methods. RESULTS: Following the intervention, a significant reduction in the rate of CR-BSI was observed in the study population from 9.66 to 3.63 infections per 1000 catheter days, with 62.4% risk reduction for CR-BSI, (P < 0.001). Improvements were also recorded in the CCI process and the rate of compliance of the ICUs team with infection control guidelines. CONCLUSIONS: The implementation of a simple and inexpensive intervention reduced the rate of CR-BSI, leading to improved process of insertion of these catheters. DISCUSSION: The continuous monitoring of the rate of CR-BSI and using checklists in every CCI process may reduce the morbidity, mortality, hospital stay, and lower hospital costs associated with centrally placed vascular catheters. PMID- 23461021 TI - [Allergic reaction induced by steroid therapy]. AB - Glucocorticoids are widely used for the treatment of allergies and various inflammatory conditions. However, steroids can cause allergic reactions, even anaphylaxis. The incidence of adverse reactions induced by steroids is up to 0.3%. The most commonly reported steroids causing anaphylaxis are hydrocortisone, prednisone and methylprednisotone. In this report we describe an 86 years old patient who developed stridor and respiratory failure immediately after treatment with hydrocortisone. The risk factors and the management of these reactions are discussed. It is important that the medical community should recognize and be aware of such reactions. PMID- 23461022 TI - [Rapidly vanishing hip--a mystery]. AB - Rapidly destructive hip disease is a rare condition, the cause of which is yet to be clarified, and is described in the literature by scant case reports. The disease was first described by Forestier in 1957, and since then many names have been proposed to describe the rapid vanishing of the femoral head, and occasionally the acetabulum. This condition initially represents as acute hip pain, and rapidly progresses to complete vanishing of the proximal femur, within a few months. We briefly discuss the literature regarding this phenomenon, and describe a case of a female patient who suffered from complete disappearance of the femoral head within 9 weeks. PMID- 23461023 TI - [What is the "seed of evil" mediating the pathway for the formation of metastases?]. AB - The metastatic process remains one of the most enigmatic aspects of cancer pathogenesis. The concept of "cancer stem cells" (CSC) has evolved over the past decade, elucidating the presence of a distinct population of cells which is defined by their high tumorigenic capacity and long-term self-renewal ability. In this editorial, we discuss the association between cancer stem cells and circulating tumor cells (CTC) (see article by Grinshpun et al. in this issue) and the role of CSC in mediating the formation of cancer metastases. Intensive research is ongoing on the clinical significance of CTC in a wide variety of malignancies; CTC are a heterogeneous population of cells which include CSC as well, a major player in the formation of metastases. A better understanding of the unique properties of CSC and their interaction with the microenvironment will enable the development of ways to detect and target this cell population. PMID- 23461024 TI - [Cultural barriers in health/medical services and the efforts to lower them]. AB - Cultural competence and cultural adaptation are currently considered important components of the quality of health/ medical services in multi-cultural societies. These include not only treatment of disease, but also primary, secondary and tertiary prevention by professionals, as well as health promotion and management by the population. Migrant populations who are in the processes of transition and acculturation are in much stronger need for cultural specific communication and adaptation. The case of immigrants from Ethiopia to Israel is unique, as the immigrants moved within a short time from highly traditional culture, with its perceptions of health, disease, and their causes, to modern health services, based on bio-medical theory and practice. The paper by Dayan and Shvartzman, discusses the important aspect of women's health and compares the situation of Ethiopian women in Israel to that of other migrant women in different parts of the world. PMID- 23461025 TI - [Tumor, metastasis and what's in between]. AB - Cancer is a major factor of morbidity and mortality worldwide. Over 90% of cancer related deaths are due to metastatic disease. Observations made more than 140 years ago described cancer cells from solid tumors in the bloodstream. yet, the significance of these circulating and disseminated cells and their contribution to the generation of metastasis remained a mystery. Recently, substantial technological advances have enabled the detection and isolation of circulating tumor cells from the peripheral blood. Currently, this technology allows quantitative analysis of circulating cancer cell content and permits a view of the genetic and phenotypic changes in this accessible population. In the future, researchers hope to use circulating tumor cells as a powerful tool for early detection, prognosis, tumor response assessment and even for treatment selection. The discovery of cancer cells in the bloodstream holds many promises in the study, diagnosis and treatment of cancer, but, at the same time, raises difficult questions regarding the identity of these cells, their contribution to the process of metastasis and their ability to aid medical decisions. This review aims to introduce the topic of circulating tumor cells to the Israeli medical community and encourage active participation in basic and translational research in this field. We believe this field holds great potential for promoting the practice of surgical oncology, tumor surveillance and clinical oncology. PMID- 23461026 TI - [Health behavior, preventative medicine, early detection, and utilization of women's health services among Ethiopian women immigrants in Israel]. AB - Immigrants differ in morbidity and mortality characteristics, as well as health services and preventative medicine utilization, compared with the non-immigrant population. As the Length of stay in the host country increases, these patterns become similar to the Local population, due to the acculturation process. Immigrant women's prenatal care is often partial and inadequate, usually occurring late in pregnancy, their contraceptive use is lower and the rate of abortions is higher. They have less screening tests for cancer detection, are diagnosed at advanced stages and their survival and cure probabilities are lower Facilitators and barriers to immigrant women's health behaviors include cultural beliefs and perceptions, length of stay in the host country, degree of acculturation, Language barriers, accessibility, primary physician involvement, role burdens, knowledge and awareness. Ethiopian women experienced a sharp transition in a variety of life aspects following their immigration to Israel. Studies show that Ethiopian women's health and health behavior are typical to those encountered among immigrant women. Their birth patterns are becoming similar to local women as their years in Israel increase, and veteran's patterns are closer to the local population. Data regarding contraceptive use is lacking; the abortion rate is four times higher in comparison with Israeli-born Jewish women, and preventive medicine, referral and early detection rates for cancer are lower. Ethiopian immigrant women in Israel are at high risk regarding their health. Understanding the underlying causes, the changes that occur as time in Israel increases, and identifying the accessibility barriers to services experienced by these women, will assist in planning cultural and needs sensitive services, including health promotion programs. PMID- 23461027 TI - [Neuro-psychiatric comorbidity among children and adolescents who suffer from epilepsy]. AB - Epilepsy is quite a common disorder in the child and adolescent population, and it has been studied for many years. Recently, a better understanding has been achieved regarding the comorbidities in epilepsy, including: major depression, anxiety, learning disabilities, etc.. The comorbidities are extensive and affect many aspects in the life of the patient, and his family members, including: psychological development, learning abilities, independence, etc.. Several mechanisms take part in these comorbidities, starting in the cell and ending with a broadened psychological effect. A better understanding of these mechanisms may assist the physicians in diagnosing their patients and tailoring a wide-approach treatment plan, thereby improving the patient's clinical status and his quality of life (and that of his family). The objective of this article is to describe some of the common comorbidities that are present in epilepsy, and outline the multi-disciplinary approach in treating the epileptic child and his/her family. PMID- 23461028 TI - [Sitting and cardiovascular morbidity and mortality]. AB - Prolonged sitting and sedentary behavior comprises a major part of the modern lifestyle: at work, leisure (watching television, Internet) and commuting/traveling. Studies have shown that adults spend about half of their time at work and even more sitting. Similarly, a significant part of the leisure time is spent doing sedentary activities usually in front of a screen (TV or a computer). However, current recommendations focus on increasing moderate-to vigorous physical activity with almost no recommendations relating to sedentary activities. Recent evidence from several research papers showed deleterious relationships of sedentary behavior with cardiovascular risk factors (e.g., obesity, type 2 diabetes mellitus and waist circumference). Furthermore, consistent independent associations have been observed between sitting time/sedentary behaviors and elevated all-cause and cardiovascular disease mortality risk. Generally, these associations have persisted following adjustment for physical activity. Recent emerging findings have shown that breaking up sedentary time potentially has a beneficial impact on cardiovascular health (independent of total sedentary time and moderate-to-vigorous intensity activity). In this article, we review the association between the time spent in various sedentary activities (occupational, leisure and commuting/transportation) and cardiovascular risk factors and cardiovascular morbidity and mortality. In addition, we review the suggested mechanisms that explain the empiric associations. PMID- 23461029 TI - [Hip arthroscopy: differential diagnosis of pain around the hip joint]. AB - Hip arthroscopy is one of the most highly evolving surgical techniques in recent years. It plays a major role in the diagnosis and treatment of a broad spectrum of hip pathologies. The evaluation of the painful hip requires meticulous history taking, elaborated physical examination, and basic and advanced imaging modalities. The differential diagnosis includes a continuously growing number of diagnoses. Once considered an "operation looking for indications", the current indications for hip arthroscopy are based on a better understanding of pathologies around the hip joint. The results of recently published intermediate and long term clinical outcome studies are encouraging. Ongoing, comprehensive understanding of the correlation between pathologies and clinical presentation will improve the surgical technique, which in turn may become a joint preserving operation. PMID- 23461030 TI - [Cellular mechanisms of regeneration of rats' liver after experimental myocardial infarction]. AB - Morphological changes and regeneration activity of the rats' liver after an experimental myocardial infarction (MI), caused by a permanent left coronary artery occlusion, were investigated. It has been shown that in 6 months after MI there were considerable changes of the rats' liver circulatory system: the quantity of vessels per unit of area increased by 118%, thickness of their walls by 19%, and the average square of vessels lumens by 159%. The percentage of connective tissue in 6 months after MI increased more than in one and a half time in comparison with control. Inflammatory and necrotic changes in rats' liver remained for 6 months after MI. The liver injury caused by MI led to activation of regeneration processes in its parenchyma. In 6 months after MI, the number of 4c- hepatocytes decreased by 12% in comparison with control, and the number of 4c x 2- and 8c-hepatocytes increased by 45 and 71%, respectively. The mean level of hepatocytes ploidy increased in 6 months after MI by 11%. The dry mass of rats' hepatocytes increased in 6 months after MI by 19% in comparison with control. Thus, liver regeneration after MI is more due to hepatocytes hypertrophy than to their polyploidization. PMID- 23461031 TI - [Life extension study on high-yield non-myeloablating bone marrow transplantation from young to old mice]. AB - Tissue renewal is the known phenomenon, when the progeny of resident or circulated stem cells (SC) replaces the vanishing cells. The delivery of stem cells via circulation should result in stem cell homing and differentiation into wide variety of tissues and gives promise as therapy for many diseases of tissue failure including aging itself. To test this hypothesis, we created chimeric mice C57BL/6 by bone marrow (BM) transplantation from young 1.5 months old donors to 21.5-months old recipient mice of the same strain C57BL/6. We applied here the recently published new transplantation technique, which allows to get high scores of chimerism due to very high amount of transplanted cells (1.5 x 10(8) per mouse or 25% of its total BM count). In the earlier works only 1% of total BM count (about 5 x 10(6) cells per mouse) was usually transplanted to lethally irradiated mice, what excluded the possibility to apply this method for life extension. As a result of the modified technique implementation, the mean post-transplantation life (starting the 21.5 months old) of treated mice was 4.9 months versus 3.4 months for untreated mice. The difference in 1.5 months counts for 44% extension of mean post-transplantation life. PMID- 23461032 TI - [Characterization of afferent neurons of spinal ganglions sensitive to capsaicin]. AB - Morphological features of TRPV1(+)-, SP(+)-, CGRP(+)-, NF200(+)-neurons has been studied in thoracic spinal ganglions in 3-month-old rats under chemical deafferentation. The results have shown that from 6.5 up to 41.3% of ganglionic neurons of control group had markers mentioned above. The heterogeneity of nociceptive neurons in control group was kept in capsaicin-treated animals. In both groups, TRPV1(+)-neurons were prevailed, populations of SP(+)-, CGRP(+)- and NF200(+)-neurons formed smaller groups. Sensitivity to capsaicin was shown in largest neurons in each population; neurons in experimental group had smaller cross-sectional area, particularly in group of TRPV1(+)-neurons. PMID- 23461033 TI - [Analysis of individual changes in heat resistance of clones of Daphnia magna at the initial stages of cultivation]. AB - 30 clones of water fleas have been studied on the basis of heat resistance (HR) of these organisms at the initial stages of cultivation. Ten clones died before the appearance of the offspring in F2; the remaining clones were multiplied successfully and produced subsequent generations. Based on the change in the individual HR level of the clones in F1 as compared with ancestors, it was concluded a violation of the mechanisms of physiological homeostasis in the population of dead clones. In the remaining clones, there were a high negative correlation between the initial individual resistance level and its change in F1 and F2 and a pronounced narrowing of the variability diapason in F1. In this animal group, the significant lability of individual-level resistance was observed as well as its ability to regulate the shift of its resistance, which provided an efficient work of the mechanisms of physiological homeostasis. PMID- 23461034 TI - [The role of AmtB, GlnK and glutamine synthetase in regulation of transcription factor TnrA in Bacillus subtilis]. AB - The nitrogen is a macroelement for all alive cells, from bacteria to animals. Although NH3/NH4+ are highly toxic to animal, they are the preferred source of nitrogen for the most microorganisms and are assimilated by glutamine synthetase in the GOGAT cycle. The nitrogen limitation triggers a number of regulatory processes and activates many genes, providing the utilizing of alternative nitrogen sources. In Bacillus subtilis the genes of nitrogen metabolism are regulated by the transcription factor TnrA. In a cells it is bound to AmtB-GlnK proteins, the interaction with Glutamine synthetase (GS) represses its DNA binding activity. Here we show the lack of AmtB leads to the nitrogen deficiency in a cell and, consequently, the increased expression of TnrA-dependent genes. In the lack of GlnK the transcription factor TnrA is constitutive bound to GS, the TnrA activity is repressed even under nitrogen limit conditions. Apparently, the TnrA activity is subjected to permanent repression by GS. In the absence of GS, the TnrA activity is strongly higher in compare to control, even under nitrogen limitation, when GS is active. These data allow to suggest that TnrA activity is regulated by the competitive binding to GlnK and GS. PMID- 23461035 TI - [Involvement of MAP-kinase cascades into the regulation of sodium butyrate induced premature cell senescence]. AB - We studied the role of p38 kinase and JNK1,2 in the activation of the complex mTORC1 and the program of senescence induced by histone deacetylase inhibitor, sodium butyrate (NaBut), in mouse embryonic fibroblasts transformed by E1A+cHa Ras oncogenes. It was found that transformants from knockouts for the genes p38, were able to implement the program of NaBut-induced senescence, according to the data of the cell cycle arrest, inhibition of proliferation, hypertrophic changes associated with the activation of mTORC1 and SA-beta-galactosidase activity. According to the behavior of these markers, cell knockouts for the genes jnk1,2 were unable to implement NaBut-induced senescence. Induction of senescence closely correlates with the activation of the complex mTORC1, as it was shown by inhibiting mTORC1 with rapamycin. We believe that JNK 1,2 kinases are required for mTORC1 activation and acquiring the markers of premature senescence, induced by NaBut in the E1A+cHa-Ras transformants. PMID- 23461036 TI - [Effect of chitosan on the cell ultrastructure and activity of hydrolases in tobacco leaves]. AB - Effect of chitosan on the mesophyll cell ultrastucture and activity of hydrolases in leaves of tobacco cv. Samsun was studied. It was shown that, in many cells, chitosan treatment stimulated the protein-synthesizing apparatus (nucleolus dimension and amount of both mitochondria and rough endoplasmic reticulum membranes increased) and, at the same time, caused some activation of lytic compartment expressed in the stimulation of the formation of dictyosomes, smooth ER elements and cytoplasmic vacuoles, which are all prominent constituents of this compartment. In biochemical experiments, it was established that chitosan substantially enhanced activity of hydrolases (acid phosphatase, RNase, proteases) in the leaves as compared to untreated leaves. In some cells chitosan treatment caused considerable destructive changes (condensation of nuclear chromatin, collapse of cytoplasm and so on) that can be classified as a result of programmed cell death development. PMID- 23461037 TI - [Structural and functional reorganization of photosynthetic apparatus in cold adaptation of wheat plants]. AB - The structural and functional characteristics of the photosynthetic apparatus (PSA) and the cold resistance of wheat seedlings were studied during low temperature adaptation. It has been established that large chloroplasts with thylakoid system of "sun type" forme in the mesophyll cells in the early hours of plants hardening. At the same time the functional reorganization of the PSA in the leaves of wheat occurs: content of pigments changes, stabilization of the pigment-protein complexes is observed, non-photochemical quenching of excess energy increases. The stabilization of photosynthesis during cold adaptation occurs due to structural and functional reorganization of the PSA. It is assumed that the reorganization of the PSA is a prerequisite for formation of increased cold resistance of leaf cells, and this, along with other physiological and biochemical changes occurring in cells and tissues of plants, allows the plants to survive in chilling. PMID- 23461038 TI - [Correlation between growth of callus and a number of nodule for pea Pisum sativum]. AB - The processes of nodulation and callusing were studied for pea Pisum sativum in a comparative aspect. Seven varieties of pea plants were used. The nodulation was characterized by the number of nodules and their mass per one plant. The frequency ratio of nodules of various weights was described by the Lorentz equation. The growth of callus was described using equation of the S-dependence. It has been shown that plants can produce maximal (optimum for nitrogen fixation) mass of nodules by an increase either in the nodules number or in the mass of each nodule. This feature is specific to the varieties of peas. It has been also found that the plants of the pea varieties, which have a large number of nodules, produce calluses of maximum size. Small calluses are characteristic of the varieties having plants with small amounts of large nodules. The data obtained has been interpreted on the assumption that the nodulation is underlined by both differentiation and proliferation, whereas the callusing is due only to the proliferation process. PMID- 23461039 TI - Clinical trials need to control for the influence of palliative care on outcomes. PMID- 23461040 TI - Palliative care always. AB - Palliative cancer care is the integration into oncologic care of therapies that address the issues that cause physical and psychosocial suffering for the patient and family. Effective provision of palliative cancer care requires an interdisciplinary team that can provide care in all settings (home, inpatient, and outpatient). There is clear evidence for improved outcomes in multiple domains-symptoms, quality of end-of-life care, provider satisfaction, cost of care-with the integration of palliative care into cancer care. As a result, there are now guideline-based recommendations for incorporating palliative care into cancer care. Unfortunately there continue to be barriers to effective integration; these include gaps in education and research, and a cultural stigma that equates palliative care with end-of-life care. These barriers will need to be addressed in order to achieve seamless palliative care integration across the continuum of cancer care for all patients and their families. PMID- 23461041 TI - mTOR inhibitors in the treatment of breast cancer. AB - The phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly dysregulated in breast cancer. In preclinical studies, hyperactivation of the PI3K pathway has been linked to resistance to both endocrine therapy and trastuzumab (Herceptin). Rapalogs, agents that primarily inhibit mTOR-raptor complex 1, have been studied in combination with endocrine therapy to overcome endocrine resistance.Trials of combination endocrine therapy and rapalogs in metastatic hormone receptor-positive breast cancer have demonstrated variable results. However, two independent trials have recently shown that combination everolimus (Afinitor) and tamoxifen or combination everolimus and exemestane (Aromasin) is more effective than either endocrine agent alone. These trials selected patients with cancer refractory to endocrine therapy, which may be important in sensitizing tumors to inhibition of this pathway. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the early clinical data with combinations of PI3K/mTOR inhibitors and anti-HER2 therapies are encouraging. Efforts to identify clinical biomarkers of response or resistance to mTOR inhibitors are ongoing. This review will summarize results of preclinical and clinical studies aswell as ongoing clinical trials with mTOR or dual PI3K/mTOR inhibitors. PMID- 23461042 TI - Evolution of the concept of focal therapy for prostate cancer. AB - The landscape of prostate cancer has been rapidly evolving, and technological advances in imaging and biopsy tools offer novel approaches to focal therapy. In this dynamic environment, the role of focal therapy for prostate cancer is being shaped both by advances in technology and by reconsidering the epidemiological and outcomes data for available treatments. Here we focus on the evolution of the concept of focal therapy and its potential roles in the management of prostate cancer. PMID- 23461043 TI - Allergy confusion. PMID- 23461044 TI - Coordinated cardiac delivery: reducing mortality in high risk fetal cardiac lesions at the University of Mississippi Medical Center. PMID- 23461045 TI - Revitalization of the University of Mississippi Children's Heart Center: report card from the first 18 months. PMID- 23461046 TI - You have to have some skin in the game. PMID- 23461047 TI - The Magic Kingdom. PMID- 23461048 TI - Main street and hospital, Booneville: home of the "Mississippi doctor" and state's first Hill-Burton Hospital. PMID- 23461049 TI - This month in the Mississippi Morbidity Report: school immunization requirements, 2012-2013 school year. PMID- 23461050 TI - Sister Mary Joseph nodule: impact on the clinician. PMID- 23461051 TI - What is your diagnosis? Radiation recall dermatitis. PMID- 23461052 TI - Dermatopathology diagnosis. Circumscribed acral hypokeratosis. PMID- 23461053 TI - Cutis tricolor. AB - Cutis tricolor is characterized by the coexistence of congenital hyperpigmented and hypopigmented patches in the context of normally pigmented skin. We report the case of a 13-year-old white adolescent girl with cutis tricolor. We analyze other reported cases of cutis tricolor as well as other cases characterized by coexistent hyperpigmented and hypopigmented patches. Cutis tricolor seems to be a rather unique cutaneous manifestation and occurs either in isolation or in association with internal manifestations. Labeling any other case characterized by hyperpigmented and hypopigmented patches as cutis tricolor, regardless of the distribution pattern, is inappropriate in our opinion. PMID- 23461054 TI - Small vessel vasculitis associated with cocaine use. AB - We report a case of cocaine-induced small vessel vasculitis in a 51-year-old woman. We postulate that levamisole, an adulterant of cocaine, likely is the cause of this increase in cocaine-induced vasculitis. Based on a literature review, we suggest some helpful tests to differentiate cocaine-induced vasculitis from true autoimmune vasculitis in the setting of midline destructive nasal lesions. PMID- 23461055 TI - Paraneoplastic subacute cutaneous lupus erythematosus: an underrecognized entity. AB - Subacute cutaneous lupus erythematosus (SCLE) is a form of cutaneous lupus erythematosus that most often presents as scaly, erythematous, papulosquamous, or annular papules and plaques in a photodistributed pattern. Subacute cutaneous lupus erythematosus is classically considered to be either idiopathic or drug induced. There have been few reports of SCLE arising in the setting of malignancy, raising the possibility that paraneoplastic SCLE may be a rare distinct subset of lupus. We report a case of SCLE arising as a paraneoplastic phenomenon in the setting of small cell lung cancer. Given the close temporal proximity of the detection of malignancy and the development of the rash in our patient, we believe this report presents a case of paraneoplastic SCLE. The presentation of new-onset idiopathic SCLE should prompt a careful review of systems and age-appropriate cancer screening, as SCLE may be a sign of an occult malignancy. PMID- 23461056 TI - Angiotensin-converting enzyme inhibitor-induced angioedema. AB - Angiotensin-converting enzyme (ACE) inhibitors frequently are prescribed for the management of cardiovascular disorders. In addition to their therapeutic potential, ACE inhibitors are associated with numerous adverse effects, some of which may be lethal. Angioedema is an uncommon but serious acute event that may affect any individual taking an ACE inhibitor. This review outlines the advances in our understanding of the pathogenesis, clinical presentation, and management of this medical emergency. PMID- 23461057 TI - Pili annulati associated with hair fragility: cause or coincidence? AB - Pili annulati is a disorder that produces a spangled appearance to the hair, caused by alternating light and dark banding of hair shafts. This phenomenon is created by abnormal cavities in the cortex of the hair shaft, which produces lighter bands seen on clinical examination. Complications of pili annulati are limited; the most noteworthy complication is increased breakage secondary to weathering of the abnormal hair shafts. We report a case of a 14-year-old adolescent girl with pili annulati and progressive hair loss of 2 months' duration. Most of her hairs were notably short, spangled, and lusterless with light and dark banding observed with handheld magnification. Light microscopy demonstrated alternating light and dark bands, and the dark bands had the typical appearance of air-filled spaces. Gentler hair grooming practices were recommended, and at a follow-up visit, the appearance of the hair had improved with darker and longer shafts. This case should alert clinicians to look for pili annulati when hair fragility is present. PMID- 23461058 TI - New-generation radiofrequency technology. AB - Radiofrequency (RF) technology has become a standard treatment in aesthetic medicine with many indications due to its versatility, efficacy, and safety. It is used worldwide for cellulite reduction; acne scar revision; and treatment of hypertrophic scars and keloids, rosacea, and inflammatory acne in all skin types. However, the most common indication for RF technology is the nonablative tightening of tissue to improve skin laxity and reduce wrinkles. Radiofrequency devices are classified as unipolar, bipolar, or multipolar depending on the number of electrodes used. Additional modalities include fractional RF; sublative RF; phase-controlled RF; and combination RF therapies that apply light, massage, or pulsed electromagnetic fields (PEMFs). This article reviews studies and case series on these devices. Radiofrequency technology for aesthetic medicine has seen rapid advancements since it was used for skin tightening in 2003. Future developments will continue to keep RF technology at the forefront of the dermatologist's armamentarium for skin tightening and rejuvenation. PMID- 23461059 TI - Treating epidermal melasma with a 4% hydroquinone skin care system plus tretinoin cream 0.025%. AB - We sought to evaluate the efficacy and tolerability of treating melasma using a 4% hydroquinone skin care system, including a proprietary cleanser, toner, 4% hydroquinone, exfoliation enhancer, and sunscreen, plus tretinoin cream 0.025%. Together these products offer not only treatment of melasma but also a complete skin care regimen. Twenty participants with mild or moderate epidermal melasma with Fitzpatrick skin types III to VI were instructed to use the hydroquinone skin care system and tretinoin cream for 12 weeks. Melasma severity, melasma pigmentation intensity, and melasma area and severity index (MASI) score were significantly reduced from week 4 onward relative to baseline (P < or = .01). The proportion of participants who felt embarrassed or self-conscious about their skin very much or a lot declined from 80% (16/20) to 20% (4/20) between baseline and week 12. Similarly, the proportion of those who made very much or a lot of effort to hide their skin discoloration declined from 90% (18/20) to 37% (7/19). In total, 85% (17/20) of participants were satisfied with the overall effectiveness of the study treatment. Three participants had adverse events probably related to treatment (dryness, erythema, peeling, and stinging sensation). The 4% hydroquinone skin care system plus tretinoin cream 0.025% is effective and well-tolerated in the treatment of melasma. PMID- 23461060 TI - The identification of miR-375 as a potential biomarker in distal gastric adenocarcinoma. AB - MicroRNAs (miRNAs) are endogenous small noncoding RNAs that negatively regulate gene expression at the posttranscriptional level and play an important role in carcinogenesis. Herein, we characterized the global expression of miRNA in distal gastric adenocarcinomas and determined if circulating miRNAs could be used as biomarkers for distal gastric adenocarcinoma. We used a microarray screening system to detect dysregulated miRNAs in distal gastric adenocarcinoma tissues. The expression of a subset of five aberrantly expressed miRNAs (miR-375, -196b, 204, -18b, and -93) were further quantified in an independent set of clinical samples of distal gastric adenocarcinoma by real-time quantitative RT-PCR (rt-qRT PCR). We also used rt-qRT-PCR to investigate the expression levels of putative miRNA biomarkers in serum and tumor cell lines. In our study, the expression of a subset of microRNAs was altered in distal gastric adenocarcinoma compared to normal tissue, miR-375 was significantly downregulated in distal gastric adenocarcinoma tissues, to a level that was significantly lower than cardia adenocarcinoma (p < 0.05). The circulating serum levels of miR-375 in patients who had distal gastric adenocarcinoma were also much lower than normal controls (p < 0.001). As a biomarker, miR-375 yielded a receiver operating characteristic area under the curve of 0.835. The specificity and sensitivity was 80% and 85%, respectively, in the discrimination of distal gastric adenocarcinoma from control, at a normalized cutoff of 0.218. The expression of miR-375 was downregulated both in distal gastric adenocarcinoma tissues and serum of patients with distal gastric adenocarcinoma. These data suggest miR-375 is a potential biomarker for distal gastric adenocarcinoma. PMID- 23461061 TI - C-Myc overexpression promotes osteosarcoma cell invasion via activation of MEK ERK pathway. AB - Osteosarcoma is a highly metastatic malignancy often with poor prognosis. c-Myc amplification is implicated in osteosarcoma pathogenesis. However, the role of c myc overexpression in osteosarcoma cell invasion remains unexplored. This study showed that c-myc overexpression enhanced MG-63 and SAOS-2 osteosarcoma cell invasion. Treatment of MEK inhibitor PD98059 or PI3K inhibitor LY294002 decreased cell invasion along with downregulation of MMP-2 and MMP-9 expression. c-Myc overexpression stimulated MEK-ERK pathway whereas inhibited the activity of PI3K AKT pathway. Specifically, inhibition of MEK-ERK pathway by PD98509 blocked the enhancement effect on cell invasion as well as MMP-2 and MMP-9 expression. The present study demonstrates that c-myc overexpression promotes osteosarcoma cell invasion, probably via activation of MEK-ERK pathway. PMID- 23461063 TI - Mir-373 affects human lung cancer cells' growth and its E-cadherin expression. AB - The aims of this study was to elucidate whether the expression of E-cadherin can be affected by the recombinant has-mir-373 eukaryotic expression plasmid vector through tests in vitro, and to analyze the relationship between the expression of E-cadherin and tumor growth. According to the has-mir-373 sequence in miRBase database, two template DNA sequences were designed. The has-mir-373 sequence and a control sequence were synthesized and cloned into pGenesil-1 eukaryotic expression plasmid vector. The recombinant plasmids were transfected into human lung cancer A549 cells by liposome-mediated method. The mir-373 expression in A549 cells was detected by using real-time quantitative polymerase chain reaction (real-time PCR). MTT (methyl thiazolyl tetrazolium) was used to analyze the growth of cancer cell cycle. RT-PCR and Western blotting were used to evaluate the levels of E-cadherin mRNA and protein expression, respectively. The expression of E-cadherin in cells was determined by immunocytochemistry. The mobility capability of transfected cells were evaluated by using wound healing assay in vitro. The fluorescent light was observed under fluorescent microscope. RT-PCR indicated that the mRNA of E-cadherin increased, and the Western blotting results also displayed that mir-373 promoted the expression of the E-cadherin protein. Compared with the control groups, MTT method and wound healing assay demonstrated that both the growth rate and migration of A549 cells transfected with the recombinant has-mir-373 eukaryotic expression plasmid was also decreased significantly (p < 0.001). The differences between the other two control groups were not significant (p > 0.05). The immunocytochemistry demonstrated a significant increase of E-cadherin protein levels in the cells transfected with mir-373, but not in the cells of the control group. Mir-373 could increase the expression levels of the E-cadherin and decrease the migration ability of human lung cancer A549 cells in vitro. PMID- 23461062 TI - Downregulation of JWA expression in human esophageal squamous cell carcinoma and its clinical significance. AB - JWA is involved in the regulation of many cellular processes. Recent studies have indicated a potential role for altered JWA expression and function in tumor development and progression. The purpose of this study was to investigate the expression and prognostic significance of JWA in human esophageal squamous cell carcinoma (ESCC). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot assays were performed to detect the expression of JWA mRNA or protein in paired sample tissues from 20 ESCC patients. Expression levels of JWA protein in archival 292 formalin-fixed, paraffin-embedded specimens were also analyzed by immunohistochemistry. Finally, the correlation between JWA expression, clinicopathological factors, and patient survival was evaluated. RT qPCR results showed that the levels of JWA mRNA were significantly lower in tumor tissue specimens than in the matched nontumor tissues. This finding was supported by Western blot analysis. Immunohistochemical staining data indicated that JWA protein level was correlated closely with the tumor cell differentiation, tumor invasion, lymph node metastasis, and distant metastasis. Kaplan-Meier survival analysis showed that low expression level of JWA resulted in a significantly poor prognosis of ESCC patients. Cox regression analysis revealed that the JWA expression level was an independent prognostic parameter for the overall survival rate of ESCC patients. In conclusion, our data suggest that JWA plays an important role in the occurrence and progress of human ESCC and that high expression level of JWA may predict a favorable prognosis in ESCC patients. PMID- 23461064 TI - The role of ZFX in non-small cell lung cancer development. AB - Zinc finger protein, X-linked (ZFX) is a transcription factor encoded by its gene on the mammalian X chromosome, and functions to control survival and activity of stem cells and lymphocytes. However, little is known about the role of ZFX in tumorigenesis. The function of ZFX in cell proliferation was investigated by the lentivirus-mediated short hairpin RNA interference (shRNA) approach in non-small cell lung cancer (NSCLC) cell culture lines. The expression profiles of ZFX in 49 pairs of tumors and corresponding matched adjacent normal tissues from NSCLC patients were examined by real-time PCR. The specific knockdown of ZFX by shRNA significantly inhibited cell viability and reduced colony formation of 95D cells. And ZFX silencing resulted in cell cycle arrest in G0/G1 phase. In addition, ZFX was overexpressed and correlated with lymph node metastasis in samples from 49 NSCLC patients. We reported for the first time that ZFX may play an important role in cell growth control and cell cycle progression of 95D cells. Furthermore, ZFX was overexpressed in samples of NSCLC and ZFX mRNA expression associated with lymph node metastasis. Therefore, our findings suggest that ZFX would be a potential target to development of therapies for NSCLC. PMID- 23461065 TI - Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer. AB - No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors. PMID- 23461066 TI - [Implications of the modern history of Hansen's disease in Japan]. PMID- 23461067 TI - [Multidisciplinary management for heart failure --prevention, diagnosis and updated treatment]. AB - Heart failure is a major cause of cardiovascular death. In this symposium, we explained etiology, prevention and the updated treatment for heart failure. In particular, the recent progress of pharmacological and cardiac implantable electronic device therapy has prolonged the survival of patients with heart failure. In addition, the treatment with ventricular assist device is now available in a candidate for heart transplantation in Hokkaido University Hospital. We hope that this symposium would help the attendance to understand the prevention and treatment for heart failure, thereby improving its prognosis. PMID- 23461068 TI - Clinical factor affecting the recovery of kidney function in clinically localized renal cell carcinoma patients who underwent nephron-sparing surgery. AB - INTRODUCTION: Nephron-sparing surgery (NSS) has become the standard treatment for small renal cell carcinoma because of its comparable oncological outcome and superior patient survival compared to total nephrectomy. However, the precise chronological course of recovery from initial kidney damage and the factors responsible for it remain unknown. MATERIALS AND METHODS: Seventy-one patients who underwent NSS were enrolled. To elucidate the chronological changes in kidney function that occur after NSS, the estimated glomerular filtration rate (eGFR) was calculated at different two points, the early (7 days after surgery) and late time points (more than 12 months after surgery), and compared with the preoperative eGFR. Perioperative factors were applied to a multivariate regression model to investigate the factors that most affect patient recovery from nephron damage. RESULTS: eGFR was decreased at the early time point but had partially recovered at the late time point. Male gender, ischemic time, and tumor size were found to be significant predictors of the initial drop in eGFR. The only significant factor that prevented later functional recovery was the presence of DM. CONCLUSION: Several perioperative factors significantly influence early kidney damage; however, the presence of DM is the only factor affecting the risk of long-term chronic kidney damage. PMID- 23461069 TI - Feasibility of cytological diagnosis of sarcoidosis with endobronchial US-guided transbronchial aspiration. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic value in sarcoidosis if the obtained histological specimen is indicative of a non-caseating epithelioid-cell granuloma. However, EBUS-TBNA in sacoidosis sometimes affords solely cytological specimens. OBJECTIVE: To investigate the relevance of EBUS-TBNA cytology specimens in diagnosing sarcoidosis. DESIGN: The study population comprised 72 patients with sarcoidosis and 116 patients who had thoracic malignancies and intrathoracic lymphadenopathy but were eventually proven to be metastasis-free (controls). The EBUS-TBNA samples obtained for these subjects were blindly evaluated for the presence of epithelioid cell clusters by 2 independent cytoscreeners and a pathologist. RESULTS: Interobserver variability in the specimen grading was minimal. The sensitivity and specificity were 65.3% and 94.0%, respectively. The sensitivity was high, at 87.5%, for the combined cytological and histological examinations. Of 7 controls whose cytological specimens showed epithelioid cell clusters, 3 were also deemed positive for sarcoidosis on histological examination, which indicated that they had sarcoid reaction to cancer. CONCLUSIONS: Cytological evaluation of the EBUS-TBNA specimens had higher sensitivity than histological evaluation alone for intrathoracic lymphadenopathy due to sarcoidosis. It should be recognized, however, that up to 6% of patients with thoracic malignancy may have sarcoid reaction in non-metastatic lymph nodes. PMID- 23461070 TI - Endpoints for clinical trials of sarcoidosis. AB - Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life. PMID- 23461071 TI - Bronchial hyperreactivity in sarcoidosis patients: correlation with airflow limitation indices. AB - Bronchial hyperreactivity (BHR) in sarcoidosis has been reported in 5 to 83% of patients, but the relationship between BHR and airway functional status being unclear. The aim of the study was to assess the prevalence and degree of BHR in a group of pulmonary sarcoidosis patients and how BHR does relate to the functional status of airways. MATERIAL AND METHODS: 56 consecutive sarcoidosis outpatients (26 f, 30 m) were included. There were 14 (25%) patients in stage I, 32 (57.1%) patients in stage II and 10 (17.9%) patients in stage III. In all patients the standard evaluation included a history, physical examination, chest radiogram, serum ACE activity and lung function assessment were done. The provocation challenge test with doubling concentrations of histamine was performed in all patients using the standardized protocol recommended by the ERS. RESULTS: 4 patients (7%) were restrictive, airway obstruction was detected in 7 (12.5%) cases. Up to 32% of patients had maximal expiratory flows at low lung volumes below the lower limit of normal (LLN). The histamine challenge test results: in 9 cases (16%) the fall in FEV1 was < 20% of the baseline; mean PC20H (n = 47) was 5.7 +/- 5.9 mg/mL, range: 0.56-26.7 mg/mL. The challenge test was regarded as positive (PC20H < or = 8 mg/mL) in 71.4% of the group. BHR expressed as ln(PC20H) correlated weakly but significantly with FEV1, FEV1%VC, MMEF and PEF. CONCLUSION: BHR occurs frequently in sarcoidosis patients and should be considered especially in patients with airflow limitation. PMID- 23461072 TI - Six-minute stepper test to assess effort intolerance in interstitial lung diseases. AB - The six-minute stepper test (6MST) is a new test for evaluating exercise tolerance. Unlike the six-minute walk test (6MWT) it can be carried out in a limited space. The aim of this study was to compare the 6MST and the 6MWT in patients with various diffuse interstitial lung disease (ILD). 6MWT and 6MST were performed the same day in 84 patients with various ILD. The covered distance during 6MWT was compared to the number of steps during the 6MST. We also compared heart rate, oxygen saturation, dyspnoea and leg tiredness on a Borg scale. All the patients successfully completed the tests, and tolerance was considered good. The number of steps completed in the 6MST was strongly correlated with the distance walked in the 6MWT (r2 = 0.5; p < 0.0001). Oxygen desaturation was less frequent and less severe (p < 0.0001), heart rate was higher (p < 0.0001) and dyspnoea and leg tiredness were more marked (p < 0.0001) in the 6MST than in the 6MWT. The 6MST is feasible for patients with ILD. It is a simple, safe, mobile test that is cheap and easy to carry out in all structures. PMID- 23461073 TI - Health-related quality of life does not predict mortality in idiopathic pulmonary fibrosis. AB - BACKGROUND: Although health-related quality of life (HRQL) has recently been considered to be an important outcome in clinical trials of idiopathic pulmonary fibrosis (IPF), its relationship with survival is unknown. OBJECTIVE: To determine the prognostic significance of HRQL scores in IPF assessed with the SGRQ. DESIGN: Eighty-seven consecutive patients with IPF, who had undergone evaluations and completed the St. George's Respiratory Questionnaire (SGRQ) at diagnosis were included in this study, as is the general practice. Cox proportional hazards analyses were performed to examine the relationship between HRQL scores and survival. RESULTS: The mean observation period was 44.2 +/- 29.6 mo, in the course of which 54 patients (62.0%) died. Univariate analysis revealed that the activity scores in the SGRQ(HR: 1.016, 95% CI: 1.004-1.029, P = 0.01) were significantly predictive of survival, although the symptoms, impacts, and total scores were not significantly related to mortality from all causes. However, multivariate analysis revealed that only the forced vital capacity percent predicted was a significant predictor of survival, and that the activity score in the SGRQwas not significantly related to mortality. CONCLUSIONS: There was no significant relationship between HRQL evaluated with the SGRQ and the subsequent mortality in IPF. The present negative result might suggest that HRQL is measuring an aspect other than one from physiological and functional impairment or disability. PMID- 23461074 TI - The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States. AB - BACKGROUND: Although numerous reports have described the clinical features of sarcoidosis in various ethnic and racial groups, many have been limited by small size, homogenous populations, and relatively short follow-up periods. We report the clinical characteristics of a large, race-sex-age diverse cohort of sarcoidosis clinic patients followed in a large university medical center for an extended period of time. METHODS: This study included clinical data for sarcoidosis patients followed over a 12-year period at a sarcoidosis clinic at the Medical University of South Carolina. RESULTS: 1774 sarcoidosis patients were identified. Black females were more common (44%) than other race/gender combinations (p = 0.01). The diagnosis of sarcoidosis occurred > 3 months after the onset of symptoms in 48% of the cohort and > 1 year after the onset of symptoms in 25%. Anti-sarcoidosis treatment was required in 61% of the patients. Pulmonary function improved over time and the median corticosteroid requirement lessened. Compared to whites, blacks had more advanced radiographic stages of sarcoidosis (p < 0.0001), more organ involvement (p < 0.0001), and more frequently required anti-sarcoidosis medication (p < 0.0001). Compared to women, men had more advanced radiographic stages of sarcoidosis (p < 0.0001). CONCLUSIONS: The analysis indicates that sarcoidosis tends to improve over time in terms of pulmonary function and medication requirements. The disease was found to be more severe in blacks than whites. Treatment was not necessarily required. These results provide a comprehensive model of the course and treatment of sarcoidosis in the clinical setting. PMID- 23461075 TI - Are clinical features in Lofgren's syndrome-related erythema nodosum different from idiopathic erythema nodosum? AB - BACKGROUND AND OBJECTIVES: We retrospectively evaluated acute sarcoidosis (Lofgren's syndrome) patients diagnosed at 2 centers and compared the clinical features of Lofgren's syndrome (LS) related erythema nodosum (EN) to patients with idiopathic IEN who were diagnosed within the same time frame. METHODS: Thirty patients (10 males, 20 females) who were diagnosed with LS and were being followed up for the last 8 years at 2 centers were included. Thirty patients (4 males, 26 females) who were admitted to the rheumatology outpatient clinics for IEN during that time period were taken as controls. The clinical and laboratory features at the initial admission, treatment modalities and response were recorded. RESULTS: Twentyfour (80%) patients with LS related EN had arthritis and/or arthralgia. Fifteen of them had only findings of periarticular ankle inflammation and 4 had polyarthritis. When LS related EN patients were compared to IEN patients, the former group had more arthritis and/or arthralgia (p < 0.001), leucocytosis (p = 0.02), lymphopenia (p = 0.005) and thrombocytosis (p = 0.05), and higher ESR (p = 0.02). Twentyfive (83.3%) patients with LS related EN were administered oral corticosteroids. In 21 patients, hilar lymphadenopathy disappeared on control chest x-ray and CT; in 3 patients, minimal residual lymph node enlargement was persistent. During a median follow-up of 54 months (range: 10-84 months), none of the LS related EN patients had clinical relapse. CONCLUSIONS: Apart from BHL, arthritis and/or arthralgia especially periarticular ankle inflammation is the feature which could be used to differentiate LS related EN from IEN. There is more need for steroids in LS patients and the symptoms quickly resolve with steroids. PMID- 23461076 TI - A prospective clinical multicentre study on adult pulmonary Langerhans' cell histiocytosis. AB - BACKGROUND: To date the clinical picture of pulmonary Langerhans' cell histiocytosis has been described only in retrospective reports. For a better understanding, the German Scientific Study Group on the Treatment of Lung Disease (WATL) conducted an open, prospective, clinical observation study. METHODS: During the period between 1994 and 2002 77 patients (40 men and 37 women) were recruited. The median observation period was 38.2 (3.2-86.7) months. RESULTS: At the initial examination 50 patients were active smokers, 26 ex-smokers and 1 had never smoked. 36% of the patients showed reduced vital capacity, 28% signs of airways obstruction. On chest radiography, 74% of the patients who stopped smoking (24/50) showed regression, while 13% remained unchanged and 13% revealed progression. In the group that continued to smoke (25/50) chest radiography showed regression in 58% of cases, no change in 25% and progression in 17%. The difference was not significant, which was also true for lung function values. 3 patients died within the observation period. CONCLUSION: The data underline the key role of smoking as the sole known risk factor. A significant effect of smoking cessation on the course could not be confirmed. The overall prognosis was good in this series as compared to previous reports. PMID- 23461077 TI - Anxiety and depression in sarcoidosis: the influence of age, gender, affected organs, concomitant diseases and dyspnea. AB - BACKGROUND: Heightened degrees of anxiety and depression are often found in patients suffering from sarcoidosis, but the reasons for that are unclear. Furthermore, age and gender differences of anxiety and depression in sarcoidosis have not been reported with reference to normative data. OBJECTIVES: The aim was to test age and gender differences of anxiety and depression in a large sample, and to examine the influence of affected organs, concomitant diseases and dyspnea. METHODS: 1197 German patients diagnosed with sarcoidosis were examined, using the Hospital Anxiety and Depression Scale (HADS) and the MRC dyspnea scale. RESULTS: Patients suffering from sarcoidosis were significantly more anxious and depressed than the general population. This effect was especially strong in young age groups. The number of affected organs, the number of concomitant diseases and the degree of dyspnea significantly predicted anxiety and depression scores in univariate analyses. Among the affected organs, muscles, nerves, and bones most significantly contributed to depression. Sleep apnea, restless legs syndrome, and arterial hypertension were associated with anxiety as well as depression. In multivariate analyses including age and gender, however, only dyspnea and the number of concomitant diseases remained predictors of anxiety and depression scores. CONCLUSIONS: The analysis of mental distress should take into account comparisons with normative values. Young patients deserve special social support. Dyspnea proved to be an important symptom in the prediction of anxiety and depression. PMID- 23461078 TI - Chest wall shrapnel-induced beryllium-sensitization and associated pulmonary disease. AB - Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD. PMID- 23461079 TI - Sarcoidosis: vaginal wall and vulvar involvement. AB - Sarcoidosis is a non-caseous granulomatous disease which could involve numerous organs including lungs, eyes, skin, nervous system, heart, liver. However, the genitourinary tract involvement was rarely reported in sarcoidosis. We report the case of a 45-year-old married woman who presented with 2 months history of a vulval mass as large as a soybean, and did not reveal any remarkable pulmonary signs. Biopsy results showed non-caseous granulomatous inflammation consistent with sarcoidosis in the vulvar lesion. To our knowledge, this is the first reported case of this entity in the world. Based on the related literature, we highlight the possibility of gynecologic involvement in sarcoidosis. PMID- 23461081 TI - Stem cells, aging and pulmonary vascular remodelling. PMID- 23461080 TI - An analysis of seasonality of sarcoidosis in the United States veteran population: 2000-2007. AB - BACKGROUND: The onset of sarcoidosis is thought to be seasonal, particularly Lofgren's syndrome. However, there are conflicting data on seasonality by country and by radiographic stage. OBJECTIVE: The objective of this study was to determine if there is seasonality of the diagnosis of sarcoidosis in outpatients in the United States. METHODS AND RESULTS: Using time series methods, we performed a retrospective analysis of 3791 incident cases of sarcoidosis in the Veteran's Health Administration national outpatient claims database (2000-2007). We did not find overall seasonality in the occurrence of new sarcoidosis in United States Veterans (p = 0.9860), even after we subdivided the United States by northern (p = 0.6824) and southern regions (p = 0.4588). CONCLUSION: The lack of seasonality in this study indicates that season is not a dominant factor in complex gene-environment-host interaction that precedes presentation of new sarcoidosis cases in the United States Veteran population. PMID- 23461082 TI - Aging successfully: a growing challenge. PMID- 23461083 TI - Why geriatrics? The rationale behind the science. PMID- 23461084 TI - Alzheimer's dementia: a brief review. PMID- 23461085 TI - Geriatric depression: a brief review. PMID- 23461086 TI - Polypharmacy: what clinicians need to know while caring for an elder. PMID- 23461087 TI - Delirium in the elderly. AB - Delirium is an acute and common problem often affecting frail and older persons in the acute care hospital, but can develop in any setting. It is associated with serious complications but can also be treatable if diagnosed early and managed properly. Preventive measures should be implemented in high risk patients, such as those with malnutrition, polypharmacy, infections, previous delirium, or dementia. Despite precautions, delirium is unavoidable in some cases and clinicians should be familiar with the typical features and varied presentations of this condition. Diagnosing delirium can be based on the DSM criteria, though multiple useful screening tools exist. Since delirium is almost always triggered by an underlying condition, an aggressive search for the causative insult(s) is essential in order that a targeted intervention be started promptly. Although there is neither any medication approved by the FDA for the treatment of delirium nor any robust evidence supporting the benefit of medications, there is general consensus that drug intervention can be attempted when non-pharmacological interventions have failed. PMID- 23461088 TI - Urinary incontinence in older adults. AB - Urinary incontinence is a common problem in the elderly which is under-reported and under-treated.It can have profound effects on the quality-of-life of affected persons and their companion or caregiver. Though common, incontinence is not an inevitable consequence of aging, but multiple anatomic and physiologic age related changes increase the risk of UI with advancing age. Many treatment modalities are available for managing UI, some more effective than others. Patient education, and careful selection of treatment modalities can significantly improve urinary incontinence, and in some cases cure it, but treatment complications and side effects are common and must be closely monitored for successful long-term management. Surgical management of stress incontinence is a safe and effective intervention that is underutilized. PMID- 23461089 TI - Late-onset hypogonadism: an undertreated condition in aging Lebanese men. PMID- 23461090 TI - Management of knee osteoarthritis: an evidence-based review of treatment options. AB - Osteoarthritis is the most common form of arthritis, and its incidence increases rapidly with age. Osteoarthritis is a progressive degenerative disease, and treatment must evolve with disease progression. Several classes of medications and treatment modalities have been used to relieve pain and preserve function. Most have been studied extensively but results of even well-designed trials can diverge. Furthermore, effect of a drug (beneficial or adverse) in an individual patient is not always predictable and may differ from the class effect. A short treatment trial may be necessary to determine efficacy. This potential discrepancy between statistical outcome and individual result is captured in the guidelines, to whatever extent possible. A summary of recommendations for select interventions compiled from multiple guidelines is presented in table II. In closing, interpretation of guideline recommendations, and how they were derived, must be clarified, since they have been a source of confusion and misinterpretation. Level of evidence (LoE) refers to the source from which the evidence was derived. It describes the quality of evidence and academic vigor, with meta-analysis of RCT being of strongest quality and expert opinion the lowest. The strength of effect describes how much of a clinical effect (usually benefit) is expected from the intervention. The strength of recommendation incorporates LoE and strength of effect, as well as cost, safety, and feasibility. An intervention with a high LoE does not necessarily trigger a strong recommendation. For example, NSAIDs have a greater effect on pain reduction than acetaminophen in most studies, but carries a lower recommendation due to concerns with long-term safety. Total knee arthroplasty has a LoE of III since no blinded RCT have studied the procedure, yet it carries a strong recommendation in advanced OA. In the five years between the publication of the EULAR and the OARIS guidelines (2003-2008), new studies were published explaining, in part, the difference in recommendations among the agencies. Future guidelines will undoubtedly evolve further. PMID- 23461091 TI - Because you are never too old: exercise and older adults. PMID- 23461092 TI - [Geriatric short-term stay unit: why and for whom?]. PMID- 23461093 TI - Long-term stay institutions in Lebanon. PMID- 23461094 TI - I had the privilege of traveling and lecturing in Africa, Asia, and Europe. PMID- 23461095 TI - The 'methodic' exploration of the ethical and pastoral dimension in interaction: the cycle of encounter. AB - Social competence can be understood as the capacity to interact with each other. As such, it is the acquisition and optimization of an interior attitude that transcends technique; it is a way of loving and doing justice to one another. A scheme is presented to explore the ethical and spiritual dimensions of the pastoral counseling process. Ethics is both an objective discipline and a relationship. Relationships are built during qualitative encounters that build respect and construct religious meanings. All encounters share this process. This article explores the logic of ethical dynamics with particular focus on pastoral counseling encounters. PMID- 23461096 TI - Mutually engaged supervisory processes: a proposed theory for ACPE supervisory education. AB - Nineteen newly certified Association for Clinical Pastoral Education (ACPE) Associate Supervisors were interviewed to determine how they learned to do Clinical Pastoral Education (CPE) supervision. Grounded theory was the qualitative research method used in gathering and analyzing data for this IRB approved study. The emerging theory, Mutually Engaged Supervisory Processes, includes nine processes: Discerning Vocation, Feedback, Support, Supervisory Practices and Identity, Theory, Increased Awareness, Shift in Personhood, Offering Presence, and Owning Authority. Member checks confirmed the trustworthiness of the results. PMID- 23461097 TI - Effectiveness of Islamic spiritual care: foundations and practices of Muslim spiritual care givers. AB - The paper discusses the effectiveness of Islamic spiritual and religious care based on the ethnographic research with 15 Muslim spiritual caregivers. Six themes emerged from the interviews with fifteen Muslim spiritual caregivers. These six themes describe what the spiritual care providers see as effective Muslim spiritual care: (1) The most effective Muslim spiritual care is rooted in the Qur'an and the Hadith; (2) Effective Muslim spiritual care also means creating a caring relationship with the patient; (3) Muslim scholars are one of the important sources of effective Islamic spiritual care; (4) The insights of psychology and the social sciences are a necessary part of effective Islamic spiritual care; (5) There is a need for continuing education; (6). Styles of effective Muslim spiritual care are varied. PMID- 23461098 TI - "Be patient and grateful"--elderly muslim women's responses to illness and suffering. AB - Muslims arriving as first generation immigrants in Western countries gradually grow old and increasingly appeal to Western healthcare. This study presents and discusses the perspectives of elderly (age > or =55) Muslim women on medicine, illness and suffering. We found that theological considerations, centring around God's almightiness, are central for these Muslim women dealing with illness and suffering in a meaningful way. This study concludes that spirituality is an important dimension of their patient care: it not only makes an impact on these patients' ritual needs (e.g. prayer), but also on the ways they deal with illness, suffering, and concrete medical decision-making. The findings are of particular importance for both Muslim and multi-faith hospital chaplains who might act as spiritual care references in medical teams, by informing physicians and nurses about potential specific sensibilities and perspectives of Muslim patients. PMID- 23461099 TI - Conditions for religious discourse in secularized ethical health care deliberation. AB - Religious discourse is no longer self-evident in professional health care ethical deliberation in the North Atlantic cultural sphere. However, in a world of pluralism, care professionals still seek substantive views of good care. Religious and non-religious beliefs should not be excluded from ethical deliberation. They offer patients and professionals a helpful language for expressing values and beliefs. Chaplains have a role to play as allies in sense making processes and resourcing care. PMID- 23461100 TI - Assessing the construction of spirituality: conceptualizing spirituality in health care settings. AB - Spirituality has become a popular term in chaplaincy and health care settings, but is defined in such a myriad of ways and in such broad terms that, as a term, it threatens to become unfit for clinical practice. Several prominent conceptualizations of spirituality are analyzed in an attempt to recover the distinctiveness of spirituality. An adequate understanding of spirituality for clinical use should run close to the lived spirituality of persons in their unique individuality, differing contexts and various persuasions. In the second place a distinct discourse on spirituality needs to be sensitive to characteristic experiences of that which is other. PMID- 23461101 TI - A Christian death in a post-modern world. PMID- 23461102 TI - People live within their own personal contexts. PMID- 23461103 TI - Spiritual/cultural competency: methods in diversity education. AB - Diversity education in clinical training such as CPE is best developed in an interactive group context, guided by methods and approaches promoting mutual disclosure that includes the leader. Each member is invited to portray a web of meaning with cultural, spiritual and religious threads that comprise a personally knitted reality, a narrative foundational to identity and interaction. Differences between people in the training context challenge previously held notions, distribute authority in the group and foster open ended learning that enriches the activities of clinical supervision. This article describes group educational methods with case examples that foster spiritual/cultural competency, each member a person in context with the opportunity to be distinct and connected, a threshold for all other dimensions of diversity learning in pastoral practice. PMID- 23461104 TI - He's home, but he's not the same: a pastoral counseling impression of family care after combat related traumatic brain injury. AB - As the occurrence of direct contact with heavy improvised explosive devices has increased in Operation Enduring Freedom, more and more veterans are returning home from combat deployment with traumatic brain injuries (TBI). Although these injuries are associated with many different neurological, physiological, and emotional symptoms, perhaps most difficult for families is the phenomenon of perceived personality change. This article examines common clinical interventions in treating personality change associated with TBI, and offers pastoral context and insights for complementary care with families during the return and reunion process. PMID- 23461105 TI - Using prayer and scripture in a Christian-based stress-coping support group for church attendances: implications for professionals. AB - This study explored the participants' perceptions of using prayer and scripture in a Christian-based stress-coping support group (CSCSG). Twenty-eight church attendances were recruited from a Presbyterian Church in Taiwan. Based on the finding from qualitative analyses using a modified grounded theory approach, four themes related to the participants' learning experiences emerged. The four themes identified were stressful life events, stress-coping experiences, integration of Christian faith with life, and spiritual connection. A follow-up survey indicated that the participants perceived the experiences gained from the CSCSG as appropriate, important, functional, and constructive in coping with stress. Research questions and implications for church professionals are discussed. PMID- 23461106 TI - Suffering: etiology and treatment. AB - Suffering comes in many forms. Certain psychological therapies rooted in the work of Victor Frankl have been shown to alleviate suffering at the end of life. Frankl asserted, with subsequent agreement from secular and religious authors, that it is important to include the transcendent when working with those who suffer. This article explores some of the causes for and treatments of suffering. It briefly argues for the importance of addressing and even embracing the transcendent. PMID- 23461107 TI - Finding the holy spaces. PMID- 23461108 TI - A song that sings me. PMID- 23461109 TI - When saying "thank you God for returning my soul" is (too) hard to do. PMID- 23461110 TI - The caregiver: when silence speaks louder than words. PMID- 23461111 TI - Ministerial authority and honest speech. PMID- 23461112 TI - [Research on WiFi-based wireless microscopy on a mobile phone and its application]. AB - We proposed and realized a new device that acquires microscopic image wirelessly based on mobile phone and WiFi system. The mobile terminals could record, display and store the image from the far end via the wireless LAN. Using this system, a series of conceptual experiments on monitoring the microscopic images of common objects and liver cancer cells were successfully demonstrated. This system is expected to have important value in the experimental investigations on wirelessly monitoring the cell culture, and small insect etc. PMID- 23461113 TI - [Development of an automatic pneumatic tourniquet system that determines pressures in synchrony with systolic blood pressure]. AB - The correlation coefficients between arterial occlusion pressure and systolic blood pressure, diastolic blood pressure, limb circumference, body mass etc were obtained through healthy volunteer experiments, in which tourniquet were applied on upper/lower extremities. The prediction equations were derived from the data of experiments by multiple regression analysis. Based on the microprocessor C8051F340, a new pneumatic tourniquet system that can determine tourniquet pressure in synchrony with systolic blood pressure was developed and verified the function and stability of designed system. Results showed that the pneumatic tourniquet which automatically adjusts occlusion pressure in accordance with systolic blood pressure could stop the flow of blood to get a bloodless field. PMID- 23461114 TI - [The development and transplantation of LCD module-based interface for medical diagnosis instrument]. AB - Based on LCD Module and Visual C++ development environment, this paper proposes a new method which can quickly develop the human-machine interface .We define a LCD module programming interface by designing Serial Communication Class(SCS). On this basis,we achieve the transplantation on an Embedded ARM Platform to fulfil the requirements of Medical Diagnostic Instruments (MDI). Experimental results show that this method has advantages of short development cycle and high level transplantation which has broad application prospects in the field of Medical Diagnosis Instrument. PMID- 23461115 TI - [Portable lung function parameters testing system based on DSP]. AB - Lung function monitoring is a critical technique for clinical medicine. Currently, the lung function testing devices used in our domestic hospitals are both expensive and bulky. A portable and accurate lung function parameters testing system is highly desired and is proposed in this paper. The hardware of the system is based on DSP technology. The breathing passage is designed with an aim suitable for the breathe and signal detection. We use the direct detection method to detect the gas flow, the breathing passage pressure and the breathing time. Thanks to the powerful data processing ability and the high operation speed of the DSP, breathing signals can be easily analyzed. Thus, several lung function parameters of clinical significance can be obtained. Experiments show that the accuracy of the system is better than 3%, and could meet the demand of the lung function testing. PMID- 23461116 TI - [Application of improved PCNN algorithm in retinal macular edema segmentation]. AB - In order to extract the outlines of macular edema from OCT images of macular, and estimate the volume of edema, we have to accurately segment the macular edema region. In this paper, an improved PCNN algorithm was proposed to conduct the above process. Combined with the adaptive base threshold, and the simplified neural network parameters, a binary image of macular edema was produced. According to the principle of maximum image entropy, the optimal number of iterations was determined as 8, which was evaluated by its misclassification rate. Simulation showed that the proposed algorithm could extract the macular edema region rapidly and accurately, providing the basis for further OCT image analysis. PMID- 23461117 TI - [Development of medical supplies management system]. AB - OBJECTIVE: This paper adopts advanced information technology to manage medical supplies, in order to improve the medical supplies management level and reduce material cost. METHODS: It develops a Medical Supplies Management System with B/S and C/S mixed structure, optimizing material management process, building large equipment performance evaluation model, providing interface solution with HIS, and realizing real-time information briefing of high value material's consumption. CONCLUSION: The medical materials are managed during its full life cycle. The material consumption of the clinical departments is monitored real timely. Through the closed-loop management with pre-event budget, mid-event control and after-event analysis, it realizes the final purpose of management yielding benefit. PMID- 23461118 TI - [The development of multifunction intravenous infusion quantitative packaging device]. AB - Aimed at tackling the compatibility issues arising from the drug reaction in intravenous infusion tube, we developed a simple, suitable and multi-function intravenous infusion tube for the special use for rescuing critical patients, the elderly, children etc. Each drug in a transfusion process can be filtered to realize quantitative packet and packet delivery. Thus, the drugs in the infusion tube are prevented from meeting with each other. No overlap, no particle pollution occurred. Stable performance and accurate dosage are maintained. As a result safety is ensured during drug delivery. PMID- 23461119 TI - [Technique and application of cell image processing]. AB - Digital image processing is widely used in medical image. Segmentation is one of the important step in computer image processing. The essay introduces the procedure and effect of cell image segmentation by watershed algorithm. PMID- 23461120 TI - [Study on the reform and improvement of the medical device registration system in China]. AB - Based on the theories of the Government Regulation and Administrative Licensure, aiming at the current situations of medical device registration system in China, some policy suggestions for future reform and improvement were provided as follows. (1) change the concepts of medical device registration administration. (2) perfect the regulations of medical device registration administration. (3) reform the medical device review organizational system. (4) Optimize the procedure of review and approval. (5) set up and maintain a professional team of review and approval staff. (6) reinforce the post-marketing supervision of medical devices. (7) foster and bring into play of the role of non-government organizations. PMID- 23461121 TI - [Statistical analysis on findings in the quality management system during inspection of IVD manufactures of China]. AB - OBJECTIVE: To explore the current state and the mainly typical problems and vulnerable parts existed in the quality management systems (QMS) of local in vitro diagnostic reagent manufactures. METHOD: To statistical analyze the problems found in the quality management system of in vitro diagnostic reagent manufactures through inspection organized by CCD, SFDA during the second half year of 2011. RESULTS: The total level of the QMS of local IVD manufacturers has risen greatly in past recent years, but a lot of problems still existed. The main vulnerable issues existed in QMS of IVD are documentation and recorder control, design control and validation, producing process control, as well as monitoring and quality control etc, to which should be paid more attention in the future improvement made by the enterprises and supervision by the administration authorities. PMID- 23461122 TI - [Clinical trial requests of indigenous diagnostic imaging ultrasound devices in first-time registration application]. AB - This article introduces the clinical requests of indigenous diagnostic imaging ultrasound devices in first-time registration application and the clinical trial requests in Technical Review Guidance of Ultrasound Imaging Diagnostic Devices (category III) Registration and puts forward some questions of the guidance's implementation. It is hoped to help concerned people. PMID- 23461123 TI - [Analysis and thinking on the post marketing quality of the disposable sterilized syringe]. AB - By scattered-sampling testing the disposable sterilized syringe according to legal inspection and explorative research methods of vitro cytotoxicity and easy oxide etc. testing, this article comprehensively evaluated and analyzed the product quality and found the potential risk. The results will help to improve the work process and product quality. PMID- 23461124 TI - [Preliminary discussion on the preparation of medical device standards]. AB - This paper discussed some specific issues in the preparation of medical device standards. On the basis of GB/T 1.1-2009, some preliminary suggestions were accordingly proposed. PMID- 23461125 TI - [Test for dangerous limits of capacitor energy]. AB - For dangerous limits of capacitor energy, according to national standards of medical device regulations' test requirement, we analysis it and list its test methods and requirement. According to capacitor energy's formation and characteristics, we put forward a simple method for its test and calculation. PMID- 23461126 TI - [The value of electronic film for improving the quality of hospital services]. AB - In this paper, by describing and comparing different implementations of electronic film combined with the actual application of the electronic film in the imaging department and the clinical departments. We elaborate electronic film for optimizing the imaging department workflow to improve service quality and patient satisfaction and other aspects of value. PMID- 23461127 TI - [2011 Shanghai customer satisfaction report of DSA/X-ray equipment's after service]. AB - To improve the manufacturer's medical equipment after-sale service, the fifth Shanghai zone customer satisfaction survey was launched by the end of 2011. The DSA/X-ray equipment was setup as an independent category for the first time. From the survey we can show that the DSA/X-ray equipment's CSI is higher than last year, the customer satisfaction scores of preventive maintenance and service contract are lower than others, and CSI of local brand is lower than imported brand. PMID- 23461128 TI - [Grade III general hospital grade assessment as an opportunity to improve the management level of medical equipment]. AB - In the grade III general hospital reassessment, The department of hospital equipment accords its demand to find the problems and gaps in the actual work, gives modification opinions and programs, and clarifies continuous improved contents in next step, so to improve the management level of medical equipment. PMID- 23461129 TI - [Clinical significance of peripheral blood circular DNA level measurements in patients with acute myocardial infarction]. AB - OBJECTIVE: To explore clinical value of circular DNA in acute myocardial infarction. METHODS: Venous blood (2 ml/head) of 40 healthy control and 40 patients with acute myocardial infarction within 48h of onset of illness and convalescent period was collected. The level of plasma circular DNA was detected by duplex real-time polymerase chain reaction assay. The levels of myocardial enzyme spectrum and cardiac troponin T (cTnT) were detected by biochemistry method. RESULTS: The level of circular DNA in control group and group of acute myocardial infarction before treatment was (21.5 +/- 10.7) ng/ml and (253.6 +/- 45.7) ng/ml, respectively (P = 0.000). The levels of serum myocardial enzyme spectrum and cTnT before treatment in patients with acute myocardial infarction were significantly higher than those of control group (P < 0.05). The level of circular DNA after treatment in patients with acute myocardial infarction was significantly decreased compared with that before treatment (P = 0.000), the levels of myocardial enzyme spectrum and cTnT were also significantly reduced (P < 0.05). There was significant correlation between the level of circular DNA and those of CK-MB and cTnT, r = 0.613, 0.654, P = 0.032, 0.021. CONCLUSION: Circular DNA can be used as a marker of sensitively reflecting myocardial cell injury. PMID- 23461130 TI - [Common malfunctions shooting to MRI OPEN MARK II]. AB - This paper introduces and analyses common malfunctions of MRI OPNE MARK II to provide reference for maintenance and preservation of the machine. PMID- 23461131 TI - Human epididymis protein 4 in cancer diagnostics: a promising and reliable tumor marker. AB - Human epididymis protein 4 (HE4) is a member of the "four-disulfide core" family that comprises a heterogeneous group of small acid- and heat-stable proteins of divergent function. Although there is an exponential growth of evidence that HE4 is a valuable tumor marker for ovarian malignancies, the exploration of the usefulness of this glycoprotein in the large tumor landscape is still ongoing. Enzyme-linked immunosorbent assay, chemiluminescent microparticle immunoassay, and bead-based array system are the preferred analytical methods for measuring HE4 concentration. Serum and urinary HE4 levels appear to be more affected by carcinogenesis than by other pathologic processes. Apart from the malignancy itself, histological type of cancer, cancer stage, and menopausal status affects HE4 concentration. An important objective in nowadays research remains the development of a tumor marker panel with a sufficient accuracy for risk assessment, early diagnosis, prognosis, and response to therapeutic treatment of cancer. PMID- 23461132 TI - Pathophysiological roles and clinical importance of biomarkers in acute coronary syndrome. AB - Early diagnosis of acute coronary syndrome (ACS) is important to guide appropriate therapy at a time when it is most likely to be of value. Accurate prognostic and risk stratification will facilitate high-risk patients to have early advanced diagnostic investigations and early appropriate interventions in a cost-effective and efficient manner, while those patients at low risk of ACS complications do not need such costly diagnostic tests and unnecessary hospital admission. Recent investigations have demonstrated that elevation of biomarkers upstream from acute-phase biomarkers, biomarkers of plaque destabilization and rupture, biomarkers of myocardial ischemia, necrosis, and dysfunction may provide an earlier assessment of patient risk and identify patients with higher risk of having an adverse event. This review provides an overview of the pathophysiology and clinical characteristics of several well-established biomarkers as well as emerging biomarkers that may have potential clinical utility in patients with ACS. Such emerging biomarkers hold promise and need to be more thoroughly evaluated before utilization in routine clinical practice. PMID- 23461133 TI - Paraoxonases: ancient substrate hunters and their evolving role in ischemic heart disease. AB - Interest in the role of paraoxonases (PON) in cardiovascular research has increased substantially over the past two decades. These multifaceted and pleiotropic enzymes are encoded by three highly conserved genes (PON1, PON2, and PON3) located on chromosome 7q21.3-22.1. Phylogenetic analysis suggests that PON2 is the ancient gene from which PON1 and PON3 arose via gene duplication. Although PON are primarily lactonases with overlapping, but distinct specificities, their physiologic substrates remain poorly characterized. The most interesting characteristic of PON, however, is their multifunctional roles in various biochemical pathways. These include protection against oxidative damage and lipid peroxidation, contribution to innate immunity, detoxification of reactive molecules, bioactivation of drugs, modulation of endoplasmic reticulum stress, and regulation of cell proliferation/apoptosis. In general, PON appear as "hunters" of old and new substrates often involved in athero- and thrombogenesis. Although reduced PON activity appears associated with increased cardiovascular risk, the correlation between PON genotype and ischemic heart disease remains controversial. In this review, we examine the biochemical pathways impacted by these unique enzymes and investigate the potential use of PON as diagnostic tools and their impact on development of future therapeutic strategies. PMID- 23461134 TI - Mucosal healing in ulcerative colitis: pathophysiology and pharmacology. AB - Ulcerative colitis (UC) is a colonic inflammatory condition with a substantial impact on the quality of life of affected persons. The disease carries a cumulative risk of need of colectomy of 20-30% and an estimated cumulative risk of colorectal cancer of 18% after 30 years of disease duration. With the introduction of the tumor necrosis factor-alpha inhibitors for the treatment of UC, it has become increasingly evident that the disease course is influenced by whether or not the patient achieves mucosal healing. Thus, patients with mucosal healing have fewer flare-ups, a decreased risk of colectomy, and a lower probability of developing colorectal cancer. Understanding the mechanisms of mucosal wound formation and wound healing in UC, and how they are affected therapeutically is therefore of importance for obtaining efficient treatment strategies holding the potential of changing the disease course of UC. This review is focused on the pathophysiological mechanism of mucosal wound formation in UC as well as the known mechanisms of intestinal wound healing. Regarding the latter topic, pathways of both wound healing intrinsic to epithelial cells and the wound-healing mechanisms involving interaction between epithelial cells and other cells of the mucosa are discussed. The biochemistry of wound healing in UC provides the basis for the subsequent description of how these pathways are affected by the current medications, and what can be learnt on how to design future treatment regimens for UC based on targeting mucosal healing. PMID- 23461135 TI - Reticulocytes in sports medicine: an update. AB - Reticulocytes are young red blood cells which develop from erythroblasts and circulate in the bloodstream for about 1-4 days before maturing into erythrocytes. With the introduction of reticulocyte count in equations and statistical models for detecting suspected blood doping, its application to sports medicine has attracted growing interest in reticulocyte behavior during training and competition seasons in athletes and experimental blood doping treatment in healthy volunteers. An update on recent publications is therefore needed to improve the interpretation of reticulocyte analysis and its variability in sportsmen. Reticulocyte count constitutes a robust parameter during the preanalytical phase, but cell stability can be assured only if blood samples are kept at constantly cold temperatures (4 degrees C) and test results will differ depending on the blood analyzer system used. Marked intraindividual variability is the principal finding to be evaluated when exercise-induced changes are observed or illicit procedures suspected. Furthermore, reticulocyte variability is greater than that of other hematological parameters such as hemoglobin or hematocrit. Ideally, any variation should be interpreted against long-term time series for the individual athlete: values obtained from large athlete cohorts ought to be used only for extrapolating outliers that deserve further examination. Reticulocyte distribution in athletes is similar to that found in the general population, and a gender effect in some sports disciplines or selected athlete groups may be seen. Reticulocyte variability is strongly influenced by seasonal factors linked to training and competition schedules and by the type of sports discipline. Published experimental data have confirmed the high sensitivity of reticulocyte analysis in identifying abnormal bone marrow stimulation by either erythropoietin administration or blood withdrawal and reinfusion. PMID- 23461136 TI - Toll-like receptors in liver disease. AB - Activation of inflammatory signaling pathways is of central importance in the pathogenesis of alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH). Recent studies demonstrated that Toll-like receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD and NASH. In this review, we emphasize the importance of gut-derived endotoxin and its recognition by TLR4 in the liver. The significance of TLR induced intracellular signaling pathways and cytokine production as well as the contribution of individual cell types to the inflammation is evaluated. The contribution of TLR signaling to the induction of liver fibrosis and to the progression of liver pathology mediated by viral pathogens is reviewed in the context of ALD and NASH. PMID- 23461137 TI - Procalcitonin in pediatrics. AB - Over the past two decades, the body of literature on the clinical usefulness of procalcitonin (PCT) in adults has grown rapidly. Although this approach has led to increased insight, it has also prompted debate regarding its potential use in diagnosis and management of severe infection. Clinicians, however, are less familiar with the use of PCT in pediatric populations. In this review, we examine PCT as a marker of severe clinical pediatric conditions including its role in systemic inflammation, infection, and sepsis. PMID- 23461138 TI - [Selectins as adhesion molecules and potential therapeutic target]. AB - Selectins belong to the family of adhesion molecules that recognize sugars as ligands through their Carbohydrate Recognition Domain (CRD). There are three types of selectin: the L-selectin (CD62L), which is constitutively expressed by most leukocyte populations, the P-selectin (CD62P) is found on activated platelets and endothelial cells, and the E-selectin (CD62E) expressed by activated endothelial cells. These three molecules exhibit high homology in their structures. Selectin-ligand interactions are among the most studied protein glycan interactions in biology. The selectins and theirs ligands are involved in regulating inflammatory and immunological events that occur at the interface of the bloodstream and vessel walls. Their molecular partners are surface glycoconjugates harboring groups of the sialyl-Lewis antigens. This review presents an inventory of our current knowledge on the structures and functions of selectins and their ligands. We also provide an update on their involvement in pathophysiological processes, especially during inflammation and tumor development. PMID- 23461139 TI - [Screening of anti-inflammatory and analgesic activities in marines macroalgae from Mediterranean Sea]. AB - Methanolic extracts of 13 seaweeds collected from the Mediterranean sea (Tunisian, Moroccan and Greek coasts) from different classes (Chlorophycae, Pheopbycae and Rhodophycae) are testedfor their analgesic and antiinflammatory effects. These activities were estimated in vivo, respectively by writhing test and carrageenan test. Nine species among 13 tested seaweeds showed an important analgesic activity. On the other hand only 5 seaweeds showed a significant anti inflammatory activity (< 0.001 compared to control group). The percentage of inhibition reached 80% for the red algae Laurencia glandulifera but was only 50% for aspirin. The screening showed different pharmacological profiles. The red algae (Laurencia glandulfera and Hypnea musciformis) and brown algae (Cystoseira barbata and Sargassum vulgare) had endowed with the double analgesic and anti inflammatory activity. The red algae Geliduim sesquipedale have only anti inflammatory activity and the other one endowed only with an analgesic activity (Enteromorpha compressa, Chaetomorpha linum, Cystoseira ericoidies, Sacchoriza bulbosa et Corralina officinalis). The simultaneous or individual presence of the analgesic and?or anti-inflammatory activities of the various extracts can find its application in the therapeutic domain. PMID- 23461140 TI - Survival study of enterotoxigenic Escherichia colistrain in seawater and wastewater microcosms. AB - In order to survey osmotic and oligotrophic stress consequence on pathogenic enterobacteria discharged in marine areas, we examined enterotoxigenic Escherichia coli (ETEC) and a reference (Ecoli O126:B16) strains during their survival (47 days) in wastewater microcosms, submerged in natural seawater and maintained in laboratory conditions. The results revealed that the survival time for the two strains was prolonged when bacterial cells were previously incubated in wastewater, with less cellular membrane damage. In addition, the wild clinical E. coli strain showed a better survival capacity than the reference E. coli strain one. For both, we noted some modifications in biochemical profiles relatively to the initial state, notably when they were previously incubated in wastewater microcosm. PMID- 23461141 TI - [Neisseria meningitidis invasive infections in children in Tunis: about 79 cases]. AB - We conducted a retrospective study of meningococcal invasive diseases (MID) contracted in children in Tunis between January 1997 and January 2006. The purpose of this study is to specify the clinical, epidemiological, therapeutic and evolutionary features of these infections and to determine antimicrobial susceptibility and the antigenic formula of N. meningitidis isolates. During the study period, we have collected 79 cases of MID arising in children aged 3 days to 11 years. The majority of children's were less than of 4 years (57.3%). We note a frequency of the MID in winter and in spring. The most frequent clinical shape was meningitis (53%). Twenty one patients (26.6%) had a fulminant meningococcal disease. In our series, the rate of lethality was equal to 17.7%. Among the 46 meningococcal isolates, the most frequent serogroup was the B (73%) followed by C and A. A high heterogeneousness of the antigenic formulae was observed The most frequent phenotype was NT: NST for the group B isolates and 4:P1.13 for the group C ones. N meningitidis with reduced susceptibility to penicillin and to amoxicillin account for 54% and 10% of all isolates respectively. The cefotaxim and the rifampin were uniformly active. PMID- 23461142 TI - Soluble human leukocyte antigen-G (SHLA-G) in Tunisian kidney transplantation. AB - To investigate the relationship between the soluble HLA-G (sHLA-G) and the appearance of acute renal rejection (AR) episodes we have quantify in this study the level of sHLA-G by enzyme-linked immunosotrbent assay in 42 kidney transplant patients classified in two groups: G1: 17patients with acute rejection (AR+) and G2: 25 patients without AR (AR-). To establish our normal sHLA-G ranges, serum samples from 18 healthy controls were tested. Pre-transplantation sHLA-G levels were significantly increased in patients (mean +/- standard error of the mean, 60.48 +/- 12.18 units/ml) than healthy subjects (19.11 +/- 4.9 units/ml) (p = 0.001). Although the difference was not statistically significant, G1 patients (AR+) revealed lower levels of sHLA-G (mean +/- standard error of the mean, 31.25 +/- 6.71 units/ml) compared to G2 patients (AR-) (53.43 +/- 1721 units/ml). Nevertheless, the course of total sHLA-G levels was nearly identical in patients with and without rejection. Nonparametric analysis revealed that pre transplantation levels of sHLA-G < 18.00 units/ ml (sensitivity: 87.8% and specificity of 72.2%) were not related to rejection. Also, multivariate analysis regarding anti-HLA antibody status, recipient age and gender showed that sHLA-G could not be an independent risk factor for renal graft rejection. However, a higher sera levels of sHLA-G seemed to contribute to better kidney allograft survival rate after 10 years of follow-up (significance tendency: p = 0.091) as shown by the survival analysis. Because of the small number of subjects studied, these results must be treated with caution. A much larger cohort of kidney transplant patients according to acute rejection would seem necessary to confirm these findings. PMID- 23461143 TI - Association of chemokine and chemokine receptor polymorphisms with activity degree of IBD in Tunisian patients. AB - Crohn's disease (CD) and ulcerative colitis (UC) have complex genetic background that is characterised by more than one susceptibility locus. To detect a possible association between the functional polymorphisms of the chemokine receptors CCR5, CCR2 and MCP-1 genes and susceptibility to CD and UC in Tunisian population, polymorphisms of CCR5-delta32, CCR5-59029-A/G, CCR2-V641 and MCP-1-2518-G/A were analysed in 194 Inflammatory bowel disease (IBD) patients and 169 healthy blood donors using PCR-RFLP and PCR-SSP methods. The patients were classified in 126 patients with CD and 68 patients with UC. The genotypic and allelic frequencies of all polymorphisms studied, did not reveal significant differences between patients and conrols and among CD and UC patients. However, analysis of CD patients revealed that those without homozygosous G/G genotype are more frequently in remission compared to those with this genotype (OR: 0.4, 95% CI: [0.174-0.928]; p = 0.03). Also, the frequency of the CCR2-641 muted allele was statistically higher in CD patients in remission disease than those in active form (OR: 0.267 95% CI: [0.09-0.78]; p = 0.01). Adjustment for known covariates factors (age, gender and immunosuppressive regimen) confirmed these univariate findings and revealed that the CCR5-59029-A/G and CCR2-V64I genotype were associated to remission form of CD (OR: 263; 95% CI: [1.01-6.80]; p = 0.047 and OR: 4.64; 95% CI: [1.01-21.31]; p = 0.049 respectively). In conclusion, the present study supports the involvement of chemokine receptor (CCR2 and CCR5) polymorphisms in activity degree of the IBD disease in Tunisian patients. PMID- 23461144 TI - [Intestinal and hepatic subcellular localization of aluminium and indium administered orally to rat]. AB - Aluminium and indium are two elements used in industrial and medical fields. The purpose of this work was to study the subcellular localization of these elements, after their single and simultaneous oral administration to rats. 2h after the administration of these two elements, the small intestine and the liver were removed.Ultrastructural study showed the presence of electron dense deposits in the lysosomes of apical parts of duodenal enterocytes. When the minerals were administered simultaneously, deposits were observed in lysosomes of duodenal and jejunal enterocytes. No deposits were seen in the hepatic tissue of treated and control rats. Microanalysis identification showed that the deposits are constituted of aluminium, indium as well as phosphorus. Our results suggested that the elements are concentrated, in lysosomes, under the form of insoluble phosphate salts and it seemed that there are no specific lysosomes for the concentration of minerals since the two elements were concentrated in the same lysosome when they are administered simultaneously. PMID- 23461145 TI - A silent composite hemoglobinopathy characterized by gene sequencing. AB - We report the case of a 35-year-old Tunisian women with a chronic anemia non investigated for a long time. Laboratory analysis using advanced technology of DNA sequencing revealed a compound heterozygote for Hb O Arab and cd 39 beta degrees-thalassemia. It's the first time that such a genotype has been characterized by gene sequencing. PMID- 23461146 TI - [Polymorphisms of the UDP-glucuronosyltransferase 1-A1 gene in Tunisian population]. AB - The UDP-glucuronosyltransferase 1A1 gene that encode the enzyme UGT1A1 responsible for glucuronidation undergoes several variations that may affect the enzymatic activity or expression and which are the cause of metabolic disorders related to the glucuronidation of bilirubin, such as Gilbert's syndrome and Crigler Najjar's syndrome. Among the most common variations, there is the repeat polymorphism A (TA) n TAA in TATA box and biallelic mutation G211A in exon 1. We consider in this work to determine their frequencies in a healthy population. The polymorphism A (TA) n TAA showed that genotype [TA7/TA7] was described as being associated with Gilbert's syndrome and was encountered in 11% of the population studied. This percentage is close to the value described in the Caucasian population, estimated at 10%. Concerning the polymorphism G211A, our results show that the mutated allele is encountered in 15.7% of our study population. This frequency differs greatly from that reported for Caucasians and Afro-Americans but it is similar to that perceived at the Japanese. All these results suggest that the Tunisian population appears to be heterogeneous view UGT1A1 gene mutation status. Regarding the origins and distribution of such polymorphisms in our population, the study reveals a high haplotypic haplotype (TA) 6-G considered ancestral. The comparison of the haplotype structure generally leads to the development of a hypothetical tree of the origin and spread of different haplotypes. PMID- 23461147 TI - [The intestinal parasites in the food handlers of Tunis area: study of 8502 stool samples (1998-2008)]. AB - The food handlers control is one of the major measures of the National program against intestinal parasitoses in Tunisia. The collected data allow regular updates of the prevalence and profile of the involved parasitic species and note possible evolutions in time. From 1998 to 2008, 8502 stool samples of food handlers working in Tunis area were examined in the laboratory of Parasitology, Pasteur Institute of Tunis. The mean prevalence of intestinal parasites was 13.5% (1152 positive samples). The protozoa were the most detected parasites (93% of the species observed). Among the pathogenic or potentially pathogenic parasites, Dientamoeba fragilis (15.5%) and Giardia intestinalis (7.6%) were the most frequently encountered. Entamoeba (E.) histolytica/dispar was diagnosed in 41 subjects (a prevalence of 05%). Hymenolepis nana was the most frequent helminth (45% of the whole parasites). Therapeutic failures were noticed in 43.8% of infection by this cestode because of the lack of the appropriate antihelminthic. The identification using PCR of cysts and/or vegetative forms of E. histolytica/dispar revealed the exclusive presence of E. dispar. PMID- 23461148 TI - Bimanual microincision cataract surgery with implantation of an Akreos MI6O lens- one year follow-up. AB - PURPOSE: To evaluate visual outcome and complications after bimanual microincision cataract surgery (MICS) with implantation of an Akreos MI60 intraocular lens (IOL). MATERIAL AND METHOD: This study comprised 40 eyes of 22 patients after MICS. The IOL was implanted through a 1.9 mm or smaller clear corneal incision. One year after operation, uncorrected and best corrected distance visual acuity, best corrected near visual acuity (logMAR), contrast sensitivities (CS) (CSV-1000), induce astigmatism, complications and patient satisfaction were analyzed. RESULTS: The Akreos lens was implanted through mean incision of 1.8 + 0.01 mm. One year after surgery the mean uncorrected and the best corrected distance visual acuity (UDVA, BCDVA) and the best corrected near visual acuity (BCNVA) significantly improved (UDVA: preoperatively--0.7 +/- 0.6; postoperatively--0.04 +/- 0.17; p < 0.005; BCDVA: preoperatively 0.61 +/- 0.6; postoperatively--0.01 +/- 0.12; p < 0.001; BCNVA: preoperatively--0.56 +/- 0.42; postoperatively--0.0 +/- 0; p < 0.005). CS in photopic adaptation were within normal age-matched limits. One year after surgery, there was not significant induced astigmatism measured by vector analysis. There were no serious postoperative complications. Visual significant PCO was observed in 1 patient. All the patients were highly satisfied with the quality of the vision. CONCLUSIONS: Our results show that MICS with Akreos MI60 lens implantation is a procedure which let receive very good visual function results, fast visual rehabilitation as well as high patients' satisfaction. PMID- 23461149 TI - Visual outcome three and six months after implantation of Acri.LISA 366D lenses. AB - PURPOSE: To evaluate 3 and 6 months binocular visual outcomes after microincision cataract surgery (MICS) with implantation of multifocal, hybrid Acri.LISA 366D 10OLs. MATERIAL AND METHODS: Three and six months after bilateral MICS with Acri.Lisa 366D implantation, 40 eyes of 20 patients were evaluated for surgical induced astigmatism (SIA--vector analysis), binocular UDVA, UNVA and UIVA (logMAR), spectacle independence, contrast sensitivities (CS-CSV-1000), subjective symptoms, patient satisfaction (Type Questionnaire) and complications. RESULTS: Three and six months after surgery, SIA was equal 0.55 D and 0.58 D subsequently. Three months postoperatively mean binocular UDVA did not differ significantly from the six-month follow-up (-0.10 +/- 0.17 versus -0.14 +/- 0.11; p = NS). All patients had very good spectacle-free visual function at all distances and were totally spectacle independent. Mesopic distance and photopic distance and near CS were within normal age-matched limits at both follow-ups and did not change during observation time. A low degree of glare/halo was detected in 75% of subjects. Overall patient satisfaction was very high (9.05/10). There were no postoperative complications. CONCLUSIONS: Multifocal Acri.LISA 366D IOL implantation in selected cataract patients provides a very good visual outcome, a high level of patient satisfaction and spectacle-free visual function. microincision cataract surgery, Acri.Lisa 3660 101 implantation, visual outcome. PMID- 23461150 TI - Pseudophakic/aphakic corneal edema--morphometric predisposing factors analysis based on the fellow eye examination. AB - PURPOSE: To find morphometric factors predisposing to the development of corneal decompensation following cataract surgery. MATERIAL AND METHODS: Study group consisted of 50 patients after keratoplasty performed as pseudophakic/aphakic corneal edema (PCE/ACE) treatment. Control group formed 50 patients after cataract removal without signs of corneal decompensation. Specific subgroups were analyzed too. The morphometric data of the fellow eye anterior chamber were obtained with Visante OCTTM. RESULTS: Anterior chamber depth and anterior chamber angle width were significantly smaller in study group (p < 0.00001, U-test). With excluded preoperative risk factors: Fuchs dystrophy, acute angle closure glaucoma attack history the significant differences were also observed (p < 0.01). In Fuchs' dystrophy and intraoperative complication subgroups comparison these two anterior chamber parameters were smaller too (p < 0.001). Anterior chamber width was also smaller in study group with p = 0.001. Central corneal thickness was higher in study group with p = 0.013. After exclusion of patients with Fuchs' dystrophy there was no difference in comparison (p = 0.34). The difference in total axial length comparison was insignificant (p = 0.18). Relative anterior microphthalmos was diagnosed in 31 patients of study group (62%) and in 17 of control (34%). CONCLUSIONS: Small anterior chamber dimensions and higher central corneal thickness due to Fuchs' dystrophy are factors influencing the risk of PCE/ACE development. PMID- 23461151 TI - [The influence of sensory deprivation on binocular vision after bilateral cataract extraction with intraocular lens implantation]. AB - PURPOSE: Cataract extraction with intraocular lens implantation is one of the most frequent surgical procedures. However, benefits associated with the surgery may be restricted by binocular vision disorders. The purpose of the study is to evaluate binocular function of vision in patients after bilateral cataract extraction in relation to the length of period between surgeries. MATERIAL AND METHODS: The study included 50 patients operated twice, due to bilateral cataract. All patients were examined six weeks after the second surgery and divided into three groups according to the operational interval (< 12 months, 12 24 months, > 24 months). Presence of asthenopic symptoms, distance and near squint angle, fusional amplitudes, stereopsis and convergence were evaluated. RESULTS: Asthenopic symptoms were present respectively in 8% (n = 1), 42% (n = 8), 37% (n = 7) of patients in groups 1, 2 and 3. Exophoria was found in 16.6% (n = 2) of cases in the first group, 17.5% (n = 3) in the second group and 31.6% (n = 6) in the third group. There was no significant difference in average prismatic fusional vergence range between groups and a negative correlation between amblyoscopic fusional convergence and the period between surgeries was found. Mean stereopsis was 76.7 +/- 62.1; 89.5 +/- 66,2; 76.8 +/- 66.7 seconds of arc in subsequent groups. Average convergence was: 6.8 < or = 6.9 cm in the first group, 7.1 +/- 3.9 cm in the second group and 7.5 +/- 5.0 cm in the third group. CONCLUSIONS: There are significant differences in binocular vision parameters in patients after bilateral cataract extraction in relation to the period between surgeries. The prolongation of this time was connected with increased number of patients complaining to asthenopic symptoms, with exophoria and reduced amblyoscopic fusional convergence. PMID- 23461152 TI - [Evaluation of colour vision according to type of implanted artificial foldable intraocular lens]. AB - PURPOSE: The aim of research was comparing the colour vision of patients with blue light filtering artificial lens to the patients with implant without blue light filter. MATERIAL AND METHODS: 99 patients (120 eyes) divided on three groups were examined. 40 patients (40 eyes) after cataract surgery with implantation of blue light filtering lens were the first group. 39 patients (40 eyes) who had implanted lens without filter were the second group. 20 patients (40 eyes) with own transparent lens were the third group. Farnsworth-Munsell 100 Hue test was used in research. Each patient made test on thirtieth day after cataract surgery. RESULTS: Following average total error score (TES) values in groups were observed: the first group--60.66, the second group--83.71, the third group--61.55. Average axis of disorder in blue-yellow range was following: patients after cataract surgery with implantation of blue light filtering lens- 5.48, patients with implant without blue light filter--7.28, control group--5.74. CONCLUSIONS: 1. Kind of artificial intraocular lens has meaning in colour vision at pseudophakic patients. 2. Blue light filter of artificial intraocular foldable lens advantageously effects perception of colours. 3. Lack of blue light filter in artificial intraocular lens gets worse colour vision especially in blue-yellow range. PMID- 23461153 TI - [Are biometric parameters of anterior segment of the eyeball influenced by type 2 diabetes?]. AB - PURPOSE: To answer the question whether biometric parameters of anterior segment of the eyeball are influenced by type 2 diabetes, at the stage when the lens is still transparent, so before cataract development. MATERIAL AND METHODS: Fifty subjects (28 women and 22 men), at the age of 63.3 +/- 11.3 years were enrolled in this prospective study. They were divided in 2 groups: patients with type 2 diabetes (24 subjects) and analogous age group in good general health - control group (26 subjects). None of the tested individuals presented lens opacities. The planned biometric measurements included: central corneal thickness, anterior chamber depth and axial lens thickness. The data were statistically analyzed. RESULTS: There was no difference between the groups of both proven and potential parameters that are associated with biometric measurements of the anterior segment of the eyeball, such as: gender, age, smoking and axial length of the eye. In diabetic patients, as opposed to the subjects in the control group, statistically significantly increased lens thickness (4.78 +/- 0.50 mm vs 4.43 +/ 0.50; p = 0.016), central corneal thickness (561.5 +/- 31.6 microm vs 542.2 +/- 35.2; p = 0.047), and the tendency for shallow anterior chamber (3.06 +/- 0.40 mm vs 3.22 +/- 0.38; p = 0.159), were observed. In patients with diabetes there was no association of the biometric parameters values with the duration of diabetes and presence of diabetic retinopathy. CONCLUSIONS: Type 2 diabetes contributes to increased axial corneal and lens thickness at the stage when the lens is transparent, albeit it does not significantly affect anterior chamber depth. PMID- 23461154 TI - [Optic nerve head drusen in children--visual function and OCT outcomes]. AB - PURPOSE: To evaluate the effect of optic nerve head drusen on retinal nerve fiber layer (RNFL) thickness in children, with the use of optical coherence tomography (OCT). MATERIAL AND METHODS: 21 patients (mean age 13.9 years) with optic nerve head drusen were studied prospectively. For statistic comparison a group of 15 control subjects (mean age 14.1 years) participated. Ophthalmologic examination, automated visual field testing and optical coherence tomography were performed in each patient. For statistical analysis we used Shapiro-Wilk and U Mann-Whitney tests. RESULTS: In the OCT measurements the nasal RNFL was significantly thinner as compared to the reference group. Neither statistically significant thinning of global RNFL between groups nor relation between subjects age and RNFL thickness was found. CONCLUSIONS: Optic nerve head drusen can lead to visual function defects, therefore early and correct diagnosis is mandatory. Optical coherence tomography is a usefull diagnostic tool used to determine the cause of disc elevation, which is especially important in childhood, when drusen can cause disc to appear papilledema-like. Overall OCT appears to be a non-invasive, sensitive and early-indicating method of RNFL thinning. PMID- 23461155 TI - Change in ocular refraction after tropicamide cycloplegia in preschool children. AB - PURPOSE: The aim of the study was to evaluate changes in ocular refraction after 1% tropicamide and its efficacy in diagnosing refractive errors in preschool children. MATERIAL AND METHODS: 116 children (232 eyes) at the age of 5 to 6 years participated in the study. An objective examination of refraction using autorefractor before and after 1% tropicamide cycloplegia (2 x 1 drop of the agent instilled 5 min apart) was performed in the study. RESULTS: After the instillation of tropicamide, the spherical component of the refractive error significantly increased by +0.78 D, while the cylindrical component (i.e. its power and axis) remained unaltered. In examining the refractive error, the mean value of the spherical component in children at the age of 5 to 6 years amounted to +1.55 D, in the cylindrical component mean value was -0.51 D, and the axis was 102 degrees. CONCLUSIONS: 1% Tropicamide appears an effective cycloplegic agent in preschool children, excluding children with high hyperopia, anisometropia, or strabismus. PMID- 23461156 TI - [Polypoidal choroidal vasculopathy with spontaneous regression of subfoveal changes--case report]. AB - PURPOSE: To report a patient with polypoidal choroidal vasculopathy (PCV) with spontaneous regression of subfoveal changes during follow-up. MATERIAL AND METHODS: The seventy six years old men was referred to the treatment of exudative type of age related macular degeneration (AMD) in the RE. The routine ophthalmological examination, the optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA) were performed. RESULTS: Decreasing of visual acuity of the RE and abnormal result of the Amsler test, hemorrhagic and exudative changes near inferior-temporalis vascular arcade were observed. Intraretinal fluid in the OCT was noted. FA revealed parapapillaris changes suggesting CNV. ICGA showed the presence of branching vascular network extending from choroidal vasculature (BVN) and polypoidal and aneurysmal vascular terminal lesion (PL) localized under retinal pigment epithelium (RPE). CONCLUSIONS: Based on the results PCV was diagnosed and the patient was referred to laserotherapy. Due to the regression of the eye fundus changes during the period of observation, confirmed by control OCT and FA the treatment was not implemented. PMID- 23461157 TI - [Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)--a report of three cases]. AB - PURPOSE: The aim of this study is to present and discuss three cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). MATERIAL AND METHODS: Three young patients (one woman and two men), developed rapid loss of vision in one or both eyes. Basic ophthalmic examination and additional diagnostic methods including: fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT) and human leucocyte antigen (HLA) class I test were performed. RESULTS: Based on the results of performed investigations the diagnosis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was established. Fundus examination revealed characteristic multifocal, placoid, creamy or grey/white subretinal lesions. Fluorescein angiography in acute stage of the disease demonstrated early hypofluorescence followed by later hyperfluorescence of the lesions. Indocyanine green angiography demonstrated hypofluorescence in all stages of the angiogram. In one case, class I HLA-B7 antigen was found. In all presented cases visual acuity markedly improved with general glicocorticosteroids. CONCLUSIONS: Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is characterized by rapid, but transient loss of visual acuity. Diagnosis is established in fluorescein angiography and prognosis for recovery is good, however in cases with poor visual acuity glicocorticosteroids might be beneficial. PMID- 23461158 TI - [Bilateral choroidal hemangioma--case report]. PMID- 23461159 TI - [Multiple evanescent white-dot syndrome--case report]. AB - The aim of the work is to present a case report of multiple evanescent white-dot syndrome in the left eye of 34 years old female. It's a rare disease entity which runs as a idiopathic inflammation of retina and choroid. Additional investigations which are performed in the clinic such as fluorescein angiography, indocyanine green angiography validated a primary diagnosis in this case. Intravenous infusion of methylprednisolone was administered with oral steroid continuation of therapy during four weeks. A quick visual improvement to 1.0 in the left eye was obtained with removalof characteristic for MEWDS alterations in additional investigations. PMID- 23461160 TI - Retinal degenerative diseases--mechanisms and perspectives of treatment. AB - Retinal degenerative diseases are an extensive group of ocular diseases, leading to vision disorders and finally irreversible vision loss. They are an significant problem, because degenerative processes exist in common ocular disorders like glaucoma or age-related macular degeneration and many other less frequently occurring disorders. In this article, we present mechanisms leading to retinal degeneration like excitotoxicity, oxidative stress, inflammation and summarize the latest reports concerning neuroprotection in the treatment of retina degenerative diseases. PMID- 23461161 TI - [New drug VEGF Trap-Eye--Eylea--and its use in the treatment of age-related macular degeneration, central retinal vein occlusion, diabetic macular edema, and choroidal neovascularization secondary to pathologic myopia]. AB - Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of choroidal and retinal neovascularization. Anti-VEGF therapy changed the standard-of-care for ocular disease with neovascularisation. This article presents one promising new drug--VEGF Trap-Eye--and results of clinical trials evaluating its efficacy in the treatment of wet age-related macular degeneration, central retinal vain occlusion, diabetic macular edema and choroidal neovascularization secondary to pathologic myopia. PMID- 23461162 TI - New approach to diagnosis and treatment of Acanthamoeba keratitis--systematic review of literature. AB - PURPOSE: To present new methods of diagnosis and treatment of Acanthamoeba keratitis. MATERIAL AND METHODS: Searching Medline base for articles in English publicated since 2006 till the beginning of 2011, describing the way and results of diagnosis and treatment Acanthamoeba keratitis. Publications include studies, reviews as well as case reports concerning discussed subject. RESULTS: 14 publications were found and used to present miscellaneous methods utilized nowadays to identify the reason of Acanthamoeba keratitis with simultaneous evaluations of its' sensitivity and specificity. The review comprises improvements of laboratory diagnosis as well as corneal imaging systems helpful to diagnose infectious keratitis. 17 publications were quoted to elaborate results of pharmacological protocols as well as surgical procedures of Acanthamoeba keratitis treatment. Outcomes of experimental investigations were also cited. CONCLUSIONS: As none of presented methods of diagnosis and treatment of Acanthamoeba keratitis have become a standardized guideline jet, still there is a great need to look for new ones. PMID- 23461164 TI - [Applications of various iris retractors]. AB - Fast development of ophthalmology which can be observed in the recent years, is connected with the development of modern technology used in the diagnostics and treatment of ocular diseases. Eyes with a narrow pupil, which doesn't respond to standard pharmacologic management applied preoperatively, are a challenge for any ophthalmic surgeon. The purpose of the study is to describe various surgical devices used for achieving adequate intraoperative pupillary diameter in cataract patients who for various reasons do not respond to pharmacologic mydriasis. PMID- 23461163 TI - [Modern knowledge based about glistening phenomenon in artificial intraocular lenses]. AB - Glistening formations is relatively common phenomenon in acrylic IOLs that appears as a tiny clear to white sparkling areas within the material of the lens optic. While the process of glistening include not only monofocal IOLs but also multifocal IOLs and phakic IOLs and even can occur in IOLs made of other materials, problem seems to be clinically crucial. Publication comprises contemporary knowledge about glistening phenomenon. glistening phenomenon, acrylic intraocular lens, phacoemulsification. PMID- 23461165 TI - The role of femtolaser in cataract surgery. AB - Having been very successful in corneal surgery, femtolasers were recently introduced into the surgery of crystalline lens. The most important indications and advantages include: perfectly centered and sized capsulotomy, liquefaction of softer lenses and fragmentation of harder lenses which allows for chopping the nucleus without the use of phaco energy. Femtolaser can also be used for creating corneal wounds (tunnels) of any size at any location, and in order to manage the preoperative astigmatism using arcuate incisions at the desired depth within the cornea. Because of controlled steps in cataract surgery, wide acceptance and spread is to be expected. PMID- 23461166 TI - [New aspects of safety assessment and food contamination with antibiotics of tetracycline group in the light of harmonization of hygienic standards in Russia and Customs Union with the international standards]. AB - To address the issue of harmonization of Russian MRLs for tetracycline in food and on the basis of the tasks of preserving the value of hygienic standard for the more restrictive level than similar standards of the Codex Alimentarius Commission in this survey we analyzed the evidences of the negative effects of subingibitory amounts of these antibiotics (lying below the MIC for clinically relevant microorganisms). The inadequacy of the microbiological JECFA ADI and the necessity of using of methodology of analyzing the effects of biological active substances in small doses for assessing the risk of food contamination of tetracycline subingibitory concentrations were demonstrated. Current scientific information on the functions of antibiotics as signaling molecules in the microbial world and the role of tetracycline as a leading factor in the regulation of transcription in microorganisms and activation of the horizontal transfer of resistance genes transferred to the family of conjugative transposons Tn916-Tn1545 also was reviewed in paper. Evidence-based data regarding the basic contribution of subingibitory concentrations of tetracycline in the spread of worst transmissible type of antibiotic resistance and the formation of new pathogens, associated with it, are represented. To reduce the risk of direct adverse effects on microbial ecosystem in the human body and its habitat, and to minimize the indirect risk of new infections, the necessity of saving the current Russian level residues of tetracycline (< or = 0.01 mg/kg of product), which is low by contrast to the Codex MRLs (< or = 0.1-1.2 mg/kg), was proved. Tetracycline concentrations in food, regulated in Russian Federation, below 0.1 MIC for clinically significant microorganisms which aren't capable to initiation of the above described negative changes. PMID- 23461167 TI - [Hygienic and toxicological safety assessment of nano- and micro-dispersed manganese oxide (III, IV)]. AB - The findings of the experimental study performed within the preliminary hygienic and toxicological assessment of nanodispersed manganese oxide (III, IV), which was endogastrics administered to white nonlinear mice once, showed that, under acute oral exposure to manganese oxide, nanodispersed particles were 2,6-fold more toxic and cumulative (class 3, according to the oral LD50 values) than dispersed solution with micro-sized particles (0.4-592 microm, class 4). Endogactric exposure to nanodispersed solution of manganese oxide (III, IV) in organisme produced such negative health effects as vasodilation and plethora, pathological inclusions and increased cell aggregation, which increased and became more prevalent with higher doses. The prediction of chronic toxicity parameters demonstrated that threshold and NOAEL doses for nanodispersed solution were 1.6 and 0.26 mg/kg, respectively, which are 2.3 times lower than for finely divided solution of manganese oxide (III, IV). PMID- 23461168 TI - [Characterization of fullerene C60 peroral toxicity to rats in the 92-day experiment]. AB - Toxicity of fullerene C60 in male Wistar rats under conditions of a daily intragastric administration at doses of 0.1; 1 and 10 mg/kg body weight for 92 days was studied. Integral, biochemical, physiological, hematological, immunological indicators were determined that characterized the body condition of animals together with fullerene C60 biodistribution in organs and tissues of rats. Majority of the results didn't show any influence of fullerene C60 on animals treated with it in the whole range of doses studied. On the other hand, some of the data not related to the action of the components used in carrier solution, demonstrated dose-dependent variation: found increased activity on 21 35% in the CYP2B1 at doses of 1 mg/kg and 10 mg/kg body weight, and reduced concentration of uric acid and increasing concentrations of urea at 10 mg/kg body weight. Nevertheless, these changes were within the physiological range of variability. However, it is worth noting an important significant (p = 0.02) increase of the absorption for antigenic proteins in the digestive tract in animals treated with fullerene C60 at a dose of 10 mg/kg, suggesting a marked effect on the intestinal wall. PMID- 23461169 TI - [The study of FTO rs9939609-gene polymorphism in the Sverdlovsk Region]. AB - Recently independent studies, including genome-wide scans, have shown that the rs9939609 single-nucleotide polymorphism (SNP) in the first intron of the fat mass and obesity associated (FTO) gene were significantly associated with obesity in populations of European origin, in certain Asian (e.g.,Japanese and Chinese) and African American populations. In this study we examined the association between rs9939609 FTO variant and obesity related parameters in 394 individuals (262 males and 132 females; ages 20-70 years) from the Sverdlovsk area, Russia. A SNP variant rs9939609 was genotyped with the use of an allelic discrimination assay. The TaqMan-based real-time PCR method was applied. The prevalence of TT, TA and AA genotypes of rs9939609 FTO gene of this study was 34%, 47.5%, 18.5%, respectively, the minor A-allele frequency was 42.3%. In comparison to males, females had significantly higher the frequency of minor A-allele and AA genotype. The AA genotype was significantly more frequent in obese individuals (defined as body mass index > or = 30 kg/m2) than in non-obese (27.7 and 13.0%, respectively). Compared to the carriers of TT genotype, the likelihood of obesity was 3.0 for the carriers of AA genotype and 1.73 for the carriers of AA+AT genotype. These results confirm that genetic variation (rs9939609) FTO gene contributes to the etiology of obesity in the Sverdlovsk area. PMID- 23461170 TI - [Effectiveness of dietary supplements--biologically active substances in patients with obesity]. AB - With the help of clinical, anthropometric and anthropometric method examination the study estimation of the effectiveness of a new food additives "Vita-Plant herbal tea N16"--with overweight and obesity. Components of a new herbal tea rich in biologically active compounds, flavonoids, phenolic acids, vitamin C and B, carotenoids, trace elements iodine, zinc, molybdenum, manganese, iron, etc. The studies were conducted on 53 patients with overweight and obesity, which were divided into two similar groups of patients were on standard low-calorie diet. The main group (28 patients) received a glass of analyzed herbal tea two times a day for 4 weeks. The control group (25 patients) were in similar conditions, but did not receive this herbal tea. Comprehensive clinical and laboratory evaluation of patients included a study of the dynamics of clinical symptoms, anthropometric data and blood biochemical parameters. Studies have shown a beneficial effect of herbal tea components on metabolism, anthropometric parameters and clinical symptoms in patients with overweight and obesity. This gives us grounds to recommend a new kind of herbal tea in the dietary of patients with this pathology. PMID- 23461171 TI - [The morbidity dynamics of acute intestinal infections in the Northern Administrative District of Moscow]. AB - Acute intestinal infections morbidity of the Northern Administrative District of Moscow population was analyzed as a part of the socio-hygienic monitoring. Long term dynamics and growth, both among total and child population (respectively on 29.5 and 72.38%) were shown. Also presents the results of laboratory tests of food and food raw materials by microbiological parameters. The percentage of unsatisfactory results on microbiological indicators in 2010 year was 5.0% (in 2009 - 5.5%, in 2008 - 7.5%). It is known, that at patients with intestinal infections not only the socio-hygienic conditions have a significant impact on the epidemic process, but also subjective factors, i.e. level of hygiene knowledge and behavior of the population. Often outbreaks of acute intestinal infections are the result of violations of food sanitation regulations among workers engaged in food production or food trade. According to the authors' opinion the current training system of decreed population groups, especially the nature of which is associated with the production, storage, transportation and food trade and drinking water needs further development and improvement. PMID- 23461172 TI - [Assessment of biological value of protein-peptide ingredients of functional drink in growing rats]. AB - The abstract is devoted to research in vivo on the growing rats of biological value of protein hydrolyzate of meat-and-bone residues of poultry, fortified by defatted cow milk. Cow milk casein was chosen as a template. PER was determined by growing method, based on lab animals' growth rate assessment. True protein digestibility was determined by balance method. The indices were fixed individually for each animal and then the group mean value was calculated. Accessibility of protein hydrolyzate of meat-and-bone residues of poultry fortified by defatted cow milk equals 100%. PER is 1.25 lower in comparison with casein, which can be explained by a lower retention. PMID- 23461173 TI - [Effects of taurine supplementation on apoptosis, lipid peroxidation and proteomic pools of subcellular fractions of rat hepatocytes in experiment]. AB - During research specific proteomic pools of subcellular fractions of rats hepatic cells typical for different states of ontogenesis were identified. Taurine supplementation during early ontogenesis leads to a production of a catalase in rats' microsomes, that may be an evidence of activation of antioxidant defense system. Majority of proteomic markers (C-type lectin, SH2B1, protein phosphatase 1), which was investigated during taurine supplement, are rather identify features of energy homeostasis, than common assessment of apoptosis or expression certain set of proteins. This fact confirms the requirement of using proteomic diagnostic during nutriproteomic studies that allows defining efficiency and probable risks of using biological active substances in nutrition. PMID- 23461174 TI - [Effect of coenzyme Q10 supplementation on apoptosis, free radical oxidative processes and proteome pool of microsomal and cytosol fractions of hepatocytes using food ration with different lipid component]. AB - Our aim was to analyze biochemical mechanism in regulation and adaptation to feeding with omega-3 and omega-6 PUFA plus coenzyme Q10-based diet in rats. The rats were supplemented with Co Q10 (100 mg/kg b.wt.) for 12 month. Male rats were fed a control, control + Q10, fish oil + Q10 palm oil + Q10 and flax oil + Q10 diet. The learning and tests were monitored in 1st, 3rd, 6th and 12th month after the start of feeding. There was studied the content of lipid peroxidation products in the liver, the level of their potential substrates polyunsaturated fatty acids of omega-3 and omega-6 families and MEC (metabolism effectiveness coefficient) index value. Growth of relative number of hepatocyte in the state of late apoptosis has been detected in rats receiving fish oil, linseed oil and palm oil as compared to the control group at the age of 1 and 3 months. In later period no differences in the invested indices, that can be the result of impact of CoQ10 and adaptation of organism to diet. Proteomic studies of microsomal fraction of hepatocytes in rats have found differences in the manifestation of catalase and cetochrome b5, associated both with age of animals and type of fat in diet. Proteomic analysis of cytosolic fraction revealed the expression of c type lectin in the later stages of ontogeny. The levels of lipid peroxidation markers obtain to minimum at 3 month in serum and at 6 month in liver. The specific proteomic changes of influence of diet composition were identified during the research. PMID- 23461175 TI - [Subpopulation content of lymphocytes in peripheral blood in patients with diabetes mellitus type 2 and obesity]. AB - In the present study was determined the relative quantity subpopulations of lymphocytes, activated T-lymphocytes and CD95-antigen (Fas/APO-1) expression on lymphocytes in the peripheral blood of patients with diabetes mellitus type 2 (DM 2) and obesity in comparison with the healthy persons. The cells were analyzed by the method of flow cytometry using Beckman Coulter FC 500 cytometer. The following of cells subsets: CD19+, CD3+, CD3+CD4+, CD3+CD8+, CD3-CD16+CD56+, CD3+CD16+CD56+, CD3+CD25+, CD3+HLA-DR+, CD45+CD95+ were investigated. In this research was establish the rise of immunoregulatory index (CD3+CD4+/CD3+CD8+) in consequence of decrease the percentages of cytotoxic T-lymphocytes in patients with DM2 and obesity in comparison with the healthy persons. In the peripheral blood of patients with DM2 and obesity were observed a greater level of activated T-lymphocytes (CD3+HLA-DR+), that reflect the increase activity of T-cell immunity. The direct correlation was found between the increased quantity of NKT cells (CD3+CD16+CD56+) and contain of triglicerides in the peripheral blood of patients with DM2. In these patients also was noted a greater level of lymphocytes expression of CD95-antigen in comparison with the patients with obesity and healthy persons. These results suggest that immune mechanisms play the important role in pathogenesesis of DM2 and obesity. PMID- 23461176 TI - [Food fortified with vitamins: the history and perspectives]. AB - The recommended daily intakes of vitamins in different countries have been compared. The data on consumption of vitamins and vitamin status are submitted. It is noted that since 2008 the values of recommended daily intakes of vitamin antioxidants C and E and folate in Russia as in other countries has been significantly increased. The recommended vitamin D consumption in Russia has been increased 2-3-fold as in most European countries and USA, while vitamin A recommended intake, on the contrary, has been reduced by 10%. Monitoring of vitamin status of various groups of adult population (by vitamin serum blood level evaluation) during the period since 2003 to 2011 has shown that that since 2003 deficiency of B group vitamins takes place in 10-47% of surveyed, vitamin D insufficiency was detected in 20.7% of adults. Thus the deficiency of these micronutrients has been determined much more often than the deficit of vitamins E and C (2.8-11%). The key causes of vitamin deficiency among the population in current conditions have been discussed. The main ways of increasing of diet vitamin value by means of fortified foods usage or/and vitamin and mineral complexes intake have been considered. The effective and safe levels of food enrichment have been examined. Harmonized with the EU documents and Codex Alimentarius acting sanitary rules and regulations which govern the enrichment of food products of mass consumption with vitamins and minerals have been commented upon. The history of food enrichment (fortification) with vitamins and salt iodization in our country and abroad has been described. Basing on the experience of several countries in which the mandatory enrichment of regularly consumed food products (flour, breakfast cereals) had compensated inadequate intake of vitamin D, group B, iodine and iron to a large extent, the conclusion on the feasibility and health benefits of fortified foods intake has been done. PMID- 23461177 TI - [Influence of combined lacto-vegetarian diet and selective beta-blocking agents on clinical and metabolic indices in patients with coronary heart disease]. AB - Clinical, hemodynamic and metabolic parameters were investigated for 42 patients with coronary heart disease, after myocardial infarct, recieved selective beta adrenoblockers. Patients were divided in two groups. The first group (24 patients) were given methoprolol (50 mg/daily) and antiatherogenic lacto vegetarian diet, the second (18 patients)--methoprolol (50 mg/daily) and standard mixed antiatherogenic diet. After the treatment, positive changes clinical and gemodynamic parameters were observed in both groups of patients. Among the clinical symptoms, a more pronounced decrease in blood pressure in the patients on vegetarian diet and a more significant increase in their exercise tolerance. The level of total cholesterol on the serum of blood decreased by 16%, low density lipoproteins cholesterol decreased by 18%, the atherogenic coefficient (KA) decreased by 31%, only in vegetarian group. High-density lipoprotein cholesterol increased in vegetarian group, by 14% and decreased in control group. Balanced antiatherogenic lacto vegetarian diet in patients with coronary heart disease prevents the hyperlipedemic effect caused by the selective beta adrenoblockers and it is an agent for preventing its negative effect on lipid metabolism. PMID- 23461178 TI - [The clinical and immunological manifestations of food intolerance in obese patients]. AB - The clinical and immunological manifestations of food intolerance in obese patients were studied. Food intolerance was diagnosed in 32.6 and 33.4% in obese patients stage 2 and stage 3 respectively, and was basically determined by 13 proteinaceous food products. The changes in immune status in obese patients created conditions for development of food intolerance. The timely diagnose food intolerance allows to personalize the diet therapy. PMID- 23461179 TI - [Body composition in patients with different degree of obesity before and after dietetic correction]. AB - The study included 400 patients with I-III obesity degree. All patients were tested before and after hypocaloric diet with energy value of 1600 kcal/day within 2 weeks. The bioimpedance analysis was spent on device "Inbody 720". The application of the hypocaloric diet is accompanied by clinically significant decrease in body weight in patients with obesity mainly due to the fatty component and visceral fat area and positive dynamics of clinical and biochemical parameters. PMID- 23461180 TI - [Some health parameters of working population in Perm area, and objectives to health improvement for recent years]. AB - The article covers objectives of health preservation, occupational longevity and complex development of industrial medicine in Perm area. PMID- 23461181 TI - [Concomitant influence of occupational and social risk factors on health of workers engaged into powder metallurgy]. AB - Results of health risk evaluation in workers engaged into powder metallurgy, using complex of hygienic, medical, epidemiologic and sociologic studies, enable to define priority occupational and social risk factors, to assess degree of their influence on the workers' health and to identify occupationally induced diseases. PMID- 23461182 TI - [Fractional and component composition of dust in the air of workplace at machinery enterprise]. AB - The authors present results of assessment of fractional and component composition of dust entering workplace of machinery enterprises. The results prove topicality of data accumulation on actual contents of dusts for more reliable and precise evaluation of the dusts mixture influence on the workers' health. PMID- 23461183 TI - [Respiratory diseases in metallurgy production workers]. AB - The authors identified features of respiratory diseases in workers of various metallurgy workshops. Cause-effect relationships are defined between occupational risk factors and respiratory diseases, with determining the affection level. PMID- 23461184 TI - [Cardiovascular risk factors in workers of oil and gas extraction enterprises]. AB - The article deals with data on levels of biochemical markers of response to chemical risk factors (benzol, toluene) of cardiovascular diseases in workers engaged into oil and gas extraction. Findings are reliable differences between the workers groups in serum benzol and toluene levels, in classic biochemical effect markers of cardiovascular diseases (total cholesterol level, low density lipoproteins, uric acid), in activity of lipid peroxidation products deteriorating endothelial dysfuction. PMID- 23461185 TI - [Features of diurnal profile of blood pressure in workers having serum aromatic hydrocarbons level]. AB - Features of diurnal profile of blood pressure in workers having serum level of benzol and ethylbenzene are high systolic and diastolic arterial blood pressure during the day, index of systolic arterial pressure time and index diastolic arterial pressure time was also high. These features should be considered in anti hypertensives prescription. PMID- 23461186 TI - [Expression of membrane and intracellular markers in workers exposed to phenols]. AB - The authors evaluated influence of phenol, o-cresol, m-cresol and p-cresol on cellular immunity in apparatus operators engaged into chemical production. Detection covered significant membrane and intracellular markers characterizing peculiarities of cellular immune reactions in contamination with phenols (CD4+ deficit, hyperproduction of FoxP3 and CD25+). PMID- 23461187 TI - [Immunologic and genetic markers of exposure to aromatic hydrocarbons in workers]. AB - Workers exposed to aromatic hydrocarbons appeared to have prevalence of heterozygous variants of CYP1A1 gene (9893 A/G) and tumor necrosis factor gene reliably higher vs. the reference group 2.5 and 3.3 times respectively, and level of anti-benzene antibodies (IgG) increased vs. the reference group. The data presented demonstrate negative immunogenetic associations of aromatic hydrocarbons influence on oil extraction operators. PMID- 23461188 TI - [Congenital abnormalities in children whose parents were exposed to methanol and formaldehyde]. AB - The authors proved relationship between congenital abnormalities in children and influence of chemical factors (methanol and formaldehyde production) on the parents. Higher risk of congenital abnormalities was seen: PR = 5.6 (chi2 = 3.54; p = 0.00001), EF = 0.95. These disorders could be connected with work conditions- exceeded MAC for methanol 3.9-fold, that for formaldehyde--2.4-fold. PMID- 23461189 TI - [Features of bone and muscular diseases in accordance with physical exertion level in workers]. AB - The authors studied changes in development and structure of bone and muscular disorders in industrial workers of Perm area. The workers' examination considered features of physical overload during the working process. The authors revealed developmental peculiarities of bone and muscular system in various occupational groups of metallurgists, oil extractors, machinery building workers. The article shows necessity of interdisciplinary approach and observation of the workers to prevent progression of bone and muscular disorders. PMID- 23461190 TI - [Mathematic concept model of accumulation of functional disorders associated with environmental factors]. AB - The mathematic concept model presented describes accumulation of functional disorders associated with environmental factors, plays predictive role and is designed for assessments of possible effects caused by heterogenous factors with variable exposures. Considering exposure changes with self-restoration process opens prospects of using the model to evaluate, analyse and manage occupational risks. To develop current theoretic approaches, the authors suggested a model considering age-related body peculiarities, systemic interactions of organs, including neuro-humoral regulation, accumulation of functional disorders due to external factors, rehabilitation of functions during treatment. General objective setting covers defining over a hundred unknow coefficients that characterize speed of various processes within the body. To solve this problem, the authors used iteration approach, successive identification, that starts from the certain primary approximation of the model parameters and processes subsequent updating on the basis of new theoretic and empirical knowledge. PMID- 23461191 TI - [Multipotent mesenchymal stromal and immune cells interaction: reciprocal effects]. AB - Adult multipotent mesenchymal stromal cells (MMSCs) are considered now as one of the key players in physiological and pathological tissue remodeling. Clarification of the mechanisms that mediate MMSC functions, is one of the most intriguing issues in modern cell physiology. Present Review summarizes current understanding of the MMSC effects on different types of immune cells. The realization of MMSC immunomodulatory capacity is considered as a contribution of direct cell-to-cell contacts, soluble mediators and of local microenvironmental factors, the most important of which is the partial pressure of oxygen. MMSCs and immune cells interaction is discussed in the terms of reciprocal effects, modifying properties of all "partner cells". Special attention is paid to the influence of immune cells on the MMSCs. "Immunosuppressive" phenomenon of MMSCs is considered as the integral part of the "response to injury" mechanism. PMID- 23461192 TI - [Involvement of Wnt signaling in hippocampal plasticity]. AB - Wnt signaling is a signal transduction pathway involving peptides of Wnt family as key molecules. In this review, the data on the role of canonical and non canonical Wnt pathway in hippocampal structural and synaptic plasticity have been analyzed. Wnt-mediated signal transduction is involved in normal functional plasticity, and the disturbances in Wnt-mediated mechanisms form a basis for the development of cerebral pathologies. A special attention is devoted to glycogen synthase kinase 3beta (GSK-3beta), one of most important from both plasticity and pathology perspectives component of the canonical Wnt pathway. The studies in this area, besides their fundamental significance, are important for translation to the medicine, and the key components of the Wnt pathway are potential targets for the developmentn of pathogenetical therapeutics for a number of socially significant cerebral pathologies. PMID- 23461193 TI - [Recovery of the atrophied muscle: from protein degradation to synthesis]. AB - The enhancement of atrophied muscle recovery after coming back to normal motor activities (landing of the spacecraft, withdrawal of the cast etc) is very important problem of rehabilitation as well as space medicine. Along with the recovery of the gravity-dependent motor control system the regrowth of the muscle mass seems to be the key event. This regrowth cause recovery of the muscle performance. The present review is dedicated to the structural and functional events, observed during 7 days after exposure of an animal to gravitational unloading (mainly in experiments with the hindlimb suspension model). The state of the main signaling pathways in muscle fibers is also considered. The data presented in the review allow to imagine how the destructive and synthetic events do interact in the initial period of recovery. The work hypotheses on the key triggering signaling mechanisms are also put forward. PMID- 23461194 TI - [Summation of GABA- and glutamate-mediated currents in rat cortical neurons]. AB - Whole-cell patch clamp recordings from isolated neurons from rat prefrontal cortex have been made to study the interaction of responses induced by application of GABA and glutamate. Two different pipette solutions were used in this research: the first one was based on CsCl, while the second one was CsF based. With CsCl-based pipette solution being used, co-application of GABA (200 microM) and glutamate (200 microM) resulted in producing a total current smaller than the sum of the two individual responses. But with CsF-based pipette solution being used, the response to co-application of GABA (200 microM) and glutamate (200 microM) was equal to the sum of the two individual responses. These results suggest that there is a cross-modulation between GABA- and glutamate-mediated responses. PMID- 23461195 TI - [Noradrenaline role in regulation of dopamine-producing neurons in rat arcuate nucleus]. AB - Among most important functions of the neuroendocrine system is the regulation of reproduction, including the inhibitory control of prolactin secretion by dopamine (DA) synthesized in the arcuate nucleus (AN). Besides DA, noradrenaline (NA) contributes to this regulation though, in contrast DA, its concrete functional role remains to be uncertain. In the previous studies, it has been suggested that NA inhibits compensatory synthesis of DA in DA-producing neurons of AN under the failure of the dopaminergic system though no evidence were obtained. Therefore, the goal of this study was to specify the role of NA in the regulation of DA producing neurons in AN. Two pharmacological models were used to this aim: a) switching off dopaminergic and noradrenergic neurons and their afferents in An or b) switching of only dopaminergic neurons and afferents that allowed us to recognize NA role in the complex catecholaminergic regulation of prolactin secretion. According to our data, the maintaining of the noradrenergic innervation of AN under the neurotoxin-induced failure of dopaminergic neurons resulted in the decrease of the expression of tyrosine hydroxylase (TH), the first enzyme ofDA synthesis, thereby enhancing DA deficit. This is considered as direct evidence of noradrenergic inhibitory control of TH expression in the neurons of AN. PMID- 23461196 TI - [The effect of ionotropic glutamate receptor antagonist on pentylenetetrazole indused seizures in Krushinsky-Molodkina rats]. AB - Krushinsky-Molodkina (KM) rats exhibit inherited susceptibility to audiogenic seizures and auditory stimuli induce generalized tonic-clonic seizures that resemble human epilepsy. The aim of this study was to compare the neurological manifestations of pentylenetetrazole (PTZ)-induced seizures in Wistar and KM rats to clarify the contribution of inherited susceptibility to audiogenic seizures, and to assess the anticonvulsant activity of NMDA receptor blockers memantine and IEM-1921 (1-phenylcyclohexylamine) in the PTZ-induced seizure model in KM rats. KM rats exhibited increased seizure severity relative to Wistar rats, and the death of KM rats was observed in 2.1 times more likely. Both NMDA receptor blockers showed anticonvulsant activity in the PTZ-induced seizure model, however IEM-1921 was more potent than memantine. IEM-1921 reduced the average intensity of the seizures by 2 points on a 5-point scale, and the total duration of generalized seizures was decreased by 41 times. IEM-1921 completely prevented the death of animals, while memantine only slightly decreased the mortality (68% in control conditions vs. 50% with administration of memantine). The results of the present study suggest that NMDA receptors are involved in the molecular mechanisms of seizures of different etiologies. PMID- 23461197 TI - [A study of participation of Hdj1 co-chaperone in the modulation of sleep and behavior using micro RNA technology in vivo]. AB - Data obtained for the last 12 years and modern hypotheses on key function of sleep and the role of Heat Shock Protein 70 kDa (HSP70) molecular chaperones family in sleep modulation are insufficient to determine assotiation of sleep quantity to the level of chaperones in the basic "center" of sleep in the ventrolateral preoptic area (VLPA) of the hypothalamus. In the present study, to reduce the content of Hdj1 major co-chaperone of Hsp70 in the VLPA we employed a novel approach based on lentiviral construction containing specific Hdj1-shRNA. The immunoblotting data showed that in 6 weeks after infection the level of Hdj1 in VLPA was reduced by 80% that was accompanied by a considerable increase in the quantity of slow-wave sleep and a marked decrease in the level of anxiety; earlier we found that elevation of Hsp70 level in the rat brain resulted in similar changes. It is suggested that the increase in quantity of slow wave sleep and the decrease in the level of anxiety can be related to a sustained disorder in the integration between molecular systems based on chaperones Hdj1 and Hsp70 and to a compensatory increase in the Hsp70 chaperone activity/level in VLPA. PMID- 23461198 TI - [Neuromuscular synaptic transmission at different stages of postnatal development in rats]. AB - On the nerve-muscle preparation of rats diaphragm muscle on different stages of postnatal development, the comparison of morphological features and functions of synaptic apparatus, including induced secretion time parameters was carried out. It was found that, along with the reduced, compared to the adult animals, area of nerve endings in the newborn the speed of the motor nerve excitation was slower, intensity of spontaneous and induced secretion of quantum fluctuations was reduced and real synaptic delays in the end plate were intense. Severe degree of acetylcholine quanta asynchronous secretion with longer open state of the ion channel in newborns synapses can compensate reduction in reliability of synaptic transmission due to a decrease of the quantal content of the postsynaptic response. PMID- 23461199 TI - [Gastroprotective action of corticotropin-releasing factor (CRF): involvement of glucocorticoids and CRF receptors type 2]. AB - The stress response involves the activation of two corticotropin-releasing factor (CRF) receptors types 1 and 2. The pituitary type 1 CRF receptors represent the primary receptors to activate the hypothalamic-pituitary-adrenocortical axis and, consequently, glucocorticoid production. Exogenous CRF induces an increase in glucocorticoid production and may protect the gastric mucosa against stress induced injury. Here we examined contribution of glucocorticoids and CRF receptors type 2 to gastroprotective effect of exogenous CRF. Gastric injury was induced by 3 him-mobilization (at 10 degrees C) in conscious rats or 3.5 h gastric ischemia-reperfusion in anaesthetized rats. Intraperitoneal administration of CRF at the doses of 1.25 or 2.5 Mg/kg increased plasma corticosterone levels and suppressed the occurrence of gastric erosion induced by each stimulus. Metyrapone injected before CRF caused an inhibition of CRF-induced corticosterone response and prevented the protective effect of CRF on the gastric mucosa against erosion caused by immobilization (at 10 degrees C). However, metyrapone injection did not influence the protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion. The protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion was prevented by the nonselective CRF receptor antagonist astressin and selective type 2 CRF receptor antagonist astressin2-B. The results obtained suggest that exogenous CRF may protect the gastric mucosa against injury through involvement of glucocorticoids and also through CRF receptors type 2. PMID- 23461200 TI - [Alpha-adrenergic regulation of two calcium signal pathways in adipocytes]. AB - Using selective receptor's agonist and antagonists we show that mouse white fat cells express alpha1A-, alpha2-adrenergic receptors, which activation with noradrenaline is capable of causing calcium responses different by formation mechanism. Adipocyte's calcium responses to alpha1-adrenoreceptor agonists are caused by alpha1A-type adrenoreceptor and suppressed by inhibitors of PLC dependent pathway. Calcium responses to alpha2-adrenoreceptors agonists are realized only in the presence of more than 200 microM of L-arginine and suppressed by inhibitors of NOS-PKG-RyR pathway. The incubation of cells with L arginine creates conditions for switching on the signal pathway with participation of eNOS --> NO --> sGC --> cGMP --> PKG --> CD38 --> RyR --> Ca2+ and for switching of the PLC - IP3R-dependent pathway. Adipocyte's calcium response to L-arginine represents a sharp impulse of the big amplitude and is mediated by alpha2-adrenoreceptors. L-arginine activating alpha2-adrenoreceptors and being the substrate of eNOS, realizes two functions in this pathway. PMID- 23461201 TI - [Permeability of pannexin 1 channels to large anions]. AB - It is widely accepted that ATP secretion in diverse cells involves pannexin 1 (Panx1) that functions as an ATP-permeable channel. We analyzed the permeability of Panx1 channels heterologically expressed in HEK-293 cells to a variety of anions, including ATP. As was demonstrated in electrophysiological experiments, relative permeabilities of studied species follow the sequence: C1- > MeSO4 > gluconate >> HEPES. This sequence suggests that ATP, which is more than twice as large as HEPES by mass, is most likely to be negligibly permeable to Panx1 channels. This inference was verified in experiments, where ATP secretion from Panx1-positive HEK-293 cells was assayed with the ATP-biosensor approach. It was shown that the heterologous expression of Panx1 in HEK-293, which normally are not ATP-secretive, did not endow transfected cells with the ability to liberate ATP in response to stimulation. Our data indicate that Panx1 alone forms anion channels with too low ATP permeability to mediate the secretory function. Nevertheless, the possibility still remains that certain ATP-permeable channels are heteromers of Panx1 and some other channel subunit(s). PMID- 23461202 TI - [Comparative analysis of gene expression in rat locomotor muscles and diaphragm]. AB - Gene expression profile in diaphragm in comparison to three principally different hindlimb muscles (soleus, red and white gastrocnemius) was studied using quantitative PCR. Expression levels of PGC-1alpha mRNA and myogenin mRNA in diaphragm were in accordance with its myosin phenotype and citrate synthase activity. However, diaphragm was characterised by atypically high content of MyoD mRNA as well as high content of IGF-1 mRNA and low content of myostatin mRNA. The latter two findings suggest high intensity of protein synthesis in diaphragm muscle fibers, although they have smaller cross sectional area than fibers in locomotor muscles. PMID- 23461203 TI - [Serotoninergic system morphofunctional aspects in control of postural and locomotion function]. AB - Different mediator systems including serotoninergic one can influence animal's locomotor behavior. It has been shown that the spinal cord in the absence of supraspinal control is able to induce the locomotor activity in hindlimbs and afferent system can activate this mechanism. In behavioral studies on the rats with complete transection of the spinal cord it has been demonstrated that the pharmacological blocking of serotoninergic system results in depression of motor activity mediated by activation of support reactions. Histological studies did not reveal any effects of activation of support reactions on the safety of neurons as well as on the distribution of synaptic contacts within L2-L4 spinal segments. At the same time it has been shown that blockade of the serotoninergic system results in alterations of cells located in 1-3 laminae of dorsal horns, and in 7 Rexed's lamina as well as in redistribution of synaptic contacts in 1-4 Rexed laminae of the spinal cord dorsal horns. PMID- 23461204 TI - [Prevalence and incidence of ESKD in Japan]. PMID- 23461205 TI - [Basic research advances 2012]. PMID- 23461206 TI - [Renal physiology]. PMID- 23461207 TI - [Hypertension and kidney]. PMID- 23461208 TI - [Nephritis and nephrotic syndrome]. PMID- 23461209 TI - [Progress in blood purification medicine in 2012]. PMID- 23461210 TI - [Chronic kidney disease in 2012]. PMID- 23461211 TI - [Acute kidney injury]. PMID- 23461212 TI - [Autopsy case of light chain deposition disease presented by nephrotic syndrome]. AB - An eighty-one-year-old male with lower leg edema and proteinuria was diagnosed as having nephrotic syndrome and was hospitalized for a detailed examination. Kidney biopsy and immunostaining revealed nodular glomerulosclerosis and deposition of lambda chains, respectively. Because these findings indicate the occurrence of light chain deposition disease (LCDD), the underlying disease was found to be multiple myeloma BJ-lambda. After the administration of melphalan and prednisolone, followed by further addition of zoledronic acid, the patient's nephrosis remitted. However, renal dysfunction gradually deteriorated further and hemodialysis was instituted. He eventually died of gastrointestinal bleeding and biliary infection. The period of time from the initial diagnosis to death was thirty months. Autopsy revealed pervasive infiltration of plasma cells and light chain deposition in multiple organs. The uncontrollable gastrointestinal bleeding appears to have been caused by light chain deposition in the vascular walls of a bile duct. Although medical treatment for elderly LCDD cases depends on chemotherapy alone, it is difficult to obtain a complete remission with melphalan and prednisolone, according to the literature. Reports on the validities of biological agents, such as bortezomib, are beginning to appear, and accumulation of further therapeutic experience is eagerly awaited. PMID- 23461213 TI - [A case of Churg-Strauss syndrome with short duration from the onset of asthma to diagnosis of vasculitis]. AB - A 68-year-old woman was hospitalized because of bronchial asthma and a high myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) level. She had suffered from rhinitis from one year before hospitalization, body weight loss from three months before, and asthma from one month before. On admission, she complained of dyspnea and body weight loss of over 6 kg. On laboratory tests, high MPO-ANCA and urinary abnormalities were found. On the next day, a renal biopsy was performed and histology showed necrotizing vasculitis with cellular crescents. Churg-Strauss syndrome (CSS) was diagnosed on the basis of the clinical course and histological findings. Prednisolone therapy induced rapid symptom remission, which was achieved within one month from the onset of asthma to the diagnosis of CSS. Early diagnosis and early care led to a good prognosis. PMID- 23461214 TI - [A case of tuberculous peritonitis in a hemodialysis patient revealed by severe diarrhea and stomachache]. AB - A 53-year-old woman was admitted to our hospital due to abdominal pain, diarrhea, and shunt occlusion caused by dehydration. She had undergone hemodialysis due to diabetic nephropathy over a ten-year period. She was hospitalized again with fever and a persistent high serum CRP level. We started antibiotic administration using cefotiam hexetil hydrochloride because of ascites and peritoneum thickening observed by abdominal computed tomography. Although her symptoms, such as abdominal pain and diarrhea, improved after the administration of antibiotics, the ascites and the peritoneum thickening did not improve. On the fourth hospital day, we attempted ascites aspiration to investigate the etiology of the peritonitis. Cytological examination suggested tuberculous peritonitis because of predominant macrophage cell proliferation, a high level of ADA concentration, and a high level of CA125 of ascites. Although QuantiFERON-tuberculosis (QFT) and the Gaffky scale were negative, we started multidrug therapy (isoniazid + rifampicin + pyrazinamide + ethambutol) on the 20th hospital day. She was finally diagnosed as mycobacterium tuberculous peritonitis based on biopsy of the tissue of the ileum and the results of colonoscopy. Administration of antituberculosis chemotherapy improved abdominal fullness and ascites and the patient was discharged on the 97th hospital day. Moreover Kuno et al. reported that serum soluble interleukin-2 receptor(sIL-2R) and CA-125 levels can be used to monitor the response to anti-tuberculosis treatment. In this case, we use these markers to monitor the response to treatment. We experienced a case of tuberculous peritonitis undergoing hemodialysis. Tuberculosis should be suspected when patients undergoing dialysis have long-term fever of unknown etiology. There are many reports stating that the sensitivity and specificity of QuantiFERON tuberculosis (QFT) and sputum culture are low in latent tuberculosis infection of dialysis patients. Accordingly it is necessary to diagnose mycobacterium tuberculous peritonitis comprehensively by the clinical symptoms and image analysis. PMID- 23461215 TI - [A case of focal segmental glomerulosclerosis with nephrotic syndrome after hematopoietic stem cell transplantatation for aplastic anemia]. AB - We report a case of pediatric severe aplastic anemia (SAA), where the patient underwent allogenic bone marrow transplantation (BMT) from an HLA mismatched family donor and developed focal segmental glomerulosclerosis (FSGS). An 11-year old girl, who had SAA, was admitted to our hospital in 200X. Complete remission was not attained after immunosuppressive therapy with rabbit-antithymocyte globulin, prednisolone (PSL), and cyclosporine A (CsA). Eight months after being diagnosed with SAA, she underwent an allogenic BMT from her mother. We used a combination of 2-Gy total body irradiation, fludarabine, and cyclophosphamide as a preparative regimen prior to the BMT. CsA and PSL were used as prophylaxis against GVHD. Since the BMT did not lead to successful engraftment, the patient required two peripheral blood stem cell transplantations (PBSCT). Engraftment was sustained and no acute or chronic GVHD was observed. Six months after the first BMT, she developed clinical nephrotic syndrome despite the continuous PSL and CsA treatments. Renal biopsy revealed a total of 12 glomeruli, one of which showed segmental sclerosis. Electron microscopy revealed diffuse effacement of the foot processes. These findings were consistent with FSGS, and she was treated with mycophenolate mofetil (MMF) in combination with PSL instead of CsA, which greatly reduced her proteinuria. In general, the most common type of nephropathy after HSCT is GVHD-related nephrotic syndrome, and the most common pathological finding is membranous nephropathy or minimal change. FSGS without GVHD after HSCT, such as that observed in our case, is rare. In this case, the renal damage appears to have been caused by the effect of circulating permeability factors with immunity change after HSCT. This case demonstrates the importance of renal biopsy as a guide to determine the extent of renal damage and as an aid to determine the possible response to therapy. PMID- 23461216 TI - [Physiological functions of sigma-1 receptors and its relation to psychic dependence]. AB - Sigma-1 receptors had been believed as a one of the opioid receptors. Recent reports have demonstrated that the sigma-1 receptor is a nonopioid receptor that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface and has been shown to be protective against neurodegeneration as an ER chaperone. In this review, we review the molecular mechanism on the cytoprotective effects of sigma-1 receptors. Furthermore, we summarize the effects of sigma-1 receptor ligand on the behavioral effects, especially on the reward-related behaviors induced by psychostimulants. The ER is a major locus for the synthesis of proteins. Under physiological conditions, the overall protein level in the ER is maintained by a balance between the protein synthesis and degradation. When the balance is perturbed, signaling pathways (the unfolded protein response (UPR) caused by ER stress or the ER overload response (EOR)) are activated to regulate the cell survival/death signalings. Sigma-1 receptor could be upregulated by ER stress and EOR, and that upregulated sigma-1 receptors attenuate UPR and EOR by increasing the chaperone activity of sigma-1 receptors and attenuation of prossessed NF-kappaB activity, respectively. On the other hand, even sigma-1 receptor could be upregulated by self-administration of methamphetamine in the ventral tegmental area, exact mechanism how sigma-1 receptor chaperone affect the behavioral effects induced by psychostimulants is not yet cleared. However, the prototypic sigma-1 receptor agonist SKF10,047 induces psychotomimetic effects, and psychotomimetic-like discriminative stimulus effects are at least in part mediated by sigma-1 receptors. Recent research showed that endogenous hallucinogen (N,N-dimethyltryptamine) might be a sigma-1 receptor regulator, indicating that sigma-1 receptor is crosely related to psychotomimetic effects. Furthermore, sigma-1 receptor agonist can enhance the discriminative stimulus effects of psychostimulants, and methamphetamine self-administration could be maintained by sigma-1 receptor agonists. These results suggest that sigma-1 receptors are involved in the psychotomimetic as well as rewarding process inside the cellular signal transduction system. PMID- 23461217 TI - [Substance use risk personality trait for adolescents]. AB - The prevention and treatment of substance use for youth are important issues in Japan. Substance use have significant risks of adverse psychological, social and physical health consequences. Personality factors in order to understand individual differences for substance use and misuse particularly were the much promise, and several personality factors have been demonstrated to be associated with risk for substance use. Conrod and Woicik (2002) developed Substance Use Risk Profile Scale (SURPS) that measures four substance use risk personalities: anxiety sensitivity, hopelessness, sensation-seeking, impulsivity being closely relevant to substance use/misuse and abuse. There are only a few studies focusing the relationship between personality factors and substance use among Japanese adolescents. Thus, this paper aimed to review the previous studies on these issues, and introduce studies regarding SURPS including our studies. PMID- 23461218 TI - [The randomized controlled trial of the prison-based Japanese Matrix Program (J MAT) for methamphetamine abusers]. AB - Methamphetamine use is subject to severe criminal punishment in Japan and approximately 22% of the prison population were confined for violations of the stimulants control law in 2009. Although the high recidivism rate is also a problem, no systematic treatment has been conducted in prison. Therefore, the development of the prison-based treatment program is necessary. In this study, the prison-based program was developed based on the Matrix Model, which is the cognitive-behavioral treatment for amphetamine users developed in the US. The program was tailored in order to address the treatment needs of the Japanese amphetamine users considering Japanese culture and the prison climate. The randomized controlled trial was conducted in order to evaluate the effectiveness the Japanese Matrix program (J-MAT). 60 prisoners were randomly assigned either to the J-MAT or the control groups and those who in the J-MAT group received the program once a week for 12 weeks. The abstinence rate could not be used as the outcome measure because the participants could not be followed after the release from prison due to the legal reasons. Therefore, the psychological variables including coping skills, self-efficacy and motivation were used as outcome measures, which are considered as the important predictive factors of abstinence. 93.3% of the J-MAT participants completed the program. The coping skills of the treated prisoners were improved significantly after treatment comparing to the control (F (1, 27) = 9.03, p < .001), however other psychological variables were not significantly improved. The results suggested the effectiveness of the J-MAT because both treatment completion and coping skills are powerful predictors of abstinence. Further study is required and in which the participants should be followed after the completion of treatment in order to compare the relapse rates between the groups and to measure the long-term treatment gain. PMID- 23461219 TI - [Does participating in AA decrease the risk for suicide in alcohol dependence?]. AB - It is well-known that presence of alcohol dependence increases the risk for suicide. But it is not understood how the risk for suicide in alcohol dependence is decreased. This study aimed to show that participating in Alcoholics Anonymous (AA) decreased, the risk for suicide in alcohol dependence. Sixty four participants in this survey were collected from voluntary AA members in Hokkaido area. They answered self-reporting questionnaires with regard to gender, age, living with family, marriage, jobs, histories of attending AA meetings, familial histories about alcohol dependence, duration of abstinence, and suicidal phenomena which were pre-suicidal thoughts, suicidal thoughts, suicidal plans, suicidal attempts were retrospectively asked before and after becoming AA members. Participating in AA caused a significant decrease (p < 0.001) in the risk for suicidal phenomena in alcohol dependence. Psychosocial treatments usually acknowledged spirituality, but might not address them directly. We referred to spirituality in AA and Japanese spirituality. We discussed the relation between spirituality in AA and prevention of suicide. PMID- 23461220 TI - [A study on clinical features of patients with benzodiazepines use disorder (BZsUD), and characteristics of psychiatric treatments which may cause BZsUD]. AB - BACKGROUND AND AIMS: The aims of present study are to clarify the clinical features of patients with benzodiazepine use disorder (BZsUD), and to examine the characteristics of psychiatric treatments which may cause BZsUD. METHODS: We conducted a medical chart and interview survey to 87 outpatients with benzodiazepine use disorder, who had consecutively visited the four hospitals, specialized in addiction problems, located in metropolitan area, during a month of December, 2011. RESULTS: Consequently, 88.5% of the patients with BZsUD reported to obtain BZs to be abused from general psychiatric clinics, and 83.9% contracted BZsUD in process of general psychiatric treatment. Among the patients who contracted BZsUD in process of psychiatric treatment, 43.8% were speculated to have the other substance-related disorders such as methamphetamine or alcohol related disorder at start of the psychiatric treatment. Further, approximately 70% of them reported that surplus BZs were prescribed without consideration of storing drugs, and over 40% also reported that BZs were prescribed without a medical examination. CONCLUSIONS: The findings of the present study may let us to propose the following four measures to be taken for prevention of BZsUD: First, latent substance-related disorders should not be overlooked, second, short-acting and high-potency BZs should not be prescribed if possible, third, storing and abusing BZs should always be considered, and finally, BZs should be prescribed with a medical examination. PMID- 23461221 TI - [Investigation of patients suspected of drinking, who visited emergency department, and their negative influence on emergency medical system]. AB - We investigated the nature of patients who have a pathological drinking problem visiting the emergency department (ED). During the investigation period, 107 (1.2%) of 8,812 referred patients, including children, were suspected of having consumed alcohol by the medical staff in the ED on the basis of the interview, the smell of alcohol on the patient's breath, pre-hospital information, etc. One hundred and seven patients were divided into either of the two groups, "problem drinkers" or "others". When the patient fulfilled at least one of the following conditions, he/she was categorized as a "problem drinker". The conditions were either drunken patients who did not cooperate with the staff in the ED, who came to the ED after drinking more than two times during the investigation period, who usually consumed over 60 g of ethanol in a day, or who injured themselves intentionally after having consumed alcohol. Statistical significance was revealed with regard to "arrival time" and "diagnosis" between both groups. In the "problem drinkers" group, a larger number of patients visited the ED during the day (08:00-18:00 hrs.) and almost half the illness were diagnosed as trauma related. The tendency of statistical significance was noted with regard to "sex" and "transportation". There was no statistical significance with regard to "age", "health insurance", "severity of illness", "opportunity to drink", or "CAGE questionnaire. PMID- 23461222 TI - Considering infant mental health before the baby arrives. PMID- 23461223 TI - Government proposes informed choice for women. PMID- 23461224 TI - Moderate increases in breastfeeding could save the NHS millions. PMID- 23461225 TI - NICE recommends dedicated NHS service for women with miscarriage or ectopic pregnancy. PMID- 23461226 TI - Over a quarter of babies with a cleft palate have their condition missed at birth. PMID- 23461227 TI - New guidance on treating postpartum hypertension. PMID- 23461228 TI - Homeopathic remedy creates debate. PMID- 23461229 TI - A pinch of salt. AB - Pregnant women in labour are generally encouraged by their carers to continue taking plenty of oral fluids. This is sometimes supplemented by intravenous fluids either due to a clinical necessity or in preparation for a caesarean section. It is important that there is clear documentation of the amount of fluids received by pregnant women in the perinatal period as excessive maternal fluid has been associated with low serum sodium in neonates. This often goes under-recognised; therefore it is important to consider this in a neonate presenting with hyponatraemia in the first day of life. Presented here is a case of neonatal hyponatraemia secondary to excessive fluid taken in the perinatal period. PMID- 23461230 TI - A group B strep infection: a mother's perspective. PMID- 23461231 TI - The midwife's role in caring for the needs of bereaved parents following a stillbirth. AB - The unexpected loss of a baby can be both a devastating and traumatic experience for parents. Inadequate care and support can potentially lead to mental health problems such as complicated or traumatic grief. This article will review the midwife's role in providing more effective meaningful and supportive care for bereaved parents following a stillbirth. It will also highlight the educational needs of student midwives to ensure they are equipped with the necessary knowledge and skills to support bereaved parents. PMID- 23461232 TI - Management of umbilical cord clamping. AB - The Royal College of Midwives (RCM) has updated its third stage of labour guidelines (RCM 2012) to be clearly supportive of a delay in umbilical cord clamping, although specific guidance on timing is yet to be announced. It is therefore imperative that both midwives and student midwives understand and are able to integrate delaying into their practice, as well as communicating to women the benefits; only in this way can we give women fully informed choices on this aspect of care. The main benefit of delayed cord clamping is the protection it can provide in reducing childhood anaemia, which is a major issue, especially in poorer countries. A review of the evidence found no risks linked to delayed clamping, and no evidence that it cannot be used in combination with the administration of uterotonic drugs. Delayed cord clamping can be especially beneficial for pre term and compromised babies. PMID- 23461233 TI - Altered sexual health after childbirth: Part 2. AB - In Part I of this two part series the possible risk factors for altered sexual health after childbirth were explored. In further emphasising the importance of this topic in maternity care provision, Part 2 considers the potential causes of altered postpartum sexual health; mode of birth and perineal trauma are discussed, and the routine postnatal consultation as an opportunity to identify altered sexual health patterns and to counsel women accordingly, are examined. PMID- 23461234 TI - By any other name: feticide. AB - This reflection is an anonymised account of a feticide which I witnessed as a second year midwifery student. Having cared for this woman I found myself unable to put it out of my mind until I wrote it down and asked my mentor and a lecturer to help me debrief. It describes the events themselves as well as my feelings, and uses the Gibbs reflective cycle (Gibbs 1988) to demonstrate insights into my own learning and future development as a midwife. PMID- 23461235 TI - Immigrant women's perceptions of their maternity care: a review of the literature. Part 2. AB - In the first of this two part article, the methods of the literature review looking at immigrant women's perceptions of their maternity were outlined along with the first two themes identified, including communication and impediments to access of maternity care. In this concluding part, the remaining three themes of the literature review will be discussed and conclusions will be drawn, with recommendations for practice. PMID- 23461236 TI - Infant feeding. 5. Managing baby related feeding challenges. AB - 'Infant feeding' is the 12th series of 'Midwifery basics' targeted at practising midwives. The aim of these articles is to inform and encourage readers to seek further information through a series of activities relating to the topic. In this fifth article Joyce Marshall considers a range of baby related issues that pose challenges for both mothers and midwives in relation to infant feeding. PMID- 23461237 TI - An introduction to the new UNICEF UK Baby Friendly Initiative standards. PMID- 23461238 TI - [The best cuff for measuring arterial pressure]. AB - Hypertension prevention, detection, follow-up and medication adjustment depend on valid blood pressure measurement. Many factors should be taken into consideration to get accurate blood pressure readings: the blood pressure measurement method, the equipment used and the patient preparation. This column will focus on the importance of the cuff for blood pressure measurement. PMID- 23461239 TI - Exposing barriers to end-of-life communication in heart failure: an integrative review. AB - BACKGROUND: End-of-life (EOL) communication is lacking despite patients with heart failure (HF) and their caregivers desiring it. AIM: To review the existing literature to identify barriers that inhibit EOL communication in the HF population. METHOD: We chose an integrative literature review method and began by searching CINAHL, Medline, PsychInfo, Web of Science, Health Source Nursing Academic, Evidence-Based Medicine Reviews (EBMR), dissertations and theses searches through the University of Victoria and through Proquest from 1995 to 2011. DATA EVALUATION: EOL communication regarding wishes, prognosis and options for care rarely happen. We noted that patients lacked understanding of HF, feared engaging health care professionals (HCP), did not wish to talk about EOL, or waited for HCPs to initiate the conversation. HCPs lacked communication skills, focused on curative therapies and found diagnosing and prognosticating HF difficult. Limited time and space for conversations played a role. CONCLUSION: The challenge of diagnosing and prognosticating HF, its unpredictable trajectory, HCP inexperience in recognizing nearing EOL and lack of communication skills lead to HCPs avoiding EOL conversations. Four categories of barriers to communication were identified: patient/caregiver, HCP, disease-specific and organizational challenges. PMID- 23461240 TI - Writing competitive scientific and clinical abstracts: tips for success. AB - Successful writing of a research or clinical abstract requires meticulous adherence to the professional society's call for abstracts and its particular specifications. The abstract must clearly answer why this research was carried out, how did you do it, what did you find, and what are the important nursing implications for clinical practice, education and research. PMID- 23461241 TI - Joint Commission announces 20,000 accredited and certified organizations. PMID- 23461243 TI - APPROVED: Revised laboratory requirement for frequency of procedure review. PMID- 23461242 TI - ACCEPTED: Revised requirements maintain alignment with CMS CoPs. PMID- 23461244 TI - New R3 report examines revised patient flow requirements. Patient flow through the ED addressed as a hospitalwide concern. PMID- 23461245 TI - Joint Commission launches nursing and rehabilitation center accreditation program. Program replaces long-term care accreditation and offers specialty certification option. PMID- 23461246 TI - Safety champions. Making health care safety everyone's business. PMID- 23461247 TI - Usefulness of CURB-65 and pneumonia severity index for influenza A H1N1v pneumonia. AB - Usefulness of CURB-65 and pneumonia severity index for influenza A H1N1v pneumonia. A. Estella. BACKGROUND: Different prognostic scales have been documented to assess the severity and indications for hospitalization and ICU admissions of community acquired pneumonia. During the past two years Influenza A H1N1v infections have been commonly attended to in emergency departments. The aim of the study was to analyse the usefulness of the application of the Pneumonia Severity Index (PSI) and CURB-65 prognostic scales in patients with primary viral pneumonia caused by influenza A H1N1v. METHODS: A retrospective study was performed at a community hospital with a 17 bed-intensive care unit. Patients admitted in hospital with influenza A H1N1v pneumonia over a two year period were analysed. CURB 65 and PSI scales were applied in the emergency department and outcome and destination of admission were analysed. RESULTS: 24 patients were registered, 19 required ICU admission and 5 patients were admitted in medical wards. Most of the patients admitted to the intensive care unit (78.9%) required mechanical ventilation. Mortality was 21.1%. Most patients admitted to the ICU had CURB 65 scale of 1 (60%), 13.3% obtained 0 and 26.7% 2. PSI scale resulted class I in a 20%, class II 40%, 26.7% class IV and 13.3% class V. The scales CURB 65 and PSI showed no differences in scores according to the destination of admission and mortality. CONCLUSIONS: Use of CURB-65 and PSI in the emergency department may underestimate the risk of patients with Influenza A H1N1v pneumonia. Based in our results, the ability of these scales to predict ICU admissions for Influenza A H1N1v pneumonia is questioned. PMID- 23461249 TI - Pulmonary function in patients with amyotrophic lateral sclerosis at disease onset. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Deteriorating pulmonary function as a reflection of progressive respiratory muscle weakness is a common feature, accounting for the majority of deaths. The aim of the study was to describe a trend in initial pulmonary function tests (PFT) of amyotrophic lateral sclerosis (ALS) patients, in addition, differentiating between the types of disease onset, bulbar, limb muscle, and a combination. METHODS: Initial PFT were gathered from 32 consecutive patients in our clinic with the diagnosis of ALS, they were categorized by the type of disease onset. Values obtained were referenced to the 95% confidence limits for normality. RESULTS: There was evidence of significant reductions in both the FEV1 (64.7% predicted) and FVC (61.2%), with preservation of the FEV1/FVC (81.7%). The MVV was significantly reduced (43%). Total lung capacity was 93.2%, the residual volumes was increased at 145.7%. Subgroup analysis failed to show significant differences between types of disease onset. In the bulbar onset group (versus the limb group) there was a trend for the MVV to be further reduced (p = 0.15) and the RV to be higher (157.4% versus 135.9%, P = 0.24). CONCLUSIONS: ALS is a devastating disease that invariably leads to respiratory failure. Abnormal spirometric variables such as the FVC and MVV, likely reflect inspiratory muscle weakness and increased RV likely reflect expiratory muscle weakness. The type of disease onset did not result in a different pattern of PFT abnormalities. PMID- 23461248 TI - Is the type of chronic pulmonary infection a determinant of lung function outcomes in adult patients with cystic fibrosis? AB - BACKGROUND AND AIM: Lung function abnormalities are the main factors responsible for the high mortality of cystic fibrosis (CF) patients. It is not yet clear whether Burkholderia cepacia infection causes more pronounced loss of lung function than pseudomonas aeruginosa infection. Our primary objective was to compare the lung function of adult CF patients with different chronic pulmonary infections. Our second objective was to compare the microbiology using patients' genetic status. METHODS: Fifty-two adult CF patients were divided into 3 groups according to their chronic pulmonary infection profile. All subjects underwent clinical evaluation, pulmonary function tests (PFT) and genetic analysis. RESULTS: The PFT parameters of chronically infected patients were significantly different from those of subjects without pulmonary infection (p < 0.0001). FVC was significantly more altered in patients infected with B. cepacia complex (p < 0.0001); in contrast, FEF25-75% was significantly more altered in patients with P. aeruginosa infection (p < 0.0001). In the groups with chronic P. aeruginosa infection and chronic B. cepacia complex infection, 58.1% and 10% of patients were homozygous for AF508, respectively. In addition to chronic infections, pancreatic insufficiency was also associated with lung function deterioration. CONCLUSION: Chronic pulmonary infection and pancreatic insufficiency are critical processes in lung function deterioration in adult CF patients. Although chronic B. cepacia complex infection causes a more pronounced lung volume reduction, chronic P. aeruginosa infection causes a more pronounced obstruction of small airways. Our results also suggest that deltaF508-homozygous patients are more susceptible to chronic P. aeruginosa infection. PMID- 23461250 TI - Ventilatory muscle strength in cystic fibrosis patients: a literature review. AB - The ventilatory mechanic changes that occur in cystic fibrosis (CF) patients may lead to alterations in the respiratory muscle strength levels. However, the findings regarding the strength profile in these patients are still contradictory. OBJECTIVE: To evaluate, trough a literature review, the respiratory muscle strength behavior in CF patients. We have performed a search in Medline/Pubmed, Scielo, IBECS and LILACS databases selecting observational cross-sectional, prospective or retrospective studies, as well as randomized clinical trials, published between 1981 and 2011, using the following terms: cystic fibrosis, respiratory muscle strength, inspiratory maximal pressure and muscle training. The majority of the studies 71.24% have shown normal or above normal respiratory muscle strength, whilst 28.57% demonstrated reduced or near normal values. Most of these findings were attributed to an increased work of breathing as a result of airway obstruction and chronic persistent cough. Taken together, the analyses of selected studies have showed conflicting findings regarding respiratory muscle strength behavior in these patients. However, most of the studies seem to indicate that CF patients presented maximum respiratory pressures normal or above predicted values. PMID- 23461251 TI - Castleman's disease presenting as a pleural mass in the thoracic cavity. AB - A 61-year-old non-smoking Turkish woman presented with chest pain for 10 months. Computed tomography of the chest revealed a solitary, relatively well circumscribed, heterogeneous mass of 4 x 6 cm diameter in left posterior-lateral hemithorax. On thoracotomy, an extraparanchymal mass destructing the ribs was determined. Mass excision and partial chest wall resection were performed. On histopathologic examination, this mass showed features of the hyaline vascular type of Castleman's disease. PMID- 23461252 TI - Pulmonary fibrosis presenting as an early manifestation of microscopic polyangiitis. AB - Microscopic polyangiitis (MPA) is a systemic small vessel vasculitis that is included in the pulmonary-renal syndromes. Although glomerulonephritis represents the major clinical feature of MPA indicative of renal involvement, diffuse alveolar haemorrhage is the classic manifestation of pulmonary involvement. However, pulmonary fibrosis is a less frequently reported pulmonary manifestation. Herein we describe a patient who was diagnosed with MPA presenting with radiographic evidence of pulmonary interstitial fibrosis as an early clinical manifestation accompanied by constitutional symptoms such as fever and weight loss. We also include a short literature review focusing on the association between pulmonary fibrosis and MPA. PMID- 23461253 TI - Giant thoracic aorta aneurysm causing airway and esophagus stenosis. PMID- 23461254 TI - Fire-eater's pneumonia: a likely hazard not uncommon in fire eaters. PMID- 23461255 TI - TMJ alias, The Great Imposter, has a co-conspirator: poor sleep. PMID- 23461256 TI - The "Minister of Defense" dies of obstructive sleep apnea. PMID- 23461257 TI - Special consideration regarding the assessment and management of patients being treated with mandibular advancement oral appliance therapy for snoring and obstructive sleep apnea. AB - This position paper, as developed by a Task Force of the American Academy of Craniofacial Pain on Mandibular Advancement Oral Appliance Therapy for Snoring and Obstructive Sleep Apnea, contains recommendations for dentists engaged in the management of patients with snoring and obstructive sleep apnea utilizing mandibular advancement oral appliances. The recommendations are supported by current scientific evidence, published standards and guidelines, and expert panel consensus. Snoring and obstructive sleep apnea (OSA) affects millions of people. Oral appliance therapy (OAT) is recognized as an effective therapy for many with primary snoring and mild to moderate OSA, as well as those with more severe OSA who cannot tolerate positive airway pressure (PAP) therapies. Dentists are playing a much larger role in the screening and management of patients with snoring and OSA as part of a multi-disciplinary team. It is also recognized that OAT has the potential to cause untoward side effects, including temporomandibular joint (TMJ) pain and dysfunction. The present paper highlights the need for dentists who manage patients using mandibular advancement OAT to be competent in the assessment, diagnosis and management of temporomandibular disorders (TMDs) and craniofacial pain disorders. The authors of this article are all clinically engaged in the management of patients with snoring and OSA, and reached consensus based on their review of the current evidence, published guidelines and clinical experience. It is the opinion of the authors that dentists experienced and knowledgeable in the assessment, diagnosis and management of TMD and craniofacial pain applying this knowledge to the management of patients with snoring and OSA using OAT will provide their patients with the best prognosis and most successful treatment outcomes. PMID- 23461258 TI - The influence of craniofacial morphology on mandibular border movements. AB - Although they are widely used as diagnostic signs of temporomandibular disorders, mandibular border movements reflect not only condylar movement, but also other factors. In the present study, the authors investigated the effect of craniofacial morphology on three different mandibular border movements: maximum jaw opening, maximum jaw protrusion, and maximum jaw laterotrusion. One hundred female subjects were selected from outpatients visiting the orthodontic clinic of Okayama University Hospital. The mandibular border movements were measured using an optical recording system in three dimensions as six degrees of freedom. The craniofacial morphology was evaluated using lateral cephalograms. The results suggest that craniofacial morphology had different influences on each mandibular border movement. In particular, during maximum jaw laterotrusion, lower incisor movement strongly reflected condylar movement, and the influence of craniofacial morphology on mandibular border movement was minimal. Therefore, lower incisor movement during maximum jaw laterotrusion appears suitable to evaluate condylar movement. PMID- 23461259 TI - Evaluation of the effects of temporomandibular joint disc displacement and its progression on dentocraniofacial morphology in symptomatic patients using posteroanterior cephalometric analysis. AB - The aim of this study was to evaluate the effects of disc displacement (DD) and its progression on dentocraniofacial morphology in symptomatic patients, and to compare the results with asymptomatic volunteers. Female patients with DD, diagnosed with magnetic resonance imaging (MRI) and posteroanterior cephalometric analysis, were included in this study. Subjects were grouped as follows: control group with bilateral normal disc position (group 1, n=20), unilateral DD with reduction (group 2, n=17), bilateral DD with reduction (group 3, n=32), unilateral DD without reduction (group 4, n=16), and bilateral DD without reduction (group 5, n=19). Thirteen cephalometric variables were measured. A significant increase in the ANS (Anterior nasal spine)-Me (Menton)-MSP (Midsagittal plane) angle in unilateral DD groups and decreases in the Ag (Antegonial notch)-Me dimension on the affected side in all DD groups were observed. Also, the maximum values of the Me-MSP dimension and ANS-Me-MSP angle were observed in group 4. The results of this study showed that the deviation of the menton point toward the disc displacement side causes a mandibular asymmetry. It can be concluded from these results that the presence of DD in female patients affects facial morphology, and its progression makes the differences more significant and remarkable. These results emphasize the importance of early diagnosis and treatment in the management of DD. PMID- 23461260 TI - Reproducibility of condyle position and influence of splint therapy on different registration techniques in asymptomatic volunteers. AB - The current study aims to analyze and quantify the effects of different registration techniques on the reproducibility of condyle position and the influence of stabilization splint therapy on the technique's reproducibility. Three-dimensional electronic-condylar-position analysis (EPA) with an ultrasound based jaw-tracking system was recorded during intermaxillary registration of manually guided centric relation (CR), maximal intercuspation (MI), and clenching force-dependent Gothic arch tracing guided centric relation (DIR method) before (T0) and after (T1) splint therapy. Patients were supplied with a stabilization splint for three months on the basis of the DIR registration. Participants were 26 asymptomatic volunteers with a mean age of 30.6 +/- 9.5 years. The registration technique was found to have a significant (p = 0.001) effect on condylar displacement in all axes before, and in X- and Y-axes after splint therapy. Condyles during DIR were found to be in a more anterior-inferior position compared with CR and MI, with the condyles in the latter position being likewise more anterior than in CR. There were significant (p < 0.03) differences in reproducibility of the condyle position dependent on the technique, both at T0 and T1. The DIR method showed the highest reproducibility, followed by MI and CR. There was no significant effect of time of investigation on the technique's reproducibility. PMID- 23461261 TI - Features of temporomandibular disorders in fibromyalgia syndrome. AB - This study aimed to investigate the prevalence of clinical features of temporomandibular disorders (TMD) in patients with fibromyalgia. The test group (FMG) consisted of 40 women with fibromyalgia (FM) compared to the control group of 40 healthy subjects using the research diagnostic criteria for temporomandibular disorders (RDC/TMD). The variables were compared using Fisher's exact test and a Mann-Whitney test. Facial pain was reported by 85% of the FM group, and 77.5% were diagnosed with myofascial TMD. Muscle pain during jaw movements, daytime bruxism/clenching, and limited mouth opening were significantly higher in the test group. There was no difference between groups in: (1) joint noises; (2) sleep bruxism/clenching; and (3) excursive or non excursive movements. Classic signs of TMD, such as joint noise and self-reporting of clenching at night, are not associated with fibromyalgia syndrome as demonstrated in the current study. However, the self-reported daytime parafunctions, muscle pain in jaw movements, and limited mouth opening are features of the patients in the current study. This study revealed specific muscle involvement of TMD is also presence in FM. PMID- 23461262 TI - Application of a cephalometric method to the temporomandibular joint in patients with or without alteration in the orientation of the mandibular condyle axis. AB - In a prior study, the spatial relationship of the mandibular condyle was studied through a cephalogram based on laminographies of the temporomandibular joint (TMJ). The present method was developed with the aim of analyzing TMJ morphology and the spatial relationship of the mandibular head within the mandibular fossa, considering references far from these structures, as they may suffer shape alterations. This study was conducted in view of the importance of the study of morphology and the hard structures relationship, which constitutes the temporomandibular joint. Its purpose is to validate a new TMJ cephalogram method by analyzing joints with and without alterations in the orientation of the condylar axis growth. Sixty joints were studied through laminographies in maximal occlusion, examining those joints with and without alterations in the orientation of the axis during condylar growth for subsequent analysis. Results showed that those joints were in a posterior position and rotation of the mandibular head, and that they presented a greater inclination in the articular eminence compared to joints without alterations in the axis orientation. Moreover, a new cephalometric method could be validated, demonstrating that changes in the condylar axis orientation imply pathology; they could also be correlated with changes in the condylar position and in the glenoid fossa morphology. PMID- 23461263 TI - Eagle's syndrome: signs and symptoms. AB - Eagle's syndrome, an uncommon sequela of an elongated styloid process, can manifest itself as a sensation of a foreign body in the throat and a retrogoniac or anterolateral neck pain often referred to the TMJ and the ear. When treating patients affected by temporomandibular disorders (TMD), complaining of atypical orofacial pain, and with a concomitant radiographic finding of a bilaterally elongated styloid, the possible coexistence of Eagle's syndrome should always be considered. The aim of this review is to present an overview of the epidemiology, pathophysiology, diagnosis, and therapy for Eagle's syndrome and to help the clinician in differential diagnosis with other conditions that can provide similar signs and symptoms. PMID- 23461264 TI - A possible case of Eagle's syndrome from an Italian ossuary (Chiavari, GE). AB - Eagle's syndrome is a rare condition associated with the temporal styloid process hypertrophy (Eagle, 1937). It is in most cases asymptomatic, but may be accompanied by dysphagia, pharyngeal or head and neck pain due to neurovascular structure compression. The current study aims to present and discuss the etiology of a possible case of Eagle's syndrome from an Italian ossuary. Skull OC 002/08 shows a unilateral hypertrophic styloid process (48 mm long; 5-7 mm thick). Areas of remodel-ed periosteal swelling are visible at the stylohyoid and stylopharyngeus muscles' insertion, along with evidence of healed trauma to both nasal bones and a depressed fracture on the upper left portion of the frontal. Several factors have been proposed as possible causes of styloid elongation, including anatomical variation, aging and trauma. Evidence of unilateral styloid hypertrophy in association with healed cranial trauma in OC 002/08 suggests a traumatic etiology for the condition. PMID- 23461265 TI - Osteochondroma of the right coronoid process (Jacob disease): a case report. AB - Oscar Jacob was the first to describe osteochondroma of the coronoid process, naming it "Jacob disease." Jacob disease rarely occurs in the oral and maxillofacial regions. The tumor usually grows progressively, leading to a mushroom-shaped enlargement of the process, and a joint-like structure is found between the coronoid process and the inner aspect of the zygomatic arch. Most of these lesions grow like a mushroom on, and do not destroy, the coronoid process. The major symptoms include restricted mouth opening and morphological changes to the zygoma. The authors present a case report on an 18-year-old male patient with pain in the right zygoma. Interincisal maximum mouth opening was 51 mm. An intraoral coronoidectomy was performed. PMID- 23461266 TI - Validation of the Focus on the Outcomes of Communication under Six outcome measure. AB - AIM: The aim of this study was to establish the construct validity of the Focus on the Outcomes of Communication Under Six (FOCUS((c)) ),a tool designed to measure changes in communication skills in preschool children. METHOD: Participating families' children (n=97; 68 males, 29 females; mean age 2y 8mo; SD 1.04y, range 10mo-4y 11mo) were recruited through eight Canadian organizations. The children were on a waiting list for speech and language intervention. Parents completed the Ages and Stages Questionnaire - Social/Emotional (ASQ-SE) and the FOCUS three times: at assessment and at the start and end of treatment. A second sample (n=28; 16 males 12 females) was recruited from another organization to correlate the FOCUS scores with speech, intelligibility and language measures. Second sample participants ranged in age from 3 years 1 month to 4 years 9 months (mean 3y 11mo; SD 0.41y). At the start and end of treatment, children were videotaped to obtain speech and language samples. Parents and speech-language pathologists (SLPs) independently completed the FOCUS tool. SLPs who were blind to the pre/post order of the videotapes analysed the samples. RESULTS: The FOCUS measured significantly more change (p<0.01) during treatment than during the waiting list period. It demonstrated both convergent and discriminant validity against the ASQ-SE. The FOCUS change corresponded to change measured by a combination of clinical speech and language measures (kappa=0.31, p<0.05). CONCLUSION: The FOCUS shows strong construct validity as a change-detecting instrument. PMID- 23461267 TI - Is saliva a potential biomarker of arsenic exposure? A case-control study in West Bengal, India. AB - Saliva is a biological fluid that has not been used extensively as a biomonitoring tool in epidemiological studies. This study presents the arsenic (As) concentrations in saliva and urine samples collected from populations of West Bengal, India who had been previously exposed to high As levels in their drinking water. We found a significant (p < 0.05) association between the Log transformed Daily Ingestion of As (MUg day(-1)) and the As concentration in saliva (r = 0.68). Additionally, As concentration of saliva and urine also had a significant positive correlation (r = 0.60, p < 0.05). Male participants, smokers, and cases of skin lesion were independently and significantly associated with an increase in salivary As. Thus our findings show that saliva is a useful biomarker of As exposure in the study population. The study also advocates that measurement of the forms of As in saliva may additionally provide insight into the internal dose and any individual differences in susceptibility to As exposure. PMID- 23461268 TI - Effects of solution temperature on solution-processed high-performance metal oxide thin-film transistors. AB - Herein, we report a novel and easy strategy for fabricating solution-processed metal oxide thin-film transistors by controlling the dielectric constant of H2O through manipulation of the metal precursor solution temperature. As a result, indium zinc oxide (IZO) thin-film transistors (TFTs) fabricated from IZO solution at 4 degrees C can be operated after annealing at low temperatures (~250 degrees C). In contrast, IZO TFTs fabricated from IZO solutions at 25 and 60 degrees C must be annealed at 275 and 300 degrees C, respectively. We also found that IZO TFTs fabricated from the IZO precursor solution at 4 degrees C had the highest mobility of 12.65 cm2/(V s), whereas the IZO TFTs fabricated from IZO precursor solutions at 25 and 60 degrees C had field-effect mobility of 5.39 and 4.51 cm2/(V s), respectively, after annealing at 350 degrees C. When the IZO precursor solution is at 4 degrees C, metal cations such as indium (In3+) and zinc ions (Zn2+) can be fully surrounded by H2O molecules, because of the higher dielectric constant of H2O at lower temperatures. These chemical complexes in the IZO precursor solution at 4 degrees C are advantageous for thermal hydrolysis and condensation reactions yielding a metal oxide lattice, because of their high potential energies. The IZO TFTs fabricated from the IZO precursor solution at 4 degrees C had the highest mobility because of the formation of many metal-oxygen metal (M-O-M) bonds under these conditions. In these bonds, the ns-orbitals of the metal cations overlap each other and form electron conduction pathways. Thus, the formation of a high proportion of M-O-M bonds in the IZO thin films is advantageous for electron conduction, because oxide lattices allow electrons to travel easily through the IZO. PMID- 23461269 TI - Pd-catalyzed tandem sp2-sp3 coupling reactions of chiral stannolanes: an efficient preparation of optically active tetrahydrobenz[f]isoindoles. AB - A novel double Migita-Kosugi-Stille coupling reaction with dihydrostannolanes, which are readily available from a radical cascade reaction, was achieved with dihalobenzenes in the presence of a palladium catalyst. Use of unsymmetrical 1 bromo-2-iodobenzene derivatives accomplished the double coupling reaction which gave tetrahydrobenz[f]isoindoles in a regioselective manner. PMID- 23461270 TI - Alterations in transcriptome and proteome on metallothioneins following oxidative stress induced by sublethal doses of cadmium and gamma rays in Plantago ovata. AB - PURPOSE: To study the oxidative stress-induced changes by sublethal doses of cadmium chloride (CdCl2) and gamma irradiation, two redox-inducing agents, on metallothionein (MT) gene and protein expression in Plantago ovata Forsk (P. ovata). MATERIALS AND METHODS: Chlorophyll content was estimated to study the stress response in P. ovata seedlings following exposure to gamma irradiation and CdCl2. Lipid peroxidation and proline content, two oxidative stress markers, were also studied. The level of metallothionein gene and protein expression was further investigated using polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), immunocytochemistry and flow cytometry. RESULTS: Three MT genes of P. ovata namely PoMT 1, PoMT 2 and PoMT 3 were isolated, sequenced and characterized and their expressions were found to be altered in the case of both oxidative stresses in a dose-dependent and tissue-specific manner. The results were in agreement with the observations from immunocytochemistry and FACS analysis. CONCLUSIONS: The results suggest that both gamma irradiation and CdCl2 alter redox balance in P. ovata. The metallothionein gene may play an important role in metal tolerance and stress balance. It is conjectured that the stress mediated imbalance is maintained by altered MT gene and protein expression. PMID- 23461271 TI - Survey of methods used to detect bacterial contamination of platelet products in the United States in 2011. AB - BACKGROUND: Testing of platelets (PLTs) for bacterial contamination is required by the AABB Standards but is not fully standardized. On January 31, 2011, a new AABB Standard, 5.1.5.1.1, specified that bacterial detection methods for PLT components shall use assays either approved by the Food and Drug Administration (FDA) or validated to provide sensitivity equivalent to these FDA-approved methods. METHODS: An Internet-based survey of AABB member institutions was conducted from May to June 2012, to document current practices used in 2011 for bacterial detection in different PLT products and to assess the impact of the new standard. RESULTS: Of 1053 AABB member institutions surveyed, 40 of 99 blood centers (40.4%) and 184 of 954 hospital blood banks or transfusion services (19.3%) responded. Sixty-four respondents manufactured PLTs. Apheresis PLTs (APs) were predominantly screened with the BacT/ALERT system (89.5%); the majority (95.2%) were cultured with at least 8 mL of product. There was substantial variation in the minimum incubation time of cultures before release of PLTs (range, 0 to >24 hr). Recalls of released AP for possible bacterial contamination were largely successful (67.3%); successful interdiction before transfusion was associated with incubation for more than 12 hours before release (p < 0.01). After Standard 5.1.5.1.1 took effect, there was a decrease in production of whole blood-derived PLT concentrates (WBPCs). Point-of-issue ("rapid") immunoassays were used to screen a substantial proportion of WBPC PLTs, but were rarely used as secondary tests for previously cultured APs. CONCLUSION: The survey identified variability in culture methods and release times with AP, while use of WBPC decreased after AABB Standard 5.1.5.1.1 became effective. PMID- 23461272 TI - Bacterial community composition associated with chironomid egg masses. AB - Chironomids (Diptera: Chironomidae) are the most widely distributed and often the most abundant insect in freshwater. They undergo a complete metamorphosis of four life stages, of which the egg, larva, and pupae are aquatic and the adult is terrestrial. Chironomid egg masses were found to be natural reservoirs of Vibrio cholerae and Aeromonas species. To expand the knowledge of the endogenous bacterial community associated with chironomid egg masses, denaturing gradient gel electrophoresis and clone analysis of 16S rRNA gene libraries were used in this study. Bacterial community composition associated with chironomid egg masses was found to be stable among different sampling periods. Cloned libraries of egg masses revealed that about 40% of the clones were related to bacteria known to degrade various toxicants. These findings were further supported when bacterial species that showed resistance to different toxic metals were isolated from egg masses and larval samples. Chironomids are found under a wide range of water conditions and are able to survive pollutants. However, little is known about their protective mechanisms under these conditions. Chironomid egg masses are inhabited by a stable endogenous bacterial community, which may potentially play a role in protecting chironomids from toxicants in polluted environments. Further study is needed to support this hypothesis. PMID- 23461273 TI - Therapist and relationship factors influencing dropout from individual psychotherapy: a literature review. AB - Among potential predictors of dropout, client variables are most thoroughly examined. This qualitative literature review examines the current state of knowledge about therapist, relationship and process factors influencing dropout. Databases searches identified 44 relevant studies published January 2000-June 2011. Dropout rates varied widely with a weighted rate of 35%. Fewer than half of the studies directly addressed questions of dropout rates in relation to therapist, relationship or process factors. Therapists' experience, training and skills, together with providing concrete support and being emotionally supportive, had an impact on dropout rates. Furthermore, the quality of therapeutic alliance, client dissatisfaction and pre-therapy preparation influenced dropout. To reduce dropout rates, therapists need enhanced skills in building and repairing the therapeutic relationship. PMID- 23461275 TI - Extended pi-conjugated molecules derived from naphthalene diimides toward organic emissive and semiconducting materials. AB - In this paper, a new synthetic way to modify naphthalene diimide (NDI) at "shoulder" positions is reported. The key step of the transformation is the intramolecular cyclization involving ethynyl and imidecarbonyl groups. The structure of the intermediate pyrylium cation was confirmed by X-ray crystal structural analysis. New conjugated molecules 1a-g were successfully synthesized in acceptable yields. Their absorption and fluorescence spectra were measured. Among them 1c-f are strongly emissive in solutions. Furthermore, 1b-f are also fluorescent in their solid states; in particular, 1b exhibits a typical aggregation-induced enhanced emission feature. Yellow-emissive microfibrils of 1d show potential optical waveguide behavior. HOMO/LUMO energies of 1a-f were determined based on their cyclic voltammograms. The results also reveal that HOMO/LUMO energies of these new conjugated molecules are influenced by the two flanking moieties. Notably, the thin film of 1c that is emissive shows p-type semiconducting behavior with hole mobility up to 0.0063 cm(2) V(-1) s(-1) based on the transfer and output characteristics of the OFET (organic field effect transistor). PMID- 23461277 TI - The levonorgestrel-releasing intrauterine system: its effect on the number of hysterectomies performed in perimenopausal women with uterine fibroids. AB - This prospective observational study was designed to determine the percentage of hysterectomies avoided following insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) in perimenopausal women with uterine fibroids and a prior indication for surgery. The study also compared the progress of patients using the LNG-IUS with those submitted to hysterectomy, with particular emphasis on the patient's satisfaction with treatment. Sixty perimenopausal patients with uterine fibroids and excessive bleeding referred for hysterectomy were included. After counseling on the possibility of non-surgical treatment, 39 patients opted to use an LNG-IUS while 21 opted for hysterectomy. Continuation of LNG-IUS use and the patient's satisfaction with the chosen procedure were assessed. A secondary analysis evaluated hemoglobin levels, clinical complications, bleeding patterns and uterine volume at ultrasonography over time. After 24 months of follow-up, four of the patients who had opted to use an LNG-IUS were submitted to surgery, while 35 continued using the device, thus avoiding hysterectomy in 89.5% of cases. LNG-IUS users were more satisfied with treatment (p = 0.02) compared to those submitted to hysterectomy. In conclusion, the use of the LNG-IUS enables the number of hysterectomies to be reduced in women with uterine fibroids and is associated with greater satisfaction compared to surgical treatment. PMID- 23461278 TI - How does psychoeducation help? A review of the effects of providing information about Tourette syndrome and attention-deficit/hyperactivity disorder. AB - Tourette syndrome (TS) and attention-deficit/hyperactivity disorder (ADHD) are common neurodevelopmental disorders that often co-occur. They are both stigmatized and misunderstood conditions. This review critically appraises studies examining interventions using psychoeducational approaches in TS and ADHD. Studies examining the impact of providing educational information (or diagnostic label) about TS and ADHD to parents, teachers and peers (child and adult) were identified by searching relevant electronic databases, reference lists and citations, and consulting colleagues. Twenty-two studies were identified, 20 of which involved teachers or peers. The studies indicate that providing educational information increases knowledge, positive attitudes and behaviours towards individuals with TS and ADHD. Provision of a diagnostic label alone appears insufficient. Parental education may improve treatment enrolment and adherence. While the findings are encouraging, there are a number of gaps in the literature. These include the effects of giving information to parents, whether changes are maintained over time, or are generalizable to the population. Studies are needed to investigate the optimal way to present educational information in everyday contexts in order to improve the lives of those with TS and ADHD. PMID- 23461279 TI - Endoscopic vessel sealing: a novel endoscopic precoagulation technique for blood vessels during endoscopic submucosal dissection. PMID- 23461280 TI - Unprecedented one-pot, domino tertiary alcohol protection-Michael type addition of halides to Morita-Baylis-Hillman adduct of isatin with RCOX/K2CO3: diastereoselective synthesis of oxindole appended beta-halo esters. AB - A facile method utilizing RCOX/K2CO3 as a novel reagent for conjugate addition of hydrogen halide, in addition to tertiary (3 degrees )-hydroxyl protection that leads to the synthesis of functionalized beta-halo Morita-Baylis-Hillman ester appended oxindoles, has been developed. The diastereoselective one-pot O acylation-hydrohalogenation observed cannot otherwise be performed by treatment with hydrohalide. Deprotection of a 3 degrees -hydroxyl protecting group has also been demonstrated by treatment with hydrochloric acid. PMID- 23461281 TI - Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: a tertiary case series. AB - We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision-making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long-term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined. PMID- 23461282 TI - Transmission Fourier transform infrared microspectroscopy allows simultaneous assessment of cutin and cell-wall polysaccharides of Arabidopsis petals. AB - A procedure for the simultaneous analysis of cell-wall polysaccharides, amides and aliphatic polyesters by transmission Fourier transform infrared microspectroscopy (FTIR) has been established for Arabidopsis petals. The combination of FTIR imaging with spectra derivatization revealed that petals, in contrast to other organs, have a characteristic chemical zoning with high amount of aliphatic compounds and esters in the lamina and of polysaccharides in the stalk of the petal. The hinge region of petals was particular rich in amides as well as in vibrations potentially associated with hemicellulose. In addition, a number of other distribution patterns have been identified. Analyses of mutants in cutin deposition confirmed that vibrations of aliphatic compounds and esters present in the lamina were largely associated with the cuticular polyester. Calculation of spectrotypes, including the standard deviation of intensities, allowed detailed comparison of the spectral features of various mutants. The spectrotypes not only revealed differences in the amount of polyesters in cutin mutants, but also changes in other compound classes. For example, in addition to the expected strong deficiencies in polyester content, the long-chain acyl CoA synthase 2 mutant showed increased intensities of vibrations in a wavelength range that is typical for polysaccharides. Identical spectral features were observed in quasimodo2, a cell-wall mutant of Arabidopsis with a defect in pectin formation that exhibits increased cellulose synthase activity. FTIR thus proved to be a convenient method for the identification and characterization of mutants affected in the deposition of cutin in petals. PMID- 23461283 TI - Effect of prophylactic intraocular pressure-lowering medication on pain during cataract surgery. AB - PURPOSE: This study evaluated the effects of acetazolamide, latanoprost, travoprost, bimatoprost, brimonidine, brinzolamide, and timolol on pain during phacoemulsification cataract surgery. METHODS: This prospective randomized comparative study included 323 eyes of 323 patients with no history of intraocular surgery or chronic eye disease who underwent uncomplicated phacoemulsification cataract surgery and foldable intraocular lens implantation under topical anesthesia. Patients were divided into 8 groups according to the preoperative prophylactic intraocular pressure (IOP)-lowering medication. The intraoperative pain was assessed postoperatively using a visual analog pain scale. The Kruskal-Wallis test investigated the differences in the visual analog pain-scale scores of the groups, and the Mann-Whitney U test investigated the pairwise comparison of the groups. RESULTS: The median visual analog pain-scale score of the group that did not receive any IOP-lowering medication was 2.0+/ 1.89. The brimonidine group exhibited the lowest visual analog pain-scale scores, and the prostanoids, especially the bimatoprost group, demonstrated the highest visual analog pain-scale scores (median+/-standard deviation were 0.0+/-1.50 and 2.0+/-1.91, respectively). The median visual analog pain-scale scores of the acetazolamide, latanoprost, travoprost, brinzolamide, and timolol groups were 0.0+/-1.62, 2.0+/-1.67, 2.0+/-1.73, 0.0+/-1.66, and 1.0+/-1.54, respectively. A pairwise comparison using the Mann-Whitney U test with Bonferroni correction revealed significant differences between the groups of acetozolamide and travoprost (p=0.001), acetozolamide and bimatoprost (p<0.001), travoprost and brimonidine (p<0.001), bimatoprost and brimonidine (p<0.001), and bimatoprost and timolol (p=0.001). CONCLUSIONS: Prophylactic application of the IOP-lowering medication may alter the pain sensation during phacoemulsification cataract surgery. PMID- 23461284 TI - Association between depression and tinnitus in a nationally representative sample of US older adults. AB - OBJECTIVES: Few population-based studies examining the association between tinnitus and depression among older adults have been conducted. Therefore, the purpose of this study was to examine the association between tinnitus and depression among a nationally representative sample of US older adults. METHODS: Data from the 2005-2006 National Health and Nutrition Examination Survey was used. 696 older adults (70-85 yr) completed questionnaires on tinnitus and depression, with depression assessed using the Patient Health Questionnaire-9. RESULTS: After controlling for firearm use, age, gender, race-ethnicity, cardiovascular/stroke history, diabetes, smoking status, body mass index, physical activity, noise exposure and elevated blood pressure, there was a significant positive association (beta coefficient: 1.28, 95% CI: 0.26-2.29, p = 0.01) between depression and tinnitus being at least a moderate problem, suggesting that those who perceived their tinnitus to be a moderate problem were more likely to be depressed than those perceiving it to be a small or no problem. Additionally, after adjustments, those who were bothered by tinnitus when going to bed were 3.06 times more likely to be depressed than those who were not bothered by tinnitus when going to bed (OR = 2.44, 95% CI: 1.03-5.76, p = 0.04). CONCLUSION: These findings suggest that individuals who perceive their tinnitus to be a problem or have problems with tinnitus when going to bed may be in need of intervention to prevent or reduce their depression symptoms so as to ensure that other areas of their life are not negatively influenced. PMID- 23461286 TI - A prospective analysis of robotic tip cover accessory failure. AB - BACKGROUND AND PURPOSE: The robotic monopolar scissors tip cover accessory (TCA) is an insulation device that prevents current leak from surfaces on the instrument other than the scissors tip. Reports of insulation failure and patient injury have been made but not systematically studied. We investigate the incidence of TCA failure and potential mechanisms that lead to malfunction. MATERIALS AND METHODS: Eighty TCAs (40 first and 40 second generation) were collected after a single urologic or gynecologic surgery at a single academic institution. Each TCA was inspected for damage under a microscope. Current leak was measured in an electrolysis solution, and electrical arcing was tested in a porcine kidney model. Log-rank and Friedman two-way analysis of variance by ranks compared failure at different angulations and power settings. Chi-square analysis compared failure between first and second generation TCAs (f-TCAs and s-TCAs). RESULTS: Visible insulation defects were detected in 39% of f-TCAs (size range <0.5-2.75 mm). Electrical arcing was observed in 33% of f-TCAs. Arcing increased with greater wrist angulation (P=0.014) and higher power settings (P=0.048). Minor damage was observed in 25% of s-TCAs. No electrical arcing was observed in any of the s-TCAs despite angulation and power strain. s-TCAs demonstrated significantly less failure than f-TCAs (P<0.001). CONCLUSION: In this study, 33% of f-TCAs demonstrated insulation failure after a single surgical use. f-TCA failure increased with greater wrist angulation and electrical power. The improved design of s-TCAs demonstrated no current leak or arcing on ex-vivo testing and appears to have significantly decreased failure potential. Centers still using the f-TCA should transition to the s-TCA and be vigilant in reporting device failures to prevent unnecessary patient morbidity. PMID- 23461285 TI - Colonization of freshwater biofilms by nitrifying bacteria from activated sludge. AB - Effluents from wastewater treatment plants (WWTPs) containing micro-organisms and residual nitrogen can stimulate nitrification in freshwater streams. We hypothesized that different ammonia-oxidizing (AOB) and nitrite-oxidizing (NOB) bacteria present in WWTP effluents differ in their potential to colonize biofilms in the receiving streams. In an experimental approach, we monitored biofilm colonization by nitrifiers in ammonium- or nitrite-fed microcosm flumes after inoculation with activated sludge. In a field study, we compared the nitrifier communities in a full-scale WWTP and in epilithic biofilms downstream of the WWTP outlet. Despite substantially different ammonia concentrations in the microcosms and the stream, the same nitrifiers were detected by fluorescence in situ hybridization in all biofilms. Of the diverse nitrifiers present in the WWTPs, only AOB of the Nitrosomonas oligotropha/ureae lineage and NOB of Nitrospira sublineage I colonized the natural biofilms. Analysis of the amoA gene encoding the alpha subunit of ammonia monooxygenase of AOB revealed seven identical amoA sequence types. Six of these affiliated with the N. oligotropha/ureae lineage and were shared between the WWTP and the stream biofilms, but the other shared sequence type grouped with the N. europaea/eutropha and N. communis lineage. Measured nitrification activities were high in the microcosms and the stream. Our results show that nitrifiers from WWTPs can colonize freshwater biofilms and confirm that WWTP-affected streams are hot spots of nitrification. PMID- 23461287 TI - Detection of living anionic species in polymerization reactions using hyperpolarized NMR. AB - Intermediates during the anionic polymerization of styrene were observed using hyperpolarized NMR. Dissolution dynamic nuclear polarization (DNP) of monomers provides a sufficient signal-to-noise ratio for detection of (13)C NMR signals in real time as the reaction progresses. Because of its large chemical shift dispersion, (13)C is well-suited to distinguish and characterize the chemical species that arise during the reaction. At the same time, incorporation of hyperpolarized small-molecule monomers is a unique way to generate polymers that exhibit a transient signal enhancement at the active site. This strategy is applicable despite the decay of the hyperpolarization of the polymer due to rapid spin-lattice relaxation. Real-time measurements on polymerization reactions provide both mechanistic and kinetic information without the need for stable isotope labeling of the molecules of interest. These capabilities are orthogonal to currently established methods that separate synthesis and analysis into two steps, making dissolution DNP an attractive method to study polymerization reactions. PMID- 23461295 TI - The biological effects and mechanisms of calcitonin gene-related peptide on human endothelial cell. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is a neuropeptide distributed in bone tissue involved in bone remodeling. Previously we demonstrated that CGRP can promote proliferation and migration of endothelial cells, relating to the expression of vascular endothelial growth factor (VEGF) and focal adhesion kinase (FAK). METHODS: CGRP1 receptor expression in human umbilical vein endothelial cells (HUVECs) was examined by immunofluorescence microscopy and real-time PCR. Tube formation was measured by a Matrigel tube formation assay. VEGF protein and mRNA levels were quantified by ELISA and real-time PCR, respectively. The expression of VEGF receptor 1 (FLT1) and VEGF receptor 2 (KDR) were measured by real-time PCR and immunoblotting assays. RESULTS: CGRP significantly induced vascular tube formation of outgrowth HUVECs in a Matrigel. The expression of FLT and KDR were significantly increased by CGRP, and CGRP enhanced the expression of CGRP1 receptors. Compared to the known angiogenesis regulator VEGF(165), CGRP had an equal or stronger effect on migration and tube formation, but not on proliferation of endothelial cells. The upregulation of calcitonin receptor-like receptor (CRLR), FAK, VEGF and its two main receptors (FLT1, KDR) by CGRP was also more pronounced than that obtained by VEGF(165). CONCLUSION: It is concluded that CGRP is a strong proangiogenic growth factor, thereby contributing to bone development and remodeling by promoting angiogenesis. PMID- 23461296 TI - Anti-Mullerian hormone and polycystic ovary syndrome: assessment of the clinical pregnancy rates in in vitro fertilization patients. AB - OBJECTIVE: The purpose of this study is to investigate the role of serum anti Mullerian hormone (AMH), follicle-stimulating hormone (FSH) and antral follicle count (AFC) for the prediction of clinical pregnancy rates (CPR) in women with polycystic ovary syndrome (PCOS) undergoing IVF treatment. DESIGN: Prospective cohort study. SETTING: University hospital. PATIENTS: One hundred and fifty consecutive women with PCOS. INTERVENTIONS: All women underwent controlled ovarian stimulation with long agonist protocol followed by IVF procedure. Outcomes of pregnant and non-pregnant groups were compared. MAIN OUTCOME MEASURE: CPR; AMH, FSH and AFC means and percentiles. RESULTS: Fifty-one (34%) clinical pregnancies were observed in 150 women. Mean AMH was 6.7 +/- 2.8 and 7.1 +/- 4.3 ng/mL in pregnant and non-pregnant women, respectively (p = 0.594). The CPR were 27.8%, 35.0% and 37.8% in <25%, 25%-75% and >75% AMH percentiles, respectively (p = 0.656). There were also no significant difference in mean FSH and AFC between pregnant and non-pregnant women (p = 0.484 and p = 0.165, respectively). CONCLUSION: AMH, FSH and AFC are not predictive for CPR in women with PCOS undergoing IVF treatment. Mean AMH values were not significantly different between pregnant and non-pregnant women. Although CRP increased in parallel with the raise in AMH percentiles, this remained insignificant. PMID- 23461297 TI - In silico identification of novel chitinase-like proteins in the silkworm, Bombyx mori, genome. AB - In insects, chitinases participate in the periodic shedding of old exoskeletons and the turnover of peritrophic membranes. Chitinase family members have been identified in dozens of species, including Tribolium castaneum, Drosophila melanogaster, and Anopheles gambiae. In this study, nine chitinases and three hypothetical chitinases have been identified in Bombyx mori L. (Lepidoptera: Bombycidae) through genome-wide searching. Phylogenetic analyses revealed that seven of them belong to the seven chitinase groups, respectively. BmCht25 and BmCht26 could not be grouped into the known chitinase groups, and might belong to two new groups of the chitinase family. BmCht10, BmCht25, and BmIDGF have glutamate amino acid substitutions in the active catalytic domain. Only BmCht5 and BmCht10 contain CBD domain and PEST sequences (rich in proline, glutamic acid, serine, and threonine). BmCht5 and BmCht26 are located on chromosome 7, and others (BmCht6, BmCht7, BmCht10, BmCht11, BmCht20, BmIDGF) are located on separate chromosomes of Bombyx mori, respectively. The present study provides important background information for future studies using Bombyx mori as a model organism for insect development and virus and host interaction. PMID- 23461298 TI - Polyphenolic composition, antioxidant activity, and polyphenol oxidase (PPO) activity of quince (Cydonia oblonga Miller) varieties. AB - Phytochemical profiles (phenolic compounds, L-ascorbic acid, antioxidant and PPO activities) of 13 different quince varieties and 5 genotypes were studied. Polyphenols were identified by LC-PDA-QTof/MS and quantified by UPLC-PDA and UPLC FL. A total of 26 polyphenolic compounds found in quince tissues were identified and presented: 9 flavan-3-ols ((-)-epicatechin, procyanidin B2, 3 procyanidin dimers and trimers, and 1 tetramer); 8 hydroxycinnamates, derivatives of caffeoylquinic and coumaroylquinic acid; and 9 kaempferol and quercetin derivatives. The content of total polyphenols was between 1709.43 (genotype 'S1') and 3436.56 mg/100 g dry weight ('Leskovac'). Flavan-3-ols, which are the major class of quince polyphenols, represented between 78 and 94% of the total polyphenolic compounds. The activity of PPO enzyme ranged from 709.85 to 1284.59 DeltaU/min, and that of L-ascorbic acid ranged from 5.86 to 26.42 mg/100 g. Some quince varieties and their products characterized by a higher content of phenolic compounds may be selected to promote their positive effect on health. PMID- 23461299 TI - Integrating palliative care information and hospice referral in medicaid primary care. AB - BACKGROUND: Hospice and palliative care (PC) remain underutilized by Medicaid patients. OBJECTIVE: Our aim was to evaluate an intervention to improve communication about advance care planning (ACP) and symptom distress, and to facilitate referral to PC and hospice. METHODS: We conducted a study in a statewide Medicaid primary care network with 510 Medicaid care managers (CMs). PC experts collaborated with leaders in the statewide primary care network on a quality improvement intervention. Training components included education and engagement with local hospice and PC providers. Quality improvement components included feedback of quality measures and a practice toolkit. Evaluation used participant surveys and tracking of key quality measures: 1) percent of at-risk subset of aged, blind, and disabled (ABD) Medicaid patients asked about ACP or symptom distress; 2) cumulative number of ABD Medicaid PC or hospice referrals; and 3) the percent of all nondual ABD Medicaid decedents enrolled in hospice. RESULTS: After training, CMs identified the following areas for expected practice change: ACP (29%), identifying/referring patients for hospice or PC (25%), supporting patients and families (21%), toolkit utilization (10%), and engaging medical providers (10%). Over one-year follow-up the percent of moderate and high risk ABD Medicaid patients asked about ACP or symptoms increased from 7% to 31% and 8% to 41%, respectively (p<0.001). The cumulative number of PC or hospice referrals increased from 8 to 155. Hospice enrollment at death was unchanged (29% to 30%, p=NS [nonsignificant]). CONCLUSIONS: A statewide intervention targeting CMs in a Medicaid primary care practice network is effective to increase communication and hospice and PC referrals; longer follow-up may be required to determine effect on hospice use. PMID- 23461300 TI - Pediatric palliative care research comes of age: what we stand to learn from children with life-threatening illness. PMID- 23461301 TI - End-of-life care discussions with nonmalignant respiratory disease patients: a systematic review. AB - BACKGROUND: Patients with nonmalignant respiratory diseases have limited access to palliative care services and health professionals do not adequately address discussions about end-of-life care preferences. OBJECTIVE: The aim of this systematic literature review was to highlight key components and challenges for patients and health professionals discussing end-of-life care in nonmalignant respiratory disease. DESIGN: A mixed methods systematic review was conducted. Included studies were assessed for quality and data were synthesized thematically, while original data were presented in tabular form. DATA SOURCES: PubMed, CINAHL, BNI, ASSIA, PsycINFO, Science Direct, and Web of Science were searched (1999-2010) for studies on end-of-life discussions. Additional studies were identified by hand searching key journals and reference lists of included articles. RESULTS: Fourteen studies were identified. Three themes involving components and challenges in end-of-life discussions were identified: the discussion, the health professional/patient relationship, and patient perceptions. CONCLUSIONS: End-of-life discussions should be initiated by health professionals, who must be aware of patient expectations regarding palliative care and end-of-life care planning. Efforts must be made to develop relationships with patients with terminal illness and allow sufficient time to discuss the end of life during clinical encounters. Future research should address palliative care uptake in nonmalignant disease and implications for health education should be addressed. PMID- 23461302 TI - The changing landscape of controlling sexually transmitted infections in the U.S. military. PMID- 23461303 TI - Sexually transmitted infections, active component, U.S. Armed Forces, 2000-2012. AB - This report summarizes incidence rates of the five most commonly diagnosed sexually transmitted infections (STIs) among active component service members of the U.S. Armed Forces during 2000 to 2012. Human papillomavirus (HPV) infections were the most common, followed in decreasing order of frequency by infections associated with chlamydia, herpes simplex virus, gonorrhea, and syphilis. Compared to their counterparts, women, younger service members, soldiers, and enlisted members had higher incidence rates of each STI. Rates tended to be lower among married personnel. Rates of chlamydia, HPV, and gonorrhea diagnoses were notably higher among women during 2006 to 2008 but rates of the latter two infections have since declined sharply. The relatively recent introduction of STI screening among young service women and the HPV vaccine are discussed. PMID- 23461304 TI - Predictive value of reportable medical events for Neisseria gonorrhoeae and Chlamydia trachomatis. AB - Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) are notifiable diseases reported under the guidelines of the Armed Forces Reportable Medical Event Guidelines and Case Definitions. Records of clinical laboratory tests (Health Level 7) were used to calculate the sensitivity, specificity, and positive predictive value (PPV) of confirmed reportable medical events (RMEs) for gonorrhea and chlamydia. The sensitivity--which reflects the proportion of "true cases" identified by an RME--was 65 percent and 62 percent for gonorrhea and chlamydia, respectively. The specificity--the percentage of individuals with negative lab tests who did not have RMEs--was high (>98%) for both infections. The PPV--the percentage of people with an RME who have a positive test--was also relatively high (>80%) for both infections. Using confirmed RMEs alone to estimate incident cases of gonorrhea and chlamydia may underestimate the true disease burden. PMID- 23461305 TI - Chlamydia trachomatis screening initiative among U.S. Army soldiers assigned to Korea. PMID- 23461306 TI - Incidence of genital warts among U.S. service members before and after the introduction of the quadrivalent human papillomavirus vaccine. AB - Human papillomavirus (HPV) is the most common sexually transmitted infection among U.S. military members. The most frequent clinical manifestation of HPV is genital warts (GW). This investigation examined the annual incidence of diagnoses of GW among U.S. service members before and after the availability of the quadrivalent HPV (HPV4) vaccine in 2006. Incidence rates of GW diagnoses markedly declined among female service members in the HPV4 vaccine-eligible age range from 2007 (following introduction of the HPV4 vaccine) through 2010. In contrast, among women 25 years and older and men of all age groups, annual rates of GW diagnoses remained relatively low and stable from 2000 through 2010. The higher rates of diagnoses of GWs among female than male service members reflect the effects of routine periodic gynecologic screening. Slight increases in the incidence of GW diagnoses among men between 2010 and 2012 may in part reflect the repeal of the U.S. military's "Don't Ask Don't Tell" policy. PMID- 23461307 TI - Human papillomavirus seroprevalence among men entering military service and seroincidence after ten years of service. AB - Vaccination against human papillomavirus (HPV) is recommended to prevent cervical cancer among women. Vaccinating men against human papillomavirus (HPV) can prevent penile, anal, and oral cancers, anogenital warts, and the transmission of HPV to their sexual partners. This study characterized HPV acquisition among male military members by evaluating both seroprevalence at entry into service and seroincidence of HPV infection after ten years of service. At entry, 29 of 200 (14.5%) male service members were positive for HPV serotypes 6, 11, 16, or 18. Of 199 initially seronegative for at least one of the four HPV serotypes, 68 (34.2%) seroconverted to one or more serotypes at ten years; more than one-third of these were seropositive for oncogenic HPV serotypes. This estimate of HPV seroprevalence among male military accessions is higher than that reported among U.S. civilian males. Vaccination to prevent genital warts and cancers resulting from HPV infection may decrease health care system burdens. Further analyses are warranted to understand the potential costs and benefits of a policy to vaccinate male service members. PMID- 23461308 TI - The U.S. military's Neisseria gonorrhoeae resistance surveillance initiatives in selected populations of five countries. AB - Multi-drug resistant Neisseria gonorrhoeae (GC) threatens the successful treatment of gonorrhea. This report presents preliminary findings with regard to the prevalence of laboratory-confirmed GC and the extent of drug-resistance among sample populations in five countries. Between October 2010 and January 2013, 1,694 subjects (54% male; 45% female; 1% unknown) were enrolled and screened for the presence of laboratory-confirmed GC in the United States, Djibouti, Ghana, Kenya, and Peru. Overall, 108 (6%) of enrolled subjects tested positive for GC. Antimicrobial susceptibility testing results were available for 66 GC isolates. Resistance to at least three antibiotics was observed at each overseas site. All isolates tested in Ghana (n=6) were resistant to ciprofloxacin, penicillin, and tetracycline. In Djibouti, preliminary results suggested resistance to penicillin, tetracycline, ciprofloxacin, cefepime, and ceftriaxone. The small sample size and missing data prevent comparative analysis and limit the generalizability of these preliminary findings. PMID- 23461309 TI - Microbial contamination of hematopoietic progenitor and other regenerative cells used in transplantation and regenerative medicine. AB - BACKGROUND: Microbial contamination of hematopoietic progenitor cells (HPCs) and other regenerative cells used in transplantation and regenerative medicine can occur during collection and after in vitro manipulation, including purging, cryopreservation, thawing, and infusion. STUDY DESIGN AND METHODS: Microbiologic culture findings on consecutive HPCs and other cell preparations at a single institution derived from peripheral blood, marrow, cord blood, and mesenchymal stromal cells during all phases of manipulation were retrospectively examined from 2005 through 2011. Results were classified as confirmed positive, false positive, and indeterminate. RESULTS: During the 6-year surveillance period, 365 patients underwent 912 procedures involving HPC or other cell-based transfusion. True positive microbial contamination was found in five of 663 (0.8%) peripheral blood and two of 34 (5.9%) marrow preparations (p = 0.04), while no contamination was found in 118 preparations from other sources. True-positive microbial contaminants included coagulase-negative staphylococci in autologous HPC products derived from peripheral blood from two patients with asymptomatic central venous catheter infections at time of apheresis and Propionibacterium acnes in one apheresis and two marrow products. Organism loads were low in all cases (<=500 colony-forming units/mL), and no adverse sequelae occurred in four patients that received contaminated products. CONCLUSION: The incidence of microbial contamination of progenitor cell products in our institution over a 6-year period was low (0.8% overall), with contaminants originating from infected central venous catheters or from skin flora. All contaminants were bacterial species of low virulence, present in low titers and, if transfused, did not result in adverse reactions. PMID- 23461310 TI - Perioperative and early oncological outcomes after robot-assisted radical prostatectomy (RARP) in morbidly obese patients: a propensity score-matched study. AB - OBJECTIVE: To evaluate the perioperative and pathological outcomes associated with robot-assisted radical prostatectomy (RARP) in morbidly obese men. PATIENTS AND METHODS: Between January 2008 and March 2012, 3041 patients underwent RARP at our institution by a single surgeon (V.P.). In all, 44 patients were considered morbidly obese with a body mass index (BMI) of >=40 kg/m(2) . A propensity score matched analysis was conducted using multivariable analysis to identify comparable groups of patients with a BMI of >=40 and <40 kg/m(2) . Perioperative, pathological outcomes and complications were compared between the two matched groups. RESULTS: There was no significant difference in operative time. However, the mean estimated blood loss was higher in morbidly obese patients, at a mean (sd) of 113 (41) vs 130 (27) mL (P = 0.049). Anastomosis was more difficult in morbidly obese patients (P = 0.001). There were no significant differences in laterality, ease of nerve sparing, or transfusion rate between the groups. There were no intraoperative complications in either group. Postoperative pathological outcomes were similar between the groups. Differences in positive surgical margins and ease of nerve sparing approached statistical significance (P = 0.097, P = 0.075 respectively). Postoperative complication rates, pain scores, length of stay and indwelling catheter duration were similar in the groups. CONCLUSIONS: RARP in morbidly obese patients is technically demanding. However, it can be accomplished with acceptable morbidity and resource use. In the hands of an experienced surgeon, it is a safe procedure and offers beneficial clinical outcomes. PMID- 23461311 TI - Association of anti-IL-12/23 biologic agents ustekinumab and briakinumab with major adverse cardiovascular events. PMID- 23461312 TI - Microsheath for microperc: 14-gauge angiocath. AB - Micropercutaneous nephrolithotomy (microperc) is the end point percutaneous nephrolithotomy (PCNL) technology for the present. In routine PCNL surgery, use of an Amplatz sheath is an important step, but in this technique, there is no Amplatz sheath. Some problems during surgery may occur because of the lack of an Amplatz sheath, which provides a tract between the skin and the collecting system. Therefore, we describe the smallest Amplatz sheath (6.6F) that is compatible with the microperc instrument and can be used during percutaneous surgery, especially in preschool pediatric patients. PMID- 23461313 TI - Sex chromosome linked genetic variance and the evolution of sexual dimorphism of quantitative traits. AB - Theory predicts that sex chromsome linkage should reduce intersexual genetic correlations thereby allowing the evolution of sexual dimorphism. Empirical evidence for sex linkage has come largely from crosses and few studies have examined how sexual dimorphism and sex linkage are related within outbred populations. Here, we use data on an array of different traits measured on over 10,000 individuals from two pedigreed populations of birds (collared flycatcher and zebra finch) to estimate the amount of sex-linked genetic variance (h(2)z ). Of 17 traits examined, eight showed a nonzero h(2)Z estimate but only four were significantly different from zero (wing patch size and tarsus length in collared flycatchers, wing length and beak color in zebra finches). We further tested how sexual dimorphism and the mode of selection operating on the trait relate to the proportion of sex-linked genetic variance. Sexually selected traits did not show higher h(2)Z than morphological traits and there was only a weak positive relationship between h(2)Z and sexual dimorphism. However, given the relative scarcity of empirical studies, it is premature to make conclusions about the role of sex chromosome linkage in the evolution of sexual dimorphism. PMID- 23461314 TI - Oxidative stress and the evolution of sex differences in life span and ageing in the decorated cricket, Gryllodes sigillatus. AB - The Free Radical Theory of Ageing (FRTA) predicts that oxidative stress, induced when levels of reactive oxygen species exceed the capacity of antioxidant defenses, causes ageing. Recently, it has also been argued that oxidative damage may mediate important life-history trade-offs. Here, we use inbred lines of the decorated cricket, Gryllodes sigillatus, to estimate the genetic (co)variance between age-dependent reproductive effort, life span, ageing, oxidative damage, and total antioxidant capacity within and between the sexes. The FRTA predicts that oxidative damage should accumulate with age and negatively correlate with life span. We find that protein oxidation is greater in the shorter lived sex (females) and negatively genetically correlated with life span in both sexes. However, oxidative damage did not accumulate with age in either sex. Previously we have shown antagonistic pleiotropy between the genes for early-life reproductive effort and ageing rate in both sexes, although this was stronger in females. In females, we find that elevated fecundity early in life is associated with greater protein oxidation later in life, which is in turn positively correlated with the rate of ageing. Our results provide mixed support for the FRTA but suggest that oxidative stress may mediate sex-specific life-history strategies in G. sigillatus. PMID- 23461315 TI - Sex-chromosome turnovers induced by deleterious mutation load. AB - In sharp contrast with mammals and birds, many cold-blooded vertebrates present homomorphic sex chromosomes. Empirical evidence supports a role for frequent turnovers, which replace nonrecombining sex chromosomes before they have time to decay. Three main mechanisms have been proposed for such turnovers, relying either on neutral processes, sex-ratio selection, or intrinsic benefits of the new sex-determining genes (due, e.g., to linkage with sexually antagonistic mutations). Here, we suggest an additional mechanism, arising from the load of deleterious mutations that accumulate on nonrecombining sex chromosomes. In the absence of dosage compensation, this load should progressively lower survival rate in the heterogametic sex. Turnovers should occur when this cost outweighs the benefits gained from any sexually antagonistic genes carried by the nonrecombining sex chromosome. We use individual-based simulations of a Muller's ratchet process to test this prediction, and investigate how the relevant parameters (effective population size, strength and dominance of deleterious mutations, size of nonrecombining segment, and strength of sexually antagonistic selection) are expected to affect the rate of turnovers. PMID- 23461316 TI - Overcoming statistical bias to estimate genetic mating systems in open populations: a comparison of Bateman's principles between the sexes in a sex-role reversed pipefish. AB - The genetic mating system is a key component of the sexual selection process, yet methods for the quantification of mating systems remain controversial. One approach involves metrics derived from Bateman's principles, which are based on variances in mating and reproductive success and the relationship between them. However, these measures are extremely difficult to measure for both sexes in open populations, because missing data can result in biased estimates. Here, we develop a novel approach for the estimation of mating system metrics based on Bateman's principles and apply it to a microsatellite-based parentage analysis of a natural population of the dusky pipefish, Syngnathus floridae. Our results show that both male and female dusky pipefish have significantly positive Bateman gradients. However, females exhibit larger values of the opportunity for sexual selection and the opportunity for selection compared to males. These differences translate into a maximum intensity of sexual selection (S'max) for females three times larger than that for males. Overall, this study identifies a critical source of bias that affects studies of mating systems in open populations, presents a novel method for overcoming this bias, and applies this method for the first time in a sex-role-reversed pipefish. PMID- 23461317 TI - Comparative analyses of sex-ratio variation in dioecious flowering plants. AB - Dioecious plant species commonly exhibit deviations from the equilibrium expectation of 1:1 sex ratio, but the mechanisms governing this variation are poorly understood. Here, we use comparative analyses of 243 species, representing 123 genera and 61 families to investigate ecological and genetic correlates of variation in the operational (flowering) sex ratio. After controlling for phylogenetic nonindependence, we examined the influence of growth form, clonality, fleshy fruits, pollen and seed dispersal vector, and the possession of sex chromosomes on sex-ratio variation. Male-biased flowering sex ratios were twice as common as female-biased ratios. Male bias was associated with long-lived growth forms (e.g., trees) and biotic seed dispersal and fleshy fruits, whereas female bias was associated with clonality, especially for herbaceous species, and abiotic pollen dispersal. Female bias occurred in species with sex chromosomes and there was some evidence for a greater degree of bias in those with heteromorphic sex chromosomes. Although the role of interactions among these correlates require further study, our results indicate that sex-based differences in costs of reproduction, pollen and seed dispersal mechanisms and sex chromosomes can each play important roles in affecting flowering sex ratios in dioecious plants. PMID- 23461318 TI - The complex interplay of sex allocation and sexual selection. AB - It is well recognized that sex allocation strategies can be influenced by sexual selection, when females adjust offspring sex ratios in response to their mates' attractiveness. Yet the reciprocal influence of strategic sex allocation on processes of sexual selection has only recently been revealed. Recent theoretical work demonstrates that sex allocation weakens selection for female preferences, leading to the decline of male traits. However, these results have been derived assuming that females have perfect knowledge of mate attractiveness and precise control over cost-free allocation. Relaxing these assumptions highlights the importance of another feedback: that adaptive sex allocation must become difficult to maintain as traits and preferences decline. When sex allocation strategies erode not only traits and preferences but also their own selective advantage, predictions can no longer be expressed as a simple linear correlation between ornament exaggeration and adaptive sex allocation. Instead, strongest sex ratio biases may be found at intermediate trait levels. PMID- 23461319 TI - MHC variation is related to a sexually selected ornament, survival, and parasite resistance in common yellowthroats. AB - Hamilton and Zuk proposed that females choose mates based on ornaments whose expression is dependent on their genetically based resistance to parasites. The major histocompatibility complex (MHC) plays an important role in pathogen recognition and is a good candidate for testing the relationships between immune genes and both ornament expression and parasite resistance. We tested the hypothesis that female common yellowthroats prefer to mate with more ornamented males, because it is a signal of their MHC-based resistance to parasites and likelihood of survival. In this species, females prefer males that have larger black facial masks as extrapair mates. Using pyrosequencing, we found that mask size was positively related to the number of different MHC class II alleles, as predicted if greater variation at the MHC allows for the recognition of a greater variety of pathogens. Furthermore, males with more MHC class II alleles had greater apparent survival, and resistance to malaria infection was associated with the presence of a particular MHC class II allele. Thus, extrapair mating may provide female warblers with immunity genes that are related to parasite resistance, survival, and the expression of a male ornament, consistent with good genes models of sexual selection. PMID- 23461320 TI - Social learners require process information to outperform individual learners. AB - Humans exhibit a rich and complex material culture with no equivalent in animals. Also, social learning, a crucial requirement for culture, is particularly developed in humans and provides a means to accumulate knowledge over time and to develop advanced technologies. However, the type of social learning required for the evolution of this complex material culture is still debated. Here, using a complex and opaque virtual task, the efficiency of individual learning and two types of social learning (product-copying and process-copying) were compared. We found that (1) individuals from process-copying groups outperformed individuals from product-copying groups or individual learners, whereas access to product information was not a sufficient condition for providing an advantage to social learners compared to individual learners; (2) social learning did not seem to affect the exploration of the fitness landscape; (3) social learning led to strong within-group convergence and also to between-group convergence, and (4) individuals used widely variable social learning strategies. The implications of these results for cumulative culture evolution are discussed. PMID- 23461321 TI - The evolutionary dynamics of spite in finite populations. AB - Spite, the shady relative of altruism, involves paying a fitness cost to inflict a cost on some recipient. Here, we investigate a density dependent dynamic model for the evolution of spite in populations of changing size. We extend the model by introducing a dynamic carrying capacity. Our analysis shows that it is possible for unconditionally spiteful behavior to evolve without population structure in any finite population. In some circumstances spiteful behavior can contribute to its own stability by limiting population growth. We use the model to show that there are differences between spite and altruism, and to refine Hamilton's original argument about the insignificance of spite in the wild. We also discuss the importance of fixing the measure of fitness to classify behaviors as selfish or spiteful. PMID- 23461322 TI - Genetic constraints on adaptation to a changing environment. AB - Genetic correlations between traits can constrain responses to natural selection. To what extent such correlations limit adaptation depends on patterns of directional selection. I derive the expected rate of adaptation (or evolvability) under randomly changing selection gradients. When directional selection gradients have an arbitrary covariance matrix, the average rate of adaptation depends on genetic correlations between traits, contrary to the isotropic case investigated in previous studies. Adaptation may be faster on average with more genetic correlation between traits, if these traits are selected to change jointly more often than the average pair of traits. However, natural selection maximizes the long-term fitness of a population, not necessarily its rate of adaptation. I therefore derive the average lag load caused by deviations of the mean phenotype from an optimum, under several forms of environmental changes typically experienced by natural populations, both stochastic and deterministic. Simple formulas are produced for how the G matrix affects long-term fitness in these contexts, and I discuss how their parameters can be estimated empirically. PMID- 23461323 TI - Adaptive divergence at the margin of an invaded range. AB - Invasive plant species threaten biological communities globally. However, relatively little is known about how evolutionary processes vary over the course of an invasion. To evaluate the importance of historical and adaptive drivers of range expansion, we compare the performance of North American populations of invasive Lonicera japonica from areas established 100-150 years ago, now the southern core of the range, to populations from the northern range margin, established within the last 65 years. Growth and survival of individuals from 17 core and 14 margin populations were compared in common gardens at both regions. After three years, margin plants were larger than core plants regardless of planting region, with 34% more branches and 36% greater biomass. Growth rate was directly related to survival, and margin plants also had 30% greater survival than core plants across both regions. Larger size of individuals from margin populations suggests either that the shorter growing period at the northern margin has selected for more rapid growth or that range expansion has selected for plants with a greater colonizing ability, including rapid establishment and growth. Because this evolution has resulted in enhanced survival and increased growth rate it may drive spread, increasing the likelihood of further invasion. PMID- 23461324 TI - Evidence for repeated loss of selective constraint in rhodopsin of amblyopsid cavefishes (Teleostei: Amblyopsidae). AB - The genetic mechanisms underlying regressive evolution-the degeneration or loss of a derived trait--are largely unknown, particularly for complex structures such as eyes in cave organisms. In several eyeless animals, the visual photoreceptor rhodopsin appears to have retained functional amino acid sequences. Hypotheses to explain apparent maintenance of function include weak selection for retention of light-sensing abilities and its pleiotropic roles in circadian rhythms and thermotaxis. In contrast, we show that there has been repeated loss of functional constraint of rhodopsin in amblyopsid cavefishes, as at least three cave lineages have independently accumulated unique loss-of-function mutations over the last 10.3 Mya. Although several cave lineages still possess functional rhodopsin, they exhibit increased rates of nonsynonymous mutations that have greater effect on the structure and function of rhodopsin compared to those in surface lineages. These results indicate that functionality of rhodopsin has been repeatedly lost in amblyopsid cavefishes. The presence of a functional copy of rhodopsin in some cave lineages is likely explained by stochastic accumulation of mutations following recent subterranean colonization. PMID- 23461326 TI - The dynamics of reciprocal selective sweeps of host resistance and a parasite counter-adaptation in Drosophila. AB - Host-parasite coevolution can result in consecutive selective sweeps of host resistance alleles and parasite counter-adaptations. To illustrate the dynamics of this important but little studied form of coevolution, we have modeled an ongoing arms race between Drosophila melanogaster and the vertically transmitted sigma virus, using parameters we estimated in the field. We integrate these results with previous work showing that the spread of a resistance allele of the ref(2)P gene in the host was followed by the spread of a virus genotype, which overcomes this resistance. In line with these observations, our model predicts that there can be rapid selective sweeps in both the host and parasite, which can drive large changes in the prevalence of infection. The virus will tend to be ahead in the arms race, as incomplete dominance slows down host adaptation and selection for host resistance is weaker than selection for parasites to overcome resistance--the "life-dinner" principle. This asymmetry in the adaptation rates results in a partial sweep of the host resistance allele, as it loses its advantage part way through the selective sweep. This well-understood natural system illustrates how the outcome of host-parasite coevolution is determined by different population genetic parameters in the field. PMID- 23461327 TI - The genomic trajectory of hybrid swarms: outcomes of repeated crosses between populations of Tigriopus californicus. AB - Introgressive hybridization between genetically divergent populations is an important evolutionary process. The degree to which repeated hybridization events between the same parental taxa lead to similar genomic outcomes is unknown. This study addressed this question by following genomic trajectories of replicate hybrid swarms of the copepod Tigriopus californicus over many generations of free mating. Swarm composition was determined both by differential reproductive success of founder individuals and subsequent selection on hybrid genotypes. For one cross, between two populations showing differential fitness in the laboratory and no hybrid breakdown, the genetic trajectory was highly repeatable: replicates rapidly became dominated by alleles from the fitter parent. In a second cross, between two populations showing similar fitness and significant F2 hybrid breakdown, alleles from alternative populations dominated different replicates. Swarms exhibited a general temporal trend of decreasing cytonuclear mismatch. Some patterns of differential introgression across the genome were strikingly congruent amongst swarm replicates, both within and between cross types, and reflected patterns of segregation distortion previously observed within controlled crosses between the same parental populations. Differences in heterozygosity between the sexes, and evidence for a previously suspected sex distortion locus, suggest that complex interactions between sex and genotype influence hybrid swarm outcome. PMID- 23461325 TI - Defense traits of larval Drosophila melanogaster exhibit genetically based trade offs against different species of parasitoids. AB - Populations of Drosophila melanogaster face significant mortality risks from parasitoid wasps that use species-specific strategies to locate and survive in hosts. We tested the hypothesis that parasitoids with different strategies select for alternative host defense characteristics and in doing so contribute to the maintenance of fitness variation and produce trade-offs among traits. We characterized defense traits of Drosophila when exposed to parasitoids with different host searching behaviors (Aphaereta sp. and Leptopilina boulardi). We used host larvae with different natural alleles of the gene Dopa decarboxylase (Ddc), a gene controlling the production of dopamine and known to influence the immune response against parasitoids. Previous population genetic analyses indicate that our focal alleles are maintained by balancing selection. Genotypes exhibited a trade-off between the immune response against Aphaereta sp. and the ability to avoid parasitism by L. boulardi. We also identified a trade-off between the ability to avoid parasitism by L. boulardi and larval competitive ability as indicated by differences in foraging and feeding behavior. Genotypes differed in dopamine levels potentially explaining variation in these traits. Our results highlight the potential role of parasitoid biodiversity on host fitness variation and implicate Ddc as an antagonistic pleiotropic locus influencing larval fitness traits. PMID- 23461328 TI - How does pollen versus seed dispersal affect niche evolution? AB - In heterogeneous landscapes, the genetic and demographic consequences of dispersal influence the evolution of niche width. Unless pollen is limiting, pollen dispersal does not contribute directly to population growth. However, by disrupting local adaptation, it indirectly affects population dynamics. We compare the effect of pollen versus seed dispersal on the evolution of niche width in heterogeneous habitats, explicitly considering the feedback between maladaptation and demography. We consider two scenarios: the secondary contact of two subpopulations, in distinct, formerly isolated habitats, and the colonization of an empty habitat with dispersal between the new and ancestral habitat. With an analytical model, we identify critical levels of genetic variance leading to niche contraction (secondary contact scenario), or expansion (new habitat scenario). We confront these predictions with simulations where the genetic variance freely evolves. Niche contraction occurs when habitats are very different. It is faster as total gene flow increases or as pollen predominates in overall gene flow. Niche expansion occurs when habitat heterogeneity is not too high. Seed dispersal accelerates it, whereas pollen dispersal tends to retard it. In both scenarios very high seed dispersal leads to extinction. Overall, our results predict a wider niche for species dispersing seeds more than pollen. PMID- 23461329 TI - Mutational meltdown in selfing Arabidopsis lyrata. AB - The majority of plant species and many animals are hermaphrodites, with individuals expressing both female and male function. Although hermaphrodites can potentially reproduce by self-fertilization, they have a high prevalence of outcrossing. The genetic advantages of outcrossing are described by two hypotheses: avoidance of inbreeding depression because selfing leads to immediate expression of recessive deleterious mutations, and release from drift load because self-fertilization leads to long-term accumulation of deleterious mutations due to genetic drift and, eventually, to extinction. I tested both hypotheses by experimentally crossing Arabidopsis lyrata plants (self-pollinated, cross-pollinated within the population, or cross-pollinated between populations) and measuring offspring performance over 3 years. There were 18 source populations, each of which was either predominantly outcrossing, mixed mating, or predominantly selfing. Contrary to predictions, outcrossing populations had low inbreeding depression, which equaled that of selfing populations, challenging the central role of inbreeding depression in mating system shifts. However, plants from selfing populations showed the greatest increase in fitness when crossed with plants from other populations, reflecting higher drift load. The results support the hypothesis that extinction by mutational meltdown is why selfing hermaphroditic taxa are rare, despite their frequent appearance over evolutionary time. PMID- 23461330 TI - A shift in the long-term mode of foraminiferan size evolution caused by the end Permian mass extinction. AB - Size is among the most important traits of any organism, yet the factors that control its evolution remain poorly understood. In this study, we investigate controls on the evolution of organismal size using a newly compiled database of nearly 25,000 foraminiferan species and subspecies spanning the past 400 million years. We find a transition in the pattern of foraminiferan size evolution from correlation with atmospheric pO2 during the Paleozoic (400-250 million years ago) to long-term stasis during the post-Paleozoic (250 million years ago to present). Thus, a dramatic shift in the evolutionary mode coincides with the most severe biotic catastrophe of the Phanerozoic (543 million years ago to present). Paleozoic tracking of pO2 was confined to Order Fusulinida, whereas Paleozoic lagenides, miliolids, and textulariids were best described by the stasis model. Stasis continued to best describe miliolids and textulariids during post Paleozoic time, whereas random walk was the best supported mode for the other diverse orders. The shift in evolutionary dynamics thus appears to have resulted primarily from the selective elimination of fusulinids at the end of the Permian Period. These findings illustrate the potential for mass extinction to alter macroevolutionary dynamics for hundreds of millions of years. PMID- 23461331 TI - Testing for phylogenetic signal in biological traits: the ubiquity of cross product statistics. AB - To evaluate rates of evolution, to establish tests of correlation between two traits, or to investigate to what degree the phylogeny of a species assemblage is predictive of a trait value so-called tests for phylogenetic signal are used. Being based on different approaches, these tests are generally thought to possess quite different statistical performances. In this article, we show that the Blomberg et al. K and K*, the Abouheif index, the Moran's I, and the Mantel correlation are all based on a cross-product statistic, and are thus all related to each other when they are associated to a permutation test of phylogenetic signal. What changes is only the way phylogenetic and trait similarities (or dissimilarities) among the tips of a phylogeny are computed. The definitions of the phylogenetic and trait-based (dis)similarities among tips thus determines the performance of the tests. We shortly discuss the biological and statistical consequences (in terms of power and type I error of the tests) of the observed relatedness among the statistics that allow tests for phylogenetic signal. Blomberg et al. K* statistic appears as one on the most efficient approaches to test for phylogenetic signal. When branch lengths are not available or not accurate, Abouheif's Cmean statistic is a powerful alternative to K*. PMID- 23461332 TI - A single lineage in early Pleistocene Homo: size variation continuity in early Pleistocene Homo crania from East Africa and Georgia. AB - The relationship between Homo habilis and early African Homo erectus has been contentious because H. habilis was hypothesized to be an evolutionary stage between Australopithecus and H. erectus, more than a half-century ago. Recent work re-dating key African early Homo localities and the discovery of new fossils in East Africa and Georgia provide the opportunity for a productive re-evaluation of this topic. Here, we test the hypothesis that the cranial sample from East Africa and Georgia represents a single evolutionary lineage of Homo spanning the approximately 1.9-1.5 Mya time period, consisting of specimens attributed to H. habilis and H. erectus. To address issues of small sample sizes in each time period, and uneven representation of cranial data, we developed a novel nonparametric randomization technique based on the variance in an index of pairwise difference from a broad set of fossil comparisons. We fail to reject the hypothesis of a single lineage this period by identifying a strong, time dependent pattern of variation throughout the sequence. These results suggest the need for a reappraisal of fossil evidence from other regions within this time period and highlight the critical nature of the Plio-Pleistocene boundary for understanding the early evolution of the genus Homo. PMID- 23461333 TI - Vaccination and reduced cohort duration can drive virulence evolution: Marek's disease virus and industrialized agriculture. AB - Marek's disease virus (MDV), a commercially important disease of poultry, has become substantially more virulent over the last 60 years. This evolution was presumably a consequence of changes in virus ecology associated with the intensification of the poultry industry. Here, we assess whether vaccination or reduced host life span could have generated natural selection, which favored more virulent strains. Using previously published experimental data, we estimated viral fitness under a range of cohort durations and vaccine treatments on broiler farms. We found that viral fitness maximized at intermediate virulence, as a result of a trade-off between virulence and transmission previously reported. Our results suggest that vaccination, acting on this trade-off, could have led to the evolution of increased virulence. By keeping the host alive, vaccination prolongs infectious periods of virulent strains. Improvements in host genetics and nutrition, which reduced broiler life spans below 50 days, could have also increased the virulence of the circulating MDV strains because shortened cohort duration reduces the impact of host death on viral fitness. These results illustrate the dramatic impact anthropogenic change can potentially have on pathogen virulence. PMID- 23461334 TI - Endurance running and its relevance to scavenging by early hominins. AB - It has been argued that endurance running ability may have been important in hominin evolution, giving hominins an enhanced ability to scavenge by allowing them to reach carcasses before other terrestrial vertebrate scavengers. This would have allowed them to exploit the carcass before eventually surrendering it on the arrival of potentially dangerous large terrestrial scavengers. Here, we use a simple spatial model to evaluate the ability of competitors to hominin scavengers to find carcasses. We argue that both hominin and nonhominin terrestrial scavengers would often first have been alerted to available carcasses by overflying aerial scavengers. Our model estimates that nonhominin scavengers will generally be able to reach the carcass within 30 min of detecting a plume of vultures above a nearby carcass. We argue that endurance running over periods greater than 30 min would not have provided a selective advantage to early hominins through increased scavenging opportunities. However, shorter distance running may have been selected, particularly if hominins could defend or usurp carcasses from other mammalian scavengers. PMID- 23461335 TI - Degree of sympatry affects reinforcement in Drosophila. AB - In a recent paper, Yukilevich (2012) showed that asymmetries between Drosophila species in the strength of premating isolation tend to match asymmetries in the costs of hybridization (inferred from asymmetries in the strength of postzygotic isolation and range sizes). The results provide novel evidence that the outcome of reinforcement can depend on the strength and frequency of selection against hybridization. Here, I reanalyze the data to demonstrate that another (unconsidered) factor, namely the quantitative degree of sympatry between species, also predictably affects reinforcement. Specifically, premating isolation is strongest at intermediate degrees of sympatry. This result complements, rather than challenges, those of Yukilevich (2012). One possible explanation for this newly discovered pattern is that when the degree of sympatry is small, selection for avoidance of hybridization is rare, but when the degree of sympatry is large, homogenizing gene flow overcomes reinforcing selection. Thus, reinforcement may depend on the balance between selection and gene flow. However, the current work examined degree of sympatry, not gene flow itself. Thus, further data on gene flow levels in Drosophila is required to test this hypothesis, which emerged from the patterns reported here. PMID- 23461336 TI - Subfunctionalization of cyprinid hypoxia-inducible factors for roles in development and oxygen sensing. AB - Among vertebrates, teleost fishes have evolved the most impressive adaptations to variable oxygen tensions in water (Shoubridge and Hochachka 1980; Nilsson and Randall 2010). Under conditions of oxygen deprivation (hypoxia), major changes in gene expression are mediated by hypoxia-inducible factors (HIF alpha). Here we show that hif alpha genes were duplicated in the teleost specific whole-genome duplication. Although one of each paralogous gene pair was lost in most teleosts, both copies were retained in cyprinids. Computational analyses suggest that these duplicates have become subfunctionalized with complementary changes in coding and regulatory sequences within each paralogous gene pair. We tested our predictions with comparisons of hif alpha transcription in zebrafish, a cyprinid, and sturgeon, an outgroup that diverged from teleosts before the duplication event. Our experiments revealed distinct transcriptional profiles in the cyprinid duplicates: while one of each paralogous pair maintained the ancestral developmental response, the other was more sensitive to changes in oxygen tension. These results demonstrate the subfunctionalization of cyprinid hif alpha paralogs for specialized roles in development and the hypoxic stress response. PMID- 23461337 TI - Pleiotropy in the wild: the dormancy gene DOG1 exerts cascading control on life cycles. AB - In the wild, organismal life cycles occur within seasonal cycles, so shifts in the timing of developmental transitions can alter the seasonal environment experienced subsequently. Effects of genes that control the timing of prior developmental events can therefore be magnified in the wild because they determine seasonal conditions experienced by subsequent life stages, which can influence subsequent phenotypic expression. We examined such environmentally induced pleiotropy of developmental-timing genes in a field experiment with Arabidopsis thaliana. When studied in the field under natural seasonal variation, an A. thaliana seed-dormancy gene, Delay Of Germination 1 (DOG1), was found to influence not only germination, but also flowering time, overall life history, and fitness. Flowering time of the previous generation, in turn, imposed maternal effects that altered germination, the effects of DOG1 alleles, and the direction of natural selection on these alleles. Thus under natural conditions, germination genes act as flowering genes and potentially vice versa. These results illustrate how seasonal environmental variation can alter pleiotropic effects of developmental-timing genes, such that effects of genes that regulate prior life stages ramify to influence subsequent life stages. In this case, one gene acting at the seed stage impacted the entire life cycle. PMID- 23461338 TI - Low metabolic rates in salamanders are correlated with weak selective constraints on mitochondrial genes. AB - Mitochondria are the site for the citric acid cycle and oxidative phosphorylation (OXPHOS), the final steps of ATP synthesis via cellular respiration. Each mitochondrion contains its own genome; in vertebrates, this is a small, circular DNA molecule that encodes 13 subunits of the multiprotein OXPHOS electron transport complexes. Vertebrate lineages vary dramatically in metabolic rates; thus, functional constraints on mitochondrial-encoded proteins likely differ, potentially impacting mitochondrial genome evolution. Here, we examine mitochondrial genome evolution in salamanders, which have the lowest metabolic requirements among tetrapods. We show that salamanders experience weaker purifying selection on protein-coding sequences than do frogs, a comparable amphibian clade with higher metabolic rates. In contrast, we find no evidence for weaker selection against mitochondrial genome expansion in salamanders. Together, these results suggest that different aspects of mitochondrial genome evolution (i.e., nucleotide substitution, accumulation of noncoding sequences) are differently affected by metabolic variation across tetrapod lineages. PMID- 23461339 TI - Alternative paths to success in a parasite community: within-host competition can favor higher virulence or direct interference. AB - Selection imposed by coinfection may vary with the mechanism of within-host competition between parasites. Exploitative competition is predicted to favor more virulent parasites, whereas interference competition may result in lower virulence. Here, we examine whether exploitative or interference competition determines the outcome of competition between two nematode species (Steinernema spp.), which in combination with their bacterial symbionts (Xenorhabdus spp.), infect and kill insect hosts. Multiple isolates of each nematode species, carrying their naturally associated bacteria, were characterized by (1) the rate at which they killed insect hosts, and by (2) the ability of their bacteria to interfere with each other's growth via bacteriocidal toxins called "bacteriocins." We found that both exploitative and interference abilities were important in predicting which species had a selective advantage in pairwise competition experiments. When nematodes carried bacteria that did not interact via bacteriocins, the faster killing isolate had a competitive advantage. Alternatively, nematodes could gain a competitive advantage when they carried bacteria able to inhibit the bacteria of their competitor. Thus, the combination of nematode/bacterial traits that led to competitive success depended on which isolates were paired, suggesting that variation in competitive interactions may be important for maintaining species diversity in this community. PMID- 23461340 TI - Antagonistic versus nonantagonistic models of balancing selection: characterizing the relative timescales and hitchhiking effects of partial selective sweeps. AB - Antagonistically selected alleles--those with opposing fitness effects between sexes, environments, or fitness components--represent an important component of additive genetic variance in fitness-related traits, with stably balanced polymorphisms often hypothesized to contribute to observed quantitative genetic variation. Balancing selection hypotheses imply that intermediate-frequency alleles disproportionately contribute to genetic variance of life-history traits and fitness. Such alleles may also associate with population genetic footprints of recent selection, including reduced genetic diversity and inflated linkage disequilibrium at linked, neutral sites. Here, we compare the evolutionary dynamics of different balancing selection models, and characterize the evolutionary timescale and hitchhiking effects of partial selective sweeps generated under antagonistic versus nonantagonistic (e.g., overdominant and frequency-dependent selection) processes. We show that the evolutionary timescales of partial sweeps tend to be much longer, and hitchhiking effects are drastically weaker, under scenarios of antagonistic selection. These results predict an interesting mismatch between molecular population genetic and quantitative genetic patterns of variation. Balanced, antagonistically selected alleles are expected to contribute more to additive genetic variance for fitness than alleles maintained by classic, nonantagonistic mechanisms. Nevertheless, classical mechanisms of balancing selection are much more likely to generate strong population genetic signatures of recent balancing selection. PMID- 23461341 TI - Development of an in vitro 3D tumor model to study therapeutic efficiency of an anticancer drug. AB - The importance and advantages of three-dimensional (3D) cell cultures have been well-recognized. Tumor cells cultured in a 3D culture system as multicellular tumor spheroids (MTS) can bridge the gap between in vitro and in vivo anticancer drug evaluations. An in vitro 3D tumor model capable of providing close predictions of in vivo drug efficacy will enhance our understanding, design, and development of better drug delivery systems. Here, we developed an in vitro 3D tumor model by adapting the hydrogel template strategy to culture uniformly sized spheroids in a hydrogel scaffold containing microwells. The in vitro 3D tumor model was to closely simulate an in vivo solid tumor and its microenvironment for evaluation of anticancer drug delivery systems. MTS cultured in the hydrogel scaffold are used to examine the effect of culture conditions on the drug responses. Free MTS released from the scaffold are transferred to a microfluidic channel to simulate a dynamic in vivo microenvironment. The in vitro 3D tumor model that mimics biologically relevant parameters of in vivo microenvironments such as cell-cell and cell-ECM interactions, and a dynamic environment would be a valuable device to examine efficiency of anticancer drug and targeting specificity. These models have potential to provide in vivo correlated information to improve and optimize drug delivery systems for an effective chemotherapy. PMID- 23461342 TI - Community-based healthcare costs for children born low birthweight, preterm and/or small for gestational age: data from the Longitudinal Study of Australian Children. AB - AIM: Children born low birthweight, preterm and/or small for gestational age (SGA) sustain substantially increased costs for hospital-based health care and additional educational support in the first few years of life. This is the first study internationally to investigate costs beyond hospital care, to community based health care and prescription medicines across early and middle childhood with actual cost data, and to examine these costs according to the severity of perinatal risk. METHOD: In the prospective Longitudinal Study of Australian Children, we followed two cohorts of children from age of 0 to 5 years (no increased perinatal risk, n = 3973; mild risk, n = 442; and moderate-to-high risk, n = 297), and from age of 4 to 9 years (no increased perinatal risk, n = 3629; mild risk, n = 465; and moderate-to-high risk, n = 361). Children were defined as mild risk if born 32-36 weeks, with birthweight 1500-2499 g, and/or SGA (<5-9th percentile), and moderate-to-high risk if born <32 weeks, birthweight <1500 g and/or extremely SGA (<5th percentile). Federal government expenditure (2011 $AUD) on healthcare attendances and prescription medication from birth to 9 years were calculated via data linkage to the Australian Medicare records. RESULTS: Mean costs per child were A$362 higher (95% CI $156; 568) from 0 to 5 years and A$306 higher (95% CI $137; 475) from 4 to 9 years, for children with any compared with no increased perinatal risk (P < 0.001). At the population level, an additional A$32m was spent per year for children 0-9 years with any relative to no increased perinatal risk. CONCLUSIONS: Perinatal risk is a major public health issue conferring considerable additional expense to community-based health care, most marked in the first year of life but persisting up to at least 10 years. Even without additionally considering burden, these findings add to the urgency of identifying effective mechanisms to reduce perinatal risk across its full spectrum. PMID- 23461343 TI - The influence of paid work, race-ethnicity, and immigrant status on health care coverage after welfare reform in Hennepin County, Minnesota. AB - A random sample of 84 past and present Temporary Assistance to Needy Families recipients in Hennepin County, Minnesota, were interviewed regarding their health care coverage and corresponding work histories over a 42-month period. Diverse racial-ethnic and immigrant groups of color were oversampled. A life history calendar technique and supplementary interview questions were utilized. The researchers found an inverse relationship between amount of paid work and health care coverage. Different racial-ethnic and immigrant groups had different patterns of health care coverage that were not explained sufficiently by amount of paid work. The authors posit that a lack of a publicly known linkage between paid work and Medicaid resulted in uninsurance for low-income workers and call for further research to explain different insurance patterns among racial-ethnic groups. PMID- 23461344 TI - Veterans Administration health care policies as a protective mechanism supporting an expected life trajectory after military service. AB - Changes in the American military since the end of military conscription, as well as the increasing number of service-connected disabilities, suggest the need for increased consideration of the effects of health policies when assessing the impact of military service on young Americans' life course. This study analyzes data from the most recent National Survey of Veterans to investigate the health status, health benefits, and health care utilization of 2,773 Gulf War veterans, in association with resumption of their civilian life trajectory. Findings suggest that this sample of veterans may have poorer health status than previous veteran cohorts and did not fully utilize veterans' health care benefits to which they were entitled. This article examines whether veterans may usefully be considered a group at risk for health disparities, in that they have greater health risks and potentially poorer health status and access than mainstream Americans. PMID- 23461345 TI - Assessment of organizational capacity for evidence-based health systems operations in Nigeria. AB - In Nigeria, health outcomes are unacceptably low largely due to the inability of the health system to function optimally. As part of a strategy to strengthen the health system, an assessment of institutional capacity for use of evidence for health system operations was conducted. The health system operations in terms of stewardship, health administration, service delivery, and access to essential medical products/technologies were fairly adequate. In terms of generation/strategic use of information, health financing, and health workforce, the operations were generally inadequate. There is need to evolve strategies that will guarantee equitable and sustained improvements across health services and health outcomes. PMID- 23461346 TI - Perceptions of need, service use, and barriers to service access among female methamphetamine users in rural Appalachia. AB - Active substance users have been characterized as ambivalent about accessing treatment services. Few studies have addressed the social context and related barriers that individuals experience in addressing substance abuse problems. These barriers appear to be heightened for female methamphetamine users living in rural areas of Appalachia. The purpose of this study is to document the willingness of active female methamphetamine users to access substance abuse treatment services, their ability to access substance abuse treatment services, and the barriers they experienced in accessing substance abuse treatment services. Findings from a sample of 153 rural female methamphetamine users revealed the majority of respondents met the criteria for substance dependence (99.3%), believed they had a drug problem (84.9%), believed they needed treatment services (62.9%), and wanted to go to treatment "now" (51.4%). However, only one fourth (26.8%) had accessed treatment, and many had experienced barriers in attempting to enter treatment services. PMID- 23461347 TI - Overweight and obesity in minority children and implications for family and community social work. AB - The 2007 California Health Interview Survey was used to examine indicators of overweight and obesity among racial and ethnic minority children age 2 to 11 (N = 6,669). The factors found to most influence overweight/obesity were race/ethnicity, poverty level, and physical activity. Neighborhood access to a park or playground within walking distance reduced the odds of overweight and obesity despite control for other factors. Findings indicate that health behaviors and environmental contexts are important to understanding obesogenic risks in ethnically-diverse communities. Future directions for family and community-based social work and implications for developing culturally sensitive strategies in addressing this growing health issue are discussed. PMID- 23461348 TI - Prisoner reentry: a public health or public safety issue for social work practice? AB - A significant literature identifies the policy, economic, health, and social challenges that confront released prisoners. This literature also describes the public health and public safety risks associated with prisoner reentry, provides recommendations for improving the reentry process, and describes the effectiveness of prison-based programs on recidivism rates. Public health and public safety risks are particularly significant in communities where large numbers of prisoners are released and few evidence-based services exist. The purpose of this article is to describe the public health and public safety risks that released prisoners experience when they reenter communities, and to discuss the social justice issues relevant for social work practice. PMID- 23461349 TI - An application of the transtheoretical model to becoming vegan. AB - This article applies the transtheoretical model TM to veganism. By and large, the TM is a model of behavioral change that incorporates different stages to describe how an individual moves from an unhealthy behavior to a healthy one. The TM construes change as a five-stage process. The five stages of change are (a) precontemplation, (b) contemplation, (c) preparation, (d) action, and (e) maintenance. In this analysis, the model is applied to a person's determination to become vegan. A person chooses to become a vegan by eliminating all animal products from his or her diets; he or she does this by progressing through the stages, as prescribed by the model. The different changes people make to their life are described in detail. It is also possible to measure the success of a person's progression based on positive health changes that he or she experiences. PMID- 23461350 TI - Portuguese women's knowledge and health beliefs about cervical cancer and its screening. AB - Currently little is known about Portuguese women's knowledge and beliefs about cervical cancer screening, so this information is crucial to the success of cervical cancer screening programs. The intention of this study was to describe the knowledge and beliefs of women in Portugal. In-depth, face-to-face, individual interviews were conducted. Twenty-five females were recruited, the age range was 30 to 60. The results showed a lack of knowledge on cervical cancer and the Pap smear test. From a public policy point of view, it may be important to further explore the extent to which perceived barriers to screening will affect screening uptake when a national screening program is implemented. PMID- 23461351 TI - Theoretical study of the decomposition of formamide in the presence of water molecules. AB - Formamide (NH2CHO, FM) has been considered an active key precursor in prebiotic chemistry on early Earth. Under certain conditions such as dry lagoons, FM can decompose to produce reactants that lead to formation of more complex biomolecules. Specifically, FM decomposition follows many reactive channels producing small molecules such as H2, CO, H2O, HCN, HNC, NH3, and HNCO with comparable energy barriers in the range of 73-82 kcal/mol. Due to the likely presence of water on prebiotic Earth and the intrinsic presence of water following FM decomposition, we explore the effects of water oligomers, (H2O)n with n = 1-3, on its dehydration, dehydrogenation, and decarbonylation reactions using quantum chemical computations. Geometries are optimized using MP2/aug-cc pVxZ calculations (x = D,T), and relative energies are evaluated using coupled cluster theory CCSD(T) with the aug-cc-pVxZ basis sets (x = D, T, Q). Where possible the coupled-cluster energies are extrapolated to the complete basis set limit (CBS). Water classically acts as an efficient bifunctional catalyst for decomposition. With the presence of one water molecule, the dehydration pathway leading to HCN is favored. When two and three water molecules are involved, dehydration remains energetically favored over other channels and attains an energy barrier of ~30 kcal/mol. PMID- 23461352 TI - The bisketene radical cation and its formation by oxidative ring-opening of cyclobutenedione. AB - Parent cyclobutenedione 1 was photolyzed and ionized in an Ar matrix at 10K. The bisketene 2 that results in both cases (in the form of its radical cation after ionization) was characterized by its IR spectrum and by high-level quantum chemical calculations. Experiment and theory show that the neutral bisketene has only a single conformation where the two ketene moieties are nearly perpendicular, whereas the radical cation is present in two stable planar conformations. The mechanism of the ring-opening reaction, both in the neutral and in the radical cation, is discussed on the basis of calculations. In the latter case it is a nonsynchronous process that involves an avoided crossing of states. PMID- 23461353 TI - Nanowormlike Li2FeSiO4-C composites as lithium-ion battery cathodes with superior high-rate capability. AB - Nanoworm-like Li2FeSiO4-C composites are synthesized using triblock copolymer Pluronic P123 (poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), EO20PO70EO20) as the structure directing agent (SDA) and under the effects of ethanol. As a polar nonaqueous cosolvent, ethanol has effects on the self-organization behavior of Pluronic P123 in water, which determines the final morphologies of the Li2FeSiO4-C composites synthesized. Li2FeSiO4-C composite nanoparticles are obtained if no ethanol is added into the system during the synthesis process. When tested as lithium-ion battery cathodes, the Li2FeSiO4-C nanoworms show superior electrochemical performances. At the rate of 1 C (1 C=166 mA g(-1)) the discharge capacity of the Li2FeSiO4-C nanoworms can reach 166 mAh g(-1) in the voltage window of 1.5-4.8 V at room temperature. At the rates of 5, 10, and 20 C, the discharge capacities of the Li2FeSiO4-C nanoworms can stabilize at 120, 110, and 90 mAh g(-1), respectively, and do not show obvious declines after hundreds of cycles. This performance of the Li2FeSiO4-C nanoworms at high rates is better than that of the Li2FeSiO4-C nanoparticles synthesized and many other Li2FeSiO4/C composites reported in the literature. The excellent electrochemical performances of the Li2FeSiO4-C nanoworms are believed to be related to the small sizes of the Li2FeSiO4 nanocrystals inside the nanoworms and the carbon that coats and embeds the nanocrystals. PMID- 23461354 TI - A novel diketopyrrolopyrrole (DPP)-based [2]rotaxane for highly selective optical sensing of fluoride. AB - A novel [2]rotaxane based on an orthogonal H-bonded motif and 3,6-di(thiophen-2 yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione (DPP) with controlled topicity was successfully constructed, displaying excellent stimulated responses toward anion and solvent polarity. The preorganized host selectively recognized F(-) with high optical sensitivity and reversibility via enhanced positive cooperativity and noncovalent interaction by evidence of a shorter fluorescence lifetime. PMID- 23461355 TI - Exploring the effectiveness of an internet-based program for reducing caregiver distress using the iCare Stress Management e-Training Program. AB - OBJECTIVE: Determine if the online iCare Stress Management e-Training Program reduces stress, bother, depression, and poor life quality for dementia family caregivers (CGs). METHOD: CGs (N = 150) were randomly assigned to the iCare Condition (ICC) or to the Education/Information-Only Condition (EOC) for a 3 month period. Change in self-report measures of stress (PSS) (primary outcome), caregiver bother(RMBPC), depression (CES-D), and quality of life (PQOL) (secondary outcomes) was determined, along with usage of new information in one's own caregiving. RESULTS: A mixed ANOVA revealed that change in perceived stress was significant for the ICC but not the EOC (p = .017). Changes in the other measures were not significant. More caregivers in the ICC used the materials in their own caregiving situation than those in the EOC. Roughly one-third of the caregivers enrolled in the study dropped prior to completion. CONCLUSION: Results are promising, but the high dropout is a concern. Future efforts to improve dropout rate and increase participant engagement are warranted. To our knowledge, this is the first attempt to present an evidence-based intervention for CGs via the Internet. PMID- 23461356 TI - Peroxisome proliferator-activated receptor-gamma activation inhibits hepatocellular carcinoma cell invasion by upregulating plasminogen activator inhibitor-1. AB - The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand activated transcription factor belonging to the nuclear receptor superfamily. Peroxisome proliferator-activated receptor-gamma ligands can inhibit cell growth and increase apoptosis of cancer cell lines, suggesting a potential role for PPARgamma as a tumor suppressor. Whereas the related studies between PPARgamma and cancer cell invasion are still poor. Our previous study indicates that beta estradiol (E2) suppresses hepatocellular carcinoma (HCC) cell invasion. We report here that E2 can activate PPARgamma of HCC cells, and activated PPARgamma suppresses cell invasion by upregulating the expression level of plasminogen activator inhibitor-1 (PAI-1). We found that PPARgamma plays an important role in the E2-induced HCC cell invasion process. Using PPARgamma agonist GW1929, a reduced invasion effect was found in HCC cell lines, and this inhibition of cell invasion was dosage-dependent. However, cell invasion was restored by treatment with PPARgamma antagonist GW9662. The activated PPARgamma upregulated the expression of cell migration-related protein PAI-1. Furthermore, knockdown of PPARgamma in HCC cells decreased the level of PAI-1 and advanced cell invasion in response to GW1929. On the contrary, overexpression of PPARgamma in HCC cells elevated the level of PAI-1 and inhibited cell invasion. These findings suggest that PPARgamma activation inhibits HCC cell invasion via the upregulation of PAI 1 and implicate that PPARgamma is a target for the treatment and prevention of HCC cell invasion. PMID- 23461357 TI - A push-pull test to measure root uptake of volatile chemicals from wetland soils. AB - This paper introduces a novel modification of the single-well "push-pull" test that uses nonvolatile and multiple volatile tracers to investigate the transport and root uptake kinetics of volatile chemicals in saturated soils. This technique provides an estimate of potential volatilization fluxes without relying on enclosure-based measurements. The new push-pull methodology was validated with mesocosm experiments, and bench-scale hydroponic measurements were performed to develop an empirical relationship for scaling root uptake rates between chemicals. A new modeling approach to interpret data using sulfur hexafluoride and helium as dual volatile tracers was developed and shown to decrease errors relative to existing analytical techniques that utilize bromide as a conservative tracer. Root uptake of the volatile tracers was diffusion-limited, and uptake rate constants (kv) in vegetated experimental mesocosms ranged from 0.021 +/- 9.0 * 10(-4) h(-1) for CFC-12 to 2.41 +/- 0.98 h(-1) for helium. Hydroponic and mesocosm experiments demonstrate that the molecular diameter is a robust empirical predictor of kv. PMID- 23461358 TI - Prevalence of depression in patients referred with snoring and obstructive sleep apnoea. AB - BACKGROUND AND AIMS: Depression and obstructive sleep apnoea are two common entities, with common symptoms that make identification of either condition difficult. Our aim was to examine, within a group of patients referred with snoring and obstructive sleep apnoea, (i) the prevalence of depression with the 14-question Hospital Anxiety and Depression Scale (HADS), (ii) the correlation between the two lead depression symptoms from the Mini-International Neuropsychiatric Interview (MINI) and HADS, and (iii) the relationship between depression symptoms with physiological markers of OSA. METHODS: An observational study of depression questionnaires in patients referred because of snoring to a sleep clinic within university-affiliated public teaching hospital. RESULTS: Ninety-seven per cent of 240 patients approached responded, and 32% had a positive HADS (score >16/42). The HADS and MINI significantly correlated (r = 0.736, P < 0.001). Fifty-three per cent had either doctor-diagnosed depression (28%) and/or a positive HADS or MINI (25%). HADS correlated with the degree of sleepiness (r = 0.252, P < 0.0001) and inversely with hypoxaemia (r=-0.231, P < 0.0003) but not with the frequency of apnoeas and hypopnoeas (r = 0.116, P > 0.05). CONCLUSION: Depending on classification, 32-53% of patients with snoring had depressive symptoms or were on treatment, which is significantly greater than the Australian average of 21%. A simplified depression questionnaire was validated. Severity of depression correlated with sleepiness and hypoxaemia but not with severity of sleep apnoea. PMID- 23461359 TI - Unethical pharmaceutical manufacturer conduct worldwide and its negative impact upon pharmacy practice. PMID- 23461360 TI - Structured practical experience for Canadian student pharmacists in Ghana. PMID- 23461361 TI - Gemcitabine-coumarin-biotin conjugates: a target specific theranostic anticancer prodrug. AB - We present here, the design, synthesis, spectroscopic characterization, and in vitro biological assessment of a gemcitabine-coumarin-biotin conjugate (5). Probe 5 is a multifunctional molecule composed of a thiol-specific cleavable disulfide bond, a coumarin moiety as a fluorescent reporter, gemcitabine (GMC) as a model active drug, and biotin as a cancer-targeting unit. Upon addition of free thiols that are relatively abundant in tumor cells, disulfide bond cleavage occurs as well as active drug GMC release and concomitantly fluorescence intensity increases. Confocal microscopic experiments reveal that 5 is preferentially taken up by A549 cells rather than WI38 cells. Fluorescence-based colocalization studies using lysosome- and endoplasmic reticulum-selective dyes suggest that thiol-induced disulfide cleavage of 5 occur in the lysosome possibly via receptor mediated endocytosis. The present drug delivery system is a new theranostic agent, wherein both a therapeutic effect and drug uptake can be readily monitored at the subcellular level by two photon fluorescence imaging. PMID- 23461362 TI - Greenhouse studies of thiamethoxam effects on pea leaf weevil, Sitona lineatus. AB - The pea leaf weevil, Sitona lineatus L. (Coleoptera: Curculionidae), has recently emerged as an important pest of field peas in the Canadian prairies. Systemic seed-coated insecticides may provide a tool for the integrated pest management of this pest. Therefore, several controlled assays were performed in order to determine effects of a recently registered neonicotinoid, (thiamethoxam) on S. lineatus damage to foliage, weevil mortality, fertility, egg viability, larval mortality, and root nodule damage. Foliage damage was reduced by thiamethoxam relative to untreated controls during the seedling stage (2(nd)-5(th) nodes), but weevil adult mortality was only 15-30%. Fertility was reduced substantially through an extra seven-day delay in the preoviposition period and reduced egg laying rate during the first 20 days of the study (92% lower than controls). Overall egg viability was lower in females fed foliage grown from thiamethoxamtreated seeds. Larval survivorship and nodule damage were also lower, but only when eggs were added to treated plants at the 2(nd) node stage. When eggs were added late, at the 5th node stage, thiamethoxam had no effect on larval survivorship or nodule damage. The results of this study led to the conclusion that seed treatments such as thiamethoxam have potential to be used as tools that will aid in the integrated pest management of S. lineatus, especially in combination with other methods such as biocontrol and trap crops. PMID- 23461363 TI - P66Shc-rac1 pathway-mediated ROS production and cell migration is downregulated by ascorbic acid. AB - The oxidative role(s) of p66Shc protein has been increasingly expanded over the last decade. However, its relation with the most potent antioxidant molecule, i.e. ascorbic acid has never been studied. We have previously shown that p66Shc mediates rac1 activation, reactive oxygen species (ROS) production and cell death. Here we studied the effect of ascorbic acid on the pathway involving p66Shc and rac1. Our results indicate a decrease in the expression of p66Shc in a dose- and time-dependent manner. We studied the effect of ascorbic acid on rac1 expression and its activity. Ascorbic acid has no effect on total rac1 expression; however, rac1 activation was inhibited in a dose-dependent manner. Results suggest that the decrease in rac1 activity is mediated through ascorbic acid-modulated p66Shc expression. The decrease in rac1 activity was evident in cells transfected with the p66shc mutant (proline motif mutant, at residues P47 to P50). Our studies indicate that p66Shc-mediated ROS upregulation is significantly decreased in the presence of ascorbic acid. Cell migration experiments point towards the inhibition of p66Shc-rac1-mediated migration in the presence of ascorbic acid. Finally, results are suggestive that ascorbic acid mediated decrease in Shc expression occurs through an increased Shc ubiquitination. Overall, the study brings out the novel role of ascorbic acid in antioxidant signal transduction. PMID- 23461364 TI - Cooperative cold denaturation: the case of the C-terminal domain of ribosomal protein L9. AB - Cold denaturation is a general property of globular proteins, but it is difficult to directly characterize because the transition temperature of protein cold denaturation, T(c), is often below the freezing point of water. As a result, studies of protein cold denaturation are often facilitated by addition of denaturants, using destabilizing pHs or extremes of pressure, or reverse micelle encapsulation, and there are few studies of cold-induced unfolding under near native conditions. The thermal and denaturant-induced unfolding of single-domain proteins is usually cooperative, but the cooperativity of cold denaturation is controversial. The issue is of both fundamental and practical importance because cold unfolding may reveal information about otherwise inaccessible partially unfolded states and because many therapeutic proteins need to be stabilized against cold unfolding. It is thus desirable to obtain more information about the process under nonperturbing conditions. The ability to access cold denaturation in native buffer is also very useful for characterizing protein thermodynamics, especially when other methods are not applicable. In this work, we study a point mutant of the C-terminal domain of ribosomal protein L9 (CTL9), which has a T(c) above 0 degrees C. The mutant was designed to allow the study of cold denaturation under near native conditions. The cold denaturation process of I98A CTL9 was characterized by nuclear magnetic resonance, circular dichroism, and Fourier transform infrared spectroscopy. The results are consistent with apparently cooperative, two-state cold unfolding. Small-angle X-ray scattering studies show that the unfolded state expands as the temperature is lowered. PMID- 23461365 TI - CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovary syndrome. AB - OBJECTIVE: Cytochrome P450 aromatase catalyzes the irreversible transformation of androgens into estrogens. The association of CYP19(TTTA)n polymorphism with the hormonal profile and the assisted reproduction outcome of women with polycystic ovary syndrome (PCOS) was explored. METHODS: One hundred and thirty-two women with PCOS and 200 with male-factor infertility, as controls, participated in the current study. The CYP19(TTTA)n polymorphism was genotyped, while the hormonal profile was determined at the third day of the menstrual cycle. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded. RESULTS: Genotype analysis revealed 6 CYP19(TTTA)n alleles with 7-12 repeats. In PCOS women, the CYP19(TTTA)7 allele presence was associated with lower serum E2 levels at the third day of the menstrual cycle (p < 0.009), lower large follicle (p < 0.02) and total oocyte numbers (p = 0.006), but with significantly higher pregnancy rates after assisted reproduction (p < 0.004). CONCLUSIONS: Potential associations of the CYP19(TTTA)7 allele with ovarian response to standard gonadotrophin stimulation and with assisted reproduction outcome were found in PCOS women, probably due to androgen/estrogen ratio alterations. PMID- 23461366 TI - Reduction of ferrylmyoglobin by theanine and green tea catechins. Importance of specific Acid catalysis. AB - Reduction of the hypervalent heme pigment ferrylmyoglobin by green tea catechins in aqueous solution of pH = 7.5 was investigated by stopped-flow spectroscopy. Reduction by the gallic acid esters epigallocatechin gallate (EGCG, k2 = 1460 L mol(-1) s(-1), 25.0 degrees C, 0.16 ionic strength) and epicatechin gallate (ECG, 1410 L mol(-1) s(-1)) was found faster than for epicatechin (EC, 300 L mol( 1) s(-1)) and epigallocatechin (EGC, 200 L mol(-1) s(-1)), even though the gallate ion (G, 330 L mol(-1) s(-1)) is similar in rate to EC. The rate for reduction by EC, EGC, ECG, EGCG, and G shows no correlation with their oxidation potentials or phenolic hydrogen-oxygen bond dissociation energy, but with the pKa of the most acidic phenol group. Theanine, with an acidity similar to that of EC, reduces ferrylmyoglobin with a similar rate (200 L mol(-1) s(-1)), in support of general acid catalysis with an initial proton transfer prior to electron transfer. PMID- 23461368 TI - [Ranibizumab in the ARMD wet form of age-related macular degeneration treatment - two years results obtained from the AMADEuS Registry]. AB - AIM: The aim of this study was the retrospective follow up of Age-Related Macular Degeneration (ARMD) wet form patients treated with ranibizumab during 24 months period. The data were recorded into the AMADEuS (Age-related MAcular DEgeneration in patientS in the Czech Republic) Registry and after their evaluation compared with treatment results obtained from other departments of ophthalmology collaborating in the AMADEuS project or results of some foreign studies as well. PATIENTS AND METHODS: The group consisted of patients registered since October 1, 2008 until June 11, 2012, followed up for 24 months period. There were 90 eyes of 89 patients. All patients were completely examined in the Macular ambulance of the Department of Ophthalmology in the Faculty Hospital Brno-Bohunice, Czech Republic, E.U., and consequently the ranibizumab (Lucentis, Novartis) was applied intravitreally in three initials doses one month apart. Thereafter, ranibizumab was applied "on demand". In 43.3 % of eyes the mostly classical, in 27.8 % of eyes occult, and in 28.9 % of eyes the minimally classical choroid neovascular membrane was present. The initial visual acuity was in 3.3 % of eyes in the range 15 - 30 letters of ETDRS optotypes (20/500 - 20/200), in 61.1 % of eyes in the range 31 - 60 letters (20/200 - 20/63), and the visual acuity better than 61 letters of ETDRS optotypes (better than 20/63) was in 35.6 % of eyes. RESULTS: The average initial best-corrected visual acuity (BCVA) in our group of patients was 54.2 letters of EDTRS (SD +/- 14.4). At the visit at three months after the start of the treatment the BCVA was 59.6 letters of EDTRS (SD +/- 15.0), at the visit after 6 months 57.3 letters of EDTRS (SD +/- 14.7), after one year of the study 54.8 letters of EDTRS (SD +/- 16), after 18 months of the study 53.4 letters of EDTRS (SD +/- 16,8), and after 24 months of the study was the BCVA 51.7 letters of EDTRS (SD +/- 16.9). The average CRT (central retinal thickness) value by means of the OCT (optic coherence tomography) examination was at the beginning of the treatment 311.4 MUm (SD +/- 117.9), after 3 months of treatment 233.5 MUm, (SD +/- 85.4), after 6 months of treatment 262.2 MUm, (SD +/- 102,4), after 12 months 261 MUm (SD +/- 88,4), after 18 months 254.9 MUm (SD +/- 70.0), and after 24 months 249 MUm (SD +/- 87.5). The average number of ranibizumab doses during the follow-up period was 5.6. After the 24 months follow-up period, the gain of 15 or more letters of EDTRS was recorded in 11.1 % of patients, the gain of 1 - 14 letters of EDTRS optotypes was recorded in 32.2 % of patients, the decrease of 14 or less letters of EDTRS optotypes was found in 21.2 % of patients, and the decrease of 15 or more letters was found in our group in 22.2 % of patients. CONCLUSION: The ARMD wet form treatment using ranibizumab is up to date the most effective available therapy. The AMADEuS registry is of great importance in the reviewing of the effectiveness of the ARMD wet form treatment. PMID- 23461369 TI - [Pars plana vitrectomy and combination therapy pars plana vitrectomy, intravitreal triamcinolon acetonid and macular lasercoagulation - one year results]. AB - PURPOSE: To compare anatomic and functional results of pars plana vitrectomy with MLI peeling (group PPV) and pars plana vitrectomy with MLI peeling, intravitreal triamcinolon acetonide 4 mg and macular lasercoagulation (group PPV + TRIAM) in eyes with diffuse diabetic macular edema (DEM). METHODS: In the group PPV eyes underwent PPV with MLI peeling and in the group PPV + TRIAM, PPV with MLI peeling, intravitreal triamcinolon acetonide 4 mg was performed at the end of surgery and macular lasercoagulation 3 weeks after surgery. Best corrected visual acuity (BCVA), central macular thickness (CMT) and macular volume were recorded before, 1, 3, 6 and 12 months after vitrectomy. RESULTS: Sixty - eight eyes from 59 subjects with DEM non responsive to lasercoagulation or with vitreomacular traction were enrolled, the group PPV 35 eyes and the group PPV + TRIAM 33 eyes. In the group PPV before and 1, 3, 6 a 12 months after surgery mean BCVA were 0,22; 0,21; 0,28; 0,32; 0,30, mean CMT were 497,69 MUm; 400,89 MUm; 356,46 MUm; 346,89 MUm; 319,49 MUm and mean macular volume were 11,48 mm3; 9,82 mm3; 9,28 mm3; 9,07 mm3, 8,83 mm3. In the group PPV + TRIAM mean BCVA were 0,18; 0,16; 0,23; 0,26; 0,26, mean CMT were 447,82 MUm; 276,03 MUm; 266,27 MUm; 268,36 MUm; 251,15 MUm, mean macular volume were 10,71 mm3; 8,03 mm3; 8,28 mm3; 7,96 mm3; 7,66 mm3. In both groups statistical significant improvement in BCVA were observed from month 3 (p = 0.0013), in CMT and macular volume from month 1 (< 0.001). To compare both groups, in the group PPV + TRIAM changes in CMT and macular volume in month 1 after combination therapy from baseline were statistical significant, but without statistical significant, change in BCVA (p = 0.229). The major complications after surgery were an elevation of intraocular pressure and cataract surgery, more often in the group PPV + TRIAM (p = 0.153, p = 0.056). CONCLUSION: Both surgical technics are effective in the treatment of DEM. Combination therapy PPV, triamcinolon acetonide 4mg and macular lasercoagulation is associated with higher number of complications after surgery (elevation of intraocular pressure and cataract surgery). PMID- 23461370 TI - [Clinical variability of Best's disease]. AB - Retrospective view of the various phenotypes 20 persons affected by classic solitary form of vitelliform macular dystrophy, in 3 pedigrees with autosomal dominant transmission and in 4 single cases. Long-term monitoring allows to observe the variability of expression, from classic course to peculiarity of the clinical expression in the disc development and their corresponding functions of the central retina. PMID- 23461371 TI - [The current state of the evidence of malignant tumors of the eye and its adnexa (dg. C69) in the Slovak Republic and in the Czech Republic]. AB - The area of ophthalmooncology includes not only intraocular tumors but also adnexal and extraocular tumors, relatively rare malignancies. To get valid data and to study the incidence, diagnosis and treatment is extremely difficult. The most frequently occurring intraocular tumor in adults is malignant melanoma, in children it is retinoblastoma. We present the results of the nationwide group of patients based on the diagnosis report C69 - Tumors of the eye and adnexa according to data of the National Cancer Registry in Slovak Republic. We monitor the incidence, distribution by age group, survival and staging. In the second part of the thesis analyzed data are compared with the data from Cancer Registry in the Czech Republic. After analyzing the data, we found that the incidence of intraocular tumors have been reported to be comparable with neighbouring countries. The classification of the disease in different stages due to TNM classifying in the report is below 50 % in Slovakia. The incidence observed in each year ranges from 0.6 to 1.0 per 100 000 inhabitants. Survival of patients with dg. C69 is comparable with other countries. The proportion of clinically defined stages of the disease is in the database of Slovakia lower than in the Czech Republic. The delay of inserting data of patients in the National Cancer Registry in Slovakia and the availability of data for analysis is currently unsatisfactory. In Slovakia are available data only up to year 2003, in Czech Republic up to year 2009. PMID- 23461372 TI - [Transnasal endoscopic surgery approach in intraorbital tumors]. AB - OBJECTIVES: To determine the role of transnasal endoscopic approach to orbital lesions. METHODS: Retrospective case series. RESULTS: Three patients underwent endoscopic diagnostic surgery for orbital lesions. In all three patients was successfully finded out the diagnosis, the orbita was decompressed. In two cases it resulted to visual recovery, in one case was determine a diagnosis of metastatic adenocarcinoma. In one case the tumor was removed totally. CONCLUSION: Using endoscopic approach to the orbit allowed good approach to the biopsy of orbital lesions, allowed decompression an in limited count of cases this access allowed a complete tumour removal. On the other hand, generally endoscopic approach is useful only for limited lesions (extraconal), usually it allowed only debunking, not the complete resection of orbital pathology. PMID- 23461373 TI - [Adjustable versus non-adjustable sutures in strabismus surgery in patients with thyroid ophthalmopathy]. AB - AIM: To evaluate the results of strabismus surgery in patients with thyroid ophthalmopathy. To determine whether adjustable suture surgery is beneficial for these patients. MATERIALS AND METHODS: This study included patients who underwent strabismus surgery associated with thyroid ophthalmopathy from June 2010 to March 2012. During the observation period, 14 patients met the inclusion criteria. Seven patients underwent non-adjustable suture surgery (five women and two men) and seven patients underwent adjustable suture surgery (five women and two men). The patients mean age was 63 years. The preoperative ocular findings were stable for at least one year in all cases. All strabismus surgeries were performed by one surgeon. The postoperative results were recorded at follow-up visits after 1 week, 1 month, 3 months and 6 months. RESULTS: In the non-adjustable suture case series, three patients were satisfied with the results (including one with a compensatory head posture). Two patients required reoperation and two prismatic correction. In the adjustable suture case series, no reoperation or prismatic correction was needed. In this group, all the patients were satisfied with the results (including one with a compensatory head posture). CONCLUSION: Adjustable suture strabismus surgery in patients with thyroid ophthalmopathy proved to be beneficial. In our adjustable suture case series, there was a lower number of reoperations and prismatic corrections. PMID- 23461374 TI - [The application of Dysport(r) - the possibilities of the side effect on the eyelids position (a clinical - histological study)]. AB - AIM: To inform about the possibility of negative influence of repeated application of the botulotoxine A derivate on the eye lid position with the changes of their tissue structure. At the same moment, the authors report on literature analysis of positive and negative influence of this neuro toxine from the medical point of view. MATERIALS AND METHODS: At the Department of Ophthalmology in the Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic, E.U., there were surgically treated three patients after repeated applications of botulotoxine A derivates. The first case was bilateral ptosis of upper eyelids; the other two were indicated because of entropium with trichiasis of lower eyelids. In the medical history, there was recorded ten years lasting above-mentioned drug treatment for blepharospasm diagnosis in a 65 years old man introducing bilateral symmetrical ptosis. Because of the following frontal muscle involvement, and partial decreasing levator palpebrae muscles function, the positioning of the upper eyelids was treated by the aponeurosis plasty with good functional result. In two female patients, aged 72 and 90 years, the indication for successful surgical treatment was chronic entropium of lower eyelids; initially ineffectively treated by means of repeated intradermal injections of botulotoxin A derivates. RESULTS: Histological examinations of the excided skin and subcutis samples taken during ectropium plasties showed unfavorable and irreversible changes including especially scarring of the eyelid and atrophy of the striated muscles. CONCLUSION: The indication of botulotoxine A derivates application should be carefully weighted and the proper indication should be chosen. From the ophthalmologic point of view, blefarospasmus only is the appropriate diagnosis, and the relative indication is the temporary induced ptosis of the upper eyelid closing the interpalpebral fissure to prevent corneal changes in lagophthalmos of various etiologies as an alternative to the tarsoraphy. Always we have to consider the frequency of applications, because repeatedly used derivate of this neurotoxine causes irreversible changes in cutaneous and subcutaneous tissue. PMID- 23461375 TI - Inhibition of lysophosphatidic acid increase by prestorage whole blood leukoreduction in autologous CPDA-1 whole blood. AB - BACKGROUND: Lysophosphatidylcholine (LPC) has been implicated in the onset of transfusion-related acute lung injury (TRALI). In plasma, LPC is converted to lysophosphatidic acid (LPA) by autotaxin (ATX). The effect of leukoreduction in the accumulation of these bioactive lipids and ATX in human autologous blood has not been fully investigated. STUDY DESIGN AND METHODS: The accumulation of choline-containing phospholipids (LPC, sphingomyelin [SM], and phosphatidylcholine [PC]), LPA, and ATX during the storage of autologous blood and the changes caused by leukoreduction were investigated. A total of 26 orthopedic patients were enrolled. Autologous blood was collected as whole blood and, after leukoreduction, preserved refrigerated until use. Prestorage leukoreduced (LR) and non-LR autologous blood samples were analyzed. The time dependent changes and the effect of the filtration were compared. RESULTS: A time dependent and significant increase in the levels of LPA was observed in both non LR and LR samples. The concentration of LPA was significantly reduced in LR compared to non-LR samples. The concentration of LPC was higher in LR compared to non-LR samples. The levels of PC, SM, and ATX were not affected by either the storage period or the leukoreduction. CONCLUSIONS: Leukoreduction of autologous whole blood effectively reduced the accumulation of LPA. On the other hand, prestorage leukoreduction resulted in an increased concentration of LPC, without significantly affecting ATX. Further studies are necessary to confirm the role of LPA in the pathogenesis of adverse effects of blood transfusion, especially TRALI. PMID- 23461376 TI - Comparison of cytokine gene polymorphism in drug-induced maculopapular eruption, urticaria and drug reaction with eosinophilia and systemic symptoms (DRESS). AB - BACKGROUND: Polymorphisms of genes controlling cytokine production have not been studied in the genetic susceptibility to cutaneous adverse drug reactions (CADR). OBJECTIVES: The objective was to determine whether polymorphisms in nine cytokine genes were associated to the occurrence of drug reaction with eosinophilia and systemic symptoms (DRESS) compared to drug-induced maculopapular eruption or urticaria and to controls without drug intolerance. METHODS: Results from 118 patients with a well-defined CADR were compared to 236 controls without drug intolerance living in the same area of France. We assessed nine polymorphisms: interleukin (IL)1-alpha-889C>T (rs 1800587), IL1-beta-511C>T (rs 16944), IL1-RN intron-2-VNTR (rs2234663), IL2-330T>G (rs 2069762), IL4-33C>T (rs 2070874), IL5 745C>T (rs 2069812), IL10-592C>A (rs 1800872), IL16-295T>C (rs 4778889) and tumour necrosis factor-alpha-308G>A (rs 1800629). RESULTS: Three polymorphisms exhibited a significant association with CADR (P < 0.05). The combination of the IL1-RN-A2 and IL1-beta-511C alleles was statistically different between cases and controls (P = 0.007) and the A2C haplotype was associated with susceptibility to CADR, particularly in drug reaction with eosinophilia and systemic symptoms (DRESS) patients (odds ratio = 3.22; 95% confidence interval = 1.23-8.41; P = 0.016). The frequency of the IL10-592A allele was higher in DRESS patients than in controls (dominant model CC vs. CA + AA: P = 0.035). These abnormalities were not evident in maculopapular eruptions or urticaria. CONCLUSIONS: This is the first study showing that IL1-cluster polymorphisms and haplotypes and the IL10 592A allele (a low IL10 producer) are associated with DRESS. These gene variants may decrease drug tolerance and promote herpes virus reactivation. PMID- 23461377 TI - Prevalence of undetected developmental delays in Iranian children. AB - BACKGROUND: Regarding the short- and long-term benefits of early intervention for childhood developmental disorders, this study was carried out to determine the prevalence of undetected developmental delays by the standardized form of the Persian version of the Ages and Stages Questionnaires (ASQ) in Iranian children. METHODS: This was a cross-sectional study. The study was carried out on 11 000, 4 to 60-month-old children; in 19 age groups, in 41 selected cities throughout the country. Ninety physicians were invited from each of the selected cities to Tehran in groups, and trained about the ASQ scoring, during a 2-day workshop. The questionnaires were completed at healthcare settings by parents of children who were apparently normal (lacking any gross developmental disorders) under the supervision of the physicians who consequently scored each child. The response rate was 95% (10 516 parents). RESULTS: Among the 10 516 children studied, 5035 (47.87%) were girls. The average percentage of children delayed in the communication, gross motor, fine motor, problem-solving and social-personal domains was 3.87%, 4.04%, 4.31%, 4.15% and 3.69%, respectively, when considering the Iranian cut-off points. In the 19 age-domain groups, most frequently in the personal-social and fine motor domains (in terms of domains), and also most frequently at 36 and 48 months of age (in terms of age ranges), girls showed significantly higher scores than boys. Boys showed significantly higher scores in two age-domain groups (gross motor domain at 20 and 22 months of age). CONCLUSIONS: The prevalence of undetected developmental delays in Iranian children screened by the ASQ questionnaires ranged from 3.69% to 4.31% in different developmental domains. PMID- 23461378 TI - Dissecting the relative contribution of OATP1B1-mediated uptake of xenobiotics into human hepatocytes using siRNA. AB - 1. Organic anion transporting polypeptide 1B1 plays a pivotal role in the disposition of many anionic drugs. Significant overlap in substrate specificity between individual OATP isoforms has hampered the identification of the relative importance of individual isoforms for hepatic uptake of xenobiotics. 2. The present study focused on the use of siRNA technology to decrease OATP1B1 selectively in human hepatocytes. Following delivery of siRNA by the novel lipid, AtuFECT01, mRNA expression of OATP1B1 was reduced by 94%-98% with no significant toxicity. Off-target effects were also shown to be minimal as evidenced by the expression of common drug metabolizing enzymes, transporters, nuclear receptors and associated co-regulators. Uptake of estrone-3-sulfate (5 nM) by OATP1B1 was reduced by 82%-95%. This methodology was subsequently used to assess the relative contribution of OATP1B1 uptake in human hepatocytes for olmesartan (42%-62%), valsartan (28%-81%), rosuvastatin (64%-72%), pitavastatin (84%-98%) and lopinavir (64%-89%). These data are consistent with previous values obtained using a relative activity factor approach. 3. The siRNA approach provides a robust and reproducible method for assessing the relative contribution of OATP1B1 to hepatic uptake of new chemical entities. The technique also has potential utility in facilitating detailed characterization of drug-drug interactions involving hepatic drug transporters. PMID- 23461380 TI - Microbial population dynamics in the faeces of wood-eating loricariid catfishes. AB - Catfishes of the genus Panaque are known for their ability to feed on wood and hence to process cellulose fibres in their digestive systems. The paper industry uses cellulose fibres and thus has an interest in exploiting this property biomimetically: it could be employed as a pretreatment to lessen the energy required by the mechanical production stage of manufacturing nanocellulose fibres. Here, we characterize the diet-associated in situ microbial diversity and population dynamic in the faeces of catfish (Panaque sp.) exposed to consecutive diets of pellet food and then wood. Fish faeces samples were collected and investigated by parallel DNA deep amplicon sequencing of the bacterial 16S rRNA SSU for both diet conditions. The most frequently occurring bacterium in the faeces was Cetobacterium sp. The dominant cellulolytic bacterial genera found in ascending relative abundance were as follows: Aeromonas sp., Flavobacterium sp., Bacteroides sp., Pseudomonas sp. and Cellvibrio sp. Diet-associated changes in the faeces microbiome were noted for Flavobacterium sp. Extensive microbial diversity was found in catfish faeces, evidenced using culture-independent molecular techniques. No significant diet-associated effects on the microbiome in terms of biodiversity were observed in the catfish faeces, but diet-associated changes in the microbial population structure were observed. SIGNIFICANCE AND IMPACT OF THE STUDY: Although catfishes are not classified as true xylivores, inhabiting their faeces are bacteria that may provide a novel source of cellulolytic enzyme. Based on this first microbiology study, the faeces and thus the gastrointestinal microbiome of Panaque catfishes are an unexplored reservoir of microbial extracts with enhanced polysaccharide transforming enzyme activity. The biomimetical exploitation of this cellulolytic activity in the form of novel enzymes or by applying a mixture of cellulolytic micro-organisms could accomplish a pretreatment to the mechanical production process of nanocellulose fibres, thus could reduce the energy consumption costs significantly. PMID- 23461381 TI - Robot-assisted partial nephrectomy: a comparison of the transperitoneal and retroperitoneal approaches. AB - PURPOSE: To present the oncologic and functional outcomes of robot-assisted partial nephrectomy (RAPN) and analyze retroperitoneal and transperitoneal approaches. PATIENTS AND METHODS: RAPN was performed on 103 patients; 44 patients underwent a retroperitoneal and 59 a transperitoneal approach. Demographic, operative, and postoperative data was collected and retrospectively analyzed on all patients. RESULTS: Overall average warm ischemic time was 20.4 (0-48) minutes, total operative time was 175.3 (85-330) minutes, and estimated blood loss was 258.1 (20-3100) mL. When retroperitoneal and transperitoneal approaches were compared, there was no significant difference in warm ischemic time but a significant reduction in both estimated blood loss and total operative time in the retroperitoneal group. CONCLUSION: Our series would suggest that if performed by a surgeon familiar with a laparoscopic retroperitoneal approach to renal surgery, retroperitoneal RAPN is at least equivalent to the more common transperitoneal approach in the outcomes assessed. PMID- 23461382 TI - Comparing discrete fracture and continuum models to predict contaminant transport in fractured porous media. AB - We used the FRAC3Dvs numerical model (Therrien and Sudicky 1996) to compare the dual-porosity (DP), equivalent porous medium (EPM), and discrete fracture matrix diffusion (DFMD) conceptual models to predict field-scale contaminant transport in a fractured clayey till aquitard. The simulations show that the DP, EPM, and DFMD models could be equally well calibrated to reproduce contaminant breakthrough in the till aquitard for a base case. In contrast, when groundwater velocity and degradation rates are modified with respect to the base case, the DP method simulated contaminant concentrations up to three orders of magnitude different from those calculated by the DFMD model. In previous simulations of well-characterized column experiments, the DFMD method reproduced observed changes in solute transport for a range of flow and transport conditions comparable to those of the field-scale simulations, while the DP and EPM models required extensive recalibration to avoid high magnitude errors in predicted mass transport. The lack of robustness with respect to variable flow and transport conditions suggests that DP models and effective porosity EPM models have limitations for predicting cause-effect relationships in environmental planning. The study underlines the importance of obtaining well-characterized experimental data for further studies and evaluation of model key process descriptions and model suitability. PMID- 23461383 TI - Electronic absorption spectrum of triacetylene cation for astronomical considerations. AB - The A(2)Pig <- X(2)Piu electronic transition (4800-6000 A) of triacetylene cation was measured in an ion trap, where the vibrational and rotational degrees of freedom were equilibrated to 25 K. The rotational profile of the origin band is predicted by a collisional-radiative rate model under conditions expected in diffuse interstellar clouds. Variation in the density of the surrounding gas, rotational temperature, and velocity dispersion are taken into account. PMID- 23461379 TI - Nanoparticle characterization: state of the art, challenges, and emerging technologies. AB - Nanoparticles have received enormous attention as a promising tool to enhance target-specific drug delivery and diagnosis. Various in vitro and in vivo techniques are used to characterize a new system and predict its clinical efficacy. These techniques enable efficient comparison across nanoparticles and facilitate a product optimization process. On the other hand, we recognize their limitations as a prediction tool, due to inadequate applications and overly simplified test conditions. We provide a critical review of in vitro and in vivo techniques currently used for evaluation of nanoparticles and introduce emerging techniques and models that may be used complementarily. PMID- 23461384 TI - Advantages of proton therapy in non-small cell lung cancers. AB - The advantage of proton therapy over conventional radiotherapy is enormous, with many clinical advantages. In this review, we summarized the important literature in the advantages of Proton Therapy in Non-small Cell Lung Cancers. PMID- 23461385 TI - In vivo and in vitro studies on renal uptake of radiolabeled affibody molecules for imaging of HER2 expression in tumors. AB - Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody ZHER2:342 was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the (111)In- and (68)Ga-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: KD1=0.8 nM, Bmax1=71,500 and KD2=9.2 nM, Bmax2=367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells. PMID- 23461386 TI - Inhibition of SENP6-induced radiosensitization of human hepatocellular carcinoma cells by blocking radiation-induced NF-kappaB activation. AB - Hepatocellular carcinoma is the most common type of liver cancer. Radiotherapy combined with chemotherapy is the treatment of choice for hepatocellular carcinoma, but radioresistance of the cancer remains a significant therapeutic hindrance. Here, we provided several lines of evidence that small ubiquitin-like modifier (SUMO)-specific protease 6 (SENP6) could be an attractive molecular target for the treatment of hepatocellular carcinoma. By using immunohistochemical and real-time PCR, we showed that SENP6 was overexpressed in more than half of the hepatocellular carcinoma tissues. The growth retardation and radiosensitization were caused by silencing of SENP6 in the hepatocellular carcinoma cell lines using lentiviral shRNA. Moreover, SENP6 was required for radiation-induced NF-kappaB activation and the half-life of IkappaBalpha, a well known inhibitor of NF-kappaB, and was extended by SENP6 silencing. Thus, our data demonstrated that SENP6 is an attractive drug target for anticancer therapy and radiosensitization. PMID- 23461387 TI - The garuganin and garugamblin diarylether heptanoids: total synthesis and determination of chiral properties using dynamic NMR. AB - The synthesis of the garuganin and garugamblin diarylether heptanoids using an intramolecular Ullmann coupling is reported. Alkene stereoisomers, vinylogous ester regioisomers, and beta-diketone congeners are also synthesized. The chiral properties and free energies of activation for racemization of the garuganin and garugamblin diarylether heptanoids and congeners are determined using dynamic NMR methods. A combination of techniques including coalescence measurements, line shape analysis, and selective inversion experiments are used to measure racemization barriers. None of the garuganin or garugamblin diarylether heptanoids are chiral, despite their reported specific rotation values. PMID- 23461388 TI - Iodine-129 in seawater offshore Fukushima: distribution, inorganic speciation, sources, and budget. AB - The Fukushima nuclear accident in March 2011 has released a large amount of radioactive pollutants to the environment. Of the pollutants, iodine-129 is a long-lived radionuclide and will remain in the environment for millions of years. This work first report levels and inorganic speciation of (129)I in seawater depth profiles collected offshore Fukushima in June 2011. Significantly elevated (129)I concentrations in surface water were observed with the highest (129)I/(127)I atomic ratio of 2.2 * 10(-9) in the surface seawater 40 km offshore Fukushima. Iodide was found as the dominant species of (129)I, while stable (127)I was mainly in iodate form, reflecting the fact that the major source of (129)I is the direct liquid discharges from the Fukushima NPP. The amount of (129)I directly discharged from the Fukushima Dai-ichi nuclear power plant to the sea was estimated to be 2.35 GBq, and about 1.09 GBq of (129)I released to the atmosphere from the accident was deposited in the sea offshore Fukushima. A total release of 8.06 GBq (or 1.2 kg) of (129)I from the Fukushima accident was estimated. These Fukushima-derived (129)I data provide necessary information for the investigation of water circulation and geochemical cycle of iodine in the northwestern Pacific Ocean in the future. PMID- 23461389 TI - Indeno[2,1-c]fluorene: a new electron-accepting scaffold for organic electronics. AB - A new class of fully conjugated indenofluorenes has been synthesized and confirmed by solid-state structure analysis. These indeno[2,1-c]fluorene molecules, containing an antiaromatic as-indacene core (in red), possess high electron affinities and show a broad absorption that reaches into the near-IR region of the electromagnetic spectrum. All of the featured compounds reversibly accept up to two electrons. Their electronic properties make this class of compounds attractive for applications in organic electronic devices. PMID- 23461390 TI - Outcomes for type 2 diabetes mellitus patients with diverse regimens. AB - AIMS AND OBJECTIVES: To compare the levels of self-care behaviour, social support and quality of life among type 2 diabetes mellitus patients who underwent three regimens: taking medicine, taking-medicine-while dieting and taking-medicine while-dieting-with exercise. BACKGROUND: Diabetes treatment is a critical concern worldwide. However, studies on self-care behaviour, social support and quality of life based on diabetes patients' diverse regimens are few. DESIGN: This study was a cross-sectional design. METHODS: We enrolled 127 outpatients aged over 40 years who visited a metabolism clinic at a medical centre in Southern Taiwan. The Self care Behaviour Scale, Social Support Scale and Quality of Life Scale were used to collect data. RESULTS: The results indicated that patients with a combined regimen of taking-medicine-while-dieting-with-regular exercise had the highest score at the levels of social support, self-care behaviour and quality of life. CONCLUSION: The study results could offer evidence-based knowledge for healthcare professionals to guide and promote social support, self-care behaviour and quality of life for people diagnosed with type 2 diabetes. RELEVANCE TO CLINICAL PRACTICE: These findings will help healthcare professionals to establish appropriate nursing strategies for type 2 diabetes patients who need to exercise regularly as part of their daily care to enhance their self-care behaviour, social support and quality of life. PMID- 23461391 TI - Characteristics and outcomes of discharges against medical advice among hospitalised patients. AB - BACKGROUND: Discharge against medical advice (DAMA) occurs when an in-patient chooses to leave the hospital before discharge is recommended by the treating clinicians. The long-term outcomes of patients who DAMA are not well documented. AIM: The objective of this long-term and hospital-wide study is to examine characteristics of patients who DAMA, their rates of readmission and mortality after self-discharge. METHODS: Administrative data of admissions to Flinders Medical Centre between July 2002 and June 2011 were used to compare readmissions and mortality among patients who DAMA with those who did not. The outcomes were adjusted for age, gender, emergency admission status, comorbidity, mental health diagnoses, and alcohol and substance abuse. RESULTS: In the study period, 1562 episodes (1.3%) of 121,986 admissions to Flinders Medical Centre were DAMA. Compared with those who did not leave against medical advice, these patients were younger, more often male, more likely of indigenous ethnicity and had less physical comorbidity, but greater mental health comorbidity. Half of the DAMA group stayed less than 3 days. In multivariate analysis, the relative risk for 7 day, 28-day and 1-year readmission in the DAMA group was 2.36 (95% confidence interval (CI), 1.99-2.81; P < 0.001), 1.66 (95% CI, 1.44-1.92; P < 0.001) and 1.31 (95% CI, 1.19-1.45; P < 0.001), respectively, compared with standard discharges. Furthermore, DAMA was associated with twofold (P = 0.02), 1.4-fold (P = 0.025) and 1.2-fold (P = 0.049) increase in 28-day, 1-year and up-to-9-year mortality, respectively, compared with non-DAMA. CONCLUSIONS: Patients who self discharged against medical advice carry a significant risk of readmission and mortality. Patients with characteristics of 'at risk of DAMA' should have greater attention paid to their care before and especially after any premature discharge. PMID- 23461392 TI - Adsorption of arginine-glycine-aspartate tripeptide onto negatively charged rutile (110) mediated by cations: the effect of surface hydroxylation. AB - Classical molecular dynamics (MD) simulations were employed to investigate the adsorption behaviors of arginine-glycine-aspartate (RGD) tripeptide onto the negatively charged hydroxylated/nonhydroxylated rutile (110) surfaces, mediated by biologically important cations (Na+ or Ca2+). The simulation results indicate that the inherent nature of the cation determines its binding strength, thereby regulating the adsorption geometry of the peptide. The sparse hydroxyl groups on the nonhydroxylated rutile diminish the probability of H-bond formation between RGD and the surface, resulting in an early desorption of the peptide even with a mediating Na+ ion. In contrast, the negatively charged aspartate (Asp) side chain is bridged to the negatively charged hydroxylated rutile by an inner-sphere Na+ ion, in coordination with the Asp-rutile hydrogen bonds at the anchoring sites. The inner- and outer-sphere Ca2+ ions are demonstrated to be capable of "trapping" RGD on both hydroxylated and nonhydroxylated rutile, in the absence of hydrogen bonds with the surface. The strongly bound inner-sphere mediating Ca2+ ion exerts a "gluing" effect on the Asp side chain, producing a tightly packed RGD-rutile complex, whereas a less localized distribution density of the outer sphere mediating Ca2+ ion results in a higher mobility of the Asp side chain. The intramolecular interaction is suggested to facilitate the structural stability of RGD adsorbed on the negative rutile in a "horseshoe" configuration. PMID- 23461394 TI - Quantitative characterization of cantharidin in the false blister beetle, Oedemera podagrariae ventralis, of the southern slopes of Mount Elborz, Iran. AB - Cantharidin, a potent vesicant and antifeedant agent, is produced by two families of beetles, Meloidae and Oedemeridae (Coleoptera). In this study, the cantharidin content of oedemerid beetles of central Iran was investigated using the GC-MS method. Cantharidin in both sexes of Oedemera podagrariae ventralis Meineitrieas (Oedemeridae) was found in an average of 3.89 ug/beetle in males and 21.68 ug/beetle in females, which are amounts sufficient to irritate human skin. The average of cantharidin in virgin and coupled beetles was 1.35 and 1.62 (ug cantharidin/mg of beetle) respectively. Females had five to six times more cantharidin in their bodies than males, but there was no significant difference between the amount of cantharidin in virgin and coupled females. The results of this study revealed the production of cantharidin in both sexes of beetle. PMID- 23461393 TI - Membrane orientation of Galpha(i)beta(1)gamma(2) and Gbeta(1)gamma(2) determined via combined vibrational spectroscopic studies. AB - The manner in which the heterotrimeric G protein complexes Gbeta1gamma2 and Galphaibeta1gamma2 interact with membranes is likely related to their biological function. We combined complementary measurements from sum frequency generation (SFG) vibrational and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy to determine the possible membrane orientations of Gbeta1gamma2 and the Galphaibeta1gamma2 heterotrimer more precisely than could be achieved using SFG alone. The most likely orientations of Gbeta1gamma2 and the Galphaibeta1gamma2 heterotrimer were both determined to fall within a similar narrow range of twist and tilt angles, suggesting that Gbeta1gamma2 may bind to Galphai without a significant change in orientation. This "basal" orientation seems to depend primarily on the geranylgeranylated C-terminus of Ggamma2 along with basic residues at the N-terminus of Galphai, and suggests that activated G protein-coupled receptors (GPCRs) must reorient G protein heterotrimers at lipid bilayers to catalyze nucleotide exchange. The innovative methodologies developed in this paper can be widely applied to study the membrane orientation of other proteins in situ. PMID- 23461395 TI - Structural evidence of a productive active site architecture for an evolved quorum-quenching GKL lactonase. AB - The in vitro evolution and engineering of quorum-quenching lactonases with enhanced reactivities was achieved using a thermostable GKL enzyme as a template, yielding the E101G/R230C GKL mutant with increased catalytic activity and a broadened substrate range [Chow, J. Y., Xue, B., Lee, K. H., Tung, A., Wu, L., Robinson, R. C., and Yew, W. S. (2010) J. Biol. Chem. 285, 40911-40920]. This enzyme possesses the (beta/alpha)8-barrel fold and is a member of the PLL (phosphotriesterase-like lactonase) group of enzymes within the amidohydrolase superfamily that hydrolyze N-acyl-homoserine lactones, which mediate the quorum sensing pathways of bacteria. The structure of the evolved N-butyryl-l-homoserine lactone (substrate)-bound E101G/R230C GKL enzyme was determined, in the presence of the inactivating D266N mutation, to a resolution of 2.2 A to provide an explanation for the observed rate enhancements. In addition, the substrate-bound structure of the catalytically inactive E101N/D266N mutant of the manganese reconstituted enzyme was determined to a resolution of 2.1 A and the structure of the ligand-free, manganese-reconstituted E101N mutant to a resolution of 2.6 A, and the structures of ligand-free zinc-reconstituted wild-type, E101N, R230D, and E101G/R230C mutants of GKL were determined to resolutions of 2.1, 2.1, 1.9, and 2.0 A, respectively. In particular, the structure of the evolved E101G/R230C mutant of GKL provides evidence of a catalytically productive active site architecture that contributes to the observed enhancement of catalysis. At high concentrations, wild-type and mutant GKL enzymes are differentially colored, with absorbance maxima in the range of 512-553 nm. The structures of the wild-type and mutant GKL provide a tractable link between the origins of the coloration and the charge-transfer complex between the alpha-cation and Tyr99 within the enzyme active site. Taken together, this study provides evidence of the modulability of enzymatic catalysis through subtle changes in enzyme active site architecture. PMID- 23461396 TI - Near-Infrared photoluminescence in the femtosecond time region in monolayer graphene on SiO2. AB - We investigate the dynamical properties of photoexcited carriers in a single monolayer of graphene at room temperature in air using femtosecond time-resolved luminescence spectroscopy. The luminescence kinetics are observed in the near infrared region of 0.7-1.4 eV and analyzed based on the two-temperature model describing the cooling of thermalized carriers via the carrier-optical phonon interaction. The observed luminescence in the range 0.7-0.9 eV is well reproduced by the model. In the range 1.0-1.4 eV, however, the luminescence, which decays in ~300 fs, cannot be reproduced by this model. These results indicate that the carrier system is not completely thermalized in ~300 fs. We also show the importance of the carrier-doping effect induced by the substrate and surrounding environment in the carrier cooling dynamics and the predominance of optical phonons over acoustic phonons in the carrier-phonon interactions even at a temperature of ~400 K. PMID- 23461398 TI - [Aortic regurgitation]. AB - This paper focuses on aortic regurgitation. It covers the findings related to etiopathogenesis, clinical signs, echocardiographic and catheter examination. It analyses the treatment criteria with a focus on cardiac surgery. PMID- 23461397 TI - MU-Opioid receptors mediate the effects of chronic ethanol binge drinking on the hippocampal neurogenic niche. AB - Ethanol exposure and withdrawal alter the generation of new neurons in the adult hippocampus. The endogenous opioid system, particularly the MU-opioid receptor (MOR), can modulate neural progenitors and also plays a critical role in ethanol drinking and dependence. In the present study, we sought to determine whether MOR contributes to the effects of ethanol on the dentate gyrus (DG) neurogenic niche. MOR wild-type (WT), heterozygous (Het) and knockout (KO) littermates were subjected to voluntary ethanol drinking in repeated limited-access two-bottle choice (2BC) sessions. MOR deficiency did not alter progenitor proliferation, neuronal differentiation and maturation, apoptosis or microglia in ethanol-naive mice. When exposed to five consecutive weeks of 2BC, MOR mutant mice exhibited a gene-dosage-dependent reduction of ethanol consumption compared with WT mice. Introducing a week of ethanol deprivation between each week of 2BC increased ethanol consumption in all genotypes and produced equivalent intakes in WT, Het and KO mice. Under the latter paradigm, ethanol drinking decreased progenitor proliferation and neuronal differentiation in the DG of WT mice. Interestingly, WT mice exhibited a strong negative correlation between ethanol intake and proliferation, which was disrupted in Het and KO mice. Moreover, MOR deficiency blocked the effect of ethanol on neuronal differentiation. MOR deficiency also protected against the neuroimmune response to ethanol drinking. Finally, chronic binge drinking induced a paradoxical decrease in apoptosis, which was independent of MOR. Altogether, our data suggest that MOR is implicated in some of the neuroplastic changes produced by chronic ethanol exposure in the DG. PMID- 23461399 TI - [Current trends in treatment and follow-up of patients with differentiated thyroid carcinoma - experience with the use of recombinant human thyrotropin]. AB - Differentiated thyroid carcinoma is the most common endocrine malignancy with an excellent prognosis in the case of its early detection. Radioiodine 131I and thyroid hormones continue to be the pivotal drugs in treatment and follow-up for more than 50 years. The therapeutical and diagnostic options were recently expanded by the use of recombinant human thyrotropin (rhTSH). Our experience with the diagnostic administration of rhTSH confirms the outcomes of official trials and also indicates that the effect of rational therapy with 131I after rhTSH is similar to the outcome after standard regime using long-term thyroid hormone withdrawal. PMID- 23461400 TI - [Practice guideline and trends for immunosuppressive treatment of glomerulonephritides according to KDIGO (Clinical Practice Guideline for Glomerulonephritis)]. AB - We summarize recommendations for glomerulonephritis treatment, established by internationally recognized experts in the field and sponsored by KDIGO (Kidney Disease Improving Global Outcomes). Up till now, the KDIGO review has been the most prestigious analysis of therapeutic trials on immunosuppressive treatment of glomerulonephritides. The 167 recommendations addresses the following forms of glomerulopathies: steroid-sensitive nephrotic syndrome and steroid resistant nephrotic syndrome in children; minimal change disease and idiopathic focal segmental glomerulosclerosis in children and adults; idiopathic membranous nephropathy; idiopathic membranoproliferative glomerulonephritis; glomerulonephritis associated with infection; immunoglobulin A nephropathy and Henoch-Schonlein purpura nephritis; lupus nephritis; pauci-immune focal and segmental necrotizing glomerulonephritis; and anti--glomerular basement membrane antibody glomerulonephritis. We focused our attention on progress in this topic in the last decade. PMID- 23461401 TI - [Opinion of the Czech Atherosclerosis Society's committee (CSAT) on the ESC/EAS guidelines related to the diagnostics and treatment of dyslipidemias issued in 2011]. AB - This position statement of the Executive Committee of the Czech Society for Atherosclerosis (CSAT) summarizes the most important aspects and novelties of the latest European guidelines for the management of dyslipidemia. In particular the position statement comments on: cardiovascular risk stratification, indications for plasma lipid and lipoprotein levels assessment as well as target lipid values, evaluation of current options for both lifestyle and pharmacological treatment of lipid metabolism disorders and, also, recommendation for laboratory monitoring of patients treated with lipid lowering agents. The statement deals with actual concepts of management of dyslipiemia in everyday practice, e.g. therapy of dyslipidemia in special patients' groups. This statement does not replace the latest guidelines but focuses on the changes from the former guidelines for dyslipidemia management, published by CSAT in 2007. PMID- 23461402 TI - Ischemic peripheral arterial disease and recurrent iliofemoral venous thrombosis in a 24-year-old man with antiphospholipid syndrome. AB - The following is a case report of a young man with antiphospholipid syndrome, present with a recurrent iliofemoral venous thrombosis and premature peripheral arterial disease. This case report highlights the high risk of recurrent thrombosis upon discontinuation of anticoagulation therapy, particularly in the presence of persistent spontaneously increased aPTT and a high antiphospholipid antibody titer. The case report also reviews the potential of endovascular treatment of iliac vein thrombosis and points out the good 24-month patency rates of stents implanted into the pelvic vein region.Key words: antiphospholipid syndrome - iliofemoral deep vein thrombosis - recurrent thrombosis - accelerated atherosclerosis - peripheral arterial disease. PMID- 23461403 TI - [Syncope as first and only sign of left atrial myxoma]. AB - Myxoma is the most frequent primary heart tumor. It is localised in the left atrium in majority of cases, but each of heart chambers may be affected. Left atrial myxoma becomes symptomatic in case it leads into mitral valve obstruction, systemic embolisation or it manifests with unspecific systemic symptoms. Echocardiography is a golden standard of myxoma diagnostics. We present a case of 61-years old woman patient in whom exercise induced syncope was the first and only sign of far gone left atrial myxoma with left ventricle inflow tract obstruction, leading to mitral pseudostenosis. PMID- 23461404 TI - [Heart transplantation and the subsequent treatment of AL amyloidosis]. AB - Severe damage to the heart caused by AL amyloid deposits is a contraindication of high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Severe heart damage caused by AL amyloid results in frequent life-threatening complications, even during the course of the classical chemotherapy treatment and it often makes keeping to the treatment schedule impossible. Scheduling heart transplantation before the treatment of AL amyloidosis will significantly improve the patients overall condition and enable them to undergo the intensive AL amyloidosis treatment with the hope that a long-term complete remission may be achieved. CASE DESCRIPTIONS: Transplantations of heart damaged by AL amyloid deposits were conducted in three patients; two men, age 48 and 54, and one woman, age 63. In the interval of 3-6 months from the heart transplantation before the scheduled AL amyloidosis treatment was initiated, an examination of bone marrow, the concentration of monoclonal immunoglobulin and free light chains was carried out. Both men had more than 10% of plasma cells in the bone marrow after the heart transplantation and the concentrations of the lambda free light chains were pathologically increased. During the first-line therapy, autologous haematopoietic stem cells were harvested from peripheral blood after mobilizaton with granulocyte growth factor (filgrastim) at the dose of 5 ug/kg twice a day. During the administration of filgrastim until the end of the haematopoietic stem cell harvest, the combined immunosuppressive treatment was reduced and a corticosteroid dose was compensatory increased. The prophylactic antiviral drug valganciclovir was discontinued during the haematopoietic stem cell harvest. High dose chemotherapy (melphalan 100 mg/m2) with autologous haematopoietic stem cell transplantation followed. In the interval from administering melphalan until the rise in neutrophil count over 2 x 109/l, antiviral prophylaxis was discontinued again, the immunosuppressive drug doses were reduced and corticoid doses were slightly increased. High-dose chemotherapy with melphalan at the of 100 mg/m2 was tolerated without major complications and without mucositis; however, in neither of the male patients did it lead to a complete haematological remission. Consequently, the second-line therapy followed using bortezomib combined with dexamethasone and also with cyclophosphamide or doxorubicin. One of these two patients reached a complete haematological remission after the bortezomib therapy; the values of free light chains were normal, immunofixation was negative, and clonal plasma cells were absent in the bone marrow. In the case of the other patient, the bortezomib therapy only induced partial remission. In this case, the third-line therapy followed, applying a combination of lenalidomide, dexamethasone and cyclophosphamide. This therapy significantly reduced the values of free light chains; however, their ratio remained pathological. To conclude, the latter response can be described as a very good partial remission. Both men currently show no signs of disease activity and are in a good clinical condition 28 and 30 months after the heart transplantation. The third heart transplantation, due to severe heart damage by AL amyloid deposits, was conducted in a woman aged 63. An examination of this woman three months after the heart transplantation showed that the original pathological values of free light chains became normal. The woman had approx. 8% of clonal plasma cells before the heart transplantation. Three months after the heart transplantation the bone marrow contained only 3% of polyclonal plasma cells. In this case, the immunosuppressive treatment with corticosteroids after the heart transplantation probably induced a complete haematologic remission. The woman is in a complete AL amyloidosis remission seven months after the heart transplantation. CONCLUSION: It was beneficial to perform the heart transplantation first and to initiate the AL amyloidosis treatment no sooner than three months after the heart transplantation in patients with severe heart damage caused by AL amyloid deposits. If the patients are in a good clinical conditions, autologous haematopoietic stem cells can be harvested after the heart transplantation and high-dose chemotherapy can be offered to the patients. If this intensive treatment does not induce remission, it is necessary to apply additional alternative treatments. PMID- 23461405 TI - Attitude of Brazilian veterinarians in the recognition and treatment of pain in horses and cattle. AB - OBJECTIVE: The objective of this study was to assess the use of analgesics, describe the attitudes of Brazilian veterinarians towards pain relief in horses and cattle and evaluate the differences due to gender, year of graduation and type of practice. STUDY DESIGN: Prospective survey. METHODS: Questionnaires were sent to 1000 large animal veterinarians by mail, internet and delivered in person during national meetings. The survey investigated the attitudes of Brazilian veterinarians to the recognition and treatment of pain in large animals and consisted of sections asking about demographic data, use of analgesic drugs, attitudes to pain relief and to the assessment of pain. Descriptive statistics were used to analyze frequencies. Simple post hoc comparisons were performed using the chi-square test. RESULTS: Eight hundred questionnaires were collected, but 87 were discarded because they were incomplete or blank. The opioid of choice for use in large animals was butorphanol (43.4%) followed by tramadol (39%). Flunixin (83.2%) and ketoprofen (67.6%) were the most frequently used NSAIDs by Brazilian veterinarians. Respondents indicated that horses received preoperative analgesics for laparotomy more frequently (72.9%) than cattle (58.5%). The most frequently administered preoperative drugs for laparotomy in horses were flunixin (38.4%) and xylazine (23.6%), whereas the preoperative drugs for the same surgical procedure in cattle were xylazine (31.8%) and the local administration of lidocaine (48%). Fracture repair was considered the most painful surgical procedure for both species. Most veterinarians (84.1%) believed that their knowledge in this area was not adequate. CONCLUSIONS AND CLINICAL RELEVANCE: Although these Brazilian veterinarians thought that their knowledge on recognition and treatment of pain was not adequate, the use of analgesic in large animals was similar in Brazil to that reported in other countries. PMID- 23461406 TI - A case of pityriasis versicolour atrophicans. PMID- 23461407 TI - Monitoring change requires a rethink of assessment practices in voice and speech. AB - Assessment for the purpose of monitoring change over time requires a different practical and statistical approach to that of assessment for diagnosing impairment. Sophisticated methods exist for identifying strengths and weaknesses in a patient's voice/speech profile, yet our understanding of the impact of repeated assessment is limited. Monitoring change necessitates that stimuli are stable in the absence of any true change in functioning, while remaining sensitive to influences that are considered to alter functioning (degeneration, therapy). The current paper discusses the issues relating to stimuli selection, identifying error within the sample and appropriate statistical models for identifying intra-individual change in the context of clinical and experimental speech or voice examinations. PMID- 23461408 TI - DFT prediction of multitopic N-heterocyclic carbenes using Clar's aromatic sextet theory. AB - Existence of several multitopic N-heterocyclic carbene (NHC) ligands with up to four carbene centers have been predicted on the basis of Clar's aromatic sextet theory. Assessment on stability and reactivity of NHCs was made by quantifying aromaticity, aromatic stabilization energy (E(aroma)), strength of carbene lone pair, proton affinity, and CuCl binding energy. On NICS(0) and HOMA scales of aromaticity, several NHCs showed high aromaticity, while E(aroma) (17.2-19.4 kcal/mol) indicated substantial stability for the N-heterocycle. Homodesmotic reactions suggested that heat of formation of most of the newly designed carbenes is very close to that of the existing bis-NHCs. Designing a multitopic ligand through branching via C(sp3) linkage was very effective as it improved the stability of the carbene. Electrostatic potential minimum (V(min)) at the carbene lone pair suggested that annelation of heterocycle to a benzenoid ring or branching through C(sp3) linkage can only marginally influence the electron donating power of the ligand. Hence, all multitopic NHCs showed proton affinity (252.3-267.4 kcal/mol) and CuCl binding energy (62.9-66.6 kcal/mol) very close to those of 1,3-dimethylimidazolidine-2-ylidene (1). It has also been demonstrated that branched multitopic 3-dimensional NHCs are attractive for designing metal organic framework with narrow (1-1.5 nm) cage/pore size. PMID- 23461409 TI - Characterization of the aroma signature of styrian pumpkin seed oil ( Cucurbita pepo subsp. pepo var. Styriaca) by molecular sensory science. AB - Application of the aroma extract dilution analysis on a distillate prepared from an authentic Styrian pumpkin seed oil followed by identification experiments led to the characterization of 47 odor-active compounds in the flavor dilution (FD) factor range of 8-8192 among which 2-acetyl-1-pyrroline (roasty, popcorn-like), 2 propionyl-1-pyrroline (roasty, popcorn-like), 2-methoxy-4-vinylphenol (clove like), and phenylacetaldehyde (honey-like) showed the highest FD factors. Among the set of key odorants, 2-propionyl-1-pyrroline and another 20 odorants were identified for the first time as constituents of pumpkin seed oil. To evaluate the aroma contribution in more detail, 31 aroma compounds showing the highest FD factors were quantitated by means of stable isotope dilution assays. On the basis of the quantitative data and odor thresholds determined in sunflower oil, odor activity values (OAV; ratio of concentration to odor threshold) were calculated, and 26 aroma compounds were found to have an OAV above 1. Among them, methanethiol (sulfury), 2-methylbutanal (malty), 3-methylbutanal (malty), and 2,3 diethyl-5-methylpyrazine (roasted potato) reached the highest OAVs. Sensory evaluation of an aroma recombinate prepared by mixing the 31 key odorants in the concentrations as determined in the oil revealed that the aroma of Styrian pumpkin seed oil could be closely mimicked. Quantitation of 11 key odorants in three commercial pumpkin seed oil revealed clear differences in the concentrations of distinct odorants, which were correlated with the overall aroma profile of the oils. PMID- 23461410 TI - Gallium-68: chemistry and radiolabeled peptides exploring different oncogenic pathways. AB - Abstract Early and specific tumor detection and also therapy selection and response evaluation are some challenges of personalized medicine. This calls for high sensitive and specific molecular imaging such as positron emission tomography (PET). The use of peptides for PET molecular imaging has undeniable advantages: possibility of targeting through peptide-receptor interaction, small size and low-molecular weight conferring good penetration in the tissue or at cellular level, low toxicity, no antigenicity, and possibility of wide choice for radiolabeling. Among beta(+)-emitter radioelements, Gallium-68 is a very attractive positron-emitter compared with carbon-11 or fluorine-18 taking into account its easy production via a (68)Ge/(68)Ga generator and well established radiochemistry. Gallium-68 chemistry is based on well-defined coordination complexes with macrocycle or chelates having strong binding properties, particularly suitable for linking peptides that allow resistance to in vivo transchelation of the metal ion. Understanding specific and nonspecific molecular mechanisms involved in oncogenesis is one major key to develop new molecular imaging tools. The present review focuses on peptide signaling involved in different oncogenic pathways. This peptide signalization might be common for tumoral and non-tumoral processes or could be specific of an oncological process. This review describes gallium chemistry and different (68)Ga-radiolabeled peptides already in use or under development aiming at developing molecular PET imaging of different oncological processes. PMID- 23461411 TI - Prevalence of verotoxigenic Escherichia coli O157 (VTEC O157) and compliance with microbiological safety standards in bovine carcasses from an industrial beef slaughter plant. AB - The presence of Salmonella spp. and levels of Enterobacteriaceae and aerobic plate count were determined in 300 bovine carcasses randomly collected in an industrial cattle slaughterhouse in Catalonia (Spain) as part of a control programme to validate good slaughter practices according to Commission Regulation No 2073/2005. The verotoxigenic Escherichia coli O157 (VTEC O157), although not currently legislated, was also investigated in the same carcasses due to the importance of bovines as a reservoir for this micro-organism. Virulence genes (vtx1, vtx2 and eae), the presence of fliCH 7 and antimicrobial susceptibility were studied in E. coli O157 isolates. Levels of Enterobacteriaceae and aerobic colonies and the presence of Salmonella were within the admissible range stipulated by current legislation. However, VTEC O157 was detected in 14.7% of carcasses. Among the VTEC O157 strains tested for antimicrobial susceptibility, 65% were multiresistant. Overall, the results of this study indicate that even with good manufacturing practices, contamination with VTEC O157 can occur and cattle meat can pose a risk to human health. These results confirm the need for a review of the appropriateness of introducing antimicrobial treatments in the processing of cattle carcasses in Europe. SIGNIFICANCE AND IMPACT OF THE STUDY: This study describes the prevalence of verotoxigenic and multidrug-resistant E. coli O157 strains in bovine carcasses. These results suggest that despite the good manufacturing practices used in the slaughterhouse studied (the largest in Catalonia slaughtering over 81 000 cattle per year), the absence of verotoxigenic E. coli O157 in bovine carcasses cannot be guaranteed. PMID- 23461412 TI - Sleep duration and quality of life in young rural Chinese residents. AB - The aim of this study was to determine the mean total sleep time (TST) and the relation between sleep duration (short sleep: < 7 hr per day; medium sleep: 7-8 hr per day; and long sleep: > 8 hr per day) and quality of life (QOL) in young Chinese rural residents. A sample of 1,632 participants was recruited in Mianyang, Sichuan province and interviewed. Expected and actual TSTs were asked using standardized questions. QOL was measured with the Chinese version of the World Health Organization Quality of Life Schedule-Brief. In the full sample, the mean expected TST was 8.8 +/- 1.3 hr, and the mean actual TST was 8.3 +/- 1.4 hr. Multivariate analyses revealed that compared to medium sleepers, short sleepers had lower QOL in the physical, psychological, and environmental domains, whereas long sleepers had higher QOL in the environmental domain. Being short or long sleepers was not associated with more major medical conditions. Given the significant associations between short sleep and poor QOL, more attention should be paid to young Chinese rural residents with short sleep. PMID- 23461414 TI - Quality of life and mental health among parents of children with cerebral palsy: the influence of self-efficacy and coping strategies. AB - AIMS AND OBJECTIVES: To explore the quality of life and mental health of caregivers of children with cerebral palsy and to examine the impact of self efficacy and coping strategies on these outcomes. BACKGROUND: Few studies analyse the impact of caring for a child with cerebral palsy on the caregivers' quality of life besides mental health. Also, less attention has been paid to the influence of caregiver's personal resources like self-efficacy or coping strategies on how they adjust to the child's illness and the care situation. DESIGN: Cross-section correlational design. METHODS: Sixty two parents of children with cerebral palsy completed measures to assess the quality of life (i.e. physical, environmental and social relationships), mental health (i.e. general mental health, depression and anxiety), self-efficacy and coping strategies. RESULTS: Parents of children with cerebral palsy had, in general terms, low levels of quality of life and mental health. Self-efficacy was related to most of the outcomes, whereas any of the coping strategies assessed was significantly related to the outcomes. CONCLUSIONS: Quality of life and mental health can be affected in caregivers of children with CP. Personal resources like self-efficacy also need attention as they can help in the understanding of the differences in these outcomes and the design of effective interventions. RELEVANCE OF CLINICAL PRACTICE: Self-efficacy should be a key element in interventions addressed to parents of children with CP to elicit a process of empowerment that can improve the well-being of the family as a whole. PMID- 23461413 TI - Differentiation and activation of equine monocyte-derived dendritic cells are not correlated with CD206 or CD83 expression. AB - Dendritic cells (DC) are the main immune mediators inducing primary immune responses. DC generated from monocytes (MoDC) are a model system to study the biology of DC in vitro, as they represent inflammatory DC in vivo. Previous studies on the generation of MoDC in horses indicated that there was no distinct difference between immature and mature DC and that the expression profile was distinctly different from humans, where CD206 is expressed on immature MoDC whereas CD83 is expressed on mature MoDC. Here we describe the kinetics of equine MoDC differentiation and activation, analysing both phenotypic and functional characteristics. Blood monocytes were first differentiated with equine granulocyte-macrophage colony-stimulating factor and interleukin-4 generating immature DC (iMoDC). These cells were further activated with a cocktail of cytokines including interferon-gamma) but not CD40 ligand to obtain mature DC (mMoDC). To determine the expression of a broad range of markers for which no monoclonal antibodies were available to analyse the protein expression, microarray and quantitative PCR analysis were performed to carry out gene expression analysis. This study demonstrates that equine iMoDC and mMoDC can be distinguished both phenotypically and functionally but the expression pattern of some markers including CD206 and CD83 is dissimilar to the human system. PMID- 23461415 TI - Alcohol-induced morphological deficits in the development of octavolateral organs of the zebrafish (Danio rerio). AB - Prenatal alcohol exposure is known to have many profound detrimental effects on human fetal development (fetal alcohol spectrum disorders), which may manifest as lifelong disabilities. However, how alcohol affects the auditory/vestibular system is still largely unknown. This is the first study to investigate morphological effects of alcohol on the developing octavolateral system (the inner ear and lateral line) using the zebrafish, Danio rerio. Zebrafish embryos of 2 hours post fertilization (hpf) were treated in 2% alcohol for 48 hours and screened at 72 hpf for morphological defects of the inner ear and lateral line. Octavolateral organs from both alcohol-treated and control zebrafish were examined using light, confocal, and scanning electron microscopy. We observed several otolith phenotypes for alcohol-treated zebrafish including zero, one, two abnormal, two normal, and multiple otoliths. Results of this study show that alcohol treatment during early development impairs the inner ear (smaller ear, abnormal otoliths, and fewer sensory hair cells) and the lateral line (smaller neuromasts, fewer neuromasts and hair cells per neuromast, and shorter kinocilia of hair cells). Early embryonic alcohol exposure may also result in defects in hearing, balance, and hydrodynamic function of zebrafish. PMID- 23461416 TI - New tools for the identification of developmentally regulated enhancer regions in embryonic and adult zebrafish. AB - We have conducted a screen to identify developmentally regulated enhancers that drive tissue-specific Gal4 expression in zebrafish. We obtained 63 stable transgenic lines with expression patterns in embryonic or adult zebrafish. The use of a newly identified minimal promoter from the medaka edar locus resulted in a relatively unbiased set of expression patterns representing many tissue types derived from all germ layers. Subsequent detailed characterization of selected lines showed strong and reproducible Gal4-driven GFP expression in diverse tissues, including neurons from the central and peripheral nervous systems, pigment cells, erythrocytes, and peridermal cells. By screening adults for GFP expression, we also isolated lines expressed in tissues of the adult zebrafish, including scales, fin rays, and joints. The new and efficient minimal promoter and large number of transactivating driver-lines we identified will provide the zebrafish community with a useful resource for further enhancer trap screening, as well as precise investigation of tissue-specific processes in vivo. PMID- 23461417 TI - Neuroprotective effect of zinc chelator DEDTC in a zebrafish (Danio rerio) Model of Hypoxic Brain Injury. AB - A study was conducted using zebrafish as a model of hypoxic brain injury to investigate the potential neuroprotective effects of zinc (Zn(2+)) chelation. The accumulation of intracellular Zn(2+) is a significant causal factor of the neuronal injury, and has been implicated in cell death followed by ischemic stroke. In this study, the zebrafish was placed in the hypoxia chamber with an extremely low level of dissolved oxygen (less than 0.8 mg/L), which is similar to the conditions in a complete global ischemic stroke. Approximately 50% of zebrafish died after a short period (~11 min) of hypoxic treatment, suggesting that this is a responsive model system for use in evaluating treatments for hypoxic brain damage. The application of DEDTC reduced intracellular Zn(2+) accumulation and produced a concentration-dependent effect by increasing the survival rate of zebrafish. Zn(2+) chelation also enhanced zebrafish tolerance for hypoxia. When the brain damages were evaluated with TTC staining, the zebrafish that were treated with DEDTC in hypoxic treatment yielded the improvement of TTC staining that was similar to the healthy zebrafish brain. The results support that rising intracellular Zn(2+) plays a critical role in the neuronal damages, and demonstrate the protective effects of Zn(2+) chelation in hypoxic-ischemic brain injury in zebrafish. PMID- 23461418 TI - Turn-on, fluorescent nuclear stains with live cell compatibility. AB - DNA-binding, green and yellow fluorescent probes with excellent brightness and high on/off ratios are reported. The probes are membrane permeable, live-cell compatible, and optimally matched to 405 nm and 514 nm laser lines, making them attractive alternatives to UV-excited and blue emissive Hoechst 33342 and DAPI nuclear stains. Their electronic structure was investigated by optical spectroscopy supported by TD-DFT calculations. DNA binding is accompanied by 27- to 75-fold emission enhancements, and linear dichroism demonstrates that one dye is a groove binder while the other intercalates into DNA. PMID- 23461419 TI - Chemical vapor deposition synthesis and Raman spectroscopic characterization of large-area graphene sheets. AB - We present a chemical vapor deposition (CVD) method to catalytically synthesize large-area, transferless, single- to few-layer graphene sheets using hexamethyldisilazane (HMDS) on a SiO2/Si substrate as a carbon source and thermally evaporated alternating Ni/Cu/Ni layers as a catalyst. The as synthesized graphene films were characterized by Raman spectroscopic imaging to identify single- to few-layer sheets. This HMDS-derived graphene layer is continuous over the entire growth substrate, and single- to trilayer mixed sheets can be up to 30 MUm in the lateral dimension. With the synthetic CVD method proposed here, graphene can be grown into tailored shapes directly on a SiO2/Si surface through vapor priming of HMDS onto predefined photolithographic patterns. The transparent and conductive HMDS-derived graphene exhibits its potential for widespread electronic and opto-electronic applications. PMID- 23461420 TI - The "visual dilator system": initial experimental evaluation of an optical tract dilation technique in percutaneous nephrolithotomy. AB - BACKGROUND AND PURPOSE: Ascertaining the optimal depth of dilator progression is a crucial factor during tract dilation in percutaneous nephrolithotomy. Dilation is generally guided under fluoroscopy, ultrasonography, or combination of both techniques, and it is still difficult to prevent overdilation causing perforation and vascular injury or underdilation causing difficulty in establishment of access. Thus, improvements in dilation technique bears clinical significance. Our aim was to evaluate the feasibility in an animal model of using the "visual dilator system" for optimal percutaneous tract dilation under real-time visual guidance. MATERIALS AND METHODS: The visual dilator system consisted of a transparent hollow dilator made of polyvinyl chloride and a rigid ureteroscope inserted within its lumen. The ureteroscope was connected to a standard endoscopic camera system. The dilator system backloaded with an access sheath was passed over a guidewire to dilate the tract and position the access sheath under visual guidance. Saline was used as irrigation to maintain clarity during dilation. The dilation technique was implemented to establish percutaneous access tract in six PCNL simulator models made from fresh porcine kidney placed inside an eviscerated chicken carcass and four female swine (eight kidneys) to experimentally evaluate its feasibility and efficacy. RESULTS: All tracts were successfully established with dilation through the intervening tissue layers, approach into the target calix, as well as access sheath placement being visually monitored through the dilator wall to confirm accuracy. All procedures were free of dilation-related complications such as collecting system perforation, excessive bleeding (in-vivo model), or loss of access. The limited number of animal models and lack of randomized comparative study with other dilator modalities were major drawbacks of the study. CONCLUSIONS: The study demonstrates feasibility of percutaneous access tract dilation using a Visual dilator system. This technique can provide visual confirmation of accuracy in dilation to improve safety and efficacy of the procedure. PMID- 23461421 TI - Economic evaluation of micafungin versus caspofungin for the treatment of candidaemia and invasive candidiasis. AB - BACKGROUND: Micafungin demonstrated non-inferiority to caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in a major randomised clinical trial. AIM: The aim of this study was to investigate if micafungin is a cost-saving option compared with caspofungin for treating candidaemia and IC. METHODS: A decision analytical model was constructed to capture downstream consequences of using either agent as initial therapy for candidaemia and IC. The main outcomes were treatment success and treatment failure (i.e. death, mycological persistence, emergent infection, clinical failure but microbiological success). Outcome probabilities and treatment pathways were derived from the literature. Cost inputs were from the latest Australian resources, and resource use was estimated by expert panel. The analysis was from the Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. RESULTS: Micafungin (AU$52 816) was associated with a lower total cost than caspofungin (AU$52 976), with a net cost-saving of $160 per patient. This was primarily due to the lower cost associated with alternative antifungal treatment in the micafungin arm. Hospitalisation was the main cost-driver for both arms. The model outcome was most sensitive to the proportion of treatment success in the micafungin arm. Uncertainty analysis demonstrated that micafungin had a 58% chance of being cost-saving compared with caspofungin. CONCLUSIONS: Micafungin was cost-equivalent to caspofungin in treating candidaemia and IC, with variation in drug acquisition cost the critical factor. PMID- 23461422 TI - Discrimination between lung homeostatic and injury-induced epithelial progenitor subsets by cell-density properties. AB - Stem/progenitor cells and their lineage derivatives are often identified by patterns and intensity of cell clusters of differentiation presentation. However, the cell biochemical facade can prove to be elusive, transient, and subject to interlaboratory disparities. To enhance current methods of lung stem cell isolation and identification and to investigate biophysical changes, which occur during homeostasis and in response to acute lung injury, we separated cells on a discontinuous density gradient, of 1.025-1.074 g/cm(3), and characterized the eluted lineages. At homeostasis, surfactant protein-C (SFTPC)-expressing cells of the alveolar type (AT)-2 lineage possessed average densities >=1.039 g/cm(3) and aquaporin-5 producing AT1 cells equilibrated at densities <1.039 g/cm(3). While 0.74%+/-0.32% of lung cells were determined proliferating or postmitotic by BrdU nucleotide uptake, 73% of CD49f-, 72% of c-KIT-, and 61% of SCA-1-positive cells (putative alveolar progenitor lineage markers) showed densities <=1.039 g/cm(3). CD49f/EpCAM(hi) progenitors, as well as c-KIT(pos)/CD45(neg) cells, could be enriched at the 1.039 g/cm(3) interface. Following acute bleomycin-induced injury, the frequency of BrdU-incorporating cells rose to 0.92%+/-0.36% and density could largely explain cell-lineage distribution. Specifically, a decline in the density of mitotic/postmitotic SFTPC-positive cells to <=1.029 g/cm(3), in conjunction with an increase in CD45-positive, and proliferating CD45 and c-KIT cells in the heaviest fraction (>=1.074 g/cm(3)) were observed. These data attest to the generation of AT2 cells from low-density precursors and emphasize a relationship between cell density and molecular expression following injury, expanding on our current understanding of lung and progenitor cell dynamics. PMID- 23461424 TI - Interhemispheric transfer of spatial and semantic information: electrophysiological evidence. AB - The goal of this study was to cast light on the existence of functional callosal channels for the interhemispheric transfer (IHT) of spatial and semantic information. To do so, we recorded event-related potentials in healthy humans while performing a primed odd-even discrimination task. Targets were visually presented numbers preceded by single-letter primes signaling the probable presentation of an odd or an even number. Primes and targets could appear either in the same or in different visual fields, thus requiring an IHT in the latter case. The P1 and N2 components were influenced by IHT of spatial information only, whereas the later N400 was influenced by IHT of both spatial and semantic information. This was not the case for the P3b, which was modulated by semantic validity only. These results provide novel evidence of the existence of a temporally separated interhemispheric exchange of spatial and semantic information. PMID- 23461425 TI - Choices in recreational water quality monitoring: new opportunities and health risk trade-offs. AB - With the recent release of new recreational water quality monitoring criteria, there are more options for regulatory agencies seeking to protect beachgoers from waterborne pathogens. Included are methods that can reduce analytical time, providing timelier estimates of water quality, but the application of these methods has not been examined at most beaches for expectation of health risk and management decisions. In this analysis, we explore health and monitoring outcomes expected at Lake Michigan beaches using protocols for indicator bacteria including culturable Escherichia coli (E. coli; EC), culturable enterococci (ENT), and enterococci as analyzed by qPCR (QENT). Correlations between method results were generally high, except at beaches with historically high concentrations of EC. The "beach action value" was exceeded most often when using EC or ENT as the target indicator; QENT exceeded the limit far less frequently. Measured water quality between years was varied. Although methods with equivalent health expectation have been established, the lack of relationship among method outcomes and annual changes in mean indicator bacteria concentrations complicates the decision-making process. The monitoring approach selected by beach managers may be a combination of available tools that maximizes timely health protection, cost efficiency, and collaboration among beach jurisdictions. PMID- 23461423 TI - Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex. AB - Abstinence from cocaine self-administration (SA) is associated with neuroadaptations in the prefrontal cortex (PFC) and nucleus accumbens (NAc) that are implicated in cocaine-induced neuronal plasticity and relapse to drug seeking. Alterations in cAMP-dependent protein kinase A (PKA) signaling are prominent in medium spiny neurons in the NAc after repeated cocaine exposure but it is unknown whether similar changes occur in the PFC. Because cocaine SA induces disturbances in glutamatergic transmission in the PFC-NAc pathway, we examined whether dysregulation of PKA-mediated molecular targets in PFC-NAc neurons occurs during abstinence and, if so, whether it contributes to cocaine seeking. We measured the phosphorylation of cAMP response element binding protein (Ser133) and GluA1 (Ser845) in the dorsomedial (dm) PFC and the presynaptic marker, synapsin I (Ser9, Ser62/67, Ser603), in the NAc after 7 days of abstinence from cocaine SA with or without cue-induced cocaine-seeking. We also evaluated whether infusion of the PKA inhibitor, 8-bromo-Rp-cyclic adenosine 3', 5'-monophosphorothioate (Rp-cAMPs), into the dmPFC after abstinence would affect cue-induced cocaine-seeking and PKA-regulated phosphoprotein levels. Seven days of forced abstinence increased the phosphorylation of cAMP response element binding protein and GluA1 in the dmPFC and synapsin I (Ser9) in the NAc. Induction of these phosphoproteins was reversed by a cue-induced relapse test of cocaine-seeking. Bilateral intra-dmPFC Rp-cAMPs rescued abstinence-elevated PKA mediated phosphoprotein levels in the dmPFC and NAc and suppressed cue-induced relapse. Thus, by inhibiting abstinence-induced PKA molecular targets, relapse reverses abstinence-induced neuroadaptations in the dmPFC that are responsible, in part, for the expression of cue-induced cocaine-seeking. PMID- 23461426 TI - A Markov model of the cost-effectiveness of pharmacist care for diabetes in prevention of cardiovascular diseases: evidence from Kaiser Permanente Northern California. AB - BACKGROUND: It has been demonstrated in previous studies that pharmacist management of patients with type 2 diabetes mellitus (T2DM) in the outpatient setting not only improves diabetes-related clinical outcomes such as hemoglobin A1c but also blood pressure (BP), total cholesterol (TC), and quality of life. Improved control of BP and TC has been shown to reduce the risks of cardiovascular disease (CVD), which has placed a heavy economic burden on the health care system. However, no study has evaluated the cost-effectiveness of pharmacist intervention programs with respect to the long-term preventive effects on CVD outcomes among T2DM patients. OBJECTIVES: To (a) quantify the long-term preventive effects of pharmacist intervention on CVD outcomes among T2DM patients using evidence from a matched cohort study in the outpatient primary care setting and (b) assess the relative cost-effectiveness of adding a clinical pharmacist to the primary care team for the management of patients with T2DM based on improvement in CVD risks with the aid of an economic model. METHODS: Clinical data between the periods of June 2007 to February 2010 were collected from electronic medical records at 2 separate clinics at Kaiser Permanente (KP) Northern California, 1 with primary care physicians only (control group) and the other with the addition of a pharmacist (enhanced care group). Patients in the enhanced care group were matched 1:1 with patients in the control group according to baseline characteristics that included age, gender, A1c, and Charlson comorbidity score. The estimated 10-year CVD risk for both groups was calculated by the United Kingdom Prospective Diabetes Study (UKPDS) Risk Engine (version 2) based on age, sex, race, smoking status, atrial fibrillation, duration of diabetes, levels of A1c, systolic BP (SBP) and TC, and high-density lipoprotein cholesterol (HDL-C) observed at 12 months. There was no statistical difference in the baseline clinical inputs to the Risk Engine (A1c [P=0.115], SBP [P=0.184], TC [P=0.055], and HDL-C [P=0.475]) between the 2 groups. A Markov model was developed to simulate the estimated CVD outcomes over 10 years and to estimate cost-effectiveness. The final outcomes examined included incremental cost and effectiveness measured by life years and per quality-adjusted life year gained. Both deterministic sensitivity analysis (SA) and probabilistic SA were conducted to examine the robustness of the results. RESULTS: The estimated risks for coronary heart disease (CHD) and stroke (both nonfatal and fatal) at the end of the follow-up were consistently lower in the enhanced care group compared with the control group, even though baseline risks in both groups were similar. The absolute risk reduction (ARR) between the enhanced care and control groups increased over time. For example, the ARR for nonfatal CHD risk in year 1 was 0.5% (1.2% vs. 0.7%), whereas the ARR increased to 5.5% in year 10 (14.8% vs. 9.3%). Similarly, the ARR between the enhanced care and the control groups was calculated as 0.3% for fatal CHD in year 1 and increased to 4.6% in year 10. Results from the Markov model suggest that the enhanced care group was shown to be a dominant strategy (less expensive and more effective) compared with the control group in the 10-year evaluation period in the base-case (average or mean results) scenario. Sensitivity analysis that took into account the uncertainty in all important variables, such as wage of pharmacists, utility weight (the degree of preference individuals have for a particular health state or condition), response rate to pharmacists' care, and uncertainty associated with the estimated 10 years of CVD risk, revealed that the relative value of enhanced care was robust to most of the variations in these parameters. Notably, the level of cost effectiveness measured by net monetary value depends on the time horizon adopted by the payers and the magnitude of CVD risk reduction. The enhanced care group has a higher chance of being considered as a cost-effective strategy when a longer time horizon such as a minimum of 4 to 5 years is adopted. CONCLUSIONS: Adding pharmacists to the health care management team for diabetic patients improves the long-term CVD risks. The longer-term CVD risk reductions were shown to be more dramatic than the short-term reduction. A longer time horizon adopted by health plans in managing T2DM patients has a higher probability of making the intervention cost-effective. PMID- 23461427 TI - Evaluation of a novel web-based prior approval application for palivizumab prophylaxis of respiratory syncytial virus in a state Medicaid program. AB - BACKGROUND: Recent disproportionate increases in use of specialty medications, such as palivizumab (Synagis), compared with steady utilization of traditional medication use, have prompted complex utilization management strategies that require frequent evaluation to facilitate cost-effectiveness while preserving patient access. Clinical criteria utilized by North Carolina (NC) Medicaid for use of palivizumab for respiratory syncytial virus (RSV) prophylaxis are consistent with the most recent guidelines published in the Red Book: Report of the Committee on Infectious Diseases. Prior to the 2011-2012 RSV season, prior approval (PA) requests were submitted by facsimile using the NC Medicaid Synagis PA form. A web-based PA application, which includes automatic approval capability, monthly dose prompts to providers, and a standardized dose projection formula, was developed for the 2011-2012 RSV season. OBJECTIVES: To evaluate the timeliness of palivizumab coverage determination, compliance with palivizumab prophylaxis regimen, and the accuracy of the dose projection formula achieved with this novel web-based PA application for palivizumab prophylaxis in NC Medicaid recipients. METHODS: A historically controlled retrospective cohort study was conducted in which all palivizumab PA submissions and supporting documentation from the 2010-2011 and 2011-2012 RSV seasons were retrospectively reviewed for date and time of original submission and final coverage determination. Submissions from the 2011-2012 season were also retrospectively reviewed for number of doses approved, number of doses administered, date of administration of each dose, and actual dosage administered. These data were used to evaluate compliance and the projected versus actual beneficiary weight and dose to assess the accuracy of the dose projection formula. Submissions lacking required information were excluded. Time from PA submission to coverage determination was compared between seasons using a 2-sample t-test. The proportion of compliant recipients was calculated based on number of doses received and dosing interval of no more than 35 days. Accuracy of the dose projection formula was evaluated using a paired Student's t-test. RESULTS: Time to coverage determination decreased overall, on average, by 3.7 days (mean [SD] 8.5 [15.4] vs. 4.8 [9.3]; P<0.001) for the 2011-2012 season using the electronic web-based PA application compared with the traditional facsimile-based system used in the 2010-2011 season. Decreased time to coverage determination was observed in both PA requests that required medical review and those that did not. Of all palivizumab recipients who were eligible to receive at least 2 doses (n=1,233), 61.1% were fully compliant with all doses, and 86.9% received all but one documentable dose. Of those who received at least 2 documented doses (n=1,091), 62.8% received all doses within 35 days of the previous dose. When both definitions of compliance were applied concurrently, 39.3% of all palivizumab recipients were considered compliant; the mean difference between projected and actual doses was 7.1 mg (95% CI: 6.8-7.5; P=0.001) or 8.6% (95% CI: 8.0-10.0). Projected and actual doses did not vary significantly in the sensitivity analysis when excluding entries with >=50% difference. CONCLUSIONS: The 2011-2012 web-based PA application improved the timeliness of palivizumab coverage determination compared with the 2010-2011 facsimile-based system. Observed compliance rates for NC Medicaid recipients were slightly lower than those reported in the literature when defined by number of doses received but were higher when defined by interval between doses. The dose projection formula used for the web-based application appears to be accurate for infants 0-2 years of age. PMID- 23461428 TI - Adherence to varenicline and associated smoking cessation in a community-based patient setting. AB - BACKGROUND: Varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, is a pharmacotherapy indicated for smoking cessation treatment. To our knowledge, no studies have described varenicline treatment adherence and efficacy from real-world treatment patterns in a U.S. primary care setting. OBJECTIVE: To estimate adherence to varenicline prescription orders and subsequent quit rates among smokers in a primary care setting. METHODS: In this retrospective cohort study, eligible patients were enrolled with Geisinger Health Plan, had an initial varenicline prescription written by a Geisinger provider between January 1, 2006, and December 31, 2009, and had a follow-up clinic visit within the subsequent 12 months. Adherence was derived from linking electronic prescriptions with adjudicated pharmacy claims. Smoking status was collected at each health care encounter. RESULTS: Of the 1,477 eligible patients, 823 (55.7%) were primary nonadherent, having failed to initiate on the prescribed varenicline therapy. Of the remaining 654 patients, 359 (54.9%) were adherent, having completed a full 12-week course of therapy, and 295 (45.1%) were partially adherent, having initiated but not completed the full course of therapy. A total of 521 patients (35.3%) ceased smoking during the 12-month follow-up period: 182 (50.7%) of the adherent cohort, 82 (27.8%) of the partially adherent population, and 257 (31.2%) of the nonadherent cohort. No significant difference was found in quit rates between the partially adherent and nonadherent patient cohorts (adjusted HR 0.88 [95% CI=0.69-1.13]). However, patients adherent to the varenicline regimen were almost twice as likely to succeed in quitting smoking compared with completely nonadherent patients (HR 1.93 [95% CI=1.59-2.33]). CONCLUSION: Smoking cessation occurred more often among individuals adherent to varenicline therapy; however, medication nonadherence was common. After prescribing varenicline, clinicians and payers could consider active patient follow-up to maximize adherence and optimize treatment outcomes. PMID- 23461429 TI - Guideline-recommended medications: variation across Medicare Advantage plans and associated mortality. AB - OBJECTIVES: To evaluate variation in the prescription of guideline-recommended medications across Medicare Advantage (MA) plans and to determine whether such variation is associated with increased mortality. METHODS: Observational study of 111,667 patients aged 65 years or older receiving care in 203 MA plans. We linked data from the Medicare Health Outcomes (HOS) Survey cohort 9 (April 2006-May 2008) with the Medicare Part D prescription benefit files (January 1, 2006 December 31, 2007) to examine variation in treatment across MA plans and its association with differences in observed (O)/expected (E) mortality ratio for 5 high-volume chronic conditions: diabetes, coronary artery disease (CAD), congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD)/asthma, and depression. RESULTS: Analysis of variance confirmed that the 203 MA plans differed significantly in their use of guideline-recommended treatment (P<=0.02). Those MA plans with higher use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (r=-0.40; P<0.0001) and beta blockers (r=-0.27; P<0.0001) in patients with CHF were significantly associated with lower O/E mortality ratios. Those MA plans with higher use of multiple guideline-recommended medications were significantly associated with lower O/E mortality ratios in CHF (r=-0.45; P<0.0001) and diabetes (r=-0.14; P<0.042). There were no significant associations between the variation in performance indicators and mortality ratios in patients with CAD and COPD/asthma. Those MA plans with higher use of antidepressant medications had significantly higher O/E mortality ratios (r=0.28, P<0.0001). CONCLUSIONS: There was wide variation across MA plans in the prescription of guideline-recommended medications that had a measurable relationship to the mortality of elderly patients with CHF and diabetes. These findings can serve to both motivate and target quality improvement programs. PMID- 23461430 TI - Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism that is characterized by a significant elevation in levels of low-density lipoprotein cholesterol (LDL-C), and patients are at very high risk for premature coronary heart disease (CHD). The etiology of FH includes known mutations in the gene of the LDL receptor, LDLR; the gene of apolipoprotein B, apo B; and the proprotein convertase subtilisin/kexin type 9 gene, PCSK9. The National Lipid Association Expert Panel on Familial Hypercholesterolemia has provided recommendations for the screening and treatment of patients with FH. Early identification and aggressive treatment of FH in individual patients, as well as screening of all first-degree relatives, are recommended to minimize the risk for premature CHD. Similar to patients with conventional hypercholesterolemia, patients with FH should receive statins as initial treatment, but patients with FH may require higher doses of statins, more potent statins, statin-based combination therapy, or adjunctive therapies. Patients with FH who have additional risk factors for, or existing, cardiovascular disease or those with an inadequate response to initial statin therapy should have access to higher doses of the most efficacious statins; statins used in combination with other LDL-C-lowering agents should also be supported by formularies; additional treatments, such as LDL-C apheresis or novel therapies, may also be required to achieve acceptable LDL-C levels. New treatment approaches include mipomersen, which was approved by the FDA in January 2013. Mipomersen is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis (called an antisense inhibitor) indicated as an adjunct to lipid lowering medications and diet to reduce LDL-C, apolipoprotein B, total cholesterol, and non-high density lipoprotein-cholesterol (non-HDL-C) levels in patients with homozygous FH (HoFH). The microsomal transfer protein lomitapide has also received FDA approval for use only in patients with HoFH. Other novel treatments currently in development include PCSK9 inhibitors. Therapies such as apheresis are likely more expensive than simple therapy with a statin but may be needed to achieve long-term reductions in complications from nonfatal and fatal cardiovascular events and hospitalizations related to myocardial infarction, cardiac revascularization, and stroke in FH patients. The cost-effectiveness of this more aggressive therapy has not been determined and should be studied. Utilization of published guidelines and the recommendations from the National Lipid Association will help to optimize the management of patients with FH. PMID- 23461431 TI - Toxicity, analgesic and anti-inflammatory activities of tectorigenin. AB - OBJECTIVE: Belamcanda chinensis has been used in oriental medicine for the treatment of inflammatory diseases. Tectorigenin is a main compound in B. chinensis and possess inhibitory activity against inflammatory responses. Thus, the current study aimed at evaluating toxicity as well as analgesic and anti inflammatory effects of tectorigenin in animal models. METHODS: Tectorigenin was employed to evaluate acute and subacute toxicity. Acetic acid-induced writhing in mice was used for analgesic test. The anti-inflammatory activity was tested in carrageenan-induced paw edema. RESULTS: LD(50) of tectorigenin was 1.78 g/kg p.o. in mice and no toxic symptoms were observed at doses up to 300 mg/kg in a subacute toxicity test during 28-day treatment. Tectorigenin at doses of 50 and 100 mg/kg had an analgesic effect on acetic acid-induced acute visceral pain in mice. In inflammatory rat model, tectorigenin at 60 mg/kg significantly reduced carrageenan-induced edema. CONCLUSION: We demonstrated that tectorigenin is a safe and promising analgesic and anti-inflammatory agent. PMID- 23461432 TI - Preliminary studies of alfaxalone for intravenous immobilization of juvenile captive estuarine crocodiles (Crocodylus porosus) and Australian freshwater crocodiles (Crocodylus johnstoni) at optimal and selected sub-optimal thermal zones. AB - OBJECTIVES: To investigate the character of immobilization given by alfaxalone in juvenile crocodiles at optimal and at suboptimal temperatures. STUDY DESIGN: Prospective, randomized partial crossover study. ANIMALS: Twenty captive male estuarine (weight 0.6-2.5 kg) and five captive male freshwater crocodiles (weight 0.2-0.6 kg). METHODS: Crocodiles were acclimatized for 24 hours at one of the following environmental temperatures; 32 degrees C, 27 degrees C, 22 degrees C or 17 degrees C, then received 3 mg kg(-1) intravenous (IV) alfaxalone into the dorsal occipital venous sinus. Duration and quality of immobilization was assessed and heart rate (HR) measured. On a separate occasion each crocodile was immobilized at one other environmental temperature. RESULTS: Alfaxalone, 3 mg kg( 1) IV, produced immobilization for 55 (range 15-100 minutes in estuarine, and 20 (range 20-25) minutes in freshwater crocodiles at 32 degrees C. There was no significant difference overall in immobilization times between temperatures, other than that, in estuarine crocodiles, duration was shorter at 32 degrees C than 22 degrees C. The character of immobilization was unpredictable, with animals recovering without warning, or having extended recoveries requiring assisted ventilation. Assisted ventilation was necessary mainly at the lower temperatures. Median HR in all temperature treatments decreased within 5 minutes post-injection, but the change in HR over the duration of immobilization was affected by the temperature, with a progressively smaller range of fall as temperature decreased. At 17 degrees C, two estuarine crocodiles appeared to re immobilize after initial recovery, became severely bradycardiac and required ventilation and re-warming. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone IV in small captive estuarine and freshwater crocodiles provides adequate induction of immobilization at various temperatures. However, the unpredictable results following induction mean it is unsuitable for field use and should be restricted to environments where intubation and ventilation are available, where animals can be warmed to optimal temperature, and where access to immersion in water can be restricted for 24 hours. PMID- 23461433 TI - Exploring the expectations, needs and experiences of general practitioners and nurses towards a proactive and structured care programme for frail older patients: a mixed-methods study. AB - AIM: To report the expectations and experiences of general practitioners and practice nurses regarding the U-CARE programme, to gain a better understanding of the barriers and facilitators in providing proactive, structured care to frail older people and to determine whether implementation is feasible. BACKGROUND: Care for older patients with complex care needs in primary care is fragmented, reactive and time consuming. A structured, proactive care programme was developed to improve physical functioning and quality of life in frail older patients. DESIGN: An explanatory mixed-methods study nested in a cluster-randomized trial. METHODS: The barriers to and needs for the provision of structured, proactive care, and expectations regarding the U-CARE programme were assessed with pre questionnaires sent to all participating general practitioners (n = 32) and practice nurses (n = 21) in October 2010. Postquestionnaires measured experiences with the programme after 5 months. Twelve months later, focus group meetings were conducted. RESULTS: Practice nurses and general practitioners reported that it was difficult to provide proactive and structured care to older patients with multi-morbidity, different cultural backgrounds and low socioeconomic status. Barriers were a lack of time and financial compensation. Most general practitioners and practice nurses indicated that the programme added value for the coordination of care and allowed them to provide structured care. CONCLUSION: This explanatory mixed-methods study showed that general practitioners and practice nurses perceived the U-CARE programme as feasible in general practice. A transition was made from reactive, ad hoc care towards a proactive and preventive care approach. PMID- 23461434 TI - Building biologics by chemical synthesis: practical preparation of di- and triantennary N-linked glycoconjugates. AB - A unified strategy for the syntheses of bi- and triantennary fully sialylated N glycans is described. The synthesis capitalizes on a global glycosylation strategy that delivers the desired undeca- and tetradecasaccharide in excellent yields. Finally, conjugation of the glycan to PSMA oligopeptide is described. PMID- 23461435 TI - Traceability of Italian Protected Designation of Origin (PDO) table olives by means of microsatellite molecular markers. AB - The aim of this work was to develop a DNA microsatellite-based method of analysis to allow traceability of the three Italian Protected Designation of Origin (PDO) table olives in comparison with fruits of another seven highly diffused table olive cultivars. The analyses were carried out by using 16 primer pairs, with a mean of five different alleles detected per primer set, and power of discrimination from 0.56 to 0.90. Allelic error rates in the range of 0-3.8% were observed. By combining data from the most reliable and highly informative microsatellites (DCA3, DCA16, DCA17, DCA18, UDO-043, and GAPU101), it was possible to identify the PDO fruits over the panel of 10 cultivars, with the probability of a chance match between different cultivars as low as 10(-9) and with 0.5% error rate. The amplification profile is independent of environmental and processing conditions and is helpful to verify the authenticity of PDO samples. PMID- 23461436 TI - Detection of nitric oxide and nitroxyl with benzoresorufin-based fluorescent sensors. AB - A new family of benzoresorufin-based copper complexes for fluorescence detection of NO and HNO is reported. The copper complexes, CuBRNO1-3, elicit 1.5-4.8-fold emission enhancement in response to NO and HNO. The three sensors differ in the nature of the metal-binding site. The photophysical properties of these sensors are investigated with assistance from density functional theory calculations. The fluorescence turn-on observed upon reaction with HNO is an unexpected result that is discussed in detail. The utility of the new sensors for detecting HNO and NO in HeLa cells and RAW 264.7 macrophages is demonstrated. PMID- 23461437 TI - [Risk sharing agreements: with orphan drugs?]. AB - OBJECTIVE: To summarize available information on share risk agreements (RSA) with orphan drugs (OD). METHODS: A bibliographic search was carried out in MEDLINE, EMBASE and INAHTA using 19 keywords and combinations thereof. Papers published as original, narrative and systematic reviews, editorials, commentaries, letters to the Editor, and special articles were included and reviewed. Public or private institutional reports or documents found in Google that contained relevant information were also reviewed. RESULTS: experience gained so far with RSA is scant. No published rigorous evaluations of outcomes of these agreements were found. It seems, however, that OD are suitable for introduction in clinical practice by means of RSA. There are two main types of RSA: financially based, and performance-outcome based. A number of theoretical advantages of SRA are described, as well as hurdles that hinder their design, implementation, and followup, and thus endangering their success. Very few RSA have clearly succeed so far. CONCLUSIONS: If thoroughly managed, RSA may reasonably contribute to value-based pricing of OD, improve their pharmacovigilance, knowledge about their comparative effectiveness, and to reducing uncertainty and its consequences on patients, industry, payers and clinicians. There are technical groups that can bring the essential knowledge to manage RSA in Spain. The challenge now is to be able to harmonize their assessments and appraisals, to put in motion the mechanisms needed to overcome those hurdles, and to provide them adequate political and institutional support. PMID- 23461438 TI - [China and India in the biotechnological pharmaceutical market]. PMID- 23461439 TI - [A new therapeutic scene in the treatment of the chronic hepatitis for virus C]. AB - The need of new alternatives for the treatment of the chronic hepa - titis C, the appearance of the new antiviral ones that act directly on the cycle of replicacion of the virus C, so called antiviral agents, they have never supposed a spectacular advance in the increase of the rates of treatment, so much for the patients before treated or naive. This new stage of the treatment is going to be, undoubtedly, more complex and, for this reason, a still major specialization will need if it is necessary to obtain an ideal managing of the patients. In addition, that these new medicaments will carry a significant increase of the expense associated with this pathology, key circumstance in the frame of economic context and of difficulty in the sustainability that Spanish public suffers the sanitary system, the individualization and the establishment of the factors that can predict the maximum benefit of every type of therapy turns out to be priority. The predictive factors of response that can affect the capture of decisions clinical practice are the stadium of fibrosis, the favorable genotype of the IL28B and the attainment of viral rapid response. The undoubted impact, so much welfare as pharmacoeconomic that the arrival of boceprevir and telaprevir will have in the hospitable centers forces us to the optimization and consensus in the use of these medicaments and to the exigency of obtaining the maximum of answers of the same ones. The latter aspect is very tied to the accomplishment of a followup pharmaceutical individualized and of quality, based on a model of Pharmaceutical Care centred on basic props as the involution of the adherence, given the additional complexity that add the new medicaments, the identification, prevention and managing of the adverse effects inherent in the triple therapy. Besides it, they were turning out to be key the establishment of new strategies of management farmacoeconomic of this type of based therapies in clinical results and with a multidisciplinary participation of all the professionals of the health involved in the managing of this therapy. PMID- 23461440 TI - [Systematic review of new protease inhibitors interactions: telaprevir and boceprevir]. AB - INTRODUCTION: The new protease inhibitors (PIs), telaprevir and boceprevir, with peginterferon and ribavirin, have increased the response rate in patients with genotype 1 chronic hepatitis C. Both are metabolized by CYP3A and they are CYP3A inhibitors. Furthermore, they are substrates, also telaprevir is an inhibitor, for P-glycoprotein. Our aim is to analyze the interactions between these IPs and other medications. METHOD: We performed a systematic review in PubMed and Cochrane database and in conference abstracts of the last 2-5 years. Another search was performed in Medline to check efficacy clinical trials in phase II and III, in Micromedex database and in label information. RESULTS: In PubMed we found two Phase I clinical trials; we did not find any article in the Cochrane database. 14 conference abstracts were selected, mainly there are phase I studies. In the free search in PubMed was located an in vitro / in vivo preclinical study which analyzed the co-administration of IPs and ritonavir. In phase II and III clinical trials, there was no mention about interactions. CONCLUSIONS: Currently, there are pharmacokinetic Phase I studies about the interaction between PIs and representative drugs (potent inducers, potent inhibitors, high protein binding drugs, etc.), but the evidence of these interactions is contradictory. Its incorporation into the therapeutic have to take into account the possibility of complex interactions and not entirely known, about their mechanism of action, which might compromise its effectiveness or increase its toxicity. PMID- 23461441 TI - [Pharmaceutical care in renal insufficiency inpatients]. AB - BACKGROUND AND OBJECTIVE: To asses the outcomes of posological adjust program in renal impairment inpatients, describe the drugs more usually involved, and determine the degree of acceptance of the pharmaceutical intervention made. MATERIAL AND METHOD: A fifteen months-prospective study, in renal insufficiency inpatients (serum creatinine > 1,4 mg/dL) treated with drugs that needs posological adjustment. The primary outcome was the ratio of adequate dosage of the treatment, according with the glomerular filtration rate. We also evaluated the global acceptation rate, the drugs inadequate prescribed more frequently, phamacokinetic analysis derived from the pharmaceutical intervention and its educative character. RESULTS: 384 patients were identified, and 341 of them presented a glomerular filtration rate between 10-50 ml/min. 2.807 prescribed drugs were reviewed, and 2.052 of them didn%#39;t require posological adjustment in renal insufficiency, 508 prescribed drugs were correctly adjusted. 247 pres - criptions were susceptible of posological adjustment and 164 of them, needed a concrete posological adjustment. We performed 200 posological recommendations, and 131 were accepted. The drugs with a higher number of interventions were enoxaparine, levofloxacin, amoxicillin-clavulanic and digoxin. CONCLUSIONS: The implementation of the pharmaceutical care program was accepted between physicians, being antibiotics the group more susceptible of doing a posological adjustment in most patients with renal impairment. PMID- 23461442 TI - Coenzyme Q10 stability in pediatric liquid oral dosage formulations. AB - OBJECTIVE, To study the stability of Coenzyme Q10 (CoQ10), used as therapeutic agent in treatment of cardiovascular and mitochondrial diseases, in three liquid formulations: two soybean oil solutions (50 mg/ml), one of them with the addition of vitamin E and an O/W emulsion (20 mg/ml) for pediatric use. Furthermore, optimize and validate a stabilityindicating HPLC method for the analysis of CoQ10 in the studied formulations. METHOD, All samples were stored at 25 degrees C. CoQ10 content of each formulation was analyzed in duplicate using fast microbore high performance liquid chromatography (Micro HPLC) at 0, 3, 6, 15, 30, 60 and 110 days. RESULTS, All formulations stayed stable at 25 degrees C during the 110 days of the study. However, the oil solutions presented greater content variations through all the study period. CONCLUSIONS, The CoQ10 emulsion can be stored for at least 110 days at 25 degrees C and it has proven to be safer when narrow dose adjustment is required. The proposed analytical method was suitable for the study of stability of different formulations meeting the validation parameters according to international guidelines. PMID- 23461443 TI - Common health problems management uncertainties in heart failure: a qualitative study. AB - BACKGROUND: Medicine review with follow up quantitative studies conducted on heart failure (HF) outpatients detected health problems that were frequently treated insufficiently: hyperuricemia, gastric injury prevention, anemia, and diabetes mellitus. OBJECTIVE: The aim of this qualitative study was to explore experiences in the pharmacological management of these health problems, and to contribute with strategies to overcome the identified obstacles. METHODS: The internal medicine specialists and cardiologists of a tertiary hospital HF clinic underwent in-depth semi-structured interviews and a constant comparative approach was used. RESULTS: Interviewees highlighted there is a lack of guidelines concerning the treatment of asymptomatic hyperuricemia in HF, thus in routine practice it is often not treated. Interviewees said that preventive strategies to avoid gastric injury in at-risk patients taking prophylactic low-dose aspirin are needed, but the most appropriate strategy is not well defined. Interviewees thought that structural support is needed for the management of HF patients with anemia, and proper clinic pathways should be created to identify which service patients should be referred to. The same lack of communication with other services appeared with diabetes mellitus. CONCLUSION: HF specialists demand a closer interaction with other specialists for a comprehensive approach to these polymedicated patients with multiple co-morbidities. And suggest that specific recommendations in HF guidelines to manage these co-morbidities specifically in HF would be helpful to shed light upon the existing confusing evidence. PMID- 23461444 TI - [Health care models for patients with multiple chronic conditions and the role of the hospital pharmacy/the hospital pharmacist]. AB - INTRODUCTION: Managing care for patients with chronic conditions currently represents one of the greatest challenges to health care systems. As a subgroup of these patients, those with multiple chronic conditions are at greater risk for death or disability, and they consume more resources. They are characterized by the coexistence of two or more chronic illnesses lasting a year or longer which require ongoing medical attention and/or interfere with their daily activities. For these polypathological patients pharmaceutical care would be of special benefit, thus, their needs should be a priority objective for hospital pharmacy. OBJECTIVE: To increase awareness of this type of patients and the characteristics of the principal approaches and health care models proposed to improve chronic disease management, as well as to emphasize the urgency for hospital pharmacists to join these models, and to present various activities that pharmacists might carry out as an integral part of these approaches. RESULTS: Numerous models exist internationally, including the Chronic Care Model and the Kaiser Permanente pyramid of risks. In our country a growing number of initiatives has culminated in the recent Seville Declaration. For the hospital pharmacy, caring for the chronically ill patient following a model that is multi-professional, cooperative, integral, and patient centered, is an enormous task. Pharmacy departments and the Spanish Society of Hospital Pharmacy should reorient their strategies for pharmaceutical care, training, and research. Of special interest are those activities designed to improve adherence, adequacy, and continuity in treatments, all the while emphasizing active patient participation. PMID- 23461446 TI - [Improvement of the outpatient clinics after the implementation of an automated robot for delivery]. AB - OBJECTIVES: To discover the improvements in logistics, management and satisfaction of the patients after the implantation of a robot of dispensation (RAD) in the external consultations of Pharmacy. MATERIAL AND METHODS: Pre-post design: implantation of RAD. The study was conducted on a third level hospital. A new circuit of drugs was designed due to a change of location of the external consultations. Modifications on the pharmacy pro grams were implemented for the integration with RAD. The immobilized stock was measured, difference among the real-virtual existences for anti-retroviral drugs; measured as a per centage of the total and the index of rotation of the stock. Satisfaction surveys of 2007 2011 were compared after the realization of the different changes in the consultations. RESULTS: The circuit of drugs as well as the computer changes made were efficient for the maintenance of the stock of drugs. The immobilized stock decreased 2.209.935,77? during the pe riod of the study. The index of rotation decreased from 1.87 to 0.79. The robot has reduced the waiting to less than 10 minutes in 90% with regard to the previous surveys. DISCUSSION: The incorporation of RAD in the consultations has meant improvements in the logistic, in the management and in. PMID- 23461445 TI - [Effectiveness of a consensus protocol for the prevention of chemotherapy-induced nausea and vomiting]. AB - OBJECTIVE: To assess the effectiveness of a consensus protocol for the prevention of CINV at our institution and level of adherence to it. METHOD: Prospective observational study. Patients treated with chemotherapy (CT) in whom a 120-hour follow-up was made after the cycle were included. We assessed the response to the therapy, categorized as: complete response (CR) (absence of nausea and vomiting, without the need of additional treatment within the 120 hours following the cycle), acute response (AR) (within the first 24 hours) and delayed response (DR) (within 24 and 120 hours), depending on whether or not these were adjusted to the hospital protocol. A descriptive statistical analysis was performed analyzing the different risk factors and level of adherence to the hospital protocol. RESULTS: A total of 167 patients were included in whom CR was observed in 71.9% of the cases (88.9% AR and 73.7% DR), with absence of vomiting in 89.8%. Seven point two percent of the cases did not adhere to the protocol. There were no differences in treatment response between the patients adhering and adhering to the protocol (CR, AR o DR) but yes in vomiting occurrence (8.3% vs. 36.4%, p = 0.014). CONCLUSION: The effectiveness of our protocol is good specially for controlling the vomiting although nausea during the delayed phase still is a not resolved matter. Vomiting control is poorer in those patients not adjusting to the protocol. PMID- 23461447 TI - [Dilution volume of intravenous drugs in patients under fluid restriction therapy]. AB - INTRODUCTION: A fluid and electrolyte balance is essential for human health. There are some situations in which fluid imbalance occurs, causing fluid overload and consequent associated problems. Patients with these problems, may benefit from the administration of parenteral drugs in the smallest possible volume. Patients in critical condition typically require a large number of drugs intravenously, and high doses of these diluted in large quantities of serum. Therefore, it seems useful to seek an optimization strategy of parenteral drug admi - nistration. OBJECTIVE: To review and collect data on minimum dilution volumes. Besides administration s routes, reconstitution, compatible diluents, infusion times. METHODS: The study included those drug substances frequently used in critically ill patients. A search through multiple sources of information has been made: technical data for Propietary medicinal products, Handbook on Injectable Drugs, Trissel L., American Society Healh-System Pharmacists, 15thEd., 2009, Thomson Micromedex(r) Healthcare Series, or by phone calls to the manufacturers of the product. RESULTS: RESULTS are shown in a table. 65 drugs were revised. CONCLUSIONS: It is considered useful the collection of these data to optimize parenteral administration in critically ill patients, or in those who require restrictive fluid therapy, because information has been collected from different sources, not always found it in the technical data of the drugs. PMID- 23461448 TI - [Desensitization to lenalidomide]. PMID- 23461449 TI - [Tacrolimus enema for the treatment of Inflammatory Bowel Disease]. PMID- 23461450 TI - [Dronedarone-associated hepatotoxicity. A propos of a case]. PMID- 23461451 TI - [Possible serotonin syndrome associated with administration of venlafaxine and tramadol]. PMID- 23461452 TI - [Possible ischaemic colitis associated with clozapine]. PMID- 23461453 TI - [Possible interaction between exemestane and clopidogrel]. PMID- 23461454 TI - [Fatal gemcitabine administration related-pulmonary toxicity]. PMID- 23461455 TI - [Severe capecitabine-associated toxicity in a patient carrying a mutation in the dihydropyrimidine dehydrogenase gen]. PMID- 23461456 TI - [Clinical evidence from indirect and mixed-treatment comparisons: some practical considerations]. PMID- 23461457 TI - [Indirect comparisons, author response]. PMID- 23461458 TI - [Crisis of conficence in antidepressants]. PMID- 23461459 TI - [Atorvastatin and Simvastatin: are they pharmacogenetically equivalent?]. PMID- 23461460 TI - [Use of lopinavir/ritonavir monotherapy]. PMID- 23461461 TI - [Inappropriate medication use in the elderly. Beers or STOPP-START criteria?]. PMID- 23461463 TI - Vibrationally hot bands of the SiCN A 2Delta - X 2Pi system. AB - We have generated SiCN in supersonic free jet expansions and observed the laser induced fluorescence (LIF) spectrum. In addition to the vibronic bands from the vibrationless level of the X (2)Pi state, the hot bands from the bending vibrational level, A (01(1)0) (2)Phi - X (01(1)0) (2)Delta and A (01(1)0) (2)Pi - X (01(1)0) (2)Sigma((-)), have been measured. The rotational energy levels were reasonably analyzed as those of the (2)K' - (2)K" transitions, but their line intensities calculated from the Honl-London factors derived in the intermediate case between Hund's case (a) and (b) could not reproduce the observed spectra. The Honl-London factors derived in the (2)Lambda' - (2)Lambda" ((2)Delta - (2)Pi) transition reasonably reproduced the spectra. It indicates that coupling between the electronic orbital and vibrational angular momenta is weak in the SiCN (2)Delta - (2)Pi system, and a basis set of |Lambda v2 l Sigma;J P MJ>, the so called "l-basis", better describes the system than that of |Lambda v2 K Sigma;J P MJ>. PMID- 23461462 TI - Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. AB - Despite preclinical studies demonstrating the functional benefit of transplanting human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) into damaged myocardium, the ability of these immature cells to adopt a more adult-like cardiomyocyte (CM) phenotype remains uncertain. To address this issue, we tested the hypothesis that prolonged in vitro culture of human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived CMs would result in the maturation of their structural and contractile properties to a more adult like phenotype. Compared to their early-stage counterparts (PSC-CMs after 20-40 days of in vitro differentiation and culture), late-stage hESC-CMs and hiPSC-CMs (80-120 days) showed dramatic differences in morphology, including increased cell size and anisotropy, greater myofibril density and alignment, sarcomeres visible by bright-field microscopy, and a 10-fold increase in the fraction of multinucleated CMs. Ultrastructural analysis confirmed improvements in the myofibrillar density, alignment, and morphology. We measured the contractile performance of late-stage hESC-CMs and hiPSC-CMs and noted a doubling in shortening magnitude with slowed contraction kinetics compared to the early-stage cells. We then examined changes in the calcium-handling properties of these matured CMs and found an increase in calcium release and reuptake rates with no change in the maximum amplitude. Finally, we performed electrophysiological assessments in hESC-CMs and found that late-stage myocytes have hyperpolarized maximum diastolic potentials, increased action potential amplitudes, and faster upstroke velocities. To correlate these functional changes with gene expression, we performed qPCR and found a robust induction of the key cardiac structural markers, including beta-myosin heavy chain and connexin-43, in late-stage hESC CMs and hiPSC-CMs. These findings suggest that PSC-CMs are capable of slowly maturing to more closely resemble the phenotype of adult CMs and may eventually possess the potential to regenerate the lost myocardium with robust de novo force producing tissue. PMID- 23461464 TI - Critical analysis of a new generation electrohydraulic lithotripter: a single institution experience with the Medispec e3000. AB - BACKGROUND AND PURPOSE: The Medispec E3000(TM) is a new generation electrohydraulic lithotripter with a wider focal width comparable to the Dornier HM3(TM). We evaluate the efficacy of this machine for management of urinary stones at our institution by shockwave lithotripsy (SWL). MATERIALS AND METHODS: There were 168 urinary calculi managed using the Medispec E3000 lithotripter over a 14-month period (10/2010-12/2011). During the first 6 months (10/2010-6/2011), a low power ramping protocol of 11-12-17 kV was used, and for the remaining 6 months (6/2011-12/2011), stones were managed with a higher power ramping protocol of 15-17-22.5 kV. A subanalysis of these groups was performed, as well as for stone location. The major end point was stone-free rate (SFR), defined as fragments <4 mm on follow-up imaging. Data were analyzed using the Fisher exact test and two-tailed Student t test. RESULTS: The study included 102 males and 66 females with an average age of 52.8 years. Mean stone size was 6.9 * 7.2 mm, which was significantly associated with SFR (P<0.0010). The overall SFR was 64.9%, with no significant difference between stones managed with the low power protocol (61.3%) and the high power protocol (70%). SFR varied by location across the upper pole (64.9%), midpolar area (57.1%), lower pole (68.4%), renal pelvis (79.2%), proximal ureter (66.6%), midureter (83.3%), and distal ureter (53.8%), but these differences were not significant (P=0.59). Efficiency quotient for the Medispec E3000TM was 54%. CONCLUSIONS: Overall, we achieved SFR of 64.9% in our initial experience with the Medispec E3000TM. Optimizing treatment parameters may further improve success rates, and further outcomes follow-up may allow a more comprehensive evaluation of the lithotripter's overall efficacy. PMID- 23461465 TI - Pushing the boundaries of intrinsically stable radicals: inverse design using the thiadiazinyl radical as a template. AB - In this study, for the first time inverse design was applied to search for the intrinsically most stable radical system in a predefined chemical space of enormous size by scanning in a rational way that entire chemical space. The focus was predominantly on thermodynamic stabilization effects, such as stabilization through resonance. Two different properties were optimized: a newly introduced descriptor called the radical delocalization value and the intrinsic stability via a previously established bond dissociation enthalpy model. The thiadiazinyl radical was chosen as case study of this new approach of inverse design in stable radical chemistry. The resulting optimal structure is found to be highly stable, intrinsically more so than other well-known stable radicals, such as verdazyls and N,N-diphenyl-N'-picrylhydrazyl, and even rivaling the intrinsic stability of nitrogen monoxide. PMID- 23461466 TI - Pinellia ternata Breitenbach attenuates ovalbumin-induced allergic airway inflammation and mucus secretion in a murine model of asthma. AB - OBJECTIVE: Pinellia ternata is an important plant in traditional Chinese medicine. This study describes the anti-inflammatory effects of a water extract of P. ternata (PTE) in allergic airway inflammation in a model of asthma in mice. MATERIALS AND METHODS: BALB/c mice were sensitized with ovalbumin (OVA) and, upon an OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevations in cytokine, chemokine, and immunoglobulin levels and overexpression of inducible nitric oxide (iNOS). RESULTS: Intragastric administration of PTE significantly attenuated OVA-induced influx of total leukocytes, eosinophils, neutrophils, macrophages and lymphocytes into lungs, and attenuated levels of interleukin (IL)-4, IL-13 and tumor necrosis factor-alpha (TNF-alpha), in a dose dependent manner. PTE also significantly reduced the plasma levels of total and OVA-specific immunoglobulin (Ig)E release into the airspace. Histological studies showed that PTE inhibited OVA-induced lung tissue eosinophilia and airway mucus production. Moreover, in whole lung tissue lysates, immunohistology showed that PTE markedly attenuated the OVA-induced increase in mucin 5AC and iNOS expression. CONCLUSIONS: These results indicate that PTE has protective effects against allergic airway inflammation. PMID- 23461467 TI - Frequency of indicator bacteria, Salmonella and diarrhoeagenic Escherichia coli pathotypes on ready-to-eat cooked vegetable salads from Mexican restaurants. AB - The presence of coliform bacteria, faecal coliforms, Escherichia coli, diarrhoeagenic E. coli pathotypes (DEP) and Salmonella were determined in ready to-eat cooked vegetable salads (RECS) from restaurants in Pachuca city, Mexico. The RECS were purchased from three types of restaurants: national chain restaurants (A), local restaurants (B) and small restaurants (C). Two restaurants for each A and B, and three for C, were included. Forty RECS samples were purchased at each A and B restaurant and 20 at each C restaurant. Of the overall total of 220 analysed samples, 100, 98.2, 72.3, 4.1 and 4.1% had coliform bacteria, faecal coliforms, E. coli, DEP and Salmonella, respectively. Identified DEP included enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC) and Shiga toxin-producing E. coli (STEC). The EPEC, ETEC and STEC were isolated each from 1.4% of samples. No E. coli O157:H7 were detected in any STEC-positive samples. The analysis of Kruskal-Wallis anova and median test of microbiological data showed that the microbiological quality of RECS did not differ between the different restaurants (P > 0.05). SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report regarding microbiological quality and Salmonella, enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC) and Shiga toxin producing E. coli (STEC) isolation from ready-to-eat cooked vegetable salads from Mexican restaurants. Ready-to-eat cooked vegetable salads could be an important factor contributing to the endemicity of EPEC, ETEC and STEC, and Salmonella caused gastroenteritis in Mexico. PMID- 23461468 TI - Crossroads in breast cancer: the intersection of clinical uncertainty and molecular profiling. PMID- 23461469 TI - Managed care restrictions: barriers to product use in cancer care. PMID- 23461470 TI - Partial fill strategies for oral oncolytics to reduce waste and drive persistency. PMID- 23461471 TI - From bench to bedside: promising colon cancer clinical trials. PMID- 23461472 TI - Focusing on clinical and economic outcomes--not guidelines. PMID- 23461473 TI - The role of companion diagnostic testing in payer decision making. PMID- 23461474 TI - Lessons from an oncology medical home collaborative. AB - The Oncology Medical Home program demonstrates an effective working model for restructuring cancer payments and care. It complements and in fact takes oncology pathways programs to a new level through creation of practice-specific preferred regimens. It eliminates practices' financial dependence on drug margins and reduces the current misalignment between cancer payments and cancer outcomes by taking a patient-centric approach. Further, it enhances practice payments for cognitive services provided by the oncology team and rewards teams for improving patient care and reducing avoidable ED visits and inpatient care. Provider-payer partnerships are necessary to evaluate experimental payment models that create greater provider accountability for Triple Aim outcomes of patient experience, individual and population health outcomes, and per capita cost. PMID- 23461475 TI - The future of oncology? Come home, the oncology medical home. PMID- 23461476 TI - Regulation and acclimation of leaf gas exchange in a pinon-juniper woodland exposed to three different precipitation regimes. AB - Leaf gas-exchange regulation plays a central role in the ability of trees to survive drought, but forecasting the future response of gas exchange to prolonged drought is hampered by our lack of knowledge regarding potential acclimation. To investigate whether leaf gas-exchange rates and sensitivity to drought acclimate to precipitation regimes, we measured the seasonal variations of leaf gas exchange in a mature pinon-juniper Pinus edulis-Juniperus monosperma woodland after 3 years of precipitation manipulation. We compared trees receiving ambient precipitation with those in an irrigated treatment (+30% of ambient precipitation) and a partial rainfall exclusion (-45%). Treatments significantly affected leaf water potential, stomatal conductance and photosynthesis for both isohydric pinon and anisohydric juniper. Leaf gas exchange acclimated to the precipitation regimes in both species. Maximum gas-exchange rates under well watered conditions, leaf-specific hydraulic conductance and leaf water potential at zero photosynthetic assimilation all decreased with decreasing precipitation. Despite their distinct drought resistance and stomatal regulation strategies, both species experienced hydraulic limitation on leaf gas exchange when precipitation decreased, leading to an intraspecific trade-off between maximum photosynthetic assimilation and resistance of photosynthesis to drought. This response will be most detrimental to the carbon balance of pinon under predicted increases in aridity in the southwestern USA. PMID- 23461477 TI - Associations between sleep problems and attentional and behavioral functioning in children with anxiety disorders and ADHD. AB - This study examined associations between sleep problems and attentional and behavioral functioning in 137 children aged 7 to 13 years with anxiety disorders (n = 39), attention deficit hyperactivity disorder (ADHD; n = 38), combined anxiety disorder and ADHD (n = 25), and 35 controls. Diagnoses were made using the semistructured diagnostic interview Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime Version. Sleep problems were assessed using the Children's Sleep Habits Questionnaire, attention was measured by the Attention Network Test, and behavioral problems were measured by teacher ratings on the Achenbach System of Empirically Based Assessment, Teacher Report Form. Sleep problems were associated with reduced efficiency of the alerting attention system for all children and with increased internalizing problems in children with anxiety disorders. PMID- 23461478 TI - Influence of film thickness and oxygen partial pressure on cation-defect-induced intrinsic ferromagnetic behavior in luminescent p-type Na-doped ZnO thin films. AB - In this article, we have investigated the effect of oxygen partial pressure (PO2) and film thickness on defect-induced room-temperature (RT) ferromagnetism (FM) of highly c-axis orientated p-type Na-doped ZnO thin films fabricated by pulse laser deposition (PLD) technique. We have found that the substitution of Na at Zn site (NaZn) can be effective to stabilize intrinsic ferromagnetic (FM) ordering in ZnO thin films with Curie temperature (TC) as high as 509 K. The saturation magnetization (MS) is found to decrease gradually with the increase in thickness of the films, whereas an increase in "MS" is observed with the increase in PO2 of the PLD chamber. The enhancement of ferromagnetic signature with increasing PO2 excludes the possibility of oxygen vacancy (VO) defects for the magnetic origin in Na-doped ZnO films. On the other hand, remarkable enhancement in the green emission (IG) are observed in the photoluminescence (PL) spectroscopic measurements due to Na-doping and that indicates the stabilization of considerable amount of Zn vacancy (VZn)-type defects in Na-doped ZnO films. Correlating the results of PL and X-ray photoelectron spectroscopy (XPS) studies with magnetic measurements we have found that VZn and Na substitutional (NaZn) defects are responsible for the hole-mediated FM in Na-doped ZnO films, which might be an effective candidate for modern spintronic technology. PMID- 23461479 TI - The interleukin-6 -147 g/c polymorphism is associated with increased risk of coronary artery disease in young South African Indian men. AB - BACKGROUND: Interleukin-6 (IL-6) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases such as coronary artery disease (CAD). The -174 IL-6 G/C promoter polymorphism influences mRNA levels and protein expression and is implicated in CAD. The Indian population in South Africa, unlike the black community, has a high prevalence of premature CAD. This polymorphism has not been fully explored in this population. The present study assessed the -174 IL-6 G/C polymorphism in young Indian patients with angiographically documented CAD and compared them with age- and gender-matched Indian and black control subjects. METHODS: Polymorphic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism, and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The -174 IL-6 C allele was found with a higher frequency (23%) in the total Indian group compared to 2% in the black participants [P<0.0001, odds ratio (OR)=0.05, 95% confidence interval (CI) 0.018-0.14). The difference in frequency was more pronounced when Indian controls were compared to black controls (29% vs. 2%, respectively) (P<0.0001, OR=0.05, 95% CI 0.02-0.17). A significant association between the -174 IL-6 G allele and CAD was found in Indian patients compared to Indian controls (84% in cases vs. 71% in Indian controls; P=0.043, OR=0.47 95% CI 0.23-0.95). Levels of IL-6 in circulation were higher in black controls (6.62+/-0.63 pg/mL) compared to Indian controls (2.51+/-0.57 pg/mL) and CAD patients (1.46+/-0.36 pg/mL) (P<0.0001). Levels of IL-6 were higher in all groups with homozygous -174 IL-6 C alleles, but only significant in the healthy Indian control group (GG 3.73+/-0.94 pg/mL vs. GC/CC 0.89+/-0.5 pg/mL, P=0.0001). CONCLUSION: The presence of the IL-6 -174 G allele influences levels of IL-6 and increases the risk of CAD in South African Indians. PMID- 23461480 TI - Effect of the time interval between fusion and activation on epigenetic reprogramming and development of bovine somatic cell nuclear transfer embryos. AB - Previous studies have shown that the time interval between fusion and activation (FA interval) play an important role in nuclear remodeling and in vitro development of somatic cell nuclear transfer (SCNT) embryos. However, the effects of FA interval on the epigenetic reprogramming and in vivo developmental competence of SCNT embryos remain unknown. In the present study, the effects of different FA intervals (0 h, 2 h, and 4 h) on the epigenetic reprogramming and developmental competence of bovine SCNT embryos were assessed. The results demonstrated that H3 lysine 9 (H3K9ac) levels decreased rapidly after fusion in all three groups. H3K9ac was practically undetectable 2 h after fusion in the 2-h and 4-h FA interval groups. However, H3K9ac was still evidently detectable in the 0-h FA interval group. The H3K9ac levels increased 10 h after fusion in all three groups, but were higher in the 2-h and 4-h FA interval groups than that in the 0 h FA interval group. The methylation levels of the satellite I region in day-7 blastocysts derived from the 2-h or 4-h FA interval groups was similar to that of in vitro fertilization blastocysts and is significantly lower than that of the 0 h FA interval group. SCNT embryos derived from 2-h FA interval group showed higher developmental competence than those from the 0-h and 4-h FA interval groups in terms of cleavage rate, blastocyst formation rate, apoptosis index, and pregnancy and calving rates. Hence, the FA interval is an important factor influencing the epigenetic reprogramming and developmental competence of bovine SCNT embryos. PMID- 23461481 TI - Energetics of adsorbed CH3 on Pt(111) by calorimetry. AB - The enthalpy and sticking probability for the dissociative adsorption of methyl iodide were measured on Pt(111) at 320 K and at low coverages (up to 0.04 ML, where 1 ML is equal to one adsorbate molecule for every surface Pt atom) using single crystal adsorption calorimetry (SCAC). At this temperature and in this coverage range, methyl iodide produces adsorbed methyl (CH(3,ad)) plus an iodine adatom (I(ad)). Combining the heat of this reaction with reported energetics for Iad gives the standard heat of formation of adsorbed methyl, DeltaH(f)(0)(CH3,ad), to be -53 kJ/mol and a Pt(111)-CH3 bond energy of 197 kJ/mol. (The error bar of +/-20 kJ/mol for both values is limited by the reported heat of formation of I(ad).) This is the first direct measurement of these values for any alkyl fragment on any surface. PMID- 23461482 TI - The effect of educational audiotape programme on anxiety and depression in patients undergoing coronary artery bypass graft. AB - AIMS AND OBJECTIVES: To investigate use of educational audiotape programme on anxiety and depression in patients undergoing coronary artery bypass graft (CABG). BACKGROUND: Anxiety and depression after CABG are the most common complications, having a negative impact on the prognosis of heart disease, leading to special needs according to their new physical and mental conditions. DESIGN: Randomised clinical trial. METHODS: This study conducted in Iran, 70 patients undergoing CABG were included and divided into two equal groups, the control group and intervention group. They were followed up for six weeks. An audiotape educational programme was given to the intervention group after surgery in addition to the routine training. But patients in the control group received only routine training. Anxiety and depression were assessed by Hospital Anxiety and Depression Scale, a standardised questionnaire for anxiety and depression. Data were collected before and six weeks after the intervention. For the comparison of mean scores between the groups, the data were analysed in spss, version 16, using independent T-test and paired T-test. RESULTS: The mean scores obtained in both anxiety and depression dimensions were significantly different between the intervention and control groups. CONCLUSIONS: Audiotape educational programme used by patients undergoing CABG decreases the level of their anxiety and depression after cardiac surgery. RELEVANCE TO CLINICAL PRACTICE: The most significant finding was the importance of audiotape educational programme to meet the needs of the CABG patients, which suggest that patient education through audiotape can be effective in self-care after heart surgery and nurses can use an audiotape containing preparatory information to improve outcomes and reduce anxiety and depression in patients having CABG. PMID- 23461483 TI - Male reproductive strategy explains spatiotemporal segregation in brown bears. AB - Spatiotemporal segregation is often explained by the risk for offspring predation or by differences in physiology, predation risk vulnerability or competitive abilities related to size dimorphism. Most large carnivores are size dimorphic and offspring predation is often intraspecific and related to nonparental infanticide (NPI). NPI can be a foraging strategy, a strategy to reduce competition, or a male reproductive strategy. Spatiotemporal segregation is widespread among large carnivores, but its nature remains poorly understood. We evaluated three hypotheses to explain spatiotemporal segregation in the brown bear, a size-dimorphic large carnivore in which NPI is common; the 'NPI - foraging/competition hypothesis', i.e. NPI as a foraging strategy or a strategy to reduce competition, the 'NPI - sexual selection hypothesis', i.e. infanticide as a male reproductive strategy and the 'body size hypothesis', i.e. body-size related differences in physiology, predation risk vulnerability or competitive ability causes spatiotemporal segregation. To test these hypotheses, we quantified spatiotemporal segregation among adult males, lone adult females and females with cubs-of-the-year, based on GPS-relocation data (2006-2010) and resource selection functions in a Scandinavian population. We found that spatiotemporal segregation was strongest between females with cubs-of-the-year and adult males during the mating season. During the mating season, females with cubs-of-the-year selected their resources, in contrast to adult males, in less rugged landscapes in relative close proximity to certain human-related variables, and in more open habitat types. After the mating season, females with cubs-of-the year markedly shifted their resource selection towards a pattern more similar to that of their conspecifics. No strong spatiotemporal segregation was apparent between females with cubs-of-the-year and conspecifics during the mating and the postmating season. The 'NPI - sexual selection hypothesis' best explained spatiotemporal segregation in our study system. We suggest that females with cubs of-the-year alter their resource selection to avoid infanticidal males. In species exhibiting NPI as a male reproductive strategy, female avoidance of infanticidal males is probably more common than observed or reported, and may come with a fitness cost if females trade safety for optimal resources. PMID- 23461485 TI - Endobronchial ultrasound transbronchial needle aspiration in older people. AB - AIM: The usefulness and safety of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) have been established recently, but no study has evaluated whether or not aging increases the risk of the procedure. In the present study, we aimed to assess the usefulness and safety of EBUS-TBNA in older patients. METHODS: The medical records and database of 109 patients who received EBUS-TBNA between 2008 and 2011 at Nagoya University Hospital, Nagoya, Japan were reviewed retrospectively. All patients underwent bronchoscopy under light sedation with midazolam. A total of 34 patients were aged 70 years or older (the older group) and 75 were aged 69 years or younger (the younger group). We analyzed patients' characteristics, changes of clinical parameters, usage doses of midazolam and lidocaine, procedure duration, geographic data of biopsied lymph nodes, diagnostic yield, and complications in both groups. RESULTS: There were more comorbidities in the older group. Four patients (11.8%) in the older group had poor performance status (2-3). Systolic blood pressure at baseline was significantly higher in the older group. There were no statistical differences between the two groups in some clinical parameters (minimum oxygen saturation [SpO2 ], reduction in SpO2 , maximum oxygen supplementation, elevation of systolic blood pressure, increase of heart rate) during the procedure. Diagnostic performance in older patients was similar to that found in younger patients. There was no difference in the frequency of complications between both groups. CONCLUSION: Safety and usefulness of EBUS-TBNA in older people were comparable with those in younger people. PMID- 23461484 TI - Gray matter volume correlates of global positive alcohol expectancy in non dependent adult drinkers. AB - Alcohol use and misuse is known to involve structural brain changes. Numerous imaging studies have examined changes in gray matter (GM) volumes in dependent drinkers, but there is little information on whether non-dependent drinking is associated with structural changes and whether these changes are related to psychological factors-such as alcohol expectancy-that influence drinking behavior. We used voxel-based morphometry (VBM) to examine whether the global positive scale of alcohol expectancy, as measured by the Alcohol Expectancy Questionnaire-3, is associated with specific structural markers and whether such markers are associated with drinking behavior in 113 adult non-dependent drinkers (66 women). Alcohol expectancy is positively correlated with GM volume of left precentral gyrus (PCG) in men and women combined and bilateral superior frontal gyri (SFG) in women, and negatively correlated with GM volume of the right ventral putamen in men. Furthermore, mediation analyses showed that the GM volume of PCG mediate the correlation of alcohol expectancy and the average number of drinks consumed per occasion and monthly total number of drinks in the past year. When recent drinking was directly accounted for in multiple regressions, GM volume of bilateral dorsolateral prefrontal cortices correlated positively with alcohol expectancy in the combined sample. To our knowledge, these results are the first to identify the structural brain correlates of alcohol expectancy and its mediation of drinking behaviors. These findings suggest that more studies are needed to investigate increased GM volume in the frontal cortices as a neural correlate of alcohol expectancy. PMID- 23461486 TI - A solid-state pH sensor for nonaqueous media including ionic liquids. AB - We describe a solid state electrode structure based on a biologically derived proton-active redox center, riboflavin (RFN). The redox reaction of RFN is a pH dependent process that requires no water. The electrode was fabricated using our previously described 'stuffing' method to entrap RFN into vapor phase polymerized poly(3,4-ethylenedioxythiophene). The electrode is shown to be capable of measuring the proton activity in the form of an effective pH over a range of different water contents including nonaqueous systems and ionic liquids (ILs). This demonstrates that the entrapment of the redox center facilitates direct electron communication with the polymer. This work provides a miniaturizable system to determine pH (effective) in nonaqueous systems as well as in ionic liquids. The ability to measure pH (effective) is an important step toward the ability to customize ILs with suitable pH (effective) for catalytic reactions and biotechnology applications such as protein preservation. PMID- 23461487 TI - Development of quinoline-based disruptors of biofilm formation against Vibrio cholerae. AB - Biofilm formation is a major cause of bacterial persistence in nosocomial infections, leading to extended treatment times and increased rates of morbidity and mortality. Despite this, there are currently no biofilm inhibitors approved for clinical use. The synthesis and biological evaluation of a library of amino alcohol quinolines as lead compounds for the disruption of biofilm formation in Vibrio cholerae is now reported. Application of selective metal-halogen exchange chemistry installed both stereocenters in one step, to afford a simpler scaffold than the initial lead molecule, with an EC50 < 10 MUM. PMID- 23461488 TI - Deletion of flbA results in increased secretome complexity and reduced secretion heterogeneity in colonies of Aspergillus niger. AB - Aspergillus niger is a cell factory for the production of enzymes. This fungus secretes proteins in the central part and at the periphery of the colony. The sporulating zone of the colony overlapped with the nonsecreting subperipheral zone, indicating that sporulation inhibits protein secretion. Indeed, strain DeltaflbA that is affected early in the sporulation program secreted proteins throughout the colony. In contrast, the DeltabrlA strain that initiates but not completes sporulation did not show altered spatial secretion. The secretome of 5 concentric zones of xylose-grown DeltaflbA colonies was assessed by quantitative proteomics. In total 138 proteins with a signal sequence for secretion were identified in the medium of DeltaflbA colonies. Of these, 18 proteins had never been reported to be part of the secretome of A. niger, while 101 proteins had previously not been identified in the culture medium of xylose-grown wild type colonies. Taken together, inactivation of flbA results in spatial changes in secretion and in a more complex secretome. The latter may be explained by the fact that strain DeltaflbA has a thinner cell wall compared to the wild type, enabling efficient release of proteins. These results are of interest to improve A. niger as a cell factory. PMID- 23461489 TI - The development of a framework for evaluating the impact of nurse consultant roles in the UK. AB - AIM: To develop a framework to evaluate the impact of nurse consultants on patient, professional and organizational outcomes and identify associated indicators of impact. BACKGROUND: Since nurse consultants were introduced into the UK in 2000, there has been growing interest in demonstrating their impact, although robust evidence of impact is lacking. Existing frameworks for evaluating the impact of advanced practice roles do not cover the four dimensions of the nurse consultant role sufficiently. DESIGN: Multiple case study. METHOD: Individual case studies of six nurse consultants in England were undertaken between December 2009-October 2010. Each case study involved interviews with the nurse consultant, healthcare staff, managers, patients and carers. Interviews explored participants' perceptions of the impact of the nurse consultant and indicators of actual and/or potential impact. Data were analysed using framework approach. FINDINGS: Three domains of impact of nurse consultant roles were identified: clinical significance, professional significance and organizational significance. Each domain included three to four indicators of impact. All nurse consultants showed some evidence of impact in all three domains although the primary focus varied across the different nurse consultants. Due to the wide diversity in nurse consultant roles there was little commonality in the specific indicators of impact across all nurse consultants. CONCLUSION: The framework for capturing the impact of nurse consultants could be used by researchers and by nurse consultants to demonstrate their impact. Further research is required to assess the suitability of the framework for capturing the impact of other advanced practice roles. PMID- 23461490 TI - Cd(II)-coordination framework: synthesis, anion-induced structural transformation, anion-responsive luminescence, and anion separation. AB - A series of Cd(II) coordination frameworks that are constructed from a new oxadiazole-bridged ligand 3,5-bis(3-pyridyl-3-(3'-methylphenyl)-1,3,4-oxadiazole (L) and CdX2 (X = NO3(-), Cl(-), Br(-), I(-), N3(-), and SCN(-)) were synthesized. The NO3(-) anion of the solid CdL2(NO3)2.2THF (1) is able to be quantitatively exchanged with Cl(-), Br(-), I(-), SCN(-), and N3(-) in the solid state. For Cl(-) and Br(-), the anion exchange resulted in a anion-induced structural transformation to form the structures of 2 and 3, respectively. In addition, the Cd(II) structure herein exhibits the anion-responsive photoluminescence, which could be a useful method to monitor the anion-exchange process. Notably, compound 1 can recognize and completely separate SCN(-)/N3(-) with similar geometry. PMID- 23461493 TI - [Towards a new model of health care delivery in pharmaceutical care to the HIV+ patient]. PMID- 23461491 TI - Impact of cabbage pectin-protein complex on microbial beta-glucuronidase activity. AB - We previously demonstrated that pectin-protein complex (PPC) isolated from white cabbage adsorbs the beta-glucuronidase (betaG) enzyme of E. coli. Concurrently, we discovered a significant increase in betaG activity in the presence of PPC. The aim of this study is to identify the structural components of PPC that are responsible for betaG adsorption and activation. PPC was isolated from white cabbage using a saline solution containing hydrochloric acid (pH 1.5) at 37 degrees C for 4 h. PPC proteins were precipitated by aqueous 10% (m/v) trichloroacetic acid to yield the pectin-protein fractions PPC1 and PPC2. PPC was digested using 1,4-alpha-d-galacturonase, yielding the PPC6 fraction. Partial acid hydrolysis of PPC revealed the galacturonan fraction, PPC3, to be the core of the macromolecule. The purified PPC4 and PPC5 fractions were isolated from PPC by ion-exchange chromatography on DEAE-cellulose. betaG activity and its adsorption in the PPC fractions were studied in vitro. Crystalline cellulose was used as a control. This study found that the PPC3 fraction (the galacturonan core) does not adsorb betaG and does not affect its activity. The adsorption of betaG in the PPC samples is inversely proportional to the degree of methyl esterification of its carbohydrate component. The PPC4 and PPC5 fractions adsorb the highest proportion of betaG (51.2% and 54%, respectively). The stimulation of betaG enzyme activity is directly proportional to the protein content of the PPC sample. The PPC and PPC1 samples have the greatest ability to increase betaG activity (57.6% and 52.1%, respectively). PMID- 23461494 TI - Stability evaluation of 7 % chloral hydrate syrup contained in mono and multi dose bottles under room and refrigeration conditions. AB - PURPOSE: To evaluate the stability of an extemporaneously prepared 7% chloral hydrate syrup under different conditions of storage and dispensing. METHODS: Three batches of 7% chloral hydrate syrup were prepared. Each batch was stored in 50 light-resistant glass containers of 60 mL with child-resistant caps and in two bottles of 1000 mL to simulate two forms of dispensing, mono and multi-dose, respectively. Twenty five mono-dose bottles and a multi-dose bottle of each batch were stored under room conditions (20 +/- 1 degrees C) and the rest of the samples were stored in the fridge (5 +/- 2 degrees C). The physical, chemical and microbiological stability was evaluated for 180 days. Stability was defined as retention of at least 95% of the initial concentration of chloral hydrate, the absence of both visible particulate matter, or color and/or odor changes and the compliance with microbiological attributes of non-sterile pharmaceutical products. RESULTS: At least 98% of the initial chloral hydrate concentration remained throughout the 180-day study period. There were no detectable changes in color, odor, specific gravity and pH and no visible microbial growth. These results were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multi-dose containers. CONCLUSIONS: Extemporaneously compounded 7% chloral hydrate syrup was stable for at least 180 days when stored in mono or multi-dose light-resistant glass containers at room temperature and under refrigeration. PMID- 23461495 TI - [Assessment of a Tiapride solution for its administration through continuous intravenous perfusion]. AB - OBJECTIVES: Tiapride is a substituted benzamide classified as an atypical neuroleptic. To our knowledge, there are no published data on its stability prepared as a continuous intravenous infusion. The current study analysed its stability in two different infusion solutions and concentrations over 48 hours. METHOD: Triplicate samples of tiapride were prepared in 0.9% sodium chloride and in 5% dextrose solutions at final concentrations of 1 and 2 mg/ml. Samples were collected in glass bottles without photoprotection and at room temperature (25 +/ 2 degrees C). Sampling times at 0, 1, 3, 6, 12, 24 and 48 hours included a visual inspection for colour changes and appearance of precipitation as well as pH determination. Tiapride was quantified at selected times by mass spectrometry using high-performance liquid chromatography. Concentration values in the samples corresponding to 0 hours were given a reference value of 100%. Concentrations in subsequent samples greater than 90% were considered stable. RESULTS: No colour change or precipitation was observed during the study period. pH values ranged between 0.1 and 0.4 units. At 48 hours, the concentration of remaining tiapride in sodium chloride 1 mg/ml and 2 mg/ml was 93.8% and 91.6%, respectively. That in 5% dextrose 1 mg/ml and 2 mg/ml was 96.8% and 94.1%, respectively. CONCLUSION: Dilutions of tiapride in 0.9% sodium chloride and in 5% dextrose solution, at concentrations of 1 mg/ml and 2 mg/ml, in glass bottles and at room temperature were stable both physically and chemically during 48 hours. PMID- 23461496 TI - [Indicators monitoring the process of specialized nutritional support. Grupo de Nutricion de la SEFH]. AB - OBJECTIVE: To identify and develop monitoring indicators of the process of specialized nutritional support that will allow measuring the level of adherence to the established practice standards. METHODS: Those practice standards considered to be key elements of the process were selected to develop performance indicators. The construction of these indicators combined the scientific evidence with expert opinion. Key goals were identified within each standard provided that its consecution would allow increasing the achievement of the standard. Particular improvement initiatives associated to each key goal were generated. Lastly, monitoring indicators were defined allowing undertaking a follow-up of the implementation of the improvement initiatives or either to assess the level of achievement of the key goals identified. RESULTS: Nineteen practice standards were selected representative of the critical points of the process. The strategic map for each standard has been defined, with the identification of 43 key goals. In order to achieve these key goals, a portfolio of improvements has been generated comprising 56 actions. Finally, 44 monitoring indicators have been defined grouped into three categories: 1. Numeric: they assess the level of goal achievement; 2. Dichotomic (yes/no): they inform on the execution of the improvement actions; 3. Results of the practice audits. CONCLUSIONS: We have made available monitoring indicators that allow assessing the level of adherence to the practice standards of the process of specialized nutritional support and the impact of the implementation of improvement actions within this process. PMID- 23461497 TI - [Incidence of drug-induced thrombocytopenia in hospitalized patients]. AB - OBJECTIVE: To find out the incidence of drug-induced thrombocytopenia and which medications are implicated, and to establish pharmaceutical activity for its prevention and resolution. METHODS: A prospective study was conducted between June and December 2009 in hospitalized patients over 18 years of age with thrombocytopenia. The medications considered to be associated with thrombocytopenia were included in a database drawn up from the bibliography. In a suspected case, the doctor was recommended to discontinue, decrease the dosage or keep the drug under observation; and a follow-up of the patient's platelet count was made in order to classify the relationship between the drug and thrombocytopenia. RESULTS: 273 patients were included (61.5% men) with a mean age of 60 +/- 15 years. Mean stay was 18 +/- 17 days. TCP incidence was 2.26%. The services most involved were Haematology (56), Intensive Care Medicine (48) and Oncology (40). TCP was moderate in 69% of cases, mild in 26 % and severe in 5%. There were 8 cases of drug-induced thrombocytopenia (0.063% incidence), which were resolved in an average of 7.6 days. The medications related were enoxaparin (2), linezolid (2), tacrolimus (2), thymoglobulin (1) and heparin (1). The doctor was recommended to discontinue the drug (2), decrease the dosage (3) or keep it under observation (3), with 100% acceptance. CONCLUSIONS: Pharmaceutical validation must incorporate an assessment of the platelet count, as it may contribute both to early identification of thrombocytopenia, and to following up platelet counts in patients receiving therapy with thrombocytopenia related drugs. PMID- 23461498 TI - [Follow-up of analytical parameters in Internal Medicine patients to detect adverse events]. AB - OBJECTIVE: To analyze the prevalence of prescription drugs, previously selected, that should be monitored by their analytical test, and the rate of alteration in these tests, with the aim of establishing priorities to facilitate monitoring. METHOD: Prospective observational study in the Internal Medicine department of a referral hospital of 350 beds. In a first phase, we selected some drugs which analytical monitoring is recommended for the medical literature, and after that, we reviewed the pharmacological treatment of all patients admitted with any of these drugs. The study was conducted in the last two month of 2011. RESULTS: We included 271 patients, 128 (47%) were women. The mean age was 74.5 +/- 14.4 years and the average stay of 7 +/- 5.8 days. These patients accounted for 83% of all patients admitted to Internal Medicine during the study period. There were 828 drugs that must be monitored; each patient had an average of 3.1 +/- 2.3. We reviewed 1837 analytical test, of which 401 (22%) were altered and 154 patients (57%) were affected for it. The pairs drug-analytical test altered most frequently found were creatinine increased and nephrotoxic drugs, hypokalemia in patients taking high efficiency diuretics and thrombocytopenia in patients treated with low molecular weight heparins. CONCLUSIONS: Our study highlights the importance of monitoring laboratory test associated with some drugs from the pharmacy department, as it demonstrates a high incidence of warning results. Our proposal for selection of drugs makes monitoring easier, and reaches large numbers of patients. PMID- 23461499 TI - [Utilization of health care resources and cost associated to fasciectomy in Dupuytren's disease in Spain]. AB - OBJECTIVE: To estimate the healthcare resource utilization and their associated costs secondary to fasciectomy of Dupuytren s disease (DD) treated under usual medical practice in Spain. METHODS: This multicenter, observational, retrospective cohort study, extracted data through the revision of medical records of three tertiary public hospitals. Each center should recruit 40 patients operated for DD, as principal diagnose of Minimum Data Set, in which the surgical procedure conducted was fasciectomy, during 2007-2009. To collect all the resources used during surgery, a specific chart form was designed. Demographic (age, gender, occupational status), clinical (stage of contracture and comorbilities) and healthcare utilization (hospitalizations, medical visits, tests, drugs) data were collected under medical routine. Comparisons between stage of contracture grouped (I: stage N, 1 & 2; II: stage 3 & 4) and centers were made. RESULTS: A total of 123 subjects (52% group I; 86.2% men; 35.8% active workers) were identified. 81.3% of patients presented at least one comorbidity, being hypertension the most frequent. 28.4% of patients were operated in ambulatory surgery and 71.6% hospitalized. All the patients had follow-up visits after surgery, 27% needed physical therapy, 88% performed preoperative tests and 8% visit the emergency room after surgery. Healthcare mean (SD) costs were as follows: fasciectomy ?1,074 (0); hospitalizations ?978 (743); ambulatory ?186 (10); follow-up visits ?260 (173); emergency rooms ?13 (53); tests ?78(43); drugs ?7 (9); physical therapy ?46 (134). Mean total costs were ?2,250 (839). There were no significant differences between study groups grouped by stage of contracture. However, the center and the severity of the CD seem explanatory variables of cost, p<0.05. CONCLUSIONS: Healthcare resources utilization for surgical treatment of Dupuytren's disease may cost ?2,250 (839) per fasciectomy treated under usual medical practice. PMID- 23461500 TI - [Knowledge of the cost of the treatments delivered from the Hospital Pharmacy Department and perception of the health status]. AB - OBJECTIVE: To assess the influence of the knowledge of the financial cost of the treatment and perception of the patient of his/her health status and the health care received from the Hospital Pharmacy Department (HPD). METHOD: During a four month period, from July to October of 2009, a questionnaire was provided to all the patients coming to the Hospital Pharmacy Department to gather their medications, except for those starting their therapies. The patients returning the completed questionnaire at a next visit were provided with the second part, in which they were informed on the monthly cost of their treatments and some questions from the main questionnaire were asked again. RESULTS: 682 questionnaires were provided, of which 240 (35.3%) were returned completed. 223 patients were given the second part, of which 151 (22.1%) were returned. In general, the patients were satisfied with their treatments (90.4%) and with the care provided at the HPD (95.4%), 69.2% had good knowledge of their treatment, and 59.2% considered themselves as good compliers, and 17.5% did not usually consult with the pharmacist at the HPD. The patient's satisfaction analysis before (7.75; SD: 1.90) and after knowing the treatment cost (7.80; SD: 1.91) did not show statistically significant differences, with the exception of those patients derived from the Infectious Disease Department (p = 0.015) that were less satisfied after knowing the cost. CONCLUSIONS: The knowledge on the treatment cost could not be related in general with changes in the attitude of the patients towards their treatments, being necessary the design of more profound studies. Besides, it should be recommended to undertake the improvement actions detected by the patients in order to increase the quality of the pharmacy care delivered. PMID- 23461501 TI - [Economic impact of the resolution of drug related problems in an Emergency Department]. AB - OBJECTIVE: Determine the economic impact of avoided cost in hospital stays by preventing drug-related problems. METHOD: Prospective observational study of six months in the emergency department. We included patients admitted for observation and pre-admission beds. A pharmacist was integrated into the healthcare team to validate / reconcile pharmacotherapy. Severity was associated DRPs detected / resolved with the risk increasing the stay of patients admitted to a clinical unit, estimating the potential cost avoided. RESULTS: El 32,5% of patients required intervention and were intercepted 444 drug-related problems, resolving 85.5%. Serious problems serious / significant unresolved affected 130 patients who were admitted, with an estimated avoided cost about 60,000 ?. It was noted that serious problems and oral cytostatics, insulin and diabetes were the groups associated with a higher average cost avoided (p <0.05). CONCLUSION: The integration of the pharmacist in the emergency team to intercept medication problems, reducing the risk of stay and increase healthcare costs. PMID- 23461502 TI - [Direct reporting by patients of adverse drug reactions in Spain]. AB - The Spanish Pharmacovigilance System for Medicinal Products for Human Use, integrated by regional centers of pharmacovigilance coordinated by the Spanish Agency for Medicines and Health Products, is responsible for developing the Program of Spontaneous Reporting of Suspected Adverse Drug Reactions in our country. Although, until now, reports were only requesting to health professionals, the current understanding of the role of patients in the clinical setting and the experience gained in other countries of our environment, have demonstrated the convenience of developing active participation systems to patients in the reporting of suspected adverse drug reactions. In addition, this is taking into account in the new European legislation on pharmacovigilance. PMID- 23461503 TI - [Fatal drug-drug interaction between 5-fluorouracil and brivudine]. PMID- 23461504 TI - [Letters to the editor]. PMID- 23461505 TI - [Letter to the editor]. PMID- 23461506 TI - [Comments to an editorial on vinflunine]. PMID- 23461508 TI - [Valproic acid serum through concentrations estimated from 12 hours post-dose concentrations in patients treated with Depakine(r) Crono]. PMID- 23461507 TI - [Experience on the participation of a Hospital Pharmacy Department in a pharmaceutical company-derived clinical trial by elaborating and distributing the investigational medical product]. PMID- 23461509 TI - [Toxic epidermal necrolysis. A report of a case]. PMID- 23461510 TI - [Comment to the article: " Program of pharmacy care in patients with chronic diseases "]. PMID- 23461511 TI - Azo complexes of osmium(II): preparation and reactivity of organic azide and hydrazine derivatives. AB - Mixed-ligand hydride complexes OsHCl(CO)(PPh3)2L (2) [L = P(OMe)3, P(OEt)3] were prepared by allowing OsHCl(CO)(PPh3)3 (1) to react with an excess of phosphite P(OR)3 in refluxing toluene. Dichloro compounds OsCl2(CO)(PPh3)2L (3, 4) were also prepared by reacting 1, 2 with HCl. Treatment of hydrides OsHCl(CO)(PPh3)2L (2), first with triflic acid and then with an excess of RN3 afforded organic azide complexes [OsCl(eta(1)-N3R)(CO)(PPh3)2L]BPh4 (5-7) [R = 4-CH3C6H4CH2, C6H5CH2, C6H5; L = P(OEt)3]. Benzylazide complexes react in CH2Cl2/ethanol solution, leading to the imine derivative [OsCl(CO){eta(1)-NH?C(H)C6H4-4 CH3}(PPh3)2{P(OEt)3}]BPh4 (8b). Hydrazine complexes [OsCl(CO)(RNHNH2)(PPh3)2L]BPh4 (9-11) [R = H, CH3, C6H5; L = P(OMe)3, P(OEt)3] were prepared by allowing hydride species OsHCl(CO)(PPh3)2L (2) to react first with triflic acid and then with an excess of hydrazine. Aryldiazene derivatives [OsCl(CO)(ArN?NH)(PPh3)2L]BPh4 (12, 13) were also prepared following two different methods: (i) by oxidizing arylhydrazine [OsCl(C6H5NHNH2)(CO)(PPh3)2L]BPh4 (11) with Pb(OAc)4 in CH2Cl2 at -30 degrees C; (ii) by allowing hydride species OsHCl(CO)(PPh3)2L (2) to react with aryldiazonium cations ArN2(+) (Ar = C6H5, 4-CH3C6H4) in CH2Cl2. The complexes were characterized spectroscopically and by X-ray crystal structure determination of OsHCl(CO)(PPh3)2[P(OEt)3] (2b) and [OsCl{eta(1)-NH?C(H)C6H4-4 CH3}(CO)(PPh3)2{P(OEt)3}]BPh4 (8b). PMID- 23461513 TI - Metabolic engineering for enhanced hydrogen production: a review. AB - Hydrogen gas exhibits potential as a sustainable fuel for the future. Therefore, many attempts have been made with the aim of producing high yields of hydrogen gas through renewable biological routes. Engineering of strains to enhance the production of hydrogen gas has been an active area of research for the past 2 decades. This includes overexpression of hydrogen-producing genes (native and heterologous), knockout of competitive pathways, creation of a new productive pathway, and creation of dual systems. Interestingly, genetic mutations in 2 different strains of the same species may not yield similar results. Similarly, 2 different studies on hydrogen productivities may differ largely for the same mutation and on the same species. Consequently, here we analyzed the effect of various genetic modifications on several species, considering a wide range of published data on hydrogen biosynthesis. This article includes a comprehensive metabolic engineering analysis of hydrogen-producing organisms, namely Escherichia coli, Clostridium, and Enterobacter species, and in addition, a short discussion on thermophilic and halophilic organisms. Also, apart from single culture utilization, dual systems of various organisms and associated developments have been discussed, which are considered potential future targets for economical hydrogen production. Additionally, an indirect contribution towards hydrogen production has been reviewed for associated species. PMID- 23461512 TI - Distribution of the different species of the Pseudallescheria boydii/Scedosporium apiospermum complex in French patients with cystic fibrosis. AB - As various new sibling species within the Pseudallescheria boydii/Scedosporium apiospermum complex have been described recently with differences in their susceptibility to antifungals, this study was conducted in order to determine their respective frequency in cystic fibrosis. Results indicated that P. boydii largely predominated (62%), followed by S. apiospermum (24%), Scedosporium aurantiacum (10%) and Pseudallescheria minutispora (4%). Scedosporium dehoogii was not recovered in this study. The multiple correspondence factor analysis highlighted geographical discrepancies within species distribution: P. boydii was rarely encountered in Northern France, while S. apiospermum was less represented in the west of the country. Additionally, we demonstrated that all species encountered in the cystic fibrosis context were capable to chronically colonize the respiratory tract of patients. Molecular typing of a large set of environmental and clinical isolates should be conducted to delineate the epidemiology of each sibling species in the complex. PMID- 23461514 TI - Brassica napus polygalacturonase inhibitor proteins inhibit Sclerotinia sclerotiorum polygalacturonase enzymatic and necrotizing activities and delay symptoms in transgenic plants. AB - Sclerotinia sclerotiorum releases a battery of polygalacturonases (PGs) during infection, which the host plant may cope with through production of polygalacturonase inhibitor proteins (PGIPs). To study the interaction between S. sclerotiorum PGs and Brassica napus PGIPs, 5 S. sclerotiorum PGs and 4 B. napus PGIPs were expressed in Pichia pastoris. SsPG3, SsPG6, and BnPGIP1 were successfully produced in the yeast system, and BnPGIP1 inhibited SsPG6 enzymatic activity in vitro. SsPG3 and SsPG6 both induced light-dependent necrosis when infiltrated into leaves, which was reduced in an Arabidopsis thaliana line expressing BnPGIP2 and to a lesser extent in a line expressing BnPGIP1. The line expressing BnPGIP2 also exhibited a delay in the onset of symptoms upon S. sclerotiorum inoculation, but no long-term effect on S. sclerotiorum disease progression was observed. The P. pastoris system was found to be suitable for expressing high levels of some S. sclerotiorum PGs, but PGIP interaction studies were best performed in planta. Arabidopsis thaliana forms necrotic lesions upon infiltration of PGs, is susceptible to S. sclerotiorum, and is easily transformed, and thus, is well-suited for the qualitative study of PG-PGIP interactions. PMID- 23461515 TI - Isolation and characterization of the grain mold fungi Cochliobolus and Alternaria spp. from sorghum using semiselective media and DNA sequence analyses. AB - Mold diseases, caused by fungal complexes including Alternaria, Cochliobolus, and Fusarium species, limit sorghum grain production. Media were tested by plating Fusarium thapsinum, Alternaria sp., and Curvularia lunata, individually and competitively. Dichloran chloramphenicol rose bengal (DRBC) and modified V8 juice (ModV8) agars, found to be useful, were compared with commonly used agar media, dichloran chloramphenicol peptone (DCPA) and pentachloronitrobenzene (PCNB). Radial growth, starting with mycelia or single-conidia and hyphal tips, demonstrated an effect of media. For isolation of grain fungi, DRBC and ModV8 were similar or superior to DCPA and PCNB. When seedlings were inoculated with conidia of C. lunata, Alternaria sp., F. thapsinum, or mixtures, the percentage of root infection ranged from 28% to 77%. For mixed inoculations, shoot weights, lesion lengths, and percentage of root infections were similar to F. thapsinum inoculations; most colonies recovered from roots were F. thapsinum. For Alternaria grain isolates, 5 morphological types, including Alternaria alternata, were distinguished by colony morphologies and conidial dimensions. Sequence analysis using a portion of the endo-polygalacturonase gene was able to further distinguish isolates. Cochliobolus isolates were identified morphologically as C. lunata, Curvularia sorghina, and Bipolaris sorghicola. Multiple molecular genotypes were apparent from rRNA internal transcribed spacer region sequences from Cochliobolus grain isolates. PMID- 23461516 TI - Time-dose-mortality data and modeling for the entomopathogenic fungus Aschersonia placenta against the whitefly Bemisia tabaci. AB - The fungus Aschersonia placenta FJSM was evaluated for control of the sweet potato whitefly, Bemisia tabaci. Bemisia tabaci nymphs (1st-4th instars) on tomato plants in the greenhouse (25-27 degrees C, 70%-85% relative humidity) were sprayed with suspensions containing 0, 10(4), 10(5), 10(6), 10(7), or 10(8) A. placenta FJSM conidia/mL. Mortality of fungus-treated 1st to 3rd instar nymphs ranged from 93% to 100% but was <25% for 4th instar nymphs; the fungus sporulated from 70% to 80% of the fungus-treated B. tabaci cadavers. LD50 and LD90 values decreased with time after treatment and increased with instar. LT50 values decreased with conidial concentration. The data were then described with time dose-mortality models. The results indicate that A. placenta FJSM has potential as a mycoinsecticide for control of B. tabaci. PMID- 23461517 TI - Legionella and non-Legionella bacteria in a biological treatment plant. AB - Legionella pneumophila were previously identified in the aeration ponds (up to 10(10) CFU/L) of a biological wastewater treatment plant at Borregaard Ind. Ltd., Sarpsborg, Norway, and in air samples (up to 3300 CFU/m(3)) collected above the aeration ponds. After 3 outbreaks of Legionnaires' disease reported in this area in 2005 and 2008, the aeration ponds of the plant were shut down by the Norwegian authorities in September 2008. The aim of the present work was to analyze the Legionella and non-Legionella bacterial communities in the aeration ponds before and during the shutdown process and to identify potential human pathogens. The non-Legionella bacterial community was investigated in selected samples during the shutdown process by 16S rDNA sequencing of clone libraries (400 clones) and growth analysis. The concentration of L. pneumophila and Pseudomonas spp. DNA were monitored by quantitative PCR. Results showed a decrease in the concentration of L. pneumophila and Pseudomonas spp. during the shutdown. This was accompanied by a significant change in the composition of the bacterial community in the aeration ponds. This study demonstrated that several advanced analytical methods are necessary to characterize the bacterial population in complex environments, such as the industrial aeration ponds. PMID- 23461518 TI - Complex integrons containing qnrB4-ampC (bla(DHA-1)) in plasmids of multidrug resistant Citrobacter freundii from wastewater. AB - Microbial populations in wastewater treatment plants (WWTPs) are increasingly being recognized as environmental reservoirs of antibiotic resistance genes. PCR amplicons for plasmid-mediated quinolone resistance determinants qnrA, qnrB, and qnrS were recorded in samples from a WWTP in Vancouver, British Columbia. Six strains of ciprofloxacin-resistant Citrobacter freundii were isolated and found to carry mutations in gyrA and parC, as well as multiple plasmid-borne resistance genes, collectively including qnrB; aac(6')-Ib-cr; beta-lactamase-encoding genes from molecular classes A (blaTEM-1), C (ampC), D (blaOXA-1, blaOXA-10); and genes for resistance to 5 other types of antibiotics. In 3 strains, large (>60 kb) plasmids carried qnrB4 and ampC as part of a complex integron in a 14 kb arrangement that has been reported worldwide but, until recently, only among pathogenic strains of Klebsiella. Analysis of single-nucleotide polymorphisms in the qnrB4-ampC regions infers 2 introductions into the WWTP environment. These results suggest recent passage of plasmid-borne fluoroquinolone and beta-lactam resistance genes from pathogens to bacteria that may be indigenous inhabitants of WWTPs, thus contributing to an environmental pool of antibiotic resistance. PMID- 23461519 TI - Lipid and fatty acid profile of Geobacillus kaustophilus in response to abiotic stress. AB - Geobacillus kaustophilus is an important food-borne, spore-forming, thermotolerant bacterium. It has a good potential for biotransformation of steroid hormones, such as progesterone and testosterone. In this study, we report G. kaustophilus membrane lipid modifications in response to temperature shock, salinity, incubation time, and pH. Total lipids significantly increased in response to increasing temperature, incubation time, and salt concentration. However, the bacterium presented a significant decrease in the accumulation of total lipids in response to pH shock. The ratio of branched-chain fatty acids/straight-chain fatty acids decreased significantly under all stress conditions. With an increase in temperature, incubation time, and salt concentration, the ratio of iso-fatty acids/anteiso-fatty acids increased significantly, while this ratio remained unaffected by changes in the pH of the growth medium. Our results suggest a modification occurs in the bacterial membrane structure in response to temperature, salinity, incubation time, and pH shock. The variable abiotic stress resulted in a multiple increase in odd numbered-carbon and low-melting-point anteiso-branched-chain fatty acids, helping the membrane keep its integrity, fluidity, and function for growth of the bacteria under abiotic stress conditions. PMID- 23461520 TI - Induction of resistance in Mycobacterium smegmatis. AB - In this work, we assayed the ability of newly prepared indolizine derivates (epimers) 6C and 6A to inhibit the growth of Mycobacterium smegmatis and used them for resistance induction. 6A inhibited the growth of M. smegmatis at a concentration of 100 MUg/mL. No inhibitory effect was observed in the presence of 6C. By incubating the bacteria with 6C and 6A, colonies resistant to 6A were observed. Finally, 37 stable resistant strains were isolated. These resistant strains were able to grow on a 5-fold higher concentration of 6A (500 MUg/mL) than the minimal inhibitory concentration of the wild type (100 MUg/mL), with no growth inhibition. Resistant strains were then tested for cross-resistance to other antibiotics: ampicillin, tetracycline, ciprofloxacin, chloramphenicol, gentamicin, and streptomycin. Determinations of resistance patterns to 6 antibiotics revealed 36 strains that were resistant to at least one drug. PMID- 23461521 TI - Vibrio fischeri exhibit the growth advantage in stationary-phase phenotype. AB - Vibrio fischeri are bioluminescent marine bacteria that can be isolated from their symbiotic animal partners or from ocean water. A V. fischeri population increases exponentially inside the light organ of the Hawaiian bobtail squid (Euprymna scolopes) while the host is quiescent during the day. This bacterial light organ population reaches stationary phase and then remains high during the night, when the squid use bacterial bioluminescence as a counter-predation strategy. At dawn, host squid release 90%-95% of the light organ contents into the ocean water prior to burying in the sand for the day. As the squid sleeps, the cycle of bacterial population growth in the light organ begins again. These V. fischeri cells that are vented into the ocean must persist under typical marine low nutrient conditions until they encounter another opportunity to colonize a host. We hypothesized that because V. fischeri regularly encounter cycles of feast and famine in nature, they would exhibit the growth advantage in stationary phase (GASP) phenotype. We found that older V. fischeri cells exhibit a Class 2 GASP response in which old cells increase dramatically in frequency while the population of young V. fischeri cells remains almost constant during co incubation. PMID- 23461522 TI - Role of a TehA homolog in Vibrio cholerae C6706 antibiotic resistance and intestinal colonization. AB - Vibrio cholerae is the causative agent of the devastating diarrheal disease cholera. A number of regulatory pathways are involved in V. cholerae pathogenesis and antibiotic resistance. For example, there are over 40 LysR-family proteins in the V. cholerae genome, but most of their functions are unknown. In this study, we examine the role of VC2323 (TehAVc) and its divergently transcribed LysR family regulator VC2324 (TehRVc) in V. cholerae pathogenesis. We found that in V. cholerae C6706, the expression of tehAVc is dependent on TehRVc. VC2323 (TehAVc), homologous to the Escherichia coli tellurite resistance protein (TehAEc), differs from TehAEc in that TehAVc has no noticeable role in tellurite resistance but instead contributes to chloramphenicol resistance. Interestingly, both tehAVc and tehRVc mutants were defective in colonization of infant mice. Though the expression of a key virulence gene tcpA was not affected in either of these mutants, tehAVc mutants failed to attach to mouse intestinal surfaces in the presence of crude bile, suggesting a new role of the TehAVc-TehRVc pair in V. cholerae pathogenesis. PMID- 23461523 TI - Hypnosis for the control of pain associated with external cephalic version: a comparative study. AB - OBJECTIVE: To assess the effectiveness of hypnosis to reduce pain and facilitate external cephalic version (ECV). DESIGN: Cohort study. SETTING: Geneva University Hospitals, Switzerland. PARTICIPANTS: 63 women attempting ECV under hypnosis from 2010 to 2011 were compared with 122 women who received standard care from 2005 through 2008. INTERVENTION: Immediately after the ECV attempt, both groups completed the same questionnaire evaluating the participants' pain (visual analogue and verbal rating scales) and experience with the procedure. Physicians also completed a questionnaire that elicited their views on the effect of hypnosis on the intervention. A chi-squared test was used to compare differences in proportions, and the Mann-Whitney U test was used for differences in continuous variables. A thematic content analysis of the obstetricians' responses to the open question regarding their experience of hypnotist accompaniment was also performed. OUTCOME MEASURES: Pain evaluated by women (visual analogue and verbal rating scales) and success rate of ECV. RESULTS: Pain intensity reported by women did not significantly differ between the hypnosis group and the standard care group (visual analogue scale score, 6.0 versus 6.3, respectively; p=.25; difference for verbal rating scale, p=0.31. In 72% of cases, physicians reported that hypnosis facilitated the procedure. The success rates in both groups were not significantly different (30% with hypnosis compared with 38% without; p=.31). Most women in both groups found the ECV attempt painful and a source of anxiety but would undergo it again if necessary. CONCLUSION: Hypnosis accompaniment during ECV does not reduce pain intensity associated with the procedure or improve the probability of a successful version. PMID- 23461524 TI - Global phosphoproteomic analysis reveals diverse functions of serine/threonine/tyrosine phosphorylation in the model cyanobacterium Synechococcus sp. strain PCC 7002. AB - Increasing evidence shows that protein phosphorylation on serine (Ser), threonine (Thr), and tyrosine (Tyr) residues is one of the major post-translational modifications in the bacteria, involved in regulating a myriad of physiological processes. Cyanobacteria are one of the largest groups of bacteria and are the only prokaryotes capable of oxygenic photosynthesis. Many cyanobacteria strains contain unusually high numbers of protein kinases and phosphatases with specificity on Ser, Thr, and Tyr residues. However, only a few dozen phosphorylation sites in cyanobacteria are known, presenting a major obstacle for further understanding the regulatory roles of reversible phosphorylation in this group of bacteria. In this study, we carried out a global and site-specific phosphoproteomic analysis on the model cyanobacterium Synechococcus sp. PCC 7002. In total, 280 phosphopeptides and 410 phosphorylation sites from 245 Synechococcus sp. PCC 7002 proteins were identified through the combined use of protein/peptide prefractionation, TiO2 enrichment, and LC-MS/MS analysis. The identified phosphoproteins were functionally categorized into an interaction map and found to be involved in various biological processes such as two-component signaling pathway and photosynthesis. Our data provide the first global survey of phosphorylation in cyanobacteria by using a phosphoproteomic approach and suggest a wide-ranging regulatory scope of this modification. The provided data set may help reveal the physiological functions underlying Ser/Thr/Tyr phosphorylation and facilitate the elucidation of the entire signaling networks in cyanobacteria. PMID- 23461525 TI - Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. AB - Statins are a class of medications that reduce cholesterol by inhibiting 3 hydroxy-3-methylglutaryl-coenzyme A reductase, which were thought to have a positive impact on dementia. We carried out the present meta-analysis to investigate whether statins might be associated with a reduction on risk of dementia. We carried out a meta-analysis of prospective cohort studies to examine the risk of dementia associated with statins. Ovid-Medline database, PubMed database, Springer Link database and Google Scholar in English search were carried out for relevant studies. Selected studies had to describe an original study defined by strict screening and diagnostic criteria. We included eight prospective cohort studies that reported relative risks with 95% confidence intervals for the association of statins and dementia risk. A random effects model was used to calculate the summary risk estimates. The studies eligible for analysis involved 2851 cases and 57020 participants. The summary relative risk of dementia for the use of statins was 0.62 (95% confidence interval 0.43-0.81), with evidence of heterogeneity (P = 0.001, I(2) = 70.8%). Findings of the present meta-analysis show that statin use was associated with a reduced risk of dementia. PMID- 23461526 TI - Does socioeconomic status matter? A meta-analysis on parent training effectiveness for disruptive child behavior. AB - Disadvantaged family socioeconomic status (SES) is often assumed to diminish parent training program effectiveness. In examining effects of SES, influences of initial problem severity have been largely ignored. In the present meta-analysis, we examined (a) whether there is a differential influence of SES on parent training effectiveness at immediate posttreatment and at 1-year follow-up controlling for levels of initial problem severity--and (b) whether SES interacts with initial problem severity in its effect on program effectiveness. Seventy five studies on parent training program effectiveness to reduce disruptive child behavior were included. Separate analyses were conducted for immediate posttreatment and approximately 1-year follow-up assessments. Immediately posttreatment, disadvantaged samples benefited less from parent training, but only when they had low levels of initial problem severity. At follow-up, disadvantaged samples benefited less from parent training regardless of initial problem severity. Initial problem severity was a strong predictor of effect sizes both immediately posttreatment and at follow-up. Parent training programs are equally effective for disadvantaged and nondisadvantaged families immediately posttreatment, at least when initial problems are severe. Maintenance of treatment gain, however, seems harder for disadvantaged families, suggesting that more sustained family support may be needed. PMID- 23461527 TI - Osteoarthritis prevention through meniscal regeneration induced by intra articular injection of meniscus stem cells. AB - Meniscus injury is frequently encountered in clinical practice. Current surgical therapy involving partial or complete meniscectomy relieves pain in the short term but often leads to osteoarthritis (OA) in the long-term. Here, this study aimed to identify and characterize a novel population of meniscus-derived stem cells (MeSCs) and develop a new strategy of articular cartilage protection by intra-articular injection of these cells. The "stemness" and immune properties of MeSCs were investigated in vitro, while the efficacy of intra-articular injection of MeSCs for meniscus regeneration and OA prevention were investigated in vivo at 4, 8, and 12 weeks postsurgery. MeSCs displayed typical stem cell characteristics such as low immunogenicity and even possessed immunosuppressive function. In a rabbit meniscus injury model, transplantation of allogenous MeSCs did not elicit immunological rejection, but promoted neo-tissue formation with better-defined shape and more matured extracellular matrix. In a rabbit experimental OA model, transplantation of MeSCs further protected joint surface cartilage and maintained joint space at 12 weeks postsurgery, whereas extensive joint surface irregularities and joint space stenosis were observed in the control group. This study thus evoked a new strategy for articular cartilage protection and meniscus regeneration by intra-articular injection of MeSCs for patients undergoing meniscectomy. PMID- 23461528 TI - High-throughput screening of small molecule ligands targeted to live bacteria surface. AB - The discovery of small molecule ligands targeted to the surface of live pathogenic bacteria would enable an entirely new class of antibiotics. We report the development and validation of a microarray-based high-throughput screening platform for bacteria that exploits 300 MUm diameter chemical spots in a 1 in. * 3 in. nanolayered glass slide format. Using 24 model compounds and 4 different bacterial strains, we optimized the screening technology, including fluorophore based optical deconvolution for automated scoring of affinity and cyan-magenta yellow-key (CMYK) color-coding for scoring of both affinity and specificity. The latter provides a lossless, one-dimensional view of multidimensional data. By linking in silico analysis with cell binding affinity and specificity, we could also begin to identify the physicochemical factors that affect ligand performance. The technology we describe could form the foundation for developing new classes of antibiotics. PMID- 23461529 TI - Lactic acid bacteria convert glucosinolates to nitriles efficiently yet differently from enterobacteriaceae. AB - Glucosinolates from the genus Brassica can be converted into bioactive compounds known to induce phase II enzymes, which may decrease the risk of cancers. Conversion via hydrolysis is usually by the brassica enzyme myrosinase, which can be inactivated by cooking or storage. We examined the potential of three beneficial bacteria, Lactobacillus plantarum KW30, Lactococcus lactis subsp. lactis KF147, and Escherichia coli Nissle 1917, and known myrosinase-producer Enterobacter cloacae to catalyze the conversion of glucosinolates in broccoli extract. Enterobacteriaceae consumed on average 65% glucoiberin and 78% glucoraphanin, transforming them into glucoiberverin and glucoerucin, respectively, and small amounts of iberverin nitrile and erucin nitrile. The lactic acid bacteria did not accumulate reduced glucosinolates, consuming all at 30-33% and transforming these into iberverin nitrile, erucin nitrile, sulforaphane nitrile, and further unidentified metabolites. Adding beneficial bacteria to a glucosinolate-rich diet may increase glucosinolate transformation, thereby increasing host exposure to bioactives. PMID- 23461530 TI - Adaptation of Listeria monocytogenes in a simulated cheese medium: effects on virulence using the Galleria mellonella infection model. AB - The aim of this study was to evaluate the effect of the acid and salt adaptation in a cheese-based medium on the virulence potential of Listeria monocytogenes strains isolated from cheese and dairy processing environment using the Galleria mellonella model. Four L. monocytogenes strains were exposed to a cheese-based medium in conditions of induction of an acid tolerance response and osmotolerance response (pH 5.5 and 3.5% w/v NaCl) and injected in G. mellonella insects. The survival of insects and the L. monocytogenes growth kinetics in insects were evaluated. The gene expression of hly, actA and inlA genes was determined by real time PCR. The adapted cells of two dairy strains showed reduced insect mortality (P < 0.05) in comparison with nonadapted cells. Listeria monocytogenes Scott A was the least virulent, whereas the cheese isolate C882 caused the highest insect mortality, and no differences (P > 0.05) was found between adapted and nonadapted cells. The gene expression results evidenced an overexpression of virulence genes in cheese-based medium, but not in simulated insect-induced conditions. Our results suggest that adaptation to low pH and salt in a cheese-based medium can affect the virulence of L. monocytogenes, but this effect is strain dependent. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, the impact of adaptation to low pH and salt in a cheese-based medium on L. monocytogenes virulence was tested using the Wax Moth G. mellonella model. This model allowed the differentiation of the virulence potential between the L. monocytogenes strains. The effect of adaptation on virulence is strain dependent. The G. mellonella model revealed to be a prompt method to test food-related factors on L. monocytogenes virulence. PMID- 23461531 TI - Lewis basic selenium catalyzed chloroamidation of olefins using nitriles as the nucleophiles. AB - A Lewis base catalyzed chloroamidation of olefinic substrates was achieved using diphenyl selenide as the catalyst. The reaction conditions are mild and suitable for a wide range of substrates including those which are acid labile. PMID- 23461532 TI - Design of experiments to optimize an in vitro cast to predict human nasal drug deposition. AB - BACKGROUND: Previous studies showed nasal spray in vitro tests cannot predict in vivo deposition, pharmacokinetics, or pharmacodynamics. This challenge makes it difficult to assess deposition achieved with new technologies delivering to the therapeutically beneficial posterior nasal cavity. In this study, we determined best parameters for using a regionally divided nasal cast to predict deposition. Our study used a model suspension and a design of experiments to produce repeatable deposition results that mimic nasal deposition patterns of nasal suspensions from the literature. METHODS: The seven-section (the nozzle locator, nasal vestibule, front turbinate, rear turbinate, olfactory region, nasopharynx, and throat filter) nylon nasal cast was based on computed tomography images of healthy humans. It was coated with a glycerol/Brij-35 solution to mimic mucus. After assembling and orienting, airflow was applied and nasal spray containing a model suspension was sprayed. After disassembling the cast, drug depositing in each section was assayed by HPLC. The success criteria for optimal settings were based on nine in vivo studies in the literature. The design of experiments included exploratory and half factorial screening experiments to identify variables affecting deposition (angles, airflow, and airflow time), optimization experiments, and then repeatability and reproducibility experiments. RESULTS: We found tilt angle and airflow time after actuation affected deposition the most. The optimized settings were flow rate of 16 L/min, postactuation flow time of 12 sec, a tilt angle of 23 degrees , nozzle angles of 0 degrees , and actuation speed of 5 cm/sec. Neither cast nor operator caused significant variation of results. CONCLUSION: We determined cast parameters to produce results resembling suspension nasal sprays in the literature. The results were repeatable and unaffected by operator or cast. These nasal spray parameters could be used to assess deposition from new devices or formulations. For human deposition studies using radiolabeled formulations, this cast could show that radiolabel deposition represents drug deposition. Our methods could also be used to optimize settings for other casts. PMID- 23461533 TI - A technique for determination of lung outline and regional lung air volume distribution from computed tomography. AB - BACKGROUND: Determination of the lung outline and regional lung air volume is of value in analysis of three-dimensional (3D) distribution of aerosol deposition from radionuclide imaging. This study describes a technique for using computed tomography (CT) scans for this purpose. METHODS: Low-resolution CT scans of the thorax were obtained during tidal breathing in 11 healthy control male subjects on two occasions. The 3D outline of the lung was determined by image processing using minimal user interaction. A 3D map of air volume was derived and total lung air volume calculated. The regional distribution of air volume from center to periphery of the lung was analyzed using a radial transform and the outer-to inner ratio of air volume determined. RESULTS: The average total air volume in the lung was 1,900+/-126 mL (1 SEM), which is in general agreement with the expected value for adult male subjects in the supine position. The fractional air volume concentration increased from the center toward the periphery of the lung. Outer-to-inner (O/I) ratios were higher for the left lung [11.5+/-1.8 (1 SD)] than for the right [10.1+/-0.8 (1 SD)] (p<0.001). When normalized for the region sizes, these ratios were 1.37+/-0.16 and 1.20+/-0.04, respectively. The coefficient of variation of repeated measurement of the normalized O/I ratio was 5.9%. CONCLUSIONS: A technique for outlining the lungs from CT images and obtaining an image of the distribution of air volume is described. The normal range of various parameters describing the regional distribution of air volume is presented, together with a measure of intrasubject repeatability. This technique and data will be of value in analyzing 3D radionuclide images of aerosol deposition. PMID- 23461535 TI - The role of NO in the posterior hypothalamus in amygdala-generated pressor responses in conscious rats. AB - The nitrergic system modulates cardiovascular functions of the central nucleus of amygdala (CeA) and the posterior hypothalamus (PH) which are involved in the central regulation of the cardiovascular system. The aim of this study was to investigate the contribution of nitric oxide (NO) in the PH in eliciting cardiovascular responses produced through electrical stimulation (ES) of the CeA. Rats were implanted with a stimulation electrode and a parenchymal cannula system into the CeA and a parenchymal cannula or a microdialysis probe into the PH. The next day, the femoral artery was cannulated for haemodynamic measurement. The CeA was electrically stimulated to produce cardiovascular response. The nitric oxide synthetase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 400 nmol/100 nl) or artificial cerebrospinal fluid were injected into the PH or the CeA before the ES of the CeA. The dialysates were collected from the PH to determine the L citrulline and the L-glutamic acid levels. L-NAME injection into the CeA but not to the PH suppressed the increases in the mean arterial pressure produced by the ES of the CeA significantly; however, heart rate was not affected by L-NAME injection into either the PH or the CeA. L-citrulline and L-glutamic acid levels in the PH were shown to be increased by the ES of the CeA. NO is involved between the PH and the CeA which has a considerable role in the central regulation of the cardiovascular system. PMID- 23461534 TI - Loading and activation of DNA replicative helicases: the key step of initiation of DNA replication. AB - Evolution has led to diversification of all living organisms from a common ancestor. Consequently, all living organisms use a common method to duplicate their genetic information and thus pass on their inherited traits to their offspring. To duplicate chromosomal DNA, double-stranded DNA must first be unwound by helicase, which is loaded to replication origins and activated during the DNA replication initiation step. In this review, we discuss the common features of, and differences in, replicative helicases between prokaryotes and eukaryotes. PMID- 23461536 TI - Pimecrolimus for psoriasis. AB - INTRODUCTION: Pimecrolimus is a calcineurin inhibitor which has a role in the treatment of psoriasis. However, it remains an off-license treatment, despite its potential use in patients with treatment-resistant psoriasis or in those who have had multiple adverse effects to other therapies. AREAS COVERED: This review covers the efficacy and role of both topical and oral Pimecrolimus in the management of psoriasis and compares them to other available treatments. The paper provides a comprehensive review of the literature on topical and oral Pimecrolimus and its utility in the treatment of patients with psoriasis following literature searches via PubMed and Embase. EXPERT OPINION: Topical Pimecrolimus is an effective, off-license treatment option particularly for facial and intertriginous psoriasis. Oral Pimecrolimus shows great promise as an alternative systemic treatment option, but Phase III trials are required before further recommendations can be made. PMID- 23461537 TI - Enhanced reactivity in dioxirane C-H oxidations via strain release: a computational and experimental study. AB - The site selectivities and stereoselectivities of C-H oxidations of substituted cyclohexanes and trans-decalins by dimethyldioxirane (DMDO) were investigated computationally with quantum mechanical density functional theory (DFT). The multiconfiguration CASPT2 method was employed on model systems to establish the preferred mechanism and transition state geometry. The reaction pathway involving a rebound step is established to account for the retention of stereochemistry. The oxidation of sclareolide with dioxirane reagents is reported, including the oxidation by the in situ generated tBu-TFDO, a new dioxirane that better discriminates between C-H bonds on the basis of steric effects. The release of 1,3-diaxial strain in the transition state contributes to the site selectivity and enhanced equatorial C-H bond reactivity for tertiary C-H bonds, a result of the lowering of distortion energy. In addition to this strain release factor, steric and inductive effects contribute to the rates of C-H oxidation by dioxiranes. PMID- 23461538 TI - Indirect and mitigated effects of pulsed resources on the population dynamics of a northern rodent. AB - Pulsed resources have significant effects on population and community dynamics in terrestrial ecosystems. Mast seeding is an important resource pulse in deciduous forests; these boom and bust cycles of seed production generate strong lagged population responses by post-dispersal seed predators such as rodents, which then cascade through multiple trophic levels and regulate population dynamics of their predators and prey. However, similar interactions in another major pulsed system, coniferous forests, are inconsistent, and the effects of interannual variation in conifer seed production on many consumer populations are largely unknown. We used large-scale manipulation and intensive monitoring to examine the population dynamics of deer mice (Peromyscus maniculatus) in relation to fall seed production by two northern conifers, white spruce (Picea glauca) and subalpine fir (Abies lasiocarpa). Previous studies have shown that spruce seeds are a preferred food source of mice, while fir seeds are generally avoided if other foods are available. Therefore, we expected that there would be a positive relationship between mouse demography and previous spruce seed production, but no effect of fir mast seeding. Supplementation of a mouse population using spruce seeds indicated that increased fall spruce seed availability can enhance overwinter survival and population densities in the following spring, summer, and fall. However, long-term population monitoring indicated that mouse demography was not positively affected by spruce mast seeding, likely due to strong interspecific competition with the North American red squirrel (Tamiasciurus hudoniscus), a dominant pre-dispersal spruce seed predator. Conversely, we observed an unexpected delayed effect of fir mast seeding, where increased fall fir seed production did not influence overwinter or spring mouse demography, but instead enhanced summer survival, body masses and pregnancy rates of overwintered adults. This led to increased summer population densities and may have been mediated by population responses of invertebrate post-dispersal seed predators to increased fir seed availability. Our results indicate that rodent responses to resource pulses in coniferous forests are more complex than in deciduous environments and reveal previously unobserved direct and indirect consumer resource dynamics that require further examination. This system is ideal for the large-scale, integrative ecosystem studies that ecologists are encouraged to pursue. PMID- 23461539 TI - A concept analysis of nursing overtime. AB - AIM: To report a concept analysis of nursing overtime. BACKGROUND: Economic constraints have resulted in hospital restructuring with the aim of reducing costs. These processes often target nurse staffing (the largest organizational expense) by increasing usage of alternative staffing strategies including overtime hours. Overtime is a multifaceted, poorly defined, and indiscriminately used concept. Analysis of nursing overtime is an important step towards development and propagation of appropriate staffing strategies and rigorous research. DESIGN: Concept analysis. DATA SOURCES: The search of electronic literature included indexes, grey literature, dictionaries, policy statements, contracts, glossaries and ancestry searching. Sources included were published between 1993-2012; dates were chosen in relation to increases in overtime hours used as a result of the healthcare structuring in the early 1990s. Approximately 65 documents met the inclusion criteria. REVIEW METHODS: Walker and Avant's methodology guided the analysis. DISCUSSION: Nursing overtime can be defined by four attributes: perception of choice or control over overtime hours worked; rewards or lack thereof; time off duty counts equally as much as time on duty; and disruption due to a lack of preparation. Antecedents of overtime arise from societal, organizational, and individual levels. The consequences of nursing overtime can be positive and negative, affecting organizations, nurses, and the patients they care for. CONCLUSION: This concept analysis clarifies the intricacies surrounding nursing overtime with recommendations to advance nursing research, practice, and policies. A nursing-specific middle-range theory was proposed to guide the understanding and study of nursing overtime. PMID- 23461540 TI - Synthesis, lanthanide coordination chemistry, and liquid-liquid extraction performance of CMPO-decorated pyridine and pyridine N-oxide platforms. AB - Syntheses for a set of new ligands containing one or two carbamoylmethylphosphine oxide (CMPO) fragments appended to pyridine and pyridine N-oxide platforms are described. Molecular mechanics analyses for gas phase lanthanide-ligand interactions for the pyridine N-oxides indicate that the trifunctional NOPOCO molecules, 2-{[Ph2P(O)][C(O)NEt2]C(H)}C5H4NO (7) and 2 {[Ph2P(O)][C(O)NEt2]CHCH2}C5H4NO (8), and pentafunctional NOPOP'O'COC'O' molecules, 2,6-{[Ph2P(O)][C(O)NEt2]C(H)}2C5H3NO (9) and 2,6 {[Ph2P(O)][C(O)NEt2]CHCH2}2C5H3NO (10), should be able to adopt, with minimal strain, tridentate and pentadentate chelate structures, respectively. As a test of these predictions, selected lanthanide coordination chemistry of the N-oxide derivatives was explored. Crystal structure analyses reveal the formation of a tridentate NOPOCO chelate structure for a 1:1 Pr(III) complex containing 7 while 8 adopts a mixed bidentate/bridging monodentate POCO/NO binding mode with Pr(III). Tridentate and tetradentate chelate structures are obtained for several 1:1 complexes of 9 while a pentadentate chelate structure is observed with 10. Emission spectroscopy for one complex, [Eu(9)(NO3)3], in methanol, shows that the Eu(III) ion resides in a low-symmetry site. Lifetime measurements for methanol and deuterated methanol solutions indicate the presence of four methanol molecules in the inner coordination sphere of the metal ion, in addition to the ligand, with the nitrate anions most likely dissociated. The solvent extraction performance of 7-10 in 1,2-dichloroethane for Eu(III) and Am(III) in nitric acid solutions was analyzed and compared with the performance of 2,6-bis(di-n octylphosphinoylmethyl)pyridine N-oxide (TONOPOP'O') and n-octyl(phenyl)-N,N diisobutylcarbamoylmethylphosphine oxide (OPhDiBCMPO) measured under identical conditions. PMID- 23461541 TI - Predicting post-stroke pneumonia: the PANTHERIS score. AB - OBJECTIVES: Stroke-associated pneumonia (SAP) is a common complication with a known negative impact on neurological outcome. We developed a score to identify patients at highest risk of SAP in order to promote prophylactic measures. MATERIALS AND METHODS: We conducted a cohort study on a neurological intensive care unit in patients suffering from acute ischemic MCA infarction. Association of predefined demographics, comorbidities, and clinical characteristics with SAP was investigated using logistic regression analysis. RESULTS: Between 2003 and 2010, a total of 335 patients were included in this analysis. Frequency of SAP was 31.3%. A 12-point scoring system was developed based on the following factors: Glasgow Coma Scale (GCS) [GCS < 9 = 5, GCS 9-12 = 2, GCS > 12 = 0], age [<60 = 0, 60-80 = 1, >80 = 2], increase in systolic arterial blood pressure >200 mmHg within the first 24 h after admission [no = 0, yes = 2], and white blood cell count >11.000/MUl [no = 0, yes = 3]. The score revealed excellent discrimination (AUC = 0.85) and calibration (Nagelkerke's R2 = 0.46) properties. Predictive properties were reproduced in an internal validation group. CONCLUSIONS: The PANTHERIS score is a simple scoring system for the prediction of SAP based on easy-to-assess parameters. By identifying patients at high risk, it may guide intense monitoring or prophylactic measures. This score needs to be validated within external datasets. PMID- 23461542 TI - A new family of mathematical models describing the human growth curve-Erratum: direct calculation of peak height velocity, age at take-off and associated quantities. AB - A new family of mathematical functions to fit longitudinal growth data was described in 1978. The ability of researchers to directly use parameters as estimates of age at peak height velocity resulted in them overlooking the possibility of directly calculating these quantities after model estimation. This erratum has corrected three mistakes in the original manuscript in the direct calculation of peak height velocity and age at take-off and has implemented the solutions in a STATA program which directly calculates the estimates, standard errors and confidence intervals for age, height and velocity at peak height velocity. PMID- 23461543 TI - Conserving large carnivores: dollars and fence. AB - Conservationists often advocate for landscape approaches to wildlife management while others argue for physical separation between protected species and human communities, but direct empirical comparisons of these alternatives are scarce. We relate African lion population densities and population trends to contrasting management practices across 42 sites in 11 countries. Lion populations in fenced reserves are significantly closer to their estimated carrying capacities than unfenced populations. Whereas fenced reserves can maintain lions at 80% of their potential densities on annual management budgets of $500 km(-2) , unfenced populations require budgets in excess of $2000 km(-2) to attain half their potential densities. Lions in fenced reserves are primarily limited by density dependence, but lions in unfenced reserves are highly sensitive to human population densities in surrounding communities, and unfenced populations are frequently subjected to density-independent factors. Nearly half the unfenced lion populations may decline to near extinction over the next 20-40 years. PMID- 23461546 TI - QM/MM excited state molecular dynamics and fluorescence spectroscopy of BODIPY. AB - Absorption and emission spectra arising from the lowest energy transition in BODIPY have been simulated in the gas phase and water using a quantum mechanics/molecular mechanics (QM/MM) approach. Kohn-Sham density functional theory (DFT) is used to calculate both ground (So) and first excited (S1) states using the maximum overlap method to obtain the S1 state. This approach gives ground and excited state structures in good agreement with structures found using multiconfigurational perturbation theory (CASPT2). Application of a post-self consistent field spin-purification relationship also yields transition energies in agreement with CASPT2 and available experimental data. Spectral bands were simulated using many structures taken from ab initio molecular dynamics simulations of the ground and first excited states. In these simulations, DFT is used for BODIPY, and in the condensed phase simulations the water molecules are treated classically. The resulting spectra show a blue shift of 0.3 eV in both absorption and emission bands in water compared to the gas phase. A Stokes shift of about 0.1 eV is predicted, and the width of the emission band in solution is significantly broader than the absorption band. These results are consistent with experimental data for BODIPY and closely related dyes, and demonstrate how both absorption and emission spectra in solution can be simulated using a quantum mechanical treatment of the electronic structure of the solute. PMID- 23461544 TI - Dose-dependent reduction of replication elongation rate by (p)ppGpp in Escherichia coli and Bacillus subtilis. AB - DNA replication is regulated in response to environmental constraints such as nutrient availability. While much is known about regulation of replication during initiation, little is known about regulation of replication during elongation. In the bacterium Bacillus subtilis, replication elongation is paused upon sudden amino acid starvation by the starvation-inducible nucleotide (p)ppGpp. However, in many bacteria including Escherichia coli, replication elongation is thought to be unregulated by nutritional availability. Here we reveal that the replication elongation rate in E. coli is modestly but significantly reduced upon strong amino acid starvation. This reduction requires (p)ppGpp and is exacerbated in a gppA mutant with increased pppGpp levels. Importantly, high levels of (p)ppGpp, independent of amino acid starvation, are sufficient to inhibit replication elongation even in the absence of transcription. Finally, in both E. coli and B. subtilis, (p)ppGpp inhibits replication elongation in a dose-dependent manner rather than via a switch-like mechanism, although this inhibition is much stronger in B. subtilis. This supports a model where replication elongation rates are regulated by (p)ppGpp to allow rapid and tunable response to multiple abrupt stresses in evolutionarily diverse bacteria. PMID- 23461547 TI - Efficiency of multiexciton generation in colloidal nanostructures. AB - Solar energy production, one of the world's most important unsolved problems, has the potential to be a source of clean, renewable energy if scientists can find a way of generating cheap and efficient solar cells. Generation of multiple excitons from single photons is one way to increase the efficiency of solar energy collection, but the process suffers from low efficiency in bulk materials. An increase of multiexciton generation efficiency in nanocrystals was proposed by Nozik in 2002 and demonstrated by Schaller and Klimov in 2004 in PbSe nanocrystals. Since then, scientists have observed efficient multiexciton generation in nanostructures made of many semiconductors using various measurement techniques. Although the experimental evidence of efficient carrier multiplication is overwhelming, there is no complete theory of this phenomenon. Researchers cannot develop such a theory without a self-consistent description of the Coulomb interaction and a knowledge of mechanisms of electron and hole thermalization in nanostructures. The full theoretical description requires the strength of the Coulomb interaction between exciton and multiexciton states and the thermalization rates, which both vary with the dimensionality of the confining potential. As a result, the efficiency of multiexciton generation depends strongly on the material and the shape of the nanostructure. In this Account, we discuss the theoretical aspects of efficient carrier multiplication in nanostructures. The Coulomb interaction couples single excitons with multiexciton states. Phenomenological many-electron calculations of the evolution of single-photon excitations have shown that efficient multiexciton generation can exist only if the rate of the Coulomb mixing between photo-created exciton and biexciton states is significantly faster than the rate of exciton relaxation. Therefore, to increase multiexciton generation efficiency, we need to either increase the exciton-biexciton mixing rate or suppress the exciton relaxation rate. Following this simple recipe, we show that multiexciton generation efficiency should be higher in semiconductor nanorods and nanoplatelets, which have stronger exciton-biexciton coupling due to the enhancement of the Coulomb interaction through the surrounding medium. PMID- 23461548 TI - Characterization of lentiviral vector production using microwell suspension cultures of HEK293T-derived producer cells. AB - ProSavin((r)) is a lentiviral vector (LV)-based gene therapy for Parkinson's disease. ProSavin((r)) is currently in a Phase I/II clinical trial using material that was generated by transient transfection of adherent human embryonic kidney (HEK)293T cells. For future large-scale productions of ProSavin((r)), we have previously reported the development and characterization of two inducible producer cell lines, termed PS5.8 and PS46.2. PS46.2 has been successfully adapted to grow in suspension cultures. The present study describes the creation of a small-scale (<2 ml) microwell-based experimental platform for the parallel investigation of ProSavin((r)) production using suspension-adapted PS46.2. This is combined with statistical design of experiments (DoE) techniques to enable rapid characterization of the process conditions that impact cell growth and LV production. The effects of postinduction period, microwell liquid fill volume, and concentration of inducer (doxycycline) on ProSavin((r)) titer and the particle:infectivity (P:I) ratio was investigated using three rounds of DoE, in order to identify appropriate factor ranges and optimize production conditions. We identified an optimal "harvest window" between approximately 26-46 hr within which maximal titers of around 6*10(4) transducing units (TU)/ml were obtained (an approximately 30-fold improvement compared to starting microwell conditions), providing that the fill volume was maintained at or below 1 ml and the doxycycline concentration was at least 1.0 MUg/ml. Insights from the microwell studies were subsequently used to rapidly establish operating conditions for ProSavin((r)) production in a 0.5-L wave bioreactor culture. The information presented herein thus aids the design and evaluation of scalable production processes for LVs. PMID- 23461549 TI - Identifying the potential of changes to blood sample logistics using simulation. AB - Using simulation as an approach to display and improve internal logistics at hospitals has great potential. This study shows how a simulation model displaying the morning blood-taking round at a Danish public hospital can be developed and utilized with the aim of improving the logistics. The focus of the simulation was to evaluate changes made to the transportation of blood samples between wards and the laboratory. The average- (AWT) and maximum waiting time (MWT) from a blood sample was drawn at the ward until it was received at the laboratory, and the distribution of arrivals of blood samples in the laboratory were used as the evaluation criteria. Four different scenarios were tested and compared with the current approach: (1) Using AGVs (mobile robots), (2) using a pneumatic tube system, (3) using porters that are called upon, or (4) using porters that come to the wards every 45 minutes. Furthermore, each of the scenarios was tested in terms of what amount of resources would give the optimal result. The simulations showed a big improvement potential in implementing a new technology/mean for transporting the blood samples. The pneumatic tube system showed the biggest potential lowering the AWT and MWT with approx. 36% and 18%, respectively. Additionally, all of the scenarios had a more even distribution of arrivals except for porters coming to the wards every 45 min. As a consequence of the results obtained in the study, the hospital decided to implement a pneumatic tube system. PMID- 23461550 TI - Rapid assessment of renal reserve in young adults by cystatin C. AB - BACKGROUND: The kidney can increase glomerular filtration rate (GFR) in response to a protein load (renal reserve). In a pilot study of healthy young adults we examined renal reserve using changes in serum cystatin C (cysC). METHODS: Glomerular filtration rate was obtained using iohexol single slope plasma disappearance. To stimulate GFR, subjects ingested a beefburger containing 60 grams of protein. CysC was measured by immunonephelometry before and 125-141 minutes after protein loading. RESULTS: All subjects were found to have a normal iohexol plasma disappearance GFR with a mean of 104.6 +/- 9.9 mL/min per 1.73 m(2). CysC decreased in each subject after the meat meal. Baseline cysC-based estimated GFR was 98.1 +/- 9.1 mL/min per 1.73 m(2) with a mean increase of 12.0 +/- 5.2 (p = 0.0003). CONCLUSIONS: Our study showed a consistent decrease in serum cysC and increase in cysC-based estimated GFR following a protein load in young adults. Further studies are needed using renal clearance methods to confirm that cysC accurately determines renal reserve in patients with and without chronic kidney disease. PMID- 23461551 TI - Enhancing the sensitivity of molecular secondary ion mass spectrometry with C60+ O2+ cosputtering. AB - In the past decade, the C60-based ion gun has been widely utilized in the secondary ion mass spectrometry (SIMS) analysis of organic and biological materials because molecular secondary-ions of high masses could be generated by cluster-ion bombardment. This technique furthers the development of SIMS in bioanalysis by eliminating the need for either heteroatom or isotope labeling. However, the intensity of high-mass parent ions was usually low and limited the sensitivity of the analysis, thus requiring an enhancement in the intensity of these molecular ions to widen the application of SIMS. In this work, the aim was to preserve samples in their original state while using a low kinetic energy O2(+) beam cosputtered with high-energy C60(+) to enhance the ion intensity through the depth-profile. Although O2(+) is generally used to enhance ion intensities in positive SIMS, it is known to alter the chemical structure and primarily provide elemental information; hence, it is not suitable for profiling organic and biological specimens. Nevertheless, owing to its high sputtering yield, cluster C60(+) ion removes and masks the structural damage, hence O2(+) may be used to enhance the ion intensity. The characteristic molecular ions of polyethylene terephthalate (PET), trehalose, and a peptide (papain inhibitor) are enhanced by 35*, 12*, and 3.5* with the use of the auxiliary O2(+) beam, respectively. This significant enhancement in ionization yield is attributed to the oxidation of molecules and formation of a hydroxyl group that serves as a proton donator. In addition to enhancing molecular SIMS signals, C60(+)-O2(+) cosputtering could also alleviate several problems, including sputtering rate decay, carbon deposition, and surface roughening, that are associated with C60(+) bombardment and produced better depth profiles. PMID- 23461553 TI - Organocatalytic domino reaction of cyanosulfones: access to complex cyclohexane systems with quaternary carbon centers. AB - When epsilon-nitro-alpha,beta-unsaturated esters are added to conjugated cyanosulfones in the presence of a bifunctional thiourea catalyst, a highly stereoselective domino reaction occurs to generate complex cyclohexanes with up to four stereogenic centers, one of which is quaternary in nature. Therefore, it is demonstrated that, like nitro compounds, sulfones can undergo an asymmetric intramolecular conjugate addition to alpha,beta-unsaturated esters in the presence of a bifunctional organocatalyst. PMID- 23461552 TI - Allogeneic mesenchymal stem cell therapy for bisphosphonate-related jaw osteonecrosis in Swine. AB - Bisphosphonates (BPs), which are used to treat a variety of clinical disorders, have the side effect of jawbone necrosis. Currently, there is no reliable treatment for BP-related osteonecrosis of the jaw (BRONJ) due to a lack of understanding of its pathogenesis. To investigate the pathogenesis of BRONJ and observe the treatment effect of bone marrow mesenchymal stem cell (BMMSC) transplantation, we established a preclinical animal model of BRONJ in miniature pigs (minipigs). After treatment with zoledronic acid, the clinical and radiographic manifestations of BRONJ could be observed in minipigs after first premolar extraction. The biological and immunological properties of BMMSCs were impaired in the BP-treated minipigs. Moreover, the ratio of Foxp3-positive regulatory T-cells (Tregs) in peripheral blood decreased, and interleukin (IL)-17 increased in the serum of BP-treated minipigs. After allogeneic BMMSC transplantation via intravenous infusion, mucosal healing and bone reconstruction were observed; IL-17 levels were reduced; and Tregs were elevated. In summary, we established a clinically relevant BRONJ model in minipigs and tested a promising allogeneic BMMSC-based therapy, which may have potential clinical applications for treating BRONJ. PMID- 23461554 TI - Post-exposure prophylaxis in resource-poor settings: review and recommendations for pre-departure risk assessment and planning for expatriate healthcare workers. AB - It is estimated that more than 3 million healthcare workers worldwide suffer needlestick and splash injuries whilst at work resulting in the potential transmission of blood-borne pathogens via exposure to bodily fluids. Under reporting and the subsequent management of occupational injuries is a problem both in the United Kingdom and abroad. Many expatriate health care workers will work in low resource settings where the risk of transmission is greatest but in contrast to wealthier countries such as the United Kingdom, there is often a lack of effective systems for its safe management. This article provides important information about this risk and how to minimise it. The reasons for an increased risk in transmission, its subsequent management and pre-departure planning are discussed, together with the evidence for initiation of post-exposure prophylaxis; current National and International guidelines as well as the urgent need for International standardisation of these is also discussed. PMID- 23461555 TI - Neuromuscular blocking effect of fluoxetine and its interaction with rocuronium. AB - As selective serotonin reuptake inhibitors have an inhibitory effect on nicotinic acetylcholine receptors, they may affect the neuromuscular transmission and interact with neuromuscular blockers. This study was designed to observe the effect of fluoxetine on neuromuscular transmission and its interaction with rocuronium using the rat phrenic nerve hemidiaphragm and rabbit head drop methods. Rat phrenic nerve hemidiaphragms were mounted and stimulated using a train of four pulses (TOF). The effect of fluoxetine was studied on both indirectly and directly stimulated basal twitch responses by plotting cumulative dose response curves (DRCs). DRCs of rocuronium were obtained in the absence, and presence of 5 MUm and 20 MUm fluoxetine to study its interaction. ED5 , ED50 and ED95 values of rocuronium DRCs in absence and presence of fluoxetine were calculated. Fluoxetine significantly inhibited twitch responses in both indirect and directly stimulated preparations. Fluoxetine (20 MUm) caused an increase in the potency of rocuronium such that the ED50 and ED95 values of rocuronium DRCs were significantly decreased. Partially inhibited twitch responses by fluoxetine (100 MUm) were not reversed by neostigmine (3.3 MUm) or 3,4 diaminopyridine (0.25 MUm). Rabbits were given fluoxetine 0.25 mg kg(-1) and 1 mg kg(-1) orally for 15 days, and on 15th day, rocuronium infusion was given, and time for head drop was recorded. The time of head drop was significantly reduced in fluoxetine pretreated as compared to control group. Fluoxetine blocks the neuromuscular transmission and increases the potency of rocuronium-induced neuromuscular block. PMID- 23461556 TI - Associations between particular types of fetal malformation and antiepileptic drug exposure in utero. AB - OBJECTIVE: To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy. METHODS: Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy). RESULTS: There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities. CONCLUSIONS: The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential. PMID- 23461557 TI - Nursing intellectual capital theory: testing selected propositions. AB - AIMS: To test the selected propositions of the middle-range theory of nursing intellectual capital. BACKGROUND: The nursing intellectual capital theory conceptualizes nursing knowledge's influence on patient and organizational outcomes. The theory proposes nursing human capital, nurses' knowledge, skills and experience, is related to the quality of patient care and nurse recruitment and retention of an inpatient care unit. Two factors in the work environment, nurse staffing and employer support for nurse continuing professional development, are proposed to influence nursing human capital's association with patient and organizational outcomes. DESIGN: A cross-sectional survey design. METHODS: The study took place in 2008 in six Canadian acute care hospitals. Financial, human resource and risk data were collected from hospital departments and unit managers. Clearly specified empirical indicators quantified the study variables. The propositions of the theory were tested with data from 91 inpatient care units using structural equation modelling. RESULTS: The propositions associated with the nursing human capital concept were supported. The propositions associated with the employer support for nurse continuing professional development concept were not. The proposition that nurse staffing's influences on patient outcomes was mediated by the nursing human capital of an inpatient unit, was partially supported. CONCLUSION: Some of the theory's propositions were empirically validated. Additional theoretical work is needed to refine the operationalization and measurement of some of the theory's concepts. Further research with larger samples of data from different geographical settings and types of hospitals is required to determine if the theory can withstand empirical scrutiny. PMID- 23461558 TI - Carbonic anhydrase inhibitors: an editorial. AB - This issue of Expert Opinion on Therapeutic Patents is dedicated to carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs), a highly dynamic research topic in the last years. Several review articles and patent analyses on diuretics and antiglaucoma, antiepileptic, anti-obesity and anticancer agents belonging to the pharmacological class of the CAIs are presented, together with a review on bacterial, fungal and protozoan CAs and their inhibition as a novel means of designing anti-infectives. PMID- 23461559 TI - Method for differentiating left superior pulmonary vein exit conduction from pseudo-exit conduction. AB - BACKGROUND: Electrical isolation of pulmonary vein (PV) conduction from the left atrium (LA) is the cornerstone of successful atrial fibrillation (AF) ablation. Exit block is confirmed by the absence of LA capture during pacing from a circular mapping catheter positioned in the PV; however, far-field capture of the left atrial appendage (LAA) (pseudo-pulmonary vein exit conduction) can occur. In this study, we evaluated a methodology for identifying pseudo-exit conduction. METHODS AND RESULTS: A total of 135 consecutive AF patients undergoing PV isolation were studied. After circumferential ablation established PV entrance block, circumferential pacing (10 mA at 2.0 msec) was performed to assess exit block. In 16 (11.9%) patients, pacing the anterior poles of the left superior PV (LSPV) captured the LA. To differentiate true PV exit conduction from pseudo-exit conduction, the ablation catheter was positioned within the LAA during PV pacing. LAA activation preceding PV capture was consistent with far-field capture and this was confirmed by demonstrating local capture and exit block with decreasing pacing output. Using this approach, 14 patients (10.4%) were identified with pseudo-exit conduction. CONCLUSIONS: Due to the close proximity between the LSPV and LAA, pseudo-exit conduction is not uncommon and may lead to the erroneous conclusion that the LSPV is not isolated. Using this method to differentiate pseudo-exit conduction from true exit conduction should prevent unnecessary ablation after achievement of complete PV isolation. PMID- 23461560 TI - Patient specific simulation of body surface ECG using the finite element method. AB - BACKGROUND: Recent studies, supported by advances in computer science, have successfully simulated the excitation and repolarization processes of the heart, based on detailed cell models of electrophysiology and implemented with realistic morphology. METHODS: In this study, we extend these approaches to simulate the body surface electrocardiogram (ECG) of specific individuals. Patient-specific finite element models of the heart and torso are created for four patients with various heart diseases, based on clinical data including computer tomography, while the parallel multi-grid method is used to solve the dynamic bi-domain problem. Personalization procedures include demarcation of nonexcitable tissue, allocation of the failing myocyte model of electrophysiology, and modification of the excitation sequence. In particular, the adjustment of QRS morphology requires iterative computations, facilitated by the simultaneous visualization of the propagation of excitation in the heart, average QRS vector in the torso, and 12 lead ECG. RESULTS: In all four cases we obtained reasonable agreement between the simulated and actual ECGs. Furthermore, we also simulated the ECGs of three of the patients under bi-ventricular pacing, and once again successfully reproduced the actual ECG morphologies. Since no further adjustments were made to the heart models in the pacing simulations, the good agreement provides strong support for the validity of the models. CONCLUSIONS: These results not only help us understand the cellular basis of the body surface ECG, but also open the possibility of heart simulation for clinical applications. PMID- 23461561 TI - Bioturbo similarity searching: combining chemical and biological similarity to discover structurally diverse bioactive molecules. AB - Virtual screening using bioactivity profiles has become an integral part of currently applied hit finding methods in pharmaceutical industry. However, a significant drawback of this approach is that it is only applicable to compounds that have been biologically tested in the past and have sufficient activity annotations for meaningful profile comparisons. Although bioactivity data generated in pharmaceutical institutions are growing on an unprecedented scale, the number of biologically annotated compounds still covers only a minuscule fraction of chemical space. For a newly synthesized compound or an isolated natural product to be biologically characterized across multiple assays, it may take a considerable amount of time. Consequently, this chemical matter will not be included in virtual screening campaigns based on bioactivity profiles. To overcome this problem, we herein introduce bioturbo similarity searching that uses chemical similarity to map molecules without biological annotations into bioactivity space and then searches for biologically similar compounds in this reference system. In benchmark calculations on primary screening data, we demonstrate that our approach generally achieves higher hit rates and identifies structurally more diverse compounds than approaches using chemical information only. Furthermore, our method is able to discover hits with novel modes of inhibition that traditional 2D and 3D similarity approaches are unlikely to discover. Test calculations on a set of natural products reveal the practical utility of the approach for identifying novel and synthetically more accessible chemical matter. PMID- 23461563 TI - Chiral iron catalysts for asymmetric synthesis. PMID- 23461562 TI - Manganese-based layered coordination polymer: synthesis, structural characterization, magnetic property, and electrochemical performance in lithium ion batteries. AB - Manganese-based layered coordination polymer ([Mn(tfbdc)(4,4'-bpy)(H2O)2], Mn LCP) with microporous structure was synthesized by reaction of 2,3,5,6 tetrafluoroterephthalatic acid(H2tfbdc) and 4,4'-bipyridine(4,4'-bpy) with manganese(II) acetate tetrahydrate in water solution. Mn-LCP was characterized by elemental analysis, IR spectra, thermogravimetric analysis, X-ray single-crystal structure analysis, and powder X-ray diffraction. Magnetic susceptibility data from 300 to 1.8K show that there is a weak antiferromagnetic exchange between Mn(II) ions in Mn-LCP. As anode material, the Mn-LCP electrode exhibits an irreversible high capacity in the first discharge process and a reversible lithium storage capacity of up to about 390 mA h/g from the fourth cycle. It might provide a new method for finding new electrode materials in lithium-ion batteries. PMID- 23461564 TI - Adenoviral gene transfer of hepatic stimulator substance confers resistance against hepatic ischemia-reperfusion injury by improving mitochondrial function. AB - Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia-reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia-reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice. PMID- 23461566 TI - Vibrating H3(+) in a uniform magnetic field. AB - Potential energy surfaces are obtained for singlet H3(+) in magnetic fields of up to 2350 T. The magnetic interaction was treated by first-order perturbation theory and the interaction terms computed ab initio. They were then fitted to a functional form and added to a recent, highly accurate adiabatic potential energy surface. In its most stable orientation, the molecule is arranged such that the magnetic field vector is in the molecular plane. The most stable configuration is no longer D3h as in the field-free case, but C2v, though the stabilization energy is extremely small, of the order of 0.01 cm(-1) for a 2350 T field. Finally, we have calculated, for a range of magnetic field strengths and orientations, all the vibrational eigenvalues that are below the barrier to linearity in the field free case. PMID- 23461565 TI - Diversity and evolutionary relationships of T7-like podoviruses infecting marine cyanobacteria. AB - Phages are extremely abundant in the oceans, influencing the population dynamics, diversity and evolution of their hosts. Here we assessed the diversity and phylogenetic relationships among T7-like cyanophages using DNA polymerase (replication), major capsid (structural) and photosynthesis psbA (host-derived) genes from isolated phages. DNA polymerase and major capsid phylogeny divided them into two discrete clades with no evidence for gene exchange between clades. Clade A phages primarily infect Synechococcus while clade B phages infect either Synechococcus or Prochlorococcus. The major capsid gene of one of the phages from clade B carries a putative intron. Nearly all clade B phages encode psbA whereas clade A phages do not. This suggests an ancient separation between cyanophages from these two clades, with the acquisition or loss of psbA occurring around the time of their divergence. A mix and match of clustering patterns was found for the replication and structural genes within each major clade, even among phages infecting different host genera. This is suggestive of numerous gene exchanges within each major clade and indicates that core phage functions have not coevolved with specific hosts. In contrast, clustering of phage psbA broadly tracks that of the host genus. These findings suggest that T7-like cyanophages evolve through clade-limited gene exchanges and that different genes are subjected to vastly different selection pressures. PMID- 23461567 TI - The one-component system ArnR: a membrane-bound activator of the crenarchaeal archaellum. AB - Linking the motility apparatus to signal transduction systems enables microbes to precisely control their swimming behaviour according to environmental conditions. Bacteria have therefore evolved a complex chemotaxis machinery, which has presumably spread through lateral gene transfer into the euryarchaeal subkingdom. By contrast Crenarchaeota encode no chemotaxis-like proteins but are nevertheless able to connect external stimuli to archaellar derived motility. This raises fundamental questions about the underlying regulatory mechanisms. Recently, we reported that the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius becomes motile upon nutrient starvation by promoting transcription of flaB encoding the filament forming subunits. Here we describe two transcriptional activators as paralogous one-component-systems Saci_1180 and Saci_1171 (ArnR and ArnR1). Deletions of arnR and arnR1 resulted in diminished flaB expression and accordingly the deletion mutants revealed impaired swimming motility. We further identified two inverted repeat sequences located upstream of the flaB core promoter of S. acidocaldarius. These cis-regulatory elements were shown to be critical for ArnR and ArnR1 mediated flaB gene expression in vivo. Finally, bioinformatic analysis revealed ArnR to be conserved not only in Sulfolobales but also in the crenarchaeal order of Desulfurococcales and thus might represent a more general control mechanism of archaeal motility. PMID- 23461568 TI - Population drinking and drink driving in Norway and Sweden: an analysis of historical data 1957-89. AB - AIM: Research suggests an association between population drinking and a large number of outcomes. However, driving while under the influence of alcohol (DWI) is conspicuously absent from this list of outcomes. The aim of this study was to estimate the relation between DWI and total consumption of alcohol on annual time series data for Norway and Sweden. DESIGN, SETTING, AND MEASUREMENTS: For Norway, we used data on convictions for DWI per 100 000 inhabitants (aged 15-69 years). The DWI proxy for Sweden comprised the proportion (%) of all police-reported traffic accidents with personal injuries where the driver was under the influence of alcohol. Data on total alcohol sales in litres of pure alcohol per inhabitant (aged 15 years and older) were used as proxy for total alcohol consumption. We focused on the period 1957-89, during which the legislation concerning DWI remained unchanged in Norway as well as in Sweden. The statistical analyses were based on co-integrated models. FINDINGS: The estimates of the association between DWI and per capita alcohol consumption were strongly significant in Norway as well as in Sweden. For Norway, the estimated elasticity equalled 2 (P < 0.001) and for Sweden 1.5 (P < 0.001). CONCLUSIONS: In Norway and Sweden, as total population level of alcohol consumption increases or decreases so does the incidence of driving while intoxicated. PMID- 23461569 TI - Susceptibility to repeated, low-dose, rectal SHIVSF162P3 challenge is independent of TRIM5 genotype in rhesus macaques. AB - Infections following repeated, low-dose (RLD), mucal S(H)IV exposures of macaques are used to model sexual HIV exposures for biomedical prevention testing. Different susceptibilities among animals can complicate study designs. In rhesus macaques, TRIM5 alleles Q, CypA, and TFP are resistance factors for infection with some S(H)IV strains, but not for SIVmac239 due to its capsid properties. SIVmac239-derived SHIVSF162P3 has been demonstrated to reproducibly infect mucosally in vaginal and rectal RLD models. To further test the suitability of SHIVSF162P3 for RLD models, we studied the influence of the TRIM5 genotype on susceptibility to rectal RLD infection and on plasma viremia by analyzing 43 male Indian rhesus macaques from control arms of completed studies. The median number of exposures required for infection was three (Q/Q, n=4) (TRIM5 alleles, number of macaques, respectively), four (Q/CypA, n=7), three (TFP/Q, n=15), three (TFP/TFP, n=15), and two (TFP/CypA, n=2); TRIM5(CypA/CypA) was not represented in our study. Median peak viremia (log10 viral copies/ml) in infected animals was 7.4 (Q/Q, n=4), 7.2 (Q/CypA, n=6), 7.3 (TFP/Q, n=13), 7.1 (TFP/TFP, n=15), and 6.5 (TFP/CypA; n=2). Neither susceptibility nor peak viremia was significantly different (log rank test, Kruskal-Wallis test, respectively). Rhesus macaques' susceptibility to RLD SHIVSF162P3 is independent of the TRIM5 TFP, CypA, and Q alleles, with the limitation that the power to detect any impact of CypA/CypA and TFP/CypA genotypes was nonexistent or low, due to absence or infrequency, respectively. The finding that TRIM5 alleles do not restrict mucosal infection or ensuing replication rates suggests that SHIVSF162P3 is indeed suitable for RLD experimentation. PMID- 23461570 TI - A robust method for transcript quantification with RNA-seq data. AB - The advent of high throughput RNA-seq technology allows deep sampling of the transcriptome, making it possible to characterize both the diversity and the abundance of transcript isoforms. Accurate abundance estimation or transcript quantification of isoforms is critical for downstream differential analysis (e.g., healthy vs. diseased cells) but remains a challenging problem for several reasons. First, while various types of algorithms have been developed for abundance estimation, short reads often do not uniquely identify the transcript isoforms from which they were sampled. As a result, the quantification problem may not be identifiable, i.e., lacks a unique transcript solution even if the read maps uniquely to the reference genome. In this article, we develop a general linear model for transcript quantification that leverages reads spanning multiple splice junctions to ameliorate identifiability. Second, RNA-seq reads sampled from the transcriptome exhibit unknown position-specific and sequence-specific biases. We extend our method to simultaneously learn bias parameters during transcript quantification to improve accuracy. Third, transcript quantification is often provided with a candidate set of isoforms, not all of which are likely to be significantly expressed in a given tissue type or condition. By resolving the linear system with LASSO, our approach can infer an accurate set of dominantly expressed transcripts while existing methods tend to assign positive expression to every candidate isoform. Using simulated RNA-seq datasets, our method demonstrated better quantification accuracy and the inference of dominant set of transcripts than existing methods. The application of our method on real data experimentally demonstrated that transcript quantification is effective for differential analysis of transcriptomes. PMID- 23461571 TI - Charge group partitioning in biomolecular simulation. AB - Molecular simulation techniques are increasingly being used to study biomolecular systems at an atomic level. Such simulations rely on empirical force fields to represent the intermolecular interactions. There are many different force fields available--each based on a different set of assumptions and thus requiring different parametrization procedures. Recently, efforts have been made to fully automate the assignment of force-field parameters, including atomic partial charges, for novel molecules. In this work, we focus on a problem arising in the automated parametrization of molecules for use in combination with the GROMOS family of force fields: namely, the assignment of atoms to charge groups such that for every charge group the sum of the partial charges is ideally equal to its formal charge. In addition, charge groups are required to have size at most k. We show NP-hardness and give an exact algorithm that solves practical problem instances to provable optimality in a fraction of a second. PMID- 23461572 TI - LoopWeaver: loop modeling by the weighted scaling of verified proteins. AB - Modeling loops is a necessary step in protein structure determination, even with experimental nuclear magnetic resonance (NMR) data, it is widely known to be difficult. Database techniques have the advantage of producing a higher proportion of predictions with subangstrom accuracy when compared with ab initio techniques, but the disadvantage of also producing a higher proportion of clashing or highly inaccurate predictions. We introduce LoopWeaver, a database method that uses multidimensional scaling to achieve better, clash-free placement of loops obtained from a database of protein structures. This allows us to maintain the above-mentioned advantage while avoiding the disadvantage. Test results show that we achieve significantly better results than all other methods, including Modeler, Loopy, SuperLooper, and Rapper, before refinement. With refinement, our results (LoopWeaver and Loopy consensus) are better than ROSETTA, with 0.42 A RMSD on average for 206 length 6 loops, 0.64 A local RMSD for 168 length 7 loops, 0.81A RMSD for 117 length 8 loops, and 0.98 A RMSD for length 9 loops, while ROSETTA has 0.55, 0.79, 1.16, 1.42, respectively, at the same average time limit (3 hours). When we allow ROSETTA to run for over a week, it approaches, but does not surpass, our accuracy. PMID- 23461573 TI - Simultaneously learning DNA motif along with its position and sequence rank preferences through expectation maximization algorithm. AB - Although de novo motifs can be discovered through mining over-represented sequence patterns, this approach misses some real motifs and generates many false positives. To improve accuracy, one solution is to consider some additional binding features (i.e., position preference and sequence rank preference). This information is usually required from the user. This article presents a de novo motif discovery algorithm called SEME (sampling with expectation maximization for motif elicitation), which uses pure probabilistic mixture model to model the motif's binding features and uses expectation maximization (EM) algorithms to simultaneously learn the sequence motif, position, and sequence rank preferences without asking for any prior knowledge from the user. SEME is both efficient and accurate thanks to two important techniques: the variable motif length extension and importance sampling. Using 75 large-scale synthetic datasets, 32 metazoan compendium benchmark datasets, and 164 chromatin immunoprecipitation sequencing (ChIP-Seq) libraries, we demonstrated the superior performance of SEME over existing programs in finding transcription factor (TF) binding sites. SEME is further applied to a more difficult problem of finding the co-regulated TF (coTF) motifs in 15 ChIP-Seq libraries. It identified significantly more correct coTF motifs and, at the same time, predicted coTF motifs with better matching to the known motifs. Finally, we show that the learned position and sequence rank preferences of each coTF reveals potential interaction mechanisms between the primary TF and the coTF within these sites. Some of these findings were further validated by the ChIP-Seq experiments of the coTFs. The application is available online. PMID- 23461574 TI - Human fetal keratocytes have multipotent characteristics in the developing avian embryo. AB - The human cornea contains stem cells that can be induced to express markers consistent with multipotency in cell culture; however, there have been no studies demonstrating that human corneal keratocytes are multipotent. The objective of this study is to examine the potential of human fetal keratocytes (HFKs) to differentiate into neural crest-derived tissues when challenged in an embryonic environment. HFKs were injected bilaterally into the cranial mesenchyme adjacent to the neural tube and the periocular mesenchyme in chick embryos at embryonic days 1.5 and 3, respectively. The injected keratocytes were detected by immunofluorescence using the human cell-specific marker, HuNu. HuNu-positive keratocytes injected along the neural crest pathway were localized adjacent to HNK-1-positive migratory host neural crest cells and in the cardiac cushion mesenchyme. The HuNu-positive cells transformed into neural crest derivatives such as smooth muscle in cranial blood vessels, stromal keratocytes, and corneal endothelium. However, they failed to form neurons despite their presence in the condensing trigeminal ganglion. These results show that HFKs retain the ability to differentiate into some neural crest-derived tissues. Their ability to respond to embryonic cues and generate corneal endothelium and stromal keratocytes provides a basis for understanding the feasibility of creating specialized cells for possible use in regenerative medicine. PMID- 23461576 TI - Analytical methodology for determination of organic aerosol functional group distributions. AB - Secondary organic aerosol (SOA) particles result from the condensation of oxidized volatile organic compounds (VOC) and consist of a complex mixture that is not conducive to complete compositional analysis. We present a simple methodology for determining the quantities of aldehydes and ketones, alcohols, and carboxylic acids in such samples via derivatization and high-performance liquid chromatography (HPLC) with ultraviolet-visible absorption detection and tandem mass spectrometry (MS/MS). Useful concentration ranges are presented with an examination of the specificity of these compounds in multiply substituted systems. Such data are valuable in modeling the formation of laboratory-generated aerosols and in identifying point sources of field-collected aerosol samples. Calibration curves on standard samples, MS/MS transitions, including collisionally induced dissociation (CID) products, and a quantitative examination of the specificity of the derivatization reagents toward multiple functional groups are presented for a series of aliphatic standard samples. These methods are then applied to filter extracts from SOA derived from 1-iodooctane photolysis at 254 nm to demonstrate the methodology on a complex system. Ultimately, this methodology enables the measurement of variations in the chemical nature of the oxygen within an SOA particle, providing a distribution of functional group concentrations. PMID- 23461575 TI - Long-term outcome of chronic hepatitis C after sustained virological response to interferon-based therapy. AB - BACKGROUND: Although the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear. AIM: To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post SVR. METHODS: The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE). RESULTS: Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5 years post therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12 years post SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (152-27 U/L), AST (87-24 U/L), alkaline phosphatase (78-69 U/L), IgG (1463-1113 mg/dL), platelet count (209 000-239 000/MUL) and AST to platelet count ratio index (APRI: 1.31-0.33). TE was performed in 69 patients and was normal (<7.0 kPA) in 60%, moderately elevated (7.1-13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (P < 0.001). CONCLUSIONS: In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma. PMID- 23461578 TI - Shape-control and electrocatalytic activity-enhancement of Pt-based bimetallic nanocrystals. AB - Due to the increasing worldwide energy demand and environ-mental concerns, the need for alternative energy sources is growing stronger, and platinum catalysts in fuel cells may help make the technologies a reality. However, the pursuit of highly active Pt-based electrocatalysts continues to be a challenge. Scientists developing electrocatalysts continue to focus on characterizing and directing the construction of nanocrystals and advancing their electrochemical applications. Although chemists have worked on Pt-based bimetallic (Pt-M) preparations in the past, more recent research shows that both shape-controlled Pt-M nanocrystals and the assembly of these nanocrystals into supercrystals are promising new directions. A solution-based synthesis approach is an effective technique for preparing crystallographic facet-directed nanocatalysts. This is aided by careful selection of the metal precursor, capping ligand, reducing agent, and solvent. Incorporating a secondary metal M into the Pt lattice and manipulating the crystal facets on the surface cooperatively alter the electrocatalytic behavior of these Pt-M bimetallic nanocrystals. Specifically, chemists have extensively studied the {111}- and {100}-terminated crystal facets because they show unique atomic arrangement on surfaces, exhibit different catalytic performance, and possess specific resistance to toxic adsorbed carbon monoxide (COads). For catalysts to have maximum efficiency, they need to have resistance to COads and other poisonous carbon-containing intermediates when the catalysts operate under harsh conditions. A necessary design to any synthesis is to clearly understand and utilize the role of each component in order to successfully induce shape controlled growth. Since chemists began to understand Pt nanocrystal shape dependent electrocatalytic activity, the main obstacles blocking proton exchange membrane fuel cells are anode poisoning, sluggish kinetics at the cathode, and low activity. In this Account, we discuss the basic concepts in preparation of Pt M bimetallic nanocrystals, focusing on several immaculate examples of manipulation at the nanoscale. We briefly introduce the prospects for applying Pt M nanocrystals as electrocatalysts based on the electronic and geometric standpoints. In addition, we discuss several key parameters in the solution-based synthesis approach commonly used to facilitate Pt-M nanocrystals, such as reaction temperature and time, the combination of organic amines and acids, gaseous adsorbates, anionic species, and solvent. Each example features various nanoscale morphologies, such as spheres, cubes, octahedrons, and tetrahedrons. Additionally, we outline and review the superior electrocatalytic performances of the recently developed high-index Pt-M nanostructures. Next, we give examples of the electrocatalytic capabilities from these shape-defined Pt-M architectures by highlighting significant accomplishments in specific systems. Then, using several typical cases, we summarize electrochemical evaluations on the Pt-based shape /composition-dependent nanocatalysts toward reactions on both the anode and the cathode. Lastly, we provide an outlook of current challenges and promising directions for shape-controlled Pt-M bimetallic electrocatalysts. PMID- 23461579 TI - Orthogonal functionalization of cyclopenta[hi]aceanthrylenes. AB - A synthetic strategy to prepare 2,7- or 4,9-functionalized cyclopenta[hi]aceanthrylenes that are capable of Suzuki cross-coupling reactions is demonstrated. This method has been utilized to create a series of thiophene derivatized compounds that were subsequently used to investigate the role of substitution pattern on the photophysical and electronic properties of cyclopenta[hi]aceanthrylenes. The orthogonal functionalization provides access to unique substitution patterns (e.g., cruciform-like architectures) and materials with small optical band gaps (1.22-1.97 eV). PMID- 23461580 TI - Experimental insights into age-exacerbated cognitive dysfunction after peripheral surgery. AB - Here I comment on the recent contribution by Barrientos et al. J. Neurosci. 32, 14641-14648 (2012) addressing treatment possibilities for surgery-induced cognitive dysfunction. It has been over 15 years since the publication of a landmark study that indicated age as a major risk factor for postoperative cognitive dysfunction (POCD) (Moller et al., Lancet 351, 857-861 1998). With increasing life expectancy, surgical procedures conducted in elderly persons are becoming more common. The prevalence of POCD may mean that some patients will exchange the incapacitating condition that led them to surgery in the first instance for another such condition, which has been created by the surgical procedure itself. The report by Barrientos and collaborators (2012) is a timely and welcome study that further examines treatment possibilities for surgery induced cognitive dysfunction. Future studies should address issues such as intensity and onset of inflammation within the brain and additional treatments possibilities beyond IL-1-ra. PMID- 23461581 TI - Incremental costs of treating tetanus with intrathecal antitetanus immunoglobulin. AB - OBJECTIVE: To estimate the incremental cost of delivering intrathecal tetanus immunoglobulin compared to an intramuscular option. METHODS: To compare the two interventions, costs were estimated using standard cost methodology. Cost categories were personnel, overhead, consumables, antibiotics to treat infection, gases for respiratory assistance and immunoglobulin. Tetanus patients, aged 12 years or older, who were part of a randomised controlled clinical trial conducted in a referral hospital in Recife, Brazil, were allocated to two groups: a control group (58) and a study group (62). Patients allocated to the control group received 3000 international units (IU) of human immunoglobulin, with preservative, intramuscularly. The study group received the same quantity of immunoglobulin also intramuscularly plus an intrathecal dose of 1000 IU of a human immunoglobulin, free of preservatives, to prevent irritation of the meninges and avoid the need for corticosteroids. Thus, the difference between the two groups was the exclusive use of intrathecal immunoglobulin. The outcome measurements were clinical progression, hospital stay, respiratory assistance and respiratory infection. RESULTS: Delivering intrathecal immunoglobulin to patients saved a total of US$ 60 389, in a 10-day intensive care treatment, by preventing a worsening of their tetanus severity (e.g. from Grade I to Grades II, III, IV). Substantial cost saving was also observed in terms of hospital stay (US$ 173 104). CONCLUSIONS: Intrathecal treatment of tetanus is cost saving. This intervention deserves consideration by doctors and decision-makers as a mean of saving resources while maintaining high-quality health outcomes. PMID- 23461582 TI - Antiepileptic drugs and high prevalence of low bone mineral density in a group of inpatients with chronic epilepsy. AB - PURPOSE: Long-term antiepileptic drug use is associated with low bone mineral density (BMD), fractures and abnormalities in bone metabolism. We aimed at determining the prevalence of bone mineral disorders in patients with refractory epilepsy treated with antiepileptic drugs. METHODS: A cross-sectional survey was conducted in adult patients (n = 205) from a residential unit of a tertiary epilepsy centre. Screening for bone mineral disorders was performed with dual energy X-ray absorptiometry (DXA) scan of spine and hip (including bone mineral density and vertebral fracture assessment) and laboratory measurements. Patient information regarding demography, epilepsy characteristics and medication use was recorded. Based on DXA T-scores, prevalence of bone mineral disorders (osteopenia and osteoporosis) was calculated. Correlations between DXA T-scores and epilepsy parameters were explored. RESULTS: Of the 205 patients, there were 10 dropouts. 80% (n = 156/195) of the patients had low BMD: 48.2% had osteopenia and 31.8% had osteoporosis. Of those having low BMD, 51.9% (n = 81/195) was between 18 and 50 years. The T-score of the femoral neck correlated significantly with total duration of epilepsy, cumulative drug load and history of fractures. Linear regression analysis showed that of the epilepsy-related parameters, only cumulative drug load significantly predicted low femoral neck T-score (P = 0.001). CONCLUSION: In this high-risk population, we obtained a very high prevalence of 80% of low BMD. Both men and women were affected as well as patients <50 years of age. This study illustrates the magnitude of the problem of bone mineral disorders in chronic epilepsy. PMID- 23461583 TI - A comparative reliability and performance study of different stent designs in terms of mechanical properties: foreshortening, recoil, radial force, and flexibility. AB - This study seeks to improve the mechanical performance of stents by conducting reliability performance testing and finite element method (FEM)-based simulations for coronary stents. Three commercially available stent designs and our own new design were tested to measure the factors affecting performance, specifically foreshortening, recoil, radial force, and flexibility. The stents used in the present experiments were 3 mm in working diameter and 18 mm of working length. The results of the experiments indicate that the foreshortening of stents A, B, C, and our new design, D, was equivalent to 2.25, 0.67, 0.46, and 0.41%, respectively. The recoil of stents A, B, C, and D was 6.00, 4.35, 3.50, and 4.36%, respectively. Parallel plate radial force measurements were A, 3.72 +/- 0.28 N; B, 3.81 +/- 0.32 N; C, 4.35 +/- 0.18 N; and D, 4.02 +/- 0.24 N. Radial forces determined by applying uniform pressure in the circumferential direction were A, 28.749 +/- 0.81 N; B, 32.231 +/- 1.80 N; C, 34.522 +/- 3.06 N; and D, 42.183 +/- 2.84 N. The maximum force of crimped stent at 2.2-mm deflection was 1.01 +/- 0.08 N, 0.82 +/- 0.08 N, 0.92 +/- 0.12 N, and 0.68 +/- 0.07 N for each of stents A, B, C and D. The results of this study enabled us to identify several factors to enhance the performance of stents. In comparing these stents, we found that our design, stent D, which was designed by a collaborative team from seven universities, performed better than the commercial stents across all parameter of foreshortening, recoil, radial force, and flexibility. PMID- 23461584 TI - RET inhibition: implications in cancer therapy. AB - INTRODUCTION: The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas. AREA COVERED: The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers. EXPERT OPINION: Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted. PMID- 23461585 TI - Synthesis of mixed ceramic Mg(x)Zn(1-x)O nanofibers via Mg2+ doping using sol-gel electrospinning. AB - We report on the synthesis of tuned energy band gap Mg(x)Zn(1-x)O nanofibers (NFs) with different Mg(2+) content via the sol-gel electrospinning (ES) technique wherein the addition of the doping material affects not only the morphologies of as-spun ZnAc/PVA and MgAc/ZnAc/PVA nanofibers but also the crystal microstructure and optical properties of calcined ZnO and Mg(x)Zn(1-x)O nanofibers. Following an appropriate aqueous solution preparation of magnesium acetate (MgAc) and zinc acetate (ZnAc) with poly(vinyl alcohol) (PVA), electrospinning is performed and then as-spun nanofibers are calcined in an air atmosphere at 600 degrees C for 3 h. As-spun and calcined nanofiber diameters and morphologies are evaluated with scanning (SEM) and transmission (TEM) electron microscopies, whereas crystalline microstructural interpretations of ZnO and Mg(x)Zn(1-x)O are conducted with wide-angle X-ray diffraction spectra (XRD). Surface chemical composition and elemental evaluation of calcined nanofibers are examined with X-ray photoelectron spectroscopy (XPS), and optical properties and crystal defect analyses of the calcined nanofibers are conducted with photoluminescence spectra (PL). We observe a sharp reduction in fiber diameter upon calcination as a result of the removal of organic species from the fibers and conversion of ceramic precursors into ceramic nanofibers, and the appearance of a range of fiber morphologies from "bead in a string" to "sesame seed" coverage depending on fiber composition. Because Zn(2+) and Mg(2+) have similar ionicity and atomic radii, some Zn(2+) atoms are replaced by Mg(2+) atoms in the crystals, leading to a change in the properties of crystal lattices. The band gap energy of the calcined fibers increases significantly with addition of Mg(2+) along with an increase in the ultraviolet (UV) photoluminescence emission of the fibers. PMID- 23461586 TI - Nitro-Mannich reaction. PMID- 23461587 TI - Geometric and electronic structures of manganese-substituted iron superoxide dismutase. AB - The active-site structures of the oxidized and reduced forms of manganese substituted iron superoxide dismutase (Mn(Fe)SOD) are examined, for the first time, using a combination of spectroscopic and computational methods. On the basis of electronic absorption, circular dichroism (CD), magnetic CD (MCD), and variable-temperature variable-field MCD data obtained for oxidized Mn(Fe)SOD, we propose that the active site of this species is virtually identical to that of wild-type manganese SOD (MnSOD), with both containing a metal ion that resides in a trigonal bipyramidal ligand environment. This proposal is corroborated by quantum mechanical/molecular mechanical (QM/MM) computations performed on complete protein models of Mn(Fe)SOD in both its oxidized and reduced states and, for comparison, wild-type (WT) MnSOD. The major differences between the QM/MM optimized active sites of WT MnSOD and Mn(Fe)SOD are a smaller (His)N-Mn-N(His) equatorial angle and a longer (Gln146(69))NH...O(sol) H-bond distance in the metal-substituted protein. Importantly, these modest geometric differences are consistent with our spectroscopic data obtained for the oxidized proteins and high-field electron paramagnetic resonance spectra reported previously for reduced Mn(Fe)SOD and MnSOD. As Mn(Fe)SOD exhibits a reduction midpoint potential (E(m)) almost 700 mV higher than that of MnSOD, which has been shown to be sufficient for explaining the lack of SOD activity displayed by the metal subtituted species (Vance, C. K.; Miller, A. F. Biochemistry 2001, 40, 13079 13087), E(m)'s were computed for our experimentally validated QM/MM optimized models of Mn(Fe)SOD and MnSOD. These computations properly reproduce the experimental trend and reveal that the drastically elevated E(m) of the metal substituted protein stems from a larger separation between the second-sphere Gln residue and the coordinated solvent in Mn(Fe)SOD relative to MnSOD, which causes a weakening of the corresponding H-bond interaction in the oxidized state and alleviates steric crowding in the reduced state. PMID- 23461588 TI - Serum anti-neuronal antibodies in amyotrophic lateral sclerosis. AB - We aimed to investigate various anti-neuronal antibodies in sera of amyotrophic lateral sclerosis (ALS) patients to detect possible autoimmune encephalitis patients imitating ALS findings and to delineate the validity of routine screening of well-characterized anti-neuronal antibodies in ALS. The patients fulfilling the revised El Escorial diagnostic criteria for definite ALS were included. Their serum samples were investigated for antiganglioside (IgM/IgG) and onconeural (IgG) antibodies by immunoblotting, for ion channel antibodies (IgG) by a cell-based assay and for IgG binding patterns to the rat brain by indirect immunohistochemistry. Thirty-five patients with definite ALS and 30 healthy individuals were included. Ganglioside antibodies were detected in 2 out of 35 (5.7%) patients with ALS. The onconeural and ion channel antibodies were negative in our series. Varied serum IgG binding patterns were identified in eight (22.9%) patients. Although autoimmune encephalitis patients may occasionally present with atypical motor neuron disease findings, definite ALS patients do not appear to exhibit onconeural or ion channel antibodies, suggesting that routine analysis of these antibodies in typical ALS is not mandatory. By contrast, some ALS patients display anti-neuronal antibodies against undetermined target antigens, prompting investigation of these novel antibodies with more advanced methods. PMID- 23461589 TI - Effects of immunosuppression on circulating adeno-associated virus capsid specific T cells in humans. AB - In humans adeno-associated virus (AAV)-mediated gene transfer is followed by expansion of AAV capsid-specific T cells, evidence of cell damage, and loss of transgene product expression, implicating immunological rejection of vector transduced cells, which may be prevented by immunosuppressive drugs. We undertook this study to assess the effect of immunosuppression (IS) used for organ transplantation on immune responses to AAV capsid antigens. Recipients of liver or kidney transplants were tested before and 4 weeks after induction of IS in comparison with matched samples from healthy human adults and an additional cohort with comorbid conditions similar to those of the transplant patients. Our data show that transplant patients and comorbid control subjects have markedly higher frequencies of circulating AAV capsid-specific T cells compared with healthy adults. On average, IS resulted in a reduction of AAV-specific CD4+ T cells, whereas numbers of circulating CD8+ effector and central memory T cells tended to increase. Independent of the type of transplant or the IS regimens, the trend of AAV capsid-specific T cell responses after drug treatment varied; in some patients responses were unaffected whereas others showed decreases or even pronounced increases, casting doubt on the usefulness of prophylactic IS for AAV vector recipients. PMID- 23461590 TI - Effect of allergen inhalation on airway oxidant stress, using exhaled breath condensate 8-isoprostane, in mild asthma. AB - OBJECTIVE: Exhaled breath condensate (EBC) 8-isoprostane concentrations are increased in asthma, but it is not known if they acutely change following bronchoprovocation. The objective of this study was to evaluate EBC 8-isoprostane concentrations following allergen-induced bronchoprovocation in asthma. METHODS: This comparison study included eight mild atopic asthmatics and six controls. Asthmatics were challenged with inhaled specific allergen, methacholine, and irrelevant allergen in random order. Controls were challenged with irrelevant allergen. EBCs collected at 0, 3, 6, 9, and 23 hours by the R-tube method were measured for 8-isoprostanes by ELISA technique. Repeated measures ANOVA technique was used for analysis. RESULTS: EBC 8-isoprostane concentrations did not change following any inhalational challenge, as compared to baseline, in either asthmatics or controls. CONCLUSIONS: EBC 8-isoprostane concentrations do not acutely change following bronchoprovocation in subjects with mild asthma. PMID- 23461592 TI - Systemic AA amyloidosis as a unique manifestation of a combined mutation of TNFRSF1A and MEFV genes. AB - We report the case of a 22-year-old Caucasian woman presenting with a new-onset nephrotic syndrome with normal renal function during the 35th week of pregnancy. AA (secondary) amyloidosis was further diagnosed at the renal biopsy. Extensive genetic testing revealed that the patient was heterozygous for both TNFRSF1A p.R92Q and MEFV p.M694I mutations leading to an autoinflammatory syndrome characterized by amyloid deposition as the sole manifestation. PMID- 23461591 TI - Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening. AB - Kappa-opioid (KOP) receptor agonists exhibit analgesic effects without activating reward pathways. In the search for nonaddictive opioid therapeutics and novel chemical tools to study physiological functions regulated by the KOP receptor, we screened in silico its recently released inactive crystal structure. A selective novel KOP receptor agonist emerged as a notable result and is proposed as a new chemotype for the study of the KOP receptor in the etiology of drug addiction, depression, and/or pain. PMID- 23461593 TI - A solitary mediastinal mass due to localized AL amyloidosis: case report and review of the literature. AB - AL amyloidosis presenting as a solitary mediastinal mass is a rare occurrence, with only a few cases reported in the literature. We describe a case of a man presenting with a mediastinal mass diagnosed as amyloidosis, confirmed by mass spectrometry to consist of lambda light chains. Here we review the literature and discuss treatment options for this rare entity. PMID- 23461594 TI - Ventricular tachycardia ablation as first line therapy: are we there yet? PMID- 23461595 TI - Synthetic biology: lessons from engineering yeast MAPK signalling pathways. AB - All living cells respond to external stimuli and execute specific physiological responses through signal transduction pathways. Understanding the mechanisms controlling signalling pathways is important for diagnosing and treating diseases and for reprogramming cells with desired functions. Although many of the signalling components in the budding yeast Saccharomyces cerevisiae have been identified by genetic studies, many features concerning the dynamic control of pathway activity, cross-talk, cell-to-cell variability or robustness against perturbation are still incompletely understood. Comparing the behaviour of engineered and natural signalling pathways offers insight complementary to that achievable with standard genetic and molecular studies. Here, we review studies that aim at a deeper understanding of signalling design principles and generation of novel signalling properties by engineering the yeast mitogen-activated protein kinase (MAPK) pathways. The underlying approaches can be applied to other organisms including mammalian cells and offer opportunities for building synthetic pathways and functionalities useful in medicine and biotechnology. PMID- 23461596 TI - Nasolacrimal system obstruction, ptosis and esotropia due to chemotherapy in acute lymphoblastic leukemia. AB - Eight-year-old girl was admitted to our clinic with the complaint of constant epiphora in the right eye. It was reported that this complaint began after the start of chemotherapy with a diagnosis of Acute Lymphoblastic Leukemia (ALL) about 5 years ago. In addition, eyelid ptosis associated with esotropia also occurred during that period. We found that nasolacrimal duct obstruction did not improve with medical treatment but ptosis and esotropia improved with pyridoxine and pyridostigmine treatment during that period. Examination of the eye on admission revealed nasolacrimal duct obstruction on the right side. Other ocular findings were normal. Nasolacrimal system obstruction, ptosis and esotropia combination has not been reported previously in patients using systemic drugs or receiving chemotherapy due to ALL. PMID- 23461597 TI - Ultrabroadband photonic structures to achieve high-performance daytime radiative cooling. AB - If properly designed, terrestrial structures can passively cool themselves through radiative emission of heat to outer space. For the first time, we present a metal-dielectric photonic structure capable of radiative cooling in daytime outdoor conditions. The structure behaves as a broadband mirror for solar light, while simultaneously emitting strongly in the mid-IR within the atmospheric transparency window, achieving a net cooling power in excess of 100 W/m(2) at ambient temperature. This cooling persists in the presence of significant convective/conductive heat exchange and nonideal atmospheric conditions. PMID- 23461598 TI - Quantitative physiology of Lactococcus lactis at extreme low-growth rates. AB - This paper describes the metabolic adaptation of Lactococcus lactis during the transition from a growing to a non-growing state using retentostat cultivation. Under retentostat cultivation, the specific growth rate decreased from 0.025 h( 1) to 0.0001 h(-1) in 42 days, while doubling time increased to more than 260 days. Viability of the overall culture was maintained above 90% but included approximately 20% damaged cells, which had lost their colony forming capacity on solid media. Although culture biomass and viability had reached a steady-state after 14 days of retentostat cultivation, the morphology of the cells changed from coccus-to-rod shape at later stages of retentostat cultivation, by which the cell's surface to volume ratio was estimated to increase 2.4-fold. Furthermore, the metabolic patterns switched between homolactic and mixed-acid fermentation during the retentostat cultivation. Retentostat cultivation enabled the calculation of accurate substrate- and energy-related maintenance coefficients and biomass yields under non-growing conditions, which were in good agreement with those calculated by extrapolation from chemostat cultivations at high dilution rates. In this study, we illustrate how retentostat cultivation allows decoupling of growth and non-growth associated processes in L. lactis, enabling the analysis of quantitative physiological responses of this bacterium to near zero-specific growth rates. PMID- 23461599 TI - Preeradication vaccine policy options for poliovirus infection and disease control. AB - With the circulation of wild poliovirus (WPV) types 1 and 3 continuing more than a decade after the original goal of eradicating all three types of WPVs by 2000, policymakers consider many immunization options as they strive to stop transmission in the remaining endemic and outbreak areas and prevent reintroductions of live polioviruses into nonendemic areas. While polio vaccination choices may appear simple, our analysis of current options shows remarkable complexity. We offer important context for current and future polio vaccine decisions and policy analyses by developing decision trees that clearly identify potential options currently used by countries as they evaluate national polio vaccine choices. Based on a comprehensive review of the literature we (1) identify the current vaccination options that national health leaders consider for polio vaccination, (2) characterize current practices and factors that appear to influence national and international choices, and (3) assess the evidence of vaccine effectiveness considering sources of variability between countries and uncertainties associated with limitations of the data. With low numbers of cases occurring globally, the management of polio risks might seem like a relatively low priority, but stopping live poliovirus circulation requires making proactive and intentional choices to manage population immunity in the remaining endemic areas and to prevent reestablishment in nonendemic areas. Our analysis shows remarkable variability in the current national polio vaccine product choices and schedules, with combination vaccine options containing inactivated poliovirus vaccine and different formulations of oral poliovirus vaccine making choices increasingly difficult for national health leaders. PMID- 23461601 TI - Slow photoelectron velocity-map imaging spectroscopy of cold thiozonide (S3(-)). AB - We report high-resolution anion photoelectron spectra of thiozonide (S3(-)) acquired by slow electron velocity-map imaging (SEVI). The ions were cryogenically cooled within an ion trap before photodetachment. We measure an electron affinity of 2.3630(9) eV, resolving discrepancies in previously reported photoelectron spectra that resulted from the presence of vibrational hot bands. The SEVI spectrum shows well-resolved, extended vibrational progressions in the symmetric stretch and bending modes of S3, yielding accurate frequencies for both. PMID- 23461602 TI - Brainstem excitability is not influenced by blood lactate levels. AB - The influence of blood lactate on brainstem excitability was tested by using the blink reflex (BR) recovery cycle on 18 sprinters. Blood lactate was measured before maximal cycling, at the end, as well as 5 and 10 min after the exhaustion. Blood lactate was associated with a decrement of R2 whereas only small changes were observed after an intravenous infusion of lactate. It seems, therefore, that lactate influences BR mainly by acting at the cortical level. PMID- 23461603 TI - Blue-emitting butterfly-shaped 1,3,5,9-tetraarylpyrenes: synthesis, crystal structures, and photophysical properties. AB - The first example of aryl-functionalized, butterfly-shaped, highly fluorescent and stable blue-emitting monomers, namely, 7-tert-butyl-1,3,5,9-tetrakis(p-R phenyl)pyrenes, were synthesized by the Suzuki-Miyaura cross-coupling reaction from a novel bromide precursor of 1,3,5,9-tetrabromo-7-tert-butylpyrene. The crystal structures and optical and electronic properties have been investigated. PMID- 23461604 TI - Cysteine-assisted tailoring of adsorption properties and particle size of polymer and carbon spheres. AB - A series of cysteine-stabilized phenolic resin-based polymer and carbon spheres were prepared by the modified Stober method. Cysteine plays a very important role in the proposed one-pot synthesis of the aforementioned spheres; namely, it acts as a particle stabilizer and a source of heteroatoms (nitrogen and sulfur) that can be introduced into these spheres. The diameter of these spheres can be tuned in the range of 70-610 nm by adjusting the cysteine amount and reaction temperature. Since polymer spheres obtained in the presence of cysteine contain sulfur and nitrogen heteroatoms, they were tested for adsorption of copper ions. It is shown that adsorption isotherms recorded for copper ions can be well fitted by Langmuir equation, giving unprecedented adsorption capacities up to ~65 mg/g. PMID- 23461605 TI - Use of polyetheretherketone as a material for solid phase extraction of hydroxylated metabolites of polycyclic aromatic hydrocarbons in human urine. AB - In this study, a novel application of polyetheretherketone (PEEK) tubing for solid phase extraction (SPE) of urinary hydroxylated metabolites of polycyclic aromatic hydrocarbons (OH-PAHs) is presented. The use of PEEK tubing for extracting nine OH-PAHs (2-5 rings) from different matrixes (e.g., urine, acid/enzymatic hydrolysis solution) was demonstrated; a facile method for fast (<2 min) quantification of urinary 1-hydroxypyrene (1-OHPyr) was also developed by the use of PEEK tubing extraction coupled to electrospray ionization tandem mass spectrometry (ESI-MS/MS). Although no optimization was performed for the extraction process, a limit of detection (LOD) as low as 0.01 MUg L(-1) was obtained, and the ratio of signal intensity of 1-OHPyr to that of 1-OHPyr-d9 (internal standard) was linearly related with the 1-OHPyr concentration over the range of 0.05-5.00 MUg L(-1) (R(2) = 0.9995). Satisfactory recoveries (87-91%) were achieved, and less than 2 min was required to carry out the whole analytical procedure including sample pretreatment and mass spectrometric detection. In a biomonitoring study, the PEEK tubing extraction based method was successfully applied to the quantification of 1-OHPyr in eight human urine samples, further confirming the potential of PEEK tubing for SPE of organic compounds. PMID- 23461606 TI - Monounsaturated fatty acid aerobic synthesis in Bradyrhizobium TAL1000 peanut nodulating is affected by temperature. AB - AIMS: The aim of this work was to clarify the mechanism of monounsaturated fatty acid (MUFA) synthesis in Bradyrhizobium TAL1000 and the effect of high temperature on this process. METHODS AND RESULTS: Bradyrhizobium TAL1000 was exposed to a high growth temperature and heat shock, and fatty acid composition and synthesis were tested. To determine the presence of a possible desaturase, a gene was identify and overexpressed in Escherichia coli. The desaturase expression was detected by RT-PCR and Western blotting. In B. TAL1000, an aerobic mechanism for MUFA synthesis was detected. Desaturation was decreased by high growth temperature and by heat shock. Two hours of exposure to 37 degrees C were required for the change in MUFA levels. A potential ?9 desaturase gene was identified and successfully expressed in E. coli. A high growth temperature and not heat shock reduced transcript and protein desaturase levels in rhizobial strain. CONCLUSIONS: In B. TAL1000, the anaerobic MUFA biosynthetic pathway is supplemented by an aerobic mechanism mediated by desaturase and is down-regulated by temperature to maintain membrane fluidity under stressful conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: This knowledge will be useful for developing strategies to improve a sustainable practice of this bacterium under stress and to enhance the bioprocess for the inoculants' manufacture. PMID- 23461607 TI - Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis. AB - OBJECTIVE: To characterize the relationship between motor resting-state connectivity of the dorsal pre-motor cortex (PMd) and clinical disability in patients with multiple sclerosis (MS). MATERIALS AND METHODS: A total of 27 patients with relapsing-remitting MS (RR-MS) and 15 patients with secondary progressive MS (SP-MS) underwent functional resting-state magnetic resonance imaging. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Independent component analysis was used to characterize motor resting-state connectivity. Multiple regression analysis was performed in SPM8 between the individual expression of motor resting-state connectivity in PMd and EDSS scores including age as covariate. Separate post hoc analyses were performed for patients with RR-MS and SP-MS. RESULTS: The EDSS scores ranged from 0 to 7 with a median score of 4.3. Motor resting-state connectivity of left PMd showed a positive linear relation with clinical disability in patients with MS. This effect was stronger when considering the group of patients with RR-MS alone, whereas patients with SP-MS showed no increase in coupling strength between left PMd and the motor resting-state network with increasing clinical disability. No significant relation between motor resting-state connectivity of the right PMd and clinical disability was detected in MS. CONCLUSIONS: The increase in functional coupling between left PMd and the motor resting-state network with increasing clinical disability can be interpreted as adaptive reorganization of the motor system to maintain motor function, which appears to be limited to the relapsing-remitting stage of the disease. PMID- 23461608 TI - Emergence of salsa and guacamole as frequent vehicles of foodborne disease outbreaks in the United States, 1973-2008. AB - Fresh salsa and guacamole often contain diced raw produce, are often made in large batches, and are often poorly refrigerated, which may make them prone to contamination that can cause foodborne illness. The safety of salsa and guacamole is increasingly important as these foods gain popularity. Since 1973, local, state, and territorial health departments have voluntarily reported foodborne disease outbreaks to the Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System (FDOSS) using a standard reporting form. FDOSS used paper-based reporting for 1973-1997 and switched to electronic reporting for 1998-2008. We reviewed all reports of outbreaks during 1973-2008 in which salsa or guacamole was reported as a vehicle. We found 136 outbreaks in which salsa or guacamole was reported as a possible vehicle, which resulted in 5,658 illnesses. Of these 136 salsa- or guacamole-associated (SGA) outbreaks additional possible food vehicles were reported for 33 (24%) outbreaks. There were no SGA outbreaks reported before 1984. Among reported outbreaks, most were caused by norovirus (24%), nontyphoidal Salmonella (19%), and Shigella (7%). Eighty-four percent of outbreaks were caused by foods prepared in restaurants or delis; of these, 19% reported ill foodworkers, and 29% reported improper storage as possible contributing factors. Among all foodborne disease outbreaks with a reported food vehicle during 1984-1997, 26 (0.9%) of 2,966 outbreaks were SGA, and during 1998-2008, 110 (1.4%) of 7,738 outbreaks were SGA. The number of reported foodborne disease outbreaks attributable to salsa or guacamole increased in the United States from 1984 to 2008, especially in later years, and especially in restaurants. Fresh salsa and guacamole require careful preparation and storage. Focused prevention strategies should reduce the risk of illness and ensure that these foods are enjoyed safely. PMID- 23461609 TI - Response of intestinal microbiota to antibiotic growth promoters in chickens. AB - Antibiotic growth promoters (AGPs) have been used as feed additives to improve average daily weight gain and feed efficiency in food animals for more than five decades. However, use of AGPs is associated with the emergence of antibiotic resistant human pathogens of animal origin, posing a significant threat to food safety and public health. Thus, development of novel alternatives to AGPs is important to mitigate antimicrobial resistance in foodborne pathogens. To achieve this goal, the mode of action of AGPs should be elucidated. In this study, the response of the chicken gut microbiota to AGPs was examined using two culture independent approaches: phospholipid fatty acid (PLFA) biomarker analysis and 16S rDNA clone library sequencing. PLFA analysis showed that AGP tylosin treatment changed composition of the microbiota in various intestinal sites; however, total viable bacterial biomass in intestine was not affected by tylosin treatment. PLFA analysis also revealed an abundant viable fungal population in chicken microbiota. Eight 16S rDNA libraries (96 clones per library) were constructed using ileal samples from chickens that received either antibiotic-free or medicated feed. The 16S rDNA clone analysis of the growth-relevant samples showed the AGP treatment influenced the diversity of ileum microbiota in the chickens primarily in the Firmicutes division. In particular, Lactobacillus spp. populations in the ileum of AGP-treated chickens were significantly lower than those from chickens receiving antibiotic-free feed. Together, this study revealed novel features of the intestinal microbiota in response to AGP treatment and suggested approach to develop potential alternatives to AGPs for mitigation of antimicrobial resistance in foodborne pathogens. PMID- 23461610 TI - Anticoagulation with fondaparinux for hemodiafiltration in patients with heparin induced thrombocytopenia: dose-finding study and safety evaluation. AB - The optimal anticoagulation regimen for hemodialysis (HD) in patients with heparin-induced thrombocytopenia (HIT) has not been defined. Hemodiafiltration (HDF) adds a large convective component to HD, thereby changing the pharmacokinetics of most anticoagulants. Data on coagulation regimens for HDF are scant. We therefore aimed to study the feasibility, effectiveness, tolerability, and pharmacokinetics of fondaparinux anticoagulation in HDF. This was a prospective observational dose-finding study. Patients were started on fondaparinux at a dose of 0.05 mg/kg postdialysis body weight. Per protocol dose escalation was performed when significant clotting was observed and reduced when the anti-Xa activity postdialysis exceeded 0.4 IU/mL. Dose adjustments were made by steps of 0.01 mg/kg postdialysis weight. Anti-Xa activity was measured using a chromogenic method calibrated with low-molecular-weight heparin and validated against fondaparinux-calibrated anti-Xa activity. Four patients with HIT were followed for 160 sessions in total. At the end of the dose titration study, three patients ended at a maintenance dose of 0.03 mg/kg and one patient at 0.04 mg/kg of fondaparinux. Significant bleeding attributable to fondaparinux did not occur. The occurrence of clotting increased parallel to the reduction of fondaparinux dose, from 0/53 and 0/15 sessions at the higher doses (0.04 and 0.05 mg/kg) to 3/75 (4%) at 0.03 mg/kg and 1/17 (6%) at 0.02 mg/kg. Fondaparinux may be safely used and provides adequate anticoagulation for HDF in patients with HIT. We recommend to adjust dosage of fondaparinux to body weight and to initiate therapy at a dose of 0.03 mg/kg to prevent accumulation. Dose titration can be achieved by targeting postdialysis anti-Xa activity. PMID- 23461611 TI - North America and South America (NA-SA) neuropathy project. AB - Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV 1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America. PMID- 23461612 TI - Immunological studies of reactive oxygen species damaged catalase in patients with systemic lupus erythematosus: correlation with disease activity index. AB - OBJECTIVES: This study was undertaken to investigate the status and contribution of oxidized catalase in systemic lupus erythematosus (SLE) and to explore whether oxidized catalase has a role in disease progression. METHODS: Catalase (CAT) was modified by reactive oxygen species (ROS). Sera from 50 SLE patients with varying levels of disease activity according to SLE Disease-Activity-Index (SLEDAI) and 45 age- and sex-matched healthy controls were evaluated for antibodies against oxidized CAT. RESULTS: Serum analysis showed significantly higher level of anti oxidized-CAT-antibodies in SLE patients compared with controls. Interestingly, not only was there an increased number of subjects positive for anti-oxidized-CAT antibodies, but also the levels of these antibodies were significantly higher among SLE patients, whose SLEDAI scores were >= 10 as compared with lower SLEDAI scores (<10). In addition, significant correlation was observed between the levels of anti-oxidized-CAT-antibodies and SLEDAI score (r = 0.796). Furthermore, sera from SLE patients had lower levels of CAT activity compared with control sera. CONCLUSIONS: These findings support an association between oxidized CAT and SLE. The stronger response observed in serum samples from patients with higher SLEDAI scores suggests that oxidized CAT may be a useful biomarker in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis. PMID- 23461614 TI - Visual sensor for the detection of trace Cu(II) ions using an immunochromatographic strip. AB - A rapid and simple immunochromatography method based on a gold nanoparticle labeled monoclonal antibody was developed for the on-site detection of copper (Cu) in water samples. This monoclonal antibody, obtained by a cell fusion technique, recognized the Cu-ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA) complex, but not metal-free EDTA, with high sensitivity and specificity. In optimized conditions, the visual limit of detection for qualitative detection of Cu(II) ions was 10 ng/mL and the LOD for semi-quantitative detection decreased to 0.45 ng/mL with the help of a scanning reader system. The detection process was achieved within 10 min with no cross-reactivity from other heavy metal ions. The recovery of the test samples ranged from 98% to 109%. To our knowledge, this antibody-based test strip for Cu(II) ions has not been previously reported. Based on the above results, this strip sensor could be used as an alternative tool for screening heavy metal pollution in the environment. PMID- 23461615 TI - Effects of green tea polyphenols on iodide-induced autoimmune thyroiditis in nonobese diabetic mice. AB - Because green tea polyphenols (GTPs) possess anti-inflammatory properties and are effective in inhibiting autoimmune diseases in experimental settings, we examined whether GTPs prevented the development of autoimmune thyroiditis in iodide treated nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis (HT). Mice were given 0.05% iodide water or iodide water supplemented with 0.2% GTPs for 8 weeks. GTPs administration led to an enhanced production of interleukin-10 by concanavalin A-stimulated splenocytes but did not interfere with thyroiditis development. Serum thyroxine levels were not influenced by GTPs. Our data suggest that administration of GTPs may not be an effective strategy for the prevention of HT. PMID- 23461613 TI - CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor. AB - During chronic viral infections, responses by virus-specific CD8(+) T cells become marginalized by the acquisition of functional defects and reduced cell numbers in a process defined as T cell exhaustion. Similarly, T cell tolerance to self-antigen is also characterized by impaired effector function and eventual deletion of self-reactive T cells. Induction of both tolerance and exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective in these distinct environments. We previously demonstrated that tolerant self-reactive CD8(+) T cells expressing dual-T cell receptors (i.e., dual-TCR) could be rescued by immunization through a second TCR specific for a foreign antigen. These data revealed that T cell tolerance was regulated at the level of the self-reactive TCR. Here, dual-TCR CD8(+) T cells were used to examine if exhaustion during persistent viral infection could be rescued by an analogous strategy of immunization through a second TCR not involved in recognition of virus. In direct contrast to the rescue achievable in tolerant CD8(+) T cells, exhausted T cells were equally impaired through both TCR. These findings suggest that exhaustion is maintained by defects downstream of the virus specific TCR, and establish that exhaustion and tolerance are distinctly regulated states of T cell dysfunction. PMID- 23461616 TI - Association between brain-derived neurothropic factor variants and asthma in Chinese Han children. AB - AIM: To identify the markers contributing to genetic susceptibility to asthma in Chinese Han children. METHODS: This study examined the potential association between childhood asthma and seven single nucleotide polymorphisms of Brain derived Neurotrophic Factor (BDNF) - SNPs, rs16917204, rs6265, rs7103873, rs16917237, rs56164415, rs13306221 and rs10767664 - using the MassARRAY system. The participants, recruited between May 2009 and July 2012, were 319 children with asthma (mean age 9.82 +/- 1.57 years) recruited from a hospital paediatric department and 309 healthy controls (mean age 10.25 +/- 1.36 years), recruited from the medical examination centre at the same hospital. RESULTS: We observed a significant association for rs6265 (chi(2) = 9.851, p = 0.002, OR = 1.427, 95% CI = 1.143-1.783), located in exon 4 of the BDNF. Another potential association was observed for rs13306221 (chi(2) = 4.316, p = 0.038, OR = 1.604, 95% CI = 1.024-2.512) in the promoter region of the BDNF. Strong linkage disequilibrium was observed in block 1 (D' > 0.9). Significantly more G-G-G haplotypes in block 1 were found in children with asthma. CONCLUSIONS: These findings point to a role for BDNF polymorphisms in Chinese Han children with asthma and may inform future genetic or biological studies on childhood asthma. PMID- 23461617 TI - Mechanisms underlying the varied mammary carcinogenicity of the environmental pollutant 6-nitrochrysene and its metabolites (-)-[R,R]- and (+)-[S,S]-1,2 dihydroxy-1,2-dihydro-6-nitrochrysene in the rat. AB - The mechanisms that can account for the remarkable mammary carcinogenicity of the environmental pollutant 6-nitrochrysene (6-NC) in the rat remain elusive. In our previous studies, we identified several 6-NC-derived DNA adducts in the rat mammary gland; one major adduct was derived from (+/-)-trans-1,2-dihydroxy-1,2 dihydro-6-nitrochrysene (1,2-DHD-6-NC). In the present study, we resolved the racemic (+/-)-1,2-DHD-6-NC into (-)-[R,R]- and (+)-[S,S]-1,2-DHD-6-NC and compared their in vivo mutagenicity and carcinogenicity in the mammary glands of female transgenic (BigBlue F344 * Sprague-Dawley)F1 rats harboring lacI/cII and Sprague-Dawley rats, respectively. Both [R,R]- and [S,S]-isomers exerted similar mutagenicity and carcinogenicity but were less potent than 6-NC. Additional in vivo and in vitro studies were then performed to explore possible mechanisms that can explain the higher potency of 6-NC than 1,2-DHD-6-NC. Using ELISA, we found that neither 6-NC nor 1,2-DHD-6-NC increased the levels of several inflammatory cytokines in plasma obtained from rats 24 h after treatment. In MCF-7 cells, as determined by immunoblotting, the effects of 6-NC and 1,2-DHD-6-NC on protein expression (p53, Akt, p38, JNK, c-myc, bcl-2, PCNA, and ERbeta) were comparable; however, the expressions of AhR and ERalpha proteins were decreased by 6-NC but not 1,2-DHD-6-NC. The expression of both receptors was decreased in mammary tissues of rats treated with 6-NC. Our findings suggest that the differential effects of 6-NC and 1,2-DHD-6-NC on AhR and ERalpha could potentially account for the higher carcinogenicity of 6-NC in the rat mammary gland. PMID- 23461619 TI - Tuning the structure and magnetism of heterometallic sodium(1+)-cobalt(2+) formate coordination polymers by varying the metal ratio and solvents. AB - Three new heterometallic formate coordination polymers formulated as [Na2Co(HCOO)4]infinity (1), [NaCo(HCOO)3]infinity (2), and [Na2Co7(HCOO)16]infinity (3) were obtained by adjusting the solvent and ratio of the reactants. In 1, a (4,4) cobalt formate layer is formed and the sodium ions connect the layers to form a three-dimensional (3D) framework. In 2, each formate ligand binds two Co(2+) and two Na(+) ions with a syn,syn,anti,anti coordination mode to form a chrial network with 4,6-connected topology. 3 is a Na(+)-ion linked 3D framework based on the cobalt formate layer, which has a 10-membered metal ring. Magnetic studies indicate the existence of ferromagnetic interactions between adjacent Co(2+) ions in 1, while dominating antiferromagnetic couplings in 2 and 3. PMID- 23461618 TI - Noninvasive fibrosis indices predict intrahepatic distant recurrence of hepatitis B-related hepatocellular carcinoma following radiofrequency ablation. AB - BACKGROUNDS & AIMS: Intrahepatic recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) occurs as a result of direct dissemination or de novo oncogenesis. Hepatocellular carcinogenesis is related to the progression of cirrhosis, and noninvasive fibrosis scoring systems reflect the severity of hepatic fibrosis. Hence, the aim of this study was to elucidate the correlation between noninvasive fibrosis indices and intrahepatic distant recurrence (IDR) of HCC after RFA. METHODS: Patients with hepatitis B virus (HBV)-related, solitary HCC undergoing RFA were prospectively enrolled. Noninvasive serum fibrosis indices were calculated at the time of RFA. IDR was defined as recurrent HCC beyond >2 cm from the ablation margin of RFA. Predictors of IDR and overall survival were analysed by a Cox regression model. RESULTS: Two hundred forty-six patients received RFA as initial treatment, and the median follow-up duration was 19.7 months (IQR, 11.9-29.8). Among these cases, 133 (45.9%) showed IDR after RFA. In multivariable analysis, serum alpha-fetoprotein (AFP) (HR, 1.000; 95% CI, 1.000-1.001; P = 0.001) and age-platelet index (API) (1.19; 1.01-1.39; P = 0.033) were independent predictors of IDR. In particular, patients with API <=7 showed a significantly higher recurrence-free survival rate than patients with API >7 (P = 0.004). With regard to overall survival, male sex (4.69; 1.52-14.52; P = 0.007), serum bilirubin (2.78; 1.31-5.90; P = 0.008) and AFP (1.000; 1.000-1.001; P = 0.006) were significantly correlated with shortened survival. CONCLUSION: High levels of AFP and API predict IDR of HBV-related HCC after RFA. Therefore, noninvasive fibrosis indices could play an important role in predicting IDR of HCC following percutaneous ablation. PMID- 23461620 TI - Renal transplantation in Nepal: beginning of a new era! AB - AIM: To assess the first year outcomes in terms of patient survival rate, graft survival rate and secondary outcomes after starting the first live related renal transplant in Tribhuvan University Teaching Hospital, Nepal. METHODS: A retrospective analysis was done of the first 70 renal transplants, who have completed a minimum of 1 year of follow up. All recipients were on Tacrolimus, Mycophenolate Mofetil, and corticosteroids. RESULTS: Patient and graft survival rate at the end of one year was 94.3% (95% confidence interval (CI) 86.2-97.8). Mean serum creatinine and estimated glomerular filtration rate at 1 year was 115 +/- 25 MUmol/L (range 63-192) and 66 +/- 15 mL/min per 1.73 m2 (range 37-102) respectively. Twenty-two episodes of biopsy proven acute rejection occurred in 18 recipients (25.7%). Three patients (4.2%) had acute tubular necrosis; however, only one (1.4%) had delayed graft function. One patient, with focal segmental glomerulosclerosis had recurrence of native kidney disease. Thirty-two episodes of urinary tract infection were observed in 22 recipients (31.4%), and Escherichia coli was the most commonly isolated organism, 17 (53.1%) out of 32 episodes. New onset diabetes mellitus after transplant occurred in 16 recipients (22.8%). CONCLUSION: One-year patient survival, graft survival and secondary outcomes of our kidney transplant recipients, with our limited facilities, were within acceptable limits. PMID- 23461621 TI - Synthesis of biotinylated episilvestrol: highly selective targeting of the translation factors eIF4AI/II. AB - Silvestrol (1) and episilvestrol (2) are protein synthesis inhibitors, and the former has shown efficacy in multiple mouse models of cancer; however, the selectivity of these potent cytotoxic natural products has not been described. Herein, it is demonstrated that eukaryotic initiation factors eIF4AI/II were the only proteins detected to bind silvestrol (1) and biotinylated episilvestrol (9) by affinity purification. Our study demonstrates the remarkable selectivity of these promising chemotherapeutics. PMID- 23461622 TI - Human SAA1-derived amyloid deposition in cell culture: a consistent model utilizing human peripheral blood mononuclear cells and serum-free medium. AB - Amyloid A (AA) amyloidosis is a fatal disease caused by extracellular deposition of fibrils derived from serum AA (SAA). AA amyloid fibril formation has previously been modeled in macrophage cultures using highly amyloidogenic mouse SAA1.1, but attempts to do the same with human SAA invariably failed. Our objective was to define conditions that support human SAA-derived amyloid formation in peripheral blood mononuclear cell (PBMC) cultures. Two conditions were found to be critical - omission of fetal calf serum and use of StemPro34, a lipid-enriched medium formulated for hematopoietic progenitor cells. Cultures maintained in serum-free StemPro34 and provided with recombinant human SAA1 in the complete absence of amyloid-enhancing factor exhibited amyloid deposition within 7 d. Amyloid co-localized with cell clusters that characteristically included cells of fibrocytic/dendritic morphology as well as macrophages. These cells formed networks that appeared to serve as scaffolding within and upon which amyloid accumulated. Cells in amyloid-forming cultures demonstrated increased adherence, survival and expression of extracellular matrix components. Of the three human SAA1 isoforms, SAA1.3 showed the most extensive amyloid deposition, consistent with it being the most prevalent isoform in Japanese patients with AA amyloidosis. Attesting to the reproducibility and general applicability of this model, amyloid formation has been documented in cultures established from eight PBMC donors. PMID- 23461623 TI - The effects of caffeic acid phenethyl ester in acute methanol toxicity on rat retina and optic nerve. AB - PURPOSE: We aimed to test caffeic acid phenethyl ester (CAPE) as an antidote for acute methanol (MeOH) toxicity and to compare it with ethanol. METHODS: This study included five groups, each containing eight rats. The groups were control, methotrexate (MTX), MeOH, ethanol and CAPE. All rats except control group were treated with intraperitoneal (i.p.) MTX (0.3 mg/kg/d) for 7 d. At the 8th day of the experiment, i.p. injection of MeOH (3 g/kg) was administered in MeOH, ethanol and CAPE groups. Four hours after MeOH treatment, 0.5 g/kg ethanol was injected i.p. in ethanol group; 10 MUmol/kg CAPE i.p. in CAPE group; serum physiologic i.p. in other groups. After 8 h, rats were anaesthetized and sacrificed. Total anti-oxidant status (TAS), total oxidant status (TOS) were measured on the dissected and excised retina and optic nerve samples. Fellow eyes were used for histopathologic evaluation and the cell count of retinal ganglion cell (RGC) layer. In addition, interactions of alcohol dehydrogenase with CAPE, ethanol, MeOH and pyrazole derivatives were investigated. RESULTS: Either CAPE or ethanol co-treatment decreased the TOS levels and increased the TAS levels compared to the MeOH group. MeOH treatment decreased the mean cell count in RGC layer. CAPE co-treatment significantly prevented cell loss (p = 0.040). Besides, in silico calculations showed that binding affinity of CAPE to alcohol dehydrogenase was higher than those of MeOH, ethanol, and pyrazole derivatives were. CONCLUSION: This study demonstrated that CAPE treatment decreased the oxidative stress in acute MeOH intoxication in the retina and optic nerve; beside that, protected RGC layer histology. In silico, CAPE had higher affinity score than MeOH, ethanol, pyrazole and pyrazole derivatives in the case of interaction with alcohol dehydrogenase. PMID- 23461624 TI - Phylogenetic detection of novel Cryptomycota in an Iowa (United States) aquifer and from previously collected marine and freshwater targeted high-throughput sequencing sets. AB - Fungi are everywhere and interact with humans in countless ways, but a large group of fungi called 'Cryptomycota' has escaped detection until very recently. Still, the extent of diversity and ecological habits of this group remain largely unknown. We interrogated publically available 18S rRNA gene datasets, obtained via high-throughput sequencing from marine and freshwater samples, for Cryptomycota sequences. Contrary to previous work, we found evidence of substantial Cryptomycota diversity in the marine upper water column. Additionally, we produced a sequencing set from a groundwater aquifer, an environment unrepresented among 18S rRNA gene pyrosequencing sets. The Cryptomycota community in this aquifer sample appears distinct from the community in both freshwater and marine environments with evidence of a unique aquifer clade. This study significantly expands the boundary of known Cryptomycota sequence diversity and characterizes the phylogenetic distribution of this diversity in aquatic environments. Furthermore, the approach utilized is generalizable to discovery of novel micro-eukaryotic diversity from any lineage. PMID- 23461625 TI - Drugs on the internet, part IV: Google's Ngram viewer analytic tool applied to drug literature. AB - Google Inc.'s digitized book library can be searched based on key words and phrases over a five-century time frame. Application of the Ngram Viewer to drug literature was assessed for its utility as a research tool. The results appear promising as a method for noting changes in the popularity of specific drugs over time, historical epidemiology of drug use and misuse, and adoption and regulation of drug technologies. PMID- 23461626 TI - Nurse-patient interaction is a resource for hope, meaning in life and self transcendence in nursing home patients. AB - BACKGROUND: Spiritual dimensions such as hope, meaning in life and self transcendence have been found to be predictors of successful ageing, life satisfaction and well-being in older individuals. Connectedness and communicating with others have been seen to facilitate hope, meaning in life and self transcendence among nursing home patients. AIMS: This study aimed to investigate the associations between hope, meaning in life, self-transcendence and nurse patient interaction in a nursing home population. DESIGN AND METHODS: A cross sectional design was employed, collecting data in 44 different Norwegian nursing homes (NHs) from 250 patients who met the inclusion criteria. Approval by all regulatory institutions dealing with research issues in Norway and the Management Unit at the 44 NHs was obtained. A sample of 202 cognitively intact nursing home patients responded to the Herth Hope Index, the Purpose in Life test, the Self Transcendence Scale and the Nurse-Patient Interaction Scale. A structural equation model (SEM) of the hypothesized relationships between the constructs was tested. RESULTS: The SEM model fit well with the present data. Significant direct relationships of nurse-patient interaction on hope, meaning in life and self transcendence were displayed. Meaning and the interconnectedness dimension of hope appeared to be particularly dynamic resources, revealing significant influences on all the constructs in the SEM model tested. CONCLUSION: Nurse patient interaction influences hope, meaning in life and self-transcendence in cognitively intact nursing home patients and might be an important resource in relation to patients' health and global well-being. Thus, care providers are above all fundamental for nursing home patients. Advancing caregivers' interacting and communicating skills might facilitate patients' health and global well-being and inspire professional caregivers as they perform their daily care practices. More research of the effectiveness of such strategies is greatly needed. LIMITATIONS: The SEM model tested comprised 20 variables, indicating a desirable sample size of n = 200, while the present effective sample was n = 187. Also, cross-sectional data do not allow making conclusion on the causality. PMID- 23461627 TI - Substrate level control of the local doping in graphene. AB - Graphene exfoliated onto muscovite mica is studied using ultrahigh vacuum scanning tunneling microscopy (UHV-STM) techniques. Mica provides an interesting dielectric substrate interface to measure the properties of graphene due to the ultraflat nature of a cleaved mica surface and the surface electric dipoles it possesses. Flat regions of the mica surface show some surface modulation of the graphene topography (24 pm) due to topographic modulation of the mica surface and full conformation of the graphene to that surface. In addition to these ultraflat regions, plateaus of varying size having been found. A comparison of topographic images and STS measurements show that these plateaus are of two types: one with characteristics of water monolayer formation between the graphene and mica, and the other arising from potassium ions trapped at the interfacial region. Immediately above the water induced plateaus, graphene is insulated from charge doping, while p-type doping is observed in areas adjacent to these water nucleation points. However, above and in the neighborhood of interfacial potassium ions, only n-type doping is observed. Graphene regions above the potassium ions are more strongly n-doped than regions adjacent to these alkali atom plateaus. Furthermore, a direct correlation of these Fermi level shifts with topographic features is seen without the random charge carrier density modulation observed in other dielectric substrates. This suggests a possible route to nanoscopic control of the local electron and hole doping in graphene via specific substrate architecture. PMID- 23461628 TI - (+)-Laburnamine, a natural selective ligand and partial agonist for the alpha4beta2 nicotinic receptor subtype. AB - (+)-Laburnamine (1), a rare alkaloid extracted from Laburnum anagyroides seeds (~4 mg from 1 kg), was shown to bind with high affinity (Ki, 293 nM) to the alpha4beta2 nicotinic receptor subtype, which is, respectively, 126 and 136 times higher than to the alpha3beta4 (Ki 37 MUM) and alpha7 subtypes (Ki 40 MUM). When its ability to release [(3)H]-dopamine from striatal slices was tested in a functional assay, compound 1 behaved as a partial agonist with an EC50 of 5.8 MUM and an Emax that was 43% that of nicotine. When incubated with nicotine in the same assay, 1 prevented a maximal effect from being reached. PMID- 23461629 TI - Synthesis and optical properties of pyrrolo[3,2-b]pyrrole-2,5(1H,4H)-dione (iDPP) based molecules. AB - We describe the synthesis and photophysical properties of a series of derivatives of pyrrolo[3,2-b]pyrrole-2,5(1H,4H)-dione-3,6-diyl (iDPP) linked to two oligothiophenes of variable length (nT). The iso-DPP-oligothiophenes (iDPPnTs) differ from the common pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione-3,6-diyl oligothiophene analogues (DPPnTs) by a different orientation of the two lactam rings in the bicyclic iDPP unit compared to DPP. In contrast to the highly fluorescent DPPnTs, the new isomeric iDPPnTs exhibit only very weak fluorescence. We demonstrate with the help of quantum-chemical calculations that this can be attributed to a different symmetry of the lowest excited state in iDPPnT (A in C2 symmetry) compared to DPPnTs (B) and the corresponding loss in oscillator strength of the lowest energy transition. Upon extending the oligothiophene moiety in the iDPPnTs molecules, the charge transfer character of the lowest A excited state becomes more pronounced. This tends to preclude high fluorescence quantum yields even in extended iDPPnTs systems. PMID- 23461630 TI - The acute effects of hemorrhagic shock on cerebral blood flow, brain tissue oxygen tension, and spreading depolarization following penetrating ballistic-like brain injury. AB - Traumatic brain injury (TBI) often occurs in conjunction with additional trauma, resulting in secondary complications, such as hypotension as a result of blood loss. This study investigated the combined effects of penetrating ballistic-like brain injury (PBBI) and hemorrhagic shock (HS) on physiological parameters, including acute changes in regional cerebral blood flow (rCBF), brain tissue oxygen tension (P(bt)O2), and cortical spreading depolarizations (CSDs). All recordings were initiated before injury (PBBI/HS/both) and maintained for 2.5 h. Results showed that PBBI alone and combined PBBI and HS produced a sustained impairment of ipsilateral rCBF that decreased by 70% from baseline (p<0.05). Significant and sustained reductions in P(bt)O2 (50% baseline; p<0.05) were also observed in the injured hemisphere of the animals subjected to both PBBI and HS (PBBI+HS). In contrast, PBBI alone produced smaller, more transient reductions in P(bt)O2 levels. The lower limit of cerebral autoregulation was significantly higher in the PBBI+HS group (p<0.05, compared to HS alone). Critically, combined injury resulted in twice the number of spontaneous CSDs as in PBBI alone (p<0.05). It also lowered the propagation speed of CSD and the threshold of CSD occurrence [induced CSD at higher mean arterial pressure (MAP)]. However, rCBF and P(bt)O2 were not responsive to the depolarizations. Our data suggest that PBBI together with HS causes persistent impairment of CBF and brain tissue oxygen tension, increasing the probability of CSDs that likely contribute to secondary neuropathology and compromise neurological recovery. PMID- 23461631 TI - UV/vis and NIR light-responsive spiropyran self-assembled monolayers. AB - Self-assembled monolayers of a 6-nitro BIPS spiropyran (SP) modified with a disulfide-terminated aliphatic chain were prepared on polycrystalline gold surfaces and characterized by UV/vis absorption, surface-enhanced Raman scattering (SERS), and X-ray photoelectron spectroscopies (XPS). The SAMs obtained are composed of the ring-closed form (i.e., spiropyran) only. Irradiation with UV light results in conversion of the monolayer to the merocyanine form (MC), manifested in the appearance of an N(+) contribution in the N 1s region of the XPS spectrum of the SAMs, the characteristic absorption band of the MC form in the visible region at 555 nm, and the C-O stretching band in the SERS spectrum. Recovery of the initial state of the monolayer was observed both thermally and after irradiation with visible light. Several switching cycles were performed and monitored by SERS spectroscopy, demonstrating the stability of the SAMs during repeated switching between SP and MC states. A key finding in the present study is that ring-opening of the surface-immobilized spiropyrans can be induced by irradiation with continuous wave NIR (785 nm) light as well as by irradiation with UV light. We demonstrate that ring-opening by irradiation at 785 nm proceeds by a two-photon absorption pathway both in the SAMs and in the solid state. Hence, spiropyran SAMs on gold can undergo reversible photochemical switching from the SP to the MC form with both UV and NIR and the reverse reaction induced by irradiation with visible light or heating. Furthermore, the observation of NIR-induced switching with a continuous wave source holds important consequences in the study of photochromic switches on surfaces using SERS and emphasizes the importance of the use of multiple complementary techniques in characterizing photoresponsive SAMs. PMID- 23461632 TI - Poor level of agreement on the management of postoperative pancreatic fistula: results of an international survey. AB - OBJECTIVES: The occurrence of postoperative pancreatic fistula (POPF) is the main cause of severe complications, including death, after pancreatic surgery. This study was conduced to evaluate current practice in the management of POPF after Whipple surgery and distal pancreatectomy (DP). METHODS: An online survey endorsed by the European-African Hepato-Pancreato-Biliary Association (E-AHPBA) was conducted among surgical departments active in pancreatic surgery. A total of 108 centres were contacted by e-mail. The survey focused on the use and timing of drainage, nutrition strategies, provision of somatostatin and antibiotic therapies, imaging strategy and indications for reoperation when POPF is diagnosed after pancreatic surgery. RESULTS: A total of 55 centres (51%) completed the survey. Overall, responses showed poor agreement among centres (Fleiss' kappa: <0.40) on 89% of items after Whipple surgery and 78% of items after DP. There was very poor or no agreement (Fleiss' kappa: <0.1) on postoperative strategies for the management of nutrition and use of somatostatin after both procedures. In the event of POPF, 42% of centres used total oral nutrition and 22% used somatostatin after Whipple surgery, and 71% used total oral nutrition and 31% used somatostatin after DP. There were significant disagreements between units conducting, respectively, more and fewer than 50 Whipple procedures per year on drain removal after DP, and imaging strategy and patient discharge after Whipple surgery and DP. CONCLUSIONS: This survey discloses important disagreements worldwide regarding the management of POPF after both Whipple surgery and DP. The standardized management of POPF would better facilitate the comparison of outcomes in future trials. PMID- 23461633 TI - Initial experiences in robot-assisted middle pancreatectomy. AB - OBJECTIVES: Initial results in robot-assisted middle pancreatectomy (MP) have been encouraging. However, data comparing outcomes of robot-assisted MP with those of open MP are limited. The aim of this study was to compare outcomes in patients undergoing open and robot-assisted MP, respectively. METHODS: Outcomes in an initial experience with seven consecutive patients undergoing robot assisted MP were compared with those in 36 patients undergoing open MP. RESULTS: The robot-assisted MP group included five women and two men with a median age of 55 years (range: 30-62 years). Median tumour size, operative time and blood loss were 3.0 cm (range: 0.5-5.0 cm), 210 min (range: 150-330 min) and 200 ml (range: 50-400 ml), respectively. Pancreaticogastrostomy was performed in all patients. No transfusion was given intraoperatively. Pathological examination revealed five serous cystic neoplasms, one mixed-type intraductal papillary mucinous neoplasm and one lipoma. Five patients experienced postoperative pancreatic fistula and one experienced post-pancreatectomy haemorrhage. No operative mortality was noted. Compared with the open MP group, the robot-assisted MP group demonstrated a shorter median length of postoperative gastrointestinal tract recovery [2 days (range: 2-3 days) versus 4 days (range: 2-11 days); P = 0.001]. CONCLUSIONS: Robot-assisted MP can be performed safely with satisfactory efficacy; patients experienced faster gastrointestinal tract recovery compared with patients undergoing open surgery. PMID- 23461634 TI - Measuring kinetic isotope effects in enzyme reactions using time-resolved electrospray mass spectrometry. AB - Kinetic isotope effect (KIE) measurements are a powerful tool for studying enzyme mechanisms; they can provide insights into microscopic catalytic processes and even structural constraints for transition states. However, KIEs have not come into widespread use in enzymology, due in large part to the requirement for prohibitively cumbersome experimental procedures and daunting analytical frameworks. In this work, we introduce time-resolved electrospray ionization mass spectrometry (TRESI-MS) as a straightforward, precise, and inexpensive method for measuring KIEs. Neither radioisotopes nor large amounts of material are needed and kinetic measurements for isotopically "labeled" and "unlabeled" species are acquired simultaneously in a single "competitive" assay. The approach is demonstrated first using a relatively large isotope effect associated with yeast alcohol dehydrogenase (YADH) catalyzed oxidation of ethanol. The measured macroscopic KIE of 2.19 +/- 0.05 is consistent with comparable measurements in the literature but cannot be interpreted in a way that provides insights into isotope effects in individual microscopic steps. To demonstrate the ability of TRESI-MS to directly measure intrinsic KIEs and to characterize the precision of the technique, we measure a much smaller (12)C/(13)C KIE associated specifically with presteady state acylation of chymotrypsin during hydrolysis of an ester substrate. PMID- 23461635 TI - Aspects of nitrogen-fixing Actinobacteria, in particular free-living and symbiotic Frankia. AB - Studies of nitrogen-fixing properties among the Gram-positive Actinobacteria revealed that some species of Arthrobacter, Agromyces, Corynebacterium, Mycobacterium, Micromonospora, Propionibacteria and Streptomyces have nitrogen fixing capacity. This is also valid for Frankia that fix nitrogen both in free living and in symbiotic conditions. Frankia symbiosis results from interaction between the Frankia bacteria and dicotyledonous plants, that is, actinorhiza. These plants, which are important in forestry and agroforestry, form, together with the legumes (Fabales), a single nitrogen-fixing clade. It has been shown that a receptor-like kinase gene, SymRK, is necessary for nodulation in actinorhizal plants as well as in legumes and arbuscular mycorrhizal fungi. Recently, the involvement of isoflavonoids as signal molecules during nodulation of an actinorhizal plant was shown. The genome sizes of three Frankia species, Frankia EANpec, ACN14a and CcI3, are different, revealing a relationship between genome size and geographical distribution. Recent genomic sequencing data of Frankia represent genomes from cluster I to IV, indicating that the genome of DgI is one of the smallest genomes in Frankia. In addition, nonsymbiotic Frankiales such as Acidothermus cellulolyticus, Blastococcus saxoobsidens, Geodermatophilus obscurus and Modestobacter marinus have a variety of genome sizes ranging from 2.4 to 5.57 Mb. PMID- 23461637 TI - Increased emphasis on darkness and rejection of a diameter criterion represent paradigm shifts in the clinical diagnosis of melanoma. PMID- 23461638 TI - Effects of epidural anesthesia on acute and chronic pain after coronary artery bypass grafting. AB - OBJECTIVE: To evaluate the effects of thoracic epidural anesthesia (TEA) as an adjunct to general anesthesia (GA) on postoperative pain after coronary artery bypass grafting (CABG). METHODS: Between April 2009 and March 2010, 40 patients with ischemic heart disease scheduled for elective CABG were prospectively randomized to receive either GA (n = 20) or GA + TEA (n = 20). Through epidural catheters, patients received an infusion of (10-20 mg/h) 0.25%-bupivacaine intraoperatively and during the first 24 hours after surgery. Study endpoints included assessment of postoperative pain at rest and with coughing, rescue analgesic need, and postoperative course. RESULTS: The differences in pain scores were decreased at rest during 6 (0.1 +/- 0.3 vs. 2.4 +/- 1.8; p < 0.05) and 12 hours (0.1 +/- 0.3 vs. 3.9 +/- 2.3; p < 0.05) and with coughing at 6 (0.1 +/- 0.3 vs. 5.6 +/- 2.2; p < 0.05), 12 (0.1 +/- 0.3 vs. 5.9 +/- 2.3; p < 0.05), and 24 hours (0.05 +/- 0.2 vs. 4.6 +/- 2.9; p < 0.05) in the GA + TEA group. At one month follow-up, pain scores were decreased in GA + TEA group (0.3 +/- 0.7 vs. 1.6 +/- 1.3; p = 003). There was no significant difference at three and six months. Mechanical ventilation time (4.7 +/- 1.2 vs. 2.9 +/- 1.1 hours; p < 0.05), intensive care unit stay (28.4 +/- 9.0 vs. 22.4 +/- 3.4 hours; p < 0.05), and hospital stay (7.2 +/- 1.1 vs. 6.1 +/- 0.3 days; p = 0.001) were reduced in the GA + TEA group. CONCLUSIONS: TEA significantly reduced the intensity of postoperative pain and analgesic consumption in the early postoperative period following CABG. The delivery of effective analgesia along with conventional medications may prevent chronic pain after surgery. PMID- 23461639 TI - Nuclear-spin selection rules in the chemistry of interstellar nitrogen hydrides. AB - Nitrogen hydrides are at the root of the nitrogen chemistry in interstellar space. The detailed modeling of their gas phase formation, however, requires the knowledge of nuclear-spin branching ratios for chemical reactions involving multiprotonated species. We investigate in this work the nuclear-spin selection rules in both exothermic and near thermoneutral ion-molecule reactions involved in the synthesis of ammonia, assuming full scrambling of protons in the reaction complexes. The formalism of Oka [ J. Mol. Spectrosc. 2004, 228, 635] is employed for highly exothermic ion-molecule and dissociative recombination reactions. For thermoneutral reactions, a simple state-to-state statistical approach is suggested, which is in qualitative agreement with both quantum scattering and microcanonical statistical calculations. This model is applied to the seven atom reaction NH4(+) + H2, of possible importance in the nuclear-spin thermalization of ammonia. PMID- 23461640 TI - Measuring T-cell responses against LCV and CMV in cynomolgus macaques using ELISPOT: potential application to non-clinical testing of immunomodulatory therapeutics. AB - A number of immunomodulatory therapeutics increase the risk of disease associated with latent herpesviruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), a member of the lymphocryptovirus (LCV) family that infects humans. The diseases associated with loss of immunity to these viruses can have major impacts on patients as well as on the commercial viability of the immunomodulatory therapeutics. In an effort to develop non-clinical methods for measuring effects on anti-viral immunity, we have developed an interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) assay to quantify the number of CMV or LCV-reactive T-cells in peripheral blood of cynomolgus macaques. After optimization of various parameters, the IFN-gamma ELISPOT assay was characterized for specificity, intra assay, monkey-to-monkey, and longitudinal variability and sensitivity to immunosuppression. The results show that nearly all animals have detectable responses against both CMV and LCV and responses were derived from T-cells specific to the virus of interest. Analyses of variability show assay reproducibility (<=23% CV), and that variability over time in anti-viral responses in individual animals (larger for LCV than for CMV) was ~2-fold in most animals over a 3-month time period, which is predicted to allow for detection of drug-induced changes when using group sizes typical of non-clinical studies. In addition, the IFN-gamma ELISPOT assay was capable of detecting decreases in the numbers of CMV and LCV reactive T-cells induced by immunosuppressive drugs in vitro. This assay may allow for non-clinical assessment of the effects of immunomodulatory therapeutics on anti-viral T-cell immunity in monkeys, and may help determine if therapeutics increase the risk of reactivating latent viral infections. PMID- 23461641 TI - ISDra2 transposition in Deinococcus radiodurans is downregulated by TnpB. AB - Transposable elements belonging to the recently identified IS200/IS605 family radically differ from classical insertion sequences in their transposition mechanism by strictly requiring single-stranded DNA substrates. This IS family includes elements encoding only the transposase (TnpA), and others, like ISDra2 from Deinococcus radiodurans, which contain a second gene, tnpB, dispensable for transposition and of unknown function to date. Here, we show that TnpB has an inhibitory effect on the excision and insertion steps of ISDra2 transposition. This inhibitory action of TnpB was maintained when ISDra2 transposition was induced by gamma-irradiation of the host cells and required the integrity of its putative zinc finger motif. We also demonstrate the negative role of TnpB when ISDra2 transposition was monitored in a heterologous Escherichia coli host, indicating that TnpB-mediated inhibition does not involve Deinococcus-specific factors. TnpB therefore appears to play a regulatory role in ISDra2 transposition. PMID- 23461642 TI - Lyme nephritis. AB - OBJECTIVE: To review what is known and highlight knowledge gaps regarding Lyme nephritis (LN). DATA SOURCES: Publications identified via PubMed using the keywords "Borrelia burgdorferi," "Borreliosis," "glomerulonephritis," "protein losing nephropathy," "autoimmunity," and "retriever," and as generated by investigators working in the fields of Borreliosis and immune-mediated glomerulonephritis. HUMAN DATA SYNTHESIS: Postborrelial immune-mediated glomerulonephritis was described recently in 6 people; 3 responded to antimicrobials/steroids, 1 to antimicrobials/angiotensin-converting enzyme inhibitor/warfarin, 1 required hemodialysis but became hemodialysis independent after 5 months and treatment with antimicrobials, steroids, plasmapheresis, immunoglobulin, and 1 did not respond to steroids and angiotensin-converting enzyme inhibitor and still requires hemodialysis. VETERINARY DATA SYNTHESIS: Lyme nephritis is seen in <1-2% of Lyme seropositive dogs, with an average onset at 5 6 years. Labrador and Golden Retrievers are predisposed to this condition. Prior or concurrent lameness is described in 9-28% cases. Historical presentations include acute progressive protein-losing nephropathy with membranoproliferative glomerulonephritis, tubular necrosis/regeneration, and interstitial nephritis, but possibly milder forms exist. Complications include thromboembolic events, hypertension, effusive disease, and oliguric/anuric renal failure. Diagnostic tests help stage disease and rule out other causes. Renal biopsy is advocated early, when intervention may help, and to prove if immune-complex disease exists. Treatment includes standard therapy for protein-losing nephropathy, long-term antimicrobials, and perhaps immunosuppressive therapy. CONCLUSIONS: There is no experimental model of LN to study predisposing factors, pathogenesis, onset, progression, treatment, or prevention. There are no predictive tests to identify the few individuals at highest risk, therefore all seropositive dogs should be screened and monitored for proteinuria. Lyme nephritis mimics other forms of protein-losing nephropathy and sometimes Leptospirosis. Renal biopsy helps show if immune-complex disease exists, but may not prove LN specifically. More studies are warranted on dogs with Lyme-specific immune-complex deposition to evaluate risk factors, understand pathogenesis, variability of expression, and to validate treatment and prevention protocols. PMID- 23461643 TI - Improving the efficiency of the photoinduced charge-separation process in a rhenium(I)-zinc porphyrin dyad by simple chemical functionalization. AB - We demonstrate here that, whereas the rhenium(I)-zinc porphyrin dyad fac [Re(CO)3(bpy)(Zn.4'MPyP)](CF3SO3) [1; 4'MPyP = 5-(4'-pyridyl)-10,15,20 triphenylporphyrin] shows no evidence for photoinduced electron transfer upon excitation in the visible region because the charge-separated state ZnP(+)-Re(-) is almost isoenergetic with the singlet excited state of the zinc porphyrin (DeltaG = -0.05 eV), the introduction of electron-withdrawing ethyl ester groups on the bpy ligand significantly improves the thermodynamics of the process (DeltaG = -0.42 eV). As a consequence, in the new dyad fac-[Re(CO)3(4,4'-DEC bpy)(Zn.4'MPyP)](CF3SO3) (4; 4,4'-DEC-bpy = 4,4'-diethoxycarbonyl-2,2' bipyridine), an efficient and ultrafast intramolecular electron-transfer process occurs from the excited zinc porphyrin to the rhenium unit upon excitation with visible light. Conversely, the introduction of electron-donor tert-butyl groups on the meso-phenyl moieties of the zinc porphyrin has a negligible effect on the photophysics of the system. For dyad 4, the time constants for the charge separation and charge-recombination processes in solvents of different polarity (PrCN, DCM, and toluene) were measured by an ultrafast time-resolved absorption technique (lambda(exc) = 560 nm). PMID- 23461644 TI - Is continuous venovenous hemofiltration effective against severe acute pancreatitis? AB - Our aim was to investigate the efficacy of continuous venovenous hemofiltration (CVVH) in treating severe acute pancreatitis (SAP). A literature search was performed using PubMed (1992-present), and all studies investigating the efficacy of CVVH in treating SAP were included. Four comparative studies and seven case series comprising a total of 354 patients were included. The overall mortality rate of patients receiving CVVH was 20% (55/275). A decreased mortality rate and decreased serum cytokine levels were reported in the CVVH groups in only two studies. The starting time point, substitution fluid flow rate, filter membrane type, hemofilter change interval, anticoagulation, and sustaining times of CVVH varied among the studies, and the impact of these parameters on the efficacy of CVVH was poorly reported. High-volume CVVH, when started early, was demonstrated to be more effective in eliminating cytokines in only one study. After the application of CVVH, the patient conditions started to improve between the 6th and 72nd hours. In conclusion, no solid clinical evidence has proven the efficacy of CVVH in treating SAP. High-volume CVVH that is started early and sustained for at least 72 h may be adopted to investigate the efficacy of CVVH for treating SAP. PMID- 23461645 TI - Source attribution of agriculture-related deposition by using total nitrogen and delta15N in epiphytic lichen tissue, bark and deposition water samples in Germany. AB - Compared with physico-chemical deposition measurement methods, lichens are able to identify the long-term overall effects of high N pollution concentrations in the air. In addition, the natural abundances of the stable isotope of N, (15)N, are being widely used in research on N cycling in ecosystems. They can also be used as instruments for source attribution. In this study, epiphytic lichens were tested to determine whether their respective N content and delta(15)N ratios can be used to estimate N deposition rates and to locate various sources of N compounds. Epiphytic lichen and bark samples were collected from around various deposition measurement field stations at different sites in the western part of Germany. The N content of epiphytic lichens reflects the species-specific, agriculture-related circumstances of N deposition at various sites in Germany. At the same time, delta(15)N signatures of the different investigated epiphytic lichen species and bark samples are highly depleted in (15)N under high ammonium deposition. The different surface types of lichens and barks exhibit different concentrations of N and delta(15)N ratios, despite being exposed to similar N deposition rates. The verification of highly negative delta(15)N ratios at sites with local and regional emitters shows that source attribution is possible by comparing different delta(15)N signatures in areas with a wide range of different N deposition types and the corresponding differences in delta(15)N among various source N pools. Especially nitrophytic lichens can support the on-site instrumentation measuring N deposition by qualification and quantification. PMID- 23461646 TI - Direct solvent-free regioselective construction of pyrrolo[1,2 a][1,10]phenanthrolines based on isocyanide-based multicomponent reactions. AB - A novel efficient one-pot four-component regioselective synthesis of pyrrolo[1,2 a][1,10]phenanthrolines in excellent yields has been developed by 1,3-dipolar cycloaddition of aldehydes, malononitrile, and isocyanides with 1,10 phenanthroline under solvent-free conditions within 3 min without using any catalyst or activation. The products were preliminarily investigated as chromogenic and fluorescent sensors for Cu(2+) ions. PMID- 23461647 TI - ICU outcomes in cystic fibrosis following invasive ventilation. PMID- 23461648 TI - Fengycin C produced by Bacillus subtilis EA-CB0015. AB - Bacillus subtilis EA-CB0015 was isolated from the phyllosphere of a banana plant and tested for its potential to produce bioactive compounds against Mycosphaerella fijiensis. Using a dual plate culture technique the cell-free supernatant of B. subtilis EA-CB0015 produced inhibition values of 89 +/- 1%. The active compounds were purified by solid-phase extraction and HPLC, and their primary structures determined using mass spectrometry and amino acid analysis. A new fengycin isoform, fengycin C, with the amino acid sequence Glu-Orn-Tyr-Thr Glu-Val-Pro-Gln-Thr-Ile was isolated. The peptidic moiety differs from fengycin B at position 9 and from fengycin A at positions 6 and 9. The beta-hydroxy fatty acyl chain is connected to the N-terminal of the decapeptide and can be saturated or unsaturated, ranging from 14 to 18 carbons. The C-terminal residue of the peptidic moiety is linked to the tyrosine residue at position 3, forming the branching point of the acyl peptide and the eight-membered cyclic lactone. PMID- 23461649 TI - Validation of a modified McGill Pain Questionnaire for orthodontic patients. AB - OBJECTIVE: To assess better and more efficiently the aspects of pain experienced by adolescent orthodontic patients, the McGill Pain Questionnaire-Short Form (MPQ SF) was modified (MMPQ-SF) and validated. MATERIALS AND METHODS: Internal and external expert panels developed a MMPQ-SF with 15 descriptors and 4-point Likert severity scales (MMPQ-SF15). Seventy-five subjects undergoing orthodontic treatment gave informed consent. Sixty-one subjects completed the MMPQ-SF15, a visual analogue scale (VAS), and the present pain index (PPI) 24 hours after an orthodontic visit. Respondents were grouped by gender and treatment stage: initial (15 female, 7 male), middle (10 female, 7 male), and end (16 female, 6 male). MMPQ-SF, VAS, and PPI scores were compared by Spearman correlation analysis. Underlying constructs were explored by factor analyses. Construct validity of the MMPQ-SF was tested by analysis of variance. RESULTS: MMPQ-SF15 and VAS (r = 0.78, r(2)s = 0.61, P < .0001), MMPQ-SF15 and PPI (r = 0.84, r(2)s = 0.71, P < .0001), and VAS and PPI (r = 0.70, r(2)s = 0.48, P < .0001) were correlated positively and significantly. A two-factor solution (localized and generalized/emotional pain; Kaiser-Meyer-Olkin = 0.88) showed that 11 descriptors (MMPQ-SF11) accounted for 64% of response variability. Generalized/emotional pain values were significantly higher during the initial stage of treatment compared to the middle (P = .011) and end stages (P = .014). CONCLUSIONS: MMPQ-SF, particularly MMPQ-SF11, demonstrated utility in assessment of localized and generalized/emotional aspects of pain in adolescent orthodontic patients and correlated well with VAS and PPI. Future application of the MMPQ-SF11 to measure orthodontic pain more specifically could lead to more appropriate management of this important facet of therapy. PMID- 23461650 TI - Vibronic and vibrational coherences in two-dimensional electronic spectra of supramolecular J-aggregates. AB - In J-aggregates of cyanine dyes, closely packed molecules form mesoscopic tubes with nanometer-diameter and micrometer-length. Their efficient energy transfer pathways make them suitable candidates for artificial light harvesting systems. This great potential calls for an in-depth spectroscopic analysis of the underlying energy deactivation network and coherence dynamics. We use two dimensional electronic spectroscopy with sub-10 fs laser pulses in combination with two-dimensional decay-associated spectra analysis to describe the population flow within the aggregate. Based on the analysis of Fourier-transform amplitude maps, we distinguish between vibrational or vibronic coherence dynamics as the origin of pronounced oscillations in our two-dimensional electronic spectra. PMID- 23461652 TI - In situ TEM and energy dispersion spectrometer analysis of chemical composition change in ZnO nanowire resistive memories. AB - Resistive random-access memory (ReRAM) has been of wide interest for its potential to replace flash memory in the next-generation nonvolatile memory roadmap. In this study, we have fabricated the Au/ZnO-nanowire/Au nanomemory device by electron beam lithography and, subsequently, utilized in situ transmission electron microscopy (TEM) to observe the atomic structure evolution from the initial state to the low-resistance state (LRS) in the ZnO nanowire. The element mapping of LRS showing that the nanowire was zinc dominant indicating that the oxygen vacancies were introduced after resistance switching. The results provided direct evidence, suggesting that the resistance change resulted from oxygen migration. PMID- 23461651 TI - Redefining the pericontusional penumbra following traumatic brain injury: evidence of deteriorating metabolic derangements based on positron emission tomography. AB - Abstract The pathophysiological changes in the pericontusional region after traumatic brain injury (TBI) have classically been considered to be ischemic. Using [F-18]fluorodeoxyglucose (FDG) and triple-oxygen PET studies, we examined the pericontusional "penumbra" to assess for increased oxygen extraction fraction (OEF), anaerobic metabolism, and tissue viability. Acute (<=4 days) CT, MRI, and PET studies were performed in eight patients with TBI who had contusions. Four regions-of-interest (ROI) containing the contusion core, pericontusional hypodense gray matter (GM), pericontusional normal-appearing GM, and remote normal-appearing GM, were defined using a semi-automatic method. The correlations of cerebral blood flow (CBF) with OEF, cerebral metabolic rate of oxygen (CMRO2), and cerebral metabolic rate of glucose (CMRglc) were examined. The oxygen-glucose ratio (OGR) in each brain region was evaluated for anaerobic metabolism. The results show that pericontusional tissue had progressively diminishing OEF, CBF, CMRO2, or CMRglc approaching the contusion core. In general, there was a preserved ratio of CBF to CMRO2 in pericontusional hypodense GM. The OGR of the pericontusional hypodense GM was low (<4.0) and was inversely correlated (r= 0.68) with time after injury. A large proportion (%area: 22-76%) of pericontusional hypodense GM tissue had CMRO2 values less than 35 MUmol/100 g/min, with this percentage increased with time after injury. PMID- 23461653 TI - The family of ammonium transporters (AMT) in Sorghum bicolor: two AMT members are induced locally, but not systemically in roots colonized by arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizal (AM) fungi contribute to plant nitrogen (N) acquisition. Recent studies demonstrated the transport of N in the form of ammonium during AM symbiosis. Here, we hypothesize that induction of specific ammonium transporter (AMT) genes in Sorghum bicolor during AM colonization might play a key role in the functionality of the symbiosis. For the first time, combining a split-root experiment and microdissection technology, we were able to assess the precise expression pattern of two AM-inducible AMTs, SbAMT3;1 and SbAMT4. Immunolocalization was used to localize the protein of SbAMT3;1. The expression of SbAMT3;1 and SbAMT4 was greatly induced locally in root cells containing arbuscules and in adjacent cells. However, a split-root experiment revealed that this induction was not systemic. By contrast, a strictly AM-induced phosphate transporter (SbPt11) was expressed systemically in the split-root experiment. However, a gradient of expression was apparent. Immunolocalization analyses demonstrated that SbAMT3;1 was present only in cells containing developing arbuscules. Our results show that the SbAMT3;1 and SbAMT4 genes are expressed in root cortical cells, which makes them ready to accommodate arbuscules, a process of considerable importance in view of the short life span of arbuscules. Additionally, SbAMT3;1 might play an important role in N transfer during AM symbiosis. PMID- 23461654 TI - Demonstration of zero optical backscattering from single nanoparticles. AB - We present the first experimental demonstration of zero backscattering from nanoparticles at optical frequencies as originally discussed by Kerker et al. [ Kerker , M. ; Wang , D. ; Giles , C. J. Opt. Soc. A 1983 , 73 , 765 ]. GaAs pillars were fabricated on a fused silica substrate and the spectrum of the backscattered radiation was measured in the wavelength range 600-1000 nm. Suppression of backscattering occurred at ~725 nm, agreeing with calculations based on the discrete dipole approximation. Particles with zero backscattering provide new functionality for metamaterials and optical antennas. PMID- 23461655 TI - Comparison of glycopyrrolate and atropine in ameliorating the adverse effects of imidocarb dipropionate in horses. AB - REASONS FOR PERFORMING STUDY: Imidocarb, an effective treatment for piroplasmosis, may cause colic and diarrhoea in horses. Atropine and glycopyrrolate are anticholinergics that could reduce the adverse effects of imidocarb. However, atropine and glycopyrrolate inhibit gastrointestinal motility, potentially causing ileus and colic. OBJECTIVES: To compare glycopyrrolate and atropine in ameliorating the adverse effects of imidocarb dipropionate in horses and to determine the effect of combinations of these drugs on the gastrointestinal tract. METHODS: A blinded, randomised, crossover study was performed in 8 healthy horses. Each horse received 0.9% saline i.m and i.v. (CON), and imidocarb 2.4 mg/kg bwt i.m. with one of 3 treatments i.v.: 0.9% saline (IMI), atropine 0.02 mg/kg bwt (IMATROP) and glycopyrrolate 0.0025 mg/kg bwt (IMGLYCO). Clinical data, gastrointestinal motility via borborygmi and frequency of contractions in the duodenum, caecum and right dorsal colon assessed with transabdominal ultrasound, and faecal data were measured. RESULTS: After imidocarb/saline treatment colic and diarrhoea were noted in 3 and 4 horses, respectively, faecal production and defaecation were increased for 3 h and faecal water percentage for 6 h. Colic was noted after atropine treatment in 4 horses, borborygmi and frequency of right dorsal colon contractions were significantly decreased for 2 h 15 min, and faecal production was not significantly different from CON. After glycopyrrolate treatment, colic was seen in one horse, frequency of intestinal contractions and faecal data were not significantly different from CON, and borborygmi was significantly decreased from CON at 1 h 15 min. CONCLUSIONS: Results of this study suggest that glycopyrrolate is superior to atropine in ameliorating the adverse effects of imidocarb. POTENTIAL RELEVANCE: Glycopyrrolate could be administered with imidocarb in horses with piroplasmosis to reduce the adverse effects of imidocarb. PMID- 23461656 TI - Plasma-free vs deconjugated metanephrines for diagnosis of phaeochromocytoma. AB - BACKGROUND: The diagnosis of phaeochromocytoma is commonly performed by the measurements of plasma-free normetanephrine and metanephrine. Plasma-deconjugated normetanephrine and metanephrine have been proposed as alternative, equivalent, but easier to measure biomarkers. OBJECTIVE: The aim of this study was to compare the diagnostic performance of plasma-free vs deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma. METHODS: The study population included a reference group of 262 normotensive and hypertensive volunteers, 198 patients with phaeochromocytoma and 528 patients initially suspected of having the tumour, but with negative investigations after at least 2 years of follow-up. Measurements were performed using liquid chromatography with electrochemical detection. RESULTS: Plasma concentrations of free normetanephrine were 17-fold higher in patients with phaeochromocytoma than in the reference population, a 72% larger (P < 0.001) difference than that for the 10-fold higher levels of plasma-deconjugated normetanephrine. In contrast, relative increases in plasma concentrations of free and deconjugated metanephrine were similar. Using upper cut-offs established in the reference population, measurements of plasma free metabolites provided superior diagnostic performance than deconjugated metabolites according to measures of both sensitivity (97% vs 92%, P = 0.002) and specificity (93% vs 89%, P = 0.012). The area under the receiver operating characteristic curve for the free metabolites was larger than that for the deconjugated metabolites (0.986 vs 0.965, P < 0.001). CONCLUSION: Measurements of plasma-free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma. PMID- 23461657 TI - A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by regulating AMPK and SIRT1 signaling, thereby reducing energy requirements during ischemia. AB - Polyphenol resveratrol (RSV) has been associated with Silent Information Regulator T1 (SIRT1) and AMP-activated protein kinase (AMPK) metabolic stress sensors and probably responds to the intracellular energy status. Our aim here was to investigate the neuroprotective effects of RSV and its association with SIRT1 and AMPK signaling in recurrent ischemia models. In this study, elderly male Wistar rats received a combination of two mild transient middle cerebral artery occlusions (tMCAOs) as an in vivo recurrent ischemic model. Primary cultured cortical neuronal cells subjected to combined oxygen-glucose deprivation (OGD) were used as an in vitro recurrent ischemic model. RSV administration significantly reduced infarct volumes, improved behavioral deficits and protected neuronal cells from cell death in recurrent ischemic stroke models in vivo and in vitro. RSV treatments significantly increased the intracellular NAD(+) /NADH ratio, AMPK and SIRT1 activities, decreased energy assumption and restored cell energy ATP level. SIRT1 and AMPK inhibitors and specific small interfering RNA (siRNA) for SIRT1 and AMPK significantly abrogated the neuroprotection induced by RSV. AMPK-siRNA and inhibitor decreased SIRT1 activities; however, SIRT1-siRNA and inhibitor had no impact on phospho-AMPK (p-AMPK) levels. These results indicated that the neuroprotective effects of RSV increased the intracellular NAD(+) /NADH ratio as well as AMPK and SIRT1 activities, thereby reducing energy ATP requirements during ischemia. SIRT1 is a downstream target of p-AMPK signaling induced by RSV in the recurrent ischemic stroke model. PMID- 23461658 TI - Disseminated Histoplasma capsulatum diagnosed on peripheral blood film. PMID- 23461659 TI - Human herpesvirus type 6 DNAemia and infection following allogeneic stem cell transplantation with a focus on long-term outcome. AB - Cases of human herpesvirus type 6 (HHV-6) infection and disease were retrospectively analysed in a cohort of 97 allogeneic haematopoietic stem cell transplantation (allo-SCT) patients in Gothenburg, Sweden (1997-2001). Altogether 54 of 97 (56%) patients were tested for HHV-6. HHV-6 DNAemia was detected in 15 of the tested patients at a median of 76 (range 24-387) days after SCT. Nine of these patients were treated against HHV-6 infection and disease for a total of 11 treatment episodes. The morbidity associated with HHV-6 DNAemia following allo SCT was in most cases moderate. The overall 1-y survival among the patients with HHV-6 DNAemia was 11/15 (73%) and the 5-y survival was 10/15 (67%), which was not significantly different from the whole cohort. PMID- 23461660 TI - Familial renal disease in soft-coated wheaten terriers. AB - OBJECTIVE: To review what is known about the familial renal diseases in soft coated wheaten terriers (SCWT), provide an update in developments in this field including the relationship with protein-losing nephropathy (PLN) and the potential association with protein-losing enteropathy (PLE). DATA SOURCES: Information was derived from studies of dogs maintained in the North Carolina State University colony, information contained within an open registry of affected dogs, and data gathered from the general population of wheaten terriers at risk as well as studies performed on banked DNA samples from affected SCWT in the general population and normal geriatric dogs seen at the University of Pennsylvania (PennVet). HUMAN DATA SYNTHESIS: A two-hit pathogenesis has been proposed in some types of human focal segmental glomerulosclerosis, specifically the subset of cases that are associated with a podocytopathy. At risk podocytes may be predisposed to injury by disease processes that would be reversible in other patients. VETERINARY DATA SYNTHESIS: Mutations were found in association with PLN in SCWT, indicating a podocytopathy that causes a change in glomerular permselectivity. This podocytopathy leads to the development of lesions resembling focal segmental glomerulosclerosis. There is also strong evidence supporting a high prevalence of food hypersensitivity reactions in SCWT, although it is unclear if these reactions have a primary or secondary role in the development of PLE. There are also suggestions of immunodysregulation in affected SCWT. CONCLUSIONS: PLN in SCWT is due to a podocytopathy. The cause of PLE has not been identified; however, it is possible that PLE develops from a functional structural abnormality in the intestines and food allergies develop as secondary phenomena. It is also possible that inflammatory events that are the result of either immunodysregulation or food allergies might lead to the development of PLE. In either case, PLE most likely exacerbates PLN in affected SCWT. PMID- 23461661 TI - Novel mutations in the gene HOXC13 underlying pure hair and nail ectodermal dysplasia in consanguineous families. PMID- 23461662 TI - Intra-operative reliability of ShapeMatch cutting guide placement in total knee arthroplasty. AB - Custom cutting guides based on pre-operative imaging have been introduced for total knee arthroplasty (TKA). The aim of this prospective cohort study was to assess the reliability of repeated placement of custom cutting guides by multiple surgeons in a group of patients undergoing TKA. Custom cutting guides (ShapeMatch(r), Stryker Orthopaedics) were designed from pre-operative MRI scans. The treating surgeon placed each guide on the femur and tibia of each patient three times without pinning the block. The three-dimensional position and orientation of the guide was measured for each repetition using a computer navigation system. The surgeon was blinded to the navigation system display. Data from 24 patients and 6 surgeons were analyzed. Intraclass correlation coefficients for all measurement parameters were in the range 0.889-0.997 (excellent), and all comparisons were statistically significant (p < 0.001). The range for femoral varus/valgus was 0.0-1.5 degrees , with 96% of patients being within 0.5 degrees . For femoral flexion/extension the range was 0.0-3.5 degrees (92% within 2.5 degrees ). On the tibia, varus/valgus had a range of 0.0-1.0 degrees (92% within 0.5 degrees ), and for slope the range was 0.0-3.5 degrees (92% within 2.5 degrees ). The high degree of agreement indicated that intra surgeon variation was minimal and that the technique is reliable. PMID- 23461664 TI - Performance indicators: the educational effect of publication pressure on young researchers in environmental sciences. PMID- 23461663 TI - Pancreatic fistula after a pancreaticoduodenectomy for ductal adenocarcinoma and its association with morbidity: a multicentre study of the French Surgical Association. AB - BACKGROUNDS: A pancreatic fistula (PF) is the most relevant complication after a pancreaticoduodenectomy (PD). This retrospective multicentric study attempts to elucidate the risk factors and complications of a PF in a large cohort of patients undergoing a PD for ductal adenocarcinoma. METHODS: Using a survey tool, clinical data of 1325 patients undergoing a PD for ductal adenocarcinoma at 37 institutions, between January 2004 and December 2009, were collected. Peri operative risk factors associated with PF and its association with morbidity and mortality were assessed. Morbidity and PF were graded according to the ISGPF (International Study group for pancreatic fistula) definition and the Dindo Clavien classification. RESULTS: Overall PF, mortality, morbidity and relaparotomy rates were 14.3%, 3.8%, 54.4% and 11.7%, respectively. PF occurred more frequently after a pancreaticojejunostomy (PJ) compared with a pancreaticogastrostomy (PG) (16.8% vs. 10.4%; P = 0.0012). Independent risk factors for PF by multivariate analysis were absence of pre-operative diabetes (P = 0.0014), PJ reconstruction (P = 0.0035), soft pancreatic parenchyma (P < 0.0001) and low-volume centre (P = 0.0286). Clinically relevant PF (grade B and C) and severe complications (Dindo-Clavien grade IIIB, IV, V) were significantly more frequent after PJ than PG (71.6% vs. 28.3%; P = 0.030 and 24.8% vs. 19.1%; P = 0.015, respectively). Overall mortality and relaparotomy rates were similar after PG and PJ. CONCLUSIONS: A soft pancreatic parenchyma, the absence of pre operative diabetes, PJ and low-volume centre are independent risk factors for PF after PD for ductal adenocarcinoma. A significantly higher incidence and clinical severity of PF are associated with PJ. PMID- 23461665 TI - Contextual influences on the drinking of male Latino immigrant day laborers. AB - This study explored self-reported alcohol use of Mexican and Central American men who had recently migrated to the United States to work. Ethnographic observation took place at a day laborer hiring site in 2006-2007 and qualitative interviewing involved 120 men with divergent drinking patterns. Short interviews were conducted informally on the street, and interviews lasting 1-2 hours addressed day laborers' perspective about how life conditions shape where drinking takes place and how much alcohol gets consumed. Resulting situations, such as roommates bringing alcohol home for extended nights of drinking, and specific strategies used to avoid excess alcohol use are addressed. PMID- 23461666 TI - "A different atmosphere of love": a qualitative study of the experiences of participants in Evangelical substance user rehabilitation programs in the Russian Federation. AB - This article explores the lived experiences of individuals who have participated in faith-based substance user rehabilitation programs in the Russian Federation. The Russian Federation has high rates of alcohol and opioid dependence and a dearth of professional treatment options. In the post-Soviet period, Evangelical Christian groups have developed substance user rehabilitation programs to attempt to address substance use and its related problems. Data were collected during 2010 via focus group interviews with participants in three Evangelical rehabilitation programs in the Volga region of the Russian Federation. Themes emerging from the qualitative data analysis process were classified into three broad categories: Typical Day, Personal Background/Decision to Enter Rehabilitation, and Helpful Aspects of Rehabilitation Process. PMID- 23461667 TI - Are mindfulness-based interventions effective for substance use disorders? A systematic review of the evidence. AB - Mindfulness-based interventions (MBIs) are increasingly suggested as therapeutic approaches for effecting substance use and misuse (SUM). The aim of this article is to review current evidence on the therapeutic efficacy of MBIs for SUM. A literature search was undertaken using four electronic databases and references of retrieved articles. The search included articles written in English published up to December 2011. Quality of included trials was assessed. In total, 24 studies were included, three of which were based on secondary analyses of previously investigated samples. Current evidence suggests that MBIs can reduce the consumption of several substances including alcohol, cocaine, amphetamines, marijuana, cigarettes, and opiates to a significantly greater extent than waitlist controls, non-specific educational support groups, and some specific control groups. Some preliminary evidence also suggests that MBIs are associated with a reduction in craving as well as increased mindfulness. The limited generalizability of the reviewed findings is noted (i.e., small sample size, lack of methodological details, and the lack of consistently replicated findings). More rigorous and larger randomized controlled studies are warranted. PMID- 23461668 TI - Prescription medication misuse among adolescents with severe mental health problems in Ontario, Canada. AB - The purpose of this study was to examine the prevalence of prescription medication misuse among adolescents with severe mental health problems in Ontario, Canada, and to explore some of the factors that influence the misuse of prescription medication. Data were obtained from the Resident Assessment Instrument for Mental Health. A total of 2,677 adolescents between the ages of 12 and 18 years who were admitted into adult mental health beds were analyzed. Logistic regression was used in estimating the likelihood of misusing prescription medication. Overall, 17% of adolescent inpatients misused prescription medication. In the multivariate model, the following were found to be associated with misuse: being female, having multiple psychiatric admissions, education, threat or danger to self, problem with addiction, history of emotional abuse, use of alcohol, past year use of opiates and cannabis, as well as symptoms of depression. Misuse of prescription medication was less likely to occur among adolescents with a diagnosis of schizophrenia and adolescents who were admitted as a result of posing a threat or danger to others. Implications of the findings are discussed with suggestions for future research. PMID- 23461669 TI - Oxo-Mo(IV)(dithiolene)thiolato complexes: analogue of reduced sulfite oxidase. AB - A series of [Mo(IV)O(mnt)(SR)(N-N)](-) (mnt = maleonitriledithiolate; R = Ph, nap, p-Cl-Ph, p-CO2H-Ph, and p-NO2-Ph; N-N = 2,2'-bipyridine (bipy) and 1,10 phenanthroline (phen)) complexes analogous to the reduced active site of enzymes of the sulfite oxidase family has been synthesized and their participation in electron transfer reactions studied. Equatorial thiolate and dithiolene ligations have been used to closely simulate the three sulfur coordinations present in the native molybdenum active site. These synthetic analogues have been shown to participate in electron transfer via a pentavalent EPR-active Mo(V) intermediate with minimal structural change as observed electrochemically by reversible oxidative responses. The role of the redox-active dithiolene ligand as an electron transfer gate between external oxidants and the molybdenum center could be envisaged in one of the analogue systems where the initial transient EPR signal with = 2.008 is replaced by the appearance of a typical Mo(V)-centered EPR ( = 1.976) signal. The appearance of such a ligand-based transient radical at the initial stage has been supported by the ligand-centered frontier orbital from DFT calculation. A stepwise rationale has been provided by computational study to show that the coupled effects of the diimine bite angle and the thiolato dihedral angle determine the metal- or ligand-based frontier orbital occupancy. DFT calculation has further supported the similarity between the reduced, semireduced, and oxidized resting state of the molybdenum center in Moco of SO with the synthesized complexes and their corresponding one-electron and fully oxidized species. PMID- 23461670 TI - Comparative effects of respiratory stimulants on hypoxic neuronal cell injury in SH-SY5Y cells and in hippocampal slice cultures from rat pups. AB - BACKGROUND: This study was conducted to clarify whether respiratory stimulants used to treat apnea of prematurity (AOP) attenuate or aggravate hypoxia-induced neuronal damage. METHODS: A human neuroblastoma cell line, SH-SY5Y cells, and hippocampal slice cultures from rat pups were exposed to hypoxia to induce cell injury. The effects of respiratory stimulants on cell injury were evaluated. RESULTS: Theophylline and doxapram did not have any effects against cell injury induced by hypoxia in SH-SY5Y cells and hippocampal slice cultures of rat pups, while caffeine protected these cells and the slice cultures from hypoxia. The protective effects of caffeine in SH-SY5Y cells disappeared with co-treatment by the adenosine A2A receptor agonist, CGS21680, and were mimicked by the adenosine A2A R antagonist, SCH58261. Meanwhile, co-treatment with phosphatidylinositol 3 kinase/AKT pathway inhibitors did not affect the protective effects of caffeine. Hydroxy radical scavenging activity of caffeine were not observed at the concentrations that produced cytoprotective activity, and radical scavengers did not have any effects on the cell injury induced by hypoxia in SH-SY5Y cells. CONCLUSIONS: Caffeine significantly attenuated cell injury induced by hypoxia in SH-SY5Y cells and hippocampal slice cultures of rat pups, at least partly through A2A R antagonism. Caffeine can protect neuronal cells from injury induced by hypoxemia, and may be a beneficial treatment for AOP with neuroprotective potential. PMID- 23461671 TI - Reproducibility of two 13CO2 breath tests dedicated to assess pancreatic exocrine function. AB - The aim of this study was to check on the reproducibility of two breath tests intended to test the pancreatic exocrine function accomplished with (13)C-mixed triglyceride ((13)C-MTG) or cornflakes naturally enriched in (13)C ((13)C-CF). The (13)CO2 content within breath samples was determined with isotope-selective non-dispersive infrared spectrometry. A 72-h monitoring performed in healthy subjects revealed that a statistically significant rise in breath (13)CO2 occurs between the 1st and the 9th hour and between the 1st and the 24th hour after intake of a test meal containing 300 mg (13)C-MTG (n=10) or 100 g (13)C-CF (n=12), respectively. In another two groups of 12 healthy volunteers each, short term reproducibility of the two tests was assessed with paired examinations taken at a median interval of two days, whereas paired examinations separated by a median of 20 days served for the medium-term reproducibility assessment. In the case of either test, the medium-term reproducibility was not any worse than the short-term one. The reproducibility of the (13)C-CF breath test tended to be slightly worse than that of the (13)C-MTG breath test: a least detectable difference in 6-h cumulative (13)C breath excretion (which is expressed as the percentage of the administered dose of the substrate) amounted to 2.7 and 4.4 % (short-term reproducibility) and to 3.5 and 4.4 % (medium-term reproducibility) in the case of the (13)C-MTG breath test and the (13)C-CF breath test, respectively. It is concluded that both tests offer a satisfactory reproducibility for use within a clinical setting. In case the lipolytic and the amylolytic activity would be required to be examined in the same patient, the (13)C-CF breath test can be executed on the next day following the (13)C-MTG breath test, whereas reciprocally, a 1-day break is recommended before accomplishment of a (13)C-MTG breath test following a (13)C-CF breath test. PMID- 23461672 TI - A case of metastatic adamantinoma responding to treatment with pazopanib. PMID- 23461673 TI - Thyroid disease and gestational diabetes mellitus (GDM): is there a connection? AB - OBJECTIVE: The primary objective of this study is to assess for differences in incidence of gestational diabetes mellitus (GDM) for patients with thyroid hypofunction versus patients with thyroid hyperfunction. METHODS: A retrospective chart review of all women with clinical thyroid disease delivering at Johns Hopkins Hospital from January 2005 to December 2008 was performed. Clinical parameters were abstracted and appropriate statistical tests were performed. RESULTS: GDM occurred in 12.3% of women in the study cohort. Of the women with hypothyroidism, 14.3% developed GDM compared to 5.8% of hyperthyroid women. Cesarean delivery was significantly higher in women with hypothyroidism versus women with hyperthyroidism (p = 0.002). There were no differences between groups with respect to preterm delivery, postpartum hemorrhage or hypertensive disorders of pregnancy. CONCLUSIONS: If larger studies confirm the trends observed in our study, consideration should be given to including women with known thyroid disease in the subset of women who should be offered screening for diabetes early in pregnancy and appropriate clinical surveillance. PMID- 23461674 TI - Kinetic resolution of racemic 2-hydroxy-gamma-butyrolactones by asymmetric esterification using diphenylacetic acid with pivalic anhydride and a chiral acyl transfer catalyst. AB - Various optically active 2-hydroxy-gamma-butyrolactone derivatives are produced via the kinetic resolution of racemic 2-hydroxy-gamma-butyrolactones with diphenylacetic acid using pivalic anhydride and (R)-benzotetramisole ((R)-BTM), a chiral acyl-transfer catalyst. Importantly, the substrate scope of this novel protocol is fairly broad (12 examples, s-value; up to over 1000). In addition, we succeeded in disclosing the reaction mechanism to afford high enantioselectivity using theoretical calculations and expounded on the substituent effects at the C 3 positions in 2-hydroxylactones. PMID- 23461675 TI - Infrared spectroscopy with heated attenuated total internal reflectance enabling precise measurement of thermally induced transitions in complex biological polymers. AB - We report an improved tool for acquiring temperature-resolved fourier transform infrared (FT-IR) spectra of complex polymer systems undergoing thermal transitions, illustrated by application to several phenomena related to starch gelatinization that have proved difficult to study by other means. Starch suspensions from several botanical origins were gelatinized using a temperature controlled attenuated total reflectance (ATR) crystal, with IR spectra collected every 0.25 degrees C. By following the 995/1022 cm(-1) peak ratio, clear transitions occurring between 59 and 70 degrees C were observed, for which the midpoints could be determined accurately by sigmoidal fits. The magnitude of the change in peak ratio was found to be strongly correlated to the enthalpy of gelatinization as measured by differential scanning calorimetry (DSC, R(2) = 0.988). An important advantage of the technique, compared to DSC, is that the signal-to-noise ratio is not reduced when measuring very broad transitions. This has the potential to allow more precise determination of the gelatinization parameters of high-amylose starches, for which gelatinization may take place over several tens of degrees C. PMID- 23461677 TI - Static cardiomyoplasty with synthetic elastic net suppresses ventricular dilatation and dysfunction after myocardial infarction in the rat: a chronic study. AB - Although static cardiomyoplasty prevents the left ventricle (LV) from dilatation, it may interfere with diastolic relaxation, or cause restriction. We developed a synthetic net with dual elasticity and tested its effect late after myocardial infarction in the rat. LV pressure-volume relationships (PVR) were successively analyzed before, after intravenous volume load, and 10 minutes after occlusion of the left anterior descending artery. Rats were then randomized into groups receiving synthetic net wrapping around the heart (NET+, n = 8) and only partially behind LV (NET-, n = 9), and they underwent the same PVR studies 6 weeks later. End-diastolic and end-systolic PVR were defined, and LV size and function were compared under standardized loading conditions. Although there was no difference in Day 0, increase in LV end-diastolic and end-systolic volumes were significantly attenuated in NET+ rats 6 weeks later when there was a significant correlation between LV volumes by PVR estimation and actual measurements, with significant differences in both measures between the groups: NET+ < NET-. The presence or absence of net did not show restrictive hemodynamics under acute volume load. Static cardiomyoplasty using a synthetic elastic net significantly attenuated LV dilatation and dysfunction without restriction late after myocardial infarction in the rat. PMID- 23461678 TI - Elevated serum thioredoxin-interacting protein in women with polycystic ovary syndrome is associated with insulin resistance. AB - OBJECTIVE: Women with polycystic ovary syndrome (PCOS) mostly have profound insulin resistance (IR) and beta-cell dysfunction. Although thioredoxin interacting protein (TXNIP) is a major regulator in IR and insulin secretion, no data on the plasma TXNIP level in patients with PCOS are available. This study aimed to determine the plasma TXNIP level and discuss the relationship between TXNIP and beta-cell dysfunction/IR in patients with PCOS. PATIENTS: Eighty-three women with PCOS and 52 controls. MEASUREMENTS: Insulin sensitivity was expressed by M value obtained from euglycaemic-hyperinsulinaemic clamp. Homoeostatic model assessment for beta-cell function (HOMA-beta), ?Ins30/?Glu30 and AUCins/glu were considered as the indices of fasting state, early-phase and total insulin secretion during oral glucose tolerance test, respectively. To evaluate beta-cell function adjusted for insulin sensitivity, disposition index (DI) was used: basal DI (DI0), early-phase DI (DI30) and total DI (DI120). Plasma TXNIP levels were measured by enzyme-linked immunosorbent assay. DESIGN: Case-control study. RESULTS: Patients with PCOS had higher serum TXNIP, whereas lower M value, DI0, DI30 and DI120 than controls (P < 0.05); their TXNIP correlated positively with weight, waist-to-hip ratio (WHR), body mass index (BMI), Ins0, Ins120 and HOMA beta and correlated negatively with M value and DI120 (P < 0.05). Multiple stepwise regression analysis indicated that TXNIP remained associated with M value in PCOS subjects, after adjusting weight, BMI, WHR, HOMA-beta, Ins0, Ins120 and DI120. However, no relationship between TXNIP and impaired beta-cell function was found. CONCLUSION: Serum TXNIP is elevated in women with PCOS and may be a contributing factor for IR. PMID- 23461679 TI - Controlling spontaneous emission with plasmonic optical patch antennas. AB - We experimentally demonstrate the control of the spontaneous emission rate and the radiation pattern of colloidal quantum dots deterministically positioned in a plasmonic patch antenna. The antenna consists of a thin gold microdisk separated from a planar gold layer by a few tens of nanometers thick dielectric layer. The emitters are shown to radiate through the entire patch antenna in a highly directional and vertical radiation pattern. Strong acceleration of spontaneous emission is observed, depending on the antenna geometry. Considering the double dipole structure of the emitters, this corresponds to a Purcell factor up to 80 for dipoles perpendicular to the disk. PMID- 23461681 TI - Surface receptor CD177/NB1 does not confer a recruitment advantage to neutrophilic granulocytes during human peritonitis. PMID- 23461676 TI - Uncovering novel actors in astrocyte-neuron crosstalk in Parkinson's disease: the Wnt/beta-catenin signaling cascade as the common final pathway for neuroprotection and self-repair. AB - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neuronal cell bodies in the substantia nigra pars compacta and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are ill-defined, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD pathophysiology, playing both protective and destructive roles. Here, the contribution of reactive astrocytes and their ability to modulate DAergic neurodegeneration, neuroprotection and neurorepair in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD will be discussed in the light of novel emerging evidence implicating wingless-type mouse mammary tumor virus integration site (Wnt)/beta-catenin signaling as a strong candidate in MPTP-induced nigrostriatal DAergic plasticity. In this work, we highlight an intrinsic Wnt1/frizzled-1/beta-catenin tone that critically contributes to the survival and protection of adult midbrain DAergic neurons, with potential implications for drug design or drug action in PD. The dynamic interplay between astrocyte-derived factors and neurogenic signals in MPTP-induced nigrostriatal DAergic neurotoxicity and repair will be summarized, together with recent findings showing a critical role of glia-neural stem/progenitor cell (NPC) interactions aimed at overcoming neurodegeneration and inducing neurorestoration. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and deciphering the signals facilitating the crosstalk between astrocytes, microglia, DAergic neurons and NPCs may have major implications for the role of stem cell technology in PD, and for identifying potential therapeutic targets to induce endogenous neurorepair. PMID- 23461682 TI - Lichen species identity and diversity of cyanobacterial toxins in symbiosis. PMID- 23461683 TI - SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1alpha complex. AB - SirT1 is a class III histone deacetylase that has been implicated in metabolic and reactive oxygen species control. In the vasculature it has been shown to decrease endothelial superoxide production, prevent endothelial dysfunction and atherosclerosis. However, the mechanisms that mediate SirT1 antioxidant functions remain to be characterized. The transcription factor FoxO3a and the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) have been shown to induce the expression of antioxidant genes and to be deacetylated by SirT1. AIMS: Here we investigated SirT1 regulation of antioxidant genes and the roles played by FoxO3a and PGC 1alpha in this regulation. RESULTS: We found that SirT1 regulates the expression of several antioxidant genes in bovine aortic endothelial cells, including Mn superoxide dismutase (MnSOD), catalase, peroxiredoxins 3 and 5 (Prx3, Prx5), thioredoxin 2 (Trx2), thioredoxin reductase 2 (TR2), and uncoupling protein 2 (UCP-2) and can be localized in the regulatory regions of these genes. We also found that knockdown of either FoxO3a or PGC-1alpha prevented the induction of antioxidant genes by SirT1 over-expression. Furthermore, SirT1 increased the formation of a FoxO3a/PGC-1alpha complex as determined by co-immunoprecipitation (IP) assays, concomitantly reducing H2O2-dependent FoxO3a and PGC-1alpha acetylation. Data showing that FoxO3a knockdown increases PGC-1alpha acetylation levels and vice versa, suggest that SirT1 activity on FoxO3a and PGC-1alpha may be dependent of the formation of a FoxO3a/PGC-1alpha complex. INNOVATION: A unifying mechanism for SirT1 activities is suggested. CONCLUSION: We show that SirT1 regulation of antioxidant genes in vascular endothelial cells depends on the formation of a FoxO3a/PGC-1alpha complex. PMID- 23461685 TI - Therapeutic patient education in children with atopic dermatitis: position paper on objectives and recommendations. AB - Poor adherence is frequent in patients with atopic dermatitis (AD), leading to therapeutic failure. Therapeutic patient education (TPE) helps patients with chronic disease to acquire or maintain the skills they need to manage their chronic disease. After a review of the literature, a group of multispecialty physicians, nurses, psychologists, and patients worked together during two international workshops to develop common recommendations for TPE in AD. These recommendations were structured as answers to nine frequently asked questions about TPE in AD: What is TPE and what are its underlying principles? Why use TPE in the management of AD? Who should benefit from TPE in AD? How can TPE be organized for AD? What is the assessment process for TPE in AD? What is the evidence of the benefit of TPE in AD? Who are the people involved in TPE? How should TPE be funded in dermatology? What are the limits of the TPE process? PMID- 23461684 TI - Systematic review and meta-analysis of fibrin sealants for patients undergoing pancreatic resection. AB - INTRODUCTION: Post-operative pancreatic fistula (POPF) is a common complication after partial pancreatic resection, and is associated with increased rates of sepsis, mortality and costs. The role of fibrin sealants in decreasing the risk of POPF remains debatable. The aim of this study was to evaluate the literature regarding the effectiveness of fibrin sealants in pancreatic surgery. METHODS: A comprehensive database search was conducted. Only randomized controlled trials comparing fibrin sealants with standard care were included. A meta-analysis regarding POPF, intra-abdominal collections, post-operative haemorrhage, pancreatitis and wound infections was performed according to the recommendations of the Cochrane collaboration. RESULTS: Seven studies were included, accounting for 897 patients. Compared with controls, patients receiving fibrin sealants had a pooled odds ratio (OR) of developing a POPF of 0.83 [95% confidence interval (CI): 0.6-1.14], P = 0.245. There was a trend towards a reduction in post operative haemorrhage (OR = 0.43 (95%CI: 0.18-1.0), P = 0.05) and intra-abdominal collections (OR = 0.52 (95%CI: 0.25-1.06), P = 0.073) in those patients receiving fibrin sealants. No difference was observed in terms of mortality, wound infections, re-interventions or hospital stay. CONCLUSION: On the basis of these results, fibrin sealants cannot be recommended for routine clinical use in the setting of pancreatic resection. PMID- 23461686 TI - Diagnosing epidermolysis bullosa type and subtype in infancy using immunofluorescence microscopy: the Stanford experience. AB - The natural history of inherited epidermolysis bullosa (EB) varies significantly across subtypes. When confronted with an infant suspected to have EB, rapidly determining the type and subtype is critical in counselling families accurately about the infant's diagnosis and prognosis. Although transmission electron microscopy (TEM) has been considered the criterion standard for EB diagnosis, immunofluorescence microscopy (IFM) using monoclonal antibodies (mAbs) to EB specific basement membrane zone proteins has several advantages, but few studies have evaluated the diagnostic utility of IFM. We sought to evaluate the clinical utility of IFM using an expanded panel of EB-specific mAbs. This was a retrospective review of pathology reports from infants younger < 1 year old with suspected EB primarily analyzed with IFM by the Stanford Dermatopathology service. Seventy-seven cases were identified for analysis, of which 20 were suboptimal for IFM analysis. Fifty-five cases were diagnosed with EB and classified as follows: EB simplex (n = 5), junctional EB (n = 31), dystrophic EB (n = 19). TEM was available in 36 of 55 cases (65%). IFM with an expanded panel of EB-specific mAbs should be considered the first-line diagnostic test to evaluate infants with clinically suspected EB. PMID- 23461687 TI - An 8-year-old boy with multiple yellow papules and bony lesions. Buschke Ollendorff syndrome. PMID- 23461688 TI - Multiple filiform keratoses and nodules in a 10-year-old girl. Nevus trichilemmocysticus. PMID- 23461689 TI - Giant cutaneous horn on the forearm of a neonate. Juvenile xanthogranuloma. PMID- 23461690 TI - The pitfalls of skin biopsies to diagnose epidermolysis bullosa. PMID- 23461691 TI - Trichoepithelioma, not Basal cell carcinoma, in an 8-year-old child. PMID- 23461692 TI - Trichoepithelioma, not Basal cell carcinoma, in an 8-year-old child. PMID- 23461693 TI - Eremohadena afzalipouri sp. nov. from Iran. AB - A new species of the genus Eremohadena Ronkay, Varga and Fabian, Eremohadena afzalipouri Shirvani sp. nov., is described from southeastern Iran. Holotype and female paratype and genitalia of both sexes are illustrated for the new species. A checklist of Iranian species of Eremohadena including nine species and subspecies is provided. PMID- 23461694 TI - Clinical experience with a lipid-free, ready-made parenteral nutrition solution in dogs: 70 cases (2006-2012). AB - OBJECTIVE: To review the clinical use of a lipid-free, ready-made amino acid and glucose parenteral nutrition (PN) solution in dogs. DESIGN: Retrospective study of dogs from 2006 to 2012 that received this form of PN. SETTING: University veterinary teaching hospital. ANIMALS: Seventy dogs presented to the hospital for treatment of various diseases in which PN was used as part of patient management. Dogs were administered PN at the discretion of the primary clinician. INTERVENTION: A lipid-free, ready-made solution containing amino acid (59 g/L) and dextrose (100 g/L) was administered intravenously as a constant rate infusion to provide nutritional support. MEASUREMENTS AND MAIN RESULTS: PN was provided for a median of 2.2 days (range 0.5-9.5 days) in the 70 dogs, totaling 168 days of PN. The PN provided a median of 5.5 g/100 kcal of protein (range 1-9.5 g/100 kcal) and a median of 2.2 mg/kg of bodyweight per minute (range 0.8-5.2 mg/kg/min) of glucose, which reflected a median of 57% of the resting energy requirement (range 9-100%). Metabolic complications developed in 43 of 67 dogs where these data were recorded, but the development of hyperkalemia was the only complication associated with a poor outcome (eg, death or euthanasia). Mechanical complications were seen in 28 dogs, and all but one of these occurred when PN was delivered through peripheral catheters. Septic complications were confirmed in 5 dogs. CONCLUSIONS: This form of PN is suitable for clinical use and can provide both protein and calories to ill dogs. It was, however, associated with a high rate of complications and requires careful patient monitoring. PMID- 23461695 TI - Clinical practice guidelines for antimicrobial prophylaxis in surgery. PMID- 23461696 TI - Predictors of sepsis in moderately severely injured patients: an analysis of the National Trauma Data Bank. AB - BACKGROUND: Post-traumatic sepsis is a significant cause of in-hospital death. However, socio-demographic and clinical characteristics that may predict sepsis in injured patients are not well known. The objective of this study was to identify risk factors that may be associated with post-traumatic sepsis. METHODS: Retrospective analysis of patients in the National Trauma Data Bank for 2007 2008. Patients older than 16 years of age with an Injury Severity Score (ISS) >= 9 points were included. Multivariable logistic regression was used to determine association of sepsis with patient (age, gender, ethnicity, and insurance status), injury (mechanism, ISS, injury type, hypotension), and clinical (major surgical procedure, intensive care unit admission) characteristics. RESULTS: Of a total of 1.3 million patients, 373,370 met the study criteria, and 1.4% developed sepsis, with an associated mortality rate of approximately 20%. Age, male gender, African-American race, hypotension on emergency department presentation, and motor vehicle crash as the injury mechanism were independently associated with post-traumatic sepsis. CONCLUSIONS: Socio-demographic and injury factors, such as age, race, hypotension on admission, and severity and mechanism of injury predict post-traumatic sepsis significantly. Further exploration to explain why these patient groups are at increased risk is warranted in order to understand better and potentially prevent this life-threatening complication. PMID- 23461697 TI - HiFSA fingerprinting applied to isomers with near-identical NMR spectra: the silybin/isosilybin case. AB - This study demonstrates how regio- and diastereo-isomers with near-identical NMR spectra can be distinguished and unambiguously assigned using quantum mechanical driven (1)H iterative Full Spin Analysis (HiFSA). The method is illustrated with four natural products, the flavonolignans silybin A, silybin B, isosilybin A, and isosilybin B, which exhibit extremely similar coupling patterns and chemical shift differences well below the commonly reported level of accuracy of 0.01 ppm. The HiFSA approach generated highly reproducible (1)H NMR fingerprints that enable distinction of all four isomers at (1)H frequencies from 300 to 900 MHz. Furthermore, it is demonstrated that the underlying numeric (1)H NMR profiles, combined with iterative computational analysis, allow parallel quantification of all four isomers, even in difficult to characterize reference materials and mixtures. The results shed new light on the historical challenges to the qualitative and quantitative analysis of these therapeutically relevant flavonolignans and open new opportunities to explore hidden diversity in the chemical space of organic molecules. PMID- 23461698 TI - Outcome of anesthetic management for children with craniofacial deformities. AB - BACKGROUND: The challenge for anesthetic management for children with craniofacial deformities is to develop comprehensive anesthetic care. The purposes of this study were to review the authors' experience with airway management and ventilator support and evaluate outcome during the perioperative period among these patients at the Tawanchai Center, Srinagarind Hospital. METHODS: A retrospective (2005-2009), descriptive study was conducted to analyze the anesthetic management and perioperative outcomes among children with craniofacial deformities at the Tawanchai Center. Techniques for airway management included direct laryngoscope (DL), DL with stylet, fiber-optic bronchoscope (FOB), laryngeal mask airway, retrograde intubation, a combination of these techniques and more than one anesthesiologist. RESULTS: Forty-five children with craniofacial deformities were classified as having the following: craniosynostosis; craniofacial microsomia; Treacher-Collins syndrome (TCS); coloboma of the eye, heart defects, atresia choanae, retarded growth and/or development, genital and/or urinary abnormalities, ear abnormalities and deafness (CHARGE) syndrome; frontoethmoidal encephalomeningocele; Pierre Robin sequence; and craniofacial cleft. Most of the patients underwent induction of anesthesia by inhalation of an anesthetic agent. The children with TCS were the most difficult group with regard to airway management with DL view (13%), and multiple airway accessories and intubation techniques were needed. The two most common methods for management of difficult airway obstructions were the use of stylet and FOB. No complications occurred during intubation and minor complications were observed during the perioperative period. CONCLUSION: A successful outcome depended on the provision of interdisciplinary craniofacial team management, comprehensive anesthetic evaluation and management, well-informed and cooperative children and supportive family members. PMID- 23461699 TI - Evaluation of MYC status in oral lichen planus in patients with progression to oral squamous cell carcinoma. AB - BACKGROUND: Malignant transformation of oral lichen planus (OLP) to oral squamous cell carcinoma (OSCC) is controversial. C-MYC is a proto-oncogene involved in various solid tumours, including OSCC. OBJECTIVES: To determine MYC status using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in OLP lesions from 10 patients with progression to OSCC (group I) and to compare this with OLP lesions from patients without progression to OSCC (group II). METHODS: We constructed two tissue microarrays with 11 OSCC samples (group IA), 17 OLP samples from the same patients (group IB) and 13 OLP specimens from 12 control patients (group II). FISH evaluation of the MYC gains was determined in 100 nonoverlapping nuclei per sample. IHC evaluation was determined by calculating the percentage C-MYC expression in the epithelial cells. RESULTS: OSCC samples showed MYC copy number gains and C-MYC overexpression in 91% and 73% of cases, respectively. MYC gains were detected in 47% of samples from group IB and were absent from all samples from group II. C-MYC was overexpressed in 87% of cases from group IB and in only 44% of control specimens (group II). The differences in MYC status between groups IB and II were statistically significant. CONCLUSIONS: OLP lesions in patients with progression to OSCC show MYC gains and C-MYC overexpression. In patients with severe OLP, determining MYC status may predict a subgroup of subjects with a higher risk of progression to OSCC. PMID- 23461700 TI - Incidental orbital calcification. PMID- 23461701 TI - A 96-well electrochemical method for the screening of enzymatic activities. AB - The rapid electrochemical screening of enzyme activities in bioelectronics is still a challenging issue. In order to solve this problem, we propose to use a 96 well electrochemical assay. This system is composed of 96 screen-printed electrodes on a printed circuit board adapted from a commercial system (carbon is used as the working electrode and silver chloride as the counter/reference electrode). The associated device allows for the measurements on the 96 electrodes to be performed within a few seconds. In this work, we demonstrate the validity of the screening method with the commercial laccase from the fungus Trametes versicolor. The signal-to-noise ratio (S/N) is found to be the best way to analyze the electrochemical signals. The S/N follows a saturation-like mechanism with a dynamic linear range of two decades ranging from 0.5 to 75 ng of laccase (corresponding to enzymatic activities from 62 * 10(-6) to 9.37 * 10(-3) MUmol min(-1)) and a sensitivity of 3027 MUg(-1) at +100 mV versus Ag/AgCl. Laccase inhibitors (azide and fluoride anions), pH optima, and interfering molecules could also be identified within a few minutes. PMID- 23461702 TI - Substrate selectivity of human intestinal UDP-glucuronosyltransferases (UGTs): in silico and in vitro insights. AB - The current drug development process aims to produce safe, effective drugs within a reasonable time and at a reasonable cost. Phase II metabolism (glucuronidation) can affect drug action and pharmacokinetics to a considerable extent and so its studies and prediction at initial stages of drug development are very imperative. Extensive glucuronidation is an obstacle to oral bioavailability because the first-pass glucuronidation [or premature clearance by UDP glucuronosyltransferases (UGTs)] of orally administered agents frequently results in poor oral bioavailability and lack of efficacy. Modeling of new chemical entities/drugs for UGTs and their kinetic data can be useful in understanding the binding patterns to be used in the design of better molecules. This review concentrates on first-pass glucuronidation by intestinal UGTs, including their topology, expression profile, and pharmacogenomics. In addition, recent advances are discussed with respect to substrate selectivity at the binding pocket, structural requirements, and mechanism of enzyme actions. PMID- 23461703 TI - Change and processes of change within interventions to promote adjustment to multiple sclerosis: learning from patient experiences. AB - This qualitative study was nested within a trial of cognitive behaviour therapy (CBT) and supportive listening for patients with multiple sclerosis (MS). It aimed to enrich understanding of the changes made during therapy and to explore processes of change. In-depth interviews with 30 participants from the treatment trial were analysed inductively and five main themes were developed. The benefits that participants described experiencing as a result of the interventions were highly variable, idiosyncratic and often departed from outcomes measured within the trial. Tuning into and sharing one's thoughts and feelings and learning specific strategies for living with MS appeared to be important processes for change, and participants identified the latter as particularly important for sustaining long-term benefits from therapy. Whether participants fully engaged with the interventions appeared to be related to their perceptions of being the right sort of candidate for the intervention, their expectations and motivations, the therapeutic relationship, adequate tailoring of the intervention, and practical issues. This study builds on previous research on factors and processes involved in adjustment to MS, the benefits of CBT for this population and highlights important issues to consider when developing psychosocial interventions for people with MS. PMID- 23461704 TI - Modulation of proprioceptive feedback during functional electrical stimulation: an fMRI study. AB - Functional electrical stimulation (FES) is sometimes used as a therapeutic modality in motor rehabilitation to augment voluntary motor drive to effect movement that would otherwise not be possible through voluntary activation alone. Effective motor rehabilitation should require that the central nervous system integrate efferent commands and appropriate afferent information to update the internal models of acquired skills. Here, we investigate whether FES-evoked (FES ev) and FES-assisted (FES-as) movement are associated with the normal integration of motor commands and sensory feedback in a group of healthy participants during functional magnetic resonance imaging (fMRI). Sensory feedback was removed with a peripheral ischaemic nerve block while the participants performed voluntary (VOL), FES-ev or FES-as movement during fMRI. Before the peripheral nerve block, secondary somatosensory area (S2) activation was greater for the FES-ev and FES as conditions than for the VOL condition. During the ischaemic nerve block, S2 activation was reduced for the FES-ev condition but not for FES-as and VOL conditions. The nerve block also reduced activation during FES in the primary somatosensory cortex and other motor areas including primary motor cortex, dorsal premotor cortex and supplementary motor area. In contrast, superior parietal lobule (area 7A) and precuneus activation was reduced as a consequence of the ischaemic nerve block in the VOL condition. These data suggest FES-related S2 activation is mainly a sensory phenomenon and does not reflect integration of sensory signals with motor commands. PMID- 23461705 TI - Soluble tag-assisted peptide head-to-tail cyclization: total synthesis of mahafacyclin B. AB - A soluble tag-assisted liquid-phase method was successfully applied to peptide head-to-tail cyclization, leading to the total synthesis of antimalarial cyclic heptapeptide, mahafacyclin B (1). The cyclization was carried out in the liquid phase with the tag remaining, which allowed rapid reaction workup and product isolation. PMID- 23461706 TI - Palladium-catalyzed arylation of simple arenes with iodonium salts. AB - The development of an arylation protocol for simple arenes with diaryliodonium salts using the Herrmann-Beller palladacycle catalyst is reported. The reaction takes simple aromatic feedstocks and creates valuable biaryls for use in all sectors of the chemical industry. PMID- 23461707 TI - Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol. AB - BACKGROUND: The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined. DESIGN AND METHODS: We analyzed 749 patients aged 1-45 yr treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard-, intermediate-, or high-risk treatment with or without hematopoietic stem cell transplantation. RESULTS: Adults aged 18-45 had significantly lower WBCs at diagnosis compared with children aged 1-9 and 10-17 yr, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; P < 0.0001) or high-risk chemotherapy with transplantation (4%, 13%, 19%; P < 0.0001). This age dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, P < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; P < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; P = 0.005) in older patients. CONCLUSIONS: Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high-risk therapy, which should be considered when comparing pediatric and adult outcomes. PMID- 23461708 TI - Efficacy of pulmonary vein isolation on left atrial function in paroxysmal and persistent atrial fibrillation and the dependency on its baseline function. AB - BACKGROUND: The effects of pulmonary vein (PV) isolation in atrial fibrillation (AF) on left atrial (LA) function or PV flow have not been well documented. METHODS: We examined the LA function and PV flow before and 3-6 months after PV isolation in 67 AF patients (34 paroxysmal [PAF] and 33 persistent [CAF]) using transesophageal echocardiography. RESULTS: AF recurred in 6/34 patients with PAF and in 6/33 patients with CAF 6 months after PV isolation. A larger LA dimension, a lower systolic PV flow velocity, and a lower ratio of systolic to diastolic PV flow velocity were related to a higher incidence of AF recurrence. The increment of left atrial appendage (LAA) flow velocity (55% vs. 22%) and systolic PV flow velocity (57% vs. 20%) after PV isolation tended to be greater in CAF than in PAF. The changes in LAA flow velocity had reverse correlations with the baseline values before PV isolation (PAF: r = -0.73, CAF: r = -0.58). The changes in mitral flow velocity during atrial contraction in PAF had reverse correlations with the baseline values before PV isolation (r = -0.84). The changes in systolic and diastolic PV flow velocity of PAF had reverse correlations with the baseline values before PV isolation (r = -0.56, r = -0.66). CONCLUSION: The baseline LA function may affect AF recurrence as well as the improvement of LA function, and the benefit of successful PV isolation might be greater in CAF than in PAF. PMID- 23461709 TI - Isotope discrimination provides new insight into biological nitrogen fixation. PMID- 23461710 TI - Quality of water in hemodialysis centers in Baghdad, Iraq. AB - Dialysis water quality is one of the important parameters all over the world because of its direct influence on the health of kidney patients. In Iraq, there are more than 20 dialysis centers; most of them contain identical units for the production of dialysis water. In this work, the quality of water used for dialysis in six dialysis centers located within Baghdad hospitals was evaluated. Samples of product water from each of the six dialysis centers were examined for total heterotrophic bacteria, endotoxin, and chemical contaminants. Endotoxin was measured on-site using a portable instrument. Bacteriological and chemical examinations were done in the laboratory after collecting samples from each dialysis center. The results showed a fluctuation in the produced water quality that makes the produced water unaccepted when compared with international standards. Bacterial counts for 60% of the analyzed samples were above the action level (50 colony-forming units[CFU]/mL), while five out of the six dialysis centers showed values higher than the maximum value (100 CFU/mL). Chemical analysis showed that the dialysis water quality suffers from elevated aluminum concentration for all dialysis centers. All hemodialysis centers need thorough monitoring and preventive maintenance to ensure good water quality. In addition, it is important to revise the design of the water treatment units according to the feed and product water quality. PMID- 23461711 TI - Assessments of functional status, comorbidities, polypharmacy, nutritional status and sarcopenia in Turkish community-dwelling male elderly. AB - Functionality, comorbidities, polypharmacy, nutritional status and sarcopenia affect the prognosis of elderly excessively. These parameters are influenced by the population, living settings and age. We aimed to study these parameters in Turkish community-dwelling male elderly. We studied 274 male elderly >=60 years of age admitted to our Geriatrics outpatient clinics. Mean age was 74.4 +/- 7.1 years; 47.4% of the subjects were >=75 years, 24.1% were >=80 years. Mean activities-of-daily-living (ADL) and instrumental ADL (IADL) scores were 9.4 and 11.1, respectively. Patients with at least one-dependence at ADL-IADL were 22.6% 47.2%, and more than half-dependence at ADL-IADL were 2.8%-17.9%, respectively. Mean number of comorbidities were 2.6. Most common diagnosis was hypertension with 65%; mean number of drugs were 4.5; 55.3% were using >=4 chronic drugs. Prevalences of malnutrition were 3.7%-6.9%, malnutrition risk were 23.5%-26.7% by the mini nutritional assessment test-long form and short form, respectively. Calf circumference was measured <31 cm in 10.5%. Our findings suggest that Turkish community-dwelling male elderly may have greater prevalences of functional dependence, sarcopenia but lower rates of malnutrition and similar rates of polypharmacy compared with the western developing countries and developed countries. This study emphasized the geographical differences in and/or between the individual countries highlighting the need for studies both country- and world-wide. PMID- 23461712 TI - Anatomic fitting of total artificial hearts for in vivo evaluation. AB - Successful anatomic fitting of a total artificial heart (TAH) is vital to achieve optimal pump hemodynamics after device implantation. Although many anatomic fitting studies have been completed in humans prior to clinical trials, few reports exist that detail the experience in animals for in vivo device evaluation. Optimal hemodynamics are crucial throughout the in vivo phase to direct design iterations and ultimately validate device performance prior to pivotal human trials. In vivo evaluation in a sheep model allows a realistically sized representation of a smaller patient, for which smaller third-generation TAHs have the potential to treat. Our study aimed to assess the anatomic fit of a single device rotary TAH in sheep prior to animal trials and to use the data to develop a three-dimensional, computer-aided design (CAD)-operated anatomic fitting tool for future TAH development. Following excision of the native ventricles above the atrio-ventricular groove, a prototype TAH was inserted within the chest cavity of six sheep (28-40 kg). Adjustable rods representing inlet and outlet conduits were oriented toward the center of each atrial chamber and the great vessels, with conduit lengths and angles recorded for future analysis. A three-dimensional, CAD-operated anatomic fitting tool was then developed, based on the results of this study, and used to determine the inflow and outflow conduit orientation of the TAH. The mean diameters of the sheep left atrium, right atrium, aorta, and pulmonary artery were 39, 33, 12, and 11 mm, respectively. The center-to-center distance and outer-edge-to-outer-edge distance between the atria, found to be 39 +/- 9 mm and 72 +/- 17 mm in this study, were identified as the most critical geometries for successful TAH connection. This geometric constraint restricts the maximum separation allowable between left and right inlet ports of a TAH to ensure successful alignment within the available atrial circumference. PMID- 23461713 TI - Publication bias in pediatric hematology and oncology: analysis of abstracts presented at the annual meeting of the American Society of Pediatric Hematology and Oncology. AB - Publication bias (PB) is a threat to the validity of medical literature, and has not been studied in the field of pediatric hematology/oncology. We analyzed the abstracts presented at the 2005 American Society of Pediatric Hematology/Oncology annual meeting to assess for PB. Abstracts were categorized by type of research, number of centers, funding status, presentation format, sample size, statistical significance, and the direction of results. Publication status was determined by searching PubMed. Thirty nine abstracts (51%) were categorized as clinical studies, 67 (36%) as basic research, and 24 (13%) as others. One hundred and twenty three abstracts (67%) were considered to have positive results, 14 (8%) negative results, and 47 (25%) with neutral or not stated results. About 62% of the abstracts were published in peer-reviewed journals at a median time to publication of 19 months (IQR = 11-29 months). Abstracts with positive results were more likely to get published than others (combined negative and neutral results) (P = .002). Factors like sample size, number of centers, or statistical significance reporting did not affect the publication rate. Our data suggests the existence of PB in the field of pediatric hematology/oncology. Still, further analysis of other international meetings is needed to validate our findings. PMID- 23461714 TI - A perforin-like protein mediates disruption of the erythrocyte membrane during egress of Plasmodium berghei male gametocytes. AB - Successful gametogenesis of the malaria parasite depends on egress of the gametocytes from the erythrocytes within which they developed. Egress entails rupture of both the parasitophorous vacuole membrane and the erythrocyte plasma membrane, and precedes the formation of the motile flagellated male gametes in a process called exflagellation. We show here that egress of the male gametocyte depends on the function of a perforin-like protein, PPLP2. A mutant of Plasmodium berghei lacking PPLP2 displayed abnormal exflagellation; instead of each male gametocyte forming eight flagellated gametes, it produced gametocytes with only one, shared thicker flagellum. Using immunofluorescence and transmission electron microscopy analysis, and phenotype rescue with saponin or a pore-forming toxin, we conclude that rupture of the erythrocyte membrane is blocked in the mutant. The parasitophorous vacuole membrane, on the other hand, is ruptured normally. Some mutant parasites are still able to develop in the mosquito, possibly because the vigorous motility of the flagellated gametes eventually leads to escape from the persisting erythrocyte membrane. This is the first example of a perforin-like protein in Plasmodium parasites having a role in egress from the host cell and the first parasite protein shown to be specifically required for erythrocyte membrane disruption during egress. PMID- 23461715 TI - Ultrasensitive label free electrical detection of insulin in neat blood serum. AB - Electrical assays potentially offer a highly sensitive, cheap, portable, automated, and multiplexed means of protein biomarker detection, characteristics with an ability to underpin both disease stratification and the development of point of care diagnostics. Most conveniently applied in a reagent free manner, all sensitive assays such as these suffer, however, from profound problems when applied in complex fluids such as blood serum. We report herein, the development, and clinical application, of a highly sensitive and selective electrical insulin biosensor based on a chemisorbed zwittorionic polymer support and a novel reagentless sensing technique based on phase monitoring electrochemical impedance spectroscopy. The polymer adlayer is exceptionally effective in both reducing background response and maintaining receptive antibody binding efficacy, while the non-Faradaic analysis avoids potential interference from background electro active molecules. Applied to the detection of even a low molecular weight protein (here, insulin), a linear range from 0.1 to 200 pM and an unprecedented femtomolar detection limit are possible in undiluted blood serum. PMID- 23461717 TI - Risk factors, antithrombotic treatment and outcome in retinal vein occlusion: an age-related prospective cohort study. AB - OBJECTIVES: Antithrombotic treatment for retinal vein occlusion (RVO) is controversial, although RVO has been surmised as a predictor of a subsequent vascular event. We aimed to evaluate risk factors, the effects of antithrombotic therapy and the occurrence of subsequent vascular events in patients with a first episode of RVO, according to age of RVO onset. METHODS: In this prospective cohort study, patients with central (CRVO) and branch RVO (BRVO) confirmed by fluorescein angiography were studied; they were divided according to age. Cardiovascular risk factors and thrombophilia were evaluated. Anticoagulants or aspirin were given for at least 3 months. Patients were followed every 6-12 months and vascular events were recorded. RESULTS: One hundred CRVO and 32 BRVO patients were enrolled. Five of 60 (8.3%) patients <50 yr and 4/72 (5.5%) over 50 yr had a hereditary thrombophilic defect. One or more cardiovascular risk factors were found in 35 (58%) patients of the younger group, and in 66 (91%) of the older group (P < 0.001). Antithrombotic treatment led to both a satisfactory recanalization of occluded veins and visual acuity improvement especially in younger patients. Vascular events occurred in 19 (14%) cases after 4 +/- 3.3 yr from RVO, more frequently in older than in younger patients (22% vs. 5%, P = 0.005). CONCLUSIONS: Distribution of cardiovascular, but not of thrombophilic risk factors seems to be influenced by age in RVO patients. Patients with a first RVO, especially those >50 yr, are likely at risk of a subsequent vascular event. PMID- 23461718 TI - News from the Biological Stain Commission No. 14. AB - In the 14(th) issue of News from the Biological Stain Commission (BSC) the BSC's International Affairs Committee presents information from the meetings of ISO/TC 212/WG 3, In vitro diagnostic products, and from the final plenary meeting of ISO/TC 212, Clinical laboratory testing and in vitro diagnostic test systems, held on 17-19 October 2011 in Las Vegas, NV. Information is also presented from the 26th meeting of CEN/TC 140, In vitro diagnostic medical devices, held on 5 December 2011 in Berlin, Germany. PMID- 23461719 TI - Diagnostic terminology for urinary cytology reports including the new subcategories 'atypical urothelial cells of undetermined significance' (AUC-US) and 'cannot exclude high grade' (AUC-H). AB - OBJECTIVE: We studied whether atypical, non-superficial urothelial cells (AUC) could be separated into new subcategories including AUC 'of undetermined significance' (AUC-US) and 'cannot exclude high grade'' (AUC-H) in order to help to standardize urine cytopathology reports, as it is widely accepted in the Bethesda system for gynaecological cytopathology. METHODS: We investigated whether AUC-US and AUC-H, defined by distinctive cytological criteria, might be separated with statistical significance according to actual diagnosis and follow up data. A series of 534 cyto-histological comparisons taken in 139 patients, including 221 AUC at various steps of their clinical history was studied. There were 513 (96.1%) postcystoscopy and 469 (87.8%) ThinPrep(r) liquid-based specimens (95.9% and 89.1% of AUC cases, respectively). Patients viewed between 1999 and 2011 had histological control in a 0- to 6-months delay and were followed-up during an additional 5.9 +/- 9.2 (0- to 56-) months period. RESULTS: The 221 AUC represented 0.8-2% of the specimens viewed during the study period. Among AUC-H cases, 70 out of 185 (37.8%) matched with high-grade lesions, compared with 3 of 38 (8.3%) of AUC-US cases (P = 0.0003). Conservatively treated patients with AUC-H more frequently developed high-grade lesions than those with AUC-US (54.1% versus 16.7%, P = 0.0007) with a 17.6-months mean delay. Nuclear hyperchromasia, a nuclear to cytoplasm (N/C) ratio > 0.7 and the combination of both were the more informative diagnostic criteria, all with P < 0.01. CONCLUSION: We conclude that the new subcategories could help to standardize urine cytopathology reports and contribute to the patient's management, provided it is validated by multicentric studies. PMID- 23461716 TI - Use of pre-operative steroids in liver resection: a systematic review and meta analysis. AB - BACKGROUND: By attenuating the systemic inflammatory response to major surgery, the pre-operative administration of steroids may reduce the incidence of complications. METHODS: A systematic review was conducted to identify randomized controlled trials (RCT) comparing pre-operative steroid administration with placebo during a liver resection. Meta-analyses were performed. RESULTS: Five RCTs were identified including a total of 379 patients. Pre-operative steroids were associated with statistically significant reductions in the levels of serum bilirubin and interleukin 6 (IL-6) on post-operative day one. There was a trend towards a lower incidence of post-operative complications and prothrombin time (PT), but this did not reach statistical significance. CONCLUSION: Pre-operative steroids may be associated with a clinically significant benefit in liver resection. PMID- 23461720 TI - A GPR18-based signalling system regulates IOP in murine eye. AB - BACKGROUND AND PURPOSE: GPR18 is a recently deorphaned lipid receptor that is activated by the endogenous lipid N-arachidonoyl glycine (NAGly) as well the behaviourally inactive atypical cannabinoid, abnormal cannabidiol (Abn-CBD). The presence and/or function of any GPR18-based ocular signalling system remain essentially unstudied. The objectives of this research are: (i) to determine the disposition of GPR18 receptors and ligands in anterior murine eye, (ii) examine the effect of GPR18 activation on intraocular pressure (IOP) in a murine model, including knockout mice for CB1, CB2 and GPR55. EXPERIMENTAL APPROACH: IOP was measured in mice following topical application of Abn-CBD, NAGly or the GPR55/GPR18 agonist O-1602, alone or with injection of the GPR18 antagonist, O 1918. GPR18 protein localization was assessed with immunohistochemistry. Endocannabinoids were measured using LC/MS-MS. KEY RESULTS: GPR18 protein was expressed most prominently in the ciliary epithelium and the corneal epithelium and, interestingly, in the trabecular meshwork. The GPR18 ligand, NAGly, was also detected in mouse eye at a level comparable to that seen in the brain. Abn-CBD and NAGly, but not O-1602, significantly reduced IOP in all mice tested. The antagonist, O-1918, blocked the effects of Abn-CBD and NAGly. CONCLUSIONS AND IMPLICATIONS: We present evidence for a functional GPR18-based signalling system in the murine anterior eye, including receptors and ligands. GPR18 agonists, Abn CBD and NAGly, reduce IOP independently of CB1, CB2 or GPR55. These findings suggest that GPR18 may serve as a desirable target for the development of novel ocular hypotensive medications. PMID- 23461721 TI - Events of wound healing/regeneration in the canine supraalveolar periodontal defect model. AB - AIM: The objective of this research was to elucidate early events in periodontal wound healing/regeneration using histological and immunohistochemical techniques. METHODS: Routine critical-size, supraalveolar, periodontal defects including a space-providing titanium mesh device were created in 12 dogs. Six animals received additional autologous blood into the defect prior to wound closure. One animal from each group was killed for analysis at 2, 5, 9, 14 days, and at 4 and 8 weeks. RESULTS: Both groups behaved similarly. Periodontal wound healing/regeneration progressed through three temporal phases. Early phase (2-5 days): heterogeneous clot consolidation and cell activation in the periodontal ligament (PDL) and trabecular bone was associated with PDL regeneration and formation of a pre-osteoblast population. Intermediate phase (9-14 days): cell proliferation (shown by PCNA immunostaining)/migration led to osteoid/bone, PDL and cementum formation. Late phase (4-8 weeks): primarily characterized by tissue remodelling/maturation. Fibrous connective tissue from the gingival mucosa entered the wound early, competing with regeneration. By day 14, the wound space was largely filled with regenerative and reparative tissues. CONCLUSION: Activation of cellular regenerative events in periodontal wound healing/regeneration is rapid; the general framework for tissue formation is broadly outlined within 14 days. Most bone formation apparently originates from endosteally derived pre-osteoblasts; the PDL possibly acting as a supplementary source, with a primary function likely being regulatory/homeostatic. Blood accumulation at the surgical site warrants exploration; supplementation may be beneficial. PMID- 23461722 TI - Synthesis of beta-halo-pyrrolidinones through a tandem sequence of 5-endo halolactamization and C-H oxidative functionalization. AB - A tandem sequence of 5-endo halolactamization and direct C-H oxidative functionalization is described. A range of beta-halo-pyrrolidinones can be efficiently synthesized using this method, making it an excellent approach for constructing natural products containing pyrrolidinones. PMID- 23461723 TI - Resuscitation skills of pediatric residents and effects of Neonatal Resuscitation Program training. AB - BACKGROUND: The Neonatal Resuscitation Program (NRP) is an effective tool in decreasing mortality and morbidity due to birth asphyxia. The aim of the study was to assess the skill and knowledge level of pediatric residents in a teaching hospital and the effects of NRP training. METHODS: Subjects consisted of pediatric residents of Dr Behcet Uz Hospital, Izmir, Turkey. They were assessed on practice exam scenarios and NRP provider course flow charts. Teams with two members were formed randomly. Each resident was evaluated on a 100 point scale covering all resuscitation steps and interventions. Exam scores were analyzed for two major parameters: resident participation in NRP training (never, within the last 6 months, and >=6 months previously) and being a senior (>18 months residency). RESULTS: A total of 49 residents enrolled in the study (94.2% of the target group). Twenty-one residents had NRP training (42.9%). Junior residents comprised 46.9% of the study group. The mean skill score was 72.1, and it was significantly higher for senior residents and residents who attended the NRP course (P < 0.05). Although there was no difference between the members within a team, residents who had not attended the NRP course performed better when paired with a resident with NRP certification. CONCLUSIONS: NRP training significantly increases the resuscitation knowledge and skill of pediatric residents, although this can be achieved by being a senior. Residents should undergo training as soon as possible to achieve a higher level of quality in resuscitating babies. PMID- 23461724 TI - Analysis of MEF2A mutations in a Chinese population with premature coronary artery disease. AB - AIMS: To assess the relationship between mutations of the myocyte enhancer factor 2A (MEF2A) and premature coronary artery disease (PCAD) in a Chinese population. METHODS AND RESULTS: The mutations in the exons 8 and 12 of the MEF2A gene were analyzed in both PCAD families and sporadic cases using direct sequencing of polymerase chain reaction products. In one PCAD family, seven members of the third generation were all diagnosed with CAD, and five of them had PCAD. All five members with PCAD displayed a mutation of the TT genotype in the site of 1353 G/T. Moreover, three of them (3/5) had a mutation of the DW genotype in the site of 1291-1293 CCG W/D. In sporadic cases, we also found that the haplotype of 1291 1293 CCG D+1305 G+1353 T was significantly associated with PCAD. CONCLUSIONS: The mutations of MEF2A exon 12 are implicated in PCAD, suggesting a strong genetic component in the pathogenesis of PCAD in the Chinese population. PMID- 23461725 TI - Association between TPH2 gene polymorphisms and attention deficit hyperactivity disorder in Korean children. AB - Attention deficit hyperactivity disorder (ADHD) is a common disorder of the school-age population. ADHD is a familial disorder and genetic studies estimate heritability at 80%-90%. The aim of the present study was to investigate the association between the genetic type and alleles for the TPH2 gene in Korean children with ADHD. The sample consisted of 142 ADHD children and 139 control children. We diagnosed ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 281 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for TPH2 polymorphism. Alleles and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of TPH2 gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the frequencies of the rs11179027 (odd ratio [OR]=2.12, 95% confidence interval [CI]=1.13-3.97, p=0.020) and rs1843809 (OR=0.48, 95% CI=0.24-0.97, p=0.040) of alleles of TPH2, but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggested that TPH2 might be related to ADHD symptoms. PMID- 23461726 TI - Selectivity and quality. PMID- 23461727 TI - Retraction of: "DNA and cell resonance: magnetic waves enable cell communication," by Konstantin Meyl, DNA and Cell Biology (2012;31:422-426). PMID- 23461728 TI - Inbreeding effects on quantitative traits in random mating and selected populations of the mulberry silkworm, Bombyx mori. AB - The objective of the present study was to estimate the level of inbreeding coefficient during inbreeding of the pedigree of random mating and selected populations of two distinct races of mulberry silkworm, Bombyx mori (Lepidoptera: Bombycidae), in the silkworm germplasm. The six generation data of the two races, namely multivoltine Pure Mysore and bivoltine NB4D2, were studied for inbreeding depression coefficient using the residual maximum likelihood method, utilizing two statistical models by analyzing six quantitative traits, namely, larval weight, cocoon weight, shell weight, shell ratio, pupation rate, and filament length. The results of the present experiment demonstrated that the inbreeding coefficient was significant in Model 1 for most of the economic traits in the random mating populations of both the races compared to those of selected populations. These results suggest that during stock maintenance, application of rigid selection for increased numbers of generations helps to retain original characteristics of the pure races while reducing the deleterious effects of inbreeding. The significance of inbreeding coefficient is discussed with reference to the inbreeding of silk moths in the silkworm germplasm. PMID- 23461729 TI - High-performance triethylsilylethynyl anthradithiophene transistors prepared without solvent vapor annealing: the effects of self-assembly during dip-coating. AB - Solution-processable small-molecule organic semiconductors have recently attracted significant attention for use as the active channel layers in organic field-effect transistors due to their good intrinsic charge carrier mobility and easy processability. Dip-coating is a good method for optimizing the film morphology and molecular ordering of the small-molecular semiconductors because the drying speed can be quantitatively controlled at the air-solution-substrate contact line. Here, we report the preparation of highly crystalline triethylsilylethynyl-anthradithiophene (TES-ADT) crystal arrays that exhibit an excellent field-effect mobility (up to 1.8 cm(2)/(V s)) via an optimized one-step dip-coating process. High-quality TES-ADT crystals were grown without solvent vapor annealing postprocessing steps, which were previously thought to be essential for improving the morphology, crystallinity, and electrical characteristics of TES-ADT thin films. An interesting correlation between the optimal pull-out rate and the self-assembly tendencies of some soluble acene semiconductors was observed, and the origin of the correlation was investigated. Our work demonstrates an alternative simple approach to achieving highly crystalline TES-ADT thin films, and further proposes a prospective method for optimizing the formation of thin films via the molecular self-assembly of soluble acenes. PMID- 23461730 TI - Discrimination of redox-responsible biomolecules by a single molecular sensor. AB - A new application of a fluorescent sensor (PyDPA) for the discrimination of redox responsible molecules is reported. Nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD(+)/NADP(+)) and flavin mononucleotide/flavin adenine dinucleotide (FMN/FAD) were differentiated by means of ratiometric fluorescence change from excimer-monomer equilibrium and time-dependent fluorescence change, respectively. PMID- 23461731 TI - Syntheses of taiwaniaquinone F and taiwaniaquinol A via an unusual remote C-H functionalization. AB - A protecting-group-free route to (-)-taiwaniaquinone F based on a ring contraction and subsequent aromatic oxidation of a sugiol derivative is reported. In addition, the first synthesis of (+)-taiwaniaquinol A is reported via short time exposure of (-)-taiwaniaquinone F to sunlight triggering a remote C-H functionalization. The hypothesis that the biogenesis of some methylenedioxy bridged natural products could proceed via similar nonenzymatic mechanisms is presented. PMID- 23461732 TI - Remotely controlled diffusion from magnetic liposome microgels. AB - The reversible, temperature-dependent change in the permeability of a phospholipid bilayer has been used for controlling the diffusion rate of encapsulated molecular payload from liposomes. Liposomes were preloaded with a fluorescent dye and immobilized in calcium alginate hydrogel microparticles that also contained iron oxide nanoparticles. The composite microparticles were produced by a drop-on-demand inkjet method. The ability of iron oxide nanoparticles to locally dissipate heat upon exposure to a radio-frequency (RF) alternating magnetic field was used to control the local temperature and therefore diffusion from the liposomes in a contactless way using an RF coil. Several different release patterns were realized, including repeated on-demand release. The internal structure of the composite alginate-liposome-magnetite microparticles was investigated, and the influence of microparticle concentration on the heating rate was determined. In order to achieve a temperature rise required for the liposome membrane melting, the concentration of alginate beads should be at least 25% of their maximum packing density for the nanoparticle concentration and specific absorption rate used. PMID- 23461733 TI - In silico prediction of human serum albumin binding for drug leads. AB - INTRODUCTION: Binding of drugs to human serum albumin (HSA) strongly influences their pharmacokinetic behavior and is associated with drug safety issues, low clearance, low brain penetration, as well as drug-drug interactions. Thus, in silico prediction of HSA binding contributes significantly to the discovery of new drug candidates. AREAS COVERED: The authors provide a short overview on the principles of HSA binding and the crystal structure of HSA, as well as discussing and analyzing the recent structure- and ligand-based HSA binding models. The authors also present the advantages and limitations of each methodology to construct efficient local or global models and outline the critical structural features contributing to HSA. EXPERT OPINION: The in silico estimation of drug binding to HSA in early drug discovery contributes to the lead optimization process. Local models are useful for the design of new compounds with reduced HSA binding for a particular target receptor, while real-time quantitative structure activity relationships or global models combining structure- and ligand-based approaches serve for compound libraries screening. However, research efforts on other important plasma proteins should be strengthened in the perspective to enable predictions of total plasma protein binding for clinical candidates. PMID- 23461734 TI - Electron tomography of Plasmodium falciparum merozoites reveals core cellular events that underpin erythrocyte invasion. AB - Erythrocyte invasion by merozoites forms of the malaria parasite is a key step in the establishment of human malaria disease. To date, efforts to understand cellular events underpinning entry have been limited to insights from non-human parasites, with no studies at sub-micrometer resolution undertaken using the most virulent human malaria parasite, Plasmodium falciparum. This leaves our understanding of the dynamics of merozoite sub-cellular compartments during infectionincomplete, in particular that of the secretory organelles. Using advances in P. falciparum merozoite isolation and new imaging techniques we present a three-dimensional study of invasion using electron microscopy, cryo electron tomography and cryo-X-ray tomography. We describe the core architectural features of invasion and identify fusion between rhoptries at the commencement of invasion as a hitherto overlooked event that likely provides a critical step that initiates entry. Given the centrality of merozoite organelle proteins to vaccine development, these insights provide a mechanistic framework to understand therapeutic strategies targeted towards the cellular events of invasion. PMID- 23461735 TI - Testing of midwife neonatal resuscitation skills with a simulator manikin in a low-risk delivery unit. AB - BACKGROUND: Expertise in neonatal resuscitation is essential for personnel involved in the care of newborns. In this observational cohort study the skills of 52 midwives in a simulated scenario were assessed. METHODS: A total of 52 midwives in a low-risk unit and five specialist nurses in a high-risk unit were tested to establish their competence in newborn resuscitation. The 52 midwives were divided into groups 1 (n = 39; no pretest training) and 2 (n = 13; 1 day training prior to study). The video-recorded test scenario was a newborn with asphyxia. Thirty items were graded by a neonatologist and nursing team in real time. Using the Angoff method, a pass score was 18.71 for skills that were graded 0 or 1. RESULTS: The average score of specialist nurses was 26 (range, 23-29). A total of 49% of midwives in group 1 and 92% in group 2 passed the test. The average score was 17.7 (range, 9-25) in group 1 and 21.9 (range, 17-27) in group 2. A total of 27% and 77% of midwives in groups 1 and 2, respectively, carried out ventilation at a frequency as per the algorithm. Mask leakage was higher in group 1 (44%) versus group 2 (23%). Five and three midwives in groups 1 and 2, respectively, overexpanded the lungs. CONCLUSION: Many midwives had imperfect resuscitation skills. A 1 day course improved such skills. The standard scenario is an objective and useful performance marker in assessing and documenting improvements in competence in delivery room resuscitation. PMID- 23461736 TI - Cyanated diazatetracene diimides with ultrahigh electron affinity for n-channel field effect transistors. AB - Several diazatetracene diimides with high electron affinity (up to 4.66 eV!) were prepared and well characterized. The LUMO energy level of these electron deficient molecules was found to be closely related to their material stability. Compound 7 with ultrahigh electron affinity suffered from reduction and hydrolysis in the presence of silica gel or water. The stable compounds 3 and 6 showed n-channel FET behavior with an average electron mobility of 0.002 and 0.005 cm(2) V(-1) s(-1), respectively, using a solution processing method. PMID- 23461737 TI - Sodium removal and peritoneal dialysis modalities: no differences with optimal prescription of icodextrin. AB - Continuous ambulatory peritoneal dialysis (CAPD) has been considered as a more efficient modality for sodium removal than automated peritoneal dialysis (APD), due to the longer dwell times and the sodium sieving phenomenon. However, because studies regarding sodium removal in peritoneal dialysis (PD) report rather controversial results and carry various methodological flaws, it remains uncertain whether they offer enough significant information regarding PD prescription and therapy. The aim of the present observational cross-sectional study was to evaluate the impact of the optimal prescription of CAPD and APD, regarding solute clearances and daily ultrafiltrate, on daily sodium removal. Forty-six (46) patients aged 52.3 +/- 14 years were studied. Twenty-six (26) patients were subjected to CAPD, and 20 patients were subjected to APD. Ten (10) patients per group were prescribed icodextrin for the long dwell to achieve optimal adequacy and ultrafiltration (UF) targets. CAPD patients removed a higher, albeit not statistically significant, daily amount of sodium (131.7 +/- 98.2 mmol) compared with APD patients (79.4 +/- 129.2 mmol). Their Kt/V urea was lower (1.48 +/- 0.3 vs. 2.17 +/- 0.33, P < 0.05), and there were no differences on daily UF (1119 +/- 533 vs. 1005 +/- 517 mL). In both groups, icodextrin use for the long dwell resulted in equal sodium removal with that of patients not prescribed icodextrin. Our results, derived from an unselected PD population, indicate that although classic CAPD may be more efficient for sodium removal than APD, the use of icodextrin as an adjuvant for higher daily UF not only increases solute clearance but also removes more sodium for both modalities. In addition, calculations of sodium removal in PD do not seem to benefit the everyday clinical practice, provided that PD patients can achieve the adequacy targets and present optimal daily UF without signs of volume overload. PMID- 23461738 TI - A theoretical rationale why furan-side monoadduct is more favorable toward diadduct formation in 8-methoxypsoralen and thymine complexes. AB - The photoinduced mechanism of formation of mono- and diadducts between 8-MOP and thymine bases is studied using the ONIOM(MPWB1K/6-31 + G(d,p):B3LYP/6 31G(d,p):UFF) and B3LYP/6-31 + G(d,p) methods. The relevant cycloaddition displays favorable energy barriers and reaction energies in the triplet excited state, which involves the initial formation of a diradical followed by ring closure via singlet-triplet interaction. The monoadduct on the pyrone side is favored over the furan side when comparing reaction energies. The distinguishing feature in the formation of the monoadducts is that the furan-side adduct displays a better photostability, which is a relatively high-barrier exothermic reaction, and thus the energy balance of the monoadduct on the furan side toward final diadduct formation is favored. PMID- 23461739 TI - To reduce alcohol-related harm we need to look beyond pubs and nightclubs. PMID- 23461740 TI - An overlooked complication of hemodialysis: hoarseness. AB - In hemodialysis patients, some degree of transient hoarseness may occur at the end of the dialysis, and it may be a wearisome, recurrent, and severe state for some hemodialysis patients. However, to date, it has not been a well-defined complication of hemodialysis. The aim of this study was to state this complication and to throw light on it. Four hundred fifty-nine hemodialysis patients were questioned about any change in voice quality during hemodialysis. The patients who had this complaint (n=70) were included in the study, and the group of patients who suffered hoarseness (subgroup 1: severe, subgroup 2: moderate, subgroup 3: mild) were compared with each other and with the control group, which did not suffer hoarseness (n=51). Hoarseness was found in 15.2% of the hemodialysis patients. The duration of their hoarseness was minimum 1 to maximum 24 hours. In the control group, coronary artery disease (P=0.056), congestive heart failure (P=0.049), autonomic neuropathy (P=0.001), severe intradialytic hypotensive attacks (P=0.000), heart valve abnormalities (P=0.000), and left ventricular diastolic dysfunction (P=0.000) were significantly lower than in hoarseness group. Older age (P=0.024), coronary artery disease (P=0.014), autonomic neuropathy (P=0.011), and intradialytic hypotensive attacks (P=0.0001), were associated with severe and moderate hoarseness. In the comparison of % change for systolic and diastolic blood pressure between the hoarseness subgroups, diastolic blood pressure change was not different (P=0.521), but systolic blood pressure change was statistically lower in mild group than moderate (P=0.033) and severe subgroup (P=0.029). Dialysis-induced hypotension may be the main contributor of transient hoarseness. Especially elderly and cardiovascularly compromised patients, who are vulnerable to rapid changes in volume status may experience it to serious extent and this complication may be mediated by autonomic nervous control related with volume depletion. PMID- 23461741 TI - A new record of longicorn beetle, Acanthophorus rugiceps, from India as a root borer on physic nut, Jatropha curcas, with a description of life stages, biology, and seasonal dynamics. AB - Longicorn beetle, Acanthophorus rugiceps Gahan (Coleoptera: Cerambycidae), is reported for the first time as a confirmed host on physic nut, Jatropha curcas L. (Malpighiales: Euphorbiaceae), from India, causing extensive damage to roots. Plants of three years age and above were prone to attack by this pest. In a six year study beginning in 2005, about 11.3 percent of plants in a 16.25 acre physic nut plantation were severely damaged by A. rugiceps. Life stages of A. rugiceps, including egg, larvae, pupae, and adult, are described with a note on their habitat, biology, and behavior. Strategies to manage this pest on physic nut are discussed. PMID- 23461742 TI - Confocal laser endomicroscopic findings in a case of signet ring cell gastric carcinoma. PMID- 23461743 TI - Intermittent invagination of a terminal ileal carcinoid tumor. PMID- 23461744 TI - Carbon dioxide insufflation for endoscopic retrograde cholangiopancreatography: is this beneficial for all patients? PMID- 23461745 TI - Continuous negative pressure can improve endoscopic naso-pancreatic drainage. PMID- 23461746 TI - Targeted nanoparticles assembled via complexation of boronic-acid-containing targeting moieties to diol-containing polymers. AB - The delivery of therapeutics via nanoscaled vehicles for solid cancer treatment can be enhanced by the incorporation of a targeting capability. Here, we describe a new method for assembling a targeted nanoparticle that utilizes the reversible covalent complexation between boronic acids and diols to achieve a targeted nanoparticle for the delivery of the anticancer drug camptothecin (CPT). CPT is conjugated to a biocompatible, hydrophilic copolymer of mucic acid and PEG (MAP). When this polymer-drug conjugate is placed in water, it self-assembles into MAP CPT nanoparticles of ca. 30 nm (diameter) and slightly negative zeta potential. The antibody Herceptin is attached to a boronic acid via a polyethylene glycol (PEG) spacer, and this boronic acid-containing targeting moiety is complexed with the diol-containing MAP to form a targeted MAP-CPT nanoparticle. The addition of Herceptin targeting agent to the MAP-CPT nanoparticles yields targeted MAP-CPT nanoparticles with increased nanoparticle size to ca. 40 nm (diameter). The main mechanisms of CPT release from MAP-CPT nanoparticles are found by in vitro analysis to be hydrolysis and nanoparticle disruption by fat. Cellular uptake of nanoparticles is enhanced by 70% compared to nontargeted version by the incorporation of a single Herceptin antibody targeting agent per nanoparticle. This single Herceptin antibody targeted MAP-CPT nanoparticle system carries ca. 60 CPT molecules per nanoparticle and shows prolonged plasma circulation with an elimination half-life of 21.2 h and AUC value of 2766 MUg.h/mL at a 10 mg CPT/kg tail vein injection in mice. PMID- 23461747 TI - Biologic width dimensions--a systematic review. AB - BACKGROUND: Consideration of the biologic width in restorative dentistry seems to be important for maintaining periodontal health. OBJECTIVE: To evaluate the dimensions of the biologic width in humans. MATERIALS AND METHODS: A systematic literature search was performed for publications published by 28 September 2012 using five different electronic databases; this search was complemented by a manual search. Two reviewers conducted the study selection, data collection, and validity assessment. The PRISMA criteria were applied. From 615 titles identified by the search strategy, 14 publications were included and six were suitable for meta-analyses. RESULTS: Included studies were published from the years 1924 to 2012. They differed with regard to measurements of the biologic width. Mean values of the biologic width obtained from two meta-analyses ranged from 2.15 to 2.30 mm, but large intra- and inter-individual variances (subject sample range: 0.2 - 6.73 mm) were observed. The tooth type and site, the presence of a restoration and periodontal diseases/surgery affected the dimensions of the biologic width. Pronounced heterogeneity among studies regarding methods and outcome measures exists. CONCLUSIONS: No universal dimension of the biologic width appears to exist. Establishment of periodontal health is suggested prior to the assessment of the biologic width within reconstructive dentistry. PMID- 23461748 TI - Cerebral hyperperfusion syndrome after revascularization surgery in patients with moyamoya disease. AB - Moyamoya disease (MMD) is a progressive occlusive disease of the distal internal carotid artery that is primarily treated by superficial temporal artery-middle cerebral artery (STA-MCA) bypass. Despite its effectiveness, several postoperative complications have been reported with STA-MCA bypass. Cerebral hyperperfusion syndrome (CHS) after STA-MCA has attracted considerable attention as a hemodynamics-related complication because more cases of CHS after STA-MCA bypass are reported in MMD than in non-MMD patients. The mechanisms underlying CHS after revascularization in MMD patients are poorly understood. This report presents a comprehensive review of the literature on CHS after revascularization in MMD patients, focusing on the pathogenesis, clinical features, imaging techniques, treatment, and prognosis of CHS. Impaired cerebrovascular autoregulation has been implicated in the pathogenesis of CHS, which is characterized by unilateral headache, face and eye pain, seizures, and focal neurological deficits secondary to cerebral edema, and intracranial hemorrhage. Imaging techniques, such as single photon emission computed tomography (SPECT), 3 T magnetic resonance imaging/angiography, and selective arterial spin-labeling magnetic resonance imaging, are valuable for identifying patients at risk for CHS. Treatment strategies include strict blood pressure control, intracranial hemorrhage prevention, and free oxygen radical scavenger administration. Most patients can achieve a satisfying prognosis after effective treatment. PMID- 23461749 TI - Wide variation and systematic bias in expert clinicians' perceptions of prognosis following brain injury. AB - BACKGROUND: The heterogeneous nature of traumatic brain injury (TBI) makes outcome prediction difficult. Although a considerable evidence base exists in the form of well-validated predictive models, these models are not widely used. We hypothesised that this prognostic gap, between the availability and use of prognostic data, leads to inaccurate perceptions of patient outcome. We investigated whether outcome predictions in TBI made by expert clinicians were consistent and accurate when compared to a well-validated prognostic model (IMPACT). METHODS: Neurosurgeons and neurointensivists were asked to predict probability of death at 6 months for 12 case vignettes describing patients with isolated TBI. Predictions were compared to IMPACT prognosis for each vignette. To interrogate potential sources of bias in clinical predictions, respondents were given one of two sets of vignettes (A or B) identical apart from one critical factor known to make a large difference to outcome. RESULTS: 27 of 33 questionnaires were returned. Clinicians were consistently more pessimistic about outcomes than the IMPACT model, predicting a significantly greater probability of death (mean difference + 16.3%, 95% CI 13.3-19.4, p < 0.001). There was wide variation between clinicians predicting outcomes for any given vignette (mean range 68.3%), and within the predictions made by each individual: 30% of clinicians were both the most pessimistic respondent, and the most optimistic, for at least one vignette. Clinicians modified their predictions appropriately for most of the factors altered between corresponding vignettes. However when the reported blood glucose was changed, clinicians' predictions deviated widely from IMPACT predictions, indicating that clinicians systematically overlooked the prognostic relevance of this information. CONCLUSION: Clinical experts' predictions of outcome in TBI are widely variable and systematically pessimistic compared to IMPACT. Clinicians overlook important factors in formulating these predictions. Use of well-validated outcome models may add value and consistency to prognostication. PMID- 23461750 TI - Effectiveness and outcomes of surgery for cerebral metastases. AB - INTRODUCTION: The main treatment modalities for single brain metastases are whole brain radiotherapy (WBRT), surgery and stereotactic radiosurgery. Current guidelines recommend complete surgical excision for single cerebral metastases and two randomised controlled trials (RCT) have also found survival benefit of surgery. However, a more recent RCT and a Cochrane review have challenged the effectiveness of surgery for cerebral metastases. This study aims to assess the effectiveness of surgery for cerebral metastases in current practice. MATERIALS AND METHODS: A retrospective review was performed for a single surgeon series of consecutive patients undergoing primary surgery for cerebral metastases between June 2005 and April 2010. The main outcome measure was the survival time after surgery. RESULTS: One hundred and twenty three patients (61 males, 62 females) were identified with a mean age of 58.4 years. Eighty three patients (67%) were under 65 years. The overall 30-day mortality rate was 2.4%. The overall median survival was 10 months. There were 26 (21%) breast cancers with median survival of 13.5 months, 32 (26%) NSCLC with 8.3 months, 24 (19%) melanomas with 6.7 months, 13 (11%) colorectal cancers with 6.4 months, and 11 (9%) renal cell cancers with 13.6 months. The differences were not significant (p > 0.05). However, when the breast cancer group was compared to the NSCLC group, the difference was significant (p = 0.005). The median survival differences were not significant (p > 0.05) with regard to the RPA class, the site (supratentorial or infratentorial) and the number of metastases (single or two). CONCLUSIONS: Median survival in this cohort was identical to those in the two RCTs that showed survival benefits from surgery. This was significantly longer than that (5.6 months) in the single series demonstrating no benefit. Therefore, our results support the previous evidence of improved outcomes with surgery. PMID- 23461751 TI - Comparison of three aids for teaching lumbar surgical anatomy. AB - Reduced surgeons' training time has resulted in a need to increase the speed of learning. Currently, anatomy education involves traditional (textbooks, physical models, cadaveric dissection/prosection) and recent (electronic) techniques. As yet there are no available data comparing their performance. The performance of three anatomical training aids at teaching the surgical anatomy of the lumbar spinal was compared. The aids used were paper-based images, a three-dimensional plastic model and a semitransparent computer model. Fifty one study subjects were recruited from a population of junior doctors, nurses, medical and nursing students. Three study groups were created which differed in the order of presenting the aids. For each subject, spinal anatomy was revised by the investigator, teaching them the anatomy using each aid. They were specifically taught the locations of the intervertebral disc, pedicles and nerve roots in the lateral recesses. They then drew these structures on a response sheet (three response sheets per subject). The computer model was the best at allowing subjects accurately to determine structure location followed by the paper-based images, the plastic model was the worst. Accuracy improved with successive models used but this trend was not significant. Subjects were not versed in spinal anatomy beforehand, so meaningful baseline measures were not available. The educational performance of surgical anatomical training aids can be measured and compared. A computer generated 3 dimensional model gave the best results with paper-based images second and the plastic model third. PMID- 23461752 TI - Preoperative magnetic resonance spectroscopy improves diagnostic accuracy in a series of neurosurgical dilemmas. AB - OBJECT: The purpose of this study was to evaluate the usefulness of preoperative magnetic resonance spectroscopy (MRS) in neurosurgical patients with diagnostically challenging intracranial lesions. METHODS: Included in this study are twenty-three consecutive patients presenting to the neurosurgery service with diagnostically challenging intracranial lesions and who were investigated by conventional MR imaging and proton ((1)H) MRS, followed by surgery with subsequent histopathological diagnosis. An experienced neuroradiologist (RJ) blinded to the final histopathology evaluated the imaging studies retrospectively. Provisional diagnoses based on preoperative clinical and conventional MR data versus preoperative MRS data were compared with definitive histopathological diagnoses. RESULTS: Compared with preoperative clinical and conventional MR data, (1)H MRS improved the accuracy of MR imaging from 60.9% to 83%. We found (1)H MRS reliably distinguished between abscess and high-grade tumour, and between high-grade glioma and low-grade glioma, but was not able to reliably distinguish between recurrent glioma and radiation necrosis. In 12/23 cases (52%) the (1)H MRS findings positively altered our clinical management. Two representative cases are presented. CONCLUSIONS: Our study supports a beneficial role for (1)H MRS in certain diagnostic intracranial dilemmas presenting to neurosurgeons. The information gleaned from preoperative (1)H MRS can be a useful adjunct to clinical and conventional MR imaging data in guiding the management of patients with intracranial pathologies, particularly high-grade tumour versus abscess, and high-grade versus low-grade glioma. Further larger prospective studies are needed to clearly define the utility of (1)H MRS in diagnostically challenging intracranial lesions in neurosurgery. PMID- 23461753 TI - p-Channel oxide thin film transistors using solution-processed copper oxide. AB - Cu2O thin films were synthesized on Si (100) substrate with thermally grown 200 nm SiO2 by sol-gel spin coating method and postannealing under different oxygen partial pressure (0.04, 0.2, and 0.9 Torr). The morphology of Cu2O thin films was improved through N2 postannealing before O2 annealing. Under relatively high oxygen partial pressure of 0.9 Torr, the roughness of synthesized films was increased with the formation of CuO phase. Bottom-gated copper oxide (CuxO) thin film transistors (TFTs) were fabricated via conventional photolithography, and the electrical properties of the fabricated TFTs were measured. The resulting Cu2O TFTs exhibited p-channel operation, and field effect mobility of 0.16 cm2/(V s) and on-to-off drain current ratio of ~1*10(2) were observed in the TFT device annealed at PO2 of 0.04 Torr. This study presented the potential of the solution based process of the Cu2O TFT with p-channel characteristics for the first time. PMID- 23461754 TI - Portal vein resection using the no-touch technique with a hepatectomy for hilar cholangiocarcinoma. AB - OBJECTIVES: To assess the safety and feasibility and discuss the oncological impact of a portal vein resection using the no-touch technique with a hepatectomy for locally advanced hilar cholangiocarcinoma. PATIENTS AND METHODS: From 2005 to March 2009, 49 patients with hilar cholangiocarcinoma underwent a major right sided hepatectomy with curative intent. Portal vein resection was performed using the no-touch technique in 36 patients (PVR group) but the portal vein was not resected in the other 13 patients (NR group). Peri-operative data and histological findings were compared between the two groups. Moreover, tumour recurrence and survival rates after surgery were calculated and compared for each group. RESULTS: Although the tumours of the patients in the PVR group were more locally advanced, the residual tumour status and tumour recurrence rate were similar and there was no significant difference in long-term survival between the two groups: 5-year survival rates in the PVR and NR groups were 59% and 51%, respectively (P = 0.353). In-hospital mortality was encountered in 2 of the 49 patients. CONCLUSION: A portal vein resection using the no-touch technique with a right-sided hepatectomy had a positive impact on survival and is feasible in terms of long-term outcomes with acceptable mortality. PMID- 23461756 TI - Circulating insulin and leptin in women with and without premenstrual disphoric disorder in the menstrual cycle. AB - Premenstrual dysphoric disorder (PMDD) is a syndrome related with mood and appetite changes during the late luteal phase. Leptin and insulin are the hormones related to appetite, and leptin may have a role in reproductive functions and mood. Our aim was to determine whether there are differences in serum leptin and insulin levels between women with and without PMDD during the follicular and luteal phases. In this study, 20 women with PMDD and 18 women without PMDD were included. Fasting blood glucose, insulin, leptin, progesterone levels and HOMA-IR were measured in the follicular and luteal phases separately. Repeated-measures analysis of variance revealed significant interactions for serum leptin, insulin and HOMA-IR levels between the diagnosis of PMDD and menstrual phases (F = 5.4, p = 0.025; F = 5.4, p = 0.026; and F = 4.7, p = 0.036, respectively). A significant correlation was found between progesterone and insulin levels in subjects without PMDD in the luteal phase (r = 0.58, p = 0.01). Whether the alterations in serum leptin and insulin are related with the changes of appetite and mood in PMDD or secondary to other factors should be clarified. PMID- 23461755 TI - Do time in child care and peer group exposure predict poor socioemotional adjustment in Norway? AB - Extensive exposure to nonparental child care during the first 4.5 years of life has been demonstrated in some American studies to negatively affect children's socioemotional functioning. Data from 935 preschool children who averaged 54.9 (SD = 3.0) months of age, from Trondheim, Norway were used to examine whether such negative effects, would emerge in Norway, a country with a different child care system. The children's externalizing problems and social competence were unrelated to their child-care experience. More time spent in child care during the first 4.5 years of life and experiencing peer groups of < 16 or > 18 children predicted greater caregiver-child conflict. The effect sizes were small. The results are discussed in terms of cross-national child-care differences. PMID- 23461757 TI - Fasudil and its analogs: a new powerful weapon in the long war against central nervous system disorders? AB - INTRODUCTION: Rho kinase (ROCK) plays a critical role in actin cytoskeleton organization and is involved in diverse fundamental cellular functions such as contraction and gene expression. Fasudil, a ROCK inhibitor, has been clinically applied since 1995 for the treatment of subarachnoid hemorrhage (SAH) in Japan. Increasing evidences indicate that fasudil could exhibit markedly therapeutic effect on central nervous system (CNS) disorders, such as Alzheimer's disease. AREAS COVERED: This article summarizes results from supporting evidence for the potential therapy for fasudil against a variety of CNS diseases. And the properties of its analogs are also summarized. EXPERT OPINION: Current therapies against CNS disorders are only able to attenuate the symptoms and fail in delaying or preventing disease progression and new approaches with disease modifying activity are desperately needed. The dramatic effects of fasudil in animal models and/or clinical applications of CNS disorders make it a promising strategy to overcome CNS disorders in human beings. Given the complex pathology of CNS disorders, further efforts are necessary to develop multifunctional fasudil derivatives or combination strategies with other drugs in order to exert more powerful effects with minimized adverse effects in the combat of CNS disorders. PMID- 23461758 TI - Exploring risk for abuse of children with chronic conditions or disabilities- parent's perceptions of stressors and the role of professionals. AB - BACKGROUND: Children with chronic conditions or disabilities are at an increased risk for abuse. High level of parental stress has been identified as possible trigger for abuse, were a combination of several factors are of importance, as lack of social support and limited resources in the neighbourhood. Suggestions for preventive measures have merely focused on parenting strategies and targeted intervention programmes. So far, little attention has been paid on how the risk for abuse might relate to parent's perceptions of stressors and the role of professionals. The purpose of the current study was therefore to explore risk factors for abuse with focus on both parent-child and parent-professional relationships. METHOD: Semi-structured in-depth interviews with 15 parents of children with chronic conditions or disability were collected and analysed according to qualitative content analysis. FINDINGS: Three major themes were found that could be seen as risk factors for child abuse: (1) Emotional demands in precarious situations between parent and child. (2) Gradual shift in responsibility from professionals to parents concerning access to and co ordination of service and support. (3) Emotionally closed environment between professionals and parents and taboo on talking about abuse. The gradual shift in responsibility had emotional implications, which could reinforce parental stress and thereby also indirect increase the risk of child abuse. The gradual shift in responsibility also seemed to generate an emotionally closed environment and reinforce the taboo on talking about abuse, which in turn hindered preventive measures. CONCLUSIONS: In the light of parent's perceptions of stressors and the role of professionals the findings indicate that abuse against children with chronic conditions or disability is not only a family matter, but also depending on qualities in service, professional support and social norms. The result pinpoints three challenges for preventive measures, all with emotional implications, parental strategies, organizational efforts and cultural awareness. PMID- 23461759 TI - Lethal cardiac arrhythmia during central venous catheterization in a uremic patient: a case report and review of the literature. AB - Double-lumen central venous catheter (CVC) is a rapid access technique for hemodialysis (HD) when an arteriovenous fistula or graft is not available. A variety of procedure-related complications have been reported, such as infection and pneumothorax, but serious cardiac complications are relatively less mentioned. We report a uremic woman with preexisting left bundle branch block who required emergent HD and received jugular double-lumen CVC insertion, which was complicated by short-duration ventricular tachycardia followed by complete atrio ventricular block and bradycardia. Pharmacological management did not reverse heart rate and rhythm. External pacing was not applied because she remained hemodynamically stable in the course of HD. Heart rate returned to sinus rhythm with left bundle branch block 4 hours later and did not recur through the whole admission period. We speculate that the transient arrhythmia might have been induced by mechanical contact with the ventricular wall during the procedure with the guided metallic wire. In conclusion, physicians responsible for CVC catheterization should pay more attention to patients with preexisting cardiac arrhythmia to prevent such technical mistakes from transpiring. PMID- 23461760 TI - Complication profile of the Berlin Heart EXCOR biventricular support in children. AB - In chronic cardiomyopathy, mechanical circulatory support (MCS) plays an increasingly important role for children as the shortage of suitable donor hearts increases waiting time on the transplant list. We report our experience with the paracorporal Berlin Heart EXCOR System (Berlin Heart AG, Berlin, Germany) used as a biventricuclar assist device (BVAD). Nine patients with a BVAD EXCOR system were treated between 2006 and 2012; out of these patients, four were less than 18 years old (6, 14, 14, and 17 years old). Their diagnoses were postcardotomy failure (n = 1), dilatative cardiomyopathy (n = 2), and terminal heart failure (n = 1). Overall survival, waiting time for heart transplantation (HTx) and complication profile for the BVAD were analyzed retrospectively. Thirty days' mortality was 25% (n = 1). One child died after 84 days on support due to cerebral bleeding. Mean support time was 218.75 days (4, 84, 262, and 525 days). Pump chamber exchange was necessary three times due to pump chamber thrombosis (n = 2) and partial pump chamber membrane rupture (n = 1). Complications included: sepsis (n = 1), drive line infection requiring intravenous antibiotics (n = 2), and recurrent epistaxis (n = 3). Two children were successfully transplanted after 262/525 days on BVAD; they are currently at home (follow-up: 1.9 and 2.3 years). The EXCOR is a life-saving MCS system suitable for long-term paracorporeal biventricular assistance. PMID- 23461761 TI - Phase-transfer-catalyzed asymmetric conjugate cyanation of alkylidenemalonates with KCN in the presence of a Bronsted acid additive. AB - Highly enantioselective conjugate cyanation of alkylidenemalonates with KCN was achieved under mild phase-transfer conditions with a bifunctional phase-transfer catalyst. The effect of Bronsted acid additives was examined based on the hypothetical catalytic cycle, and the Bronsted acid additive was found to be essential to promote the conjugate cyanation efficiently. PMID- 23461762 TI - NHC-Cu-catalyzed protoboration of monosubstituted allenes. Ligand-controlled site selectivity, application to synthesis and mechanism. AB - Two types of NHC-Cu complexes catalyze protoborations of terminal allenes to afford valuable 1,1- or trisubstituted vinylboron species with high site selectivity and stereoselectivity. The scope of the method, application to natural product synthesis, and mechanistic basis for the observed selectivity trends are presented. PMID- 23461763 TI - Grazing-incidence neutron-induced fluorescence probes density profiles of labeled molecules at solid/liquid interfaces. AB - We report on the use of characteristic prompt gamma-fluorescence after neutron capture induced by an evanescent neutron wave to probe densities and depth profiles of labeled molecules at solid/liquid interfaces. In contrast to classical scattering techniques and X-ray fluorescence, this method of "grazing incidence neutron-induced fluorescence" combines direct chemical specificity, provided by the label, with sensitivity to the interface, inherent to the evanescent wave. We demonstrate that the formation of a supported lipid membrane can be quantitatively monitored from the characteristic fluorescence of (157)Gd(3+) ions bound to the headgroup of chelator lipids. Moreover, we were able to localize the (157)Gd(3+) ions along the surface normal with nanometer precision. This first proof of principle with a well-defined model system suggests that the method has a great potential for biology and soft matter studies where spatial resolution and chemical sensitivity are required. PMID- 23461764 TI - Comparison of recombinant human erythropoietin and darbepoetin alpha in children. AB - BACKGROUND: The aim was to compare the clinical efficacy of recombinant human erythropoietin (rHuEPO) and darbepoetin alpha (DA) in the treatment of anemia in children with chronic kidney disease (CKD). METHOD: Thirty-four (13 female, 21 male) CKD patients were enrolled in the study. Mean age was 11.42 +/- 4.05 years. Nine patients were on hemodialysis, 18 were on peritoneal dialysis and seven patients were in CKD stage 4. RESULTS: Seventeen patients received rHuEPO and the remaining 17 patients received DA. Hemoglobin (Hb) was not significantly different between the two groups during monthly follow up and at the end of 6 months (P > 0.05), but there was a significant increase within each group at the end of 6 months (P = 0.01 for rHuEPO; P = 0.02 for DA). Hb was not different between the patients on and not on dialysis in both groups at the end of the study (P > 0.05). The efficacy of the s.c. and i.v. routes was similar within each group (P > 0.05). Systolic hypertension was observed in only one patient in the DA group, no other adverse effect was observed in either groups. CONCLUSION: DA is a reasonable alternative to rHuEPO in the treatment of anemia in pediatric CKD patients, due to its clinical efficacy, convenience of use, patient compliance and tolerability. PMID- 23461765 TI - Left ear advantages in detecting emotional tones using dichotic listening task in an Arabic sample. AB - Advantages associated with the left ear (right brain hemisphere) have been reported in some studies. Of these, some have specifically suggested that the left ear has a more heightened ability to detect emotional tones. Meanwhile others have pointed to factors such as age and gender as potentially leading to manifestations of human laterality. This study investigates which brain hemisphere is more involved in emotional processing of auditory information in Arab participants. We aimed to replicate the previous studies because no single study has been done in the Arabic region previously. Additionally, people in this region prefer to use the right side of their body, e.g., hand, ear, foot, etc., for most daily tasks. To acquire data a dichotic listening task (DLT) was administered to 28 male and 23 female (Edinburgh, UK) university students aged 19 to 38; 13 were left-handed and 38 were right-handed. The results showed a significant left ear advantage in the auditory processing of emotional information. There was a significant negative correlation between ear preference and handedness. Left ear advantage related only to handedness. Thus right-handed participants were more likely than left-handers to have a left ear advantage. The relationship between ear preference and gender was non-significant. The conclusion that might be drawn from this study is that the left ear (right hemisphere) is more involved in emotional processing than the right ear (left hemisphere), especially for right-handed people. PMID- 23461766 TI - Descriptions of immatures of the South American plant hopper, Taosa (C.) longula. AB - Descriptions of the immature stages of Taosa (Cuernavaca) longula Remes Lenicov (Hemiptera: Fulgoroidea: Dictyopharidae) and a key for their identification is provided for specimens collected on the water hyacinth, Eichhornia crassipes (Martius) Solms-Laubach (Commelinales: Pontederiaceae), in northeastern Argentina and Peru. Newly emerged nymphs from eggs collected in the field were reared in rearing chambers, and each stage was fixed to microscopic examination and illustration. Fifth nymphal instars can be easily recognized from congeners by the brown marked pattern coloration, shorter vertex, and the distinguishable median carina along the frons. Information on behavior and developmental time is also included. PMID- 23461768 TI - Studying the correlation of renin-angiotensin-system (RAS) components and insulin resistance in polycystic ovary syndrome (PCOs). AB - OBJECTIVE: It is estimated that 5-7% of women of reproductive age have polycystic ovary syndrome (PCOS). Chronic anovulation, hyperandrogenism, and insulin resistance (IR) are the main characters of this complex syndrome. IR, diabetes and obesity are all strongly correlated with PCOS; moreover, the possibility of direct androgen mediated renin-angiotensin system (RAS) stimulation in women with PCOS is also reported. The aim of the present study was to investigate the correlation between RAS, IR and PCOS. STUDY DESIGN: Thirty one women with PCOS, diagnosed by the Rotterdam criteria, were compared with thirty six control subjects. Both case and control groups were evaluated regarding to their basal hormonal profile, fasting blood sugar, IR, angiotensin converting enzyme (ACE) activity, plasma renin activity (PRA) and angiotensin II (AngII) levels. RESULTS: Compared to controls both ACE activity (p = 0.04) and AngIotaIota levels (p = 0.01) were significantly higher in case group. No significant differences between patients and controls were found in PRA. The results demonstrated that IR (p = 0.02) and fasting insulin (p = 0.004) were higher in case group, there was also a positive correlation between ACE activity and IR in case group (p = 0.02, r = 0.2). CONCLUSION: These results may suggest that there is an important correlation between ACE activity and IR in patients with PCOS. PMID- 23461767 TI - Superficial white matter: effects of age, sex, and hemisphere. AB - Structural and diffusion imaging studies demonstrate effects of age, sex, and asymmetry in many brain structures. However, few studies have addressed how individual differences might influence the structural integrity of the superficial white matter (SWM), comprised of short-range association (U-fibers), and intracortical axons. This study thus applied a sophisticated computational analysis approach to structural and diffusion imaging data obtained from healthy individuals selected from the International Consortium for Brain Mapping (ICBM) database across a wide adult age range (n=65, age: 18-74 years, all Caucasian). Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were sampled and compared at thousands of spatially matched SWM locations and within regions-of-interest to examine global and local variations in SWM integrity across age, sex, and hemisphere. Results showed age-related reductions in FA that were more pronounced in the frontal SWM than in the posterior and ventral brain regions, whereas increases in RD and AD were observed across large areas of the SWM. FA was significantly greater in left temporoparietal regions in men and in the posterior callosum in women. Prominent leftward FA and rightward AD and RD asymmetries were observed in the temporal, parietal, and frontal regions. Results extend previous findings restricted to the deep white matter pathways to demonstrate regional changes in the SWM microstructure relating to processes of demyelination and/or to the number, coherence, or integrity of axons with increasing age. SWM fiber organization/coherence appears greater in the left hemisphere regions spanning language and other networks, while more localized sex effects could possibly reflect sex-specific advantages in information strategies. PMID- 23461769 TI - Child-care subsidies and school readiness in kindergarten. AB - The federal child-care subsidy program represents one of the government's largest investments in early care and education. Using data from the nationally representative Early Childhood Longitudinal Study-Birth Cohort, this study examines associations, among subsidy-eligible families, between child-care subsidy receipt when children are 4 years old and a range of school readiness outcomes in kindergarten (sample n ~ 1,400). Findings suggest that subsidy receipt in preschool is not directly linked to subsequent reading or social emotional skills. However, subsidy receipt predicted lower math scores among children attending community-based centers. Supplementary analyses revealed that subsidies predicted greater use of center care, but this association did not appear to affect school readiness. PMID- 23461771 TI - Double lumen esophagus: a rare complication of gastroesophageal reflux disease. AB - Double lumen esophagus or esophagogastric fistula is a very rare endoscopic finding. Approximately 11 cases have been reported in the past. Formation of an esophagogastric fistula is predisposed by previous esophagogastric surgery, persistent gastroesophageal reflux, esophageal ulcer or esophageal carcinoma. Dysphagia and odynophagia are common symptoms. Endoscopy is the procedure of choice for diagnosis. Symptomatic management is the mainstay of treatment. Early diagnosis andmanagement of gastroesophageal reflux is essential to prevent reflux related fistulas. We report the case of a 48-year-old man with a history of dysphagia who was found to have esophagogastric fistula on endoscopy. He was treated conservatively with proton pump inhibitors leading to symptomatic improvement. PMID- 23461772 TI - Long-term return behavior of Chinese whole blood donors. AB - BACKGROUND: It is important to understand donor return behavior to maintain sufficient numbers of blood donors in developing countries where blood supplies are often inadequate. STUDY DESIGN AND METHODS: A total of 54,267 whole blood (WB) donors who donated between January 1 and March 31, 2008, at the five blood centers in China were followed for 2.5 years. Logistic regression was conducted to identify factors associated with their return behavior. A recurrent-event Cox proportional-hazard model was used to evaluate the overall effect of demographic variables and return behavior among first-time donors. RESULTS: Donors with previous donation history were more likely to return and the number of previous returns was positively associated with future return (odds ratios, 3.31, 4.82, and 8.16 for one, two to three, and more than three times compared to none). Thirty-four percent of donors (first-time donor, 21%; repeat donor, 54%) made at least one return donation, with 14% returning in the first 9 months. The multivariable logistic regression model for all WB donors and the Cox proportional hazard model for first-time donors showed consistent predictors for return: female sex, older age (>= 25 years), larger volume (300 or 400 mL), and donating in satellite collection site. CONCLUSION: Encouraging first-time donors to make multiple donations is important for keeping adequate blood supply. The finding that first-time and repeat donors shared the same predictors for return indicates that retention strategies on repeat donors may be effective on first time donors. Studies on motivators and barriers to return are needed, so that successful retention strategies can be tailored. PMID- 23461773 TI - Arabidopsis thaliana bZIP44: a transcription factor affecting seed germination and expression of the mannanase-encoding gene AtMAN7. AB - Endo-beta-mannanases (MAN; EC. 3.2.1.78) catalyze the cleavage of beta1->4 bonds in mannan polymers and have been associated with the process of weakening the tissues surrounding the embryo during seed germination. In germinating Arabidopsis thaliana seeds, the most highly expressed MAN gene is AtMAN7 and its transcripts are restricted to the micropylar endosperm and to the radicle tip just before radicle emergence. Mutants with a T-DNA insertion in AtMAN7 have a slower germination than the wild type. To gain insight into the transcriptional regulation of the AtMAN7 gene, a bioinformatic search for conserved non-coding cis-elements (phylogenetic shadowing) within the Brassicaceae MAN7 gene promoters has been done, and these conserved motifs have been used as bait to look for their interacting transcription factors (TFs), using as a prey an arrayed yeast library from A. thaliana. The basic-leucine zipper TF AtbZIP44, but not the closely related AtbZIP11, has thus been identified and its transcriptional activation upon AtMAN7 has been validated at the molecular level. In the knock out lines of AtbZIP44, not only is the expression of the AtMAN7 gene drastically reduced, but these mutants have a significantly slower germination than the wild type, being affected in the two phases of the germination process, both in the rupture of the seed coat and in the breakage of the micropylar endosperm cell walls. In the over-expression lines the opposite phenotype is observed. PMID- 23461774 TI - The headgroup evolution of cationic lipids for gene delivery. AB - Cationic lipids are one of the most widely used nonviral vectors for gene delivery and are especially attractive because they can be easily synthesized and extensively characterized. Additionally, they can best facilitate the elucidation of structure-activity relationships by modifying each of their constituent domains. The polar hydrophilic headgroups enable the condensation of nucleic acids by electrostatic interactions with the negatively charged phosphate groups of the genes, and further govern transfection efficiency. The headgroups of cationic lipids play a crucial role for gene delivery; they can be quaternary ammoniums, amines, aminoacids or peptides, guanidiniums, heterocyclic headgroups, and some unusual headgroups. This review summarizes recent research results concerning the nature (such as the structure and shape of cationic headgroup) and density (such as the number and the spacing of cationic headgroup) of head functional groups for improving the design of efficient cationic lipids to overcome the critical barriers of in vitro and in vivo transfection. PMID- 23461776 TI - Sorafenib inhibits liver regeneration in rats. AB - BACKGROUND: Sorafenib is a multikinase inhibitor with antiangiogenic and antiproliferative properties, approved for the treatment of hepatocellular carcinoma. The effect of Sorafenib on liver regeneration in healthy rats was investigated. METHODS: Sixty Wistar rats received either Sorafenib (group S; 15 mg/kg) or placebo for 14 days prior to resection and until sacrifice. After a 70% partial hepatectomy, the rats were euthanized on post-operative days (POD) 2, 4 or 8. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using stereological methods on sections prepared by systematic uniform random sampling. RESULTS: Seven animals (12%) died after surgery. Death rates were similar in treated rats and controls. At hepatectomy, the body weight was significantly lower in group S rats. The liver weight and regeneration rates were lower in group S rats on PODs 2, 4 and 8. Hepatocyte proliferation was significantly lower in group S animals on PODs 2 and 4. Alanine aminotransferase ALAT was significantly higher in the Sorafenib-treated group on PODs 2, 4 and 8. Alkaline phosphatase ALP and bilirubin levels were similar in the two groups, although bilirubin was elevated in group S rats on POD 8. CONCLUSION: In this rat model, Sorafenib did not increase post-hepatectomy mortality, but was associated with a significant impaired liver weight gain, regeneration rates and hepatocyte proliferation. PMID- 23461777 TI - Update on the Child's Challenging Behaviour Scale following evaluation using Rasch analysis. AB - BACKGROUND: The Child's Challenging Behaviour Scale (CCBS) was designed to measure a mother's rating of her child's challenging behaviours. The CCBS was initially developed for mothers of school-aged children with developmental disability and has previously been shown to have good psychometric properties using classical test theory techniques. The aim of this study was to use Rasch analysis to fully evaluate all aspects of the scale, including response format, item fit, dimensionality and targeting. METHODS: The sample consisted of 152 mothers of a school-aged child (aged 5-18 years) with a disability. Mothers were recruited via websites and mail-out newsletters through not-for-profit organizations that supported families with disabilities. Respondents completed a survey which included the 11 items of the CCBS. Rasch analysis was conducted on these responses using the RUMM2030 package. RESULTS: Rasch analysis of the CCBS revealed serious threshold disordering for nine of the 11 items, suggesting problems with the 5-point response format used for the scale. The neutral midpoint of the response format was subsequently removed to create a 4-point scale. High levels of local dependency were detected among two pairs of items, resulting in the removal of two items (item 7 and item 1). The final nine-item version of the scale (CCBS Version 2) was unidimensional, well targeted, showed good fit to the Rasch model, and strong internal consistency. CONCLUSIONS: To achieve fit to the Rasch model it was necessary to make two modifications to the CCBS scale. The resulting nine-item scale with a 4-point response format showed excellent psychometric properties, supporting its internal validity. PMID- 23461778 TI - PROSPER: a randomised comparison of surgical treatments for rectal prolapse. AB - AIM: Rectal prolapse is a profoundly disabling condition, occurring mainly in elderly and parous women. There is no accepted standard surgical treatment, with previous studies limited in methodological quality and size. PROSPER aimed to address these deficiencies by comparing the relative merits of different procedures. METHOD: In a pragmatic, factorial (2 * 2) design trial, patients could be randomised between abdominal and perineal surgery (i), and suture vs resection rectopexy for those receiving an abdominal procedure (ii) or Altemeier's vs Delorme's for those receiving a perineal procedure (iii). Primary outcome measures were recurrence of the prolapse, incontinence, bowel function and quality of life scores (Vaizey, bowel thermometer and EQ-5D) measured up to 3 years. RESULTS: Two hundred and ninety-three patients were recruited: 49 were randomised between surgical approaches (i); 78 between abdominal procedures (ii); and 213 between perineal procedures (iii). Recurrence rates were higher than anticipated, but not significantly different in any comparison: Altemeier's vs Delorme's 24/102 (24%) and 31/99 (31%) [hazard ratio (HR) 0.81; 95% CI 0.47, 1.38; P = 0.4]; resection vs suture rectopexy 4/32 (13%) and 9/35 (26%) (HR 0.45; 95% CI 0.14, 1.46; P = 0.2); perineal vs abdominal 5/25 (20%) and 5/19 (26%) (HR 0.83; 95% CI 0.24, 2.86; P = 0.8). Vaizey, bowel thermometer and EQ-5D scores were not significantly different in any of the comparisons. CONCLUSION: No significant differences were seen in any of the randomised comparisons, although substantial improvements from baseline in quality of life were noted following all procedures. PMID- 23461779 TI - Staged thyroidectomy: time to consider intraoperative neuromonitoring as standard of care. PMID- 23461780 TI - Improving carbene-copper-catalyzed asymmetric synthesis of alpha-aminoboronic esters using benzimidazole-based precursors. AB - By using a benzimidazole core and N-substitutions to tune the electronic properties of the corresponding N-heterocyclic carbenes, a one-pot protocol for efficient synthesis of alpha-aminoboronic esters without the need of a glovebox was developed in this work. The starting materials for the transformation can also be extended from aldehydes to ketones. An alternative protocol with short reaction time using preformed carbene-copper chloride is also described. PMID- 23461781 TI - Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. AB - INTRODUCTION: People with chronic kidney disease (CKD) of stages 3 - 5 (creatinine clearance < 60 ml/min) represent ~ 25% of patients with type 2 diabetes mellitus (T2DM), but the problem is underrecognized or neglected in clinical practice. However, most oral antidiabetic agents have limitations in case of renal impairment (RI), either because they require a dose adjustment or because they are contraindicated for safety reasons. AREAS COVERED: The author performed an extensive literature search to analyze the influence of RI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice. EXPERT OPINION: As a result of PK interferences and for safety reasons, the daily dose should be reduced according to glomerular filtration rate (GFR) or even the drug is contraindicated in presence of severe CKD. This is the case for metformin (risk of lactic acidosis) and for many sulfonylureas (risk of hypoglycemia). At present, however, the exact GFR cutoff for metformin use is controversial. New antidiabetic agents are better tolerated in case of CKD, although clinical experience remains quite limited for most of them. The dose of DPP-4 inhibitors should be reduced (except for linagliptin), whereas both the efficacy and safety of SGLT2 inhibitors are questionable in presence of CKD. PMID- 23461782 TI - Diastolic dyssynchrony should be assessed as well as systolic dyssynchrony in patients with chronic kidney disease. PMID- 23461784 TI - Tough germanium nanoparticles under electrochemical cycling. AB - Mechanical degradation of the electrode materials during electrochemical cycling remains a serious issue that critically limits the capacity retention and cyclability of rechargeable lithium-ion batteries. Here we report the highly reversible expansion and contraction of germanium nanoparticles under lithiation delithiation cycling with in situ transmission electron microscopy (TEM). During multiple cycles to the full capacity, the germanium nanoparticles remained robust without any visible cracking despite ~260% volume changes, in contrast to the size-dependent fracture of silicon nanoparticles upon the first lithiation. The comparative in situ TEM study of fragile silicon nanoparticles suggests that the tough behavior of germanium nanoparticles can be attributed to the weak anisotropy of the lithiation strain at the reaction front. The tough germanium nanoparticles offer substantial potential for the development of durable, high capacity, and high-rate anodes for advanced lithium-ion batteries. PMID- 23461785 TI - Facile synthesis of versatile enantioenriched alpha-substituted hydroxy esters through a Bronsted acid catalyzed kinetic resolution. AB - An efficient synthesis of enantioenriched alpha-substituted gamma-hydroxy esters via a kinetic resolution event is described. Bulky racemic esters in the presence of a chiral Bronsted acid selectively lactonize to yield a recoverable enantioenriched hydroxy ester and lactone. These esters are highly versatile building blocks that can readily be converted to synthetically useful materials. PMID- 23461783 TI - Serological testing for coeliac disease in Type 1 diabetes mellitus: is immunoglobulin A level measurement necessary? AB - AIMS: Immunoglobulin A (IgA) measurement is advocated when case finding for coeliac disease in patients with Type 1 diabetes mellitus. Currently, there is a paucity of contemporary studies assessing IgA deficiency in Type 1 diabetes. This study evaluates the prevalence of IgA deficiency in individuals with Type 1 diabetes, compared with patients with coeliac disease and control subjects. In addition, we evaluate whether routine IgA measurement is justifiable when case finding for coeliac disease in patients with Type 1 diabetes. METHODS: All patients were assessed using IgA endomysial antibodies, IgA anti-tissue transglutaminase antibodies and total IgA levels. Altogether, 2434 individuals were tested: 1000 patients with Type 1 diabetes, 234 patients with coeliac disease and 1200 population control subjects. Definitive IgA deficiency was defined as total IgA levels < 0.07 g/l. RESULTS: The prevalence of IgA deficiency was significantly more common in patients with Type 1 diabetes (0.9%, n = 9/1000; P = 0.036) and coeliac disease (1.29%, n = 3/234; P = 0.041) when compared with population control subjects (prevalence of 0.17%, 2/1200). No statistical difference between Type 1 diabetes and coeliac disease for IgA deficiency was identified (P = 0.87). Of patients in the group with Type 1 diabetes, 3.3% (33/1000) had coeliac disease, and of those only one patient had IgA deficiency leading to an antibody-negative presentation. Both IgA-deficient individuals within the population control subjects had normal duodenal biopsies and no relevant symptoms. CONCLUSIONS: IgA deficiency is more common in Type 1 diabetes compared with population control subjects. Despite this, very few individuals with Type 1 diabetes and IgA deficiency appear to have villous atrophy on biopsy. These outcomes question the practice of routine IgA measurement when case finding for coeliac disease in patients with Type 1 diabetes. PMID- 23461786 TI - Segregation in like-charged polyelectrolyte-surfactant mixtures can be precisely tuned via manipulation of the surfactant mass ratio. AB - In this study, we consider segregative phase separation in aqueous mixtures of quaternary ammonium surfactants didecyldimethylammonium chloride (DDQ) and alkyl (C12, 70%; C14 30%) dimethyl benzyl ammonium chloride (BAC) upon the addition of poly(diallyldimethylammonium) chloride (pDADMAC) as a function of both concentration and molecular weight. The nature of the surfactant type is dominant in determining the concentration at which separation into an upper essentially surfactant-rich phase and lower polyelectrolyte-rich phase is observed. However, for high-molecular-weight pDADMAC there is a clear indication of an additional depletion flocculation effect. When the BAC/DDQ ratio is tuned, the segregative phase separation point can be precisely controlled. We propose a phase separation mechanism for like-charged quaternary ammonium polyelectrolyte/surfactant/water mixtures induced by a reduction in the ionic atmosphere around the surfactant headgroup and possible ion pair formation. An additional polyelectrolyte-induced depletion flocculation effect was also observed. PMID- 23461787 TI - A cost utilization analysis of intrathecal therapy for refractory cancer pain: identifying factors associated with cost benefit. AB - OBJECTIVE: Intrathecal therapy (ITT) for cancer pain is characterized by high initial cost followed by low maintenance costs. Non-ITT pain management is associated with steadily increasing cumulative cost that can equal the cost of ITT over time. The intent of this modeling project is to identify factors associated with relatively rapid achievement of cost-benefit with ITT. DESIGN: A retrospective chart review was performed on 36 patients with cancer pain who underwent ITT and survived beyond 4 weeks. METHODS: Data on the cost of conventional opioid therapy prior to ITT and at 4-6 weeks were collected and projected over time. ITT costs included all intrathecal pump implantation and maintenance costs. Pre-ITT opioid regimens were stratified into high-cost conventional (HCC-high-dose, nongeneric, or use of intravenous patient-controlled analgesia, N = 12) and low-cost conventional (low-dose or generic, N = 24) regimens. RESULTS: The median daily cost of opioid medications pre-ITT was $21.26 (25th-75th percentile $10.31-78.85, range 0-$971.97) vs $0 (25th-75th percentile $0-0.70), P = 0.007, post-ITT. In the HCC group, the median daily cost was $172.47 (25th-75th percentile $67.29-406.20). The median daily cost of ITT medications was $16.01 (25th-75th percentile $9.52-23.23).When these data were used to model costs over the long term, including pump implantation costs, cost benefit for all patients compared with conventional therapy was predicted at 344 months but at 7.4 months in the HCC group. Seven patients (19%) achieved cost equivalence within 6 months and three of these within the first 3 months. CONCLUSIONS: In selected patients on high-cost opioid regimens, ITT may become cost-beneficial within 6 months. Factors associated with earlier attainment of ITT cost-benefit include the use of parenteral therapy, high-dose opioids, and the use of nongeneric opioid products. PMID- 23461788 TI - Nonoperative management of aortic valve thrombus in a patient with left ventricular assist device. PMID- 23461789 TI - Quality of life in children treated with restrictive diet for inherited metabolic disease. AB - BACKGROUND: The aim of this study was to investigate the quality of life (QoL) of a group of patients with inherited metabolic diseases (IMD) who were treated with restrictive diet. METHOD: A total of 68 patients (35 boys, 51.5%; 33 girls, 48.5%) with IMD (organic acidemia [OA], n = 14; disorder of carbohydrate metabolism [CMD], n = 33; and disorder of amino acid metabolism [AMD], n = 21) and their parents were inteviewed. Both parents completed a QoL Scale for Metabolic Diseases-Parent Form, a KINDL parent questionnaire, and a depression form. All patients aged >=4 years completed a questionnaire themselves, including the KINDL-Kid and KINDL-Kiddo self-reports. The semi-standardized interviews were carried out with patients and their parents in a clinical setting. RESULTS: The patients with bad diet compliance had lower scores for school labeling and perception of disease on both the parent and child questionnaire forms (P < 0.05). The patients were then divided into three groups (OA, CMD, AMD) for further analysis. Differences were seen between groups with regard to scores of physical function and school performance according to QoL Scale for Metabolic Diseases-Parent Form (P < 0.01). According to parent perceptions, the CMD patients had better QoL with regard to emotional wellbeing. CONCLUSION: As negative effects of the disease increased, the QoL of IMD patients and their parents decreased in terms of emotional, physical, and cognitive function. Application of expanded newborn scanning programs, early diagnosis, regular follow up, and family education would lessen the effects of the disease and improve the QoL of both families and children. PMID- 23461790 TI - Sulfonylation of quinoline N-oxides with aryl sulfonyl chlorides via copper catalyzed C-H bonds activation. AB - An efficient and concise one-pot protocol to synthesize sulfonylated quinoline N oxides via copper-catalyzed C-H bond activation has been developed. Commercially available and less expensive aryl sulfonyl chlorides were used as the sulfonylation reagents. Various 2-aryl sulfonyl quinolines were obtained in up to 91% yields in chemo- and regioselective manners. PMID- 23461791 TI - Peritoneal fluid cytokines and matrix metalloproteinases as early markers of anastomotic leakage in colorectal anastomosis: a literature review and meta analysis. AB - AIM: There has been recent interest in the measurement of peritoneal fluid cytokines in the early postoperative period to help diagnose anastomotic leakage at a preclinical stage. The currently available literature on the early diagnosis of colorectal anastomotic leakage by estimation of drain fluid cytokines or matrix metalloproteinases (MMP) is reviewed. METHOD: A literature search was performed in PubMed, EMBASE and the Cochrane library for all publications studying the feasibility of diagnosing colorectal anastomotic leakage earlier by estimation of peritoneal fluid cytokine or MMP levels. A meta-analysis of the most commonly measured cytokines was performed. RESULTS: Eight publications were included. Tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were most frequently studied. Most studies found significantly higher levels of TNF alpha and IL-6 in patients with anastomotic leakage during the first three postoperative days. In the meta-analysis IL-6 levels were significantly higher from day 1 and TNF-alpha from day 2. MMP-9 was most often significantly elevated in patients with anastomotic leakage. CONCLUSION: Measurement of drain fluid cytokines and MMP has the potential to diagnose colorectal anastomotic leakage at a preclinical stage, but is not yet ready for clinical use. Further research is needed, possibly using IL-6 in combination with other cytokines and MMP as markers. PMID- 23461792 TI - CDK2 knockdown enhances head and neck cancer cell radiosensitivity. AB - PURPOSE: Cyclin-dependent kinase 2 (CDK2) is critically involved in cell cycling and has been proposed as a potential cancer target. It remains largely elusive whether CDK2 targeting alters the tumor cell radiosensitivity. MATERIALS AND METHODS: CDK2(-/-) and wild type (WT) mouse embryonic fibroblasts (MEF) as well as six human head and neck squamous cell carcinoma (HNSCC) cell lines (SAS, FaDu, Cal-33, HSC-4, UTSCC-5, UTSCC-8) were used. Upon CDK2 knockdown using small interfering technology, colony formation, DNA double-strand breaks (DSB), cell cycle distribution and expression and phosphorylation of major proteins regulating cell cycle and DNA damage repair were examined. RESULTS: CDK2(-/-) MEF and CDK2 HNSCC knockdown cell cultures were more radiosensitive than the corresponding controls. Repair of DSB was attenuated under CDK2 knockout or knockdown. In contrast to data in MEF, combined CDK2 knockdown with irradiation showed no cell cycling alterations in SAS and FaDu cultures. Importantly, CDK2 knockdown failed to radiosensitize SAS and FaDu when cultured in a more physiological three-dimensional (3D) extracellular matrix environment. CONCLUSIONS: Our findings suggest that targeting of CDK2 radiosensitizes HNSCC cells growing as monolayer. Additional studies performed under more physiological conditions are warranted to clarify the potential of CDK2 as target in radiotherapy. PMID- 23461793 TI - Classifying prosocial behavior: children's responses to instrumental need, emotional distress, and material desire. AB - This study investigates the diversity of early prosocial behavior by examining the ability of ninety-five 2- to 4-year-olds to provide aid to an adult experimenter displaying instrumental need, emotional distress, and material desire. Children provided appropriate aid in response to each of these cues with high consistency over multiple trials. In contrast to the consistency with which the children provided aid within each task, there were no cross-task correlations, and the tendency to respond to each of the cues revealed unique developmental trajectories. Taken together, these results provide preliminary support for the importance of examining the cues to which children are responding and of differentiating between varieties of aid when considering the development of prosocial behavior. PMID- 23461794 TI - The spatio-temporal distribution patterns of biting midges of the genus Culicoides in Salta province, Argentina. AB - The goal of this survey was to analyze the spatio-temporal distribution patterns of Culicoides Latreille species (Diptera: Ceratopogonidae) and their relationship with environmental variables in Salta, northwestern Argentina. Culicoides were collected monthly from January 2003 through December 2005. The influence of the climatic variables on population abundance was analyzed with a multilevel Poisson regression. A total of 918 specimens belonging to five species were collected. The most abundant species was Culicoides paraensis Goeldi (65.5%), followed by Culicoides lahillei Iches (14.6%) and Culicoides debilipalpis Lutz (7.6%). The highest seasonal abundance for C. paraensis, C. debilipalpis and C. lahillei occurred during the spring and summer. A Poisson regression analysis showed that the mean maximum and minimum temperature and the mean maximum and minimum humidity were the variables with the greatest influence on the population abundance of Culicoides species. PMID- 23461795 TI - A nanofibrous PHBV tube with Schwann cell as artificial nerve graft contributing to rat sciatic nerve regeneration across a 30-mm defect bridge. AB - A nanofibrous PHBV nerve conduit has been used to evaluate its efficiency based on the promotion of nerve regeneration in rats. The designed conduits were investigated by physical, mechanical and microscopic analyses. The conduits were implanted into a 30-mm gap in the sciatic nerves of the rats. Four months after surgery, the regenerated nerves were evaluated by macroscopic assessments and histology. This polymeric conduit had sufficiently high mechanical properties to serve as a nerve guide. The results demonstrated that in the nanofibrous graft with cells, the sciatic nerve trunk had been reconstructed with restoration of nerve continuity and formatted nerve fibers with myelination. For the grafts especially the nanofibrous conduits with cells, muscle cells of gastrocnemius on the operated side were uniform in their size and structures. This study proves the feasibility of artificial conduit with Schwann cells for nerve regeneration by bridging a longer defect in a rat model. PMID- 23461796 TI - PELPIII: the class III pistil-specific extensin-like Nicotiana tabacum proteins are essential for interspecific incompatibility. AB - Pre-zygotic interspecific incompatibility (II) involves an active inhibition mechanism between the pollen of one species and the pistil of another. As a barrier to fertilization, II effectively prevents hybridization and maintains species identity. Transgenic ablation of the mature transmitting tract (TT) in Nicotiana tabacum resulted in the loss of inhibition of pollen tube growth in Nicotiana obtusifolia (synonym Nicotiana trigonophylla) and Nicotiana repanda. The role of the TT in the II interaction between N. tabacum and N. obtusifolia was characterized by evaluating N. obtusifolia pollen tube growth in normal and TT-ablated N. tabacum styles at various post-pollination times and developmental stages. The II activity of the TT slowed and then arrested N. obtusifolia pollen tube growth, and was developmentally synchronized. We hypothesize that proteins produced by the mature TT and secreted into the extracellular matrix inhibit interspecific pollen tubes. When extracts from the mature TT of N. tabacum were injected into the TT-ablated style prior to pollination, the growth of incompatible pollen tubes of N. obtusifolia and N. repanda was inhibited. The class III pistil-specific extensin-like protein (PELPIII) was consistently associated with specific inhibition of pollen tubes, and its requirement for II was confirmed through use of plants with antisense suppression of PELPIII. Inhibition of N. obtusifolia and N. repanda pollen tube growth required accumulation of PELPIII in the TT of N. tabacum, supporting PELPIII function in pre-zygotic II. PMID- 23461797 TI - Quantifying baseline emission factors of air pollutants in China's regional power grids. AB - Drawing lessons from the clean development mechanism (CDM), this paper developed a combined margin methodology to quantify baseline emission factors of air pollutants in China's regional power grids. The simple average of baseline emission factors of SO2, NOX, and PM2.5 in China's six power grids in 2010 were respectively 1.91 kg/MWh, 1.83 kg/MWh and 0.32 kg/MWh. Several low-efficient mitigation technologies, such as low nitrogen oxide burner (LNB), were suggested to be replaced or used together with other technologies in order to virtually decrease the grid's emission factor. The synergies between GHG and air pollution mitigation in China's power sector was also notable. It is estimated that in 2010, that every 1% CO2 reduction in China's power generation sector resulted in the respective coreduction of 1.1%, 0.5%, and 0.8% of SO2, NOX, and PM2.5. Wind is the best technology to achieve the largest amount of coabatement in most parts of China. This methodology is recommended to be used in making comprehensive air pollution control strategies and in cobenefits analysis in future CDM approval processes. PMID- 23461798 TI - Transrectal ultrasonography-guided injection of long-acting steroids in the treatment of recurrent/resistant anastomotic stenosis after radical prostatectomy. AB - BACKGROUND AND PURPOSE: Different techniques have been used for the treatment of patients with anastomotic stenosis after radical prostatectomy (RP). In this retrospective study, we analyzed our experience with urethral dilation and consecutive transrectal ultrasonography (TRUS)-guided injections of long-acting steroids in the scar area. PATIENTS AND METHODS: We reviewed the records of patients who underwent RP in our department from 2002 to 2010 and presented to the outpatient clinics with symptomatic anastomotic stenosis. Patients were treated with: Urethral dilation, cold knife (CK) urethrotomy, transurethral resection (TUR) of stenosis and dilation/resection of the strictures with consecutive TRUS-guided injection of a long-acting steroid (dilation+TRUS steroids). Patients remained under follow-up, which included the assessment of voiding and continence patterns, as well as cystourethroscopy. RESULTS: In 32 (10.8%) patients, symptomatic anastomotic stenosis was diagnosed. Initial urethral dilation succeeded in only 3 (10.3%) patients; thus, 29 remained with recurrent/resistant stenosis. Urethral dilation+TRUS-steroids was performed in 14 patients, while 8 patients underwent CK and in 7 TUR was performed. Patients in the dilation+TRUS-steroids group had lower re-treatment rates, and none of these patients became incontinent. Patients in the TUR group needed no re-treatment; however, they had the highest incontinence rate (57.1%). As a result, the highest efficiency quotient was in the dilation+TRUS-steroids with the lowest in the TUR group. CONCLUSION: Urethral dilation with consecutive TRUS-guided injections of steroids has the highest efficiency quotient and can be performed under local anesthesia with a low risk of incontinence. PMID- 23461799 TI - Type 1 diabetes structured education: What are the core self-management behaviours? AB - AIMS: Study aims were to (1) describe and compare the way diabetes structured education courses have evolved in the UK, (2) identify and agree components of course curricula perceived as core across courses and (3) identify and classify self-care behaviours in order to develop a questionnaire assessment tool. METHODS: Structured education courses were selected through the Type 1 diabetes education network. Curricula from five courses were examined and nine educators from those courses were interviewed. Transcripts were analysed using framework analysis. Fourteen key stakeholders attended a consensus meeting, to identify and classify Type 1 diabetes self-care behaviours. RESULTS: Eighty-three courses were identified. Components of course curricula perceived as core by all diabetes educators were: carbohydrate counting and insulin dose adjustment, hypoglycaemia management, group work, goal setting and empowerment, confidence and control. The broad areas of self-management behaviour identified at the consensus meeting were carbohydrate counting and awareness, insulin dose adjustment, self-monitoring of blood glucose, managing hypoglycaemia, managing equipment and injection sites; and accessing health care. Specific self-care behaviours within each area were identified. CONCLUSIONS: Planned future work will develop an updated questionnaire tool to access self-care behaviours. This will enable assessment of the effectiveness of existing structured education programmes at producing desired changes in behaviour. It will also help people with diabetes and their healthcare team identify areas where additional support is needed to initiate or maintain changes in behaviour. Provision of such support may improve glycaemia and reduce diabetes-related complications and severe hypoglycaemia. PMID- 23461800 TI - Establishment of a simple predictive scoring system for pancreatic fistula after laparoscopy-assisted gastrectomy. AB - BACKGROUND: The potential severity of postoperative pancreatic fistula (POPF) after laparoscopy-assisted gastrectomy (LAG) necessitates efforts to identify predictive factors for POPF. The aim of the present study was to identify predictive factors for POPF and to establish a predictive scoring system for POPF after LAG. PATIENTS AND METHODS: Between June 2004 and March 2011, 277 gastric cancer patients who underwent curative resection with LAG were enrolled. POPF was defined according to the International Study Group for Pancreatic Fistula grading system. Risk factors for POPF were evaluated using logistic regression analysis, and a scoring system for POPF was established. RESULTS: In the derivation cohort, multivariate analysis revealed the risk factors for POPF as patient age <=70 years (5 points), amylase level of postoperative day 1 drainage fluid >454 IU/L(5 points), total number of retrieved lymph nodes >21 (5 points), body mass index >21.45 kg/m(2) (4 points), and operating time >337 min (2 points). In the validation cohort, at the cut-off point for high risk (score >=15), the model had a negative predictive value of 94.5%, a positive predictive value of 57.4%, a sensitivity of 88.6%, and a specificity of 75.0% (C statistic = 0.857). CONCLUSION: This study demonstrated that POPF after LAG is associated with specific preoperative and postoperative factors. With a simple predictive scoring system, patients at high risk for POPF can be accurately identified. This simple predictive scoring system will be useful for many clinicians to assess the risk of POPF after LAG and start treating at-risk patients earlier. PMID- 23461801 TI - Power spectral density of free-standing viscoelastic films by adiabatic approximation. AB - In a previous study, we calculated the surface dynamics of noisy viscoelastic supported films by using an adiabatic approximation. An expression was derived for the time-dependent power spectral density (PSD), which was found to produce good agreement with experiment. In this study, we extend the treatment to viscoelastic free-standing films. Two sets of surface capillary normal modes, namely, the squeezing and bending modes, were found. The frequency dispersion relation of the former resembles that of supported films. The latter is distinctively different and diverges at long wavelengths. By incorporating the experimental conditions, we obtained satisfactory agreement between theory and experiment. PMID- 23461802 TI - The effects of red blood cell preparation method on in vitro markers of red blood cell aging and inflammatory response. AB - BACKGROUND: Studies are currently under way examining whether the age of stored red blood cells (RBCs) affects clinical outcome in transfusion recipients. The effects of storage duration on the RBC storage lesion are well documented, while fewer studies are available regarding the effect of RBC production method. In this study, we compared in vitro RBC quality variables and markers of inflammatory response in apheresis and whole blood (WB)-derived RBCs, specifically those prepared after an overnight room temperature hold (RTH) of WB. STUDY DESIGN AND METHODS: SAGM RBCs, prepared from WB after overnight RTH (n = 10), were compared to SAGM RBCs prepared using an apheresis device (Alyx, n = 10). As a control, SAGM RBCs were also prepared within 2 hours of WB collection (2-hr WB, n = 10). All RBCs were stored at 4 degrees C for 42 days with weekly assay of in vitro variables, cytokines and/or chemokines, and neutrophil activation after incubation with RBC supernatant. RESULTS: RTH WB RBCs exhibited decreased levels of 2,3-diphosphoglycerate acid (2.3 MUmol/g hemoglobin [Hb] +/- 2.1 vs. 13.7 +/- 1.3 MUmol/g Hb) and morphology (160 +/- 10 vs. 192 +/- 5) on Day 1 and increased hemolysis (0.45 +/- 0.21% vs. 0.31 +/- 0.09%) and microparticles (6.1 +/- 2.8/10(3) RBCs vs. 3.9 +/- 1.1/10(3) RBCs) on Day 42 compared to apheresis RBCs. Gro-alpha and ENA-78 cytokine levels were significantly higher in RTH WB than Alyx RBCs during storage. CD11b expression was highest in neutrophils exposed to supernatant from RTH WB RBCs (p < 0.05). CONCLUSION: RBC preparation method has a meaningful effect on the RBC storage lesion, which should be taken into account in addition to length of storage. PMID- 23461803 TI - Asymmetric synthesis of 1-heteroaryl-1-arylalkyl tertiary alcohols and 1-pyridyl 1-arylethanes by lithiation-borylation methodology. AB - The synthesis of highly enantioenriched alpha-heterocyclic tertiary alcohols has been achieved via lithiation-borylation of a configurationally stable lithiated carbamate and heterocyclic pinacol boronic esters followed by oxidation. Protodeboronation of the alpha-heterocyclic tertiary boronic esters using TBAF.3H2O or CsF gave highly enantioenriched 1-pyridyl-1-arylethanes in high er. PMID- 23461804 TI - Cross- versus homo-photocyclodimerization of anthracene and 2 anthracenecarboxylic acid mediated by a chiral hydrogen-bonding template. Factors controlling the cross-/homo-selectivity and enantioselectivity. AB - Competitive cross-/homo-photocyclodimerization of anthracene (AN) and 2 anthracenecarboxylic acid (AC) mediated by a chiral hydrogen-bonding template (TKS) was investigated under various conditions. The cross-photocyclodimerization was favored by a factor of 4-5 at all temperatures and wavelengths examined to afford the AC-AN cross-dimer in 80-84% yield even at AN/AC = 1 and in 98% yield at AN/AC = 10. The enantiomeric excesses (ee's) obtained were 27-47% for the homo dimers and 21-24% for the cross-dimer. The absolute configuration of the cross dimer was determined by comparing the experimental and theoretical circular dichroism spectra and further correlated with the re/si enantiotopic-face selectivity upon AC-TKS complexation in the ground state. Detailed analyses of the complexation behavior and the fluorescence lifetime and cyclodimerization rate of excited re/si complexes revealed that the product's ee is critically controlled not only by the relative abundance of the re/si complexes in the ground and excited states but also by their relative photocyclodimerization rate. Crucially, the ground-state thermodynamics and the excited-state kinetics are not synergistic but offsetting in enantiotopic-face selectivity, and the latter overwhelms the former to give the homo- and cross-dimers in modest ee's. Finally, some practical strategies for enhancing the enantioselectivity in chiral template mediated photochirogenesis have been proposed. PMID- 23461805 TI - TMPZnOPiv*LiCl: a new base for the preparation of air-stable solid zinc pivalates of sensitive aromatics and heteroaromatics. AB - A wide range of aryl and heteroaryl zinc pivalates bearing sensitive functionalities were prepared by selective metalation using TMPZnOPiv*LiCl, a new hindered zinc amide base. The new zinc reagents are easy-to-handle solids, which maintain their activity almost entirely (>95%) after 4 h of air exposure and smoothly undergo Negishi cross-couplings and reactions with various electrophiles such as Cu(I)-catalyzed acylations and allylations. PMID- 23461806 TI - Redox regulation of protein kinases. AB - Reactive oxygen species (ROS) have been long regarded as by-products of a cascade of reactions stemming from cellular oxygen metabolism, which, if they accumulate to toxic levels, can have detrimental effects on cellular biomolecules. However, more recently, the recognition of ROS as mediators of cellular communications has led to their classification as signalling mediators in their own right. The prototypic redox-regulated targets downstream of ROS are the protein tyrosine phosphatases, and the wealth of research that has focused on this area has come to shape our understanding of how redox-signalling contributes to and facilitates protein tyrosine phosphorylation signalling cascades. However, it is becoming increasingly apparent that there is more to this system than simply the negative regulation of protein tyrosine phosphatases. Identification of redox-sensitive kinases such as Src led to the slow emergence of a role for redox regulation of tyrosine kinases. A flow of evidence, which has increased exponentially in recent times as a result of the development of new methods for the detection of oxidative modifications, demonstrates that, by concurrent oxidative activation of tyrosine kinases, ROS fine tune the duration and amplification of the phosphorylation signal. A more thorough understanding of the complex regulatory mechanism of redox-modification will allow targeting of both the production of ROS and their downstream effectors for therapeutic purposes. The present review assesses the most relevant recent literature that demonstrates a role for kinase regulation by oxidation, highlights the most significant findings and proposes future directions for this crucial area of redox biology. PMID- 23461807 TI - Multiple endocrine neoplasia type 2A due to an exon 8 (G533C) mutation in a large North American kindred. AB - BACKGROUND: Medullary thyroid cancer, although most commonly sporadic, may be part of the multiple endocrine neoplasia type 2 (MEN2) syndromes, generally due to mutations in the RET proto-oncogene. The majority of these mutations are located in exons 10, 11, and 13-16. More rarely, mutations in other exons have been described. We report for the first time a family from the United States with a rare mutation involving exon 8 of the RET proto-oncogene, corresponding to a p.Gly533Cys substitution (G533C) leading to the development of MEN2A syndrome in several affected family members. This mutation had only been previously described in a large family in Brazil and in 7.75% of patients with apparently sporadic medullary thyroid cancer (MTC) in Greece. METHODS: Given a strong index of suspicion, a genetic analysis to evaluate for uncommon mutations in the RET proto oncogene identified the presence of the G533C missense mutation, despite initial negative screening for common mutations. We describe a family with a total of 47 individuals from five generations with multiple members affected with this mutation. RESULTS: Our data suggest that in patients with this mutation, pheochromocytoma is more common than previously reported, and that in some cases this mutation may be associated with a more aggressive phenotype than initially described. CONCLUSIONS: MEN2A due to the G533C mutation in exon 8 may be more common and more aggressive than previously recognized. In patients with medullary thyroid cancer with negative screening for common mutations in the RET oncogene but a strong index of suspicion, DNA sequence analysis of less commonly involved exons should be considered. PMID- 23461808 TI - Measures of participation outcomes related to hand use for 2- to 12-year-old children with disabilities: a systematic review. AB - Many interventions have been used to improve children's hand-related impairments or hand skill performance in functional activities so as to promote life participation. There is thus a need to have suitable instruments assessing children's participation in life situations that specifically require hand use in order to support and evaluate such interventions. This systematic review investigated the availability of potential instruments that can be used to assess children's participation specifically in life situations requiring hand use. Clinical utility and evidence for psychometric properties were also sourced. Database searches initially identified measures that were used to evaluate participation of children aged 2-12 years, involved self- or proxy report or interview administration and had generic application for a range of disabilities/diagnoses. These measures were further evaluated to determine if they fulfilled the above inclusion criteria and contained at least 60% of the items involving hand use. Further searches for psychometric evidence were undertaken for the eligible measures. Fourteen measures were identified and nine met the inclusion criteria. However, none of these measures, except for the Children Helping Out: Responsibilities, Expectations, and Supports (CHORES), contained all items related to hand use. Most of the included measures had limited psychometric properties. Only the Children's Assessment of Participation and Enjoyment/Preferences for Activities of Children (CAPE/PAC), the School Function Assessment-Participation section (SFA-P) and the Children Participation Questionnaire (CPQ) revealed sufficient evidence of validity and reliability. The findings suggest a need for adapting existing participation measures or developing new ones that specifically assess participation in life situations requiring hand use to support interventions. PMID- 23461809 TI - Prescription opioid forgery: reporting to law enforcement and protection of medical information. AB - OBJECTIVE: To review confidentiality requirements of prescribers who become aware of a forged prescription. DESIGN: A case is reviewed in which a prescriber believes that a prescription has been forged. RESULTS: The literature and law related to prescription forgery and confidentiality are reviewed. Although prescription forgery is a crime, the prescriber's responsibility for reporting to law enforcement is not clear under current state and federal law. Federal laws and regulations, including the Health Insurance Portability and Accountability Act (HIPAA), do not permit prescribers in all circumstances to disclose prescription fraud to law enforcement. CONCLUSIONS: Under common circumstances, HIPAA may prohibit prescribers from reporting prescription forgery to law enforcement. However, collaborating with a dispensing pharmacist may offer a lawful pathway to reporting prescription forgery. State legislature may consider laws that clarify the reporting responsibilities of prescribers in cases of prescription forgery. PMID- 23461810 TI - Controlled delivery of low-dose bone morphogenetic protein-2 using heparin conjugated fibrin in the posterolateral lumbar fusion of rabbits. AB - The heparin-conjugated fibrin (HCF) system has been developed to deliver bone morphogenetic proteins (BMPs) for a long-term period and thus enhance bone regeneration. In the present study, we tested the effectiveness of the delivery system for spinal fusion with a very low dose of BMP-2. A total of 15 rabbits underwent posterolateral lumbar spine, divided into three groups. The control group received only collagen sponges without BMP-2, another group (BMP-only group) received collagen sponges loaded with BMP-2 (10 MUg each side), and the last group (BMP/HCF group) received collagen sponges filled with HCF loaded with BMP-2 (10 MUg each side). All animals were euthanized 8 weeks after surgery, and the fusion was assessed by radiographs, manual palpation, computed tomography scan, and mechanical testing. No case in the BMP/HCF group or in the control group achieved solid fusion, while all cases in BMP-only group showed evidence of solid fusion. BMP/HCF group had significantly lower fusion rate and tensile strength than BMP-only group at the dose of 10 MUg of BMP-2. The HCF long-term delivery system with the low dose of BMP-2 (10 MUg) is ineffective for the induction of lumbar posterolateral fusion in the rabbits. PMID- 23461811 TI - 2012 Liver resections in the 21st century: we are far from zero mortality. AB - OBJECTIVES: Recent improvements in surgical technique have extended the indications for liver resection. The aims of this study were to assess whether this extension is associated with a changing patient profile and to evaluate how this potential shift has influenced mortality after liver resection in order to define standard expectations for hepatectomy. METHODS: The characteristics and postoperative outcomes of all patients undergoing elective hepatectomy from 2000 to 2009 were reviewed retrospectively. Multivariate analysis was conducted to determine the factors associated with mortality in the subgroup of patients with malignant disease. RESULTS: Among the 2012 patients in whom hepatectomies were performed, the percentage of patients operated for malignancy increased from 66.4% in 2000 to 82.3% in 2009 (P < 0.001). These patients experienced higher mortality (4.5% versus 0.7%; P < 0.001), were significantly older, and displayed greater comorbidity and underlying parenchymal disease compared with those with benign lesions. Mortality over the entire study period was 3.5% and was fairly stable, dropping from 3.8% in 2000 to 3.1% in 2009 (P = 0.686). On multivariate analysis, age of >60 years, an American Society of Anesthesiologists score of >=3, major resection, vascular procedure, severe fibrosis (F3-F4) and steatosis of >30% were associated with increased mortality in patients with malignant disease. CONCLUSIONS: The profile of patients undergoing liver resection has changed and now includes more high-risk patients with diseased parenchyma undergoing major hepatectomy for malignancy. This change in patient profile is responsible for the stability in mortality rates over the years. PMID- 23461812 TI - Physical Activity Questionnaire for children and adolescents: English norms and cut-off points. AB - BACKGROUND: The Physical Activity Questionnaire for Children and Adolescents (PAQ C/-A) provides general estimates of physical activity levels. Following recent expert recommendations for using the PAQ for population surveillance, the aim of this paper was twofold: first, to describe normative PAQ data for English youth; and second, to determine a criterion-referenced PAQ-score cut-off point. METHODS: Participants (n = 7226, 53% boys, 10-15 years) completed an anglicized version of the PAQ. Peak oxygen uptake (VO2peak ) was predicted from PACER lap count according to latest FITNESSGRAM standards and categorized into "at-risk" and "no risk" for metabolic syndrome. ROC curves were drawn for each age-sex group to identify PAQ scores, which categorized youth into "sufficiently active" versus "low-active" groups, using cardiorespiratory fitness as the criterion-referenced standard. RESULTS: PAQ scores were higher in boys than in girls and declined with age. Mean PAQ score was a significant, albeit relatively weak (area under the curve < 0.7) discriminator between "at-risk" and "no-risk." PAQ scores of >=2.9 for boys and >=2.7 for girls were identified as cut-off points, although it may be more appropriate to use lower, age-specific PAQ scores for girls of 13, 14 and 15 years (2.6, 2.4, 2.3, respectively). CONCLUSION: The normative and criterion referenced PAQ values may be used to standardize and categorize PAQ scores in future youth population studies. PMID- 23461814 TI - First trimester PAPP-A MoM values predictive for breech presentation at term of pregnancy. AB - INTRODUCTION: Our aim was to state the role of first trimester pregnancy associated plasma protein A (PAPP-A)-multiple of the median (MoM) value as a predictor for breech presentation at term of pregnancy. MATERIALS AND METHODS: In this retrospective study, we present data for 1100 singleton full-term deliveries that took place in a third-level hospital setting in northeast Italy between January 2004 and July 2007. For each case, PAPP-A, free beta-human chorionic gonadotropin and nuchal translucency were measured during prenatal trisomies screening (between 11 weeks and 13 weeks and 6 d). A wide range of predictive factors for breech presentation at term of pregnancy and other confounding elements were considered. RESULTS: Of the 1100 singleton deliveries at term considered in our study, 40 babies were in breech presentation. Using bivariate analysis and multivariate logistic regression, a lower PAPP-A MoM than 0.63 (first quartile of our distribution) in the first trimester (OR 2.41, CI.95 1.25 4.67), and placental index at term higher than the median value (OR 2.04, CI.95 1.00-4.17) were proven to be associated with breech presentation at term. CONCLUSIONS: A low PAPP-A during the first trimester was a predictive factor for breech presentation at term of pregnancy. Acknowledging and acting on this predictor could enable improved management of breech foetuses in the future. PMID- 23461815 TI - Pseudoporphyria in a hemodialysis patient successfully treated with oral glutamine. PMID- 23461818 TI - Hydration dynamics of aqueous nitrate. AB - Aqueous nitrate, NO3(-)(aq), was studied by 2D-IR, UV-IR, and UV-UV time-resolved spectroscopies in combination with molecular dynamics (MD) simulations with the purpose of determining the hydration dynamics around the anion. In water, the D3h symmetry of NO3(-) is broken, and the degeneracy of the asymmetric-stretch modes is lifted. This provides a very sensitive probe of the ion-water interactions. The 2D-IR measurements reveal excitation exchange between the two nondegenerate asymmetric-stretch vibrations on a 300-fs time scale concomitant with fast anisotropy decay of the diagonal-peak signals. The MD simulations show that this is caused by jumps of the transition dipole orientations related to fluctuations of the hydrogen bonds connecting the nitrate ion to the nearest water molecules. Reorientation of the ion, which is associated with the hydrogen-bond breaking, was monitored by time-resolved UV-IR and UV-UV spectroscopy, revealing a 2-ps time constant. These time scales are very similar to those reported for isotope labeled water, suggesting that NO3(-)(aq) has a labile hydration shell. PMID- 23461817 TI - Genes, environments, and developmental research: methods for a multi-site study of early substance abuse. AB - The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables. PMID- 23461819 TI - Short-term outcome after neoadjuvant high-dose-rate endorectal brachytherapy or short-course external beam radiotherapy in resectable rectal cancer. AB - AIM: Total mesorectal excision with preoperative radiotherapy reduces local recurrence in rectal cancer, but radiotherapy increases the risk of complications. This study compared the immediate postoperative outcome after external beam radiotherapy with outome after high-dose-rate endorectal brachytherapy (HDREBT). METHOD: Patients (n = 318) treated with preoperative HDREBT (6.5 Gy, daily, over 4 days) followed by surgery 4-8 weeks later were matched with 318 patients from the Swedish Rectal Cancer Register treated with short-course radiotherapy (SCRT; 5 Gy, daily, over 5 days) and surgery in the subsequent week and with 318 patients who had surgery only (i.e. no preoperative radiotherapy; RT-) All 954 patients were followed for 30 days after surgery. Complications were divided into surgical, cardiovascular and infectious. RESULTS: The SCRT group had fewer cardiovascular complications (3.1%) than did HDREBT (9.4%, P = 0.002) and RT- (7.2%, P = 0.03) groups. There was less perioperative bleeding in HDREBT patients (379.3 ml) than in SCRT (947.2 ml; P < 0.0001) or RT- (918.9 ml) patients, and the re-intervention rate was lower in HDREBT (4.1%) patients than in SCRT (14.2%; P = 0.005) and RT- (12.3%; P < 0.005) patients. The HDREBT group had fewer R2 resections than did the SCRT and RT- groups, but had a higher proportion of R0 resections compared with the RT- group (P = 0.03). CONCLUSION: No major differences in postoperative complications were found. HDREBT patients had a higher rate of cardiovascular complications, but less perioperative bleeding and fewer re-interventions. A longer interval between radiotherapy and surgery may be beneficial for tumour regression and this could be reflected in the number of radical resections. PMID- 23461820 TI - Non-enzymatic hydrolysis of RNA in workers of the ant Nylanderia pubens. AB - During preparation of total RNA from Nylanderia pubens (Forel) (Hymenoptera: Formicidae) workers for use in expression library construction, severe RNA degradation consistently occurred. This degradation was masked by spectrophotometric analysis but clearly evident by microfluidic-based assay. Although not specifically identified, the degrading entity was endogenous and localized to the abdomen (terminal abdominal segments) of adult ants. RNA degradation was not observed in preparations of larvae, non-melanized pupae, or eggs. Various RNase and protease inhibitors had no protective effect. However, the metal chelating agent ethylenediaminetetraacetic acid prevented RNA degradation and provides insight into the occurrence. PMID- 23461821 TI - Facile synthesis of silver nanoparticles stabilized by cationic polynorbornenes and their catalytic activity in 4-nitrophenol reduction. AB - We report the facile one-pot single-phase syntheses of silver nanoparticles stabilized by norbornene type cationic polymers. Silver nanoparticles (AgNPs) stabilized by polyguanidino oxanorbornenes (PG) at 5 and 25 kDa and polyamino oxanorbornenes (PA) at 3 and 15 kDa have been synthesized by the reduction of silver ions with NaBH4 in aqueous solutions at ambient temperature. The four different silver nanoparticles have been characterized by UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and transmission electron microscopy (TEM) for their particle size distributions. Interestingly, PG stabilizes the silver nanoparticles better than PA as evident from our spectroscopic data. Furthermore, the AgNP-PG-5K (5K = 5 kDa) was found to serve as an effective catalyst for the reduction of 4-nitrophenol to 4 aminophenol in the presence of NaBH4. The reduction has a pseudo-first-order rate constant of 5.50 * 10(-3) s(-1) and an activity parameter of 1375 s(-1) g(-1), which is significantly higher than other systems reported in the literature. PMID- 23461822 TI - Polypoid change in cytomegalovirus gastritis following treatment. PMID- 23461823 TI - Possible involvement of signal transducer and activator of transcription-3 in cell-cell interactions of peritoneal macrophages and endometrial stromal cells in human endometriosis. AB - OBJECTIVE: To investigate interactions between peritoneal macrophages and endometrial stromal cells (ESCs) involved in the development of endometriosis. DESIGN: Clinicopathologic and in vitro studies. SETTING: Department of Obstetrics and Gynecology and Department of Pathology, Kumamoto University Hospital. PATIENT(S): Women undergoing laparoscopy or laparotomy to treat endometriosis or other benign gynecologic conditions. INTERVENTION(S): We collected samples of peritoneal fluid (ascites), endometrium, and endometriotic tissues. We cocultured ESCs in vitro with or without human macrophages. MAIN OUTCOME MEASURE(S): Macrophage phenotypes in peritoneal fluid were determined via immunostaining. Proliferation of ESCs and activation of signal transducer and activator of transcription-3 (Stat3) in cocultures were evaluated. RESULT(S): The endometriosis group had a significantly higher total number of macrophages in ascites compared with the control group, but the ratios of CD163+ alternatively activated macrophages (M2) in the two groups did not differ significantly. Coculture with M2 macrophages significantly up-regulated ESC proliferation and Stat3 activation in ESCs in vitro. Proliferation of ESCs was suppressed after Stat3 was down-regulated by small interfering RNA. Stat3 was activated in epithelial cells and ESCs in human endometriotic lesions. CONCLUSION(S): Interactions between M2 macrophages and ESCs via Stat3 activation may play an important role in the development of endometriosis. PMID- 23461824 TI - Obesity and poor reproductive outcome: female and male body weight matter. PMID- 23461825 TI - Signal transducer and activator of transcription 6 directly regulates human ORMDL3 expression. AB - Orosomucoid-like 3 (ORMDL3) has been associated with asthma and a series of autoimmune disorders, and is involved in endoplasmic reticulum-mediated inflammatory responses. However, its clinical significance and the molecular mechanism underlying its expression are still largely unclear. To elucidate the mechanisms of human ORMDL3 transcriptional regulation, we cloned a 1.5 kb genomic DNA fragment containing the putative promoter region and evaluated its transcriptional activity in a luciferase reporter system by deletion analysis. We identified a 68 bp region that functions as a minimal promoter. Bioinformatics analysis predicted that the -64 to -56 bp region contained a signal transducer and activator of transcription 6 (STAT6) binding site. Electrophoretic mobility shift assay and chromatin immunoprecipitation demonstrated that STAT6 bound to its binding site within the ORMDL3 promoter. STAT6 over-expression or knockdown trans-activated or trans-inhibited, respectively, the ORMDL3 promoter containing the STAT6-binding motif. Treatment with interleukins 4 or 13 increased ORMDL3 promoter activity as well as endogenous ORMDL3 expression. Immunoprecipitation and ChIP/Re-ChIP assays revealed that STAT6 and p300 exist in the same protein complex that binds to the ORMDL3 promoter. Our study confirmed that STAT6 plays important roles in regulating the expression of human ORMDL3 by directly binding to the promoter region, which may shed light on a possible role in various human diseases. PMID- 23461826 TI - Prevalence and risk factors of depression in the elderly nursing home residents in Singapore. AB - OBJECTIVES: Depression is a common health problem in elderly nursing home (NH) residents and is often under-recognized and under-treated. This study aimed to determine the prevalence rates of depression and identify the risk factors associated with depression in the elderly NH population in Singapore. METHODS: A sample of 375 residents in six NHs in Singapore, aged 55 years and above, was assessed with the Structural Clinical Interview (SCID), based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. The association of demographic, functional and health-related characteristics with depression was examined using multivariate logistic regression analyses. RESULTS: Overall point prevalence for depression in the elderly NH residents was found to be 21.1% (95% confidence intervals (CI): 17.1%-25.6%). The prevalence rate for minor depression in the elderly NH residents was 14.4% (95% CI: 11.1%-18.5%) and 6.7% (95% CI: 4.5%-9.8%) for major depression. Significant risk factors that were found to be associated with depression were length of stay for more than 2 years, known history of depression, pain, and no or lack of social contact. CONCLUSION: The prevalence rates for depression were high among NH residents in Singapore. More attention is needed to care for the psychosocial needs of elderly NH residents in Singapore. PMID- 23461827 TI - Trends in transfusion-transmissible infections among Australian blood donors from 2005 to 2010. AB - BACKGROUND: Routine monitoring of trends in transfusion-transmissible infections (TTIs) is essential to maintaining and improving transfusion safety. Although periodic studies have been published there is no comprehensive trend analysis for TTIs in Australian donors. This study determined recent trends in TTIs for which testing is conducted in Australia and described key attributes of infected blood donors. STUDY DESIGN AND METHODS: This is a retrospective analysis using data on donation testing for TTIs (2005-2010) from the national blood service donor database and data on postdonation interviews with TTI-positive donors (2008-2010) from a risk factor database incorporating responses to standardized interview questions. The study measured the prevalence and incidence of TTIs in Australia and assessed their time trends. Multivariate analysis of time trends was conducted using Poisson regression models. RESULTS: Overall, the prevalence and incidence of TTIs in 2005 to 2010 remained low and steady. The prevalence of hepatitis C virus decreased (rate ratio [RR], 0.93; 95% confidence interval [CI], 0.89-0.97) and the prevalence of active syphilis increased (RR, 1.51; 95% CI, 1.15-1.99) significantly during the study period. Prevalence of TTIs among Australian blood donors was substantially lower than that in the general population and no unique risk factors were identified in test-positive blood donors when compared with the general population. CONCLUSION: Both the prevalence and the incidence of TTIs in Australian blood donors remained low, with a steady or declining trend for most infections except active syphilis. The lower prevalence of TTIs in blood donors compared with the general population reflects the effectiveness of donor education and donor selection measures in Australia. PMID- 23461828 TI - Meta-para-linked octaaza[1(8)]cyclophanes and their polycationic states. AB - Octaazacyclophanes, octaaza[1(8)]m,p,m,p,m,p,m,p-cyclophane (2) and octaaza[1(8)]m,p,p,p,m,p,p,p-cyclophane (3), as ring-size extended congeners of tetraaza[1(4)]m,p,m,p-cyclophane were synthesized, and the electronic states of their polycationic species were investigated by quantum chemical calculations, electrochemical measurements (cyclic voltammetry (CV) and differential pulse voltammetry (DPV)), UV-vis-NIR spectroelectrochemical measurements, and pulsed electron spin resonance (ESR) spectroscopy. These octaazacyclophanes exhibited multiredox activities depending on different linkage patterns along the macrocyclic molecular skeletons, and both molecules were oxidizable up to their respective octacations. Spectroelectrochemical measurements demonstrated that p phenylenediamine (PD) moieties in 2 could be converted from the semiquinoidal structure to the quinoidal sturcture with increasing oxidation number, whereas higher oxidation states of 3 did not show definite quinoidal deformation of PD moieties. A pulsed ESR spectrum gave evidence about formation of the almost pure spin-triplet state for 3(2+), whereas the high-spin states of 2(2+) and 2(4+) are virtually degenerate with the competing low-spin states even at low temperatures, probably due to the fragility of spin-coupling pathway caused by facile conformational changes. PMID- 23461829 TI - Factors predicting distress among parents/caregivers of children with neurological disease and home enteral nutrition. AB - BACKGROUND & AIMS: Caregivers of children with chronic diseases included in a home enteral nutrition (HEN) programme are at risk of experiencing a feeling of burden, high level of anxiety and psychological distress. The aims of this study were: first, to examine the prevalence of symptoms of anxiety-depression in caregivers of children with neurological diseases requiring HEN by gastrostomy tube (GT); second, to compare the characteristics of caregivers with high or low risk of exhibiting symptoms of anxiety-depression; and third, to investigate possible associations to child disease severity and nutrition support mode. METHODS: A cross-sectional observational study was performed in 58 caregivers of children (31 boys, aged 0.3-18 years) with neurological diseases and GT feeding. The characteristics of caregivers with high or low risk of presenting symptoms of anxiety-depression were compared regarding the following variables: socio demographic characteristics, the primary caregiver's intrapsychic factors, anthropometric parameters of the child, length of HEN, type of nutrients delivered by GT and infusion regime. RESULTS: All primary caregivers were mothers. Fifty-three per cent of them showed high risk of exhibiting symptoms of anxiety-depression. Mothers with high or low risk of presenting symptoms of anxiety-depression were comparable in age and family socio-economic status. They were also similar in terms of age, anthropometric conditions and length of HEN in their children.No differences were found between the two groups of mothers according to the level of the child's motor function impairment, type of nutrients delivered by GT and infusion regime. Higher levels of psychological distress and perception of burden overload were found in mothers with high risk of exhibiting symptoms of anxiety-depression. CONCLUSIONS: This study found a high prevalence of symptoms of anxiety-depression, perception of burden overload and psychological distress in caregivers of children with HEN. Thus, greater practical and emotional support is required for these families. PMID- 23461830 TI - Determination of disk diffusion and MIC quality control guidelines for GSK2251052: a novel boron-containing antibacterial. AB - GSK2251052 is a boron-containing antimicrobial agent in clinical development for the treatment of serious Gram-negative bacterial infections. These GSK2251052 quality control (QC) studies were performed to establish ranges for control strains (broth microdilution [BMD] MIC and disk diffusion zones) as follows: Pseudomonas aeruginosa ATCC 27853 (2-8 MUg/mL and 15-24 mm), Escherichia coli ATCC 25922 (0.5-2 MUg/mL and 23-30 mm), Haemophilus influenzae ATCC 49247 (0.25-1 MUg/mL and 22-31 mm), Streptococcus pneumoniae ATCC 49619 (0.25-1 MUg/mL and 19 28 mm), Bacteroides fragilis ATCC 25285 (1-4 MUg/mL [BMD] and 1-4 MUg/mL [agar dilution]), and Bacteroides thetaiotaomicron ATCC 29741 (1-8 MUg/mL [BMD] and 2-8 MUg/mL [agar dilution]). These ranges, approved by Clinical and Laboratory Standards Institute, will be crucial in accurately evaluating GSK2251052 in vitro potency. PMID- 23461831 TI - Identification error of Aeromonas aquariorum: a causative agent of septicemia. AB - A genetic reidentification of 7 Aeromonas blood isolates revealed that phenotype based identification systems misidentified 5 (71.4%) isolates. In Aeromonas strains, A. aquariorum was the most common misidentified organism and showed the most potent cytotoxic activities against human blood cell lines, suggesting that the correct identification of A. aquariorum is important. PMID- 23461833 TI - Long-term stability of tensiomyography measured under different muscle conditions. AB - Tensiomyography (TMG) is a technique utilised to measure mechanical and contractile properties of skeletal muscle. Aim of this study was to assess long term stability of TMG across a variety of muscle conditions. Gastrocnemius Medialis of 21 healthy males was measured using TMG in rested conditions, after a warm-up, after a maximal voluntary contraction and after a fatigue protocol. Participants were re-tested on a second occasion 4weeks apart. Among the parameters examined, Contraction Time, Sustain Time and Delay time exhibited a good level of absolute reliability (CV=3.8-9.4%) and poor to excellent level of relative reliability (ICC=0.56-0.92). On the other hand, relative reliability was good to excellent for muscle Displacement (ICC=0.86-0.96), whereas its level of absolute reliability was questionable (CV=8.0-14.8%). Minimum detectable change was less than 20% in most conditions for the aforementioned parameters. Half relaxation Time yielded overall insufficient reliability. In general, the level of reliability tended to increase after the maximal voluntary contraction and the fatigue protocol were administered, probably because of more controlled conditions preceding the measurement. Information about the long-term stability of TMG across different muscle conditions is essential when intervention studies are undertaken with an exercising population, particularly athletes. PMID- 23461834 TI - Kinematics, kinetics and muscle activation patterns of the upper extremity during simulated forward falls. AB - The purpose of this study was to explore the effects of fall type and fall height on the kinematics, kinetics, and muscle activation of the upper extremity during simulated forward falls using a novel fall simulation method. Twenty participants were released in a prone position from a Propelled Upper Limb Fall ARrest Impact System. Impacts occurred to the hands from two fall heights (0.05m and 0.10m) and three fall types (straight-arm, bent-arm, self-selected). Muscle activation from six muscles (biceps brachii, brachioradialis, triceps brachii, anconeus, flexor carpi radialis and extensor carpi radialis) was collected and upper extremity joint kinematics were calculated. Peak Fx (medio-lateral), as well as Fx and Fz (inferior-superior) load rate increased between the 0.05m and 0.10m heights. With respect to fall type, the straight-arm falls resulted in significantly greater Fy (anterior-posterior) impulse and Fy and Fz load rates. The change in elbow flexion angle was greater during the self-selected and bent-arm falls compared to the straight-arm falls; a pattern also seen in the wrist flexion/extension angles. All muscles experienced peak % MVIC prior to the time of the peak force. The results of this study suggest that, to some extent, individuals are capable of selecting an upper extremity posture that allows them to minimize the effects of an impact and it has confirmed the presence of a preparatory muscle activation response. PMID- 23461835 TI - Reno-portal anastomosis as an approach to pediatric kidney transplantation in the setting of inferior vena cava thrombosis. AB - In pediatric renal transplantation in the setting of IVC thrombosis, the retrohepatic IVC or gonadal veins are often used for outflow. However, if use of systemic venous outflow is unsuccessful, options become limited. We report the use of the portal vein for venous outflow in kidney retransplantation in the setting of IVC thrombosis. The patient is a 19-month-old male who developed end stage renal failure at seven months of age secondary to hypotension after spontaneous rupture of an accessory renal vein. The IVC was occluded during emergent laparotomy, and the patient developed extensive IVC thrombosis. The first two transplant attempts used the retrohepatic IVC for venous outflow. Despite good initial flow, in both instances the renal vein thrombosed on post operative day 1. In an unsuccessful salvage attempt of the second transplant, a reno-portal anastomosis was performed. With few options for vascular access, a third transplant was attempted. The reno-portal stump from the second transplant was used for outflow. The patient recovered well from his third transplant (creatinine 0.6 mg/dL 35 months post-surgery), demonstrating that the portal vein can be used for outflow in cases of extensive IVC thrombosis. PMID- 23461836 TI - Kinetics of degradation and adsorption-desorption isotherms of thiobencarb and oxadiargyl in calcareous paddy fields. AB - Herbicides are an important source of contamination in paddy fields. Monitoring their fate and chemical interactions is therefore imperative for sustaining the environment and human health. To meet this purpose, field experiments were conducted to investigate kinetics of thiobencarb and oxadiargyl dissipation in soil and water of two paddy fields. Their adsorption and desorption isotherms were also determined in the soil samples. Variation in concentration was monitored for 60d in soil solution phase and for 315d in soil solid phase. In soil solution, concentrations of both herbicides were rapidly reduced within 5d and reached steady state within 20-30d. Analysis of experimental data resolved a half-life ~2-4d for both herbicides. In soil solid phase, adsorption reaction played a dominant role in the first 10d. Afterwards, degradation reactions regulated the process. Variation in concentration was minimized after about 150d for thiobencarb and 80d for oxadiargyl. The half-lives were calculated ~50d for thiobencarb and ~20d for oxadiargyl, indicating that association with soil particles protect them effectively against degradation reactions. Adsorption isotherms confirmed that both herbicides were strongly adsorbed on soil particles. Furthermore, desorption data indicated that after four successive desorption steps, less than 9% thiobencarb and 1% oxadiargyl were released. This denotes that electrolyte ions in solution cannot adequately compete with and replace adsorbed thiobencarb and oxadiargyl molecules. This would lead to a considerable hysteresis between adsorption and desorption isotherms as was observed experimentally. Overall, it was concluded that both herbicides are among non-persistent and immobile herbicides in the paddy soils. PMID- 23461837 TI - Spectroscopic studies of the effect of aerobic conditions on the chemical characteristics of humic acid in landfill leachate and its implication for the environment. AB - Humic acids (HAs) that extracted from leachates from semi-aerobic and anaerobic landfills test field at different stabilization times were characterized by elemental composition, Fourier transform infrared spectroscopy (FTIR), and Carbon 13 Cross-Polarization Magic-Angle-Spinning Nuclear Magnetic Resonance ((13)C CP/MAS NMR). The higher sulfur (S) content of HA in the anaerobic landfill leachate after a short stabilization time showed that the S released from the organic matter degradation was more easily stabilized under anaerobic conditions, which indicate that HA from anaerobic landfill leachate was more chemically reactive and played a more important role in mobilizing heavy metal, especially mercury, at early landfill stabilization times. However, the S content of HA from the semi-aerobic landfill increased over time, suggesting that more S was stabilized in HA as the landfill stabilization time was extended. The analytical results for the FTIR and NMR showed that the HA from the anaerobic landfill contained more aromatic groups, while HA from the semi-aerobic landfill had more oxygen-containing groups. The aromatic components of the HA from both the anaerobic and semi-aerobic landfills increased over time, suggesting that the maturity and humification degree of HA increased during the stabilization process. PMID- 23461838 TI - Electron transfer capacity dependence of quinone-mediated Fe(III) reduction and current generation by Klebsiella pneumoniae L17. AB - Quinone groups in exogenous electron shuttles can accelerate extracellular electron transfer (EET) from bacteria to insoluble terminal electron acceptors, such as Fe(III) oxides and electrodes, which are important in biogeochemical redox processes and microbial electricity generation. However, the relationship between quinone-mediated EET performance and electron-shuttling properties of the quinones remains incompletely characterized. This study investigates the effects of a series of synthetic quinones (SQs) on goethite reduction and current generation by a fermenting bacterium Klebsiella pneumoniae L17. In addition, the voltammetric behavior and electron transfer capacities (ETCs) of SQ, including electron accepting (EAC) and donating (EDC) capacities, is also examined using electrochemical methods. The results showed that SQ can significantly increase both the Fe(III) reduction rates and current outputs of L17. Each tested SQ reversibly accepted and donated electrons as indicated by the cyclic voltammograms. The EAC and EDC results showed that Carmine and Alizarin had low relative capacities of electron transfer, whereas 9,10-anthraquinone-2,6 disulfonic acid (AQDS), 2-hydroxy-1,4-naphthoquinone (2-HNQ), and 5-hydroxy-1,4 naphthoquinone (5-HNQ) showed stronger relative ETC, and 9,10-anthraquinone-2 carboxylic acid (AQC) and 9,10-anthraquinone-2-sulfonic acid (AQS) had high relative ETC. Enhancement of microbial goethite reduction kinetics and current outputs by SQ had a good linear relationship with their ETC, indicating that the effectiveness of quinone-mediated EET may be strongly dependent on the ETC of the quinones. Therefore, the presence of quinone compounds and fermenting microorganisms may increase the diversity of microbial populations that contribute to element transformation in natural environments. Moreover, ETC determination of different SQ would help to evaluate their performance for microbial EET under anoxic conditions. PMID- 23461839 TI - VUV photolysis of naphthalene in indoor air: Intermediates, pathways, and health risk. AB - To evaluate the health risk of vacuum ultraviolet (VUV) photolysis of naphthalene (NP) in indoor air, intermediates were detected by gas chromatograph-mass spectrometry and proton transfer reaction-mass spectrometry. Results showed that 13 volatile organic compounds (VOCs) in gas phase and five semi-volatile organic compounds (SVOCs) in oil phase were the main intermediates. VUV photolysis pathways of NP can be divided into five stages including functionalization, partition, condensation, fragmentation, and mineralization. Initially NP was converted into several SVOCs via functionalization by oxidative radicals. SVOCs with high boiling points and polarity groups would partition between aerosol and gas phase. Certain amount of SVOCs in aerosol phase were transformed to oily substances by condensation, which can be washed out by conventional gas washing technique like wet scrubber easily. A majority of SVOCs in gas phase were converted to VOCs by fragmentation, which can be further mineralized into CO2. The accumulation of VOCs, especially highly harmful aldehydes, resulted in an increase of health risk influence index (eta) to 150 after VUV irradiation of 2.81min, while the mineralization of VOCs led to a sharp decline of eta to 28 after VUV irradiation of 7.01min. It can be concluded that the mineralization of VOCs is a key factor to alleviate the health risk of photolysis. The results will guide a safe and economical application of VUV photolysis technology in indoor air purification. PMID- 23461840 TI - Successful treatment of radiation-induced proctitis pain by blockade of the ganglion impar in an elderly patient with prostate cancer: a case report. AB - OBJECTIVE: Chronic rectal pain secondary to radiation-induced proctitis is fast becoming a leading cause of chronic pain, especially for prostate cancer survivors. Currently, many elderly patients resort to increased opioid intake to alleviate the pain. However, this increase in opioid consumption often leads to constipation and further aggravates the anorectal pain, thus leading to a perpetual, vicious cycle. We reasoned that blocking the ganglion impar could attenuate this sympathetically maintained pain, which would lead to a reduction in the consumption of opioids, lessen constipation, and lead to an improvement in the patient's quality of life. STUDY DESIGN: Case report. SETTING: An academic tertiary pain management clinic. RESULTS: The authors report the case of a 73 year-old African American man with a history of prostate cancer who presented to the pain management clinic for evaluation and treatment of his chronic anorectal pain secondary to radiation-induced proctitis. The patient underwent a ganglion impar block, using the transcoccygeal technique, and consequently reported excellent pain relief with little or no use for opioid pain medications at a 2 month follow-up. Ultimately, this approach led to improved mobility and an increase in the patient's quality of life. CONCLUSIONS: Based on this case's success, a prospective study or randomized control trial evaluating the efficacy of the ganglion impar block as a treatment option for chronic anorectal pain secondary to radiation-induced proctitis appears warranted. PMID- 23461841 TI - Serum free fatty acid levels in PCOS patients treated with glucophage, magnesium oxide and spironolactone. AB - To assess the effect of glucophage, magnesium oxide and spironolactone in altering free fatty acids (FFAs), 36 PCOS women were randomly divided into three groups. Group 1 (n = 14) was treated with 500 mg glucophage po bid, group 2 (n = 10) was treated with 400 mg magnesium oxide po bid and group 3 (n = 12) was treated with 50 mg spironolactone po bid for 12 weeks. A glucose tolerance test with 75 g glucose load was performed before and after treatment, collecting blood at 0, 1 and 2 h for insulin, glucose, FFA and aldosterone. Amount of FFA before and after treatment were compared by repeated measure ANOVA and represented as area under the curve. FFA levels before treatment were 0.83 +/- 0.23, 0.77 +/- 0.15 and 0.85 +/- 0.28 and after treatment were 0.77 +/- 0.48, 0.71 +/- 0.18 and 0.66 +/- 0.25 for glucophage, magnesium oxide and spironolactone-treated patients, respectively. The FFA levels were unchanged in the groups treated with glucophage and magnesium oxide but were significantly (p < 0.03) decreased in the group treated with spironolactone. Since FFAs are known to be involved in the development of insulin resistance, these results suggest that spironolactone may be useful for lowering insulin resistance in PCOS patients. PMID- 23461845 TI - Distinguishing single DNA nucleotides based on their times of flight through nanoslits: a molecular dynamics simulation study. AB - Transport of single molecules in nanochannels or nanoslits might be used to identify them via their transit (flight) times. In this paper, we present molecular dynamics simulations of transport of single deoxynucleotide 5' monophoshates (dNMP) in aqueous solution under pressure-driven flow, to average velocities between 0.4 and 1.0 m/s, in 3 nm wide slits with hydrophobic walls. The simulation results show that, while moving along the slit, the mononucleotides are adsorbed and desorbed from the walls multiple times. For the simulations, the estimated minimum slit length required for separation of the dNMP flight time distributions is about 5.9 MUm, and the minimum analysis time per dNMP is about 10 MUs. These are determined by the nature of the nucleotide wall interactions, channel width, and by the flow characteristics. A simple analysis using realistic dNMP velocities shows that, in order to reduce the effects of diffusional broadening and keep the analysis time per dNMP reasonably small, the nucleotide velocity should be relatively high. Tailored surface chemistry could lead to further reduction of the analysis time toward its minimum value for a given driving force. PMID- 23461842 TI - Diagnostic and therapeutic management of eosinophilic oesophagitis in children and adults: results from a Spanish registry of clinical practice. AB - BACKGROUND: Eosinophilic oesophagitis has emerged as a common cause of oesophageal symptoms. AIMS: To document practice variation in care provided to eosinophilic oesophagitis patients in Spain and to assess adherence to available guidelines. METHODS: A prospective survey-based registry including data from all patients receiving care from gastroenterologists and allergists throughout Spain was developed. RESULTS: Data from 705 patients (82% adults, male:female ratio 4.1:1) were collected from 26 Spanish hospitals. 42.7% received care in teaching hospitals. Adults presented dysphagia and food impaction more frequently; vomiting and weight loss predominated in children (p < 0.01). A mean diagnostic delay of 54.7 and 28.04 months was documented for adults and children, respectively. Normal endoscopic exams were reported in 27.6% and directly related to the experience in managing the disease (p < 0.05). Paediatric patients, non teaching hospitals and greater experience in managing eosinophilic oesophagitis were associated with increased frequency in eosinophil count reports and with taking gastric and duodenal biopsies (p < 0.001). Initial therapy consisted of topical steroids (61.7% of patients), proton pump inhibitors (52.4%), dietary modifications (51.26%) and endoscopic dilation (7.2%). Referrals to allergy units occurred more frequently in teaching hospitals (p = 0.003) where food restrictions generally followed allergy test results (p < 0.001). CONCLUSIONS: Availability of facilities and the physician's experience constituted the most important factors in explaining differences in patient management. PMID- 23461846 TI - Factors associated with guideline-based hepatitis C virus (HCV) treatment initiation in HIV/HCV-coinfected patients: role of comorbidities and physicians' perceptions. AB - OBJECTIVES: Many HIV-infected patients with chronic hepatitis C virus (HCV) infection do not receive treatment for HCV infection, often because of contraindications or poor adherence to anti-HIV therapy. The aim of this study was to identify factors influencing guideline-based HCV treatment initiation in a large cohort of HIV/HCV-coinfected patients. METHODS: Between 2005 and 2011, 194 (40.5%) of 479 coinfected patients not previously treated for HCV infection started this treatment based on current recommendations, i.e. a Metavir score >F1 for liver fibrosis; HCV genotype 2 or 3 infection; or HCV genotype 1 or 4 infection and low HCV viral load (<800000 IU/mL), whatever the fibrosis score. Clinical and biological data were compared between patients who started HCV therapy during follow-up and those who did not. RESULTS: In multivariate analyses, good adherence to treatment for HIV infection, as judged by the patient's physician, was associated with HCV treatment initiation [odds ratio (OR) 2.37; 95% confidence interval (CI) 1.17-4.81; P=0.017], whereas patients with children (OR 0.53; 95% CI 0.30-0.91; P=0.022) and those with cardiovascular disease or respiratory distress (OR 0.10; 95% CI 0.01-0.78; P=0.03) were less likely to be treated. CONCLUSIONS: Adherence to treatment for HIV infection, as judged by the patient's physician, appears to have a major influence on the decision to begin treatment for HCV infection in coinfected patients. This calls for specific therapeutic education and adherence support in order to ensure timely anti-HCV therapy in this population. PMID- 23461847 TI - A ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium, caused both cholinergic and adrenergic responses in the isolated mouse atrium. AB - An isolated atrial preparation of the mouse is useful for analyzing the actions of drugs on the myocardium, autonomic neurons and endocardial endothelium. The aim of the present study was to examine the functions of intrinsic neurons of the atrium using a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium (DMPP). DMPP (1-100 MUM) caused a negative chronotropic action followed by a positive chronotropic action in spontaneously beating right atria and also caused biphasic inotropic actions consisting of initial inhibition followed by potentiation of electrical field stimulation (EFS)-induced contraction in the left atria. Inotropic actions in the left atria induced by DMPP were characterized using some autonomic drugs and M2 and/or M3 muscarinic receptor knockout (M2R-KO, M3R-KO and M2M3R-KO) mice. Atropine and hexamethonium decreased the initial negative inotropic actions of DMPP. In the atria from pertussis toxin-treated, M2R-KO and M2/M3R-KO mice, the negative inotropic actions were abolished. On the other hand, the following positive inotropic actions were decreased by hexamethonium, atropine and atenolol. In the atria from reserpine-treated mice, positive inotropic actions were also decreased. The positive inotropic action induced by DMPP was almost the same in M2R-KO mice but was reduced in both M3R-KO mice and M2/M3R-KO mice. In conclusion, DMPP caused biphasic inotropic/chronotropic actions in the mouse atrium through activation of intrinsic cholinergic and adrenergic neurons. M2 and M3 muscarinic receptors and beta1-adrenoceptor are thought to be involved in these actions. PMID- 23461848 TI - Local anesthetics inhibit nitric oxide production and L-arginine uptake in cultured bovine aortic endothelial cells. AB - Previous studies have shown that local anesthetics have various effects on nitric oxide (NO) production, but the mechanisms remain unclear. The purpose of this study was to evaluate the effects of local anesthetics on NO production and 2 amino-5-guanidinopentanoic acid (l-arginine) uptake in one cell line. Cultured bovine aortic endothelial cells (BAEC) were stimulated with bradykinin and/or acetylcholine to activate endothelial NO synthase (NOS). BAEC were also incubated with interleukin-1beta and lipopolysaccharide to stimulate inducible NOS. NO production was measured with the rapid spectrophotometric method, and l-arginine uptake was measured with high performance liquid chromatography. To assess the effects of local anesthetics, NO production and l-arginine uptake were measured in the presence or absence of procaine or lidocaine. NO was produced in BAEC stimulated with bradykinin and acetylcholine or interleukin-1beta and lipopolysaccharide, but NO production was not affected by the addition of superoxide dismutase. In the cells stimulated with bradykinin and acetylcholine, 10 MUM each of procaine and lidocaine significantly inhibited NO production by 35% and 20%, respectively. In the cells incubated with interleukin-1beta and lipopolysaccharide, the same quantities of procaine and lidocaine significantly inhibited NO production by 15% and 10%, respectively. Both procaine and lidocaine significantly suppressed l-arginine uptake in BAEC stimulated with either bradykinin/acetylcholine or interleukin-1beta/lipopolysaccharide. It is suggested that inhibitory effects of procaine and lidocaine on NO production are partially due to suppression of l-arginine uptake. PMID- 23461849 TI - Ameliorative effect of Curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice. AB - Epilepsy is a chronic neurological disorder and generally associated with certain psychiatric comorbidities. Among several comorbidities depressive behavior and cognitive impairment has been reported to be most debilitating comorbidity associated with epilepsy. This study was envisaged to evaluate the ameliorative effect of Curcumin on depression like behavior and cognitive impairment observed in pentylenetetrazole kindled animals. Male Swiss Albino mice were kindled with subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.). Successfully kindled animals were used in the study to observe the effect of different treatments. Treatment groups received phenytoin (30 mg/kg) and Curcumin (50, 100 and 200mg/kg) for 15 days. The animals were challenged with pentylenetetrazole (35 mg/kg, i.p.) on day 5, 10 and 15 and seizure severity score, immobility period, number of mistakes and step down latency were recorded. On 15th day, all the animals were sacrificed after behavioral evaluations and their brain was isolated and homogenized to estimate brain norepinephrine, serotonin, total nitrite level and acetylcholinesterase activity. Phenytoin treatment significantly improved the depressive like behavior along with its anticonvulsant effect, however was unable to improve memory impairment. Curcumin significantly attenuated seizure severity, depression like behavior and memory impairment in kindled animals, in dose dependent manner. These results were supported by the biochemical modulation of brain monoamine, nitrosative stress level and acetylcholinesterase activity. Thus present study concluded that Curcumin has the ameliorative effect on seizure severity, depression like behavior and memory impairment in pentylenetetrazole kindled mice, possibly via central monoaminergic modulation and inhibitory effect on nitrosative stress and acetylcholinesterase activity. PMID- 23461850 TI - Neuroprotective effects of salvianolic acid B on an Abeta25-35 peptide-induced mouse model of Alzheimer's disease. AB - Salvianolic acid B (SalB) is a polyphenolic compound found in Salvia miltiorrhiza Bunge that has several anti-oxidative and anti-inflammatory effects. In the present study, we investigated whether SalB has neuroprotective effects in an amyloid beta (Abeta) peptide-induced Alzheimer's disease mouse model. Mice were injected with Abeta25-35 peptide intracerebroventricularly and were subsequently administered SalB once daily for 7 days. Subchronic SalB administration (10mg/kg) significantly ameliorated the Abeta25-35 peptide-induced memory impairment in the passive avoidance task (P<0.05). SalB treatment also reduced the number of activated microglia and astrocytes that were observed during the inflammatory reaction after the administration of the Abeta25-35 peptide. Moreover, SalB markedly reduced inducible nitric oxide synthase and cyclooxygenase-2 expression levels and thiobarbituric acid reactive substances, which were increased by the administration of the Abeta25-35 peptide. Furthermore, SalB administration significantly rescued the Abeta25-35 peptide-induced decrease of choline acetyltransferase and brain-derived neurotrophic factor protein levels. These results suggest that SalB exerts neuroprotective activity via anti-inflammatory and anti-oxidative effects and that SalB may be a potential candidate for Alzheimer's disease therapy. PMID- 23461851 TI - Involvement of P2Y11 receptor in IFN-gamma-induced IL-6 production in human keratinocytes. AB - Extracellular ATP and P2 receptors are reported to be involved in interleukin-6 (IL-6) production by human keratinocytes, but the role of extracellular ATP in cytokine-induced IL-6 production remains unclear. In this study, we investigated the involvement of various P2 receptors in IL-6 production induced by the Th1 cytokine interferon-gamma (IFN-gamma) in a human keratinocyte cell line, HaCaT. IFN-gamma increased IL-6 production in HaCaT cells. A non-selective antagonist of P2Y receptors (suramin), a selective P2Y11 receptor antagonist (NF157), ecto nucleotidase (apyrase), and a soluble adenylate cyclase inhibitor (KH7) all inhibited IL-6 production. It was further confirmed that ATP was released from HaCaT cells stimulated with IFN-gamma. These results suggest that extracellular ATP and P2Y11 receptor are involved in IFN-gamma-induced IL-6 production. Knockdown of P2Y11 receptor suppressed IL-6 production, strongly supporting this idea. In conclusion, these data demonstrate that P2Y11 receptor mediates IFN gamma-induced IL-6 production in human keratinocytes, and suggest the importance of purinergic signaling in IFN-gamma-induced skin inflammatory conditions, such as psoriasis. PMID- 23461852 TI - Antihyperalgesic and antiallodynic effect of sirolimus in rat model of adjuvant arthritis. AB - Sirolimus is an immunosupressive drug that specifically inhibit the activation of T-lymphocytes. This study was undertaken to investigate whether treatment with sirolimus exert analgesic effect in rat adjuvant-induced arthritis, an animal model of rheumatoid arthritis. Arthritis was induced by a single subcutaneous injection of Freund's complete adjuvant to male Wistar rats that were divided into four groups; control (saline), vehicle (ethanol), sirolimus 0.75 and sirolimus 1.5. Sirolimus (0.75 and 1.5mg/kg/day) was administered intraperitoneally using Monday-Wednesday-Friday dosing schedule for 29 days, this dosing regimen revealed acceptable trough blood concentrations in arthritic rats. Adjuvant inoculation resulted in paw inflammation, hyperalgesia and allodynia as assessed by pletismometer, analgesymeter and dynamic plantar aesthesiometer respectively. Light microscopic evaluation of the arthritic metacarpophalangeal joints revealed synovial hypertrophy with inflammatory cellular infiltration, cartilage destruction and partial subchondral bone resorption. ELISA tests of serum TNF-alpha, IL-1beta or IL-6 did not show any change in arthritic rats, while Western blotting analysis revealed a significant increase in TNF-alpha (P<0.001), but not IL-1beta or IL-6, protein expression in the lumbar spinal cord of arthritic rats. Treatment with sirolimus significantly decreased the arthritic lesions (P<0.001) and paw swelling (P<0.05), alleviated the histological features in the metacarpophalangeal joint, resulted in antihyperalgesic and antiallodynic effects without affecting the locomotor activity and prevented the increased spinal cord TNF-alpha level (P<0.05). It seems that prevention of the increased TNF-alpha expression in the spinal cord may partially contribute to the antihyperalgesic effect of sirolimus in adjuvant arthritic rats and sirolimus could be a promising immunosupressive agent in the treatment of arthritic pain. PMID- 23461853 TI - The anti-diabetic drug glibenclamide is an agonist of the transient receptor potential Ankyrin 1 (TRPA1) ion channel. AB - The anti-diabetic drug glibenclamide inhibits K(ATP) channels in pancreatic beta cells and stimulates insulin release. It also causes adverse effects, among which are abdominal pain, gastrointestinal disturbances and nocturia. We report that glibenclamide activates human TRPA1 in a concentration range that is commonly used to induce inhibition of K(ATP) channels in vitro. Glibenclamide generates calcium transients in HEK293t cells transiently transfected with human TRPA1, which are inhibited by the selective TRPA1 antagonist HC030031 and also evokes outwardly rectifying currents mediated by recombinant TRPA1. Glibenclamide activates a subpopulation of mouse primary sensory neurons, most of which are also sensitive to the selective TRPA1 agonist mustard oil. This glibenclamide sensitivity is completely abolished by genetic ablation of TRPA1. Taken together, our data demonstrate that glibenclamide is an agonist of human TRPA1, which may explain some of the adverse effects of the drug. PMID- 23461854 TI - Morphine deteriorates spatial memory in sodium salicylate treated rats. AB - Tolerance and cross-tolerance for the effects of morphine (M) and sodium salicylate on nociception and learning were examined. The anti-nociceptive effects were measured by using the classic tail flick (TF) and hot plate (HP) tests and learning was measured with the Morris water maze (MWM). Tolerance or cross-tolerance was induced by daily injection (i.p.) of morphine sulfate (10mg/kg for 7 days) or sodium salicylate (300 mg/kg for 6 days). The injection of sodium salicylate increased both TF and HP latencies. This anti-nociceptive effect was progressively decreased across six injections and tolerance to sodium salicylate was developed. When M was injected to sodium salicylate-tolerant rats, a weakened anti-nociceptive effect was seen, indicating cross-tolerance to M. Acute treatment with M also increased TF latency. This anti-nociceptive effect was successively decreased across seven injections and tolerance to M was developed. When sodium salicylate was injected to M-tolerant rats, a diminished anti-nociceptive effect was seen, indicating cross-tolerance to sodium salicylate. Acute M impaired water maze performance, while chronic M and sodium salicylate had no effects on MWM performance. However, when M was injected to rats that had received sodium salicylate after each training trial for 7 days, these rats spent less time in target quadrant as compared to M and saline groups. It is concluded that chronic sodium salicylate induces tolerance to anti nociceptive effects of M and vice versa. Also chronic salicylate may produce lasting metaplastic changes in brain mechanisms behind spatial learning and memory, which can be visualized in cross-sensitization to morphine. PMID- 23461855 TI - Improvement of the circulatory function partially accounts for the neuroprotective action of the phytoestrogen genistein in experimental ischemic stroke. AB - We tested the hypothesis that the phytoestrogen genistein protects the brain against ischemic stroke by improving the circulatory function in terms of reduced production of thromboxane A2 and leukocyte-platelet aggregates, and of preserved vascular reactivity. Ischemia-reperfusion (90 min-3 days, intraluminal filament) was induced in male Wistar rats, and functional score and cerebral infarct volume were the end points examined. Genistein (10mg/kg/day) or vehicle (beta cyclodextrin) was administered at 30 min after ischemia or sham-operation. Production of thromboxane A2 and leukocyte-platelet aggregates, as well as reactivity of carotid artery to U-46619 (thromboxane A2 analogue) and to platelet releasate was measured. At 3 days post-ischemia, both improvement in the functional examination and reduction in the total infarct volume were shown in the ischemic genistein-treated group. Genistein significantly reverted both the increased thromboxane A2 concentration and the increased leukocyte-platelet aggregates production found in samples from the ischemic vehicle-treated group. Both U-46619 and platelet releasate elicited contractions of the carotid artery, which were significantly lower in the ischemic vehicle-treated group. Genistein significantly restored both the decreased U-46619- and the decreased platelet releasate-elicited contractile responses. In conclusion, genistein protects the brain against an ischemia-reperfusion challenge, at least in part, by its beneficial effects on the circulatory function. PMID- 23461857 TI - Exploring the folding pattern of a polymer chain in a single crystal by combining single-molecule force spectroscopy and steered molecular dynamics simulations. AB - Understanding the folding pattern of a single polymer chain within its single crystal will shed light on the mechanism of crystallization. Here, we use the combined techniques of atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) and steered molecular dynamics (SMD) simulations to study the folding pattern of a polyethylene oxide (PEO) chain in its single crystal. Our results show that the folding pattern of a PEO chain in the crystal formed in dilute solution follows the adjacent re-entry folding model. While in the crystal obtained from the melt, the nonadjacent folding with large and irregular loops contributes to big force fluctuations in the force-extension curves. The method established here can offer a novel strategy to directly unravel the chain-folding pattern of polymer single crystals at single-molecule level. PMID- 23461858 TI - Can acute dermal systemic toxicity tests be replaced with oral tests? A comparison of route-specific systemic toxicity and hazard classifications under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS). AB - Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification criteria to determine the dermal classification reduced the concordance to 15% and the relative 'under classification' to 1%, but increased the relative 'over-classification' to 84%. Both under- and over-classification are undesirable, and mitigation strategies are discussed. Finally, no substance with an oral LD50 of >2000mg/kg was classified for acute systemic toxicity by the dermal route, suggesting that dermal testing for acute systemic toxicity of such substances adds nothing to the hazard characterisation and should be removed from routine regulatory data requirements. PMID- 23461856 TI - Cancer stem-like cell properties are regulated by EGFR/AKT/beta-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma. AB - We report that the epidermal growth factor receptor (EGFR) pathway plays a critical role in regulating cancer stem-like cells (CSCs) in nasopharyngeal carcinoma (NPC), one of the most common malignant tumors in Southeast Asia. Effects of EGFR on maintaining CSCs are mainly mediated by AKT signaling, and beta-catenin is responsible for governing CSC properties in response to EGFR/AKT activation. Significantly, CSCs are enriched by cisplatin and decreased by gefitinib in NPC xenograft models. Upon reimplantation in secondary mice, tumor cells derived from cisplatin-treated mice grew rapidly, whereas regrowth of tumor cells from gefitinib-treated mice was severely diminished. We further demonstrate that expression of EGFR correlates with expression of beta-catenin and Nanog in primary tumor specimens from NPC patients. These findings provide mechanistic and preclinical evidence supporting the use of gefitinib alone or in combination with a chemotherapeutic agent in first-line therapy for patients with NPC. In addition, our results suggest that targeting beta-catenin represents a rational clinical modality for patients whose tumors harbor activated EGFR or AKT. PMID- 23461859 TI - Photochemical targeting of antigens to the cytosol for stimulation of MHC class-I restricted T-cell responses. AB - Tumour chemotherapy with drugs is typically associated with severe systemic and local side effects for which reason immunotherapy represents a safer alternative. However, vaccination often fails to generate the required cytotoxic CD8 T-cell responses due to insufficient access of antigens to the cytosol and the MHC class I pathway of antigen presentation. One important issue of tumour research is therefore to develop strategies that allow cytosolic targeting or endosomal escape of tumour antigens. The objective of the current study was to test whether endocytosed antigen could be delivered to MHC class I by means of photochemical internalisation (PCI). Briefly, the antigen and the photosensitiser Amphinex were loaded in vitro onto bone-marrow-derived murine dendritic cells (DCs). After light activation, which is supposed to cause disruption of OVA- and Amphinex containing endosomes, the DCs were cultured with OVA-specific CD8 T cells or used for immunisation of mice. PCI facilitated CD8 T-cell responses as measured by IFN gamma secretion in vitro and CD8 T-cell proliferation in vivo. In conclusion, the current proof-of-concept study is the first to describe PCI-mediated immunisation and the results revealed the feasibility of this novel technology in autologous vaccination for stimulation of CD8 T-cell responses. PMID- 23461861 TI - Biodistribution of Nanostructured Lipid Carriers (NLCs) after intravenous administration to rats: influence of technological factors. AB - Nanoparticles for medical applications are frequently administered via parenteral administration. In this study, the tissue distribution of three lipid formulations based on Nanostructured Lipid Carriers (NLCs) after intravenous administration to rats was evaluated. NLCs were prepared by a high pressure homogenization method and varied in terms of particle size, surface charge, and surfactant content. The (99m)Tc radiolabeled NLCs were intravenously administered to rats, and radioactivity levels in blood and tissues were measured. Cmax, AUC0 24, and MRT0-24 were obtained from the radioactivity level versus time profiles. The radiolabeled nanocarriers exhibited a long circulation time since radioactivity was detected in blood even 24 h post-injection. No differences on the MRT values in blood among the NLCs were observed, in spite of the different particle size and surface charge. The highest radioactivity levels were measured in the kidney, followed by the bone marrow, the liver, and the spleen. In the kidney, there was a higher accumulation of the positive nanoparticles, and in the liver, uptake of negative nanoparticles was higher than positive ones. NLCs with the largest particle size showed a higher uptake in the lung and lower accumulation in liver and bone marrow, in comparison with the smaller ones. PMID- 23461860 TI - Microneedle/nanoencapsulation-mediated transdermal delivery: mechanistic insights. AB - A systematic study was undertaken to gain more insight into the mechanism of transdermal delivery of nanoencapsulated model dyes across microneedle (MN) treated skin, a complex process not yet explored. Rhodamine B (Rh B) and fluorescein isothiocyanate (FITC) as model hydrophilic and hydrophobic small/medium-size molecules, respectively, were encapsulated in poly lactic-co glycolic acid (PLGA) nanoparticles (NPs) and delivered through full thickness porcine skin pretreated with MN array. Permeation through MN-treated skin was affected by physicochemical characteristics of NPs and the encapsulated dyes. Dye flux was enhanced by smaller particle size, hydrophilicity, and negative zeta potential of NPs. Regarding encapsulated dyes, solubility at physiological pH and potential interaction with skin proteins proved to outweigh molecular weight as determinants of skin permeation. Data were verified using confocal laser scanning microscopy imaging. Findings coupled with the literature data are supportive of a mechanism involving influx of NPs, particularly of smaller size, deep into MN created channels, generating depot dye-rich reservoirs. Molecular diffusion of the released dye across viable skin layers proceeds at a rate determined by its molecular characteristics. Data obtained provide mechanistic information of importance to the development of formulation strategies for more effective intradermal and transdermal MN-mediated delivery of nanoencapsulated therapeutic agents. PMID- 23461862 TI - D category IV: a group of clinically relevant and phylogenetically diverse partial D. AB - BACKGROUND: The D typing strategies in several European countries protect carriers of D category VI (DVI) from anti-D immunization but not carriers of other partial D. Besides DVI, one of the clinically most important partial D is D category IV (DIV). A detailed description and direct comparison of the different DIV types was missing. STUDY DESIGN AND METHODS: RHD nucleotide sequences were determined from genomic DNA. D epitope patterns were established with commercial monoclonal anti-D panels. RESULTS: DIV comprises several variants of the D antigen with distinct serology, molecular structures, evolutionary origins, and ethnic prevalences. The DIV phenotype is determined by 350H shared by all, but not limited to, DIV variants which are further divided into DIVa and DIVb. The DIVa phenotype is expressed by DIV Type 1.0 harboring 350H and the dispersed amino acids 62F, 137V, and 152T. The DIVb phenotype is expressed by DIV Type 3 to Type 5 representing RHD-CE-D hybrids. Four of the six postulated DIV variants were encountered among 23 DIV samples analyzed. Of 12 DIV carriers with anti-D, 10 were female and seven likely immunized by pregnancy. Two DIV-related alleles are newly described: DWN, which differs from DIV Type 4 by 350D and epitope pattern. DNT carries 152T, known to cause a large D antigen density. CONCLUSION: DIV alleles arose from at least two independent evolutionary events. DIV Type 1.0 with DIVa phenotype belongs to the oldest extant human RHD alleles. DIV Type 2 to Type 5 with DIVb phenotype arose from more recent gene conversions. Anti-D immunization, especially dreaded in pregnancies, will be avoided not only in carriers of DVI but also in carriers of other D variants like DIV, if our proposed D typing strategy is adopted. PMID- 23461863 TI - Polycyclic aromatic hydrocarbons in residential dust: sources of variability. AB - BACKGROUND: There is interest in using residential dust to estimate human exposure to environmental contaminants. OBJECTIVES: We aimed to characterize the sources of variability for polycyclic aromatic hydrocarbons (PAHs) in residential dust and provide guidance for investigators who plan to use residential dust to assess exposure to PAHs. METHODS: We collected repeat dust samples from 293 households in the Northern California Childhood Leukemia Study during two sampling rounds (from 2001 through 2007 and during 2010) using household vacuum cleaners, and measured 12 PAHs using gas chromatography-mass spectrometry. We used a random- and a mixed-effects model for each PAH to apportion observed variance into four components and to identify sources of variability. RESULTS: Median concentrations for individual PAHs ranged from 10 to 190 ng/g of dust. For each PAH, total variance was apportioned into regional variability (1-9%), intraregional between-household variability (24-48%), within-household variability over time (41-57%), and within-sample analytical variability (2-33%). Regional differences in PAH dust levels were associated with estimated ambient air concentrations of PAH. Intraregional differences between households were associated with the residential construction date and the smoking habits of residents. For some PAHs, a decreasing time trend explained a modest fraction of the within-household variability; however, most of the within-household variability was unaccounted for by our mixed-effects models. Within-household differences between sampling rounds were largest when the interval between dust sample collections was at least 6 years in duration. CONCLUSIONS: Our findings indicate that it may be feasible to use residential dust for retrospective assessment of PAH exposures in studies of health effects. PMID- 23461864 TI - Severe lung injury and lung biopsy in children post-hematopoietic stem cell transplantation: The differences between allogeneic and autologous transplantation. AB - To review outcome of children post-allogeneic (allo) and autologous (auto) SCT with severe lung injury who had lung biopsy and to determine whether the diagnoses provided by lung biopsy had an impact on outcome. Retrospective study was carried out from January 2000 to June 2010. Nine hundred and eighteen children (0-18 yr) received SCT (allo 476, auto 442), and 59 biopsies were performed in 48 patients. Most common result of lung biopsy was non-infectious inflammation and recurrent disease in allo- and autorecipients, respectively. In a multivariate analysis, survival of allorecipients who had management change was inferior (p = 0.002; HR: 3.12). These patients were extremely sick, and management change was the last attempt to stabilize their respiratory status. There was a trend toward superior survival for children who had biopsy after 100 days following SCT (p = 0.09; HR: 0.55) and a trend toward inferior survival for those with proven infections within two wk of biopsy (p = 0.07; HR: 2.14). Only 31% of allorecipients and 25% of autorecipients survived. There were no biopsy related complications. Lung biopsy itself appears to be well tolerated, although requiring a biopsy seems to carry a poor prognosis; this seems to be due to different causes, auto (relapse), allo (non-infectious inflammation). PMID- 23461865 TI - Elevated glycodelin-A concentrations in serum and peritoneal fluid of women with ovarian endometriosis. AB - The aim of this study was to evaluate serum and peritoneal fluid (PF) glycodelin A concentrations in women with ovarian endometriosis. Ninety-nine matched pairs of serum and PF samples were included in our study. The case group comprised 57 women with ovarian endometriosis and the control group 42 healthy women undergoing sterilization or patients with benign ovarian cysts. Glycodelin-A concentrations were measured using ELISA. Endometriosis patients had significantly higher serum and PF glycodelin-A concentrations compared to controls, and this increase was observed in both proliferative and secretory cycle phases. Glycodelin-A concentrations were more than 10-fold higher in PF than in serum and correlated with each other. Intensity and frequency of menstrual pain positively correlated with glycodelin-A concentrations. Sensitivity and specificity of glycodelin-A as a biomarker for ovarian endometriosis were 82.1% and 78.4% in serum, and 79.7% and 77.5% in PF, respectively. These results indicate that Glycodelin-A has a potential role as a biomarker to be used in combination with other, independent marker molecules. PMID- 23461866 TI - The miRNA and mRNA changes in rat hippocampi after chronic constriction injury. AB - OBJECTIVE: We elaborated the rat hippocampi in order to assess for central nervous system changes following a peripheral neuropathic injury. DESIGN, SETTING, SUBJECTS: We examined the gene changes in the hippocampi of chronic constriction injury (CCI) rats with TaqMan(r) low-density array analysis (TLDA) and quantitative real-time polymerase chain reaction (qRT-PCR) of miR-125b, -132, and messenger RNAs (mRNAs) of neuropeptide Y, brain-derived neural factor, N methyl-D-aspartate glutamate 2A receptor, gamma-aminobutyric acid A a1 receptor, gamma-aminobutyric acid A b1 receptor, gamma-aminobutyric acid B b2 receptor, serotonin 1A receptor, serotonin 2A receptor, serotonin 2C receptor, and serotonin 3A receptor on days 0, 7, and 15 after surgery. INTERVENTIONS: None. OUTCOME MEASURES: Two behavioral tests (thermal and mechanical stimulation tests) were performed three times at 5-minute intervals to assess pain thresholds. MicroRNA (miRNA) changes were examined by TLDA. mRNA changes were examined by qRT PCR. Statistical significance was determined by Tukey-Kramer's method and paired t-test. RESULTS: All rats showed mechanical and thermal hypersensitivity on the ipsilateral side. Out of 373 miRNAs analyzed, 237 were expressed, and 51 changed their expressions after CCI. By TLDA, cluster analysis found obvious miRNA changes on day 7 that tended to recover by day 15. For miR-125b, the relative expression decreased to 0.70 +/- 0.30 at day 7 and recovered to 1.65 +/- 0.19 at day 15. The miR-132 relative expressions were 0.69 +/- 0.30 and 0.70 +/- 0.15, respectively. The mRNA changes followed the miRNA changes. CONCLUSIONS: Our results showed that the peripheral nerve injury altered rat hippocampal miRNA. PMID- 23461867 TI - Two incorrect assertions about study of hospital standardised mortality ratios in the West Midlands. PMID- 23461869 TI - Biomedical PhD education--an international perspective. AB - The PhD, otherwise known as the doctor of philosophy or Dr. Phil., is an internationally recognized degree, indicating that the PhD graduate has received training in research under supervision. Traditionally, the PhD was the route to an academic career, with most successful PhD graduates receiving tenured university positions. However, over the past 20-30 years, and particularly the past 10 years, the situation has changed dramatically. Governments in many countries have invested massively in PhD education, believing that trained researchers will contribute to the 'knowledge society', and thus increase the competitiveness of their countries in the future economies of the world. Thus, only a small fraction of PhD graduates now end up in academic research. Yet, the PhD remains a research degree, and indeed, institutions have become heavily dependent on PhD students for their research output. The situation has thus created a paradox. On the one hand, it has become essential for institutions to have many PhD students and for the research performed to be of the highest level. On the other hand, the careers of PhD students are not necessarily going to be directly related to the research performed during their PhD studies. The purpose of this article is to explore how this seeming paradox is being addressed in biomedicine and to show that far from being inconsistent that the two aspects are in fact complementary. The article is based on the author's experience as Head of Aarhus Graduate School of Health Sciences 2002-2011 and his work with graduate schools across Europe and internationally through the organization ORPHEUS. PMID- 23461870 TI - Preparation and characterization of light-switchable polymer networks attached to solid substrates. AB - Surface-attached polymer networks that carry light-responsive nitrospiropyran groups in a hydrophilic PDMAA matrix were prepared on planar silicon and glass surfaces and were characterized with respect to their switching behavior under the influence of an external light trigger. Functional polymers bearing light responsive units as well as photo-cross-linkable benzophenone groups were first synthesized using free radical copolymerization. The number of spiropyran groups in the copolymer was controlled by adjusting the concentration of the respective monomer in the copolymerization feed. The polymer films were prepared by spin coating the functional polymers from solution and by ultraviolet light (UV) induced cross-linking utilizing benzophenone photochemistry. On substrates with immobilized benzophenone groups, the complete polymer network is linked to the surface. The dry thickness of the films can be controlled over a wide range from a few nanometers up to more than 1 MUm. The integration of such light-switchable organic moieties into a surface-attached polymer network allows one to increase the overall number of light-responsive groups per surface area by adjusting the amount of surface-attached polymer networks. The spiropyran's function in dry (solvent-free) and swollen polymer films can be reversibly switched by UV and visible irradiation. In addition, the switching in water is faster than in the dry state. Therefore, implementing light-responsive spiropyran functions in polymer films linked to solid surfaces could allow for switching of the chemical and optical surface properties in a fast and spatially controlled fashion. PMID- 23461871 TI - The role of interleukin 1beta in the anti-adipogenic action of macrophages on human preadipocytes. AB - When adipose tissue accumulates in obesity, the ability of preadipocytes to differentiate permits a hyperplastic expansion of functional adipocytes that preserves insulin sensitivity. Adipose infiltration by macrophages is associated with an adipogenic deficit and the appearance of inflamed, insulin-resistant hypertrophied adipocytes. Interleukin 1beta (IL1beta) has been reported to account for the anti-adipogenic action of macrophages in a mouse model. Using the THP-1 human macrophage cell line and human primary preadipocytes, our objective was to determine whether IL1beta was necessary for the ability of conditioned medium from THP-1 macrophages (THP-1-MacCM) to: i) stimulate human preadipocyte inhibitor of kappaB kinase beta (IKKbeta) and ii) inhibit human adipocyte differentiation. IL1beta is present in THP-1-MacCM, and THP-1-MacCM or IL1beta (500 pg/ml; its concentration in THP-1-MacCM) acutely stimulated IKKbeta phosphorylation and inhibitor of kappaB (IkappaB) degradation in preadipocytes. IL1beta was sufficient to inhibit adipogenesis on its own, and this was blocked by SC-514, an IKKbeta inhibitor, as has been reported for THP-1-MacCM. IkappaB degradation by IL1beta-immunodepleted THP-1-MacCM was attenuated, whereas IKKbeta phosphorylation and the inhibition of adipocyte differentiation were unchanged. Therefore, in contrast to what has been suggested for mouse cell models, IL1beta is not required for the ability of MacCM to inhibit adipogenesis in human cell models. PMID- 23461872 TI - Summaries of evidence: an adjunct to knowledge translation? PMID- 23461873 TI - Cochrane review summary: Education for contraceptive use by women after childbirth. PMID- 23461874 TI - SAPC hot topic: The changing primary care research landscape. PMID- 23461876 TI - Dwindling Drugs: is there anything we can do? PMID- 23461878 TI - Recognition of pain medicine as a vocational scope of practice in New Zealand. PMID- 23461877 TI - Urinary metabolites of organophosphate flame retardants: temporal variability and correlations with house dust concentrations. AB - BACKGROUND: A reduction in the use of polybrominated diphenyl ethers (PBDEs) because of human health concerns may result in an increased use of and human exposure to organophosphate flame retardants (OPFRs). Human exposure and health studies of OPFRs are lacking. OBJECTIVES: We sought to define the degree of temporal variability in urinary OPFR metabolites in order to inform epidemiologic study design, and to explore a potential primary source of exposure by examining the relationship between OPFRs in house dust and their metabolites in urine. METHODS: Nine repeated urine samples were collected from 7 men over the course of 3 months and analyzed for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPP), metabolites of the OPFRs tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP), respectively. Intraclass correlation coefficients (ICCs) were calculated to characterize temporal reliability. Paired house dust and urine samples were collected from 45 men. RESULTS: BDCPP was detected in 91% of urine samples, and DPP in 96%. Urinary BDCPP showed moderate-to-strong temporal reliability (ICC range, 0.55-0.72). ICCs for DPP were lower, but moderately reliable (range, 0.35-0.51). There was a weak [Spearman r (r(S)) = 0.31] but significant (p = 0.03) correlation between urinary BDCPP and TDCPP concentrations in house dust that strengthened when nondetects (r(S) = 0.47) were excluded. There was no correlation between uncorrected DPP and TPP measured in house dust (r(S) < 0.1). CONCLUSIONS: Household dust may be an important source of exposure to TDCPP but not TPP. Urinary concentrations of BDCPP and DPP were moderately to highly reliable within individuals over 3 months. PMID- 23461880 TI - Epidemiology and molecular identification of Anisakis pegreffii (Nematoda: Anisakidae) in the horse mackerel Trachurus trachurus from northern Morocco. AB - Anisakis infection parameters were studied in horse mackerel (Trachurus trachurus) taken from two areas of northern Morocco (Tetouan and Tangier), which showed a mean prevalence of 54.9%. Identification of the ITS1-5.8S-ITS2 fragment by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) showed A. pegreffii to be the dominant species; no A. simplex s.s. were detected. The presence of A. pegreffii in horse mackerel was not influenced by the sex (P = 0.46) or catch area (Atlantic versus Mediterranean, P = 0.52) of the fish, but was significantly related to their length, weight, liver weight and gonad weight, and to the season of their capture (P < 0.05). A low prevalence (8.6%) and mean intensity (1.0) was detected in the muscle, probably related to the reduced ability of A. pegreffii to penetrate muscle. The risk of the presence of A. pegreffii in the muscle was fivefold higher in fish caught during the summer than during any other season. Susceptible members of the human population can minimize the risk of infection by avoiding the consumption of larger horse mackerel specimens during the summer. PMID- 23461881 TI - Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives. AB - A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Specifically, 1-(-1-(4-methoxyphen- yl)-3-phenylallylidene)thiosemicarbazide (18) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 0.274 MUM. The inhibition mechanism analysis of 1-(-1-(2,4-dihydroxyphenyl)-3-phenylallylidene) thiosemicarbazide (16) and 1-(-1-(4-methoxyphenyl)-3-phenylallylidene) thiosemicarbazide (18) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest. PMID- 23461882 TI - Rethinking disaster mental health response in a post-9/11 world. PMID- 23461883 TI - A review and retrospective analysis of mental health services provided after the September 11 attacks. AB - OBJECTIVE: Various mental health services were provided in New York City in the response to the September 11 attacks. This article describes these services and the subsequent research in disaster psychiatry to identify recommended practices for future disasters. METHOD: A PubMed search identified 198 articles since the 9/11 attacks that included "New York City," and either "9/11" or "disaster," and either "psychiatry" or "mental health." The abstracts of all of these articles were reviewed to identify articles that described clinical services and those articles were then reviewed in detail. Additional reports on 9/11-related services were identified through book chapters. RESULTS: Acute services included debriefings and other single-time outreach interventions. Postacute phase interventions included community outreach with the goal of addressing normative psychological sequelae, multisession interventions based on evidence-based treatments, and hospital-based psychiatric services provided in the context of general health screenings for response workers. CONCLUSIONS: Many programs integrated medical and nonmedical services. The professional literature in the decade since this disaster has shifted recommended practices away from psychological debriefings in the acute phase to the implementation of psychological first aid (PFA). Many of the acute 9/11-related services actually closely resembled PFA. In the postacute phase, resources need to be made available for more resource-intensive psychiatric treatment for the fraction of survivors who develop psychiatric illness. PMID- 23461884 TI - Assessing children's disaster reactions and mental health needs: screening and clinical evaluation. AB - OBJECTIVE: To present a framework for assessing children's disaster reactions and mental health needs. METHODS: We reviewed the relevant literature and clinical experience to identify information on assessment approaches in children and to construct an assessment framework based on disaster exposure. RESULTS: Child disaster mental health assessment includes 2 components-screening and clinical evaluation-but these have not been fully explicated or distinguished in the literature. Screening can be used to assess large numbers of children across exposure groups. Clinical evaluation is appropriate for children who are directly exposed to a disaster, for those whose family members and (or) close associates are directly exposed, and for those who are identified through screening as being at risk for psychiatric disturbance. Clinical evaluation includes a full diagnostic assessment (posttraumatic stress disorder and other disorders) with the goals of identifying psychopathology, determining the need for clinical care, and guiding intervention planning and referral. Children with psychiatric conditions should be referred to treatment, while those with psychological distress but without psychiatric illness may benefit from psychosocial interventions. CONCLUSIONS: Screening is appropriate to identify children at risk for psychiatric disturbance who will need further evaluation to determine diagnosis. Screening should not be used to dictate treatment decisions. Children who screen positive for psychiatric risk should receive a full clinical evaluation. Children determined to be suffering from psychiatric disorders should receive, or be referred for, formal treatment. Children without psychiatric disorders may benefit from psychosocial interventions. PMID- 23461885 TI - Teachers' ratings of childhood behaviours predict adolescent and adult crime among 3016 males and females. AB - OBJECTIVE: To examine associations of teacher-rated conduct problems (CP) and hurtful and uncaring behaviours (HUB) at age 6 and 10 with criminal convictions up to age 24 among 1593 males and 1423 females, and to determine whether aggressive behaviour at age 12 mediated the associations of CP and HUB with criminal convictions. METHOD: Teachers assessed HUB and CP at ages 6 and 10 and ratings above the 90th percentile at each age and within each sex were used to assign participants to 1 of 4 groups. Teachers assessed proactive, reactive, indirect, and verbal aggression at age 12. Juvenile and adult criminal records were obtained. RESULTS: High CP and HUB males, aged 6, were 4 times more likely than males with lower ratings to acquire convictions for violent crimes and 5 times more likely to acquire convictions for nonviolent crimes by age 24. High HUB and CP females, aged 6, were 5 times more likely than females with lower ratings to have a conviction for a nonviolent offence by age 24. Among males, both aged 6 and 10, high HUB without CP were associated with elevations at risk of convictions for violent and nonviolent crimes, while among females the elevations at risk were limited to convictions for nonviolent crimes. Different types of aggressive behaviour mediated associations of high HUB and CP with subsequent criminal convictions, but not the association of HUB without CP and crime. CONCLUSIONS: Teachers in elementary schools rated behaviours that, from age 6 onward, significantly predicted criminal convictions into early adulthood. PMID- 23461879 TI - Timetree of Aselloidea reveals species diversification dynamics in groundwater. AB - A key challenge for biologists is to document and explain global patterns of diversification in a wide range of environments. Here, we explore patterns of continental-scale diversification in a groundwater species-rich clade, the superfamily Aselloidea (Pancrustacea: Isopoda). Our analyses supported a constant diversification rate during most of the course of Aselloidea evolution, until 4 15 Ma when diversification rates started to decrease. This constant accumulation of lineages challenges the view that groundwater species diversification in temperate regions might have been primarily driven by major changes in physical environment leading to the extinction of surface populations and subsequent synchronous isolation of multiple groundwater populations. Rather than acting synchronously over broad geographic regions, factors causing extinction of surface populations and subsequent reproductive isolation of groundwater populations may act in a local and asynchronous manner, thereby resulting in a constant speciation rate over time. Our phylogeny also revealed several cases of parapatric distributions among closely related surface-water and groundwater species suggesting that species diversification could also arise from a process of disruptive selection along the surface-subterranean environmental gradient. Our results call for re-evaluating the spatial scale and timing of factors causing diversification events in groundwater. PMID- 23461886 TI - Maternal pre-pregnancy body mass index and internalizing and externalizing problems in offspring. AB - OBJECTIVE: To determine if maternal pre-pregnancy body mass index (BMI) is associated with increased levels of internalizing and externalizing symptomatology in offspring throughout childhood and adolescence, and if these links persist after adjusting for the confounders of these associations. METHOD: We examined links between maternal pre-pregnancy BMI and internalizing and externalizing symptoms in the offspring of 2785 members of the Western Australian Pregnancy (Raine) Cohort. Mothers rated these problems using the Child Behavior Checklist when their children were 5, 8, 10, 14, and 17 years of age. Growth curves were generated using multilevel linear regression to examine associations and to determine if changes in levels of these symptoms varied over time by maternal BMI. RESULTS: Increased maternal pre-pregnancy BMI was associated with stably elevated levels of externalizing problems, and exhibited a statistically significant interaction with internalizing problems over time, indicating that youth born to mothers with higher maternal pre-pregnancy BMIs had less rapid decreases in internalizing scores as they got older. Significant positive associations between maternal pre-pregnancy BMI and elevated levels of internalizing problems emerged at age 8 and increased through 17. These findings persisted despite adjustment for confounders. CONCLUSIONS: Exposure to elevated maternal pre-pregnancy BMI is associated with increased levels of internalizing and externalizing problems throughout childhood and adolescence. Further work is required to establish if these associations are causal. If elevated maternal pre pregnancy BMI is causally linked to psychopathology in offspring, it could provide a potentially realizable target for the prevention of mental health problems in youth. PMID- 23461887 TI - Developing an evaluation framework for consumer-centred collaborative care of depression using input from stakeholders. AB - OBJECTIVE: To develop a framework for research and evaluation of collaborative mental health care for depression, which includes attributes or domains of care that are important to consumers. METHODS: A literature review on collaborative mental health care for depression was completed and used to guide discussion at an interactive workshop with pan-Canadian participants comprising people treated for depression with collaborative mental health care, as well as their family members; primary care and mental health practitioners; decision makers; and researchers. Thematic analysis of qualitative data from the workshop identified key attributes of collaborative care that are important to consumers and family members, as well as factors that may contribute to improved consumer experiences. RESULTS: The workshop identified an overarching theme of partnership between consumers and practitioners involved in collaborative care. Eight attributes of collaborative care were considered to be essential or very important to consumers and family members: respectfulness; involvement of consumers in treatment decisions; accessibility; provision of information; coordination; whole-person care; responsiveness to changing needs; and comprehensiveness. Three inter related groups of factors may affect the consumer experience of collaborative care, namely, organizational aspects of care; consumer characteristics and personal resources; and community resources. CONCLUSION: A preliminary evaluation framework was developed and is presented here to guide further evaluation and research on consumer-centred collaborative mental health care for depression. PMID- 23461888 TI - Reciprocal prospective associations between depressive symptoms and perceived relationship with parents in early adolescence. AB - OBJECTIVE: Adolescent depressive symptoms are associated with difficult family relationships. Family systems and interpersonal theories of depression suggest that this association could reflect a circular process in which symptoms and family functioning affect each other over time. Few longitudinal studies have tested this hypothesis, and the results of these studies have been equivocal. In this study, we examine reciprocal prospective associations in early adolescence between depressive symptoms and 2 important aspects of parent-child relationships: communication and conflict. METHODS: Participants were 3862 students who annually filled out self-reports. Path analysis was used to examine prospective associations between depressive symptoms and perceived communication and conflict with parents from the age of 12 to 13 and 14 to 15 years. Independence of these associations was assessed by controlling for family context (parental separation and family socioeconomic status) and adolescent behaviour problems (delinquent behaviours and substance use). Sex differences were evaluated with multiple group analysis. RESULTS: Reciprocal prospective associations were found between depressive symptoms and perceived conflict with parents, but not between depressive symptoms and communication with parents. Depressive symptoms were found to predict poorer communication with parents over time, but communication was not predictive of lower depressive symptoms in subsequent years. All paths were sex-invariant and independent from family context and behaviour problems. CONCLUSION: This study highlights the importance of considering the potential impact of adolescent symptomatology on parent-child relationships and suggests that reciprocity may characterize the association between depressive symptoms and negative aspects of parent-child relationships. The role of adolescent perceptions in the interplay between depressive symptoms and family relationships remains to be clarified. PMID- 23461889 TI - Examining the nature of the association between attention-deficit hyperactivity disorder and nicotine dependence: a familial risk analysis. AB - OBJECTIVE: To use familial risk analysis to examine the association between attention-deficit hyperactivity disorder (ADHD) and nicotine dependence (ND). METHOD: Subjects were children with (n = 257) and without (n = 229) ADHD of both sexes ascertained from pediatric and psychiatric referral sources and their first degree relatives (N = 1627). RESULTS: ND in probands increased the risk for ND in relatives irrespective of ADHD status. There was no evidence of cosegregation or assortative mating between these disorders. Patterns of familial risk analysis suggest that the association between ADHD and ND is most consistent with the hypothesis of independent transmission of these disorders. CONCLUSIONS: These findings may have important implications for the identification of a subgroup of children with ADHD at high risk for ND based on parental history of ND. PMID- 23461890 TI - Improvement of subcutaneous bioartificial pancreas vascularization and function by coencapsulation of pig islets and mesenchymal stem cells in primates. AB - Insufficient oxygenation can limit the long-term survival of encapsulated islets in subcutaneous tissue. Transplantation of coencapsulated pig islets with adipose or bone marrow mesenchymal stem cells (AMSCs or BM-MSCs, respectively) was investigated with regard to implant vascularization, oxygenation, and diabetes correction in primates. The in vivo impact of MSCs on graft oxygenation and neovascularization was assessed in rats with streptozotocin (STZ)-induced diabetes that were subcutaneously transplanted with islets coencapsulated with AMSCs (n = 8) or BM-MSCs (n = 6). Results were compared to islets encapsulated alone (n = 8). STZ diabetic primates were subcutaneously transplanted with islets coencapsulated with BM-MSCs (n = 4) or AMSCs (n = 6). Recipients were monitored metabolically and immunologically, and neoangiogenesis was assessed on explanted grafts. Results were compared with primates transplanted with islets encapsulated alone (n = 5). The cotransplantation of islets with BM-MSCs or AMSCs in diabetic rats showed significantly higher graft oxygenation than islets alone (3% and 3.6% O2 for islets + BM-MSCs or AMSCs, respectively, vs. 2.2% for islets alone). A significantly better glycated hemoglobin correction (28 weeks posttransplantation) was found for primates transplanted with islets and MSCs (7.4% and 8.1%, respectively) in comparison to islets encapsulated alone (10.9%). Greater neoangiogenesis was found in the periphery of coencapsulated islets and AMSCs in comparison to islets alone (p < 0.01). In conclusion, the coencapsulation of pig islets with MSCs can improve significantly the islets' survival/function in vitro. The coencapsulation of islets with MSCs improves implant oxygenation and neoangiogenesis. However, the cotransplantation of islets with MSCs improves only slightly the long-term function of a subcutaneous bioartificial pancreas in a primate preclinical model. PMID- 23461891 TI - Rejuvenation of aged pig facial skin by transplanting allogeneic granulocyte colony-stimulating factor-induced peripheral blood stem cells from a young pig. AB - Following a stroke, the administration of stem cells that have been treated with granulocyte colony-stimulating factor (GCSF) can ameliorate functional deficits in both rats and humans. It is not known, however, whether the application of GCSF-mobilized peripheral blood stem cells (PBSCs) to human skin can function as an antiaging treatment. We used a Lanyu pig (Sus scrofa) model, since compared with rodents, the structure of a pig's skin is very similar to human skin, to provide preliminary data on whether these cells can exert antiaging effects over a short time frame. GCSF-mobilized PBSCs from a young male Lanyu pig (5 months) were injected intradermally into the cheek skin of aged female Lanyu pigs, and tissues before and after the cell injections were compared to determine whether this treatment caused skin rejuvenation. Increased levels of collagen, elastin, hyaluronic acid, and the hyaluronic acid receptor CD44 were observed in both dermal and subcutaneous layers following the injection of PBSCs. In addition, the treated skin tissue was tighter and more elastic than adjacent control regions of aged skin tissue. In the epidermal layer, PBSC injection altered the levels of both involucrin and integrin, indicating an increased rate of epidermal cell renewal as evidenced by reductions in both cornified cells and cells of the spinous layers and increases in the number of dividing cells within the basal layer. We found that the exogenous PBSCs, visualized using fluorescence in situ hybridization, were located primarily in hair follicles and adjacent tissues. In summary, PBSC injection restored young skin properties in the skin of aged (90 months) pigs. On the basis of our preliminary data, we conclude that intradermal injection of GCSF-mobilized PBSCs from a young pig can rejuvenate the skin in aged pigs. PMID- 23461892 TI - Factors affecting successful isolation of human corneal endothelial cells for clinical use. AB - Corneal transplantation is a common transplant procedure used to improve visual acuity by replacing the opaque or distorted host tissue with clear healthy donor tissue. However, its clinical utility is limited due to a lack of donor supply of high-quality corneas. Bioengineered neocorneas, created using an expandable population of human donor-derived corneal endothelial cells (HCECs), could address this shortage. Thus, the objective of this study was to evaluate HCEC sourcing with various isolation methods, including enzymatic digestion, culture medium components, and adhesive proteins. HCECs were obtained from corneas obtained from various aged donors after endothelial keratoplasty. Under a dissection microscope, the Descemet's membrane, including the attached corneal endothelium, was stripped from the stroma, and the cells were isolated and expanded by explant culture or by enzymatic digestion with enzymes such as collagenase II, dispase, or trypsin. In order to improve the initial cell attachment, tissue culture plates were coated with collagen IV, fibronectin, or fibronectin-collagen combination coating mix (FNC) before cell plating. We were able to successfully obtain HCECs from 32% (86/269) of donor corneas. Donor age and isolation method influenced the characteristics of the resulting in vitro HCEC culture. Under all conditions tested, FNC-coated plates showed higher quality cultures than the other coatings tested. These results suggest that donor age and HCEC isolation methodology are the two factors that most directly affect the quality of the resulting HCEC culture in vitro. These factors should guide the methodological development for the clinical expansion of HCECs for the generation of bioengineered neocorneas. PMID- 23461893 TI - Assessment of nurses' perceptions of patient safety culture in a Saudi Arabia hospital. AB - The purpose of this study was to identify factors that nurses perceive as contributing to the culture of patient safety in a hospital in Saudi Arabia. A total of 498 registered nurses employed in the hospital completed the survey. The majority of nurses perceived a positive patient safety culture. There were significant differences in nurses' perceptions of patient safety culture based on gender, age, years of experience, Arabic versus non-Arabic speaking, and length of shift. PMID- 23461894 TI - Phthalate concentrations and dietary exposure from food purchased in New York State. AB - BACKGROUND: Phthalates have been found in many personal care and industrial products, but have not previously been reported in food purchased in the United States. Phthalates are ubiquitous synthetic compounds and therefore difficult to measure in foods containing trace levels. Phthalates have been associated with endocrine disruption and developmental alteration. OBJECTIVES: Our goals were to report concentrations of phthalates in U.S. food for the first time, specifically, nine phthalates in 72 individual food samples purchased in Albany, New York, and to compare these findings with other countries and estimate dietary phthalate intake. METHODS: A convenience sample of commonly consumed foods was purchased from New York supermarkets. Methods were developed to analyze these foods using gas chromatography-mass spectroscopy. Dietary intakes of phthalates were estimated as the product of the food consumption rate and concentration of phthalates in that food. RESULTS: The range of detection frequency of individual phthalates varied from 6% for dicyclohexyl phthalate (DCHP) to 74% for di-2 ethylhexyl phthalate (DEHP). DEHP concentrations were the highest of the phthalates measured in all foods except beef [where di-n-octyl phthalate (DnOP) was the highest phthalate found], with pork having the highest estimated mean concentration of any food group (mean 300 ng/g; maximum, 1,158 ng/g). Estimated mean adult intakes ranged from 0.004 MUg/kg/day for dimethyl phthalate (DMP) to 0.673 MUg/kg/day for DEHP. CONCLUSIONS: Phthalates are widely present in U.S. foods. While estimated intakes for individual phthalates in this study were more than an order of magnitude lower than U.S. Environmental Protection Agency reference doses, cumulative exposure to phthalates is of concern and a more representative survey of U.S. foods is indicated. PMID- 23461895 TI - Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study. AB - OBJECTIVE: Interferon-gamma-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC. DESIGN: In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS 936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure-response relationship and histological improvement. RESULTS: 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS 936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108-235 MUg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events. CONCLUSIONS: Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose-response studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00656890. PMID- 23461897 TI - Butyrate-producing bacteria as pharmabiotics for inflammatory bowel disease. PMID- 23461896 TI - Protective role of gluteofemoral obesity in erosive oesophagitis and Barrett's oesophagus. AB - OBJECTIVE: Abdominal obesity has been associated with erosive oesophagitis (EO) and Barrett's oesophagus (BO). As gluteofemoral obesity protects against diabetes mellitus and cardiovascular disease, we hypothesised that gluteofemoral obesity would be inversely associated with EO and BO. DESIGN: We conducted a cross sectional study on 822 male colorectal cancer screenees who were recruited to also undergo upper endoscopy. An additional 80 patients with BO clinically detected by upper endoscopy referred for clinical indications were recruited shortly after their diagnoses of BO. Logistic regression was used to estimate the effects of abdominal obesity (waist circumference), gluteofemoral obesity (hip circumference) and waist-to-hip ratio (WHR) on EO and BO (vs neither condition). RESULTS: There were 225 cases of either BO or EO and 675 controls. After adjustment for potential confounders, a positive association was observed between waist circumference and BO and/or EO, which became stronger with further adjustment for hip circumference. In contrast, hip circumference was inversely associated with BO and/or EO. Compared with the lowest quartile of WHR, the adjusted ORs were 1.32 (95% CI 0.747 to 2.33) for the 2nd quartile, 1.54 (95% CI 0.898 to 2.63) for the 3rd quartile, and 2.68 (95% CI 1.57 to 4.55) for the highest quartile. Similar results were obtained for BO and EO treated as separate outcomes. CONCLUSIONS: In a population of older, mostly overweight men, the distribution of obesity is associated with the presence of EO and BO. Abdominal obesity appears to increase the risk of these outcomes, whereas gluteofemoral obesity may be protective. PMID- 23461899 TI - Trajectories of symptom dimensions in short-term response to antipsychotic treatment in patients with a first episode of non-affective psychosis. AB - BACKGROUND: Trajectory patterns of positive, disorganized and negative dimension symptoms during antipsychotic treatment in drug-naive patients with first-episode psychosis have yet to be examined by using naturalistic data. METHOD: This pragmatic clinical trial randomized 161 drug-naive patients with a first episode of psychosis to olanzapine, risperidone or haloperidol. Patients were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and Positive Symptoms (SAPS) at baseline and at the end of weeks 1, 2, 3, 4 and 6 of antipsychotic treatment. Censored normal models of response trajectories were developed with three dimensions of the SAPS-SANS scores (positive, disorganized and negative) in order to identify the different response trajectories. Diagnosis, cannabis use, duration of untreated psychosis (DUP), smoking and antipsychotic class were examined as possible predictive variables. RESULTS: Patients were classified in five groups according to the positive dimension, three groups according to the disorganized dimension and five groups according to the negative dimension. Longer DUPs and cannabis use were associated with higher scores and poorer responses in the positive dimension. Cannabis use was associated with higher scores and poorer responses in the disorganized dimension. Only schizophrenia diagnosis was associated with higher scores and poorer responses in the negative dimension. CONCLUSIONS: Our results illustrate the heterogeneity of short-term response to antipsychotics in patients with a first episode of psychosis and highlight markedly different patterns of response in the positive, disorganized and negative dimensions. DUP, cannabis use and diagnosis appeared to have a prognostic value in predicting treatment response with different implications for each dimension. PMID- 23461900 TI - In silico target fishing for the potential targets and molecular mechanisms of baicalein as an antiparkinsonian agent: discovery of the protective effects on NMDA receptor-mediated neurotoxicity. AB - The flavonoid baicalein has been proven effective in animal models of parkinson's disease; however, the potential biological targets and molecular mechanisms underlying the antiparkinsonian action of baicalein have not been fully clarified. In the present study, the potential targets of baicalein were predicted by in silico target fishing approaches including database mining, molecular docking, structure-based pharmacophore searching, and chemical similarity searching. A consensus scoring formula has been developed and validated to objectively rank the targets. The top two ranked targets catechol-O methyltransferase (COMT) and monoamine oxidase B (MAO-B) have been proposed as targets of baicalein by literatures. The third-ranked one (N-methyl-d-aspartic acid receptor, NMDAR) with relatively low consensus score was further experimentally tested. Although our results suggested that baicalein significantly attenuated NMDA-induced neurotoxicity including cell death, intracellular nitric oxide (NO) and reactive oxygen species (ROS) generation, extracellular NO reduction in human SH-SY5Y neuroblastoma cells, baicalein exhibited no inhibitory effect on [(3) H]MK-801 binding study, indicating that NMDAR might not be the target of baicalein. In conclusion, the results indicate that in silico target fishing is an effective method for drug target discovery, and the protective role of baicalein against NMDA-induced neurotoxicity supports our previous research that baicalein possesses antiparkinsonian activity. PMID- 23461901 TI - Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. AB - PURPOSE: Autophagy is a critical survival pathway for cancer cells under conditions of nutrient or oxygen limitation, or cell stress. As a consequence of antiangiogenic therapy, solid tumors encounter hypoxia induction and imbalances in nutrient supply. We wished to determine the role of autophagy in protection of tumor cells from the effects of antiangiogenic therapy and chemotherapy. We examined the effect of inhibiting autophagy on hypoxic colon cancer cells in vitro and on bevacizumab- and oxaliplatin-treated mouse xenografts in vivo. EXPERIMENTAL DESIGN: The autophagic response to hypoxia and DNA-damaging agents was assessed by fluorescent microscopic imaging, autophagy-related gene expression, and by electron microscopic ultrastructural analysis. Pharmacologic and molecular approaches to autophagy inhibition were taken in a panel of colon cancer cell lines. Mouse xenograft models were treated with combinations of oxaliplatin, bevacizumab, and chloroquine to assess effects on tumor growth reduction and on pharmacodynamic markers of autophagy inhibition. RESULTS: Autophagy was induced in colon cancer models by exposure to both hypoxia and oxaliplatin. Inhibition of autophagy, either with chloroquine or by downregulation of beclin1 or of ATG5, enhanced sensitivity to oxaliplatin under normal and hypoxic conditions in a synergistic manner. Both bevacizumab and oxaliplatin treatments activate autophagy in HT29 murine xenografts. The addition of chloroquine to bevacizumab-based treatment provided greater tumor control in concert with evidence of autophagy inhibition. CONCLUSIONS: These findings implicate autophagy as a mechanism of resistance to antiangiogenic therapies and support investigation of inhibitory approaches in the management of this disease. PMID- 23461902 TI - Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. AB - PURPOSE: Multidrug resistance-associated protein 4 (ABCC4) shares many features with P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), including broad substrate affinity and expression at the blood-brain barrier (BBB). However, the pharmacologic relevance of ABCC4 at the BBB is difficult to evaluate, as most drugs are also substrates of ABCB1 and/or ABCG2. EXPERIMENTAL DESIGN: We have created a mouse strain in which all these alleles are inactivated to assess their impact on brain delivery of camptothecin analogues, an important class of antineoplastic agents and substrates of these transporters. Wild-type (WT), Abcg2(-/-), Abcb1a/b(-/-), Abcc4(-/-), Abcb1a/b;Abcg2(-/-), Abcg2;Abcc4(-/ ), and Abcb1a/b;Abcg2;Abcc4(-/-) mice received i.v. topotecan, irinotecan, SN-38, or gimatecan alone or with concomitant oral elacridar. Drug levels were analyzed by high-performance liquid chromatography (HPLC). RESULTS: We found that additional deficiency of Abcc4 in Abcb1a/b;Abcg2(-/-) mice significantly increased the brain concentration of all camptothecin analogues by 1.2-fold (gimatecan) to 5.8-fold (SN-38). The presence of Abcb1a/b or Abcc4 alone was sufficient to reduce the brain concentration of SN-38 to the level in WT mice. Strikingly, the brain distribution of gimatecan in brain of WT mice was more than 220- and 40-fold higher than that of SN-38 and topotecan, respectively. CONCLUSION: Abcc4 limits the brain penetration of camptothecin analogues and teams up with Abcb1a/b and Abcg2 to form a robust cooperative drug efflux system. This concerted action limits the usefulness of selective ABC transport inhibitors to enhance drug entry for treatment of intracranial diseases. Our results also suggest that gimatecan might be a better candidate than irinotecan for clinical evaluation against intracranial tumors. PMID- 23461909 TI - Ten years' experience with a pyrocarbon prosthesis replacing the proximal interphalangeal joint. A prospective clinical and radiographic follow-up. AB - We prospectively assessed the subjective, objective, and radiographic results at 1, 2, and 5 years in 65 patients who had pyrocarbon proximal interphalangeal prostheses inserted between 2001 and 2010. Further operations were done on 10 of the 89 joints (four for prosthetic extraction and arthrodesis, two for component changes, and four for soft tissue procedures). At 1 year, the visual analogue scale score for pain at rest had improved to 0 cm from a pre-operative 4 cm, pain at activity from 6 to 1.8 cm, and Disability of the Arm, Shoulder and Hand score from 40 to 25. Range of movement and grip strength were unchanged. At 5 years, 31 joints (21 patients) had a complete radiographic follow-up. Seven proximal and 12 distal components showing zones of osteolysis at 1 year had stabilized and were inert or integrated at 5 years. Three proximal and three distal components had osteolytic zones at 5 years. Forty-seven of 59 patients were pain-free at rest at 1 year, and 19 of 21 at 5 years. No late revisions or loosening occurred. PMID- 23461910 TI - Symmetrical peripheral gangrene of all fingers and toes: creating a thumb by on top plasty in a difficult situation. PMID- 23461911 TI - Recurrent primary abscesses in the hand: consider panton-valentine leukocidin positive Staphylococcus aureus. PMID- 23461912 TI - The hand in the mitt: a technical tip for applying negative pressure in hand wounds. PMID- 23461914 TI - [National Institute of Rehabilitation]. PMID- 23461913 TI - Carpal tunnel syndrome associated with underlying Kienbock's disease. PMID- 23461915 TI - [Steroid drugs and GM-CSF modulates activity of Egr-1 in glioma cells]. AB - INTRODUCTION: The Egr-1 protein is a transcriptional factor responsive to early growth. Transcriptional regulation of the promoter has been described like responsive to physical stress, osmotic changes, and cellular growth marker. However, there is no report about the pharmacological effect on the transcriptional regulation in gliomas. Hereby we report the modulation of the Egr 1 promoter transcriptional activity induced by the Granulocytes Macrophages Colony Stimulating Factor (GM-CSF) and steroid drugs in human glioma cells (CH235 GM Grade II, U373-GM Grade III, D54-GM Grade IV) using a reporter system transduced by a recombinant adenoviral vector AdEgr-1/luc7. METHODS: Human glioma cells shows with different malignity grade (CH235-GM Grado II; U373-GM Grado III; D54-GM Grado IV) were transduced with no replicative adenoviral vector AdEgr 1/Luc7 and exposed to drugs as progesterone, beta-estradiol and betametasone, and GM-CSF. Transcriptional activity of the egr-1 promoter was quantified by Luciferase reporter gene, cloned downstream to the tata box. Luciferase activity was quantified from whole cell proteins using luminometry assays. RESULTS: U373 GM cell line with GM-CSF, shows an increment on transcriptional activity of Egr-1 promoter, also in endogen way. U373-GM showed a positive regulation of Egr-1, with steroid drugs on the times analyzed. Steroid drugs as progesterone, beta estradiol and betametasone, shows a pleiotropic behavior on CH235-GM and D54-GM, glioma cell lines. CONCLUSIONS: Inhibition or activation response of Egr-1 promoter shows new framework to explore a mechanism of action of steroid drugs on genetic and epigenetic regulation on tumoral process. PMID- 23461916 TI - [Spatial-temporal analysis and clinical findings of gait: comparison of two modalities of treatment in children with cerebral palsy-spastic hemiplegia. Preliminary report]. AB - INTRODUCTION: Cerebral palsy is the most common cause of disability among children. Parent's main concerns are the acquisition and improvement of gait. The aim of this study was to compare long term results of the effect of two modalities of gait training. METHODS: Quantitative measurement of gait and clinical assessment of the gross motor function classification system and Modified Ashworth Scale were perfomed in 14 patients with Cerebral palsy -spastic hemiplegia and randomizedly assigned into two groups of treatment: the first one using a driven gait orthosis (Lokomat((r))) and the second a gait training a long a rail inside a hydrotherapy tank. Measurements and assessments, above described, were performed immediately and one year after the treatment concluded. RESULTS: Significant change was observed in the gross motor function classification system from II to I among children (p=0.042) and a positive correlation between the shape functional of the march and the gross motor function classification system (r = 0.54, p = 0.042). Patients on the Lokomat((r)) training improved on gait symmetry over patients on the conventional therapy (p = 0.05). A year after, this intervention showed tendency to kept the gait patterns only on patients treated with the Lokomat((r)) CONCLUSION: Benefit obtained with either modality was evident for both groups. However, residual effects observed on the Lokomat group, either in clinical assessment or gait parameters, were more promising than in the conventional therapy. Due to the size of the sample used in this study the results are not conclusive and more research must be done on this subject in long term time horizon. PMID- 23461917 TI - [Measurement of acetylcholine and sleep patterns]. AB - INTRODUCTION: Acetylcholine is an essential neurotransmitter in the central nervous system as it has an effect on sleep, memory and learning. Intracerebral microdialysis is an in vivo surgical technique that is used to measure the concentration of substances in the extracellular space. METHODS: The rats were stereotaxically implanted with microdialysis cannulae guided to the hypothalamic medial preoptic area and bipolar stainless steel electrodes to obtain sleep records simultaneously with microdialysis samplings during 24 hours exposed to clean air followed by 24 hours of exposure to ozone. Microdialysis fractions were injected into chromatograph system. RESULTS: Results showed that paradoxical sleep and wakefulness decreased by 54.2% and 27.9%, respectively, while slow wave sleep increased by 35.1% during the ozone exposure phase and a concomitant decrease of extracellular acetylcholine of 56.2% was observed during the light dark phase. CONCLUSION: That surgical method employed using electroencephalography and intracerebral microdialysis allows the quantification of extracellular acetylcholine and simultaneously with patterns related to sleep. We propose that the decrease in paradoxical sleep is the behavioral expression of disruptions of cholinergic modulation and, that post-exposure effects observed in the hypothalamic medial preoptic area can be explained on the basis of the hypothalamic role in the sleep-wake cycle. PMID- 23461918 TI - [Intraventricular yohimbine infusion induces noradrenergic changes in motor cerebral injured rats and enhances motor recovery]. AB - INTRODUCTION: It has been proposed that noradrenaline is one of the neurotransmitters involved in the functional recovery. In this sense, it has been proposed that the alpha-2 noradrenergic receptors play an important role in the functional reinstatement. OBJECTIVE: the aim of this work was to study the role of the alpha-2 noradrenergic receptors on the noradrenaline contents in cerebellum and pons of rats iron-injured in the motor cortex. METHODS: Fifteen male Wistar rats were allocated in three groups: control (n = 5) with intracortical infusion of saline (0.9%), injured (n = 5) with intracortical infusion of dextran iron and intraventricular infusion of saline, and injured + yohimbine (alpha-2 receptor antagonist; n = 5) that received an intracortical infusion of dextran iron and also an intraventricular infusion of yohimbine. Motor behavior was assessed by means of the beam-walking paradigm. Three days after surgeries, the animals were sacrificed and the left and right sides of the pons and the cerebellar hemispheres were extracted. Tissues were prepared for noradrenaline analysis by means of high performance liquid chromatography. RESULTS: We observed that the yohimbine-treated animals had a noradrenaline increase in the right side of the pons and a decrease in the right cerebellar hemisphere. CONCLUSION: It is concluded that the blockage of the alpha-2 receptors leads to an increase of noradrenaline in the locus coeruleus, which retards the effects of the cerebral injury. PMID- 23461919 TI - [Viability of the parietal bone autografts preserved in adipose tissue. Preliminary report of an experimental study in rats]. AB - INTRODUCTION: Decompressive craniectomy is an alternative in cases where there is increased intracranial pressure. Bone autografts are accepted as a method of reconstruction of the skull. The aim of this paper is to describe the macroscopic and radiological findings of autologous parietal bone in rats after storage in adipose tissue as a reservoir. METHODS: We used 20 Wistar rats which underwent a craniectomy. 4 groups were formed: group I, the bone flap fat remained for 14 days, group II, the flap remained for 21 days, in group III, for 28 days and in group IV for 35 days. They were euthanized 70 days after reattached. RESULTS: When removing the flap of subcutaneous fat, a high bright whitish microvasculature and presence in 11 of the flaps. Following 70 days of re injertarse was found that 56.25% of the animals presented terraced edges, reflecting some consolidation in the radiological analysis 31.25% of cases showed areas of consolidation. Animals in group II and III findings showed more consolidation. CONCLUSIONS: The bone flap remained viable during their stay in adipose tissue. Fibrous tissue and neovasculature were important findings that reflect the proper process of bone healing. You need the histological studies complemented biomechanics, neurological and bioacoustics. PMID- 23461920 TI - [Bacteriological study of oral cavity of people of Mexican origin to determine etiology agents of human infections in hand bite]. AB - INTRODUCTION: Hand infections secondary to human bites often leave serious consequences on the functioning of the hand. Such infections are caused by different bacteria. Most bacteriological studies have been made to people of Anglo-Saxon origin or descent, and based on these findings; provide treatment to patients of different origins which may not always be as effective. METHODS: Descriptive, internal stratified 17 patients were isolated samples of oral cavity and dental plaque bacterial species to identify and define the possible treatment according to the species identified. RESULTS: Microorganisms were isolated Gram (+) and Gram (-) belonging to the normal flora of the oral cavity and dental plaque in all the cases studied, presenting a variable number of microorganisms according to age but not by sex. The group of Gram-positive bacteria isolated showed sensitivity to: erythromycin, chloramphenicol and ciprofloxacin. In the group of Gram negative: kanamycin, amoxicillin + clavulanic acid, ciprofloxacin and norfloxacin, E. Corrodens sensitive to the group of quinolones as ciprofloxacin, norfloxacin as well as ceftriaxone and cefoperazone sulbactam. CONCLUSIONS: The bacterial species that are commonly found in normal flora of the oral cavity and dental plaque may be potential pathogens in a hand injury where to find the appropriate conditions for their development. PMID- 23461921 TI - [Transpedicular dynamics stabilization in the treatment of lumbar stenosis. Fourth years follow-up]. AB - INTRODUCTION: We need to evaluate the efficacy and safety of the use of dynamic fixation in patients with narrow lumbar through comparing the assessment of two years with 4 years of follow-up. METHODS: Prospective, longitudinal, autocontrol deliberately and sequential intervention, in lumbar stenosis patients who made treatment with dynamic stabilization posterior type Acuflex. An evaluation of four of final follow-up. RESULTS: 18 patients who completed follow-up two years results as a basis for comparison: 18 patients, 14 female and 4 male, average age 44.05 years. Pain evaluated with numerical visual scale was found in the lower back at 24 months in an average of 2.84 and 48 months in 3.26. We measured the functional level of Oswestry at two years to be 24% and at four years 22.44%, with a p = 0.373. In the magnetic resonance for classification of patients 15 Pfirrmann without changes and three with increase of a degree. According to patients 2 Modic changes one of type 0 to type III and another to type I. We have observed that five patients have required second surgery for removal of material findings. CONCLUSIONS: There is no change between 2 and 4 years in the scale of Oswestry and pain with visual numerical scale functionality. The average height in discs had change with statistical significance, in the comparative period. The intervertebral discs had changes in 3 patients with direct relationship between scale of Pfirrmann and Modic. The rest of patients keep rehydration and normal disc height. PMID- 23461922 TI - [Semiconstrained bipolar implant arthroplasty of the distal radioulnar joint. Case report]. AB - INTRODUCTION: The distal radioulnar joint is of paramount importance for the proper function of the upper extremity. There is a wide variety of procedures for the treatment of its advanced pathology but none of them is capable of providing a stable load-bearing joint. CLINICAL CASE: We present the case of a 54 year old man who was treated by a semiconstrained bipolar distal radioulnar joint arthroplasty (Aptis) who had a distal radioulnar impingement secondary to a distal ulnar resection (Darrach) previously performed to treat a fracture dislocation of the distal radioulnar joint. CONCLUSION: This case was the first semiconstrained bipolar distal radioulnar joint arthroplasty (Aptis) performed in Mexico. This treatment is capable of providing provides a stable load-bearing joint. PMID- 23461923 TI - [Total hip arthroplasty in patients with cerebral vascular event. Case report]. AB - INTRODUCTION: Associated neurological disorders pose a challenge hip joint reconstruction. The imbalance and poor muscle tone predispose to dislocation and loosening of the prosthesis. CLINICAL CASE: The following is the case of a 67 years old patient with a hemorrhagic cerebral vascular event with a secondary left hemiparesis. Ten years later had a femoral neck fracture on the affected side. Initially she was treated with conservative management resulting in pain and discapacity, valued with WOMAC scale as 12 points. Two years later was treated with total hip arthroplasty with large diameter femoral head. We present the follow up of 41 months, asymptomatic, walking using a cane and a WOMAC score of 41, with no signs of radiological loosening or dislocation. CONCLUSIONS: There is no experience documented in neurological disorders associated with hip diseases that requires a total hip arthroplasty. Loosening of the implants, dislocation and heterotopic ossification has been described as complications of the procedure. Large heads in total hip arthroplasty and a correct surgical technique associated with a multidisciplinary management in patients with neurological disorders offers an opportunity as a treatment in patient with hip disorders. PMID- 23461924 TI - [Giant Baker's cyst treated with intralessional methotrexate]. AB - INTRODUCTION: Synovial cyst is composed by a fibrous wall; lining by a thin layer of synovial cells containing synovial fluid, the prototype of these, in the knee is the Baker's cyst, which is located abnormally in the gastrocnemius semimembranous bursa. Baker's cyst prevalence ranges from 5 - 38%. Clinical diagnosis is supported by the presence of increased volume of soft tissues located in the popliteal region. CLINICAL CASE: A 74 year-old woman with longstanding active rheumatoid arthritis who developed a large, recurrent Baker's cyst. The Baker's cyst had two flare-ups of pain and soft tissue swelling which eventually limited knee movements; was treated with needle aspiration guided by ultrasound and synovectomy with methotrexate twice. At 18-months follow-up, the patient remains without evidence of recurrence. CONCLUSIONS: Local infiltration of methotrexate represents an alternative therapy for those refractory Baker's cyst with partial response to conventional treatment, where the surgical procedure carries a high risk. PMID- 23461925 TI - [Importance of stimulation of the areas involved in the mathematical processing: effects on neurodevelopment]. AB - This paper aims to discuss and analyze the role of mathematics in neurodevelopment, for which discusses the historical, ontogenetic and physiological bases involved. The methodology of this paper is a deductive analysis, describing the use of mathematics in ancient cultures to the specialization of brain regions. Sensory perceptions are useful for the acquisition and development of cortical functions thus sensory stimulations is essential for the maturation of specialized neurologic functions. PMID- 23461926 TI - [Platelets-rich plasma: a versatile tool for regenerative medicine?]. AB - Platelet-rich plasma is a blood product concentrate obtained by centrifugation of whole blood that is characterized by a high concentration of platelets (4 to 6 times their normal values). The high concentration of trophic factors contained in the granules of platelets, have led to suggest that the application of platelet-rich plasma can help to stimulate or accelerate the repair or regeneration of a number of tissues. Since their first application in the treatment of skin ulcers in 1980, a considerable number of novel applications in different fields of medicine have emerged (Ophthalmology, Otorhinolaryngology, Maxillofacial Surgery surgical wounds, musculoskeletal disorders, burns, Esthetic Surgery, repair of peripheral nerves, etc.), some of these applications with clearly positive or very promising results. Despite the large amount of experimental and clinical literature about the usefulness of platelet-rich plasma in different areas of regenerative medicine, there are few therapeutic indications in which it is fully demonstrated its effectiveness. This fact highlights the importance of carry out methodologically appropriate clinical trials in the near future, in order to improve the evidence level of platelet rich plasma treatment. The purpose of this article is to perform an update and critical review about the biological basis of platelet-rich plasma, to review indications for which there is more scientific support on its use, and finally to describe their new indications that are currently under research. PMID- 23461927 TI - Large outbreak of cholera caused by El Tor variant Vibrio cholerae O1 in the eastern coast of Odisha, India during 2009. AB - A large outbreak of cholera reported during April-July 2009 in the Kendrapada district of Odisha, India was investigated. Forty-one rectal swabs and 41 water samples, collected from diarrhoeal patients and from different villages were bacteriologically analysed for the isolation of bacterial enteriopathogens, antibiogram profile and detection of various toxic genes. The bacteriological analysis of rectal swabs and environmental water samples revealed the presence of V. cholerae O1 Ogawa biotype El Tor. The V. cholerae strains were resistant to ciprofloxacin, co-trimoxazole, chloramphenicol, streptomycin, ampicillin, furazolidone and nalidixic acid. The multiplex polymerase chain reaction (PCR) assay on V. cholerae strains revealed the presence of ctxA and tcpA genes. The mismatch amplification of mutation assay (MAMA) PCR on clinical and environmental isolates of V. cholerae revealed that the strains were El Tor biotype, which harboured the ctxB gene of the classical strain. The random amplified polymorphic DNA PCR analysis and pulsed-field gel electrophoresis results indicated that the V. cholerae isolates belonged to the same clone. This investigation gives a warning that the El Tor variant of V. cholerae has spread to the coastal district causing a large outbreak that requires close monitoring and surveillance on diarrhoeal outbreaks in Odisha. PMID- 23461928 TI - A novel repair of end colostomy prolapse. PMID- 23461929 TI - Complete small bowel obstruction resulting from a mushroom bezoar. PMID- 23461930 TI - Ectopic liver tissue sequestered in the lung. PMID- 23461931 TI - Complications of spilled gallstones after laparoscopic cholecystectomy. PMID- 23461932 TI - A comparative study of minimally invasive treatment of cholecystocholedocholithiasis. PMID- 23461933 TI - Gasless laparoscopic-assisted repair for traumatic intraperitoneal urinary bladder rupture. PMID- 23461934 TI - Management of an incidentally discovered hypoglossal paraganglioma. PMID- 23461935 TI - Fenestration treatment for polycystic liver disease improved quality of life. PMID- 23461936 TI - External iliac artery injury after a bicycle accident. PMID- 23461937 TI - Delorme's procedure revisited for an incarcerated transverse loop colostomy prolapse repair. PMID- 23461938 TI - Metastatic pancreatic insulinoma with treatment-limiting thrombocytopenia. PMID- 23461939 TI - Traumatic pseudoaneurysm of the superficial temporal artery. PMID- 23461940 TI - Colonic perforation in a case of adult Hirschsprung's disease with acetylcholinesterase-negative neuronal fibers. PMID- 23461941 TI - Ureteral inguinoscrotal hernia: a hidden hazard, stents may prevent injury. PMID- 23461942 TI - A simple method to secure a finger splint. PMID- 23461943 TI - Role of laparoscopy on staged management of gallstone ileus. PMID- 23461944 TI - History of the Department of Surgery at Albany Medical Center. AB - Surgeons have always played an integral role in the history of the Albany Medical Center and Albany Medical College. In addition to supporting vital patient care and teaching programs, the Department of Surgery has played an important administrative role providing the college with five deans. The origins of the Department of Surgery reach back to 1910 when the American Medical Association sponsored Flexner report proposed dramatic changes in the structure and format of medical education in the United States. In response to the recommendations of the report, the medical center restructured its faculty and curriculum to meet the demands of a rapidly advancing profession. One result of this reorganization was the formation of the Department of Surgery in 1912. Dr. Arthur Elting was named the first Chair of the Department in 1915. This report will review the history of the Department, focusing on the eight surgeons who have served as Chair. PMID- 23461945 TI - John Chalmers DaCosta (1863-1933): restoration of the old operating table. AB - John Chalmers DaCosta was an influential chairman and the first Samuel D. Gross Professor of Surgery at Jefferson Medical College in Philadelphia. He was well known throughout the field as a skilled surgeon, passionate speaker, and exceptional writer. In addition to countless accomplishments during his career, DaCosta was deeply dedicated to the preservation and commemoration of surgical history. This ideology was exemplified when he set out on a mission to recover the old wooden operating table used by many of his iconic mentors including Samuel D. Gross, Joseph Pancoast, and William W. Keen. This table was originally used for surgical demonstrations and anatomy lessons in a lecture room of the Ely Building and later in the great amphitheater of the Jefferson Sansom Street Hospital. It was found forgotten in the basement of the College Building and was promptly refurbished, donned with dedicatory plaques, and returned to its honored position in the medical college. Dr. DaCosta also contributed a detailed article recalling the history of the table and the notable leaders in surgery who taught and practiced on its surface. The old table currently stands proudly in the entranceway of the Department of Surgery where it will remain as a cherished symbol of the early beginnings of surgical practice and education. PMID- 23461946 TI - Evaluating deceased donor registries: identifying predictive factors of donor designation. AB - The objectives of this study were to evaluate and compare the performance of the deceased donor registries of the 50 states and the District of Columbia and to identify possible predictive factors of donor designation. Data were collected retrospectively by Donate Life America using a questionnaire sent to Donor Designation Collaborative state teams between 2007 and 2010. By the end of 2010, there were 94,669,081 designated donors nationwide. This accounted for 39.8 per cent of the U.S. population aged 18 years and over. The number of designated organ donors and registry-authorized recovered donors increased each year; however, the total number of recovered donors in 2010 was the lowest since 2004. Donor designation rate was significantly higher when license applicants were verbally questioned at the Department of Motor Vehicles (DMV) regarding their willingness to register as a donor and when DMV applicants were not given an option on DMV application forms to contribute money to support organ donation, compared with not being questioned verbally, and being offered an option to contribute money. State registries continue to increase the total number of designated organ donors; however, the current availability of organs remains insufficient to meet the demand. These data suggest that DMV applicants who are approached verbally regarding their willingness to register as a donor and not given an option on DMV application forms to contribute money to support organ donation might be more likely to designate themselves to be a donor. PMID- 23461947 TI - Airway pressure release ventilation in morbidly obese surgical patients with acute lung injury and acute respiratory distress syndrome. AB - Morbidly obese patients with body mass index greater than 40 kg/m(2) and respiratory failure requiring critical care services are increasingly seen in trauma and acute care surgical centers. Baseline respiratory pathophysiology including decreased pulmonary compliance with dependent atelectasis and abnormal ventilation-perfusion relationships predisposes these patients to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) as well as prolonged stays in the intensive care unit. Airway pressure release ventilation (APRV) is an increasingly used alternative mode for salvage therapy in patients with hypoxemic respiratory failure that also provides lung protection from ventilator induced lung injury. APRV provides the conceptual advantage of an "open lung" approach to ventilation that may be extended to the morbidly obese patient population with ALI and ARDS. We discuss the theoretical benefits and a recent clinical experience of APRV ventilation in the morbidly obese patient with respiratory failure at a Level I trauma, surgical critical care, and acute care surgery center. PMID- 23461948 TI - Obesity does not increase morbidity and mortality after laparotomy for trauma. AB - Obesity has been suggested to be a risk factor for increase morbidity and mortality after trauma and surgery. Trauma laparotomy provides an opportunity to assess the effect of body mass index (BMI) on patients subjected to both trauma and surgery. We hypothesized that obesity would have a deleterious effect on outcomes. A retrospective review was conducted of all patients 18 years of age or older undergoing laparotomy for trauma between July 2001 and June 2011. Patients were stratified according to BMI into the following four groups: underweight (16 to 22 kg/m(2)), normal (23 to 27 kg/m(2)), overweight (28 to 34 kg/m(2)), and obese (35 kg/m(2) or higher). Data on the patient's hospital course included length of stay, mortality, respiratory failure, infectious complications, wound dehiscence, and organ failure. A total of 1,297 patients underwent laparotomy. Seven per cent of the study group was obese and 24 per cent was underweight. There was no difference among mean Injury Severity Score, percent of patients arriving in shock, and mean number of units of packed red blood cells administered during their hospital stay. Obese patients had longer intensive care unit and hospital lengths of stay. There were no differences in ventilator days or mortality. Using univariate statistics, obese patients had increased rates of respiratory and renal failure, bacteremia with and without septic shock, and abdominal wound dehiscence. Subjecting the data to logistic regression analysis, BMI was no longer an independent predictor of any complication. Although obese trauma patients do have increased infectious morbidity, wound dehiscence, and a prolonged length of stay, increased BMI is not an independent predictor of increased morbidity or mortality after trauma laparotomy. PMID- 23461949 TI - Laparoscopic lower anterior rectal resection using a curved stapler: original technique and preliminary experience. AB - Laparoscopic low anterior rectal resection (LLAR), allowing better visualization and rectal mobilization, can reduce postoperative pain and recovery. A contour curved stapler (CCS) is a very helpful device because of its curved profile that consents better access into the pelvic cavity and allows to perform rectal closure and section in one shot, especially in the presence of a narrow pelvis, complex anatomy, or large tumors. We developed an original technique of laparoscopic rectal resection using CCS. Between 2005 and 2009, in 36 cases, we performed LLAR with a three-trocar technique, starting with mobilization of left colonic flexure followed by the section of inferior mesenteric vessels. The rectum was prepared up to the levator ani with total mesorectal excision. The Lapdisc was inserted trough a suprapubic midline incision, allowing the CCS stapler placement into the pelvic cavity. After the rectal section, the anastomosis was then performed with a circular stapler. Ileostomy was performed if neoadjuvant radiotherapy and chemotherapy have been carried out or if the anastomosis was below 4 cm from the anal verge. Mean operative time was 135 minutes and no intra- or postoperative bleeding occurred. In 27 patients we performed temporary ileostomy. In two cases we observed anastomotic leakage; one of these patients already had ileostomy. No anastomotic stenosis occurred after one-year follow-up. This procedure simplifies the section of the lower rectum, reduces leaking rate resulting from technical difficulties, and does not nullify the benefits of laparoscopy. PMID- 23461950 TI - Pediatric trauma experience in a combat support hospital in eastern Afghanistan over 10 months, 2010 to 2011. AB - We reviewed the pediatric trauma experience of one Combat Support Hospital (CSH) in Afghanistan to focus on injuries, surgery, and outcomes in a war zone. We conducted a review of all pediatric patients over 10 months in an eastern Afghanistan CSH. We studied 41 children (1 to 18 years; mean, 8.5 years; median, 9 years), 28 (68.2%) with penetrating injuries. Blasts (13 patients) and burns (nine) were the most common mechanisms. At arrival 19 (46.3%) underwent endotracheal intubation, four (9.8%) had no palpable blood pressure, 10.6 per cent (four of 38) a Glasgow coma score of 5 or less, 30.6 per cent (11 of 36) base deficits of 6 or less, and 41.7 per cent (15 of 36) hematocrit 30 or less. Red cells were given in 14 (34.1%) and plasma in 11 (26.8%). Of 32 total nonburn patients, 12 (37.5%) had multiple system injuries. Three-fourths of injuries were severe (75.8% [47 of 62] Abbreviated Injury Score 3 or greater). Thirty-two patients (78.0%) required major operations: burn and wound care, orthopedic, chest, abdominal, vascular, and neurosurgical. Second operations were performed in 16 (39.0%), most often burn and orthopedic procedures. Six died (14.6%), 13 were transferred to other hospitals (31.7%), and 20 were discharged to home (48.8%; two not noted). Broad experience in operative trauma care, pediatric resuscitation, and critical care is a priority for military surgeons. PMID- 23461951 TI - The differential effects of intermediate complications with postoperative mortality. AB - Most attempts at understanding perioperative mortality have been based on assessing individual patient risk factors, types of operations, and hospital characteristics. The hypothesis of this study is that there is a relationship between postoperative mortality and postoperative complications; therefore, understanding this relationship may provide a basis for prevention and rescue. Using the 2007 SemiAnnual National Surgical Quality Improvement Program Report, we obtained data for each reporting hospital's rates of observed mortality, overall observed morbidity, observed cardiac, respiratory, renal complications, venothromboemoblic events (VTEs), surgical site infections (SSIs), and urinary tract infections (UTIs). Simple and multiple linear regression analyses were done comparing absolute rate of observed mortality with absolute rate of observed morbidity and each morbidity group. One hundred ninety-seven hospitals were included in the study. There were statistically significant associations between observed mortality rates and observed morbidity rates, cardiac complications, respiratory complications, and VTE rates. Renal complications, SSIs, and UTIs showed no statistically significant association with observed morbidity. This study demonstrates that rates of observed morbidity, especially cardiac, respiratory, and VTE complications, are associated with observed mortality. These findings suggest that care providers should focus efforts at prevention and rescue of cardiac, respiratory, and VTE complications. PMID- 23461952 TI - Injured adolescents, not just large children: difference in care and outcome between adult and pediatric trauma centers. AB - Adolescent injury victims receive care at adult trauma centers (ATCs) and pediatric trauma centers (PTCs). The purpose of this study was to identify care variations and their impact on the outcome of adolescent trauma patients treated at PTC versus ATC. We queried the Pennsylvania Trauma Systems Foundation database for trauma patients between 13 and 18 years of age from 2005 to 2010. Mortality and hospital complication rates between ATC and PTC were compared in univariable and multivariable analysis. In addition, the differences in the delivery of care were also compared. Of 9033 total patients, 6027 (67%) received care at an ATC. Patients in the ATC group were older (16.7 vs. 14.9 years, P < 0.001) and more severely injured (Injury Severity Score: 14.5 vs. 12.2, P < 0.001). Admission diagnostic computed tomography (CT), emergent laparotomy and craniotomy, blood transfusion, and drug screening were more frequently performed at an ATC. After adjustment for potential confounders in multivariable regression models, treatment at a PTC was significantly associated with fewer CTs for transferred patients (odds ratio [OR], 0.28; P < 0.001) and with less frequent emergent laparotomy for all patients (OR, 0.65; P = 0.007). The ATC group had a significantly higher hospital mortality rate (2.9 vs. 0.9%, P < 0.001) and complication rate (9.7 vs. 4.8%, P < 0.001). However, these outcomes were not significantly different between PTC and ATC in multivariable regression models. In the state of Pennsylvania, there were no significant differences in risk adjusted outcomes between PTC and ATC despite significant difference in use of CT scanning and emergent laparotomy. PMID- 23461953 TI - American College of Surgeons National Surgical Quality Improvement Program as a quality improvement tool: a single institution's experience with vascular surgical site infections. AB - Vascular surgical site infections (VSSIs) result in significant patient morbidity and hospital cost. The objective of this study is to report a single hospital's experience using the National Surgical Quality Improvement Program (NSQIP) as an instrument to decrease VSSIs. After review of initial NSQIP data, changes in antibiotic dosage and timing, surgical preparation, patient warming, and oxygenation were put into practice. Records of all patients undergoing vascular surgical operations during a two-year period were reviewed and VSSIs were identified. Statistical comparisons were made between groups before and after implementation of these changes. A total of 478 cases met our criteria. Practice changes were introduced in October 2009 and fully implemented by January 2010. Two hundred forty-three cases were performed in 2009 and 235 in 2010. When operations during the two time periods were compared, significantly fewer VSSIs were identified in 2010 than in 2009 (P = 0.036). NSQIP enabled our institution to identify an unacceptably high level of VSSIs. By implementing changes in our clinical practice, we were able to significantly lower our rate of VSSI. PMID- 23461954 TI - Transverse incisions for resection of ileocolic Crohn's disease. AB - Laparoscopic ileocecectomy is advocated as the ideal surgical approach for ileocecal Crohn's disease. Our experience suggests that equivalent outcomes are accomplished through a small right lower quadrant (RLQ) transverse incision in this patient population. We conducted a retrospective chart review of 39 patients undergoing ileocectomy for Crohn's disease using a RLQ transverse incision between 1991 and 2009. The mean operative time was 99 minutes with a mean length of hospital stay of 4.2 days and mean duration until return of bowel function of 2.9 days. There were no deaths or major complications. Long-term follow-up revealed four patients (13%) who required hospitalization for small bowel obstructions, one patient (3%) developed an incisional hernia, and no patients required an ileostomy. Ileocecectomy performed for Crohn's disease using a RLQ transverse incision yielded similar hospital lengths of stay and time to return of bowel function as those published for laparoscopic resection. This approach may result in shorter operative times when compared with the inexperienced surgeon performing a laparoscopic resection. Long-term follow-up revealed the risk for future RLQ ileostomy is low and the development of hernias or bowel obstruction is unlikely. PMID- 23461955 TI - Lymph node ratio as a predictor of survival in gastric carcinoma. AB - According to the American Joint Committee on Cancer (AJCC), the number of metastatic lymph nodes is the main prognostic factor in gastric cancer. Lymph node ratio (LNR) has been proposed as a better predictor of survival. We included patients resected for gastric cancer in a referral center in Mexico City. Number of metastatic nodes was analyzed according to AJCC 2002 and 2010. We divided LNR into four stages. Survival was calculated with the Kaplan-Meier method and curves compared with the log-rank test. P < 0.05 was significant. Two hundred patients were included. Median number of retrieved and metastatic nodes were 18 and 2.5, respectively. Median survival was 44 months. AJCC 2010 was a better predictor of survival than the 2002 version (P < 0.001). Median survival for LNR 0, 1, 2, and 3 was 117, 68, 44, and 14 months, respectively (P < 0.001). In patients with less than 15 nodes removed, AJCC was not a predictor of survival (P = 0.09) but LNR was (P = 0.04). Nodal staging in AJCC 2010 is a better predictor of survival than the 2002 edition. LNR is useful in the group of patients with suboptimal node dissection. PMID- 23461956 TI - Safety and effectiveness of vessel sealing for dissection during pancreaticoduodenectomy. AB - Traditional pancreaticoduodenectomy dissection techniques are tedious and time consuming. The LigaSure((r)) Vessel Sealing System is an alternative to standard dissection methods. LigaSure((r)) can be used in replace of ligatures, clips, and sutures in most of the pancreaticoduodenectomy procedure. The objective of this study was to examine our experience with LigaSure((r)) in pancreaticoduodenectomies and to show the safety and time-effectiveness. Forty three pancreaticoduodenectomies were performed by a single surgeon using the LigaSure((r)) device in place of traditional dissection techniques. A retrospective chart review was conducted to evaluate patient management and outcome. Demographics, preoperative, intraoperative, and postoperative data were analyzed. The average patient age was 61 years. Primary pathologic diagnoses were: periampullary carcinoma (56%), chronic pancreatitis (5%), cystic lesion (26%), neuroendocrine tumor (7%), and other (5%). Our patient population demonstrated American Society of Anesthesiologists Class I (2%), Class II (14%), III (75%), and IV (9%). Average operative time was 4:11 hours. The study group required an average of 0.49 +/- 1.35 units of blood. Eight patients (19%) received blood transfusion, receiving an average of 2.63 +/- 2.13 units. Patients had a median hospital stay of 10 days (range, 5 to 41 days). An oral diet was ordered for most patients by Day 4. Fourteen patients (32.5%) had a complication, including two patients requiring additional surgery for drainage of abscess. There were no postoperative deaths. The use of LigaSure((r)) is a practical and safe alternative to standard dissection techniques. Operative time, blood loss, and complication rate are favorable compared with published series. PMID- 23461957 TI - The impact of colorectal cancer screening in a veteran hospital population. AB - Colon and rectal cancer is the second most common cause of cancer death in the United States. Screening effectively decreases colorectal cancer mortality. This study aims to evaluate the impact of colorectal cancer screening within a Veterans Affairs Medical Center and treatment outcomes. Institutional Review Board approval was obtained for a retrospective analysis of all colorectal cancer cases that were identified through the Tumor Registry of the Robley Rex VA Medical Center from 2000 to 2009. Data collected included age at diagnosis, race, risk factors, diagnosis by screening versus symptomatic evaluation, screening test, tumor location and stage, operation performed, operative mortality, and survival. A value of P < 0.05 on Fisher's exact, chi(2), analysis of variance, or Cox regression analyses was considered significant. Three hundred fifty-four patients with colorectal cancer (255 colon, 99 rectal) were identified. One hundred twenty-one patients (34%) were diagnosed by screening. In comparison with those diagnosed by symptom evaluation (n = 233), these patients had earlier stage cancers, were more likely to have a curative intent procedure, and had improved 5 year survival rates. Older patients (older than 75 years old) were more likely to present with symptoms. High-risk patients were more likely to have colonoscopic screening than fecal occult blood testing. More blacks had Stage IV disease than nonblacks. Curative intent 30-day operative mortality was 2.1 per cent for colectomy and 0 per cent for rectal resection. Screening for colorectal cancer in the veteran population allows for better survival, detection at an earlier stage, and higher likelihood of resection. PMID- 23461958 TI - Trauma transfers and definitive imaging: patient benefit but at what cost? AB - Many patients undergo computed tomography (CT) scan before transfer to definitive care. Despite this, studies are often repeated on arrival to the trauma center. We evaluated a policy to provide formal in-house interpretation of images performed at outside hospitals. A 3-month retrospective analysis was performed. Two groups were compared. Patients in the in-house interpretation (IHI) group underwent in-house interpretation of outside images. Those images not meeting criteria were placed in the comparison group without in-house radiologic interpretation. Demographics, CT scan data, billing and productivity loss, and extrapolated cancer risk reduction were analyzed. There were no significant differences in demographic or injury data. Fewer total CT scans were performed in the IHI group (223 vs. 320, P = 0.04). The IHI group underwent fewer repeated CT scans (25 vs. 62, P = 0.02; odds ratio [OR], 0.53). Fewer patients were exposed to repeat CT scans (17 vs. 32; OR, 0.48). Total hospital billings decreased by $188,285 ($4,592/patient) in the IHI group. Uncaptured work relative value units totaled 152.19 (3.71/patient) in the IHI group. Radiation exposure decreased by 8 per cent. Use of outside hospital imaging as the definitive evaluation of injured patients is safe and results in an overall decrease in radiation exposure and healthcare cost. PMID- 23461959 TI - Clinical outcome using the fluency stent graft for transjugular intrahepatic portosystemic shunt in patients with portal hypertension. AB - The objective of this study was to evaluate the clinical outcomes using the Fluency stent graft for transjugular intrahepatic portosystemic shunt (TIPS) in patients with portal hypertension. From January 2008 to December 2011, 150 patients (110 male and 40 female with a mean age of 51 years) with portal hypertension underwent TIPS creation with the Fluency stent graft. Indications for TIPS treatment were variceal bleeding in 134 cases and refractory ascites in 16 cases. The clinical results pre- and postprocedure were evaluated. All 150 patients underwent a successful TIPS procedure without any technical complications. The portal pressure decreased from 24.3 +/- 3.2 mmHg preoperatively to 15.1 +/- 2.7 mmHg postoperatively (P < 0.001), and the portal flow velocity increased from 18.3 +/- 4.6 cm/s to 55.6 +/- 15.8 cm/s (P < 0.001). Emergency TIPS was performed in 18 patients with uncontrolled variceal bleeding. During hospitalization, the rates of shunt occlusion, hepatic encephalopathy, variceal rebleeding, and death were 1.3, 0.0, 1.3, and 2.0 per cent, respectively. At a mean follow-up of 24.1 +/- 8.8 months, the rates of shunt occlusion, hepatic encephalopathy, variceal rebleeding, and death were 10.0, 15.3, 11.3, and 10.0 per cent, respectively. The main causes of death were hepatic failure, hepatic carcinoma, and recurrent variceal bleeding. The Fluency stent graft is effective in TIPS creation with high patency rates and improves the results of TIPS for portal hypertension. PMID- 23461960 TI - Should uncooperative trauma patients with suspected head injury be intubated? AB - In trauma patients with a suspicion for traumatic brain injury (TBI), a head computed tomography (CT) scan is imperative. However, uncooperative patients often cannot undergo imaging without sedation and may need to be intubated. Our hypothesis was that among mildly injured trauma patients, in whom there is a suspicion of a head injury, uncooperative patients have higher rates of TBI and intubation should be considered to obtain a CT scan. We found that uncooperative patients intubated for diagnostic purposes were more likely to have moderate to severe TBI than nonintubated patients (21.4 vs. 8.4%, P < 0.0001) and uncooperative behavior leading to intubation was an independent predictor of TBI (odds ratio, 2.5; 95% confidence interval, 1.5 to 4.5). Of patients with brain injury, intubated patients more often had a head abbreviated injury scale score of 4 (20.8 vs. 7.9%, P = 0.04). Uncooperative intubated patients had longer hospital stays (3.6 vs. 2.6 days, P = 0.003) and higher mortality (0.9 vs. 0.2%, P = 0.02) than nonintubated patients. Uncooperative behavior may be an early warning sign of TBI and the trauma surgeon should consider intubating uncooperative trauma patients if there is suspicion for brain injury based on the mechanism of their trauma. PMID- 23461961 TI - Extrahepatic cholangiocarcinoma developing in the setting of AIDS cholangiopathy. PMID- 23461962 TI - Liver resection for noncolorectal, nonneuroendocrine metastases: a single-center experience. PMID- 23461963 TI - Do resident training levels affect outcomes in assisting complex laparoscopic operations? PMID- 23461964 TI - Tracheal injuries diagnosed during thyroid surgery. PMID- 23461965 TI - The impact of tumor size on survival of patients with pT4aN0M0 gastric cancer. PMID- 23461966 TI - Can regional tattoos impact sentinel lymph node identification? PMID- 23461967 TI - After the applause: how to use PowerPoint effectively during the question and answer portion of a presentation. PMID- 23461969 TI - Theoretical characterization of galanin receptor type 3 (Gal3 ) and its interaction with agonist (GALANIN) and antagonists (SNAP 37889 and SNAP 398299): an in silico analysis. AB - In this study, we report on modeling of galanin receptor type 3 and its interaction with agonist and antagonists using in silico methodologies. Comparative structural modeling of galanin receptor type 3 was based on multiple templates. With the availability of reported selective galanin receptor type 3 antagonists, docking was carried out into the predicted binding site. Similarly, galanin, a reported agonist, was also modeled and then docked into the receptor's active site. CoMFA models were developed using ligand-based (q(2) = 0.537, r(2) = 0.961, noc = 5), and receptor-guided (docked mode 1: q(2) = 0.574, r(2) = 0.946, noc = 5), (docked mode 2: q(2) = 0.499, r(2) = 0.954, noc = 5) alignment schemes. CoMFA contour analysis revealed that bulky substitution around the meta position of the phenyl ring, as well as optimal substitution (para) of the phenyl ring, could produce molecules with improved activity. We also found that Gln79, Ile82, Asp86, Trp88, His99, Ile102, Tyr103, Glu170, Pro174, Ala175, Asp185, Arg273, His277, and Tyr281 are crucial, and mutational studies on these residues could be helpful. The results obtained from this study can further be exploited for structure-based drug design and also help the researchers to identify novel antagonists targeting galanin receptor type 3. PMID- 23461970 TI - Don't blame it on the weather! PMID- 23461971 TI - Revisiting gastric decompression tube insertion after endonasal neurosurgery: blamed if you do, blamed if you do not. PMID- 23461972 TI - Neuraxial anesthesia in CADASIL syndrome. PMID- 23461973 TI - Anaesthetic management of a patient with brugada syndrome for craniotomy and tumor excision. PMID- 23461974 TI - Clinician managers don't want to know. PMID- 23461976 TI - [Hearing impairment and tinnitus in patients with type 2 diabetes]. AB - INTRODUCTION: Hearing impairment is one of the most frequent chronic health issue. The incidence of hearing impairment and tinnitus increases with age. AIM: The aim of the authors was to determine the prevalence of hearing impairment and tinnitus in type 2 diabetic patients and to examine the possible associations between hearing impairment and/or tinnitus and increased HbA1c levels. METHODS: 103 patients with type 2 diabetes (47 men, 56 women; age, 61.6+/-10.3 years, mean+/-SD; range, 33-88 years) evaluated at the 2nd Department of Medicine, Semmelweis University were enrolled in this study and the results were compared to those obtained from 589 type 2 diabetic (253 men, 336 women; age, 55.4+/-11.0 years, mean+/-SD; range, 26-97 years) and 15 622 non-diabetic patients (7002 men, 8620 women; age, 55.1+/-11.1 years, mean+/-SD; range, 26-98 years) who participated in a comprehensive health screening programme in Hungary. Hearing impairment was determined using the Interacoustics model AS608 screening audiometer in all patient groups. Tinnitus was evaluated with questionnaire. RESULTS: It was found that hearing impairment and/or tinnitus occurred in a very high proportion of type 2 diabetic patients evaluated at the 2nd Department of Medicine, Semmelweis University (80% of cases) as compared to type 2 diabetic (34% of cases) and non-diabetic patients (14% of cases) enrolled in the national health screening programme. There was no significant correlation between increased HbA1c levels and hearing impairment or tinnitus in type 2 diabetic patients. CONCLUSION: These results suggest that the prevalence of hearing impairment and tinnitus is higher and develop at an earlier age in patients with type 2 diabetes. The results indicate a high prevalence of hearing impairment and tinnitus in type 2 diabetic patients. PMID- 23461975 TI - Silibinin synergizes with histone deacetylase and DNA methyltransferase inhibitors in upregulating E-cadherin expression together with inhibition of migration and invasion of human non-small cell lung cancer cells. AB - Aggressive cancers in the epithelial-to-mesenchymal transition (EMT) phase are characterized by loss of cell adhesion, repression of E-cadherin, and increased cell mobility. Non-small cell lung cancer (NSCLC) differs in basal level of E cadherin; predominantly exhibiting silenced expression due to epigenetic-related modifications. Accordingly, effective treatments are needed to modulate these epigenetic events that in turn can positively regulate E-cadherin levels. Herein, we investigated silibinin, a natural flavonolignan with anticancer efficacy against lung cancer, either alone or in combination with epigenetic therapies to modulate E-cadherin expression in a panel of NSCLC cell lines. Silibinin combined with HDAC inhibitor Trichostatin A [TSA; 7-[4-(dimethylamino)phenyl]-N-hydroxy 4,6-dimethyl-7-oxohepta-2,4-dienamide] or DNMT inhibitor 5'-Aza-deoxycytidine (Aza) significantly restored E-cadherin levels in NSCLC cells harboring epigenetically silenced E-cadherin expression. These combination treatments also strongly decreased the invasion/migration of these cells, which further emphasized the biologic significance of E-cadherin restoration. Treatment of NSCLC cells, with basal E-cadherin levels, by silibinin further increased the E cadherin expression and inhibited their migratory and invasive potential. Additional studies showed that silibinin alone as well as in combination with TSA or Aza downmodulate the expression of Zeb1, which is a major transcriptional repressor of E-cadherin. Overall these findings demonstrate the potential of combinatorial treatments of silibinin with HDAC or DNMT inhibitor to modulate EMT events in NSCLC cell lines, leading to a significant inhibition in their migratory and invasive potentials. These results are highly significant, since loss of E-cadherin and metastatic spread of the disease via EMT is associated with poor prognosis and high mortalities in NSCLC. PMID- 23461977 TI - [Prevalence of osteoporosis in patients with severe peripheral artery disease]. AB - INTRODUCTION: Recent studies highlighted a significant association between bone mineral density and atherosclerosis. Cardiovascular disease is the main cause of death in Western countries, while the prevalence of osteoporosis reached 9% in Hungary. AIM: The aim of this study was to investigate the prevalence of osteoporosis among patients with peripheral vascular disease. METHODS: In a cross sectional study bone mineral density using dual-energy X-ray absorptiometry in 172 patients with lower limb ischemia was investigated. According to previous medical history and blood tests, risk factors of atherosclerosis were also assessed and serum markers of bone turnover and other factors that could influence osteoporosis were evaluated. RESULTS: Prior to bone mineral density screening, osteoporosis was known in 9% of patients. Based on osteodensitometric evaluation, 37% of the patients were diagnosed as having osteopenia and 31% as having osteoporosis. According to risk factors, different patient groups were created. Significantly more female than male patients had osteoporosis, while smoking, age and body mass index failed to affect the prevalence of osteoporosis. CONCLUSION: These results suggest that patients with severe atherosclerosis need to be regularly screened and, if necessary, treated for osteoporosis. PMID- 23461978 TI - [Teenage and adult pregnancy: different correlations between socio-economic status and smoking]. AB - INTRODUCTION: Smoking occurs frequently during pregnancy, thereby putting mother and child at health risks. Low socio-economic status is a risk factor for smoking. AIM: To investigate the relationship between smoking and low income in teenage and adult pregnancy, which is an important measure of poor socioeconomic status. METHOD: The authors used subject-level data from the US NSDUH database, which contains information on pregnancies and smoking. RESULTS: Teenage pregnancy is associated with higher, whereas adult pregnancy with lower prevalence of smoking, compared to the age-matched female population. The association between income and smoking is age-dependent. Among adults there is an inverse relationship (high income -- low-risk of smoking), while in teenage pregnancy smoking increases with income. CONCLUSIONS: To investigate in teenage and adult pregnancy the relationship between smoking and low income, which is an important measure of poor socio-economic status. Higher socioeconomic status may be associated with risky behaviour, thereby increasing both the risk of smoking and early pregnancy. PMID- 23461979 TI - [Severe anemia caused by haemorrhoids: the casae of a young man with toxic cirrhosis]. AB - A 38-year-old alcoholic man with severe iron deficient anaemia, and bloody-mucous stool was found to have haemorrhoidal bleeding. In spite of intravenous iron supplements haemoglobin levels were falling. He was admitted because of deteriorating condition, jaundice, severe anaemia (haemoglobin, 38 g/l) and iron deficiency. Except of toxic (alcohol) agent all other causes of liver disease could be excluded. Sclero-, and medical therapy, and abstinence resulted in a rapid improvement in his condition and subsequently rectal bleeding also disappeared. Bleeding from the upper gastrointestinal tract is a well known and serious complication in liver cirrhosis, however, a voluminous blood loss resulting in a life-threatening anaemia from lower gastrointestinal tract or haemorrhoids, as it was detected in this patient, is quite rare. Sclerotherapy seems to be an effective method with only minor complications when compared with other invasive techniques. However, the patient's compliance even in liver cirrhosis with haemorrhoidal nodes is essential for long-term success. PMID- 23461980 TI - [Giant uterine leiomyoma causing acute symptoms]. AB - The case history of a 71-year-old woman with acute dyspnoea caused by a giant leiomyoma and severe acute anemia due to intratumoral hemorrhage is presented. Urgent operation was performed, and a 13.5 kg pendular tumor was removed. The cornerstones of the differential diagnoses and therapy of giant abdominal tumors is discussed. PMID- 23461981 TI - [Comments on the interpretation of the term "medical devices"]. AB - The Court of Justice of the European Union made a decision on medical devices as non-medicinal products for intended use in interpreting the concept of free movement of goods, such as operating principles concerning the subject matter of the interpretation of Directive 93/42/ EEC - in preliminary ruling according to article 267 of TFEU - on 22 November 2012. With its decision, given assigned explained the concept of the scope of medical devices. The decision of the Court is binding not only for the national court initiating a request for the preliminary ruling, but also for all courts of the Member States. Official reference: Dated judgement 22 November 2012 of the Court of Justice of the European Union to C-219/ Case no. 11 - in preliminary ruling according to article 267 of TFEU. Interpreted provisions: Directive 2007/47/EC of The European Parliament and of the Council of 5 September 2007 as amended by the Council Directive 93/42/EEC of 14 June 1993 concerning medical devices 1st (2) a) first, second and third indent. PMID- 23461982 TI - [David Livingstone (1813-1873) -- not just an Africa explorer, but also a contributor to the development of tropical medicine]. PMID- 23461983 TI - [The heart of women is not like it used to be, either. Cardiovascular risk factors and their treatment. Interview with Dr. Gabor Simonyi by Anna Radnai]. PMID- 23461984 TI - Increased risk of prostate cancer following sexually transmitted infection in an Asian population. AB - The relationship between sexually transmitted infections (STIs) and prostate cancer (PC) remains inconclusive. Moreover, all such studies to date have been conducted in Western populations. This study aimed to investigate the risk of PC following STI using a population-based matched-cohort design in Taiwan. The study cohort comprised 1055 patients with STIs, and 10 550 randomly selected subjects were used as a comparison cohort. Cox proportional hazards regression analysis revealed that the hazard ratio for PC during the 5-year follow-up period for patients with a STI was 1.95 (95% confidence interval 1.18-3.23), that of comparison subjects after adjusting for urbanization level, geographical region, monthly income, hypertension, diabetes, hyperlipidaemia, obesity, chronic prostatitis, history of vasectomy, tobacco use disorder, and alcohol abuse. We concluded that the risk of PC was higher for men who were diagnosed with a STI in an Asian population. PMID- 23461985 TI - Increasing incidence of primary hyperparathyroidism in Denmark. AB - INTRODUCTION: Primary hyperparathyroidism is a common endocrine disorder with different epidemiological patterns among countries. In Denmark, the incidence of primary hyperparathyroidism was last described in 1999 when it was reported to follow an increasing trend. In the present study, we evaluated trends in the incidence of primary hyperparathyroidism in Denmark up to 2010. MATERIAL AND METHODS: All patients diagnosed with primary hyperparathyroidism from 1977 to 2010 were included. Annual incidence rates were calculated. RESULTS: The overall incidence was clearly increased at the end of 2010 with an annual rate of 16 per 100,000. Following a cyclic curve, year-to-year incidence rates were fluctuating. During the entire period, the incidence was higher in women than in men. Furthermore, in women above the age of 50 years, a five-fold increase in incidence was observed, while there was no difference in the increase among men above the age of 50 years compared with men under the age of 50 years. CONCLUSION: The incidence of primary hyperparathyroidism in Denmark continues its remarkable rise. The overall increase in incidence may be the result of more frequent plasma calcium measurements as well as the prevailing obesity epidemic. The dramatic increase in incidence observed among women over the age of 50 years requires further studies. The causes of the cyclic trend observed are uncertain, as no seasonal variation was seen. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23461986 TI - Suboptimal pain treatment after craniotomy. AB - INTRODUCTION: Only few studies have investigated pain, nausea, sedation and analgesic strategies in post-craniotomy patients. The aim of this observational study was to explore pain, nausea, sedation and analgesic procedures after craniotomy, and to evaluate the quality of current analgesic therapy administered to post-craniotomy patients. MATERIAL AND METHODS: A total of 59 patients undergoing supratentorial or infratentorial craniotomy were included over a three month period. The intensity of pain, nausea and sedation was evaluated at 1, 2, 4, 8 and 24 h after extubation. Post-operative analgesic consumption at 0-48 h after extubation was noted. Post-operative morphine consumption in relation to gender, surgical procedure, administration of preoperative steroids and application of surgical drains was evaluated. RESULTS: Fifty patients completed the study. After the first post-operative hour, 56% suffered from moderate-to severe pain, which decreased to 38% at 24 h post-operatively. Patients receiving preoperative steroids experienced significantly less pain than patients who did not receive preoperative steroids (p = 0.04). The mean post-operative morphine consumption 0-48 h post-operatively was 28.8 mg (+/- 23.6 mg). Only 52% of the patients received the planned amount of acetaminophen of 4,000 mg/day. CONCLUSION: Pain following craniotomy is moderate to severe in a substantial number of patients. The quality of the analgesic treatment leaves room for improvement. Administration of preoperative steroids may reduce post-craniotomy pain. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23461987 TI - Elderly patients with community-acquired pneumonia are not treated according to current guidelines. AB - INTRODUCTION: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality in elderly patients, and the most important cause of death in the developed world. Optimised treatment and care will benefit patients as well as the health economy. This study investigated in-hospital compliance with guidelines for treatment and care of patients with CAP. MATERIAL AND METHODS: A retrospective nationwide study examining 100 patient records from 20 Danish hospitals regarding patients 65 years and older admitted for CAP. RESULTS: A total of 74 patients with a mean age 81.6 years were included. The mean length of stay was 9.2 days, 30- and 90-day mortality rates were 12.2 and 17.6% and readmission rates 4% (seven days) and 9.5% (30 days). Severity assessment was made in two cases. Observations of vital parameters were unsystematic and the respiratory rate was measured only in six cases. Diagnostic tests and treatment initiation were mostly in accordance with guidelines. The mean number of days on intravenous antibiotics was 5.5. Nutrition and mobilisation were neglected or only sporadically addressed. No systematic plan for treatment and care was found. CONCLUSION: While medical treatment mainly concurred with guidelines, a potential for reduced costs by early discharge planning and use of systematic assessment tools for site-of-care and treatment decisions was indicated. The lack of systematic interventions in the prevention and treatment of malnutrition and functional decline constitutes a threat to a successful final patient outcome. FUNDING: The Danish Ministry of Health funded the study. TRIAL REGISTRATION: The Danish Data Register approved the project (J. No. 2010-41-5358). PMID- 23461988 TI - MMR vaccination of children with egg allergy is safe. AB - INTRODUCTION: Measles, mumps and rubella (MMR) vaccination is part of the Danish Childhood Vaccination Programme. It is known that children may react with anaphylaxis to MMR vaccines containing traces of egg protein. In Denmark, national clinical guidelines recommend that children with egg allergy be referred to vaccination at a paediatric ward despite changed recommendations in other countries. The purpose of this study was to determine whether children with egg allergy presented with anaphylactic/allergic reactions to MMR vaccination and to discuss whether Danish recommendations should be upheld. MATERIAL AND METHODS: Data collected through evaluation of the histories of children referred to the Paediatric Ward at Hillerod Hospital from 01.01.2008 to 28.02.2011 and coded according to action diagnosis and/or supplementary diagnosis in International Classification of Diseases 10 (ICD-10) for food allergy, oedema angioneurotica and tentative diagnosis as well as the procedure code for oral food challenge. A total of 32 patients were included, all were both sensitized to egg and had been MMR vaccinated. RESULTS: The 32 patients had received a total of 41 doses of MMR vaccine. None of them had shown anaphylactic/allergic reactions to the MMR vaccines. 23% of the vaccines were given with considerable delay. CONCLUSION: Based on our study, we conclude that the Priorix MMR vaccine may be administered just as safely to children diagnosed with egg allergy as to other children. We found no evidence in support of the current Danish recommendations. We therefore recommend that the Statens Serum Institut, the Danish Paediatric Society and/or the Danish Health and Medicines Authority reconsider these recommendations. FUNDING: not relevant TRIAL REGISTRATION: not relevant. PMID- 23461989 TI - Active surveillance can reduce overtreatment in patients with low-risk prostate cancer. AB - INTRODUCTION: The incidence of prostate cancer in Denmark rose approximately 50% from 2000 to 2009 in parallel with the introduction of prostate-specific antigen (PSA)-testing. Available evidence indicates a significant overtreatment of patients with low-risk prostate cancer. Active surveillance has been proposed as an observation strategy to reduce overtreatment and limit curatively intended therapy to those patients who need it. We reported the first Danish results from an active surveillance cohort. MATERIAL AND METHODS: A total of 167 patients were prospectively followed in an active surveillance programme. RESULTS: The median follow-up was 3.4 years (1.1-9.5). At entry the median age was 65 years (51-73), 94% had a Gleason score <= 6, 87.4% had a PSA <= 10 ng/ml and 99% <= cT2a. Ten patients progressed on digital rectal examination, 40 patients progressed due to a short PSA doubling time, and 34 patients progressed on re-biopsy. A total of 59 patients discontinued active surveillance. The estimated five-year probability of remaining on active surveillance was 60.0% (95% confidence interval 50.9-69.1%). CONCLUSION: Active surveillance as a management strategy for patients with clinically localized, low-risk prostate cancer is accepted by patients, seems feasible and can reduce overtreatment. However, long-term follow-up data are lacking and considerable uncertainties about optimal selection and progression criteria remain. FUNDING: The authors received financial support from the IMK Almene Fond. TRIAL REGISTRATION: not relevant. PMID- 23461990 TI - Phonosurgery of vocal fold polyps, cysts and nodules is beneficial. AB - INTRODUCTION: This study reports our experience with microscopic phonosurgery (PS) of benign lesions of the vocal folds. MATERIAL AND METHODS: During the five year period from 2003 to 2007, a total of 97 patients had PS for vocal fold polyps (n = 63), vocal fold cysts (n = 17), vocal fold nodules (n = 12) or vocal fold oedema (n = 5). Their average age was 41 years; 62% were women and 69% were smokers. Post-operative voice therapy was given to 45 patients. Post-operative clinical evaluation was available for data analysis in 89 patients (92%). Voice quality was assessed using the Multi-Dimensional Voice Program (MDVP), video stroboscopy and self-reported assessment. The median follow-up time was 3.9 months. RESULTS: Post-operative voice quality was reported as unaffected in 85%, improved but moderately affected in 13%, and severely affected in one patient with a cyst and vocal fold sulcus. Unaffected voice quality was obtained in 91% of patients not receiving voice therapy and in 77% of patients receiving voice therapy. All lesions except one polyp in the anterior commissure were completely removed. MDVP was performed both pre- and post-operatively in 22% of patients. The effect was a significant improvement of jitter (p = 0.013), shimmer (p = 0.001) and Soft Phonation Index (p = 0.013). CONCLUSION: PS is a quick and effective treatment with uncommon and transient post-operative complications. Objective assessment of the voice pre- and post-operatively should be used consistently and applied in controlled studies evaluating the additional impact of pre- and post-operative voice therapy. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23461991 TI - The validity of the schizophrenia diagnosis in the Danish Psychiatric Central Research Register is good. AB - INTRODUCTION: The Danish Psychiatric Central Research Register (DPCRR) has been used extensively for research purposes during the past decades. The aim of this study was to investigate the validity of the International Classification of Diseases (ICD)-10 schizophrenia diagnosis in the DPCRR. MATERIAL AND METHODS: A random sample of 300 patients with a first-time diagnosis of schizophrenia (ICD 10 codes F20.0-F20.3 and F20.9) in 2009 was drawn from the register to assess its validity. The case records were reviewed by a Schedules for Clinical Assessment in Neuropsychiatry-certified psychiatric resident using the ICD-10 diagnostic criteria as reference. RESULTS: The sample of 300 patients with schizophrenia represented 23.3% of all incident cases (n = 1,288) registered in 2009. We obtained 291 (97.0%) of the case records (nine were lost or inaccessible). Two case records (0.7%) were excluded because of foreign citizenship as these patients had prior episodes in other countries. Thirteen cases (4.3%) were erroneously registered as schizophrenia in the DPCRR. Of the remaining 276 patients, 269 (97.5%) fulfilled the ICD-10 diagnostic criteria for schizophrenia. In a worst case model including all 300 case records, the validity of the schizophrenia diagnosis was 89.7%. CONCLUSION: According to this assessment of patient case records, the diagnosis of schizophrenia in the DPCRR has a high validity and is well-suited for research. FUNDING: Aalborg Psychiatric Hospital funded the study, but the institution had no influence on the planning of the study or the preparation of the manuscript. TRIAL REGISTRATION: not relevant. PMID- 23461992 TI - Optimized surgical space during low-pressure laparoscopy with deep neuromuscular blockade. AB - INTRODUCTION: Laparoscopic cholecystectomy (LC) can be performed using low intra abdominal pressure (< 12 mmHg), but surgical conditions may not be optimal. The present study aimed at comparing surgical space conditions using either deep, continuous muscle relaxation or moderate blockade during low-pressure (8 mmHg) LC. We hypothesized that a deep neuromuscular block would be associated with a higher proportion of optimal surgical space conditions. MATERIAL AND METHODS: This was an investigator-initiated, patient- and assessor-blinded study. Up to 72 patients scheduled for elective LC were randomised to either deep neuromuscular blockade (post-tetanic count 0-1) or moderate neuromuscular blockade, where at least one response to train-of-four nerve stimulation was present. The primary outcome was surgical space conditions at the time during surgery when conditions were worst. The secondary outcomes included the proportion of procedures completed at pneumoperitoneum 8 mmHg, post-operative pain, and incidence of nausea and vomiting. RESULTS: This study was the first randomised study to assess the association between depth of neuromuscular blockade and surgical space conditions during low-pressure LC. The study findings may be applicable to a general surgical population undergoing LC. FUNDING: The University of Copenhagen, Denmark and Sophus Johansens Foundation of 1981, Denmark funded this study, which was also financed by a research grant from the Investigator Initiated Studies Program of Merck Sharp and Dohme Corp. TRIAL REGISTRATION: NCT 01523886. PMID- 23461993 TI - Endoscopic dacryocystorhinostomy seems promising for lacrimal stenosis. AB - INTRODUCTION: Acquired nasolacrimal drainage obstruction (ANLDO) is a common ophthalmic problem with symptoms like epiphora and dacryocystitis. The standard surgery for ANLDO is dacrocystorhinostomy (DCR) in which the lacrimal sac is connected directly to the nose. There are two types of DCR, external (exDCR) and endonasal (enDCR). Our aim was to determine the total outcome of enDCR and specifically to analyze the success rate in relation to obstruction levels as there only have been few former reports on these aspects. MATERIAL AND METHODS: A retrospective chart review was performed at the Department of Otorhinolaryngology at the Hospital of Holstebro in the 2005-2010 period. All patients were evaluated by an ophthalmologist before surgery. The ophthalmologist categorized the site of obstruction as proximal (from punctum to the end of the common canaliculus) or distal (saccus and the nasolacrimal duct). The need for additional nasal surgery was evaluated by an otorhinolaryngologist. The surgical outcome was evaluated at the second follow-up six months after surgery and the subjective improvement and the patency of the neo-ostium were determined. RESULTS: A total of 61 operations were performed of which 55 were included. The success rate after enDCR was 91%. Categorizing the level of obstruction, 41% were distal of which 92% were successful, and 59% were proximal of which 90% were successful. CONCLUSION: We suggest enDCR for both distal and proximal stenosis of the lacrimal system as the obstruction level seems to have no influence on the success rates. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23461994 TI - The most important reason for lack of organ donation is family refusal. AB - INTRODUCTION: There is a worldwide shortage of organs for transplantation. This survey aims to compare two periods in the 2000s at a large neuro-intensive care unit with respect to de facto organ donors, potential organ donors and reasons for non-donation. MATERIAL AND METHODS: This survey is a retrospective examination of all patients who died in the Neuro-intensive Care Unit at Rigshospitalet from 1/1 2000 to 30/6 2003 ("the first period") and from 1/1 2007 to 30/6 2010 ("the second period"). RESULTS: The number of patients who died in the Neuro-intensive Care Unit was 350 in the first period and 270 in the second period. Approximately half of all deceased patients in a neuro-intensive care unit are potential organ donors. Of the potential donors, 42 (27%) in the first and 48 (37%) in the second period became de facto donors. The main reason for non donation among potential organ donors was lack of consent from next of kin (44% and 40%). The median time from brain death to recovery of organs in the second period was 5 h 45 m. DISCUSSION: The conversion rate tends to rise. Few people took an active standing against organ donation (10% and 2%); yet many family members refused to consent to organ donation. Consent was provided by the deceased in only 12% and 21% of the cases. The Danish organ procurement team is highly effective with a median time from brain death to recovery of organs of 5 h 45 m. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23461995 TI - Urinary biomarkers in hydronephrosis. AB - Hydronephrosis is diagnosed in 0.5-1% of all newborns, and ureteropelvic junction obstruction (UPJO) accounts for 35% of those cases. A urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation, and growth, and in the most severe cases, this will ultimately lead to progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The clinical management of these patients remains a controversial topic. The aim is to preserve renal function by identifying the 15-20% of children who require early surgical intervention from those for whom watchful waiting may be appropriate because of spontaneous resolving/stabilization without significant loss of renal function. Although the patients attend regular follow ups, including repetitive blood tests, ultrasonographies, and the more invasive diuretic renograms, the surgeons still miss reliably biomarkers that could be used as predictors for renal parenchymal damage and decreased renal function, and thereby provide more clear indications for surgical intervention. The aim of this PhD thesis was to further elucidate the pathophysiology of obstructive nephropathy (study I) and to search for potential candidate biomarkers that may have a predictive and/or diagnostic value in the management of hydronephrosis (study II). Study I: Urine and kidney cytokine profiles in experimental unilateral acute and chronic hydronephrosis. AIM: To study the dynamics of the urinary secretion of cytokines after the release of unilateral ureteral obstruction, and to study whether the urinary concentrations of these compounds reliably reflects changes in the renal parenchyma. This was tested in 2 experimental rat models: an acute obstruction model and a chronic obstruction model. RESULTS: The acute obstruction model demonstrated significant differences in the renal levels of IL-1beta, IL-6, TNF-alpha, and IL-10 in comparison with controls, and these differences were associated with similar differences in their urinary excretion. Such results were not obtained in the chronic obstruction model in which significant differences were only demonstrated in the urinary concentrations of IL-6. Study II: Candidate urinary biomarkers in hydronephrosis a clinical study. AIM: To study the dynamics of the urinary excretion of selected potential biomarkers in children after the relief of UPJO, and to compare their findings with healthy controls. RESULTS: Twenty-eight children with UPJO were included in the study from 2007-2011 together with 13 healthy children. Pre-, peri- and post-operatively (1 year) urine samples were collected. The median age of the patients was 8.1 (3.5-14.5) years. Five proteins (EGF, IP-10, MCP-1, RANTES, and MIP-1alpha) were examined in study IIa, and 4 proteins (NGAL, CyC, betaM-2, and OPN) were examined in study IIb. In brief, significantly increased urinary concentrations of EGF and MCP-1 were demonstrated in children with UPJO compared to controls, which was followed by a decline in the post operative period to levels similar to the controls. This indicates that the urinary concentrations of EGF and MCP-1 are regulated as a response to the obstruction, suggesting that they may have a potential as urinary biomarkers in hydronephrosis. In general, urine from the obstructed kidney exhibited higher concentrations of the proteins compared to urine from the nonobstructed kidney. Furthermore, CyC, beta-2M, and OPN were negatively correlated with age, and IP-10 and MCP-1 were negatively correlated with DRF. In conclusion, this PhD study confirmed increased concentrations of selected proteins in urine from kidneys suffering from obstruction. Interestingly, it was observed that some urinary proteins had an age-dependent excretion. Further investigations are required to test the ability of the examined proteins to identify an obstruction and reveal disease progression and, thereby, be useful clinical tools. PMID- 23461996 TI - Nutrition, growth, and allergic diseases among very preterm infants after hospital discharge. AB - The aims of this PhD thesis were: 1. Primarily to investigate the effect, of adding human milk fortifier to mother's milk while breastfeeding very preterm infants after hospital discharge, on growth until 1 year corrected age (CA) 2. Secondarily to describe breastfeeding rate and factors associated with breastfeeding among very preterm infants at hospital discharge. 3. To describe possible feeding-problems during the intervention-period, and allergic diseases during the first year of life, among very preterm infants related to their nutrition after hospital discharge. 4. To describe the content of macronutrients in human milk from mothers delivering very preterm. This PhD thesis is based on a prospective, randomized, and controlled interventional birth cohort study. A total of 633 very preterm infants with a gestational age (GA) <= 32 + 0 weeks were recruited consecutively from July 2004 until August 2008 of whom 157 were excluded due to diseases or circumstances influencing nutrition. Further 156 refused participation in the interventional part of the study, but data on breastfeeding, weight, and some epidemiological data until discharge were available. Results on breastfeeding rate at discharge were therefore based on data from 478 infants, and parents of 320 infants accepted participation in the intervention study. Of these 320 infants, 207 were exclusively breastfed and they were shortly before hospital discharge randomized to either breastfeeding without (group A) or with fortification (group B) until 4 months CA. Infants (n = 113) who were bottle-fed at discharge (group C) were given a preterm formula (PF) until 4 months CA. Infants were examined at the outpatient clinics at term, and at 2, 4, 6, and 12 months CA, where parameters on growth, allergic diseases, possible feeding problems, blood-samples, and milk samples were obtained. Data on duration of exclusively breastfeeding and time of introduction to formula and/or complementary food were also recorded. Among the 478 infants 60% (n = 285) were exclusively breastfed, 35% (n = 167) were exclusively bottle-fed, and 5% (n=26) were both breast- and bottle-fed at discharge. Compared to mothers in lower social groups and mothers who smoked, mothers in higher social groups and "non smokers" were significantly (p = 0.000 and p = 0.003 respectively) more often breastfeeding their very preterm infants at discharge. Single birth infants tended more often to be breastfed (p = 0.09). Infant age at discharge and duration of hospitalization did not influence breastfeeding at discharge. Increase in weight Z-score from birth to discharge was largest in the bottle-fed group compared to the breastfed group (p = 0.000), probably due to feeding practice the last week(s) of hospitalization. In the intervention study, 207 exclusively breastfed very preterm infants were randomized to group A (n = 102) and B (n = 105) respectively. The duration of breastfeeding was not influenced by fortification of mother's milk after hospital discharge. There was no significant difference on growth comparing group A and B at 12 months CA. Both boys and girls in group C achieved catch-up in weight and length earlier as compared to group A and B. Per protocol (PP) analysis showed that girls, but not boys, were longer and had a larger head circumference but were not heavier in group B (n = 51) compared to group A (n = 73) at 2 and 4 months CA (p<0.05). Protein-concentration in mothers' milk declined significantly from 2 weeks (1.8 g/100 ml) to 6 weeks after birth (1.4 g/100 ml) and declined further to 1.2 g/100 ml 12 weeks after birth. The incidence and the prevalence at 12 months CA of recurrent wheezing was 39.2% and 32.7% respectively, while atopic dermatitis was 18.0% and 12.1% respectively. Predisposition to allergic disease increased the risk of developing atopic dermatitis (p = 0.04) (OR 2.6 (95% CI 1.0-6.4)), and the risk of developing recurrent wheezing (p = 0.02) (OR 2.7 (95% CI 1.2-6.3)). Boys had an increased risk of developing recurrent wheezing (p = 0.003) (OR 3.1 (95% CI 1.5 6.5)). In conclusion breastfeeding can successfully be established in very preterm infants. Fortification of human milk after hospital discharge while breastfeeding was possible without influencing the duration of breastfeeding. Fortification in the amount given in this study did, however, not affect growth significantly at 1 year of age. An increased amount of protein was correlated with increased BUN-values indicating a better growth potential. Fortification of mother's milk or preterm formula was not associated with an increased risk of developing allergic diseases. Future follow-up of this cohort investigating e.g. growth, allergic diseases, and neuropsychological development is planned at 6 years of age. The definition of optimal growth and nutrition of preterm infants is though still a question for debate and further investigations are needed. PMID- 23461998 TI - Circadian regulation of epithelial functions in the intestine. AB - Many physiological functions exhibit a diurnal rhythmicity that is influenced by biological clocks and feeding rhythms. In this review, we discuss the growing evidence showing the important role of circadian rhythms in regulating intestinal mucosa. First, we introduce the molecular timing system and the interrelationship between the master biological clock in the suprachiasmatic nuclei of the brain and the peripheral intestinal clock and provide evidence that the intestinal clock is entrained with the external environment. Second, we review the circadian rhythmicity of enterocyte proliferation and the largely unknown regulatory mechanisms behind these rhythms. Finally, we focus on the circadian clock control of food processing that functions by regulating the expression of digestive enzymes and intestinal nutrient and salt transporters. The concepts to be discussed highlight the ability of the intestinal epithelium to utilize self sustained clock signals together with signals associated with changes in the cellular environment and to use endogenous temporal control of the gastrointestinal functions to meet varying physiological and pathophysiological demands. The fact that internal de-synchronizations within the body, such as those that occur in shift workers or with changes in food intake behaviour, are often associated with malfunctions of the gastrointestinal tract indicates that more information about the connections between the circadian clock and intestinal mucosa/transporting enterocytes could provide clues for future therapies. PMID- 23461999 TI - Biomedical application of phosphoproteomics in neurodegenerative diseases. AB - Phosphorylation and dephosphorylation of proteins trigger many critical events involved in cellular response, such as regulation of enzymatic activity, protein conformational change, protein-protein interaction, and cellular localization. Any malfunction of protein phosphorylation leads to a diseased state such as diabetes, cancer, and even neurodegenerative diseases. In order to comprehend the molecular view of the complex biological processes of these diseases in depth, very sensitive and detailed analytical methods are necessary for identification of the phosphorylated residues in a protein. As part of these efforts, phosphoproteomics has been developed and applied for the elucidation of neurodegenerative diseases. In this review, we present a brief summary of phosphoproteomics approaches that are now routinely used in biomedical research, and describe the biomedical application of phosphoproteomics especially in Alzheimer's and other neurodegenerative diseases. PMID- 23461997 TI - Global association between cortical thinning and white matter integrity reduction in schizophrenia. AB - Previous neuroimaging studies have revealed that both gray matter (GM) and white matter (WM) are altered in several morphological aspects in schizophrenia patients. Although several studies reported associations between GM and WM alterations in restricted regions, the existence of a global association between GM and WM pathologies is unknown. Considering the wide distribution of GM morphological changes and the profound genetic background of WM abnormalities, it would be natural to postulate a global association between pathologies of GM and WM in schizophrenia. In this investigation, we studied 35 schizophrenia patients and 35 healthy control subjects using T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) and investigated the association between GM thickness and WM fractional anisotropy (FA) as a proxy of pathology in each tissue. To investigate cortical thickness, surface-based analysis was used. The mean cortical thickness for the whole brain was computed for each hemisphere, and group comparisons were performed. For DTI data, mean FA for the whole brain was calculated, and group comparisons were performed. Subsequently, the correlation between mean cortical thickness and mean FA was investigated. Results showed that the mean cortical thickness was significantly thinner, and the mean FA was significantly lower in schizophrenia patients. Only in the patient group the mean cortical thickness and mean FA showed significant positive correlations in both hemispheres. This correlation remained significant even after controlling for demographic and clinical variables. Thus, our results indicate that the GM and WM pathologies of schizophrenia are intertwined at the global level. PMID- 23462000 TI - Improved methodology for identification of cryptomonads: combining light microscopy and PCR amplification. AB - Cryptomonads are unicellular, biflagellate algae. Generally, cryptomonad cells cannot be preserved well because of their fragile nature, and an improved methodology should be developed to identify cryptomonads from natural habitats. In this study, we tried using several cytological fixatives, including glutaraldehyde, formaldehyde, and their combinations to preserve field samples collected from various waters, and the currently used fixative, Lugol's solution was tested for comparison. Results showed that among the fixatives tested, glutaraldehyde preserved the samples best, and the optimal concentration of glutaraldehyde was 2%. The cell morphology was well preserved by glutaraldehyde. Cells kept their original color, volume, and shape, and important taxonomic features such as furrow/gullet complex, ejectosomes, as well as flagella could be observed clearly, whereas these organelles frequently disappeared in Lugol's solution preserved samples. The osmotic adjustments and buffers tested could not preserve cell density significantly higher. Statistical calculation showed the cell density in the samples preserved by 2% glutaraldehyde remained stable after 43 days of the fixation procedure. In addition, DNA was extracted from glutaraldehyde preserved samples by grinding with liquid nitrogen and the 18S rDNA sequence was amplified by PCR. The sequence was virtually identical to the reference sequence, and phylogenetic analyses showed very close relationship between it and sequences from the same organism. To sum up, the present study demonstrated that 2% unbuffered glutaraldehyde, without osmotic adjustments, can preserve cryptomonads cells for identification, in terms of both light microscopy and phylogenetic analyses based on DNA sequences. PMID- 23462001 TI - Correlation between Sorangium cellulosum subgroups and their potential for secondary metabolite production. AB - Phylogenetic analysis of the groEL1 and xynB1 gene sequences from Sorangium cellulosum strains isolated in Korea previously revealed the existence of at least 5 subgroups (A-E). In the present study, we used sequence analysis of polymerase chain reaction-amplified biosynthetic genes of strains from the 5 subgroups to indicate correlations between S. cellulosum subgroups and their secondary metabolic gene categories. We detected putative biosynthetic genes for disorazol, epothilone, ambruticin, and soraphen in group A, group C, group D, and group E strains, respectively. With the exception of KYC3204, culture extracts from group A, group B, and group C strains exhibited no noticeable antimicrobial inhibitory activities. By contrast, culture extracts from group D strains inhibited the growth of Candida albicans, whereas culture extracts from group E strains inhibited the growth of C. albicans and Staphylococcus aureus. High performance liquid chromatography analysis of the culture extracts from the strains of each subgroup revealed unique peak patterns. Our findings indicate the existence of at least 5 subgroups of S. cellulosum strains, each of which has the potential to produce a unique set of secondary metabolites. PMID- 23462002 TI - Development of a genome-wide random mutagenesis system using proofreading deficient DNA polymerase delta in the methylotrophic yeast Hansenula polymorpha. AB - The thermotolerant methylotrophic yeast Hansenula polymorpha is attracting interest as a potential strain for the production of recombinant proteins and biofuels. However, only limited numbers of genome engineering tools are currently available for H. polymorpha. In the present study, we identified the HpPOL3 gene encoding the catalytic subunit of DNA polymerase delta of H. polymorpha and mutated the sequence encoding conserved amino acid residues that are important for its proofreading 3'-->5' exonuclease activity. The resulting HpPOL3* gene encoding the error-prone proofreading-deficient DNA polymerase delta was cloned under a methanol oxidase promoter to construct the mutator plasmid pHIF8, which also contains additional elements for site-specific chromosomal integration, selection, and excision. In a H. polymorpha mutator strain chromosomally integrated with pHIF8, a URA3(-) mutant resistant to 5-fluoroorotic acid was generated at a 50-fold higher frequency than in the wild-type strain, due to the dominant negative expression of HpPOL3*. Moreover, after obtaining the desired mutant, the mutator allele was readily removed from the chromosome by homologous recombination to avoid the uncontrolled accumulation of additional mutations. Our mutator system, which depends on the accumulation of random mutations that are incorporated during DNA replication, will be useful to generate strains with mutant phenotypes, especially those related to unknown or multiple genes on the chromosome. PMID- 23462003 TI - Diversity and active mechanism of fengycin-type cyclopeptides from Bacillus subtilis XF-1 against Plasmodiophora brassicae. AB - Bacillus subtilis XF-1, a strain with demonstrated ability to control clubroot disease caused by Plasmodiophora brassicae, was studied to elucidate its mechanism of antifungal activity against P. brassicae. Fengycin-type cyclopeptides (FTCPs), a well-known class of compounds with strong fungitoxic activity, were purified by acid precipitation, methanol extraction, and chromatographic separation. Eight homologs of fengycin, seven homologs of dehydroxyfengycin, and six unknown FTCPs were characterized with LC/ESI-MS, LC/ESI-MS/MS, and NMR. FTCPs (250 microg/ml) were used to treat the resting spores of P. brassicae (10(7)/ml) by detecting leakage of the cytoplasm components and cell destruction. After 12 h treatment, the absorbencies at 260 nm (A(260)) and at 280 nm (A(280)) increased gradually to approaching the maximum of absorbance, accompanying the collapse of P. brassicae resting spores, and nearly no complete cells were observed at 24 h treatment. The results suggested that the cells could be cleaved by the FTCPs of B. subtilis XF-1, and the diversity of FTCPs was mainly attributed to a mechanism of clubroot disease biocontrol. PMID- 23462004 TI - Expression and purification of human farnesoid X receptor-ligand binding domain as soluble form using a dual cistronic expression vector. AB - In this study, we show the expression and purification of the human recombinant farnesoid X receptor (FXR)- ligand binding domain (LBD) protein in E. coli using a double cistronic vector, pACYCDuet-1, as a soluble form. We describe here the expression and characterization of a biologically active FXR-LBD(248-476). When expressed in the influence of bacterial promoters (P(T7) and P(Tac)) of the single cistronic expression vectors, the human recombinant FXR-LBD(248-476) was found to be totally insoluble. However, by using a double cistronic expression vector, we were able to obtain the human recombinant FXR-LBD(248-476) in a soluble form. To allow for biological activities, we have subcloned into the pACYCDuet-1 vector, expressed in E. coli cells at some optimized conditions, and purified and characterized the human recombinant active FXR-LBD(248-476) proteins using the fluorescence polarization assay. This suggests that the expression of FXR-LBD in a double cistronic vector improves its solubility and probably assists its correct folding for the biologically active form of the proteins. We suggest that this may represent a new approach to high expression of other nuclear receptors and may be useful as well for other classes of heterodimeric protein partners. PMID- 23462005 TI - Identification of novel irreversible inhibitors of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) from Haemophilus influenzae. AB - Uridinediphospho-N-acetylglucosamine enolpyruvyl transferase (MurA, E.C. 2.5.1.7) is an essential bacterial enzyme that catalyzes the first step of the cell wall biosynthetic pathway, which involves the transfer of an enolpyruvyl group from phosphoenolpyruvate to uridinediphospho-Nacetylglucosamine. In this study, novel inhibitors of Haemophilus influenzae MurA (Hi MurA) were identified using high throughput screening of a chemical library from the Korea Chemical Bank. The identified compounds contain a quinoline moiety and have much lower effective inhibitory concentrations (IC(50)) than fosfomycin, a wellknown inhibitor of MurA. These inhibitors appear to covalently modify the sulfhydryl group of the active site cysteine (C117), since the C117D mutant Hi MurA was not inhibited by these compounds and excess dithiothreitol abolished their inhibitory activities. The increased mass value of Hi MurA after treatment with the identified inhibitor further confirmed that the active-site cysteine residue of Hi MurA is covalently modified by the inhibitor. PMID- 23462006 TI - Fuzzy logic control of rotating drum bioreactor for improved production of amylase and protease enzymes by Aspergillus oryzae in solid-state fermentation. AB - In this study, we compared the performance of two control systems, fuzzy logic control (FLC) and conventional control (CC). The control systems were applied for controlling temperature and substrate moisture content in a solidstate fermentation for the biosynthesis of amylase and protease enzymes by Aspergillus oryzae. The fermentation process was achieved in a 200 L rotating drum bioreactor. Three factors affecting temperature and moisture content in the solid state fermentation were considered. They were inlet air velocity, speed of the rotating drum bioreactor, and spray water addition. The fuzzy logic control system was designed using four input variables: air velocity, substrate temperature, fermentation time, and rotation speed. The temperature was controlled by two variables, inlet air velocity and rotational speed of bioreactor, while the moisture content was controlled by spray water. Experimental results confirmed that the FLC system could effectively control the temperature and moisture content of substrate better than the CC system, resulting in an increased enzyme production by A. oryzae. Thus, the fuzzy logic control is a promising control system that can be applied for enhanced production of enzymes in solidstate fermentation. PMID- 23462007 TI - Efficient enantioselective synthesis of (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol by Leifsonia xyli CCTCC M 2010241 using isopropanol as co-substrate. AB - (R)-[3,5-Bis(trifluoromethyl)phenyl] ethanol is a key chiral intermediate for the synthesis of aprepitant. In this paper, an efficient synthetic process for (R) [3,5- bis(trifluoromethyl)phenyl] ethanol was developed via the asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone, catalyzed by Leifsonia xyli CCTCC M 2010241 cells using isopropanol as the co-substrate for cofactor recycling. Firstly, the substrate and product solubility and cell membrane permeability of biocatalysts were evaluated with different co-substrate additions into the reaction system, in which isopropanol manifested as the best hydrogen donor of coupled NADH regeneration during the bioreduction of 3,5 bis(trifluoromethyl) acetophenone. Subsequently, the optimization of parameters for the bioreduction were undertaken to improve the effectiveness of the process. The determined efficient reaction system contained 200 mM of 3,5 bis(trifluoromethyl) acetophenone, 20% (v/v) of isopropanol, and 300 g/l of wet cells. The bioreduction was executed at 30 degrees C and 200 rpm for 30 h, and 91.8% of product yield with 99.9% of enantiometric excess (e.e.) was obtained. The established bioreduction reaction system could tolerate higher substrate concentrations of 3,5- bis(trifluoromethyl) acetophenone, and afforded a satisfactory yield and excellent product e.e. for the desired (R)-chiral alcohol, thus providing an alternative to the chemical synthesis of (R)-[3,5 bis(trifluoromethyl)phenyl] ethanol. PMID- 23462008 TI - Optimization of beta-glucosidase production by a strain of Stereum hirsutum and its application in enzymatic saccharification. AB - A high beta-glucosidase (BGL)-producing strain, Stereum hirsutum, was identified and isolated and showed a maximum BGL activity (10.4 U/ml) when cultured with Avicel and tryptone as the carbon and nitrogen sources, respectively. In comparison with other BGLs, BGL obtained from S. hirsutum showed a higher level of activity to cellobiose (V(max) = 172 U/mg, and k(cat) = 281/s). Under the optimum conditions (600 rpm, 30 degrees C, and pH 6.0), the maximum BGL activity of 10.4 U/ml with the overall productivity of 74.5 U/l/h was observed. BGL production was scaled up from a laboratory scale (7-L fermenter) to a pilot scale (70-L fermenter). When S. hirsutum was cultured in fed-batch culture with rice straw as the carbon source in a 70-L fermenter, a comparable productivity of 78.6 U/l/h was obtained. Furthermore, S. hirsutum showed high levels of activity of other lignocellulases (cellobiohydrolase, endoglucanase, xylanase, and laccase) that are involved in the saccharification of biomasses. Application of S. hirsutum lignocellulases in the hydrolysis of Pinus densiflora and Catalpa ovata showed saccharification yields of 49.7% and 43.0%, respectively, which were higher than the yield obtained using commercial enzymes. PMID- 23462009 TI - Spontaneous release of bacteriophage particles by Lactobacillus rhamnosus pen. AB - The identification of bacteriophage proteins on the surface of Lactobacillus rhamnosus Pen was performed by LC-MS/MS analysis. Among the identified proteins, we found a phage-derived major tail protein, two major head proteins, a portal protein, and a host specificity protein. Electron microscopy of a cell surface extract revealed the presence of phage particles in the analyzed samples. The partial sequence of genes encoding the major tail protein for all tested L. rhamnosus strains was determined with specific primers designed in this study. Next, RT-PCR analysis allowed detection of the expression of the major tail protein gene in L. rhamnosus strain Pen at all stages of bacterial growth. The transcription of genes encoding the major tail protein was also proved for other L. rhamnosus strains used in this study. The present work demonstrates the spontanous release of prophage-encoded particles by a commercial probiotic L. rhamnosus strain, which did not significantly affect the bacterial growth of the analyzed strain. PMID- 23462010 TI - Statistical optimization for Monacolin K and yellow pigment production and citrinin reduction by Monascus purpureus in solid-state fermentation. AB - Monacolin K and yellow pigment, produced by Monascus sp., have each been proven to be beneficial compounds as antihypercholesterolemic and anti-inflammation agents, respectively. However, citrinin, a human toxic substance, was also synthesized in this fungus. In this research, solidstate fermentation of M. purpureus TISTR 3541 was optimized by statistical methodology to obtain a high production of monacolin K and yellow pigment along with a low level of citrinin. Fractional factorial design was applied in this study to identify the significant factors. Among the 13 variables, five parameters (i.e., glycerol, methionine, sodium nitrate, cultivation time, and temperature) influencing monacolin K, yellow pigment, and citrinin production were identified. A central composite design was further employed to investigate the optimum level of these five factors. The maximum production of monacolin K and yellow pigment of 5,900 mg/kg and 1,700 units/g, respectively, and the minimum citrinin concentration of 0.26 mg/kg were achieved in the medium containing 2% glycerol, 0.14% methionine, and 0.01% sodium nitrate at 25 degrees C for 16 days of cultivation. The yields of monacolin K and yellow pigment were about 3 and 1.5 times higher than the basal medium, respectively, whereas citrinin was dramatically reduced by 36 times. PMID- 23462011 TI - Isolation of a Korean domestic microalga, Chlamydomonas reinhardtii KNUA021, and analysis of its biotechnological potential. AB - A freshwater microalga, Chlamydomonas reinhardtii KNUA021, was characterized for its potential as a biochemical feedstock. Its optimal growth was observed when the culture was incubated at 25 degrees C and pH 9.4. However, the isolate was capable of survival and growth under a variety of temperatures (10-30 degrees C) and pH (pH 4.0-12.0) conditions. The total lipid content of the isolate was 21.7% of dry weight and it was found that a high-value fatty alcohol, hexadecenol (C(20)H(40)O), was autotrophically produced by strain KNUA021. In addition, a nutritionally important C(18:3) omega3 (alpha-linolenic acid, ALA) was also identified in this photosynthetic microorganism as one of the major fatty acids. Hence, C. reinhardtii KNUA021 appears to show promise for use in the production of microalgae-based biochemicals. PMID- 23462012 TI - Syntrophic propionate degradation response to temperature decrease and microbial community shift in an UASB reactor. AB - Propionate is an important intermediate product during the methane fermentation of organic matter, and its degradation is crucial for maintaining the performance of an anaerobic digester. In order to understand the effect of temperature on propionate degradation, an upflow anaerobic sludge blanket (UASB) reactor with synthetic wastewater containing propionate as a sole carbon source was introduced. Under the hydraulic retention time (HRT) of 10 h and influent propionate of 2,000 mg/l condition, propionate removal was above 94% at 30-35 degrees C, whereas propionate conversion was inhibited when temperature was suddenly decreased stepwise from 30 degrees C to 25 degrees C, to 20 degrees C, and then to 18 degrees C. After a long-term operation, the propionate removal at 25 degrees C resumed to the value at 30- 35 degrees C, whereas that at 20 degrees C and 18 degrees C was still lower than the value at 35 degrees C by 8.1% and 20.7%, respectively. Microbial community composition analysis showed that Syntrophobacter and Pelotomaculum were the major propionate-oxidizing bacteria (POB), and most POB had not changed with temperature decrease in the UASB. However, two POB were enriched at 18 degrees C, indicating they were low temperature tolerant. Methanosaeta and Methanospirillum were the dominant methanogens in this UASB and remained constant during temperature decrease. Although the POB and methanogenic composition hardly changed with temperature decrease, the specific CODPro removal rate of anaerobic sludge (SCRR) was reduced by 21.4%-46.4% compared with the control (35 degrees C) in this system. PMID- 23462013 TI - Characterization of a blend-biosurfactant of glycolipid and lipopeptide produced by Bacillus subtilis TU2 isolated from underground oil-extraction wastewater. AB - Biosurfactants have versatile properties and potential industrial applications. A new producer, B. subtilis TU2, was isolated from the underground oil-extraction wastewater of Shengli Oilfield, China. Preliminary flask culture showed that the titer of biosurfactant obtained from the broth of TU2 was ~1.5 g/l at 48 h (718 mg/l after purification), with a reduced surface tension of 32.5 mN/m. The critical micelle concentration was measured as 50 mg/l and the surface tension maintained stability in solution with 50 g/l NaCl and 16 g/l CaCl(2) after 5 days of incubation at 70 degrees C. FT-IR spectra exhibited the structure information of both glycolipid and lipopeptide. MALDI-TOF-MS analyses confirmed that the biosurfactant produced by B. subtilis TU2 was a blend of glycolipid and lipopeptide, including rhamnolipid, surfactin, and fengycin. The blended biosurfactant showed 86% of oil-washing efficiency and fine emulsification activity on crude oil, suggesting its potential application in enhanced oil recovery. PMID- 23462014 TI - An beta-1,4-xylanase with exo-enzyme activity produced by Paenibacillus xylanilyticus KJ-03 and its cloning and characterization. AB - Paenibacillus xylanilyticus KJ-03 was isolated from soil samples obtained from a field with Amorphophallus konjac plants. A gene encoding xylanase was isolated from KJ-03 and cloned using a fosmid library. The xynA gene encodes xylanase; it consists of 1,035 bp and encodes 345 amino acids. The amino acid sequence deduced from the P. xylanilyticus KJ-03 xylanase showed 81% and 69% identities with those deduced from the P. polymyxa E681 and Paenibacillus sp. HPL-001 xylanases, respectively. The xynA gene comprises a single domain, consisting of a catalytic domain of the glycosyl hydrolase (GH) 10 family. The xynA gene was expressed in Escherichia coli BL21 (trxB), and the recombinant xylanase was purified by Niaffinity chromatography. The purified xylanase showed optimum activity with birchwood xylan as a substrate at 40 degrees C and pH 7.4. Treatment with Mg(2+) and Li(+) showed a slight decrease in XynA activity; however, treatment with 5 mM Cu(2+) completely inhibited its activity. The results of the thin layer chromatography analysis indicated that the major hydrolysis product was xylobiose and small amounts of xylose and xylotriose. XynA showed increased activity with oat spelt xylan and birchwood xylan, but showed only slight activity with locust bean gum. PMID- 23462015 TI - Functions of monocyte chemotactic protein-3 in transgenic mice fed a high-fat, high-cholesterol diet. AB - Monocyte chemotactic protein-3 (MCP-3), a chemokine that is in a superfamily of structurally related small chemotactic cytokines involved in leukocyte trafficking, is regarded as a key factor in atherogenesis. In this study, we examined the changes in atherogenic parameters including hepatic lipid accumulation and oxidative balance in MCP- 3-overexpressing transgenic mice (MCP 3 mice) under atherogenic conditions. To induce an extreme atherogenic condition, mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks. The body weight and food intake were not changed by MCP-3 overexpression in the aorta. On a HFHC diet, the MCP-3 mice had higher plasma levels of total cholesterol and a higher atherogenic index compared with wild-type mice, although there were no differences in the plasma HDL-cholesterol and triglyceride levels. Furthermore, an increase in lipid accumulation was observed in the aortas as well as the livers of the HFHC diet-fed MCP-3 mice compared with wild-type mice. The activities of antioxidant enzymes increased in the livers of the HFHC diet-fed MCP-3 mice, whereas supplementation with antioxidants, naringin and hesperidin, reversed the activities of the hepatic antioxidant enzymes in HFHC diet-fed MCP-3 mice, indicating that there might be more oxidative damage to the tissues in the HFHC diet-fed MCP-3 mice leading to progression towards atherosclerosis and hepatic steatosis. Microarray analyses of the aorta revealed atherosclerosis-, PPARs-, lipoprotein receptor, and apolipoprotein-related genes that were affected by the HFHC diet in MCP-3 mice. These findings suggest that aortic MCP-3 overexpression may contribute to the development of atherosclerosis and hepatic steatosis under atherogenic conditions. PMID- 23462016 TI - Lactobacillus plantarum HY7712 ameliorates cyclophosphamide-induced immunosuppression in mice. AB - Lactic acid bacteria (LAB) in fermented foods have attracted considerable attention recently as treatment options for immune diseases, the incidence of which has been increasing worldwide. The ability of 500 strains of LAB, isolated from kimchi, to induce TNF--alpha production in peritoneal macrophages was investigated. Lactobacillus plantarum HY7712 most strongly induced TNF--alpha production as well as NF-kappaB activation. However, HY7712 inhibited NF-kappaB activation in LPS-stimulated peritoneal macrophages. When HY7712 was orally treated in cyclophosphamide (CP)-immunosuppressed mice for 5 or 15 days, it reversed the body and spleen weights, blood RBC and WBC levels, and splenocyte and bone marrow cells that were reduced by CP. Orally administered HY7712 increased concanavalin A-induced T cell proliferation to 84.5% of the normal group on day 15, although treatment with CP alone markedly reduced it to 53.7% of the normal group. Furthermore, orally administered HY7712 significantly induced the expressions of IL-2 and IFN-gamma in ConA-induced splenic cytotoxic T cells of CP-treated mice. Orally administered HY7712 restored the CP-impaired phagocytosis of macrophages in mice. Orally administered HY7712 also restored the cytotoxicity of NK and cytotoxic T cells derived from spleen and bone marrow against YAC-1 in CP-immunosuppressed mice. Based on these findings, orally administered HY7712 may accelerate the recovery of cyclophosphamide-caused immunosuppression, without evident side effects, by immunopotentiating NK and Tc cells, and may provide a mechanistic basis for using HY7712 as an alternative means in lessening chemotherapyinduced immunosuppression in cancer patients. PMID- 23462017 TI - Characterization and zoonotic potential of uropathogenic Escherichia coli isolated from dogs. AB - The aim of this study was to investigate the characteristics of canine uropathogenic Escherichia coli (UPEC) and the interaction between canine UPEC and human bladder epithelial cells. Ten E. coli isolates collected from dogs with cystitis were analyzed for antimicrobial resistance patterns, the presence of virulence factors, and biofilm formation. The ability of these isolates to induce cytotoxicity, invade human bladder epithelial cells, and stimulate an immune response was also determined. We observed a high rate of antimicrobial resistance among canine UPEC isolates. All virulence genes tested (including adhesins, iron acquisition, and protectin), except toxin genes, were detected among the canine UPEC isolates. We found that all isolates showed varying degrees of biofilm formation (mean, 0.26; range, 0.07 to 0.82), using a microtiter plate assay to evaluate biofilm formation by the isolates. Cytotoxicity to human bladder epithelial cells by the canine UPEC isolates increased in a time-dependent manner, with a 56.9% and 36.1% reduction in cell viability compared with the control at 6 and 9 h of incubation, respectively. We found that most canine UPEC isolates were able to invade human bladder epithelial cells. The interaction between these isolates and human bladder epithelial cells strongly induced the production of proinflammatory cytokines such as IL-6 and IL-8. We demonstrated that canine UPEC isolates can interact with human bladder epithelial cells, although the detailed mechanisms remain unknown. The results suggest that canine UPEC isolates, rather than dogspecific pathogens, have zoonotic potential. PMID- 23462018 TI - Gene cloning and characterization of MdeA, a novel multidrug efflux pump in Streptococcus mutans. AB - Multidrug resistance, especially multidrug efflux mechanisms that extrude structurally unrelated cytotoxic compounds from the cell by multidrug transporters, is a serious problem and one of the main reasons for the failure of therapeutic treatment of infections by pathogenic microorganisms as well as of cancer cells. Streptococcus mutans is considered one of the primary causative agents of dental caries and periodontal disease, which comprise the most common oral diseases. A fragment of chromosomal DNA from S. mutans KCTC3065 was cloned using Escherichia coli KAM32 as host cells lacking major multidrug efflux pumps. Although E. coli KAM32 cells were very sensitive to many antimicrobial agents, the transformed cells harboring a recombinant plasmid became resistant to several structurally unrelated antimicrobial agents such as tetracycline, kanamycin, rhodamin 6G, ampicillin, acriflavine, ethidium bromide, and tetraphenylphosphonium chloride. This suggested that the cloned DNA fragment carries a gene encoding a multidrug efflux pump. Among 49 of the multidrug resistant transformants, we report the functional gene cloning and characterization of the function of one multidrug efflux pump, namely MdeA from S. mutans, which was expressed in E. coli KAM32. Judging from the structural and biochemical properties, we concluded that MdeA is the first cloned and characterized multidrug efflux pump using the proton motive force as the energy for efflux drugs. PMID- 23462019 TI - An intersectional approach to social determinants of stress for African American men: men's and women's perspectives. AB - Stress is a key factor that helps explain racial and gender differences in health, but few studies have examined gendered stressors that affect men. This study uses an intersectional approach to examine the sources of stress in African American men's lives from the perspectives of African American men and important women in their lives. Phenomenological analysis was used to examine data from 18 exploratory focus groups with 150 African American men, ages 30 years and older, and eight groups with 77 African American women. The two primary sources of stress identified were seeking to fulfill socially and culturally important gender roles and being an African American man in a racially stratified society. A central focus of African American men's daily lives was trying to navigate chronic stressors at home and at work and a lack of time to fulfill roles and responsibilities in different life domains that are traditionally the responsibility of men. Health was rarely mentioned by men as a source of stress, though women noted that men's aging and weathering bodies were a source of stress for men. Because of the intersection of racism and economic and social stressors, men and women reported that the stress that African American men experienced was shaped by the intersection of race, ethnicity, age, marital status, and other factors that combined in unique ways. The intersection of these identities and characteristics led to stressors that were perceived to be of greater quantity and qualitatively different than the stress experienced by men of other races. PMID- 23462022 TI - Sparse time series chain graphical models for reconstructing genetic networks. AB - We propose a sparse high-dimensional time series chain graphical model for reconstructing genetic networks from gene expression data parametrized by a precision matrix and autoregressive coefficient matrix. We consider the time steps as blocks or chains. The proposed approach explores patterns of contemporaneous and dynamic interactions by efficiently combining Gaussian graphical models and Bayesian dynamic networks. We use penalized likelihood inference with a smoothly clipped absolute deviation penalty to explore the relationships among the observed time course gene expressions. The method is illustrated on simulated data and on real data examples from Arabidopsis thaliana and mammary gland time course microarray gene expressions. PMID- 23462023 TI - Catheter interventions for "double steal" from isolation of the subclavian artery associated with patent arterial duct. AB - Isolation of the subclavian artery is associated with "steal" of blood from the carotid circulation to the arm, through the circle of Willis and the vertebral artery. When associated with a patent arterial duct, there is an additional "steal" of blood from the arm to the lungs, through the arterial duct because of the lower pulmonary vascular resistance. When this combination manifests clinically with arm ischaemia on the side of the isolated subclavian artery, closure of the arterial duct will prevent the "steal" of blood from the subclavian artery to the pulmonary artery and may improve the blood flow to the arm. We report three patients with this unusual combination of the "steal" phenomenon that improved after interventional closure of the arterial duct. This report discusses the embryological basis of the defect, clinical and echocardiographic clues to diagnose this unusual anomaly, angiographic findings, and transcatheter management options. PMID- 23462021 TI - Test for interactions between a genetic marker set and environment in generalized linear models. AB - We consider in this paper testing for interactions between a genetic marker set and an environmental variable. A common practice in studying gene-environment (GE) interactions is to analyze one single-nucleotide polymorphism (SNP) at a time. It is of significant interest to analyze SNPs in a biologically defined set simultaneously, e.g. gene or pathway. In this paper, we first show that if the main effects of multiple SNPs in a set are associated with a disease/trait, the classical single SNP-GE interaction analysis can be biased. We derive the asymptotic bias and study the conditions under which the classical single SNP-GE interaction analysis is unbiased. We further show that, the simple minimum p value-based SNP-set GE analysis, can be biased and have an inflated Type 1 error rate. To overcome these difficulties, we propose a computationally efficient and powerful gene-environment set association test (GESAT) in generalized linear models. Our method tests for SNP-set by environment interactions using a variance component test, and estimates the main SNP effects under the null hypothesis using ridge regression. We evaluate the performance of GESAT using simulation studies, and apply GESAT to data from the Harvard lung cancer genetic study to investigate GE interactions between the SNPs in the 15q24-25.1 region and smoking on lung cancer risk. PMID- 23462024 TI - Anticipating and managing opioid side effects in the elderly. AB - Pain is a common complaint in the elderly, and opioids are useful agents for management of both acute and chronic pain. Opioids are known to cause a variety of adverse effects, and these adverse effects can be particularly problematic for the frail elderly patient and may limit their use. As a result, this can lead to undertreatment of pain and poor patient outcome. Understanding, anticipating, and managing opioid side effects is an important component of care for the elderly patient. PMID- 23462025 TI - Drug-induced rash: nuisance or threat? AB - Drug-induced rash is the most commonly reported drug reaction and occurs in a dizzying array of presentations. Changes in lean and fat body tissue, gastrointestinal acid and mucosal permeability, cardiac output, and renal and hepatic metabolism can affect drug absorption, distribution, metabolism, and elimination. Elders may develop cutaneous eruptions from drugs or biologics and be more sensitive to topical medications. Almost all medications have been associated with rash to some degree. Consultant pharmacists should be able to distinguish between the rashes that are uncomfortable from those that are potentially life-threatening. Some drug therapies tend to induce or aggravate "companion" rashes. With select medications, rash is a clinical indicator that the medication is working. Extensive or unusually painful drug-induced skin conditions are rare, but often require fast action by health care providers to direct the patient to life-saving help. Many of these rashes are associated with high mortality, severe complications, and potential chronic disability. Awareness of the drugs that are most likely to cause a rash can help consultant pharmacists work with the clinical team to arrange appropriate care. PMID- 23462026 TI - Interactive approach by pharmacy students to educate older adults on the safe use of over-the-counter medications. AB - OBJECTIVES: The objective of this study was to evaluate a pharmacy student-led interactive educational program for older adults on the safe use of over-the counter (OTC) medications. METHODS: This was a prospective, interventional study evaluating an educational program covering 12 common OTC topics. Doctor of pharmacy students and a geriatric specialist faculty advisor developed and delivered a 30-minute presentation tailored to older adults, accompanied by various interactive learning methods, including a question and answer session. Following the program, participants completed a questionnaire to address the helpfulness and report intentions of behavior change. RESULTS: A total of 88 individuals attended the presentations, and 64 participants voluntarily completed the anonymous post-program survey; 91.8% of the participants indicated the intervention was either "very helpful" or "moderately helpful." The majority of subjects stated they would make changes to the way they use OTCs (79.3%) and discuss OTC use with their providers (88.3%). The three most beneficial topics included vitamins/minerals, reading a drug label, and sleep medications. CONCLUSION: An interactive educational program on the safe use of OTC medications was helpful and generated positive intentions regarding behavior change in OTC use among older adults. PMID- 23462027 TI - Colchicine-antimicrobial drug interactions: what pharmacists need to know in treating gout. AB - OBJECTIVE: Review the magnitude and clinical relevance of drug-drug interactions between a new formulation of colchicine, used to treat gout, and antibiotics. SETTING AND PRACTICE DESCRIPTION: Relevant to community and institutional pharmacists servicing patients with gout. PRACTICE INNOVATION: Pharmacists have clear roles for the identification of drug-drug interactions, providing recommendations for alternative therapy or dose adjustments/modifications, and monitoring for interactionrelated adverse events. MAIN OUTCOME MEASURES: Colchicine is metabolized via cytochrome P450 3A4 (CYP3A4); therefore, coadministration with agents that inhibit this isoenzyme can produce elevated colchicine plasma concentrations, resulting in severe and sometimes fatal adverse events. Knowledge of the potential for drug-drug interactions involving antibiotics (e.g., macrolide antibiotics, azole antifungals) allows pharmacists to help patients avoid serious adverse events. RESULTS: Pharmacokinetic studies have demonstrated that the maximum plasma concentration (C(max)) and drug exposure (as assessed by area under the plasma concentration time curve [AUC]) of colchicine are increased by 277% and 282%, respectively, after coadministration with clarithromycin. Similarly, coadministration with ketoconazole increases colchicine C(max) and AUC by 102% and 212%, respectively. Other antibiotics that are strong CYP3A4 inhibitors include itraconazole and telithromycin, whereas erythromycin and fluconazole are moderate inhibitors of the isoenzyme CYP3A4. Coadministration of CYP3A4 inhibitors (particularly clarithromycin) and colchicine has resulted in acute colchicine toxicity manifested by severe gastrointestional toxicity, bone marrow suppression, multiorgan failure, and death. CONCLUSION: Pharmacist awareness of potentially clinically significant interactions between colchicine and antibiotics that inhibit CYP3A4 can help to ensure the efficacy of colchicine is realized while mitigating serious toxicities and minimizing the risk of adverse events. PMID- 23462028 TI - Charles bonnet syndrome: treating nonpsychiatric hallucinations. AB - Charles Bonnet syndrome (CBS) is characterized by recurrent or persistent complex visual hallucinations that occur in visually impaired individuals with intact cognition and no evidence of psychiatric illness. Patients usually retain insight into the unreal nature of their hallucinations.3,4 CBS is often misdiagnosed, and predominantly affects elderly patients with vision changes (e.g., age-related macular degeneration, glaucoma, and cataract). While many require only the assurance of the benign nature of the hallucinations, nonpharmacological and pharmacological interventions have been reported to be useful in the treatment of CBS. This case involves an 83-year-old female, with a two-year history of CBS, who presented to the clinic with worsening visual hallucinations over the past few months. She was starting to lose insight into her hallucinations secondary to her new diagnosis of dementia. Several pharmacological agents were explored to determine the most appropriate choice for our patient. Ultimately, this patient was started on donepezil (reported to be successful in a CBS case report), which helped improve her cognitive function. At future follow-up visits, her hallucinations improved and her cognitive function stabilized. Pharmacists should be aware of CBS and its treatment options to properly assist physicians in the medication-selection process to alleviate distress experienced by patients with CBS. In patients who may benefit from pharmacological treatment, physicians should weigh the risks and benefits of the different treatment options. Donepezil can be a favorable option in CBS patients with Alzheimer's type dementia. PMID- 23462029 TI - Factors influencing the 99th percentile of cardiac troponin I evaluated in community-dwelling individuals at 70 and 75 years of age. AB - BACKGROUND: We aimed to investigate the effects of sex, prevalent cardiovascular disease (CVD), and aging on the 99th percentile of cardiac troponin I (cTnI). METHODS: cTnI was measured using a high-sensitivity assay (Abbott Diagnostics) in 814 community-dwelling individuals at both 70 and 75 years of age. We determined the cTnI 99th percentiles separately using nonparametric methods in the total sample, in men and women, and in individuals with and without CVD. RESULTS: The cTnI 99th percentile at baseline was 55.2 ng/L for the total cohort. Higher 99th percentiles were noted in men (69.3 ng/L) and individuals with CVD (74.5 ng/L). The cTnI 99th percentile in individuals free from CVD at baseline (n = 498) increased by 51% from 38.4 to 58.0 ng/L during the 5-year observation period. Relative increases ranging from 44% to 83% were noted across all subgroups. Male sex [odds ratio, 5.3 (95% CI, 1.5-18.3)], log-transformed N-terminal pro-B-type natriuretic peptide [odds ratio, 1.9 (95% CI, 1.2-3.0)], and left-ventricular mass index [odds ratio, 1.3 (95% CI, 1.1-1.5)] predicted increases in cTnI concentrations from below the 99th percentile (i.e., 38.4 ng/L) at baseline to concentrations above the 99th percentile at the age of 75 years. CONCLUSIONS: cTnI concentration and its 99th percentile threshold depend strongly on the characteristics of the population being assessed. Among elderly community dwellers, higher concentrations were seen in men and individuals with prevalent CVD. Aging contributes to increasing concentrations, given the pronounced changes seen with increasing age across all subgroups. These findings should be taken into consideration when applying cTnI decision thresholds in clinical settings. PMID- 23462030 TI - MicroRNA Involvement in Human Cancers. PMID- 23462031 TI - More questions than answers in Mid Staffs mortality investigation. PMID- 23462032 TI - Pandemic response in low-resource settings requires effective syndromic surveillance. PMID- 23462033 TI - [Rigid endoscopes for esophagoscopy is no longer indicated]. PMID- 23462034 TI - [Foreign body impactions can be a mouthful]. PMID- 23462035 TI - [Treatment of foreign body impactions in oesophagus]. AB - Foreign body impactions in oesophagus occur frequently. The causes are oesophageal pathology (anatomical, functional or inflammatory diseases). X-ray may be performed to determine the diagnosis or suspected perforation. Treatment can be conservative with carbonated drinks and observation for up to 24 hours, as up to two thirds of the impactions pass spontaneously. There is no evidence for medical treatment with buscopane, diazepam or glucagone. Emergent endoscopy is performed at risk of perforation by erosive or sharp objects, by obstruction over 24 hours, at risk of aspiration and complete obstruction. PMID- 23462036 TI - [Interpretation in the Danish health-care system]. AB - Communication between health professional and patient is central for treatment and patient safety in the health-care system. This systematic review examines the last ten years of specialist literature concerning interpretation in the Danish health-care system. Structural search in two databases, screening of references and recommended literature from two scientists led to identification of seven relevant articles. The review showed that professional interpreters were not used consistently when needed. Family members were also used as interpreters. These results were supported by international investigations. PMID- 23462037 TI - [Sparse effect of long-term treatment with macrolides in patients with chronic obstructive pulmonary disease]. AB - Macrolides have been proposed to have a positive effect in patients with inflammatory lung diseases, including patients with chronic obstructive pulmonary disease (COPD), who suffer from acute exacerbations. Increased use of macrolides for long-term treatment of patients with COPD has been observed. The evidence of a treatment effect of macrolides in this area is sparse, but some studies suggest that it might be beneficial on the number of exacerbations and the length between them. At present there is not sufficient evidence to issue a general recommendation for prescribing macrolides for the long-term treatment of COPD. PMID- 23462038 TI - [Psoriasis is associated with type 2 diabetes]. AB - Psoriasis is a chronic inflammatory skin disease with a global prevalence of 2 3%. In recent years it has been established that patients with psoriasis carry an increased risk of type 2 diabetes, but the underlying pathophysiological mechanisms remain unclear. The association is most likely due to a combination of shared genes, immunoinflammatory mechanisms and a number of diabetes risk factors in patients with psoriasis. The current review summarises the evidence in the field and calls for attention on diabetes risk assessment, preventive measures and treatment in patients with psoriasis. PMID- 23462039 TI - [Seminoma metastasis in the small bowel]. AB - Approximately 95% of testicular cancers are germ-cell tumours and these are divided into non-seminoma and pure seminoma. They rarely metastasize to the gastrointestinal tract (< 5%) and pure seminoma are the least likely to do so with an incidence of < 1%. We describe an unusual case of a 67-year-old man, who presented with gastrointestinal complaints, the first symptoms of testicular seminoma being a small bowel metastasis. The patient had a palpable testicular mass which was not detected until after the tumour in the small bowel had been resected and histology revealed metastasis from a seminoma. PMID- 23462040 TI - [Idiopathic intracranial hypertension is a rare cause of headache in children]. AB - Idiopathic intracranial hypertension is often believed to be an illness exclusively occurring in obese women in their twenties and thirties. This case describes a four-year-old boy presenting with headache, vomiting photophobia and double vision for six days. He did not have a fever; and all exams and tests, including a magnetic resonance imaging of the brain showed normal values. During the eye examination, he was found to have bilateral papilloedema and when undergoing lumbar puncture an elevated pressure of 230 mm H(2)O was discovered. The patient was diagnosed with idiopathic intracranial hypertension and treated with azetazolamide. Within few days, his symptoms disappeared. PMID- 23462041 TI - [Lipoma as the cause of intussusception of the rectum in a 46-year-old woman]. AB - We present a case with a 46-year-old woman who had experienced six days of abdominal pain and some days of anal bleeding. She had no prior medical history. At the clinical examination it was found that she had a soft abdomen, but there was tenderness in the lower part. A computed tomography showed an intussusception of the sigmoideum into the rectum. An oncological resection was performed, since it could not at the time of the operation be determined if it was a malignant proces. The histology showed a benign submucosal lipoma. PMID- 23462042 TI - [Pancreatic pseudocyst as a differential diagnosis to dissections aortic aneyrism]. AB - Pancreatic pseudocyst, a common complication of acute or chronic pancreatitis, can be an important differential diagnosis to aorta aneurism. A 46-year-old man under investigation for lung cancer presented with chest pain, dysphagia and dyspnoea. A chest X-ray showed opacity in the mediastinum opposite aorta. A computed tomography revealed a pseudocyst extending from the body of pancreas into the thorax. A mediastinal pseudocyst can cause symptoms due to compression or invasion of surrounding structures. The pseudocyst was successfully treated using endoscopic ultrasound guided transgastric drainage. PMID- 23462043 TI - [A solitary neurofibroma in the parotid gland from nervus vagus]. AB - A 37-year-old male, without stigmata of neurofibromatosis type 1, developed a firm mass below the right ear over several months without facial palsy. Clinical examination and ultra-sonography revealed a tumour in the parotid gland. Fine needle aspirationbiopsy was inconclusive. During complete resection, the tumour revealed an unusual anatomic location from the superficial lobe of the parotid to the deep and further into the parapharyngeal space. The pathological examination showed a solitary neurofibroma. In this case report, preoperative diagnosis, therapy and follow-up of this rare tumour in the parotid gland from n. vagus are discussed. PMID- 23462044 TI - Predicting quality of work life on nurses' intention to leave. AB - PURPOSE: The purpose of this study was to explore the relationship between quality of work life (QWL) and nurses' intention to leave their organization (ITLorg). DESIGN: A descriptive cross-sectional survey design was conducted using purposive sampling of 1,283 nurses at seven hospitals in Taiwan. Data were collected from March to June 2012. METHODS: Three questionnaires, including the Chinese version of the Quality of Nursing Work Life scale (C-QNWL), a questionnaire of intention to leave the organization, and a demographic questionnaire, with two informed consent forms were delivered to the nurses at their workplaces. Descriptive data, Pearson's correlations, and the ordinal regression model were analyzed. FINDINGS: Over half (52.5%) of nurses had ITLorg. Seven QWL dimensions were significantly negatively correlated with ITLorg (r = 0.17 to -0.37, p < .01). Significant predictors (p < .05) of ITLorg (the pseudo R(2) = 0.282) were being single, having a diploma or lower educational level, working in a nonteaching hospital. Four of the QWL dimensions--supportive milieu with job security and professional recognition, work arrangement and workload, work or home life balance, and nursing staffing and patient care--were also predictors of ITLorg. Three QWL dimensions were not predictors of ITLorg. CONCLUSIONS: This study showed that individual-related variables (being single, having a diploma or lower educational level), a work-related variable (working at a nonteaching hospital), and the four QWL dimensions play a significant role in nurses' ITLorg. After the QWL dimensions were added to the regression, the variance explained by the model more than doubled. CLINICAL RELEVANCE: To reduce nurses' ITLorg, nursing administrators may offer more focused interventions to improve the supportive milieu with job security and professional recognition, work arrangement and workload, work or home life balance, and nursing staffing and patient care. PMID- 23462045 TI - The injury burden of the 2010 Haiti earthquake: a stratified cluster survey. AB - INTRODUCTION: On January 12, 2010, a 7.0 magnitude earthquake devastated metropolitan Port au Prince and surrounding areas and resulted in widespread injury, mortality and displacement. This study aimed to estimate the injury rate among the affected population and the resulting demand of emergency medical care in the aftermath of the earthquake. METHODS: In January 2011, a cross-sectional stratified cluster (60*20 household) survey of the earthquake-affected population in metropolitan Port au Prince was conducted to assess their well-being, unmet needs and perceptions of humanitarian assistance one year post-earthquake. Mixed effects simple and multiple logistic regressions were used to measure the total unadjusted and adjusted odds of injury. RESULTS: A total of 261 injuries were reported in the pre-earthquake population of 6489 individuals with reported injury status. The overall earthquake injury rate was estimated at 40.2 injuries/1000 (CI: 35.6-45.3). Individual characteristics such as age, gender, and education status were not significantly associated with risk of injury. Elevated injury rates were observed among households residing in camps at 46.7/1000 (CI: 39.7-54.5) as compared to those in neighbourhoods where the injury rate was 33.7/1000 (CI: 27.8-40.5) (p=0.018). Extrapolation of the survey injury rate to the affected population yields an estimated 124,577 earthquake injuries (range 110,048-140,033) which is substantially lower than the 300,000 reported injuries. CONCLUSIONS: Estimates of the injury burden in disasters in lower- and middle-income countries is essential for disaster preparedness and response planning in future natural disasters. Given the difficulties in reporting injuries in emergencies, including both challenges of aggregating information and lack of standardized definitions and inclusion/exclusion criteria for injuries that are not severe, ascertaining the injury burden of disasters will be a persistent challenge. PMID- 23462046 TI - Computerized prescriber order entry and opportunities for medication errors: comparison to tradition paper-based order entry. AB - PURPOSE: Predefined error opportunity categories were used as a surrogate for medication errors to assess the impact of computerized prescriber order entry (CPOE) on the potential for error in the prescribing and order entry phases of the medication-use process. METHODS: This study was performed in a neonatal intensive care unit at a 535-bed tertiary care center. Pre- and post-CPOE implementation incidence of error opportunity was compared by evaluating 500 orders before and after implementation using 18 predefined criteria. RESULTS: A total of 14 913 opportunities for error (OE) existed in our sample of 1000 medication orders. The number of orders with zero OE improved from 42% (n = 209) to 98% (n = 480; P < .0001), in the pre- and postgroups, respectively. The odds ratio with 95% confidence interval was 0.058 (0.036-0.094) in favor of CPOE. CONCLUSIONS: The implementation of CPOE was associated with a reduction in OEs in the prescribing phase or order entry phase of the medication-use process. PMID- 23462047 TI - Acetabular osteoid osteoma excision by controlled hip dislocation: a case report. AB - Osteoid osteoma of the acetabulum is rare and its treatment represents a challenge for the orthopedic surgeon. We report a case of a 12-year-old boy with osteoid osteoma in the acetabulum who was treated with a controlled hip dislocation and a gamma probe guide to facilitate excision. The diagnosis was confirmed by pathology. The patient was asymptomatic immediately after surgery and remained so at long-term follow-up. PMID- 23462049 TI - Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment. AB - Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [(3)H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [(3)H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n = 6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium- and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex. PMID- 23462048 TI - Abnormal N-linked glycosylation of cortical AMPA receptor subunits in schizophrenia. AB - Numerous studies have demonstrated brain region- and subunit-specific abnormalities in the expression of subunits of the AMPA subtype of glutamate receptors in schizophrenia. In addition, abnormalities in the expression of proteins that regulate the forward trafficking of AMPA receptors through the cell have been reported. These findings suggest abnormal trafficking of AMPA receptors as a mechanism underlying dysregulated glutamate neurotransmission in schizophrenia. AMPA receptor subunits (GluR1-4) assemble to form AMPA receptor complexes in the lumen of the endoplasmic reticulum (ER). These subunits undergo the posttranslational modification of N-linked glycosylation in the ER and the Golgi apparatus before the assembled receptors are transported to the plasma membrane. In this study, we measured expression of AMPA receptors and the extent of their N-glycosylation using Western blot analysis in the dorsolateral prefrontal cortex in subjects with schizophrenia (N = 35) and a comparison group (N = 31). N-glycosylation was assessed using molecular mass shift assays following digestion with endoglycosidase H (Endo H), which removes immature high mannose-containing sugars, and with peptide-N-glycosidase F (PNGase F), which removes all N-linked sugars. Of the four AMPA receptor subunits, only GluR4 was significantly increased in schizophrenia. GluR2 and GluR4 were both sensitive to Endo H and PNGase F treatment. Endo H-mediated deglycosylation of GluR2 resulted in a significantly smaller pool of GluR2 protein to shift in schizophrenia, reflecting less N-linked high mannose and/or hybrid sugars on the GluR2 protein in this illness. This was confirmed by immunoisolation of GluR2 and probing with Concanavalin A, a mannose specific lectin; in subjects with schizophrenia GluR2 was significantly less reactive to Concanavalin A. Altered N-linked glycosylation of the GluR2 subunit in schizophrenia suggests abnormal trafficking of AMPA receptors from the ER to the synaptic membrane in schizophrenia. PMID- 23462050 TI - Plasmacytoid dendritic cells: key players in viral infections and autoimmune diseases. AB - OBJECTIVE: Describe the main activation and inhibitory pathways and receptors by which pDC regulate type I interferon secretion, as well as its association with autoimmune pathology. METHODS: A PubMed search for articles was conducted using the following key words: plasmacytoid dendritic cells, autoimmune diseases, viral infections and type I interferon. The search was limited to publications in English and from 1957 to 2012. Sixty-five of these articles are included in this review. The most relevant primary research articles identified were critically evaluated and compiled together. Particularly, areas of consensus and controversy were identified and analyzed. RESULTS: Plasmacytoid dendritic cells have been closely related to viral infections and autoimmune disease, mainly because of these immune cells are able to secrete large amounts of type I interferon. This function is linked with their expression of Toll-like receptors, specially TLR7 and TLR9, which are designed to sense nucleic acids in the early endosomes. Activated pDC can promote immunity and autoimmunity, however, the exact mechanisms by which pDC promote one vs. the other are not well understood. CONCLUSIONS: Plasmacytoid dendritic cells play a key role in both, immunity and autoimmunity. Current evidence suggests that the sustained overproduction of type I interferon drives aberrant immune responses and the development of autoimmune pathology. PMID- 23462051 TI - The half-life of guidelines for Waldenstrom's macroglobulinaemia; short stickiness for a sticky disease? PMID- 23462052 TI - Guideline for diagnosis and treatment of Waldenstrom's macroglobulinaemia. AB - On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenstrom's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012. PMID- 23462053 TI - Chocolate/cocoa and human health: a review. AB - Chocolate/cocoa has been known for its good taste and proposed health effects for centuries. Earlier, chocolate used to be criticised for its fat content and its consumption was a sin rather than a remedy, associated with acne, caries, obesity, high blood pressure, coronary artery disease and diabetes. Therefore, many physicians tended to warn patients about the potential health hazards of consuming large amounts of chocolate. However, the recent discovery of biologically active phenolic compounds in cocoa has changed this perception and stimulated research on its effects in ageing, oxidative stress, blood pressure regulation, and atherosclerosis. Today, chocolate is lauded for its tremendous antioxidant potential. However, in many studies, contradictory results and concerns about methodological issues have made it hard for health professionals and the public to understand the available evidence on chocolate's effects on health. The purpose of this review is to interpret research done in the last decade on the benefits and risks of chocolate consumption. PMID- 23462054 TI - MiRNA s in oesophageal squamous cancer. AB - Oesophageal cancer is a common cancer worldwide with a very poor prognosis. Oesophageal squamous cell carcinoma (OSCC) is the major subtype of oesophageal cancer but also one of the least studied cancers worldwide. Although the molecular genetics of OSCC have been widely studied, the molecular mechanism of OSCC carcinogenesis is not completely understood. MicroRNA (miRNA) is now essential to understanding the molecular mechanism of cancer progression. Recent findings include the following: 1) recent findings regarding the functions of miRNA; 2) some of the latest findings on expression profile of miRNA involved in OSCC; 3) miRNAs and their target genes and molecular mechanisms in OSCC; and 4) the therapeutic-clinical potential of miRNAs in OSCC. We can make full use of this knowledge to guide us to evaluate and improve the patient's condition and choose the most fitting medical treatment or explore new approaches to improve the survival ratio of OSCC patients. PMID- 23462055 TI - Educational disparities in mortality among patients with type 2 diabetes in The Netherlands (ZODIAC-23). AB - BACKGROUND: Relative mortality differences between educational level in mortality have been reported among diabetic as well as among non-diabetic subjects in Europe, but data on absolute differences are lacking. We studied the effect of educational disparities on mortality in a Dutch prospective cohort of type 2 diabetes mellitus (T2DM) patients. METHODS: This study was part of the ZODIAC study, a prospective observational study of patients with T2DM. Data on educational level were first collected on 19 May 1998, and from this date on, 858 patients were included in 1998; educational level was known for 656 patients. Vital status was assessed in 2009. The relationship between mortality and educational level was studied using a Cox proportional hazard model, the relative index of inequality (RII), slope index of inequality (SII) and the population attributable risk (PAR). Educational level was divided into four categories; the highest educational level was used as reference. RESULTS: After a median follow up time of 9.7 years, 365 out of 858 patients had died. The hazard ratio of primary education for total mortality was 3.02 (95% CI 1.44-6.34). The RII was 2.85 (95% CI 1.21-6.67), the absolute difference in the risk for mortality (SII) was 384 deaths (95% CI 49-719) per 10,000 follow-up years. PAR for patients with the lowest level of education was 51.4%. CONCLUSIONS: A low educational level had a higher impact on mortality than having a macrovascular complication. Given the substantial differences in mortality between educational levels in T2DM, more understanding of underlying (modifiable) mechanisms is necessary. PMID- 23462056 TI - Unresectable pancreatic tumour? The issue is tissue. AB - The majority of tumours in the pancreas are adenocarcinomas for which therapeutic options are limited and which are associated with an unsatisfactory prognosis. However, alternative diagnoses may result in other therapeutic approaches with often a more favourable outcome. Hence, it is crucial to obtain a histological diagnosis before a definitive therapeutic plan can be devised. In this manuscript, a small series of pancreatic tumours other than adenocarcinoma are described. PMID- 23462057 TI - Acute left-sided abdominal pain. PMID- 23462058 TI - What's crawling in this sputum? PMID- 23462059 TI - A large soft tissue mass of the chest wall. PMID- 23462060 TI - A survey on diagnostic methods and treatment strategies used in patients with Waldenstrom's macroglobulinaemia in The Netherlands. AB - BACKGROUND: Waldenstrom's macroglobulinaemia (WM) is defined as a lymphoplasmacytic lymphoma primarily located in the bone marrow, accompanied by an immunoglobulin M (IgM) monoclonal protein in the serum. The symptoms are highly variable, which can sometimes lead to a diagnostic delay. Currently, there is a wide range of therapeutic options used for the management of WM but no approved therapeutic agents are available specifically for this disease. METHODS: An online survey was prepared and sent out to haematologists and haemato oncologists in The Netherlands, together with an invitational letter to participate. Information was gathered about the preferred methods of diagnosing and treating patients with WM in general, and about the last WM patient diagnosed in their department. RESULTS: 83 (31.8%) responses were obtained, out of which 68 (81.9%) contained responses to all three parts of the survey. The respondents most commonly used either rituximab-CVP or chlorambucil as first-line treatment, whereas rituximab in combination with purine analogues was the most frequently applied second-line treatment. The prevention of an IgM 'flare' was managed by the respondents in various ways, and rituximab maintenance treatment was not commonly used. CONCLUSION: This survey indicates that in general the diagnostic methods and treatment options for WM are well known to a representative number of Dutch haematologists. The areas of uncertainty are knowledge about asymptomatic vs symptomatic disease, risk of hyperviscosity in relation to IgM level, and the occurrence and prevention of an IgM 'flare'. These issues should be addressed in clinical research and guidelines to improve care for WM patients in The Netherlands. PMID- 23462061 TI - The prevention of contrast-induced nephropathy in Dutch hospitals. PMID- 23462062 TI - Acute groove pancreatitis due to isoniazid. PMID- 23462063 TI - Assessment of reverse flow as a means of cerebral protection during carotid artery stent placement with diffusion-weighted and transcranial Doppler imaging. AB - PURPOSE: To assess the effectiveness of flow reversal as an alternative means of cerebral protection by using transcranial Doppler recordings and diffusion weighted imaging (DWI) as surrogate markers of brain injury. MATERIALS AND METHODS: Eighteen patients with symptomatic carotid artery disease were recruited. Magnetic resonance imaging was performed before the intervention and at 3 and 24 hours and 30 days after the intervention to detect new ischemic lesions with DWI. Transcranial Doppler recordings were made during the procedure to assess for microembolic signals (MESs). Data were compared against data from a historical control cohort of patients who underwent CAS placement with or without filter protection (n = 15 each) under the same protocol in a different study. RESULTS: There were fewer periprocedural new lesions on DWI in the reverse-flow cohort compared with the historical control cohort with filter protection (P = .084). Reverse flow revealed significantly fewer MESs during the whole procedure compared with the filter-protected group (P = .01) but not the unprotected group (P = .55). There was a marked decrease in MES counts for reverse flow protection during the embologenic stages of the procedure (P = .004). CONCLUSIONS: Use of the reverse flow device was associated with fewer overall lesions on DWI and proportionately fewer positive scans compared with the use of filter-type devices (P = .08, not significant). Transcranial Doppler recordings demonstrated a significant reduction in embolization to the brain during carotid artery stent placement with the use of reverse-flow cerebral protection. PMID- 23462064 TI - Quantification and reduction of reflux during embolotherapy using an antireflux catheter and tantalum microspheres: ex vivo analysis. AB - PURPOSE: To demonstrate in a porcine model that reflux during embolotherapy can be relatively quantified (ie, as embolization efficiency) and that nontarget embolization can be eliminated by using an antireflux microcatheter. MATERIALS AND METHODS: Renal artery embolization was performed with radiopaque tantalum microspheres (concentration of 1 g/20 mL) in three swine. Second-order right renal arteries (n = 3) underwent embolization with a 3-F antireflux catheter, and second-order left renal arteries (n = 3) underwent embolization with a 4-F end hole catheter as a control. After embolization, kidneys were explanted and underwent micro-computed tomographic (microCT) imaging. Three-dimensional volumetric and multiplanar imaging of the kidneys was performed to assess vascular distribution. Digital Imaging and Communications in Medicine data were analyzed, with a threshold algorithm used to create binary images. The number of positive values in a region of interest in the target embolized tissue (upper pole or lower pole) and the nontarget adjacent tissue was determined, and embolization efficiency was calculated. Wilcoxon rank-sum statistical analysis was performed to compare nontarget embolization between infusion catheters. RESULTS: All renal arteries underwent successful embolization with tantalum microspheres, with 20 mL (1 g) administered in all dose deliveries. MicroCT provided high-resolution visualization of the renal parenchyma at 70-MUm resolution. In control renal arteries, a standard 4-F end-hole catheter had an embolization efficiency of 72%+/- 13. In experimental renal arteries, the antireflux microcatheter had an embolization efficiency of 99.9%+/- 1.0 (P< . 05). CONCLUSIONS: A significant decrease in nontarget embolization (ie, reduction in reflux) was possible with an antireflux microcatheter compared with a conventional end-hole catheter. PMID- 23462065 TI - Caval penetration by retrievable inferior vena cava filters: a retrospective comparison of Option and Gunther Tulip filters. AB - PURPOSE: To compare the frequency of vena caval penetration by the struts of the Option and Gunther Tulip cone filters on postplacement computed tomography (CT) imaging. MATERIALS AND METHODS: All patients who had an Option or Gunther Tulip inferior vena cava (IVC) filter placed between January 2010 and May 2012 were identified retrospectively from medical records. Of the 208 IVC filters placed, the positions of 58 devices (21 Option filters, 37 Gunther Tulip filters [GTFs]) were documented on follow-up CT examinations obtained for reasons unrelated to filter placement. In cases when multiple CT studies were obtained after placement, each study was reviewed, for a total of 80 examinations. Images were assessed for evidence of caval wall penetration by filter components, noting the number of penetrating struts and any effect on pericaval tissues. RESULTS: Penetration of at least one strut was observed in 17% of all filters imaged by CT between 1 and 447 days following placement. Although there was no significant difference in the overall prevalence of penetration when comparing the Option filter and GTF (Option, 10%; GTF, 22%), only GTFs showed time-dependent penetration, with penetration becoming more likely after prolonged indwelling times. No patient had damage to pericaval tissues or documented symptoms attributed to penetration. CONCLUSIONS: Although the Gunther Tulip and Option filters exhibit caval penetration at CT imaging, only the GTF exhibits progressive penetration over time. PMID- 23462066 TI - Cost and effectiveness of radiofrequency ablation versus limited surgical resection for stage I non-small-cell lung cancer in elderly patients: is less more? AB - PURPOSE: To retrospectively evaluate cost and mortality in 84 patients older than 65 years of age with stage IA or IB non-small-cell lung cancer treated with radiofrequency (RF) ablation or limited surgical resection (ie, wedge resection or segmentectomy) from the perspective of the payer, Medicare. MATERIALS AND METHODS: From August 2000 to November 2009, 56 patients were treated with RF ablation and 28 with surgery who met the inclusion criteria. Patient health histories and billing charges from initial treatment to the study endpoint were collected. Charges were converted to 2009 Medicare reimbursement fees and cumulated by month. Time-event data were analyzed by using the Kaplan-Meier method. Survival functions and median survival estimates were reported with standard errors. Patient cohorts' survival functions were compared based on the Wilcoxon weighted chi(2) statistic. RESULTS: Group demographics were comparable with the exception of age, with patients treated with RF ablation an average of 4 years older (95% confidence interval, 0.85-6.76). The overall mortality rate was lower in patients treated with surgery than in those treated with RF ablation (chi(2) = 8.0225, P = .0046), with a median cost per month lived for RF ablation recipients of $620.74, versus $1,195.92 for those treated with surgery (P = .0002, Wilcoxon rank-sum test). CONCLUSIONS: Patients treated with surgery showed a significant increase in survival; however, those treated with RF ablation were significantly older. For patients who are not surgical candidates, RF ablation provides an alternative treatment option at a significantly lower cost. PMID- 23462067 TI - Percutaneous interventions on the hemodialysis reliable outflow vascular access device. AB - PURPOSE: To determine the outcomes of percutaneous interventions for prolonging the patency of the Hemodialysis Reliable Outflow (HeRO) device. MATERIALS AND METHODS: Between January 2007 and August 2011, 73 percutaneous interventions were performed on 26 HeRO devices in 25 patients. The graft was implanted in the upper arm with the outflow catheter tip in the superior vena cava or right atrium. Procedural reports, angiographic images, and clinical notes were retrospectively reviewed. The primary and secondary patency rates after intervention were calculated using the Kaplan-Meier method. RESULTS: The mean time from HeRO implantation to initial dysfunction or thrombosis was 171 days. In 60 (82%) procedures, the HeRO device was thrombosed. An intragraft stenosis was the most common lesion identified (59%; n = 43) followed by an arterial anastomosis stenosis identified in 18% (n = 13). In 22% (n = 16) of procedures in which the HeRO device was thrombosed, an underlying cause was not identified after thrombectomy. The 3-, 6-, and 12-month primary patency rates after intervention were 47%, 37%, and 26% for first-time interventions. The secondary patency rates were 80%, 70%, and 64%. The only complication was pulmonary embolism resulting in death 2 days after HeRO thrombectomy. CONCLUSIONS: Percutaneous interventions on thrombosed and failing HeRO devices yielded acceptable primary and secondary patency rates after intervention in these patients with few, if any, alternatives for hemodialysis access. PMID- 23462068 TI - Diastolic dysfunction measured by tissue Doppler imaging in children with end stage renal disease: a report of the RICH-Q study. AB - INTRODUCTION: Early detection of cardiovascular disease in children with end stage renal disease is essential in order to prevent cardiovascular morbidity and mortality in early adulthood. Tissue Doppler imaging has shown to be a promising method to detect and quantify subtle abnormalities in diastolic function. We therefore compared assessment of diastolic function by conventional echocardiography and tissue Doppler imaging. METHODS: We performed conventional echocardiography and tissue Doppler imaging in 38 children with end-stage renal disease and 76 healthy controls. We compared outcomes on parameters related to diastolic function (E/a ratio for conventional echocardiography and E/E' ratio for tissue Doppler imaging) for both groups using multiple linear regression analysis. Diastolic dysfunction was defined as E/a ratio <1 or E/E' ratio > 95th percentile for age. To assess the intra-observer reproducibility, the coefficient of variation was calculated. RESULTS: Children with end-stage renal disease had on average a lower E/a ratio (p = 0.004) and a higher mitral and septal E/E' ratio (both p < 0.001) compared with controls. In all, two children with end stage renal disease (5%) had diastolic dysfunction according to the E/a ratio, 11 according to the mitral E/E' ratio (29%), and 16 according to the septal E/E' ratio (42%) compared with none of the controls (p = 0.109, p < 0.001, and p < 0.001, respectively). The coefficients of variation of the mitral (7%) and septal E/E' ratio (4%) were smaller than the coefficient of variation of the E/a ratio (11%). CONCLUSIONS: Tissue Doppler imaging is a more sensitive and reliable method to detect diastolic dysfunction than conventional E/a ratio in children with end-stage renal disease. PMID- 23462069 TI - Deformed knowledge. PMID- 23462070 TI - Narrative medicine as a means of training medical students toward residency competencies. AB - OBJECTIVE: This study sought to explore the perceived influence of narrative medicine training on clinical skill development of fourth-year medical students, focusing on competencies mandated by ACGME and the RCPSC in areas of communication, collaboration, and professionalism. METHODS: Using grounded theory, three methods of data collection were used to query twelve medical students participating in a one-month narrative medicine elective regarding the process of training and the influence on clinical skills. Iterative thematic analysis and data triangulation occurred. RESULTS: Response rate was 91% (survey), 50% (focus group) and 25% (follow-up). Five major findings emerged. Students perceive that they: develop and improve specific communication skills; enhance their capacity to collaborate, empathize, and be patient-centered; develop personally and professionally through reflection. They report that the pedagogical approach used in narrative training is critical to its dividends but misunderstood and perceived as counter-culture. CONCLUSION/PRACTICE IMPLICATIONS: Participating medical students reported that they perceived narrative medicine to be an important, effective, but counter-culture means of enhancing communication, collaboration, and professional development. The authors contend that these skills are integral to medical practice, consistent with core competencies mandated by the ACGME/RCPSC, and difficult to teach. Future research must explore sequelae of training on actual clinical performance. PMID- 23462071 TI - Toxocara-induced hepatic inflammation: immunohistochemical characterization of lymphocyte subpopulations and Bcl-2 expression. AB - Toxocariasis is a soil-transmitted helminthic disease due to infection of humans by larvae of Toxocara canis (T. canis). It is one of the most commonly reported zoonotic infections in the world. The aim of this study was to characterize the key immune cells and activity of Bcl-2 in hepatic inflammation during the course of experimental infection by T. canis. Mice experimentally infected with T. canis were divided into two groups: mice with primary infection by Toxocara, and those infected after sensitization by Toxocara excretory-secretory antigen. CD4+, CD8+, and Bcl-2-expressing T lymphocytes were identified in the liver by immunohistochemistry at different durations post-infection. Recruitment of both CD4+ and CD8+ T lymphocytes within the inflammatory reaction in the liver was observed, with difference in count and localization. These cells were detected within and around Toxocara-induced granulomas as well as in isolated inflammatory foci in the portal tracts or within the hepatic parenchyma. The antiapoptotic protein Bcl-2 showed no significant change at different periods post-infection. On the other hand, immunization of mice with Toxocara excretory-secretory antigen prior to experimental infection caused earlier and more pronounced recruitment of CD4+ and CD8+ T cells to the liver and enhanced expression of Bcl-2. Moreover, CD8+ cells became more diffuse within the inflammatory infiltrate. These results suggest a dynamic change in key immune cells according to the duration of infection as well as the immune status of the host. PMID- 23462072 TI - Recruitment to online therapies for depression: pilot cluster randomized controlled trial. AB - BACKGROUND: Raising awareness of online cognitive behavioral therapy (CBT) could benefit many people with depression, but we do not know how purchasing online advertising compares to placing free links from relevant local websites in increasing uptake. OBJECTIVE: To pilot a cluster randomized controlled trial (RCT) comparing purchase of Google AdWords with placing free website links in raising awareness of online CBT resources for depression in order to better understand research design issues. METHODS: We compared two online interventions with a control without intervention. The pilot RCT had 4 arms, each with 4 British postcode areas: (A) geographically targeted AdWords, (B) adverts placed on local websites by contacting website owners and requesting links be added, (C) both interventions, (D) control. Participants were directed to our research project website linking to two freely available online CBT resource sites (Moodgym and Living Life To The Full (LLTTF)) and two other depression support sites. We used data from (1) AdWords, (2) Google Analytics for our project website and for LLTTF, and (3) research project website. We compared two outcomes: (1) numbers with depression accessing the research project website, and then chose an onward link to one of the two CBT websites, and (2) numbers registering with LLTTF. We documented costs, and explored intervention and assessment methods to make general recommendations to inform researchers aiming to use similar methodologies in future studies. RESULTS: Trying to place local website links appeared much less cost effective than AdWords and although may prove useful for service delivery, was not worth pursuing in the context of the current study design. Our AdWords intervention was effective in recruiting people to the project website but our location targeting "leaked" and was not as geographically specific as claimed. The impact on online CBT was also diluted by offering participants other choices of destinations. Measuring the impact on LLTTF use was difficult as the total number using LLTTF was less than 5% of all users and record linkage across websites was impossible. Confounding activity may have resulted in some increase in registrations in the control arm. CONCLUSIONS: Practitioners should consider online advertising to increase uptake of online therapy but need to check its additional value. A cluster RCT using location targeted adverts is feasible and this research design provides the best evidence of cost-effectiveness. Although our British pilot study is limited to online CBT for depression, a cluster RCT with similar design would be appropriate for other online treatments and countries and our recommendations may apply. They include ways of dealing with possible contamination (buffer zones and AdWords techniques), confounding factors (large number of clusters), advertising dose (in proportion to total number of users), record linkage (landing within target website), and length of study (4-6 months). TRIAL REGISTRATION: clinicaltrials.gov (Registration No. NCT01469689); http://clinicaltrials.gov/ct2/show/NCT01469689 (Archived by WebCite at http://www.webcitation.org/6EtTthDOp). PMID- 23462073 TI - FDA-iRISK--a comparative risk assessment system for evaluating and ranking food hazard pairs: case studies on microbial hazards. AB - Stakeholders in the system of food safety, in particular federal agencies, need evidence-based, transparent, and rigorous approaches to estimate and compare the risk of foodborne illness from microbial and chemical hazards and the public health impact of interventions. FDA-iRISK (referred to here as iRISK), a Web based quantitative risk assessment system, was developed to meet this need. The modeling tool enables users to assess, compare, and rank the risks posed by multiple food-hazard pairs at all stages of the food supply system, from primary production, through manufacturing and processing, to retail distribution and, ultimately, to the consumer. Using standard data entry templates, built-in mathematical functions, and Monte Carlo simulation techniques, iRISK integrates data and assumptions from seven components: the food, the hazard, the population of consumers, process models describing the introduction and fate of the hazard up to the point of consumption, consumption patterns, dose-response curves, and health effects. Beyond risk ranking, iRISK enables users to estimate and compare the impact of interventions and control measures on public health risk. iRISK provides estimates of the impact of proposed interventions in various ways, including changes in the mean risk of illness and burden of disease metrics, such as losses in disability-adjusted life years. Case studies for Listeria monocytogenes and Salmonella were developed to demonstrate the application of iRISK for the estimation of risks and the impact of interventions for microbial hazards. iRISK was made available to the public at http://irisk.foodrisk.org in October 2012. PMID- 23462074 TI - Dynamic effects of free chlorine concentration, organic load, and exposure time on the inactivation of Salmonella, Escherichia coli O157:H7, and non-O157 Shiga toxin-producing E. coli. AB - This study evaluated the dynamic effects of free-chlorine (FC) concentration, contact time, and organic load on the inactivation of Salmonella, Escherichia coli O157:H7, and non-O157 Shiga toxin-producing E. coli (STEC) in suspension. Bacterial cells from four strains each of Salmonella, E. coli O157:H7, and non O157 STEC were inoculated separately or as a multistrain cocktail into solutions with varying FC concentrations. Lettuce or tomato extract was used to simulate the organic matter present during commercial fresh and fresh-cut produce wash operations. After exposure to FC for various lengths of time, the bacterial survival and water-quality changes were determined. In the absence of organic matter in a wash solution, pathogen inactivation is primarily a function of initial FC concentration (P < 0.0001), exposure time (P < 0.0001), and pathogen strains (P < 0.0001). In general, an over 4.5-log CFU/ml pathogen reduction was found after exposure to >0.5 mg/liter FC for over 30 s, or to >1.0 mg/liter FC for over 5 s. When the combination of FC concentration and contact time were less than or equal to the above conditions, survival of pathogens was strain dependant and ranked as: Salmonella > E. coli O157:H7 > non-O157 STEC. When organic matter was present in the wash solution, pathogen inactivation efficacy was specifically dependent on the residual FC concentration, which directly relates to both the initial FC concentration and the organic load. Prevention of pathogen survival in chlorinated produce wash solutions can be achieved by maintaining sufficient FC concentration and reducing the accumulation of organic matter. PMID- 23462075 TI - Prevalence and molecular epidemiological characterization of antimicrobial resistant Escherichia coli isolates from Japanese black beef cattle. AB - We investigated the prevalence of antimicrobial-resistant Escherichia coli in Japanese black beef cattle from the three major production regions of Japan. We collected and examined 291 fecal samples from Japanese black beef cattle in Hokkaido, Chubu, and Kyushu. Of the 3,147 E. coli isolates, 1,397 (44.4%) were resistant to one or more antibiotics; these included 553 (39.8%) of 1,388 isolates from Hokkaido, 352 (54.4%) of 647 isolates from Chubu, and 492 (44.2%) of 1,112 isolates from Kyushu. The difference in resistance rates between the three regions was significant. The antibiotics with the highest rates of resistance were oxytetracycline and dihydrostreptomycin (35.8% each), followed by ampicillin (21.4%). Further, E. coli isolates from calves had higher resistance rates than those from growing cattle and mature cattle, and the calf isolates showed high rates of resistance to gentamicin (20.2%), enrofloxacin (9.4%), and ceftiofur (4.2%). In addition, the high degrees of similarity in the genotypes of the isolates and in the resistance patterns on each farm suggest that resistance bacteria and resistance genes were horizontally transferred. Most isolates, in each of the three regions, harbored resistance genes such as blaTEM, strA, strB, aphA1, aphAI-IAB, and catI. In contrast to the isolates from Kyushu, most of which harbored aacC2, tetB, and dfrA12, the isolates from Hokkaido and Chubu harbored a variety of resistance genes. Furthermore, the prevalence of genes for resistance to dihydrostreptomycin, gentamicin, chloramphenicol, and trimethoprim differed significantly between the regions. This is the first large-scale study describing and comparing antimicrobial-resistant bacteria from different regions in Japan. The results will contribute to improving food safety and promoting careful usage of antimicrobial agents. PMID- 23462076 TI - Fate of Escherichia coli O157:H7 in mechanically tenderized beef prime rib following searing, cooking, and holding under commercial conditions. AB - We evaluated the effect of commercial times and temperatures for searing, cooking, and holding on the destruction of Escherichia coli O157:H7 (ECOH) within mechanically tenderized prime rib. Boneless beef ribeye was inoculated on the fat side with ca. 5.7 log CFU/g of a five-strain cocktail of ECOH and then passed once through a mechanical tenderizer with the fat side facing upward. The inoculated and tenderized prime rib was seared by broiling at 260 degrees C for 15 min in a conventional oven and then cooked in a commercial convection oven at 121.1 degrees C to internal temperatures of 37.8, 48.9, 60.0, and 71.1 degrees C before being placed in a commercial holding oven maintained at 60.0 degrees C for up to 8 h. After searing, ECOH levels decreased by ca. 1.0 log CFU/g. Following cooking to internal temperatures of 37.8 to 71.1 degrees C, pathogen levels decreased by an additional ca. 2.7 to 4.0 log CFU/g. After cooking to 37.8, 48.9, or 60.0 degrees C and then warm holding at 60.0 degrees C for 2 h, pathogen levels increased by ca. 0.2 to 0.7 log CFU/g. However, for prime rib cooked to 37.8 degrees C, pathogen levels remained relatively unchanged over the next 6 h of warm holding, whereas for those cooked to 48.9 or 60.0 degrees C pathogen levels decreased by ca. 0.3 to 0.7 log CFU/g over the next 6 h of warm holding. In contrast, after cooking prime rib to 71.1 degrees C and holding for up to 8 h at 60.0 degrees C, ECOH levels decreased by an additional ca. 0.5 log CFU/g. Our results demonstrated that to achieve a 5.0-log reduction of ECOH in blade tenderized prime rib, it would be necessary to sear at 260 degrees C for 15 min, cook prime rib to internal temperatures of 48.9, 60.0, or 71.1 degrees C, and then hold at 60.0 degrees C for at least 8 h. PMID- 23462077 TI - Airborne microbial composition in a high-throughput poultry slaughtering facility. AB - A high-throughput chicken slaughtering facility in Beijing was systematically investigated for numbers of airborne microorganisms. Samples were assessed for counts of aerobic bacteria, Staphylococcus aureus, total coliforms, Escherichia coli, Pseudomonas aeruginosa, Listeria monocytogenes, Bacillus cereus, and Salmonella. During a 4-month period (September to December 2011), samples were collected for 10 min three times daily (preproduction, production, and postproduction). Samples were collected for three consecutive days of each month with an FA-1 sampler from six sampling sites: receiving-hanging, soaking-scalding and defeathering, evisceration, precooling, subdividing, and packing. Humidity, temperature, wind velocity, and airborne particulates also were recorded at each sampling site and time. The highest counts of microorganisms were recorded in the initial stages of processing, i.e., the receiving-hanging and defeathering areas, with a definite decline toward the evisceration, prechilling, subdividing, and packing areas; the prechilling area had the lowest microbial counts of 2.4 * 10(3) CFU/m(3). Mean total coliforms counts ranged from 8.4 * 10(3) to 140 CFU/m(3). Maximum E. coli counts were 6.1 * 10(3) CFU/m(3) in the soaking scalding and defeathering area. B. cereus, P. aeruginosa, and S. aureus represented only a small proportion of the microbial population (1,900 to 20 CFU/m(3)). L. monocytogenes and Salmonella were rarely detected in evisceration, precooling, subdividing, and packing areas. Our study identified the levels of bioaerosols that may affect chicken product quality. This finding could be useful for improved control of microbial contamination to ensure product quality. PMID- 23462078 TI - Commercial thermal process for inactivating Salmonella Poona on surfaces of whole fresh cantaloupes. AB - Outbreaks of salmonellosis by Salmonella Poona and listeriosis by Listeria monocytogenes have been associated with the consumption of cantaloupes. Commercial washing processes for cantaloupes are limited in their ability to inactivate and/or remove this human pathogen. Our objective was to develop a commercial-scale surface pasteurization process for enhancing microbiological safety of cantaloupes. Whole cantaloupes, surface inoculated with Salmonella Poona RM 2350, were stored at 32 degrees C for 24 h prior to processing. Temperature-penetration profiles indicated that the surface temperature of the whole cantaloupe was 26 and 30 degrees C below that of the hot water temperature after 2 min of immersion at 82 and 92 degrees C, respectively. Hot water treatments at 92 degrees C for 60 and 90 s reduced Salmonella Poona populations in excess of 5 log CFU/g of rind. Cantaloupes that were treated and stored at 4 degrees C for 9 days retained their firmness quality and maintained nondetectable levels of Salmonella Poona as compared with the controls. Also, levels of Salmonella Poona on fresh-cut cantaloupe prepared from hot water-treated cantaloupes and stored for 9 days at 4 degrees C were nondetectable as compared with the controls. These results indicate that surface pasteurization at 92 degrees C for 90 s will enhance the microbiological safety of cantaloupes and will extend the shelf life of this commodity as well. The process parameter of 90 s or less falls within the commercial requirements of the whole-cantaloupe processor-packer industry. PMID- 23462079 TI - Frequency of Salmonella and Listeria monocytogenes in five commercial brands of chicken eggs using a combined method of enrichment and nested-PCR. AB - Eggs or egg-based foods, either raw or undercooked, have been identified as vehicles of Salmonella outbreaks. The low numbers of Salmonella organisms in eggs makes it difficult to detect them in frequency studies. The nested-PCR (n-PCR) technique shows more sensitivity and specificity than bacteriological culture methods (BCMs). A preenrichment method followed by enrichment and n-PCR is a good alternative for the investigation of Salmonella and Listeria monocytogenes in eggs. A total of 2,650 chicken eggs representing five commercial brands were purchased from 10 grocery stores. Ten eggs of each brand were combined in order to obtain 265 pooled samples (53 per brand). The shells and yolks of 100 pooled samples were analyzed for Salmonella, while the shells of 65 pooled samples were analyzed for L. monocytogenes, using BCM and a combined method of enrichment and n-PCR (CM-n-PCR). Sixteen eggshell pooled samples tested positive for Salmonella by CM-n-PCR, compared with only two by BCM. Three egg yolk pooled samples tested positive for this pathogen by CM-n-PCR; none tested positive by BCM. Three eggshell pooled samples tested positive for L. monocytogenes by CM-n-PCR and none by BCM. In Mexico, as in other countries, official methods for detection of Salmonella and L. monocytogenes in foods are based on standard bacteriological culture techniques. The inclusion of more sensitive methods such as the one used in the present investigation would increase the probability of detecting positive samples, particularly in those foods in which a very low number of cells is expected. PMID- 23462080 TI - Effect of pulsed light treatments on the growth and resistance behavior of Listeria monocytogenes 10403S, Listeria innocua, and Escherichia coli ATCC 25922 in a liquid substrate. AB - Pulsed light (PL) treatment can effectively inactivate a large proportion of contaminating bacteria on surfaces and in clear solutions. An important issue that needs to be investigated is whether repeated exposure to PL treatment causes any changes to the growth and resistance behavior of the bacteria surviving the treatment. To test this, three challenge microorganisms were used: Listeria monocytogenes, Listeria innocua, and Escherichia coli. Cells of the challenge bacteria were treated with either low or high PL doses. Survivors of the PL treatment were enumerated, isolated, regrown, and exposed again to PL treatment. PL inactivation curves were generated for the survivors of each exposure cycle (as well as controls) to examine possible differences induced by repeated treatments. Growth curves of L. monocytogenes, L. innocua, and E. coli isolates recovered from exposure to either 1.1 or 10.1 J/cm(2) were not significantly different from the growth curves of untreated cells. Reduction levels of up to 4 and up to 6 log CFU were obtained after exposure to 1.1 and 10.1 J/cm(2), respectively, both for the controls and the repeatedly treated and recovered isolates. These results show that PL did not significantly change the growth kinetics or resistance to PL of the target microorganisms after up to 10 exposures. These findings have significance for the practical application of PL treatment, as they indicate that this technology does not select for microorganisms with increased resistance. PMID- 23462081 TI - Antimicrobial activity of nanodispersed thymol in tryptic soy broth. AB - Food safety is a continuing challenge for the food industry due to sporadic illness outbreaks caused by foodborne pathogens. Plant essential oils have been studied extensively as natural antimicrobials to control foodborne pathogens. However, their hydrophobic nature makes application in foods difficult because of their low water solubility, adverse impact on sensory quality, and binding with food components, which can interfere with antimicrobial efficacy. The objective of this study was to characterize antimicrobial activities of transparent nanodispersions of thymol encapsulated in whey protein isolate-maltodextrin conjugates, with comparison to free thymol. Tests were conducted for Escherichia coli O157:H7 strains ATCC 43889 and 43894, Salmonella Typhimurium strain 2576, Listeria monocytogenes strains Scott A and 101, and Staphylococcus aureus strains 27708 and SA113 in tryptic soy broth at various pHs and temperatures. Results indicate that the MIC for nanodispersed and free thymol against all strains of both gram-negative and gram-positive pathogens tested was 500 ppm at pH 6.8 and at the optimal growth temperature, with the exception of E. coli O157:H7 and L. monocytogenes strain Scott A, which were inhibited by 300 ppm of free thymol. Nanodispersed thymol was further tested at 500 ppm for inhibition of E. coli O157:H7 and L. monocytogenes at 35, 32, 25, and 4 degrees C in tryptic soy broth adjusted to pH 5.5 and 3.5. At pH 5.5, L. monocytogenes was completely inhibited after 3 h, and E. coli O157:H7 showed a reduction of 1.0 to 3.0 log CFU/ml after 48 h. At pH 3.5, L. monocytogenes controls did not grow, but E. coli O157:H7 survived. At both pH 5.5 and 3.5, no significant effect of temperature on antimicrobial activity was observed at 500 mg/ml nanodispersed thymol. The present study demonstrated that transparent nanodispersions of thymol have promising antimicrobial activity against a broad spectrum of foodborne pathogens. PMID- 23462082 TI - Effect of packaging systems and pressure fluids on inactivation of Clostridium botulinum spores by combined high pressure and thermal processing. AB - Several studies have been published on the inactivation of bacterial spores by using high pressure processing in combination with heat. None of the studies investigated the effect of the packaging system or the pressurizing fluid on spore inactivation. The objective of this study was to select and validate an appropriate packaging system and pressure transfer fluid for inactivation of Clostridium botulinum spores by using high pressure processing in combination with thermal processing. Inactivation of spores packaged in three packaging systems (plastic pouches, cryovials, and transfer pipettes) was measured in two pressure test systems (laboratory-scale and pilot-scale) at 700 MPa and >105 degrees C. Total destruction (>6.6-log reduction) of the spores packaged in the graduated tube part of transfer pipettes was obtained after processing for up to 10 min at 118 degrees C and 700 MPa in both pressure test systems, compared with the spores packaged either in plastic pouches or cryovials. Reduction of spores packaged in plastic pouches was lowest (<4.8 log) for both pressure test systems when processed at the same conditions (i.e., 700 MPa and 118 degrees C). Within the pilot-scale pressure system, increasing the process temperature from 118 to 121 degrees C at 700 MPa for 10 min resulted in only a small increase in spore reduction (<5.1 log) for spores packaged in plastic pouches, whereas there were no recoverable spores for either of the other two packaging systems. Use of plastic pouches for packaging spores in inactivation kinetic studies could lead to erroneous conclusions about the effect of high pressure in combination with heat. BioGlycol is the pressure-heat transfer fluid of choice, as compared with Duratherm oil, to maximize the temperature response rate during pressurization within the laboratory-scale pressure test system. PMID- 23462083 TI - Mating-disruption trials for control of Mediterranean flour moth, Ephestia kuehniella Zeller (Lepidoptera: Pyralidae), in traditional flour mills. AB - In the present work, 3 years of field trials (from 2007 to 2009) were carried out to evaluate use of the pheromone (9Z, 12E)-tetradecadienyl acetate (TDA) for mating disruption (MD) of the Mediterranean flour moth, Ephestia kuehniella Zeller. Dispensers containing the pheromone TDA were placed in two traditional flour mills. Pheromone-baited funnel traps were used to monitor the population fluctuations of E. kuehniella males throughout the entire experimental period; female oviposition was assessed by placement of petri cups containing wheat germ semolina flour bait. According to our results, the use of MD dispensers does not interfere completely with the reproduction of E. kuehniella. However, looking at the overall data, there was a significant reduction in both adults and larvae in treated mills after the MD application. According to hazard analysis and critical control point procedures, treatment should be accompanied by general cleaning of the facilities, including corners and inside machinery, where insects can hide and reproduce. In integrated pest management programs, the use of mating disruption can lead to a drastic reduction in the need for chemical treatments, with improvement in food quality. PMID- 23462084 TI - Effect of frying instructions for food handlers on acrylamide concentration in French fries: an explorative study. AB - The objective of this study was to obtain insight into the effect of frying instructions on food handlers' control decisions in restaurants and to investigate the impact of control decisions on the variation and concentration of acrylamide in French fries. The concentrations of acrylamide and reducing sugars were analyzed, the frying temperature and time were measured, and thawing practices were observed. The results obtained before and after instructions were provided to the food handlers were compared for restaurants as a group and for each restaurant. Frying instructions supported food handlers' decisions to start frying when the oil temperature reached 175 degrees C; all handlers started frying at the correct temperature. However, the effect of the instructions on the food handlers' decisions for frying time differed; most handlers increased the frying time beyond 240 s to achieve crispier French fries with a final color dictated by their preference. Providing instructions did not result in a significant difference in the mean concentration of acrylamide in French fries for the restaurants as a group. However, data analyzed for each restaurant revealed that when food handlers properly followed the instructions, the mean concentration of acrylamide was significantly lower (169 MUg/kg) than that before instructions were provided (1,517 MUg/kg). When food handlers did not complying with the frying instructions, mean acrylamide concentrations were even higher than those before instructions were provided. Two different strategies were developed to overcome the noncompliant behavior of food handlers: establishing requirements for the features of commercial fryers and strict monitoring of compliance with instructions. PMID- 23462085 TI - Analyzing consumers' reactions to news coverage of the 2011 Escherichia coli O104:H4 outbreak, using the Extended Parallel Processing Model. AB - This article describes and analyzes Flemish consumers' real-life reactions after reading online newspaper articles related to the enterohemorrhagic Escherichia coli (EHEC) O104:H4 outbreak associated with fresh produce in May and June 2011 in Germany. Using the Extended Parallel Processing Model (EPPM) as the theoretical framework, the present study explored the impact of Flemish (Belgian) online news coverage on consumers' perception of the risk induced by the EHEC outbreak and their behavioral intentions as consumers of fresh produce. After the consumers read a newspaper article related to the outbreak, EPPM concepts were measured, namely, perceived severity, susceptibility, self-efficacy, and affective response, combined with behavioral intentions to eat less fresh produce, to rinse fresh produce better, and to alert loved ones concerning the risk. The consumers' reactions were measured by inserting a link to an online survey below every online newspaper article on the EHEC outbreak that appeared in two substantial Flemish newspapers. The reactions of 6,312 respondents were collected within 9 days for 17 different online newspaper articles. Looking at the perceived values of the EPPM concepts, the perceived severity and the perceived susceptibility of the risk were, as expected, high. However, the consumers thought they could prevent the risk from happening, which stresses the importance of increasing consumers' knowledge of emerging food safety risks. Furthermore, analyses showed the moderating role of government trust and its influence on the way consumers perceived the risk, how worried they were, and their behavioral intentions. PMID- 23462086 TI - Observational trial of safe food handling behavior during food preparation using the example of Campylobacter spp. AB - Campylobacter infections are one of the most prominent worldwide food-related diseases. The primary cause of these infections is reported to be improper food handling, in particular cross-contamination during domestic preparation of raw chicken products. In the present study, food handling behaviors in Austria were surveyed and monitored, with special emphasis on Campylobacter cross contamination. Forty participants (25 mothers or fathers with at least one child <=10 years of age and 15 elderly persons >=60 years of age) were observed during the preparation of a chicken salad (chicken slices plus lettuce, tomato, and cucumber) using a direct structured observational scoring system. The raw chicken carcasses and the vegetable part of the salad were analyzed for Campylobacter. A questionnaire concerning knowledge, attitudes, and interests related to food safety issues was filled out by the participants. Only 57% of formerly identified important hygiene measures were used by the participants. Deficits were found in effective hand washing after contact with raw chicken meat, but proper changing and cleaning of the cutting board was noted. Campylobacter was present in 80% of raw chicken carcasses, albeit the contamination rate was generally lower than the limit of quantification (10 CFU/g). In the vegetable part of the prepared product, no Campylobacter was found. This finding could be due to the rather low Campylobacter contamination rate in the raw materials and the participants' use of some important food handling behaviors to prevent cross-contamination. However, if the initial contamination had been higher, the monitored deficits in safe food handling could lead to quantifiable risks, as indicated in other published studies. The results of the observational trial and the questionnaire indicated knowledge gaps in the food safety sector, suggesting that further education of the population is needed to prevent the onset of foodborne diseases. PMID- 23462087 TI - Bacterial flora and antimicrobial resistance in raw frozen cultured seafood imported to Denmark. AB - Intensified aquaculture includes the use of antimicrobials for disease control. In contrast to the situation in livestock, Escherichia coli and enterococci are not part of the normal gastrointestinal flora of fish and shrimp and therefore not suitable indicators of antimicrobial resistance in seafood. In this study, the diversity and phenotypic characteristics of the bacterial flora in raw frozen cultured and wild-caught shrimp and fish were evaluated to identify potential indicators of antimicrobial resistance. The bacterial flora cultured on various agar media at different temperatures yielded total viable counts of 4.0 * 10(4) to 3.0 * 10(5) CFU g(-1). Bacterial diversity was indicated by 16S rRNA sequence analysis of 84 isolates representing different colony types; 24 genera and 51 species were identified. Pseudomonas spp. (23% of isolates), Psychrobacter spp. (17%), Serratia spp. (13%), Exiguobacterium spp. (7%), Staphylococcus spp. (6%), and Micrococcus spp. (6%) dominated. Disk susceptibility testing of 39 bacterial isolates to 11 antimicrobials revealed resistance to ampicillin, amoxicillin clavulanic acid, erythromycin, and third generation cephalosporins. Resistance to third generation cephalosporins was found in Pseudomonas, a genus naturally resistant to most beta-lactam antibiotics, and in Staphylococcus hominis. Half of the isolates were susceptible to all antimicrobials tested. Results indicate that identification of a single bacterial resistance indicator naturally present in seafood at point of harvest is unlikely. The bacterial flora found likely represents a processing rather than a raw fish flora because of repeated exposure of raw material to water during processing. Methods and appropriate indicators, such as quantitative PCR of resistance genes, are needed to determine how antimicrobials used in aquaculture affect resistance of bacteria in retailed products. PMID- 23462088 TI - Molecular characterization of Pseudomonas fluorescens isolates involved in the Italian "blue mozzarella" event. AB - Between June and September 2010, widespread Italian consumer reports of unusual blue spoilage on fresh dairy products were publicized, resulting in the so-called blue mozzarella event. An inordinately high number of samples from mozzarella and whey cheese products of Italian and German production subsequently tested positive for Pseudomonas fluorescens. The aim of this study was to verify whether a selected P. fluorescens strain was responsible for this apparently unusual event. Molecular characterization of 181 isolated P. fluorescens strains was conducted using a newly optimized pulsed-field gel electrophoresis protocol. Although a high number of pulsotypes was found (132), only four pulsotypes were associated with more than one production plant, and only one German isolate had the same pulsotype as was detected in two Italian plants. This is the only evidence of possible cross-contamination among cheeses from the two countries. The overall results did not support the spread of contamination from German to Italian plants or the presence of one environmental strain that spread in both countries. PMID- 23462089 TI - Chronic or accidental exposure of oysters to norovirus: is there any difference in contamination? AB - Bivalve molluscan shellfish such as oysters may be contaminated by human pathogens. Currently, the primary pathogens associated with shellfish-related outbreaks are noroviruses. This study was conducted to improve understanding of oyster bioaccumulation when oysters were exposed to daily contamination or one accidental contamination event, i.e., different modes of contamination. Oysters were contaminated with two representative strains of norovirus (GI.1 and GII.3) and then analyzed with real-time reverse transcription PCR. Exposure to a repeated virus dose for 9 days (mimicking a growing area subjected to frequent sewage contamination) led to an additive accumulation that was not significantly different from that obtained when the same total dose of virus was added all at once (as may happen after accidental sewage discharge). Similarly, bioaccumulation tests performed with mixed strains revealed additive accumulation of both viruses. Depuration may not be efficient for eliminating viruses; therefore, to prevent contaminated shellfish from being put onto the market, continuous sanitary monitoring must be considered. All climatic events or sewage failures occurring in production areas must be recorded, because repeated low dose exposure or abrupt events may lead to similar levels of accumulation. This study contributes to an understanding of norovirus accumulation in oysters and provides suggestions for risk management strategies. PMID- 23462090 TI - Reduction of pesticide residues in tomatoes and other produce. AB - There is interest in reducing pesticide residues in fruits and vegetables in order to minimize human exposure. The objectives of this study were to (i) determine the effect of various washing treatments with and without sonication on pesticide removal from tomatoes and (ii) assess the effectiveness of a water wash on select samples using a produce-washing flume. In the first set of experiments, tomatoes were contaminated with acephate, malathion, carbaryl, bifenthrin, cypermethrin, permethrin, cyhalothrin, chlorothalonil, and imidacloprid and were dried overnight. Subsets of the tomatoes were then washed (10 degrees C, 1 min) with one of the following: water, sodium hypochlorite (80 MUg/ml, pH 7), peroxyacetic acid (80 MUg/ml), or Tween 20 (0.1%) with and without sonication. In general, the effect of sonication depended on the washing treatment and on the pesticide. A separate experiment measured pesticide residues in contaminated samples before and after being washed in a flume (22 degrees C, 1 min). Pesticide residues in contaminated produce were reduced from about 40 to 90% when washed for 1 min in the flume. PMID- 23462091 TI - Potential of chlorophyll-rich feed ingredients to improve detection of fecal contamination in the abattoir. AB - The use of fecal fluorescence to improve detection of contamination of carcasses in the abattoir was previously reported. However, incidents of false negatives can result when animals are offered diets that contain little chlorophyll (e.g., concentrate). Here, we investigated the potential of incorporating a high chlorophyll-containing feed ingredient (concentrated alfalfa extract; CAE) into the diets of sheep and cattle to improve fecal fluorescence intensity. The sheep experiment evaluated the fecal fluorescence of animals from pasture, when fed a concentrate-barley straw diet and when the concentrate diet incorporated CAE (100 g of dry matter a day). Fecal chlorophyll and metabolite content was highest on the pasture-fed animals and increased significantly over the concentrate diet when CAE was included. Subsequently fluorescent intensity was increased from 15,000 to 36,000 arbitrary units for concentrate and CAE-concentrate diets, respectively, compared with 59,000 for the pasture-fed animals. The cattle experiment investigated the potential of CAE to improve fluorescence of feces from a concentrate diet as well as a silage diet at two levels of incorporation (75 and 150 g CAE/kg of dry matter intake). This study also determined the fluorescence of digesta and carcass contamination in the abattoir on a subset of carcasses. In agreement with the sheep study, CAE significantly improved fluorescence of feces and digesta when added to a concentrate diet, but had little effect on improving fecal fluorescence from the silage-fed animals. This was thought to be related to greater chlorophyll degradation in the rumen or/and the dark nature of the silage feces acting as a quencher of emitted fluoresced light. Incorporating high-chlorophyll-containing plant ingredients into ruminant concentrate diets will improve detection of fecal contamination by reducing false negative readings. However, they will have little effect on false-positive readings due to the range of wavelengths emitted by natural chlorophyll and its metabolites. Implications and potential solutions for this are discussed. PMID- 23462092 TI - Expedited response to the questions posed by the United States Department of Agriculture agricultural marketing service to support ground beef purchase for the federal food and nutrition assistance programs. PMID- 23462093 TI - Predicting and preventing mold spoilage of food products. AB - This article is a review of how to quantify mold spoilage and consequently shelf life of a food product. Mold spoilage results from having a product contaminated with fungal spores that germinate and form a visible mycelium before the end of the shelf life. The spoilage can be then expressed as the combination of the probability of having a product contaminated and the probability of mold growth (germination and proliferation) up to a visible mycelium before the end of the shelf life. For products packed before being distributed to the retailers, the probability of having a product contaminated is a function of factors strictly linked to the factory design, process, and environment. The in-factory fungal contamination of a product might be controlled by good manufacturing hygiene practices and reduced by particular processing practices such as an adequate air renewal system. To determine the probability of mold growth, both germination and mycelium proliferation can be mathematically described by primary models. When mold contamination on the product is scarce, the spores are spread on the product and more than a few spores are unlikely to be found at the same spot. In such a case, models applicable for a single spore should be used. Secondary models can be used to describe the effect of intrinsic and extrinsic factors on either the germination or proliferation of molds. Several polynomial models and gamma-type models quantifying the effect of water activity and temperature on mold growth are available. To a lesser extent, the effect of pH, ethanol, heat treatment, addition of preservatives, and modified atmospheres on mold growth also have been quantified. However, mold species variability has not yet been properly addressed, and only a few secondary models have been validated for food products. Once the probability of having mold spoilage is calculated for various shelf lives and product formulations, the model can be implemented as part of a risk management decision tool. PMID- 23462094 TI - [Axillary approach for surgical closure of atrial septal defect]. AB - Mid-line sternotomy is the routine approach for surgical repair of congenital heart diseases. However, its noticeable scar is a constant reminder of having undergone heart surgery. Several alternative approaches have been developed for simple cardiac conditions to hide the scar. Our series, consisting of 26 patients with axillary closure of atrial septal defect, is presented. The median age was 5.45 years (range 3-13), and median weight was 19.84 Kg. (range 13-37). The defect was closed directly in 13 cases, and with an autologous pericardial patch in the other 13. The number of surgical steps and time taken were the same as in median sternotomy. Functional recovery, intensive care unit stay, and hospital discharge were also standard. The cosmetic result, assessed both by patients and relatives, was excellent. PMID- 23462095 TI - [Association between paracetamol exposure and asthma: update and practice guidelines]. AB - Asthma prevalence has increased over the last few decades, especially in developed countries, and possibly due to different reasons. An association between paracetamol use or exposure at different periods of life, including gestation and childhood, and asthma prevalence has been observed in the last few years. Causality can not be established from observational reports, due to the arguable presence of many confounding factors and biases. Randomised trials are needed to elucidate the nature of this association. The Spanish Paediatric societies subscribing to this paper consider that current evidence is insufficient to discourage the use of paracetamol during gestation or in children with or at risk of asthma. PMID- 23462096 TI - [Gastroenteritis-related seizures: study of incidence and clinical analysis]. AB - INTRODUCTION: Benign convulsions associated with gastroenteritis are now increasingly recognized as clinical condition to the extent that it has become an independent entity under the heading of non-epileptic situational seizures. The aim of this study is to determine the annual incidence in the reference population of our hospital and the clinical characterization of seizures associated to gastroenteritis, in the absence or presence of fever for comparison. PATIENTS AND METHOD: All seizures associated with gastroenteritis treated in our hospital were prospectively collected over a period of two calendar years. The children included were aged 6 months to 6 years with seizures in the context of gastroenteritis without electrolyte abnormalities, and divided into two groups, with and without fever. RESULTS: There were 14 cases from a reference population of 39,900 with a homogeneous semiological presentation. CONCLUSION: The annual incidence was estimated at 1/10 000 children for afebrile seizures associated with gastroenteritis. The clinical behaviour and the incidence of seizures associated with fever and gastroenteritis was similar, but with an appearance somewhat earlier from the onset of symptoms, and at a slightly higher age. PMID- 23462097 TI - Sequence dependence of C-end rule peptides in binding and activation of neuropilin-1 receptor. AB - Neuropilin-1 (NRP-1) is a hub receptor that plays an essential role in angiogenesis and vascular permeability. It is over-expressed in the new blood vessels grown by tumor cells and is a target for anti-tumor treatments. Peptides that expose the consensus sequence R/K/XXR/K at the C-terminus (C-end rule or CendR peptides) bind to NRP-1 and are internalized into the cell. We used peptide phage display binding assays and molecular dynamics (MD) simulations to study the potential role of the central residues of CendR peptides in binding and activation of the NRP-1 receptor. The high stability of RPAR-receptor domain complex stems from the formation of a characteristic pattern of three hydrogen bonds between the peptide C-terminus and the residues in the NRP-1 loop III. Any changes in the peptide structure that fail to preserve this triad result in a less-stable complex. We performed a systematic study of RXXR mutants, where X=A/D/S/R/P, in order to test the effect of replacement of A or P on the binding capabilities. Our results, both experimental and computational, show that RRAR, RDAR, RPDR, RPRR and RPPR are capable of binding NRP-1. However, only RPPR and RPRR segments form an optimal organization around loop III with low potential energy. In other analogs, the absence of these stabilizing interactions always results in higher potential energy of the complexes. The binding of RPAR analogs does not guarantee receptor activation; only stable complexes that are properly stabilized via loop III appear able to trigger NRP-1 activation. PMID- 23462098 TI - Structural insight into the lactoferrin receptors from pathogenic Neisseria. AB - Neisseria are pathogenic bacteria that cause gonorrhea, septicemia, and meningitis. Like other pathogenic bacteria, Neisseria must acquire iron for survival from their local environment within the human host. Instead of secreting siderophores to scavenge iron, Neisseria steal iron from human iron binding proteins such as hemoglobin, transferrin and lactoferrin for survival. Recently we reported the crystal structures of the Neisseria meningitidis transferrin receptors TbpA and TbpB, as well as the structures of apo and holo human transferrin. We also analyzed these proteins using small angle X-ray scattering and electron microscopy to provide the molecular details explaining how Neisseria are able to interact with and extract iron from transferrin. Here, we utilize the structural reports, as well as the recently reported structure of the N-lobe of LbpB from Moraxella bovis, to assemble improved 3D homology models for the neisserial lactoferrin import receptors LbpA and LbpB, both of which are important vaccine targets against N. meningitidis. We then analyzed these models to gain structural insights into the lactoferrin-iron import system and form a mechanistic model fashioned in parallel to the homologous transferrin-iron import system. PMID- 23462099 TI - Role of trimer-trimer interaction of bacteriorhodopsin studied by optical spectroscopy and high-speed atomic force microscopy. AB - Bacteriorhodopsin (bR) trimers form a two-dimensional hexagonal lattice in the purple membrane of Halobacterium salinarum. However, the physiological significance of forming the lattice has long been elusive. Here, we study this issue by comparing properties of assembled and non-assembled bR trimers using directed mutagenesis, high-speed atomic force microscopy (HS-AFM), optical spectroscopy, and a proton pumping assay. First, we show that the bonds formed between W12 and F135 amino acid residues are responsible for trimer-trimer association that leads to lattice assembly; the lattice is completely disrupted in both W12I and F135I mutants. HS-AFM imaging reveals that both crystallized D96N and non-crystallized D96N/W12I mutants undergo a large conformational change (i.e., outward E-F loop displacement) upon light-activation. However, lattice disruption significantly reduces the rate of conformational change under continuous light illumination. Nevertheless, the quantum yield of M-state formation, measured by low-temperature UV-visible spectroscopy, and proton pumping efficiency are unaffected by lattice disruption. From these results, we conclude that trimer-trimer association plays essential roles in providing bound retinal with an appropriate environment to maintain its full photo-reactivity and in maintaining the natural photo-reaction pathway. PMID- 23462100 TI - Structure of the ParM filament at 8.5A resolution. AB - The actin-like protein ParM forms the cytomotive filament of the ParMRC system, a type II plasmid segregation system encoded by Escherichia coli R1 plasmid. We report an 8.5A resolution reconstruction of the ParM filament, obtained using cryo-electron microscopy. Fitting of the 3D density reconstruction with monomeric crystal structures of ParM provides insights into dynamic instability of ParM filaments. The structural analysis suggests that a ParM conformation, corresponding to a metastable state, is held within the filament by intrafilament contacts. This filament conformation of ParM can be attained only from the ATP bound state, and induces a change in conformation of the bound nucleotide. The structural analysis also provides a rationale for the observed stimulation of hydrolysis upon polymerisation into the filament. PMID- 23462102 TI - Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons. AB - During neuronal development, axons navigate long distances, eventually forming precise connections with such targets as peripheral tissues. Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. We found that phosphorylation of Ser(1194) in Dock6 inhibited its GEF activity and suppressed axonal growth of embryonic sensory neurons and axon regeneration of postnatal sensory neurons in vitro and in vivo. At early developmental stages, when axons are growing, the protein phosphatase PP2A interacted with and dephosphorylated Dock6, thereby increasing the activity of Dock6. At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching. Thus, the phosphorylation status of Dock6 at Ser(1194) determines whether it promotes axon extension or branching in sensory neurons, revealing interplay between kinase and phosphatase action on a Rho-GEF during axon growth. PMID- 23462103 TI - Emotional work and diversity in clinical placements of nursing students. AB - PURPOSE: To learn how students experience clinical placements in a setting of diversity and how they cope with the emotional challenges involved. DESIGN: This study is based on inductive, qualitative research undertaken with Israeli nursing students. METHOD: In-depth interviews were conducted with 20 students: 10 Arabs (5 men and 5 women), 9 Jews (2 men and 7 women), and 1 Circassian. The interviews were analyzed through coding and categorization. FINDINGS: The students' experiences are characterized by emotional strains of various sorts-stress, ambivalence, disgust, frustration, and conflict-that arise in three types of relationships: relationships with patients, with the clinical instructors, and with other students who are on their teams. The data show that diversity has an impact on all these relationships. The data further show that the students cope with the emotional strains by using several strategies of emotional work: distancing, self-strengthening, self-motivation work, and minimizing significance. CONCLUSIONS AND IMPLICATIONS: (a) Nursing students' experiences during their clinical placements should be understood in terms of emotional challenges, and their emotional work and coping strategies call for appropriate forms of support. (b) The diversity of the clinical placement environment should be considered as an important factor, both in understanding students' experiences and learning processes and in designing the support that they need. CLINICAL RELEVANCE: Culturally diverse settings entail distinct challenges that impact students' emotional reaction to clinical work. Understanding the types of emotional work students do in the process of their clinical experience is critical for educators seeking to promote genuinely caring and effective nursing in culturally diverse settings. PMID- 23462101 TI - The small GTPase ARF6 stimulates beta-catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis. AB - beta-Catenin has a dual function in cells: fortifying cadherin-based adhesion at the plasma membrane and activating transcription in the nucleus. We found that in melanoma cells, WNT5A stimulated the disruption of N-cadherin and beta-catenin complexes by activating the guanosine triphosphatase adenosine diphosphate ribosylation factor 6 (ARF6). Binding of WNT5A to the Frizzled 4-LRP6 (low density lipoprotein receptor-related protein 6) receptor complex activated ARF6, which liberated beta-catenin from N-cadherin, thus increasing the pool of free beta-catenin, enhancing beta-catenin-mediated transcription, and stimulating invasion. In contrast to WNT5A, the guidance cue SLIT2 and its receptor ROBO1 inhibited ARF6 activation and, accordingly, stabilized the interaction of N cadherin with beta-catenin and reduced transcription and invasion. Thus, ARF6 integrated competing signals in melanoma cells, thereby enabling plasticity in the response to external cues. Moreover, small-molecule inhibition of ARF6 stabilized adherens junctions, blocked beta-catenin signaling and invasiveness of melanoma cells in culture, and reduced spontaneous pulmonary metastasis in mice, suggesting that targeting ARF6 may provide a means of inhibiting WNT/beta-catenin signaling in cancer. PMID- 23462104 TI - Effects of seaweed-restructured pork diets enriched or not with cholesterol on rat cholesterolaemia and liver damage. AB - Seaweed enriched-restructured pork (RP) is a potential functional food. However, indications of adverse effects associated with herbal medications, which include among others liver failure, toxic hepatitis, and death have been reported. Cholesterol feeding produces hepatomegalia and fat liver infiltration. The effect of seaweed-RP diet, cholesterol-enriched or not, on plasma cholesterol, liver damage markers, structure, and cytochrome CYP4A-1 were evaluated after 5 wk. Eight rat groups were fed a mix of 85% AIN-93M rodent-diet plus 15% RP. The Cholesterol-control (CC), Cholesterol-Wakame (CW), Cholesterol-Nori (CN) and Cholesterol-Sea Spaghetti (CS) groups respectively consumed similar diets to control (C), Wakame (W), Nori (N), and Sea Spaghetti (S) but as part of hypercholesterolaemic diets. CN and CS significantly blocked the hypercholesterolaemic effect observed in CC group. After 5-wk, N and S diets increased the CYP4A-1 expression. However, seaweed-RPs were unable to reduce the histological liver alterations observed in CC group. Larger and more abundant hepatocellular alterations were found in CS and CN rats suggesting that the hypocholesterolaemic effects of these seaweed-RPs seem to be a two-edged sword as they increased liver damage. Future studies are needed to understand the involved mechanisms. PMID- 23462105 TI - Correlation between aflatoxin M1 content of breast milk, dietary exposure to aflatoxin B1 and socioeconomic status of lactating mothers in Ogun State, Nigeria. AB - Aflatoxin M1 (AF M1), a hydroxylated metabolite of AF B1, is an important toxin that can contaminate the milk of lactating mothers. A correlation study was conducted to determine the relationship between AF M1 content of breast milk, dietary exposure to AF B1 and socioeconomic status of lactating mothers in the three Senatorial districts of Ogun State, Nigeria. Equal amounts of breast milk (20 ml) and food rations (40 kg) obtained from 50 volunteer lactating mothers and eighty-two frequently consumed food commodities in the preceding month were used for the study. The level of contamination of the foods by AF B1 was low (0.16 0.33 MUg/kg) and differed significantly (p<0.05) across the state but did not exceed the EU limit of 2 MUg/kg. The occurrence level of AF B1 was however high (93.75-94.45%) and was more pronounced in Ogun East Senatorial district (94.45%). Eighty-two percent of the breast milk was contaminated with AF M1 (3.49-35 ng/l) and 16% exceeded the EU limit of 25 ng/l while a 100% occurrence risk was recorded in Ogun Central Senatorial district. The socioeconomic status of the mothers also significantly influenced their dietary exposure and exposure risk of the sucklings to AF M1. PMID- 23462106 TI - Epidemiological and clinical features of human coronavirus infections among different subsets of patients. AB - BACKGROUND: Epidemiological and clinical data of human coronaviruses (HCoVs) infections are restricted to span 1-3 years at most. We conducted a comprehensive 9-year study on HCoVs by analyzing 1137 respiratory samples from four subsets of patients (asymptomatic, general community, with comorbidities, and hospitalized) in Sao Paulo, Brazil. METHODS: A pan-coronavirus RT-PCR screening assay was performed, followed by species-specific real-time RT-PCR monoplex assays. RESULTS: Human coronaviruses were detected in 88 of 1137 (7.7%) of the samples. The most frequently detected HCoV species were NL63 (50.0%) and OC43 (27.3%). Patients with comorbidities presented the highest risk of acquiring coronavirus infection (odds ratio=4.17; 95% confidence interval=1.9-9.3), and children with heart diseases revealed a significant HCoV infection presence. Dyspnea was more associated with HCoV-229E infections (66.6%), and cyanosis was reported only in HCoV-OC43 infections. There were interseasonal differences in the detection frequencies, with HCoV-229E being predominant in the year 2004 (61.5%) and HCoV NL63 (70.8%) in 2008. CONCLUSIONS: Our data provide a novel insight into the epidemiology and clinical knowledge of HCoVs among different subsets of patients, revealing that these viruses may cause more than mild respiratory tract disease. PMID- 23462107 TI - Ethnic minority health in Vietnam: a review exposing horizontal inequity. AB - BACKGROUND: Equity in health is a pressing concern and reaching disadvantaged populations is necessary to close the inequity gap. To date, the discourse has predominately focussed on reaching the poor. At the same time and in addition to wealth, other structural determinants that influence health outcomes exist, one of which is ethnicity. Inequities based on group belongings are recognised as 'horizontal', as opposed to the more commonly used notion of 'vertical' inequity based on individual characteristics. OBJECTIVE: The aim of the present review is to highlight ethnicity as a source of horizontal inequity in health and to expose mechanisms that cause and maintain this inequity in Vietnam. DESIGN: Through a systematic search of available academic and grey literature, 49 publications were selected for review. Information was extracted on: a) quantitative measures of health inequities based on ethnicity and b) qualitative descriptions explaining potential reasons for ethnicity-based health inequities. RESULTS: Five main areas were identified: health-care-seeking and utilization, maternal and child health, nutrition, infectious diseases, and oral health and hygiene. Evidence suggests the presence of severe health inequity in health along ethnic lines in all these areas. Research evidence also offers explanations derived from both external and internal group dynamics to this inequity. It is reported that government policies and programs appear to be lacking in culturally adaptation and sensitivity, and examples of bad attitudes and discrimination from health staff toward minority persons were identified. In addition, traditions and patriarchal structures within ethnic minority groups were seen to contribute to the maintenance of harmful health behaviors within these groups. CONCLUSION: Better understandings of the scope and pathways of horizontal inequities are required to address ethnic inequities in health. Awareness of ethnicity as a determinant of health, not only as a covariate of poverty or living area, needs to be improved, and research needs to be designed with this in mind. PMID- 23462108 TI - Cage-like silica nanoparticles-functionalized silica hybrid monolith for high performance capillary electrochromatography via "one-pot" process. AB - A cage-like silica nanoparticles-functionalized silica hybrid monolith for high performance capillary electrochromatography (CEC) has been prepared via "one-pot" process. In this process, the polycondensation of hydrolyzed alkoxysilanes and in situ reaction of mercaptopropyltrimethoxysilane (MPTS) with sodium 3-mercapto-1 propanesulfonate modified octavinyloctasilasesquioxane (MPS-OVS) simultaneously occurred in a pretreated capillary. The characterization and evaluation results indicated that the obtained MPS-OVS hybrid monolithic capillary column has homogeneous macroporous morphology with a permeability of 5.37*10(-13)m(2) and strong electro osmotic flow (EOF) over a wide pH range from 2.7 to 11.2. The EOF on the MPS-OVS hybrid monolithic column reached its maximum of 0.327cm(2)kV(-1)s( 1) at pH 9.7. The best theoretical efficiency of ~470,000plates/m was obtained for 2-aminophenol in CEC. Anilines and phenols were well separated on the MPS-OVS hybrid monolithic column by CEC, indicating typical reversed-phase and cation exchange chromatographic retention mechanisms of the column. The monolith was further applied to the separation of bovine serum albumin (BSA) tryptic digests, and the result indicated its potential in the analysis of some complex samples. PMID- 23462109 TI - Optimization of pressurized liquid extraction using a multivariate chemometric approach for the determination of anticancer drugs in sludge by ultra high performance liquid chromatography-tandem mass spectrometry. AB - The present paper describes an analytical method for the determination of 2 widely administered anticancer drugs, ifosfamide and cyclophosphamide, contained in sewage sludge. The method relies on the extraction from the solid matrix by pressurized liquid extraction, sample purification by solid-phase extraction and analysis by ultra high performance liquid chromatography coupled with tandem mass spectrometry. The different parameters affecting the extraction efficiency were optimized using an experimental design. Solvent nature was the most decisive factor for the extraction but interactions between some parameters also appeared very influent. The method was applied to seven different types of sludge for validation. The performances of the analytical method displayed high variability between sludges with limits of detection spanning more than one order of magnitude and confirming the relevance of multi-sample validation. Matrix effect has been determined as the most limiting analytical step for quantification with different extent depending on analyte and sludge nature. For each analyte, the use of deuterated standard spiked at the very beginning ensured the complete compensation of losses regardless of the sample nature. The suitability of the method between freshly spiked and aged samples has also been verified. The optimized method was applied to different sludge samples to determine the environmental levels of anticancer drugs. The compounds were detected in some samples reaching 42.5MUg/kgDM in ifosfamide for the most contaminated sample. PMID- 23462110 TI - Development and validation of an efficient automated method for the analysis of 300 pesticides in foods using two-dimensional liquid chromatography-tandem mass spectrometry. AB - In this study, a fully automated system was developed for the determination of more than 300 different pesticides from various food commodities. The samples were extracted with acetonitrile prior to the injection into the two-dimensional LC-system. No manual clean-up was needed. The separation of analytes and matrix compounds was carried out by a YMC-Pack Diol (2.1 mm*100 mm; 5 MUm; 120A) HILIC column in the first dimension. All analytes eluted within one small fraction at the beginning of the run. With a packed loop interface this fraction was transferred to the analytical reversed phase separation performed on an Agilent Poroshell 120 EC-C18 (2.1 mm*100 mm; 2.7 MUm; 120A). Some very polar compounds with a stronger retention on the HILIC column were measured directly. The method was validated for over 300 pesticides in cucumber, lemon, wheat flour, rocket, and black tea. For the large majority of the analytes, the recovery was between 70% and 120% and the relative standard deviation was clearly under 20%. The limits of detection for nearly all the compounds were at least at 0.01 mg/kg. For over 50% of the analytes, good sensitivity was observed even at 0.001 mg/kg. In spite of the injection of a pure sample extract, the method showed robust results even with dirty matrices like hops and tea. PMID- 23462111 TI - Balancing fidelity and adaptation: implementing evidence-based chronic disease prevention programs. AB - OBJECTIVES: To describe adaptations that community-based organizations (CBOs) made to evidence-based chronic disease prevention intervention programs and to discuss reasons for those adaptations. DESIGN: The process evaluation used project report forms, interviews, and focus groups to obtain information from organizational staff. SETTING: Programs were conducted in community-based organizations (n = 12) in rural southwest Georgia including churches, worksites, community coalitions, a senior center, and a clinical patient setting. PARTICIPANTS: Site coordinators (n = 15), organizational leaders (n = 7), and project committee members (n = 25) involved in program implementation at 12 funded organizations. INTERVENTION: The Emory Cancer Prevention and Control Research Network awarded mini grants to rural CBOs to implement one of 5 evidence based nutrition or physical activity programs. These sites received funding and technical assistance from Emory and agreed to conduct all required elements of the selected evidence-based program. MAIN OUTCOME MEASURES: Program implementation and context were explored, including completion of core elements, program adaptation, and reasons for adaptation that occurred at sites implementing evidence-based chronic disease prevention programs. RESULTS: Five major types of adaptations were observed: changing educational materials, intended audience, and program delivery; adding new activities; and deleting core elements. Sites had intentional or unintentional reasons for making program adaptations including enhancing engagement in the program, reaching specific audiences, increasing program fit, and reinforcing program messages. Reasons for not completing core elements (program deletions) included various types of "turbulence" or competing demands (eg, leadership/staff transitions and time constraints). CONCLUSIONS: The types of adaptations and reasons described in this evaluation support the idea that adaptation is a natural element of implementing evidence-based interventions. Building this understanding into dissemination strategies may help researchers and funders better reach communities with evidence-based interventions that are a relevant fit, while striving for fidelity. PMID- 23462112 TI - Vertical transmission of a Drosophila endosymbiont via cooption of the yolk transport and internalization machinery. AB - Spiroplasma is a diverse bacterial clade that includes many vertically transmitted insect endosymbionts, including Spiroplasma poulsonii, a natural endosymbiont of Drosophila melanogaster. These bacteria persist in the hemolymph of their adult host and exhibit efficient vertical transmission from mother to offspring. In this study, we analyzed the mechanism that underlies their vertical transmission, and here we provide strong evidence that these bacteria use the yolk uptake machinery to colonize the germ line. We show that Spiroplasma reaches the oocyte by passing through the intercellular space surrounding the ovarian follicle cells and is then endocytosed into oocytes within yolk granules during the vitellogenic stages of oogenesis. Mutations that disrupt yolk uptake by oocytes inhibit vertical Spiroplasma transmission and lead to an accumulation of these bacteria outside the oocyte. Impairment of yolk secretion by the fat body results in Spiroplasma not reaching the oocyte and a severe reduction of vertical transmission. We propose a model in which Spiroplasma first interacts with yolk in the hemolymph to gain access to the oocyte and then uses the yolk receptor, Yolkless, to be endocytosed into the oocyte. Cooption of the yolk uptake machinery is a powerful strategy for endosymbionts to target the germ line and achieve vertical transmission. This mechanism may apply to other endosymbionts and provides a possible explanation for endosymbiont host specificity. IMPORTANCE: Most insect species, including important disease vectors and crop pests, harbor vertically transmitted endosymbiotic bacteria. Studies have shown that many facultative endosymbionts, including Spiroplasma, confer protection against different classes of parasites on their hosts and therefore are attractive tools for the control of vector-borne diseases. The ability to be efficiently transmitted from females to their offspring is the key feature shaping associations between insects and their inherited endosymbionts, but to date, little is known about the mechanisms involved. In oviparous animals, yolk accumulates in developing eggs and serves to meet the nutritional demands of embryonic development. Here we show that Spiroplasma coopts the yolk transport and uptake machinery to colonize the germ line and ensure efficient vertical transmission. The uptake of yolk is a female germ line-specific feature and therefore an attractive target for cooption by endosymbionts that need to maintain high-fidelity maternal transmission. PMID- 23462113 TI - Evolutionary Genomics of Salmonella enterica Subspecies. AB - ABSTRACT Six subspecies are currently recognized in Salmonella enterica. Subspecies I (subspecies enterica) is responsible for nearly all infections in humans and warm-blooded animals, while five other subspecies are isolated principally from cold-blooded animals. We sequenced 21 phylogenetically diverse strains, including two representatives from each of the previously unsequenced five subspecies and 11 diverse new strains from S. enterica subspecies enterica, to put this species into an evolutionary perspective. The phylogeny of the subspecies was partly obscured by abundant recombination events between lineages and a relatively short period of time within which subspeciation took place. Nevertheless, a variety of different tree-building methods gave congruent evolutionary tree topologies for subspeciation. A total of 285 gene families were identified that were recruited into subspecies enterica, and most of these are of unknown function. At least 2,807 gene families were identified in one or more of the other subspecies that are not found in subspecies I or Salmonella bongori. Among these gene families were 13 new candidate effectors and 7 new candidate fimbrial clusters. A third complete type III secretion system not present in subspecies enterica (I) isolates was found in both strains of subspecies salamae (II). Some gene families had complex taxonomies, such as the type VI secretion systems, which were recruited from four different lineages in five of six subspecies. Analysis of nonsynonymous-to-synonymous substitution rates indicated that the more-recently acquired regions in S. enterica are undergoing faster fixation rates than the rest of the genome. Recently acquired AT-rich regions, which often encode virulence functions, are under ongoing selection to maintain their high AT content. IMPORTANCE We have sequenced 21 new genomes which encompass the phylogenetic diversity of Salmonella, including strains of the previously unsequenced subspecies arizonae, diarizonae, houtenae, salamae, and indica as well as new diverse strains of subspecies enterica. We have deduced possible evolutionary paths traversed by this very important zoonotic pathogen and identified novel putative virulence factors that are not found in subspecies I. Gene families gained at the time of the evolution of subspecies enterica are of particular interest because they include mechanisms by which this subspecies adapted to warm-blooded hosts. PMID- 23462114 TI - Stochastic assembly leads to alternative communities with distinct functions in a bioreactor microbial community. AB - ABSTRACT The processes and mechanisms of community assembly and its relationships to community functioning are central issues in ecology. Both deterministic and stochastic factors play important roles in shaping community composition and structure, but the connection between community assembly and ecosystem functioning remains elusive, especially in microbial communities. Here, we used microbial electrolysis cell reactors as a model system to examine the roles of stochastic assembly in determining microbial community structure and functions. Under identical environmental conditions with the same source community, ecological drift (i.e., initial stochastic colonization) and subsequent biotic interactions created dramatically different communities with little overlap among 14 identical reactors, indicating that stochastic assembly played dominant roles in determining microbial community structure. Neutral community modeling analysis revealed that deterministic factors also played significant roles in shaping microbial community structure in these reactors. Most importantly, the newly formed communities differed substantially in community functions (e.g., H2 production), which showed strong linkages to community structure. This study is the first to demonstrate that stochastic assembly plays a dominant role in determining not only community structure but also ecosystem functions. Elucidating the links among community assembly, biodiversity, and ecosystem functioning is critical to understanding ecosystem functioning, biodiversity preservation, and ecosystem management. IMPORTANCE Microorganisms are the most diverse group of life known on earth. Although it is well documented that microbial natural biodiversity is extremely high, it is not clear why such high diversity is generated and maintained. Numerous studies have established the roles of niche-based deterministic factors (e.g., pH, temperature, and salt) in shaping microbial biodiversity, the importance of stochastic processes in generating microbial biodiversity is rarely appreciated. Moreover, while microorganisms mediate many ecosystem processes, the relationship between microbial diversity and ecosystem functioning remains largely elusive. Using a well-controlled laboratory system, this study provides empirical support for the dominant role of stochastic assembly in creating variations of microbial diversity and the first explicit evidence for the critical role of community assembly in influencing ecosystem functioning. The results presented in this study represent important contributions to the understanding of the mechanisms, especially stochastic processes, involved in shaping microbial biodiversity. PMID- 23462116 TI - [West Syndrome in a 2-month-old girl]. PMID- 23462115 TI - Evolutionary analysis points to divergent physiological roles of type 1 fimbriae in Salmonella and Escherichia coli. AB - Salmonella and Escherichia coli mannose-binding type 1 fimbriae exhibit highly similar receptor specificities, morphologies, and mechanisms of assembly but are nonorthologous in nature, i.e., not closely related evolutionarily. Their operons differ in chromosomal location, gene arrangement, and regulatory components. In the current study, we performed a comparative genetic and structural analysis of the major structural subunit, FimA, from Salmonella and E. coli and found that FimA pilins undergo diverse evolutionary adaptation in the different species. Whereas the E. coli fimA locus is characterized by high allelic diversity, frequent intragenic recombination, and horizontal movement, Salmonella fimA shows structural diversity that is more than 5-fold lower without strong evidence of gene shuffling or homologous recombination. In contrast to Salmonella FimA, the amino acid substitutions in the E. coli pilin heavily target the protein regions that are predicted to be exposed on the external surface of fimbriae. Altogether, our results suggest that E. coli, but not Salmonella, type 1 fimbriae display a high level of structural diversity consistent with a strong selection for antigenic variation under immune pressure. Thus, type 1 fimbriae in these closely related bacterial species appear to function in distinctly different physiological environments. IMPORTANCE: E. coli and Salmonella are enteric bacteria that are closely related from an evolutionary perspective. They are both notorious human pathogens, though with somewhat distinct ecologies and virulence mechanisms. Type 1 fimbriae are rod-shaped surface appendages found in most E. coli and Salmonella isolates. In both species, they mediate bacterial adhesion to mannose receptors on host cells and share essentially the same morphology and assembly mechanisms. Here we show that despite the strong resemblances in function and structure, they are exposed to very different natural selection environments. Sequence analysis indicates that E. coli, but not Salmonella, fimbriae are subjected to strong immune pressure, resulting in a high level of major fimbrial protein gene shuffling and interbacterial transfer. Thus, evolutionary analysis tools can provide evidence of divergent physiological roles of functionally similar traits in different bacterial species. PMID- 23462117 TI - Aryl hydrocarbon receptor controls murine mast cell homeostasis. AB - We propose that the aryl hydrocarbon receptor (AhR), a unique chemical sensor, is critical in controlling mast cell differentiation, growth, and function in vitro and in vivo. In antigen-stimulated mast cells, exposure to AhR ligands resulted in a calcium- and reactive oxygen species (ROS)-dependent increase of reversible oxidation in and reduced activity of SHP-2 phosphatase, leading to enhanced mast cell signaling, degranulation, and mediator and cytokine release, as well as the in vivo anaphylactic response. Surprisingly, significant mast cell deficiency was noted in AhR-null mice due to defective calcium signaling and mitochondrial function, concomitant with reduced expression of c-kit and cytosolic STAT proteins, as well as enhanced intracellular ROS and apoptosis. Consequently, AhR null mast cells responded poorly to stimulation, demonstrating a critical role of AhR signaling in maintaining mast cell homeostasis. PMID- 23462119 TI - Cardiac remodeling during and after renin-angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats. AB - This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral administration of indole-3 carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically and the hearts were excised for molecular and immunohistochemical analyses. Echocardiographic studies revealed that four weeks of RAS-stimulation incited a cardiac remodeling process characterized by increased left ventricular (LV) wall thickness, decreased LV volumes, and shortening of the left ventricle. Hypertrophic genes were highly upregulated, whereas in substantial activation a fibrotic response was absent. Four weeks after withdrawal of I3C, (pro)renin levels were normalized in all IHR. While in adult IHR BP returned to normal, hypertension was sustained in young IHR. Despite the latter, myocardial hypertrophy was fully regressed in both young and adult IHR. We conclude that (pro)renin-induced severe hypertension in IHR causes an age-independent fully reversible myocardial concentric hypertrophic remodeling, despite a continued elevated BP in young IHR. PMID- 23462120 TI - A patient with obstructive jaundice. PMID- 23462118 TI - Characterization of the TGF-beta1 signaling abnormalities in the Gata1low mouse model of myelofibrosis. AB - Primary myelofibrosis (PMF) is characterized by fibrosis, ineffective hematopoiesis in marrow, and hematopoiesis in extramedullary sites and is associated with abnormal megakaryocyte (MK) development and increased transforming growth factor (TGF)-beta1 release. To clarify the role of TGF-beta1 in the pathogenesis of this disease, the TGF-beta1 signaling pathway of marrow and spleen of the Gata1(low) mouse model of myelofibrosis (MF) was profiled and the consequences of inhibition of TGF-beta1 signaling on disease manifestations determined. The expression of 20 genes in marrow and 36 genes in spleen of Gata1(low) mice was altered. David-pathway analyses identified alterations of TGF beta1, Hedgehog, and p53 signaling in marrow and spleen and of mammalian target of rapamycin (mTOR) in spleen only and predicted that these alterations would induce consequences consistent with the Gata1(low) phenotype (increased apoptosis and G1 arrest both in marrow and spleen and increased osteoblast differentiation and reduced ubiquitin-mediated proteolysis in marrow only). Inhibition of TGF beta1 signaling normalized the expression of p53-related genes, restoring hematopoiesis and MK development and reducing fibrosis, neovascularization, and osteogenesis in marrow. It also normalized p53/mTOR/Hedgehog-related genes in spleen, reducing extramedullary hematopoiesis. These data identify altered expression signatures of TGF-beta1 signaling that may be responsible for MF in Gata1(low) mice and may represent additional targets for therapeutic intervention in PMF. PMID- 23462121 TI - Guidelines for colonoscopy surveillance: a clinical conundrum. PMID- 23462122 TI - Genomic decoding of intrahepatic cholangiocarcinoma reveals therapeutic opportunities. PMID- 23462123 TI - Investing in academic medicine research mentoring: low cost, high return. PMID- 23462124 TI - Fecal microbiota transfer may increase irritable bowel syndrome and inflammatory bowel diseases-associated bacteria. PMID- 23462125 TI - A common finding in an uncommon location. PMID- 23462126 TI - EndoFLIP assessment of achalasia therapy: interpreting the distensibility data is a bit of a stretch. PMID- 23462127 TI - The cheesecake factory: lessons for expanding the menu for colorectal cancer screening. PMID- 23462128 TI - A rare cause of nausea and vomiting. PMID- 23462129 TI - Regulation of host gene expression by gut microbiota. PMID- 23462130 TI - A rare submucosal tumor of the stomach. PMID- 23462131 TI - A cauliflower-appearing mass in the colon. PMID- 23462132 TI - Ustekinumab for moderate-to-severe Crohn's disease. PMID- 23462133 TI - Bile acids as modulators of gut microbiota linking dietary habits and inflammatory bowel disease: a potentially dangerous liaison. PMID- 23462134 TI - Predicting clinical outcomes with elastography in primary biliary cirrhosis: one step closer? PMID- 23462135 TI - MRI evidence of trigeminal sensory neuropathy in Sjogren's Syndrome. PMID- 23462136 TI - Crystal structure of Ruminococcus albus cellobiose 2-epimerase: structural insights into epimerization of unmodified sugar. AB - Enzymatic epimerization is an important modification for carbohydrates to acquire diverse functions attributable to their stereoisomers. Cellobiose 2-epimerase (CE) catalyzes interconversion between d-glucose and d-mannose residues at the reducing end of beta-1,4-linked oligosaccharides. Here, we solved the structure of Ruminococcus albus CE (RaCE). The structure of RaCE showed strong similarity to those of N-acetyl-D-glucosamine 2-epimerase and aldose-ketose isomerase YihS with a high degree of conservation of residues around the catalytic center, although sequence identity between them is low. Based on structural comparison, we found that His184 is required for RaCE activity as the third histidine added to two essential histidines in other sugar epimerases/isomerases. This finding was confirmed by mutagenesis, suggesting a new catalytic mechanism for CE involving three histidines. PMID- 23462137 TI - Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands. AB - Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand. PMID- 23462139 TI - Re:imagine: a report on the UHC Annual Conference 2012. PMID- 23462140 TI - Priority interventions to reduce HIV transmission in sex work settings in sub Saharan Africa and delivery of these services. AB - INTRODUCTION: Virtually no African country provides HIV prevention services in sex work settings with an adequate scale and intensity. Uncertainty remains about the optimal set of interventions and mode of delivery. METHODS: We systematically reviewed studies reporting interventions for reducing HIV transmission among female sex workers in sub-Saharan Africa between January 2000 and July 2011. Medline (PubMed) and non-indexed journals were searched for studies with quantitative study outcomes. RESULTS: We located 26 studies, including seven randomized trials. Evidence supports implementation of the following interventions to reduce unprotected sex among female sex workers: peer-mediated condom promotion, risk-reduction counselling and skills-building for safer sex. One study found that interventions to counter hazardous alcohol-use lowered unprotected sex. Data also show effectiveness of screening for sexually transmitted infections (STIs) and syndromic STI treatment, but experience with periodic presumptive treatment is limited. HIV testing and counselling is essential for facilitating sex workers' access to care and antiretroviral treatment (ART), but testing models for sex workers and indeed for ART access are little studied, as are structural interventions, which create conditions conducive for risk reduction. With the exception of Senegal, persistent criminalization of sex work across Africa reduces sex workers' control over working conditions and impedes their access to health services. It also obstructs health-service provision and legal protection. CONCLUSIONS: There is sufficient evidence of effectiveness of targeted interventions with female sex workers in Africa to inform delivery of services for this population. With improved planning and political will, services - including peer interventions, condom promotion and STI screening - would act at multiple levels to reduce HIV exposure and transmission efficiency among sex workers. Initiatives are required to enhance access to HIV testing and ART for sex workers, using current CD4 thresholds, or possibly earlier for prevention. Services implemented at sufficient scale and intensity also serve as a platform for subsequent community mobilization and sex worker empowerment, and alleviate a major source of incident infection sustaining even generalized HIV epidemics. Ultimately, structural and legal changes that align public health and human rights are needed to ensure that sex workers on the continent are adequately protected from HIV. PMID- 23462141 TI - The practitioner proposes a treatment change and the patient declines: what to do next? AB - OBJECTIVE: This study describes how pain practitioners can elicit the beliefs that are responsible for patients' judgments against considering a treatment change and activate collaborative decision making. METHODS: Beliefs of 139 chronic pain patients who are in treatment but continue to experience significant pain were reduced to 7 items about the significance of pain on the patient's life. The items were aggregated into 4 decision models that predict which patients are actually considering a change in their current treatment. RESULTS: While only 34% of study participants were considering a treatment change overall, the percentage ranged from 20 to 70, depending on their ratings about current consequences of pain, emotional influence, and long-term impact. Generalized linear model analysis confirmed that a simple additive model of these 3 beliefs is the best predictor. CONCLUSION: Initial opposition to a treatment change is a conditional judgment and subject to change as specific beliefs become incompatible with patients' current conditions. These beliefs can be elicited through dialog by asking 3 questions. PMID- 23462142 TI - Medical and surgical management of primary cardiac tumours in infants and children. AB - Primary cardiac tumours in infants and children are extremely rare, with an estimated incidence of 0.2% according to echocardiographic studies. Owing to their rarity, there is very little literature available, and most knowledge is based on collections of case reports. Therefore, we reviewed retrospectively our 27 years of clinical experience on the overall management of cardiac tumours among children in order to improve not only our knowledge but also to provide others with information about the incidence, clinical presentation, management, and long-term outcome of this rare disease. Between April, 1982 and April, 2009, 52 children were diagnosed with cardiac tumours at our Institution. Medical records and follow-up echocardiographic evaluations were studied. The diagnosis was prenatal in 35% of the patients. The most frequent tumour types were rhabdomyomas (61.5%), fibromas (15.4%), and myxomas (5.8%). There were no cases of primary malignant tumours. All diagnoses were achieved using two-dimensional echocardiography, and for 12 patients a pathological analysis was carried out. A total of 41 patients (79%) were managed medically, whereas 11 (21%) patients underwent surgical treatment. At a mean follow-up of 7.2 +/- 5.4 years, two patients died of complications related to cardiac transplantation; all the remaining patients are in excellent clinical condition. In conclusion, cardiac tumours in paediatric practice are usually clinically and histologically benign. Only a few cases need surgery. Up to one-third of the cardiac masses are detectable prenatally. Rhabdomyoma is the most common histotype, followed by fibroma and myxoma. The long-term prognosis is generally good. PMID- 23462143 TI - Treatment with 5-azacytidin upregulates the expression of CD20 in CD20-negative B cell acute lymphoblastic leukemia: a case report. PMID- 23462144 TI - Impact of antithymocyte globulin on the need for platelet transfusions during reduced-intensity conditioning administration before allogeneic stem cell transplantation. PMID- 23462145 TI - Molecular characterization of a manganese superoxide dismutase and copper/zinc superoxide dismutase from the mussel Mytilus galloprovincialis. AB - The full-length cDNA sequences coding respectively for a manganese superoxide dismutase (Mg-MnSOD) and copper/zinc superoxide dismutase (Mg-CuZnSOD) were cloned from Mytilus galloprovincialis. Mg-MnSOD and Mg-CuZnSOD cDNAs encoded a polypeptide of 228 and 211 amino acids, respectively. Sequence analysis indicated Mg-MnSOD was a mitochondrial MnSOD and Mg-CuZnSOD was an intracellular CuZnSOD. Multiple alignment analysis showed that both Mg-MnSOD and Mg-CuZnSOD sequences had the common features conserved in MnSODs and CuZnSODs, respectively. Phylogenetic analysis revealed that Mg-MnSOD clustered together with MnSODs from other mollusks, whereas Mg-CuZnSOD clustered with other mollusk intracellular CuZnSODs with a wider phylogenetic distance. By quantitative real-time RT-PCR (qPCR) analysis, both Mg-MnSOD and Mg-CuZnSOD transcripts were detected in all tissues examined with the highest expression level in hepatopancreas. Following bacterial challenge, the expression level of Mg-MnSOD and Mg-CuZnSOD increased first and subsequently decreased to the original level in hemocytes. In hepatopancreas, Mg-CuZnSOD mRNA was up-regulated significantly at 72 h and 96 h post challenge, while the level of Mg-MnSOD transcript had no significant change. Therefore, Mg-MnSOD and Mg-CuZnSOD expressions were inducible and they were probably involved in the immune response against bacterial challenge. These results suggest that these SODs may play important roles in the immune defense system of M. galloprovincialis and perhaps contribute to the protective effects against oxidative stress in this mussel. PMID- 23462146 TI - Innate immunity of finfish: primordial conservation and function of viral RNA sensors in teleosts. AB - During the past decade, huge progress has been made in research into teleost PAMPs (pathogen-associated molecule patterns) recognition receptors (PRRs). Numerous fish PRR genes have been identified, and the primordial functions of PRRs involved in the innate immune response to viral infection (especially those responsible for sensing viral RNA) have been increasingly clarified in teleosts. Particular progress has been made in our understanding of Toll-like receptors (TLRs) and retinoic acid inducible gene I (RIG-I)-like receptors (RLRs). However, there are important evolutionary differences between teleosts and mammals; for instance, seven TLR repertoires (TLR5S, -14, -19, -20, -21, -22 and -23) are present in teleosts but not in mammals, indicating that some TLRs likely possess different functions. Thus, comparison of PRRs in teleosts and mammals may help us understand the immune responses triggered by host-pathogen interactions in teleosts. In this article, the evolutionary conservations and divergences in the PRR mechanisms of teleosts and mammals are examined, with a focus on their molecular features and the recognition of viral RNA by fish TLRs and RLRs. In addition, the mechanism of type I interferon gene expression in teleosts, which is enhanced after the recognition of viral RNA by fish TLRs and RLRs, is also introduced. PMID- 23462147 TI - An opioid growth factor receptor (OGFR) for [Met5]-enkephalin in Chlamys farreri. AB - Opioid growth factor receptor (OGFR) is a receptor for [Met(5)]-enkephalin and plays important roles in the regulation of cell growth and embryonic development. In the present study, a cDNA of 2381 bp for the scallop Chlamys farreri OGFR (designated as CfOGFR) was identified by rapid amplification of cDNA ends (RACE) approach and expression sequence tag (EST) analysis. The complete cDNA sequence of CfOGFR contained an open reading frame (ORF) of 1200 bp, which encoded a protein of 399 amino acids. The amino acid sequence of CfOGFR shared 33-64% similarity with other OGFRs. There was a low complexity domain and a conserved OGFR_N domain at the N-terminal of CfOGFR. The mRNA transcripts of CfOGFR were constitutively expressed in the tested tissues with the highest expression level in hepatopancreas. During the early embryonic development, the mRNA transcripts of CfOGFR could be detected in different development stages, where the expression level presented a downward trend as a whole. The stimulations of LPS, Glu and poly (I:C) significantly induced the expression of CfOGFR mRNA in hemocytes (P < 0.05), while PGN stimulation exerted no influence. Co-IP and western blot results revealed that the CfOGFR in hemocytes displayed high affinity and specificity to [Met(5)]-enkephalin. Exogenous [Met(5)]-enkephalin was observed to inhibit the proliferation of HEK293T cells transfected with pcDNA3.1(+)-CfOGFR in a time and dosage dependent manner. These results collectively indicated that CfOGFR, as a homolog of OGFRs in C. farreri, played an important role in cells proliferation, and might be involved in the immune response of scallops. PMID- 23462148 TI - Impaired TLR2 and TLR7 response in olive flounder infected with viral haemorrhagic septicaemia virus at host susceptible 15 degrees C but high at non susceptible 20 degrees C. AB - The olive flounder (Paralichthys olivaceus) is susceptible to viral haemorrhagic septicaemia virus (VHSV) at 15 degrees C but no mortality is observed at 20 degrees C even though the virus can grow profusely in vitro. Thus, we designed an experiment to better understand the immune response of olive flounder to VHSV when the host reared at 15 degrees C or 20 degrees C and infected with the virus. Olive flounder (18-22 g) reared at 15 +/- 0.5 degrees C or 20 +/- 0.5 degrees C were intra-peritoneally injected with VHSV (10(7.8) TCID50/fish) and sampled (n = 5) for head kidney at 3, 6, 12 hpi, 1, 2, 4 and 7 dpi; similarly, mock injected control groups (n = 5). Real-time PCR-based absolute quantification method was followed to quantify copies of VHSV gRNA and mRNA, while the immune gene expression of the olive flounder was quantified relative to internal control, beta-actin. Viral infection resulted in a cumulative mortality of 24% in olive flounder reared at 15 degrees C, but no mortality was recorded in the 20 degrees C group or control groups. TLR2 and TLR7 expression at 15 degrees C was enhanced during early-infection phase (3-6 hpi) and recovery phase (4-7 dpi) when viral transcription was low, but expression was significantly reduced (12 hpi-1 dpi) at peak-infection period. However, the 20 degrees C group showed low viral transcription and expressed high level of TLR7 and a moderately higher unchanged level of TLR2. In both the groups, TLR3 expression was unaffected. Nevertheless, expression of MDA5 and LGP2 increased significantly irrespective of rearing temperature at the time of peak infection, hence at 15 degrees C VHSV down regulated expression of TLR2 and TLR7 but not MDA5 or LGP2. Comparatively, at 15 degrees C IRF3 expressed high but IRF7 remained very low. Interleukins (IL-1beta, IL-6 and IL-8) were significantly elevated in both the groups, but quicker and for a shorter period at 20 degrees C. In the 15 degrees C group, an extended period of expression of ILs could create an unsafe prolonged inflammatory condition. The olive flounders expressed high ISGs at 15 degrees C but were lagging by 12 h than 20 degrees C group. Based on these findings, we concluded that viral-mediated disruption of TLR2 and TLR7 expression in the 15 degrees C group could have delayed the host interferon response and provided a window for high viral growth. However, an effective host immune response at 20 degrees C contained VHSV from reaching the critical limit. PMID- 23462149 TI - Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention: results from the SLIM study. AB - BACKGROUND AND AIMS: The Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM), a randomized controlled trial, directed at diet and physical activity in impaired glucose tolerant subjects was effective to improve glucose tolerance and prevent type 2 diabetes. The aim of this study was to determine the effects of the SLIM lifestyle intervention on the incidence and prevalence of the metabolic syndrome (MetS) during the active intervention and four years thereafter. METHODS AND RESULTS: MetS was diagnosed according to the NCEP ATP III criteria. At baseline, 66.4% of all participants (n = 146, age 57 +/ 7 years, BMI 29.7 +/- 3.6, 51.3% female) fulfilled the criteria for MetS. No significant difference in MetS prevalence was observed between the intervention (63.9%) and control group (68.9%). At the end of active intervention (average duration 4.2 +/- 2.0 years), prevalence of MetS was significantly lower in the intervention group (52.6%, n = 57) compared to the control group (74.6%, n = 59) (p = 0.014). Furthermore, in participants without MetS at baseline, cumulative incidence of MetS was 18.2% in the intervention group at the end of active intervention, compared to 73.7% in the control group (Log-rank test, p = 0.011). Four years after stopping active intervention, the reduced incidence of MetS was maintained (Log-rank test, p = 0.002). CONCLUSION: In conclusion, a combined diet and-exercise intervention to improve glucose tolerance, not only prevented type 2 diabetes, but also reduced the prevalence of MetS and prevented MetS development, showing the long-term impact of lifestyle intervention on cardiovascular risk reduction. PMID- 23462150 TI - H+ /K+ ATPase expression in human parietal cells and gastric acid secretion in elderly individuals. AB - OBJECTIVE: To investigate whether the ultrastructure and hydrogen potassium adenosine triphosphate (H+ /K+ ATPase) expression of human parietal cells were associated with aging. METHODS: In all, 50 participants who underwent gastroscopy due to dyspepsia were divided into two age groups, with 19 in the younger group (YG, aged 20-59 years) and 31 in the elder group (EG, aged >=60 years). The ultrastructure of their parietal cell was determined by electron microscopy (EM), and the expressions of H+ /K+ ATPase alpha-subunit mRNA and beta-unit protein were detected. Furthermore, 24-h esophageal pH monitoring was performed in the two groups. RESULTS: EM images showed no distinct difference in the morphology and distribution of parietal cells or the acid secretion-related organelle between the two groups. There were no differences between YG and EG in the proportion of mitochondria and the tubulovesicular system area. The expressions of H+ /K+ ATPase alpha-subunit mRNA and beta-subunit protein showed no age related alteration between YG and EG. The expression of H+ /K+ ATPase alpha subunit mRNA in EG was higher than that in YG, whereas the expression of beta subunit protein was significantly higher in those aged >=80 years than in the YG. No significant difference was found in the 24-h esophageal pH monitoring between YG and EG. CONCLUSION: Acid secretion-related organelles in parietal cells do not degenerate with aging, the expression of H+ /K+ ATPase even shows a trend to increase, indicating the existence of intact molecular biological basis for acid secretion in healthy elderly individuals. PMID- 23462151 TI - Trends of heroin use and heroin injection epidemics in Europe: findings from the EMCDDA treatment demand indicator (TDI). AB - We estimate trends and geographical differences in the heroin epidemic in the European Union plus Croatia and Turkey by analyzing aggregated data on first heroin treatment admissions (cases) during 2000-2009. In 2005-2009 the proportion of drug injectors was higher in Central and Eastern European countries (CEECs) than in Western European countries (WECs), whereas the opposite occurred with mean age at first heroin use and first treatment. During this period, the number of cases, cases per center, and proportion of injectors in WECs declined, whereas mean age at first treatment and first heroin use increased. The opposite occurred in Turkey, except for proportion of injectors, while trends were less clear in the other CEECs. In the 7 WECs with data, trends in 2000-2005 and 2005-2009 were similar. This suggests that the number of recent-onset heroin users and heroin injectors may have declined some years before the study period, especially in WECs. PMID- 23462152 TI - Willingness and appropriateness of peers participating in emerging adults' substance misuse treatment. AB - This study investigates the feasibility of adapting empirically-supported family treatments for emerging adult peer dyads. Data were collected (n=84) from emerging adults and their peers. Peers completed measures of substance use, willingness to participate in their friends' treatments, and an adapted version of the Significant Other Behavior Questionnaire (SBQ), which measures concerned significant others' (CSO) responses to another's use such a punishing, supporting, or withdrawing from the user. Peers were more likely to support sobriety or enable use, versus punishing use or withdrawing from their friends. Overall, peers were quite willing to assist in treatment, but heavily using peers were less enthusiastic. For some emerging adults, their current peers may represent untapped resources to integrate into treatment, and providing peer enhanced treatments may expand the reach of services to non-treatment seeking populations. PMID- 23462153 TI - Pirfenidone should be prescribed for patients with idiopathic pulmonary fibrosis. PMID- 23462154 TI - Macrolides and pneumonia. PMID- 23462155 TI - Pirfenidone for IPF: pro/con debate; the 'con' viewpoint. PMID- 23462156 TI - The Emperor's New Clothes II--time for regulators to wake up and take responsibility for unnecessary asthma morbidity: time for the second aerosol 'transition'. AB - The rate of technological improvement continues to accelerate. Regulators in every field dealing with consumer products continue to set ever higher standards to protect consumers from adverse events and use 'recalls' to remove products that prove to be harmful from the market. In the field of medical products in general the issues of 'human factors' and 'usability' are now, quite rightly, a major issue at least among regulators in the USA. The elephant in the inhaled therapy room is of course the continued use of obsolete, portable inhalers which few patients can use effectively for the treatment of asthma. Countless studies have demonstrated that the inability of patients to use these devices effectively is a major factor in perpetuating unnecessarily high levels of morbidity. They fail to meet basic usability standards and do not incorporate the facility to provide feedback to patient and clinician. More than 20 years ago regulators deemed that pressurised metered dose inhalers containing chlorofluorocarbons should be removed from the market on environmental grounds even though their use accounted for less than 0.5% of chlorofluorocarbon use. Surely asthmatic patients require the same level of protection. Unfortunately regulators appear determined to fossilise the field in a 1950's time warp by ensuring that the failings of obsolete technology are perpetuated in any 'generic' device. The time has come for regulators to meet their obligations to 'protect the public health by assuring the safety, effectiveness, and security of drugs, vaccines and other biological products, medical devices....' and mandate the phasing out of these antiquated devices within the next decade in order to reduce the unacceptably high burden of preventable morbidity and death associated with their use. PMID- 23462159 TI - Another chemokine target bites the dust? PMID- 23462160 TI - Evolution in surgical approach and techniques for lung cancer. PMID- 23462161 TI - Short communication: imputing genotypes using PedImpute fast algorithm combining pedigree and population information. AB - Routine genomic evaluations frequently include a preliminary imputation step, requiring high accuracy and reduced computing time. A new algorithm, PedImpute (http://dekoppel.eu/pedimpute/), was developed and compared with findhap (http://aipl.arsusda.gov/software/findhap/) and BEAGLE (http://faculty.washington.edu/browning/beagle/beagle.html), using 19,904 Holstein genotypes from a 4-country international collaboration (United States, Canada, UK, and Italy). Different scenarios were evaluated on a sample subset that included only single nucleotide polymorphism from the Bovine low-density (LD) Illumina BeadChip (Illumina Inc., San Diego, CA). Comparative criteria were computing time, percentage of missing alleles, percentage of wrongly imputed alleles, and the allelic squared correlation. Imputation accuracy on ungenotyped animals was also analyzed. The algorithm PedImpute was slightly more accurate and faster than findhap and BEAGLE when sire, dam, and maternal grandsire were genotyped at high density. On the other hand, BEAGLE performed better than both PedImpute and findhap for animals with at least one close relative not genotyped or genotyped at low density. However, computing time and resources using BEAGLE were incompatible with routine genomic evaluations in Italy. Error rate and allelic squared correlation attained by PedImpute ranged from 0.2 to 1.1% and from 96.6 to 99.3%, respectively. When complete genomic information on sire, dam, and maternal grandsire are available, as expected to be the case in the close future in (at least) dairy cattle, and considering accuracies obtained and computation time required, PedImpute represents a valuable choice in routine evaluations among the algorithms tested. PMID- 23462162 TI - Comparative study of flavor in cholesterol-removed Gouda cheese and Gouda cheese during ripening. AB - This study was performed to compare the flavor compounds of cholesterol-removed Gouda cheese (CRGC) and those of Gouda cheese (control) during ripening. The CRGC was made using milk treated with cross-linked beta-cyclodextrin (beta-CD). The solid-phase microextraction (SPME) method was used to extract flavor compounds from Gouda cheese. In both CRGC and control cheese, 31 flavor compounds were identified, including 6 free fatty acids, 5 esters, 5 ketones, 1 aldehyde, 3 lactones, 5 alcohols, and 6 miscellaneous compounds. Free fatty acids were the most abundant flavor compounds quantified in CRGC and control cheese. In the early stage of ripening, concentrations of flavor compounds in CRGC and control cheese were 16.42 and 10.38 mg/kg, respectively. At 6 mo, they increased to 40.90 and 67.89 mg/kg, respectively. A group of esters was the second abundant flavor compound in CRGC and control cheese. At the initial stage of ripening, total concentrations of esters were 12.94 (CRGC) and 10.95 mg/kg (control) and they increased to 22.73 (CRGC) and 27.68 mg/kg (control). Total concentrations of ketones were 1.96 (CRGC) and 6.49 mg/kg (control) at the initial stage of ripening. After 6 mo of ripening, total concentrations reached 11.32 (CRGC) and 52.43 mg/kg (control). In the case of the lactones, at the early stage of ripening, total concentrations of CRGC and control cheese were 0.63 and 0.84mg/kg, respectively, and then increased to 1.73 (CRGC) and 3.25mg/kg (control) at the end of ripening. Based on the results of this study, the flavor compounds of CRGC and control showed slightly different profiles during ripening. PMID- 23462163 TI - Jersey calf performance in response to high-protein, high-fat liquid feeds with varied fatty acid profiles: intake and performance. AB - The objective of this study was to determine whether altering the fatty acid (FA) profile of milk replacer (MR) with coconut oil, which contains a high concentration of medium-chain FA, to more closely match the FA profile typically found in whole milk from Jersey cows, would improve Jersey calf performance. Male (n=18) and female (n=32) Jersey calves were assigned at birth to 1 of 4 liquid diets: (1) pasteurized Jersey saleable whole milk [pSWM; 27.9% crude protein (CP) and 33.5% fat]; (2) 29.3% CP and 29.1% fat MR, containing 100% of fat as edible lard (100:00); (3) 28.2% CP and 28.0% fat MR, containing 80% of fat as lard and 20% as coconut oil (80:20); and (4) 28.2% CP and 28.3% fat MR, containing 60% of the fat as lard and 40% as coconut oil (60:40). Calves were fed their respective liquid diet twice daily during wk 1 through 7 and once daily until weaning (approximately wk 8). Calves had ad libitum access to grain and water, and calves were monitored 1 wk postweaning. Average daily gain and body weight did not differ by treatment. Calves fed pSWM tended to have greater hip height (HH) than calves fed 80:20 (80.5 vs. 79.7 cm). Coconut oil tended to have a quadratic effect on HH, with calves fed 100:00, 80:20, and 60:40 at 79.2, 79.7, and 78.5 cm, respectively. No difference was observed in withers height between pSWM and 80:20. Coconut oil had a quadratic effect on withers height, with calves fed 100:00, 80:20, and 60:40 at 76.6, 77.5, and 76.5 cm, respectively. Change in HH from birth to 9 wk tended to be greater for calves fed pSWM than calves fed 80:20 (0.218 vs. 0.194 cm/d). Calves fed pSWM had higher milk dry matter intake (DMI) than calves fed 80:20 (0.580 vs. 0.518 kg/d). No effect of coconut oil was observed on milk DMI. Grain DMI and total DMI did not differ among treatments. Calves fed pSWM had an increase in days with a fecal score >2 compared with calves fed 80:20 (4.24 vs. 2.00 d). Coconut oil had a quadratic effect on fecal score, with calves fed 100:00, 80:20, and 60:40 scoring 4.00, 2.00, and 3.63 d, respectively. Respiratory score did not differ among treatments. In conclusion, DMI and average daily gain were similar among treatments. However, differences among treatments in skeletal growth and fecal scores are indicative of some possible benefits of medium-chain FA on calf health and performance. PMID- 23462164 TI - Prevalence and antimicrobial susceptibility of Acinetobacter from raw bulk tank milk in Korea. AB - The objective of this study was to determine the prevalence of Acinetobacter spp. in bulk tank milk (BTM) samples from different provinces of Korea and to analyze their antimicrobial susceptibility. Altogether, 2,287 BTM samples were investigated. Among them, Acinetobacter spp. were isolated from 176 BTM samples. Out of 176 Acinetobacter spp., 57 isolates were identified as Acinetobacter baumannii. None of the isolates were resistant to cefepime, imipenem, meropenem, ciprofloxacin, levofloxacin, or colistin. Resistance to amikacin, gentamicin, piperacillin, and cefotaxime was 2.3, 7.4, 2.3, and 4.0%, respectively. Acinetobacter spp. were least susceptible to tetracycline (17.6%), followed by trimethoprim-sulfamethoxazole (15.9%), ceftazidime (10.8%), and ampicillin sulbactam (10.2%). Overall, A. baumannii strains were susceptible to most of the antimicrobial agents tested compared with other Acinetobacter spp. The Acinetobacter isolates showed 17 different patterns of antimicrobial resistance. The most frequent resistance profile observed was ampicillin-sulbactam (n=13), followed by tetracycline (n=9), ceftazidime-tetracycline (n=8), and trimethoprim sulfamethoxazole-tetracycline (n=8). The results of this study confirmed that Acinetobacter, including A. baumannii strains, are present in BTM, which clearly showed the importance of examining BTM not only for foodborne pathogens but also for Acinetobacter spp., which could be of public health concern. To the best of our knowledge, this is the first report of Acinetobacter spp. in BTM samples from Korea. PMID- 23462165 TI - Short communication: estimation of genetic parameters for residual feed intake and feeding behavior traits in dairy heifers. AB - Data from a 2-yr feeding trial of Holstein-Friesian heifers (n=842) were used to examine the heritability of feeding behavior traits and their relationships with residual feed intake (RFI), a measure of feed efficiency. Five traits were assessed: number of meals, feeding duration, dry matter intake (DMI), eating rate, and average meal size. For estimating genetic parameters, all traits were simultaneously fitted in a multivariate model with a genomic relationship matrix calculated from heifers' high-density genotype data. All 5 traits were moderately heritable (0.45-0.50), which was slightly higher than the estimate for RFI (0.40 +/- 0.09). Two traits had modest genetic correlations with RFI (DMI and feeding duration; 0.45 +/- 0.13 and 0.27 +/- 0.15, respectively), and 2 traits had modest phenotypic correlations with RFI (DMI and eating rate; 0.52 +/- 0.03 and 0.23 +/- 0.04, respectively). The results indicate that feeding behavior (1) may differ between efficient and inefficient animals and (2) may be useful for selecting animals with better feed efficiency. However, the limitation is that measurements on DMI are still essential. It is therefore possible that a more efficient selection tool for RFI may be the use of high-density DNA markers to make direct genomic predictions for RFI. PMID- 23462166 TI - Effect of fatty acids on the beta-oxidation system and thioesterase of Lactococcus lactis subspecies lactis. AB - The influence of fatty acids on the beta-oxidation system and thioesterase of Lactococcus lactis was investigated in this study. The results showed that fatty acids (C8:0-C16:0) significantly inhibited the growth of Lactococcus lactis, and laurate (C12:0) had the highest bactericidal effects. We detected the maximum activity of beta-oxidation at different incubation times (8, 12, and 18h) to be 6.460, 7.751, and 8.203, respectively, and the maximum activity of thioesterase at different incubation times (8, 12, and 18h) to be 19.498, 27.180, and 12.800, respectively. Fatty acids were seen to induce the beta-oxidation system and activity of thioesterase; decanoic acid (C10:0) and palmitic acid (C16:0) were also seen to induce the beta-oxidation system of Lactococcus lactis, but the induced ability was significantly different. Octanoic acid (C8:0) and palmitic acid (C16:0) were seen to induce thioesterase activity in Lactococcus lactis. When 1mM palmitic acid (C16:0) was added to M17 broth, the activity of thioesterase increased 5-fold after 2min; however, adding octanoic acid (C8:0) changed the activity little. Evidence showed that the ability to induce the beta oxidation system and thioesterase activity was related to the fatty acids' chain lengths. PMID- 23462167 TI - Effect of replacing soybean meal protein with protein from upland cottonseed, Pima cottonseed, or extruded Pima cottonseed on production of lactating dairy cows. AB - Pima cotton production is increasing in the United States, but Pima cottonseed generally contains higher concentrations of the antinutritive pigment gossypol than conventional upland cottonseed. Heating promotes the reaction of gossypol with protein, reducing gossypol absorption and toxicity. The objective of this study was to assess the nutritional value for dairy cattle of Pima cottonseed cake (PCSC) that was heated and oil largely removed by an experimental extrusion process, compared with upland cottonseed (UCS) and Pima cottonseed (PCS). The PCS had greater crude protein (CP) and ether extract, less neutral detergent fiber (NDF) and acid detergent fiber (ADF), similar total gossypol, but higher (-) gossypol isomer compared with UCS. Extrusion reduced lipid content by 73%, increased concentrations of CP, NDF, and ADF, and reduced total gossypol, (+) gossypol, and (-)-gossypol in PCSC versus PCS. Forty lactating Holsteins (8 with ruminal cannulas) were blocked by days in milk into 5 squares in a replicated, incomplete 8 * 8 Latin square, and were fed diets containing, on a dry matter (DM) basis, 30% alfalfa silage, 31% corn silage, 21 to 25% high-moisture corn, and about 15% CP. Diets were fed as total mixed rations for ad libitum intake. Supplemental CP was from (1) solvent soybean meal (SSBM) only or 50% from SSBM plus 50% from (2) UCS, (3) PCS, (4) PCSC, (5) UCS plus PCS, and (6) UCS plus PCSC, or (7) 50% from expeller soybean meal (ESBM) plus 50% from PCS, and (8) 50% from ESBM plus 50% from PCSC. Periods were 4 wk long (total of 16 wk); production data were collected over the last 2 wk and blood and ruminal samples were taken on d 28 of each period. Data were analyzed using Proc Mixed of SAS (SAS Institute Inc., Cary, NC). Diet affected dry matter intake, with greatest intake on diet 6 and lowest intake on diets 1 and 3. The highest milk fat content was observed on diet 5 and the greatest fat yield on diet 7; fat content and yield were lowest on diet 1 (soybean meal control). Milk fat secretion was proportional to dietary fat content, indicating that cottonseed oil was used effectively for milk fat synthesis. We observed a trend for an effect on milk protein yield with the greatest protein secretion occurring on diet 7. Milk urea was lowest on diets 3, 7, and 8. Ruminal concentrations of branched-chain volatile fatty acids were lower, or tended to be lower, when PCSC replaced either UCS or PCS in the diet, suggesting reduced degradation and increased escape of PCSC protein. Among cottonseed-containing diets, total gossypol intake was lowest on PCSC, intermediate on PCS, and highest on UCS. Total gossypol and both (+)- and (-) isomers of gossypol were higher in blood plasma on PCS and lower on PCSC than on the corresponding diets containing UCS, indicating that the extrusion process reduced gossypol absorption. In this trial, production on diets supplemented with UCS, PCS, or PCSC was comparable to that on diets containing soybean meal. PMID- 23462168 TI - Increased milk protein synthesis in response to exogenous growth hormone is associated with changes in mechanistic (mammalian) target of rapamycin (mTOR)C1 dependent and independent cell signaling. AB - The objective of this study was to determine if increased milk protein synthesis observed in lactating dairy cows treated with growth hormone (GH) was associated with mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) regulation of downstream factors controlling nucleocytoplasmic export and translation of mRNA. To address this objective, biochemical indices of mammary growth and secretory activity and the abundance and phosphorylation status of mTORC1 pathway factors were measured in mammary tissues harvested from nonpregnant lactating dairy cows 6 d after treatment with a slow-release formulation of GH or saline (n=4/group). Treatment with GH increased mammary parenchymal weight and total protein content and tended to increase ribosome number and cell size, whereas protein synthetic efficiency, capacity, and cell number were unchanged. Cellular abundance of the mTORC1 components mTOR and (phosphorylated) mTOR(Ser2448) increased, as did complex eukaryotic initiation factor 4E:eukaryotic initiation factor 4E binding protein 1 (eIF4E:4EBP1), whereas no change was observed for mTORC1-downstream targets 4EBP1, 4EBP1(Ser65), p70/p85(S6K) and p70(S6K)Thre389/p85(S6K)Thre412. Changes in activation were not observed for any of the targets measured. These results indicate that GH treatment influences signaling to mTORC1 but not downstream targets involved in the nucleocytoplasmic export and translation of mRNA. Increased eIF4E:4EBP1 complex formation indicates involvement of the mitogen-activated protein kinase (MAPK) pathway. Abundance of MAPK pathway components eIF4E, eIF4E(Ser209), eIF4E:eIF4G complex, MAP kinase interacting serine/threonine-protein kinase 1 (MKNK1), MKNK1(Thr197202), and ribosomal protein S6 kinase, 90kDa, polypeptide 1 (RPS6KA1) increased significantly in response to GH, whereas relative activation of the proteins was unchanged. Expression of IGFBP3 and IGFBP5 increased, that of IGF1R decreased, and that of IGF1 remained unchanged in response to GH. PatSearch analysis of the milk caseins alphaS1-casein, alphaS2-casein, and beta-casein, MAPK signaling target RPS6KA1, and proliferation gene IGFBP3 mRNA indicated that all contained putative eIF4E-sensitivity elements. In response to GH, these genes were all upregulated, suggesting that increased abundance of eIF4E and eIF4E(Ser209) plays a role in mediating their nucleocytoplasmic export. We propose that, in response to GH, the IGF1-IGF1R-MAPK signaling cascade regulates eIF4E-mediated nucleocytoplasmic export and translation of mRNA, whereas mTOR controls cell renewal, cell turnover, and rRNA transcription through an alternative signaling cascade. PMID- 23462169 TI - Data quality in the Norwegian dairy herd recording system: agreement between the national database and disease recording on farm. AB - The majority of herds in Norway participate in the national dairy herd recording system. For disease events, this involves transferring information registered on farm, using individual cow health cards (CHC), to the central cattle database (CCD). Before using data from such a database, validation with an aim of describing data quality should be performed, but is rarely done. In this study, diagnostic events from CHC and CCD from 74 dairy herds were compared. Events in 2008 from female cattle with minimum age of 1 yr were included (n=1,738). Discrepancies between the 2 data sources and assessment of data quality were evaluated using agreement between events on CHC and in CCD, calculating completeness and correctness for the CCD, and using a multivariable regression model for agreement (1/0). The agreement evaluation described the concordance between the 2 data sources, whereas the calculations of completeness and correctness depended on a reference data source assumed to be more reliable. Completeness of the CCD was defined as the proportion of diagnostic events on the CHC that was recorded therein. Correctness was defined as the proportion of the CCD events that was also recorded on the CHC, and with the same date and diagnostic code. The agreement was up to 87.5%, the majority of disagreement being caused by unreported events on the CHC (between 10 and 12% of all events). Completeness of the CCD was regarded as high, between 0.87 and 0.88, and correctness excellent, between 0.97 and 0.98. The multivariable regression model found 4 factors that increased the odds for diagnostic events being in agreement between CHC and CCD. These were the events occurring during the 305-d lactation period; the herd size being 75 cows or less; the event occurring during the spring, summer, or winter rather than autumn; and lastly, the diagnostic code for the disease event being preprinted on the CHC, involving a simple check mark as opposed to writing a 3-digit code. The model found a high degree of clustering within herd. In conclusion, disease data in the Norwegian national database for dairy cows are valid to use for epidemiologic research, having in particular an excellent correctness, but it is of concern that at least 10% of data are missing. The proportion of unreported data should be taken into consideration whenever data from this database are used. Reasons for discrepancies found are important to be aware of in any work aiming to improve data transfer from farm to central databases. PMID- 23462170 TI - Comparison of metabolic, hematological, and peripheral blood leukocyte cytokine profiles of dairy cows and heifers during the periparturient period. AB - The periparturient period presents major physiological challenges for the dairy cow. It is a period that is affected by metabolic stressors, major changes in endocrine status, and altered immune function, which together result in an increased risk of disease. Immunological, hematological, and metabolic profiles from the periparturient period of heifers (primipara) were compared with those of cows (pluripara) to test the hypothesis that at the time of calving they have qualitatively different peripheral blood profiles. Blood samples were collected from 22 Holstein-Friesian animals on 3 occasions: approximately 2 wk before calving, within 24h after calving, and approximately 2 wk after calving. Quantitative PCR was used to measure the expression of a selected set of cytokines and receptors by peripheral blood leukocytes. Additional analyses included hemoglobin concentration, red cell, platelet and white cell counts (total and differentiated), and clinical diagnostic biochemical profiles. Total leukocyte counts, neutrophils, and lymphocytes were higher in heifers than cows before calving and within 24h after calving. Alkaline phosphatase was consistently higher in heifers than cows and several significant differences were observed between the 2 groups with regards to cytokine and cytokine-receptor mRNA expression. The results warrant further investigation from the perspective of identifying risk factors for metabolic and parturient disease in dairy cattle. PMID- 23462171 TI - Short communication: use of a mechanical brush by Holstein dairy cattle around parturition. AB - Grooming is a normal behavior that may contribute to relief of stress. The purpose of this study was to investigate the effect of access to a mechanical brush on auto-grooming behavior in parturient cows. The hypothesis was that cows would increase the total time spent scratching using the brush if they had access to a brush around the time of calving, whereas auto-grooming would be lower for the brush group compared with the no-brush group. The use of a mechanical brush was analyzed both in a group-housed pen (72 to 48 h before calving) and in an individual maternity pen (6h before to 6h after calving) in 16 multiparous Holstein cows. In the maternity pen, cows were randomly assigned to have access to the brush or not. The provision of a mechanical brush in the individual maternity pen did not change the amount of time spent auto-grooming but cows did use the brush before calving and after the calf was removed. Despite being housed in pens containing a brush, cows failed to use it when the calf was present. However, cows with access to a brush spent more time licking their calves in the first hour postcalving (beta=8.7 min; 95% confidence interval: 1.5, 15.8) than cows that did not have access to a brush. Regardless of treatment, cows increased the time spent auto-grooming and scratching following separation of their newborn calf (beta=1.4 min; 95% confidence interval: 0.46, 2.3 and beta=0.07 min; 95% confidence interval: 0.02, 0.12, respectively). Further research is warranted to investigate possible benefits of mechanical brush devices at the time of calving, particularly for cows that experience difficult calving and require manual or mechanical assistance. PMID- 23462172 TI - Cows and herds constitute distinct hierarchical levels of heterogeneity in the variability of and association between milk yield and pregnancy outcome in dairy cows. AB - The objectives of this study were to investigate heterogeneity in the variance of and the association between milk yield (MY) and pregnancy outcome (PO) in dairy cows, formally separating the within-herd (i.e., cow-level residual effects) from the between-herd (i.e., herd-level random effects) components. Based on a recently developed extension to bivariate generalized hierarchical linear mixed models, we specified functions of residual and random effect variances and covariances as linear combinations of fixed and random effects to infer upon heterogeneity in the variation of and the association between MY and PO at first postpartum insemination. As potential sources of heterogeneity, we evaluated various management practices and herd attributes of interest by assessing model fit using the deviance information criterion. Our data consisted of 89,105 Dairy Herd Improvement Association cow records from 379 dairy herds in Michigan. Within herds, no evidence of a cow-level (residual) association between MY and PO was observed, as the corresponding association parameter did not significantly depart from zero. However, the herd-level (random effects) relationship between MY and PO was antagonistic and depended on management practices that determine the baseline level of fertility for a herd. In other words, herds with greater average MY at the time of first postpartum insemination had lower pregnancy rates, but within such herds, cows with higher daily yields did not seem to be any more or less likely to become pregnant than lower-yielding herdmates. Nevertheless, Michigan counties differed in the magnitude of the herd-level association between MY and PO, thus indicating that regional environmental conditions or management practices may partially alleviate the herd-level antagonism between MY and PO. The heterogeneity in variability of MY was substantial and primarily explained at the cow level by management conditions and other herd-specific attributes. In summary, the nature of the variability of and the association between MY and PO in dairy cows is complex due to the heterogeneous contributions of both cow- and herd-level components. Further research should be pursued to investigate additional management scenarios that ameliorate or even enhance the association between MY and PO in commercial dairy cows during first postpartum insemination. PMID- 23462173 TI - Bovine lactoferrin inhibits lung cancer growth through suppression of both inflammation and expression of vascular endothelial growth factor. AB - Lung cancers are among the most common cancers in the world, and the search for effective and safe drugs for the chemoprevention and therapy of pulmonary cancer has become important. In this study, bovine lactoferrin (bLF) was used in both in vitro and in vivo approaches to investigate its activity against lung cancer. A human lung cancer cell line, A549, which expresses a high level of vascular endothelial growth factor (VEGF) under hypoxia, was used as an in vitro system for bLF treatment. A strain of transgenic mice carrying the human VEGF-A165 (hVEGF-A165) gene, which induces pulmonary tumors, was used as an in vivo lung cancer therapy model. We found that bLF significantly decreased proliferation of A549 cells by decreasing the expression of VEGF protein in a dose-dependent manner. Furthermore, oral administration of bLF at 300 mg/kg of body weight 3 times a week for 1.5 mo to the transgenic mice overexpressing hVEGF-A165 significantly eliminated expression of hVEGF-A165 and suppressed the formation of tumors. Additionally, treatment with bLF significantly decreased the levels of proinflammatory cytokines, such as tumor necrosis factor-alpha, and antiinflammatory cytokines, such as IL-4 and IL-10. Levels of IL-6, which is both a proinflammatory and an antiinflammatory cytokine, were also reduced. Treatment with bLF decreased levels of tumor necrosis factor-alpha, IL-4, IL-6, and IL-10 cytokines, resulting in limited inflammation, which then restricted growth of the lung cancer. Our results revealed that bLF is an inhibitor of angiogenesis and blocks lung cell inflammation; as such, it has considerable potential for therapeutic use in the treatment of lung cancer. PMID- 23462174 TI - Feed restriction, but not l-carnitine infusion, alters the liver transcriptome by inhibiting sterol synthesis and mitochondrial oxidative phosphorylation and increasing gluconeogenesis in mid-lactation dairy cows. AB - Abomasal carnitine infusion during acute feed restriction increases hepatic fatty acid oxidation and decreases liver lipid in dairy cows. Eight mid-lactation Holstein cows were used in a replicated 4*4 Latin square design with 14-d periods. A 2*2 factorial arrangement was used to determine the effects of water infusion+ad libitum dry matter intake (DMI), water infusion+restricted DMI (50% of previous 5-d average), l-carnitine infusion (20 g/d)+ad libitum DMI, or l carnitine infusion+restricted DMI. Liver RNA from 7 healthy cows was used for transcriptome profiling using a bovine microarray. An ANOVA with a false discovery rate was used to identify treatment and interaction effects. A substantial transcriptome change was observed only with DMI restriction, resulting in 312 (155 downregulated, 157 upregulated) differentially expressed genes. Quantitative PCR was performed to verify microarray data and measure expression of additional genes not present on the microarray. The quantitative PCR data confirmed the effect of feed restriction but not of l-carnitine treatment. Feed restriction increased expression of GPX3 and of genes associated with gluconeogenesis (PC, PDK4), inflammation (SAA3), and signaling (ADIPOR2). In contrast, feed restriction downregulated BBOX, a key for l-carnitine biosynthesis, and the transcription factor HNF4A. The bioinformatics functional analysis of genes affected by DMI restriction uncovered biosynthesis of cholesterol and energy generation by mitochondrial respiration as the most relevant and inhibited functions. The data also indicated an increase of flux toward gluconeogenesis. We interpreted those results as a likely response of the liver to spare energy and provide glucose for the lactating mammary gland during feed deprivation. PMID- 23462175 TI - Effects of increasing amounts of corn dried distillers grains with solubles in dairy cow diets on methane production, ruminal fermentation, digestion, N balance, and milk production. AB - The objective of this study was to examine the effects of including corn dried distillers grains with solubles (DDGS) in the diet at the expense of corn and soybean meal on enteric CH4 emissions, ruminal fermentation characteristics, digestion (in sacco and apparent total-tract digestibility), N balance, and milk production of dairy cows. Twelve lactating Holstein cows were used in a triplicated 4*4 Latin square design (35-d periods) and fed (ad libitum intake) a total mixed ration containing (dry matter basis) 0, 10, 20, or 30% DDGS. Dry matter intake increased linearly, whereas apparent-total tract digestibility of dry matter and gross energy declined linearly as DDGS level in the diet increased. Increasing the proportion of DDGS in the diet decreased the acetate:propionate ratio, but this decrease was the result of reduced acetate concentration rather than increased propionate concentration. Milk yield increased linearly (up to +4kg/d) with increasing levels of DDGS in the diet and a tendency was observed for a quadratic increase in energy-corrected milk as the proportion of DDGS in the diet increased. Methane production decreased linearly with increasing levels of DDGS in the diet (495, 490, 477, and 475 g/d for 0, 10, 20, and 30% DDGS diets, respectively). When adjusted for gross energy intake, CH4 losses also decreased linearly as DDGS proportion increased in the diet by 5, 8, and 14% for 10, 20, and 30% DDGS diets, respectively. Similar decreases (up to 12% at 30% DDGS) were also observed when CH4 production was corrected for digestible energy intake. When expressed relative to energy-corrected milk, CH4 production declined linearly as the amount of DDGS increased in the diet. Total N excretion (urinary and fecal; g/d) increased as the amount of DDGS in the diet increased. Efficiency of N utilization (milk N secretion as a proportion of N intake) declined linearly with increasing inclusion of DDGS in the diet. However, productive N increased linearly with increasing proportions of DDGS in the diet, suggesting better efficiency of N use by the animal. Results from this study show that feeding DDGS to dairy cows can help to mitigate enteric CH4 emissions without negatively affecting intake and milk production. PMID- 23462176 TI - Invited review: sensors to support health management on dairy farms. AB - Since the 1980s, efforts have been made to develop sensors that measure a parameter from an individual cow. The development started with individual cow recognition and was followed by sensors that measure the electrical conductivity of milk and pedometers that measure activity. The aim of this review is to provide a structured overview of the published sensor systems for dairy health management. The development of sensor systems can be described by the following 4 levels: (I) techniques that measure something about the cow (e.g., activity); (II) interpretations that summarize changes in the sensor data (e.g., increase in activity) to produce information about the cow's status (e.g., estrus); (III) integration of information where sensor information is supplemented with other information (e.g., economic information) to produce advice (e.g., whether to inseminate a cow or not); and (IV) the farmer makes a decision or the sensor system makes the decision autonomously (e.g., the inseminator is called). This review has structured a total of 126 publications describing 139 sensor systems and compared them based on the 4 levels. The publications were published in the Thomson Reuters (formerly ISI) Web of Science database from January 2002 until June 2012 or in the proceedings of 3 conferences on precision (dairy) farming in 2009, 2010, and 2011. Most studies concerned the detection of mastitis (25%), fertility (33%), and locomotion problems (30%), with fewer studies (16%) related to the detection of metabolic problems. Many studies presented sensor systems at levels I and II, but none did so at levels III and IV. Most of the work for mastitis (92%) and fertility (75%) is done at level II. For locomotion (53%) and metabolism (69%), more than half of the work is done at level I. The performance of sensor systems varies based on the choice of gold standards, algorithms, and test sizes (number of farms and cows). Studies on sensor systems for mastitis and estrus have shown that sensor systems are brought to a higher level; however, the need to improve detection performance still exists. Studies on sensor systems for locomotion problems have shown that the search continues for the most appropriate indicators, sensor techniques, and gold standards. Studies on metabolic problems show that it is still unclear which indicator reflects best the metabolic problems that should be detected. No systems with integrated decision support models have been found. PMID- 23462177 TI - A dynamic model to predict fat and protein fluxes and dry matter intake associated with body reserve changes in cattle. AB - The objective of this paper was to develop the structure and concepts of a dynamic model to simulate dry matter intake (DMI) pattern and the fluxes of fat and protein in the body reserves of cattle associated with changes in body condition score (BCS) for application within the structure of applied nutrition models. This model was developed to add the capability of evaluating the effects of factors affecting pre- and postcalving DMI, daily energy and protein balances, and changes in BCS over a reproductive cycle. Input variables are average DMI, diet metabolizable energy, and animal information (body weight, BCS, milk production, and calf birth body weight) from each diet fed over the reproductive cycle. Because the depletion and repletion of body reserves in cattle is a complex system of coordinated metabolic processes that reflect hormonal and physiological changes caused by negative or positive energy balances, the system dynamics modeling methodology was used to develop this model. The model was used to evaluate the effect of the dynamic interactions between dietary supply and animal requirements for energy and protein on the fluxes of body fat and body protein of dairy cows over the reproductive cycle and Monte Carlo simulations were used to assess the sensitivity of the parameters. The main long-term factor affecting DMI pattern was the growth of the gravid uterus causing an increase in the volume of abdominal organs and a compression of the rumen, consequentially reducing feed intake. Changes in body reserves (fat and protein) were computed based on metabolizable energy balance, assuming different efficiency of utilization coefficients for fat and protein during repletion and mobilization. The model was evaluated with data from 37 dairy cows individually fed 3 different diets over the lactation and dry periods. The model was successful in simulating the observed pattern of DMI (mean square error was 3.59, 3.97, and 3.66 for diets A, B, and C, respectively), but it tended to underpredict DMI during late lactation [around 200 to 285 d in milk (DIM)] for all diets, suggesting changes in the model structure might be needed. The predicted BCS pattern had a trend similar to the observed values. Assuming that observed BCS represents actual body fat, the model tended to overpredict observed BCS during early lactation (0.125 BCS for 0 to 120 DIM) and underpredict it during late lactation (0.06 BCS for 180 to 270 DIM). A long-term simulation (5 lactations and 4 dry periods) with diet A indicated that the cows on this diet would have a net loss of body fat if all conditions were constant. PMID- 23462178 TI - Preliminary study to assess mycotoxin concentrations in whole corn in the California feed supply. AB - Mycotoxins are naturally occurring environmental contaminants recognized worldwide in a variety of food and feed products. Produced as secondary metabolites by filamentous fungi, mycotoxins can have acute and chronic effects. Differing seasonal weather patterns and harvesting and storage conditions put corn grain at high risk for mycotoxin contamination. The objective of this study was to assess the risk of mycotoxin exposure posed to California livestock from whole corn. Random samples (n=50) of whole corn were collected and analyzed for 6 different mycotoxins, including aflatoxins, fumonisins, ochratoxins, trichothecenes (deoxynivalenol and T-2 toxin), and zearalenone. The samples represented a cross section of the corn entering California from various corn growing states (n=43) as well as additional samples from California-grown corn (n=7). The experiment was a randomized sampling design. Over the course of a 6-mo period, 16 trains in California (100-110 railcars) and 5 California grain elevators were randomly sampled. Aflatoxins were detected in 14 samples, with 1 sample containing a concentration of 41.3 MUg/kg (as-is basis), which was above the action level of 20 MUg/kg for corn fed to dairy cattle. The average concentration of aflatoxins for the 13 samples below the regulatory action level was 8.69 MUg/kg (range 4.67 to 13.82 MUg/kg). Deoxynivalenol was found in 15 samples and averaged 553 MUg/kg (range 340 to 1,072 MUg/kg), which was below the federal advisory level of 5,000 MUg/kg for grain fed to dairy cattle. Fumonisins were found in 38 samples and averaged 1,687 MUg/kg (range 435 to 4,843 MUg/kg), which was below the federal guidance level of 30,000 MUg/kg in corn for dairy cattle. Ochratoxins, T-2 toxins, and zearalenone were not detected in any samples of whole corn. Fumonisins were the most prevalent mycotoxins found. PMID- 23462179 TI - Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes. AB - BACKGROUND & AIMS: Studies of the transcriptional networks that regulate nuclear receptor-mediated proliferation of quiescent hepatocytes could lead to new information about liver growth and hepatoprotective strategies. METHODS: We used quantitative real-time PCR to analyze expression of neuron-derived orphan receptor 1 (Nor-1) and its target genes during liver regeneration after hepatectomy in mice, and in hepatocellular carcinoma (HCC) samples from patients. We used adenoviral vectors to express Nor-1 in normal liver (Ad/CMV/V5-Nor-1), or reduce its level with small hairpin RNAs (Ad/BLOCK-iT/Nor-1(small hairpin RNA)) after partial hepatectomy. RESULTS: Levels of Nor-1 messenger RNA and protein, and transcription of Nor-1 target genes (Ccnd1 and Vcam-1), increased during the late priming and proliferative phases of liver regeneration after partial hepatectomy. Levels of NOR-1 messenger RNA and transcription of its target gene CCND1 and of the NOR-1 subfamily member NUR-77 also increased in human HCC samples compared with paired HCC-free tissue. Ad-Nor-1(small hairpin RNA) reduced the hepatocyte proliferation after hepatectomy. Overexpression of Nor-1 in normal livers of mice induced proliferation of quiescent hepatocytes independently of interleukin-6 and tumor necrosis factor-alpha signaling. In gene expression profile analysis, Nor-1 altered expression of genes involved in the cell cycle, proliferation, and tumorigenesis. CONCLUSIONS: In mice, the orphan nuclear receptor Nor-1 activates proliferation of quiescent hepatocytes and is required for hepatocyte proliferation after partial hepatectomy. Nor-1 and its gene targets are also up-regulated in human HCC samples. Nor-1 activates a transcriptional program that induces hepatocyte proliferation independently of inflammatory signaling pathways. PMID- 23462180 TI - A genetic screen identifies interferon-alpha effector genes required to suppress hepatitis C virus replication. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is a leading cause of end stage liver disease. Interferon-alpha (IFNalpha) is an important component of anti-HCV therapy; it up-regulates transcription of IFN-stimulated genes, many of which have been investigated for their antiviral effects. However, all of the genes required for the antiviral function of IFNalpha (IFN effector genes [IEGs]) are not known. IEGs include not only IFN-stimulated genes, but other nontranscriptionally induced genes that are required for the antiviral effect of IFNalpha. In contrast to candidate approaches based on analyses of messenger RNA (mRNA) expression, identification of IEGs requires a broad functional approach. METHODS: We performed an unbiased genome-wide small interfering RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with small interfering RNAs incubated with IFNalpha and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further. RESULTS: The screen identified 120 previously unreported IEGs. From these, we more fully evaluated the following: asparagine-linked glycosylation 10 homolog (yeast, alpha-1,2-glucosyltransferase); butyrylcholinesterase; dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2); glucokinase (hexokinase 4) regulator; guanylate cyclase 1, soluble, beta 3; MYST histone acetyltransferase 1; protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform; peroxisomal proliferator activated receptor-gamma-DBD-interacting protein 1; and solute carrier family 27 (fatty acid transporter), member 2; and demonstrated that they enabled IFNalpha mediated suppression of HCV at multiple steps of its life cycle. Expression of these genes had more potent effects against flaviviridae because a subset was required for IFNalpha to suppress dengue virus but not influenza A virus. In addition, many of the host genes detected in this screen (92%) were not transcriptionally stimulated by IFNalpha; these genes represent a heretofore unknown class of non-IFN-stimulated gene IEGs. CONCLUSIONS: We performed a whole genome loss-of-function screen to identify genes that mediate the effects of IFNalpha against human pathogenic viruses. We found that IFNalpha restricts HCV via actions of general and specific IEGs. PMID- 23462181 TI - Crosstalk between casein kinase II and Ste20-related kinase Nak1. AB - Although the sterile 20 (Ste20) serine/threonine protein kinase was originally identified as a component of the S. cerevisiae mating pathway, it has homologs in higher eukaryotes and is part of a larger family of Ste20-like kinases. Ste20 like kinases are involved in multiple cellular processes, such as cell growth, morphogenesis, apoptosis and immune response. Carrying out such a diverse array of biological functions requires numerous regulatory inputs and outputs in the form of protein-protein interactions and post-translational modifications. Hence, a thorough knowledge of Ste20-like kinase binding partners and phosphorylation sites will be essential for understanding the various roles of these kinases. Our recent study revealed that Schizosaccharomyces pombe Nak1 (a conserved member of the GC-kinase sub-family of Ste20-like kinases) is in a complex with the leucine rich repeat-containing protein Sog2. Here, we show a novel and unexpected interaction between the Nak1-Sog2 kinase complex and Casein kinase 2 (Cka1, Ckb1 and Ckb2) using tandem-affinity purification followed by mass spectrometric analysis. In addition, we identify unique phosphosites on Nak1, Sog2 and the catalytic subunit of casein kinase 2, Cka1. Given the conserved nature of these kinases, we expect this work will shed light on the functions of these proteins both in yeast and higher eukaryotes. PMID- 23462182 TI - Anchoring proteins encounter mitotic kinases. PMID- 23462183 TI - Dissecting cellular responses to irradiation via targeted disruptions of the ATM CHK1-PP2A circuit. AB - Exposure of proliferating cells to genotoxic stresses activates a cascade of signaling events termed the DNA damage response (DDR). The DDR preserves genetic stability by detecting DNA lesions, activating cell cycle checkpoints and promoting DNA damage repair. The phosphoinositide 3-kinase-related kinases (PIKKs) ataxia telangiectasia-mutated (ATM), ATM and Rad 3-related kinase (ATR) and DNA-dependent protein kinase (DNA-PK) are crucial for sensing lesions and signal transduction. The checkpoint kinase 1 (CHK1) is a traditional ATR target involved in DDR and normal cell cycle progression and represents a pharmacological target for anticancer regimens. This study employed cell lines stably depleted for CHK1, ATM or both for dissecting cross-talk and compensatory effects on G(2)/M checkpoint in response to ionizing radiation (IR). We show that a 90% depletion of CHK1 renders cells radiosensitive without abrogating their IR mediated G(2)/M checkpoint arrest. ATM phosphorylation is enhanced in CHK1 deficient cells compared with their wild-type counterparts. This correlates with lower nuclear abundance of the PP2A catalytic subunit in CHK1-depleted cells. Stable depletion of CHK1 in an ATM-deficient background showed only a 50% reduction from wild-type CHK1 protein expression levels and resulted in an additive attenuation of the G(2)/M checkpoint response compared with the individual knockdowns. ATM inhibition and 90% CHK1 depletion abrogated the early G(2)/M checkpoint and precluded the cells from mounting an efficient compensatory response to IR at later time points. Our data indicates that dual targeting of ATM and CHK1 functionalities disrupts the compensatory response to DNA damage and could be exploited for developing efficient anti-neoplastic treatments. PMID- 23462184 TI - CDK4 inhibition restores G(1)-S arrest in MYCN-amplified neuroblastoma cells in the context of doxorubicin-induced DNA damage. AB - Relapse with drug-resistant disease is the main cause of death in MYCN-amplified neuroblastoma patients. MYCN-amplified neuroblastoma cells in vitro are characterized by a failure to arrest at the G(1)-S checkpoint after irradiation- or drug-induced DNA damage. We show that several MYCN-amplified cell lines harbor additional chromosomal aberrations targeting p53 and/or pRB pathway components, including CDK4/CCND1/MDM2 amplifications, p16INK4A/p14ARF deletions or TP53 mutations. Cells with these additional aberrations undergo significantly lower levels of cell death after doxorubicin treatment compared with MYCN-amplified cells, with no additional mutations in these pathways. In MYCN-amplified cells CDK4 expression is elevated, increasing the competition between CDK4 and CDK2 for binding p21. This results in insufficient p21 to inhibit CDK2, leading to high CDK4 and CDK2 kinase activity upon doxorubicin treatment. CDK4 inhibition by siRNAs, selective small compounds or p19(INK4D) overexpression partly restored G(1)-S arrest, delayed S-phase progression and reduced cell viability upon doxorubicin treatment. Our results suggest a specific function of p19(INK4D), but not p16(INK4A), in sensitizing MYCN-amplified cells with a functional p53 pathway to doxorubicin-induced cell death. In summary, the CDK4/cyclin D-pRB axis is altered in MYCN-amplified cells to evade a G(1)-S arrest after doxorubicin induced DNA damage. Additional chromosomal aberrations affecting the p53-p21 and CDK4-pRB axes compound the effects of MYCN on the G(1) checkpoint and reduce sensitivity to cell death after doxorubicin treatment. CDK4 inhibition partly restores G(1)-S arrest and sensitizes cells to doxorubicin-mediated cell death in MYCN-amplified cells with an intact p53 pathway. PMID- 23462185 TI - Sinonasal teratocarcinosarcoma: a clinicopathologic and immunohistochemical study of 6 cases. AB - Teratocarcinosarcoma (TCS) is a rare and unusual malignant neoplasm of the sinonasal tract with a heterogenous morphology and an aggressive behavior. Patients are predominantly adults with a male predominance. The aim of this study was to describe clinicopathologic and immunohistochemical features of 6 cases of TCS. The ages ranged from 18 to 67 years (mean, 33 years) with a male-to-female ratio of 5:1. Most tumors were located in the nasal cavity. Nasal obstruction and epistaxis were the common presenting symptoms. Histologically, all tumors exhibited a heterogeneous morphology with varying proportions of benign and malignant epithelial, mesenchymal, and neuroepithelial elements. Adenocarcinoma was the malignant epithelial component in all cases. The mesenchymal elements were composed of benign to malignant spindle cells. Osteosarcomatous areas were seen in 2 cases and rhabdomyosarcoma in 1 case. Rhabdoid differentiation was also seen in 1 case. Immunohistochemical stains CKAE1/AE3 and CK Cam 5.2 were positive in the epithelial elements, vimentin in mesenchymal, and CD56 and neuron-specific enolase in neuroepithelial elements. Follow-up was available in 4 patients and ranged from 21 to 40 months (mean, 31 months). Lung and dura metastasis, respectively, were seen in 1 patient each. However, all 4 patients are alive and free of disease to date. In conclusion, TCS is a rare but highly malignant tumor with aggressive behavior characterized by benign and malignant epithelial, mesenchymal, and neuroepithelial components. Two patients in our series were younger than 20 years. The occurrence of rhabdoid differentiation and osteosarcomatous component seen in our series were rarely described in literature. Recognition of all the components requires adequate sampling, which is crucial for a correct diagnosis. PMID- 23462186 TI - Evaluation on a clinical course of subdural hematoma in patients undergoing epidural blood patch for spontaneous cerebrospinal fluid leak. AB - OBJECTIVE: Subdural hematoma (SDH) is a frequent complication of spontaneous intracranial hypotension (SIH), in which epidural blood patch (EBP) may be applied as a treatment to stop cerebrospinal fluid (CSF) leak. However, a clinical course of SDH in SIH patients has not been sufficiently evaluated. We retrospectively evaluated the temporal relationships between EBP and SDH in the patients with SIH. METHODS: Twenty-nine consecutive patients, diagnosed as SIH, were studied. Clinical records and images were retrospectively evaluated. When orthostatic headache continued for 2 weeks regardless of conservative treatment, EBP was performed under fluoroscopy. RESULTS: We detected 13(45%) cases of SDH (mean age 44 years, 8 males and 5 females). In 6 patients, SDHs disappeared after effective EBP, i.e., after the disappearance of orthostatic headache. In 3 patients, SDHs were enlarged or recurred after effective EBP, and in 4 patients, SDHs were first detected after effective EBP. CONCLUSION: The knowledge of the presence of these types of SDH (enlarged or recurred or detected after EBP) may deserve clinical attention. PMID- 23462187 TI - Melphalan continues to rock the myeloma world. PMID- 23462188 TI - Chimerism patterns of long-term stable mixed chimeras posthematopoietic stem cell transplantation in patients with nonmalignant diseases: follow-up of long-term stable mixed chimerism patients. AB - Long-term stable mixed chimerism (MC) is a rare phenomenon after hematopoietic stem cell transplantation (HSCT) characterized by 5% to 95% residual recipient hematopoietic cells. The underlying mechanisms of MC are largely unknown. In this study we compared full donor chimerism with long-lasting stable MC for a median of 9.5 years (range, 5 to 16.5) post-HSCT in patients with nonmalignant diseases. Several factors significantly associated with the likelihood of stable MC development were identified by univariate analysis, eg, younger donor age, sibling donor, and conditioning regimen. Despite a limited patient cohort, our multivariate analysis could confirm that a sibling donor was associated with stable MC development. Furthermore, development of acute-graft-versus-host disease and blood stream infection was significantly more prevalent in the full donor chimerism patient group. Additionally, significant fluctuations in the recipient-to-donor chimerism ratio decreased over time after HSCT in MC patients. PMID- 23462189 TI - March editorial. PMID- 23462190 TI - Effects of compound X, a novel potent inhibitor of acyl-coenzyme A:cholesterol O acyltransferase, on the adrenal gland of rats. AB - To investigate the adrenal toxicity of a novel inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase, compound X (CX), histopathological examinations, fat staining, adrenal cholesterol measurement, blood biochemistry, plasma corticosterone and ACTH measurement, ACTH-stimulation assay, and adrenal gene expression analyses were done in rats in repeated-dose studies (experiment 1: 0, 3, 10, 30 and 150mg/kg for 4, 8, 15 and 28 days; experiment 2: 0, 3, 10,30 and 150mg/kg for 28 days; experiment 3: 0, 10, 30, 100 and 300mg/kg for 28 days). CX induced morphologic changes such as vacuolation and hypertrophy in the zona fasciculata (ZF) at >=10mg/kg, and eosinophilic changes in the ZF at 150mg/kg. Vacuolation decreased in a dose-dependent manner and was replaced by eosinophilic changes. Inflammatory and fibrous changes were observed at >=30mg/kg. These changes were expressed at early stages of dosing and were not exacerbated by extension of the administration period. Oil-red-O/Filipin staining showed depletion of cholesterol ester in dose-dependent manner and enabled adrenal cholesterol measurement. Filipin staining also revealed vacuoles to be composed of cholesterol esters. No significant changes were observed during the dosing period of CX for plasma corticosterone and ACTH levels. Gene-expression analyses showed up-regulation of Star and Abca1 mRNA levels at 300mg/kg. In conclusion, CX induced adrenal toxicity, but CX did not influence adrenocortical functions, and exacerbation of adrenal toxicities by extension of the administration period was not observed. Up-regulation of genes related to the transport of FC, such as Star and Abca1, were observed in CX groups, and these genes may be involved in the maintenance of adrenal structure and function in rats given CX. PMID- 23462191 TI - Psychological resources of adults with developmental dyslexia. AB - The aim of our study was to describe specific psychological resources of adults with developmental dyslexia and compare them with psychological resources of adults without developmental dyslexia. Potential differences were analyzed in visual-spatial, creative, and motivational abilities. No evidence was found for either creative, or visuospatial superiority in adults with developmental dyslexia. The results suggest, however, that visual-spatial processing of nonverbal material by adults with developmental dyslexia allows them to efficiently execute tasks that are based on sequential material. Moreover, the participants with specific difficulties in reading and writing exhibited a significantly higher level of aspirations than their peers without such difficulties with a comparable level of educational achievement. These results suggest that succeeding in different fields by highly functioning adult dyslexics may depend on personality and motivational factors, rather than cognitive factors. PMID- 23462192 TI - Changes in sevoflurane plasma concentration with delivery through the oxygenator during on-pump cardiac surgery. AB - BACKGROUND: It is unclear what factors affect the uptake of sevoflurane administered through the membrane oxygenator during cardiopulmonary bypass (CPB) and whether this can be monitored via the oxygenator exhaust gas. METHODS: Stable delivery of sevoflurane was administered to 30 elective cardiac surgery patients at 1.8 vol% (inspiratory) via the anaesthetic circuit and ventilator. During CPB, sevoflurane was administered in the oxygenator fresh gas supply (Compactflo EvolutionTM; Sorin Group, Milano, Italy). Sevoflurane plasma concentration (SPC) was measured using gas chromatography. Changes were correlated with bispectral index (BIS), patient temperature, haematocrit, plasma albumin concentration, oxygenator fresh gas flow, and the sevoflurane concentration in the oxygenator exhaust at predefined time points. RESULTS: The mean SPC pre-bypass was 54.9 ug ml(-1) [95% confidence interval (CI): 50.6-59.1]. SPC decreased to 43.2 ug ml(-1) (95% CI: 40.3-46.1; P<0.001) after initiation of CPB, and was lower still during rewarming and weaning from bypass, 39.4 ug ml(-1) (95% CI: 36.6-42.3; P<0.001). BIS did not exceed a value of 55. SPCs were higher during hypothermia (P<0.001) and with an increase in oxygenator fresh gas flow (P=0.015), and lower with haemodilution (P=0.027). No correlation was found between SPC and the concentration of sevoflurane in the oxygenator exhaust gas (r=-0.04; 95% CI: 0.18 to 0.09; P=0.53). CONCLUSIONS: The uptake of sevoflurane delivered via the membrane oxygenator during CPB seems to be affected by hypothermia, haemodilution, and changes in the oxygenator fresh gas supply flow. Measuring the concentration of sevoflurane in the exhaust from the oxygenator is not useful for monitoring sevoflurane administration during bypass. PMID- 23462193 TI - Identification of nuclear factor-kappaB sites in the Slc2a4 gene promoter. AB - Glucose transporter GLUT4 protein, codified by Slc2a4 gene plays a key role in glycemic homeostasis. Insulin resistance, as in obesity, has been associated to inflammatory state, in which decreased GLUT4 is a feature. Inflammatory NF-kappaB transcriptional factor has been proposed as a repressor of Slc2a4; although, the binding site(s) in Slc2a4 promoter and the direct repressor effect have never been reported yet. A motif-based sequence analysis of mouse Slc2a4 promoter revealed two putative kappaB sites located inside -83/-62 and -134/-113 bp. Eletrophoretic mobility assay showed that p50 and p65 NF-kappaB subunits bind to both putative kappaB sites. Chromatin immunoprecipitation assay using genomic DNA from adipocytes confirmed p50- and p65-binding to Slc2a4 promoter. Moreover, transfection experiments revealed that NF-kappaB binds to the -134/-113bp region of the mouse Slc2a4 gene promoter, inhibiting the Slc2a4 gene transcription. The current findings demonstrate the existence of two kappaB sites in Slc2a4 gene promote, and that NF-kappaB has a direct repressor effect upon the Slc2a4 gene, providing an important link between insulin resistance and inflammation. PMID- 23462194 TI - In vitro evaluation of the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. AB - Anaplastic thyroid carcinoma (ATC) is a severe thyroid malignancy with poor prognosis, due to its early metastasis and unresponsiveness to both radiation and chemotherapy. Nevirapine, a non-nucleoside reverse transcriptase inhibitor, has been used as a re-differentiation agent to treat cancers in several human cancer models. So far, the effects of nevirapine on human thyroid anaplastic carcinoma cells have not been documented. The aim of this study was to evaluate the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. Cell proliferation was determined by methly thiazolyl tetrazolium (MTT) assay. Cell apoptosis was analyzed by Hoechst 33258 staining. The mRNA expression of NIS and TSHR was determined by real-time quantitative reverse transcription-polymerase chain reaction (real time RT-PCR). Iodine uptake was determined by (125)I radioactivity assay. At all doses (100, 200, 350, 500 MUmol/L) tested, nevirapine significantly inhibited cell proliferation after 48 h treatment. At high dose (500 MUmol/L), nevirapine significantly increased the percentage of apoptotic cells compared with control (P<0.01). At lower doses (200 MUmol/L and 350 MUmol/L), nevirapine did not induce cell apoptosis, but up regulated NIS and THSR mRNA expression in a dose-dependent manner. In FRO cells pre-treated with nevirapine, the increase in NIS expression had no obvious effect on iodine uptake. These findings indicate that nevirapine has an anti proliferative effect on FRO cells, which correlates with an induction of cell differentiation. PMID- 23462195 TI - The effect of the essential oil of Eugenia caryophyllata in animal models of depression and locomotor activity. AB - OBJECTIVE: The essential oil of Eugenia caryophyllata (clove oil; Family: Myrtaceae) is used in dental care as an antiseptic and analgesic. The present study investigates the effect of clove oil on animal models of depression and locomotion. METHODS: Clove oil was administered in doses of 0.025, 0.05, and 0.1 ml/kg/day, intraperitoneally (i.p.) for 3 weeks. The forced swim test (FST) and the tail suspension test (TST) were used to assess depression. To evaluate locomotor activity, the rota rod test and the photoactometer procedure were performed. RESULTS: In the FST, it was observed that the duration of immobility was significantly decreased (P < 0.01) in animals treated with clove oil (0.05 and 0.1 ml/kg); however, the clove oil dose of 0.025 ml/kg showed an insignificant increase in the immobile period. The TST demonstrated that pretreatment with clove oil decreases (P < 0.01) the immobile period significantly at all the three administered doses. Similarly, the photoactometer procedure showed increased locomotor activity at all the three doses, although significant (P < 0.05) only at 0.1 ml/kg. In addition, the rota rod test showed that animals treated with clove oil (0.1 ml/kg) enhanced muscle coordination as demonstrated by a significant increase (P < 0.05) in the latency to fall from the rota rod as compared to the control. However, the lowest administered dose (0.025 ml/kg, i.p.) decreased the latency to fall from the rota rod significantly (P < 0.05) compared to the control. Clove oil (0.05 ml/kg) also showed a decrease in the latency to fall from the rota rod although the result was not statistically significant. DISCUSSION: Thus, it can be concluded that pretreatment with clove oil decreases depression and enhances locomotor activity similar to that exhibited by psychostimulants. PMID- 23462196 TI - Contralateral occlusion of the internal carotid artery increases the risk of patients undergoing carotid endarterectomy. AB - BACKGROUND: Controversy exists about whether occlusion of the contralateral internal carotid artery in patients undergoing carotid endarterectomy (CEA) is associated with a worse perioperative prognosis and outcome. METHODS: A systematic review of electronic information sources was undertaken to identify studies comparing perioperative and early outcomes of CEA in patients with occluded and patent contralateral carotid arteries. The methodologic quality of selected studies was independently appraised by two reviewers. Fixed- and random effects models were applied to synthesize outcome data. RESULTS: Our literature search located 46 articles eligible for inclusion in the review and analysis. The total population comprised 27,265 patients having undergone 28,846 CEAs (occluded contralateral artery group, 3120; patent contralateral artery group, 25,726). Patients with an occluded contralateral carotid artery had increased incidence of stroke (odds ratio [OR], 1.65, 95% confidence interval [CI], 1.30-2.09), transient ischemic attack (OR, 1.57, 95% CI, 1.11-2.21), stroke/transient ischemic attack (OR, 1.52; 95% CI, 1.21-1.90), and death (OR, 1.76; 95% CI, 1.19 2.59) <=30 days of treatment compared with those with a patent contralateral vessel. No difference in the incidence of myocardial infarction between the two groups was identified (OR, 1.45; 95% CI, 0.73-2.89). CONCLUSIONS: Patients undergoing CEA in the presence of an occluded contralateral carotid artery had increased perioperative and early postoperative risk. Our analysis is limited by heterogeneity in symptom status and practices of intraoperative cerebral protection among the studies. Careful consideration should be given in this subgroup of patients with regard to selection and perioperative and postoperative care to minimize the risk. PMID- 23462197 TI - Development of a versatile enzyme immunoassay for non-invasive assessment of glucocorticoid metabolites in a diversity of taxonomic species. AB - Endocrinology is a useful tool for conservation biologists and animal managers, and measuring glucocorticoids can help understand biological mechanisms associated with species decline and animal welfare. The current study describes the development and optimization of a glucocorticoid enzyme immunoassay (EIA) to non-invasively assess adrenal activity in a variety of taxa. The antiserum (CJM006) was raised in rabbits to a corticosterone-3-CMO-BSA immunogen and used in a standard competitive EIA system. However, the EIA initially produced results with unacceptably high inter-assay variation, attributed to consistent patterns observed within the optical density of developing plates. To determine the cause of this variability, a number of factors were examined using synthetic corticosterone standard and endogenous faecal extract, including: plate type (Nunc MaxiSorp(r) II versus Immulon IB plates); the use of non-specific secondary antibody; type (artificial versus natural) and presence (light versus dark) of light during incubation; plate loading temperature (4 degrees C versus room temperature); and substrate reagent temperature (4 degrees C versus room temperature). Results indicated that variability was associated with plate location effects, which were not initially detected because control samples were always run in the same positions across plates. Light and temperature were the two major factors that affected EIA reliability. For this assay, the standard protocol required slight modification, with the optimal protocol using Nunc MaxiSorp(r) plates, room temperature substrate reagents and dark incubation conditions. Following optimization, this EIA was then validated biochemically for 38 species, through parallel displacement curves and interference assessment tests of faecal and urine samples. Additionally, biological validation was performed opportunistically in a subset of species, with use of this EIA demonstrating significant elevations in faecal glucocorticoid metabolites following potentially challenging events. In summary, this glucocorticoid EIA cross-reacts with excreted glucocorticoid metabolites across a wide range of taxa, including ungulates, primates, felids, birds, rodents and amphibians. We conclude that when used with optimal reagent and incubation conditions, this EIA will be useful for non-invasive monitoring of adrenal activity in a wide range of wildlife species. PMID- 23462198 TI - Adolescents' civic engagement and alcohol use: longitudinal evidence for patterns of engagement and use in the adult lives of a British cohort. AB - Participation in discretionary activities during adolescence may facilitate the development of social networks that recruit youth into adult civic life or provide risky contexts that promote alcohol problems. Using data from the 1970 British Cohort Study, latent class analysis was used to identify adolescents' patterns of civic engagement, alcohol use, and other out-of-school activities at age 16, and test longitudinal links with adult civic engagement and alcohol use at ages 26, 30, and 34. Three classes were identified for both genders. The latent class characterized by involvement in more activities was more likely to be civically engaged in adulthood. The class characterized by the most alcohol use in adolescence had the highest likelihood of adult alcohol use and problems. Results are discussed in light of the health risks associated with each latent class and potential interventions that could be tailored to adolescents based on their patterns of activities. PMID- 23462199 TI - What will I be when I grow up? The impact of gender identity threat on adolescents' occupational preferences. AB - The present study examined the impact of gender identity threat on adolescents' occupational preferences. Two hundred and ninety-seven adolescents (45% girls, M age = 14.4, SD = .54) participated in the experiment. There were substantial differences between boys' and girls' occupational preferences. Importantly, adolescents who received a threat to their gender identity became more stereotypical in job preferences, suggesting a causal link between threatened gender identity and stereotypical preferences. A comparison threat to one's capability did not have this effect, indicating a unique effect of gender identity threat. Further, individual differences in gender identity concerns predicted gender stereotypical preferences, and this finding was replicated with an independent sample (N = 242). In conclusion, the results suggest that threats to adolescents' gender identity may contribute to the large gender segregation on the labor market. PMID- 23462200 TI - Biodegradable porous sheet-like scaffolds for soft-tissue engineering using a combined particulate leaching of salt particles and magnetic sugar particles. AB - Scaffolds serving as artificial extracellular matrixes (ECMs) play a pivotal role in the process of tissue regeneration by providing optimal cellular environments for penetration, ingrowth, and vascularization. Stacks of sheet-like scaffold can be engineered to become artificial ECMs, suggesting a great potential for achieving complex 3-D tissue regeneration to support cell survival and growth. In this study, we proposed and investigated a combined particulate leaching of magnetic sugar particles (MSPs) and salt particles for the development of a sheet like scaffold. MSPs were fabricated by encapsulating NdFeB particles inside sugar spheres and were controlled using magnetic fields as a porogen to control pore size, pore structure and pore density while fabricating the scaffold. We studied the influence of the strength of the magnetic fields in controlling the coating thickness of the unmagnetized MSPs during the fabrication of the sheet-like scaffolds. The experimental relationship between magnetic flux density and the thickness of the MSP layer was illustrated. Furthermore, we investigated the infiltration capacity of different concentrations of poly(L-lactide-co-E caprolactone) (PLCL) as a scaffold material on MSP clusters. Following polymer casting and removal of the sugar template, spherical pores were generated inside the scaffolds. Cultivation of NIH/3T3 fibroblasts on the fabricated scaffold proves that the proposed method can be applied in the cell sheet fabrication. PMID- 23462201 TI - Optimizing outcomes in schizophrenia: long-acting depots and long-term treatment. AB - Antipsychotics are the mainstay of treatment for patients with schizophrenia. However, these medications only work if they are taken and perhaps work best if they are taken for longer periods of time than seen in typical research trials. Here we explore the idea of "time as drug" by reviewing the data showing the potential benefits of long-term antipsychotic use. We also discuss the utility of depot antipsychotic formulations for improving the chances of attaining long-term therapeutic results. PMID- 23462202 TI - Methods for presenting and visualising electrocardiographic data: From temporal signals to spatial imaging. AB - INTRODUCTION: The electrocardiogram (ECG) is a recording of the electrical activity of the heart. It is commonly used to non-invasively assess the cardiac activity of a patient. Since 1938, ECG data has been visualised as 12 scalar traces (known as the standard 12-lead ECG). Although this is known as the standard approach, there has been a myriad of alternative methods proposed to visualise ECG data. The purpose of this paper is to provide an overview of these methods and to introduce the field of ECG visualisation to early stage researchers. A scientific purpose is to consider the future of ECG visualisation within routine clinical practice. METHODS: This paper structures the different ECG visualisation methods using four categories, i.e. temporal, vectorial, spatial and interactive. Temporal methods present the data with respect to time, vectorial methods present data with respect to direction and magnitude, spatial methods present data in 2D or 3D space and interactive methods utilise interactive computing to facilitate efficient interrogation of ECG data at different levels of detail. CONCLUSION: Spatial visualisation has been around since its introduction by Waller and vector based visualisation has been around since the 1920s. Given these approaches have already been given the 'test of time', they are unlikely to be replaced as the standard in the near future. Instead of being replaced, the standard is more likely to be 'supplemented'. However, the design and presentation of these ECG visualisation supplements need to be universally standardised. Subsequent to the development of 'standardised supplements', as a requirement, they could then be integrated into all ECG machines. We recognise that without intuitive software and interactivity on mobile devices (e.g. tablet PCs), it is impractical to integrate the more advanced ECG visualisation methods into routine practice (i.e. epicardial mapping using an inverse solution). PMID- 23462203 TI - Risk of people with mental illnesses dying by homicide. PMID- 23462204 TI - Mental disorders and vulnerability to homicidal death: Swedish nationwide cohort study. AB - OBJECTIVE: To determine the risk of people with mental disorders being victims of homicide. DESIGN: National cohort study. SETTING: Sweden. PARTICIPANTS: Entire adult population (n = 7,253,516). MAIN OUTCOME MEASURES: Homicidal death during eight years of follow-up (2001-08); hazard ratios for the association between mental disorders and homicidal death, with adjustment for sociodemographic confounders; potential modifying effect of comorbid substance use. RESULTS: 615 homicidal deaths occurred in 54.4 million person years of follow-up. Mortality rates due to homicide (per 100,000 person years) were 2.8 among people with mental disorders compared with 1.1 in the general population. After adjustment for sociodemographic confounders, any mental disorder was associated with a 4.9 fold (95% confidence interval 4.0 to 6.0) risk of homicidal death, relative to people without mental disorders. Strong associations were found irrespective of age, sex, or other sociodemographic characteristics. Although the risk of homicidal death was highest among people with substance use disorders (approximately ninefold), the risk was also increased among those with personality disorders (3.2-fold), depression (2.6-fold), anxiety disorders (2.2 fold), or schizophrenia (1.8-fold) and did not seem to be explained by comorbid substance use. Sociodemographic risk factors included male sex, being unmarried, and low socioeconomic status. CONCLUSIONS: In this large cohort study, people with mental disorders, including those with substance use disorders, personality disorders, depression, anxiety disorders, or schizophrenia, had greatly increased risks of homicidal death. Interventions to reduce violent death among people with mental disorders should tackle victimisation and homicidal death in addition to suicide and accidents, which share common risk factors. PMID- 23462205 TI - A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis. AB - Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the leading causes of death worldwide despite extensive research, directly observed therapy using multidrug regimens, and the widespread use of a vaccine. The majority of patients harbor the bacterium in a state of metabolic dormancy. New drugs with novel modes of action are needed to target essential metabolic pathways in M. tuberculosis; ATP-competitive enzyme inhibitors are one such class. Previous screening efforts for ATP-competitive enzyme inhibitors identified several classes of lead compounds that demonstrated potent anti-mycobacterial efficacy as well as tolerable levels of toxicity in cell culture. In this report, a probe based chemoproteomic approach was used to selectively profile the M. tuberculosis ATP-binding proteome in normally growing and hypoxic M. tuberculosis. From these studies, 122 ATP-binding proteins were identified in either metabolic state, and roughly 60% of these are reported to be essential for survival in vitro. These data are available through ProteomeXchange with identifier PXD000141. Protein families vital to the survival of the tubercle bacillus during hypoxia emerged from our studies. Specifically, along with members of the DosR regulon, several proteins involved in energy metabolism (Icl/Rv0468 and Mdh/Rv1240) and lipid biosynthesis (UmaA/Rv0469, DesA1/Rv0824c, and DesA2/Rv1094) were found to be differentially abundant in hypoxic versus normal growing cultures. These pathways represent a subset of proteins that may be relevant therapeutic targets for development of novel ATP-competitive antibiotics. PMID- 23462206 TI - Extensive mass spectrometry-based analysis of the fission yeast proteome: the Schizosaccharomyces pombe PeptideAtlas. AB - We report a high quality and system-wide proteome catalogue covering 71% (3,542 proteins) of the predicted genes of fission yeast, Schizosaccharomyces pombe, presenting the largest protein dataset to date for this important model organism. We obtained this high proteome and peptide (11.4 peptides/protein) coverage by a combination of extensive sample fractionation, high resolution Orbitrap mass spectrometry, and combined database searching using the iProphet software as part of the Trans-Proteomics Pipeline. All raw and processed data are made accessible in the S. pombe PeptideAtlas. The identified proteins showed no biases in functional properties and allowed global estimation of protein abundances. The high coverage of the PeptideAtlas allowed correlation with transcriptomic data in a system-wide manner indicating that post-transcriptional processes control the levels of at least half of all identified proteins. Interestingly, the correlation was not equally tight for all functional categories ranging from r(s) >0.80 for proteins involved in translation to r(s) <0.45 for signal transduction proteins. Moreover, many proteins involved in DNA damage repair could not be detected in the PeptideAtlas despite their high mRNA levels, strengthening the translation-on-demand hypothesis for members of this protein class. In summary, the extensive and publicly available S. pombe PeptideAtlas together with the generated proteotypic peptide spectral library will be a useful resource for future targeted, in-depth, and quantitative proteomic studies on this microorganism. PMID- 23462207 TI - Proteomic differences between hepatocellular carcinoma and nontumorous liver tissue investigated by a combined gel-based and label-free quantitative proteomics study. AB - Proteomics-based clinical studies have been shown to be promising strategies for the discovery of novel biomarkers of a particular disease. Here, we present a study of hepatocellular carcinoma (HCC) that combines complementary two dimensional difference in gel electrophoresis (2D-DIGE) and liquid chromatography (LC-MS)-based approaches of quantitative proteomics. In our proteomic experiments, we analyzed a set of 14 samples (7 * HCC versus 7 * nontumorous liver tissue) with both techniques. Thereby we identified 573 proteins that were differentially expressed between the experimental groups. Among these, only 51 differentially expressed proteins were identified irrespective of the applied approach. Using Western blotting and immunohistochemical analysis the regulation patterns of six selected proteins from the study overlap (inorganic pyrophosphatase 1 (PPA1), tumor necrosis factor type 1 receptor-associated protein 1 (TRAP1), betaine-homocysteine S-methyltransferase 1 (BHMT)) were successfully verified within the same sample set. In addition, the up-regulations of selected proteins from the complements of both approaches (major vault protein (MVP), gelsolin (GSN), chloride intracellular channel protein 1 (CLIC1)) were also reproducible. Within a second independent verification set (n = 33) the altered protein expression levels of major vault protein and betaine-homocysteine S-methyltransferase were further confirmed by Western blots quantitatively analyzed via densitometry. For the other candidates slight but nonsignificant trends were detectable in this independent cohort. Based on these results we assume that major vault protein and betaine-homocysteine S-methyltransferase have the potential to act as diagnostic HCC biomarker candidates that are worth to be followed in further validation studies. PMID- 23462208 TI - Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. AB - The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15-20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1-8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS. PMID- 23462209 TI - An anatomical study in the oriental nose of the location of the vibrissae-bearing area in relation to the lower lateral cartilage. AB - BACKGROUND: There is no well-known indicator that can assist with a precise intranasal incision during open rhinoplasty on the caudal border of the lower lateral cartilage. However, the vibrissae-bearing area is clinically known as a good landmark for cartilage. The aim of this study was to investigate the features of the vibrissae-bearing area in relation to the lower lateral cartilage. METHODS: Twenty-four heminoses of fixed Japanese cadavers were dissected to clarify the anatomical location of the vibrissae-bearing area in relation to the lower lateral cartilage. RESULTS: The medial part of the vibrissae-bearing area was precisely located on the medial crus of the lower lateral cartilage. Via a transitional state at the dome, the lateral part was located cephalic to the lateral crus in a manner in which the vibrissae-bearing area was adjacent to the lateral crus (adjacent type) in 22 cases, whilst the vibrissae-bearing area overlapped the lateral crus to some extent (overlap type) in two cases. CONCLUSIONS: The anatomical location of the vibrissae-bearing area in relation to the lower lateral cartilage is almost uniform, suggesting its utility as an open rhinoplasty incision landmark. PMID- 23462210 TI - Low rate of fistula formation after Sommerlad palatoplasty with or without lateral incisions: an analysis of risk factors for formation of fistulas after palatoplasty. AB - The aim of palate repair is to restore normal eating and drinking function and normal speech development and still maintain undisturbed facial growth. The repair should be performed with a low frequency of complications. A number of factors are thought to contribute to the formation of fistulas after palatoplasty; they include patient factors and treatment issues. The aim of this study was to review all patients operated on with palatoplasties according to Sommerlad in our clinic, examine the fistula frequency and analyse risk factors for the development of fistulas after palate repair. During the study period, 175 patients were operated on with palatoplasties according to Sommerlad by the senior cleft surgeon. The group included 150 native patients and 25 adopted children. In the native population, seven patients developed fistulas and the fistula frequency was thus 5%. In the non-native group four patients developed fistulas, which gave a fistula frequency of 16%. In conclusion, the fistula frequency after Sommerlad repair of cleft palate is low in our material and few patients need fistula repair. The liberal usage of Langenbeck flaps might give a lower fistula rate. The most common place for fistulas is the junction of the soft and hard palate. No clear difference could be seen between different types of clefts. Syndromes and associated malformation seem to play a small role in the formation of fistulas. The fistula frequency in the non-native population is higher. A number of factors are different in the non-native population. PMID- 23462211 TI - Antitubercular diterpenoids from Vitex trifolia. AB - A new halimane diterpenoid, 13-hydroxy-5(10),14-halimadien-6-one (1) and two new labdane diterpenoids, 6alpha,7alpha-diacetoxy-13-hydroxy-8(9),14-labdadien (2) and 9-hydroxy-13(14)-labden-15,16-olide (3), were isolated for the first time, along with fifteen known compounds, from the hexane soluble fraction of methanolic extract of Vitex trifolia leaves. The structures of these new diterpenoids were elucidated by spectral analysis. Their relative configurations were established using analysis of NOESY correlations and coupling constants observed in (1)H NMR. Compounds 2, 3 and another known diterpenoid, isoambreinolide (4) were evaluated for antitubercular activity. 3 and 4 exhibited antitubercular activity (MIC=100 and 25 MUg/ml) against Mycobacterium tuberculosis H37Rv in BACTEC-460 assay. PMID- 23462212 TI - Anti-secretory and cyto-protective effects of chebulinic acid isolated from the fruits of Terminalia chebula on gastric ulcers. AB - In continuation of our drug discovery program on Indian medicinal plants, the gastro protective mechanism of chebulinic acid isolated from Terminalia chebula fruit was investigated. Chebulinic acid was evaluated against cold restraint (CRU), aspirin (AS), alcohol (AL) and pyloric ligation (PL) induced gastric ulcer models in rats. Potential anti-ulcer activity of chebulinic acid was observed against CRU (62.9%), AS (55.3%), AL (80.67%) and PL (66.63%) induced ulcer models. The reference drug omeprazole (10 mg/kg, p.o.) showed 77.73% protection against CRU, 58.30% against AS and 70.80% against PL model. Sucralfate, another reference drug (500 mg/kg, p.o.) showed 65.67% protection in AL induced ulcer model. Chebulinic acid significantly reduced free acidity (48.82%), total acidity (38.29%) and upregulated mucin secretion by 59.75% respectively. Further, chebulinic acid significantly inhibited H(+) K(+)-ATPase activity in vitro with IC50 of 65.01 MUg/ml as compared to the IC50 value of omeprazole (30.24 MUg/ml) confirming its anti-secretory activity. PMID- 23462213 TI - A Chinese herb formula decreases the monocarboxylate transporter-mediated absorption of valproic acid in rats. AB - Huang-Qin-Tang (HQT), a Chinese medicine prescription containing Scutellariae Radix (SR), Paeoniae Radix (PR), Glycyrrhizae Radix (GR) and JuJubae Fructus (JF), was used for the treatments of cold with symptoms of abdominalgia and diarrhea. Valproic acid (VPA) is an antiepileptic drug with narrow therapeutic window. This study investigated the effect of coadministration of HQT on the pharmacokinetics of VPA, a probe drug for monocarboxylate transporter (MCT). Rats were administered VPA alone (200.0 mg/kg) and coadministered HQT (8.0 g/kg) at 0.5h before VPA and 1.5h after VPA in crossover designs. In addition, the chronic effect of HQT was also evaluated by coadministration of the 7th dose at 0.5h before VPA. The serum concentration of VPA was determined by a fluorescence polarization immunoassay. The results showed that coadministration of HQT at 0.5h before VPA significantly decreased the AUC(0-t) and Cmax by 62% and 77%, respectively, whereas coadministration of HQT at 1.5h after VPA exerted no significant influence. When the 7th dose of HQT was given at 0.5h before VPA, the AUC(0-t) and Cmax of VPA were markedly decreased by 65% and 82%, respectively. Mechanism study revealed that the MCT-mediated uptake of fluorescein was inhibited by HQT and each component herbs. In conclusion, the MCT-mediated absorption of VPA was significantly decreased by concomitant administration of HQT. PMID- 23462214 TI - Efficacy of entecavir switch therapy in chronic hepatitis B patients with incomplete virological response to telbivudine. AB - BACKGROUND: The roadmap concept suggests the use of on-treatment HBV DNA to guide treatment strategy of chronic hepatitis B patients treated by telbivudine. Our aim was to validate the roadmap approach of entecavir switch therapy in patients with incomplete response to telbivudine. METHODS: Consecutive chronic hepatitis B patients on telbivudine monotherapy were studied. Incomplete virological response was defined as detectable HBV DNA after 6-12 months of treatment. Maintained virological response was defined as undetectable HBV DNA until the last follow up. RESULTS: Among the 79 patients on telbivudine, 39 (49%) had undetectable HBV DNA after 6-12 months of telbivudine treatment and 40 (51%) had incomplete virological response. In total, 33 incomplete responders switched to entecavir at 11 months (6-23), and 26 (79%) achieved maintained virological response after 25 months (4-46). Low HBV DNA level before switch therapy was the independent factor associated with maintained virological response to entecavir (P=0.01). A total of 24 of 25 (96%) patients with HBV DNA<2,000 IU/ml, versus 2 of 8 (25%) patients with HBV DNA>=2,000 IU/ml, had maintained virological response after switching to entecavir. Although rtM204I and/or rtL180M was detected in 3 of 7 patients with incomplete virological response to entecavir, none of the patients with HBV DNA<2,000 IU/ml during telbivudine treatment harboured these amino acid substitutions. CONCLUSIONS: Roadmap approach using entecavir switch at month 6-12 among incomplete responders to telbivudine is recommended if the HBV DNA is <2,000 IU/ml at the time of switching. PMID- 23462215 TI - Should we still screen for type 2 diabetes after ADDITION-Cambridge? A low-income world perspective. AB - The worldwide growing epidemic of diabetes is driven by the increase in type 2 diabetes. The very insidious natural history of type 2 diabetes and the availability of simple means to detect it as well as its preceding silent stages make type 2 diabetes and ideal disease for screening. Although public policies for type 2 diabetes screening do exist in many developed countries, issues related to its benefits on disease outcomes and its cost-effectiveness have been a concern. Recent results from the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION) Cambridge show that screening for type 2 diabetes is not associated with a reduction in mortality, either all-cause, cardiovascular or diabetes-related, after 10 years of follow-up. It seems crucial to raise the awareness of the medical community on the high risk of misinterpretation of these results as the death knell of type 2 diabetes screening. To that end, we discuss here some potential explanations of the lack of benefit, and we suggest a cautious uptake of the results, especially in low-income countries where type 2 diabetes screening is by far more likely to yield substantial health benefits. PMID- 23462216 TI - Adipokines and vascular health in treated HIV infection: an obesity paradox? AB - We examined the relationship between plasma adipokine concentrations and ultrasound measures of vascular health in 100 HIV-infected adults on antiretroviral therapy. Leptin was positively correlated with flow-mediated dilation of the brachial artery and negatively with carotid intima-media thickness. These relationships were independent of traditional risk factors and trunk fat in women but not men. Neither adiponectin nor resistin was associated with either measure of vascular health. PMID- 23462217 TI - Polymorphisms in the interleukin-7 receptor alpha gene and mortality in untreated HIV-infected individuals. AB - OBJECTIVES: Recently, polymorphisms in the gene encoding the interleukin-7 receptor alpha (IL7Ralpha) have been shown to influence the CD4 cell count in HIV infected individuals. The objective of this study was to examine the impact of 10 single nucleotide polymorphisms (SNPs) in or in close proximity to the IL7Ralpha on mortality among 152 untreated HIV infected in a Zimbabwean cohort. METHODS: Patients were followed prospectively, median time of follow-up 3.9 year. SNPs were genotyped using competitive allele-specific PCR. Cox regression was used for survival analyses. RESULTS: We found an increased mortality among carriers of the IL7Ralpha, rs6897932, T-allele (hazard ratio: 2.56 [95% confidence interval (CI) 1.22-5.35], P=0.013). This association remained significant after adjusting for age, sex, baseline HIV-RNA and baseline CD4 cell count (hazard ratio=2.36 (95% CI 1.06-2.58), P=0.036). CONCLUSION: The results suggest an association between the IL7Ralpha, rs6897932, T-allele and increased mortality among untreated HIV infected, Zimbabwean individuals. PMID- 23462218 TI - MHC-driven HIV-1 control on the long run is not systematically determined at early times post-HIV-1 infection. AB - INTRODUCTION: Human leukocyte antigen (HLA) class I-driven long-term protection against HIV-1 is mainly associated with HLA-B*27 and HLA-B*57. This effect is observed early after infection. Clarification needs to be established concerning the moment of action for the other HLA-B or HLA-C alleles. METHODS: HLA-B and HLA C alleles from 111 individuals that control HIV-1 disease for over 8 years and from 747 seroconverters frequencies were compared. Also, HLA-B and HLA-C influence on early levels of plasma HIV-RNA, cellular HIV-DNA, CD4, CD8 and CD4/CD8 ratio was evaluated among the seroconverters. We performed univariate, multivariate and haplotypic analyses in order to disentangle the respective contribution of the HLA-B and HLA-C genes. RESULTS: The haplotypes analysis shows three patterns of protective effects of HLA-B and HLA-C alleles or haplotypes. First, the HLA B*57, HLA-B*27, HLA-B*13 and HLA-C*14 alleles, which have a strong effect on long-term disease control, also influence at least one of the early infection phenotypes. Second, HLA-B*52 has a strong effect during early time points on HIV-RNA without significant effect on the long-term control of HIV-1. Finally, the HLA-B*14-C*08 haplotype has a strong effect on the long-term protection, without influencing early viral control. CONCLUSION: Our study highlighted independent effects of HLA-B and HLA-C alleles on HIV-disease progression. Furthermore, some alleles appeared to be specifically associated with either long-term control or early virological parameters, suggesting different immunological mechanisms according to the disease stages. PMID- 23462219 TI - Cost-effectiveness of point-of-care viral load monitoring of antiretroviral therapy in resource-limited settings: mathematical modelling study. AB - BACKGROUND: Monitoring of HIV viral load in patients on combination antiretroviral therapy (ART) is not generally available in resource-limited settings. We examined the cost-effectiveness of qualitative point-of-care viral load tests (POC-VL) in sub-Saharan Africa. DESIGN: Mathematical model based on longitudinal data from the Gugulethu and Khayelitsha township ART programmes in Cape Town, South Africa. METHODS: Cohorts of patients on ART monitored by POC-VL, CD4 cell count or clinically were simulated. Scenario A considered the more accurate detection of treatment failure with POC-VL only, and scenario B also considered the effect on HIV transmission. Scenario C further assumed that the risk of virologic failure is halved with POC-VL due to improved adherence. We estimated the change in costs per quality-adjusted life-year gained (incremental cost-effectiveness ratios, ICERs) of POC-VL compared with CD4 and clinical monitoring. RESULTS: POC-VL tests with detection limits less than 1000 copies/ml increased costs due to unnecessary switches to second-line ART, without improving survival. Assuming POC-VL unit costs between US$5 and US$20 and detection limits between 1000 and 10,000 copies/ml, the ICER of POC-VL was US$4010-US$9230 compared with clinical and US$5960-US$25540 compared with CD4 cell count monitoring. In Scenario B, the corresponding ICERs were US$2450-US$5830 and US$2230-US$10380. In Scenario C, the ICER ranged between US$960 and US$2500 compared with clinical monitoring and between cost-saving and US$2460 compared with CD4 monitoring. CONCLUSION: The cost-effectiveness of POC-VL for monitoring ART is improved by a higher detection limit, by taking the reduction in new HIV infections into account and assuming that failure of first-line ART is reduced due to targeted adherence counselling. PMID- 23462220 TI - Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AB - OBJECTIVES: To assess the incidence, predictors, and outcomes of Kaposi sarcoma associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. DESIGN: Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. METHODS: KS-IRIS case definition was standardized across sites. Cox regression and Kaplan Meier survival analysis were used to identify the incidence and predictors of KS IRIS and Kaposi sarcoma-associated mortality. RESULTS: Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log10 copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/MUl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). CONCLUSION: KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa. PMID- 23462221 TI - Positive impact of a large-scale HIV prevention programme among female sex workers and clients in South India. AB - OBJECTIVE: Estimate the potential impact of Avahan, the India AIDS Initiative, among female sex workers (FSWs) and their clients in five districts of Karnataka state, south India. DESIGN: Examination of time trends in sexually transmitted infection (STI)/HIV prevalence from serial cross-sectional surveys, combined with mathematical modelling. METHODS: Survey data from each district were used to monitor changes in FSW STI/HIV prevalence during Avahan. A deterministic model, parameterized with district-specific survey data, was used to simulate HIV/HSV 2/syphilis transmission among high-risk groups in each district. Latin hypercube sampling was used to obtain multiple parameter sets that reproduced district specific HIV prevalence trends. A Bayesian framework tested whether self-reported increases in consistent condom use (CCU) during Avahan were more compatible with FSW HIV prevalence trends than assuming no or slow (preintervention rates) CCU increases, and were used to estimate HIV incidence and infections averted. RESULTS: Declines in FSW HIV prevalence occurred over 5 years in all districts, and were statistically significant in three. Self-reported increases in CCU were more consistent with observed declines in HIV prevalence in three districts. In all five districts, an estimated 25-64% (32-70%) HIV infections were averted among FSWs (clients) over 5 years. This corresponded to 142-2092 FSW infections averted depending on the district (two-fold to nine-fold more among clients). CONCLUSION: Empirical HIV prevalence trends combined with Bayesian modelling have provided plausible evidence that Avahan has reduced HIV transmission among FSWs and their clients. If current CCU levels are sustained, FSW HIV prevalence could decline to low levels by 2015, with many more infections averted. PMID- 23462222 TI - Pulmonary inflammation after ethanol exposure and burn injury is attenuated in the absence of IL-6. AB - Alcohol consumption leads to an exaggerated inflammatory response after burn injury. Elevated levels of interleukin-6 (IL-6) in patients are associated with increased morbidity and mortality after injury, and high systemic and pulmonary levels of IL-6 have been observed after the combined insult of ethanol exposure and burn injury. To further investigate the role of IL-6 in the pulmonary inflammatory response, we examined leukocyte infiltration and cytokine and chemokine production in the lungs of wild-type and IL-6 knockout mice given vehicle or ethanol (1.11 g/kg) and subjected to a sham or 15% total body surface area burn injury. Levels of neutrophil infiltration and neutrophil chemoattractants were increased to a similar extent in wild-type and IL-6 knockout mice 24 h after burn injury. When ethanol exposure preceded the burn injury, however, a further increase of these inflammatory markers was seen only in the wild-type mice. Additionally, signal transducer and activator of transcription-3 (STAT3) phosphorylation did not increase in response to ethanol exposure in the IL-6 knockout mice, in contrast to their wild-type counterparts. Visual and imaging analysis of alveolar wall thickness supported these findings and similar results were obtained by blocking IL-6 with antibody. Taken together, our data suggest a causal relationship between IL-6 and the excessive pulmonary inflammation observed after the combined insult of ethanol and burn injury. PMID- 23462223 TI - Starvation and re-feeding affect Hsp expression, MAPK activation and antioxidant enzymes activity of European sea bass (Dicentrarchus labrax). AB - In the context of food deprivation in fish (wild and farmed), understanding of cellular responses is necessary in order to develop strategies to minimize stress caused by starvation in the aquaculture section. The present study evaluates the effects of long term starvation (1F-3S: one-month feeding-three-month starvation) and starvation/re-feeding (2S-2F: two-month starvation-two-month re-feeding) compared to the control group (4F-0S: four-month feeding-zero month starvation) on cellular stress response and antioxidant defense in organs, like the intestine, the liver, the red and white muscle of European sea bass Dicentrarchus labrax. Molecular responses were addressed through the expression of Hsp70 and Hsp90, the phosphorylation of stress-activated protein kinases and particularly p38 mitogen-activated protein kinase (p38 MAPK) and the extracellular signal regulated kinases (ERK-1/2). For the determination of the effect of the oxidative stress caused by food deprivation and/or re-feeding, the (maximum) activities of antioxidant enzymes such as glutathione peroxidise (GPx), catalase (CAT) and superoxide dismutase (SOD) as well as the determination of thiobarbituric acid reactive substances (TBARS) were studied. The experimental feeding trials caused a tissue distinct and differential response on the cellular and antioxidant capacity of sea bass not only during the stressful process of starvation but also in re-feeding. Specifically, the intestine phosphorylation of ERKs and antioxidant enzymatic activities increased in the 2S-2F fish group, while in the 1F-3S group an increase was detected in the levels of the same proteins except for GPx. In the liver and the red muscle of 2S-2F fish, decreased Hsp70 and phosphorylated p38 MAPK levels and increased Hsp90 levels were observed. Additionally, SOD activity decreased in the red muscle of 2S-2F and 1F-3S groups. In the liver and red muscle of 1F-3S group Hsp70 levels increased, while the activation of p38 MAPK in the liver decreased. In the white muscle, Hsp90 levels decreased and the phosphorylation of p38 MAPK increased in both feeding regimes compared to control. In the same tissue, GPx and catalase levels were decreased in 2S-2F regime, while SOD levels were decreased in 1F-3S regime. PMID- 23462224 TI - An antibody-like peptide that recognizes malignancy among thyroid nodules. AB - There is an urgent need for biomarkers to identify malignant thyroid nodules from indeterminate follicular lesions. We have used a subtractive proteomic strategy to identify novel biomarkers by selecting ligands to goiter tissue from a 12-mer random peptide phage-displayed library using the BRASIL method (Biopanning and Rapid Analysis of Selective Interactive Ligands). After three rounds of selection, two highly reactive clones to the papillary thyroid tumor cell line NPA were further evaluated, and their specific binding to tumor proteins was confirmed using phage-ELISA. The antibody-like peptide CaT12 was tumor-specific, which was further tested by immunohistochemistry against TMAs (tissue microarrays) comprised of 775 human benign and malignant tissues, including 232 thyroid nodular lesions: 15 normal thyroid tissues, 53 nodular goiters (NG), 54 follicular adenomas (FA); 69 papillary thyroid carcinomas (PTC); and 41 follicular carcinomas (FC). CaT12 was able to identify PTC among thyroid nodular lesions with 91.2% sensitivity and 85.1% specificity, despite its non-specificity for thyroid tissues. Additionally, the CaT12 peptide helped characterize follicular lesions distinguishing the follicular variant of PTC (FVPTC) from FA with 91.9% accuracy; FVPTC from NG with 83.1% accuracy; FVPTC from the classic PTC with 57.7% accuracy; and FVPTC from FC with 88.7% accuracy. In conclusion, our strategy to select differentially expressed ligands to thyroid tissue was highly effective and resulted in a useful antibody-like biomarker that recognizes malignancy among thyroid nodules and may help distinguish follicular patterned lesions. PMID- 23462225 TI - EMT in developmental morphogenesis. AB - Carcinomas, cancers of epithelial origin, constitute the majority of all cancers. Loss of epithelial characteristics is an early step in carcinoma progression. Malignant transformation and metastasis involve additional loss of cell-cycle control and gain of migratory behaviors. Understanding the relationships among epithelial homeostasis, cell proliferation, and cell migration is therefore fundamental in understanding cancer. Interestingly, these cellular events also occur frequently during animal development, but without leading to tumor formation. Can we learn anything about carcinomas from developmental biology? In this review, we focus on one aspect of carcinoma progression, the Epithelial Mesenchymal Transition (EMT), and provide an overview of how the EMT is involved in normal amniote development. We discuss 12 developmental and morphogenetic processes that clearly involve the EMT. We conclude by emphasizing the diversity of EMT processes both in terms of their developmental context and of their cellular morphogenesis. We propose that there is comparable diversity in cancer microenvironment and molecular regulation of cancer EMTs. PMID- 23462226 TI - Increased expression of sphingosine kinase in the amnion during labor. AB - INTRODUCTION: Sphingosine-1-phosphate (S1P), a bioactive lipid, has been reported to regulate inflammation processes. The onset of labor is thought to be related to inflammation. We therefore hypothesized that S1P might be involved in the onset of labor. METHODS: The expression of sphingosine kinase (SPHK)-1, which produces S1P, and S1P lyase (SPL)-1, which irreversibly inactivates S1P, were examined in the fetal membranes. The expression levels were compared between amnions from cases of elective Caesarean deliveries (pre-labor) and those from vaginal deliveries (post-labor). In primary cultured human amnion cells, the expression levels of prostaglandin-endoperoxide synthase (PTGS)-2 were examined in the presence or absence of S1P treatment. RESULTS: SPHK-1 and SPL-1 were both expressed in the amnion. The expression of SPHK-1 in the post-labor amnions increased compared with that in the pre-labor amnions. The expression of PTGS-2, a key regulator of labor, also increased in the post-labor amnion. However, the SPL-1 expression in the pre-labor amnion was not significantly different from that in the post-labor amnion. S1P1-3 and 5, which were coupled with Gi protein, were consistently found in the amnion cells. The treatment with S1P increased the expression of PTGS-2, and this was completely suppressed by a Gi inhibitor in the amnion cells. DISCUSSION: We are herein provide the first evidence of increased SPHK-1 expression in post-labor amnions, and that S1P increases the PTGS-2 expression in amnion cells. CONCLUSIONS: Our results suggest that S1P might play a role in the onset of labor via the induction of PTGS-2. PMID- 23462227 TI - Assessment of baseline characteristics, glycemic control and oral antidiabetic treatment in Asian patients with diabetes: The Registry for Assessing OAD Usage in Diabetes Management (REASON) Asia study. AB - BACKGROUND: To assess baseline characteristics, glycemic control, and treatment with oral antidiabetic drugs (OAD) in type 2 diabetes mellitus (T2DM) patients. METHODS: This multinational, observational study recruited patients >= 21 years of age who were newly diagnosed and/or treated with OAD monotherapy for <6 months but were inadequately controlled. In cross-sectional phase, data on demographics, medical history, diabetic complications and comorbidities, OAD treatment, glycosylated hemoglobin (HbA1c), and fasting blood glucose (FBG) were collected. In longitudinal phase evaluating 6-month follow-up of sulfonylurea (SU)-treated patients, additional data on reasons for not achieving HbA1c targets were collected. RESULTS: Of 1487 patients (mean [+/- SD] age 52.0 +/- 11.6 years; 46.7% men; mean BMI 25.8 +/- 4.4 kg/m(2) ) recruited, 75.9% were newly diagnosed, 73.3% had central obesity, 43.8% had hypertension, and 60.5% had dyslipidemia. The mean HbA1c was 9.8 +/- 2.4%, and the mean FBG was 11.3 +/- 4.3 mmol/L. At T0 (baseline) and T6 (month 6 visit), 99.8% (n=1066) and 97.1% (n=830) patients received SU, respectively. There was decrease from T0 to T6 in mean HbA1c (10.2% vs 7.3%, respectively; P<0.0001) and mean FBG (12.0 vs 7.6 mmol/L, respectively; P<0.0001). Number of patients with HbA1c <7% increased from T0 (4.5%) to T6 (46.8%). Reasons for not achieving target HbA1c included poor diabetes education (50.7%), non-compliance to OADs (21.4%), and fear of hypoglycemia (19.7%). CONCLUSION: Marked reductions in HbA1c and FBG are achievable in T2DM patients managed with OADs. However, patient education and compliance are important for achieving and maintaining treatment targets. PMID- 23462229 TI - Arterial stiffness and endothelial function in obstructive sleep apnoea/hypopnoea syndrome. AB - BACKGROUND: Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is associated with increased cardiovascular morbidity and mortality. Our study examined arterial stiffness and endothelial function in subjects with OSAHS with no known cardiovascular disease compared to well-matched controls. METHODS: Twenty subjects with OSAHS (defined as apnoea-hypopnoea index [AHI] > or =15 and Epworth Sleepiness Scale score > or =11) without cardiovascular disease and 20 well matched controls underwent a comprehensive evaluation of arterial stiffness and endothelial function. Arterial stiffness was measured by applanation tonometry and cardiovascular magnetic resonance imaging (MRI) and endothelial function assessed by measuring vascular reactivity after administration of glyceryl trinitrate and salbutamol. RESULTS: Subjects with OSAHS had increased arterial stiffness (augmentation index 19.3 [10.9] vs. 12.6 (10.2)%; p=0.017) and impaired endothelial function (change in augmentation index following salbutamol -4.3 (3.2) vs. -8.0 (4.9)%; p=0.02) compared to controls. Aortic distensibility, a measure of arterial stiffness, was negatively correlated with the AHI. CONCLUSIONS: Our findings suggest that even in the absence of known cardiovascular disease, subjects with OSAHS have increased arterial stiffness and impaired endothelial function and are at increased risk for cardiovascular disease. PMID- 23462228 TI - Long-term CB1 receptor blockade enhances vulnerability to anxiogenic-like effects of cannabinoids. AB - Compelling evidence has documented the anxiolytic and mood-enhancing properties of cannabis. In susceptible users, however, consumption of this drug is conducive to panic, paranoia and dysphoria. We hypothesized that the up-regulation of CB1 receptors (CB1Rs) in select brain regions may enhance the vulnerability to cannabinoid-induced anxiety. To test this possibility, we assessed the behavioral impact of a potent cannabinoid agonist (CP55,940; 0.05-0.1 mg/kg, IP) on C57BL/6 male mice, respectively subjected to a prolonged pre-treatment of either the selective CB1R antagonist/inverse agonist AM251 (1 mg/kg/day IP, for 21 days, followed by a 3-day clearance period before testing) or its vehicle (VEH1). Anxiety-like responses were studied in the novel open field, elevated plus maze (EPM) and social interaction assays. While CP55,940 induced anxiolytic-like effects in the EPM in VEH1-exposed animals, it elicited opposite actions in AM251 exposed mice. In this last group, CP55,940 also reduced rearing and social interaction in comparison to its vehicle (VEH2). The divergent effects of CP55,940 in AM251- and VEH1-pretreated animals were confirmed in 129SvEv mice. Immunoblotting analyses on brain samples of C57BL/6 mice revealed that AM251 pre treatment caused a significant up-regulation of CB1R expression in the prefrontal cortex and striatum, but also a down-regulation of these receptors in the hippocampus and midbrain. Notably, CB1R levels in the prefrontal cortex were negatively correlated with anxiolysis-related indices in the EPM; furthermore, midbrain CB1R expression was positively correlated with the total duration of social interaction. These results suggest that regional variations in brain CB1R expression may differentially condition the behavioral effects of cannabinoids with respect to anxiety-related responses. PMID- 23462230 TI - Second messenger/signal transduction pathways in major mood disorders: moving from membrane to mechanism of action, part I: major depressive disorder. AB - The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [gamma-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid-based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3beta, and NFkappaB/DeltaFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed. PMID- 23462231 TI - Agreement of flicker chronoscopy for structural glaucomatous progression detection and factors associated with progression. AB - PURPOSE: To evaluate agreement of flicker chronoscopy for structural glaucomatous progression detection and factors associated with progression. DESIGN: Retrospective cohort study. METHODS: Two glaucoma fellowship-trained ophthalmologists, masked to temporal sequence, independently graded serial flicker chronoscopy images from 1 eye of a cohort of glaucoma patients for features of structural progression. Agreement between graders was determined, as was accuracy for determining the temporal order of images. After adjudication, simple and multiple logistic models were constructed to determine baseline variables associated with increased odds of progression. RESULTS: Fifty of 103 included eyes/patients (48.5%) had at least 1 sign of structural progression. Temporal sequence was incorrectly determined in 14 of 206 cases (6.4%). Interobserver agreements for identifying baseline photographs (kappa = 0.9), global progression (kappa = 0.7), parapapillary atrophy (PPA) progression (kappa = 0.7), disc hemorrhages (kappa = 0.7), neuroretinal rim loss (kappa = 0.5), and retinal nerve fiber layer (RNFL) loss (kappa = 0.2) were calculated. Age was significantly associated with global (1.8; 1.3-2.6, P < .001) (odds ratio; 95% confidence interval, significance) and PPA progression (1.7; 1.2-2.4, P = .002). Lower corneal hysteresis was associated with global progression (0.78; 0.56-0.99, P = .049) and RNFL loss (0.5; 0.3-0.9, P = .02). Goldmann-correlated intraocular pressure (1.0, 0.7-1.4, P = .9), visual field mean deviation (1.0, 0.9-1.0, P = .2), and central corneal thickness (0.9, 0.8-1.0, P = .1) were not significantly associated with progression. On multivariable analysis, only age was associated with global progression (1.8; 1.2-2.5, P = .002). CONCLUSION: Flicker chronoscopy demonstrated acceptable interobserver agreement in structural progression detection. Corneal hysteresis and age were both associated with progression, but age was the only significant factor on multivariable analysis. PMID- 23462232 TI - Cytotoxicity of ganciclovir on cultured human corneal endothelial cells. AB - BACKGROUND: Intraocular cytomegalovirus (CMV) infections, including endotheliitis and retinitis, have been reported to threaten the host's vision. These infections have been treated with systemic or intravitreal GCV injection. Intracameral GCV injection can be an effective treatment option that avoids systemic side effects. The cytotoxic effect of ganciclovir (GCV) on cultured human corneal endothelial cells (HCECs) was evaluated. METHODS: HCECs were cultured and exposed to various concentrations (0-20 mg/ml) of GCV (Cytovene((r))). Cell viability was assessed by the Cell Counting Kit-8 method and live/dead viability/cytotoxicity assays. Cell morphology was assessed using phase-contrast microscopy after 48 h exposure to GCV. Cell cycle and apoptosis were analysed using NC-3000 to evaluate the effect of GCV on HCECs. The cell proliferation rate was evaluated by a bromodeoxyuridine proliferation assay. RESULTS: Cytotoxicity tests showed that GCV had a dose-dependent cytotoxic effect on HCECs. GCV concentrations of >=5 mg/ml resulted in a significant reduction in cell viability. Higher concentrations of GCV resulted in cell cycle delay, low proliferation rate, and an increased number of apoptotic cells, indicating activation of the pro apoptotic pathway. CONCLUSIONS: Our results suggest that intracameral GCV concentrations of >=5 mg/ml may increase the risk of corneal endothelial damage, although GCV concentrations of <=0.5 mg/ml do not decrease cell viability. PMID- 23462233 TI - Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. AB - Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. PMID- 23462234 TI - [Clinical problems in medical mycology: problem number 46]. AB - A 49 year old-man, without known previous diseases, who suffered an acute lung infection, is presented. He was a smoker and belonged to a high socioeconomic class. He suddenly presented high fever, dry cough and legs' pain. Thorax X-ray and CT scan showed two excavated pneumonic infiltrates in the lower part of the right lung. He was treated with antibacterial antibiotics without clinical response. A transparietal fine needle lung biopsy was performed and the histopathology and cytological studies revealed an epithelioid granuloma with capsulated yeasts. Cryptococcus neoformans antigenemia was positive 1/128, and brain MR, as well as CSF studies, allowed to rule out a central nervous system compromise. The patient was successfully treated with itraconazole by oral route at a daily dose of 400mg during 6 months. Post-treatment thorax CT scan showed a thin walled lung cavity as a sequela. PMID- 23462235 TI - Purine receptor mediated actin cytoskeleton remodeling of human fibroblasts. AB - Earlier studies have shown that activation of adenosine A1 receptors on peripheral pain fibers contributes to acupuncture-induced suppression of painful input. In addition to adenosine, acupuncture triggers the release of other purines, including ATP and ADP that may bind to purine receptors on nearby fibroblasts. We here show that purine agonists trigger increase in cytosolic Ca(2+) signaling in a cultured human fibroblasts cell line. The profile of agonist-induced Ca(2+) increases indicates that the cells express functional P2yR2 and P2yR4 receptors, as well as P2yR1 and P2xR7 receptors. Unexpectedly, purine-induced Ca(2+) signaling was associated with a remodeling of the actin cytoskeleton. ATP induced a transient loss in F-actin stress fiber. The changes of actin cytoskeleton occurred slowly and peaked at 10min after agonist exposure. Inhibition of ATP-induced increases in Ca(2+) by cyclopiazonic acid blocked receptor-mediated cytoskeleton remodeling. The Ca(2+) ionophore failed to induce cytoskeletal remodeling despite triggering robust increases in cytosolic Ca(2+). These observations indicate that purine signaling induces transient changes in fibroblast cytoarchitecture that could be related to the beneficial effects of acupuncture. PMID- 23462236 TI - Intrapleural hyperthermic perfusion chemotherapy in subjects with metastatic pleural malignancies. AB - OBJECTIVES: Malignant pleural effusion (MPE) means poor prognosis in the majority of cases. Intrapleural Hyperthermic perfusion chemotherapy (HIPEC) looks promising approach for these patients. We aimed to investigate whether cytoreductive surgery followed by HIPEC provides any survival benefit in cases with metastatic MPEs. METHODS: Between January 2009 and December 2011, 19 patients with metastatic MPEs were treated with HIPEC following surgical interventions such as pleurectomy/decortication and/or lung resection (group 1). Comparison was done with historical control groups consisted of patients who received either talc pleurodesis or pleurectomy/decortication followed by systemic treatment for the management of metastatic MPEs between June 2007 and June 2008 (group 2 and 3). Statistical analyses including overall survival, disease free interval were done for the group comparisons. RESULTS: Median survival in group 1, 2 and 3 were 15.4, 6, 8 months, respectively. One year survival was 54.7% in group 1 where it was 0.6% and 0.8% in group 2 and 3, respectively. There was no operative mortality. Morbidity was occurred in 1 patient in group 1 (5.3%). CONCLUSIONS: HIPEC combined with cytoreductive surgery seems to be a promising treatment option for subjects with metastatic MPEs. Further studies are needed for the optimization of HIPEC method, drug of choice, and the best combination therapy for the multimodal treatment. PMID- 23462237 TI - Latitude modifies the effect size of factors related to recurrent wheeze in the first year of life. AB - BACKGROUND: Although the association between latitude and asthma prevalence has been studied to a certain extent, its influence on the magnitude of the association of risk/protective factors with recurrent wheeze in infants has never been reported. METHODS: The adjusted odd ratios (aOR) of various risk/protective factors for recurrent wheeze from 31,920 infants from 19 centres of the "Estudio Internacional de Sibilacias en Lactantes" (EISL) in very different parts of the world were used to build a meta-regression using the strength of the aOR of each factor as dependent variable and centre latitude as explanatory variable. The meta-regression was further adjusted for continent. RESULTS: There was a positive significant correlation between latitude and the magnitude of the aOR between recurrent wheeze and having cold(s) during the first three months of life (p = 0.004); attending a nursery school (p = 0.011); and having additional siblings (p = 0.003). Furthermore, there was a negative correlation for having been breastfed for at least three months (p = 0.044). Heterogeneity (as measured by I2) of the magnitude of aORs between centres was quite high except for breast feeding: 73.1% for colds; 66.9% for nursery school; 52.6% for additional siblings; and 18.1% for breast feeding. Latitude explained a considerable amount of that heterogeneity: 63.8% for colds; 52.8% for nursery school; 86.6% for additional siblings; and 100% for breast feeding, probably as a consequence of its low heterogeneity. CONCLUSION: The magnitude in which some risk/protective factors are associated to recurrent wheeze during the first year of life varies significantly with latitude. PMID- 23462238 TI - [Cardiovascular manifestations of human toxocariasis]. AB - Toxocariasis is a parasitic infection produced by helminths that cannot reach their adult stage in humans. For their etiological species (Toxocara canis and Toxocara cati), man is a paratenic host. Infection by such helminths can produce a variety of clinical manifestations, such as: visceral larvae migrans syndrome, ocular larvae migrans syndrome and covert toxocariasis. In the visceral larvae migrans syndrome, the organs that are mainly involved include liver, lungs, skin, nervous system, muscles, kidneys and the heart. Regarding the latter, the importance of cardiovascular manifestations in toxocariasis, as well as its clinical relevance, has increasingly begun to be recognized. The current article is based on a systematic information search, focused mainly on the clinical and pathological aspects of cardiovascular manifestations in toxocariasis, including its pathophysiology, laboratory findings, diagnosis and therapeutical options, with the objective of highlighting its importance as a zoonosis and its relevance to the fields of cardiovascular medicine in adults and children. PMID- 23462240 TI - Mu-rhythm changes during the planning of motor and motor imagery actions. AB - Motor imagery is a mental representation of motor behavior which has been widely used to study the cognitive basis of movement. The assumption that real movements and motor imagery (virtual movements) use the same neurobiological basis has been questioned by functional magnetic resonance data. The functional similarity in the planning of real and virtual movements was studied here by analyzing event related EEG recordings of the Mu-activity in the sensitive-motor cortex, pre motor cortex and supplementary motor cortex. A visual stimulus (an arrow) which displayed the information needed for planning a motion (which can be executed or imaged later after the display of a second stimulus) induced a short-lasting phase-locked Mu-response (PLr) which was wider and more widespread when it was used for the motor planning of real or virtual movements than when it was passively watched. The phase-locked Mu-response was accompanied by a persistent decrease of the Mu-rhythms which were not phase-locked to stimuli (NPLr), a response which also was more marked and generalized when stimuli were used for motor planning than when they were passively observed. PLr and NPLr were similar during motor testing and imagery testing, suggesting that both tasks activated the Mu rhythms to a similar degree. This congruency between real and virtual movements was observed in the three cortical areas studied, where the amplitude, latency and duration of the phase-locked and non-phase-locked Mu response was similar in both cases. These noticeable similarities support the idea that the same cortical mechanisms are recruited during the planning of real and virtual movements, a fact that can be analyzed better when an event-related paradigm and a high time-resolution method are used. PMID- 23462239 TI - Neural competition as a developmental process: early hemispheric specialization for word processing delays specialization for face processing. AB - Little is known about the impact of learning to read on early neural development for word processing and its collateral effects on neural development in non-word domains. Here, we examined the effect of early exposure to reading on neural responses to both word and face processing in preschool children with the use of the Event Related Potential (ERP) methodology. We specifically linked children's reading experience (indexed by their sight vocabulary) to two major neural markers: the amplitude differences between the left and right N170 on the bilateral posterior scalp sites and the hemispheric spectrum power differences in the gamma band on the same scalp sites. The results showed that the left lateralization of both the word N170 and the spectrum power in the gamma band were significantly positively related to vocabulary. In contrast, vocabulary and the word left-lateralization both had a strong negative direct effect on the face right-lateralization. Also, vocabulary negatively correlated with the right lateralized face spectrum power in the gamma band even after the effects of age and the word spectrum power were partialled out. The present study provides direct evidence regarding the role of reading experience in the neural specialization of word and face processing above and beyond the effect of maturation. The present findings taken together suggest that the neural development of visual word processing competes with that of face processing before the process of neural specialization has been consolidated. PMID- 23462241 TI - Multilevel alterations in the processing of audio-visual emotion expressions in autism spectrum disorders. AB - The abilities to recognize and integrate emotions from another person's facial and vocal expressions are fundamental cognitive skills involved in the effective regulation of social interactions. Deficits in such abilities have been suggested as a possible source for certain atypical social behaviors manifested by persons with autism spectrum disorders (ASD). In the present study, we assessed the recognition and integration of emotional expressions in ASD using a validated set of ecological stimuli comprised of dynamic visual and auditory (non-verbal) vocal clips. Autistic participants and typically developing controls (TD) were asked to discriminate between clips depicting expressions of disgust and fear presented either visually, auditorily or audio-visually. The group of autistic participants was less efficient to discriminate emotional expressions across all conditions (unimodal and bimodal). Moreover, they necessitated a higher signal-to-noise ratio for the discrimination of visual or auditory presentations of disgust versus fear expressions. These results suggest an altered sensitivity to emotion expressions in this population that is not modality-specific. In addition, the group of autistic participants benefited from exposure to bimodal information to a lesser extent than did the TD group, indicative of a decreased multisensory gain in this population. These results are the first to compellingly demonstrate joint alterations for both the perception and the integration of multisensory emotion expressions in ASD. PMID- 23462242 TI - The influence of explicit conceptual knowledge on perception of physical motions: An ERP study. AB - Event-related potential is used to study the influence of explicit conceptual knowledge on the perception of physical motions. Participants holding correct or wrong physics concept performed an oddball task with a pair of stimuli. For half of the blocks, the motion consistent with the physical law was the oddball stimulus and the motion inconsistent with the physical law was the standard stimulus and vice versa. The participants holding correct conceptual knowledge showed the larger parietal P3 to the incorrect target stimulus. By contrast, the participants holding wrong conceptual knowledge showed the larger parietal P3 to the correct target stimulus. The results suggest that explicit conceptual knowledge could affect the perception of physical motions. People tend to bias their perception toward the existing explicit knowledge. This study could be helpful for understanding the contribution of education to human perception. PMID- 23462243 TI - Impact of lymphadenectomy in uterine endometrioid carcinoma. AB - AIMS: To investigate the role of lymphadenectomy in uterine endometrioid carcinoma based on the 2009 FIGO staging system. METHODS: Using an institution maintained cancer registry database, all patients who were treated surgically for endometrial cancer from 1991 to 2008 in two medical centers were analyzed. Kaplan Meier and Cox proportional hazards methods were used to determine the role of lymphadenectomy. RESULTS: From 961 women with uterine endometrioid carcinoma, 680 underwent lymphadenectomy and 281 did not. Young age, early-stage disease, low grade tumor, and lymphadenectomy were favorable independent prognostic factors. The five-year disease-specific survival (DSS) of stages IA, IB, II, and III, and the two-year DSS of stage IV patients who underwent lymphadenectomy were 97.8%, 88.3%, 91.5%, 70.5%, and 32.1%, respectively, compared to 98.7%, 70.0%, 73.3%, 42.9%, and 16.6% in those without lymphadenectomy (p > 0.05 for stage IA; p < 0.01 for stages IB-IV, log-rank test). In high-risk patients (i.e., poorly differentiated, outer-half myometrial invasion, and stages II-IV), more extensive lymph node resection was associated with an improved five-year DSS, from 71.3% (1 10 nodes removed) and 85.3% (11-20 nodes removed) to 86.8% (>20 nodes removed) (p = 0.02, log-rank test). For stage IIIC-IV patients with nodal metastasis, the extent of node resection also significantly improved the five-year DSS, from 34.4% (1-10 nodes removed) and 62.4% (11-20 nodes removed) to 79.6% (>20 nodes removed) (p = 0.04, log-rank test). CONCLUSIONS: Lymphadenectomy improves the survival of patients with uterine endometrioid carcinoma stage IB to stage IV. The extent of lymphadenectomy also improves the survival of high-risk patients and those with nodal disease. PMID- 23462244 TI - Is the sentinel lymph node pathology protocol in breast cancer patients associated with the risk of regional recurrence? AB - BACKGROUND: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN) in breast cancer patients. Previously, we reported that ultra-staging led to more axillary lymph node dissections (ALND). The question was, whether ultra-staging is effective in reducing the risk of regional relapse. METHODS: From January 2002 to July 2003, 541 patients from 4 hospitals were prospectively registered when they underwent a SN biopsy. In hospitals A, B, and C, 3 levels of the SN were examined pathologically, whereas in hospital D at least 7 additional levels were examined. Patients with a positive SN, including isolated tumor cells, underwent an ALND. This analysis focuses on the 341 patients with a negative SN. Primary endpoint was 5-year regional recurrence rate. RESULTS: In hospital D 34% of the patients had a negative SN as compared to 71% in hospitals A, B, and C combined (p < 0.001). At 5 years follow-up, 9 (2.6%) patients had developed a regional lymph node relapse. In hospital D none of the patients had a regional recurrence, as compared to 9 (2.9%) cases of recurrence in hospitals A, B, and C. CONCLUSION: The less intensified SN pathology protocol appeared to be associated with a slightly increased risk of regional recurrence. The absolute risk was still less than 3%, and does not seem to justify the intensified SN pathology protocol of hospital D. PMID- 23462245 TI - Takayasu's arteritis and its role in causing renal artery stenosis. AB - Takayasu's arteritis is a systemic vasculitis that involves medium- and large sized arteries. Renal artery involvement is a potential manifestation of TA that occurs in 60% of the patients in India and the Far East. This manifestation can lead to renal failure and/or renovascular hypertension. Renovascular hypertension is generally resistant to medical therapy and often requires additional invasive management strategies, such as angioplasty or surgical bypass. In this review, we present the epidemiology, clinical manifestations, diagnosis and treatment of Takayasu's arteritis with particular emphasis on renal artery stenosis. The aim is to increase the awareness of this condition among clinicians because early diagnosis and the timely introduction of treatment can lead to improved outcomes in this poorly understood clinical enigma. PMID- 23462247 TI - Pituitary tumor with gigantism, acromegaly and preclinical Cushing's disease diagnosed from the 10th row. AB - A 7'3" basketball player was noted to have 2 to 3 times thicker tissue in his hands than 6'10" players by an endocrinologist sitting 10 rows above the player in a basketball arena. This led to the diagnosis of pituitary gigantism where the history revealed that he was 7'3" at 15 years of age. At age 19 when the acryl enlargement was noted, a diagnostic workup revealed elevated growth hormones and insulin-like growth factor 1 (IGF-1) with a 2 * 1.3 cm pituitary tumor. His history suggested that his epiphyseal plates had closed at age 15, and because he continued to produce IGF-1, he now has acromegaly. His elevated adrenocorticotropic hormone (ACTH) before surgery suggests that he also had preclinical Cushing's disease. After pituitary transsphenoidal surgery, all acryl enlargement in hands and ligaments disappeared. His growth hormone, IGF-1 and ACTH returned to normal 2 weeks after surgery. PMID- 23462246 TI - Management of primary immune thrombocytopenia, 2012: a survey of oklahoma hematologists-oncologists. AB - BACKGROUND: Management options for patients with primary immune thrombocytopenia (ITP) have increased, and treatment of patients with ITP has changed during the past 10 years. METHODS: To document current practice and to determine how current practice is related to recommendations of 2 recent practice guidelines for ITP, an International Consensus report and an American Society of Hematology (ASH) guideline, the authors surveyed practicing hematologists-oncologists in Oklahoma. Surveys were specific for children or adults. Each survey had 3 questions describing patients with a new diagnosis and patients who had not achieved remission with initial treatment. Questions were adapted from the clinical scenarios of the ASH guideline. RESULTS: Twelve (92%) Oklahoma pediatric hematologists-oncologists responded; 82 (81%) Oklahoma adult hematologists oncologists responded. For a child with a new diagnosis of ITP, a platelet count of 8000/uL and minor bleeding, 5 (42%) hematologists-oncologists selected observation without drug treatment (recommended by both guidelines). For an adult with a platelet count of 9000/uL who had failed to respond to initial treatment with corticosteroids and IVIg, 32 (39%) selected splenectomy (recommended by the ASH guideline); 30 (37%) selected rituximab and 13 (16%) selected thrombopoietin receptor agonists (both recommended by the International Consensus report). Hematologists-oncologists who had more years in practice were more likely to select splenectomy (P = 0.047). CONCLUSIONS: In a time of changing management for patients with ITP, these data document reported current management in Oklahoma and provide a basis for serial comparisons across time and for comparisons with other regions and comparison of management with patient outcomes. PMID- 23462248 TI - Tuberculosis reactivation in referrals to public health clinics in Texas. AB - BACKGROUND: Screening for and treatment of latent tuberculosis infection (LTBI) have been essential components of the TB elimination strategy. METHODS: To estimate the rate of and to identify risk factors for reactivation TB in patients in Texas with LTBI, we retrospectively analyzed 51,959 patients with LTBI identified in Texas Department of State Health Services TB clinics from 1995 to 2008. RESULTS: We identified 200 cases of reactivation TB among the 51,959 patients in this database. The overall rate of reactivation TB was 0.038 cases per 100 person-years (95% confidence interval [CI]: 0.032-0.043). The reactivation rate in patients who did not receive a complete treatment was 0.058. The relative risk (RR) for reactivation was higher in men (RR = 1.15; 95% CI: 0.86-1.54), patients older than 50 years (RR = 1.13; 95% CI: 1.04-1.22), African American (RR = 1.21; 95% CI: 1.09-1.34), U.S.-born referrals (RR = 1.4; 95% CI: 1.11-1.76), referrals with abnormal X-rays (RR = 1.07; 95% CI: 1.03-1.12) and patients receiving treatment other than isoniazid (RR = 1.08; 95% CI: 1.03-1.13). CONCLUSIONS: The current rate of reactivation TB in Texas is much lower than rates reported in the United States in the 1950s. Certain patients are at increased risk for reactivation and should be monitored more closely during LTBI therapy. PMID- 23462249 TI - Zolpidem arouses patients in vegetative state after brain injury: quantitative evaluation and indications. AB - BACKGROUND: To investigate the efficacy and indications of zolpidem, a nonbenzodiazepine hypnotic, inducing arousal in vegetative state patients after brain injury. METHODS: One hundred sixty-five patients were divided into 4 groups, according to area of brain damage and injury mechanism. All patients' brains were imaged by Tc-ECD single-photon emission computerized tomography (SPECT), before and 1 hour after treatment with 10 mg of zolpidem. Simultaneously, 3 quantitative indicators of brain function and damage were obtained using cerebral state monitor. Thirty-eight patients withdrew from the study after the first zolpidem dose. The remaining 127 patients received a daily dose of 10 mg of zolpidem for 1 week and were monitored again at the end of this week. RESULTS: One hour after treatment with zolpidem, cerebral state index was increased and burst suppression reduced in both brain contrecoup contusion and space-occupying brain compression groups (P < 0.05). SPECT showed, 1 hour after medication, that cerebral perfusion was improved in both brain contrecoup contusion and space-occupying brain compression groups, but no changes were seen in primary and secondary brain stem injury groups. In the 127 patients' group, after 1 week of zolpidem treatment, all parameters obtained from cerebral state monitor were not statistically different compared with those after the initial medication (P > 0.05). CONCLUSIONS: Zolpidem is an effective medicine to restore brain function in patients in vegetative state after brain injury, especially for those whose brain injuries are mainly in non-brain-stem areas. Improvement of brain function is sudden rather than gradual. PMID- 23462250 TI - Resistant hypertension: coarctation of the aorta. PMID- 23462251 TI - A prime-boost vaccination of mice with attenuated Salmonella expressing a 30-mer peptide from the Trichinella spiralis gp43 antigen. AB - Protection against Trichinella infections has been achieved using various parasite antigens and adjuvants. Recently, we reported that immunization of mice with an attenuated Salmonella strain displaying a 30-mer peptide (residues 210 239) from the Trichinella spiralis gp43 antigen using the ShdA autotransporter induced partial protection against T. spiralis infection. To improve the efficacy of vaccination, we used the MisL autotransporter system to display the Ts30mer peptide on the surface of Salmonella enterica ser. Typhimurium in combination with a prime-boost vaccination strategy. This vector and immunization regimen induced superior protection against T. spiralis when compared to our previously reported approach. Data presented herein showed a significant reduction in adult worm and muscle larvae burdens, high IgG titers, and increased production of intestinal mucus with entrapped adult worms. This prime-boost vaccination scheme is a suitable strategy to elicit enhanced protective immunity against T. spiralis. PMID- 23462252 TI - Analysis of the effect of a 2-(trifluoromethyl)-1H-benzimidazole derivative on Trichinella spiralis muscle larvae. AB - Albendazole and mebendazole are widely used in the treatment of trichinellosis; however, chemotherapy failure has been reported. In an effort to develop new anthelminthic compounds, we examined a previously synthesized 2-(trifluoromethyl) 1H-benzimidazole derivative (1) that showed good in vitro activity against Trichinella spiralis muscle larvae but low in vivo efficacy. In order to improve the solubility of compound 1, an inclusion complex with 2-hydroxypropyl-beta cyclodextrin (1/HP-betaCD) was prepared. When 1/HP-betaCD was tested in vivo, it significantly reduced the ML burden (84%). In addition, a proteomic analysis of T. spiralis ML treated with 1 revealed significant changes in the expression levels of proteins involved in energy metabolism and the cytoskeleton of the parasite. Compound (1) also induced extensive ultrastructural changes in the cuticle, hypodermis and midgut of the parasite. PMID- 23462253 TI - Epidemiology and prevalence of Toxoplasma gondii infection in the Iberian hare (Lepus granatensis). AB - Hares are important game species in Europe and their meat is consumed by humans. Toxoplasmosis is an important cause of mortality in hares in Nordic countries but little is known of Toxoplasma gondii infection in the Iberian hare (Lepus granatensis). Sera from 298 Iberian hares from Navarra (North Spain) were assayed for antibodies against T. gondii by the modified agglutination test. The samples were collected at necropsy during three consecutive years (2009-2011). Titers of 1:25 and higher were found in 34 hares (11.4%; CI95%: 7.8-14.9). Significant differences in seroprevalence were observed among geographical areas, years of sampling and age groups. The highest seroprevalence and the highest titers were observed in 2009, indicating fluctuating rates of transmission. Significantly higher seroprevalence was observed in the juvenile age group compared to the adult hare group. More than 40% of juvenile hares were seropositive the first year of study, seroprevalence drastically decreased in the juvenile animals sampled in the second year and was negligible in those sampled in the third year in this group. No clinical cases were detected in the study area and T. gondii was not detected by PCR in the liver of the 34 seropositive hares tested. These data may indicate that most juvenile seropositive hares did not survive as adults in the consecutive year or that there is a short-term humoral immune response against T. gondii in Iberian hares. PMID- 23462254 TI - Inflammatory phenotype of the nurse cell harboring Trichinella spp. AB - The nurse cell (NC), formed from muscle cells upon infection with the parasitic nematode Trichinella spp. constitutes a confined habitat for muscle larvae of encapsulating species. Signaling pathway-directed analysis of microarray data allowed identification of the stage of NC cell cycle arrest as being of G1-like type, accompanied by cellular senescence. In accord with the specificity of senescent cellular systems, up-regulation of pro-inflammatory molecules was also found within the NC preparations. Potential immune-related activities associated with NCs as inferred from the aforementioned analysis, are reviewed herein. Transcriptional data suggest that the NC which harbors the larvae may exhibit the following immune-related functions: (i) production of complement components, (ii) antigen presentation and phagocytosis, (iii) pro-inflammatory cytokine secretion, (iv) oxidative stress generation and (v) eicosanoid synthesis. PMID- 23462255 TI - Trichinella infection in Serbia in the first decade of the twenty-first century. AB - In Serbia, infection with Trichinella spp. has been recognized as a human health and animal husbandry problem for almost a century. The rate of swine infection gradually decreased from 0.14% to 0.02% between 2001 and 2010. For the past 5 years, Trichinella infections among swine were detected at levels higher than 0.05% in 3 districts of Serbia while prevalence persisted at lower levels for the rest of the country. During this 10-year period, there were 2257 cases of human trichinellosis, including 3 deaths; however, a significant decrease in the number of cases was reported during the last 5 years (fewer than 200 cases per year). The fact that prevalence data presented here are similar to prevalence data from 1990 indicates that this period of 10 years was needed to overcome the re emergence of Trichinella infection in swine and humans that occurred during the last decade of the previous century. PMID- 23462256 TI - Automatic processing of duration in children with attention-deficit/hyperactivity disorder. AB - Individuals with attention-deficit/hyperactivity disorder (ADHD) often exhibit deficits in processing information about time. Most studies, however, have required participants to perform active tasks and consequently it is unclear if performance deficits are due to impaired processing of temporal information, attentional deficits, or to impairments at a later stage of decision-making. This study used mismatch negativity (MMN) to examine automatic processing of temporal information in children with ADHD. The sample consisted of 11 children with typical development (8 boys; mean age/SD = 9.3/0.6 years) and 12 with ADHD (10 boys; mean age/SD = 8.9/0.8 years). Using the MMN paradigm, responses to standards and four deviants (hard/easy frequency, hard/easy duration) were elicited during the same sequence. The children's ability to actively discriminate each deviant was also assessed. Both groups exhibited MMNs to all deviants suggesting successful automatic discrimination. Furthermore, amplitude and latency measures were roughly comparable across groups. No group differences were seen on the active discrimination task, but performance was worse for duration than for frequency deviants. These results suggest that children with ADHD are able to automatically process temporal information, so deficits reported in active discrimination paradigms are likely due to deficits in subjective perception or usage of temporal information. PMID- 23462257 TI - Self-motion effects on hydrodynamic pressure sensing: part I. forward-backward motion. AB - In underwater locomotion, extracting meaningful information from local flows is as desirable as it is challenging, due to complex fluid-structure interaction. Sensing and motion are tightly interconnected; hydrodynamic signals generated by the external stimuli are modified by the self-generated flow signals. Given that very little is known about self-generated signals, we used onboard pressure sensors to measure the pressure profiles over the head of a fusiform-shape craft while moving forward and backward harmonically. From these measurements we obtained a second-order polynomial model which incorporates the velocity and acceleration of the craft to estimate the surface pressure within the swimming range up to one body length/second (L s(-1)). The analysis of the model reveals valuable insights into the temporal and spatial changes of the pressure intensity as a function of craft's velocity. At low swimming velocities (<0.2 L s(-1)) the pressure signals are more sensitive to the acceleration of the craft than its velocity. However, the inertial effects gradually become less important as the velocity increases. The sensors on the front part of the craft are more sensitive to its movements than the sensors on the sides. With respect to the hydrostatic pressure measured in still water, the pressure detected by the foremost sensor reaches values up to 300 Pa at 1 L s(-1) swimming velocity, whereas the pressure difference between the foremost sensor and the next one is less than 50 Pa. Our results suggest that distributed pressure sensing can be used in a bimodal sensing strategy. The first mode detects external hydrodynamic events taking place around the craft, which requires minimal sensitivity to the self-motion of the craft. This can be accomplished by moving slowly with a constant velocity and by analyzing the pressure gradient as opposed to absolute pressure recordings. The second mode monitors the self-motion of the craft. It is shown here that distributed pressure sensing can be used as a speedometer to measure the craft's velocity. PMID- 23462258 TI - Coronary computed tomography angiography for selecting coronary artery bypass graft surgery candidates. AB - BACKGROUND: There have been limited reports on the diagnostic performance and prognostic value of coronary computed tomography angiography (CCTA) for selecting coronary artery bypass graft (CABG) candidates. METHODS: There were 1,018 patients with suspected coronary artery disease who underwent 64-slice multidetector CCTA between July 2009 and January 2010. Of them, we excluded 324 patients who denied further treatment (n=7), who were lost for unidentified reasons (n=107), or who were transferred to local clinics (n=210). The total analysis cohort consisted of 694 patients. We established eligible CABG criteria defined as three-vessel disease, left main coronary disease, and left main coronary artery equivalent disease. Diagnostic performance was determined using conventional coronary angiography as the reference standard. For assessment of the prognostic utility of CCTA, electronic medical records were reviewed to screen for the occurrence of a major adverse cardiac event, defined as cardiac death, nonfatal myocardial infarction, or revascularization. RESULTS: The overall sensitivity, specificity, positive predictive value, and negative predictive value of CCTA for the selection of CABG candidates were 83.3%, 96.2%, 90.9%, and 92.7%, respectively. The presence of CABG criteria on CCTA was an independent prognostic factor for predicting a major adverse cardiac event (hazard ratio, 12.508; 95% confidence interval, 7.353 to 21.278; p<0.0001). CONCLUSIONS: We found CCTA had a high diagnostic performance for selecting CABG candidates and predicted major adverse cardiac events in CABG candidates referred for CCTA owing to suspected coronary artery disease. PMID- 23462259 TI - Role of surgical ventricular restoration in the treatment of ischemic cardiomyopathy. AB - BACKGROUND: Surgical ventricular restoration (SVR) has been applied as a valuable adjunct procedure for patients undergoing coronary artery bypass grafting (CABG) to correct the geometry of the left ventricle on the basis of myocardial revascularization. It is necessary to find out at least which patient cohort is more likely to benefit from this procedure. METHODS: A case-control study was conducted on 221 patients with ejection fraction (EF)<=0.35 and New York Heart Association (NYHA) class III or IV, who received CABG+SVR or CABG alone from 1998 to 2008. Comparisons were made between CABG+SVR and CABG alone within two groups of patients: group 1 (preoperative left ventricular end-systolic volume index [LVESVI]<80 mL/m2, n=127) and group 2 (preoperative LVESVI>=80 mL/m2, n=94). Outcomes included improvement in EF, NYHA class, readmissions, and survival. RESULTS: Patients in either group receiving SVR achieved significant LVESVI reduction postoperatively (p<0.001). In group 1, EF improvement (defined as over .05 improvement in EF) was observed in 53.7% of CABG+SVR patients compared with 48.5% for CABG patients (p 0.570). A similar percentage of patients improved to NYHA class I or II (63.0% for CABG+SVR versus 55.9% for CABG, p=0.430). Readmissions after CABG+SVR were 27.8% compared with 38.2% after CABG (p=0.225). There was no difference in survival between CABG+SVR and CABG (p=0.709). In group 2, the CABG+SVR patients showed greater EF improvement (55.6% versus 30.8%, p=0.020) and were more likely to improve to NYHA class I or II (58.3% versus 36.5%, p=0.044). Readmissions were fewer for the CABG+SVR patients than for the CABG patients (30.6% versus 57.7%, p=0.012). CABG+SVR yielded better survival than did CABG (p=0.031). CONCLUSIONS: Patients with much advanced LVESVI are more likely to benefit from surgical ventricular restoration, and this surgical procedure still holds its ground in the treatment of ischemic cardiomyopathy. PMID- 23462260 TI - Cold histidine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. AB - BACKGROUND: The present study aimed to compare myocardial protection, as assessed by cardiac troponin-I release, and short-term outcomes between two groups of neonates undergoing the arterial switch operation (ASO) with either Custodiol cardioplegia (Custodiol HTK, Kohler Chemie GmbH, Bensheim, Germany) or repeated oxygenated warm blood cardioplegia. METHODS: A total of 218 neonates were enrolled retrospectively from February 2007 through February 2011. All analyses were stratified on the type of procedure (ASO+/-ventricular septal defect closure +/- aortic arch repair). Troponin concentrations within the first week of surgery were analyzed using mixed models for repeated measurements. To counteract the confounding effect of the coronary anatomy, a sensitivity analysis was conducted after 1:1 matching. RESULTS: Overall 30 patients had Custodiol cardioplegia, and 188 had warm blood cardioplegia. High-risk coronary anatomy (single right coronary artery giving rise to the left, intramural course) was associated with higher troponin concentrations and a higher 30-day mortality rate postoperatively, and was more prevalent in the Custodiol group when compared with the warm blood cardioplegia group. Postoperative troponin concentrations were higher in the Custodiol group both before (p<0.001) and after matching on the coronary anatomy (p=0.03). The 30-day mortality rate was higher in the Custodiol group, 10% versus 1.1% (p=0.009), but only a nonsignificant trend was noted after matching. CONCLUSIONS: The use of Custodiol cardioplegia in neonates undergoing ASO was associated with a larger troponin release when compared with warm blood cardioplegia, suggesting poor myocardial protection. The difference noted in 30 day mortality was not due to the use of Custodiol. PMID- 23462261 TI - Surgery in adults with congenital heart disease: risk factors for morbidity and mortality. AB - BACKGROUND: Patients with congenital heart disease are frequently surviving into adulthood, and many of them will require surgery. Unfortunately, outcome data in this patient population are limited. We aimed to identify risk factors associated with adverse events in adults with congenital heart disease undergoing cardiac surgery and establish long-term survival data. METHODS: We retrospectively studied 458 adult patients who underwent cardiac surgery for congenital heart disease between 2000 and 2010. We constructed logistic models to assess risk factors for mortality, major adverse event (stroke, renal failure, prolonged ventilation, prolonged coma, deep sternal infection, reoperation, and operative mortality), and prolonged length of stay (>7 days). Long-term, all-cause mortality was also measured. RESULTS: Sixteen patients died (3.49%). Risk factors for mortality included a history of cerebrovascular disease (odds ratio [OR]: 4.51), New York Heart Association (NYHA) class 3 or 4 (OR: 8.88), and surgery on the aorta or the aortic valve (OR: 5.74). Ninety-four patients suffered a major adverse event (20.5%). Significant risk factors were male gender (OR: 2.28), NYHA class of 3 or 4 (OR 2.58), 2 concomitant major operations (OR: 2.15), and cardiopulmonary bypass time of greater than 100 minutes (OR: 3.18). Last, 90 patients (19.7%) remained in the hospital longer than 7 days. Significant risk factors for a prolonged length of stay included chronic lung disease (OR: 3.05), NYHA class of 3 or 4 (OR: 3.69), surgery by an adult cardiac surgeon (OR 2.58), 2 concomitant major operations (OR: 3.28), and cardiopulmonary bypass time of greater than 100 minutes (OR: 2.41). Survival at 1, 5, and 10 years was 97.6%, 95.2%, and 93.4%, respectively. CONCLUSIONS: Surgery in adults with congenital heart disease can be performed with low morbidity and mortality. Nonetheless, there remain important risk factors for adverse events. Awareness and modification of risk factors may help improve outcomes. PMID- 23462262 TI - Internal mammary artery harvesting influences antibiotic penetration into presternal tissue. AB - BACKGROUND: Internal mammary artery (IMA) harvesting for coronary artery bypass grafting (CABG) influences tissue perfusion and represents a risk factor for deep sternal wound infection (DSWI). Cephalosporins are routinely administered for prophylaxis during cardiac operations to decrease perioperative wound infections. We hypothesized that mammary artery preparation impairs antibiotic penetration into presternal tissue during CABG. METHODS: Eight patients undergoing skeletonized left mammary artery harvesting for CABG were included. Standard antibiotic prophylaxis was administered: 4 g of cefazolin before skin incision and an additional 2 g during skin closure. Concentrations of cefazolin were measured in subcutaneous tissue on the presternal right and left sides (surgically affected) after sternotomy and additionally in subcutaneous tissue on the thigh (surgically unaffected) by microdialysis over a 10-hour period. RESULTS: Mean peak tissue concentration and the area under the curve (AUC) on the left sternal side were significantly reduced compared with the right side and compared with the thigh (mean peak concentration, 13.1+/-5.8 versus 24.1+/-4.7 and 27.8+/-9.7 MUg/mL; p=0.005 and p=0.013; AUC 74.2+/-31.0 versus 110.4+/-25.0 and 140.3+/-46.3 MUg*hours per milliliter; p=0.004 and p=0.002). Mean subcutaneous concentrations of cefazolin on the left sternal side exceeded the minimal inhibitory concentration (MIC90) of Staphylococcus epidermidis of 4 MUg/mL in only 5 of 8 (37.5%) patients after 5 hours. CONCLUSIONS: IMA harvesting significantly impairs local antibiotic penetration during CABG. Common antibiotic dosing schemas should be reevaluated in this cardiac surgical setting. PMID- 23462263 TI - Septuagenarians bridged to heart transplantation with a ventricular assist device have outcomes similar to younger patients. AB - BACKGROUND: Although orthotopic heart transplantation (OHT) is increasingly being offered to older patients, few studies have evaluated outcomes in patients older than 70 years of age. We undertook this study to characterize the outcomes of septuagenarians bridged to transplantation (BTT) in the modern era. METHODS: We conducted a retrospective cohort study of all adult OHT in the United Network for Organ Sharing database from 2005 to 2011. Primary stratification was by age 70 years or older. Subgroup analysis evaluated patients who received BTT. The primary outcome was survival as determined by the Kaplan-Meier method. RESULTS: From January 2005 to December 2011, 12,274 adults underwent OHT, including 3,243 (26.4%) who received BTT. In the entire cohort, 11,996 (97.7%) recipients were aged 18 to 70 years, and 277 (2.3%) were 70 years of age or older. Overall, patients 70 years or older who underwent OHT had decreased 90-day survival (93.6% versus 88.8%; p<0.01), 1-year survival (89.0% versus 81.6%; p<0.01), and 2-year survival (85.4% versus 79.9%; p<0.01) compared with recipients of other ages. However in the BTT subgroup, recipients 70 years and older (n=43) had similar 90 day (91.2% versus 84.7%; p=0.2), 1-year (86.1% versus 81.7%; p=0.4), and 2-year (82.8% versus 81.7%; p=0.6) survival compared with recipients of other ages (n=3,200). After adjusting for multiple recipient and donor factors, age greater than or equal to 70 years was still not associated with an increased hazard of mortality at 90 days, 1 year, or 2 years. These results were verified by analysis of a propensity-matched cohort. CONCLUSIONS: Although patients older than the age of 70 years undergoing OHT have decreased survival, among patients who received BTT, septuagenarians have outcomes similar to those of younger recipients. In carefully selected patients dependent on left ventricular assist devices (LVADs), recipient age greater than or equal to 70 years should not be viewed as a contraindication to OHT. PMID- 23462264 TI - Reoperative multivalve surgery in adult congenital heart disease. AB - BACKGROUND: Repeat operations are common in adult congenital heart disease (ACHD) and valve-related procedures are the most frequent indication for intervention. The purpose of this study is to review a single institution's experience with a large number of patients with ACHD undergoing reoperation requiring multivalve intervention. METHODS: Data from the most recent repeat median sternotomy of 254 consecutive ACHD patients with simultaneous intervention on 2 or more valves were analyzed. Mean age of 136 (54%) female and 118 (46%) male patients was 37.9 years (range, 18 to 83). Diagnoses were conotruncal anomaly 132 (52%), Ebstein tricuspid valve 41(16%), pulmonary stenosis and right ventricular outflow tract obstruction 37 (14%), atrioventricular septal defect 22 (9%), and other 22 (9%). It was the second sternotomy in 130 (51%) patients, third in 80 (31%), fourth in 34 (13%), and fifth in 10 (4%). RESULTS: Intervention was on 2 valves in 219 patients (86.2%), 3 in 34 patients (13.4%), and 4 in 1 patient (0.4%). The most common valve combination was tricuspid and pulmonary (117, 43%). Early mortality overall was 4.7% (12 of 254) and 2.9% (7 of 239) after elective operation. Potentially modifiable risk factors identified for early mortality were preoperative hematocrit less than 35 (p=0.01), cross-clamp time (p<0.001), and cardiopulmonary bypass time (p<0.001). Late survival was 96%, 89%, and 77% at 1, 5, and 10 years, respectively. Independent risk factors for late mortality were prolonged ventilation (p=0.002), coronary artery disease (p=0.005), and cardiac injury (p=0.018). CONCLUSIONS: The need for simultaneous intervention on multiple valves is relatively common in ACHD, particularly with conotruncal anomalies. Prolonged bypass and cross-clamp times, lower hematocrit, and acquired coronary artery disease are significant predictors of adverse outcome. The number or position of valves requiring intervention did not affect early or late survival. PMID- 23462265 TI - High-dose donepezil (23 mg/day) for the treatment of moderate and severe Alzheimer's disease: drug profile and clinical guidelines. AB - To provide healthcare professionals with a comprehensive assessment of donepezil 23 mg and its role in treating Alzheimer's disease (AD), the Donepezil 23 mg Expert Working Group (EWG) convened in June 2011 to critically evaluate the clinical trial database for this higher dose formulation and the members' clinical experience with its use. Discussions were based on a large, 6-month, phase 3 clinical trial in patients with moderate to severe AD that compared continuing donepezil 10 mg/day versus switching to 23 mg/day. In this trial, donepezil 23 mg/day demonstrated significantly greater cognitive benefits (mean change in Severe Impairment Battery score, 2.11 points; P < 0.001). Prespecified analyses showed that benefits were significant irrespective of concomitant memantine use. The EWG considered integrating these new data into clinical practice approaches. Dementia severity, tolerability of the 10 mg dose, and need for additional therapy were key selection criteria, as was monitoring of gastrointestinal side effects, as consideration of titration strategies is an important aspect of implementation. The EWG concluded that donepezil 23 mg is an efficacious therapy for moderate to severe AD, with or without concomitant memantine, extending the treatment opportunities available to manage moderate to severe AD dementia. EWG guidelines offer assistance to clinicians in choosing and implementing treatment options. PMID- 23462266 TI - A neural computational model for animal's time-to-collision estimation. AB - The time-to-collision (TTC) is the time elapsed before a looming object hits the subject. An accurate estimation of TTC plays a critical role in the survival of animals in nature and acts as an important factor in artificial intelligence systems that depend on judging and avoiding potential dangers. The theoretic formula for TTC is 1/tau~theta'/sin theta, where theta and theta' are the visual angle and its variation, respectively, and the widely used approximation computational model is theta'/theta. However, both of these measures are too complex to be implemented by a biological neuronal model. We propose a new simple computational model: 1/tau~Mtheta-P/(theta+Q)+N, where M, P, Q, and N are constants that depend on a predefined visual angle. This model, weighted summation of visual angle model (WSVAM), can achieve perfect implementation through a widely accepted biological neuronal model. WSVAM has additional merits, including a natural minimum consumption and simplicity. Thus, it yields a precise and neuronal-implemented estimation for TTC, which provides a simple and convenient implementation for artificial vision, and represents a potential visual brain mechanism. PMID- 23462267 TI - Inhibition of aquaporin-4 significantly increases regional cerebral blood flow. AB - The effects of the aquaporin-4 (AQP-4) inhibitor TGN-020 on regional cerebral blood flow (rCBF) was examined in wild-type (WT) and AQP-4 knockout (KO) mice in vivo. Although baseline absolute rCBF of WT and KO mice were equivalent (158.9 +/ 17.7 and 155.5 +/- 10.4 ml/100 g/min, respectively), TGN-020 produced a significant increase in rCBF compared with saline-treated WT mice (control), reaching a plateau 20 min after administration (118.45 +/- 8.13%, P<0.01). TGN 020 showed no effect on KO mice, supporting the concept that the observed increase in rCBF in WT mice was AQP-4 dependent. Administration of acetazolamide (positive control) produced an even greater increase in rCBF in WT compared with TGN-020 and a similar response in KO mice as well, reaching a sustained plateau 5 min after administration (138.50 +/- 9.75 and 138.52 +/- 9.76%, respectively, P<0.01 compared with baseline or saline-treated control mice). The study demonstrated that AQP-4 plays a role in regulation of rCBF. PMID- 23462269 TI - Decision support models for solid waste management: review and game-theoretic approaches. AB - This paper surveys decision support models that are commonly used in the solid waste management area. Most models are mainly developed within three decision support frameworks, which are the life-cycle assessment, the cost-benefit analysis and the multi-criteria decision-making. These frameworks are reviewed and their strengths and weaknesses as well as their critical issues are analyzed, while their possible combinations and extensions are also discussed. Furthermore, the paper presents how cooperative and non-cooperative game-theoretic approaches can be used for the purpose of modeling and analyzing decision-making in situations with multiple stakeholders. Specifically, since a waste management model is sustainable when considering not only environmental and economic but also social aspects, the waste management bargaining game is introduced as a specific decision support framework in which future models can be developed. PMID- 23462268 TI - Regulation of TREM2 expression by an NF-kB-sensitive miRNA-34a. AB - Genetic deficits and loss of function for the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in Alzheimer's disease. In this study, we provide evidence that TREM2 is downregulated in samples of sporadic Alzheimer hippocampal CA1 compared with age matched controls. A nuclear factor-kB (NF-kB)-sensitive miRNA-34a (encoded at chr1p36.22), upregulated in Alzheimer's disease, was found to target the 299 nucleotide human TREM2 mRNA 3'-untranslated region (3'-UTR) and downregulate the expression of a TREM2-3'-UTR reporter vector. A stabilized anti-miRNA-34a (AM 34a) quenched this pathogenic response. The results suggest that an epigenetic mechanism involving an NF-kB-mediated, miRNA-34a-regulated downregulation of TREM2 expression may shape innate immune and phagocytic responses that contribute to inflammatory neurodegeneration. PMID- 23462270 TI - Generation and distribution of PAHs in the process of medical waste incineration. AB - After the deadly earthquake on May 12, 2008 in Wenchuan county of China, several different incineration approaches were used for medical waste disposal. This paper investigates the generation properties of polycyclic aromatic hydrocarbons (PAHs) during the incineration. Samples were collected from the bottom ash in an open burning slash site, surface soil at the open burning site, bottom ash from a simple incinerator, bottom ash generated from the municipal solid waste (MSW) incinerator used for medical waste disposal, and bottom ash and fly ash from an incinerator exclusively used for medical waste. The species of PAHs were analyzed, and the toxicity equivalency quantities (TEQs) of samples calculated. Analysis results indicate that the content of total PAHs in fly ash was 1.8*10(3) times higher than that in bottom ash, and that the strongly carcinogenic PAHs with four or more rings accumulated sensitively in fly ash. The test results of samples gathered from open burning site demonstrate that Acenaphthylene (ACY), Acenaphthene (ACE), Fluorene (FLU), Phenanthrene (PHE), Anthracene (ANT) and other PAHs were inclined to migrate into surrounding environment along air and surface watershed corridors, while 4- to 6-ring PAHs accumulated more likely in soil. Being consistent with other studies, it has also been confirmed that increases in both free oxygen molecules and combustion temperatures could promote the decomposition of polycyclic PAHs. In addition, without the influence of combustion conditions, there is a positive correlation between total PCDD/Fs and total PAHs, although no such relationship has been found for TEQ. PMID- 23462271 TI - Outdoor activity during class recess reduces myopia onset and progression in school children. AB - PURPOSE: The aim of this study was to investigate the effect of outdoor activity during class recess on myopia changes among elementary school students in a suburban area of Taiwan. DESIGN: Prospective, comparative, consecutive, interventional study. PARTICIPANTS: Elementary school students 7 to 11 years of age recruited from 2 nearby schools located in a suburban area of southern Taiwan. INTERVENTION: The children of one school participated in the interventions, whereas those from the other school served as the control group. The interventions consisted of performing a recess outside the classroom (ROC) program that encouraged children to go outside for outdoor activities during recess. The control school did not have any special programs during recess. MAIN OUTCOME MEASURES: Data were obtained by means of a parent questionnaire and ocular evaluations that included axial length and cycloplegic autorefraction at the beginning and after 1 year. RESULTS: Five hundred seventy-one students were recruited for this study, of whom 333 students participated in the interventional program, and 238 students were in the control school. At the beginning of the study, there were no significant differences between these 2 schools with regard to age, gender, baseline refraction, and myopia prevalence (47.75% vs. 49.16%). After 1 year, new onset of myopia was significantly lower in the ROC group than in the control group (8.41% vs. 17.65%; P<0.001). There was also significantly lower myopic shift in the ROC group compared with the control group (-0.25 diopter [D]/year vs. -0.38 D/year; P = 0.029). The multivariate analysis demonstrated that the variables of intervention of the ROC program and higher school year proved to be a protective factor against myopia shift in nonmyopic subjects (P = 0.020 and P = 0.017, respectively). For myopic subjects, school year was the only variable significantly associated with myopia progression (P = 0.006). CONCLUSIONS: Outdoor activities during class recess in school have a significant effect on myopia onset and myopic shift. Such activities have a prominent effect on the control of myopia shift, especially in nonmyopic children. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23462272 TI - Features of recurrence after excimer laser phototherapeutic keratectomy for anterior corneal pathologies in North China. AB - PURPOSE: To study long-term clinical patterns of recurrence of anterior corneal pathologies after excimer laser phototherapeutic keratectomy (PTK). DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Thirty patients (44 eyes) with anterior corneal pathologies who underwent PTK and experienced recurrence after long-term follow-up between March 1997 and April 2012. Preoperative diagnoses included band keratopathy in 7 eyes, anterior basement membrane dystrophy (ABMD) in 8 eyes, granular dystrophy in 15 eyes, lattice dystrophy in 10 eyes, and macular corneal dystrophy (MCD) in 4 eyes. METHODS: Data of each patient were collected regarding the recurrence of primary disease after PTK. RTVue (Optovue, Inc., Fremont, CA) optical coherence tomography (OCT) was used to detect the depth of recurrent deposits. Confocal microscopy was used to evaluate the cellular alterations associated with recurrent corneal disease. MAIN OUTCOME MEASURES: Interval, location, morphology of the recurrence, depth of recurrent deposits, and cellular alterations in recurrent disease. RESULTS: The mean follow-up (from the first PTK to the last visit) was 95 months (range, 80-120 months). The disease recurrence was symptomatic in all 8 eyes treated for ABMD and 2 eyes treated for lattice dystrophy and asymptomatic in the other cases. Significant recurrence of band keratopathy, ABMD, MCD, lattice dystrophy, and granular dystrophy developed at an average of 7.8, 12.4, 13.5, 19.7, and 23.7 months after PTK, respectively. RTVue OCT images indicated that the recurrent deposits involved the anterior corneal stroma (80-150 MUm) and were mainly within 8 mm around the corneal center. Morphologic changes included disorganized stromal fibers, decreased density and disordered arrangement of nerve fibers, and inconspicuous keratocyte nuclei, occasionally accompanied by decreased keratocyte density and endothelial cell density. CONCLUSIONS: The features of disease recurrence after PTK are closely related to the original corneal pathology. Recurrence in this series was fastest in patients with band keratopathy and, sequentially, ABMD, MCD, lattice dystrophy, and granular dystrophy. RTVue OCT imaging and confocal microscopy were valuable tools for the diagnosis of recurrent corneal opacities. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23462274 TI - Abstracts of the10th International Congress on SLE. April 18-21, 2013. Buenos Aires, Argentina. PMID- 23462273 TI - Reading performance in infantile nystagmus. AB - OBJECTIVE: To characterize reading deficits in infantile nystagmus (IN), to determine optimal font sizes for reading in IN, and to investigate whether visual acuity (VA) and severity of nystagmus are good indicators of reading performance in IN. DESIGN: Prospective cross-sectional study. PARTICIPANTS AND CONTROLS: Seventy-one participants with IN (37 idiopathic, 34 with albinism) and 20 age matched controls. METHODS: Reading performance was assessed using Radner reading charts and was compared with near logarithm of the minimum angle of resolution (logMAR) VA, nystagmus intensity, and foveation characteristics as quantified using eye movement recordings. MAIN OUTCOME MEASURES: Reading acuity (smallest readable font size), maximum reading speed, critical print size (font size below which reading is suboptimal), near logMAR VA, nystagmus intensity, and foveation characteristics (using the eXpanded Nystagmus Acuity Function). RESULTS: Using optimal reading conditions, maximum reading speeds were 18.8% slower in albinism and 14.7% slower in idiopathic IN patients compared with controls. Reading acuities were significantly worse (P<0.001) in IN patients compared with controls. Also, the range of font sizes over which reading speeds were less than the optimum were much larger in IN patients compared with controls (P<0.001). Reading acuity was correlated strongly to near VA (r(2) = 0.74 albinism, r(2) = 0.55 idiopathic), but was better than near VA in participants with poor VA. Near VA was a poor predictor of maximum reading speed. Nystagmus intensity and foveation were poor indicators of both reading acuity and maximum reading speed. CONCLUSIONS: Maximum reading speeds can be near normal in IN when optimal font sizes are provided, even in individuals with poor VA or intense nystagmus. However, reading performance in IN is acutely sensitive to font size limitations. Font sizes for optimal reading speeds in IN may be as much as 6 logMAR lines worse than the near VA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23462276 TI - Molecular cloning and characterization of cat, gpx1 and Cu/Zn-sod genes in pengze crucian carp (Carassius auratus var. Pengze) and antioxidant enzyme modulation induced by hexavalent chromium in juveniles. AB - Hexavalent chromium (Cr(6+)) is a common pollutant transient metal with high toxicity in the environment. The toxicological effects partly result from oxidative damage due to the production of excessive reactive oxygen species (ROS) in the reductive process of Cr(6+). To explore the influence of ROS induced directly by Cr(6+) on the oxidative stress generation and antioxidant system, the full length cDNAs of antioxidant-related genes cat, gpx1 and Cu/Zn-sod were successfully acquired from pengze crucian carp first and analyzed. Furthermore, the mRNA expression of the antioxidant genes encompassing catalase (cat), copper/zinc superoxide dismutase (Cu/Zn-sod) and glutathione peroxidase (gpx1), antioxidant enzyme activities of CAT, SOD, and GPx and total protein content were further studied in the gill, intestine and liver of pengze crucian carp (Carassius auratus var. Pengze) juveniles upon acute exposure to Cr(6+) at concentrations of 0.1, 1.0, 10 and 100 mg/L for 4 days. Differential significant changes of the antioxidant enzymes and gene expression were observed in different tissues. The findings contribute to better understanding the antioxidant mechanisms induced by Cr(6+) and selecting the organic-specific sensitive biomarkers to monitor the safety of the aquatic ecosystem. PMID- 23462277 TI - The plant vascular system: evolution, development and functions. AB - The emergence of the tracheophyte-based vascular system of land plants had major impacts on the evolution of terrestrial biology, in general, through its role in facilitating the development of plants with increased stature, photosynthetic output, and ability to colonize a greatly expanded range of environmental habitats. Recently, considerable progress has been made in terms of our understanding of the developmental and physiological programs involved in the formation and function of the plant vascular system. In this review, we first examine the evolutionary events that gave rise to the tracheophytes, followed by analysis of the genetic and hormonal networks that cooperate to orchestrate vascular development in the gymnosperms and angiosperms. The two essential functions performed by the vascular system, namely the delivery of resources (water, essential mineral nutrients, sugars and amino acids) to the various plant organs and provision of mechanical support are next discussed. Here, we focus on critical questions relating to structural and physiological properties controlling the delivery of material through the xylem and phloem. Recent discoveries into the role of the vascular system as an effective long-distance communication system are next assessed in terms of the coordination of developmental, physiological and defense-related processes, at the whole-plant level. A concerted effort has been made to integrate all these new findings into a comprehensive picture of the state-of-the-art in the area of plant vascular biology. Finally, areas important for future research are highlighted in terms of their likely contribution both to basic knowledge and applications to primary industry. PMID- 23462278 TI - Inflammometry in pediatric asthma: a review of fractional exhaled nitric oxide in clinical practice. AB - The burden of pediatric asthma remains high with one-third of patients being under- or overtreated because of the unique challenges in the assessment and management of childhood asthma. Until recently, there has been no point of care tool for assessing the underlying airway inflammation (i.e., inflammometry) in asthma. Recently, fractional exhaled nitric oxide (FeNO) has emerged as an important biomarker for the assessment and management of asthma. Recent evidence indicates that FeNO identifies T-helper cell type 2 (Th2)-mediated airway inflammation with a high positive and negative predictive value for identifying corticosteroid responsive airway inflammation. This article examines the evidence for FeNO as a predictor of Th2-mediated inhaled corticosteroid (ICS) responsive airway inflammation and reviews recent studies evaluating the role of FeNO, whether helpful or not, in the assessment and management of pediatric asthma. FeNO is a reliable adjunct to traditional tests in the assessment of suspected asthma. Importantly, it is useful for identifying and for excluding ICS responsive airway inflammation. Although individual study results have varied, collectively, asthma managed using FeNO is associated with lower exacerbation rates compared with clinical algorithms alone. Finally, FeNO may be useful in identifying patients at risk for future impairment or loss of asthma control during reduction/cessation of ICS treatment. FeNO testing has an important role in the assessment of pediatric patients with suspected asthma and in the management of pediatric patients with established asthma. Additional studies will continue to define the exact role of FeNO testing in pediatric asthma. PMID- 23462279 TI - Evaluation of performance of an accelerator-based BNCT facility for the treatment of different tumor targets. AB - PURPOSE: Encouraging Boron Neutron Capture Therapy (BNCT) clinical results obtained in recent years have stimulated intense research to develop accelerator based neutron sources to be installed in clinical facilities. In this work an assessment of an accelerator-based BNCT facility for the treatment of different tumor targets was performed, comparing the accelerator-derived results with reported reactor-based trials under similar conditions and subjected to the same clinical protocols. MATERIALS AND METHODS: A set of real image studies was used to cover clinical-like cases of brain and head-and-neck tumors. In addition, two clinical cases of malignant nodular melanoma treated at the RA-6 BNCT facility in Argentina were used to thoroughly compare the clinical dosimetry with the accelerator-derived results. RESULTS: The minimum weighted dose delivered to the clinical target volume was higher than 30 Gy and 14 Gy for the brain tumor and head-and-neck cases, respectively, in agreement with those achieved in clinical applications. For the melanoma cases, the minimum tumor doses were equal or higher than those achieved with the RA-6 reactor for identical field orientation and protocol. The whole-body dose assessment showed that the maximum photon equivalent doses for those normal organs close to the beam direction were below the upper limits considered in the protocols used in the present work. CONCLUSIONS: The obtained results indicate not only the good performance of the proposed beam shaping assembly design associated to the facility but also the potential applicability of accelerator-based BNCT in the treatment of both superficial and deep-seated tumors. PMID- 23462280 TI - Simulation-assisted burn disaster planning. AB - The aim of the study was to evaluate the Swedish medical systems response to a mass casualty burn incident in a rural area with a focus on national coordination of burn care. Data were collected from two simulations of a mass casualty incident with burns in a rural area in the mid portion of Sweden close to the Norwegian border, based on a large inventory of emergency resources available in this area as well as regional hospitals, university hospitals and burn centres in Sweden and abroad. The simulation system Emergo Train System((r)) (ETS) was used and risk for preventable death and complications were used as outcome measures: simulation I, 18.5% (n=13) preventable deaths and 15.5% (n=11) preventable complications; simulation II, 11.4% (n=8) preventable deaths and 11.4% (n=8) preventable complications. The last T1 patient was evacuated after 7h in simulation I, compared with 5h in simulation II. Better national coordination of burn care and more timely distribution based on the experience from the first simulation, and possibly a learning effect, led to a better patient outcome in simulation II. The experience using a system that combines both process and outcome indicators can create important results that may support disaster planning. PMID- 23462281 TI - The beneficial role of thiamine in Parkinson disease. AB - Parkinson disease (PD) is the second most common form of neurodegeneration among elderly individuals. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. In this paper, we review the evidence for an association between PD and thiamine. Interestingly, a significant association has been demonstrated between PD and low levels of serum thiamine, and thiamine supplements appear to have beneficial clinical effects against PD. Multiple studies have evaluated the connection between thiamine and PD pathology, and candidate pathways involve the transcription factor Sp1, p53, Bcl-2, caspase 3, tyrosine hydroxylase, glycogen synthase kinase-3beta, vascular endothelial growth factor, advanced glycation end products, nuclear factor kappa B, mitogen activated protein kinase, and the reduced form of nicotinamide adenine dinucleotide phosphate. Thus, a review of the literature suggests that thiamine plays a role in PD, although further investigation into the effects of thiamine in PD is needed. PMID- 23462282 TI - Facile synthesis of novel D-ring modified steroidal dienamides via rearrangement of 2H-pyrans. AB - A simple and practical method for synthesis of the D-ring modified steroidal dienamides (4a-k) from the steroidal alpha,alpha-dicyanoalkene 3 and aldehydes via vinylogous aldol reaction was first reported. By using NaOAc as a base, the desired products were obtained in moderate to good yields in ethanol under mild conditions. All the synthesized steroidal dienamides are new and are currently being evaluated for their biological activities. PMID- 23462283 TI - Chronic hypoxia leads to a glycolytic phenotype and suppressed HIF-2 signaling in PC12 cells. AB - BACKGROUND: Along with other regulators of cell metabolism, hypoxia-inducible factors HIF-1 and HIF-2 differentially regulate cell adaptation to hypoxia. Switches in HIF-1/HIF-2 signaling in chronic hypoxia have not been fully investigated. METHODS: Proliferation, viability, apoptosis, neuronal and bioenergetic markers, mitochondrial function, respiration, glycolysis, HIF signalling, responses to O2 and glucose deprivation (OGD) were examined using tumor PC12 and SH-SY5Y cells continuously grown at 3% O2. RESULTS: Hypoxic PC12 cells (H-cells) exhibit reduced proliferation and histone H4 acetylation, NGF independent differentiation, activation of AMPK, inhibition of Akt, altered mitochondria and response to NGF. Cellular cytochrome c is increased with no effect on apoptosis. Reduction in respiration has minor effect on cellular ATP which is maintained through activated uptake (GLUT1) and utilization (HK2, PFK2) of glucose. H-cells exhibit resistance to OGD linked to increased glycogen stores. HIF-2alpha protein is decreased without changes in mRNA. Unlike HIF 1alpha, HIF-2alpha is not stabilized pharmacologically or by O2 deprivation. Capacity for HIF-2alpha stabilization is partly restored when H-cells are cultured at normoxia. In low-respiring SH-SY5Y cells cultured under the same conditions HIF-2alpha stabilization and energy budget are not affected. CONCLUSIONS: In chronically hypoxic PC12 cells glycolytic energy budget, increased energy preservation and low susceptibility to OGD are observed. HIF 2alpha no longer orchestrates adaptive responses to anoxia. GENERAL SIGNIFICANCE: Demonstrated switch in HIF-1/HIF-2 signaling upon chronic hypoxia can facilitate cell survival in energy crisis, by regulating balance between energy saving and decrease in proliferation, on one hand and active cell growth and tumor expansion, on the other. PMID- 23462284 TI - OnabotulinumtoxinA improves tactile and mechanical pain perception in painful diabetic polyneuropathy. AB - OBJECTIVES: Diabetic neuropathic pain may be relieved by onabotulinumtoxinA (BoNT/A). However, whether BoNT/A changes sensory perception in neuropathic patients remains unknown. This study used a double-blind crossover design to explore the possible effect of BoNT/A on sensory perception. METHODS: Eighteen patients with painful diabetic polyneuropathy underwent 2 consecutive 12-week periods of treatment either in the sequence of saline (control) and then BoNT/A (SB cohort, n=9) or BoNT/A followed by saline (BS cohort, n=9). Sensory perception was assessed according to the tactile threshold [TT, logarithmized force (g) of von Frey filaments] and mechanical pain threshold [PT, logarithmized weight (g) of weighted syringes], both being averages from 4 individual measurements of bilateral medial and lateral feet obtained at baseline (before injections) and at weeks 1, 4, 8, and 12 after treatment. RESULTS: In either the SB or the BS cohort, there was a decrease in the TT and the PT after treatment with BoNT/A but not with saline. In the analysis merging both cohorts (n=18), BoNT/A resulted in a significant decrease in TT and PT at weeks 1, 4, 8, and 12 (all Ps<0.05 vs. saline). The longitudinal effect of BoNT/A on TT and PT remained significant when baseline values, treatment sequences, and periods were controlled using generalized estimating equations. DISCUSSION: BoNT/A may improve tactile and mechanical pain perception in painful diabetic polyneuropathy. The beneficial effects of BoNT/A deserves further study to elucidate the exact mechanism and potential for preventing insensate injuries. PMID- 23462285 TI - Pain medicine versus pain management: ethical dilemmas created by contemporary medicine and business. AB - The world of health care and the world of business have fundamentally different ethical standards. In the past decades, business principles have progressively invaded medical territories, leading to often unanticipated consequences for both patients and providers. Multidisciplinary pain management has been shown to be more effective than all other forms of health care for chronic pain patients; yet, fewer and fewer multidisciplinary pain management facilities are available in the United States. The amazing increase in interventional procedures and opioid prescriptions has not led to a lessening of the burden of chronic pain patients. Ethical dilemmas abound in the treatment of chronic pain patients: many are not even thought about by providers, administrators, insurance companies, or patients. We call for increased pain educational experiences for all types of health care providers and the separation of business concepts from pain-related health care. PMID- 23462286 TI - Correlates of spousal empathic accuracy for pain-related thoughts and feelings. AB - OBJECTIVES: This study explored correlates of spousal ability to infer the thoughts and feelings of individuals with chronic pain (ICPs). METHODS: Participant couples (N=57), who consisted of at least 1 couple member with chronic pain, engaged in a videotaped discussion about pain, after which they completed an empathic accuracy procedure where spouses of ICP were asked to infer thoughts/feelings of ICPs. RESULTS: Overall levels of partner empathic accuracy were similar to other studies of couples. Several characteristics of the pain experience and the marital relationship correlated with empathic accuracy for thoughts and feelings. Specifically, partner catastrophizing about the ICP's pain was associated with less empathic accuracy for thoughts, whereas ICP pain severity was related to a greater empathic accuracy for feelings. Several significant interactions were also found, with marital satisfaction and partner's own pain experience acting as moderators. DISCUSSION: These findings provide support for models of empathy that argue that characteristics of the pain condition and characteristics of the observer are important contributors to observers' understanding of pain. In addition, the findings support previous research that suggests there are different processes for understanding the emotional versus the cognitive experience of others. PMID- 23462287 TI - NLRP3 inflammasomes show high expression in aorta of patients with atherosclerosis. AB - OBJECTIVES: The aim of the present study was to investigate the expression of NLRP3 in aorta of patients with coronary atherosclerosis and to explore the association between aortic expression levels of NLRP3 and atherosclerotic risk factors. METHODS: We collected small pieces of ascending aorta from 36 patients undergoing coronary artery bypass graft (CABG) surgery, and the arterial tissues from 10 subjects without atherosclerosis through the kidney donation program were taken as control. The expression of NLRP3 of the research and control group was determined by immunohistochemistry. Gensini score was used to evaluate the severity of coronary atherosclerosis. RESULTS: NLRP3 was strongly expressed in aorta of CABG patients. The aortic NLRP3 expression was elevated in patients with hypertension or diabetes, and smokers. The NLRP3 expression in aorta was positively correlated with total cholesterol, low density lipoprotein cholesterol, and lipoprotein(a) (P<0.05); but negatively correlated with high density lipoprotein cholesterol (P<0.05). Spearman correlation revealed that aortic NLRP3 expression had significant correlation with Gensini coronary severity scores (P<0.05). CONCLUSIONS: NLRP3 was overexpressed in aorta of patients with coronary atherosclerosis and the aortic NLRP3 expression is correlated with the severity of coronary artery disease and the atherosclerotic risk factors. PMID- 23462288 TI - Variable gearing in a biologically inspired pneumatic actuator array. AB - A fundamental feature of pennate muscles is that muscle fibers are oriented at an angle to the line of action and rotate as they shorten, becoming more oblique throughout a contraction. This change in fiber orientation (pennation angle) can amplify the shortening velocity of a fiber and increase output velocity of the muscle. The velocity advantage resulting from dynamic changes in pennation angle can be characterized as a gear ratio (muscle velocity/fiber velocity). A recent study has shown that a pennate muscle's gear ratio varies automatically depending on the load such that a muscle operates with a high gear during rapid contractions and low gear during forceful contractions. We examined whether this variable gearing behavior can be replicated in a pennate array of artificial muscles. We used McKibben type pneumatic actuators, which shorten in tension when filled with compressed gas. Similar to muscle fibers, the actuators expand radially during shortening, a feature thought to be a critical part of the variable gearing mechanism in pennate muscles. We arranged McKibben actuators in an array oriented to mimic a pennate muscle, and quantified the system's gear ratio during contraction against a range of loads. Video was used to measure the gear ratio during each contraction. We find that similar to pennate muscles, the gear ratio decreases significantly with increasing load and that variable gearing results from load-dependent variation in the amount of actuator rotation. These results support the idea that variable gearing in pennate muscles is mediated by difference is fiber rotation and the direction of muscle bulging. The behavior of our artificial muscle array also highlights the potential benefits of bio inspired architectures in artificial muscle arrays, including the ability to vary force and speed automatically in response to variable loading conditions. PMID- 23462289 TI - Characterization of neuronal cell death in the spiral ganglia of a mouse model of endolymphatic hydrops. AB - HYPOTHESIS: Spiral ganglion neurons (SGN) in the Phex male mouse, a murine model of postnatal endolymphatic hydrops (ELH) undergo progressive deterioration reminiscent of human and other animal models of ELH with features suggesting apoptosis as an important mechanism. BACKGROUND: Histologic analysis of the mutant's cochlea demonstrates ELH by postnatal Day (P) 21 and SGN loss by P90. The SGN loss seems to occur in a consistent topographic pattern beginning at the cochlear apex. METHODS: SGN were counted at P60, P90, and P120. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative PCR, and immunohistochemical analyses of activated caspase-3, caspase-8, and caspase-9 were performed on cochlear sections obtained from mutants and controls. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling assay (TUNEL) was carried out on 2 mutants and 2 controls. RESULTS: Corrected SGN counts in control mice were greater in the apical turn of the cochleae at P90 and P120, respectively (p < 0.01). Increased expression of activated caspase-3, caspase-8, and caspase-9 was seen in the mutant. At later time points, activated caspase expression gradually declined in the apical turns and increased in basal turns of the cochlea. Quantitative and semiquantitative PCR analysis confirmed increased expression of caspase-3, caspase-8, and caspase-9 at P21 and P40. TUNEL staining demonstrated apoptosis at P90 in the apical and basal turns of the mutant cochleae. CONCLUSION: SGN degeneration in the Phex /Y mouse seems to mimic patterns observed in other animals with ELH. Apoptosis plays an important role in the degeneration of the SGN in the Phex male mouse. PMID- 23462290 TI - Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function. AB - Rett syndrome (RTT), an X-linked postnatal disorder, results from mutations in Methyl CpG-binding protein 2 (MECP2). Survival and breathing in Mecp2(NULL/Y) animals are improved by an N-terminal tripeptide of insulin-like growth factor I (IGF-I) treatment. We determined that Mecp2(NULL/Y) animals also have a metabolic syndrome and investigated whether IGF-I treatment might improve this phenotype. Mecp2(NULL/Y) mice were treated with a full-length IGF-I modified with the addition of polyethylene glycol (PEG-IGF-I), which improves pharmacological properties. Low-dose PEG-IGF-I treatment slightly improved lifespan and heart rate in Mecp2(NULL/Y) mice; however, high-dose PEG-IGF-I decreased lifespan. To determine whether insulinotropic off-target effects of PEG-IGF-I caused the detrimental effect, we treated Mecp2(NULL/Y) mice with insulin, which also decreased lifespan. Thus, the clinical benefit of IGF-I treatment in RTT may critically depend on the dose used, and caution should be taken when initiating clinical trials with these compounds because the beneficial therapeutic window is narrow. PMID- 23462291 TI - Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. AB - Two siblings from consanguineous parents died perinatally with a condition characterized by generalized hypotonia, respiratory insufficiency, arthrogryposis, microcephaly, congenital brain malformations and hyperglycinemia. Catalytic activities of the mitochondrial respiratory complexes I and II were deficient in skeletal muscle, a finding suggestive of an inborn error in mitochondrial biogenesis. Homozygosity mapping identified IBA57 located in the largest homozygous region on chromosome 1 as a culprit candidate gene. IBA57 is known to be involved in the biosynthesis of mitochondrial [4Fe-4S] proteins. Sequence analysis of IBA57 revealed the homozygous mutation c.941A > C, p.Gln314Pro. Severely decreased amounts of IBA57 protein were observed in skeletal muscle and cultured skin fibroblasts from the affected subjects. HeLa cells depleted of IBA57 showed biochemical defects resembling the ones found in patient-derived cells, including a decrease in various mitochondrial [4Fe-4S] proteins and in proteins covalently linked to lipoic acid (LA), a cofactor produced by the [4Fe-4S] protein LA synthase. The defects could be complemented by wild-type IBA57 and partially by mutant IBA57. As a result of the mutation, IBA57 protein was excessively degraded, an effect ameliorated by protease inhibitors. Hence, we propose that the mutation leads to partial functional impairment of IBA57, yet the major pathogenic impact is due to its proteolytic degradation below physiologically critical levels. In conclusion, the ensuing lethal complex biochemical phenotype of a novel metabolic syndrome results from multiple Fe/S protein defects caused by a deficiency in the Fe/S cluster assembly protein IBA57. PMID- 23462292 TI - Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23. AB - Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 * 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 * 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk. PMID- 23462293 TI - Absence of cell-surface EpCAM in congenital tufting enteropathy. AB - Mutations in the epithelial cell adhesion molecule (EpCAM; CD326) gene are causal for congenital tufting enteropathy (CTE), a disease characterized by intestinal abnormalities resulting in lethal diarrhea in newborns. Why the different mutations all lead to the same disease is not clear. Here, we report that most mutations, including a novel intronic variant, will result in lack of EpCAM's transmembrane domain, whereas two mutations allow transmembrane localization. We find that these mutants are not routed to the plasma membrane, and that truncated mutants are secreted or degraded. Thus, all epcam mutations lead to loss of cell surface EpCAM, resulting in CTE. PMID- 23462294 TI - Does research help to safeguard protected areas? AB - Although many protected areas are foci for scientific research, they also face growing threats from illegal encroachment and overharvesting. Does the presence of field researchers help to limit such threats? Although evidence is largely anecdotal, researchers do appear to provide some protective effects, both actively (such as by deterring poachers) and passively (such as by benefiting local communities economically and thereby generating support for protected areas). However, much remains unknown about the generality and impacts of such benefits. A key priority is to develop a better understanding of the advantages and limitations of field research for aiding protected areas and their biodiversity. PMID- 23462295 TI - Immunomodulatory effects of azithromycin on the establishment of lipopolysaccharide tolerance in mice. AB - Recent reports suggest that azithromycin can shift macrophage polarization towards the alternatively activated M2 phenotype. In order to investigate its immunomodulatory activity in vivo, the influence of azithromycin on survival and cytokine production was assessed in the LPS tolerance model which is characterized by an M2 skewed response. For induction of tolerance, mice received an intraplantar injection of 30 MUg LPS, 24 h prior to intravenous challenge with 350 MUg LPS. Azithromycin (100 mg/kg) was administered orally, 2 h before LPS application. Influence of treatment on survival and cytokine concentration in serum was monitored. Azithromycin alone, instead of LPS, could not induce an LPS tolerant state. However, when administered before LPS priming it significantly increased survival, which was enhanced by concomitant azithromycin before LPS challenge. Azithromycin had no effect on survival when administered only prior to the LPS challenge. Tolerance induction by LPS priming was associated, upon LPS challenge, with decreased serum concentrations of pro-inflammatory cytokines, TNFalpha, IL-12p40 and CCL5, and increased serum concentrations of the anti inflammatory cytokines, IL-10 and IL-1ra. Azithromycin treatment, prior to LPS priming, further reduced serum TNFalpha and CCL5, yielding the greatest inhibition when the macrolide was also given prior to LPS challenge. Serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra, were unchanged following azithromycin treatment. In summary, we have confirmed the immunomodulatory activity of azithromycin, as reflected in its ability to augment tolerance induction to LPS, promoting increased survival and reduced pro inflammatory cytokine production, without affecting overt inflammation to LPS or anti-inflammatory cytokine production. PMID- 23462296 TI - Microarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines. AB - Multiple drug resistance of cancer cells is multifactorial. A microarray technique may provide information about new candidate genes playing a role in drug resistance. Drug membrane transporters from ABC and SLC families play a main role in this phenomenon. This study demonstrates alterations in ABC and SLC gene expression levels in methotrexate, cisplatin, doxorubicin, vincristine, topotecan and paclitaxel-resistant variant of W1 ovarian cancer cell line. Resistant W1 cell lines were derived by stepwise selection of cells in increasing concentration of drugs. Affymetrix GeneChip((r)) Human Genome U219 Array Strip was used for hybridizations. Statistical significance was determined by independent sample t-test. The genes having altered expression levels in drug resistant sublines were selected and filtered by scater plot. Genes up/downregulated more than threefolds were selected and listed. Among ABC genes, seven were upregulated and three were downregulated. Three genes: ABCB1, ABCB4 and ABCG2 were upregulated very significantly (over tenfold). One ABCA8 was significantly downregulated. Among 38 SLC genes, 18 were upregulated, 16 were downregulated and four were up- or downregulated dependent on the cell line. Expression of 10 SLC genes was changed very significantly (over tenfold). Four genes were significantly increased: SLC6A1, SLC9A2, SLC12A1, SLC16A6 and six genes were significantly decreased: SLC2A14, SLC7A3, SLC7A8, SLC7A11, SLC16A14, SLC38A9. Based on the expression profiles, our results provide a preliminary insight into the relationship between drug resistance and expression of membrane transporters involved in drug resistance. Correlation of specific drug transporter with drug resistance requires further analysis. PMID- 23462297 TI - Utility of B-type natriuretic peptides in preeclampsia: a systematic review. AB - BACKGROUND: Preeclampsia and its complications may be associated with elevated B type natriuretic peptide levels during and after pregnancy. METHODS: We conducted a systematic review to determine whether preeclampsia and/or related cardiovascular complications, eclampsia and preterm delivery are associated with elevated natriuretic peptide levels. Three bibliographic databases were searched, using the terms "natriuretic peptide", "pregnancy", "preeclampsia", "eclampsia" and "BNP". Twelve studies fulfilled our inclusion criteria for full paper analysis. The data were too heterogeneous to allow for meaningful quantitative analyses. RESULTS: In healthy patients, B-type natriuretic peptide levels did not change during pregnancy. Compared with normal pregnancies, preeclamptic patients were shown to have significantly higher natriuretic peptide levels in the third trimester, which remained elevated for 3-6 months postpartum. Several papers suggested that cardiovascular dysfunction in preeclampsia is associated with NP elevation. Abnormalities were elevated systemic vascular resistance and cardiac filling pressures, decreased cardiac output, left ventricular diastolic dysfunction, and elevated left ventricular mass index. One investigation found that natriuretic peptide levels were higher in preeclamptic women who subsequently had preterm delivery, compared with those who delivered after 34 weeks. There were no data on natriuretic peptide levels in eclampsia. CONCLUSIONS: Preeclampsia is associated with elevated natriuretic peptide levels. Cardiovascular complications and preterm delivery in this setting may also be associated with elevated natriuretic peptide levels. Large prospective studies of natriuretic peptide measurement in preeclampsia are needed to determine whether elevated levels predict the development of severe preeclampsia and/or associated complications. PMID- 23462298 TI - A qualitative analysis of parturients' perspectives on neuraxial labor analgesia. AB - BACKGROUND: The decision to use, or not use, neuraxial analgesia is complex and likely multi-factorial. The objectives of this study were to understand parturients' concerns about neuraxial analgesia, and the reasons for not anticipating the use of neuraxial analgesia using qualitative methodology. METHODS: English-speaking, term parturients, who had not requested or received labor analgesia, were recruited for this mixed-methods study. In addition to a quantitative survey, the results of which have been published elsewhere, women were asked open-ended questions regarding concerns about neuraxial analgesia and reasons for not anticipating its use. Answers were recorded verbatim and analyzed using qualitative methodology. RESULTS: Interviews were conducted with 509 women. Thirty-nine percent of patients expressed some concern about neuraxial analgesia. These concerns were thematically represented by misunderstandings about neuraxial analgesia, general fears about the procedure, and lack of trust in providers. Many of the concerns were misunderstandings that were not supported by the medical literature. Of the 129 patients who did not anticipate using neuraxial analgesia, 23% stated that this was because they desired a natural childbirth and/or control over their labor experience, whereas 46% cited concerns about the procedure and its complications as the basis for their decision. CONCLUSION: Many women who anticipate not using neuraxial analgesia may be basing their decision on an inaccurate understanding of the risks of the procedure. Improved patient education and counseling that target specific areas of concern may address these misunderstandings. PMID- 23462299 TI - Does body mass index influence the degree of pelvic tilt produced by a Crawford wedge? AB - BACKGROUND: A pelvic tilt of 15 degrees is standard practice when positioning a woman for caesarean section, and is commonly produced by tilting the operating table or placing a wedge under the right hip. This study investigated whether body mass index affects the degree of pelvic tilt produced when a wedge is used. METHODS: Women undergoing category 3 and 4 caesarean sections were stratified into three groups according to their body mass index at antenatal booking: <= 25kg/m(2), 25.1-35kg/m(2) and >35kg/m(2). Twenty women were recruited into each group. Lateral tilt at caesarean section was provided with a Crawford wedge under the right hip and the degree of pelvic tilt was measured using a protractor device. RESULTS: The median [range] pelvic tilt angle for the groups in order of ascending body mass index were 15 degrees [12-22 degrees ], 19 degrees [11-29 degrees ] and 17 degrees [2-28 degrees ]. There was a significant increase in the variability of pelvic tilt with increasing body mass index (P=0.001). The proportion of patients with pelvic tilt <15 degrees was observed to be 20%, 15% and 30% for women of body mass index <= 25kg/m(2), 25.1-35kg/m(2) and >35kg/m(2), respectively. CONCLUSION: Variability in pelvic tilt increased with body mass index and was greatest with a booking body mass index >35kg/m(2). PMID- 23462300 TI - Development of a foundation for a case definition of post-treatment Lyme disease syndrome. AB - OBJECTIVES: The study objective is to demonstrate the clinical and research utility of an operationalized definition of post-treatment Lyme disease syndrome (PTLDS), as proposed by the Infectious Diseases Society of America. METHODS: Seventy-four patients with confirmed erythema migrans and 14 controls were enrolled. Patient-reported symptoms and health function (SF-36) were collected pre-treatment and at follow-up visits over 6 months post-treatment. RESULTS: Eight (11%) patients met our operationalized definition of PTLDS, which included self-reported symptoms of fatigue, widespread musculoskeletal pain or cognitive complaints, and functional impact as measured by a T score of <45 on the composite SF-36. No controls met the functional impact criteria. Forty-three (60% patients returned to their previous health status when measured at 6 months post treatment. Twenty (28%) patients had either residual symptoms or functional impact, but not both, and did not meet criteria for PTLDS. CONCLUSIONS: This operationalized definition of PTLDS allows for identification of those patients who are treated for early Lyme disease and have significant post-treatment illness, as they have both residual symptoms and impact on daily life functioning. With further refinement and improvement of this operationalized definition, the true incidence of PTLDS can be determined and future studies can be designed to examine its pathophysiology and treatment. PMID- 23462301 TI - Human brucellosis in the People's Republic of China during 2005-2010. AB - Brucellosis is a worldwide re-emerging zoonotic disease. It remains a serious public health problem in many developing countries including China. This review summarizes the epidemiological characteristics, morbidity, and endemic distributions of human brucellosis in the People's Republic of China for the period 2005-2010. From 2005 to 2010, the incidence of human brucellosis rose substantially in China, especially in the provinces of Inner Mongolia, Shanxi3, Heilongjiang, Hebei, Jilin, and Shanxi1. Meanwhile human brucellosis increased gradually in some southern provinces, such as Henan, Guangdong, and Fujian. Due to the rapid expansion of human brucellosis in China, surveillance and prevention of this disease has been greatly challenged. PMID- 23462302 TI - Intra- and intersexual selection on male body size in the annual killifish Austrolebias charrua. AB - Since many traits are involved in both female mating decisions and male contest outcomes, female mate choice and male competition can act in concert to intensify sexual selection on male traits, or in opposition to weaken it. In the sexually dimorphic annual killifish, Austrolebias charrua, we evaluated the effect of male body size on female mate choice, male-male competition, and their interaction. We carried out an experiment with three consecutive stages: (i) female choice test between males of different size in a classic two-choice device, (ii) agonistic interactions between males used in the previous stage, and (iii) a second female choice test to evaluate preference consistency in females that either were allowed or were prevented from observing the male competition. Larger males were preferred by females and became socially dominant in agonistic interactions. Further, females were consistent in their choices, and this consistency was independent of whether they had observed or not the male contest. Our research shows that, in A. charrua, intrasexual competition and female mate choice act in concert with respect to male body size. The unique life-history of Austrolebias and the high repeatability of mate-choice assays make this system a promising candidate for studies of behavioural evolution. PMID- 23462303 TI - Collaboration between doctors and nurses in children's cancer care: insights from a European project. AB - PURPOSE: It has long been recognised that effective cancer care is not possible without multi-professional team working. Collaboration and multi-professional working however are known to be less than straightforward. This project aimed to use a collaborative approach to explore and facilitate professional groups to work together more effectively in the field of children's cancer care. METHOD: Based on an earlier project in Italy, a three-year seminar series was organised involving both a doctor and nurse from 15 paediatric haematology/oncology units across Europe. Participants had to be able to speak English and commit to participate in annual seminars as well as the development and implementation of a local project to enhance doctor-nurse collaboration in their own unit. Appreciative Inquiry was the methodological approach used to address organisational as well as interpersonal change. RESULTS: Fifteen doctor-nurse teams were initially selected from a range of different countries, and 10 completed the project. Key outcomes reported include implementation and successful completion of projects, publication of the results achieved, participant satisfaction with improvements in collaboration. Feedback from participants would suggest that change had been implemented and possibly sustained. CONCLUSIONS: Active involvement and group support were required for success. More formal relationships needed to be activated with participating centres to guarantee support for those involved in implementing lasting change. A web-based resource to allow other programmes and centres to use the resources developed has been made available. The same approach, we believe, could be used to improve multi-professional working in the care of other childhood illnesses. PMID- 23462304 TI - Gender differences in the use of colorectal cancer tests among older Chinese adults. AB - PURPOSE: The study aimed to explore the gender difference in using colorectal cancer (CRC) tests among Chinese aged 50 years or over. METHODS: A cross sectional study was conducted in 2004 Chinese older adults through anonymous telephone survey which covered socio-demographic variables, health status, use of complementary therapy, health-related perceptions and use of CRC tests. RESULTS: The uptake rate of flexible sigmoidoscopy (FS)/colonoscopy was 14% for males and 10% for females, with males significantly more likely to have had the test after adjusting for their differences in socio-demographics, health status, use of complementary therapies, health-related perceptions and recommendation received from health professionals (adjusted OR = 1.5, 95% CI: 1.1-2.0, p = 0.005). The uptake of fecal occult blood test was nearly the same (19%) for both genders. Further interaction analyses indicates that the effect of a family history of cancer on the uptake of a FS/colonoscopy is significantly weaker in males than in females (the interaction odds ratio = 0.4, 95% CI: 0.2-0.8, p = 0.011), whereas a male perceived that visiting a doctor is good for health will be more likely to have an uptake of a FS/colonoscopy than a female with such perception (the interaction odds ratio = 2.1, 95% CI: 1.1-3.8, p = 0.018). CONCLUSIONS: The uptake of CRC tests was low in this average-risk population. More effort is needed to educate the public about the importance and benefits of CRC tests. In view of the gender differences in some determinants of FS/colonoscopy uptake, particular attention should be given to develop gender-specific strategies to improve the rate. PMID- 23462305 TI - Genome-wide analysis of plant-specific Dof transcription factor family in tomato. AB - The Dof (DNA binding with One Finger) family encoding single zinc finger proteins has been known as a family of plant-specific transcription factors. These transcription factors are involved in a variety of functions of importance for different biological processes in plants. In the current study, we identified 34 Dof family genes in tomato, distributed on 11 chromosomes. A complete overview of SlDof genes in tomato is presented, including the gene structures, chromosome locations, phylogeny, protein motifs and evolution pattern. Phylogenetic analysis of 34 SlDof proteins resulted in four classes constituting six clusters. In addition, a comparative analysis between these genes in tomato, Arabidopsis and rice was also performed. The tomato Dof family expansion has been dated to recent duplication events, and segmental duplication is predominant for the SlDof genes. Furthermore, the SlDof genes displayed differential expression either in their transcript abundance or in their expression patterns under normal growth conditions. This is the first step towards genome-wide analyses of the Dof genes in tomato. Our study provides a very useful reference for cloning and functional analysis of the members of this gene family in tomato and other species. PMID- 23462306 TI - Unstable pelvic ring injury with hemodynamic instability: what seems the best procedure choice and sequence in the initial management? AB - INTRODUCTION: Most fatalities related to pelvic ring injuries occur early and are caused by massive retroperitoneal bleeding. The objective of our study is to determine the optimal sequence of surgical procedures to restore hemodynamic stability in patients with unstable pelvic ring injuries. PATIENTS AND METHODS: This was a retrospective review of all patients with pelvic fractures and hemodynamic instability admitted to our level 1 trauma center between January 1998 and December 2008. We entered into our polytrauma database the following patient characteristics: age, sex, mechanism of injury, Injury Severity Score (ISS), classification of injury, timing of operative intervention, and type of operative procedures. Patients were divided into four groups (according to the sequence of surgical procedures performed within 24 hours following admission), as follows: group 1: patients treated with external fixation only; group 2: patients receiving external fixation followed by angiography; group 3: patients receiving external fixation followed by laparotomy +/- angiography; and group 4: patients treated by immediate laparotomy or angiography before skeletal fixation. RESULTS: Eighty of 136 patients admitted with a pelvic fracture were classified, as unstable AO/OTA type B or C pelvic ring injury, and 70/80 were hemodynamically unstable. Eight patients died shortly after arrival and two remained stable without requiring any early procedure. Sixty patients went immediately to the operating room. Twenty-nine patients were placed in group 1 with 100% survival, 12 in group 2 with 91% survival, 11 in group 3 with 82% survival, and eight patients placed in group 4 with 0% survival (P<0.001). CONCLUSIONS: The management of hemorrhagic instability linked to pelvic ring disruption involves a sequence of therapeutic events, which is more important than the events themselves. Pelvic bone stabilization by pelvic clamp or external fixator followed by arteriography seems to be the more secure. Angiographic embolization is the method of choice whenever haemodynamic instability coexists with an unstable pelvic disruption. Laparotomy and packing are restricted to extreme severe cases in remote hospitals with skillful surgeons! Actually aortic balloon is a good solution to control uncontrollable bleeding. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23462307 TI - Effect of age at treatment on cognitive performance in patients with cystinosis. AB - OBJECTIVE: To determine whether early treatment with cysteamine affects cognitive functioning in patients with nephropathic cystinosis. STUDY DESIGN: Forty-six subjects aged 3-18 years with cystinosis underwent cognitive testing to determine intelligence, visual-spatial abilities, and visual-motor skills. An age-matched control group (n = 85; age 2-22 years) underwent the same tests. Age at diagnosis and age at initiation of treatment with cysteamine were recorded at the time of testing. RESULTS: Patients with cystinosis treated at or after age 2 years (late treatment group) scored significantly lower on verbal, performance, and full scale IQ measures, as well as on a test of visual-spatial skills, compared with patients treated before age 2 years (early-treatment group) and controls. Both groups of subjects with cystinosis demonstrated impaired visual-motor skills compared with controls, with no difference between the early-treatment and late treatment groups. CONCLUSION: Early treatment with cysteamine appears to improve intellectual function in patients with nephropathic cystinosis. However, the lack of improvement in visual-motor function with early cysteamine treatment suggests possibly different mechanisms underlying visual-motor performance compared with other areas of cognition in this disorder. PMID- 23462308 TI - Preclinical assessment of ketamine. AB - Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neurodegeneration and/or neuroprotection. The precise mechanisms are not completely understood. This review is to examine the work on ketamine and to address how developmental biology may be utilized when combined with biochemical, pathological, and pharmacokinetic assessments to produce a bridging model that may decrease the uncertainty in extrapolating preclinical data to human conditions. Advantages of using preclinical models to study critical issues related to ketamine anesthesia have been described. These include the relationships between ketamine-induced neurotoxicity/protection and the preclinical models/approaches in elucidating mechanisms associated with ketamine exposure. The discussions focus on the following: (1) the doses and time-course over which ketamine is associated with damage to, or protection of, neural cells, (2) how ketamine directs or signals neural cells to undergo apoptosis or necrosis, (3) how such exposures can trigger mitochondrial dysfunction, (4) how antioxidants and knockdowns of specific transcription modulators or receptors affect neurotoxicity induced by ketamine, and (5) whether the potential neural damage can be monitored after ketamine exposure in living animals using positron emission tomography. PMID- 23462309 TI - Action of hexachlorobenzene on tumor growth and metastasis in different experimental models. AB - Hexachlorobenzene (HCB) is a widespread organochlorine pesticide, considered a possible human carcinogen. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). We have found that HCB activates c Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration, in an AhR dependent manner in MDA-MB-231 breast cancer cells. The aim of this study was to investigate in vitro the effect of HCB (0.005, 0.05, 0.5, 5MUM) on cell invasion and metalloproteases (MMPs) 2 and 9 activation in MDA-MB-231 cells. Furthermore, we examined in vivo the effect of HCB (0.3, 3, 30mg/kg b.w.) on tumor growth, MMP2 and MMP9 expression, and metastasis using MDA-MB-231 xenografts and two syngeneic mouse breast cancer models (spontaneous metastasis using C4-HI and lung experimental metastasis using LM3). Our results show that HCB (5MUM) enhances MMP2 expression, as well as cell invasion, through AhR, c-Src/HER1 pathway and MMPs. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism, in MDA-MB-231 cells. HCB (0.3 and 3mg/kg b.w.) enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. In vivo, using MDA-MB-231 model, the pesticide (0.3, 3 and 30mg/kg b.w.) activated c Src, HER1, STAT5b, and ERK1/2 signaling pathways and increased MMP2 and MMP9 protein levels. Furthermore, we observed that HCB stimulated lung metastasis regardless the tumor hormone-receptor status. Our findings suggest that HCB may be a risk factor for human breast cancer progression. PMID- 23462310 TI - Acute airway effects of airborne formaldehyde in sensitized and non-sensitized mice housed in a dry or humid environment. AB - We investigated the role of air humidity and allergic sensitization on the acute airway response to inhaled formaldehyde (FA) vapor. Mice were sensitized to the immunogen ovalbumin (OVA) by three intraperitoneal injections followed by two aerosol challenges, giving rise to allergic airway inflammation. Control mice were sham sensitized by saline injections and challenged by saline aerosols. Once sensitized, the mice were housed at high (85-89%) or low (<10%) relative humidity, respectively for 48h prior to a 60-min exposure to either 0.4, 1.8 or about 5ppm FA. Before, during and after exposure, breathing parameters were monitored. These included the specific markers of nose and lung irritations as well as the expiratory flow rate, the latter being a marker of airflow limitation. The sensory irritation response in the upper airways was not affected by allergic inflammation or changes in humidity. At high relative humidity, the OVA-sensitized mice had a decreased expiratory airflow rate compared to the saline control mice after exposure to approximately 5ppm FA. This is in accordance with the observations that asthmatics are more sensitive than non asthmatics to higher concentrations of airway irritants including FA. In the dry environment, the opposite trend was seen; here, the saline control mice had a significantly decreased expiratory airflow rate compared to OVA-sensitized mice when exposed to 1.8 and 4ppm FA. We speculate that increased mucus production in the OVA-sensitized mice has increased the "scrubber effect" in the nose, consequently protecting the conducting and lower airways. PMID- 23462311 TI - Metabolic responses to iron deficiency in roots of Carrizo citrange [Citrus sinensis (L.) Osbeck. x Poncirus trifoliata (L.) Raf]. AB - The effects of iron (Fe) deficiency on the low-molecular-weight organic acid (LMWOA) metabolism have been investigated in Carrizo citrange (CC) [Citrus sinensis (L.) Osb. * Poncirus trifoliata (L.) Raf.] roots. Major LMWOAs found in roots, xylem sap and root exudates were citrate and malate and their concentrations increased with Fe deficiency. The activities of several enzymes involved in the LMWOA metabolism were also assessed in roots. In the cytosolic fraction, the activities of malate dehydrogenase (cMDH) and phosphoenolpyruvate carboxylase (PEPC) enzymes were 132 and 100% higher in Fe-deficient conditions, whereas the activity of pyruvate kinase was 31% lower and the activity of malic enzyme (ME) did not change. In the mitochondrial fraction, the activities of fumarase, MDH and citrate synthase enzymes were 158, 117 and 53% higher, respectively, in Fe-deficient extracts when compared with Fe-sufficient controls, whereas no significant differences between treatments were found for aconitase (ACO) activity. The expression of their corresponding genes in roots of Fe deficient plants was higher than that measured in Fe-sufficient controls, except for ACO and ME. Also, dicarboxylate-tricarboxylate carrier (DTC) expression was significantly increased in Fe-deficient roots. In conclusion, Fe deficiency in CC seedlings causes a reprogramming of the carbon metabolism that involves an increase of anaplerotic fixation of carbon via PEPC and MDH activities in the cytosol and a shift of the Krebs cycle in the mitochondria towards a non-cyclic mode, as previously described in herbaceous species. In this scheme, DTC could play an important role shuttling both malate and reducing equivalents between the cytosol and the mitochondria. As a result of this metabolic switch malate and citrate concentrations in roots, xylem sap and root exudates increase. PMID- 23462312 TI - Why do trees adjust water relations and hydraulic architecture in response to nutrient availability? PMID- 23462313 TI - Limits to the height growth of Caragana korshinskii resprouts. AB - Predawn leaf water potential (LWP), the LWP between 09:00 and 10:30 h (termed minimum LWP), stem xylem hydraulic conductivity, foliar nitrogen, leaf gas exchange and leaf traits were measured on the same days in adults and 1-year-old to 7-year-old resprouts that had regrown after removing all the aboveground shoots. Height growth and accumulation of aboveground biomass quickly decreased with resprout age and there was no difference between 7-year-old resprouts and the uncut adults. Predawn LWP showed no significant difference between resprouts and adults, but the minimum LWP decreased gradually from -2.0 MPa in 1-year-old resprouts to -3.0 MPa in 7-year-old resprouts. The decrease in minimum LWP was associated with increased hydraulic resistance, as indicated by the gradual decrease in leaf area-specific hydraulic conductivity (KL) and sapwood area specific hydraulic conductivity (KS) and the associated increase in stem native percentage loss of hydraulic conductivity in older than 2-year-old resprouts. The leaf nitrogen content per unit area (Narea) also decreased steadily from 3.6 g m( 2) in 1-year-old resprouts to 1.7 g m(-2) in 7-year-old resprouts. With the decline in LWP and Narea, the rate of leaf photosynthesis per unit area (Aarea) decreased from 20 MU mol m(-2) s(-1) in 1-year-old resprouts to 11 MU mol m(-2) s(-1) in 7-year-old resprouts. In adults, although KS decreased further compared with 7-year-old resprouts, the minimum LWP, KL, Narea and the rate of photosynthesis increased by 0.3 MPa, 29, 34 and 23%, respectively. The results show that a progressive loss of stem hydraulic conductivity and a steady decrease in foliar nitrogen with age were associated with a decrease in the photosynthetic rate of Caragana korshinskii Kom. resprouts, possibly changing the allocation of photosynthetic assimilates and slowing resprout height growth. PMID- 23462314 TI - Current world literature. PMID- 23462316 TI - Evolving dual targeting of a prokaryotic protein in yeast. AB - Dual targeting is an important and abundant phenomenon. Indeed, we estimate that more than a third of the yeast mitochondrial proteome is dual localized. The enzyme fumarase is a highly conserved protein in all organisms with respect to its sequence, structure, and enzymatic activity. In eukaryotes, it is dual localized to the cytosol and mitochondria. In Saccharomyces cerevisiae, the dual localization of fumarase is achieved by the reverse translocation mechanism; all fumarase molecules harbor a mitochondrial targeting sequence (MTS), are targeted to mitochondria, begin their translocation, and are processed by mitochondrial processing peptidase in the matrix. A subset of these processed fumarase molecules in transit is then fully imported into the matrix, whereas the majority moves back into the cytosol by reverse translocation. The proposed driving force for fumarase distribution is protein folding during import. Here, we asked how reverse translocation could have evolved on a prokaryotic protein that had already acquired expression from the nuclear genome and a targeting sequence. To address this question, we used, as a model, the Escherichia coli FumC Class II fumarase, which is homologous to eukaryotic fumarases (~58% identity and ~74% similarity to the yeast Fum1). Starting with an exclusively mitochondrial targeted FumC (attached to a strong MTS), we show that two randomly acquired mutations within the prokaryotic FumC sequence are sufficient to cause substantial dual targeting by reverse translocation. In fact, the unmutated MTS FumC also has some ability to be dual targeted but only at low temperatures. Our results suggest that in this case, evolution of dual targeting by reverse translocation is based on naturally occurring and fortuitously conserved features of fumarase folding. PMID- 23462317 TI - Evolutionary balancing is critical for correctly forecasting disease-associated amino acid variants. AB - Computational predictions have become indispensable for evaluating the disease related impact of nonsynonymous single-nucleotide variants discovered in exome sequencing. Many such methods have their roots in molecular evolution, as they use information derived from multiple sequence alignments. We show that the performance of current methods (e.g., PolyPhen-2 and SIFT) is improved significantly by optimizing their statistical models on evolutionarily balanced training data, where equal numbers of positive and negative controls within each evolutionary conservation class are used. Evolutionary balancing significantly reduces the false-positive rates for variants observed at highly conserved sites and false-negative rates for variants observed at fast evolving sites. Use of these improved methods enables more accurate forecasting when concordant diagnosis from multiple methods is regarded as a more reliable indicator of the prediction. Applied to a large exome variation data set, we find that the current methods produce concordant predictions for less than half of the population variants. These advances are implemented in a web resource for use in practical applications (www.mypeg.info, last accessed March 13, 2013). PMID- 23462318 TI - Thermal effects on photon-induced quantum transport in a single quantum dot. AB - We theoretically investigate laser induced quantum transport in a single quantum dot attached to electrical contacts. Our approach, based on a nonequilibrium Green function technique, allows us to include thermal effects on the photon induced quantum transport and excitonic dynamics, enabling the study of non Markovian effects. By solving a set of coupled integrodifferential equations, involving correlation and propagator functions, we obtain the photocurrent and the dot occupation as a function of time. Two distinct sources of decoherence, namely, incoherent tunneling and thermal fluctuations, are observed in the Rabi oscillations. As temperature increases, a thermally activated Pauli blockade results in a suppression of these oscillations. Additionally, the interplay between photon and thermally induced electron populations results in a switch of the current sign as time evolves and its stationary value can be maximized by tuning the laser intensity. PMID- 23462320 TI - Program Obesity Zero (POZ)--a community-based intervention to address overweight primary-school children from five Portuguese municipalities. AB - OBJECTIVE: Results of the WHO European Childhood Obesity Surveillance Initiative indicated that on average one out of four primary-school children is overweight or obese. Portugal presented one of the highest prevalences of obesity. Childhood obesity prevention and treatment should be a top priority. The aim of the present study was to evaluate the effectiveness of Program Obesity Zero (POZ), a multi component, community-, family- and school-based childhood obesity intervention. DESIGN: Parents and children attended four individual nutrition and physical activity counselling sessions, a one-day healthy cooking workshop and two school extracurricular sessions of nutrition education. Waist circumference, BMI, physical activity level, sedentary behaviours, and nutrition and physical activity knowledge, attitudes and behaviour were assessed at baseline and after 6 months. Diet was assessed using two 24 h recalls, at baseline and at 6 months. SETTING: Five Portuguese municipalities and local communities. SUBJECTS: Two hundred and sixty-six overweight children (BMI >= 85th percentile) aged 6-10 years, from low-income families in five Portuguese municipalities, were assigned to the intervention. RESULTS: Children showed reductions in waist circumference ( 2.0 cm; P < 0.0001), mean BMI (-0.7 kg/m2; P < 0.0001) and BMI-for-age percentile (-1.7; P < 0.0001) at 6 months. Overall, children's intake of fruit and vegetables was <400 g/d throughout the intervention. After 6 months, higher fibre consumption and an apparent decrease in sugary soft drinks intake to a quarter of that observed at baseline (mean intake: 198 ml/d at baseline), with improvements in physical activity levels and screen time <2 h/d, were also observed. CONCLUSIONS: The findings suggested that POZ is a promising intervention programme, at municipality level, to tackle childhood overweight and obesity. PMID- 23462321 TI - DOalpha-beta+ expression in favor of HLA-DR engagement in exosomes. AB - The expression of DObeta and not DOalpha, in addition to the high intracellular DR, low DM levels and absence of surface DR expression in K562 and HL-60 cells introduce alternative regulatory pathways in DR trafficking and consequently the antigen presentation process. The present study attempted to define the naturally occurring DOalpha negative state and explain the role of DObeta in the intracellular DR accumulation in K562 and HL-60 cells. Despite the absence of DOalpha, the DObeta chain was detected in the endosomal compartments. The lack of DOalpha was found to be partially responsible for the absence of DR from the cell membrane since stable K562-DOalpha transfectants allowed expression of membrane DR. This expression could be significantly increased upon DM induction by IFN gamma, indicating that DM was another limiting factor for the migration of DR to the cell surface of K562 and HL-60 cells. Furthermore, intracellular DR co localized with the exosome specific marker CD9, while culture supernatants were shown to contain exosome-engaged and exosome free DR activity as evaluated by SDS page followed by western blot, ELISA and transmission electron microscopy analysis. These findings indicated that in DOalpha-beta+ cells, DR molecules were programmed to secretion rather than surface expression. The presented results provide novel regulatory processes as to DR trafficking, avoiding expression to the cell surface. PMID- 23462319 TI - Monetary reward processing in obese individuals with and without binge eating disorder. AB - BACKGROUND: An important step in obesity research involves identifying neurobiological underpinnings of nonfood reward processing unique to specific subgroups of obese individuals. METHODS: Nineteen obese individuals seeking treatment for binge eating disorder (BED) were compared with 19 non-BED obese individuals (OB) and 19 lean control subjects (LC) while performing a monetary reward/loss task that parses anticipatory and outcome components during functional magnetic resonance imaging. Differences in regional activation were investigated in BED, OB, and LC groups during reward/loss prospect, anticipation, and notification. RESULTS: Relative to the LC group, the OB group demonstrated increased ventral striatal and ventromedial prefrontal cortex activity during anticipatory phases. In contrast, the BED group relative to the OB group demonstrated diminished bilateral ventral striatal activity during anticipatory reward/loss processing. No differences were observed between the BED and LC groups in the ventral striatum. CONCLUSIONS: Heterogeneity exists among obese individuals with respect to the neural correlates of reward/loss processing. Neural differences in separable groups with obesity suggest that multiple, varying interventions might be important in optimizing prevention and treatment strategies for obesity. PMID- 23462322 TI - Laparoscopic partial sleeve duodenectomy (PSD) for nonampullary duodenal neoplasms: avoiding a whipple by separating the duodenum from the pancreatic head. AB - OBJECTIVE: To learn the clinical outcome of patients undergoing laparoscopic partial sleeve duodenectomy (PSD) for lesions, which require sleeve resection of the duodenum. Traditionally, these lesions require en bloc excision of the head of the pancreas performed in an open fashion. METHODS: A retrospective review of medical records of patients with nonampullary large or circumferential duodenal lesions, which were not amenable to endoscopic or local resection for complete removal, was performed. Characteristics, complications, and technical details were analyzed. RESULTS: Ten patients (5 men and 5 women; mean age, 70 years) with duodenal lesions including adenoma (n = 5), adenocarcinoma (n = 2), lymphangiolipoma (n = 1), leiomyoma (n = 1), and neuroendocrine tumor (n = 1) were included. All patients underwent a laparoscopic approach with either a proximal PSD (n = 3) or distal PSD (n = 7) after separation of the duodenum from the pancreatic head. Reconstruction was carried out by a side-to-side duodenojejunostomy (n = 7), end-to-side duodenojejunostomy (n = 2), or gastrojejunostomy (n = 1). Mean length of stay was 5.6 days, and complications were 20%. CONCLUSIONS: Laparoscopic PSD seems to be a safe and easily applicable technique for treatment of duodenal lesions not involving the ampulla, which requires separation of the duodenum from the pancreas head with sleeve resection of the duodenum and subsequent reconstruction. PMID- 23462323 TI - Mixed acinar-endocrine carcinoma of the pancreas: new clinical and pathological features in a contemporary series. AB - OBJECTIVE: The objective of this study was to characterize the novel clinical and pathological features of mixed acinar-endocrine carcinoma of the pancreas. METHODS: This was a retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of mixed acinar-endocrine carcinoma of the pancreas at Cedars-Sinai Medical Center between 2005 and 2011. Additional immunohistochemistry was performed on the specimens of some patients. RESULTS: Five patients were identified. The median age at presentation was 74 years (range, 59-89 years), and all patients were male. The presenting symptoms were all related to tumor mass effects. The median size of the tumor was 10 cm (range, 3.9-16 cm). Preoperative clinical diagnosis aided by fine-needle aspiration biopsy was incorrect in all 5 cases. Most tumors (3/5) exhibited predominantly endocrine differentiation without hormonal production. Only 10% to 30% of cells were truly amphicrine, whereas most were differentiated into either endocrine or acinar phenotype. The clinical behavior ranged from moderate to aggressive with postoperative survival from 2.5 months to more than 3 years. Four patients received neoadjuvant or adjuvant chemotherapy with variable responses. CONCLUSIONS: Mixed acinar-endocrine carcinoma of the pancreas appears to be not uncommon in men, may harbor predominantly endocrine component, is often misdiagnosed by cytology, and exhibits variable clinical behavior. Mixed acinar endocrine carcinoma of the pancreas should be considered in older patients with sizable pancreatic mass and may warrant aggressive surgical resection and chemotherapy. PMID- 23462324 TI - Gemcitabine plus capecitabine in unselected patients with advanced pancreatic cancer. AB - OBJECTIVES: Gemcitabine in combination with capecitabine (GEMCAP) is a treatment option for patients with advanced pancreatic cancer (APC), but data are lacking concerning outcomes in unselected patients not enrolled to a randomized trial. METHODS: Baseline demographic, clinical, toxicity, tumor response, and survival data were collected for previously untreated patients with APC receiving off protocol GEMCAP at a single institution between 2005 and 2009. RESULTS: Data from 113 patients were included in the study. The mean age was 65 years; 51% of patients had metastatic disease; and 80% were of World Health Organization performance status 0 or 1. Patients received a mean of 20 weeks of chemotherapy. The objective response rate was 9.7%; the median overall survival was 8.7 months (95% confidence interval, 6.7-10.7), and 34% of patients were alive 1 year after starting treatment. Performance status (0 or 1 vs 2) was a significant prognostic factor (P < 0.0001). Grade 3 or 4 adverse events, excluding nonfebrile neutropenia, were experienced by 37 patients (33%), the commonest being lethargy (8%), hand-foot syndrome (8%), diarrhea (7%), thrombocytopenia (4%), and febrile neutropenia (6%). CONCLUSIONS: Gemcitabine in combination with capecitabine is effective and tolerable in unselected patients with APC, and outcomes are comparable with those of patients receiving GEMCAP in clinical trials. PMID- 23462325 TI - Uridine triphosphate increases proliferation of human cancerous pancreatic duct epithelial cells by activating P2Y2 receptor. AB - OBJECTIVES: The aim of this study was to investigate the effect of uridine triphosphate (UTP) on the proliferation of human cancerous pancreatic duct epithelial cells. METHODS: Proliferation was measured by immunoassay for bromodeoxyuridine incorporation into the pancreatic cell line PANC-1. Effect of UTP was assayed using selective P2 agonist and antagonist, small interfering RNA, intracellular signal inhibitors, and Western blot. RESULTS: Incubation of PANC-1 cells with UTP or MRS2768, a selective P2Y2 receptor agonist, resulted in a dose- and time-dependent increase of proliferation. The messenger RNA transcript and protein of P2Y2 receptor were expressed in PANC-1 cells. P2 receptor antagonist suramin and small interfering RNA against P2Y2 receptor significantly decreased the proliferative effect of UTP and MRS2768. Activation of P2Y2 receptor by UTP transduced to phospholipase C, inositol 1,4,5-triphosphate (IP3), and protein kinase C. Uridine triphosphate-induced proliferation was mediated by protein kinase D, Src-family tyrosine kinase, Ca/calmodulin-dependent protein kinase II, phosphatidylinositol 3-kinase (PI3K), Akt, and phospholipase D. Uridine triphosphate increased phosphorylation of Akt through protein kinase C, Src family tyrosine kinase, Ca/calmodulin-dependent protein kinase II, and PI3K. CONCLUSIONS: Uridine triphosphate increases proliferation of human pancreatic duct epithelial cells by activation of P2Y2 receptor and PI3K/Akt pathway. This could be helpful for discovering the long-term roles of P2Y2 receptor in pancreatic cells. PMID- 23462326 TI - Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues. AB - OBJECTIVES: The aim of this study was to evaluate transcript levels of all 49 human ATP-binding cassette transporters (ABCs) in one of the most drug-resistant cancers, namely, the pancreatic ductal adenocarcinoma (PDAC). Association of ABCs levels with clinical-pathologic characteristics and KRAS mutation status was followed as well. METHODS: Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients. The transcript profile of ABCs was assessed using quantitative real-time polymerase chain reaction with a relative standard curve. KRAS mutations in exon 2 were assessed by high resolution melting analysis and sequencing. RESULTS: Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical-pathologic characteristics. KRAS mutations did not change the global expression profile of ABCs. CONCLUSIONS: The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues. The observed up-regulation of ABCB4, ABCB11, ABCC1, ABCC3, ABCC5, ABCC10, and ABCG2 in tumors may contribute to the generally poor treatment response of PDAC. The up-regulation of ABCA1, ABCA7, and ABCG1 implicates a serious impairment of cellular cholesterol homeostasis in PDAC. On the other hand, the observed down-regulation of ABCA3, ABCC6, ABCC7, and ABCC8 suggests a possible role of stem cells in the development and progression of PDAC. PMID- 23462327 TI - The differentiation of pancreatic tumor-initiating cells by vitronectin can be blocked by cilengitide. AB - OBJECTIVE: Pancreatic cancer is a leading cancer type and its molecular pathology is poorly understood. The only potentially curative therapeutic option available is complete surgical resection; however, this is inadequate as most of the patients are diagnosed at an advanced or metastatic stage. Tumor-initiating cells (TICs) constitute a subpopulation of cells within a solid tumor that sustain tumor growth, metastasis, and chemo/radioresistance. Within pancreatic cancer, TICs have been identified based on the expression of specific cell surface markers. METHODS: We use a sphere formation assay to enrich putative TICs and use human serum as a driver of differentiation. We demonstrate by using specific blocking reagents that we can inhibit the differentiation process and maintain TIC-associated markers and genes. RESULTS: We can induce differentiation of pancreatospheres with the addition of human serum, and we identified vitronectin as an inducer of differentiation. We inhibit differentiation by human serum using an arginine-glycine-aspartate-specific peptide, which is Cilengitide; hence, demonstrating this differentiation is mediated via specific integrin receptors. CONCLUSIONS: Overall, our studies further the definition of pancreatic TICs and provide further insight into both the maintenance and differentiation of this lethal population. PMID- 23462328 TI - Variation in the gamma-glutamyltransferase 1 gene and risk of chronic pancreatitis. AB - OBJECTIVE: Individuals with chronic pancreatitis are at increased risk for pancreatic cancer. We hypothesized that genetic variation in the gamma glutamyltransferase 1 (GGT1) gene, which was recently reported associated with pancreatic cancer risk in a genome-wide association study, is also associated with risk of chronic pancreatitis. METHODS: Associations between common polymorphisms in GGT1 and chronic pancreatitis were evaluated using data and samples from the North American Pancreatitis Study 2. Patients (n = 496) and control subjects (n = 465) were genotyped for 4 single-nucleotide polymorphisms: rs4820599, rs2017869, rs8135987, and rs5751901. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) for chronic pancreatitis risk were calculated using multiple logistic regression models. Interactions with cigarette smoking and alcohol use were explored. RESULTS: Single-nucleotide polymorphisms rs8135987 and rs4820599 were both statistically significantly associated with risk of chronic pancreatitis; compared with common allele homozygotes, individuals with at least 1 minor allele were at increased risk (rs8135987: OR, 1.36; 95% CI, 1.03-1.80 [P(trend) = 0.01]; rs4820599: OR, 1.39; 95% CI, 1.04-1.84 [P(trend) = 0.0]; adjusted for age, sex, race, smoking status, and alcohol use). No significant interactions with cigarette smoking and alcohol use were observed. CONCLUSION: Our results suggest that common variation in the GGT1 gene may also affect risk of chronic pancreatitis. PMID- 23462330 TI - Evaluation of clinical meaning of histological subtypes of intraductal papillary mucinous neoplasm of the pancreas. AB - OBJECTIVES: Prognostic value of histological subtypes of pancreatic intraductal papillary mucinous neoplasm (IPMN) has been reported to have conflicting results. The authors investigated the clinicopathological characteristics and prognostic significance of the histological subtypes of IPMNs with various degrees of dysplasia. METHODS: Two hundred thirteen patients with surgically treated pancreatic IPMN at a single tertiary care referral center were included. Pathological slides were thoroughly reviewed by a specialized pathologist. RESULTS: Of the 213 patients, 38 low-grade, 97 intermediate-grade, and 18 high grade dysplasia and 59 IPMNs with an associated invasive carcinoma (invasive IPMN) were identified. Histological subtypes consisted of 135 gastric (63.4%), 38 intestinal (17.8%), 38 pancreatobiliary (17.8%), and 2 oncocytic types (0.9%). Histological subtypes were associated with radiological type (P < 0.001), degree of dysplasia (P < 0.001), and T stage (P < 0.001). The proportions of invasive IPMN were 14.1%, 42.1%, 57.9%, and 100% of gastric, intestinal, pancreatobiliary, and oncocytic types, respectively. Disease-specific survival was not affected by histological subtype in overall patients (P = 0.881). For invasive IPMNs, histological subtypes had a marginal significance on survival (P = 0.050), which lost statistical significance after multivariate analysis (P = 0.341). CONCLUSIONS: Although histological subtypes are associated with the degree of dysplasia, histological subtypes have limited prognostic value for pancreatic IPMNs. PMID- 23462329 TI - Metformin inhibits the growth of human pancreatic cancer xenografts. AB - OBJECTIVE: Pancreatic ductal adenocarcinoma is a devastating disease, with an overall 5-year survival rate of only 3% to 5%. As the current therapies offer very limited survival benefits, novel therapeutic strategies are urgently required to treat this disease. Here, we determined whether metformin administration inhibits the growth of PANC-1 and MiaPaCa-2 tumor xenografts in vivo. METHODS: Different xenograft models, including orthotopic implantation, were used to determine whether intraperitoneal or oral administration of metformin inhibits the growth of pancreatic cancer in vivo. RESULTS: We demonstrate that metformin given once daily intraperitoneally at various doses (50-250 mg/kg) to nude mice inhibited the growth of PANC-1 xenografts in a dose dependent manner. A significant effect of metformin was obtained at 50 mg/kg and maximal effect at 200 mg/kg. Metformin administration also caused a significant reduction in the phosphorylation of ribosomal S6 protein and ERK in these xenografts. Metformin also inhibited the growth of pancreatic cancer xenografts when administered orally (2.5 mg/mL) either before or after tumor implantation. Importantly, oral administration of metformin also inhibited the growth of MiaPaCa-2 tumors xenografted orthotopically. CONCLUSIONS: The studies presented here provide further evidence indicating that metformin offers a potential novel approach for pancreatic ductal adenocarcinoma prevention and therapy. PMID- 23462331 TI - Four novel GALC gene mutations in two Chinese patients with Krabbe disease. AB - Krabbe disease (OMIM #245200) is a rare autosomal recessive leukodystrophy caused by deficiency of galactocerebrosidase (GALC) activity. We identified four novel mutations of the GALC gene in two unrelated Chinese families with Krabbe disease: one insertion mutation, c.1836_1837insT, and one nonsense mutation, c.599C>A (p.S200X), in an infantile patient, and one deletion mutation, c.1911+1_1911+5delGTAAG, and one missense mutation, c.2041G>A, in an adult late onset patient. This is the first identification of GALC mutations in the Chinese population. PMID- 23462332 TI - The TERT MNS16A polymorphism contributes to cancer susceptibility: meta-analysis of the current studies. AB - The MNS16A polymorphism in the telomerase reverse transcriptase (TERT) gene has been implicated in cancer risk in multiple populations and various types of cancers; however, the results of previous studies exploring this association were inconclusive. To more precisely evaluate the relationship between the TERT MNS16A polymorphism and cancer risk, we performed a meta-analysis based on 8 studies described in 7 articles comprising 7864 controls and 4355 cases. The summary odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated to assess the strength of the association in a fixed-effects model or a random-effects model where appropriate. Heterogeneity among articles and their publication bias were also tested. Overall, the pooled results indicated that the MNS16A polymorphism was significantly associated with increased cancer risk in the homozygote comparison model (SS vs. LL: OR=1.280, 95% CI 1.060-1.547) and the recessive model (SS vs. LL+SL: OR=1.201, 95% CI 1.004-1.436). In the stratified analyses, a statistically significant association was observed among Caucasians and in population-based studies. We also performed the analyses by cancer type, and a significantly increased risk of glioma was found in four genetic models. Our results suggest that the TERT MNS16A polymorphism most likely contributes to an increased risk of cancer. Moreover, the same relationship was found when the studies were stratified by cancer type, ethnicity and source of controls. PMID- 23462333 TI - Characterization of the cDNA and in vitro expression of the ram seminal plasma protein RSVP14. AB - In previous studies we have shown that seminal plasma (SP) proteins can prevent and repair cold-shock membrane damage to ram spermatozoa. Three proteins of approximately 14, 20 and 22kDa, mainly responsible for this protective ability, were identified in ram SP. They are exclusively synthesized in the seminal vesicles and, consequently, named RSVP14, RSVP20 and RSVP22. The aim of this study is to characterize and express the RSVP14 gene to provide new insights into the mechanisms through which SP proteins are able to protect spermatozoa. Additionally, a first approach has been made to the recombinant protein production. The cDNA sequence obtained encodes a 129 amino acid chain and presents a 25-amino acid signal peptide, one potential O-linked glycosylation site and seven phosphorylation sites on tyrosine, serine and threonine residues. The sequence contains two FN-2 domains, the signature characteristic of the bovine seminal plasma (BSP) protein family and related proteins of different species. More interestingly, it was shown that RSVP14 contains four disulphide bonds and a cholesterol recognition/interaction amino acid consensus (CRAC) domain, also found in BSP and similar proteins. Analysis of the relationships between RSVP14 and other mammalian SP proteins revealed a 76-85% identity, particularly with the BSP protein family. The recombinant protein was obtained in insect cell extracts and in Escherichia coli in which RSVP14 was detected in both the pellet and the supernatant. The results obtained corroborate the role of RSVP14 in capacitation and might explain its protective effect against cold-shock injury to the membranes of ram spermatozoa. Furthermore, the biochemical and functional similarities between RSVP14 and BSP proteins suggest that it might play a similar role in sperm functionality. PMID- 23462334 TI - Association between rs10118757(A/G) in methylthioadenosine phosphorylase gene and coronary artery disease in Chinese Hans. AB - Studies focusing on the association of gene methylthioadenosine phosphorylase (MTAP) with the risk of coronary artery disease (CAD) and myocardial infarction (MI) are limited. In this study, we explored the effects of rs10118757 in MTAP gene on CAD and MI by performing association analysis in a Chinese Han population. rs10118757 was genotyped in 1007 CAD patients (including 338 MI patients) and 885 healthy controls. Allelic analysis showed that allele A of rs10118757 was associated with increased risk of CAD, with OR (95%CI)=1.193 (1.035-1.376), and P=0.015. After adjusted for age, BMI, gender, hypertension and smoking, rs10118757 was still significantly associated with CAD under additive and dominant models, with OR (95%CI)=1.252 (1.070-1.465), P=0.005, and OR (95%CI)=1.698 (1.168-2.467), P=0.006, respectively. Compared to additive model, dominant model may be the best-fitting model (P=6.63E-10 vs P=6.70E-10). As reported previously, rs10118757 was not associated with MI in the current study. Our study firstly reported that SNP rs10118757 was associated with CAD risk in a Chinese Han population, indicating that MTAP gene may play a potential role in the pathophysiological process of CAD. PMID- 23462335 TI - Is alcoholism learned? Insights from the fruit fly. AB - Alcohol addiction is a complex, unique human disease. Breaking addiction down into contributing endophenotypes enables its study in a variety of model systems. The Drosophila model system has been most often used to study alcohol sensitivity, tolerance, and physiological dependence. However, none of these endophenotypes can account for the near-permanent quality of the addicted state. It has been recently discussed that addictive drugs may hijack the learning-and memory machinery to produce persistent behavioral changes. Learning and memory is amenable to experimental study, and provides us with a window into how alcohol affects higher-order mental functions that are likely to contribute compulsive drug use. Here, we review the Drosophila literature that links alcohol-related behaviors to learning and memory. PMID- 23462336 TI - The role of impulsivity in relapse vulnerability. AB - Drug dependence in humans is often accompanied by behavioral disturbances such as maladaptive levels of impulsivity. In turn, there is accumulating evidence from preclinical laboratory animal and clinical studies indicating that impulsive behavior might be causally linked to several distinct processes in drug addiction, including the onset, maintenance and relapsing nature of drug use. This leads to the question as to whether pharmacological or behavioral approaches aimed at ameliorating impulsivity might prove effective therapeutic interventions in human drug dependence. This paper reviews evidence for an important role of impulsivity as a determinant of drug dependence with a particular focus on relapse vulnerability and addresses the implications of these findings for the clinical management of relapse prevention. PMID- 23462337 TI - Percutaneous treatment of sciatica caused by a herniated disc: an exploratory study on the use of gaseous discography and Discogel((r)) in 79 patients. AB - OBJECTIVES: Sciatica is a common disease; between 13% and 40% of the general population will experience at least one episode of sciatica due to spinal disc herniation and nerve root irritation. In some specialist centres, percutaneous intradiscal techniques can be applied as an intermediate measure between conservative treatment and surgery, with a view to avoiding the adverse events associated with surgical discectomy. Discogel((r)) is a percutaneously implanted medical device for the treatment of lumbar sciatica due to a herniated disc. We performed an open, prospective, observational study in order to (a) determine whether the prior use of air disc manometry could limit the risk of nerve root irritation reportedly associated with nucleolysis and administration of Discogel((r)) and (b) investigate the technique's efficacy and safety. METHOD: A total of 79 Discogel((r))-treated patients were systematically reviewed. A nurse anaesthetist evaluated each patient's pain levels during the procedure itself. The therapist assessed the patient on inclusion and 8weeks after the Discogel((r)) procedure. A third assessment was based on a telephone interview (by an independent assessor) at least 4months after the procedure. RESULTS: Pain levels immediately after the Discogel((r)) procedure (1.7+/-2.0) were markedly lower than before the procedure (5.5+/-2.3). There were no complications. Two months after Discogel((r)) administration, the initial pain level had fallen by an average of 74+/-34%. The outcome was quite stable over time (mean follow-up: 8months). At the end of the follow-up period, 60.7% of the patients were free of pain, 76% considered the treatment outcome to be good or very good, 74% had returned to work and 76% would recommend the treatment to a friend. CONCLUSION: The favourable outcomes associated with the procedure should now be confirmed in a controlled trial. PMID- 23462338 TI - Long-term transanal irrigation's continuation at home. Preliminary study. AB - OBJECTIVE: To determine the long-term outcome of Peristeen's home use. METHOD: Retrospective study on the 16 first patients treated by Peristeen in the department of physical and readaptation medicine of Limoges universitary hospital, by the mean of phone interviews. RESULTS: Successful outcome was achieved in 62.5% patients after a mean follow-up of 2.6 years. All patients had neurogenic bowel disorders, including 75% of constipation. Most of cases of Peristeen discontinuation occurred at the treatment beginning, one month after introduction in two thirds of cases. In patients who were still using transanal irrigation (TAI), mean grade of satisfaction with the Peristeen system was 9.12/10, despite the high rate of technical problems (77.8% of cases). CONCLUSION: This study highlights the limits of Peristeen's long-term using and suggests the interest of a specific therapeutic education to Peristeen and of a systematic control consultation within the 3 first months of treatment. PMID- 23462339 TI - L2. Neutrophil transmigration in vivo: mechanisms, dynamics and contribution to dissemination of systemic inflammation. PMID- 23462340 TI - [Interest of laparoscopy in infertile couple with normal hysterosalpingography]. AB - OBJECTIVES: The diagnostic laparoscopy has long been the key consideration in the export of female infertility. This place is being reconsidered, especially in the case of normal hysterosalpingogrophy (HSG), because of the advent of assisted reproductive technologies which are more efficient, and because of the improvement of medical imaging techniques which are more sensitive and specific. We wanted to clarify the place of the diagnostic laparoscopy in the balance of female infertility in normal HSG. PATIENTS AND METHODS: It is a retrospective study on a series of 100 observations of infertile patients with a normal HSG and having a diagnostic laparoscopy in the department of Gynecology and Obstetrics at Farhat Hached hospital in Sousse (Tunisia) from 1st January 1993 to 1st March 2003. RESULTS: The mean age was 32.3years; the mean duration of infertility was 70.47months. Laparoscopy revealed pelvic abnormalities in 45% of cases, dominated by disease tubo-adhesions (23%), endometriosis was found in 6% of cases. These anomalies are considered major in 23% of cases and minor in 22% of cases. Conducting a surgical procedure in the same operating time (adhesiolysis, tubal plastic surgery, electrocoagulation of endometriosis implants) could improve the prognosis of fertility. Only 20 patients were followed among the 45 with pelvic abnormalities, seven pregnancies have been completed (35% of cases). DISCUSSION AND CONCLUSION: Laparoscopy has improved the prognosis for the fertility of our patients by treating abnormalities involved in infertility. It is estimated that the prognosis can be improved by selecting patients with risk factors for pelvic abnormalities. PMID- 23462341 TI - Risk factors for low vitamin D status in Korean adolescents: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2009. AB - OBJECTIVE: To evaluate the prevalence of vitamin D deficiency and predictors for low vitamin D status in Korean adolescents living between latitudes 33 degrees and 39 degrees N. DESIGN: A descriptive cross-sectional study. SETTING: Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2009. SUBJECTS: A total of 1510 healthy adolescents aged 12-18 years (806 male, mean age 14.7 years) participated. Possible predictors for low vitamin D status (log transformed 25-hydroxyvitamin D (25(OH)D) concentrations) were evaluated. RESULTS: The prevalence of vitamin D deficiency (25(OH)D<20 ng/ml) was 89.1% in spring, 53.7% in summer, 63.9% in autumn and 90.5% in winter. Winter season, older age, higher education level reached, being female, being obese, a lack of vitamin D supplementation, lower milk consumption (0-<200 ml/d) and a lack of physical activity were unadjusted predictors (all P < 0.05). Multiple linear regression analysis showed that winter season (P < 0.001), higher education level (P < 0.001) and a lack of vitamin D supplementation (P = 0.012) were independent predictors for low vitamin D status. The modifying effect of season on the association between vitamin D supplement use and vitamin D status was significant (P < 0.001). CONCLUSIONS: Vitamin D deficiency was highly prevalent in Korean adolescents, especially those in higher school grades. Vitamin D supplementation may contribute to maintain a better vitamin D status with lower seasonal variation. Further studies are required to determine optimal vitamin D intakes to maintain sufficient vitamin D status for Korean adolescents. PMID- 23462342 TI - Design and methods of a multi-site, multi-behavioral treatment trial for menopausal symptoms: the MsFLASH experience. AB - BACKGROUND: Behavioral strategies are recommended for menopausal symptoms, but little evidence exists regarding efficacy. PURPOSE: Describe design and methodology of a randomized controlled 3 by 2 factorial trial of yoga, exercise and omega-3 fatty acids. METHODS: Women from three geographic areas with a weekly average of >=14 hot flashes/night sweats, who met exclusion/inclusion criteria, were randomized to 12weeks of: 1) yoga classes and daily home practice; 2) supervised, facility-based aerobic exercise training; or 3) usual activity. Women in each arm were further randomized to either omega-3 supplement or placebo. Standardized training, on-going monitoring, and site visits were adopted to ensure consistency across sites and fidelity to the intervention. Participant adherence to the intervention protocol was monitored continuously, and retention was actively encouraged by staff. Information on adverse events was systematically collected. RESULTS: Of 7377 women who responded to mass mailings, 355 (4.8%) were randomized; mean age was 54.7 (sd=3.7), 26.2% were African American, 81.7% were post-menopausal, and mean baseline frequency of daily hot flashes/night sweats was 7.6 (sd=3.8). Adherence of >=80% was 59% for yoga, 77% for exercise training, and 80% for study pills. Final week 12 data were collected from 95.2% CONCLUSIONS: Conducting a multi-site, multi-behavioral randomized trial for menopausal symptoms is challenging but feasible. Benefits included cost effective study design, centralized recruitment, and methodologic standardization. PMID- 23462344 TI - The site of transcranial magnetic stimulation for post-traumatic stress disorder. PMID- 23462343 TI - The Counseling Older Adults to Control Hypertension (COACH) trial: design and methodology of a group-based lifestyle intervention for hypertensive minority older adults. AB - The disproportionately high prevalence of hypertension and its associated mortality and morbidity in minority older adults is a major public health concern in the United States. Despite compelling evidence supporting the beneficial effects of therapeutic lifestyle changes on blood pressure reduction, these approaches remain largely untested among minority elders in community-based settings. The Counseling Older Adults to Control Hypertension trial is a two-arm randomized controlled trial of 250 African-American and Latino seniors, 60 years and older with uncontrolled hypertension, who attend senior centers. The goal of the trial is to evaluate the effect of a therapeutic lifestyle intervention delivered via group classes and individual motivational interviewing sessions versus health education, on blood pressure reduction. The primary outcome is change in systolic and diastolic blood pressure from baseline to 12 months. The secondary outcomes are blood pressure control at 12 months; changes in levels of physical activity; body mass index; and number of daily servings of fruits and vegetables from baseline to 12 months. The intervention group will receive 12 weekly group classes followed by individual motivational interviewing sessions. The health education group will receive an individual counseling session on healthy lifestyle changes and standard hypertension education materials. Findings from this study will provide needed information on the effectiveness of lifestyle interventions delivered in senior centers. Such information is crucial in order to develop implementation strategies for translation of evidence-based lifestyle interventions to senior centers, where many minority elders spend their time, making the centers a salient point of dissemination. PMID- 23462345 TI - Convulsive syncope after single-pulse TMS. PMID- 23462346 TI - Maternal care and paternal protection influence response to psychotherapy treatment for adult depression. AB - BACKGROUND: Adverse childhood experiences of neglect, overprotection and abuse, well-recognized risk factors for the development of adult psychopathology, were examined as predictors of response to psychotherapy treatment for adults with depression. METHODS: Outpatients in a randomized clinical trial of interpersonal psychotherapy (IPT) or cognitive-behavioral therapy (CBT) completed the parental bonding instrument (PBI) at baseline to establish levels of care and protection. Childhood abuse was asked about using clinical interviews. The PBI variables were examined in tertiles while the abuse variables were categorized as "none," "some," and "severe." Associations between these childhood adversities and treatment response were examined in those who completed the trial. RESULTS: Of 177 outpatients with depression who were randomized, 159 completed an adequate trial of therapy. Within these 159 patients, 57% were categorized as responders to treatment. The mean percentage improvement on the MADRS was 57.7% (+/-31.4). Across both treatments, patients reporting intermediate levels of maternal care had the best response to treatment. Also across both treatments, the interaction effects of maternal care and paternal protection by treatment were statistically significant. Examining the two therapies independently, maternal care and paternal protection were associated with a differential response to IPT but not CBT. Reports of abuse, whether physical, emotional or sexual, did not impact treatment response. LIMITATIONS: This study examined patients who completed treatment, which may have attenuated the findings. Two categories of childhood adversity were measured although a range of other adverse childhood experiences exist. The results were from exploratory analyses and require replication. CONCLUSIONS: Maternal care, demonstrating a robust main effect across treatments, appears to be the childhood variable most strongly associated with response to psychotherapy in this sample. In addition, maternal care and paternal protection were associated with a differential response to treatment. These results suggest that the quality of on-going intra-familial relationships has a greater impact on treatment response than experiences of abuse. The findings may aid clinicians in selecting which psychotherapy to use, depending on a patient's childhood history. PMID- 23462347 TI - Psychological strains found in the suicides of 72 celebrities. AB - The interpretation of suicide involves theories from many disciplines, and the strain theory of suicide is a social-psychological model that attempts to account for this complicated behavior. We have earlier explored the presence of psychological strains in a number of diverse samples of suicides and in the present study, we identified the strains experienced throughout the lives as documented in the biographies of 72 celebrities. The biographies were systematically identified through a number of requirements and composed by one of the authors of this study years before the strain theory of suicide was proposed. A graduate student coder, who was unaware of the strain theory of suicide, was hired to carry out a content analysis of the biography essays and categorize the life events and the responses of the suicide in terms of the four types of strains. Of the 72 suicides, one had no strains, one had all the four strains, four had only one, 30 had two, and 36 had three strains. The most common strain was aspiration strain (97%), followed by deprivation strain (89%), value strain (54%) and coping deficiency strain (4%). It is also noted that religious celebrities were more likely to experience value strain, while those celebrities who had experienced a downhill path in their careers were more likely to experience deprivation and coping strains. This analysis of the 72 celebrity suicides supported the strain theory of suicide. PMID- 23462348 TI - Persistent visual impairment in multiple sclerosis: prevalence, mechanisms and resulting disability. AB - OBJECTIVE: The objective of this article is to evaluate in multiple sclerosis (MS) patients the prevalence of persistent complaints of visual disturbances and the mechanisms and resulting functional disability of persistent visual complaints (PVCs). METHODS: Firstly, the prevalence of PVCs was calculated in 303 MS patients. MS-related data of patients with or without PVCs were compared. Secondly, 70 patients with PVCs performed an extensive neuro-ophthalmologic assessment and a vision-related quality of life questionnaire, the National Eye Institute Visual Functionary Questionnaire (NEI-VFQ-25). RESULTS: PVCs were reported in 105 MS patients (34.6%). Patients with PVCs had more frequently primary progressive MS (30.5% vs 13.6%) and more neuro-ophthalmologic relapses (1.97 vs 1.36) than patients without PVCs. In the mechanisms/disability study, an afferent visual and an ocular-motor pathways dysfunction were respectively diagnosed in 41 and 59 patients, mostly related to bilateral optic neuropathy and bilateral internuclear ophthalmoplegia. The NEI-VFQ 25 score was poor and significantly correlated with the number of impaired neuro-ophthalmologic tests. CONCLUSION: Our study emphasizes the high prevalence of PVC in MS patients. Regarding the nature of neuro-ophthalmologic deficit, our results suggest that persistent optic neuropathy, as part of the progressive evolution of the disease, is not rare. We also demonstrate that isolated ocular motor dysfunctions induce visual disability in daily life. PMID- 23462349 TI - White-matter lesions drive deep gray-matter atrophy in early multiple sclerosis: support from structural MRI. AB - BACKGROUND: In MS, the relationship between lesions within cerebral white matter (WM) and atrophy within deep gray matter (GM) is unclear. OBJECTIVE: To investigate the spatial relationship between WM lesions and deep GM atrophy. METHODS: We performed a cross-sectional structural magnetic resonance imaging (MRI) study (3 Tesla) in 249 patients with clinically-isolated syndrome or relapsing-remitting MS (Expanded Disability Status Scale score: median, 1.0; range, 0-4) and in 49 healthy controls. Preprocessing of T1-weighted and fluid attenuated T2-weighted images resulted in normalized GM images and WM lesion probability maps. We performed two voxel-wise analyses: 1. We localized GM atrophy and confirmed that it is most pronounced within deep GM; 2. We searched for a spatial relationship between WM lesions and deep GM atrophy; to this end we analyzed WM lesion probability maps by voxel-wise multiple regression, including four variables derived from maxima of regional deep GM atrophy (caudate and pulvinar, each left and right). RESULTS: Atrophy of each deep GM region was explained by ipsilateral WM lesion probability, in the area most densely connected to the respective deep GM region. CONCLUSION: We demonstrated that WM lesions and deep GM atrophy are spatially related. Our results are best compatible with the hypothesis that WM lesions contribute to deep GM atrophy through axonal pathology. PMID- 23462350 TI - Relating localized protein motions to the reaction coordinate in coenzyme B12 dependent enzymes. AB - The classical picture of enzyme catalysis relies on controlling the entropic and enthalpic contributions by manipulating reaction barriers and co-locating reactants and cofactors to facilitate the reaction chemistry. Catalysis is linked inextricably to the geometry of the enzyme-substrate complex and the chemical/physical properties of the active site, and probably to dynamical contributions that guide reactants along the desired reaction coordinate. Coenzyme B12-dependent enzymes have remarkable catalytic power and unique properties that enable detailed analysis of the reaction chemistry and associated dynamics. Here we discuss recent developments that are beginning to provide atomistic insight into how coenzyme B12-dependent enzymes steer reactants along the reaction coordinate. Such insight will ultimately generate 'movies' of the catalytic process across all relevant time scales. In the longer term, this will enable more predictive engineering of this class of enzyme to achieve new and desirable chemical outcomes. PMID- 23462351 TI - The effect of pre-storage whole-blood leukocyte reduction on cytokines/chemokines levels in autologous CPDA-1 whole blood. AB - BACKGROUND: In this study, we aimed to investigate the effectiveness of pre storage leukocyte filtration of autologous blood (AB), especially focusing on the cytokines/chemokines accumulation on blood products. MATERIALS AND METHODS: After approval of the ethics committee of the University of Tokyo, a total of 26 orthopedic patients, who donated AB prior to surgery after informed consent, were enrolled. The effects of filtration on blood cell counts were analyzed, and the accumulation of cytokines and chemokines were measured on pre- and post leukoreduced (LR) samples, using the Luminex system. The time-dependent changes of the cytokines/chemokines and the effect of the filtration on their concentration were analyzed, and compared with the normal plasma levels reported in the literature. RESULTS: LR effectively reduced the number of leukocytes and platelets, without affecting that of red cells. The concentration of most of the cytokines/chemokines analyzed, except the EGF, sCD40-L and sFas-L, decreased time dependently of storage or did not change in pre-LR samples. However, EGF, sCD40L and sFas-L were significantly reduced by LR. Some, such as IL-8 and RANTES, were also importantly decreased by LR, and others, such as IL-1beta and TNF-alpha, were not significantly affected by LR. CONCLUSIONS: Leukocyte filtration effectively removes platelets and leukocytes from AB, thus preventing the accumulation of cytokines/chemokines. Since adverse effects due to AB transfusion, although rare, are observed, there is need to consider the implementation of pre-storage leukocyte reduction (PSLR) for AB. PMID- 23462352 TI - Cardiopulmonary resuscitation in hospitalized children with cardiovascular disease: estimated prevalence and outcomes from the kids' inpatient database. AB - OBJECTIVE: Hospitalized children with cardiovascular disease may be at increased risk of cardiac arrest; however, little data exist regarding prevalence, risk factors, or outcomes of cardiopulmonary resuscitation in these patients. We sought to characterize national estimates of cardiopulmonary resuscitation and death after cardiopulmonary resuscitation for hospitalized children with cardiovascular disease. SETTING: A total of 3,739 hospitals in 38 states participating in Kids' Inpatient Database. DESIGN: Retrospective analysis of the 2000, 2003, and 2006 Healthcare Cost and Utilization Project Kids' Inpatient Database was performed. Sample weighting was employed to produce national estimates. MEASUREMENTS AND MAIN RESULTS: Cardiovascular disease was identified in 2.2% of the estimated 22,175,468 (95% confidence interval 21,391,343 22,959,592) hospitalizations. Cardiopulmonary resuscitation occurred in 0.74% (3,698; 95% confidence interval 3,205-4,191) of hospitalizations of children with cardiovascular disease, compared with 0.05% (11,726; 95% confidence interval 10,647-12,805) without cardiovascular disease (odds ratio 13.8, 95% confidence interval 12.8-15.0). The highest frequency of cardiopulmonary resuscitation occurred with myocarditis (3.0% of admissions), heart failure (2.0%), and coronary pathology (2.0%). Compared with other forms of cardiovascular disease identified in this study, single-ventricle patients were the only subgroup who exhibited a higher mortality after cardiopulmonary resuscitation (mortality 65% vs. 55%; odds ratio 1.7 [95% confidence interval 1.2-2.6]), while those who had undergone cardiac surgery exhibited a lower mortality rate (mortality 48% vs. 57%; odds ratio 0.6 [95% confidence interval 0.5-0.8]). CONCLUSIONS: Cardiopulmonary resuscitation occurs in approximately 7 per 1,000 hospitalizations of children with cardiovascular disease, a rate greater than ten fold that observed in hospitalizations of children without cardiovascular disease. Single-ventricle patients demonstrated increased mortality after cardiopulmonary resuscitation, while recent cardiac surgery was associated with a reduced odds of death after cardiopulmonary resuscitation. Further studies are needed to confirm these findings and develop techniques to prevent cardiac arrest in this high-risk population. PMID- 23462353 TI - Pentobarbital for refractory intracranial hypertension: time to "go retro"? PMID- 23462354 TI - Hypercoagulability among pediatric patients with diabetic ketoacidosis: the clot thickens. PMID- 23462355 TI - The critically ill pediatric hematopoietic stem cell transplant patient: what have we learned? PMID- 23462356 TI - We can safely and effectively implement tight glycemic control in the pediatric cardiac ICU: but should we? PMID- 23462357 TI - Red cell transfusion: risk marker or risk factor in cardiac children?. PMID- 23462358 TI - Early minimal enteral supplementation in severely burned children receiving parenteral nutrition. PMID- 23462359 TI - Family communication in the PICU: beyond the conference room. PMID- 23462360 TI - Epidemiologic challenges in sepsis to the developing countries. PMID- 23462361 TI - New approach to insert peripherally inserted central catheter in critically ill pediatric patients. PMID- 23462362 TI - The authors reply to Gaspar et al. PMID- 23462363 TI - Undetermined complexity of the pathophysiology of diabetic ketoacidosis in undernourished children. PMID- 23462364 TI - The authors reply to Dr. Prashanth. PMID- 23462365 TI - Is change in regional (somatic) near-infrared spectroscopy not a useful indictor of clinically detectable low cardiac output in children after surgery for congenital heart defects? PMID- 23462366 TI - Skin penetration enhancers. AB - The skin has evolved to prevent excessive water loss from the internal organs and to limit the ability of xenobiotics and hazardous substances to enter the body. Notwithstanding this barrier function, a number of strategies have been developed by scientists to deliver drugs to and through the skin. The aim of this review is to consider the various types of chemical penetration enhancers (CPEs) which have been investigated in the scientific literature. Potential pathways for CPEs to exert their action are examined with reference to the physical chemistry of passive skin transport. The emphasis is on those studies which have focussed on human and porcine skin because of the limitations associated with skin permeation data collated from other species. Where known, the mechanisms of action of these compounds are also discussed. Examples of enhancers used in commercial topical and transdermal formulations are provided. It is proposed that overall the effects of CPEs on the skin barrier may best be explained by a Diffusion Partition-Solubility theory. Finally, some of the limitations of studies in the literature are considered and the importance of monitoring the fate of the penetration enhancer as well as the active is highlighted. PMID- 23462367 TI - Broadening of a THz pulse as a measure of the porosity of pharmaceutical tablets. AB - THz pulse time delay was measured from ethylcellulose tablets having nominal porosities 13%, 22% and 30%. It is suggested that the observed pulse broadening of sample THz pulse is due to scattering and dispersion of the THz wave in a porous tablet. A parameter related to the pulse broadening is suggested as a sensitive measure for the porosity and porosity change of the tablet. PMID- 23462368 TI - Interactions between human multidrug resistance related protein (MRP2; ABCC2) and excipients commonly used in self-emulsifying drug delivery systems (SEDDS). AB - The aim of this study was to investigate the multidrug resistance related protein 2 (MRP2) inhibition effect of excipients commonly employed in the formulation of self-emulsifying drug delivery systems (SEDDS). Cytotoxicity and safe dosages of fifteen excipients, including five surfactants, three oils, three co-surfactants and four solid carriers, were compared using MTT assay. Caco-2 cell permeability and MRP2 vesicles transport assays were used in the inhibition analysis. Scutellarin was shown to be a substrate of MRP2 and used as a probe in the inhibition assay. Twelve excipients decreased efflux ratio of scutellarin in Caco 2 model, among them six excipients showed inhibition effect on MRP2 in MRP2 transport model. In Caco-2 model, Cremophor EL, Maisine 35-1, PEG 2000 and beta cyclodextrin reduced efflux ratio of scutellarin the most in the four different excipients groups. The efflux reduction mechanism was further validated by MRP2 transport assay in inhibiting MRP2 activity in Cremophor EL and PEG 2000. It is suggested that scutellarin quantified by LC-MS can be used as a model drug for MRP2 inhibition analysis using Caco-2 permeability and vesicles transport analyses. Together they constitute a sensitive and rapid screening method for assessing interactions between excipients and MRP2 in SEDDS formulation. PMID- 23462369 TI - Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer. AB - Prostate cancer is the second most frequently diagnosed cancer of men. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, the majority of prostate cancer patients receiving the androgen ablation therapy will ultimately develop recurrent castration-resistant tumors within 3 years. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities in animal models. We therefore propose that administration of CAPE is a potential adjuvant therapy for patients with castration-resistant prostate cancer. PMID- 23462370 TI - "Nanogold detoxifying machine" to remove idle nanogold particles from blood stream of cancer patients treated with antibody-nanogold therapeutics. AB - This hypothesis would help to elevate safety in nanogold-therapy of some cancers. It has no previous record in published media and there is no existing protocol for what is expressed in this paper. The hypothesis makes some experimental recommendations for future research at the interface of nanotechnology and biological systems. It is about reducing toxicity and side effects of nanogold particles (NGPs) in cancer patients treated with antibody-nanogold therapeutics. The hypothesis expresses that how to eliminate idle NGPs from blood stream of treated cancer patients in order to reduce undesirable deposition and accumulation of NGPs in non-target tissues and organs in post therapy. In this regard, at the end of therapy period, blood of treated cancer patient which contains idle nanogold-antibodies is passed through a machine named "Nanogold detoxifying machine" (NDM). This machine behaves like "hemodialysis machine" used for patients with lost kidney function but, instead of dialysis membrane, NDM is equipped with impermeable membrane containing nanotubes to which cancer specific antigens (CSAs) are attached. While blood circulates in NDM, CSAs attract and immobilize the idle nanogold-antibodies. Implementation of NDM clears patient's blood from idle nanogold-antibodies which were not attached to their targets, the cancer cells. Elimination of idle NGPs from blood would minimize side effects resulting from their deposition or accumulation on non-target cells or tissues. Since NDM reduces anxieties about side effects, it would provide patients with better feelings too. NDM would enhance efficacy of NGPs targeted toward specific cancers. Before using it for clinical trials in human cases, NDM should pass animal evaluations; however, research works should optimize its implementation. I think NDM method holds great promise to reduce the time, effort, and expense in cancer research, screening, detection, and therapy. PMID- 23462371 TI - Can dehydroepiandrostenedione (DHEA) target PRL-3 to prevent colon cancer metastasis? AB - Colorectal cancer (CRC) is a frequently diagnosed cancer and causing significant mortality in the patients. Metastasis caused by CRC is mainly responsible for this cancer-related deaths. Despite recent advancements in the treatment methods, prognosis remains poor. Therefore, effective treatment strategies need to be designed for successful management of this disease. Dehydroepiandrostenedione (DHEA), a 17-ketosteroid hormone produced by adrenal glands, gonads and including gastrointestinal tract is required for several physiological processes. Deregulation of DHEA levels leads to various disease conditions including cancer. In fact, several experimental studies strongly suggest that DHEA could be used as a chemopreventive agent against colon cancer. Prenlyation of certain membrane proteins such as phosphatase of regenerating liver-3 (PRL-3) is crucial for metastatic progression of colon cancer cells. The ability of DHEA to target prenylation pathway could be utilized to inhibit PRL-3 prenylation for successful prevention of CRC metastases. As DHEA is a widely consumed drug for various ailments, incorporation of DHEA in the treatment regimen may be beneficial to prevent or delay the occurrence of metastasis resulting from CRC. PMID- 23462372 TI - Increased density of AKAP5-expressing neurons in the anterior cingulate cortex of subjects with bipolar disorder. AB - Brain anatomical abnormalities as well as cognitive and emotional processing deficits have been reported for the prefrontal cortex in bipolar disorder, which are in part attributable to cellular and laminar abnormalities in postsynaptic protein expression. A kinase anchoring protein (AKAP) 5/79 plays a key role in postsynaptic signalling of excitatory synapses. We aimed to reveal if the cellular expression of AKAP5/79 protein is altered in the anterior cingulate cortex and the dorsolateral prefrontal cortex in bipolar disorder. Ten subjects with bipolar disorder and ten control cases were investigated by use of immunohistochemical and morphometric techniques. Compared with controls in subjects with bipolar disorder, the numerical density of AKAP5-expressing neurons was significantly increased in the left (p = 0.002) and right (p = 0.008) anterior cingulate cortex. Layer-specific counting revealed that left side layers II (p = 0.000), III (p = 0.001) and V (p = 0.005) as well as right side layers III (p = 0.007), IV (p = 0.007) and V (p = 0.004) had significantly increased AKAP5-positive cell densities in bipolar disorder. In contrast, no statistically significant differences were found for the dorsolateral prefrontal cortex. However, we observed a more intense intraneuronal immunostaining in both prefrontal areas in bipolar disorder patients. Elevated cell numbers and increased intracellular expression of AKAP, together with the altered expression patterns of most intracellular interaction partners of this protein in bipolar disorder as known from the literature, might point to disease-related abnormalities of the AKAP-associated signalosome in prefrontal cortex neurons. PMID- 23462373 TI - Vestibular schwannoma surgical treatment. AB - Neurosurgical intervention remains the main step in the effective management of vestibular schwannomas. Extensive studies on vestibular schwannoma treatment have placed emphasis on preserving quality of life and neurological functions, particularly of the facial and vestibulocochlear nerves. Facial nerve preservation and hearing preservation have been achieved by significant advances in skull base microsurgical techniques and intraoperative neuromonitoring. Diffusion tensor imaging is a powerful and accurate method for preoperatively identifying the facial nerve in relation to vestibular schwannomas. Endoscopy offers excellent illumination of the anatomical structures and provides panoramic vision inside the surgical area. In this report, we focused on facial nerve and vestibulocochlear nerve preservation and analyzed the major techniques used for identifying the nerve-tumor relationship. PMID- 23462374 TI - Effect of magnetism on kinetics of gamma-alpha transformation and pattern formation in iron. AB - The kinetics of polymorphous gamma-alpha transformation in Fe is studied numerically within a model taking into account both the lattice and the magnetic degrees of freedom, based on first-principle calculations of the total energy for different magnetic states. It is shown that a magnetoelastic phenomenon, namely the strong sensitivity of the potential relief along the Bain deformation path to the magnetic state, is crucial for a picture of the transformation. With increasing temperature, a scenario for the phase transformation evolves from a homogeneous lattice instability at T < M(s) (M(s) is the temperature of the beginning of the martensitic transformation) to the growth and nucleation of embryos of the new phase at T > M(s). In the latter case, the formation of a tweed-like structure occurs, with a strong short-range order and slow interphase fluctuations. PMID- 23462375 TI - Sex-related analysis of short- and long-term clinical outcomes and bleeding among patients treated with primary percutaneous coronary intervention: an evaluation of the RISK-PCI data. AB - BACKGROUND: Unfavourable effect of female sex on short- and long-term clinical outcomes has been demonstrated in unselected ST-elevation acute myocardial infarction (STEMI) patients; the results are conflicting in patients who undergo primary percutaneous coronary intervention (PPCI). The objective of this substudy was to determine whether there are sex-related differences in the 30-day and 1 year clinical outcomes and bleeding after PPCI for STEMI. METHODS: We analyzed 2096 STEMI patients enrolled in the Risk Scoring Model to Predict Net Adverse Cardiovascular Outcomes After Primary Percutaneous Coronary Intervention (RISK PCI) trial from February 2006 to December 2009. Composite efficacy end point comprised all-cause mortality, nonfatal infarction, and stroke. Safety end point was bleeding classified according to the Thrombolysis in Myocardial Infarction (TIMI) criteria. Net adverse cardiovascular events included composite efficacy end point and total bleeding. RESULTS: Women in our study were older and presented later than men. After adjustment for potential confounders, there was no difference between sexes with respect to the composite efficacy end point. A higher rate of total bleeding was observed in women (adjusted odds ratio [OR], 1.67; 95% confidence interval [CI], 1.07-2.61 at 30 days, adjusted OR, 1.63; 95% CI, 1.08-2.47 at 1 year) compared with men. Total bleeding was associated with increased mortality at 30 days (OR, 4.87; 95% CI, 2.79-8.47) and at 1 year (OR, 4.43; 95% CI, 2.79-7.02) after PPCI. CONCLUSIONS: We did not find a significant sex-related difference with respect to the composite efficacy end point. Women had a higher rate of total bleeding which was associated with increased short- and long-term mortality. Specific measures aimed at preventing bleeding in women might improve the prognosis of PPCI patients. PMID- 23462377 TI - Neighbourhood and consumer food environment is associated with dietary intake among Supplemental Nutrition Assistance Program (SNAP) participants in Fayette County, Kentucky. AB - OBJECTIVE: The aim of the study was to determine the association between dietary outcomes and the neighbourhood food environment (street network distance from home to stores) and consumer food environment (Nutrition Environment Measurement Survey-Stores (NEMS-S) audit). DESIGN: The neighbourhood food environment was captured by creating 0?5-mile and 1-mile network distance (street distance) around each participant's home and the nearest food venue (convenience store, grocery store, supermarket, farmers' market and produce stand). The consumer food environment was captured by conducting NEMS-S in all grocery stores/supermarkets within 0?5 and 1 mile of participants' homes. SETTING: Fayette County, KY, USA. SUBJECTS: Supplemental Nutrition Assessment Program (SNAP) participants, n 147. RESULTS: SNAP participants who lived within 0?5 mile of at least one farmers' market/produce stand had higher odds of consuming one serving or more of vegetables (OR56?92; 95% CI 4?09, 11?69), five servings or more of grains (OR51?76; 95% CI 1?01, 3?05) and one serving or more of milk (OR53?79; 95% CI 2?14, 6?71) on a daily basis. SNAP participants who lived within 0?5 mile of stores receiving a high score on the NEMS-S audit reported higher odds of consuming at least one serving of vegetables daily (OR53?07; 95% CI 1?78, 5?31). CONCLUSIONS: Taken together, both the neighbourhood food environment and the consumer food environment are associated with a healthy dietary intake among SNAP participants. PMID- 23462376 TI - Outcomes of early- and late-identified children at 3 years of age: findings from a prospective population-based study. AB - OBJECTIVE: To address the question of whether, on a population level, early detection and amplification improve outcomes of children with hearing impairment. DESIGN: All families of children who were born between 2002 and 2007, and who presented for hearing services below 3 years of age at Australian Hearing pediatric centers in New South Wales, Victoria, and Southern Queensland were invited to participate in a prospective study on outcomes. Children's speech, language, functional, and social outcomes were assessed at 3 years of age, using a battery of age-appropriate tests. Demographic information relating to the child, family, and educational intervention was solicited through the use of custom-designed questionnaires. Audiological data were collected from the national database of Australian Hearing and records held at educational intervention agencies for children. Regression analysis was used to investigate the effects of each of 15 predictor variables, including age of amplification, on outcomes. RESULTS: Four hundred and fifty-one children enrolled in the study, 56% of whom received their first hearing aid fitting before 6 months of age. On the basis of clinical records, 44 children (10%) were diagnosed with auditory neuropathy spectrum disorder. There were 107 children (24%) reported to have additional disabilities. At 3 years of age, 317 children (70%) were hearing aid users and 134 children (30%) used cochlear implants. On the basis of parent reports, about 71% used an aural/oral mode of communication, and about 79% used English as the spoken language at home. Children's performance scores on standardized tests administered at 3 years of age were used in a factor analysis to derive a global development factor score. On average, the global score of hearing-impaired children was more than 1 SD below the mean of normal-hearing children at the same age. Regression analysis revealed that five factors, including female gender, absence of additional disabilities, less severe hearing loss, higher maternal education, and (for children with cochlear implants) earlier age of switch-on were associated with better outcomes at the 5% significance level. Whereas the effect of age of hearing aid fitting on child outcomes was weak, a younger age at cochlear implant switch-on was significantly associated with better outcomes for children with cochlear implants at 3 years of age. CONCLUSIONS: Fifty-six percent of the 451 children were fitted with hearing aids before 6 months of age. At 3 years of age, 134 children used cochlear implants and the remaining children used hearing aids. On average, outcomes were well below population norms. Significant predictors of child outcomes include: presence/absence of additional disabilities, severity of hearing loss, gender, maternal education, together with age of switch-on for children with cochlear implants. PMID- 23462378 TI - Purification, characterization and gene cloning of Da-36, a novel serine protease from Deinagkistrodon acutus venom. AB - A serine protease termed Da-36 was isolated from crude venom of Deinagkistrodon acutus. The enzyme was a single chain protein with an apparent molecular weight of 36,000 on SDS-PAGE with an isoelectric point of 6.59. Da-36 could clot human plasma by cleaving the Aalpha, Bbeta and gamma chains of fibrinogen and also exhibited arginine esterase activity. The proteolytic activity of Da-36 toward TAME was strongly inhibited by PMSF and moderately affected by benzamidine and aprotinin, indicating that it was a serine protease. Meanwhile, Da-36 showed stability with wide temperature (20-50 degrees C) and pH value ranges (pH 6-10). Divalent metal ions of Ca(2+), Mg(2+), and Mn(2+) had no effects but Zn(2+) and Cu(2+) inhibited the arginine esterase activity of Da-36. Total DNA was extracted directly from the lyophilized crude venom and the gene (5.5 kbp) coding for Da-36 had been successfully cloned. Sequence analysis revealed that the Da-36 gene contained five exons and four introns. The mature Da-36 was encoded by four separate exons. The deduced mature amino acid sequence of Da-36 was in good agreement with the determined N-terminal sequence of the purified protein and shared high homology with other serine proteases isolated from different snake venoms. Blast search using amino acid sequence of Da-36 against public database revealed that Da-36 showed a maximal identity of 90% with both Dav-X (Swiss-Prot: Q9I8W9.1) and thrombin-like protein 1 (GenBank: AAW56608.1) from the same snake species, indicating that Da-36 is a novel serine protease. PMID- 23462379 TI - Ribosome-inactivating proteins: from toxins to useful proteins. AB - Ribosome-inactivating proteins (RIPs) either single-chain (type 1) or two-chain (type 2) are frequent in plants, often in multiple forms. They are RNA N glycosidases, have antiviral, antifungal and insecticidal activity. Their expression in plants is increased under stressful conditions. They are investigated for practical applications in medicine and in agriculture. In medicine, RIPs have been linked to, or fused with, appropriate antibodies or other carriers to form "immunotoxins" or other conjugates specifically toxic to the cells target of the carrier, with the aim of eliminating malignant or other undesired cells. In agriculture, it has been observed that an enhanced expression of RIPs confers to plants an increased resistance to viruses, fungi, insects, and also to drought and salinity. PMID- 23462380 TI - Non-front-fanged colubroid snakes: a current evidence-based analysis of medical significance. AB - Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as "colubrids") comprise about 70% of extant snake species and include several taxa now known to cause lethal or life threatening envenoming in humans. Although the medical risks of bites by only a handful of species have been documented, a growing number of NFFC are implicated in medically significant bites. The majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties and their potential for causing harm in humans is unknown. Increasingly, multiple NFFC species are entering the commercial snake trade posing an uncertain risk. Published case reports describing NFFC bites were assessed for evidence-based value, clinical detail and verified species identification. These data were subjected to meta-analysis and a hazard index was generated for select taxa. Cases on which we consulted or personally treated were included and subjected to the same assessment criteria. Cases involving approximately 120 species met the selection criteria, and a small subset designated Hazard Level 1 (most hazardous), contained 5 species with lethal potential. Recommended management of these cases included antivenom for 3 species, Dispholidus typus, Rhabdophis tiginis, Rhabdophis subminiatus, whereas others in this subset without commercially available antivenoms (Thelotornis spp.) were treated with plasma/erythrocyte replacement therapy and supportive care. Heparin, antifibrinolytics and/or plasmapheresis/exchange transfusion have been used in the management of some Hazard Level 1 envenomings, but evidence based analysis positively contraindicates the use of any of these interventions. Hazard Level 2/3 species were involved in cases containing mixed quality data that implicated these taxa (e.g. Boiga irregularis, Philodryas olfersii, Malpolon monspessulanus) with bites that caused rare systemic effects. Recommended management may include use of acetylcholinesterase inhibitors (e.g. neostigmine) and wound care on a case-by-case basis. Hazard level 3 species comprised a larger group capable of producing significant local effects only, often associated with a protracted bite (eg Heterodon nasicus, Borikenophis (Alsophis) portoricensis, Platyceps (Coluber) rhodorachis). Management is restricted to wound care. Bites by Hazard level 4 species comprised the majority of surveyed taxa and these showed only minor effects of no clinical importance. This study has produced a comprehensive evidence-based listing of NFFC snakes tabulated against medical significance of bites, together with best-practice management recommendations. This analysis assumes increasing importance, as there is growing exposure to lesser-known NFFC snakes, particularly in captive collections that may uncover further species of significance in the future. Careful and accurate documentation of bites by verified species of NFFC snakes is required to increase the evidence base and establish the best medical management approach for each species. PMID- 23462381 TI - Modulation of membrane phospholipids, the cytosolic calcium influx and cell proliferation following treatment of B16-F10 cells with recombinant phospholipase D from Loxosceles intermedia (brown spider) venom. AB - The mechanism through which brown spiders (Loxosceles genus) cause dermonecrosis, dysregulated inflammatory responses, hemolysis and platelet aggregation, which are effects reported following spider bites, is currently attributed to the presence of phospholipase-D in the venom. In the present investigation, through two-dimensional immunoblotting, we observed immunological cross-reactivity for at least 25 spots in crude Loxosceles intermedia venom, indicating high expression levels for different isoforms of phospholipase-D. Using a recombinant phospholipase-D from the venom gland of L. intermedia (LiRecDT1) in phospholipid degrading kinetic experiments, we determined that this phospholipase-D mainly hydrolyzes synthetic sphingomyelin in a time-dependent manner, generating ceramide 1-phosphate plus choline, as well as lysophosphatidylcholine, generating lysophosphatidic acid plus choline, but exhibits little activity against phosphatidylcholine. Through immunofluorescence assays with antibodies against LiRecDT1 and using a recombinant GFP-LiRecDT1 fusion protein, we observed direct binding of LiRecDT1 to the membrane of B16-F10 cells. We determined that LiRecDT1 hydrolyzes phospholipids in detergent extracts and from ghosts of B16-F10 cells, generating choline, indicating that the enzyme can access and modulate and has activity against membrane phospholipids. Additionally, using Fluo-4, a calcium sensitive fluorophore, it was shown that treatment of cells with phospholipase-D induced an increase in the calcium concentration in the cytoplasm, but without altering viability or causing damage to cells. Finally, based on the known endogenous activity of phospholipase-D as an inducer of cell proliferation and the fact that LiRecDT1 binds to the cell surface, hydrolyzing phospholipids to generate bioactive lipids, we employed LiRecDT1 as an exogenous source of phospholipase-D in B16-F10 cells. Treatment of the cells was effective in increasing their proliferation in a time- and concentration-dependent manner, especially in the presence of synthetic sphingomyelin in the medium. The results described herein indicate the ability of brown spider phospholipase-D to induce the generation of bioactive phospholipids, calcium influx into the cytoplasm and cell proliferation, suggesting that this molecule can be used as a bioactive tool for experimental protocols in cell biology. PMID- 23462382 TI - Meningoencephalitis of unknown origin: investigation of prognostic factors and outcome using a standard treatment protocol. AB - Meningoencephalitis of unknown origin (MUO) is a common inflammatory CNS disease in dogs, with a variable and unpredictable outcome. MRI and cerebrospinal fluid (CSF) features were prospectively evaluated to establish their utility as prognostic markers for predicting mortality, relapse and long-term outcome in 39 dogs with MUO. MRI and CSF analysis were performed at initial diagnosis and three months into treatment with prednisolone and cytosine arabinoside. When possible, MRI was repeated every 12 months thereafter. Median survival time was 26 days. All deaths occurred within 52 days of diagnosis (22/39; 56 per cent). One-third (13/39) died within 72 hours of diagnosis. Outcome was good or excellent in 12/17 surviving dogs. Loss of the cerebral sulci and foramen magnum herniation on MRI were associated with increased risk of mortality. An abnormal CSF analysis at the three-month re-examination was associated with increased risk of relapse (P=0.04). The combination of MRI and CSF analysis provided a greater sensitivity for predicting relapse than one modality alone. Discontinuing treatment before MRI lesions resolved always resulted in relapse. The presence of certain MRI characteristics may indicate an increased risk of mortality. Dogs alive three months following diagnosis have a very low risk of death due to MUO. PMID- 23462383 TI - Renal pelvis rupture in a kidney with ureteropelvic junction obstruction and extrarenal calyces. AB - The extrarenal calyx (ERC) is a rare congenital anomaly, associated with various other abnormalities of the urogenital system. We report a unique case of ERC in a solitary functioning kidney with a massively dilated pelvis that developed spontaneous rupture. A dismembered pyeloplasty was performed at the time of rupture. The patient did well post-operatively with a stable creatinine and stable SFU grade 2 hydronephrosis. PMID- 23462384 TI - Constipation in children with isolated overactive bladders. AB - OBJECTIVE: To evaluate the prevalence of constipation in children with isolated overactive bladder (IOAB) and no micturition complaints. MATERIALS AND METHODS: A questionnaire was used to evaluate constipation in 51 children with IOAB, as well as in a control group of 74 children between the ages of 4 and 14 years. The Rome III criteria for children were used to assess constipation. IOAB was defined as the presence of symptoms such as urgency with or without daytime incontinence or frequency, a bell-shaped uroflow, and no post-residual urine. RESULTS: Mean patient ages were 7.94 (+/-2.8) and 8.28 (+/-3.4) years in the OAB and control group, respectively (p = 0.54). Twenty-eight (54.9%) of the OAB group were girls, and 34 (45.9%) were girls in the control group (p = 0.32). More of the children with IOAB had constipation than those without urinary symptoms (54.9% vs. 29.7%, p = 0.005; or 2.87, 95% CI: 1.3-6.0). The results were statistically significant regarding the following Rome III criteria: "history of stool retention", "presence of painful or hard bowel movements", "the presence of a large fecal mass in the rectum" and "large diameter stools which may obstruct the toilet". Within the group with OAB, constipation was more common among males (p = 0.05). There was no association between the type of OAB symptoms and constipation. The average dysfunctional voiding symptom score was 9.76 (+/-4.1). Eleven children (21.6%) presented alterations on ultrasound. Girls with OAB presented more frequently with UTI than boys (18 vs. 10, p = 0.13). CONCLUSION: This was the first comparative study with respect to constipation in children with IOAB and without urinary symptoms. Children with IOAB have a greater risk of having constipation compared to those with no urinary symptoms. PMID- 23462385 TI - The 'double hitch' manoeuvre in laparoscopic pyeloplasty - early experience. AB - Intra-corporeal anastomosis in laparoscopic pyeloplasty is laborious, time consuming and challenging. 14 children underwent laparoscopic dismembered pyeloplasty using a three port, transperitoneal approach over a one year period in whom a novel approach ("double hitch" manoeuvre) (Group-2, n = 9) was used and operating times compared with the conventional "single hitch" (Group-1, n = 5). The mean operating time in Group 1 (172.4 min) and in Group 2 (129.5 min) was significantly different. Mean follow up in Group-1 and Group-2 was 14 and 6 months respectively. Utilisation of the "double hitch" manoeuvre in laparoscopic pyeloplasty reduces the operating time and probably makes it less laborious. PMID- 23462386 TI - Abuse of people with cognitive impairment by family caregivers in Japan (a cross sectional study). AB - Caregiving is often stressful in an aging society. Our research questions were two. First, In Japan, how often does abusive behavior by the caregivers of elders with clinically mild cognitive dysfunction (mild cognitive impairment and clinically mild dementia) occur? Second, what risk factors affect the abusive behavior? We studied 123 Japanese caregivers and care recipients who had been referred to the Memory Clinic at Okayama University Hospital. We used the Japanese version of the modified Conflict Tactics Scale (m-CTS) to measure abusive behaviors. We estimate the prevalence of abusive behavior meeting threshold (m-CTS score of 2 or higher) for abuse case on the modified m-CTS. The prevalence of abusive behavior was 15.4%. Stepwise multiple regression analysis revealed that the sex of caregivers and scores on the Neuropsychiatric Inventory (NPI), Zarit Caregiver Burden scale, and Addenbrooke's Cognitive Examination had significant effects on the m-CTS scores. We demonstrated that in Japan, caregivers of the elderly with even clinically mild cognitive dysfunction exhibit abusive behavior toward them. The severity of the disease might reflect the prevalence of and factors that affect the abusive conflict score. PMID- 23462387 TI - The association between overcommitment to work and depressive symptoms is moderated by the polymorphic region of the 5-HTT gene. PMID- 23462388 TI - Molecular evolution and epidemiology of echovirus 6 in Finland. AB - Echovirus 6 (E-6) (family Picornaviridae, genus Enterovirus) is one of the most commonly detected enteroviruses worldwide. The aim of this study was to determine molecular evolutionary and epidemiologic patterns of E-6. A complete genome of one E-6 strain and the partial VP1 coding regions of 169 strains were sequenced and analyzed along with sequences retrieved from the GenBank. The complete genome sequence analysis suggested complex recombination history for the Finnish E-6 strain. In VP1 region, the phylogenetic analysis suggested three major clusters that were further divided to several subclusters. The evolution of VP1 coding region was dominated by negative selection suggesting that the phylogeny of E-6 VP1 gene is predominantly a result of synonymous substitutions (i.e. neutral genetic drift). The partial VP1 sequence analysis suggested wide geographical distribution for some E-6 lineages. In Finland, multiple different E-6 lineages have circulated at the same time. PMID- 23462389 TI - Objective way to support embryo transfer: a probabilistic decision. AB - STUDY QUESTION: Is it feasible to identify factors that significantly affect the clinical outcome of IVF-ICSI cycles and use them to reliably design a predictor of implantation? SUMMARY ANSWER: The Bayesian network (BN) identified top-history embryos, female age and the insemination technique as the most relevant factors for predicting the occurrence of pregnancy (AUC, area under curve, of 0.72). In addition, it could discriminate between no implantation and single or twin implantations in a prognostic model that can be used prospectively. WHAT IS KNOWN ALREADY: The key requirement for achieving a single live birth in an IVF-ICSI cycle is the capacity to estimate embryo viability in relation to maternal receptivity. Nevertheless, the lack of a strong predictor imposes several restrictions on this strategy. STUDY DESIGN, SIZE, DURATION: Medical histories, laboratory data and clinical outcomes of all fresh transfer cycles performed at the International Institute for Reproductive Medicine of Lugano, Switzerland, in the period 2006-2008 (n = 388 cycles), were retrospectively evaluated and analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were unselected for age, sperm parameters or other infertility criteria. Before being admitted to treatment, uterine anomalies were excluded by diagnostic hysteroscopy. To evaluate the factors possibly related to embryo viability and maternal receptivity, the class variable was categorized as pregnancy versus no pregnancy and the features included: female age, number of previous cycles, insemination technique, sperm of proven fertility, the number of transferred top-history embryos, the number of transferred top-quality embryos, the number of follicles >14 mm and the level of estradiol on the day of HCG administration. To assess the classifier, the indicators of performance were computed by cross-validation. Two statistical models were used: the decision tree and the BN. MAIN RESULTS AND THE ROLE OF CHOICE: The decision tree identified the number of transferred top history embryos, female age and the insemination technique as the features discriminating between pregnancy and no pregnancy. The model achieved an accuracy of 81.5% that was significantly higher in comparison with the trivial classifier, but the increase was so modest that the model was clinically useless for predictions of pregnancy. The BN could more reliably predict the occurrence of pregnancy with an AUC of 0.72, and confirmed the importance of top-history embryos, female age and insemination technique in determining implantation. In addition, it could discriminate between no implantation, single implantation and twin implantation with the AUC of 0.72, 0.64 and 0.83, respectively. LIMITATIONS, REASONS FOR CAUTION: The relatively small sample of the study did not permit the inclusion of more features that could also have a role in determining the clinical outcome. The design of this study was retrospective to identify the relevant features; a prospective study is now needed to verify the validity of the model. WIDER IMPLICATIONS OF THE FINDINGS: The resulting predictive model can discriminate with reasonable reliability between pregnancy and no pregnancy, and can also predict the occurrence of a single pregnancy or multiple pregnancy. This could represent an effective support for deciding how many embryos and which embryos to transfer for each couple. Due to its flexibility, the number of variables in the predictor can easily be increased to include other features that may affect implantation. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant, CTI Medtech Project Number: 9707.1 PFLS-L, Swiss Confederation. No competing interests are declared. PMID- 23462390 TI - External validation of the endometriosis fertility index (EFI) staging system for predicting non-ART pregnancy after endometriosis surgery. AB - STUDY QUESTION: Can the ability of the endometriosis fertility index (EFI) to predict non-assisted reproductive technology (ART) pregnancy after endometriosis surgery be confirmed by an external validation study? SUMMARY ANSWER: The significant relationship between the EFI score and the time to non-ART pregnancy observed in our study represents an external validation of this scoring system. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: The EFI was previously developed and tested prospectively in a single center, but up to now no external validation has been published. Our data provide validation of the EFI in an external fertility unit on a robust scientific basis, to identify couples with a good prognosis for spontaneous conception who can therefore defer ART treatment, regardless of their revised American Fertility Society (rAFS) endometriosis staging. DESIGN: Retrospective cohort study where the EFI was calculated based on history and detailed surgical findings, and related to pregnancy outcome in 233 women attempting non-ART conception immediately after surgery; all data used for EFI calculation and analysis of reproductive outcome had been collected prospectively as part of another study. PARTICIPANTS AND SETTING: The EFI score was calculated (score 0-10) for 233 women with all rAFS endometriosis stages (minimal-mild, n = 75; moderate-severe, n = 158) after endometriosis surgery (1 September 2006-30 September 2010) in a university hospital-based reproductive medicine unit with combined expertise in reproductive surgery and medically assisted reproduction. All participants attempted non-ART conception immediately after surgery by natural intercourse, ovulation induction with timed intercourse or intrauterine insemination (with or without ovulation induction or controlled ovarian stimulation). DATA ANALYSIS METHOD: All analyses were performed for three different definitions of pregnancy [overall (any HCG >25 IU/l), clinical and ongoing >20 weeks]. Six groups were distinguished (EFI scores 1-3, 4, 5, 6, 7+8, 9+10), and Kaplan-Meier (K-M) estimates for cumulative pregnancy rate were calculated. Subjects were censored when they were lost to follow-up, had subsequent surgery for endometriosis, started ovarian suppression or underwent ART. As K-M estimates might overestimate the actual event rate, cumulative incidence estimates treating ART as competing event were also calculated. Cox regression analysis was used to assess the performance of EFI and constituting variables. Performance of the score (prediction, discrimination) was quantified with the following methods: mean squared error of prediction (Brier score), areas under the receiver-operating curve and global concordance index C(tau). MAIN RESULTS AND THE ROLE OF CHANCE: There was a highly significant relationship between the EFI and the time to non-ART pregnancy (cumulative overall pregnancy rate, P = 0.0004), with the K-M estimate of cumulative overall pregnancy rate at 12 months after surgery equal to 45.5% [95% confidence interval (CI) 39.47-49.87] ranging from 16.67% (95% CI 5.01-47.65) for EFI scores 0-3, to 62.55% (95% CI 55.18-69.94) for EFI scores 9-10. For each increase of 1 point in the EFI score, the relative risk of becoming pregnant increased by 31% (95% CI 16-47%; i.e. hazard ratio 1.31). The 'least function score'-which assesses the tubal/ovarian function at conclusion of surgery-was found to be the most important contributor to the total EFI score among all the other variables (age, duration of infertility, prior pregnancy, AFS endometriosis lesion and total score). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The EFI score had a moderate performance in the prediction of the pregnancy rate. Indeed, the decrease in prediction error was rather small, as shown by the decrease in Brier score from 0.213 to 0.198, and low estimates for R² (13%) and C(tau) (0.629). GENERALIZABILITY TO OTHER POPULATIONS: As the EFI was validated externally in our own European population after initial testing by Adamson and Pasta (Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94:1609-1615) in an American population, it appears that the EFI can be used clinically to counsel infertile endometriosis patients receiving reproductive surgery in specialized centers about their post-operative conception options. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by funds obtained via the Clinical Research Fund of the University Hospitals Leuven, Belgium, via the Ferring Chair in Reproductive Medicine and Surgery, and the Serono Chair in Reproductive Medicine granted to the Leuven University Fertility Center. The authors have no conflicts of interest to declare. PMID- 23462391 TI - An 11-year-old girl with right-sided weakness secondary to cerebral abscesses: a case report. AB - A previously healthy 11-year-old girl who presented to the emergency department with 8 days of headache and right-sided weakness was found to have 2 cerebral abscesses. Brain abscess is an uncommon finding for children in the emergency department. With this case, we review the clinical presentation, evaluation, and management of this unusual but potentially life-threatening condition. PMID- 23462392 TI - Gray-scale and color Doppler ultrasound imaging findings of an ovarian inguinal hernia and torsion of the herniated ovary: a case report. AB - Inguinal hernia is extremely rare among girls. The hernia sac may sometimes involve intestinal structures, but ovaries in the sac are uncommon. Early diagnosis of a possible ovarian torsion is essential because potential amenable benefits can be achieved with surgery. A baby girl was admitted to our pediatric emergency unit with the complaints of swelling and erythema of the left groin. Then gray-scale ultrasonography and color Doppler ultrasonography was performed immediately at the emergency radiology room. In our case, ovarian torsion was diagnosed by gray-scale ultrasonography and color Doppler ultrasonography. After the diagnosis of ovarian torsion, the patient underwent surgery. It is possible to diagnose inguinal emergencies by high-resolution ultrasonography and color Doppler ultrasonography. PMID- 23462394 TI - Spondylodiscitis: a rare complication of button battery ingestion in a 10-month old boy. AB - Nowadays, button battery ingestion accounts for one of the common foreign body ingestions among pediatric population. Unexpected manifestations in this setting, particularly after late removal, are confusing and might be misleading and postpone the proper management. We report a case of button battery ingestion in a 10-month-old boy who was primarily considered uncomplicated. However, he was readmitted with neck stiffness, which later turned to be due to spondylodiscitis. Based on this report, we strongly recommend considering spondylodiscitis as a late but serious complication of button battery ingestion in any patient who presents with restricted neck movement following foreign body ingestion. PMID- 23462393 TI - Severe facial and ocular injuries from a potato gun. AB - Potato guns or spud guns are homemade firearms built primarily for recreational use. Information on how to make these can be found easily by searching the topic on the Internet. There is a surplus of Web sites dedicated to providing information to anyone looking to make one of their own. We present an interesting case that illustrates the extent of trauma, which can be caused by these dangerous devices. Despite the growing information available for consumers of any age, there is little information for clinicians regarding these devices and the serious threat of injury that they pose. The current trauma and injury databases, unfortunately, do not gather data pertaining specifically to these devices. In addition, because they are homemade and primarily built for recreational purposes, their use is not controlled or regulated by the government. It is important for clinicians to be aware of homemade firearms such as potato guns, be prepared to manage injury from these devices, and as with other weapons or firearms provide patients and families with the appropriate anticipatory guidance. PMID- 23462395 TI - Pulmonary emboli associated with isolated lower-extremity venous malformation: a case report. AB - Pulmonary thromboembolism is a relatively rare entity in the pediatric population; however, it should always be part of the differential diagnosis in patients with the appropriate clinical presentation. We report the case of a 13 year-old girl with a history of a lower-extremity venous malformation status post sclerotherapy 2 years prior but otherwise healthy who presented with painless hemoptysis. She was found to have multiple bilateral pulmonary emboli on computed tomographic angiography of the chest. Magnetic resonance venography of the lower extremities showed stable venous changes from prior studies and no obvious source of emboli. She was started on anticoagulation and was discharged home. PMID- 23462396 TI - A tale of 2 torsions: ovarian torsion in infants and toddlers. AB - Abdominal pain is a common chief complaint in both the emergency department and the primary care setting. Although most patients are ultimately diagnosed with benign self-limited conditions, the differential diagnosis in infants and toddlers does include ovarian torsion. In this article, we present 2 cases involving female infants younger than 18 months who were found to have ovarian torsion during evaluation in our pediatric emergency department. We discuss the clinical presentation, risk factors, diagnosis, management, and potential long term complications of ovarian torsion, with special attention to the younger population. PMID- 23462397 TI - Seizures and methemoglobinemia in an infant after excessive EMLA application. AB - Topical anesthetics are commonly used in many health care settings and for many clinical conditions. However, there are a number of potential adverse effects associated with their use. Their widespread administration can convey a false sense of security and failure to appreciate possible complications. We present the case of an infant with extensive vascular malformations treated with EMLA cream who developed seizures and methemoglobinemia from lidocaine and prilocaine toxicity. We describe the pathophysiology of these morbidities, the use of pulse oximetry in this setting, and the clinical presentation and treatment of methemoglobinemia. PMID- 23462398 TI - Is acute dystonia an emergency? Sometimes, it really is! AB - Most cases of acute dystonia are mild and easy to manage; nevertheless, some of them can be fatal because of the involvement of certain muscle groups such as the laryngeal muscles, thus requiring urgent intervention. In the literature, approach to life-threatening acute dystonia has not been investigated thoroughly, although the diagnosis is a challenge, and treatment should be offered immediately. Herein the management of life-threatening acute dystonia is discussed via 2 case reports. PMID- 23462399 TI - New biomedical devices that use near-infrared technology to assist with phlebotomy and vascular access. AB - Obtaining intravenous access in children is often challenging. Devices using the novel technology of near-infrared imaging have been developed and marketed to facilitate intravenous catheter placement and phlebotomy. We review the technology of near-infrared imaging and the evidence for its use in the pediatric emergency population. PMID- 23462402 TI - A teenager with multiple organ system dysfunction. PMID- 23462403 TI - IT in the ED: past, present, and future. AB - Over the past 40 years, information technology in the emergency department (ED) has evolved from primitive tracking, order entry, and laboratory reporting systems to complex multifunctional applications that permeate all aspects of patient care and ED operations. Spurred by incentive programs and technological improvements, both ED physicians and administrators view these systems as a way to increase staff efficiency, to improve patient care quality and safety, to satisfy compliance and reporting obligations, and to reduce costs. As organizations implement and optimize systems, it is helpful to look back at how these technologies were developed, to review the current impacts and effects of their use, and to glimpse the future of information technology in the ED. PMID- 23462404 TI - Monteggia fracture-dislocation. PMID- 23462401 TI - Assessment and management of bullied children in the emergency department. AB - Bullying is an important public health issue in the United States. Up to 30% of children report exposure to such victimization. Not only does it hurt bully victim, but it also negatively impacts the bully, other children, parents, school staff, and health care providers. Because bullying often presents with accompanying serious emotional and behavioral symptoms, there has been an increase in psychiatric referrals to emergency departments. Emergency physicians may be the first responders in the health care system for bullying episodes. Victims of bullying may present with nonspecific symptoms and be reluctant to disclose being victimized, contributing to the underdiagnosis and underreporting of bully victimization. Emergency physicians therefore need to have heightened awareness of physical and psychosocial symptoms related to bullying. They should rapidly screen for bullying, assess for injuries and acute psychiatric issues that require immediate attention, and provide appropriate referrals such as psychiatry and social services. This review defines bullying, examines its presentations and epidemiology, and provides recommendations for the assessment and evaluation of victims of bullying in the emergency department. PMID- 23462405 TI - ECGs in the ED. PMID- 23462406 TI - Liquid detergent capsule ingestion: a new pediatric epidemic? PMID- 23462407 TI - A dangerous complication of thoracocentesis. PMID- 23462408 TI - England's NHS is struggling to boost productivity despite drive for efficiency, finds analysis. PMID- 23462409 TI - CCGs must commission for England's whole population, not just for "those with sharp elbows," conference hears. PMID- 23462410 TI - NHS spending on independent services is up by more than 10%. PMID- 23462411 TI - Leading doctors condemn NHS tendering processes. PMID- 23462412 TI - UK improves health outcomes but not as fast as similar countries. PMID- 23462413 TI - In vivo and in vitro antidiabetic effect of Cistus laurifolius L. and detection of major phenolic compounds by UPLC-TOF-MS analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Turkish folk medicine, various parts of Cistus laurifolius L. are used to treat gastric ulcer and various types of pains. Additionally the tea prepared from the leaves is used to decrease symptoms of diabetes. MATERIALS AND METHODS: In the present study, the hypoglycemic effects of aqueous and ethanol extracts of Cistus laurifolius were investigated in normal, glucose loaded hyperglycemic and streptozocin (STZ)-induced diabetic rats. alpha-Glucosidase and alpha-amylase enzyme inhibitory effects were determined to evaluate the mechanism of action. Total phenolic content of the extracts were determined by using Folin-Ciocalteu reagent and Ultra Performance Liquid Chromatography-Time of Flight Mass Spectrometer (UPLC-TOF-MS) was used to detect the major phenolic compounds in the extract. RESULTS: Results indicated that blood glucose levels of the STZ-induced diabetic rats were decreased by ethanol extract at of 250 and 500mg/kg doses as compared to control group (16% 34%). In glucose loaded animals, extracts have shown a weak hypoglycemic effect (11%-20%). Additionally, the ethanol extract of Cistus laurifolius is found to be a potent inhibitor of alpha-glucosidase and alpha-amylase, possibly due to several polyphenolic compounds present within the extract. Twelve major flavonoids (apigenin, quercetin, kaempferol, naringenin, quercitrin and their derivatives), gallic, ellagic and chlorogenic acid in chromatographic fingerprint were analyzed by the on-line UPLC-TOF-MS system. CONCLUSIONS: Due to having inhibitory effect on blood glucose level and carbohydrate digesting enzymes (alpha-glucosidase and alpha-amylase), Cistus laurifolius leaves might be beneficial for diabetic patients. PMID- 23462414 TI - Does the selection of medicinal plants by Brazilian local populations suffer taxonomic influence? AB - ETHNOPHARMACOLOGICAL RELEVANCE: The analysis of the influence of taxonomic affiliation on the selection of medicinal plants by Brazilian local populations can help elucidate theoretical aspects of medicinal plant selection. MATERIALS AND METHODS: Ethnobotanical medicinal plant studies were compiled and the resulting medicinal flora was compared to the total angiosperm flora with a Bayesian approach and the IDM model. RESULTS: A total of 35 families were considered to be overused and six were classified as underused for the Bayesian approach. On the other hand, the IDM model considered 13 families as overused and five as underused (all of them were also highlighted by the Bayesian approach). A high overuse level of Bixaceae, Amaranthaceae, Anacardiaceae and Smilacaceae was recorded for both Bayesian and IDM model, while Orchidaceae, Melastomataceae, Eriocaulaceae, Poaceae and Bromeliaceae were considered as underused for both analyses. The most dissimilar body system in terms of family composition was 'mental and behavioral disorders'. It was also found that the body systems are different from one another in the proportion of taxonomic groups, which could indicate chemical specificity in the treatment of diseases. CONCLUSIONS: Results indicate that the chemical specificity of taxonomic groups directly influences medicinal plant selection. Moreover, when data presented here are compared to other studies, there is clearly an overuse pattern for families like Lamiaceae, Rosaceae and Euphorbiaceae and an underuse pattern for Poaceae and Orchidaceae. PMID- 23462415 TI - The neuropsychological and neurophysiological profile of women with pseudoseizure. AB - OBJECTIVE: Our aim in this study was to compare the assessments of neuropsychological tests and the p50 neurophysiological test of patients with seizure diagnosed as conversion disorder and healthy control subjects, and to investigate the neurological status in conversion disorder with pseudoseizure. METHODS: A total of 22 female conversion disorder patients with convulsions diagnosed according to SCID-I/CV and 22 healthy women were included in the assessment. The participants were administered WMS-R, the cancellation test, and the Stroop test as neuropsychological tests and p50 was assessed as a neurophysiological test. RESULTS: The patient's results for the neuropsychological tests were found to be significantly low compared to the control group. The p50 sensory gating ratios of the patient group were statistically significantly lower than the controls. There was no significant correlation between the neuropsychological test scores and gating ratios of the patient and control groups. CONCLUSIONS: This study is the first to check sensory gating in conversion disorder patients with pseudoseizure and its most important result is finding reduced p50 sensory gating in patients. Our results suggest that these patients have a neurological tendency to this disease due to functional neurophysiological features. PMID- 23462416 TI - Vitamin A status after prophylactic intramuscular vitamin A supplementation in extremely low birth weight infants. AB - BACKGROUND: Vitamin A supplementation (VAS) is recommended to prevent bronchopulmonary dysplasia (BPD). Our objective was to evaluate the effect of VAS on vitamin A (VA) status. We hypothesized that VAS would improve VA status in extremely low birth weight (ELBW) infants. MATERIALS AND METHODS: Retrospective chart review of infants 1 year before and after initiation of VAS (5000 IU 3 times a week intramuscularly [IM]; total 12 doses). Linear regression was used to model impact of VAS on VA status (retinol level and retinol/retinol binding protein [RBP] ratio). Models were adjusted for time and generalized estimating equations were used to account for intraindividual correlation. RESULTS: Sixty seven infants (mean gestational age 26 +/- 2 weeks; mean body weight 803 +/- 142 g) were included; 35 received VAS and 32 did not (no-VAS). Both groups had similar baseline characteristics. Infants who received VAS had mean retinol levels that were 9.0 mcg/dL (95% confidence interval [CI], 4.9-13.2; P < .001) higher and mean retinol/RBP ratios that were 0.21 (95% CI, 0.07-0.36; P = .005) higher than the no-VAS group. Retinol and retinol/RBP ratio increased with time (P < .001). Fewer infants in the VAS group had VA deficiency (retinol/RBP ratios <0.7) compared with the no-VAS group. Culture-positive sepsis was more common in the VAS group (48% vs 12%; P = .002). CONCLUSIONS: VA status in ELBW infants was improved and maintained over the first month of life with IM VAS. Because of concerns for potential risks of repeated injections, further studies are indicated to evaluate the optimal mode of VA delivery in preterm infants. PMID- 23462417 TI - A.S.P.E.N. policy on academic misconduct. PMID- 23462418 TI - Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis. AB - PURPOSE: Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. METHODS AND MATERIALS: 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. RESULTS: Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. CONCLUSION: High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma. PMID- 23462420 TI - Retrospective evaluation reveals that long-term androgen deprivation therapy improves cause-specific and overall survival in the setting of dose-escalated radiation for high-risk prostate cancer. AB - PURPOSE: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). METHODS AND MATERIALS: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. RESULTS: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. CONCLUSION: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10. PMID- 23462419 TI - Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. AB - PURPOSE: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. METHODS AND MATERIALS: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. RESULTS: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-gamma+/tumor necrosis factor-alpha+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. CONCLUSIONS: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM. PMID- 23462421 TI - Multicenter collaborative quality assurance program for the province of Ontario, Canada: first-year results. AB - PURPOSE: The objective of this work was to develop a collaborative quality assurance (CQA) program to assess the performance of intensity modulated radiation therapy (IMRT) planning and delivery across the province of Ontario, Canada. METHODS AND MATERIALS: The CQA program was designed to be a comprehensive end-to-end test that can be completed on multiple planning and delivery platforms. The first year of the program included a head-and-neck (H&N) planning exercise and on-site visit to acquire dosimetric measurements to assess planning and delivery performance. A single dosimeter was used at each institution, and the planned to measured dose agreement was evaluated for both the H&N plan and a standard plan (linear-accelerator specific) that was created to enable a direct comparison between centers with similar infrastructure. RESULTS: CQA program feasibility was demonstrated through participation of all 13 radiation therapy centers in the province. Planning and delivery was completed on a variety of infrastructure (treatment planning systems and linear accelerators). The planning exercise was completed using both static gantry and rotational IMRT, and planned to-delivered dose agreement (pass rates) for 3%/3-mm gamma evaluation were greater than 90% (92.6%-99.6%). CONCLUSIONS: All centers had acceptable results, but variation in planned to delivered dose agreement for the same planning and delivery platform was noted. The upper end of the range will provide an achievable target for other centers through continued quality improvement, aided by feedback provided by the program through the use of standard plans and simple test fields. PMID- 23462422 TI - Evaluation of 4-dimensional computed tomography to 4-dimensional cone-beam computed tomography deformable image registration for lung cancer adaptive radiation therapy. AB - PURPOSE: To evaluate 2 deformable image registration (DIR) algorithms for the purpose of contour mapping to support image-guided adaptive radiation therapy with 4-dimensional cone-beam CT (4DCBCT). METHODS AND MATERIALS: One planning 4D fan-beam CT (4DFBCT) and 7 weekly 4DCBCT scans were acquired for 10 locally advanced non-small cell lung cancer patients. The gross tumor volume was delineated by a physician in all 4D images. End-of-inspiration phase planning 4DFBCT was registered to the corresponding phase in weekly 4DCBCT images for day to-day registrations. For phase-to-phase registration, the end-of-inspiration phase from each 4D image was registered to the end-of-expiration phase. Two DIR algorithms-small deformation inverse consistent linear elastic (SICLE) and Insight Toolkit diffeomorphic demons (DEMONS)-were evaluated. Physician delineated contours were compared with the warped contours by using the Dice similarity coefficient (DSC), average symmetric distance, and false-positive and false-negative indices. The DIR results are compared with rigid registration of tumor. RESULTS: For day-to-day registrations, the mean DSC was 0.75 +/- 0.09 with SICLE, 0.70 +/- 0.12 with DEMONS, 0.66 +/- 0.12 with rigid-tumor registration, and 0.60 +/- 0.14 with rigid-bone registration. Results were comparable to intraobserver variability calculated from phase-to-phase registrations as well as measured interobserver variation for 1 patient. SICLE and DEMONS, when compared with rigid-bone (4.1 mm) and rigid-tumor (3.6 mm) registration, respectively reduced the average symmetric distance to 2.6 and 3.3 mm. On average, SICLE and DEMONS increased the DSC to 0.80 and 0.79, respectively, compared with rigid tumor (0.78) registrations for 4DCBCT phase-to-phase registrations. CONCLUSIONS: Deformable image registration achieved comparable accuracy to reported interobserver delineation variability and higher accuracy than rigid-tumor registration. Deformable image registration performance varied with the algorithm and the patient. PMID- 23462423 TI - Motion interplay as a function of patient parameters and spot size in spot scanning proton therapy for lung cancer. AB - PURPOSE: To quantify the impact of respiratory motion on the treatment of lung tumors with spot scanning proton therapy. METHODS AND MATERIALS: Four-dimensional Monte Carlo simulations were used to assess the interplay effect, which results from relative motion of the tumor and the proton beam, on the dose distribution in the patient. Ten patients with varying tumor sizes (2.6-82.3 cc) and motion amplitudes (3-30 mm) were included in the study. We investigated the impact of the spot size, which varies between proton facilities, and studied single fractions and conventionally fractionated treatments. The following metrics were used in the analysis: minimum/maximum/mean dose, target dose homogeneity, and 2 year local control rate (2y-LC). RESULTS: Respiratory motion reduces the target dose homogeneity, with the largest effects observed for the highest motion amplitudes. Smaller spot sizes (sigma ~ 3 mm) are inherently more sensitive to motion, decreasing target dose homogeneity on average by a factor 2.8 compared with a larger spot size (sigma ~ 13 mm). Using a smaller spot size to treat a tumor with 30-mm motion amplitude reduces the minimum dose to 44.7% of the prescribed dose, decreasing modeled 2y-LC from 87.0% to 2.7%, assuming a single fraction. Conventional fractionation partly mitigates this reduction, yielding a 2y-LC of 71.6%. For the large spot size, conventional fractionation increases target dose homogeneity and prevents a deterioration of 2y-LC for all patients. No correlation with tumor volume is observed. The effect on the normal lung dose distribution is minimal: observed changes in mean lung dose and lung V20 are <0.6 Gy(RBE) and <1.7%, respectively. CONCLUSIONS: For the patients in this study, 2y LC could be preserved in the presence of interplay using a large spot size and conventional fractionation. For treatments using smaller spot sizes and/or in the delivery of single fractions, interplay effects can lead to significant deterioration of the dose distribution and lower 2y-LC. PMID- 23462424 TI - Toothbrushing for preventing ventilator-associated pneumonia. PMID- 23462425 TI - Photon dressed electronic states in topological insulators: tunneling and conductance. AB - We have obtained analytic results for the surface states of three-dimensional topological insulators in the presence of circularly polarized light. This electron-photon interaction results in an energy gap as well as a novel energy dispersion of the dressed electron-photon states, different from both graphene and the standard two-dimensional electron gas (2DEG). Additionally, we made calculations of the ballistic conductance and Klein tunneling in both two- and three-dimensional topological insulators as well as investigating how these phenomena are affected in the presence of circularly polarized light. We have found a critical energy for an incoming particle, separating two substantially different types of tunneling. PMID- 23462426 TI - [Severe cannabis intoxication in a four-month old infant]. PMID- 23462427 TI - [Epidemiology and long-term outcome of sepsis in elderly patients]. AB - OBJECTIVES: A study was made of the epidemiological data of sepsis requiring admission to the ICU in patients over 65 years of age, with an evaluation of independent predictors of survival at 2 years. DESIGN: A prospective cohort study was made. PATIENTS: Patients meeting criteria for sepsis upon admission to the ICU. SETTING: A 40-bed ICU in a tertiary hospital. RESULTS: The study group included 237 elderly patients (>= 65 years of age) and 281 controls (<65 years of age) (n=518). At least one chronic comorbid condition was present in 70% of the elderly patients as compared to only 56.1% of patients under age 65 (P<.01). There were several epidemiological differences between the groups: the prevalence of chronic diseases (diabetes, chronic obstructive pulmonary disease, and chronic heart failure), presentation as septic shock (52.3% vs 42%; P<.05), and the abdomen as the source of sepsis (52% vs 36%; P<.01) were all more frequent in elderly patients. Nine percent of the global patients discharged from hospital died in the 2-year follow-up period, but this rate reached 20% among the elderly. Independent predictors of 2-year mortality in the elderly were: chronic heart failure (adjusted hazard ratio [aHR] 2.24, 95% confidence interval [CI 95%] 1.28 3.94; P<.01), acute renal failure (aHR 3.64, 95%CI 2.10-6.23; P<.01), acute respiratory failure (aHR 3.67, 95%CI 2.31-5.86; P<.01), and inappropriate empirical antimicrobial therapy (aHR 2.19, 95%CI 1.32-3.62; P<.01). CONCLUSIONS: Sepsis showed different demographic characteristics and clinical presentations in the elderly. In the aging cohort, after adjusting for potential confounders, inadequate empirical antimicrobial therapy was associated to a 2-fold decrease in survival at two years. PMID- 23462428 TI - [Role of biomarkers in the differential diagnosis of acute respiratory failure in the immediate postoperative period of lung transplantation]. AB - Lung transplant recipients are at high risk of suffering many complications during the immediate postoperative period, such as primary graft dysfunction, acute graft rejection or infection. The most common symptom is the presence of acute respiratory failure, and the use of biomarkers could be useful for establishing an early diagnosis of these conditions. Different biomarkers have been studied, but none have proven to be the gold standard in the differential diagnosis of acute respiratory failure. This paper offers a review of the different biomarkers that have been studied in this field. PMID- 23462429 TI - CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers. AB - Variation in the CYP2A6 gene, which decreases the rate of nicotine metabolic inactivation, is associated with higher adult smoking cessation rates during clinical trials. We hypothesized that slow metabolism is associated with increased quitting during adolescence. White adolescent smokers (N=308, aged 12 17, 36.3% male) from a cohort study were genotyped for CYP2A6, resulting in 7.8% slow, 14.0% intermediate and 78.2% normal metabolizers. Overall, 144 smokers quit smoking, as indicated by being abstinent for at least 12 months. In logistic regression analyses, the odds ratio for quitting was 2.25 (95% confidence interval 1.05, 4.80; P=0.037) for slow metabolizers relative to normal metabolizers. A linear trend toward increased quitting with decreasing CYP2A6 activity was also observed (odds ratio=1.44, 95% confidence interval 1.02, 2.01; P=0.034). Thus, CYP2A6 slow metabolism is associated with increased adolescent smoking cessation, indicating that even early in the smoking history, genetic variation is influencing smoking cessation. PMID- 23462430 TI - Global processing of orientation in amblyopia. AB - We set out to determine whether extra-striate ventral stream function was compromised in amblyopia and to compare any observed deficit with previous data on comparable dorsal stream function. We devised a multi-element orientation task where orientation coherence sensitivity could be measured in a comparable way to motion coherence. The use of spatial frequency narrowband elements allowed for accurate correction of any upstream contrast sensitivity influence and ensured that the orientation bandwidth of our elements did not covary with the measured coherence. Using a standard equivalent noise analysis, we varied both the local orientation bandwidth of individual elements as well as the global orientation bandwidth of the element array to obtain estimates of both local and global internal noise and efficiency. The results show that for this ventral stream task there is only a subtle amblyopic deficit in processing global orientation relative to control observers. This deficit is present for both amblyopic and fixing eyes, and appears to reflect poorer efficiency in processing local orientation, suggesting a subtle deficit at the input stage to extra-striate cortex where orientation coherence is processed. PMID- 23462431 TI - Management of immune cytopenias in patients with systemic lupus erythematosus - Old and new. AB - There are various immune cytopenias associated with systemic lupus erythematosus (SLE). The most common one is anemia; however, there are different etiologies for the anemia caused by SLE. Anemia could be due to chronic disease, secondary to renal insufficiency, blood loss, drug induced or autoimmune hemolysis. There are other very rare causes of anemia secondary to SLE which include red cell aplasia, aplastic anemia, and microangiopathic hemolytic anemia. Treatment of the anemia would be according to the cause. Leukopenia, neutropenia, and lymphopenia are hematologic complications associated with SLE, and in majority of cases no treatment is required. Thrombocytopenia is one of the complications of SLE and is usually treated by steroids. However, there are significant numbers of patients which will either not respond to or relapse after treatment. This article summarizes immune cytopenias seen in patients with SLE, and it also discusses management of these cytopenias. PMID- 23462432 TI - The future of immunoglobulin therapy: an overview of the 2nd international workshop on natural antibodies in health and disease. AB - On March 15-17th, 2012 the 2nd international workshop on natural antibodies sponsored by CSL Behring AG took place in Bern, Switzerland. The focus of this workshop centered on new directions and in particular explored the "Future of Immunoglobulin Therapy". Our international speakers addressed the major themes of understanding the origins of the immunoglobulin (Ig) repertoire and how we use it in our everyday lives to maintain homeostasis and fight infections and diseases. This Ig repertoire is already used as a therapeutic tool in the form of intravenous immunoglobulin (IVIG) for patients suffering from immunodeficiency and autoimmune disorders. The question now arises: what else can we learn and apply for the future of Ig therapy? Are there new directions, new ways of using the repertoire? These questions were discussed in sections covering modified Igs with modified efficacy including catalytic antibodies, the role of Fc receptors and complement inducing autoimmune mediated damage, Ig therapy beyond IgG in particular taking a look at the role of IgA and the therapeutic consequences of the different etiologies of excess amyloid beta in Alzheimer's disease and patients with Downs' syndrome. A major topic addressed the application of biomarkers to define new autoimmune diseases, to refine current therapies with a view to optimising the management of chronic diseases using both genetic and biomarker profiles to forewarn of possible future complications and to monitor fluctuations in disease status. Indeed, some of these topics push the frontiers of autoimmunity beyond its traditional scope and serve the purpose of making us re-evaluate the potential of using the Ig repertoire. PMID- 23462433 TI - Evaluation of genetic variation in the international Brown Swiss population. AB - The international Brown Swiss cattle population pedigree was studied to measure genetic variations and to identify the most influential animals. Twenty-two countries provided pedigree information on 71 497 Brown Swiss bulls used for artificial insemination (AI). The total number of animals with the pedigree is 181 094. The mean inbreeding coefficient for the pedigree population was 0.77%. There was, in most cases, an increase in the mean inbreeding coefficient, with the highest value at 2.89% during the last 5-year period (2000 to 2004). The mean average relatedness for the pedigree population was 1.1%. The effective population size in 2004 was 204. There was notable variation between average generation intervals for the four parental pathways. The longest average generation interval, at 8.73 years, was observed in the sire-son pathway. The average generation interval for the whole population was 6.53 years. Most genetically influential individuals were sires. The highest contributing founder was a sire with a 3.22% contribution, and the highest contributing founder dam made a contribution of 1.75%. The effective number of founders and the effective number of ancestors were 141 and 88, respectively. The study showed that genetic variation within the pedigree population has been decreasing over recent years. Increasing the number of AI bulls with a low individual coefficient of inbreeding could help to maintain a good level of genetic variation in the Brown Swiss population. PMID- 23462434 TI - Pulmonary complications of biological therapies in children and adults with rheumatic diseases. AB - The management of rheumatic conditions, including those occurring in children, has improved dramatically over the last decade following the introduction of biologic disease-modifying anti-rheumatic drugs (bDMARDS) into the therapeutic arsenal. The benefits have been realised in multiple aspects of disease including signs and symptoms, bone and cartilage destruction, disability and quality of life. Overall, bDMARDS have an acceptable safety profile in the short to medium term in adults and children, however, that following longer term use remains unclear. As these drugs target key signalling molecules and cells of the immune system, adverse events are not unanticipated. In this review we will discuss pulmonary complications of biologic therapies used in the management of rheumatic diseases in both children and adults. PMID- 23462435 TI - Early childhood caries and body mass index in young children from low income families. AB - The relationship between early childhood caries (ECC) and obesity is controversial. This cross-sectional survey investigated this association in children from low-income families in Goiania, Goias, Brazil and considered the role of several social determinants. A questionnaire examining the characteristics of the children and their families was administered to the primary caregiver during home visits. In addition, children (approximately 6 years of age) had their height, weight, and tooth condition assessed. The primary ECC outcome was categorized as one of the following: caries experience (decayed, missing, filled tooth: "dmft" index > 0), active ECC (decayed teeth > 0), or active severe ECC (decayed teeth >= 6). Descriptive, bivariate and logistic regression analyses were conducted. The participants in the current study consisted of 269 caregiver-child dyads, 88.5% of whom were included in the Family Health Program. Caregivers were mostly mothers (67.7%), were 35.3 +/- 10.0 years old on average and had 9.8 +/- 3.1 years of formal education. The mean family income was 2.3 +/- 1.5 times greater than the Brazilian minimum wage. On average, the children in the current study were 68.7 +/- 3.8 months old. Of these, 51.7% were boys, 23.4% were overweight or obese, 45.0% had active ECC, and 17.1% had severe ECC. The average body mass index (BMI) of the children was 15.9 +/- 2.2, and their dmft index was 2.5 +/- 3.2. BMI was not associated with any of the three categories of dental caries (p > 0.05). In contrast, higher family incomes were significantly associated with the lack of caries experience in children (OR 1.22, 95%CI 1.01-1.50), but the mother's level of education was not significantly associated with ECC. PMID- 23462436 TI - Water sources and their protection from the impact of microbial contamination in rural areas of Beijing, China. AB - Bacterial contamination of drinking water is a major public health problem in rural China. To explore bacterial contamination in rural areas of Beijing and identify possible causes of bacteria in drinking water samples, water samples were collected from wells in ten rural districts of Beijing, China. Total bacterial count, total coliforms and Escherichia coli in drinking water were then determined and water source and wellhead protection were investigated. The bacterial contamination in drinking water was serious in areas north of Beijing, with the total bacterial count, total coliforms and Escherichia coli in some water samples reaching 88,000 CFU/mL, 1,600 MPN/100 mL and 1,600 MPN/100 mL, respectively. Water source types, well depth, whether the well was adequately sealed and housed, and whether wellhead is above or below ground were the main factors influencing bacterial contamination levels in drinking water. The bacterial contamination was serious in the water of shallow wells and wells that were not closed, had no well housing or had a wellhead below ground level. The contamination sources around wells, including village dry toilets and livestock farms, were well correlated with bacterial contamination. Total bacterial counts were affected by proximity to sewage ditches and polluting industries, however, proximity to landfills did not influence the microbial indicators. PMID- 23462440 TI - Three-dimensional knee joint moments during performance of the bodyweight squat: effects of stance width and foot rotation. AB - The purpose of this investigation was to assess the effects of stance width and foot rotation angle on three-dimensional knee joint moments during bodyweight squat performance. Twenty-eight participants performed 8 repetitions in 4 conditions differing in stance or foot rotation positions. Knee joint moment waveforms were subjected to principal component analysis. Results indicated that increasing stance width resulted in a larger knee flexion moment magnitude, as well as larger and phase-shifted adduction moment waveforms. The knee's internal rotation moment magnitude was significantly reduced with external foot rotation only under the wide stance condition. Moreover, squat performance with a wide stance and externally rotated feet resulted in a flattening of the internal rotation moment waveform during the middle portion of the movement. However, it is speculated that the differences observed across conditions are not of clinical relevance for young, healthy participants. PMID- 23462443 TI - Effect of hopping frequency on bilateral differences in leg stiffness. AB - Understanding the degree of leg stiffness during human movement would provide important information that may be used for injury prevention. In the current study, we investigated bilateral differences in leg stiffness during one-legged hopping. Ten male participants performed one-legged hopping in place, matching metronome beats at 1.5, 2.2, and 3.0 Hz. Based on a spring-mass model, we calculated leg stiffness, which is defined as the ratio of maximal ground reaction force to maximum center of mass displacement at the middle of the stance phase, measured from vertical ground reaction force. In all hopping frequency settings, there was no significant difference in leg stiffness between legs. Although not statistically significant, asymmetry was the greatest at 1.5 Hz, followed by 2.2 and 3.0 Hz for all dependent variables. Furthermore, the number of subjects with an asymmetry greater than the 10% criterion was larger at 1.5 Hz than those at 2.2 and 3.0 Hz. These results will assist in the formulation of treatment-specific training regimes and rehabilitation programs for lower extremity injuries. PMID- 23462444 TI - Relationship between bilateral differences in single-leg jumps and asymmetry in isokinetic knee strength. AB - The aims of the study were to investigate the differences in kinematics and kinetics between the dominant and nondominant leg during single-leg jumps without arm swing, and to determine the relationship between bilateral asymmetry in isokinetic knee strength and the single-leg jump. Isokinetic knee strength and single-leg jump kinematics and kinetics were measured in 11 male participants. The bilateral asymmetry index was calculated for each parameter. For isokinetic knee strength, there were no significant differences between the dominant and nondominant legs. Significant correlations were observed for the bilateral asymmetry index for isokinetic knee strength at 180 degrees per second and the bilateral asymmetry indexes for maximum flexion angle and the mean knee joint torque during the single-leg jumps. In conclusion, the findings of the current study suggest an association between knee strength imbalances and the joint angle, as well as the torque produced in single-leg jumps, although no relationship between knee strength and jump height was observed. PMID- 23462448 TI - Determination of gait events using an externally mounted shank accelerometer. AB - Biomechanical analysis requires the determination of specific foot contact events. This is typically achieved using force platform information; however, when force platforms are unavailable, alternative methods are necessary. A method was developed for the determination of gait events using an accelerometer mounted to the distal tibia, measuring axial accelerations. The aim of the investigation was to determine the efficacy of this method. Sixteen participants ran at 4.0 m/s +/- 5%. Synchronized tibial accelerations and vertical ground reaction forces were sampled at 1000 Hz as participants struck a force platform with their dominant foot. Events determined using the accelerometer, were compared with the corresponding events determined using the force platform. Mean errors of 1.68 and 5.46 ms for average and absolute errors were observed for heel strike and of 3.59 and 5.00 ms for toe-off. Mean and absolute errors of 5.18 and 11.47 ms were also found for the duration of the stance phase. Strong correlations (r = .96) were also observed between duration of stance obtained using the two different methods. The error values compare favorably to other alternative methods of predicting gait events. This suggests that shank-mounted accelerometers can be used to accurately and reliably detect gait events. PMID- 23462449 TI - A cellular automaton model of Schistosoma japonicum infection. AB - Due to the life cycle complexity of Schistosoma japonicum and the characteristics of schistosomias is immuno-epidemiology, it is very challenging to give a group of certain rules and thus describe the transmission dynamics of S. japonicum with modelling approaches. Most existing epidemiological models for schistosomias is based on differential equations only track average worm burden without taking into account the individual variations, thus bear limitations on individual infection status monitoring and interpretation. In this paper, an improved stochastic model based on cellular automaton (I-SjCA, briefly) has been introduced to describe the transmission dynamics of human schistosomiasis japonica in an endemic area in China. This model reflects the process of the pathogen invasion from exposure to worm development and worm death when the infection is cleared; it also incorporates seasonality of infection, and stochastic behaviour of each individual in the study field. We show that based on the data collected from the 706 study participants, the model-predicted prevalence and intensity of S. japonicum in the 2nd year of investigation is comparable with the observation. Furthermore, we illustrate the use of model for evaluating possible control strategies for schistosomiasis in context of simulated prevalence and individual infection probability. The simulation results suggest that chemotherapy should cover no less than 85% of the S. japonicum infected population to guarantee an effective drug control program, and the best time for annual chemotherapy with praziquantel is the beginning of spring in the endemic area. Our findings indicate that I-SjCA model based on the cellular automaton can effectively simulate the transmission process. It is anticipated that our cellular automaton transmission model can serve as a tool for understanding schistosomiasis transmission dynamics and thus be conductive to build an effective control program. PMID- 23462450 TI - Safety and efficacy studies on trivalent inactivated vaccines against infectious coryza. AB - The safety and efficacy of an inactivated oil-emulsion infectious coryza vaccine containing three Avibacterium paragallinarum isolates (one each of Page serovars A, B, and C) was evaluated. The safety of six batches of the vaccine was confirmed by testing with chickens vaccinated with a single large dose or vaccinated repeatedly with a normal dose. Efficacy tests were carried out on three batches of vaccine using both specific pathogen free (SPF) chickens and conventional chickens. In SPF chickens given a single vaccination at 42 days of age, the protection rate against all three serovars of Av. paragallinarum was at least 80% at 30 days post vaccination. The conventional chickens, which were immunized at 42 and 110 days of age, were challenged at 9 months post the second vaccination and the protection rate was at least 80% for all three serovars. The effect of storage on the vaccine was evaluated in SPF chickens using three batches of vaccine stored at 4-8 degrees C for 1 year. The protection rate against challenge from all three serovars (single vaccination at 42 days of age and challenge at 30 days post-vaccination) was at least 80%. PMID- 23462451 TI - The specific heat of the electron-doped La-1038 compound (Ca0.85La0.15)10(FeAs)10(Pt3As8). AB - The specific heat of polycrystalline (Ca0.85La0.15)10(FeAs)10(Pt3As8), an electron-doped iron-based superconductor (T(c)(onset) = 34.6 K) with Ca/La ions and Pt3As8 separating the FeAs layers, was measured between 0.4 and 48 K.This compound has been recently reported to represent an electron-doped variant of the non-superconducting 10-3-8 phase, featuring a superconducting transition in the range of that of the 10-4-8 phase. This family of compounds is unique among the iron pnictide superconductors discovered to date due to the second metal pnictide layer, Pt3As8, present in the structure competing with the familiar FeAs layer for the electron from the Ca/La. This superconductor is further unusual in that it has a rather low crystalline symmetry (triclinic) for such a high superconducting transition temperature. The specific heat gamma is found to be approximately 26 mJ/(Ca/La mol)K(2), comparable to 122 iron-based superconductors electron-doped on the Fe sites and a factor of two smaller than 122 compounds hole-doped on the cation site, e.g., Ba(1-x)K(x)Fe2As2. The present work also investigates the discontinuity in the specific heat at T(c), DeltaC, to compare with the global trend, established by Bud'ko, Ni and Canfield (BNC), of DeltaC/T(c) versus T(c) found for essentially all iron-based superconductors. The result is a value lower than the BNC trend by a factor of ten, consistent with a severely broadened superconducting transition. PMID- 23462452 TI - Serial enrichment of spermatogonial stem and progenitor cells (SSCs) in culture for derivation of long-term adult mouse SSC lines. AB - Spermatogonial stem and progenitor cells (SSCs) of the testis represent a classic example of adult mammalian stem cells and preserve fertility for nearly the lifetime of the animal. While the precise mechanisms that govern self-renewal and differentiation in vivo are challenging to study, various systems have been developed previously to propagate murine SSCs in vitro using a combination of specialized culture media and feeder cells(1-3). Most in vitro forays into the biology of SSCs have derived cell lines from neonates, possibly due to the difficulty in obtaining adult cell lines(4). However, the testis continues to mature up until ~5 weeks of age in most mouse strains. In the early post-natal period, dramatic changes occur in the architecture of the testis and in the biology of both somatic and spermatogenic cells, including alterations in expression levels of numerous stem cell-related genes. Therefore, neonatally derived SSC lines may not fully recapitulate the biology of adult SSCs that persist after the adult testis has reached a steady state. Several factors have hindered the production of adult SSC lines historically. First, the proportion of functional stem cells may decrease during adulthood, either due to intrinsic or extrinsic factors(5,6). Furthermore, as with other adult stem cells, it has been difficult to enrich SSCs sufficiently from total adult testicular cells without using a combination of immunoselection or other sorting strategies(7). Commonly employed strategies include the use of cryptorchid mice as a source of donor cells due to a higher ratio of stem cells to other cell types(8). Based on the hypothesis that removal of somatic cells from the initial culture disrupts interactions with the stem cell niche that are essential for SSC survival, we previously developed methods to derive adult lines that do not require immunoselection or cryptorchid donors but rather employ serial enrichment of SSCs in culture, referred to hereafter as SESC(2,3). The method described below entails a simple procedure for deriving adult SSC lines by dissociating adult donor seminiferous tubules, followed by plating of cells on feeders comprised of a testicular stromal cell line (JK1)(3). Through serial passaging, strongly adherent, contaminating non-germ cells are depleted from the culture with concomitant enrichment of SSCs. Cultures produced in this manner contain a mixture of spermatogonia at different stages of differentiation, which contain SSCs, based on long-term self renewal capability. The crux of the SESC method is that it enables SSCs to make the difficult transition from self-renewal in vivo to long-term self-renewal in vitro in a radically different microenvironment, produces long-term SSC lines, free of contaminating somatic cells, and thereby enables subsequent experimental manipulation of SSCs. PMID- 23462453 TI - CXCL12/CXCR4 axis promotes mesenchymal stem cell mobilization to burn wounds and contributes to wound repair. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) play a crucial role in tissue repair. Their role in thermal burn wound regeneration and the relevant mechanism, however, is rarely studied. METHODS: BM-MSCs from green fluorescent protein transgenic male mice were transfused to irradiated recipient female C57BL/6 mice. Twenty-one days later, the female mice were inflicted with burn wounds. The size of the burned area was measured by an in vivo fluorescence imaging system, and BM-MSC chemotaxis and epithelialization were estimated by fluorescence in situ hybridization and immunofluorescence technology. The expression of CXCL12 and CXCR4 in the wound margin was detected by enzyme-linked immunosorbent assay and immunohistochemistry. The importance of CXCL12/CXCR4 signaling in BM-MSC chemotaxis was further estimated by blocking CXCR4 in vivo and in vitro. RESULTS: In vivo imaging results showed that BM-MSCs migrated to the injured margins. Fluorescence in situ hybridization and immunofluorescence technology revealed that Y chromosome-positive cells derived from green fluorescent protein transgenic mice were detected to be colocalized with keratin protein. Enzyme-linked immunosorbent assay revealed increased levels of CXCL12 and CXCR4 protein in the wound sites of BM-MSC-treated chimeric mice after burn. Immunohistochemistry also disclosed that CXCL12 levels were elevated at postburn day 7 compared with day 0. Furthermore, pretreatment of the BM-MSCs with the CXCR4 antagonist AMD3100 significantly inhibited the mobilization of BM-MSCs in vitro and in vivo, which attenuated wound closure. CONCLUSION: BM-MSC migration to the burned margins promotes the epithelialization of the wound, and mobilization of BM-MSCs is mediated by CXCL12/CXCR4 signaling. PMID- 23462454 TI - Prognostic impact of atypical chemokine receptor expression in patients with gastric cancer. AB - BACKGROUND: Atypical chemokine receptors (ACRs), which serve as a decoy receptor to attract chemokines, including DARC, D6, and CCX-CKR, have an important role in inhibiting invasion and metastasis of cancer cells; however, their expression in gastric cancer has not been characterized. The purpose of this study was to determine the predictive value of ACRs for overall survival in gastric cancer. METHODS: We performed immunohistochemical analysis on formalin-fixed, paraffin embedded cancer tissue and used Western blot analysis on cell lines with an antibody against ACR protein. We investigated tumor material from total of 282 consecutive gastric specimens, composed of 101 normal gastric tissues, 181 peri carcinoma tissues (2 cm away from the carcinoma), and their relationships to clinicopathologic features and survival, using a tissue micro-array. RESULTS: We found the expression of ACRs to be lower in gastric cancer cell lines or tissues than in normal cell line, peri-carcinoma, or normal tissues, respectively (P < 0.05). In univariate analysis, the three proteins and their co-expression were significantly associated with higher overall survival. In multivariate analysis, each of these molecules was not favorable for overall survival; however, their co expression was an independently prognostic factor for overall survival (hazard ratio, 0.276; 95% confidence interval, 0.173-0.444; P < 0.001). CONCLUSIONS: These findings highlight the possibility that the multiple loss of ACRs may occur during the development of tumorigenesis, and their co-expression in gastric cancer may be predictive of favorable outcomes. PMID- 23462455 TI - The effects of hyperbaric oxygen application against cholestatic oxidative stress and hepatic damage after bile duct ligation in rats. AB - BACKGROUND: The aim of this study was to evaluate the preventive and therapeutic potential of hyperbaric oxygen therapy (HBO) on the liver tissue against bile duct ligation (BDL)-induced oxidative damage and fibrosis in rats. MATERIALS AND METHODS: We divided 32 adult male Sprague Dawley rats into four groups: sham, sham plus HBO, BDL, and BDL plus HBO; each group contained eight animals. We placed the sham plus HBO and BDL plus HBO groups in an experimental hyperbaric chamber in which we administered pure oxygen at 2.5 atmospheres absolute 100% oxygen for 90 min on 14 consecutive days. RESULTS: The application of BDL clearly increased the tissue malondialdehyde level, myeloperoxidase activity, and hydroxyproline content and decreased the antioxidant enzymes (superoxide dismutase and catalase activities) and glutathione level. Hyperbaric oxygen therapy treatment significantly decreased the elevated tissue malondialdehyde level, myeloperoxidase activity, and hydroxyproline content and increased the reduced superoxide dismutase and catalase activities and glutathione level in the tissues. The changes demonstrating the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells, and neutrophil infiltration into the widened portal areas were observed in BDL group. Treatment of BDL with HBO attenuated alterations in liver histology. Alpha smooth muscle actin, cytokeratin-positive ductular proliferation, and the activity of terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling in the BDL decreased with HBO treatment. CONCLUSIONS: The data indicate that HBO attenuates BDL-induced oxidative injury, hepatocytes damage, bile duct proliferation, and fibrosis. The hepatoprotective effect of HBO is associated with antioxidative potential. PMID- 23462456 TI - Gall bladder cancer and the role of dietary and lifestyle factors: a case-control study in a North Indian population. AB - Most patients with gall bladder cancer (GBC) present in the advanced stage with a poor response to therapy. Prevention or early detection is the best way to prevent death, but this requires identification of susceptible subgroups. Keeping this in mind, this study was carried out to evaluate the association between selected demographic, lifestyle, and dietary factors and GBC. A hospital-based case-control study was carried out at the All India Institute of Medical Sciences (New Delhi, India). Cases were defined as newly registered confirmed primary GBC patients. Controls were defined as healthy relatives of patients other than that of GBC. Data were collected from February 2008 to October 2009 using a semistructured interview schedule from both cases and controls. Analysis was carried out using SPSS version 15 and Epi-Info version 6. Factors found to be significant in the bivariate analysis were entered in a multivariate logistic regression analysis. A total of 122 cases and 122 controls were included in the study. There was no significant difference in age (P=0.06) and sex (P=0.66) between the cases and the controls. In the bivariate analysis, factors found to be significantly associated with GBC were illiteracy [odds ratio (OR) 8.00, P=0.000], lower socioeconomic status (OR 2.45, P=0.000), parity more than 3 (OR 9.06, P=0.000), age at first pregnancy less than 20 years (OR 2.03, P=0.018), and the use of nonliquefied petroleum gas cooking fuel (OR 4.17, P=0.000). Higher vitamin C intake had a protective effect (OR 0.33, P=0.004). In the multivariate analysis, education, intake of vitamin C, parity, and type of fuel used were significant factors. The risk factors for GBC that have been identified in the present study delineate a high-risk population group that can be targeted for preventive measures including improvement in socioeconomic status, education and lifestyle, and dietary intervention, and avoidance of the use of nonliquefied petroleum gas as cooking fuel. PMID- 23462457 TI - Evaluation of the frequency of and survival from second primary cancers in North Portugal: a population-based study. AB - A marked increase in cancer survival and in the frequency of second primary cancers (SPCs) has been observed in the latest decades, propelling the investigation of their burden at a population level. We aimed to quantify the proportion of SPCs among the incident cases in North Portugal and to describe their survival. We identified all SPCs (excluding skin nonmelanoma) registered by the North Region Cancer Registry (RORENO) from 2000 to 2003 according to the International Association of Cancer Registries and the International Agency for Research on Cancer guidelines. We classified tumors diagnosed more than 2 months after a first primary cancer (FPC) as metachronous. The observed survival was computed using vital status in December 2010. A total of 1607 SPCs (3.8% of all cancers) were registered (77.9% metachronous). The most frequent metachronous SPC topographies and the corresponding most frequent FPCs were of the colon (12.2%; FPC: prostate, breast, and stomach), lung (10.5%; FPC: bladder, stomach, and colon), and stomach (9.7%; FPC: prostate, breast, and bladder). The overall 5 year survival of individuals with metachronous SPCs was 47.4%; within the subgroups with higher (63.1%) and lower survival (31.1%), there were no significant differences across groups of FPCs with expectably different survival. The proportion of SPCs was that anticipated for a registry with approximately one decade of activity. The most common cancers in the general population were also frequent metachronous SPCs, whereas the most frequent FPCs were high incidence and survival cancers. The survival of metachronous SPCs did not vary with the survival expected for the FPCs. PMID- 23462458 TI - Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer. AB - Recent diagnostic procedure advances have considerably improved early lung cancer detection. However, the invasive, unpleasant, and inconvenient nature of current diagnostic procedures limits their application. There is a great need for novel noninvasive biomarkers for early lung cancer diagnosis. In the present study, we aimed to determine whether microRNA (miRNA) blood signatures are suitable for early detection of lung cancer. Using quantitative reverse transcriptase PCR analysis, we first selected and identified three aberrant plasma expression miRNAs (miR-21, miR-145, and miR-155) in a training set of 62 patients and 60 healthy smokers to define a panel that had high diagnostic efficiency for lung cancer. Then, we validated the detective ability of this miRNA panel in a testing set of 34 malignant tumor patients, 30 patients with benign pulmonary nodules and 32 healthy smokers. In the training set, miR-21 and miR-155 showed higher plasma expression levels, whereas miR-145 showed a lower expression level in patients with malignant cancer, compared with healthy controls (P <= 0.001). The three miRNAs used in combination produced the area under receiver operating characteristic curve at 0.847, which helped distinguish lung cancer from healthy smokers with 69.4% sensitivity and 78.3% specificity. A logistic regression model with the best prediction was constructed on the basis of miR-21, miR-145, and miR 155. Validation of the miRNA panel in the testing set confirmed their diagnostic value, which yields a significant improvement over any single one. Plasma miR-21, miR-145, and miR-155 have strong potential as novel noninvasive biomarkers for early detection of lung cancer. PMID- 23462459 TI - Excess body weight and increased Breslow thickness in melanoma patients: a retrospective study. AB - Excess body weight has been shown to increase the risk for development of several common cancers, such as postmenopausal breast, colon, endometrium, kidney, and esophagus cancers. The main aim of the present study was to investigate the potential relationship between excess body weight, assessed in terms of BMI, and Breslow thickness in 605 patients affected by primary cutaneous melanoma. Particularly, we evaluated the occurrence of thick melanoma (>1 mm) in overweight compared with nonoverweight patients. The effect of BMI (>=25 vs. <25 kg/m2) on the risk of having a diagnosis of thick melanoma was estimated in terms of odds ratio (OR) by logistic regression analysis, adjusted for age, sex, and histological type. Significant differences in overweight versus nonoverweight patients were found with respect to sex distribution. In fact, the occurrence of thick melanoma was greater in overweight women than in nonoverweight women (OR=1.64). When the analysis was restricted to postmenopausal women, the corresponding OR increased further to 2.50. In conclusion, a positive association between excess body weight and the risk of thick melanoma was found only in female patients. On stratifying patients into subgroups, the relationship between the risk of being diagnosed with a thick melanoma (>1.0 mm) and overweight status (BMI>=25 kg/m2) was significantly affected by both sex and menopausal status. Despite limitations because of both the study design and the relatively small numbers of patients in certain subgroups, overweight status may be associated with an increased Breslow thickness in postmenopausal women. PMID- 23462460 TI - Current evidence on the relationship between three polymorphisms in the CYP1A2 gene and the risk of cancer. AB - CYP1A2 is an important cytochrome P450 enzyme that is involved in the metabolism of many clinical drugs and activation of some precarcinogens. Functional CYP1A2 polymorphisms are considered to exert significant effects on the risk of cancer, but the conclusions are inconsistent. Three commonly studied CYP1A2 polymorphisms, namely rs762551 (A>C), rs2069514 (G>A), and rs3569413 (T>delT), were selected to explore their association with the risk of development of cancer by meta-analysis of published case-control studies. Two investigators independently searched the PubMed, Embase, China National Knowledge Infrastructure, and the Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP1A2 polymorphisms and the risk of cancer were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. For rs762551, 37 studies were eligible (16 825 cases and 21 513 controls); for rs2069514, 15 studies were eligible (3677 cases and 5127 controls); and for rs3569413, eight studies were eligible (1607 cases and 2043 controls). The results showed that no significant associations with the risk of cancer were found in any model (allele contrast, codominant, dominant, or recessive model) in terms of rs2069514 and rs3569413 when all studies were pooled into a meta analysis. However, when stratified by cancer type, a statistically significantly elevated risk of cancer was only found in lung cancer for rs3569413 (delT-allele vs. T-allele: OR=1.50, 95% CI=1.16-1.95). In the subgroup analysis by ethnicity, a significantly increased risk of cancer was found in the Caucasian population for rs3569413 (delT-allele vs. T-allele: OR=1.63, 95% CI=1.01-2.63). With respect to rs762551, we found that carriers of the C-allele showed an increased overall risk of developing cancer compared with A-allele carriers (C-allele vs. A-allele: OR=1.08, 95% CI=1.01-1.16). Further subgroup analyses showed that the rs762551 polymorphism was associated with an increased risk of cancer in the subgroup of Caucasians (C-allele vs. A-allele: OR=1.14, 95% CI=1.00-1.28; dominant model: OR=1.19, 95% CI=1.02-1.37). These results suggest that the rs3569413 polymorphism of the CYP1A2 gene is associated with an increased risk of lung cancer and the rs762551 polymorphism of the CYP1A2 gene might be a potential biomarker for the risk of cancer among Caucasians. Further large and well-designed studies are required to confirm this conclusion. PMID- 23462461 TI - Dietary restriction in C. elegans: recent advances. AB - The nematode Caenorhabditis elegans continues to serve as a useful model of life extension caused by dietary restriction. Using this model, downstream effectors of dietary restriction-induced longevity have been elucidated, including neuropeptides and cell-surface receptors. Although it remains possible that different forms of dietary restriction may utilize both specific and overlapping mechanisms to promote longevity, the nematode model has revealed roles for autophagy, metabolic energy-sensing and the hypoxic response. The nematode has also been used to identify specific tissues required for life extension via DR, including coelomocytes, intestine, and neurons. PMID- 23462463 TI - Patient reporting of clinical incidents. PMID- 23462462 TI - Staged repair for aortic arch reconstruction and intracardiac repair following bilateral pulmonary artery banding in 3 critical patients. AB - Bilateral pulmonary artery banding has been performed as a first palliation for hypoplastic left heart syndrome with a poor preoperative condition. We report 3 patients with aortic arch reconstruction and intracardiac repair following bilateral pulmonary artery banding in moribund patients after birth. Our patients successfully received arch reconstruction, pulmonary debanding and patch closure of the ventricular septal defect at the age of 2 or 3 months after birth with a body weight of 3.5 and 4.5 kg, respectively. No postoperative neurological deficits were observed, and postoperative morbidity was significantly reduced. More than 75% of cerebral oxygenation may provide higher urinary output due to higher renal blood flow through collateral circulation. This technique reduces the risk of perioperative neurological damage. PMID- 23462464 TI - Primary primitive neuroectodermal tumour of the kidney in adults. AB - Primitive neuroectodermal tumour (PNET) is a neural crest tumour derived from neuroectoderm. Renal PNET is a very rare tumour occurring during childhood or adolescence. We report two cases of PNET involving kidney in adults. Presenting signs and symptoms include abdominal/flank pain and/or haematuria. Microscopy reveals the tumour consisted of small round cells with round nuclei and scant cytoplasm. Diagnosis was confirmed by immunohistochemistry with diffuse membranous positivity of tumour cells with CD99. As these tumours have an aggressive clinical course with rapid death in many reported cases, it is important to differentiate them from other small round-cell tumours. PMID- 23462465 TI - First report of colistin-resistant KPC-2 producing ST258-Klebsiella pneumoniae in Spain. PMID- 23462466 TI - [Notifiable infectious diseases: knowledge and notification among hospital physicians]. AB - INTRODUCTION: Notifiable infectious diseases represent a public health hazard, which is why they are under surveillance and must be reported. We tried to assess hospital physicians' knowledge of hospital physicians on notifiable infectious diseases and their self-reported attitudes to notification. METHODS: An observational study was conducted using a questionnaire with 11 multiple choice questions, two yes/no questions and one short-answer question. It was distributed to all senior doctors and residents in 19 medical and surgical departments. RESULTS: A total of 248 questionnaires were sent out, with a response rate of 79.84%. More than three-quarters (76.3%) of the respondents were senior doctors. As regards specific knowledge about whether a particular disease is a notifiable disease, 29.5% identified correctly 100% of the named diseases, 3.2% could not identify any of them. All urgent named notifiable infectious diseases were correctly identified by 25.3% of physicians. Statistically significant differences were found in the knowledge of notifiable diseases knowledge in medical and surgical departments, as well as for senior doctors (P=.047) and residents (P=.035). A high percentage of medical services (40%) and surgical (70%) department reported never failing to notify. When asked about the causes of under-reporting, 72% did not know whether notification was mandatory or not, and 88% did not know what diseases must be notified. CONCLUSIONS: Although many respondents are aware that diseases notification is part of their daily activity, many of them admit under-reporting. There is insufficient knowledge about what diseases are considered notifiable infectious diseases and how to notify them. PMID- 23462467 TI - Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells. AB - Intercellular communication depends on the correct organization of the signal transduction complexes. In many signalling pathways, the mechanisms controlling the overall cell polarity also localize components of these pathways to different domains of the plasma membrane. In the Drosophila ectoderm, the JAK/STAT pathway components are highly polarized with apical localization of the receptor, the associated kinase and the STAT92E protein itself. The apical localization of STAT92E is independent of the receptor complex and is due to its direct association with the apical determining protein Bazooka (Baz). Here, we find that Baz-STAT92E interaction depends on the presence of the Drosophila Src kinases. In the absence of Src, STAT92E cannot bind to Baz in cells or in whole embryos, and this correlates with an impairment of JAK/STAT signalling function. We believe that the requirement of Src proteins for STAT92E apical localization is mediated through Baz, as we can co-precipitate Src with Baz but not with STAT92E. This is the first time that a functional link between cell polarity, the JAK/STAT signalling pathway and the Src kinases has been established in a whole organism. PMID- 23462468 TI - Coronary veins determine the pattern of sympathetic innervation in the developing heart. AB - Anatomical congruence of peripheral nerves and blood vessels is well recognized in a variety of tissues. Their physical proximity and similar branching patterns suggest that the development of these networks might be a coordinated process. Here we show that large diameter coronary veins serve as an intermediate template for distal sympathetic axon extension in the subepicardial layer of the dorsal ventricular wall of the developing mouse heart. Vascular smooth muscle cells (VSMCs) associate with large diameter veins during angiogenesis. In vivo and in vitro experiments demonstrate that these cells mediate extension of sympathetic axons via nerve growth factor (NGF). This association enables topological targeting of axons to final targets such as large diameter coronary arteries in the deeper myocardial layer. As axons extend along veins, arterial VSMCs begin to secrete NGF, which allows axons to reach target cells. We propose a sequential mechanism in which initial axon extension in the subepicardium is governed by transient NGF expression by VSMCs as they are recruited to coronary veins; subsequently, VSMCs in the myocardium begin to express NGF as they are recruited by remodeling arteries, attracting axons toward their final targets. The proposed mechanism underlies a distinct, stereotypical pattern of autonomic innervation that is adapted to the complex tissue structure and physiology of the heart. PMID- 23462469 TI - A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development. AB - Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor Flt4. When expressed in endothelial cells, vegfc(um18) could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis. PMID- 23462470 TI - Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. AB - Progesterone-RankL paracrine signaling has been proposed as a driver of stem cell expansion in the mammary gland, and Elf5 is essential for the differentiation of mammary epithelial progenitor cells. We demonstrate that Elf5 expression is induced by progesterone and that Elf5 and progesterone cooperate to promote alveolar development. The progesterone receptor and Elf5 are expressed in a mutually exclusive pattern, and we identify RankL as the paracrine mediator of the effects of progesterone on Elf5 expression in CD61+ progenitor cells and their consequent differentiation. Blockade of RankL action prevented progesterone induced side branching and the expansion of Elf5(+) mature luminal cells. These findings describe a mechanism by which steroid hormones can produce the expansion of steroid hormone receptor-negative mammary epithelial cells. PMID- 23462471 TI - Modular development of the teleost trunk along the dorsoventral axis and zic1/zic4 as selector genes in the dorsal module. AB - Teleost fish exhibit remarkable diversity in morphology, such as fins and coloration, particularly on the dorsal side. These structures are evolutionary adaptive because their back is highly visible to other individuals. However, owing to the late phenotypic appearance (from larva to adult) and lack of appropriate mutants, the genetic mechanisms that regulate these dorsoventrally asymmetric external patterns are largely unknown. To address this, we have analyzed the spontaneous medaka mutant Double anal fin (Da), which exhibits a mirror-image duplication of the ventral half across the lateral midline from larva to adult. Da is an enhancer mutant for zic1 and zic4 in which their expression in dorsal somites is lost. We show that the dorsoventral polarity in Da somites is lost and then demonstrate using transplantation techniques that somites and their derived tissues globally determine the multiple dorsal-specific characteristics of the body (fin morphology and pigmentation) from embryo to adult. Intriguingly, the zic1/zic4 expression in the wild type persists throughout life in the dorsal parts of somite derivatives, i.e. the myotome, dermis and vertebrae, forming a broad dorsal domain in the trunk. Comparative analysis further implies a central role for zic1/zic4 in morphological diversification of the teleost body. Taken together, we propose that the teleost trunk consists of dorsal/ventral developmental modules and that zic1/zic4 in somites function as selector genes in the dorsal module to regulate multiple dorsal morphologies. PMID- 23462472 TI - Notch signaling coordinates cellular proliferation with differentiation during zebrafish fin regeneration. AB - Zebrafish can completely regenerate amputated fins via formation of a blastema, a proliferative mass of undifferentiated precursor cells. During regenerative growth, blastema proliferation must be tightly coordinated with cellular differentiation, but little is known about how this is achieved. Here, we show that Notch signaling is essential for maintenance of blastema cells in a proliferative undifferentiated state. We found that the Notch pathway is activated in response to fin amputation in the highly proliferative region of the blastema. Chemical interference with Notch signaling resulted in a complete block of regeneration. Notch signaling was not required for the earliest known cellular processes during blastema formation, i.e. dedifferentiation and migration of osteoblasts, but specifically interfered with proliferation of blastema cells. Interestingly, overactivation of the pathway via misexpression of the intracellular domain of the Notch receptor (NICD) likewise inhibited regenerative outgrowth. In NICD-overexpressing fins, overall blastemal cell proliferation was not enhanced, but expanded into proximal regions where cellular differentiation normally occurs. Similarly, blastemal and epidermal gene expression territories invaded proximal regions upon sustained Notch activation. Concomitantly, NICD overexpression suppressed differentiation of osteoblasts and caused an expansion of the undifferentiated blastema. Together, these data suggest that Notch signaling activity maintains blastemal cells in a proliferative state and thus coordinates proliferation with differentiation during regenerative growth. PMID- 23462473 TI - Temporal control of BMP signalling determines neuronal subtype identity in the dorsal neural tube. AB - The conventional explanation for how a morphogen patterns a tissue holds that cells interpret different concentrations of an extrinsic ligand by producing corresponding levels of intracellular signalling activity, which in turn regulate differential gene expression. However, this view has been challenged, raising the possibility that distinct mechanisms are used to interpret different morphogens. Here, we investigate graded BMP signalling in the vertebrate neural tube. We show that defined exposure times to Bmp4 generate distinct levels of signalling and induce specific dorsal identities. Moreover, we provide evidence that a dynamic gradient of BMP activity confers progressively more dorsal neural identities in vivo. These results highlight a strategy for morphogen interpretation in which the tight temporal control of signalling is important for the spatial pattern of cellular differentiation. PMID- 23462474 TI - SOX2 maintains the quiescent progenitor cell state of postnatal retinal Muller glia. AB - Within discrete regions of the developing mammalian central nervous system, small subsets of glia become specialized to function as neural stem cells. As a result of their self-renewal and neurogenic capacity, these cells later serve to replenish neurons and glia during persistent or injury-induced adult neurogenesis. SOX2, an HMG box transcription factor, plays an essential role in the maintenance of both embryonic and adult neural progenitors. It is unclear, however, which biological mechanisms regulated by SOX2 are required for neural stem cell maintenance. In this study, we address this question through genetic analysis of SOX2 function in differentiating postnatal Muller glia, a cell type that maintains neurogenic capacity in the adult retina. By utilizing molecular analysis and real-time imaging, we show that two progenitor characteristics of nascent Muller glia - their radial morphology and cell cycle quiescence - are disrupted following conditional genetic ablation of Sox2 in the mouse postnatal retina, leading to Muller cell depletion and retinal degeneration. Moreover, we demonstrate that genetic induction of the Notch signaling pathway restores Muller glial cell identity to Sox2 mutant cells, but does not secure their quiescent state. Collectively, these results uncouple the roles of SOX2 and the Notch signaling pathway in the postnatal retina, and uncover a novel role for SOX2 in preventing the depletion of postnatal Muller glia through terminal cell division. PMID- 23462475 TI - Jun N-terminal kinase maintains tissue integrity during cell rearrangement in the gut. AB - Tissue elongation is a fundamental morphogenetic process that generates the proper anatomical topology of the body plan and vital organs. In many elongating embryonic structures, tissue lengthening is driven by Rho family GTPase-mediated cell rearrangement. During this dynamic process, the mechanisms that modulate intercellular adhesion to allow individual cells to change position without compromising structural integrity are not well understood. In vertebrates, Jun N terminal kinase (JNK) is also required for tissue elongation, but the precise cellular role of JNK in this context has remained elusive. Here, we show that JNK activity is indispensable for the rearrangement of endoderm cells that underlies the elongation of the Xenopus gut tube. Whereas Rho kinase is necessary to induce cell intercalation and remodel adhesive contacts, we have found that JNK is required to maintain cell-cell adhesion and establish parallel microtubule arrays; without JNK activity, the reorganizing endoderm dissociates. Depleting polymerized microtubules phenocopies this effect of JNK inhibition on endoderm morphogenesis, consistent with a model in which JNK regulates microtubule architecture to preserve adhesive contacts between rearranging gut cells. Thus, in contrast to Rho kinase, which generates actomyosin-based tension and cell movement, JNK signaling is required to establish microtubule stability and maintain tissue cohesion; both factors are required to achieve proper cell rearrangement and gut extension. This model of gut elongation has implications not only for the etiology of digestive tract defects, but sheds new light on the means by which intra- and intercellular forces are balanced to promote topological change, while preserving structural integrity, in numerous morphogenetic contexts. PMID- 23462476 TI - Sox2 marks epithelial competence to generate teeth in mammals and reptiles. AB - Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of successional tooth formation: tooth replacement and serial addition of primary teeth. We observed specific Sox2 expression in the dental lamina that gives rise to successional teeth in mammals with one round of tooth replacement as well as in reptiles with continuous tooth replacement. Sox2 was also expressed in the dental lamina during serial addition of mammalian molars, and genetic lineage tracing indicated that Sox2(+) cells of the first molar give rise to the epithelial cell lineages of the second and third molars. Moreover, conditional deletion of Sox2 resulted in hyperplastic epithelium in the forming posterior molars. Our results indicate that the Sox2(+) dental epithelium has competence for successional tooth formation and that Sox2 regulates the progenitor state of dental epithelial cells. The findings imply that the function of Sox2 has been conserved during evolution and that tooth replacement and serial addition of primary teeth represent variations of the same developmental process. The expression patterns of Sox2 support the hypothesis that dormant capacity for continuous tooth renewal exists in mammals. PMID- 23462477 TI - Increasing physical activity in young primary school children--it's child's play: a cluster randomised controlled trial. AB - OBJECTIVE: To explore the effects of an innovative school-based intervention for increasing physical activity. METHODS: 226 children (5-7 years old) randomly selected from 12 Australian primary schools were recruited to a cluster randomised trial with schools randomly allocated to intervention or control conditions. The 13-week intervention comprised: (1) altering the school playground by introducing loose materials and (2) a teacher-parent intervention exploring perceptions of risk associated with children's free play. The primary outcomes were total accelerometer counts and moderate-vigorous physical activity during break times. Testing took place in Sydney, 2009-2010. RESULTS: 221 participants were tested at baseline. Mixed-effect multilevel regression revealed a small but significant increase from the intervention on total counts (9400 counts, 95% CI 3.5-15.2, p=0.002) and minutes of MVPA (1.8 min, 95% CI 0.5-3.1, p=0.006); and a decrease in sedentary activity (2.1 min, 95% CI 0.5-3.8, p=0.01) during break times. We retested children in one intervention school after 2 years; they maintained the gains. CONCLUSIONS: Capturing children's intrinsic motivations to play while simultaneously helping adults reconsider views of free play as risky provided increases in physical activity during break times. Using accelerometry as the sole measure of physical activity may underestimate the effect. TRIAL REGISTRATION: ACTRN12611000089932. PMID- 23462478 TI - Access to medical care: how do women in Canada and the United States compare? AB - OBJECTIVES: The purpose of this study is to determine if access to medical care and utilization of cancer screenings differs between women in the United States and Canada. This study examined this question by comparing women in Canada to women in the United States who have insurance coverage and those who do not. METHOD: This study used data from the 2002/03 Joint Canada United States Survey of Health and examined access to medical care and cancer screenings. A binary probit model was used to address several measures of access to medical care and cancer screening utilization. RESULTS: This study finds five significant differences between insured American and Canadian women. Canadian women are better off in terms of ever having a mammogram, having a regular doctor, and having access to needed medicine, but fare worse in terms of having had a recent mammogram and having perceived unmet healthcare needs. With the exception of having recent mammograms, there is no statistical difference between uninsured and insured American women. CONCLUSION: Although this study does not show that one group is strictly better off, it does show that there are significant differences between the two groups of women. PMID- 23462479 TI - Parenting quality and television viewing among 10 year old children. AB - OBJECTIVE: This study aims to examine the associations between parenting quality and children's screen-time. METHODS: Data from the US National Institute Study of Early Child Care and Youth Development, collected in 2001, were analysed. Videotaped interaction tasks of 874 mother-child dyads were rated for ten parenting qualities (i.e., agency, persistence, negativity, affection, felt security, affective mutuality, autonomy granting, stimulation of cognitive development, quality of assistance & hostility). Children (aged 10-11yrs) self reported television viewing on weekdays and weekends. Associations between parenting quality and television viewing were examined using logistic regression. RESULTS: Greater felt security was associated with lower odds of watching >2h of television on weekdays among boys (p=0.05). High agency was associated with greater odds of watching >2h of television per day on weekdays among girls (p=0.02). High supportive presence and quality of child assistance were associated with lower odds of watching >2h of television on Saturdays (p=0.05) among girls. CONCLUSION: Child agency (i.e., self-direction and confidence) was associated with greater television viewing whereas parenting characterised by perceived security, support and structured yet flexible guidance was associated with lower television viewing. Parent-child interactions and communication may be an appropriate target for sedentary behaviour interventions. PMID- 23462480 TI - Smoking prevalence in Italy 2011 and 2012, with a focus on hand-rolled cigarettes. AB - OBJECTIVE: To provide updated information on smoking prevalence in Italy, with a focus on type of tobacco product, including hand-rolled (HR) cigarettes. METHOD: Two nationally representative surveys were conducted in 2011 and 2012 in Italy on a total sample of 6167 adults. Information on type of tobacco most frequently smoked was collected. RESULTS: Current smokers were 21.7% (22.7% in 2011 and 20.8% in 2012) overall, 25.3% among men and 18.4% among women. Among smokers, 94.6% most frequently consumed manufactured cigarettes, 4.6% HR cigarettes, 0.5% cigars, 0.2% cigarillos, and 0.2% pipe and none smokeless tobacco. HR cigarette use was more frequent in men (6.9%) than in women (1.7%), in 2012 (5.9%) than in 2011 (3.4%), and among the young (15-24 years; 9.1%). The average estimated price of one HR cigarette was 0.09? and that of a manufactured cigarette was 0.18?. CONCLUSION: In 2012 we observed the lowest reported overall smoking prevalence in Italy, though change since 2008 has been limited. The proportion of HR cigarettes on total tobacco trade has appreciably increased, particularly among young male smokers, who appear to switch to affordable cigarettes in a period of economic crisis. Fiscal policies aiming to equalise the cost of different cigarette types are needed in Italy. PMID- 23462481 TI - Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations. AB - Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2, EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson's disease (PD) or parkinsonism. Changes in a long list of additional genes have been suggested as causes for parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1), frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11, UCHL1). This review summarizes the clinical features of diseases caused by mutations in these genes, and their frequencies. Point mutations and multiplications in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early onset parkinsonism with a low risk for cognitive decline and a pathological process usually restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity of several mutations remains unconfirmed. Although some mutations occur with high frequency in specific populations, worldwide all are very rare. The genetic cause of the majority of patients with sporadic or hereditary PD remains unknown in most populations. Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted individually based on clinical phenotype and estimated frequency of the mutation in the patient's population. PMID- 23462482 TI - Age-, gender-, and socioeconomic status-specific incidence of Parkinson's disease and parkinsonism in northeast Scotland: the PINE study. AB - There have been few high quality incidence studies of Parkinson's disease (PD). We measured age-, gender- and socioeconomic-specific incidence rates for parkinsonism and PD in north-east Scotland, and compared our results with those of previous high quality studies. Incident patients were identified prospectively over three years by several overlapping methods from primary care practices (total population 311,357). Parkinsonism was diagnosed if patients had two or more cardinal motor signs. Drug-induced parkinsonism was excluded. Patients had yearly follow-up to improve diagnostic accuracy. Incidence rates using clinical diagnosis at latest follow-up were calculated for all parkinsonism and for PD by age, gender and socioeconomic status. Meta-analysis with similar studies was performed. Of 377 patients identified at baseline with possible or probable parkinsonism, 363 were confirmed as incident patients after median follow-up of 26 months (mean age 74.8 years, SD 9.8; 61% men). The crude annual incidence of parkinsonism was 28.7 per 100,000 (95% confidence interval (CI) 25.7-31.8) and PD 17.9 per 100,000 (95% CI 15.5-20.4). PD was more common in men (age-adjusted male to female ratio 1.87:1, 95% CI 1.55-2.23) but there was no difference by socioeconomic status. Meta-analysis of 12 studies showed an incidence of PD (adjusted to the 1990 Scottish population) of 14.6 per 100,000 (95% CI 12.2-17.3) with considerable heterogeneity (I(2) 95%), partially explained by population size and recruitment duration. The incidence of PD was similar to other high quality studies. The incidence of PD was not affected by socioeconomic status. PMID- 23462484 TI - Nociceptive brain activation in patients with neuropathic pain related to Parkinson's disease. AB - BACKGROUND: Patients suffering from Parkinson's disease (PD) frequently experience painful sensations that may be due to central modification of nociception in PD. We compared pain thresholds and cerebral activity in nociceptive areas using Positron Emission Tomography (PET) during nociceptive stimulation before (OFF condition) and after (ON condition) levodopa challenge between nine PD patients with and nine PD patients without neuropathic pain. METHODS: Pain thresholds were determined using a cold pressor test in the two conditions. We used H2(15)O PET to study the regional cerebral blood flow changes in subjects while they received alternate randomized noxious and innocuous cold stimuli during OFF and ON periods. RESULTS: Pain thresholds were not significantly different between PD patients with and without pain in either condition (OFF and ON). In both groups of PD patients, levodopa significantly raised pain threshold (F1,16 = 26.71; p < 0.0001) with a mean variation of -2.7 (+/-2.3 degrees C). In the OFF condition, PD patients with pain had a lower pain activation in the right prefrontal cortex and posterior insula and a higher pain activation in the right anterior cingulate cortex (BA32/8) than pain-free patients. Levodopa significantly reduced pain-induced-activation in the right insula and in the anterior cingulate cortex in both groups. CONCLUSION: Levodopa decreased nociceptive perception in both PD patients with and without pain. In PD patients with neuropathic pain the medial affective pathway was preferentially recruited whereas pain-free PD patients exhibited a greater activation in lateral discriminative nociceptive areas. PMID- 23462483 TI - Diabetes is associated with postural instability and gait difficulty in Parkinson disease. AB - BACKGROUND: Comorbid diabetes may be associated with more severe motor impairment in Parkinson disease. In normal elderly individuals, diabetes is associated with parkinsonian features, including gait difficulty and rigidity, though not tremor. Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown. METHODS: We performed a case-control study (n = 39) involving 13 Parkinson disease subjects (age 66.4yrs +/- 5.5; duration of disease 6.9yrs +/- 4.4) with diabetes and 26 age, gender, and duration-of disease-matched Parkinson disease controls without diabetes. All subjects underwent [(11)C]dihydrotetrabenazine vesicular monoamine transporter type-2 positron emission tomography imaging to assess striatal dihydrotetrabenazine distribution volume ratio and Unified Parkinson disease rating scale motor examination to determine rigidity, bradykinesia, tremor, and postural instability and gait difficulty subscores. Magnetic resonance imaging scans were analyzed to assess leukoaraiosis burden. RESULTS: After controlling for nigrostriatal dopaminergic denervation, Parkinson disease subjects with diabetes displayed greater postural instability and gait difficulty subscores (t = 3.81, p = 0.0005). There were no differences in bradykinesia, rigidity, or tremor subscores between cases and controls. The association between diabetes and postural instability and gait difficulty persisted after controlling for comorbid hypertension and body mass index. Leukoaraiosis, distal vibratory sense, and levodopa dose equivalents did not differ significantly between cases and controls. CONCLUSIONS: Diabetes may contribute to postural instability and gait difficulty in Parkinson disease through mechanisms other than nigrostriatal dopaminergic denervation. PMID- 23462485 TI - Does the addition of Vocera hands-free communication device improve interruptions in an academic emergency department? AB - OBJECTIVE: Emergency department (ED) interruptions occur frequently. Recently, a hands-free communication device (HCD; Vocera) was added to the population of communications devices (a cellular telephone and a pager) in our ED. The research purpose was to determine whether this addition improved interruption times and our hypothesis was the device would decrease length of interruptions. METHODS: This was a prospective cohort study of interruptions in an academic ED level 1 trauma center before and after introduction of an HCD. Interruptions were defined a priori and based on previous literature. We studied a convenience sampling of shifts. Length of interruption time was recorded. Three investigators collected interruption data, including nine different ED attendings. RESULTS: Of 511 interruptions, there were no significant differences in types of interruptions pre- versus post-HCD. Before HCD use, we collected 40 hours of data with 65 interruptions (mean 1.6/hour). Post-HCD, 180 hours of data were collected with 446 interruptions (mean 2.5/hour). There was a significant difference in length of time of interruptions, with an average of 9 minutes pre-HCD versus 4 minutes post-HCD (P = 0.012 diff 4.9; 95% confidence interval 1.8-8.1). HCD calls were significantly shorter than non-HCD calls (1 vs 5 minutes; P < 0.001). Comparing data collectors for type of interruption during the same 4-hour shift resulted in kappa = 0.73. CONCLUSIONS: The addition of Vocera HCD may improve interruptions by shortening call length. PMID- 23462486 TI - Medical care of pregnant women in eastern North Carolina with human immunodeficiency virus. AB - OBJECTIVES: To assess the time lag between the diagnosis of human immunodeficiency virus (HIV) and the initiation of antiretroviral therapy (ART) in pregnant women. METHODS: A retrospective chart review of 105 deliveries from HIV-positive women from January 2001 to June 2009 was undertaken. RESULTS: One hundred five HIV-infected pregnant women were identified and studied. Forty-eight women were diagnosed during the prenatal visit: 21 in the first trimester, 17 in the second trimester, and 10 in the third trimester. Forty-five had undetectable viral loads at delivery. The time lag between diagnosis of HIV and initiation of ART was 1 month for 31% and 3 months for 28.5%. CONCLUSIONS: The time lag between diagnosis of HIV and initiation of ART was more than 1 month in 69% of the expectant mothers, which may have contributed to the failure in viral suppression. Implementation of HIV screening and a more effective means of communication between prenatal and HIV clinics are required to help reduce vertical transmission of the virus to neonates. PMID- 23462487 TI - Commentary on "Medical care of pregnant women in eastern North Carolina with human immunodeficiency virus". PMID- 23462488 TI - Prevalence and impact of anemia in hospitalized patients. AB - OBJECTIVE: The prevalence of anemia is increasing in the general population similarly to other comorbidities and is associated with high mortality in a variety of settings. Most studies, however, have analyzed older adults or specific comorbidities, and the independent impact of anemia on outcomes in a general population of hospitalized patients has not been clearly defined. METHODS: Retrospective analysis of a medical records database of all consecutive patient discharges (aged 18 years or older) admitted to our institution from January 1, 1999 through December 31, 2008. RESULTS: A total of 179,516 admissions were included. Of these, 18,589 patients were diagnosed as having anemia (10.4%). There were 123,586 patients younger than 65 years. The prevalence of anemia among all of the discharges was characterized by a significant linear increase across the 10-year time frame, from 8.7% (1999) to 12.8% (2008), as was the average number of comorbidities. Over time, anemic patients were characterized by increasing comorbidity. Anemia was significantly associated with mortality (6.5% vs 2.5%; P < 0.001, odds ratio 2.68). This association remained significant after additional adjustment for demographic characteristics and comorbidities. The risk of mortality was significantly higher in patients younger than 65 years than it was in patients older than 65 (odds ratio 3.2 vs 2.1, respectively). CONCLUSIONS: The prevalence of anemia increased during a 10-year time frame, as did the average number of associated comorbid conditions. With adjustment for time, demographic factors, and additional comorbidities, anemia remained independently associated with mortality. This association was stronger in younger patients. PMID- 23462489 TI - Commentary on "prevalence and impact of anemia in hospitalized patients". PMID- 23462490 TI - Community-acquired pneumonia with risk for drug-resistant pathogens. AB - BACKGROUND: Pneumonia is a leading infectious cause of morbidity and mortality in the United States. The Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) have published treatment guidelines for community-acquired pneumonia (CAP) based upon the site of acquisition and specific pathogen risk. The literature demonstrates improved outcomes with guideline-concordant empiric therapy. A subset of patients with CAP has risk factors for drug-resistant pathogens (DRPs). IDSA/ATS treatment guidelines do not provide clear recommendations for empiric treatment, and clinical studies have not provided descriptive data for this group. METHODS: A retrospective chart review of all admissions between January 1, 2008 and April 19, 2009 with an International Classification of Diseases-9 code and physician-documented diagnosis of pneumonia at two community hospitals were performed. IDSA pneumonia type and presence of risk factors for DRP were recorded for each patient, and the empiric antibiotic therapy received was evaluated. Admissions were excluded if immunosuppression or pregnancy was present. RESULTS: Of the 400 admissions reviewed, 343 patients were included. A total of 228 patients (71%) had CAP. Forty-three percent of patients with CAP had risk factors for DRP. Only 2% of this group received an antibiotic regimen with coverage of the specific DRP risk factor present. The most common DRPs not receiving coverage in this group were Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. P. aeruginosa and methicillin resistant S. aureus occurred more commonly in culture-positive patients with CAP with DRP risk factors but did not achieve statistical significance. A larger sample size would be needed to determine whether this difference is significant. CONCLUSIONS: Risk factors for DRP occurred commonly in our CAP population. Patients with CAP with risk for DRP may be a distinct group who are without clear guidance on treatment. Future studies are needed to define the risk of DRP and the impact upon empiric therapy for patients with CAP. PMID- 23462491 TI - Integrated models of education and service involving community-based health care for underserved populations: Tulane student-run free clinics. AB - OBJECTIVES: Throughout the United States numerous models of local programs, including student-run clinics, exist to address the issue of access to care. The role of these clinics in serving the local community and contributing to medical education has been documented only in limited detail, however. The purpose of this article is to describe the clinic models, patient demographics, and services provided by four student-run clinics in New Orleans. METHODS: This is a retrospective, multisite chart review study of adult patients examined at student run clinics between January 1, 2010 and July 31, 2011. RESULTS: During a 19-month period, 859 patients collectively were seen at the clinics, for a total of 1455 visits. The most common reasons for seeking care were medication refills (21.6%) and musculoskeletal pain (12.0%). Counseling and health education were provided primarily for smoking cessation (9.0%), diabetes management (7.1%), and hypertension management (5.8%). Nearly one-fifth of patients were given a referral to primary care services. In the 2010-2011 academic year, 87.6% of preclinical medical students volunteered at >=1 of these clinics and spent 4508 hours during 1478 shifts. CONCLUSIONS: This article highlights the role of student-run clinics in the community, the safety-net healthcare system, and medical education. Future directions include the establishment of a new clinic, fundraising, and prospective studies to further assess the impact of student-run clinics. PMID- 23462492 TI - Comparison of breast-feeding knowledge, attitudes, and beliefs before and after educational intervention for rural Appalachian high school students. AB - OBJECTIVES: Breast-feeding rates in rural and southeastern regions of the United States are lower than national rates and Healthy People 2020 targets. The objectives of this study were to understand current breast-feeding knowledge, attitudes, and beliefs among rural southern Appalachian adolescents and to explore whether a high school educational intervention designed to address the five tenets (knowledge, attitudes, intentions, perceived behavioral control, and subjective norms) of the theory of planned behavior may be effective in increasing future rates of breast-feeding in this population. METHODS: An educational session including an interactive game was developed and administered to occupational health science students during a single class period in two county high schools. A presurvey and a postsurvey administered 2 weeks after the intervention were completed by students. Pre- and postsurveys were analyzed using paired t tests and Cohen d and potential differences based on sex and grade were explored. RESULTS: Both pre- and postsurveys were completed by 107 students (78%). Knowledge, attitudes about breast-feeding benefits, subjective norms, and intentions significantly improved following the intervention. Baseline knowledge and attitudes about breast-feeding benefits for mothers were low and demonstrated the greatest improvement. CONCLUSIONS: Offering breast-feeding education based on the theory of planned behavior in a single high school class session was effective in improving student knowledge, attitudes, and beliefs about breast feeding and intention to breast-feed. PMID- 23462493 TI - Does ambulance response time influence patient condition among patients with specific medical and trauma emergencies? AB - OBJECTIVES: The relation between patient outcome and ambulance response times is unknown. We sought to measure the influence of shorter response times on patient outcomes. The objective of the study was to determine whether ambulance response time makes a difference in the outcomes of emergency medical services (EMS) patients with specific traumatic and medical emergencies. METHODS: This study was conducted in a metropolitan EMS system serving a population of 800,000, including urban and rural areas. Cases were included if the private EMS service was the first medical provider on scene, the case was priority 1, and the patients were 13 years old and older. A 14-month time period was used for the data evaluation. Four diagnoses were examined: motor vehicle crash injuries, penetrating trauma, difficulty breathing, and chest pain complaints. Data collected included ambulance response times, initial vital signs, and the number of vital signs out of range. Cases seen at the single major trauma center were selected for evaluation of hospital outcome. Correlation coefficients were used to evaluate interactions between independent and outcome variables. RESULTS: Of the 2164 cases we reviewed, the EMS service responded significantly faster to trauma complaints at 4.5 minutes (n = 254) than medical complaints at 5.9 minutes (n = 1910). In the trauma center sample of 559 cases, response time was not related to hospital days (P = 0.5), admissions (P = 0.7), intensive care unit admissions (P = 0.4), or deaths (P = 0.3). CONCLUSIONS: This study showed that in cases seen at a major trauma center, longer response times were not associated with worse outcomes for the diagnostic groups tested. PMID- 23462494 TI - Commentary on "Does ambulance response time influence patient condition among patients with specific medical and trauma emergencies?". PMID- 23462496 TI - Discordance between patient and surgeon satisfaction after total joint arthroplasty. AB - We surveyed 331 patients undergoing total hip or knee arthroplasty pre operatively, and patients and surgeons were both surveyed 6 and 12 months post operatively. We identified variables (demographic factors, operative factors and patient expectations) as possible predictors for discordance in patient-surgeon satisfaction. At 12 months, 94.5% of surgeons and 90.3% of patients recorded satisfaction with the outcome. The discordance between patient and surgeon satisfaction was mainly due to patient dissatisfaction-surgeon satisfaction. In an adjusted analysis, the strongest predictors of discordance in patient-surgeon satisfaction were unmet patient expectations and the presence of complications. Advice to potential joint arthroplasty candidates regarding the decision to proceed with surgery should be informed by patient reported outcomes, rather than the surgeon's opinion of the likelihood of success. PMID- 23462495 TI - Management of hyperglycemia in hospitalized noncritical patients. AB - Randomized trials designed to determine optimum blood glucose (BG) levels among hospitalized noncritically ill patients are limited. In this group of patients, experts generally recommend premeal BG targets of 100 to 140 mg/dL, and random BG <180 mg/dL. Scheduled insulin is the mainstay therapy to control hyperglycemia in patients admitted to general wards and should include three components: basal, prandial, and correction insulin. Insulin doses should take into account the severity of hyperglycemia, weight, type of diabetes, age, caloric intake, renal function, and propensity for hypoglycemia. Limited data suggest that the traditional mixed-split insulin regimen formed of neutral protamine hagedorn regular insulin is similar in efficacy and frequency of hypoglycemia to a more expensive and complex insulin analog regimen formed of twice-daily detemir and mealtime glulisine; however, based on extrapolation of data derived from trials of diabetic outpatients, basal insulin analogs such as glargine or detemir may be used instead of neutral protamine hagedorn insulin if there is concern about hypoglycemia. In patients with erratic meal intake, the use of short-acting insulin analogs may be preferred to regular insulin. Further studies are required to determine the ideal glycemic goals and insulin treatment strategies for control of hyperglycemia in hospitalized noncritically ill patients. PMID- 23462497 TI - A novel method for accurate and reproducible functional cup positioning in total hip arthroplasty. AB - Cup positioning is an important variable for short and long term function, stability, and durability of total hip arthroplasty (THA). This novel method utilizes internal and external bony landmarks, and the transverse acetabular ligament for positioning the acetabular component. The cup is placed parallel and superior to the transverse ligament and inside the anterior wall notch of the true acetabulum, then adjusted for femoral version and pelvic tilt and obliquity based on weight bearing radiographs. In 78 consecutive THAs, the mean functional anteversion and abduction angles were 17.9 degrees +/- 4.7 degrees and 41.7 degrees +/- 3.8 degrees , respectively. 96% of the functional anteversion measurements and 100% of the functional abduction angles were within the safe zone. This technique is an easy, reproducible, and accurate method for functional cup placement. PMID- 23462498 TI - Variability in the relationship between the distal femoral mechanical and anatomical axes in patients undergoing primary total knee arthroplasty. AB - Currently, an intramedullary (IM) guide is often used for performing the distal femoral resection in total knee arthroplasty (TKA). However, this method assumes that in most patients, the distal femoral mechanical-anatomical angle (FMAA) is 5 degrees . Preoperative, standing, AP hip-to-ankle radiographs were reviewed in 493 patients undergoing primary TKA, and the FMAA was digitally measured. Correlation coefficients relative to several radiographic measurements, along with demographic variables, were performed. A significant number of patients (28.6%) had an FMAA outside the range of 5 degrees +/- 2 degrees (range 2.0 degrees -9.6 degrees ). The only measurement demonstrating a fair/moderate correlation with the FMAA was the neck-shaft angle (r = -0.55). Using an IM resection guide, without obtaining AP hip-to-ankle radiographs to determine each patient's true FMAA, may lead to malalignment of the femoral component. PMID- 23462499 TI - Valgus bracing affords short-term treatment solution across walking and sit-to stand activities. AB - Since activities of daily living do not exist in isolation this prospective study examined biomechanical function during level walking and sit-to-stand activities over two months of brace use by subjects with varying grades of knee osteoarthritis. Kinematic and kinetic data were collected using infrared cameras and force platforms; clinical scores compared perceived and measured functional effects. There was no significant change in pain for any grades of OA but activity levels were significantly higher at one month in the moderate OA grades and at two months for the low OA grades. Mechanical constraints and changes in movement strategies were consistent across tasks and OA grade. This study provides valuable data for further studies aimed at refining the use and optimization of valgus bracing efficacy. PMID- 23462500 TI - Immediate complications following hip and knee arthroplasty: does race matter? AB - Black race has been associated with a higher rate of complications following total joint arthroplasty, such as infection, deep vein thrombosis, pulmonary embolism, and death. We hypothesized that there would be no significant association between black race and adverse outcome when medical conditions were adjusted for. Data on 585,269 patients from the Nationwide Inpatient Samples were assessed by multivariable logistic regression analysis. Black race was significantly associated with postoperative complication and death. Comorbidities do not account for racial differences in adverse events. Black race was an independent predictive factor for increased complications and death following hip and knee arthroplasty. PMID- 23462501 TI - Pandemic influenza in the 2009/2010 season in central Poland: the surveillance study of laboratory confirmed cases. AB - We retrospectively studied confirmed cases of influenza obligatorily reported to health authorities in central Poland during the 2009/2010 season. Each case was traced and examined with a questionnaire. The samples were tested for influenza A and B by RT-PCR. A total of 561 cases of influenza, including 185 in children under 14 years old, were detected. Four hundred and eighty four people were hospitalized, including 142 children under 14. Thirty two patients died, all with pre-existing risk factors. The most common complications were pneumonia, cardiac arrest, septic shock, circulatory insufficiency, multi-organ failure and myocarditis. The majority of patients (388/484) were treated with oseltamivir. Fifty three patients were mechanically ventilated, 52 patients were given oxygen. Only 11 out of the 561 patients were immunized against seasonal influenza. In conclusion, pandemic influenza affects all age groups, but it is more common in younger patients. Pandemic influenza is becoming an emerging health risk for the Polish population. PMID- 23462503 TI - End-of-life experiences and expectations of Africans in Australia: cultural implications for palliative and hospice care. AB - The ageing and frail migrants who are at the end of life are an increasing share of migrants living in Australia. However, within such populations, information about end-of-life experiences is limited, particularly among Africans. This article provides some insights into the sociocultural end-of-life experiences of Africans in Australia and their interaction with the health services in general and end-of-life care in particular. It provides points for discussion to consider an ethical framework that include Afro-communitarian ethical principles to enhance the capacity of current health services to provide culturally appropriate and ethical care. This article contributes to our knowledge regarding the provision of culturally appropriate and ethical care to African patients and their families by enabling the learning of health service providers to improve the competence of palliative care systems and professionals in Australia. Additionally, it initiates the discussion to highlight the importance of paying sufficient attention to a diverse range of factors including the migration history when providing palliative and hospice care for patients from African migrant populations. PMID- 23462502 TI - Entering the second century of maize quantitative genetics. AB - Maize is the most widely grown cereal in the world. In addition to its role in global agriculture, it has also long served as a model organism for genetic research. Maize stands at a genetic crossroads, as it has access to all the tools available for plant genetics but exhibits a genetic architecture more similar to other outcrossing organisms than to self-pollinating crops and model plants. In this review, we summarize recent advances in maize genetics, including the development of powerful populations for genetic mapping and genome-wide association studies (GWAS), and the insights these studies yield on the mechanisms underlying complex maize traits. Most maize traits are controlled by a large number of genes, and linkage analysis of several traits implicates a 'common gene, rare allele' model of genetic variation where some genes have many individually rare alleles contributing. Most natural alleles exhibit small effect sizes with little-to-no detectable pleiotropy or epistasis. Additionally, many of these genes are locked away in low-recombination regions that encourage the formation of multi-gene blocks that may underlie maize's strong heterotic effect. Domestication left strong marks on the maize genome, and some of the differences in trait architectures may be due to different selective pressures over time. Overall, maize's advantages as a model system make it highly desirable for studying the genetics of outcrossing species, and results from it can provide insight into other such species, including humans. PMID- 23462504 TI - Aspects of indignity in nursing home residences as experienced by family caregivers. AB - The overall purpose of this cross-country Nordic study was to gain further knowledge about maintaining and promoting dignity in nursing home residents. The purpose of this article is to present results pertaining to the following question: How is nursing home residents' dignity maintained, promoted or deprived from the perspective of family caregivers? In this article, we focus only on indignity in care. This study took place at six different nursing home residences in Sweden, Denmark and Norway. Data collection methods in this part of this study consisted of individual research interviews. Altogether, the sample consisted of 28 family caregivers of nursing home residents. The empirical material was interpreted using a hermeneutical approach. The overall theme that emerged was as follows: 'A feeling of being abandoned'. The sub-themes are designated as follows: deprived of the feeling of belonging, deprived of dignity due to acts of omission, deprived of confirmation, deprived of dignity due to physical humiliation, deprived of dignity due to psychological humiliation and deprived of parts of life. PMID- 23462505 TI - Cooperative activation of gene expression by agonists and antagonists mediated by estrogen receptor heteroligand dimer complexes. AB - Estrogen receptor (ER) antagonists are generally thought to inhibit estrogen action through competitive inhibition, resulting in receptor binding to antagonist rather than agonist. However, microarray analyses reveal a group of genes for which ER agonist and antagonist cooperatively regulate expression, suggesting additional models of combined agonist/antagonist action must exist. In conjunction with a chimeric reporter gene and two modified ERs, one [ERalpha(GSCKV)] with a mutation in the DNA-binding domain and the other (ERalpha G521R) with a ligand-binding specificity mutation, we herein demonstrate that ER agonist and antagonist cooperatively activate gene expression through an ER heteroligand dimer complex (ER-HLD) consisting of one subunit of the receptor dimer bound to agonist and another occupied by antagonist. Coimmunoprecipitation experiments confirmed interaction between the agonist-bound and antagonist-bound receptors. This cooperative activation of gene expression was enhanced by steroid receptor coactivator 3 coactivator, and required each ligand-bound subunit of the dimer to bind to DNA, as well as both activation function 1 domains for maximal transcriptional activity. Ligand combinations able to induce ER-HLD transcriptional activity include the agonists 17beta-estradiol or conjugated estrogens with the antagonists tamoxifen, raloxifene, bazedoxifene, or fulvestrant. Moreover, ER-HLD can activate transcription in the context of a natural promoter. Taken together, these findings broaden our understanding of the complex relationship between ER agonist and antagonist, and suggest a novel model by which cell and tissue selective effects of antiestrogens may be achieved. PMID- 23462506 TI - Identification of functionally relevant lysine residues that modulate human farnesoid X receptor activation. AB - Base amino acid lysine residues play an important role in regulation of nuclear receptors [e.g., farnesyl X receptor (FXR)], leading to enhanced or suppressed biologic activity. To understand the molecular mechanisms and the subsequent effects in modulating FXR functions in diverse biologic processes, we individually replaced eight highly conserved lysine residues of human FXR (hFXR) with arginine. The effects of each mutated FXR on target gene activation, subcellular localization, protein-protein association, and protein-DNA interaction were investigated. Results demonstrated that K122R, K210R, K339R, and K460R mutants of hFXR significantly impaired target gene [organic solute transporter alpha/beta and bile salt export pump (BSEP)] promoter reporter activity in a ligand-dependent fashion. None of the four mutants affected the nuclear localization of FXR. Protein interaction studies show that K210R slightly but significantly decreased FXR/retinoid X receptor (RXR) binding affinity but enhanced the interaction of FXR with lysine methyltransferase Set7/9 by ~21%. K460R decreased the FXR interaction with Set7/9 by ~45% but had no significant effects on interaction with RXR. Electrophoretic mobility shift assays demonstrated that hFXR-K210R and -K339R reduced the protein-DNA (IR1 element at hBSEP promoter) binding affinity by ~80 and ~90%, respectively. Computational based protein modeling studies were consistent with these results and provided further insights into the potential underlying mechanisms responsible for these results. In conclusion, four highly conserved lysine residues of hFXR, K122, K210, K339, and K460, have been identified that play a critical role in FXR target gene regulation and molecular interaction (protein-protein and protein DNA). PMID- 23462507 TI - Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration. AB - G protein-coupled receptor signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, i.e., signaling networks. In this work we present an exhaustive study of the cross-talk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and Chinese hamster ovary-transfected cells. By desensitization assays we demonstrated the existence of a crossdesensitization between both receptors independent of protein kinase A or C. H1R-agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment of 48 hours. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the cross-talk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. To evaluate potential heterodimerization of the receptors, sensitized emission fluorescence resonance energy transfer experiments were performed in human embryonic kidney 293T cells using H1R-cyan fluorescent protein and H2R yellow fluorescent protein. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor crossdesensitization, which was mediated by G protein-coupled receptor kinase 2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands. PMID- 23462509 TI - Reply: To PMID 22959762. PMID- 23462508 TI - The 140-kD isoform of CD56 (NCAM1) directs the molecular pathogenesis of ischemic cardiomyopathy. AB - Despite recent advances in understanding the relevance of cell adhesion-related signaling in the pathogenesis of ischemic cardiomyopathy (ICM) in animal models, substantial questions remain unanswered in the human setting. We have previously shown that the neural cell adhesion molecule CD56 [neural cell adhesion molecule (NCAM1)] is specifically overexpressed in ICM; it was the aim of the current study to further elucidate the role of CD56 in the pathogenesis of human ICM. We used quantitative real-time PCR and IHC in human ICM and a rat model of coronary obstruction to demonstrate that CD56(140kD), the only extraneuronally expressed NCAM1 isoform with a cytoplasmic protein domain capable of inducing intracellular signaling, is the only up-regulated CD56 isoform in failing cardiomyocytes in human ICM in vivo. In subsequent analyses of the cellular effects of CD56(140kD) overexpression in the development of ICM using differential whole transcriptome expression analyses and functional in vitro cardiomyocyte cell culture assays, we further show that the up-regulation of CD56(140kD) is associated with profound gene expression changes, increased apoptosis, and reduced Ca(2+) signaling in failing human cardiomyocytes. Because apoptosis and Ca(2+)-related sarcomeric dysfunction are molecular hallmarks of ICM in humans, our results provide strong evidence that CD56(140kD) up-regulation plays a pivotal role in the pathogenesis of ICM and may be a target for future immunotherapeutic strategies in the treatment of this common and often fatal disease. PMID- 23462510 TI - A peculiar inheritance: the patient had a net-like pattern of pigmentation on her vulva and perianal skin. PMID- 23462511 TI - Do oral contraceptive pills really protect against venous thromboembolism, especially in polycystic ovary syndrome patients? Prescription bias or not? PMID- 23462512 TI - The Study of Dynamical Potentials of Highly Excited Vibrational States of HOBr. AB - The vibrational nonlinear dynamics of HOBr in the bending and O-Br stretching coordinates with anharmonicity and Fermi 2:1 coupling are studied with dynamical potentials in this article. The result shows that the H-O stretching vibration mode has significantly different effects on the coupling between the O-Br stretching mode and the H-O-Br bending mode under different Polyad numbers. The dynamical potentials and the corresponding phase space trajectories are obtained when the Polyad number is 27, for instance, and the fixed points in the dynamical potentials of HOBr are shown to govern the various quantal environments in which the vibrational states lie. Furthermore, it is also found that the quantal environments could be identified by the numerical values of action integrals, which is consistent with former research. PMID- 23462513 TI - An interview with Derek Lowe. PMID- 23462514 TI - IkappaB kinase beta inhibitor downregulates pain-related neuropeptide production in the sensory neurons innervating injured lumbar intervertebral discs in the dorsal root ganglia of rats. AB - BACKGROUND CONTEXT: Nuclear factor-kappaB (NF-kappaB) is an essential gene transcriptional regulator of inflammatory cytokines, and it plays important roles in numerous conditions, including inflammatory and neuropathic pain, especially when discogenic pain is involved. Phosphorylation of IkappaB protein through IkappaB kinase (IKK) is the first step in the activation of NF-kappaB activation and the upregulation of NF-kappaB-responsive genes. PURPOSE: To investigate whether IKK inhibition alters the properties of pain-related neuropeptides in the rat lumbar degenerative intervertebral disc (IVD) model. STUDY DESIGN: Retrograde neurotracing and immunofluorescent investigation of pain-related neuropeptide (calcitonin gene-related peptide [CGRP]) in the sensory innervation of injured lumbar IVD in rat dorsal root ganglia (DRGs). METHODS: Forty female Sprague Dawley rats were equally divided into four groups: naive, sham, and two agent treated groups (vehicle [saline] group and anti-IKKbeta [IMD-0560, IKKbeta inhibitor] group). The L5-L6 IVDs of the agent-treated rats were exposed and injured by repeated punctures. The retrograde neurotracer Fluoro-Gold (FG) and corresponding treatment agents were intradiscally applied. In the sham group, FG alone was applied onto uninjured IVDs. One week later, L1-L3 DRGs were harvested and immunolabeled for CGRP as a pain marker. The proportions of FG-labeled CGRP immunoreactive (-ir) DRG neurons were assessed. RESULTS: Fluoro-Gold-labeled DRG neurons were almost equally prevalent at each DRG level. The proportions of FG labeled CGRP-ir DRG neurons in the two agent-treated groups were significantly increased in comparison with those in the naive and the sham groups (p<.05) and were significantly decreased in the anti-IKKbeta group in comparison with that in the vehicle group (p<.05). CONCLUSIONS: The neuropeptide CGRP as a pain marker was upregulated in DRG neurons innervating the injured IVDs, and intradiscal inhibition of IKKbeta significantly suppressed CGRP production in the DRG neurons innervating the rat IVD, suggesting the possible analgesic effect of IKKbeta inhibition in discogenic pain. PMID- 23462515 TI - Gorham disease of the craniocervical junction: X-ray, computed tomography, and magnetic resonance imaging findings. AB - BACKGROUND CONTEXT: Gorham disease of massive osteolysis is a spontaneous, idiopathic, and progressive form of primary osteolysis. It has no age, sex, or race predilection, and patients are mostly asymptomatic until severe deformity or pathological fracture becomes evident. PURPOSE: A patient with craniocervical involvement is presented, describing imaging findings with a review of the literature to provide an insight into the disorder. STUDY DESIGN/SETTING: Case report and review of the literature. METHODS: X-ray, computed tomography, and magnetic resonance imaging findings of a patient with findings related to the site of involvement. RESULTS: All images demonstrate osteolysis typically described for the disease. Differential diagnosis and key features are indicated. Operative findings and pathological analysis were also consistent with the findings. Patient's follow-up is also reported. CONCLUSIONS: This benign appearing yet disabling disease may become fatal in relation to the site involved. Acknowledging imaging findings may provide early diagnosis for timely intervention or supportive management. PMID- 23462516 TI - Characteristics of obstructive sleep apnea in patients with Parkinson's disease. AB - Parkinson's disease (PD) patients frequently develop obstructive sleep apnea (OSA). In order to clarify the clinical significance of OSA in PD, we compared descriptive variables between PD patients with OSA (PD+OSA) and without (PD-OSA), and between the PD+OSA group and a group of OSA patients without PD (control OSA). The apnea hypopnea index (AHI) cutoff of 15 episodes/hour on polysomnogram (PSG) was used to assign 107 PD patients to groups; OSA-related symptoms and PSG findings were then compared. Demographic and PSG variables were compared between PD+OSA patients and 31 OSA controls. Twenty-four patients with PD (22.4%) were classified as PD+OSA. There were no significant differences in descriptive variables between the PD+OSA and PD-OSA groups. The PD+OSA group had a higher arousal index on PSG than the PD-OSA group, although the two groups had similar ESS scores. The PD+OSA patients had a lower respiratory arousal index and a smaller decrease in oxygen saturation than the control OSA group, despite having a similar AHI. The prevalence of OSA in PD did not differ from that in the general elderly population, indicating that the clinical significance of OSA as a contributor to daytime sleepiness in PD is low. PMID- 23462517 TI - Competence areas of nursing students in Europe. AB - The focus of this study is on European nursing education, where there have been several reforms over the last two decades attempting to harmonise curricula and degree structures. One of the most powerful reforms was started by the Bologna Declaration in 1999; since then, significant progress has been made towards achieving the European Higher Education Area (EHEA) and the implementation of the European Qualifications Framework (EQF) in education practice. The Directive of recognition of professional qualifications (2005/36/EC) regulates nursing education. All these strategies aim to harmonise nursing education, but specific competence areas in nursing are still missing within the European Union (EU). The purpose of this review was to seek competence areas for nursing students within the EU as identified in previous studies and other documents. Altogether, 67 competence areas were identified and classified into eight main categories: (1) professional and ethical values and practice, (2) nursing skills and intervention, (3) communication and interpersonal skills, (4) knowledge and cognitive ability, (5) assessment and improving quality in nursing, (6) professional development, (7) leadership, management and teamwork, and (8) research utilisation. In order to obtain a comprehensive concept of competence, more research is needed on nursing students' competence areas across the EU due to the fact that the EU is a common labour market and nurses are educated for the EU as a whole. Nursing is a global profession and nurse competence is central to patient care outcomes, so it is also internationally important that nurses have good competence. PMID- 23462518 TI - Criticality: the experience of developing an interactive educational tool based on board games. AB - Critical care services have seen many changes over recent years prompted by the seminal paper by the Department of Health (2000) Comprehensive critical care: A review of adult critical care services. This led to the expansion of critical care services with the resultant recruitment of large numbers of nurses new to critical care. Northumbria and other Universities within the UK were commissioned to provide formal education to critical care nurses and developed Foundations in Acute and Critical Care Module to provide nurses new to critical care, or from other acute clinical settings, with the knowledge and skills to manage this complex group of patients. The aim of this paper is to share the authors' experience of developing "Criticality" a board game designed to formatively assess learning amongst critical care nurses following a formal taught module in a Higher Education Institution (HEI) and prior to the summative assessment. Author experience suggests that Criticality is a useful revision tool and also fun and interactive which helped the students to identify strengths and weaknesses in their knowledge base and thus direct their revision prior to summative assessment. PMID- 23462519 TI - Control of bluetongue in Europe. AB - Since 1998, bluetongue virus (BTV) serotypes 1, 2, 4, 6, 8, 9, 11 and 16 have spread throughout Europe. In 2006, BTV serotype 8 (BTV-8) emerged unexpectedly in northern Europe throughout a region including Belgium, France, Germany, Luxembourg and the Netherlands. In the following year, it spread rapidly throughout the rest of Europe. In 2008, two more BTV serotypes were detected in northern Europe: BTV-6 in the Netherlands and Germany and BTV-11 in Belgium. The European incursion of BTV has caused considerable economic losses, comprising not only direct losses from mortality and reduced production but also indirect losses because of ensuing bans on trade of ruminants between BTV-infected and non infected areas. Given the significance of the disease, all affected countries have established control and eradication measures, which have evolved with the availability of detection and prevention tools such as vaccines. Before 2005, BTV vaccination campaigns in affected countries used only modified live virus vaccines and only sheep were vaccinated, except in Italy, where all susceptible domestic ruminant species were included. After 2005, inactivated vaccines became available and cattle and goats were included in the vaccination campaigns. This review looks at how bluetongue disease has evolved in Europe and how effective vaccination strategies have been. PMID- 23462520 TI - Staphylococcus nepalensis in the guano of bats (Mammalia). AB - Thirty randomly selected mesophilic isolates from the six years old guano sample from mixed Myotis myotis and M. blythii summer roosts colony were isolated and identified as Staphylococcus nepalensis using MALDI TOF analysis. 16S rRNA gene sequencing of selected five isolates and subsequent phylogenetic analysis confirmed that all sequences showed the highest similarity to S. nepalensis sequences. Several virulence factors were produced by tested isolates, mainly capsule formation and resistance to tetracycline, ampicillin, gentamycin, and chloramphenicol antibiotics. Our experiments show that the majority of cultivable mesophilic bacteria from the guano of bats belong to the S. nepalensis species. This is the first report on the occurrence of this species in the guano of bats and our results indicate that the guano accumulated near or directly in human dwellings and buildings may represent a significant risk for human health. PMID- 23462521 TI - Potency of an inactivated influenza vaccine prepared from a non-pathogenic H5N1 virus against a challenge with antigenically drifted highly pathogenic avian influenza viruses in chickens. AB - Antigenic variants of H5N1 highly pathogenic avian influenza virus (HPAIV) have selected and are prevailing in poultry populations in Asia. In the present study, the potency of inactivated influenza vaccine prepared from a non-pathogenic H5N1 avian influenza virus, A/duck/Hokkaido/Vac-3/2007 (H5N1), was assessed by challenging with H5N1 HPAIV variants, A/muscovy duck/Vietnam/OIE-559/2011 (H5N1), A/whooper swan/Hokkaido/4/2011 (H5N1), and A/peregrine falcon/Hong Kong/810/2009 (H5N1) belonging to clades 1, 2.3.2.1, and 2.3.4, respectively. All chickens immunized with the Vac-3 vaccine survived without showing any clinical signs after intranasal challenge either with A/whooper swan/Hokkaido/4/2011 (H5N1) or A/muscovy duck/Vietnam/OIE-559/2011 (H5N1). After challenge with A/peregrine falcon/Hong Kong/810/2009 (H5N1), 10 out of 12 vaccinated chickens survived and the other 2 died on 4 or 7 post-challenge days. The Vac-3 vaccine of 2.4-fold antigen concentration conferred complete protective immunity in chickens against challenge with A/peregrine falcon/Hong Kong/810/2009 (H5N1). PMID- 23462522 TI - Magnetic phase diagram of the olivine-type Mn2GeO4 single crystal estimated from magnetic, resonance and thermodynamic properties. AB - Mn2GeO4 single crystals with the olivine structure grown by the modified flux method have been investigated. Pronounced magnetic phase transitions at T1 = 47.7 K, T2 = 17 K and T3 = 5.5 K, with T2 being dependent on an applied magnetic field, have been found. Based on the data of magnetic, resonance and temperature measurements, the entire phase diagram of Mn2GeO4 has been built. Mn2GeO4 is shown to be a material with a complex magnetic structure consisting of two magnetic subsystems. PMID- 23462523 TI - Nima- and Aurora-related kinases of malaria parasites. AB - Completion of the life cycle of malaria parasite requires a succession of developmental stages which vary greatly with respect to proliferation status, implying a tightly regulated control of the parasite's cell cycle, which remains to be understood at the molecular level. Progression of the eukaryotic cell cycle is controlled by members of mitotic kinase of the families CDK (cyclin-dependent kinases), Aurora, Polo and NIMA. Plasmodium parasites possess cyclin-dependent protein kinases and cyclins, which strongly suggests that some of the principles underlying cell cycle control in higher eukaryotes also operate in this organism. However, atypical features of Plasmodium cell cycle organization and important divergences in the composition of the cell cycle machinery suggest the existence of regulatory mechanisms that are at variance with those of higher eukaryotes. This review focuses on several recently described Plasmodium protein kinases related to the NIMA and Aurora kinase families and discusses their functional involvement in parasite's biology. Given their demonstrated essential roles in the erythrocytic asexual cycle and/or sexual stages, these enzymes represent novel potential drug targets for antimalarial intervention aiming at inhibiting parasite replication and/or blocking transmission of the disease. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). PMID- 23462524 TI - Temperature, myocardial infarction, and mortality: effect modification by individual- and area-level characteristics. AB - BACKGROUND: Although several studies have examined associations between temperature and cardiovascular-disease-related mortality, fewer have investigated the association between temperature and the development of acute myocardial infarction (MI). Moreover, little is known about who is most susceptible to the effects of temperature. METHODS: We analyzed data from the Worcester Heart Attack Study, a community-wide investigation of acute MI in residents of the Worcester (MA) metropolitan area. We used a case-crossover approach to examine the association of apparent temperature with acute MI occurrence and with all-cause in-hospital and postdischarge mortality. We examined effect modification by sociodemographic characteristics, medical history, clinical complications, and physical environment. RESULTS: A decrease in an interquartile range in apparent temperature was associated with an increased risk of acute MI on the same day (hazard ratio = 1.15 [95% confidence interval = 1.01-1.31]). Extreme cold during the 2 days prior was associated with an increased risk of acute MI (1.36 [1.07 1.74]). Extreme heat during the 2 days prior was also associated with an increased risk of mortality (1.44 [1.06-1.96]). Persons living in areas with greater poverty were more susceptible to heat. CONCLUSIONS: Exposure to cold increased the risk of acute MI, and exposure to heat increased the risk of dying after an acute MI. Local area vulnerability should be accounted for as cities prepare to adapt to weather fluctuations as a result of climate change. PMID- 23462525 TI - Functional CYP1A1 genetic variants, alone and in combination with smoking, contribute to development of head and neck cancers. AB - CYP1A1 plays an essential role in pathogenesis of head and neck cancers. Functional CYP1A1 Ile462Val and MspI single nucleotide polymorphisms (SNP) are considered to have significant effects on risk of head and neck cancers. Several case-control studies have examined how these genetic polymorphisms are involved in development of this group of malignancies, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically examine the associations between these functional genetic variants and head and neck cancer risk. A total of 28 studies are eligible for CYP1A1 Ile462Val SNP (4639 patients and 4701 controls), and 22 studies for MspI SNP (4168 patients and 4638 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. There was no association between Ile462Val polymorphism and head and neck cancer risk (OR = 1.23, 95% CI = 0.99-1.53, P = 0.062). However, in a stratified analysis, a statistically significant correlation between this SNP and pharyngeal cancer risk was observed (OR = 1.76, 95% CI = 1.32-2.33, P < 0.001). For MspI SNP, our data indicated that carriers of TC and CC genotypes had a 34% increased risk to develop head and neck cancers compared to TT carriers (95% CI = 1.15 1.57, P < 0.001). This effect was even more pronounced in smokers (OR = 2.98, 95% CI = 1.69-5.26, P < 0.001), demonstrating that gene-smoking interaction intensifying carcinogenesis may exist. These findings reveal that the functional CYP1A1 MspI genetic variant, alone and in combination with smoking, plays a more important role in pathogenesis of head and neck cancers. PMID- 23462526 TI - Cell cycle arrest, extracellular matrix changes and intrinsic apoptosis in human melanoma cells are induced by Boron Neutron Capture Therapy. AB - Boron Neutron Capture Therapy (BNCT) involves the selective accumulation of boron carriers in tumor tissue followed by irradiation with a thermal or epithermal neutron beam. This therapy is therefore a cellular irradiation suited to treat tumors that have infiltrated into healthy tissues. BNCT has been used clinically to treat patients with cutaneous melanomas which have a high mortality. Human normal melanocytes and melanoma cells were treated with BNCT at different boronophenylalanine concentrations for signaling pathways analysis. BNCT induced few morphological alterations in normal melanocytes, with a negligible increase in free radical production. Melanoma cells treated with BNCT showed significant extracellular matrix (ECM) changes and a significant cyclin D1 decrease, suggesting cell death by necrosis and apoptosis and cell cycle arrest, respectively. BNCT also induced a significant increase in cleaved caspase-3 and a decrease in the mitochondrial electrical potential with selectivity for melanoma cells. Normal melanocytes had no significant differences due to BNCT treatment, confirming the data from the literature regarding the selectivity of BNCT. The results from this study suggest that some signaling pathways are involved in human melanoma treatment by BNCT, such as cell cycle arrest, ECM changes and intrinsic apoptosis. PMID- 23462527 TI - IL4R and IL13 polymorphic variants and development of antibodies to surface antigen of hepatitis B virus in hemodialysis patients in response to HBV vaccination or infection. AB - We searched for an association between the interleukin 4 receptor gene (IL4R) rs1805015 and interleukin 13 gene (IL13) rs20541 polymorphisms and the development of antibodies to hepatitis B surface antigen (anti-HBs) in the case of hepatitis B virus (HBV) vaccination or infection in hemodialysis (HD) patients. HD patients who failed to respond to HBV vaccination did not differ in genotype frequencies of IL4R (TT 72.7%, CT 22.6%, CC 4.7%) and IL13 (CC 59.0%, CT 34.2%, TT 6.8%) from vaccine responders (IL4R TT 68.0%, CT 27.3%, CC 4.7%; IL13 CC 55.0%, CT 38.5%, TT 6.5%). HD patients who did not develop anti-HBs despite HBV infection also did not differ in genotype frequencies of IL4R (TT 67.8%, CT 26.8%, CC 5.4%) and IL13 (CC 60.7%, CT 33.9%, TT 5.4%) from HD patients who developed an anti-HBs response (IL4R TT 65.4%, CT 30.8%, CC 3.8%; IL13 CC 60.5%, CT 34.6%, TT 4.9%). In HD patients, neither the IL4R nor IL13 polymorphism is associated with anti-HBs development irrespective of whether an immunization is provoked by HBV vaccination or HBV infection. PMID- 23462528 TI - Steps for clinicians and public health officials to take to reach persons of faith, for the sake of protecting all against vaccine-preventable diseases. PMID- 23462529 TI - Sustainability of National Immunization Programme (NIP) performance and financing following Global Alliance for Vaccines and Immunization (GAVI) support to the Democratic Republic of the Congo (DRC). AB - BACKGROUND: The Global Alliance for Vaccines and Immunization (GAVI) is a public private global health partnership aiming to increase access to immunisation in poor countries. The Democratic Republic of the Congo (DRC) is the third largest recipient of GAVI funds in terms of cumulative disbursed support. We provided a comprehensive assessment of GAVI support and analysed trends in immunisation performance and financing in the DRC from 2002 to 2010. METHODS: The scope of the analysis includes GAVI's total financial support and the value of vaccines and syringes purchased by GAVI for the DRC from 2002 to 2010. Data were collected through a review of published and grey literature and interviews with key stakeholders in the DRC. We assessed the allocation and use of GAVI funds for each of GAVI's support areas, as well as trends in immunisation performance and financing. FINDINGS: DTP3 coverage increased from 2002 (38%) to 2007 (72%) but had decreased to a level below 70% in 2008 (68%) and 2010 (63%). The overall funding for vaccines increased from US$5.4 million in 2006 to US$30.5 million in 2010 (mostly from GAVI support for new vaccines). However, during the same period, the funding from national (government) and international (GAVI and other donors) sources for routine immunisation services (except vaccines) decreased from US$36.4 million to US$24.4 million. This drop in overall funding (33%) primarily affected surveillance, transport, and cold chain equipment. INTERPRETATION: GAVI support to DRC has enhanced significant progress in routine immunisation performance and financing during 2002-2010. Although progress has been partly sustained, the initial observed increase in DTP3 coverage and available funding for routine immunisation halted towards the end of the analysis period, coinciding with tetravalent and pentavalent vaccine introduction. These findings highlight the need for additional efforts to ensure the sustainability of routine immunization program performance and financing. PMID- 23462530 TI - Use of prothrombin complex concentrates and fibrinogen concentrates in the perioperative setting: a systematic review. AB - The use of prothrombin complex concentrates (PCCs) and fibrinogen concentrates (FIBCs) to achieve hemostasis in the perioperative setting as alternatives to allogeneic blood products remains controversial. To examine the efficacy and safety of PCCs and FIBCs, we conducted a systematic review-in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement-to compare the use of these transfusion alternatives in bleeding surgical patients. We performed a literature search of English articles published between July 1997 and July 2012 in MEDLINE via PubMed, The Cochrane Library, and CINAHL. Five randomized trials and 15 nonrandomized studies with a comparator group were included in the final review. Studies were sorted into 1 of the following 3 clinical settings: cardiac surgery, non-cardiac surgery, and reversal of warfarin anticoagulation. Risk of bias was assessed using the Cochrane risk of bias tool. With the exception of 2 randomized controlled trials, the existing body of literature on the use of PCCs and FIBCs in the perioperative setting was assessed to have a high degree of methodological bias. Overall, prospective studies in the cardiac surgery grouping suggested that patients receiving FIBC and/or PCCs required less allogeneic blood transfusion and had less chest tube drainage. In studies of warfarin reversal, PCCs more rapidly corrected the International Normalized Ratio compared to plasma; however, in the setting of intracranial hemorrhage, functional outcomes were poor regardless of the reversal strategy. With regards to safety outcomes, reporting was not uniform and raises concerns of underreporting. Adequately powered, methodologically sound trials would be required for more definitive conclusions to be drawn about the efficacy of PCCs and FIBC over conventional blood components for the treatment of perioperative coagulopathy in bleeding patients. PMID- 23462531 TI - Oleodaphnoic acid and coriaceol, two new natural products from the stem bark of Wikstroemia coriacea. AB - Fractionation of the chloroform extract of Wikstroemia coriacea led to the isolation of two new compounds, oleodaphnoic acid (1), a guaiane-type sesquiterpenoid, and coriaceol (2), an 1,5-diphenyl-1-pentanone analogue, together with nine known compounds. The structures of 1 and 2 were elucidated by extensive spectroscopic data analysis. The known compounds were oleodaphnal (3), indicanone (4), (5R,8R,8aR)-3,8-dimethyl-4,5,6,7,8,8a-hexahydro-5-(1 methylethenyl)-2(1H)-azulenone, (5), 1,5 diphenyl-1-pentanone (6), (+)-3-hydroxy 1,5-diphenyl-1-pentanone (7), umbelliferone (8), daphnoretin (9), beta sitostenone (10) and (-)-hinokinin (11). PMID- 23462532 TI - Polyphenols, antioxidant potential and color of fortified wines during accelerated ageing: the Madeira Wine case study. AB - Polyphenols, antioxidant potential and color of three types of fortified Madeira wines were evaluated during the accelerated ageing, named as estufagem. The traditional estufagem process was set to 45 degrees C for 3 months. Overheating conditions, 1 month at 70 degrees C, were also examined. Total polyphenols (TP), total monomeric anthocyanins (TMA) and total flavonoids (TF) were assessed by spectrophotometric methods, while individual polyphenols and furans were simultaneously determined by HPLC-DAD. Antioxidant potential (AP) was estimated by ABTS, DPPH and FRAP assays, while color was evaluated by Glories and CIELab. Traditional estufagem decreased the TP and AP up to 20% and 26%, respectively, with final values similar to other wines. TMA of the Madeira wines from red grapes decreased during estufagem. Six hydroxybenzoic acids, three hydroxycinnamic acids, one stilbene, three flavonols and three flavan-3-ols were found in these wines. The prominent phenolics were hydroxycinnamates and hydroxybenzoates, even after estufagem. Most polyphenols decreased, with the exception of caffeic, ferulic, p-coumaric, gallic and syringic acids. Finally, both chromatic systems revealed that all wines tended to similar chromatic characteristics after estufagem. The study suggests that estufagem can be applied without high impact on polyphenols and antioxidant potential of these fortified wines. PMID- 23462533 TI - Trajectory data analyses for pedestrian space-time activity study. AB - It is well recognized that human movement in the spatial and temporal dimensions has direct influence on disease transmission(1-3). An infectious disease typically spreads via contact between infected and susceptible individuals in their overlapped activity spaces. Therefore, daily mobility-activity information can be used as an indicator to measure exposures to risk factors of infection. However, a major difficulty and thus the reason for paucity of studies of infectious disease transmission at the micro scale arise from the lack of detailed individual mobility data. Previously in transportation and tourism research detailed space-time activity data often relied on the time-space diary technique, which requires subjects to actively record their activities in time and space. This is highly demanding for the participants and collaboration from the participants greatly affects the quality of data(4). Modern technologies such as GPS and mobile communications have made possible the automatic collection of trajectory data. The data collected, however, is not ideal for modeling human space-time activities, limited by the accuracies of existing devices. There is also no readily available tool for efficient processing of the data for human behavior study. We present here a suite of methods and an integrated ArcGIS desktop-based visual interface for the pre-processing and spatiotemporal analyses of trajectory data. We provide examples of how such processing may be used to model human space-time activities, especially with error-rich pedestrian trajectory data, that could be useful in public health studies such as infectious disease transmission modeling. The procedure presented includes pre-processing, trajectory segmentation, activity space characterization, density estimation and visualization, and a few other exploratory analysis methods. Pre-processing is the cleaning of noisy raw trajectory data. We introduce an interactive visual pre processing interface as well as an automatic module. Trajectory segmentation(5) involves the identification of indoor and outdoor parts from pre-processed space time tracks. Again, both interactive visual segmentation and automatic segmentation are supported. Segmented space-time tracks are then analyzed to derive characteristics of one's activity space such as activity radius etc. Density estimation and visualization are used to examine large amount of trajectory data to model hot spots and interactions. We demonstrate both density surface mapping(6) and density volume rendering(7). We also include a couple of other exploratory data analyses (EDA) and visualizations tools, such as Google Earth animation support and connection analysis. The suite of analytical as well as visual methods presented in this paper may be applied to any trajectory data for space-time activity studies. PMID- 23462534 TI - Binding analysis between L-histidine immobilized and oligonucleotides by SPR and NMR. AB - Saturation transfer difference (STD) NMR technique and surface plasmon resonance (SPR) are used to study amino acid affinity supports-nucleotides interactions with L-histidine amino acid immobilized on a surface as model support. We have immobilized L-histidine ligand on a carboxymethyldextran-modified gold surface intended for surface plasmon resonance and we analyze the binding profiles of synthetic polynucleotides (1-6 base, sugar and backbone) by determining the equilibrium dissociation constant (KD). The SPR binding profile (square-shaped) is identical for all the complexes and the highest binding affinity can be found for polyA6 followed by polyG6. As expected, the 5'-mononucleotides have the lowest affinity. To further study the structural aspects of the interaction we investigate the polynucleotide binding preferences to L-histidine chromatography support by STD-NMR spectroscopy. These results revealed that an increase in the number of bases and backbone to 6 units leads to more contacts with the support, where the main driving force for the interaction with polynucleotides are through the base, except for polyC6, which is mainly through sugar-phosphate backbone. Therefore, the combination of SPR measurements with STD-NMR technique allowed to establish fine details of the molecular recognition process involved in amino acid affinity supports-nucleotides complexes. PMID- 23462535 TI - Structural and stability studies of the human mtHsp70-escort protein 1: an essential mortalin co-chaperone. AB - Mitochondrial Hsp70 is involved in both protein import and folding process, among other essential functions. In mammalian cells, due to its role in the malignant process, it receives the name of mortalin. Despite its importance in protein and mitochondrial homeostasis, mortalin tends to self-aggregate in vitro and in vivo, the later leads to mitochondrial biogenesis failure. Recently, a zinc-finger protein, named Hsp70-escort protein 1 (Hep1, also called Zim17/TIM15/DNLZ), was described as an essential human mitochondrial mortalin co-chaperone which avoids its self-aggregation. Here, we report structural studies of the human Hep1 (hHep1). The results indicate that hHep1 shares some structural similarities with the yeast ortholog despite the low identity and functional differences. We also observed that hHep1 oligomerizes in a concentration-dependent fashion and that the zinc ion, which is essential for hHep1 in vivo function, has an important protein-structure stabilizing effect. PMID- 23462536 TI - Intraoperative and percutaneous iridium-192 high-dose-rate brachytherapy for previously irradiated lesions of the spine. AB - PURPOSE: Advances in stereotactic radiosurgery have improved local control of spine metastases, but local failure is still a problem and repeat irradiation is limited by normal tissue tolerance. A novel high-dose-rate (HDR) brachytherapy technique has been developed to treat these previously irradiated lesions. METHODS AND MATERIALS: Five patients with progressive disease at previously irradiated sites in the spine who were not amenable to further external beam radiation were treated. Catheters were placed intraoperatively in 2 patients and percutaneously implanted in 3 patients with image-guided techniques. Conformal plans were generated to deliver dose to target tissues and spare critical structures. Patients received single-fraction treatment using HDR iridium-192 brachytherapy. RESULTS: Median dose was 14 Gy (range, 12-18 Gy) with a median gross total volume D90 of 75% (range, 31-94%); spinal cord/cauda equina dose constraints were met. At a median followup of 9 months, no local progression of disease has been observed. Four patients had reduction in pain 1-4 weeks after treatment. No brachytherapy-related complications have been observed. CONCLUSIONS: Intraoperative and percutaneous iridium-192 HDR spine brachytherapy techniques were not associated with complications or acute toxicity. There has been no local progression at treated sites, and most patients experienced reduction in cancer-related pain. PMID- 23462538 TI - Disappearance of the gallstones under SMOFLipid: true or coincidental association? PMID- 23462537 TI - Effects of rye and whole wheat versus refined cereal foods on metabolic risk factors: a randomised controlled two-centre intervention study. AB - BACKGROUND & AIMS: Intervention studies investigating the effects of wholegrain intake on glucose and insulin metabolism have provided conflicting results. Aim of this study was the evaluation of glucose and insulin metabolism in response to long-term consumption of rye and whole wheat compared with a diet containing the same amount of refined cereal foods, in individuals with metabolic syndrome from two European locations (Kuopio-Finland/Naples-Italy). METHODS: 146 individuals of both genders, age range 40-65 years with metabolic syndrome, were recruited to this study with parallel groups. After a 2-4 week run-in period, participants were assigned to a diet based on wholegrain (wholegrain group) or on refined cereal products (control group), each one for a duration of 12 weeks. Peripheral insulin sensitivity, assessed by FSIGT, lipids and inflammatory markers were measured before and at the end of intervention. RESULTS: 61 participants in the control group and 62 in the wholegrain group completed the dietary intervention. Compliance to the two diets was good. At the end of the intervention, insulin sensitivity indices and secretion (SI, QUICKI, DI, dAIRG) and lipids and inflammatory markers did not change significantly in the wholegrain and control groups as compared with baseline and no differences between the two groups were observed. CONCLUSIONS: Wholegrain cereal foods consumption compared with refined cereals for 12 weeks did not affect peripheral insulin sensitivity. The study was registered with ClinicalTrials.gov identifier NCT00945854. PMID- 23462539 TI - Structural characterization of recombinant alpha-1-antitrypsin expressed in a human cell line. AB - Human alpha-1-antitrypsin (A1PI) is a plasma protein with the function of protecting lung tissues from proteolytic destruction by enzymes from inflammatory cells. A1PI deficiency is an inherited disorder associated with pulmonary emphysema and a higher risk of chronic obstructive pulmonary disease (COPD). Here we present the structural characterization of a recombinant form of human A1PI (Hu-recA1PI) expressed in the human PER.C6 cell line using an array of analytical and biochemical techniques. Hu-recA1PI had the same primary structure as plasma derived A1PI (pd-A1PI) except reduced N-terminal heterogeneity. The secondary and tertiary structures were indistinguishable from pd-A1PI. Like pd-A1PI, Hu-recA1PI was modified by N-linked glycosylation on N46, N83, and N246. Unlike pd-A1PI, most glycans on recA1P1 were core fucosylated via alpha(1-6) linkage. In addition, significantly higher amounts of tri- and tetraantennary glycans were observed. These differences in glycosylation contributed to the apparent higher molecular weight and lower isoelectric point (pI) of Hu-recA1PI than pd-A1PI. Hu recA1PI contained both alpha(2-3)- and alpha(2-6)-linked sialic acids and had very similar sialylation levels as pd-A1PI. Hu-recA1PI glycans were differentially distributed, with N46 containing mostly biantennary glycans, N83 containing primarily tri- and tetraantennary glycans, and N247 containing exclusively biantennary glycans. PMID- 23462540 TI - Measuring oxidative phosphorylation in human skin fibroblasts. AB - An approach has been developed to quantitate oxidative phosphorylation in harvested human skin fibroblasts that have been permeabilized with digitonin. In protocol 1, state 3 rates are measured with complex I and II substrates, followed by uncoupled maximal oxidative capacity measured in the presence of these combined substrates as well as through complex IV. In protocol 2, state 3 rates are measured using palmitoylcarnitine to monitor fatty acid oxidation and duroquinol to assess the flux through complex III; uncoupled duroquinol oxidation measures maximal oxidative capacity through complex III. The activity of citrate synthase is determined in every experiment as a marker of the amount of mitochondria per chamber. Data are expressed on the basis of cell count (per million fibroblasts), of protein, or of citrate synthase activity. Cell growth conditions are optimized, and it is necessary to keep cultured cells from reaching confluency. Cultures in passages 3 to 10 show reproducible oxidative phosphorylation data. Based on the data from the 15 normal human skin fibroblast lines, we are evaluating the use of this approach to diagnose systemic mitochondrial disease and avoid issues associated with open skeletal muscle biopsy. PMID- 23462541 TI - [Complications after lung transplantation in chronic obstructive pulmonary disease]. AB - BACKGROUND AND OBJECTIVE: Lung transplantation (LT) in chronic obstructive pulmonary disease (COPD) is a procedure with a high rate of morbimortality. The aim of this paper is to analyze the early and late rates of complications and mortality in COPD patients undergoing LT. PATIENTS AND METHOD: Retrospective study of 107 COPD patients transplanted in the Hospital Universitario La Fe, between 1991 and 2008. Preoperative variables were collected as well as all the complications, medical and surgical, occurred in the follow-up, which are expressed as mean or percentage as appropriate. The 30-day mortality and long term survival were established. RESULTS: A total of 94 men (87.9%) and 13 women (12.1%) were transplanted with a mean age (SD) of 52.58 (8.05) years with 71% of double-lung LT. BODE score was 7.24 (1.28). The rate of primary graft dysfunction was 39.3%. The most common surgical complications were phrenic paralysis (16.8%), hemothorax (17.8%) and pleural effusion (30.8%). There was a high number of postoperative hospitalization (30%) and medical complications such as hypertension (36%), diabetes mellitus (16.7%) and renal failure (40%), secondary to treatment. Perioperative mortality was 14% and 34.5% after a year, being the most frequent causes infections (34.6%) and chronic rejection (BOS) (17.8%). Five year survival was 40.9% with bronchiectasis and smoking history being the risk factors. CONCLUSIONS: LT is a procedure with a high early mortality rate associated with high medical and surgical complications that affect the outcome. PMID- 23462542 TI - [Considerations about survival following lung transplantation in chronic obstructive pulmonary disease]. PMID- 23462543 TI - [Hereditary pheochromocytoma and paraganglioma: the disease with ten faces]. PMID- 23462544 TI - [Chronic myeloid leukemia and resistance to tyrosine kinase inhibitors: ABL mutations, much ado about nothing?]. PMID- 23462545 TI - Next generation sequencing reveals the association of DRB3*02:02 with type 1 diabetes. AB - The primary associations of the HLA class II genes, HLA-DRB1 and HLA-DQB1, and the class I genes, HLA-A and HLA-B, with type 1 diabetes (T1D) are well established. However, the role of polymorphism at the HLA-DRB3, HLA-DRB4, and HLA DRB5 loci remains unclear. In two separate studies, one of 500 subjects and 500 control subjects and one of 366 DRB1*03:01-positive samples from selected multiplex T1D families, we used Roche 454 sequencing with Conexio Genomics ASSIGN ATF 454 HLA genotyping software analysis to analyze sequence variation at these three HLA-DRB loci. Association analyses were performed on the two HLA-DRB loci haplotypes (DRB1-DRB3, -DRB4, or -DRB5). Three common HLA-DRB3 alleles (*01:01, *02:02, *03:01) were observed. DRB1*03:01 haplotypes carrying DRB3*02:02 conferred a higher T1D risk than did DRB1*03:01 haplotypes carrying DRB3*01:01 in DRB1*03:01/*03:01 homozygotes with two DRB3*01:01 alleles (odds ratio [OR] 3.4 [95% CI 1.46-8.09]), compared with those carrying one or two DRB3*02:02 alleles (OR 25.5 [3.43-189.2]) (P = 0.033). For DRB1*03:01/*04:01 heterozygotes, however, the HLA-DRB3 allele did not significantly modify the T1D risk of the DRB1*03:01 haplotype (OR 7.7 for *02:02; 6.8 for *01:01). These observations were confirmed by sequence analysis of HLA-DRB3 exon 2 in a targeted replication study of 281 informative T1D family members and 86 affected family-based association control (AFBAC) haplotypes. The frequency of DRB3*02:02 was 42.9% in the DRB1*03:01/*03:01 patients and 27.6% in the DRB1*03:01/*04 (P = 0.005) compared with 22.6% in AFBAC DRB1*03:01 chromosomes (P = 0.001). Analysis of T1D associated alleles at other HLA loci (HLA-A, HLA-B, and HLA-DPB1) on DRB1*03:01 haplotypes suggests that DRB3*02:02 on the DRB1*03:01 haplotype can contribute to T1D risk. PMID- 23462546 TI - Bilateral thigh pain after treatment for prostate cancer. PMID- 23462547 TI - Mid Staffs inquiry. Changing behaviour with a human factors approach. PMID- 23462548 TI - Signals from chloroplasts and mitochondria for iron homeostasis regulation. AB - Iron (Fe) is an essential element for human nutrition. Given that plants represent a major dietary source of Fe worldwide, it is crucial to understand plant Fe homeostasis fully. A major breakthrough in the understanding of Fe sensing and signaling was the identification of several transcription factor cascades regulating Fe homeostasis. However, the mechanisms of activation of these cascades still remain to be elucidated. In this opinion, we focus on the possible roles of mitochondria and chloroplasts as cellular Fe sensing and signaling sites, offering a new perspective on the integrated regulation of Fe homeostasis and its interplay with cellular metabolism. PMID- 23462549 TI - Evolution of the plant-microbe symbiotic 'toolkit'. AB - Beneficial associations between plants and arbuscular mycorrhizal fungi play a major role in terrestrial environments and in the sustainability of agroecosystems. Proteins, microRNAs, and small molecules have been identified in model angiosperms as required for the establishment of arbuscular mycorrhizal associations and define a symbiotic 'toolkit' used for other interactions such as the rhizobia-legume symbiosis. Based on recent studies, we propose an evolutionary framework for this toolkit. Some components appeared recently in angiosperms, whereas others are highly conserved even in land plants unable to form arbuscular mycorrhizal associations. The exciting finding that some components pre-date the appearance of arbuscular mycorrhizal fungi suggests the existence of unknown roles for this toolkit and even the possibility of symbiotic associations in charophyte green algae. PMID- 23462550 TI - Quality of life of former premature infants during adolescence and beyond. AB - Interest in determining the quality of life of children and adults is now considered a priority. This is a result of a shift in thinking with greater transparency in finding out not only the health outcomes, but also the personal burden of illness and life satisfaction for the individual. However, there is still no consensus on the definition of quality of life or the appropriate tools to measure the same. In the last three decades there has been an exponential increase in the number of publications measuring quality of life, particularly in former premature infants. Most studies show that despite disabilities, children rate their quality of life almost equivalent to that of children born at term, and higher than that predicted by health professionals. This review will focus on the conceptual framework and measurement of self-reported quality of life in the context of former premature infants at adolescence and young adulthood. PMID- 23462551 TI - Psychosocial development of adolescent preterm children. PMID- 23462552 TI - Spin-flop and antiferromagnetic phases of the ferromagnetic half-twist ladder compounds Ba3Cu3In4O12 and Ba3Cu3Sc4O12. AB - The title compounds have dominant ferromagnetic exchange interactions within one dimensional (1D) half-twist ladders of s = 1/2 Cu(2+) ions and antiferromagnetic (AFM) interactions between ladders, leading to ordered 3D phases at temperatures below 20 K. Here we show that a microscopic 1D model of the paramagnetic (PM) phase combined with a phenomenological model based on sublattice magnetization describes the observed temperature and field dependent magnetism. The model identifies AFM, spin-flop and PM phases whose boundaries have sharp features in the experimental magnetization M(T,H) and specific heat C(P)(T,H). Exact diagonalization of the 1D model, possible for 24 spins due to special structural features of half-twist ladders, yields the magnetization and spin susceptibility of the PM phase. AFM interactions between ladders are included at the mean-field level using the field, H(AF), obtained from modelling the ordered phases. Isotropic exchange J1 =- 135 K and g-tensor g = 2.1 within ladders, plus exchange and anisotropy fields H(AF) and H(A), describe the ordered phases and are almost quantitative for the PM phase. PMID- 23462553 TI - GAG depletion increases the stress-relaxation response of tendon fascicles, but does not influence recovery. AB - Cyclic and static loading regimes are commonly used to study tenocyte metabolism in vitro and to improve our understanding of exercise-associated tendon pathologies. The aims of our study were to investigate if cyclic and static stress relaxation affected the mechanical properties of tendon fascicles differently, if this effect was reversible after a recovery period, and if the removal of glycosaminoglycans (GAGs) affected sample recovery. Tendon fascicles were dissected frombovine-foot extensors and subjected to 14% cyclic (1Hz) or static tensile strain for 30min. Additional fascicles were incubated overnight in buffer with 0.5U chondroitinase ABC or in buffer alone prior to the static stress relaxation regime. To assess the effect of different stress-relaxation regimes, a quasi-static test to failure was carried out, either directly post loading or after a 2h recovery period, and compared with unloaded control fascicles. Both stress-relaxation regimes led to a significant reduction in fascicle failure stress and strain, but this was more pronounced in the cyclically loaded specimens. Removal of GAGs led to more stress relaxation and greater reductions in failure stress after static loading compared to controls. The reduction in mechanical properties was partially reversible in all samples, given a recovery period of 2h. This has implications for mechanical testing protocols, as a time delay between fatiguing specimens and characterization of mechanical properties will affect the results. GAGs appear to protect tendon fascicles from fatigue effects, possibly by enabling sample hydration. PMID- 23462554 TI - An investigation of the potential application of chitosan/aloe-based membranes for regenerative medicine. AB - A significant number of therapeutics derived from natural polymers and plants have been developed to replace or to be used in conjunction with existing dressing products. The use of the therapeutic properties of aloe vera could be very useful in the creation of active wound dressing materials. The present work was undertaken to examine issues concerning structural features, topography, enzymatic degradation behavior, antibacterial activity and cellular response of chitosan/aloe vera-based membranes. The chitosan/aloe vera-based membranes that were developed displayed satisfactory degradation, roughness, wettability and mechanical properties. A higher antibacterial potency was displayed by the blended membranes. Moreover, in vitro assays demonstrated that these blended membranes have good cell compatibility with primary human dermal fibroblasts. The chitosan/aloe vera-based membranes might be promising wound dressing materials. PMID- 23462556 TI - The good, the bad and the ugly in the changing healthcare landscape: the role of nurse practitioners in meeting increasing demand for primary care (the good), CMS and contractor oversight of home health agencies (the bad), and the sad demise of the Medicaid hospice benefit in Louisiana (the ugly). PMID- 23462555 TI - Mutational analysis clopidogrel resistance and platelet function in patients scheduled for coronary artery bypass grafting. AB - Clopidogrel is an oral antiplatelet pro-drug prescribed to 40 million patients worldwide who are at risk for thrombotic events or receiving percutaneous coronary intervention (PCI). However about a fifth of patients treated with clopidogrel do not respond adequately to the drug. From a cohort of 105 patients on whom we had functional data on clopidogrel response, we used ultra-high throughput sequencing to assay mutations in CYP2C19 and ABCB1, the two genes genetically linked to respond. Testing for mutations in CYP2C19, as recommended by the FDA, only correctly predicted if a patient would respond to clopidogrel 52.4% of the time. Similarly, testing of the ABCB1 gene only correctly foretold response in 51 (48.6%) patients. These results are clinically relevant and suggest that until additional genetic factors are discovered that predict response more completely, functional assays are more appropriate for clinical use. PMID- 23462558 TI - Is self-administration of subcutaneous immunoglobulin therapy safe in a home care setting? AB - Clinical practice based on best evidence can help ensure that patients receive safe and appropriate care from nurses. Members of a nursing inquiry council at a pediatric-based organization addressed the issue of patient-administered immunoglobulin therapy in the home care setting through conducting an evidence based practice (EBP) project. Following the steps of EBP, an EBP change was implemented that allowed families the option of immunoglobulin therapy administration by the patient (or a caregiver) or a home healthcare nurse. Outcomes measured indicated that self-administration positively impacted patient and family satisfaction and posed no additional safety risks. PMID- 23462560 TI - Hoarding in the home: a toolkit for the home healthcare provider. AB - Hoarding is a mental health disorder characterized by difficulties with discarding possessions, yielding cluttered and chaotic home environments that can pose significant safety concerns, impairment to functioning, and distress for those who live in and encounter these situations. Understanding the condition and the strategies available to support individuals who hoard are important skills for the home care provider and are described here in the context of one community organization's response via the development of a Community Clutter and Hoarding Toolkit. PMID- 23462562 TI - Online resources for culturally and linguistically appropriate services in home healthcare and hospice: part 4: resources for European patients. AB - Provision of culturally and linguistically appropriate care for home care and hospice patients is a national mandate. Finding patient-education materials in languages other than English can be a challenge for clinicians in workplaces lacking affiliation with a hospital that provides multilingual resources to its patients. Many hospitals, government agencies, and foundations have made appropriate resources freely available on the Internet. However, identifying them is time consuming. This article reviews a variety of sources for access to patient-education materials in the multiple languages of Europe. PMID- 23462564 TI - Home health and hospice: a time of change. PMID- 23462565 TI - Don't say the word.... PMID- 23462566 TI - Quantifying the mechanical properties of the endothelial glycocalyx with atomic force microscopy. AB - Our understanding of the interaction of leukocytes and the vessel wall during leukocyte capture is limited by an incomplete understanding of the mechanical properties of the endothelial surface layer. It is known that adhesion molecules on leukocytes are distributed non-uniformly relative to surface topography (3), that topography limits adhesive bond formation with other surfaces (9), and that physiological contact forces (~ 5.0 - 10.0 pN per microvillus) can compress the microvilli to as little as a third of their resting length, increasing the accessibility of molecules to the opposing surface (3, 7). We consider the endothelium as a two-layered structure, the relatively rigid cell body, plus the glycocalyx, a soft protective sugar coating on the luminal surface (6). It has been shown that the glycocalyx can act as a barrier to reduce adhesion of leukocytes to the endothelial surface (4). In this report we begin to address the deformability of endothelial surfaces to understand how the endothelial mechanical stiffness might affect bond formation. Endothelial cells grown in static culture do not express a robust glycocalyx, but cells grown under physiological flow conditions begin to approximate the glycocalyx observed in vivo (2). The modulus of the endothelial cell body has been measured using atomic force microscopy (AFM) to be approximately 5 to 20 kPa (5). The thickness and structure of the glycocalyx have been studied using electron microscopy (8), and the modulus of the glycocalyx has been approximated using indirect methods, but to our knowledge, there have been no published reports of a direct measurement of the glycocalyx modulus in living cells. In this study, we present indentation experiments made with a novel AFM probe on cells that have been cultured in conditions to maximize their glycocalyx expression to make direct measurements of the modulus and thickness of the endothelial glycocalyx. PMID- 23462567 TI - Radiology online: information, education, and networking--a summary of the 2012 Intersociety Committee Summer Conference. AB - The "new online" (Web 2.0) world is evolving rapidly, and the digital information, education, and networking resources available to radiologists have exploded over the past 2 decades. The 2012 Intersociety Committee Summer Conference attendees explored the online resources that have been produced by societies, universities, and commercial entities. Specific attention was given to identifying the best products and packaging them in tablet computers for use by residents and practicing radiologists. The key functions of social networking websites and the possible roles they can play in radiology were explored as well. It was the consensus of the attendees that radiologic digital resources and portable electronic devices have matured to the point that they should become an integral part of our educational programs and clinical practice. PMID- 23462568 TI - Introducing first-year radiology residents to the ACR at the AMCLC from 2009 2011: the potential impact for ACR and state radiological society memberships. AB - PURPOSE: This study was designed to determine if first-year radiology resident attendance at the ACR AMCLC over a period of 3 years from 2009 to 2011 led to increased resident knowledge regarding the ACR and Minnesota Radiological Society (MRS), and whether resident involvement in the conference would influence their decisions to participate in the ACR and state radiological societies in the future. METHODS: All first-year radiology residents from the University of Minnesota and the Mayo Clinic residency programs were invited to attend the ACR AMCLC from 2009 to 2011. Local radiology and radiation oncology groups provided funding for travel and hotel expenses, and both residency programs granted residents one day off from clinical duties to travel. Preconference and postconference questionnaires were used to assess residents' knowledge of the general structure and function of the ACR and MRS. Postconference questionnaires were also used to assess residents' satisfaction with the conference and determine their likelihood of joining the ACR and MRS in the future. RESULTS: A total of 46 residents from the residency programs attended the conference over this time period. Residents' knowledge regarding the ACR and MRS increased after the conference, with improved performance on postconference objective and subjective responses. The number of issues residents identified as important to radiology increased after the conference. The vast majority of residents had a very positive experience at the conference and were "highly likely" or "likely" to join the ACR and MRS in the future. CONCLUSIONS: Results from the first 3 years of this ongoing study indicate that attending the ACR AMCLC has been an overwhelmingly positive experience for first-year radiology residents from the University of Minnesota and the Mayo Clinic programs. Residents' knowledge regarding the ACR and MRS increased nearly 2-fold following the conference. Future state radiological society and ACR membership rates among the participants in our study could potentially be higher than the current national average. Furthermore, we believe the residents' experiences at the conference play an important role in their development as more connected, informed, and politically active radiologists in the future. PMID- 23462569 TI - NMR-based metabonomic in hippocampus, nucleus accumbens and prefrontal cortex of methamphetamine-sensitized rats. AB - (1)H NMR spectroscopy was applied to investigate the changes of cerebral metabolites in brain hippocampus, nucleus accumbens (NAC) and prefrontal cortex (PFC) of the rats subjected to subcutaneous twice-daily injections of 2.5mg/kg methamphetamine (MAP) for 7 days. The results indicated that MAP exposure induced significant behavioral sensitization and altered cerebral metabolites in rats. The neurotransmitters glutamate, glutamine and GABA significantly decreased in hippocampus, NAC and PFC. Specifically, increased succinic acid semialdehyde, a metabolism product of GABA, was observed in hippocampus. Additionally, decreased serotonin was observed in both NAC and PFC, whereas decreased dopamine was only observed in NAC after repeated MAP treatment. Glutathione obviously decreased in above brain regions, whereas acetylcysteine declined in hippocampus and NAC, and taurine declined in NAC and PFC. Homocysteic acid was elevated in hippocampus and NAC by repeated MAP administration. Membrane ingredients like phosphocholine elevated in response to MAP administration in NAC and PFC. N-Acetyl-aspartate, a marker of neuronal viability, decreased in the three regions; however, myo inositol, a glial cell marker, increased in hippocampus and PFC. Tricarboxylic acid cycle intermediate products, such as alpha-ketoglutarate, succinate, citrate and the methionine significantly decreased in above three brain regions after MAP administration; however, ADP decreased in hippocampus. These results indicate that repeated MAP treatment causes neurotransmitters disturbance, imbalance between oxidative stress and antioxidants, and gliosis in hippocampus, NAC and PFC. Profound metabolic changes detected across brain regions provide the first evidence of metabonomic changes in MAP-induced sensitized rats. PMID- 23462570 TI - Simultaneous perfusion and permeability measurements using combined spin- and gradient-echo MRI. AB - The purpose of this study was to estimate magnetic resonance imaging-based brain perfusion parameters from combined multiecho spin-echo and gradient-echo acquisitions, to correct them for T1-, T2-, and T2-*-related contrast agent (CA) extravasation effects, and to simultaneously determine vascular permeability. Perfusion data were acquired using a combined multiecho spin- and gradient-echo (SAGE) echo-planar imaging sequence, which was corrected for CA extravasation effects using pharmacokinetic modeling. The presented method was validated in simulations and brain tumor patients, and compared with uncorrected single-echo and multiecho data. In the presence of CA extravasation, uncorrected single-echo data resulted in underestimated CA concentrations, leading to underestimated single-echo cerebral blood volume (CBV) and mean transit time (MTT). In contrast, uncorrected multiecho data resulted in overestimations of CA concentrations, CBV, and MTT. The correction of CA extravasation effects resulted in CBV and MTT estimates that were more consistent with the underlying tissue characteristics. Spin-echo perfusion data showed reduced large-vessel blooming effects, facilitating better distinction between increased CBV due to active tumor progression and elevated CBV due to the presence of cortical vessels in tumor proximity. Furthermore, extracted permeability parameters were in good agreement with elevated T1-weighted postcontrast signal values. PMID- 23462571 TI - Cerebral blood volume affects blood-brain barrier integrity in an acute transient stroke model. AB - Insufficient vascular reserve after an ischemic stroke may induce biochemical cascades that subsequently deteriorate the blood-brain barrier (BBB) function. However, the direct relationship between poor cerebral blood volume (CBV) restoration and BBB disruption has not been examined in acute stroke. To quantify BBB integrity at acute stages of transient stroke, in particular for cases in which extravasation of the standard contrast agent (Gd-DTPA) is not observed, we adopted the water exchange index (WEI), a novel magnetic resonance image-derived parameter to estimate the water permeability across the BBB. The apparent diffusion coefficient (ADC) and R2 relaxation rate constant were also measured for outlining the tissue abnormality, while fractional CBV and WEI were quantified for assessing vascular alterations. The significantly decreased ADC and R2 in the ischemic cortices did not correlate with the changes in CBV or WEI. In contrast, a strong negative correlation between the ipsilesional WEI and CBV was found, in which stroke mice were clustered into two groups: (1) high WEI and low CBV and (2) normal WEI and CBV. The low CBV observed for mice with a disrupted BBB, characterized by a high WEI, indicates the importance of CBV restoration for maintaining BBB stability in acute stroke. PMID- 23462572 TI - Detrimental effects of leptin on intracerebral hemorrhage via the STAT3 signal pathway. AB - Leptin, one of the most important adipokines, is not only an energy regulator but also a regulator of innate immunity. Inflammation plays a key role in the tissue damage after intracerebral hemorrhage (ICH), and we sought to investigate whether leptin has a detrimental effect on ICH. After the injection of a high replacement dose (0.04 mg/kg) and two pharmacologic doses (4 and 8 mg/kg) of leptin, brain water contents increased significantly compared with that of control mice (P<0.05), which was confirmed when comparing the results with leptin-deficient ob/ob and wild-type (WT) mice (78.8%+/-0.6% versus 79.7%+/-0.6%, P<0.05). The number of Ox6-positive microglia/macrophages was increased in the leptin-injected group and decreased in ob/ob compared with WT mice. Among the candidate signal transducers, an increase in signal transduction and activator of transcription 3 (STAT3) levels was found after leptin injection. When we administered NSC74859, a specific inhibitor of phosphorylated STAT3 (pSTAT3), the water content became normalized. Activity of pSTAT3 was found mainly in Ox6-positive microglia/macrophages, but not in either neurons or astrocytes. We demonstrate that leptin plays a critical role in the secondary brain injury around a hematoma and is a novel mediator of the inflammation. This detrimental effect of leptin on ICH is mediated by the STAT3 signaling pathway in inflammatory cells. PMID- 23462573 TI - Intradural lumbar disc herniation associated with degenerative spine disease and rheumatoid arthritis. AB - STUDY DESIGN: A case report. OBJECTIVE: To demonstrate a case of intradural lumbar disc herniation including imaging studies, intraoperative imaging, and an intraoperative video. SUMMARY OF BACKGROUND DATA: The first case of lumbar intradural disc herniation was reported as early as 1942; since then more than 150 cases have been reported, mostly in the lumbar spine. Gadolinium-enhanced magnetic resonance image (MRI) is considered the "gold standard" for diagnosing this entity, although it is rarely performed routinely in lumbar disc disease and diagnosis is often made intraoperatively. METHODS: A 70-year-old man presented to the emergency department as a referral complaining of lower back pain, loss of sensation in the right thigh, and difficulty walking. On examination, he showed uneven gait, right-sided foot drop (1/5), hypesthesias in the right inguinal area and ventral thigh, and a positive straight leg raise test on the right. Anal sphincter tone was within normal limits. A magnetic resonance image of the lumbar spine showed a large mediolateral herniated disc at L3-L4, with caudal displacement and unclear signal changes intradurally. RESULTS: Intraoperatively, the herniated disc was found upon opening the dural sac. CONCLUSION: Intradural disc herniations are a rare entity. The opening and inspection of the dural sack should be considered when the correct spinal level can be confirmed and insufficient herniated disc material can be visualized extradurally. PMID- 23462574 TI - Preoperative magnetic resonance imaging is associated with baseline neurological status and can predict postoperative recovery in patients with cervical spondylotic myelopathy. AB - STUDY DESIGN: A blinded observational study of consecutive patients, prospectively enrolled and followed up to 1 year postoperatively. OBJECTIVE: To assess whether quantitative assessment of preoperative magnetic resonance imaging (MRI) predicts baseline patient status and postoperative neurological recovery. SUMMARY OF BACKGROUND DATA: Factors that can predict neurological recovery in patients with cervical spondylotic myelopathy (CSM) postoperatively are of great interest. Currently, the literature regarding the significance of MRI signal changes in relation to prognosis is inconsistent and conflicting. METHODS: A total of 57 consecutive patients with CSM were studied preoperatively and 1 year postoperatively. Modified Japanese Orthopaedic Association (mJOA), Nurick Grade, SF-36, neck disability index, 30-meter walk cadence (Wc) and time (Wt), grip strength, and Berg Balance Scale were administered at baseline and 1 year after surgery. Preoperative status and postoperative recovery were assessed in relation to quantitative MRI measurements pre- and postoperatively using univariate and multivariate analysis. RESULTS: Low T1 signal change preoperatively was associated with a lower mJOA (P = 0.0030), higher Nurick Grade (P = 0.0298), decreased grip (P = 0.0152), impaired Wt, Wc (P<= 0.0001) and poor Berg Balance Scale (P = 0.0005) at baseline. Focal high T2 signal was associated with lower mJOA scores and higher Nurick Grade compared with diffuse T2 (P = 0.0035 P = 0.0079) or no T2 signal (P = 0.0680 P = 0.0122). Preoperative segmentation of T2 signal, showed a significant increase in Wt, Wc, and Berg Balance Scale (P = 0.0266; P = 0.0167; P = 0.0042). Preoperative T1 signal was associated with lower postoperative grip (P = 0.0260), greater Wt, Wc (P = 0.0360, P = 0.0090). Preoperative focal T2 signal had a significant association with poorer postoperative Wt, Wc (P = 0.0220) and Nurick Grade (P = 0.0230). Preoperative maximal cord compromise was negatively correlated with postoperative SF-36 mental score (P = 0.0130). CONCLUSION: MRI signal changes are predictive of baseline neurological status and postoperative recovery. MRI indicators of poorer outcome include the presence of low T1 signal, focal increased T2 signal and segmentation of T2 signal changes. LEVEL OF EVIDENCE: 2. PMID- 23462575 TI - Effect of smoking on the perioperative outcomes of patients who undergo elective spine surgery. AB - STUDY DESIGN: Retrospective analysis of the prospectively collected American College of Surgeons National Surgical Quality Improvement database. OBJECTIVE: We assessed whether preoperative cigarette smoking and smoking duration predicted adverse, early, perioperative outcomes in patients undergoing elective spine surgery. SUMMARY OF BACKGROUND DATA: Prior studies have assessed the association of smoking and long-term outcomes for a number of spine surgery procedures, with conflicting findings. The association between smoking and 30-day outcomes for spine surgery is unknown. METHODS: A total 14,500 adults, classified as current (N = 3914), prior (N = 2057), and never smokers. Using propensity scores, current and prior smokers were matched to never smokers. Logistic regression was used to predict adverse postoperative outcomes. The relationship between pack-years and adverse outcomes was tested. Sensitivity analyses were conducted limiting the study sample to patients who underwent spine fusion (N = 4663), and using patient subgroups by procedure. RESULTS: In unadjusted analyses, prior smokers were significantly more likely to have prolonged hospitalization (1.2, 95% confidence interval [CI]: 1.1-1.3) and major complications (1.3, 95% CI: 1.1-1.6) compared with never smokers. No association was found between smoking status and adverse outcomes in adjusted, matched patient models. Current smokers with more than 60 pack-years were more likely to die within 30 days of surgery (3.0, 95% CI, 1.1 7.8), compared with never smokers. Sensitivity analyses confirmed these findings. CONCLUSION: The large National Surgical Quality Improvement population was carefully matched for a wide range of baseline comorbidities, including 29 variables previously suggested to influence perioperative outcomes. Although previous studies conducted in subgroups of spine surgery patients have suggested a deleterious effect for smoking on long-term outcomes in patients undergoing spine surgery, our analysis did not find smoking to be associated with early (30 d) perioperative morbidity or mortality. PMID- 23462576 TI - Comparison of radicular symptoms caused by lumbar disc herniation and lumbar spinal stenosis in the elderly. AB - STUDY DESIGN: Comparative study using combined data from 2 prospective cohort studies. OBJECTIVE: To expose the differences between the clinical characteristics of neurogenic claudication from magnetic resonance image documented lumbar spinal stenosis (LSS) and lumbosacral radicular syndrome from acute, magnetic resonance image-documented, lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: LSS and LDH are the common lumbar disorders that produce lower extremity pain. Though known factors such as pain induced by walking for LSS and the rapid onset of symptoms for LDH are useful for differentiating these disorders, exploration of differences in other factors has received limited study. METHODS: This study included participants aged 60 yr or older from 2 previous studies. One examined walking limitations caused by LSS and the second the natural history of LDH in elderly adults. The clinical features of both groups were compared by calculating means, medians, and standard deviations for continuous variables, and frequencies for categorical variables. chi test was used to explore differences between LSS and LDH for categorical variables, and Student t test or Mann-Whitney test for continuous variables. RESULTS: Participants with LSS had more medical comorbidity, less intense leg pain, and less disability than those with LDH. Leg pain was more common in the anterior thigh, anterior knee and shin in LDH, and in the posterior knee in LSS. Trunk flexion was more impaired in LDH. Positive straight leg raising and femoral stretch signs were common in LDH, and rare in LSS. Abnormal Achilles reflexes were noted more frequently in LSS. CONCLUSION: In addition to established factors, greater leg pain intensity, greater disability, and pain in the anterior leg are more common in the elderly with LDH than in the elderly with LSS. Normal trunk flexion, absence of nerve root tension signs and abnormal Achilles reflexes are more common in LSS. LEVEL OF EVIDENCE: 3. PMID- 23462577 TI - Hospital outcomes and complications of anterior and posterior cervical fusion with bone morphogenetic protein. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: A nationwide population based database was analyzed to identify the incidence of complications and mortality associated with bone morphogenetic protein (BMP) utilization in cervical spine fusion surgery. SUMMARY OF BACKGROUND DATA: "Off-label" use of BMP as an adjunct in cervical fusions has been associated with increased complication rates in small case series. The incidence of complications with utilization of BMP is not well characterized on a national level. METHODS: Data from the Nationwide Inpatient Sample were obtained for each year from 2002-2009. Patients undergoing anterior cervical fusion (ACF) or posterior cervical fusion for diagnoses of cervical myelopathy and/or radiculopathy were identified and separated into cohorts ("BMP" and "No BMP"). Patient demographics and comorbidities were compared. Complications, length of stay, costs, and mortality rates were assessed. Student t test and chi test were used to assess significant differences. A P value of less than 0.0005 was used to denote significance. RESULTS: A total of 213,421 ACFs and 20,334 posterior cervical fusions were identified from 2002-2009; 6.2% of all ACFs and 12.5% of posterior cervical fusions utilized BMP. Patients receiving BMP in the ACF group were older with greater comorbidities than patients who did not receive BMP (P < 0.0005). Both surgical groups with BMP experienced increased length of stay and costs. Overall complication rates were significantly greater when BMP was utilized in ACFs (P < 0.0005) due to a significantly higher rate of dysphagia (37.2 vs. 22.5 per 1000 cases) (P < 0.0005). CONCLUSION: Our study found that "off-label" use of BMP as an adjunct to cervical fusions was associated with increased rates of dysphagia in ACFs and increased costs for all cervical fusions. Our study does not measure long-term outcomes after discharge; however, the impact of increased inhospital costs, length of stay, and incidence of dysphagia with utilization of BMP should be considered prior to its use in cervical fusions. PMID- 23462578 TI - Clinical and radiological outcomes of microscopic partial pediculectomy for degenerative lumbar foraminal stenosis. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the clinical outcomes of microscopic partial pediculectomy for degenerative lumbar craniocaudal foraminal stenosis, risk factors for postsurgical scoliosis progression, and feasibility of postsurgical pedicle screw insertion. SUMMARY OF BACKGROUND DATA: Previous studies have evaluated surgical strategies for degenerative lumbar foraminal stenosis. Although less invasive decompression surgery is an option for surgical treatment, postsurgical instability and salvaging fusion surgery remain as problems. No analysis has focused on the radiological progression and feasibility of pedicle screw setting after pediculectomy. METHODS: Microscopic partial pediculectomy by our original method was performed as a first-choice surgical treatment for lumbar radiculopathy due to degenerative craniocaudal foraminal stenosis. This study included 50 consecutive patients followed up for a minimum of 2 years. Clinical outcomes were evaluated with Japanese Orthopaedic Association (JOA) scores and a numerical rating scale. Radiological changes were obtained from standing radiographs. Foraminal height and the minimum pedicle diameter were measured by reconstructed images on multidetector row computed tomography. RESULTS: The preoperative Japanese Orthopaedic Association score of 14.2 +/- 4.2 significantly improved to 21.5 +/- 6.2, and 60% of patients were satisfied. The numerical rating scale for lumbar back pain, leg pain, and leg numbness significantly improved. Nine patients (18%) showed lumbar Cobb angle progression of 5 degrees or more within 2 years, and the risk factor for scoliosis progression was surgery at L3-L4 or L4 L5 by multivariate logistic regression analysis. Foraminal height was enlarged from 5.4 mm preoperatively to 8.9 mm postoperatively. The postoperative minimum pedicle diameter was 8.7 +/- 1.6 (5.9-11.7) mm. CONCLUSION: Microscopic lumbar partial pediculectomy provided satisfactory clinical outcomes, but early postsurgical scoliosis progression was likely to occur in patients who underwent the surgery at L3-L4 or L4-L5. Even if a second surgical procedure is needed, pedicle screws can be set on the resected pedicle. LEVEL OF EVIDENCE: 4. PMID- 23462579 TI - Extrinsic bronchial obstruction caused by scoliosis. AB - STUDY DESIGN: A case report. OBJECTIVE: To emphasize the importance of monitoring the breathing capacity in patients with moderate to severe scoliosis, even in adulthood. SUMMARY OF BACKGROUND DATA: Diseases that disturb the structure of the chest wall affect the function of the respiratory pump. Restrictive respiratory pattern is caused by severe scoliosis. However, scoliosis may provoke obstructive changes due to compression of the airways. It can be a direct compression because of imprinting of vertebral bodies, or an indirect one, due to rotation forces. METHODS.: We have collected data from the patients' clinical history and have reviewed similar published cases. RESULTS: CASE PRESENTATION: a white female, with frequent respiratory tract infections during her childhood. She was diagnosed as having 55 degrees right T5-T11 scoliosis. At age of 26, an increase of her pulmonary symptoms appeared with difficulty to expel mucus and medium efforts dyspnea. A computed axial tomographic scan showed T8 vertebral body pushing against the right intermediate bronchus. A bronchoscopy found a decrease in the bronchial area, with near contact between the walls. Lung function test: 41% forced vital capacity (FVC), 43% forced expiratory volume in 1 second (FEV1), and 91 FEV1/FVC1. The patient underwent surgical correction using rods and pedicle screws; she had improvement of symptoms, image tests, and pulmonary function (70% FVC, 71% FEV1, and 101 FEV1/FVC). CONCLUSION: Increased frequency and severity of respiratory tract infections, difficulty in expelling mucus and dyspnea are warning signs of compromised airways. Spirometry tests and image tests such as computed axial tomography and bronchoscopy are essential for diagnosis. Surgical approach may be the treatment of choice. PMID- 23462580 TI - Sleeve gastrectomy and Roux-en-Y gastric bypass are equally effective in correcting insulin resistance. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are associated with glucose metabolism improvement although data on insulin resistance remission rates after these procedures are lacking. AIMS: Primary aim was to compare insulin resistance remission rates achieved after LRYGB and LSG, using population-specific HOMA-IR cut-off points. Secondary objectives were to analyze factors associated with type 2 diabetes mellitus (T2DM) complete remission according to the new American Diabetes Association criteria and to examine changes in HOMA-B during follow-up. METHODS: Non randomized, prospective cohort study of patients undergoing LRYGB or LSG with a minimal follow-up of 24 months. Patients on insulin therapy were excluded. RESULTS: At baseline, 56 (48.7%) of the 115 LRYGB group and 48 (61.5%) of the 78 LSG group had insulin resistance, and 29 (25.2%) and 20 (25.6%) T2DM, respectively. No differences were detected in insulin resistance remission rate (92.9% LRYGB and 87.5% LSG, p = 0.355) nor in T2DM complete remission at 2 years (62.1 vs 60% respectively, p = 0.992). Factors independently associated with T2DM complete remission were diabetes treatment and a greater decrease in 3-month HOMA IR index. The HOMA-B index showed a progressive decline during follow-up. CONCLUSION: Both surgical techniques are equally effective in achieving insulin resistance normalization in the majority of severely obese patients. Three-month HOMA-IR reduction after surgery was the main predictor of T2DM complete remission. PMID- 23462581 TI - Effectiveness of home- and community-based rehabilitation in a large cohort of patients disabled by cerebrovascular accident: evidence of a dose-response relationship. AB - OBJECTIVES: To (1) assess the effectiveness of home- and community-based rehabilitation (HCBR) in a large cohort of individuals with disabilities secondary to cerebrovascular accident (CVA); and (2) evaluate the responsiveness to treatment of the Mayo-Portland Adaptability Inventory (MPAI-4) to changes resulting from HCBR in this patient group. DESIGN: Retrospective analysis of program evaluation data for treatment completers and noncompleters. SETTING: HCBR conducted in 7 geographically distinct U.S. cities. PARTICIPANTS: Individuals with CVA (n=738) who completed the prescribed course of rehabilitation (completed course of treatment [CCT]) compared with 150 individuals who were precipitously discharged (PD) before program completion. INTERVENTION: HCBR delivered by certified professional staff on an individualized basis. MAIN OUTCOME MEASURES: Mayo-Portland Adaptability Inventory (MPAI-4) completed by professional consensus on admission and at discharge. RESULTS: With the use of analysis of covariance, MPAI-4 total scores at discharge for CCT participants were compared with those of PD participants, with admission MPAI-4, age, length of stay, and time since event as covariates. CCT participants showed greater improvement than PD participants (F=99.48, P<.001) with a moderate effect size (partial eta(2)=.10). Group differences and effect sizes were similar for the 3 index scores: Ability (F=75.96, P<.001; partial eta(2)=.08), Adjustment (F=99.67, P<.001; partial eta(2)=.10), and Participation (F=69.15, P<.001; partial eta(2)=.07). CONCLUSIONS: Individuals in the CCT group who received the entire planned course of HCBR showed greater improvement on all MPAI-4 indexes than those in the PD group who were discharged before completing the prescribed program. This dose response relationship provides evidence of a causal relationship between treatment and outcome. PMID- 23462582 TI - Less depressive symptoms are associated with smaller hippocampus in subjective memory impairment. AB - Although individuals with subjective memory impairment (SMI) tend to be at an increased risk for dementia and the majority of them have depressive symptoms, it remains unclear whether SMI with depression is associated with an increased or decreased risk of dementia. The purpose of this study was to investigate the relationship between depressive symptoms and hippocampal/amygdalar volume, a reliable biomarker in the prediction of progression to dementia in SMI. Ninety subjects with SMI participated in the study, and 28 healthy participants without memory complaints served as a normal control (NC) group. 3-D T1-weighted structural MRI scans were completed in all subjects. When the volumes of hippocampus and amygdala were compared among the groups, the SMI group showed significantly smaller volumes than the NC group. When multiple regression analysis was conducted in all subjects, neither hippocampal nor amygdalar volume showed significant interaction effect between group and Geriatric Depression Scale (GDS). However, when the analysis was conducted within each group, lower GDS score was associated with smaller hippocampal volume in the SMI group, and higher GDS score was associated with smaller amygdalar volume in the NC group. Thus, individuals with SMI and less depressive symptoms tend to have smaller hippocampus, which could be associated with more risk of dementia, than normal individuals. PMID- 23462583 TI - Placental transfer of (125)Iodinated humanized immunoglobulin G2Deltaa in the Sprague Dawley rat. AB - Antibody-like biopharmaceuticals cross the placenta by utilizing transport pathways available for transfer of maternal antibodies to the conceptus. To characterize the timing and magnitude of this transfer in the rat, embryo/fetal biodistribution of maternally administered radiolabeled humanized IgG2 was quantified over the course of gestation using gamma counting and whole body autoradiography. The result was humanized IgG2 found in rat embryo/fetal tissues as early as gestation day 11 with a >1000-fold increase in the amount of total IgG2 by day 21. The concentration of IgG2 in rat embryo/fetal tissues generally remained unchanged from gestation day 11 to 17 with a slight increase from day 17 to 21. In addition, fetal-maternal tissue concentration ratios remained stable during organogenesis with a slight increase from gestation day 17 to 21. Based on the empirical amount of antibody present in the embryo/fetus during specific developmental windows, direct antibody binding to biological targets could potentially result in adverse developmental outcomes. PMID- 23462584 TI - Role of probiotics in short bowel syndrome in infants and children--a systematic review. AB - Short bowel syndrome (SBS) is a cause of significant morbidity and mortality in children. Probiotics, due to their beneficial effects on the gastrointestinal tract (e.g., improving gut barrier function, motility, facilitation of intestinal adaptation and decreasing pathogen load and inflammation) may have a therapeutic role in the management of SBS. To conduct a systematic review of the current evidence for the effects of probiotic supplementation in children with SBS, the standard Cochrane methodology for systematic reviews was used. The databases, Pubmed, Embase, ACTR, CENTRAL, and the international trial registry, and reference lists of articles were searched for randomised (RCT) or quasi randomised controlled trials reporting on the use of probiotics in SBS. Our search revealed no RCTs on the use of probiotics in children with SBS. We found one small cross-over RCT (placebo controlled crossover clinical trial), one case control study and nine case reports on the use of probiotics in children with SBS. In the crossover RCT, there was no consistent effect on intestinal permeability (primary outcome) after supplementation with Lactobacillus rhamnosus (LGG) in nine children with SBS. The case control study (four cases: four controls) reported a trend for increase in height and weight velocity and improvement in non-clinical outcomes, such as gut flora, lymphocyte count and serum prealbumin. Five of the nine case reports showed that children (n = 12) with SBS were benefited (e.g., cessation of diarrhoea, improved faecal flora, weight gain and weaning from parenteral nutrition) by probiotic supplementation. The remaining four reported on the adverse effects, such as Lactobacillus sepsis (n = 3) and d-lactic acidosis (n = 2). There is insufficient evidence on the effects of probiotics in children with SBS. The safety and efficacy of probiotic supplementation in this high-risk cohort needs to be evaluated in large definitive trials. PMID- 23462585 TI - Daily dietary selenium intake in a high selenium area of Enshi, China. AB - Enshi is a high selenium (Se) region in Hubei, China, where human selenosis was observed between 1958 and 1963. This study investigated the daily dietary Se intake of residents in Shadi, a town located 72 km northeast of Enshi City, to assess the risk of human selenosis in the high Se area. Foods consumed typically by the local residents and their hair samples were analyzed for total Se concentration. Concentrations of Se in different diet categories were as follows: cereals: 0.96 +/- 0.90 mg kg(-1) DW in rice and 0.43 +/- 0.55 mg kg(-1) DW in corn; tuber: 0.28 +/- 0.56 mg kg(-1) in potato and 0.36 +/- 0.12 mg kg(-1) in sweet potato; vegetables: ranging from 0.23 +/- 1.00 mg kg(-1) in carrot to 1.57 +/- 1.06 mg kg(-1) in kidney bean; animal proteins: 1.99 +/- 1.11 mg kg(-1) in chicken and egg. Based on the food Se concentrations and the daily per-capita consumption, the estimated daily Se intake in Shadi was 550 +/- 307 ug per capita. Moreover, the Se concentrations in the hairs of local adult residents were 3.13 +/- 1.91 mg kg(-1) (n = 122) and 2.21 +/- 1.14 mg kg(-1) (n = 122) for females and males, respectively, suggesting that females might be exposed to higher levels of Se from daily cooking. Although there was no human selenosis occurrence in recent years, the high level of the daily Se intake suggested that the potential risk of selenosis for local residents, especially females, might be a matter of concern. PMID- 23462586 TI - Effect of antioxidants and B-group vitamins on risk of infections in patients with type 2 diabetes mellitus. AB - Previous studies have revealed that diabetic patients have a decline in immunity and an increased risk of infections, and this may be associated with poor micronutrient status. The aim of this study was to measure the effect of dietary supplements on risk of infection in patients with type 2 diabetes mellitus. One hundred patients with type 2 diabetes mellitus were randomly assigned to receive an oral dose of daily B-group vitamins and antioxidant vitamins (n = 50) or an identical placebo (n = 50) daily for 90 days. Patients had baseline, three and 12 month assessment for nutritional status, fruits and vegetables intake, physical activity and self-reported infections. Supplementation with antioxidants and B group vitamins significantly increased the plasma concentration of vitamin E and folate and reduced homocysteine in the intervention group (p-values were 0.006, 0.001 and 0.657, respectively). The number of infections reported by the treatment group after three months of supplements was less than that reported by the placebo group, 9 (27%) vs. 15 (36%) (p = 0.623). Corresponding numbers of infections at 12 months were 25 (67.5%) and 27 (56.3%), respectively (p = 0.488). Up to 90% of the diabetic patients were either overweight or obese with a sedentary life style, and their body weight increased further during three months of follow up. The study showed that multivitamin supplements improved vitamin blood concentrations; however, this did not reduce the number of infections in diabetic patients. PMID- 23462587 TI - Rearranged abietane diterpenoids from the roots of Clerodendrum trichotomum and their cytotoxicities against human tumor cells. AB - The roots of the medicinal ornamental plant Clerodendrum trichotomum yielded a series of rearranged abietane diterpenoids, including three 17(15->16)-abeo abietane (1-3) and three 17(15->16),18(4->3)-diabeo-abietane (4-6) derivatives. Their structures were elucidated by means of spectroscopic methods. The absolute configuration of (10R,16R)-12,16-epoxy-11,14,17-trihydroxy-6-methoxy-17(15->16) abieta-5,8,11,13-tetraene-7-one (1) was deduced by a combination of single crystal X-ray diffraction analysis and the observed Cotton effects in its circular dichroism (CD) spectrum. All isolates were tested for their cytotoxicities against five human cancer cell lines (BGC-823, Huh-7, KB, KE-97, and Jurkat). Among them, compounds 4, 6, 9, 10, 12, and 14, each possessing a common 17(15->16),18(4->3)-diabeo-abietane framework, were found to have remarkable cytotoxic effects with IC50 values ranging from 0.83 to 50.99 MUM. PMID- 23462588 TI - The liquid<->amorphous transition and the high pressure phase diagram of carbon. AB - The phase diagram of carbon is mapped to high pressure using a computationally tractable potential model. The use of a relatively simple (Tersoff-II) potential model allows a large range of phase space to be explored. The coexistence (melting) curve for the diamond crystal/liquid dyad is mapped directly by modelling the solid/liquid interfaces. The melting curve is found to be re entrant and belongs to a conformal class of diamond/liquid coexistence curves. On supercooling the liquid a phase transition to a tetrahedral amorphous form (ta-C) is observed. The liquid <-> amorphous coexistence curve is mapped onto the pT plane and is found to also be re-entrant. The entropy changes for both melting and the amorphous -> liquid transitions are obtained from the respective coexistence curves and the associated changes in molar volume. The structural change on amorphization is analysed at different points on the coexistence curve including for transitions that are both isochoric and isocoordinate (no change in nearest-neighbour coordination number). The conformal nature of the melting curve is highlighted with respect to the known behaviour of Si. The relationship of the observed liquid/amorphous coexistence curve to the Si low- and high-density amorphous (LDA/HDA) transition is discussed. PMID- 23462589 TI - On the development of new biocatalytic processes for practical pharmaceutical synthesis. AB - Biocatalysis has established itself as a scalable and green technology for the production of a broad range of pharmaceutical APIs and intermediates. The number and scope of biocatalysts employed on large scale to deliver cost-advantaged and quality-advantaged processes to important substances continue to expand. This review discusses the recent developments in the field, including examples of processes leveraging hydrolases, reductases, transaminases, oxidases and other biocatalysts, focused on the preparation of important investigational and launched therapeutics. Biocatalysts recently discovered, and in some cases rediscovered, for the interesting chemistry they enable are likely to further substantiate the expansion of the biocatalysis field. PMID- 23462590 TI - Submucous cleft palate: variations in bony defects of the hard palate. AB - We have analysed bony defects of the hard palate in patients with submucous cleft palate to find out whether velopharyngeal insufficiency (VPI) is dependent on the extent of these defects. We evaluated the maxillofacial structures associated with cleft palate by 3-dimensional computed tomography (CT) in 23 children diagnosed with submucous cleft palate. Bony defects of the hard palate were divided into Type I, defined as absent posterior nasal spine (n=12), Type II, V shaped bony notch (moderate, n=7), and Type III, as bony defect extending into the incisive foramen (severe, n=4) defects, respectively. VPI was found in 10, 3, and 4 patients, respectively. Neither VPI nor the degree of bifid uvula was significantly associated with the types of bony defects. PMID- 23462591 TI - Reliability of volumetric imaging software for cone-beam computed tomogram scans in the anterior maxilla. AB - PURPOSE: This study aimed to compare buccal bone thickness in the maxillary anterior region provided by cone-beam computed tomography scans of cadaveric specimens using 2 different volumetric imaging software. METHODS: Cone-beam computed tomography scans of the maxilla of 15 cadaver heads were obtained from a database at the School of Dentistry, University of Michigan. Buccal bone thickness of the right and left maxillary canines and lateral and central incisors was measured at 2.0 mm below the crestal bone margin using 2 different volumetric software. RESULTS: A tooth-by-tooth comparison revealed strong correlation between measurements from the 2 software for the right canine (r = 0.859), lateral incisor (r = 0.817), and left lateral incisor (r = 0.933). When comparing tooth groups, there was a moderate correlation for central incisors (r = 0.635) and a strong correlation for canines (r = 0.820) and lateral incisors (r = 0.863). Measurements from both software were strongly correlated (r = 0.807) with 95.56% of the measurements in agreement. CONCLUSIONS: Measurements from 2 different volumetric imaging software were in agreement and either software can be used in analyzing soft and hard tissue volumes. PMID- 23462592 TI - Buccal bone crest dynamics after immediate implant placement and ridge preservation techniques: review of morphometric studies in animals. AB - PURPOSE: To review morphometric studies performed in animals assessing the dynamics of the buccal bone crest after immediate implant placement and ridge preservation techniques. MATERIAL AND METHOD: A bibliographic search in PubMed was performed. Studies that analyzed morphometrically in animals the buccal bone crest dynamics after immediate implant placement or ridge preservation techniques were included. Twenty-five studies met the inclusion criteria. RESULTS: Immediate implant placement does not prevent the resorption of the buccal bone crest. To minimize this resorption, 2 mm width of the buccal bone crest, palatal/lingual implant placement, and an adequate implant diameter for the width of the ridge are required. The regeneration of the gap after immediate implant placement limits the resorption of the buccal bone crest. Flap elevation and implant surface showed no relation with this resorption. Ridge preservation techniques associated with mucogingival surgery minimize buccal bone crest resorption. Biomaterials are more effective than autograft. CONCLUSIONS: Immediate implant placement does not prevent the resorption of the buccal bone crest after dental extraction. Ridge preservation techniques minimize this resorption. PMID- 23462593 TI - Measuring cation transport by Na,K- and H,K-ATPase in Xenopus oocytes by atomic absorption spectrophotometry: an alternative to radioisotope assays. AB - Whereas cation transport by the electrogenic membrane transporter Na(+),K(+) ATPase can be measured by electrophysiology, the electroneutrally operating gastric H(+),K(+)-ATPase is more difficult to investigate. Many transport assays utilize radioisotopes to achieve a sufficient signal-to-noise ratio, however, the necessary security measures impose severe restrictions regarding human exposure or assay design. Furthermore, ion transport across cell membranes is critically influenced by the membrane potential, which is not straightforwardly controlled in cell culture or in proteoliposome preparations. Here, we make use of the outstanding sensitivity of atomic absorption spectrophotometry (AAS) towards trace amounts of chemical elements to measure Rb(+) or Li(+) transport by Na(+),K(+)- or gastric H(+),K(+)-ATPase in single cells. Using Xenopus oocytes as expression system, we determine the amount of Rb(+) (Li(+)) transported into the cells by measuring samples of single-oocyte homogenates in an AAS device equipped with a transversely heated graphite atomizer (THGA) furnace, which is loaded from an autosampler. Since the background of unspecific Rb(+) uptake into control oocytes or during application of ATPase-specific inhibitors is very small, it is possible to implement complex kinetic assay schemes involving a large number of experimental conditions simultaneously, or to compare the transport capacity and kinetics of site-specifically mutated transporters with high precision. Furthermore, since cation uptake is determined on single cells, the flux experiments can be carried out in combination with two-electrode voltage-clamping (TEVC) to achieve accurate control of the membrane potential and current. This allowed e.g. to quantitatively determine the 3Na(+)/2K(+) transport stoichiometry of the Na(+),K(+)-ATPase and enabled for the first time to investigate the voltage dependence of cation transport by the electroneutrally operating gastric H(+),K(+)-ATPase. In principle, the assay is not limited to K(+)-transporting membrane proteins, but it may work equally well to address the activity of heavy or transition metal transporters, or uptake of chemical elements by endocytotic processes. PMID- 23462594 TI - Techno-economic assessment of biofuel development by anaerobic digestion of European marine cold-water seaweeds. AB - The techno-economic characteristics of macro-algae utilisation from European temperate zones was evaluated in a selected Anaerobic Digester (AD) using the chemical process modelling software ECLIPSE. The assessment covered the mass and energy balance of the entire process followed by the economic feasibility study, which included the total cost estimation, net present value calculation, and sensitivity analysis. The selected plant size corresponded to a community based AD of 1.6 MWth with a macro-algae feed rate of 8.64 tonnes per day (dry basis). The produced biogas was utilised in a combined heat and power plant generating 237 kWenet electricity and 367 kWth heat. The breakeven electricity-selling price in this study was estimated at around ?120/MWh. On the ground of different national and regional policies, this study did not account for any government incentives. However, different support mechanisms such as Feed-in-Tariffs or Renewable Obligation Certificates can significantly improve the project viability. PMID- 23462595 TI - Exploring novel ultrafine Eri silk bioscaffold for enzyme stabilisation in cellobiose hydrolysis. AB - The suitability of optimised ultrafine Eri silk microparticles as novel enzyme supports was studied for potential application in biofuel production. beta glucosidase (BGL) from Aspergillus niger was immobilised on Eri silk fibrion particles via an adsorption method resulting in a 62% immobilisation yield. Soluble and immobilised enzymes exhibited pH-optima at pH 4.0 and 5.0, respectively with optimum activity at 60 degrees C. The Michaelis constant (K(M)) was 0.16 and 0.27 mM for soluble and immobilised BGL respectively. The immobilisation support has a protective effect on the enzyme by increasing rigidity; this is reflected by an increase in stability under thermal denaturation at 70 degrees C. Immobilised enzyme retained more than 50% of initial activity for up to eight cycles. Maximum cellobiose hydrolysis by immobilised BGL was achieved at 20 h. Crystalline ultrafine Eri silk particles were found to be a promising viable, environmentally sound and stable matrix for binding BGL for cellobiose hydrolysis. PMID- 23462596 TI - Evidence for a metabolic mechanism in the improvement of type 2 diabetes after sleeve gastrectomy in a rodent model. AB - BACKGROUND: Sleeve gastrectomy (SG) is at least as effective at producing weight loss as gastric banding but may be superior in producing remission of type 2 diabetes mellitus (T2DM). The objective of this study was to elucidate mechanisms of diabetes improvement in SG beyond caloric restriction. We studied SG in Zucker Diabetic Fatty (ZDF) rats. METHODS: Twenty-eight ZDF rats were randomly assigned to 1 of 3 groups: SG, sham-operated ad lib fed (AL), or sham-operated pair fed (PF). SG and AL rats had free access to food. PF rats were fed the average daily intake of the SG group. Comparisons of caloric intake, weight loss, intraperitoneal glucose tolerance testing (IPGTT), insulin, and total ghrelin were performed preoperatively and at postoperative days 10, 20, and 30. Differences between means were evaluated using one-way ANOVA and the paired t test as appropriate. RESULTS: Postoperatively, SG rats had lower daily caloric intake than the AL controls (78.3+/-10.5 kcal versus 104.7+/-4.6 kcal). Both SG and PF groups had sustained weight loss (-5.3+/-3.8 g and -27.5+/-2.6 g, respectively); however, SG rats had significantly lower AUC for glucose after IPGTT than both controls. This is in contrast to AL controls that experienced weight gain (34.1+/-4.7 g) and increases in AUC for glucose after IPGTT. CONCLUSION: Although SG is considered a restrictive procedure, there is evidence for a metabolic effect by virtue of decreased insulin resistance, which may not be reproduced by PF controls. PMID- 23462597 TI - IFNgamma/TNFalpha specific-cells and effector memory phenotype associate with active tuberculosis. AB - OBJECTIVES: Controversial results were reported on the role of polyfunctional T cells in tuberculosis (TB). Our aim was to simultaneously characterize the Mycobacterium tuberculosis (Mtb)-specific immune response as cytokine production and memory phenotype by flow cytometry after in vitro stimulation with region of difference 1 ("RD1") recombinant proteins (ESAT-6 and CFP-10) in patients at different TB stage in a low TB endemic country. To assess the specificity of these findings, we evaluated the response to cytomegalovirus (CMV), an unrelated antigen. METHODS: We enrolled subjects with active TB, cured TB, latent TB infection (LTBI). Cytokine and phenotype profiles of T-cells from whole blood stimulated with "RD1" proteins and CMV were characterized by multi-parametric flow cytometry. RESULTS: Bifunctional IFNgamma(+) TNFalpha(+) CD4(+) T-cells and effector memory phenotype significantly associated with active TB compared to the LTBI group (p = 0.008, at least p <= 0.009 respectively) whereas "RD1"-T-cell response in cured TB and LTBI was characterized by a central memory phenotype (at least p <= 0.013 and p <= 0.004 respectively vs active TB). In contrast, response to CMV antigen was not associated with a TB-specific status. CONCLUSION: We identified qualitative associations between Mtb-specific T-cell and TB status in terms of functional capacity and memory status. These immune correlates may be helpful to trace natural history of TB. PMID- 23462598 TI - Mid Staffs inquiry. Bring back absolute accountability. PMID- 23462599 TI - A no-go result on the purification of quantum states. AB - The information encoded in a quantum system is generally spoiled by the influences of its environment, leading to a transition from pure to mixed states. Reducing the mixedness of a state is a fundamental step in the quest for a feasible implementation of quantum technologies. Here we show that it is impossible to "transfer" part of such mixedness to a "trash" system without losing some of the initial information. Such loss is lower-bounded by a value determined by the properties of the initial state to purify. We discuss this interesting phenomenon and its consequences for general quantum information theory, linking it to the information theoretical primitive embodied by the quantum state-merging protocol and to the behaviour of general quantum correlations. PMID- 23462600 TI - Immunohistochemical evaluation of ERG expression in various benign and malignant tissues. AB - The transmembrane protease, serine 2-E twenty-six related gene (TMPRSS2-ERG) fusion leading to ERG overexpression, was detected in approximately 50% of prostate cancers (ranging from 35-70%). However, the published data on ERG expression in tumors from other organs and normal tissues were limited. In this study, we investigated the expression of ERG in TMA sections of various normal tissues (N=452) and carcinomas (N=1,129) from various organs, including 90 cases of low to intermediate-grade (L-MG) prostatic adenocarcinomas and 36 cases of high-grade (HG) prostatic adenocarcinomas, using a single immunostaining system (Dako). Also included were prostatic biopsies of radiation atypia (N=20), atrophy (N=20), and high-grade prostatic intraepithelial lesion (HGPIN) (N=18). ERG expression was detected in 44% (40/90) of L-MG prostatic adenocarcinomas; in 22% (8/36) of HG prostatic adenocarcinomas; and in 22% (4/18) of HGPIN. No ERG expression was detected in non-prostate carcinomas, normal tissues including prostate and seminal vesicles, benign prostatic tissue with radiation atypia, and atrophy. Our data demonstrate that ERG is a highly specific marker, which may have important implications in the interpretation of prostate biopsies with limited cancers. In addition, its high diagnostic specificity may be useful in identifying a prostatic primary when working on a tumor of uncertain origin. Partly presented at the United States and Canadian Academy of Pathology Annual Meeting in March 2011. PMID- 23462601 TI - Biological correlates of biochemical recurrence free survival using multiple markers in a large tissue microarray cohort. AB - BACKGROUND: High-throughput analyses yielded a large number of predictive biomarkers in prostatic cancer (PCa) patients. Combinations of these biomarkers and with clinical features could improve on prediction. MATERIALS AND METHODS: Tissue microarrays (640 patients) with triplicate cores of non-neoplastic prostate, benign prostatic hyperplasia (BPH), and index tumor were immunostained with antibodies to numerous biomarkers, digitized, and quantified. We used tree based classification algorithms to stratify patients into 3 risk strata on the basis of their clinical and pathologic data. Markers were tested for prognostic ability in each stratum (stratum 1 had <10% risk of recurrence; stratum 3 had >60% likelihood of recurrence over a period >12 years). Sub stratification of the clinico-pathologic strata was also pursued. RESULTS: We identified a number of significant predictors for PSA recurrence free survival, which were used to construct a predictive model that combines clinical and biomarker data. In the low-risk clinico-pathologic stratum, the markers were predominantly related to non-neoplastic tissues, in the moderate-risk stratum to stromal-epithelial interactions and angiogenesis, while those in the high-risk stratum were mostly oncogenes. Substratification of the intermediate risk group using stromal quantitation and proliferative index successfully, up or down, staged the risk strata for most patients. CONCLUSIONS: The fact that different biomarkers are most predictive of disease recurrence within different risk subgroups suggests an association between biological processes and prognostic ability. This is the first time that subgroup analysis of markers finds that prognostic ability is associated with biological processes and is proof of concept that distinct phenotypes are associated with risk of recurrence in different types of cancer. PMID- 23462602 TI - Sweat testing to monitor drug exposure. AB - It may be advantageous to use sweat, rather than blood or urine, to monitor individuals' drug exposure for the purposes of drug treatment programs, employment initiatives, and forensic investigations. Forty-eight patients receiving methadone at the Public Service for the Treatment of Drug Dependence of Perugia (Italy) were monitored for 14 days by the analysis of methadone and cocaine present in two sweat patches, each worn for 7 days. The results were compared to those from the analysis of urine samples collected at the beginning of the study and after 7 days, as well as those from the analysis of hair collected on the fourteenth day. Sweat patch analysis was positive for methadone and its metabolite EDDP in 100% of patients. Some individuals were positive for cocaine in urine, sweat, and hair while others were positive for cocaine in only one of those samples. Results suggest analysis of a sweat patch indicates an individual's drug use or drug washout for the previous week, and provides an alternative to blood or urine analyses. PMID- 23462603 TI - Identification of PRODH mutations in Korean neonates with type I hyperprolinemia. AB - BACKGROUND: Hyperprolinemia is a rare inherited metabolic disorder characterized by a high proline level in blood and/or urine and various neuropsychiatric symptoms. Type I hyperprolinemia is caused by a proline oxidase deficiency, which is encoded by the PRODH gene on chromosome 22q11. Herein, we present a study of Korean patients with type I hyperprolinemia who were diagnosed during newborn screening by tandem mass spectrometry and confirmed by molecular analysis. METHODS: Four neonates were referred to our hospital for workup of high proline levels in newborn screening test. We analyzed the biochemical findings and the PRODH gene was amplified by long-range PCR to confirm molecular genetic abnormalities. RESULTS: All patients had high plasma proline levels, ranging from 742 to 1192 MUmol/L (reference range, 77.4 - 244.6 MUmol/L). In molecular analysis, 4 disease-associated mutant alleles were identified: c.1414G>A (p.A472T), c.1279G>A (p.V427M), c.1357C>T (p.R453C) and c.1562A>G (p.Q521R). All mutations were missense and c.1279G>A included the majority of mutant alleles. No relationships between type of mutation and clinical outcomes were observed. CONCLUSION: We found that distinct molecular alterations of the PRODH gene result in abnormal proline levels. Newborn screening and molecular analysis are necessary to identify patients before clinical expression of metabolic disease. PMID- 23462604 TI - The role of insulin-like growth factor I and hypoxia inducible factor 1alpha in vascular endothelial growth factor expression in type 2 diabetes. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in diabetic vascular complications, and its expression is affected directly or indirectly by hypoxia inducible factor-1alpha (HIF-1alpha) and insulin-like growth factor-I (IGF-I) in tumors and certain normal cell lines. However, little is known about the role of HIF-1alpha/ IGF-I in VEGF expression in patients with diabetic vascular complications. The aim of this study was to elucidate the associations between HIF-1alpha, IGF-I, and VEGF in type 2 diabetes mellitus (T2DM) patients with or without vascular complications. METHODS: Sixty patients with T2DM, with(A), and without vascular disease (B) and 26 controls were enrolled. Clinical parameters, HIF-1alpha, IGF-I and VEGF were assessed in the study and associations among them were analyzed by Spearman rank correlation. RESULTS: Serum levels of VEGF, HIF-1alpha and IGF-I were significantly higher in the diabetic patients than in the controls. Positive correlations existed between VEGF and HIF-1alpha and between HIF-1alpha and IL-6 in both groups A and B and in the control group. CONCLUSIONS: Our data demonstrate that HIF-1alpha and IL-6 could regulate VEGF expression, and that higher levels of HIF-1alpha, IL-6, and VEGF may contribute to the pathogenesis of diabetic micro-angiopathy. PMID- 23462606 TI - The effects of intermittent hypoxia training on mitochondrial oxygen consumption in rats exposed to skeletal unloading. AB - Intermittent hypoxia training (IHT) may reduce the oxidative stress-induced damage caused by extreme influences such as ischemia, exhaustive physical exercise, acute hypoxia, and stress. The aim of the present study is to investigate the effects of IHT on hepatic mitochondrial oxygen consumption, lipid peroxidation, and selected biochemical parameters used as diagnostic tools in a skeletal unloading model in rats. Our data showed that the IHT method significantly improved liver tolerance of unloading by reorganizing mitochondrial energy metabolism due to NADH-dependent oxidation. Aminotransferase activity was decreased compared to levels in untreated rats. Succinate dehydrogenase activity and lipid peroxidation remained unchanged when compared between groups. Moreover, skeletal unloading in the growing rats induced an activation of the rate of mitochondrial respiration in state 3 at succinate oxidation and decreased oxygen consumption at alpha-ketoglutarate oxidation. Adaptation of rats to IHT in our experiment significantly improved the rate of oxidative phosphorylation and the efficiency of phosphorylation in liver mitochondria at alpha-ketoglutarate oxidation. IHT seems to be a hepatoprotective method, and its use in maintaining a healthy liver and preventing unloading-induced liver damage deserves consideration and further examination. PMID- 23462605 TI - Sinonasal undifferentiated carcinoma (SNUC): morphoproteomic-guided treatment paradigm with clinical efficacy. AB - Sinonasal undifferentiated carcinoma (SNUC) is a rare and highly malignant tumor that occurs in the nasal cavity and/or paranasal sinuses. Prognosis is poor despite multimodality treatment. Currently, there is no optimal standard of treatment, partially due to a lack of research defining the biology of such tumors. This report discusses two SNUC cases where patients received a novel chemotherapeutic approach using cisplatin, etoposide, Adriamycin (doxorubicin), metformin, and adjuvant melatonin therapies based on morphoproteomic-guidance, followed by consolidation with chemoradiation therapy. This resulted in excellent and objective tomographic and magnetic resonance imaging and clinical responses including complete responses in the induction phase utilizing morphoproteomic guided therapies. Later, endoscopic excision of the tumor bed failed to reveal any residual tumor. Morphoproteomics helped to define the biology of these SNUC tumors and provided targets for the agents employed, creating a new treatment paradigm for such tumors. This treatment regimen poses a new effective regimen to treat SNUC. PMID- 23462607 TI - The optimal time window of ischemic preconditioning (IPC) on the reperfusion injury in moderate to severe hepatocirrhosis in rats. AB - PURPOSE: To evaluate the effects of different-time ischemic preconditioning (IPC) schemes on the ischemia-reperfusion (I/R) injury in moderate to severe hepatocirrhosis in rats and to identify the optimal time window of IPC. METHODS: A total of 90 male SD rats with moderate to severe hepatocirrhosis were randomly divided into 5 groups (IR group, 5-10 min-IPC group, 8-10 min-IPC group, 10-10 min-IPC group and 15-10 min-IPC group), in which the liver was preconditioned by IPC of various durations, and then subjected to I/R injury in the last four groups. Thirty-six normal (non-cirrhotic) SD rats were divided into 2 groups (IR group and 10-10 min-IPC group). Ischemia-reperfusion injury was induced by clamping of the portal triad for 30 min followed by reperfusion for 30 min. Hepatocellular viability was assessed by measuring the concentration of ALT and AST in serum. The concentration of NO in serum and those of MDA, MPO, and SOD in the liver tissue were also assessed at 1h, 4h, and 24h after the operation respectively. RESULTS: After 30-30min of I/R, the levels of ALT and AST were significantly elevated in the IR group and the groups under IPC, but the elevations were significantly lower in the 5-10 min-IPC group and the 8-10 min IPC group, especially at 4h after I/R (P<0.05). The levels of MDA and MPO in liver tissue were lower in the 5-10 min-IPC and 8-10min-IPC groups than in the rest of the IPC groups and IR group in the cirrhotic rats, and the level of SOD was higher (P <0.05). The level of serum NO was significantly higher in the 5-10 min-IPC and 8-10min-IPC groups than in the rest of the cirrhotic groups (P <0.05). CONCLUSIONS: The 5-10 min through 8-10 min-IPC achieves the highest protective effect on the I/R injury of moderate to severe hepatocirrhosis. With the aggravation of liver cirrhosis, the pre-implementation time has been shortened. Thus, IPC of 5-10min may be effective for severe liver cirrhosis. PMID- 23462608 TI - Clinical and genetic analysis of a Korean patient with X-linked chondrodysplasia punctata: identification of a novel splicing mutation in the ARSE gene. AB - X-linked recessive chondrodysplasia punctata (CDPX1) is a rare congenital disorder of bone and cartilage development, characterized by punctate calcification in areas of endochondral bone formation, leading to stippled epiphyses, severe nasal and midfacial hypoplasia, short stature, and brachytelephalangy. CDPX1 is caused by mutations in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most affected males have milder symptoms, some have significant medical problems including respiratory compromise and cervical spinal stenosis due to dysplastic vertebrae. Herein, we present the case of a male infant with the characteristic features of CDPX1 and severe spinal cord compression. Direct sequencing analysis revealed a novel variation (c.430G>A) in the ARSE gene that was thought to be a missense mutation (p.Gly144Arg), but proved to be a novel splicing mutation (r.[430g>a; 430_431ins430+1_430+21) adding seven amino acids between p.Ile143 and p.Gly144 (p.Ile143_Gly-144insSerMetTyrValPheLysSer). This report expands the spectrum of mutations of the ARSE gene and, to the best of our knowledge, is the first clinically and genetically confirmed case of CDPX1 with severe spinal cord compression in Korea. PMID- 23462609 TI - C86Y: as a destructive homozygous mutation deteriorating Pex7p function causing rhizomelic chondrodysplasia punctata type I. AB - Rhizomelic Chondrodysplasia Punctata (RCDP) type 1 is a peroxisomal biogenesis disorder with a genetic abnormality in PEX7 gene. In the present study, mutational analysis was performed on two Iranian RCDP patients with distinct clinical phonotype. Mutation detection was carried out by sequencing of RT-PCR product consisting the whole length of PEX7 cDNA. Sequence data revealed the same missense homozygous mutation of G to A at nucleotide 257 in exon3 of PEX7 coding sequence in both patients. Moreover, genomic analysis of the PEX7 gene confirmed the RT-PCR data. This mutation caused one amino acid residue substitution of Cys to Tyr at codon 86 located on WD1 repeat domain region of Pex7p, which severely affected the functionality of PEX7 protein. Back-transfection of vector encoding mutant Pex7p did not restore the normal peroxisomal function in RCDP patient's fibroblast cells dissimilar to the native type of PEX7. PMID- 23462610 TI - Neuroblastoma in an adult: case presentation and literature review. AB - Neuroblastoma is the most common malignancy in children less than one year of age, but is rare in adults. Adult neuroblastoma differs from pediatric cases by lacking classical features including low incidence of MYCN amplification, elevated urinary catecholamimes, and MIBG avidity. The diagnosis may not be initially considered because of the rarity, which emphasizes the importance of immunohistochemical staining and cytogenetic testing in aiding the diagnosis. We present a case of neuroblastoma in a 39-year-old woman who failed to respond to intensive therapy for this malignancy and died within a year after diagnosis. PMID- 23462611 TI - Two acute myeloblastic leukemia cases concomitant with hemophagocytic lymphohistiocytosis and review of the literature. AB - We present two patients with acute myeloblastic leukemia (FAB AML-M7 and AML-M2) complicated by hemophagocytic lymphohistiocytosis (HLH) and relevant literature review. To our knowledge, our first case is the first and youngest patient having AML-M7 associated with HLH reported in the literature. Our cases and cases in the literature highlight the high mortality rate of leukemia associated with HLH and the need for further investigation for the most appropriate therapy. PMID- 23462612 TI - Thrombotic thrombocytopenic purpura with unusual 33 recurrences: a case report. AB - The hereditary or acquired deficiency of ADAMTS-13 activity leads to an excess of high molecular weight von Willebrand factor multimers in plasma, leading to platelet aggregation and diffuse intravascular thrombus formation, resulting in thrombotic thrombocytopenic purpura (TTP). We report a 36 year old male with a long history of TTP associated with 33 relapses. As a result of early transfusions, the patient acquired Hepatitis C. This time, the patient presented with a TTP relapse after a 10 year remission, following PEG-interferon-Alpha (IFA) therapy for Hepatitis C. Since IFA has been reported to activate autoimmune reactions, it may have augmented production of ADAMTS-13 antibody. PMID- 23462613 TI - Temporary impairment of semen quality following recent acute fever. AB - The impact of an acute fever on semen variables is unclear. This paper reports negative effects and recovery of the sperm quality in a man who had an acute fever of 38 degrees -39 degrees C, due to a throat infection. The study evaluated the sperm quality in semen specimens collected, as follows: 1) one month before the fever; 2) 1-day after the fever; 3) 20 days after antimicrobial therapy. The first and third specimens were quite similar for all semen parameters. However, the second specimen showed unexpected results: not only a decrease in the sperm count, but also an increase of small-head sperm. This study aims to discuss this finding's implications for clinical and laboratory practice. PMID- 23462614 TI - Filiform polyposis in a patient without inflammatory bowel disease. AB - Filiform polyposis is a rare condition of uncertain pathogenesis that is usually found in patients with a history of inflammatory bowel disease. Here I report a case of filiform polyposis with no associated inflammatory bowel disease. Numerous finger-like polypoid lesions with the appearance of stalactites were noted in the transverse colon at the time of colonoscopy. Filiform polyps may be misinterpreted on colonoscopy as unusual villous adenomas or small carcinomas. Endoscopists should be familiar with the varied morphology of filifform polypsis in order to arrive at a correct diagnosis, and to ensure proper management. PMID- 23462615 TI - Letter to editor: comparative evaluation of four commercial serological antibody detection kits for the diagnosis of tuberculosis in China. AB - Rapid antibody detection has been used widely as a diagnostic aid in the diagnosis of tuberculosis (TB), especially for bacterium-negative TB. We evaluated the diagnostic value of four commercial antibody detection kits with 501 sera from TB patients and controls. The sensitivities and specificities of the four kits were as follows: (1) Rapid test A 71.8% and 91.4% (85.5% for non-TB diseases and 92.8% for healthy controls); (2) Rapid test B 74.2% and 83.1% (63.9% for non-TB diseases and 92.8% for healthy controls); (3) Rapid test C 21.0% and 95.2% (for non-TB diseases); (4) Rapid test D 6.3% and 98.8% (for non-TB diseases). Overall the four commercial serological antibody detection kits performed very differently. Therefore, careful evaluation should be undertaken before any of these commercial serological assays can be recommended as a screening test for TB. PMID- 23462616 TI - Prostate cancer and physical activity: adaptive response to oxidative stress. AB - Prostate cancer is the most common form of cancer affecting men in the Western world. Its relative incidence increases exponentially with age and a steady increase is observed with extended life span. A sedentary lifestyle represents an important risk factor and a decrease in prostate cancer prevalence is associated with exercise. However, the molecular mechanisms involved in this process remain unknown. We hypothesize that reactive oxygen species generated by physical exercise are a key regulatory factor in prostate cancer prevention. Aging is correlated with increased oxidative stress (OS), which in turn provides a favorable environment for tumorigenesis. Running training is known to enhance the antioxidant defense system, reducing oxidative stress. In this context, the decrease in OS induced by exercise may delay the development of prostate cancer. This review focuses on oxidative stress-based mechanisms leading to prostate cancer sensitization to exercise, which could have some impact on the development of novel cancer therapeutic strategies. PMID- 23462617 TI - KSRP silencing favors neural differentiation of P19 teratocarcinoma cells. AB - Understanding the molecular mechanisms that control the balance between multipotency and differentiation is of great importance to elucidate the genesis of both developmental disorders and cell transformation events. To investigate the role of the RNA binding protein KSRP in controlling neural differentiation, we used the P19 embryonal carcinoma cell line that is able to differentiate into neuron-like cells under appropriate culture conditions. We have recently reported that KSRP controls the differentiative fate of multipotent mesenchymal cells owing to its ability to promote decay of unstable transcripts and to favor maturation of selected micro-RNAs (miRNAs) from precursors. Here we report that KSRP silencing in P19 cells favors neural differentiation increasing the expression of neuronal markers. Further, the expression of two master transcriptional regulators of neurogenesis, ASCL1 and JMJD3, was enhanced while the maturation of miR-200 family members from precursors was impaired in KSRP knockdown cells. These molecular changes can contribute to the reshaping of P19 cells transcriptome that follows KSRP silencing. Our data suggests that KSRP function is required to maintain P19 cells in a multipotent undifferentiated state and that its inactivation can orient cells towards neural differentiation. PMID- 23462618 TI - Pro-inflammatory effects and oxidative stress in lung macrophages and epithelial cells induced by ambient particulate matter. AB - The objective of this study was to compare the toxicological effects of different source-related ambient PM10 samples in regard to their chemical composition. In this context we investigated airborne PM from different sites in Aachen, Germany. For the toxicological investigation human alveolar epithelial cells (A549) and murine macrophages (RAW264.7) were exposed from 0 to 96 h to increasing PM concentrations (0-100 MUg/ml) followed by analyses of cell viability, pro inflammatory and oxidative stress responses. The chemical analysis of these particles indicated the presence of 21 elements, water-soluble ions and PAHs. The toxicological investigations of the PM10 samples demonstrated a concentration- and time-dependent decrease in cell viability and an increase in pro-inflammatory and oxidative stress markers. PMID- 23462620 TI - Role of acute phase proteins in the immune response of rabbits infected with Trypanosoma evansi. AB - The aim of this study was to characterize the response of acute phase proteins (APP) in rabbits experimentally infected with Trypanosoma evansi (T. evansi), and to relate the findings with serum immunoglobulins levels, in order to verify the relation between APP and the immune response of rabbits. A total of 12 animals were used in this experiment and divided into 2 groups, control and infected, of six rabbits each. The experimental period was 118 days, and blood was collected on days 0, 5, 20, 35, 65, 95 and 118 post-infection (PI). The infection with T. evansi stimulated APP and immunoglobulins production, once the infected animals showed an increase in C-reactive protein, haptoglobin, alpha 2-macroglobulin and IgM levels. The elevation in IgM levels observed in this study, when related to the increase in C-reactive protein and haptoglobin levels, suggests the involvement of these proteins in host defense against flagellated protozoa, with possible participation in the control of the parasitemia in rabbits infected with T. evansi. PMID- 23462619 TI - The Citrobacter rodentium mouse model: studying pathogen and host contributions to infectious colitis. AB - This protocol outlines the steps required to produce a robust model of infectious disease and colitis, as well as the methods used to characterize Citrobacter rodentium infection in mice. C. rodentium is a gram negative, murine specific bacterial pathogen that is closely related to the clinically important human pathogens enteropathogenic E. coli and enterohemorrhagic E. coli. Upon infection with C. rodentium, immunocompetent mice suffer from modest and transient weight loss and diarrhea. Histologically, intestinal crypt elongation, immune cell infiltration, and goblet cell depletion are observed. Clearance of infection is achieved after 3 to 4 weeks. Measurement of intestinal epithelial barrier integrity, bacterial load, and histological damage at different time points after infection, allow the characterization of mouse strains susceptible to infection. The virulence mechanisms by which bacterial pathogens colonize the intestinal tract of their hosts, as well as specific host responses that defend against such infections are poorly understood. Therefore the C. rodentium model of enteric bacterial infection serves as a valuable tool to aid in our understanding of these processes. Enteric bacteria have also been linked to Inflammatory Bowel Diseases (IBDs). It has been hypothesized that the maladaptive chronic inflammatory responses seen in IBD patients develop in genetically susceptible individuals following abnormal exposure of the intestinal mucosal immune system to enteric bacteria. Therefore, the study of models of infectious colitis offers significant potential for defining potentially pathogenic host responses to enteric bacteria. C. rodentium induced colitis is one such rare model that allows for the analysis of host responses to enteric bacteria, furthering our understanding of potential mechanisms of IBD pathogenesis; essential in the development of novel preventative and therapeutic treatments. PMID- 23462621 TI - Effects of oral clenbuterol on the clinical and inflammatory response to endotoxaemia in the horse. AB - Pro-inflammatory cytokines, such as IL-1beta and TNFalpha, play a major role in activating leukocytes and endothelial cells during the systemic inflammatory response to endotoxin in the horse. beta2 agonist drugs, such as clenbuterol, inhibit leukocyte activation. This study aimed to determine the effects of oral clenbuterol on clinical and leukocyte responses, including production of TNFalpha, in an in vivo endotoxin challenge model. In a randomised crossover design, horses received either clenbuterol or a placebo product prior to the administration of low dose endotoxin (30 ng/kg over 30 min). Clinical signs were measured and leukocyte counts and serial blood samples were obtained over 6 h. Pre-treatment with oral clenbuterol (0.8 MUg/kg) significantly reduced (P=0.046) the peak rectal temperature and the peak plasma TNFalpha concentration (P=0.026) following endotoxin challenge. These data suggest that oral clenbuterol at the therapeutic dose has anti-inflammatory effects in horses challenged with a low dose of endotoxin. PMID- 23462622 TI - Comparison and intercalibration of vegetation indices from different sensors for monitoring above-ground plant nitrogen uptake in winter wheat. AB - Various sensors have been used to obtain the canopy spectral reflectance for monitoring above-ground plant nitrogen (N) uptake in winter wheat. Comparison and intercalibration of spectral reflectance and vegetation indices derived from different sensors are important for multi-sensor data fusion and utilization. In this study, the spectral reflectance and its derived vegetation indices from three ground-based sensors (ASD Field Spec Pro spectrometer, CropScan MSR 16 and GreenSeeker RT 100) in six winter wheat field experiments were compared. Then, the best sensor (ASD) and its normalized difference vegetation index (NDVI (807, 736)) for estimating above-ground plant N uptake were determined (R2 of 0.885 and RMSE of 1.440 g.N.m(-2) for model calibration). In order to better utilize the spectral reflectance from the three sensors, intercalibration models for vegetation indices based on different sensors were developed. The results indicated that the vegetation indices from different sensors could be intercalibrated, which should promote application of data fusion and make monitoring of above-ground plant N uptake more precise and accurate. PMID- 23462623 TI - Clinical applications of fast liquid chromatography: a review on the analysis of cardiovascular drugs and their metabolites. AB - One of the major challenges facing the medicine today is developing new therapies that enhance human health. To help address these challenges the utilization of analytical technologies and high-throughput automated platforms has been employed; in order to perform more experiments in a shorter time frame with increased data quality. In the last decade various analytical strategies have been established to enhance separation speed and efficiency in liquid chromatography applications. Liquid chromatography is an increasingly important tool for monitoring drugs and their metabolites. Furthermore, liquid chromatography has played an important role in pharmacokinetics and metabolism studies at these drug development stages since its introduction. This paper provides an overview of current trends in fast chromatography for the analysis of cardiovascular drugs and their metabolites in clinical applications. Current trends in fast liquid chromatographic separations involve monolith technologies, fused-core columns, high-temperature liquid chromatography (HTLC) and ultra-high performance liquid chromatography (UHPLC). The high specificity in combination with high sensitivity makes it an attractive complementary method to traditional methodology used for routine applications. The practical aspects of, recent developments in and the present status of fast chromatography for the analysis of biological fluids for therapeutic drug and metabolite monitoring, pharmacokinetic studies and bioequivalence studies are presented. PMID- 23462624 TI - Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors. AB - Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst2. Pasireotide is a sst multireceptor ligand with affinity for sst1, sst2, sst3 and sst5 and this broader binding profile may translate into a higher efficacy with respect to suppression of hormone production and cell growth in certain tumors. Experimental animal studies and in vitro studies with cultured tumor cells have shown that pasireotide strongly suppresses growth hormone and adrenocorticotropin production. In addition, pasireotide can influence tumor cell growth via effects on apoptosis and angiogenesis. In this review, the role of somatostatin receptors in pituitary and neuroendocrine tumors is briefly discussed followed by an overview of possible applications of pasireotide based on recent trials in patients with acromegaly, Cushing's disease and neuroendocrine tumors. PMID- 23462625 TI - The development of regorafenib and its current and potential future role in cancer therapy. AB - Regorafenib is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types, in preclinical and clinical studies. Preclinical data show inhibitory activity of angiogenic, stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1, 2 and 3, tyrosine-protein kinase receptor TIE-2, platelet derived growth factor receptor beta, fibroblast growth factor receptor 1, proto oncogene tyrosine-protein kinase receptor Ret, mast/stem cell growth factor receptor Kit, RAF proto-oncogene serine/threonine-protein kinase and wild-type and V600E mutant serine/threonine-protein kinase B-raf. Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3-weeks on/1-week-off schedule, or 100 mg daily on a continuous schedule, with adverse effects typical of other multikinase inhibitors. Phase II studies demonstrated clinical benefit in a variety of tumor types, mostly associated with prolonged stable disease. Phase III studies include the CORRECT trial, which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies. There is still much work to be done to determine the role of regorafenib in the future of cancer therapy. This review will focus on the development of regorafenib, from early preclinical work through phase I, II and III trials, as well as highlighting the current role and potential future directions of this novel agent. PMID- 23462626 TI - 2012 in review - part II: overcoming the obstacles in the pharma/biotech industry. AB - As highlighted in the first part of this review published last month, the year 2012 saw the approval of a remarkable number of new drugs, and among the new drugs reaching the market, a significant proportion were orphan drugs developed for treating less prevalent diseases. These drugs are certainly not expected to become blockbusters, but are of high interest because of their efficacy in a narrow spectrum of patients. This trend aligns with the general tendency of staying away from fit-for-all blockbusters into personalized medicine as one of the strategies for overcoming the patent cliff that resulted in a long list of drugs going off patent and being approved as generics also during last year. The emerging scenario resulting from new developments in the form of new drugs and biosimilars and newly available generic medications paralleled by strategic movements within the pharmaceutical industry to reinforce their position in the market, as reflected by merger and acquisition deals accompanied by significant efforts into prioritization resulting in spin-off and split transactions, is reviewed in this second part. This paper includes a significant amount of data in tables for quick review and to profile the new strategic movements in drug pipelines. Further information, including details on mechanisms of action, current status, itemized pharmacology, pharmacokinetic and clinical trial research findings and updated information can be found in the proprietary databases Thomson Reuters Integrity(SM) and Thomson Reuters CortellisTM. PMID- 23462627 TI - Maternal plasma biomarkers for down syndrome: present and future. AB - Down syndrome is the most common cause of mental retardation and has an incidence of between 1:600 and 1:800 pregnancies. It is the condition for which prenatal diagnosis is requested the most and most developed countries have adopted a screening program based around maternal plasma/serum testing and ultrasound. Advances have been made recently to eliminate invasive testing for genetic diagnosis of this condition based on the analysis of free fetal DNA in maternal plasma. But, routine noninvasive prenatal diagnosis for trisomy 21 still appears to be years away. Screening based on assessment of various biomarkers present in maternal plasma represents a front-line test to assess the risk of the mother carrying an aneuploid fetus. Recent comparative proteomics techniques have resulted in studies that have assessed maternal plasma from mothers carrying normal and trisomy 21 fetuses and various gestational ages. Over 100 biomarker candidates have been described, but little consensus has emerged. This may be due to a number of compounded factors, but interesting to note that other neurological disorders have overlapping biomarkers. This article describes these developments and how these biomarkers could contribute to future screening in an emerging era where next-generation sequencing of free fetal DNA will be established in prenatal diagnostics, which appears imminent. PMID- 23462628 TI - A report from the American college of rheumatology/association of rheumatology health professionals (ACR/ARHP) - 2012 annual meeting (November 9-14, 2012 - Washington, D.C., USA). AB - The annual meeting of the American College of Rheumatology (ACR), jointly held with the Association of Rheumatology Health Professionals (ARHP), brought together attendees focused on all aspects of rheumatology, including researchers looking into treatment options and various services around the care of rheumatologic conditions. As well as networking opportunities at the meeting, there were a wide range of symposia and posters available covering various conditions and levels of research. There were also educational and meet-the professor sessions. This report will cover a selection of interesting talks from poster and oral sessions on the latest preclinical and clinical research. PMID- 23462629 TI - Left ventricular hypertrabeculation/noncompaction coincidentally found in sporadic inclusion body myositis. PMID- 23462630 TI - The increasing incidence of Streptococcus bovis endocarditis: a New York dairy farmer with epidural abscess. PMID- 23462631 TI - The Three Graces: canons of beauty or disease repulsion. AB - BACKGROUND: The theme of the Three Graces has been approached by several artists and writers but very few physicians. METHODS: Here distinct versions of the Three Graces are considered through the lens of medical analysis and contemporary conceptions of ideal beauty. RESULTS: Graces have been traced back to the same origins as the Nymphs, old goddesses of nature and representation, and being also a paradigm of beauty. This is in stark contrast to Rubens's Three Graces, who present womanly traits such as voluptuousness and full, round forms. It is paradoxical that when analysed medically, these painted women show signs of disease that inevitably affect our reading of the image. Medical conditions include presence of overweight close to obesity with a calculated BMI between 26 and 29 associated with an increased risk of cardiovascular disease. CONCLUSIONS: Today canons of beauty comprise women with BMI of 20 or less, a figure associated with increased risks of anorexia and suicide. It seems we approach the paradox that beauty and repulsion will always go hand in hand, shifting together with our changing perception over time. PMID- 23462632 TI - Drug-eluting balloons for peripheral artery disease: a meta-analysis of 7 randomized clinical trials and 643 patients. PMID- 23462633 TI - Effects of contemporary management on clinical outcomes in elderly patients with acute myocardial infarction. PMID- 23462634 TI - Risk assessment of depression by questionnaire for patients with heart failure. PMID- 23462635 TI - Three-dimensional echocardiography for cor triatriatum in adults. PMID- 23462636 TI - Effect of motivational mobile phone short message service on aspirin adherence after coronary stenting for acute coronary syndrome. PMID- 23462637 TI - How to transform peripheral extracorporeal membrane oxygenation in the simplest mid-term paracorporeal ventricular assist device. AB - Extracorporeal membrane oxygenation (ECMO) provides excellent support to circulation. However, ECMO capacity to effectively assist the heart, and in particular the left ventricle, is limited. We herein review the modifications of left ventricular dynamics during peripheral ECMO, highlight the importance of left ventricle venting and describe a method for the conversion of a femoro femoral ECMO into a paracorporeal left ventricular assist device. PMID- 23462638 TI - Giant congenital right atrium: a very rare entity diagnosed in an adult patient. PMID- 23462639 TI - Natural variation and genetic constraints on drought tolerance. AB - Drought is a central abiotic stress for both natural plant populations and agricultural crops. Substantial natural genetic variation in drought resistance traits has been identified in plant populations, crop species, and laboratory model systems. In particular, studies in Arabidopsis thaliana have discovered variation in a number of key physiological traits involved in plant-water relations that may underlie evolved drought stress responses among accessions. Despite this abundant variation, we still know little about the complex genetic architecture of drought tolerance or its role in constraining evolution. Unfortunately, few natural allelic variants have been cloned for drought related traits--progress cloning QTL, the use of RNA-sequencing methods for evaluating gene expression responses to soil drying, and improved methodology for exploring complex multivariate data all hold promise for moving the field forward. In particular, a better understanding of the molecular nature of pleiotropic gene action and the genetics of phenotypic plasticity will give insight into local adaptation in plants and provide new avenues for improving crops. PMID- 23462640 TI - Regulation of the mitochondrial tricarboxylic acid cycle. AB - Recent years have seen considerable advances in our understanding of the particular physiological roles of the constituent enzymes of the tricarboxylic acid (TCA) cycle. Despite acquiring a fairly comprehensive overview of the functional importance of these proteins relatively little is known concerning how this important pathway is regulated. In this review we concentrate on the mitochondrial reactions since this organelle is the only one in which a full cycle can, at least theoretically, operate. We summarize what is known about the regulation of the enzymes of the pathway both from historical kinetic studies as well as discussing more recent transcriptional and proteomic studies and our enhanced understanding of subcellular compartmentation within the context of metabolic regulation. PMID- 23462641 TI - The enhanced membrane interaction and perturbation of a cell penetrating peptide in the presence of anionic lipids: toward an understanding of its selectivity for cancer cells. AB - Cell penetrating peptides (CPPs) are usually short, highly cationic peptides that are capable of crossing the cell membrane and transport cargos of varied size and nature in cells by energy- and receptor-independent mechanisms. An additional potential is the newly discovered anti-tumor activity of certain CPPs, including RW16 (RRWRRWWRRWWRRWRR) which is derived from penetratin and is investigated here. The use of CPPs in therapeutics, diagnosis and potential application as anti-tumor agents increases the necessity of understanding their mode of action, a subject yet not totally understood. With this in mind, the membrane interaction and perturbation mechanisms of RW16 with both zwitterionic and anionic lipid model systems (used as representative models of healthy vs tumor cells) were investigated using a large panoply of biophysical techniques. It was shown that RW16 autoassociates and that its oligomerization state highly influences its membrane interaction. Overall a stronger association and perturbation of anionic membranes was observed, especially in the presence of oligomeric peptide, when compared to zwitterionic ones. This might explain, at least in part, the anti tumor activity and so the selective interaction with cancer cells whose membranes have been shown to be especially anionic. Hydrophobic contacts between the peptide and lipids were also shown to play an important role in the interaction. That probably results from the tryptophan insertion into the fatty acid lipid area following a peptide flip after the first electrostatic recognition. A model is presented that reflects the ensemble of results. PMID- 23462642 TI - Identification of conserved microRNAs and their targets in the model legume Lotus japonicus. AB - MicroRNAs (miRNAs) are a new class of non-protein coding small RNAs that regulate gene expression at the post-transcriptional level in plants and animals. Although thousands of miRNAs were identified in many plant species, only 3 miRNAs have been reported in Lotus Japonicus, a model legume plant. In this study, 80 potential miRNA candidates were identified in 28 ESTs and 52 GSSs of L. japonicus using a homology-based computational analysis. A total of 735 miRNA targets were predicted and some of them encoded transcription factors as well as genes that function in stress response, signal transduction, methylation and others. Quantitative real-time PCR (qRT-PCR) analysis indicated that miR156a, miR160a and miR399a participated in seed germination of L. japonicus. GO and KEGG analysis suggested that the predicted miRNAs might target genes involved in lipid, nitrogen, starch sucrose metabolism and signal transduction. PMID- 23462643 TI - Quinic acid derivatives from Pimpinella brachycarpa exert anti-neuroinflammatory activity in lipopolysaccharide-induced microglia. AB - Five new quinic acid derivatives (1-5), together with 10 known quinic acid derivatives (6-15), were isolated from the MeOH extract of Pimpinella brachycarpa (Umbelliferae). Their structures were established on the basis of spectroscopic analyses including extensive 2D NMR studies (COSY, HMQC and HMBC). Isolated compounds 1-15 were evaluated for their inhibitory activities on nitric oxide (NO) production in an activated murine microglial cell line. Compounds 2, 3, 8 and 11 significantly inhibited NO production without high cell toxicity in lipopolysaccharide (LPS)-activated BV-2 cells, a microglia cell line (IC50=4.66, 12.52, 9.04 and 12.11 MUM, respectively). PMID- 23462644 TI - The hydrophobic substituent in aminophospholipids affects the formation kinetics of their Schiff bases. AB - Schiff bases (SBs) are the initial products of non-enzymatic glycation reactions, which are associated to some diabetes-related diseases. In this work, we used physiological pH and temperature conditions to study the formation kinetics of the SBs of 1,2-dihexanoyl-sn-glycero-3-phosphoethanolamine (DPHE) and 1,2 dihexanoyl-sn-glycero-3-phospho-l-serine (DHPS) with various glycating compounds and with pyridoxal 5'-phosphate (an effective glycation inhibitor). Based on the obtained results, the hydrophobic environment simultaneously decreases the nucleophilic character of the amino group (k1) and increases its pKa, thereby increasing the formation rate of SB (kobs). Therefore, the presence of hydrophobic chains in aminophospholipids facilitates the formation and stabilization of SBs, and also, in a biological environment, their glycation. Additionally, the results confirm the inhibitory action of B6 vitamers on aminophospholipid glycation. PMID- 23462646 TI - Precedents in law for punishing gross negligence. PMID- 23462645 TI - Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells. AB - Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which changed in two directions/trajectories: one trajectory by the repression of either Pou5f1 or Sox2; the other trajectory by the repression of either Esrrb, Sall4, Nanog, or Tcfap4. The data suggest that the trajectories of gene expression change are already preconfigured by the gene regulatory network and roughly correspond to extraembryonic and embryonic fates of cell differentiation, respectively. These data also indicate the robustness of the pluripotency gene network, as the transient repression of most TFs did not alter the transcriptomes. PMID- 23462647 TI - Alternative splicing of iodothyronine deiodinases in pituitary adenomas. Regulation by oncoprotein SF2/ASF. AB - Pituitary tumors belong to the group of most common neoplasms of the sellar region. Iodothyronine deiodinase types 1 (DIO1) and 2 (DIO2) are enzymes contributing to the levels of locally synthesized T3, a hormone regulating key physiological processes in the pituitary, including its development, cellular proliferation, and hormone secretion. Previous studies revealed that the expression of deiodinases in pituitary tumors is variable and, moreover, there is no correlation between mRNA and protein products of the particular gene, suggesting the potential role of posttranscriptional regulatory mechanisms. In this work we hypothesized that one of such mechanisms could be the alternative splicing. Therefore, we analyzed expression and sequences of DIO1 and DIO2 splicing variants in 30 pituitary adenomas and 9 non-tumorous pituitary samples. DIO2 mRNA was expressed as only two mRNA isoforms. In contrast, nine splice variants of DIO1 were identified. Among them, five were devoid of exon 3. In silico sequence analysis of DIO1 revealed multiple putative binding sites for splicing factor SF2/ASF, of which the top-ranked sites were located in exon 3. Silencing of SF2/ASF in pituitary tumor GH3 cells resulted in change of ratio between DIO1 isoforms with or without exon 3, favoring the expression of variants without exon 3. The expression of SF2/ASF mRNA in pituitary tumors was increased when compared with non-neoplastic control samples. In conclusion, we provide a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF. PMID- 23462648 TI - Transcatheter arterial embolisation for haemorrhage from the inferior epigastric artery after acupuncture: a case report. AB - We report a rare case of haemorrhage from the inferior epigastric artery, which was injured after acupuncture. The haemorrhage was successfully controlled by transcatheter arterial embolisation. To the best of our knowledge, this is the first report describing the use of transcatheter arterial embolisation for inferior epigastric artery haemorrhage following acupuncture. PMID- 23462650 TI - Characterisation of chemical component migration in automotive paint by synchrotron infrared imaging. AB - Synchrotron infrared chemical imaging was employed to examine and assess the extent of interlayer component migration within multilayer automotive paint samples, with a particular emphasis on the cross-linking additive melamine. Two dimensional infrared chemical images revealed that melamine consistently diffuses in select paint samples from the underlying basecoat into the outermost clear coat layer. Pigments from the basecoat were also found to migrate into the adjoining layers. This is significant as the relative abundance of both melamine and pigments will vary greatly depending upon the region of the layer analysed. This component migration will undoubtedly impact the information gleaned from a questioned sample via library searching software or multivariate statistics. As a result, appropriate analytical protocols will need to be utilised to mitigate the effects of interlayer pigment and melamine diffusion, so as to afford a true representation of the composition of the coating for forensic identification purposes. PMID- 23462649 TI - Cardiovascular outcomes and the physical and chemical properties of metal ions found in particulate matter air pollution: a QICAR study. AB - BACKGROUND: This paper presents an application of quantitative ion character activity relationships (QICAR) to estimate associations of human cardiovascular (CV) diseases (CVDs) with a set of metal ion properties commonly observed in ambient air pollutants. QICAR has previously been used to predict ecotoxicity of inorganic metal ions based on ion properties. OBJECTIVES: The objective of this work was to examine potential associations of biological end points with a set of physical and chemical properties describing inorganic metal ions present in exposures using QICAR. METHODS: Chemical and physical properties of 17 metal ions were obtained from peer-reviewed publications. Associations of cardiac arrhythmia, myocardial ischemia, myocardial infarction, stroke, and thrombosis with exposures to metal ions (measured as inference scores) were obtained from the Comparative Toxicogenomics Database (CTD). Robust regressions were applied to estimate the associations of CVDs with ion properties. RESULTS: CVD was statistically significantly associated (Bonferroni-adjusted significance level of 0.003) with many ion properties reflecting ion size, solubility, oxidation potential, and abilities to form covalent and ionic bonds. The properties are relevant for reactive oxygen species (ROS) generation, which has been identified as a possible mechanism leading to CVDs. CONCLUSION: QICAR has the potential to complement existing epidemiologic methods for estimating associations between CVDs and air pollutant exposures by providing clues about the underlying mechanisms that may explain these associations. PMID- 23462651 TI - Colo-colic intussusception secondary to lipomatous polyp in an adult. AB - A woman in her early 50s presented with a 2-week history of gradually worsening colicky abdominal pain with associated vomiting, loose stools and reduced appetite. There was no malaena or perrectal bleeding. On examination, there was tenderness in the epigastric region with an associated palpable fullness. Subsequent imaging revealed a substantial colo-colic intussusception with the lead point being a lipoma of the ascending colon. Subsequent colonic resection was undertaken with histology confirming a lipomatous polyp. PMID- 23462652 TI - An unusual case of E coli meningitis in a patient with Marfan's syndrome. AB - Spontaneous non-traumatic Escherichia coli meningitis is very rare in adults. We report a case of a 48-year-old woman with Marfan's syndrome with E coli meningitis. Apparently, the relation between an increased risk of meningitis and Marfan's syndrome is not well known. This patient was discharged on intravenous antibiotic therapy after a diagnosis of E coli meningitis without looking for the cause by imaging studies previously. Her blood cultures were negative ruling out haematogenous spread. Our work-up revealed extensive dural ectasia with intrasacral meningoceles extending into the pelvis possibly acting as a portal of entry for the bacteria into the brain from the gastrointestinal tract. PMID- 23462653 TI - Ultrasound in the acute scrotum: the truth and the false. PMID- 23462654 TI - Ho:Yag laser for sialolithiasis of Wharton's duct. AB - OBJECTIVE: To assess the feasibility of intracorporeal lithotripsy with holmium YAG laser under sialoendoscopic guidance for sialolithiasis of Wharton's duct. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral university hospital. METHODS: This study was conducted on 16 patients with sialolithiasis of Wharton's duct. Diagnosis was confirmed at ultrasound examination. Patients with stones ranging from 5 to 8 mm in diameter were enrolled in the study. The selected patients underwent intracorporeal lithotripsy with holmium Yag laser under endoscopic control. Debris was removed using sialoendoscopic forceps or a wire basket during the same procedure. After a 3 month follow-up, radiological tests were rerun. RESULTS: Stone fragmentation was possible in all cases. All patients experienced a regular postoperative course. Postoperative ultrasound examinations revealed residual stones in 3 patients, 1 of whom was asymptomatic. Three patients complained of residual symptoms after 3 months of follow-up. These patients were treated successfully during a second sialoendoscopic procedure. CONCLUSIONS: In our experience, endoscopic laser lithotripsy was proved to be a feasible technique for Wharton's duct lithiasis in clinical practice. PMID- 23462655 TI - Closing the clinical gap: translating best practice knowledge to performance with guidelines implementation. AB - Unsustainable health care costs coupled with opportunity for improvement in health care outcomes in the United States are stimulating meaningful transformation in the way we deliver care. One approach in this transformation focuses on minimizing unnecessary variation in physician practices, instead focusing on evidence-based medicine in a more uniform manner. Clinical practice guidelines contain evidence-based recommendations, articulate goals of care, and can help to reduce unnecessary variation. While thousands of clinical practice guidelines are in existence, a clinical gap exists between knowledge and clinical performance. With thoughtful guidelines implementation strategies in place, organizations can begin to close the gap and translate best practice knowledge into care. Health systems that have done this effectively have seen improved clinical outcomes, improved patient satisfaction, and lower cost per patient. PMID- 23462656 TI - Salivary morbidity and quality of life following radioactive iodine for well differentiated thyroid cancer. AB - OBJECTIVE: Determine the prevalence of sialadenitis in a group of patients treated with radioactive iodine (RAI) for well-differentiated thyroid cancer and assess whether RAI treatment is associated with a reduction in swallowing-related or global head and neck quality of life. STUDY DESIGN: Retrospective self administered questionnaire study. SETTING: Academic, tertiary care, National Cancer Institute-designated cancer center. SUBJECTS AND METHODS: Surviving patients seen for well-differentiated thyroid cancer were identified by review of the cancer center registry. Patients were mailed a baseline questionnaire, the M. D. Anderson Dysphagia Inventory (MDADI), the University of Washington Quality of Life Questionnaire (UW-QOL), and the Xerostomia-Related Quality of Life Scale (XeQOLS). RESULTS: The study included 121 women and 24 men, with a mean age of 52 years. Radioactive iodine exposure was correlated with an increase in sialadenitis and was dose dependent (R (2) = 0.335, P < .001). Sialadenitis was 2.47 times more likely to occur in patients who received greater than 150 mCi when compared with those who received less than 150 mCi (P = .04). Radioactive iodine exposure of over 150 mCi was also associated with a reduction in the recreation domain of the UW-QOL (P = .04), the daily swallowing domain of the MDADI (P = .02), and the psychological/personal, pain, and social domains of the XeQOLS (P = .03, .03, and .04, respectively). CONCLUSION: Patients treated with RAI exhibited an increased risk for sialadenitis as well as a reduction in swallowing-related and global head and neck quality of life. Our findings suggest these patients should be screened for salivary morbidity and may benefit from both pre-RAI prophylaxis and post-RAI intervention. PMID- 23462658 TI - "What can I do to improve your care today?"--one question closer to patient centered care. PMID- 23462657 TI - Variations in antibiotic prescribing of acute rhinosinusitis in United States ambulatory settings. AB - OBJECTIVE: To identify variations in antibiotic treatment of acute rhinosinusitis (ARS) on a national level. STUDY DESIGN: Cross-sectional study of a national database. SETTING: Otolaryngology and primary care ambulatory settings. SUBJECTS AND METHODS: A nationally representative sample of adult outpatient visits was extracted from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey data for 2006 to 2009. Antibiotic prescriptions associated with ARS were tabulated. Statistical analyses were conducted to identify variations in antibiotic prescribing by patient and physician characteristics. RESULTS: Antibiotics were prescribed in 82.3% +/- 2.6% of 18.7 million visits for ARS (mean age, 46.2 years; 65.9% female). The ratio of primary care physician (PCP) to otolaryngologist (ENT) ARS visits was 18.6:1. Antibiotic prescription rates were inversely related to increasing age groups of 18 to 39, 40 to 64, and >= 65 years (87.8%, 81.2%, and 71.0%, respectively; P = .02). Physicians in general medicine outpatient departments, internal medicine, and family medicine were more likely to prescribe antibiotics compared with ENTs (adjusted odds ratio [OR], 7.9 [95% confidence interval (CI), 3.5-17.8]; 6.9 [2.5-19.2]; and 3.9 [2.0 7.7], respectively). The most commonly prescribed antibiotics were azithromycin, amoxicillin, and amoxicillin/clavulanate acid (27.5%, 15.5%, and 14.6%, respectively). The ENTs selected broad-spectrum antibiotics more often than PCPs (94.3% vs 75.7% of visits with antibiotics were broad-spectrum agents; P = .01). CONCLUSION: Antibiotics were prescribed frequently despite recent consensus guidelines that discourage antibiotic use in mild cases. Furthermore, antibiotic prescription was more likely for younger patients and in primary care settings. This highlights the need to promote awareness of practice guidelines. PMID- 23462659 TI - Continuing medical education: Pakistan, a developing country's perspective. PMID- 23462660 TI - Impacts of organizational context on quality improvement: don't forget internal management! PMID- 23462663 TI - Design and use of multiplexed chemostat arrays. AB - Chemostats are continuous culture systems in which cells are grown in a tightly controlled, chemically constant environment where culture density is constrained by limiting specific nutrients.(1,2) Data from chemostats are highly reproducible for the measurement of quantitative phenotypes as they provide a constant growth rate and environment at steady state. For these reasons, chemostats have become useful tools for fine-scale characterization of physiology through analysis of gene expression(3-6) and other characteristics of cultures at steady-state equilibrium.(7) Long-term experiments in chemostats can highlight specific trajectories that microbial populations adopt during adaptive evolution in a controlled environment. In fact, chemostats have been used for experimental evolution since their invention.(8) A common result in evolution experiments is for each biological replicate to acquire a unique repertoire of mutations.(9-13) This diversity suggests that there is much left to be discovered by performing evolution experiments with far greater throughput. We present here the design and operation of a relatively simple, low cost array of miniature chemostats-or ministats-and validate their use in determination of physiology and in evolution experiments with yeast. This approach entails growth of tens of chemostats run off a single multiplexed peristaltic pump. The cultures are maintained at a 20 ml working volume, which is practical for a variety of applications. It is our hope that increasing throughput, decreasing expense, and providing detailed building and operation instructions may also motivate research and industrial application of this design as a general platform for functionally characterizing large numbers of strains, species, and growth parameters, as well as genetic or drug libraries. PMID- 23462664 TI - Electrogenerated chemiluminescence of bismuth sulfide nanorods modified electrode in alkaline aqueous solution. AB - Electrogenerated chemiluminescence (ECL) behavior of a bismuth sulfide nanorods modified glassy carbon electrode (NR-GCE) was investigated in alkaline aqueous solution for the first time. One weak ECL peak of the NR-GCE was observed around 1.70 V when the electrode potential was scanned from 0.0 V to -2.0 V. The intensity of the ECL peak was enhanced greatly in the presence of either H2O2 or persulfate. The dissolved oxygen, the pH and the supporting electrolytes of the working solution could influence ECL emission noticeably. Under the optimal conditions, the ECL signal displayed a good linear relationship with the concentration of hydrogen peroxide in the range of 5.0 * 10(-7) to 1.0 * 10(-4) mol L(-1) with a correlation coefficient of 0.997 and a detection limit of 2.0 * 10(-7) mol L(-1) at the signal-to-noise ratio of 3. A possible ECL mechanism of the NR-GCE was also proposed. PMID- 23462665 TI - Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. AB - OBJECTIVE: Glucagon-like peptide-1 receptor agonists such as exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between "responders" (reduction in energy intake after exenatide infusion) and "nonresponders." RESEARCH DESIGN AND METHODS: We performed a randomized, double blinded, placebo-controlled, cross-over fMRI study with intravenous administration of exenatide in obese male volunteers. During brain scanning with continuous exenatide or placebo administration, participants rated food and nonfood images. After each scanning session, energy intake was measured using an ad libitum buffet. Functional hypothalamic connectivity was assessed by eigenvector centrality mapping, a measure of connectedness throughout the brain. RESULTS: Responders showed significantly higher connectedness of the hypothalamus, which was specific for the food pictures condition, in the exenatide condition compared with placebo. Nonresponders did not show any significant exenatide-induced changes in hypothalamic connectedness. CONCLUSIONS: Our results demonstrate a central hypothalamic effect of peripherally administered exenatide that occurred only in the group that showed an exenatide dependent anorexigenic effect. These findings indicate that the hypothalamic response seems to be the crucial factor for the effect of exenatide on energy intake. PMID- 23462666 TI - Significant coronary stenosis in asymptomatic Chinese with different glycemic status. AB - OBJECTIVE: To evaluate coronary artery stenosis in early diabetes or prediabetes asymptomatic of myocardial ischemia in community-dwelling Chinese adults. RESEARCH DESIGN AND METHODS: Age- and sex-matched participants with normal glucose regulation (NGR), prediabetes, or diabetes diagnosed within 5 years, asymptomatic of coronary artery disease (CAD), were randomly selected from a community-dwelling Chinese population aged 40-60 years. Dual-source computed tomography coronary angiography was used to evaluate the existence and extent of coronary stenosis, which was considered significant if >50% narrowing of vessel lumen was detected. RESULTS: After excluding uninterpretable segments attributable to motion artifacts, a total of 135 participants with NGR, 132 with prediabetes, and 134 with diabetes participated in data analysis. Significant coronary stenosis was detected in 10 (7.4%), 10 (7.6%), and 22 (16.4%) individuals with NGR, prediabetes, and diabetes, respectively (P for trend = 0.029). Diabetes, rather than prediabetes, was associated with a significant 2.34 fold elevated risk [odds ratio (OR) 2.34 (95% CI 1.01-5.43); P = 0.047] of significant coronary stenosis as compared with that associated with NGR. Levels of glucose evaluation were independently and significantly associated with risks of significant coronary stenosis in diabetes. Each 1-SD increase in fasting plasma glucose, 2-h postload plasma glucose, and HbA1c conveyed 2.11-fold, 1.73 fold, and 1.81-fold higher risks of significant coronary stenosis, respectively, after adjustment for other conventional cardiovascular risk factors. CONCLUSIONS: Using a noninvasive CAD diagnostic modality such as dual-source computed tomography coronary angiography, we detected a markedly elevated risk of significant coronary stenosis with early diabetes in asymptomatic Chinese adults. PMID- 23462667 TI - Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion. AB - OBJECTIVE: Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the KATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide. RESEARCH DESIGN AND METHODS: To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed. RESULTS Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 +/- 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of KATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5'-triphosphate inhibition were associated with the most severe neurologic symptoms. CONCLUSIONS: We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion. PMID- 23462668 TI - Molecular structure analysis and spectroscopic characterization of 5-ethyl-5 phenyl-1,3-diazinane-4,6-dione with experimental (FT-IR and FT-Raman) techniques and quantum chemical calculations. AB - In this work, the FT-IR and FT-Raman spectra of 5-ethyl-5-phenyl-1,3-diazinane 4,6-dione have been recorded. The optimum molecular geometry, normal mode wavenumbers, infrared and Raman intensities, Raman scattering activities, corresponding vibrational assignments and Mullikan atomic charges were investigated with the help of HF and B3LYP(DFT) methods using 6-31G(d,p) basis set. The assignments of vibrational spectra have been carried out with the help of normal co-ordinate analysis (NCA) following the scaled quantum mechanical force field (SQMFF) methodology. The stability of molecule has been analyzed by NBO analysis. The calculated HOMO and LUMO energies show that charge transfer interactions take place within the molecule. Finally, the Mulliken population analysis on atomic charges of the title compound has been calculated. PMID- 23462669 TI - [Acute polyradiculoneuritis and myasthenia gravis: when one train hides another...]. PMID- 23462670 TI - Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine. AB - BACKGROUND: This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP). METHODS: Serum samples were collected from 25 Japanese and 6 Swedish FAP amyloidogenic transthyretin (ATTR) Valine30Methionine (V30M) patients, 4 asymptomatic Japanese ATTR V30M gene carriers, and 24 Japanese healthy volunteers. Study methods included enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. RESULTS: Three Japanese and 5 Swedish patients had significantly higher levels of antibodies against ATTR than did healthy volunteers and asymptomatic gene carriers (P<0.05). All 8 patients with higher antibody levels were late-onset cases. The ratio of wild-type TTR to ATTR V30M in serum from the high-antibody group was higher than that of the low-antibody group. ELISA results revealed two epitopes at positions 24-35 and 105-115 of ATTR V30M. We found a significant positive correlation between levels of the antibody at positions 24-35 and the age at FAP onset (r=0.751, P<0.05). An age-dependent increase in the occurrence of antibodies was observed in these patients with an epitope at positions 24-35. CONCLUSIONS: These findings may help explain the differences in early- and late-onset FAP and/or the progression of FAP. PMID- 23462671 TI - Carrier free rapamycin loaded drug eluting stent: in vitro and in vivo evaluation. AB - In the search for improving the performance of drug eluting stent (DES) various developments are in progress worldwide including use of carrier free DES, use of biodegradable polymers, biodegradable stents etc. In this work, carrier free rapamycin (RM) coated DES has been prepared, and evaluated by in vitro and in vivo procedures necessary for clinical development. In vitro drug release from the developed stents was carried in different release media, normal saline isopropanol (NS-IP), phosphate buffer (PB), phosphate buffer saline (PBS) and in human plasma. Simultaneously, drug released at site of implantation and biocompatibility of developed stents was determined after subcutaneous implantation in the SD rats. Developed stent coating method enables fabrication of controllable and homogeneous crystalline RM coatings on stent scaffolds. Continuous release of RM was observed in different release conditions with different release rate, maximum in NS-IP and least in PB. Similarly, after subcutaneous implantation of these stents, RM was found in surrounding tissues and in implanted stent up to 28 days. Biocompatibility studies showed no evidence for presence of necrosis, foreign body giant cell reaction or any type of increased severity of inflammatory reaction, proving potential of developed stents for further clinical development. PMID- 23462672 TI - Polyalkylcyanoacrylates as in situ formed diffusion barriers in multimaterial drug carriers. AB - Polymeric hydrogels typically release their drug payload rapidly due to their high water content and the diffusivity for drug molecules. This study proposes a multimaterial system to sustain the release by covering the hydrogel with a poly(alkyl-2-cyanoacrylate) [PACA]-based film, which should be formed by an in situ polymerization on the hydrogel surface initiated upon contact with water. A series of PACA-hydrogel hybrid systems with increasing PACA side chain hydrophobicity was prepared using physically crosslinked alginate films and hydrophilic diclofenac sodium as model hydrogel/drug system. Successful synthesis of PACA at the hydrogel surface was confirmed and the PACA layer was identified to be most homogeneous for poly(n-butyl-2-cyanoacrylate) on both the micro- and nanolevel. At the same time, the diclofenac release from the hybrid systems was substantially sustained from ~1day for unmodified hydrogels up to >14days depending on the type of PACA employed as diffusion barrier. Overall, in situ polymerized PACA films on hydrogels may be widely applicable to various hydrogel matrices, different matrix sizes as well as more complex shaped hydrogel carriers. PMID- 23462674 TI - Highly accelerated T1-weighted abdominal imaging using 2-dimensional controlled aliasing in parallel imaging results in higher acceleration: a comparison with generalized autocalibrating partially parallel acquisitions parallel imaging. AB - PURPOSE: The purpose of this study was to evaluate the feasibility and technical quality of an abdominal 3-dimensional interpolated breath-hold (volumetric interpolated breath-hold examination [VIBE]) magnetic resonance examination using the new parallel acquisition technique, controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA). MATERIALS AND METHODS: In this institutional review board-approved study, 15 volunteers underwent an abdominal magnetic resonance imaging examination including axial unenhanced 3-dimensional VIBE sequences with the conventional parallel acquisition technique, generalized autocalibrating partially parallel acquisitions parallel imaging (GRAPPA), with an acceleration factor (R) of 2, 3, 4, and 2 * 2 in comparison with a CAIPIRINHA VIBE sequence with an acceleration factor of 2 * 2. Images were evaluated regarding the overall image quality, liver edge sharpness, and parallel imaging artifacts. Signal-to-noise ratio was evaluated using 2 different methods. In a second study population, 17 patients were examined with our new routine protocol for abdominal imaging that now comprises VIBE sequences with CAIPIRINHA with R = 2 * 2. RESULTS: In the volunteer population, the overall image quality of CAIPIRINHA with R = 2 * 2 was significantly higher compared with GRAPPA with R = 3, 4, and 2 * 2 (P < 0.05). There were significantly less parallel imaging artifacts with CAIPIRINHA with R = 2 * 2 (P < 0.05). Acquisition time varied between 21.1 (GRAPPA with R = 2, 320 matrix) and 6.9 seconds (CAIPIRINHA with R = 2 * 2, 256 matrix). Signal-to-noise ratio performance of CAIPIRINHA with R = 2 * 2 was superior to GRAPPA with R = 3, 4, and 2 * 2. In the patient population, VIBE sequences with CAIPIRINHA with R = 2 * 2 showed consistently good image quality, minimal motion artifacts, and minimal parallel imaging artifacts. CONCLUSIONS: The CAIPRINHA-VIBE with an acceleration factor of R = 2 * 2 is feasible in a clinical setting and is characterized by fast and robust imaging with an image quality comparable with a 2-fold acceleration with GRAPPA. PMID- 23462673 TI - Applicators for magnetic resonance-guided ultrasonic ablation of benign prostatic hyperplasia. AB - OBJECTIVES: The aims of this study were to evaluate in a canine model applicators designed for ablation of human benign prostatic hyperplasia (BPH) in vivo under magnetic resonance imaging (MRI) guidance, including magnetic resonance thermal imaging (MRTI), determine the ability of MRI techniques to visualize ablative changes in prostate, and evaluate the acute and longer term histologic appearances of prostate tissue ablated during these studies. MATERIALS AND METHODS: An MRI-compatible transurethral device incorporating a tubular transducer array with dual 120 degrees sectors was used to ablate canine prostate tissue in vivo, in zones similar to regions of human BPH (enlarged transition zones). Magnetic resonance thermal imaging was used for monitoring of ablation in a 3-T environment, and postablation MRIs were performed to determine the visibility of ablated regions. Three canine prostates were ablated in acute studies, and 2 animals were rescanned before killing at 31 days postablation. Acute and chronic appearances of ablated prostate tissue were evaluated histologically and were correlated with the MRTI and postablation MRI scans. RESULTS: It was possible to ablate regions similar in size to enlarged transition zone in human BPH in 6 to 18 minutes. Regions of acute ablation showed a central "heat-fixed" region surrounded by a region of more obvious necrosis with complete disruption of tissue architecture. After 31 days, ablated regions demonstrated complete apparent resorption of ablated tissue with formation of cystic regions containing fluid. The inherent cooling of the urethra using the technique resulted in complete urethral preservation in all cases. CONCLUSIONS: Prostatic ablation of zones of size and shape corresponding to human BPH is possible using appropriate transurethral applicators using MRTI, and ablated tissue may be depicted clearly in contrast-enhanced magnetic resonance images. The ability accurately to monitor prostate tissue heating, the apparent resorption of ablated regions over 1 month, and the inherent urethral preservation suggest that the magnetic resonance-guided techniques described are highly promising for the in vivo ablation of symptomatic human BPH. PMID- 23462675 TI - Measurement of placental perfusion by dynamic contrast-enhanced MRI at 4.7 T. AB - PURPOSE: The purposes of this study were to develop quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) at 4.7 T for perfusion measurement and to evaluate the ability of this technique to distinguish between low and normal levels of placental perfusion in a controlled rat model. MATERIALS AND METHODS: This study was approved by the animal care committee. Poor placental perfusion in the left uterine horn was achieved by ligation of the left uterine vascular pedicle on the 17th embryonic day in 12 pregnant rats. High-temporal resolution DCE-MRI (<1 second) was performed on the 19th embryonic day. Single compartment analysis was used to calculate placental blood flow (F), volume fraction (Vb), and time delay (Dt) for each placenta and its 2 layers in both uterine horns. Mixed regression analysis was used to compare parameters between the ligated and nonligated horn and between placental layers. RESULTS: We examined 53 placentas: 11 on the ligated side and 42 on the control side. On the control side, the mean (SD) values were 115 (72) mL/min per 100 mL for F, 38.6% (11.7%) for Vb, and 5.5 (5.3) seconds for Dt. Placental blood flow was significantly lower on the ligated side (66 [30] mL/min per 100 mL; P = 0.001).Placental blood flow and Vb were significantly higher, whereas Dt was significantly lower in the inner layer than in the outer layer in both horns (P=0.0001). CONCLUSIONS: Quantitative analyses of perfusion are feasible with DCE MRI at 4.7 T.Dynamic contrast-enhanced magnetic resonance imaging can differentiate between low and normal levels of placental perfusion in a rat model. Dynamic contrast-enhanced magnetic resonance imaging at 4.7 T is a promising preclinical tool for quantifying and monitoring microvascularization. PMID- 23462676 TI - Percutaneous abscess drainage using near real-time MR guidance in an open 1.0-T MR scanner: proof of concept. AB - OBJECTIVES: The aims of our study were (1) to assess the feasibility, effectiveness, and safety of exclusively magnetic resonance (MR)-guided freehand percutaneous abscesses drainage using a 1.0-T open MR scanner and (2) to evaluate the optimal method to visualize drainage catheters in situ. MATERIAL AND METHODS: In vitro studies in a dedicated MR gelatin phantom were performed to assess visualization of 8 different sizes of drainage catheters after instillation of sole 0.9% sodium chloride (NaCl) and diluted (1.0%) or concentrated (12.0%) gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) using a T1-weighted (T1w) 2-dimensional fast field echo (FFE) and a T2-weighted single-shot (ssh) turbo spin-echo (TSE) fast dynamic sequence. The catheter artifacts were evaluated with regard to the contrast-to-noise ratio (CNR), the artifact width using the full width at half-maximum (FWHM) method, and the artifact intensity, being the product of the CNR and the FWHM. We used the general linear model procedure as the global test and the Tukey studentized range test for post hoc analysis. In vivo MR-guided freehand drainage was prospectively performed in patients with increased systemic inflammation markers and abdominal, retroperitoneal, and pelvic abscess collections. This study had been approved by the institutional review board. All patients provided written informed consent. Technical success was the primary efficacy variable. The secondary efficacy variables were visibility of the puncture needle and drainage catheter artifact, using a qualitative 5-point rating scale, intervention and procedure time, and rate of postinterventional complications. RESULTS: The FWHM, the CNR, and the artifact intensity of the drainage catheters filled with 0.9% NaCl or diluted or concentrated Gd-DTPA increased according to the drainage catheter size in an almost linear fashion in both image weighting (all P <= 0.006; all R(2) >= 0.73). The T1w FFE sequence yielded the highest FWHM, CNR, and artifact intensity of all groups, using 12.0% Gd-DTPA instillation (all P < 0.001), and the least FWHM and artifact intensity, using 1.0% Gd-DTPA instillation (all P < 0.022; all P < 0.009). The T2w ssh TSE yielded higher FWHM, using 12.0% Gd-DTPA instillation, whereas the CNR was higher for 0.9% NaCl instillation (all P < 0.001). Magnetic resonance-guided abscess drainage was performed in 22 patients with 24 abdominal, retroperitoneal, or pelvic abscess collections. The technical success rate of in vivo MR-guided freehand drainage was 100%. Visibility of the puncture needle was excellent (>=4.4 [0.5] points). Visibility of the drainage catheters was rated with 3.9 (0.9) and 4.5 (0.8) points using T2w ssh TSE with 0.9% NaCl and 12.0% Gd DTPA instillation as well as 4.8 (0.5) and 4.2 (0.8) points using T1w FFE with 1.0% and 12.0% Gd-DTPA instillation, respectively. The procedure and intervention time was 52.4 (16.4) minutes (range, 28-78 minutes) and 27.4 (7.2) minutes (range, 17-40 minutes). Two minor and no major complications were recorded. CONCLUSIONS: Magnetic-resonance-guided freehand percutaneous abscesses drainage using fast dynamic sequences in an open 1-T MR scanner is feasible, effective, and safe. Visualization of drainage catheters can be facilitated by instillation of 0.9% NaCl or diluted or concentrated contrast media. PMID- 23462678 TI - Simultaneous 18F choline positron emission tomography/magnetic resonance imaging of the prostate: initial results. AB - PURPOSE: The purposes of this study were to evaluate the feasibility of simultaneous 18F choline positron emission tomography (PET) and magnetic resonance imaging (MRI) of the prostate and to present the first clinical results of the method. MATERIALS AND METHODS: From March 2012 to October 2012, a total of 15 consecutive patients were examined with simultaneous 18F choline PET/MRI. At the time of the examination, 8 patients had histologically proven prostate cancer, 2 patients had repeated prostate biopsies with negative results, and 5 patients had suspected prostate cancer with an elevated or rising prostate specific antigene level but did not have a prostate biopsy. Sequence protocol comprised T2-weighted high-resolution images and diffusion-weighted images of the prostate in addition to PET imaging. Image quality was assessed by 2 radiologists, and the PET images were evaluated qualitatively and quantitatively. RESULTS: Simultaneous PET/MRI of the prostate was accomplished successfully in all patients. The method proved to be robust without technical failure, and the image quality was rated to be diagnostic in all examinations except in 1 diffusion-weighted imaging (DWI) data set that was judged to be nondiagnostic because of susceptibility artifacts. High-resolution T2-weighted images allowed exact correlation of elevated focal or diffuse choline uptake to suspicious T2 weighted lesions of the prostate. A high accordance was found between PET and DWI. However, PET-positive lesions were found in 3 patients wherein DWI did not indicate tumor in suspicious T2-weighted lesions. CONCLUSIONS: Simultaneous positron emission tomography/magnetic resonance imaging of the prostate has the advantage of combining high-resolution prostate images, functional studies, and metabolic/molecular imaging. The PET component adds diagnostic confidence to the MRI-based parameters in identifying and localizing tumor in the prostate. PMID- 23462677 TI - Effect of MRI acoustic noise on cerebral fludeoxyglucose uptake in simultaneous MR-PET imaging. AB - Integrated scanners capable of simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) data acquisition are now available for human use. Although the scanners' manufacturers have made substantial efforts to understand and minimize the mutual electromagnetic interference between the 2 modalities, the potential physiological inference has not been evaluated. In this study, we have studied the influence of the acoustic noise produced by the magnetic resonance (MR) gradients on brain fludeoxyglucose (FDG) uptake in the Siemens MR-BrainPET prototype. Although particular attention was paid to the primary auditory cortex (PAC), a brain-wide analysis was also performed. METHODS: The effects of the MR on the PET count rate and image quantification were first investigated in phantoms. Next, 10 healthy volunteers underwent 2 simultaneous FDG-PET/MR scans in the supine position with the FDG injection occurring inside the MR-BrainPET, alternating between a "quiet" (control) environment in which no MR sequences were run during the FDG uptake phase (the first 40 minutes after radiotracer administration) and a "noisy" (test) environment in which MR sequences were run for the entire time. Cortical and subcortical regions of interest were derived from the high-resolution morphological MR data using FreeSurfer. The changes in the FDG uptake in the FreeSurfer-derived regions of interest between the 2 conditions were analyzed from parametric and static PET images, and on a voxel-by-voxel basis using SPM8 and FreeSurfer. RESULTS: Only minimal to no electromagnetic interference was observed for most of the MR sequences tested, with a maximum drop in count rate of 1.5% and a maximum change in the measured activity of 1.1% in the corresponding images. The region of interest-based analysis showed statistically significant increases in the right PAC in both the parametric (9.13% [4.73%]) and static (4.18% [2.87%]) images. The SPM8 analysis showed no statistically significant clusters in any images when a P < 0.05 (corrected) was used; however, a P < 0.001 (uncorrected) resolved bilateral statistically significant clusters of increased FDG uptake in the area of the PAC for the parametric image (left, 8.37% [1.55%]; right, 8.20% [1.17%]) but only unilateral increase in the static image (left, 8.68% [3.89%]). CONCLUSIONS: Although the operation of the BrainPET prototype is virtually unaffected by the MR scanner, the acoustic noise produced by the MR gradients causes a focal increase in the FDG uptake in the PAC, which could affect the interpretation of pathological (or brain-activation-related) changes in the FDG uptake in this region if the expected effects are of comparable amplitude. PMID- 23462679 TI - Static network analysis of a pork supply chain in Northern Germany Characterisation of the potential spread of infectious diseases via animal movements. AB - Transport of live animals is a major risk factor in the spread of infectious diseases between holdings. The present study analysed the pork supply chain of a producer community in Northern Germany. The structure of trade networks can be characterised by carrying out a network analysis. To identify holdings with a central position in this directed network of pig production, several parameters describing these properties were measured (in-degree, out-degree, ingoing and outgoing infection chain, betweenness centrality and ingoing and outgoing closeness centrality). To obtain the importance of the different holding types (multiplier, farrowing farms, finishing farms and farrow-to-finishing farms) within the pyramidal structure of the pork supply chain, centrality parameters were calculated for the entire network as well as for the individual holding types. Using these centrality parameters, two types of holdings could be identified. In the network studied, finishing and farrow-to-finishing farms were more likely to be infected due to the high number of ingoing trade contacts. Due to the high number of outgoing trade contacts multipliers and farrowing farms had an increased risk to spread a disease to other holdings. However, the results of the centrality parameters degree and infection chain were not always consistent, such that the indirect trade contacts should be taken into consideration to understand the real importance of a holding in spreading or contracting an infection. Furthermore, all calculated parameters showed a highly right-skewed distribution. Networks with such a degree distribution are considered to be highly resistant concerning the random removal of nodes. But by strategic removal of the most central holdings, e.g. by trade restrictions or selective vaccination or culling, the network structure can be changed efficiently and thus decompose into fragments. Such a fragmentation of the trade networks is of particular importance from an epidemiological perspective. PMID- 23462680 TI - Gene expression profiling in breast cancer: a clinical perspective. AB - Gene expression profiling tests are used in an attempt to determine the right treatment for the right person with early-stage breast cancer that may have spread to nearby lymph nodes but not to distant parts of the body. These new diagnostic approaches are designed to spare people who do not need additional treatment (adjuvant therapy) the side effects of unnecessary treatment, and allow people who may benefit from adjuvant therapy to receive it. In the present review we discuss in detail the major diagnostic tests available such as MammaPrint dx, Oncotype dx, PAM50, Mammostrat, IHC4, MapQuant DX, Theros-Breast Cancer Gene Expression Ratio Assay, and their potential clinical applications. PMID- 23462681 TI - A validated web-based nomogram for predicting positive surgical margins following breast-conserving surgery as a preoperative tool for clinical decision-making. AB - BACKGROUND: Breast-conserving therapy, consisting of lumpectomy and adjuvant radiotherapy, is considered standard treatment for early-stage breast cancer. One of the most important risk factors of local recurrence is the presence of positive surgical margins following lumpectomy. We aimed to develop and validate a predictive model (nomogram) to predict for positive margins following the first attempt at lumpectomy as a preoperative tool for clinical decision-making. METHODS: Patients with clinical T1-2N0-1Mx-0 histology-proven invasive breast carcinoma who underwent BCT throughout the North-East region of The Netherlands between June 2008 and July 2009 were selected from the Netherlands Cancer Registry (n = 1185). Results from multivariate logistic regression analyses served as the basis for development of the nomogram. Nomogram calibration and discrimination were assessed graphically and by calculation of a concordance index, respectively. Nomogram performance was validated on an external independent dataset (n = 331) from the University Medical Center Groningen. RESULTS: The final multivariate regression model included clinical, radiological, and pathological variables. Concordance indices were calculated of 0.70 (95% CI: 0.66-0.74) and 0.69 (95% CI: 0.63-0.76) for the modeling and the validation group, respectively. Calibration of the model was considered adequate in both groups. A nomogram was developed as a graphical representation of the model. Moreover, a web-based application (http://www.breastconservation.com) was build to facilitate the use of our nomogram in a clinical setting. CONCLUSION: We developed and validated a nomogram that enables estimation of the preoperative risk of positive margins in breast-conserving surgery. Our nomogram provides a valuable tool for identifying high-risk patients who might benefit from preoperative MRI and/or oncoplastic surgery. PMID- 23462682 TI - Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women. AB - The present meta-analysis examines randomized trials of third-generation aromatase inhibitors (AIs) as alternatives to tamoxifen in three treatment settings: monotherapy, sequenced therapy and extended therapy. Eleven randomized controlled trials (RCTs) were chosen based on their similarity in terms of study design and included 34,070 post-menopausal women who had undergone surgery for estrogen-sensitive early breast cancer. DFS was significantly improved by AI monotherapy (Hazard Ratio (HR): 0.89, p = 0.001), sequenced therapy (HR: 0.7, p < 0.00001) and extended therapy (HR: 0.62, p < 0.00001). All of the patients benefited significantly from sequenced therapy (HR: 0.81, p = 0.003), and hormone receptor-positive patients benefited from AI monotherapy (HR = 0.92, p = 0.046) with respect to OS. AI monotherapy conferred significantly lower risks for thromboembolic events (OR = 0.61; p < 0.001) and endometrial cancer (OR = 0.26; p < 0.001) compared with tamoxifen monotherapy; however, there was a greater risk of cardiovascular events (OR = 1.20; p = 0.030). Sequenced therapy was also superior in terms of endometrial cancer but was inferior with respect to fractures, thromboembolic and cardiovascular events. PMID- 23462684 TI - Hierarchical nanostructures with unique Y-shaped interconnection networks in manganese substituted cobalt oxides: the enhancement effect on electrochemical sensing performance. AB - A general redox procedure was successfully developed for the controlled synthesis of substituted cobalt oxides with hierarchical flower-like nanostructures comprising unique Y-shaped interconnections. The substitution and nanostructures synergistically enhance the material's electrochemical activities for highly efficient sensing of H2O2. PMID- 23462683 TI - Hoxa-5 acts in segmented somites to regulate cervical vertebral morphology. AB - The vertebrate axial skeleton (vertebral column and ribs) is derived from embryonic structures called somites. Mechanisms of somite formation and patterning are largely conserved along the length of the body axis, but segments acquire different morphologies in part through the action of Hox transcription factors. Although Hox genes' roles in axial skeletal patterning have been extensively characterized, it is still not well understood how they interact with somite patterning pathways to regulate different vertebral morphologies. Here, we investigated the role of Hoxa-5 in after somite segmentation in chick. Hoxa-5 mRNA is expressed in posterior cervical somites, and within them is restricted mainly to a sub-domain of lateral sclerotome. RNAi-based knockdown leads to cartilage defects in lateral vertebral elements (rib homologous structures) whose morphologies vary within and outside of the Hoxa-5 expression domain. Both knockdown and misexpression suggest that Hoxa-5 acts via negative regulation of Sox-9. Further, Hoxa-5 misexpression suggests that spatial and/or temporal restriction of Hoxa-5 expression is necessary for proper vertebral morphology. Finally, the restriction of Hoxa-5 expression to lateral sclerotome, which we hypothesize is important for its patterning function, involves regulation by signaling pathways that pattern somites, Fgf-8 and Shh. PMID- 23462685 TI - Singers' phonation threshold pressure and ratings of self-perceived effort on vocal tasks. AB - OBJECTIVES/HYPOTHESIS: This study was designed to determine if singers' self ratings of vocal effort could predict phonation threshold pressure (PTP). It was hypothesized that effort ratings on the more complex task of singing "Happy Birthday" would best predict PTP. STUDY DESIGN: A multiple regression analysis was performed with PTP as the predicted variable and self-ratings on four phonatory tasks as the predictor variables. METHODS: Participants were 48 undergraduate and graduate students majoring in vocal performance. They produced /pi/ syllable trains as softly as possible for the measurement of PTP. They then rated their self-perceived vocal effort while softly producing the following: (1) sustained "ah" (comfortable, midrange pitch); (2) "ah" glide (chest to head voice); (3) Staccato "ah" in head voice (not falsetto); and (4) Happy Birthday in head voice (not falsetto). RESULTS: No ratings of vocal effort predicted PTP. The lack of correlation between PTP and ratings of Happy Birthday remained when separately evaluating graduate versus undergraduate students or males versus females. Informal evaluation of repeated ratings over time suggested the potential for effective self-monitoring. CONCLUSIONS: Students' ratings of self perceived vocal effort were poor predictors of PTP. This may be because of the use of "effortless" imagery during singing instruction or consistent positive feedback regarding vocal performance. It is possible that self-rating could become an effective tool to predict vocal health if task elicitation instructions were more precise, and the student and voice teacher worked collaboratively to improve self-evaluation. PMID- 23462686 TI - Vocal indices of stress: a review. AB - OBJECTIVE: Identification of stress patterns in the voice has multiple potential applications. The objective was to review literature pertaining to the effects of various forms of stress upon the healthy voice. STUDY DESIGN: Literature review, discussion of results, and direction for further study. METHODS: This review article offers a model of stress and a review of the historical and recent research into the effects of stress on the voice. Electronic databases were searched using the key words. No studies were excluded on the basis of design; however, an attempt was made to include in the discussion studies which primarily address physiological and acoustic vocal parameters. The results of greater than 50 studies examining the effect of stressors ranging from lie and guilt to high altitude and space flight upon the voice were included in the review. RESULTS: Increase in fundamental frequency is the most commonly reported effect of stress in well-controlled trials. The trend, however, is not universal. A reduction in noise as reflected by the diminished vocal jitter is reported, but less frequently. CONCLUSIONS: Stress types, gender, and individual differences in baseline autonomic tone may explain the primarily equivocal findings of effects of stressor exposure or perceived stress on voice; and as such, the article concludes with a discussion of directions for future study. PMID- 23462687 TI - SOX2 overexpression correlates with poor prognosis in laryngeal squamous cell carcinoma. AB - OBJECTIVE: The aim of present study was to investigate the expression of SOX2, a key transcription factor, in LSCC and to assess its prognostic significance. METHODS: SOX2 expression of 161 LSCC tissues was detected by immunohistochemistry using a tissue microarray and statistically analyzed for its correlation with clinicopathological charateristics and patient outcome. In addition, SOX2 expression was also observed in 20 self-paired fresh LSCC tissues by western blot. RESULTS: SOX2 was overexpressed in LSCC tissues as compared to the corresponding adjacent normal tissues. SOX2 expression was significantly associated with tumour T classification (p<0.001), clinical stage (p<0.001), lymph node metastasis (p=0.007) and recurrence (p=0.001). Univariate analysis revealed that patients with high SOX2 expression were significantly related to overall survival (p<0.001). Multivariate survival analysis further demonstrated that SOX2 expression was an independent prognostic factor for LSCC patients. CONCLUSION: SOX2 may contribute to the malignant progression of laryngeal squamous cell carcinoma (LSCC), and present as a useful prognostic marker and a potential therapeutic target for LSCC patients. PMID- 23462688 TI - P2X receptor-dependent erythrocyte damage by alpha-hemolysin from Escherichia coli triggers phagocytosis by THP-1 cells. AB - The pore-forming exotoxin alpha-hemolysin from E. coli causes a significant volume reduction of human erythrocytes that precedes the ultimate swelling and lysis. This shrinkage results from activation of Ca2+-sensitive K+ (KCa3.1) and Cl- channels (TMEM16A) and reduced functions of either of these channels potentiate the HlyA-induced hemolysis. This means that Ca2+-dependent activation of KCa3.1 and TMEM16A protects the cells against early hemolysis. Simultaneous to the HlyA-induced shrinkage, the erythrocytes show increased exposure of phosphatidylserine (PS) in the outer plasma membrane leaflet, which is known to be a keen trigger for phagocytosis. We hypothesize that exposure to HlyA elicits removal of the damaged erythrocytes by phagocytic cells. Cultured THP-1 cells as a model for erythrocytal phagocytosis was verified by a variety of methods, including live cell imaging. We consistently found the HlyA to very potently trigger phagocytosis of erythrocytes by THP-1 cells. The HlyA-induced phagocytosis was prevented by inhibition of KCa3.1, which is known to reduce PS exposure in human erythrocytes subjected to both ionomycin and HlyA. Moreover, we show that P2X receptor inhibition, which prevents the cell damages caused by HlyA, also reduced that HlyA-induced PS-exposure and phagocytosis. Based on these results, we propose that erythrocytes, damaged by HlyA-insertion, are effectively cleared from the blood stream. This mechanism will potentially reduce the risk of intravascular hemolysis. PMID- 23462689 TI - Temporal variability of pesticide concentrations in homes and implications for attenuation bias in epidemiologic studies. AB - BACKGROUND: Residential pesticide exposure has been linked to adverse health outcomes in adults and children. High-quality exposure estimates are critical for confirming these associations. Past epidemiologic studies have used one measurement of pesticide concentrations in carpet dust to characterize an individual's average long-term exposure. If concentrations vary over time, this approach could substantially misclassify exposure and attenuate risk estimates. OBJECTIVES: We assessed the repeatability of pesticide concentrations in carpet dust samples and the potential attenuation bias in epidemiologic studies relying on one sample. METHODS: We collected repeated carpet dust samples (median = 3; range, 1-7) from 21 homes in Fresno County, California, during 2003-2005. Dust was analyzed for 13 pesticides using gas chromatography-mass spectrometry. We used mixed-effects models to estimate between- and within-home variance. For each pesticide, we computed intraclass correlation coefficients (ICCs) and the estimated attenuation of regression coefficients in a hypothetical case-control study collecting a single dust sample. RESULTS: The median ICC was 0.73 (range, 0.37-0.95), demonstrating higher between-home than within-home variability for most pesticides. The expected magnitude of attenuation bias associated with using a single dust sample was estimated to be <= 30% for 7 of the 13 compounds evaluated. CONCLUSIONS: For several pesticides studied, use of one dust sample to represent an exposure period of approximately 2 years would not be expected to substantially attenuate odds ratios. Further study is needed to determine if our findings hold for longer exposure periods and for other pesticides. PMID- 23462690 TI - In vivo measurement of the mouse pulmonary endothelial surface layer. AB - The endothelial glycocalyx is a layer of proteoglycans and associated glycosaminoglycans lining the vascular lumen. In vivo, the glycocalyx is highly hydrated, forming a substantial endothelial surface layer (ESL) that contributes to the maintenance of endothelial function. As the endothelial glycocalyx is often aberrant in vitro and is lost during standard tissue fixation techniques, study of the ESL requires use of intravital microscopy. To best approximate the complex physiology of the alveolar microvasculature, pulmonary intravital imaging is ideally performed on a freely-moving lung. These preparations, however, typically suffer from extensive motion artifact. We demonstrate how closed-chest intravital microscopy of a freely-moving mouse lung can be used to measure glycocalyx integrity via ESL exclusion of fluorescently-labeled high molecular weight dextrans from the endothelial surface. This non-recovery surgical technique, which requires simultaneous brightfield and fluorescent imaging of the mouse lung, allows for longitudinal observation of the subpleural microvasculature without evidence of inducing confounding lung injury. PMID- 23462691 TI - Mid Staffs inquiry. Political mindset needs to change. PMID- 23462692 TI - Mesoporous single-crystal CoSn(OH)6 hollow structures with multilevel interiors. AB - Hollow nanostructures represent a unique class of functional nanomaterials with many applications. In this work, a one-pot and unusual "pumpkin-carving" protocol is demonstrated for engineering mesoporous single-crystal hollow structures with multilevel interiors. Single-crystal CoSn(OH)6 nanoboxes with uniform size and porous shell are synthesized by fast growth of CoSn(OH)6 nanocubes and kinetically-controlled etching in alkaline medium. Detailed investigation on reaction course suggests that the formation of a passivation layer of Co(III) species around the liquid-solid interface is critical for the unusual hollowing process. With reasonable understanding on the mechanism involved, this approach shows high versatility for the synthesis of CoSn(OH)6 hollow architectures with a higher order of interior complexity, such as yolk-shell particles and multishelled nanoboxes. The obtained CoSn(OH)6 hollow nanostructures can be easily converted to hollow nanostructures of tin-based ternary metal oxides with excellent photocatalytic and electrochemical properties. PMID- 23462693 TI - Co-occurrence of cardiometabolic diseases and frailty in older Chinese adults in the Beijing Longitudinal Study of Ageing. AB - BACKGROUND: all cardiometabolic disorders become more common with age. Frailty and increased vulnerability to adverse outcomes are also common with aging. Even so, how commonly elderly people who are affected by cardiometabolic disorders are also frail remains unclear. OBJECTIVES: (i) to evaluate the prevalence of cardiometabolic disorders in relation to frailty. (ii) To estimate to which extent cardiometabolic diseases, when compared with frailty, affects mortality. METHODS: this is a secondary analysis of the Beijing Longitudinal Study of Ageing, a population-based representative cohort study (n = 3,257) assembled in 1992 and followed to 2007. The baseline frailty index (FI) considered 35 potential health deficits. People with an FI >0.22 were considered frail. The relationships between frailty and cardiometabolic disorders and mortality outcomes were evaluated using the Cox proportional hazard model, adjusted for baseline age, sex and education. RESULTS: the mean FI was 0.11 in men (SD = 0.10) and 0.14 (SD = 0.11) in women. On average, the FI increased with each cardiometabolic disorder (e.g. in men, mean +/- SD = 0.16 +/- 0.11 with hypertension, 0.23 +/- 0.14 with stroke). As the number of disorders increased, so did the mean FI, and the proportion with the FI >0.22. For each condition, people with the FI >0.22 had a higher mortality, even after adjusting for sex, age and education. CONCLUSION: cardiometabolic disorders do not occur in isolation and commonly increase not just together, but in the presence of other health deficits. Healthcare providers who work with older adults with such problems need to develop methods to adapt their treatments to the needs of frail older adults. PMID- 23462694 TI - Acute-on-chronic liver failure - its definition remains unclear. PMID- 23462695 TI - Association of the ADRA2A polymorphisms with the risk of type 2 diabetes: a meta analysis. AB - OBJECTIVES: Results from the published studies on the association of ADRA2A (adrenoceptor alpha 2A) variants with type 2 diabetes (T2D) are conflicting and call for further assessment. The aim of this meta-analysis was to quantitatively summarize the effects of the two recently reported ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 on T2D risk. DESIGN AND METHODS: We searched all the publications about the association between the ADRA2A SNPs and T2D from PubMed and ISI database updated on September 2012. Meta-analysis of the overall odds ratios (ORs) with 95% confidence intervals (CIs) was calculated by using the software STATA 11.0. RESULTS: Twelve studies with 40,828 subjects from seven eligible papers were included in the meta-analysis. Overall, the present meta-analysis failed to support a positive association between ADRA2A SNPs (rs553668 and rs10885122) and susceptibility to T2D (OR=1.05, p=0.17, 95% CI: 0.98, 1.12; and OR=1.06, p=0.11, 95% CI: 0.99, 1.13; respectively). However, in the subgroup analysis by ethnicity, the significant association between rs553668 and the risk of T2D was obtained in Europeans under the recessive genetic model (OR=1.36, p=0.02, 95% CI: 1.05, 1.76). CONCLUSIONS: This meta-analysis suggested that the AA genotype of rs553668 in ADRA2A might be a genetic risk factor that increases T2D susceptibility in Europeans. However, rs10885122 was unlikely substantially contribute to T2D susceptibility. PMID- 23462696 TI - Newborn screening for hepatorenal tyrosinemia-I by tandem mass spectrometry using pooled samples: a four-year summary by the New England newborn screening program. AB - OBJECTIVE: The objective of this study is to develop an isotope dilution liquid chromatography tandem mass spectrometry assay to screen for hepatorenal tyrosinemia (HT) from newborn filter paper samples using pooled extracts to increase high throughput screening. DESIGN AND METHODS: Succinylacetone (SUAC), the marker for HT, was extracted from dried blood spots with the formation of the hydrazone derivative of SUAC; up to eight sample extracts were pooled and the SUAC-derivative was analyzed by mass spectrometry methods with an injection-to injection time of one minute. If any pooled sample extract screened positive, then the samples comprising the pooled sample were assayed individually. RESULTS: Two newborn infants were identified with high levels of SUAC (7 & 23MUM) and later confirmed to have HT. Three older children whose initial filter paper samples were taken at 195days to 614days of age with elevated SUAC (range 4.9 5MUM) were identified; one of the three had clinical signs of HT and was placed on treatment (diagnosis of the other two are unavailable). CONCLUSION: MS/MS analysis of pooled dried blood sample extracts permits sensitive, reduced instrumental analytical time and increase high throughput screening for HT. PMID- 23462697 TI - Limited clinical value of multiple blood markers in the diagnosis of ischemic stroke. AB - OBJECTIVES: No ideal blood marker exists for the diagnosis of ischemic stroke. Combined use of multiple blood markers would enhance the ability of clinical diagnosis of ischemic stroke. DESIGN AND METHODS: Blood concentrations of neuronal markers (NSE, VSNL-1, hFABP, and Ngb), astroglial markers (S100B and GFAP), inflammatory markers (IL-6 and TNF-alpha), blood-brain barrier marker (MMP 9), and hemostatic markers (PAI-1) were measured within 6-24 h of stroke onset. The area under the receiver operator characteristic (AUROC) curve of patients with ischemic stroke and stroke-mimic was compared after adding individual or a combination of blood markers to the clinical diagnostic assessment (age, atrial fibrillation, and Face-Arm-Speech Test [FAST]). RESULTS: Despite acute elevations of blood IL-6, S100B, MMP-9, hFABP, and PAI-1 in univariate analysis, only IL-6, S100B, and MMP-9 were independently associated with ischemic stroke in multivariate analysis. The addition of biomarkers (IL-6, S100B, and MMP-9) did not improve the diagnostic performance of baseline clinical models with added biomarkers versus baseline clinical models alone (AUROC, 0.865 vs. 0.837, p=0.069). CONCLUSIONS: IL-6, S100B, and MMP-9 markers are elevated in the peripheral blood during the acute phase of ischemic stroke. However, the clinical usefulness of these biomarkers is limited due to low discriminating ability when compared to clinical parameters alone in diagnosis of ischemic stroke. PMID- 23462698 TI - Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver. AB - Unsafe use of alcohol results in approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths. Serum insulin levels are often elevated in alcoholism and may result in diabetes, which is why alcoholic liver disease and diabetes often are present together. Because there is a sizable population with these diseases alone or in combination, the purpose of this study was to determine whether transporter expression in human liver is affected by alcoholic cirrhosis, diabetes, and alcoholic cirrhosis coexisting with diabetes. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals and can be determinants of drug-induced liver injury. Drug transporter expression and transcription factor-relative mRNA and protein expression in normal, diabetic, cirrhotic, and cirrhosis with diabetes human livers were quantified. Cirrhosis significantly increased ABCC4, 5, ABCG2, and solute carrier organic anion (SLCO) 2B1 mRNA expression and decreased SLCO1B3 mRNA expression in the liver. ABCC1, 3 5, and ABCG2 protein expression was also upregulated by alcoholic cirrhosis. ABCC3-5 and ABCG2 protein expression was also upregulated in diabetic cirrhosis. Cirrhosis increased nuclear factor E2-related factor 2 mRNA expression, whereas it decreased pregnane-X-receptor and farnesoid-X-receptor mRNA expression in comparison with normal livers. Hierarchical cluster analysis indicated that expressions of ABCC2, 3, and 6; SLCO1B1 and 1B3; and ABCC4 and 5 were more closely related in the livers from this cohort. Overall, alcoholic cirrhosis altered transporter expression in human liver. PMID- 23462699 TI - Transfer of memory trace of cerebellum-dependent motor learning in human prism adaptation: a model study. AB - Accumulating experimental evidence suggests that the memory trace of ocular reflex adaptation is initially encoded in the cerebellar cortex, and later transferred to the cerebellar nuclei for consolidation through repetitions of training. However, the memory transfer is not well characterized in the learning of voluntary movement. Here, we implement our model of memory transfer to interpret the data of prism adaptation (Martin, Keating, Goodkin, Bastian, & Thach, 1996a, 1996b), assuming that the cerebellar nuclear memory formed by memory transfer is used for normal throwing. When the subject was trained to throw darts wearing prisms in 30-40 trials, the short-term memory for recalibrating the throwing direction by gaze would be formed in the cerebellar cortex, which was extinguished by throwing with normal vision in a similar number of trials. After weeks of repetitions of short-term prism adaptation, the long term memory would be formed in the cerebellar nuclei through memory transfer, which enabled one to throw darts to the center wearing prisms without any training. These two long-term memories, one for throwing with normal vision and the other for throwing wearing prisms, are assumed to be utilized automatically under volitional control. Moreover, when the prisms were changed to new prisms, a new memory for adapting to the new prisms would be formed in the cerebellar cortex, just to counterbalance the nuclear memory of long-term adaptation to the original prisms in a similar number of trials. These results suggest that memory transfer may occur in the learning of voluntary movements. PMID- 23462700 TI - FindZebra: a search engine for rare diseases. AB - BACKGROUND: The web has become a primary information resource about illnesses and treatments for both medical and non-medical users. Standard web search is by far the most common interface to this information. It is therefore of interest to find out how well web search engines work for diagnostic queries and what factors contribute to successes and failures. Among diseases, rare (or orphan) diseases represent an especially challenging and thus interesting class to diagnose as each is rare, diverse in symptoms and usually has scattered resources associated with it. METHODS: We design an evaluation approach for web search engines for rare disease diagnosis which includes 56 real life diagnostic cases, performance measures, information resources and guidelines for customising Google Search to this task. In addition, we introduce FindZebra, a specialized (vertical) rare disease search engine. FindZebra is powered by open source search technology and uses curated freely available online medical information. RESULTS: FindZebra outperforms Google Search in both default set-up and customised to the resources used by FindZebra. We extend FindZebra with specialized functionalities exploiting medical ontological information and UMLS medical concepts to demonstrate different ways of displaying the retrieved results to medical experts. CONCLUSIONS: Our results indicate that a specialized search engine can improve the diagnostic quality without compromising the ease of use of the currently widely popular standard web search. The proposed evaluation approach can be valuable for future development and benchmarking. The FindZebra search engine is available at http://www.findzebra.com/. PMID- 23462701 TI - Advance care planning education in pulmonary rehabilitation: A qualitative study exploring participant perspectives. AB - BACKGROUND: Advance care planning is considered to have an important role in the management of people with chronic lung disease; however, uptake in clinical practice remains limited. Participant acceptance of the inclusion of an advance care planning information session in pulmonary rehabilitation and maintenance programmes could support a practical solution. AIM: To evaluate the introduction of a structured group advance care planning information session from the perspective of participants in pulmonary rehabilitation and maintenance programmes. DESIGN: Prospective qualitative study with semi-structured interview transcripts analysed using iterative thematic analysis. SETTING/PARTICIPANTS: Participants in pulmonary rehabilitation and maintenance programmes at a tertiary metropolitan hospital and two affiliated community sites. RESULTS: Sixty-seven participants with a range of chronic lung diseases were interviewed with ages ranging from 39 to 88 years, forced expiratory volume in 1 s (FEV1) ranging from 18% to 130% predicted and 6-min walk distance ranging from 105 to 619 m. Sixteen participants (24%) had previously heard of advance care planning. Major themes were that participants valued the advance care planning information and thought pulmonary rehabilitation was an appropriate setting. The group education format was well accepted and perceived to have advantages over individual sessions. Participants were happy to receive the information from a non-medical facilitator. Non-attendees had usually missed the session for reasons unrelated to content. A small number of participants felt advance care planning was not appropriate for them, but all recognised its value for other participants. CONCLUSIONS: Participants in our pulmonary rehabilitation and maintenance programmes value the opportunity to participate in a structured, group-based advance care planning session. Consideration should be given to broader inclusion of advance care planning education into existing pulmonary rehabilitation and maintenance programmes for people with chronic respiratory disease. PMID- 23462702 TI - The use of non-invasive ventilation at end of life in patients with motor neurone disease: a qualitative exploration of family carer and health professional experiences. AB - BACKGROUND: Non-invasive ventilation improves quality and quantity of life in patients with motor neurone disease who have respiratory failure. Use of non invasive ventilation may, however, result in complex clinical issues for end-of life care, with concerns as to whether and how it should be withdrawn. AIM: This study aimed to describe carer and health professional experiences of end-of-life care of motor neurone disease patients using non-invasive ventilation. DESIGN/PARTICIPANTS: This article reports data from qualitative interviews with family carers and professionals following the death of patients with motor neurone disease who were using non-invasive ventilation in the final phase of the disease. RESULTS: Ten of the 20 patients initiated on non-invasive ventilation were using it in the end-of-life phase of their disease, with 5 using it for 24 h/day. Interviews were carried out with nine family carers and 15 professionals. Nine recurring themes were identified in the data. Both carers and health-care professionals perceived that the terminal phase of motor neurone disease was unexpectedly rapid and that this often led to unplanned interactions with the emergency services. Carers of patients who used non-invasive ventilation perceived non-invasive ventilation as aiding patient comfort and anxiety at the end of life. CONCLUSIONS: The use of non-invasive ventilation was described as beneficial and was not perceived by carers or most professionals to have adversely impacted patient's end-of-life experience. This study highlights variation in patient wishes regarding usage towards the end of life, uncertainty regarding appropriate management among professionals and the importance of disseminating end-of-life wishes. PMID- 23462703 TI - Adrenal insufficiency and adrenal replacement therapy. Current status in Spain. AB - Adrenal insufficiency (AI) is a rare endocrine disease, associated to increased mortality if left untreated. It can be due to a primary failure of the adrenal glands (primary AI) or malfunctioning of the hypothalamic-pituitary-adrenal axis (HPA) (secondary AI). The lack of data on incidence/prevalence of adrenal insufficiency in Spain complicates any evaluation of the magnitude of the problem in our country. Initial symptoms are non-specific, so often there is a delay in diagnosis. Current therapy with available glucocorticoids is associated with decreased quality of life in patients with treated AI, as well as with increased mortality and morbidity, probably related to both over-treatment and lack of hydrocortisone, associated with non-physiological peaks and troughs of the drug over the 24 hours. The availability of a new drug with a modified dual release (immediate and retarded), that requires one only daily dose, improves and simplifies the treatment, increases compliance as well as quality of life, morbidity and possibly mortality. This revision deals with the knowledge on the situation both globally and in Spain, prior to the availability of this new drug. PMID- 23462704 TI - Radiotherapy for benign brain tumours coming of age; example of vestibular schwannoma. PMID- 23462705 TI - Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. AB - BACKGROUND AND PURPOSE: Stereotactic ablative radiotherapy (SABR) has improved the survival for medically inoperable patients with peripheral early-stage non small cell lung cancer (NSCLC). We performed a systematic review of outcomes for central lung tumours. MATERIAL AND METHODS: The systematic review was performed following PRISMA guidelines. Survival outcomes were evaluated for central early stage NSCLC. Local control and toxicity outcomes were evaluated for any centrally located lung tumour. RESULTS: Twenty publications met the inclusion criteria, reporting outcomes for 563 central lung tumours, including 315 patients with early-stage NSCLC. There was heterogeneity in the planning, prescribing and delivery of SABR and the common toxicity criteria used to define toxicities (versions 2.0-4.0). Tumour location (central versus peripheral) did not impact overall survival. Local control rates were >= 85% when the prescribed biologically equivalent tumour dose was >= 100 Gy. Treatment-related mortality was 2.7% overall, and 1.0% when the biologically equivalent normal tissue dose was <= 210 Gy. Grade 3 or 4 toxicities may be more common following SABR for central tumours, but occurred in less than 9% of patients. CONCLUSIONS: Post-SABR survival for early-stage NSCLC is not affected by tumour location. SABR achieves high local control with limited toxicity when appropriate fractionation schedules are used for central tumours. PMID- 23462706 TI - Dosimetric impact of interobserver variability in MRI-based delineation for cervical cancer brachytherapy. AB - PURPOSE AND BACKGROUND: To study the dosimetric impact of interobserver delineation variability (IODV) in MRI-based cervical cancer brachytherapy. MATERIALS AND METHODS: MR images of six patients were distributed to 10 experienced observers worldwide. They were asked to delineate the target volumes and the organs at risk (OARs) for each patient. Two types of reference contours were created (Expert Consensus - EC and Simultaneous Truth and Performance Level Estimation - STAPLE). Optimised plans based on both EC- and STAPLE-contours were prepared. These plans were transferred to each of the observer contour sets and the resulting DVH parameters (D(90) and D(2cc)) were calculated. For each patient the standard deviation (SD) for the 10 observers was calculated. RESULTS: A mean relative SD of 8-10% was found for GTV and High Risk CTV (HR-CTV) D(90) analysing one single fraction. For rectum and bladder the mean relative SD for D(2cc) was 5 8% while sigmoid was at 11%. For the whole treatment the IODV in HR-CTV caused an uncertainty of +/-5 Gy(alpha/beta=10) (1SD). The corresponding figure for OARs was +/-2-3 Gy(alpha/beta=3). The results were not sensitive as to which structure set was used for the optimisation. CONCLUSIONS: For the target volumes the dosimetric impact of IODV was smallest for the GTV and HR-CTV, while IODV had an even smaller impact on the bladder and rectum. PMID- 23462707 TI - Critical structure movement in cervix brachytherapy. AB - BACKGROUND AND PURPOSE: To investigate critical structure movement and subsequent dose received during conformal MR-guided cervix brachytherapy. MATERIALS AND METHODS: 21 patients (36 HDR fractions) undergoing brachytherapy for cervical cancer underwent a second MR immediately prior to treatment (pre-treatment MR). Bowel (including sigmoid), bladder and rectum were outlined on both planning and pre-treatment MR scans and dosimetry compared. RESULTS: No statistically significant differences were found between the volumes of the OAR doses across the two scans but there were large variations between patients with differences of up to 3.3 Gy observed. The percentage of fractions for which D2cc was within 10% of that planned was 61.1%, 41.7% and 47.2% for bladder, rectum and bowel, respectively. The average time between MR scans was found to be 4.75 h (SD+/-1.2; range 3.2-9.9 h), with no correlation found with critical structure movement within this range. CONCLUSIONS: OAR movement is difficult to predict though significant changes occur in individual patients. In 61% of cases in our sample the D2cc dose changed by at least 10% for at least one OAR from that planned. Pre treatment imaging with subsequent adjustment of dosimetry will minimise the impact of organ movement on delivered dose. PMID- 23462709 TI - Coronary artery calcification and ECG pattern of left ventricular hypertrophy or strain identify different healthy individuals at risk. AB - PURPOSE: To improve risk stratification for development of ischaemic heart disease, several markers have been proposed. Both the presence of coronary artery calcification (CAC) and ECG pattern of left ventricular hypertrophy/strain have been shown to provide independent prognostic information. In this study, we investigated the association between established risk factors, ECG measurements and the presence of coronary artery calcification. METHOD: A random sample of healthy men and women aged 50 or 60 years were invited to the screening study. Established risk factors were measured. A noncontrast computed tomographic (CT) scan was performed to assess the CAC score. ECG analysis included left ventricular hypertrophy (LVH) using the Sokolow-Lyon criteria and the Cornell voltage * QRS duration product, and strain pattern based on ST segment depression and T-wave abnormalities. The association between the presence of CAC, clinical variables and ECG findings was evaluated by means of multivariate logistic regression. RESULTS: Of 1825 invited individuals, 1226 accepted the screening. The prevalence of hypertension was 50%. Hypertensive patients frequently had LVH and/or strain when compared with nonhypertensive individuals (21 vs. 14%, P < 0.0001) as well as CAC (52 vs. 38%, P < 0.0001). In multiple logistic regressions analyses, there was no association between the ECG abnormalities and the presence of CAC. CONCLUSION: There appears to be no relationship between CAC and ECG suspected LVH and/or strain. We propose that these markers identify different individuals at risk and together may have additive prognostic value. PMID- 23462710 TI - Synthesis and characterization of ultrathin metal coordination Prussian blue nanoribbons. AB - Ultrathin metal coordination Prussian blue (PB) nanoribbons with tunable width have been successfully synthesized. The morphology and microstructure of PB nanoribbons are characterized using UV-vis, FT-IR, AFM, TEM and XRD. PB nanoribbons synthesized possess an ultrathin thickness of approximately 1 nm and narrow width. The width of PB ribbons can be tuned by varying the chain length of polymeric precursors. The PB hybrid nanoribbons synthesized exhibit enhanced thermal stability and electrochemical activity. The merit of narrow and tunable width as well as ultrathin thickness of PB hybrid nanoribbons along with enhanced thermal stability and electrochemical activity makes them potentially useful in nano-devices, biosensors and so on. PMID- 23462708 TI - Th17 lymphocytes in respiratory syncytial virus infection. AB - Infection by respiratory syncytial virus (RSV) affects approximately 33 million infants annually worldwide and is a major cause of hospitalizations. Helper T lymphocytes (Th) play a central role in the immune response during such infections. However, Th lymphocytes that produce interleukin 17 (IL-17), known as Th17 lymphocytes, in addition to been protective can also cause pathology that accompany this type of infection. The protective effects of Th17 is associated with better prognosis in most infected individuals but heightened Th17 responses causes inflammation and pathology in others. Studies employing animal models haves shown that activated Th17 lymphocytes recruit neutrophils and facilitate tertiary lymphoid structure development in infected lungs. However, IL-17 also inhibits the ability of CD8+ lymphocytes to clear viral particles and acts synergistically with the innate immune system to exacerbate inflammation. Furthermore, IL-17 enhances IL-13 production which, in turn, promotes the activation of Th2 lymphocytes and excessive mucus production. Studies of these animal models have also shown that a lack of, or inadequate, responses by the Th1 subset of T lymphocytes enhances Th17-mediated responses and that this is detrimental during RSV co-infection in experimental asthma. The available evidence, therefore, indicates that Th17 can play contradictory roles during RSV infections. The factors that determine the shift in the balance between beneficial and adverse Th17 mediated effects during RSV infection remains to be determined. PMID- 23462711 TI - Synthesis of novel isoflavene-propranolol hybrids as anti-tumor agents. AB - Isoflavene-propranolol hybrid molecules were developed as potentially novel anti tumour agents. Isoflavene itself has potent anti-cancer activity while propranolol can enhance anti-proliferative and anti-angiogenic properties of 5 fluorouracil and paclitaxel. The hybrids were produced via nucleophilic addition of substituted amine groups to a dioxiran intermediate, which was in turn generated from the Williamson-type reaction of isoflavene with (+/-) epichlorohydrin. These analogues were tested in anti-cancer cell viability assays against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines, and were found to exhibit potent anti-proliferative activities. These compounds also displayed anti-angiogenic and anti-proliferative effects in HMEC-1 human microvascular endothelial cell lines. Notably, the most potent hybrid molecules synthesized in this work showed enhanced potency against cancer cell lines compared to either isoflavene or propranolol alone, while retaining significant selectivity for cancer cells over MRC-5 normal lung fibroblast cells. PMID- 23462712 TI - Cytotoxic effect of (1-methyl-1H-imidazol-2-yl)-methanamine and its derivatives in Pt(II) complexes on human carcinoma cell lines: a comparative study with cisplatin. AB - The synthesis and pharmacological characterisation of (1-methyl-1H-imidazol-2-yl) methanamine and its derivatives in Pt(II) complexes are described. Six out of eleven new Pt(II) complexes showed a significant cytotoxic effect on NCI-H460 lung cancer cell line with EC50 values between 1.1 and 0.115 mM, determined by MTT assay. Compound Pt-4a showed a particularly more potent cytotoxic effect than the previously described Pt(II) complex with 2,2'-bipyridine, [Pt(bpy)Cl2], with an EC50 value equal to 172.7 MUM versus 726.5 MUM respectively, and similar potency of cisplatin (EC50=78.3 MUM) in NCI-H460 cell line. The determination of the intracellular and DNA-bound concentrations of (195)Pt, as marker of the presence of the complexes, showed that the cytotoxic compound Pt-4a readily diffused into the cells to a similar extent of cisplatin and directly interacted with the nuclear DNA. Pt-4a induced both p53 and p21(Waf) expression in NCI-H460 cells similar to cisplatin. A direct comparison of the cytotoxic effect between compound Pt-4a and cisplatin on 12 different cancer cell lines demonstrated that compound Pt-4a was in general less potent than cisplatin, but it had a comparable cytotoxic effect on non-small-cell lung cancer NCI-H460 cells, and the colorectal cancer cells HCT-15 and HCT-116. Altogether, these results suggested that the Pt(II) complex with 1-methyl-1H-imidazol-2-yl)-methanamine (compound Pt-4a), displayed a significant cytotoxic activity in cancer cells. Similarly to cisplatin this compound interacts with nuclear DNA and induces both p53 and p21(waf), and thus it represents an interesting starting point for future optimisation of new Pt(II) complexes forming DNA adducts. PMID- 23462713 TI - Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi. AB - A scaffold hopping exercise undertaken to expand the structural diversity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days. PMID- 23462714 TI - Improvement of sigma1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones. AB - The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective alpha-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2'-bipyridyl/Ag2CO3, whereas the beta-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both alpha-positions providing 4'-mono-, 6'-mono- and 4',6'-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1'-position of 13, 3'-position of 14, 4'-position of 18) showed increased sigma1 affinity compared to the non arylated parent compounds. A phenyl moiety at the 'left' position (2'-position in 20a) also increased the sigma1 affinity but to a lower extent. A considerable reduction of sigma1 affinity was observed after introducing an aryl moiety in 6' position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the sigma1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products. PMID- 23462715 TI - Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: selectivity switching by C/Si exchange. AB - We previously reported that bis-phenol derivatives, including LG190178 (3a), possess not only vitamin D receptor (VDR) agonistic activity, but also androgen receptor (AR) antagonistic activity. Here, we describe the design, synthesis and evaluation of silicon-containing bis-phenol derivatives, with the objective of obtaining increased selectivity toward VDR or AR. We found that replacement of the quaternary carbon in the bis-phenol skeleton with silicon increased AR antagonistic activity and reduced VDR-agonistic activity, that is, the AR selectivity of the silicon-containing compounds was higher than that of corresponding carbon compounds. To our knowledge, this is the first report of nuclear receptor (NR) selectivity switching by sila-substitution (C/Si exchange). Among the compounds synthesized, AR-selective ligand (S,R)-3b exhibited more potent anti-androgenic activity (IC50=0.072 MUM) than hydroxyflutamide, a well known androgen antagonist (IC50=1.4 MUM), in SC-3 cell proliferation assay. These results suggest that sila-substitution is a useful approach for structural development of selective AR ligands. PMID- 23462716 TI - Synthesis and in vitro evaluation of new derivatives of 2-substituted-6 fluorobenzo[d]thiazoles as cholinesterase inhibitors. AB - A series of novel cholinesterase inhibitors based on 2-substituted 6 fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound. PMID- 23462717 TI - Comparison of various sampling schemes and accumulation profiles in covariance spectroscopy with exponentially decaying 2D signals. AB - Two-dimensional covariance (COV2D) spectroscopy offers an alternative approach to 2D Fourier transformation (FT2D) to obtain homo-nuclear correlation NMR spectra. Considerable saving in experimental time, without loss of resolution, can be achieved by incorporating COV2D with: (i) uniform sampling with a t1 cut-off (CUO) or non-uniform sampling (NUS), and (ii) constant or Gaussian accumulation profiles. We find that covariance treatment, combined with the CUO sampling and Gaussian accumulation profile provides better gain in experimental time, with respect to that required with FT2D NMR. This is in contrast with the maximum entropy (MaxEnt) reconstruction for 2D spectra, which works better with the NUS scheme rather than with the CUO scheme. We further discuss the experimental conditions that define this optimum acquisition, and explain how these parameters can easily be optimized 'on the fly' according to the desired resolution, which is quite sample-dependent. PMID- 23462718 TI - Mid Staffs inquiry. IHI Open School's quality improvement initiative. PMID- 23462719 TI - Biology of primary breast cancer in older women treated by surgery: with correlation with long-term clinical outcome and comparison with their younger counterparts. AB - BACKGROUND: As age advances breast cancer appears to change its biological characteristics, however, very limited data are available to define the precise differences between older and younger patients. METHODS: Over 36 years (1973 2009), 1758 older (>=70 years) women with early operable primary breast cancer were managed in a dedicated clinic. In all, 813 underwent primary surgery and 575 good quality tumour samples were available for biological analysis. The pattern of biomarkers was analysed using indirect immunohistochemistry on tissue microarrays. Comparison was made with a previously characterised series of younger (<70 years) patients. RESULTS: There was high expression of oestrogen receptor (ER), PgR, Bcl2, Muc1, BRCA1 and 2, E-cadherin, luminal cytokeratins, HER3, HER4, MDM2 and 4 and low expression of human epidermal growth factor receptor (HER)-2, Ki67, p53, EGFR and CK17. Oestrogen receptor and axillary stage appeared as independent prognostic factors. Unsupervised partitional clustering showed six biological clusters in older patients, five of which were common in the younger patients, whereas the low ER luminal cluster was distinct in the older series. The luminal phenotype showed better breast cancer-specific survival, whereas basal and HER2-overexpressing tumours were associated with poor outcome. CONCLUSION: Early operable primary breast cancer in older women appears as a distinct biological entity, with existence of a novel cluster. Overall older women showed less aggressive tumour biology and ER appeared as an independent prognostic factor alongside the time-dependent axillary stage. These biological characteristics may explain the differences in clinical outcome and should be considered in making therapeutic decisions. PMID- 23462720 TI - BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. AB - BACKGROUND: Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane. METHODS: The GOG 172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with ?10% staining were defined as aberrant and >10% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P=0.014) but not PFS (P=0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P=0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P=0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.47-0.97, P=0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival. CONCLUSION: Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel. PMID- 23462721 TI - Utility of risk-weighted surgical-pathological factors in early-stage cervical cancer. AB - BACKGROUND: Surgical-pathological risk factors were evaluated by weighting the magnitude of significance of multiple risk factors correlating to survival and treatment response in cervical cancer. METHODS: Multivariate analysis was performed for survival outcomes entering seven pathological factors obtained from 540 radical hysterectomy specimens in stage IA2-IIB cervical cancer cases. Hazard ratio (HR) in each risk factor was determined, and the sum of HR scores for the corresponding risk factors was determined per case. Survival curves and postoperative treatment response (concurrent chemoradiotherapy (CCRT) vs radiotherapy alone) were evaluated based on the extent of HR-weighted scores. RESULTS: Hazard ratios for risk factors relating to disease-free survival (DFS) was: lympho-vascular space invasion 3.95, nodal metastasis 3.88, adenocarcinoma 3.40, large tumour 2.36, positive margin 1.99, deep stromal invasion 1.29, and parametria invasion 1.21. The HR-weighted scoring method showed a high predictive value for recurrence (area-under-curve 0.836, P<0.001). Hazard ratio-weighted scores were negatively correlated to DFS, and the cases with score ?12.5 showed 5 year DFS rate of 23.8%. Tumours with larger score offset the benefits of CCRT over radiotherapy alone for postoperative adjuvant treatment (P<0.001). CONCLUSION: Surgical-pathological risk factors provide valuable information for survival and management of early-stage cervical cancer when number and significance of risks are weighted. PMID- 23462722 TI - Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients. AB - BACKGROUND: Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib. METHODS: Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation. RESULTS: Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m(-2). Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m( 2) experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3-13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009). CONCLUSION: Patients with sarcopenia and a BMI<25 kg m(-2) experienced significantly more DLTs during the first cycle of treatment. PMID- 23462723 TI - ING1b-inducible microRNA203 inhibits cell proliferation. AB - BACKGROUND: The ING family of type II tumour suppressors serve as both epigenetic 'readers' and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) 'writers' of the epigenetic histone code. The ING1 protein has also been implicated in regulating microRNA (miRNA) levels. In this study, we identify a link between ING1b and the miRNA epigenetic network. METHODS: Primary fibroblasts infected with adenoviruses expressing GFP control or GFP plus ING1b were examined for alterations in miRNA profiles using a miRNA PCR array. Additional experiments confirmed specificity and consequences of altered miRNA expression. RESULTS: MicroRNAs miR-203, miR-375, miR-449b and miR-200c were increased by ING1b overexpression. Ectopic expression of miR-203 inhibited U2OS and MDA-MB-231 cancer cell growth, and induced G1 cell cycle arrest in U2OS cells as estimated by flow cytometry. Transfection with miR-203 inhibitor reversed the proliferation inhibition induced by ING1b in U2OS cells. CHIP assays showed that ING1b bound to the promoter of miR-203. Western blot analyses showed that CDK6, c-Abl and Src were downregulated by the transfection of miR-203. CONCLUSION: These results indicate that ING1b epigenetically regulates several miRNAs including miR-203. The several-fold increase in miR-203 by ING1b might inhibit cancer cell proliferation through coordinate downregulation of CDK6, c-Abl and Src. PMID- 23462724 TI - A randomised double-blind placebo-controlled phase II study of AGI004 for control of chemotherapy-induced diarrhoea. AB - BACKGROUND: AGI004 is a controlled-release transdermal patch preparation of mecamylamine. We conducted a randomised placebo-controlled phase II study of two dose levels of AGI004 in chemotherapy-induced diarrhoea (CID). METHODS: Adult patients receiving chemotherapy who had experienced diarrhoea (NCI grade 1-2) during previous cycles of chemotherapy were eligible. In all, 64 patients were randomised to receive AGI004 4 mg then 8 mg per 24 h transdermal patch or placebo for two sequential cycles of chemotherapy. Patients' severity of diarrhoea was physician-assessed using NCI grade of diarrhoea and patient-assessed using information recorded in daily diaries of bowel movements. RESULTS: Overall AGI004 doubled the odds of a response to treatment on the first day of chemotherapy based on physician assessment of NCI grade of diarrhoea compared with placebo (odds ratio=2.0, 90% confidence interval: 0.9-4.5) and there was a trend to improved response rates for AGI004 for the full treatment cycle although these results were not statistically significant. There was also evidence of significantly improved response rates based on patient assessment of diarrhoea both overall (P=0.05) and at the 8-mg dose level (P=0.02) compared with placebo. CONCLUSION: AGI004 demonstrated effectiveness in reducing chemotherapy-associated diarrhoea, with results suggesting response across multiple measurements of diarrhoea. Treatment was well tolerated with no drug-related adverse events. Further evaluation of this agent in the management of CID is warranted. PMID- 23462726 TI - Application of a probabilistic modelling approach for evaluation of nitrogen, phosphorus and organic carbon removal efficiency during four successive cycles of aquifer storage and recovery (ASR) in an anoxic carbonate aquifer. AB - Aquifer storage is increasingly being recognised in its role as a treatment process barrier within a multiple barrier approach to water reuse. Aquifers are postulated to have the ability to provide sustainable treatment for removal of nitrogen, phosphorus and organic carbon, the dominant nutrient hazards in water recycling, but, to date this treatment performance has remained difficult to validate in field studies. This study applied a statistical method, proposed for validation of the performance of advanced water treatment processes, to evaluate nutrient removal during aquifer storage and recovery (ASR) with recycled water. Analysis of observed water quality changes during four successive ASR cycles with highly variable source water quality was used to describe the removal efficiencies for selected nutrients by an anoxic carbonate aquifer. The use of this method was found to be suitable to calculate removal efficiencies for total organic carbon (TOC) and total nitrogen (TN) over four ASR cycles with temporally variable concentrations of nutrients in the tertiary treated wastewater injectant. TOC and TN removal was dominated by redox processes, aerobic respiration and denitrification. Median removal of TOC ranged from 25 to 40% and TN from 46 to 87% over the four cycles. There was no observable reduction in this removal with time, suggesting that removal of TOC and TN by redox processes can be sustained in an ASR system. Contrastingly, total phosphorous (TP) was subject to reversible removal via adsorption and desorption processes and as a result, removal efficiency could not be calculated with this method. Thus in general, results indicated that this statistical method could be used to characterise the capacity of the anoxic carbonate aquifer treatment barrier for removal of carbon and nitrogen, but not for removal of phosphorus. PMID- 23462725 TI - Short-term psychological impact of the BRCA1/2 test result in women with breast cancer according to their perceived probability of genetic predisposition to cancer. AB - BACKGROUND: The effect of BRCA1/2 gene test result on anxiety, depression, cancer related thought intrusion or avoidance and perceived control over cancer risk was assessed in breast cancer (BC) patients, according to their perceived probability of genetic predisposition to cancer. METHODS: Two hundred and forty-three (89% response rate) women with BC completed questionnaires after an initial genetic counselling visit (T1), of which 180 (66%) completed questionnaires again after receiving the BRCA1/2 results (T2). The discrepancy between women's perceived probability of cancer genetic predisposition at T1 and the geneticist's computed estimates was assessed. RESULTS: In all, 74% of women received a negative uninformative (NU), 11% a positive BRCA1/2 and 15% an unclassified variant (UV) result. On hierarchical regression analysis, in women with a positive BRCA1/2 result (vs NU or UV), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted lower levels of anxiety at T2 (beta=-0.28; P<0.01), whereas in women receiving a UV result (vs NU or positive BRCA1/2), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted higher levels of anxiety (beta=0.20; P<0.01), depression (beta=0.19; P<0.05) and intrusion (beta=0.18; P<0.05) at T2. CONCLUSION: The type of BRCA1/2 test result differently affects distress according to women's perceived probability of genetic predisposition before testing. PMID- 23462727 TI - Autofluorescence generation and elimination: a lesson from glutaraldehyde. AB - Glutaraldehyde causes especially high autofluorescence. It reacted with proteins and peptides to generate visible to near-IR emitters. A model indicated that ethylenediamine and a secondary amine in the molecule were key components for the formation of emissive species. The mechanism enables us to control the generation and elimination of autofluorescence. PMID- 23462728 TI - Insomnia and the risk of incident heart failure: a population study. AB - AIMS: Insomnia is highly prevalent among heart failure patients, but only a few small studies have investigated insomnia symptoms and risk of heart failure. We aimed to assess the prospective association between self-reported insomnia symptoms and the risk of incident heart failure in a large Norwegian cohort. METHODS AND RESULTS: Baseline data on insomnia symptoms, including difficulty initiating sleep, difficulty maintaining sleep and having non-restorative sleep, socio-demographic variables, and health status, including established cardiovascular risk factors, were collected from 54 279 men and women 20-89 years of age who participated in the Nord-Trondelag Health study (HUNT) between 1995 and 1997 and were free from known heart failure at baseline. The cohort was followed for incident heart failure from baseline through 2008. We used Cox proportional hazard models to assess the association of baseline insomnia symptoms with the risk of heart failure. A total of 1412 cases of heart failure occurred during a mean follow-up of 11.3 years (SD = 2.9 years), either identified at hospitals or by the National Cause of Death Registry. There was a dose-dependent association between the number of insomnia symptoms and risk of heart failure. The multi-adjusted hazard ratios were 0.96 (0.57-1.61), 1.35 (0.72 2.50), and 4.53 (1.99-10.31) for people with one, two, and three insomnia symptoms, compared with people with none of the symptoms (P for trend 0.021). CONCLUSIONS: Insomnia is associated with an increased risk of incident heart failure. If our results are confirmed by others and causation is proved, evaluation of insomnia symptoms might have consequences for cardiovascular prevention. PMID- 23462729 TI - Value of computed tomography in determining the nature of papillary thyroid microcarcinomas: evaluation of the computed tomographic characteristics. AB - OBJECTIVE: This study was designed to assess the value of computed tomography (CT) in determining the nature of papillary thyroid microcarcinomas (PTMCs). METHODS: Four hundred fifty-two thyroid CT scan cases with pathological data at our department that were performed from January 2011 to January 2012 were analyzed, of which a total of 87 tumors in 73 cases were confirmed as 0.5-1.0 cm diameter PTMC; the CT images of PTMC were analyzed, suitable window width (W) and window level (L) of PTMC were determined, as well as observation of the density and shape of tumors, tumor boundaries before and after contrast enhancement, thyroid edge interruption, calcification, lymph node metastasis, and complications. RESULTS: Plain scan W 140-180, L 80-120 and contrast-enhanced scan W 160-200, L 110-150 were conducive to the display of PTMC. Among 87 tumors in this group, aside from 10 tumors and intratumoral calcification that were not shown up, plain CT scans of 77 (88.5%) tumors showed homogeneous low density; 59(67.8%) tumors were irregular shaped; 64 (73.6%) tumors showed plain thyroid scan edge interruption; after contrast enhancement, 65 (74.7%) tumor contours were relatively obscure compared with plain scan, and relative low-density range of the tumors narrowed down; 16 (18.4%) tumors were calcified, of which 15 (93.8%) were fine granular calcifications; lymph node metastasis were found pathologically in 18 (24.7%) cases, of which 8 (44.4%, 8/18) cases were CT findings. Among the 10 (11.4%) tumors that did not show up on CT, 7 were complicated with Hashimoto's thyroiditis, 2 were masked by clavicle artifacts, and 1 was masked by nodular goiter. CONCLUSION: Plain scan W 140-180, L 80-120 and contrast-enhanced scan W 160-200, L 110-150 were conducive to the display of PTMC. The tumor-shaped irregularity, smaller relative low-density area after contrast enhancement than plain scan, thyroid edge interruption, fine granular calcification, and neck lymph node abnormalities contributed to the diagnosis of PTMC; Hashimoto's thyroiditis, clavicle artifacts, and nodular goiter could mask the tumor, which required adequate attention. PMID- 23462730 TI - FDG PET/CT findings of a ruptured pulmonary hydatid cyst with histopathological correlation. AB - We present a case of ruptured pulmonary hydatid cyst in a patient with hemoptysis and suspected pulmonary malignancy, for which the (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) findings of absent metabolic activity within the cyst and hypermetabolism within a pericystic region of parenchymal consolidation were clues to the diagnosis. Our report is the first to correlate PET/CT findings in a ruptured cyst with histopathology. Moreover, this case demonstrates that even in nonendemic regions, ruptured pulmonary hydatid cyst should be considered in the differential for pulmonary malignancy. The ability of PET/CT to distinguish cyst rupture has implications for surgical management. PMID- 23462731 TI - Branchial fistula arising from pyriform sinus: positive esophagogram despite active infection. PMID- 23462732 TI - Sonographic findings of ectopic prostatic tissue in the bladder: a case report and review of the literature. AB - Ectopic prostatic tissue in the bladder has rarely been reported, and there is currently no report about the sonographic findings of this entity. In this study, we present the imaging findings of ectopic prostatic tissue in the bladder on transrectal ultrasonography. PMID- 23462733 TI - Advanced gastrointestinal endoscopic procedures: indications, imaging findings, and implications for the radiologist. AB - There are a variety of advanced gastrointestinal endoscopic procedures, many of which are guided by endosonography, which are performed by interventional gastroenterologists or minimally-invasive surgeons. The purpose of this pictorial review is to briefly describe several advanced gastrointestinal endoscopically guided procedures, to review the implications for radiologists interpreting the associated imaging examinations, and to demonstrate the expected preprocedural imaging findings, as well as the expected and the unexpected postprocedural findings, in patients undergoing these procedures. PMID- 23462734 TI - Regional ADC measurements during normal brain aging in the clinical range of b values: a DWI study. AB - The aim of our work was to evaluate the apparent diffusion coefficient (ADC) values of normal brain over a wide age range and in different cerebral structures, including the white and grey matter. A population of 89 subjects (39 male, 50 female, age range: 3-69 years) was divided into age groups designated as 1-7 as follows: 3-9; 10-19; 20-29; 30-39; 40-49; 50-59; 60-69 years old. All subjects underwent a head MRI using a 1,5 T GE system with diffusion-weighted imaging using spin echo echo planar imaging (EPI) for b=0, 500, 1000, and 1200 s/mm(2). The ADC values of the following 10 regions of interest were analysed: head of the caudate nucleus (L=left and R=right side), thalamus (L and R side), centrum semiovale (L and R side), pons, respectively, as well as in cerebellum (L and R side) and vermis of the cerebellum. The ADC values of the studied brain structures showed a polynomial dependence on age indicating a logarithmic decline in children, some stabilisation during adulthood and a small trend of increasing diffusivity for subjects over the age of 50 years old. Significant interhemispheric differences in the ADC values were mainly found for thalamus, especially in older age groups. Moreover, the best differentiation of the examined structures was found in the mature brain. The knowledge of age-dependent diffusion changes in the human brain can be helpful in the proper interpretation of diffusion-weighted images in clinical practice. PMID- 23462740 TI - Single electrospun porous NiO-ZnO hybrid nanofibers as anode materials for advanced lithium-ion batteries. AB - Porous NiO-ZnO hybrid nanofibers were prepared by a single-nozzle electrospinning technique combined with subsequent heating treatment. The resultant nanofibers are composed of interconnected primary nanocrystals and numerous nanopores with heterostructures between NiO and ZnO. Such characteristics of the structure can lead to excellent electrochemical performances when the nanofiber was evaluated as an anode material for lithium-ion batteries. The porous NiO-ZnO nanofiber electrode delivers a high discharge capacity of 949 mA h g(-1) after 120 cycles at 0.2 A g(-1), and maintains around 707 mA h g(-1) at a current density as high as 3.2 A g(-1). Even after cycling at high rates, the electrode still retains a high discharge capacity of up to 1185 mA h g(-1) at 0.2 A g(-1). PMID- 23462735 TI - Nicotine-induced cessation of embryonic development is reversed by gamma tocotrienol in mice. AB - BACKGROUND: This study aimed to evaluate the adverse effects of various doses of nicotine and protective effects of different concentrations of gamma-tocotrienol (gamma-TCT) on in vitro embryonic development and lipid peroxidation in mice. MATERIAL AND METHODS: A) Effects of various doses of nicotine on in vitro embryonic development: Female mice were treated with 1.0, 3.0, or 5.0 mg/kg/day nicotine for 7 consecutive days. Animals were superovulated, cohabited overnight, and sacrificed. Embryos were cultured in vitro. Plasma was assayed. B) Effects of concomitant treatment of nicotine concurrently with various doses of gamma-TCT on in vitro embryonic development: Female mice were treated with nicotine (5.0 mg/kg/day), gavaged gamma-TCT of 30, 60, or 90 mg/kg/day or nicotine concurrently with gamma-TCT of 3 different doses for 7 consecutive days. Animals were superovulated, cohabited overnight, and sacrificed. Embryos were cultured and plasma was assayed. RESULTS: A) Effects of various doses of nicotine on in vitro embryonic development: Number of hatched blastocysts decreased in 1.0 and 3.0 mg/kg/day nicotine groups. Nicotine at 5.0 mg/kg/day stopped embryo development at morula. MDA concentrations increased following all nicotine doses. B) Effects of concomitant treatment of nicotine concurrently with various doses of gamma-TCT on in vitro embryonic development: Embryo development was completed in all groups. MDA concentration increased only in the group treated with nicotine concurrently with 30 mg/kg/day gamma-TCT. CONCLUSIONS: Nicotine impairs in vitro embryo development and increases MDA in plasma. The deleterious impact of nicotine on embryo development is reversed by supplementing gamma-TCT concurrently with nicotine. PMID- 23462741 TI - Perioperative and long-term outcomes after pancreaticoduodenectomy in elderly patients 80 years of age and older. AB - PURPOSE: Although a pancreaticoduodenectomy (PD) has been recently regarded as a safe surgical procedure at high-volume centers, the efficacy of PD for patients 80 years of age and older is controversial. The aim of this study was to evaluate the perioperative and long-term outcomes following PD in patients 80 years of age and older. METHODS: Elderly patients 80 years of age and older who underwent PD between 2001 and 2009 were identified. The perioperative and long-term outcomes were compared with patients younger than 80 years of age. RESULTS: Of 561 total patients, 22 patients (3.9 %) were 80 years of age or older. Mortality occurred in one patient (4.5 %). Postoperative major complications (Clavien-Dindo classification >= grade III) occurred in six patients (27.3 %) in this group, which was significantly higher than in patients younger than 80 years of age (P = 0.008). The survival of the elderly patients undergoing PD for pancreatic cancer was significantly shorter than that for the same patient group with other diseases (median survival, 13 versus 82 months; P = 0.014). Only one elderly patient with pancreatic cancer survived more than 3 years. CONCLUSIONS: PD for pancreatic cancer in patients aged 80 and older should be carefully selected, because it is associated with a higher incidence of severe postoperative complications and a small change of long-term survival. PMID- 23462743 TI - Synthesis of ligands containing N-oxide donor atoms and their assembly into metallosupramolecular structures. AB - A series of ligands that contain both N-donor and N-oxide donor atoms have been synthesised and ligands L5, L6, L7 and L8 contain, 4, 6, 5, and 6 donor atoms respectively. The smallest ligand L5 forms a mononuclear complex with Cu2+ ([Cu(L5)(ClO4)2(MeCN)]) whereas L6 and L7 form dinuclear double helicates with Ni2+ and Cu2+ respectively ([Ni2(L6)2]4+ and [Cu2(L7)2]4+). L8 forms a tetranuclear cyclic helicate upon reaction with Co2+ ([Co4(L8)4]8+) and in all cases the complexes are characterised by single-crystal X-ray diffraction and ESI MS. The N-oxide units imparts flexibility in the ligand strand and where the unoxidised ligand strand forms a cyclic helicate, the incorporation of an N-oxide unit allows the formation of the dinuclear double helicate. PMID- 23462742 TI - Structural basis for the interaction of unstructured neuron specific substrates neuromodulin and neurogranin with Calmodulin. AB - Neuromodulin (Nm) and neurogranin (Ng) are neuron-specific substrates of protein kinase C (PKC). Their interactions with Calmodulin (CaM) are crucial for learning and memory formation in neurons. Here, we report the structure of IQ peptides (24aa) of Nm/Ng complexed with CaM and their functional studies with full-length proteins. Nm/Ng and their respective IQ peptides are intrinsically unstructured; however, upon binding with CaM, IQ motifs adopt a helical conformation. Ser41 (Ser36) of Nm (Ng) is located in a negatively charged pocket in the apo CaM and, when phosphorylated, it will repel Nm/Ng from CaM. These observations explain the mechanism by which PKC-induced Ser phosphorylation blocks the association of Nm/Ng with CaM and interrupts several learning- and memory-associated functions. Moreover, the present study identified Arg as a key CaM interacting residue from Nm/Ng. This residue is crucial for CaM-mediated function, as evidenced by the inability of the Ng mutant (Arg-to-Ala) to potentiate synaptic transmission in CA1 hippocampal neurons. PMID- 23462744 TI - Microstructure of parapapillary atrophy: beta zone and gamma zone. AB - PURPOSE: To examine the morphologic features of parapapillary atrophy by using enhanced depth imaging optical coherence tomography (EDI-OCT) and color fundus photographs. METHODS: The clinical observational comparative study included 80 normal eyes of 46 subjects and 80 eyes of 46 patients with primary open-angle glaucoma. Both groups did not vary significantly in axial length (P = 0.62) and refractive error (P = 0.30). Color fundus photographs and cross-sectional B-scan images obtained by EDI-OCT were examined. On the EDI-OCT images, we measured a gamma zone defined as the region between the temporal disc margin to the beginning of Bruch's membrane, and a beta zone defined as Bruch's membrane without retinal pigment epithelium. RESULTS: The gamma zone (mean area: 1.13 +/- 2.04 mm(2)) was significantly associated with longer axial length (P < 0.001; standardized coefficient beta: 0.48), longer vertical disc diameter (P < 0.001; beta: 0.43), older age (P = 0.008; beta: 0.22), and the absence of glaucoma (P = 0.03; beta: -0.19). The beta zone (mean area: 0.85 +/- 0.60 mm(2)) was associated with longer axial length (P < 0.001; beta: 0.39) and the presence of glaucoma (P < 0.001; beta: 0.48). CONCLUSIONS: In addition to associations with older age, increasing myopia, and larger disc size, the EDI-OCT-defined gamma zone of parapapillary atrophy was associated with the absence of glaucoma, whereas the EDI-OCT-defined beta zone was associated with the presence of glaucoma. Differentiation between the beta zone and the gamma zone may be clinically useful. PMID- 23462745 TI - Ocular rigidity, ocular pulse amplitude, and pulsatile ocular blood flow: the effect of axial length. AB - PURPOSE: Previous studies have shown a negative correlation between axial length (AL) and pulsatile ocular blood flow (POBF). This relation has been questioned because of the possible confounding effect of ocular volume on ocular rigidity (OR). The purpose of this study was to investigate the relation between AL, as a surrogate parameter for ocular volume, and OR, ocular pulse amplitude (OPA), and POBF. METHODS: Eighty-eight cataract patients were enrolled in this study. A computer-controlled device comprising a microdosimetric pump and a pressure sensor was used intraoperatively. The system was connected to the anterior chamber and used to raise the intraocular pressure (IOP) from 15 to 40 mm Hg, by infusing the eye with a saline solution. After each infusion step, the IOP was continuously recorded for 2 seconds. Blood pressure and pulse rate were measured during the procedure. The OR coefficient was calculated from the pressure volume data. OPA and POBF were measured from pressure recordings. RESULTS: Median AL was 23.69 (interquartile range 3.53) mm. OR coefficient was 0.0218 (0.0053) MUL(-1). A negative correlation between the OR coefficient and AL (rho = -0.641, P < 0.001) was documented. Increasing AL was associated with decreased OPA (rho = 0.637, P < 0.001 and rho = -0.690, P < 0.001) and POBF (rho = -0.207, P = 0.053 and rho = -0.238, P = 0.028) at baseline and elevated IOP, respectively. CONCLUSIONS: Based on manometric data, increasing AL is associated with decreased OR, OPA, and POBF. These results suggest decreased pulsatility in high myopia and may have implications on ocular pulse studies and the pathophysiology of myopia. PMID- 23462746 TI - Development and efficacy of a drug-releasing soft contact lens. AB - PURPOSE: The purpose of this study was to investigate the uptake and the release of antibiotics from a newly synthesized drug delivery hydrogel soft contact lens (SCL) using an ion ligand mechanism. METHODS: The antibiotics used were Gatifloxacin (GFLX) and Moxifloxacin (MFLX). The uptake amount and the sustained release kinetics of antibiotics were investigated in vitro, and were also compared with newly synthesized SCLs, etafilcon A and polymacon. The antibiotic concentrations in the cornea, aqueous humor, and crystalline lens, and the effect against bacterial proliferation were investigated in vivo using rabbit subjects. Additionally the drug release efficacy of the new SCL was compared with that of eye drop administrations. RESULTS: In vitro, antibiotic uptake was increased with the weight percent (wt%) of the anionic group, and the released amount of antibiotics was highest during the initial 1 hour period, which then decreased over the next 72 hours. The released antibiotics volume of the new SCLs was significantly higher throughout 72 hours than that of the other two materials, etafilcon A and polymacon (P < 0.01). Whereas in vivo, the concentrations found in the cornea and aqueous humor were higher than those for the eye drop groups (P < 0.05 or P < 0.01). Antibiotic release at those sites decreased over 72 hours. No bacterial populations were detectable in the group treated with the new SCL presoaked in antibiotics throughout the experimental periods. CONCLUSIONS: The new SCLs released the antibiotics over several days, and showed improved penetration into the eye, along with prevention of bacterial proliferation. PMID- 23462747 TI - Substitution at IL1RN and deletion at SLC4A11 segregating with phenotype in familial keratoconus. AB - PURPOSE: Keratoconus (KTCN) is a thinning and anterior protrusion of the cornea that results in altered refractive powers and loss of visual acuity. Despite numerous studies, the reasons for development and progression of KTCN remain unknown. Genetic studies have led to identification of several loci linked with KTCN, including a locus in one multigenerational Ecuadorian family. The purpose of this study was to identify sequence variants in candidate genes segregating with the KTCN phenotype in another Ecuadorian family. METHODS: Nonparametric linkage analysis was performed in Ecuadorian family KTCN-019. Candidate genes IL1A, IL1B, IL1RN, and SLC4A11 were selected and examined in this family by direct sequencing of all exons, promoters, and intron-exon junctions. RESULTS: Two novel suggestive loci were identified in 2q13-q14.3 and 20p13-p12.2. Screening of the candidate genes revealed 66 sequence variants, including five novel variants, in both coding and noncoding regions. The substitution c.214+242C > T in the IL1RN gene was observed in all affected individuals and three apparently unaffected family members. The novel deletion of 54 nucleotides in position c.2558+149_2558+203 in SLC4A11 was observed in all patients but one, as well as two healthy individuals and one person with an unknown phenotype. CONCLUSIONS: The analyses of selected genes have led to identification of numerous sequence variants in the examined Ecuadorian family. Both substitution c.214+242C > T in IL1RN and novel deletion c.2558+149_2558+203del54 in SLC4A11 were observed significantly more frequently in family members with KTCN (P = 0.004525 and P = 0.00761, respectively), suggesting involvement of these two genes in KTCN etiology in the studied family. PMID- 23462748 TI - Unique response profile of trabecular meshwork cells to the novel selective glucocorticoid receptor agonist, GW870086X. AB - PURPOSE: Glucocorticoid (GC)-induced glaucoma is an undesirable side effect of traditional GCs. Ocular hypertension responsible for GC-induced glaucoma is due to alterations in conventional outflow homeostasis. The present study evaluates a novel selective GC receptor agonist (SEGRA), GW870086X, in two different in vitro models of the human conventional outflow pathway. METHODS: Primary cultures of human trabecular meshwork (TM) cell monolayers were treated with dexamethasone (DEX), prednisolone (PRED), or GW870086X for 5 days and then assayed for cellular expression and secretion of fibronectin, myocilin, tissue plasminogen activator (tPA), and/or matrix metalloproteinase-2 (MMP2). In parallel, TM cell monolayers on permeable filters treated for 5 days with GCs were assayed for changes in hydraulic conductivity. RESULTS: All three GCs increased fibronectin and myocilin secretion in a concentration-dependent manner (P < 0.05). In addition, DEX increased cellular fibronectin and both DEX and PRED significantly increased cellular myocilin (P < 0.0001), while GW870086X did neither. Interestingly, DEX and PRED significantly decreased tPA expression (P <= 0.01), while GW870086X had the opposite effect and increased tPA expression in a concentration-dependent manner (P = 0.01). For MMP2, only DEX treatment consistently decreased secretion (P < 0.01). In a functional assay, only PRED treatment significantly decreased hydraulic conductivity of TM cell monolayers (P < 0.05). CONCLUSIONS: All three GCs induced differential responses from TM cells. While the novel SEGRA GW870086X increases fibronectin and myocilin secretion similar to two traditional GCs, effects on the matrix degradation enzymes MMP2 and tPA differed significantly, suggesting that GW870086X favors matrix turnover. Consequently, effects on conventional outflow homeostasis may also be dissimilar. PMID- 23462749 TI - The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. AB - PURPOSE: To evaluate the effect of Rho kinase (ROCK)-inhibitor eye drops on a corneal endothelial dysfunction primate model and human clinical case series of corneal endothelial dysfunction. METHODS: As a corneal-endothelial partially injured model, the corneal endothelium of seven cynomolgus monkeys was damaged by transcorneal freezing; 10 mm of rock inhibitor Y-27632 was then applied topically 6 times daily. The phenotype of the reconstructed corneal endothelium was evaluated by immunohistochemical analysis and noncontact specular microscopy. For clinical study, the effect of Y-27632 eye drops after transcorneal freezing was evaluated in eight corneal endothelial dysfunction patients: four central corneal edema patients and four diffuse corneal edema patients. RESULTS: Slit-lamp microscopy revealed that both Y-27632-treated and -nontreated corneas became hazy after transcorneal freezing, and then recovered their transparency within 4 weeks. ROCK inhibitor Y-27632 promoted recovery of corneal endothelial cell density and wound healing in terms of both morphology and function. The percentage of ZO-1 and Na(+)/K(+)-ATPase positive cells in the regenerated area in the Y-27632 group was significantly higher than in the controls. Noncontact specular microscopy revealed that corneal endothelial cell density was significantly higher in the Y-27632 group compared with the controls at 4 weeks; cell density reached approximately 3000 cells/mm(2), as opposed to 1500 cells/mm(2) in the control group. In addition to the animal study findings, the clinical study findings showed that Y-27632 eye drops effectively improved corneal edema of corneal endothelial dysfunction patients with central edema. CONCLUSIONS: These findings show that rock inhibitor Y-27632 eye drops promote corneal endothelial wound healing in a primate animal model and suggest the possibility of Y-27632 as a novel therapeutic modality for certain forms of corneal endothelial dysfunction. (http://www.umin.ac.jp/ctr/ number, UMIN000003625.). PMID- 23462750 TI - How useful is population data for informing visual field progression rate estimation? AB - PURPOSE: Bayesian estimators allow the frequency of visual field progression rates in the population (the prior distribution) to constrain rate estimates for individuals. We examined the benefits of a prior distribution accounting for one of progression's major risk factors--whether intraocular pressure is treated--to gauge the maximum benefit expected from developing priors for other glaucoma risk factors. METHODS: Our prior distribution was derived from published data from either treated (matched-prior condition) or untreated (unmatched-prior condition) glaucoma patients. We simulated MD values (6-monthly) with true underlying progression rates drawn from the same distribution as the prior for the matched prior condition. We estimated rates through linear regression, and determined the likelihood of obtaining this estimate as a function of a range of true underlying progression rates (the likelihood function). The maximum likelihood estimate of rate was the most likely value of the posterior distribution (the product of the prior distribution and likelihood function). RESULTS: For short (4) visual field series, the matched-prior condition, unmatched-prior condition, and linear regression gave median errors (estimated minus true rate) of 0.02, 0.20, and 0.00 dB/y, respectively. Positive predictive values for determining rapidly progressing (<-1 dB/y) rates were 0.46, 0.42, and 0.38, with negative predictive values of 0.93, 0.94, and 0.95. For more extended series the magnitude of the differences between techniques decreased, although the order was unchanged. CONCLUSIONS: Performance shifts in bayesian estimators of visual field progression are modest even when prior distributions do not reflect large risk factors, such as IOP treatment. PMID- 23462751 TI - Association between choroidal morphology and anti-vascular endothelial growth factor treatment outcome in myopic choroidal neovascularization. AB - PURPOSE: To investigate associations between outcome of anti-vascular endothelial growth factor (VEGF) therapy and choroidal morphology in eyes with myopic choroidal neovascularization (CNV). METHODS: Fifty-two eyes of 46 patients with myopic CNV received a single intravitreal anti-VEGF injection, followed by as needed injections. Baseline choroidal thickness was measured at the fovea and 1.5 and 3 mm nasal, temporal, superior, and inferior to the fovea using enhanced depth imaging optical coherence tomography. Measurements were compared between eyes with and without CNV resolution after a single injection and between those with and without CNV recurrence within 1 year of initial injection. Associations between treatment outcomes and morphologic or clinical factors were assessed using regression analyses. RESULTS: Patients received 1.8 +/- 1.3 intravitreal injections during follow-up. Eyes with CNV resolution after a single anti-VEGF injection had a significantly thicker inferior choroid than those without resolution (67.3 +/- 32.9 vs. 44.5 +/- 17.6 MUm, P = 0.002). The subfoveal choroid was thinner in eyes with recurring CNV than in those without recurrence (35.7 +/- 23.7 vs. 52.0 +/- 20.8 MUm, P = 0.029). Associations were found between inferior choroidal thickness and CNV resolution (P = 0.019) and between subfoveal choroidal thickness and 1-year recurrence rates (P = 0.016). Adjusted odds ratios were 9.1 for CNV resolution with an inferior choroidal thickness >49 MUm and 5.6 for recurrence within 1 year with a subfoveal choroidal thickness <=47.5 MUm. CONCLUSIONS: A thinner subfoveal/inferior choroid at baseline may indicate poor anatomic outcome after intravitreal anti-VEGF treatment in eyes with myopic CNV. PMID- 23462753 TI - Targeted sequencing of 179 genes associated with hereditary retinal dystrophies and 10 candidate genes identifies novel and known mutations in patients with various retinal diseases. AB - PURPOSE: Hereditary retinal dystrophies (HRDs) are a group of monogenic diseases characterized by an irreversible loss of photoreceptors. HRDs exhibit significant genetic and clinical heterogeneities challenging traditional techniques for determining disease-causal mutations. This study aims to develop an efficient molecular diagnostic platform for HRDs, and to determine the genetic basis for 25 randomly collected Chinese families with a variety of HRDs. METHODS: We designed a high throughput sequence capture microarray targeting 179 genes associated with HRDs and 10 candidate genes. We combined sequence capture with next-generation sequencing (NGS) to screen for mutations in the cohort of Chinese families. Variants detected by NGS were filtered, validated, and prioritized by pathogenicity analysis. Genotypes and phenotypes were correlated. RESULTS: We identified four recurrent single mutations, two compound mutations, and eight novel putative causative mutations, including five putative pathogenic alleles (e.g., premature stop codons and frame shifts) and three novel missense variants that are very likely pathogenic. These findings provided specific genetic diagnoses in 14 of 25 families (56%). Among these, identification of a mutation in VCAN in a family with a complicated phenotype helped to finalize the clinical diagnosis as Wagner syndrome. In another five families, 11 potential novel pathogenic variants were identified. CONCLUSIONS: A substantial number of potential new genes and new mutations associated with HRDs remain to be discovered. Identification of the novel HRDs-causing mutations in our study not only provides a better understanding of genotype-phenotype relationships in these diseases, but also demonstrates that the approach described herein is an effective method for large scale mutation detection among diverse and complicated HRDs cases. PMID- 23462752 TI - Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration. AB - PURPOSE: Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid beta 1-40 (Abeta 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE; however, its effect in vivo is not known. The purpose of this study was to examine the effect of Abeta 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model. METHODS: Wild-type rats received intravitreal injections of Abeta 1-40, and eyes were taken at days 1, 4, 14, and 49 postinjection. The RPE, neuroretina, and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry, and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness. RESULTS: Abeta 1-40 stimulated upregulation of IL-6, TNF-alpha, IL-1beta, IL-18, caspase-1, NLRP3, and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1beta and IL-6 immunoreactivity was found in retinal sections, and elevated levels of IL-1beta and IL-18 were found in the vitreous of Abeta injected eyes. Abeta 1-40 induced a moderate increase in CD11b/c-reactive cells on day 1 postinjection only. No evidence of the proapoptotic XAF1 protein, p53, TUNEL immunoreactivity, or retinal thinning was observed. CONCLUSIONS: These results confirm earlier in vitro work and support the proinflammatory role of drusen component Abeta 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful for understanding cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD. PMID- 23462754 TI - Glaucoma detection ability of ganglion cell-inner plexiform layer thickness by spectral-domain optical coherence tomography in high myopia. AB - PURPOSE: To compare the glaucoma detection ability of macular ganglion cell-inner plexiform layer (GCIPL) thickness measured with Cirrus spectral-domain optical coherence tomography (SD-OCT) with that of peripapillary retinal nerve fiber layer (RNFL) thickness in high myopia. METHODS: In 49 highly myopic and 54 nonhighly myopic glaucoma patients--along with 78 healthy myopic subjects--two scans, including one macular scan and one peripapillary RNFL scan, were obtained using Cirrus SD-OCT. For 44 randomly selected glaucoma patients, three macular scans were taken for reproducibility measurements. The glaucoma detection abilities of macular GCIPL and peripapillary RNFL thicknesses were compared between the highly myopic and nonhighly myopic groups. Diagnostic power was assessed by area under the receiver operating characteristic (AUROC) curves and sensitivity. Repeatability was assessed by intraclass correlation coefficient (ICC) and coefficient of variation (CV). RESULTS: All of the macular GCIPL and peripapillary RNFL thickness measurements excepting the 3 o'clock peripapillary RNFL sector showed an AUROC over 0.5. The best parameters for discriminating normal from glaucomatous eyes were inferior RNFL (0.906) and inferotemporal GCIPL (0.852) thickness in the highly myopic group, and average RNFL (0.920) and minimum GCIPL (0.908) thickness in the nonhighly myopic group. The best peripapillary RNFL and macular GCIPL thickness parameters showed no statistically significant differences. All of the ICCs of the macular GCIPL ranged between 0.96 and 0.99, and the CV was <3%. CONCLUSIONS: In cases of high myopia, the glaucoma detection ability of macular GCIPL thickness was high and comparable with that of peripapillary RNFL thickness. PMID- 23462755 TI - A key role for ROCK in TNF-alpha-mediated diabetic microvascular damage. AB - PURPOSE: Leukocyte adhesion releases tumor necrosis factor (TNF)-alpha that contributes to endothelial damage in early diabetic retinopathy (DR). Rho/Rho kinase (ROCK) signaling mediates retinal endothelial damage in early DR. However, whether ROCK regulates TNF-alpha-mediated diabetic vascular damage is unknown. Here, the contribution of ROCK to TNF-alpha-mediated microvascular damage is investigated. METHODS: In DR patients and nondiabetic control subjects, the levels of membranous (m) TNF-alpha on neutrophils, soluble (s) TNF-alpha and its receptors in sera, were measured. In cultured microvascular endothelial cells, phosphorylation of myosin phosphatase target protein (MYPT)-1, a downstream target of ROCK, was investigated with TNF-alpha or DR sera pretreatment. TNF alpha-induced intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS) phosphorylation were measured with and without ROCK inhibition by fasudil or ROCK-specific small-interfering RNA (siRNA). In isolated neutrophils from control subjects, MYPT-1 phosphorylation was investigated in the presence of TNF-alpha. The impact of ROCK inhibition by fasudil on TNF-alpha induced integrin (CD18, CD11a, CD11b) and intracellular cytoskeletal changes were investigated. RESULTS: The serum levels of mTNF-alpha, sTNF-alpha, and its receptors were significantly elevated in DR patients. TNF-alpha as well as DR sera promoted MYPT-1 phosphorylation in endothelial cells, which was significantly reduced by anti-TNF-alpha neutralizing antibody. TNF-alpha-induced ICAM-1 expression, eNOS dephosphorylation, cytoskeletal changes, and CD11b/18 expression in neutrophils were significantly suppressed by fasudil as well as ROCK-specific siRNA. CONCLUSIONS: ROCK is a key mediator of TNF-alpha signaling in diabetic microvessels. The important role of TNF-alpha in early DR provides a new rationale for ROCK inhibition beyond the previously shown mechanisms. PMID- 23462756 TI - Detection of audiovisual speech correspondences without visual awareness. AB - Mounting physiological and behavioral evidence has shown that the detectability of a visual stimulus can be enhanced by a simultaneously presented sound. The mechanisms underlying these cross-sensory effects, however, remain largely unknown. Using continuous flash suppression (CFS), we rendered a complex, dynamic visual stimulus (i.e., a talking face) consciously invisible to participants. We presented the visual stimulus together with a suprathreshold auditory stimulus (i.e., a voice speaking a sentence) that either matched or mismatched the lip movements of the talking face. We compared how long it took for the talking face to overcome interocular suppression and become visible to participants in the matched and mismatched conditions. Our results showed that the detection of the face was facilitated by the presentation of a matching auditory sentence, in comparison with the presentation of a mismatching sentence. This finding indicates that the registration of audiovisual correspondences occurs at an early stage of processing, even when the visual information is blocked from conscious awareness. PMID- 23462757 TI - Gender differences in multitasking reflect spatial ability. AB - Demands involving the scheduling and interleaving of multiple activities have become increasingly prevalent, especially for women in both their paid and unpaid work hours. Despite the ubiquity of everyday requirements to multitask, individual and gender-related differences in multitasking have gained minimal attention in past research. In two experiments, participants completed a multitasking session with four gender-fair monitoring tasks and separate tasks measuring executive functioning (working memory updating) and spatial ability (mental rotation). In both experiments, males outperformed females in monitoring accuracy. Individual differences in executive functioning and spatial ability were independent predictors of monitoring accuracy, but only spatial ability mediated gender differences in multitasking. Menstrual changes accentuated these effects, such that gender differences in multitasking (and spatial ability) were eliminated between males and females who were in the menstrual phase of the menstrual cycle but not between males and females who were in the luteal phase. These findings suggest that multitasking involves spatiotemporal task coordination and that gender differences in multiple-task performance reflect differences in spatial ability. PMID- 23462760 TI - The cover. Mountain landscape from Clavadel. PMID- 23462762 TI - "Official information"--medical! PMID- 23462763 TI - New HIPAA rule aims to improve privacy and security of patient records. PMID- 23462764 TI - FDA committee: More restrictions needed on hydrocodone combination products. PMID- 23462765 TI - NIH panel: Name change, new priorities advised for polycystic ovary syndrome. PMID- 23462766 TI - FDA warning: New batch of fake bevacizumab found. PMID- 23462774 TI - Fish oil vs olive oil for postoperative atrial fibrillation. PMID- 23462775 TI - Fish oil vs olive oil for postoperative atrial fibrillation--reply. PMID- 23462776 TI - Genetic variants modifying the influence of vitamin D. PMID- 23462777 TI - Genetic variants modifying the influence of vitamin D--reply. PMID- 23462778 TI - Opioid overdose fatality prevention. PMID- 23462779 TI - Opioid overdose fatality prevention--reply. PMID- 23462780 TI - Predicting 10-year mortality for older adults. PMID- 23462782 TI - Keeping an eye on distracted driving. PMID- 23462783 TI - Improving opioid prescribing: the New York City recommendations. PMID- 23462784 TI - A piece of my mind. Swimming in the Sea of Galilee. PMID- 23462785 TI - Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. AB - IMPORTANCE: Herpes zoster reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti TNF) therapy elevates herpes zoster risk. OBJECTIVES: To ascertain whether initiation of anti-TNF therapy compared with nonbiologic comparators is associated with increased herpes zoster risk. DESIGN, SETTING, AND PATIENTS: We identified new users of anti-TNF therapy among cohorts of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared herpes zoster incidence between new anti-TNF users (n=33,324) and patients initiating nonbiologic disease modifying antirheumatic drugs (DMARDs) (n=25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007). Within these cohorts, we used Cox regression models to compare propensity score-adjusted herpes zoster incidence between new anti-TNF and nonbiologic DMARD users while controlling for baseline corticosteroid use. MAIN OUTCOME MEASURES: Incidence of herpes zoster cases occurring after initiation of new anti-TNF or nonbiologic DMARD therapy. RESULTS: Among 33,324 new users of anti-TNF therapy, we identified 310 herpes zoster cases. Crude incidence rates among anti-TNF users were 12.1 per 1000 patient-years (95% CI, 10.7-13.6) for RA, 11.3 per 1000 patient-years (95% CI, 7.7-16.7) for inflammatory bowel disease, and 4.4 per 1000 patient-years (95% CI, 2.8-7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64-2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77-1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88-1.36). CONCLUSION AND RELEVANCE: Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens. PMID- 23462786 TI - Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. AB - IMPORTANCE: Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions. OBJECTIVE: To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy. DESIGN, SETTING, AND PATIENTS: Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011. MAIN OUTCOME MEASURES: Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation. RESULTS: Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio [HR], 2.96 [95% CI, 1.87-4.69]; absolute risk difference, 16.2% [95% CI, 8.2%-24.2%]; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 [95% CI, 3.15-8.72]; absolute risk difference, 22.6% [95% CI, 14.6%-30.6%]; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 [95% CI, 1.50-3.92]; P < .001) and the extent (HR, 1.11 [95% CI, 1.06-1.16]; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 [95% CI, 1.95-5.31], P < .001; and by fibrosis extent: HR, 1.15 [95% CI, 1.10-1.20], P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 [95% CI, 2.75-7.74], P < .001; and by fibrosis extent: HR, 1.10 [95% CI, 1.05-1.16], P < .001), and the HF composite (by fibrosis presence: HR, 1.62 [95% CI, 1.00-2.61], P = .049; and by fibrosis extent: HR, 1.08 [95% CI, 1.04-1.13], P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 [95% CI, 0.11-0.41]; P = .001 and 0.29 [95% CI, 0.11-0.48]; P = .002, respectively). CONCLUSIONS AND RELEVANCE: Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation. PMID- 23462788 TI - Chronic back pain with possible prescription opioid misuse. AB - IMPORTANCE: Data on the effectiveness and safety of long-term opioid therapy for chronic pain are limited. Opioid adherence monitoring includes urine drug testing. Determining whether a patient's opioid prescription should be discontinued after an unexpected urine test result can be clinically complex. OBJECTIVE: To review safe opioid prescribing practices and appropriate interpretation and management of unexpected urine drug test results. EVIDENCE REVIEW: Systematic reviews of the effectiveness and safety of long-term opioid therapy for chronic noncancer pain. Clinical management recommendations are derived from clinical guidelines generated by several professional medical organizations including the American Pain Society, the American Academy of Pain Medicine, and the Federation of State Medical Boards. FINDINGS: Informed consent and patient-prescriber agreements are important strategies to ensure that patients understand treatment goals and potential opioid risks. Monitoring for benefit and opioid misuse is accomplished by having frequent face-to-face assessments, performing urine drug tests, monitoring pill counts, and reviewing prescription drug monitoring program data, when available. CONCLUSIONS AND RELEVANCE: The underlying causes for worrisome behaviors such as urine drug test results that are negative for the prescribed opioid should be fully investigated. Subsequent opioid prescriptions should be based on the revised risk and benefit assessment. PMID- 23462787 TI - Prevalence of regional myocardial thinning and relationship with myocardial scarring in patients with coronary artery disease. AB - IMPORTANCE: Regional left ventricular (LV) wall thinning is believed to represent chronic transmural myocardial infarction and scar tissue. However, recent case reports using delayed-enhancement cardiovascular magnetic resonance (CMR) imaging raise the possibility that thinning may occur with little or no scarring. OBJECTIVE: To evaluate patients with regional myocardial wall thinning and to determine scar burden and potential for functional improvement. DESIGN, SETTING, AND PATIENTS: Investigator-initiated, prospective, 3-center study conducted from August 2000 through January 2008 in 3 parts to determine (1) in patients with known coronary artery disease (CAD) undergoing CMR viability assessment, the prevalence of regional wall thinning (end-diastolic wall thickness <=5.5 mm), (2) in patients with thinning, the presence and extent of scar burden, and (3) in patients with thinning undergoing coronary revascularization, any changes in myocardial morphology and contractility. MAIN OUTCOMES AND MEASURES: Scar burden in thinned regions assessed using delayed-enhancement CMR and changes in myocardial morphology and function assessed using cine-CMR after revascularization. RESULTS: Of 1055 consecutive patients with CAD screened, 201 (19% [95% CI, 17% to 21%]) had regional wall thinning. Wall thinning spanned a mean of 34% (95% CI, 32% to 37% [SD, 15%]) of LV surface area. Within these regions, the extent of scarring was 72% (95% CI, 69% to 76% [SD, 25%]); however, 18% (95% CI, 13% to 24%) of thinned regions had limited scar burden (<=50% of total extent). Among patients with thinning undergoing revascularization and follow-up cine-CMR (n = 42), scar extent within the thinned region was inversely related to regional (r = -0.72, P < .001) and global (r = -0.53, P < .001) contractile improvement. End-diastolic wall thickness in thinned regions with limited scar burden increased from 4.4 mm (95% CI, 4.1 to 4.7) to 7.5 mm (95% CI, 6.9 to 8.1) after revascularization (P < .001), resulting in resolution of wall thinning. On multivariable analysis, scar extent had the strongest association with contractile improvement (slope coefficient, -0.03 [95% CI, -0.04 to -0.02]; P < .001) and reversal of thinning (slope coefficient, -0.05 [95% CI, -0.06 to 0.04]; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CAD referred for CMR and found to have regional wall thinning, limited scar burden was present in 18% and was associated with improved contractility and resolution of wall thinning after revascularization. These findings, which are not consistent with common assumptions, warrant further investigation. PMID- 23462789 TI - Antiplatelet therapy to prevent cardiovascular events and mortality in patients with intermittent claudication. AB - CLINICAL QUESTION: Do antiplatelet therapies reduce risk of all-cause mortality, cardiovascular disease (CVD) mortality, and cardiovascular events in patients with intermittent claudication? Which antiplatelet is most strongly associated with a reduced risk of all-cause and CVD mortality? BOTTOM LINE: In patients with intermittent claudication, antiplatelet therapies are associated with lower all cause and CVD mortality compared with placebo. Compared with all antiplatelet therapies, the strongest evidence exists for thienopyridines, such as clopidogrel. PMID- 23462791 TI - Cardiovascular imaging in clinical practice: what does late gadolinium enhance? PMID- 23462792 TI - JAMA patient page. Tuberculosis. PMID- 23462793 TI - [B-cell neoplasms with plasmacellular and plasmablastic differentiation]. AB - Plasma cell malignancies are tumors of terminally differentiated B-cells in which the neoplastic plasma cells are the dominant and proliferating tumor cell component. Plasma cell myeloma (PCM) is one of the most common hematological neoplasms and typically does not cause diagnostic problems. A morphologically and immunophenotypically detectable plasmacellular orplasmablastic differentiation is, however, commonly observed in a wide range of mature B-cell lymphomas. A confident separation of the distinct entities requires the integration of clinical and morphological findings as well as an adequate phenotyping of both the plasma cell and the B-cell component if present. Detection of lymphotropic viruses, specific translocations and novel molecular markers, such as the MYD88 L265P mutation occurring in the vast majority of lymphoplasmacytic lymphomas complement our diagnostic repertoire. In this review we describe the most commonly observed diagnostic problems in separating small B-cell lymphomas from PCM and high-grade B-cell non-Hodgkin lymphoma (B-NHL) with plasmablastic differentiation from extramedullary spread of aggressive PCM and provide helpful criteria for routine diagnostics. PMID- 23462794 TI - Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. AB - AIMS/HYPOTHESIS: To date, the molecular function of most of the reported type 2 diabetes-associated loci remains unknown. The introduction or removal of cytosine phosphate-guanine (CpG) dinucleotides, which are possible sites of DNA methylation, has been suggested as a potential mechanism through which single nucleotide polymorphisms (SNPs) can affect gene function via epigenetics. The aim of this study was to examine if any of 40 SNPs previously associated with type 2 diabetes introduce or remove a CpG site and if these CpG-SNPs are associated with differential DNA methylation in pancreatic islets of 84 human donors. METHODS: DNA methylation was analysed using pyrosequencing. RESULTS: We found that 19 of 40 (48%) type 2 diabetes-associated SNPs introduce or remove a CpG site. Successful DNA methylation data were generated for 16 of these 19 CpG-SNP loci, representing the candidate genes TCF7L2, KCNQ1, PPARG, HHEX, CDKN2A, SLC30A8, DUSP9, CDKAL1, ADCY5, SRR, WFS1, IRS1, DUSP8, HMGA2, TSPAN8 and CHCHD9. All analysed CpG-SNPs were associated with differential DNA methylation of the CpG SNP site in human islets. Moreover, six CpG-SNPs, representing TCF7L2, KCNQ1, CDKN2A, ADCY5, WFS1 and HMGA2, were also associated with DNA methylation of surrounding CpG sites. Some of the type 2 diabetes CpG-SNP sites that exhibit differential DNA methylation were further associated with gene expression, alternative splicing events determined by splice index, and hormone secretion in the human islets. The 19 type 2 diabetes-associated CpG-SNPs are in strong linkage disequilibrium (r2 > 0.8) with a total of 295 SNPs, including 91 CpG SNPs. CONCLUSIONS/INTERPRETATION: Our results suggest that the introduction or removal of a CpG site may be a molecular mechanism through which some of the type 2 diabetes SNPs affect gene function via differential DNA methylation and consequently contributes to the phenotype of the disease. PMID- 23462795 TI - Programming of DNA methylation in type 2 diabetes. PMID- 23462796 TI - Imatinib mesilate-induced phosphatidylinositol 3-kinase signalling and improved survival in insulin-producing cells: role of Src homology 2-containing inositol 5'-phosphatase interaction with c-Abl. AB - AIMS/HYPOTHESIS: It is not clear how small tyrosine kinase inhibitors, such as imatinib mesilate, protect against diabetes and beta cell death. The aim of this study was to determine whether imatinib, as compared with the non-cAbl-inhibitor sunitinib, affects pro-survival signalling events in the phosphatidylinositol 3 kinase (PI3K) pathway. METHODS: Human EndoC-betaH1 cells, murine beta TC-6 cells and human pancreatic islets were used for immunoblot analysis of insulin receptor substrate (IRS)-1, Akt and extracellular signal-regulated kinase (ERK) phosphorylation. Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] plasma membrane concentrations were assessed in EndoC-betaH1 and MIN6 cells using evanescent wave microscopy. Src homology 2-containing inositol 5'-phosphatase 2 (SHIP2) tyrosine phosphorylation and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) serine phosphorylation, as well as c-Abl co-localisation with SHIP2, were studied in HEK293 and EndoC-betaH1 cells by immunoprecipitation and immunoblot analysis. Gene expression was assessed using RT-PCR. Cell viability was measured using vital staining. RESULTS: Imatinib stimulated ERK(thr202/tyr204) phosphorylation in a c-Abl-dependent manner. Imatinib, but not sunitinib, also stimulated IRS-1(tyr612), Akt(ser473) and Akt(thr308) phosphorylation. This effect was paralleled by oscillatory bursts in plasma membrane PI(3,4,5)P3 levels. Wortmannin induced a decrease in PI(3,4,5)P3 levels, which was slower in imatinib-treated cells than in control cells, indicating an effect on PI(3,4,5)P3-degrading enzymes. In line with this, imatinib decreased the phosphorylation of SHIP2 but not of PTEN. c-Abl co-immunoprecipitated with SHIP2 and its binding to SHIP2 was largely reduced by imatinib but not by sunitinib. Imatinib increased total beta-catenin levels and cell viability, whereas sunitinib exerted negative effects on cell viability. CONCLUSIONS/INTERPRETATION: Imatinib inhibition of c-Abl in beta cells decreases SHIP2 activity, which results in enhanced signalling downstream of PI3 kinase. PMID- 23462797 TI - Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice. AB - AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively. METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK 8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high fat-fed mice. RESULTS: (pGlu-Gln)-CCK-8 had prominent (p < 0.01 to p < 0.001), acute feeding-suppressive effects, which were significantly augmented (p < 0.05 to p < 0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p < 0.05 to p < 0.001), energy intake (p < 0.01), circulating triacylglycerol (p < 0.01), non-fasting glucose (p < 0.05 to p < 0.001) and triacylglycerol deposition in liver and adipose tissue (p < 0.001). All treatment regimens improved glucose tolerance (p < 0.05 to p < 0.001) and insulin sensitivity (p < 0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p < 0.001) energy expenditure. CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes. PMID- 23462798 TI - Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice. AB - AIMS/HYPOTHESIS: The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study. METHODS: We crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp). RESULTS: Although PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription. CONCLUSIONS/INTERPRETATION: Our results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp. PMID- 23462800 TI - Mid Staffs inquiry. The whole hospital system needs to be addressed nationally. PMID- 23462799 TI - A cross-sectional multicenter study of cognitive and behavioural features in multiple system atrophy patients of the parkinsonian and cerebellar type. AB - Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group ( http://www.emsa-sg.org ), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies. PMID- 23462801 TI - MeCAT--comparing relative quantification of alpha lactalbumin using both molecular and elemental mass spectrometry. AB - Chemical tagging with stable isotopes is one of the best established methods for the quantification of proteins using mass spectrometry, especially in non proliferating cells and tissue. The absolute quantification of proteins is still a challenge. Metal-coded affinity tagging (MeCAT), used to label proteins and peptides with lanthanide ions, allows both, relative and absolute, quantitative determination. MeCAT loaded with lanthanide ions allows the use of inductively coupled plasma mass spectrometry (ICP-MS) enabling very accurate and sensitive quantification of peptides and proteins based on the metal ion signal. Furthermore, multiplex assays are possible that are not limited to 4- or 8-plex analyses when using different lanthanides. Naturally, different lanthanides also lead to different molecular masses for the same labelled peptides which can be distinguished easily. This enables the relative quantification in electrospray MS based on the relative signal intensities of the differentially labelled peptides. We have studied MeCAT labelled peptides, using LC/ESI-MS and LC/ESI-MS/MS with infrared multiphoton dissociation (IRMPD) to show that both the molecular masses and the specific fragments resulting from the MS/MS experiments can be used for relative quantification. The results are compared with high performance liquid chromatography (HPLC)/ICP-MS and direct ICP-MS analysis as standard methods. We show that the ESI and IRMPD based methods deliver quantitative results comparable to ICP-MS. PMID- 23462802 TI - The indication and application of computer-assisted navigation in oral and maxillofacial surgery-Shanghai's experience based on 104 cases. AB - OBJECTIVE: To explore the indication and application of computer-assisted navigation in oral and maxillofacial surgery. PATIENTS AND METHODS: One hundred and four patients including 34 zygomatic-orbital-maxillary fractures, 27 unilateral TMJ ankylosis, 29 craniofacial fibrous dysplasia, 9 mandibular angle hypertrophia, 3 cartilage/bone tumours of jaw and 2 cases with facial foreign bodies were enrolled in this study. CT scans were performed and data was saved in DICOM (digital imaging and communications in medicine) format. The osteotomy lines, amount and range of resection, the reduction position of bony segments and the reconstruction morphology was determined and displayed by preoperative simulation with mirroring and superimposing procedures. All operations were performed under the guidance of navigation system. The accuracy of navigation was evaluated by comparing the postoperative CT 3-D model with preoperative surgical planning. RESULTS: Through registration, an accurate match between the intraoperative anatomy and the CT images was achieved. The systematic error checked by computer was within 1 mm. All operations were performed successfully with the guidance of real-time navigation. The mean error between virtual simulation and surgical results was 1.46 +/- 0.24 mm. All patients healed uneventfully and function and profile was improved significantly. CONCLUSIONS: With the opportunity to perform preoperative planning, surgical simulation and postoperative prediction, computer-assisted navigation shows great value in improving the accuracy of maxillofacial surgery, reducing operation risk and postsurgical morbidity, and restoring facial symmetry. It is regarded as a valuable technique in these potentially complicated procedures. PMID- 23462803 TI - Congenital and prolonged adult-onset deafness cause distinct degradations in neural ITD coding with bilateral cochlear implants. AB - Bilateral cochlear implant (CI) users perform poorly on tasks involving interaural time differences (ITD), which are critical for sound localization and speech reception in noise by normal-hearing listeners. ITD perception with bilateral CI is influenced by age at onset of deafness and duration of deafness. We previously showed that ITD coding in the auditory midbrain is degraded in congenitally deaf white cats (DWC) compared to acutely deafened cats (ADC) with normal auditory development (Hancock et al., J. Neurosci, 30:14068). To determine the relative importance of early onset of deafness and prolonged duration of deafness for abnormal ITD coding in DWC, we recorded from single units in the inferior colliculus of cats deafened as adults 6 months prior to experimentation (long-term deafened cats, LTDC) and compared neural ITD coding between the three deafness models. The incidence of ITD-sensitive neurons was similar in both groups with normal auditory development (LTDC and ADC), but significantly diminished in DWC. In contrast, both groups that experienced prolonged deafness (LTDC and DWC) had broad distributions of best ITDs around the midline, unlike the more focused distributions biased toward contralateral-leading ITDs present in both ADC and normal-hearing animals. The lack of contralateral bias in LTDC and DWC results in reduced sensitivity to changes in ITD within the natural range. The finding that early onset of deafness more severely degrades neural ITD coding than prolonged duration of deafness argues for the importance of fitting deaf children with sound processors that provide reliable ITD cues at an early age. PMID- 23462804 TI - Quality of life in relation to social and disease factors in patients with type 2 diabetes in Lithuania. AB - BACKGROUND: Diabetic patients are more than twice as costly to manage as non diabetic patients, due mainly to the high costs associated with management of diabetic complications. As in most nations of the world, the number of patients with DM is increasing every year in Lithuania. The aim of this study was to determine relation between quality of the life and disease and social factors of patients with type 2 diabetes in Lithuania. MATERIAL AND METHODS: Independently prepared questions about the subjects of the survey were: gender; age; weight; education; social and marital status; duration of the disease (in years); treatment method; complications; morbidity with arterial hypertension; change in dietary habits after diagnosis of diabetes (started to eat accordingly to recommendations of the therapist); how often nourishment is taken accordingly to recommendations of the therapist; if beginning to exercise after diagnosis of the diabetes; and if exercising, exercises at least 2-3 times per week. Body mass index was calculated as the relation between body mass in kg and height m square (BMI=kg/m2). The hospital anxiety and depression (HAD) scale was used for the evaluation of depression and anxiety. Quality of life of patients was evaluated with the SF-36 questionnaire. We surveyed 1022 patients with type 2 diabetes (372 men and 650 women). Association between quality of the life and explanatory parameters (disease and social factors) were analyzed using the logistic regression analysis model. RESULTS: We found that women had lower scores than men in all fields of quality of life (p<0.001). Peroral treatment had a positive impact on the quality of life (QL) fields of the role limitations due to emotional problems (ORa 0.16. 95% CI 0.07-0.34; p<0.001). Treatment with insulin had a positive effect on restriction of activity because of emotional problems (ORa - 0.23. 95% CI 0.11-0.49; p<0.001) and mental health (ORa - 0.38. 95% CI 0.19-0.78; p=0.008), but had a negative impact on bodily pain (ORa - 3.95. 95% CI 1.41-11.09; p=0.009) and physical health (ORa - 4.14. 95% CI 2.03-8.47; p<0.001). CONCLUSIONS: Age and BMI are less important factors that can influence quality of life. Peroral treatment positively acted on the role limitations due to emotional problems, bodily pain, and mental health, but had a strong negative effect on emotional state. PMID- 23462805 TI - Pathology vs medical oncology: the crucial exchange of accurate information. PMID- 23462806 TI - Y-box binding protein-1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma. AB - BACKGROUND: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. METHODS: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. RESULTS: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. CONCLUSION: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS. PMID- 23462807 TI - Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. AB - BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required. PMID- 23462810 TI - Easy access to benzylic esters directly from alkyl benzenes under metal-free conditions. AB - An efficient metal free protocol has been developed for the synthesis of benzylic esters via a cross dehydrogenative coupling (CDC) involving alkylbenzene(s) as a self- or as a cross-coupling partner(s) via the intermediacy of Ar-COOH and the benzylic carbocation obtained from the other half of the alkylbenzene; both symmetrical as well as unsymmetrical esters can be prepared using Bu4NI and TBHP. PMID- 23462808 TI - A nanomaterial-based breath test for distinguishing gastric cancer from benign gastric conditions. AB - BACKGROUND: Upper digestive endoscopy with biopsy and histopathological evaluation of the biopsy material is the standard method for diagnosing gastric cancer (GC). However, this procedure may not be widely available for screening in the developing world, whereas in developed countries endoscopy is frequently used without major clinical gain. There is a high demand for a simple and non-invasive test for selecting the individuals at increased risk that should undergo the endoscopic examination. Here, we studied the feasibility of a nanomaterial-based breath test for identifying GC among patients with gastric complaints. METHODS: Alveolar exhaled breath samples from 130 patients with gastric complaints (37 GC/32 ulcers / 61 less severe conditions) that underwent endoscopy/biopsy were analyzed using nanomaterial-based sensors. Predictive models were built employing discriminant factor analysis (DFA) pattern recognition, and their stability against possible confounding factors (alcohol/tobacco consumption; Helicobacter pylori) was tested. Classification success was determined (i) using leave-one-out cross-validation and (ii) by randomly blinding 25% of the samples as a validation set. Complementary chemical analysis of the breath samples was performed using gas chromatography coupled with mass spectrometry. RESULTS: Three DFA models were developed that achieved excellent discrimination between the subpopulations: (i) GC vs benign gastric conditions, among all the patients (89% sensitivity; 90% specificity); (ii) early stage GC (I and II) vs late stage (III and IV), among GC patients (89% sensitivity; 94% specificity); and (iii) ulcer vs less severe, among benign conditions (84% sensitivity; 87% specificity). The models were insensitive against the tested confounding factors. Chemical analysis found that five volatile organic compounds (2-propenenitrile, 2-butoxy-ethanol, furfural, 6 methyl-5-hepten-2-one and isoprene) were significantly elevated in patients with GC and/or peptic ulcer, as compared with less severe gastric conditions. The concentrations both in the room air and in the breath samples were in the single p.p.b.v range, except in the case of isoprene. CONCLUSION: The preliminary results of this pilot study could open a new and promising avenue to diagnose GC and distinguish it from other gastric diseases. It should be noted that the applied methods are complementary and the potential marker compounds identified by gas-chromatography/mass spectrometry are not necessarily responsible for the differences in the sensor responses. Although this pilot study does not allow drawing far-reaching conclusions, the encouraging preliminary results presented here have initiated a large multicentre clinical trial to confirm the observed patterns for GC and benign gastric conditions. PMID- 23462812 TI - Octahedral Co3O4 particles threaded by carbon nanotube arrays as integrated structure anodes for lithium ion batteries. AB - Octahedral Co3O4 particles threaded by ultra-long multi-walled carbon nanotube (MWCNT) arrays were prepared by a hydrothermal process and subsequent calcination. The Co3O4 octahedron with the (111) facets attaches to MWCNTs uniformly and closely. The composite can be used as an integrated anode for lithium ion batteries (LIBs) without any other additives (such as conductive additives and polymer binder), which exhibits a high reversible capacity of 725 mA h g(-1) at a current density of 100 mA g(-1), and excellent cyclic stability without capacity degradation over 100 cycles at a current density of 500 mA g( 1). The high performance can be attributed to the unique structure: (i) the ultra long MWCNT array facilitates fast electron transfer; (ii) the tight adhesion between Co3O4 and MWCNTs prevents particle drifting and agglomeration; (iii) the free space between MWCNTs promotes fast ion transport and alleviates the large volume variation during discharge-charge process. This work demonstrates the great potential of MWCNT arrays as substrate and provides insights for the design and direct use of MWCNT array-based materials in LIBs, which will be helpful for future development of high-performance electrode materials. PMID- 23462811 TI - Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. AB - In mammalians, toll-like receptors (TLR) signal-transduction pathways induce the expression of a variety of immune-response genes, including inflammatory cytokines. It is therefore plausible to assume that TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the substantia nigra in Parkinson disease (PD). Accordingly, recent data indicate that TLR4 is up-regulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in a mouse model of PD. Here, we wished to evaluate the role of TLR4 in the acute mouse MPTP model of PD: TLR4-deficient mice and wild-type littermates control mice were used for the acute administration way of MPTP or a corresponding volume of saline. We demonstrate that TLR4-deficient mice are less vulnerable to MPTP intoxication than wild-type mice and display a decreased number of Iba1+ and MHC II+ activated microglial cells after MPTP application, suggesting that the TLR4 pathway is involved in experimental PD. PMID- 23462813 TI - Rapid evaluation of catalysts and MAO activators by kinetics: what controls polymer molecular weight and activity in metallocene/MAO catalysts? AB - The influence of methylaluminoxane (MAO) catalyst activators of different concentrations and preparative histories on the performance of 1-hexene polymerisations was investigated by kinetic methods, using rac-Me2Si(2-Me Benz[e]Ind)2ZrCl2 as the standard catalyst precursor. Fast sampling and analysis allow the time dependence of monomer conversion and the growth of the number average polymer molecular weight to be determined at a sufficiently short timescale to make this a feasible method for routine catalyst evaluation. Differences in productivity, polymer molecular weight and active species count are shown to be primarily a linear function of the trimethylaluminium concentration. The results in toluene and heptane as solvents are compared; the data show that the inferior performance in heptane is due to a substantially lower active species concentration. PMID- 23462814 TI - Effect of surface morphology on friction of graphene on various substrates. AB - The friction of graphene on various substrates, such as SiO2, h-BN, bulk-like graphene, and mica, was investigated to characterize the adhesion level between graphene and the underlying surface. The friction of graphene on SiO2 decreased with increasing thickness and converged around the penta-layers due to incomplete contact between the two surfaces. However, the friction of graphene on an atomically flat substrate, such as h-BN or bulk-like graphene, was low and comparable to that of bulk-like graphene. In contrast, the friction of graphene folded onto bulk-like graphene was indistinguishable from that of mono-layer graphene on SiO2 despite the ultra-smoothness of bulk-like graphene. The characterization of the graphene's roughness before and after folding showed that the corrugation of graphene induced by SiO2 morphology was preserved even after it was folded onto an atomically flat substrate. In addition, graphene deposited on mica, when folded, preserved the same corrugation level as before the folding event. Our friction measurements revealed that graphene, once exfoliated from the bulk crystal, tends to maintain its corrugation level even after it is folded onto an atomically flat substrate and that ultra-flatness in both graphene and the substrate is required to achieve the intimate contact necessary for strong adhesion. PMID- 23462815 TI - Evaluation of recombinant outer membrane protein based vaccine against Salmonella Typhimurium in birds. AB - Food-borne diseases caused by Salmonella enterica from poultry sources represent an important public health problem and no reliable control by vaccination has proved effective despite research. The aim of the present study was to evaluate the use of recombinant OmpC protein for immunization of birds to elucidate its protection against virulent Salmonella Typhimurium. The recombinant OmpC protein was prepared after cloning and expressing ompC gene and was characterized by SDS PAGE and Western blot analyses. The protein preparations were tested as vaccine candidate in layer birds by comparing the immune response, protection and organ clearance against crude lysate and control. The biologically functional recombinant 43 kDa truncated OmpC protein proved to be a good immunogen which induced a significantly high humoral immune response than control. At the same time, it primed a stable cell-mediated immune response. A protective index (based on faecal shedding of organism) of rOmpC based preparations ranged between 50 and 75% as observed for 3 weeks after challenge. Therefore, the protein preparations conferred satisfactory protection against challenge infections with virulent strains of S. Typhimurium as evidenced by limited faecal shedding and minimal detection of Salmonella from edible tissues and eggs. These findings suggest the possibility to explore the use of S. enterica OMP protein for the production of novel vaccine. PMID- 23462817 TI - Xanthine oxidase inhibition attenuates skeletal muscle signaling following acute exercise but does not impair mitochondrial adaptations to endurance training. AB - The aim of this research was to examine the impact of the xanthine oxidase (XO) inhibitor allopurinol on the skeletal muscle activation of cell signaling kinases' and adaptations to mitochondrial proteins and antioxidant enzymes following acute endurance exercise and endurance training. Male Sprague-Dawley rats performed either acute exercise (60 min of treadmill running, 27 m/min, 5% incline) or 6 wk of endurance training (5 days/wk) while receiving allopurinol or vehicle. Allopurinol treatment reduced XO activity to 5% of the basal levels (P < 0.05), with skeletal muscle uric acid levels being almost undetectable. Following acute exercise, skeletal muscle oxidized glutathione (GSSG) significantly increased in allopurinol- and vehicle-treated groups despite XO activity and uric acid levels being unaltered by acute exercise (P < 0.05). This suggests that the source of ROS was not from XO. Surprisingly, muscle GSSG levels were significantly increased following allopurinol treatment. Following acute exercise, allopurinol treatment prevented the increase in p38 MAPK and ERK phosphorylation and attenuated the increase in mitochondrial transcription factor A (mtTFA) mRNA (P < 0.05) but had no effect on the increase in peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), nuclear respiratory factor-2, GLUT4, or superoxide dismutase mRNA. Allopurinol also had no impact on the endurance training-induced increases in PGC-1alpha, mtTFA, and mitochondrial proteins including cytochrome c, citrate synthase, and beta hydroxyacyl-CoA dehydrogenase. In conclusion, although allopurinol inhibits cell signaling pathways in response to acute exercise, the inhibitory effects of allopurinol appear unrelated to exercise-induced ROS production by XO. Allopurinol also has little effect on increases in mitochondrial proteins following endurance training. PMID- 23462818 TI - Comparison of the EuroSCORE II and Society of Thoracic Surgeons 2008 risk tools. AB - OBJECTIVES: Risk stratification in cardiac surgery is uniquely detailed, led latterly by the EuroSCORE and the Society of Thoracic Surgeons (STS) risk calculators. The recently published EuroSCORE II (ES2) algorithms update estimated mortality in a broad spectrum of cardiac procedures. The 2008 STS tool, in comparison, predicts multiple outcomes for specific procedures. We sought to identify and compare the external validity of both contemporaneous tools in our population. METHODS: Data from our hospital database were collated for the period February 2001 to March 2010. Logistic regression coefficients from the risk calculations were applied to the data and the results presented as receiver operating characteristic (ROC) curves. Statistical analyses were performed using the area under the ROC curve (AUROC) and the Hosmer-Lemeshow (H-L) goodness-of fit test, with comparisons using the DeLong method. RESULTS: A total of 15 497 procedures were identified, of which 14 432 were appropriate for STS risk scoring (i.e. valve and/or graft procedures with no tricuspid valve operations etc.). For all procedures, ES2 and STS were equivalent (AUROC 0.818 vs 0.805, respectively, P = 0.343). For procedures appropriate for STS risk scoring, results were similar (AUROC ES2 vs STS, 0.816 vs 0.810, P = 0.714), whereas for procedures excluded by STS, the result was marginally worse (AUROC ES2 vs STS, 0.773 vs 0.784, P = 0.751). Goodness of fit in all cases was poor, primarily where risk was higher than 15% (H-L P < 0.0001). CONCLUSIONS: EuroSCORE II and STS both provide equivalent discrimination in predicting mortality in a British population, including those undergoing procedures for which the STS does not normally predict. Accounting for decile-grouped Hosmer-Lemeshow tests not being ideal for the assessment of calibration, both tools show good calibration for patients with low to moderate risk, with divergence from ~15% predicted risk. PMID- 23462816 TI - Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II infused mice. AB - An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7-8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving beta-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid beta-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS. PMID- 23462819 TI - Re: Risk factor analysis for the recurrence of resected solitary fibrous tumours of the pleura: a 33-year experience and proposal for a scoring system. PMID- 23462821 TI - Suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation. AB - This document explains some of the relevant methodological issues involved in planning a clinical study using survival and time-to-event outcome data, particularly in the field of haematopoietic stem cell transplantation, and indicates the appropriate statistical methods to use for the analysis. As the majority of these methods are commonly used in survival and event-history analysis, this document discusses their potential and limitations with reference to common SCT research situations. Some reference is given to methods, recently appearing in the literature that may be capable of handling complex investigations. These guidelines also address various practical issues, such as recoding or transforming variables in regression models or reporting results. PMID- 23462822 TI - A planar microelectrode array for simultaneous detection of electrically evoked dopamine release from distinct locations of a single isolated neuron. AB - Neurotransmission is a key process of communication between neurons. Although much is known about this process and the influence it has on the function of the body, little is understood about the dynamics of signalling from structural regions of a single neuron. In this study we have fabricated and characterised a microelectrode array (MEA) which was utilised for simultaneous multi-site recordings of dopamine release from an isolated single neuron. The MEA consisted of gold electrodes that were created in plane with the insulation layer using a chemical mechanical planarization process. The detection limit for dopamine measurements was 11 +/- 3 nM and all the gold electrodes performed in a consistent fashion during amperometric recordings of 100 nM dopamine. Fouling of the gold electrode was investigated, where no significant change in the current was observed over 4 hours when monitoring 100 nM dopamine. The MEA was accessed using freshly isolated dopaminergic somas from the pond snail, Lymnaea stagnalis, where electrically evoked dopamine release was clearly observed. Measurements were conducted at four structural locations of a single isolated neuron, where electrically evoked dopamine release was observed from the cell body, axonal regions and the terminal. Over time, the release of dopamine varied over the structural regions of the neuron. Such information can provide an insight into the signalling mechanism of neurons and how they potentially form synaptic connections. PMID- 23462823 TI - A new technique of branched stent graft treatment for ruptured thoracoabdominal aortic aneurysms. AB - Endovascular repair of thoracoabdominal aortic aneurysms (TAAAs) using a branched stent graft is a technically challenging procedure. A 64-year-old man with multiple medical problems, including severe renal impairment, is presented with a ruptured type IV TAAA. He underwent emergency repair using an off-the-shelf branched stent graft and carbon dioxide as the exclusive contrast agent. PMID- 23462824 TI - No-go theorem for passive single-rail linear optical quantum computing. AB - Photonic quantum systems are among the most promising architectures for quantum computers. It is well known that for dual-rail photons effective non-linearities and near-deterministic non-trivial two-qubit gates can be achieved via the measurement process and by introducing ancillary photons. While in principle this opens a legitimate path to scalable linear optical quantum computing, the technical requirements are still very challenging and thus other optical encodings are being actively investigated. One of the alternatives is to use single-rail encoded photons, where entangled states can be deterministically generated. Here we prove that even for such systems universal optical quantum computing using only passive optical elements such as beam splitters and phase shifters is not possible. This no-go theorem proves that photon bunching cannot be passively suppressed even when extra ancilla modes and arbitrary number of photons are used. Our result provides useful guidance for the design of optical quantum computers. PMID- 23462825 TI - Mid Staffs inquiry. Culture change is not easy but not that difficult. PMID- 23462827 TI - Menopause: an important milestone in women's health. AB - Menopause, a natural process in a woman's life, is defined as the cessation of menstrual period for 12 consecutive months. In Singapore, the average age of natural menopause is 49 years of age. We discuss the challenges faced by menopausal women and provide an example of a holistic approach to the management of women during this important stage of their lives. PMID- 23462828 TI - Comparison of results from novice and trained personnel using the Macintosh laryngoscope, Pentax AWS(r), C-MACTM and Bonfils intubation fibrescope: a manikin study. AB - INTRODUCTION: Indirect laryngoscopes offer improved laryngeal view and higher success rates of intubation, particularly for difficult airways. We hypothesised that: (a) the time required for intubation, overall success rates and ease of intubation with indirect laryngoscopes would be better than with the Macintosh laryngoscope; and (b) novices may achieve higher success rates and intubate faster using indirect laryngoscopes. METHODS: In a cross-sectional observational study, 13 novices and 13 skilled anaesthetists were recruited. Participants were compared when intubating a manikin simulating normal and difficult airway scenarios using the Macintosh laryngoscope, Pentax Airway Scope(r) (AWS), C MAC[TM] and Bonfils intubation fibrescope. RESULTS: There was no significant difference in intubation success rates between the groups. Skilled anaesthetists intubated faster than novices with Pentax AWS in the difficult airway scenario (22 s vs. 33 s, p = 0.047). The mean intubation times for C-MAC and Pentax AWS were shorter than for the Macintosh laryngoscope and Bonfils intubation fibrescope in both difficult (C-MAC: 24 s, Pentax AWS: 28 s, Macintosh: 80 s, Bonfils: 61 s; p < 0.001) and normal (C-MAC: 17 s, Pentax AWS: 19 s, Macintosh: 39 s, Bonfils: 38 s; p = 0.002) airway scenarios. CONCLUSION: We found that intubation success was more than 85% with all indirect laryngoscopes compared to 69% for the Macintosh laryngoscope. Both C-MAC and Pentax AWS achieved faster intubation times compared to the Macintosh laryngoscope and Bonfils intubation fibroscope for both airway scenarios. Skilled anaesthetists were 33% faster than novices when intubating a difficult airway using Pentax AWS. PMID- 23462829 TI - Audits and critical incident reporting in paediatric anaesthesia: lessons from 75,331 anaesthetics. AB - INTRODUCTION: This study reports our experience of audit and critical incidents observed by paediatric anaesthetics from 2000 to 2010 at a paediatric teaching hospital in Singapore. METHODS: Data pertaining to patient demographics, practices and critical incidents during anaesthesia and in the perioperative period were prospectively collected via an audit form and retrospectively analysed thereafter. RESULTS: A total of 2,519 incidents were noted at the 75,331 anaesthetics performed during the study period. There were nine deaths reported. The majority of incidents reported were respiratory critical incidents (n = 1,757, 69.8%), followed by cardiovascular incidents (n = 238, 9.5%). Risk factors for critical incidents included age less than one year, and preterm and former preterm children. CONCLUSION: Critical incident reporting has value, as it provides insights into the system and helps to identify active and system errors, thus enabling the formulation of effective preventive strategies. By creating and maintaining an environment that encourages reporting, we have maintained a high and consistent reporting rate through the years. The teaching of analysis of critical incidents should be regarded by all clinicians as an important tool for improving patient safety. PMID- 23462830 TI - Incidence of phantom limb phenomena after lower limb amputations in a Singapore tertiary hospital. AB - INTRODUCTION: Phantom limb sensations (PLS), phantom limb pain (PLP) and stump pain (SP) are well-recognised postamputation phenomena. However, there is a dearth of related epidemiological data in Asian populations. This study was conducted to fill the information gap. METHODS: Telephone interviews were conducted with patients who underwent lower limb amputations at a tertiary hospital in Singapore. Information was obtained on phantom limb characteristics, perioperative pain and functional assessment. RESULTS: A total of 159 patients underwent amputations over a 31-month period. At the time of the interview, 47 patients had died and 66 were contactable, of whom 49 patients were interviewed. Of these, 31 (63%) patients experienced PLS. 22 patients had postoperative pain, with 9 having both PLP and SP, 3 having PLP alone and 10 having SP alone. Among the 12 patients with PLP, at least 6 (50%) experienced constant or daily pain and 7 (58%) scored their pain as moderate-to-severe. Among those with PLP and/or SP (n = 22), 5 were distressed by the pain, 11 were on analgesics and 3 received medical follow-up. 7 (32%) patients reported functional limitations secondary to PLP or SP. Altogether, 28 (57%) patients were wheelchair or bed bound. CONCLUSION: The incidence of PLP was 25% in our cohort. Although this is lower than that reported in other studies, it remains significant, as some patients suffered moderate-to-severe pain. The difference in incidence may be due to differences in the ethnic composition and/or indications for amputation in our group. Follow-up and care could improve the outcomes in these patients. PMID- 23462831 TI - Bell's palsy in Singapore: a view from the patient's perspective. AB - INTRODUCTION: Bell's palsy is a well-recognised disease with robust research on its possible aetiologies and epidemiology, but scant information on patients' concerns and concepts regarding the condition is available. We aimed to evaluate the ideas, concerns and expectations of patients with Bell's palsy in Singapore. METHODS: A cross-sectional study was conducted at a single tertiary-care hospital in Singapore. Participants were all patients with newly diagnosed Bell's palsy referred to the otolaryngology department either from the emergency department or by general practitioners. Participants were given a self-administered questionnaire and their facial nerve palsies were graded by the consultant doctor. RESULTS: A total of 52 patients were recruited, of which 41 were available for analysis. 78.0% of patients were concerned that they were having a stroke upon presentation of the symptoms. Other beliefs about the cause of the disease included overwork or stress (36.6%), something that the patient had eaten (9.8%) and supernatural forces (2.4%). About 50% of patients had tried some form of complementary or alternative therapy other than the steroids/medicines prescribed by their general practitioner or emergency physician. While 39.0% of patients agreed that the Internet had helped them understand more about their condition in addition to the information provided by the physician, 9.8% of them specifically disagreed with this statement. CONCLUSION: We have found that patients with Bell's palsy in Singapore are not very knowledgeable about the disease. Although the Internet is a useful resource, a physician's explanation of the disease and its natural progression remains of utmost importance. PMID- 23462832 TI - Raised troponin I in Chinese patients with acute pulmonary embolism suggests complicated clinical course and may predict intensive care unit admission. AB - INTRODUCTION: Acute pulmonary embolism (PE) is an uncommon but potentially fatal disease. Acute right ventricular failure, which can be demonstrated by echocardiography, is known to be an adverse prognostic factor in patients with acute PE. However, this diagnostic test is not always available in emergency departments and it is also an operator-dependent investigation. This study aimed to investigate whether cardiac troponin I (cTnI) levels could predict clinical outcomes in Chinese patients with PE. METHODS: This was a retrospective cohort study performed in a tertiary regional hospital in Hong Kong. For this study, 100 patients who were diagnosed with acute PE between January 1, 2002 and December 31, 2009 were recruited. Information, including demographic data, presenting symptoms and vital signs at presentation, predisposing factors for PE, results of diagnostic procedures and clinical outcomes, was collected from the medical records of these patients. RESULTS: 71% of recruited patients had elevated cTnI levels. High cTnI levels were associated with haemodynamic instability (odds ratio [OR] 5.30, 95% confidence interval [CI] 1.32-27.71; p = 0.019) and complicated clinical course (OR 6.34, 95% CI 1.76-22.9; p = 0.002). CONCLUSION: Elevated cTnI level was associated with a complicated clinical course in patients with acute PE. We suggest that measurements of cTnI levels be used for the early risk stratification of patients with PE in the emergency departments of hospitals. PMID- 23462833 TI - Hypolipidaemic and anti-inflammatory effects of fixed dose combination of atorvastatin plus ezetimibe in Indian patients with dyslipidaemia. AB - INTRODUCTION: We aimed to assess the efficacy of fixed dose combination of atorvastatin plus ezetimibe in Indian patients with dyslipidaemia. METHODS: A double-blind study was conducted to assess the effect of fixed dose combination of ezetimibe 10 mg plus atorvastatin 10 mg on lipid profile, oxidised low-density lipoprotein (ox-LDL), high-sensitivity C-reactive protein (hsCRP) and soluble intercellular cell adhesion molecule (sICAM) in dyslipidaemic patients with or at high risk of coronary artery disease, and compare it with atorvastatin 10 mg monotherapy. 30 patients were randomised to receive ezetimibe plus atorvastatin or atorvastatin once daily for four weeks. RESULTS: Of the 30 patients, 10 men and 5 women (mean age 54.3 +/- 1.6 years) received ezetimibe plus atorvastatin, while 13 men and 2 women (mean age 53.7 +/- 2.8 years) received only atorvastatin. The combination treatment significantly reduced total cholesterol (percentage treatment difference -14.4 +/- 6.5, 95% confidence interval [CI] -1.0 to -27.7; p = 0.041) and LDL cholesterol (LDL-C; percentage treatment difference 19.9 +/- 6.1, 95% CI -7.4 to -32.4; p = 0.003) compared to atorvastatin monotherapy. 13 patients on combination treament achieved the National Cholesterol Education Program target for LDL-C as compared to 9 patients on atorvastatin monotherapy (p = 0.032). Significant reductions in very low-density lipoprotein cholesterol, triglyceride, ox-LDL and sICAM were observed with combination treatment compared to atorvastatin monotherapy. However, no significant change was seen in high-density lipoprotein cholesterol or hsCRP levels between the two groups. CONCLUSION: Combination treatment with atorvastatin and ezetimibe had relatively better lipid-lowering and anti inflammatory efficacy than atorvastatin monotherapy. PMID- 23462834 TI - Evaluation of the National Cervical Cancer Screening Programme in Singapore. AB - INTRODUCTION: A retrospective observational study was performed to evaluate the effectiveness of CervicalScreen Singapore (CSS), a National Cervical Cancer Screening Programme. METHODS: National trends on incidence, mortality of cervical cancer and carcinoma in situ of the cervix before and after the launch of CSS were examined. Linear regression was used to calculate the average annual percentage change in age-standardised incidence and mortality rates. We also examined the operational measures of CSS, such as the women who joined the CSS programme and the diagnostic accuracy of Pap smears. The study was confined to women who consented to join CSS at government-funded polyclinics. RESULTS: Nationally, there was a greater decline in the age-standardised incidence and mortality rates in the period 2004-2008 as compared to the period 1987-2003. Under CSS, a total of 99,759 Pap smears were performed on 81,087 women in the period 2004-2008. However, the number of first screens decreased from 18,434 in 2004 to 11,624 in 2008. Among women aged 25-69 years who had their first Pap smear screening and who were recommended for routine rescreen in three years, 10% had a subsequent rescreen within three years. Overall, the CSS programme was able to detect 0.37 invasive cancers per 1,000 screens in women aged 25-69 years. CONCLUSION: The CSS programme has contributed to a decline in the mortality and incidence of cervical cancer in Singapore. However, the challenges of increasing the screening uptake among eligible women need to be addressed. PMID- 23462835 TI - The anatomical safe zone for medial opening oblique wedge high tibial osteotomy. AB - INTRODUCTION: The end of medial opening oblique wedge high tibial osteotomy (HTO) points into a narrow area between the articular cartilage of the posterolateral proximal tibia and proximal tibiofibular joint (PTFJ) at the tibial site, which is an anatomical safe zone (ASZ) for osteotomy. We studied the ASZ and its relation to the fibular tip, including the level of posterior cruciate ligament (PCL) insertion, to avoid penetration into the knee and PTFJ, and PCL injury by osteotomy. METHODS: Ten pairs of embalmed cadaveric legs were disarticulated at the knee joint and then examined. Soft tissues at the proximal tibia were removed. The posterior capsule of the PTFJ was incised to identify the articular cartilage of the PTFJ at the tibial site. The height of the fibular tip and the thickness of the ASZ were measured and calculated to determine the relationship between the ASZ and fibular tip. The level of PCL insertion was measured from the posterior articular surface of the proximal tibia to the distal attachment of the PCL. RESULTS: The average height of the fibular tip and the thickness of the ASZ were 5.43 +/- 1.53 mm and 4.12 +/- 1.60 mm, respectively. On average, the fibular tip was 1.31 +/- 1.28 mm higher than the ASZ, and the level of PCL insertion was 10.10 +/- 1.88 mm. CONCLUSION: To ensure safety during medial opening oblique wedge HTO, the end of osteotomy should point accurately into the ASZ at a level just below the fibular tip as reference. Proximal osteotomy thickness should not be less than 10 mm at the level of PCL insertion. PMID- 23462836 TI - Clinics in diagnostic imaging (144). Lateral meniscal ossicle. AB - A 35-year-old female patient with previous left knee anterior cruciate ligament repair for a skiing injury presented six years later with a traumatic lateral patellar subluxation. Radiographs and magnetic resonance imaging of her left knee joint showed an ossific structure in the region of the lateral meniscus. This was diagnosed as a meniscal ossicle and confirmed during successful arthroscopic excision. The imaging features of meniscal ossicles are reported. PMID- 23462837 TI - Cavernoma of the conus medullaris mimicking transverse myelitis. AB - We present an interesting case of conus medullaris cavernoma that was initially treated as transverse myelitis. Haemorrhagic lumbar puncture led us to perform magnetic resonance (MR) imaging, which showed the presence of a cavernous angioma at the D12-L1 level. The total excision of the lesion was followed by dramatic improvement. We suggest that MR imaging be performed early in all suspected cases of transverse myelitis so that emergency surgical intervention can be offered before the development of permanent neurological deficits. PMID- 23462838 TI - Computed tomographic findings of cerebral fat embolism following multiple bone fractures. AB - Fat embolism to the lungs and brain is an uncommon complication following fractures. Few reports with descriptions of computed tomographic (CT) findings of emboli to the brain or cerebral fat embolism are available. We report a case of cerebral fat embolism following multiple skeletal fractures and present its CT findings here. PMID- 23462839 TI - Lipid-rich variant of pancreatic endocrine tumour with inhibin positivity and microscopic foci of microcystic adenoma-like areas: emphasis on histopathology. AB - Pancreatic endocrine tumours (PETs) are uncommon tumours with typical morphology characterised by relatively uniform cuboidal cells arranged in nests and festoons, with distinctive nuclear salt-and-pepper chromatin. A lipid-rich variant poses diagnostic difficulties in the midst of other pancreatic tumours and metastatic goblet cell carcinoid. A 22-year-old man presented with symptoms of abdominal pain and jaundice. His liver function test and blood glucose level were normal, but computed tomography of the abdomen suggested the presence of a tumour in the head of the pancreas. Specimen obtained by pancreaticoduodenectomy revealed an infiltrating yellow-tan tumour composed of nests and a cribriform arrangement of polygonal vacuolated cells with pyknotic nuclei, along with focal classical areas of PET. Two foci of early serous microcystic adenoma were seen. Immunohistochemistry contributed to the arrival of a conclusive diagnosis. Von Hippel-Lindau disease was excluded in our patient, as other supportive classical features of the syndrome were absent. PMID- 23462840 TI - Regular paracetamol in severe dengue: a lethal combination? AB - An eight-month-old female infant with severe dengue disease, who was repeatedly given therapeutic paracetamol for severe dengue, developed fulminant liver failure with encephalopathy, gastrointestinal haemorrhage and severe coagulopathy. She responded to supportive measures and N-acetylcysteine infusion. This case highlights the potential danger of administering repeated therapeutic doses of paracetamol in childhood severe dengue disease with hepatitis. PMID- 23462841 TI - The femur: a good alternative source of bone graft using a new reamer system when options run out. AB - Following a post-traumatic incident, orthopaedic surgeons often struggle to look for an abundant source of alternative bone graft because the bone defect is too big or when nonunion is refractory to treatment. We present two cases where the patients' bone grafts were harvested from the healthy femur. This process involved the use of a new intramedullary reamer, which allowed the bone graft to be harvested simultaneously during the reaming process. PMID- 23462842 TI - Idiopathic spinal cord herniation. AB - Idiopathic spinal cord herniation (ISCH) is a rare cause of progressive myelopathy. This condition has recently seen an increased frequency of diagnosis, possibly due to increased awareness and the use of magnetic resonance (MR) imaging. ISCH is characterised by herniation of the thoracic spinal cord through an anterior or anterolateral dural defect. Patients usually present with a Brown Sequard-like syndrome, which is gradually progressive and may evolve into severe paraparesis. This disease has a characteristic radiological appearance, and in most cases, excellent postsurgical outcome. We report ISCH and its imaging appearance in a 31-year-old woman with classical presentation, and discuss the current concepts regarding the aetiopathogenesis, radiological features and management of the disease. PMID- 23462843 TI - Artefactual spikes in electrocardiography: a worthwhile introspection. AB - Electrical devices, which have become an integral part of our daily life, may influence the electrical recording of the heart. These disturbances from external sources outside of the heart's own activity produce changes in the electrocardiography (ECG) of the patient, simulating rhythmic disturbances of the heart. Understanding these disturbances is essential in order to better interprete the ECG. Common sources of electrical interferences include external devices, such as alternating current and improper earthing, and surgical procedures like diathermy. We report a case of electrical interference in a patient's ECG due to an inserted bladder stimulator. This case report highlights the importance of precise identification of artefacts in the interpretation of ECG, as well as prompt localisation and elimination of the source of interference. PMID- 23462844 TI - Ion-exchanged route synthesis of Fe2N-N-doped graphitic nanocarbons composite as advanced oxygen reduction electrocatalyst. AB - Fe2N nanoparticles and nitrogen-doped graphitic nanosheet composites (Fe2N-NGC) have been synthesized by an ion-exchanged route, which can serve as an efficient non-precious metal electrocatalyst with a 4e(-) reaction pathway for oxygen reduction reactions (ORR). PMID- 23462848 TI - Phthalide: a direct building-block towards P,O and P,N hemilabile ligands. Application in the palladium-catalysed Suzuki-Miyaura cross-coupling of aryl chlorides. AB - The direct synthesis of new hemilabile ligands from the economical, readily available lactone phthalide is described. Pd-complexes of one such ligand were found highly effective in general Suzuki-Miyaura cross-coupling reactions, including deactivated and hindered aryl chlorides. PMID- 23462847 TI - Studying permethrin exposure in flight attendants using a physiologically based pharmacokinetic model. AB - Assessment of potential health risks to flight attendants from exposure to pyrethroid insecticides, used for aircraft disinsection, is limited because of (a) lack of information on exposures to these insecticides, and (b) lack of tools for linking these exposures to biomarker data. We developed and evaluated a physiologically based pharmacokinetic (PBPK) model to assess the exposure of flight attendants to the pyrethroid insecticide permethrin attributable to aircraft disinsection. The permethrin PBPK model was developed by adapting previous models for pyrethroids, and was parameterized using currently available metabolic parameters for permethrin. The human permethrin model was first evaluated with data from published human studies. Then, it was used to estimate urinary metabolite concentrations of permethrin in flight attendants who worked in aircrafts, which underwent residual and pre-flight spray treatments. The human model was also applied to analyze the toxicokinetics following permethrin exposures attributable to other aircraft disinsection scenarios. Predicted levels of urinary 3-phenoxybenzoic acid (3-PBA), a metabolite of permethrin, following residual disinsection treatment were comparable to the measurements made for flight attendants. Simulations showed that the median contributions of the dermal, oral and inhalation routes to permethrin exposure in flight attendants were 83.5%, 16.1% and 0.4% under residual treatment scenario, respectively, and were 5.3%, 5.0% and 89.7% under pre-flight spray scenario, respectively. The PBPK model provides the capability to simulate the toxicokinetic profiles of permethrin, and can be used in the studies on human exposure to permethrin. PMID- 23462849 TI - Effects of resveratrol on topoisomerase II-alpha activity: induction of micronuclei and inhibition of chromosome segregation in CHO-K1 cells. AB - In recent years, a great interest has emerged in resveratrol (RSV) activity in the prevention of various pathologies including cancer. We recently showed that RSV is able to interfere with topoisomerase II-alpha (TOPO2) activity in cancer cells, thus inducing a delay in S-phase progression with concomitant phosphorylation of the histone H2AX. TOPO2 is mainly active in proliferating cells and is involved in the resolution of supercoiled DNA and chromosome segregation during mitosis. Here, we studied the effects of RSV in CHO-K1 cells concerning to chromosome damage and segregation as a consequence of TOPO2 inhibition. We show an increase in micronuclei and in polyploid and endoreduplicated cells due to incorrect chromosome segregation. Furthermore, since incomplete segregation can also affect the normal distribution of mitotic figures, we checked mitosis progression showing an increase in metaphase in relation to ana-telophase after RSV treatment. On the whole, our data show that RSV affects chromosome stability and segregation in proliferating cells, probably interfering with TOPO2 activity. PMID- 23462850 TI - High-throughput comet assay using 96 minigels. AB - The single-cell gel electrophoresis--the comet assay--has proved to be a sensitive and relatively simple method that is much used in research for the analysis of specific types of DNA damage, and its use in genotoxicity testing is increasing. The efficiency of the comet assay, in terms of number of samples processed per experiment, has been rather poor, and both research and toxicological testing should profit from an increased throughput. We have designed and validated a format involving 96 agarose minigels supported by a hydrophilic polyester film. Using simple technology, hundreds of samples may be processed in one experiment by one person, with less time needed for processing, less use of chemicals and requiring fewer cells per sample. Controlled electrophoresis, including circulation of the electrophoresis solution, improves the homogeneity between replicate samples in the 96-minigel format. The high throughput method described in this paper should greatly increase the overall capacity, versatility and robustness of the comet assay. PMID- 23462851 TI - Thirdhand smoke causes DNA damage in human cells. AB - Exposure to thirdhand smoke (THS) is a newly described health risk. Evidence supports its widespread presence in indoor environments. However, its genotoxic potential, a critical aspect in risk assessment, is virtually untested. An important characteristic of THS is its ability to undergo chemical transformations during aging periods, as demonstrated in a recent study showing that sorbed nicotine reacts with the indoor pollutant nitrous acid (HONO) to form tobacco-specific nitrosamines (TSNAs) such as 4-(methylnitrosamino)-4-(3 pyridyl)butanal (NNA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The goal of this study was to assess the genotoxicity of THS in human cell lines using two in vitro assays. THS was generated in laboratory systems that simulated short (acute)- and long (chronic)-term exposures. Analysis by liquid chromatography-tandem mass spectrometry quantified TSNAs and common tobacco alkaloids in extracts of THS that had sorbed onto cellulose substrates. Exposure of human HepG2 cells to either acute or chronic THS for 24h resulted in significant increases in DNA strand breaks in the alkaline Comet assay. Cell cultures exposed to NNA alone showed significantly higher levels of DNA damage in the same assay. NNA is absent in freshly emitted secondhand smoke, but it is the main TSNA formed in THS when nicotine reacts with HONO long after smoking takes place. The long amplicon-quantitative PCR assay quantified significantly higher levels of oxidative DNA damage in hypoxanthine phosphoribosyltransferase 1 (HPRT) and polymerase beta (POLB) genes of cultured human cells exposed to chronic THS for 24h compared with untreated cells, suggesting that THS exposure is related to increased oxidative stress and could be an important contributing factor in THS mediated toxicity. The findings of this study demonstrate for the first time that exposure to THS is genotoxic in human cell lines. PMID- 23462852 TI - Multiple cytotoxic and genotoxic effects induced in vitro by differently shaped copper oxide nanomaterials. AB - In nanotoxicology, the capacity of nanoparticles of the same composition but different shape to induce cytotoxicity and genotoxicity is largely unknown. A series of cytotoxic and genotoxic responses following in vitro exposure to differently shaped CuO nanoparticles (CuO NPs, mass concentrations from 0.1 to 100 MUg/ml) were assessed in murine macrophages RAW 264.7 and in peripheral whole blood from healthy volunteers. Cytotoxicity, cytostasis and genotoxicity were evaluated by the colorimetric assay of formazan reduction [3-[4,5-dimethylthiazol 2-yl]-2,5-diphenyl tetrazolium bromide (MTT)] and by the cytokinesis-block micronucleus cytome (CBMN Cyt) assay. The comet assay was applied for detecting DNA strand breaks and information on oxidative damage to DNA (oxidised purines and pyrimidines). The MTT assay revealed a decrease in cell viability in RAW 264.7 cells and peripheral blood lymphocytes (PBL) with significant dose-effect relationships for the different CuO NP shapes. The comet assay revealed a dose dependent increase in primary DNA damage, and a significant increase in oxidative damage to DNA was also detectable, as well as increased frequency of micronuclei in binucleated cells, often in a dose-related manner. Proliferative activity, cytotoxicity and apoptotic markers showed a significant trend in the two cell types. Finally, we have differentiated clastogenic events from aneugenic events by fluorescence in situ hybridisation with human and murine pancentromeric probes, revealing for the first time characteristic aneugenic responses related to the shape of CuO NPs and cell type. Independently of size and shape, all CuO NPs revealed a clear-cut cytotoxic and genotoxic potential; this suggests that CuO NPs are good candidates for positive controls in nanotoxicology. PMID- 23462855 TI - Steroid management in newly diagnosed glioblastoma. AB - Glucocorticoids ameliorate neurologic symptoms in patients with glioblastoma, but their adverse effects limit long-term use. This study sought to identify factors associated with steroid taper success or failure in the early stages of glioblastoma treatment. We retrospectively reviewed steroid prescribing practices from date of surgery until one month following radiotherapy (RT) completion among 85 patients with newly diagnosed glioblastoma who were treated on a prospective clinical trial with RT and temozolomide. Sufficient information on steroid dosing was available in 72 patients included in the final analysis. The mean age was 54 years, and 65 % were men. Thirty-nine percent had a gross-total resection. Fifteen patients (21 %) tolerated steroid taper without requiring dose increase during the study. Men and patients with Karnofsky performance scale 90-100 were more likely to have a successful steroid taper. The most common symptom of taper failure was headache, but the reason for steroid increase differed among the different time intervals examined: worsening neurologic deficit in the early post operative period, headache and non-focal symptoms during RT, and headache and seizure post-RT. Of the 50 patients in whom steroid use during RT was known, 36 (72 %) underwent dose reduction and of those, 21 (58 %) required an increase. The successful early taper of steroids in glioblastoma was associated with male gender and better functional status. Steroids are often tapered during RT, but there is frequent taper failure with this approach. A prospective trial with standardized steroid dosing regimens would be needed to verify these findings. PMID- 23462853 TI - The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer. AB - Our group has previously published the Diagnosis-Specific Graded Prognostic Assessment (GPA) showing the prognostic factors associated with survival in patients with brain metastases (BM). The purpose of this study is to investigate the relationship of breast cancer subtype to the time interval from primary diagnosis (PD) to development of BM (TPDBM), number of BM at initial BM presentation and survival. We analyzed our previously described multi institutional retrospective database of 865 breast cancer patients treated for newly-diagnosed BM from 1993 to 2010. Several factors found to be associated with survival were incorporated into the Breast-GPA, including tumor subtype. The GPA database was further analyzed to determine if the subtype correlated with the TPDBM, number of BM, and survival from PD. After exclusions for incomplete data, 383 patients remained eligible for analysis. The subtypes were approximated as follows: Luminal B: triple positive; HER2: HER2 positive/ER/PR negative; Luminal A; ER/PR positive/HER2 negative; Basal: triple negative. Patients with Basal (90), HER2 (119), Luminal B (98) and Luminal A (76) tumor subtypes had a median TPDBM of 27.5, 35.8, 47.4 and 54.4 months (p < 0.01), median survival from PD of 39.6, 66.4, 90.3 and 72.7 months (p < 0.01) and median survival from BM of 7.3, 17.9, 22.9 and 10.0 months (p < 0.01), respectively. Tumor subtype is an important prognostic factor for survival in patients with breast cancer and BM. Although TPDBM is not an independent prognostic factor for survival (and thus not part of the Breast-GPA), the TPDBM does correlate with tumor subtype but does not correlate with the number of BM. Patients with Basal and HER2 tumor subtypes have short TPDBM. Prospective studies are needed to determine if screening brain MRIs are indicated in patients with Basal or HER2 subtypes. PMID- 23462854 TI - Retrospective analysis of treatment outcome of pediatric ependymomas in Korea: analysis of Korean multi-institutional data. AB - We analyzed the treatment outcomes of intracranial ependymomas in Korean children aged <18 years. Data for 96 patients were collected from five hospitals. Survival rates were calculated using the Kaplan-Meier method. Log-rank tests for univariate analyses and Cox regression model for multivariate analysis were conducted to identify prognostic factors for survival. The median age of the patients was 4 years (range, 0.3-17.9 years). The median follow-up was 55 months (range, 2-343 months). Age <3 years was an important factor for selecting adjuvant therapy after surgery. Among children aged <3 and >= 3 years, adjuvant radiotherapy (RT) was applied to 55 and 84 %, respectively, and adjuvant chemotherapy to 52 and 10 %, respectively. The 5 year local progression-free survival (LPFS), disease-free survival (DFS), and overall survival (OS) rates were 54, 52, and 79 %, respectively. Gross total resection was the most significant prognostic factor for all survival endpoints. Age >= 3 years and RT were significant prognostic factors for superior LPFS and DFS. However, the significance of age was lost in multivariate analysis for DFS. LPFS, DFS, and OS were superior in patients who started RT within 44 days after surgery (the median time) than in patients who started RT later in the patients aged >= 3 years. Postoperative RT was a strong prognostic factor for intracranial ependymomas. Our results suggest that early use of RT is an essential component of treatment, and should be considered in young children. PMID- 23462856 TI - Impact of different protocols of nutritional supplements on the status of vitamin A in class III obese patients after Roux-en-Y gastric bypass. AB - BACKGROUND: This study aims to investigate the nutritional status of vitamin A (VA) using biochemical and functional indicators in subjects with class III obesity, before and after RYGB, supplemented with three protocols. METHODS: The sample comprised 90 patients, with BMI >=40 kg/m(2), divided into three groups: G1 that received routine supplementation containing 5,000 IU of retinol daily; G2 that received 10,000 IU of retinol daily; and G3 that received routine supplementation plus complementary of 50,000 IU of retinol intramuscularly every month. The status of VA was evaluated before (T0), 30 days (T1), and 180 days (T2) after surgery. RESULTS: The vitamin A deficiency (VAD) in G1, G2, and G3 was respectively 20.7, 21.2, and 20.2 % as regards retinol and 37.8, 63.3, and 40 % as regards beta-carotene in T0; 26.7, 10, and 23.4 % as regards retinol and 68, 37, and 32 % as regards beta-carotene in T1; and 21, 8.7, and 20.2 % as regards retinol and 63.3, 20, and 32 % as regards beta-carotene in T2. A reduction of retinol and beta-carotene with increasing BMI and waist circumference was observed in T0. The prevalence of night blindness (XN) in groups 1, 2, and 3 was respectively 23.3, 26.7, and 16.7 % in T0; 56.7, 40, and 60 % in T1; and 70, 43, and 63.3 % in T2. CONCLUSION: The study showed high prevalence of VAD. Among the supplementation protocols used, the one containing 10,000 IU of retinol showed the best impact. However, in cases of more severe VAD, intramuscular supplementation should be considered. The prevalence of XN, justifies attention to this segment of population. PMID- 23462857 TI - Laparoscopic sleeve gastrectomy for morbid obesity: 5 years experience from an Asian center of excellence. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is emerging as a popular "stand alone" bariatric procedure. We report our 5 years experience with LSG as a single stage bariatric procedure with which to study the technical progress, learning curve, complications, and follow-up results. METHODS: Prospectively collected data of 228 patients (145 females and 83 males), who underwent LSG for morbid obesity, from February 2007 to March 2012, was retrospectively analyzed. RESULTS: The mean age was 34.68 years (range, 18-62 years) and the mean preoperative body mass index (BMI) was 37.42 +/- 4.75 kg/m(2) (range, 32.08-65.69 kg/m(2)). Mean operative time was 60.63 +/- 27.37 min. The mean BMI decreased to 26.15 +/- 3.71 kg/m(2) at 3 years (p < 0.001) and to 27.94 +/- 4.08 kg/m(2) at 5 years (p < 0.001). Mean percentage excess weight loss was 71.96 +/- 21.30 % at 3 years and 63.71 +/- 20.08 % at 5 years. The 30-day readmission rate was 3.07 %.Overall complication rate was 4.3 %, including strictures, leaks, peritonitis, gastrocutaneous fistula, and one (0.43 %) mortality. One patient with weight regain and another with stricture underwent conversion to Roux-en-Y gastric bypass. Complication rates significantly decreased after the first 50 cases (p = 0.022), suggesting an initial learning curve. Resolution of diabetes, hypertension, and hyperlipidemia was 66.67, 100, and 50 %, respectively, at 5 years. CONCLUSIONS: LSG as a single-stage bariatric procedure is safe and durable, achieving weight loss and resolution of comorbidities up to 5 years. Adherence to technical details is pivotal in reducing complications associated with the initial learning phase. PMID- 23462858 TI - Laparoscopic removal of poor outcome gastric banding with concomitant sleeve gastrectomy. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has a significant incidence of long-term failure, which may require an alternative revisional bariatric procedure to remediate. Unfortunately, there is few data pinpointing which specific revisional procedure most effectively addresses failed gastric banding. Recently, it has been observed that laparoscopic sleeve gastrectomy (LSG) is a promising primary bariatric procedure; however, its use as a revisional procedure has been limited. This study aims to evaluate the safety and efficacy of LSG performed concomitantly with removal of a poor-outcome LAGB. METHODS: A retrospective review was performed on patients who underwent LAGB removal with concomitant LSG at King Saud University in Saudi Arabia between September 2007 and April 2012. Patient body mass index (BMI), percentage of excess weight loss (%EWL), duration of operation, length of hospital stay, complications after LSG, and indications for revisional surgery were all reviewed and compared to those of patients who underwent LSG as a primary procedure. RESULTS: Fifty-six patients (70 % female) underwent conversion of LAGB to LSG concomitantly, and 128 (66 % female) patients underwent primary LSG surgery. The revisional and primary LSG patients had similar preoperative ages (mean age 33.5 +/- 10.7 vs. 33.6 +/- 9.0 years, respectively; p = 0.43). However, revisional patients had a significantly lower BMI at the time of surgery (44.4 +/- 7.0 kg/m(2) vs. 47.9 +/- 8.2; p < 0.01). Absolute BMI postoperative reduction at 24 months was 14.33 points in the revision group and 18.98 points in the primary LSG group; similar %EWL was achieved by both groups at 24 months postoperatively (80.1 vs. 84.6 %). Complications appeared in two (5.5 %) revisional patients and in nine (7.0 %) primary LSG patients. No mortalities occurred in either group. CONCLUSIONS: Conversion of LAGB by means of concomitant LSG is a safe and efficient procedure and achieves similar outcomes as primary LSG surgery alone. PMID- 23462859 TI - Anatomical basis for the low incidence of internal hernia after a laparoscopic Roux-en-Y gastric bypass without mesenteric closure. AB - BACKGROUND: Different techniques have been designed to reduce the rate of internal hernia (IH) after laparoscopic bariatric surgery, and mesenteric closure is possibly the most controversial. We propose a laparoscopic Roux-en-Y gastric bypass (LRYGB) procedure without mesenteric closure with several specific technical details to avoid IH. To support this view, we have reviewed the outcome of our LRYGB patients and have carried out an anatomical study on cadavers. METHODS: A retrospective observational study was carried out using the Unit's prospective database. The patients selected were those who were operated on for morbid obesity using LRYGB and who presented to the Emergency Unit with symptoms of intestinal obstruction (IO). Data concerning demographics, weight progress, technical details of the surgery, follow-up percentage, morbidity, and mortality were collected. Furthermore, an anatomical model was made in order to recreate the surgery on cadavers. RESULTS: Only 1.6 % of postoperative IO and very few (0.3 %) of IH cases were associated with our technique of LRYGB without mesenteric closure. The anatomical model showed two large potential hernia spaces, but their supramesocolic situation, the orientation of the bowel loops, leaving the mesentery and omentum undivided and the antecolic passage of the alimentary limb made intestinal herniation difficult even though the mesenteric spaces were not closed. CONCLUSIONS: With a proper technique, the closure of mesenteric spaces after a LRYGB is not essential to avoid postoperative IH in bariatric patients, as evidenced in an anatomical model. PMID- 23462860 TI - Timing of pregnancy after gastric bypass-a national register-based cohort study. AB - BACKGROUND: Current recommendations suggest postponing pregnancy by at least 1 year after gastric bypass. During the first postoperative year, women are in a catabolic phase with a rapid weight loss which may increase the risk of adverse pregnancy and neonatal outcomes. This study tested the hypothesis that the risk of adverse pregnancy and neonatal outcomes is increased in women who conceive during the first year after gastric bypass surgery. METHODS: This is a national register-based cohort study covering all Danish deliveries during 2004-2010 in women with prior Roux-en-Y gastric bypass surgery. Only the first postoperative birth was included. The risk of adverse pregnancy and neonatal outcomes was compared between women who conceived within the first postoperative year and women who conceived later. Data were extracted from the Danish National Patient Registry and The Danish Medical Birth Register. RESULTS: Of 286 women who had a singleton delivery after Roux-en-Y gastric bypass surgery, 158 women conceived within the first year and 128 later. There was no statistically significant difference (p > 0.05) between the two groups regarding neonatal birth weight, gestational age, risk of preeclampsia, gestational diabetes mellitus, labor induction, cesarean section, postpartum hemorrhage (>500 ml), preterm birth (before 37 weeks), small for gestational age, large for gestational age, or Apgar score (5 min ) below 7, or in the need of neonatal intensive care. CONCLUSIONS: This study showed no evidence to support a recommendation to delay pregnancy until after the first postoperative year. At present, the optimal time for pregnancy after gastric bypass is unknown. PMID- 23462861 TI - Ethnic minorities have equal access to bariatric surgery in the UK and Ireland. AB - Under-representation of ethnic minority groups in bariatric surgery rates has been reported in the USA. Ethnic minorities form 7.9 % of the UK population, but comparable data on provision of bariatric surgery for these groups have not previously been reported in the UK. We calculated an estimate of rates of bariatric surgery amongst ethnic groups in the UK and Ireland using data from the National Bariatric Surgery Registry and census data from the UK and Ireland. The number of procedures recorded per 1,000 morbidly obese patients was 5.2 for Caucasian patients, 5.2 for Asian patients and 5.2 for Black patients. The identical rates across different ethnic groups suggest that bariatric services are provided equitably in the UK, with ethnic minority groups achieving equal access. PMID- 23462862 TI - Correlation between age and weight loss after bariatric surgery. AB - BACKGROUND: Conflicting evidence exists regarding age as a predictive factor in excess weight loss after bariatric surgery. The objective of this cross-sectional study is to evaluate differences in excess BMI loss (%EBMIL) 1 year after surgery in patients older and younger than 45 years. METHODS: Adult obese patients fulfilling selection criteria underwent either Roux-en-Y gastric bypass or sleeve gastrectomy and were grouped according to age < and >=45 years with follow-up at least 1 year. Both groups were compared in terms of excess BMI loss (%EBMIL) and other clinical outcomes. Possible relationship between %EBMIL, age, surgical technique, and presence of comorbidities such as diabetes mellitus, hypertension (HT), and dyslipidemia (DL) was searched. RESULTS: Three hundred thirty-seven patients (72.5 % female), 196 (50.1 %) younger than 45 years and 141 (49.9 %) with age >=45 years. There was significant difference between age group and %EBMIL 12 months after surgery (p < 0.001), showing better results in younger patients. No differences were found in terms of gender, preoperative body mass index (BMI), surgical technique, nor presence of DL. Using multiple regression, we found significant interaction effect between age group (p < 0.001), presence of HT (p = 0.001), and %EBMIL at follow-up. CONCLUSIONS: Patients younger than 45 years lose greater amount of excess BMI than older patients after bariatric surgery. This tendency might be useful as a preoperative weight loss predictor in bariatric patients. PMID- 23462863 TI - Peculiar reactivity of a di-imine copper(II) complex regarding its binding to albumin protein. AB - A set of four di-imine copper(II) complexes containing pyridine, pyrazine and/or imidazole moieties, [Cu(apyhist)H2O](2+) 1 (apyhist = 2-(1H-imidazol-4-yl)-N-(1 (pyridin-2-yl)ethylidene)ethanamine), [Cu(apzhist)OH](+) 2 (apzhist = 2-(1H imidazol-4-yl)-N-(1-(pyrazin-2-yl)ethylidene)ethanamine), [Cu(apyepy)OH](+) 3 (apyepy = 2-(pyridin-2-yl)-N-(1-(pyridin-2-yl)ethylidene)ethanamine), and [Cu(apzepy)H2O](2+) 4 (apzepy = N-(1-(pyrazin-2-yl)ethylidene)-2-(pyridin-2 yl)ethanamine), were investigated regarding their capability of interacting with serum albumin (human, HSA and bovine, BSA), by using spectroscopic techniques, CD, UV/Vis and EPR. Like other similar di-imine copper(II) complexes, most of them showed an expected preferential insertion of the metal ion at the primary N terminal site of the protein, very selective for copper and characterized by a CD band at 560 nm. Further insertion of the copper ion at a secondary site is expected when using an excess of the metal. However, one of these studied complexes, [Cu(apyhist)H2O](2+) 1, exhibited anomalous behaviour interacting only at this secondary metal binding site of albumin, characterized by a CD band at 370 nm, and attributed to the coordination of copper at the Cys34 pocket. Analogous experiments with HSA previously treated with N-ethyl-maleimide (NEM), that oxidizes the protein Cys34 residue and obstructs the metal coordination, verified these results. Additional data obtained by EPR spectroscopy complemented those results. DFT calculations, considering some structural and electronic characteristics of such series of di-imine ligands and of the corresponding copper complexes, suggested molecular recognition of the apyhist ligand at the protein cavity as a feasible explanation for this unexpected and peculiar behaviour of complex 1. PMID- 23462864 TI - Reversible binding and quantification of heparin and chondroitin sulfate in water using redox-stable biferrocenylene SAMs. AB - A biferrocenylene (BFD) thiol conjugate was prepared and self-assembled on a gold surface. The resulting SAMs with their extraordinary stability in the monocationic state were used to detect and quantify heparin (3-300 * 10(-5) g L( 1) = 0.003-0.3 U mL(-1)) and chondroitin sulfate (3-250 * 10(-5) g L(-1)) in aqueous buffer by cyclic voltammetry, square wave voltammetry and surface plasmon resonance. As a proof of concept, heparin quantification was performed in a blood plasma sample. Moreover, controlled binding and release of heparin was realised by switching the BFD-SAM between the monocationic and neutral state. PMID- 23462865 TI - The Pauson-Khand reaction of medium sized trans-cycloalkenes. AB - Medium sized trans-cycloalkenes are unusually reactive in the intermolecular Pauson-Khand reaction (PKR) with regard to typical monocyclic alkenes. This is due to the ring strain imparted by the E stereochemistry. The PKR of these alkenes offers a modular, regioselective and straightforward entry to trans fused [n.3.0] bicyclic scaffolds (n = 6-8). PMID- 23462866 TI - Radioactive iodine in the treatment of medullary thyroid carcinoma: a controlled multicenter study. AB - OBJECTIVE: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients. DESIGN: Retrospective multicenter study in eight University Medical Centers in The Netherlands. METHODS: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease. RESULTS: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification. CONCLUSIONS: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC. PMID- 23462867 TI - A review of current state of knowledge concerning Perkinsus marinus effects on Crassostrea virginica (Gmelin) (the eastern oyster). AB - The eastern oyster, Crassostrea virginica (Gmelin), is both an important component of our estuaries and an important farmed food animal along the east and south coasts of the United States. Its populations have been significantly diminished in the wild due to decades of overfishing beginning in the 1890 s. Unfortunately, in 1950, a new disease in eastern oysters caused by the protistan agent, Perkinsus marinus, was identified. The disease, resulting from infection with this protozoan, leads to high mortality of both wild and cultured eastern oysters. Current restoration efforts are hampered by the disease, as is the aquaculture of this economically important food. The parasite infects hemocytes and causes hemolytic anemia and general degeneration of the tissues, leading to death. Ongoing research efforts are attempting to develop oysters resistant to the disease. Transport regulations exist in may states. Infection with P. marinus is listed as a reportable disease by the World Health Organization. PMID- 23462868 TI - GPs' complaints go unheard. PMID- 23462870 TI - Lymphoma 'type K.'-in memory of Karl Lennert (1921-2012). PMID- 23462873 TI - Reversible protein affinity-labelling using bromomaleimide-based reagents. AB - Reversible protein biotinylation is readily affected via conjugation with a bromomaleimide-based reagent followed by reductive cleavage. The intermediate biotinylated protein constructs are stable at physiological temperature and pH 8.0. Quantitative reversibility is elegantly delivered under mild conditions of using a stoichiometric amount of a bis-thiol, thus providing an approach that will be of general interest in chemical biology and proteomics. PMID- 23462874 TI - Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson's disease epidemiology. AB - This study explores the effect of continuous exposure to bright light on neuromelanin formation and dopamine neuron survival in the substantia nigra. Twenty-one days after birth, Sprague-Dawley albino rats were divided into groups and raised under different conditions of light exposure. At the end of the irradiation period, rats were sacrificed and assayed for neuromelanin formation and number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rats exposed to bright light for 20 days or 90 days showed a relatively greater number of neuromelanin-positive neurons. Surprisingly, TH-positive neurons decreased progressively in the substantia nigra reaching a significant 29% reduction after 90 days of continuous bright light exposure. This decrease was paralleled by a diminution of dopamine and its metabolite in the striatum. Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution. PMID- 23462875 TI - Use of the International Classification of Diseases, 9th revision, coding in identifying chronic hepatitis B virus infection in health system data: implications for national surveillance. AB - OBJECTIVE: With increasing use electronic health records (EHR) in the USA, we looked at the predictive values of the International Classification of Diseases, 9th revision (ICD-9) coding system for surveillance of chronic hepatitis B virus (HBV) infection. MATERIALS AND METHODS: The chronic HBV cohort from the Chronic Hepatitis Cohort Study was created based on electronic health records (EHR) of adult patients who accessed services from 2006 to 2008 from four healthcare systems in the USA. Using the gold standard of abstractor review to confirm HBV cases, we calculated the sensitivity, specificity, positive and negative predictive values using one qualifying ICD-9 code versus using two qualifying ICD 9 codes separated by 6 months or greater. RESULTS: Of 1 652 055 adult patients, 2202 (0.1%) were confirmed as having chronic HBV. Use of one ICD-9 code had a sensitivity of 83.9%, positive predictive value of 61.0%, and specificity and negative predictive values greater than 99%. Use of two hepatitis B-specific ICD 9 codes resulted in a sensitivity of 58.4% and a positive predictive value of 89.9%. DISCUSSION: Use of one or two hepatitis B ICD-9 codes can identify cases with chronic HBV infection with varying sensitivity and positive predictive values. CONCLUSIONS: As the USA increases the use of EHR, surveillance using ICD 9 codes may be reliable to determine the burden of chronic HBV infection and would be useful to improve reporting by state and local health departments. PMID- 23462876 TI - Using electronic health records to save money. AB - OBJECTIVES: Health information technology, especially electronic health records (EHRs), can be used to improve the efficiency and effectiveness of healthcare providers. This study assessed the cost-savings of incorporating a list of preferred specialty care providers into the EHRs used by all primary care physicians (PCPs), accompanied by a comprehensive implementation plan. METHODS: On January 1, 2005, all specialty clinic providers at the Israeli Defense Forces were divided into one of four financial classes based on their charges, class 1, the least expensive, being the most preferred, followed by classes 2-4. This list was incorporated into the EHRs used by all PCPs in primary care clinics. PCPs received comprehensive training. Target referral goals were determined for each class and measured for 4 years, together with the total cost of all specialist visits in the first year compared to the following years. Quality assessment (QA) scores were used as a measure of the program's effect on the quality of patient care. RESULTS: During 2005-2008, a marginally significant decline in referrals to class 1 was observed (r=-0.254, p=0.078), however a significant increase in referral rates to class 2 was observed (r=0.957, p=0.042), concurrent with a decrease in referral rates to classes 3 and 4 (r=-0.312, p=0.024). An inverse correlation was observed between year and total costs for all visits to specialists (2008 prices; r=-0.96, p=0.04), and between the mean cost of one specialist visit over the 4 years, indicating a significant reduction in real costs (2008 prices; r=-0.995, p=0.005). QA was not affected by these changes (r=0.94, p=0.016). CONCLUSIONS: From a policy perspective, our data suggest that EHR can facilitate effective utilization of healthcare providers and decrease costs. PMID- 23462877 TI - Surgical treatment of central grade 1 chondrosarcoma of the appendicular skeleton. AB - BACKGROUND: Diagnosis and treatment of low-grade chondrosarcoma remain controversial. We performed a review of a single-center series with the aims of assessing the oncologic outcome of these patients, verifying if intralesional curettage can be adequate treatment, and defining clinical criteria to support the surgeon and the oncologist in decision-making for surgery and subsequent follow-up. MATERIALS AND METHODS: A retrospective review of 85 patients was performed (61 females and 24 males, age range 20-76 years). The site of the lesion was the femur in 35 cases, humerus in 33, tibia in 15, and fibula in 2. Sixty-four patients were treated by intralesional curettage. Twenty-one patients with aggressive radiological patterns were treated with wide resection. RESULTS: Mean follow-up was 67 months (range 24-206 months). Two patients developed local recurrence, both after intralesional curettage. The difference in incidence of recurrence was not statistically significant between the two groups. No distant metastases were observed. Postsurgical complications were significantly higher in the resection group. CONCLUSIONS: Low-grade chondrosarcoma of the appendicular skeleton without aggressive radiological patterns can be treated with intralesional surgery with good oncological outcome and very low rate of postsurgical complications. Wide resection, following surgical principles of malignant bone tumors, should be considered only when aggressive biologic behavior is evident on imaging. PMID- 23462878 TI - The effects of N-Methyl-D-Aspartate receptor blockade during the early neurodevelopmental period on emotional behaviors and cognitive functions of adolescent Wistar rats. AB - The N-Methyl-D-Aspartate (NMDA) receptor is expressed abundantly in the brain and plays an important role in neuronal development, learning and memory, neurodegenerative diseases, and neurogenesis. In this study, we evaluated the effects of NMDA receptor blockade during the early neurodevelopmental period on exploratory locomotion, anxiety-like behaviors and cognitive functions of adolescent Wistar rats. NMDA receptor hypofunction was induced 7-10 days after birth using MK-801 in rats (0.25 mg/kg twice a day for 4 days via intraperitoneal injection). The open-field (OF), elevated plus maze (EPM) and passive avoidance (PA) tests were used to evaluate exploratory locomotion, anxiety-like behaviors and cognitive functions. In the OF test, MK-801 caused an increase in locomotion behavior (p < 0.01) and in the frequency of rearing (p < 0.05). In the EPM test, MK-801 treatment increased the time spent in the open arms, the number of open arm entries and the amount of head dipping (p < 0.01). MK-801 treatment caused no statistical difference compared to the control group in the PA test (p > 0.05). Chronic NMDA receptor blockade during the critical period of maturation for the glutamatergic brain system (postnatal days 7-10) produces locomotor hyperactivity and decreased anxiety levels, but has no significant main effect on cognitive function during adolescence. PMID- 23462879 TI - Changes in Ataxin-10 expression after sciatic nerve crush in adult rats. AB - Ataxin-10 is a cytoplasmic protein that belongs to the family of armadillo repeat proteins and the ataxin proteins are ubiquitously expressed in nervous tissue. A loss of Ataxin-10 in primary neuronal cells causes increased apoptosis of cerebellar neurons. Knockdown of ATXN10 with siRNA in HeLa cells results in cytokinesis defects-multinucleation. Because of the essential role of Ataxin-10 in nervous system and cellular cytokinesis, we investigated the spatiotemporal expression of Ataxin-10 in a rat sciatic nerve crush (SNC) model. After never injury, we observed that Ataxin-10 had a significant up-regulation from 3d, peaked at day 5 and then gradually decreased to the normal level at 4 weeks. At its peak expression, Ataxin-10 expressed mainly in Schwann cells and macrophages of the distal sciatic nerve segment from injury, but had few co-localizations in axons. Besides, the peak expression of Ataxin-10 was in parallel with proliferating cell nuclear antigen (PCNA), and Ataxin-10 co-labeled with PCNA. Thus, all of our findings suggested that Ataxin-10 may be involved in the pathophysiology of sciatic nerve after SNC. PMID- 23462882 TI - Simulated annealing and density functional theoretical prediction of macrocyclic ligand conformations, protonation sites and complex metal-ligand exchange reaction directions. AB - The prediction of conformations and protonation sites for the macrocyclic ligands H2DO2A (1,4,7,10-tetraazacyclododecane-1,7-diacetic acid) and H2ODO2A (1-oxa 4,7,10-triazacyclododecane-4,10-diacetic acid) has been performed employing the simulated annealing (SA) method and density functional theory (DFT) calculations using the B3LYP/6-31G* method in a vacuum and aqueous solution. These SA method/DFT calculations reveal that, in contrast to the H2ODO2A ligand system, the H2DO2A ligand system is (i) pre-organized for trivalent lanthanide (Ln) and other metal ion complexation, (ii) structurally more symmetrical and slightly more compact in aqueous solution (i.e. more and/or shorter intra-molecular hydrogen bonds), and (iii) with a greater degree of partial positive charge accumulation on the hydrogen atoms bonded to macrocyclic ring nitrogen atoms when protonated. The H2ODO2A ligand system is not pre-organized. These observations are in accord with the experimental findings that the LnODO2A(+) complexes are less thermodynamically stable and kinetically more labile as compared to those of the corresponding LnDO2A(+) complexes. The results on the prediction of the ligand protonation sites are consistent with those experimentally obtained via NMR spectroscopy. The calculations of the first and second protonation constants are, however, not as accurate as compared to those experimentally determined using either the thermodynamic cycle (TC) or the isodesmic reaction (IRn) methodology, although the latter gave relatively better results. The lowest energy structures of the LnL(+) and ZnL (Ln = Eu, Y; L = DO2A, ODO2A) complexes are also calculated using the same method. The Gibb's free energies (DeltaGaq) for a number of ligand and/or metal ion exchange reactions such as LnDO2A(+) + HnODO2A((2-n)-) -->/<-- LnODO2A(+) + HnDO2A((2-n)-) (Ln = Eu, Y; n = 0, 1, 2), LnDO2A(+) + Ln'ODO2A(+) -->/<-- LnODO2A(+) + Ln'DO2A(+) (Ln = Eu, Ln' = Y), LnDO2A(+) + Ln'(3+) -->/<-- Ln'ODO2A(+) + Ln(3+) (Ln = Eu, Ln' = Y) and LnDO2A(+) + ZnODO2A -->/<-- LnODO2A(+) + ZnDO2A (Ln = Eu, Y) have been calculated in aqueous phase and the reaction directions in some cases could be predicted to be consistent with experimental or expected results. The errors between the calculated and experimental Gibb's free energy data are in the range DeltaG(aq,calc) - DeltaG(aq,exp) = -1.89 to +7.00 kcal mol(-1) in seven selected cases involving LnDO2A(+), LnODO2A(+) (Ln = Eu, Y), ZnDO2A and ZnODO2A complexes. The predicted reaction directions with the small core effective core potential (ECP) data are not necessarily better than those using large core ECP. However, the former takes much longer computer time to obtain the energy data. PMID- 23462880 TI - Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. AB - The incidence of acute and chronic spinal cord injury (SCI) in the United States is more than 10,000 per year, resulting in 720 cases per million persons enduring permanent disability each year. The economic impact of SCI is estimated to be more than 4 billion dollars annually. Preclinical studies, case reports, and small clinical trials suggest that early treatment may improve neurological recovery. To date, no proven therapeutic modality exists that has demonstrated a positive effect on neurological outcome. Emerging data from recent preclinical and clinical studies offer hope for this devastating condition. This review gives an overview of current basic research and clinical studies for the treatment of SCI. PMID- 23462881 TI - The role of epigenetics in Lynch syndrome. AB - Recognition by Warthin of the familial clustering of colorectal and gynaecological cancers a century ago laid the foundation for the recognition of familial cancer. By tracking afflicted pedigrees, Lynch defined the clinical characteristics and argued for a heritable genetic component to this autosomal dominant cancer susceptibility condition, now termed Lynch syndrome. This was proven in the 1990s, with the discovery of deleterious germline mutations of the mismatch repair genes as its cause. Yet despite the genetic revolution at the turn of the twenty-first century, no pathogenic mutation was identifiable in approximately one-third of cases with suspected Lynch syndrome. In the past decade, the alternative mechanism of constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, was identified in a proportion of these outstanding cases. This epigenetic defect, characterized by methylation and transcriptional inactivation of a single genetic allele within normal tissues, predisposes to the development of Lynch-type cancers. MSH2 and some MLH1 epimutations have been linked to genetic alterations within their vicinity and demonstrate dominant inheritance, whilst other MLH1 epimutations are reversible between generations and demonstrate non-Mendelian inheritance. This review charts the discovery of mismatch repair epimutations, their aetiological role in Lynch syndrome and the mechanistic basis for their variable inheritance patterns. PMID- 23462883 TI - DPP4 inhibitor-induced polyarthritis: a report of three cases. AB - Dipeptidyl peptidase-4 (DPP4) inhibitors are a novel therapy widespread used in type 2 diabetes mellitus. We describe 3 cases of polyarthritis which delay of appearance strongly suggests a link with DPP4 inhibitors. Three patients presented with bilateral, symmetrical, seronegative polyarthritis after introduction of DPP4 inhibitors (sitagliptine (n = 2) and vildagliptine (n = 1)). Two patients also developed xerostomia and xerostomia, and laboratory test results showed normal values of CRP and erythrocyte sedimentation rate. Joints X rays were normal. One patient was diagnosed with primary Sjogren's syndrome and treated with hydroxychloroquine, methotrexate and prednisone, with a poor efficacy. When sitagliptine was stopped, all symptoms disappeared, leading to methotrexate and prednisone discontinuation within a month. There were no immunological abnormalities in the 2 other patients, but a chronic viral hepatitis B was found in one patient. Eventually, discontinuation of DPP4 inhibitors led to resolution of symptoms in 1 and 3 weeks for both patients. DPP4 inhibitors seemed to trigger bilateral, non-erosive, seronegative polyarthritis in our 3 patients. DPP4, also known as CD26, is expressed on many cells including lymphocytes and fibroblasts, and its inhibition may lead to immunomodulating effect as suggested by clinical and in vitro studies. PMID- 23462884 TI - Polymorphism of TaSAP1-A1 and its association with agronomic traits in wheat. AB - TaSAP1, a member of the stress association protein (SAP) gene family from wheat, is involved in response to several abiotic stresses, including drought, salt and cold. In this study, TaSAP1-A1, a TaSAP1 member on chromosome 7A, and its flanking sequences were isolated. Polymorphism analysis indicated that the average nucleotide diversity (pi) of the whole region was 0.00296. The highest nucleotide diversity occurred in the promoter region (pi = 0.00631) and no polymorphism was identified in the coding region. Three markers T7AM5, T7AM2606 and T7AM39 located in the promoter region, were developed from sequence variations (InDel5-1810, SNP-2606 and InDel39-1637). Six haplotypes were identified among 300 accessions based on the three markers. TaSAP1-A1 was located on chromosome 7A using marker T7AM39 and was flanked by markers Xwmc530 and Xbarc174. QTL for yield-related traits, including 1,000-grain weight, number of grains per spike and grain yield, were located in the same region. In marker- and haplotype-trait association analyses, TaSAP1-A1 was significantly associated with 1,000-grain weight, number of grains per spike, spike length, peduncle length and total number of spikelets per spike in multiple environments. These results provide useful information for marker-assisted selection for yield-related traits under well-watered and drought-stressed conditions. PMID- 23462885 TI - A health-care system perspective on implementing genomic medicine: pediatric acute lymphoblastic leukemia as a paradigm. AB - The promise of genomic medicine has received great attention over the past decade, projecting how genomics will soon guide the prevention, diagnosis, and treatment of human diseases. However, this evolution has been slower than forecast, even where evidence is often strong (e.g., pharmacogenomics). Reasons include the requirement for institutional resources and the need for the will to push beyond barriers impeding health-care changes. Here, we illustrate how genomics has been deployed to advance the treatment of childhood leukemia. PMID- 23462886 TI - Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer. AB - It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12 week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-gamma agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-gamma agonists. PMID- 23462887 TI - Molecular characterization of a novel monopartite begomovirus isolated from Pouzolzia zeylanica in China. AB - The complete genome sequence of a monopartite begomovirus isolate TY01 was obtained from diseased Pouzolzia zeylanica plants exhibiting golden mosaic symptoms in Baise, Guangxi Province, China. It consisted of 2723 nucleotides (nt) and encoded two ORFs (CP and AV2) in the virion-sense DNA and five ORFs (AC1-AC5) in the complementary-sense DNA. Compared with the DNA-A sequences of other begomoviruses, it has the highest (78.5 %) nucleotide sequence identity with ageratum yellow vein virus (AYVV) isolate AFSP6D from Thailand, which is less than the 89 % identity in the complete genome that has been defined as the threshold value for demarcation of species in the genus Begomovirus, family Geminiviridae. Phylogenetic analysis showed that TY01 was grouped in a separate clade from the other 28 begomovirus isolates. These results indicate that isolate TY01 is a member of a novel Begomovirus species, for which the name "Pouzolzia golden mosaic virus" (PGMV) is proposed. PMID- 23462888 TI - Molecular epidemiology and phylogenetic analysis of porcine epidemic diarrhea virus (PEDV) field isolates in Korea. AB - Porcine epidemic diarrhea virus (PEDV) has caused devastating enteric disease in Korean pig farms since its first identification in 1992 in Korea. In the present study, the molecular epidemiology, genetic diversity, and phylogenetic relationship of Korean PEDV field isolates to other reference strains were analyzed using the complete E gene. Genetic analysis showed that each PEDV group had several unique characteristics, which indicated that a specific group PEDVs may be differentiated from another group PEDVs. Phylogenetic analysis showed that recent prevalent Korean PEDV field isolates are closely related to the Chinese field strains and differ genetically from the European strains and the vaccine strains used in Korea, which raises questions of whether a new-type PEDV vaccine may be necessary for preventing PEDV infection more effectively in Korea. Notably, a large deletion identified only in the attenuated DR13 can be utilized as a genetic marker, and the methods developed in this study will help to rapidly detect and differentiate PEDVs. PMID- 23462889 TI - Derivation of a nomogram to estimate probability of revisit in at-risk older adults discharged from the emergency department. AB - Estimation of the risk of revisit to the emergency department (ED) soon after discharge in the older population may assist discharge planning and targeting of post discharge intervention in high risk patients. In this study we sought to derive a risk prediction calculator for this purpose. In a prospective observational study in two tertiary ED, we conducted a comprehensive assessment of people aged 65 and over, and followed them for a minimum of 28 days post discharge. Cox proportional hazard models relating any unplanned ED revisit in the follow up period to observed risk factors were used to compute a probability nomogram. From 1,439 patients, 189 (13.1 %) had at least one unplanned revisit within 28 days. Revisit probability was weighted towards chronic and difficult to modify risk factors such as depression, malignancy and cognitive impairment. We conclude that the risk of revisit post discharge is calculable using a probability nomogram. However, revisit is largely related to immutable factors reflecting chronic illness burden, and does not necessarily reflect poor ED care during the initial index presentation. PMID- 23462890 TI - Subclinical hyperthyroidism and cardiovascular manifestations: a reevaluation of the association. AB - Subclinical hyperthyroidism (SH) has been reported associated with atrial fibrillation (AF), heart failure (HF) and coronary heart disease events, including mortality. An expert opinion indicates that AF is the possible link between SH and the other important cardiovascular (CV) manifestations. We analyzed the data of three recent studies including 60,883 subjects of whom 2,284 SH patients. In these subjects, the ratio between the AF events and each of the other above reported CV events varied from 0.14 to 0.4 in SH and from 0.2 to 2.4 in euthyroidism (ET). The general pattern of this ratio in 6 comparisons performed was not significantly higher for SH than ET. This data suggest that AF is not the major link between SH and the related CV manifestations. We suggest that a further link to be considered is the higher frequency of the early atherosclerosis manifestations such as carotid intima media thickness or carotid integrated back scatter, observed in SH. This atherogenic effect of SH can affect the occurrence of all the above clinical CV manifestations. PMID- 23462891 TI - Sirtuins: the molecular basis of beneficial effects of physical activity. AB - The research of the last decade highlighted the existence of a family of genes activated by cellular stresses that allow the cells to reactivate defense and repair activities regardless of age. The prolonged activation of these genes enhances the organism health and lifespan. Members of this gene family are called sirtuins (SIRT). The founding member of the SIRT protein family, Sir2 is a limiting component of yeast longevity. Many members of this family have been also identified as key longevity regulators in species ranging from yeast to fly. On the other hand, the role of SIRTs in the regulation of mammalian ageing has been questioned. While SIRTs' effects on lifespan are still a matter of scientific debate, the beneficial effects of SIRTs in terms of physical health and quality of aging are widely accepted. Increasing evidence suggests a pivotal role for SIRTs in mediating the adaptive response to physical exercise. The following review summarizes the knowledge so far acquired on sirtuins' role in mediating beneficial effects of physical exercise. In particular, the first paragraph gives an overture on mammalian sirtuins defining their localization, function when possible, and substrates. In the second paragraph, we discuss recent data regarding alteration of sirtuins expression and activity after physical exercise collected by our laboratory and others'. PMID- 23462892 TI - Sudden death and physical exercise: timely diagnosis of congenital anomalies of the coronary arteries with the new 320-slide multi-detector computed tomography. AB - Congenital abnormalities of the coronary arteries here described are an uncommon form of structural heart disease. Nevertheless, they deserve attention because may cause chest pain and, in some cases, sudden cardiac death even during exercise. Traditional angiography has limitations due to its projectional and invasive nature. The recent development of the 320-slide multi-detector computer tomography with low radiation exposure has the potential to modify the current diagnostic work-up, as it allows even in young people a timely identification of clinical significant coronary anomalies minimizing the risks related to radiation exposure. PMID- 23462893 TI - Feto-placental vascular dysfunction as a prenatal determinant of adult cardiovascular disease. AB - Low birthweight is associated with increased rates of coronary heart disease, stroke, hypertension and non-insulin-dependent diabetes during adult life. This is thought to be the consequence of a 'programming', whereby a stimulus or insult at a critical, sensitive period of early life has permanent effects on structure, physiology and metabolism. Programming of the fetus may, hence, result from adaptations to a condition where placental nutrient supply fails to match fetal demand. Recently, compensatory feto-placental up-regulation of the nitric oxide system during fetal growth restriction (FGR) was shown. Particularly, restricted hypoxic fetuses present an elevation of nitrites and a reduction of asymmetric dimethylarginine. S-nitrosohemoglobin is consumed under hypoxic conditions. These events are followed by nitric oxide pathway down-regulation postnatally, increasing susceptibility to cardiovascular disorders later in life. The relative hyperoxia would favor any such occurrence through depletion of tetrahydrobiopterin secondary to oxygen radical formation. This concept may lead to new therapeutic strategies, based on tetrahydrobiopterin supplementation, free radical scavenging, L-arginine administration and/or inhaled NO therapy in FGR hypoxic newborns, to improve their postnatal adaptation and to reduce the risk of metabolic pathologies in adult age. PMID- 23462894 TI - Vitamin D and heart. AB - The authors briefly review the biological effects of vitamin D on the heart and discuss the experimental and clinical studies related to the potential protective effect of vitamin D on the cardiovascular system. Experimental and observational studies in man strongly suggest that vitamin D supplementation can benefit heart failure patients and improve cardiovascular health in the population. However, presently there are limited randomized controlled studies. The authors highlight the hypothesis that vitamin D-induced mechanisms activating calcium channels may represent a novel target for therapy in patients with heart failure. PMID- 23462895 TI - Clinical testing of an innovative tool for the assessment of biomechanical strategies: the Timed "Up and Go" Assessment of Biomechanical Strategies (TUG ABS) for individuals with stroke. AB - OBJECTIVE: To investigate the reliability and construct and criterion- related validities of the Timed "Up and Go" Assessment of Biomechanical Strategies (TUG ABS), when used with subjects with hemiparesis due to stroke within clinical settings. DESIGN/METHODS: Construct validity was investigated by the following methods: the known groups, convergence, discriminant analyses, and the opinions of clinical professionals, who used the TUG-ABS with subjects with stroke. The criterion-related validity was investigated by comparing the realtime and video observation scores. Inter-rater reliability was investigated by two independent examiners using both realtime and video observations. RESULTS: The TUG-ABS differentiated people with stroke from healthy controls (p < 0.001), was correlated with the time spent to perform the TUG (rs = -0.85; p < 0.001), and correctly classified 98% of the subjects with stroke (p < 0.001). In addition, all of the clinicians who used the TUG-ABS in their clinical settings, provided positive evaluations. Agreement was also observed between real-time and video observations (0.27 <= kappa <= 0.85; p < 0.01). Furthermore, the TUG-ABS was reliable for both real-time (0.24 <= kappa <= 1.00; p < 0.05) and video observations (0.15 <= kappa <= 0.94; p < 0.05). CONCLUSION: The TUG-ABS demonstrated good construct and criterion-related validities, as well as reliability, when applied in subjects with stroke within clinical settings, which supported the theoretical assumptions employed for its development. PMID- 23462897 TI - Occupational medicine, worker's compensation, and the performing arts. PMID- 23462898 TI - Forte Fortissimo for amateur musicians: no effect on otoacoustic emissions. AB - Many amateur musicians are likely to be exposed to high sound levels during rehearsals. Measuring otoacoustic emissions (OAE) is an objective technique to assess hearing ability and can be used as an early predictor of hearing loss. This study aimed to record sound levels at an amateur brass band rehearsal and to examine the cochlear function of the musicians by evaluating distortion product (DP) OAE amplitudes before and after sound exposure. Twenty-four brass band musicians and 10 office workers were examined with personal noise measurements and DPOAE tests before and after a music rehearsal or one office workday, respectively. The sound levels in the brass band ranged from 92 to 100 dBA, LaEQ 96 dBA. However, the amateur brass band members had no change in DPOAEs after this exposure compared to pre-exposure levels and compared to office workers. PMID- 23462899 TI - Musicians seeking psychiatric help: a preliminary study of psychiatric characteristics. AB - Musicians are at increased risk for mental disorders, in particular performance anxiety. Likely causes are high levels of occupational stress, special personality traits, and coping skills. In this cross-sectional study, routine outcome monitoring (ROM) data on clinical and psychosocial characteristics were collected from the first 50 musicians visiting our outpatient psychiatric clinic for performing artists and were compared to those of a large sample of psychiatric outpatients (n=1,498) and subjects from the general population. Of the musician outpatients, 82% (n=41) met the criteria of an Axis I psychiatric disorder. Performance anxiety could not be accurately diagnosed with the MINI plus, and in a few cases it masked different psychiatric disorders. Musician outpatients scored significantly better on functional scales despite their Axis I disorder, with equal scores on scales measuring distress compared to general outpatients. Musicians displayed significantly higher mean scores on the DAPP-sf subscale measuring narcissistic personality traits than general outpatients and non-patient controls (p=0.001). Diagnostic challenges, in particular regarding performance anxiety, of musicians seeking psychiatric care are thoroughly discussed. Musicians with psychiatric disorders may constitute a group of patients with specific characteristics who may benefit from specialized psychiatric care, and health professionals should be aware of the high prevalence of psychiatric disorders in musicians. PMID- 23462900 TI - Eating behavior and nutrition knowledge among musical theatre students. AB - Eating is a central part in human (social) life. Athletic performance and physical attractiveness are linked to appropriate nutritional behavior, especially for performing artists. Eating behavior and nutrition knowledge have not been examined in musical theatre students so far, which this study aims to analyze. We administered a cross-sectional questionnaire study to 37 musical theatre students. Results for the Eating Disorder Examination-Questionnaire (EDE Q) showed non-pathological values for 92% of all participants, but 81% of participants answered correctly on only 30-59% of questions on the General Nutrition Knowledge Questionnaire (GNKQ). Our study results reveal the need for specific nutritional knowledge transfer programs for this target group. PMID- 23462901 TI - Attitudes and practices of parents of teenage musicians to health issues related to playing an instrument: a pilot study. AB - A pilot study was designed to investigate the attitudes and practices of parents of teenage musicians concerning health issues related to playing an instrument. Participants were a convenience sample of parents of children at two metropolitan high schools, one an academically selective public high school, and the other a specialised music public high school. Information came from a questionnaire completed by the parents. The 24 children ranged in age from 12 to 17 yrs. Parents' responses suggested that they recognised the importance of their children having good knowledge of health and normal body function in order to optimise the children's musical performance and to minimise the adverse impact of the playing on their children's health. The parental responses were similar in both the academically selective and musically selective schools despite the fact that half of the parents of children at the musically selective school seemed to accept that pain associated with playing an instrument is normal, whereas all of the parents from the academically selective school disagreed with this proposition. A more detailed study of the issues considered in this pilot study appears warranted. PMID- 23462902 TI - Bilateral differences in peak force, power, and maximum plie depth during multiple grande jetes. AB - A lateral bias has been previously reported in dance training. The aim of this study was to investigate whether there are any bilateral differences in peak forces, power, and maximum knee flexion during a sequence of three grand jetes and how they relate to leg dominance. A randomised observational design was selected for the study. Volunteers consisted of 20 female dancers in the last year of pre-professional training. All volunteers completed three different tests to determine leg dominance prior to completing a three grande jete sequence. The lead leg for the jump sequence was randomised. Peak take-off power, relative landing force (BW), and maximum knee flexion angles were measured using a Myotest accelerometer and integrated goniometer. Results indicated that 90% of dancers reported right leg dominance. A significant difference was noted in peak take-off power among the jumps (p<0.01); post hoc test indicated jump 3 was significantly greater than jump 1. Mean maximum take-off knee angles increased over the three jump sequence with the left leg having a significantly deeper plie than the right (p<0.01). Landing data showed an increase in peak force and a decrease in maximum knee angles across the jump sequence. The present data indicate different bilateral strategies during take-off and landing during grand jetes in female dancers resulting in increased forces during the jumps on the non-dominant side. These differences need to be addressed by incorporating appropriate modifications in training methodology that eliminates the observed bilateral differences. PMID- 23462903 TI - A combination of constraint-induced therapy and motor control retraining in the treatment of focal hand dystonia in musicians: a long-term follow-up study. AB - Focal hand dystonia (FHD) in musicians is a painless, task-specific motor disorder characterized by involuntary loss of control of individual finger movements. The aim of this study was to investigate the long-term effects of a combined behavioral therapy intervention aimed at normalizing finger movement patterns. METHODS: Eight musicians with FHD had taken part in the 1-year study involving intensive constraint-induced therapy and motor control retraining at slow speed as the interventions. Four of these subjects volunteered to take part in this 4-year follow-up. A quasi-experimental, repeated measures design was used, with 9 testing sessions over 4 years. Video recordings of the subjects playing two pieces were used for data analysis. The Frequency of Abnormal Movements scale (FAM) was the main outcome measure. It was hypothesized that there would be significant differences in FAM scores achieved over the 4-year period. RESULTS: The results from the ANOVA revealed a significant decrease, by approximately 80%, in the number of abnormal movements for both pieces over the 4 year period (F=7.85, df=8, p<0.001). Tukey's post-hoc test revealed that significant improvements occurred after 6 months of therapy (p-values between p<0.001 and p=0.044). Although the results were not significant between month 12 and follow-up at year 4, the trend revealed that the progress achieved during the first year of intensive retraining was maintained at year 4. CONCLUSIONS: A 1 year period of intensive task-specific retraining may be a successful strategy with long-term, lasting effects for the treatment of musician's FHD. Results suggest that retraining strategies may need to be carried out for at least 6 months before statistically significant changes are noted. PMID- 23462904 TI - Performing arts medicine-a bibliographic retrospective of the early literature: an historical examination of bibliographic references pre-1975. AB - Performing arts medicine (PAM) emerged as a medical specialty around 1985. Prior to this time, relatively few publications addressed the identification and concerns of musicians' and dancers' medical problems. To determine what number and types of publications occurred prior to the actual beginnings of PAM as a discipline, and to determine how these original topics compared with present-day publications, a retrospective review of the current bibliographic database of the Performing Arts Medicine Association (PAMA) was undertaken. Out of a total of 12,600 entries to date, 489 references were found published from 1798 through 1974, which represent only 3.9% of the current database listings. One-sixth of the references were originally written in a language other than English. Journal articles were by far the most numerous type of publication. Topics with the highest number of entries included the neurobiology of music (n=77), dental/orofacial matters (71), and biographical accounts of composers or musicians and their illnesses (59). Other frequently published topics included hearing loss, physiology of playing instruments, and instrumental technique and teaching. Early topics with multiple publications included composers' biographies, dystonias, and surgery to improve finger independence for playing piano. Subjects whose publications occurred principally in the last two decades of this review included dermatological disorders, hearing loss, and ballet physiology, teaching, and technique. Those which remain popular to the present day include hearing loss, performance anxiety, focal dystonia, and dental/orofacial problems. PMID- 23462905 TI - Underutilization of worker's compensation insurance among professional orchestral musicians. AB - Orchestral musicians commonly have playing-related symptoms (PRS) but few use worker's compensation (WC) insurance for assessment and treatment. The purpose of this study was to examine the frequency of, and factors related to, filing a WC claim among musicians. METHODS: An online questionnaire was completed by 261 members of the International Conference of Symphony and Opera Musicians (ICSOM). The responses were analyzed to describe the frequency and type of injuries, perceived cause of PRS, and severity of injury in musicians who did and did not file a WC claim. RESULTS: Of the musicians, 93% reported PRS in the 12 months prior to the study. Only 9 musicians filed WC claims during their careers, and all claims were for upper extremity injuries. The most frequent reason for not filing a WC claim was insufficient severity. Yet among musicians describing their PRS as not severe enough for a WC claim, 47% had symptoms for >15 minutes after playing and 16% had symptoms that interfered with daily activities. CONCLUSION: These data suggest there is frequent under-reporting of injuries to WC among professional orchestral musicians. Although most musicians reported PRS that persisted after playing, the most common reason for not filing a WC claim was insufficient severity of symptoms perceived by the musicians. Future research should focus on clearly defining severity for PRS-related injuries and determining when treatment for overuse syndromes should be paid for through the WC system. PMID- 23462906 TI - Put doctors and nurses back at the heart of decision making. PMID- 23462907 TI - A disease-drug-phenotype matrix inferred by walking on a functional domain network. AB - Protein domains are classified as units of structure, evolution and function, and thus form the molecular backbone of biosphere. Although functional networks at the protein level have been reported to be of value in predicting diseases (phenotypes or drugs), they have not previously been applied at the sub-protein resolution (protein domain in this case). We herein introduce a domain network with a functional perspective. This network has nodes consisting of protein domains (at the superfamily/evolutionary level), with edges weighted by the semantic similarity according to domain-centric Gene Ontology (dcGO) annotations, which henceforth we call "dcGOnet". By globally exploring this network via a random walk, we demonstrate its predictive value on disease, drug, or phenotype related ontologies. On cross-validation recovering ontology labels for domains, we achieve an overall area under the ROC curve of 89.0% for drugs, 87.3% for diseases, 87.6% for human phenotypes and 88.2% for mouse phenotypes. We show that the performance using global information from this network is significantly better than using local information, and also illustrate that the better performance is not sensitive to network size, or the choice of algorithm parameters, and is universal to different ontologies. Based on the dcGOnet and its global properties, we further develop an approach to build a disease-drug phenotype matrix. The predicted interconnections are statistically supported using a novel randomization procedure, and are also empirically supported by inspection for biological relevance. Most of the high-ranking predictions recover connections that are well known, but others uncover connections that have only suggestive or obscure support in the literature; we show that these are missed by simpler methods, in particular for drug-disease connections. The value of this work is threefold: we describe a general methodology and make the software available, we provide the functional domain network itself, and the ranked drug disease-phenotype matrix provides rich targets for investigation. All three can be found at . PMID- 23462908 TI - Editorial: Modern methods in plant natural products themed issue. PMID- 23462909 TI - Fundamental role for HIF-1alpha in constitutive expression of human beta defensin 1. AB - Antimicrobial peptides are secreted by the intestinal epithelium to defend from microbial threats. The role of human beta defensin-1 (hBD-1) is notable because its gene (beta-defensin 1 (DEFB1)) is constitutively expressed and its antimicrobial activity is potentiated in the low-oxygen environment that characterizes the intestinal mucosa. Hypoxia-inducible factor (HIF) is stabilized even in healthy intestinal mucosa, and we identified that epithelial HIF-1alpha maintains expression of murine defensins. Extension to a human model revealed that basal HIF-1alpha is critical for the constitutive expression of hBD-1. Chromatin immunoprecipitation identified HIF-1alpha binding to a hypoxia response element in the DEFB1 promoter whose importance was confirmed by site-directed mutagenesis. We used 94 human intestinal samples to identify a strong expression correlation between DEFB1 and the canonical HIF-1alpha target GLUT1. These findings indicate that basal HIF-1alpha is critical for constitutive expression of enteric DEFB1 and support targeting epithelial HIF for restoration and maintenance of intestinal integrity. PMID- 23462910 TI - Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation. AB - Bacterial-induced intestinal inflammation is crucially dependent on interleukin (IL)-23 and is associated with CD4(+) T helper type 1 (Th1) and Th17 responses. However, the relative contributions of these subsets during the induction and resolution of colitis in T-cell-sufficient hosts remain unknown. We report that Helicobacter hepaticus-induced typhlocolitis in specific pathogen-free IL-10(-/-) mice is associated with elevated frequencies and numbers of large intestinal interferon (IFN)-gamma(+) and IFN-gamma(+)IL-17A(+) CD4(+) T cells. By assessing histone modifications and transcript levels in IFN-gamma(+), IFN-gamma(+)IL 17A(+), and IL-17A(+) CD4(+) T cells isolated from the inflamed intestine, we show that Th17 cells are predisposed to upregulate the Th1 program and that they express IL-23R but not IL-12R. Using IL-17A fate-reporter mice, we further demonstrate that H. hepaticus infection gives rise to Th17 cells that extinguish IL-17A secretion and turn on IFN-gamma within 10 days post bacterial inoculation. Together, our results suggest that bacterial-induced Th17 cells arising in disease-susceptible hosts contribute to intestinal pathology by switching phenotype, transitioning via an IFN-gamma(+)IL-17A(+) stage, to become IFN gamma(+) ex-Th17 cells. PMID- 23462911 TI - TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice. AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a TNF superfamily member, induces damage of the epithelial cells (ECs) and production of inflammatory mediaters through its receptor Fn14 in a model of acute colitis. In our current study of chronic colitis induced by repeated rectal injection of a hapten, we found that inflammation, fibrosis, and T helper 2 (Th2)-type immunity were significantly reduced in Fn14 gene knockout (KO) mice when compared with wild-type (WT) control mice. Expression of thymic stromal lymphopoietin (TSLP) was lower in Fn14 KO colon ECs than in WT ECs. TWEAK potentiates the induction of TSLP by interleukin-13 (IL-13) in colon explants from WT but not in Fn14 KO tissue. TSLP receptor KO mice exhibit milder chronic colitis, similar to that in Fn14 KO mice. TWEAK and IL-13 synergistically promote fibroblast proliferation. Thus we propose an IL-13-TWEAK/Fn14-TSLP axis as a key mechanism underlying chronic colitis with fibrosis. PMID- 23462912 TI - Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion. AB - Resolution of inflammation is an active process mediated by pro-resolution lipid mediators. As resolvin (Rv) D1 is produced in the cornea, pro-resolution mediators could be effective in regulating inflammatory responses to histamine in allergic conjunctivitis. Two key mediators of resolution are the D-series resolvins RvD1 or aspirin-triggered RvD1 (AT-RvD1). We used cultured conjunctival goblet cells to determine whether histamine actions can be terminated during allergic responses. We found cross-talk between two types of G protein-coupled receptors (GPRs), as RvD1 interacts with its receptor GPR32 to block histamine stimulated H1 receptor increases in intracellular [Ca(2+)] ([Ca(2+)]i) preventing H1 receptor-mediated responses. In human and rat conjunctival goblet cells, RvD1 and AT-RvD1 each block histamine-stimulated secretion by preventing its increase in [Ca(2+)]i and activation of extracellular regulated-protein kinase (ERK)1/2. We suggest that D-series resolvins regulate histamine responses in the eye and offer new treatment approaches for allergic conjunctivitis or other histamine dependent pathologies. PMID- 23462913 TI - Serum 25-hydroxyvitamin d and cancer risk in older adults: results from a large German prospective cohort study. AB - BACKGROUND: Several observational studies assessed the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and the risk of cancer but results were inconclusive. METHODS: We measured 25(OH)D concentrations in a population based cohort study of 9,949 men and women ages 50 to 74 years in Saarland, Germany. Comprehensively adjusted Cox regression models were applied to estimate HRs and 95% confidence intervals (CI) for the association between season standardized 25(OH)D concentrations and total and site-specific cancer incidence. RESULTS: Overall, during a median of 8 years of follow-up, 873 subjects developed cancer; the most common being prostate (171), breast (137), lung (136), and colorectal (136) cancer. Low season-standardized 25(OH)D (<30, 35, 40, or 36 nmol/L in winter, spring, summer, and autumn, respectively) was neither significantly associated with total cancer incidence (HR, 1.10; 95% CI, 0.93 1.30) nor with site-specific cancer incidence. However, a significantly increased overall cancer risk was observed for low 25(OH)D among men, nonobese subjects and subjects reporting low fish consumption and for high 25(OH)D in nonsmokers and nonobese subjects. Accordingly, restricted cubic splines to investigate dose response relationships curves showed an inverse association of 25(OH)D levels and total cancer risk in men but not in women. CONCLUSIONS: 25(OH)D concentrations were significantly associated with overall cancer incidence in subgroups of this large cohort from Germany. No significant association was observed with site specific cancers but this could be due to a limited statistical power for these endpoints. IMPACT: Further research should clarify whether and to what extent specific risk groups might profit from vitamin D supplementation. PMID- 23462914 TI - Adherence to the WCRF/AICR guidelines for cancer prevention is associated with lower mortality among older female cancer survivors. AB - BACKGROUND: The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines encourage cancer survivors to follow its cancer prevention recommendations. We evaluated whether adherence to the WCRF/AICR guidelines for cancer prevention was associated with lower mortality among older female cancer survivors. METHODS: From 2004 to 2009, 2,017 participants in the Iowa Women's Health Study who had a confirmed cancer diagnosis (1986-2002) and completed the 2004 follow-up questionnaire were followed. Adherence scores for the WCRF/AICR guidelines for body weight, physical activity, and diet were computed assigning one, 0.5 or 0 points to each of eight recommendations depending on the degree of adherence. All-cause (n = 461), cancer-specific (n = 184), and cardiovascular disease (CVD)-specific mortality (n = 145) were compared by the total adherence score and by adherence scores for each of the three components of the recommendations. RESULTS: Women with the highest (6-8) versus lowest (0-4) adherence score had lower all-cause mortality [HR = 0.67; 95% confidence of interval (CI), 0.50-0.94]. Meeting the physical activity recommendation was associated with lower all-cause (Ptrend < 0.0001), cancer specific (Ptrend = 0.04), and CVD-specific mortality (Ptrend = 0.03). Adherence to dietary recommendations was associated with lower all-cause mortality (Ptrend < 0.05), whereas adherence to the body weight recommendation was associated with higher all-cause mortality (Ptrend = 0.009). CONCLUSIONS: Adherence to the WCRF/AICR guidelines was associated with lower all-cause mortality among older female cancer survivors. Adherence to the physical activity recommendation had the strongest association with lower all-cause and disease-specific mortality. IMPACT: Older cancer survivors may decrease their risk of death by leading a healthy lifestyle after a cancer diagnosis. PMID- 23462915 TI - Risk assessment of upper tract urothelial carcinoma related to aristolochic acid. AB - BACKGROUND: Aristolochic acid is a toxin found in plants of the genus Aristolochia, to which humans can be exposed either through certain Chinese herbal medicines or through inadvertent commingling with food crops. Our objective was to estimate cumulative exposures of aristolochic acid associated with increased risk of end-stage renal disease (ESRD), and to conduct a systematic review and meta-analysis on aristolochic acid-induced upper tract urothelial carcinoma (UUC). METHODS: Using epidemiologic studies on aristolochic acid-related disease from multiple different regions of the world, a systematic review was conducted in which relative risks (RR), HRs, and ORs were derived or extracted directly, and a meta-analysis was conducted. One study was used to estimate a benchmark dose lower confidence limit (BMDL) for aristolochic acid related ESRD. RESULTS: Mean values for risk ratios, ORs, RRs, or HRs, of UUC caused by aristolochic acid ranged from 1 to 49. A meta-analysis of these studies resulted in a pooled OR of 5.97 [95% confidence interval (CI), 2.78-12.84] for this aristolochic acid-related cancer. The obtained BMDL for aristolochic acid related ESRD was 0.42 g cumulative aristolochic acid exposure. CONCLUSIONS: Aristolochic acid exposure is significantly associated with an increased risk of UUC, and there is a dose-dependent relationship between cumulative aristolochic acid exposure and ESRD risk. IMPACT: Individuals who use certain Chinese herbal medicines may significantly increase their risk of developing UUC and/or ESRD, as would individuals who are inadvertently exposed to aristolochic acid through commingling of Aristolochia plants with harvested food crops. PMID- 23462916 TI - Biomarker discovery for heterogeneous diseases. AB - BACKGROUND: Modern genomic and proteomic studies reveal that many diseases are heterogeneous, comprising multiple different subtypes. The common notion that one biomarker can be predictive for all patients may need to be replaced by an understanding that each subtype has its own set of unique biomarkers, affecting how discovery studies are designed and analyzed. METHODS: We used Monte Carlo simulation to measure and compare the performance of eight selection methods with homogeneous and heterogeneous diseases using both single-stage and two-stage designs. We also applied the selection methods in an actual proteomic biomarker screening study of heterogeneous breast cancer cases. RESULTS: Different selection methods were optimal, and more than two-fold larger sample sizes were needed for heterogeneous diseases compared with homogeneous diseases. We also found that for larger studies, two-stage designs can achieve nearly the same statistical power as single-stage designs at significantly reduced cost. CONCLUSIONS: We found that disease heterogeneity profoundly affected biomarker performance. We report sample size requirements and provide guidance on the design and analysis of biomarker discovery studies for both homogeneous and heterogeneous diseases. IMPACT: We have shown that studies to identify biomarkers for the early detection of heterogeneous disease require different statistical selection methods and larger sample sizes than if the disease were homogeneous. These findings provide a methodologic platform for biomarker discovery of heterogeneous diseases. PMID- 23462917 TI - Transforming epidemiology for 21st century medicine and public health. AB - In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits. PMID- 23462918 TI - A review of NCI's extramural grant portfolio: identifying opportunities for future research in genes and environment in cancer. AB - BACKGROUND: Genetic and environmental factors jointly influence cancer risk. The NIH has made the study of gene-environment (GxE) interactions a research priority since the year 2000. METHODS: To assess the current status of GxE research in cancer, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Years 2007 to 2009. Publications attributed to selected grants were also evaluated. RESULTS: From the 1,106 research grants identified in our portfolio analysis, a random sample of 450 grants (40%) was selected for data abstraction; of these, 147 (33%) were considered relevant. The most common cancer type was breast (20%, n = 29), followed by lymphoproliferative (10%, n = 14), colorectal (9%, n = 13), melanoma/other skin (9%, n = 13), and lung/upper aerodigestive tract (8%, n = 12) cancers. The majority of grants were studies of candidate genes (68%, n = 100) compared with genome-wide association studies (GWAS) (8%, n = 12). Approximately one-third studied environmental exposures categorized as energy balance (37%, n = 54) or drugs/treatment (29%, n = 43). From the 147 relevant grants, 108 publications classified as GxE or pharmacogenomic were identified. These publications were linked to 37 of the 147 grant applications (25%). CONCLUSION: The findings from our portfolio analysis suggest that GxE studies are concentrated in specific areas. There is room for investments in other aspects of GxE research, including, but not limited to developing alternative approaches to exposure assessment, broadening the spectrum of cancer types investigated, and conducting GxE within GWAS. IMPACT: This portfolio analysis provides a cross-sectional review of NCI support for GxE research in cancer. PMID- 23462919 TI - Cultivating cohort studies for observational translational research. AB - BACKGROUND: "Discovery" research about molecular markers for diagnosis, prognosis, or prediction of response to therapy has frequently produced results that were not reproducible in subsequent studies. What are the reasons, and can observational cohorts be cultivated to provide strong and reliable answers to those questions? Experimental METHODS: Selected examples are used to illustrate: (i) what features of research design provide strength and reliability in observational studies about markers of diagnosis, prognosis, and response to therapy? (ii) How can those design features be cultivated in existing observational cohorts, for example, within randomized controlled clinical trial (RCT), other existing observational research studies, or practice settings like health maintenance organization (HMOs)? RESULTS: Examples include a study of RNA expression profiles of tumor tissue to predict prognosis of breast cancer, a study of serum proteomics profiles to diagnose ovarian cancer, and a study of stool-based DNA assays to screen for colon cancer. Strengths and weaknesses of observational study design features are discussed, along with lessons about how features that help assure strength might be "cultivated" in the future. CONCLUSIONS AND IMPACT: By considering these examples and others, it may be possible to develop a process of "cultivating cohorts" in ongoing RCTs, observational cohort studies, and practice settings like HMOs that have strong features of study design. Such an effort could produce sources of data and specimens to reliably answer questions about the use of molecular markers in diagnosis, prognosis, and response to therapy. PMID- 23462921 TI - Gene variants in angiogenesis and lymphangiogenesis and cutaneous melanoma progression. AB - BACKGROUND: Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in 2 independent series of patients with melanoma. METHODS: Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 single-nucleotide polymorphisms (SNP) in 26 genes and SLN metastasis were estimated as ORs and 95% confidence intervals (CI) using logistic regression. Competing risk regression was used to estimate HRs and 95% CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 patients with melanoma who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma. RESULTS: In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGF receptor (EGFR), FLT1, interleukin (IL)-10, platelet-derived growth factor D (PDGFD), PIK3CA, and toll-like receptor (TLR)-3 were associated with the risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Furthermore, in a meta-analysis, 3 additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma-specific death (TLR3 rs7668666). CONCLUSIONS: These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma. IMPACT: Additional research attempting to replicate these results is warranted. PMID- 23462920 TI - Inflammatory plasma markers and pancreatic cancer risk: a prospective study of five U.S. cohorts. AB - Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha receptor II (TNF-alphaR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1,094 controls from Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL-6, and TNF-alphaR2 and the risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 [95% confidence interval (CI), 0.74-1.63; Ptrend = 0.81] for CRP, 1.19 (95% CI, 0.81 1.76; Ptrend = 0.08) for IL-6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-alphaR2. In conclusion, prediagnostic levels of circulating CRP, IL-6, and TNF-alphaR2 were not associated with the risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer. PMID- 23462922 TI - Comparison of nicotine and carcinogen exposure with water pipe and cigarette smoking. AB - BACKGROUND: Smoking tobacco preparations in a water pipe (hookah) is widespread in many places of the world and is perceived by many as relatively safe. We investigated biomarkers of toxicant exposure with water pipe compared with cigarette smoking. METHODS: We conducted a crossover study to assess daily nicotine and carcinogen exposure with water pipe and cigarette smoking in 13 people who were experienced in using both products. RESULTS: When smoking an average of 3 water pipe sessions compared with smoking 11 cigarettes per day (cpd), water pipe use was associated with a significantly lower intake of nicotine, greater exposure to carbon monoxide (CO), and a different pattern of carcinogen exposure compared with cigarette smoking, with greater exposure to benzene, and high molecular weight polycyclic aromatic hydrocarbon (PAH), but less exposure to tobacco-specific nitrosamines, 1,3-butadiene, acrolein, acrylonitrile, propylene oxide, ethylene oxide, and low molecular weight PAHs. CONCLUSIONS: A different pattern of carcinogen exposure might result in a different cancer risk profile between cigarette and water pipe smoking. Of particular concern is the risk of leukemia related to high levels of benzene exposure with water pipe use. IMPACT: Smoking tobacco in water pipes has gained popularity in the United States and around the world. Many believe that water pipe smoking is not addictive and less harmful than cigarette smoking. We provide data on toxicant exposure that will help guide regulation and public education regarding water pipe health risk. PMID- 23462923 TI - Identification of PTHrP(12-48) as a plasma biomarker associated with breast cancer bone metastasis. AB - BACKGROUND: Breast cancer bone metastasis is a complication that significantly compromises patient survival due, in part, to the lack of disease-specific biomarkers that allow early and accurate diagnosis. METHODS: Using mass spectrometry protein profiling, plasma samples were screened from three independent breast cancer patient cohorts with and without clinical evidence of bone metastasis. RESULTS: The results identified 13 biomarkers that classified all 110 patients with a sensitivity of 91% and specificity of 93% [receiver operating characteristics area under the curve (AUC = 1.00)]. The most discriminatory protein was subsequently identified as a unique 12-48aa peptide fragment of parathyroid hormone-related protein (PTHrP). PTHrP(12-48) was significantly increased in plasma of patients with bone metastasis compared with patients without bone metastasis (P < 0.0001). Logistic regression models were used to evaluate the diagnostic potential of PTHrP(12-48) as a single biomarker or in combination with the measurement of the clinical marker N-telopeptide of type I collagen (NTx). The PTHrP(12-48) and NTx logistic regression models were not significantly different and classified the patient groups with high accuracy (AUC = 0.85 and 0.95), respectively. Interestingly, in combination with serum NTx, the plasma concentration of PTHrP(12-48) increased diagnostic specificity and accuracy (AUC = 0.99). CONCLUSIONS: These data show that PTHrP(12-48) circulates in plasma of patient with breast cancer and is a novel and predictive biomarker of breast cancer bone metastasis. Importantly, the clinical measurement of PTHrP(12-48) in combination with NTx improves the detection of breast cancer bone metastasis. IMPACT: In summary, we present the first validated, plasma biomarker signature for diagnosis of breast cancer bone metastasis that may improve the early diagnosis of high-risk individuals. PMID- 23462924 TI - Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer. AB - BACKGROUND: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. METHODS: Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. RESULTS: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041). CONCLUSIONS: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. PMID- 23462925 TI - Bridging the gap between biologic, individual, and macroenvironmental factors in cancer: a multilevel approach. AB - To address the complex nature of cancer occurrence and outcomes, approaches have been developed to simultaneously assess the role of two or more etiologic agents within hierarchical levels including the: (i) macroenvironment level (e.g., health care policy, neighborhood, or family structure); (ii) individual level (e.g., behaviors, carcinogenic exposures, socioeconomic factors, and psychologic responses); and (iii) biologic level (e.g., cellular biomarkers and inherited susceptibility variants). Prior multilevel approaches tend to focus on social and environmental hypotheses, and are thus limited in their ability to integrate biologic factors into a multilevel framework. This limited integration may be related to the limited translation of research findings into the clinic. We propose a "Multi-level Biologic and Social Integrative Construct" (MBASIC) to integrate macroenvironment and individual factors with biology. The goal of this framework is to help researchers identify relationships among factors that may be involved in the multifactorial, complex nature of cancer etiology, to aid in appropriate study design, to guide the development of statistical or mechanistic models to study these relationships, and to position the results of these studies for improved intervention, translation, and implementation. MBASIC allows researchers from diverse fields to develop hypotheses of interest under a common conceptual framework, to guide transdisciplinary collaborations, and to optimize the value of multilevel studies for clinical and public health activities. PMID- 23462927 TI - Caffeine-containing energy drink improves sprint performance during an international rugby sevens competition. AB - The aim of this study was to determine the effects of a caffeine-containing energy drink on physical performance during a rugby sevens competition. A second purpose was to investigate the post-competition urinary caffeine concentration derived from the energy drink intake. On two non-consecutive days of a friendly tournament, 16 women from the Spanish National rugby sevens Team (mean age and body mass = 23 +/- 2 years and 66 +/- 7 kg) ingested 3 mg of caffeine per kg of body mass in the form of an energy drink (Fure((r)), ProEnergetics) or the same drink without caffeine (placebo). After 60 min for caffeine absorption, participants performed a 15-s maximal jump test, a 6 * 30 m sprint test, and then played three rugby sevens games against another national team. Individual running pace and instantaneous speed during the games were assessed using global positioning satellite (GPS) devices. Urine samples were obtained pre and post competition. In comparison to the placebo, the ingestion of the energy drink increased muscle power output during the jump series (23.5 +/- 10.1 vs. 25.6 +/- 11.8 kW, P = 0.05), running pace during the games (87.5 +/- 8.3 vs. 95.4 +/- 12.7 m/min, P < 0.05), and pace at sprint velocity (4.6 +/- 3.3 vs. 6.1 +/- 3.4 m/min, P < 0.05). However, the energy drink did not affect maximal running speed during the repeated sprint test (25.0 +/- 1.5 vs. 25.0 +/- 1.7 km/h). The ingestion of the energy drink resulted in a higher post-competition urine caffeine concentration than the placebo (3.3 +/- 0.7 vs. 0.2 +/- 0.1 MUg/mL; P < 0.05). In summary, 3 mg/kg of caffeine in the form of a commercially available energy drink considerably enhanced physical performance during a women's rugby sevens competition. PMID- 23462926 TI - Family history of colorectal cancer in BRAF p.V600E-mutated colorectal cancer cases. AB - BACKGROUND: Previous reports suggest that relatives of colorectal cancer (CRC) affected probands carrying the BRAF p.V600E mutation are at an increased risk of CRC and extracolonic cancers (ECC). In this study, we estimated the association between a family history of either CRC or ECC and risk of CRC with a BRAF p.V600E mutation. METHODS: Population-based CRC cases (probands, ages 18-59 years at diagnosis), recruited irrespective of family cancer history, were characterized for BRAF p.V600E mutation and mismatch repair (MMR) status. ORs and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: The 690 eligible probands showed a mean age at CRC diagnosis of 46.9 +/- 7.8 years, with 313 (47.9%) reporting a family history of CRC and 53 (7.7%) that were BRAF-mutated. Probands with BRAF-mutated, MMR-proficient CRCs were less likely to have a family history of CRC than probands that were BRAF wild-type (OR, 0.46; 95% CI, 0.24-0.91; P = 0.03). For probands with a BRAF-mutated CRC, the mean age at diagnosis was greater for those with a CRC-affected first- or second-degree relative (49.3 +/- 6.4 years) compared with those without a family history (43.8 +/- 10.2 years; P = 0.04). The older the age at diagnosis of CRC with the BRAF p.V600E mutation, the more likely these probands were to show a family history of CRC (OR, 1.09 per year of age; 95% CI, 1.00-1.18; P = 0.04). CONCLUSIONS: Probands with early-onset, BRAF-mutated, and MMR-proficient CRC were less likely to have a family history of CRC than probands that were BRAF-wild type. IMPACT: These findings provide useful insights for cancer risk assessment in families and suggest that familial or inherited factors are more important in early-onset, BRAF-wild-type CRC. PMID- 23462928 TI - midD-encoded 'rhizomimosinase' from Rhizobium sp. strain TAL1145 is a C-N lyase that catabolizes L-mimosine into 3-hydroxy-4-pyridone, pyruvate and ammonia. AB - Rhizobium sp. strain TAL1145 catabolizes mimosine, which is a toxic non-protein amino acid present in Leucaena leucocephala (leucaena). The objective of this investigation was to study the biochemical and catalytic properties of the enzyme encoded by midD, one of the TAL1145 genes involved in mimosine degradation. The midD-encoded enzyme, MidD, was expressed in Escherichia coli, purified and used for biochemical and catalytic studies using mimosine as the substrate. The reaction products in the enzyme assay were analyzed by HPLC and mass spectrometry. MidD has a molecular mass of ~45 kDa and its catalytic activity was found to be optimal at 37 degrees C and pH 8.5. The major product formed in the reaction had the same retention time as that of synthetic 3-hydroxy-4-pyridone (3H4P). It was confirmed to be 3H4P by MS/MS analysis of the HPLC-purified product. The K m, V max and K cat of MidD were 1.27 * 10(-4) mol, 4.96 * 10(-5) mol s(-1) mg(-1), and 2,256.05 s(-1), respectively. Although MidD has sequence similarities with aminotransferases, it is not an aminotransferase because it does not require a keto acid as the co-substrate in the degradation reaction. It is a pyridoxal-5'-phosphate (PLP)-dependent enzyme and the addition of 50 MUM hydroxylamine completely inhibited the reaction. However, the supplementation of the reaction with 0.1 MUM PLP restored the catalytic activity of MidD in the reaction containing 50 MUM hydroxylamine. The catalytic activity of MidD was found to be specific to mimosine, and the presence of its structural analogs including L-tyrosine, L-tryptophan and L-phenylalanine did not show any competitive inhibition. In addition to 3H4P, we also identified pyruvate and ammonia as other degradation products in equimolar quantities of the substrate used. The degradation of mimosine into a ring compound, 3H4P with the release of ammonia indicates that MidD of Rhizobium sp. strain TAL1145 is a C-N lyase. PMID- 23462929 TI - Neuroprotective properties of the excitatory amino acid carrier 1 (EAAC1). AB - Extracellular glutamate should be maintained at low levels to conserve optimal neurotransmission and prevent glutamate neurotoxicity in the brain. Excitatory amino acid transporters (EAATs) play a pivotal role in removing extracellular glutamate in the central nervous system (CNS). Excitatory amino acid carrier 1 (EAAC1) is a high-affinity Na+-dependent neuronal EAAT that is ubiquitously expressed in the brain. However, most glutamate released in the synapses is cleared by glial EAATs, but not by EAAC1 in vivo. In the CNS, EAAC1 is widely distributed in somata and dendrites but not in synaptic terminals. The contribution of EAAC1 to the control of extracellular glutamate levels seems to be negligible in the brain. However, EAAC1 can transport not only extracellular glutamate but also cysteine into the neurons. Cysteine is an important substrate for glutathione (GSH) synthesis in the brain. GSH has a variety of neuroprotective functions, while its depletion induces neurodegeneration. Therefore, EAAC1 might exert a critical role for neuroprotection in neuronal GSH metabolism rather than glutamatergic neurotransmission, while EAAC1 dysfunction would cause neurodegeneration. Despite the potential importance of EAAC1 in the brain, previous studies have mainly focused on the glutamate neurotoxicity induced by glial EAAT dysfunction. In recent years, however, several studies have revealed regulatory mechanisms of EAAC1 functions in the brain. This review will summarize the latest information on the EAAC1-regulated neuroprotective functions in the CNS. PMID- 23462930 TI - Di-maltol-polyamine ligands to form heterotrinuclear metal complexes: solid state, aqueous solution and magnetic characterization. AB - The binding properties of the two ligands (L) N,N'-bis[(3-hydroxy-4-pyron-2 yl)methyl]-N,N'-dimethylethylendiamine (Malten) and 4,10-bis[(3-hydroxy-4-pyron-2 yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (Maltonis) towards M(II) transition metal ions (M(II) = Cu(II) for Malten and Co(II) for Maltonis, respectively), were investigated in aqueous solution. Each compound contains two 3-hydroxy-2-methyl-4-pyrone units (Maltol) symmetrically spaced by a different polyamine fragment. The formation of only mononuclear complexes was detected and the main species present in a wide range of pH is the neutral [M(II)(H-2L)] complex. This is able to stabilize one hard M(III) metal ion such as Gd(III) and Y(III), giving rise to the formation of new hetero-trinuclear complexes of M(II) M(III)-M(II) sequence. The trinuclear species having the formula {M(III)[M(II)(H 2L)]2}(3+) (M(II) = Cu(II) and M(III) = Y(III) or Gd(III) for Malten and M(II) = Co(II) and M(III) = Gd(III) for Maltonis) are also formed in a wide range of pH, including pH = 7 and can be isolated in high yield as a perchlorate salt. The crystal structures of all the studied hetero-trinuclear species highlight that such systems are formed thanks to the synergy between the different stereochemical requirement of the transition metal (Cu(II) or Co(II)) and the different donor atoms set of the ligands which preorganize the maltol units for the binding of the hard M(III) metal, otherwise difficult to bind in water, through L/M(II)/M(III) self-assembling. The magnetic properties of the hetero trinuclear spin systems were investigated; in the M(II)-Gd(III)-M(II) species, Gd(III) interacts with the two 3d ions of this class of compounds by similar coupling mechanism. PMID- 23462931 TI - Potential biological fate of emulsion-based delivery systems: lipid particles nanolaminated with lactoferrin and beta-lactoglobulin coatings. AB - PURPOSE: To develop lipid particles coated by nanolaminated protein coatings as potential oral delivery systems to encapsulate, protect, and deliver lipophilic bioactives. METHODS: Nanolaminated protein coatings were formed by sequential electrostatic deposition of cationic lactoferrin (LF) and anionic beta lactoglobulin (BLG) at pH 6.5: LF, LF-BLG, LF-BLG-LF, and LF-BLG-LF-BLG. Changes in physicochemical properties were characterized after exposure to environmental stresses (pH 2 to 9; 0 to 200 mM NaCl) and simulated gastrointestinal tract (GIT) conditions (mouth, stomach, small intestine). Triglyceride digestion and beta carotene bioaccessibility were also measured. RESULTS: The pH and salt dependence of the electrical charge and aggregation stability of the emulsions were strongly influence by the structure of the interfacial coatings. All emulsions behaved similarly under simulated GIT conditions: extensive droplet aggregation occurred in the stomach and small intestine; triglycerides were rapidly and fully digested after exposure to intestinal fluids; the bioaccessibility of beta-carotene was low (< 4%). CONCLUSIONS: Nanolaminated protein coatings may be useful for stabilizing encapsulated lipids in functional food and pharmaceutical products during storage, but releasing them after ingestion. Protein coatings had little impact on triglyceride digestion, but they greatly reduced beta-carotene bioaccessibility, possibly due to binding to lactoferrin. PMID- 23462932 TI - Hepatocyte nuclear factor 4 alpha and farnesoid X receptor co-regulates gene transcription in mouse livers on a genome-wide scale. AB - PURPOSE: Farnesoid X receptor (Fxr) is a ligand-activated nuclear receptor critical for liver function. Reports indicate that the functions of Fxr in the liver may overlap with those of hepatocyte nuclear factor 4alpha (Hnf4alpha), but studies of their precise genome-wide interaction to regulate gene transcription in the liver are lacking. Thus, we compared the genome-wide binding of Fxr and Hnf4alpha in the liver of mice and characterized their cooperative activity on binding to and activating target gene transcription. METHODS: Genome-wide ChIP Seq data of Fxr and Hnf4alpha in mouse liver were analyzed by MACS, BEDTools, and DAVID. Co-immunoprecipitation, ChIP-qPCR, and luciferase assays were done to test for protein-protein interaction and cooperative binding. RESULTS: ChIP-seq analysis showed nearly 50% binding sites of Fxr and Hnf4alpha in mouse liver overlap and Hnf4alpha bound to shared target sites upstream and in close proximity to Fxr. Moreover, genes co-bound by Fxr and Hnf4alpha are enriched in complement and coagulation cascades and drug metabolism. A direct Fxr-Hnf4alpha protein interaction dependent on Fxr activity was detected and transcriptional assays suggest that Hnf4alpha can increase Fxr transcriptional activity. Conversely, binding assays showed Hnf4alpha can be either Fxr-dependent or independent at different shared binding sites. CONCLUSION: Our results showed that Fxr cooperates with Hnf4alpha in the liver to modulate gene transcription. This study provides the first evidence on a genome-wide scale of both cooperative and independent interactions between Fxr and Hnf4alpha in regulating gene transcription in the liver. PMID- 23462934 TI - Effects of iontophoresis, hydration, and permeation enhancers on human nail plate: infrared and impedance spectroscopy assessment. AB - PURPOSE: To investigate whether permeation enhancement techniques affect the nail plate. METHODS: Infrared and impedance spectroscopies examined the effects of hydration, iontophoresis and N-acetyl-L-cysteine on the human nail. RESULTS: While significant shifts to higher wavenumbers were observed for the symmetric and asymmetric -CH2 stretching vibrations these changes were essentially the same for the three treatments suggesting they were principally due to hydration alone. Spectral changes associated with amide bonds from nail protein were particularly evident post-treatment with N-acetyl-L-cysteine. The alternating current conductivity and permittivity of the nail, particularly at low frequencies, increased with hydration. Iontophoresis increased the low frequency ac conductivity of the nail but had less effect on the nail capacitance/permittivity. Further, the effects seemed to return gradually to baseline after termination of current passage. Treatment with N-acetyl-L-cysteine produced a greater perturbation, leading to increased low-frequency conductivity and a shift of the frequency-dependent conductivity region to a higher frequency. CONCLUSIONS: Overall, the effects of iontophoresis on infrared and impedance spectroscopic profiles of the nail were attributable simply to increased hydration and similar to those observed after skin iontophoresis. In contrast, both spectroscopy techniques indicated that N-acetyl-L-cysteine disrupted nail structure in line with the enhancer's known effect on keratin. PMID- 23462935 TI - Response to the comment on the article "physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions". PMID- 23462933 TI - Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. AB - Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered. PMID- 23462936 TI - A mutation in a coproporphyrinogen III oxidase gene confers growth inhibition, enhanced powdery mildew resistance and powdery mildew-induced cell death in Arabidopsis. AB - KEY MESSAGE: A gene encoding a coproporphyrinogen III oxidase mediates disease resistance in plants by the salicylic acid pathway. A number of genes that regulate powdery mildew resistance have been identified in Arabidopsis, such as ENHANCED DISEASE RESISTANCE 1 to 3 (EDR1 to 3). To further study the molecular interactions between the powdery mildew pathogen and Arabidopsis, we isolated and characterized a mutant that exhibited enhanced resistance to powdery mildew. The mutant also showed dramatic powdery mildew-induced cell death as well as growth defects and early senescence in the absence of pathogens. We identified the affected gene by map-based cloning and found that the gene encodes a coproporphyrinogen III oxidase, a key enzyme in the tetrapyrrole biosynthesis pathway, previously known as LESION INITIATION 2 (LIN2). Therefore, we designated the mutant lin2-2. Further studies revealed that the lin2-2 mutant also displayed enhanced resistance to Hyaloperonospora arabidopsidis (H.a.) Noco2. Genetic analysis showed that the lin2-2-mediated disease resistance and spontaneous cell death were dependent on PHYTOALEXIN DEFICIENT 4 (PAD4), SALICYLIC ACID INDUCTION DEFICIENT 2 (SID2), and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1), which are all involved in salicylic acid signaling. Furthermore, the relative expression levels of defense-related genes were induced after powdery mildew infection in the lin2-2 mutant. These data indicated that LIN2 plays an important role in cell death control and defense responses in plants. PMID- 23462937 TI - A three-dimensional finite element model of round window membrane vibration before and after stapedotomy surgery. AB - Piston stapes prostheses are implanted in patients with refractory conductive or mixed hearing loss due to stapes otosclerosis to stimulate the perilymph with varying degrees of success. The overclosure effect described by the majority of researchers affects mainly low and medium frequencies, and a large number of patients report a lack of satisfactory results for frequencies above 2 kHz. The mechanics of perilymph stimulation with the piston have not been studied in a systematic manner. The objective of this study was to assess the influence of stapedotomy surgery on round window membrane vibration and to estimate the postoperative outcomes using the finite element (FE) method. The study hypothesis is that the three-dimensional FE model developed of the human inner ear, which simulates the round window (RW) membrane vibration, can be used to assess the influence of stapedotomy on auditory outcomes achieved after the surgical procedure. An additional objective of the study was to enable the simulation of RW membrane vibration after stapedotomy using a new type of stapes prosthesis currently under investigation at Warsaw University of Technology. A three dimensional finite element (FE) model of the human inner ear was developed and validated using experimental data. The model was then used to simulate the round window membrane vibration before and after stapedotomy surgery. Functional alterations of the RW membrane vibration were derived from the model and compared with the results of experimental measurements from temporal bones of a human cadaver. Piston stapes prosthesis implantation causes an approximately fivefold (14 dB) lower amplitude of the RW membrane vibrations compared with normal anatomical conditions. A satisfactory agreement between the FE model and the experimental data was found. The new prosthesis caused an increase of 20-30 dB in the RW displacement amplitude compared with the 0.4-mm piston prosthesis. In all frequencies, the FE model predicted a RW displacement curve that was above the experimental curves for the normal ear. The stapedotomy can be well simulated by the FE model to predict the auditory outcomes achieved following this otosurgery procedure. The 3D FE model developed in this study may be used to optimize the geometry of a new type of stapes prosthesis in order to achieve a similar sound transmission through the inner ear as for a normal middle ear. This should provide better auditory outcomes for patients with stapedial otosclerosis. PMID- 23462938 TI - Measuring the efficiencies of visiting nurse service agencies using data envelopment analysis. AB - This study develops a measure of the efficiency of visiting nurse (VN) agencies in Japan, examining the issues related to the measurement of efficiency, and identifying the characteristics that influence efficiency. We have employed a data envelopment analysis to measure the efficiency of 108 VN agencies, using the numbers of 5 types of staff as the input variables and the numbers of 3 types of visits as the output variables. The median efficiency scores of the VN agencies were found to be 0.80 and 1.00 according to the constant returns to scale (CRS) and variable returns to scale (VRS) models, respectively, and the median scale efficiency score was 0.95. This study supports using both the CRS and VRS models to measure the scale efficiency of VN service agencies. We also found that relatively efficient VN agencies filled at least 30 % of staff positions with experienced workers, and so concluded that this characteristic has a direct influence on the length of visits. PMID- 23462939 TI - Voluntary food fortification in the United States: potential for excessive intakes. AB - BACKGROUND: Historically, the voluntary addition of micronutrients to foods in the United States has been regarded as an important means to lessen problems of nutrient inadequacy. With expanding voluntary food fortification and widespread supplement use, it is important to understand how voluntary food fortification has an impact on the likelihood of excessive usual intakes. Our objective was to investigate whether individuals in the United States with greater frequency of exposure to micronutrients from voluntarily fortified foods (vFF) are more likely to have usual intakes approaching or exceeding the respective tolerable upper intake levels (UL). SUBJECTS/METHODS: The National Cancer Institute method was applied to data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) to estimate the joint distribution of usual intake from both vFF and non-vFF sources for 12 nutrients and determine the probability of consuming these nutrients from vFF on a given day. For each nutrient, we estimated the distribution of usual intake from all food sources by quintile of probability of consuming vFF and compared the distributions with ULs. RESULTS: An increased probability of consuming zinc, retinol, folic acid, selenium and copper from vFF was associated with a greater risk of intakes above the UL among children. Among adults, increased probability of consuming calcium and iron from vFF was associated with a greater risk of intakes above the UL among some age/sex groups. CONCLUSION: The high nutrient exposures associated with vFF consumption in some population subgroups suggest a need for more careful weighing of the risks and benefits of uncontrolled food fortification. PMID- 23462940 TI - Iodine status in schoolchildren living in northeast Italy: the importance of iodized-salt use and milk consumption. AB - BACKGROUND: The aims of the study were: (i) to determine iodine status of schoolchildren living in northeast Italy; (ii) to assess dietary habits and iodine status and (iii) to investigate the level of knowledge concerning iodine sufficiency and ways to ameliorate iodine status. METHODS: One thousand three hundred seventy-five consecutive 12-13 year-old completed questionnaires collecting demographic data and information about the use of iodized salt and food frequency habits. Iodine concentration in urine samples (UIC) and in commercially available milk samples has been measured. RESULTS: The median UIC was found to be 81 MUg/l (95% confidence interval (CI) 74-87); 40% of the subjects had an UIC of >= 100 MUg/l. Iodine deficiency was prevalent in subjects living in hilly areas. Median iodine concentration in milk was 264 MUg/l. Only the combined use of iodized salt plus daily milk normalized UIC, resulting into a median value of 108 MUg/l. A logistic regression model confirmed independent associations between low UIC and low intake of milk, use of non-iodized salt and geographical location (P<0.0001). Only 45% of the subjects were aware of the importance of iodine. CONCLUSIONS: Northeast Italy is still characterized by mild iodine deficiency. An adequate iodine status was achieved only when iodized salt was combined with daily milk intake. The national iodine prophylaxis program has led to greater consumption of iodized salt and, it is now used in 60-70% of the Italian households. The low level of awareness highlights the need for public programs to promote knowledge and efforts to improve iodine status. PMID- 23462941 TI - Plasma 25 hydroxyvitamin D level and blood gene expression profiles: a cross sectional study of the Norwegian Women and Cancer Post-genome Cohort. AB - BACKGROUND/OBJECTIVES: Vitamin D deficiency has been associated with increased risk of developing several diseases, but much is unknown about the molecular effects involved. Gene expression technology is increasingly being used to elucidate molecular mechanisms related to nutritional factors, and in this study of free-living, middle-aged Norwegian women, we aimed at identifying gene expression pathways in the blood associated with vitamin D status. SUBJECTS/METHODS: Blood samples and questionnaires were collected as a part of the Norwegian Women and Cancer Post-genome Cohort (500 invited subjects, 218 included). Plasma 25 hydroxyvitamin D (25(OH)D) concentrations were measured using high-performance liquid chromatography, and we compared groups with sufficient versus deficient vitamin D status (25(OH)D >50 nmol/l (n=66) versus <37.5 nmol/l (n=83)), to identify differences in gene expression profiles obtained using full-genome microarrays. RESULTS: In a targeted pathway-level analysis, several immunological processes, immune cell functions and major signaling pathways were differentially regulated according to vitamin D status (P<0.01). To a certain degree, results from in vitro studies reported in the literature were reflected in this population setting. CONCLUSIONS: We conclude that vitamin D status measured as 25(OH)D was associated with molecular pathways that may ultimately affect the potential onset of diseases. The use of gene expression analysis in a population setting may give valuable input to the study of effects of nutritional factors. PMID- 23462942 TI - Factors associated with the timing of introduction of complementary feeding: the Generation R Study. AB - BACKGROUND/OBJECTIVES: Many parents do not follow recommendations for the timing of introduction of complementary feeding. The aim of this study was to identify determinants associated with the timing of introduction of complementary feeding in a multiethnic birth cohort. SUBJECTS/METHODS: Subjects were 3561 mothers and infants participating in a prospective cohort study. The timing of introduction of complementary feeding and maternal and infant characteristics were obtained by parent-derived questionnaires. Regression analyses were performed to identify determinants for the timing of introduction of complementary feeding (<3, 3-6 and >= 6 months). RESULTS: In total, 62% of infants were introduced to complementary feeding before the age of 6 months. Determinants for very early (<3 months) introduction were being a single parent and infant day care attendance. Determinants for early (3-6 months) introduction were young maternal age, multiple parities, no infant family history of asthma, atopy and no infant history of allergy to cow's milk. Determinants for both very early and early introduction were low educational level and not fully breastfeeding for 4 months. Maternal educational level was only significantly associated with the timing of introduction in mothers of Western origin. CONCLUSIONS: This study confirmed determinants for the timing of introduction of complementary feeding that have been identified by previous studies, which may be appropriate targets for education and guidance. Moreover, mothers whose infants attend day care and have a family history of asthma, atopy or allergy to cow's milk may need guidance to follow infant feeding recommendations. PMID- 23462944 TI - Beyond breast carcinomas: the attenuating effect on tumor growth in other systemic malignancies by raloxifene. PMID- 23462943 TI - Effect of a dairy- and calcium-rich diet on weight loss and appetite during energy restriction in overweight and obese adults: a randomized trial. AB - BACKGROUND/OBJECTIVES: A diet rich in dairy and calcium (Ca) has been variably associated with improvements in body composition and decreased risk of type 2 diabetes. Our objective was to determine if a dietary pattern high in dairy and Ca improves weight loss and subjective appetite to a greater extent than a low dairy/Ca diet during energy restriction in overweight and obese adults with metabolic syndrome. SUBJECTS/METHODS: A total of 49 participants were randomized to one of two treatment groups: Control (low dairy, ~ 700 mg/day Ca, -500 kcal/day) or Dairy/Ca (high dairy, ~ 1400 mg/day Ca, -500 kcal/day) for 12 weeks. Body composition, subjective ratings of appetite, food intake, plasma satiety hormones, glycemic response and inflammatory cytokines were measured. RESULTS: Control (-2.2 +/- 0.5 kg) and Dairy/Ca (-3.3 +/- 0.6 kg) had similar weight loss. Based on self-reported energy intake, the percentage of expected weight loss achieved was higher with Dairy/Ca (82.1 +/- 19.4%) than Control (32.2 +/- 7.7%; P=0.03). Subjects in the Dairy/Ca group reported feeling more satisfied (P=0.01) and had lower dietary fat intake (P=0.02) over 12 weeks compared with Control. Compared with Control, Dairy/Ca had higher plasma levels of peptide tyrosine tyrosine (PYY, P=0.01) during the meal tolerance test at week 12. Monocyte chemoattractant protein-1 was reduced at 30 min with Dairy/Ca compared with Control (P=0.04). CONCLUSIONS: In conclusion, a dairy- and Ca-rich diet was not associated with greater weight loss than control. Modest increases in plasma PYY concentrations with increased dairy/Ca intake, however, may contribute to enhanced sensations of satisfaction and reduced dietary fat intake during energy restriction. PMID- 23462945 TI - Iron status and linear growth: a prospective study in school-age children. AB - BACKGROUND: Studies regarding the role of iron on linear growth have yielded heterogeneous results. Some trials indicate that iron supplementation of iron replete infants leads to slower-length gain. However, little is known of the relation between iron status and linear growth in school-age children. METHODS: We quantified plasma ferritin, mean corpuscular volume (MCV), and hemoglobin in 2714 children aged 5-12 years at recruitment into a cohort study. Height was measured periodically for a median of 30 months. Height-for-age Z-scores (HAZ) were calculated using the World Health Organization growth reference. Mixed effects models with restricted cubic splines were used to construct population HAZ-for-age growth curves for sex- and age-specific quartiles of each iron status indicator. RESULTS: Ferritin and MCV were each inversely related to attained HAZ among boys after the adjustment for baseline age, baseline body mass index-for age Z-score and socioeconomic status. There was a decreasing monotonic relation between quartiles of ferritin and estimated change in HAZ from ages 6 to 14 years (P trend=0.001); boys in the 4th quartile experienced a HAZ change that was 0.46 Z lower than that of boys in the 1st quartile (P=0.0006). Similarly, we observed smaller HAZ change among boys in the highest quartile of MCV in comparison with those in the 1st quartile (P trend=0.001). Hemoglobin was not related to linear growth in boys. None of the iron-status indicators were associated with linear growth in girls. CONCLUSIONS: Higher iron status, as indicated by ferritin and MCV, is related to slower linear growth in iron-replete school-age boys. PMID- 23462946 TI - Nutritional care in children with cystic fibrosis: are our patients becoming better? AB - Over the last 30 years, major advances have occurred in our understanding of the disorder cystic fibrosis (CF) with the discoveries of the underlying chloride transport defect and the 'CF gene', the CF transmembrane conductance regulator gene. Equally important from a clinical and patient perspective are the improvements in median survival from less than 10 to 20 years prior to 1980, approaching 30 years during the 1980s and over 45 years more recently. Improved antibiotic regimens and lung clearance therapy contributed to the enhanced survival, but a key factor accredited as adding a further 10 years to the median survival was improving and then maintaining normal growth and nutrition. In the main, the latter were achieved by adherence to a 'high-fat high-energy' diet rather than the advocated virtually universal policy of the 'low fat', which was associated with wasting and linear growth failure. The high-fat diet in conjunction with better control of malabsorption due to microspheric pancreatic enzyme replacement therapy, attention to adequate fat-soluble vitamin supplementation and newborn screening has ensured that at least 80-90% of children with CF will achieve better health and survival through their adult years. PMID- 23462947 TI - New dietary reference values for vitamin D in the Netherlands. PMID- 23462948 TI - Postprandial total and HMW adiponectin following a high-fat meal in lean, obese and diabetic men. AB - BACKGROUND/OBJECTIVES: Recent work suggests that macronutrients are pro inflammatory and promote oxidative stress. Reports of postprandial regulation of total adiponectin have been mixed, and there is limited information regarding postprandial changes in high molecular weight (HMW) adiponectin. The aim of this study was to assess the effect of a standardised high-fat meal on metabolic variables, adiponectin (total and HMW), and markers of inflammation and oxidative stress in: (i) lean, (ii) obese non-diabetic and (iii) men with type 2 diabetes mellitus (T2DM). SUBJECTS/METHODS: Male subjects: lean (n=10), obese (n=10) and T2DM (n=10) were studied for 6 h following both a high-fat meal and water control. Metabolic variables (glucose, insulin, triglycerides), inflammatory markers (interleukin-6 (IL6), tumour necrosis factor (TNF)alpha, high-sensitivity C-reactive protein (hsCRP), nuclear factor (NF)kappaB expression in peripheral blood mononuclear cells (p65)), indicators of oxidative stress (oxidised low density lipoprotein (oxLDL), protein carbonyl) and adiponectin (total and HMW) were measured. RESULTS: No significant changes in TNFalpha, p65, oxLDL or protein carbonyl concentrations were observed. Overall, postprandial IL6 decreased in subjects with T2DM but increased in lean subjects, whereas hsCRP decreased in the lean cohort and increased in obese subjects. There was no overall postprandial change in total or HMW adiponectin in any group. Total adiponectin concentrations changed over time following the water control, and the response was significantly different in lean subjects compared with subjects with T2DM (P=0.04). CONCLUSIONS: No consistent significant postprandial inflammation, oxidative stress or regulation of adiponectin was observed in this study. Findings from the water control suggest differential basal regulation of total adiponectin in T2DM compared with lean controls. PMID- 23462949 TI - Determinants of adherence to gluten-free diet in Greek children with coeliac disease: a cross-sectional study. AB - BACKGROUND/OBJECTIVE: A strict and lifelong commitment to a gluten-free diet (GFD) remains one of the most challenging issues in children with coeliac disease. The present study aimed to record compliance rates and investigate the connection between dietary compliance and demographics, disease-related factors and parental knowledge. SUBJECTS/METHODS: Parents of 90 Greek children diagnosed with coeliac disease were recruited from the outpatient gastroenterology clinic of a children's hospital in Athens, Greece. Dietary compliance and a range of demographic and clinical data were obtained from parents through a specially constructed questionnaire. Further data included parental perceived and actual knowledge about coeliac disease and GFD. Compliant and noncompliant groups were compared for measured factors and a multivariate approach was followed to elicit independent effects of compliance determinants. RESULTS: Overall, 44.4% of children with coeliac disease were reported to be compliant to a strict GFD. A 1 year increase in the age of the child was associated with 15% lower odds of adhering to a strict diet after adjusting for other variables (odds ratio (OR)=0.85, 95% CI: 0.75-0.96). Parental perceived knowledge was also independently and significantly associated with dietary compliance (OR=3.3, 95% CI=1.1-9.8). No statistically significant correlation emerged between dietary compliance and other clinical or demographic variables. DISCUSSION: Low compliance rates to GFD were observed in children with coeliac disease. Information based on children's age and perceived parental knowledge can be used to develop risk profiles that health care professionals can utilise to identify children likely to be noncompliant and thus adjust their counselling strategy accordingly. PMID- 23462950 TI - Dental infection as a triggering factor in palmoplantar pustulosis. PMID- 23462951 TI - A new fluorometric turn-on assay for alkaline phosphatase and inhibitor screening based on aggregation and deaggregation of tetraphenylethylene molecules. AB - Based on the consideration that compound 1 with a -PO3H2 group can be hydrolyzed into compound 3 which shows low solubility in aqueous solutions and thus aggregation can occur easily, a new fluorescence turn-on assay has been constructed for alkaline phosphatase (ALP) with compound 1. ALP at concentrations as low as 18 mU mL(-1) can be assayed with compound 1. Moreover, compound 1 has been successfully applied for ALP assay in living cells. Also, compound 1 is useful for screening inhibitors of ALP. PMID- 23462953 TI - Active regulator of SIRT1 is required for ribosome biogenesis and function. AB - Active regulator of SIRT1 (AROS) binds and upregulates SIRT1, an NAD(+)-dependent deacetylase. In addition, AROS binds RPS19, a structural ribosomal protein, which also functions in ribosome biogenesis and is implicated in multiple disease states. The significance of AROS in relation to ribosome biogenesis and function is unknown. Using human cells, we now show that AROS localizes to (i) the nucleolus and (ii) cytoplasmic ribosomes. Co-localization with nucleolar proteins was verified by confocal immunofluorescence of endogenous protein and confirmed by AROS depletion using RNAi. AROS association with cytoplasmic ribosomes was analysed by sucrose density fractionation and immunoprecipitation, revealing that AROS selectively associates with 40S ribosomal subunits and also with polysomes. RNAi-mediated depletion of AROS leads to deficient ribosome biogenesis with aberrant precursor ribosomal RNA processing, reduced 40S subunit ribosomal RNA and 40S ribosomal proteins (including RPS19). Together, this results in a reduction in 40S subunits and translating polysomes, correlating with reduced overall cellular protein synthesis. Interestingly, knockdown of AROS also results in a functionally significant increase in eIF2alpha phosphorylation. Overall, our results identify AROS as a factor with a role in both ribosome biogenesis and ribosomal function. PMID- 23462954 TI - Splicing proofreading at 5' splice sites by ATPase Prp28p. AB - Fidelity and efficiency of pre-mRNA splicing are critical for generating functional mRNAs, but how such accuracy in 5' splice site (SS) selection is attained is not fully clear. Through a series of yeast genetic screens, we isolated alleles of prp28 that improve splicing of suboptimal 5'SS substrates, demonstrating that WT-Prp28p proofreads, and consequently rejects, poor 5'SS. Prp28p is thought to facilitate the disruption of 5'SS-U1 snRNA pairing to allow for 5'SS-U6 snRNA pairing in the catalytic spliceosome; unexpectedly, 5'SS proofreading by Prp28p is dependent on competition with the stability of the 5'SS:U6 duplex, but not the 5'SS:U1 duplex. E404K, the strongest prp28 allele containing a mutation located in the linker region between adenosine triphosphatase (ATPase) subdomains, exhibited lower RNA-binding activity and enhanced splicing of suboptimal substrates before first-step catalysis, suggesting that decreased Prp28p activity allows longer time for suboptimal 5'SS substrates to pair with U6 snRNA and thereby reduces splicing fidelity. Residue E404 is critical for providing high splicing activity, demonstrated here in both yeast and Drosophila cells. Thus, the subdomain linker in Prp28p plays important roles both in splicing efficiency across species and in proofreading of 5'SS. PMID- 23462955 TI - The effect of cortical button location on its post-operative migration in anatomical double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: To investigate the effect of EndoButton (Smith & Nephew Endoscopy, Andover, MA, USA) location on post-operative migration in anterior cruciate ligament (ACL) reconstruction. METHODS: Seventy-seven patients underwent anatomical double-bundle ACL reconstruction using EndoButtons. Comparing patient radiographs immediately post-operatively with those at 1 year, migration was defined when EndoButtons moved more than 1 mm or rotated over 5 degrees . Initial location of EndoButtons was evaluated on radiographs immediately post operatively. We measured distances from the EndoButton to the posterior and distal edge of the femur (D1, D2) on lateral radiographs and distances from the EndoButton to the lateral and distal edge of the femur (D3, D4) on anteroposterior radiographs. The relationship between supracondylar line and the ratio of migration was also investigated. RESULTS: D1 in the migrated group were significantly lower than those in the non-migrated group (11.8 +/- 12.7 vs. 16.0 +/- 10.2 mm). D2, D3 and D4 were not of significant difference in the two groups. The ratio of migration in the area posterior to the supracondylar line was significantly higher than that in the anterior area (54.3 vs. 15.1%). CONCLUSION: EndoButtons, which was located distally and posteriorly, especially in the area posterior to the lateral supracondylar line, migrated more frequently, although migration of the button had no effect on the clinical parameters evaluated in this study. CLINICAL RELEVANCE: It is preferable to settle EndoButton anteriorly to the lateral supracondylar line in order to avoid its migration for the graft tension due to our findings about the relationship between initial location of EndoButton and the rate of migration. LEVEL OF EVIDENCE: Prognostic case series, Level IV. PMID- 23462956 TI - Treatment for Staphylococcus aureus infection following open wedge high tibial osteotomy using antibiotic-impregnated calcium phosphate cement. AB - This report describes a case of Staphylococcus aureus infection following open wedge high tibial osteotomy, which was successfully treated with by implant removal and replacement with antibiotic-impregnated calcium phosphate cement along with external fixation. The infection occurred 7 months after primary surgery and was treated by implant removal, debridement, external fixation, and application of vancomycin impregnated calcium phosphate cement to fill the defect. Subsequently, the infection resolved completely, and the osteotomy healed with no correction loss. Compared with conventional bone cement, calcium phosphate cement might be an optimal material for certain cases of infection after open wedge high tibial osteotomy because of its higher antibiotic retention, biocompatibility, osteoconductivity, and compatibility with heatlabile antibiotics. LEVEL OF EVIDENCE: V. PMID- 23462957 TI - The effect of infraspinatus hypotrophy and weakness on the arthroscopic treatment of spinoglenoid notch cyst associated with superior labrum anterior-to-posterior lesions. AB - PURPOSE: Patients with spinoglenoid notch cyst associated with superior labrum anterior-to-posterior (SLAP) lesions were evaluated. The patients were all treated by arthroscopic cyst decompression combined with SLAP repair. The hypothesis of the study was that the patients who underwent prolonged conservative treatment period prior to surgery would exhibit significant infraspinatus hypotrophy and weakness, and their postoperative clinical and functional outcomes would be less satisfactory. METHODS: Sixteen patients exhibited positive MRI and EMG findings with clinical signs of weakness and pain. The median age was 40.5 years (range 32-52), and the study group consisted of 11 males and 5 females with a median follow-up period of 26 months (12-48). The median duration of symptoms and conservative treatment prior to the surgical intervention was 3.5 months (1-14). Seven patients in group A exhibited infraspinatus hypotrophy. Group B comprised 9 patients without infraspinatus hypotrophy. RESULTS: The results of the pre- and postoperative Constant scores, visual analogue scale (VAS) scores, and external rotation strength test rates were compared between groups. They all improved in terms of pain, strength, and function (P < 0.05). Significant differences were observed between the pre- and postoperative external rotation strengths and Constant scores (P < 0.05). However, no significant difference was observed between the pre- and postoperative VAS scores (n.s.). A significant correlation was observed in group A between surgical timing, the preoperative external rotation strength ratio (P = 0.04) and the postoperative VAS scores (P = 0.013). CONCLUSION: The arthroscopic treatment was satisfactory with good clinical outcomes. Infraspinatus hypotrophy occurred in cases of prolonged surgical duration and significantly affected external rotation strength and functional outcomes. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 23462958 TI - Pulmonary vein stump thrombus: an early complication following upper division segmentectomy of the left lung. AB - We report a rare case of a pulmonary vein stump thrombus detected by a contrast enhanced computed tomography for transient syncope 2 days after upper division segmentectomy of the left lung for metastatic pulmonary tumor. The thrombus disappeared without embolic events after anticoagulation with intravenous heparin followed by oral warfarin. Considering this case and previous reports, thoracic surgeons should be aware of pulmonary vein stump thrombus, a latent source of systemic embolization, after pulmonary resection, especially lobectomy or segmentectomy of the left upper lobe. This possible serious complication can occur at any time from the early postoperative period. PMID- 23462959 TI - Is stone diameter a variable in the decision process of employing a ureteral stent in patients undergoing uncomplicated ureterorenoscopy and associated intracorporeal lithotripsy? AB - INTRODUCTION: A number of randomized trials and meta-analysis in patients who underwent ureteroscopic stone removal investigated the effects of placing a ureteral stent at the end of the procedure on complication rates. However, none of these investigates the stone diameter and its possible influence on complication rates and, as such, if it should be considered a possible variable in the decision process of placing or not a ureteral stent. MATERIALS AND METHODS: A bibliographic search covering the period from January 1990 to March 2012 was conducted in PubMed, MEDLINE and EMBASE. This analysis is based on the fifteen remaining studies which fulfilled the predefined inclusion criteria. All statistical evaluations were performed using SAS version 9.2. and by RevMan 5.0. RESULTS: A total of 1,416 patients were included. All the studies were published after 2000. Mean stone diameter ranged between 5.3 and 13.3 mm in the non-stented group and between 6.26 and 13.28 mm in the stented group. Meta-analysis showed that stone diameter was not statistically different for stented or non-stented subgroups, whereas surgical operative time was shorter for the non-stented subgroup. The effect of stone diameter, irrespectively if patients were operated with or without stents were grouped or considered separately, did not influence complications of fever, haematuria, unplanned medical visits after surgery and urinary tract infections. CONCLUSIONS: Stone diameter is not a variable in the pre- or intraoperative decision process of placing or not placing a ureteral stent in patients undergoing uncomplicated ureterorenoscopy with intracorporeal lithotripsy. PMID- 23462960 TI - Lactating Ctcgrp nulls lose twice the normal bone mineral content due to fewer osteoblasts and more osteoclasts, whereas bone mass is fully restored after weaning in association with up-regulation of Wnt signaling and other novel genes. AB - The maternal skeleton resorbs during lactation to provide calcium to milk and the lost mineral content is restored after weaning. The changes are particularly marked in Ctcgrp null mice, which lose 50% of spine mineral content during lactation but restore it fully. The known calciotropic hormones are not required for skeletal recovery to occur; therefore, unknown factors that stimulate bone formation may be responsible. We hypothesized that the genes responsible for regulating postweaning bone formation are differentially regulated in bone or marrow, and this regulation may be more marked in Ctcgrp null mice. We confirmed that Ctcgrp null mice had twice as many osteoclasts and 30-40% fewer osteoblasts as compared with wild-type mice during lactation but no deficit in osteoblast numbers after weaning. Genome-wide microarray analyses on tibial RNA showed differential expression of 729 genes in wild-type mice at day 7 after weaning vs prepregnancy, whereas the same comparison in Ctcgrp null mice revealed only 283 genes. Down-regulation of Wnt family inhibitors, Sost and Dkk1, and inhibition of Mef2c, a sclerostin stimulator, were observed. Ctsk, a gene expressed during osteoclast differentiation, and Igfbp2, which stimulates bone resorption, were inhibited. Differential regulation of genes involved in energy use was compatible with a net increase in bone formation. The most marked changes occurred in genes not previously associated with bone metabolism. In conclusion, the postlactation skeleton shows dynamic activity with more than 700 genes differentially expressed. Some of these genes are likely to promote bone formation during postweaning by stimulating the proliferation and activity of osteoblasts, inhibiting osteoclasts, and increasing energy use. PMID- 23462961 TI - Antiproliferative, antiinvasive, and proapoptotic activity of folate receptor alpha-targeted liposomal doxorubicin in nonfunctional pituitary adenoma cells. AB - There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)alpha is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FRalpha-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FRalpha and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9, and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FRalpha plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FRalpha. PMID- 23462963 TI - Protection and Systemic Translocation of siRNA Following Oral Administration of Chitosan/siRNA Nanoparticles. AB - Harnessing the RNA interference pathway offers a new therapeutic modality; however, solutions to overcome biological barriers to small interfering RNA (siRNA) delivery are required for clinical translation. This work demonstrates, by direct northern and quantitative PCR (qPCR) detection, stability, gastrointestinal (GI) deposition, and translocation into peripheral tissue of nonmodified siRNA after oral gavage of chitosan/siRNA nanoparticles in mice. In contrast to naked siRNA, retained structural integrity and deposition in the stomach, proximal and distal small intestine, and colon was observed at 1 and 5 hours for siRNA within nanoparticles. Furthermore, histological detection of fluorescent siRNA at the apical regions of the intestinal epithelium suggests mucoadhesion provided by chitosan. Detection of intact siRNA in the liver, spleen, and kidney was observed 1 hour after oral gavage, with an organ distribution pattern influenced by nanoparticle N:P ratio that could reflect differences in particle stability. This proof-of-concept work presents an oral delivery platform that could have the potential to treat local and systemic disorders by siRNA.Molecular Therapy - Nucleic Acids (2013) 2, e76; doi:10.1038/mtna.2013.2; published online 5 March 2013. PMID- 23462962 TI - cAMP response element-binding protein interacts with and stimulates the proteasomal degradation of the nuclear receptor coactivator GRIP1. AB - The glucocorticoid receptor interacting protein (GRIP1) belongs to the p160 steroid receptor coactivator family that plays essential roles in nuclear receptor-dependent transcriptional regulation. Previously, we reported that the cAMP-dependent protein kinase (PKA) induces ubiquitination leading to degradation of GRIP1. Here we show that the cAMP response element-binding protein (CREB) downregulates GRIP1 and is necessary for the PKA-stimulated degradation of GRIP1, which leads to changes in the expression of a subset of genes regulated by estrogen receptor-alpha in MCF-7 breast cancer cells. Our data of domain-mapping and ubiquitination analyses suggest that CREB promotes the proteasomal breakdown of ubiquitinated GRIP1 through 2 functionally independent protein domains containing amino acids 347 to 758 and 1121 to 1462. We provide evidence that CREB interacts directly with GRIP1 and that CREB Ser-133 phosphorylation or transcriptional activity is not required for GRIP1 interaction and degradation. The basic leucine zipper domain (bZIP) of CREB is important for the interaction with GRIP1, and deletion of this domain led to an inability to downregulate GRIP1. We propose that CREB mediates the PKA-stimulated degradation of GRIP1 through protein-protein interaction and stimulation of proteasomal degradation of ubiquitinated GRIP1. PMID- 23462964 TI - Transient Expression of an LEDGF/p75 Chimera Retargets Lentivector Integration and Functionally Rescues in a Model for X-CGD. AB - Retrovirus-based vectors are commonly used as delivery vehicles to correct genetic diseases because of their ability to integrate new sequences stably. However, adverse events in which vector integration activates proto-oncogenes, leading to clonal expansion and leukemogenesis hamper their application. The host cell-encoded lens epithelium-derived growth factor (LEDGF/p75) binds lentiviral integrase and targets integration to active transcription units. We demonstrated earlier that replacing the LEDGF/p75 chromatin interaction domain with an alternative DNA-binding protein could retarget integration. Here, we show that transient expression of the chimeric protein using mRNA electroporation efficiently redirects lentiviral vector (LV) integration in wild-type (WT) cells. We then employed this technology in a model for X-linked chronic granulomatous disease (X-CGD) using myelomonocytic PLB-985 gp91(-/-) cells. Following electroporation with mRNA encoding the LEDGF-chimera, the cells were treated with a therapeutic lentivector encoding gp91(phox). Integration site analysis revealed retargeted integration away from genes and towards heterochromatin-binding protein 1beta (CBX1)-binding sites, in regions enriched in marks associated with gene silencing. Nevertheless, gp91(phox) expression was stable for at least 6 months after electroporation and NADPH-oxidase activity was restored to normal levels as determined by superoxide production. Together, these data provide proof of-principle that transient expression of engineered LEDGF-chimera can retarget lentivector integration and rescues the disease phenotype in a cell model, opening perspectives for safer gene therapy.Molecular Therapy - Nucleic Acids (2013) 2, e77; doi:10.1038/mtna.2013.4; published online 5 March 2013. PMID- 23462965 TI - Validation of different instruments for caffeine measurement among premenopausal women in the BioCycle study. AB - Effects of caffeine on women's health are inconclusive, in part because of inadequate exposure assessment. In this study we determined 1) validity of a food frequency questionnaire compared with multiple 24-hour dietary recalls (24HDRs) for measuring monthly caffeine and caffeinated beverage intakes; and 2) validity of the 24HDR compared with the prior day's diary record for measuring daily caffeinated coffee intake. BioCycle Study (2005-2007) participants, women (n = 259) aged 18-44 years from western New York State, were followed for 2 menstrual cycles. Participants completed a food frequency questionnaire at the end of each cycle, four 24HDRs per cycle, and daily diaries. Caffeine intakes reported for the food frequency questionnaires were greater than those reported for the 24HDRs (mean = 114.1 vs. 92.6mg/day, P = 0.01) but showed high correlation (r = 0.73, P < 0.001) and moderate agreement (K = 0.51, 95% confidence interval: 0.43, 0.57). Women reported less caffeinated coffee intake in their 24HDRs compared with their corresponding diary days (mean = 0.51 vs. 0.80 cups/day, P < 0.001) (1 cup = 237 mL). Although caffeine and coffee exposures were highly correlated, absolute intakes differed significantly between measurement tools. These results highlight the importance of considering potential misclassification of caffeine exposure. PMID- 23462966 TI - Regional epidemiologic assessment of prevalent periodontitis using an electronic health record system. AB - An oral health surveillance platform that queries a clinical/administrative data warehouse was applied to estimate regional prevalence of periodontitis. Cross sectional analysis of electronic health record data collected between January 1, 2006, and December 31, 2010, was undertaken in a population sample residing in Ladysmith, Wisconsin. Eligibility criteria included: 1) residence in defined zip codes, 2) age 25-64 years, and 3) >=1 Marshfield dental clinic comprehensive examination. Prevalence was established using 2 independent methods: 1) via an algorithm that considered clinical attachment loss and probe depth and 2) via standardized Current Dental Terminology (CDT) codes related to periodontal treatment. Prevalence estimates were age-standardized to 2000 US Census estimates. Inclusion criteria were met by 2,056 persons. On the basis of the American Academy of Periodontology/Centers for Disease Control and Prevention method, the age-standardized prevalence of moderate or severe periodontitis (combined) was 407 per 1,000 males and 308 per 1,000 females (348/1,000 males and 269/1,000 females using the CDT code method). Increased prevalence and severity of periodontitis was noted with increasing age. Local prevalence of periodontitis was consistent with national estimates. The need to address potential sample selection bias in future electronic health record-based periodontitis research was identified by this approach. Methods outlined herein may be applied to refine oral health surveillance systems, inform dental epidemiologic methods, and evaluate interventional outcomes. PMID- 23462967 TI - 'Marker-of-self' functionalization of nanoscale particles through a top-down cellular membrane coating approach. AB - We investigate the 'marker-of-self' functionalization of nanoparticles through coating of natural RBC membranes. The membrane translocation approach is shown to be highly efficient and bestows nanoparticles with correctly oriented and functional immunomodulatory proteins such as CD47 at equivalent density to natural RBCs. PMID- 23462968 TI - Probing the fractal pattern and organization of Bacillus thuringiensis bacteria colonies growing under different conditions using quantitative spectral light scattering polarimetry. AB - Development of methods for quantification of cellular association and patterns in growing bacterial colony is of considerable current interest, not only to help understand multicellular behavior of a bacterial species but also to facilitate detection and identification of a bacterial species in a given space and under a given set of condition(s). We have explored quantitative spectral light scattering polarimetry for probing the morphological and structural changes taking place during colony formations of growing Bacillus thuringiensis bacteria under different conditions (in normal nutrient agar representing favorable growth environment, in the presence of 1% glucose as an additional nutrient, and 3 mM sodium arsenate as toxic material). The method is based on the measurement of spectral 3*3 Mueller matrices (which involves linear polarization measurements alone) and its subsequent analysis via polar decomposition to extract the intrinsic polarization parameters. Moreover, the fractal micro-optical parameter, namely, the Hurst exponent H, is determined via fractal-Born approximation-based inverse analysis of the polarization-preserving component of the light scattering spectra. Interesting differences are noted in the derived values for the H parameter and the intrinsic polarization parameters (linear diattenuation d, linear retardance delta, and linear depolarization Delta coefficients) of the growing bacterial colonies under different conditions. The bacterial colony growing in presence of 1% glucose exhibit the strongest fractality (lowest value of H), whereas that growing in presence of 3 mM sodium arsenate showed the weakest fractality. Moreover, the values for delta and d parameters are found to be considerably higher for the colony growing in presence of glucose, indicating more structured growth pattern. These findings are corroborated further with optical microscopic studies conducted on the same samples. PMID- 23462969 TI - In vivo high spatiotemporal resolution visualization of circulating T lymphocytes in high endothelial venules of lymph nodes. AB - Lymph nodes (LN) are major checkpoints for circulating T lymphocytes to recognize foreign antigens collected from peripheral tissue. High endothelial venule (HEV) in LN facilitates the effective transmigration of circulating T lymphocytes from the blood into LN. There have been many efforts to visualize T lymphocytes trafficking across HEV to understand the underlying mechanism. However, due to insufficient spatiotemporal resolution and the lack of an in vivo labeling method, clear visualization of dynamic behaviors of rapidly flowing T lymphocytes in HEV and their transmigration have been difficult. In this work, we adapted a custom-designed video-rate laser scanning confocal microscopy system to track individual flowing T lymphocytes in the HEV in real time in vivo. We demonstrate that the HEVs in LN can be clearly identified in vivo with its distinctive cuboidal morphology of endothelial cells fluorescently labeled by intravenously injected anti-CD31 antibody conjugated with Alexa fluorophore. By visualizing the adaptively transferred T lymphocytes, we successfully analyzed dynamic flowing behaviors of T lymphocytes and their transendothelial migration while interacting with the endothelial cells in HEV. PMID- 23462971 TI - Protease- and acid-catalyzed labeling workflows employing (18)O-enriched water. AB - Stable isotopes are essential tools in biological mass spectrometry. Historically, (18)O-stable isotopes have been extensively used to study the catalytic mechanisms of proteolytic enzymes(1-3). With the advent of mass spectrometry-based proteomics, the enzymatically-catalyzed incorporation of (18)O atoms from stable isotopically enriched water has become a popular method to quantitatively compare protein expression levels (reviewed by Fenselau and Yao(4), Miyagi and Rao(5) and Ye et al.(6)). (18)O-labeling constitutes a simple and low-cost alternative to chemical (e.g. iTRAQ, ICAT) and metabolic (e.g. SILAC) labeling techniques(7). Depending on the protease utilized, (18)O-labeling can result in the incorporation of up to two (18)O-atoms in the C-terminal carboxyl group of the cleavage product(3). The labeling reaction can be subdivided into two independent processes, the peptide bond cleavage and the carboxyl oxygen exchange reaction(8). In our PALeO (protease-assisted labeling employing (18)O-enriched water) adaptation of enzymatic (18)O-labeling, we utilized 50% (18)O-enriched water to yield distinctive isotope signatures. In combination with high-resolution matrix-assisted laser desorption ionization time of-flight tandem mass spectrometry (MALDI-TOF/TOF MS/MS), the characteristic isotope envelopes can be used to identify cleavage products with a high level of specificity. We previously have used the PALeO-methodology to detect and characterize endogenous proteases(9) and monitor proteolytic reactions(10-11). Since PALeO encodes the very essence of the proteolytic cleavage reaction, the experimental setup is simple and biochemical enrichment steps of cleavage products can be circumvented. The PALeO-method can easily be extended to (i) time course experiments that monitor the dynamics of proteolytic cleavage reactions and (ii) the analysis of proteolysis in complex biological samples that represent physiological conditions. PALeO-TimeCourse experiments help identifying rate limiting processing steps and reaction intermediates in complex proteolytic pathway reactions. Furthermore, the PALeO-reaction allows us to identify proteolytic enzymes such as the serine protease trypsin that is capable to rebind its cleavage products and catalyze the incorporation of a second (18)O-atom. Such "double-labeling" enzymes can be used for postdigestion (18)O-labeling, in which peptides are exclusively labeled by the carboxyl oxygen exchange reaction. Our third strategy extends labeling employing (18)O-enriched water beyond enzymes and uses acidic pH conditions to introduce (18)O-stable isotope signatures into peptides. PMID- 23462972 TI - Anionic sulfonated and carboxylated PPI dendrimers with the EDA core: synthesis and characterization of selective metal complexing agents. AB - Herein we describe the synthesis and characterization of new sulfonated and carboxylated poly(propyleneimino) (PPI) dendrimers with the ethylenediamino (EDA) core, at generations 1, 2 and 3. By means of UV-Vis and EPR spectroscopy, using Cu(2+) as a probe, we concluded that these dendrimers show a specific pattern in the coordination of metal ions. In agreement with the UV-Vis studies, EPR spectra of carboxylated compounds are constituted by 3 different signals which appear and then disappear with increasing copper concentration, corresponding to the saturation of different copper complexation sites. At the lowest copper concentration up to a 1:1 molar ratio between Cu(II) and the dendrimer, the spectrum is characteristic of a CuN2O2 coordination at the core of the dendrimer. The spectrum appearing at higher Cu(II) concentrations indicates a peripheral location of the ions coordinating one nitrogen and 3 oxygen atoms in a square planar geometry in restricted mobility conditions. For the highest concentrations tested, copper ions are confined at the external dendrimer surface with CuO4 coordination. For sulfonate systems, the EPR results are in line with a weaker interaction of Cu(II) with the nitrogen sites and a stronger interaction with the oxygen (SO3(-)) groups with respect to the interactions measured by EPR for carboxylate systems. PMID- 23462974 TI - Expression of hypothalamic-pituitary-adrenal axis in common skin diseases: evidence of its association with stress-related disease activity. AB - Hypothalamic-pituitary-adrenal (HPA) axis hormones and their receptors expressed in the skin are known to function locally, but how these hormones affect the maintenance of skin homeostasis or the pathogenesis of skin diseases is not fully understood. We comprehensively reviewed the distribution and function of the central and peripheral HPA axis in various stress-related skin diseases. Previous studies have shown altered expression of central and peripheral HPA axis hormones in chronic inflammatory skin diseases and skin tumours, and that hyper-active lesional HPA axis hormones may negatively feedback to the central HPA axis and interact with some cytokines and neuropeptides, leading to symptom deterioration. This provides an evidence-based understanding of the expression of the central and peripheral HPA axis in common skin diseases and its association with disease activity. PMID- 23462973 TI - OsWRKY28, a PAMP-responsive transrepressor, negatively regulates innate immune responses in rice against rice blast fungus. AB - WRKY transcription factors form a large family of plant-specific transcription factors and participate in plant defense responses either as positive or negative regulators. In this study, we comprehensively analyzed the role of one of the group IIa WRKY transcription factors in rice, OsWRKY28, in the regulation of basal defense responses to a compatible race of the rice blast fungus Magnaporthe oryzae, strain Ina86-137. The expression analyses of the group IIa WRKY transcription factors in rice revealed that OsWRKY28, together with OsWRKY71, exhibit an early-induced expression prior to the late-induced expressions of OsWRKY62 and OsWRKY76. The GFP-OsWRKY28 fusion protein localized mainly in the nuclei of onion epidermal cells, and the maltose-binding protein-fused OsWRKY28 recombinant protein specifically bound to W-box elements. A transient reporter gene assay clearly showed that OsWRKY28 functions as a transcriptional repressor. Overexpression of OsWRKY28 in rice plants resulted in enhanced susceptibility to Ina86-137. Finally, transcriptome analysis revealed that the induction of several defense-related genes in the wild type after Ina86-137 infection was counteracted in OsWRKY28-overexpressing rice plants. These results strongly suggest that OsWRKY28 is a negative regulator of basal defense responses against Ina86-137 and acts as a modulator to maintain the responses at an appropriate level by attenuating the activation of defense-related gene expression levels. PMID- 23462976 TI - Genomic analysis reveals the biotechnological ability of Enterococcus italicus to produce glutathione. AB - Through the analysis of the recently available genome shotgun sequence of Enterococcus italicus DSM 15952(T) type strain (Accession PRJNA61487, ID 61487), we found the presence of a gene encoding a bifunctional enzyme, termed gamma-GCS GS or GshF, involved in glutathione production and not influenced by feedback inhibition. The gshF gene exhibited high nucleotide and amino acid sequence similarity to other reported sequences from the Enterococcus genus and was constitutively expressed both in osmotic shock or in common cultural conditions. Several experimental studies concerning the culture medium, physiological stress, cell extract obtainment, and scaling-up showed that in selected conditions E. italicus was able to accumulate up to 250 MUM of intracellular glutathione, which represented the main thiol group present into the cells. This is the first report regarding the production of glutathione by E. italicus, a species that could be used as a safe adjunct culture for glutathione-enriched dairy foods. PMID- 23462977 TI - Development of a UPLC-MS/MS method for the determination of ten anticancer drugs in hospital and urban wastewaters, and its application for the screening of human metabolites assisted by information-dependent acquisition tool (IDA) in sewage samples. AB - In the present work, the development, optimization, and validation (including a whole stability study) of a fast, reliable, and comprehensive method for the analysis of ten anticancer drugs in hospital and urban wastewater is described. Extraction of these pharmaceutical compounds was performed using automated off line solid-phase extraction followed by their determination by ultra-performance liquid chromatography coupled to a triple quadrupole-linear ion trap mass spectrometer. Target compounds include nine cytotoxic agents: cyclophosphamide, ifosfamide, docetaxel, paclitaxel, etoposide, vincristine, tamoxifen, methotrexate, and azathioprine; and the cytotoxic quinolone, ciprofloxacin. Method detection limits (MDL) ranged from 0.8 to 24 ng/L. Levels found of cytostatic agents in the hospital and wastewater influents did not differ significantly, and therefore, hospitals cannot be considered as the primary source of this type of contaminants. All the target compounds were detected in at least one of the influent samples analyzed: Ciprofloxacin, cyclophosphamide, tamoxifen, and azathioprine were found in most of them and achieving maximum levels of 14.725, 0.201, 0.133, and 0.188 MUg/L, respectively. The rest of target cancer drugs were less frequently detected and at values ranging between MDL and 0.406 MUg/L. Furthermore, a feasible, useful, and advantageous approach based on information acquisition tool (information-dependent acquisition) was used for the screening of human metabolites in hospital effluents, where the hydroxy tamoxifen, endoxifen, and carboxyphosphamide were detected. PMID- 23462978 TI - Low-cost reduced graphene oxide-based conductometric nitrogen dioxide-sensitive sensor on paper. AB - The fabrication concept for a low-cost sensor device using reduced graphene oxide (rGO) as the sensing material on a porous paper substrate is presented. The sensors were characterized using conductivity and capacitance measurements, atomic force microscopy and X-ray photoelectron spectroscopy. The effects of different reducing agents, graphene oxide (GO) flake size and film thickness were studied. The sensor was sensitive to NO2, and devices based on a thin (10-nm) hydrazine-reduced GO layer had the best sensitivity, reaching a 70% reduction in resistance after 10 min of exposure to 10 ppm NO2. The sensitivity was high enough for the detection of sub-parts per million levels of NO2. Desorption of gas molecules, i.e. the recovery of the sensor, could be accelerated by UV irradiation. The structure and preparation of the sensor are simple and up scalable, allowing their fabrication in bulk quantities, and the fabrication concept can be applied to other materials, too. PMID- 23462979 TI - Reagentless D-sorbitol biosensor based on D-sorbitol dehydrogenase immobilized in a sol-gel carbon nanotubes-poly(methylene green) composite. AB - A reagentless D-sorbitol biosensor based on NAD-dependent D-sorbitol dehydrogenase (DSDH) immobilized in a sol-gel carbon nanotubes-poly(methylene green) composite has been developed. It was prepared by durably immobilizing the NAD(+) cofactor with DSDH in a sol-gel thin film on the surface of carbon nanotubes functionalized with poly(methylene green). This device enables selective determination of D-sorbitol at 0.2 V with a sensitivity of 8.7 MUA mmol(-1) L cm(-2) and a detection limit of 0.11 mmol L(-1). Moreover, this biosensor has excellent operational stability upon continuous use in hydrodynamic conditions. PMID- 23462980 TI - Sputter-induced cross-contamination in analytical AES and XPS instrumentation: utilization of the effect for the in situ deposition of ultrathin functional layers. AB - Cross-contamination is observed on sample surfaces by Auger electron spectroscopy and X-ray photoelectron spectroscopy if multiple samples are mounted on one sample holder and a neighbouring sample was sputter depth profiling. During sputter depth profiling, sputtered material is deposited on inner surfaces of the instrument. In a secondary sputter process, which is due to species leaving the primary sputter target with higher kinetic energy, the previously deposited material is transported from the inner surfaces to the other samples mounted on the sample holder. This reflective sputtering is utilized to deposit ultrathin layers on sample surfaces for X-ray photoelectron spectroscopy binding energy referencing purposes and to build up ultrathin conductive layers to make possible Auger electron spectroscopy measurements on insulating samples. PMID- 23462981 TI - A high-throughput LC-MS/MS method suitable for population biomonitoring measures five serum folate vitamers and one oxidation product. AB - Small specimen volume and high sample throughput are key features needed for routine methods used for population biomonitoring. We modified our routine eight probe solid phase extraction (SPE) LC-MS/MS method for the measurement of five folate vitamers [5-methyltetrahydrofolate (5-methylTHF), folic acid (FA), plus three minor forms: THF, 5-formylTHF, 5,10-methenylTHF] and one oxidation product of 5-methylTHF (MeFox) to require less serum volume (150 MUL instead of 275 MUL) by using 96-well SPE plates with 50 mg instead of 100 mg phenyl sorbent and to provide faster throughput by using a 96-probe SPE system. Total imprecision (10 days, two replicates/day) for three serum quality control pools was 2.8-3.6% for 5-methylTHF (19.5-51.1 nmol/L), 6.6-8.7% for FA (0.72-11.4 nmol/L), and <=11.4% for the minor folate forms (<1-5 nmol/L). The mean (+/-SE) recoveries of folates spiked into serum (3 days, four levels, two replicates/level) were: 5-methylTHF, 99.4 +/- 3.6%; FA, 100 +/- 1.8%; minor folates, 91.7-108%. SPE extraction efficiencies were >=85%, except for THF (78%). Limits of detection were <=0.3 nmol/L. The new method correlated well with our routine method [n = 150, r = 0.99 for 5-methylTHF, FA, and total folate (tFOL, sum of folate forms)] and produced slightly higher tFOL (5.6%) and 5-methylTHF (7.3%) concentrations, likely due to the faster 96-probe SPE process (1 vs. 5 h), resulting in improved SPE efficiency and recovery compared to the eight-probe SPE method. With this improved LC-MS/MS method, 96 samples can be processed in ~2 h, and all relevant folate forms can be accurately measured using a small serum volume. PMID- 23462982 TI - [Nature or nurture: effects of parental ametropia on children's refractive errors]. AB - PURPOSE: The aim of this study was to quantify the degree of association between juvenile refraction errors and parental refraction status. METHODS: Using a simple questionnaire we conducted a cross-sectional study to determine the prevalence and magnitudes of refractive errors and of parental refraction status in a sample (n=728) of 10- to 18-year-old Austrian grammar school students. RESULTS: Students with myopia or hyperopia were more likely to have ametropic parents and refraction was more myopic in juveniles with one or two parents being ametropic. The prevalence of myopia in children with 2 ametropic parents was 54%, decreasing to 35% in pupils with 1 and to 13% in children with no ametropic parents. The odds ratio for 1 and 2 compared with no ametropic parents was 8.3 and 3.7 for myopia and 1.3 and 1.6 for hyperopia, respectively. Furthermore, the data indicate a stronger influence of the maternal ametropia on children's refractive errors than paternal ametropia. CONCLUSIONS: Genetic factors play a significant role in refractive error and may be of dominant influence for school myopia under conditions of low environmental variation. PMID- 23462983 TI - Self-harm in postpartum depression and referrals to a perinatal mental health team: an audit study. AB - There is a paucity of research on self-harm during pregnancy and the postpartum period despite suicide being a leading cause of death and high rates of mental disorder during this time. This audit describes a cohort of women referred to a new perinatal mental health team (PMHT) based in a large maternity hospital in the UK over a 12-month period. The audit was conducted in two stages. Stage one describes the clinical and socio-demographic characteristics of 225 pregnant women referred to the team after screening positive for a significant mental health history. Stage two determines the veracity of data on a subgroup of 73 pregnant women referred for previous postpartum depression (PPD), 58 % of whom disclosed an episode of self-harm with the 'intent to kill themselves' to the maternity staff when they first booked in for antenatal care. Previous PPD accounted for the largest majority of referrals (32 %) to the PMHT followed by depression (27 %) and self-harm (10 %). The majority of women (85 %) referred to the PMHT were engaged. Eight percent were so unwell at the point of referral they required an admission to the hospital. Attempted suicide in the subgroup of 73 women with previous PPD ranged from 24-49 %. The findings from this audit suggest that self-harm in PPD warrants further investigation. PMID- 23462984 TI - Fluorescence sensing of adenosine deaminase based on adenosine induced self assembly of aptamer structures. AB - A new approach is proposed for simple detection of adenosine deaminase (ADA) based on adenosine induced self-assembly of two pieces of single-stranded DNA (ssDNA). These ssDNA are two fragments of the aptamer that has a strong affinity for adenosine and are labeled with carboxyfluorescein and black hole quencher-1, respectively. The complementarities of the bases in the two pieces of ssDNA are insufficient to form a stable structure. In the presence of adenosine, however, the ssDNA can be assembled into the intact aptamer tertiary structure, which results in fluorescence quenching of the carboxyfluorescein-labeled aptamer fragment. As a result, the adenosine-ssDNA complex shows a low background signal, which is rather desired for achieving sensitive detection. Reaction of the complex with ADA causes a great fluorescence enhancement by converting adenosine into inosine that has no affinity for the aptamer. This behaviour leads to the development of a simple and sensitive fluorescent method for assaying ADA activity, with a detection limit of 0.05 U mL(-1), which is more sensitive than most of the existing approaches. Furthermore, the applicability of the method has been demonstrated by detecting ADA in mouse serum samples. PMID- 23462985 TI - Hierarchical flower-like Co3-xFexO4 ferrite hollow spheres: facile synthesis and catalysis in the degradation of methylene blue. AB - A facile method is proposed for the synthesis of three-dimensional (3D) flower like Co3-xFexO4 ferrite (CF) hollow spheres, using SiO2@FeOOH as precursor. The CF hollow spheres are efficient for the catalytic degradation of methylene blue (MB) in the presence of H2O2 at 80 degrees C. The obtained CF hollow spheres were characterized using transmission electron microscopy, field emission scanning electron microscopy, X-ray diffraction, X-ray photo-electron spectroscopy, and N2 adsorption-desorption isotherm measurements. The formation of 3D hierarchical flower-like superstructure was influenced by the relative amount of urea used. As the mole ratio of CoCl2 and urea decreased, the structure of the products was tailored from yolk-like spheres to hollow spheres with different sized void interiors. Moreover, N2 adsorption-desorption isotherm analysis showed that the CF hollow spheres have a large specific surface area (163 m(2) g(-1)) which provided more activity sites. The CF hollow spheres can catalyze the oxidation of MB efficiently. These results indicate that the designed CF hollow spheres exhibit promising capability for the degradation of dyes. PMID- 23462986 TI - Low RKIP expression associates with poor prognosis in bladder cancer patients. AB - Urothelial bladder cancer (UBC) is a heterogeneous type of disease. It is urgent to screen biomarkers of tumour aggressiveness in order to clarify the clinical behaviour and to personalize therapy in UBC patients. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor, and its downregulation is associated with metastatic events in an increasing number of solid tumours. We evaluated the clinical and prognostic significance of RKIP expression in patients with high risk of progression UBC. Using immunohistochemistry, we determined RKIP expression levels in a series of 81 patients with high-grade pT1/pTis or muscle invasive UBC. Staining of CD31 and D2-40 was used to assess blood and lymphatic vessels, in order to distinguish between blood and lymphatic vessel invasion (LVI). We found that 90 % of pT1/pTis tumours, 94 % of non-muscle invasive papillary tumours and 76 % of the cases without LVI occurrence expressed RKIP in >10 % of cells. In this group, we observed a subgroup of tumours (42 %) in which the tumour centre was significantly more intensely stained than the invasion front. This heterogeneous pattern was observed in 63 % of the cases with LVI. Low RKIP expression was associated with poorer 5-year disease-free and overall survival rates, and remained as an independent prognostic factor for disease-free survival. Loss of RKIP expression may be an important prognostic factor for patients with high risk of progression bladder cancer. PMID- 23462987 TI - Naturally occurring autoantibodies interfere with beta-amyloid metabolism and improve cognition in a transgenic mouse model of Alzheimer's disease 24 h after single treatment. AB - There is evidence that naturally occurring antibodies directed against Abeta (nAbs-Abeta) have a role in Abeta-metabolism and Abeta-clearance. The presence of nAbs-Abeta leads to a reduction in amyloid fibrillation and thus a reduction in their toxicity. We investigated the effects of nAbs-Abeta in respect to oligomerization and used the Tg2576 transgenic mouse model in order to investigate the rapid effect with a single-dose (24 h) on oligomer breakdown and cytokine secretion along with immunohistochemical characterization of synaptic plasticity. nAbs-Abeta were able to reduce toxic oligomer concentration with an increase in Abeta-monomers. Cytokine secretion was significantly reduced. Synaptic plasticity was also improved after administration of nAbs. Finally, single treatment lead to a significant improvement in cognition. This study demonstrates the efficacy of nAbs-Abeta and presents evidence that several hallmarks of the disease are targeted by nAbs-Abeta. PMID- 23462988 TI - Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. AB - Sapropterin, a synthetic form of tetrahydrobiopterin (BH4), has been reported to improve symptoms in children with autism spectrum disorder (ASD). However, as BH4 is involved in multiple metabolic pathway that have been found to be dysregulated in ASD, including redox, pterin, monoamine neurotransmitter, nitric oxide (NO) and immune metabolism, the metabolic pathway by which sapropterin exerts its therapeutic effect in ASD effect remains unclear. This study investigated which metabolic pathways were associated with symptomatic improvement during sapropterin treatment. Ten participants (ages 2-6 years old) with current social and/or language delays, ASD and a central BH4 concentration ?30 nM l(-1) were treated with a daily morning 20 mg kg(-1) dose of sapropterin for 16 weeks in an open-label fashion. At baseline, 8 weeks and 16 weeks after starting the treatment, measures of language, social function and behavior and biomarkers of redox, pterin, monoamine neurotransmitter, NO and immune metabolism were obtained. Two participants discontinued the study, one from mild adverse effects and another due to noncompliance. Overall, improvements in subscales of the Preschool Language Scale (PLS), Vineland Adaptive Behavior Scale (VABS), Aberrant Behavior Checklist (ABC) and autism symptoms questionnaire (ASQ) were seen. Significant changes in biomarkers of pterin, redox and NO were found. Improvement on several subscales of the PLS, VABS, ABC and ASQ were moderated by baseline and changes in biomarkers of NO and pterin metabolism, particularly baseline NO metabolism. These data suggest that behavioral improvement associated with daily 20 mg kg(-1) sapropterin treatment may involve NO metabolism, particularly the status of pretreatment NO metabolism. PMID- 23462991 TI - Nanoscale light-matter interactions in atomic cladding waveguides. AB - Alkali vapours, such as rubidium, are being used extensively in several important fields of research such as slow and stored light nonlinear optics quantum computation, atomic clocks and magnetometers. Recently, there is a growing effort towards miniaturizing traditional centimetre-size vapour cells. Owing to the significant reduction in device dimensions, light-matter interactions are greatly enhanced, enabling new functionalities due to the low power threshold needed for nonlinear interactions. Here, taking advantage of the mature platform of silicon photonics, we construct an efficient and flexible platform for tailored light vapour interactions on a chip. Specifically, we demonstrate light-matter interactions in an atomic cladding waveguide, consisting of a silicon nitride nano-waveguide core with a rubidium vapour cladding. We observe the efficient interaction of the electromagnetic guided mode with the rubidium cladding and show that due to the high confinement of the optical mode, the rubidium absorption saturates at powers in the nanowatt regime. PMID- 23462993 TI - Mid-Pliocene warm-period deposits in the High Arctic yield insight into camel evolution. AB - The mid-Pliocene was a global warm period, preceding the onset of Quaternary glaciations. Here we use cosmogenic nuclide dating to show that a fossiliferous terrestrial deposit that includes subfossil trees and the northern-most evidence of Pliocene ice wedge casts in Canada's High Arctic (Ellesmere Island, Nunavut) was deposited during the mid-Pliocene warm period. The age estimates correspond to a general maximum in high latitude mean winter season insolation, consistent with the presence of a rich, boreal-type forest. Moreover, we report that these deposits have yielded the first evidence of a High Arctic camel, identified using collagen fingerprinting of a fragmentary fossil limb bone. Camels originated in North America and dispersed to Eurasia via the Bering Isthmus, an ephemeral land bridge linking Alaska and Russia. The results suggest that the evolutionary history of modern camels can be traced back to a lineage of giant camels that was well established in a forested Arctic. PMID- 23462990 TI - Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. AB - The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized. PMID- 23462992 TI - An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells. AB - Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin-glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic induced pluripotent stem cells using a Sleeping Beauty transposon system carrying the micro-utrophin gene, differentiate these cells into skeletal muscle progenitors and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin-glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance towards the future treatment of muscular dystrophies using genetically corrected autologous induced pluripotent stem cells. PMID- 23462989 TI - A role for synaptic plasticity in the adolescent development of executive function. AB - Adolescent brain maturation is characterized by the emergence of executive function mediated by the prefrontal cortex, e.g., goal planning, inhibition of impulsive behavior and set shifting. Synaptic pruning of excitatory contacts is the signature morphologic event of late brain maturation during adolescence. Mounting evidence suggests that glutamate receptor-mediated synaptic plasticity, in particular long-term depression (LTD), is important for elimination of synaptic contacts in brain development. This review examines the possibility (1) that LTD mechanisms are enhanced in the prefrontal cortex during adolescence due to ongoing synaptic pruning in this late developing cortex and (2) that enhanced synaptic plasticity in the prefrontal cortex represents a key molecular substrate underlying the critical period for maturation of executive function. Molecular sites of interaction between environmental factors, such as alcohol and stress, and glutamate receptor mediated plasticity are considered. The accentuated negative impact of these factors during adolescence may be due in part to interference with LTD mechanisms that refine prefrontal cortical circuitry and when disrupted derail normal maturation of executive function. Diminished prefrontal cortical control over risk-taking behavior could further exacerbate negative outcomes associated with these behaviors, as for example addiction and depression. Greater insight into the neurobiology of the adolescent brain is needed to fully understand the molecular basis for heightened vulnerability during adolescence to the injurious effects of substance abuse and stress. PMID- 23462994 TI - Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. AB - The tumour suppressor alternative reading frame (ARF) is one of the most frequently mutated proteins in human cancer. It has been well established that ARF is able to stabilize and activate p53 by directly inhibiting Mdm2. ARF mediated p53 activation in response to oncogenic stress is thought to be an important determinant of protection against cancer. However, little is known regarding the control of ARF in cells. Here, we show that Siva1 is a specific E3 ubiquitin ligase of ARF. Siva1 physically interacts with ARF both in vitro and in vivo. Through direct interaction, Siva1 promotes the ubiquitination and degradation of ARF, which in turn affects the stability of p53. Functionally, Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53 dependent manner. Our results uncover a novel regulatory mechanism for the control of ARF stability, thereby revealing an important function of Siva1 in the regulation of the ARF-Mdm2-p53 pathway. PMID- 23462995 TI - The origins of the enigmatic Falkland Islands wolf. AB - The origins of the extinct Falkland Islands wolf (FIW), Dusicyon australis, have remained a mystery since it was first recorded by Europeans in the seventeenth century. It is the only terrestrial mammal on the Falkland Islands (also known as the Malvinas Islands), which lie ~460 km from Argentina, leading to suggestions of either human-mediated transport or overwater dispersal. Previous studies used ancient DNA from museum specimens to suggest that the FIW diverged from its closest living relative, the South American maned wolf (Chrysocyon brachyurus) around 7 Ma, and colonized the islands ~330 ka by unknown means. Here we retrieve ancient DNA from subfossils of an extinct mainland relative, Dusicyon avus, and reveal the FIW lineage became isolated only 16 ka (8-31 ka), during the last glacial phase. Submarine terraces, formed on the Argentine coastal shelf by low sea-stands during this period, suggest that the FIW colonized via a narrow, shallow marine strait, potentially while it was frozen over. PMID- 23462997 TI - X-ray observation of a helium atom and placing a nitrogen atom inside He@C60 and He@C70. AB - Single crystal X-ray analysis has been used as a powerful method to determine the structure of molecules. However, crystallographic data containing helium has not been reported, owing to the difficulty in embedding helium into crystalline materials. Here we report the X-ray diffraction study of He@C60 and the clear observation of a single helium atom inside C60. In addition, the close packing of a helium atom and a nitrogen atom inside fullerenes is realized using two stepwise insertion techniques, that is, molecular surgery to synthesize the fullerenes encapsulating a helium atom, followed by nitrogen radio-frequency plasma methods to generate the fullerenes encapsulating both helium and nitrogen atoms. Electron spin resonance analysis reveals that the encapsulated helium atom has a small but detectable influence on the electronic properties of the highly reactive nitrogen atom coexisting inside the fullerene, suggesting the potential usage of helium for controlling electronic properties of reactive species. PMID- 23462996 TI - COG complexes form spatial landmarks for distinct SNARE complexes. AB - Vesicular tethers and SNAREs (soluble N-ethylmalemide-sensitive fusion attachment protein receptors) are two key protein components of the intracellular membrane trafficking machinery. The conserved oligomeric Golgi (COG) complex has been implicated in the tethering of retrograde intra-Golgi vesicles. Here, using yeast two-hybrid and co-immunoprecipitation approaches, we show that three COG subunits, namely COG4, 6 and 8, are capable of interacting with defined Golgi SNAREs, namely STX5, STX6, STX16, GS27 and SNAP29. Comparative analysis of COG8 STX16 and COG4-STX5 interactions by a COG-based mitochondrial relocalization assay reveals that the COG8 and COG4 proteins initiate the formation of two different tethering platforms that can facilitate the redirection of two populations of Golgi transport intermediates to the mitochondrial vicinity. Our results uncover a role for COG sub-complexes in defining the specificity of vesicular sorting within the Golgi. PMID- 23462998 TI - Fractional Bloch oscillations in photonic lattices. AB - Bloch oscillations, the oscillatory motion of a quantum particle in a periodic potential, are one of the most fascinating effects of coherent quantum transport. Originally studied in the context of electrons in crystals, Bloch oscillations manifest the wave nature of matter and are found in a wide variety of different physical systems. Here we report on the first experimental observation of fractional Bloch oscillations, using a photonic lattice as a model system of a two-particle extended Bose-Hubbard Hamiltonian. In our photonic simulator, the dynamics of two correlated particles hopping on a one-dimensional lattice is mapped into the motion of a single particle in a two-dimensional lattice with engineered defects and mimicked by light transport in a square waveguide lattice with a bent axis. PMID- 23462999 TI - A hydrothermal anvil made of graphene nanobubbles on diamond. AB - The hardness and virtual incompressibility of diamond allow it to be used in high pressure anvil cell. Here we report a new way to generate static pressure by encapsulating single-crystal diamond with graphene membrane, the latter is well known for its superior nano-indentation strength and in-plane rigidity. Heating the diamond-graphene interface to the reconstruction temperature of diamond (~1,275 K) produces a high density of graphene nanobubbles that can trap water. At high temperature, chemical bonding between graphene and diamond is robust enough to allow the hybrid interface to act as a hydrothermal anvil cell due to the impermeability of graphene. Superheated water trapped within the pressurized graphene nanobubbles is observed to etch the diamond surface to produce a high density of square-shaped voids. The molecular structure of superheated water trapped in the bubble is probed using vibrational spectroscopy and dynamic changes in the hydrogen-bonding environment are observed. PMID- 23463000 TI - High-pressure synthesis of a polyethylene/zeolite nano-composite material. AB - Meso/micro-porous solids, such as zeolites, are complex materials used in an impressive range of applications. Here we photo-polymerized ethylene using non catalytic high-pressure techniques at 0.5-1.5 GPa under ultraviolet (351-364 nm) irradiation on a sub-nanometre scale in the channels of a pure SiO2 zeolite, silicalite, to obtain a unique nano-composite material with drastically modified mechanical properties. The structure obtained contains single polyethylene chains, which adapt very well to the confining channels as shown by optical spectroscopy and X-ray diffraction. The formation of this nano-composite results in significant increases in bulk modulus and density, and the thermal expansion coefficient changes sign from negative to positive with respect to silicalite. Mechanical properties may thus be tuned by varying the amount of polymerized ethylene. Our findings could allow the high-pressure, catalyst-free synthesis of a unique generation of technological, functional materials based on simple hydrocarbons polymerized in confining meso/micro-porous solids. PMID- 23463001 TI - A magnetic non-reciprocal isolator for broadband terahertz operation. AB - A Faraday isolator is an electromagnetic non-reciprocal device, a key element in photonics. It is required to shield electromagnetic sources against the effect of back-reflected light, as well as to limit the detrimental effect of back propagating spontaneous emissions. A common isolator variant, the circulator, is widely used to obtain a complete separation between forward- and backward propagating waves, thus enabling the realization of a desired transfer function in reflection only. Here we demonstrate a non-reciprocal terahertz Faraday isolator, operating on a bandwidth exceeding one decade of frequency, a necessary requirement to achieve isolation with the (few-cycle) pulses generated by broadband sources. The exploited medium allows a broadband rotation, up to 194 degrees /T, obtained using a SrFe12O19 terahertz-transparent permanent magnet. This in turn enables the design of a stand-alone complete terahertz isolator without resorting to an external magnetic field bias, as opposed to all the optical isolators realized so far. PMID- 23463002 TI - alpha-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKalpha in vitro. AB - The AMP-activated protein kinase (AMPK) regulates metabolism in normal and pathological conditions and responds to nutrients, hormones, anti-diabetic drugs and physical exercise. AMPK is activated by the kinase LKB1 and inactivated by phosphatases whose identities remain uncertain. Here we show that AMPK associates with alpha-SNAP, an adapter that enables disassembly of cis-SNARE complexes formed during membrane fusion. Knockdown of alpha-SNAP activates AMPK to phosphorylate its endogenous substrates acetyl CoA carboxylase and Raptor, and provokes mitochondrial biogenesis. AMPK phosphorylation is rescued from alpha SNAP RNA interference by LKB1 knockdown or expression of wild-type but not mutated alpha-SNAP. Recombinant wild-type but not mutated alpha-SNAP dephosphorylates pThr172 in AMPKalpha in vitro. Overexpression of wild-type but not mutated alpha-SNAP prevents AMPK activation in cells treated with agents to elevate AMP concentration. The mouse alpha-SNAP mutant hyh (hydrocephalus with hop gait) shows enhanced binding and inhibition of AMPK. By negatively controlling AMPK, alpha-SNAP therefore potentially coordinates membrane trafficking and metabolism. PMID- 23463003 TI - Aldara activates TLR7-independent immune defence. AB - Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara. PMID- 23463004 TI - Third-party social evaluation of humans by monkeys. AB - Humans routinely socially evaluate others not only following direct interactions with them but also based on others' interactions with third parties. In other species, 'eavesdropping' on third-party interactions is often used to gain information about foraging or mating opportunities, or others individuals' aggressiveness or fighting ability. However, image scoring for potential cooperativeness is less well studied. Here we ask whether a non-human primate species, tufted capuchin monkeys (Cebus apella), socially evaluates humans after witnessing third-party interactions involving a helpful intervention or failure to help. We find that the monkeys accept food less frequently from those who persistently reject another's requests for help. This negative social evaluation effect is robust across conditions, and tightly linked to explicit refusal to help. Evaluation of potential helpfulness based on third-party interactions may thus not be unique to humans. PMID- 23463005 TI - Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. AB - Abnormal aggregation of alpha-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular alpha synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of alpha-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric alpha-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases. PMID- 23463006 TI - UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi methylated DNA and methylated H3K9. AB - Epigenetic inheritance of DNA methylation in mammals requires a multifunctional protein UHRF1, which is believed to recruit DNMT1 to DNA replication forks through a unique hemi-methylated CpG-binding activity. Here we demonstrate that the UHRF1 mutants deficient in binding either hemi-methylated CpG or H3K9me2/3, but not both, are able to associate with pericentric heterochromatin, recruit Dnmt1 and partially rescue DNA methylation defects in mouse Uhrf1 null ES cells. Furthermore, we present evidence that the flip out of the methylated cytosine induced by UHRF1 binding is unlikely essential for subsequent DNA methylation by DNMT1. Together, our study demonstrates that UHRF1 can target DNMT1 for DNA maintenance methylation through binding either H3K9me2/3 or hemi-methylated CpG, and that the presence of both binding activities ensures high fidelity DNA maintenance methylation. In addition, our study indicates that UHRF1 mediates cross-talk between H3K9 methylation and DNA methylation at the level of DNA methylation maintenance. PMID- 23463007 TI - Haemogenic endocardium contributes to transient definitive haematopoiesis. AB - Haematopoietic cells arise from spatiotemporally restricted domains in the developing embryo. Although studies of non-mammalian animal and in vitro embryonic stem cell models suggest a close relationship among cardiac, endocardial and haematopoietic lineages, it remains unknown whether the mammalian heart tube serves as a haemogenic organ akin to the dorsal aorta. Here we examine the haemogenic activity of the developing endocardium. Mouse heart explants generate myeloid and erythroid colonies in the absence of circulation. Haemogenic activity arises from a subset of endocardial cells in the outflow cushion and atria earlier than in the aorta-gonad-mesonephros region, and is transient and definitive in nature. Interestingly, key cardiac transcription factors, Nkx2-5 and Isl1, are expressed in and required for the haemogenic population of the endocardium. Together, these data suggest that a subset of endocardial/endothelial cells serve as a de novo source for transient definitive haematopoietic progenitors. PMID- 23463008 TI - MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. AB - The chromatin template imposes an epigenetic barrier during the process of somatic cell reprogramming. Using fibroblasts derived from macroH2A double knockout (dKO) mice, here we show that these histone variants act cooperatively as a barrier to induced pluripotency. Through manipulation of macroH2A isoforms, we further demonstrate that macroH2A2 is the predominant barrier to reprogramming. Genomic analyses reveal that macroH2A1 and macroH2A2, together with H3K27me3, co-occupy pluripotency genes in wild-type (wt) fibroblasts. In particular, we find macroH2A isoforms to be highly enriched at target genes of the K27me3 demethylase, Utx, which are reactivated early in iPS reprogramming. Finally, while macroH2A dKO-induced pluripotent cells are able to differentiate properly in vitro and in vivo, such differentiated cells retain the ability to return to a stem-like state. Therefore, we propose that macroH2A isoforms provide a redundant silencing layer or terminal differentiation 'lock' at critical pluripotency genes that presents as an epigenetic barrier when differentiated cells are challenged to reprogram. PMID- 23463009 TI - The interaction between OsMADS57 and OsTB1 modulates rice tillering via DWARF14. AB - Rice tillering is a multigenic trait that influences grain yield, but its regulation molecular module is poorly understood. Here we report that OsMADS57 interacts with OsTB1 (TEOSINTE BRANCHED1) and targets D14 (Dwarf14) to control the outgrowth of axillary buds in rice. An activation-tagged mutant osmads57-1 and OsMADS57-overexpression lines showed increased tillers, whereas OsMADS57 antisense lines had fewer tillers. OsMIR444a-overexpressing lines exhibited suppressed OsMADS57 expression and tillering. Furthermore, osmads57-1 was insensitive to strigolactone treatment to inhibit axillary bud outgrowth, and OsMADS57's function in tillering was dependent on D14. D14 expression was downregulated in osmads57-1, but upregulated in antisense and OsMIR444a overexpressing lines. OsMADS57 bound to the CArG motif [C(A/T)TTAAAAAG] in the promoter and directly suppressed D14 expression. Interaction of OsMADS57 with OsTB1 reduced OsMADS57 inhibition of D14 transcription. Therefore, OsMIR444a regulated OsMADS57, together with OsTB1, target D14 to control tillering. This regulation mechanism could have important application in rice molecular breeding programs focused on high grain yield. PMID- 23463010 TI - Actin-based confinement of calcium responses during Shigella invasion. AB - Shigella, the agent of bacillary dysentery, invades epithelial cells by locally inducing actin reorganization. Upon cell invasion, Shigella induces calcium (Ca(2+)) signalling, but its role in invasion has remained unclear. Here we show that components involved in inositol 1, 4, 5- trisphosphate (InsP3) signalling are implicated in Shigella invasion. Although global Ca(2+) responses are dispensable for bacterial invasion, local Ca(2+) responses of unprecedented long duration are associated with invasion sites. Fluorescence recovery after photo bleaching experiments indicate that diffusion of small solutes is hindered at Shigella-invasion sites and that diffusion hindrance is dependent on bacterially induced actin reorganization. Computational simulations and experimental challenge of the model support the notion that local accumulation of InsP3 permitted by restricted diffusion and enrichment of InsP3 receptors account for sustained local Ca(2+) increases at entry sites. Thus, cytoskeletal reorganization through diffusion hindrance shapes the duration of local Ca(2+) signals. PMID- 23463011 TI - Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. AB - In eukaryotes, deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates, altering their stabilities, localizations or activities. Here we show that many DUBs of the USP and UCH subfamilies can be reversibly inactivated upon oxidation by reactive oxygen species in vitro and in cells. Oxidation occurs preferentially on the catalytic cysteine, abrogating the isopeptide-cleaving activity without affecting these enzymes' affinity to ubiquitin. Sensitivity to oxidative inhibition is associated with DUB activation wherein the active site cysteine is converted to a deprotonated state prone to oxidation. We demonstrate that this redox regulation is essential for mono-ubiquitination of proliferating cell nuclear antigen in response to oxidative DNA damage, which initiates a DNA damage-tolerance programme. These findings establish a novel mechanism of DUB regulation that may be integrated with other redox-dependent signalling circuits to govern cellular adaptation to oxidative stress, a process intimately linked to aging and cancer. PMID- 23463012 TI - Regulation of A20 and other OTU deubiquitinases by reversible oxidation. AB - Protein ubiquitination is a highly versatile post-translational modification that regulates as diverse processes as protein degradation and kinase activation. Deubiquitinases hydrolyse ubiquitin modifications from proteins and are hence key regulators of the ubiquitin system. Ovarian tumour deubiquitinases comprise a family of fourteen human enzymes, many of which regulate cellular signalling pathways. Ovarian tumour deubiquitinases are cysteine proteases that cleave polyubiquitin chains in vitro and in cells, but little is currently known about their regulation. Here we show that ovarian tumour deubiquitinases are susceptible to reversible oxidation of the catalytic cysteine residue. High resolution crystal structures of the catalytic domain of A20 in four different oxidation states reveal that the reversible form of A20 oxidation is a cysteine sulphenic acid intermediate, which is stabilised by the architecture of the catalytic centre. Using chemical tools to detect sulphenic acid intermediates, we show that many ovarian tumour deubiquitinases undergo reversible oxidation upon treatment with H2O2, revealing a new mechanism to regulate deubiquitinase activity. PMID- 23463013 TI - Phantom pain is associated with preserved structure and function in the former hand area. AB - Phantom pain after arm amputation is widely believed to arise from maladaptive cortical reorganization, triggered by loss of sensory input. We instead propose that chronic phantom pain experience drives plasticity by maintaining local cortical representations and disrupting inter-regional connectivity. Here we show that, while loss of sensory input is generally characterized by structural and functional degeneration in the deprived sensorimotor cortex, the experience of persistent pain is associated with preserved structure and functional organization in the former hand area. Furthermore, consistent with the isolated nature of phantom experience, phantom pain is associated with reduced inter regional functional connectivity in the primary sensorimotor cortex. We therefore propose that contrary to the maladaptive model, cortical plasticity associated with phantom pain is driven by powerful and long-lasting subjective sensory experience, such as triggered by nociceptive or top-down inputs. Our results prompt a revisiting of the link between phantom pain and brain organization. PMID- 23463014 TI - Synthesis of functionalised N-heterocyclic carbene ligands bearing a long spacer and their use in olefin metathesis. AB - A synthetic route to backbone functionalised imidazolinium salts-NHC ligand precursors has been developed. These tagged NHC ligands can be used to obtain a homogeneous Hoveyda-type catalyst (19) containing a quaternary ammonium group on a C-8 long spacer. Products of olefin metathesis reactions promoted by complex 19 can be readily purified from Ru-residues by filtration of the reaction mixture through a small amount of silica gel. PMID- 23463016 TI - Acquired reactive perforating collagenosis: a rare association with dermatomyositis. PMID- 23463015 TI - Identification of olfactory volatiles using gas chromatography-multi-unit recordings (GCMR) in the insect antennal lobe. AB - All organisms inhabit a world full of sensory stimuli that determine their behavioral and physiological response to their environment. Olfaction is especially important in insects, which use their olfactory systems to respond to, and discriminate amongst, complex odor stimuli. These odors elicit behaviors that mediate processes such as reproduction and habitat selection(1-3). Additionally, chemical sensing by insects mediates behaviors that are highly significant for agriculture and human health, including pollination(4-6), herbivory of food crops(7), and transmission of disease(8,9). Identification of olfactory signals and their role in insect behavior is thus important for understanding both ecological processes and human food resources and well-being. To date, the identification of volatiles that drive insect behavior has been difficult and often tedious. Current techniques include gas chromatography-coupled electroantennogram recording (GC-EAG), and gas chromatography-coupled single sensillum recordings (GC-SSR)(10-12). These techniques proved to be vital in the identification of bioactive compounds. We have developed a method that uses gas chromatography coupled to multi-channel electrophysiological recordings (termed 'GCMR') from neurons in the antennal lobe (AL; the insect's primary olfactory center)(13,14). This state-of-the-art technique allows us to probe how odor information is represented in the insect brain. Moreover, because neural responses to odors at this level of olfactory processing are highly sensitive owing to the degree of convergence of the antenna's receptor neurons into AL neurons, AL recordings will allow the detection of active constituents of natural odors efficiently and with high sensitivity. Here we describe GCMR and give an example of its use. Several general steps are involved in the detection of bioactive volatiles and insect response. Volatiles first need to be collected from sources of interest (in this example we use flowers from the genus Mimulus (Phyrmaceae)) and characterized as needed using standard GC-MS techniques(14-16). Insects are prepared for study using minimal dissection, after which a recording electrode is inserted into the antennal lobe and multi-channel neural recording begins. Post-processing of the neural data then reveals which particular odorants cause significant neural responses by the insect nervous system. Although the example we present here is specific to pollination studies, GCMR can be expanded to a wide range of study organisms and volatile sources. For instance, this method can be used in the identification of odorants attracting or repelling vector insects and crop pests. Moreover, GCMR can also be used to identify attractants for beneficial insects, such as pollinators. The technique may be expanded to non-insect subjects as well. PMID- 23463017 TI - Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients. AB - Placental growth factor (PlGF), a VEGF-homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. Here, we addressed the expression, function, and prognostic value of PlGF in neuroendocrine tumors (NETs). PlGF was determined in NET patients' sera collected retrospectively (n=88) and prospectively (n=87) using Roche Elecsys and correlated with clinicopathological data. Tumoral PlGF was evaluated by immunohistochemistry, effects of PlGF on proliferation and migration in vitro were assessed using different NET cell lines and effects on tumor growth in vivo in orthotopic xenografts. Circulating and tumoral PlGF was elevated in patients with pancreatic NETs (pNETs) compared with control sera and respective healthy tissue. De novo PlGF expression occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced NET proliferation and migration in vitro and, conversely, neutralizing antibodies to PlGF reduced tumor growth in vivo. Elevated circulating PlGF levels in NET patients correlated with advanced tumor grading and were associated with reduced tumor-related survival in pNETs. Subsequent determinations confirmed and extended our observation of elevated PlGF levels in a prospective cohort of grade 1 and grade 2 pNETs (n=30) and intestinal NETs (n=57). In low-grade pNETs, normal circulating PlGF levels were associated with better survival. In intestinal NETs, circulating PlGF above median emerged as an independent prognostic factor for shorter time-to-progression in multivariate analyses. These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter and therapeutic target. PMID- 23463018 TI - Measurement bias of the SF-36 Health Survey in older adults with chronic conditions. AB - PURPOSE: The objectives of this study were to investigate the psychometric properties of the SF-36 in a sample of older adults with chronic conditions and to test whether measurement bias exists based on the levels of comorbidity. METHODS: Participants included were 979 cognitively intact older adults with comorbidities who were interviewed at their homes. We examined the psychometric properties of the SF-36 and conducted confirmatory factor analysis (CFA) to investigate the assumption of measurement invariance by the levels of comorbidity. RESULTS: Overall data quality was high and scaling assumptions were generally met with few exceptions. Floor and ceiling effects were present for the role-physical and role-emotional subscales. Using CFA, we found that a three factor measurement model fits the data well. We identified two violations of measurement invariance. Results showed that participants with high comorbidity level place more emphasis on social functioning (SF) and bodily pain (BP) in relation to physical health-related quality of life (HRQoL) than those with low comorbidity level. CONCLUSIONS: Measurement bias was present for the SF and BP components of the SF-36 physical HRQoL measure. Researchers should be cautious when considering the use of SF-36 in clinical studies among older adults with comorbidities. PMID- 23463019 TI - Comparison of the responsiveness of the SF-36, the Oxford Knee Score, and the Knee Society Clinical Rating System in patients undergoing total knee replacement. AB - OBJECTIVES: To compare the responsiveness of the Knee Society (KS) Clinical Rating System, the general health status measure Short Form 36 (SF-36), and both the raw and Rasch-based scores of the condition-specific Oxford Knee Score (OKS) in patients undergoing total knee replacement (TKR) METHODS: Data were prospectively collected as part of routine care from adult patients who underwent TKR between 2001 and 2006. OKS data fit the Rasch partial credit model after removing items regarding limping and kneeling. Responsiveness was assessed using effect size (ES), standardised response mean (SRM), and relative validity (RV). RESULTS: Among 702 patients with complete data at baseline and two follow-ups, the pain subscale of the KS (KS-P), raw-OKS, and Rasch-OKS consistently had higher levels of responsiveness than all eight SF-36 and the other KS subscales. At 6-month follow-up, Rasch-OKS had the largest ES and KS-P had the largest SRM (2.7 and 2.0, respectively). When compared to raw-OKS, the RVs of KS-P, Rasch OKS, SF-36 bodily pain, and SF-36 physical functioning were 1.1, 0.66, 0.49, and 0.36, respectively. A similar ordering of responsiveness was observed at 24-month follow-up. CONCLUSION: The OKS and KS-P are more responsive than most SF-36 subscales in TKR patients. Raw-OKS and Rasch-OKS have comparable responsiveness. Different responsiveness indices may give different results. PMID- 23463020 TI - Characteristics of stable isotope signature of diet in tissues of captive Japanese macaques as revealed by controlled feeding. AB - We determined the magnitude of isotopic fractionation of carbon and nitrogen stable isotope ratios (as enrichment factors, Deltadelta(13)C and Deltadelta(15)N, respectively) between the tissues and diets of captive Japanese macaques (Macaca fuscata) using a controlled feeding experiment, to provide basic data for reconstructing their feeding habits. The Deltadelta(13)C and Deltadelta(15)N values, respectively, were 0.9 +/- 0.2 0/00 (mean +/- standard deviation, SD) and 3.0 +/- 0.3 0/00 for whole blood, 1.3 +/- 0.2 0/00 and 4.3 +/- 0.3 0/00 for plasma, and 0.8 +/- 0.2 0/00 and 3.0 +/- 0.2 0/00 for red blood cells. However, the Deltadelta(13)C and Deltadelta(15)N values for hair were 2.8 +/- 0.3 0/00 and 3.4 +/- 0.2 0/00, respectively. No difference was detected in the delta(13)C and delta(15)N values of hair sampled from different parts of the body. We investigated the effects of diet on delta(13)C in growing hair by alternating the diet of the macaques each month between two diets that differed markedly in delta(13)C. Hair regrown after shaving repeatedly recorded the delta(13)C of the diet consumed during the time of hair growth. On the other hand, hair naturally grown during the diet-change experiment did not show a clear pattern. One possible reason is that the hair had grown abnormally under unnatural indoor conditions and showed complicated isotope signatures. To reconstruct the long-term feeding history of Japanese macaques, we need to further clarify the relationships between the stable isotope signature of diet and various body tissues. PMID- 23463021 TI - UVA-riboflavin collagen cross-linking: a misnomer perhaps, but it works! PMID- 23463022 TI - Genetic correlates of proliferative vitreoretinopathy. PMID- 23463023 TI - Clinical utility gene card for: Diamond-Blackfan anemia--update 2013. PMID- 23463025 TI - Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes. AB - Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript. PMID- 23463024 TI - Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration. AB - Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease with an age at onset generally below 65 years. Mutations in progranulin (GRN) have been reported to be able to cause FTLD through haploinsufficiency. We have sequenced GRN in 121 patients with FTLD and detected six different mutations in eight patients: p.Gly35Glufs*19, p.Asn118Phefs*4, p.Val200Glyfs*18, p.Tyr294*, p.Cys404* and p.Cys416Leufs*30. Serum was available for five of the mutations, where the serum-GRN levels were found to be >50% reduced compared with FTLD patients without GRN mutations. Moreover, the p.Cys416Leufs*30 mutation segregated in an affected family with different dementia diagnoses. The mutation frequency of GRN mutation was 6.6% in our FTLD cohort. PMID- 23463026 TI - A global map for dissecting phenotypic variants in human lincRNAs. AB - Large intergenic noncoding RNAs (lincRNAs) are emerging as key factors of multiple cellular processes. Cumulative evidence has linked lincRNA polymorphisms to diverse diseases. However, the global properties of lincRNA polymorphisms and their implications for human disease remain largely unknown. Here we performed a systematic analysis of naturally occurring variants in human lincRNAs, with a particular focus on lincRNA polymorphism as novel risk factor of disease etiology. We found that lincRNAs exhibited a relatively low level of polymorphisms, and low single-nucleotide polymorphism (SNP) density lincRNAs might have a broad range of functions. We also found that some polymorphisms in evolutionarily conserved regions of lincRNAs had significant effects on predicted RNA secondary structures, indicating their potential contribution to diseases. We mapped currently available phenotype-associated SNPs to lincRNAs and found that lincRNAs were associated with a wide range of human diseases. Some lincRNAs could be responsible for particular diseases. Our results provided not only a global perspective on genetic variants in human lincRNAs but also novel insights into the function and etiology of lincRNA. All the data in this study can be accessed and retrieved freely via a web server at http://bioinfo.hrbmu.edu.cn/lincPoly. PMID- 23463028 TI - Dithiocarbamate-capped silver nanoparticles as a resonance light scattering probe for simultaneous detection of lead(II) ions and cysteine. AB - We investigated the suitability of dithiocarbamate (DTC) capped Ag nanoparticles (NPs) as resonance light scattering (RLS) probes for the simultaneous sensing of Pb(2+) and cysteine. The DTC capping ligands are generated by a very simple in situ method through reaction of carbon disulfide with diethanolamine as primary precursor molecules under ultrasonic irradiation. This strategy was based on the fact that Pb(2+) could induce the aggregation of DTC-Ag NPs due to the strong metal affinity of DTC along with an enhanced RLS signal. After optimizing some experimental conditions (including the pH value of the solution, concentration of DTC-Ag NPs, and ion strength), a very simple and facile sensing system has been developed for the detection of Pb(2+) in water based on RLS technology. The proposed system promises excellent selectivity, a wide linear response range and high sensitivity for Pb(2+). The linear response range for Pb(2+) was from 0.01 MUM to 60 MUM. The limit of detection (S/N = 3sigma) for Pb(2+) was as low as 4 nM. The proposed method was successfully used to detect Pb(2+) in river and tap water samples, indicating the potential of this new, sensitive and selective method in water quality monitoring. Meanwhile, due to the strong binding preference of cysteine toward Pb(2+) by the formation of Pb(2+)-S bonds, Pb(2+) was removed from the surfaces of the DTC-Ag NPs, leading to redispersion of DTC Ag NPs, along with a decreased RLS signal. The possibility of the proposed system for the sensing of cysteine was also investigated. PMID- 23463027 TI - Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy. AB - Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. PMID- 23463029 TI - Serotonin precursor (5-hydroxytryptophan) causes substantial changes in the fighting behavior of male crickets, Gryllus bimaculatus. AB - This study demonstrates that injection of the serotonin precursor 5-HTP causes substantial changes in the behavioral state, fighting behavior and ability to establish winner-loser relationships in male crickets (Gryllus bimaculatus). The characteristic features of 5-HTP-treated crickets include an elevated posture, enhanced general activity, longer duration of fighting, enhanced rival singing and a decreased ability to produce a clear fight loser. In addition, 5-HTP treated males showed a slightly delayed latency to spread their mandibles, a decreased number of attacks and an equal potential to win in comparison to controls (physiological solution-treated males). The obtained results imply a significant role for serotonin in the regulation of social status-related behaviors in G. bimaculatus. Specifically, these data indicate that a decrease in serotonergic activity may be functionally important for the control of loser behavior and that some behavioral features of dominant male crickets are likely to be connected with the activation of the serotonergic system. PMID- 23463030 TI - Branched tellurium hollow nanofibers by galvanic displacement reaction and their sensing performance toward nitrogen dioxide. AB - Electrospinning and galvanic displacement reaction were combined to synthesize ultra-long hollow tellurium (Te) nanofibers with controlled dimensions, morphology and crystallinity by simply tailoring the electrolyte concentration applied. Within different morphologies of nanofibers, the branched Te nanostructure shows the greatest sensing performance towards NO2 at room temperature. PMID- 23463031 TI - Compatibility of lithium salts with solvent of the non-aqueous electrolyte in Li O2 batteries. AB - The stability of lithium salts, especially in the presence of reduced oxygen species, O2 and H2O (even in a small amount), plays an important role in the cyclability and capacity of Li-O2 cells. This combined experimental and computational study provides evidence that the stability of the electrolyte used in Li-O2 cells strongly depends on the compatibility of lithium salts with solvent. In the case of the LiPF6-1NM3 electrolyte, the decomposition of LiPF6 occurs in the cell as evidenced by in situ XRD, FT-IR and XPS analysis, which triggers the decomposition of 1NM3 solvent due to formation of HF from the decomposition of LiPF6. These reactions lead to degradation of the electrolyte and cause poor cyclability of the cell. The same reactions are not observed when LiTFSI and LiCF3SO3 are used as the lithium salts in 1NM3 solvent, or LiPF6 is used in TEGDME solvent. PMID- 23463032 TI - Synthesis and reactivity of a cyclopentadienyl-indenyl ligand ring-coupled by a chiral bridge derived from ethyl (S)-(-) lactate. AB - In order to prepare a new unsymmetrical chiral ligand, C9H7CH(CH3)CH2C5H5, with an indenyl moiety connected to a cyclopentadienyl unit by a chiral ethylene bridge, we reacted the optically active tosylate 4, derived from ethyl (S)-(-) lactate, with LiCp. The only product resulting from this reaction was an optically active spirocyclopropane 6 obtained with a high diastereoselectivity (81.8% de). We also observed that, when the reduction of the ethyl indene lactate 2 was realized with an excess of LiAlH4 in Et2O under reflux, spirocyclopropane 6 was obtained in high yield with the same diastereoselectivity. When tosylate 4 was reacted with MgCp2, in place of LiCp, ligand 5 was obtained in good yield as a mixture of two double-bond isomers of the Cp unit. Ligand 5 was fully structurally characterized after conversion into transition monometallic complexes such as C9H7CH(CH3)CH2eta(5)-C5H4Mo(CO)3Me 7 and C9H7CH(CH3)CH2eta(5) C5H4Rh(COD) 9, in which the indene moiety was kept intact due to the difference in reactivity of the indenyl moiety with respect to the cyclopentadienyl unit. An attempt to prepare a heterobimetallic complex from the sodium indenide salt of 7 and [RhCl(COD)]2, afforded a rhodium cyclopentadienyl complex 9, resulting from a metal exchange reaction with loss of the molybdenum part initially coordinated to the Cp unit, and conservation of the optical purity. An homobimetallic rhodium complex 10 could be prepared by deprotonation of ligand 5 with TlOEt, followed by quenching with [RhCl(COD)]2. The bis-rhodium complex 10 is obtained as a mixture of two diastereoisomers 10a and 10b with respect to the planar chirality of the indenyl ring system, with a good diastereoisomeric excess de = 70%. The structures of both complexes 9 and major (pS)-diastereoisomer 10a were determined by single crystal X-ray diffraction. PMID- 23463033 TI - Theoretical studies on the reaction mechanism of PP1 and the effects of different oxidation states of the Mn-Mn center on the mechanism. AB - Protein phosphatase 1 (PP1) is a dinuclear metalloenzyme that catalyzes the dephosphorylation of serine and threonine residues. In this work, the catalytic reaction mechanism of PP1 was theoretically investigated by hybrid density functional theory. Firstly, an initial model of the Mn(II)-Mn(II) active site of PP1 was constructed on the basis of the high-resolution crystal structure, and stationary points along the reaction pathway were optimized and analyzed. The calculations provide strong support for the mechanism of the dephosphorylation by PP1 and suggest that His125 plays the role of donating a proton to the leaving group. Furthermore, reaction models with the Mn-Mn centers at different oxidation states [Mn(III)-Mn(II) and Mn(III)-Mn(III) centers] were designed. Our calculations show that increasing the oxidation state of one or both Mn(II) can shorten the bond lengths between the metal ions and the ligands, and increase the energy barrier of the related reactions. We found it interesting that artificially adding a negatively charged hydroxy ligand into the Mn(III)-Mn(II) center can recover the shortened coordination bonds and lower the increased energy barrier. Our investigation suggests that the definite oxidation states of the metal centers should be significantly correlated to the negative charges of the ligands not only in phosphoprotein phosphatases, but also in purple acid phosphatases and Escherichia coli 5'-nucleotidase. This means that all the members of phosphoprotein phosphatases adopt homodivalent centers, and suggests the heterovalent active sites of purple acid phosphatases have evolved from homodivalent ones. PMID- 23463035 TI - A case of atypical fibrous histiocytoma with positivity for CD163 and CD44. PMID- 23463036 TI - Thou shalt not steal. PMID- 23463034 TI - A cross-sectional observation of burnout in a sample of Irish junior doctors. AB - BACKGROUND: Stress and burnout are common among doctors. Excess levels of stress have been shown to have detrimental personal and professional effects as well as a negative influence on patient care. AIM: The aim of our pilot study was to assess the levels of burnout among a cohort of interns. METHODS: A voluntary written self-assessment of burnout levels was distributed to interns in two teaching hospitals. The Maslach Burnout inventory is a 22-question survey assessing the three components of the burnout syndrome-emotional exhaustion (EE), depersonalisation (DP) and personal achievement (PA). RESULTS: Twenty-seven surveys were distributed to interns in two hospitals with a 96.3 % (n = 26) response rate. The mean age was 25.1 years (range 24-31 years). 14 were medical interns, 12 were surgical interns at the time of completion. Overall, the mean EE score was 23.4 (range 11-29), representing moderate levels of EE. The mean DP score was 9.4 (range 4-14), representing moderate levels of DP. The mean PA score was 18.9 (range 12-29), representing high levels of PA. There were no significant differences noted between levels of EE, DP or PA among male or female interns, medical or surgical interns or those who worked in a peripheral or university hospital. CONCLUSION: Burnout is reported among interns in our pilot study. Measures need to be taken to heighten awareness of burnout among doctors and to educate physicians regarding self-awareness and personal health. PMID- 23463037 TI - [When the executive function falters]. PMID- 23463038 TI - [Good planning leads to better research]. PMID- 23463039 TI - [Management ideology and documentation]. PMID- 23463040 TI - [Comment on Jon Magnussen]. PMID- 23463042 TI - [Satisfaction cemetery]. PMID- 23463043 TI - [The main character--who is it?]. PMID- 23463044 TI - [Them and us]. PMID- 23463047 TI - [The editor responds]. PMID- 23463048 TI - [References and challenges]. PMID- 23463049 TI - [The challenges of subject criticism]. PMID- 23463050 TI - [Not unclear about severity of illness]. PMID- 23463051 TI - [V. Bruun Wyller replies]. PMID- 23463052 TI - [Correct definition of p-value?]. PMID- 23463053 TI - [E. Skovlund replies]. PMID- 23463055 TI - [Abstainers--a risk group?]. PMID- 23463056 TI - [W. Pedersen replies]. PMID- 23463059 TI - [Health expenditure in Norway is not particularly high]. PMID- 23463060 TI - [Creative titles and their impact on society, science and authors]. PMID- 23463063 TI - Atlantoaxial rotatory fixation--a cause of torticollis. AB - BACKGROUND: A rare, but important cause of torticollis in children is atlantoaxial rotatory fixation. If the patient remains undiagnosed for more than three months, surgery is generally the only therapeutic alternative. In this article we present our experiences of surgical treatment of late-diagnosed atlantoaxial rotatory fixation in children. MATERIAL AND METHOD: This article is based on a review of the case notes of patients who underwent surgery for atlantoaxial rotatory fixation in the Department for Neurosurgery at Oslo University Hospital, Rikshospitalet, during the period 2004-10. RESULTS: The material sample consists of six children aged from seven to 14 years. Five had suffered minor trauma to the upper neck region, while one had had an upper respiratory tract infection. The diagnosis was made 5-36 months after the onset of symptoms. In three of the patients, an attempt was made at closed reduction without success. A CT scan one year postoperatively showed a normal position of the atlantoaxial joint in two patients and partial reduction in three. In the sixth patient there was bone fusion at the time of the operation, and open reduction was unsuccessful. All six patients had reduced rotational movement of the neck at the one-year check-up. INTERPRETATION: All our patients were diagnosed more than five months after the onset of symptoms. Full or partial reduction was achieved in five of the six. PMID- 23463064 TI - [Executive function deficits following stroke]. AB - BACKGROUND: Executive function deficit is a cognitive dysfunction resulting in a reduced ability to initiate, control and monitor targeted behaviour. Our clinical experience indicates that this often remains undiagnosed following stroke. METHOD: The article is based on literature searches using the search terms "Stroke" and "Executive function" via the search engine McMaster Plus, in the databases Cochrane Library and PubMed, coupled with the authors' own experience. RESULTS: Executive function deficit is a common form of stroke-related cognitive dysfunction which often accompanies emotional instability and depression. The condition is an important risk factor for loss of self-sufficiency and for reduced survival. Diagnosis is based on the patient's history and observation, supplemented by cognitive testing. Executive function deficits also occur in patients with no clinical signs of stroke, but who have image diagnostic signs of cerebral ischaemia, and with other cerebral diseases such as Parkinson's disease and dementia. Executive function is mainly located in the prefrontal cortex and the subcortical circuits, but executive function deficits are also seen in cases of lesions in other areas of the brain. The treatment of executive function deficits focuses on compensatory strategies and on recovery of lost function. INTERPRETATION: Executive function deficits are common with stroke-related cognitive impairment, and may affect the prognosis. There is a need for systematic testing and strategies for treatment and prevention. PMID- 23463065 TI - [Epilepsy in the elderly]. AB - BACKGROUND: Diagnostic work-up and treatment of patients who have developed epilepsy after the age of 65 can both be difficult. Epilepsy is one of the most common neurological conditions in the elderly, and the incidence of de novo geriatric epilepsy is rising. The aim of this review is to provide guidance on the management of epilepsy in this patient group. METHOD: The review is based on a discretionary selection of original articles and reviews found in PubMed using the search term combination 'epilepsy' and 'elderly', and the authors' personal experience. RESULTS: The seizures, which are most commonly of the focal type, are not infrequently overlooked or misdiagnosed. Cerebrovascular disease is the underlying cause of about half of the cases. When selecting an anticonvulsant, it is important to take age-related physiological changes and comorbidities into consideration. Because elderly patients have a narrower therapeutic window than younger persons and greater susceptibility to cognitive and other side effects, a low starting dose and slower dose titration are particularly important. INTERPRETATION: The results of studies of young epilepsy patients cannot be extrapolated to apply to elderly patients. More studies directly targeting this patient population are therefore needed. As a general rule, we do not recommend starting on enzyme-inducing drugs such as phenytoin, phenobarbital and carbamazepine, partly because of their high interaction potential. PMID- 23463066 TI - [Nasogastric tube astray]. PMID- 23463067 TI - A man in his 40s with repeated seizures. PMID- 23463068 TI - Seizures that are not epileptic. PMID- 23463069 TI - [When robots control hospitals]. PMID- 23463070 TI - [Medical effects of nuclear weapons]. PMID- 23463071 TI - [Peripheral intravenous catheters?]. PMID- 23463073 TI - Adenoid cystic carcinoma: clinical and molecular features. AB - The clinical features and common molecular alterations of adenoid cystic carcinoma (ACC) are reviewed in this paper. ACC is an uncommon neoplasm that most frequently arises in salivary glands and related tissue in the head and neck region. ACC has distinct histologic features, with cribriform and tubular growth patterns of basaloid cells displaying a predominantly myoepithelial cellular phenotype. This neoplasm also has uncommon clinical features of rare regional lymph node metastasis and a prolonged but relentlessly progressive clinical course. Clinical outcome in ACC is correlated to histologic grade, which is correlated to the degree of aneuploidy and genetic alterations present in the tumor genomes. Recent studies have identified that the majority of ACC contain alterations of the MYB gene, usually resulting in a fusion gene product with the NFIB gene by a t(6;9) translocation event. The molecular consequences of this alteration are incompletely understood, as are secondary molecular alterations that contribute to the neoplastic phenotype of ACC. PMID- 23463074 TI - The importance of diagnosing NUT midline carcinoma. AB - NUT midline carcinoma (NMC) is an aggressive subset of squamous cell carcinoma, genetically defined by rearrangement of the NUT gene. The rearrangements most often take the form of BRD4-NUT fusions, and in a minority of cases, BRD3-NUT or NUT-variant fusions. The simple karyotypes of NMCs, in contrast to the complex ones of typical squamous cell carcinoma, suggest an alternate, genetic shortcut to squamous cancer. Although originally thought to be a disease of the mediastinum, NMC frequently (35 %) arises in the head and neck. Diagnosis is made simply by demonstration of nuclear immunoreactivity to NUT protein, and ancillary studies to characterize the fusion oncogene, though not required for diagnosis, are recommended. The prognosis is dismal, with a 6.7 month median survival, and treatment with conventional chemotherapeutic regimens is ineffective. The oncogenic mechanism of the dual bromodomains and the p300-binding portion of BRD4 NUT is to sequester p300 to localized regions of chromatin, leading to global transcriptional repression and blockade of differentiation. Two therapies which target this mechanism have emerged, including bromodomain inhibitors (BETi) and histone deacetylase inhibitors (HDACi), both of which induce differentiation and growth arrest of NMC cells, both in vitro and in vivo. BETi is available to adults with NMC through a phase I clinical trial, and clinical response to HDACi has been demonstrated in pediatric patients. The emergence of these promising targeted therapies gives hope that NMC may one day be effectively treated and provides a strong rationale for diagnostic testing for NMC. PMID- 23463076 TI - Sunshine, supplements, CBT and more. PMID- 23463075 TI - Bioproduction of prostaglandins in a transgenic liverwort, Marchantia polymorpha. AB - Prostaglandins are biologically active substances used in a wide range of medical treatments. Prostaglandins have been supplied mainly by chemical synthesis; nevertheless, the high cost of prostaglandin production remains a factor. To lower the cost of prostaglandin production, we attempted to produce prostaglandins using a liverwort, Marchantia polymorpha L., which accumulates arachidonic acid, which is known as a substrate of prostaglandins. Here we report the first bioproduction of prostaglandins in plant species by introducing a cyclooxygenase gene from a red alga, Gracilaria vermiculophylla into the liverwort. The transgenic liverworts accumulated prostaglandin F2alpha, prostaglandin E2 and prostaglandin D2 which were not detected in the wild-type liverwort. Moreover, we succeeded in drastically increasing the bioproduction of prostaglandins using an in vitro reaction system with the extracts of transgenic liverworts. PMID- 23463077 TI - Something fishy: the issue of omega-3 blinding in psychiatric clinical trials. PMID- 23463078 TI - Muscle dysmorphia: towards a diagnostic consensus. PMID- 23463079 TI - What is an eating disorder? Implications for current and future diagnostic criteria. PMID- 23463080 TI - Acquired brain injury needs to be acknowledged at the national mental health policy level. PMID- 23463081 TI - Commentary on: 'muscle dysmorphia: towards a diagnostic consensus'. PMID- 23463082 TI - Video-gaming disorder and behavioural addictions. PMID- 23463083 TI - Response to: 'what should we tell medical students and residents about euthanasia and assisted suicide?'. PMID- 23463084 TI - Brain and mood changes over 2 years in healthy controls and adults with heart failure and ischaemic heart disease. AB - AIMS: Heart failure (HF) has been associated with cognitive dysfunction, a high prevalence of mood disorders, and a relative loss of grey matter in several brain regions. This study aimed to determine if, compared with controls with and without ischaemic heart disease (IHD), adults with HF show evidence of progressive loss of cerebral grey matter, and whether morphological changes are associated with changes in cognition, depression and anxiety symptoms over a follow-up period of 2 years. METHODS AND RESULTS: This was a 24-month longitudinal study of 19 participants with systolic HF, 43 with IHD, and 45 controls. Subjects were older than 45 years and free of cognitive impairment at the start of follow-up. We acquired magnetic resonance images and used Statistical Parametric Mapping version 8 (SPM8) to investigate changes in the distribution of cerebral grey matter volume over time. We used the Cambridge Cognitive Examination of the Elderly (CAMCOG) and the Hospital Anxiety and Depression Scale (HADS) to assess 2-year changes in cognitive function and mood. Changes in total grey matter volume and cognitive function were similar across the three study groups, but participants with HF showed evidence of increasing severity of anxiety and depressive symptoms. HF was associated with subtle regional loss of grey matter in the right and left thalamus, left caudate, left and right posterior cingulate, left and right parahippocampal gyri, left superior and middle temporal gyri, and right inferior parietal lobule compared with controls and, to a lesser extent, participants with IHD. CONCLUSION: HF and IHD are not associated with a disproportional loss of cerebral grey matter or cognitive decline over 2 years compared with cardiologically healthy controls. Adults with HF experience increasing symptoms of anxiety and depression over 2 years compared with controls, and this increased vulnerability is associated with a relative loss of grey matter in brain regions that are important for the modulation of emotions. PMID- 23463085 TI - Lack of independent significance of a close (<1 mm) circumferential resection margin involvement in esophageal and junctional cancer. AB - BACKGROUND: For rectal cancer, an involved circumferential resection margin (CRM), defined as tumor cells within 1 mm of the CRM, is of established prognostic significance. This definition for the esophagus, however, is controversial, with the UK Royal College of Pathologists (RCP) recommending the 1 mm definition, while the College of American Pathologists (CAP) advises that only tumor cells at the cut margin (0 mm) define an incomplete (R1) resection. The aim of this study was to compare the clinical significance of both definitions in patients with pT3 tumors. METHODS: CAP- and RCP-defined CRM status in patients treated by surgery only or by multimodal therapy was recorded prospectively in a comprehensive database from May 2003 to May 2011. Kaplan-Meier survival curves were generated, and factors affecting survival were assessed by univariate and multivariate analysis. RESULTS: A total of 157 of 340 patients had pT3 esophageal tumors, with RCP-positive CRM in 60 %, and 18 % by CAP. There were no significant differences between RCP-positive CRM and negative margins for node-positive disease, local recurrence, and survival. CAP-positive CRM was associated with positive nodes (P = 0.036) and poorer survival (P = 0.023). Multivariate analysis revealed nodal invasion to be the only independent prognostic variable (P = 0.004). CONCLUSIONS: A CRM margin of <1 mm is common in pT3 esophageal tumors, a finding consistent with other reports. The <1 mm definition was not associated with node positivity, local recurrence, or survival, in contrast to actual involvement at the margin, suggesting lack of independent prognostic significance of the RCP definition and possible superiority of the CAP criteria for prospective registration of CRM. PMID- 23463086 TI - Hyaluronic acid as a marker of hepatic sinusoidal obstruction syndrome secondary to oxaliplatin-based chemotherapy in patients with colorectal liver metastases. AB - BACKGROUND: A considerable number of patients develop sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy for colorectal liver metastases (CLMs). SOS is associated with adverse outcomes after major hepatectomy. Hyaluronic acid (HA) is a marker of hepatic sinusoidal endothelial cell function and may serve as an accurate marker of SOS. This study aimed to assess the value of systemic HA levels and fractional extraction (FE) of HA by the splanchnic area and liver as markers of SOS after oxaliplatin-based chemotherapy for CLMs. METHODS: Forty patients were studied. The presence of SOS was assessed histopathologically. Blood samples from the radial artery and portal and hepatic veins were collected. HA levels were determined by ELISA and the FE of HA was estimated. RESULTS: SOS was present in 23 patients, 11 of whom demonstrated moderate or severe SOS. Preoperative HA levels were significantly higher in patients with moderate or severe SOS (group B, n = 11) compared to patients with no or mild SOS (group A, n = 29) (51.6 +/- 10.2 ng/mL vs. 32.1 +/- 3.5 ng/mL, p = 0.030). A cutoff HA level of 44.1 ng/mL yielded a sensitivity of 67 % and specificity of 83 % for detection of SOS. The positive predictive value was 50 % and the negative predictive value 91 %. Both groups exhibited a similar FE of HA by the splanchnic area (-7.9 +/- 8.5 % in Group A vs. 7.3 +/- 3.6 % in Group B, p = 0.422) and liver (-10.7 +/- 6.2 % in Group A vs. 4.6 +/- 2.3 % in Group B, p = 0.265). CONCLUSIONS: Systemic HA levels can be used to detect patients at risk of SOS after oxaliplatin-based chemotherapy for CLMs. Additional investigations into the presence of SOS are indicated in patients with elevated HA levels. PMID- 23463087 TI - Hyaluronic acid as a marker of sinusoidal obstruction syndrome after oxaliplatin based chemotherapy for colorectal liver metastases: don't forget the tumor. PMID- 23463088 TI - Guiding breast-conserving surgery in patients after neoadjuvant systemic therapy for breast cancer: a comparison of radioactive seed localization with the ROLL technique. AB - BACKGROUND: Radioguided occult lesion localization (ROLL) with technetium-99 m colloid (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with nonpalpable breast tumors. Radioactive seed localization is a relatively new technique that localizes the tumor with a radioactive iodine-125 ((125)I) seed. The feasibility and outcome of these techniques after neoadjuvant systemic treatment has not been widely investigated. METHODS: All patients treated with neoadjuvant systemic treatment between 2007 and 2010 in the Netherlands Cancer Institute who underwent breast-conserving surgery with the ROLL-(99m)Tc technique (n = 83) or with (125)I seed localization (n = 71) were analyzed. The weight of the resected specimen, the margins, and the percentage of patients requiring a second surgical intervention as a result of positive margins were assessed. RESULTS: Patient and tumor characteristics and systemic treatment regimens were comparable between both groups. The median weight of the resected specimen (53 vs. 48 g), the median smallest margin (3.5 vs. 3.0 mm), and the risk for additional surgery for incomplete resections (7 vs. 8 %) did not differ significantly between patients treated with the ROLL-(99m)Tc technique and (125)I seed localization. CONCLUSIONS: The ROLL-(99m)Tc technique and (125)I seed localization demonstrate comparable results when used to perform breast conserving surgery after neoadjuvant systemic treatment. Because (125)I seed localization does not require additional radiological localization shortly before surgery, it simplifies surgery scheduling. Therefore, we prefer (125)I seed localization to perform breast-conserving surgery after neoadjuvant systemic treatment. PMID- 23463089 TI - The evolving role of partial breast irradiation in early-stage breast cancer. AB - Whole breast irradiation (WBI) over 5-7 weeks has long been considered standard adjuvant treatment after breast-conserving surgery. Recently the concept of irradiating the whole breast has been challenged by accelerated partial breast irradiation (APBI), which exclusively targets the lumpectomy site plus margin. We review the evidence supporting APBI from modern clinical trials, the pros and cons of various APBI techniques, and the controversies regarding the applicability of APBI to specific patient groups. PMID- 23463090 TI - Analysis of factors that influence the accuracy of magnetic resonance imaging for predicting response after neoadjuvant chemotherapy in locally advanced breast cancer. AB - PURPOSE: The purpose of this study was to evaluate the accuracy of breast magnetic resonance imaging (MRI) to predict residual lesion size after neoadjuvant chemotherapy (NAC) and to determine the factors that influence the accuracy of response prediction. METHODS: This study comprised 166 patients who underwent MRI before and after NAC, but before surgery. The longest diameter of the residual cancer was measured using MRI and correlated with pathologic findings. Patients were further divided into subgroups according to various radiologic and histopathologic factors. Pathologic complete response (pCR) was defined as the absence of residual invasive cancer cells. The Pearson correlation was used to correlate tumor size as determined by MRI and pathology, and the Mann Whitney U test and Kruskal-Wallis test were used to compare MRI-pathologic size discrepancies according to various clinical, histopathologic factors, and MRI findings. RESULTS: Of the 166 women, 40 achieved pCR. The overall sensitivity, specificity, and accuracy for diagnosing invasive residual disease by using MRI were 96, 65, and 89 %, respectively. The Pearson's correlation coefficient between the tumor sizes measured using MRI and pathology was 0.749 (P < 0.001). The size discrepancy was significantly greater in patients with estrogen receptor positive cancer (P = 0.037), in cancers with low nuclear grade (P = 0.007), and in cancers shown as diffuse non-mass-like enhancement on MRI (P = 0.001). CONCLUSIONS: Size prediction is less accurate in cases with estrogen receptor positive breast cancer, low nuclear grade, and diffuse non-mass-like enhancement on initial MRI. PMID- 23463091 TI - The prognostic nutritional index predicts long-term outcomes of gastric cancer patients independent of tumor stage. AB - PURPOSE: The aim of this study was to investigate the impact of the prognostic nutritional index (PNI) on the long-term outcomes in gastric cancer patients. METHODS: This study reviewed the medical records of 548 patients with gastric cancer who underwent gastrectomy. The PNI was calculated as 10 * serum albumin (g/dl) + 0.005 * total lymphocyte count (per mm(3)). The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value of the PNI. The multivariate analysis was performed to identify the prognostic factors. RESULTS: The mean PNI was significantly lower in patients with T3-T4 tumors (P < 0.001) and lymph node metastasis (P < 0.001) than in those without such factors. Patients who had a postoperative complication had a lower mean PNI than those without (P = 0.023). When the ROC curve analysis was performed, the optimal cutoff value of the PNI for predicting the 5-year survival was 48. In the multivariate analysis, a low PNI was an independent predictor for poor overall survival (P < 0.001). In the subgroup analysis, the overall and relapse-free survival rates were significantly lower in the PNI-low group than in the PNI-high group among patients with stage I and stage III disease. CONCLUSIONS: The PNI is a simple and useful marker for predicting the long-term outcomes of gastric cancer patients independent of the tumor stage. Based on our results, we suggest that the PNI should be included in the routine assessment of gastric cancer patients. PMID- 23463092 TI - Quantitative shear wave elastography as a prognostic implication of papillary thyroid carcinoma (PTC): elasticity index can predict extrathyroidal extension (ETE). AB - OBJECTIVE: To investigate whether the quantitative elasticity index of shear wave elastography (SWE) can predict extrathyroidal extension (ETE) of papillary thyroid carcinoma (PTC) preoperatively. METHODS: A total of 208 patients with pathology confirmed PTC whom underwent SWE during preoperative staging US between April 2011 to June 2012 were included.SWE indices of E mean, E max, E min of the index malignancy, the ratios between E mean of the lesion and parenchyma (E ratio P), and muscle (E ratio-M), and grayscale US findings, including ETE, multifocality, bilaterality, and central and lateral lymph node (LN) metastasis were evaluated. The correlations of SWE indices and grayscale US findings with pathologic prognostic factors of PTC were analyzed by Chi square or Fisher's exact test, and multivariate regression analysis. RESULTS: ETE was associated with E mean, E max, E min, and E ratio-M (P = 0.005, 0.009, 0.016 and <0.001, respectively), multifocality was associated with E mean, E max, and E min (P = 0.028, 0.007, and 0.004, respectively), and central LN metastasis was associated with E ratio-M (P = 0.03). On multivariate analysis, E mean and E min were independent factors for predicting ETE (P = 0.032, 0.049, respectively). CONCLUSIONS: Quantitative elasticity index of SWE could predict pathologic ETE, and SWE could be a complimentary method to grayscale US for preoperative prediction of prognostic factors of PTC. PMID- 23463093 TI - Prospective study of adjuvant radiotherapy on preventing lymph node metastasis after Ivor-lewis esophagectomy in esophageal cancer. AB - PURPOSE: To investigate whether Ivor-Lewis esophagectomy combined with adjuvant radiotherapy prevents lymphatic metastatic recurrence in esophageal cancer patients. METHODS: A total of 113 stage IIA esophageal squamous cell carcinoma patients after Ivor-Lewis esophagectomy were accepted mRNA expression of Mucoid 1 (MUC1) gene detection. Positive patients were enrolled onto the adjuvant radiotherapy group (with postoperative adjuvant radiotherapy). Negative patients were enrolled onto the control group (without postoperative adjuvant radiotherapy or chemotherapy). The radiotherapy area consisted of the neck, supraclavicular region, and superior mediastinum (including paraesophageal and paratracheal region). Survival difference was compared by the chi(2) test, and the Kaplan Meier method was performed to calculate the survival rate and recurrence rate. Logistic regression analysis was performed to determined independent risk factors. RESULTS: The radiotherapy area lymphatic metastatic recurrence rate in adjuvant radiotherapy group (16.7 %, 5 of 30) was lower than patients without postoperative adjuvant radiotherapy (45.8 %, 38 of 83) (P < 0.05). Only compared to positive patients without postoperative adjuvant radiotherapy (60.0 %, 6 of 10) was the rate (16.7 %, 5 of 30) significantly lower (P < 0.01). Cancer recurrence was recognized in 48.6 % (55 of 113) patients within 3 years after surgery, including 38.1 % (43 of 113) patients with radiotherapy area recurrence. Logistic analysis revealed that T status (P < 0.01) and adjuvant radiotherapy (P < 0.05) were independent risk factors of lymph node metastasis in the first 3 years after surgery. CONCLUSIONS: In MUC1 mRNA-positive esophageal squamous cell carcinoma patients, adjuvant radiotherapy could significantly reduce the lymph node metastasis rate in the radiotherapy area after Ivor-Lewis esophagectomy. Compared with traditional therapeutic methods, Ivor-Lewis esophagectomy combined with adjuvant radiotherapy can achieve similar curative effects in MUC1 mRNA positive patients. PMID- 23463094 TI - Long-term survival outcomes of Video-assisted Thoracic Surgery (VATS) lobectomy after transitioning from open lobectomy. AB - BACKGROUND: Open lobectomy continues to be more commonly performed than video assisted thoracic surgery (VATS) lobectomy. We previously described the short term safety of an approach for transitioning from open lobectomy to VATS. We now assess its long-term safety by evaluating survival results of the initial VATS cases after transition. METHODS: From a prospective database, survival of stage I non-small cell lung cancer was compared between the first 40 VATS lobectomy and the 40 open lobectomy performed just before the transitioning to VATS. All patients underwent staging by positron emission tomographic scan and mediastinoscopy. Survival was estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Patient and intraoperative characteristics were not different between the two groups, except for operative time, which was longer for VATS (median 132 vs. 150 min, p = 0.023) and tumor size, which was smaller for VATS (median 2 vs. 2.5 cm, p = 0.002). There was no difference in morbidity and mortality. Median follow-up was 118 months for the open group and 81 months for the VATS group. The 5-year disease-free survival for stage IA (90 % open vs. 97 % VATS, p = 0.439) and IB (74 % open vs. 79 % VATS, p = 0.478) were not different. The 5-year overall survival for stage IA (91 % open vs. 97 % VATS, p = 0.152) and IB (55 % open vs. 67 % VATS, p = 0.198) were also not different. CONCLUSIONS: The transition from open to VATS lobectomy is safe with regards to both short-term morbidity and long-term survival. Surgeons currently performing open lobectomy should consider transitioning to the VATS procedure. PMID- 23463095 TI - Quantitative FRET (Forster Resonance Energy Transfer) analysis for SENP1 protease kinetics determination. AB - Reversible posttranslational modifications of proteins with ubiquitin or ubiquitin-like proteins (Ubls) are widely used to dynamically regulate protein activity and have diverse roles in many biological processes. For example, SUMO covalently modifies a large number or proteins with important roles in many cellular processes, including cell-cycle regulation, cell survival and death, DNA damage response, and stress response 1-5. SENP, as SUMO-specific protease, functions as an endopeptidase in the maturation of SUMO precursors or as an isopeptidase to remove SUMO from its target proteins and refresh the SUMOylation cycle (1,3,6,7). The catalytic efficiency or specificity of an enzyme is best characterized by the ratio of the kinetic constants, kcat/KM. In several studies, the kinetic parameters of SUMO-SENP pairs have been determined by various methods, including polyacrylamide gel-based western-blot, radioactive-labeled substrate, fluorescent compound or protein labeled substrate (8-13). However, the polyacrylamide-gel-based techniques, which used the "native" proteins but are laborious and technically demanding, that do not readily lend themselves to detailed quantitative analysis. The obtained kcat/KM from studies using tetrapeptides or proteins with an ACC (7-amino-4-carbamoylmetylcoumarin) or AMC (7-amino-4-methylcoumarin) fluorophore were either up to two orders of magnitude lower than the natural substrates or cannot clearly differentiate the iso- and endopeptidase activities of SENPs. Recently, FRET-based protease assays were used to study the deubiquitinating enzymes (DUBs) or SENPs with the FRET pair of cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) (9,10,14,15). The ratio of acceptor emission to donor emission was used as the quantitative parameter for FRET signal monitor for protease activity determination. However, this method ignored signal cross-contaminations at the acceptor and donor emission wavelengths by acceptor and donor self-fluorescence and thus was not accurate. We developed a novel highly sensitive and quantitative FRET-based protease assay for determining the kinetic parameters of pre-SUMO1 maturation by SENP1. An engineered FRET pair CyPet and YPet with significantly improved FRET efficiency and fluorescence quantum yield, were used to generate the CyPet-(pre SUMO1)-YPet substrate (16). We differentiated and quantified absolute fluorescence signals contributed by the donor and acceptor and FRET at the acceptor and emission wavelengths, respectively. The value of kcat/KM was obtained as (3.2 +/- 0.55) x10(7) M(-1)s(-1) of SENP1 toward pre-SUMO1, which is in agreement with general enzymatic kinetic parameters. Therefore, this methodology is valid and can be used as a general approach to characterize other proteases as well. PMID- 23463097 TI - Oestrogen receptors are prognostic factors in malignant peritoneal mesothelioma. AB - BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and fatal cancer. Females are found to survive longer than males after treatment, suggesting a possible involvement of hormonal factors. Estradiol is involved in cellular proliferation of a number of cancers and acts mainly through oestrogen receptors (ERs). Hence, we examined the expression of oestrogen receptors with correlation to prognosis. METHODS: Oestrogen receptors expression was examined using immunohistochemistry on 42 paraffin-embedded sections of MPM tumours. Kaplan Meier survival curves were analysed to determine the significance of ER expression in relation to prognosis. RESULTS: ER-beta (nuclear) was detected in 33 (79 %) patients. ER-beta was also detected in the cellular cytoplasm of 9 (21 %) patients. Presence of ER-beta (nuclear) was associated with favourable survival (univariate analysis, P = 0.001), whereas the presence of ER-beta (cytoplasm) was associated with a poor survival (P = 0.014). Multivariate Cox regression analysis revealed the absence of ER-beta (nuclear) and the presence of ER-beta (cytoplasm) to be independent predictive factors for poor disease outcome (hazard ratio 5.4, 95 % confidence interval 1.86-15.75; P = 0.002 and hazard ratio 8.0, 95 % confidence interval 1.8-34; P = 0.005), respectively. ER-alpha (nuclear) was detected in only 4 (9 %) of patients and not statistically significant (univariate analysis, P = 0.066). CONCLUSION: The presence of ER-beta (cytoplasm) is associated with poor prognosis. The favourable survival association observed in patients with ER-beta (nuclear) raises a question about the molecular mechanisms of the tumorigenic roles of ER-beta in each cellular compartment and requires further studies. PMID- 23463096 TI - Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment. AB - OBJECTIVES: To investigate the therapeutic utility of an attenuated bacterium carrying a plasmid that co-expresses Endostatin, an inhibitor of tumor neovasculogenesis, and a shRNA that targets Stat3 to suppress prostate cancer growth. METHODS: Plasmid pEndo-Si-Stat3 was constructed and introduced into an attenuated strain of Salmonella enterica serovar typhimurium. The resultant recombinant bacterium was used as a vector to deliver the plasmid to tumor cells growing in vivo. Tumor-associated gene and protein expression changes were measured by using RT-PCR and Western blot analyses. Expression of Endostatin in tumor tissue was detected by ELISA. The presence of vector bacteria in tissues was monitored and tumor destruction was assessed by using TUNEL and H&E staining assays. RESULTS: Bacterially delivered pEndo-Si-Stat3 decreased Stat3 levels and increased Endostatin expression in mouse tumors, resulting in a significant suppression of tumor growth (P < 0.01). Expression of Bcl-2 and PCNA was down regulated and Caspase3 expression was up-regulated to promote apoptosis of tumor cells. CONCLUSIONS: Successful delivery by attenuated Salmonella of the combination therapeutic plasmid simultaneously knocked down the expression of Stat3 and resulted in over-expression of Endostatin, which synergistically inhibited prostate cancer growth. PMID- 23463098 TI - Efficacy and toxicity of Trastuzumab and Paclitaxel plus Capecitabine in the first-line treatment of HER2-positive metastatic breast cancer. AB - PURPOSE: Combinations of trastuzumab with paclitaxel or capecitabine are effective therapies in human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC). This retrospective study evaluated the efficacy and toxicity of trastuzumab and paclitaxel plus capecitabine in the first-line therapy for patients with HER2-positive MBC. METHODS: A total of 40 patients with HER2 positive MBC treated between January 2008 and January 2011 were evaluated retrospectively in 6 institutions. Three patients with performance score of 3 who died before response assessment were excluded from the study. The patients were given trastuzumab 8 mg/kg loading dose followed by then 6 mg/kg dose on day 1 and paclitaxel 175 mg/m(2) on day 1 plus capecitabine 825 mg/m(2) twice daily on days 1-14 every 3 weeks. RESULTS: A total of 287 cycles of chemotherapy were administered with a median of 8 treatment cycles per patient (range 3-12). Median follow-up period was 24.7 months (range 4.7-51). There were 9 patients (24.3 %) with complete responses, 21 (56.8 %) with partial responses, 4 (10.8 %) with stable disease and 3 (8.1 %) with progressive disease resulting in an overall response rate (ORR) of 81.1 %. Median progression-free survival and overall survival were 14 and 38.4 months, respectively. Rates of grade 3 adverse events were neutropenia (n = 4, 10.8 %), cardiac dysfunction (n = 1, 2.7 %), hand-foot syndrome (n = 2, 5.4 %), nausea (n = 2, 5.4 %), vomiting (n = 2, 5.4 %), fatigue (n = 1, 2.7 %), diarrhea (n = 1, 2.7 %), neuropathy (n = 1, 2.7 %) and alopecia (n = 1, 2.7 %). CONCLUSIONS: Combination of trastuzumab and paclitaxel plus capecitabine is an effective and well-tolerated regimen in the first-line therapy for women with HER2-positive MBC. PMID- 23463100 TI - Circular RNAs: splicing's enigma variations. PMID- 23463099 TI - Transcription-coupled eviction of histones H2A/H2B governs V(D)J recombination. AB - Initiation of V(D)J recombination critically relies on the formation of an accessible chromatin structure at recombination signal sequences (RSSs) but how this accessibility is generated is poorly understood. Immunoglobulin light-chain loci normally undergo recombination in pre-B cells. We show here that equipping (earlier) pro-B cells with the increased pre-B-cell levels of just one transcription factor, IRF4, triggers the entire cascade of events leading to premature light-chain recombination. We then used this finding to dissect the critical events that generate RSS accessibility and show that the chromatin modifications previously associated with recombination are insufficient. Instead, we establish that non-coding transcription triggers IgL RSS accessibility and find that the accessibility is transient. Transcription transiently evicts H2A/H2B dimers, releasing 35-40 bp of nucleosomal DNA, and we demonstrate that H2A/H2B loss can explain the RSS accessibility observed in vivo. We therefore propose that the transcription-mediated eviction of H2A/H2B dimers is an important mechanism that makes RSSs accessible for the initiation of recombination. PMID- 23463101 TI - GW182 proteins cause PABP dissociation from silenced miRNA targets in the absence of deadenylation. AB - GW182 family proteins interact with Argonaute proteins and are required for the translational repression, deadenylation and decay of miRNA targets. To elicit these effects, GW182 proteins interact with poly(A)-binding protein (PABP) and the CCR4-NOT deadenylase complex. Although the mechanism of miRNA target deadenylation is relatively well understood, how GW182 proteins repress translation is not known. Here, we demonstrate that GW182 proteins decrease the association of eIF4E, eIF4G and PABP with miRNA targets. eIF4E association is restored in cells in which miRNA targets are deadenylated, but decapping is inhibited. In these cells, eIF4G binding is not restored, indicating that eIF4G dissociates as a consequence of deadenylation. In contrast, PABP dissociates from silenced targets in the absence of deadenylation. PABP dissociation requires the interaction of GW182 proteins with the CCR4-NOT complex. Accordingly, NOT1 and POP2 cause dissociation of PABP from bound mRNAs in the absence of deadenylation. Our findings indicate that the recruitment of the CCR4-NOT complex by GW182 proteins releases PABP from the mRNA poly(A) tail, thereby disrupting mRNA circularization and facilitating translational repression and deadenylation. PMID- 23463103 TI - Zinc(II) complexes containing bis-benzimidazole derivatives as a new class of apoptosis inducers that trigger DNA damage-mediated p53 phosphorylation in cancer cells. AB - In the present study, two zinc(II) complexes containing bis-benzimidazole derivatives, Zn(bpbp)Cl2 (1) and [Zn(bpbp)2](ClO4)2.CH3CH2OH.H2O (2) (bpbp = 2,6 bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine), have been designed, synthesized and evaluated for their in vitro anticancer activities. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. The complexes were identified as potent antiproliferative agents against a panel of five human cancer cell lines by comparing with cisplatin. Complex 2 demonstrated dose-dependent growth inhibition on MCF-7 human breast carcinoma cells with IC50 at 2.9 MUM. Despite this potency, the complexes possessed great selectivity between human cancer cells and normal cells. Induction of apoptosis in MCF-7 cells by complex 2 was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Further investigation on intracellular mechanisms revealed that complex 2 was able to induce p53-dependent apoptosis in cancer cells by triggering DNA damage. On the basis of this evidence, we suggest that Zn(II) complexes containing bis-benzimidazole derivatives may be candidates for further evaluation as chemotherapeutic agents for human cancers. PMID- 23463102 TI - PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development. AB - Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells. PMID- 23463104 TI - The era of ERAS: a new standard of perioperative care. PMID- 23463105 TI - Fast-track elective colectomy: single-surgeon experience of 100 consecutive cases. AB - AIMS: In 2005, the senior author (AGH) initiated an Enhanced Recovery After Surgery (ERAS) or 'fast-track' programme for elective colonic surgery at the Manukau Surgery Centre aimed at improving perioperative care. We reviewed the senior author's experience of elective colectomy conducted within the ERAS programme and evaluated clinical outcomes. METHODS: Using a prospectively maintained database, consecutive patients who underwent elective colonic resection by the senior author within the ERAS programme at the Manukau Surgery Centre between December 2005 and March 2012 were reviewed. Demographic and operative data were recorded and clinical outcomes including complications, hospital stay and readmissions were evaluated for 30 days postoperatively. RESULTS: 100 consecutive patients were reviewed. The median age of patients was 70 years (range: 16-92) and the most common indication for surgery was malignancy (81 cases). Right-sided colectomy was performed in 52 cases while 45 patients had a left-sided colectomy and 3 patients underwent subtotal colectomy. The median day to discharge was 3 days while total hospital stay was 4 days which incorporated 21 readmissions for mostly minor complications. Major complications occurred in only 8 patients and included 4 anastomotic leaks. CONCLUSION: In one surgeon's experience, elective colectomy performed within an optimised perioperative care environment achieves shorter hospital stay with a low rate of major complications. PMID- 23463106 TI - The role of capsule endoscopy in small bowel pathology: a review of 122 cases. AB - AIM: Small bowel capsule endoscopy (CE) has been introduced in New Zealand (NZ) in all of the tertiary and some secondary centres over the last few years. We describe our experience with CE from a single centre in NZ. METHODS: In this 2 year, retrospective, study of 122 consecutive patients, data was collected on multiple variables from the patient clinical, laboratory, and radiology records. Pillcam of Given Imaging Diagnostic System (Given Imaging Ltd, Yogneam, Israel) was used to image the small bowel. Descriptive statistics were used to analyse the data. RESULTS: Good preparation was noted in 69% of the cases. The most common indication for referral was obscure GI bleeding (70%). The overall diagnostic yield for relevant findings was 52%, with angioectasia as the most common specific finding (37%). The diagnostic yield in those with overt bleeds improved with inpatient status (74%). Incomplete examinations were noted in 12% and were significantly more common in the male gender. Preliminary imaging (barium, CT/MR) was noted to have a lower diagnostic yield. Enteroscopies were considered in 25% of the patients post CE procedure. CONCLUSION: Apart from a lower diagnostic yield in patients with overt bleeds, our data is consistent with that reported in literature and support the role of CE as the minimally invasive gold standard investigation for small bowel imaging. PMID- 23463107 TI - A dedicated dermatology clinic for renal transplant recipients: first 5 years of a New Zealand experience. AB - AIM: Cancer following organ transplantation is a growing public health concern. We describe the first 5 years' experience of a dedicated dermatology clinic for renal transplant recipients, the first of its type in New Zealand. METHODS: Data from patients seen in the clinic were collected on a nephrology/dermatology database. RESULTS: 86 of 99 transplant recipients had a baseline dermatology assessment. Seventy-one skin cancers (45 squamous, 25 basal cell carcinomas, 1 melanoma) were found in 17 patients. Eighteen of these were an incidental finding at the baseline post-transplant examination of 7 patients: they had not been noted either by the patient or by their nephrologist. A further 44 cancers were found in 13 patients at follow-up examinations in the dedicated clinic. Squamous and basal cell carcinomas received definitive treatment after 26 and 38 days (median) respectively. A brief analysis showed this to be a cost-effective way of diagnosing and treating skin cancer in this cohort of patients. CONCLUSION: The clinic is enabling prompt diagnosis and cost-effective treatment of skin cancers developing in renal transplant recipients and is also identifying significant numbers of pre-existing skin cancers in these patients. PMID- 23463108 TI - Wrapped in controversy: trends in fundoplication at myotomy for achalasia in Christchurch, New Zealand. AB - AIM: A surgical approach to the management of achalasia involves myotomy, typically with added anti-reflux procedure. The most appropriate fundoplication in this setting (total Nissen, partial anterior Dor, or partial posterior Toupet) remains controversial. We present the trends in fundoplication procedures performed at myotomy in Christchurch between 1997 and 2009, and compare this with the literature. METHODS: 34 cases of achalasia managed with myotomy and various types of fundoplication in Christchurch between 1997 and 2009 were separated into two temporal groups, and the type of surgery in each group analysed. Data was obtained from the clinical records on specific short and long-term postoperative complications. RESULTS: There is a decrease over time in myotomy without fundoplication and in total Nissen fundoplications performed. The number of posterior fundoplications remains equal over both time periods; however the proportion of anterior fundoplications is significantly increased in the later group. Three cases of mucosal perforation occurred during myotomy associated with anterior fundoplication, and reintervention rates were highest in myotomy only and anterior fundoplication patients. CONCLUSION: Trends in anti-reflux surgery in Christchurch reflect the development of the evidence base in the literature. The change in fundoplication procedure is not clearly explained by the complication rates. PMID- 23463109 TI - Endovascular aortic repair: can we predict who will not get long-term benefit? AB - AIM: The aim of this study is to review our endovascular aortic repair (EVAR) experience in Dunedin Public Hospital as well as assessing the applicability of Mount Sinai score and the American Society of Anesthesiologists physical status classification (ASA) in finding which patients will be most likely to benefit from EVAR. METHODS: A retrospective study of 54 patients who had EVAR from 2000 to December 2009 in Dunedin Public Hospital was conducted. Univariate, bivariate and multivariate regressions analyses were used in assessing the data with the occurrence of postoperative complications and mortality as the primary outcome variable. RESULTS: The overall mortality at 30 days was 1.8%. The Mount Sinai score and smoking status were both found to be significant predictors of mortality. DISCUSSION: The Mount Sinai score was a good predictor for mortality as it factors in the patient's comorbidities. This study indicates that smoking status was an important factor and it should be added to long-term risk predicting models. PMID- 23463110 TI - Index cholecystectomy: a continuing challenge for a provincial hospital. AB - AIMS: To review the management of acute gallstone disease at a provincial New Zealand centre and compare to current national/international practice. METHODS: All patients presenting to Nelson Hospital with acute gallstone-related pathology were identified from the study period. The first presentation within the audit period was defined as the index admission. Length of stay and interventions were recorded. Waiting lists were compared. RESULTS: Between January 2004 to December 2010, 390 patients were admitted with acute gallstone-related pathology to Nelson Hospital. The index cholecystectomy rate was 17% (57/329) after exclusion of 61 ineligible patients; 158/329 patients subsequently underwent elective cholecystectomy, with patients waiting a median time of 97 days (range 7-1922). There were 132 Emergency Department visits (median one (range 0-8)), and 59 readmissions with acute gallstone-related pathology for those waiting for cholecystectomy. Of the 37 admitted with gallstone pancreatitis, 11 underwent cholecystectomy within 2 weeks of index admission. Waiting lists remained unchanged over time. CONCLUSIONS: Nelson Hospital has a low rate of index cholecystectomy. High numbers of patients represent to the emergency department or are readmitted whilst waiting for definitive surgery. Patients presenting with gallstone pancreatitis fail to receive treatment in accordance with international management guidelines. PMID- 23463111 TI - Outcomes of open carpal tunnel decompression. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the commonest peripheral neuropathy in the UK. The aim of this study was to characterise the satisfaction and evaluate the symptoms of postoperative patients having undergone open carpal tunnel decompression. METHOD: A questionnaire comprising of 6 sections was sent to 241 eligible participants. Subjects were asked to provide their demographic information and to quantify preoperative and postoperative numbness and tingling. The target population was also asked to indicate areas of postoperative numbness and tingling on a Katz hand diagram. Symptom severity and quality of life scores were also assessed. RESULTS: This study received 89 usable responses. From analysis of the Katz hand diagrams if was possible to distinguish that 17 subjects (19.1%) had 'persistent' symptoms following carpal tunnel decompression and 72 subjects (80.9%) showed signs of symptomatic improvement. The 17 individuals with persistent symptoms were further assessed for significance between variables. Of these, most were of older age, mainly female, unemployed, with lower mental health and vitality scores. With significance testing, it was shown that lower mental health scores may contribute to a poorer response to surgery (p=0.096). CONCLUSION: Most subjects experienced a positive response to surgical intervention, however, it may be necessary to screen patients for signs of depression before undertaking any surgery. By taking a more holistic preoperative assessment and aiding patients to seek treatment for any mental health conditions, this study postulates that outcomes of open carpal decompression could be improved. PMID- 23463112 TI - Flatulence on airplanes: just let it go. AB - Flatus is natural and an invariable consequence of digestion, however at times it creates problems of social character due to sound and odour. This problem may be more significant on commercial airplanes where many people are seated in limited space and where changes in volume of intestinal gases, due to altered cabin pressure, increase the amount of potential flatus. Holding back flatus on an airplane may cause significant discomfort and physical symptoms, whereas releasing flatus potentially presents social complications. To avoid this problem we humbly propose that active charcoal should be embedded in the seat cushion, since this material is able to neutralise the odour. Moreover active charcoal may be used in trousers and blankets to emphasise this effect. Other less practical or politically correct solutions to overcome this problem may be to restrict access of flatus-prone persons from airplanes, by using a methane breath test or to alter the fibre content of airline meals in order to reduce its flatulent potential. We conclude that the use of active charcoal on airlines may improve flight comfort for all passengers. PMID- 23463113 TI - A rare neoplasm of the thyroid gland. AB - Burkitt's lymphoma of the thyroid gland is a rare malignancy. We present a case of a 58-year-old female who developed a rapid enlargement of her thyroid gland. Core biopsy confirmed the diagnosis of Burkitt's lymphoma. The tumour resolved after three cycles of chemotherapy. This case report emphasises the importance of considering lymphoma when dealing with thyroid nodules and goitres, as its management is different from that of other thyroid pathologies and delaying treatment has an impact on prognosis. PMID- 23463114 TI - Empyema and psoas abscess in a previously undiagnosed diabetic patient. AB - A 48-year-old man presented with a 2-month history of polyuria, polydypsia, chest pain, fever, cough and extreme weight loss. He was diagnosed with diabetic ketoacidosis and investigations revealed widespread infection with an empyema complicated by bronchopleural fistula, and iliopsoas, suprapubic and periarticular abscesses. Streptococcus milleri was cultured from all sites. A multidisciplinary medical and surgical approach was required for treatment. This case highlights the immunosuppression, and life-threatening complications arising from undiagnosed diabetes mellitus. PMID- 23463115 TI - Medical image. Reflex anoxic seizures in a toddler. AB - We report a toddler with frequent pallid type breath-holding or reflex anoxic seizure episodes successfully treated with pacemaker implantation. A rhythm strip (from an ambulatory ECG monitor that shows an 18-second period of asystole) is shown. PMID- 23463117 TI - Do all antidepressants cause QT prolongation--how good is the evidence? PMID- 23463116 TI - The important persisting problem of smoking in cars with children: new data from a multi-year national survey of young people. PMID- 23463118 TI - Low yearly completion rate of HDC investigations is a cause for concern. PMID- 23463119 TI - Diabetes and infections-hepatitis C: is there type 2 diabetes excess in hepatitis C infection? AB - Individual epidemiologic studies as well as the pooled analysis of observational studies have indicated the association between type 2 diabetes (T2D) and hepatitis C virus infection (HCV). Whether HCV infection is the cause of diabetes or diabetic patients are more prone to get HCV infection is still in question. The objective of the present review was to provide answers to this issue, based on available evidence from epidemiologic, molecular, experimental and therapeutic studies. Our current understanding of how chronic HCV infection could induce T2D is incomplete, but it seems twofold based on both direct and indirect roles of the virus. HCV may directly induce insulin resistance (IR) through its proteins. HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. The peroxisome proliferator-activated receptors (PPARs) are also implicated. PPARalpha/gamma, together with their obligate partner RXR, are the main nuclear receptors expressed in the liver. PPARalpha upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. Decreased activity of PPARs could attribute to HCV-induced IR. Immune-mediated mechanisms may be involved in the indirect role of HCV in inducing IR. It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. In summary, we illustrate that HCV infection is accompanied by multiple defects in the upstream insulin signaling pathway in the liver that may contribute to the observed prevalence of IR and diabetes. Future studies are needed to resolve this issue. PMID- 23463120 TI - Efficacy of low-intensity pulsed ultrasound treatment for surgically managed fresh diaphyseal fractures of the lower extremity: multi-center retrospective cohort study. AB - BACKGROUND: There are no evidence on the effects of low-intensity pulsed ultrasound (LIPUS) on surgically managed fresh fractures. We therefore performed a multicenter retrospective cohort study to investigate the effects of LIPUS on surgically managed fresh fractures. METHODS: This study included patients surgically treated for diaphyseal fractures of the femur or tibia between August 2009 and July 2010 at 14 institutions. Outcome was the union period. We performed an overall comparison of the LIPUS group (78 cases) with the control group (63 cases), as well as subgroup analyses comparing outcomes for fracture sites, fracture types, soft tissue conditions, and fixation methods between the groups. RESULTS: There was no significant difference between the groups in terms of distribution of cases by fracture site, fracture type, soft tissue condition, fixation method. Analyses comparing subgroups, however, showed significant differences between the two groups, particularly in relation to type C fractures, regardless of whether all cases or only closed-fracture cases were analyzed: there was an approximately 30 % reduction in the union period for type C fractures in the LIPUS group. There were also cases requiring reoperation due to lack of stability, even among the type C fractures. CONCLUSIONS: LIPUS is effective for surgically managed, fresh, type C comminuted diaphyseal fractures of the lower limbs when there is appropriate stability at the fracture site. PMID- 23463121 TI - Nationwide retrospective cohort survey of orthopedic injuries in members of the Taiwanese population with psychiatric disorders, 2000-2005. AB - BACKGROUND: The relationship between psychiatric disorders and musculoskeletal injuries is interesting but has not been investigated in depth. STUDY DESIGN: A retrospective cohort study, based on a large-sample nationwide database, was performed during 2000-2005 in Taiwan. METHODS: All subjects matching the inclusion criteria of psychiatric-associated ICD9-CM diagnostic codes in 2000 were selected as the inception cohort population. Another cohort-based case control study was designed, and one sex-matched and age-matched (1:1) control group randomly selected from the population without any prevalent psychiatric disorder in 2000 and incident psychiatric disorder in 2001-2005 was used for comparison. RESULTS: 64,662 Taiwanese people with any prevalent psychiatric disorder were enrolled in this study in 2000. The 6-year cumulative incidences of orthopedic injuries were 13.61/10,000 for femoral neck/femur fracture and 4.64/10,000, 3.40/10,000, 3.25/10,000, and 3.09/10,000 for radius/ulna or hand fracture, tibia/fibula or patella fracture, ankle or foot fracture, and humeral fracture, respectively. Compared with the control group, this Taiwanese population with prevalent psychiatric disorders had fewer incidences of all orthopedic injuries during the 6 years since 2000, and their cumulative incidence ratios ranged from 0.04 to 0.4 for the different injury sites. For lower-limb fractures, compared with the age stratum of less than 20-years-old, the odds ratios (OR) for the age strata 80-years-old or more and 60-79-years-old were 15.84 (95 % CI 4.55-55.20) and 6.11 (95 % CI 1.92-19.49), respectively. The people with organic psychotic conditions had a significantly greater tendency to suffer upper-limb and lower-limb fractures than those with other psychiatric diagnoses (the ranges of ORs were 3.23-16.67 and 2.13-25.00, respectively). CONCLUSION: Subjects with prevalent psychiatric disorders had fewer occurrences of orthopedic injuries than the general population. Among this specific population, an organic psychotic condition and old age were risk factors for suffering fracture of a limb. PMID- 23463122 TI - Femoral neck fractures: prognosis based on a new classification after superselective angiography. AB - BACKGROUND: Vascular injury after femoral neck fracture can determine its prognosis. This study aimed to determine methods of evaluating femoral neck fracture and accurately predicting the prognosis. METHODS: Forty-five patients with a single femoral neck fracture all underwent digital subtraction angiography (DSA) and were divided into three types by DSA. DSA showing three to six supporting band vascular images crossing the fracture line was classified as type I. DSA showing one to two supporting band vascular images crossing the fracture line was classified as type II. When DSA did not show vascular images crossing the fracture line, it was classified as type III. The 45 patients were divided according to age into elderly, middle-aged and youth groups. All cases were given internal fixation operations by a hollow screw under a C-brachial machine. After a follow-up of 6-60 months, avascular necrosis of the femoral head (ANFH) and fracture healing of different type and different ages of patients were evaluated according to symptoms and imaging examinations. RESULTS: (1) For DSA types I, II and III, the rates of ANFH were 0, 7.14 and 100 %, respectively, and the rates of fracture disunion were 13.3, 7.15 and 0 %, respectively. Therefore, the rate of ANFH is negatively related to the visible supporting band vascular amount on DSA. (2) In the young group, the proportions of types I, II and III were 6.7, 26.67 and 66.7 %, respectively, 18.18, 36.36 and 45.45 % in the middle-aged group and 63.16, 31.58 and 5.27 % in the elderly group. The rates of necrosis for elderly, middle-aged and youth were 10.53, 45.45 and 66.67 %, respectively, and the rates of fracture disunion were 0, 0 and 6.67 %, respectively. So we can draw the conclusion that the amount of supporting band vascular images is inversely proportional to age and the union is directly related to age, but independent of the supporting band vascular amount of DSA showing. CONCLUSION: The new classification after superselective angiography is valuable for predicting the prognosis of femoral neck fractures. PMID- 23463123 TI - Less invasive surgery with wrist arthroscopy for distal radius fracture. AB - BACKGROUND: We developed a surgical procedure that can facilitate arthroscopic intervention for volar locking plate fixation for distal radius fracture (DRF) with a less invasive technique. This study is to investigate the effectiveness of our original procedure for the treatment of DRF. METHODS: One hundred fifty-five wrists of 153 consecutive patients underwent our original procedure: the plate presetting arthroscopic reduction technique (PART) for DRF. The fractures consisted of 37 extra-articular and 118 intra-articular fractures. The fractures were reduced, anatomical alignment was regained with the aid of an image intensifier, and the volar locking plate was preset. Wrist arthroscopy was then performed and the intra-articular condition assessed. If there were any residual dislocations of the intra-articular fragments, these were reduced arthroscopically, and soft tissue injuries were subsequently treated. The traction was then removed, and the plate was securely fixed. One hundred forty five patients were followed up from 12 to 48 months. The final outcome was evaluated with the Mayo modified wrist score and Disability of the Arm, Shoulder and Hand questionnaire (DASH). The effectiveness of arthroscopy was also investigated. RESULT: On arthroscopic inspection, intra-articular dislocations were found to be residual in 35.2 %, even if reduction seemed to have been achieved when viewed with the image intensifier. Scapholunate interosseous ligament injury was recognized in 28.9 %, and triangular fibrocartilage complex injury was observed in 63.2 %. The final outcome was 112 excellent, 31 good, and 2 fair. The mean DASH score was 4.1. CONCLUSION: We developed the PART to simplify the combination of volar locking plating and arthroscopy. This technique was less invasive and effective in the treatment of DRF. PMID- 23463124 TI - Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL). AB - Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL. PMID- 23463125 TI - Reactivation of herpes simplex virus and cytomegalovirus in a case of thymoma associated graft-versus-host disease-like erythroderma. PMID- 23463126 TI - The origin and evolution of neuroendoscopy. AB - INTRODUCTION: Neuroendoscopy has become an integral field within neurosurgery. It has allowed neurosurgeons unprecedented access to deep structures within both the cranial and spinal compartments, while allowing for minimal incisions, tissue retraction, and postoperative healing time. DISCUSSION: In this article, we trace the origins of this vital field to ancient times, and show that much of its success is due to the brilliant minds of some luminaries such as Philipp Bozzini and Harold Hopkins. Through close collaborations between clinicians, scientists, and engineers neuroendoscopy has become an invaluable tool in the armamentarium of neurosurgeons to help solve a wide array of clinical problems. PMID- 23463127 TI - Dose-dependent relapse of hiatus hernia after administration of intrathecal baclofen treatment--a rare complication. AB - INTRODUCTION: Intrathecal baclofen treatment (ITB) is widely used in children with cerebral palsy. Although this treatment effectively reduces spasticity, diverse side effects are reported. CASE REPORT: We report about a boy with severe asphyxia-induced encephalopathy with bilateral cerebral palsy. After starting the intrathecal baclofen treatment, he episodically showed symptoms of severe gastroesophageal reflux with pale skin color, vomiting, massive drooling, acid regurgitation, and reduced well-being. An open ventral semifundoplication was done some years ago to treat a gastroesophageal reflux. These symptomatic episodes occurred strongly dose-dependent and were not observed during the short test procedure. CONCLUSION: For the first time, a strong dose-dependent treatment with ITB was documented as a cause for the above episodes and relapsing re herniations. PMID- 23463128 TI - Changes of amplitude integration electroencephalogram (aEEG) in different maturity preterm infant. AB - BACKGROUND: With the improvement of perinatal care and neonatal intensive care technology in recent years, a preterm infant, especially with small gestational age and very low birth weight, survives more and more. At the same time, adverse neurodevelopmental prognosis caused by brain damage in preterm infant also increased significantly. Preterm infant brain injury has become the most important factor for early death and neurodevelopment of preterm infant. METHODS: Amplitude integration electroencephalogram (aEEG) has an important clinical value in the assessment of brain development in the maturity of preterm infant. With the application of a neonatal brain function monitor, we value the aEEG graphic continuity, periodicity, narrowband lower margin amplitude, and bandwidth score and analyze wide- and narrowband on the lower bounds of voltage and bandwidth. RESULTS: The graphics of preterm infant aEEG become mature with the growth of the gestational age (1). With the growth of corrected gestational age, the aEEG graphics of preterm infant has the following feature: lower bound voltage of narrowband rising and width narrowing of narrowband (2). Extrauterine life can speed up the maturation of aEEG graphics (3). CONCLUSIONS: The aEEG technology is a noninvasive, operable, and simple analysis and suitable for application in the newborn intensive care unit. PMID- 23463130 TI - Lyapunov exponents computation for hybrid neurons. AB - Lyapunov exponents are a basic and powerful tool to characterise the long-term behaviour of dynamical systems. The computation of Lyapunov exponents for continuous time dynamical systems is straightforward whenever they are ruled by vector fields that are sufficiently smooth to admit a variational model. Hybrid neurons do not belong to this wide class of systems since they are intrinsically non-smooth owing to the impact and sometimes switching model used to describe the integrate-and-fire (I&F) mechanism. In this paper we show how a variational model can be defined also for this class of neurons by resorting to saltation matrices. This extension allows the computation of Lyapunov exponent spectrum of hybrid neurons and of networks made up of them through a standard numerical approach even in the case of neurons firing synchronously. PMID- 23463129 TI - Suprasellar granular cell tumor of the neurohypophysis in a child: unusual presentation in pediatric age of a rare tumor. AB - PURPOSE: Granular cell tumors (GCT) of the neurohypophysis are rare, solitary, nodular-shaped lesions, mostly presenting in the adult age with a female predilection. They rarely grow to a sufficient size to cause mass effect related symptoms and they may be found in most cases incidentally at autopsy of older patients. Few cases of symptomatic GCT of the neurohypophysis have been reported in the literature and only one of these in a pediatric patient in the first decade of life, who presented with central precocious puberty. METHODS: We report the case of a 11-year-old boy with a large suprasellar GCT of the neurohypophysis, complaining severe headache and pituitary insufficiency. Before our referral, the child was operated at another insitution through a pterional approach for tumor biopsy and underwent chemotherapy because of the misleading diagnosis of glioma. RESULTS: The patient was operated on by a fronto-orbito zygomatic approach with subtotal tumor resection. At last follow-up examination, a partial hypopituitarism was detected. The quality of life with replacement therapy was excellent. Fractionated radiotherapy on tumor remnant was advised. CONCLUSIONS: The reported case is exceptional because the tumor developed in a male pediatric patient, causing clinical symptoms related to intracranial hypertension and unusual endocrinological features. GCT has to be considered in the differential diagnosis of suprasellar masses, to avoid misleading interpretation and consequent wrong therapeutic management. PMID- 23463131 TI - Successful treatment of idiopathic recurrent pericarditis with interleukin-1 receptor antagonist (Anakinra). PMID- 23463132 TI - Characteristics and hemodynamic effects of extubation failure in children undergoing complete repair for tetralogy of Fallot. AB - This study aimed to identify the prevalence, etiology, and outcomes of extubation failure in children after complete repair for tetralogy of Fallot at a single tertiary-care, academic children's hospital. The secondary aim of this study was to determine the cardiorespiratory effects of the transition from positive pressure ventilation to spontaneous breathing in children with extubation success and extubation failure. For this study, extubation was defined as the need for reintubation within 96 h after extubation. Demographics as well as pre-, intra-, post-, and periextubation data were collected in a retrospective observational format for patients who underwent complete repair for tetralogy of Fallot during the period January 2001-June 2011. Patients with multiple aortopulmonary collateral arteries or associated complete atrioventricular septal defects were excluded from the study. The cardiorespiratory variables collected before and immediately after extubation included heart rate, respiratory rate, mean arterial blood pressure, central venous pressures, near-infrared spectroscopy, oxygen saturations, and lactate levels. The clinical outcomes evaluated included the success or failure of extubation and the hospital length of stay. Descriptive and univariate statistics were used to compare the group with extubation failure and the group with extubation success. Extubation failure occurred for 7 % (12/164) of the 164 eligible patients during the study period. The median age of the patients at surgery was 200 days (range 98-356 days), and their median weight was 6.8 kg (range 5.2-8.5 kg). For 6 % (10/164) of the patients, intubation was performed before surgery. The median duration of mechanical ventilation was 33 h (range 19.5-73 h), and the median hospital stay was 10 days (range 7-15 days). Of the 12 patients with extubation failure, 2 had extubation failure in first 2 h after extubation, 6 had failure in 2-24 h, 3 had failure in 24-48 h, and 1 had failure in 48-96 h. The patients in the extubation success and extubation failure groups were similar in age, sex, and body weight at the time of surgery. All preexisting conditions also were similar in the two groups. The intraoperative variables and postoperative complications did not differ between the two groups. The hospital stay was longer for the children with extubation failure (p < 0.001). The partial pressure of oxygen in arterial blood (PaO2), tachycardia, mean arterial blood pressure, and inotrope score improved significantly at conversion from positive-pressure ventilation to spontaneous ventilation in the patients with extubation success. This study demonstrated that extubation failure in patients after complete repair for tetralogy of Fallot is low and that the etiology is diverse. The majority of extubation failures in these patients occurred in the first 24 h. Extubation success in the children after repair for tetralogy of Fallot was associated with improvement in PaO2, tachycardia, and mean arterial pressure, with a decrease in inotrope score. Extubation failure is associated with a longer hospital stay. PMID- 23463133 TI - Tolvaptan increases serum sodium in pediatric patients with heart failure. AB - This study aimed to evaluate the use of tolvaptan in a consecutive series of pediatric patients with heart failure. Patients 18 years of age or younger with heart failure prescribed tolvaptan between January 2009 and October 2011 were retrospectively identified at Children's Medical Center Dallas. Laboratory parameters, urine output, fluid balance, and concurrent medications were recorded at baseline and at specified intervals after a single dose of tolvaptan. The 28 patients in the study had a median age of 2 years (range 1 month-18 years). The median tolvaptan dose administered was 0.3 mg/kg (range 0.1-1.3 mg/kg). The study patients had a median baseline serum sodium concentration of 127 mmol/L, and the increases in sodium were 2.5 mmol/L at 12 h, 5 mmol/L at 24 h, 4 mmol/L at 48 h, and 5 mmol/L at 72 h (all p < 0.001). Urine output was increased at 24 h (p < 0.001) and 48 h (p = 0.03), and fluid balance changes were significantly different at 24 h (p = 0.004). The changes in potassium, blood urea nitrogen, and serum creatinine were not significant at any interval. When controlling for traditional diuretic therapy, increases in serum sodium concentration and urine output remained statistically significant. A single dose of tolvaptan increased serum sodium concentrations for the majority in this small series of pediatric patients with heart failure. These results suggest that tolvaptan can be safely and effectively administered to pediatric patients. Prospective, randomized controlled trials are needed to evaluate the safety and efficacy of its use further. PMID- 23463134 TI - Epidemiology and risk factors for coronary artery abnormalities in children with complete and incomplete Kawasaki disease during a 10-year period. AB - Kawasaki disease (KD) is an acute systemic vasculitis of childhood. The diagnosis is based on clinical criteria. However, the presentation of KD is incomplete/atypical for approximately 20 % of patients. Kawasaki disease is complicated with coronary artery lesions (CALs) and considered the most common cause of acquired heart disease in children. The medical records of children discharged with KD from a tertiary pediatric hospital in Athens, Greece, during a decade (2001-2010) were retrospectively analyzed. During the study period, KD was diagnosed for 86 children younger than 14 years of age. Complete diagnostic criteria were fulfilled by 64 of the children (74.4 %), whereas 25.6 % were considered incomplete cases. Cardiovascular complications were detected in 48 children (55.8 %) and CALs in 28 children (32.6 %). The prevalence of CALs did not differ significantly between complete and incomplete/atypical KD (42.2 vs 4.5 %; P = 0.001). Logistic regression analysis showed that erythema in the lips and oral cavity was associated with the development of CALs [odds ratio (OR), 3.03; 95 % confidence interval (CI), 1.051-8.783; P = 0.040]. Conversely, children with incomplete/atypical KD (OR, 0.092; 95 % CI, 0.010-0.816; P = 0.032) and previous antibiotic treatment (OR, 0.17; 95 % CI, 0.036-0.875; P = 0.034) were less likely to experience CALs. Children with an incomplete/atypical presentation of KD or before antibiotic treatment may be at lower risk for the development of CALs. Future multicenter studies may help to establish this association better. PMID- 23463135 TI - Microgavage of zebrafish larvae. AB - The zebrafish has emerged as a powerful model organism for studying intestinal development(1-5), physiology(6-11), disease(12-16), and host-microbe interactions(17-25). Experimental approaches for studying intestinal biology often require the in vivo introduction of selected materials into the lumen of the intestine. In the larval zebrafish model, this is typically accomplished by immersing fish in a solution of the selected material, or by injection through the abdominal wall. Using the immersion method, it is difficult to accurately monitor or control the route or timing of material delivery to the intestine. For this reason, immersion exposure can cause unintended toxicity and other effects on extraintestinal tissues, limiting the potential range of material amounts that can be delivered into the intestine. Also, the amount of material ingested during immersion exposure can vary significantly between individual larvae(26). Although these problems are not encountered during direct injection through the abdominal wall, proper injection is difficult and causes tissue damage which could influence experimental results. We introduce a method for microgavage of zebrafish larvae. The goal of this method is to provide a safe, effective, and consistent way to deliver material directly to the lumen of the anterior intestine in larval zebrafish with controlled timing. Microgavage utilizes standard embryo microinjection and stereomicroscopy equipment common to most laboratories that perform zebrafish research. Once fish are properly positioned in methylcellulose, gavage can be performed quickly at a rate of approximately 7 10 fish/ min, and post-gavage survival approaches 100% depending on the gavaged material. We also show that microgavage can permit loading of the intestinal lumen with high concentrations of materials that are lethal to fish when exposed by immersion. To demonstrate the utility of this method, we present a fluorescent dextran microgavage assay that can be used to quantify transit from the intestinal lumen to extraintestinal spaces. This test can be used to verify proper execution of the microgavage procedure, and also provides a novel zebrafish assay to examine intestinal epithelial barrier integrity under different experimental conditions (e.g. genetic manipulation, drug treatment, or exposure to environmental factors). Furthermore, we show how gavage can be used to evaluate intestinal motility by gavaging fluorescent microspheres and monitoring their subsequent transit. Microgavage can be applied to deliver diverse materials such as live microorganisms, secreted microbial factors/toxins, pharmacological agents, and physiological probes. With these capabilities, the larval zebrafish microgavage method has the potential to enhance a broad range of research fields using the zebrafish model system. PMID- 23463136 TI - Prenatal diagnosis of trisomy 21 by quantitatively pyrosequencing heterozygotes using amniotic fluid as starting material of PCR. AB - Allelic ratio of an SNP has been used for prenatal diagnosis of fetal trisomy 21 by MALDI-TOF mass spectrometry (MS). Because MALDI-TOF MS is challenging in quantification performance, pyrosequencing was proposed to replace MS by better quantification of allelic ratios. To achieve a simple and rapid clinical diagnostic, PCR with "HpH Buffer" (a buffer with a high pH) was developed to directly amplify amniotic fluid. By the established assay, 114 samples of amniotic fluid were analyzed by pyrosequencing five SNPs of each sample; the allelic ratios of euploid heterozygotes were thus calculated to determine the cut off values for prenatal diagnosis of trisomy 21. The panel of five SNPs were high in heterozygosity so that at least one heterozygote was found in each sample, and 86% of the samples had at least two heterozygotes, giving a nearly 100% sensitivity (population coverage) of the assay. By using the cut-off values of each SNP, 20 pre-diagnosed clinical samples were detected as trisomy 21 carriers with a confidence level over 99%, indicating that our method and karyotyping analysis were consistent in results. In conclusion, this pyrosequencing-based approach, coupled with direct amplification of amniotic fluid, is accurate in quantitative genotyping and simple in operation. We believe that the approach could be a promising alternative to karyotyping analysis in prenatal diagnosis. PMID- 23463137 TI - High prevalence of cestodes in Artemia spp. throughout the annual cycle: relationship with abundance of avian final hosts. AB - Brine shrimp, Artemia spp., act as intermediate hosts for a range of cestode species that use waterbirds as their final hosts. These parasites can have marked influences on shrimp behavior and fecundity, generating the potential for cascading effects in hypersaline food webs. We present the first comprehensive study of the temporal dynamics of cestode parasites in natural populations of brine shrimp throughout the annual cycle. Over a 12-month period, clonal Artemia parthenogenetica were sampled in the Odiel marshes in Huelva, and the sexual Artemia salina was sampled in the Salinas de Cerrillos in Almeria. Throughout the year, 4-45 % of A. parthenogenetica were infected with cestodes (mean species richness = 0.26), compared to 27-72 % of A. salina (mean species richness = 0.64). Ten cestode species were recorded. Male and female A. salina showed similar levels of parasitism. The most prevalent and abundant cestodes were those infecting the most abundant final hosts, especially the Greater Flamingo Phoenicopterus ruber. In particular, the flamingo parasite Flamingolepis liguloides had a prevalence of up to 43 % in A. parthenogenetica and 63.5 % in A. salina in a given month. Although there was strong seasonal variation in prevalence, abundance, and intensity of cestode infections, seasonal changes in bird counts were weak predictors of the dynamics of cestode infections. However, infection levels of Confluaria podicipina in A. parthenogenetica were positively correlated with the number of their black-necked grebe Podiceps nigricollis hosts. Similarly, infection levels of Anomotaenia tringae and Anomotaenia microphallos in A. salina were correlated with the number of shorebird hosts present the month before. Correlated seasonal transmission structured the cestode community, leading to more multiple infections than expected by chance. PMID- 23463138 TI - Some characteristics of IL-5-producing T cells in mouse liver induced by Schistosoma japonicum infection. AB - Schistosome infection could cause significant liver damage in animal; Th2 cells play an important role in the progress of this disease. In our study, C57BL/6 mice were infected by Schistosoma japonicum and lymphocytes were isolated from the liver to detect some characteristics of interleukin-5 (IL-5)-producing T cells by different methods. The results revealed that S. japonicum infection could induce a large amount of IL-5 in mouse liver T cells by the means of fluorescent bead immunoassay and RT-PCR. Although, mouse liver contained many T cell subsets, such as Th cells, Tc cells, NKT cells, and gammadelta T cells. Fluorescence activated cell sorting results indicated that Th cells were the main source of IL-5 in the T cell population after phorbol 12-myristate 13-acetate and ionomycin stimulation. Moreover, the percentage of IL-5-producing Th cells continued to increase from 4 to 8 weeks after S. japonicum infection, which differed from the changes of IFN-gamma(+) Th1 cells, IL-4(+) Th2 cells, and IL 17A(+) Th17 cells during S. japonicum infection. Additionally, cytokines co expression results demonstrated that 36.2 % of IL-5(+) Th cells could express IL 4, and 10 % of it could produce IFN-gamma or IL-17A. Collectively, these findings implied that IL-5-producing Th cells posses some properties which differ from other cytokines secreting Th cells. PMID- 23463139 TI - Should GPs be fined for rises in avoidable emergency admissions to hospital? Yes. PMID- 23463140 TI - Should GPs be fined for rises in avoidable emergency admissions to hospital? No. PMID- 23463141 TI - Doctors claim to have cured girl of HIV. PMID- 23463142 TI - Company denies that its coding advice is aimed at improving mortality data. PMID- 23463143 TI - GPs face pressure from patients after Specsavers markets its NHS audiology service. PMID- 23463144 TI - Nicholson insists he will oversee NHS reorganisation, despite calls for resignation. PMID- 23463145 TI - Sampling animal movement paths causes turn autocorrelation. AB - Animal movement models allow ecologists to study processes that operate over a wide range of scales. In order to study them, continuous movements of animals are translated into discrete data points, and then modelled as discrete models. This discretization can bias the representation of the movement path. This paper shows that discretizing correlated random movement paths creates a biased path by creating correlations between successive turning angles. The discretization also biases statistical tests for correlated random walks (CRW) and causes an overestimate in distances travelled; a correction is given for these biases. This effect suggests that there is a natural scale to CRWs, but that distance discretized CRWs are in a sense, scale invariant. Perhaps a new null model for continuous movement paths is needed. Authors need to be aware of the biases caused by discretizing correlated random walks, and deal with them appropriately. PMID- 23463146 TI - Electrophoretically deposited reduced graphene oxide platform for food toxin detection. AB - Reduced graphene oxide (RGO) due to its excellent electrochemical properties and large surface area, has recently aroused much interest for electrochemical biosensing application. Here, the chemically active RGO has been synthesized and deposited onto an indium tin oxide (ITO) coated glass substrate by the electrophoretic deposition technique. This novel platform has been utilized for covalent attachment of the monoclonal antibodies of aflatoxin B1 (anti-AFB1) for food toxin (AFB1) detection. The electron microscopy, X-ray diffraction, and UV visible studies reveal successful synthesis of reduced graphene oxide while the XPS and FTIR studies suggest its carboxylic functionalized nature. The electrochemical sensing results of the anti-AFB1/RGO/ITO based immunoelectrode obtained as a function of aflatoxin concentration show high sensitivity (68 MUA ng(-1) mL cm(-2)) and improved detection limit (0.12 ng mL(-1)). The association constant (ka) for antigen-antibody interaction obtained as 5 * 10(-4) ng mL(-1) indicates high affinity of antibodies toward the antigen (AFB1). PMID- 23463147 TI - The hypocholesterolemic effect of capsaicinoids in ovariectomized rats fed with a cholesterol-free diet was mediated by inhibition of hepatic cholesterol synthesis. AB - Previous studies showed that capsaicinoid supplementation favorably modifies the plasma lipoprotein profile. The present study investigated the effect of capsaicinoids on plasma lipids and gene expressions of key receptors and enzymes involved in cholesterol metabolism in ovariectomized (OVX) rats. OVX rats were fed with a cholesterol-free diet and orally administered 0 mg kg(-1) bw (OVX CON), 5 mg kg(-1) bw (OVX-LD), 10 mg kg(-1) bw (OVX-MD), and 15 mg kg(-1) bw (OVX HD) capsaicinoids daily for 28 days. As the capsaicinoids dose increased, body weight gain and concentrations of plasma triglyceride, total cholesterol, and low density lipoprotein cholesterol, as well as total lipid accumulation were significantly decreased. In addition, the mRNA levels of hepatic 3-hydroxyl-3 methylglutaryl CoA reductase and cholesterol-7alpha-hydroxylase were down regulated, whereas those of transient receptor potential vanilloid type-1, ileal apical sodium-dependent bile acid transporter, and intestinal bile acid binding protein were up-regulated. The excretion of small intestinal bile acid contents and fecal bile acid also decreased. These results suggest that capsaicinoids can prevent ovarian hormone deficiency-induced hypercholesterolemia by inhibiting the hepatic cholesterol synthesis. PMID- 23463148 TI - In vitro comparison of different carrier materials with rat bone marrow MSCs. AB - OBJECTIVES: Injectable or implantable scaffolds seeded with autologous chondrogenic cells may represent a promising option for treatment of cartilage defects in the future. Current problems with the autologous chondrocyte implantation including dedifferentiation and the development of fibrocartilage suggest the use of alternative chondrogenic cell sources such as mesenchymal stromal cells (MSCs). The aim of this study was to compare the early effects of different scaffolds on the proliferation and metabolic activity of chondrogenic MSCs in vitro. MATERIALS AND METHODS: Multipotent stromal cells were isolated from rat bone marrow, phenotyped by flow cytometry, and differentiated into distinct lineages proved by lineage-specific staining and gene expression (RT PCR) pattern. Cell proliferation on Tutodent(r) Membrane, Bio-Gide(r), TissuFleece E, and Belotero(r) Soft was quantified by the MTT and WST-1 assay and direct determination of total cell numbers. Potential cytotoxic effects of eluates obtained from the materials were quantified by lactate dehydrogenase (LDH) and 5-bromo-2-deoxyuridine (BrdU) assay. RESULTS: TissuFleece E displayed the best results regarding cell proliferation on the biomaterials and metabolic activity (MTT, WST-1) (p < 0.001). Yet, the eluates of TissuFleece E caused an increased LDH release and lower values in the BrdU test. Cell proliferations on Bio-Gide(r), Tutodent(r) Membrane, and Belotero(r) Soft were similar to the control. The eluates of Belotero(r) Soft exhibited the highest LDH release and lowest values in the BrdU assay (p < 0.05). CONCLUSIONS: Our results support the use of Tissufleece E as scaffold for chondrogenic rat MSCs. However, it should be prewashed with culture medium before seeding of the cells. CLINICAL RELEVANCE: Tissufleece E may serve as a promising carrier material for chondrogenic MSCs for cartilage tissue engineering attempts. PMID- 23463149 TI - An elective course on the basic and clinical sciences aspects of vitamins and minerals. AB - Objective. To develop and implement an elective course on vitamins and minerals and their usefulness as dietary supplements. Design. A 2-credit-hour elective course designed to provide students with the most up-to-date basic and clinical science information on vitamins and minerals was developed and implemented in the doctor of pharmacy (PharmD) curriculum. In addition to classroom lectures, an active-learning component was incorporated in the course in the form of group discussion. Assessment. Student learning was demonstrated by examination scores. Performance on pre- and post-course surveys administered in 2011 demonstrated a significant increase in students' knowledge of the basic and clinical science aspects of vitamins and minerals, with average scores increasing from 61% to 86%. At the end of the semester, students completed a standard course evaluation. Conclusion. An elective course on vitamin and mineral supplements was well received by pharmacy students and helped them to acquire knowledge and competence in patient counseling regarding safe, appropriate, effective, and economical use of these products. PMID- 23463150 TI - Heat shock protein expression analysis in canine osteosarcoma reveals HSP60 as a potentially relevant therapeutic target. AB - Heat shock proteins (HSP) are highly conserved across eukaryotic and prokaryotic species. These proteins play a role in response to cellular stressors, protecting cells from damage and facilitating recovery. In tumor cells, HSPs can have cytoprotective effects and interfere with apoptotic cascades. This study was performed to assess the prognostic and predictive values of the gene expression of HSP family members in canine osteosarcoma (OS) and their potential for targeted therapy. Gene expressions for HSP were assessed using quantitative PCR (qPCR) on 58 snap-frozen primary canine OS tumors and related to clinic pathological parameters. A significant increased expression of HSP60 was found in relation to shorter overall survival and an osteoblastic phenotype. Therefore, the function of HSP60 was investigated in more detail. Immunohistochemical analysis revealed heterogeneous staining for HSP60 in tumors. The highest immunoreactivity was found in tumors of short surviving dogs. Next HSP expression was shown in a variety of canine and human OS cell lines by qPCR and Western blot. In two highly metastatic cell lines HSP60 expression was silenced using siRNA resulting in decreased cell proliferation and induction of apoptosis in both cell lines. It is concluded that overexpression of HSP60 is associated with a poor prognosis of OS and should be evaluated as a new target for therapy. PMID- 23463151 TI - Acute shift in glutamate concentrations following experimentally induced panic with cholecystokinin tetrapeptide--a 3T-MRS study in healthy subjects. AB - According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks. PMID- 23463152 TI - An orexin hotspot in ventral pallidum amplifies hedonic 'liking' for sweetness. AB - Orexin (hypocretin) is implicated in stimulating appetite as well as arousal, and in both food reward and drug reward. The ventral pallidum (VP) receives orexin projections from lateral hypothalamus neurons (LH), and orexin terminals are especially dense in the posterior half of VP, which is also the location of an opioid hedonic hotspot. The VP hotspot is a roughly cubic-millimeter site where mu opioid stimulation can amplify the hedonic impact of sweetness, expressed as an increase in 'liking' reactions to sucrose taste. The anatomical overlap in posterior VP between opioid hotspot and orexin inputs raises the possibility that the hedonic hotspot might allow orexin to amplify 'liking' too. We examined whether microinjections of orexin-A into the VP hotspot enhance the hedonic impact of sucrose, as assessed via affective taste reactivity measures of 'liking' reactions, and additionally compared effects at nearby sites in adjacent LH and extended amygdala. Taste reactivity results indicated that orexin stimulation specifically in the VP hotspot nearly doubled the magnitude of positive 'liking' reactions elicited by the taste of sucrose. Mapping results for localization of function, aided by Fos plume measures of the local spread of orexin impact, suggested that hedonic enhancement was generated by essentially the same cubic-millimeter of posterior VP previously identified as the opioid hotspot. By contrast, microinjection sites in the anterior half of VP, or in LH or extended amygdala, generally failed to produce any hedonic enhancement. We conclude that an orexin hedonic hotspot exists in posterior VP, with similar boundaries to the opioid hotspot. An orexin hedonic hotspot may permit regulatory hypothalamic circuitry to make foods more 'liked' during hunger by acting through VP. Dysfunction in a VP orexin hotspot in addiction or mood disorders might also contribute to some types of affective psychopathology. PMID- 23463153 TI - Esophageal stents in malignant and benign disorders. AB - Endoscopic stent placement is an effective palliative treatment for malignant dysphagia and fistula, leading to rapid symptom relief. However, recurrent dysphagia and other stent-related complications are common, for which reason continuously new design modifications are implemented. Although some of these changes facilitate stent placement, complications remain and occur at similar rates. Recently, stents have also been used in benign esophageal disorders. Covered stents have the ability to effectively seal esophageal perforations and leaks, reducing the need for invasive surgery. This benefit does not pertain to patients with refractory benign esophageal strictures, in whom stents have limited long-term effect and are associated with a high complication rate. The initial results of fully covered metal stents in refractory esophageal variceal bleeding are encouraging, but their definite role remains to be further elucidated. This review provides an overview of indications, techniques, and management of complications of stents in malignant and benign esophageal disease. PMID- 23463154 TI - Comparison of serum cystatin C and creatinine changes after cardiopulmonary bypass in patients with normal preoperative kidney function. AB - PURPOSE: Serum creatinine is used ubiquitously to estimate glomerular filtration rate and to diagnose acute kidney injury after cardiac surgery. Serum cystatin C is a novel biomarker that has emerged as a possible diagnostic alternative to serum creatinine. It is unclear if the dynamic changes in serum cystatin C immediately following cardiopulmonary bypass (CPB) differ from those of serum creatinine in patients with normal preoperative kidney function. METHODS: We compared changes in serum levels of creatinine and cystatin C by measuring them serially in 19 patients undergoing CPB. Within-patient differences for serum creatinine and serum cystatin C were compared by repeated measures ANOVA. RESULTS: Serum creatinine and cystatin C levels showed significant correlation with each other. Both biomarkers showed a significant decrease after CPB, but their serum concentrations reverted to pre-CPB levels within 12 h. Serum levels of serum creatinine remained unchanged from baseline levels throughout 72-h post CPB. In contrast, serum cystatin C levels rose further and became significantly higher compared to baseline within 48 h. Serum cystatin C remained significantly elevated at 48- and 72-h post-CPB. CONCLUSIONS: Processes that determine the serum concentrations of serum creatinine and cystatin C in the post-CPB period affect the two biomarkers differently, suggesting that the two are not interchangeable as diagnostic markers of glomerular filtration rate. Future studies are needed to examine if these discrepancies are related to differences in their production rates, in their ability to detect small changes in glomerular filtration rate, or to a combination of these, and to determine the effect of such differences on the diagnostic and prognostic accuracy of the two biomarkers. PMID- 23463155 TI - Sonographic evaluation of para- and perirenal fat thickness is an independent predictor of early kidney damage in obese patients. AB - PURPOSE: To determine whether para- and perirenal fat ultrasonographic thickness (PFUT) is related to increased urinary albumin excretion and whether PFUT is an independent indicator of early kidney damage in obese subjects. METHOD: Sixty seven nonhypertensive, nondiabetic obese patients and 34 age- and sex-matched normal healthy volunteers were involved in this study. Clinical characteristics, blood biochemistry, PFUT, and urinary albumin/creatinine ratio (ACR) of the subjects were measured. The intraoperator and interoperator coefficient of variation was 5.6 and 3.2 %, respectively. RESULTS: ACR and PFUT were significantly higher in obese patients than those of normal healthy volunteers. PFUT was higher in obese patients with microalbuminuria than those with normoalbuminuria. Correlation analysis showed PFUT had a positive correlation with body mass index (BMI, r = 0.677, P < 0.01), waist circumference (WC, r = 0.686, P < 0.01), plasma free fatty acids (FFAs, r = 0.589, P < 0.01), and ACR (r = 0.610, P < 0.01). ACR had a positive correlation with BMI (r = 0.444, P < 0.01), WC (r = 0.440, P < 0.01), and plasma FFAs (r = 0.496, P < 0.01). Multivariate regression analyses showed that ACR could be predicted by PFUT. CONCLUSIONS: PFUT may be an independent predictor of early kidney damage in nonhypertensive, nondiabetic obese patients, and PFUT could be a useful tool for the assessment of visceral fat and early kidney damage in obese patients. PMID- 23463156 TI - Glomerular filtration rate in prospective living kidney donors. AB - PURPOSE: Measurements of glomerular filtration rate (GFR) are frequently interpreted assuming a linear variation with age. Nonlinear relationships may give a better representation of the changes associated with normal ageing. METHODS: This was a retrospective study of 904 subjects (468 women, 436 men; age range 18-84 years) undergoing assessment as prospective living kidney donors. GFR was evaluated from (51)Cr-EDTA plasma clearance using blood samples taken at 2, 3 and 4 h. The slope-intercept GFR was corrected for body surface area (BSA) using the Haycock formula and for the fast exponential using the Brochner-Mortensen equation. The relationship between age, gender and GFR was examined using best fit curve analysis. Nonlinear relationships with age were explored using fractional polynomials. RESULTS: There was no gender difference in BSA-corrected GFR over five decades of age (P = 0.40). However, female donors with a body mass index >30 kg/m(2) had a statistically significantly lower GFR than nonobese women (P < 0.01). The best-fit relationship between age and GFR was nonlinear and described using a fractional polynomial model of degree 1 (GFR = 103.9-0.0061 * Age(2) mL/min/1.73 m(2)) with a root mean standard error of 12.9 mL/min/1.73 m(2). The residual variance for this model was significantly smaller than for the best-fit linear model (P = 0.006). CONCLUSIONS: GFR measurements in prospective living kidney donors are best corrected for age using a nonlinear relationship. PMID- 23463157 TI - [We cannot care alone: volunteers in dementia care at Nurnberg General Hospital]. AB - BACKGROUND: People with dementia have specific care needs especially in an acute care setting. Professionals in clinical routine have limited capacities in meeting the needs of dementia patients as far as communication, interaction and orientation are concerned. AIMS: For 2 years, the Department of Internal Medicine and Geriatrics at Nurnberg General Hospital has hosted volunteers in dementia care who accompany and visit people with dementia during their acute care stay. We present the organization of the volunteer training program, training content, and preliminary evaluation results. METHODS: We chose a mixed methods approach for research and evaluation. Baseline data, motivational profile of volunteers, paper and pencil data on attitudes, skills and knowledge before and after training were assessed. RESULTS: Preliminary results show a positive effect on attitudes, skills, and knowledge after volunteer training. Volunteers and professionals need continual support and education to enable volunteers to act as an integrative part of the acute geriatric care team. CONCLUSION: The admission to an acute care setting is often frightening and confusing for dementia patients. Trained volunteers have the potential to make the hospital stay more pleasant for people with dementia. PMID- 23463158 TI - [Dementia in acute hospitals]. PMID- 23463159 TI - Visualisation of the rectoanal inhibitory reflex with a modified contrast enema in children with suspected Hirschsprung disease. AB - BACKGROUND: Patients with Hirschsprung disease lack the normal rectoanal inhibitory reflex, which can be studied with anorectal manometry or US. OBJECTIVE: To see whether the rectoanal inhibitory reflex could be visualised with a modified contrast enema, thereby increasing the diagnostic accuracy of the contrast enema and reducing the number of rectal biopsies. MATERIALS AND METHODS: Fifty-nine boys and 42 girls (median age, 12 months) with suspected Hirschsprung disease were examined with a modified contrast enema, supplemented with two injections of cold, water-soluble contrast medium, to induce the reflex. Two paediatric radiologists evaluated the anonymised examinations in consensus. The contrast enema findings were correlated with the results of rectal biopsy or clinical follow-up. RESULTS: Five boys and one girl (median age, 7.5 days) were diagnosed with Hirschsprung disease. The negative predictive value of the rectoanal inhibitory reflex was 100%. A contrast enema with signs of Hirschsprung disease in combination with an absent rectoanal inhibitory reflex had the specificity of 98% and sensitivity of 100% for Hirschsprung disease. CONCLUSION: The modified contrast enema improves the radiological diagnosis of Hirschsprung disease. By demonstrating the rectoanal inhibitory reflex in children without Hirschsprung disease, we can reduce the proportion of unnecessary rectal biopsies. PMID- 23463160 TI - Developing a pediatric endovascular thrombolysis program: a single-center experience. AB - Deep venous thrombosis (DVT) is being increasingly recognized as a significant issue in children. Despite the low incidence of DVT, the risks of pulmonary embolism and death in children are significant. Post-thrombotic syndrome, a syndrome of chronic venous insufficiency, can have long-term adverse consequences in children and adolescents. Adult studies have shown that catheter-directed therapy can reduce the incidence of post-thrombotic syndrome. Safety of catheter directed therapy in adolescents has also been demonstrated. These reasons compelled us to institute a pediatric endovascular thrombolysis program at our institute for management of pediatric DVT. We describe the process of developing a multi-disciplinary thrombolysis program involving interventional radiology (pediatric and adult), pediatric hematology, critical care, anesthesia and vascular surgery, and describe the role of each specialty in the development of the program. We also describe our experience with patient selection, endovascular therapy procedure, pre-, intra- and post-procedure monitoring, and follow-up management for endovascular therapy for DVT. PMID- 23463161 TI - Development of a practicable non-contact bedside autonomic activation monitoring system using microwave radars and its clinical application in elderly people. AB - We developed a practicable, non-contact, autonomic activation monitoring system using microwave radars without imposing any stress on monitored individuals. Recently, the rapid increase in the aging population has raised concerns in developed countries. Thus, hospitals and care facilities will need to perform long-term health monitoring of elderly patients. The system allows monitoring of geriatric autonomic dysfunctions caused by chronic diseases, such as diabetes or myocardial infarction (MI), while measuring vital signs in non-contact way. The system measures heart rate variability (HRV) of elderly people in bed using dual, 24-GHz, compact microwave radars attached beneath the bed mattress. HRV parameters (LF, HF, and LF/HF) were determined from the cardiac peak-to-peak intervals, which were detected by radars using the maximum entropy method. We tested the system on 15 elderly people with and without diabetes or MI (72-99 years old) from 7:00 p.m. to 6:00 a.m. at a special nursing home in Tokyo. LF/HF obtained by the system correlated significantly (R = 0.89; p < 0.01) with those obtained by Holter electrocardiography (ECG). Diabetic subjects showed significantly lower LF (radar) than non-diabetic (119.8 +/- 57.8 for diabetic, 405.9 +/- 112.6 for non-diabetic, p < 0.01). HF (radar) of post-MI subjects was significantly lower than that of non-MI (219.7 +/- 131.7 for post-MI and 580.0 +/ 654.6 for non-MI, p < 0.05). Previous studies using conventional ECG reveal that diabetic neuropathy decreases LF, and also MI causes parasympathetic attenuation which leads to HF reduction. Our study showed that average SDNN of post-MI patients is smaller than 50 ms which is known to have high mortality. The non contact autonomic activation monitoring system allows a long-term health management especially during sleeping hours for elderly people at healthcare facilities. PMID- 23463162 TI - Elucidating the fuzziness in physician decision making in ARDS. AB - The current standard of care for patients suffering from acute respiratory distress syndrome (ARDS) is ventilation with a tidal volume of 6 ml/kg predicted body weight (PBW), but variability remains in the tidal volumes that are actually used. This study aims to identify patient scenarios for which there is discordance between physicians in choice of tidal volume and positive end expiratory pressure (PEEP) in ARDS patients. We developed an algorithm based on fuzzy logic for encapsulating the expertise of individual physicians regarding their use of tidal volume and PEEP in ARDS patients. The algorithm uses three input measurements: (1) peak airway pressure (PAP), (2) PEEP, and (3) arterial oxygen saturation (SaO2). It then generates two output parameters: (1) the deviation of tidal volume from 6 ml/kg PBW, and (2) the change in PEEP from its current value. We captured 6 realizations of intensivist expertise in this algorithm and assessed their degree of concordance using a Monte Carlo simulation. Variability in the tidal volume recommended by the algorithm increased for PAP > 30 cmH2O and PEEP > 5 cmH2O. Tidal volume variability decreased for SaO2 > 90 %. Variability in the recommended change in PEEP increased for PEEP > 5 cmH2O and for SaO2 near 90 %. Intensivists vary in their management of ARDS patients when peak airway pressures and PEEP are high, suggesting that the current goal of 6 ml/kg PBW may need to be revisited under these conditions. PMID- 23463163 TI - Microporous organic polymers for gas storage and separation applications. AB - Microporous organic polymers (MOPs), an emerging class of functional porous materials featured with the pure organic component have been widely studied in recent years. These materials have potential uses in areas such as storage, separation, and catalysis. In this Perspective, we focused on the gas storage and separation of MOPs. The targeted design and synthesis of MOPs toward the enhancement of gas capacity and selectivity are discussed. Furthermore, special emphasis is given to the post-synthesis modification of MOPs which have been proved to be effective methods to accurately tune the desired properties. PMID- 23463164 TI - Utilizing a cranial window to visualize the middle cerebral artery during endothelin-1 induced middle cerebral artery occlusion. AB - Creation of a cranial window is a method that allows direct visualization of structures on the cortical surface of the brain(1-3). This technique can be performed in many locations overlying the rat cerebrum, but is most easily carried out by creating a craniectomy over the readily accessible frontal or parietal bones. Most frequently, we have used this technique in combination with the endothelin-1 middle cerebral artery occlusion model of ischemic stroke to quantify the changes in middle cerebral artery vessel diameter that occur with injection of endothelin-1 into the brain parenchyma adjacent to the proximal MCA(4, 5). In order to visualize the proximal portion of the MCA during endothelin -1 induced MCAO, we use a technique to create a cranial window through the temporal bone on the lateral aspect of the rat skull (Figure 1). Cerebral arteries can be visualized either with the dura intact or with the dura incised and retracted. Most commonly, we leave the dura intact during visualization since endothelin-1 induced MCAO involves delivery of the vasoconstricting peptide into the brain parenchyma. This bypasses the need to incise the dura directly over the visualized vessels for drug delivery. This protocol will describe how to create a cranial window to visualize cerebral arteries in a step-wise fashion, as well as how to avoid many of the potential pitfalls pertaining to this method. PMID- 23463168 TI - Protein fibrillation and nanoparticle interactions: opportunities and challenges. AB - Due to their ultra-small size, nanoparticles (NPs) have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technology. NPs are recognized as promising and powerful tools to fight against the human brain diseases such as multiple sclerosis or Alzheimer's disease. In this review, after an introductory part on the nature of protein fibrillation and the existing approaches for its investigations, the effects of NPs on the fibrillation process have been considered. More specifically, the role of biophysicochemical properties of NPs, which define their affinity for protein monomers, unfolded monomers, oligomers, critical nuclei, and other prefibrillar states, together with their influence on protein fibrillation kinetics has been described in detail. In addition, current and possible-future strategies for controlling the desired effect of NPs and their corresponding effects on the conformational changes of the proteins, which have significant roles in the fibrillation process, have been presented. PMID- 23463170 TI - Suspended GaN nanowires as NO2 sensor for high temperature applications. AB - We propose a gas sensor operable over a wide temperature range and using suspended GaN nanowires functionalized with Pt-Pd. The sensor is batch-fabricated by directly integrating the GaN nanowires onto batch-processed silicon microelectrodes in parallel. The high thermal stability of the sensor originates from a large band gap of GaN nanowires that enables the detection of NO2 gas at an elevated temperature of up to 350 degrees C without a decrease in responsiveness. Exposed to NO2 at 100-1000 ppm at 350 degrees C, the sensor shows a linear increment in relative response with respect to the change in gas concentration. The sensor results in a two- to four-fold increase in responsiveness to NO2 at 100 ppm compared to NH3 at 100 ppm and CO2 at 1000 ppm. The nanowires suspended over a substrate provide increased surface area that could interact with gas molecules for enhanced responsiveness, and prevent any unnecessary interactions between the nanowires and the substrate. PMID- 23463169 TI - Deep sequencing of Lotus corniculatus L. reveals key enzymes and potential transcription factors related to the flavonoid biosynthesis pathway. AB - Lotus corniculatus L. is used worldwide as a forage crop due to its abundance of secondary metabolites and its ability to grow in severe environments. Although the entire genome of L. corniculatus var. japonicus R. is being sequenced, the differences in morphology and production of secondary metabolites between these two related species have led us to investigate this variability at the genetic level, in particular the differences in flavonoid biosynthesis. Our goal is to use the resulting information to develop more valuable forage crops and medicinal materials. Here, we conducted Illumina/Solexa sequencing to profile the transcriptome of L. corniculatus. We produced 26,492,952 short reads that corresponded to 2.38 gigabytes of total nucleotides. These reads were then assembled into 45,698 unigenes, of which a large number associated with secondary metabolism were annotated. In addition, we identified 2,998 unigenes based on homology with L. japonicus transcription factors (TFs) and grouped them into 55 families. Meanwhile, a comparison of four tag-based digital gene expression libraries, built from the flowers, pods, leaves, and roots, revealed distinct patterns of spatial expression of candidate unigenes in flavonoid biosynthesis. Based on these results, we identified many key enzymes from L. corniculatus which were different from reference genes of L. japonicus, and five TFs that are potential enhancers in flavonoid biosynthesis. Our results provide initial genetics resources that will be valuable in efforts to manipulate the flavonoid metabolic pathway in plants. PMID- 23463171 TI - A model of membrane contraction predicting initiation and completion of bacterial cell division. AB - Bacterial cell division involves a complex and dynamic sequence of events whereby polymers of the protein FtsZ assemble at the division plane and rearrange to achieve the goal of contracting the cell membrane at the site of cell division, thus dividing the parent cell into two daughter cells. We present a mathematical model (which we refer to as CAM-FF: Critical Accumulation of Membrane-bound FtsZ Fibres) of the assembly of the contractile ring in terms of the accumulation of short linear polymers of FtsZ that associate and dissociate from the cell membrane. In prokaryotes, the biochemical function of FtsZ is thought to underpin the assembly and at least the initial kinetic force of ring contraction. Our model extends earlier work of Surovtsev et al. [PLoS Comput. Biol., 2008, 4, e1000102] by adding (i) the kinetics of FtsZ accumulation on cell membrane anchor proteins and (ii) the physical forces required to deform the cell against its surface tension. Moreover, we provide a more rigorous treatment of intracellular diffusion and we revise some of the model parameter values in light of the experimental evidence now available. We derive a critical contraction parameter which links the chemical population dynamics of membrane-bound FtsZ molecules to the force of contraction. Using this parameter as a tool to predict the ability of the cell to initiate division, we are able to predict the division outcome in cells depleted of key FtsZ-binding proteins. PMID- 23463172 TI - Meningioma. AB - Meningiomas represent the most common primary brain tumor and comprise 3 World Health Organization (WHO) grades, the most frequent being WHO grade I (90%). Surgery is mandatory to establish the diagnosis and to remove the tumor; however, complete resection can be achieved in only <50% of patients. Depending on the extent of resection, tumor location and the WHO grade radiation therapy can be applied. The issue of systemic treatment such as chemotherapy or targeted therapy (eg, somatostatin receptors, antiangiogenic agents) is yet not solved, particularly as current data are derived from small uncontrolled series in patients with long-standing disease and after several pretreatments. A more thorough understanding of molecular genetics, signaling pathways and prognostic factors in meningiomas should lead to the design of studies which stratify according to these factors. These studies have to be conducted in newly diagnosed patients after incomplete resection and in tumors of WHO grade II and III. PMID- 23463173 TI - Genetic characterization of avian-origin H3N2 canine influenza viruses isolated from Guangdong during 2006-2012. AB - Canine influenza virus (CIV) is an emerging pathogen that causes severe and acute respiratory disease in dogs. In 2006, the H3N2 canine influenza virus was first identified in dogs from Guangdong province in China. Up to now, nine CIVs have been isolated from different populations in Guangdong. The nine isolates were grouped together with the canine H3N2 viruses isolated from dogs and felines in Korea, when the eight phylogenetic trees constructed were compared. These findings emphasize the importance of CIV surveillance in this region for understanding the genesis of this virus, and it is important to remain aware of the potential of H3N2 CIV to be transmitted from dogs to the human population. PMID- 23463174 TI - Longitudinal HIV-1 gp120-C2V3C3 phylogenetic surveillance and tropism evolution in patients under HAART. AB - This 8-year longitudinal study was aimed to analyze the HIV-1 gp120-C2V3C3 sequence dynamics, their phylogenetic relationships and tropism evolution in patients under HAART. Such viral analysis comprised two compartments: plasma and PBMC. Fifty gp120-C2V3C3 genomic sequences were characterized from 16 patients: 41 from plasma when viremia was measurable and 9 from PBMCs if plasma viral load was undetectable. The vast majority of HIV isolates (43 out of 50) were ascribed to BF subtype, irrespective of the compartment (plasma or mononuclear-cells) analyzed. A statistically well-supported clustering phenomenon was observed for each patient sampling data. Each cluster comprised viral sequences from both compartments analyzed. In the vast majority of cases, the viral sequences obtained along active production periods were intermingled with those identified from proviral sequences. A substantial stability of co-receptor tropism for the HIV BF subtype was observed over an 8-year followup. PMID- 23463175 TI - Molecular characterization of the interaction between the N-terminal region of Potato virus X (PVX) coat protein (CP) and Nicotiana benthamiana PVX CP interacting protein, NbPCIP1. AB - Using yeast two-hybrid assays and a Nicotiana benthamiana cDNA library, we previously identified an N. benthamiana protein, NbPCIP1, that interacts with Potato virus X (PVX) coat protein (CP). We also previously determined that NbPCIP1 enhances PVX replication in plants. To determine the domains and/or amino acid residues required for PVX CP and NbPCIP1 interaction, here we used yeast two hybrid and beta-galactosidase filter assays to test the effects of deletion and site-directed mutations on the interaction. Truncation analysis revealed that the N-terminal region of PVX CP interacts with NbPCIP1. To identify which N-terminal region PVX CP amino acid(s) interact with NbPCIP1, we substituted the 12 charged amino acids on the PVX CP N-terminal region to alanine. Yeast two-hybrid, beta galactosidase filter, and bimolecular fluorescence complementation (BiFC) assays confirmed that ten of the 12 alanine-substituted mutations blocked the interaction with NbPCIP1. The results suggest that the N-terminal region of PVX CP including its helical structure is important for interaction with NbPCIP1. PMID- 23463176 TI - Functional dyspepsia: Glimmers of hope for functional dyspepsia. PMID- 23463178 TI - Moral judgment competence of medical students: a transcultural study. AB - The authors conducted a cross-sectional short-term study using Lind's Moral Judgment Test (MJT) to compare moral judgment competence (C-score) among students from a medical school in the Northeast region of Brazil and a medical school in the Northern region of Portugal. This study compares the C-scores of groups in the first and eighth semesters of study within each medical school and groups from corresponding semesters between the two medical schools. This study also evaluates the influence of such factors as age and gender on moral competence. A regression of moral judgment competence among the students in their eighth semester versus the students in the first semester of Brazilian medical school (p < 0.001) and a stagnation of moral competence among students in their eighth semester versus the first semester students in the Portuguese medical school (p = 0.06) were observed. For both the first semester and eighth semester groups, the students in the Portuguese medical school had higher C-scores than the students in the Brazilian medical school. In the analysis of the students' performances in terms of MJT dilemmas, the phenomenon of "moral segmentation" was observed in all of the groups, and the students performed better on the worker's dilemma than on the doctor's dilemma. Among students in the same semester of study, older students had lower C-scores. There was generally no significant difference between men's and women's C-scores. PMID- 23463177 TI - Altered functions of alveolar macrophages and NK cells involved in asbestos related diseases. AB - Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure. We focused on alveolar macrophages (AM) and natural killer (NK) cells in asbestosis and mesothelioma, respectively, and examined their functions upon exposure to asbestos or in patients with mesothelioma. Exposure to asbestos caused rat AM to exhibit high production of transforming growth factor-beta (TGF-beta) with prolonged survival in the absence of other cells, not simultaneously with the apoptosis caused by asbestos. The NK cell line showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, and primary NK cells in culture with asbestos and peripheral blood NK cells in mesothelioma shared a decrease in expression of NKp46, a representative activating receptor. The AM finding indicates that AM contribute to asbestosis by playing a direct role in the fibrogenic response, as well as the inflammatory response. The response of NK cells indicates that exposure to asbestos has an immune-suppressive effect, as well as a tumorigenic effect. Our studies therefore reveal novel effects of asbestos exposure on AM and tumor immunity, which may represent valuable information for construction of a strategy for prevention and cure of asbestosis and malignant mesothelioma. PMID- 23463179 TI - A small-scale randomized controlled trial of the self-help version of the New Forest Parent Training Programme for children with ADHD symptoms. AB - The efficacy of a self-help parent training programme for children with attention deficit hyperactivity disorder (ADHD) was evaluated. The New Forest Parenting Programme Self-help (NFPP-SH) is a 6-week written self-help psychological intervention designed to treat childhood ADHD. Forty-three children were randomised to either NFPP-SH intervention or a waiting list control group. Outcomes were child ADHD symptoms measured using questionnaires and direct observation, self-reported parental mental health, parenting competence, and the quality of parent-child interaction. Measures of child symptoms and parental outcomes were assessed before and after the intervention. ADHD symptoms were reduced, and parental competence was increased by self-help intervention. Forty five percent of intervention children showed clinically significant reductions in ADHD symptoms. Self-help intervention did not lead to improvements in parental mental health or parent-child interaction. Findings provide support for the efficacy of self-help intervention for a clinical sample of children with ADHD symptoms. Self-help may provide a potentially cost-effective method of increasing access to evidence-based interventions for clinical populations. PMID- 23463180 TI - Effectiveness of telephone-assisted parent-administered behavioural family intervention for preschool children with externalizing problem behaviour: a randomized controlled trial. AB - Externalizing problem behaviour is one of the most common childhood disorders. Parent training is an effective treatment for these children and there is growing interest in the effects of parent-administered interventions with minimal therapist contact. This randomized controlled study examined the efficacy of a telephone-assisted parent-administered behavioural intervention (bibliotherapy) in families with preschool children with externalizing problem behaviour. Families were randomly assigned to a treatment group (n = 26) and an untreated waitlist control group (n = 22). The intervention comprised the reading of an 11 chapter self-help book and 11 weekly telephone consultations. Compared to the control group, the treatment group demonstrated significant decreases in parent reported externalizing and internalizing child problem behaviour and dysfunctional parenting practices. Moreover, treated parents reported less parenting-related strains and decreases in parental depression, anxiety, and stress. The results suggest that telephone-assisted self-administered parent training is an effective alternative to more intensive forms of behavioural family intervention for preschool children with externalizing problem behaviour. PMID- 23463181 TI - Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice. AB - OBJECTIVE: We investigated whether dexmedetomidine provided protective effects on cecal ligation and puncture (CLP)-induced septic mice, through suppressing the expression of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha) and interlukin-6 (IL-6)] and high mobility group box 1 (HMGB1). METHODS: The model of sepsis was set up by CLP in 136 male BALB/c mice (40 mice for survival studies and 96 for cytokine studies) which were divided into four groups, including a C, CLP, DEX + CLP and CLP + DEX group. The serum levels of TNF-alpha, IL-6 and HMGB1 were detected at 6, 12, 24 and 48 h after operations, and lung HMGB1 mRNA were analyzed at 24 and 48 h. The mortality rates were calculated 7 days after the operations. RESULTS: The mortality rates 7 days after operations were significantly lower in the CLP + DEX (50 %) and DEX + CLP (30 %) groups than in the CLP group (90 %). Serum concentrations of IL-6 and TNF-alpha decreased significantly in dexmedetomidine administration groups compared with the CLP group. The levels of HMGB1 and lung HMGB1 mRNA were lower in the dexmedetomidine administration groups than in the CLP group. There was a significant correlation between lung HMGB1 mRNA and serum HMGB1(r = 0.858). CONCLUSIONS: Dexmedetomidine could reduce the mortality rate and inhibit pro-inflammatory cytokine responses during polymicrobial sepsis in mice. PMID- 23463182 TI - NDRG2: a newly identified mediator of insulin cardioprotection against myocardial ischemia-reperfusion injury. AB - The N-myc downstream-regulated gene 2 (NDRG2) is involved in cell apoptosis and survival. Although reported to be highly expressed in the cardiac tissue, the biological function of NDRG2 in the heart remains to be established. Insulin exerts protective effects against myocardial ischemia/reperfusion (I/R) injury through the PI3K/Akt pathway. Here, we examined the changes in phosphorylation of NDRG2, a novel substrate and phosphoprotein of Akt, in insulin-induced protection against myocardial I/R. Rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, as well as significantly up-regulated myocardial Akt and NDRG2 phosphorylation levels compared with the I/R group. These effects of insulin were blocked by pretreatment with the PI3K inhibitor wortmannin or Akt inhibitor. To further ascertain the role of NDRG2 in insulin-induced cardioprotection, cardiomyocytes were transduced with a lentivirus encoding shRNA targeting NDRG2 (loss-of function), which rendered the cells more susceptible to I/R injury and significantly blunted the anti-apoptotic effect of insulin. Moreover, the NDRG2 shRNA lentivirus was tested in vivo, and NDRG2 knockdown aggravated myocardial I/R injury and attenuated the insulin-mediated cardioprotection against I/R injury. Taken together, these results suggest a novel role of PI3K/Akt/NDRG2 signaling in the cardioprotective effect of insulin. PMID- 23463183 TI - Niche partition of Bacteriovorax operational taxonomic units along salinity and temporal gradients in the Chesapeake Bay reveals distinct estuarine strains. AB - The predatory Bacteriovorax are Gram-negative bacteria ubiquitous in saltwater systems that prey upon other Gram-negative bacteria in a similar manner to the related genus Bdellovibrio. Among the phylogenetically defined clusters of Bacteriovorax, cluster V has only been isolated from estuaries suggesting that it may be a distinct estuarine phylotype. To assess this hypothesis, the spatial and temporal distribution of cluster V and other Bacteriovorax phylogenetic assemblages along the salinity gradient of Chesapeake Bay were determined. Cluster V was expected to be found in significantly greater numbers in low to moderate salinity waters compared to high salinity areas. The analyses of water and sediment samples from sites in the bay revealed cluster V to be present at the lower salinity and not high salinity sites, consistent with it being an estuarine phylotype. Cluster IV had a similar distribution pattern and may also be specifically adapted to estuaries. While the distribution of clusters V and IV were similar for salinity, they were distinct on temperature gradients, being found in cooler and in warmer temperatures, respectively. The differentiation of phylotype populations along the salinity and temporal gradients in Chesapeake Bay revealed distinct niches inhabited by different phylotypes of Bacteriovorax and unique estuarine phylotypes. PMID- 23463185 TI - A 6-year antifungal stewardship programme in a teaching hospital. AB - PURPOSE: To describe the antifungal stewardship programme in our hospital and to assess its impact on total antifungal prescriptions and their cost, and on the process of care measures regarding the diagnostic and therapeutic management of invasive aspergillosis and candidaemia. METHODS: We conducted a prospective observational study describing the multifaceted antifungal stewardship programme in place at our French teaching tertiary-care hospital since 2005. Several actions were implemented successively, including the systematic evaluation of all costly antifungal prescriptions (echinocandins, lipid formulations of amphotericin B, posaconazole and voriconazole). RESULTS: A total of 636 antifungal prescriptions were discussed by the antifungal management team from 2005 to 2010 inclusive, mainly from the haematology department (72 %). In 344/636 cases (54 %), a piece of advice was fed back to the physician in charge of the patient, with an 88 % compliance rate. Optimal standard of care was achieved for galactomannan antigen testing, performance of chest computed tomography (CT) scan and voriconazole therapeutic drug monitoring for invasive aspergillosis, with no combination therapies used since 2008. Regarding candidaemia, optimal standard of care was achieved for the timing of antifungal therapy, recommended first-line therapy, duration of therapy and the removal of central venous catheters. Total antifungal prescriptions (in defined daily doses, DDD) and their cost were contained between 2003 and 2010. CONCLUSIONS: The implementation of an antifungal stewardship programme was feasible, sustainable and well accepted. We observed an improved quality of care for some process of care measures, and antifungal use and cost were contained in our hospital. PMID- 23463186 TI - Epidemiology of invasive fungal infections in the intensive care unit: results of a multicenter Italian survey (AURORA Project). AB - PURPOSE: The aims of this study are to evaluate the epidemiology of invasive fungal infections (IFIs) in patients admitted to an intensive care unit (ICU) in Southern Italy and the in vitro antifungal susceptibility of isolates. METHODS: A surveillance program was implemented in 18 ICUs. IFI cases were recorded using a standardized form. RESULTS: A total of 105 episodes of IFIs occurred in 5,561 patients during the 18-month study. The main infections were caused by yeasts, more than filamentous fungi (overall incidence of 16.5 cases per 1,000 admissions and 2.3 cases per 1,000 admissions, respectively). The overall crude mortality rate was high (42.8 %), particularly for mold infections (61.5 %). All yeast infections were Candida bloodstream infections. Over half (59.8 %) were caused by Candida non-albicans, with C. parapsilosis being the most common (61.8 %). In the multivariate model, trauma admission diagnosis, prolonged stay in the ICU, and parenteral nutrition were independently associated with candidemia due to C. parapsilosis [odds ratio (OR) 3.5, (1.8-5.2); OR 3.5, (1.02-3.5); OR 3.6, (1.28 6.99), respectively]. Among mold infections, 12 patients suffered from invasive pulmonary aspergillosis, with Aspergillus fumigatus as the predominant pathogen (41.7 %). One case of brain scedosporiosis was identified. Overall, azoles and echinocandins resistance was uncommon. CONCLUSIONS: Candida non-albicans species are the most frequent cause of candidemia in ICU patients. Mold infections are associated with a high mortality rate. This study confirms the importance of the epidemiological surveillance on IFIs in the ICU setting for documenting species distribution and antimicrobial susceptibility patterns to guide therapeutic choices. PMID- 23463187 TI - Tissue factor-mediated activation of the prothrombin complex concentrate (PCC) is differently inhibited by dabigatran, rivaroxaban, and apixaban: potential clinical implication. AB - Currently, several newer oral anticoagulants namely dabigatran (anti-IIa), rivaroxaban (anti-Xa), and apixaban are available for various clinical implications. Another oral anti-Xa edoxaban is under development. A parenteral anti-Xa drug namely otamixaban is also under development for cardiovascular interventions. Bleeding complications have been reported in the new oral anticoagulants and have been managed by conventional approaches with limited success. Prothrombin complex concentrates (PCCs) are reported to neutralize the anticoagulant activity of these agents. The PCCs are also able to generate endogenous factor Xa and IIa along with other proteases that are capable of neutralizing the circulating anti-Xa or anti-IIa activities of the newer anticoagulants. The generation of Xa and IIa is also dependent on the type of tissue factor available for their activation. These reported studies suggest that different tissue factors differentially activate a PCC namely Profilnine SD. Furthermore, dabigatran differs from rivaroxaban and other factor Xa inhibitors in its inhibitory profile. PMID- 23463188 TI - Variations in the circulating heparin levels during maintenance hemodialysis in patients with end-stage renal disease. AB - Unfractionated heparin has remained the anticoagulant of choice in patients undergoing hemodialysis. However, wide variations in the heparinization responses have been observed in patients anticoagulated with this drug. The purpose of this investigation was to measure circulating heparin levels in patients with end stage renal disease (ESRD) prior to and after maintenance hemodialysis. This study included 119 patients with ESRD undergoing maintenance hemodialysis who received heparin during dialysis. Citrated blood samples were collected prior to and immediately after the dialysis session and analyzed utilizing clot-based methods such as activated partial thromboplastin time (APTT), Heptest, and prothrombinase-induced clotting time (PiCT). Circulating anti-Xa levels, antithrombin III levels, and thrombin generation (TG) were also measured. The circulating heparin levels ranged from 0 to 1.08 IU/mL with a mean of 0.07 +/- 0.11 for the APTT and a range of 0 to 1.98 for the Heptest with a mean of 0.09 +/ 0.26 U/mL. There was no significant difference in circulating levels of heparin between pre- and post-hemodialysis samples using APTT, Heptest, and PiCT, whereas the TG and anti-Xa tests showed a statistically significant P value <0.05 when comparing the 2 groups. The presence of detectable levels of heparin in the predialysis plasma samples for almost two-thirds (87 of 119) of the patients suggests that residual heparin circulates in these patients for a longer period of time. In all, 5% of postdialysis samples, 6 of 119, contained >0.25 U/mL of heparin, which may be related to a central catheter vascular access flushed with heparin. These findings suggest that patients on maintenance hemodialysis may accumulate a detectable amount of heparin due to the decreased renal clearance. PMID- 23463189 TI - Neurotrophic molecules in the treatment of neurodegenerative disease with focus on the retina: status and perspectives. AB - Neurotrophic factors are operationally defined as molecules that promote the survival and differentiation of neurons. Chemically, they belong to divergent classes of molecules but most of the classic neurotrophic factors are proteins. Together with stem cells, viral vectors and genetically engineered cells, they constitute important tools in neuroprotective and regenerative neurobiology. Protein neurotrophic molecules signal through receptors located on the cell membrane. Their downstream signaling exploits pathways that are often common to chemically different factors and frequently target a relatively restricted set of transcription factors, RNA interference and diverse molecular machinery involved in the life vs. death decisions of neurons. Application of neurotrophic factors with the aim of curing or, at least, improving the outcome of neurodegenerative diseases requires (1) profound knowledge of the complex molecular pathology of the disease, (2) the development of animal models as closely as possible resembling the human disease, (3) the identification of target cells to be addressed, (4) intense efforts in chemical engineering to ensure the stability of molecules or to design carriers and small analogs with the ability to cross the blood-brain barrier and (5) scrutinity with regard to possible side effects. Last, but not least, engineering efforts to optimize administration, e.g., by designing the right canulae and infusion devices, are important for the successful translation of preclinical advances into clinical benefit. This article presents selected examples of neurotrophic factors that are currently being tested in animal models or developed for transfer to the clinic, with a major focus on factors with the potential of becoming applicable in various forms of retinal degeneration. PMID- 23463190 TI - Direct laser writing of sub-50 nm nanofluidic channels buried in glass for three dimensional micro-nanofluidic integration. AB - We report on the fabrication of nanofluidic channels directly buried in silicate glass with transverse widths down to less than 50 nm using three-dimensional (3D) femtosecond laser direct writing. Using this technique, integrated micro nanofluidic systems have been produced by simultaneously writing micro- and nanofluidic channels arranged into various 3D configurations in glass substrates. The fabricated micro- and nanofluidic systems have been used to demonstrate DNA analysis, e.g. stretching of DNA molecules. Our technique offers new opportunities to develop novel 3D micro-nanofluidic systems for a variety of lab on-a-chip applications. PMID- 23463191 TI - Near-infrared to near-infrared upconverting NaYF4:Yb3+,Tm3+ nanoparticles-aptamer Au nanorods light resonance energy transfer system for the detection of mercuric(II) ions in solution. AB - A new luminescence resonant energy transfer (LRET) system has been designed that utilizes near-infrared (NIR)-to-NIR upconversion lanthanide nanophosphors (UCNPs) as the donor, and Au nanorods (Au NRs) as the acceptor. The UCNPs were excited by a near-infrared (980 nm) wavelength and also emitted at a near-infrared wavelength (804 nm) using an inexpensive infrared continuous wave laser diode. The Au NRs showed a high absorption band around 806 nm, which provided large spectral overlap between the donor and the acceptor. Hg(2+) ions were added to an aqueous solution containing the UCNPs and Au NRs that were modified with a Hg(2+) aptamer. Then, a sandwich-type LRET system was developed for the detection of Hg(2+) ions that had high sensitivity and selectivity in the NIR region. The method was successfully applied to the sensing of Hg(2+) ions in water and human serum samples. PMID- 23463192 TI - Excitation polarization provides structural resolution of individual non-blinking nano-objects. AB - We propose to combine the method of fluorescence intensity centroid localization with rotation of the plane of excitation polarization. Polarized light interacts selectively with differently oriented fluorophores; thus yielding topological information on the nanometer scale, without any need for fluorophore blinking. The method is applicable to photostable individual systems, when most of the traditional super-resolution methods fail. A theoretical study is supported by experiments on 30 nm long cyclodextrin-encapsulated single polyrotaxane conjugated polymer chains. PMID- 23463193 TI - Purification, partial characterization, and covalent immobilization-stabilization of an extracellular alpha-amylase from Aspergillus niveus. AB - An extracellular amylase secreted by Aspergillus niveus was purified using DEAE fractogel ion exchange chromatography and Sephacryl S-200 gel filtration. The purified protein migrated as a single band in 5 % polyacrylamide gel electrophoresis (PAGE) and 10 % sodium dodecyl sulfate (SDS-PAGE). The enzyme exhibited 4.5 % carbohydrate content, 6.6 isoelectric point, and 60 and 52 kDa molar mass estimated by SDS-PAGE and Bio-Sil-Sec-400 gel filtration column, respectively. The amylase efficiently hydrolyzed glycogen, amylose, and amylopectin. The end-products formed after 24 h of starch hydrolysis, analyzed by thin layer chromatography, were maltose, maltotriose, maltotetraose, and maltopentaose, which classified the studied amylase as an alpha-amylase. Thermal stability of the alpha-amylase was improved by covalent immobilization on glyoxyl agarose (half-life of 169 min, at 70 degrees C). On the other hand, the free alpha-amylase showed a half-life of 20 min at the same temperature. The optima of pH and temperature were 6.0 and 65 degrees C for both free and immobilized forms. PMID- 23463194 TI - The burden and costs of prevention and management of genital disease caused by HPV in women: a population-based registry study in Finland. AB - The aim of this study was to evaluate the total burden and health care provider costs of prevention, management and treatment of HP-related genital disease outcomes including all organized and opportunistic screening tests. Information about HPV-related disease outcomes in the Finnish female population of 2.7 million was obtained from nationwide population-based registry data. We estimated the incidence, health care resource use, health provider costs and life years lost due to cervical, vaginal and vulvar cancer and intraepithelial neoplasia (CIN, VaIN, VIN), cervical adenocarcinoma in situ, and external genital warts. The average annual disease burden of HPV-related genital disease in the female population of Finland comprises altogether 241 cases of cervical, vaginal and vulvar cancer, 2,898 new cases of CIN, 34,432 cases of minor cytological abnormalities, and almost 4,000 cases of external genital warts. The total annual costs of screening, further diagnostics and treatment of HPV-related genital disease were ? 44.7 million of which the annual costs due to cervical cancer screening were ? 22.4 million and due to diagnostics, management and treatment of HPV-related genital disease outcomes were ? 22.3 million. The latter included ? 8.4 million due to minor cervical abnormalities detected by the current cervical screening practice. The extensive opportunistic Pap testing fails to keep the incidence of cervical cancer from increasing among women aged 30-34. In addition opportunistic screening among this and younger age group detects a significant number of cytological abnormalities, most of which are probably treated unnecessarily. PMID- 23463195 TI - The origin of hepatitis C virus. AB - The origin of hepatitis C virus (HCV) can be conceptualised at several levels. Firstly, origins might refer to its dramatic spread throughout the Western world and developing countries throughout the twentieth century. As a blood-borne virus, this epidemic was fuelled by new parenteral transmission routes associated with medical treatments, immunisation, blood transfusion and more recently injecting drug use. At another level, however, origins might refer to the immediate sources of HCV associated with its pandemic spread, now identified as areas in Central and West sub-Saharan Africa and South and South East Asia where genetically diverse variants of HCV appear to have circulated for hundreds of years. Going back a final step to the actual source of HCV infection in these endemic areas, non-human primates have been long suspected as harbouring viruses related to HCV with potential cross-species transmission of variants corresponding to the 7 main genotypes into humans. Although there is tempting analogy between this and the clearly zoonotic origin of HIV-1 from chimpanzees in Central Africa, no published evidence to date has been obtained for infection of HCV-like viruses in either apes or Old World monkey species. Indeed, a radical re think of both the host range and host-specificity of hepaciviruses is now required following the very recent findings of a non-primate hepacivirus (NPHV) in horses and potentially in dogs. Further research on a much wider range of mammals is needed to better understand the true genetic diversity of HCV-like viruses and their host ranges in the search for the ultimate origin of HCV in humans. PMID- 23463196 TI - Cell culture systems for hepatitis C virus. AB - Due to the obligatory intracellular lifestyle of viruses, cell culture systems for efficient viral propagation are crucial to obtain a detailed understanding of the virus-host cell interaction. For hepatitis C virus (HCV) the development of permissive and authentic culture models continues to be a challenging task. The first efforts to culture HCV had limited success and range back to before the virus was molecularly cloned in 1989. Since then several major breakthroughs have gradually overcome limitations in culturing the virus and sequentially permitted analysis of viral RNA replication, cell entry, and ultimately the complete replication cycle in cultured cells in 2005. Until today, basic and applied HCV research greatly benefit from these tremendous efforts which spurred multiple complementary cell-based model systems for distinct steps of the HCV replication cycle. When used in combination they now permit deep insights into the fascinating biology of HCV and its interplay with the host cell. In fact, drug development has been much facilitated and our understanding of the molecular determinants of HCV replication has grown in parallel to these advances. Building on this groundwork and further refining our cellular models to better mimic the architecture, polarization and differentiation of natural hepatocytes should reveal novel unique aspects of HCV replication. Ultimately, models to culture primary HCV isolates across all genotypes may teach us important new lessons about viral functional adaptations that have evolved in exchange with its human host and that may explain the variable natural course of hepatitis C. PMID- 23463197 TI - Animal models for hepatitis C. AB - Hepatitis C remains a global epidemic. Approximately 3 % of the world's population suffers from chronic hepatitis C, which is caused by hepatitis C virus (HCV)-a positive sense, single-stranded RNA virus of the Flaviviridae family. HCV has a high propensity for establishing a chronic infection. If untreated chronic HCV carriers can develop severe liver disease including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Antiviral treatment is only partially effective, costly, and poorly tolerated. A prophylactic or therapeutic vaccine for HCV does not exist. Mechanistic studies of virus-host interactions, HCV immunity, and pathogenesis as well as the development of more effective therapies have been hampered by the lack of a suitable small animal model. Besides humans, chimpanzees are the only species that is naturally susceptible to HCV infection. While experimentation in these large primates has yielded valuable insights, ethical considerations, limited availability, genetic heterogeneity, and cost limit their utility. In search for more tractable small animal models, numerous experimental approaches have been taken to recapitulate parts of the viral life cycle and/or aspects of viral pathogenesis that will be discussed in this review. Exciting new models and improvements in established models hold promise to further elucidate our understanding of chronic HCV infection. PMID- 23463198 TI - Hepatitis C virus entry. AB - Hepatitis C virus (HCV) is a hepatotropic virus and a major cause of chronic hepatitis and liver disease worldwide. Initial interactions between HCV virions and hepatocytes are required for productive viral infection and initiation of the viral life cycle. Furthermore, HCV entry contributes to the tissue tropism and species specificity of this virus. The elucidation of these interactions is critical, not only to understand the pathogenesis of HCV infection, but also to design efficient antiviral strategies and vaccines. This review summarizes our current knowledge of the host factors required for the HCV-host interactions during HCV binding and entry, our understanding of the molecular mechanisms underlying HCV entry into target cells, and the relevance of HCV entry for the pathogenesis of liver disease, antiviral therapy, and vaccine development. PMID- 23463199 TI - Hepatitis C virus proteins: from structure to function. AB - Great progress has been made over the past years in elucidating the structure and function of the hepatitis C virus (HCV) proteins, most of which are now actively being pursued as antiviral targets. The structural proteins, which form the viral particle, include the core protein and the envelope glycoproteins E1 and E2. The nonstructural proteins include the p7 viroporin, the NS2 protease, the NS3-4A complex harboring protease and NTPase/RNA helicase activities, the NS4B and NS5A proteins, and the NS5B RNA-dependent RNA polymerase. NS4B is a master organizer of replication complex formation while NS5A is a zinc-containing phosphoprotein involved in the regulation of HCV RNA replication versus particle production. Core to NS2 make up the assembly module while NS3 to NS5B represent the replication module (replicase). However, HCV proteins exert multiple functions during the viral life cycle, and these may be governed by different structural conformations and/or interactions with viral and/or cellular partners. Remarkably, each viral protein is anchored to intracellular membranes via specific determinants that are essential to protein function in the cell. This review summarizes current knowledge of the structure and function of the HCV proteins and highlights recent advances in the field. PMID- 23463200 TI - Hepatitis C virus RNA translation. AB - After infection of a cell, the positive-strand RNA genome of Hepatitis C Virus (HCV) directly serves as the template for translation in the cytosol. By the use of an internal ribosome entry site (IRES) element in the 5'-untranslated region (5'-UTR) of the viral RNA, the HCV RNA bypasses the need for nuclear processing events like capping and directly recruits the translation apparatus to the viral RNA to start translation of the viral proteins. In this review, I discuss the structure and function of the HCV IRES, focusing on (1) the recruitment of the cellular translation machinery to the IRES, including canonical and noncanonical translation initiation factors, (2) noncanonical RNA-binding proteins that modulate IRES activity, and (3) microRNAs that have an influence on the efficiency of HCV RNA translation. PMID- 23463201 TI - Hepatitis C virus RNA replication. AB - Genome replication is a crucial step in the life cycle of any virus. HCV is a positive strand RNA virus and requires a set of nonstructural proteins (NS3, 4A, 4B, 5A, and 5B) as well as cis-acting replication elements at the genome termini for amplification of the viral RNA. All nonstructural proteins are tightly associated with membranes derived from the endoplasmic reticulum and induce vesicular membrane alterations designated the membranous web, harboring the viral replication sites. The viral RNA-dependent RNA polymerase NS5B is the key enzyme of RNA synthesis. Structural, biochemical, and reverse genetic studies have revealed important insights into the mode of action of NS5B and the mechanism governing RNA replication. Although a comprehensive understanding of the regulation of RNA synthesis is still missing, a number of important viral and host determinants have been defined. This chapter summarizes our current knowledge on the role of viral and host cell proteins as well as cis-acting replication elements involved in the biogenesis of the membranous web and in viral RNA synthesis. PMID- 23463203 TI - Innate immune responses to hepatitis C virus. AB - The innate immune response provides the first line of defense against invading viral pathogens. Incoming viruses are sensed by dedicated host factors that, when triggered, initiate multiple signal transduction pathways. Activation of these pathways leads to the induction of highly orchestrated transcriptional programs designed to limit virus replication and spread. In recent years, our understanding of innate immune responses targeting hepatitis C virus (HCV) has increased substantially, largely due to the development of new systems and methodologies to study HCV-host interactions in vitro and in vivo. However, significant gaps still remain. Here, we aim to provide a comprehensive view of the innate immune response to HCV, focusing primarily on knowledge gained from cell culture models of HCV infection, as well as data from human patients infected with HCV. While some paradigms of the host response to HCV revealed in cell culture translate to human infection in vivo, others are less clear. Further insight into the similarities and differences in these systems will not only reveal directions for future studies on HCV immunity, but may also guide the development of novel strategies to control HCV and other viral infections. PMID- 23463204 TI - Adaptive immune responses in hepatitis C virus infection. AB - The adaptive immune response plays a central role in the outcome of hepatitis C virus (HCV) infection. Indeed, spontaneous viral clearance is associated with an early neutralizing antibody response as well as vigorous and sustained HCV specific CD4+ and CD8+ T cell responses. In persistent HCV infection, however, all three components of the antiviral adaptive immune response fail due to different viral evasion strategies. In this chapter, we will describe the components of a successful immune response against HCV and summarize the mechanisms of immune failure. We will also highlight characteristics of protective CD8+ T cell responses which is the key factor to the design of an efficacious vaccine. PMID- 23463205 TI - Liver injury and disease pathogenesis in chronic hepatitis C. AB - Chronic hepatitis C virus (HCV) infection is a leading cause of liver-specific morbidity and mortality in humans, including progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma. It has also been associated with altered function in other organs, including those of the endocrine, hematopoietic, and nervous systems. Disease results from both direct regulation of cellular metabolism and signaling pathways by viral proteins as well as indirect consequences of the host response to HCV infection, including inflammatory responses stemming from immune recognition of the virus. Recent in vitro studies have begun to reveal molecular mechanisms responsible for virus-induced changes in cell metabolism and cellular kinase cascades that culminate in pathologic consequences in the liver, such as steatosis, insulin resistance, and carcinogenesis. Here we discuss how these findings may be relevant to disease pathogenesis in patients, and suggest future directions in the field. PMID- 23463202 TI - Virion assembly and release. AB - Hepatitis C Virus (HCV) particles exhibit several unusual properties that are not found in other enveloped RNA viruses, most notably their low buoyant density and interaction with serum lipoproteins. With the advent of systems to grow HCV in cell culture, the molecular basis of HCV particle assembly and release can now be addressed. The process of virus assembly involves protein-protein interactions between viral structural and nonstructural proteins and the coordinated action of host factors. This chapter reviews our current understanding of these interactions and factors. PMID- 23463206 TI - Hepatitis C virus-specific directly acting antiviral drugs. AB - The major targets for direct-acting antivirals (DAAs) are the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers several target sites: the catalytic domain for nucleoside/nucleotide analogs and different allosteric sites for non-nucleoside inhibitors. Two protease inhibitors have already been approved and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development pipeline. Not only these agents can achieve very high cure rates when combined with PEG-IFN and RBV, but have also started to provide promising results when combined in IFN-free, all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small molecule drug development are emerging, such as p7 or NS4B. Current research is focusing on defining the most efficacious DAA combination regimens, i.e., those which provide the highest rates of viral eradication, broadest spectrum of action, minimal or no clinical resistance, shortest treatment duration, and good tolerability. PMID- 23463207 TI - Treatment of chronic hepatitis C: current and future. AB - Resolution of the three-dimensional structures of several Hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral agents (DAA). Numerous families of drugs that potently inhibit the HCV life cycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3-4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-alpha and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN alpha and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3 4A protease inhibitors, nucleoside/nucleotide analogue inhibitors, and non nucleoside inhibitors of HCV RNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A and host-targeted agents, such as cyclophilin A inhibitors and microRNA-122 antagonists. The proof of concept that IFN-free regimens can lead to HCV eradication has recently been brought. This chapter provides an overview of the current treatment of HCV infection and discusses the future of HCV therapy with new anti-HCV drugs. PMID- 23463209 TI - Successful use of fidaxomicin in recurrent Clostridium difficile infection in a child. PMID- 23463208 TI - Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis. AB - OBJECTIVES: The antipsychotic drug thioridazine is active in the murine model of tuberculosis infection, which is predominantly intracellular in nature. Recent clinical reports suggest that thioridazine may play a role in the treatment of drug-resistant tuberculosis. We studied the tuberculocidal activity of thioridazine in guinea pigs, which develop necrotic lung granulomas histologically resembling their human counterparts. METHODS: Pharmacokinetic studies were performed in guinea pigs to establish human-equivalent doses of thioridazine. Guinea pigs were aerosol-infected with ~100 bacilli of Mycobacterium tuberculosis and single-drug treatment was started 4 weeks later with a range of thioridazine doses daily (5 days/week) for up to 4 weeks. Control animals received no treatment or 60 mg/kg isoniazid. RESULTS: The human equivalent dose of thioridazine was determined to be 5 mg/kg with saturable absorption noted above 50 mg/kg. At the start of treatment, the lung bacterial burden was ~6.2 log10 cfu. Although isoniazid reduced bacillary counts more than 10-fold, thioridazine monotherapy showed limited killing over the range of doses tested, reducing lung bacillary counts by 0.3-0.5 log10 following 1 month of treatment. Thioridazine was tolerated up to 40 mg/kg. CONCLUSIONS: Thioridazine has limited bactericidal activity against extracellular bacilli within necrotic granulomas. Its contribution to the sterilizing activity of combination regimens against drug-susceptible and drug-resistant tuberculosis remains to be determined. PMID- 23463210 TI - High secondary resistance to quinolones in German Helicobacter pylori clinical isolates. AB - OBJECTIVES: The aim of this study was to update data on levofloxacin/ciprofloxacin and triple resistance (resistance to metronidazole, clarithromycin and levofloxacin/ciprofloxacin) in Helicobacter pylori clinical isolates and to identify the impact of prior eradication therapies on their development. METHODS: We tested the antimicrobial susceptibility to amoxicillin, metronidazole, clarithromycin, levofloxacin/ciprofloxacin, tetracycline and rifampicin of 5296 clinical H. pylori strains isolated between 2006 and 2011. Information on prior eradication therapies was gathered and their impact on the development of antimicrobial resistance, in particular to levofloxacin/ciprofloxacin and triple resistance, was analysed. RESULTS: From 2006 onwards, both levofloxacin/ciprofloxacin and triple resistance have steadily increased and peaked in 2011 with 29.1% and 18.6%, respectively. Unsuccessful prior eradication attempts proved a major risk factor for resistance development. Patients who had undergone unsuccessful eradication attempts harboured levofloxacin/ciprofloxacin- and triple-resistant isolates significantly more often than untreated individuals (26.7% and 18.1% versus 10.6% and 1.6%). Levofloxacin/ciprofloxacin and triple resistance occurred significantly more often in patients who had received quinolones when compared with patients who had not (44.5% versus 23.1% and 28.7% versus 15.6%). We did not observe any significant differences in resistance rates in the different German federal states. CONCLUSIONS: Resistance to levofloxacin/ciprofloxacin and triple resistance have continuously risen and reached worrying numbers. Hence we strongly advise against the use of quinolones in empirical second-line therapies for H. pylori without prior susceptibility testing and/or a carefully taken patient medical history. PMID- 23463211 TI - Antibacterial activity and mode of action of tert-butylhydroquinone (TBHQ) and its oxidation product, tert-butylbenzoquinone (TBBQ). AB - OBJECTIVES: The antioxidant tert-butylhydroquinone (TBHQ) is a food additive reported to have antibacterial activity, and may therefore have application in the healthcare setting. This study sought to characterize the antibacterial activity and mode of action of TBHQ and its oxidation product, tert butylbenzoquinone (TBBQ). METHODS: The stability of TBHQ/TBBQ was studied in buffer. Susceptibility testing was performed by broth microdilution, and killing and lytic activity were evaluated by viable counting and culture turbidity measurements. Mode of action studies included following the incorporation of radiolabelled precursors into macromolecules. The effect of TBHQ/TBBQ upon bacterial and mammalian membranes was assessed using the BacLight(TM) assay and by monitoring the haemolysis of equine erythrocytes. RESULTS: TBHQ underwent oxidation in solution to form TBBQ. When oxidation was prevented, TBHQ lacked useful antibacterial activity, indicating that TBBQ is responsible for the antibacterial activity attributed to TBHQ. TBBQ demonstrated activity against Staphylococcus aureus SH1000 (MIC 8 mg/L) and against a panel of clinical S. aureus isolates (MIC90 16 mg/L). TBBQ at 4* MIC caused a >4 log10 drop in cell viability within 6 h without lysis, and eradicated staphylococcal biofilms at 8* MIC. TBBQ did not display preferential inhibition of any single macromolecular synthetic pathway, but caused loss of staphylococcal membrane integrity without haemolytic activity. CONCLUSIONS: TBBQ is responsible for the antibacterial activity previously ascribed to TBHQ. TBBQ prompts loss of staphylococcal membrane integrity; it is rapidly and extensively bactericidal, but is non-lytic. In view of the potent and selective bactericidal activity of TBBQ, this compound warrants further investigation as a candidate antistaphylococcal agent. PMID- 23463212 TI - Population pharmacokinetics and pharmacodynamic evaluation of intravenous and enteral moxifloxacin in surgical intensive care unit patients. AB - OBJECTIVES: To describe the plasma concentration-time profile of moxifloxacin after intravenous and enteral administration in intensive care unit (ICU) patients and to provide a pharmacodynamic (PD) evaluation with regard to pneumonia. PATIENTS AND METHODS: Twenty-five adult patients from a cardiothoracic/mixed surgical ICU were enrolled. Moxifloxacin was given as a standard dose (400 mg once daily). Therapy was successfully switched to enteral administration on day 5 in 16 patients. A rich data sampling schedule was performed after intravenous (day 4) and enteral (day 8) administration. Moxifloxacin concentrations were analysed by HPLC. A population pharmacokinetic (PK) model was developed using NONMEM VII. Simulated concentration-time profiles were evaluated for their probability of attaining PK/PD target values relevant for community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). RESULTS: A linear-elimination two-compartment model described the data adequately. Parameter estimates (coefficient of variation of inter-individual variability) were: absorption rate constant, 1.09/h (135%); enteral bioavailability, 76% (20.0%); central volume of distribution, 55.6 L; peripheral volume of distribution, 59.6 L (15.3%); inter-compartmental clearance, 47.7 L/h; and clearance, 11.3 L/h (23.7%). Both intravenously and enterally administered standard-dose moxifloxacin reliably attained the PK/PD target values for pathogens with MICs <= 0.25 mg/L for CAP and <= 0.125 mg/L for HAP. CONCLUSIONS: Drug exposure to moxifloxacin in ICU patients was more variable than in healthy volunteers. The standard dosing provides sufficient drug exposure for treatment of CAP but for HAP it does so only when a highly susceptible pathogen is present. Intravenous/enteral sequential therapy may be considered for cautiously selected cases in ICU patients. PMID- 23463213 TI - Azole resistance in Aspergillus fumigatus from bronchoalveolar lavage fluid samples of patients with chronic diseases. AB - OBJECTIVES: Triazole resistance in Aspergillus fumigatus has been increasing. We explored the A. fumigatus azole resistance profiles in bronchoalveolar lavage (BAL) fluid samples from Danish patients examined for aspergillosis. METHODS: A total of 94 BAL samples from 87 patients were evaluated by galactomannan (GM) test and A. fumigatus CYP51A profiling by PCR. RESULTS: Aspergillus spp. were isolated from 27/48 (56.3%) cultured samples, including 23 A. fumigatus with one resistant strain (4.3%). Samples were classified into GM-positive (>=3.0), GM intermediate (0.5 to <3.0) and GM-negative (<0.5) groups, where the CYP51A PCR was positive in 81.8% (36/44), 56.3% (18/32) and 38.9% (7/18) of samples, respectively. Nine CYP51A PCR-positive samples (9/61, 14.8%) were found to have mutations resulting in amino acid substitutions. M220V was detected from a sample culture positive for susceptible A. fumigatus and P216L was found in a culture negative BAL sample. Conversely, no mutation was found in one sample culture positive for azole-resistant A. fumigatus. The tandem repeat/L98H mutation was not detected. CONCLUSIONS: Our study shows that azole resistance in A. fumigatus can be cryptic and may go undiagnosed. The combination of improved culture/susceptibility tests and the direct molecular detection of resistance markers will facilitate prompt institution of appropriate antifungal therapy. PMID- 23463214 TI - Identification of Enterobacteriaceae isolates with OXA-48 and coproduction of OXA 181 and NDM-1 in Norway. PMID- 23463215 TI - Dermatological adverse events from BRAF inhibitors: a growing problem. AB - The development of targeted therapies has ushered in a new era in the management of melanoma. Inhibitors of the RAS-RAF-MEK-ERK pathway have taken the center stage with development at a rapid pace. Vemurafenib was recently approved by regulatory agencies, and other agents (e.g. dabrafenib) are in various stages of clinical testing. These agents are producing remarkable results for patients, but are also presenting new challenges. Clinical toxicities and drug resistance are topmost issues. Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations. Published trials and initial observations reflect a toxicity profile (e.g. squamous cell carcinomas/keratoacanthomas, maculopapular rashes, hyperkeratosis) that is distinct from cutaneous toxicities from EGFR and mTOR inhibitors (acneiform rash, paronychia, xerosis). Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities, skill sets unique to dermatologists. All these pose significant challenges to clinicians, and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life. In this manuscript, we provide an overview of the emerging scientific literature on dermatological adverse events arising out of BRAF inhibition. PMID- 23463217 TI - Senescence: back to telomeres. PMID- 23463218 TI - Development: A good hair day for ROS. PMID- 23463216 TI - Diversity in the origins of proteostasis networks--a driver for protein function in evolution. AB - Although the sequence of a protein largely determines its function, proteins can adopt different folding states in response to changes in the environment, some of which may be deleterious to the organism. All organisms--Bacteria, Archaea and Eukarya--have evolved a protein homeostasis, or proteostasis, network comprising chaperones and folding factors, degradation components, signalling pathways and specialized compartmentalized modules that manage protein folding in response to environmental stimuli and variation. Surveying the origins of proteostasis networks reveals that they have co-evolved with the proteome to regulate the physiological state of the cell, reflecting the unique stresses that different cells or organisms experience, and that they have a key role in driving evolution by closely managing the link between the phenotype and the genotype. PMID- 23463219 TI - Cell signalling: DDX3 in command of CK1epsilon. PMID- 23463220 TI - Cell signalling: Where the mTOR action is. PMID- 23463221 TI - News from the funding front: upcoming opportunities, proposals welcomed. PMID- 23463222 TI - Glycoscience: integrating a key macromolecule more fully into the curriculum. PMID- 23463223 TI - Recent research in science teaching and learning. PMID- 23463224 TI - The teaching demonstration: what faculty expect and how to prepare for this aspect of the job interview. AB - Many institutions require candidates for faculty positions to present a teaching demonstration as part of the interview process. To help job candidates prepare for this and to assist departments in planning how to structure this portion of the interview, we surveyed biology faculty from community and liberal arts colleges and master's- and PhD-granting institutions concerning how their departments assess teaching potential. We also asked survey respondents to share advice on how candidates can prepare for teaching demonstrations. Here we report on the survey results and offer suggestions based on comments from respondents. PMID- 23463225 TI - Addressing the challenge of diversity in the graduate ranks: good practices yield good outcomes. AB - In this paper, we examine the impact of implementing three systemic practices on the diversity and institutional culture in biomedical and public health PhD training at Brown University. We hypothesized that these practices, designed as part of the National Institutes of Health-funded Initiative to Maximize Student Development (IMSD) program in the Division of Biology and Medicine, would have a positive effect on underrepresented minority (URM) recruitment and retention and objective measures of student success. These practices include: 1) develop strategic partnerships with selected undergraduate institutions; 2) provide a personalized education program of student support and skill-based modules to supplement discipline-based course work; and 3) transform institutional culture by engaging faculty in supporting diversity-related goals and practices. Data comparing URM numbers and key academic milestones before and after implementation of IMSD practices support the initial hypothesis and effectiveness of these practices at Brown. Program components are broadly applicable as best practices for others seeking to improve URM recruitment and achievements of graduate students traditionally underrepresented in the sciences. PMID- 23463226 TI - Stereotyped: investigating gender in introductory science courses. AB - Research in science education has documented achievement gaps between men and women in math and physics that may reflect, in part, a response to perceived stereotype threat. Research efforts to reduce achievement gaps by mediating the impact of stereotype threat have found success with a short values-affirmation writing exercise. In biology and biochemistry, however, little attention has been paid to the performance of women in comparison with men or perceptions of stereotype threat, despite documentation of leaky pipelines into professional and academic careers. We used methodologies developed in physics education research and cognitive psychology to 1) investigate and compare the performance of women and men across three introductory science sequences (biology, biochemistry, physics), 2) document endorsement of stereotype threat in these science courses, and 3) investigate the utility of a values-affirmation writing task in reducing achievement gaps. In our study, analysis of final grades and normalized learning gains on content-specific concept inventories reveals no achievement gap in the courses sampled, little stereotype threat endorsement, and no impact of the values-affirmation writing task on student performance. These results underscore the context-dependent nature of achievement gaps and stereotype threat and highlight calls to replicate education research across a range of student populations. PMID- 23463227 TI - Figure facts: encouraging undergraduates to take a data-centered approach to reading primary literature. AB - The ability to interpret experimental data is essential to understanding and participating in the process of scientific discovery. Reading primary research articles can be a frustrating experience for undergraduate biology students because they have very little experience interpreting data. To enhance their data interpretation skills, students used a template called "Figure Facts" to assist them with primary literature-based reading assignments in an advanced cellular neuroscience course. The Figure Facts template encourages students to adopt a data-centric approach, rather than a text-based approach, to understand research articles. Specifically, Figure Facts requires students to focus on the experimental data presented in each figure and identify specific conclusions that may be drawn from those results. Students who used Figure Facts for one semester increased the amount of time they spent examining figures in a primary research article, and regular exposure to primary literature was associated with improved student performance on a data interpretation skills test. Students reported decreased frustration associated with interpreting data figures, and their opinions of the Figure Facts template were overwhelmingly positive. In this paper, we present Figure Facts for others to adopt and adapt, with reflection on its implementation and effectiveness in improving undergraduate science education. PMID- 23463228 TI - Questions for assessing higher-order cognitive skills: it's not just Bloom's. AB - We present an exploratory study of biologists' ideas about higher-order cognition questions. We documented the conversations of biologists who were writing and reviewing a set of higher-order cognition questions. Using a qualitative approach, we identified the themes of these conversations. Biologists in our study used Bloom's Taxonomy to logically analyze questions. However, biologists were also concerned with question difficulty, the length of time required for students to address questions, and students' experience with questions. Finally, some biologists demonstrated an assumption that questions should have one correct answer, not multiple reasonable solutions; this assumption undermined their comfort with some higher-order cognition questions. We generated a framework for further research that provides an interpretation of participants' ideas about higher-order questions and a model of the relationships among these ideas. Two hypotheses emerge from this framework. First, we propose that biologists look for ways to measure difficulty when writing higher-order questions. Second, we propose that biologists' assumptions about the role of questions in student learning strongly influence the types of higher-order questions they write. PMID- 23463229 TI - CREATE cornerstone: introduction to scientific thinking, a new course for STEM interested freshmen, demystifies scientific thinking through analysis of scientific literature. AB - The Consider, Read, Elucidate hypotheses, Analyze and interpret data, Think of the next Experiment (CREATE) strategy for teaching and learning uses intensive analysis of primary literature to improve students' critical-thinking and content integration abilities, as well as their self-rated science attitudes, understanding, and confidence. CREATE also supports maturation of undergraduates' epistemological beliefs about science. This approach, originally tested with upper-level students, has been adapted in Introduction to Scientific Thinking, a new course for freshmen. Results from this course's initial semesters indicate that freshmen in a one-semester introductory course that uses a narrowly focused set of readings to promote development of analytical skills made significant gains in critical-thinking and experimental design abilities. Students also reported significant gains in their ability to think scientifically and understand primary literature. Their perceptions and understanding of science improved, and multiple aspects of their epistemological beliefs about science gained sophistication. The course has no laboratory component, is relatively inexpensive to run, and could be adapted to any area of scientific study. PMID- 23463230 TI - Improvement in generic problem-solving abilities of students by use of tutor-less problem-based learning in a large classroom setting. AB - Problem-based learning (PBL) was originally introduced in medical education programs as a form of small-group learning, but its use has now spread to large undergraduate classrooms in various other disciplines. Introduction of new teaching techniques, including PBL-based methods, needs to be justified by demonstrating the benefits of such techniques over classical teaching styles. Previously, we demonstrated that introduction of tutor-less PBL in a large third year biochemistry undergraduate class increased student satisfaction and attendance. The current study assessed the generic problem-solving abilities of students from the same class at the beginning and end of the term, and compared student scores with similar data obtained in three classes not using PBL. Two generic problem-solving tests of equal difficulty were administered such that students took different tests at the beginning and the end of the term. Blinded marking showed a statistically significant 13% increase in the test scores of the biochemistry students exposed to PBL, while no trend toward significant change in scores was observed in any of the control groups not using PBL. Our study is among the first to demonstrate that use of tutor-less PBL in a large classroom leads to statistically significant improvement in generic problem-solving skills of students. PMID- 23463231 TI - Developing the inner scientist: book club participation and the nature of science. AB - The leap from science student to scientist involves recognizing that science is a tentative, evolving body of knowledge that is socially constructed and culturally influenced; this is known as The Nature of Science (NOS). The aim of this study was to document NOS growth in first-year premedical students who participated in a science book club as a curricular option. The club read three acclaimed nonfiction works that connect biology to medicine via the history of scientific ideas. Students' NOS status was assessed as informed, transitional, or naive at the beginning and end of the academic year using the Views of Nature of Science Questionnaire-Form C (VNOS-C). Focus group interviews and document analysis of assignments and exams provided qualitative evidence. VNOS-C scores improved over the academic year regardless of book club participation. Students who participated in book club had marginally better NOS status at the end of the year but also at the beginning, suggesting that book club may have attracted rather than produced students with higher NOS status. It is notable that an improvement in NOS understanding could be detected at all, as there have been few reports of NOS growth in the literature in which NOS was not an explicit topic of instruction. PMID- 23463232 TI - Evolving impressions: undergraduate perceptions of graduate teaching assistants and faculty members over a semester. AB - Undergraduate experiences in lower-division science courses are important factors in student retention in science majors. These courses often include a lecture taught by faculty, supplemented by smaller sections, such as discussions and laboratories, taught by graduate teaching assistants (GTAs). Given that portions of these courses are taught by different instructor types, this study explored student ratings of instruction by GTAs and faculty members to see whether perceptions differed by instructor type, whether they changed over a semester, and whether certain instructor traits were associated with student perceptions of their instructors' teaching effectiveness or how much students learned from their instructors. Students rated their faculty instructors and GTAs for 13 instructor descriptors at the beginning and near the end of the semester in eight biology classes. Analyses of these data identified differences between instructor types; moreover, student perception changed over the semester. Specifically, GTA ratings increased in perception of positive instructional descriptors, while faculty ratings declined for positive instructional descriptors. The relationship of these perception changes with student experience and retention should be further explored, but the findings also suggest the need to differentiate professional development by the different instructor types teaching lower-division science courses to optimize teaching effectiveness and student learning in these important gateway courses. PMID- 23463233 TI - Implementing recommendations for introductory biology by writing a new textbook. AB - We redesigned the undergraduate introductory biology course by writing a new textbook (Integrating Concepts in Biology [ICB]) that follows first principles of learning. Our approach emphasizes primary data interpretation and the utility of mathematics in biology, while de-emphasizing memorization. This redesign divides biology into five big ideas (information, evolution, cells, emergent properties, homeostasis), addressing each at five levels of organization (molecules, cells, organisms, populations, ecological systems). We compared our course outcomes with two sections that used a traditional textbook and were taught by different instructors. On data interpretation assessments administered periodically during the semester, our students performed better than students in the traditional sections (p = 0.046) and exhibited greater improvement over the course of the semester (p = 0.015). On factual content assessments, our students performed similarly to students in the other sections (p = 0.737). Pre- and postsemester assessment of disciplinary perceptions and self-appraisal indicate that our students acquired a more accurate perception of biology as a discipline and may have developed a more realistic evaluation of their scientific abilities than did the control students (p < 0.05). We conclude that ICB improves critical thinking, metacognition, and disciplinary perceptions without compromising content knowledge in introductory biology. PMID- 23463234 TI - Deciphering microRNA code in pain and inflammation: lessons from bladder pain syndrome. AB - MicroRNAs (miRNAs), a novel class of molecules regulating gene expression, have been hailed as modulators of many biological processes and disease states. Recent studies demonstrated an important role of miRNAs in the processes of inflammation and cancer, however, there are little data implicating miRNAs in peripheral pain. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. BPS is a chronic inflammatory condition that might share some of the pathogenetic mechanisms with its common co-morbidities inflammatory bowel disease (IBD), asthma and autoimmune diseases. Using miRNA profiling in BPS and the information about validated miRNA targets, we delineated the signaling pathways activated in this and other inflammatory pain disorders. This review projects the miRNA profiling and functional data originating from the research in bladder cancer and immune-mediated diseases on the BPS-specific miRNAs with the aim to gain new insight into the pathogenesis of this enigmatic disorder, and highlighting the common regulatory mechanisms of pain and inflammation. PMID- 23463235 TI - Expanding roles for the evolutionarily conserved Dmrt sex transcriptional regulators during embryogenesis. AB - Dmrt genes encode a large family of transcription factors characterized by the presence of a DM domain, an unusual zinc finger DNA binding domain. While Dmrt genes are well known for their important role in sexual development in arthropodes, nematodes and vertebrates, several new findings indicate emerging functions of this gene family in other developmental processes. Here, we provide an overview of the evolution, structure and mechanisms of action of Dmrt genes. We summarize recent findings on their function in sexual regulation and discuss more extensively the role played by these proteins in somitogenesis and neural development. PMID- 23463236 TI - Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes. AB - The development of the endocrine pancreas is controlled by a hierarchical network of transcriptional regulators. It is increasingly evident that this requires a tightly interconnected epigenetic "programme" to drive endocrine cell differentiation and maintain islet function. Epigenetic regulators such as DNA and histone-modifying enzymes are now known to contribute to determination of pancreatic cell lineage, maintenance of cellular differentiation states, and normal functioning of adult pancreatic endocrine cells. Persistent effects of an early suboptimal environment, known to increase risk of type 2 diabetes in later life, can alter the epigenetic control of transcriptional master regulators, such as Hnf4a and Pdx1. Recent genome-wide analyses also suggest that an altered epigenetic landscape is associated with the beta cell failure observed in type 2 diabetes and aging. At the cellular level, epigenetic mechanisms may provide a mechanistic link between energy metabolism and stable patterns of gene expression. Key energy metabolites influence the activity of epigenetic regulators, which in turn alter transcription to maintain cellular homeostasis. The challenge is now to understand the detailed molecular mechanisms that underlie these diverse roles of epigenetics, and the extent to which they contribute to the pathogenesis of type 2 diabetes. In-depth understanding of the developmental and environmental epigenetic programming of the endocrine pancreas has the potential to lead to novel therapeutic approaches in diabetes. PMID- 23463237 TI - Bridging epigenomics and complex disease: the basics. AB - The DNA sequence largely defines gene expression and phenotype. However, it is becoming increasingly clear that an additional chromatin-based regulatory network imparts both stability and plasticity to genome output, modifying phenotype independently of the genetic blueprint. Indeed, alterations in this "epigenetic" control layer underlie, at least in part, the reason for monozygotic twins being discordant for disease. Functionally, this regulatory layer comprises post translational modifications of DNA and histones, as well as small and large noncoding RNAs. Together these regulate gene expression by changing chromatin organization and DNA accessibility. Successive technological advances over the past decade have enabled researchers to map the chromatin state with increasing accuracy and comprehensiveness, catapulting genetic research into a genome-wide era. Here, aiming particularly at the genomics/epigenomics newcomer, we review the epigenetic basis that has helped drive the technological shift and how this progress is shaping our understanding of complex disease. PMID- 23463239 TI - [The various facets of psychotherapy]. AB - In the last decades, psychotherapy has gained increasing importance in the field of psychiatric treatment. Notably, disorder-specific and evidence-based psychotherapeutic strategies now dominate the field as compared to traditional schools of psychotherapy. It should not be neglected that patients, besides being offered a specifically tailored psychological therapy for their disorder, are also in need of reliable moral support and help. Therapeutic creativity frequently is an important skill to gain access to patients. PMID- 23463240 TI - Molecular dynamics simulation of cetyltrimethylammonium bromide and sodium octyl sulfate mixtures: aggregate shape and local surfactant distribution. AB - To examine the self-assembly of cationic-anionic (catanionic) surfactant mixtures, we performed molecular dynamical (MD) simulations at fixed surfactant numbers but different ratios of cationic cetyltrimethylammonium bromide (CTAB) and anionic sodium octyl sulfate (SOS) aqueous mixtures, which were investigated previously (J. Phys. Chem. 1996, 100, 5874-5879). The simulation results show that with an increase of CTAB, there are two different potential aggregation evolving paths. For SOS-rich mixtures, the aggregation transition is sphere-disc rod, while in CTAB-rich mixtures, it is rod-sphere. Furthermore, a disc micelle model was built to explain the shape of the aggregates with varying compositions of CTAB and SOS. In the model, the surfactant distribution in disc micelles is spontaneously adjusted according to the different curvature of the disc surface. The short-tailed SOS tends to stay in the edge region of high curvature, while in the disc center, where the curvature is very low, equimolar mixing of cationic and anionic surfactants is better for the arrangement of CTAB and SOS. Based on this model, the relation between the shape and composition of CTAB and SOS aggregates is well established by analyzing the local surfactant distribution. These new simulations on the evolving mechanism of aggregate shape are very important for the full understanding of the complex phase behavior in cationic and anionic mixtures and for the self-assembly of other mixed surfactant systems. PMID- 23463238 TI - Novel insights into the biology of interleukin-32. AB - Interleukin (IL)-32 is known as a proinflammatory cytokine that is likely involved in several diseases, including infections, chronic inflammation, and cancer. Since the first report in 2005, IL-32 has been the subject of numerous studies to unravel the biological function of this molecule. For example, silencing of endogenous IL-32 in primary or cell lines of human origin consistently suppressed responses to Toll-like receptors. The protein folding structure of the six isoforms of IL-32 does not resemble that of any classical cytokine and as of this writing, a specific IL-32 receptor has not been identified. Instead, we propose a mechanism by which exposure to extracellular IL 32 or overexpression of the molecule results in binding to intracellular partners that influences functions such as gene expression, cell death, or survival. As such, this review offers insights into the role of IL-32 in several diseases, host defense, inflammation, immune function, and cancer. Finally, possibilities to target IL-32 in several diseases are proposed. PMID- 23463241 TI - Boardroom ethics and the syndrome of senior silence. PMID- 23463242 TI - Indirect trophic interactions with an invasive species affect phenotypic divergence in a top consumer. AB - While phenotypic responses to direct species interactions are well studied, we know little about the consequences of indirect interactions for phenotypic divergence. In this study we used lakes with and without the zebra mussel to investigate effects of indirect trophic interactions on phenotypic divergence between littoral and pelagic perch. We found a greater phenotypic divergence between littoral and pelagic individuals in lakes with zebra mussels and propose a mussel-mediated increase in pelagic and benthic resource availability as a major factor underlying this divergence. Lakes with zebra mussels contained higher densities of large plankton taxa and large invertebrates. We suggest that this augmented resource availability improved perch foraging opportunities in both the littoral and pelagic zones. Perch in both habitats could hence express a more specialized foraging morphology, leading to an increased divergence of perch forms in lakes with zebra mussels. As perch do not prey on mussels directly, we conclude that the increased divergence results from indirect interactions with the mussels. Our results hence suggest that species at lower food web levels can indirectly affect phenotypic divergence in species at the top of the food chain. PMID- 23463243 TI - Parasitism rate, parasitoid community composition and host specificity on exposed and semi-concealed caterpillars from a tropical rainforest. AB - The processes maintaining the enormous diversity of herbivore-parasitoid food webs depend on parasitism rate and parasitoid host specificity. The two parameters have to be evaluated in concert to make conclusions about the importance of parasitoids as natural enemies and guide biological control. We document parasitism rate and host specificity in a highly diverse caterpillar parasitoid food web encompassing 266 species of lepidopteran hosts and 172 species of hymenopteran or dipteran parasitoids from a lowland tropical forest in Papua New Guinea. We found that semi-concealed hosts (leaf rollers and leaf tiers) represented 84% of all caterpillars, suffered a higher parasitism rate than exposed caterpillars (12 vs. 5%) and their parasitoids were also more host specific. Semi-concealed hosts may therefore be generally more amenable to biological control by parasitoids than exposed ones. Parasitoid host specificity was highest in Braconidae, lower in Diptera: Tachinidae, and, unexpectedly, the lowest in Ichneumonidae. This result challenges the long-standing view of low host specificity in caterpillar-attacking Tachinidae and suggests higher suitability of Braconidae and lower suitability of Ichneumonidae for biological control of caterpillars. Semi-concealed hosts and their parasitoids are the largest, yet understudied component of caterpillar-parasitoid food webs. However, they still remain much closer in parasitism patterns to exposed hosts than to what literature reports on fully concealed leaf miners. Specifically, semi concealed hosts keep an equally low share of idiobionts (2%) as exposed caterpillars. PMID- 23463244 TI - Integrating environmental variation, predation pressure, phenotypic plasticity and locomotor performance. AB - The Wujiang River, a tributary of the Three Gorges Reservoir, has many dams along its length. These dams alter the river's natural habitat and produce various flow regimes and degrees of predator stress. To test whether the swimming performance and external body shape of pale chub (Zacco platypus) have changed as a result of alterations in the flow regime and predator conditions, we measured the steady (U(crit)) and unsteady (fast-start) swimming performances and morphological characteristics of fish collected from different sites along the Wujiang River. We also calculated the maximum respiratory capacity and cost of transport (COT). We demonstrated significant differences in swimming performance and morphological traits among the sampling sites. Steady swimming performance was positively correlated with water velocity and negatively correlated with the abundance of predators, whereas unsteady swimming performance was negatively correlated with water velocity. The body shape was significantly correlated with both swimming performance and ecological parameters. These findings suggested that selection pressure on swimming performance results in a higher U(crit) and a more streamlined body shape in fast-flow and (or) in habitats with low predator stress and subsequently results in a lower COT. These characteristics were accompanied by a poorer fast-start performance than that of the fish from the slow-flow and (or) high-predator habitats. The divergence in U(crit) may also be due in part to variation in respiratory capacity. PMID- 23463245 TI - Physiological and molecular analysis of carbon source supplementation and pH stress-induced lipid accumulation in the marine diatom Phaeodactylum tricornutum. AB - A detailed physiological and molecular analysis of lipid accumulation under a suite of conditions including nitrogen limitation, alkaline pH stress, bicarbonate supplementation, and organic acid supplementation was performed on the marine diatom Phaeodactylum tricornutum. For all tested conditions, nitrogen limitation was a prerequisite for lipid accumulation and the other culturing strategies only enhanced accumulation highlighting the importance of compounded stresses on lipid metabolism. Volumetric lipid levels varied depending on condition; the observed rankings from highest to lowest were for inorganic carbon addition (15 mM bicarbonate), organic acid addition (15 carbon mM acetate), and alkaline pH stress (pH 9.0). For all lipid-accumulating cultures except acetate supplementation, a common series of physiological steps were observed. Upon extracellular nitrogen exhaustion, culture growth continued for approximately 1.5 cell doublings with decreases in specific protein and photosynthetic pigment content. As nitrogen limitation arrested cell growth, carbohydrate content decreased with a corresponding increase in lipid content. Addition of the organic carbon source acetate appeared to activate alternative metabolic pathways for lipid accumulation. Molecular level data on more than 50 central metabolism transcripts were measured using real-time PCR. Analysis of transcripts suggested the central metabolism pathways associated with bicarbonate transport, carbonic anhydrases, and C4 carbon fixations were important for lipid accumulation. Transcriptomic data also suggested that repurposing of phospholipids may play a role in lipid accumulation. This study provides a detailed physiological and molecular-level foundation for improved understanding of diatom nutrient cycling and contributes to a metabolic blueprint for controlling lipid accumulation in diatoms. PMID- 23463246 TI - Echinocandins: production and applications. AB - The first echinocandin-type antimycotic (echinocandin B) was discovered in the 1970s. It was followed by the isolation of more than 20 natural echinocandins. These cyclic lipo-hexapeptides are biosynthesized on non-ribosomal peptide synthase complexes by different ascomycota fungi. They have a unique mechanism of action; as non-competitive inhibitors of beta-1,3-glucan synthase complex they target the fungal cell wall. Results of the structure-activity relationship experiments let us develop semisynthetic derivatives with improved properties. Three cyclic lipohiexapeptides (caspofungin, micafungin and anidulafungin) are currently approved for use in clinics. As they show good fungicidal (Candida spp.) or fungistatic (Aspergillus spp.) activity against the most important human pathogenic fungi including azole-resistant strains, they are an important addition to the antifungal armamentarium. Some evidence of acquired resistance against echinocandins has been detected among Candida glabrata strains in recent years, which enhanced the importance of data collected on the mechanism of acquired resistance developing against the echinocandins. In this review, we show the structural diversity of natural echinocandins, and we summarize the emerging data on their mode of action, biosynthesis and industrial production. Their clinical significance as well as the mechanism of natural and acquired resistance is also discussed. PMID- 23463247 TI - Characterization of two novel family 12 xyloglucanases from the thermophilic Rhizomucor miehei. AB - Two novel glycoside hydrolase (GH) family 12 xyloglucanase genes (designated RmXEG12A and RmXEG12B) were cloned from the thermophilic fungus Rhizomucor miehei. Both genes contained open reading frames of 729 bp encoding 242 amino acids. Their deduced amino acid sequences shared 68% identity with each other and less than 60% with other xyloglucanases. The two genes, without the sequences for the signal peptides, were cloned and successfully expressed in Escherichia coli as active xyloglucanases, designated RmXEG12A and RmXEG12B, with similar molecular masses--25.6 and 25.9 kDa, respectively. RmXEG12A showed optimal activity at pH 6.5 and 65 degrees C, RmXEG12B at pH 5.0 and 60 degrees C. Both recombinant xyloglucanases displayed very high specific activities, 6,681.4 and 3,092.2 U mg(-1), respectively, toward tamarind xyloglucan, but no activity toward carboxymethylcellulose, Avicel, or p-nitrophenyl derivatives. The main products of tamarind xyloglucan hydrolysis by the two xyloglucanases were XXXG, XXLG/XLXG, and XLLG (where G is an unsubstituted beta-D-Glc residue, X is a xylosylated beta-D-Glc residue, and L is a beta-D-Glc residue substituted by xylosyl-galactose). PMID- 23463248 TI - Biodegradability and biodegradation pathways of endosulfan and endosulfan sulfate. AB - Endosulfan and endosulfan sulfate are persistent organic pollutants that cause serious environmental problems. Although these compounds are already prohibited in many countries, residues can be detected in soils with a history of endosulfan application. Endosulfan is transformed in the environment into endosulfan sulfate, which is a toxic and persistent metabolite. However, some microorganisms can degrade endosulfan without producing endosulfan sulfate, and some can degrade endosulfan sulfate. Therefore, biodegradation has the potential to clean up soil contaminated with endosulfan. In this review, we provide an overview of aerobic endosulfan degradation by bacteria and fungi, and a summary of recent advances and prospects in this research field. PMID- 23463249 TI - Identification of critical residues for the activity and thermostability of Streptomyces sp. SK glucose isomerase. AB - The role of residue 219 in the physicochemical properties of D-glucose isomerase from Streptomyces sp. SK strain (SKGI) was investigated by site-directed mutagenesis and structural studies. Mutants G219A, G219N, and G219F were generated and characterized. Comparative studies of their physicochemical properties with those of the wild-type enzyme highlighted that mutant G219A displayed increased specific activity and thermal stability compared to that of the wild-type enzyme, while for G219N and G219F, these properties were considerably decreased. A double mutant, SKGI F53L/G219A, displayed a higher optimal temperature and a higher catalytic efficiency than both the G219A mutant and the wild-type enzyme and showed a half-life time of about 150 min at 85 degrees C as compared to 50 min for wild-type SKGI. Crystal structures of SKGI wild-type and G219A enzymes were solved to 1.73 and 2.15 A, respectively, and showed that the polypeptide chain folds into two structural domains. The larger domain consists of a (beta/alpha)8 unit, and the smaller domain forms a loop of alpha helices. Detailed analyses of the three-dimensional structures highlighted minor but important changes in the active site region as compared to that of the wild-type enzyme leading to a displacement of both metal ions, and in particular that in site M2. The structural analyses moreover revealed how the substitution of G219 by an alanine plays a crucial role in improving the thermostability of the mutant enzyme. PMID- 23463250 TI - Influence of fungal elicitors on biosynthesis of natamycin by Streptomyces natalensis HW-2. AB - To investigate the effect of fungal elicitors on biosynthesis of natamycin in the cultures of Streptomyces natalensis HW-2, the biomass and filtrate of the broth from Aspergillus niger AS 3.6472, Penicillium chrysogenum AS 3.5163, A. oryzae AS 3.2068, and Saccharomyces cerevisiae AS 2.2081 were used to induce natamycin production in S. natalensis HW-2. The results showed that the biomass of P. chrysogenum AS 3.5163 could enhance the yield of natamycin from 0.639 to 0.875 g l(-1). The elicitor from the fermentation broth of P. chrysogenum AS 3.5163 showed the highest inducing efficiency with the yield of natamycin enhanced from 0.632 to 1.84 g l(-1). The elicitor that was cultured for 2 days showed the strongest inducing activity during the fermentation of S. natalensis HW-2 for 24 h, and the yield of natamycin was enhanced from 0.637 to 2.12 g l(-1). The biochemical parameters were examined at the end of fermentation and the results demonstrated that both the growth of cells and the concentration of residual sugar could be influenced. The residual sugar decreased from 5.03 to 4.27 g l( 1), and the biomass decreased from 10.26 to 6.87 g l(-1). Finally, the elicitor was identified as a low molecular weight substance with a similar polarity to that of butyl alcohol by primary qualitative analysis. PMID- 23463251 TI - Design, expression and characterization of a novel coexpression system of two antiarthritic molecules. AB - The complexity of rheumatoid arthritis (RA) pathogenesis makes combined blockade of multiple targets an attractive therapeutic strategy. The combination therapy with anti-TNF plus anti-T-cell has been mostly reported to provide greater efficacy than anti-TNF alone. TNFR (p75)-Fc fusion protein, which has been proven effective in clinics, is chosen as the TNF antagonist in this study. CTLA4-FasL fusion molecule, which has been well characterized in our previous studies for its suppressive effect in rat arthritis model, is chosen as the T-cell antagonist. In this study, furin cleavage site and 2A self-processing sequence were introduced to link upstream TNFR-Fc and downstream CTLA4-FasL and mediate separate coexpression of the two fusion proteins in a single recombinant adeno associated virus (rAAV) vector. Using this expression system, we generated two fusion proteins with same size as their individual counterparts in vitro and in vivo, and the proteins desirably retained their parent biological activities. In vivo results demonstrated that furin-2A technology is able to regulate separate coexpression of these proteins under arthritic inflammatory conditions. This study describes a single rAAV vector for production of two antiarthritic molecules antagonizing both TNF and T cells, which may serve as an attractive expression system for RA gene therapy. PMID- 23463253 TI - A method for non-invasive full-field imaging and quantification of chemical species. AB - We present a novel method for full-field scalar visualization and quantification of species concentration fields. We term this method species-altered fluorescence imaging (SAFI). The method employs electrically neutral fluorescent dyes whose quantum yields are selectively quenched or enhanced by species of interest. SAFI enables simultaneous imaging of material interfaces and provides non-invasive, scalar-field quantitation of two-dimensional species concentration fields. We describe criteria for choosing SAFI dyes and tabulate 35 promising SAFI dyes and their relevant properties. Next, we describe species concentration quantification with SAFI via Stern-Volmer quenching and discuss the sensitivity and resolution of our method. We demonstrate this method with two dyes, 6-methoxy-N-(3 sulfopropyl)quinolinium (SPQ) and 10-(3-sulfopropyl)acridinium betaine (SAB). We demonstrate our method in full-field visualization of several challenging electrokinetic flows: isotachophoresis (ITP) in both cationic and anionic modes, and in a convective electrokinetic instability (EKI) flow. Through these experiments we collectively quantify ion concentration shock velocities, simultaneously measure concentrations of five species, and quantify the development of an unsteady, chaotic, 2D flow. PMID- 23463252 TI - Gastric stasis in migraineurs: etiology, characteristics, and clinical and therapeutic implications. AB - BACKGROUND: Migraine is a disabling neurological disorder often complicated by gastrointestinal conditions such as gastric stasis. The association between migraine and gastric stasis has received very little attention in the literature, but the existing evidence suggests that they may share a common etiology. RESULTS: Patients with migraine and those with gastric stasis exhibit abnormal autonomic nervous system function. Furthermore, empirical studies demonstrate that migraineurs experience significant delays in gastric emptying, both during and outside of attacks, when compared to non-migrainous controls. CONCLUSION: More research is needed to establish the relationship between gastric stasis and migraine burden and to determine the impact of gastric stasis on migraine treatment. PMID- 23463254 TI - The influence of nasal abnormalities in adherence to continuous positive airway pressure device therapy in obstructive sleep apnea patients. AB - BACKGROUND: The few studies that examine the effect of nasal abnormalities on continuous positive airway pressure device (CPAP) adherence are controversial. The aim of this study was to evaluate the contribution of nasal abnormalities in CPAP adherence. METHODS: We included patients with moderate to severe OSA. The patients were submitted to rhinoscopy, nasofibroscopy, nasal inspiratory peak flow, and acoustic rhinometry. The patients who used a CPAP for 4 h or more per night for at least 70 % of the nights over a 6-month period were considered to have good adherence. RESULTS: Thirty-four patients finished the study. Eleven (33.4 %) were female and 23 (67.6 %) were male. Sixteen (47.1 %) patients had good adherence. The body mass index (p = 0.030), neck circumference (p = 0.006), and apnea-hypopnea index (p = 0.032) were higher, and the oxyhemoglobin saturation minimum was lower (p = 0.041) in the good adherence group. Nasal parameters showed no differences between good and poor adherence groups. In Spearman's correlation, surprisingly, there was a negative correlation between the highest number of hours of CPAP use with smaller values of nasal minimal cross-sectional areas in the supine position (r, 0.375; p = 0.029). In the linear regression model, the nasal findings that predicted increased of the CPAP use were the following: lower scores of nasal symptoms (p = 0.007) and lower nasal volume in supine position (p = 0.001). CONCLUSIONS: The majority of the nasal parameters evaluated in this study did not influence CPAP adherence. PMID- 23463255 TI - Striational antibodies in a paraneoplastic context. AB - INTRODUCTION: The clinical significance of striational antibodies (StrAbs) detected in the course of paraneoplastic antibody testing is unknown. METHODS: We compared all 203 striational antibody (StrAb)-seropositive patients identified (2004-2005) during evaluation for paraneoplastic antibodies with age- and sex matched seronegative controls. RESULTS: Thymoma and myasthenia gravis (MG) were significantly more common among cases (P<0.0001). Cancers more rarely detected after StrAb detection were adenocarcinoma in 5 patients and sarcoma in 3 patients. All patients who had a cancer identified after StrAb testing had a titer of >= 1:7680 or a coexisting muscle AChR-binding antibody. Autoimmune disorders more commonly observed among cases (with any StrAb value) included: hypothyroidism; rheumatoid arthritis; and pernicious anemia (all P<0.05). CONCLUSIONS: StrAbs may serve as a diagnostic clue for an autoimmune diagnosis. There is a low likelihood of oncological significance in patients with StrAb titers <1:7680 without coexisting paraneoplastic Abs. PMID- 23463256 TI - Minimally invasive plate osteosynthesis for humeral shaft fracture: a reproducible technique with the assistance of an external fixator. AB - BACKGROUND: Minimally invasive plate osteosynthesis (MIPO) has become a popular option for treatment of humeral shaft fractures. However, indirect reduction might risk unpromising results, with mal-alignment/mal-union or nonunion. The purpose of this study was to describe a reproducible MIPO technique that used an external fixator during the procedure as a tool for reduction and maintenance, and to assess the outcomes in patients with humeral shaft fracture. METHODS: Of 31 consecutive cases of humeral shaft fracture in 30 patients, 29 were included in this study. There were seven simple (type A) and 22 comminuted (type B or C) fractures. After the insertion of one Schanz pin on each proximal and distal humerus, a provisional reduction was achieved by connecting the pins with a monolateral external fixator. The MIPO procedure was then performed over the anterior aspect of the humerus. To evaluate the efficacy of the provisional reduction by external fixator, coronal and sagittal alignments were assessed. We also assessed bony and functional results, including complications, from this technique. RESULTS: There was no case of mal-union >10 degrees , and mean angulation was 1.3 degrees (range 0 degrees -9 degrees ) in the coronal plane and 1.2 degrees (range 0 degrees -8 degrees ) in the sagittal plane. Twenty eight of 29 fractures were united, including three delayed unions, with a mean union time of 19.1 weeks (range 12.3-38.4 weeks) and a mean follow-up of 20.8 months (range 13.5-31.0 months). There was one hypertrophic nonunion that healed after fixing with two additional screws. Except one patient with associated injury in the elbow, all patients recovered to pre-injury joint motion. There were two cases of postoperative radial nerve palsy that both recovered completely. We attributed them to manipulation, and not to the Schanz pins or plate fixation. CONCLUSIONS: Surgical treatment of humeral shaft fractures with external fixator-assisted reduction and MIPO resulted in excellent reductions and high union rates. PMID- 23463257 TI - Impact of concomitant injuries on outcomes after traumatic brain injury. AB - BACKGROUND: Patients with traumatic brain injury (TBI) frequently have concomitant injuries; we aimed to investigate their impact on outcomes. METHODS: Between February 2002 and April 2010, 17 Austrian centers prospectively enrolled 863 patients with moderate and severe TBI into observational studies. Data on accident, treatment, and outcomes were collected. Patients who survived until intensive care unit (ICU) admission and had survivable TBI were selected, and were assigned to "isolated TBI" or "TBI + injury" groups. Six-month outcomes were classified as "favorable" if Glasgow Outcome Scale (GOS) scores were five or four, and were classified as "unfavorable" if GOS scores were three or less. Univariate statistics (Fisher's exact test, t test, chi(2)-test) and logistic regression were used to identify factors associated with hospital mortality and unfavorable outcome. RESULTS: Of the 767 patients, 403 (52.5 %) had isolated TBI, 364 (47.5 %) had concomitant injuries. Patients with isolated TBI had higher mean age (53 vs. 44 years, P = 0.001); hospital mortality (30.0 vs. 27.2 %, P = 0.42) and rate of unfavorable outcome (50.4 vs. 41.8 %, P = 0.02) were higher, too. There were no significant mortality differences for factors like age groups, trauma mechanisms, neurologic status, CT findings, or treatment factors. Concomitant injuries were associated with higher mortality (33.3 vs. 12.5 %, P = 0.05) in patients with moderate TBI, and were significantly associated with more ventilation, ICU, and hospitals days. Logistic regression revealed that age, Glasgow Coma Scale score, pupillary reactivity, severity of TBI and CT score were the main factors that influenced outcomes. CONCLUSIONS: Concomitant injuries have a significant effect upon the mortality of patients with moderate TBI. They do not affect the mortality in patients with severe TBI. PMID- 23463258 TI - Incongruity affecting osteochondral repair by mosaicplasty technique in an animal model. AB - OBJECTIVE: To compare the influence of the different osteochondral incongruity grades on the osteochondral repair by the mosaicplasty technique in a goat model. METHODS: The acute defects were created in the weight-bearing area of the medial femoral condyle of the goats. Mosaicplasty was done to repair the defects. While implanting the cylindrical osteochondral grafts, different osteochondral sunk, or elevated incongruities were created. The goats were killed 12 weeks after operation to receive gross and histology observation, which was evaluated by the histological grading scale of O'Driscoll et al. The specimens were also taken for transmission electron microscope examination. Two factors analysis of variance and Student-Newman-Kewls test were used to compare the specimen. RESULTS: Minimal steps, which were less than the thickness of cartilage, possess a capacity for remodeling that can correct initial incongruities while preserving hyaline characteristics. However, the step more than the thickness of cartilage could not be repaired satisfactorily. CONCLUSIONS: The incongruity could have an influence on the repair by the mosaicplasty technique in a goat model. The limited incongruity could be repaired by a vigorous remodeling process. PMID- 23463259 TI - Treatment of large posttraumatic tibial bone defects using the Ilizarov method: a subjective outcome assessment. AB - BACKGROUND: The treatment of large posttraumatic tibial bone defects using the Ilizarov method was shown to be successful in several studies. These studies, however, typically focus on the radiological and functional outcome using objective parameters only. The aim of the present study was therefore to assess the objective and subjective outcome of a consecutive series of patients with large posttraumatic tibial bone defects using the Ilizarov method. Additionally, it was our goal to assess the physical and mental stress for the patients and their relatives during the long treatment period and the general health status at final follow-up. METHODS: A consecutive series of 15 patients with posttraumatic tibial bone defects of >30 mm after sustaining open tibial fractures and failure of internal fixation was included. The objective outcome was assessed at final follow-up using Paley's criteria. For the assessment of the subjective outcome, all patients were asked to evaluate their satisfaction with the function of the lower leg, the cosmetic appearance and overall outcome as well. The physical and mental stress of the treatment for the patients and the nearest relative of patients were assessed at the time of frame removal using a custom-made questionnaire. The SF-36 was used to evaluate the general health status at final follow-up. RESULTS: Solid bone union with stable soft tissue coverage and eradication of infection was achieved in all patients despite a high complication rate. The functional outcome at final follow-up was excellent or good in all patients. The patients' satisfaction with the overall outcome and the function of the lower extremity was high as well. The fear of amputation and complications was the major subjective burden for both the patients and their relatives. The long external fixation time is another relevant issue. CONCLUSION: The Ilizarov method is a safe option for the treatment of large posttraumatic tibial bone defects after failure of internal fixation despite the high complication rate. It is essential to comment this to the patients and their relatives prior to the application of the frame increase their compliance with the long and emotionally draining treatment. The Ilizarov method is worth the effort only in patients, who will presumably comply with this treatment option and all of its drawbacks. PMID- 23463260 TI - The effect of N-alkyl substituents on the usability of imidazolium cation-based ionic liquids in microemulsion systems: a technical note. PMID- 23463261 TI - Photodegradation of fleroxacin injection: II. Kinetics and toxicological evaluation. AB - Photodegradation kinetics of fleroxacin were investigated in different injections. Five commercial formulations were analyzed before and after irradiation by determining residual volumes of fleroxacin with high-pressure liquid chromatography (HPLC), and different decomposition functions and models were obtained. Concentration levels of fleroxacin in injections caused the differences in photodegradation kinetics instead of ingredients. Influences of different pH values and presence of NaCl on photodegradation of fleroxacin were observed. Low pH value decreased the efficacy of photolysis and enhanced photostability of fleroxacin injections. Tentative structure of a new degradation product afforded was proposed. An acute toxicity assay using the bioluminescent bacterium Q67 was performed for fleroxacin injections after exposure to light. The research proved that fleroxacin was more photolabile in dilute injection, and acute toxicity of dilute injection increased more rapidly than that of concentrated injection during irradiation. PMID- 23463262 TI - Chitosan-modified PLGA nanoparticles with versatile surface for improved drug delivery. AB - Shortage of functional groups on surface of poly(lactide-co-glycolide) (PLGA) based drug delivery carriers always hampers its wide applications such as passive targeting and conjugation with targeting molecules. In this research, PLGA nanoparticles were modified with chitosan through physical adsorption and chemical binding methods. The surface charges were regulated by altering pH value in chitosan solutions. After the introduction of chitosan, zeta potential of the PLGA nanoparticle surface changed from negative charge to positive one, making the drug carriers more affinity to cancer cells. Functional groups were compared between PLGA nanoparticles and chitosan-modified PLGA nanoparticles. Amine groups were exhibited on PLGA nanoparticle surface after the chitosan modification as confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The modified nanoparticles showed an initial burst release followed by a moderate and sustained release profile. Higher percentage of drugs from cumulative release can be achieved in the same prolonged time range. Therefore, PLGA nanoparticles modified by chitosan showed versatility of surface and a possible improvement in the efficacy of current PLGA-based drug delivery system. PMID- 23463263 TI - Nano-extrusion: a one-step process for manufacturing of solid nanoparticle formulations directly from the liquid phase. AB - This paper presents a novel one-step process for converting a liquid stabilized nano-suspension into a solid formulation via hot-melt extrusion combined with an internal devolatilization process (nano-extrusion, NANEX). A polymer (Soluplus(r)) was fed into the extruder and molten, after which a stable nano suspension was added via side-feeding devices. The solvent (water) was removed by devolatilization and the polymer solidified at the outlet. The solid material can be tableted or filled in a capsule directly. The results showed that the obtained extrudates comprised nanocrystals in the de-aggregated form, confirming that a solid nano-formulation was prepared. This method is capable of overcoming many of the problems associated with other processes involving solid nano-dosage forms and poses a straightforward approach towards manufacturing such products. PMID- 23463264 TI - Graphene-hollow PPy sphere 3D-nanoarchitecture with enhanced electrochemical performance. AB - A rationally designed graphene-hollow polypyrrole (PPy) nanoarchitecture in which hollow PPy spheres were inserted between graphene layers was constructed by mixing graphene oxide and polystyrene (PS)@PPy core-shell sphere, followed by reduction of graphene oxide and etching of PS. The as-prepared graphene-hollow PPy nanoarchitecture was explored as electrode material for supercapacitor applications. The specific capacitance may gradually rise to as high as 500 F g( 1) with a charging/discharging current density of 5 A g(-1), and remains stable even after 10,000 cycles. Analysis indicates that the tailored nanoarchitecture enhances specific area of the electrode and promotes synergetic effect between RGO and PPy, thus leading to a significantly enhanced electrochemical performance. PMID- 23463265 TI - Global and local chemical reactivities of mutagen X and simple derivatives. AB - Registered by the World Health Organization (WHO), 3-chloro-4-(dichloromethyl)-5 hydroxy-2(5H)-furanone (MX) is one of the strongest bacterial mutagens ever tested, as highlighted by the Ames Salmonella typhimurium TA100 assay. We provide new insights concerning this mutagenic activity on the basis of global and local theoretically defined electrophilicity indices. Our results further support the idea that mutagenicity of MX and its analogues is related more closely to one electron transfer processes from the electron-rich biological environment than to adduct formation processes. We also stress that, although the Z-open tautomers are intrinsically more electrophilic than furanone ring analogues, the observed mutagenic activity is significantly correlated only to the electrophilicity response of the ring forms. In that context, we also emphasize that it is electrophilicity at the C alpha in the alpha-beta unsaturated carbonyl moiety that exhibits a strong correlation with the observed mutagenic activity. PMID- 23463266 TI - Conformational analysis of alternariol on the quantum level. AB - With the help of theoretical calculations we explain the phenomenon of nonplanarity of crystalline alternariol. We find out that the different orientations of the hydroxyl groups of alternariol influence its planarity and aromaticity and lead to different twists of the structure. The presence of the intramolecular hydrogen bond stabilizes the planar geometry while the loss of the bond results in a twist of over 14 degrees . This effect is thought to be involved while cutting DNA strands by alternariol. PMID- 23463268 TI - Microglia maketh the male. PMID- 23463270 TI - Learning to forget. PMID- 23463273 TI - Chiral aryl iodide catalysts for the enantioselective synthesis of para-quinols. AB - Molecular modelling of an iodine(III) phenoxide was used as a starting point in the design of chiral aryl iodide catalysts for stereoselective oxidative dearomatization reactions. Using this approach, catalysts derived from 8 iodotetralone and tartaric acid were constructed and used to synthesize enantioenriched para-quinols from phenols. PMID- 23463274 TI - Immunosafety of recombinant human C1-inhibitor in hereditary angioedema: evaluation of ige antibodies. AB - BACKGROUND: Recombinant human C1-inhibitor (rhC1INH) purified from milk of transgenic rabbits is used for the treatment of acute attacks in patients with hereditary angioedema (HAE) due to C1-inhibitor (C1INH) deficiency. OBJECTIVE: The objective was to investigate the risk of rhC1INH inducing IgE antibodies or eliciting anaphylactic reactions. METHODS: In subjects treated with rhC1INH, we retrospectively analysed the frequency and clinical relevance of pre-exposure and potentially newly induced IgE antibodies against rabbit and other animal allergens including cow's milk by the ImmunoCAP((r)) Specific IgE blood test system. RESULTS: 130 HAE patients and 14 healthy subjects received 300 administrations of rhC1INH, 65 subjects (47.4 %) on one occasion; 72 (52.6 %) on at least two occasions (range 2-12; median 2). Five subjects had pre-existing anti-rabbit epithelium IgE; the subject with the highest levels and a previously undisclosed rabbit allergy developed an anaphylactic reaction upon first exposure to rhC1INH, whereas the other four subjects with lower pre-existing IgE levels (Class 1-3), did not. No other anaphylactic reactions were identified in any of the subjects exposed to rhC1INH. Analysis of post-exposure samples revealed that the risk of inducing new or boosting existing IgE responses to rabbit or cow's milk allergens was negligible. CONCLUSION: The propensity of rhC1INH to induce IgE antibodies following repeated administration of rhC1INH is low. Subjects with substantially elevated anti-rabbit epithelium IgE antibodies and/or clinical allergy to rabbits may have an increased risk for an allergic reaction. No other risk factors for allergic reactions to rhC1INH have been identified. PMID- 23463272 TI - The changing scene of amyotrophic lateral sclerosis. AB - Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding. PMID- 23463275 TI - High levels of perfluoroalkyl acids in eggs and embryo livers of great cormorant (Phalacrocorax carbo sinensis) and herring gull (Larus argentatus) from Lake Vanern, Sweden. AB - In the eggs and developing chick livers in the two wild bird species, great cormorant and herring gull, the concentrations of a range of 15 perfluoroalkyl acids (PFAAs) were determined. Eggs of the two species were collected from Lake Vanern, Sweden, and analysed either as undeveloped egg (whole egg or separated into yolk and albumen) or incubated until start of the hatching process when the chick liver was removed and analysed. High levels of PFAAs were found in all matrixes except albumen. The predominant PFAA was perfluorooctane sulfonate (PFOS), which was found in the MUg/g wet weight (ww) range in some samples of cormorant whole egg, yolk and liver and herring gull egg yolk and liver. The average concentration in yolk was 1,506 ng/g ww in cormorant and 589 ng/g ww in herring gull. The average liver concentrations of PFOS were 583 ng/g ww in cormorant and 508 ng/g ww in herring gull. At these concentrations, biochemical effects in the developing embryo or effects on embryo survival cannot be ruled out. For perfluoroalkyl carboxylates (PFCAs), the liver/egg and liver/yolk concentration ratios increased with PFCA chain length in cormorant but not in herring gull, indicating that chain length could possibly affect egg-to-liver transfer of PFCAs and that species differences may exist. PMID- 23463276 TI - Application of a new generation of complexing agents in removal of heavy metal ions from different wastes. AB - Complexing agents are extensively applied in many fields of industry. They are used to provide effective controlling trace metal ions in cleaning industries, textile, pulp and paper production, water treatment, agriculture, food industries, etc. Recently, the low biodegradability of these ligands and their accumulation in the environment has become a cause for concern. Therefore, replacement of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid by more environmentally friendly chelating agents is highly desirable. So far, these acids and their salts have been applied as components of household chemistry, cosmetics, modern microelement fertilizers and agrochemicals. This paper reviews the sorption of heavy metal ions such as Cu(II), Zn(II), Cd(II) and Pb(II) in the presence of the above-mentioned complexing agents on commercially available anion exchangers of different matrix. The obtained sorption results were fitted using the Langmuir and Freundlich sorption isotherm models. The kinetic data were also analysed using the Lagergren, Ho and McKay sorption kinetic equations. The studies were carried out considering the effects of such important parameters as phase contact time, initial concentration, pH and temperature. PMID- 23463277 TI - Heterogeneous Fenton-like discoloration of Rhodamine B using natural schorl as catalyst: optimization by response surface methodology. AB - A cationic dye, Rhodamine B (RhB), could be efficiently discolored by heterogeneous Fenton-like reaction catalyzed by natural schorl. In this work, with the main goal of the optimization for RhB discoloration, central composite design under the response surface methodology (RSM) was employed for the experiment design and process optimization. The significance of a second-order polynomial model for predicting the optimal values of RhB discoloration was evaluated by the analysis of variance and 3D response surface and counter plots for the interactions between two variables were constructed. The Pareto graphic analysis of the discoloration process indicated that, among all the variables, solution pH (X 3, 47.95 %) and H2O2 concentration (X 1, 24.39 %) had the largest influences on the heterogeneous Fenton-like discoloration of RhB. Based on the model prediction, the optimum conditions for RhB discoloration were determined to be 45 mM H2O2 concentration, 2.5 g/L schorl dosage, solution pH 2, and 110 min reaction time, with the maximum RhB discoloration ratio of 98.86 %. The corresponding experimental value of RhB discoloration ratio under the optimum conditions was determined as 99.31 %, which is very close to the optimized one, implying that RSM is a powerful and satisfactory strategy for the process optimization. PMID- 23463278 TI - Solar photocatalysis for treatment of Acid Yellow-17 (AY-17) dye contaminated water using Ag@TiO2 core-shell structured nanoparticles. AB - Wastewater released from textile industries causes water pollution, and it needs to be treated before discharge to the environment by cost effective technologies. Solar photocatalysis is a promising technology for the treatment of dye wastewater. The Ag@TiO2 nanoparticles comprising of Ag core and TiO2 shell (Ag@TiO2) have unique photocatalytic property of inhibition of electron-hole recombination and visible light absorption, which makes it a promising photocatalyst for use in solar photocatalysis and with higher photocatalytic rate. Therefore, in the present work, the Ag@TiO2 nanoparticles synthesized by one pot method with postcalcination step has been used for the degradation of Acid Yellow-17 (AY-17) dye under solar light irradiation. The Ag@TiO2 nanoparticles were characterized using thermogravimetric-differential thermal analysis, X-ray diffraction, transmission electron microscopy, selected area electron diffraction, and energy dispersive X-ray analysis. The catalyst has been found to be very effective in solar photocatalysis of AY-17, as compared to other catalysts. The effects of pH, catalyst loading, initial dye concentration, and oxidants on photocatalysis were also studied. The optimized parameters for degradation of AY-17 using Ag@TiO2 were found to be pH 3, dye/catalyst ratio of 1:10 (g/g), and 2 g/L of (NH4)2S2O8 as oxidant. Efficient decolorization and mineralization of AY-17 was achieved. The kinetics of color, total organic carbon, and chemical oxygen demand removal followed the Langmuir-Hinshelwood model. Ag@TiO2 catalyst can be reused thrice without much decline in efficiency. The catalyst exhibited its potential as economic photocatalyst for treatment of dye wastewater. PMID- 23463279 TI - Characterization of major pollution events (dust, haze, and two festival events) at Agra, India. AB - Total suspended particulate (TSP) samples were collected during dust, haze, and two festival events (Holi and Diwali) from February 2009 to June 2010. Pollutant gases (NO2, SO2, and O3) along with the meteorological parameters were also measured during the four pollution events at Agra. The concentration of pollutant gases decreases during dust events (DEs), but the levels of the gases increase during other pollution events indicating the impact of anthropogenic emissions. The mass concentrations were about two times higher during pollution events than normal days (NDs). High TSP concentrations during Holi and Diwali events may be attributed to anthropogenic activities while increased combustion sources in addition to stagnant meteorological conditions contributed to high TSP mass during haze events. On the other hand, long-range transport of atmospheric particles plays a major role during DEs. In the dust samples, Ca(2+), Cl(-), NO3 (-), and SO4 (2-) were the most abundant ions and Ca(2+) alone accounted for 22 % of the total ionic mass, while during haze event, the concentrations of secondary aerosols species, viz., NO3 (-), SO4 (2-), and NH4 (+), were 3.6, 3.3, and 5.1 times higher than the normal days. During Diwali, SO4 (2-) concentration (17.8 MUg m(-3)) was highest followed by NO3 (-), K(+), and Cl(-) while the Holi samples were strongly enriched with Cl(-) and K(+) which together made up 32.7 % of the total water-soluble ions. The ion balances indicate that the haze samples were acidic. On the other hand, Holi, Diwali, and DE samples were enriched with cations. The carbonaceous aerosol shows strong variation with the highest concentration during Holi followed by haze, Diwali, DEs, and NDs. However, the secondary organic carbon concentration follows the order haze > DEs > Diwali > Holi > NDs. The scanning electron microscope/EDX results indicate that KCl and carbon-rich particles were more dominant during Holi and haze events while DE samples were enriched with particles of crustal origin. PMID- 23463280 TI - Interaction between nitrogen and phosphorus cycles in mining-affected aquatic systems-experiences from field and laboratory measurements. AB - The main objectives of this study were to (a) study the interaction between N and P cycles in mining-affected aquatic systems and (b) to quantify release rates of sedimentary soluble reactive phosphorus (SRP) that may be related to this interaction. Sediment cores and water from Lake Brutrasket (Boliden, northern Sweden) were collected and a time series of water sampling and flow measurements was conducted in the Brubacken stream connected to the lake. Factors affecting SRP release were studied in a sediment incubation experiment and water column experiments. Field and laboratory measurements indicated that pH and dissolved oxygen are two important factors for SRP release. At the end of the low-oxygen incubation, an SRP concentration of 56 MUg L(-1) resulted in a sedimentary flux of 1.1 mg SRP m(-2) day(-1). This is ~10 times higher than the flux of 0.12 mg SRP m(-2) day(-1) obtained from depth integration of vertical SRP profiles measured in the lake, and ~100 times higher than the external flux of 0.014 mg SRP m(-2) d(-1) into the lake (based on catchment area). Field measurements indicated that oxidation of organic matter and mining-related chemicals (ammonium and thiosulphates) may result in increased internal SRP flux from the sediment. Increased P loading in the lake as a result of low-oxygen conditions could change water column total nitrogen/total phosphorus ratios from 27 to 17, consequently changing the lake from being P-limited to be co-limited by N and P. The obtained findings point to possible interaction between the cycles of nitrogen (oxygen consumption) and P (flux from sediment) that may be important for nutrient regulation in mine water recipients. PMID- 23463281 TI - Gas/particle partitioning of polycyclic aromatic hydrocarbons in coastal atmosphere of the north Yellow Sea, China. AB - Samples of gas- and particle-phase polycyclic aromatic hydrocarbons (PAHs) were collected at three sampling stations (Xiaomai Island, Laohutan, and Zhangzi Island) in the north Yellow Sea, China during November 2008 and September 2009 to study their atmospheric transport potential and the gas/particle distributions. The composition of PAHs was dominated by gaseous compounds. The percentages of the particle-phase PAHs to the total concentrations were found to be higher during the heating period than the non-heating period. The ratios of naphthalene and acenaphthene to phenanthrene, chrysene and dibenzo(a,h)anthracene showed an increasing trend from Xiaomai Island to Zhangzi Island, which can be called as the local atmospheric distillation of PAHs. Gas/particle partitioning coefficients (K p) and their relationship with the sub-cooled liquid vapor pressures (poL) of PAHs were investigated. The regressions of logK p versus logpoL gave significant correlations for all samples of the three sites with r (2) values in the range 0.56-0.66 (p<0.01). Both Junge-Pankow adsorption model and octanol-air partition coefficient absorption model tended to underestimate the sorption for most PAHs, but the absorption model appeared to be more suitable for predicting the particle fraction of PAHs than the Junge-Pankow model. PMID- 23463282 TI - Spatial distribution and mobility of organic carbon (POC and DOC) in a coastal Mediterranean environment (Saronikos Gulf, Greece) during 2007-2009 period. AB - Particulate (POC) and dissolved organic carbon (DOC) is an important parameter for the pollution assessment of coastal marine systems, especially those affected by anthropogenic, domestic, and industrial activities. In the present paper, a similar marine system (Saronikos Gulf) located in the west-central Aegean Sea (eastern Mediterranean Sea) was examined, in terms of the temporal and spatial distribution of organic carbon (POC and DOC), with respect to marine sources and pathways. POC was maximum in winter in the Saronikos Gulf, due to the bloom of phytoplankton, whereas in the Elefsis Bay (located in the north side of the Saronikos Gulf) in summer, since phytoplankton grazes in the Bay in the end of summer (except for winter). Approximately 60 % of the bulk DOC of the water column was estimated as non-refractory (labile and semi-labile), due to the major anthropogenic, domestic, and industrial effects of the region and the shallow depths. The spatial distribution of POC and DOC mainly affects the northeastern section of the Gulf, since that region has been accepted major organic discharges for a long time period, in connection to the relatively long renewal times of its waters. PMID- 23463283 TI - CacyBP/SIP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2. AB - Our former report indicates that calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) is over-expressed in the SGC7901/ADR cell line. However, the potential role of CacyBP/SIP in the development of multidrug resistance (MDR) of pancreatic cancer is still uncertain. In this paper, we investigated the role of CacyBP/SIP in MDR of pancreatic cancer cells and its possible underlying mechanisms, and found that CacyBP/SIP was over-expressed in the Gemcitabine induced MDR pancreatic cancer cell PC-3/Gem compared with its parental cell PC-3. Up-regulation of CacyBP/SIP expression could enhance resistance of chemotherapy drugs on PC-3 cells and inhibit Adriamycin-induced apoptosis accompanied by decreased accumulation of intracellular Adriamycin. Furthermore, CacyBP/SIP could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene. In addition, the decrease of CacyBP/SIP expression using RNA interference or P-gp inhibitor could partially reverse CacyBP/SIP-mediated MDR. In brief, our study demonstrated that CacyBP/SIP could enhance the MDR phenotype of pancreatic cancer cells by increasing the expression of P-gp and Bcl-2, thus inhibiting apoptosis of pancreatic cancer cell. PMID- 23463284 TI - Staphylococcus aureus screening and decolonization in orthopaedic surgery and reduction of surgical site infections. AB - BACKGROUND: Staphylococcus aureus is the most common organism responsible for orthopaedic surgical site infections (SSIs). Patients who are carriers for methicillin-sensitive S. aureus or methicillin-resistant S. aureus (MRSA) have a higher likelihood of having invasive S. aureus infections. Although some have advocated screening for S. aureus and decolonizing it is unclear whether these efforts reduce SSIs. QUESTIONS/PURPOSES: The purposes of this study were to determine (1) whether S. aureus screening and decolonization reduce SSIs in orthopaedic patients and (2) if implementing this protocol is cost-effective. METHODS: Studies for this systematic review were identified by searching PubMed, which includes MEDLINE (1946-present), EMBASE.com (1974-present), and the Cochrane Library's (John Wiley & Sons) Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTAD), and the NHS Economic Evaluation Database (NHSEED). Comprehensive literature searches were developed using EMTREE, MeSH, and keywords for each of the search concepts of decolonization, MRSA, and orthopedics/orthopedic surgery. Studies published before 1968 were excluded. We analyzed 19 studies examining the ability of the decolonization protocol to reduce SSIs and 10 studies detailing the cost-effectiveness of S. aureus screening and decolonization. RESULTS: All 19 studies showed a reduction in SSIs or wound complications by instituting a S. aureus screening and decolonization protocol in elective orthopaedic (total joints, spine, and sports) and trauma patients. The S. aureus screening and decolonization protocol also saved costs in orthopaedic patients when comparing the costs of screening and decolonization with the reduction of SSIs. CONCLUSIONS: Preoperative screening and decolonization of S. aureus in orthopaedic patients is a cost-effective means to reduce SSIs. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 23463285 TI - Antibiotics in the treatment of low-velocity gunshot-induced fractures: a systematic literature review. AB - BACKGROUND: Low-velocity gunshots are often associated with extremity fractures. There is no consensus, however, on the use of antibiotics for these injuries. QUESTIONS/PURPOSES: We performed a literature review to answer the following questions: (1) Are antibiotics needed for the treatment of these fractures? (2) Is gram-negative coverage necessary? (3) How long should antibiotics be administered? And (4) which is the optimal administration route? METHODS: We conducted a MEDLINE((r)) search and found only two relevant prospective, randomized studies. Further searches identified all case series with information on the use of antibiotics in gunshot fractures. In total, 33 studies provided enough data to answer the study questions. An assessment of the quality of the identified studies was performed. Twenty-three studies met at least 1/2 of the quality items of the assessment tool. RESULTS: Antibiotics did not significantly reduce the infection rate for fractures treated nonoperatively (1.7% with antibiotics versus 5.1% without) with the numbers available. There was no significant difference in infection rates when gram-negative coverage was added, either in nonoperatively treated fractures (1.7% versus 2.8%) or in operatively treated fractures (0% versus 2.5%). Duration of antibiotic administration did not significantly affect the infection rate. No difference was found between intravenous and oral antibiotic administration for nonoperatively treated fractures. CONCLUSIONS: This literature review could not demonstrate a significant benefit with the use of antibiotics for low-velocity gunshot fractures treated nonoperatively; however, the statistical power for these comparisons was low in the available literature, which is insufficiently strong to recommend a treatment. Gram-negative coverage did not alter the infection rates in gunshot fractures, nor did longer duration of antibiotic administration. For fractures treated nonoperatively, oral antibiotics are as efficacious as intravenous antibiotics. PMID- 23463286 TI - Letter to the editor: Intramedullary nails result in more reoperations than sliding hip screws in two-part intertrochanteric fractures. PMID- 23463287 TI - A silver ion-doped calcium phosphate-based ceramic nanopowder-coated prosthesis increased infection resistance. AB - BACKGROUND: Despite progress in surgical techniques, 1% to 2% of joint arthroplasties become complicated by infection. Coating implant surfaces with antimicrobial agents have been attempted to prevent initial bacterial adhesion to implants with varying success rates. We developed a silver ion-containing calcium phosphate-based ceramic nanopowder coating to provide antibacterial activity for orthopaedic implants. QUESTIONS/PURPOSES: We asked whether titanium prostheses coated with this nanopowder would show resistance to bacterial colonization as compared with uncoated prostheses. METHODS: We inserted titanium implants (uncoated [n = 9], hydroxyapatite-coated [n = 9], silver-coated [n = 9]) simulating knee prostheses into 27 rabbits' knees. Before implantation, 5 * 10(2) colony-forming units of Staphylococcus aureus were inoculated into the femoral canal. Radiology, microbiology, and histology findings were quantified at Week 6 to define the infection, microbiologically by increased rate of implant colonization/positive cultures, histologically by leukocyte infiltration, necrosis, foreign-body granuloma, and devitalized bone, and radiographically by periosteal reaction, osteolysis, or sequestrum formation. RESULTS: Swab samples taken from medullary canals and implants revealed a lower proportion of positive culture in silver-coated implants (one of nine) than in uncoated (eight of nine) or hydroxyapatite-coated (five of nine) implants. Silver-coated implants also had a lower rate of colonization. No cellular inflammation or foreign-body granuloma was observed around the silver-coated prostheses. CONCLUSIONS: Silver ion-doped ceramic nanopowder coating of titanium implants led to an increase in resistance to bacterial colonization compared to uncoated implants. CLINICAL RELEVANCE: Silver-coated orthopaedic implants may be useful for resistance to local infection but will require in vivo confirmation. PMID- 23463288 TI - Valgus hip with high antetorsion causes pain through posterior extraarticular FAI. AB - BACKGROUND: Valgus hips with increased antetorsion present with lack of external rotation and posterior hip pain that is aggravated with hip extension and external rotation. This may be the result of posterior femoroacetabular impingement (FAI). QUESTIONS/PURPOSES: We asked whether (1) the range of motion (ROM); (2) the location of anterior and posterior bony collision zones; and (3) the prevalence of extraarticular impingement differ between valgus hips with increased antetorsion compared with normal hips and hips with idiopathic FAI. METHODS: Surface models based on CT scan reconstructions of 13 valgus hips with increased antetorsion, 22 hips with FAI, and 27 normal hips were included. Validated three-dimensional collision detection software was used to quantify the simulated hip ROM and the location of impingement on the acetabular and the femoral sides. RESULTS: Hips with coxa valga and antetorsion showed decreased extension, external rotation, and adduction, whereas internal rotation in 90 degrees of flexion was increased. Impingement zones were more anteroinferior on the femur and posteroinferior on the acetabular (pelvic) side; and the zones were more frequently extraarticular, posterior, or to a lesser degree anterior against the inferior iliac spine. We found a higher prevalence of extraarticular impingement for valgus hips with increased antetorsion. CONCLUSIONS: Valgus hips with increased antetorsion predispose to posterior extraarticular FAI and to a lesser degree anteroinferior spine impingement. PMID- 23463289 TI - Emerging ideas: Instability-induced periprosthetic osteolysis is not dependent on the fibrous tissue interface. AB - BACKGROUND: Stable initial fixation of a total joint arthroplasty implant is critical to avoid the risk of aseptic loosening and premature clinical failure. With implant motion, a fibrous tissue layer forms at the bone-implant interface, leading to implant migration and periprosthetic osteolysis. At the time of implant revision surgery, proresorptive signaling cytokines are expressed in the periimplant fibrous membrane. However, the exact role of this fibrous tissue in causing periprosthetic osteolysis attributable to instability remains unknown. QUESTIONS/HYPOTHESES: We propose an alternative mechanism of periprosthetic osteolysis independent of the fibrous tissue layer, where pressurized fluid flow along the bone-implant interface activates mechanosensitive osteocytes in the periprosthetic bone, causing the release of proresorptive cytokines and subsequent osteoclast differentiation and osteolysis. METHOD OF STUDY: An animal model for instability-induced osteolysis that mimics the periprosthetic bone implant interface will be used. In this model, a fibrous tissue membrane is allowed to form in the periprosthetic zone, and pressurized fluid flow transmitted through this membrane reliably creates osteolytic lesions in the periprosthetic bone. In this study, half of the rats will have the fibrous tissue present, while the other half will not. We will determine whether the fibrous tissue membrane is essential for the release of proosteoclastic cytokines, leading to osteoclast differentiation and periprosthetic bone loss, by measuring the volume of bone resorption and presence of proresorptive cytokines at the bone implant interface. SIGNIFICANCE: We will determine whether the fibrous tissue membrane is crucial for osteoclastogenic signaling in the setting of periimplant osteolysis. In the future, this will allow us to test therapeutic interventions, such as specific cytokine inhibitors or alterations in implant design, which may translate into new, clinically relevant strategies to prevent osteolysis. PMID- 23463291 TI - Reply: To PMID 22105560. PMID- 23463290 TI - The influence of botulinum toxin A injections into the calf muscles on genu recurvatum in children with cerebral palsy. AB - BACKGROUND: With cerebral palsy (CP), an equinus deformity may lead to genu recurvatum. Botulinum toxin A (BtA) injection into the calf muscles is a well accepted treatment for dynamic equinus deformity. QUESTIONS/PURPOSES: The purpose of this study was to determine whether BtA injections into the calf muscles to decrease equinus would decrease coexisting genu recurvatum in children with diplegic CP. METHODS: In a retrospective study, 13 children (mean age, 5 years) with spastic diplegic CP showing equinus and coexisting primary genu recurvatum, who were treated with BtA injections into the calf muscles, were included. Evaluations were done before and 6 and 18 weeks after intervention using three dimensional gait analysis and clinical examinations according to a standardized protocol. Basic statistical analyses (power analysis, ANOVA) were performed to compare genu recurvatum before treatment and at 6 and 18 weeks after injection with BtA. RESULTS: During stance phase, maximum ankle dorsiflexion was increased substantially from -3.0 degrees +/- 14.3 degrees before to 6.2 degrees +/- 14.2 degrees 6 weeks after the injections. Despite this, with the numbers available, the amount of recurvatum in stance did not improve with treatment at either 6 or 18 weeks. There was significant improvement of knee hyperextension during stance phase of 6.2 degrees between baseline and 18 weeks after BtA injection, but a genu recurvatum was still present in most patients. CONCLUSIONS: Despite improvement of ankle dorsiflexion after injection with BtA, genu recurvatum did not show relevant improvement at 6 or 18 weeks after injection with the numbers available. Because knee hyperextension remained in most patients, other factors leading to genu recurvatum should be taken into consideration. In addition, a botulinum toxin-induced weakness of the gastrocnemius may explain why recurvatum gait was not significantly reduced. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23463292 TI - Protective role of AQP3 in UVA-induced NHSFs apoptosis via Bcl2 up-regulation. AB - Aquaporin-3 (AQP3), a water/glycerol-transporting protein that facilitates water, urea, and glycerol transport, can inhibit arsenite-induced apoptosis by up regulating Bcl-2. However, whether it has a protective role in ultraviolet A (UVA)-induced apoptosis in normal human skin fibroblasts is not known. In this study, we demonstrate that mild UVA treatment fails to induce oxidative cell stress and apoptosis in normal human skin fibroblasts (NHSFs) overexpressing AQP3. After severe UVA irradiation, there was an increase in oxidative cell stress and apoptosis when AQP3 levels decreased. We also found that silencing AQP3 sensitized NHSFs to low-dose UVA. Overexpressing AQP3 was protective against high-dose UVA-induced oxidative stress and apoptosis. Besides, we observed that Bcl-2 may be involved in UVA-induced apoptosis. Our findings suggested that the water/glycerol-transporting protein AQP3 plays a role in resistance to UVA induced apoptosis. PMID- 23463293 TI - A study for the cause of ferulic acid-induced quenching of tyrosine fluorescence and whether it is a reliable marker of intermolecular interactions or not. AB - Intrinsic fluorescence of peptides and proteins is extensively used to monitor their specific interactions with several natural and synthetic molecules known to have wide-ranging beneficial or detrimental effects on health. A consequence of these interactions would be a significant decrease of the fluorescence emission intensity of Tyrosine (Tyr) and/or Tryptophan (Trp) residues in the protein due to structural rearrangements of proteic microenvironment. However fluorescence quenching can be also caused by "trivial" artefacts. In this study we examined the effect of Ferulic acid (FA) on Tyr fluorescence. FA is a natural anti-oxidant suggested to bind to and to modify the structural properties of several proteins thus altering their biological activities. Fluorescence spectroscopy experiments on Tyr and on proteins containing Tyr and no Trp like beta amyloid peptides and Insulin were performed. Our results suggest that Tyr fluorescence loss can mainly result from an inner filter effect rather than from specific interactions with FA. PMID- 23463294 TI - A straightforward immunoassay applicable to a wide range of antibodies based on surface enhanced fluorescence. AB - A straightforward immunoassay based on surface enhanced fluorescence (SEF) has been demonstrated using a fluorescent immune substrate and antibody functionalized-silver nanoparticles. Unlike the conventional SEF-based immunoassay, which usually uses the dye-labeled antibodies and the metallic nanostructured-substrates, the presented immune system does not need the antibodies to be labeled with dye molecules. Thus, this immunoassay can be easily applied to the detection of a wide range of target antigens, which is of great importance for its practical application. The experimental results show that this immunoassay has a good specificity as well as the capacity of quantitative detection. Basically, the surface density of the immuno-adsorbed silver nanoparticles increases with the increased amount of target antigens, resulting in a fluorescence enhancement up to around 7 fold. The dose-responsive performance of the immunoassay has been investigated and the limit of detection (LOD) is 1 ng/mL. Due to its simple preparation method and the wide range of detectable antigens, this presented immunoassay is expected to be helpful for extending the SEF-based application. PMID- 23463295 TI - Bifunctional calix[4]arene sensor for Pb(II) and Cr2O7(2-) ions. AB - A readily available chromionophore 5,11,17,23-tetra-tert-butyl-25,27 bis(hydrazidecarbonylmethoxy)-26,28-dihydroxycalix[4]arene (HCC4) was employed as a chromogenic sensing probe selective for Pb(II) and Cr2O7(2-) ions among a series of various ions such as Li(I), Na(I), K(I), Rb(I), Ba(II), Sr(II), Al(III), Cd(II), Co(II), Cu(II), Hg(II), Ni(II), Pb(II) and Zn(II) as well as Cr2O7(2-), CH3CO2(-), Br(-), Cl(-), F(-), I(-), ClO4(-) and NO3(-) that have been examined by UV-visible and fluorescence spectroscopic techniques. The HCC4 in DCM MeCN system forms 2:1 (ligand-metal) complex with Pb(II). It also shows 2:1 stoichiometry with Cr2O7(2-). The complexation phenomenon has been confirmed by FTIR spectroscopy that favors the selective nature of HCC4 with Pb(II) and Cr2O7(2-). Thermal gravimetric analysis (TGA) also supports its utility in drastic conditions. PMID- 23463296 TI - On the fluorescence of luminol in a silver nanoparticles complex. AB - The photophysical properties of luminol in a silver nanoparticles complex have been studied by steady-state and time resolved fluorescence spectroscopy. The effect of the serum albumin on the luminol fluorescence in the silver nanoparticles has been also investigated. It was found that the fluorescence quantum yield value of luminol in a silver nanoparticles complex is phi = 0.00407. The decrease of the average fluorescence lifetime value of the luminol in the silver nanoparticles complex was found to be low, = 1.712 ns. The luminol does not bind to the serum albumins in the presence of silver nanoparticles. The formation of a new species of luminol on silver nanoparticles is discussed. The results have influence regarding the use of luminol as an assay for bio-analytical applications. PMID- 23463297 TI - St. John's Wort in patients non-responders to clopidogrel undergoing percutaneous coronary intervention: a single-center randomized open-label trial (St. John's Trial). AB - We assessed if St. John's Wort (SJW) improves platelet response in patients (pts) resistant to clopidogrel after percutaneous coronary intervention (PCI). Stable angina pts non-responders to 600 mg clopidogrel (P2Y12 reaction units (PRU) >240) were randomized (2:1) to SJW (n = 15) or placebo (n = 8). SJW (300 mg * 3/day) was administrated for 2 weeks after PCI. Platelet reactivity was assessed by VerifyNowTM before (BL), 2 (T1), and 4 weeks (T2) after PCI. PRU significantly changed during protocol in SJW (BL (316 +/- 60) vs. T1 (170 +/- 87) vs. T2 (220 +/- 96), p < 0.0001) and placebo group (BL (288 +/- 36) vs. T1 (236 +/- 31) vs. T2 (236 +/- 62), p = 0.046). Yet, PRU changes from BL were higher at T1 in SJW than in placebo group (Delta%, -47 +/- 24 vs. -16 +/- 15, p = 0.0033), with no differences at T2 between the groups (Delta%, -30 +/- 29 vs. -17 +/- 24, p = 0.30). Residual platelet reactivity improved with SJW during the first month post PCI. PMID- 23463298 TI - Characterisation of Co@Fe3O4 core@shell nanoparticles using advanced electron microscopy. AB - Cobalt nanoparticles were synthesised via the thermal decomposition of Co2(CO)8 and were coated in iron oxide using Fe(CO)5. While previous work focused on the subsequent thermal alloying of these nanoparticles, this study fully elucidates their composition and core@shell structure. State-of-the-art electron microscopy and statistical data processing enabled chemical mapping of individual particles through the acquisition of energy-filtered transmission electron microscopy (EFTEM) images and detailed electron energy loss spectroscopy (EELS) analysis. Multivariate statistical analysis (MSA) has been used to greatly improve the quality of elemental mapping data from core@shell nanoparticles. Results from a combination of spatially resolved microanalysis reveal the shell as Fe3O4 and show that the core is composed of oxidatively stable metallic Co. For the first time, a region of lower atom density between the particle core and shell has been observed and identified as a trapped carbon residue attributable to the organic capping agents present in the initial Co nanoparticle synthesis. PMID- 23463299 TI - Biosynthesis of silver nanoparticles by the endophytic fungus Epicoccum nigrum and their activity against pathogenic fungi. AB - There is an enormous interest in developing safe, cost-effective and environmentally friendly technologies for nano-materials synthesis. In the present study, extracellular biosynthesis of silver nanoparticles was achieved by Epicoccum nigrum, an endophytic fungus isolated from the cambium of Phellodendron amurense. The reduction of the silver ions was monitored by UV-visible spectrophotometry, and the characterization of the Ag NPs was carried out by X ray diffraction and transmission electron microscopy. The synthesized Ag NPs were exceptionally stable. It was found that an alkaline pH favored the formation of Ag NPs and elevated temperature accelerated the reduction process. Furthermore, the antifungal activity of the Ag NPs was assessed using a microdilution method. The biosynthesized Ag NPs showed considerable activity against the pathogenic fungi. The current research opens a new path for the green synthesis of Ag NPs and the process is easy to scale up for biomedical applications. PMID- 23463300 TI - Evaluation of bovine and human teeth exposed to thermocycling for microleakage under bonded metal brackets. AB - INTRODUCTION: Bovine teeth are commonly used as substitutes for human teeth in scientific investigations. The present study was performed in vitro with the objective of comparing bovine and human enamel subjected to thermocycling for microleakage beneath metal brackets. MATERIALS AND METHODS: A total of 50 bovine and human teeth (25 per group) void of defects or carious decay were extracted and stored in chloramine B (0.5%). A light-curing adhesive (TransbondTM XT) was used as instructed by the manufacturer (3M Unitek, Monrovia, CA, USA) to bond a metal bracket (discovery(r); Dentaurum, Ispringen, Germany) to the surface of each tooth following 30 s of enamel etching (phosphoric acid 35%). After 24 h of dye penetration in methylene blue (0.5%), the cervical and incisal bracket surfaces were analyzed by light microscopy for excess bonding material, dye penetration, and microleakage at the bracket-adhesive and adhesive-enamel interfaces. Staining and evaluation was repeated after thermocycling (5000 cycles at 5/55 degrees C). RESULTS: Before thermocycling, the number of human teeth showing marginal gaps was one-third the number of bovine teeth (p<0.001). After thermocycling, the distribution of gaps was similar (p=0.180). The adhesive enamel interface was most frequently affected (on 74% of human and 64% of bovine teeth). No dye penetration in either group after examining a horizontal slice through the bracket basis was observed. CONCLUSION: Immediately after bonding, less microleakage was observed around the base of metal brackets on human than bovine teeth. These marginal gaps were, however, superficial in both groups, none of them involving deep penetration of dye under the bracket base. PMID- 23463301 TI - Changes in soft-tissue profiles after treatment of class II/1 patients with bite jumping appliances. AB - We performed this study to describe changes in the soft-tissue profile after orthodontic treatment with Trankmann's bite-jumping appliances. A total of 69 patients thus treated were compared to a control group of 36 age-matched patients based on cephalograms. Statistical analysis included mean values, standard deviations, t-tests, and Pearson's correlation testing. Highly significant (p<0.001) changes in total profile angle (N'-Ns-Pog') were observed over the course of treatment. Furthermore, a mildly significant (p<0.05) correlation with SNA angles was noted. Changes in the soft-tissue profile angle (N'-Sn-Pog') were moderately significant (p<0.001). The profile angles of the upper lip (Sn-SS-Ls) and lower lip (Pog'-Sm-Li) did not reveal significant changes. We observed highly significant (p<0.001) findings in the esthetic line (NsPog') advancement relative to the Ls and Li landmarks and in increases in lower-face height. Midface heights remained unchanged. Our results indicate that treatment with bite-jumping appliances results in increased facial convexity, advancement of the esthetic line, and increased lower-face height. The cumulative effects of growth and treatment do not, however, appear pronounced enough to result in a preference for or against treatment with a bite-jumping appliance. PMID- 23463305 TI - Host versus flu: antibodies win a round? PMID- 23463306 TI - Breaking symmetry in SMCs. PMID- 23463307 TI - DNA methylation: a matter of culture. PMID- 23463308 TI - The helix turns at 60: writhing free in chromosomes. PMID- 23463309 TI - The dynamic epigenome. PMID- 23463310 TI - Regulation of nucleosome dynamics by histone modifications. AB - Chromatin is a dynamic structure that must respond to myriad stimuli to regulate access to DNA, and chemical modification of histones is a major means by which the cell modulates nucleosome mobility and turnover. Histone modifications are linked to essentially every cellular process requiring DNA access, including transcription, replication and repair. Here we consider properties of the major types of histone modification in the context of their associated biological processes to view them in light of the cellular mechanisms that regulate nucleosome dynamics. PMID- 23463311 TI - Determinants of nucleosome positioning. AB - Nucleosome positioning is critical for gene expression and most DNA-related processes. Here we review the dominant patterns of nucleosome positioning that have been observed and summarize the current understanding of their underlying determinants. The genome-wide pattern of nucleosome positioning is determined by the combination of DNA sequence, ATP-dependent nucleosome remodeling enzymes and transcription factors that include activators, components of the preinitiation complex and elongating RNA polymerase II. These determinants influence each other such that the resulting nucleosome positioning patterns are likely to differ among genes and among cells in a population, with consequent effects on gene expression. PMID- 23463312 TI - DNA methylation dynamics in health and disease. AB - DNA methylation is an epigenetic mark that is erased in the early embryo and then re-established at the time of implantation. In this Review, dynamics of DNA methylation during normal development in vivo are discussed, starting from fertilization through embryogenesis and postnatal growth, as well as abnormal methylation changes that occur in cancer. PMID- 23463313 TI - Epigenetic programming and reprogramming during development. AB - Cell identity is determined by specific gene expression patterns that are conveyed by interactions between transcription factors and DNA in the context of chromatin. In development, epigenetic modifiers are thought to stabilize gene expression and ensure that patterns of DNA methylation and histone modification are reinstated in cells as they divide. Global erasure of epigenetic marks occurs naturally at two stages in the mammalian life cycle, but it can also be artificially engineered using a variety of reprogramming strategies. Here we review some of the recent advances in understanding how epigenetic remodeling contributes to conversion of cell fate in vivo and in vitro. We summarize current models of epigenetic erasure and discuss the various enzymes and mechanisms that may operate in cellular reprogramming. PMID- 23463320 TI - Removal of airborne toxic chemicals by porous organic polymers containing metal catecholates. AB - Porous organic polymers bearing metal-catecholate groups were evaluated for their ability to remove airborne ammonia, cyanogen chloride, sulphur dioxide, and octane by micro-breakthrough analysis. For ammonia, the metal-catecholate materials showed remarkable uptake under humid conditions. PMID- 23463314 TI - Functional implications of genome topology. AB - Although genomes are defined by their sequence, the linear arrangement of nucleotides is only their most basic feature. A fundamental property of genomes is their topological organization in three-dimensional space in the intact cell nucleus. The application of imaging methods and genome-wide biochemical approaches, combined with functional data, is revealing the precise nature of genome topology and its regulatory functions in gene expression and genome maintenance. The emerging picture is one of extensive self-enforcing feedback between activity and spatial organization of the genome, suggestive of a self organizing and self-perpetuating system that uses epigenetic dynamics to regulate genome function in response to regulatory cues and to propagate cell-fate memory. PMID- 23463315 TI - Structure and function of long noncoding RNAs in epigenetic regulation. AB - Genomes of complex organisms encode an abundance and diversity of long noncoding RNAs (lncRNAs) that are expressed throughout the cell and fulfill a wide variety of regulatory roles at almost every stage of gene expression. These roles, which encompass sensory, guiding, scaffolding and allosteric capacities, derive from folded modular domains in lncRNAs. In this diverse functional repertoire, we focus on the well-characterized ability for lncRNAs to function as epigenetic modulators. Many lncRNAs bind to chromatin-modifying proteins and recruit their catalytic activity to specific sites in the genome, thereby modulating chromatin states and impacting gene expression. Considering this regulatory potential in combination with the abundance of lncRNAs suggests that lncRNAs may be part of a broad epigenetic regulatory network. PMID- 23463321 TI - Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques. AB - Higher systemic levels of the proinflammatory cytokine interleukin-6 (IL-6) were found to be associated with lower gray matter volume and tissue density in old rhesus macaques. This association between IL-6, and these brain indices were attenuated by long-term 30 % calorie restriction (CR). To extend these findings, the current analysis determined if a CR diet in 27 aged rhesus monkeys compared to 17 normally fed controls reduced circulating levels of another proinflammatory cytokine, interleukin-8 (IL-8), and raised levels of anti-inflammatory interleukin-10 (IL-10). Further, these cytokines were regressed onto imaged brain volume and microstructure using voxel-wise regression analyses. CR significantly lowered IL-8 and raised IL-10 levels. Across the two dietary conditions, higher IL-8 predicted smaller gray matter volumes in bilateral hippocampus. Higher IL-10 was associated with more white matter volume in visual areas and tracts. Consuming a CR diet reduced the association between systemic IL-8 and hippocampal volumes. Conversely, CR strengthened associations between IL-10 and microstructural tissue density in the prefrontal cortex and other areas, particularly in a region of dorsal prefrontal cortex, which concurred with our prior findings for IL-6. Consumption of a CR diet lowered proinflammatory and increased anti-inflammatory cytokine concentrations, which lessened the statistical association between systemic inflammation and the age-related alterations in important brain regions, including the hippocampus. PMID- 23463322 TI - Health work by older people with chronic illness: how much time does it take? AB - PURPOSE: People living with chronic illness report spending a lot of time managing their health, attempting to balance the demands of their illness/es with other activities. This study was designed to measure the time older people with chronic illness spend on specific health-related activities. Key methods: Data were collected in 2010 using a national survey of people aged 50 years and over selected from the membership of National Seniors Australia, the Diabetes Services Scheme and The Lung Foundation. Respondents provided recall data on time used for personal health care, non-clinical health activity; and health service interactions. MAIN RESULTS: While most people with a chronic illness spend on average less than 30 minutes a day on health-related activities, the highest decile of respondents averaged at least 2 hours each day. People with COPD report the highest expenditure of time. The greatest amount of time was spent on daily personal health care activities. MAIN CONCLUSION: For a minority of people with chronic illness, time demands for health-related activities can be so great that other activities must be affected. Some time demands are amenable to system interventions that would result in a more patient-centered organisation of care. PMID- 23463323 TI - Metabolic and morphological changes of an oil accumulating trebouxiophycean alga in nitrogen-deficient conditions. AB - Oil-rich algae have promising potential for a next-generation biofuel feedstock. Pseudochoricystis ellipsoidea MBIC 11204, a novel unicellular green algal strain, accumulates a large amount of oil (lipids) in nitrogen-deficient (-N) conditions. Although the oil bodies are easily visualized by lipophilic staining in the cells, little is known about how oil bodies are metabolically synthesized. Clarifying the metabolic profiles in -N conditions is important to understand the physiological mechanisms of lipid accumulations and will be useful to optimize culture conditions efficiently produce industrial oil. Metabolome and lipidome profiles were obtained, respectively, using capillary electrophoresis- and liquid chromatography-mass spectrometry from P. ellipsoidea in both nitrogen-rich (+N; rapid growth) and -N conditions. Relative quantities of more than 300 metabolites were systematically compared between these two conditions. Amino acids in nitrogen assimilation and N-transporting metabolisms were decreased to 1/20 the amount, or less, in -N conditions. In lipid metabolism, the quantities of neutral lipids increased greatly in -N conditions; however, quantities of nearly all the other lipids either decreased or only changed slightly. The morphological changes in +N and -N conditions were also provided by microscopy, and we discuss their relationship to the metabolic changes. This is the first approach to understand the novel algal strain's metabolism using a combination of wide-scale metabolome analysis and morphological analysis. PMID- 23463324 TI - Efficient gene targeting in a Candida guilliermondii non-homologous end-joining pathway-deficient strain. AB - The yeast, Candida guilliermondii, has been widely studied due to its biotechnological interest as well as its biological control potential. It integrates foreign DNA predominantly via ectopic events, likely through the well known non-homologous end-joining (NHEJ) pathway involving the Ku70p/Ku80p heterodimer, Lig4p, Nej1p and Lif1p. This phenomenon remains highly deleterious for targeted gene knock-out strategies that require the homologous recombination process. Here, we have constructed a ku70 mutant strain derived from the ATCC 6260 reference strain of C. guilliermondii. Following a series of disruption attempts of various genes (FCY1, ADE2 and TRP5), using several previously described dominant selectable markers (URA5, SAT-1 and HPH#), we demonstrated that the efficiencies of homologous gene targeting in such a NHEJ-deficient strain was very high compared to the wild type strain. The C. guilliermondii ku70 deficient mutant thus represents a powerful recipient strain to knock-out genes efficiently in this yeast. PMID- 23463325 TI - MTHFR C677T polymorphism was an ethnicity-dependent risk factor for cervical cancer development: evidence based on a meta-analysis. AB - INTRODUCTION: Many studies have studied the associations between 5, 10-methylene tetrahydrofolate reductase (MTHFR) polymorphisms and susceptibilities of cervical cancer and cervical intraepithelial neoplasia (CIN); however, the results were inconsistent. The aim of this study was to further assess the relationships by the method of meta-analysis. MATERIALS AND METHODS: Two investigators independently searched the PubMed, Embase, Wang Fang (Chinese database) and CNKI (China National Knowledge Infrastructure), with latest update to July 1st, 2011. The pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were used to assess the strength of the associations by using fixed- or random-effect model. RESULTS: Ten case-control studies were included in this meta-analysis including a total of 1,803 cervical cancer or CIN cases and 2,363 controls. Pooled analyses showed that T allele of MTHFR C677T was significantly associated with increased CIN risk [OR (95 % CI): 1.28 (1.03-1.50) for CT vs. CC], especially for low-grade CIN risk. In addition, MTHFR C677T rather than A1298C polymorphism was associated with risk of cervical cancer. Stratifying analyses for ethnicity indicated that T allele of MTHFR C677T was associated with increased cervical cancer risk for Asian [OR (95 % CI): 1.56 (1.17-2.08) for TT vs. CC; 1.53 (1.19-1.96) for TT vs. C carriers] while decreased risk for Caucasian [OR (95 % CI): 0.63 (0.45-0.89) for TT vs. CC; 0.66 (0.56-0.79) for T carriers vs. CC]. CONCLUSION: This meta analysis suggested that there was no association between MTHFR A1298C polymorphism and cervical cancer risk. However, MTHFR C677T was an ethnicity dependent risk factor for cervical cancer occurrence. In addition, T allele of C677T was significantly associated with risk of low grade of CIN incidence. Because of modest limitations of our study, well-designed studies with large sample size were needed to confirm our findings in the future. PMID- 23463326 TI - T-cadherin expression in uterine leiomyoma. AB - OBJECTIVE: T-cadherin is a tumor-suppressor with low expression in many malignant tumors, but with high expression in endothelial cells and so on. In this study we investigated whether T-cadherin was expressed and if together with bFGF play a role in the occurrence and development of uterine leiomyoma. METHOD: Uterine leiomyoma, the adjacent normal myometrium, control normal myometrium without uterine leiomyoma and vascular features of myoma were collected. Immunohistochemistry, western blot and relative quantitative real time PCR were used to evaluate bFGF and T-cadherin on the three specimens. Data were statistically analysed. RESULTS: T-cadherin was observed on the leiomyoma cellular layers but not in the endochylema, extracellular matrix and leiomyoma vascular endothelial cell, bFGF in the leiomyoma endochylema but not observed in the extracellular matrix and leiomyoma vascular endothelial cell. The protein and mRNA expression of bFGF and T-cadherin in uterine leiomyoma were significantly with higher expression than that in adjacent normal myometrium and control normal myometrium. In addition, T-cadherin correlated well with bFGF. There was relationship between T-cadherin and color Doppler flow imaging (CDFI). CONCLUSION: bFGF and T-cadherin have high expressions in uterine leiomyoma, and T cadherin is associated with CDFI, indicating that a cross talk between bFGF and T cadherin plays an important role in the occurrence and development of uterine leiomyoma or even malignant tumors. PMID- 23463327 TI - Screening, gene sequencing and characterising of lipase for methanolysis of crude palm oil. AB - Staphylococcus sp. WL1 lipase (LipFWS) was investigated for methanolysis of crude palm oil (CPO) at moderate temperatures. Experiments were conducted in the following order: searching for the suitable bacterium for producing lipase from activated sludge, sequencing lipase gene, identifying lipase activity, then synthesising CPO biodiesel using the enzyme. From bacterial screening, one isolated specimen which consistently showed the highest extracellular lipase activity was identified as Staphylococcus sp. WL1 possessing lipFWS (lipase gene of 2,244 bp). The LipFWS deduced was a protein of 747 amino acid residues containing an alpha/beta hydrolase core domain with predicted triad catalytic residues to be Ser474, His704 and Asp665. Optimal conditions for the LipFWS activity were found to be at 55 degrees C and pH 7.0 (in phosphate buffer but not in Tris buffer). The lipase had a K(M) of 0.75 mM and a V(max) of 0.33 mMmin( 1) on p-nitrophenyl palmitate substrate. The lyophilised crude LipFWS performed as good as the commonly used catalyst potassium hydroxide for methanolysis of CPO. ESI-IT-MS spectra indicated that the CPO was converted into biodiesel, suggesting that free LipFWS is a worthy alternative for CPO biodiesel synthesis. PMID- 23463328 TI - Silaffin peptides as a novel signal enhancer for gravimetric biosensors. AB - Application of biomimetic silica formation to gravimetric biosensors has been conducted for the first time. As a model system, silaffin peptides fused with green fluorescent protein (GFP) were immobilized on a gold quartz crystal resonator for quartz crystal microbalances using a self-assembled monolayer. When a solution of silicic acid was supplied, silica particles were successfully deposited on the Au surface, resulting in a significant change in resonance frequency (i.e., signal enhancement) with the silaffin-GFP. However, frequency was not altered when bare GFP was used as a control. The novel peptide enhancer is advantageous because it can be readily and quantitatively conjugated with sensing proteins using recombinant DNA technology. As a proof of concept, this study shows that the silaffin domains can be employed as a novel and efficient biomolecular signal enhancer for gravimetric biosensors. PMID- 23463329 TI - Patients utilizing a free clinic: physical and mental health, health literacy, and social support. AB - This cross sectional study assessed the physical and mental health, health literacy and social support of the uninsured utilizing a free clinic to develop intervention programs and research projects to improve the health of free clinic patients. Free clinics are nonprofit organizations that provide underserved and uninsured individuals access to a broad array of free or low cost healthcare services. English or Spanish speaking patients (N = 187) aged 18 years or older completed a self-administered survey. Physical, mental and oral health, health literacy, and social support were measured using standardized instruments. Eighty two participants (45 US born and 37 non-US born) chose the English version of the survey (English speakers) while 105 participants (2 US born and 103 non-US born) chose the Spanish version (Spanish speakers). Overall, both the physical and mental health functioning of the participants was lower than that of the US general population. The participants reported being moderately depressed. US-born English speakers reported the poorest physical and mental health while Spanish speakers reported the best physical health and the lowest level of depression. A higher level of health literacy was associated with better physical health functioning, whereas reporting higher social support was associated with better mental health functioning and less severe depression. Because most free clinics have limited resources, developing services and programs that fit free clinics' circumstances are needed. Our study finding indicates that health literacy education, mental health services, and social support are key services needed by free clinic patients to achieve better health. PMID- 23463330 TI - Thyroglobulin levels and thyroglobulin doubling time independently predict a positive 18F-FDG PET/CT scan in patients with biochemical recurrence of differentiated thyroid carcinoma. AB - PURPOSE: To assess the relationship between serum thyroglobulin (Tg) levels, Tg doubling time (Tg-DT) and the diagnostic performance of (18)F-FDG PET/CT in detecting recurrences of (131)I-negative differentiated thyroid carcinoma (DTC). METHODS: Included in the present study were 102 patients with DTC. All patients were treated by thyroid ablation (e.g. thyroidectomy and (131)I), and underwent (18)F-FDG PET/CT due to detectable Tg levels and negative conventional imaging. Consecutive serum Tg measurements performed before the (18)F-FDG PET/CT examination were used for Tg-DT calculation. The (18)F-FDG PET/CT results were assessed as true or false after histological and/or clinical follow-up. RESULTS: Serum Tg levels were higher in patients with a positive (18)F-FDG PET/CT scan (median 6.7 ng/mL, range 0.7-73.6 ng/mL) than in patients with a negative scan (median 1.8 ng/mL, range 0.5-4.9 ng/mL; P < 0.001). In 43 (88 %) of 49 patients with a true-positive (18)F-FDG PET/CT scan, the Tg levels were >5.5 ng/mL, and in 31 (74 %) of 42 patients with a true-negative (18)F-FDG PET/CT scan, the Tg levels were <=5.5 ng/mL. A Tg-DT of <1 year was found in 46 of 49 patients (94 %) with a true-positive (18)F-FDG PET/CT scan, and 40 of 42 patients (95 %) with a true-negative scan had a stable or increased Tg-DT. Moreover, combining Tg levels and Tg-DT as selection criteria correctly distinguished between patients with a positive and a negative scan (P<0.0001). CONCLUSION: The accuracy of (18)F-FDG PET/CT significantly improves when the serum Tg level is above 5.5 ng/mL during levothyroxine treatment or when the Tg-DT is less than 1 year, independent of the absolute value. PMID- 23463331 TI - PSMA as a target for radiolabelled small molecules. PMID- 23463333 TI - Determination of robenidine residues in chicken muscle by high performance liquid chromatography with ultraviolet detection. AB - A simple, robust and reliable method for the determination of residual robenidine in chicken muscle using high performance liquid chromatography with ultraviolet (UV) detection was developed and validated according to the Codex Alimentarius Commission guidelines. Chicken muscle was extracted by acetonitrile/formic acid (98:2, v/v) and defatted with hexane. Analytes were isocratically separated on a Luna C18 column (4.6 * 150 mm, 5 MUm) using 70 % methanol in water containing 0.1 % trifluoroacetic acid at a flow rate of 1.0 mL/min at 30 degrees C. UV detection was performed at 312 nm. The method was validated by assessing performance parameters including selectivity, linearity, limit of quantification (LOQ), precision, accuracy, recovery, stability and robustness. A calibration curve that was constructed over 0.05-0.5 MUg/g showed correlation coefficients of more than 0.999. The intra- and inter-day precisions (as coefficient of variation) were 1.45-3.32 and 2.63-4.99 %, respectively. The intra- and inter-day accuracies were 99.4-105.3 and 98.3-101.6 %, respectively. The recoveries were in the range of 76.6-81.8 % and the LOQ was 0.05 MUg/g. The developed method showed suitable performance for the determination of robenidine residues in chicken muscle. PMID- 23463332 TI - Phellinus baumii ethyl acetate extract alleviated collagen type II induced arthritis in DBA/1 mice. AB - Mushrooms have a long history of dietary benefits in Asia due to their health promoting effects. Phellinus baumii, a wild mushroom, has been reported to have anti-platelet, anti-inflammatory, anti-obesity and free radical scavenging activities. However, its anti-rheumatoid arthritis (RA) property remains poorly understood. Hence, we investigated the protective effect of Phellinus baumii ethyl acetate extract (PBEAE) against bovine collagen type II induced arthritis (CIA) in DBA/1 mice. PBEAE (50 and 150 mg/kg) reduced the CIA score and leukocyte count in draining lymph nodes (DLNs) and inflamed joints. PBEAE also attenuated the expressions of CD3+ (T cells), CD19+ (B cells), CD4+ (T-helper), CD8+ (T cytotoxic), MHC class II/CD11c+ (antigen-presenting cells), double positives (B220+/CD23+ and CD3+/CD69+: early lymphocyte activation markers) and CD4+/CD25+ (activated T-helper) leukocyte subpopulations in DLNs. Likewise, CD3+ and Gr 1+CD11b+ (neutrophil) counts in inflamed joints were also decreased. Furthermore, PBEAE reduced the serum levels of anti-collagen type immunoglobulin G, tumor necrosis factor-alpha and interleukin (IL)-1beta and IL-6. Taken together, PBEAE impaired cellular recruitment to the inflamed joint and alleviated CIA, and thus could be considered as a potential agent against rheumatoid arthritis. PMID- 23463334 TI - Formulation and pharmacokinetic evaluation of once-daily sustained-released system of nifedipine with solid dispersion and coating techniques. AB - A novel sustained-release system was developed for poorly water-soluble drugs by applying solid dispersion (SD) technique to improve the solubility. The SD systems composed of polyvinyl pyrrolidone and stearic acid could not control the release of nifedipine. When the above SD granules were coated with ethylcellolulose (EC10, 45 and 100cp), the dissolution rate extended from 16 to 20 h. When the concentration of EC100cp was increased to 4-6 %, the sustained release formulation F7 and F8 prepared with 4 % EC100cp and 6 % EC100cp, respectively, could control the drug release in a better manner, namely, they could control drug release in the initial hours with a high cumulative amount of drug at 24 h. The mechanism of drug release from F7 and F8 was diffusion coupled with erosion. When immediate-release capsules was orally administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma drug level up to 24 h was obtained for F7 and F8. Furthermore, the oral bioavailability of F7 and F8 was significantly improved. The results suggested that this novel sustained-release system would be a promising system to improve the solubility and sustain the absorption of poorly water-soluble drugs. PMID- 23463335 TI - Aromatic polyketides from a sponge-derived fungus Metarhizium anisopliae mxh-99 and their antitubercular activities. AB - In our screening for antitubercular agents, five naphtho-gamma-pyrones including two new naphtho-gamma-pyrones glycosides, indigotides G and H (1 and 2), and two diphenyl ethers were isolated from the extract of a sponge-derived fungus Metarhizium anisopliae mxh-99. Their structures were established on the basis of chemical and spectroscopic evidence. The antitubercular activities of all the compounds were evaluated against Mycobacterium phlei. The known isochaetochromin B2 (6) and ustilaginoidin D (7) exhibited the highest activity with MICs 50.0 MUg/mL. PMID- 23463336 TI - Effects of dried Citrus unshiu peels on gastrointestinal motility in rodents. AB - Aqueous extracts of the dried mature (ANP-W) and immature Citrus unshiu peels (CUP-W) have been used as a traditional folk medicine for the treatment of gastrointestinal (GI) motility disorders in Korea. In the present study, neither ANP-W nor CUP-W exhibited significant toxicity even at an oral dose of 5 g/kg to mice. The effects of ANP-W and CUP-W on GI motor function were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal mice and rats with experimental GI motility dysfunctions (GMDs). In normal mice, the ITR was significantly increased by ANP-W (0.1-1 g/kg) in a dose dependent manner, whereas CUP-W elicited no significant change. GMD was induced by appropriate surgery or an intraperitoneal injection of acetic acid to the rats. The ITR in the GMD rats was significantly retarded compared to that in normal rats. However, the retardation was significantly inhibited by ANP-W (0.1-1 g/kg) in a dose dependent manner. The above results suggest that ANP-W has the potential for development as a prokinetic agent that may prevent or alleviate GMD in human patients. PMID- 23463337 TI - Maltoheptaose promotes nanoparticle internalization by Escherichia coli. AB - Nanoparticles conjugated with d-maltoheptaose (G7) showed a striking increase in the internalization by Escherichia coli. This applies to strains with and without the maltodextrin transport channel and particles ranging from a few to a hundred nanometers. PMID- 23463339 TI - Decoding representations of face identity that are tolerant to rotation. AB - In order to recognize the identity of a face we need to distinguish very similar images (specificity) while also generalizing identity information across image transformations such as changes in orientation (tolerance). Recent studies investigated the representation of individual faces in the brain, but it remains unclear whether the human brain regions that were found encode representations of individual images (specificity) or face identity (specificity plus tolerance). In the present article, we use multivoxel pattern analysis in the human ventral stream to investigate the representation of face identity across rotations in depth, a kind of transformation in which no point in the face image remains unchanged. The results reveal representations of face identity that are tolerant to rotations in depth in occipitotemporal cortex and in anterior temporal cortex, even when the similarity between mirror symmetrical views cannot be used to achieve tolerance. Converging evidence from different analysis techniques shows that the right anterior temporal lobe encodes a comparable amount of identity information to occipitotemporal regions, but this information is encoded over a smaller extent of cortex. PMID- 23463338 TI - Intraovarian transplantation of primordial follicles fails to rescue chemotherapy injured ovaries. AB - Busulfan and cyclophosphamide (B/C)-treated mice exhibited a marked increase in apoptosis and a concomitant decrease in the ovarian weight. Histological and RT PCR analysis indicate that the period of germ cell depletion in the B/C-treated ovaries coincides with decreased expression of genes Figla, Lhx8, Nobox, c-kit, and Sox3. However, depletion of the ovarian germ cells is mediated by autophagy independent pathways that involve Fas/FasL-, TNF-, and/or p53-signalings. Treatment with B/C resulted in the cease of the reproductive function to produce their offspring during the 15(th) week post-treatment period in female mice. Furthermore, injection of the 3 * 10(6) GFP positive primordial follicles into the ovaries of the B/C treated mouse did not show apparent colonization of the transplanted follicles within the recipient ovaries. The present results suggest that B/C treatment is closely associated with an increased risk of premature ovarian failure. PMID- 23463340 TI - Imagine all the people: how the brain creates and uses personality models to predict behavior. AB - The behaviors of other people are often central to envisioning the future. The ability to accurately predict the thoughts and actions of others is essential for successful social interactions, with far-reaching consequences. Despite its importance, little is known about how the brain represents people in order to predict behavior. In this functional magnetic resonance imaging study, participants learned the unique personality of 4 protagonists and imagined how each would behave in different scenarios. The protagonists' personalities were composed of 2 traits: Agreeableness and Extraversion. Which protagonist was being imagined was accurately inferred based solely on activity patterns in the medial prefrontal cortex using multivariate pattern classification, providing novel evidence that brain activity can reveal whom someone is thinking about. Lateral temporal and posterior cingulate cortex discriminated between different degrees of agreeableness and extraversion, respectively. Functional connectivity analysis confirmed that regions associated with trait-processing and individual identities were functionally coupled. Activity during the imagination task, and revealed by functional connectivity, was consistent with the default network. Our results suggest that distinct regions code for personality traits, and that the brain combines these traits to represent individuals. The brain then uses this "personality model" to predict the behavior of others in novel situations. PMID- 23463341 TI - Lipopolysaccharide-binding protein: a potential marker of febrile urinary tract infection in childhood. AB - BACKGROUND: Urinary tract infections (UTIs) are encountered frequently in children, and their early diagnosis and treatment are important. This study evaluates the diagnostic value of serum concentrations of lipopolysaccharide binding protein (LBP), an acute-phase protein, in children with febrile UTI and compares it to those of the total white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6). METHODS: The study population comprised 77 consecutive patients with a first-episode febrile UTI (33 boys) with a median age of 11 months [interquartile range (IQR), 5.5-33 months], 21 healthy controls (11 boys) with a median age of 10 months (IQR, 5-20.5 months) and 58 febrile controls with a fever due to other causes (28 boys) with a median age of 12.5 months (IQR, 7-30 months). LBP, IL-6, PCT, and CRP were measured for both patients and control groups. RESULTS: The serum levels of LBP (p < 0.001), CRP (p < 0.001), PCT (p = 0.001), IL-6 (p = 0.002), ESR (p = 0.020), and WBC (p < 0.001) were higher in patients with febrile UTI than in the healthy and febrile control groups. The LPB cut-off value for best sensitivity and specificity in patients with febrile UTI was >43.23 mg/l. Furthermore, the area under the receiver operating characteristic curve was significantly greater for LBP than for CRP (p = 0.014), PCT (p < 0.001), ESR (p < 0.001), WBC (p = 0.002) and IL-6 (p = 0.006). CONCLUSIONS: The results of this study suggest that the serum LBP concentration constitutes a reliable biologic marker for the diagnosis of a febrile UTI in children. PMID- 23463342 TI - Serum microRNAs levels in primary focal segmental glomerulosclerosis. AB - BACKGROUND: MicroRNAs (miRNAs, miRs) are involved in most physiological, developmental, and pathological processes. miR-192 and miR-205 are expressed preferentially in the renal cortex and closely relevant to the renal cell biology. In the present study, we aim to measure the serum levels of miR-192 and miR-205 and their correlation with clinicopathological data in patients with primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). METHODS: Fifty-six patients (35 male, 21 female) with idiopathic nephrotic syndrome (FSGS 30, MCD 26) and 20 healthy controls were enrolled in the study. We quantified the serum levels of miR-192 and miR-205 in patients with FSGS and MCD by RT-qPCR. RESULTS: Patients with FSGS had higher serum levels of miR-192 and miR-205 than those with MCD (324.49 +/- 42.74 fmol/l versus 90.19 +/- 27.14 fmol/l, p < 0.01, 2.25 +/- 0.69 fmol/l versus 0.60 +/- 0.51 fmol/l, p < 0.01, respectively). The level of miR-192 was positively correlated with the proteinuria in patients with FSGS and MCD (r = 0.62, p < 0.001, r = 0.84, p < 0.001, respectively). Similarly, the level of miR-205 was positively correlated with the proteinuria in patients with FSGS (r = 0.54, p = 0.002). In addition, the serum level of miR-192 was significantly correlated with the degree of interstitial fibrosis in patients with FSGS (r = 0.342, p < 0.05). CONCLUSIONS: miR-192 and miR-205 have the potential as markers to differentiate FSGS from MCD. PMID- 23463343 TI - Coke- and sintering-resistant monolithic catalysts derived from in situ supported hydrotalcite-like films on Al wires for dry reforming of methane. AB - Monolithic catalysts derived from in situ supported hydrotalcite-like films on Al wires display high resistance to coke formation and sintering in the dry reforming of methane due to their hierarchical porous structure, well dispersed metallic nickel species, more basic sites and strong metal-support interaction effect. PMID- 23463344 TI - A new preoperative radiological assessment in LeFort I surgery: anterior nasal spine-sphenoidal rostrum. AB - OBJECTIVE: The aim of this study is to assess the distance between the anterior nasal spine and the sphenoidal rostrum related to the LeFort I surgery in a Turkish population sample. MATERIAL AND METHODS: We retrospectively reviewed multidetector computerized tomography (MDCT) scans of 209 patients (134 males and 75 females). The images were obtained on a 64-MDCT scanner. The imaging parameters were 0.5 * 64 mm slice thickness, 0.5/0.3 mm increment, 120 kV, 250 mAs, 0.5 sn rotation time, 0.641 pitch, and 512 matrix. The distance between the anterior nasal spine and the sphenoidal rostrum was assessed with the Vitrea 2 software program. RESULTS: The study group consisted of 134 male (mean age 57.90 +/- 5.86) and 75 female (mean age 54.84 +/- 4.31) patients. The distance between the anterior nasal spine and the sphenoidal rostrum was ranging between 40.4 and 70.9 mm (average 58.3 +/- 5.9) in males and 45.0 and 63.2 mm in (average 55.2 +/- 4.3) females. In addition, no statistically significant differences were found between genders. CONCLUSION: The results of the current study showed that after 40 mm proceeding of the ball end nasal osteotome, the surgeons must be aware of penetrating the sphenoidal rostrum. PMID- 23463345 TI - Dysfunctional endothelial cells directly stimulate cancer inflammation and metastasis. AB - Although the influence of context-dependent endothelial cell (EC) regulation of vascular disease and repair is well-established, the privileged roles ECs play as paracrine regulators of tumor progression has only recently become appreciated. We hypothesized that if the same endothelial physiology governs vascular and cancer biology then EC control in cancer should follow endothelial regulation of vascular health. Healthy ECs promote vascular repair and inhibit tumor invasiveness and metastasis. Dysfunctional ECs have the opposite effects in vascular disease, and we now ask if dysfunctionally activated ECs will promote cancer cell inflammatory signaling and aggressive properties. Indeed, while factors released from quiescent ECs induce balanced inflammatory signaling, correlating with decreased proliferation and invasiveness, factors released from dysfunctional ECs robustly activated NF-kappaB and STAT3 signaling within cancer cells, correlating with increased in vitro invasiveness and decreased proliferation and survival. Furthermore, matrix-embedded dysfunctional ECs stimulated intratumoral pro-inflammatory signaling and spontaneous metastasis, while simultaneously slowing primary tumor growth, when implanted adjacent to Lewis lung carcinoma tumors. These studies may broaden our appreciation of the roles of endothelial function and dysfunction, increase understanding and control of the tumor microenvironment, and facilitate optimization of anti-angiogenic and vascular-modifying therapies in cancer and other diseases. PMID- 23463346 TI - Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification. AB - Hepatocellular carcinoma (HCC) is one of the commonest causes of death from cancer. A plethora of metabolomic investigations of HCC have yielded molecules in biofluids that are both up- and down-regulated but no real consensus has emerged regarding exploitable biomarkers for early detection of HCC. We report here a different approach, a combined transcriptomics and metabolomics study of energy metabolism in HCC. A panel of 31 pairs of HCC tumors and corresponding nontumor liver tissues from the same patients was investigated by gas chromatography-mass spectrometry (GCMS)-based metabolomics. HCC was characterized by ~2-fold depletion of glucose, glycerol 3- and 2-phosphate, malate, alanine, myo-inositol, and linoleic acid. Data are consistent with a metabolic remodeling involving a 4 fold increase in glycolysis over mitochondrial oxidative phosphorylation. A second panel of 59 HCC that had been typed by transcriptomics and classified in G1 to G6 subgroups was also subjected to GCMS tissue metabolomics. No differences in glucose, lactate, alanine, glycerol 3-phosphate, malate, myo-inositol, or stearic acid tissue concentrations were found, suggesting that the Wnt/beta catenin pathway activated by CTNNB1 mutation in subgroups G5 and G6 did not exhibit specific metabolic remodeling. However, subgroup G1 had markedly reduced tissue concentrations of 1-stearoylglycerol, 1-palmitoylglycerol, and palmitic acid, suggesting that the high serum alpha-fetoprotein phenotype of G1, associated with the known overexpression of lipid catabolic enzymes, could be detected through metabolomics as increased lipid catabolism. CONCLUSION: Tissue metabolomics yielded precise biochemical information regarding HCC tumor metabolic remodeling from mitochondrial oxidation to aerobic glycolysis and the impact of molecular subtypes on this process. PMID- 23463347 TI - Activation of the EGFR/Akt/NF-kappaB/cyclinD1 survival signaling pathway in human cholesteatoma epithelium. AB - Cholesteatoma is a benign keratinizing squamous epithelial lesion characterized by the hyper-proliferation of keratinocytes with abundant production of keratin debris in the middle ear. The epidermal growth factor receptor (EGFR)/Akt/nuclear factor-kappa B (NF-kappaB)/cyclinD1 signaling pathway is one of the most important pathways in regulating cell survival and proliferation. We hypothesized that the EGFR/Akt/NF-kappaB/cyclinD1 signaling pathway may be activated and involved in the cellular hyperplasia mechanism in acquired cholesteatoma epithelium. Immunohistochemical staining of phosphorylated EGFR (p-EGFR), phosphorylated Akt (p-Akt), activated NF-kappaB and cyclinD1 protein was performed in 40 cholesteatoma samples and 20 samples of normal external auditory canal (EAC) epithelium. Protein expression of p-EGFR, p-Akt, activated NF-kappaB and cyclinD1 in cholesteatoma epithelium was significantly increased when compared with normal EAC epithelium (p < 0.01). In cholesteatoma epithelium, a significant positive association was observed between p-EGFR and p-Akt expression and between the expressions of p-Akt and NF-kappaB, NF-kappaB and cyclinD1, respectively (p < 0.01). No significant relationships were observed between the levels of investigated proteins and the degree of bone destruction (p > 0.05). The increased protein expression of p-EGFR, p-Akt, NF-kappaB and cyclinD1 and their associations in cholesteatoma epithelium suggest that the EGFR/Akt/NF kappaB/cyclinD1 survival signaling pathway is active and may be involved in the regulatory mechanisms of cellular hyperplasia in cholesteatoma epithelium. PMID- 23463348 TI - The predictive value of Muller's maneuvre for CPAP titration in OSAHS patients. AB - To investigate the role of awake upper airways (UA) endoscopy assessment as a parameter of prediction for CPAP titration in OSAHS patient therapy. Retrospective analysis of UA endoscopic assessment with Mueller's maneuvre and the application of the nose oropharynx hypopharynx score (NOHs) was conducted to obtain a numeric score representing the grade of severity of UA obstruction. Other commonly used predictive parameters for CPAP titration were also included in the study: anthropometric [BMI, neck circumference (NC)] and polysomnographic parameters (AHI, ODI). 3 groups of patients were identified: (1) 67/90 patients requiring intermediate CPAP values, (2) 13/90 patients requiring high CPAP values, and (3) 10/90 patients requiring low pressure values. BMI (p = 0.0013) was the only monitored parameter to show significant statistical value as a CPAP titration predictor. However, higher values of anthropometric parameters (NOHs >=9, BMI >35, NC >45) showed a sensitivity of 69.2% as a single parameter and 76.9% as combined parameters, and specificity between 66.2 and 72.7% as a single parameter and 43.4% as combined parameters, unequivocally identifying patients requiring high therapeutic CPAP value. A lower cut-off of anthropometric parameters (NOHs <=6, BMI <=29, NC <42) showed sensitivity between 40 and 60% as a single parameter and of 90% as combined parameters, and specificity between 68.7 and 80.2% as a single parameter which increased to 93.7% as combined parameters, identifying patients requiring a low therapeutic CPAP value. The results show that anthropometric and polygraphic parameters have no significant independent predictive value for CPAP titration, with the exception of BMI. However, anthropometric parameters showed good levels of sensitivity and specificity in OSAHS patients requiring high or low levels of CPAP therapy. PMID- 23463349 TI - Endoscopic transcanal stapedotomy: how I do it. AB - Current paper presents a surgical technique and preliminary results of the first eight consecutive fully endoscopic transcanal stapedotomies. All eight procedures were performed under local anesthesia by the same surgeon using rigid endoscopes of 3-mm diameter, 14-cm length, 0 degrees and 30 degrees . A posterior tympanomeatal flap was elevated transmeatally with the 0 degrees endoscope and then transposed anteriorly. Stapes fixation was confirmed, the stapes tendon was cut with curved micro-scissors, and the stapes was separated from the incus in the incudo-stapedial joint. The anterior and posterior stapedial crus were carefully fractured, and the superstructure was removed. The hole in the foot plate was created with a Skeeter microdrill using a 0.5-mm-diameter diamond burr. A platinum/fluoroplastic piston prosthesis (0.4-mm diameter) was placed into this hole and fitted along the long process of the incus. The tympano-meatal flap was repositioned, and the external auditory canal was filled with Gelfoam((r)). The chorda tympani nerve was preserved in all cases. A 4.5-mm prosthesis was used in six cases and a 4.75-mm prosthesis in two. Pure tone audiograms demonstrated improved air- and bone-conduction threshold averages across the three speech frequencies (0.5-1.2 kHz) 6 months after surgery (64 vs. 29.8 dB and 30.6 vs. 25.1 dB, respectively). The average postoperative air-bone gap was within 10 dB in six ears and between 10 and 15 dB in the other two ears. Our preliminary results indicate that transcanal fully endoscopic stapedotomy is a feasible and safe technique for surgical management of hearing loss associated with otosclerosis. PMID- 23463350 TI - Ri/Nova gene-associated paraneoplastic subacute motor neuronopathy. PMID- 23463351 TI - Subwavelength metallic waveguides as a tool for extreme confinement of THz surface waves. AB - Research on surface waves supported by metals at THz frequencies is experiencing a tremendous growth due to their potential for imaging, biological sensing and high-speed electronic circuits. Harnessing their properties is, however, challenging because these waves are typically poorly confined and weakly bound to the metal surface. Many design strategies have been introduced to overcome these limitations and achieve increased modal confinement, including patterned surfaces, coated waveguides and a variety of sub-wavelength geometries. Here we provide evidence, using a combination of numerical simulations and time-resolved experiments, that shrinking the transverse size of a generic metallic structure always leads to solutions with extreme field confinement. The existence of such a general behavior offers a new perspective on energy confinement and should benefit future developments in THz science and technology. PMID- 23463354 TI - Simple alcohols promoted direct C-H arylation of unactivated arenes with aryl halides. AB - Simple and cheap alcohols can promote the direct arylation of unactivated arenes with aryl iodides and bromides in the presence of potassium tert-butoxide. This transition-metal-free aromatic C-H transformation offers a cheap and easy practical way to synthesize biaryls under mild conditions. PMID- 23463353 TI - Prediction of drug disposition on the basis of its chemical structure. AB - The chemical structure of any drug determines its pharmacokinetics and pharmacodynamics. Detailed understanding of relationships between the drug chemical structure and individual disposition pathways (i.e., distribution and elimination) is required for efficient use of existing drugs and effective development of new drugs. Different approaches have been developed for this purpose, ranging from statistics-based quantitative structure-property (or structure-pharmacokinetic) relationships (QSPR) analysis to physiologically based pharmacokinetic (PBPK) models. This review critically analyzes currently available approaches for analysis and prediction of drug disposition on the basis of chemical structure. Models that can be used to predict different aspects of disposition are presented, including: (a) value of the individual pharmacokinetic parameter (e.g., clearance or volume of distribution), (b) efficiency of the specific disposition pathway (e.g., biliary drug excretion or cytochrome P450 3A4 metabolism), (c) accumulation in a specific organ or tissue (e.g., permeability of the placenta or accumulation in the brain), and (d) the whole-body disposition in the individual patients. Examples of presented pharmacological agents include "classical" low-molecular-weight compounds, biopharmaceuticals, and drugs encapsulated in specialized drug-delivery systems. The clinical efficiency of agents from all these groups can be suboptimal, because of inefficient permeability of the drug to the site of action and/or excessive accumulation in other organs and tissues. Therefore, robust and reliable approaches for chemical structure-based prediction of drug disposition are required to overcome these limitations. PBPK models are increasingly being used for prediction of drug disposition. These models can reflect the complex interplay of factors that determine drug disposition in a mechanistically correct fashion and can be combined with other approaches, for example QSPR-based prediction of drug permeability and metabolism, pharmacogenomic data and tools, pharmacokinetic pharmacodynamic modeling approaches, etc. Moreover, the PBPK models enable detailed analysis of clinically relevant scenarios, for example the effect of the specific conditions on the time course of the analyzed drug in the individual organs and tissues, including the site of action. It is expected that further development of such combined approaches will increase their precision, enhance the effectiveness of drugs, and lead to individualized drug therapy for different patient populations (geriatric, pediatric, specific diseases, etc.). PMID- 23463355 TI - Continuous-flow pump model study: the effect on pump performance of pump characteristics and cardiovascular conditions. AB - This model study evaluates the effect of pump characteristics and cardiovascular data on hemodynamics in atrio-aortic VAD assistance. The model includes a computational circulatory sub-model and an electrical sub-model representing two rotary blood pumps through their pressure-flow characteristics. The first is close to a pressure generator-PG (average flow sensitivity to pressure variations, -0.047 l mmHg(-1)); the second is closer to a flow generator-FG (average flow sensitivity to pressure variations, -0.0097 l mmHg(-1)). Interaction with VAD was achieved by means of two interfaces, behaving as impedance transformers. The model was verified by use of literature data and VAD onset conditions were used as a control for the experiments. Tests compared the two pumps, at constant pump speed, in different ventricular and circulatory conditions: maximum ventricular elastance (0.44-0.9 mmHg cm(-3)), systemic peripheral resistance (781-1200 g cm(-4) s(-1)), ventricular diastolic compliance C p (5-10-50 cm(3) mmHg(-1)), systemic arterial compliance (0.9-1.8 cm(3) mmHg( 1)). Analyzed variables were: arterial and venous pressures, flows, ventricular volume, external work, and surplus hemodynamic energy (SHE). The PG pump generated the highest SHE under almost all conditions, in particular for higher C p (+50 %). PG pump flow is also the most sensitive to E max and C p changes (-26 and -33 %, respectively). The FG pump generally guarantees higher external work reduction (54 %) and flow less dependent on circulatory and ventricular conditions. The results are evidence of the importance of pump speed regulation with changing ventricular conditions. The computational sub-model will be part of a hydro-numerical model, including autonomic controls, designed to test different VADs. PMID- 23463352 TI - Developmental changes in the expression and function of cytochrome P450 3A isoforms: evidence from in vitro and in vivo investigations. AB - The aim of this review is to discuss our current understanding of the developmental changes of the drug-metabolizing enzyme cytochrome P450 (CYP) 3A and its impact on drug therapy. In the last 10 years, several methods have been used to study the ontogeny of specific CYP3A isoforms in vitro and in vivo. Although most studies confirm previous findings that CYP3A4/5 activity is low at birth and reaches adult values in the first years of life, there are still important gaps in our knowledge of the exact developmental patterns of individual CYP3A isoforms, especially in this age range. Moreover, most in vivo clinical studies have also failed to cover the whole pediatric age range. To date, this information gap still hampers the design of age-specific dosing guidelines of CYP3A substrate drugs, especially in neonates and infants. Innovative study methods, including opportunistic sampling and sensitive analytical assays used in combination with physiologically based pharmacokinetics, and population pharmacokinetic model concepts may help to improve our understanding of the ontogeny of CYP3A and aid the application of this knowledge in clinical practice. PMID- 23463356 TI - Metabolomic and proteomic insights into carbaryl catabolism by Burkholderia sp. C3 and degradation of ten N-methylcarbamates. AB - Burkholderia sp. C3, an efficient polycyclic aromatic hydrocarbon degrader, can utilize nine of the ten N-methylcarbamate insecticides including carbaryl as a sole source of carbon. Rapid hydrolysis of carbaryl in C3 is followed by slow catabolism of the resulting 1-naphthol. This study focused on metabolomes and proteomes in C3 cells utilizing carbaryl in comparison to those using glucose or nutrient broth. Sixty of the 867 detected proteins were involved in primary metabolism, adaptive sensing and regulation, transport, stress response, and detoxification. Among the 41 proteins expressed in response to carbaryl were formate dehydrogenase, aldehyde-alcohol dehydrogenase and ethanolamine utilization protein involved in one carbon metabolism. Acetate kinase and phasin were 2 of the 19 proteins that were not detected in carbaryl-supported C3 cells, but detected in glucose-supported C3 cells. Down-production of phasin and polyhydroxyalkanoates in carbaryl-supported C3 cells suggests insufficient carbon sources and lower levels of primary metabolites to maintain an ordinary level of metabolism. Differential metabolomes (~196 identified polar metabolites) showed up-production of metabolites in pentose phosphate pathways and metabolisms of cysteine, cystine and some other amino acids, disaccharides and nicotinate, in contract to down-production of most of the other amino acids and hexoses. The proteomic and metabolomic analyses showed that carbaryl-supported C3 cells experienced strong toxic effects, oxidative stresses, DNA/RNA damages and carbon nutrient deficiency. PMID- 23463357 TI - Queering the fertility clinic. AB - A sociologist examines contemporary engagements of queer bodies and identities with fertility biomedicine. Drawing on social science, media culture, and the author's own empirical research, three questions frame the analysis: 1. In what ways have queers on the gendered margins moved into the center and become implicated or central users of biomedicine's fertility offerings? 2. In what ways is Fertility Inc. transformed by its own incorporation of various gendered and queered bodies and identities? And 3. What are the biosocial and bioethical implications of expanded queer engagements and possibilities with Fertility Inc.? The author argues that "patient" activism through web 2.0 coupled with a largely unregulated free-market of assisted reproduction has included various queer identities as "parents-in-waiting." Such inclusions raise a set of ethical tensions regarding how to be accountable to the many people implicated in this supply and demand industry. PMID- 23463358 TI - The portrayal of bone tumours in the press. AB - The media are pivotal in educating and informing the general public. The stories they cover and how they cover them has a powerful influence on public perceptions. There have been no previous reports of the portrayal of bone tumours in the press. LexisNexisTM Professional search engine used to retrieve articles from all United Kingdom National Newspapers over one year containing terms "bone tumour/bone tumour" and 46 other named bone and joint tumours from May 2009 to May 2010. A total of 253 relevant articles were found. Seven per cent solely bone tumour related, 41% main theme and 52% mentioned in passing. 52% mentioned tumour type. These were 51% multiple myeloma, 15% Ewing's sarcoma, 9% sarcoma unspecified, 6% clear cell sarcoma, 4.5% epithelial sarcoma, 4% synovial sarcoma, 3% osteosarcoma, 3% bony metastasis and 1.5% chondrosarcoma. Benign bone tumours not mentioned. Article focus: chemotherapy 17%, surgeon/doctor 7% and new surgical technique 2%. The overall attitudinal tone of the articles were 52% negative, 32% neutral and 16% positive. Only 13% quoted an oncologist, and 1% an orthopaedic surgeon. Quality of medical information provided was limited with 90% providing no meaningful medical information and this medical information being correct only 68% of the time. Articles with quotes from a doctor were significantly more likely to contain meaningful medical information than those without-33 versus 4%, respectively (p < 0.001 Chi-squared test)-and there was a trend for them to be more factually correct overall-68 versus 50% (p = 0.192 Fisher's exact Test). PMID- 23463359 TI - Future of medicine: models in predictive diagnostics and personalized medicine. AB - Molecular medicine is undergoing fundamental changes driving the whole area towards a revolution in modern medicine. The breakthrough was generated the fast developing technologies in molecular biology since the first draft sequence of the human genome was published. The technological advances enabled the analysis of biological samples from cells and organs to whole organisms in a depth that was not possible before. These technologies are increasingly implemented in the medical and health care system to study diseases and refine diagnostics. As a consequence, the understanding of diseases and the health status of an individual patient is now based on an enormous amount of data that can only be interpreted in the context of the body as a whole. Systems biology as a new field in the life sciences develops new approaches for data integration and interpretation. Systems medicine as a specialized aspect of systems biology combines in an interdisciplinary approach all expertise necessary to decipher the human body in all its complexity. This created new challenges in the area of information and communication technologies to provide the infrastructure and technology needed to cope with the data flood that will accompany the next generation of medicine. The new initiative 'IT Future of Medicine' aims at driving this development even further and integrates not only molecular data (especially genomic information), but also anatomical, physiological, environmental, and lifestyle data in a predictive model approach-the 'virtual patient'-that will allow the clinician or the general practitioner to predict and anticipate the optimal treatment for the individual patient. The application of the virtual patient model will allow truly personalized medicine. PMID- 23463360 TI - Metal uptake and nanoparticle synthesis in hairy root cultures. AB - : Hairy roots are a convenient experimental tool for investigating the interactions between plant cells and metal ions. Hairy roots of species capable of hyperaccumulating Cd and Ni have been applied to investigate heavy metal tolerance in plants; hairy roots of nonhyperaccumulator species have also been employed in metal uptake studies. Furnace treatment of hairy root biomass containing high concentrations of Ni has been used to generate Ni-rich bio-ore suitable for metal recovery in phytomining applications. Hairy roots also have potential for biological synthesis of quantum dot nanocrystals. As plant cells intrinsically provide the confined spaces needed to limit the size of nanocrystals, hairy roots cultured in bioreactors under controlled conditions are a promising vehicle for the manufacture of peptide-capped semiconductor quantum dots. PMID- 23463361 TI - Female and male victims of violence in an urban emergency room--prevalence, sociodemographic characteristics, alcohol intake, and injury patterns. AB - BACKGROUND: Violence as well as alcohol-attributable injuries is a dominant public health issue worldwide. Victims, being injured, frequently visit emergency rooms (ER). METHODS: We interviewed all the patients seeking help in an urban emergency room reporting being victims of violent behavior over a period of 3 months (from November 2011 to January 2012). RESULTS: Our results showed that 1 out of 23 patients seeking help in our ER was due to forcible means. A total of 15 % of all victims reported domestic violence (75 % women) and others (90 % men) reported brawl as the reason for seeking help. Overall, 80 % of the victims were younger than 40 years. In case of domestic violence, two-third (only women) reported that they were hurt by their intimate partner. At total of 50 % were treated for head wounds and 35 % had injuries of their extremities. One-third of the patients were alcoholized. The victims of brawls mainly suffer from head injuries (69 %). Half of this patient group was under the influence of alcohol. CONCLUSIONS: To conclude, victims of violence seek for help in emergency rooms daily. Alcohol consumption is the main factor for violent behavior. Public health programs to prevent alcohol related violence and therefore, alcohol-attributable injuries have to be implemented. Addressing the need to enhance the awareness of the health professionals has to be an imperative. PMID- 23463362 TI - Determination of nitrite and glucose in water and human urine with light-up chromogenic response based on the expeditious oxidation of 3,3',5,5' tetramethylbenzidine by peroxynitrous acid. AB - Contamination of food and drinking water by dangerous levels of nitrite has always been of strong concern and toxicity of this inorganic anion calls for convenient detection methods. Although some visible approaches were developed to deal with this problem, using environmentally incompatible organic reagents or functionalized nanoparticles may greatly limit their wide applications. In this article, we report a method to visibly detect nitrite in less than 1 min at room temperature. The efficacy of the method relies on a specific reaction of HNO2 with H2O2 to produce peroxynitrous acid (HOONO), which oxidizes colorless 3,3',5,5'-tetramethylbenzidine (TMB) to its golden yellow diimine product in seconds, with the regeneration of HNO2. Therefore, HNO2 can be regarded as a catalyst for the oxidation of TMB by H2O2. Because color visualization of the TMB H2O2 system (system I) is dependent upon the concentration of HNO2, it offers a unique avenue for the determination of nitrite. With this method, 1 MUM of nitrite could be detected by the perception of yellow color in solution and less than 0.5 MUM of nitrite be quantified with a spectrophotometer. The limit of detection (LOD) was 0.1 MUM (S/N = 3). More interestingly, we found that the TMB HNO2 system (system II) could be reversibly designed to detect H2O2 and then glucose with the help of glucose oxidase. We evaluated the applicability of the TMB-HOONO platform in the determination of nitrite in drinking water and urinary glucose, obtaining satisfactory results. Being sensitive, selective, time efficient, and cost-effective, the two methods derived from the three-component reaction platform are feasible for quantification of nitrite and glucose in routine laboratory practice or rapid assay outside the laboratory. PMID- 23463363 TI - Emergent properties and trends of a new class of carbon nanocomposites: graphene nanoribbons encapsulated in a carbon nanotube. AB - Using density functional theory calculations, we show that recently synthesized carbon nanocomposites of graphene nanoribbons encapsulated in a carbon nanotube (GNR@CNT) possess rich emergent electronic and magnetic properties that offer new functionality and tunability and display systematic trends that are sensitive to the matchup of constitutive GNRs and CNTs. The encapsulation of H-passivated GNRs in metallic armchair CNTs always leads to a metallic complex while those in semiconducting zigzag CNTs can be either metallic or semiconducting depending on the chirality of GNRs. In particular, the complex of armchair GNRs in a zigzag CNT exhibits an oscillating electronic band gap with changing GNR width and a well-separated spatial distribution of electrons and holes localized in the CNT and GNR components, respectively. When bare large zigzag GNRs are encapsulated in an armchair CNT, the resulting complex shows strong structural stability and enhanced magnetism and, most interestingly, such GNR@CNT configurations can be tuned to be metallic or semiconducting depending on relative bond position and magnetic order. These results offer key insights for understanding and predicting emergent properties of GNR@CNT, which establish a roadmap for guiding design and synthesis of specific nanocomposite configurations with tailor-made properties for nanoelectronic, photovoltaic and spintronic applications. PMID- 23463364 TI - Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. AB - Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-gamma) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN-gamma production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. CONCLUSION: Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity. PMID- 23463365 TI - Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation. AB - Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100beta, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas. PMID- 23463366 TI - Excessive motor overflow reveals abnormal inter-hemispheric connectivity in Friedreich ataxia. AB - This study sought to characterise force variability and motor overflow in 12 individuals with Friedreich ataxia (FRDA) and 12 age- and gender-matched controls. Participants performed a finger-pressing task by exerting 30 and 70 % of their maximum finger force using the index finger of the right and left hand. Control of force production was measured as force variability, while any involuntary movements occurring on the finger of the other, passive hand, was measured as motor overflow. Significantly greater force variability in individuals with FRDA compared with controls is indicative of cortico-cerebellar disruption affecting motor control. Meanwhile, significantly greater motor overflow in this group provides the first evidence of possible abnormal inter hemispheric activity that may be attributable to asymmetrical neuronal loss in the dentate nucleus. Overall, this study demonstrated a differential engagement in the underlying default processes of the motor system in FRDA. PMID- 23463367 TI - Postradiation lower motor neuron syndrome: case series and literature review. AB - A variety of neurological syndromes has been described after irradiation of the distal spinal cord and cauda equina, mainly as treatment for testicular cancer and lymphoma. One of these syndromes is a rare lower motor neuron syndrome, manifested by flaccid paraparesis. Medical files of patients with postradiation lower motor neuron syndrome treated in our neuromuscular clinic from 2005 to 2012 were reviewed. The diagnosis was based on past irradiation of the distal spinal cord and cauda equina, slowly progressive lower limb weakness, characteristic electrophysiological studies, and no alternative diagnosis. In addition, a systematic review of the literature on similar cases was performed using PUBMED. We identified five patients with postradiation lower motor neuron syndrome in our clinic charts. Three of them were irradiated due to seminoma, and the other two due to lymphoma. 45 additional similar cases were found in a literature search, mainly male (89 %), with testicular cancer (67 %), irradiated at mean age of 33 years, with an average irradiation dose of 5,225 cGy (range 3,000-14,600), and a latency period between irradiation and symptoms onset ranging from 3 months to 27 years (average 9 years). Magnetic resonance imaging was done only in few, showing gadolinium enhancement of the cauda equina in close to half of them (7/16). Our patients and those previously described in the literature form a distinct clinical and electrophysiological syndrome that might be more frequent then previously expected, and should be not overlooked. PMID- 23463368 TI - Effects of pharmacological concentrations of dietary zinc oxide on growth of post weaning pigs: a meta-analysis. AB - Pharmacological dietary zinc (Zn) concentrations of 1,000 to 3,000 mg/kg diet from Zn oxide have been found to increase growth in post-weaning pigs. However, results were inconsistent among studies. A frequentist meta-analysis, in which effects were numerically described with standardized effect sizes (Hedges's g), was conducted in order to identify and quantify the responses in average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio (G/F) in post-weaning pigs upon dietary Zn supplementation from Zn oxide. The inability of independent continuous variables to explain significant heterogeneity obtained with fixed effect models necessitated the use of random effects models to calculate summary statistics. Dietary Zn supplementation increased (P < 0.05) ADG (mean effect size = 1.086, 95 % confidence intervals = 0.905-1.266, 26 studies, 72 comparisons), ADFI (mean effect size = 0.794, 95 % confidence intervals = 0.616-0.971, 25 studies, 71 comparisons), and G/F (mean effect size = 0.566, 95 % confidence intervals = 0.422-0.710, 24 studies, 70 comparisons). Zinc oxide provided a feasible alternative to in-feed antibiotics to improve growth in post weaning pigs, and its reduction in diets due to potential environmental pollution will have to be negated by alternative feed additives and management strategies in order to prevent economic losses. PMID- 23463369 TI - Feasibility of following up gamma-hydroxybutyric acid concentrations in sodium oxybate (Xyrem(r))-treated narcoleptic patients using dried blood spot sampling at home: an exploratory study. AB - BACKGROUND: Gamma-hydroxybutyric acid (GHB), well known as a party drug, especially in Europe, is also legally used (sodium oxybate, Xyrem((r))) to treat a rare sleep disorder, narcolepsy with cataplexy. This exploratory study was set up to measure GHB concentrations in dried blood spots (DBS) collected by narcoleptic patients treated with sodium oxybate. Intra- and inter-individual variation in clinical effects following sodium oxybate administration has been reported. The use of DBS as a sampling technique, which is stated to be easy and convenient, may provide a better insight into GHB concentrations following sodium oxybate intake in a real-life setting. OBJECTIVE: The aim was twofold: evaluation of the applicability of a recently developed DBS-based gas chromatography-mass spectrometry (GC-MS) method, and of the feasibility of the sampling technique in an ambulant setting. METHODS: Seven narcoleptic patients being treated with sodium oxybate at the Department for Respiratory Diseases of Ghent University Hospital were asked to collect DBS approximately 20 min after the first sodium oxybate (Xyrem((r)); UCB Pharma Ltd, Brussels, Belgium) intake on a maximum of 7 consecutive days. Using an automatic lancet, patients pricked their fingertip and, after wiping off the first drop of blood, subsequent drops were collected on a DBS card. The DBS cards were sent to the laboratory by regular mail and, before analysis, were visually inspected to record DBS quality (large enough, symmetrically spread on the filter paper with even colouration on both sides of the filter paper). RESULTS: Of the seven patients, three patients succeeded to collect five series of DBS, one patient decided to cease participation because of nausea, one was lost during follow-up and two patients started falling asleep almost immediately after the intake of sodium oxybate. Analysing the DBS in duplicate resulted in acceptable within-DBS card precision. DBS with acceptable quality were obtained by patients without supervision. CONCLUSION: Our results demonstrate the acceptable precision of the complete procedure, from sampling at home to quantitative analysis in the laboratory. Given the intra- and inter individual variability in clinical effects seen with sodium oxybate, the easy adaptation of DBS sampling opens the possibility of following up GHB concentrations in patients in real-life settings in future studies. PMID- 23463371 TI - Glucagonlike Peptide 1-based drugs and pancreatitis: clarity at last, but what about pancreatic cancer? PMID- 23463370 TI - Plant lipidomics based on hydrophilic interaction chromatography coupled to ion trap time-of-flight mass spectrometry. AB - Plants synthesize a wide range of hydrophobic compounds, generally known as lipids. Here, we report an application of liquid chromatography ion trap time-of flight mass spectrometry (LC-IT-TOF-MS) for plant lipidomics. Using hydrophilic interaction chromatography (HILIC) for class separation, typical membrane lipids including glycerolipids, steryl glucosides and glucosylceramides, and hydrophobic plant secondary metabolites such as saponins were analyzed simultaneously. By this method, we annotated approximately 100 molecules from Arabidopsis thaliana. To demonstrate the application of this method to biological study, we analyzed Arabidopsis mutant trigalactosyldiacylglycerol3 (tgd3), which has a complex metabolic phenotype including the accumulation of unusual forms of galactolipids. Lipid profiling by LC-MS revealed that tgd3 accumulated an unusual form of digalactosyldiacylglycerol, annotated as Gal(beta1 -> 6)betaGalDG. The compositional difference between normal and unusual forms of digalactosyldiacylglycerol was detected by this method. In addition, we analyzed well-known Arabidopsis mutants ats1-1, fad6-1, and fad7-2, which are also disrupted in lipid metabolic genes. Untargeted lipidome analysis coupled with multivariate analysis clearly discriminated the mutants and their distinctive metabolites. These results indicated that HILIC-MS is an efficient method for plant lipidomics. PMID- 23463372 TI - Laccase production by Coriolopsis caperata RCK2011: optimization under solid state fermentation by Taguchi DOE methodology. AB - Laccase production by Coriolopsis caperata RCK2011 under solid state fermentation was optimized following Taguchi design of experiment. An orthogonal array layout of L18 (2(1) * 3(7)) was constructed using Qualitek-4 software with eight most influensive factors on laccase production. At individual level pH contributed higher influence, whereas, corn steep liquor (CSL) accounted for more than 50% of the severity index with biotin and KH2PO4 at the interactive level. The optimum conditions derived were; temperature 30 degrees C, pH 5.0, wheat bran 5.0 g, inoculum size 0.5 ml (fungal cell mass = 0.015 g dry wt.), biotin 0.5% w/v, KH2PO4 0.013% w/v, CSL 0.1% v/v and 0.5 mM xylidine as an inducer. The validation experiments using optimized conditions confirmed an improvement in enzyme production by 58.01%. The laccase production to the level of 1623.55 Ugds(-1) indicates that the fungus C. caperata RCK2011 has the commercial potential for laccase. PMID- 23463373 TI - Blood perfusion and bone formation before and after minimally invasive periacetabular osteotomy analysed by Positron Emission Tomography combined with Computed Tomography. AB - PURPOSE: Sufficient blood perfusion is essential for successful bone healing after periacetabular osteotomy (PAO). The purpose of this study was to quantify blood perfusion and bone formation before and after PAO analysed by positron emission tomography (PET) combined with computed tomography (CT). METHODS: Twelve dysplastic patients (nine women) were included consecutively in the study and all were operated upon by the senior author (KS). Median age was 33 (23-55) years. Initially, two patients were PET scanned in a pilot study to test our models for calculation of the physiological parameters. The following ten patients had their hip joints PET/CT scanned immediately before PAO and three to four weeks after. Oxygen-15-water was used to quantify blood perfusion and Flourine-18-fluoride was used to produce quantitative images interpreted as new bone formation in the acetabular fragment. RESULTS: The blood perfusion of the operated acetabulum before surgery was 0.07 +/- 0.02 ml/min/ml, and after surgery 0.19 +/- 0.03 ml/min/ml (p = 0.0003). Blood perfusion of the non-operated acetabulum was 0.07 +/- 0.02 ml/min/ml before PAO and 0.07 +/- 0.02 ml/min/ml after surgery (p = 0.47). The fluoride-clearance per volume bone of the operated acetabulum was 0.02 +/- 0.01 ml/min/ml preoperatively, and 0.06 +/- 0.01 ml/min/ml postoperatively (p = 0.0005). Fluoride-clearance of the non-operated acetabulum was 0.01 +/- 0.01 ml/min/ml before PAO and 0.02 +/- 0.01 ml/min/ml after PAO (p = 0.49). CONCLUSION: Blood perfusion and new bone formation increased significantly in the acetabular fragment. Thus, the results of this study do not support the concern about surgically damaged vascularity after PAO. PMID- 23463374 TI - Monitoring the HIV-1 integrase enzymatic activity using atomic force microscopy in a 2LTR system. AB - Integration of the HIV cDNA into the host chromosome is a key event in the viral replication cycle. It is mediated by the viral integrase (IN) enzyme, which is an attractive anti-HIV drug target. Here we present the first AFM imaging of IN mediated DNA integration products in a two-LTR system. PMID- 23463375 TI - Correlates of elevated distress thermometer scores in breast cancer patients. AB - PURPOSE: Distress is prevalent in breast cancer patients and can be detrimental to quality of life, performance status, treatment adherence, and satisfaction with medical care. The National Comprehensive Cancer Network developed the distress thermometer (DT) as a self-assessment tool for screening distress in cancer patients. Given time and financial constraints, it is important to refine screening criteria to identify patients with elevated risk for distress. In this study, we identify clinical and epidemiological factors that are associated with an increased likelihood of elevated DT scores (>= 4 and >= 7). METHODS: We assessed 229 female patients with the DT at their initial consultation for breast cancer at the Huntsman Cancer Hospital between September 2007 and December 2008. Descriptive statistics and logistic regression models were used to analyze DT and patient data. RESULTS: Patients undergoing their initial distress thermometer screening within 30 days of receiving a diagnosis of breast cancer had the highest likelihood of scoring >= 4 and >= 7 on the DT screening tool. Emotional and physical concerns were associated with scores >= 4 and scores >= 7. Spiritual concerns became significant in patients reporting scores >= 7. Patients who were non-Caucasian, unemployed, had a prior history of depression, presented for recurrent disease, or who had been recently diagnosed had a higher likelihood of scores >= 4 and scores >= 7. CONCLUSIONS: Four groups of patients should be targeted for aggressive screening; patients with a prior diagnosis of depression, patients presenting with recurrent disease, unemployed patients, and non Caucasian patients. Interventions should address physical, emotional, and spiritual concerns. PMID- 23463376 TI - The motivation to reproject gated blood pool SPECT data as planar data. PMID- 23463377 TI - Raman microspectroscopy and vibrational sum frequency generation spectroscopy as probes of the bulk and surface compositions of size-resolved sea spray aerosol particles. AB - Sea spray aerosol (SSA) represents one of the largest aerosol components in our atmosphere. SSA plays a major role in influencing climate; however the overall impacts remain poorly understood due to the overall chemical complexity. SSA is comprised of a mixture of inorganic and organic components in varying proportions that change as a function of particle size and seawater composition. In this study, nascent SSA particles were produced using breaking waves, resulting in compositions and sizes representative of the open ocean. The composition of individual SSA particles ranging in size from ca. 0.15 to 10 MUm is measured using Raman microspectroscopy, while the interfacial composition of collections of size-resolved particles is probed by sum frequency generation (SFG). Raman spectra of single particles have bands in the 980 to 1030 cm(-1) region associated with the symmetric stretch of the sulfate anion, the 2800 to 3000 cm( 1) region associated with carbon-hydrogen stretches, and from 3200-3700 cm(-1) associated with the oxygen-hydrogen stretches of water. The relative intensities of these features showed a strong dependence on particle size. In particular, submicrometer particles exhibited a larger amount of organic matter compared to supermicrometer particles. However, for external surfaces of homogeneous SSA particles (i.e. particles without a solid inclusion), and also the interfaces of mixed-phase particles, there was a strong SFG response in the aliphatic C-H stretching region for both sub- and supermicrometer particles. This finding suggests that organic material present in supermicrometer particles primarily resides at the interface. The presence of methylene contributions in the SFG spectra indicated disordered alkyl chains, in contrast to what one might expect for a surfactant layer on a sea salt particle. Changes in peak frequencies and relative intensities in the C-H stretching region are seen for some particles after the addition of bacteria, phytoplankton, and growth medium to the seawater. This study provides new insights into the bulk and surface composition of SSA particles and represents a step forward in our understanding of this globally abundant aerosol. It also provides insights into the development of model systems for SSA that may more accurately represent the organic layer at the surface. PMID- 23463378 TI - Reduction of cirrhosis and hepatocellular carcinoma with antiviral therapy in chronic hepatitis B. PMID- 23463379 TI - Ca2+/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor kappa B kinase complex activation in Helicobacter pylori infection. AB - Helicobacter pylori, a class I carcinogen, induces a proinflammatory response by activating the transcription factor nuclear factor-kappa B (NF-kappaB) in gastric epithelial cells. This inflammatory condition could lead to chronic gastritis, which is epidemiologically and biologically linked to the development of gastric cancer. So far, there exists no clear knowledge on how H. pylori induces the NF kappaB-mediated inflammatory response. In our study, we investigated the role of Ca(2+) /calmodulin-dependent kinase II (CAMKII), calmodulin, protein kinases C (PKCs) and the CARMA3-Bcl10-MALT1 (CBM) complex in conjunction with H. pylori induced activation of NF-kappaB via the inhibitor of nuclear factor-kappa B kinase (IKK) complex. We use specific inhibitors and/or RNA interference to assess the contribution of these components. Our results show that CAMKII and calmodulin contribute to IKK complex activation and thus to the induction of NF kappaB in response to H. pylori infection, but not in response to TNF-alpha. Thus, our findings are specific for H. pylori infected cells. Neither the PKCs alpha, delta, theta, nor the CBM complex itself is involved in the activation of NF-kappaB by H. pylori. The contribution of CAMKII and calmodulin, but not PKCs/CBM to the induction of an inflammatory response by H. pylori infection augment the understanding of the molecular mechanism involved and provide potential new disease markers for the diagnosis of gastric inflammatory diseases including gastric cancer. PMID- 23463380 TI - Attentional biases and memory for emotional stimuli in men and male rhesus monkeys. AB - We examined attentional biases for social and non-social emotional stimuli in young adult men and compared the results to those of male rhesus monkeys (Macaca mulatta) previously tested in a similar dot-probe task (King et al. in Psychoneuroendocrinology 37(3):396-409, 2012). Recognition memory for these stimuli was also analyzed in each species, using a recognition memory task in humans and a delayed non-matching-to-sample task in monkeys. We found that both humans and monkeys displayed a similar pattern of attentional biases toward threatening facial expressions of conspecifics. The bias was significant in monkeys and of marginal significance in humans. In addition, humans, but not monkeys, exhibited an attentional bias away from negative non-social images. Attentional biases for social and non-social threat differed significantly, with both species showing a pattern of vigilance toward negative social images and avoidance of negative non-social images. Positive stimuli did not elicit significant attentional biases for either species. In humans, emotional content facilitated the recognition of non-social images, but no effect of emotion was found for the recognition of social images. Recognition accuracy was not affected by emotion in monkeys, but response times were faster for negative relative to positive images. Altogether, these results suggest shared mechanisms of social attention in humans and monkeys, with both species showing a pattern of selective attention toward threatening faces of conspecifics. These data are consistent with the view that selective vigilance to social threat is the result of evolutionary constraints. Yet, selective attention to threat was weaker in humans than in monkeys, suggesting that regulatory mechanisms enable non-anxious humans to reduce sensitivity to social threat in this paradigm, likely through enhanced prefrontal control and reduced amygdala activation. In addition, the findings emphasize important differences in attentional biases to social versus non-social threat in both species. Differences in the impact of emotional stimuli on recognition memory between monkeys and humans will require further study, as methodological differences in the recognition tasks may have affected the results. PMID- 23463381 TI - Platinum nanostructures via self-assembly of an amyloid-like peptide: a novel electrocatalyst for the oxygen reduction. AB - An aniline-GGAAKLVFF peptide (AFP) was prepared by solid-phase synthesis. The peptide can readily self-assemble into fibrils. Platinum nanoparticles (Pt NPs) were directly immobilized on the surface of the AFP fibrils via electrostatic interaction. Compared to other currently available techniques for the fabrication of metal-peptide fibrils, the noncovalent functionalization strategy is able to deposit nanoparticles on peptide fibrils with different morphologies and high metal loading, which is important for applications in catalysis, electronic materials and other corresponding fields. The Pt-AFP fibrils were employed to modify the electrode, which exhibits high electrocatalytic activities towards oxygen reduction. Thus, the Pt-AFP fibrils hold great potential for polymer electrolyte fuel cells and other electrochemical applications. PMID- 23463382 TI - Molecular cloning and expression of alpha-globin and beta-globin genes from crocodile (Crocodylus siamensis). AB - The first report of complete nucleotide sequences for alpha- and beta-globin chains from the Siamese hemoglobin (Crocodylus siamensis) is given in this study. The cDNAs encoding alpha- and beta-globins were cloned by RT-PCR using the degenerate primers and by the rapid amplification of cDNA ends method. The full length alpha-globin cDNA contains an open reading frame of 423 nucleotides encoding 141 amino acid residues, whereas the beta-globin cDNA contains an open reading frame of 438 nucleotides encoding 146 amino acid residues. The authenticity of both alpha- and beta-globin cDNA clones were also confirmed by the heterologous expression in Escherichia coli (E. coli). This is the first time that the recombinant C. siamensis globins were produced in prokaryotic system. Additionally, the heme group was inserted into the recombinant proteins and purified heme-bound proteins were performed by affinity chromatography using Co(2+)-charged Talon resins. The heme-bound proteins appeared to have a maximum absorbance at 415 nm, indicated that the recombinant proteins bound to oxygen and formed active oxyhemoglobin (HbO2). The results indicated that recombinant C. siamensis globins were successfully expressed in prokaryotic system and possessed an activity as ligand binding protein. PMID- 23463384 TI - [Retroperitoneal mass]. AB - Castleman's disease is presented in the following article in more detail using the case report of a 55-year-old patient with abdominal pain without any significant pre-existing medical conditions. A computer tomography of the abdomen demonstrated a retroperitoneal tumor in the lower abdomen below the aortic bifurcation. Because malignancy of the tumor could not be excluded, surgical extirpation was performed without complications. Histopathological examination revealed the diagnosis of a localized castleman's tumor. Castleman's disease is a rare disease of the lymph nodes of unknown etiology. In the prognosis, benign forms can be distinguished from malignant forms. PMID- 23463385 TI - Protective effect of L-ascorbic acid on nickel induced pulmonary nitrosative stress in male albino rats. AB - Nickel sulfate stimulates inducible nitric oxide synthase (i-NOS) and increases serum nitric oxide concentration by overproduction of reactive nitrogen species due to nitrosative stress. The present study was undertaken to assess possible protective role of L-ascorbic acid as an antioxidant against nickel induced pulmonary nitrosative stress in male albino rats. We studied the effect of the simultaneous treatment with L-ascorbic acid (50 mg/100 g b. wt.; orally) and nickel sulfate (2.0 mg/100 g b. wt.; i.p.) on nitric oxide synthesis by quantitative evaluation of serum i-NOS activities, serum and lung nitric oxide, L ascorbic acid and protein concentrations of Wistar strain male albino rats. We have further studied histopathological changes in lung tissue after nickel sulfate treatment along with simultaneous exposure of L-ascorbic acid. Nickel sulfate treatment significantly increased the serum i-NOS activity, serum and pulmonary nitric oxide concentration and decreased body weight, pulmonary somatic index, serum and lung L-ascorbic acid and protein concentration as compared to their respective controls. Histopathological changes induced by nickel sulfate showed loss of normal alveolar architecture, inflammation of bronchioles, infiltration of inflammatory cells and patchy congestion of alveolar blood vessels. The simultaneous administration of L-ascorbic acid and nickel sulfate significantly improved all the above biochemical parameters along with histopathology of lung tissues of rats receiving nickel sulfate alone. The study clearly showed a protective role of L-ascorbic acid against nickel induced nitrosative stress in lung tissues. PMID- 23463383 TI - A dynamic model of the proteins that form the initial iron-sulfur cluster biogenesis machinery in yeast mitochondria. AB - The assembly of iron-sulfur clusters (ISCs) in eukaryotes involves the protein Frataxin. Deficits in this protein have been associated with iron inside the mitochondria and impair ISC biogenesis as it is postulated to act as the iron donor for ISCs assembly in this organelle. A pronounced lack of Frataxin causes Friedreich's Ataxia, which is a human neurodegenerative and hereditary disease mainly affecting the equilibrium, coordination, muscles and heart. Moreover, it is the most common autosomal recessive ataxia. High similarities between the human and yeast molecular mechanisms that involve Frataxin have been suggested making yeast a good model to study that process. In yeast, the protein complex that forms the central assembly platform for the initial step of ISC biogenesis is composed by yeast frataxin homolog, Nfs1-Isd11 and Isu. In general, it is commonly accepted that protein function involves interaction with other protein partners, but in this case not enough is known about the structure of the protein complex and, therefore, how it exactly functions. The objective of this work is to model the protein complex in order to gain insight into structural details that end up with its biological function. To achieve this goal several bioinformatics tools, modeling techniques and protein docking programs have been used. As a result, the structure of the protein complex and the dynamic behavior of its components, along with that of the iron and sulfur atoms required for the ISC assembly, have been modeled. This hypothesis will help to better understand the function and molecular properties of Frataxin as well as those of its ISC assembly protein partners. PMID- 23463386 TI - An error analysis perspective for patient alignment systems. AB - PURPOSE: This paper analyses the effects of error sources which can be found in patient alignment systems. As an example, an ultrasound (US) repositioning system and its transformation chain are assessed. The findings of this concept can also be applied to any navigation system. METHODS AND MATERIALS: In a first step, all error sources were identified and where applicable, corresponding target registration errors were computed. By applying error propagation calculations on these commonly used registration/calibration and tracking errors, we were able to analyse the components of the overall error. Furthermore, we defined a special situation where the whole registration chain reduces to the error caused by the tracking system. Additionally, we used a phantom to evaluate the errors arising from the image-to-image registration procedure, depending on the image metric used. We have also discussed how this analysis can be applied to other positioning systems such as Cone Beam CT-based systems or Brainlab's ExacTrac. RESULTS: The estimates found by our error propagation analysis are in good agreement with the numbers found in the phantom study but significantly smaller than results from patient evaluations. We probably underestimated human influences such as the US scan head positioning by the operator and tissue deformation. Rotational errors of the tracking system can multiply these errors, depending on the relative position of tracker and probe. CONCLUSIONS: We were able to analyse the components of the overall error of a typical patient positioning system. We consider this to be a contribution to the optimization of the positioning accuracy for computer guidance systems. PMID- 23463387 TI - A Boolean view separates platelet activatory and inhibitory signalling as verified by phosphorylation monitoring including threshold behaviour and integrin modulation. AB - Platelets are critical for haemostasis and blood clotting. However, since under normal circumstances blood should flow without clotting, its function is regulated via a complex interplay of activating and inhibiting signal transduction pathways. Understanding this network is crucial for treatment of cardiovascular and bleeding diseases. Detailed protein interaction and phosphorylation data are explored to establish a simplified Boolean model of the central platelet cascades. We implemented the model by means of CellNetAnalyzer and showed how different signalling events coalesce into a fully activated system state. Furthermore, we examined the networks' inherent threshold behaviour using the semi-quantitative modelling software SQUAD. Finally, predictions are verified monitoring phosphorylations which mark different activation phases as modelled. The model can also be applied to simulate different pharmacological conditions as they modify node activity (aspirin, clopidogrel, milrinon, iloprost, combination) and is available for further studies. It agrees well with observations. Activatory pathways are diversified to cope with complex environmental conditions. Platelet activation needs several activation steps to integrate over different network subsets, as they are formed by the interplay of activating kinases, calcium mobilization, and the inhibiting cAMP-PKA system. System stability analysis shows two phases: a sub-threshold behaviour, characterized by integration over different activatory and inhibitory conditions, and a beyond threshold phase, represented by competition and shutting down of counter regulatory pathways. The integrin network and Akt-protein are critical for stable effector response. Dynamic threshold-analysis reveals a dependency of the relative activating input strength necessary to irreversibly engage the system from the absolute inhibitory signal strength. PMID- 23463388 TI - Development of a ligase detection reaction/CGE method using a LIF dual-channel detection system for direct identification of allelic composition of mutated DNA in a mixed population of excess wild-type DNA. AB - We developed an inexpensive LIF dual-channel detection system and applied it to a ligase detection reaction (LDR)/CGE method to identify the allelic composition of low-abundance point mutations in a large excess of wild-type DNA in a single reaction with a high degree of certainty. Ligation was performed in a tube with a nonlabeled common primer and multiplex discriminating primers, each labeled with a different standard fluorophore. The discriminating primers were directed against three mutant variations in codon 12 of the K-ras oncogene that have a high diagnostic value for colorectal cancer. LDR products generated from a particular K-ras mutation through successful ligation events were separated from remaining discriminating primers by CGE, followed by LIF detection using the new system, which consists of two photomultiplier tubes, each with a unique optical filter. Each fluorophore label conjugated to the corresponding LDR product produced a distinct fluorescence signal intensity ratio from the two detection channels, allowing spectral discrimination of the three labels. The ability of this system to detect point mutations in a wild-type sequence-dominated population, and to disclose their allelic composition, was thus demonstrated successfully. PMID- 23463389 TI - Effects of protease-activated receptors (PARs) on intracellular calcium dynamics of acinar cells in rat lacrimal glands. AB - Protease-activated receptors (PARs) represent a novel class of seven transmembrane domain G-protein coupled receptors, which are activated by proteolytic cleavage. PARs are present in a variety of cells and have been prominently implicated in the regulation of a number of vital functions. Here, lacrimal gland acinar cell responses to PAR activation were examined, with special reference to intracellular Ca(2+) concentration ([Ca(2+)]i) dynamics. In the present study, detection of acinar cell mRNA specific to known PAR subtypes was determined by reverse transcriptase polymerase chain reaction. Only PAR2 mRNA was detected in acinar cells of lacrimal glands. Both trypsin and a PAR2 activating peptide (PAR2-AP), SLIGRL-NH2, induced an increase in [Ca(2+)]i in acinar cells. The removal of extracellular Ca(2+) and the use of Ca(2+) channel blockers did not inhibit PAR2-AP-induced [Ca(2+)]i increases. Furthermore, U73122 and xestospongin C failed to inhibit PAR2-induced increases in [Ca(2+)]i. The origin of the calcium influx observed after activated PAR2-induced Ca(2+) release from intracellular Ca(2+) stores was also evaluated. The NO donor, GEA 3162, mimicked the effects of PAR2 in activating non-capacitative calcium entry (NCCE). However, both calyculin A (100 nM) and a low concentration of Gd(3+) (5 MUM) did not completely block the PAR2-AP-induced increase in [Ca(2+)]i. These findings indicated that PAR2 activation resulted primarily in Ca(2+) mobilization from intracellular Ca(2+) stores and that PAR2-mediated [Ca(2+)]i changes were mainly independent of IP3. RT-PCR indicated that TRPC 1, 3 and 6, which play a role in CCE and NCCE, are expressed in acinar cells. We suggest that PAR2-AP differentially regulates both NCCE and CCE, predominantly NCCE. Finally, our results suggested that PAR2 may function as a key receptor in calcium-related cell homeostasis under pathophysiological conditions such as tissue injury or inflammation. PMID- 23463390 TI - Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the Jordanian Arab population. AB - Autoimmune thyroid diseases (AITDs) (Hashimoto thyroiditis and Graves' disease) are complex polygenic disorders with multiple genes thought to contribute to the risk of disease. The contribution of these genes differs by different populations. The PTPN22 gene is reported to be associated with multiple autoimmune diseases, but results of association are conflicting in different populations. The SMOC2 gene is reported to be associated with families with autoimmune vitiligo that had other autoimmunities including thyroid disease. The study aims to investigate the association of PTPN22 and SMOC2 single nucleotide polymorphisms with thyroid disease in a cohort of Jordanian patients. We collected blood samples from 204 thyroid patients and 216 normal controls. We used PCR-RFLP to genotype rs2476601 in PTPN22 and rs13208776 in SMOC2 genes. Both of the SNPS did not show significant association with thyroid disease, even after stratification according to subtype of disease (Hashimoto thyroiditis and Graves' disease) or gender. We reanalyzed SMOC2 SNP using a dominant and recessive models and we got marginal significance when using a dominant model with female-only patients (P = 0.052). PTPN22 SNP did not show association with autoimmune thyroid disease in our patient cohort. This may be due to the low frequency of this SNP in the Jordanian population. SMOC2 SNP, on the other hand, may play a role in AITD susceptibility as a dominant polymorphism. Additional samples might be needed to confirm or exclude association of SMOC2 with AITD. PMID- 23463391 TI - Load-collapse-release cascades of amphiphilic guest molecules in charged dendronized polymers through spatial separation of noncovalent forces. AB - The ability to pack guest molecules into charged dendronized polymers (denpols) and the possibility to release these guest molecules from subsequently densely aggregated denpols in a load-collapse-release cascade is described. Charged denpols, which constitute molecular objects with a persistent, well-defined envelope and interior, are capable of incorporating large amounts of amphiphilic guest molecules. Simultaneously, multivalent ions can coordinate to the surfaces of charged denpols, leading to counterion-induced aggregation of the already guest-loaded host structures. Thus, although the local guest concentration in denpol-based molecular transport might already be initially high due to the dense guest packing inside the dendritic denpol scaffolding, the "local" guest concentration can nonetheless be further increased by packing (through aggregation) of the host-guest complexes themselves. Subsequent release of guest compounds from densely aggregated dendronized polymers is then possible (e.g., through increasing the solution concentration of imidazolium-based ions). Augmented with this release possibility, the concept of twofold packing of guests, firstly through hosting itself and secondly through aggregation of the hosts, gives rise to a load-collapse-release cascade that strikingly displays the high potential of dendronized macromolecules for future molecular transport applications. PMID- 23463393 TI - Conformationally restricted pyrrolidines by intramolecular [2+2] photocycloaddition reactions. AB - Intramolecular [2+2] photocycloaddition reactions of diversely substituted N-Boc protected 4-(allylaminomethyl)-2(5H)-furanones resulted in rigid products (53 75%) with three spatially defined positions for further functionalisation. PMID- 23463392 TI - What are the exercise-based injury prevention recommendations for recreational alpine skiing and snowboarding? A systematic review. AB - BACKGROUND: Skiing and snowboarding are two activities that significantly contribute to the total number of sports-related injuries reported per year. Strength, endurance and cardiovascular fitness are central components in sports injury prevention. Providing exercises and training recommendations specific to recreational skiers and snowboarders is important in both injury prevention and reducing the prevalence and cost associated with alpine winter sports injuries. OBJECTIVE: The aim of this paper was to systematically review the literature for injury prevention recommendations specific to recreational alpine skiers and snowboarders. The focus was to discern recommendations that targeted physical fitness, exercise and/or training in the prevention of musculoskeletal injuries in these two sports. DATA SOURCES: Fourteen electronic databases were searched in October 2011 using relevant MeSH terms and key words. STUDY SELECTION: Articles were included if they addressed injury prevention, recreational alpine skiing or snowboarding and musculoskeletal injuries. Only original research articles published in peer-reviewed journals, and in the English-language, were reviewed. Articles on elite athletes were excluded. STUDY APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers quality assessed articles meeting inclusion criteria using a modified version of the Downs and Black Quality Assessment Checklist. Data on study population, study design, study location and injury prevention recommendation(s) were extracted from articles using a standard form and subsequently categorized to facilitate data synthesis. RESULTS: A total of 30 articles met the inclusion criteria and were reviewed, having an average +/- standard deviation quality score of 72% +/- 17% (range: 23-100 %). Overall, 80 recommendations for the prevention of musculoskeletal injuries in recreational alpine skiers and snowboarders were identified and classified into five main groups: equipment (n = 24), education and knowledge (n = 11), awareness and behaviour (n = 15), experience (n = 10) and third-party involvement (n = 20). No recommendations pertained to physical fitness, exercise and/or training per se, or its role in preventing injury. LIMITATIONS: A comprehensive meta-analysis was not possible because several articles did not report data in sufficient detail. CONCLUSIONS: The importance of targeting physical fitness in injury prevention is accepted in sports medicine and rehabilitation; yet, there was a paucity of articles included in this review that explicitly investigated this aspect with regards to recreational alpine skiing and snowboarding. The most frequent recommendations for preventing skiing and snowboarding injuries concerned equipment or the involvement of third parties. The dominance of equipment-related measures in the injury prevention literature may be rationalized from a sports biomechanics viewpoint, as these activities involve high velocities and impact forces. Nonetheless, this also indicates a need for appropriate levels of strength, endurance and conditioning to meet the technical demands of these sports. Bearing this in mind, future research is encouraged to investigate the role of physical fitness, exercise and training in decreasing the incidence and severity of skiing and snowboarding injuries in recreational athletes. PMID- 23463394 TI - Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. AB - BACKGROUND: The purpose of the present study was to determine whether intrahepatic injection of (131)I-lipiodol (Lipiodol) is effective against recurrence of surgically resected hepatocellular carcinoma (HCC). METHODS: From June 2001 through March 2007, this nationwide multi-center prospective randomized controlled trial enrolled 103 patients 4-6 weeks after curative resection of HCC with complete recovery (52: Lipiodol, 51: Control). Follow-up was every 3 months for 1 year, then every 6 months. Primary and secondary endpoints were recurrence free survival (RFS) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR). The design was based on information obtained from a similar trial that had been conducted in Hong Kong. RESULTS: The Lipiodol group showed a small, and nonsignificant, improvement over control in RFS (HR = 0.75; 95 % confidence interval [95 % CI] 0.46-1.23; p = 0.25) and OS (HR = 0.88; 95 % CI 0.51-1.51; p = 0.64). Only two serious adverse events were reported, both with hypothyroidism caused by (131)I-lipiodol and hepatic artery dissection during angiography. CONCLUSIONS: The randomized trial provides insufficient evidence to recommend the routine use of (131)I-lipiodol in these patients. PMID- 23463395 TI - Lessons for surgeons in the final moments of Air France Flight 447. AB - BACKGROUND: All surgeons make mistakes, and learning from critical incidents may help improve performance. The present study aimed to highlight lessons for surgeons from analysis of the final moments of Air France Flight 447. All of the authors work in teams and situations where safety, technical performance, and non technical skills are critical. This review was born out of discussions regarding the events of Flight 447; specifically, whether the airline disaster was relevant to their work, and whether they could learn anything from it. METHODS: The study is based on review of the crash reports of Flight 447, which lost flight speed indication after formation of ice prevented air from entering flight speed indicators during a storm. Following a subsequent stall, the aircraft fell at a rate of >10,000 feet/min until it crashed into the Atlantic Ocean, killing 228 passengers and crew. RESULTS: There were errors in decision making, reasoning, communication, and teamwork. Such non-technical skills failures have been recognized previously and can be addressed by existing non-technical skills training. A reliance on autopilot meant that the pilots were unfamiliar with high altitude flying when the autopilot is disengaged. They were unprepared for and affected by such a sudden and serious problem; an event called "surprise and startle" by the accident investigation. The absence of the senior pilot (who was on a scheduled break) in the critical final minutes slowed error recognition and recovery. CONCLUSIONS: Unintended consequences of modern safety strategies may be under-recognized and can lead to adverse events. Both simulation-based and non simulation-based training should include "surprise and startle" events beyond the scenarios trainees might expect. Likewise, in the face of increasing reliance on modern technology, surgeons should ensure that they would be able to perform procedures in the absence of such technologies. Specific training may improve surgeons' non-technical skills, and recognition of such skills could also be used to help select future surgeons. PMID- 23463396 TI - Impact of skin grafting of venous leg ulcers on functional status and pain. AB - BACKGROUND: Disability and pain were assessed in patients with venous leg ulcers treated with split-thickness skin grafts to evaluate to what extent skin grafting improves functional status in this population. METHODS: A prospective, nonrandomized, multicenter case-control study was conducted from July 2008 to December 2010 in two hospitals in Brazil. One hundred patients with venous leg ulcers were divided into two treatment groups of 50 patients each: the control group (conservative treatment) and the surgery group (skin grafting). Patients were assessed at baseline (day 0) and on days 30, 90, and 180. Disability was measured with the Disability Index of the Health Assessment Questionnaire (HAQ DI). The visual analog scale (VAS) and McGill Pain Questionnaire (MPQ) were used to assess pain. RESULTS: Surgery group patients reported significantly lower (p = 0.0001) overall HAQ-DI scores (lower disability levels) 180 days postoperatively (HAQ-DI = 0.18) compared with baseline (HAQ-DI = 2.65); mean overall HAQ-DI scores for control patients was 1.70 on day 180, with a significant difference between groups (p = 0.0001). The surgery group showed significant improvement on all HAQ-DI categories and reported significantly lower pain intensity (VAS pain scores) on days 30, 90, and 180 compared with controls (p = 0.0001). The MPQ was used to assess the sensory, affective, evaluative, and miscellaneous dimensions of pain in the two groups; there were significant differences between groups on days 30, 90, and 180 (p = 0.0001). CONCLUSIONS: Patients with venous leg ulcers treated with split-thickness skin grafts showed improvement in functional status compared with controls. PMID- 23463397 TI - Obstacles to surgical services in a rural Cameroonian district hospital. AB - BACKGROUND: There are significant obstacles to the delivery of surgical care in low income countries. Few studies have defined or characterized these constraints. The present study aimed to identify financial and demographic factors limiting the utilization of surgical services in rural Cameroon. METHODS: A review was performed of all surgical records for patients presenting for surgery at the District Hospital of Kolofata in rural Cameroon over the 3-year study period (2004-2007). Disability-adjusted life years (DALYs) were calculated using disease- and patient-specific outcomes while accounting for postoperative morbidity. Univariate and multivariate analysis identified factors associated with failure to return for care. RESULTS: During the study period, 1,213 patients presented for preoperative evaluation, were informed of the cost to be paid preoperatively, and had surgery scheduled. Of these, 544 patients did not return for treatment, representing 2,163 DALYs potentially lost. Multivariate analysis revealed significant factors associated with increased likelihood of not returning for care as required preoperative payment >$US 310 (OR 0.44-0.86) and a recommended procedure for cancer (OR 0.47-0.86) or cutaneous disease (OR 0.28 0.95). Factors associated with increased odds of returning were male gender (OR 1.03-1.98), preoperative payment <$US 50 (OR 2.86-16.2), and a procedure with low DALYs (OR 1.71-9.89). The average cost per DALY for all operations performed was $US 27.13. CONCLUSIONS: Although surgery addresses a significant disease burden and is reported to be a cost-effective public health intervention, utilization is limited by high costs, demographic factors, and patient perceptions of surgical diseases. PMID- 23463398 TI - Reflux symptoms and side effects among patients with gastroesophageal reflux disease at baseline, during treatment with PPIs, and after Nissen fundoplication. AB - BACKGROUND: There are no prospective studies available on the behavior of extraesophageal and esophageal symptoms and treatment-related side effects in patients without effective antireflux medication, receiving the most effective antireflux medication, and after laparoscopic fundoplication. METHODS: Extraesophageal and esophageal reflux symptoms and treatment-related side effects were assessed in 60 patients while they were on no effective antireflux medication (three-week washout period), after three month of treatment with double-dose esomeprazole, and 3 months after laparoscopic Nissen fundoplication. Esophageal and extraesophageal reflux symptoms, rectal flatulence, and bloating were analyzed with the visual analog scale. In addition, dysphagia, rectal flatulence, and bloating were recorded as none, mild, moderate, or severe. RESULTS: Both extraesophageal and esophageal reflux symptoms decreased after treatment with esomeprazole and were further reduced after fundoplication. Dysphagia and flatulence did not increase from baseline after surgery. Bloating decreased both after treatment with esomeprazole and after fundoplication. In contrast, dysphagia and increased flatus were found more often after surgery than during treatment with esomeprazole. Dysphagia and rectal flatulence were less common during treatment with esomeprazole than at baseline or after surgery. CONCLUSIONS: Both extraesophageal and esophageal reflux symptoms decreased after treatment with esomeprazole and were reduced further after fundoplication. Any treatment-related side effect was not increased after surgery when compared to baseline. However, compared to esomeprazole there was more dysphagia and flatulence after fundoplication. PMID- 23463399 TI - Perioperative fluid restriction in major abdominal surgery: systematic review and meta-analysis of randomized, clinical trials. AB - BACKGROUND: Fluid management is a fundamental component of surgical care. Recently, there has been considerable interest in perioperative fluid restriction as a method of facilitating recovery following elective major surgery. A number of randomized trials have addressed the issue in various surgical specialities, and a recent meta-analysis proposed uniform definitions regarding fluid amount as well as examining fluid restriction in patients undergoing colonic resection. METHODS: Medline, Embase, trial registries, conference proceedings, and article reference lists were searched to identify randomized, controlled trials of perioperative fluid restriction versus "standard" perioperative fluid management, as per definitions formulated previously. All of the studies involved patients undergoing colonic resection. The primary outcome measure was postoperative morbidity. Secondary endpoints included mortality, renal failure, time to first flatus, and length of hospital stay. A random effects model was applied. RESULTS: Seven randomized, controlled trials with a total of 856 patients investigating standard versus restrictive fluid regimes, as denoted by the definitions, were included. Perioperative fluid restriction had no effect on the risk of postoperative complications (OR 0.49 (95 % confidence interval (CI) 0.2-1.18; P = 0.101). There was no detectable effect on death and fluid restriction did not reduce hospital stay (Pooled weighted mean difference -0.25; 95 % CI 0.72-0.21; P = 0.29). CONCLUSIONS: Perioperative fluid restriction does not significantly reduce the risk of complications following major abdominal surgery. Furthermore, it does not appear to reduce length of hospital stay. PMID- 23463400 TI - Post-transplantation sequential entecavir monotherapy following 1-year combination therapy with hepatitis B immunoglobulin. AB - BACKGROUND: Combination therapy of intravenous hepatitis B immunoglobulin (ivHBIG) and nucleos(t)ide (NA) analogues is the best post-liver transplantation (LT) prophylactic measure for hepatitis B virus (HBV). However, to reduce the long-term drawbacks of ivHBIG, we evaluated the efficacy of sequential entecavir (ETV) monotherapy. METHODS: Twenty-nine candidates with HBV-related liver disease were prospectively enrolled. The patients were selected if the patient was suitable for one of the following inclusion criteria: (1) NA-naive patients except for ETV, and (2) negative HB e antigen (HBeAg) and undetectable HBV DNA at the time of LT. Post-LT HBV prophylaxis consisted of 1-year combination therapy with ETV (0.5 mg daily) plus ivHBIG per 5 weeks, followed by ETV monotherapy. The primary endpoint was the 2-year recurrence rate of HB. The median follow-up period was 31 months. RESULTS: At the time of transplantation, HBeAg was positive in 21% and HBV DNA was detectable in 52% of the study participants. No HBV recurrence was reported during the first year. During the second year, HBV recurrence was noted in one who suffered from HCC recurrence without viral mutation. Recurrence free survival rates were 96.6 and 96.4% at 1- and 2-year post-transplant by intention-to-treat analysis. One patient died of fungal infection. CONCLUSION: Sequential ETV monotherapy after 1-year combination therapy might be safe in NA-naive replicators as well as non-replicators. PMID- 23463401 TI - Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia-Pacific region. AB - Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide. Although hepatitis B still remains the most common risk factor worldwide, chronic hepatitis C virus (HCV) infection is the driving force for the increased incidence of HCC especially in Western countries and Japan. In hepatitis B virus (HBV)-endemic areas, after successful vaccination programs against HBV, chronic HCV infection is now emerging as an important cause of chronic liver diseases. Unlike patients with chronic hepatitis B, those with chronic hepatitis C (CHC) develop HCC in the presence of established cirrhosis in most cases. However, a significant minority of CHC develops HCC in the absence of cirrhosis. Although HCV is a RNA virus with little potential for integrating its genetic material into host genome, various HCV proteins, including core, envelope, and nonstructural proteins, have oncogenic properties by inducing oxidative stress, disturbing cellular regulatory pathways associated with proliferation and apoptosis, and suppressing host immune responses. Overall, a combination of virus-specific, host genetic, environmental, and immune-related factors are likely to determine progression to HCC. Strategies aimed at eliminating the virus may provide opportunities for effective prevention of the development of HCC. Pegylated interferon plus ribavirin therapy appears to be effective at reducing the risk of HCC in patients who achieve sustained virologic responses. In summary, with the emerging importance of CHC, mechanisms of HCV associated hepatocellular carcinogenesis should be clarified to provide insight into advanced therapeutic and preventive approaches, which eventually decrease the incidence and mortality of HCC. PMID- 23463402 TI - Physiological roles of dietary glutamate signaling via gut-brain axis due to efficient digestion and absorption. AB - Dietary glutamate (Glu) stimulates to evoke the umami taste, one of the five basic tastes, enhancing food palatability. But it is also the main gut energy source for the absorption and metabolism for each nutrient, thus, only a trace amount of Glu reaches the general circulation. Recently, we demonstrated a unique gut sensing system for free Glu (glutamate signaling). Glu is the only nutrient among amino acids, sugars and electrolytes that activates rat gastric vagal afferents from the luminal side specifically via metabotropic Glu receptors type 1 on mucosal cells releasing mucin and nitrite mono-oxide (NO), then NO stimulates serotonin (5HT) release at the enterochromaffin cell. Finally released 5HT stimulates 5HT3 receptor at the nerve end of the vagal afferent fiber. Functional magnetic resonance imaging (f-MRI, 4.7 T) analysis revealed that luminal sensing with 1 % (w/v) monosodium L-glutamate (MSG) in rat stomach activates both the medial preoptic area (body temperature controller) and the dorsomedial hypothalamus (basic metabolic regulator), resulting in diet-induced thermogenesis during mealing without changes of appetite for food. Interestingly, rats were forced to eat a high fat and high sugar diet with free access to 1 % (w/w) MSG and water in a choice paradigm and showed the strong preference for the MSG solution and subsequently, they displayed lower fat deposition, weight gain and blood leptin. On the other hand, these brain functional changes by the f-MRI signal after 60 mM MSG intubation into the stomach was abolished in the case of total vagotomized rats, suggesting that luminal glutamate signaling contributes to control digestion and thermogenesis without obesity. PMID- 23463403 TI - Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. PMID- 23463404 TI - Ginsenoside Rd blocks AIF mitochondrio-nuclear translocation and NF-kappaB nuclear accumulation by inhibiting poly(ADP-ribose) polymerase-1 after focal cerebral ischemia in rats. AB - Our previous clinical and basic studies have demonstrated that ginsenoside Rd (GS Rd) has remarkable neuroprotective effects after cerebral ischemia but the underlying mechanisms are still unknown. In our latest studies, we revealed that GS-Rd could prevent mitochondrial release of apoptosis-inducing factor (AIF) and reduce inflammatory response following transient focal ischemia in rats. Poly(ADP ribose) polymerase-1 (PARP-1) is required for both AIF release from mitochondria and NF-kappaB-mediated inflammation. Here, we investigated whether GS-Rd could act on PARP-1 and subsequently affect AIF translocation and NF-kappaB activation. Sprague-Dawley rats were treated with GS-Rd (10 mg/kg) 30 min before surgery with the right middle cerebral artery occlusion, and at different time points following cerebral ischemia, brain tissues were collected for western blotting analysis. Our results showed that GS-Rd significantly attenuated ischemia triggered increased levels of Poly(ADP-ribose), an enzymatic product catalyzed by PARP-1, but not altered the expression of PARP-1 per se. Meanwhile, GS-Rd pretreatment reduced AIF mitochondrio-nuclear translocation and inhibited NF kappaB p65 subunit nuclear accumulation after cerebral ischemia. Therefore, our findings provide the first evidence that GS-Rd can inhibit PARP-1 activity and sequential AIF translocation and NF-kappaB nuclear accumulation, which may be responsible for GS-Rd's neuroprotection against both neuronal cell death and inflammation after ischemic stroke. PMID- 23463405 TI - Tracking reading: dual task costs of oral reading for young versus older adults. AB - A digital pursuit rotor was used to monitor oral reading costs by time-locking tracking performance to the auditory wave form produced as young and older adults were reading out short paragraphs. Multilevel modeling was used to determine how paragraph-level predictors of length, grammatical complexity, and readability and person-level predictors such as speaker age or working memory capacity predicted reading and tracking performance. In addition, sentence-by-sentence variation in tracking performance was examined during the production of individual sentences and during the pauses before upcoming sentences. The results suggest that dual tasking has a greater impact on older adults' reading comprehension and tracking performance. At the level of individual sentences, young and older adults adopt different strategies to deal with grammatically complex and propositionally dense sentences. PMID- 23463406 TI - Both total testosterone and sex hormone-binding globulin are independent risk factors for metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China. AB - BACKGROUND: Metabolic syndrome is often beneficial from testosterone replacement therapy. Although testosterone and sex hormone-binding globulin (SHBG) are inversely associated with the risk of metabolic syndrome, it is controversial whether the association between testosterone and metabolic syndrome is independent of SHBG. METHODS: Testosterone, SHBG and metabolic syndrome were evaluated in 2361 men aged 20-73 years, who participated in the population-based Fangchenggang Area Male Health and Examination Survey. Total testosterone, SHBG and other biochemical profiles were measured. Free testosterone and bioavailable testosterone were calculated on the basis of Vermeulen's formula. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria for Asian population. The independent associations with metabolic syndrome were determined by multivariate logistic regression analysis. RESULTS: Men with metabolic syndrome had a lower level of total testosterone, bioavailable testosterone, free testosterone, or SHBG than those without metabolic syndrome (all p < 0.001). Both total testosterone and SHBG were inversely correlated with body mass index or homeostasis model assessment of insulin resistance (all age-adjusted p < 0.001). Men within the lowest quartile of total testosterone [odds ratio (OR) = 4.86, 95% confidence interval (CI) = 2.72-8.68], bioavailable testosterone (OR = 3.04, 95% CI = 1.81 5.10), free testosterone (OR = 3.08, 95% CI = 1.81-5.27) or SHBG (OR = 4.28, 95% CI = 2.52-7.27) had a risk of metabolic syndrome after adjusting for age, smoking, homeostasis model assessment of insulin resistance and body mass index. Total testosterone remained inversely associated with metabolic syndrome after further adjusting for SHBG (OR = 0.95, 95% CI = 0.92-0.99), while SHBG remained inversely associated with metabolic syndrome after further adjusting for total testosterone (OR = 0.99, 95% CI = 0.97-1.00). CONCLUSION: Total testosterone and SHBG are independent risk factors of metabolic syndrome. Prospective studies are needed to explore whether the association between sex hormones and metabolic syndrome was mediated by insulin resistance or obesity. PMID- 23463407 TI - [The importance of neighborhood social cohesion and social capital for the well being of older adults in the community]. AB - PURPOSE OF THE STUDY: We aimed to investigate whether social capital (obtaining support through indirect ties such as from neighbors) and social cohesion (interdependencies among neighbors) within neighborhoods positively affect the well-being of older adults. DESIGN AND METHODS: This cross-sectional study included 945/1440 (66 % response rate) independently living older adults (aged >70 years) in Rotterdam. We fitted a hierarchical random-effects model to account for the hierarchical structure of the study design: 945 older adults (level 1) nested in 72 neighborhoods (level 2). RESULTS: Univariate analyses showed that being born in the Netherlands, house ownership, education, income, social capital of individuals, neighborhood security, neighborhood services, neighborhood social capital, and neighborhood social cohesion were significantly related to the well being of older adults. Multilevel analyses showed that social capital of individuals, neighborhood services, neighborhood social capital, and neighborhood social cohesion predicted the well-being of older adults. Single and poor older adults reported lower well-being than did better-off and married older adults. However, the effects of marital status and income were mediated by neighborhood services, social capital, and social cohesion. Neighborhood services, social capital and social cohesion may act as buffer against the adverse effects of being single and poor on the well-being of older adults. IMPLICATIONS: The results of this study support the importance of social capital of individuals, as well as social capital within the neighborhood and social cohesion within the neighborhood for well-being of older adults. The well-being of older adults may also be enhanced through the improvement of quality of neighborhood services. PMID- 23463408 TI - Skin graft coverage of critical marginal wounds in microsurgical cases. AB - Skin graft coverage of critical marginal wounds in microsurgical cases is the earliest described method for coverage of exposed vessels, nerves, and other vital structures at the margins of replanted or transplanted tissue. A case of immediate graft coverage of vein and nerve graft repairs in a gunshot wound is presented with a 5-year follow-up demonstrating stable coverage, salvage of the microsurgical reconstruction, and no contracture. Compared to recently described strategies of interval biosynthetic dressings and delayed skin grafting, immediate skin grafts application remains the most effective management of these wounds. PMID- 23463409 TI - [Current aspects of paediatric cholesteatomas]. AB - Cholesteatomas can be subclassified into genuine and acquired forms. Whilst epidermoid formations are the generally accepted cause of genuine cholesteatomas, metaplasia, immigration, proliferation and retraction pocket theories have all been proposed to explain the development of acquired cholesteatomas. Clinically, paediatric cholesteatomas exhibit more extensive and aggressive growth than those arising in adulthood. Molecular biological differences in terms of angiogenesis, cytokine expression and particularly the more marked inflammatory responses of the perimatrix could potentially explain these clinical differences. The surgical therapy of paediatric cholesteatomas should be adapted to the individual pathological findings, although where possible a canal wall up procedure is preferred during initial surgery. The "inside-out" mastoidectomy tracking technique combines the benefits of a good surgical overview with those of a physiological postoperative auditory canal. PMID- 23463410 TI - [Hypoglossal nerve paresis following a marathon]. PMID- 23463412 TI - [CT-assisted navigation for retrosigmoidal implantation of the Bonebridge]. AB - The Bonebridge is an active bone conduction implant (BCI) that is primarily indicated in patients with conductive and combined hearing loss. However, many of these patients present with a radical cavity as a result of previous surgery. In these cases, the implant should not be introduced into the mastoid region, but rather via a retrosigmoid approach to maintain separation from the pathological alteration. To ensure the best possible acoustic transduction, the Bone Conduction-Floating Mass Transducer (BC-FMT) should be positioned near to the cochlea. This requires precise identification of the sigmoid sinus, which cannot be achieved accurately enough using external anatomical landmarks. We thus report on two patients in whom the Bonebridge was implanted via a retrosigmoid approach using CT-guided navigation. PMID- 23463411 TI - [Gelatin-thrombin matrix-mediated hemostasis: application in tonsillectomy]. AB - BACKGROUND: To assess the feasibility of omitting thermal coagulation following cold knife tonsillectomy, we compared the use of a local thrombin hemostat (FloSeal(r), FS) to bipolar electrocautery (EK). PATIENTS AND METHODS: A total of 181 patients with chronic tonsillitis or tonsillar hypertrophy were stratified in terms of patient characteristics and randomized before undergoing tonsillectomy. The follow-up period continued until postoperative day 20. RESULTS: FS-treated patients reported lower postoperative pain intensity scores (p = 0.011) and significantly reduced pain duration (p < 0.001). Whilst wound healing appeared to be improved in FS patients, the rates of postoperative hemorrhage remained unchanged. Use of an FS enabled inexperienced surgeons (< 100 procedures) to reduce their operating time by 8 min (p = 0.05), although no effect was observed for experienced surgeons. CONCLUSION: Hemostasis is effectively mediated by an FS and its application reduces postoperative pain intensity and duration. Although we observed accelerated wound healing and reduced operating times owing to a more calculable rate of hemostasis, this did not influence the rates of postoperative hemorrhage. PMID- 23463413 TI - [Treatment of chronic rhinosinusitis using balloon sinuplasty. A quality of life analysis]. AB - BACKGROUND: Balloon sinuplasty (functional endoscopic dilation surgery, FEDS) has become established as a safe therapeutic procedure for treatment of chronic rhinosinusitis. Our goal was to assess the effect on quality of life (QoL) using validated tools and identify predictive factors. MATERIALS AND METHODS: A consecutive cohort of 14 patients was evaluated using the disease-specific QoL questionnaire Sino-Nasal Outcome Test 20 (SNOT-20). The measured postoperative changes were then correlated to the results of preoperative CT scan analyses performed according to Lund. RESULTS: Both the overall SNOT-20 scores and those corresponding to subsections regarding primary nasal symptoms (PNS) and secondary rhinogenic symptoms (SRS) showed a highly significant improvement (p < 0.01). Changes in PNS but not in SRS correlated with the CT scan analyses (p < 0.05). Eighty five percent of patients said that they would choose to undergo FEDS again. CONCLUSIONS: FEDS is an effective technique that can alleviate symptoms and improve QoL. Patient selection should not be based on CT data alone but a CT scan can be used to determine whether or not the FEDS technique is applicable to the individual patient. PMID- 23463414 TI - [Obstructive sleep apnea syndrome in the setting of Gorlin-Goltz syndrome]. AB - Goltz-Gorlin syndrome is a rare autosomal dominant hereditary disease associated with a high rate of spontaneous mutation. Diagnosis is based on clinically defined major and minor criteria. The disease is caused by a gene mutation locating to chromosome 9q22-31. We report on a young Goltz-Gorlin syndrome patient with obstructive sleep apnea syndrome. Due to intolerance to continuous positive airway pressure (CPAP) therapy and in order to avoid a tracheotomy, we opted for an alternative therapy comprising interdisciplinary multi-level surgery. PMID- 23463415 TI - [Pediatric otology: a long-term challenge]. PMID- 23463416 TI - Identification of myosin heavy chain isoforms in porcine longissimus dorsi muscle by electrophoresis and mass spectrometry. AB - Myosin heavy chain (MHC) isoforms have been considered as makers for muscle fiber types in relation to meat quality, whereas MHC isoforms in porcine skeletal muscle have not been fully identified. The improved technique of SDS-PAGE and 2DE were used to separate porcine MHC isoforms. Western blotting with monoclonal antibodies including BA-F8 (anti-MHC slow/I), SC-71 (anti-MHC 2a and 2x), 10F5 (anti-MHC 2b), and BF-35 (anti-MHC slow/I and 2a) and MS were used to confirm MHC migration rate and identify MHC isoforms from separated bands and spots. Up to 45% w/v of glycerol, 8% w/v of acrylamide content, and 25 h of electrophoretic time at 70 V allowed a clear separation of MHC isoforms. Major MHC isoforms such as slow, 2a, 2x, and 2b were clearly separated by SDS-PAGE. A total of 23 MHC spots were separated and identified by 2DE and MS. Therefore, four MHC isoforms such as slow/I, 2a, 2x, and 2b could be identified by the improved SDS-PAGE technique, 2DE and MS. Therefore, these techniques allow more accurate and accessible analysis in muscle fiber typing and in relationship between MHC isoforms, muscle fiber characteristics, and pork quality. PMID- 23463417 TI - Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells. AB - Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib-induced cell death in two different MM cell lines (bortezomib resistant KMS20 cells and bortezomib-sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine-5'-triphosphate and mitochondrial Ca(2+) concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2 methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision-making. PMID- 23463418 TI - Surgical approach to cervical esophagogastric anastomoses for post-esophagectomy complications. AB - In gastric tube reconstruction, anastomotic leakage and stricture occasionally occur. Additionally, new or recurrent cancer may occur in the esophageal remnant or at the anastomotic site. Such complications, after cervical anastomoses, led to our adoption of a procedure to approach the anastomosis by manubrium and proximal left clavicle resection. This procedure was applied to seven patients between April 2000 and March 2011. The mean age of the patients was 69.9 years (range, 65-76 years); all were men. The mean operative time was 506 min (range, 374-845 min), with an average blood loss of 297 ml (range, 180-606 ml). Esophagogastric anastomoses were performed in two cases, and free jejunal graft transplantations were performed in the remaining five cases; oral intake became possible for all patients. Limited range of motion or other movement disorders of the neck and upper limbs, due to the upper sternum and clavicle resection, were not observed. This invasive surgical procedure can be acceptable for patients who are facing life-threatening consequences or significant decreases in quality of life and are resistant to conservative treatment. PMID- 23463419 TI - Deregulation of glutamate dehydrogenase in human neurologic disorders. AB - Mammalian glutamate dehydrogenase is an allosterically regulated enzyme that is central to glutamate metabolism. It contributes to important cellular processes, including Krebs cycle anaplerotic mechanisms, energy production, and ammonia homeostasis. In addition to this housekeeping hGDH1, humans have acquired through duplication an hGDH2 isoenzyme expressed in neural tissues with distinct regulatory properties. There is increasing evidence that deregulation of human GDHs leads to human disorders. Thus, in hGDH1, regulatory mutations that attenuate GTP inhibition can result in the hyperinsulinism/hyperammonemia syndrome, which is often associated with epileptic seizures, mental retardation, and generalized dystonia. Also, transgenic overexpression of GLUD1 in neurons has resulted in age-dependent degeneration of the CA1 behippocampal region, associated with upregulation of alpha-synuclein and other proteins linked to major human movement disorders. With regard to hGDH2, a rare T1492G variation in the GLUD2 gene, resulting in substitution of Ala for Ser445 in the regulatory domain of hGDH2, interacts significantly with Parkinson's disease (PD) onset. In two independent Greek and one North American PD cohorts, Ser445Ala hemizygous males, but not heterozygous females, developed PD 6-13 years earlier than subjects with other genotypes. The Ala445-hGDH2 variant displays increased catalytic activity that is amenable to inhibition by estrogens. Enhanced glutamate oxidation by Ala445-hGDH2 is thought to accelerate nigral cell degeneration in hemizygous males, and inhibition of the overactive variant by estrogens may protect heterozygous females. Hence, deregulation of hGDH1 and hGDH2 may play a role in degenerative processes, so these observations identify novel targets for therapeutic intervention in human disorders. PMID- 23463420 TI - Synthesis of rhombic hierarchical YF3 nanocrystals and their use as upconversion photocatalysts after TiO2 coating. AB - A facile method has been developed to synthesize uniform nanoscale YF3 architectures. Interestingly, the unique YF3 nanostructure exhibits a flat and rhombic appearance which is formulated through the hierarchical assembly of YF3 nanocrystals along a specific crystalline orientation. Investigations on the formation process suggest that an assembly disassembly process is responsible for the construction of this novel structure. Enabled by doping with different lanthanides ions, the products can exhibit various down- or up-conversion luminescences, showing their potentials in serving as versatile host matrixes. The tunable luminescent properties allow designing effective upconversion photocatalysts when the doped YF3 nanostructures are coated with a TiO2 shell on their surface. In particular, the YF3@TiO2 hybrid structures have the porous nature that is partially inherited from the YF3 architectures, whose high surface to-volume ratio facilitates their use as photocatalysts. In this article, we have demonstrated that the YF3:Yb,Tm@TiO2 structures exhibit satisfactory photocatalytic activities under the irradiation of both UV and near IR light. As compared with the conventional TiO2 catalysts, the hybrid structures here offer better performance in photocatalysis in the full solar spectrum. It is anticipated that this work provides a new approach to designing photocatalysts with responses to a broader spectral range. PMID- 23463421 TI - High risk of new episode of symptomatic vasospasm in unaffected arteries in subarachnoid hemorrhage patients receiving targeted endovascular treatment for symptomatic focal vasospasm. AB - BACKGROUND: There is controversy whether asymptomatic vasospasm in other arteries should be concurrently treated (global treatment) in patients receiving targeted endovascular treatment [percutaneous-transluminal-angioplasty (PTA) and/or intra arterial (IA) vasodilators] for focal symptomatic vasospasm. OBJECTIVE: To determine the rates of occurrence of new symptomatic vasospasm in previously asymptomatic arterial distributions among patients with aneurysmal subarachnoid hemorrhage (SAH) who underwent targeted endovascular treatment for focal symptomatic vasospasm. METHODS: We identified all patients with SAH who had received targeted endovascular treatment during a 4-year period. We ascertained any new occurrence of symptomatic vasosopasm requiring endovascular treatment in previously unaffected (and untreated) arterial distributions within the same hospitalization. Blinded reviewers quantitatively graded angiographic vasospasm (<25, 26-49, >=50 %) in all major arteries for each patient at the time of targeted treatment. RESULTS: Of the 41 patients who received targeted endovascular treatment (PTA in 41 % and vasodilators in 59 %), 11 (27 %) developed new symptomatic vasospasm in previously asymptomatic vascular distributions requiring endovascular treatment. Moderate severity of angiographic vasospasm in asymptomatic arteries at the time of targeted treatment tended to predict the occurrence of new symptomatic vasospasm. The rate of death and disability at discharge [modified Rankin scale (mRS) of 3-6] was 82 % (9/11) among those who developed a new episode of symptomatic vasospasm compared with 70 % (21/30) in those who did not (P = 0.58). CONCLUSIONS: High risk of new occurrence of ischemic symptoms in previously asymptomatic (and untreated) arterial distributions among patients receiving targeted treatment should be recognized. Further studies should evaluate the benefit of performing global endovascular treatment during the initial targeted endovascular treatment session. PMID- 23463422 TI - No exacerbation of perihematomal edema with intraventricular tissue plasminogen activator in patients with spontaneous intraventricular hemorrhage. AB - INTRODUCTION: In severe spontaneous intraventricular hemorrhage (IVH), intraventricular (IVR) administration of tissue plasminogen activator (rtPA) clears blood from the ventricles more rapidly than with external ventricular drainage (EVD) alone. However, experimental studies suggest tPA may be neurotoxic in compromised brain tissue and may exacerbate perihematomal edema. METHODS: We used computerized volumetrics to assess change in intracerebral hemorrhage (ICH), IVH, ventricular, and perihematomal edema (PHE) volumes at 2-4 (T1) and 5-9 (T2) days following diagnostic CT scans (T0) of 24 patients (12 tPA-treated; 12 controls) with IVH requiring EVD. Controls from a hospital registry were matched by IVH and ICH volume to tPA-treated patients who came from a multicenter trial involving 52 patients with IVH. RESULTS: There were no significant differences between matched pairs in admission ICH and IVH volumes. IVR tPA resulted in more rapid clearance of IVH as determined by T2-T0 decrease in median IVH volume (tPA: -18.7 cc, iqr 14.9; control:-6.9 cc, iqr 6.4; P = 0.002). Median ratios of PHE to ICH volume were not significantly different in control versus tPA-treated patients at T1 and T2 [control:tPA = 0.55:0.56 (T1); P = 0.84 and 0.81:0.71 (T2); P = 1.00]. Total ventricular volume was significantly larger in the control group at T2 (mean: 57.57 +/- 10.32 vs. tPA: 24.80 +/- 2.67 cc; P = 0.01). Bacterial ventriculitis was more frequent in the control group (5 vs. 1 episodes; P = 0.06) as was shunt dependence (4 vs. 0 cases; P = 0.03). CONCLUSIONS: For case matched large IVH with small ICH volume, IVR tPA enhances lysis of intraventricular blood clots and has no significant impact on PHE. PMID- 23463423 TI - Perimesencephalic subarachnoid hemorrhage triggered by hypoxic training during swimming. AB - INTRODUCTION: Perimesencephalic subarachnoid hemorrhage is a rare neurologic condition of unclear etiology. Multiple mechanisms have been postulated as potential triggers, but none are universally accepted. METHODS: Single observational case report and review of the literature. RESULTS: We describe a patient who developed perimesencephalic subarachnoid hemorrhage in the setting of "hypoxic training" (breath-holding while swimming). We describe the plausible pathophysiologic events that caused the hemorrhage. CONCLUSION: The occurrence of perimesencephalic subarachnoid hemorrhage during hypoxic training suggests that acute venous congestion may be a triggering factor. The increasing popularity of hypoxic training demands vigilance from health care providers. PMID- 23463424 TI - What does Islam say about dieting? AB - Dieting is very important to maintain a healthy and peaceful life. Today, most of the health problems are related with dieting. Thus, the modern health science recommends a number of suggestions regarding dieting for better health such as learning the five basic food groups (grains, vegetables, fruits, dairy, and meat); eating three times a day; decreasing the amount of fat; increasing the amount of fruits, vegetables and grains; including an adequate amount of iron; and avoiding excessive rich food, salt, sugar, and fat. Religion can also play a vital role for our good health and lifestyle. The main concern of this paper was to present an analytical justification regarding what Islam as a religion advocates about dieting along with the modern food and nutrition sciences. PMID- 23463426 TI - Rebuilding graduate medical education. PMID- 23463425 TI - An update on serine deficiency disorders. AB - Serine deficiency disorders are caused by a defect in one of the three synthesising enzymes of the L-serine biosynthesis pathway. Serine deficiency disorders give rise to a neurological phenotype with psychomotor retardation, microcephaly and seizures in newborns and children or progressive polyneuropathy in adult patients. There are three defects that cause serine deficiency of which 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, the defect affecting the first step in the pathway, has been reported most frequently. The other two disorders in L-serine biosynthesis phosphoserine aminotransferase (PSAT) deficiency and phosphoserine phosphatase (PSP) deficiency have been reported only in a limited number of patients. The biochemical hallmarks of all three disorders are low concentrations of serine in cerebrospinal fluid and plasma. Prompt recognition of affected patients is important, since serine deficiency disorders are treatable causes of neurometabolic disorders. The use of age-related reference values for serine in CSF and plasma can be of great help in establishing a correct diagnosis of serine deficiency, in particular in newborns and young children. PMID- 23463427 TI - Medical education on a collision course: sooner rather than later? AB - BACKGROUND: The escalating cost of medical education does not have transparency. This results in high percentages of medical students with progressively rising levels of indebtedness that are only exceeded by the increases in tuition. Indebtedness is a factor in specialty choice along with the "business" of medicine that reimburses procedural-based physicians much more than cognitive primary care-based services. In response to perceived increased physician demand by 2025, medical schools have increased enrollments, and new schools are online or in development. Despite the inevitable increase in medical graduates, the number of residency positions is static and may even contract. While these phenomena are being studied individually, almost no one is examining the bigger picture: increasing numbers of highly indebted students vying for static numbers of residency positions, especially in the more highly remunerative specialties. The workforce is out of balance now, and the desired workforce outcomes are not universally agreed upon, let alone how to achieve them. This collision of forces is imminent. Family medicine can become "counter culture" once again and advocate for change with education/cost data, political expertise, and outcome measures. Returning to our roots by advocating ultimately for the patient is fundamental to our discipline. PMID- 23463428 TI - A proposal for reform of the structure and financing of primary care graduate medical education. AB - BACKGROUND AND OBJECTIVES: Accessible, high-quality, cost-effective health care systems are anchored in primary care, yet decreasing production from graduate medical education (GME) jeopardizes the primary care workforce and the nation's health. The GME Initiative recommends Congress (1) invigorates primary care physician (PCP) supply through GME benchmarking and enforcement by creating a workforce that is at least 40% PCPs, holding teaching hospitals accountable, and increasing the primary care residency position cap, (2) establishes a GME system supported by all insurers-public and private-and implements a fixed floor funding of direct GME (DME) at $100,000 per resident per year for residencies that produce graduates who truly go on to practice primary care, (3) reallocates some indirect GME (IME) to support primary care residency education, including enhanced PCP education outside hospitals, including teaching health centers, (4) restores funding for the 1997 full-time equivalent (FTE) PCP residency slots cut for training outside the teaching hospital, (5) allows states expanding Medicaid through the Patient Protection and Affordable Care Act (ACA) to increase PCP education capacity through Medicaid DME and/or IME at the enhanced Federal Medical Assistance Percentage (FMAP). PMID- 23463429 TI - The length of training pilot: does anyone really know what time it takes? AB - BACKGROUND AND OBJECTIVES: With funding from the American Board of Family Medicine, the Review Committee for Family Medicine of the Accreditation Council for Graduate Medical Education has undertaken a project to examine the length of training for family medicine residents. This project comes at a time when concerns are being raised regarding how well family medicine residents are being prepared for independent practice, especially in view of the changing health care environment. The declining performance of recent graduates on the American Board of Family Medicine certification examination and reports of narrowing of the scope of practice of family physicians have only heightened these concerns. This special article is meant to provide a historical review of the issue as well as an overview of the project. PMID- 23463430 TI - Early pregnancy failure management among family physicians. AB - BACKGROUND AND OBJECTIVES: Family physicians, as primary care providers for reproductive-aged women, frequently initiate or refer patients for management of early pregnancy failure (EPF). Safe and effective options for EPF treatment include expectant management, medical management with misoprostol, and aspiration in the office or operating room. Current practice does not appear to reflect patient preferences or to utilize the most cost-effective treatments. We compared characteristics and practice patterns among family physicians who do and do not provide multiple options for EPF care. METHODS: We performed a secondary analysis of a national survey of women's health providers to describe demographic and practice characteristics among family physicians who care for women with EPF. We used multivariate logistic regression to identify correlates of providing more than one option for EPF management. RESULTS: The majority of family physicians provide only one option for EPF; expectant management was most frequently used among our survey respondents. Misoprostol and office-based aspiration were rarely used. Providing more than one option for EPF management was associated with more years in practice, smaller county population, larger proportions of Medicaid patients, intrauterine contraception provision, and prior training in office based aspiration. CONCLUSIONS: Family physicians are capable of providing a comprehensive range of options for EPF management in the outpatient setting but few providers currently do so. To create a more patient-centered and cost effective model of care for EPF, additional resources should be directed at education, skills training, and system change initiatives to prepare family physicians to offer misoprostol and office-based aspiration to women with EPF. PMID- 23463431 TI - A long-term evaluation of a required reproductive health training rotation with opt-out provisions for family medicine residents. AB - BACKGROUND: Family physicians are critical to reproductive health care provision. Previous studies have evaluated the immediate impact of training family physicians in abortion and reproductive health care but have not conducted long term follow-up of those trained. METHODS: In a cross-sectional survey performed in 2009, all 2003--2008 graduates from four family medicine residency programs with a required abortion training rotation with opt-out provisions were asked to participate in a confidential online follow-up survey that was linked to rotation evaluations. The follow-up surveys addressed current reproductive health practice, desire to integrate services in ideal practice, perceived barriers, and desired support for provision of services. RESULTS: Of 183 eligible graduates, 173 had contact information, and 116 completed the survey. The majority of respondents had provided a range of reproductive health services since residency. Of full training participants, many had performed IUD insertion (72%), endometrial biopsies (55%), miscarriage management (52%), and abortion (27%), compared to 39%, 22%, 17%, and 0% of opt-out training participants, respectively. Of those residents intending future abortion provision, 40% went on to do so. In multivariate analysis among full participants, procedural volume was positively correlated with future abortion provision after controlling for intention to provide abortions, gender, and residency program (adjusted OR=1.42 [95% CI=1.03- 1.94]). While most respondents considered comprehensive reproductive health services including miscarriage management and abortion as important to include in their ideal practice, many faced barriers to providing all the services they desired. CONCLUSIONS: Family medicine residency graduates fully participating in abortion training reported increased provision of most reproductive health services compared to opt-out graduates. Many intending to provide abortions reported a variety of barriers to provision. Training programs that provide assistance for overcoming obstacles to practice initiation may improve comprehensive reproductive health provision among graduates. PMID- 23463432 TI - Residency program solutions: making a difference in quality residency education. AB - BACKGROUND: Residency Program Solutions (RPS) consultants assist family medicine residency programs in solving issues perceived as limiting quality resident education. Residencies ask RPS to assist in preparing for accreditation site visits by the Residency Review Committee-Family Medicine (RC-FM). The RPS Criteria for Excellence in Family Medicine Education (RPS Criteria) may have influenced the accreditation standards of the RC-FM. RPS consultations also may affect accreditation visit cycle length and number of RC-FM citations. METHODS: The authors reviewed the RC-FM Program Requirements for Family Medicine Residency Education and the RPS Criteria from 1978 to 2007, comparing statements between the two documents for "nearly verbatim" and equivalent "must" or "should" requirements. The average number of citations and cycle length for programs seeking a Comprehensive Accreditation Program (CAP) Consultation from 2004--2010 were compared to cohort programs evaluated at the same RC-FM meeting using an independent samples t test. RESULTS: The strongest relationship between the RC-FM requirements and the RPS criteria occurred in 1983--1984. Nine "nearly verbatim" statements, 15 "must-should" or "must-must" statements, and 11 "should-should" statements existed. Over time, additional concurrences between organizational statements occurred. Residency programs with CAP consultations benefited significantly by both a decrease in number of citations and an increase in the length of accreditation cycle. CONCLUSIONS: The RPS Criteria have positively impacted iterations of RC-FM requirements. Family medicine residency programs concerned about successful accreditation by the RC-FM will likely benefit from RPS CAP consultations by increased length of accreditation cycle and/or a decreased number of citations. PMID- 23463433 TI - Learning environment: the impact of clerkship location on instructional quality. AB - BACKGROUND AND OBJECTIVES: Students provide variable feedback on instructional quality at ambulatory training sites. We hypothesized several strengths and weaknesses of placing students at resident and non-resident training sites, including differences in faculty behaviors, patient characteristics, work environment, learning opportunities, and levels of student engagement. We systematically assessed for differences in learning quality between clerkship sites with and without residents. METHODS: Students completed the MedED IQ, a validated survey assessing four domains of instructional quality, after completing a required primary care rotation. We calculated descriptive and summary statistics and two sample tests of proportion analyzing student agreement with each MedEd IQ item with respect to the presence or absence of resident learners. RESULTS: Of 149 total, 113 (75.8%) students completed the MedEd IQ site survey. A greater percentage of students at resident training sites (25.8%) than at non-resident sites (7.3%) agreed with the statement "The opportunities were too diverse, preventing me from developing proficiency." A greater percentage of students at resident training sites (19.4%) than at non-resident sites (1.2%) agreed with the statement "The health care team was not supportive of my learning." There were no differences between sites with or without residents on 14 items measuring preceptor actions or seven items measuring student involvement. CONCLUSIONS: Ambulatory clerkship sites with and without residents provide comparable quality learning experiences and precepting. Students placed at resident training sites may be overwhelmed with diverse opportunities and have a less supportive learning environment than students placed at non-resident sites. Future research should evaluate the impact of health care team development programs designed to foster a more supportive training environment for medical students. Ways of aligning residency and medical student education goals within the training setting should be explored. PMID- 23463434 TI - Clinical utility of the chronic obstructive pulmonary disease knowledge questionnaire. AB - BACKGROUND AND OBJECTIVES: Although typically symptomatic, chronic obstructive pulmonary disease (COPD) is undertreated as compared to many asymptomatic conditions such as hypertension. Unfortunately, many patients lack basic information about their major disease states, including COPD. The purpose of this study was to assess the clinical utility of the valid and reliable COPD Questionnaire (COPD-Q) in a sample of underserved patients carrying a diagnosis of COPD. METHODS: This prospective, descriptive study enrolled COPD patients at a family medicine residency teaching clinic. Patients were administered a telephone survey assessing COPD knowledge, demographic data, and health literacy. Data regarding COPD clinical outcomes were gathered through the electronic medical record. RESULTS: Average total COPD-Q score was 7.6 plus or minus 2.1 (total possible score=13). Total COPD-Q scores were significantly related to health literacy and educational attainment. CONCLUSIONS: The COPD-Q is a valid, reliable tool used to assess COPD knowledge in a setting that includes patients with limited health literacy. It is useful in identifying key knowledge deficits that will allow the clinician to offer focused, individualized patient education and counseling. PMID- 23463435 TI - Voices of recovery: a family physician's experience of aphasia. PMID- 23463439 TI - Social accountability across the continuum of medical education: a call for common missions for professional, accreditation, certification, and licensure organizations. PMID- 23463440 TI - Template-free synthesis of Ta3N5 nanorod arrays for efficient photoelectrochemical water splitting. AB - We report the template-free synthesis of Ta3N5 nanorod array films grown on Ta foil by a combination of a vapor-phase hydrothermal process and subsequent nitriding. The Ta3N5 nanorod array film modified with Co(OH)x when used as a photoanode in a photoelectrochemical cell for water splitting yields a stable photocurrent density of 2.8 mA cm(-2) at 1.23 VRHE under AM 1.5G simulated sunlight. The incident photon-to-current conversion efficiency at 480 nm is determined to be 37.8%. PMID- 23463441 TI - Synthesis, characterization, Co-S bond reactivity of a vitamin B12 model complex having pentafluorophenylthiolate as an axial ligand. AB - Heptamethyl (aquo)(pentafluorophenylthiolate)cobyrinate perchlorate, [(H2O)(C6F5S)Cob(III)7C1ester]ClO4, was synthesized as a B12 model complex having a thiolate ligand in the axial position. The axial ligand change in heptamethyl (diaquo)cobyrinate diperchlorate, [(H2O)2Cob(III)7C1ester](ClO4)2, from H2O to C6F5S(-) afforded the B12-thiolate complex. The B12-thiolate model complex was characterized by UV-vis, NMR and ESI-mass spectroscopies. The coordination of C6F5S(-) to the cobalt center affected the spectroscopic properties of the corrin ring through the electronic interaction between the axial ligand (C6F5S(-)) and the equatorial ligand (corrin). The photolysis of the B12-thiolate model complex led to the homolytic cleavage of the Co(iii)-S bond to form the Co(II) complex and the phenyl thiyl radical. The thermolysis of the B12-thiolate model complex also led to the homolytic cleavage of the Co(III)-S bond. Furthermore, the reactivity of the Co(III)-S bond of the B12-thiolate model complex was applied to the catalytic oxidation of C6F5SH to C6F5S-SC6F5. PMID- 23463442 TI - Patterns and Predictors of Disclosure of Sexual Orientation to Healthcare Providers among Lesbians, Gay Men, and Bisexuals. AB - : The present study sought to identify patterns and predictors of disclosure of sexual orientation to healthcare providers among lesbian, gay, and bisexual (LGB) adults. METHODS: Respondents were 396 self-identified LGB individuals ages 18-59, recruited from diverse community venues in New York City, with equal numbers of men and women and Whites, Blacks, and Latinos. Respondents were interviewed at baseline and 1-year follow-up. We assessed the relationships among disclosure of sexual orientation, demographic characteristics, health, and minority stress. RESULTS: Rates of nondisclosure to healthcare providers were significantly higher among bisexual men (39.3%) and bisexual women (32.6%) compared with gay men (10%) and lesbians (12.9%). Bivariate and multivariate logistic regression models predicting disclosure of sexual orientation indicated that patient age, level of education, immigration status, medical history, level of internalized homophobia, and degree of connectedness to the LGB community were significant factors, along with sexual identity. Nondisclosure of sexual orientation was related to poorer psychological wellbeing at one year follow-up. CONCLUSION: Our findings suggest that interventions targeting sexual minorities ought to carefully tailor messages to subpopulations. In particular, interventionists and clinicians ought to be mindful of differences between bisexually- and gay/lesbian-identified individuals. PMID- 23463444 TI - Migration of polyurethane high-volume low-pressure cuffed endotracheal tubes after neck flexion and extension. PMID- 23463443 TI - Personality traits of the Five-Factor Model are associated with work-related stress in special force police officers. AB - PURPOSE: The police work is particularly stressful. The aim of this work was to clarify whether the personality factors are associated with perceived stress levels or reactivity to environmental stressors in a special body of police. METHODS: The police officers in charge of guaranteeing public order at the L'Aquila G8 meeting were subjected to a control of their levels of work-related stress in anticipation of the event. Personality was assessed by the Italian version of the Five-Factor Model questionnaire, while stress was measured three times (during routine work in January 2009, preparation and imminence of the event, in April and July 2009, respectively) with the demand/control/support model of Karasek and the effort/reward imbalance model of Siegrist. A total of 289 of 294 officers took part in the survey. RESULTS: Some personality traits of the Five-Factor Model were associated with stress levels and stress reactivity. Neuroticism (low emotional stability) showed the strongest associations with job strain (demand/control ratio) (beta = 0.115, p < 0.05) and effort/reward imbalance (beta = 0.270, p < 0.001) and was associated with most of the stress variables. High agreeableness was associated with low effort/reward imbalance (beta = -0.157, p < 0.01). CONCLUSIONS: Personality factors may mitigate or increase the strain induced by environmental stressors. PMID- 23463445 TI - Inflation of impact factors by journal self-citation in cardiovascular science. PMID- 23463446 TI - Phantom shocks: innocent bystander or complication of implantable cardioverter defibrillator therapy? PMID- 23463447 TI - Preparation and characterization of a polystyrene/bovine serum albumin nanoparticle-coated capillary for chiral separation using open-tubular capillary electrochromatography. AB - Polystyrene (PS) nanoparticles coated by BSA, hereafter denoted as PS/BSA, were prepared and chemically immobilized for the first time onto a capillary inner wall for open-tubular CEC (OTCEC). EOF and scanning electron micrography were used to characterize the prepared nanoparticle-coated capillaries. To investigate the performance of the prepared columns in OTCEC, chiral separation of d,l tryptophan (dl-Trp) was performed in monolayer BSA-modified capillary and PS/BSA nanoparticle-coated columns. The results indicated that the nanoparticle-modified column afforded a higher resolution compared with the monolayer type. Rapid enantioseparation of dl-Trp (within 3 min) was achieved with the PS/BSA immobilized column using an electroosmotic pump-assisted CEC. Enantiomer separations of other compounds like dl-tyrosine and warfarin were also achieved with the column. Besides, run-to-run and column-to-column repeatabilities of the PS/BSA-coated column in the chiral separation were systematically introduced. PMID- 23463448 TI - Characterization of the vaginal fungal flora in pregnant diabetic women by 18S rRNA sequencing. AB - Pregnancy and diabetes are regarded as individual risk factors for vaginal candidiasis. The high prevalence of vaginal candidiasis in pregnant diabetic women can be explained by disruption of the balance of the vaginal normal flora. However, little is known about the overall structure and composition of the vaginal fungal flora in pregnant diabetic women. In the present study, the diversity and richness of the vaginal fungal flora in healthy non-pregnant women (group HN), healthy pregnant women (group HP), women with gestational diabetes mellitus (group GDM), and pregnant women with diabetes mellitus type I (group T1DM) were investigated using an 18S rRNA gene clone library method. Our data demonstrated that the composition of the vaginal fungal flora in the four groups could be divided into two phyla (Ascomycetes, 20/26, and Basidiomycetes, 6/26). The most predominant vaginal fungal species belonged to the Candida and Saccharomyces genera, uncultured fungi, and a large number of low-abundance taxa that were unrecorded or underrepresented in previous studies using cultivation dependent methods. Variation in operational taxonomic units (OTUs) between the study cohorts was generally high in the clone libraries, as 9, 13, 17, and 20 phylotypes were identified in groups HN, HP, GDM, and T1DM, respectively. The Shannon indices of groups GDM and T1DM (with poorer glycemic control) were significantly higher compared to groups HN and HP (p < 0.05). The data presented here revealed an increased diversity and varied composition of the vaginal fungal flora in pregnant diabetic women and demonstrated that poor glycemic control might be associated with disturbances in the vaginal fungal flora. PMID- 23463449 TI - Flip angle mapping with the accelerated 3D look-locker sequence. AB - PURPOSE: A new approach to mapping the flip angle quickly and efficiently in 3D based on the Look-Locker technique is presented. METHODS: We modified the accelerated 3D Look-Locker T1 measurement technique to allow rapid measurement of flip angle. By removing the inversion pulses and interleaving two radio frequency pulses with different amplitude, it is possible to fit directly for the true flip angle using a reduced number of parameters. This technique, non-inverted Double Angle Look-Locker, allows quick and efficient mapping of the flip angle in 3D. RESULTS: non-inverted Double Angle Look-Locker is validated in vitro against the actual flip angle imaging technique for a range of flip angles and T1 values. Flip angle maps produced with non-inverted Double Angle Look-Locker can be acquired in approximately 1 min, and are accurate to within 10% of the actual flip angle imaging measurement. It is shown to accurately measure the excited slab profile of several different pulses. An application to correcting in vivo DESPOT T1 data is presented. CONCLUSION: The presented technique is a rapid method for mapping flip angles across a 3D volume, capable of producing a flip angle map in approximately 1 min. PMID- 23463451 TI - Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation-a matched pair analysis. AB - Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p = 0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted. PMID- 23463452 TI - Life-threatening bleeding tendency provoked by an acquired isolated factor X deficiency associated with respiratory infection. PMID- 23463453 TI - Positive association between high-sensitivity C-reactive protein and incidence of type 2 diabetes mellitus in Japanese workers: 6-year follow-up. AB - BACKGROUND: Elevated high-sensitivity C-reactive protein (hs-CRP), a marker of low-grade systemic inflammation, may be involved in the etiology of type 2 diabetes mellitus (T2DM). However, whether inflammation precedes development of T2DM independent of cigarette smoking and obesity remains to be confirmed. METHODS: We studied 4213 civil servants in a local government in Japan aged 35-66 years at baseline in 2002, who donated blood samples and were followed 6 years. Hazard ratios (HR) of T2DM according to the hs-CRP quartiles [range Q1: 0.02-0.18 (reference), Q2: 0.18-0.33, Q3: 0.33-0.67 and Q4: 0.67-9.62 mg/L) were estimated by Cox proportional hazards model adjusted for gender, age, body mass index, alcohol intake, smoking status (current, past and never), number of cigarettes per day, physical activity, family history of diabetes (Model 1) and variables in Model 1 + glucose (Model 2). RESULTS: The geometric mean [95% confidence interval (CI)] of hs-CRP was 0.36 mg/L (0.34-0.37). During the follow-up, 156 new T2DM cases were confirmed. In total sample, Model 2 HRs (95% CIs) for hs-CRP quartiles Q2-Q4 compared with Q1 were 0.69 (0.36-1.26), 1.47 (0.91-2.39) and 1.78 (1.10 2.88), respectively (p for linear trend = 0.014). Stratified analysis revealed that a statistically significant association was observed only in normal weight non-current smokers with Model 2 HRs (CIs) being 0.79 (0.29-2.17), 2.63 (1.25 5.56) and 3.19 (1.49-6.86) for Q2-Q4 compared with Q1, respectively (p for linear trend = 0.0006). The relationship did not change materially after further adjusting for log-homeostasis model assessment or exclusion of past smokers. CONCLUSIONS: These findings imply that higher hs-CRP itself or existence of chronic systemic inflammation precedes onset of T2DM independent of obesity and smoking. PMID- 23463454 TI - Direct-to-consumer television advertising exposure, diagnosis with high cholesterol, and statin use. AB - BACKGROUND: While statin drugs are recommended for secondary prevention of coronary heart disease (CHD), there is no medical consensus on whether or not a statin should be added to lifestyle change efforts for primary prevention of CHD. Previous research suggests that exposure to direct-to-consumer advertising (DTCA) increases drug demand among those at comparatively low risk. Research has yet to examine whether individual-level DTCA exposure may influence statin use among men and women at high, moderate, or low risk for future cardiac events. OBJECTIVE: To determine the relationship between estimated exposure to DTCA for statin drugs and two clinical variables: diagnosis with high cholesterol and statin use. DESIGN: We used logistic regression to analyze repeated cross-sectional surveys of the United States population, merged with data on the frequency of DTCA appearances on national, cable, and local television, between 2001 and 2007. PARTICIPANTS: American adults (n=106,685) aged 18 and older. MAIN MEASURES: Levels of exposure to statin DTCA, based on ad appearances and TV viewing patterns; self-reports of whether or not a respondent has been diagnosed with high cholesterol, and whether or not a respondent took a statin in the past year. KEY RESULTS: Adjusting for potential confounders, we estimate that exposure to statin ads increased the odds of being diagnosed with high cholesterol by 16 to 20 %, and increased statin use by 16 to 22 %, among both men and women (p<0.05). These associations were driven almost exclusively by men and women at low risk for future cardiac events. There was also evidence of a negative association between DTCA exposure and statin use among high-risk women (p<0.05) CONCLUSIONS: This study provides new evidence that DTCA may promote over-diagnosis of high cholesterol and over-treatment for populations where risks of statin use may outweigh potential benefits. PMID- 23463455 TI - Preventing prescription opioid overdose deaths. PMID- 23463456 TI - BMI change patterns and disability development of middle-aged adults with diabetes: a dual trajectory modeling approach. AB - BACKGROUND: Few longitudinal studies have examined associations between body mass index (BMI) changes in adults with diabetes and the development of disability. OBJECTIVE: To investigate association patterns between BMI and disability in middle-aged adults with diabetes. DESIGN AND SETTING: Retrospective cohort design with data from the 1992-2006 Health and Retirement Study (HRS). A group-based joint trajectory method identified distinct BMI change trajectories and their link to subsequent disability trajectories. PARTICIPANTS: U.S. nationally representative adults aged 51-61 who reported a diagnosis of diabetes in the 1992 HRS (N = 1,064). MEASUREMENTS: BMI and self-reported disability score were the main variables. Sociodemographic, clinical, behavioral, and diabetes-related factors were also examined. RESULTS: Four distinct weight trajectories (stable normal weight, 28.7 %; stable overweight, 46.2 %; loss and regain obese, 18.0 %; weight cumulating morbidly obese, 7.1 %) and three disability trajectories (little or low increase, 34.4 %; moderate increase, 45.4 %; chronic high increase, 20.2 %) best characterized the long-term patterns of BMI and disability change in middle-aged adults with diabetes. Adults in stable normal weight had the highest probability of being in the little/low increase disability group; however, one in five adults in that group progressed into chronic high disability, a higher proportion compared to the stable overweight group. CONCLUSIONS: Although there were various ways in which the two trajectories were linked, the beneficial impacts of optimizing weight in adults with diabetes were supported. In addition, the complexity of diabetes control in those with relatively normal weight was highlighted from this study. PMID- 23463458 TI - Copper-catalyzed extended Pummerer reactions of ketene dithioacetal monoxides with alkynyl sulfides and ynamides with an accompanying oxygen rearrangement. AB - The first examples of metal-catalyzed extended Pummerer reactions through the activation of sulfoxides are described. The copper-catalyzed reactions of ketene dithioacetal monoxides with alkynyl sulfides and ynamides provided a wide variety of gamma,gamma-disulfanyl-beta,gamma-unsaturated carbonyl compounds with an accompanying oxygen rearrangement. The products can be easily converted into 1,4 dicarbonyl compounds and substituted heteroaromatics. DFT calculations and mechanistic experiments revealed a new interesting stepwise addition/oxygen rearrangement mechanism. PMID- 23463457 TI - Cost-effectiveness of procalcitonin-guided antibiotic use in community acquired pneumonia. AB - BACKGROUND: Although prior randomized trials have demonstrated that procalcitonin guided antibiotic therapy effectively reduces antibiotic use in patients with community-acquired pneumonia (CAP), uncertainties remain regarding use of procalcitonin protocols in practice. OBJECTIVE: To estimate the cost effectiveness of procalcitonin protocols in CAP. DESIGN: Decision analysis using published observational and clinical trial data, with variation of all parameter values in sensitivity analyses. PATIENTS: Hypothetical patient cohorts who were hospitalized for CAP. INTERVENTIONS: Procalcitonin protocols vs. usual care. MAIN MEASURES: Costs and cost per quality adjusted life year gained. KEY RESULTS: When no differences in clinical outcomes were assumed, consistent with clinical trials and observational data, procalcitonin protocols cost $10-$54 more per patient than usual care in CAP patients. Under these assumptions, results were most sensitive to variations in: antibiotic cost, the likelihood that antibiotic therapy was initiated less frequently or over shorter durations, and the likelihood that physicians were nonadherent to procalcitonin protocols. Probabilistic sensitivity analyses, incorporating procalcitonin protocol-related changes in quality of life, found that protocol use was unlikely to be economically reasonable if physician protocol nonadherence was high, as observational study data suggest. However, procalcitonin protocols were favored if they decreased hospital length of stay. CONCLUSIONS: Procalcitonin protocol use in hospitalized CAP patients, although promising, lacks physician nonadherence and resource use data in routine care settings, which are needed to evaluate its potential role in patient care. PMID- 23463459 TI - How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale. AB - Metal pollutants are a global health risk due to their ability to contribute to a variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is implicated in anemia, osteomalacia, hepatic disorder, and neurological disorder. In this review, we outline how this intracellular generator of reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished mitochondrial activity, anerobiosis, and the channeling of alpha-ketoacids towards anti-oxidant defense. The resulting metabolic reconfiguration leads to fat accumulation and a reduction in ATP synthesis, characteristics that are common to numerous medical disorders. Hence, the ability of Al toxicity to create an oxidative environment promotes dysfunctional metabolic processes in astrocytes and hepatocytes. These molecular events triggered by Al-induced ROS production are the potential mediators of brain and liver disorders. PMID- 23463460 TI - [Granulomatous lung and systemic diseases]. AB - Granuloma formation occurs in the human body if there is a particle which persists in phagocytes and which the immune system cannot eliminate. The immune reaction of granuloma formation evolved in order to combat mycobacteria with the aim of localizing mycobacteria and to avoid spreading of mycobacteria throughout the body. Granulomatous lung diseases are often accompanied by severe, systemic inflammation. However, acute phase proteins may be only slightly elevated. The spectrum of granulomatous lung diseases is broad. Sarcoidosis is the most common granulomatous lung disease. To diagnose sarcoidosis, other infectious granulomatous lung diseases such as tuberculosis, atypical mycobacterial and fungal infection have to be ruled out. Pulmonary granuloma also evolve in the context of autoimmune diseases such as rheumatoid arthritis, granulomatosis with polyangiitis (GBA, Wegener's) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Furthermore, immunodeficiencies such as common variable immunodeficiency (CVID) and immune reconstitution syndrome in HIV can be associated with systemic granulomatous inflammation. Finally, occupational lung disease, particularly hypersensitivity pneumonitis, silicosis, hard metal lung, and chronic berylliosis are associated with pulmonary granuloma formation. PMID- 23463461 TI - [Rheumatoid arthritis. Systemic inflammation and cardiovascular morbidity]. AB - In recent years it could be shown that systemic inflammation, which typically occurs in chronic inflammatory rheumatic diseases, significantly contributes to cardiovascular morbidity and mortality. All rheumatic diseases inherit this enhanced risk for cardiovascular complications with rheumatoid arthritis being one of the most prominent. As the underlying pathophysiological mechanisms are very similar with respect to endothelial damage all rheumatic diseases and specifically rheumatoid arthritis should be monitored and treated with disease modifying drugs and biological agents as consistently as possible to be able to improve the long-term outcome of affected patients as much as possible. PMID- 23463462 TI - [Anticytokine therapy]. AB - Anticytokine therapies have revolutionized the treatment of chronic inflammatory diseases, particularly autoimmune diseases such as rheumatoid arthritis. As the first introduced principle of cytokine blockade in the 1990s, tumor necrosis factor (TNF)-alpha antagonists still represent the leading anticytokine therapy. There are currently five TNF antagonists available with indications in the fields of rheumatology, dermatology, and gastroenterology. Other therapeutic approaches have been introduced in the last 10 years, e.g., the blockade of interleukin (IL) 1, IL-6, and IL-12/23. The advantages of cytokine blockers are their rapid onset of action with high response rates and a tolerable safety profile. Nevertheless, anticytokine therapy can cause increased rates of tuberculosis and hepatitis B infections or reactivation. An appropriate screening before therapy is mandatory, and thorough monitoring of the disease course before and during therapy is also important. The development of further anticytokine drugs for the induction and maintenance of remission is, therefore, required. PMID- 23463463 TI - SnO2@CdS nanowire-quantum dots heterostructures: tailoring optical properties of SnO2 for enhanced photodetection and photocatalysis. AB - Rationally designed SnO2@CdS nanowire-quantum dots (QDs) heterostructures were realized by a wet-chemical method via hydroxide cluster growth mechanism on high crystalline quality SnO2 nanowires, which were synthesized by a vapor transport method. The heterostructures showed enhanced photon harvesting capability and photodetection sensitivity at visible regime than that of wide band gap homogeneous SnO2 nanowires, as characterized by UV-Vis absorption and photoconductivity measurements. In addition, the SnO2@CdS nanowire-QDs heterostructures showed enhanced photocatalytic activity by more than 109% in a conceptual demonstration of photodegradation of methylene blue solution. Our results suggest that the SnO2@CdS nanowire-QDs heterostructures exhibit considerable promise for highly sensitive visible-light photodetectors and highly efficient photocatalysis. PMID- 23463464 TI - Replication of genome wide association identified candidate genes confirm the role of common and rare variants in PAX7 and VAX1 in the etiology of nonsyndromic CL(P). AB - Following recent genome wide association studies (GWAS), significant genetic associations have been identified for several genes with nonsyndromic cleft lip with or without cleft palate (CL(P)). To replicate two of these GWAS signals, we investigated the role of common and rare variants in the PAX7 and VAX1 genes. TaqMan genotyping was carried out for SNPs in VAX1 and PAX7 and transmission disequilibrium test (TDT) was performed to test for linkage and association in each population. Direct sequencing in and around the PAX7 and VAX1 genes in 1,326 individuals of European and Asian ancestry was done. The TDT analysis showed strong associations with markers in VAX1 (rs7078160, P = 2.7E-06 and rs475202, P = 0.0002) in a combined sample of Mongolian and Japanese CL(P) case-parent triads. Analyses using parent-of-origin effects showed significant excess transmission of the minor allele from both parents with the effect in the mothers (P = 6.5E-05, OR (transmission) = 1.91) more striking than in the fathers (P = 0.004, OR (transmission) = 1.67) for VAX1 marker rs7078160 in the combined Mongolian and Japanese samples when all cleft types were combined. The rs6659735 trinucleotide marker in PAX7 was significantly associated with all the US cleft groups combined (P = 0.007 in all clefts and P = 0.02 in CL(P)). Eight rare missense mutations found in PAX7 and two rare missense mutations in VAX1. Our study replicated previous GWAS findings for markers in VAX1 in the Asian population, and identified rare variants in PAX7 and VAX1 that may contribute to the etiology of CL(P). Determining the role of rare variants clearly warrants further investigation. PMID- 23463466 TI - Expert's Comment concerning Grand Rounds Case entitled "Congenital C1 arch deficiency: Grand Round presentation" (by M. Elmalky, S. Elsayed, G. Arealis, H. Mehdian doi:10.1007/s00586-013-2682-z). PMID- 23463465 TI - Function of the master energy regulator adenosine monophosphate-activated protein kinase in stroke. AB - Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved signaling molecule that is emerging as one of the most important energy sensors in the body. AMPK monitors cellular energy status and is activated via phosphorylation when energy stores are low. This allows for maintenance of energy homeostasis by promoting catabolic pathways for ATP production and limiting processes that consume ATP. Growing number of stimuli have been shown to activate AMPK, and AMPK has been implicated in many diverse biological processes, including cell polarity, autophagy, and senescence. The effect of AMPK activation and its biological functions are extremely diverse and depend on both the overall energy "milieu" and the location and duration of activation. AMPK has tissue- and isoform-specific functions in the brain vs. periphery. These functions and the pathways activated also appear to differ by cell location (hypothalamus vs. cortex), cell type (astrocyte vs. neuron), and duration of exposure. Short bursts of AMPK activation have been found to be involved in ischemic preconditioning and neuronal survival; however, prolonged AMPK activity during ischemia leads to neuronal cell death. AMPK may also underlie some of the beneficial effects of hypothermia, a potential therapy for ischemic brain injury. This review discusses the role of AMPK in ischemic stroke, a condition of severe energy depletion. PMID- 23463467 TI - The correlation between cervical range of motion and misplacement of cervical pedicle screws during cervical posterior spinal fixation surgery using a CT-based navigation system. AB - PURPOSE: The aim of this study was to analyze the correlation between cervical range of motion and cervical pedicle screw (CPS) misplacement in cervical posterior spinal fusion surgery using a CT-based navigation system. METHODS: A total of 46 consecutive patients with cervical posterior spinal fusion surgery using CPSs were evaluated retrospectively. We analyzed the cervical range of motion (ROM) and the misplacement of CPSs that were placed using either separate or single-time multilevel registration with a CT-based navigation system to determine the optimum registration procedure. The screw-inserted vertebra was indicated as Registered vertebra-Pedicle Screw inserted vertebra (Re-PS) = 0, 1, 2, or 3 depending on its distance (level) from the registered vertebra. Grades 0 (no perforation) and 1 (perforations <2 mm) were categorized as "no misplacement." Grades 2 (perforations ? 2 mm but < 4 mm) and 3 (perforations ? 4 mm) were categorized as "misplacement." We analyzed the correlations between CPS misplacement and Re-PS, and between CPS misplacement and preoperative cervical ROM. RESULTS: Our analysis included 196 screws in patients having a mean age of 53.2 years (range 5-84 years). Level of insertion relative to registration was Re PS = 0 in 129 screws, Re-PS = 1 in 53, Re-PS = 2 in 10 and Re-PS = 3 in 4. The misplacement rates were 12.2 % (24 screws) overall, 6.2 % in Re-PS = 0, 22.6 % in Re-PS = 1, 20 % in Re-PS = 2, and 50 % in Re-PS = 3. The rate of CPS misplacement increased significantly with a Re-PS = 1 and a Re-PS = 2 and 3 compared to a Re PS = 0. There was a significant difference in the cervical ROM in each grade and both misplacement groups: 1.8 in Grade 0, 2.3 in Grade 1, 7.8 in Grade 2, 12.9 in Grade 3, 11 in the misplacement group and 1.9 in the no misplacement group. CONCLUSIONS: The precision of CPS placement in CT-based navigation surgery was evaluated. The misplacement rate in single-time multilevel registration increased to 23.4 % compared to 6.2 % for separate registration. As the distance increased between the registered level and the level of CPS insertion, the preoperative cervical ROM and the rate of CPS misplacement significantly increased. Thus, the rate of misplacement of CPSs is reduced when performing separate registration. Furthermore, when there is greater preoperative cervical ROM, separate registration would likely improve the safety and accuracy of CPS insertion. PMID- 23463468 TI - Successful large-volume cerebrospinal fluid aspiration for an accidental overdose of intrathecal cytarabine. AB - Intrathecal therapy with cytarabine is widely used in the treatment of acute lymphocytic leukemia. We report the first case of accidental intrathecal cytarabine overdose in an adult patient. Overdose of intrathecal chemotherapy has been reported to cause severe neurological damage including seizures, coma and death. Methotrexate levels can help guide intrathecal dosing of methotrexate, but no such test is commercially available for cytarabine. There are no standardized treatment recommendations for the management of this medical emergency. Intrathecal methotrexate overdose has been variously treated with cerebrospinal fluid drainage or exchange. Ventriculo-lumbar perfusion, steroids and leucovorin have also been used. It seems crucial to quickly remove as much drug as possible from the cerebrospinal fluid. Our patient was successfully treated with large volume cerebrospinal fluid aspiration through an Ommaya reservoir. She did not suffer any significant immediate or late complications at 4 months of follow-up. PMID- 23463469 TI - [Reduced neuropathic risk via enhanced glucose control?]. PMID- 23463470 TI - [Lifestyle intervention in type 2 diabetes: is remission possible? Overcoming thinking barriers--lifestyle interventions have great benefits!]. PMID- 23463471 TI - [Trends in pneumology: defining positions]. PMID- 23463472 TI - [Inpatient or outpatient treatment of pulmonary embolism? Outpatient treatment!]. PMID- 23463473 TI - [Inpatient or outpatient treatment of pulmonary embolism? Inpatient treatment!]. PMID- 23463474 TI - [Hemoptysis--targets in diagnostic and therapy]. AB - Hemoptysis (coughing up blood) is an extremely alarming situation for the patient, caused by various different underlying diseases. First of all, a peripheral venous catheter should be placed and oxygen should be supplied as patients are threatened by impaired gas exchange caused by the bleeding. Bronchoscopy should be performed immediately, although computed tomography of the thorax may give valuable diagnostic information and should be performed if permitted by the clinical situation. Rigid bronchoscopy should be performed as it allows a broader spectrum of therapeutic options. PMID- 23463475 TI - [55-year-old woman with progressive exertional dyspnoea and radiological pulmonary changes]. PMID- 23463476 TI - [Pulmonary sarcoidosis: current diagnosis and treatment]. AB - Sarcoidosis is a multisystemic granulomatous disorder of unknown origin, which can involve multiple organs. However the lymph node and lung manifestations dominate. Most frequent symptoms are cough, fatigue, dyspnea and exercise limitations. About one third of the patients have no symptoms. The lung function test is mostly restrictive. The clinical course is very variable, spontaneous remissions occur in about 60 %. Acute sarcoidosis is a highly inflammatory disease with a very good prognosis even without steroid therapy. Chronic pulmonary sarcoidosis can lead to progressive loss of lung function. Indications to therapy are severe symptoms and loss of lung function as well as progressive lung involvement with fibrosis pattern. In chronic disease corticosteroids are effective in the majority of patients. Other immunosuppressives, cytotoxic and immunomodulatory agents are reserved for patients with severe side-effects to steroid-therapy or for patients, who cannot maintained on reasonable low doses of steroids. Lung transplantation is an option for life-threatening cases failing medical therapy. PMID- 23463477 TI - [Aspirin-exacerbated respiratory disease]. AB - Aspirin sensitivity is an important underlying disease in patients with nasal polyps, intrinsic asthma or urticaria. The terms "Aspirin- (or analgetics-) induced asthma" or "Aspirin-exacerbated respiratory disease" (AERD) describe the syndrome of chronic rhinosinusititis, polyposis nasi, asthma and acute reaction after ingestion of non-steroid antiinflammatory drugs (NSAID). The disease affects mainly women in the third decade or older. Nasal symptoms often appear many years previous to asthma and acute intolerance reactions. Nasal polyps not rarely require surgical interventions. However, polyps often relapse after weeks or few months after resection. The intrinsic asthma is difficult to control and patients often require treatment with oral steroids. The disease is not caused by the ingestion of NSAID, the sensitivity represents a phenomenon of the underlying metabolic disorder. Aspirin sensitivity is not an allergic disease based on IgE mediated reactions. In contrast it is due to a metabolic overexpression of cysteinyl leucotrienes. Thus, skin tests and specific antibodies in the blood are always negative. Recent studies indicate that NSAID sensitivity may be proven and differentiated by sophisticated in vitro tests. However, nasal, bronchial, and oral provocation testing remains the standard of diagnosis. Aspirin desensitization is the most relevant therapeutical approach which improves nasal symptoms in the majority of patients and may stabilize intrinsic asthma. PMID- 23463479 TI - Fluorescent magnetic Fe3 O4 /rare Earth colloidal nanoparticles for dual-modality imaging. AB - Fluorescent magnetic colloidal nanoparticles (FMCNPs) are produced by a two-step, seed emulsifier-free emulsion polymerization in the presence of oleic acid and sodium undecylenate-modified Fe3 O4 nanoparticles (NPs). The Fe3 O4 /poly(St-co GMA) nanoparticles are first synthesized as the seed and Eu(AA)3 Phen is copolymerized with the remaining St and GMA to form the fluorescent polymer shell in the second step. The uniform core-shell structured FMCNPs with a mean diameter of 120 nm exhibit superparamagnetism with saturation magnetization of 1.92 emu/g. Red luminescence from the FMCNPs is confirmed by the salient fluorescence emission peaks of europium ions at 594 and 619 nm as well as 2-photon confocal scanning laser microscopy. The in vitro cytotoxicity test conducted using the MTT assay shows good cytocompatibility and the T2 relaxivity of the FMCNPs is 353.86 mM(-1) S(-1) suggesting its potential in magnetic resonance imaging (MRI). In vivo MRI studies based on a rat model show significantly enhanced T2 -weighted images of the liver after administration and prussian blue staining of the liver tissue slice reveals accumulation of FMCNPs in the organ. The cytocompatibility, superparamagnetism, and excellent fluorescent properties of FMCNPs make them suitable for biological imaging probes in MRI and optical imaging. PMID- 23463480 TI - Cytokine response to acute running in recreationally-active and endurance-trained men. AB - To compare the cytokine response to exhaustive running in recreationally-active (RA) and endurance-trained (ET) men. Eleven RA men (VO2max 55 +/- 7 mL.min( 1).kg(-1)) and 10 ET men (VO2max 68 +/- 7 mL.min(-1).kg(-1)) followed a controlled diet and refrained from volitional exercise for 8 days. On the fourth day, participants completed 60 min of treadmill running (65 % VO2max), followed by intermittent running to exhaustion (70 % VO2max). Fasting blood was obtained at baseline, after 20, 40 and 60 min of exercise, at the end of intermittent exercise, during 2 h of recovery and on four follow-up days (FU1-FU4). Tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra) and creatine kinase (CK) were measured. Exercise increased the concentrations of all cytokines and CK, but there were no significant differences between groups. IL-1beta increased (2.2-2.5 fold, P < 0.001) during exercise, while TNF-alpha was increased (1.6-2.0-fold, P < 0.001) during exercise and for 2 h post-exercise. IL-6 (71-84-fold, P < 0.001) and IL-1ra (52-64-fold, P < 0.001) were increased throughout exercise and up to FU1, peaking immediately after exercise and at 1.5-2 h post-exercise, respectively. CK concentrations were increased (P < 0.001) throughout exercise and up to FU4, peaking at FU1, but were not associated with changes in any cytokines. Exhaustive running resulted in modest and transient increases in TNF alpha and IL-1beta, and more marked and prolonged increases in IL-6 and IL-1ra, but improved training status did not affect this response. Increased CK might indicate either exercise-induced muscle cell disruption or increased cell permeability, although neither appears to have contributed to the increased cytokine concentrations. PMID- 23463481 TI - Anti-vascular endothelial growth factor therapy in the era of personalized medicine. AB - PURPOSE: To review the role of anti-vascular endothelial growth factor (anti VEGF) therapies in the personalized medicine era. METHODS: We searched PubMed for prospective clinical trials published through October 2012 of anti-VEGF agents approved by the U.S. Food and Drug Administration or the European Medicines Agency. RESULTS: The use of anti-VEGF drugs as single agents or in combination with other targeted or cytotoxic agents was associated with improved response rates and progression-free survival. Anti-VEGF therapy exerts its action by blocking tumor vessel formation and, thus, proliferation. Some investigators demonstrated modest to no improvement in overall survival, although the maintenance of anti-VEGF therapy beyond progression was shown to result in longer overall survival. The use of anti-VEGF therapy was associated with adverse events (i.e., thromboembolism, hemorrhage, myocardial infarction, and hypertension) and transformation to a more invasive phenotype. CONCLUSIONS: The development of multikinase targeting agents that include anti-VEGF properties warrants further investigation. The role of anti-VEGF therapy is evolving in the era of personalized medicine, and its use needs to be reassessed in tumor types with effective FDA-approved targeted agents, especially in light of its relatively high cost. PMID- 23463482 TI - Phase II trial of paclitaxel and cisplatin as neoadjuvant chemotherapy for locally advanced gastric cancer. AB - PURPOSE: Paclitaxel-cisplatin (TC) combination is effective and well tolerated in patients with unresectable gastric cancer. We investigated the efficacy and safety of TC for locally advanced gastric cancers in a neoadjuvant setting. METHODS: Patients received 2-4 courses of paclitaxel (80 mg/m(2)) and cisplatin (25 mg/m(2)) on days 1, 8, and 15 in a 4-weekly schedule, followed by radical gastrectomy. Primary endpoint was the pathological response rate: percentage of tumors in which one-third or more parts were affected. RESULTS: All 52 patients enrolled were eligible. Thirty-six (69.7 %) patients completed two or more courses of chemotherapy. Forty-three patients (82.7 %) underwent surgery, 33 (63.5 %) had R0 resection, and there was no treatment-related death. The pathological response was 34.6 % (95 % CI 22.0-49.1) for all registered patients; the null hypothesis of tumor response <=10 % was rejected (p < 0.0001). The 3 year overall survival was 41.5 % (95 % CI 27.4-55.0). CONCLUSIONS: The neoadjuvant chemotherapy with TC was safe and effective for patients with locally advanced gastric cancer, and further study is needed to confirm the effectiveness of this regimen. PMID- 23463483 TI - In non-obese patients, duration of action of rocuronium is directly correlated with body mass index. AB - BACKGROUND: Administration of neuromuscular blocking agents using a dose calculated on actual body weight carries a risk of prolonged duration of action in obese patients whose body mass index (BMI) is > 30 kg . m(-2). In the present study, we hypothesized that there could be a correlation between BMI and the duration of action of rocuronium administered according to actual body weight in non-obese patients, in particular, overweight (BMI 25-30 kg . m(-2)) and underweight patients (BMI < 18.5 kg . m(-2)). METHODS: Sixteen female patients (BMI 15-30 kg . m(-2), aged 45-60 yr) scheduled for elective surgery under total intravenous anesthesia were included in this study. Rocuronium 0.9 mg . kg(-1) was administered, and adductor pollicis train-of-four responses following ulnar nerve stimulation were monitored every minute with acceleromyography. The times from the injection of rocuronium until spontaneous recovery of first twitch to 5% (5% Duration) and 25% (25% Duration) of baseline were measured, and the correlation with BMI was analyzed. RESULTS: A significant correlation between 5% Duration and BMI (r(2) = 0.56; P < 0.001) was found by linear regression analysis. A significant correlation was also found between 25% Duration and BMI (r(2) = 0.49; P = 0.003). CONCLUSION: In adult female patients with a BMI in the range of 15-30 kg . m(-2), the duration of action of rocuronium increases with BMI when the drug is administered on the basis of mg per actual kg body weight. PMID- 23463484 TI - Direct determination of pregabalin in human urine by nonaqueous CE-TOF-MS. AB - Determination of pregabalin in urine samples was carried out by nonaqueous CE with TOF-MS via ESI, with a mixture of 10 mM ammonium formate and 0.05% acetic acid in methanol. By using TOF-MS, accurate mass information was obtained, thus causing a great improvement in qualitative ability. In order to avoid ionic suppression, urine samples dilution 1:10 was used. This was the only treatment to urine samples before the injection. Despite this dilution, the detection limit was as low as 0.03 MUg/mL for pregabalin. The method was validated with respect to accuracy, precision, and linearity, LOD, and LOQ. This method was applied to the analysis of urine samples from seven different cancer patients undergoing treatment with pregabalin. The developed method may find wide application for the routine determination of pregabalin in biological samples in order to establish a more efficient and safe dosage. PMID- 23463485 TI - Evaluation of tibial osteopathy occurrence in neurofibromatosis type 1 Italian patients. AB - Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disorder characterized by high penetrance, widely variable expressivity and occurrence of specific skeletal changes such as tibial osteopathy (TO). We collected data on patients referred to the Italian Neurofibromatosis Study Group in order to compare clinical features between 49 NF1 patients with TO, and 98 age-matched NF1 patients without TO, and to determine whether the presence of TO is associated with a different risk of developing the typical NF1 complications. We assessed both groups for: age at diagnosis of NF1, gender distribution, family history, gender inheritance, presence of scoliosis, sphenoid wing osteopathy, other skeletal abnormalities, macrocrania, hydrocephalus, plexiform neurofibromas, tumors, optic pathway gliomas, T2H (high-signal intensity areas on T2 weighted brain MRI), epilepsy, headache, mental retardation, cardiovascular malformations, and Noonan phenotype. Patients of both groups were subdivided by gender and re evaluated for these items. Statistical comparison was carried out between the two groups of patients for each feature. We collected data on type of treatment and on the clinical conditions of NF1-TO patients after follow-up. Patient's age at NF1 diagnosis was significantly younger in NF1-TO subjects compared with NF1 subjects without TO, and the incidence of T2H was significantly reduced in NF1-TO males compared with NF1 males without TO. The presence of TO does not imply that there is an increased risk of developing typical complications of NF1 (e.g., optic pathway glioma, plexiform neurofibroma, etc.), however, it does allow us to make an earlier diagnosis of NF1. PMID- 23463486 TI - Single shot fast spin echo diffusion imaging with correction for non-linear phase errors using tailored RF pulses. AB - PURPOSE: The use of tailored RF excitation pulses for prospective correction of non-linear motion-induced phase patterns is shown to enable diffusion-weighted (DW) fast spin echo (FSE) imaging in vivo. Echo-planar imaging (EPI) remains the most used sequence for DW imaging. Despite being highly sensitive to field inhomogeneities, EPI is robust to motion-induced phase shifts. FSE sequences are much less sensitive to field inhomogeneities, but require precise control of the transverse magnetization phase, which is hard to achieve with DW. Real time measurements and correction of phase ramps due to rigid-body motion had been proposed, but performance remained unsatisfactory because of non-linear phase patterns related to pulsatile motion. METHODS: Reproducible non-linear phase components are calibrated using 2D-EPI navigators and tailored RF excitation pulses designed. Real time correction of rigid-body motion was not yet implemented. RESULTS: Phase correction was confirmed with full signal DW-FSE images obtained on co-operative subjects. Full diffusion tensor acquisitions were obtained and color-coded maps displaying principal fiber directionality calculated. Results were consistent with corresponding EPI acquisitions except for absence of spatial distortions. CONCLUSION: Combining the proposed method with real time compensation of rigid-body motion has the potential to allow high quality, distortion free diffusion imaging throughout the brain. PMID- 23463487 TI - A fully integrated continuous-flow system for asymmetric catalysis: enantioselective hydrogenation with supported ionic liquid phase catalysts using supercritical CO(2) as the mobile phase. AB - A continuous-flow process based on a chiral transition-metal complex in a supported ionic liquid phase (SILP) with supercritical carbon dioxide (scCO(2)) as the mobile phase is presented for asymmetric catalytic transformations of low volatility organic substrates at mild reaction temperatures. Enantioselectivity of >99% ee and quantitative conversion were achieved in the hydrogenation of dimethylitaconate for up to 30 h, reaching turnover numbers beyond 100000 for the chiral QUINAPHOS-rhodium complex. By using an automated high-pressure continuous flow setup, the product was isolated in analytically pure form without the use of any organic co-solvent and with no detectable catalyst leaching. Phase-behaviour studies and high-pressure NMR spectroscopy assisted the localisation of optimum process parameters by quantification of substrate partitioning between the IL and scCO(2). Fundamental insight into the molecular interactions of the metal complex, ionic liquid and the surface of the support in working SILP catalyst materials was gained by means of systematic variations, spectroscopic studies and labelling experiments. In concert, the obtained results provided a rationale for avoiding progressive long-term deactivation. The optimised system reached stable selectivities and productivities that correspond to 0.7 kgL(-1)h(-1) space-time yield and at least 100 kg product per gram of rhodium, thus making such processes attractive for larger-scale application. PMID- 23463488 TI - Satavaptan treatment for ascites in patients with cirrhosis: a meta-analysis of effect on hepatic encephalopathy development. AB - Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites. PMID- 23463489 TI - Gut microbiota and hepatic encephalopathy. AB - There is a strong relationship between liver and gut; while the portal venous system receives blood from the gut, and its contents may affect liver functions, liver in turn, affects intestinal functions through bile secretion. There is robust evidence that the pathogenesis of hepatic encephalopathy (HE) is linked to alterations in gut microbiota and their by-products such as ammonia, indoles, oxindoles, endotoxins, etc. In the setting of intestinal barrier and immune dysfunction, these by-products are involved in the pathogenesis of complications of liver cirrhosis including HE and systemic inflammation plays an important role. Prebiotics, probiotics and synbiotics may exhibit efficacy in the treatment of HE by modulating the gut flora. They improve derangement in flora by decreasing the counts of pathogenic bacteria and thus improving the endotoxemia, HE and the liver disease. Current evidence suggest that the trials evaluating the role of probiotics in the treatment of HE are of not high quality and all trials had high risk of bias and high risk of random errors. Therefore, the use of probiotics for patients with HE cannot be currently recommended. Further RCTs are required. This review summarizes the main literature findings about the relationships between gut flora and HE, both in terms of the pathogenesis and the treatment of HE. PMID- 23463490 TI - Allele-specific marker development and selection efficiencies for both flavonoid 3'-hydroxylase and flavonoid 3',5'-hydroxylase genes in soybean subgenus soja. AB - Color is one of the phenotypic markers mostly used to study soybean (Glycine max L. Merr.) genetic, molecular and biochemical processes. Two P450-dependent mono oxygenases, flavonoid 3'-hydroxylase (F3'H; EC1.14.3.21) and flavonoid 3',5' hydroxylase (F3'5'H, EC1.14.13.88), both catalyzing the hydroxylation of the B ring in flavonoids, play an important role in coloration. Previous studies showed that the T locus was a gene encoding F3'H and the W1 locus co-segregated with a gene encoding F3'5'H in soybean. These two genetic loci have identified to control seed coat, flower and pubescence colors. However, the allelic distributions of both F3'H and F3'5'H genes in soybean were unknown. In this study, three novel alleles were identified (two of four alleles for GmF3'H and one of three alleles for GmF3'5'H). A set of gene-tagged markers was developed and verified based on the sequence diversity of all seven alleles. Furthermore, the markers were used to analyze soybean accessions including 170 cultivated soybeans (G. max) from a mini core collection and 102 wild soybeans (G. soja). For both F3'H and F3'5'H, the marker selection efficiencies for pubescence color and flower color were determined. The results showed that one GmF3'H allele explained 92.2 % of the variation in tawny and two gmf3'h alleles explained 63.8 % of the variation in gray pubescence colors. In addition, two GmF3'5'H alleles and one gmF3'5'h allele explained 94.0 % of the variation in purple and 75.3 % in white flowers, respectively. By the combination of the two loci, seed coat color was determined. In total, 90.9 % of accessions possessing both the gmf3'h-b and gmf3'5'h alleles had yellow seed coats. Therefore, seed coat colors are controlled by more than two loci. PMID- 23463491 TI - Genomic inversion caused by gamma irradiation contributes to downregulation of a WBC11 homolog in bloomless sorghum. AB - Epicuticular wax (bloom) plays important roles in protecting the tissues of sorghum (Sorghum bicolor (L.) Moench) plants from abiotic stresses. However, reducing wax content provides resistance to greenbug and sheath blight-a useful trait in agricultural crops. We generated a sorghum bloomless (bm) mutant by gamma irradiation. One bm population segregated for individuals with and without epicuticular wax at a frequency of 72:22, suggesting that the bm mutation was under the control of a single recessive nuclear gene. Genes differentially expressed in the wild-type and the bm mutant were identified by RNA-seq technology. Of the 31 downregulated genes, Sb06g023280 was the most differentially expressed and was similar to WBC11, which encodes an ABC transporter responsible for wax secretion in Arabidopsis. An inversion of about 1.4 Mb was present in the region upstream of the Sb06g023280 gene in the bm mutant; it is likely that this inversion changed the promoter sequence of the Sb06g023280 gene. Using genomic PCR, we confirmed that six independent F2 bm mutant-phenotype plants carried the same inversion. Therefore, we concluded that the inversion involving the Sb06g023280 gene inhibited wax secretion in the bloomless sorghum. PMID- 23463492 TI - Fast track genetic improvement of ascochyta blight resistance and double podding in chickpea by marker-assisted backcrossing. AB - Ascochyta blight (AB) caused by the fungus Ascochyta rabiei Pass. Lab. is one of the major diseases of chickpea worldwide and a constraint to production in western Canada. The use of varieties with high levels of resistance is considered the most economical solution for long-term ascochyta blight management in chickpea. QTL for resistance to ascochyta blight have been identified in chickpea. The availability of molecular markers associated with QTL for ascochyta blight resistant and double podding provides an opportunity to apply marker assisted backcrossing to introgress the traits into adapted chickpea cultivars. In the present study, molecular markers that were linked to the QTL for ascochyta blight resistance and the double podding trait, and those unlinked to the resistance were used in foreground and background selection, respectively, in backcrosses between moderately resistant donors (CDC Frontier and CDC 425-14) and the adapted varieties (CDC Xena, CDC Leader and FLIP98-135C). The strategy included two backcrosses and selection for two QTL for ascochyta blight resistance and a locus associated with double podding. The fixation of the elite genetic background was monitored with 16-22 SSR markers to accelerate restoration of the genetic background at each backcross. By the BC2F1 generation, plants with improved ascochyta blight resistance and double podding were identified. The selected plants possessed the majority of elite parental type SSR alleles on all fragments analyzed except the segment of LG 4, LG 6 and LG 8 that possessed the target QTL. The results showed that the adapted variety could be efficiently converted into a variety with improved resistance in two backcross generations. PMID- 23463493 TI - Identification of genetic markers linked to anthracnose resistance in sorghum using association analysis. AB - Anthracnose in sorghum caused by Colletotrichum sublineolum is one of the most destructive diseases affecting sorghum production under warm and humid conditions. Markers and genes linked to resistance to the disease are important for plant breeding. Using 14,739 SNP markers, we have mapped eight loci linked to resistance in sorghum through association analysis of a sorghum mini-core collection consisting of 242 diverse accessions evaluated for anthracnose resistance for 2 years in the field. The mini-core was representative of the International Crops Research Institute for the Semi-Arid Tropics' world-wide sorghum landrace collection. Eight marker loci were associated with anthracnose resistance in both years. Except locus 8, disease resistance-related genes were found in all loci based on their physical distance from linked SNP markers. These include two NB-ARC class of R genes on chromosome 10 that were partially homologous to the rice blast resistance gene Pib, two hypersensitive response related genes: autophagy-related protein 3 on chromosome 1 and 4 harpin-induced 1 (Hin1) homologs on chromosome 8, a RAV transcription factor that is also part of R gene pathway, an oxysterol-binding protein that functions in the non-specific host resistance, and homologs of menthone:neomenthol reductase (MNR) that catalyzes a menthone reduction to produce the antimicrobial neomenthol. These genes and markers may be developed into molecular tools for genetic improvement of anthracnose resistance in sorghum. PMID- 23463494 TI - Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. AB - OBJECTIVE: To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). METHODS: Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune-cell subsets were determined by flow cytometry, whereas thymic function was assessed using T-cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous system-autoreactive antigen-specific T-cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T-cell responses. RESULTS: Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses. INTERPRETATION: Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT. PMID- 23463495 TI - EdU induces DNA damage response and cell death in mESC in culture. AB - Recently, a novel DNA replication precursor analogue called 5-ethynyl-2' deoxyuridine (EdU) has been widely used to monitor DNA synthesis as an alternative to bromodeoxyuridine. Use of EdU benefits from simplicity and reproducibility and the simple chemical detection systems allows excellent preservation of nuclear structure. However, the alkyne moiety is highly reactive, raising the possibility that incorporation might compromise genome stability. To assess the extent of possible DNA damage, we have analysed the effect of EdU incorporation into DNA during short- and long-term cell culture using a variety of cell lines. We show that EdU incorporation has no measurable impact on the rate of elongation of replication forks during synthesis. However, using different cell lines we find that during long-term cell culture variable responses to EdU incorporation are seen, which range from delayed cell cycle progression to complete cell cycle arrest. The most profound phenotypes were seen in mouse embryonic stem cells, which following incorporation of EdU accumulated in the G2/M-phase of the cell cycle before undergoing apoptosis. In long-term cell culture, EdU incorporation also triggered a DNA damage response in all cell types analysed. Our study shows that while EdU is extremely useful to tag sites of on-going replication, for long-term studies (i.e. beyond the cell cycle in which labelling is performed), a careful analysis of cell cycle perturbations must be performed in order to ensure that any conclusions made after EdU treatment are not a direct consequence of EdU-dependent activation of cell stress responses. PMID- 23463496 TI - The COBLL1 C allele is associated with lower serum insulin levels and lower insulin resistance in overweight and obese children. AB - BACKGROUND: Childhood obesity is a growing epidemic worldwide, and it is associated with metabolic complications, such as insulin resistance. Recently, a genetic variation (rs7607980) in the COBLL1 gene has been associated with lower insulin resistance in adults. The aim of the study was to investigate if the association between COBLL1 rs7607980 genetic variant and lower insulin resistance was present early in life. METHODS: This sequence variant was genotyped in 878 overweight and obese children (mean age: 10 years) from Sardinia, Italy, from the outpatient clinic of the Pediatric Endocrine Unit, at the Regional Hospital for Microcitaemia in Cagliari. Insulin resistance was assessed by measurement of fasting circulating insulin levels before and after an oral glucose tolerance test and by HOMA-IR. RESULTS: The COBLL1 rs7607980 C allele was associated with lower fasting insulin and HOMA-IR levels (p = 0.002 and p = 0.035, respectively) in overweight and obese children. Importantly, lower insulin levels were also observed 2 h after oral glucose tolerance test in C allele carriers (p = 0.009). CONCLUSIONS: The present study shows for the first time, the association between COBLL1 rs7607980 C allele, lower serum insulin levels and lower insulin resistance in overweight and obese children. PMID- 23463497 TI - A paradigm shift in flap selection protocols for zones of the lower extremity using perforator flaps. AB - BACKGROUND: Significant lower limb wounds often require soft tissue coverage using vascularized flaps. Traditionally, local muscles have been used for the proximal lower extremity and free flaps for the distal leg and foot, but perforator flaps over the past decade have been shown to be a reliable alternative. METHODS: The evolution of our lower limb flap selection for the period 1996 to 2000 was retrospectively compared with our current approach using perforator flaps. Flap selection was never random, but based according to wound location, severity, and flap availability. RESULTS: In the preperforator flap era, 101 of 122 (82.8%) flaps were muscle flaps. Over the last 5 years, this relative usage decreased to 36.4%, whereas perforator flaps were chosen almost half the time (49.6%). Local flaps still predominated as the choice for the proximal lower limb, and free flaps more distally, with perforator free flaps chosen twice as often as muscle flaps. Major complications occurred most commonly in the more distal lower extremity and were related to microsurgical catastrophes and not flap subtype. CONCLUSIONS: Perforator flaps can be another soft tissue choice for all zones of the lower extremity, recognizing that function preservation is their major asset as no muscle need be included. Peninsular, propeller, or advancement perforator flaps proved to be valuable local nonmicrosurgical flap alternatives. PMID- 23463499 TI - Surgical treatment of high-grade dysplastic spondylolisthesis using intraoperative electrophysiological monitoring: report of two cases and review of the literature. AB - Treatment of high-grade dysplastic spondylolisthesis in adolescents remains challenging. Surgical treatment of spondylolisthesis has been recommended in adolescents with pain refractory to conservative treatment, slippage progression, or severe slippage on presentation. Controversy exists as to the optimal surgical approach for high-grade spondylolisthesis. Moreover, some authors reported the incidence of L5 root palsy during the reduction procedure. We performed 2 cases of surgical treatment using intraoperative electrophysiological monitoring for patients with high-grade dysplastic spondylolisthesis in adolescence. Each patient received treatment consisting of decompression of nerve with surgical microscope, reduction, and circumferential fusion with transpedicular and monosegmental fixation surgery with intraoperative neurological monitoring with transcranial electric motor evoked potentials and continuous spontaneous electromyography recording. Intraoperative monitoring did not show any abnormal changes. The patients got well after surgery, and they showed no postoperative motor paralysis of the extremities. A postoperative radiogram showed reduction of the slippage, and computed tomogram showed bone union between L5 and S1 vertebral body. This report describes 2 cases of surgical treatment using intraoperative electrophysiological monitoring with transcranial electric motor evoked potentials and continuous spontaneous electromyography for patients with high grade dysplastic spondylolisthesis in adolescence. We successfully perform the surgery without any neurological deficit using intraoperative electrophysiological monitoring. PMID- 23463500 TI - From lamprey to salamander: an exploratory modeling study on the architecture of the spinal locomotor networks in the salamander. AB - The evolutionary transition from water to land required new locomotor modes and corresponding adjustments of the spinal "central pattern generators" for locomotion. Salamanders resemble the first terrestrial tetrapods and represent a key animal for the study of these changes. Based on recent physiological data from salamanders, and previous work on the swimming, limbless lamprey, we present a model of the basic oscillatory network in the salamander spinal cord, the spinal segment. Model neurons are of the Hodgkin-Huxley type. Spinal hemisegments contain sparsely connected excitatory and inhibitory neuron populations, and are coupled to a contralateral hemisegment. The model yields a large range of experimental findings, especially the NMDA-induced oscillations observed in isolated axial hemisegments and segments of the salamander Pleurodeles waltlii. The model reproduces most of the effects of the blockade of AMPA synapses, glycinergic synapses, calcium-activated potassium current, persistent sodium current, and [Formula: see text]-current. Driving segments with a population of brainstem neurons yields fast oscillations in the in vivo swimming frequency range. A minimal modification to the conductances involved in burst-termination yields the slower stepping frequency range. Slow oscillators can impose their frequency on fast oscillators, as is likely the case during gait transitions from swimming to stepping. Our study shows that a lamprey-like network can potentially serve as a building block of axial and limb oscillators for swimming and stepping in salamanders. PMID- 23463498 TI - Perioperative interventions to reduce chronic postsurgical pain. AB - Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan. PMID- 23463501 TI - Horse-like walking, trotting, and galloping derived from kinematic Motion Primitives (kMPs) and their application to walk/trot transitions in a compliant quadruped robot. AB - This manuscript proposes a method to directly transfer the features of horse walking, trotting, and galloping to a quadruped robot, with the aim of creating a much more natural (horse-like) locomotion profile. A principal component analysis on horse joint trajectories shows that walk, trot, and gallop can be described by a set of four kinematic Motion Primitives (kMPs). These kMPs are used to generate valid, stable gaits that are tested on a compliant quadruped robot. Tests on the effects of gait frequency scaling as follows: results indicate a speed optimal walking frequency around 3.4 Hz, and an optimal trotting frequency around 4 Hz. Following, a criterion to synthesize gait transitions is proposed, and the walk/trot transitions are successfully tested on the robot. The performance of the robot when the transitions are scaled in frequency is evaluated by means of roll and pitch angle phase plots. PMID- 23463503 TI - Pathology in context. PMID- 23463504 TI - Letter to the editor. PMID- 23463502 TI - Mapping the global emergence of Batrachochytrium dendrobatidis, the amphibian chytrid fungus. AB - The rapid worldwide emergence of the amphibian pathogen Batrachochytrium dendrobatidis (Bd) is having a profound negative impact on biodiversity. However, global research efforts are fragmented and an overarching synthesis of global infection data is lacking. Here, we provide results from a community tool for the compilation of worldwide Bd presence and report on the analyses of data collated over a four-year period. Using this online database, we analysed: 1) spatial and taxonomic patterns of infection, including amphibian families that appear over- and under-infected; 2) relationships between Bd occurrence and declining amphibian species, including associations among Bd occurrence, species richness, and enigmatic population declines; and 3) patterns of environmental correlates with Bd, including climate metrics for all species combined and three families (Hylidae, Bufonidae, Ranidae) separately, at both a global scale and regional (U.S.A.) scale. These associations provide new insights for downscaled hypothesis testing. The pathogen has been detected in 52 of 82 countries in which sampling was reported, and it has been detected in 516 of 1240 (42%) amphibian species. We show that detected Bd infections are related to amphibian biodiversity and locations experiencing rapid enigmatic declines, supporting the hypothesis that greater complexity of amphibian communities increases the likelihood of emergence of infection and transmission of Bd. Using a global model including all sampled species, the odds of Bd detection decreased with increasing temperature range at a site. Further consideration of temperature range, rather than maximum or minimum temperatures, may provide new insights into Bd-host ecology. Whereas caution is necessary when interpreting such a broad global dataset, the use of our pathogen database is helping to inform studies of the epidemiology of Bd, as well as enabling regional, national, and international prioritization of conservation efforts. We provide recommendations for adaptive management to enhance the database utility and relevance. PMID- 23463505 TI - Structural sensitivity of a prokaryotic pentameric ligand-gated ion channel to its membrane environment. AB - Although the activity of the nicotinic acetylcholine receptor (nAChR) is exquisitely sensitive to its membrane environment, the underlying mechanisms remain poorly defined. The homologous prokaryotic pentameric ligand-gated ion channel, Gloebacter ligand-gated ion channel (GLIC), represents an excellent model for probing the molecular basis of nAChR sensitivity because of its high structural homology, relative ease of expression, and amenability to crystallographic analysis. We show here that membrane-reconstituted GLIC exhibits structural and biophysical properties similar to those of the membrane reconstituted nAChR, although GLIC is substantially more thermally stable. GLIC, however, does not possess the same exquisite lipid sensitivity. In particular, GLIC does not exhibit the same propensity to adopt an uncoupled conformation where agonist binding is uncoupled from channel gating. Structural comparisons provide insight into the chemical features that may predispose the nAChR to the formation of an uncoupled state. PMID- 23463506 TI - The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. AB - Extracellular vesicles are emerging as a potent mechanism of intercellular communication because they can systemically exchange genetic and protein material between cells. Tetraspanin molecules are commonly used as protein markers of extracellular vesicles, although their role in the unexplored mechanisms of cargo selection into exosomes has not been addressed. For that purpose, we have characterized the intracellular tetraspanin-enriched microdomain (TEM) interactome by high throughput mass spectrometry, in both human lymphoblasts and their derived exosomes, revealing a clear pattern of interaction networks. Proteins interacting with TEM receptors cytoplasmic regions presented a considerable degree of overlap, although some highly specific CD81 tetraspanin ligands, such as Rac GTPase, were detected. Quantitative proteomics showed that TEM ligands account for a great proportion of the exosome proteome and that a selective repertoire of CD81-associated molecules, including Rac, is not correctly routed to exosomes in cells from CD81-deficient animals. Our data provide evidence that insertion into TEM may be necessary for protein inclusion into the exosome structure. PMID- 23463507 TI - Mycobacterium tuberculosis MutT1 (Rv2985) and ADPRase (Rv1700) proteins constitute a two-stage mechanism of 8-oxo-dGTP and 8-oxo-GTP detoxification and adenosine to cytidine mutation avoidance. AB - Approximately one third of the world population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. A better understanding of the pathogen biology is crucial to develop new tools/strategies to tackle its spread and treatment. In the host macrophages, the pathogen is exposed to reactive oxygen species, known to damage dGTP and GTP to 8-oxo-dGTP and 8-oxo-GTP, respectively. Incorporation of the damaged nucleotides in nucleic acids is detrimental to organisms. MutT proteins, belonging to a class of Nudix hydrolases, hydrolyze 8-oxo-G nucleoside triphosphates/diphosphates to the corresponding nucleoside monophosphates and sanitize the nucleotide pool. Mycobacteria possess several MutT proteins. However, a functional homolog of Escherichia coli MutT has not been identified. Here, we characterized MtuMutT1 and Rv1700 proteins of M. tuberculosis. Unlike other MutT proteins, MtuMutT1 converts 8-oxo-dGTP to 8-oxo-dGDP, and 8-oxo-GTP to 8-oxo-GDP. Rv1700 then converts them to the corresponding nucleoside monophosphates. This observation suggests the presence of a two-stage mechanism of 8-oxo-dGTP/8-oxo-GTP detoxification in mycobacteria. MtuMutT1 converts 8-oxo-dGTP to 8-oxo-dGDP with a Km of ~50 MUM and Vmax of ~0.9 pmol/min per ng of protein, and Rv1700 converts 8 oxo-dGDP to 8-oxo-dGMP with a Km of ~9.5 MUM and Vmax of ~0.04 pmol/min per ng of protein. Together, MtuMutT1 and Rv1700 offer maximal rescue to E. coli for its MutT deficiency by decreasing A to C mutations (a hallmark of MutT deficiency). We suggest that the concerted action of MtuMutT1 and Rv1700 plays a crucial role in survival of bacteria against oxidative stress. PMID- 23463508 TI - Cysteine-rich domain 1 of CD40 mediates receptor self-assembly. AB - The activation of CD40 on B cells, macrophages, and dendritic cells by its ligand CD154 (CD40L) is essential for the development of humoral and cellular immune responses. CD40L and other TNF superfamily ligands are noncovalent homotrimers, but the form under which CD40 exists in the absence of ligand remains to be elucidated. Here, we show that both cell surface-expressed and soluble CD40 self assemble, most probably as noncovalent dimers. The cysteine-rich domain 1 (CRD1) of CD40 participated to dimerization and was also required for efficient receptor expression. Modelization of a CD40 dimer allowed the identification of lysine 29 in CRD1, whose mutation decreased CD40 self-interaction without affecting expression or response to ligand. When expressed alone, recombinant CD40-CRD1 bound CD40 with a K(D) of 0.6 MUM. This molecule triggered expression of maturation markers on human dendritic cells and potentiated CD40L activity. These results suggest that CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state. PMID- 23463509 TI - The REV7 subunit of DNA polymerase zeta is essential for primordial germ cell maintenance in the mouse. AB - REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene expression, and carcinogenesis. In vitro studies show that REV7 interacts with several proteins and regulates their function. It has been reported that human REV7 is highly expressed in the adult testis by Northern blot analysis. However, the significance of REV7 in mammalian development has not been elucidated. Here, we present analyses of REV7-deficient (Rev7(-/-)) mice to clarify the significance of Rev7 in mouse development. In WT mice (Rev7(+/+)), Rev7 expression was ubiquitously observed in the embryo and confined to germ cells in the testes after birth. Rev7(-/-) mice exhibited growth retardation and a partial embryonic lethal phenotype. Mice that survived to adulthood were infertile in both sexes and showed germ cell aplasia in the testes and ovaries. Analyses of Rev7(-/-) embryos revealed that primordial germ cells (PGCs) were present at embryonic day 8.5 (E8.5). However, progressive loss of PGCs was observed during migration, and PGCs were absent in the genital ridges at E13.5. An increase of apoptotic cells was detected not only among PGCs but also in the forebrain of the Rev7(-/-) embryo, whereas cell proliferation was unaffected. Moreover, DNA damage accumulation and increased levels of histone methylation were detected in Rev7(-/-) embryos, and expression of Oct4 and Nanog was deregulated by REV7 deficiency at E8.5. These findings indicate that Rev7 is essential for PGC maintenance by prevention of apoptotic cell death in the mouse. PMID- 23463510 TI - A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair. AB - In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair. PMID- 23463511 TI - Single-molecule investigation of substrate binding kinetics and protein conformational dynamics of a B-family replicative DNA polymerase. AB - Replicative DNA polymerases use a complex, multistep mechanism for efficient and accurate DNA replication as uncovered by intense kinetic and structural studies. Recently, single-molecule fluorescence spectroscopy has provided new insights into real time conformational dynamics utilized by DNA polymerases during substrate binding and nucleotide incorporation. We have used single-molecule Forster resonance energy transfer techniques to investigate the kinetics and conformational dynamics of Sulfolobus solfataricus DNA polymerase B1 (PolB1) during DNA and nucleotide binding. Our experiments demonstrate that this replicative polymerase can bind to DNA in at least three conformations, corresponding to an open and closed conformation of the finger domain as well as a conformation with the DNA substrate bound to the exonuclease active site of PolB1. Additionally, our results show that PolB1 can transition between these conformations without dissociating from a primer-template DNA substrate. Furthermore, we show that the closed conformation is promoted by a matched incoming dNTP but not by a mismatched dNTP and that mismatches at the primer template terminus lead to an increase in the binding of the DNA to the exonuclease site. Our analysis has also revealed new details of the biphasic dissociation kinetics of the polymerase-DNA binary complex. Notably, comparison of the results obtained in this study with PolB1 with those from similar single molecule studies with an A-family DNA polymerase suggests mechanistic differences between these polymerases. In summary, our findings provide novel mechanistic insights into protein conformational dynamics and substrate binding kinetics of a high fidelity B-family DNA polymerase. PMID- 23463512 TI - Identification of the thiol isomerase-binding peptide, mastoparan, as a novel inhibitor of shear-induced transforming growth factor beta1 (TGF-beta1) activation. AB - TGF-beta1 is a disulfide-bonded homodimeric protein produced by platelets and other cells that plays a role in many physiologic and pathologic processes. TGF beta1 is secreted as an inactive large latent complex (LLC) comprised of TGF beta1, latency-associated peptide, and latent TGF-beta binding protein 1. We previously demonstrated that shear force can activate LLC and that thiol disulfide exchange contributes to the process. We have now investigated the role of thiol isomerases in the activation of LLC in platelet releasates (PR) and recombinant LLC. The wasp venom peptide mastoparan, which inhibits the chaperone activity of PDI, inhibited stirring- and shear-induced activation of latent TGF beta1 by 90 and 75% respectively. To identify the proteins that bind to mastoparan either directly or indirectly, PR were chromatographed on a mastoparan affinity column. Latent TGF-beta binding protein 1, latency-associated peptide, TGF-beta1, clusterin, von Willebrand factor, multimerin-1, protein disulfide isomerase (PDI), ERp5, ERp57, and ERp72 eluted specifically from the column. Anti PDI RL90 attenuated the inhibitory effect of mastoparan on LLC activation. Furthermore, reduced PDI inhibited activation of PR LLC, whereas oxidized PDI had no effect. We conclude that thiol isomerases and thiol-disulfide exchange contribute to TGF-beta1 activation and identify a number of molecules that may participate in the process. PMID- 23463513 TI - Transcomplementation by a truncation mutant of cystic fibrosis transmembrane conductance regulator (CFTR) enhances DeltaF508 processing through a biomolecular interaction. AB - We previously showed that a truncation mutant of CFTR missing the first four transmembrane segments of TMD1, Delta264 CFTR, binds to key elements in the ER quality control mechanism to increase the amounts of the mature C band of both wt and DeltaF508 CFTR through transcomplementation. Here, we created a new construct, Delta27-264 CFTR. Even though Delta27-264 CFTR is rapidly degraded in the proteasome, steady state protein can be detected by Western blot. Delta27-264 CFTR can also increase the amounts of the mature C band of both wt and DeltaF508 CFTR through transcomplementation. Electrophysiology experiments show that Delta27-264 CFTR can restore chloride channel currents. Further experiments with the conduction mutant S341A show conclusively that currents are indeed generated by rescued channel function of DeltaF508 CFTR. Immunoprecipitation studies show that Delta27-264 binds to DeltaF508-CFTR, suggesting a bimolecular interaction. Thus the adeno-associated viral vector, rAAV-Delta27-264 CFTR, is a highly promising CF gene therapy vector, because it increases the amount of mature band C protein both from wt and DeltaF508 CFTR, and rescues channel activity of DeltaF508 CFTR. PMID- 23463514 TI - How subvisible particles become invisible-relevance of the refractive index for protein particle analysis. AB - The aim of the present study was to quantitatively assess the relevance of transparency and refractive index (RI) on protein particle analysis by the light based techniques light obscuration (LO) and Micro-Flow Imaging (MFI). A novel method for determining the RI of protein particles was developed and provided an RI of 1.41 for protein particles from two different proteins. An increased RI of the formulation by high protein concentration and/or sugars at pharmaceutically relevant levels was shown to lead to a significant underestimation of the subvisible particle concentration determined by LO and MFI. An RI match even caused particles to become "invisible" for the system, that is, not detectable anymore by LO and MFI. To determine the influence of formulation RI on particle measurements, we suggest the use of polytetrafluoroethylene (PTFE) particles to test a specific formulation for RI effects. In case of RI influences, we recommend also using a light-independent technique such as resonant mass measurement (RMM) (Archimedes) for subvisible particle analysis in protein formulations. PMID- 23463516 TI - Changes in membrane fatty acid composition of Pseudomonas aeruginosa in response to UV-C radiations. AB - The changes in lipid composition enable the micro-organisms to maintain membrane functions in the face of environmental fluctuations. The relationship between membrane fatty acid composition and UV-C stress was determined for mid exponential phase and stationary phase Pseudomonas aeruginosa. The total lipids were obtained by dichloromethane/methanol (3:1) and were quantified by GC. The TLC analysis of phospholipids showed the presence of three major fractions phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. Significant modifications, as manifested by an increase of UFA, were obtained. Interestingly, this microorganism showed a remarkable capacity for recovery from the stressful effects of UV-C. PMID- 23463515 TI - Isolation and identification of environmental mycobacteria in the waters of a hemodialysis center. AB - The use of poorly treated water during hemodialysis may lead to contamination with nontuberculous mycobacteria (NTM). This study aimed to isolate and identify NTM species in the water of a Brazilian hemodialysis center. We collected 210 samples of water from the hydric system of the unit (post-osmosis system, hemodialysis rooms, reuse system, and hemodialysis equipment) and from the municipal supply network; we isolated the NTM by a classic microbiological technique and identified them by the PCR restriction enzyme pattern of the hsp65 gene (PRA). Fifty-one (24.3 %) of the collected samples tested positive for NTM; both the municipal supply network (2 samples, 3.2 %) and the hydric system of the hemodialysis center (49 samples, 96.1 %) contained NTM. We isolated and identified potentially pathogenic bacteria such as Mycobacterium lentiflavum (59.0 %) and M. kansasii (5.0 %), as well as rarely pathogenic bacteria like M. gordonae (24.0 %), M. gastri (8.0 %), and M. szulgai (4.0 %). The ability of NTM to cause diseases is well documented in the literature. Therefore, the identification of NTM in the water of a Brazilian hemodialysis center calls for more effective water disinfection procedures in this unit. PMID- 23463517 TI - Proteome analysis of the two-component SalK/SalR system in Epidemic Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 (SS2) is a major swine pathogen of significant commercial importance worldwide and an emerging zoonotic agent of human streptococcal toxic shock-like syndrome. We previously reported that the Chinese highly pathogenic SS2 strains specifically harbor an 89K pathogenicity island, and the SalK/SalR two-component system encoded within this island mediates a piglet-lethal phenotype. However, its regulatory mechanism remains obscure. In the present study, we performed a proteome analysis to identify the target proteins regulated by the SalK/SalR system. This expression profiling analysis reveals 14 down-regulated proteins and 1 up-regulated protein. In partial accord with our previous microarray analysis, 9 out of the 14 down-regulated genes are also repressed at the transcriptional level. From the 9 matched genes, 5 were selected and further subjected to gene knockout and experimental infection of mice. The results show that the selected 5 genes are potential virulence factors and participate to various extents in the pathogenesis of SS2 infection, and may contribute to the attenuation of virulence mediated by the SalK/SalR system. PMID- 23463518 TI - Plasma pharmacochemistry combined with microdialysis to screen potential bioactive components and their metabolites in Anemarrhena asphodeloides saponin extract using ultrahigh-performance liquid chromatography/quadrupole-time-of flight mass spectrometry. AB - Although various techniques have been employed to analyze drug metabolites, the metabolism of multicomponent herbal medicine has seldom been fully addressed. In contrast to chemical drugs, a number of compounds in herbal medicine could get into circulation and then be metabolized. Metabolism study on active constituents in herbal medicine is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of herbal medicine. The present work aims to elucidate the multicomponent metabolic characteristics of a herbal medicine by the combination of plasma pharmacochemistry and microdialysis sampling. Anemarrhena asphodeloides, a well-known traditional Chinese medicine, was chosen as a model. After oral administration of A. asphodeloides saponin extract to rats, microdialysis samples were collected continuously in the jugular vein and analyzed by ultrahigh-performance LC/quadrupole-TOF MS. The identification of compounds in biosamples was achieved by accurate mass measurement and detailed fragmentation pathway analysis. The results showed that unbound constituents in blood circulation of the rat included seven parent saponins and six metabolites, which might be the potential active components in vivo. Among which, three metabolites have not been previously reported and were identified in this study. It is the first report on systemic metabolism of total saponins of A. asphodeloides in mammalian plasma. PMID- 23463519 TI - Reorientation of microfluidic channel enables versatile dielectrophoretic platforms for cell manipulations. AB - Dielectrophoresis is a versatile tool for the sorting, immobilization, and characterization of cells in microfluidic systems. The performance of dielectrophoretic systems strongly relies on the configuration of microelectrodes, which produce a nonuniform electric field. However, once fabricated, the microelectrodes cannot be reconfigured to change the characteristics of the system. Here, we show that the reorientation of the microfluidic channel with respect to the microelectrodes can be readily utilized to alter the characteristics of the system. This enables us to change the location and density of immobilized viable cells across the channel, release viable cells along customized numbers of streams within the channel, change the deflection pattern of nonviable cells along the channel, and improve the sorting of viable and nonviable cells in terms of flow throughput and efficiency of the system. We demonstrate that the reorientation of the microfluidic channel is an effective tool to create versatile dielectrophoretic platforms using the same microelectrode design. PMID- 23463520 TI - Is postoperative adjuvant chemoradiotherapy necessary for high-risk oropharyngeal squamous cell carcinoma? AB - BACKGROUND: High-risk factors for recurrence of head and neck squamous cell carcinoma after surgical resection include involvement of >= 2 regional lymph nodes, extracapsular spread, and microscopic involvement of resected mucosal margins. Adjuvant chemoradiotherapy is thought to improve postoperative locoregional control and survival. In this paper, we evaluate the efficacy of adjuvant therapy for high-risk oropharyngeal squamous cell carcinoma (OPSCC) (i.e., with >= 2 lymph nodes, positive extracapsular spread, or positive margins). METHODS: This is a retrospective analysis of 45 high-risk OPSCC patients who underwent surgery without adjuvant therapy (n = 19), with radiotherapy (n = 17), or with chemoradiotherapy (n = 9). RESULTS: The median follow-up period was 41.0 months. Radiotherapy patients showed a trend toward longer overall survival than patients without adjuvant therapy [hazard ratio (HR) = 0.32, p = 0.176]. However, overall survival for the chemoradiotherapy group seemed to be the same as that for the no adjuvant therapy group (HR = 0.79, p = 0.779). Multivariate analysis found that the relative risk of recurrence for patients without adjuvant therapy compared with any adjuvant therapy was 3.02 (p = 0.101). The relative recurrence risk in radiotherapy patients was 0.95 compared with that in chemoradiotherapy patients (p = 0.971). However, pathological T stage was significantly associated with disease-free survival for high-risk OPSCC. CONCLUSIONS: Although the current study uses data from a small retrospective sample of patients, our results suggest that the addition of chemotherapy to radiotherapy may not be necessary as an adjuvant therapy for all high-risk OPSCC. A novel prognostic factor, such as pathological T-stage, should be considered for selecting those patients with high-risk OPSCC who would benefit from adjuvant therapy. PMID- 23463521 TI - Old but new methods in radiation oncology: hyperbaric oxygen therapy. AB - The presence of hypoxic tumor cells is widely regarded as one of the main reasons behind the failure to control malignant tumors with radiotherapy treatments. Since hyperbaric oxygenation (HBO) improves the oxygen supply to the hypoxic tumor cells, HBO therapy has previously been used in combination with simultaneous radiotherapy to treat malignant tumors. In some clinical trials, significant improvements in local control and survival have been seen in cancers of the head and neck and the uterine cervix. However, the delivery of simultaneous HBO therapy and radiotherapy is both complex and time-consuming, with some trials reporting increased side effects. As a result, the regimen of HBO therapy in combination with simultaneous radiotherapy has yet to be used as a standard treatment for malignant tumors. In recent years, however, radiotherapy immediately after HBO therapy has been emerging as an attractive approach for overcoming hypoxia in cancer treatment. Several studies have reported that radiotherapy immediately after HBO therapy was safe and seemed to be effective in patients with high-grade gliomas. Also, this approach may protect normal tissues from radiation injury. To accurately estimate whether the delivery of radiotherapy immediately after HBO therapy can be beneficial in patients with high-grade gliomas and other cancers, further prospective studies are warranted. PMID- 23463522 TI - Antinociceptive effects of H3 (R-methylhistamine) and GABA(B) (baclofen)-receptor ligands in an orofacial model of pain in rats. AB - The present study explored the antinociceptive effects of H3 (R-methylhistamine) and GABA(B) (baclofen) receptor ligands in an orofacial model of pain in rats. Orofacial pain was induced by subcutaneous injection of formalin (50 MUl, 5 %) in the upper lip region, and the number of jumps and time spent face rubbing was recorded for 40 min. Formalin produced a marked biphasic pain response; first phase, 0-10 min (jumps), and second phase, 15-40 min, (rubbing). Baclofen (50 MUg) injected into the rat wiskerpad 5 min before formalin administration suppressed both phases of pain whereas R-alpha-methylhistamine (12.5 MUg) abolished the first phase only. Brains were taken immediately after behavioral testing was completed. HPLC/ED analysis showed that 5-hydroxytryptamine (5-HT) turnover was increased in hippocampus, thalamus, and brain stem of all formalin groups, excepting the baclofen group in which the balance of 5-HT metabolism was restored to control values. These findings demonstrate that GABA(B) receptors represent peripheral targets for analgesia. Consequently, locally administered baclofen may be a useful approach in treating inflammatory trigeminal pain. PMID- 23463523 TI - Treatment with gentamicin on a murine model of protothecal mastitis. AB - The aim of this study was to establish a murine protothecal mastitis model and to evaluate the treatment efficiency of gentamicin. Challenge routes were determined with a pathogenic Prototheca zopfii genotype 2 (P. zopfii) strain. 25 BALB/c mice were inoculated in mammary glands with graded dosages (10(3), 10(4), 10(5), 10(6), 10(7) CFU of P. zopfii) and killed on the 7th day. Another 25 animals were also killed at 1, 3, 5, 7, and 9 days after inoculation of 1 * 10(6) CFU of P. zopfii, the milk somatic cell counts, pathological section of mammary glands, and P. zopfii burden were observed. The antimicrobial activity was tested using disc diffusion test and minimum inhibitory concentrations. Gentamicin was given intramuscularly to analyze the therapeutic effect. The results showed that the best infection route was intra-mammary gland, and the mastitis model was established with 1 * 10(6) CFU of P. zopfii. After infection, the somatic cell counts increased significantly. The pathological reaction mainly consisted of infiltration of inflammatory cells, destruction of acini, accumulation of lymphocyte cells and the severity of the changes was dosage and time-dependent. The P. zopfii burden revealed that P. zopfii continuously replicated. In vitro susceptibility tests indicated that the Prototheca strains were antimicrobial susceptible to gentamicin at concentrations between 0.03 and 4 MUg/ml. In vivo therapeutic assay demonstrated that high concentrations of gentamicin (>=20 mg/kg) could inhibit the growth of P. zopfii. We conclude that the murine model of protothecal mastitis was established successfully and gentamicin may be an effective choice for treatment of P. zopfii. PMID- 23463524 TI - Veronaea botryosa: molecular identification with amplified fragment length polymorphism (AFLP) and in vitro antifungal susceptibility. AB - Inter- and intraspecific genomic variability of 18 isolates of Veronaea botryosa originating from clinical and environmental sources was studied using amplified fragment length polymorphism (AFLP). The species was originally described from the environment, but several severe cases of disseminated infection in apparently healthy individuals have been reported worldwide. All tested strains of V. botryosa, identified on the basis of sequencing and phenotypic and physiological criteria prior to our study, were confirmed by AFLP analysis, yielding a clear separation of V. botryosa as a rather homogeneous group from related species. In vitro antifungal susceptibility testing resulted in MIC90s across all strains in increasing order posaconazole (0.25 MUg/ml), itraconazole (1 MUg/ml), voriconazole (4 MUg/ml), terbinafine (4 MUg/ml), caspofungin (8 MUg/ml), anidulafungin (8 MUg/ml), isavuconazole (16 MUg/ml), amphotericin B (16 MUg/ml), and fluconazole (32 MUg/ml). Overall, the isolates showed a uniform pattern of low MICs of itraconazole and posaconazole, but high MICs for remaining agents. The echinocandins (caspofungin and anidulafungin) had no activity against V. botryosa. There was no statistically significant difference between susceptibilities of environmental (n = 11) and clinical (n = 7) isolates of V. botryosa (P > 0.05). PMID- 23463526 TI - Patient perception of deep brain stimulation hardware. PMID- 23463525 TI - Digestion products of the PH20 hyaluronidase inhibit remyelination. AB - OBJECTIVE: Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that remyelinate spared axons. The glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and has been implicated in the failure of OPC maturation and remyelination. We tested the hypothesis that OPCs in demyelinating lesions express a specific hyaluronidase, and that digestion products of this enzyme inhibit OPC maturation. METHODS: Mouse OPCs grown in vitro were analyzed for hyaluronidase expression and activity. Gain of function studies were used to define the hyaluronidases that blocked OPC maturation. Mouse and human demyelinating lesions were assessed for hyaluronidase expression. Digestion products from different hyaluronidases and a hyaluronidase inhibitor were tested for their effects on OPC maturation and functional remyelination in vivo. RESULTS: OPCs demonstrated hyaluronidase activity in vitro and expressed multiple hyaluronidases, including HYAL1, HYAL2, and PH20. HA digestion by PH20 but not other hyaluronidases inhibited OPC maturation into OLs. In contrast, inhibiting HA synthesis did not influence OPC maturation. PH20 expression was elevated in OPCs and reactive astrocytes in both rodent and human demyelinating lesions. HA digestion products generated by the PH20 hyaluronidase but not another hyaluronidase inhibited remyelination following lysolecithin-induced demyelination. Inhibition of hyaluronidase activity lead to increased OPC maturation and promoted increased conduction velocities through lesions. INTERPRETATION: We determined that PH20 is elevated in demyelinating lesions and that increased PH20 expression is sufficient to inhibit OPC maturation and remyelination. Pharmacological inhibition of PH20 may therefore be an effective way to promote remyelination in multiple sclerosis and related conditions. PMID- 23463528 TI - [New spirometric reference values for children and adolescents in Germany considering height and non-linear age effects: the LUNOKID-study]. AB - BACKGROUND: Comparing children's lung function with reference values is important for diagnosing respiratory diseases. The values by Zapletal et al., commonly used nowadays, are not appropriate for the current stage of children's development. We have now developed new reference values and a lower limit of normal (LLN) for children in Germany, divided into small-range age and height categories. MATERIAL AND METHODS: We examined 4- to 18-year-old children in 3 German communities under field conditions. 1943 children were healthy and had a visually acceptable lung function which also fulfilled international quality criteria. We used the regression model LMS, which was introduced by Stanojevic and Quanjer in this context. RESULTS: There were significant differences between the measured lung function and the predicted values according to Zapletal et al. The lung function did not only depend on the child's height, but also in a non-linear way on the age. The variation coefficient did not depend on age. CONCLUSIONS: To avoid diagnostic errors, the currently often used reference values according to Zapletal et al. should no longer be used. The non-linear dependence on age corresponds to the recently published results by Stanojevic and Quanjer. PMID- 23463529 TI - [Correct inhalation therapy: instructions provided by Internet-based video screens. An initiative of the German Airway League]. AB - BACKGROUND: Inhalation therapy is well recognized as a cornerstone treatment of airway diseases. In daily practice, however, high failure rates of inhalation technique are evident, which substantially attenuates the treatment success. METHODS: In 2011 the German Airway League has initiated the production of video screens for correct inhalation aimed at providing an efficient and globally available platform for information. All devices regularly used have been filmed and published via internet and DVD; thereby, video screens, spoken text passages, and visual insertion of information have been combined. Here, all important steps of inhalation therapy like preparation, performance, and termination have been covered. RESULTS: Video screens of 20 different devices lasting between 1:42 and 3:11 min:sec have been produced between July 2011 and January 2013 and published on the YouTube channel of the German Airway League with more than 70.000 clicks so far (27. February 2013). CONCLUSIONS: Pragmatic, internet-based video screens on the correct inhalation therapy are available and are cost-free. Further studies aimed at evaluating the benefits of these screens are necessary. PMID- 23463530 TI - [Chronic rhinosinusitis--a common piece in pneumological puzzles]. PMID- 23463532 TI - A facile method to determine the absolute structure of achiral molecules: supramolecular-tilt structures. AB - Achiral compounds 4-methoxy-4-(p-methoxyphenyl)cyclohexanoneethylene ketal (2), 4 hydroxy-4-(p-methoxy phenyl)cyclohexanoneethylene ketal (3), and 3,5-dimethyl-4 nitropyrazole (4) crystallized in chiral structures and the samples showed an enantiomeric excess. We have determined the absolute structures of these compounds by using X-ray diffraction with copper radiation at low temperatures. Moreover, we have also established the prevalent absolute structures in these samples, by comparing their calculated and solid-state vibrational circular dichroism (VCD) spectra. The consistency of this method was confirmed by using (R,R)-2,8-diiodo-4,10-dimethyl-6 H,12H-5,11-methano-dibenzo[b,f][1,5]diazocine, Troger's base, (R,R)-1, as a chiral compound of known absolute configuration. PMID- 23463533 TI - Patient with esophageal cancer showing remission of nephrotic syndrome after esophagectomy: report of a case. AB - A 73-year-old male patient was admitted to our hospital due to bilateral leg edema and proteinuria in April 2009. After admission, nephrotic syndrome (membranous nephropathy) was diagnosed. At that point, a cancer screening test was performed; however, no abnormalities were noted. Medical treatment with prednisolone and cyclosporine was started, which resulted in the temporary improvement of markers of laboratory data. The patient was re-examined in November of the same year, and esophageal cancer (squamous cell carcinoma, T2N0M0 Stage IIA according to the UICC TNM classification) was detected in the lower thoracic esophagus. Subtotal esophagectomy was performed via right thoracolaparotomy with two-field lymph node dissection. Although the patient's course was complicated by respiratory failure, he was discharged after 38 days. After performing esophagectomy, prompt amelioration of the nephrotic syndrome occurred, allowing the withdrawal of prednisolone and cyclosporine. There has been no recurrence of esophageal cancer or relapse of nephrotic syndrome during a period of 18 months after esophagectomy. PMID- 23463534 TI - Infradiaphragmatic malperfusion of acute aortic dissection associated with previous abdominal aortic aneurysm repair. AB - PURPOSE: To evaluate the association of previous abdominal aortic aneurysm (AAA) graft replacement with infradiaphragmatic malperfusion in patients with acute aortic dissection. METHODS: Between November 2006 and June 2011, 133 patients were referred to our hospital for management of acute aortic dissection. Eight (6.0 %) of these patients had undergone AAA graft replacement prior to the acute aortic dissection. We compared the computed tomography (CT) images of these 8 patients with those of the remaining 125 patients without previous AAA graft replacement, in terms of organ ischemia as a complication induced by acute aortic dissection. RESULTS: Infradiaphragmatic malperfusion from acute aortic dissection was confirmed in four of the eight patients who had undergone AAA graft replacement. Contrasted CT scan images indicated that the main cause of infradiaphragmatic malperfusion was collapse of the true lumen from compression by the false lumen into the suprarenal aorta. Although there was no significant difference between the groups in terms of cerebral ischemia and myocardial ischemia, bilateral leg ischemia and visceral ischemia occurred more frequently in the patients who had undergone AAA graft replacement. CONCLUSION: Previous AAA graft replacement is a risk factor for infradiaphragmatic malperfusion in patients with acute aortic dissection. PMID- 23463535 TI - Incremental change in acute esophageal necrosis: report of two cases. AB - Acute esophageal necrosis, also called "black esophagus" because of its characteristic appearance on endoscopy, is a life-threatening disease; however, its temporal evolution on endoscopy is not well understood. We describe the serial changes in acute esophageal necrosis in two patients, who underwent four upper endoscopic examinations each. Serial endoscopy demonstrated progressive necrosis extending from the lower esophagus proximally to involve the middle or upper thoracic esophagus in both patients. The first patient was treated with transhiatal esophagectomy, followed by esophageal reconstruction, and medical control of repeated duodenal ulcer bleeding. The second patient died of esophageal perforation, as a complication of Sengstaken-Blakemore tube stent placement to control esophageal bleeding. We report these cases to demonstrate the importance of early detection and prompt surgical treatment of acute esophageal necrosis. PMID- 23463536 TI - Laparoscopic gastrectomy for patients with a history of upper abdominal surgery: results of a matched-pair analysis. AB - PURPOSE: The safety and feasibility of laparoscopic gastrectomy (LG) for patients who have undergone previous upper abdominal surgery (PUAS) remain unclear. A matched-pair analysis was conducted to compare the short-term outcomes of LG between patients with gastric cancer who had undergone PUAS and those who had not. METHODS: A matched-pair analysis was performed to compare the short-term outcomes of LG between 22 patients who had undergone PUAS and 66 who had not (control group). To compare the outcome to that of open gastrectomy (OG) following PUAS, a total of 143 consecutive OG patients treated during the same study period were also reviewed. RESULTS: Cholecystectomy was the most common type of PUAS, followed by gastrectomy. There were no significant differences between the groups in terms of the length of the operation, blood loss, and the number of retrieved lymph nodes or the rate of conversion to open surgery. The postoperative morbidity in the PUAS group (3/22, 13.6 %) was comparable to that of the control group (7/66, 10.6 %, P = 0.6981). There was no mortality within 30 days in either group. When compared to OG following PUAS (n = 23), LG was performed with significantly less blood loss with an equivalent postoperative outcome. CONCLUSIONS: LG following PUAS is considered to be a safe and feasible surgical modality. PUAS should therefore not be regarded as a contraindication for LG. PMID- 23463537 TI - Impact of postoperative infliximab maintenance therapy on preventing the surgical recurrence of Crohn's disease: a single-center paired case-control study. AB - PURPOSE: Preventing a recurrence of Crohn's disease is a problem that remains to be solved. We evaluated the impact of using infliximab as a postoperative therapy on preventing the surgical recurrence of Crohn's disease. METHODS: We performed a pair-matched study comparing 100 patients who had received postoperative infliximab maintenance therapy with those who had not between 1995 and 2010. The patients were matched by gender, Vienna classification and age at the time of the operation. Crohn's disease-related reoperation was evaluated as surgical recurrence. RESULTS: In the postoperative infliximab maintenance therapy group, infliximab was administrated within 8 weeks after the operation. The median follow-up period was 36 months in the postoperative infliximab maintenance therapy group and 51 months in the control group. Surgical recurrences were recognized in 37 patients (three in the postoperative infliximab maintenance therapy group and 34 in the control group). A univariate analysis by the Kaplan Meier method identified a body mass index >18 at the time of the operation (HR 0.19, p = 0.01) and postoperative infliximab maintenance therapy (HR 0.22, p = 0.0022) as factors related to the reduction of surgical recurrence. The multivariate analysis revealed that postoperative infliximab maintenance therapy was the only significant factor preventing surgical recurrence. CONCLUSION: Postoperative infliximab maintenance therapy for Crohn's disease prevents surgical recurrence, at least within 3 years after the operation. PMID- 23463538 TI - Intraoperative thrombectomy for occluded carotid arteries in patients with acute aortic dissection: report of two cases. AB - The present study describes two cases in which intraoperative thrombectomy was performed for occluded or severely stenosed carotid arteries in patients with acute aortic dissection complicated by cerebral malperfusion. A Fogarty catheter was inserted into the true lumen of the occluded branch under hypothermic circulatory arrest, and thrombi within the false lumen were removed. The arch vessels were patent on subsequent computed tomographic imaging, and no neurological complications were found postoperatively. In these cases, the choice of appropriate management strategies took into consideration the brain ischemic time and the presence or absence of cerebral infarction. This technique represents a useful option for the management of this clinical scenario. PMID- 23463539 TI - Hyperphagia, mild developmental delay but apparently no structural brain anomalies in a boy without SOX3 expression. AB - The transcription factor SOX3 is widely expressed in early vertebrate brain development. In humans, duplication of SOX3 and polyalanine expansions at its C terminus may cause intellectual disability and hypopituitarism. Sox3 knock-out mice show a variable phenotype including structural and functional anomalies affecting the branchial arches and midline cerebral structures such as the optic chiasm and the hypothalamo-pituitary axis. SOX3 is claimed to be required in normal brain development and function in mice and humans, as well as in pituitary and craniofacial development. We report on an 8-year-old boy with a 2.1 Mb deletion in Xq27.1q27.2, which was found to be inherited from his healthy mother. To our knowledge, this is the smallest deletion including the entire SOX3 gene in a male reported to date. He is mildly intellectually disabled with language delay, dysarthria, behavior problems, minor facial anomalies, and hyperphagia. Hormone levels including growth, adrenocorticotropic and thyroid stimulating hormones are normal. Magnetic resonance imaging (MRI) at age 6 years showed no obvious brain anomalies. Genetic redundancy between the three members of the B1 subfamily of SOX proteins during early human brain development likely explains the apparently normal development of brain structures in our patient who is nullisomic for SOX3. PMID- 23463541 TI - Can C-peptide mediated anti-inflammatory effects retard the development of microvascular complications of type 1 diabetes? AB - Hyperglycemia is considered to be the major cause of microvascular complications of diabetes. Growing evidence highlights the importance of hyperglycemia-mediated inflammation in the initiation and progression of microvascular complications in type 1 diabetes. We hypothesize that lack of proinsulin C-peptide and lack of its anti-inflammatory properties contribute to the development of microvascular complications. Evidence gathered over the past 20 years shows that C-peptide is a biologically active peptide in its own right. It has been shown to reduce formation of reactive oxygen species and nuclear factor-kappaB activation induced by hyperglycemia, resulting in inhibition of cytokine, chemokine and cell adhesion molecule formation as well as reduced apoptotic activity. In addition, C peptide stimulates and induces the expression of both Na+, K+-ATPase and endothelial nitric oxide synthase. Animal studies and small-scale clinical trials in type 1 diabetes patients suggest that C-peptide replacement combined with regular insulin therapy exerts beneficial effects on kidney and nerve dysfunction. Further clinical trials in patients with microvascular complications including measurements of inflammatory markers are warranted to explore the clinical significance of the aforementioned, previously unrecognized, C-peptide effects. PMID- 23463540 TI - A mathematical model of the coupled mechanisms of cell adhesion, contraction and spreading. AB - Recent research has shown that cell spreading is highly dependent on the contractility of its cytoskeleton and the mechanical properties of the environment it is located in. The dynamics of such process is critical for the development of tissue engineering strategy but is also a key player in wound contraction, tissue maintenance and angiogenesis. To better understand the underlying physics of such phenomena, the paper describes a mathematical formulation of cell spreading and contraction that couples the processes of stress fiber formation, protrusion growth through actin polymerization at the cell edge and dynamics of cross-membrane protein (integrins) enabling cell substrate attachment. The evolving cell's cytoskeleton is modeled as a mixture of fluid, proteins and filaments that can exchange mass and generate contraction. In particular, besides self-assembling into stress fibers, actin monomers able to polymerize into an actin meshwork at the cell's boundary in order to push the membrane forward and generate protrusion. These processes are possible via the development of cell-substrate attachment complexes that arise from the mechano sensitive equilibrium of membrane proteins, known as integrins. After deriving the governing equation driving the dynamics of cell evolution and spreading, we introduce a numerical solution based on the extended finite element method, combined with a level set formulation. Numerical simulations show that the proposed model is able to capture the dependency of cell spreading and contraction on substrate stiffness and chemistry. The very good agreement between model predictions and experimental observations suggests that mechanics plays a strong role into the coupled mechanisms of contraction, adhesion and spreading of adherent cells. PMID- 23463542 TI - Oxymorphone active uptake at the blood-brain barrier and population modeling of its pharmacokinetic-pharmacodynamic relationship. AB - The aim of this study was to characterize the blood-brain barrier (BBB) transport and pharmacokinetics-pharmacodynamics (PKPD) relationship of oxymorphone and to further elucidate its possible contribution to oxycodone analgesia. The BBB transport of oxymorphone was studied using microdialysis in male Sprague-Dawley rats. Samples from microdialysis blood and brain probes, brain tissue, and plasma were analyzed by liquid chromatography with tandem mass spectrometry. The effect was measured as tail-flick latency. The study consisted of a PKPD experiment with combined microdialysis and antinociceptive measurements (n = 8), and another antinociceptive effect experiment (n = 9) using a 10 times lower dose. The combined data were analyzed with an integrated PKPD model in nonlinear mixed effect modeling utilizing a specific method (M3) for handling missing PD observations. The concentration of unbound oxymorphone was higher in brain than in blood, with a ratio of 1.9 (RSE, 9.7%), indicating active uptake at the BBB. The integrated PKPD model described the oxymorphone BBB transport and PKPD relationship successfully, with an EC50 in the brain of 63 ng/mL, and the M3 method was able to address the issue of censored observations. Oxymorphone has active uptake transport at the BBB in rats, with moderate uptake clearance to the brain. Its contribution to analgesia after oxycodone administration is not significant. PMID- 23463543 TI - Changes in use of disease-modifying antirheumatic drugs for rheumatoid arthritis in the United States during 1983-2009. AB - OBJECTIVE: Use of nonbiologic disease-modifying antirheumatic drugs (DMARDs) and/or biologic DMARDs is generally recommended to improve the prognosis of patients with rheumatoid arthritis (RA). The objective of this study was to describe the changing trends in DMARD use for RA over the past 2 decades. METHODS: We analyzed data from an open longitudinal cohort of RA patients recruited from rheumatologists' practices in northern California. We examined baseline demographic and clinical characteristics of the participants and their long-term DMARD use through annual comprehensive structured telephone interviews. RESULTS: A total of 1,507 established RA patients were recruited through 5 enrollment periods between 1983 and 2009. Between 1983 and 2009, the use of any DMARD increased from 71% of all patients to 83% (P for trend < 0.0001). In 2009, 43% received a biologic DMARD, 34% were on both nonbiologic and biologic DMARDs, and 40% were treated with only nonbiologic DMARDs. The 4 most commonly used nonbiologic DMARDs in 2009 were methotrexate (49%), hydroxychloroquine (30%), leflunomide (13%), and sulfasalazine (7%). Etanercept (20%) was the most commonly used biologic DMARD in 2009, followed by infliximab (10%), adalimumab (9%), and abatacept (6%). Use of oral steroids was common (40-50%) and remained similar throughout the study period. CONCLUSION: There has been a significant increase in the use of DMARDs for RA over the past 2 decades. However, 15% of the individuals with a clinical diagnosis of RA were not receiving DMARDs in 2009. Future research should focus on sociodemographic and clinical factors associated with DMARD use for RA. PMID- 23463544 TI - Forensic drug analysis and microfluidics. AB - The analysis of drugs of abuse in microfluidic devices has the potential to provide solutions to today's on-site analysis challenges. The use of such devices has not been limited to miniaturising conventional analytical methods used routinely in forensic laboratories; new and interesting approaches have been implemented in microfluidics and benefit from the ability to control minute amounts of liquids in the small channels. The microfluidic platforms developed so far have been used successfully to carry out single or multiple analytical processes and offer a great opportunity for new technologies for on-site drug testing. PMID- 23463545 TI - Gas-phase intramolecular protein crosslinking via ion/ion reactions: ubiquitin and a homobifunctional sulfo-NHS ester. AB - Gas-phase intra-molecular crosslinking of protein ubiquitin cations has been demonstrated via ion/ion reactions with anions of a homobifunctional N hydroxysulfosuccinimide (sulfo-NHS) ester reagent. The ion/ion reaction between multiply-protonated ubiquitin and crosslinker monoanions produces a stable, charge-reduced complex. Covalent crosslinking is indicated by the consecutive loss of 2 molecules of sulfo-NHS under ion trap collisional activation conditions. Covalent modification is verified by the presence of covalently crosslinked sequence ions produced by ion-trap collision-induced dissociation of the ion generated from the losses of sulfo-NHS. Analysis of the crosslinked sequence fragments allows for the localization of crosslinked primary amines, enabling proximity mapping of the gas-phase 3-D structures. The presence of two unprotonated reactive sites within the distance constraint of the crosslinker is required for successful crosslinking. The ability to covalently crosslink is, therefore, sensitive to protein charge state. As the charge state increases, fewer reactive sites are available and protein structure is more likely to become extended because of intramolecular electrostatic repulsion. At high charge states, the reagent shows little evidence for covalent crosslinking but does show evidence for 'electrostatic crosslinking' in that the binding of the sulfonate groups to the protein is sufficiently strong that backbone cleavages are favored over reagent detachment under ion trap collisional activation conditions. PMID- 23463546 TI - In-line desalting of proteins from buffer and synthetic urine solution prior to ESI-MS analysis via a capillary-channeled polymer fiber microcolumn. AB - Presented here is a novel in-line solid phase extraction (SPE) method utilizing a capillary-channeled polymer (C-CP) fiber microcolumn prior to introduction to an electrospray ionization (ESI) source. The high permeability of the microcolumn allows for operation under syringe pump or HPLC driven flow, ultimately providing greater mass spectral clarity and accurate molecular weight determinations for different protein/buffer combinations. Studies presented here focus on the desalting of several target proteins from a standard phosphate buffered saline (PBS) matrix and a synthetic urine solution prior to ESI-MS determinations. In every case, responses for MUM-level proteins in PBS improve from the situation of not permitting molecular weight determinations to values that are precise to better than +/-10 Da, without internal standards, with relative improvements in the signal-to-background ratios (S/B) on the order of 3,000*. De-salting of a myoglobin-spiked (12 MUM) synthetic urine results in equally-improved spectral quality. PMID- 23463547 TI - Optimization of heme precursors for the expression of human cytochrome P450 2A13 and its co-expression with oxidoreductase in baculovirus/sf9 system. AB - Human cytochrome P450 2A13 (CYP2A13), mainly expressed in respiratory tract, is active towards numerous toxicants. To establish the metabolism in vitro, we expressed CYP2A13 and NADPH-CYP450 oxidoreductase (POR) in a baculovirus/sf9 system. Due to the deficiency of sf9 cells in heme incorporation, we investigated the effects of different heme precursors on the expression of CYP2A13, POR and their co-expression. The present results showed that both CYP2A13 and POR were presented the highest expression levels or activity with 0.2 mM delta aminolaevulinic acid (5-ALA), 0.02 mM Fe(3+) and 0.5-1.0 MUg/ml hemin. The combination of 0.2 mM 5-ALA and 0.02 mM Fe(3+) significantly improved CYP2A13 expression and content compared with heme precursors alone, so was POR activity. A multiplicity of infection (MOI) value of 5 pfu/cell for CYP2A13 baculovirus particles induced very high CYP2A13 expression. When co-infected with different POR MOI values, a viral ratio of 5 : 2 was associated with the highest CYP2A13 activity, whereas POR activity dose dependently increased with POR MOI. Furthermore, the expressed CYP2A13 in the optimized conduction could eliminate its substrate aflatoxin B1 at a significantly higher than those in other condition (P < 0.01). Our results provide an efficient approach for expressing functionally characterized, highly active and homogeneous CYP2A13 proteins. PMID- 23463548 TI - Substrate elasticity affects bovine satellite cell activation kinetics in vitro. AB - Satellite cells support efficient postnatal skeletal muscle hypertrophy through fusion into the adjacent muscle fiber. Nuclear contribution allows for maintenance of the fiber myonuclear domain and proficient transcription of myogenic genes. Niche growth factors affect satellite cell biology; however, the interplay between fiber elasticity and microenvironment proteins remains largely unknown. The objective of the experiment was to examine the effects of hepatocyte growth factor (HGF) and surface elasticity on bovine satellite cell (BSC) activation kinetics in vitro. Young's elastic modulus was calculated for the semimembranosus (SM) and LM muscles of young bulls (5 d; n = 8) and adult cows (27 mo; n = 4) cattle. Results indicate that LM elasticity decreased (P < 0.05) with age; no difference in Young's modulus for the SM was noted. Bovine satellite cells were seeded atop polyacrylamide bioscaffolds with surface elasticities that mimic young bull and adult cow LM or traditional cultureware. Cells were maintained in low-serum media supplemented with 5 ng/mL HGF or vehicle only for 24 or 48 h. Activation was evaluated by proliferating cell nuclear antigen (PCNA) immunocytochemistry. Results indicate that BSC maintained on rigid surfaces were activated at 24 h and refractive to HGF supplementation. By contrast, fewer (P < 0.05) BSC had exited quiescence after 24 h of culture on surfaces reflective of either young bull (8.1 +/- 1.7 kPa) or adult cow (14.6 +/- 1.6 kPa) LM. Supplementation with HGF promoted activation of BSC cultured on bioscaffolds as measured by an increase (P < 0.05) in PCNA immunopositive cells. Culture on pliant surfaces affected neither activation kinetics nor numbers of Paired box 7 (Pax7) immunopositive muscle stem cells (P > 0.05). However, with increasing surface elasticity, an increase (P < 0.05) in the numbers of muscle progenitors was observed. These results confirm that biophysical and biochemical signals regulate BSC activation. PMID- 23463549 TI - Carcass fat quality of pigs is not improved by adding corn germ, beef tallow, palm kernel oil, or glycerol to finishing diets containing distillers dried grains with solubles. AB - The objective of this experiment was to test the hypothesis that the reduced carcass fat quality that is often observed in pigs fed diets containing distillers dried grains with solubles (DDGS) may be ameliorated if corn germ, beef tallow, palm kernel oil, or glycerol is added to diets fed during the finishing period. A total of 36 barrows and 36 gilts (initial BW 43.7 +/- 2.0 kg) were individually housed and randomly allotted to 1 of 6 dietary treatments in a 2 * 6 factorial arrangement, with gender and diet as main factors. Each dietary treatment had 12 replicate pigs. A corn-soybean meal control diet and a diet containing corn, soybean meal, and 30% DDGS were formulated. Four additional diets were formulated by adding 15% corn germ, 3% beef tallow, 3% palm kernel oil, or 5% glycerol to the DDGS-containing diet. Growth performance, carcass characteristics, and LM quality were determined, and backfat and belly fat samples were collected for fatty acid analysis. There was no gender * diet interaction for any of the response variables measured. For the entire finisher period (d 0 to 88), diet had no effect on ADG, but pigs fed 3% palm kernel oil tended (P < 0.10) to have less ADFI and greater G:F than pigs fed the control diet. Barrows had greater (P < 0.01) ADG and ADFI, and less (P < 0.001) G:F than gilts. Pigs fed the DDGS diet had reduced (P < 0.05) loin eye area compared with pigs fed the control diet, but diet had no effect on other carcass characteristics. Barrows had greater (P < 0.001) final BW at the end of both phases, greater (P < 0.001) HCW and backfat thickness, and tended (P = 0.10) to have greater dressing percentage, but less (P < 0.001) fat-free lean percentage than gilts. Backfat of pigs fed the 5 DDGS-containing diets had less (P < 0.05) L* values than pigs fed the control diet and backfat of gilts had greater (P < 0.001) a* and b* values than barrows. Pigs fed the control diet had greater (P < 0.05) belly flop distance compared with pigs fed the 5 DDGS-containing diets, but no differences were observed among pigs fed the diets containing DDGS. Barrows had heavier (P < 0.001) bellies and greater (P < 0.001) belly flop distances than gilts. Diet had no effect on carcass fat iodine value (IV), but gilts tended (P = 0.07) to have greater backfat IV and greater (P = 0.05) belly fat IV than barrows. In conclusion, the hypothesis that carcass fat quality of pigs fed diets containing DDGS can be improved by inclusion of corn germ, beef tallow, palm kernel oil, or glycerol in finishing diets could not be confirmed. PMID- 23463550 TI - Intestinal integrity, endotoxin transport and detoxification in pigs divergently selected for residual feed intake. AB - Microbes and microbial components potentially impact the performance of pigs through immune stimulation and altered metabolism. These immune modulating factors can include endotoxin from gram negative bacterial outer membrane component, commonly referred to as lipopolysaccharide (LPS). In this study, our objective was to examine the relationship between intestinal barrier integrity, endotoxin and inflammation with feed efficiency (FE), using pig lines divergently selected for residual feed intake (RFI) as a model. Twelve gilts (62 +/- 3 kg BW) from the low RFI (LRFI, more efficient) and 12 from the high RFI (HRFI, less efficient) were used. Individual performance data was recorded for 5 wk. At the end of the experimental period, ADFI of LRFI pigs was less (P < 0.001), ADG not different between the 2 lines (P = 0.72) but the G:F of LRFI pigs was greater than for HRFI pigs (P = 0.019). Serum endotoxin concentration (P < 0.01) and the acute phase protein haptoglobin (P < 0.05) were greater in HRFI pigs. Transepithelial resistance of the ileum, transport of fluorescein isothiocyanate labeled-Dextran and-LPS in ileum and colon, as well as tight junction protein mRNA expression in ileum, did not differ between the lines, indicating the 2 lines did not differ in transport characteristics at the intestinal level. Ileum inflammatory markers, myeloperoxidase (P < 0.05) and IL-8 (P < 0.10), were found to be greater in HRFI pigs. Alkaline phosphatase (ALP) activity was significantly increased in the LRFI pigs in ileum and liver tissues and negatively correlated with blood endotoxin (P < 0.05). Lysozyme activity in the liver was not different between the lines; however, the LRFI pigs had a twofold greater lysozyme activity in ileum (P < 0.05). Despite the difference in their activity, ALP or lysozyme mRNA expression was not different between the lines in either tissue. Decreased endotoxin and inflammatory markers and the enhanced activities of antimicrobial enzymes in the LRFI line may not fully explain the difference in the FE between the lines, but they have the potential to prevent the growth potential in HRFI pigs. Further studies are needed to identify the other mechanisms that may contribute to the greater endotoxin and acute phase proteins in the HRFI pigs and the greater FE in the LRFI pigs. PMID- 23463551 TI - Phenotypic and genetic relationships of feed efficiency with growth performance, ultrasound, and carcass merit traits in Angus and Charolais steers. AB - Feed efficiency is of particular importance to the beef industry, as feed costs represent the single largest variable cost in beef production systems. Selection for more efficient cattle will lead to reduction of feed related costs, but should not have adverse impacts on quality of the carcass. In this study, we evaluated phenotypic and genetic correlations of residual feed intake (RFI), RFI adjusted for end-of-test ultrasound backfat thickness (RFIf), and RFI adjusted for ultrasound backfat thickness and LM area (RFIfr) with growth, ultrasound, and carcass merit traits in an Angus population of 551 steers and in a Charolais population of 417 steers. In the Angus steer population, the phenotypic and genetic correlation of RFI with carcass merit traits including HCW, carcass backfat, carcass LM area, lean meat yield, and carcass marbling were not significant or weak with correlations coefficients ranging from -0.0007 +/- 0.05 to 0.18 +/- 0.21. In the Charolais steer population, the phenotypic and genetic correlations of RFI with the carcass merit traits were also weak, with correlation coefficients ranging from -0.07 +/- 0.06 to 0.19 +/- 0.18, except for the genetic correlation with carcass average backfat, which was moderate with a magnitude of 0.42 +/- 0.29. Inclusion of ultrasound backfat thickness in the model to predict the expected daily DMI for maintenance explained on average an additional 0.5% variation of DMI in the Angus steers and 2.3% variation of DMI in the Charolais steer population. Inclusion of both the ultrasound backfat and LM area in the model explained only 0.7% additional variance in DMI in the Angus steer population and only 0.6% in the Charolais steer population on top of the RFIf model. We concluded that RFIf adjusted for ultrasound backfat at the end of the test will lead to decreases of both the phenotypic and genetic correlations with carcass backfat and marbling score to a greater extent for late-maturing beef breeds such as Charolais than for early-maturing beef breeds such as Angus. However, further inclusion of ultrasound LM area on top of the final ultrasound backfat in the model of calculating RFI had little effect in reducing the correlations of RFI with the carcass merit traits. PMID- 23463552 TI - Genetic associations between daily BW gain and live fleshiness of station-tested young bulls and carcass and meat quality traits of commercial intact males in Piemontese cattle. AB - The aim of this study was to investigate genetic relationships between beef traits of station-tested young bulls and carcass and meat quality traits (MQ) of commercial intact males in Piemontese cattle. Phenotypes for daily gain (DG) and live fleshiness traits (width at withers: WW; shoulder muscularity: SM; loin width: LW; loin thickness: LT; thigh muscularity: TM; thigh profile: TP) and thinness of the shin bone (BT) were available for 3,109 and 2,183 performance tested young bulls, respectively. Carcass daily gain (CDG), carcass conformation (SEUS), pH at 24 h (pH24h) and 8 d after slaughter (pH8d), lightness (L*), redness (a*), yellowness (b*), hue angle (HA), saturation index (SI), drip loss (DL), cooking loss (CL), and shear force (SF) were assessed for 1,208 commercial intact males. (Co) variance components were estimated in a set of twelve 9-traits analyses using REML and linear animal models including all performance-test traits and 1 carcass or MQ trait at a time. Heritabilities +/- SE of beef traits ranged from 0.26 +/- 0.03 (LW) to 0.47 +/- 0.01 (DG), whereas those of carcass traits and MQ from 0.06 +/- 0.03 (CL) to 0.63 +/- 0.04 (HA). The genetic correlation (rg) between DG and CDG was 0.75 +/- 0.10, indicating that DG, as measured at the test station, is a good indicator of the carcass gain achieved by commercial animals under farms conditions. Daily BW gain of station-tested bulls correlated positively with color traits (from 0.11 +/- 0.12 to 0.54 +/- 0.09), ph8d (rg +/- SE = 0.31 +/- 0.11), DL (rg +/- SE = 0.29 +/- 0.17), and CL (rg +/- SE = 0.27 +/- 0.18). Live fleshiness of station-tested bulls exhibited genetic correlations with MQ of commercial animals that were positive for L* and b* (from 0.13 +/- 0.08 to 0.65 +/- 0.14) and negative for pH (from -0.27 +/- 0.15 to -0.57 +/- 0.11), CL (from -0.16 +/- 0.23 to -0.43 +/- 0.22), and SF (TM: rg +/- SE = 0.31 +/- 0.15; TP: rg +/- SE = -0.41 +/- 0.17). The thinness of the shin bone correlated unfavorably with CDG (rg +/- SE = -0.74 +/- 0.07) and favorably with SEUS (rg +/- SE = 0.65 +/- 0.17), CL (rg +/- SE = -0.39 +/- 0.13), and SF (rg +/- SE = -0.32 +/- 0.17). The estimated genetic correlations indicate that selection to increase DG, as measured at the test station, exerts moderate adverse effects on MQ. Because selection emphasis is greater for live fleshiness than for DG, the correlated response in MQ and carcass traits is expected to be influenced to a greater extent by selection for muscularity, even though these traits are less heritable than DG. PMID- 23463553 TI - Effects of increasing co-product inclusion and reducing dietary protein on growth performance, carcass characteristics, and jowl fatty acid profile of growing finishing pigs. AB - Dietary inclusion of co-products (Co-P) provides opportunities for diversifying the feedstuff matrix by using local feedstuffs, reducing feed costs, and producing value-added pork. In 2 studies, we determined effects of Co-P (canola meal, distillers dried grains with solubles, and co-extruded oil seed and field pea) inclusion level and reduced dietary CP concentration on growth performance, carcass characteristics, and jowl fatty acid profiles of growing-finishing pigs. Pigs were fed isoenergetic and isolysinic diets over 4 growth phases with 8 pen observations per dietary regimen. At slaughter, carcasses were characterized for all pigs and jowl fat was collected from 2 pigs per pen. In Exp. 1, 1,056 pigs (initial BW, 35.3 +/- 0.4 kg) were fed 3 levels of dietary Co-P (low, mid, and high) and 2 CP concentrations (low and normal). Overall (d 0 to 86), increasing Co-P inclusion from low to mid or high decreased (P < 0.001) ADFI and ADG of pigs. Low CP concentration increased (P < 0.05) ADFI and ADG compared with normal CP concentration. An interaction (P = 0.026) occurred between dietary Co-P inclusion and CP concentration for G:F; low CP reduced (P < 0.05) G:F compared with normal CP for pig fed low Co-P, but G:F did not differ between CP concentrations for pigs fed mid and high Co-P. Increasing dietary Co-P inclusion from low to high increased (P < 0.001) alpha-linolenic acid (ALA) in jowl fat but decreased (P < 0.001) carcass weight and loin depth. In Exp. 2, 1,008 pigs (initial BW, 30.3 +/- 0.4 kg) were assigned to 5 dietary regimens with Co-P increasing from 2.0 to 50.0% or a sixth regimen with 10% extra supplemental AA for the 37.5% Co-P diet. Overall (d 0 to 97), increasing Co-P inclusion did not affect ADFI, ADG, and G:F. Increasing dietary Co-P inclusion linearly decreased (P < 0.01) carcass weight, dressing percentage, backfat thickness, and loin depth but linearly increased (P < 0.001) jowl ALA. Supplementing 10% extra AA to the 37.5% Co-P diet did not affect growth performance or dressing percentage but increased (P = 0.014) carcass leanness and decreased (P = 0.023) backfat thickness compared with the 37.5% Co-P diet, indicating that dietary AA supply did not limit BW gain. In conclusion, Co-P can be included by up to 50% in diets for growing-finishing pigs without affecting G:F. However, increasing dietary Co P may reduce ADG, ADFI, and carcass weight even if diets are balanced for dietary NE and standardized ileal digestible AA content. PMID- 23463554 TI - Eicosapentaenoic and docosahexaenoic acids increase insulin sensitivity in growing steers. AB - An experiment was conducted to determine the effect of dietary n-3 long chain PUFA on insulin sensitivity in growing steers. Steers (n = 12, initial BW = 336.3 kg, SEM = 7.7) were adapted to a basal diet that was 70% concentrate mix and 30% orchardgrass hay. Steers were fed a daily amount of 0.26 Mcal ME per kg BW (0.75). After 3 wk steers were transitioned to 1 of 2 treatment (Trt) diets (n = 6 per diet) containing added Ca salts of fatty acids at 4% of DM using a source of fat that was enriched in n-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid (FOFA), or a source of fat without n-3 fatty acids and a greater percentage of C16:0 and C18:1 (LCFA). Three intravenous (i.v.) glucose tolerance tests (IVGTT) were conducted, 1 during the basal diet, and 2 after transition to treatment diets at time 1 (T1; d 4 Trt) and time 2 (T2; d 39 Trt). Three i.v. insulin challenge tests (IC) were conducted the day after each IVGTT. Measurements on the basal diet were used as covariates. For IVGTT, there was a diet by time interaction (P < 0.05) for glucose area under the response curve (AUC). The AUC50 (mM glucose * 50 min) at T1 was less (P = 0.02) for LCFA (126.2) than FOFA (151.8), AUC50 at T2 tended to be greater (P = 0.07) for LCFA (165.9) than FOFA (146.0). Preinfusion insulin concentration was greater (P < 0.001) before the IVGTT and IC for steers fed LCFA (40.4 and 40.2 uIU/mL) than for steers fed FOFA (23.7 and 27.1 uIU/mL), respectively. Glucose clearance did not differ between treatments. For IC, minimum glucose concentration was greater (P = 0.02) and glucose AUC150 was less (P < 0.01) for steers fed LCFA than for steers fed FOFA. Values for glucose concentration were 1.8 mM and 1.5 mM and for AUC150 (mM glucose * 150 min) were 203.1 and 263.6 for steers fed LCFA and FOFA, respectively. Insulin clearance (fraction/min) was greater (P < 0.01) for steers fed LCFA (0.121) than FOFA (0.101). The insulin AUC60 (uIU/mL * 60 min) postinfusion was less for LCFA (17,674) than FOFA (19,997), and tended to be greater (P = 0.06) at T1 (19,552) than T2 (18,119). Plasma NEFA concentrations at T2 during IVGTT were greater (P < 0.05) in steers fed FOFA than in steers fed LCFA. The results indicated that supplementing with long-chain n-3 PUFA (FOFA) increased insulin sensitivity in growing steers compared with feeding a supplement with greater concentration of SFA (LCFA). PMID- 23463555 TI - Evaluation of Columbia, USMARC-Composite, Suffolk, and Texel rams as terminal sires in an extensive rangeland production system: IV. Postfabrication carcass component weights. AB - Postfabrication carcass component weights of 517 crossbred wether lambs were analyzed to evaluate 4 terminal-sire breeds. Wethers were produced over 3 yr from single-sire matings of 22 Columbia, 22 USMARC-Composite (Composite), 21 Suffolk, and 17 Texel rams to adult Rambouillet ewes. Lambs were reared to weaning in an extensive western rangeland production system and finished in a feedlot on a high energy finishing diet. When wethers reached a mean BW of 54.4, 61.2, or 68.0 kg, they were transported to The Ohio State University abattoir for harvest. After refrigeration for approximately 24 h, chilled carcass weight (CCW) was measured, carcasses were fabricated according to Style A of Institutional Meat Purchase Specifications, and postfabrication weights were recorded. At comparable numbers of days on feed, Suffolk-sired lambs had heavier (P < 0.04) neck, breast, shoulder, foreshank, rack, loin, leg, sirloin, roast-ready rack, trimmed loin, and boneless leg cuts than progeny of the other sire breeds. Boneless sirloins were heavier (P < 0.01) for Suffolk-sired than Composite-sired lambs but did not differ from those for Columbia- or Texel-sired lambs. Columbia- and Suffolk-sired lambs had heavier (P < 0.01) hindshanks than Texel-sired lambs. Suffolk-sired lambs had heavier (P < 0.01) high-value cuts (rack, loin, leg, and sirloin) and trimmed high-value cuts than progeny of the other sire breeds. Cutting loss (CCW wholesale cut weights) and high-value trimming loss were greatest (P < 0.02) for Suffolk-sired lambs and least for Texel- and Composite-sired lambs. Sire breed did not affect (P > 0.06) flank weight. Data adjusted to comparable CCW reduced the number of significant sire-breed effects and changed sire-breed rankings of carcass component weights, for which sire breeds differed. After adjusting, Suffolk-sired lambs had lighter (P < 0.05) loins than Columbia- and Composite sired lambs, Composite-sired lambs had heavier (P < 0.05) high-value cuts than Suffolk-sired lambs, and Suffolk- and Columbia-sired lambs had heavier (P < 0.05) necks than Texel-sired lambs. At predicted backfat thickness of 6.6 mm, Composite sired lambs had a greater (P < 0.05) percentage of high-value cuts than Suffolk sired lambs before but not after trimming. Producers can use these results to select terminal-sire breeds that will complement their production system and improve lamb value. PMID- 23463556 TI - Digestive capacity in weanling and mature horses. AB - The ability of young and mature horses to digest DM, OM, and NDF was compared using 6 weanling colts and 6 mature (13.2 +/- 3.0 yr) geldings. Each colt was paired with a gelding, and the pair was adapted to a diet containing 67% alfalfa cubes and 33% concentrate for 21 d. During the adaptation period, horses were accustomed to housing and all handling procedures. The adaptation period was also used to adjust the amount of feed offered to minimize orts and to maintain similar rates of intake within a pair. After the adaptation period, a 5-d fecal collection period using fecal collection harnesses ensued. The average age of the weanling colts at the start of the 5-d collection period was 181.8 +/- 2.9 d. On the morning of the first collection day, Co-EDTA (9 mg Co/kg BW(0.75)) and ytterbium-labeled hay fiber (9 mg Yb/kg BW(0.75)) were added to the concentrate portion of the diet, and horses were closely observed for complete consumption of the markers before additional feed was offered. The fecal collection bags were emptied every 1 to 2 h, and each collection was weighed and subsampled for later measurement of Co and Yb concentrations, which were used to determine the mean retention time (MRT) of the fluid and particulate phases of digesta, respectively. The remaining feces for each horse were composited each day and then subsampled for measurement of DM digestibility (DMD), NDF digestibility (NDFD), and OM digestibility (OMD). During the fecal collection period, DMI was similar between colts and geldings (91.4 and 91.2 g/kg BW(0.75), respectively). There were no differences between colts and mature geldings for DMD, OMD, or NDFD. Across both ages, the MRT of the particulate phase was 24.9 h compared with 21.8 h for the fluid phase (P = 0.002). However, MRT for the particulate phase was not different between colts and mature geldings (24.7 and 25.2 h, respectively). There was no difference in the MRT for the fluid phase between colts and mature geldings (21.5 and 22.0 h, respectively). The results indicated that the digestibility of DM, OM, and NDF in a diet consisting of good-quality cubed forage and concentrate is similar for weanling colts and mature geldings. PMID- 23463557 TI - Measures of antioxidant status of the horse in response to selenium depletion and repletion. AB - Selenium plays a role in the antioxidant mechanism via the selenoenzyme glutathione peroxidase (GSH-Px). Change in Se status because of Se depletion or supplementation is associated with a change in GSH-Px activity and could potentially affect antioxidant status. This study evaluated the impact of change in Se status on measures of antioxidant status and oxidative stress in adult horses. Twenty-eight horses were blocked by age and gender and were randomly allocated to 1 of 4 dietary treatment groups: low Se (LS), adequate Se (AS), high organic Se (SP), and high inorganic Se (SS). For 196 d, LS, SP, and SS received a low-Se diet (0.06 mg Se/kg DM) to allow for depletion of Se stores, whereas AS received an adequate Se diet (0.12 mg Se/kg DM). Then, for the next 189 d, LS and AS were maintained on the same diets, whereas SP was supplemented with Se-yeast and SS with sodium selenite to allow for a total dietary Se intake of 0.3 mg Se/kg DM. Blood samples were collected throughout the study. Variables of interest included whole blood Se and GSH-Px activity, serum vitamin E concentration, total antioxidant capacity (TAC), serum malondialdehyde (MDA), and triiodothyronine and thyroxine concentrations. Data were analyzed using ANOVA with repeated measures. Whole blood Se and GSH-Px activity decreased in LS, SP, and SS during the depletion phase and increased in SP and SS with supplementation (treatment * time, P < 0.001). At the conclusion of the supplementation period, GSH-Px activity was greater in SP and SS compared with AS and LS (P < 0.05). Vitamin E status remained adequate throughout the study, and no differences existed between treatments. Serum TAC did not change in response to Se depletion or repletion. Serum MDA was greater for AS than LS during depletion (P < 0.05) but similar across treatments after supplementation. Overall, change in Se status did not have a large impact on TAC or MDA, possibly because the horses maintained an adequate vitamin E status. However, Se supplementation at 0.3 mg/kg DM increased GSH-Px activity above that of the horses fed an adequate diet based on the 2007 NRC recommendations, indicating a potential benefit to feeding greater Se diets to horses kept in low-Se areas. PMID- 23463558 TI - Effect of rate of body weight gain of steers during the stocker phase. II. Visceral organ mass and body composition of growing-finishing beef cattle. AB - Two experiments were conducted to examine the effect of rate of BW gain during the stocker phase on visceral organ mass and body composition of growing finishing cattle that had grazed dormant native range (DNR) or winter wheat pasture (WP). In each experiment, fall-weaned steers were allotted randomly to 1 of these stocker production programs: 1) control, 1.02 kg . steer(-1) . d(-1) of a 40% CP cottonseed meal-based supplement during grazing of DNR (CON); 2) corn/soybean meal-based supplement fed at 1% of BW during grazing of DNR (CORN); 3) grazing WP at a high stocking rate to achieve a reduced rate of BW gain (LGWP); and 4) grazing WP at a low stocking rate to achieve an increased rate of BW gain (HGWP). In Exp. 1, 3 steers per treatment were harvested after winter grazing (138 d). The remaining WP steers were transitioned into a finishing phase and DNR steers were allowed to graze the same pastures for another 115 d before entering a feedyard. In Exp. 2, steers grazed respective pastures until each treatment reached an estimated HCW of 200 kg (262, 180, 142, and 74 d, respectively, for CON, CORN, LGWP, and HGWP treatments), at which time 4 steers per treatment were randomly selected for intermediate harvest before finishing. At the end of the finishing period, 4 additional steers from each treatment were randomly selected for final carcass measurements. All steers were fed to a common 12th rib fat thickness of 1.27 cm. After winter grazing in Exp. 1, HGWP steers had the greatest (P < 0.01) mesenteric/omental fat, total viscera, total splanchnic tissue mass, and carcass and empty body fat, compared with the other treatments. In Exp. 2 at intermediate harvest, WP steers had greater (P < 0.03) mesenteric/omental fat, total viscera, and total splanchnic tissue mass, compared with CORN steers, with CON steers being intermediate. Also, the WP steers had greater (P < 0.02) carcass and empty body fat, compared with CORN steers, with CON steers being intermediate. At final harvest in Exp. 2, LGWP steers had the least total viscera and total splanchnic tissue mass, compared with the other treatments. However, there were no differences (P > 0.53) among treatments for carcass or empty body fat. Stocker systems using WP or DNR result in cattle with differences in body fat and visceral organ mass before finishing; this may influence feedlot efficiency, even though there were no differences in body fat and visceral organ mass at the end of the finishing period. PMID- 23463559 TI - Effect of creatine supplementation during the last week of gestation on birth intervals, stillbirth, and preweaning mortality in pigs. AB - We hypothesized that creatine supplementation would reduce birth intervals, stillbirth rate, and preweaning survival in pigs because of its reported improvement of athletic performance in humans. In Exp. 1, gilts (n = 42) and first parity sows (n = 75) were mated at estrus. Beginning on d 110 of gestation, dams received either no treatment or 20 g creatine daily until farrowing. At farrowing in November 2008, pigs were monitored by video camera to determine individual piglet birth intervals. On d 1, piglets were weighed, euthanized, and the cerebellum, brain stem, and spinal cord were collected from the largest and smallest piglets in each litter to measure myelin basic proteins, myelin cholesterol, glucocerebrosides, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin. Preweaning mortality of the remaining piglets was recorded, including whether a piglet had been overlayed by the dam. A second experiment was performed using gilts (n = 90), farrowing in July 2010, to test differential effects of creatine supplementation during hot, humid weather when dams typically have more difficulty farrowing. Once again, gilts were provided either no supplementation or 20 g creatine daily from d 110 to the day of farrowing. Gilts were video recorded during farrowing, piglets were weighed on d 1, and preweaning mortality (including overlays) was recorded. In Exp. 1, creatine supplementation had no effect on birth intervals or stillbirth rate. Creatine supplementation improved the amount of myelin lipids in brain regions of piglets, particularly the brain stem. Creatine supplementation also reduced overlays of low birth weight piglets from gilts but not second parity sows. Data from Exp. 2 were combined with gilt data from Exp. 1 to examine the effect of creatine, season, and their interaction. There were no effects of treatment or season on birth intervals, stillbirth rates, or overall preweaning mortality. Creatine treatment reduced the incidence of overlays in low birth weight piglets in the combined data set. These results suggest that creatine supplementation improved myelination and may reduce the incidence of low birth weight piglets being crushed by the dam. PMID- 23463560 TI - Hepatic mitochondrial efficiency in lines of mice differing in feed intake. AB - Selection was practiced for high (MH) and low (ML) heat loss using direct calorimetry to create lines of mice differing in feed intake per unit average BW (FI/BW). A total of 25 generations of selection was practiced during maintenance of an unselected control (MC). As a percentage of MC, mice of MH and ML lines differed in heat loss and FI/BW by 56 and 34%, respectively, when selection ceased. The purpose of this study was to determine hepatic mitochondrial efficiency in mice at maintenance across the genetic lines. After measurement of feed intakeand BW over a 2-wk period, mice were euthanized, and their livers were extracted. Livers were homogenized and mitochondria were isolated in buffer for measurement of oxygen consumption and, hence, mitochondrial activity using a Clark-type oxygen electrode. Mitochondria of ML mice expressed greater (P < 0.03) respiratory control ratio by 22% than that for MH mice, revealing greater degree of uncoupling during electron transport in MH mice. Difference in FI/BW (P < 0.001) was large with MH mice consuming 34% more than ML mice. The respiratory control ratio differed between mice of MH and ML lines as expected; however, regression analysis revealed that it explained essentially no variation in feed intake per BW. PMID- 23463561 TI - Technical report: serial collections of placentomes during parturition in cattle and subsequent reproductive performance. AB - Placental separation is a complex physiological event in reproductive physiology and the underlying molecular mechanisms remain unclear. When comparing different experiments the timing of tissue collections is a significant consideration due to the variability in time between fetal expulsion and expulsion of the placenta (30 min to >24 h). This makes comparison of tissues samples across animals difficult and supports the need for serial tissue collections within animal. Additionally, the instrument most commonly used, a modified Richter-Resinsinger effeminator, for placentome collections is difficult to obtain and there are no data in the literature record regarding subsequent reproductive performance of animals subjected placentome collections. To facilitate continued research into the physiology behind placental separation, we designed an instrument from readily available components and performed serial transvaginal placentome collections in cattle. Three placentomes at 2-h intervals were collected after expulsion of the calf in 18 multiparous cows. There was no incidence of mortality and all cows resumed estrous after the procedure. Neither time from placentome collection nor age had a significant effect on pregnancy status at diagnosis (P > 0.05). These results demonstrate the viability of and utility of this device for collecting multiple placentomes in cattle. PMID- 23463562 TI - Piglet birth weight and litter uniformity: effects of weaning-to-pregnancy interval and body condition changes in sows of different parities and crossbred lines. AB - Piglet birth weight and litter uniformity were studied in sows of different parities and crossbred lines in relation to: 1) weaning-to-pregnancy interval (WPI) and 2) sow body condition changes (in BW and backfat thickness) during lactation and gestation in sows with a short WPI (<=7d). At the Institute for Pig Genetics (IPG) research farm, individual piglet birth weights and sow body condition (BW and backfat thickness at farrowing and weaning) were measured for 949 TOPIGS20 and 889 TOPIGS40 sows with >4 total born piglets, inseminated between 2003 and 2011. In all analyses, mean piglet birth weight and birth weight SD and CV were corrected for total number born. Total number born was greater in sows with a WPI of 8 to 21 d (+1.2 piglets; n = 72) and >21 d (+0.7 piglets; n = 182), compared with sows with a WPI <=7 d (P < 0.01; n = 1,584). Mean piglet birth weight was not affected by WPI. Birth weight SD (-23 g) and CV (-1.7%) were lower in sows with a WPI >21 d, compared with sows with a WPI <=7 d (P < 0.01). Effects of WPI were independent of sow parity. Effects of body condition changes in sows with a WPI <=7 d were studied separately in TOPIGS20 sows inseminated between 2006 and 2011 (n = 808), and in TOPIGS40 sows inseminated between 2003 and 2008 (n = 747). Sow body condition loss during lactation was not related with subsequent total number born or mean piglet birth weight. Only in TOPIGS20 sows, more BW loss during lactation was related with greater subsequent birth weight SD (beta = 0.83 g/kg, P < 0.01; beta = 1.62 g/%, P < 0.01). Additionally, more backfat loss during lactation was related with greater subsequent birth weight SD (beta = 5.11 g/mm, P < 0.01) and CV (beta = 0.36%/mm, P < 0.01), independent of sow parity. Sow BW increase during gestation was negatively related with total number born [TOPIGS20: beta = -0.06 and -0.05 piglet/kg BW increase for parity 2 (P < 0.01), and 3 and 4 (P < 0.01), respectively; TOPIGS40: beta = -0.04 piglet/kg BW increase (P < 0.01), independent of sow parity]. Sow BW increase during gestation was positively related with birth weight SD [TOPIGS20: beta = 0.63 g/kg BW increase (P = 0.01), independent of sow parity]. Sow body condition increase during gestation was not related with mean piglet birth weight. To conclude, this study shows that litter uniformity is compromised by severe sow body condition loss during lactation and improved in sows with a prolonged WPI. These effects are likely related with (insufficient) restoration of follicle development. PMID- 23463563 TI - The effects of heat stress and plane of nutrition on metabolism in growing pigs. AB - Heat stress (HS) jeopardizes pig health, reduces performance variables, and results in a fatter carcass. Whether HS directly or indirectly (via reduced feed intake) is responsible for the suboptimal production is not known. Crossbred gilts (n = 48; 35 +/- 4 kg BW) were housed in constantly climate-controlled rooms in individual pens and exposed to 1) thermal-neutral (TN) conditions (20 degrees C; 35% to 50% humidity) with ad libitum intake (n = 18), 2) HS conditions (35 degrees C; 20% to 35% humidity) with ad libitum intake (n = 24), or 3) pair-fed [PF in TN conditions (PFTN), n = 6, to eliminate confounding effects of dissimilar feed intake (FI)]. Pigs in the TN and HS conditions were sacrificed at 1, 3, or 7 d of environmental exposure, whereas the PFTN pigs were sacrificed after 7 d of experimental conditions. Individual rectal temperature (Tr), skin temperature (Ts), respiration rates (RR), and FI were determined daily. Pigs exposed to HS had an increase (P < 0.01) in Tr (39.3 degrees C vs. 40.8 degrees C) and a doubling in RR (54 vs. 107 breaths per minute). Heat-stressed pigs had an immediate (d 1) decrease (47%; P < 0.05) in FI, and this magnitude of reduction continued through d 7; by design the nutrient intake pattern for the PFTN controls mirrored the HS group. By d 7, the TN and HS pigs gained 7.76 and 1.65 kg BW, respectively, whereas the PFTN pigs lost 2.47 kg BW. Plasma insulin was increased (49%; P < 0.05) in d 7 HS pigs compared with PFTN controls. Compared with TN and HS pigs, on d 7 PFTN pigs had increased plasma NEFA concentrations (110%; P < 0.05). Compared with TN and PFTN controls, on d 7 circulating N(tau)-methylhistidine concentrations were increased (31%; P < 0.05) in HS pigs. In summary, despite similar nutrient intake, HS pigs gained more BW and had distinctly different postabsorptive bioenergetic variables compared with PFTN controls. Consequently, these heat-induced metabolic changes may in part explain the altered carcass phenotype observed in heat-stressed pigs. PMID- 23463564 TI - Presence and biological activity of antibiotics used in fuel ethanol and corn co product production. AB - Antibiotics are used in ethanol production to control bacteria from competing with yeast for nutrients during starch fermentation. However, there is no published scientific information on whether antibiotic residues are present in distillers grains (DG), co-products from ethanol production, or whether they retain their biological activity. Therefore, the objectives of this study were to quantify concentrations of various antibiotic residues in DG and determine whether residues were biologically active. Twenty distillers wet grains and 20 distillers dried grains samples were collected quarterly from 9 states and 43 ethanol plants in the United States. Samples were analyzed for DM, CP, NDF, crude fat, S, P, and pH to describe the nutritional characteristics of the samples evaluated. Samples were also analyzed for the presence of erythromycin, penicillin G, tetracycline, tylosin, and virginiamycin M1, using liquid chromatography and mass spectrometry. Additionally, virginiamycin residues were determined, using a U.S. Food and Drug Administration-approved bioassay method. Samples were extracted and further analyzed for biological activity by exposing the sample extracts to 10(4) to 10(7) CFU/mL concentrations of sentinel bacterial strains Escherichia coli ATCC 8739 and Listeria monocytogenes ATCC 19115. Extracts that inhibited bacterial growth were considered to have biological activity. Physiochemical characteristics varied among samples but were consistent with previous findings. Thirteen percent of all samples contained low (<=1.12 mg/kg) antibiotic concentrations. Only 1 sample extract inhibited growth of Escherichia coli at 10(4) CFU/mL, but this sample contained no detectable concentrations of antibiotic residues. No extracts inhibited Listeria monocytogenes growth. These data indicate that the likelihood of detectable concentrations of antibiotic residues in DG is low; and if detected, they are found in very low concentrations. The inhibition in only 1 DG sample by sentinel bacteria suggests that antibiotic residues in DG were inactivated during the production process or are present in sublethal concentrations. PMID- 23463565 TI - Impacts of maternal selenium supply and nutritional plane on visceral tissues and intestinal biology in 180-day-old offspring in sheep. AB - Objectives were to investigate the effects of maternal Se supply and nutritional plane during gestation on offspring visceral tissues and indices of intestinal growth, vascularity, and function at 180 d of age. Rambouillet ewe lambs (n = 82, approximately 240 d of age; 52 +/- 0.8 kg BW at breeding) were allocated to a 2 * 3 factorial arrangement of treatments. Treatments included dietary Se [adequate Se (ASe, 9.5 ug/kg BW) or high Se (HSe, 81.8 ug/kg BW)] initiated at breeding and nutritional plane [60% (restricted, RES), 100% (control, CON), and 140% (high, HI) of requirements] initiated at d 50 of gestation. Ewes were fed pelleted diets and housed individually indoors. At parturition, lambs were immediately removed and fed artificial colostrum for the first 20 h followed by ad libitum access to milk replacer. At 180 +/- 2 d of age, lambs were euthanized and tissues were harvested. Birth weight was affected by nutritional treatments (P < 0.001), with decreased birth weight in RES and HI compared with CON. Offspring from RES and HI ewes had decreased (P = 0.07) blood volume compared with CON, and those born to HSe ewes had increased (P < 0.04) total visceral adiposity. Within offspring from CON ewes, those from HSe ewes had greater (P < 0.02) intestinal mass compared with ASe ewes. Within offspring from HSe ewes, both RES and HI had reduced (P <= 0.05) intestinal mass compared with CON. Jejunal capillary area density was greater (P = 0.08) in offspring from ewes fed HSe compared with ASe. In addition, area per capillary was greater (P <= 0.09) in CON compared with RES. Maternal nutritional plane tended (P <= 0.11) to alter total small intestinal vascularity, with lambs from CON being greater than RES. Expression of most mRNA for measured angiogenic factors and receptors was not altered (P <= 0.13) by maternal treatments; however, expression of glucagon-like peptide-2 (GLP-2) was decreased (P = 0.07) in offspring from RES compared with CON ewes. Offspring from ewes fed HI diets had increased (P = 0.08) jejunal mucosal maltase activity. In conclusion, maternal Se supply and nutritional plane during gestation resulted in measurable changes in offspring visceral tissues and intestinal biology, including perirenal fat, blood volume, intestinal mass, total jejunal crypt cell proliferation, area per capillary in jejunal villi, GLP-2 mRNA expression, and maltase activity at 180 d. Additional work is needed to determine impacts on intestinal function and nutrient uptake. PMID- 23463566 TI - Effects of feeding lauric acid on ruminal protozoa numbers, fermentation, and digestion and on milk production in dairy cows. AB - The objectives of this study were 1) to determine the level of lauric acid (LA) addition to the diet necessary to effectively suppress ruminal protozoa (RP) to the extent observed when a single dose was given directly into the rumen, 2) to assess LA effects on production and ruminal metabolism, and 3) to determine the time needed for RP to reestablish themselves after LA is withdrawn from the diet of lactating dairy cows. In Exp. 1, 2 Holstein cows fitted with ruminal cannulae were used in a split-plot design pilot study. Both cows consumed the same level of LA, starting with 0 g/d and increasing to 129, 270, and 438 g/d mixed into the diet. Diets were fed as total mixed ration (TMR) and contained (DM basis) 30% corn silage, 30% alfalfa silage, and 40% concentrate. Lauric acid intake linearly decreased DMI (P = 0.03), RP numbers (P < 0.01), ruminal acetate molar proportion (P = 0.03), and ruminal ammonia concentration (P = 0.03). Lauric acid intake linearly increased ruminal valerate molar proportion (P = 0.02). A quadratic response of LA consumption was observed on total ruminal VFA concentration (P < 0.01) and propionate molar proportion (P < 0.01), with maximum responses at 270 g/d of LA intake. A quadratic response of LA consumption was also observed on total ruminal free amino acid (TAA) concentration (P < 0.01), with minimum concentration at 270 g/d of LA intake. After withdrawing the greatest LA dose from the diet, RP returned to their original numbers in 12 d. In Exp. 2, 48 multiparous Holstein cows (8 with ruminal cannulae) were blocked by days in milk into 12 blocks of 4 cows (2 blocks of cannulated cows) and randomly assigned within replicated 4 * 4 Latin squares to balanced dietary treatment sequences. Diets were fed as TMR and contained (DM basis) 36% corn silage, 29% alfalfa silage, and 35% concentrate, and LA intake levels were 0, 220, 404, and 543 g/d mixed in the TMR. In Exp. 2, LA linearly reduced RP (P < 0.01), ruminal ammonia (P < 0.01), and total free AA concentration (P < 0.01); however, dietary LA also linearly decreased DM intake (P < 0.01). Intake of LA linearly reduced ruminal total VFA concentration (P < 0.01); DM, OM, NDF, and CP digestibility (P < 0.01); and milk production and milk components (P < 0.01). Therefore, LA does not appear to be a feasible RP suppressant for feeding in practical diets. PMID- 23463567 TI - Relationships among performance, residual feed intake, and temperament assessed in growing beef heifers and subsequently as 3-year-old, lactating beef cows. AB - Seventy-four beef heifers were used to evaluate relationships among performance, residual feed intake (RFI), and temperament measured as growing heifers (Phase 1) and subsequently as 3-yr-old lactating beef cows (Phase 2) in the same cohort. In both phases, females were housed in a covered facility and fed similar forage based diets, and individual feed intakes, BW, BCS, chute scores (CS), exit velocities (EV), and pen scores (PS) were collected throughout the 70-d feeding trials. In Phase 2, cows were milked on trial d 14 (lactation d 28 +/- 3.5) and trial d 70 (lactation d 84 +/- 3.5) to determine energy-corrected milk (ECM) production. Ultrasonic backfat thickness (BF), and ribeye area (REA) were evaluated on d 0 and 70 of the trial in Phase 2. Heifers were ranked by RFI and placed into Low (<0.5 SD mean RFI; n = 27), Medium (within +/- 0.5 SD; n = 23), and High (>0.5 SD mean RFI; n = 24) RFI groups. Body weight, BCS, and ADG were similar among all RFI groups; however, daily DMI differed for all groups (P < 0.01) and was greater (10.76 +/- 0.24 kg/d) for High, intermediate (9.88 +/- 0.25 kg/d) for Medium, and less (8.52 +/- 0.23 kg/d) for Low RFI heifers. When cow performance was analyzed based on RFI rank as heifers, BW, BCS, ADG, RFI, d 14 and d 70 ECM, BF, and REA were similar among RFI groups; however, cows that were most efficient as heifers (Low) had decreased (P < 0.05) daily DMI values (10.30 +/- 0.41 kg/d) compared with cows that ranked Medium (11.60 +/- 0.44 kg/d) or High (11.50 +/- 0.43 kg/d) as heifers. The Pearson rank correlation between Phase 1 and 2 RFI was r = 0.13 (P = 0.30), and Pearson rank correlations showed no relationship (P > 0.1) between RFI and temperament. Phase 1 CS was negatively associated with ADG in Phase 1 (r = -0.28; P = 0.02) and 2 (r = -0.32; P = 0.01), and positively associated with d 14 (r = 0.24; P = 0.04) and 70 (r = 0.25; P = 0.03) ECM. Phase 2 CS was negatively associated with Phase 2 ADG (r = -0.29; P = 0.01) and positively associated with d 14 (r = 0.46; P = 0.001) and 70 (r = 0.33; P = 0.004) ECM. Phase 2 PS also tended to be negatively associated with DMI in Phase 1 (r = -0.20; P = 0.096) and 2 (r = -0.20; P = 0.08). In this study, heifers that were most feed efficient subsequently consumed less feed as lactating cows and maintained similar performance. Feed efficiency was not associated with differences in temperament; however, more excitable females had poorer BW gains and tended to have reduced feed intakes but produced more ECM. PMID- 23463568 TI - Influence of dietary fiber type and amount on energy and nutrient digestibility, fecal characteristics, and fecal fermentative end-product concentrations in captive exotic felids fed a raw beef-based diet. AB - Little nutritional or metabolic information has been collected from captive exotic cats fed raw diets. In particular, fiber types and concentrations for use in raw meat-based diets for captive exotic felids have not been well studied. Our objective was to evaluate the effects of fiber type and concentration on apparent total tract energy and macronutrient digestibility, fecal characteristics, and fecal fermentative end-products in captive exotic felids. Four animals of each captive exotic species (jaguar (Panthera onca), cheetah (Acinonyz jubatus), Malayan tiger (Panthera tigris corbetti), and Siberian tiger (Panthera tigris altaica) were randomized in four 4 * 4 Latin square designs (1 Latin square per species) to 1 of the 4 raw beef-based dietary treatments (94.7 to 96.7% beef trimmings): 2 or 4% cellulose or 2 or 4% beet pulp. Felid species, fiber type, and fiber concentration all impacted digestibility and fecal fermentative end products. Inclusion of beet pulp increased (P <= 0.05) fecal short-chain fatty acids and fecal output in all cats. Inclusion of 2 and 4% cellulose, and 4% beet pulp increased (P <= 0.05) fecal bulk and diluted fecal branched-chain fatty acid concentrations compared with 2% beet pulp. Apparent total tract DM, OM, fat, and GE digestibility coefficients decreased (P <= 0.05) linearly with BW of cats. Additionally, fecal moisture, fecal score, and concentrations of fermentative end products increased (P <= 0.05) with BW. Although the response of many outcomes was dependent on cat size, in general, beet pulp increased wet fecal weight, fecal scores, and fecal metabolites, and reduced fecal pH. Cellulose generally reduced DM and OM digestibility, but increased dry fecal weight and fecal percent DM. Although beet pulp and cellulose fibers were tested individually in this study, these data indicate that the optimum fiber type and concentration for inclusion in captive exotic felid diets is likely a combination of fermentable and nonfermentable fibers, with the optimal fiber blend being dependent on species. Smaller cats, such as cheetahs and jaguars, tolerated fermentable fibers, whereas larger cats, such as Malayan and Siberian tigers, appeared to require more insoluble fibers that limit fermentation and provide fecal bulk. Further research is required to test whether these trends hold true when fed in combination. PMID- 23463569 TI - Immune modulation effect of porcine placenta extracts in weaned the pig. AB - In a previous study, we established a collection of appropriate porcine placental extracts using PBS at 80 degrees C (PE-PBS80) as a food supplement to increase immune activities in a mice model. In this study, piglets were treated with 0.1%, 0.3%, and 0.5% PE-PBS80 for 3 wk after weaning. Experiments were performed at 2 separate farms using 2 different pig varieties. Composition of white blood cells, lymphocyte activation, and cytokine concentrations were analyzed to assess the immune modulation effect. In Exp. 1, the number of white blood cells increased significantly in the PE-PBS80 treatment and T- and B-cell activation increased as well (P < 0.01). Interestingly, piglets in all treatments in Exp. 2 were naturally infected by a rotavirus at the third day of the experiment but recovered after d 10. Increased lymphocyte activation was observed in the PE PBS80 treatment (P < 0.01) regardless of viral infection. Additionally, unlike in Exp. 1, the percentage of granulocytes and concentrations of interferon-gamma, IL 1beta, and IgG increased in the PE-PBS80 treatment (P < 0.01) and were more active in the 0.3% PE-PBS80 treatment compared with the control and the other treatment. In conclusion, 0.3% PE-PBS80 treatment modulated immune activities in antigen-infected piglets. Therefore, the PE-PBS80 pig placental extract, particularly the 0.3% supplement to the normal diet, could be useful as an alternative feed supplement to modulate immune activity during the early piglet period. PMID- 23463570 TI - Investigation of sainfoin (Onobrychis viciifolia) cultivar differences on nitrogen balance and fecal egg count in artificially infected lambs. AB - Research in ruminant nutrition and helminth control with forages, which contain condensed tannins (CT), suggests that varying responses may depend not only on CT concentration but also on CT composition. An experiment was designed to test this by feeding 2 dried sainfoin cultivars (Visnovsky and Perly), which differed in CT properties, to lambs that were artificially infected with the abomasal blood sucking nematode Haemonchus contortus. Twenty-four infected lambs received 1 of these 2 cultivars; the feeds were either untreated or treated with the CT-binding polyethylene glycol over 4 wk (n = 6). The 2 cultivars were also fed to 2 * 6 uninfected lambs. Nutrient digestibility, N balance, ADG, plasma urea, together with indicators of infection [fecal egg count (FEC), abomasal worm count, per capita female fecundity, erythrocytic indices, and serum protein], were determined. The specific effects of sainfoin cultivar, CT, and infection were evaluated by contrast analysis. Digestibility of both NDF and ADF were less (P < 0.001) with Perly compared with Visnovsky. The apparent nutrient digestibility was reduced (P < 0.001) by CT. However, no clear cultivar effects were evident on N excretion and retention. Condensed tannins reduced (P = 0.05) body N retention and shifted (P < 0.001) N excretion from urine to feces. Unlike cultivar and CT, infection decreased (P = 0.002) ADG. Plasma urea concentration was decreased (P = 0.007) in Perly- compared with Visnovsky-fed lambs and was decreased (P < 0.001) by CT. Plasma concentrations of essential and semiessential AA were increased (P < 0.001) by CT. The groups of infected lambs did not clearly differ in abomasal worm counts and erythrocytic indicators. In the last 2 to 3 wk of the experiment, FEC was decreased (P <= 0.01) when feeding CT. The lack of substantial cultivar effects suggests that the differences in CT properties may have been too small to result in nutritional and anthelmintic effects. The present results indicate that sainfoin CT had a mitigating effect on FEC and, consequently, pasture infectivity. However, the reduction was too small to expect any significant benefits in an Haemonchus-dominated system. Therefore, the use of sainfoin for controlling H. contortus should only be one component within an integrated worm control system. PMID- 23463571 TI - Fatty acid biosynthesis and lipogenic enzyme activities in subcutaneous adipose tissue of feedlot steers fed supplementary palm oil or soybean oil. AB - We hypothesized that supplementing finishing diets with palm oil would promote adipocyte differentiation in subcutaneous adipose tissue of feedlot steers, and that soybean oil supplementation would depress adipocyte differentiation. Twenty eight Angus steers were assigned randomly to 3 groups of 9 or 10 steers and fed a basal diet without additional fat (control), with 3% palm oil (rich in palmitic acid), or with 3% soybean oil (rich in polyunsaturated fatty acids), for 10 wk, top-dressed daily. Palm oil had no effect (P > 0.05) on ADG, food intake, or G:F, whereas soybean oil depressed ADG (P = 0.02), food intake (P = 0.04), and G:F (P = 0.05). Marbling scores tended (P = 0.09) to be greater in palm oil-fed steers (Modest(09)) than in soybean oil-fed steers (Small(55)). Subcutaneous adipocyte mean volume was greater in palm oil-fed steers (515.9 pL) than in soybean supplemented cattle (395.6 pL; P = 0.01). Similarly, glucose and acetate incorporation into total lipids in vitro was greater in subcutaneous adipose tissue of palm oil-fed steers (119.9 and 242.8 nmol.3h(-1).10(5) cells, respectively) than adipose tissue of soybean oil-fed steers in (48.9 and 95.8 nmol.3h(-1).10(5) cells, respectively). Glucose-6-phosphate dehydrogenase and NADP-malate dehydrogenase activities were greater (P <= 0.05) in subcutaneous adipose tissue of palm oil-fed steers than in adipose tissue of control steers. Palm oil did not increase palmitic acid or decrease oleic acid in subcutaneous adipose tissue or LM, but decreased (P <= 0.05) myristoleic, palmitoleic, and cis vaccenic acid in adipose tissue, indicating a depression in stearoyl-coenzyme A desaturase activity. Soybean oil increased the proportion of alpha-linolenic acid in adipose tissue and muscle and increased linoleic acid and 18:1trans-10 in muscle. We conclude that palm oil supplementation promoted lipid synthesis in adipose tissue without depressing feed efficiency or increasing the palmitic acid content of beef. PMID- 23463573 TI - The Midwest Nursing Research Society Advances Science to Improve Health. PMID- 23463572 TI - Effects of starch- vs. fiber-based energy supplements during winter grazing on partitioning of fat among depots and adipose tissue gene expression in growing cattle and final carcass characteristics. AB - Fifty-five normal-weaned Angus steers (268 +/- 22 kg; 265 +/- 16 d of age) were used to evaluate the effects of starch- vs. fiber-based energy supplements for stocker cattle grazing low-quality dormant native range on growth performance, body composition, and adipose tissue development of different fat depots. Steers were randomly allotted to 4 treatments: 1.02 kg.steer(-1).d(-1) of a 40% CP cottonseed meal-based supplement (CON), corn/soybean meal-based supplement fed at 1% of BW (CORN), soybean hull/soybean meal-based supplement fed at 1% of BW (SBH), or dried distillers grains with solubles fed at 1% of BW (DDGS). All supplements were individually fed 5 d/wk during the 121-d winter grazing phase. After winter grazing, 3 steers per treatment were harvested to determine body composition and carcass characteristics, and collect subcutaneous (SC) and perirenal (PR) adipose tissue samples. The remaining steers grazed cool-season grass pastures for 74 d without supplementation before finishing. Steers were fed a common finishing diet for 113 d before harvest, at which time carcass characteristics were collected at a commercial abattoir. Energy supplementation increased (P < 0.01) winter grazing ADG compared with CON steers, and CORN steers had greater (P < 0.01) ADG than SBH and DDGS steers. Energy supplementation increased (P < 0.04) mesenteric/omental fat mass but did not influence (P > 0.13) 12th rib fat thickness or marbling score at intermediate harvest compared with CON steers. The mRNA expression of genes involved in lipogenesis and markers of adipogenesis were greater (P < 0.05) in PR adipose tissue of energy-supplemented steers compared with CON steers but not in SC adipose tissue. Fiber-supplemented steers had greater (P < 0.01) mRNA expression of fatty acid synthase and fatty acid binding protein 4 compared with CORN steers in PR adipose tissue but not SC adipose tissue. At final harvest, energy-supplemented steers had greater (P < 0.05) KPH and yield grade than CON steers, but no differences (P = 0.75) in marbling score were observed. Neither energy supplementation nor type of energy supplement influenced intramuscular fat deposition in stocker cattle grazing dormant native range. These data suggest that the total energy intake and stage of animal maturity during grazing supplementation were not great enough to influence marbling deposition. PMID- 23463574 TI - Perspectives of aging among persons living with chronic obstructive pulmonary disease. AB - Among pulmonary rehabilitation attendees, we explored their tendency to downplay versus acknowledge physical and psychosocial health limitations, and the subsequent impact either strategy had on how they perceive their own aging process. Participants (N = 87) were 44 to 82 years of age, and diagnosed with chronic obstructive pulmonary disease (COPD). The St. George's Respiratory Questionnaire measured their health limitations. The Attitudes to Aging Questionnaire captured their perspectives of aging. Participants downplayed their symptoms and psychosocial impact, and remained most positive about psychosocial loss and carefully reserved about psychological growth. Acknowledged activity impairment had negative consequences, however, for their perspectives of physical change. These findings signify a balanced identity and perspective of aging that supports the Identity Process Theory. We encourage nurses and other practitioners, and researchers in pulmonary rehabilitation setting, to use this theory to better understand how people with COPD adapt to aging. PMID- 23463576 TI - Beside the Geriatric Depression Scale: the WHO-Five Well-being Index as a valid screening tool for depression in nursing homes. AB - OBJECTIVE: The aim of the study was to compare criterion validities of the WHO Five Well-being Index (WHO-5) and the Geriatric Depression Scale 15-item version (GDS-15) and 4-item version (GDS-4) as screening instruments for depression in nursing home residents. METHODS: Data from 92 residents aged 65-97 years without severe cognitive impairment (Mini Mental State Examination >=15) were analysed. Criterion validities of the WHO-5, the GDS-15 and the GDS-4 were assessed against diagnoses of major and minor depression provided by the Structured Clinical Interview for DSM-IV. Subanalyses were performed for major and minor depression. Areas under the receiver operating curve (AUCs) as well as sensitivities and specificities at optimal cut-off points were computed. RESULTS: Prevalence of depressive disorder was 28.3%. The AUC value of the WHO-5 (0.90) was similar to that of the GDS-15 (0.82). Sensitivity of the WHO-5 (0.92) at its optimal cut-off of <=12 was significantly higher than that of the GDS-15 (0.69) at its optimal cut-off of >=7. The WHO-5 was equally sensitive for the subgroups of major and minor depression (0.92), whereas the GDS-15 was sensitive only for major depression (0.85), but not for minor depression (0.54). For specificity, there was no significant difference between WHO-5 (0.79) and GDS-15 (0.88), but both instruments outperformed the GDS-4 (0.53). CONCLUSIONS: The WHO-5 demonstrated high sensitivity for major and minor depression. Being shorter than the GDS-15 and superior to the GDS-4, the WHO-5 is a promising screening tool that could help physicians improve low recognition rates of depression in nursing home residents. PMID- 23463577 TI - Measurement of statistical evidence on an absolute scale following thermodynamic principles. AB - Statistical analysis is used throughout biomedical research and elsewhere to assess strength of evidence. We have previously argued that typical outcome statistics (including p values and maximum likelihood ratios) have poor measure theoretic properties: they can erroneously indicate decreasing evidence as data supporting an hypothesis accumulate; and they are not amenable to calibration, necessary for meaningful comparison of evidence across different study designs, data types, and levels of analysis. We have also previously proposed that thermodynamic theory, which allowed for the first time derivation of an absolute measurement scale for temperature (T), could be used to derive an absolute scale for evidence (E). Here we present a novel thermodynamically based framework in which measurement of E on an absolute scale, for which "one degree" always means the same thing, becomes possible for the first time. The new framework invites us to think about statistical analyses in terms of the flow of (evidential) information, placing this work in the context of a growing literature on connections among physics, information theory, and statistics. PMID- 23463575 TI - Does celiac disease influence survival in lymphoproliferative malignancy? AB - Celiac disease (CD) is associated with both lymphoproliferative malignancy (LPM) and increased death from LPM. Research suggests that co-existing autoimmune disease may influence survival in LPM. Through Cox regression we examined overall and cause-specific mortality in 316 individuals with CD+LPM versus 689 individuals with LPM only. CD was defined as having villous atrophy according to biopsy reports at any of Sweden's 28 pathology departments, and LPM as having a relevant disease code in the Swedish Cancer Register. During follow-up, there were 551 deaths (CD: n = 200; non-CD: n = 351). Individuals with CD+LPM were at an increased risk of death compared with LPM-only individuals [adjusted hazard ratio (aHR) = 1.23; 95% confidence interval (CI) = 1.02-1.48]. However, this excess risk was only seen in the first year after LPM diagnosis (aHR = 1.76), with HRs decreasing to 1.09 in years 2-5 after LPM diagnosis and to 0.90 thereafter. Individuals with CD and non-Hodgkin lymphoma (NHL) were at a higher risk of any death as compared with NHL-only individuals (aHR = 1.23; 95% CI = 0.97-1.56). This excess risk was due to a higher proportion of T cell lymphoma in CD patients. Stratifying for T- and B cell status, the HR for death in individuals with CD+NHL was 0.77 (95% CI = 0.46-1.31). In conclusion, we found no evidence that co-existing CD influences survival in individuals with LPM. The increased mortality in the first year after LPM diagnosis is related to the predominance of T-NHL in CD individuals. Individuals with CD+LPM should be informed that their prognosis is similar to that of individuals with LPM only. However, this study had low statistical power to rule our excess mortality in patients with CD and certain LPM subtypes. PMID- 23463578 TI - Cooperative iron-Bronsted acid catalysis: enantioselective hydrogenation of quinoxalines and 2H-1,4-benzoxazines. PMID- 23463579 TI - Carotid plaque hemorrhage on magnetic resonance imaging strongly predicts recurrent ischemia and stroke. AB - OBJECTIVE: There is a recognized need to improve selection of patients with carotid artery stenosis for carotid endarterectomy (CEA). We assessed the value of magnetic resonance imaging (MRI)-defined carotid plaque hemorrhage (MRIPH) to predict recurrent ipsilateral cerebral ischemic events, and stroke in symptomatic carotid stenosis. METHODS: One hundred seventy-nine symptomatic patients with >= 50% stenosis were prospectively recruited, underwent carotid MRI, and were clinically followed up until CEA, death, or ischemic event. MRIPH was diagnosed if the plaque signal intensity was >150% that of the adjacent muscle. Event-free survival analysis was done using Kaplan-Meier plots and Cox regression models controlling for known vascular risk factors. We also undertook a meta-analysis of reported data on MRIPH and recurrent events. RESULTS: One hundred fourteen patients (63.7%) showed MRIPH, suffering 92% (57 of 62) of all recurrent ipsilateral events and all but 1 (25 of 26) future strokes. Patients without MRIPH had an estimated annual absolute stroke risk of only 0.6%. Cox multivariate regression analysis proved MRIPH as a strong predictor of recurrent ischemic events (hazard ratio [HR] = 12.0, 95% confidence interval [CI] = 4.8-30.1, p < 0.001) and stroke alone (HR = 35.0, 95% CI = 4.7-261.6, p = 0.001). Meta-analysis of published data confirmed this association between MRIPH and recurrent cerebral ischemic events in symptomatic carotid artery stenosis (odds ratio = 12.2, 95% CI = 5.5-27.1, p < 0.00001). INTERPRETATION: MRIPH independently and strongly predicts recurrent ipsilateral ischemic events, and stroke alone, in symptomatic >= 50% carotid artery stenosis. The very low stroke risk in patients without MRIPH puts into question current risk-benefit assessment for CEA in this subgroup. PMID- 23463580 TI - EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences. AB - TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA-binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN-P63alpha-specific REs derived from genes closely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability. PMID- 23463581 TI - Aplasia cutis congenita of the scalp in a female infant with anophthalmia/microphthalmia-esophageal atresia syndrome negative for SOX2 mutation. PMID- 23463582 TI - Flow injection chemiluminescence determination of naphazoline hydrochloride in pharmaceuticals. AB - A simple and sensitive flow injection chemiluminescence (FI-CL) method was developed for the determination of naphazoline hydrochloride (NPZ). The method is based on the enhancing effect of NPZ on the weak CL signal from the reaction of KIO4 with H2 O2 . Experimental parameters that affected the CL signal, including the pH of the KIO4 solution, concentrations of KIO4 , H2 O2 and disodium-EDTA and flow rate were optimized. Under the optimum conditions, the increment of CL intensity was linearly proportional to the concentration of NPZ in the range 5.0 * 10(-6) to 70 * 10(-6) mol/L. The detection limit was 1.0 * 10(-6) mol/L and the relative standard deviation for 50 * 10(-6) mol/L NPZ solution was 2.8% (n = 11). In addition, a high throughput of 120 samples/h was achieved. The utility of this method was demonstrated by determining NPZ in pharmaceuticals. PMID- 23463583 TI - Is tendinitis an inflammatory disease initiated and driven by pro-inflammatory cytokines such as interleukin 1beta? AB - Tendonitis and tendinitis are terms used to describe an inflamed and painful tendon. Tendinopathy, is a descriptive term for describing clinical conditions arising from tendon injury and overuse both within and around tendons. The aim of this mini-review is to explore the role of pro-inflammatory cytokines, particularly interleukin-1beta (IL-1beta) in tendon disorders. A number of investigators including our group have proposed that pro-inflammatory cytokines such as IL-1beta are initiators of tendinopathies, stimulating inflammation, apoptosis and extracellular matrix (ECM) degradation. This is one of the reasons why IL-1beta is frequently used in culture models of tendon inflammation to study the inflammatory and catabolic responses of tenocytes. However, some researchers oppose this view and suggest that although IL-1beta may play a role in rheumatoid arthritis (RA) and osteoarthritis (OA), the involvement of IL-1beta in the development of tendinopathy is questionable. This mini-review discusses the relevant papers published in this area and summarises the evidence for and against the involvement of pro-inflammatory cytokines such as IL-1beta in tendonitis. Reaching a consensus will be important for the development and refinement of biomimetic models of tendon inflammation and the formulation of new therapeutic strategies for the treatment of tendon injuries. PMID- 23463584 TI - Gene delivery of albumin binding peptide-interferon-gamma fusion protein with improved pharmacokinetic properties and sustained biological activity. AB - We have demonstrated that gene delivery of a fusion protein of mouse interferon (IFN) gamma with mouse serum albumin (IFNgamma-MSA) was effective in prolonging the circulation half-life of IFNgamma in mice. However, the fusion to MSA greatly reduced the biological activity of IFNgamma to less than 1%. In this study, we designed IFNgamma fusion proteins with a 20 amino-acid long albumin-binding peptide (ABP) to prolong the in vivo half-life of IFNgamma without reducing its biological activity. IFNgamma-ABP and ABP-IFNgamma, two fusion proteins with the ABP being fused to the C- or N-terminal of IFNgamma, retained 40%-50% biological activities determined using a gamma-activated sequence-dependent luciferase assay. These fusion proteins exhibited the ability to bind to MSA. Gene delivery of IFNgamma-ABP or ABP-IFNgamma to mice using the hydrodynamic injection method resulted in a sustained concentration of IFNgamma in the serum compared with gene delivery of IFNgamma. In addition, the growth of mouse colon carcinoma CT-26 cells in the lung was efficiently inhibited by gene delivery of the IFNgamma fusion proteins. These results indicate that the fusion of ABP is a useful approach to achieving prolonged retention in the blood circulation through binding to serum albumin and retaining biological activity. PMID- 23463585 TI - Limb-specific emotional modulation of cervical spinal cord neurons. AB - Emotional stimuli receive prioritized attentional and motoric processing in the brain. Recent data have indicated that emotional stimuli enhance activity in the cervical spinal cord as well. In the present study, we used fMRI to investigate the specificity of this emotion-dependent spinal cord activity. We examined whether the limb depicted in a passively viewed image (upper vs. lower) differentially influenced activity in the cervical segments that innervate the upper limbs, and whether this effect was enhanced by emotion. Participants completed four fMRI runs: neutral-upper limb, neutral-lower limb, negative-upper limb, and negative-lower limb. The results indicated main effects of limb and emotion, with upper limbs and negative stimuli eliciting greater activity than lower limbs and neutral stimuli, respectively. For upper-limb runs, negative stimuli evoked more activity than did neutral stimuli. Additionally, negative stimuli depicting upper limbs produced stronger responses than did negative stimuli depicting lower limbs. These results suggest that emotional stimuli augment limb-specific responses in the spinal cord. PMID- 23463586 TI - International consensus for provisions of quality-driven care in childhood-onset systemic lupus erythematosus. AB - OBJECTIVE: To obtain international consensus around processes that support the delivery of high-quality care to patients with childhood-onset systemic lupus erythematosus (SLE) based on current recommendations and scientific evidence. METHODS: To identify process quality indicators (QIs) for the medical care of children and adolescents with childhood-onset SLE, we sent 2 Delphi questionnaires internationally to 340 physicians who treat these patients. We set consensus at 80% of completed responses. RESULTS: Two hundred ninety-seven physicians (87%) responded to the first Delphi questionnaire and 265 physicians (76%) responded to the second questionnaire. The group achieved consensus for 26 QIs addressing laboratory testing at diagnosis, health maintenance measures, diagnosis and therapy of lupus nephritis, general preventive strategies, surveillance for medication safety, counseling and evaluation of cardiovascular risk factors, as well as transition planning. Of the 26 process QIs for use in childhood-onset SLE, 11 matched those established for adults with SLE, 9 required modification, and consensus was reached for an additional 6 QIs specific to children. CONCLUSION: An international consensus for a set of process QIs for childhood-onset SLE was reached that considers unique aspects of children with childhood-onset SLE. The presented set of QIs for children and adolescents with childhood-onset SLE defines agreed-upon standards of medical care. PMID- 23463587 TI - Pending templates imprinted polymers-hypothesis, synthesis, adsorption, and chromatographic properties. AB - This is the first time when protein-imprinted polymers are prepared with "pending templates." The polymers were synthesized in the presence of a real sample (chicken egg white), rather than any known commercial proteins. Compared with a simultaneously synthesized nonimprinted control polymer, the polymers show higher adsorption capacity for abundant components (as "pending templates") in the original sample. Chromatography experiments indicated that the columns made of the imprinted polymers could retain abundant species (imprinted) and separate them from those not imprinted. Thus, the sample could be split into dimidiate subfractions with reduced complexities. "Pending template imprinting" suggests a new way to investigate molecular imprinting, especially to dissect, simplify, and analyze complicated samples through a series of polymers just imprinted by the samples per se. PMID- 23463588 TI - Tuning the work-function via strong coupling. AB - The tuning of the molecular material work-function via strong coupling with vacuum electromagnetic fields is demonstrated. Kelvin probe microscopy extracts the surface potential (SP) changes of a photochromic molecular film on plasmonic hole arrays and inside Fabry-Perot cavities. Modulating the optical cavity resonance or the photochromic film effectively tunes the work-function, suggesting a new tool for tailoring material properties. PMID- 23463589 TI - Synthesis and electrochemical performance of graphene-like WS2. AB - Graphene-like and platelike WS2 were obtained by solid-state reactions. High resolution (HR) TEM, BET, and Raman scattering studies show that the graphene like WS2 is a few-layer-structured material. It exhibits better electrochemical performances than the platelike WS2. Structural characterization indicates that metallic W and Li2S are the end products of discharge (0.01 V versus Li(+)/Li), whereas metallic W and S are the recharge (3.00 V) products. In addition, X-ray absorption near-edge structure (XANES) characterization shows that the d electrons of W deviate towards the Li (or S) atom during the discharge/charge process, thus forming a weak bond between W and Li2S (or S). PMID- 23463590 TI - Fusion within and between whorls of floral organs in Galipeinae (Rutaceae): structural features and evolutionary implications. AB - BACKGROUND AND AIMS: Most genera of the neotropical Galipeinae (tribe Galipeeae, Rutoideae) exhibit several forms and degrees of fusion between the floral organs, including the union of petals into an apparently sympetalous corolla, the joining of the stamens among themselves and to the corolla, and the partial to complete connation of carpels. Though these and others floral traits are currently used in the circumscription of species in Galipeinae, few studies have shown in detail in which way (postgenital or congenital) and to what extent these fusions occur. To elucidate these anatomical conditions, a structural study of the flowers of the Galipeinae species was carried out. METHODS: Flowers of six species from three genera of Galipeinae were studied in their morphology, anatomy and development with stereomicroscopy, light microscopy and scanning electron microscopy (SEM). KEY RESULTS: The floral tube is formed by synorganization of stamens with petals in all species, and exhibits three main patterns: (1) Conchocarpus heterophyllus and C. minutiflorus have a floral tube formed by marginal coherence/adherence of petals and filaments due to interwining trichomes (postgenital connection); (2) Erythrochiton brasiliensis has a tube formed by congenital fusion of petals and filaments; and (3) Galipea jasminiflora and Conchocarpus macrophyllus have a tube formed distally with the first pattern, and proximally with the second pattern. Although floral tubes seem to be homologous within Galipeinae, this is not true at the level of the family: the floral tube of Correa (from an only distantly related clade of the family) is formed by postgenital union of the petals representing a convergent structure. The gynoecium of the studied species of Galipeinae shows a great variability in the extent of fusion of carpel flanks. Even though different structures for the mature gynoecium were found in each genus, all genera show postgenitally fused carpel apices, which is related to the formation of a compitum, as described earlier for other members of Rutaceae. CONCLUSIONS: The degree and diversity of fusions of floral organs in Galipeinae is unique within the order Sapindales. A study of the amount of diversification of Galipeinae in South America and comparison with other clades of Rutaceae would be of interest. PMID- 23463591 TI - A computational platform for robotized fluorescence microscopy (II): DNA damage, replication, checkpoint activation, and cell cycle progression by high-content high-resolution multiparameter image-cytometry. AB - Dissection of complex molecular-networks in rare cell populations is limited by current technologies that do not allow simultaneous quantification, high resolution localization, and statistically robust analysis of multiple parameters. We have developed a novel computational platform (Automated Microscopy for Image CytOmetry, A.M.I.CO) for quantitative image-analysis of data from confocal or widefield robotized microscopes. We have applied this image cytometry technology to the study of checkpoint activation in response to spontaneous DNA damage in nontransformed mammary cells. Cell-cycle profile and active DNA-replication were correlated to (i) Ki67, to monitor proliferation; (ii) phosphorylated histone H2AX (gammaH2AX) and 53BP1, as markers of DNA-damage response (DDR); and (iii) p53 and p21, as checkpoint-activation markers. Our data suggest the existence of cell-cycle modulated mechanisms involving different functions of gammaH2AX and 53BP1 in DDR, and of p53 and p21 in checkpoint activation and quiescence regulation during the cell-cycle. Quantitative analysis, event selection, and physical relocalization have been then employed to correlate protein expression at the population level with interactions between molecules, measured with Proximity Ligation Analysis, with unprecedented statistical relevance. PMID- 23463592 TI - Research opportunities in intraoperative radiation therapy: the next decade 2013 2023. AB - The reality of intraoperative radiation therapy (IORT) practice is consistent with an efficient and highly precise radiation therapy technique to safely boost areas at risk for local recurrence. Long-term clinical experience has shown that IORT-containing multi-modality regimens appear to improve local disease control, if not survival in many diseases. Research with IORT is a multidisciplinary scenario that covers knowledge from radiation beam adapted development to advance molecular biology for bio-predictability of outcome. The technical parameters employed in IORT procedures are important information to be recorded for quality assurance and clinical results analysis. In addition, specific treatment planning systems for IORT procedures are available, to help in the treatment decision making process. A systematic revision of opportunities for research and innovation in IORT is reported including radiation beam modulation, delivery, dosimetry and planning; infrastructure and treatment factors; experimental and clinical radiobiology; clinical trials, innovation and translational research development. PMID- 23463593 TI - VEGF and TSP1 levels correlate with prognosis in advanced non-small cell lung cancer. AB - PURPOSE: There is a need for biomarkers that may help in selecting the most effective anticancer treatments for each patient. We have investigated the prognostic value of a set of angiogenesis, inflammation and coagulation markers in patients treated for advanced non-small cell lung cancer. PATIENTS AND METHODS: Peripheral blood samples were obtained from 60 patients before first line platinum-based chemotherapy +/- bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Angiogenesis, inflammation and coagulation markers vascular endothelial growth factor (VEGF), their soluble receptors 1 (VEGFR1) and 2 (VEGFR2), thrombospondin-1 (TSP-1), interleukin-6 (IL6), sialic acid (SA) and tissue factor (TF) were quantified by ELISA. RESULTS: Except for TSP-1, pre- and post-treatment levels of all markers were higher in patients than in controls (p < 0.05). There was a positive and significant correlation between VEGF and VEGFR2 before treatment. VEGF also correlated with inflammatory markers IL-6 and SA. Moreover, there was a positive and significant correlation between levels of VEGFR1 and TF. Decreased levels of TSP-1 and increased levels of VEGF were associated with shorter survival. Bevacizumab significantly modified angiogenesis parameters and caused a decrease of VEGF and an increase of TSP-1. CONCLUSION: Angiogenesis, inflammation and coagulation markers were increased in NSCLC patients. Increased levels of VEGF and low levels of TSP-1 correlated with a poor prognosis. PMID- 23463594 TI - Predictive and prognostic value of LPS-stimulated cytokine secretion in metastatic non-small cell lung cancer. AB - OBJECTIVE: Cancer patients usually develop malnutrition which may alter their innate immune system integrity. The aim of this study was to investigate the clinical relevance of chemokine response after lipopolysaccharide (LPS) stimulation in metastatic non-small cell lung cancer (NSCLC). METHODS: Blood samples from metastatic NSCLC patients were incubated with LPS before the onset of systemic therapy. Interleukin (IL)-6 and IL-8 levels at baseline and after LPS stimulation were measured and the fold change compared to baseline levels was evaluated as the stimulation index for each cytokine per patient. Results were correlated with sex, age, smoking status, histologic subtype, performance status (PS), albumin, Mini Nutritional Assessment (MNA) status and clinical outcomes. RESULTS: Totally 103 patients were evaluated. Mean (+/-SD) stimulation index was 37.6 (+/-57.8) for IL-6 and 76.7 (+/-133.4) for IL-8. The disease control rate after first-line chemotherapy was 44/80 (55 %) and the mean (+/-SD) progression free survival (PFS) and overall survival (OS) were 4.2 (+/-3.9) and 9.2 (+/-1.1) months, respectively. MNA, PS, albumin, IL-6 and IL-8 stimulation indices were univariately associated with PFS and OS. IL-8 stimulation index emerged as an independent predictor of both PFS and OS, along with PS, and albumin levels. CONCLUSION: The extent of IL-6 and IL-8 stimulation after ex vivo induction with LPS is an important predictor of clinical outcome in metastatic NSCLC patients. PMID- 23463595 TI - Intimal-medial thickness and carotid arteries lumen in irradiated patients for head and neck cancer: preliminary data of an observational study. AB - OBJECTIVES: To investigate the effect of external beam radiotherapy (EBRT) for head and neck cancer (HNC) the intimal-medial thickness (IMT) and the lumen of the carotid artery. METHODS: Patients with HNC and an indication for EBRT were enrolled. A carotid artery color Doppler examination was performed before and 6 and 12 months after EBRT. RESULTS: From 2008 to 2011, 50 patients were enrolled. The mean carotid IMT was 0.9 vs. 1.02 mm before and 6 months after EBRT, respectively (p = 0.0001). The common carotid artery lumen was narrowed without statistical significance, 6 months after EBRT (p = 0.3). 1 year from EBRT, the IMT increase and the lumen reduction were statistically significant (p = 0.001, p = 0.01, respectively). Neurological events (stroke or TIA) were not observed. CONCLUSIONS: Our data showed a significant IMT increase 6 months from EBRT without a corresponding narrowing of the common carotid lumen while a significant increase 12 months after EBRT. PMID- 23463596 TI - Long-term improvement of musician's dystonia after stereotactic ventro-oral thalamotomy. AB - OBJECTIVE: Musician's dystonia is a task-specific movement disorder that causes twisting or repetitive abnormal finger postures and movements, which tend to occur only while playing musical instruments. Such a movement disorder will probably lead to termination of the careers of affected professional musicians. Most of the currently available treatments have yet to provide consistent and satisfactory results. We present the long-term follow-up results of ventro-oral thalamotomy for 15 patients with musician's dystonia. METHODS: Between October 2003 and September 2010, 15 patients with medically intractable task-specific focal hand dystonia that occurred only while playing musical instruments underwent ventro-oral thalamotomy. We used Tubiana's musician's dystonia scale to evaluate the patients' pre- and postoperative neurological conditions. RESULTS: All patients except 1 (93%) experienced dramatic improvement of dystonic symptoms immediately after ventro-oral thalamotomy. The mean follow-up period was 30.8 months (range=4-108 months). None of the patients experienced recurrence or deterioration of symptoms during the follow-up periods. INTERPRETATION: Ventro oral thalamotomy remarkably improved musician's dystonia, and the effect persisted for a long duration. PMID- 23463598 TI - Fiber type composition of the architecturally distinct regions of human supraspinatus muscle: a cadaveric study. AB - The human supraspinatus muscle is clinically important as it is frequently injured in older adults and the elderly. We have previously shown that the supraspinatus has a complex architecture with two distinct regions each consisting of three parts. Further we have found dynamic changes in architectural parameters such as fiber bundle length markedly vary between these regions. Fiber types of the supraspinatus have not been thoroughly investigated throughout its volume and are of interest to clinicians treating supraspinatus pathologies. In this study we investigated the distribution of fiber types within the distinct regions and parts of supraspinatus. Samples of supraspinatus were excised from six distinct parts of each muscle from five formalin embalmed specimens (one male, four female; mean age 77+/-11.1 years) free of tendon pathology. Samples were frozen in liquid nitrogen and then cryosectioned. Serial sections were labeled using immunohistochemical techniques and antibodies against fast or slow myosin heavy chain isoforms. The mean percentage of Type I (slow) fibers ranged from 56.73% to 63.97%. Results demonstrated significant variations in fiber type distribution. The middle part of the anterior region has a significantly greater percentage of Type I fibers compared to that of the posterior. The superficial part of the anterior region has a greater percentage of Type II (fast) fibers compared to the middle and deep parts. Findings aid in highlighting the distinct functions of the anterior and posterior regions, and prompt the need to re evaluate assessment and treatment techniques established on a limited understanding of the fiber type distribution. PMID- 23463597 TI - GEnomes Management Application (GEM.app): a new software tool for large-scale collaborative genome analysis. AB - Novel genes are now identified at a rapid pace for many Mendelian disorders, and increasingly, for genetically complex phenotypes. However, new challenges have also become evident: (1) effectively managing larger exome and/or genome datasets, especially for smaller labs; (2) direct hands-on analysis and contextual interpretation of variant data in large genomic datasets; and (3) many small and medium-sized clinical and research-based investigative teams around the world are generating data that, if combined and shared, will significantly increase the opportunities for the entire community to identify new genes. To address these challenges, we have developed GEnomes Management Application (GEM.app), a software tool to annotate, manage, visualize, and analyze large genomic datasets (https://genomics.med.miami.edu/). GEM.app currently contains ~1,600 whole exomes from 50 different phenotypes studied by 40 principal investigators from 15 different countries. The focus of GEM.app is on user friendly analysis for nonbioinformaticians to make next-generation sequencing data directly accessible. Yet, GEM.app provides powerful and flexible filter options, including single family filtering, across family/phenotype queries, nested filtering, and evaluation of segregation in families. In addition, the system is fast, obtaining results within 4 sec across ~1,200 exomes. We believe that this system will further enhance identification of genetic causes of human disease. PMID- 23463599 TI - Single-doped white organic light-emitting device with an external quantum efficiency over 20%. AB - A white OLED with a maximum EQE of 20.1%, CIE coordinates of (0.33, 0.33) and CRI of 80 is fabricated based on platinum(II) bis(N-methyl-imidazolyl)benzene chloride (Pt-16). The device emission spectrum and the chemical structure of Pt 16 are shown in the inset of the efficiency versus luminance graph. PMID- 23463600 TI - Facile preparation of polysaccharide-coated capillaries using a room temperature ionic liquid for chiral separations. AB - In this study, the dissolution of polysaccharides into an ionic liquid was investigated and applied as a coating onto the capillary walls of a fused-silica capillary in open-tubular CEC. The coating was evaluated by examining the chiral separation of two analytes (thiopental, sotalol) with three cellulose derivatives (cellulose acetate, cellulose acetate phthalate, and cellulose acetate butyrate). Baseline separation of thiopental enantiomers was achieved by use of each polysaccharide coating (Rs: 7.0, 8.1, 7.1), while sotalol provided partial resolution (Rs: 0.7, 1.0, 0.9). In addition, reproducibility of the cellulose coated capillaries was evaluated by estimating the run-to-run and capillary-to capillary RSD values of the EOF. Both stability and reproducibility were very good with RSD values of less than 7%. PMID- 23463602 TI - Liver transplantation for biliary atresia: does the insurance type really make a difference? PMID- 23463601 TI - Serum urate levels and consumption of common beverages and alcohol among Chinese in Singapore. AB - OBJECTIVE: Western studies suggest that beverages may affect serum urate (SU) levels, but data from Asian populations are scarce. We evaluated the associations between beverages and SU levels in Singaporean Chinese. METHODS: The study population consisted of 483 subjects ages 45-74 years from the Singapore Chinese Health Study cohort, recruited between 1993 and 1998. Lifestyle factors, medical histories, and diet were collected through in-person interviews. SU levels and other biomarkers were measured from blood collected between 1994 and 1996. RESULTS: The mean age was 57.6 years and 44% were men. The geometric mean SU level was 321 MUmoles/liter (range 157-719). Mean SU levels increased with alcohol consumption (P = 0.024 for trend). The mean SU level of daily alcohol drinkers was 42.6 MUmoles/liter higher than that of nondrinkers. Similarly, increasing frequency of green tea intake was associated with rising SU levels. The highest mean SU level was observed in daily green tea drinkers (difference of 25.0 MUmoles/liter) relative to nondrinkers (P = 0.009 for trend). Compared to nondrinkers, daily alcohol drinkers had an almost 5-fold increase in association with hyperuricemia (odds ratio [OR] 4.83, 95% confidence interval [95% CI] 1.10 21.23), whereas daily green tea drinkers had a 2-fold increase in association with hyperuricemia (OR 2.12, 95% CI 1.03-4.36). The present study did not show elevated levels of SU in individuals who consumed black tea, coffee, fruit juice, or soda. CONCLUSION: Alcohol consumption increases SU levels. The finding that daily drinking of green tea is associated with hyperuricemia needs validation in future studies. PMID- 23463603 TI - A catalyst-free, one-pot three-component aminomethylation of alpha-substituted nitroacetates: theoretical and experimental studies into the rate-accelerating effects of the solvent methanol. AB - 3, 2, 1 go! An unprecedented one-pot, catalyst-free, three-component aminomethylation of alpha-substituted nitroacetates, formalin, and amines has been reported, thereby enabling the highly efficient synthesis of alpha,beta diamino acid precursors with great structural diversity. PMID- 23463604 TI - CeO2-based Pd(Pt) nanoparticles grafted onto Fe3O4/graphene: a general self assembly approach to fabricate highly efficient catalysts with magnetic recyclable capability. AB - New Pd(Pt) catalysts have been fabricated by assembling multicomponents of Fe3O4 and CeO2/Pd(Pt) on the surface of reduced graphene oxide (RGO) nanosheets in layers. The as-obtained Pd(Pt) catalysts exhibit extremely high catalytic activity in the selective hydrogenation reaction of nitrobenzene. Owing to the presence of Fe3O4, the catalysts can be easily recycled from the catalytic system through magnetic separation. Their high activity, stability, and magnetic recyclability make the as-obtained hybrids very promising as catalysts in catalytic applications. Compared to other traditional multishell magnetic catalysts that were prepared by means of layer-by-layer technology, our process is much more facile and more easily controlled. PMID- 23463605 TI - A computational platform for robotized fluorescence microscopy (I): high-content image-based cell-cycle analysis. AB - Hardware automation and software development have allowed a dramatic increase of throughput in both acquisition and analysis of images by associating an optimized statistical significance with fluorescence microscopy. Despite the numerous common points between fluorescence microscopy and flow cytometry (FCM), the enormous amount of applications developed for the latter have found relatively low space among the modern high-resolution imaging techniques. With the aim to fulfill this gap, we developed a novel computational platform named A.M.I.CO. (Automated Microscopy for Image-Cytometry) for the quantitative analysis of images from widefield and confocal robotized microscopes. Thanks to the setting up of both staining protocols and analysis procedures, we were able to recapitulate many FCM assays. In particular, we focused on the measurement of DNA content and the reconstruction of cell-cycle profiles with optimal parameters. Standard automated microscopes were employed at the highest optical resolution (200 nm), and white-light sources made it possible to perform an efficient multiparameter analysis. DNA- and protein-content measurements were complemented with image-derived information on their intracellular spatial distribution. Notably, the developed tools create a direct link between image-analysis and acquisition. It is therefore possible to isolate target populations according to a definite quantitative profile, and to relocate physically them for diffraction limited data acquisition. Thanks to its flexibility and analysis-driven acquisition, A.M.I.CO. can integrate flow, image-stream and laser-scanning cytometry analysis, providing high-resolution intracellular analysis with a previously unreached statistical relevance. PMID- 23463606 TI - Knock down of caveolin-1 affects morphological and functional hallmarks of human endothelial cells. AB - Caveolin-1 (CAV1) is the principal structural component of caveolae which functions as scaffolding protein for the integration of a variety of signaling pathways. In this study, we investigated the involvement of CAV1 in endothelial cell (EC) functions and show that siRNA-induced CAV1 silencing in the human EC line EA.hy926 induces distinctive morphological changes, such as a marked increase in cell size and formation of stress fibers. Design-based stereology was employed in this work to make unbiased quantification of morphometric properties such as volume, length, and surface of CAV1 silenced versus control cells. In addition, we showed that downregulation of CAV1 affects cell cycle progression at G1/S phase transition most likely by perturbation of AKT signaling. With the aim to assess the contribution of CAV1 to typical biological processes of EC, we report here that CAV1 targeting affects cell migration and matrix metalloproteinases (MMPs) activity, and reduces angiogenesis in response to VEGF, in vitro. Taken together our data suggest that the proper expression of CAV1 is important not only for maintaining the appropriate morphology and size of ECs but it might represent a prospective molecular target for studying key biological mechanisms such as senescence and tumorigenesis. PMID- 23463607 TI - Towards a Universal Clinical Genomics Database: the 2012 International Standards for Cytogenomic Arrays Consortium Meeting. AB - The 2012 International Standards for Cytogenomic Arrays (ISCA) Consortium Meeting, "Towards a Universal Clinical Genomic Database," was held in Bethesda, Maryland, May 21-22, 2012, and was attended by over 200 individuals from around the world representing clinical genetic testing laboratories, clinicians, academia, industry, research, and regulatory agencies. The scientific program centered on expanding the current focus of the ISCA Consortium to include the collection and curation of both structural and sequence-level variation into a unified clinical genomics database, available to the public through resources such as the National Center for Biotechnology Information's ClinVar database. Here, we provide an overview of the conference, with summaries of the topics presented for discussion by over 25 different speakers. Presentations are available online at www.iscaconsortium.org. PMID- 23463608 TI - Twenty-one years of microemulsion electrokinetic chromatography (1991-2012): a powerful analytical tool. AB - Microemulsion electrokinetic chromatography (MEEKC) is a CE separation technique, which utilizes buffered microemulsions as the separation media. In the past two decades, MEEKC has blossomed into a powerful separation technique for the analysis of a wide range of compounds. Pseudostationary phase composition is so critical to successful resolution in EKC, and several variables could be optimized including surfactant/co-surfactant/oil type and concentration, buffer content, and pH value. Additionally, MEEKC coupled with online sample preconcentration approaches could significantly improve the detection sensitivity. This review comprehensively describes the development of MEEKC from the period 1991 to 2012. Areas covered include basic theory, microemulsion composition, improving resolution and enhancing sensitivity methods, detection techniques, and applications of MEEKC. PMID- 23463609 TI - Transparent stretchable single-walled carbon nanotube-polymer composite films with near-infrared fluorescence. AB - We report transparent stretchable single-walled carbon nanotube-polymer composite films that emit pronounced Raman and near-infrared fluorescence with a fine spatial resolution. The independent modulation in Raman and fluorescence spectra is demonstrated in response to touch and temperature. The optical signal transduction of transparent stretchable optoelectronic films may enable a paradigm shift in touch-sensing devices eliminating electrical interconnects. PMID- 23463610 TI - Differences between women and men with recent-onset axial spondyloarthritis: results from a prospective multicenter French cohort. AB - OBJECTIVE: To clarify sex differences in early axial spondyloarthritis (SpA). METHODS: In total, 475 patients included in the Devenir des Spondylarthropathies Indifferenciees Recentes (Outcome of Recent Undifferentiated Spondylarthropathies) cohort, a prospective multicenter French cohort of patients with early inflammatory back pain suggestive of SpA, and fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA were studied. The clinical and imaging features were compared between sexes and according to the clinical or imaging arm of the ASAS criteria using univariate and multivariate analysis. RESULTS: Comparisons between the 239 men and 236 women showed that women had higher disease activity when measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Patient Global Score and higher fatigue and functional scores despite having less radiographic sacroiliitis and magnetic resonance imaging (MRI) inflammation of sacroiliac joints and the spine than men. Disease activity measured by the C-reactive protein (CRP)-based Ankylosing Spondylitis Disease Activity Score was not different between men and women. In contrast to patients classified with the clinical arm, disease activity and functional scores did not differ between women and men with sacroiliitis on imaging scans, except for fatigue and the Ankylosing Spondylitis Quality of Life questionnaire. Women with sacroiliitis had more peripheral involvement and more family history, whereas HLA-B27 positivity, elevated CRP, and MRI inflammation of the spine were associated with male sex. CONCLUSION: Women with early axial SpA according to the ASAS criteria had greater disease activity when measured by the BASDAI and worse functioning despite fewer radiologic abnormalities than men. The differences in disease expression may be confounding factors to establish the diagnosis of SpA and to assess disease activity in women, suggesting that the imaging arm is a pivotal measure in the ASAS criteria. PMID- 23463611 TI - Pregnancy after a diagnosis of estrogen receptor-positive breast cancer does not affect prognosis. PMID- 23463612 TI - Parenchymal alterations in cirrhotic livers in patients with hepatopulmonary syndrome or portopulmonary hypertension. AB - Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are distinct pulmonary vascular complications of cirrhosis. Little is known about possible associated hepatic histopathological features. Explanted livers from patients clinically diagnosed with HPS (n = 8) or PPH (n = 7) and cirrhotic explants from controls (n = 30) without HPS or PPH were evaluated with trichrome histochemistry, anti-glutamine synthetase (anti-GS), and anti-CD34 immunohistochemistry (IHC). Trichrome stains were characterized by cirrhotic nodules (CNs) of various sizes, including incomplete septal cirrhosis (ISC). ISC was overrepresented in the HPS (4/8 or 50%) and PPH livers (3/7 or 43%); in addition, neither group had micronodular cirrhosis. The control explants showed the entire spectrum of nodules: micronodular, macronodular, mixed CNs, and ISC (P = 0.04). The variability of cirrhosis severity was shown with the Laennec grading system (0-6). The cirrhosis of the majority of the HPS (6/8) and PPH livers (6/7) was scored as mild, whereas the control explants were more evenly distributed across the mild (14/30) and moderate/severe grades (16/30). GS positivity was retained in a perivenular location as the dominant pattern in each explant group. CD34 staining detected capillarized sinusoids of CNs as well as vascular channels within septa, but no significant differences were found between the groups. None of the observed light microscopy or histochemistry and IHC patterns showed a correlation with the underlying liver disease. Although our results demonstrate variable architectural and vascular remodeling within and between explant livers regardless of the presence or types of pulmonary complications, there were differences in explants with HPS or PPH versus controls that correlated with less severe cirrhosis. PMID- 23463613 TI - Transition to next generation analysis of the whole mitochondrial genome: a summary of molecular defects. AB - The diagnosis of mitochondrial disorders is challenging because of the clinical variability and genetic heterogeneity. Conventional analysis of the mitochondrial genome often starts with a screening panel for common mitochondrial DNA (mtDNA) point mutations and large deletions (mtScreen). If negative, it has been traditionally followed by Sanger sequencing of the entire mitochondrial genome (mtWGS). The recently developed "Next-Generation Sequencing" (NGS) technology offers a robust high-throughput platform for comprehensive mtDNA analysis. Here, we summarize the results of the past 6 years of clinical practice using the mtScreen and mtWGS tests on 9,261 and 2,851 unrelated patients, respectively. A total of 344 patients (3.7%) had mutations identified by mtScreen and 99 (3.5%) had mtDNA mutations identified by mtWGS. The combinatorial analyses of mtDNA and POLG revealed a diagnostic yield of 6.7% in patients with suspected mitochondrial disorders but no recognizable syndromes. From the initial mtWGS-NGS cohort of 391 patients, 21 mutation-positive cases (5.4%) have been identified. The mtWGS-NGS provides a one-step approach to detect common and uncommon point mutations, as well as deletions. Additionally, NGS provides accurate, sensitive heteroplasmy measurement, and the ability to map deletion breakpoints. A new era of more efficient molecular diagnosis of mtDNA mutations has arrived. PMID- 23463614 TI - A four-component reaction involving in situ generated organometallic reagents: straightforward access to beta-amino esters. AB - Four in one: A straightforward synthesis of beta(2,3)-amino esters is described through a new zinc-mediated, cobalt-catalyzed four-component reaction between organic bromides, alkyl acrylates, amines, and aldehydes (see scheme). Synthesis involves a Mannich-related conjugate addition/aza-aldol domino sequence, allowing the formation of three single bonds in one step. A reaction mechanism, emphasizing the crucial role of zinc salts, is described. PMID- 23463616 TI - A novel fluorescent sensor for measurement of CFTR function by flow cytometry. AB - Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis. CFTR-dependent iodide transport measured by fluorescent quenching of ectopically expressed halide-sensitive yellow fluorescent protein (YFP) is widely being used to study CFTR function by microscopy or plate readers. Since YFP fluorescence in these systems is dependent on YFP expression levels and iodide concentration, differences in sensor expression level between experimental units are normalized at the start of each experiment. To allow accurate measurement of CFTR function by flow cytometry, we reasoned that co-expression of an iodide insensitive fluorescent protein would allow for normalization of sensor expression levels and more accurate quantification of CFTR function. Our data indicated that dsRed and mKate fluorescence are iodide insensitive, and we determined an optimal format for co-expression of these fluorescent proteins with halide-sensitive YFP. We showed using microscopy that ratiometric measurement (YFP/mKate) corrects for differences in sensor expression levels. Ratiometric measurements were essential to accurately measure CFTR function by flow cytometry that we here describe for the first time. Mixing of wild type or mutant CFTR expressing cells indicated that addition of approximately 10% of wild type CFTR expressing cells could be distinguished by ratiometric YFP quenching. Flow cytometric ratiometric YFP quenching also allowed us to study CFTR mutants associated with differential residual function upon ectopic expression. Compared with conventional plate-bound CFTR function assays, the flow cytometric approach described here can be used to study CFTR function in suspension cells. It may be further adapted to study CFTR function in heterologous cell populations using cell surface markers and selection of cells that display high CFTR function by cell sorting. PMID- 23463615 TI - Crossmodal correspondences between odors and contingent features: odors, musical notes, and geometrical shapes. AB - Olfactory experiences represent a domain that is particularly rich in crossmodal associations. Whereas associations between odors and tastes, or other properties of their typical sources such as color or temperature, can be straightforwardly explained by associative learning, other matchings are much harder to explain in these terms, yet surprisingly are shared across individuals: The majority of people, for instance, associate certain odors and auditory features, such as pitch (Belkin, Martin, Kemp, & Gilbert, Psychological Science 8:340-342, 1997; Crisinel & Spence, Chemical Senses 37:151-158, 2012b) or geometrical shapes (Hanson-Vaux, Crisinel, & Spence, Chemical Senses 38:161-166, 2013; Seo, Arshamian, et al., Neuroscience Letters 478:175-178, 2010). If certain odors might indeed have been encountered while listening to certain pieces of music or seeing certain geometrical shapes, these encounters are very unlikely to have been statistically more relevant than others; for this reason, associative learning from regular exposure is ruled out, and thus alternative explanations in terms of metaphorical mappings are usually defended. Here we argue that these associations are not primarily conceptual or linguistic, but are grounded in structural perceptual or neurological determinants. These cases of crossmodal correspondences established between contingent environmental features can be explained as amodal, indirect, and transitive mappings across modalities. Surprising associations between odors and contingent sensory features can be investigated as genuine cases of crossmodal correspondences, akin to other widespread cases of functional correspondences that hold, for instance, between auditory and visual features, and can help reveal the structural determinants weighing on the acquisition of these crossmodal associations. PMID- 23463617 TI - A good manuscript review for the European Journal of Cardiovascular Nursing. PMID- 23463618 TI - Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy. AB - AIM: Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel-IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM((r)) to describe the time course of clopidogrel-IM in plasma and to design a sparse-sampling strategy to predict clopidogrel-IM exposures for use in characterizing anti-platelet activity. METHODS: Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel-IM using reverse phase high performance liquid chromatography. A two-compartment (2-CMT) PK model with first-order absorption and elimination plus an absorption lag-time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3-12 post-dose samples. RESULTS: A two-compartment model with EHC provided the best fit and reduced bias in C(max) (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two-compartment model, AUC(0-24) was similar for both models (median PE% = 1.39%). The OSS for fitting the two-compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re-fitting this model to a reduced dataset considering only these sampling times. CONCLUSIONS: A two-compartment model considering EHC best characterized the time course of clopidogrel-IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel-IM exposures. PMID- 23463619 TI - Roles of I(f) and intracellular Ca2+ release in spontaneous activity of ventricular cardiomyocytes during murine embryonic development. AB - In recent years, the contribution of I(f), an important pacemaker current, and intracellular Ca(2+) release (ICR) from sarcoplasmic reticulum to pacemaking and arrhythmia has been intensively studied. However, their functional roles in embryonic heart remain uncertain. Using patch clamp, Ca(2+) imaging, and RT-PCR, we found that I(f) regulated the firing rate in early and late stage embryonic ventricular cells, as ivabradine (30 uM), a specific blocker of I(f), slowed down action potential (AP) frequency. This inhibitory effect was even stronger in late stage cells, though I(f) was down-regulated. In contrast to I(f), ICR was found to be indispensable for the occurrence of APs in ventricular cells of different stages, because abolishment of ICR with ryanodine and 2-aminoethoxydiphenyl borate (2-APB), specific blockers of ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs), completely abolished APs. In addition, we noticed that RyR- and IP3R-mediated ICR coexisted in early-stage ventricular cells and RyRs functionally dominated. While at late stage RyRs, but not IP3Rs, mediated ICR. In both early and late stage ventricular cells, Na-Ca exchanger current (I(Na/Ca)) mediated ICR-triggered depolarization of membrane potential and resulted in the initiation of APs. We also observed that different from I(f), which presented as the substantial component of the earlier diastolic depolarization current, application of ryanodine, and/or 2-APB slowed the late phase of diastolic depolarization. Thus, we conclude that in murine embryonic ventricular cells I(f) regulates firing rate, while RyRs and IP3Rs (early stage) or RyRs (late stage)-mediated ICR determines the occurrence of APs. PMID- 23463620 TI - Human immunodeficiency virus status has no effect on survival in patients with non-small cell lung cancer. PMID- 23463621 TI - Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists. AB - The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up- and down regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma. PMID- 23463622 TI - Efficient small bandgap polymer solar cells with high fill factors for 300 nm thick films. AB - A high-molecular-weight conjugated polymer based on alternating electron-rich and electron-deficient fused ring systems provides efficient polymer solar cells when blended with C60 and C70 fullerene derivatives. The morphology of the new polymer/fullerene blend reduces bimolecular recombination and allows reaching high fill factors and power conversion efficiencies for films up to 300 nm thickness. PMID- 23463623 TI - Improving the care of patients with rheumatic diseases who have cardiovascular risk: comment on the article by Gossec et al. PMID- 23463624 TI - A randomized phase II study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II. AB - BACKGROUND: Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have non-overlapping toxic effects and synergy pre clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study. PATIENTS AND METHODS: Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m(2) b.i.d. days 1-28) alone (C) or with oral cyclophosphamide (100 mg/m(2) days 1-14 of a 28-day cycle) (CCy) for up to six cycles. RESULTS: Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) -13.4 to 29.1]. Significant toxic effect was uncommon: grade >=3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade >=3 fatigue in 2 (5%) versus 5 patients (13%) and grade >=2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival. CONCLUSION: The difference in tumour response suggests a reasonable chance that CCy is superior to C alone. PMID- 23463625 TI - Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group. AB - BACKGROUND: This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m(2)/day 1 plus capecitabine 1000 mg/m(2) bid/days 1-14 or with irinotecan 200 mg/m(2)/day 1 plus capecitabine 800 mg/m(2) bid/days 1-14 both every 21 days. The primary end point was 6 months progression-free survival (PFS). RESULTS: A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx bevacizumab: n = 127; mCapIri-bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%-84%) and 84% (95% CI, 77%-90%). Median PFS and OS were 10.4 months (95% CI, 9.0-12.0) and 24.4 months (95% CI, 19.3-30.7) with CapOx bevacizumab, and 12.1 months (95% CI, 10.8-13.2) and 25.5 months (95% CI, 21.0 31.0) with mCapIri-bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx-bevacizumab and in 16% with mCapIri bevacizumab. CONCLUSIONS: Both, CapOx-bevacizumab and mCapIri-bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri. PMID- 23463626 TI - Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. AB - BACKGROUND: Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS: Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS: A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS: Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients. PMID- 23463627 TI - R-phycoerythrin-conjugated antibodies are inappropriate for intracellular staining of murine plasma cells. AB - Phycoerythrin (PE) is a type of phycobiliproteins found in cyanobacteria and red algae. PE-conjugated antibodies are broadly used for flow cytometry and immunofluorescence microscopy. Because nonspecific binding of antibodies results in decreased analytic accuracy, numerous efforts have been made to unveil cases and mechanisms of nonspecific bindings. However, nonspecific binding of specific cell types by a fluorescent dye-conjugated form of antibody has been rarely reported. In the present study, we discovered that PE-conjugated antibodies, but not FITC- or APC-antibodies, selectively stained lamina propria plasma cells (LP PCs) from the murine small intestine after membrane permeabilization. We demonstrated that LP-PC-selective staining with PE-antibodies was not due to interactions of antibody-epitope or antibody-Fc receptor. This unexpected staining by PE-antibody was not dependent on the mouse strain of LP-PCs, experimental methods, or origin species of the antibody, but dependent on PE itself. This phenomenon was also observed in plasma cells isolated from bone marrow, spleen, and mesenteric lymph nodes. Furthermore, in vitro activated B cells and in vivo generated LP-PCs were also selectively stained by PE-conjugated antibodies. Taken together, these results show that PE-conjugated antibodies are inappropriate for intracellular staining of murine plasma cells. PMID- 23463628 TI - In vivo performance evaluation and establishment of IVIVC for osmotic pump based extended release formulation of milnacipran HCl. AB - The objective of the present study was to carry out a pharmacokinetics evaluation of an oral modified release formulation [Aquarius EKX 19102 SRX-2 based osmotic pump (OP)] containing highly soluble milnacipran HCl (MH) as a model drug. It was also aimed at developing an in vitro-in vivo correlation (IVIVC) model for a developed OP. In vivo plasma concentration data were obtained from six healthy male New Zealand albino rabbits after administration of immediate-release milnacipran HCl solution (IRMHSOL) and milnacipran HCl osmotic pump (MHOP). In vitro samples were analysed using an in house developed spectrophotometry method and in vivo samples were analysed using a RP-HPLC method developed by the author. A deconvolution based Level A model was attempted through a correlation of the percent in vivo input obtained through deconvolution and the percent in vitro dissolution obtained experimentally. A good correlation between the percentages dissolved vs absorbed (R(2) = 0.978) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of the percent prediction error, which was found to be below 15%. In a nutshell, the success of the present study warrants further studies in patient volunteers to assess the ability of the MHOP to provide an effective therapy for depression. PMID- 23463629 TI - Should minors be considered as potential living liver donors? AB - For many patients, living donor liver transplantation represents their only hope of receiving a lifesaving graft. In certain (albeit rare) cases, a minor will be the only suitable donor. Living liver donation by minors has been reported in several countries. In the academic literature and professional guidelines, little attention is paid to the development of an ethical framework for this practice. The focus is frequently limited to the donation of regenerative tissues and kidneys. However, liver donation differs in important respects because of the increased medical risks and the lack of substitute therapies. Therefore, in this article, we assess whether living liver donation by minors is ethically appropriate. We argue that living liver donation by minors is justifiable only if minors possess the capacity to consent to donation or if the procedure is in their best interests. Although minors may possess adult-like levels of cognitive maturity, they lack sufficient psychosocial maturity to give valid consent to donation. In addition, living liver donation is generally not in a minor's best interests. With respect to the latter, the potential psychological benefits that a minor may experience as a result of living liver donation are insufficiently empirically supported and are unlikely to outweigh the short- and long-term medical and psychological risks. Therefore, we conclude that minors should not be considered as potential living liver donors. PMID- 23463630 TI - The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. AB - Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital neutropenia (CN) and cyclic neutropenia (CyN). We screened CN (n = 395) or CyN (n = 92) patients for ELANE mutations and investigated the impact of mutations on mRNA expression, protein expression, and activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN patients, 69 of them were novel. CyN-associated mutations were predicted to be more benign than CN-associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R mutations, malignant transformation, and the need for hematopoietic stem cell transplantation was significantly higher in CN patients with ELANE mutation than in ELANE mutation negative patients. Cellular elastase activity was reduced in neutrophils from CN/CyN patients, irrespective of the mutation status. In CN, enzymatic activity was significantly lower in patients with ELANE mutations compared with those with wild-type ELANE. Despite differences in the spectrum of mutations in CN or CyN, type or localization of mutation only partially determine the clinical phenotype. Specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation. PMID- 23463631 TI - Control of Fiat (factor inhibiting ATF4-mediated transcription) expression by Sp family transcription factors in osteoblasts. AB - FIAT (factor inhibiting ATF4-mediated transcription) represses Osteocalcin gene transcription and inhibits osteoblast activity by heterodimerizing with ATF4 to prevent it from binding DNA. It thus appears important to identify and characterize the molecular mechanisms that control Fiat gene expression in osteoblasts. In silico sequence analysis identified a canonical GC-box within a 1,400 bp region of the proximal Fiat gene promoter. Electrophoretic mobility shift assays (EMSA) with MC3T3-E1 osteoblastic cells nuclear extracts indicated that the transcription factors Sp1 and Sp3, but not Sp7/OSTERIX, bound this proximal GC-box. Chromatin immunoprecipitation confirmed interaction of the two transcription factors with the Fiat promoter GC-element in living osteoblasts. Transient transfection studies showed that Sp1 dose-dependently activated the expression of a Fiat-luciferase reporter construct while both the long or short isoforms of Sp3 dose-dependently inhibited transcription from the Fiat reporter construct. Transfection of an Sp7/OSTERIX expression vector did not affect expression of the Fiat-luciferase reporter. Co-transfection of increasing amounts of the Sp3 expression vector in the context of maximal Sp1-dependent Fiat luciferase activation led to dose-dependent repression of the expression of the reporter. Using RNA knockdown, we measured a reduction in steady-state Fiat expression when Sp1 was inhibited, and a reciprocal increase upon Sp3 knockdown. In parallel, treatment of osteoblasts with WP631, which prevents Sp1/DNA interactions, strongly inhibited the expression of Fiat and reduced the occupancy of the Fiat promoter proximal GC-box by Sp1. Taken together, our results suggest an interplay between Sp1 and Sp3 as a mechanism involved in the control of Fiat gene expression in osteoblasts. PMID- 23463632 TI - Increased copy-number and not DNA hypomethylation causes overexpression of the candidate proto-oncogene CYP24A1 in colorectal cancer. AB - In colorectal cancer (CRC) the vitamin D catabolizing enzyme 1,25 dihydroxyvitamin D 24-hydroxylase (CYP24A1) is overexpressed with a potentially significant, positive impact on the catabolism of 1,25-dihydroxyvitamin D3 (1,25 D3 ). However, the underlying mechanism of CYP24A1 overexpression is poorly understood. In the present study, we investigated possible causes including hypomethylation of the CYP24A1 promoter, amplification of the CYP24A1 gene locus (20q13.2), and altered expression of CYP24A1-specific transcription factors. We quantified CYP24A1 gene copy-number, performed bisulfite sequencing of the CYP24A1 promoter to assess DNA methylation, and measured mRNA expression of CYP24A1, 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1), vitamin D receptor (VDR) and retinoid X receptor (RXR). We found that 77 (60%) out of 127 colorectal tumors showed increased CYP24A1 gene copy-number and that more than 6 copies of CYP24A1 correlated positively with CYP24A1 mRNA expression suggestive of a causal relationship. No differences in CYP24A1 promoter methylation were found between tumor tissue and adjacent mucosa from the same patient or between tissues with high or low mRNA expression, thus excluding DNA hypomethylation as a possible cause of CYP24A1 overexpression in CRC. Furthermore, mRNA expression of several factors involved in replication licensing positively correlated with CYP24A1 mRNA expression, raising the possibility that CYP24A1 overexpression might favor increased proliferation in tumors by suppressing local 1,25-D3 levels. We conclude that high copy-number gain is a key determinant of CYP24A1 overexpression in CRC. Other postulated causes of CYP24A1 overexpression including promoter hypomethylation and enhanced VDR and/or RXR expression do not appear to be involved. PMID- 23463634 TI - All-graphene core-sheath microfibers for all-solid-state, stretchable fibriform supercapacitors and wearable electronic textiles. PMID- 23463633 TI - Screening for lectins from basidiomycetes and isolation of Punctularia atropurpurascens lectin. AB - Aqueous extracts of basidiomycete fungi were screened for the presence of lectins by hemagglutination (HA) assays with mouse, rabbit, and sheep red blood cells. From mycelia and/or fruiting bodies, 23 extracts were prepared; 15 extracts exhibited HA activity towards mouse erythrocytes, with specific activities ranging from 12 to 440 lectin units (LU) mg(-1) protein. In HA inhibition assays, 43 carbohydrates including mono-, di-, tri-, tetrasaccharides, glycoproteins, and polysaccharides were tested as haptens, to determine the saccharide-binding specificities of the lectins. A novel lectin with specificity towards N-acetyl glucosamine was purified from mycelia of Punctularia atropurpurascens using affinity chromatography on chitosan-Sepharose. The lectin has a subunit molecular mass of 67 kDa determined by SDS-PAGE and a pI of 5.0. PMID- 23463635 TI - Transfusion-transmitted malaria in Ghana. AB - BACKGROUND: In sub-Saharan Africa, the prevalence of malaria parasitemia in blood donors varies from 0.6% to 50%. Although the burden of TTM in malaria-endemic countries is unknown, it is recommended that all donated blood is screened for malaria parasites. This study aimed to establish the incidence of TTM and identify a suitable screening test. METHODS: Pregnant women, children, and immunocompromised malaria-negative transfusion recipients in a teaching hospital in Ghana were recruited over the course of 1 year. Parasites detected in recipients within 14 days of the transfusion were genotyped and compared to parasites in the transfused blood. The presence of genotypically identical parasites in the recipient and the transfused blood confirmed transfusion transmitted malaria. Four malaria screening tests were compared to assess their usefulness in the context of African blood banks. RESULTS: Of the 50 patients who received transfusions that were positive for Plasmodium falciparum by polymerase chain reaction (PCR), 7 recipients developed PCR-detectable parasitemia. In only 1 of the 50 recipients (2%) was the parasite identical to that in the transfused blood. The prevalence of P. falciparum malaria in transfused blood was 4.7% (21/445) by microscopy, 13.7% (60/440) by rapid diagnostic test, 18% (78/436) by PCR, and 22.2% (98/442) by enzyme immunoassay. CONCLUSIONS: Although malaria parasites are commonly detected in blood donors in malaria-endemic areas, transfusion-transmitted malaria occurs infrequently. Policies recommend screening blood donors for malaria, but none of the commonly used methods is sufficiently sensitive to be used by blood banks in malaria-endemic countries. PMID- 23463636 TI - Treatment of pediatric refractory coccidioidomycosis with combination voriconazole and caspofungin: a retrospective case series. AB - BACKGROUND: Coccidioidomycosis is a spectrum of diseases caused by the dimorphic fungi Coccidioides. Current regimens for severe or disseminated disease include fluconazole, itraconazole, or amphotericin; newer triazoles (ie, voriconazole, posaconazole) have been demonstrated to be useful in refractory disease. Previous reported experience with combination triazole and caspofungin therapy has been very limited; however, the utility of this combination for treatment of other invasive fungal diseases suggests potential benefit in refractory coccidioidomycosis. METHODS: We conducted a retrospective review of 9 pediatric patients treated with combination voriconazole and caspofungin (V/C) salvage therapy for refractory coccidioidomycosis at two children's hospitals between January 2000 and June 2012. RESULTS: Nine children with refractory coccidioidomycosis were treated with V/C salvage therapy after failing conventional therapy consisting of a triazole, amphotericin B, or a combination of both. Eight of the 9 patients are currently in remission; 1 patient with central nervous system involvement continues to progress. CONCLUSIONS: We report our positive clinical experience treating medically refractory coccidioidomycosis in the pediatric population with concurrent voriconazole and caspofungin therapy. Additional in vitro and in vivo evaluations are warranted to support the role of V/C salvage therapy for refractory coccidioidomycosis. PMID- 23463637 TI - Pediatric coccidioidomycosis in central California: a retrospective case series. AB - BACKGROUND: Coccidioidomycosis, an endemic fungal infection seen throughout the southwestern United States, is not well described in children. METHODS: We performed a retrospective observational study of all children admitted to Children's Hospital Central California with coccidioidomycosis from 1 January 2010 to 1 September 2011. RESULTS: Thirty-three children, aged 6 months to 17 years, were hospitalized during the study period. These included patients with pneumonia (n = 28), pleural effusion (n = 13), pleural empyema (n = 4), lung abscess (n = 7), pericarditis (n = 2), osteomyelitis (n = 5), meningitis/cerebritis (n = 2), and vocal cord infection (n = 1). Mediastinitis, with radiographic evidence of purulence and necrotic/abscessed lymph nodes in the mediastinum, was present in 7 patients (21%) and tended to occur more often in younger children (median age, 3 years [range, 0.5-11 years] vs 7 years [range, 0.6-17 years] for non-mediastinitis patients; P = .10). Seven patients were admitted to the intensive care unit and 10 required surgical intervention. One patient died of meningitis. Hospitalizations were longer for patients with mediastinitis (median, 130 days [range, 58-200 days] vs 43 days [range, 3-273 days for non-mediastinitis patients]; P < .01) and those with maximum coccidioidal complement fixing antibody titers >=1:128 (median, 174 days [range, 53-273 days] vs 33 days [range, 3-200 days] for those with maximum titers <1:128; P < .01). CONCLUSIONS: Coccidioidomycosis causes a substantial disease burden in the children of central California. Mediastinitis is common and tends to occur in younger children. Patients with mediastinitis or elevated coccidioidal complement fixation titers require longer hospitalizations. Further research is needed on the prevention and treatment of this disease. PMID- 23463638 TI - Elements of style in managing coccidioidomycosis. PMID- 23463639 TI - A new assay: specific interferon-gamma detection for the diagnosis of previous Q fever. PMID- 23463640 TI - Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. AB - BACKGROUND: Despite substantial interest in biomarkers, their impact on clinical outcomes and variation with bacterial strain has rarely been explored using integrated databases. METHODS: From September 2006 to May 2011, strains isolated from Clostridium difficile toxin enzyme immunoassay (EIA)-positive fecal samples from Oxfordshire, United Kingdom (approximately 600,000 people) underwent multilocus sequence typing. Fourteen-day mortality and levels of 15 baseline biomarkers were compared between consecutive C. difficile infections (CDIs) from different clades/sequence types (STs) and EIA-negative controls using Cox and normal regression adjusted for demographic/clinical factors. RESULTS: Fourteen day mortality was 13% in 2222 adults with 2745 EIA-positive samples (median, 78 years) vs 5% in 20,722 adults with 27,550 EIA-negative samples (median, 74 years) (absolute attributable mortality, 7.7%; 95% CI, 6.4%-9.0%). Mortality was highest in clade 5 CDIs (25% [16 of 63]; polymerase chain reaction (PCR) ribotype 078/ST 11), then clade 2 (20% [111 of 560]; 99% PCR ribotype 027/ST 1) versus clade 1 (12% [137 of 1168]; adjusted P < .0001). Within clade 1, 14-day mortality was only 4% (3 of 84) in ST 44 (PCR ribotype 015) (adjusted P = .05 vs other clade 1). Mean baseline neutrophil counts also varied significantly by genotype: 12.4, 11.6, and 9.5 * 10(9) neutrophils/L for clades 5, 2 and 1, respectively, vs 7.0 * 10(9) neutrophils/L in EIA-negative controls (P < .0001) and 7.9 * 10(9) neutrophils/L in ST 44 (P = .08). There were strong associations between C. difficile-type-specific effects on mortality and neutrophil/white cell counts (rho = 0.48), C-reactive-protein (rho = 0.43), eosinophil counts (rho = -0.45), and serum albumin (rho = -0.47). Biomarkers predicted 30%-40% of clade-specific mortality differences. CONCLUSIONS: C. difficile genotype predicts mortality, and excess mortality correlates with genotype-specific changes in biomarkers, strongly implicating inflammatory pathways as a major influence on poor outcome after CDI. PCR ribotype 078/ST 11 (clade 5) leads to severe CDI; thus ongoing surveillance remains essential. PMID- 23463641 TI - Specific interferon gamma detection for the diagnosis of previous Q fever. AB - BACKGROUND: Current practice for diagnosis of Q fever, caused by the intracellular pathogen Coxiella burnetii, relies mainly on serology and, in prevaccination assessment, on skin tests (STs), which both have drawbacks. In this study, C. burnetii-specific interferon gamma (IFN-gamma) production was used as a new diagnostic tool for previous Q fever, circumventing most of these drawbacks. Our aim was to compare this test to serology and ST. METHODS: One thousand five hundred twenty-five individuals from an endemic area with a risk for chronic Q fever were enrolled. IFN-gamma production was measured after in vitro stimulation of whole blood with C. burnetii antigens. Various formats using different C. burnetii antigens were tested. Serology and ST were performed in all individuals. RESULTS: In all assay formats, C. burnetii-specific IFN-gamma production was higher (P < .0001) in seropositive or ST-positive subjects than in seronegative and ST-negative subjects. Whole blood incubated for 24 hours with C. burnetii Nine Mile showed optimal performance. After excluding subjects with equivocal serology and/or borderline ST results, IFN-gamma production was 449 +/- 82 pg/mL in the positive individuals (n = 219) but only 21 +/- 3 pg/mL in negative subjects (n = 908). Using Bayesian analysis, sensitivity and specificity (87.0% and 90.2%, respectively) were similar to the combination of serology and ST (83.0% and 95.6%, respectively). Agreement with the combination of serology and ST was moderate (84% concordance; kappa = 0.542). CONCLUSIONS: Specific IFN gamma detection is a novel diagnostic assay for previous C. burnetii infection and shows similar performance and practical advantages over serology and ST. Future studies to investigate the clinical value in practice are warranted. PMID- 23463642 TI - Does infection with specific Clostridium difficile strains or clades influence clinical outcome? PMID- 23463643 TI - Source control review in clinical trials of anti-infective agents in complicated intra-abdominal infections. AB - In clinical trials of complicated intra-abdominal infections, assessment of adequacy of the initial surgical approach to the management of the infection is of considerable importance in determining outcome. Antibiotic therapy would not be expected to adequately treat the infection if the surgical procedure was inadequate with respect to source control. Inclusion of such cases in an efficacy analysis of a particular therapeutic antibiotic may confound the results. We analyzed the source control review process used in double-blind clinical trials of antibiotics in complicated intra-abdominal infections identified through systematic review. We searched MEDLINE (PubMed) and ClinicalTrials.gov databases to identify relevant articles reporting results from double-blind clinical trials that used a source control review process. Eight prospective, randomized, double blind, multicenter, clinical trials of 5 anti-infective agents in complicated intra-abdominal infections used a source control review process. We provide recommendations for an independent, adjudicated source control review process applicable to future clinical trials. PMID- 23463644 TI - Patterned three-dimensional encapsulation of embryonic stem cells using dielectrophoresis and stereolithography. AB - Controlling the assembly of cells in three dimensions is very important for engineering functional tissues, drug screening, probing cell-cell/cell-matrix interactions, and studying the emergent behavior of cellular systems. Although the current methods of cell encapsulation in hydrogels can distribute them in three dimensions, these methods typically lack spatial control of multi-cellular organization and do not allow for the possibility of cell-cell contacts as seen for the native tissue. Here, we report the integration of dielectrophoresis (DEP) with stereolithography (SL) apparatus for the spatial patterning of cells on custom made gold micro-electrodes. Afterwards, they are encapsulated in poly (ethylene glycol) diacrylate (PEGDA) hydrogels of different stiffnesses. This technique can mimic the in vivo microscale tissue architecture, where the cells have a high degree of three dimensional (3D) spatial control. As a proof of concept, we show the patterning and encapsulation of mouse embryonic stem cells (mESCs) and C2C12 skeletal muscle myoblasts. mESCs show high viability in both the DEP (91.79% +/- 1.4%) and the no DEP (94.27% +/- 0.5%) hydrogel samples. Furthermore, we also show the patterning of mouse embryoid bodies (mEBs) and C2C12 spheroids in the hydrogels, and verify their viability. This robust and flexible in vitro platform can enable various applications in stem cell differentiation and tissue engineering by mimicking elements of the native 3D in vivo cellular micro-environment. PMID- 23463646 TI - Inhibition of TNF-alpha-induced MUC5AC mucin gene expression and production by wogonin through the inactivation of NF-kappaB signaling in airway epithelial cells. AB - In this study, we investigated whether wogonin significantly affects MUC5AC mucin gene expression and production in human airway epithelial cells. Confluent NCI H292 cells were pretreated with wogonin for 30 min and then stimulated with tumor necrosis factor-alpha (TNF-alpha) for 24 h or the indicated periods. The MUC5AC mucin gene expression and mucin protein production were measured by RT-PCR and ELISA, respectively. We found that incubation of NCI-H292 cells with wogonin significantly inhibited mucin production and down-regulated MUC5AC gene expression induced by TNF-alpha in a dose-dependent fashion. To elucidate the action mechanism of wogonin, effect of wogonin on TNF-alpha-induced NF-kappaB signaling pathway was investigated by western blot analysis. Wogonin inhibited NF kappaB activation induced by TNF-alpha. Inhibition of IKK by wogonin led to the suppression of IkappaB phosphorylation and degradation, p65 nuclear translocation and NF-kappaB-regulated gene expression. This, in turn, led to the down regulation of MUC5AC protein production in NCI-H292 cells. Wogonin also inhibited the gene products involved in cell survival (Bcl-2) and proliferation (cyclooxygenase-2). These results suggest that wogonin inhibits the NF-kappaB signaling pathway, which may explain its role in the inhibition of MUC5AC mucin gene expression and production. PMID- 23463647 TI - Effect of maternal and postweaning folic acid supplementation on global and gene specific DNA methylation in the liver of the rat offspring. AB - SCOPE: Intrauterine and early-life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use, and periconceptional supplementation. We investigated the effect of maternal and postweaning folic acid supplementation on DNA methylation in the rat offspring. METHODS AND RESULTS: Female rats were placed on a control or folic acid-supplemented diet during pregnancy and lactation. At weaning, pups from each maternal diet group were randomized to the control or supplemented diet for 11 weeks. At weaning, maternal folic acid supplementation significantly decreased global (p < 0.001) and site-specific DNA methylation of the Ppar-gamma, ER-alpha, p53, and Apc genes (p < 0.05) in the liver. At 14 weeks of age, postweaning, but not maternal, folic acid supplementation significantly decreased global DNA methylation (p < 0.05). At 14 weeks of age, both maternal and postweaning folic acid supplementation significantly increased DNA methylation of the Ppar-gamma, p53, and p16 genes (p < 0.05) whereas only postweaning FA supplementation significantly increased DNA methylation of the ER-alpha and Apc genes (p < 0.05). CONCLUSION: Our data suggest that maternal and postweaning folic acid supplementation can significantly modulate global and gene-specific DNA methylation in the rat offspring. The functional ramifications of the observed DNA methylation changes need to be determined in future studies. PMID- 23463648 TI - Ulnar nerve lesion at the wrist related to pisotriquetral joint arthropathy. AB - INTRODUCTION: Ulnar nerve lesions at the wrist (UNLW) are always difficult to localize clinically and sometimes electrophysiologically. Finding conduction block when studying ulnar motor nerve conduction (CB) across the wrist is sometimes the only way to demonstrate that the ulnar deep motor branch (UDMB) is entrapped. METHODS: An elderly woman who had bilateral carpal tunnel syndrome (CTS) and thumb osteoarthritis for many years experienced worsening of left hand impairment recently. RESULTS: Electrodiagnostic and ultrasound examinations revealed an acute and severe UDMB lesion related to pisotriquetral joint effusion. The patient received a local injection of a corticosteroid that provided rapid recovery. CONCLUSIONS: The diagnosis of UDMB lesion is especially difficult when CTS coexists, but CTS may allow for early diagnosis, if CB at the wrist is not overlooked. Chondrocalcinosis was responsible for the systemic inflammation, the CTS, the pisotriquetral joint effusion, and the UDBM compression, which has not been reported previously. PMID- 23463649 TI - Cadmium affects focal adhesion kinase (FAK) in mesangial cells: involvement of CaMK-II and the actin cytoskeleton. AB - The toxic metal ion cadmium (Cd(2+)) induces pleiotropic effects on cell death and survival, in part through effects on cell signaling mechanisms and cytoskeletal dynamics. Linking these phenomena appears to be calmodulin-dependent activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II). Here we show that interference with the dynamics of the filamentous actin cytoskeleton, either by stabilization or destabilization, results in disruption of focal adhesions at the ends of organized actin structures, and in particular the loss of vinculin and focal adhesion kinase (FAK) from the contacts is a result. Low-level exposure of renal mesangial cells to CdCl2 disrupts the actin cytoskeleton and recapitulates the effects of manipulation of cytoskeletal dynamics with biological agents. Specifically, Cd(2+) treatment causes loss of vinculin and FAK from focal contacts, concomitant with cytoskeletal disruption, and preservation of cytoskeletal integrity with either a calmodulin antagonist or a CaMK-II inhibitor abrogates these effects of Cd(2+). Notably, inhibition of CaMK-II decreases the migration of FAK-phosphoTyr925 to a membrane-associated compartment where it is otherwise sequestered from focal adhesions in a Cd(2+) dependent manner. These results add further insight into the mechanism of the CaMK-II-dependent effects of Cd(2+) on cellular function. PMID- 23463650 TI - Preparing for the inevitable: the death of a living liver donor. AB - Living donor liver transplantation (LDLT) is associated with a low but finite and well-documented risk of donor morbidity and mortality, so organizations and individuals involved in this activity must accept the fact that a donor death is a question of when and not if. Studies in the field of crisis management show that preparing for the inevitable not only is critical in preparing institutions to better respond to catastrophic events but more importantly plays a crucial role in preventing them. This article describes the background of crisis management with specific reference to the death of a living liver donor and proposes a general framework that can be adopted by LDLT programs around the world. PMID- 23463651 TI - Nine months of combined training improves ex vivo skeletal muscle metabolism in individuals with type 2 diabetes. AB - CONTEXT: Type 2 diabetes (T2D) has features of disordered lipid and glucose metabolism, due in part to reduced mitochondrial content. OBJECTIVE: Our objective was to investigate effects of different types of exercise on mitochondrial content and substrate oxidation in individuals with T2D (ancillary study of the randomized controlled trial Health Benefits of Aerobic and Resistance Training in Individuals with Type 2 Diabetes, HART-D). INTERVENTION: T2D individuals were randomized to aerobic training (AT, n = 12), resistance training (RT, n = 18), combination training (ATRT, n = 12), or nonexercise control (n = 10). Blood draws, peak oxygen consumption tests, dual-energy x-ray absorptiometry scans and muscle biopsies of vastus lateralis were performed before and after 9 months. Ex vivo substrate oxidations ((14)CO2), mitochondrial content, and enzyme activities were measured. Glycated hemoglobin A1c and free fatty acids were also determined. RESULTS: Mitochondrial content increased after RT and ATRT. Octanoate oxidation increased after AT and ATRT, whereas palmitate, pyruvate, and acetate oxidations increased in all exercise groups. Exercise induced responses in mitochondrial DNA were associated with improvements in peak oxygen consumption, beta-hydroxyacyl-coenzyme A dehydrogenase activity, and palmitate oxidation. CONCLUSIONS: Nine months of AT and RT significantly improved most aspects of skeletal muscle mitochondrial content and substrate oxidation, whereas the combination improved all aspects. These exercise responses were associated with clinical improvements, indicating that long-term training, especially combination, is an effective lifestyle therapy for individuals with T2D by way of improving muscle substrate metabolism. PMID- 23463652 TI - Preoperative ultrasonographic features of papillary thyroid carcinoma predict biological behavior. AB - BACKGROUND: Although ultrasound (US) features of papillary thyroid carcinoma (PTC) are well established, little is known regarding biological behavior according US features. We investigated whether there was a difference in biological behavior between PTCs that did and did not meet malignant US criteria. PATIENTS AND METHODS: We retrospectively reviewed clinical records and histological and US findings of the index tumors in 488 patients who underwent surgery for PTC. Benign-looking PTC (B-PTC) was defined as showing none of the accepted US criteria for malignancy. Malignant-looking PTCs (M-PTCs) and B-PTCs were compared in terms of patients' age, sex, tumor size, histological subtype, multifocality, lymph node (LN) metastasis, extrathyroidal extension, stage, recurrence, and distant metastasis. RESULTS: B-PTCs accounted for 74 (15%) of all 488 PTCs. Mean tumor size was not significantly different between the groups, with 1.10 cm for M-PTC and 1.11 cm for B-PTC (P = .947). Univariate and multivariate analysis indicated that M-PTC more frequently had LN metastasis, extrathyroidal extension, and a higher stage than B-PTC (all P < .05). The results were significant in tumors >=1.0 cm, whereas there were no significant differences in tumors <1 cm. As the number of malignant US features increased, multifocality, extrathyroidal extension, LN metastasis, and a higher stage were more likely. CONCLUSION: PTCs that did not meet malignant US criteria had better prognostic indicators than PTCs that met US criteria. Therefore, US features at the time of diagnosis can serve as a useful tool for predicting biological behavior in PTC. PMID- 23463653 TI - Ovarian antral follicle subclasses and anti-mullerian hormone during normal reproductive aging. AB - CONTEXT: The interindividual variation in the age-related decline of ovarian follicles is wide. Hence, it is important to identify reliable, sensitive, and specific markers to assess the ovarian reserve of the individual woman. OBJECTIVE: The aim of this study was to characterize the relation between age and ovarian reserve parameters in a population of healthy women with regular menstrual cycle. DESIGN AND SETTING: We conducted a prospective, population based, cross-sectional study. PARTICIPANTS: A total of 366 health care workers aged 21-41 years employed at a University Hospital were included. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Serum anti-Mullerian hormone (AMH) concentration, antral follicle count (AFC), antral follicle size categories (small: 2-4 mm; intermediate: 5-7 mm; and large: 8-10 mm), and ovarian volume were measured. RESULTS: Serum AMH level declined by 5.6% per year (95% confidence interval 3.7-7.4%, P < .001), AFC (2-10 mm) declined by 4.4% per year (3.2-5.7%, P < .001), and ovarian volume declined by 1.1% per year (0.2-2.0, P = .002), respectively. The mean proportion of small follicles decreased with age (P = .04), the proportion of intermediate follicles displayed no significant change with age (P = .58), and the mean proportion of large follicles increased with age (P < .001). The prevalence of large follicles increased with decreasing serum AMH concentration [odds ratio 1.04 per 1 pmol/L (1.02-1.06), P < .001, area under the curve 0.66], and with decreasing total AFC [odds ratio 1.04 per follicle (1.02 1.05), P < .001, area under the curve 0.62]. CONCLUSION: Chronological age was inversely related to serum AMH concentration, total AFC, and ovarian volume. Subclasses of AFC sized 2-4 and 5-7 mm decreased with increasing age, whereas AFC sized 8-10 mm increased with increasing age. Within AFC, a shift toward larger follicles with increasing age was observed. The occurrence of large follicles was more strongly related to biological age in terms of AMH and AFC than chronological age. PMID- 23463654 TI - Identification of ATP synthase as a lipid peroxide protein adduct in pancreatic islets from humans with and without type 2 diabetes mellitus. AB - CONTEXT: Most current knowledge of pancreatic islet pathophysiology in diabetes mellitus has come from animal models. Even though islets from humans are readily available, only a few come from diabetic donors. We had the uncommon opportunity to acquire islets from humans with type 2 diabetes and used it to perform a study not previously done with human or animal islets. OBJECTIVES: Oxidative stress has been proposed as a mechanism for impaired beta-cell function in type 2 diabetes. Lipid peroxides caused by reactive oxygen species are damaging to body tissues. The objective was to determine whether lipid peroxide-protein adducts occur in pancreatic islets of humans with type 2 diabetes. DESIGN: Immunoblots with two antibodies to hydroxynonenal and 2 other antibodies we generated against reactive small aliphatic compounds were used to detect lipid peroxide-protein adducts in islets of patients with type 2 diabetes and controls. RESULTS: The antibodies reacted strongly to >=5 islet proteins. The major hydroxynonenal adduct in the islets of type 2 diabetes patients was a 52-kDa protein seen with all 4 antibodies that was also seen in islets of nondiabetic humans, rat islets, and insulinoma cells and in mitochondria of various rat tissues. Nano-LC-MS/MS (liquid chromatography-tandem mass spectrometry) and MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight) analysis identified the protein as the beta-chain of the mitochondrial F-ATP synthase, an enzyme responsible for 95% of ATP formed in tissues. CONCLUSIONS: Lipid peroxide-protein adducts occur in beta-cells in the nondiabetic state and in diabetes. Lipid peroxidation is thought to be damaging to tissues. Analogous to various other unhealthy characteristics, the presence in nondiabetic individuals of lipid peroxide protein adducts does not necessarily indicate they are not detrimental. PMID- 23463655 TI - Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients. AB - CONTEXT: Vitamin D3 might benefit prostate cancer (PCa) patients because prostate cells can locally synthesize the active hormone calcitriol. OBJECTIVE: Our objective was to determine the effects of oral vitamin D3 on vitamin D metabolites and PCa proliferative activity in prostate tissue. DESIGN AND SETTING: We conducted a double-blind randomized clinical trial at surgical oncology clinics in Toronto, Canada. PATIENTS: PCa patients (Gleason 6 or 7) participated in the study. Of 66 subjects who were enrolled, 63 completed the dosing protocol. INTERVENTION: Vitamin D3 (400, 10 000, or 40 000 IU/d) was orally administered before radical prostatectomy. MAIN OUTCOME MEASURES: We evaluated vitamin D metabolite levels and Ki67 labeling in surgical prostate tissue. Safety measures, PTH, and prostate-specific antigen (PSA) were also assessed. RESULTS: Prostate tissue and serum levels of vitamin D metabolites, including calcitriol, increased dose dependently (P < .03) and were significantly higher in the 40 000-IU/d group than in every other dose group (P < .03). Prostate vitamin D metabolites correlated positively with serum levels (P < .0001). Ki67 measures did not differ significantly among vitamin D dose groups. However, cross-sectional analysis indicated that the calcitriol level attained in prostate was inversely associated with Ki67 intensity and Ki67 (3+) percent positive nuclei in PCa and benign tissue (P < .05). Safety measures did not change adversely with dosing. Compared with the 400-IU/d group, serum PTH and PSA were lower in the combined higher-dose groups at the end of the study (P < .02). CONCLUSIONS: Oral vitamin D3 raised prostate calcitriol levels (level 1 evidence) and modestly lowered both PSA and PTH. Although Ki67 expression did not differ among dose groups, its levels correlated inversely with prostate calcitriol. These suggestions of clinical benefit justify continued clinical research. PMID- 23463656 TI - Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin angiotensin-aldosterone system in healthy men. AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) is an incretin hormone with multiple actions in addition to control of glucose homeostasis. GLP-1 is known to cause natriuresis in humans, but the effects on basic renal physiology are still partly unknown. SUBJECTS AND METHODS: Twelve healthy young males were examined in a randomized, controlled, double-blinded, single-day, crossover trial to evaluate the effects of 2 hours GLP-1 infusion on kidney functions. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed with (51)Cr-EDTA and (123)I hippuran, respectively, using a constant infusion renal clearance technique based on timed urine sampling. RESULTS: GLP-1 had no significant effect on either GFR [+1.9%, 95% confidence interval (-0.8; 4.6%)] or RPF [+2.4%, 95% confidence interval (-3.6; 8.8%)]. Fractional urine excretion of lithium increased 9% (P = .013) and renal sodium clearance increased 40% (P = .007). Angiotensin II decreased 19% (P = .003), whereas renin, aldosterone, and the urinary excretion of angiotensinogen showed no significant changes. glp-1 did not affect blood pressure but induced a small transient increase in heart rate. CONCLUSION: The results indicate that although GLP-1 markedly reduces proximal tubule sodium reabsorption, the acute effects on GFR and RPF are very limited in healthy humans. The finding of GLP-1's ability to reduce angiotensin II concentration is novel and should be further elucidated. PMID- 23463658 TI - Pharmacodynamics of cinacalcet over 48 hours in patients with controlled secondary hyperparathyroidism: useful data in clinical practice. AB - CONTEXT: Cinacalcet induces immediate changes in serum PTH levels, but the pharmacodynamic effect throughout the daily dosing interval in controlled patients is unknown. Also, in patients with reduced PTH, it is unknown what happens in the first 24 hours after withdrawal. OBJECTIVE: Our aim was to describe the effect over 48 hours of cinacalcet in hemodialysis patients with controlled secondary hyperparathyroidism. DESIGN: This was a phase 4, open-label, single-arm, single-dose, single-center clinical trial. SETTING: The study was conducted at a public hospital (Hospital Perpetuo Socorro, Alicante, Spain). PATIENTS: We included 10 patients on cinacalcet for 6 months or longer with intact PTH (iPTH) levels 100-400 pg/mL [8 men, mean age of 66 years (range 39-82 years)], chronically treated with 30 mg (n = 6), 60 mg (n = 3), or 90 mg (n = 1) of cinacalcet. INTERVENTION: A single dose (30-90 mg) was administered at baseline. MAIN OUTCOME MEASURES: iPTH (Duo Kit Scantibodies and Elecsys Roche), PTH 1-84, ionized calcium, phosphorus (P), and calcitonin were determined at baseline and at 1, 3, 6, 12, 24, and 48 hours. RESULTS: There was a significant reduction in iPTH between 1 and 6 hours, and values returned to baseline at 24 hours [maximum mean (95% confidence interval) percent change from baseline: -50%( 34; -66) at 3 hours]. A transient increase in calcitonin and a decrease in P were also observed, with no changes in calcium. At 48 hours, there was a significant increase in iPTH [+51% (26; 76)] and P. Changes in PTH were similar with the 3 determination methods. CONCLUSIONS: In hemodialysis patients with secondary hyperparathyroidism controlled by cinacalcet, a transient (1-6 hours) reduction in PTH and P and an increase in calcitonin are observed after each daily dose, with return to baseline at 24 hours. After calcimimetics discontinuation, PTH was significantly increased at 48 hours. The assay used to measure PTH does not influence relative changes induced by cinacalcet. PMID- 23463657 TI - Challenges to the measurement of estradiol: an endocrine society position statement. AB - OBJECTIVE: The objective of the study was to evaluate the current state of clinical assays for estradiol in the context of their applications. PARTICIPANTS: The participants were appointed by the Council of The Endocrine Society and charged with attaining the objective using published data and expert opinion. EVIDENCE: Data were gathered from published sources via online databases (principally PubMed, Ovid MEDLINE, Google Scholar), and the clinical and laboratory experience of the participants. CONSENSUS PROCESS: The statement was an effort of the committee and was reviewed by each member. The Clinical Affairs Committee, the Council of The Endocrine Society, and JCEM reviewers reviewed the manuscript and made recommendations. CONCLUSIONS: The measurement of estradiol in biological fluids is important in human biology from cradle to grave. In addition to its centrality in sexual development, it has significant effects on skin, blood vessels, bone, muscle, coagulation, hepatic cells, adipose tissue, the kidney, the gastrointestinal tract, brain, lung, and pancreas. Alterations in its plasma concentration have been implicated in coronary artery disease, stroke, and breast cancer. Although modern immunoassays and liquid chromatography/tandem mass spectrometry-based methods for estradiol are reasonably well suited to the diagnosis and management of infertility (nonetheless, imprecision and method-to method differences remain problematic), the very low concentrations that appear to be crucial in nonreproductive tissues are a separate and more difficult issue. Such levels of estradiol are too low to be routinely measured accurately or precisely, and further evolution of analytical methods and the way in which estradiol is standardized is needed. PMID- 23463659 TI - Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years. AB - Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long-term follow in young persons. Our cohort included 33,346 subjects, aged 26-61 years at baseline, in a representative, population based study enrolling subjects from 1974 to 1992. Median follow-up time was 28 years. Plasma creatinine was analyzed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40-52), 7,498 older women (age 47-57) and 1,688 younger women (age 35-43). Glomerular filtration rate (GFR) was estimated using the CKD-EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR >= 60 mL/min/1.73 m(2) ), or moderate kidney dysfunction (eGFR<60 mL/min/1.73 m(2) ). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; p = 0.004). However, we found no association with overall long-term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high-risk groups and biological mechanisms. PMID- 23463660 TI - Activation of hydrogen peroxide by ionic liquids: mechanistic studies and application in the epoxidation of olefins. AB - Imidazolium-based ionic liquids that contain perrhenate anions are very efficient reaction media for the epoxidation of olefins with H2O2 as an oxidant, thus affording cyclooctene in almost quantitative yields. The mechanism of this reaction does not follow the usual pathway through peroxo complexes, as is the case with long-known molecular transition-metal catalysts. By using in situ Raman, FTIR, and NMR spectroscopy and DFT calculations, we have shown that the formation of hydrogen bonds between the oxidant and perrhenate activates the oxidant, thereby leading to the transfer of an oxygen atom onto the olefin demonstrating the special features of an ionic liquid as a reaction environment. The influence of the imidazolium cation and the oxidant (aqueous H2O2, urea hydrogen peroxide, and tert-butyl hydrogen peroxide) on the efficiency of the epoxidation of cis-cyclooctene were examined. Other olefinic substrates were also used in this study and they exhibited good yields of the corresponding epoxides. This report shows the potential of using simple complexes or salts for the activation of hydrogen peroxide, owing to the interactions between the solvent medium and the active complex. PMID- 23463661 TI - Cerebellar degeneration in Lurcher mice under confocal laser scanning microscope. AB - Lurcher mutant mice represent a natural model of genetically-determined olivocerebellar degeneration caused by a mutation in the delta2 glutamate receptor gene. They suffer from progressive postnatal loss of cerebellar Purkinje cells and a decrease of granule cells and inferior olive neurons. Their wild type littermates serve as healthy controls. A confocal laser scanning microscope was used aiming investigation the dynamics of changes in the cerebellar cortex of Lurcher and wild type mice derived from two strains during the period of 8-21 postnatal days. Fluorescent double-staining was used to visualize mainly the Purkinje cells in cerebellar slices. In wild types, only normal Purkinje cells of round or regular drop-shaped were present, when staining intensity of other individual cell structures differed in dependence on the age of the animal. In Lurcher mutants, there were still some normal-shaped cells. Nevertheless, depending on the animal's age, a wide variety of stages of the cell degeneration were depicted. The main characteristics of Purkinje cell degeneration in the early stage are: disruption of the continuity of the Purkinje cell layer, dark spots in cell nuclei and an irregular coloring of the cytoplasm. Later, the cells and their nuclei were deformed, often with two main dendrites sprouting from the cell body. Finally, the cell and nucleus margins were unclear, dendrites were significantly thickened, showing signs of shrinkage and fragmentation. Cell nucleoli underwent changes in number and appearance. No differences between the Lurcher mice of both strains (C3H and B6CBA) under examination were found. PMID- 23463662 TI - Transformation of xanthohumol by Aspergillus ochraceus. AB - Microbial transformation of xanthohumol isolated from agro-residue (spent hops), by Aspergillus ochraceus was investigated. A new aurone, (Z)-2"-(2''' hydroxyisopropyl)-dihydrofurano[4",5":6,7]-3',4'-dihydroxy-4-methoxyaurone, was obtained as a main transformation product. Three minor metabolites were identified as 2"-(2'''-hydroxyisopropyl)-dihydrofurano[4",5":3',4']-2',4 dihydroxy-6'-methoxychalcone, (2S,2"S)-2"-(2'''-hydroxyisopropyl) dihydrofurano[4",5":7,8]-4'-hydroxy-5-methoxyflavanone and (2S,2"R)-2"-(2''' hydroxyisopropyl)-dihydrofurano[4",5":7,8]-4'-hydroxy-5-methoxyflavanone. Their structures were elucidated on the basis of spectroscopic evidences. The antioxidant properties of xanthohumol and its metabolites were investigated using the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. The major biotransformation product, was 8.6-fold stronger antioxidant than xanthohumol and 2.3-fold than ascorbic acid. PMID- 23463664 TI - Nanoparticle accumulation in angiogenic tissues: towards predictable pharmacokinetics. AB - Nanoparticles are increasingly used in medical applications such as drug delivery, imaging, and biodiagnostics, particularly for cancer. The design of nanoparticles for tumor delivery has been largely empirical, owing to a lack of quantitative data on angiogenic tissue sequestration. Using fluorescence correlation spectroscopy, the deposition rate constants of nanoparticles into angiogenic blood vessel tissue are determined. It is shown that deposition is dependent on surface charge. Moreover, the size dependency strongly suggests that nanoparticles are taken up by a passive mechanism that depends largely on geometry. These findings imply that it is possible to tune nanoparticle pharmacokinetics simply by adjusting nanoparticle size. PMID- 23463663 TI - Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. AB - Spindle cell rhabdomyosarcoma (RMS) is a rare form of RMS with different clinical characteristics between children and adult patients. Its genetic hallmark remains unknown and it remains debatable if there is pathogenetic relationship between the spindle cell and the so-called sclerosing RMS. We studied two pediatric and one adult spindle cell RMS by next generation RNA sequencing and FusionSeq data analysis to detect novel fusions. An SRF-NCOA2 fusion was detected in a spindle cell RMS from the posterior neck in a 7-month-old child. The fusion matched the tumor karyotype and was confirmed by FISH and RT-PCR, which showed fusion of SRF exon 6 to NCOA2 exon 12. Additional 14 spindle cell (from 8 children and 6 adults) and 4 sclerosing (from 2 children and 2 adults) RMS were tested by FISH for the presence of abnormalities in NCOA2, SRF, as well as for PAX3 and NCOA1. NCOA2 rearrangements were found in two additional spindle cell RMS from a 3-month old and a 4-week-old child. In the latter tumor, TEAD1 was identified by rapid amplification of cDNA ends (RACE) to be the NCOA2 gene fusion partner. None of the adult tumors were positive for NCOA2 rearrangement. Despite similar histomorphology in adults and young children, these results suggest that spindle cell RMS is a heterogeneous disease genetically as well as clinically. Our findings also support a relationship between NCOA2-rearranged spindle cell RMS occurring in young childhood and the so-called congenital RMS, which often displays rearrangements at 8q13 locus (NCOA2). PMID- 23463665 TI - Of body and mind: if breathing helps cope with stress, does impaired breathing promote anxiety? PMID- 23463666 TI - Sex and the heart: timing is everything. PMID- 23463667 TI - One size does not fit all: regional cerebral blood flow and arterial carbon dioxide tension. PMID- 23463669 TI - Electrophysiological and ultrasonographic findings in ulnar neuropathy with Martin-Gruber anastomosis. AB - INTRODUCTION: It is important to understand the presence of Martin-Gruber anastomosis in patients with complete ulnar neuropathy at the elbow. CASE REPORT: We describe a patient with complete ulnar neuropathy at the elbow and Martin Gruber anastomosis in the forearm, mimicking incomplete ulnar neuropathy with complete conduction block in the forearm segment. Ultrasonography of the ulnar nerve around the elbow demonstrated severe swelling of the ulnar nerve, which was compatible with severe ulnar neuropathy at the elbow. CONCLUSIONS: This case report demonstrates that combination of ultrasonography with electrophysiological studies can provide more detailed information about the changes of nerve structures and lesion sites. PMID- 23463670 TI - Sorafenib induces endometrial carcinoma apoptosis by inhibiting Elk-1-dependent Mcl-1 transcription and inducing Akt/GSK3beta-dependent protein degradation. AB - Endometrial carcinoma (EC) is one of the main gynecologic malignancies affecting women, but effective treatments are currently lacking. In the present study, we investigated the effect of sorafenib, a general kinase inhibitor, on several EC cell lines (HEC1A, HEC1B, and RL95-2). Sorafenib induced cell death in EC cells with the following order of sensitivity: HEC1A > HEC1B > RL95-2. Sorafenib suppressed several anti-apoptotic proteins in HEC1A cells, including myeloid cell leukemia 1 (Mcl-1). Ectopic overexpression of Mcl-1 prevented the cell killing effect of sorafenib. Sorafenib suppressed Mcl-1 at the gene transactivation level by inactivating the ERK/Elk-1 pathway. Accordingly, the inhibitory effect of sorafenib on Mcl-1 expression decreased following knockdown of Elk-1 using short hairpin RNA (shRNA). Elk-1 overexpression rescued both the inhibitory effect of sorafenib on Mcl-1 expression and the cell killing effect of sorafenib. Furthermore, sorafenib reduced the stability of the Mcl-1 protein by enhancing its ubiquitination and degradation by the proteasome via the AKT/GSK3beta and the ERK pathways. Similar results were detected in other EC cell lines. These results indicate that sorafenib induces apoptosis in EC cells by down-regulating the anti apoptotic protein Mcl-1 via transcriptional inhibition and protein degradation. Our results thus support the notion that sorafenib may be used in endometrial cancer therapy. PMID- 23463671 TI - Quantitative assessment of craniofacial morphology in Johanson-Blizzard syndrome. AB - BACKGROUND: Here we apply objective, reliable methods of dysmorphology diagnosis to a patient with Johanson-Blizzard syndrome (MIM #243800). Using an extensive normative database, we computed standardized scores on a graded continuum for operational definitions of nasal alar hypoplasia, a commonly observed feature of this condition. CASE: Most of these measurements in this case were greater than 2 standard deviations below the mean, adjusted for age, gender, and ethnicity. CONCLUSION: This report provides a worked example of quantitative anthropometric assessment in the context of a case report, using tools that may find general application in clinical genetics. PMID- 23463672 TI - Preparation of gradient surfaces by using a simple chemical reaction and investigation of cell adhesion on a two-component gradient. AB - This article describes a simple method for the generation of multicomponent gradient surfaces on self-assembled monolayers (SAMs) on gold in a precise and predictable manner, by harnessing a chemical reaction on the monolayer, and their applications. A quinone derivative on a monolayer was converted to an amine through spontaneous intramolecular cyclization following first-order reaction kinetics. An amine gradient on the surface on a scale of centimeters was realized by modulating the exposure time of the quinone-presenting monolayer to the chemical reagent. The resulting amine was used as a chemical handle to attach various molecules to the monolayer with formation of multicomponent gradient surfaces. The effectiveness of this strategy was verified by cyclic voltammetry (CV), matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS), MS imaging, and contact-angle measurements. As a practical application, cell adhesion was investigated on RGD/PHSRN peptide/peptide gradient surfaces. Peptide PHSRN was found to synergistically enhance cell adhesion at the position where these two ligands are presented in equal amounts, while these peptide ligands were competitively involved in cell adhesion at other positions. This strategy of generating a gradient may be further expandable to the development of functional gradient surfaces of various molecules and materials, such as DNA, proteins, growth factors, and nanoparticles, and could therefore be useful in many fields of research and practical applications. PMID- 23463674 TI - Hydrogen-bond-promoted palladium catalysis: allylic alkylation of indoles with unsymmetrical 1,3-disubstituted allyl acetates using chiral bis(sulfoxide) phosphine ligands. PMID- 23463676 TI - Cycling progenitors maintain epithelia while diverse cell types contribute to repair. AB - It has recently been shown that stem and progenitor cells undergo population self renewal to maintain epithelial homeostasis. The fate of individual cells is stochastic but the production of proliferating and differentiating cells is balanced across the population. This new paradigm, originating in mouse epidermis and since extended to mouse oesophagus and mouse and Drosophila intestine, is in contrast to the long held model of epithelial maintenance by exclusively asymmetric division of stem cells. Recent lineage tracing studies have now shown that wound responses vary between tissues, and that a stem cell reserve is not essential as cycling progenitors and even differentiating cells contribute to regeneration. PMID- 23463675 TI - The somatic affairs of BRAF: tailored therapies for advanced malignant melanoma and orphan non-V600E (V600R-M) mutations. AB - BRAF V600R-M-D are uncommon mutations, not included in the experimental protocols of BRAF selective inhibitors. We report the evaluation of correlations among different types of BRAF somatic mutations in melanoma and their management with BRAF inhibitors. 21 patients with BRAF mutated metastatic melanoma were enrolled in the protocol with BRAF inhibitors for compassionate use at the University of Modena. Hot spot V600E mutations were found in 19 patients. V600R mutation and double (V600E -V600M) mutation were identified in two melanomas. In one case, V600K mutation was found. Two screening failures were noted. Mean progression free survival at follow-up of to 8 weeks, was 7.6 months. Five patients had a very short follow-up and the experimental protocol is still ongoing, so we cannot provide complete follow-up data. However, all of them are still under treatment and disease progression free. An objective response with few side effects was observed in all patients. in vitro studies with the aim of testing drug sensitivity. PMID- 23463677 TI - Electrospun silicon nanoparticle/porous carbon hybrid nanofibers for lithium-ion batteries. PMID- 23463678 TI - Get political: the case for greater virological leadership. PMID- 23463679 TI - Early inflammatory response in soft tissues induced by thin calcium phosphates. AB - The inflammatory response to titanium and hydroxyapatite (HA)-coated titanium in living tissue is controlled by a number of humoral factors, of which monocyte chemoattractant protein-1 (MCP-1) has been specifically linked to the recruitment of monocytes. These cells subsequently mature into tissue-bound macrophages. Macrophages adhering to the proteins adsorbed at the implant surface play a pivotal role in initiating the rejection or integration of the foreign material. Despite this, little is known about the initial inflammatory events that occur in soft tissues following the implantation of titanium and HA-coated titanium implants. In this study, circular discs of commercially pure titanium (c.p. Ti) with either a thin crystalline HA coating or amorphous HA coating or uncoated were implanted subcutaneously into rats. The implants were retrieved after 24 and 72 h. The lactate dehydrogenase (LD) activity, DNA content, expression of MCP-1, interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha), as well as monocyte and polymorphonuclear granulocyte counts in the exudate surrounding the implants were analyzed. There were significantly higher DNA and LD levels around the titanium implants at 24 h compared with HA-coated titanium. A rapid decrease in MCP-1 levels was observed for all the implants over the period of observation. No statistically significant differences were found between the two HA-coated implants. Our results suggest a difference in the early soft-tissue response to HA-coated implants when compared with titanium implants, expressed as a downregulation of inflammatory cell recruitment. This suggests that thin HA coatings are promising surfaces for soft tissue applications. PMID- 23463680 TI - Effects of temperature and fatigue on the electromechanical delay components. AB - INTRODUCTION: Neuromuscular activation can be influenced by both muscle temperature (Tm) and fatigue. METHODS: To assess the effects of Tm and fatigue on the electromechanical delay (EMD), 15 participants performed voluntary isometric contractions of different intensities under neutral (TmN), low (TmL), and high (TmH) Tm, before and after a fatiguing exercise. During contraction, electromyogram (EMG), mechanomyogram (MMG), and force (F) were recorded from the biceps brachii muscle. The EMD and the latencies between EMG and MMG (Deltat EMG MMG, which includes the electrochemical processes of EMD) and between MMG and F (Deltat MMG-F, which includes the mechanical processes of EMD) were calculated. RESULTS: TmL increased only Deltat EMG-MMG, both before and after fatigue. Fatigue lengthened EMD, Deltat EMG-MMG, and Deltat MMG-F under all Tm to a similar extent. CONCLUSIONS: While fatigue increased all EMD components, muscle cooling affected only the electrochemical but not the mechanical processes of EMD. PMID- 23463681 TI - A conventional surfactant becomes CO2-responsive in the presence of switchable water additives. AB - We have developed a new benign means of reversibly breaking emulsions and latexes by using "switchable water", an aqueous solution of switchable ionic strength. The conventional surfactant sodium dodecyl sulfate (SDS) is not normally stimuli responsive when CO2 is used as the stimulus but becomes CO2 -responsive or "switchable" in the presence of a switchable water additive. In particular, changes in the air/water surface tension and oil/water interfacial tension can be triggered by addition and removal of CO2 . A switchable water additive, N,N dimethylethanolamine (DMEA), was found to be an effective and efficient additive for the reversible reduction of interfacial tension and can lower the tension of the dodecane/water interface in the presence of SDS surfactant to ultra-low values at very low additive concentrations. Switchable water was successfully used to reversibly break an emulsion containing SDS as surfactant, and dodecane as organic liquid. Also, the addition of CO2 and switchable water can result in aggregation of polystyrene (PS) latexes; the later removal of CO2 neutralizes the DMEA and decreases the ionic strength allowing for the aggregated PS latex to be redispersed and recovered in its original state. PMID- 23463682 TI - Gold-catalyzed oxidative cyclizations on 1,4-enynes: evidence for a gamma substituent effect on Wagner-Meerwein rearrangements. PMID- 23463684 TI - Broad-spectrum antibacterial activity of carbon nanotubes to human gut bacteria. AB - Carbon nanotubes (CNTs) hold promise in manufacturing, environmental, and biomedical applications, as well as food and agricultural industries. Previous observations have shown that CNTs have antimicrobial activity; however, the impact of CNTs to human gut microbes has not been investigated. Here, the antibacterial activity of CNTs against the microbes commonly encountered in the human digestion system--L. acidophilus, B. adolescentis, E. coli, E. faecalis, and S. aureus--are evaluated. The bacteria studied include pathogenic and non pathogenic, gram-positive and negative, and both sphere and rod strains. In this study, CNTs, including single-walled CNTs (SWCNTs, 1-3 MUm), short and long multi walled CNTs (s-MWCNTs: 0.5-2 MUm; l-MWCNTs: >50 MUm), and functionalized multi walled CNTs (hydroxyl- and carboxyl-modification, 0.5-2 MUm), all have broad spectrum antibacterial effects. Notably, CNTs may selectively lyse the walls and membranes of human gut microbes, depending on not only the length and surface functional groups of CNTs, but also the shapes of the bacteria. The mechanism of antibacterial activity is associated with their diameter-dependent piercing and length-dependent wrapping on the lysis of microbial walls and membranes, inducing release of intracellular components DNA and RNA and allowing a loss of bacterial membrane potential, demonstrating complete destruction of bacteria. Thin and rigid SWCNT show more effective wall/membrane piercing on spherical bacteria than MWCNTs. Long MWCNT may wrap around gut bacteria, increasing the area making contact with the bacterial wall. This work suggests that CNTs may be broad spectrum and efficient antibacterial agents in the gut, and selective application of CNTs could reduce the potential hazard to probiotic bacteria. PMID- 23463685 TI - Deep brain stimulator artifact in needle electromyography: effects and distribution in paraspinal and upper limb muscle. AB - INTRODUCTION: Deep brain stimulators (DBS) have become a more widespread treatment option for individuals with centrally mediated movement disorders. Such devices are expected to create artifact in standard needle electromyographic (EMG) recordings. METHODS: Five subjects with DBS were studied with standard concentric needle electrode EMG in paraspinal and upper limb muscles. RESULTS: All subjects showed EMG artifact directly related to, and corresponding with, the DBS unit settings. The artifact was very prominent in all paraspinal muscles, although the amplitude was less in lumbar compared with cervical levels. With a large ground electrode next to the insertion site, the artifact was sufficiently small to allow standard EMG examination of upper limb muscles. CONCLUSIONS: The DBS artifact is so prominent in paraspinal muscles that it will not allow standard EMG examination for diagnostic purposes such as radiculopathy. The artifact itself can easily be distinguished from pathological insertional and spontaneous activity. PMID- 23463686 TI - In vivo effects of tailored laminin-332 alpha3 conjugated scaffolds enhances wound healing: a histomorphometric analysis. AB - Surface modification techniques have been used to develop biomimetic scaffolds by incorporating cell adhesion peptides. In our previous work, we have shown the tethering of laminin-332 alpha3 chain to type I collagen scaffold using microbial transglutaminase (mTGase), promotes cell adhesion, migration, and proliferation. In this study, we evaluated the wound healing properties of tailored laminin-332 alpha3 chain (peptide A: PPFLMLLKGSTR) tethered to a type I collagen scaffold using mTGase by incorporating transglutaminase substrate peptide sequences containing either glutamine (peptide B: PPFLMLLKGSTREAQQIVM) or lysine (peptide C: PPFLMLLKGSTRKKKKG) in rat full-thickness wound model at two different time points (7 and 21 days). Histological evaluations were assessed for wound closure, epithelialization, angiogenesis, inflammatory, fibroblastic cellular infiltrations, and quantified using stereological methods (p < 0.05). Peptide A and B tethered to collagen scaffold using mTGase stimulated neovascularization, decreased the inflammatory cell infiltration and prominently enhanced the fibroblast proliferation which significantly accelerated the wound healing process. We conclude that surface modification by incorporating motif of laminin 332 alpha3 chain (peptide A: PPFLMLLK GSTR) domain and transglutaminase substrate to the laminin-332 alpha3 chain (peptide B: PPFLMLLKGSTREAQQIVM) using mTGase may be a potential candidate for tissue engineering applications and skin regeneration. PMID- 23463687 TI - Intracranial hemangiopericytoma: MR imaging findings and diagnostic usefulness of minimum ADC values. AB - PURPOSE: To describe the clinical and magnetic resonance (MR) imaging features of primary intracranial hemangiopericytoma (HPC), and to assess the usefulness of minimum apparent diffusion coefficient (MinADC) value of HPC in the differential diagnosis from meningioma. MATERIALS AND METHODS: From 2004 to 2010, fifteen patients with primary intracranial HPC were included. The clinical data, conventional MR findings (n = 15), and diffusion weighted image (DWI) features (n = 10) were retrospectively analyzed. MinADC value of the HPCs (n = 10) was measured on ADC map and was compared with that of meningiomas (n = 37). RESULTS: In 15 cases of HPC, isointense signal was detected on both T1-weighted images (T1WI) and T2-weighted images (T2WI) in 11 cases, and heterogeneous signal was demonstrated in 4 cases. Isointensity (n = 9) and iso- and slight hyperintensity (n = 1) were shown on DWI. The mean MinADC value of HPC [(1.116 +/- 0.127) * 10( 3) mm(2) /s] was significantly higher than that of meningioma [(0.875 +/- 0.104) * 10(-3) mm(2) /s] (P < 0.01). For the differentiation between HPC and meningioma, the critical cutoff MinADC value was 0.991 * 10(-3) mm(2) /s, which provided the best combination of sensitivity (88.9%) and specificity (82.4%). CONCLUSION: MinADC value may be an useful tool for the differentiation between HPC and meningioma. PMID- 23463688 TI - A robust palladium(II)-porphyrin complex as catalyst for visible light induced oxidative C-H functionalization. AB - A series of palladium(II)-porphyrin complexes that display dual emissions with lifetimes up to 437 MUs have been synthesized. Among the four complexes, PdF20TPP is an efficient and robust catalyst for photoinduced oxidative C-H functionalization by using oxygen as terminal oxidant. alpha-Functionalized tertiary amines were obtained in good to excellent yields by light irradiation (lambda>400 nm) of a mixture of PdF20TPP, tertiary amine, and nucleophile (cyanide, nitromethane, dimethyl malonate, diethyl phosphite, and acetone) under aerobic conditions. Four examples of intramolecular cyclized amine compounds could be similarly prepared. Comparison of the UV-visible absorption spectra before and after the photochemical reaction revealed that PdF20TPP was highly robust (>95 % recovery). The practical application of PdF20TPP has been revealed by the photochemical reactions performed by using a low catalyst loading (0.01 mol %) and on a 10 mmol scale. The PdF20TPP catalyst could sensitize photoinduced oxidation of sulfides to sulfoxides in excellent yields. Mechanistic studies revealed that the photocatalysis proceeded by singlet-oxygen oxidation. PMID- 23463689 TI - Low-avidity anticitrullinated protein antibodies (ACPA) are associated with a higher rate of joint destruction in rheumatoid arthritis. AB - OBJECTIVES: Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. METHODS: We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high avidity ACPA were studied. RESULTS: Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind 'new' citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-gamma receptors, low-avidity ACPA were more potent in activating the complement system. CONCLUSIONS: Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome. PMID- 23463690 TI - Herpes zoster infection risk in patients with rheumatoid arthritis on tumour necrosis factor inhibitors. PMID- 23463692 TI - Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children. AB - BACKGROUND AND AIM: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. METHODS: Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. RESULTS: Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. CONCLUSIONS: Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease. PMID- 23463691 TI - Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is characterised by autoimmunity to citrullinated proteins, and there is increasing epidemiologic evidence linking Porphyromonas gingivalis to RA. P gingivalis is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response. OBJECTIVES: To examine the immune response to PPAD in patients with RA, individuals with periodontitis (PD) and controls (without arthritis), confirm PPAD autocitrullination and identify the modified arginine residues. METHODS: PPAD and an inactivated mutant (C351A) were cloned and expressed and autocitrullination of both examined by immunoblotting and mass spectrometry. ELISAs using PPAD, C351A and another P gingivalis protein arginine gingipain (RgpB) were developed and antibody reactivities examined in patients with RA (n=80), individuals with PD (n=44) and controls (n=82). RESULTS: Recombinant PPAD was a potent citrullinating enzyme. Antibodies to PPAD, but not to Rgp, were elevated in the RA sera (median 122 U/ml) compared with controls (median 70 U/ml; p<0.05) and PD (median 60 U/ml; p<0.01). Specificity of the anti-peptidyl citrullinated PPAD response was confirmed by the reaction of RA sera with multiple epitopes tested with synthetic citrullinated peptides spanning the PPAD molecule. The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA. CONCLUSIONS: The peptidyl citrulline-specific immune response to PPAD supports the hypothesis that, as a bacterial protein, it might break tolerance in RA, and could be a target for therapy. PMID- 23463693 TI - Comment on predictors of preterm birth in patients with mild systemic lupus erythematosus by Clowse et al. PMID- 23463694 TI - One-pot conversion of sugar and sugar polyols to n-alkanes without C-C Dissociation over the Ir-ReOx /SiO2 catalyst combined with H-ZSM-5. AB - High (>=95 % C) yields of n-hexane and n-pentane were obtained by hydrogenolysis of aqueous sorbitol and xylitol, respectively, at 413-443 K by using the Ir-ReOx /SiO2 catalyst combined with H-ZSM-5 as a cocatalyst and n-dodecane as a cosolvent. The direct production of n-hexane from glucose or cellobiose can be achieved by using the same system. The catalyst can be reused simply by the removal of the n-dodecane phase, which contains the product alkane, and the addition of fresh n-dodecane and substrate. PMID- 23463695 TI - Biodegradable ZnO@polymer core-shell nanocarriers: pH-triggered release of doxorubicin in vitro. PMID- 23463696 TI - Gram-scale synthesis of graphene sheets by a catalytic arc-discharge method. AB - Flake graphite is used as carbon source and ZnO or ZnS as catalyst in the synthesis of high-quality graphene sheets. A catalytic growth mechanism for cathode-part graphene synthesis in the arc-discharge apparatus and an exfoliation mechanism for wall-part graphene synthesis are introduced. N-doped cathode-part graphene and undoped wall-part graphene are formed simultaneously. PMID- 23463697 TI - Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. AB - Dietary fat exerts a potent stimulatory effect on feeding. This effect is mediated, at least in part, by a cephalic mechanism that involves recruitment of the vagus nerve and subsequent activation of endocannabinoid signaling in the gut. Here, we used a sham-feeding protocol in rats to identify fatty-acid constituents of dietary fat that might be responsible for triggering small intestinal endocannabinoid signaling. Sham feeding rats with a corn oil emulsion increased endocannabinoid levels in jejunum, relative to animals that received either mineral oil (which contains no fatty acids) or no oil. Sham-feeding emulsions containing oleic acid (18:1) or linoleic acid (18:2) caused, on average, a nearly 2-fold accumulation of jejunal endocannabinoids, whereas emulsions containing stearic acid (18:0) or linolenic acid (18:3) had no such effect. In a 2-bottle-choice sham-feeding test, rats displayed strong preference for emulsions containing 18:2, which was blocked by pretreatment with the peripherally restricted CB1 cannabinoid receptor antagonists, AM6546 and URB447. Our results suggest that oral exposure to the monoenoic and dienoic fatty acid component of dietary fat selectively initiates endocannabinoid mobilization in the gut, and that this local signaling event is essential for fat preference. PMID- 23463698 TI - Dysfunction of dopamine homeostasis: clues in the hunt for novel Parkinson's disease therapies. AB - Parkinson's disease is the second most common neurodegenerative disorder and, at present, has no cure. Both environmental and genetic factors have been implicated in the etiology of the disease; however, the pathogenic pathways leading to neuronal degeneration are still unclear. Parkinson's disease is characterized by the preferential death of a subset of neurons in the mesencephalon that use dopamine as neurotransmitter for synaptic communication. Dopamine is a highly reactive molecule that can lead to cytotoxicity if not properly stored and metabolized. Targeting any of the pathways that tightly control this neurotransmitter holds great therapeutic expectations. In this article we present a comprehensive overview of the cellular pathways that control dopamine fate and discuss potential therapeutic approaches to counteract or slow Parkinson's disease onset and progression. PMID- 23463700 TI - Pompe disease, the must-not-miss diagnosis: A report of 3 patients. AB - INTRODUCTION: Pompe disease is a progressive and debilitating neuromuscular disorder that presents with a heterogeneous array of signs and symptoms including proximal muscle weakness, respiratory insufficiency, and/or elevated creatine kinase levels. It mimics other neuromuscular disorders, making its diagnosis challenging and often significantly delayed, thereby increasing morbidity and early mortality of the disease. METHODS: Three Pompe disease patients are discussed to highlight the challenging path to diagnosis and the common cluster of symptoms that could lead to timely and accurate diagnosis. RESULTS: After significant delays in diagnosis, Pompe disease was diagnosed on the basis of the pattern of proximal weakness. CONCLUSIONS: Suspicion and recognition of the characteristic symptoms of Pompe disease may improve both the timing and accuracy of the diagnosis, which will improve clinical outcomes and minimize disease progression. PMID- 23463699 TI - Regulation of Wnt4 in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with persistent inflammation and oxidative stress in susceptible individuals. Using microarray analysis of bronchial biopsy samples from patients with COPD and controls, we identified Wnt4 as being up-regulated in COPD. Analysis of bronchial biopsy samples showed a very strong correlation between Wnt4 and IL8 gene expression, suggesting that Wnt4 plays a role in chronic lung inflammation. In vitro, Wnt4 induced proliferation and inflammation in human epithelial cells (BEAS-2B) and normal primary human bronchial epithelial cells in a concentration-dependent manner. This effect was enhanced in the presence of interleukin-1beta (IL-1beta) as a result of activation of the p38 and c-Jun NH2-terminal kinase mitogen activated protein kinase pathways. Hydrogen peroxide, but not proinflammatory stimuli, up-regulated Wnt4 expression in epithelial cells. In monocytic THP-1 and primary airway smooth muscle cells, Wnt4 induced inflammation and enhanced the inflammatory response to lipopolysaccharide and IL-1beta but did not induce proliferation. In addition, these other cell types did not have enhanced Wnt4 expression in response to hydrogen peroxide. Our results indicate that airway epithelial activation, due to oxidative stress, may lead to Wnt4 induction. Wnt4, in turn, acts through the noncanonical pathway to activate epithelial cell remodeling and IL8 gene expression, leading to neutrophil infiltration and inflammation. PMID- 23463702 TI - Localization of function-specific segments of the primary motor pathway in children with Sturge-Weber syndrome: a multimodal imaging analysis. AB - PURPOSE: To explore whether diffusion-weighted imaging (DWI) can localize specific segments of primary motor areas in children with Sturge-Weber syndrome (SWS), this study investigated the corticospinal tract (CST) between precentral gyrus (PCG) and posterior limb of internal capsule (PIC). MATERIALS AND METHODS: DWI was performed on 32 healthy children and seven children with unilateral SWS affecting the sensorimotor area variably. A hierarchical dendrogram was applied to find PCG-segments uniquely connected to PIC-segments. The resulting PCG clusters were used to image primary motor pathways in DWI and find metabolic abnormalities of primary motor areas in positron emission tomography (PET) scans. RESULTS: In healthy children, five PCG-clusters were found to have unique CST courses, corresponding to CST segments of mouth/lip, fingers, and leg/ankle primary motor areas determined by functional magnetic resonance imaging (fMRI). In children with SWS, reduced streamlines in these PCG clusters were highly correlated with glucose-hypometabolism on PET (R(2) = 0.2312, P = 0.0032). Impaired CST segment corresponding to finger movements correlated with severity of hand motor deficit. CONCLUSION: The presented method can detect impaired CST segments corresponding to specific motor functions in young children who cannot cooperate for fMRI. This approach can be clinically useful for a noninvasive presurgical evaluation of cortical motor areas in such children. PMID- 23463703 TI - Tissue growth into three-dimensional composite scaffolds with controlled micro features and nanotopographical surfaces. AB - Controlling topographic features at all length scales is of great importance for the interaction of cells with tissue regenerative materials. We utilized an indirect three-dimensional printing method to fabricate polymeric scaffolds with pre-defined and controlled external and internal architecture that had an interconnected structure with macro- (400-500 MUm) and micro- (~25 MUm) porosity. Polycaprolactone (PCL) was used as model system to study the kinetics of tissue growth within porous scaffolds. The surface of the scaffolds was decorated with TiO2 and bioactive glass (BG) nanoparticles to the better match to nanoarchitecture of extracellular matrix (ECM). Micrometric BG particles were also used to reveal the effect of particle size on the cell behavior. Observation of tissue growth and enzyme activity on two-dimensional (2D) films and three dimensional (3D) scaffolds showed effects of nanoparticle inclusion and of surface curvature on the cellular adhesion, proliferation, and kinetics of preosteoblastic cells (MC3T3-E1) tissue growth into the pore channels. It was found that the presence of nanoparticles in the substrate impaired cellular adhesion and proliferation in 3D structures. Evaluation of alkaline phosphate activity showed that the presence of the hard particles affects differentiation of the cells on 2D films. Notwithstanding, the effect of particles on cell differentiation was not as strong as that seen by the curvature of the substrate. We observed different effects of nanofeatures on 2D structures with those of 3D scaffolds, which influence the cell proliferation and differentiation for non load-bearing applications in bone regenerative medicine. PMID- 23463704 TI - Mercury-the real story. PMID- 23463705 TI - Artificial allosteric receptors. AB - Cooperative effects in the binding of two or more substrates to different binding sites of a receptor that are a result of a conformational change caused by the binding of the first substrate--also referred to as the effector--are called allosteric effects. In biological systems, allosteric regulation is a widely used mechanism to control the function of proteins and enzymes in cellular metabolism. Inspired by this a lot of efforts have been made in supramolecular chemistry to implement this concept into artificial systems to control functions as molecular recognition, signal amplification, or even reactivity and catalysis. This review gives an up-to-date overview over the different approaches that have been reported ever since the first examples from the late 1970s/early 1980s. It covers both homo- and heterotropic examples and is divided according to the nature of the effector--cationic, anionic, or neutral--effectors and systems that use combinations of those. PMID- 23463706 TI - Polio and politics in Pakistan. PMID- 23463707 TI - Two-dimensional sectioned images and three-dimensional surface models for learning the anatomy of the female pelvis. AB - In the Visible Korean project, serially sectioned images of the pelvis were made from a female cadaver. Outlines of significant structures in the sectioned images were drawn and stacked to build surface models. To improve the accessibility and informational content of these data, a five-step process was designed and implemented. First, 154 pelvic structures were outlined with additional surface reconstruction to prepare the image data. Second, the sectioned and outlined images (in a browsing software) as well as the surface models (in a PDF file) were placed on the Visible Korean homepage in a readily-accessible format. Third, all image data were visualized with interactive elements to stimulate creative learning. Fourth, two-dimensional (2D) images and three-dimensional (3D) models were superimposed on one another to provide context and spatial information for students viewing these data. Fifth, images were designed such that structure names would be shown when the mouse pointer hovered over the 2D images or the 3D models. The state-of-the-art sectioned images, outlined images, and surface models, arranged and systematized as described in this study, will aid students in understanding the anatomy of female pelvis. The graphic data accompanied by corresponding magnetic resonance images and computed tomographs are expected to promote the production of 3D simulators for clinical practice. PMID- 23463708 TI - Aligned carbon nanotubes for high-efficiency Schottky solar cells. AB - The development of low-cost and high-efficiency silicon Schottky solar cells has drawn considerable interest in recent years. A facial approach for the fabrication of carbon nanotube-silicon (CNT-Si) Schottky solar cells by using aligned double-walled CNTs drawn from a CNT array is demonstrated. The aligned CNTs help to form high CNT-Si junction density and provide efficient charge transport paths. The power conversion efficiency (PCE) reaches 10.5%, which is higher than that of solar cells fabricated using pristine and random CNT networks. Furthermore, the cell fabrication is scalable, and the solar cells fabricated in one batch show very small PCE fluctuations. PMID- 23463709 TI - Sustained viral suppression and higher CD4+ T-cell count reduces the risk of persistent cervical high-risk human papillomavirus infection in HIV-positive women. AB - BACKGROUND: Studies analyzing the impact of combination antiretroviral therapy (cART) on cervical infection with high-risk human papillomavirus (HR-HPV) have generated conflicting results. We assessed the long-term impact of cART on persistent cervical HR-HPV infection in a very large cohort of 652 women who underwent follow-up of HIV infection for a median duration of 104 months. METHODS: Prospective cohort of HIV-infected women undergoing HIV infection follow up who had HR-HPV screening and cytology by Papanicolaou smear performed yearly between 2002 and 2011. RESULTS: At baseline, the median age was 38 years, the race/ethnic origin was sub-Sarahan Africa for 84%, the median CD4(+) T-cell count was 426 cells/uL, 79% were receiving cART, and the HR-HPV prevalence was 43%. The median interval of having had an HIV load of <50 copies/mL was 40.6 months at the time of a HR-HPV-negative test result, compared with 17 months at the time of a HR-HPV-positive test result (P < .0001, by univariate analysis). The median interval of having had a CD4(+) T-cell count of >500 cells/uL was 18.4 months at the time of a HR-HPV-negative test result, compared with 4.45 months at the time of a HR-HPV-positive test result (P < .0001). In multivariate analysis, having had an HIV load of <50 copies/mL for >40 months (odds ratio [OR], 0.81; 95% confidence interval [CI], .76-.86; P < .0001) and having had a CD4(+) T-cell count of >500 cells/uL for >18 months (OR, 0.88; 95% CI, .82-.94; P = .0002) were associated with a significantly decreased risk of HR-HPV infection. CONCLUSION: Sustained HIV suppression for >40 months and a sustained CD4(+) T-cell count of >500 cells/uL for >18 months are independently and significantly associated with a decreased risk of persistent cervical HR-HPV infection. PMID- 23463710 TI - Synthesis of Cu(core) Pt(shell) nanoparticles as model structures for core-shell electrocatalysts by direct platinum electrodeposition on copper. AB - The synthesis of Cu(core)Pt(shell) model catalysts by the direct electrochemical deposition of Pt on Cu particles is presented. Cu particles with an average diameter of 200 nm have been deposited on glassy-carbon electrodes by double pulse electrodeposition from a copper sulfate solution. Subsequent deposition from a platinum nitrate solution under potential control allows for a high selectivity of the Pt deposition towards Cu. Using a combination of cyclic voltammetry, XPS and sputtering, the structure of the generated particles has been analyzed and their core-shell configuration proven. It is shown that the electrocatalytic activity for the oxygen reduction is similar to that of other PtCu catalyst systems. The synthesized structures could allow for the analysis of structure-activity relations of core-shell catalysts on the way to the simple and controlled synthesis of supported Cu(core)Pt(shell) nanoparticles as oxygen reduction catalysts. PMID- 23463711 TI - Professor Gavin Mooney 1943-2012. PMID- 23463712 TI - Should behavioural economic policy be anti-regulatory? PMID- 23463713 TI - Nano-sized collagen I molecules enhanced the differentiation of rat mesenchymal stem cells into cardiomyocytes. AB - The aim of this study was to investigate the ability of nano-sized collagen I molecules (nanoparticles or nanofibrils) and a 5-azacytidine (5-aza) treatment to enhance the differentiation of rat mesenchymal stem cells (MSCs) toward a cardiomyogenic phenotype in vitro. Second passaged MSCs were cocultured with nano sized collagen I molecules for 24 h and then treated with 10 MUM 5-aza for 24 h. The results demonstrated that the size of the cells increased significantly and acquired a flattened, triangular-shaped morphology after treatment with nano sized collagen I molecules and 5-aza. The cells are connecting with adjoining cells by forming myotube-like structures. Additional treatment of the MSCs with nano-sized collagen I fibrils significantly increased two transcription factors GATA-4 (12.6-fold increase) and Nkx2.5 (4.8-fold increase) expressions compared with MSC groups treated only with 5-aza at 3-day culturing. Furthermore, MSCs pretreated with nano-sized collagen fibrils significantly increased the expressions of cardiac genes of troponin I, beta-myosin heavy chain, and cardiac alpha-actin compared with MSC groups treated only with 5-aza (all, p < 0.01 or better). These results indicate that culturing MSCs with nano-sized collagen I molecules, which may act as scaffolds or soluble protein ingredients, leads to alterations in gene expression and affects the differentiation fate induced with 5-aza. PMID- 23463715 TI - Aggregation-induced emission of tetraphenylethene-hexaphenylbenzene adducts: effects of twisting amplitude and steric hindrance on light emission of nonplanar fluorogens. AB - A series of nonplanar tetraphenylethene (TPE)-hexaphenylbenzene (HPB) adducts was designed and synthesized by Diels-Alder reaction of the acetylene precursors and tetraphenylcyclopentadienone. All of the adducts showed aggregation-induced emission features. The twisting amplitude and steric hindrance of the TPE and HPB units were found to play a crucial role in their fluorescence behaviors in the aggregated state. PMID- 23463716 TI - Evaluation of virtual microscopy in medical histology teaching. AB - Histology stands as a major discipline in the life science curricula, and the practice of teaching it is based on theoretical didactic strategies along with practical training. Traditionally, students achieve practical competence in this subject by learning optical microscopy. Today, students can use newer information and communication technologies in the study of digital microscopic images. A virtual microscopy program was recently introduced at Ghent University. Since little empirical evidence is available concerning the impact of virtual microscopy (VM) versus optical microscopy (OM) on the acquisition of histology knowledge, this study was set up in the Faculty of Medicine and Health Sciences. A pretest-post test and cross-over design was adopted. In the first phase, the experiment yielded two groups in a total population of 199 students, Group 1 performing the practical sessions with OM versus Group 2 performing the same sessions with VM. In the second phase, the research subjects switched conditions. The prior knowledge level of all research subjects was assessed with a pretest. Knowledge acquisition was measured with a post test after each phase (T1 and T2). Analysis of covariance was carried out to study the differential gain in knowledge at T1 and T2, considering the possible differences in prior knowledge at the start of the study. The results pointed to non-significant differences at T1 and at T2. This supports the assumption that the acquisition of the histology knowledge is independent of the microscopy representation mode (VM versus OM) of the learning material. The conclusion that VM is equivalent to OM offers new directions in view of ongoing innovations in medical education technology. PMID- 23463717 TI - Synthesis of boron-doped graphene monolayers using the sole solid feedstock by chemical vapor deposition. AB - Substitutionally boron-doped monolayer graphene film is grown on a large scale by using a sole phenylboronic acid as the source in a low-pressure chemical vapor deposition system. The B-doped graphene film is a homogeneous monolayer with high crystalline quality, which exhibits a stable p-type doping behavior with a considerably high room-temperature carrier mobility of about 800 cm(2) V(-1) s( 1) . PMID- 23463718 TI - Modeling diffusion in foamed polymer nanocomposites. AB - Two-way multicomponent diffusion processes in polymeric nanocomposite foams, where the condensed phase is nanoscopically reinforced with impermeable fillers, are investigated. The diffusion process involves simultaneous outward permeation of the components of the dispersed gas phase and inward diffusion of atmospheric air. The transient variation in thermal conductivity of foam is used as the macroscopic property to track the compositional variations of the dispersed gases due to the diffusion process. In the continuum approach adopted, the unsteady state diffusion process is combined with tortuosity theory. The simulations conducted at ambient temperature reveal distinct regimes of diffusion processes in the nanocomposite foams owing to the reduction in the gas-transport rate induced by nanofillers. Simulations at a higher temperature are also conducted and the predictions are compared with experimentally determined thermal conductivities under accelerated diffusion conditions for polyurethane foams reinforced with clay nanoplatelets of varying individual lamellar dimensions. Intermittent measurements of foam thermal conductivity are performed while the accelerated diffusion proceeded. The predictions under accelerated diffusion conditions show good agreement with experimentally measured thermal conductivities for nanocomposite foams reinforced with low and medium aspect ratios fillers. The model shows higher deviations for foams with fillers that have a high aspect ratio. PMID- 23463719 TI - Tuning the surface structure of nitrogen-doped TiO2 nanofibres--an effective method to enhance photocatalytic activities of visible-light-driven green synthesis and degradation. AB - Nitrogen-doped TiO2 nanofibres of anatase and TiO2(B) phases were synthesised by a reaction between titanate nanofibres of a layered structure and gaseous NH3 at 400-700 degrees C, following a different mechanism than that for the direct nitrogen doping from TiO2. The surface of the N-doped TiO2 nanofibres can be tuned by facial calcination in air to remove the surface-bonded N species, whereas the core remains N doped. N-Doped TiO2 nanofibres, only after calcination in air, became effective photocatalysts for the decomposition of sulforhodamine B under visible-light irradiation. The surface-oxidised surface layer was proven to be very effective for organic molecule adsorption, and the activation of oxygen molecules, whereas the remaining N-doped interior of the fibres strongly absorbed visible light, resulting in the generation of electrons and holes. The N-doped nanofibres were also used as supports of gold nanoparticle (Au NP) photocatalysts for visible-light-driven hydroamination of phenylacetylene with aniline. Phenylacetylene was activated on the N-doped surface of the nanofibres and aniline on the Au NPs. The Au NPs adsorbed on N-doped TiO2(B) nanofibres exhibited much better conversion (80 % of phenylacetylene) than when adsorbed on undoped fibres (46 %) at 40 degrees C and 95 % of the product is the desired imine. The surface N species can prevent the adsorption of O2 that is unfavourable for the hydroamination reaction, and thus, improve the photocatalytic activity. Removal of the surface N species resulted in a sharp decrease of the photocatalytic activity. These photocatalysts are feasible for practical applications, because they can be easily dispersed into solution and separated from a liquid by filtration, sedimentation or centrifugation due to their fibril morphology. PMID- 23463720 TI - Do healthcare professionals discuss the emotional impact of cancer with patients? AB - BACKGROUND: It is known that cancer may affect patients' emotions and their relationships with other people and that those with strong emotional support may enjoy improved outcomes. We sought to determine the frequency with which healthcare professionals discuss the impact of cancer on patients' emotions and relationships with others. METHODS: Data regarding healthcare professionals' discussions of the emotional impact of cancer and relevant covariates were obtained from the 2010 National Health Interview Survey. Statistical analyses were performed using sudaan software (Research Triangle Institute, Raleigh, NC, USA). RESULTS: Of the 2074 people with a prior diagnosis of cancer surveyed, 701 (33.8%) claimed that a doctor, nurse, or other healthcare professional had discussed with them 'how cancer could affect their emotions or relationships with others'. Of these, 586 (84.5%) reported that they were 'very satisfied' with how well their emotional and social needs were met; 73.4% of those who had not had this discussion reported being very satisfied. Patients with leukemia/lymphoma, younger patients, African Americans, and those with a lower degree of education were most likely to report having discussions about emotional issues. Gender was not correlated with these discussions (30.6% in men vs. 33.3% in women). On multivariate analysis, age, race, and cancer type remained independent significant predictors of having a discussion regarding the emotional impact of cancer. CONCLUSION: Only a third of cancer patients discussed the emotional impact of a cancer diagnosis with their healthcare professional. Age, race, and type of malignancy affect the likelihood of having these discussions. PMID- 23463722 TI - Equivalence of students' scores on timed and untimed anatomy practical examinations. AB - Untimed examinations are popular with students because there is a perception that first impressions may be incorrect, and that difficult questions require more time for reflection. In this report, we tested the hypothesis that timed anatomy practical examinations are inherently more difficult than untimed examinations. Students in the Doctor of Physical Therapy program at Thomas Jefferson University were assessed on their understanding of anatomic relationships using multiple choice questions. For the class of 2012 (n = 46), students were allowed to circulate freely among 40 testing stations during the 40-minute testing session. For the class of 2013 (n = 46), students were required to move sequentially through the 40 testing stations (one minute per item). Students in both years were given three practical examinations covering the back/upper limb, lower limb, and trunk. An identical set of questions was used for both groups of students (untimed and timed examinations). Our results indicate that there is no significant difference between student performance on untimed and timed examinations (final percent scores of 87.3 and 88.9, respectively). This result also held true for students in the top and bottom 20th percentiles of the class. Moreover, time limits did not lead to errors on even the most difficult, higher order questions (i.e., items with P-values < 0.70). Thus, limiting time at testing stations during an anatomy practical examination does not adversely affect student performance. PMID- 23463723 TI - A de novo deletion at 16q24.3 involving ANKRD11 in a Japanese patient with KBG syndrome. AB - KBG syndrome is a rare autosomal dominant congenital syndrome comprising developmental delay with various neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism, and skeletal anomalies. ANKRD11 was recently identified as the gene responsible for this syndrome. To date, there have been only five KBG syndrome families described, each carrying a single base substitution or a 1- to 14-bp deletion of this gene. Here, we present a patient with clinically confirmed KBG syndrome carrying a de novo 690-kb deletion at 16q24.3 involving part of ANKRD11. He had characteristic facial appearance, macrodontia of the upper central incisors, hand anomalies, delayed bone age and intellectual impairment without autistic features. Interestingly, the deleted region overlaps with the critical region for 16q24.3 microdeletion syndrome. We discuss the clinical entities of KBG syndrome and 16q24.3 microdeletion syndrome from a clinical and genetic point of view. PMID- 23463724 TI - Zebrafish as a model for the study of neutrophil biology. AB - To understand inflammation and immunity, we need to understand the biology of the neutrophil. Whereas these cells can readily be extracted from peripheral blood, their short lifespan makes genetic manipulations impractical. Murine knockout models have been highly informative, and new imaging techniques are allowing neutrophils to be seen during inflammation in vivo for the first time. However, there is a place for a new model of neutrophil biology, which readily permits imaging of individual neutrophils during inflammation in vivo, combined with the ease of genetic and chemical manipulation. The zebrafish has long been the model of choice for the developmental biology community, and the availability of genomic resources and tools for gene manipulation makes this an attractive model. Zebrafish innate immunity shares many features with mammalian systems, including neutrophils with morphological, biochemical, and functional features, also shared with mammalian neutrophils. Transgenic zebrafish with neutrophils specifically labeled with fluorescent proteins have been generated, and this advance has led to the adoption of zebrafish, alongside existing models, by a number of groups around the world. The use of these models has underpinned a number of key advances in the field, including the identification of a tissue gradient of hydrogen peroxide for neutrophil recruitment following tissue injury and direct evidence for reverse migration as a regulatable mechanism of inflammation resolution. In this review, we discuss the importance of zebrafish models in neutrophil biology and describe how the understanding of neutrophil biology has been advanced by the use of these models. PMID- 23463726 TI - Cancer-related self-efficacy following a consultation with an oncologist. AB - OBJECTIVE: When receiving a cancer diagnosis, patients are often faced with psychological distress and loss of control. As a result, their psychological well being may be influenced by their perceived ability to cope with disease-related and treatment-related challenges. Research indicates that the patient-oncologist relationship may have an impact on patients' self-efficacy. The aim was to examine predictors of self-efficacy following a consultation in an oncology outpatient clinic and the predictors of change. METHODS: A total of 226 patients (mean age: 61 years, 40% male) attending an oncology outpatient clinic completed questionnaires before and after a consultation including the Hospital Anxiety and Depression Scale, two domain-specific self-efficacy scales measuring coping self efficacy and decision self-efficacy, the Physician-Patient Relationship Inventory, and the Information Satisfaction Questionnaire. RESULTS: While most patients experienced an increase in self-efficacy following the consultation, some patients experienced lower self-efficacy post-consultation. In the multivariate analysis, depressive symptoms emerged as a relatively strong predictor of both coping self-efficacy and decision self-efficacy, whereas marital status was a significant predictor of coping self-efficacy, and satisfaction with information significantly predicted decision self-efficacy. No significant associations were found between self-efficacy and the patients' ratings of the physician-patient relationship. CONCLUSION: Depression seems to be a potential risk factor for lower cancer-related self-efficacy, following an oncologist consultation. By identifying patients who exhibit symptoms of depression, health professionals can increase their attention on empowering these patients. Furthermore, our results suggest that patients' experience of self efficacy depends on what particular challenges they have to overcome. PMID- 23463725 TI - Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists. AB - Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB2 can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB2 agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB2 expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB2 surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up regulation of CB2 may allow for the use of synthetic CB2 agonist to limit HIV-1 infection. Two commercially available CB2 agonists, JWH133 and GP1a, and a resorcinol-based CB2 agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB2 agonist was present. Furthermore, CB2 activation also partially inhibited the expression of HIV-1 pol. CB2 agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB2-mediated suppression in viral replication. However, CB2 may affect the HIV-1 replication machinery. Results from a single round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB2 ligands. Together, these results indicate that CB2 may offer a means to limit HIV-1 infection in macrophages. PMID- 23463727 TI - NIR-emitting quantum dot-encoded microbeads through membrane emulsification for multiplexed immunoassays. AB - NIR-emitting CdSeTe/CdS/ZnS core/shell/shell QD-encoded microbeads are combined with common flow cytometry with one laser for multiplexed detection of hepatitis B virus (HBV). A facile one-pot synthetic route is developed to prepare CdSeTe/CdS/ZnS core/shell/shell QDs with high photoluminescence quantum yield and excellent stability in liquid paraffin, and a Shirasu porous glass (SPG) membrane emulsification technique is applied to incorporate the QDs into polystyrene maleic anhydride (PSMA) microbeads to obtain highly fluorescent QD-encoded microbeads. The relatively wide NIR photoluminescence full width half maximum of the CdSeTe/CdS/ZnS QDs is used to develop a 'single wavelength' encoding method to obtain different optical codes by changing the wavelengh and emission intensity of the QDs incorporated into the microbeads. Moreover, a detection platform combining NIR-emitting CdSeTe/CdS/ZnS QD-encoded microbeads and Beckman Coulter FC 500 flow cytometry with one laser of 488 nm is successfully used to conduct a 2-plex hybridization assay for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and a 3-plex hybridization assay for hepatitis B surface antibody (HBsAb), hepatitis B e antibody (HBeAb), and hepatitis B core antibody (HBcAb), which suggests the promising application of NIR QD-encoded microbeads for multiplex immunoassays. PMID- 23463728 TI - Intensive mode delivery of a neuroanatomy unit: lower final grades but higher student satisfaction. AB - In 2011, Macquarie University moved to a three-session academic year which included two 13-week sessions (traditional mode) and one seven-week session (intensive mode). This study was designed to compare the intensive and traditional modes of delivery in a unit of undergraduate neuroanatomy. The new intensive mode neuroanatomy unit provided the same quantity and quality of material to the same standard, delivered by the same teachers and over the same total hours, but in a shorter timeframe. All students enrolled in session 2 (traditional mode) and session 3 (intensive mode) were invited to participate in this study. The main outcome measures were the final course grades and level of satisfaction with the course. Although there was no significant difference between the two cohorts in self-rated level of knowledge (P = 0.148), the traditional mode cohort achieved significantly higher final grades compared to the intensive mode cohort (P = 0.001). Similarly, the distribution of final grades was also different between the two cohorts. The two cohorts were equally satisfied with the unit overall, and with the lectures and tutorials. However, the intensive mode cohort was more satisfied with the laboratory practical classes compared to the traditional mode cohort (P < 0.001). Thus this study demonstrates that in the case of neuroanatomy, which is high in content, when the course is taught to the same standards as exist in the traditional mode of delivery, the students do not do as well even though they enjoy the course equally. PMID- 23463730 TI - Interstitial duplication of 2q32.1-q33.3 in a patient with epilepsy, developmental delay, and autistic behavior. AB - Duplications of the 2q33 region are rare; to date, only 13 patients have been reported to have this chromosomal abnormality. The reported duplications are of varying size, and the patients shared developmental delay and minor dysmorphic findings. In this study, we identified a duplication of 2q32.1-q33.3 in a patient with psychomotor developmental delay, epilepsy, and autistic behavior. The duplicated region of this patient was reciprocal to the 2q32-q33 deletion syndrome. Chromosomal microarray testing confirmed the 19.5 Mb of duplication that includes over 100 genes, some of which could have functional relevance to the neurological features of this patient. The SATB homeobox 2 gene (SATB2)-the primary gene responsible for the 2q32-q33 deletion syndrome-may be one of them, because of its expression in the cortical projection neurons of the developing brain. The duplication of the potassium channel tetramerisation domain-containing 18 gene (KCTD18) and the ADAM metallopeptidase domain 23 gene (ADAM23) may also contribute to the phenotype. FISH analysis confirmed a tandem configuration of the duplicated segments. This result is in agreement with our previous study, in which we observed that duplicated segments as interstitial duplications are generally inserted in the tandem configuration. PMID- 23463732 TI - Cyclodextrin insulation prevents static quenching of conjugated polymer fluorescence at the single molecule level. AB - Conjugated polymers (CPs) are promising materials for fluorescence imaging application. However, a significant problem in this field is the unexplained abnormally low fluorescence brightness (or number of fluorescence photons detected per one excitation photon) exhibited by most of CP single chains in solid polymer hosts. Here it is shown that this detrimental effect can be fully avoided for short chains of polyfluorene-bis-vinylphenylene (PFBV) embedded in a host polymer matrix of PMMA, if the conjugated backbone is insulated by cyclodextrin rings to form a polyrotaxane (PFBV-Rtx). Fluorescence kinetics and quantum yields are measured for the polymers in liquid solutions, pristine films, and solid PMMA blends. The fluorescence brightness of PFBV-Rtx single chains dispersed in a solid PMMA is very close to that expected for a chain with 100% fluorescence quantum yield, while the unprotected PFBV chains of the same length possess 4 times lower brightness. Despite this, the fluorescence decay kinetics are the same for both polymers, suggesting the presence of static or ultrafast fluorescence quenching in the unprotected polymer. About 80% of an unprotected PFBV chain is estimated to be completely quenched. The hypothesis is that the cyclodextrin rings prevent the quenching by working as 'bumpers' reducing the mechanical forces applied by the host polymer to the conjugated backbone and help retaining its conformational freedom. While providing a recipe for making CP fluorescence bright at the single-molecule level, these results identify a lack of fundamental understanding in the community of the influence of the environment on excited states in conjugated materials. PMID- 23463731 TI - Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid. AB - We previously reported that lysophosphatidic acid (LPA) inhibits the neuronal differentiation of human embryonic stem cells (hESC). We extended these studies by analyzing LPA's effects on the expansion of neural stem/progenitor cells (NS/PC) derived from hESCs and human induced pluripotent stem cells (iPSC), and we assessed whether data obtained on the neural differentiation of hESCs were relevant to iPSCs. We showed that hESCs and iPSCs exhibited comparable mRNA expression profiles of LPA receptors and producing enzymes upon neural differentiation. We demonstrated that LPA inhibited the expansion of NS/PCs of both origins, mainly by increased apoptosis in a Rho/Rho-associated kinase (ROCK) dependent mechanism. Furthermore, LPA inhibited the neuronal differentiation of iPSCs. Lastly, LPA induced neurite retraction of NS/PC-derived early neurons through Rho/ROCK, which was accompanied by myosin light chain (MLC) phosphorylation. Our data demonstrate the consistency of LPA effects across various sources of human NS/PCs, rendering hESCs and iPSCs valuable models for studying lysophospholipid signaling in human neural cells. Our data also highlight the importance of the Rho/ROCK pathway in human NS/PCs. As LPA levels are increased in the central nervous system (CNS) following injury, LPA-mediated effects on NS/PCs and early neurons could contribute to the poor neurogenesis observed in the CNS following injury. PMID- 23463734 TI - Incidence and risk of mood disorders in patients with breast cancers in Taiwan: a nationwide population-based study. AB - OBJECTIVE: The objective of this study is to assess the incidence and risk of mood disorders, including major depression, anxiety, and bipolar disorders, in Taiwanese patients after the diagnosis of breast cancer compared with a matched cohort. METHODS: From January 2000 to December 2005, 26,629 newly diagnosed breast cancer patients were enrolled by the Taiwan National Health Insurance program database. The control cohort was selected randomly from 1,000,000 National Health Insurance beneficiaries from a population of 21,400,826 enrolled throughout Taiwan. Each patient was matched with one subject without breast cancer by age, sex, and presence of comorbidities with the same diagnosis index date. The diagnosis of mood disorders was defined by compatible International Classification of Diseases, 9th revision, clinical modification codes plus the prescription of antidepressants for at least 30 days. RESULTS: The overall incidence rate ratio of mood disorders was 1.33 (95% CI 1.28-1.39, p < 0.001) in the breast cancer cohort compared with the matched cohort. The incidence rate ratios for specific mood disorders were 2.06 for bipolar disorder (95% CI 1.37 3.15 p = 0.0003), 1.94 for major depressive disorder (95% CI 1.76-2.13 p < 0.001), and 1.22 for anxiety (95% CI 1.16-1.27 p < 0.001). Independent risk factors for developing mood disorders included breast cancer, as well as age, hypertension, chronic obstructive pulmonary disease, autoimmune disease, ischemic heart disease, and cerebrovascular disease. CONCLUSIONS: Breast cancer is a prominent risk factor for mood disorders, including major depressive disorder, anxiety, and bipolar disorder. The impact is most potent in the first year after diagnosis. Psychological support is a critical issue in these patients. PMID- 23463735 TI - Sodium-glucose cotransporter inhibition: therapeutic potential for the treatment of type 2 diabetes mellitus. AB - Results from randomized controlled trials have demonstrated that the risk of microvascular complications can be reduced by intensive glycaemic control in patients with type 2 diabetes mellitus (T2DM). However, only about half of patients with diagnosed diabetes achieve recommended glycaemic goals. New therapies with complementary mechanisms of action that are independent of insulin secretion or action may provide additional therapeutic options to enable patients to achieve glycaemic control. The kidney plays an important role in glucose homeostasis, primarily by the reabsorption of filtered glucose. The sodium glucose cotransporter 2 (SGLT2), located in the proximal convoluted tubule, is responsible for the majority of glucose reabsorption by the kidney. SGLT2 inhibitors offer a novel approach to treat T2DM and reduce hyperglycaemia by increasing urinary excretion of glucose. Dapagliflozin, an SGLT2 inhibitor recently approved in Europe for the treatment of T2DM, improves glycaemic control in patients with T2DM when used as monotherapy or when added to other diabetes medications, such as metformin, sulfonylureas, pioglitazone, and insulin. As a class, SGLT2 inhibitors are well tolerated and have a low propensity to cause hypoglycaemia. An increase in signs, symptoms, and other events suggestive of genital and, in some studies, urinary tract infections has been reported with SGLT2 inhibitors. Results from ongoing and future clinical trials will help define the role for this new class of investigational compounds, with its unique mechanism of action, as a treatment option for reducing hyperglycaemia in patients with T2DM. PMID- 23463738 TI - Lyophilic nonwettable surface based on an oil/water/air/solid four-phase system. PMID- 23463737 TI - Simpson-Golabi-Behmel syndrome type 1 and hepatoblastoma in a patient with a novel exon 2-4 duplication of the GPC3 gene. AB - Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months. PMID- 23463739 TI - Pharmacogenetics of risperidone: a systematic review of the clinical effects of CYP2D6 polymorphisms. AB - OBJECTIVE: To summarize and evaluate the pharmacogenetic literature pertaining to the effects of CYP2D6 polymorphism on clinical outcomes of risperidone therapy. DATA SOURCES: A systematic literature search was performed using the search terms risperidone, pharmacogenetics, cytochrome P-450 enzyme system, cytochrome P-450 CYP2D6, and polymorphism (genetic) in MEDLINE (1946-October 2012), EMBASE (1980 October 2012), PubMed (1947-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and Google Scholar. STUDY SELECTION AND DATA EXTRACTION: Identified articles were included if they measured the association between CYP2D6 genetic polymorphisms and clinical outcomes in at least 2 patients taking risperidone. The data elements extracted from these articles consisted of study design, number of subjects, indication for risperidone therapy, CYP2D6 phenotype status, mean daily dose of risperidone, and effects on clinical outcomes. DATA SYNTHESIS: The identified citations consisted of 10 prospective nonrandomized, uncontrolled cohort studies, 1 retrospective cohort study, 1 prospective case control study, and 1 retrospective case series. Studies were of variable quality and none provided high-quality evidence; they included heterogeneous patient populations with varying clinical diagnoses and drug therapy regimens. Most studies reported nonsignificant trends but were limited by power to detect statistical significance and short trial duration. However, increased risk of adverse effects (including QT interval prolongation) was observed in patients with inactive alleles. CONCLUSIONS: While there were trends toward increased adverse effects in poor metabolizers, most outcomes were not significant. As such, routine genotyping should not be used for screening. Future usefulness cannot be ruled out, as many studies had significant limitations that preclude determination of clinical relevance. Adequately powered clinical and epidemiologic studies are warranted to clarify the role of CYP2D6 genotyping in practice. PMID- 23463736 TI - Hierarchical approaches for systems modeling in cardiac development. AB - Ordered cardiac morphogenesis and function are essential for all vertebrate life. The heart begins as a simple contractile tube, but quickly grows and morphs into a multichambered pumping organ complete with valves, while maintaining regulation of blood flow and nutrient distribution. Though not identical, cardiac morphogenesis shares many molecular and morphological processes across vertebrate species. Quantitative data across multiple time and length scales have been gathered through decades of reductionist single variable analyses. These range from detailed molecular signaling pathways at the cellular levels to cardiac function at the tissue/organ levels. However, none of these components act in true isolation from others, and each, in turn, exhibits short- and long-range effects in both time and space. With the absence of a gene, entire signaling cascades and genetic profiles may be shifted, resulting in complex feedback mechanisms. Also taking into account local microenvironmental changes throughout development, it is apparent that a systems level approach is an essential resource to accelerate information generation concerning the functional relationships across multiple length scales (molecular data vs physiological function) and structural development. In this review, we discuss relevant in vivo and in vitro experimental approaches, compare different computational frameworks for systems modeling, and the latest information about systems modeling of cardiac development. Finally, we conclude with some important future directions for cardiac systems modeling. PMID- 23463740 TI - Alteplase for the treatment of catheter occlusion in pediatric patients. AB - OBJECTIVE: To review the literature pertaining to the efficacy of alteplase for restoration of patency of occluded venous and dialysis catheters in pediatric patients. DATA SOURCES: A MEDLINE search was conducted and cross-referenced with an EMBASE search through November 2012. Search terms included alteplase, tissue plasminogen activator, and catheter. STUDY SELECTION AND DATA EXTRACTION: Search results were limited to humans, English language, and ages from neonates to 18 years. Pertinent studies discussing efficacy of alteplase for restoration of occluded venous or dialysis catheter function were included. Case reports, review articles, and studies that specified inclusion of hemophilia patients or more than 75% of children with malignancy were excluded. DATA SYNTHESIS: Fibrinolytics are the drug class of choice for restoration of patency (defined as the ability to withdraw a blood sample) of thrombus-occluded catheters. The trials used to support Food and Drug Administration approval of alteplase for central venous catheter (CVC) occlusions generally had low pediatric enrollment; however, additional small studies are available that support use of alteplase for this indication in children. Alteplase doses of 0.5-2 mg instilled into the lumen of a CVC with dwell times ranging from 30 to more than 240 minutes plus the potential for repeat dosing were reported. Overall efficacy ranged from approximately 50% to 90%, with greater efficacy generally reported with larger doses and longer dwell times. Alteplase doses of 2-2.5 mg with dwell times of 60-120 minutes were observed in 2 studies of occluded peritoneal or hemodialysis catheters, in which efficacy was reported in 57-100% of cases. Limitations of current studies of alteplase for catheter occlusion in children include small study populations and relative lack of pediatric-specific prospective trials. CONCLUSIONS: Alteplase appears to show efficacy for treatment of thrombus-related venous catheter occlusion in pediatric patients; however, data regarding its use in occluded dialysis catheters are limited. PMID- 23463741 TI - Comment: intranasal fentanyl spray: a novel dosage form for the treatment of breakthrough cancer pain. PMID- 23463742 TI - Use of number needed to treat in cost-effectiveness analyses. AB - OBJECTIVE: To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs). DATA SOURCES: PubMed and EconLit were searched from 1966 to September 2012. STUDY SELECTION AND DATA EXTRACTION: Reviews, editorials, non-English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures. DATA SYNTHESIS: A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice-focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics-focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA. CONCLUSIONS: CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications. PMID- 23463743 TI - Cethromycin: a new ketolide antibiotic. AB - OBJECTIVE: To review the pharmacology, chemistry, microbiology, in vitro susceptibility, mechanism of resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, dosage, and administration of cethromycin, a new ketolide antibiotic. DATA SOURCES: Literature was obtained through searching PubMed (1950-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and a bibliographic review of published articles. Search terms included cethromycin, ABT-773, ketolide antibiotic, and community acquired pneumonia. STUDY SELECTION AND DATA EXTRACTION: All available in vitro and preclinical studies, as well as Phase 1, 2, and 3 clinical studies published in English were evaluated to summarize the pharmacology, chemistry, microbiology, efficacy, and safety of cethromycin in the treatment of respiratory tract infections. DATA SYNTHESIS: Cethromycin, a new ketolide, has a similar mechanism of action to telithromycin with an apparently better safety profile. Cethromycin displays in vitro activity against selected gram-positive, gram-negative, and atypical bacteria. The proposed indication of cethromycin is treatment of mild to moderate community-acquired bacterial pneumonia in patients aged 18 years or older. Based on clinical studies, the recommended dose is 300 mg orally once a day without regard to meals. Cethromycin has an orphan drug designation for tularemia, plague, and anthrax prophylaxis. The Food and Drug Administration denied approval for the treatment of community-acquired pneumonia in 2009; a recent noninferiority trial showed comparable efficacy between cethromycin and clarithromycin. Preliminary data on adverse effects suggest that cethromycin is safe and gastrointestinal adverse effects appear to be dose-related. CONCLUSIONS: Cethromycin appears to be a promising ketolide for the treatment of mild to moderate community-acquired pneumonia. It was denied approval by the FDA in 2009 pending more evidence to show its efficacy, with more recent studies showing its noninferiority to antibiotics for the same indication. PMID- 23463744 TI - Comment: intranasal fentanyl spray: a novel dosage form for the treatment of breakthrough cancer pain. PMID- 23463745 TI - Comment: intranasal fentanyl spray: a novel dosage form for the treatment of breakthrough cancer pain. Authors' reply. PMID- 23463747 TI - Risk association of HbA1c variability with chronic kidney disease and cardiovascular disease in type 2 diabetes: prospective analysis of the Hong Kong Diabetes Registry. AB - BACKGROUND: In type 2 diabetes, tight glycaemic control lowers the risk of diabetic complications, but it remains uncertain whether variability of glycaemia influences outcomes. We examined the association of glycated haemoglobin (HbA1c ) variability with incident chronic kidney disease and cardiovascular disease in a prospective cohort of 8439 Chinese patients with type 2 diabetes recruited from 1994 to 2007. METHODS: Intrapersonal mean and SD of serially measured HbA1c were calculated. Chronic kidney disease was defined as estimated glomerular filtration rate <60 ml/min per 1.73 m2. Cardiovascular disease was defined as events of ischemic heart disease, heart failure, ischemic stroke or peripheral vascular disease. RESULTS: Over a median follow-up period of 7.2 years, 19.7 and 10.0% of patients developed chronic kidney disease and cardiovascular disease, respectively. Patients who progressed to chronic kidney disease had higher mean HbA1c (7.8 +/- 1.3% vs 7.4 +/- 1.2%, p < 0.001) and SD (1.0 +/- 0.8% vs 0.8 +/- 0.6%, p < 0.001) than nonprogressors. Similarly, patients who developed cardiovascular disease had higher mean HbA1c (7.7 +/- 1.3% vs 7.4 +/- 1.2%, p < 0.001) and SD (1.4 +/- 1.1% vs 1.1 +/- 0.8%, p < 0.001) than patients who did not develop cardiovascular disease. By using multivariate-adjusted Cox regression analysis, adjusted SD was associated with incident chronic kidney disease and cardiovascular disease with corresponding hazard ratios of 1.16 (95% CI 1.11 1.22), p < 0.001) and 1.27 (95% CI 1.15-1.40, p < 0.001), independent of mean HbA1c and other confounding variables. CONCLUSIONS: Long-term glycaemic variability expressed by SD of HbA1c predicted development of renal and cardiovascular complications. PMID- 23463748 TI - Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man. AB - Glucagon-like peptide 1 (GLP1) analogs have been associated with an increased incidence of thyroid C-cell hyperplasia and tumors in rodents. This effect may be due to a GLP1 receptor (GLP1R)-dependent mechanism. As the expression of GLP1R is much lower in primates than in rodents, the described C-cell proliferative lesions may not be relevant to man. Here, we aimed to establish primary thyroid cell cultures of rat and human to evaluate the expression and function of GLP1R in C-cells. In our experiments, GLP1R expression was observed in primary rat C cells (in situ hybridization) but was not detected in primary human C-cells (mRNA and protein levels). The functional response of the cultures to the stimulation with GLP1R agonists is an indirect measure of the presence of functional receptor. Liraglutide and taspoglutide elicited a modest increase in calcitonin release and in calcitonin expression in rat primary thyroid cultures. Contrarily, no functional response to GLP1R agonists was observed in human thyroid cultures, despite the presence of few calcitonin-positive C-cells. Thus, the lack of functional response of the human cultures adds to the weight of evidence indicating that healthy human C-cells have very low levels or completely lack GLP1R. In summary, our results support the hypothesis that the GLP1R agonist induced C-cell responses in rodents may not be relevant to primates. In addition, the established cell culture method represents a useful tool to study the physiological and/or pathological roles of GLP1 and GLP1R agonists on normal, non transformed primary C-cells from rats and man. PMID- 23463749 TI - Trilateral retinoblastoma in a patient with Peutz-Jeghers syndrome. AB - Germline loss of function mutations in tumor suppressor genes RB1 and LKB1/STK11 are associated with the autosomal dominant cancer predisposing syndromes familial retinoblastoma and Peutz-Jeghers syndrome (PJS), respectively. We present a rare case of a young woman with trilateral retinoblastoma diagnosed as an infant who survived and was then diagnosed with PJS as a teenager. There was no family history of either disorder. Analysis of the LKB1/STK11 gene sequence identified a germline frameshift mutation (c.107del) leading to a nonsense mutation near the N terminus of the protein, confirming a clinical diagnosis of Peutz-Jeghers syndrome. Extensive RB1 gene analysis failed to detect germline mutations or deletions, and immunohistochemical analysis of her ocular tumors demonstrated nuclear staining of immunoreactive pRB. This result suggests that the RB1 gene is intact. We estimate the chance of trilateral retinoblastoma and PJS occurring in the same individual at approximately 1 in 134 billion live births, and we discuss the possibility that this case could be explained by a putative modifier of pRB action that is associated with the LKB1/STK11 pathway. PMID- 23463751 TI - Prediction of recanalization trumps prediction of tissue fate: the penumbra: a dual-edged sword. AB - BACKGROUND AND PURPOSE: To determine whether infarct core or penumbra is the more significant predictor of outcome in acute ischemic stroke, and whether the results are affected by the statistical method used. METHODS: Clinical and imaging data were collected in 165 patients with acute ischemic stroke. We reviewed the noncontrast head computed tomography (CT) to determine the Alberta Score Program Early CT score and assess for hyperdense middle cerebral artery. We reviewed CT-angiogram for site of occlusion and collateral flow score. From perfusion-CT, we calculated the volumes of infarct core and ischemic penumbra. Recanalization status was assessed on early follow-up imaging. Clinical data included age, several time points, National Institutes of Health Stroke Scale at admission, treatment type, and modified Rankin score at 90 days. Two multivariate regression analyses were conducted to determine which variables predicted outcome best. In the first analysis, we did not include recanalization status among the potential predicting variables. In the second, we included recanalization status and its interaction between perfusion-CT variables. RESULTS: Among the 165 study patients, 76 had a good outcome (modified Rankin score <=2) and 89 had a poor outcome (modified Rankin score >2). In our first analysis, the most important predictors were age (P<0.001) and National Institutes of Health Stroke Scale at admission (P=0.001). The imaging variables were not important predictors of outcome (P>0.05). In the second analysis, when the recanalization status and its interaction with perfusion-CT variables were included, recanalization status and perfusion-CT penumbra volume became the significant predictors (P<0.001). CONCLUSIONS: Imaging prediction of tissue fate, more specifically imaging of the ischemic penumbra, matters only if recanalization can also be predicted. PMID- 23463750 TI - Toward the virtual stomach: progress in multiscale modeling of gastric electrophysiology and motility. AB - Experimental progress in investigating normal and disordered gastric motility is increasingly being complimented by sophisticated multiscale modeling studies. Mathematical modeling has become a valuable tool in this effort, as there is an ever-increasing need to gain an integrative and quantitative understanding of how physiological mechanisms achieve coordinated functions across multiple biophysical scales. These interdisciplinary efforts have been particularly notable in the area of gastric electrophysiology, where they are beginning to yield a comprehensive and integrated in silico organ modeling framework, or 'virtual stomach'. At the cellular level, a number of biophysically based mathematical cell models have been developed, and these are now being applied in areas including investigations of gastric electrical pacemaker mechanisms, smooth muscle electrophysiology, and electromechanical coupling. At the tissue level, micro-structural models are being creatively developed and employed to investigate clinically significant questions, such as the functional effects of ICC degradation on gastrointestinal (GI) electrical activation. At the organ level, high-resolution electrical mapping and modeling studies are combined to provide improved insights into normal and dysrhythmic gastric electrical activation. These efforts are also enabling detailed forward and inverse modeling studies at the 'whole body' level, with implications for diagnostic techniques for gastric dysrhythmias. These recent advances, together with several others highlighted in this review, collectively demonstrate a powerful trend toward applying mathematical models to effectively investigate structure-function relationships and overcome multiscale challenges in basic and clinical GI research. PMID- 23463752 TI - Quantitative video-oculography to help diagnose stroke in acute vertigo and dizziness: toward an ECG for the eyes. AB - BACKGROUND AND PURPOSE: Strokes can be distinguished from benign peripheral causes of acute vestibular syndrome using bedside oculomotor tests (head impulse test, nystagmus, test-of-skew). Using head impulse test, nystagmus, test-of-skew is more sensitive and less costly than early magnetic resonance imaging for stroke diagnosis in acute vestibular syndrome but requires expertise not routinely available in emergency departments. We sought to begin standardizing the head impulse test, nystagmus, test-of-skew diagnostic approach for eventual emergency department use through the novel application of a portable video oculography device measuring vestibular physiology in real time. This approach is conceptually similar to ECG to diagnose acute cardiac ischemia. METHODS: Proof-of concept study (August 2011 to June 2012). We recruited adult emergency department patients with acute vestibular syndrome defined as new, persistent vertigo/dizziness, nystagmus, and (1) nausea/vomiting, (2) head motion intolerance, or (3) new gait unsteadiness. We recorded eye movements, including quantitative horizontal head impulse testing of vestibulo-ocular-reflex function. Two masked vestibular experts rated vestibular findings, which were compared with final radiographic gold-standard diagnoses. Masked neuroimaging raters determined stroke or no stroke using magnetic resonance imaging of the brain with diffusion weighted imaging obtained 48 hours to 7 days after symptom onset. RESULTS: We enrolled 12 consecutive patients who underwent confirmatory magnetic resonance imaging. Mean age was 61 years (range 30-73), and 10 were men. Expert-rated video oculography-based head impulse test, nystagmus, test-of-skew examination was 100% accurate (6 strokes, 6 peripheral vestibular). CONCLUSIONS: Device-based physiological diagnosis of vertebrobasilar stroke in acute vestibular syndrome should soon be possible. If confirmed in a larger sample, this bedside eye ECG approach could eventually help fulfill a critical need for timely, accurate, efficient diagnosis in emergency department patients with vertigo or dizziness who are at high risk for stroke. PMID- 23463753 TI - Increased corticospinal tract fractional anisotropy can discriminate stroke onset within the first 4.5 hours. AB - BACKGROUND AND PURPOSE: The role of diffusion tensor imaging in determining stroke age remains unclear. We tested the ability of diffusion tensor imaging metrics to discriminate ischemic stroke <4.5 hours of onset. METHODS: We enrolled 60 consecutive patients for multimodal 1.5 T MRI within 12 hours of middle cerebral artery ischemic stroke onset. We measured fractional anisotropy (FA), mean diffusivity (MD), apparent diffusion coefficient (ADC), and T2-weighted signal intensity in affected ipsilateral and unaffected contralateral deep gray matter, cortical gray matter, deep white matter in the corticospinal tract (CST), and subcortical white matter and calculated ipsilateral-to-contralateral ratios (r). Hyperintensity in infarcted tissue was considered fluid-attenuated inversion recovery-positive. RESULTS: We analyzed the 48 patients (17 women; mean age, 68 +/- 14 years) with known onset. In 25 (52.1%) patients, onset was <= 4.5 hours (mean, 182.3 +/- 65.6 minutes). Variables differing significantly between infarcts <4.5 hours and >4.5 hours were rFA CST (P = 0.001), rMD cortical gray matter (P = 0.036), rADC cortical gray matter (P = 0.009), rT2 CST (P = 0.006), and fluid-attenuated inversion recovery (P<0.001). rFA at CST was the most reliable to discriminate infarcts <4.5 hours (Goodman-Kruskal = 0.76). The sensitivity, specificity, and positive and negative predictive values for infarct <4.5 hours of onset by rFA at CST >0.970 were 93.8%, 84.6%, 88.2%, and 91.7%, respectively. CONCLUSIONS: These preliminary results suggest rFA at CST may be a surrogate marker of acute stroke age. PMID- 23463754 TI - Letter by Tsuda regarding article, "Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging". PMID- 23463755 TI - Endovascular stroke therapy: tirofiban is associated with risk of fatal intracerebral hemorrhage and poor outcome. AB - BACKGROUND AND PURPOSE: To investigate the relationship between severe bleeding complications and outcome after mechanical thrombectomy with or without glycoprotein-IIb/IIIa inhibitor tirofiban treatment. METHODS: The study included prospectively collected data of consecutive patients with acute ischemic stroke in whom mechanical thrombectomy was perfomed in the years 2006 to 2011. RESULTS: Of 162 patients, 128 patients had anterior circulation stroke, and 34 patients had posterior circulation stroke. Additional treatment with tirofiban was given to 30 of 128 patients with anterior circulation stroke and to 20 of 34 patients with posterior circulation stroke. Treatment with tirofiban did not influence recanalization rates. Fatal intracerebral hemorrhage occurred more frequently in tirofiban-treated patients in the entire cohort (12.0% vs 2.7%; P=0.03) and in tirofiban-treated patients with anterior circulation stroke (13.3% vs 3.1%; P=0.05). Logistic regression found age (odds ratio, 1.17; 95% confidence interval, 1.00-1.37; P=0.05) and tirofiban treatment (odds ratio, 3.03; 95% confidence interval, 1.50-4.05; P=0.04) to be independent predictors for fatal intracerebral hemorrhage. Tirofiban treatment was also an independent predictor for poor outcome (odds ratio, 6.60; 95% confidence interval, 1.06-41.52; P=0.04) in addition to National Institute of Health Stroke Scale (odds ratio, 1.08; 95% confidence interval, 1.00-1.17; P=0.05). CONCLUSIONS: In endovascular stroke therapy, additional treatment with the glycoprotein-IIb/IIIa inhibitor tirofiban is associated with increased risk of fatal intracerebral hemorrhage and poor outcome. PMID- 23463756 TI - Letter by Bruno and Switzer regarding article, "Prestroke modified Rankin Stroke Scale has moderate interobserver reliability and validity in an acute stroke setting". PMID- 23463757 TI - Low plasma arginine:asymmetric dimethyl arginine ratios predict mortality after intracranial aneurysm rupture. AB - BACKGROUND: Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, predicts mortality in cardiovascular disease and has been linked to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). In this prospective study, we assessed whether circulating ADMA, arginine:ADMA ratio, and nitrite/nitrate levels were associated with survival and cerebral vasospasm in SAH patients. METHODS: One hundred and eleven patients were observed day 1 to 15 after SAH, with serial measurements of transcranial Doppler flow velocities (VMCA) and plasma biomarkers. Clinical status was assessed by the World Federation of Neurosurgical Societies grading scale. RESULTS: Overall 30 day mortality was 18%, but differed between patients grouped by low, midrange, and high arginine:ADMA ratio in the first week after SAH. Mortality rates were 14/37, 1/37, and 5/37 in the 3 groups, respectively (P-logrank=0.0003). Cox regression showed that low versus midrange or high arginine:ADMA was associated with a hazard ratio of 4.1 independent of World Federation of Neurosurgical Societies grade (95% confidence interval, 1.5-10.9; P=0.006). ADMA or arginine:ADMA had no association to VMCA, but there was an inverse relationship between VMCA and nitrite/nitrate levels (P<0.0001). The NOS3 894G/G genotype was associated with 15% lower VMCA (P=0.01). ATbG-NOS3 haplotype homozygosity was associated with up to 64% higher nitrite/nitrate levels (P=0.003). CONCLUSIONS: This study suggests that plasma arginine:ADMA ratios predict mortality after SAH. Both clinical and physiological measures of changes in cerebral hemodynamics are coupled to the nitric oxide system. PMID- 23463758 TI - De novo and recurrent aneurysms in pediatric patients with cerebral aneurysms. AB - BACKGROUND AND PURPOSE: Long-term angiographic follow-up studies on pediatric aneurysm patients are scarce. METHODS: We gathered long-term clinical and angiographic follow-up data on all pediatric aneurysm patients (<= 18 years at diagnosis) treated at the Department of Neurosurgery, Helsinki University Central Hospital, between 1937 and 2009. RESULTS: Fifty-nine patients with cerebral aneurysms in childhood had long-term clinical and radiological follow-up (median, 34 years; range, 4-56 years). Twenty-four patients (41%) were diagnosed with altogether 25 de novo and 11 recurrent aneurysms, with 9 (25%) of the aneurysms being symptomatic. New subarachnoid hemorrhage occurred in 7 patients; 4 of these patients died. Eight patients (33%) had multiple new aneurysms. The annual rate of hemorrhage was 0.4%, and the annual rate for the development of de novo or recurrent aneurysm was 1.9%. There were no de novo aneurysms in 7 patients with previously unruptured aneurysms. However, 1 recurrent aneurysm was diagnosed. Current and previous smoking (risk ratio, 2.44; 95% confidence interval, 1.07 5.55) was the only statistically significant risk factor for de novo and recurrent aneurysm formation in patients with previous subarachnoid hemorrhage, whereas hypertension, sex, or age at onset had no statistically significant effect. Smoking was also a statistically significant risk factor for new subarachnoid hemorrhage. CONCLUSIONS: Patients with ruptured intracranial aneurysms in childhood have a high risk for new aneurysms and new subarachnoid hemorrhage, especially if they start to smoke as adults. Life-long angiographic follow-up is mandatory. PMID- 23463759 TI - Recent advances in the study of testicular nuclear receptor 4. AB - Testicular nuclear receptor 4 (TR4), also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2), is a transcriptional factor and a member of the nuclear receptor family. TR4 was initially cloned from human and rat hypothalamus, prostate, and testes libraries. For almost two decades, its specific tissue distribution, genomic organization, and chromosomal assignment have been well investigated in humans and animals. However, it has been very difficult to study TR4's physiological functions due to a lack of specific ligands. Gene knock-out animal techniques provide an alternative approach for defining the biological functions of TR4. In vivo studies of TR4 gene knockout mice (TR4(-/-)) found that they display severe spinal curvature, subfertility, premature aging, and prostate prostatic intraepithelial neoplasia (PIN) development. Upstream modulators, downstream target gene regulation, feedback mechanisms, and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been identified in studies using the TR4( /-) phenotype. With the establishment of a tissue-specific TR4(-/-) mouse model, research on TR4 will be more convenient in the future. PMID- 23463760 TI - Dual liver transplantation. AB - Reperfusion is the key strategy in acute ST-segment elevation myocardial infarction (STEMI) care, and it is time-dependent. Shortening the time from symptom to reperfusion and choosing the optimal reperfusion strategy for STEMI patients are great challenges in practice. We need to improve upon the problems of low reperfusion rate, non-standardized treatment, and economic burden in STEMI care. This article briefly reviews the current status of reperfusion strategy in STEMI care, and also introduces what we will do to bridge the gap between the guidelines and implementation in the clinical setting through the upcoming China STEMI early reperfusion program. PMID- 23463761 TI - Pancreatic cystic neoplasms: a review of preoperative diagnosis and management. AB - Pancreatic cystic neoplasms (PCNs) are a diverse group of neoplasms in the pancreas, and are more increasingly encountered with widespread abdominal screening and improved imaging techniques. The most common types of PCNs are serous cystic neoplasms (SCNs), mucinous cystic neoplasms (MCNs), and intraductal papillary mucinous neoplasms (IPMNs). Clinicians frequently feel bewildered in the differential diagnosis and subsequent management among the various types of lesions in the pancreas, which may lead to overtreatment or delayed treatment. The current review provides recent developments in the understanding of the three most common types of PCNs, the latest modalities used in preoperative diagnosis and differential diagnosis, as well as the most up to date management. Suggestions for diagnosis and differential diagnosis of SCNs, MCNs, and IPMNs are also provided for young surgeons. Better understanding of these neoplasms is essential for clinicians to make accurate diagnosis and to provide the best management for patients. PMID- 23463762 TI - Is there a real diagnostic impact of elastosonography and contrast-enhanced ultrasonography in the management of thyroid nodules? AB - Ultrasonography (US) and the new applications US elastography (USE) and contrast enhanced US (CEUS) are used in the screening of thyroid nodules, for which fine needle aspiration biopsy (FNAB) is the best single diagnostic test. The aim of the study was to compare the sensitivity, specificity, positive predictive value (PPV), and accuracy of the four examinations in nodules with cytological and histological diagnoses. The study used data from US, FNAB, USE (elasticity (ELX 2/1) index), and CEUS (Peak index and time to peak (TTP) index) evaluated in 73 thyroid nodules in 63 consecutive patients likely to undergo surgery. Cytological histological correlation was available for 38 nodules. No correlation emerged between nodule size and cytological results. A significant (P=0.03) positive correlation between cumulative US findings and cytological results was found. In addition, significant correlations between cumulative US findings and cytology (P=0.02) and between cumulative US findings and histology (P<0.0001) were found. US showed the best specificity and PPV, and FNAB the best sensitivity. There was no significant difference in the ELX 2/1 index, Peak index, or TTP index among nodules subdivided according to cytological scores. No significant correlation was found between ELX 2/1 index, Peak index, and TTP index, on the one hand, and nodule size, US cumulative findings, cytology, and histology on the other hand. The sensitivity of the ELX 2/1 index was high, but its specificity was very low. The accuracy and PPV of USE were lower than those of the other procedures. Only the correlation between Peak index and cumulative US findings reached a value close to significance. Our ultimate aim is to minimise unnecessary thyroidectomy. US and FNAB continue to play a central diagnostic role. The use of a US score showed high specificity and PPV. The specificity of FNAB was low in this selected series because of the numbers of indeterminate cytological responses. USE and CEUS are innovative techniques that need to be standardized. The ELX 2/1 index, Peak index, and TTP index seem to be unrelated to histology. The best statistical data on USE and CEUS concerned their sensitivity and PPV, respectively. At present, USE and CEUS are too time-consuming and of limited utility in selecting patients for surgery. PMID- 23463763 TI - Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population. AB - OBJECTIVE: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). METHODS: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. RESULTS: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. CONCLUSIONS: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum. PMID- 23463765 TI - Endostatin inhibits hypertrophic scarring in a rabbit ear model. AB - OBJECTIVE: The present study was designed to use an in vivo rabbit ear scar model to investigate the efficacy of systemic administration of endostatin in inhibiting scar formation. METHODS: Eight male New Zealand white rabbits were randomly assigned to two groups. Scar model was established by making six full skin defect wounds in each ear. For the intervention group, intraperitoneal injection of endostatin was performed each day after the wound healed (about 15 d post wounding). For the control group, equal volume of saline was injected. Thickness of scars in each group was measured by sliding caliper and the scar microcirculatory perfusion was assessed by laser Doppler flowmetry on Days 15, 21, 28, and 35 post wounding. Rabbits were euthanatized and their scars were harvested for histological and proteomic analyses on Day 35 post wounding. RESULTS: Macroscopically, scars of the control group were thicker than those of the intervention group. Significant differences between the two groups were observed on Days 21 and 35 (p<0.05). Scar thickness, measured by scar elevation index (SEI) at Day 35 post wounding, was significantly reduced in the intervention group (1.09+/-0.19) compared with the controls (1.36+/-0.28). Microvessel density (MVD) observed in the intervention group (1.73+/-0.94) was significantly lower than that of the control group (5.63+/-1.78) on Day 35. The distribution of collagen fibers in scars treated with endostatin was relatively regular, while collagen fibers in untreated controls were thicker and showed disordered alignment. Western blot analysis showed that the expressions of type I collagen and Bcl-2 were depressed by injection of endostatin. CONCLUSIONS: Our results from the rabbit ear hypertrophic scar model indicate that systemic application of endostatin could inhibit local hypertrophic scar formation, possibly through reducing scar vascularization and angiogenesis. Our results indicated that endostatin may promote the apoptosis of endothelial cells and block their release of platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), thereby controlling collagen production by fibroblasts. Blood vessel-targeted treatment may be a promising strategy for scar therapy. PMID- 23463764 TI - Characterization of cancer stem-like cells in the side population cells of human gastric cancer cell line MKN-45. AB - OBJECTIVE: Side population (SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer. Many kinds of cell lines and tissues have demonstrated the presence of SP cells, including several gastric cancer cell lines. This study is aimed to identify the cancer stem-like cells in the SP of gastric cancer cell line MKN-45. METHODS: We used fluorescence activated cell sorting (FACS) to sort SP cells in the human gastric carcinoma cell line MKN-45 (cells labeled with Hoechst 33342) and then characterized the cancer stem-like properties of SP cells. RESULTS: This study found that the SP cells had higher clone formation efficiency than major population (MP) cells. Five stemness related gene expression profiles, including OCT-4, SOX-2, NANOG, CD44, and adenosine triphosphate (ATP)-binding cassette transporters gene ABCG2, were tested in SP and MP cells using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Western blot was used to show the difference of protein expression between SP and MP cells. Both results show that there was significantly higher protein expression in SP cells than in MP cells. When inoculated into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, SP cells show higher tumorigenesis tendency than MP cells. CONCLUSIONS: These results indicate that SP cells possess cancer stem cell properties and prove that SP cells from MKN-45 are gastric cancer stem-like cells. PMID- 23463766 TI - Periodontal status and associated risk factors among childbearing age women in Cixi City of China. AB - OBJECTIVE: To investigate the periodontal status and associated risk factors among women of childbearing age to increase the awareness of oral health. METHODS: The study was conducted on childbearing age women in Cixi, a city in Zhejiang Province in the southeast of China. A total of 754 women participated in periodontal examination while receiving prenatal care. Data of the women were collected from the Cixi Family Planning Commission and during an interview. Clinical periodontal indices, such as bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL) were measured during the examination. Statistical analysis on subject-based data was performed. RESULTS: The prevalence of periodontal disease among childbearing age women in Cixi was high (84.7%). A significant association was found between the disease and educational level, pregnancy, taking oral contraceptives, stress, alcohol consumption, overweight, dental visit, and teeth brushing (P<0.05). Women who suffered periodontal disease showed deep PD, obvious BOP, and clinical attachment loss. Among this population, pregnancy was closely associated with higher BOP percentage; teeth brushing no more than once per day or brushing for less than 1 min (P<0.001) after adjusting for age and stress. CONCLUSIONS: The periodontal status of childbearing age women in Cixi needs to be improved urgently. Attention towards the periodontal health should be warranted, especially for those in special statuses and with poor awareness. PMID- 23463767 TI - Prevalence of sensitization to weed pollens of Humulus scandens, Artemisia vulgaris, and Ambrosia artemisiifolia in northern China. AB - OBJECTIVE: Weed pollens are common sources of allergens worldwide. The prevalence of weed pollen sensitization is not yet fully known in China. The purpose of this study was to investigate the prevalence of sensitization to weed allergens from Artemisia, Ambrosia, and Humulus in northern China. METHODS: A total of 1144 subjects (aged from 5 to 68 years) visiting our clinic from June to October 2011 underwent intradermal testing using a panel of 25 allergen sources. Subjects with positive skin responses to any pollen were further tested for their serum concentrations of IgE antibodies against Artemisia vulgaris, Ambrosia artemisiifolia, and Humulus scandens, and against the purified allergens, Art v 1 and Amb a 1. RESULTS: Of 1144 subjects, 170 had positive intradermal reactions to pollen and 144 donated serum for IgE testing. The prevalence of positive intradermal responses to pollens of Artemisia sieversiana, Artemisia annua, A. artemisiifolia, and H. scandens was 11.0%, 10.2%, 3.7%, and 6.6%, respectively. Among the intradermal positive subjects, the prevalence of specific IgE antigens to A. vulgaris was 58.3%, to A. artemisiifolia 14.7%, and to H. scandens 41.0%. The prevalence of specific IgE antigens to the allergen Art v 1 was 46.9%, and to Amb a 1 was 11.2%. The correlation between the presence of IgE antibodies specific to A. vulgaris and to the Art v 1 antigen was very high. Subjects with A. artemisiifolia specific IgE also had A. vulgaris specific IgE, but with relatively high levels of A. vulgaris IgE antibodies. There were no correlations between the presence of IgE antibodies to H. scandens and A. vulgaris or to H. scandens and A. artemisiifolia. CONCLUSIONS: The intradermal prevalence of weed pollen sensitization among allergic subjects in northern China is about 13.5%. Correlations of specific IgE antibodies suggest that pollen allergens from Artemisia and Humulus are independent sources for primary sensitization. PMID- 23463768 TI - Anethum graveolens Linn. (dill) extract enhances the mounting frequency and level of testicular tyrosine protein phosphorylation in rats. AB - OBJECTIVE: To investigate the effect of Anethum graveolens (AG) extracts on the mounting frequency, histology of testis and epididymis, and sperm physiology. METHODS: Male rats induced by cold immobilization before treating with vehicle or AG extracts [50, 150, and 450 mg/kg body weight (BW)] via gastric tube for consecutive 1, 7, and 14 d were examined for mounting frequency, testicular phosphorylation level by immunoblotting, sperm concentration, sperm acrosome reaction, and histological structures of testis and epididymis, respectively. RESULTS: AG (50 mg/kg BW) significantly increased the mounting frequency on Days 1 and 7 compared to the control group. Additionally, rat testis treated with 50 mg/kg BW AG showed high levels of phosphorylated proteins as compared with the control group. In histological analyses, AG extract did not affect the sperm concentration, acrosome reaction, and histological structures of testis and epididymis. CONCLUSIONS: AG extract enhances the aphrodisiac activity and is not harmful to sperm and male reproductive organs. PMID- 23463769 TI - Effects of huangqi and bear bile on recurrent parotitis in children: a new clinical approach. AB - OBJECTIVE: To evaluate the pharmacological effects of traditional Chinese medicine, bear bile capsule and Huangqi granule, on recurrent parotitis in children. METHODS: In this prospective, controlled, and randomized study, a total of 151 young children were divided into three groups: Group A included massaging the children's parotid region and melting vitamin C in their mouth daily; Group B included swallowing bear bile capsule and Huangqi granule daily; and Group C included massages and vitamin C as prescribed in Group A, and traditional Chinese medicine as prescribed in Group B. Children were treated individually for one month and then a follow-up study was conducted for 1 to 3.5 years. Analysis of variance (ANOVA) and Ridit analysis were employed for statistical analysis. RESULTS: The recurrence rate decreased in every group, but was significantly more in Groups B and C when compared to Group A. The recurrences significantly decreased (P<0.01) in Group B and their recovery rate was as high as 63%, significantly better than those of the other groups (P<0.01). CONCLUSIONS: Huangqi and bear bile could be a novel clinical approach for treating recurrent parotitis in children. PMID- 23463771 TI - Liquid chromatography-tandem mass spectrometry method for simultaneous quantification of urapidil and aripiprazole in human plasma and its application to human pharmacokinetic study. AB - A sensitive and selective liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for simultaneous determination of urapidil and aripiprazole in human plasma. A simple liquid-liquid extraction with ethyl acetate was used for the sample preparation. Chromatographic separation was achieved on a Phenomenex C18 (4.6 * 50 mm, 5 um) column with 0.1% formic acid acetonitrile (10:90, v/v) as the mobile phase with flow rate of 0.6 mL/min. The quantitation of the target compounds was determined in a positive ion multiple reaction monitoring mode. Calibration plots were linear over the range of 2.0 2503.95 ng/mL for urapidil and 1.0-500.19 ng/mL for aripiprazole. The lower limit of quantitation for urapidil and aripiprazole was 2.0 and 1.0 ng/mL, respectively. Mean recovery was in the range of 69.94-75.62% for both analytes and internal standards. Intra-day and inter-day precisions of the assay at three concentrations were 2.56-5.89% with accuracy of 92.31-97.83% for urapidil, and 3.14-6.84% with accuracy of 91.38-94.42% for aripiprazole. The method was successfully applied to human pharmacokinetic study of urapidil and aripiprazole in healthy human male volunteers. PMID- 23463770 TI - New quantitative trait loci for carotid atherosclerosis identified in an intercross derived from apolipoprotein E-deficient mouse strains. AB - Carotid atherosclerosis is the primary cause of ischemic stroke. To identify genetic factors contributing to carotid atherosclerosis, we performed quantitative trait locus (QTL) analysis using female mice derived from an intercross between C57BL/6J (B6) and BALB/cJ (BALB) apolipoprotein E (Apoe(-/-)) mice. We started 266 F(2) mice on a Western diet at 6 wk of age and fed them the diet for 12 wk. Atherosclerotic lesions in the left carotid bifurcation and plasma lipid levels were measured. We genotyped 130 microsatellite markers across the entire genome. Three significant QTLs, Cath1 on chromosome (Chr) 12, Cath2 on Chr5, and Cath3 on Chr13, and four suggestive QTLs on Chr6, Chr9, Chr17, and Chr18 were identified for carotid lesions. The Chr6 locus replicated a suggestive QTL and was named Cath4. Six QTLs for HDL, three QTLs for non-HDL cholesterol, and three QTLs for triglyceride were found. Of these, a significant QTL for non HDL on Chr1 at 60.3 cM, named Nhdl13, and a suggestive QTL for HDL on ChrX were new. A significant locus for HDL (Hdlq5) was overlapping with a suggestive locus for carotid lesions on Chr9. A significant correlation between carotid lesion sizes and HDL cholesterol levels was observed in the F(2) population (R = -0.153, P = 0.0133). Thus, we have identified several new QTLs for carotid atherosclerosis and the locus on Chr9 may exert effect through interactions with HDL. PMID- 23463772 TI - Effects of balance training on functional outcome after total knee replacement in patients with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of additional balance training on mobility and function outcome in patients with knee osteoarthritis after total knee replacement. DESIGN: A prospective intervention study and randomized controlled trial. SETTING: A university-based teaching hospital. PARTICIPANTS: Patients who received total knee replacement surgery were recruited sequentially from the orthopedic department. They were randomly assigned to either the experimental group or control group. INTERVENTIONS: The control group received conventional function training for eight weeks. The experimental group not only received the same conventional training as the control group, but also received additional balance exercises in each admission. MAIN OUTCOME MEASURES: Before and after training we took the following measurements: distance of functional forward reach; duration of single leg stance; timed sit-to-stand test; timed up-and-down stair test; timed 10-m walk; timed up-and-go test; and the Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: 58 patients in the experimental group with a mean (SD) age of 71.4 (6.6) years and 55 in the control group with mean (SD) age of 72.9 (7.3) years, completed the study. After eight weeks intervention with additional balance exercises, the experimental group demonstrated significant changes in 10-m walk (P < 0.001, 95% confidence interval (CI): 3.6 to 4.4 seconds) and in timed up-and-go (P < 0.001, 95% confidence interval: 2.6 to 3.4 seconds) tests. Significant changes of all other measures and Western Ontario and McMaster Universities Osteoarthritis Index score were also observed in the experimental group (all P < 0.001). CONCLUSION: Additional balance training exerted a significant beneficial effect on the function recovery and mobility outcome in patients with knee osteoarthritis after total knee replacement. PMID- 23463773 TI - Allosteric regulation of transport activity by heterotrimerization of Arabidopsis ammonium transporter complexes in vivo. AB - Ammonium acquisition by plant roots is mediated by AMMONIUM TRANSPORTERs (AMTs), ubiquitous membrane proteins with essential roles in nitrogen nutrition in all organisms. In microbial and plant cells, ammonium transport activity is controlled by ammonium-triggered feedback inhibition to prevent cellular ammonium toxicity. Data from heterologous expression in yeast indicate that oligomerization of plant AMTs is critical for allosteric regulation of transport activity, in which the conserved cytosolic C terminus functions as a trans activator. Employing the coexpressed transporters AMT1;1 and AMT1;3 from Arabidopsis thaliana as a model, we show here that these two isoforms form functional homo- and heterotrimers in yeast and plant roots and that AMT1;3 carrying a phosphomimic residue in its C terminus regulates both homo- and heterotrimers in a dominant-negative fashion in vivo. (15)NH4(+) influx studies further indicate that allosteric inhibition represses ammonium transport activity in roots of transgenic Arabidopsis expressing a phosphomimic mutant together with functional AMT1;3 or AMT1;1. Our study demonstrates in planta a regulatory role in transport activity of heterooligomerization of transporter isoforms, which may enhance their versatility for signal exchange in response to environmental triggers. PMID- 23463775 TI - Genomic distribution of maize facultative heterochromatin marked by trimethylation of H3K27. AB - Trimethylation of histone H3 Lys-27 (H3K27me3) plays a critical role in regulating gene expression during plant and animal development. We characterized the genome-wide distribution of H3K27me3 in five developmentally distinct tissues in maize (Zea mays) plants of two genetic backgrounds, B73 and Mo17. There were more substantial differences in the genome-wide profile of H3K27me3 between different tissues than between the two genotypes. The tissue-specific patterns of H3K27me3 were often associated with differences in gene expression among the tissues and most of the imprinted genes that are expressed solely from the paternal allele in endosperm are targets of H3K27me3. A comparison of the H3K27me3 targets in rice (Oryza sativa), maize, and Arabidopsis thaliana provided evidence for conservation of the H3K27me3 targets among plant species. However, there was limited evidence for conserved targeting of H3K27me3 in the two maize subgenomes derived from whole-genome duplication, suggesting the potential for subfunctionalization of chromatin regulation of paralogs. Genomic profiling of H3K27me3 in loss-of-function mutant lines for Maize Enhancer of zeste-like2 (Mez2) and Mez3, two of the three putative H3K27me3 methyltransferases present in the maize genome, suggested partial redundancy of this gene family for maintaining H3K27me3 patterns. Only a portion of the targets of H3K27me3 required Mez2 and/or Mez3, and there was limited evidence for functional consequences of H3K27me3 at these targets. PMID- 23463774 TI - MAP18 regulates the direction of pollen tube growth in Arabidopsis by modulating F-actin organization. AB - For fertilization to occur in plants, the pollen tube must be guided to enter the ovule via the micropyle. Previous reports have implicated actin filaments, actin binding proteins, and the tip-focused calcium gradient as key contributors to polar growth of pollen tubes; however, the regulation of directional pollen tube growth is largely unknown. We reported previously that Arabidopsis thaliana MICROTUBULE-ASSOCIATED PROTEIN18 (MAP18) contributes to directional cell growth and cortical microtubule organization. The preferential expression of MAP18 in pollen and in pollen tubes suggests that MAP18 also may function in pollen tube growth. In this study, we demonstrate that MAP18 functions in pollen tubes by influencing actin organization, rather than microtubule assembly. In vitro biochemical results indicate that MAP18 exhibits Ca(2+)-dependent filamentous (F) actin-severing activity. Abnormal expression of MAP18 in map18 and MAP18 OX plants was associated with disorganization of the actin cytoskeleton in the tube apex, resulting in aberrant pollen tube growth patterns and morphologies, inaccurate micropyle targeting, and fewer fertilization events. Experiments with MAP18 mutants created by site-directed mutagenesis suggest that F-actin-severing activity is essential to the effects of MAP18 on pollen tube growth direction. Our study demonstrates that in Arabidopsis, MAP18 guides the direction of pollen tube growth by modulating actin filaments. PMID- 23463777 TI - Subtalar distraction arthrodesis using fresh-frozen allogeneic femoral head augmented with local autograft. AB - BACKGROUND: Tricortical autograft has been commonly used in subtalar distraction arthrodesis (SDA) for severe calcaneal malunion. Structural allograft enriched with orthobiological agents is an alternative. This study was performed to evaluate the results of SDA using fresh-frozen allogeneic femoral head without the addition of orthobiological agents. MATERIALS AND METHODS: We retrospectively reviewed 15 consecutive SDA procedures (13 patients) with allogeneic femoral head augmented with local autograft for the treatment of severe calcaneal malunion. Clinical outcome was evaluated with the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, visual analog scale (VAS) pain score, Short Form-12 (SF-12), range of motion (ROM) of the ankle joint, and patient satisfaction rate. Radiographic assessment included the talar declination angle (TDA), calcaneal inclination angle (CIA), lateral talocalcaneal angle (LTCA), heel height, calcaneal length, and union time. RESULTS: At a median follow-up of 36.0 months (range, 24-47 months), all 15 feet (100%) achieved union, at a median of 13.0 weeks (range, 12-18 weeks). The AOFAS score and VAS pain score improved significantly, with a satisfaction rate of 93.3%. The TDA, CIA, LTCA, and heel height improved significantly. The median increase in heel height was 8.6 mm (range, 1.9-20.1 mm). There was a significant reduction in calcaneal length. Complications included 1 varus malalignment, 1 complex regional pain syndrome, 1 hardware irritation, and 1 sural neuralgia. CONCLUSION: This study found that SDA using fresh-frozen femoral head allograft without an orthobiological agent was cost-effective and may have outcomes comparable to those using autograft or allograft enriched with orthobiological agents. PMID- 23463776 TI - Empty pericarp5 encodes a pentatricopeptide repeat protein that is required for mitochondrial RNA editing and seed development in maize. AB - In flowering plants, RNA editing is a posttranscriptional mechanism that converts specific cytidines to uridines in both mitochondrial and plastidial transcripts, altering the information encoded by these genes. Here, we report the molecular characterization of the empty pericarp5 (emp5) mutants in maize (Zea mays). Null mutation of Emp5 results in abortion of embryo and endosperm development at early stages. Emp5 encodes a mitochondrion-targeted DYW subgroup pentatricopeptide repeat (PPR) protein. Analysis of the mitochondrial transcripts revealed that loss of the EMP5 function abolishes the C-to-U editing of ribosomal protein L16 at the rpl16-458 site (100% edited in the wild type), decreases the editing at nine sites in NADH dehydrogenase9 (nad9), cytochrome c oxidase3 (cox3), and ribosomal protein S12 (rps12), and surprisingly increases the editing at five sites of ATP synthase F0 subunit a (atp6), apocytochrome b (cob), nad1, and rpl16. Mutant EMP5-4 lacking the E+ and DYW domains still retains the substrate specificity and editing function, only at reduced efficiency. This suggests that the E+ and DYW domains of EMP5 are not essential to the EMP5 editing function but are necessary for efficiency. Analysis of the ortholog in rice (Oryza sativa) indicates that rice EMP5 has a conserved function in C-to-U editing of the rice mitochondrial rpl16-458 site. EMP5 knockdown expression in transgenics resulted in slow growth and defective seeds. These results demonstrate that Emp5 encodes a PPR-DYW protein that is required for the editing of multiple transcripts in mitochondria, and the editing events, particularly the C-to-U editing at the rpl16-458 site, are critical to the mitochondrial functions and, hence, to seed development in maize. PMID- 23463778 TI - Cannulated screw delivery of bone marrow aspirate concentrate to a stress fracture nonunion: technique tip. PMID- 23463779 TI - A prospective pilot study of B2A-coated ceramic granules (Amplex) compared to autograft for ankle and hindfoot arthrodesis. AB - BACKGROUND: To reduce fusion nonunion, autogenous bone graft is often incorporated into foot and ankle fusion procedures. B2A peptide-coated ceramic granules, with encouraging results in pilot studies of transforaminal lumbar interbody fusion, were here reformulated into Amplex with a coating concentration of 225 MUg B2A/cm(3) ceramic granules (B2A-granule) with the goal of eliminating autogenous bone graft in foot and ankle arthrodesis. The purpose of this study was to perform a multicenter prospective randomized pilot clinical trial designed to compare the safety and effectiveness of B2A-granule to autogenous bone graft in patients undergoing foot and ankle arthrodesis surgery. METHODS: This study was a multicenter, prospective, randomized, pilot clinical trial designed to compare safety and effectiveness of B2A-granule to autogenous bone graft in patients undergoing foot and ankle arthrodesis surgery. Twenty-four patients were enrolled and randomized (1:1) into 2 groups: autogenous bone graft control and B2A-granule. Primary outcome measures at 6 months (with follow-up at 9 and 12 months) included radiographic fusion assessed by computerized tomography and Ankle Osteoarthritis Scale scores for pain and disability. RESULTS: Radiographic fusion success rates were similar in both groups (100% in the B2A-granule group, 92% autograft). Both the B2A-granule group and the autograft group had improvements in the pain and disability scores over the course of the study. Graft harvest-site pain affected only autograft-treated patients. There were no adverse events attributed to the graft material in either the B2A-granule or autograft group. CONCLUSION: The results of this pilot study are supportive of a larger clinical trial to assess the safety and efficacy of B2A-granule as a bone graft substitute in foot and ankle fusions. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 23463780 TI - Midterm results and complications after minimally invasive distal metatarsal osteotomy for treatment of hallux valgus. AB - BACKGROUND: Minimally invasive distal metatarsal osteotomy (MIDMO) is a common technique used to correct the hallux valgus deformity, but controversy remains regarding the expected outcomes of this surgery. METHODS: Seventy-two patients (85 feet) suffering from hallux valgus underwent MIDMO with a modified Bosch technique. Patients were prospectively evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) hallux score, and the AOFAS recovery rate was calculated. Before surgery and at follow-up, the hallux valgus (HVA), intermetatarsal (IMA), and distal metatarsal articular (DMAA) angles were measured, and the severity of disease was categorized according to the preoperative HVA. The tibial sesamoid position and articular congruence were evaluated. Postoperative complications were noted. RESULTS: After an average follow-up of 73.3 +/- 38.1 months, the total AOFAS score improved from 47.6 +/- 13.3 to 87.3 +/- 11.5 (P < .001). The HVA decreased from 34.7 +/- 8.2 to 14.8 +/- 7.8 degrees, the IMA from 14.7 +/- 4 to 6.6 +/- 3.6 degrees, and the DMAA from 20.9 +/- 9.8 to 9 +/- 6.6 degrees (P < .001 for all). Postoperative improvement in AOFAS was inversely related to the preoperative severity of disease (P < .001, beta = -.378). Sixteen (18.8%) deformity recurrences were noted, 9 of which were observed in patients with preoperative HVA more than 40 degrees. Worse preoperative congruence of the metatarsophalangeal joint and tibial sesamoid position correlated with a higher rate of recurrence of the disease after surgery (P = .001, beta = -.353 and P < .001, beta = .427, respectively). CONCLUSIONS: Satisfactory clinical and radiological results can be expected after MIDMO, but caution should be exercised when using this technique because of the likelihood of possible complications (29.4% overall complication rate). Predictors of surgical outcomes can be used to select the best candidates for this surgery. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23463781 TI - In vivo visualizations of drought-induced embolism spread in Vitis vinifera. AB - Long-distance water transport through plant xylem is vulnerable to hydraulic dysfunction during periods of increased tension on the xylem sap, often coinciding with drought. While the effects of local and systemic embolism on plant water transport and physiology are well documented, the spatial patterns of embolism formation and spread are not well understood. Using a recently developed nondestructive diagnostic imaging tool, high-resolution x-ray computed tomography, we documented the dynamics of drought-induced embolism in grapevine (Vitis vinifera) plants in vivo, producing the first three-dimensional, high resolution, time-lapse observations of embolism spread. Embolisms formed first in the vessels surrounding the pith at stem water potentials of approximately -1.2 megapascals in drought experiments. As stem water potential decreased, embolisms spread radially toward the epidermis within sectored vessel groupings via intervessel connections and conductive xylem relays, and infrequently (16 of 629 total connections) through lateral connections into adjacent vessel sectors. Theoretical loss of conductivity calculated from the high-resolution x-ray computed tomography images showed good agreement with previously published nuclear magnetic resonance imaging and hydraulic conductivity experiments also using grapevine. Overall, these data support a growing body of evidence that xylem organization is critically important to the isolation of drought-induced embolism spread and confirm that air seeding through the pit membranes is the principle mechanism of embolism spread. PMID- 23463782 TI - Arabidopsis and Brachypodium distachyon transgenic plants expressing Aspergillus nidulans acetylesterases have decreased degree of polysaccharide acetylation and increased resistance to pathogens. AB - The plant cell wall has many significant structural and physiological roles, but the contributions of the various components to these roles remain unclear. Modification of cell wall properties can affect key agronomic traits such as disease resistance and plant growth. The plant cell wall is composed of diverse polysaccharides often decorated with methyl, acetyl, and feruloyl groups linked to the sugar subunits. In this study, we examined the effect of perturbing cell wall acetylation by making transgenic Arabidopsis (Arabidopsis thaliana) and Brachypodium (Brachypodium distachyon) plants expressing hemicellulose- and pectin-specific fungal acetylesterases. All transgenic plants carried highly expressed active Aspergillus nidulans acetylesterases localized to the apoplast and had significant reduction of cell wall acetylation compared with wild-type plants. Partial deacetylation of polysaccharides caused compensatory up regulation of three known acetyltransferases and increased polysaccharide accessibility to glycosyl hydrolases. Transgenic plants showed increased resistance to the fungal pathogens Botrytis cinerea and Bipolaris sorokiniana but not to the bacterial pathogens Pseudomonas syringae and Xanthomonas oryzae. These results demonstrate a role, in both monocot and dicot plants, of hemicellulose and pectin acetylation in plant defense against fungal pathogens. PMID- 23463783 TI - Thylakoid terminal oxidases are essential for the cyanobacterium Synechocystis sp. PCC 6803 to survive rapidly changing light intensities. AB - Cyanobacteria perform photosynthesis and respiration in the thylakoid membrane, suggesting that the two processes are interlinked. However, the role of the respiratory electron transfer chain under natural environmental conditions has not been established. Through targeted gene disruption, mutants of Synechocystis sp. PCC 6803 were generated that lacked combinations of the three terminal oxidases: the thylakoid membrane-localized cytochrome c oxidase (COX) and quinol oxidase (Cyd) and the cytoplasmic membrane-localized alternative respiratory terminal oxidase. All strains demonstrated similar growth under continuous moderate or high light or 12-h moderate-light/dark square-wave cycles. However, under 12-h high-light/dark square-wave cycles, the COX/Cyd mutant displayed impaired growth and was completely photobleached after approximately 2 d. In contrast, use of sinusoidal light/dark cycles to simulate natural diurnal conditions resulted in little photobleaching, although growth was slower. Under high-light/dark square-wave cycles, the COX/Cyd mutant suffered a significant loss of photosynthetic efficiency during dark periods, a greater level of oxidative stress, and reduced glycogen degradation compared with the wild type. The mutant was susceptible to photoinhibition under pulsing but not constant light. These findings confirm a role for thylakoid-localized terminal oxidases in efficient dark respiration, reduction of oxidative stress, and accommodation of sudden light changes, demonstrating the strong selective pressure to maintain linked photosynthetic and respiratory electron chains within the thylakoid membrane. To our knowledge, this study is the first to report a phenotypic difference in growth between terminal oxidase mutants and wild-type cells and highlights the need to examine mutant phenotypes under a range of conditions. PMID- 23463784 TI - A Nostoc punctiforme sugar transporter necessary to establish a Cyanobacterium plant symbiosis. AB - In cyanobacteria-plant symbioses, the symbiotic nitrogen-fixing cyanobacterium has low photosynthetic activity and is supplemented by sugars provided by the plant partner. Which sugars and cyanobacterial sugar uptake mechanism(s) are involved in the symbiosis, however, is unknown. Mutants of the symbiotically competent, facultatively heterotrophic cyanobacterium Nostoc punctiforme were constructed bearing a neomycin resistance gene cassette replacing genes in a putative sugar transport gene cluster. Results of transport activity assays using (14)C-labeled fructose and glucose and tests of heterotrophic growth with these sugars enabled the identification of an ATP-binding cassette-type transporter for fructose (Frt), a major facilitator permease for glucose (GlcP), and a porin needed for the optimal uptake of both fructose and glucose. Analysis of green fluorescent protein fluorescence in strains of N. punctiforme bearing frt::gfp fusions showed high expression in vegetative cells and akinetes, variable expression in hormogonia, and no expression in heterocysts. The symbiotic efficiency of N. punctiforme sugar transport mutants was investigated by testing their ability to infect a nonvascular plant partner, the hornwort Anthoceros punctatus. Strains that were specifically unable to transport glucose did not infect the plant. These results imply a role for GlcP in establishing symbiosis under the conditions used in this work. PMID- 23463785 TI - Preparation of an novel botanic biopreservative and its efficacy in keeping quality of peeled Penaeus vannamei. AB - A novel botanic biopreservative was successfully prepared by the combination of the bamboo leaves extracts and ebony extracts, designated as ebony-bamboo leaves complex extracts (EBLCE), whose antimicrobial activity was assessed according to an inhibition zone method against 10 common pathogenic and spoilage microorganisms. It was found that EBLCE was more effective from all the chosen microorganisms, as compared by potassium sorbate. Due to its excellent antimicrobial activity, and some additional properties like edibility, safety and economy, EBLCE was selected for further study to evaluate the efficacy in prolonging shelf life and improving the quality of peeled Penaeus vannamei during storage at 4 degrees C, based on periodical microbiological, chemical and sensory analysis. As a result, EBLCE was observed to prevent spoilage of peeled P. vannamei efficiently as reflected by a distinct decrease in total viable count, pH and total volatile basic nitrogen, as well as a slower decline in the sensory evaluation scores. Therefore, a prolonged shelf life of 16 days was obtained for EBLCE pre-treated peeled shrimps with comparison of 6 days for the control group, demonstrating EBLCE as a promising alternative for preserving food. PMID- 23463786 TI - Building capacity and capability for patient safety education: a train-the trainers programme for senior doctors. AB - OBJECTIVES: To develop, implement and evaluate a training programme for senior doctors to become faculty leaders for patient safety training. METHODS: Senior doctors were recruited from across 20 hospitals in the North Western Deanery, England, UK. The intervention comprised a half-day course in patient safety theory, root cause analysis and small-group facilitation, following which participants were invited to sign up as faculty for a region-wide patient safety training programme for trainees 'Lessons Learnt'. Course evaluation comprised a prospective longitudinal study conducted in 2010-2012. Patient safety knowledge, attitudes and skills were evaluated pre and post course and retention further evaluated 8 months post course. RESULTS: 216 senior doctors volunteered as faculty of whom 122 were appointed. Participants reported high levels of satisfaction with the course. Objective scores of patient safety knowledge significantly improved immediately post course (MedianPre course=70%, MedianPost course=80%, p<0.001) and were sustained at 8 months (Median8 month post course=90%). Similarly, measures of attitudes and self-reported safety skills also significantly improved post course and were sustained. Upon completion of the course, 88/122 (72%) participants facilitated 213 'Lessons Learnt' sessions from January 2011 to July 2012 (mean 2, range 1-8 sessions per faculty member). Trainee satisfaction with faculty was high. CONCLUSIONS: There is considerable appetite for senior doctors to engage with training in patient safety as teachers and learners. Training senior doctors in patient safety is feasible, acceptable and effective as a means of building capacity and capability for delivering training in this rapidly emerging field. PMID- 23463790 TI - Stress responses at the endometrial-placental interface regulate labyrinthine placental differentiation from trophoblast stem cells. AB - Development can happen in one of two ways. Cells performing a necessary function can differentiate from stem cells before the need for it arises and stress does not develop. Or need arises before function, stress develops and stress signals are part of the normal stimuli that regulate developmental mechanisms. These mechanisms adjust stem cell differentiation to produce function in a timely and proportional manner. In this review, we will interpret data from studies of null lethal mutants for placental stress genes that suggest the latter possibility. Acknowledged stress pathways participate in stress-induced and -regulated differentiation in two ways. These pathways manage the homeostatic response to maintain stem cells during the stress. Stress pathways also direct stem cell differentiation to increase the first essential lineage and suppress later lineages when stem cell accumulation is diminished. This stress-induced differentiation maintains the conceptus during stress. Pathogenic outcomes arise because population sizes of normal stem cells are first depleted by decreased accumulation. The fraction of stem cells is further decreased by differentiation that is induced to compensate for smaller stem cell populations. Analysis of placental lethal null mutant genes known to mediate stress responses suggests that the labyrinthine placenta develops during, and is regulated by, hypoxic stress. PMID- 23463791 TI - Public perception of cancer survival rankings. AB - Past research has observed that certain subgroups (e.g., individuals who are overweight/obese) have inaccurate estimates of survival rates for particular cancers (e.g., colon cancer). However, no study has examined whether the lay public can accurately rank cancer survival rates in comparison with one another (i.e., rank cancers from most deadly to least deadly). A sample of 400 Indiana adults aged 18 to 89 years (M = 33.88 years) completed a survey with questions regarding perceived cancer survival rates. Most cancers were ranked accurately; however, breast and stomach cancer survival rankings were highly distorted such that breast cancer was perceived to be significantly more deadly and stomach cancer significantly less deadly than reality. Younger participants also overestimated the survival rate for pancreatic cancer. These distortions mirror past content analytic work demonstrating that breast, stomach, and pancreatic cancers are misrepresented in the news. PMID- 23463792 TI - Perceived environmental church support and physical activity among Black church members. AB - BACKGROUND: Churches are an appealing setting for implementing health-related behavior change programs. PURPOSE: The objective of the study was to examine the relationship between perceived environmental church support for physical activity (PA) and PA behaviors. METHOD: Black church members from South Carolina (n = 309) wore an Actigraph accelerometer prior to the initiation of an intervention. Relationships between moderate to vigorous PA (MVPA; counts >=1,952), light PA (LPA; counts 100-1951), sedentary behavior (counts <100), and perceived environmental church support for PA (total, spoken informational, written informational, instrumental) were examined. Support * Gender interactions examined whether relationships differed by gender. RESULTS: The mean age was 54.0 +/- 12.3 years and mean body mass index was 32.9 +/- 7.2 kg/m(2). On average, participants engaged in 14.4 +/- 13.7 minutes/day of MVPA, 289.8 +/- 82.4 minutes/day of LPA, and were sedentary 548.9 +/- 102.2 minutes/day. Total, spoken informational, and written informational church support were significantly related to higher levels of LPA and lower levels of sedentary behavior in men but not women. The relationship between written informational support and MVPA approached significance for men but not women. Instrumental church support was not associated with PA behaviors. CONCLUSION: The church environment may have an important influence on Black church members' PA behavior, particularly men's, and thus should be targeted in interventions. PMID- 23463793 TI - Rasch analysis of the General Self-Efficacy Scale in spinal cord injury. AB - This study examined the psychometric properties of the General Self-Efficacy Scale by applying Rasch analysis to data from 102 persons with spinal cord injury. Our results suggest that the General Self-Efficacy Scale is a psychometrically robust instrument suitable for application in a spinal cord injury population. The General Self-Efficacy Scale shows an overall fit to the Rasch model (chi(2) = 15.5, df = 20, p = .75), high reliability (rp = 0.92), ordered response scale structure, and no item bias by gender, age, education, and lesion levels. However, the analyses indicate a ceiling effect and potential to enhance the differentiation of the General Self-Efficacy Scale across self efficacy levels. PMID- 23463794 TI - Photo quiz. To scan or not to scan? PMID- 23463797 TI - Crossing borders: one world, global health. PMID- 23463799 TI - Population genetics and a study of speciation using next-generation sequencing: an educational primer for use with "Patterns of transcriptome divergence in the male accessory gland of two closely related species of field crickets". AB - Understanding evidence for the genetic basis of reproductive isolation is imperative for supporting students' understanding of mechanisms of speciation in courses such as Genetics and Evolutionary Biology. An article by Andres et al. in the February 2013 issue of GENETICS illustrates how advances in DNA sequencing are accelerating studies of population genetics in species with limited genetic and genomic resources. Andres et al. use the latest sequencing technologies to systematically identify and characterize sites in the DNA that vary within, and have diverged between, species to explore speciation in crickets. This primer, coupled with that article, will help instructors introduce and reinforce important concepts in genetics and evolution while simultaneously introducing modern methodology in the undergraduate classroom. Related article in GENETICS: Andres, J. A., E. L. Larson, S. M. Bogdanowicz, and R. G. Harrison, 2013 Patterns of transcriptome divergence in the male accessory gland of two closely related species of field crickets. Genetics 193: 501-513. PMID- 23463802 TI - Explaining the 'immigration advantage' and the 'biculturalism paradox': an application of the theory of demoralization. AB - BACKGROUND: Recent immigrants have better mental health than the natives ('immigration advantage'). Biculturals have better mental health than the monoculturals ('biculturalism paradox'). MATERIAL: Mexican immigrants have lower rates of psychopathology than the U.S. population. This is less true for Cubans and not true for Puerto Ricans. The 'advantage' also occurs in other groups. Biculturals have better mental health and endorse both cultures. DISCUSSION: The theory of demoralization predicts that borrowing values from both cultures and applying them judiciously are more conducive to mental health than indiscriminately subscribing to either culture. CONCLUSION: The findings are consistent with the theory of demoralization. PMID- 23463798 TI - Long noncoding RNAs: past, present, and future. AB - Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years as a potentially new and crucial layer of biological regulation. lncRNAs of all kinds have been implicated in a range of developmental processes and diseases, but knowledge of the mechanisms by which they act is still surprisingly limited, and claims that almost the entirety of the mammalian genome is transcribed into functional noncoding transcripts remain controversial. At the same time, a small number of well-studied lncRNAs have given us important clues about the biology of these molecules, and a few key functional and mechanistic themes have begun to emerge, although the robustness of these models and classification schemes remains to be seen. Here, we review the current state of knowledge of the lncRNA field, discussing what is known about the genomic contexts, biological functions, and mechanisms of action of lncRNAs. We also reflect on how the recent interest in lncRNAs is deeply rooted in biology's longstanding concern with the evolution and function of genomes. PMID- 23463803 TI - Ageism and social integration of older adults in their neighborhoods in Israel. AB - PURPOSE: The article aims to examine the extent to which ageism is connected with the social integration of older adults in their neighborhoods and to identify factors that explain social integration. DESIGN AND METHODS: A convenience sample that included 300 older adults aged 65 and older and 300 younger people under the age of 65 who resided in 3 neighborhoods in Tel-Aviv with varied socioeconomic status were interviewed. Kogan's Attitudes toward Old People scale was used to probe ageism. Social integration index included 3 dimensions: frequency of participation in activities in the neighborhood, familiarity with neighbors, and sense of neighborhood. Hierarchical regression analyses examined 3 groups of independent variables: older adults' sociodemographic characteristics, their perceived health and outdoor mobility, and neighborhoods' characteristics including level of ageism. RESULTS: Neighborhoods varied by levels of ageism and social integration. Higher level of social integration of older neighborhoods' residents was explained by a combination of factors: younger age, better self rated health, and fewer limitations of outdoor mobility, lower levels of ageism reported by a sample of younger respondents, and higher socioeconomic status of the neighborhood. IMPLICATIONS: To enable better social integration, intergeneration programs should be developed to decrease ageism, and in order to make communities more age-friendly, there is need to facilitate accessibility to services and public spaces. PMID- 23463804 TI - Subcutaneous abatacept for the treatment of rheumatoid arthritis. AB - The efficacy, safety and tolerability of i.v. abatacept are well established in patients with active RA. A s.c. abatacept formulation is now available in some countries. Here, we review clinical data for s.c. abatacept. Six trials are presented (Phase II dose-finding study, ACQUIRE, ALLOW, ACCOMPANY, ATTUNE and AMPLE) and issues important to both patients and clinicians are addressed. The primary focus assesses whether the i.v. and s.c. abatacept formulations have similar efficacy, including whether the recommended fixed dose of s.c. abatacept is comparable to the weight-tiered i.v. dosing and whether efficacy is sustained with long-term treatment. Safety and immunogenicity are also discussed, including the short- and long-term safety of s.c. abatacept, and whether immunogenicity is increased following a switch from i.v. to s.c. abatacept, after withdrawal or reintroduction of s.c. abatacept or in the absence of MTX. Year 1 data from the AMPLE study, comparing s.c. abatacept with the TNF antagonist adalimumab, are discussed. Although fewer patient-years of exposure are available for s.c. compared with i.v. abatacept, observations suggest that s.c. abatacept has a similar long-term efficacy to the i.v. formulation, improving the signs, symptoms, disease activity and physical function in patients with RA. With continued treatment, these improvements are maintained over time with high retention rates, similar to i.v. abatacept. s.c. abatacept is associated with low immunogenicity and short- and long-term safety that is consistent with i.v. abatacept. In addition, s.c. abatacept demonstrates comparable efficacy, kinetics of response, safety and radiographic inhibition to adalimumab. PMID- 23463806 TI - Efficacy of ambrisentan in the treatment of digital ulcers in patients with systemic sclerosis: a preliminary study. PMID- 23463805 TI - Urinary free light chain is a potential biomarker for ISN/RPS class III/IV lupus nephritis. AB - OBJECTIVES: To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN. METHODS: Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of kappa-LCs, lambda LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled. RESULTS: Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary lambda-FLC levels were significantly correlated with the urinary protein-creatinine ratio in the class III/IV LN subset (rs = 0.67, P < 0.01). Moreover, the LC-secreting CD19( )/CD138(+) cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138(+) cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary lambda-FLCs could not be detected in any of the patients. CONCLUSION: The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN. PMID- 23463807 TI - 2010 ACR/EULAR classification criteria for rheumatoid arthritis predict increased mortality in patients with early arthritis: results from the Norfolk Arthritis Register. PMID- 23463808 TI - Sustained inflammation of the aortic wall despite tocilizumab treatment in two cases of Takayasu arteritis. PMID- 23463809 TI - Performance of the EuroSCORE models in emergency cardiac surgery. AB - BACKGROUND: Accurate risk-adjustment models are useful for clinical decision making and are important for minimizing any tendency toward risk-averse clinical practice. In cardiac surgery, emergency patients are potentially at greatest risk of inappropriate risk-averse clinical decisions. UK cardiac surgery outcomes are currently risk-adjusted with EuroSCORE models. The objective of this study was to assess the performance of the EuroSCORE models in emergency cardiac surgery. METHODS AND RESULTS: The National Institute for Cardiovascular Outcomes Research database was used to identify adult cardiac surgery procedures performed in the United Kingdom between April 2008 and March 2011. A subset of procedures (July 2010-March 2011) was used for EuroSCORE II validation. The outcome measure was in hospital mortality. Model calibration (Hosmer-Lemeshow test, calibration plots, calculation of calibration intercept and slope) and discrimination (area under receiver-operating characteristic curve [area under the curve]) were assessed. In total, 109 988 cardiac procedures at 41 hospitals were included, of which 3342 were defined as emergency procedures. Compared with performance in all cardiac surgery and nonemergency cardiac surgery, the logistic EuroSCORE and EuroSCORE II models had poorer discrimination (area under the curve, 0.703 and 0.690, respectively) and poorer calibration for emergency surgery. The EuroSCORE risk factors of female sex, chronic pulmonary disease, neurological disease, active endocarditis, unstable angina, recent myocardial infarction, and pulmonary hypertension were not identified as important risk factors for emergency cardiac surgery. CONCLUSIONS: Both EuroSCORE models demonstrated poor calibration and comparatively poor discrimination for emergency cardiac surgery. This has important implications when these models are used for clinical decision making or to adjust governance analyses. PMID- 23463810 TI - Critical care cardiology research: a call to action. PMID- 23463812 TI - Relaxation practice for health in the United States: findings from the National Health Interview Survey. AB - Despite the popularity of relaxation practices as mind-body therapy in the United States, little is known about those who practice these techniques. Using cross sectional data from the 2007 National Health Interview Survey Alternative Medicine Supplement, this study examined potential correlates of engagement in relaxation practices, including sociodemographic characteristics, health behaviors, medical conditions, physical activity, drinking, smoking, and prayer for health. Individuals who engaged in relaxation practices were less likely to be older, male, Hispanic, high income, or residents in the South and Midwest. They were more likely to be college-educated, uninsured, and have one to two chronic conditions. Those with higher psychological distress and with asthma and pulmonary diseases practiced relaxation techniques more than individuals without these conditions. Findings suggest that relaxation practice is associated with lifestyles habits such as regular physical activity and prayer for health. Thus, relaxation practice has the potential to enhance health behaviors and lifestyle change. PMID- 23463800 TI - Regulation of cation balance in Saccharomyces cerevisiae. AB - All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker's yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na(+) and K(+), the divalent cations, Ca(2+) and Mg(2+), and the trace metal ions, Fe(2+), Zn(2+), Cu(2+), and Mn(2+). Signal transduction pathways that are regulated by pH and Ca(2+) are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment. PMID- 23463811 TI - A pharmacist-led, American Heart Association Heart360 Web-enabled home blood pressure monitoring program. AB - BACKGROUND: To determine whether a pharmacist-led, Heart360-enabled, home blood pressure monitoring (HBPM) intervention improves blood pressure (BP) control compared with usual care (UC). METHODS AND RESULTS: This randomized, controlled trial was conducted in 10 Kaiser Permanente Colorado clinics. Overall, 348 patients with BP above recommended levels were randomized to the HBPM (n=175) or UC (n=173) groups. There were no statistically significant differences in baseline characteristics between the groups; however, there was a trend toward a higher baseline BP for the HBPM group compared with the UC group (148.8 versus 145.5 mm Hg for systolic BP; 89.6 versus 88.0 mm Hg for diastolic BP). At 6 months, the proportion of patients achieving BP goal was significantly higher in the HBPM group (54.1%) than in the UC group (35.4%; P<0.001). Compared with the UC group, the HBPM group experienced a -12.4-mm Hg larger (95% confidence interval, -16.3 to -8.6) reduction in systolic BP and a -5.7-mm Hg larger (95% confidence interval, -7.8 to -3.6) reduction in diastolic BP. The impact of the intervention on BP reduction was even larger for the subgroup of patients with diabetes mellitus or chronic kidney disease. The HBPM group had more e-mail and telephone contacts and greater medication regimen intensification. The proportion of patients reporting high satisfaction with hypertension care was significantly greater in the HBPM group (58%) than in the UC group (42%), P<0.001. CONCLUSIONS: A pharmacist-led, Heart360-supported, home BP monitoring intervention led to greater BP reductions, superior BP control, and higher patient satisfaction than UC. PMID- 23463813 TI - Holistic nurses' stories of personal healing. AB - The purpose of this study was to uncover the nature, experiences, and meaning of personal healing for holistic nurses through their narrative accounts. The study employed a qualitative descriptive design with methods of narrative and story inquiry. Participants were nurse attendees at an American Holistic Nurses' Association conference who volunteered for the study. They were invited to share a story about healing self or another. Twenty-five stories were collected; seven were about personal healing, and these are the focus of this analysis. Data were analyzed using a hybrid approach from narrative and story inquiry methods. Eleven themes were clustered under three story segments. The themes within the Call to the Healing Encounter are the following: recognition of the need to resolve a personal or health crisis, knowledge of or engagement in self-care practices, and reliance on intuitive knowing. Themes under the Experience of Healing are the following: connections; profound sensations, perceptions, and events; awareness of the reciprocal nature of healing; inner resolution: forgiveness, awakening, and acceptance; use of multiple holistic approaches; and witnessing manifestations of healing. The themes for Insights are the following: gratitude and appreciation and ongoing journey. A metastory synthesizing the themes is presented, and findings are related to existing literature on healing. PMID- 23463814 TI - Mucin-type proteins produced in the Trichoplusia ni and Spodoptera frugiperda insect cell lines carry novel O-glycans with phosphocholine and sulfate substitutions. AB - The O-glycans of a recombinant mucin-type protein expressed in insect cell lines derived from Trichoplusia ni (Hi-5) and Spodoptera frugiperda (Sf9) were characterized. The P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL-1/mIgG2b) fusion protein carrying 106 potential O-glycosylation sites and 6 potential N glycosylation sites was expressed and purified from the Hi-5 and Sf9 cell culture medium using affinity chromatography and gel filtration. Liquid chromatography mass spectrometry (LC-MS) of O-glycans released from PSGL-1/mIgG2b revealed a large repertoire of structurally diverse glycans, which is in contrast to previous reports of only simple glycans. O-Glycans containing hexuronic acid (HexA, here glucuronic acid and galacturonic acid) were found to be prevalent. Also sulfate (Hi-5 and Sf9) and phosphocholine (PC; Sf9) O-glycan substitutions were detected. Western blotting confirmed the presence of O-linked PC on PSGL 1/mIG2b produced in Sf9 cells. To our knowledge, this is the first structural characterization of PC-substituted O-glycans in any species. The MS analyses revealed that Sf9 oligosaccharides consisted of short oligosaccharides (<6 residues) low in hexose (Hex) and with terminating N-acetylhexosamine (HexNAc) units, whereas Hi-5 produced a family of large O-glycans with (HexNAc-HexA-Hex) repeats and sulfate substitution on terminal residues. In both cell lines, the core N-acetylgalactosamine was preferentially non-branched, but small amounts of O-glycan cores with single fucose or hexose branches were found. PMID- 23463816 TI - What will it take? The quest to achieve indexing by the national library of medicine. PMID- 23463817 TI - Redesign of the pharmacy practice model at a tertiary care teaching hospital. PMID- 23463815 TI - Dissecting the molecular relationship among various cardiogenic progenitor cells. AB - RATIONALE: Multiple progenitors derived from the heart and bone marrow (BM) have been used for cardiac repair. Despite this, not much is known about the molecular identity and relationship among these progenitors. To develop a robust stem cell therapy for the heart, it is critical to understand the molecular identity of the multiple cardiogenic progenitor cells. OBJECTIVE: This study is the first report of high-throughput transcriptional profiling of cardiogenic progenitor cells carried out on an identical platform. METHOD AND RESULTS: Microarray-based transcriptional profiling was carried out for 3 cardiac (ckit(+), Sca1(+), and side population) and 2 BM (ckit(+) and mesenchymal stem cell) progenitors, obtained from age- and sex-matched wild-type C57BL/6 mice. Analysis indicated that cardiac-derived ckit(+) population was very distinct from Sca1(+) and side population cells in the downregulation of genes encoding for cell-cell and cell matrix adhesion proteins, and in the upregulation of developmental genes. Significant enrichment of transcripts involved in DNA replication and repair was observed in BM-derived progenitors. The BM ckit(+) cells seemed to have the least correlation with the other progenitors, with enrichment of immature neutrophil specific molecules. CONCLUSIONS: Our study indicates that cardiac ckit(+) cells represent the most primitive population in the rodent heart. Primitive cells of cardiac versus BM origin differ significantly with respect to stemness and cardiac lineage-specific genes, and molecules involved in DNA replication and repair. The detailed molecular profile of progenitors reported here will serve as a useful reference to determine the molecular identity of progenitors used in future preclinical and clinical studies. PMID- 23463818 TI - Should all pharmacists in direct patient care settings be authorized to inject medications? PMID- 23463819 TI - Drug shortages in health care institutions: perspectives in early 2013. PMID- 23463820 TI - Availability of drug samples in hospitals: opportunity or threat? PMID- 23463821 TI - Appropriateness of Triple Therapy after COPD Exacerbation. PMID- 23463822 TI - [Not Available]. PMID- 23463823 TI - Tribute to the reviewers of the canadian journal of hospital pharmacy. PMID- 23463824 TI - So we think we can dance. PMID- 23463825 TI - Achieving the CSHP's Vision for Hospital Pharmacy in Canada. PMID- 23463826 TI - Gaussian random ellipsoid geometry-based morphometric recovery of irregular particles using light scattering spectroscopy. AB - The purpose of this study is to extend the capabilities of multispectral optical imaging techniques for morphological characterization of irregular particles, encountered in several applications. We have utilized the Gaussian random ellipsoid model to quantize the shape elongation and deviation in complex-shaped particles. Compared with the Gaussian random sphere model, it is more realistic and is applicable to wider range of irregular particles with minimum possible of free parameters. By processing the reduced light scattering spectra, the proposed inverse technique can simultaneously recover the size, volume fraction, elongation, and shape deformation of particles that are randomly oriented within a colloidal suspension. The discrete dipole approximation is employed in forward light scattering calculations and input synthetic data generation. To investigate the robustness of our algorithm in coping with real scenarios, we have added different levels of noise to the observed scattering spectra. The results demonstrate the potential of our technique to non-invasively recover the morphology parameters of irregular particles. PMID- 23463827 TI - Contribution from cancer epidemiological studies in china. PMID- 23463828 TI - Ultraviolet A1 phototherapy of mycosis fungoides. PMID- 23463829 TI - Cutaneous metastasis of hepatocellular carcinoma following skin injury after transcatheter arterial chemoembolization. PMID- 23463830 TI - Rare manifestation of giant molluscum contagiosum on the scalp in old age. PMID- 23463831 TI - Medical concern for colloidal silver supplementation: argyria of the nail and face. PMID- 23463832 TI - A rapidly regressed giant plantar wart following biopsy. PMID- 23463833 TI - Refractory atopic dermatitis in childhood: improvement with methotrexate? PMID- 23463834 TI - Eruptive penile syringomas spreading to the pubic area and lower abdomen. PMID- 23463835 TI - Henoch-Schonlein Purpura during Isotretinoin Therapy. PMID- 23463836 TI - Eosinophilic pustular folliculitis involving labial mucosa, which improved with naproxen. PMID- 23463837 TI - Myopericytoma of the facial cheek. PMID- 23463838 TI - Localized involutional lipoatrophy in a child. PMID- 23463839 TI - Stamp-form contact plate: a simple and useful culture method for microorganisms of the skin. PMID- 23463840 TI - Intractable tufted angioma associated with kasabach-merritt syndrome. PMID- 23463841 TI - Bullous annular erythema as a cutaneous sign of vaginal stump adenocarcinoma. PMID- 23463842 TI - Congenital malalignment of the fourth toenail with congenital curved nail of the contralateral fourth toe. PMID- 23463843 TI - Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. PMID- 23463844 TI - Screening, isolation, and decolonization strategies for vancomycin-resistant enterococci or extended spectrum Beta-lactamase-producing organisms: a systematic review of the clinical evidence and health services impact. PMID- 23463845 TI - A systematic review of intravitreal bevacizumab for the treatment of diabetic macular edema. PMID- 23463846 TI - Highlights in applied evolutionary biology. PMID- 23463848 TI - Synchronous multifocal osteosarcoma with hypocalcemia. PMID- 23463849 TI - Usage of a curved chisel when resecting osteochondroma in the long bone. PMID- 23463850 TI - An epidemiological perspective on bovine tuberculosis spotlighting facts and dilemmas in Iran, a historically zebu-dominant farming country. AB - For the whole 20th century, bovine tuberculosis (BTB) challenged the international community efforts to control this zoonotic disease. Asia and Africa accommodate the largest BTB-infected zebu cattle in the world. Similar to other few Asian nations, Iran has been actively running its BTB-control plan for the last four decades. BTB however, is still a number-one health concern for Iranian veterinary practitioners and also farmers across the country. Why is that? Here we have addressed this question in the light of most recent epidemiological data as well as microbiology and molecular biology observations. PMID- 23463852 TI - Angioleiomyoma in a rare location: a case report. AB - A case report of a 38-year-old man with a 10 year history of left buttock mass associated with pain and numbness. A computed tomography scan showed a subcutaneous enhancing 1cm lesion that was not communicating with surrounding structures to include neurovascular structures. The mass was removed without complication and sent to pathology for extensive review. This case report signifies the importance of maintaining a broad differential with a subcutaneous mass presentation and includes thorough histology and pathology for angioleiomyoma. PMID- 23463853 TI - Patient-centered medical education: has an educational paradigm finally found a name? PMID- 23463854 TI - Developing the Ho'ouna Pono substance use prevention curriculum: collaborating with Hawaiian youth and communities. AB - This article briefly outlines a collaboration among communities on Hawai'i Island and a university-based research team to develop, implement, and evaluate a school based substance use prevention curriculum called Ho'ouna Pono. In addition to providing a rationale for the project, the goal of this paper is fourfold. First, an overview of the Ho'ouna Pono research results to date (2007-2013) is provided. Second, within this overview, the ways in which selected results informed program development are highlighted. Third, the curriculum is briefly described, and finally, the role of the students and community in the video production is described. PMID- 23463856 TI - Automating the study of population variation of electrocardiographic features. PMID- 23463858 TI - An implementation of time-efficient respiratory-gated PET acquisition by repeated breath-holds. AB - BACKGROUND: Respiratory gating in positron emission tomography (PET) is used to improve detection of small tumors in the lower lung regions and in the liver, and to obtain a better estimate of the standardized uptake value (SUV). PURPOSE: To develop a time-efficient method for acquisition of respiratory-gated PET/CT that would produce one single high quality image volume corresponding to a breath-hold state. MATERIAL AND METHODS: An instrument was developed that displayed to the patient either red or green numbers, counting down from a chosen maximum to one at a rate of one dial per second. The patient was instructed to repeatedly hold the breath in moderate inspiration when red numbers were displayed and to breathe freely during display of green numbers. PET data were acquired in list mode and trigger signals were sent to the scanner and inserted into the list file each time the color of the countdown numbers switched from green to red. Data acquired during breath-holds were used to create one single image volume. RESULTS: High quality breath-hold images were obtained from 10 min data acquisition at one bed position. Improved image quality compared to standard whole-body PET was demonstrated by a significant reduction of noise (standard deviation) in regions of normal liver tissues. CONCLUSION: The instruction to perform repeated breath holds was well understood by patients and they cooperated satisfactorily. When the new procedure is used the duration of the data acquisition may typically be reduced by a factor of 4 compared to conventional respiratory-gated protocols where the patient breathes freely. PMID- 23463859 TI - Clinical and radiological features of invasive Klebsiella pneumoniae liver abscess syndrome. AB - BACKGROUND: Recently, a striking new clinical manifestation of Klebsiella pneumoniae (KP) infection referred to as invasive KP liver abscess syndrome (IKPLAS), defined by liver abscess with contemporaneous metastatic KP infections at other body sites has been documented. Until now, however, there have been relatively few reports regarding its radiologic features. PURPOSE: To describe the clinical and radiological features of IKPLAS patients, and to compare them with those with KP liver abscess without metastatic infections to ascertain possible predictors of IKPLAS. MATERIAL AND METHODS: From January 2008 to May 2010, 35 patients (26 men and 9 women; mean age, 59.4 years) with both liver abscess and metastatic KP infections were diagnosed with IKPLAS. Their clinical and radiological features were retrospectively evaluated and compared with those of 25 contemporaneous non-metastatic patients to investigate predictive factors for metastatic infections. RESULTS: The rate of intensive care unit admissions and overall mortality was 34.3% and 17.1% in IKPLAS patients, and was significantly higher than those of the non-metastatic group (8% and 0%, respectively). As for metastatic infections, the lung was the most common site and multiple nodules or masses (n = 9) were the most common manifestations. Univariate analysis revealed that liver abscess <=5.8 cm, bilobar involvement of abscess and altered mentality were significantly related with IKPLAS. At multivariate analysis, liver abscess <=5.8 cm was proven to be a significant independent predictor of IKPLAS (OR, 3.6; P = 0.038). In addition, altered mentality was present solely in IKPLAS (25.7% vs. 0%) although its P value (P = 0.052) did not reach a statistical significance at multivariate analysis. CONCLUSION: IKPLAS has significantly worse prognosis than non-metastatic KP abscess patients. In patients with KP liver abscess, liver abscess <=5.8 cm can be used as an independent predictor of IKPLAS and altered mentality as a very specific feature in diagnosing IKPLAS. PMID- 23463857 TI - Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. AB - BACKGROUND: ECG QRS duration, a measure of cardiac intraventricular conduction, varies ~2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias. METHODS AND RESULTS: We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P=1.2*10(-8) (eMERGE) and P=2.5*10(-20) (CHARGE) and rs6795970 in SCN10A with P=6*10(-6) (eMERGE) and P=5*10(-27) (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 "heart healthy" study population. CONCLUSIONS: We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias. PMID- 23463860 TI - Treatment of postoperative main portal vein and superior mesenteric vein thrombosis with balloon angioplasty and/or stent placement. AB - BACKGROUND: Thrombolysis and mechanical thrombectomy have been used to treat postoperative main portal vein and superior mesenteric vein thrombosis. PURPOSE: To evaluate the safety and efficacy of balloon angioplasty and/or stent placement without thrombolysis or thrombectomy for treating such thromboses. MATERIAL AND METHODS: Fourteen patients with postoperative main portal vein or superior mesenteric vein thrombosis underwent percutaneous transhepatic balloon angioplasty and/or stent placement without thrombolysis or thrombectomy. The rates of technical and clinical success, major complications, and recurrence were evaluated retrospectively. RESULTS: Initial technical success was achieved in 13 of the 14 patients (93%). After the procedures, these 13 patients showed brisk portal inflow, without a significant amount of residual thrombus in the stented lumen or embolism. One patient was considered to be a technical failure despite showing a brisk portal inflow because 50% stenosis and partial residual thrombus remained in the stented lumen. Initial clinical success was achieved in 13 patients. One patient with technical success died of acute respiratory distress syndrome 8 days after the procedure, whereas one patient with technical failure achieved clinical success. One patient experienced acute rethrombosis 8 days after the procedure. During the median follow-up period of 16.3 months, rethrombosis occurred in six patients (43%), including one patient with acute rethrombosis. CONCLUSION: Balloon angioplasty and/or stent placement without thrombolysis or thrombectomy may be a safe and effective treatment modality for postoperative main portal vein and superior mesenteric vein thrombosis. PMID- 23463861 TI - MRI findings with arthroscopic correlation for tear of discoid lateral meniscus: comparison between children and adults. AB - BACKGROUND: Discoid lateral meniscus is more susceptible to tear than normal meniscus. A comparison study for tear types of discoid lateral meniscus between children and adults has not been reported. PURPOSE: To compare tear type of surgically proven discoid lateral meniscus between adults and children, and to analyze diagnostic performance for tear type of discoid lateral meniscus using magnetic resonance imaging (MRI). MATERIAL AND METHODS: Knee MR examinations of 53 children and 84 adults who had discoid lateral menisci identified at arthroscopic surgery were retrospectively evaluated with consensus by two radiologists for tear type including displacement of torn meniscus. MRI findings were compared with surgery as the reference standard. The difference of tear type and displacement of torn meniscus between children and adults in arthroscopic finding was analyzed using the Fisher's exact test or the Chi-squared test with Bonferroni's correction. RESULTS: At arthroscopy, complex tear (children, n = 22; adults, n = 56) and peripheral tear (children, n = 17; adults, n = 8) differed significantly between children and adults (P = 0.006 for complex tear, P = 0.002 for peripheral tear). Displacement of torn meniscus was seen in 28 cases of children and 41 cases of adults, not a statistically significant difference. In children, the positive predictive value (PPV) for horizontal tears was 90%, for peripheral tears 60%, and for complex tears 57%. PPV in adults for horizontal tears was 78%, peripheral tears 25%, and for complex tears 89%. CONCLUSION: Complex tears were more commonly found in adults than children and peripheral tears were more commonly found in children than adults. MRI has a high PPV for diagnosing the type of tear in discoid lateral meniscus for horizontal tears in children and adults and for complex tears in adults. PMID- 23463862 TI - Cross-camera comparison of ROI-based semi-quantitative 123I-IBZM SPECT data in healthy volunteers using an anthropomorphic phantom for calibration. AB - BACKGROUND: In (123)I-Iolopride (IBZM) SPECT reference values may diverge between camera systems. If multicenter pooling of normal material databases is needed, differences in measured semi-quantitative data due to equipment performance and reconstruction parameters have to be investigated in each instance to determine the comparability. PURPOSE: To explore the differences in (123)I-IBZM measured uptake ratios between two different gamma cameras in healthy controls, the intra rater reproducibility of the image evaluation method and the possibility to equalize uptake ratios by calibration through an anthropomorphic phantom. MATERIAL AND METHODS: Differences in ROI-based semi-quantitative data from two different gamma camera systems, the three-headed brain dedicated Neurocam and the two-headed multipurpose hybrid system Infinia Hawkeye, were studied using image data from a group of healthy volunteers and an anthropomorphic brain-phantom scanned with both cameras. Several reconstruction methods and corrections were applied. To test the reliability of the ROI method, the intra-observer reproducibility was determined for the ROI method in this study. RESULTS: The ROI method had a high reliability. Differences in mean measured uptake (123)I-IBZM ratios in healthy controls varied between 2.9% and 6.5% depending on reconstruction and correction for attenuation and scatter. After calibration, the differences decreased. There were no statistically significant differences between corrected ratios from the two camera systems in the study when images were reconstructed with attenuation correction. CONCLUSION: The conformity of uptake ratios in attenuation corrected (123)I-IBZM images derived from the two different cameras was improved by using an anthropomorphic phantom for calibration. PMID- 23463863 TI - Value of true whole-body FDG-PET/CT scanning protocol in oncology: optimization of its use based on primary diagnosis. AB - BACKGROUND: No standardized field of view (FOV) currently exists for whole-body (WB) positron emission tomography/computed tomography (PET/CT). Limited WB PET/CT FOV can exclude portions of the head, upper, and lower extremities, because there is little perceived clinical benefit to be gained from imaging these areas. PURPOSE: To determine how often utilizing WB PET/CT changes the clinical stage and management compared to each of the limited WB FOVs used for PET/CT. MATERIAL AND METHODS: We retrospectively identified 556 oncologic patients (804 PET/CT studies) who underwent staging or restaging PET/CT between November 2010 and November 2011. Abnormal hypermetabolic areas that were suspicious for malignancy in areas that are outside of some of the limited fields of view including in the brain, scalp, and calvarium (above the orbital ridge), in the proximal upper extremity (distal to the humeral neck), distal upper extremity (beyond the elbow), proximal lower extremity (distal to the lesser trochanter), and distal lower extremity (beyond the knees) were recorded. RESULTS: A total of 8.5% (47/556) of patients had abnormal findings outside the most limited FOV (skull base to upper thighs) used in PET/CT. More patients had abnormal hypermetabolic lesions in the lower extremity (5.9%) than in the upper extremity (2.3%). Similarly, more patients had abnormal lesions in the proximal (6.5%) compared to the distal (1.4%) upper and lower extremities. The stage was only changed in one patient (0.2%), however new lesions noted in the brain changed management in six patients (1.1%). Melanoma, lymphoma, multiple myeloma, sarcomas and stage IV lung, breast, prostate, bladder, testicular, and renal cancer were more likely to have findings outside the most limited FOV (skull base to upper thighs). CONCLUSION: WB FOV detects additional sites of disease compared to the limited WB FOV, and although these lesions rarely change stage, some of these lesions may change clinical management. PMID- 23463864 TI - Quality and value of nuclear medicine and molecular imaging: the impact of health care reform. PMID- 23463866 TI - Impact Commentaries. Action discrimination: impact of apraxia. PMID- 23463867 TI - Demographic and motor features associated with the occurrence of neuropsychiatric and sleep complications of Parkinson's disease. AB - OBJECTIVE: To determine whether four key neuropsychiatric and sleep related features associated with Parkinson's disease (PD) are associated with the motor handicap and demographic data. BACKGROUND: The growing number of recognised non motor features of PD makes routine screening of all these symptoms impractical. Here, we investigated the hypothesis that standard demographic data and the routine assessment of motor signs is associated with the presence of dementia, psychosis, clinically probable rapid eye movement (REM) sleep behavior disorder (cpRBD) and restless legs syndrome (RLS). METHODS: 775 patients with PD underwent standardised assessment of motor features and the presence of dementia, psychosis, cpRBD and RLS. A stepwise feature elimination procedure with fitted logistic regression models was applied to identify which/if any combination of demographic and motor factors is associated with each of the four studied non motor features. A within-study out-of-sample estimate of the power of the predicted values of the models was calculated using standard evaluation procedures. RESULTS: Age and Hoehn&Yahr (H&Y) stage were strongly associated with the presence of dementia (p value<0.001 for both factors in the final selected model) while a combination of age, disease duration, H&Y stage, dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors was associated with the presence of psychosis. Disease duration and H&Y stage were the significant indicators of cpRBD, and the lack of significant motor asymmetry was the only significant feature associated with RLS-type symptoms but the evidence of association was weak. CONCLUSIONS: Demographic and motor features routinely collected in patients with PD can estimate the occurrence of neuropsychiatric and sleep-related features of PD. PMID- 23463868 TI - Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) plays an essential role in the pathophysiology of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome. Anti-VEGF antibody (bevacizumab) appears to be an attractive therapeutic option. The aim of this study is to investigate the effects of bevacizumab for patients with POEMS syndrome. METHODS: We reported six POEMS patients treated with bevacizumab and reviewed the literature. RESULTS: The serum VEGF levels decreased immediately after bevacizumab administration in all six patients. However, four patients had entirely no clinical response, and two of them died. The remaining two showed improvement that could be explained by combined treatments. We also reviewed the literature and found 11 patients treated with bevacizumab; of these, only one was treated with bevacizumab alone. 10 had combined treatments, and four died without any response. CONCLUSIONS: Both our experience and the literature suggest ambiguous effects of bevacizumab; inhibition of VEGF alone may be insufficient because multiple cytokines are upregulated, or aberrant neo-vascularization may have already fully developed in the advanced stage of POEMS syndrome. PMID- 23463869 TI - Case series analysis, meta-analysis or no analysis in the evaluation of neurosurgical techniques: get better or get out. PMID- 23463871 TI - Pathophysiological insights into ALS with C9ORF72 expansions. AB - OBJECTIVE: Expansions of a hexanucleotide repeat in C9ORF72 are a common cause of familial amyotrophic lateral sclerosis (ALS) and a small proportion of sporadic ALS cases. We sought to examine clinical and neurophysiological features of familial and sporadic ALS with C9ORF72 expansions. METHODS: C9ORF72 was screened for expansions in familial and sporadic ALS. Clinical features of expansion positive cases are described. Cortical excitability studies used novel threshold tracking transcranal magnetic stimulation techniques with motor evoked responses recorded over the abductor pollicis brevis. RESULTS AND CONCLUSIONS: Analysis of large clinical cohorts identified C9ORF72 expansions in 38.5% (72/187) of ALS families and 3.5% (21/606) of sporadic ALS cases. Two expansion positive families were known to carry reported ANG mutations, possibly implicating an oligogenic model of ALS. 6% of familial ALS cases with C9ORF72 expansions were also diagnosed with dementia. The penetrance of ALS was 50% at age 58 years in male subjects and 63 years in female subjects. 100% penetrance of ALS was observed in male subjects by 86 years, while 6% of female subjects remained asymptomatic at age 82 years. Gender specific differences in age of onset were evident, with male subjects significantly more likely to develop ALS at a younger age. Importantly, features of cortical hyperexcitability were apparent in C9ORF72-linked familial ALS as demonstrated by significant reduction in short interval intracortical inhibition and cortical silent period duration along with an increase in intracortical facilitation and motor evoked potential amplitude, indicating that cortical hyperexcitability is an intrinsic process in C9ORF72-linked ALS. PMID- 23463872 TI - Sunshine and multiple sclerosis. PMID- 23463870 TI - Changes to anti-JCV antibody levels in a Swedish national MS cohort. AB - BACKGROUND: The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). OBJECTIVE: To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. METHODS: An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. RESULTS: Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. CONCLUSIONS: Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted. PMID- 23463873 TI - Cortical thinning is associated with disease stages and dementia in Parkinson's disease. AB - OBJECTIVE: To investigate the pattern of cortical thinning in Parkinson's disease (PD) across different disease stages and to elucidate to what extent cortical thinning is related to cognitive impairment. DESIGN: Ninety-six subjects including 39 controls and 57 PD patients participated in this study. PD subjects were divided into three groups (early, n=24; moderate, n=18; with dementia, n=15). High field structural brain MRI images were acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Vertex-wise group comparisons were performed and cortical thickness was correlated with motor and cognitive measures. RESULTS: We found a positive correlation between Mini-Mental State Examination scores and cortical thickness in the anterior temporal, dorsolateral prefrontal, posterior cingulate, temporal fusiform and occipitotemporal cortex. Unified Parkinson's Disease Rating Scale-III (motor subsection) scores showed a robust negative correlation with caudate volumes. We found that disease stage in PD was associated with thinning of the medial frontal (premotor and supplementary motor cortex), posterior cingulate, precuneus, lateral occipital, temporal and dorsolateral prefrontal cortex. Discriminant analysis and a receiver operating characteristics approach showed that mean cortical thickness and hippocampus volume have 80% accuracy in identifying PD patients with dementia. PD stage and PD dementia can be characterised by a specific pattern of cortical thinning. CONCLUSIONS: We conclude that measuring cortical thickness can be useful in assessing disease stage and cognitive impairment in patients with PD. In addition, cortical thickness may be useful in identifying dementia in PD. PMID- 23463874 TI - The relationship of copper to DNA damage and damage prevention in humans. AB - Copper ions are well suited to facilitate formation of reactive oxygen species (ROS) that can damage biomolecules, including DNA and chromatin. That this can occur in vitro with isolated DNA or chromatin,or by exposure of cultured mammalian cells to copper complexed with various agents, has been well demonstrated. Whether that is likely to occur in vivo is not as clear. This review addresses the question of whether and how copper ions or complexes - in forms that could be present in vivo, damage DNA and chromosome structure and/or promote epigenetic changes that can lead to pathology and diseases, including cancer and neurological conditions such as Alzheimer's disease, Lewy body dementias, and spongiform encephalopathies. This question is considered in light of our knowledge that copper-dependent enzymes are important contributors to antioxidant defense, and that the mammalian organism has robust mechanisms for maintaining constant levels of copper not only in body fluids but in its major organs. Overall,and except in unusual genetic states that lead to copper overload in specific cells (particularly those in liver), it appears that excessive intake of copper is not a significant factor in the development of disease states. PMID- 23463875 TI - Reply to MacLeod et al.: Multiple myeloma plasma cells have chameleon characteristics. PMID- 23463876 TI - Reply to Boogert et al.: The devil is unlikely to be in association or distraction. PMID- 23463877 TI - [Maternal obesity and neonatal mortality]. PMID- 23463878 TI - Abstracts of the 10th International Congress of Andrology. February 23-26, 2013. Melbourne, Australia. PMID- 23463879 TI - Spleen rupture associated with septic emboli and endocarditis in a hemodialysis patient. AB - We present an uremic patient on chronic hemodialysis with splenic septic emboli associated with active infective endocarditis and anaerobic bacteremia complicated by ruptured spleen. A 62-year-old female patient was admitted because of fever and pain in the left upper abdomen and swelling and hematoma around the left brachiocephalic arteriovenous fistula. Transthoracic echocardiography revealed mobile hyperechoic mass (vegetation) on the anterior mitral valve. Abdominal ultrasound scan showed multiple hypoechoic lesions of the enlarged spleen, described as possible necroses or abscesses, and computed tomography showed low-density inhomogeneous lesions in the enlarged spleen with large perisplenic hematoma, with spleen rupture. Blood culture revealed anaerobic Gram negative bacilli ( Bacteroides spp.), ampicillin resistant. This is the first report of splenic rupture associated with anaerobic bacteremia and splenic septic emboli in a uremic patient on chronic hemodialysis. Splenic septic emboli with abscess/infarction in hemodialysis patients are a rare disorder but could be a consequence of dialysis access site infection and might predispose to splenic rupture. Ultrasound scan of abdomen is fast, inexpensive and easy to perform. As mortality is high, early surgical intervention on vascular access is mandatory. PMID- 23463880 TI - Cytokine secretion and markers of inflammation in relation to acidosis among chronic hemodialysis patients. AB - BACKGROUND: Various cytokines are increased in hemodialysis (HD) patients, and are considered prognostic markers. Metabolic acidosis is common among chronic HD patients and is associated with survival. The relationship between acidosis and cytokines in HD patients has not been fully explored. The study aim was to measure pro- and anti-inflammatory cytokines in HD patients, with relation to bicarbonate levels. METHODS: Forty-seven stable HD patients were included (male/female 28/19, mean age 70.4 +/- 14.5 years). Blood tests were taken before a midweek dialysis session. Cytokine secretion from peripheral blood mononuclear cells was measured. RESULTS: Acidosis versus no acidosis (serum HCO3 - 21.5 +/- 0.2 vs. 24.9 +/- 0.3 mEq/l, p < 0.001) was associated with decreased secretion of the anti-inflammatory interleukin-10 (IL-10, 1.16 +/- 0.11 vs. 1.71 +/- 0.20 ng/ml, p = 0.023). Patients with acidosis had higher parathyroid hormone (PTH), calcium-phosphate product, protein intake and transferrin. Higher IL-10 was associated with increased IL-6 secretion, higher bicarbonate, younger age and lower PTH. CONCLUSIONS: In stable chronic HD patients, a possible direct relation exists between metabolic acidosis and IL-10. PMID- 23463881 TI - Statement on matching language to the type of evidence used in describing outcomes data. PMID- 23463882 TI - Reply: To PMID 22495332. PMID- 23463884 TI - Preface. Improving photosynthesis. PMID- 23463885 TI - Response to Schiavenato, von Baeyer, and Craig's letter to the editor. PMID- 23463883 TI - ACE2, angiotensin-(1-7), and Mas: the other side of the coin. AB - The renin-angiotensin system (RAS) has recently been extended by the addition of a novel axis consisting of the angiotensin-converting enzyme 2 (ACE2), the heptapeptide angiotensin (1-7) (Ang-(1-7)), and the G protein-coupled receptor Mas. ACE2 converts the vasoconstrictive and pro-oxidative peptide angiotensin II (Ang II) into Ang-(1-7) which exerts vasodilatory and antioxidative effects via its receptor Mas. Thereby, ACE2 regulates the local actions of the RAS in cardiovascular tissues and the ACE2/Ang-(1-7)/Mas axis exerts protective actions in hypertension, diabetes, and other cardiovascular disorders. Consequently, this novel RAS axis represents a promising therapeutic target for cardiovascular and metabolic diseases. PMID- 23463886 TI - Severity of familial isolated retinitis pigmentosa across different inheritance patterns among an Asian Indian cohort. AB - PURPOSE: To predict the progression to legal blindness in patients with isolated inherited retinitis pigmentosa. METHODS: This retrospective study evaluated patients with isolated inherited retinitis pigmentosa for age at onset, duration of the disease, and best-corrected visual acuity in an Asian Indian cohort. The Mann-Whitney U test was used to analyze the variables. RESULTS: Of 134 patients evaluated, 72% were autosomal recessive, 17% were autosomal dominant, and 11% were X-linked recessive pedigrees. Median age at onset was 8 years for X-linked recessive, 11 years for autosomal recessive, and 21 years for autosomal dominant disease, which was statistically significant. The refractive error due to axial myopia was significantly high in X-linked recessive (-3.50 diopter sphere) compared to autosomal recessive (-1 diopter sphere) and autosomal dominant (0.00 diopter sphere) cases (P < .000). Legal blindness occurred in 50% of X-linked recessive and autosomal recessive cases but in only 32% of autosomal dominant cases. CONCLUSION: Identifying the gene defects involved in this cohort will help understand the phenotype variability. PMID- 23463887 TI - Where art and biology meet. PMID- 23463888 TI - W. Tecumseh Fitch. PMID- 23463889 TI - Glenis Paulette replies. PMID- 23463890 TI - Choosing options for life-sustaining care. Advance planning will ensure your wishes are followed. PMID- 23463891 TI - Green tea may lower heart disease risk. Here's what studies have revealed about this popular beverage. PMID- 23463892 TI - Radial artery grafts prove durable. PMID- 23463893 TI - [Genitourinary tumor]. PMID- 23463894 TI - [Paradigm shift of chemotherapy for kidney cancer]. PMID- 23463895 TI - [Treatment of muscular layer invasiveness bladder cancer]. PMID- 23463896 TI - [Update of treatment for prostate cancer]. PMID- 23463897 TI - [Topics on testis cancer: treatment strategy for stage I testis cancer]. PMID- 23463898 TI - Cyclic denaturation and renaturation of double-stranded DNA by redox-state switching of DNA intercalators. AB - Hybridization of complementary nucleic acid strands is fundamental to nearly all molecular bioanalytical methods ranging from polymerase chain reaction and DNA biosensors to next generation sequencing. For nucleic acid amplification methods, controlled DNA denaturation and renaturation is particularly essential and achieved by cycling elevated temperatures. Although this is by far the most used technique, the management of rapid temperature changes requires bulky instrumentation and intense power supply. These factors so far precluded the development of true point-of-care tests for molecular diagnostics. To overcome this limitation we explored the possibility of using electrochemical means to control reversible DNA hybridization by using the electroactive intercalator daunomycin (DM). We show that redox-state switching of DM altered its properties from DNA binding to nonbinding, under otherwise constant conditions, and thus altered the thermodynamic stability of duplex DNA. The operational principle was demonstrated using complementary synthetic 20mer and 40mer DNA oligonucleotides. Absorbance-based melting curve analysis revealed significantly higher melting temperatures for DNA in the presence of oxidized compared to chemically reduced DM. This difference was exploited to drive cyclic electrochemically controlled denaturation and renaturation. Analysis with in situ UV-vis and circular dichroism spectroelectrochemistry, as two independent techniques, indicated that up to 80% of the DNA was reversibly hybridized. This remarkable demonstration of electrochemical control of five cycles of DNA denaturation and renaturation, under otherwise constant conditions, could have wide-ranging implications for the future development of miniaturized analytical systems for molecular diagnostics and beyond. PMID- 23463899 TI - Resolution of intracardiac and pulmonary thrombi without anticoagulation in a patient with Behcet's disease: a case report. AB - Intracardiac and pulmonary thrombi are rare but serious manifestations of Behcet's disease, the treatment of such cases is a challenge to the treating physician and use of anticoagulants can hold a great risk to some patients. We report a patient who was found to have multiple right intraventricular and bilateral pulmonary artery thrombi and was clinically diagnosed with Behcet's disease. Early in the course of his treatment, the patient developed massive haemoptysis which precluded the further use of anticoagulants. The patient was treated with immunosuppressants alone and had complete resolution of his symptoms and documented resolution of the thrombi. In a review of the literature, only 3 out of around 50 patients reported to have intracardiac thrombi complicating Behcet's disease were treated without anticoagulants (1, 2) even though there is no clear evidence to support the benefit of anticoagulation to treat arterial or thrombotic lesions (3). We conclude that intracardiac thrombi in patients with Behcet's disease may resolve with immunosuppressants without anticoagulation, which is especially important in patients with contraindication to anticoagulation. PMID- 23463900 TI - Remediation of polychlorinated biphenyl impacted sediment by concurrent bioaugmentation with anaerobic halorespiring and aerobic degrading bacteria. AB - Bioremediation of sediments contaminated with commercial polychlorinated biphenyls (PCBs) is potentially achievable by the sequential activity of anaerobic halorespiration to convert higher chlorinated congeners to less chlorinated congeners that are susceptible to aerobic respiratory degradation. The efficacy of bioaugmentation with anaerobic halorespiring Dehalobium chlorocoercia DF1 and aerobic Burkholderia xenovorans LB400 added concurrently with granulated activated carbon (GAC) as a delivery system was determined in 2 L laboratory mesocosms containing weathered Aroclor-contaminated sediment from Baltimore Harbor, MD, USA. The greatest effect was seen in the mesocosm bioaugmented with both DF1 and LB400 together, which resulted in an 80% decrease by mass of PCBs, from 8 to <2 mg/kg after 120 days. There was no significant increase in lesser-chlorinated congeners, indicating that both anaerobic dechlorination by DF1 and aerobic degradation by LB400 occurred. In contrast, nonbioaugmented controls containing filtered culture supernatant showed only a 25% decrease in total levels of PCBs after 365 days, which was likely due to biostimulation of the indigenous population by the medium. Direct colony counts and molecular analysis targeting a putative reductive dehalogenase gene of D. chlorocoercia or the bphA gene of LB400 showed the presence of viable DF1 and LB400 in bioaugmented mesocosms after 365 days, indicating that both nonindigenous strains were sustainable within the indigenous microbial community. These results suggest that an in situ treatment employing the simultaneous application of anaerobic and aerobic microorganisms could be an effective and environmentally sustainable strategy to reduce PCBs levels in contaminated sediment. PMID- 23463901 TI - Monitoring guanidinium-induced structural changes in ribonuclease proteins using Raman spectroscopy and 2D correlation analysis. AB - Assessing the stability of proteins by comparing their unfolding profiles is a very important characterization and quality control step for any biopharmaceutical, and this is usually measured by fluorescence spectroscopy. In this paper we propose Raman spectroscopy as a rapid, noninvasive alternative analytical method and we shall show this has enhanced sensitivity and can therefore reveal very subtle protein conformational changes that are not observed with fluorescence measurements. Raman spectroscopy is a powerful nondestructive method that has a strong history of applications in protein characterization. In this work we describe how Raman microscopy can be used as a fast and reliable method of tracking protein unfolding in the presence of a chemical denaturant. We have compared Raman spectroscopic data to the equivalent samples analyzed using fluorescence spectroscopy in order to validate the Raman approach. Calculations from both Raman and fluorescence unfolding curves of [D]50 values and Gibbs free energy correlate well with each other and more importantly agree with the values found in the literature for these proteins. In addition, 2D correlation analysis has been performed on both Raman and fluorescence data sets in order to allow further comparisons of the unfolding behavior indicated by each method. As many biopharmaceuticals are glycosylated in order to be functional, we compare the unfolding profiles of a protein (RNase A) and a glycoprotein (RNase B) as measured by Raman spectroscopy and discuss the implications that glycosylation has on the stability of the protein. PMID- 23463902 TI - Focal dermal hypoplasia: updates. AB - Focal dermal hypoplasia (FDH), or Goltz-Gorlin syndrome, is a rare syndrome and may result in multisystem disorders. Several reviews of FDH have been published. However, the last comprehensive review of this disorder appeared more than 20 years ago. To date, a number of new clinical manifestations have been reported and considerable knowledge has accumulated regarding etiology and pathogenetic mechanisms. The purpose of this review is to gather these more recent data and to provide organized and reliable information. So we reviewed 159 cases of FDH that had been reported from 1990 to 2012, summarized the new discoveries, and suggested a potential standard for the diagnosis of FDH. We also reported on a Chinese girl with FDH, who was clinically and histologically in accord with FDH, as an example. PMID- 23463903 TI - Traumatic abdominal wall herniation: case series review and discussion. AB - BACKGROUND: Traumatic abdominal wall hernia (TAWH) is a rare type of hernia occurring secondary to blunt trauma to the abdomen. Its management remains controversial within the surgical community, mainly due to complexities in diagnosis, appropriate surgical approach and timing of closure. METHOD: Cases were identified retrospectively, via interviews with trauma surgeons at a Tertiary Trauma Centre, the Royal Brisbane & Women's Hospital, in Brisbane, Australia. In addition, data were collected via in-house trauma and operative databases. RESULTS: Five cases of TAWH were identified over a 3-year period. All cases involved injuries sustained from motor vehicle or motor bike accidents. Diagnosis was purely clinical in one case and clinically suspected, then confirmed by computed tomography in the remainder. Herniation was managed by immediate closure in one instance, delayed/staged closure in three cases and conservative management in the remainder. In addition, three of the five patients were obese. At minimal 3-month follow-up, no evidence of recurrence of herniation was present in four of the five cases. One case was lost to follow-up. CONCLUSIONS: TAWH is a complex injury to manage and no one approach is all encompassing. Correct diagnosis is essential as this allows proper planning for the method and timing of repair. This series highlighted that incorrect seatbelt placement, especially in the obese population, may be a risk factor for increased incidence of TAWH. PMID- 23463904 TI - Semen analysis of Golden Retriever healthy dogs and those affected by muscular dystrophy. AB - This study aimed to characterise canine flow cytometry semen analysis, as well as seminal reactive oxygen species dosage using the Golden Retriever breed as model of study. Moreover, we searched for the influence of muscular dystrophy in Golden Retriever dogs on semen parameters. Thirty-seven semen samples were obtained from healthy Golden Retrievers (n = 15) and from muscular dystrophy affected dogs (n = 22). Sperm-rich fractions were analysed by standardised breeding soundness examination in addition to the assay of fluorescence assisted cell sorting for acrosome integrity, mitochondrial activity and DNA fragmentation. Volume of ejaculate, per cent of motile spermatozoa and vigour were similar between groups; there were no differences in the per cent of minor and major defects. Integrity of acrosomal membrane, mitochondrial potential and sperm DNA fragmentation had no significant differences between groups either. Animals from control group had higher concentration of spontaneous seminal oxidative species in comparison with affected animals. Dogs affected by dystrophy had seminal parameters similar to those observed in healthy dogs except for the lower concentration of oxidative species. Future studies aiming to establish reference values for canine seminal parameters should be considered preferably with distinction of breeds. PMID- 23463905 TI - Job enrichment: creating meaningful career development opportunities for nurses. AB - AIM: This paper presents an evaluation of a career development policy in South Australia which increased the number of senior staff nurse positions and provided senior registered nurses with time away from clinical duties to undertake agreed projects. We use Kanter's model of structural power and commitment theory to understand the dimensions of this policy. BACKGROUND: Development strategies for experienced staff who wish to remain at the bedside are needed, especially in smaller health services with limited opportunities for horizontal or vertical mobility. METHODS: Face-to-face semistructured interviews were conducted with 54 senior staff nurses who participated in the career structure arrangements. RESULTS: The policy enhanced the structure of opportunity in three ways: by increasing the number of senior staff nurse positions, the ladder steps were improved; undertaking strategic projects developed new skills; and the job enrichment approach facilitated time out from the immediate pressures of ward work and challenged nurses in a different way. CONCLUSIONS: Through job enrichment, South Australia has found a novel way of providing meaningful career development opportunities for experienced nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Methods of job enrichment need to be considered as part of career development policy, especially where movement between clinical facilities is limited and staff wish to remain at the bedside. PMID- 23463906 TI - Wound-healing effects of low-level laser therapy in diabetic rats involve the modulation of MMP-2 and MMP-9 and the redistribution of collagen types I and III. AB - The present study aimed to determine if LLLT restores the balance between mRNA expression of matrix metalloproteinases (MMP-2 and MMP-9) and also the balance between collagen types I and III during the healing process of diabetic wounds. One hundred and twenty male Wistar rats were distributed in Control (untreated non-diabetic rats: UND); Laser (laser treated in non-diabetic rats: LTND); Diabetic (diabetic rats non-laser treated rats: UD); and Diabetic+ Laser (diabetic rats laser treated: DLT) groups. The diabetes model using streptozotocin efficiently induced diabetes, as demonstrated through increased levels of blood glucose. Diode laser (50 mW, 660 nm, 4 J/cm(2), 80 s) was applied a single time after scare induction. Twenty-four hours after LLLT application, rats were euthanized, the scarred areas were collected for MMP-2 and MMP-9 mRNA analysis and also for histological analysis (inflammation and types I and III collagen). The results demonstrated that scare in untreated diabetic rats significantly increased the MMP-2 and MMP-9 expression compared with that in non diabetic rats (p < 0.05), while LLLT significantly reduced MMP-2 and MMP-9 expression compared with that in untreated diabetic rats (p < 0.05). To conclude, the results also showed that LLLT was able to alter the expression of MMP-9 as well as accelerate the production of collagen and increase the total percentage of collagen type III in diabetic animals. PMID- 23463907 TI - Inhibition of innate co-receptor TREM-1 signaling reduces CD4(+) T cell activation and prolongs cardiac allograft survival. AB - The innate receptor "triggering-receptor-expressed-on-myeloid-cells-1" (TREM-1) enhances downstream signaling of "pattern recognition receptor" (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM 1(+) antigen-presenting cells (APC) on alloreactive CD4(+) lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1(+) CD11b(+) MHC-II(+) F4/80(+) CCR2(+) APC and IFNgamma producing CD4(+) cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4(+) and CD8(+) cell infiltration. Remarkably, temporary inhibition of TREM 1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFNgamma-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4(+) lymphocytes. PMID- 23463909 TI - Efficiency of sodium oxybate in episodic cluster headache. AB - We report the case of a 60-year-old man suffering from episodic cluster headache treated successfully with sodium oxybate. Sodium oxybate may be a therapeutic option in attacks of episodic cluster headache. PMID- 23463908 TI - Subungual glomus tumors: surgical approach and outcome based on tumor location. AB - BACKGROUND: Subungual glomus tumors are uncommon tumors that present with a classic triad of temperature sensitivity, pain, and localized tenderness. Different surgical approaches can be performed according to the anatomic location of the tumor. OBJECTIVE: To investigate the outcome of surgical excision of subungual glomus tumors according to anatomic location. METHODS: The records of 22 Korean patients diagnosed with subungual glomus tumor by histopathologic examination who underwent surgical excision over a 7-year period (2005-2011) were retrospectively reviewed. Local complications including persistence of symptoms, surgical methods, and tumor recurrence were evaluated through long-term follow up. RESULTS: In the 22 patients, 13 tumors were located in the nail matrix and nine in the nail bed. No recurrence was observed after a mean follow-up of 36.6 months. Eight of the 13 patients with nail matrix involvement had complications such as nail deformity, decreased sensation, and prolonged pain sensation, whereas only one of the nine patients with nail bed lesion had prolonged pain sensation. CONCLUSIONS: Careful dissection and complete removal of the tumor offered cure without recurrence; anatomic location of the subungual glomus tumor at initial presentation may predict postoperative complications. PMID- 23463910 TI - Genetic variability of the tokay gecko based on mitochondrial and nuclear DNA. AB - With largely allopatric distribution, the black tokay and the red tokay are two distinct morphs of the subspecies Gekko gecko gecko. In consideration of their different morphological characteristics, the taxonomic status of G. g. gecko is disputed. Through detailed morphological comparison, it has been proposed that the black tokay should be elevated to species ranking, but without strong genetic evidence. In order to further investigate the taxonomic status of the tokay gecko (G. gecko), we used one mitochondrial marker (ND2) and three nuclear markers (RAG1, c-mos, and ITS2) to explore the phylogenetic and taxonomic relationship of the tokay gecko. Our results revealed a deep phylogeographical divergence in tokay gecko and at the same time provided us with the evidence of possible introgressive hybridization or/and incomplete lineage sorting between the black tokay and the red tokay. The elevation of the black tokay to species level is also supported by our results. However, due to limited sampling and genetic data, this elevation should be further corroborated by more genetic evidence. PMID- 23463911 TI - Room-temperature photoinduced direct C-H-arylation via base-promoted homolytic aromatic substitution. AB - Conceptually different approach toward biaryl syntheses by photoinduced direct C H arylation of benzene and thiophene in the presence of t-BuOK is reported. The reaction proceeds through photo- and base-promoted homolytic aromatic substitution. The o-, m- and p- substituted ArI, as well as the electron-donating and electron-withdrawing nature of the substituents were found be good to excellent substrates. Heteroaryl, ArBr, ArCl and double C-H arylation were successfully achieved. PMID- 23463913 TI - Comparing femtosecond multiphoton dissociative ionization of tetrathiafulvene with imaging photoelectron photoion coincidence spectroscopy. AB - In this paper we describe femtosecond photoionization and the imaging photoelectron photoion coincidence spectroscopy of tetrathiafulvene, TTF. Femtosecond photoionization of TTF results in the absorption of up to twelve 808 nm photons leading to ion internal energies up to 12.1 eV as deduced from the photoelectron spectrum. Within this internal energy a variety of dissociation channels are accessible. In order to disentangle the complex ionic dissociation, we utilized the imaging photoelectron photoion coincidence (iPEPICO) technique. Above the dissociation threshold, iPEPICO results show that the molecular ion (m/z = 204) dissociates into seven product ions, six of which compete in a 1.0 eV internal energy window and are formed with the same appearance energy. Ab initio calculations are reported on the possible fragment ion structures of five dissociation channels as well as trajectories showing the loss of C2H2 and C2H2S from high internal energy TTF cations. A three-channel dissociation model is used to fit the PEPICO data in which two dissociation channels are treated as simple dissociations (one with a reverse barrier), while the rest involve a shared barrier. The two lower energy dissociation channels, m/z = 146 and the channel leading to m/z = 178, 171, 159, 140, and 127, have E0 values of 2.77 +/- 0.10 and 2.38 +/- 0.10 eV, respectively, and are characterized by DeltaS(?)(600 K) values of -9 +/- 6 and 1 +/- 6 J K(-1) mol(-1), respectively. Competing with them at higher internal energy is the cleavage of the central bond to form the m/z = 102 fragment ion, with an E0 value of 3.65 +/- 0.10 eV and DeltaS(?)(600 K) = 83 +/- 10 J K(-1) mol(-1). PMID- 23463912 TI - Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis. AB - HISTORY: A 4-year old, 500 kg Thoroughbred female horse diagnosed with bilateral forelimb laminitis and cellulitis on the left forelimb became severely painful and refractory to non-steroidal anti-inflammatory therapy (flunixin meglumine on days 1, 2, 3 and 4; and phenylbutazone on days 5, 6 and 7) alone or in combination with gabapentin (days 6 and 7). PHYSICAL EXAMINATION: Pain scores assessed independently by three individuals with a visual analog scale (VAS; 0 = no pain and 10 = worst possible pain) were 8.5 on day 6, and it increased to 9.5 on day 7. Non-invasive blood pressure monitoring revealed severe hypertension. MANAGEMENT: As euthanasia was being considered for humane reasons, a decision was made to add an experimental new drug, trans-4-{4-[3-(4-Trifluoromethoxy-phenyl) ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), which is a soluble epoxide hydrolase (sEH) inhibitor, to the treatment protocol. Dose and frequency of administration were selected based on the drug potency against equine sEH to produce plasma concentrations within the range of 30 nmol L(-1) and 2.5 MUmol L( 1) . Pain scores decreased sharply and remarkably following t-TUCB administration and blood pressure progressively decreased to physiologic normal values. Plasma concentrations of t-TUCB, measured daily, were within the expected range, whereas phenylbutazone and gabapentin plasma levels were below the suggested efficacious concentrations. FOLLOW UP: No adverse effects were detected on clinical and laboratory examinations during and after t-TUCB administration. No new episodes of laminitis have been noted up to the time of writing (120 days following treatment). CONCLUSIONS: Inhibition of sEH with t-TUCB was associated with a significant improvement in pain scores in one horse with laminitis whose pain was refractory to the standard of care therapy. No adverse effects were noticed. Future studies evaluating the analgesic and protective effects of these compounds in painful inflammatory diseases in animals are warranted. PMID- 23463914 TI - Community understandings of and responses to gender equality and empowerment in Rakai, Uganda. AB - Women's rights and gender empowerment programmes are now part of the international agenda for improving global public health, the benefits of which are well documented. However, the public health community has, yet, to address how people define and understand gender equality and how they enact the process of empowerment in their lives. This study uses safe homes and respect for everyone (SHARE), an anti-violence intervention in rural Rakai, Uganda, as a case study to investigate perceptions of gender equality. Investigators analysed 12 focus groups of adult women and men to explore how macro-level concepts of gender equality are being processed on an interpersonal level and the effects on health outcomes. Respondents generally agreed that women lack basic rights. However, they also expressed widespread disagreement about the meanings of gender equality, and reported difficulties integrating the concepts of gender equality into their interpersonal relationships. Community members reported that equality, with the resulting shift in gender norms, could expose women to adverse consequences such as violence, infidelity and abandonment with increased sexual health risks, and potential adverse effects on education. Efforts to increase women's rights must occur in conjunction with community-based work on understandings of gender equality. PMID- 23463915 TI - Mobile computer application for promoting physical activity. AB - Despite evidence that physical activity reduces the risk of falls and other causes of disability and death, the majority of older adults do not engage in physical activity on a regular basis. Mobile technology applications have emerged as potential resources for promoting physical activity behavior. This article describes features of a new application, Ready~Steady, highlighting approaches used in its design and development, and implications for clinical practice. Iterative processes enabled the design, development, implementation, and evaluation of the application consistent with the wellness motivation theory, as well as established user-specific strategies and theoretical design principles. Implications in terms of potential benefits and constraints are discussed. Integrating technology that promotes health and wellness in the form of mobile computer applications is a promising adjunct to nursing practice. PMID- 23463916 TI - Susceptibility of stored-product psocids to aerosol insecticides. AB - The efficacies of commercial methoprene and esfenvalerate aerosols for control of stored-product psocid pests were evaluated in simulated field studies. The efficacies of methoprene, esfenvalerate EC, the carrier Isopar-MTM, and a combination of methoprene and esfenvalerate aerosols for control of Liposcelis decolor (Pearman) (Psocoptera: Liposcelididae) and Liposcelis entomophila (Enderlein) nymphs were assessed, and the effects of direct and indirect exposure of Liposcelis bostrychophila Badonnel, L. decolor, and Liposcelis paeta Pearman adults to esfenvalerate EC aerosol were evaluated. The greatest nymphal mortality attained was 76%, indicating that the four aerosols tested were ineffective against L. decolor and L. entomophila nymphs. In the direct and indirect exposure studies, the greatest adult mortalities attained for the three psocid species were 62 and 32%, respectively. Based on these data, esfenvalerate aerosol is ineffective for control of L. bostrychophila, L. decolor, L. entomophila, and L. paeta psocid species. This study shows that methoprene, esfenvalerate EC, and a combination of methoprene and esfenvalerate aerosols were ineffective against the four psocid species tested when applied at rates that are usually effective against other stored-product insect pests. PMID- 23463917 TI - Opening Pandora's box: how DSM-5 is coming to grief. PMID- 23463918 TI - Childhood lung function and the association with beta2-adrenergic receptor haplotypes. AB - AIM: To determine associations between ADRB2 polymorphisms and lung function through childhood, and possible modification by gender, pet keeping or tobacco smoke. METHODS: Four ADRB2 single nucleotide polymorphisms (rs1042711, rs1042713, rs1042714 and rs1800888) were genotyped in 953 children from the prospective birth cohort 'Environment and Childhood Asthma' study and analysed for association with flow-volume parameters at birth (tidal breathing) and at 10 years of age (maximally forced), stratified by environmental exposures. RESULTS: The risk of reduced lung function was reduced in 10-year-old children carrying the most common ADRB2 haplotype (CGGC) (OR 0.45 (95% CI 0.25, 0.82)), whereas there was no association between lung function at birth and ADRB2 haplotypes. Tobacco smoke exposure, gender and pet keeping did not significantly interact with the haplotypes in influencing lung function. CONCLUSION: This study demonstrates a possible protective effect by the ADRB2 haplotype I (CGGC) on reduced FEV1 in 10-year-old children, whereas no ADRB2 geno-/haplotypes were significantly associated with neonatal lung function. The ADRB2 gene thus appears to contribute to lung function development in childhood, independently of smoking, pets and gender. PMID- 23463919 TI - The influence of static eye and head position on the ventriloquist effect. AB - Orienting responses to audiovisual events have shorter reaction times and better accuracy and precision when images and sounds in the environment are aligned in space and time. How the brain constructs an integrated audiovisual percept is a computational puzzle because the auditory and visual senses are represented in different reference frames: the retina encodes visual locations with respect to the eyes; whereas the sound localisation cues are referenced to the head. In the well-known ventriloquist effect, the auditory spatial percept of the ventriloquist's voice is attracted toward the synchronous visual image of the dummy, but does this visual bias on sound localisation operate in a common reference frame by correctly taking into account eye and head position? Here we studied this question by independently varying initial eye and head orientations, and the amount of audiovisual spatial mismatch. Human subjects pointed head and/or gaze to auditory targets in elevation, and were instructed to ignore co occurring visual distracters. Results demonstrate that different initial head and eye orientations are accurately and appropriately incorporated into an audiovisual response. Effectively, sounds and images are perceptually fused according to their physical locations in space independent of an observer's point of view. Implications for neurophysiological findings and modelling efforts that aim to reconcile sensory and motor signals for goal-directed behaviour are discussed. PMID- 23463920 TI - Zinc oxide nanoparticle removal from wounded human skin. AB - AIM: Nanoparticle removal from skin is relevant given the concern over topical nanoparticle toxicity. Zinc oxide nanoparticles (ZnO-NPs) are commonly used in sunscreens and their use is currently debated. This study explores the penetration and removal of ZnO-NPs from injured skin. MATERIALS & METHODS: Ex vivo/in vivo human skin was tape-stripped and/or microneedled followed by ZnO-NP application. After 2 h, treated skin was washed three-times using soapy water. Multiphoton tomography assessed the ZnO-NP signal before and after washing. RESULTS: Washing once removed over 85 and 83% of ZnO-NP signal from ex vivo intact and tape-stripped skin, respectively (p < 0.05) but only 28% (p = 0.5) was removed from puncture sites. A similar trend was found in vivo with removal of 85 and 93% of ZnO-NP signal from intact and tape-stripped skin, respectively (p < 0.05). CONCLUSION: Washing is effective for the removal of ZnO-NPs from superficial layers of intact and tape-stripped skin, but not from puncture wounds. PMID- 23463921 TI - Implications of electronic health record meaningful use legislation for nursing clinical information system development and refinement. AB - PURPOSE: To describe what electronic health record meaningful use requirements mean for nursing clinical information system (CIS) development. CONCLUSIONS: The nursing CIS in many, if not most hospitals, has a number of critical design inadequacies that constrain the meaningful use of nursing data to ensure quality outcomes for patients and data-based maturing of the nursing profession. IMPLICATIONS: It is the responsibility and obligation of nurses to ensure that CISs are designed for the meaningful use of nursing clinical data. To accomplish these ends, interoperable clinical nursing data must be documented in a properly integrated operational CIS, and must be retrievable and stored in data repositories for analysis and reports. PMID- 23463922 TI - Biopsy-proven giant cell arteritis patients with coronary artery disease have increased risk of aortic aneurysmal disease and arterial thrombosis. PMID- 23463923 TI - [The story of surgery is an endless adventure]. PMID- 23463924 TI - Pre-operative ultrasound for breast tumour measurements: is there potential for mismanagement? AB - The pre-operative size of breast tumour is the most important factor in determining feasibility of breast conserving surgery in operable breast cancer. Currently there is no consensus on the most accurate modality to measure tumour size. A prospective study of consecutive and unselected symptomatic patients with invasive breast cancer who had primary surgery between January 2006 and December 2007 was conducted. Patients with multi-focal and multi-centric tumours were excluded. The aim of this study was to find the correlation between histological size of invasive breast cancer and pre-operative tumour size as measured by ultrasound. Over this two year period, data for 192 patients was analysed for this study. The mean tumour diameter on ultrasound and histology was 19.5mm and 29 mm respectively. The difference between the means in the two modalities was found to be statistically significant (P<0.001).Ultrasound underestimates the true size of breast tumours as determined histologically. Inaccurate tumour size measurements may result in re-operations to achieve adequate margins. PMID- 23463925 TI - Two cases of right atrial myxoma in redo patients. A mere coincidence? AB - We describe two cases of right atrial myxoma in redo patients who had previously undergone to coronary artery by-pass grafting (CABGs) and mitral valve replacement respectively. Both of patients experienced effort dyspnea and were assessed by trans-thoracic echocardiography, revealing the right atrial masses. They were operated on for myxoma resection and postoperative course was uneventful. Our report deals with the interesting topic of the location of benign masses that are usually more common in the left atrium. Should we hypothesize that the right atrial manipulation during the previous surgery induces the onset of the right atrial mass? It is an interesting matter to debate. PMID- 23463926 TI - Actual status of preoperative diagnosis of thyroid cancer in Albania. AB - INTRODUCTION: Thyroid cancer is the most common endocrine malignancy and accounts for almost 1% of human cancer. It is well known that the majority of cases occur in women in the middle decades of life. Thyroid cancer is a relatively rare disease; on the other hand clinically apparent thyroid nodules are present in 4 7% of the adult population. Most thyroid nodules are not malignant, with reported malignancy rates from 3-12%. It is important for the surgeon to know beforehand the diagnosis of malignancy, in order to perform a more radical operation on the thyroid gland. PATIENTS AND METHODS: In our study we have analyzed the preoperative clinical data of 84 patients operated in the First Clinic of General Surgery, UHC "Mother Theresa" in Tirana; all with a positive histopathologic diagnosis of thyroid cancer. The data comprised age, sex, age distribution, blood group, time-lapse from the first endocrinologic visit, clinical examination, signs and symptoms, imaging, functional tests, preoperative FNA, admission diagnosis, associated diseases and preoperative treatment. RESULTS: From the study emerged that only 9,3% of these patients were diagnosed preoperatively as thyroid cancer. Another related problem is the low percentage of preoperative FNA - only 22%. Among the signs and symptoms related to thyroid cancer we found that 40 and 33% of these patient presented dyspnea and dysphagia, respectively. The physical examination revealed apparent nodular growth of the thyroid gland in 81% and nodular hard consistency in 79% of cases. The proper endocrinologist consultation lacked in 23% of cases. CONCLUSION: In our opinion, close collaboration between endocrinologists and surgeons in a multidisciplinary frame is the key to correct preoperative thyroid cancer diagnosis and optimal treatment. PMID- 23463927 TI - Parotid gland oncocytoma in HCV-positive patient with non-Hodgkin's lymphoma. Case report. AB - We report a case of parotid gland oncocytoma in a patient with chronic infection from hepatitis C virus (HCV) and associated non-Hodgkin's lymphoma and xerophthalmia. Our case confirms the triple tropism of the HCV: hepatotropism, lymphotropism and sialotropism. PMID- 23463928 TI - Incidental cancer in patients surgically treated for benign thyroid disease. Our experience at a single institution. AB - Increased incidence of incidental cancer in patients operated for benign thyroid disease has been reported. We report our experience about incidental thyroid cancer (ITC) in order to better characterize this nosologic entity. Between 2001 and 2009 a total of 568 patients underwent surgery for benign thyroid disease. Patients with preoperative cytology undetermined or positive for malignancy were excluded. The most frequent indication for surgery was multinodular or diffuse nontoxic goiter. We performed total thyroidectomy in 499 cases and emithyroidectomy in 69 cases. Final histology revealed ITC in 53 patients (9.3%): 44 had papillary carcinoma (20 classic variant and 24 follicular variant), 4 follicular carcinoma, 4 medullary carcinoma and 1 primitive thyroid paraganglioma. The preoperative diagnosis was multinodular or diffuse goiter in 45 cases of ITC and uninodular goiter in 8 cases. We performed total thyroidectomy in 46 case, emithyroidectomy in 4 patients with past history of lobectomy, emithyroidectomy in 3 patients with following radicalization and central neck dissection. In 14 patients the tumor was multifocal and in 12 of these patients the tumor foci were bilateral. The lesion was a microcarcinoma in 34 cases. Mean diameter of the ITC was 1.14 cm. We retrospectively reconsidered the results of preoperative ultrasound examinations in relation to the exact position of the tumor in the specimens and we found a statistically significant association between echogenicity and papillary histotype. Twenty-six patients were followed up at our Hospital. The mean follow-up period was 38.2 months. A relapse was observed in 3/26 patients. Incidental thyroid cancer in patients operated for benign disease has its own surgical and oncological relevance. A correct preoperative assessment, with a careful selection of nodules for fine needle aspiration cytology on the basis of ultrasound pattern, could better address the choice of surgical procedure. The non irrelevant incidence of incidental thyroid cancer, the eventuality of multifocality and bilaterality and the possible occurrence of relapse, support that total thyroidectomy without residuum is a valuable option for treating benign thyroid conditions such as multinodular goitre. When an incidental cancer is diagnosed after emithyroidectomy, a radicalization with central neck dissection could be considered. We suggest that natural history of papillary microtumors and the correct surgical approach for these lesions could be better defined with a more extensive use of "Porto proposal" criteria. PMID- 23463929 TI - Diagnosis of intra-abdominal injuries can be challenging in multitrauma patients with associated injuries. Our experience and review of the literature. AB - INTRODUCTION: Trauma is the most common cause of death and disability among patients during the first four decades of life. Abdominal trauma is reported to be the 3rd most common injured region. Clinical examination may be unreliable in the evaluation of these patients especially in the presence of associated injuries. Therefore the use of diagnostic tools is essential in the management of the injured patient with abdominal trauma and additional injuries. PATIENTS AND METHODS: During 1 year period from December 2010 to November 2011 we recorded the patients that presented to the emergency department of our hospital and were found to suffer from intra-abdominal injuries. These patients were divided in two groups depending on whether they had additional comorbid injuries or not. Several parameters were recorded and compared between the two groups, such as mechanism of injury, general status and hemodynamic stability of the patient on presentation, physical examination, use of imaging modalities and concomitant findings, need for surgical intervention and mortality rates. Furthermore the discrepancy between physical findings and final diagnosis after the use of diagnostic adjuncts is reported. RESULTS: We recorded 31 patients with abdominal trauma. 13 (42%) patients were found to suffer from abdominal trauma and associated injuries (Group I), whereas 18 (58%) presented with abdominal trauma alone (Group II). The patients of the first group presented hemodynamic instability in 38% of cases while the patients of the second in 22% of cases. Reduced consciousness was present in 38% in group I versus 17% in group II. Signs of abdominal injury during clinical examination were present in only 15% in group I versus 72% in group II that represented a remarkable difference between the two groups. Conservative treatment was possible in 15% of patients with additional injuries and in 22% of patients with abdominal injury alone. In group I there were two deaths whereas in group II all patients survived. CONCLUSION: In patients with abdominal trauma, associated injuries seem to add to the severity of injury and indicate a worse prognosis. Clinical examination is unreliable and misleading in the majority of these patients and the use of diagnostic tools cannot be overemphasized. PMID- 23463930 TI - Extracranial association of arteriovenous and venous malformations. Case report. AB - Association of multiple vascular malformations of the face is a rare condition. An arteriovenous malformation (AVM) with a venous malformation as the draining vein is also a rarity. We report a case of extracranial mixed vascular malformations that deformed the normal architecture of the lower face. Removal of the AVM was followed by stability of the jaw and tongue malformation, indicating the AVM used the venous malformation as its draining vein. This approach spared the patient severe cosmetic and functional sequelae. PMID- 23463931 TI - Recurrent gallstone ileus: case report and literature review. AB - The gallstone ileus is a rare complication of cholelithiasis and it represents the 1-4% of small intestinal mechanical obstruction. Gallstone is generally wedged in the terminal ileum, even if unusual locations have been described. The literature reports a very high morbidity and mortality, often because misdiagnosis or delayed diagnosis. There is no unique opinion in literature about the choice between one-stage and two-stage surgery. We report a clinical case that summarizes the diagnostic and therapeutic difficulties of gallstone ileus. PMID- 23463932 TI - Prepuce-sparing plasty and simple running suture for phimosis. AB - AIM: Circumcision is the most common procedure for phimosis. In recent years, the value of foreskin properties as well as aesthetic reasons determined to other operations preserving the foreskin. We report 5-years experience with a technique that preserve the physical foreskin appearance intact. PATIENTS AND METHODS: Fifty-two patients, eligible to undergo phimosis surgery, underwent prepuce sparing plasty and simple running suture. Evaluation of results was made with photos comparative and verified by using presence/absence of recurrence, scarring evaluation, and VAS for patient satisfaction. RESULTS: Forty-eight patients reported no complications. There were no cases of bleeding, infection, pathological scarring, phimosis recurrence. The scar showed a good pliability and a thin thickness. Patient satisfaction was high. CONCLUSIONS: The association of prepuce-sparing plasty and simple running suture highlighted an effective and easy method for the correction of acquired phimosis in adult patients, with excellent functional and cosmetic results. PMID- 23463933 TI - Endovascular treatment of multiple anomalous splenic artery aneurysms in a Jehovah witness. AB - PURPOSE: The present report describes a full endovascular treatment of a multiple anomalous (Splenic artery aneurysms) SAA with combination of coils embolization and proximal occlusion of the splenic artery with the Amplatzer vascular plug. CASE REPORT: A 53-year-old Jehovah witness woman presented with multiple aneurysms arising from an anomalous splenic artery. An endovascular treatment was performed by implantation of multiple coils and an Amplatzer Vascular Plug. A CT scan 2 months after the procedure showed complete thrombosis of the aneurysms. DISCUSSION: Aneurysms involving an anomalous or aberrant splenic artery are rarely reported in the literature. Their surgical treatment involves potential difficulties as a consequence of anatomical position and vascular anomalies. A fully endovascular technique can be much more attractive compared to any surgical management, providing an effective and minimally invasive option. PMID- 23463934 TI - Effects of SORL1 gene on Alzheimer's disease. Focus on gender, neuropsychiatric symptoms and pro-inflammatory cytokines. AB - It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation. PMID- 23463935 TI - Neuroinflammation and complexes of 17beta-hydroxysteroid dehydrogenase type 10- amyloid beta in Alzheimer's disease. AB - Multifunctional mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 plays a role in the development of Alzheimer's disease. However, changes in its expression in the brain or cerebrospinal fluid are not fully specific for this type of dementia. Our previous study revealed that complexes of the enzyme and amyloid beta in cerebrospinal fluid could serve as a more specific biomarker of Alzheimer's disease than either the enzyme or amyloid beta individually when compared to autoimmune multiple sclerosis. In this study, enzyme-linked immunosorbent assay and the surface plasmon resonance biosensor method were used to analyse cerebrospinal fluid of patients with various neuroinflammatory diseases. Significant differences in the levels of the total enzyme, complexes, amyloid beta 1-42 and total tau/phospho-tau were found in Alzheimer's disease patients while differences in complexes, total amyloid beta and amyloid beta 1- 42 were observed in patients with neuroinflammatory diseases (except for multiple sclerosis) when compared to non-neuroinflammatory controls. The interactions of the enzyme with amyloid beta appeared to depend strongly on neuroinflammation sensitive amyloid beta. Our data demonstrated that oligomerisation/aggregation of intracellular amyloid beta peptides was important in Alzheimer's disease while extracellular amyloid beta could play a role in neuroinflammatory diseases. Phospho-tau is currently the best biomarker of Alzheimer's disease. PMID- 23463936 TI - Pro-inflammatory cytokines IL-1beta and TNF-alpha are not associated with plasma homocysteine concentration in Alzheimer's disease. AB - Increased concentrations of pro-inflammatory blood cytokines and plasma homocysteine (Hcy) are frequently reported in Alzheimer's disease (AD). Hcy appears to have immunomodulating and pro-inflammatory activities. Further, emerging evidence from animal and non-AD human studies implicates Hcy in potentiating the activities of proinflammatory cytokines; Hcy toxicity may also, in part, be mediated by these cytokines. As little is known about the potential relationship between these inflammatory markers specific to AD, the aim of this study was to assess potential impact of Hcy on the widely reported increases in cytokine concentrations in AD. Blood concentrations of two proinflammatory cytokines, IL-1beta and TNF-alpha, along with Hcy were assessed in 40 AD patients and 30 cognitively intact controls. Mean blood concentrations of IL-1beta and TNF alpha differed significantly between the AD and control groups (p=0.001 and p<0.001 resp). This difference survived adjustment for age and gender on logistic regression. Hcy was significantly correlated with age only in the patient (r(s)=0.38, p=0.02) but not the control group. There was no significant correlation between IL-1beta and Hcy, and between TNF-alpha, and Hcy in either the AD or the control group. Hence, our AD data did not replicate results obtained from animal and non-AD human studies which have linked pro-inflammatory cytokines concentrations to Hcy. A different inflammatory focus may exist in AD which may be influenced at least in a significant part by non-vascular pathogenesis. However, these results indirectly support the notion that the observed mild hyperhocysteinemia in AD may be due to non-inflammatory factors. PMID- 23463937 TI - A systematic review and economic evaluation of new-generation computed tomography scanners for imaging in coronary artery disease and congenital heart disease: Somatom Definition Flash, Aquilion ONE, Brilliance iCT and Discovery CT750 HD. AB - BACKGROUND: Computed tomography (CT) is important in diagnosing and managing many conditions, including coronary artery disease (CAD) and congenital heart disease. Current CT scanners can very accurately diagnose CAD requiring revascularisation in most patients. However, imaging technologies have developed rapidly and new generation computed tomography (NGCCT) scanners may benefit patients who are difficult to image (e.g. obese patients, patients with high or irregular heart beats and patients who have high levels of coronary calcium or a previous stent or bypass graft). OBJECTIVE: To assess the clinical effectiveness and cost effectiveness of NGCCT for diagnosing clinically significant CAD in patients who are difficult to image using 64-slice computed tomography and treatment planning in complex congenital heart disease. DATA SOURCES: Bibliographic databases were searched from 2000 to February/March 2011, including MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) database and Science Citation Index (SCI). Trial registers and conference proceedings were searched. REVIEW METHODS: Systematic review methods followed published guidance. Risk of bias was assessed using QUADAS-2. Results were stratified by patient group. Summary sensitivity and specificity were calculated using a bivariate summary receiver operating characteristic, or random effects model. Heterogeneity was assessed using the chi squared statistic and I(2)-statistic. Cost-effectiveness of NGCCT was modelled separately for suspected and known CAD, evaluating invasive coronary angiography (ICA) only, ICA after positive NGCCT (NGCCT-ICA), and NGCCT only. The cost effectiveness of NGCCT, compared with 64-slice CT, in reducing imaging-associated radiation in congenital heart disease was assessed. RESULTS: Twenty-four studies reported accuracy of NGCCT for diagnosing CAD in difficult-to-image patients. No clinical effectiveness studies of NGCCT in congenital heart disease were identified. The pooled per-patient estimates of sensitivity were 97.7% [95% confidence interval (CI) 88.0% to 99.9%], 97.7% (95% CI 93.2% to 99.3%) and 96.0% (95% CI 88.8% to 99.2%) for patients with arrhythmias, high heart rates and previous stent, respectively. The corresponding estimates of specificity were 81.7% (95% CI 71.6% to 89.4%), 86.3% (95% CI 80.2% to 90.7%) and 81.6% (95% CI 74.7% to 87.3%), respectively. In patients with high coronary calcium scores, previous bypass grafts or obesity, only per-segment or per-artery data were available. Sensitivity estimates remained high (> 90% in all but one study). In patients with suspected CAD, the NGCCT-only strategy appeared most cost effective; the incremental cost-effectiveness ratio (ICER) of NGCCT-ICA compared with NGCCT only was L71,000. In patients with known CAD, the most cost-effective strategy was NGCCT-ICA (highest cost saving, dominates ICA only). The ICER of NGCCT only compared with NGCCT-ICA was L726,230. For radiation exposure only, the ICER for NGCCT compared with 64-slice CT in congenital heart disease ranged from L521,000 for the youngest patients to L90,000 for adults. LIMITATIONS: Available data were limited, particularly for obese patients and patients with previous bypass grafts. All studies of the accuracy of NGCCT assume that the reference standard (ICA) is 100% sensitive and specific; however, there is some evidence that ICA may sometimes underestimate the extent and severity of stenosis. Patients with more than one criterion that could contribute to difficulty in imaging were often excluded from studies; the effect on test accuracy of multiple difficult to image criteria remains uncertain. CONCLUSIONS: NGCCT may be sufficiently accurate to diagnose clinically significant CAD in some or all difficult-to-image patient groups. Economic analyses suggest that NGCCT is likely to be considered cost-effective for difficult-to-image patients with CAD, at current levels of willingness to pay in the NHS. For patients with suspected CAD, NGCCT only would be most favourable; for patients with known CAD, NGCCT-ICA would be most favourable. No studies assessing the effects of NGCCT on therapeutic decision making, or subsequent patient outcomes, were identified. The ideal study to address these questions would be a large multi-centre RCT. However, one possible alternative might be to establish a multicentre tracker study. High quality test accuracy studies, particularly in obese patients, patients with high coronary calcium, and those with previous bypass grafts are needed to confirm the findings of our systematic review. These studies should include patients with multiple difficult to image criteria. FUNDING: The National Institute for Health Research Health Technology Assessment programme. This project was funded by the HTA programme, on behalf of NICE, as project number 10/107/01. PMID- 23463938 TI - Genetic variation among Clonorchis sinensis isolates from different hosts and geographical locations revealed by sequence analysis of mitochondrial and ribosomal DNA regions. AB - The present study examined genetic variability among Clonorchis sinensis isolates from four different geographical localities (Guangzhou, Nanning, Jiamusi and Daqing) and host species (cats, dogs, human and rabbits) in Mainland China by sequence analyses of two mitochondrial DNA (mtDNA) genes, namely NADH dehydrogenase subunits 2, 5 (nad2 and nad5) and ribosomal internal transcribed spacer 1 (ITS1). A portion of the ITS1, nad2 (pnad2) and nad5 (pnad5) was amplified by polymerase chain reaction separately from adult C. sinensis individuals and the amplicons were subjected to sequencing from both directions. The length of the sequences of ITS1, pnad2 and pnad5 was 643, 666 and 771 bp, respectively. The intraspecific sequence variations within C. sinensis were 0 1.7% for ITS1, 0-1.4% for pnad2 and 0-0.9% for pnad5. The interspecific sequence variations within other zoonotic trematodes, which were published previously, were 4.5-84.9% for ITS1, 21.9-43.6% for pnad2 and 19.2-48.9% for pnad5. The A+T contents of the sequences were 45.26-45.88% (ITS1), 62.91-63.51% (pnad2) and 58.24-58.63% (pnad5). Phylogenetic analyses using ribosomal and mitochondrial sequence data set, with three different computational algorithms (Bayesian inference, maximum parsimony and maximum likelihood), all revealed distinct groups with high statistical support. These findings demonstrated the existence of low-level intraspecific variations in ribosomal DNA (rDNA) and mtDNA sequences among C. sinensis isolates from four different regions and hosts in China and elucidated that mtDNA sequences and rDNA sequences provided reliable genetic markers for phylogenetic studies of zoonotic trematodes. PMID- 23463939 TI - Parasitoids (Hymenoptera: Braconidae: Aphidiinae) of northeastern Iran: aphidiine aphid-plant associations, key and description of a new species. AB - Aphid parasitoids of the subfamily Aphidiinae (Hymenoptera: Braconidae) of northeastern Iran were studied in this paper. A total of 29 species are keyed and illustrated with line drawings. The aphidiines presented in this work have been reared from 42 aphid host taxa occurring on 49 plant taxa from a total of 33 sampling sites. Sixty-six aphidiine-aphid-plant associations are presented. Trioxys metacarpalis sp. nov. from Chaitaphis tenuicaudata Nevsky (Hemiptera: Aphididae) on Kochia scoparia, is described. The species diversity based on the comparative faunistic analysis is discussed. PMID- 23463940 TI - Synthesis and evaluation of 18F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography. AB - Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging. PMID- 23463941 TI - Squaramide-tertiary amine catalyzed asymmetric cascade sulfa-Michael/Michael addition via dynamic kinetic resolution: access to highly functionalized chromans with three contiguous stereocenters. AB - An efficient asymmetric cascade sulfa-Michael/Michael addition reaction catalyzed by a chiral bifunctional squaramide-tertiary amine catalyst has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chromans with three contiguous stereocenters, including one quaternary center. In addition, a novel cascade sulfa Michael/retro-sulfa Michael/sulfa-Michael/Michael reaction process, involving dynamic kinetic resolution, is described. PMID- 23463942 TI - Evaluating research for clinical significance: using critically appraised topics to enhance evidence-based neuropsychology. AB - Meehl's (1973, Psychodiagnosis: Selected papers. Minneapolis: University of Minnesota Press) distinction between statistical and clinical significance holds special relevance for evidence-based neuropsychological practice. Meehl argued that despite attaining statistical significance, many published findings have limited practical value since they do not inform clinical care. In the context of an ever expanding clinical research literature, accessible methods to evaluate clinical impact are needed. The method of Critically Appraised Topics (Straus, Richardson, Glasziou, & Haynes, 2011, Evidence-based medicine: How to practice and teach EBM (4th ed.). Edinburgh: Elsevier Churchill-Livingstone) was developed to provide clinicians with a "toolkit" to facilitate implementation of evidence based practice. We illustrate the Critically Appraised Topics method using a dementia screening example. We argue that the skills practiced through critical appraisal provide clinicians with methods to: (1) evaluate the clinical relevance of new or unfamiliar research findings with a focus on patient benefit, (2) help focus of research quality, and (3) incorporate evaluation of clinical impact into educational and professional development activities. PMID- 23463943 TI - New insight into biomarkers of human mercury exposure using naturally occurring mercury stable isotopes. AB - Human exposure to methylmercury (MeHg) and elemental mercury vapor (Hg(0)(g)) are often estimated using total Hg concentrations in hair and urine, respectively. We investigated whether Hg stable isotopes could be used to better distinguish between exposure to Hg(0)(g) versus MeHg. We found that hair from North American dental professionals was characterized by high positive Delta(199)Hg values (mean = 1.860/00, 1 SD = 0.120/00, n = 11). This confirms that among people who regularly consume fish, total Hg concentrations in hair reflect exposure to MeHg. In contrast, we found that urine from the same individuals was characterized by a range of Delta(199)Hg values (0.29 to 1.770/00, 2 SD = 0.060/00, n = 12) that were significantly correlated to the number of dental amalgams in each individual's mouth. We hypothesize that fish-derived MeHg is demethylated within the body, causing mass-dependent fractionation and the excretion of inorganic Hg in urine. Mercury in urine therefore represents a mixture of demethylated fish derived MeHg and amalgam-derived inorganic Hg. We estimate that the majority (>70%) of Hg in urine from individuals with <10 dental amalgams is derived from ingestion of MeHg in fish. These data suggest that within populations that consume fish, urine total Hg concentrations may overestimate Hg exposure from personal dental amalgams. PMID- 23463945 TI - An updated meta-analysis of the Fc receptor-like 3 -169T/C polymorphism and rheumatoid arthritis risk. AB - OBJECTIVES: Published studies have shown conflicting results concerning the association between the -169T/C promoter polymorphism in the Fc receptor-like 3 (FCRL3) gene and rheumatoid arthritis (RA). In this study we conducted an up-to date meta-analysis to examine the relationship. METHOD: We searched the PubMed database for all papers published up to 20 April 2012. Overall, 18 case-control studies with 12 620 cases and 12 613 controls were retrieved based on the search criteria for RA susceptibility related to the FCRL3 -169T/C polymorphism. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed using the Egger test. RESULTS: We found that the FCRL3 -169T/C polymorphism increased the risk for RA overall in genetic models (allelic contrast: OR 1.09, 95% CI 1.03-1.14, p = 0.001; homozygote comparison: OR 1.20, 95% CI 1.08-1.34, p = 0.001; dominant genetic model: OR 1.03, 95% CI 1.01-1.05, p = 0.001). Stratified analysis by race also showed a significant positive association with Asians and Caucasians. Subgroup analysis of rheumatoid factor (RF) revealed a slightly positive relationship between the FCRL3 -169T/C polymorphism and RF-positive RA risk. No obvious evidence of publication bias was detected in the overall analysis. CONCLUSION: Our study indicates that the FCRL3 -169T/C polymorphism is significantly associated with increased RA risk. PMID- 23463946 TI - Differences in parents', nurses' and physicians' views of NICU parent support. AB - AIM: To measure the perceptions of parent support by parents, nurses and physicians. METHODS: Perceptions were compared among parents (n = 227), nurses (n = 178) and physicians (n = 43) in four neonatal intensive care units (NICU) using two versions of the Nurse Parent Support Tool (NPST and NPSTpro). RESULTS: Overall, parents reported receiving support from nurses some or most of the time and their perceptions were correlated with aspects of their NICU experience. Nurses reported giving support to parents almost all of the time. The mean difference between parent and nurse ratings was smallest for instrumental support (0.26, 0.16-0.36; p < 0.001) and greatest for emotional support (0.82, 0.67-0.97; p < 0.001). Physicians overall reported that they gave support to parents most of the time, significantly less frequently than nurses (mean difference 0.58, 0.45 0.71; p < 0.001). They rated their support as most frequent on answering parents' questions satisfactorily and as least frequent on teaching parents how to give care to their baby. CONCLUSION: NICU nurses and physicians should be encouraged to critically reflect on whether the type and consistency of support they provide to parents is in line with parents' perceptions and needs. Further research is needed on effective methods for health professionals to support parents of NICU infants. PMID- 23463944 TI - A biocompatible in vivo ligation reaction and its application for noninvasive bioluminescent imaging of protease activity in living mice. AB - The discovery of biocompatible reactions had a tremendous impact on chemical biology, allowing the study of numerous biological processes directly in complex systems. However, despite the fact that multiple biocompatible reactions have been developed in the past decade, very few work well in living mice. Here we report that D-cysteine and 2-cyanobenzothiazoles can selectively react with each other in vivo to generate a luciferin substrate for firefly luciferase. The success of this "split luciferin" ligation reaction has important implications for both in vivo imaging and biocompatible labeling strategies. First, the production of a luciferin substrate can be visualized in a live mouse by bioluminescence imaging (BLI) and furthermore allows interrogation of targeted tissues using a "caged" luciferin approach. We therefore applied this reaction to the real-time noninvasive imaging of apoptosis associated with caspase 3/7. Caspase-dependent release of free D-cysteine from the caspase 3/7 peptide substrate Asp-Glu-Val-Asp-D-Cys (DEVD-(D-Cys)) allowed selective reaction with 6 amino-2-cyanobenzothiazole (NH(2)-CBT) in vivo to form 6-amino-D-luciferin with subsequent light emission from luciferase. Importantly, this strategy was found to be superior to the commercially available DEVD-aminoluciferin substrate for imaging of caspase 3/7 activity. Moreover, the split luciferin approach enables the modular construction of bioluminogenic sensors, where either or both reaction partners could be caged to report on multiple biological events. Lastly, the luciferin ligation reaction is 3 orders of magnitude faster than Staudinger ligation, suggesting further applications for both bioluminescence and specific molecular targeting in vivo.